PMID- 23624634 TI - Comparative evaluation of in vivo osteogenic differentiation of fetal and adult mesenchymal stem cell in rat critical-sized femoral defect model. AB - Mesenchymal stem cells (MSCs) can be obtained from various sources. MSCs from different origins appear to have different preferences for differentiation. In this study, we have compared the in vivo osteogenic potential of adult MSCs from adipose tissue (AT) and bone marrow (BM) with fetal MSCs from umbilical cord (UC) and umbilical cord blood (UCB) by using a rat critical-sized femoral defect model. We have also sought to determine whether pretreatment with an osteogenic medium promotes osteogenesis in MSCs. Study groups were divided as follows: (1) defect only, (2) scaffold only, (3) AT MSCs in scaffolds, (4) BM MSCs in scaffolds, (5) UC MSCs in scaffolds and (6) UCB MSCs in scaffolds. Groups with MSCs were further divided with respect to their pretreatment. At 12 weeks after surgery, in vivo osteogenesis was measured radiographically and by micro-computed tomography (CT). Based on quantitative assessment by micro-CT, no significant difference of the mean bone volume fraction value (BV/TV) was seen between adult MSCs (AT and BM MSCs) and fetal MSCs (UC and UCB MSCs). The mean BV/TVs were significantly higher in non-pretreated BM MSC (14.2+/-1.4%) and UCB MSC (14.0+/ 1.2%) and pretreated UC MSC (14.8+/-2.0%) than in those with the scaffold only (11.3+/-1.3%; P<0.05). In addition, AT (from 10.4+/-1.2% to 13.1+/-2.2%) and UC (from 10.3+/-0.7% to 14.8+/-2.0%) MSCs from solid tissues showed a significant increase in the mean BV/TV with pretreatment (P<0.05). In contrast, BM MSC (from 14.2+/-1.4% to 10.9+/-1.2%) and UCB MSC (from 14.0+/-1.2% to 11.6+/-1.0%) from non-solid tissues showed a significant decrease with pretreatment (P<0.05). PMID- 23624635 TI - Telavancin shows superior activity to vancomycin with multidrug-resistant Staphylococcus aureus in a range of in vitro biofilm models. AB - The activity of telavancin was compared with vancomycin against methicillin resistant Staphylococcus aureus (MRSA) in planktonic culture and biofilms grown using a range of in vitro models. Antibiotic efficacy was determined using 24 clinical isolates, including healthcare-associated (HA)-MRSA, community associated (CA)-MRSA and isolates with reduced (intermediate) susceptibility to vancomycin (VISA). Activity against biofilms was compared using three models: 96 peg plates, 96-well flat-bottom plates and a flow-cell system. Cell death was evaluated using a metabolic dye and Live/Dead staining. The planktonic minimum inhibitory concentration (MIC) range for telavancin was lower than that for vancomycin (0.06-0.25 mg/l and 0.5-8 mg/l, respectively). Vancomycin (100 * MIC) killed, on average, 59% of cells in HA-MRSA biofilms grown on 96-peg plates, 44% of cells in CA-MRSA biofilms and 26% of cells in VISA biofilms. Telavancin (100 * MIC) killed, on average, 63%, 49% and 41% of cells, respectively. The antibiotics showed similar efficacy against MRSA biofilms but telavancin was more effective against those formed by VISA isolates. In the flow-cell system, antibiotic cell killing was enhanced with both antibiotics, killing up to 80% of biofilm associated cells. The variance in cell killing displayed when biofilms were grown using different systems highlights the importance of selecting an appropriate model for antimicrobial efficacy tests. The flow-cell system more closely reflects conditions encountered during infection and is possibly more clinically relevant than a 96-well plate system. Despite differences between the models evaluated, telavancin typically demonstrated improved efficacy over vancomycin, indicating the potential value of the agent in the treatment of biofilm-mediated infections caused by S. aureus, especially multidrug-resistant isolates. PMID- 23624636 TI - Predictors of thromboembolism during coil embolization in patients with unruptured intracranial aneurysm. AB - OBJECTIVES: To identify the incidence of thromboembolic complications based on magnetic resonance imaging (MRI) and to explore the potential risk factors for thromboembolism (TE) during the periprocedural period of elective coil embolization for unruptured intracranial aneurysms. METHODS: We retrospectively reviewed all aneurysm cases treated with coil insertion between January 2008 and March 2011. Two hundred eighty-two coiling procedures for unruptured aneurysms were included in this study. The patients' demographic characteristics were documented and records reviewed for abnormalities in diffusion-weighted imaging (DWI) seen on post-procedure MRI, intraoperative thrombus formation, and clinical signs of stroke. RESULTS: Overall, there were 87 (30.9 %) procedure-related complications in 282 aneurysms treated: 2 (0.7 %) procedural ruptures, 5 (1.8 %) symptomatic infarctions, and 80 (28.3 %) asymptomatic infarctions. Thromboembolic events during the procedure were observed more often in the the hyperlipidemia group (32/71 aneurysms, 45.1 %) than in the normal lipid profile group (39/196 aneurysms, 25.6 %; p = 0.002; chi-squre test). The coiling technique and size of the aneurysm were also associated with TE (p < 0.001 and p = 0.004). CONCLUSION: Hyperlipidemia seems to be associated with a significant increase in the rate of thromboembolic events. In preventive procedures, modifiable risk factors should be managed to reduce complications. Although permanent deficits are rare, the high rate of thromboembolic events suggests that improvements in the technique, such as the addition of antiplatelet agents and the development of new embolic materials, are necessary. PMID- 23624637 TI - Modelling pathology from autolog fresh cadaver organs as a novel concept in neurosurgical training. AB - BACKGROUND: The aim of neurosurgical cadaver training for residents and fellows is not only to obtain a high level of skills, but also to keep the number of complications during the learning curve as low as possible. To move this process forward, we have worked out a novel method in further training. METHODS: Tumours can be modelled from the autolog organs. We can then implant the modelled tumour from the opposite direction and a colleague can remove the pathology from the correct approach. RESULTS: We have experienced improving skills in difficult microsurgical operations. CONCLUSION: We have performed more than 800 fresh cadaver operations over the last 6 years. The last 70 cases have been performed with modelling pathology. In our department, we introduce a regular weekly program in our cadaver operating theatre. The consideration could be useful not only for the young neurosurgeons but also for experienced colleagues. PMID- 23624638 TI - Nonequilibrium fluctuations of mechanically stretched single red blood cells detected by optical tweezers. AB - We study the thermal and out-of-equilibrium mechanical dynamics of single, living human red blood cells (RBCs) by combining two-probe passive and active microrheology techniques. Both experiments were performed quasisimultaneously on the same cell using two identical polystyrene probes, biochemically attached to the cell membrane. We obtained compelling evidence of nonequilibrium fluctuations in the RBCs under physiological condition and without the influence of any external chemicals. The spectral distributions of metabolically driven forces and viscoelastic response were evaluated in the relaxed and stretched states, intended to simulate the varying natural environment of the cells during blood circulation. We found that the internally generated forces are more pronounced in the stretched state, suggesting a stress-dependent RBC activity. PMID- 23624639 TI - Ventricular diastolic abnormalities in the critically ill. AB - PURPOSE OF REVIEW: Left-ventricular diastolic dysfunction is associated with various conditions frequently encountered in ICU patients. Due to prolonged relaxation and increased left-ventricular stiffness, patients with diastolic dysfunction are at high risk of developing abrupt pulmonary venous congestion. The present review describes the clinical spectrum of left-ventricular diastolic abnormalities in ICU patients. RECENT FINDINGS: Left-ventricular diastolic dysfunction is associated with a preserved ejection fraction in half of the patients presenting with acute pulmonary edema. These patients may have dramatic presentation, such as flash pulmonary edema during a hypertensive crisis. Left ventricular diastolic dysfunction is frequently involved in patients who fail extubation and may trigger weaning pulmonary edema. Sepsis and myocardial ischemia may also be associated with left-ventricular diastolic dysfunction. The diagnosis of left-ventricular diastolic dysfunction practically relies on two dimensional and Doppler echocardiography. Further large-scale clinical studies are needed to better characterize the prevalence, the clinical relevance and time course of left-ventricular diastolic dysfunction in ICU patients. SUMMARY: Left ventricular diastolic dysfunction accounts for a growing proportion of cardiogenic pulmonary edema and weaning failure in ICU patients. It may be reversible when induced by sepsis or myocardial ischemia. Its prognostic value in the ICU settings remains to be further investigated. PMID- 23624640 TI - An IP-based healthcare provider shift design approach to minimize patient handoffs. AB - The new Accreditation Council for Graduate Medical Education (ACGME) duty-hour standards for residents and fellows went into effect in 2011. These regulations were designed to reduce fatigue-related medical errors and improve patient safety. The new shift restrictions, however, have led to more frequent transitions in patient care (handoffs), resulting in greater opportunity for communication breakdowns between caregivers, which correlate with medical errors and adverse events. Recent research has focused on improving the quality of these transitions through standardization of the handoff protocols; however, no attention has been given to reducing the number of transitions in patient care. This research leverages integer programming methods to design a work shift schedule for trainees that minimizes patient handoffs while complying with all ACGME duty-hour standards, providing required coverage, and maintaining physician quality of life. In a case study of redesigning the trainees' schedule for a Mayo Clinic Medical Intensive Care Unit (MICU), we show that the number of patient handoffs can be reduced by 23 % and still meet all required and most desired scheduling constraints. Furthermore, a 48 % reduction in handoffs could be achieved if only the minimum required rules are satisfied. PMID- 23624641 TI - Anger regulation style, anger arousal and acute pain sensitivity: evidence for an endogenous opioid "triggering" model. AB - Findings suggest that greater tendency to express anger is associated with greater sensitivity to acute pain via endogenous opioid system dysfunction, but past studies have not addressed the role of anger arousal. We used a 2 * 2 factorial design with Drug Condition (placebo or opioid blockade with naltrexone) crossed with Task Order (anger-induction/pain-induction or pain-induction/anger induction), and with continuous Anger-out Subscale scores. Drug * Task Order * Anger-out Subscale interactions were tested for pain intensity during a 4-min ischemic pain task performed by 146 healthy people. A significant Drug * Task Order * Anger-out Subscale interaction was dissected to reveal different patterns of pain intensity changes during the pain task for high anger-out participants who underwent pain-induction prior to anger-induction compared to those high in anger-out in the opposite order. Namely, when angered prior to pain, high anger out participants appeared to exhibit low pain intensity under placebo that was not shown by high anger-out participants who received naltrexone. Results hint that people with a pronounced tendency to express anger may suffer from inadequate opioid function under simple pain-induction, but may experience analgesic benefit to some extent from the opioid triggering properties of strong anger arousal. PMID- 23624642 TI - Women's sun protection cognitions in response to UV photography: the role of age, cognition, and affect. AB - This study examined the impact of ultraviolet (UV) photography, cognition versus affect, and age on women's sun-related cognitions and a proxy measure of sun protection behavior. Participants (N = 114) were recruited via public advertisements and came to the lab to view a photo showing their UV damage. In addition, some participants received instructions to focus on either their thoughts (cognition) or feelings (affect) about their photograph before completing the survey. Women in the affect condition reported the lowest perceived vulnerability to skin cancer and highest absent/exempt beliefs (beliefs that one is unlikely to develop skin cancer if she hasn't already). Condition by age interactions showed that, among those in the cognition and control (no instructions) conditions, older women reported higher perceived vulnerability and lower absent/exempt beliefs, and took more sunscreen than younger women. However, older women reported higher absent/exempt beliefs and higher sun-risk willingness than younger women in the affect condition. PMID- 23624643 TI - Beta-adrenoceptor antagonists affect amyloid nanostructure; amyloid hydrogels as drug delivery vehicles. AB - Beta-adrenocepetor antagonists (beta-blockers) alter the nanostructure of lysozyme amyloids, resulting in different drug release profiles. PMID- 23624644 TI - Rac1 signaling protects monocytic AML cells expressing the MLL-AF9 oncogene from caspase-mediated apoptotic death. AB - We investigated the relevance of signaling mechanisms regulated by the Ras homologous GTPase Rac1 for survival of acute myeloid leukemia (AML) cells harbouring the MLL-AF9 oncogene due to t(9;11)(p21;q23) translocation. Monocytic MLL-AF9 expressing cells (MM6, THP-1) were hypersensitive to both small-molecule inhibitors targeting Rac1 (EHT 1864, NSC 23766) (IC50EHT ~12.5 MUM) and lipid lowering drugs (lovastatin, atorvastatin) (IC50Lova ~7.5 MUM) as compared to acute myelocytic leukemia (NOMO-1, HL60) and T cell leukemia (Jurkat) cells (IC50EHT >30 MUM; IC50Lova >25 MUM). Hypersensitivity of monocytic cells following Rac1 inhibition resulted from caspase-driven apoptosis as shown by profound activation of caspase-8,-9,-7,-3 and substantial (~90 %) decrease in protein expression of pro-survival factors (survivin, XIAP, p-Akt). Apoptotic death was preceded by S139-posphorylation of histone H2AX (gammaH2AX), a prototypical surrogate marker of DNA double-strand breaks (DSBs). Taken together, abrogation of Rac1 signaling causes DSBs in acute monocytic leukemia cells harbouring the MLL-AF9 oncogene, which, together with downregulation of survivin, XIAP and p-Akt, results in massive induction of caspase-driven apoptotic death. Apparently, Rac1 signaling is required for maintaining genetic stability and maintaining survival in specific subtypes of AML. Hence, targeting of Rac1 is considered a promising novel strategy to induce lethality in MLL-AF9 expressing AML. PMID- 23624645 TI - Catalyst-free, one-pot, three-component synthesis of 5-amino-1,3-aryl-1Eta pyrazole-4-carbonitriles in green media. AB - An efficient, one-pot, three-component synthesis of various biologically important heterocyclic compounds is described via a tandem Knoevengel-cyclo condensation reaction of aromatic aldehydes, malono derivatives, and phenyl hydrazine derivatives in water and ethanol at room temperature. PMID- 23624646 TI - Annular atrophic plaques on the face in a father and a son: Christianson's disease, a real entity? PMID- 23624647 TI - Structural characterization by NMR of a double phosphorylated chimeric peptide vaccine for treatment of Alzheimer's disease. AB - Rational design of peptide vaccines becomes important for the treatment of some diseases such as Alzheimer's disease (AD) and related disorders. In this study, as part of a larger effort to explore correlations of structure and activity, we attempt to characterize the doubly phosphorylated chimeric peptide vaccine targeting a hyperphosphorylated epitope of the Tau protein. The 28-mer linear chimeric peptide consists of the double phosphorylated B cell epitope Tau229 237[pThr231/pSer235] and the immunomodulatory T cell epitope Ag85B241-255 originating from the well-known antigen Ag85B of the Mycobacterium tuberculosis, linked by a four amino acid sequence -GPSL-. NMR chemical shift analysis of our construct demonstrated that the synthesized peptide is essentially unfolded with a tendency to form a beta-turn due to the linker. In conclusion, the -GPSL- unit presumably connects the two parts of the vaccine without transferring any structural information from one part to the other. Therefore, the double phosphorylated epitope of the Tau peptide is flexible and accessible. PMID- 23624648 TI - Phenolic constituents, antioxidant and preliminary antimycoplasmic activities of leaf skin and flowers of Aloe vera (L.) Burm. f. (syn. A. barbadensis Mill.) from the Canary Islands (Spain). AB - The methanol extracts of leaf skins and flowers of Aloe vera from the Canary Islands were analyzed for their phenolic profiles and screened for their antioxidant and antimycoplasmic activities. The use of reversed phase high performance liquid chromatography (RP-HPLC) allowed the identification of 18 phenolic constituents. Leaf skin extracts were characterized by the abundance of catechin, sinapic acid and quercitrin. Gentisic acid, epicatechin and quercitrin were the most prominent phenolic compounds of the flowers. The in vitro antioxidant activities determined by using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and ferric antioxidant reducing power (FRAP) assays revealed that both extracts exhibited antioxidant activity, being the leaf skin extract the most active fraction. The leaf skin extract was also found to be active against the microbial strains tested. Therefore, A. vera extracts from leaf skin and flowers can be considered as good natural antioxidant sources. PMID- 23624649 TI - 2'-Deoxythymidine adducts from the anti-HIV drug nevirapine. AB - Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used against HIV-1. Currently, NVP is the most widely used anti-HIV drug in developing countries, both in combination therapy and to prevent mother-to-child transmission of HIV. Despite its efficacy against HIV, NVP produces a variety of toxic responses, including hepatotoxicity and skin rash. It is also associated with increased incidences of hepatoneoplasias in rodents. In addition, epidemiological data suggest that NNRTI use is a risk factor for non-AIDS defining cancers in HIV-positive patients. Current evidence supports the involvement of metabolic activation to reactive electrophiles in NVP toxicity. NVP metabolism includes oxidation to 12-hydroxy-NVP; subsequent Phase II sulfonation produces an electrophilic metabolite, 12-sulfoxy-NVP, capable of reacting with DNA to yield covalent adducts. Since 2'-deoxythymidine (dT) adducts from several alkylating agents are regarded as having significant mutagenic/carcinogenic potential, we investigated the formation of NVP-dT adducts under biomimetic conditions. Toward this goal, we initially prepared and characterized synthetic NVP-dT adduct standards using a palladium-mediated Buchwald-Hartwig coupling strategy. The synthetic standards enabled the identification, by LC-ESI-MS, of 12-(2'-deoxythymidin-N3-yl)-nevirapine (N3-NVP dT) in the enzymatic hydrolysate of salmon testis DNA reacted with 12-mesyloxy NVP, a synthetic surrogate for 12-sulfoxy-NVP. N3-NVP-dT, a potentially cytotoxic and mutagenic DNA lesion, was also the only dT-specific adduct detected upon reaction of dT with 12-mesyloxy-NVP. Our data suggest that N3-NVP-dT may be formed in vivo and play a role in the hepatotoxicity and/or putative hepatocarcinogenicity of NVP. PMID- 23624650 TI - A lead (II) 3D coordination polymer based on a marine cyclic peptide motif. AB - The crystal structure of a naturally occurring cyclic tetrapeptide cyclo(Gly-L Ser-L-Pro-L-Glu) [cyclo(GSPE)] was obtained. The conformation of synthesized cyclo(GSPE) fixes the coordination to lead ion in a 1:1 ratio. This cyclo(GSPE) Pb complex was constructed as an asymmetric 3D network in the crystalline state. The polymerization of a heavy metal ion with a rigid asymmetric cyclic tetrapeptide represents the first example of a new class of macrocyclic complexes. PMID- 23624651 TI - Ingestion of carbohydrate during recovery in exercising people. AB - PURPOSE OF REVIEW: The primary focus of this brief review is to describe the effect of carbohydrate (CHO) supplementation alone or in combination with protein on two responses during postexercise recovery that are not specifically related to the usual emphasis on glycogen resynthesis; that is, rapid postexercise rehydration, and recovery from exercise-induced muscle damage. RECENT FINDINGS: Evidence from postexercise rapid rehydration studies suggests that the addition of CHO to a rehydration solution may increase the rate of fluid restoration compared with water placebo. Adding protein to a CHO solution may further accentuate the beneficial effects. An additional postexercise concern for active individuals is the development of postexercise muscle soreness, a response that is pronounced with novel, eccentric exercise. Ingestion of CHO supplements, especially those combined with protein may help to minimize the exercise-induced muscle damage that is accompanied by muscle soreness, and reduced muscle function. SUMMARY: The practical implications of these findings are that CHO supplementation, especially in combination with protein, can enhance the rate of recovery relative to fluid balance and muscle damage; thus, these nutritional interventions should be considered for purposes in addition to the usual focus on glycogen resynthesis. PMID- 23624652 TI - Sugar-sweetened beverages and cardio-metabolic disease risks. AB - PURPOSE OF REVIEW: Sucrose-sweetened beverages (SSB) have for decades been implicated in cardiometabolic diseases. The purpose of this review is to summarize recent epidemiological but particularly recent human intervention studies on the metabolic effects associated/induced by SSB. RECENT FINDINGS: Recent epidemiological studies support the positive association between SSB intake and enhanced risk for metabolic syndrome, type 2 diabetes, coronary heart diseases, and stroke. From the human intervention studies rather similar results are obtained with enhanced accumulation of fat in the liver, muscle, and in the visceral fat depot induced by SSB. Moreover, SSB induces enhanced levels of circulating triglycerides and enhanced de-novo lipogenesis in the liver. The specific effect of SSB on body weigh/obesity is still not completely elucidated but SSB enhances body weight/fat mass even though not to a significant degree in all studies. Concerning the mechanisms for SSB to induce these metabolic aberrations most of the studies are in agreement with the fact that it is mainly fructose (free or as part of the sucrose molecule) that is the main driver of these metabolic aberrations presumably primarily by inducing lipid synthesis in and release from the liver. SUMMARY: There are now convincing evidences for enhanced cardiometabolic risk after higher intake of SSB where both epidemiological studies and human intervention studies are pointing in the same direction. A so-called 'well tolerated' intake of SSB is not determined. Accordingly, intake of SSB should generally be reduced as much as possible to improve the health of the population. PMID- 23624653 TI - Overexpression of Numb suppresses tumor cell growth and enhances sensitivity to cisplatin in epithelioid malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is a highly aggressive and conventional treatment-resistant tumor with a dismal prognosis. Among the three histological subtypes of MPM, the epithelioid is the most common type. Numb is considered as a tumor suppressor playing a critical role in controlling asymmetric cell division, maintenance of stem cell compartments, ubiquitination of specific substrates and regulating Notch-, Hedgehog- and TP53-activated pathways. The present study was designed to analyze the role of Numb in epithelioid MPM. We investigated the expression of Numb in 39 epithelioid MPM and 22 normal pleural tissues by immunohistochemistry. Furthermore, we overexpressed Numb in NCI-H2452, an epithelioid human MPM cell line, and investigated the effect of Numb overexpression on the proliferation, apoptosis and sensitivity to cisplatin in cells. The expression of Numb was significantly lower in MPM compared to the control group and Numb had an inverse correlation with the ki-67 labeling index. Loss of Numb expression was associated with poor prognosis in epithelioid MPM. Overexpression of Numb in NCI-H2452 cells significantly inhibited proliferation, promoted apoptosis and enhanced sensitivity to cisplatin. Moreover, Numb overexpression activated caspase-9 and caspase-3 through release of cytochrome c as well as downregulation of XIAP and survivin. We speculate that cytochrome c/caspase signaling is a possible mechanism through which Numb enhances the apoptosis of NCI-H2452 cells. These results suggest that Numb may be involved in epithelioid MPM development, and its upregulation may confer sensitivity to cisplatin, suggesting potential therapeutic options for MPM. PMID- 23624654 TI - Healing of normal and osteopenic bone with titanium implant and low-level laser therapy (GaAlAs): a histomorphometric study in rats. AB - The study investigates the influence of low-level laser therapy (LLLT) on bone healing in the femur of osteopenic and normal rats with titanium implants. Ovariectomy and control group were randomly submitted to LLLT, which was applied by gallium-aluminum-arsenium (GaAlAs) laser at the surgical site before and after placing the implant, for seven times. Histomorphometric and statistical analysis were performed. Most irradiated groups showed higher values than the nonirradiated groups. The GaAlAs infrared diode laser may improve the osseointegration process in osteopenic and normal bone, particularly based on its effects in the initial phase of bone formation. PMID- 23624656 TI - Complete genome sequence of the original Taiwanese isolate of sweet potato latent virus and its relationship to other potyviruses infecting sweet potato. AB - The complete genome of sweet potato latent virus (SPLV) was determined to be 10081 nucleotides long excluding the 3' poly (A) tail. The genome contains a single large open reading frame encoding a polyprotein of 3247 amino acids. Its genomic organization is typical of potyviruses and contains motifs conserved in members of the genus Potyvirus. Pairwise comparisons show that SPLV shares identities of 50.0 %-56.3 % to other potyviruses at the genomic sequence level. Phylogenetic analysis shows that SPLV is closely related to four other sweet potato potyviruses in the sweet potato feathery mottle virus lineage, but it lacks the unique PISPO in the P1 region of those viruses. The genome analyses confirm that SPLV is a distinct sweet potato virus in the genus Potyvirus. PMID- 23624655 TI - Functional bracing of ACL injuries: current state and future directions. AB - PURPOSE: Functional braces are commonly prescribed to treat anterior cruciate ligament (ACL) injury. The results of the existing literature on functional brace use are mixed. The purpose of this study was to evaluate the history and current state of functional ACL bracing and to identify design criteria that could improve upon current bracing technologies. METHODS: A literature search was performed through the PubMed MEDLINE database in April 2013 for the keywords "anterior cruciate ligament" and "brace". Articles published between January 1, 1980, and April 4, 2013, were retrieved and reviewed. Current functional braces used to treat ACL injury were identified. The function of the native ACL was carefully studied to identify design requirements that could improve upon current bracing technologies. RESULTS: Biomechanical evaluations of functional brace effects at time zero have been mixed. Functional brace use reportedly does not improve long-term patient outcomes following ACL reconstruction, but has been shown to reduce subsequent injury rates while skiing in both ACL-deficient and reconstructed skiers. In situ force in the ACL varies with flexion angle and activity. Currently, no brace has been designed and validated to replicate the force-flexion behavior of the native ACL. CONCLUSIONS: Biomechanical and clinical evidence suggests current functional bracing technologies do not sufficiently restore normal biomechanics to the ACL-deficient knee, protect the reconstructed ACL, and improve long-term patient outcomes. Further research into a functional brace designed to apply forces to the knee joint similar in magnitude to the native ACL should be pursued. LEVEL OF EVIDENCE: III. PMID- 23624657 TI - Bacterial lipoxygenases, a new subfamily of enzymes? A phylogenetic approach. AB - Lipoxygenases (EC. 1.13.11.12) are a non-heme iron enzymes consisting of one polypeptide chain folded into two domains, the N-terminal domain and the catalytic moiety beta-barrel domain. They catalyze the dioxygenation of 1Z,4Z pentadiene moieties of polyunsaturated fatty acids obtaining hydroperoxy fatty acids. For years, the presence of lipoxygenases was considered a eukaryotic feature, present in mammals, plants, small marine invertebrates, and fungi, but now, some lipoxygenase sequences have been detected on prokaryotic organisms, changing the idea that lipoxygenases are exclusively a eukaryotic affair. Lipoxygenases are involved in different types of reactions on eukaryote organisms where the biological role and the structural characteristics of these enzymes are well studied. However, these aspects of the bacterial lipoxygenases have not yet been elucidated and are unknown. This revision discusses biochemical aspects, biological applications, and some characteristics of these enzymes and tries to determine the existence of a subfamily of bacterial lipoxygenases in the context of the phylogeny of prokaryotic lipoxygenases, supporting the results of phylogenetic analyzes with the comparison and discussion of structural information of the first prokaryotic lipoxygenase crystallized and other eukaryotic lipoxygenases structures. PMID- 23624658 TI - Analysis of fermentation selectivity of purified galacto-oligosaccharides by in vitro human faecal fermentation. AB - The in vitro fermentation of several purified galacto-oligosaccharides (GOS), specifically the trisaccharides 4'-galactosyl-lactose and 6'-galactosyl-lactose and a mixture of the disaccharides 6-galactobiose and allolactose, was carried out. The bifidogenic effect of GOS at 1% (w/v) was studied in a pH-controlled batch culture fermentation system inoculated with healthy adult human faeces. Results were compared with those obtained with a commercial GOS mixture (Bimuno GOS). Changes in bacterial populations measured through fluorescence in situ hybridization and short-chain fatty acid (SCFA) production were determined. Bifidobacteria increased after 10-h fermentation for all the GOS substrates, but the changes were only statistically significant (P<0.05) for the mixture of disaccharides and Bimuno-GOS. Acetic acid, whose formation is consistent with bifidobacteria metabolism, was the major SCFA synthesized. The acetate concentration at 10 h was similar with all the substrates (45-50 mM) and significantly higher than the observed for formic, propionic and butyric acids. All the purified GOS could be considered bifidogenic under the assayed conditions, displaying a selectivity index in the range 2.1-3.0, which was slightly lower than the determined for the commercial mixture Bimuno-GOS. PMID- 23624659 TI - A review on recent developments in mass spectrometry instrumentation and quantitative tools advancing bacterial proteomics. AB - Proteomics has evolved substantially since its early days, some 20 years ago. In this mini-review, we aim to provide an overview of general methodologies and more recent developments in mass spectrometric approaches used for relative and absolute quantitation of proteins. Enhancement of sensitivity of the mass spectrometers as well as improved sample preparation and protein fractionation methods are resulting in a more comprehensive analysis of proteomes. We also document some upcoming trends for quantitative proteomics such as the use of label-free quantification methods. Hopefully, microbiologists will continue to explore proteomics as a tool in their research to understand the adaptation of microorganisms to their ever changing environment. We encourage them to incorporate some of the described new developments in mass spectrometry to facilitate their analyses and improve the general knowledge of the fascinating world of microorganisms. PMID- 23624660 TI - Purification and characterization of salicylate 5-hydroxylase, a three-component monooxygenase from Ralstonia sp. strain U2. AB - Salicylate is an important intermediate in the bacterial degradation of polycyclic aromatic hydrocarbons and salicylate hydroxylases play essential roles in linking the peripheral and ring-cleavage catabolic pathways. Unlike the well characterized salicylate 1-hydroxylases, the rarely occurred salicylate 5 hydroxylase (S5H) has not been characterized in detail. In this study, the three component Fe-S protein complex (NagAaGHAb) of S5H from Ralstonia sp. strain U2 was purified, and its biochemical and catalytic properties were characterized. The oxygenase component NagGH exhibited an alpha3beta3 heterohexameric structure and contained one Rieske-type [2Fe-2S] cluster and one mononuclear iron per alpha subunit. NagAa is the ferredoxin-NADP+ reductase component containing flavin and plant type [2Fe-2S] cluster. The ferredoxin component NagAb was characterized as a [2Fe-2S] dimer which remains remarkably stable in denaturing gel electrophoresis after being heated at 100 degrees C for 1 h. Purified NagAa and NagAb, NagGH catalyzed the hydroxylation of salicylate to gentisate with a specific activity of 107.12 +/- 14.38 U/g and showed an apparent K(m) for salicylate of 102.79 +/- 27.20 MUM and a similar K(m) value for both NADH and NADPH (59.76 +/- 7.81 MUM versus 56.41 +/- 12.76 MUM). The hydroxylase exhibited different affinities for two hydroxysalicylates (2,4-dihydroxybenzoate K(m) of 93.54 +/- 18.50 MUM versus 2,6-dihydroxybenzoate K(m) of 939.80 +/- 199.46 MUM). Interestingly, this S5H also showed catalytic activity to the pollutant 2 nitrophenol and exhibited steady-state kinetic data of the same order of magnitude as those for salicylate. This study will allow further comparative studies of structure-function relationships of the ring hydroxylating mono- and di-oxygenase systems. PMID- 23624662 TI - Serum C-reactive protein level and distribution in chronic obstructive pulmonary disease versus healthy controls: a case-control study from Iran. AB - Inflammation has a contributive role in the development and progression of chronic obstructive pulmonary disease (COPD).The present study was designed to determine the level and the distribution of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in COPD compared with controls. Ninety patients with COPD presented to an outpatient hospital clinic and 50 controls who were selected among personals of the same hospital entered the study. Serum high sensitive CRP (hs-CRP) was measured by immunoturbidimetric method and the ESR by Westergren method. Receiver operating characteristic curve was applied to determine a cutoff point for differentiation of the COPD and control group. In statistical analysis, the patients and controls were compared regarding levels and distribution of hs-CRP and ESR. Mean age of patients and controls was 67 +/- 11.6 and 51.3 +/- 6.7 years, respectively (p = 0.001). Mean hs-CRP was significantly higher (4.76 +/- 5.6 vs 1.72 +/- 1.68 mg/L, p = 0.001) but mean ESR was nonsignificantly higher (9.1 +/- 11.2 vs 7.2 +/- 7.4 m/h, p = 0.95) in patients than control. Serum hs-CRP at 1.55 mg/L, differentiated patients and controls at sensitivity of 77.3 % and specificity of 60 %. Serum hs-CRP >3 mg/L was observed in 39 (44.3 %) patients and 9 (18 %) controls (p = 0.001) and >6 mg/L in 22 (25 %) patients and 2 (4 %) controls (p = 0.001).Serum hs-CRP was significantly correlated with ESR in patient but not in control group (Spearman correlation coefficient = 0.516, p = 0.001). Serum hs-CRP and ESR was not correlated with age, weigh, smoking, and the severity of COPD. The results of this study indicated a systemic inflammatory process in COPD. Since inflammation has an important contribution in development of future pulmonary and extrapulmonary complications, serum CRP assessment will provide additional information beyond that achieved by conventional method of pulmonary function test. PMID- 23624663 TI - The relationship between N-acetylcysteine, hyperbaric oxygen, and inflammation in a rat model of acetaminophen-induced nephrotoxicity. AB - An overdose of acetaminophen (APAP) produces acute tubular necrosis. The aim of this study was to observe the effects of hyperbaric oxygen (HBO) only and combined with N-acetylcysteine (NAC) on inflammatory cytokines in kidney. Thirty two male Sprague-Dawley rats were divided into four groups: sham, control (APAP), NAC, and NAC + HBO. In the APAP, NAC, and NAC + HBO groups, renal injury was induced by oral administration of 1 g/kg APAP. The NAC group received NAC (100 mg/kg/day). NAC + HBO group received NAC (100 mg/kg/day) intraperitoneally and HBO underwent at 2.8 ATA pressure with 100 % oxygen inhalation for 90 min every 12 h for 5 days. Rats in the sham group received distilled water only by gastric tube. All animals were killed on 6 days after APAP or distilled water administration. Creatinine, urea, neopterin, tumor necrosis factor-alpha (TNF alpha), and interleukin (IL)-6 levels were measured in sera. There was a significant increase in serum creatinine and urea levels in the control group compared to the sham group (in both, p = 0.001). NAC and NAC + HBO significantly decreased serum neopterin, TNF-alpha, and IL-6 levels compared to control group. APAP administration caused tubular necrosis in the renal. NAC and NAC + HBO treatments significantly reduced APAP-induced renal damage. The results of this study showed that renal dysfunction in APAP toxicity was attenuated by the use of HBO and NAC treatments. The combination of NAC and HBO treatments might be recommended as an effective treatment modality for APAP-induced nephrotoxicity. PMID- 23624664 TI - Comprehensive macromolecular conformations mapped by quantitative SAXS analyses. PMID- 23624665 TI - Measuring image resolution in optical nanoscopy. AB - Resolution in optical nanoscopy (or super-resolution microscopy) depends on the localization uncertainty and density of single fluorescent labels and on the sample's spatial structure. Currently there is no integral, practical resolution measure that accounts for all factors. We introduce a measure based on Fourier ring correlation (FRC) that can be computed directly from an image. We demonstrate its validity and benefits on two-dimensional (2D) and 3D localization microscopy images of tubulin and actin filaments. Our FRC resolution method makes it possible to compare achieved resolutions in images taken with different nanoscopy methods, to optimize and rank different emitter localization and labeling strategies, to define a stopping criterion for data acquisition, to describe image anisotropy and heterogeneity, and even to estimate the average number of localizations per emitter. Our findings challenge the current focus on obtaining the best localization precision, showing instead how the best image resolution can be achieved as fast as possible. PMID- 23624666 TI - Are MOOCs the future of medical education? PMID- 23624667 TI - Healthwatch must engage with patients if it is to fulfil its remit, conference hears. PMID- 23624668 TI - Handheld device for counterfeit drug detection to be tested in Africa. PMID- 23624669 TI - Health effects of Greece's austerity measures are "worse than imagined," report researchers. PMID- 23624670 TI - Controlled electrochemical deposition and transformation of hetero nanoarchitectured electrodes for energy storage. AB - A review of electrochemically synthesized nanomaterials with different controllable architectures for electrochemical energy storage devices is shown. It is demonstrated that these nano-architectures can be created either by electrodeposition or by the electrochemical transformation of materials. Electrochemical synthesis is presented here as it provides intimate contact between the electrode and current collector and also promotes an electronic pathway for all materials to be connected to the circuit. Although still in their infancy, electrosynthesized nano-architectures show promise to be used in future electrochemical energy storage devices as utilization of this method bypasses the need for bulky conductive additives and electrochemically inactive binders. Furthermore, electrochemical transformations can be used to create additional architectural features or change the chemical make-up of the electrode. This review is meant to show the creativity of current science when it comes to these nano-architectured electrodes. It is organized by technique used for synthesis including hard template, soft template, and template-free synthesis along with electrochemical transformation techniques. PMID- 23624671 TI - C-reactive protein is elevated in atypical but not nonatypical depression: data from the National Health and Nutrition Examination survey (NHANES) 1999-2004. AB - Little is known about the association of depression subtypes with inflammatory markers predictive of coronary artery disease. In a sample of younger adults representative of the U.S. population, we examined differences in serum C reactive protein (CRP) among individuals with atypical major depressive disorder (MDD; n = 16), nonatypical MDD (n = 93), and no MDD (n = 1,682). Adults with atypical MDD exhibited higher CRP levels than those with no MDD (mean difference = 1.56 mg/L) or nonatypical MDD (mean difference = 1.40 mg/L), even after adjustment for potential cofounders, anxiety disorders, body mass, and smoking. Nearly twice as many adults with atypical MDD had CRP levels in the high cardiovascular risk range than did those with no MDD or nonatypical MDD. CRP levels of adults with nonatypical MDD or no MDD did not differ. Individuals with atypical depression may be partially driving the overall depression-inflammation relationship and may be a subgroup at elevated risk for coronary artery disease. PMID- 23624672 TI - The diversity and fitness effects of infection with facultative endosymbionts in the grain aphid, Sitobion avenae. AB - Mutualisms with facultative, non-essential heritable microorganisms influence the biology of many insects, and they can have major effects on insect host fitness in certain situations. One of the best-known examples is found in aphids where the facultative endosymbiotic bacterium Hamiltonella defensa confers protection against hymenopterous parasitoids. This symbiont is widely distributed in aphids and related insects, yet its defensive properties have only been tested in two aphid species. In a wild population of the grain aphid, Sitobion avenae, we identified several distinct strains of endosymbiotic bacteria, including Hamiltonella. The symbiont had no consistent effect on grain aphid fecundity, though we did find a significant interaction between aphid genotype by symbiont status. In contrast to findings in other aphid species, Hamiltonella did not reduce aphid susceptibility to two species of parasitoids (Aphidius ervi and Ephedrus plagiator), nor did it affect the fitness of wasps that successfully completed development. Despite this, experienced females of both parasitoid species preferentially oviposited into uninfected hosts when given a choice between genetically identical individuals with or without Hamiltonella. Thus, although Hamiltonella does not always increase resistance to parasitism, it may reduce the risk of parasitism in its aphid hosts by making them less attractive to searching parasitoids. PMID- 23624673 TI - Homeostasis in leaf water potentials on leeward and windward sides of desert shrub crowns: water loss control vs. high hydraulic efficiency. AB - Phenotypic plasticity in morphophysiological leaf traits in response to wind was studied in two dominant shrub species of the Patagonian steppe, used as model systems for understanding effects of high wind speed on leaf water relations and hydraulic properties of small woody plants. Morpho-anatomical traits, hydraulic conductance and conductivity and water relations in leaves of wind-exposed and protected crown sides were examined during the summer with nearly continuous high winds. Although exposed sides of the crowns were subjected to higher wind speeds and air saturation deficits than the protected sides, leaves throughout the crown had similar minimum leaf water potential (PsiL). The two species were able to maintain homeostasis in minimum PsiL using different physiological mechanisms. Berberis microphylla avoided a decrease in the minimum PsiL in the exposed side of the crown by reducing water loss by stomatal control, loss of cell turgor and low epidermal conductance. Colliguaja integerrima increased leaf water transport efficiency to maintain transpiration rates without increasing the driving force for water loss in the wind-exposed crown side. Leaf physiological changes within the crown help to prevent the decrease of minimum PsiL and thus contribute to the maintenance of homeostasis, assuring the hydraulic integrity of the plant under unfavorable conditions. The responses of leaf traits that contribute to mechanical resistance (leaf mass per area and thickness) differed from those of large physiological traits by exhibiting low phenotypic plasticity. The results of this study help us to understand the unique properties of shrubs which have different hydraulic architecture compared to trees. PMID- 23624674 TI - Gymnosperms have increased capacity for electron leakage to oxygen (Mehler and PTOX reactions) in photosynthesis compared with angiosperms. AB - Oxygen plays an important role in photosynthesis by participating in a number of O2-consuming reactions. O2 inhibits CO2 fixation by stimulating photorespiration, thus reducing plant production. O2 interacts with photosynthetic electron transport in the chloroplasts' thylakoids in two main ways: by accepting electrons from PSI (Mehler reaction); and by accepting electrons from reduced plastoquinone (PQ) mediated by the plastid terminal oxidase (PTOX). In this study, we show, using 101 plant species, that there is a difference in the potential for photosynthetic electron flow to O2 between angiosperms and gymnosperms. We found, from measurements of Chl fluorescence and leaf absorbance at 830 nm, (i) that electron outflow from PSII, as determined by decay kinetics of Chl fluorescence after application of a saturating light pulse, is more rapid in gymnosperms than in angiosperms; (ii) that the reaction center Chl of PSI (P700) is rapidly and highly oxidized in gymnosperms during induction of photosynthesis; and (iii) that these differences are dependent on oxygen. Finally, rates of O2 uptake measured by mass spectrometry in the absence of photorespiration were significantly promoted by illumination in dark-adapted leaves of gymnosperms, but not in those of angiosperms. The light-stimulated O2 uptake was around 10% of the maximum O2 evolution in gymnosperms and 1% in angiosperms. These results suggest that gymnosperms have increased capacity for electron leakage to oxygen in photosynthesis compared with angiosperms. The involvement of the Mehler reaction and PTOX in the electron flow to O2 is discussed. PMID- 23624675 TI - Transcriptome analysis of Japanese pear (Pyrus pyrifolia Nakai) flower buds transitioning through endodormancy. AB - The transcriptomes of endodormant and ecodormant Japanese pear (Pyrus pyrifolia Nakai 'Kosui') flower buds were analyzed using RNA-seq technology and compared. Among de novo assembly of 114,191 unigenes, 76,995 unigenes were successfully annotated by BLAST searches against various databases. Gene Ontology (GO) enrichment analysis revealed that oxidoreductases were enriched in the molecular function category, a result consistent with previous observations of notable changes in hydrogen peroxide concentration during endodormancy release. In the GO categories related to biological process, the abundance of DNA methylation related gene transcripts also significantly changed during endodormancy release, indicating the involvement of epigenetic regulation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis also showed the changes in transcript abundance of genes involved in the metabolism of various phytohormones. Genes for both ABA and gibberellin biosynthesis were down-regulated, whereas the genes encoding their degradation enzymes were up-regulated during endodormancy release. In the ethylene pathway, 1-aminocyclopropane-1-carboxylate synthase (ACS), a gene encoding the rate-limiting enzyme for ethylene biosynthesis, was induced towards endodormancy release. All of these results indicated the involvement of phytohormones in endodormancy release. Furthermore, the expression of dormancy associated MADS-box (DAM) genes was down-regulated concomitant with endodormancy release, although changes in the abundance of these gene transcripts were not as significant as those identified by transcriptome analysis. Consequently, characterization of the Japanese pear transcriptome during the transition from endormancy to ecodormancy will provide researchers with useful information for data mining and will facilitate further experiments on endodormancy especially in rosaceae fruit trees. PMID- 23624676 TI - Metabolomics: is it useful for inflammatory bowel diseases? AB - PURPOSE OF REVIEW: The assessment of metabolite profiles in biofluids has become a powerful method for the detection of biomarker molecules and disease mechanisms. This review outlines the recent advances in the use of metabolomic techniques to study inflammatory bowel diseases (IBDs). RECENT FINDINGS: The last few years have seen an increase in the studies of experimental and human IBD focusing on the search for small metabolites, such as amino acids, bases, and tricarboxylic acid cycle intermediates. Experimental methods for the screening of metabolites in serum, urine, fecal extracts, and colon tissue include H NMR spectroscopy, gas chromatography-mass spectrometry, and liquid chromatography methods. Several studies demonstrate that IBD patients and healthy individuals, as well as the IBD subtypes, can be distinguished using metabolic profiling. Metabolomic data of fecal extracts and urine have revealed disruptions in bacterial populations, findings that are indicative of a possible involvement of the microbiome in the development of IBDs. SUMMARY: Metabolites from biofluids can be detected in IBDs by different experimental methods that allow successful separation of IBD subtypes from healthy cohorts. Knowledge of a unique metabolomic fingerprint in IBDs could be useful for diagnosis, treatment, and detection of disease mechanisms. PMID- 23624677 TI - Opening wedge high tibial osteotomy: plate position and biomechanics of the medial tibial plateau. AB - PURPOSE: To ascertain whether changing position and size of the spacer may modify the load and displacement of the tibial plateau when performing an opening wedge high tibial osteotomy. METHODS: Fifteen sawbones tibia models were used. In the axial plane, the anterior, medial, and posterior thirds of the tibial plateau were marked, and the medial and posterior thirds were called "point 1" and "point 2", respectively. A 7.5-mm-stainless steel indenter was used to apply the load over these two points: the load applied to point 1 simulated the load to that site when the knee was extended, and the load to point 2 simulated the load to the same area when the knee was flexed. Maximum load (N) and displacement (mm) were calculated. RESULTS: The system was shown to withstand higher loads with less displacement when the plate was posterior than it could do with the plate in the middle position. Significant differences were also found when comparing the anterior and middle position of the plate with the greatest displacement when the plate was anterior. The differences were increased when comparing the anterior and posterior positions of the plate. No statistical differences (n.s.) were found when using different spacers. The maximum stiffness was achieved if the plate was posterior and in point 1 indenter position, in which the force vector stands on the points of the lateral and medial supports (FMU = 198.8 +/- 61.5 N). The lowest stiffness was observed when the plate was anterior, and the force was applied to point 2 (FMU = 29.7 +/- 5.1 N). CONCLUSIONS: Application of the plate in a more posterior position provides greater stability. PMID- 23624678 TI - Linear eruptions on the calf in a six-week-old boy: a quiz. PMID- 23624679 TI - Recombination in human coxsackievirus B5 strains that caused an outbreak of viral encephalitis in Henan, China. AB - In 2011, human coxsackievirus B5 (CVB5) caused an outbreak of viral encephalitis in Henan, China. Complete genome sequence analysis based on two isolates showed that the 5' half of the genome (nt 1-4540) had high similarity (>97 %) to that of CVB5 strain GU376747, and the 3' half (nt 4700-7402) showed high similarity (>96 %) to that of human coxsackievirus B3 (CVB3) strain GQ141875. These isolates had the highest similarity (97.7 %) to the Changchun strain, based on the complete genome, rather than to other CVB5 strains isolated from Henan in recent years. There were therefore at least two groups of CVB5 circulating in Henan Province, which evolved at different rates. PMID- 23624680 TI - Novel seadornavirus (family Reoviridae) related to Banna virus in Europe. AB - Banna virus, whose genome is composed of 12 segments of double-stranded RNA, is a member of the genus Seadornavirus in the family Reoviridae and is thought to be an emerging mosquito-transmitted human pathogen in Southeast Asia. A novel phylogenetic relative of Banna virus (Balaton virus, BALV, JX947843-JX947850 and KC522611-KC522612) was identified using viral metagenomics in the intestinal contents of freshwater carp (Cyprinus carpio) in Hungary. The amino acid sequence identity of Balaton virus to homologous proteins of Banna viruses was 25-26 % for segment 12 (VP12) and 61-62 % for segment 1 (VP1), indicating that Balaton virus potentially represents a novel seadornavirus species. This study demonstrates that seadornaviruses are genetically diverse, not restricted geographically to Southeast Asia and present in an aquatic environment. PMID- 23624681 TI - Solvent-induced lone pair activity tuning and vapoluminescence in a Pt2Pb cluster. AB - We report a novel cluster, [{Pt(C6F5)(bzq)}2Pb(Spy)2] 1, that displays reversible vapoluminescence to specific organic vapours; this behaviour can be related to the stereochemical activity of the lone pair around the Pb(II) in the ground state and to the distinct distortion of the coordination environment (1 and 1 solvent) upon photoexcitation. PMID- 23624682 TI - Transcriptome analysis of candidate genes and signaling pathways associated with light-induced brown film formation in Lentinula edodes. AB - High-throughput Illumina RNA-seq was used for deep sequencing analysis of the transcriptome of poly(A)+ RNA from mycelium grown under three different conditions: 30 days darkness (sample 118), 80 days darkness (313W), and 30 days darkness followed by 50 days in the light (313C), in order to gain insight into the molecular mechanisms underlying the process of light-induced brown film (BF) formation in the edible mushroom, Lentinula edodes. Of the three growth conditions, BF formation occurred in 313C samples only. Approximately 159.23 million reads were obtained, trimmed, and de novo assembled into 31,511 contigs with an average length of 1,746 bp and an N 50 of 2,480 bp. Based on sequence orientations determined by a BLASTX search against the NR, Swiss-Prot, COG, and KEGG databases, 24,246 (76.9 %) contigs were assigned putative descriptions. Comparison of 313C/118 and 313C/313W expression profiles revealed 3,958 and 5,651 significantly differentially expressed contigs (DECs), respectively. Annotation using the COG database revealed that candidate genes for light-induced BF formation encoded proteins linked to light reception (e.g., WC-1, WC-2, phytochrome), light signal transduction pathways (e.g., two-component phosphorelay system, mitogen-activated protein kinase pathway), and pigment formation (e.g., polyketide synthase, O-methyltransferase, laccase, P450 monooxygenase, oxidoreductase). Several DECs were validated using quantitative real-time polymerase chain reaction. Our report is the first to identify genes associated with light-induced BF formation in L. edodes and represents a valuable resource for future genomic studies on this commercially important mushroom. PMID- 23624683 TI - Microbial community structure and dynamics during anaerobic digestion of various agricultural waste materials. AB - The influence of the feedstock type on the microbial communities involved in anaerobic digestion was investigated in laboratory-scale biogas reactors fed with different agricultural waste materials. Community composition and dynamics over 2 months of reactors' operation were investigated by amplicon sequencing and profiling terminal restriction fragment length polymorphisms of 16S rRNA genes. Major bacterial taxa belonged to the Clostridia and Bacteroidetes, whereas the archaeal community was dominated by methanogenic archaea of the orders Methanomicrobiales and Methanosarcinales. Correlation analysis revealed that the community composition was mainly influenced by the feedstock type with the exception of a temperature shift from 38 to 55 degrees C which caused the most pronounced community shifts. Bacterial communities involved in the anaerobic digestion of conventional substrates such as maize silage combined with cattle manure were relatively stable and similar to each other. In contrast, special waste materials such as chicken manure or Jatropha press cake were digested by very distinct and less diverse communities, indicating partial ammonia inhibition or the influence of other inhibiting factors. Anaerobic digestion of chicken manure relied on syntrophic acetate oxidation as the dominant acetate-consuming process due to the inhibition of aceticlastic methanogenesis. Jatropha as substrate led to the enrichment of fiber-degrading specialists belonging to the genera Actinomyces and Fibrobacter. PMID- 23624684 TI - Novel expression system for Corynebacterium acetoacidophilum and Escherichia coli based on the T7 RNA polymerase-dependent promoter. AB - The industrially important species of corynebacteria viz. Corynebacterium acetoacidophilum appear to be alternative hosts for recombinant protein production; despite many efforts, a strong promoter-based system in corynebacteria has not been established so far. Described here is a T7 promoter based expression system which was functional in both gram-positive C. acetoacidophilum and gram-negative Escherichia coli in an external inducer independent manner. This is the very first report of a T7 expression system for Corynebacterium sp. Also, it is a useful addition in the existing T7 expression systems of E. coli. PMID- 23624685 TI - Metal nanoparticle fluids with magnetically induced electrical switching properties. AB - We report the successful preparation of solvent-free metal nanoparticle (NP) fluids with multiple-functionalities, such as rheological properties, magnetism, ionic conductivity, and electrical properties, allowing for facile synthesis and mass production. The gold nanoparticles (AuNPs) used in this study were synthesized using tetraoctylammonium bromide (TOABr) in toluene and then directly phase-transferred to solvent-free low-molecular-weight (Mw) imidazolium-type ionic liquid media containing thiol groups (i.e., IL-SH). Magnetic metal fluids (i.e., MIL-SH-AuNPs) were prepared by the addition of FeCl3 powder to metal fluids (i.e., IL-SH-AuNPs). These fluids showed relatively high ionic and electrical conductivities compared with those of conventional metal NP fluids based on organic ILs with high Mw. Furthermore, it was demonstrated that these fluids could be used as electric switches operated using an external magnetic field in organic media. PMID- 23624687 TI - Correlation of TP53 mutations with HCV positivity in hepatocarcinogenesis: identification of a novel TP53 microindel in hepatocellular carcinoma with HCV infection. AB - Although it is known that chronic hepatitis C virus (HCV) infection may contribute to tumor initiation and development, the molecular processes causing hepatocellular carcinoma (HCC) remain unclear. Microindels are unique, infrequent mutations that result in inserted and deleted sequences at the same nucleotide position, and are important contributors to cancer. To date, microindels in the p53 tumor suppressor gene (TP53) have not been fully examined in tumors. In the present study, 116 cases of HCC were screened for mutations in the TP53 gene (exon 5-8) by single-stranded conformational polymorphism analysis followed by direct sequencing. A special type of complex TP53 mutation, 616ins14del1 (14-1 microindel), was identified in a case of HCC with HCV infection. This rare TP53 microindel led to the generation of a truncated protein of 211 amino acids that lacked the DNA-binding domain and tetramerization domain. Immunohistochemistry showed loss of p53 protein expression and downregulation of p21(WAF/CIP), Mdm2 and Bax in the tumor cells, indicating an impaired p53 signaling pathway. Nineteen of the 116 (16.4%) HCCs carried a total of 19 TP53 mutations. Notably, 5 of the 13 HCV-positive (38.5%) cases contained a TP53 mutation, and there was a significant association between TP53 mutations and HCV positivity (P=0.0379). No correlation of TP53 mutations with hepatitis B virus (HBV) positivity was observed. In summary, we identified a novel TP53 microindel in HCC, and provided evidence of HCC characterized by HCV infections typically associated with mutational inactivation of the TP53 gene. PMID- 23624686 TI - ISPMD consensus on the management of premenstrual disorders. AB - The second consensus meeting of the International Society for Premenstrual Disorders (ISPMD) took place in London during March 2011. The primary goal was to evaluate the published evidence and consider the expert opinions of the ISPMD members to reach a consensus on advice for the management of premenstrual disorders. Gynaecologists, psychiatrists, psychologists and pharmacologists each formally presented the evidence within their area of expertise; this was followed by an in-depth discussion leading to consensus recommendations. This article provides a comprehensive review of the outcomes from the meeting. The group discussed and agreed that careful diagnosis based on the recommendations and classification derived from the first ISPMD consensus conference is essential and should underlie the appropriate management strategy. Options for the management of premenstrual disorders fall under two broad categories, (a) those influencing central nervous activity, particularly the modulation of the neurotransmitter serotonin and (b) those that suppress ovulation. Psychotropic medication, such as selective serotonin reuptake inhibitors, probably acts by dampening the influence of sex steroids on the brain. Oral contraceptives, gonadotropin-releasing hormone agonists, danazol and estradiol all most likely function by ovulation suppression. The role of oophorectomy was also considered in this respect. Alternative therapies are also addressed, with, e.g. cognitive behavioural therapy, calcium supplements and Vitex agnus castus warranting further exploration. PMID- 23624688 TI - A hybrid LSSVR/HMM-based prognostic approach. AB - n a health management system, prognostics, which is an engineering discipline that predicts a system's future health, is an important aspect yet there is currently limited research in this field. In this paper, a hybrid approach for prognostics is proposed. The approach combines the least squares support vector regression (LSSVR) with the hidden Markov model (HMM). Features extracted from sensor signals are used to train HMMs, which represent different health levels. A LSSVR algorithm is used to predict the feature trends. The LSSVR training and prediction algorithms are modified by adding new data and deleting old data and the probabilities of the predicted features for each HMM are calculated based on forward or backward algorithms. Based on these probabilities, one can determine a system's future health state and estimate the remaining useful life (RUL). To evaluate the proposed approach, a test was carried out using bearing vibration signals. Simulation results show that the LSSVR/HMM approach can forecast faults long before they occur and can predict the RUL. Therefore, the LSSVR/HMM approach is very promising in the field of prognostics. PMID- 23624689 TI - Nanostructured surfaces and detection instrumentation for photonic crystal enhanced fluorescence. AB - Photonic crystal (PC) surfaces have been demonstrated as a compelling platform for improving the sensitivity of surface-based fluorescent assays used in disease diagnostics and life science research. PCs can be engineered to support optical resonances at specific wavelengths at which strong electromagnetic fields are utilized to enhance the intensity of surface-bound fluorophore excitation. Meanwhile, the leaky resonant modes of PCs can be used to direct emitted photons within a narrow range of angles for more efficient collection by a fluorescence detection system. The multiplicative effects of enhanced excitation combined with enhanced photon extraction combine to provide improved signal-to-noise ratios for detection of fluorescent emitters, which in turn can be used to reduce the limits of detection of low concentration analytes, such as disease biomarker proteins. Fabrication of PCs using inexpensive manufacturing methods and materials that include replica molding on plastic, nano-imprint lithography on quartz substrates result in devices that are practical for single-use disposable applications. In this review, we will describe the motivation for implementing high-sensitivity fluorescence detection in the context of molecular diagnosis and gene expression analysis though the use of PC surfaces. Recent efforts to improve the design and fabrication of PCs and their associated detection instrumentation are summarized, including the use of PCs coupled with Fabry-Perot cavities and external cavity lasers. PMID- 23624690 TI - Seedling discrimination with shape features derived from a distance transform. AB - The aim of this research is an improvement of plant seedling recognition by two new approaches of shape feature generation based on plant silhouettes. Experiments show that the proposed feature sets possess value in plant recognition when compared with other feature sets. Both methods approximate a distance distribution of an object, either by resampling or by approximation of the distribution with a high degree Legendre polynomial. In the latter case, the polynomial coefficients constitute a feature set. The methods have been tested through a discrimination process where two similar plant species are to be distinguished into their respective classes. The used performance assessment is based on the classification accuracy of 4 different classifiers (a k-Nearest Neighbor, Naive-Bayes, Linear Support Vector Machine, Nonlinear Support Vector Machine). Another set of 21 well-known shape features described in the literature is used for comparison. The used data consisted of 139 samples of cornflower (Centaura cyanus L.) and 63 samples of nightshade (Solanum nigrum L.). The highest discrimination accuracy was achieved with the Legendre Polynomial feature set and amounted to 97.5%. This feature set consisted of 10 numerical values. Another feature set consisting of 21 common features achieved an accuracy of 92.5%. The results suggest that the Legendre Polynomial feature set can compete with or outperform the commonly used feature sets. PMID- 23624691 TI - DRIFTS sensor: soil carbon validation at large scale (Pantelleria, Italy). AB - A fast and accurate measurement of soil carbon is needed in current scientific issues. Today there are many sensors suitable for these purposes, but choosing the appropriate sensor depends on the spatial scale at which the studies are conducted. There are few detailed studies that validate these types of measures allowing their immediate use. Here it is validated the quick use of a sensor in execution at Pantelleria, chosen for size, use and variability of the parameter measured, to give an operational tool for carbon stocks studies. The DRIFT sensor used here has been validated in the first 60 cm of the soil of the whole island, and it has shown predictivity higher than 90%. PMID- 23624692 TI - n-Butyl cyanoacrylate-induced multiple retinal arteriolar occlusions. AB - We report a case of multiple retinal arteriolar occlusions due to delayed embolisation of N-butylcyanoacrylate glue, initially injected in the external carotid artery for the management of Carotid body tumour. Ocular massage and anterior chamber paracentesis were unfruitful and patient suffered irreversible visual loss in the affected eye. Embolisation of N-butyl cyanoacrylate glue into the retinal vasculature after intratumoral injection should be kept in mind as a rare but possible complication by radiologists and ophthalmologists. PMID- 23624693 TI - Decreases in the numbers of peripheral blood regulatory T cells, and increases in the levels of memory and activated B cells, in patients with active eosinophilic granulomatosis and polyangiitis. AB - PURPOSE: Eosinophilic granulomatosis with polyangiitis (EGPA), a rare disease characterized by the presence of allergic granulomatosis and necrotizing vasculitis, is often effectively treated with corticosteroids. However, relapse rates are high and, for unknown reasons, some EGPA patients suffer frequent relapses after entry into initial remission. Regulatory T (Treg) cells and B cells are implicated in the development and progression of EGPA. Here, we explored the influence of Treg cells and a co-stimulatory factor present on B cells on the development and course of EGPA. METHODS: We studied 45 EGPA patients (19 of whom experienced frequent relapses and 26 of whom seldom relapsed) and 67 (control) patients with general asthma. We determined the counts or percentages of whole-blood cells exhibiting the following characteristics: FOXP3(+) cells among CD4(+) Treg cells; CTLA-4(+) cells among CD4(+)/CD25(+) Treg cells; and CD27(+), CD80(+), CD86(+), or CD95(+) cells among CD19(+) B cells. We also measured serum IgG concentrations. RESULTS: Compared with patients with asthma or seldom-relapsing EGPA, frequently relapsing EGPA patients with active disease exhibited decreased counts of Treg cells and increased percentages of B cells that scored as CD80(+), CD27(+), or CD95(+). Patients with frequently relapsing EGPA had increased percentages of CD27(+) and CD95(+) B cells, and fewer CD19(+) B cells, than did patients in the other two groups. Lower CD19(+) B cell counts were associated with reduced Treg cell counts and a lower serum IgG concentration. CONCLUSION: In patients with frequently relapsing EGPA, decreases in Treg cell numbers and increased percentages of activated B cells may induce apoptosis of B cells. PMID- 23624694 TI - Graphene transfer: a stamp for all substrates. PMID- 23624695 TI - Long-distance coherent coupling in a quantum dot array. AB - Controlling long-distance quantum correlations is central to quantum computation and simulation. In quantum dot arrays, experiments so far rely on nearest neighbour couplings only, and inducing long-distance correlations requires sequential local operations. Here, we show that two distant sites can be tunnel coupled directly. The coupling is mediated by virtual occupation of an intermediate site, with a strength that is controlled via the energy detuning of this site. It permits a single charge to oscillate coherently between the outer sites of a triple dot array without passing through the middle, as demonstrated through the observation of Landau-Zener-Stuckelberg interference. The long distance coupling significantly improves the prospects of fault-tolerant quantum computation using quantum dot arrays, and opens up new avenues for performing quantum simulations in nanoscale devices. PMID- 23624696 TI - Direct observation and dynamics of spontaneous skyrmion-like magnetic domains in a ferromagnet. AB - The structure and dynamics of submicrometre magnetic domains are the main factors determining the physical properties of magnetic materials. Here, we report the first observation of skyrmion-like magnetic nanodomains in a ferromagnetic manganite, La0.5Ba0.5MnO3, using Lorentz transmission electron microscopy (LTEM). The skyrmion-like magnetic domains appear as clusters above the Curie temperature. We found that the repeated reversal of magnetic chirality is caused by thermal fluctuation. The closely spaced clusters exhibit dynamic coupling, and the repeated magnetization reversal becomes fully synchronized with the same chirality. Quantitative analysis of such dynamics was performed by LTEM to directly determine the barrier energy for the magnetization reversal of skyrmion like nanometre domains. This study is expected to pave the way for further investigation of the unresolved nature and dynamics of magnetic vortex-like nanodomains. PMID- 23624697 TI - Using nanoscale thermocapillary flows to create arrays of purely semiconducting single-walled carbon nanotubes. AB - Among the remarkable variety of semiconducting nanomaterials that have been discovered over the past two decades, single-walled carbon nanotubes remain uniquely well suited for applications in high-performance electronics, sensors and other technologies. The most advanced opportunities demand the ability to form perfectly aligned, horizontal arrays of purely semiconducting, chemically pristine carbon nanotubes. Here, we present strategies that offer this capability. Nanoscale thermocapillary flows in thin-film organic coatings followed by reactive ion etching serve as highly efficient means for selectively removing metallic carbon nanotubes from electronically heterogeneous aligned arrays grown on quartz substrates. The low temperatures and unusual physics associated with this process enable robust, scalable operation, with clear potential for practical use. We carry out detailed experimental and theoretical studies to reveal all of the essential attributes of the underlying thermophysical phenomena. We demonstrate use of the purified arrays in transistors that achieve mobilities exceeding 1,000 cm(2) V(-1) s(-1) and on/off switching ratios of ~10,000 with current outputs in the milliamp range. Simple logic gates built using such devices represent the first steps toward integration into more complex circuits. PMID- 23624698 TI - A general method for transferring graphene onto soft surfaces. AB - Recent advances in chemical vapour deposition have led to the fabrication of large graphene sheets on metal foils for use in research and development. However, further breakthroughs are required in the way these graphenes are transferred from their growth substrates onto the final substrate. Although various methods have been developed, as yet there is no general way to reliably transfer graphene onto arbitrary surfaces, such as 'soft' ones. Here, we report a method that allows the graphene to be transferred with high fidelity at the desired location on almost all surfaces, including fragile polymer thin films and hydrophobic surfaces. The method relies on a sacrificial 'self-releasing' polymer layer placed between a conventional polydimethylsiloxane elastomer stamp and the graphene that is to be transferred. This self-releasing layer provides a low work of adhesion on the stamp, which facilitates delamination of the graphene and its placement on the new substrate. To demonstrate the generality and reliability of our method, we fabricate high field-strength polymer capacitors using graphene as the top contact over a polymer dielectric thin film. These capacitors show superior dielectric breakdown characteristics compared with those made with evaporated metal top contacts. Furthermore, we fabricate low-operation-voltage organic field-effect transistors using graphene as the gate electrode placed over a thin polymer gate dielectric layer. We finally demonstrate an artificial graphite intercalation compound by stacking alternate monolayers of graphene and 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ). This compound, which comprises graphene sheets p-doped by partial hole transfer from the F4TCNQ, shows a high and remarkably stable hole conductivity, even when heated in the presence of moisture. PMID- 23624699 TI - Evaluation of acquired acid resistance of enamel surrounding orthodontic brackets irradiated by laser and fluoride application. AB - Demineralization of enamel around orthodontic brackets is a clinical problem which can lead to some esthetic concerns like white spot lesions. The aim of this in vitro study was to evaluate the effect of the Er, Cr:YSGG laser and fluoride application on the acid resistance of enamel adjacent to orthodontic brackets. A total of 60 healthy, permanent, human premolars were selected and bonded with brackets, then they were randomly assigned to four groups (n = 15): topical APF gel (1.23% F, pH 3.5, for 4 min); Er,Cr:YSGG laser (P:0.25 W, E:12.5 mJ, RR:20 Hz, PD:140 MUs, 11% air, without water, for 10 s); fluoride + laser group (F + L), and control group (C). All specimens were demineralized for 10 days in a 0.2 M acetate buffer solution, and the calcium content were subsequently determined with atomic absorption spectrometry. There were significant differences between the calcium content of F + L and F group in comparison to control group. The least concentration of calcium was seen in F + L group, and the most value was observed in C group. Combination of Er, Cr:YSGG laser with fluoride and fluoride alone decreased enamel solubility significantly more than laser alone. In addition, combination of laser and fluoride leads to less consumption of fluoride amount. And patients can use it at the beginning of treatment instead of daily use of fluoride. So we suggest using it in preventing enamel demineralization around orthodontic brackets. PMID- 23624700 TI - From solvated ions to ion-pairing: a THz study of lanthanum(III) hydration. AB - Ion radius and charge density are important parameters that determine the solvation behavior in aqueous electrolyte solutions. Here, we report on high precision THz absorption measurements of solvated LaCl3 and LaBr3 using narrow band (75-90 cm(-1)) p-Ge laser and wideband (30-350 cm(-1)) Fourier transform spectroscopy. The concentration dependent absorption up to 3.3 M shows a prominent nonlinearity indicating ion pair formation with increasing electrolyte concentration. A more detailed analysis in terms of a chemical equilibrium model allowed us to separate the ion and ion pair contributions from bulk and solvation water. Thus we were able to characterize anion and cation solvation independently. The center frequencies of the Cl(-) and Br(-) rattling modes are in agreement with those found in aqueous alkali and earth alkali halide solutions. The coupling between anion and cation hydration is found to be small. Based upon our detailed analysis we propose increasing formation of solvent shared ion pairs with increasing solute concentration. The well defined ion resonances imply that in spite of its high charge density La(3+) acts locally on the water structure. Terahertz absorption spectroscopy is found here to be an experimental tool which allows us to directly observe solute hydration shells as well as ion pair formation. PMID- 23624701 TI - The impact of different health dimensions on overall quality of life related to kyphoplasty and non-surgical management. AB - This study uses data from a previously published randomised trial where balloon kyphoplasty was compared to non-surgical management. Of the improved overall quality of life, 60 % was caused by decreased pain. However, ignoring other dimensions of quality of life would underestimate the procedure's effect. INTRODUCTION: Acute back pain has been viewed as the most important factor lowering quality of life (QoL) for patients suffering vertebral fractures. The objective of this study was to quantify the impact of different health dimensions on overall QoL using patient-reported outcome measurements (PROMs) collected in Fracture Reduction Evaluation (FREE) trial. METHODS: The analysis was based on patients included in the 2-year-long randomised controlled FREE trial studying the efficacy and safety of balloon kyphoplasty procedure (BKP) compared to non surgical management (NSM). The PROMs included were EQ-5D, Short Form (SF)-36, visual analogue scale (VAS) pain and the Roland-Morris Disability Questionnaire (RMDQ). The health dimensional contribution to the overall QoL improvements was analysed by isolating the impact of each dimension on QoL in the SF-36 and EQ-5D, respectively. A correlation analysis of the QoL improvement was performed to investigate the relationships between the four instruments. RESULTS: Changes in pain explained 60 % of the quality-adjusted life years (QALY) gained in BKP vs. NSM followed by self-care (17 %), mobility (16 %) and usual activities (10 %) (EQ 5D). Health dimensions capturing the mental state had little impact on the QALY gained. The SF-36 dimensional analysis showed similar results. The correlation analysis showed that the correlation between VAS pain, RMDQ and QALY improvement was fairly weak. CONCLUSIONS: Changes in the pain dimension of health are the most important drivers for changes of overall QoL in patients treated with BKP or NSM. However, ignoring the impact of other dimensions would lead to an underestimation of the actual improvement in overall QoL. PMID- 23624702 TI - Clinical and histopathological features of itch in patients with alopecia areata. PMID- 23624703 TI - Expression and modification proteomics during skeletal muscle ageing. AB - Skeletal muscle ageing is characterized by a progressive and dramatic loss of muscle mass and strength leading to decreased muscular function resulting in muscle weakness which is often referred to as sarcopenia. Following the standardisation of "omics" approaches to study the genome (genomics) and the transcriptome (transcriptomics), the study of the proteins encoded by the genome, referred to as proteomics, is a tremendous challenge. Unlike the genome, the proteome varies in response to many physiological or pathological factors. In addition, the proteome is orders of magnitude more complex than the transcriptome due to post-translational modifications, protein oxidation and limited protein degradation. Proteomic studies, including the analysis of protein abundance as well as post-translational modified proteins have been shown to provide valuable information to unravel the key molecular pathways implicated in complex biological processes, such as tissue and organ ageing. In this article, we will describe proteomic approaches for the analysis of protein abundance as well as the specific protein targets for oxidative damage upon oxidative stress and/or during skeletal muscle ageing. PMID- 23624704 TI - Does freezing and dynamic flexing of frozen branches impact the cavitation resistance of Malus domestica and the Populus clone Walker? AB - Frost damage to the xylem conduits of trees is a phenomenon of eco-physiological importance. It is often documented in terms of the percentage loss of conductivity (PLC), an indicator of air filling of the conduits. However, trees that refill their conduits in spring could be impacted more by damage to the conduits that reduce cavitation resistance, making them more susceptible to future drought events. We investigated whether ice formation, dynamic flexing of frozen branches or freeze-thaw events could reduce the cavitation resistance (cause "frost fatigue") in first-year shoots of apple (Malus domestica) and clonal hybrid cottonwood (Walker). Frost fatigue was measured in terms of P50 (the negative xylem pressure required to cause a 50 % loss of conductivity). All treatment groups showed significant frost fatigue, with the exception of the pre flushed, constantly frozen poplar branches. The P50 following freeze treatments was approximately 50 % of the pre-freeze values. The effect tended to be greater in freeze-thawed branches. Dynamic bending of the branches had no effect on either PLC or P50. In three out of four cases, there was a significant correlation between P50 and PLC. Frost fatigue occurred in both apple and poplar, two unrelated species with different drought and frost tolerances, suggesting that it may be a widespread phenomenon that could impact the ecophysiology of temperate forests. PMID- 23624705 TI - Introduction of new oral antiplatelet drugs in myocardial infarction hospital network: initial experience. PMID- 23624706 TI - Enhanced lithium storage in Fe2O3-SnO2-C nanocomposite anode with a breathable structure. AB - A novel nanocomposite architecture of a Fe2O3-SnO2-C anode, based on clusters of Fe2O3 and SnO2 nanoparticles dispersed along the conductive chains of Super P LiTM carbon black (Timcal Ltd.), is presented as a breathable structure in this paper for lithium-ion batteries. The synthesis of the nanocomposite is achieved by combining a molten salt precipitation process and a ball milling method for the first time. The crystalline structure, morphology, and electrochemical characterization of the synthesised product are investigated systematically. Electrochemical results demonstrate that the reversible capacity of the composite anode is 1110 mA h g(-1) at a current rate of 158 mA g(-1) with only 31% of initial irreversible capacity in the first cycle. A high reversible capacity of 502 mA h g(-1) (higher than the theoretical capacity of graphite, ~372 mA h g( 1)) can be obtained at a high current rate of 3950 mA g(-1). The electrochemical performance is compared favourably with those of Fe2O3-SnO2 and Fe2O3-SnO2-C composite anodes for lithium-ion batteries reported in the literature. This work reports a promising method for the design and preparation of nanocomposite electrodes for lithium-ion batteries. PMID- 23624707 TI - Conversion of levulinic acid to 2-butanone by acetoacetate decarboxylase from Clostridium acetobutylicum. AB - In this study, a novel system for synthesis of 2-butanone from levulinic acid (gamma-keto-acid) via an enzymatic reaction was developed. Acetoacetate decarboxylase (AADC; E.C. 4.1.1.4) from Clostridium acetobutylicum was selected as a biocatalyst for decarboxylation of levulinic acid. The purified recombinant AADC from Escherichia coli successfully converted levulinic acid to 2-butanone with a conversion yield of 8.4-90.3 % depending on the amount of AADC under optimum conditions (30 degrees C and pH 5.0) despite that acetoacetate, a beta keto-acid, is a natural substrate of AADC. In order to improve the catalytic efficiency, an AADC-mediator system was tested using methyl viologen, methylene blue, azure B, zinc ion, and 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) as mediators. Among them, methyl viologen showed the best performance, increasing the conversion yield up to 6.7-fold in comparison to that without methyl viologen. The results in this study are significant in the development of a renewable method for the synthesis of 2-butanone from biomass-derived chemical, levulinic acid, through enzymatic decarboxylation. PMID- 23624708 TI - High expression of a plectasin-derived peptide NZ2114 in Pichia pastoris and its pharmacodynamics, postantibiotic and synergy against Staphylococcus aureus. AB - NZ2114, a new variant of plectasin, was overexpressed in Pichia pastoris X-33 via pPICZalphaA for the first time. The total secreted protein of fermentation supernatant reached 2,390 mg/l (29 degrees C) and 2,310 mg/l (25 degrees C), and the recombinant NZ2114 (rNZ2114) reached 860 mg/l (29 degrees C) and 1,309 mg/l (25 degrees C) at 96 h induction in a 5-l fermentor, respectively.The rNZ2114 was purified by cation exchange chromatography, and its yield was 583 mg/l with 94.8 % purity. The minimal inhibitory concentration (MIC) of rNZ2114 to four ATCC strains of Staphyloccocus aureus was evaluated from 0.028 to 0.90 MUM. Meanwhile, it showed potent activity (0.11-0.90 MUM) to 20 clinical isolates of MRSA. The rNZ2114 killed over 99.9 % of tested S. aureus (ATCC 25923 and ATCC 43300) in Mueller-Hinton medium within 6 h when treated with 4 * MIC. The postantibiotic effect of rNZ2114 to S. aureus ATCC 25923 and ATCC 43300 was 18.6 45.6 and 1.7-3.5 h under 1*, 2*, and 4* MIC, respectively. The fractional inhibitory concentration index (FICI) indicated a synergistic effect between rNZ2114 and kanamycin, streptomycin, and vancomycin against S. aureus ATCC 25923 (FICI = 0.125), and additivity between rNZ2114 and ampicillin, spectinomycin (FICI = 0.625), respectively. To S. aureus ATCC 43300 [methicillin-resistant S. aureus (MRSA)], rNZ2114 showed a synergistic effect (FICI = 0.125-0.3125) with kanamycin, ampicillin, streptomycin, and vancomycin, and antagonism with spectinomycin (FICI = 8.0625). The rNZ2114 caused only less than 0.1 % hemolytic activity in the concentration of 128 MUg/ml, and showed a good thermostability from 20 to 80 degrees C. In addition, it exhibited the highest activity at pH 8.0. These results suggested that large-scale production of NZ2114 is feasible using the P. pastoris expression system, and it could be a new potential antimicrobial agent for the prevention and treatment of S. aureus especially for MRSA infections. PMID- 23624709 TI - High-efficiency production of bioactive recombinant human fibroblast growth factor 18 in Escherichia coli and its effects on hair follicle growth. AB - Using fusion tags, expression of recombinant human fibroblast growth factor 18 (rhFGF18) in mammalian cells and Escherichia coli has been extensively used for fundamental research and clinical applications, including chondrogenesis and osteogenesis, hair growth, and neuroprotection. However, high-level rhFGF18 expression is difficult and the products are often not homogeneous. Furthermore, fusion-tagged protein has higher immunogenicity and lower bioactivity, and the removal of the fused tag is expensive. To overcome the limitations of fusion tagged expression of protein and to prepare soluble highly bioactive rhFGF18, we have developed a rapid and efficient expression strategy. Optimized hFGF18 gene was amplified by polymerase chain reaction and cloned into pET22b and pET3c vectors, then transformed into E. coli strains Origima (DE3) and BL21 (DE3)PlysS. The best combination of plasmid and host strain was selected, and only Origima (DE3)/pET3c-rhFGF18 was screened for high-level expressed rhFGF18. Under optimal conditions in a 30-L fermentor, the average bacterial yield and expression level of rhFGF18 of three batches were more than 652 g and 30 % respectively, after treatment with 1 mM isopropyl-thio-beta-galactopyranoside for 10 h at 25 degrees C. The target protein was purified by CM Sepharose FF and heparin affinity chromatography. The purity of rhFGF18 was shown by HPLC to be higher than 95 %, and the yield was 155 mg/L. In vitro MTT assays demonstrated that the purified rhFGF18 could stimulate significant proliferation of NIH3T3 cells, and animal experiments showed that rhFGF18 could effectively regulate hair growth. In conclusion, this may be a better method of producing rhFGF18 to meet the increasing demand in its pharmacological application. PMID- 23624710 TI - Effects of vanillin, quillaja saponin, and essential oils on in vitro fermentation and protein-degrading microorganisms of the rumen. AB - This study investigated the effects of vanillin on methanogenesis and rumen fermentation, and the responses of ruminal protein-degrading bacteria to vanillin (at concentrations of 0, 0.76 and 1.52 g/L), essential oils (clove oil, 1 g/L; origanum oil, 0.50 g/L, and peppermint oil, 1 g/L), and quillaja saponin (at concentration of 0 and 6 g/L) in vitro. Methane production, degradabilities of feed substrate, and ammonia concentration decreased linearly with increasing doses of vanillin. Concentration of total volatile fatty acids also decreased, whereas proportion of butyrate tended to increase linearly with increasing doses of vanillin. Protozoa population decreased, but abundances of Ruminococcus flavefaciens, Prevotella bryantii, Butyrivibrio fibrisolvens, Prevotella ruminicola, Clostridium aminophilum, and Ruminobacter amylophilus increased with increasing doses of vanillin. Origanum and clove oils resulted in lower ammonia concentrations compared to control and peppermint oil. All the tested essential oils decreased abundances of protozoa, Selenomonas ruminantium, R. amylophilus, P. ruminicola and P. bryantii, with the largest decrease resulted from origanum oil followed by clove oil and peppermint oil. The abundances of Megasphaera elsdenii, C. aminophilum, and Clostridium sticklandii were deceased by origanum oil while that of B. fibrisolvens was lowered by both origanum and clove oils. Saponin decreased ammonia concentration and protozoal population, but increased the abundances of S. ruminantium, R. amylophilus, P. ruminicola, and P. bryantii, though the magnitude was small (less than one log unit). The results suggest that reduction of ammonia production by vanillin and saponin may not be caused by direct inhibition of major known proteolytic bacteria, and essential oils can have different inhibitory effects on different proteolytic bacteria, resulting in varying reduction in ammonia production. PMID- 23624711 TI - Systemic vascular hemodynamic changes due to 17-beta-estradiol intranasal administration. AB - PURPOSE: According to the literature, estradiol has a direct vasodilator action by means of endothelium-derived relaxing factor synthesis. The present study aims to evaluate the acute hemodynamic effects of intranasal 17-beta-estradiol on cerebral and lower limb arterial circulation in postmenopausal women. METHODS: Sixteen healthy women in natural menopause (mean age: 54 +/- 3 years) were investigated for at least 6 months, each receiving 300 ug of intranasal 17-beta estradiol. We evaluated the heart rate, systolic/diastolic blood pressure, peak systolic velocity, end-diastolic velocity, and velocity-time integral (VTI) at the level of internal carotid and posterior tibial arteries, before and after 30, 60, and 180 minutes of drug administration. RESULTS: After intranasal 17-beta estradiol administration, the internal carotid artery VTI showed statistically significant (P < .05) variations at all the time intervals after administration of the drug (30, 60, and 180 minutes) when compared with "time zero" (T0, ie, the speed recorded at baseline before drug administration). No significant variation was found at the posterior tibial artery. The systolic/diastolic blood pressure and heart rate did not significantly differ before and after drug administration. CONCLUSIONS: The administration of a single intranasal dose of 17-beta-estradiol in healthy postmenopausal women increased cerebral perfusions, whereas the effect on peripheral circulation was much more limited. PMID- 23624712 TI - 4-Chlorobenzoyl berbamine, a novel berbamine derivative, induces apoptosis in multiple myeloma cells through the IL-6 signal transduction pathway and increases FOXO3a-Bim expression. AB - Multiple myeloma (MM) is an incurable hematopoietic malignancy, although many novel therapeutic agents have been explored. In the present study, we showed that 4-chlorobenzoyl berbamine (BBD9), a novel derivative of berbamine, inhibited the growth of 4 MM cell lines (U266, RPMI 8226, MM1.R and MM1.S). After a 24-h treatment with BBD9, the half maximal inhibitory concentration (IC(50)) values were 1.8, 2.3, 1.5 and 2.4 ug/ml, respectively, using MTT assays. In BBD9-treated U266 and RPMI 8226 cells, Annexin V (AV)-propidium iodide (PI) staining and FACS analysis demonstrated that apoptosis was involved in this inhibition. This was confirmed by western blot analysis indicating activation and cleavage of caspase 3, -8, -9 and PARP. BBD9 also induced G2/M phase cell cycle arrest in these cells. To investigate the mechanisms responsible for BBD9-induced apoptosis, U266 cells were incubated with 0, 1 or 2 ug/ml of BBD9 combined with 0 or 150 ng/ml of interleukin (IL)-6. MTT assays showed that IL-6 partially abrogated the BBD9 induced cell growth inhibition. Furthermore, BBD9 inhibited autocrine IL-6 production, and downregulated membrane IL-6 receptor (IL-6R) expression. Crucial proteins downstream of the IL-6 signaling pathway, including AKT and STAT3, were inactivated in BBD9-treated U266 cells, although exogenous IL-6 did not abrogate this effect. Forkhead transcription factor class 3a (FOXO3a), a nuclear transcription factor downstream from AKT, was upregulated in the nuclei of BBD9 treated U266 cells. Bim, the target gene of FOXO3a, was upregulated at both the protein and mRNA levels, as shown by western blot analysis and quantitative PCR. These results suggest that BBD9 induces apoptosis in MM cells through the inhibition of the IL-6 signaling pathway, leading to FOXO3a activation and upregulation of pro-apoptotic Bim. PMID- 23624713 TI - A novel approach for evaluating nerve function in healthy elderly persons: a pilot study. AB - BACKGROUND: Motor nerve function decreases with age and can cause abnormalities in motor function. Using newly designed methods, we used evoked electromyograms to evaluate change in motor nerve function. MATERIAL AND METHODS: Motor function was assessed by grip strength, timed up-and-go test, 5-m normal walk, and 5-m fastest walk. In addition, motor nerve conduction velocity was calculated by measuring latency differences (NCV) in elderly and young subjects. We also investigated motor nerve conduction velocity by correlation coefficient (NCVCC) and the difference between NCV and NCVCC (DNCV). RESULTS: Significant differences were observed in the motor function of elderly and young persons in grip strength, the timed up-and-go test, and the 5-m fastest walk; however, no difference was observed in the 5-m normal walk test. NCVCC was lower than NCV in both elderly and young. The correlation coefficient peak of the NCVCC calculation was lower in elderly than in young. A negative correlation was observed between correlation coefficient peak and DNCV in elderly subjects. CONCLUSIONS: NCVCC compares the overall shape of compound muscle action potential and reflects not only the fastest motor unit, but also the motor nerve conduction velocity of other motor unit components. A significant negative correlation between DNCV and the correlation coefficient peak was observed only in elderly subjects, suggesting that older individuals, including those that maintain a high level of physical strength, experience a loss of motor nerve function. Thus, changes in motor nerve function among elderly persons can potentially be further examined for clinical use. PMID- 23624714 TI - BINDING PROTEIN is a master regulator of the endoplasmic reticulum stress sensor/transducer bZIP28 in Arabidopsis. AB - BINDING PROTEIN (BiP) is a major chaperone in the endoplasmic reticulum (ER) lumen, and this study shows that BiP binds to the C-terminal tail of the stress sensor/transducer bZIP28, a membrane-associated transcription factor, retaining it in the ER under unstressed conditions. In response to ER stress, BiP dissociates from bZIP28, allowing it to be mobilized from the ER to the Golgi where it is proteolytically processed and released to enter the nucleus. Under unstressed conditions, BiP binds to bZIP28 as it binds to other client proteins, through its substrate binding domain. BiP dissociates from bZIP28 even when bZIP28's exit from the ER or its release from the Golgi is blocked. Both BiP1 and BiP3 bind bZIP28, and overexpression of either BiP detains bZIP28 in the ER under stress conditions. A C-terminally truncated mutant of bZIP28 eliminating most of the lumenal domain does not bind BiP and is not retained in the ER under unstressed conditions. BiP binding sites in the C-terminal tail of bZIP28 were identified in a phage display system. BiP was found to bind to intrinsically disordered regions on bZIP28's lumen-facing tail. Thus, the dissociation of BiP from the C-terminal tail of bZIP28 is a major switch that activates one arm of the unfolded protein response signaling pathway in plants. PMID- 23624715 TI - The Arabidopsis B-BOX protein BBX25 interacts with HY5, negatively regulating BBX22 expression to suppress seedling photomorphogenesis. AB - ELONGATED HYPOCOTYL5 (HY5) is a basic domain/leucine zipper (bZIP) transcription factor, central for the regulation of seedling photomorphogenesis. Here, we identified a B-BOX (BBX)-containing protein, BBX25/SALT TOLERANCE HOMOLOG, as an interacting partner of HY5, which has been previously found to physically interact with CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1). BBX25 physically interacts with HY5 both in vitro and in vivo. By physiological and genetic approaches, we showed that BBX25 is a negative regulator of seedling photomorphogenesis. BBX25 and its homolog BBX24 regulate deetiolation processes and hypocotyl shade avoidance response in an additive manner. Moreover, genetic relationships of bbx25 and bbx24 with hy5 and cop1 revealed that BBX25 and BBX24 additively enhance COP1 and suppress HY5 functions. BBX25 accumulates in a light-dependent manner and undergoes COP1-mediated degradation in dark and light conditions. Furthermore, a protoplast cotransfection assay showed that BBX24 and BBX25 repress BBX22 expression by interfering with HY5 transcriptional activity. As HY5 binds to the BBX22 promoter and promotes its expression, our results identify a direct mechanism through which the expression of BBX22 is regulated. We suggest that BBX25 and BBX24 function as transcriptional corepressors, probably by forming inactive heterodimers with HY5, downregulating BBX22 expression for the fine-tuning of light-mediated seedling development. PMID- 23624716 TI - Suicide ideation in pediatric and adult survivors of childhood brain tumors. AB - Survivors of pediatric brain tumors are at risk for long-term psychological morbidities. The current study investigated the prevalence and predictors of suicide ideation (SI) in a clinical sample of youth and adult survivors. Retrospective chart reviews were completed for 319 survivors of pediatric brain tumors who were assessed via clinical interview during routine neuro-oncology clinic visits between 2003 and 2007. Survivors were, on average, 18.0 years of age (SD = 4.9) and 10 years from diagnosis (SD = 5.0) at their most recent follow up. The most common diagnosis was low-grade glioma (n = 162) followed by embryonal tumors (PNET/medulloblastoma; n = 64). Multivariable logistic regression was used to calculate odds ratios (OR) and 95 % confidence intervals (CI) for SI. Nearly 12 % of survivors (11.7 %, n = 37) reported SI. Five survivors (1.5 %) had documented suicide attempts, though none were fatal. In a multivariable model, adjusting for sex and age, history of depression (OR = 20.6, 95 % CI = 4.2-101.1), psychoactive medication treatment (OR = 4.5, 95 % CI = 1.8 11.2), observation or surgery only treatment (OR = 3.7, 95 % CI = 1.5-9.1), and seizures (OR = 3.6, 95 % CI = 1.1-11.1) were significantly associated with SI in survivors. Survivors of pediatric brain tumors appear to be at risk for experiencing SI. Our results underscore the importance of a multidisciplinary approach to providing follow-up care for childhood brain tumor survivors, including routine psychological screenings. PMID- 23624717 TI - Clinical features of supervoiders who suffer from lower urinary tract symptoms: a propensity score-matching study. AB - PURPOSE: To evaluate the clinical characteristics of patients with maximal urine flow rate (Q max) >= 25 ml/s complaining of lower urinary tract symptoms (LUTS), using propensity score-matching analysis to compare with the control group. METHODS: Medical records from a prospectively maintained database for first visit male patients with LUTS/benign prostatic hyperplasia between 2010 and 2012 were used to select 818 patients. Of these patients, 68 men with Q max >= 25 ml/s were defined as the supervoider group, and 68 patients were selected for the control group using propensity scores, which were calculated for each patient using multivariable logistic regression model based on the following covariates: age, prostate volume, voided urine volume, and post-voided residual volume. International Prostate Symptom Score (IPSS), quality of life score, and Overactive Bladder Symptom Score (OABSS) were also analyzed. RESULTS: Mean Q max was 30.82 +/- 5.13 in supervoiders and 15.95 +/- 4.88 ml/s in controls (p < 0.001). There were statistical differences in IPSS between supervoiders and controls (12.63 +/- 5.81 vs. 16.13 +/- 6.90; p = 0.002). Although the IPSS voiding symptom sub-score in supervoiders was lower than controls (5.09 +/- 3.35 vs. 7.40 +/- 4.00; p < 0.001), there were no significant differences in storage symptom and post-micturitional symptom sub-scores. In OABSS and subdomain scores for frequency, nocturia, and urgency, there were no significant differences between the groups. However, the urge incontinence subdomain score was significantly higher in supervoiders versus controls (0.69 +/- 1.26 vs. 0.18 +/- 0.52; p = 0.003). CONCLUSIONS: Supervoiders experience comparable levels of storage and post-micturition symptoms, but display more severe urge incontinence despite milder voiding symptoms and better uroflowmetric measurements than propensity score-matched controls. PMID- 23624718 TI - Radical prostatectomy versus high dose permanent prostate brachytherapy using iodine-125 seeds for patients with high risk prostate cancer: a matched cohort analysis. AB - OBJECTIVE: To compare the biochemical outcomes reported after radical prostatectomy (RP) versus high dose permanent prostate brachytherapy (HDPPB) using iodine-125 seeds in the treatment of matched high risk prostate cancer (HiPCa). METHODS: In this retrospective review, 55 HiPCa patients treated between March 2006 and August 2011, who underwent HDPPB using iodine-125 seeds combined with external beam radiation therapy (EBRT) or androgen deprivation therapy (ADT), were compared with 55 HiPCa patients who underwent RP. Patients were matched for age, prostate-specific antigen (PSA), clinical stage, and Gleason scores. The biochemical outcomes after HDPPB and RP were compared via Kaplan Meier analysis. RESULTS: Of the 110 patients analyzed, the mean ages, PSA, and Gleason biopsy scores were similar between the two cohorts. Among patients who underwent HDPPB, 20 patients (36.4%) had received adjuvant EBRT. Of this subsample, most patients (98.2%) had received adjuvant ADT for 3 months. Among patients with RP, 20 patients (36.4%) had received adjuvant EBRT, whereas 28 patients had received adjuvant ADT. The mean implanted seed numbers were 92.8, the mean D90 was 218.7 Gy, and the mean V100 was 96.1% after HDPPB. With regard to oncological outcomes, biochemical disease-free survival rates were similar between the two cohorts (82.6 vs. 81.1%, p = 0.982). Urethrorectal fistula developed in one patient with HDPPB. CONCLUSION: RP and HDPPB, using iodine-125 seeds with combined treatment modalities, exhibited similar biochemical recurrence-free survival rates among HiPCa patients. Further prospective studies with greater sample sizes and longer follow-up periods are needed to validate these results. PMID- 23624719 TI - Neoadjuvant targeted molecular therapies in patients undergoing nephrectomy and inferior vena cava thrombectomy: is it useful? AB - OBJECTIVE: To assess the effect of neoadjuvant targeted molecular therapies (TMTs) on size and level of inferior vena cava tumor thrombi and to evaluate their impact on surgical management. METHODS: We retrospectively analyzed the data of 14 patients treated for a clear cell renal cell carcinoma with inferior vena cava thrombi by neoadjuvant TMT before nephrectomy. Clinical, pathological and perioperative data were gathered retrospectively at each institution. The primitive tumor size and the thrombus size were defined by computed tomography before TMT. The tumor thrombus level was defined according to the Novick's classification. RESULTS: Before TMT, thrombus level was staged I for 1 (7%), II for 10 (72%) and III (21%) for 3 patients. First-line therapy was sunitinib in 11 cases and sorafenib in 3 cases. Median therapy duration was two cycles (1-5). Three patients experienced major adverse effects (grade III) during TMT. Following TMT, 6 (43%) patients had a measurable decrease, 6 (43%) had no change, and 2 (14%) had an increase in the thrombus. One patient (7%) had a downstage of thrombus level, 12 (85%) had stable thrombi, and 1 (7%) had an upstage. Regarding primary tumor, 7 (50%), 5 (36%) and 2 (14%) patients had a decrease, stabilization and an increase in tumor size, respectively. CONCLUSION: Neoadjuvant TMT appears to have limited effects on renal tumor thrombi. This retrospective study failed to demonstrate a significant impact of neoadjuvant TMT on surgical management of clear cell renal cell carcinoma with inferior vena cava tumor thrombi. PMID- 23624720 TI - Prurigo pigmentosa-like persistent papules and plaques in a patient with adult onset Still's disease. PMID- 23624721 TI - Lysophosphatidic acid stimulates osteoclast fusion through OC-STAMP and P2X7 receptor signaling. AB - Bone is continuously remodeled by bone formation and resorption, and cooperative bone metabolism is precisely regulated to maintain homeostasis. Osteoclasts, which are responsible for bone resorption, are differentiated through multiple steps that include cell fusion at the last step of differentiation, yielding multinuclear cells. However, the factors involved in and the precise mechanism of cell fusion are still unknown. To determine the molecules involved in osteoclast fusion, we examined the effect of lysophosphatidic acid (LPA), which has been reported to participate in the progression of cancer bone metastasis. LPA had no effect on osteoclast formation and bone resorption under receptor activator of nuclear factor kappa B ligand (RANKL) conditions, whereas LPA stimulated osteoclast fusion, thereby causing increased osteoclast diameter and bone resorptive capacity under a RANKL-limited condition. This result encouraged us to assess what molecules are needed for LPA-stimulated osteoclast fusion. Interestingly, LPA stimulated osteoclast stimulatory transmembrane protein (OC STAMP) and P2X7 receptor mRNA expression during osteoclast fusion under a RANKL limiting condition. siRNA-induced OC-STAMP or P2X7 receptor knockdown significantly suppressed the LPA-stimulated increase in osteoclast diameter and bone resorptive capacity in differentiating cultures. Using cyclosporin A as an inhibitor, we revealed that NF-ATc1 directly regulates OC-STAMP and P2X7 receptor expression during LPA-stimulated osteoclast fusion. These results suggest that LPA is a critical regulator of osteoclast fusion by inducing the OC-STAMP and P2X7 receptor. Therefore, LPA signaling might be useful to help understand their effects on osteoclast formation and as a therapeutic target for patients with pathologically increased osteoclast formation. PMID- 23624722 TI - Identification and characterization of an iron ABC transporter operon in Gluconacetobacter diazotrophicus Pal 5. AB - Gluconacetobacter diazotrophicus is a nitrogen-fixing bacterium and endophyte of sugarcane. We have cloned and sequenced the genes coding for the components of the iron ABC-type acquisition system of G. diazotrophicus. Sequence analysis revealed three ORFs, (feuA, feuB, and feuC) organized as an operon and encoding polypeptides of 346 (38 kDa), 342 (34.2 kDa), and 240 (26 kDa) amino acids, respectively. The deduced translation products of the feu operon showed similarity with a periplasmic solute-binding protein (FeuA), permease (FeuB), and ATPase (FeuC) involved in Fe transport. The role of FeuB in the survival of G. diazotrophicus under iron depletion was evaluated by comparing the ability of wild-type and FeuB-Km(R) -mutant strains in a medium without iron supplementation and in a medium containing 2, 2'-dipyridyl (DP). Growth of the mutant was affected in the medium containing DP. The operon was expressed at higher levels in cells depleted for iron than in those that contained the metal. A decrease in nitrogenase activity was observed with the FeuB-Km(R) -mutant strain that with the wild-type under iron deficiency conditions, suggesting that the Feu operon play role in Fe nutrition of G. diazotrophicus. PMID- 23624724 TI - Naphthalene biodegradation in temperate and arctic marine microcosms. AB - Naphthalene, the smallest polycyclic aromatic hydrocarbon (PAH), is found in abundance in crude oil, its major source in marine environments. PAH removal occurs via biodegradation, a key process determining their fate in the sea. Adequate estimation of PAH biodegradation rates is essential for environmental risk assessment and response planning using numerical models such as the oil spill contingency and response (OSCAR) model. Using naphthalene as a model compound, biodegradation rate, temperature response and bacterial community composition of seawaters from two climatically different areas (North Sea and Arctic Ocean) were studied and compared. Naphthalene degradation was followed by measuring oxygen consumption in closed bottles using the OxiTop((r)) system. Microbial communities of untreated and naphthalene exposed samples were analysed by polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE) and pyrosequencing. Three times higher naphthalene degradation rate coefficients were observed in arctic seawater samples compared to temperate, at all incubation temperatures. Rate coefficients at in situ temperatures were however, similar (0.048 day(-1) for temperate and 0.068 day(-1) for arctic). Naphthalene biodegradation rates decreased with similar Q10 ratios (3.3 and 3.5) in both seawaters. Using the temperature compensation method implemented in the OSCAR model, Q10 = 2, biodegradation in arctic seawater was underestimated when calculated from the measured temperate k1 value, showing that temperature difference alone could not predict biodegradation rates adequately. Temperate and arctic untreated seawater communities were different as revealed by pyrosequencing. Geographic origin of seawater affected the community composition of exposed samples. PMID- 23624723 TI - Membrane lipids and proteins as modulators of urothelial endocytic vesicles pathways. AB - The increased studies on urinary bladder umbrella cells as an important factor for maintaining the permeability barrier have suggested new pathways for the discoidal/fusiform endocytic vesicles which is one of the main features of the umbrella cells. The biological role of these vesicles was defined, for many years, as a membrane reservoir for the umbrella cell apical plasma membrane which are subject to an increased tension during the filling phase of the micturition cycle and, therefore, the vesicles are fused with the apical membrane. Upon voiding, the added membrane is reinserted via a non-clathrin or caveolin dependant endocytosis thereby restoring the vesicle cytoplasmic pool. However, in the last decade, new evidence appeared indicating alternative pathways of the endocytic vesicles different than the cycling process of exocytosis/endocytosis. The purpose of this review is to analyze the molecular modulators, such as membrane lipids and proteins, in the permeability of endocytic vesicles, the sorting of endocytosed material to lysosomal degradation pathway and recycling of both membrane and fluid phases. PMID- 23624725 TI - Performance and granulation in an upflow anaerobic sludge blanket (UASB) reactor treating saline sulfate wastewater. AB - An upflow anaerobic sludge blanket reactor was employed to treat saline sulfate wastewater. Mesophilic operation (35 +/- 0.5 degrees C) was performed with hydraulic retention time fixed at 16 h. When the salinity was 28 g L(-1), the chemical oxygen demand and sulfate removal efficiencies were 52 and 67 %, respectively. The salinity effect on sulfate removal was less than that on organics removal. The methane productions were 887 and 329 cm(3) L(-1) corresponding to the NaCl concentrations of 12 and 28 g L(-1), respectively. High salinity could stimulate microbes to produce more extracellular polymeric substances (EPSs) and granulation could be performed better. Besides, with the high saline surroundings, a great deal of Na(+) compressed the colloidal electrical double-layer, neutralized the negative charge of the sludge particles and decreased their electrostatic repulsion. The repulsion barrier disappeared and coagulation took place. The maximum size of granules was 5 mm, which resulted from the coupled triggering forces of high EPSs and Na(+) contents. Sulfate reducing bacteria (SRB) were dominant in the high saline surroundings while the methane-producing archaea dominated in the low saline surroundings. The SRB were affected least by the salinity. PMID- 23624726 TI - Bisphosphonate therapy for chronic recurrent multifocal osteomyelitis. PMID- 23624727 TI - MRI characteristics of nodular fasciitis of the musculoskeletal system. AB - OBJECTIVE: To evaluate MRI imaging appearances of nodular fasciitis in a pathologic-proven series of 29 patients. MATERIALS AND METHODS: Review of the orthopedic oncology and pathology databases yielded 51 cases of histologically proven nodular fasciitis. MR imaging was available in 29 patients. Three musculoskeletal radiologists retrospectively reviewed all cases in consensus. Imaging features evaluated included location in the body, size, compartmental localization, relationship to fascia, signal characteristics, enhancement pattern, transcompartmental extension, and osseous and intra-articular involvement. RESULTS: There were 15 male and 14 female patients. Mean age was 33 years (range, 16-59 years). Lesions ranged in size from 1.6 to 9 cm with 84 % of lesions measuring less than 4 cm. Twenty-three lesions were located in the upper arm or shoulder girdle. Nine lesions were subcutaneous in location, nine were intra-muscular, and 11 were inter-muscular. Lesions were consistently ovoid in shape with broad fascial contact. They exhibited internal homogenous low T1 and heterogeneous intermediate T2 signal with surrounding edema and slightly inhomogeneous enhancement. Twelve lesions exhibited central non-enhancing areas. Trans-compartmental spread was demonstrated in nine lesions. Osseous changes were seen in five cases and included extrinsic cortical saucerization, medullary edema, and transcortical osseous invasion. Two lesions demonstrated intra articular extension. CONCLUSIONS: MR imaging features of nodular fasciitis are generally non-specific and can be mistaken for a soft tissue sarcoma. This series, the largest MRI series of musculoskeletal cases in the literature, confirms the predilection of nodular fasciitis for the upper extremity in young adults but also demonstrates that aggressive imaging features such as transcompartmental spread, and osseous and intra-articular involvement may be seen in association with this benign soft tissue lesion. PMID- 23624729 TI - Reversible immobilization of invertase on Cu-chelated polyvinylimidazole-grafted iron oxide nanoparticles. AB - Polyvinylimidazole (PVI)-grafted iron oxide nanoparticles (PVIgMNP) were prepared by grafting of telomere of PVI on the iron oxide nanoparticles. Different metal ions (Cu(2+), Zn(2+), Cr(2+), Ni(2+)) ions were chelated on polyvinylimidazole grafted iron oxide nanoparticles, and then the metal-chelated magnetic particles were used in the adsorption of invertase. The maximum invertase immobilization capacity of the PVIgMNP-Cu(2+) beads was observed to be 142.856 mg/g (invertase/PVIgMNP) at pH 5.0. The values of the maximum reaction rate (V max) and Michaelis-Menten constant (Km) were determined for the free and immobilized enzymes. The enzyme adsorption-desorption studies, pH effect on the adsorption efficiency, affinity of different metal ions, the kinetic parameters and storage stability of free and immobilized enzymes were evaluated. PMID- 23624730 TI - Enhancement of epsilon-poly-L-lysine production coupled with precursor L-lysine feeding in glucose-glycerol co-fermentation by Streptomyces sp. M-Z18. AB - epsilon-Poly-L-lysine (epsilon-PL), one of the only two homo-poly amino acids known in nature, is used as a preservative. In this study, strategies of feeding precursor L-lysine into 5 L laboratory scale fermenters, including optimization of L-lysine concentration and time, was investigated to optimize the production of epsilon-PL by Streptomyces sp. M-Z18. The optimized strategy was then used in epsilon-PL fed-batch fermentation in which glucose and glycerol served as mixed carbon sources. In this way, a novel epsilon-PL production strategy involving precursor L-lysine coupled with glucose-glycerol co-fermentation was developed. Under optimal conditions, epsilon-PL production reached 37.6 g/l, which was 6.2 % greater than in a previous study in which glucose and glycerol co-fermentation was performed without added L-lysine (35.14 g/l). To the best of our knowledge, this is the first report of the enhancement of epsilon-PL production through L lysine feeding to evaluate the use of fermenters. Meanwhile, the role of L-lysine in the promotion of epsilon-PL production, participating epsilon-PL synthesis as a whole, was first determined using the L-[U-(13)C] lysine labeling method. It has been suggested that the bottleneck of epsilon-PL synthesis in Streptomyces sp. M-Z18 is in the biosynthesis of precursor L-lysine. The information obtained in the present work may facilitate strain improvement and efficient large-scale epsilon-PL production. PMID- 23624731 TI - [Nutritional assessment and perioperative nutritional support in gastric cancer patients]. AB - Weight loss and malnutrition are common in cancer patients. Although weight loss is predominantly due to loss of fat mass, the morbidity risk is given by the decrease in muscle mass. The assessment of nutritional status is essential for a diagnosis of nutritional compromise and required for the multidisciplinary approach. Subjective global assessment (SGA) is made by the patients nutritional symptoms and weight loss. The objective assessment, a significant weight loss (>10%) for 6 months is considered an indicator of nutritional deficiency. The mean body index, body fat mass and body protein mass are decreased as cancer stage increases. The biochemical data of albumin, cholesterol, triglyceride, Zn, transferrin, total lymphocyte count are decreased in advanced cancer stage. Daily energy intake, cabohyderate and Vit B1 intake is decreased according to cancer stage. The patients are divided into three groups according to SGA. The three groups showed a significant difference in body weight, 1 month weight loss%, 6 month weight loss%, body mass index, mid arm circumference, albumin, energy intake, as well as carbohyderate intake protein and energy malnutrition. Nutritional assessment is of great importance because undernutrition has been shown to be associated with increase in stomach cancer associated morbidity and mortality. The authors concluded that nutritional assessment should be done in cancer patients preoperatively, and with adequate nutritional support, the morbidity and mortality would be decreased. PMID- 23624732 TI - Helicobacter pylori infection and duodenal gastric metaplasia in healthy young adults. AB - BACKGROUND/AIMS: Duodenal ulcers occur relatively frequently in adolescents, like in adults, and may relate to Helicobacter pylori infection and duodenal gastric metaplasia (DGM). This study investigated the association between H. pylori infection and DGM in healthy adults aged 20-29. METHODS: Between 1995 and 2005, endoscopic biopsies of the duodenum, antrum and body were taken from healthy, young volunteers, who were first-year medical students, faculty staff, residents, and research assistants of Gyeongsang National University in Jinju, Korea. Urease tests were performed and the extent of DGM and histopathological grades according to the Updated Sydney System were determined. RESULTS: In total, 662 subjects were enrolled (429 males and 233 females). The median age was 22.3 years. The overall incidence of DGM was 11.5% but DGM was more frequent in males (15.4%) than in females (4.3%) (p<0.0001). While H. pylori positivity rates changed significantly during the 1995-2005 period (p<0.01), the incidences of DGM did not. DGM was observed in 7.2% and 14.9% of subjects who were and were not colonized with H. pylori, respectively. DGM was also associated with less severe chronic gastritis and the absence of active gastritis in both the antrum and body, and the absence of follicles in the antrum (p<0.05). CONCLUSIONS: These findings suggested that DGM is not rare in healthy young adults and is unrelated to gastric H. pylori infection. PMID- 23624733 TI - [Therapeutic outcomes of endoscopic submucosal dissection in undifferentiated type early gastric cancer]. AB - BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) has been accepted as a standard treatment of early gastric cancer (EGC). However, the indication of ESD in undifferentiated-type EGC was controversial. The aim of this study was to evaluate the therapeutic outcomes of ESD in undifferentiated-type EGC according to expanded indication. METHODS: At Soonchunhyang University Bucheon Hospital, a total of 82 lesions in 81 patients with undifferentiated-type EGC were treated with ESD. The therapeutic outcomes of ESD were evaluated by resection method (en bloc resection; piecemeal resection), histologic curative resection, complications and recurrence rates after ESD. RESULTS: The rate on en bloc resection and complete resection rate were 87.8% (72/82) and 80.5% (66/82), respectively. In signet ring cell carcinoma, the complete resection rate was higher than those in poorly differentiated adenocarcinoma and poorly differentiated adenocarcinoma with signet ring cell features, but there was no statistical significance (89.3% vs. 75.0%, 76.7%; p=0.347). The lateral margin positivity rate in poorly differentiated adenocarcinoma, signet ring cell carcinoma and poorly differentiated adenocarcinoma with signet ring cell features were 12.5%, 3.6% and 13.3%, respectively (p=0.395). The vertical margin positivity rate were 12.5%, 3.6% and 10.0%, respectively (p=0.485). The overall recurrence rate was 3.0% during a mean follow-up period of 37.4 months. CONCLUSIONS: ESD may be considered as a feasible treatment for undifferentiated type EGC according to expanded indication. The therapeutic outcome of ESD in undifferentiated-type EGC is likely to be favorable, though further longer follow up studies are needed. PMID- 23624734 TI - Factors associated with vaccination among inflammatory bowel disease patients in Korea. AB - BACKGROUND/AIMS: Vaccinations are generally recommended in patients with inflammatory bowel disease (IBD). However, several studies showed low rates of vaccinations in IBD patients. Furthermore, vaccination rate among IBD patients in Korea has never been investigated. We investigated the vaccination rate among IBD patients in Korea and evaluated some factors that might affect the vaccination rate. METHODS: From November 2011 to February 2012, a total of 192 patients with IBD who visited Samsung Medical Center (Seoul, Korea) answered the IRB-approved questionnaire. The questionnaire included their sex, age, residence, past medical history, type of IBD, duration of illness, medications, history of vaccination about measles-mumps-rubella (MMR), varicella, tetanus-diphtheria (Td), influenza, hepatitis A and B, pneumococcus and human papilloma virus (HPV). RESULTS: One hundred twenty one (63.0%) male and 71 (37.0%) female answered the questionnaire. The mean age of the enrolled patients was 39.7 (18-76) years. Eighty four patients (43.8%) had ulcerative colitis and 108 patients (56.3%) had Crohn's disease (CD). The percentage of the patients who had got vaccination was 42.2% for MMR, 34.9% for varicella, 15.6% for Td, 37.5% for influenza, 15.6% for hepatitis A, 52.6% for hepatitis B, 6.3% for pneumococcus and 11.3% for HPV respectively. Not knowing the necessity or the existence were the common reasons for non-vaccination. Age less than 40 years, CD patients and duration of illness less than 10 years were associated with a higher vaccination rate (p=0.002, 0.015 and 0.020, respectively). CONCLUSIONS: Immunization rates for recommended vaccinations were very low in patients with IBD. Efforts to improve vaccination rate are needed. PMID- 23624735 TI - Prevalence of occult hepatitis B virus infection in hemodialysis patients. AB - BACKGROUND/AIMS: The prevalence of occult HBV infection depends on the prevalence of HBV infection in the general population. Hemodialysis patients are at increased risk for HBV infection. The aim of this study was to determine the prevalence of occult HBV infection in hemodialysis patients. METHODS: Total of 98 patients undergoing hemodialysis in CHA Bundang Medical Center (Seongnam, Korea) were included. Liver function tests and analysis of HBsAg, anti-HBs, anti-HBc and anti-HCV were performed. HBV DNA testing was conducted by using two specific quantitative methods. RESULTS: HBsAg was detected in 4 of 98 patients (4.1%), and they were excluded. Among 94 patients with HBsAg negative and anti-HCV negative, one (1.1%) patient with the TaqMan PCR test and 3 (3.2%) patients with the COBAS Amplicor HBV test were positive for HBV DNA. One patient was positive in both methods. Two patients were positive for both anti-HBs and anti-HBc and one patient was negative for both anti-HBs and anti-HBc. CONCLUSIONS: The present study showed the prevalence of occult HBV infection in HBsAg negative and anti HCV negative patients on hemodialysis at our center was 3.2%. Because there is possibility of HBV transmission in HBsAg negative patients on hemodialysis, more attention should be given to prevent HBV transmission. PMID- 23624736 TI - Salvage technique for endoscopic removal of a sharp fish bone impacted in the esophagus using a transparent cap and detachable snares. AB - A sharp, impacted fish bone in the esophagus is an indication for urgent endoscopy. Endoscopic removal of such an object is a challenging task. An endoscopic protector hood is then used to remove the object. However, an endoscopic hood protector is not always available. In a patient with a large hiatal hernia, the protector hood may not return to the original shape when it passes through the gastroesophageal junction and therefore may not properly protect the esophageal mucosa from the sharp foreign body. In our case, it was impossible to deploy the endoscopic hood protector through the gastroesophageal junction despite multiple attempts. We propose an alternative solution for such cases. We safely removed a large sharp-edged flat fish bone that was folded and compressed using a detachable snare after releasing and pushing the fish bone into the stomach using an endoscope equipped with a transparent cap used for dilating the esophageal wall. This method of using an endoscopic cap and detachable snare is a safe, useful alternative for endoscopically removing a large sharp-edged flat foreign body from the upper gastrointestinal tract. This alternative technique has not been reported in the English medical literature. PMID- 23624737 TI - Septic pylephlebitis as a rare complication of Crohn's disease. AB - Thrombophlebitis of the portal venous system (PVS) with superimposed bacterial infection (septic pylephlebitis) is an extremely rare complication of Crohn's disease (CD), and therefore diagnosis of septic pylephlebitis is difficult without high clinical suspicion. A 16-year old male patient who was diagnosed with CD 3 months earlier was admitted with recurrent fever and abdominal pain. CD activity had been well controlled with conventional medical treatment during a follow-up period. Abdominal contrast-enhanced computed tomography showed massive thrombosis in the PVS without evidence of intra-abdominal infection, and blood cultures were positive for Streptococcus viridians. There was no evidence of deep vein thrombosis or pulmonary thromboembolism, and all laboratory tests for thrombophilia were normal. Based on these findings, the patient was diagnosed with septic pylephlebitis complicated with CD, and was successfully treated with intravenous antibiotic therapy combined with anticoagulation. This case suggests that early comprehensive evaluation is crucial for immediate diagnosis and proper treatment of septic pylephlebitis in patients with CD who present with fever and abdominal pain of unknown origin, even with stable disease activity and absence of other intra-abdominal infections. PMID- 23624738 TI - [A case of epidural abscess occurred after liver abscess complicated by transarterial chemoembolization in a patient with metastatic cancer to liver]. AB - Transarterial chemoembolization (TACE) is one of the most effective therapies for unresectable hepatocelluar carcinoma or metastatic hypervascular tumors. Abscess occurring in the other organs beside the liver after TACE is a complication that often occurs, sometimes potentially fatal. We report a case of spinal epidural abscess occurred after liver abscess complicated by TACE in a patient with metastatic neuroendocrine tumors to the liver. A 67-year-old female underwent TACE first for the metastatic lesions to liver, with a history of pancreatoduodenectomy for the primary pancreatic neuroendocrine tumor. Four days after TACE, sudden high fever occurred, and liver abscess was found on abdominal CT. Two days later, back pain and radiating pain to the right leg occurred, and lumbar spine MRI showed spinal epidural abscess. After intravenous antibiotics for 8 weeks and partial laminectomy, the patient recovered and was discharged without complications. PMID- 23624739 TI - [A case of angiographic embolization of aortoenteric fistula caused by endovascular stent grafting for an abdominal aortic aneurysm]. AB - Aortoenteric fistula (AEF) developed after treatment for an abdominal aortic aneurysm (AAA) is a rare but usually fatal complication. We report a rare case of AEF bleeding after endovascular stent grafting for AAA which was managed angiographically. An 81-year-old man presented with hematochezia and acute abdominal pain for 1 day ago. Four years ago, an aortic stent was implanted in the infrarenal aorta for AAA. Endoscopies were performed to evaluate the hematochezia. Evidence of gastrointestinal bleeding was observed, but a clear bleeding point was not detected on upper endoscopy and colonoscopy. Contrast enhanced computed tomography performed subsequently showed that the bleeding point was located in the fourth portion of the duodenum as an AEF caused by an inflammatory process in the stent-graft. Intra-arterial angiography showed a massive contrast leakage into the bowel via a small fistula from around the aortic stent graft site. Embolization was successfully performed by injecting a mixture of glue and lipiodol into the AEF tract. The patient was discharged with no evidence of gastrointestinal bleeding after the embolization. PMID- 23624740 TI - Striatum-specific expression of Cre recombinase using the Gpr88 promoter in mice. AB - We generated a transgenic (Tg) mouse line expressing Cre recombinase under the control of the Gpr88 promoter within a bacterial artificial chromosome clone. We crossed the established Tg mice with reporter mice (CAG-CAT-Z Tg), which express Escherichia coli lacZ in response to Cre-mediated excision of the loxP-flanked chloramphenicol acetyltransferase gene, and examined the Cre activity in the Tg mouse brains by assessing beta-galactosidase activity. Cre activity was specifically detected in the caudate-putamen, nucleus accumbens, and olfactory tubercle of the Gpr88-Cre Tg mouse brain. Medium spiny neurons within the caudate putamen exhibited Cre activity. Thus, Gpr88-Cre Tg mice could be a useful tool for analyzing the function of the basal ganglia by using Cre/loxP systems. PMID- 23624741 TI - More than 10 years after the first 'savior siblings': parental experiences surrounding preimplantation genetic diagnosis. AB - Preimplantation genetic diagnosis (PGD) to create a healthy donor for a sibling's hematopoetic stem cell transplantation for a child with Fanconi Anemia (FA) was first reported in 2001. Yet we know little about the experiences of parents who have encountered decision making surrounding PGD and human leukocyte antigen (HLA)-typing. The first aim of this study was to understand parents' awareness, perceptions and beliefs about reproductive decision-making including emotional, cognitive, moral dimensions as well as regret surrounding the use of this technology. The second aim was to describe the experiences and rationale of parents of children with a single gene disorder regarding the factors that influenced their decision making surrounding the use of natural pregnancy and/or PGD and HLA-typing. Parents from two national FA support networks in the US and Canada responded to an emailed survey about reproductive decision making and outcomes surrounding natural pregnancy and PGD and HLA-typing. Descriptive statistics and Pearson's Chi-Square tests were used to describe and compare data. Our results indicate that the most important factors in the PGD decision making process were the health of the child and cognitive appraisals followed by emotional responses and then moral judgments. A significant difference was noted in parents considering natural pregnancy before and after 2001 (p = 0.01). Unexpected findings were that less than 35 % of parents were offered PGD by any health care professional and only 70 % were aware PGD with HLA-typing was a reproductive option. Our research suggests that the option of PGD and HLA-typing may influence parents' reproductive decision making choices. PMID- 23624743 TI - The mGluR2/3 agonist LY379268 induced anti-reinstatement effects in rats exhibiting addiction-like behavior. AB - Medication development for cocaine-addicted patients is difficult, and many promising preclinical candidates have failed in clinical trials. One reason for the difficulty in translating preclinical findings to the human condition is that drug testing is typically conducted in behavioral procedures in which animals do not show addiction-like traits. Recently, a DSM-IV-based animal model has been developed that allows studying the transition to an addiction-like behavior. Changes in synaptic plasticity are involved in the transition to cocaine addiction. In particular, it has been shown that metabotropic glutamate receptor 2/3 (mGluR2/3)-mediated long-term depression is suppressed in the prelimbic cortex in addict-like rats. We therefore hypothesized that cocaine-seeking in addict-like rats could be treated with an mGluR2/3 agonist. Indeed, addict-like rats that were treated systemically with the mGluR2/3 agonist LY379268 (0, 0.3, and 3 mg/kg) showed a pronounced reduction in cue-induced reinstatement of cocaine-seeking. In an attempt to dissect the role played by mGluR2 and mGluR3 in cue-induced reinstatement, we analyzed the mRNA expression patterns in several relevant brain areas but did not find any significant differences between cocaine addict-like and non-addict-like rats, suggesting that the behavioral differences observed are due to translational rather than transcriptional regulation. Another possibility to study the contributions of mGluR2 and mGluR3 in mediating addictive-like behavior is the use of knockout models. Because mGluR2 knockouts cannot be used in operant procedures due to motoric impairment, we only tested mGluR3 knockouts. These mice did not differ from controls in reinstatement, suggesting that mGluR2 receptors are critical in mediating addictive-like behavior. PMID- 23624744 TI - The anodic stripping voltammetry of nanoparticles: electrochemical evidence for the surface agglomeration of silver nanoparticles. AB - Analytical expressions for the anodic stripping voltammetry of metallic nanoparticles from an electrode are provided. First, for reversible electron transfer, two limits are studied: that of diffusionally independent nanoparticles and the regime where the diffusion layers originating from each particle overlap strongly. Second, an analytical expression for the voltammetric response under conditions of irreversible electron transfer kinetics is also derived. These equations demonstrate how the peak potential for the stripping process is expected to occur at values negative of the formal potential for the redox process in which the surface immobilised nanoparticles are oxidised to the corresponding metal cation in the solution phase. This work is further developed by considering the surface energies of the nanoparticles and its effect on the formal potential for the oxidation. The change in the formal potential is modelled in accordance with the equations provided by Plieth [J. Phys. Chem., 1982, 86, 3166-3170]. The new analytical expressions are used to investigate the stripping of silver nanoparticles from a glassy carbon electrode. The relative invariance of the stripping peak potential at low surface coverages of silver is shown to be directly related to the surface agglomeration of the nanoparticles. PMID- 23624742 TI - Divergent functional effects of sazetidine-a and varenicline during nicotine withdrawal. AB - Smoking is the largest preventable cause of death in the United States. Furthermore, a recent study found that <10% of quit attempts resulted in continuous abstinence for 1 year. With the introduction of pharmacotherapies like Chantix (varenicline), a selective alpha4beta2 nicotinic partial agonist, successful quit attempts have significantly increased. Therefore, novel subtype specific nicotinic drugs, such as sazetidine-A, present a rich area for investigation of therapeutic potential in smoking cessation. The present studies examine the anxiety-related behavioral and functional effects of the nicotinic partial agonists varenicline and sazetidine-A during withdrawal from chronic nicotine in mice. Our studies indicate that ventral hippocampal-specific infusions of sazetidine-A, but not varenicline, are efficacious in reducing nicotine withdrawal-related anxiety-like phenotypes in the novelty-induced hypophagia (NIH) paradigm. To further investigate functional differences between these partial agonists, we utilized voltage-sensitive dye imaging (VSDi) in ventral hippocampal slices to determine the effects of sazetidine-A and varenicline in animals chronically treated with saline, nicotine, or undergoing 24 h withdrawal. These studies demonstrate a functional dissociation of varenicline and sazetidine-A on hippocampal network activity, which is directly related to previous drug exposure. Furthermore, the effects of the nicotinic partial agonists in VSDi assays are significantly correlated with their behavioral effects in the NIH test. These findings highlight the importance of drug history in understanding the mechanisms through which nicotinic compounds may be aiding smoking cessation in individuals experiencing withdrawal-associated anxiety. PMID- 23624745 TI - Management of chronic neuropathic pain of different causes with the combination of oral methadone along with ketamine: A report of 18 cases. PMID- 23624746 TI - Increased electrical nerve stimulation threshold of the sciatic nerve in patients with diabetic foot gangrene: a prospective parallel cohort study. AB - CONTEXT: Peripheral neuropathy may affect nerve conduction in patients with diabetes mellitus. OBJECTIVE: This study was designed to test the hypothesis that the electrical stimulation threshold for a motor response of the sciatic nerve is increased in patients suffering from diabetic foot gangrene compared to non diabetic patients. DESIGN: Prospective non-randomised trial with two parallel groups. SETTING: Two university-affiliated hospitals. PARTICIPANTS: Patients scheduled for surgical treatment of diabetic foot gangrene (n = 30) and non diabetic patients (n = 30) displaying no risk factors for neuropathy undergoing orthopaedic foot or ankle surgery. MAIN OUTCOME MEASURE: The minimum current intensity required to elicit a typical motor response (dorsiflexion or eversion of the foot) at a pulse width of 0.1 ms and a stimulation frequency of 1 Hz when the needle tip was positioned under ultrasound control directly adjacent to the peroneal component of the sciatic nerve. RESULTS: The non-diabetic patients were younger [64 (SD 12) vs. 74 (SD 7) years] and predominantly female (23 vs. 8). The geometric mean of the motor stimulation threshold was 0.26 [95% confidence interval (95% CI) 0.24 to 0.28] mA in non-diabetic and 1.9 (95% CI 1.6 to 2.2) mA in diabetic patients. The geometric mean of the electrical stimulation threshold was significantly (P < 0.001) increased by a factor of 7.2 (95% CI 6.1 to 8.4) in diabetic compared to non-diabetic patients. CONCLUSION: The electrical stimulation threshold for a motor response of the sciatic nerve is increased by a factor of 7.2 in patients with diabetic foot gangrene, which might hamper nerve identification. PMID- 23624747 TI - Faceting preferences for Au(N) and Pd(N) nanoclusters with high-symmetry motifs. AB - The structural preferences of nanoparticles are important for understanding their chemical properties and potential applications, and remain widely debated. Based on recent experimental observations, we present calculations on the stability of high-symmetry AuN and PdN clusters of various structural motifs, performing a systematic search of faceting preferences using mathematical constructs, a semi empirical potential with two different parameter sets, and a quasi-Newtonian minimisation technique. We have studied the preferred ratios of (100) and (111) faces for two experimentally observed nanostructures: (a) FCC crystals, comparing octahedra with 8 (111) faces to cuboctahedra where the vertices have been systematically removed (for N < 1500); and (b) Marks-decahedra, with differing "stellation" depths (for N < 6000). For PdN and AuN we see preference towards minimisation of (100) surfaces using the parameter sets of both Cleri and Rosato [Cleri and Rosato, Phys. Rev. B: Condens. Matter Mater. Phys., 1993, 48, 22] and Baletto et al. [Baletto et al., J. Chem. Phys., 2002, 116, 3856]. Fully stellated Marks-decahedra are found to be unfavourable at large sizes, with truncated facets identified which are similar to recent experimental observations. We find however that these stellations are deeper in PdN particles than AuN. Truncated octahedra are found to prefer much reduced (100) surfaces and increased (111) surface areas. PMID- 23624748 TI - RU486, a glucocorticoid receptor antagonist, induces apoptosis in U937 human lymphoma cells through reduction in mitochondrial membrane potential and activation of p38 MAPK. AB - RU486 (mifepristone) exerts an anticancer effect on cancer cells via induction of apoptosis. However, the molecular mechanisms are not fully understood. Here, we investigated the effect of RU486 on the apoptosis of U937 human leukemia cells. RU486 markedly increased apoptosis in U937 cells as well as in MDA231 human breast carcinoma, A549 human lung adenocarcinoma epithelial and HCT116 human colorectal carcinoma cells. RU486 increased dose-dependent release of mitochondrial cytochrome c, and reduced the mitochondrial membrane potential (MMP, Deltapsim) in RU486-treated U937 cells. We also found that overexpression of Bcl-2 completely blocked RU486-mediated apoptosis. However, reactive oxygen species signaling had no effect on RU486-induced apoptosis. RU486 increased the phosphorylation of p38 MAPK and JNK, but p38 MAPK only was associated with RU486 mediated apoptosis. Taken together, RU486 induces apoptosis through reduction in the mitochondrial membrane potential and activation of p38 MAPK in U937 human leukemia cells. PMID- 23624750 TI - Germline mutations in NF1 and BRCA1 in a family with neurofibromatosis type 1 and early-onset breast cancer. AB - Neurofibromatosis type 1 (NF1) is a common dominant autosomal disorder caused by mutations in the NF1 gene. The main manifestations of NF1 are cafe-au-lait spots, neurofibromas, intertriginous freckling, Lisch nodules, and malignancy, including peripheral nerve sheath tumors, central nervous system gliomas, and a variety of other tumors not so clearly defined. The association between NF1 and breast cancer or other gynecologic malignancies seems uncommon and has been scarcely referred in the literature. We describe a family with two females affected by both NF1 and early-onset breast cancer, and a male with NF1. We evaluated whether the concomitance of both disorders could be attributed to a NF1 mutation and its supposed increased risk of breast cancer or to the concurrence of two NF1 and BRCA1/2 germline mutations. Mutation analyses identified a frameshift mutation in BRCA1 and a nonsense mutation in NF1. Our findings stress the importance of considering all phenotypic features in families with both NF1 and breast tumors. To offer a specific risk assessment and management of both conditions, NF1 and BRCA1/2 cancer predisposing genes should be analyzed. PMID- 23624749 TI - Promoter methylation of AREG, HOXA11, hMLH1, NDRG2, NPTX2 and Tes genes in glioblastoma. AB - Epigenetic alterations alone or in combination with genetic mechanisms play a key role in brain tumorigenesis. Glioblastoma is one of the most common, lethal and poor clinical outcome primary brain tumors with extraordinarily miscellaneous epigenetic alterations profile. The aim of this study was to investigate new potential prognostic epigenetic markers such as AREG, HOXA11, hMLH1, NDRG2, NTPX2 and Tes genes promoter methylation, frequency and value for patients outcome. We examined the promoter methylation status using methylation-specific polymerase chain reaction in 100 glioblastoma tissue samples. The value for clinical outcome was calculated using Kaplan-Meier estimation with log-rank test. DNA promoter methylation was frequent event appearing more than 45 % for gene. AREG and HOXA11 methylation status was significantly associated with patient age. HOXA11 showed the tendency to be associated with patient outcome in glioblastomas. AREG gene promoter methylation showed significant correlation with poor patient outcome. AREG methylation remained significantly associated with patient survival in a Cox multivariate model including MGMT promoter methylation status. This study of new epigenetic targets has shown considerably high level of analyzed genes promoter methylation variability in glioblastoma tissue. AREG gene might be valuable marker for glioblastoma patient survival prognosis, however further analysis is needed to clarify the independence and appropriateness of the marker. PMID- 23624751 TI - Risk factors for non-invasive and invasive local recurrence in patients with ductal carcinoma in situ. AB - We aimed to identify clinicopathologic factors associated with local recurrence (LR) in a large population of DCIS patients treated with breast-conserving therapy between 1990-2001 in three health plans. Regression methods were used to estimate relative risks (RR) of LR. Among 2,995 patients, 325 had a LR [10.9 %; median follow-up 4.8 years (range 0.5-15.7)]. After adjusting for health plan and treatment, risk of LR was increased among women <45 years (RR = 2.1, 95 % CI 1.5 2.8), African-Americans (RR = 1.6; 95 % CI 1.1-2.1) and those with DCIS detected because of signs/symptoms (RR = 1.6; 95 % CI 1.2-2.0). After also adjusting for age and diagnosis year, pathologic features associated with increased LR were larger lesion size (RR = 2.9 for >=20 low power fields of DCIS; 95 % CI 1.6-5.6) and involved (RR = 2.9; 95 % CI 1.6-5.2), or close margins (RR = 2.4; 95 % CI 1.6 3.8). Presentation with symptoms/signs was associated with increased risk of invasive recurrence; while African-American race, larger tumor size, and involved/close tumor margins were more strongly associated with increased risk of DCIS recurrence. Our findings suggest some risk factors differ for non-invasive and invasive LRs and that most factors are only moderately associated with increased LR risk. Future research efforts should focus on non-clinicopathologic factors to identify more powerful risk factors for LR. PMID- 23624752 TI - Remission of bullous pemphigoid after rituximab treatment in a psoriasis patient on regular low-dose methotrexate. PMID- 23624753 TI - Vitexin protects against cardiac hypertrophy via inhibiting calcineurin and CaMKII signaling pathways. AB - Vitexin is a flavone glycoside isolated from the leaf of Crataeguspinnatifida Bunge, the utility of which has been demonstrated in several cardiovascular diseases. However, its role in cardiac hypertrophy remains unclear. In the present study, we aimed to determine whether vitexin prevents cardiac hypertrophy induced by isoproterenol (ISO) in cultured neonatal rat ventricular myocytes in vitro and pressure overload-induced cardiac hypertrophy in mice in vivo. The results revealed that vitexin (10, 30, and 100 MUM) dose-dependently attenuated cardiac hypertrophy induced by ISO in vitro. Furthermore, vitexin (3, 10, and 30 mg kg(-1)) prevented cardiac hypertrophy induced by transverse aortic constriction as assessed by heart weight/body weight, left ventricular weight/body weight and lung weight/body weight ratios, cardiomyocyte cross sectional area, echocardiographic parameters, and gene expression of hypertrophic markers. Further investigation demonstrated that vitexin inhibited the increment of the resting intracellular free calcium induced by ISO. Vitexin also inhibited the expression of calcium downstream effectors calcineurin-NFATc3 and phosphorylated calmodulin kinase II (CaMKII) both in vitro and in vivo. Taken together, our results indicate that vitexin has the potential to protect against cardiac hypertrophy through Ca2+-mediated calcineurin-NFATc3 and CaMKII signaling pathways. PMID- 23624754 TI - Fractions of cardiovascular diseases and mental disorders attributable to psychosocial work factors in 31 countries in Europe. AB - OBJECTIVES: The aim of this study was to evaluate the fractions of cardiovascular diseases and mental disorders attributable to three psychosocial work factors, job strain, effort-reward imbalance (ERI) and job insecurity, in 31 countries in Europe. METHODS: The prevalence of exposure (Pe) to job strain, ERI and job insecurity was calculated using the sample of 29,680 workers from 31 countries of the 2005 European Working Conditions Survey. Relative risks (RR) were obtained from three published meta-analyses. Pe and RR estimates were used to calculate attributable fractions (AF). RESULTS: Pe estimates were 26.90, 20.44 and 14.11% for job strain, ERI and job insecurity in Europe, and significant differences were observed between countries. The job strain and ERI AFs for cardiovascular diseases were, respectively, 4.46% (significantly different from zero for Europe and all countries, but without any differences between countries) and 18.21% (not significantly different from zero for Europe and without differences between countries). The significant job strain and job insecurity AFs for mental disorders were 18.16 and 4.53% in Europe, without any significant difference between countries. The significant ERI AF for mental disorders was 14.81%, and significant differences were found between countries; the 3 highest AFs were observed in Greece, Slovenia and Turkey, and the 3 lowest in Bulgaria, Ireland and Latvia. CONCLUSION: This study is the first one to provide fractions of cardiovascular diseases and mental disorders attributable to three psychosocial work factors for the whole Europe and to explore the differences between 31 countries. These results may be useful to guide European and national prevention policies as well as to evaluate the economic costs of diseases attributable to these exposures. PMID- 23624756 TI - Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease. AB - AIM: Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects. METHODS: This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, AUC0-72 h and AUC0-infinity were calculated. Tolerance assessments were conducted throughout the study. RESULTS: ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean tmax of huperzine A was 0.76-0.82 h; the AUC0-72 h and Cmax of huperzine A showed approximately dose proportional increase over the dose range of 0.5-1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed. CONCLUSION: ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers. PMID- 23624757 TI - Population pharmacokinetics of ciclosporin in Chinese children with aplastic anemia: effects of weight, renal function and stanozolol administration. AB - AIM: To develop a population pharmacokinetic model for the immunosuppressant ciclosporin in Chinese children with aplastic anemia and to identify covariates influencing ciclosporin pharmacokinetics. METHODS: A total of 102 children with either acquired or congenital aplastic anemia aged 8.8+/-3.6 years (range 0.9 17.6 years) were included. Therapeutic drug monitoring (TDM) data for ciclosporin were collected. The population pharmacokinetic model of ciclosporin was described using the nonlinear mixed-effects modeling (NONMEM) VI software. The final model was validated using bootstrap and normalized prediction distribution errors. RESULTS: A one-compartment model with first-order absorption and elimination was developed. The estimated CL/F was 15.1, which was lower than those of children receiving stem cell or kidney transplant reported in the West (16.9-29.3). The weight normalized CL/F was 0.45 (range: 0.27-0.70) Lh(-1).kg(-1). The covariate analysis identified body weight, serum creatinine and concomitant administration of the anabolic steroid stanozolol as individual factors influencing the CL/F of ciclosporin. CONCLUSION: Our model could be used to optimize the ciclosporin dosing regimen in Chinese children with aplastic anemia. PMID- 23624755 TI - Sesamin ameliorates arterial dysfunction in spontaneously hypertensive rats via downregulation of NADPH oxidase subunits and upregulation of eNOS expression. AB - AIM: Sesamin is one of the major lignans in sesame seeds with antihyperlipidemic, antioxidative and antihypertensive activities. The aim of this study was to examine the effects of sesamin on arterial function in spontaneously hypertensive rats (SHRs). METHODS: SHRs were orally administered sesamin (40, 80 and 160 mg.kg(-1).d(-1)) for 16 weeks. After the rats were killed, thoracic aortas were dissected out. The vasorelaxation responses of aortic rings to ACh and nitroprusside were measured. The expression of eNOS and NADPH oxidase subunits p47(phox) and p22(phox) in aortas were detected using Western blotting and immunohistochemistry. Aortic nitrotyrosine was measured with ELISA. The total antioxidant capacity (T-AOC) and MDA levels in aortas were also determined. RESULTS: The aortic rings of SHRs showed significantly smaller ACh-induced and nitroprusside-induced relaxation than those of control rats. Treatment of SHRs with sesamin increased both the endothelium-dependent and endothelium-independent relaxation of aortic rings in a dose-dependent manner. In aortas of SHRs, the level of T-AOC and the expression of nitrotyrosine, p22(phox) and p47(phox) proteins were markedly increased, while the level of MDA and the expression of eNOS protein were significantly decreased. Treatment of SHRs with sesamin dose dependently reversed these biochemical and molecular abnormalities in aortas. CONCLUSION: Long-term treatment with sesamin improves arterial function in SHR through the upregulation of eNOS expression and downregulation of p22(phox) and p47(phox) expression. PMID- 23624758 TI - Positive allosteric modulators to peptide GPCRs: a promising class of drugs. AB - The task of finding selective and stable peptide receptor agonists with low molecular weight, desirable pharmacokinetic properties and penetrable to the blood-brain barrier has proven too difficult for many highly coveted drug targets, including receptors for endothelin, vasoactive intestinal peptide and galanin. These receptors and ligand-gated ion channels activated by structurally simple agonists such as glutamate, glycine and GABA present such a narrow chemical space that the design of subtype-selective molecules capable of distinguishing a dozen of glutamate and GABA receptor subtypes and possessing desirable pharmacokinetic properties has also been problematic. In contrast, the pharmaceutical industry demonstrates a remarkable success in developing 1,4 benzodiazepines, positive allosteric modulators (PMAs) of the GABAA receptor. They were synthesized over 50 years ago and discovered to have anxiolytic potential through an in vivo assay. As exemplified by Librium, Valium and Dormicum, these allosteric ligands of the receptor became the world's first blockbuster drugs. Through molecular manipulation over the past 2 decades, including mutations and knockouts of the endogenous ligands or their receptors, and by in-depth physiological and pharmacological studies, more peptide and glutamate receptors have become well-validated drug targets for which an agonist is sought. In such cases, the pursuit for PAMs has also intensified, and a working paradigm to identify drug candidates that are designed as PAMs has emerged. This review, which focuses on the general principles of finding PAMs of peptide receptors in the 21st century, describes the workflow and some of its resulting compounds such as PAMs of galanin receptor 2 that act as potent anticonvulsant agents. PMID- 23624759 TI - Friend or foe: the role of microRNA in chemotherapy resistance. AB - Chemotherapy has been widely used in treating cancer patients. Despite the tremendous progress in cancer treatment achieved during the last decades, drug resistance still accounts for most of the tumor relapses in chemotherapy-treated patients. Emerging evidence shows that microRNAs play an important role in regulating the drug sensitivity of tumor cells. However, the mechanism of microRNA-mediated drug resistance is not fully understood. Current data suggest that microRNAs can be categorized as oncogenic or tumor-suppressive based on their functions and targets. In tumor cells undergoing drug treatment, microRNAs can function either by decreasing expression of genes associated with multiple drug resistance or by promoting escape from apoptosis and inducing tumor stem cell development. This review aims to provide an updated understanding of the role of microRNAs in regulating chemotherapy resistance and a discussion of potential therapeutic applications. PMID- 23624760 TI - Effect of myocardial contractility on hemodynamic end points under concomitant microvascular disease in a porcine model. AB - In this study, coronary diagnostic parameters, pressure drop coefficient (CDP: ratio of trans-stenotic pressure drop to distal dynamic pressure), and lesion flow coefficient (LFC: ratio of % area stenosis (%AS) to the CDP at throat region), were evaluated to distinguish levels of %AS under varying contractility conditions, in the presence of microvascular disease (MVD). In 10 pigs, %AS and MVD were created using angioplasty balloons and 90-MUm microspheres, respectively. Simultaneous measurements of pressure drop, left ventricular pressure (p), and velocity were obtained. Contractility was calculated as (dp/dt)max, categorized into low contractility <900 mmHg/s and high contractility >900 mmHg/s, and in each group, compared between %AS <50 and >50 using analysis of variance. In the presence of MVD, between the %AS <50 and >50 groups, values of CDP (71 +/- 1.4 and 121 +/- 1.3) and LFC (0.10 +/- 0.04 and 0.19 +/- 0.04) were significantly different (P < 0.05), under low-contractility conditions. A similar %AS trend was observed under high-contractility conditions (CDP: 18 +/- 1.4 and 91 +/- 1.4; LFC: 0.08 +/- 0.04 and 0.25 +/- 0.04). Under MVD conditions, similar to fractional flow reserve, CDP and LFC were not influenced by contractility. PMID- 23624761 TI - Comparison of the abilities of the plasma triglyceride/high-density lipoprotein cholesterol ratio and the metabolic syndrome to identify insulin resistance. AB - This study compares the ability of an elevated triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio, using sex-specific cut-points, to identify insulin-resistant individuals within a population without known cardiac disease or diabetes with that obtained using the diagnostic criteria of the metabolic syndrome (MetS). Measurements were made of waist circumference (WC), systolic and diastolic blood pressure, fasting plasma glucose, fasting plasma insulin (FPI), plasma TG and plasma HDL-C concentrations in 1102 women and 464 men. These data were used to classify subjects as being insulin resistant (FPI concentration in the upper quartile) and having the MetS or an elevated TG/HDL-C ratio (>2.5 and >3.5 for women and men, respectively). The sensitivity and specificity with which the two indices identified insulin-resistant subjects were similar (43% and 81% for TG/HDL-C ratio and 45% and 82% for MetS), as the number of individuals was found with either an elevated TG/HDL-C ratio (n = 386) or the MetS (n = 384). Eighty-one per cent of the individuals were identified concordantly. Cardio-metabolic risk profiles in 'low-risk' individuals identified by a low TG/HDL-C ratio were comparable to those who did not have the MetS, and this was also the case when comparing 'high-risk' groups identified by having the MetS or an elevated TG/HDL-C ratio. These findings suggest that TG/HDL-C concentration ratio is as adequate as MetS diagnosis to identify insulin resistant subjects. PMID- 23624762 TI - Prevalence and predictors of diabetes and cardiometabolic risk among construction workers in Ireland: the Construction Workers Health Trust screening study. AB - Construction workers (CW) are at increased risk for a range of chronic diseases. We screened 983 CW for diabetes and cardiometabolic risk. The age range was 18-64 years, with mean age of 36.3 years. Self-reported questionnaires, Finnish diabetes risk score and fasting blood tests were collected at the workplace. The unadjusted prevalence of pre-diabetes and type 2 diabetes mellitus were 3.6% and 1.2%, respectively; 21% of CW had the metabolic syndrome (MetS). The majority were either overweight (48.3%) or obese (21.8%). In a regression model, age remained the strongest predictor of fasting glucose (p < 0.001). Pre-diabetes and diabetes mellitus were significantly associated with presence of the MetS [odds ratio (OR) 5.6; 95% confidence interval (CI): 2.8-11.5, p < 0.001 and OR 5.5; 95% CI: 1.6-18.7, p = 0.006, respectively]. Subjects engaged in greater physical activity outside of work had lower body mass index (26.9 vs. 28.8 kg/m(2), p = 0.03), waist circumference (95.8 vs. 98.1 cm, p = 0.03) and fasting serum triglycerides (1.1 vs. 1.4 mmol/L, p = 0.03) compared to those who were sedentary. Despite their youth and a physically demanding occupation, CW are at risk of cardiometabolic diseases. This risk increases with age and the MetS. Screening tools may be useful to identify those who are at risk. PMID- 23624764 TI - Detection of multiple muscle involvement in eosinophilic myositis with 18F-FDG PET/CT. PMID- 23624765 TI - Reverse blood flow-glucose metabolism mismatch indicates preserved oxygen metabolism in patients with revascularised myocardial infarction. AB - PURPOSE: Positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) has been reported to be unreliable for identifying viable myocardium in acute myocardial infarction (AMI), especially in areas with discordance in myocardial blood flow (MBF) and glucose metabolism. In myocardium with decreased FDG uptake but preserved MBF, referred to as exhibiting reverse mismatch, myocardial viability remains controversial and little is known about the metabolic state. The aims of this study were to clarify substrate use and to estimate myocardial viability in infarct areas exhibiting reverse mismatch. METHODS: Eighteen AMI patients with successful revascularisation were included in this study. Two weeks after onset, (11)C-acetate and (18)F-FDG PET were performed to evaluate regional oxygen consumption (k mono), MBF and glucose metabolism. Free fatty acid (FFA) metabolism was evaluated with (123)I-15-(p-iodophenyl)-3-(R, S) methylpentadecanoic acid (BMIPP) single photon emission computed tomography (SPECT). To assess wall motion, movement in left ventricular endocardial surface was calculated using ECG-gated (99m)Tc-tetrofosmin SPECT. RESULTS: The %k mono values in reverse mismatch segments (52.6 +/- 13.6%) were not significantly different from those in non-infarct segments (60.4 +/- 12.8%, p = 0.071) and normal match segments (preserved MBF and FDG uptake) (58.6 +/- 11.6%, p = 0.396), although regional wall motion was more severely impaired (3.06 +/- 2.52 mm vs 6.78 +/- 3.17 mm, p < 0.0001, and vs 5.30 +/- 2.33 mm, p = 0.042, respectively). Compared to segments with reduced match (reduced MBF and FDG uptake), %k mono and %BMIPP uptake were significantly higher in reverse mismatch segments (52.6 +/- 13.6% vs 37.4 +/- 8.9%, p = 0.0002, and 58.8 +/- 10.6% vs 40.2 +/- 10.7%, p < 0.0001). CONCLUSION: Reverse mismatch in reperfused AMI patients, high oxygen consumption and FFA metabolism were observed despite decreased glucose metabolism. We conclude that reverse mismatch indicated the myocardium with early restoration of MBF and aerobic FFA metabolism. PMID- 23624766 TI - Incidence of metachronous gastric cancer in the remnant stomach after synchronous multiple cancer surgery. AB - BACKGROUND: In the preoperative evaluation for gastric cancer, high-resolution endoscopic technologies allow us to detect small accessory lesions. However, it is not known if the gastric remnant after partial gastrectomy for synchronous multiple gastric cancers has a greater risk for metachronous cancer. The purpose of this study was to determine the incidence of metachronous cancer in this patient subset compared with that after solitary cancer surgery. METHODS: Data on a consecutive series of 1,281 patients gastrectomized for early gastric cancer from 1991 to 2007 were analyzed retrospectively. The 715 gastric remnants after distal gastrectomy were periodically surveyed by endoscopic examination in Shikoku Cancer Center. Among those surveyed cases, 642 patients were pathologically diagnosed with solitary lesion (SO group) and 73 patients with synchronous multiple lesions (MU group) at the time of the initial surgery. RESULTS: In the follow-up period, 15 patients in the SO group and 3 patients in the MU group were diagnosed as having metachronous cancer in the gastric remnant. The cumulative 4-year incidence rate was 1.9 % in the SO group and 5.5 % in the MU group. The difference did not reach the significant level by the log-rank test. CONCLUSIONS: The incidence of metachronous cancer is higher after multiple cancer surgery; however, the difference is not statistically significant. PMID- 23624768 TI - The correlation between mineralization degree and bone tissue stiffness in the porcine mandibular condyle. AB - The aim of this study was to correlate the local tissue mineral density (TMD) with the bone tissue stiffness. It was hypothesized that these variables are positively correlated. Cancellous and cortical bone samples were derived from ten mandibular condyles taken from 5 young and 5 adult female pigs. The bone tissue stiffness was assessed in three directions using nanoindentation. At each of three tested sides 5 indents were made over the width of 5 single bone elements, resulting in a total number of 1500 indents. MicroCT was used to determine the local TMD at the indented sites. The TMD and the bone tissue stiffness were higher in bone from the adult animals than from the young ones, but did not differ between cancellous and cortical bone. In the adult group, both the TMD and the bone tissue stiffness were higher in the center than at the surface of the bone elements. The mean TMD, thus ignoring the local mineral distribution, had a coefficient of determination (R(2)) with the mean bone tissue stiffness of 0.55, p < 0.05, whereas the correlation between local bone tissue stiffness and the concomitant TMD appeared to be weak (R (2) 0.07, p < 0.001). It was concluded that the mineralization degree plays a larger role in bone tissue stiffness in cancellous than in cortical bone. Our data based on bone from the mandibular condyle suggest that the mineralization degree is not a decisive determinant of the local bone tissue stiffness. PMID- 23624769 TI - Isolation of porcine monocyte population: a simple and efficient method. AB - Monocytes are important mediators of inflammatory processes and are in the focus of immunological studies. While the preparation of human monocytes is widely established, little is published on the isolation of porcine monocytes for experimental studies. The aim of this study is to establish a cost efficient method of preparing and culturing porcine monocytes of considerable purity and reasonable yield. In our method, we combined and modified different protocols of human monocyte preparation. The blood of a single pig is harvested and treated with EDTA to prevent coagulation. Peripheral blood mononuclear cells are obtained by a density gradient centrifugation using a Bicoll gradient and monocytes are harvested by culturing on serum-treated culture flasks, rinsing and tapping. A high yield is obtained by constant cooling of flasks and tubes. The purity of the culture is evaluated by the expression of CD14, using flow cytometry. Using this method, we reached a purity of 92.6 % (+/- 3.06 %). With this procedure, we established a reliable method to prepare and cultivate porcine monocytes which can be performed cost effectively and does not require special equipment. PMID- 23624770 TI - Cognitive vulnerabilities as predictors of stress generation in early adolescence: pathway to depressive symptoms. AB - Although individuals with depression have been found to experience a higher rate of stress in their lives, it remains unclear to what extent other personal characteristics may contribute to stress generation. The current study extended past research by examining the effects of two theoretically and empirically supported cognitive vulnerabilities to depression (negative cognitive style and rumination) as predictors of dependent interpersonal and achievement events, independent events, and relational peer victimization. In a diverse sample of 301 early adolescents (56 % female; M(age) = 12.82 years), we found that negative cognitive style prospectively predicted the experience of dependent interpersonal stress and relational victimization, and that rumination did not predict stress in any of the domains. Furthermore, the occurrence of intervening stress mediated the associations between negative cognitive style and subsequent depressive symptoms. Additionally, whereas negative cognitive style predicted relational victimization among both boys and girls, girls were particularly vulnerable to developing depressive symptoms following the occurrence of relational victimization. Thus, a negative cognitive style may contribute to the occurrence of stressful events, which in turn increases depressive symptoms. Girls may be particularly reactive to relational victimization, representing one pathway through which sex differences in depression may emerge. PMID- 23624771 TI - Early adolescent growth in depression and conduct problem symptoms as predictors of later substance use impairment. AB - Most studies of adolescent substance use and psychological comorbidity have examined the contributions of conduct problems and depressive symptoms measured only at particular points-in-time. Yet, during adolescence, risk factors such as conduct problems and depression exist within a developmental context, and vary over time. Though internalizing and comorbid pathways to substance use have been theorized (Hussong et al. Psychology of Addictive Behaviors 25:390-404, 2011), the degree to which developmental increases in depressive symptoms and conduct problems elevate risk for substance use impairment among adolescents, in either an additive or potentially a synergistic fashion, is unclear. Using a school based sample of 521 adolescents, we tested additive and synergistic influences of changes in depressive symptoms and conduct problems from 6th to 9th grade using parallel process growth curve modeling with latent interactions in the prediction of late adolescent (12th grade) substance use impairment, while examining gender as a moderator. We found that the interaction between growth in depression and conduct disorder symptoms uniquely predicted later substance use problems, in addition to main effects of each, across boys and girls. Results indicated that adolescents whose parents reported increases in both depression and conduct disorder symptoms from 6th to 9th grade reported the most substance use-related impairment in 12th grade. The current study demonstrates that patterns of depression and conduct problems (e.g., growth vs. decreasing) are likely more important than the static levels at any particular point-in-time in relation to substance use risk. PMID- 23624772 TI - Sexual risk behavior and symptoms of historical loss in American Indian men. AB - Native Americans in the United States are not typically regarded as a most at risk population for HIV or other sexually transmitted infections (STIs), despite emerging evidence which suggests otherwise. As a result, Native Americans lack access to key prevention services and programs. In planning prevention programs for this unique population, however, it is important to take into account the cultural factors that may be implicated in health risk behaviors. Historical Loss is a type of historical trauma that has been reported in Native Americans, and which may be related to health behaviors. We examined whether Historical Loss was associated with sexual risk behaviors in a sample of 120 American Indian men living in Fort Peck Reservation in northeastern Montana who completed questions regarding Historical Loss and sexual risk behaviors. Symptoms of Historical Loss that reflected Anxiety/Depression and Anger/Avoidance were associated with an increased likelihood of individuals' having sex with multiple concurrent partners. Health interventions that aim to address HIV/STI prevention should take symptoms of Historical Loss into account, as Historical Loss could be a potential factor that will mitigate HIV, STI, and pregnancy prevention efforts in this population. PMID- 23624773 TI - Rotational thrombolelastometry produces potentially clinical useful results within 10 min in bleeding emergency department patients: the DEUCE study. AB - OBJECTIVES AND BACKGROUND: For the first time in the Emergency Department (ED), to assess the use of rotational thromboelastometry (ROTEM) in patients presenting with all-cause haemodynamic shock, specifically (a) to establish whether a 5- min (A5) or a 10-min result (A10) is accurate compared with a final maximum clot firmness (MCF) result; (b) to compare time to A10 and formal laboratory coagulation result; (c) to assess whether bleeding ED trauma, gastrointestinal and aortic aneurysm patients are coagulopathic according to ROTEM; and (d) to compare ROTEM results with formal laboratory coagulation parameters. METHODS: Patients presenting to the ED in haemodynamic shock were recruited. A citrated coagulation sample was taken and once a ROTEM researcher arrived in the ED, was subjected to ROTEM analysis. RESULTS: Between 28 September 2010 and 31 August 2011, 40 patients were recruited (15 gastrointestinal bleeds, 20 major trauma cases and five ruptured abdominal aortic aneurysms). A10 and MCF correlated well (kappa=0.98); A5 and MCF correlated less well (kappa=0.91). The mean time to result (SD) was 57 (28) min for the formal laboratory coagulation result and 50 (45) min for the ROTEM A10 result (including delay to start of analysis). Seven patients were coagulopathic on ROTEM. CONCLUSION: Eighteen percent of bleeding ED patients are coagulopathic using ROTEM including 25% of trauma patients. A 10-min ROTEM clot firmness (A10) is an excellent surrogate for MCF and allows a result to be obtained earlier than formal laboratory results and potentially within 10 min of the patient arriving in the ED. PMID- 23624774 TI - Microfluidics and Raman microscopy: current applications and future challenges. AB - Raman microscopy systems are becoming increasingly widespread and accessible for characterising chemical species. Microfluidic systems are also progressively finding their way into real world applications. Therefore, it is anticipated that the integration of Raman systems with microfluidics will become increasingly attractive and practical. This review aims to provide an overview of Raman microscopy-microfluidics integrated systems for researchers who are actively interested in utilising these tools. The fundamental principles and application strengths of Raman microscopy are discussed in the context of microfluidics. Various configurations of microfluidics that incorporate Raman microscopy methods are presented, with applications highlighted. Data analysis methods are discussed, with a focus on assisting the interpretation of Raman-microfluidics data from complex samples. Finally, possible future directions of Raman microfluidic systems are presented. PMID- 23624775 TI - Implication of NGF and endocannabinoid signaling in the mechanism of action of sesamol: a multi-target natural compound with therapeutic potential. AB - RATIONALE: Sesamol, a natural compound with anti-inflammatory, antioxidant and neuroprotective properties, has shown promising antidepressant-like effects. However, its molecular target(s) have not been well defined, which merits further investigation. OBJECTIVES: Based on the interaction between the neurotrophin and endocannabinoid (eCB) systems and their contribution to emotional reactivity and antidepressant action, we aimed to investigate the involvement of nerve growth factor (NGF) and eCB signalling in the mechanism of action of sesamol. METHODS: Following acute and 4-week intraperitoneal (i.p.) administration of sesamol (40, 80 and 100 mg/kg), the classical antidepressant amitriptyline (2.5, 5 and 10 mg/kg) or the benzodiazepine flurazepam (5, 10 and 20 mg/kg), brain regional levels of NGF and eCB contents were quantified in rats by Bio-Rad protein assay and isotope-dilution liquid chromatography/mass spectrometry, respectively. In the case of any significant change, the cannabinoid CB1 and CB2 receptor antagonists (AM251 and SR144528) were administered i.p. 30 min prior to the injection of sesamol, amitriptyline or flurazepam. RESULTS: Following the chronic treatment, sesamol, similar to amitriptyline, resulted in the sustained elevation of NGF and eCB contents in dose-dependent and brain region-specific fashion. Neither acute nor chronic treatment with flurazepam altered brain NGF or eCB contents. Pretreatment with 3 mg/kg AM251, but not SR144528, prevented the elevation of NGF protein levels. AM251 exerted no effect by itself. CONCLUSIONS: Sesamol, similar to amitriptyline, is able to affect brain NGF and eCB signalling under the regulatory drive of the CB1 receptors. PMID- 23624777 TI - Pruritus assessment in clinical trials: consensus recommendations from the International Forum for the Study of Itch (IFSI) Special Interest Group Scoring Itch in Clinical Trials. AB - Chronic pruritus is a common symptom and there is an urgent need to test new anti pruritic substances in high-quality clinical trials. However, no widely accepted standardized and validated method for objectively measuring pruritus is yet available. A special interest group of the International Forum for the Study of Itch has been established to assess scoring methods and questionnaires for use in clinical trials. This paper presents our current recommendations. The set of measures we recommend includes pruritus intensity scales, instruments for assessment of scratch lesions, chronic pruritus course, quality of life and patient benefits. PMID- 23624776 TI - Short and long access to cocaine self-administration activates tyrosine phosphatase STEP and attenuates GluN expression but differentially regulates GluA expression in the prefrontal cortex. AB - RATIONALE: Dephosphorylation of extracellular signal-regulated kinase (ERK) and cyclic AMP response element binding protein (CREB) in the dorsomedial prefrontal cortex (dmPFC) at the end of short access (ShA) cocaine self-administration is implicated in cocaine seeking. However, what receptors and phosphatases mediate this effect and whether ERK/CREB and related phospho-proteins in the dmPFC react similarly during early withdrawal from long access (LgA) cocaine self administration are unknown. OBJECTIVES: The effects of ShA vs. LgA cocaine self administration on the phosphorylation of protein phosphatase 2A (PP2A) and striatal-enriched protein tyrosine phosphatase (STEP), as well as GluN and GluA receptor subtype expression in the dmPFC during early withdrawal, were compared. METHODS: Rats self-administered cocaine or received saline during 2- or 6-h daily sessions for 10-11 days. Two hours after the final session, the dmPFC was dissected out and processed for immunoblotting. RESULTS: Similar to previous findings after ShA cocaine, phospho-ERK and phospho-CREB in the dmPFC were decreased after LgA cocaine. Cocaine elevated phospho-PP2A (deactivation) and decreased phospho-STEP (activation) in both ShA and LgA cocaine rats. GluN1, GluN2B, and phospho-GluN2B Tyr1472 in the dmPFC were decreased after ShA and LgA cocaine. Further, a significant reduction of GluA2, GluA1, and phospho-GluA1 Ser845 was found only in LgA rats. CONCLUSIONS: Activation of phospho-STEP may underlie ERK and CREB dephosphorylation in the dmPFC as well as internalization and degradation of GluN complexes during early withdrawal from both ShA and LgA cocaine self-administration, whereas differential alteration of AMPA receptor subunits after ShA and LgA cocaine self-administration depends on cocaine intake. PMID- 23624778 TI - Clinicopathological significance of KU70/KU80, a key DNA damage repair protein in breast cancer. AB - Although the role of BRCA1 and the homologous recombination (HR) pathway in breast cancer (BC) has been extensively studied, the alternative repair pathway for DNA double-strand breaks (DSBs), non-homologous end-joining (NHEJ) remains to be defined. Ku proteins bind to DNA DSB ends and play a key role in NHEJ. In this study we aimed to assess the expression and biological significance of the KU70/KU80 heterodimer in the different molecular classes of BC. The expression of KU70/KU80 was assessed immunohistochemically in a well-characterised and annotated series of 1302 unselected invasive BC cases with a long-term follow-up together with 25 cases with known BRCA1 mutations. The results were correlated with clinicopathological parameters, other DNA repair proteins and patient outcome. The expression of KU70/KU80 protein was further evaluated in various BC cell lines using western blotting and reverse-phase protein microarray (RPPA). Nuclear KU70/KU80 expression was correlated with features of poor prognosis including higher histological grade, lymphovascular invasion, negative oestrogen receptor expression, basal-like phenotype, P53 and CHK1 positivity. KU70/KU80 was expressed in all BRCA1-associated tumours and showed an inverse correlation with nuclear BRCA1 protein and aberrant cytoplasmic RAD51 expression. RPPA confirmed these results and showed higher expression of KU70/KU80 in BRCA1-deficient cell line compared to BRCA1-proficient cell line. KU70/KU80 expression showed an association with disease-free interval; however, it was not an independent predictor of outcome. As a conclusion, KU70/KU80 may play a role in DNA DSBs repair in HR-deficient tumours. Further study of other NHEJ markers in sporadic BC is warranted. PMID- 23624779 TI - High plasma-GFAP levels in metastatic myxopapillary ependymoma. AB - Myxopapillary ependymoma (MPE) is a rare tumor of the distal spinal cord. Despite benign histopathology, local recurrences occur in ~30 % of patients and distant metastases have been described in few cases. MPE tumor cells typically express glial fibrillary acidic protein (GFAP), which could be released to the circulation. In this current report, we investigated circulating plasma-GFAP in a series of MPE patients. We analyzed circulating plasma-GFAP using a commercially available ELISA kit in 3 patients with completely resected MPE, 1 patient with locally advanced MPE and 2 patients with pleuropulmonary metastases of MPE. As controls we used blood samples of age and gender-matched healthy volunteers (n = 3), 6 glioblastoma patients with known plasma-GFAP status (positive for 3 and negative for 3 patients) and 3 brain metastases patients with known plasma-GFAP negativity. We found very high concentrations of plasma-GFAP in two MPE patients with pleuropulmonary metastases, while in none of the other MPE patients circulating plasma-GFAP was detectable. Circulating GFAP could be useful as marker for early detection or follow-up of distant metastases in MPE patients. PMID- 23624780 TI - Epigenetic modification after inhibition of IGF-1R signaling in human central nervous system atypical teratoid rhabdoid tumor (AT/RT). AB - OBJECTIVE: This study investigated epigenetic modifications in human central nervous system atypical teratoid rhabdoid tumors (AT/RTs), in response to inhibition of insulin-like growth factor receptor 1 (IGF-1R). MATERIALS AND METHODS: Tumor tissue was obtained from two pediatric patients, tissue was dissociated, and primary cultures were established. Cultured cells were treated with picropodophyllin (PPP; 0, 1, and 2 MUM for 48 h), a selective IGF-1R inhibitor. Histone acetylation and methylation patterns (H3K9ac, H3K18ac, H3K4me3, H3K27me3) and levels of histone deacetylases (HDACs; HDAC1, HDAC3, and SirT1) and histone acetyl transferases (GCN5 and p300) were examined. H3K9ac and H3K18ac decreased in response to treatment with PPP. HDAC levels showed a biphasic response, increasing with 1 MUM PPP, but then decreasing with 2 MUM PPP. CONCLUSION: Inhibition of IGF-1R modified epigenetic status in AT/RT. Determining the mechanisms behind these modifications will guide the development of novel therapeutic targets for this malignant embryonal cancer. PMID- 23624781 TI - Pediatric intracranial arteriovenous shunts: a global overview. AB - INTRODUCTION: Cerebral arteriovenous shunts (CAVS) in the pediatric population cannot be compared to those in adults as they present different anatomical, physiological, and pathological characteristics concerning the arterial and venous vasculature and the cerebrospinal fluid physiology. These lesions develop in a maturing brain, of which expression is difficult to assess, with a potential for recovery different from that in adults. DISCUSSION: Their impact on the brain will be different in the antenatal period, in neonates, in infants, and in children, with variable symptoms according to each age group. We review different classifications of pediatric CAVS (according to the anatomical space in which they develop, their type and architecture, and the age at which they reveal), describe their evolution, and discuss the current role of endovascular treatment in the management of these vascular lesions. PMID- 23624782 TI - Association of MDM2 SNP309 and TP53 Arg72Pro polymorphisms with risk of endometrial cancer. AB - The incidence of endometrial cancer, a common gynecological malignancy, is increasing in Japan. We have previously shown that the ER/MDM2/p53/p21 pathway plays an important role in endometrial carcinogenesis. In the present study, we investigated the effects of germline single nucleotide polymorphisms in murine double minute 2 (MDM2) SNP309, TP53 Arg72Pro, ESR1 PvuII and XbaI, and p21 codon 31 on endometrial cancer risk. We evaluated these polymorphisms in DNA samples from 125 endometrial cancer cases and 200 controls using polymerase chain reaction-based restriction fragment length polymorphism. The association of each genetic polymorphism with endometrial cancer was examined by the odds ratio and 95% confidence interval, which were obtained using logistic regression analysis. The SNP309 GG genotype non-significantly increased the risk of endometrial cancer. The 95% confidence interval for the GG genotype vs. the TT genotype of MDM2 SNP309 was 1.76 (0.93-3.30). Endometrial cancer was not associated with tested SNP genotypes for TP53, ESR1 and p21. The combination of SNP309 GG + TG and TP53 codon 72 Arg/Arg significantly increased endometrial cancer risk. The adjusted OR was 2.53 (95% confidence interval, 1.03-6.21) and P for the interaction was 0.04. This result was supported by in vitro data showing that endometrial cancer cell lines with the SNP309 G allele failed to show growth inhibition by treatment with RITA, which reduces p53-MDM2 binding. The presence of the SNP309 G allele and TP53 codon 72 Arg/Arg genotype is associated with an increased risk of endometrial cancer in Japanese women. PMID- 23624783 TI - In situ loading of gold nanoparticles on Fe3O4@SiO2 magnetic nanocomposites and their high catalytic activity. AB - In this work, a facile approach was successfully developed for in situ catalyzing Au nanoparticles loaded on Fe3O4@SiO2 magnetic nanospheres via Sn(2+) linkage and reduction. After the Fe3O4@SiO2 MNPs were first prepared via a sol-gel process, only one step was needed to synthesize the Fe3O4@SiO2-Au magnetic nanocomposites (Fe3O4@SiO2-Au MNCs), so that both the synthesis step and the reaction cost were remarkably decreased. Significantly, the as-synthesized Fe3O4@SiO2-Au MNCs showed high performance in the catalytic reduction of 4-nitrophenol to 4-aminophenol and could be reused for several cycles with convenient magnetic separability. This approach provided a useful platform based on Fe3O4@SiO2 MNPs for the fabrication of Au or other noble metal magnetic nanocatalysts, which would be very useful in various catalytic reductions. PMID- 23624784 TI - Effect of intravenous coadministration of human stroma cell lines on engraftment of long-term repopulating clonal myelodysplastic syndrome cells in immunodeficient mice. AB - Engraftment of clonal hematopoietic precursor cells from patients with myelodysplastic syndrome (MDS) in immunodeficient mice has been difficult to achieve by intravenous (i.v.) injection. We used i.v. coadministration of the human marrow stroma cell line HS27a with CD34+ MDS cells in Nod.cg-Prkdc(scid) Il2rg(tm1wjll) (NSG) mice to provide signals that would facilitate engraftment. Hematopoietic cells from 24 MDS patients were transplanted. Cells from all patients were engrafted, and engraftment was documented in 44 of 46 evaluable mice (95%). Immunohistochemistry revealed human HS27a stroma colocalizing with human hematopoietic cells in mouse spleens. Human CD34+ precursors harvested from marrow and spleen of primary murine recipients, when combined with HS27a cells, were also engrafted successfully in secondary NSG recipients, showing persistence of the original clonal characteristics. This observation supports the concept that clonal markers were present in long-term repopulating cells. We suggest that HS27a stroma cells 'traveled' in direct contact with hematopoietic precursors and enabled their propagation. An essential signal for engraftment appears to be CD146, which is prominently expressed on HS27a cells. This xenotransplantation model will allow to further dissect signals that control engraftment of MDS cells and should be amenable to in vivo treatment studies. PMID- 23624785 TI - Effect of post-exercise protein-leucine feeding on neutrophil function, immunomodulatory plasma metabolites and cortisol during a 6-day block of intense cycling. AB - Whey protein and leucine ingestion following exercise increases muscle protein synthesis and could influence neutrophil function during recovery from prolonged intense exercise. We examined the effects of whey protein and leucine ingestion post-exercise on neutrophil function and immunomodulators during a period of intense cycling. In a randomized double-blind crossover, 12 male cyclists ingested protein/leucine/carbohydrate/fat (LEUPRO 20/7.5/89/22 g h(-1), respectively) or isocaloric carbohydrate/fat control (CON 119/22 g h(-1)) beverages for 1-3 h post-exercise during 6 days of high-intensity training. Blood was taken pre- and post-exercise on days 1, 2, 4 and 6 for phorbol myristate acetate (PMA)-stimulated neutrophil superoxide (O2 (-)) production, immune cell counts, amino acid and lipid metabolism via metabolomics, hormones (cortisol, testosterone) and cytokines (interleukin-6, interleukin-10). During recovery on day 1, LEUPRO ingestion increased mean concentrations of plasma amino acids (glycine, arginine, glutamine, leucine) and myristic acid metabolites (acylcarnitines C14, myristoylcarnitine; and C14:1-OH, hydroxymyristoleylcarnitine) with neutrophil priming capacity, and reduced neutrophil O2 production (15-17 mmol O2 (-) cell(-1) +/- 90 % confidence limits 20 mmol O2 (-) cell(-1)). On day 2, LEUPRO increased pre-exercise plasma volume (6.6 +/- 3.8 %) but haematological effects were trivial. LEUPRO supplementation did not substantially alter neutrophil elastase, testosterone, or cytokine concentrations. By day 6, however, LEUPRO reduced pre-exercise cortisol 21 % (+/ 15 %) and acylcarnitine C16 (palmitoylcarnitine) during exercise, and increased post-exercise neutrophil O2 (-) (33 +/- 20 mmol O2 (-) cell(-1)), relative to control. Altered plasma amino acid and acylcarnitine concentrations with protein leucine feeding might partly explain the acute post-exercise reduction in neutrophil function and increased exercise-stimulated neutrophil oxidative burst on day 6, which could impact neutrophil-dependent processes during recovery from intense training. PMID- 23624786 TI - Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1-7. AB - Earlier work showed that apoptosis of alveolar epithelial cells (AECs) in response to endogenous or xenobiotic factors is regulated by autocrine generation of angiotensin (ANG) II and its counterregulatory peptide ANG1-7. Mutations in surfactant protein C (SP-C) induce endoplasmic reticulum (ER) stress and apoptosis in AECs and cause lung fibrosis. This study tested the hypothesis that ER stress-induced apoptosis of AECs might also be regulated by the autocrine ANGII/ANG1-7 system of AECs. ER stress was induced in A549 cells or primary cultures of human AECs with the proteasome inhibitor MG132 or the SP-C BRICHOS domain mutant G100S. ER stress activated the ANGII-generating enzyme cathepsin D and simultaneously decreased the ANGII-degrading enzyme ACE-2, which normally generates the antiapoptotic peptide ANG1-7. TAPI-2, an inhibitor of ADAM17/TACE, significantly reduced both the activation of cathepsin D and the loss of ACE-2. Apoptosis of AECs induced by ER stress was measured by assays of mitochondrial function, JNK activation, caspase activation, and nuclear fragmentation. Apoptosis induced by either MG132 or the SP-C BRICHOS mutant G100S was significantly inhibited by the ANG receptor blocker saralasin and was completely abrogated by ANG1-7. Inhibition by ANG1-7 was blocked by the specific mas antagonist A779. These data show that ER stress-induced apoptosis is mediated by the autocrine ANGII/ANG1-7 system in human AECs and demonstrate effective blockade of SP-C mutation-induced apoptosis by ANG1-7. They also suggest that therapeutic strategies aimed at administering ANG1-7 or stimulating ACE-2 may hold potential for the management of ER stress-induced fibrotic lung disorders. PMID- 23624787 TI - FABP5 deficiency enhances susceptibility to H1N1 influenza A virus-induced lung inflammation. AB - The early inflammatory response to influenza A virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which inflammatory cells invade the respiratory tract remain unclear. Uncontrolled inflammation and oxidative stress cause lung damage in response to influenza A infection. We have previously shown that the fatty acid binding protein 5 (FABP5) has anti-inflammatory properties. We speculate that, as a transporter of fatty acids, FABP5 plays an important protective role against oxidative damage to lipids during infection as well. Using FABP5-/- and wild-type (WT) mice infected with influenza A virus, we showed that FABP5-/- mice had increased cell infiltration of macrophages and neutrophils compared with WT mice. FABP5-/- mice presented lower viral burden but lost as much weight as WT mice. The adaptive immune response was also increased in FABP5-/- mice as illustrated by the accumulation of T and B cells in the lung tissues and increased levels of H1N1-specific IgG antibodies. FABP5 deficiency greatly enhanced oxidative damage and lipid peroxidation following influenza A infection and presented with sustained tissue inflammation. Interestingly, FABP5 expression decreased following influenza A infection in WT lung tissues that corresponded to a decrease in the anti-inflammatory molecule PPAR-gamma activity. In conclusion, our results demonstrate a previously unknown contribution of FABP5 to influenza A virus pathogenesis by controlling excessive oxidative damage and inflammation. This property could be exploited for therapeutic purposes. PMID- 23624788 TI - The role of disturbed blood flow in the development of pulmonary arterial hypertension: lessons from preclinical animal models. AB - Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasoproliferative disorder characterized by the development of unique neointimal lesions, including concentric laminar intima fibrosis and plexiform lesions. Although the histomorphology of neointimal lesions is well described, the pathogenesis of PAH and neointimal development is largely unknown. After three decades of PAH pathobiology research the focus has shifted from vasoconstriction towards a mechanism of cancer-like angioproliferation. In this concept the role of disturbed blood flow is seen as an important trigger in the development of vascular remodeling. For instance, in PAH associated with congenital heart disease, increased pulmonary blood flow (i.e., systemic-to-pulmonary shunt) is an essential trigger for the occurrence of neointimal lesions and PAH development. Still, questions remain about the exact role of these blood flow characteristics in disease progression. PAH animal models are important for obtaining insight in new pathobiological processes and therapeutical targets. However, as for any preclinical model the pathophysiological mechanism and clinical course has to be comparable to the human disease that it mimics. This means that animal models mimicking human PAH ideally are characterized by: a hit recognized in human disease (e.g., altered pulmonary blood flow), specific vascular remodeling resembling human neointimal lesions, and disease progression that leads to right ventriclular dysfunction and death. A review that underlines the current knowledge of PAH due to disturbed flow is still lacking. In this review we will summarize the current knowledge obtained from PAH animal models associated with disturbed pulmonary blood flow and address questions for future treatment strategies for PAH. PMID- 23624789 TI - Quantitative microscopy of the lung: a problem-based approach. Part 1: basic principles of lung stereology. AB - The growing awareness of the importance of accurate morphometry in lung research has recently motivated the publication of guidelines set forth by a combined task force of the American Thoracic Society and the European Respiratory Society (20). This official ATS/ERS Research Policy Statement provides general recommendations on which stereological methods are to be used in quantitative microscopy of the lung. However, to integrate stereology into a particular experimental study design, investigators are left with the problem of how to implement this in practice. Specifically, different animal models of human lung disease require the use of different stereological techniques and may determine the mode of lung fixation, tissue processing, preparation of sections, and other things. Therefore, the present companion articles were designed to allow a short practically oriented introduction into the concepts of design-based stereology (Part 1) and to provide recommendations for choosing the most appropriate methods to investigate a number of important disease models (Part 2). Worked examples with illustrative images will facilitate the practical performance of equivalent analyses. Study algorithms provide comprehensive surveys to ensure that no essential step gets lost during the multistage workflow. Thus, with this review, we hope to close the gap between theory and practice and enhance the use of stereological techniques in pulmonary research. PMID- 23624790 TI - Lipopolysaccharide-induced phosphorylation of c-Met tyrosine residue 1003 regulates c-Met intracellular trafficking and lung epithelial barrier function. AB - c-Met, the receptor tyrosine kinase whose natural ligand is hepatocyte growth factor, is known to have a key role in cell motility. We have previously shown that lysophosphatidic acid (LPA) induced a decrease in c-Met activation via serine phosphorylation of c-Met at cell-cell contacts. Here, we demonstrate that lipopolysaccharide (LPS) treatment of human bronchial epithelial cells induced internalization of c-Met via phosphorylation at its tyrosine residue 1003. In addition, it induced epithelial barrier dysfunction as evidenced by a decrease in transepithelial resistance (TER) in a time-dependent manner. Pretreatment with a c-Met inhibitor (PHA-665752) or inhibition of protein kinase C (PKC)-alpha attenuated the LPS-mediated phosphorylation of c-Met and its internalization. LPS induced c-Met tyrosine 1003 phosphorylation, activation of PKCalpha, and c-Met internalization were, however, reversed by pretreatment of cells with LPA, which increased c-Met accumulation at cell-cell contacts. Inhibition of LPS-mediated c Met tyrosine (Y1003) phosphorylation and internalization by prior treatment with PHA-665752, inhibition of PKCalpha, or overexpression of c-MetY1003A mutant attenuated LPS-induced reduction of TER. Furthermore, we found that c-Met accumulation at cell-cell contacts contributed to LPA-enhanced epithelial barrier integrity, since downregulation of c-Met by specific small-interfering RNA attenuated LPA-increased TER. The data reveal a novel biological function of c Met in the regulation of lung epithelial barrier integrity. PMID- 23624791 TI - Distinct responses of protein turnover regulatory pathways in hypoxia- and semistarvation-induced muscle atrophy. AB - The balance of muscle protein synthesis and degradation determines skeletal muscle mass. We hypothesized that hypoxia-induced muscle atrophy and alterations in the regulation of muscle protein turnover include a hypoxia-specific component, in addition to the observed effects of reduction in food intake in response to hypoxia. Mice were subjected to normoxic, hypoxic (8% oxygen), or pair-fed conditions for 2, 4, and 21 days. Cell-autonomous effects of hypoxia on skeletal muscle were also assessed in differentiated C2C12 myotubes. Hypoxia induced an initial rapid loss of body and muscle weight, which remained decreased during chronic hypoxia and could only in part be explained by the hypoxia-induced reduction of food intake (semistarvation). Regulatory steps of protein synthesis (unfolded protein response and mammal target of rapamycin signaling) remained active in response to acute and sustained hypoxia but not to semistarvation. Activation of regulatory signals for protein degradation, including increased expression of Murf1, Atrogin-1, Bnip3, and Map1lc3b mRNAs, was observed in response to acute hypoxia and to a lesser extent following semistarvation. Conversely, the sustained elevation of Atrogin-1, Bnip3, and Map1lc3b mRNAs and the increased activity of their upstream transcriptional regulator Forkhead box O1 were specific to chronic hypoxia because they were not observed in response to reduced food intake. In conclusion, altered regulation of protein turnover during hypoxia-induced muscle atrophy resulted from an interaction of semistarvation and a hypoxia-specific component. The finding that food restriction but not hypoxia induced semistarvation inhibited regulatory steps in protein synthesis suggests a hypoxia-specific impairment of the coordination between protein-synthesis signaling and protein-degradation signaling in skeletal muscle. PMID- 23624793 TI - Which is the best surgical approach for anorectal gastrointestinal stromal tumors in the post-imatinib era? PMID- 23624792 TI - Efficient delivery of RNA interference oligonucleotides to polarized airway epithelia in vitro. AB - Polarized and pseudostratified primary airway epithelia present barriers that significantly reduce their transfection efficiency and the efficacy of RNA interference oligonucleotides. This creates an impediment in studies of the airway epithelium, diminishing the utility of loss-of-function as a research tool. Here we outline methods to introduce RNAi oligonucleotides into primary human and porcine airway epithelia grown at an air-liquid interface and difficult to-transfect transformed epithelial cell lines grown on plastic. At the time of plating, we reverse transfect small-interfering RNA (siRNA), Dicer-substrate siRNA, or microRNA oligonucleotides into cells by use of lipid or peptide transfection reagents. Using this approach we achieve significant knockdown in vitro of hypoxanthine-guanine phosphoribosyltransferase, IL-8, and CFTR expression at the mRNA and protein levels in 1-3 days. We also attain significant reduction of secreted IL-8 in polarized primary pig airway epithelia 3 days posttransfection and inhibition of CFTR-mediated Cl- conductance in polarized air liquid interface cultures of human airway epithelia 2 wk posttransfection. These results highlight an efficient means to deliver RNA interference reagents to airway epithelial cells and achieve significant knockdown of target gene expression and function. The ability to reliably conduct loss-of-function assays in polarized primary airway epithelia offers benefits to research in studies of epithelial cell homeostasis, candidate gene function, gene-based therapeutics, microRNA biology, and targeting the replication of respiratory viruses. PMID- 23624794 TI - Sacral nerve stimulation in the treatment of severe faecal incontinence: long term clinical, manometric and quality of life results. AB - BACKGROUND: Faecal incontinence (FI) is a complex and multifactorial health problem. Treatment has to be individualised, analysing the aetiology and gravity in every case. Sacral nerve stimulation (SNS) has been shown to effectively improve treatment of FI. METHODS: Fifty patients with severe FI treated with SNS between March 2002 and December 2010 were analysed. Preoperative assessment included physical examination, anorectal manometry and anal endosonography. Anal continence was evaluated using the Wexner continence grading system. Quality of life was evaluated using the Fecal Incontinence Quality of life Scale (FIQLS). Follow-up appointments were scheduled at 1, 6 and 12 months and annually thereafter. Wexner score, FIQLS and the ability to defer defecation were assessed at each visit. RESULTS: Fifty patients underwent a permanent implant. The overall mean follow-up period was 55.52 +/- 31.84 months. After 6 months, SNS significantly improved FI and positively impacted quality of life, as evidence by significant improvements in all 4 scales of the FIQLS. Anorectal manometry showed a trend towards an increase in maximum resting pressure and maximum pressure. After the first assessment at 6 months, Wexner score and FIQLS remained stable. Ability to defer defecation was also maintained. During follow-up, 3 patients (6 %) experienced implant site pain and episodes of extremity pain and paresthesias that were refractory to medical management and required device explantation. The implant site infection rate was 2 %. CONCLUSIONS: Analysis of our long-term results confirms the safety and effectiveness of SNS in the management of patients with FI. PMID- 23624796 TI - Light-triggered self-assembly of a dichromonyl compound in water. AB - External control over self-assembling structures is achieved by incorporating an azobenzene photoswitch into the structure of a dichromonyl compound. The self assembly of dichromonyl compounds into fibers leads to the formation of a hydrogel and can be triggered with visible light. PMID- 23624795 TI - Shiga toxin-producing Escherichia coli: factors involved in virulence and cattle colonization. AB - Shiga toxin-producing Escherichia coli (STEC) cause hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS) in humans. Outbreaks are linked to bovine food sources. STEC O157:H7 has been responsible for the most severe outbreaks worldwide. However, non-O157 serotypes have emerged as important enteric pathogens in several countries. The main virulence factor of STEC is the production of Shiga toxins 1 and 2. Additional virulence markers are a plasmid encoded enterohemolysin (ehxA), an autoagglutinating adhesin (Saa), a catalase peroxidase (katP), an extracellular serine protease (espP), a zinc metalloprotease (stcE), a subtilase cytotoxin (subAB), among others. Other virulence factors are intimin and adhesins that had a roll in the adherence of STEC to bovine colon. This review focuses on the virulence traits of STEC and especially on those related to the adhesion to bovine colon. The known of the interaction between STEC and the bovine host is crucial to develop strategies to control cattle colonization. PMID- 23624797 TI - Parental knowledge of pre-school child oral health. AB - The dental health of preschool children has extensive implications on the oral heath of the individual as he grows into an adult. Parents/guardians of preschool children play a central role in enforcing proper oral hygiene and preventive regime in these children. This study was conducted with the aim of describing the views of parents/guardians about the dental health of pre-school children. Response was obtained on a 21 point questionnaire from randomly visiting parents of the outpatient section of Rajah Muthiah dental college and Hospital, Annamalainagar, India. The findings of the present study point towards poor awareness among the parents/guardians of preschool children, pertaining to their childs' oral health and this could directly translate to poor oral health among the children in this area. PMID- 23624798 TI - NX-DCP as a novel biomarker would be related to liver function in cirrhotic patients with hepatocellular carcinoma. PMID- 23624799 TI - What is the optimal treatment for acute cholecystitis in elderly patients? PMID- 23624801 TI - Antibody-dependent cell lysis by NK cells is preserved after sarcoma-induced inhibition of NK cell cytotoxicity. AB - Osteosarcoma and Ewing's sarcoma tumor cells are susceptible to IL15-induced or antibody-mediated cytolytic activity of NK cells in short-term cytotoxicity assays. When encountering the tumor environment in vivo, NK cells may be in contact with tumor cells for a prolonged time period. We explored whether a prolonged interaction with sarcoma cells can modulate the activation and cytotoxic activity of NK cells. The 40 h coculture of NK cells with sarcoma cells reversibly interfered with the IL15-induced expression of NKG2D, DNAM-1 and NKp30 and inhibited the cytolytic activity of NK cells. The inhibitory effects on receptor expression required physical contact between NK cells and sarcoma cells and were independent of TGF-beta. Five days pre-incubation of NK cells with IL15 prevented the down-regulation of NKG2D and cytolytic activity in subsequent cocultures with sarcoma cells. NK cell FcgammaRIIIa/CD16 receptor expression and antibody-mediated cytotoxicity were not affected after the coculture. Inhibition of NK cell cytotoxicity was directly linked to the down-regulation of the respective NK cell-activating receptors. Our data demonstrate that the inhibitory effects of sarcoma cells on the cytolytic activity of NK cells do not affect the antibody-dependent cytotoxicity and can be prevented by pre-activation of NK cells with IL15. Thus, the combination of cytokine-activated NK cells and monoclonal antibody therapy may be required to improve tumor targeting and NK cell functionality in the tumor environment. PMID- 23624802 TI - Analysis of surrogate gene expression markers in peripheral blood of melanoma patients to predict treatment outcome of adjuvant pegylated interferon alpha 2b (EORTC 18991 side study). AB - We analysed mRNA levels of interferon response genes (ISG15, STAT1, CXCL10) of inhibitors of the JAK/STAT pathway (STAT3, SOCS1, SOCS3) and of cytokines (TNFalpha, IL10, TGFbeta1) in peripheral blood of 91 stage III melanoma patients enrolled in EORTC 18991 trial to find biomarkers indicative for disease stage and predictive for efficacy of pegylated interferon alpha-2b (PEG-IFNalpha-2b) therapy. mRNA levels were analysed at baseline and after 6 months. Univariate and multivariate analyses were performed to estimate the prognostic and predictive role of mRNA levels for distant metastasis-free survival (DMFS) and relapse-free survival (RFS). Compared to healthy controls, melanoma patients showed significantly higher TGFbeta1 mRNA levels. In a multivariate model, increasing SOCS1 and SOCS3 mRNA levels were associated with worse RFS (P = 0.02 and P = 0.04, respectively) and DMFS (P = 0.05 and P = 0.05, respectively) due to negative correlation between, respectively, SOCS1/SOCS3 mRNA levels and ulceration or Breslow thickness. No impact of PEG-IFNalpha-2b on mRNA levels was observed except for ISG15 mRNA levels, which decreased in the treatment arm (P = 0.001). It seems that patients with a decrease >60 % of ISG15 mRNA levels during 6 months PEG-IFNalpha-2b had inferior outcome. PMID- 23624803 TI - Deduced sequences of the membrane fusion and attachment proteins of canine distemper viruses isolated from dogs and wild animals in Korea. AB - Canine distemper virus (CDV) causes highly contagious respiratory, gastrointestinal, and neurological diseases in wild and domestic animal species. Despite a broad vaccination campaign, the disease is still a serious problem worldwide. In this study, six field CDV strains were isolated from three dogs, two raccoon dogs, and one badger in Korea. The full sequence of the genes encoding fusion (F) and hemagglutinin (H) proteins were compared with those of other CDVs including field and vaccine strains. The phylogenetic analysis for the F and H genes indicated that the two CDV strains isolated from dogs were most closely related to Chinese strains in the Asia-1 genotype. Another four strains were closely related to Japanese strains in the Asia-2 genotype. The six currently isolated strains shared 90.2-92.1% and 88.2-91.8% identities with eight commercial vaccine strains in their nucleotide and amino acid sequences of the F protein, respectively. They also showed 90.1-91.4% and 87.8-90.7% identities with the same vaccine strains in their nucleotide and deduced amino acid sequences of the H protein, respectively. Different N-linked glycosylation sites were identified in the F and H genes of the six isolates from the prototype vaccine strain Onderstepoort. Collectively, these results demonstrate that at least two different CDV genotypes currently exist in Korea. The considerable genetic differences between the vaccine strains and wild-type isolates would be a major factor of the incomplete protection of dogs from CDV infections. PMID- 23624804 TI - Adaptive all the way down: building responsive materials from hierarchies of chemomechanical feedback. AB - A living organism is a bundle of dynamic, integrated adaptive processes: not only does it continuously respond to constant changes in temperature, sunlight, nutrients, and other features of its environment, but it does so by coordinating hierarchies of feedback among cells, tissues, organs, and networks all continuously adapting to each other. At the root of it all is one of the most fundamental adaptive processes: the constant tug of war between chemistry and mechanics that interweaves chemical signals with endless reconfigurations of macromolecules, fibers, meshworks, and membranes. In this tutorial we explore how such chemomechanical feedback - as an inherently dynamic, iterative process connecting size and time scales - can and has been similarly evoked in synthetic materials to produce a fascinating diversity of complex multiscale responsive behaviors. We discuss how chemical kinetics and architecture can be designed to generate stimulus-induced 3D spatiotemporal waves and topographic patterns within a single bulk material, and how feedback between interior dynamics and surface wide instabilities can further generate higher order buckling and wrinkling patterns. Building on these phenomena, we show how yet higher levels of feedback and spatiotemporal complexity can be programmed into hybrid materials, and how these mechanisms allow hybrid materials to be further integrated into multicompartmental systems capable of hierarchical chemo-mechano-chemical feedback responses. These responses no doubt represent only a small sample of the chemomechanical feedback behaviors waiting to be discovered in synthetic materials, and enable us to envision nearly limitless possibilities for designing multiresponsive, multifunctional, self-adapting materials and systems. PMID- 23624805 TI - Carbon nanofibers with radially grown graphene sheets derived from electrospinning for aqueous supercapacitors with high working voltage and energy density. AB - Improvement of energy density is an urgent task for developing advanced supercapacitors. In this paper, aqueous supercapacitors with high voltage of 1.8 V and energy density of 29.1 W h kg(-1) were fabricated based on carbon nanofibers (CNFs) and Na2SO4 electrolyte. The CNFs with radially grown graphene sheets (GSs) and small average diameter down to 11 nm were prepared by electrospinning and carbonization in NH3. The radially grown GSs contain between 1 and a few atomic layers with their edges exposed on the surface. The CNFs are doped with nitrogen and oxygen with different concentrations depending on the carbonizing temperature. The supercapacitors exhibit excellent cycling performance with the capacity retention over 93.7% after 5000 charging discharging cycles. The unique structure, possessing radially grown GSs, small diameter, and heteroatom doping of the CNFs, and application of neutral electrolyte account for the high voltage and energy density of the present supercapacitors. The present supercapacitors are of high promise for practical application due to the high energy density and the advantages of neutral electrolyte including low cost, safety, low corrosivity, and convenient assembly in air. PMID- 23624806 TI - Iron and zinc complexation in wild-type and ferritin-expressing wheat grain: implications for mineral transport into developing grain. AB - We have used synchrotron-based X-ray fluorescence and absorption techniques to establish both metal distribution and complexation in mature wheat grains. In planta, extended X-ray absorption fine structure (EXAFS) spectroscopy reveals iron phytate and zinc phytate structures in aleurone cells and in modified aleurone cells in the transfer region of the grain: iron is coordinated octahedrally by six oxygen atoms and fewer than two phosphorous atoms. Zinc is coordinated tetrahedrally by four oxygen atoms and approximately 1.5 phosphorus atoms in an asymmetric coordination shell. We also present evidence of modified complexation of both metals in transgenic grain overexpressing wheat ferritin. For zinc, there is a consistent doubling of the number of complexing phosphorus atoms. Although there is some EXAFS evidence for iron phytate in ferritin expressing grain, there is also evidence of a structure lacking phosphorus. This change may lead to an excess of phosphorus within the storage regions of grain, and in turn to the demonstrated increased association of phosphorus with zinc in ferritin-expressing grains. Derivative X-ray absorption spectra also suggest that mineral complexation in the transfer region of ferritin-expressing grains is quite different from that in wild-type grain. This may explain why the raised levels of minerals transported to the developing grain accumulate within the crease region of the transgenic grain. PMID- 23624807 TI - 2-Phenylpyridine ruthenacycles as effectors of glucose oxidase activity: inhibition by Ru(II) and activation by Ru(III). AB - Cyclometalated Ru(II) derivatives of 2-phenylpyridine (Hphpy) [Ru(phpy)(bpy)2]Cl (1a) and [Ru(phpy)(phen)2]Cl (1b) (bpy is 2,2'-bipyridine, phen is 1,10 phenanthroline) behave as noncompetitive inhibitors of glucose oxidase from Aspergillus niger in the enzyme-catalyzed oxidation of D-glucose by O2 into the corresponding lactone at pH 5.0 and 25 degrees C. The enzymatic activity has been measured by monitoring the O2 consumption. The inhibition constants K i are 0.036 and 0.017 M for 1a and 1b, respectively, indicating that 1b inhibits the enzymatic activity more efficiently than 1a. The well-known coordination compound [Ru(bpy)3]Cl2 (2) behaves, in contrast, as a competitive inhibitor, with K i = 0.018 M under the same conditions. The monophasic consumption of O2 in the case of 1a, 1b, and 2 is replaced by a distinct two-phase kinetics in the presence of the cyclometalated Ru(III) compound [Ru(phpy)(bpy)2]Cl2 (3), which was obtained from 1a in the presence of a large excess of H2O2 and the iron TAML activator. Interestingly, the rates of the first and the second phases are influenced by 3 in a different way. The rate of the first phase is noticeably higher in the presence of Ru(III), although the dependence is nonmonotonic and maximal acceleration is observed at the lowest loadings of 3. The rate of the second phase decreases monotonically on increasing the concentration of the ruthenium complex in solution. The nonmonotonic action of 3 was confirmed by using the doubly cyclometalated Ru(III) derivative [Ru(phpy)2(bpy)]Cl. The diverse rate variations induced by 3 accounted for acceleration by Ru(III) of the O2 reduction by the reduced form of glucose oxidase during the first phase, which ceases after the enzymatic reduction of Ru(III) to the Ru(II) species, the latter behaving similarly to 1a as the inhibitor of the enzyme. PMID- 23624808 TI - Central manipulation of dopamine receptors attenuates the orexigenic action of ghrelin. AB - OBJECTIVE: Recent evidence suggests that ghrelin, a peptidic hormone stimulating food intake, interacts with the dopamine signaling. This interaction has been demonstrated to modulate several effects of ghrelin, such as locomotor activity, memory, and food intake. Ghrelin increases dopamine levels in the shell of the nucleus accumbens stimulating food intake, while ablation of the ghrelin receptor attenuates the hypophagia caused by the activation of dopamine receptor 2. However, it is not known whether the orexigenic action of ghrelin is due to changes in central dopamine receptors. MATERIALS AND METHODS: We used Sprague Dawley rats injected with different dopamine receptor agonists, antagonists, and ghrelin. RESULTS: We demonstrate that the specific central blockade of dopamine receptor 1, 2, and 3 (D1, D2, and D3, respectively) reduces the orexigenic action of ghrelin. Similarly, specific central stimulation, either singly of dopamine receptor 1 or dopamine receptors 2 and 3 simultaneously, causes a significant decrease in ghrelin-induced food intake. Co-stimulation of all three receptors (D1, D2, and D3) also led to a marked attenuation in ghrelin-induced food intake. Importantly, the reduction in ghrelin-induced feeding was not caused by malaise or any type of behavioral alteration. CONCLUSION: Taken together, these data indicate that dopamine receptors play an important role in acute stimulation of feeding behavior induced by central injection of ghrelin. PMID- 23624809 TI - Effects of intravenous nicotine on prepulse inhibition in smokers and non smokers: relationship with familial smoking. AB - RATIONALE: The reinforcing properties of nicotine may be, in part, derived from its ability to enhance certain forms of cognitive processing. Several animal and human studies have shown that nicotine increases prepulse inhibition (PPI) of the startle reflex. However, it remains unclear whether these effects are related to smoking susceptibility. OBJECTIVES: The current study examined the effects of intravenously delivered nicotine on PPI in smokers and non-smokers, as well as its association with a quantitative index of familial smoking. METHODS: The sample consisted of 30 non-smokers and 16 smokers, who completed an initial assessment, followed on a separate day by a laboratory assessment of PPI prior to and following each of two intravenous nicotine infusions. Separate doses were used in smoker and non-smoker samples. RESULTS: Analyses indicated that both nicotine infusions acutely enhanced PPI among non-smokers, and this enhancement was positively related to the degree of smoking among first and second-degree relatives. Smokers also displayed PPI enhancement after receiving the first infusion, but this effect was unrelated to familial smoking. CONCLUSIONS: These data suggest that the PPI paradigm may have utility as an endophenotype for cognitive processes which contribute to smoking risk. PMID- 23624810 TI - Antiaggressive activity of central oxytocin in male rats. AB - RATIONALE: A substantial body of research suggests that the neuropeptide oxytocin promotes social affiliative behaviors in a wide range of animals including humans. However, its antiaggressive action has not been unequivocally demonstrated in male laboratory rodents. OBJECTIVE: Our primary goal was to examine the putative serenic effect of oxytocin in a feral strain (wild type Groningen, WTG) of rats that generally show a much broader variation and higher levels of intermale aggression than commonly used laboratory strains of rats. METHODS: Resident animals were intracerebroventricularly (icv) administered with different doses of synthetic oxytocin and oxytocin receptor antagonist, alone and in combination, in order to manipulate brain oxytocin functioning and to assess their behavioral response to an intruder. RESULTS: Our data clearly demonstrate that acute icv administered oxytocin produces dose-dependent and receptor selective changes in social behavior, reducing aggression and potentiating social exploration. These antiaggressive effects are stronger in the more offensive rats. On the other hand, administration of an oxytocin receptor antagonist tends to increase (nonsignificantly) aggression only in low-medium aggressive animals. CONCLUSIONS: These results suggest that transiently enhancing brain oxytocin function has potent antiaggressive effects, whereas its attenuation tends to enhance aggressiveness. In addition, a possible inverse relationship between trait aggression and endogenous oxytocinergic signaling is revealed. Overall, this study emphasizes the importance of brain oxytocinergic signaling for regulating intermale offensive aggression. This study supports the suggestion that oxytocin receptor agonists could clinically be useful for curbing heightened aggression seen in a range of neuropsychiatric disorders like antisocial personality disorder, autism, and addiction. PMID- 23624811 TI - High-affinity nicotinic acetylcholine receptor expression and trafficking abnormalities in psychiatric illness. AB - RATIONALE: Nicotinic acetylcholine receptors (nAChRs) are a critical component of the cholinergic system of neurotransmission in the brain that modulates important physiological processes such as reward, cognition, and mood. Abnormalities in this system are accordingly implicated in multiple psychiatric illnesses, including addiction, schizophrenia, and mood disorders. There is significantly increased tobacco use, and therefore nicotine intake, in patient populations, and pharmacological agents that act on various nicotinic receptor subtypes ameliorate clinical features of these disorders. Better understanding of the molecular mechanisms underlying cholinergic dysfunction in psychiatric disease will permit more targeted design of novel therapeutic agents. RESULTS: The objective of this review is to describe the multiple cellular pathways through which chronic nicotine exposure regulates nAChR expression, and to juxtapose these mechanisms with evidence for altered expression of high-affinity nAChRs in human psychiatric illness. Here, we summarize multiple studies from pre-clinical animal models to human in vivo imaging and post-mortem experiments demonstrating changes in nAChR regulation and expression in psychiatric illness. CONCLUSIONS: We conclude that a mechanistic explanation of nAChR abnormalities in psychiatric illness will arise from a fuller understanding of normal nAChR trafficking, along with the detailed study of human tissue, perhaps using novel biotechnological advances, such as induced pluripotent stem cells. PMID- 23624812 TI - Bacterial physiology: SofG and BacP keep bacteria moving. PMID- 23624813 TI - Organophosphonates revealed: new insights into the microbial metabolism of ancient molecules. AB - Organophosphonates are ancient molecules that contain the chemically stable C-P bond, which is considered a relic of the reducing atmosphere on primitive earth. Synthetic phosphonates now have a wide range of applications in the agricultural, chemical and pharmaceutical industries. However, the existence of C-P compounds as contemporary biogenic molecules was not discovered until 1959, with the identification of 2-aminoethylphosphonic acid in rumen protozoa. Here, we review advances in our understanding of the biochemistry and genetics of microbial phosphonate metabolism, and discuss the role of these compounds and of the organisms engaged in their turnover within the P cycle. PMID- 23624815 TI - An unexpected diagnosis in children with male phenotype and bilateral nonpalpable gonad: congenital adrenal hyperplasia with female genotype. AB - PURPOSE: Female pseudohermaphroditism is the most frequent form of ambiguous genitalia in children with congenital adrenal hyperplasia (CAH). However, a small group of children with complete urethral development in contrast to 46XX karyotype can be encountered. We aimed to define the characteristics of patients with 46XX CAH but having fully developed male external genitalia. METHODS: The records of 11 children with CAH and 46XX karyotype but having male phenotype, encountered from 1990 to 2012 were reviewed retrospectively. The age, presenting signs and symptoms, diagnostic studies, surgical procedures, early results and outcome were noted. All patients were evaluated by gender assignment team and the decision of the family was also taken into consideration during gender assignment. RESULTS: Eleven children (mean age 3.64 +/- 3 years) (range 5 days-10 years) were enrolled. The main presenting signs were nonpalpable gonads (n = 7), hyperpigmentation (n = 2), jaundice (n = 1) and electrolyte imbalance (n = 1). All patients had bilateral nonpalpable gonads and male phenotype with mean phallus length of 4.5 +/- 1.7 cm. Urethral meatus is located at normal position (n = 6) or hypospadiac (n = 5). Labioscrotal fusion was complete in all cases and they were classified as 4th (n = 3) or 5th (n = 8) degree of virilization according to Prader's classification. All children had CAH and 46XX genotype. Pelvic ultrasound (n = 8) and genitocystogram (n = 9) were used, and genitocystoscopy was performed (n = 6). Male gender was assigned in most (n = 10) and female gender in one. Corrective surgery could be performed in 10 patients. The surgical procedures were hysterectomy + bilateral salphingo-oophorectomy + vaginectomy (n = 9), chordee release (n = 3) and then second-stage (n = 2) or one stage urethra repair (n = 1), and pure one-stage urethra repair (n = 1). One case underwent surrenalectomy before the diagnosis of CAH. Mastectomy (n = 1) and fistula repair (n = 3) were additional operations. Only one child could be undergone feminizing genitoplasty and another was lost to follow-up. CONCLUSION: Unfortunately, most of the children underwent surgery in adverse to genotype because of constituted sexual identity. Children with male phenotype and bilateral nonpalpable gonads should undergo promptly biochemical analyses for CAH and early chromosomal analysis. PMID- 23624814 TI - Interplay between viruses and host sumoylation pathways. AB - Post-translational modification by members of the small ubiquitin-like modifier (SUMO) family of proteins is important for the regulation of many cellular proteins and pathways. As obligate parasites, viruses must engage with the host cell throughout their replication cycles, and it is therefore unsurprising that there are many examples of interplay between viral proteins and the host sumoylation system. This article reviews recent advances in this field, summarizing information on sumoylated viral proteins, the varied ways in which viruses engage with SUMO-related pathways, and the consequences of these interactions for viral replication and engagement with innate and intrinsic immunity. PMID- 23624816 TI - Comorbidity and outcomes after surgery among women with breast cancer: analysis of nationwide in-patient sample database. AB - To examine the effect of comorbidity on risk of postoperative complications, prolonged hospitalization (defined as above median length of stay), non-routine disposition, and in-patient death among women with breast cancer after surgery. Nationwide in-patient sample is a nationwide clinical and administrative database. Discharges of patients aged 40 years and older who underwent surgery for breast cancer from 2005 to 2009 were identified. Information about patients and hospitals characteristics were obtained. Comorbidities were identified and used to calculate Charlson comorbidity index (CCI) score. We divided patients based on these scores into four groups: 0, 1, 2, and >=3. Multivariate logistic regression analyses were used to examine risk adjusted association between CCI score and the aforementioned outcomes. We identified 70,536 patients' discharges. Compared to a CCI score of zero as a reference group, CCI scores of 1, 2, and >=3 increased the risk of post-operative complications by 1.7-fold, 2.6-fold, and 4.6 fold, respectively (p < 0.001). Patients with CCI scores of 1, 2, and >=3 had higher risk of non-routine disposition by 1.3-folds, 1.7-folds, and 2.2-folds, respectively (p < 0.001). Patients with CCI scores of 1, 2, and >=3 had higher risk of prolonged hospitalization by 1.2-folds, 1.6-folds, and 2.3-folds, respectively (p < 0.001). Similarly, CCI scores of 1, 2, and >=3 increased risk of in-patient death by 3.1-folds (p 0.05), 5.4-folds (p 0.008), and 15.8-folds (p < 0.001), respectively. Comorbidity associated with worse in-hospital outcomes among women with breast cancer after surgery. Effective control of comorbidity in breast cancer patients may reduce post-operative morbidity and mortality. PMID- 23624817 TI - Adiponectin pathway polymorphisms and risk of breast cancer in African Americans and Hispanics in the Women's Health Initiative. AB - Adiponectin, a protein secreted by the adipose tissue, is an endogenous insulin sensitizer with circulating levels that are decreased in obese and diabetic subjects. Recently, circulating levels of adiponectin have been correlated with breast cancer risk. Our previous work showed that polymorphisms of the adiponectin pathway are associated with breast cancer risk. We conducted the first study of adiponectin pathways in African Americans and Hispanics in the Women's Health Initiative SNP Health Association Resource cohort of 3,642 self identified Hispanic women and 8,515 self-identified African American women who provided consent for DNA analysis. Single nucleotide polymorphisms (SNPs) from three genes were included in this analysis: ADIPOQ, ADIPOR1, and ADIPOR2. The genome-wide human SNP array 6.0 (909,622 SNPs) ( www.affymetrix.com ) was used. We found that rs1501299, a functional SNP of ADIPOQ that we previously reported was associated with breast cancer risk in a mostly Caucasian population, was also significantly associated with breast cancer incidence (HR for the GG/TG genotype: 1.23; 95 % CI 1.059-1.43) in African American women. We did not find any other SNPs in these genes to be associated with breast cancer incidence. This is the first study assessing the role of adiponectin pathway SNPs in breast cancer risk in African Americans and Hispanics. RS1501299 is significantly associated with breast cancer risk in African American women. As the rates of obesity and diabetes increase in African Americans and Hispanics, adiponectin and its functional SNPs may aid in breast cancer risk assessment. PMID- 23624818 TI - Pretreatment levels of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers. AB - Immune signatures in breast tumors differ by estrogen receptor (ER) status. The purpose of this study was to assess associations between ER phenotypes and circulating levels of cytokines that co-ordinate cell-mediated [T-helper type 1 (Th1)] and humoral [T-helper type 2 (Th2)] immunity. We conducted a case-case comparison of 523 women with newly diagnosed breast cancer to evaluate associations between 27 circulating cytokines, measured using Luminex XMap technology, and breast cancer phenotypes [ER(-) vs. ER(+); triple negative breast cancer (TNBC) vs. luminal A (LumA)]. Ratios of Th1 to Th2 cytokines were also evaluated. Levels of interleukin (IL)-5, a Th-2 cytokine, were higher in ER(-) than in ER(+) tumors. The highest tertile of IL-5 was more strongly associated with ER(-) (OR = 2.33, 95 % CI 1.40-3.90) and TNBCs (OR = 2.78, 95 % CI 1.53 5.06) compared to ER(+) and LumA cancers, respectively, particularly among premenopausal women (OR = 4.17, 95 % CI 1.86-9.34, ER(-) vs. ER(+); OR = 5.60, 95 % CI 2.09-15.01, TNBC vs. LumA). Elevated Th1 cytokines were also detected in women with ER(-) and TNBCs, with women in the highest tertile of interferon alpha2 (OR = 2.39, 95 % CI 1.31-4.35) or tumor necrosis factor-alpha (OR = 2.27, 95 % CI 1.21-4.26) being twice as likely to have TNBC versus LumA cancer. When cytokine ratios were examined, women with the highest ratios of Th1 cytokines to IL-5 levels were least likely to have ER(-) or TNBCs compared to ER(+) or LumA cancers, respectively. The strongest associations were in premenopausal women, who were up to 80 % less likely to have TNBC than LumA cancers (IL-12p40/IL-5, OR = 0.19, 95 % CI 0.07-0.56). These findings indicate that immune function is associated with ER(-) and TNBC and may be most relevant among younger women, who are likely to be diagnosed with these aggressive phenotypes. PMID- 23624819 TI - Could 18F-FDG-PET/CT avoid unnecessary thyroidectomies in patients with cytological diagnosis of follicular neoplasm? AB - PURPOSE: Preoperative diagnosis of thyroid nodules with "follicular neoplasm" (FN) based on fine-needle aspiration cytology (FNAC) forces thyroidectomy to exclude malignancy. This study explores if (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) provides information enough to prevent unnecessary thyroidectomies in this clinical setting. METHODS: This is a prospective study involving 46 consecutive patients scheduled for thyroidectomy due to follicular neoplasm diagnosis in FNAC (36 follicular, 10 Hurthle cell neoplasms, Bethesda classification) since January 2009 until April 2012. All patients underwent preoperative (18)F-FDG-PET/CT. Abnormal (18)F-FDG thyroid uptake was assessed visually and by measuring the maximum standard uptake value (SUV max). Results were compared with definitive pathology reports. RESULTS: Thirteen out of 46 patients (28.3 %) were finally diagnosed with thyroid cancer. Focal uptake correlated with a greater risk of malignancy (p = 0.009). (18)F-FDG-PET/CT focal uptake showed sensitivity, specificity, positive and negative predictive values and overall accuracy of 92.3, 48.5, 41.4, 94.1 and 60.9 %, respectively. The optimal threshold SUV max to discriminate malignancy was 4.2 with an area under receiver-operating characteristic curve of 0.76 (95 % confidence interval, 0.60-0.90). Use of (18)F-FDG-PET/CT could reduce by 13-25 % the number of thyroidectomies performed for definitive benign nodules. However, it has demonstrated worse predictive ability in the subgroup of patients with diffuse uptake, oncocytic pattern in FNAC and lesions smaller than 2. CONCLUSIONS: (18)F-FDG-PET/CT can play a role in the management of thyroid nodules larger than 2 cm cytologically reported as follicular neoplasm without oncocytic differentiation, allowing the avoidance of a significant number of thyroidectomies for definitive benign lesions. PMID- 23624821 TI - Interleukin-15 administration increases graft-versus-tumor activity in recipients of haploidentical hematopoietic SCT. AB - Utilizing a clinically relevant haploidentical (HI) murine transplant model, lethally irradiated B6D2F1 (H2K(b/d)) mice were transplanted with T cell-depleted (TCD) BM from B6CBAF1 (H2K(b/k)) mice. We found that administration of IL-15 significantly increases the numbers of CD8+ T and natural killer (NK) cells in spleen and BM after transplantion without GVHD. Graft-versus-tumor (GVT) potency of the graft was evaluated upon tumor challenge using P815 tumor cells (H2(d)). IL-15 administration without T-cell infusion did not result in any survival improvement. However, IL-15 in combination with very low-dose T-cell infusion (1 * 10(4)) significantly increased GVT activity and improved survival in recipients of HI hematopoietic SCT (HSCT). This effect was observed when IL-15 was given at a later time point, rather than immediately following transplantation. IL-15 administration also specifically increased slow-proliferative CD8+ T-cell proliferation and IFN-gamma secretion in CD8+ T cells in recipients of CFSE (carboxyfluorescein succinimidyl ester)-labeled HI T-cell infusion, whereas there was no effect on CD4+ T-cell proliferation, suggesting the critical effect of IL 15 on CD8+ T-cell homeostasis in HI host. We conclude that IL-15 can be used for enhancing antileukemia effect of HI-HSCT, which requires presence of donor derived T cells. PMID- 23624822 TI - Crude extract of Ceriporia lacerata has a protective effect on dexamethasone induced cytotoxicity in INS-1 cells via the modulation of PI3K/PKB activity. AB - Excessive and/or long-term glucocorticoid therapy reduces beta-cell mass and induces hyperglycemia, which contribute to the development of steroid-induced diabetes. Ceriporia (C.) lacerata is one of the white-rot fungi and has been used in bioremediations, such as lignocellulose degradation, in nature. The pharmacologic effect of C. lacerata on steroid-induced beta-cell toxicity is not known. In this study, we evaluated the effect of a crude extract from a submerged cultivation of C. lacerata on the survival and apoptosis of INS-1 rat insulin secreting cells exposed to dexamethasone (Dex), a synthetic diabetogenic glucocorticoid. Treatment with the C. lacerata crude extract (CLCE) largely blocked the Dex-induced reduction in survival and apoptosis of INS-1 cells. Moreover, CLCE treatment inhibited Dex-induced protein kinase B (PKB) dephosphorylation without affecting Dex-induced extracellular signal-regulated protein kinase-1/2 dephosphorylation and MKP-1 upregulation. Importantly, the protective effect of CLCE on Dex-induced cytotoxicity in INS-1 cells was attenuated by LY294002, an inhibitor of PI3K/PKB. CLCE treatment, however, did not protect the INS-1 cells from the cytotoxic effects triggered by other insults, such as interleukin-1beta (an inflammatory cytokine), streptozotocin (a diabetogenic drug), thapsigargin (a calcium mobilizing agent), and tunicamycin (an ER stress inducer). Collectively, these findings demonstrate for the first time the ability of CLCE to specifically protect INS-1 cells from Dex-induced cytotoxicity through the modulation of the PI3K/PKB pathway. It is suggested that CLCE may be applied for the prevention and/or treatment of steroid diabetes in which reduction of beta-cell survival and induction of beta-cell apoptosis play pathogenic roles. PMID- 23624823 TI - Renal consequences of parenteral nutrition. AB - Parenteral nutrition (PN) can be described as the "Intravenous administration of nutrients necessary to sustain life in those who would otherwise have died or suffered serious disease". PN is indicated in children who cannot be fully fed by the oral or intestinal route, usually as a result of intestinal failure. Intradialytic parenteral nutrition (IDPN) is rarely indicated in children on dialysis and does not confer a benefit over enteral supplements in the compliant patient with adequate intestinal function. Renal and metabolic consequences of PN are potentially life-threatening and include disorders of glucose homeostasis, acid-base and fluid and electrolyte disturbances, nephrolithiasis, impaired renal function and metabolic bone disease. Many of these complications are avoidable. Adequate clinical and biochemical assessment and monitoring of children receiving PN by a multidisciplinary nutrition support team is recommended to mitigate against the risks of these complications. PMID- 23624824 TI - Inhibition of ROS-activated p38MAPK pathway is involved in the protective effect of H2S against chemical hypoxia-induced inflammation in PC12 cells. AB - We have demonstrated the neuroprotection of hydrogen sulfide (H2S) against chemical hypoxia-induced injury by inhibiting p38MAPK pathway. The present study attempts to evaluate the effect of H2S on chemical hypoxia-induced inflammation responses and its mechanisms in PC12 cells. We found that treatment of PC12 cells with cobalt chloride (CoCl2, a hypoxia mimetic agent) enhanced IL-6 secretion, nitric oxide (NO) generation and expression levels of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS). L-canavanine, a selective iNOS inhibitor, partly blocked CoCl2-induced cytotoxicity, apoptosis and mitochondrial insult. In addition, 7-Nitroindazole (7-NI), an inhibitor of nNOS, also partly attenuated the CoCl2-induced cytotoxicity. The inhibition of p38MAPK by SB203580 (a selective p38MAPK inhibitor) or genetic silencing of p38MAPK by RNAi (Si-p38) depressed not only CoCl2-induced iNOS expression, NO production, but also IL-6 secretion. In addition, N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger, conferred a similar protective effect of SB203580 or Si-p38 against CoCl2-induced inflammatory responses. Importantly, pretreatment of PC12 cells with exogenous application of sodium hydrosulfide (a H2S donor, 400 MUmol/l) for 30 min before exposure to CoCl2 markedly attenuated chemical hypoxia stimulated iNOS and nNOS expression, NO generation and IL-6 secretion as well as p38MAPK phosphorylation in PC12 cells. Taken together, we demonstrated that p38MAPK-iNOS pathway contributes to chemical hypoxia-induced inflammation and that H2S produces an anti-inflammatory effect in chemical hypoxia-stimulated PC12 cells, which may be partly due to inhibition of ROS-activated p38MAPK-iNOS pathway. PMID- 23624825 TI - The activity of class I, II, III and IV of alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) in brain cancer. AB - The brain being highly sensitive to the action of alcohol is potentially susceptible to its carcinogenic effects. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the main enzymes involved in ethanol metabolism, which leads to the generation of carcinogenic acetaldehyde. Human brain tissue contains various ADH isoenzymes and possess also ALDH activity. The purpose of this study was to compare the capacity for ethanol metabolism measured by ADH isoenzymes and ALDH activity in cancer tissues and healthy brain cells. The samples were taken from 62 brain cancer patients (36 glioblastoma, 26 meningioma). For the measurement of the activity of class I and II ADH isoenzymes and ALDH activity, the fluorometric methods were used. The total ADH activity and activity of class III and IV isoenzymes were measured by the photometric method. The total activity of ADH, and activity of class I ADH were significantly higher in cancer cells than in healthy tissues. The other tested classes of ADH and ALDH did not show statistically significant differences of activity in cancer and in normal cells. Analysis of the enzymes activity did not show significant differences depending on the location of the tumor. The differences in the activity of total alcohol dehydrogenase, and class I isoenzyme between cancer tissues and healthy brain cells might be a factor for metabolic changes and disturbances in low mature cancer cells and additionally might be a reason for higher level of acetaldehyde which can intensify the carcinogenesis. PMID- 23624826 TI - Activation of AMP-activated protein kinase alleviates homocysteine-mediated neurotoxicity in SH-SY5Y cells. AB - Mammalian AMP-activated protein kinase (AMPK) acts as a metabolite-sensing protein kinase in multiple tissues. Recent studies have shown that AMPK activation also regulates intracellular signaling pathways involved in cellular survival and apoptosis. Previously, we have reported that AMPK activation alleviates the endoplasmic reticulum (ER) stress-mediated neurotoxicity and tau hyperphosphorylation caused by palmitate. Therefore, we investigated whether AMPK activation alleviates ER stress-mediated neurotoxicity in SH-SY5Y human neuroblastoma cells incubated with homocysteine. Regulation of AMPK activity by isoflavone was also determined to investigate the underlying mechanism of its neuroprotective effect. Treatment of SH-SY5Y human neuroblastoma cells with N (1) (beta-D-ribofuranosyl)-5-aminoimidazole-4-carboxamide (AICAR), a pharmacological activator of AMPK, significantly protected cells against cytotoxicity imposed by tunicamycin and homocysteine. Homocysteine significantly suppressed AMPK activation, which was alleviated by AICAR. We observed a significant inhibition of the unfolded protein response by AICAR in cells incubated with homocysteine, suggesting a protective role of AMPK activation against ER stress-mediated neurotoxicity. AICAR also significantly reduced tau hyperphosphorylation by inactivating glycogen synthase kinase-3beta and c-Jun N-terminal kinase in cells incubated with homocysteine. Furthermore, treatment of cells with soy isoflavone, genistein and daidzein significantly activated AMPK, which was repressed by tunicamycin and homocysteine. Therefore, our results suggest that AMPK activation by isoflavone as well as AICAR alleviates homocysteine-mediated neurotoxicity in SH-SY5Y cells. PMID- 23624827 TI - Telmisartan ameliorates neurotrophic support and oxidative stress in the retina of streptozotocin-induced diabetic rats. AB - Neurodegeneration is an early event in the diabetic retina which may lead to diabetic retinopathy. One of the potential pathways in damaging retinal neurons is the activation of renin angiotensin system including angiotensin II type 1 receptor (AT1R) in the diabetic retina. The purpose of this study was to determine the effect of telmisartan, an AT1R blocker on retinal level of brain derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and tyrosine hydroxylase (TH), glutathione (GSH) and caspase activity in the diabetic rats. The dysregulated levels of these factors are known to cause neurodegeneration in diabetic retina. Three weeks streptozotocin induced diabetic rats were orally treated or untreated with telmisartan (10 mg/kg/day). After 4 weeks of treatments, the levels of BDNF and GSH were found to be increased systemically in the sera as well as in the retina of diabetic rats compared to untreated rats as measured by enzyme-linked immunosorbent assay and biochemical techniques (p < 0.05). The caspase-3 activity in the telmisartan treated diabetic retina was decreased compared to untreated diabetic rats (p < 0.05). Western blotting experiments showed the expression levels of BDNF, CNTF and TH were increased compared to untreated diabetic rats (p < 0.05). Thus, our findings show a beneficial effect of AT1R blocker telmisartan in efficiently increasing neurotrophic support, endogenous antioxidant GSH content, and decreasing signs of apoptosis in diabetic retina. PMID- 23624828 TI - Antitumor effects of a novel histone deacetylase inhibitor NK-HDAC-1 on breast cancer. AB - Histone deacetylases (HDACs) are overexpressed in various types of primary human cancer and have become attractive targets for cancer therapy. We designed and synthesized a series of new class of HDAC inhibitors (HDACi). Among these, S-(E) 3-(1-(1-(benzo[d]oxazol-2-yl)-2-methylpropyl)-1H-1,2,3-triazol-4-yl)-N hydroxyacrylamide (NK-HDAC-1) showed potent antitumor activity. In the present study, we examined the antitumor effects of NK-HDAC-1 on breast cancer in vitro and in vivo. The inhibitory effects of NK-HDAC-1 on HDAC enzyme activity and cell growth were more potent compared to suberoylanilide hydroxamic acid (SAHA). NK HDAC-1 caused G1 cell cycle arrest at concentrations below 0.2 uM and G2/M arrest at concentrations above 0.4 uM through p21 upregulation and cyclin D1 downregulation. NK-HADC-1 induced hyperacetylation of histone H3 and H4 around the promoter region of p21. NK-HDAC-1 promoted apoptosis in MDA-MB-231 breast cancer cells by activating both the intrinsic and the extrinsic pathway NK-HDAC-1 at doses of 3, 10 and 30 mg/kg reduced the tumor volume in MDA-MB-231 xenografts by 25.9, 48.8 and 63.6%, respectively. The results suggested that NK-HDAC-1 may be a promising therapeutic candidate in treating human breast cancer. PMID- 23624829 TI - Ionic Ni(II) complexes containing a triphenylphosphine ligand and an imidazolium cation: synthesis, structures and catalysis for aryl Grignard cross-coupling of aryl halides. AB - Novel ionic Ni(II) complexes of general formula [R2im][Ni(PPh3)Cl3] (R2im = 1,3 bis(2,6-diisopropylphenyl)imidazolium cation, IPrim, 1a; R2im = 1,3 diisopropylimidazolium cation, (i)Prim, 2a) were easily prepared in high yields by the direct reaction of Ni(PPh3)2Cl2 with 1 equiv. of N,N' dihydrocarbylimidazolium salt, [R2im]Cl. Their bromide analogs [R2im][Ni(PPh3)Br3] (R2im = IPrim, 1b; R2im = (i)Prim, 2b) were synthesized by the same reaction in the presence of excess NaBr. The reaction of Ni(DME)Cl2 (DME = 1,2-dimethoxyethane) with 2 equiv. of [IPrim]Cl led to the formation of the complex [IPrim]2[NiCl4] (3) in an almost quantitative yield. All these complexes were characterized by elemental analysis, electrospray ionization mass spectrometry (ESI-MS), and (1)H NMR spectroscopy; X-ray crystallography was performed for 1a, 1b, 2a, and 2b. A catalytic study of the cross-coupling reactions of aryl Grignard reagents with aryl halides revealed that complexes 1a and 1b possessed the highest activities. In comparison, complexes 2a, 2b, 3, and the related biscarbene Ni(II) complex Ni(IPr)2Cl2 [IPr = 1,3-bis(2,6 diisopropylphenyl)imidazol-2-ylidene] exhibited moderate activities; the least active complexes were Ni(PPh3)2Cl2 and [NEt4][Ni(PPh3)Cl3]. PMID- 23624830 TI - On becoming a coach: a pilot intervention study with managers in long-term care. AB - BACKGROUND: Health care leaders have called for the development of communication and leadership skills to improve manager-employee relationships, employee job satisfaction, quality care, and work environments. PURPOSES: The aim of the study reported here was to pilot how a 2-day coaching workshop ("Coaching for Impressive CARE") conducted as a leadership development strategy influenced frontline care managers' coaching practices in residential long-term care (LTC) settings. We had four objectives: (a) to identify managers' perceptions of their role as a coach of employee performance in LTC facilities, (b) to understand managers' intentions to coach employee performance, (c) to examine opportunities and factors that contributed to or challenged implementation of workshop coaching skills in daily leadership/management practice, and (d) to examine managers' reports of using coaching practices and employee responses after the workshop. METHODS: We used an exploratory/descriptive design involving pre-/post-workshop surveys, e-mail reminders, and focus groups to examine participation of 21 LTC managers in a 2-day coaching workshop and their use of coaching practices in the workplace. FINDINGS: Focus group findings provided examples of how participants used their coaching skills in practice (e.g., communicating empathy) and how staff responded. Factors contributing to and challenging implementation of these coaching skills in the workplace were identified. Attitudes and intentions to be a coach increased significantly, and some coaching skills were used more frequently after the workshop, specifically planning for performance change with employees. PRACTICE IMPLICATIONS: The coaching workshop was feasible to implement, well received by participants, influenced their willingness to become coaches, and had some noted impact on their use of coaching behaviors in the workplace. Coaching skills by managers to improve staff performance with residents in LTC facilities can be learned. PMID- 23624831 TI - Corporate governance and the adoption of health information technology within integrated delivery systems. AB - BACKGROUND: Although several previous studies have found "system affiliation" to be a significant and positive predictor of health information technology (IT) adoption, little is known about the association between corporate governance practices and adoption of IT within U.S. integrated delivery systems (IDSs). PURPOSES: Rooted in agency theory and corporate governance research, this study examines the association between corporate governance practices (centralization of IT decision rights and strategic alignment between business and IT strategy) and IT adoption, standardization, and innovation within IDSs. METHODOLOGY/APPROACH: Cross-sectional, retrospective analyses using data from the 2011 Health Information and Management Systems Society Analytics Database on adoption within IDSs (N = 485) is used to analyze the correlation between two corporate governance constructs (centralization of IT decision rights and strategic alignment) and three IT constructs (adoption, standardization, and innovation) for clinical and supply chain IT. Multivariate fractional logit, probit, and negative binomial regressions are applied. FINDINGS: Multivariate regressions controlling for IDS and market characteristics find that measures of IT adoption, IT standardization, and innovative IT adoption are significantly associated with centralization of IT decision rights and strategic alignment. Specifically, centralization of IT decision rights is associated with 22% higher adoption of Bar Coding for Materials Management and 30%-35% fewer IT vendors for Clinical Data Repositories and Materials Management Information Systems. A combination of centralization and clinical IT strategic alignment is associated with 50% higher Computerized Physician Order Entry adoption, and centralization along with supply chain IT strategic alignment is significantly negatively correlated with Radio Frequency Identification adoption PRACTICE IMPLICATIONS: : Although IT adoption and standardization are likely to benefit from corporate governance practices within IDSs, innovation is likely to be delayed. In addition, corporate governance is not one-size-fits-all, and contingencies are important considerations. PMID- 23624832 TI - Correlates and risk markers for sleep disturbance in participants of the Autism Treatment Network. AB - We explored possible cognitive, behavioral, emotional, and physiological risk markers for sleep disturbance in children with autism spectrum disorders. Data from 1,583 children in the Autism Treatment Network were analyzed. Approximately 45 potential predictors were analyzed using hierarchical regression modeling. As medication could confound findings, it was included in the analyses as a covariate. Results revealed that anxiety, autism symptom severity, sensory sensitivities, and GI problems were associated with sleep disturbance. IQ positively predicted sleep disturbance, and children with Asperger's Disorder were more vulnerable than others. The amount of variance in sleep outcomes explained by predictor variables was modest (i.e., R (2) from .104 to .201). Predictor variables were evaluated in the context of a bidirectional theoretical framework. PMID- 23624833 TI - Multisensory speech perception in children with autism spectrum disorders. AB - This study examined unisensory and multisensory speech perception in 8-17 year old children with autism spectrum disorders (ASD) and typically developing controls matched on chronological age, sex, and IQ. Consonant-vowel syllables were presented in visual only, auditory only, matched audiovisual, and mismatched audiovisual ("McGurk") conditions. Participants with ASD displayed deficits in visual only and matched audiovisual speech perception. Additionally, children with ASD reported a visual influence on heard speech in response to mismatched audiovisual syllables over a wider window of time relative to controls. Correlational analyses revealed associations between multisensory speech perception, communicative characteristics, and responses to sensory stimuli in ASD. Results suggest atypical speech perception is linked to broader behavioral characteristics of ASD. PMID- 23624834 TI - Transmission of macrolide-resistant Mycoplasma pneumoniae within a family. AB - Outbreaks of Mycoplasma pneumoniae have occurred in closed surroundings, including among families, university students, in military camps, and in schools, but available data on outbreaks of macrolide-resistant (MR) M. pneumoniae are limited. We encountered a family outbreak of MR M. pneumoniae pneumonia in four sisters (16, 14, 10, and 8 years of age). M. pneumoniae was isolated from all four patients, and an A-to-G transition at position 2063 in domain V of the 23S rRNA gene was identified. Although three of four patients received azithromycin, which is the first-choice antimycoplasmal agent, this agent was not effective. All isolates had an identical antibiotic susceptibility pattern. The MIC values for 14- and 15-membered macrolides, such as erythromycin, clarithromycin, and azithromycin, were >128, >128, and 64 MUg/ml, respectively. On admission, all four patients were diagnosed with suspected M. pneumoniae pneumonia using the Japanese Respiratory Society (JRS) guidelines scoring system. We carried out culture and polymerase chain reaction tests for the detection of M. pneumoniae in their parents (mother, 49 years old, and father, 56 years old) four times, but no M. pneumoniae organism was detected using either test. In conclusion, MR M. pneumoniae strains can occur in outbreaks in closed surroundings, such as within families, as well as macrolide-sensitive strains. To prevent outbreaks of M. pneumoniae infection, especially MR M. pneumoniae, in closed populations, physicians should pay careful attention to the potential occurrence of infections involving MR M. pneumoniae. PMID- 23624835 TI - Genetic and physical interactions between the yeast ELG1 gene and orthologs of the Fanconi anemia pathway. AB - Fanconi anemia (FA) is a human syndrome characterized by genomic instability and increased incidence of cancer. FA is a genetically heterogeneous disease caused by mutations in at least 15 different genes; several of these genes are conserved in the yeast Saccharomyces cerevisiae. Elg1 is also a conserved protein that forms an RFC-like complex, which interacts with SUMOylated PCNA. The mammalian Elg1 protein has been recently found to interact with the FA complex. Here we analyze the genetic interactions between elg1Delta and mutants of the yeast FA like pathway. We show that Elg1 physically contacts the Mhf1/Mhf2 histone-like complex and genetically interacts with MPH1 (ortholog of the FANCM helicase) and CHL1 (ortholog of the FANCJ helicase) genes. We analyze the sensitivity of double, triple, quadruple and quintuple mutants to methylmethane sulfonate (MMS) and to hydroxyurea (HU). Our results show that genetic interactions depend on the type of DNA damaging agent used and show a hierarchy: Chl1 and Elg1 play major roles in the survival to these genotoxins and exhibit synthetic fitness reduction. Mph1 plays a lesser role, and the effect of the Mhf1/2 complex is seen only in the absence of Elg1 on HU-containing medium. Finally, we dissect the relationship between yeast FA-like mutants and the replication clamp, PCNA. Our results point to an intricate network of interactions rather than a single, linear repair pathway. PMID- 23624837 TI - A new path to oncogene-induced senescence: at the crossroads of splicing and translation. PMID- 23624836 TI - A non-canonical mode of microtubule organization operates throughout pre implantation development in mouse. AB - In dividing animal cells, the centrosome, comprising centrioles and surrounding pericentriolar-material (PCM), is the major interphase microtubule-organizing center (MTOC), arranging a polarized array of microtubules (MTs) that controls cellular architecture. The mouse embryo is a unique setting for investigating the role of centrosomes in MT organization, since the early embryo is acentrosomal, and centrosomes emerge de novo during early cleavages. Here we use embryos from a GFP::CETN2 transgenic mouse to observe the emergence of centrosomes and centrioles in embryos, and show that unfocused acentriolar centrosomes first form in morulae (~16-32-cell stage) and become focused at the blastocyst stage (~64 128 cells) concomitant with the emergence of centrioles. We then used high resolution microscopy and dynamic tracking of MT growth events in live embryos to examine the impact of centrosome emergence upon interphase MT dynamics. We report that pre-implantation mouse embryos of all stages employ a non-canonical mode of MT organization that generates a complex array of randomly oriented MTs that are preferentially nucleated adjacent to nuclear and plasmalemmal membranes and cell cell interfaces. Surprisingly, however, cells of the early embryo continue to employ this mode of interphase MT organization even after the emergence of centrosomes. Centrosomes are found at MT-sparse sites and have no detectable impact upon interphase MT dynamics. To our knowledge, the early embryo is unique among proliferating cells in adopting an acentrosomal mode of MT organization despite the presence of centrosomes, revealing that the transition to a canonical mode of interphase MT organization remains incomplete prior to implantation. PMID- 23624838 TI - Oncogene interference through targeting of chromatin regulators. PMID- 23624839 TI - Arsenic reverses glioblastoma resistance to mTOR-targeted therapies. PMID- 23624840 TI - Dynamic changes in the genomic localization of DNA replication-related element binding factor during the cell cycle. AB - DREF was first characterized for its role in the regulation of transcription of genes encoding proteins involved in DNA replication and found to interact with sequences similar to the DNA recognition motif of the BEAF-32 insulator protein. Insulators are DNA-protein complexes that mediate intra- and inter-chromosome interactions. Several DNA-binding insulator proteins have been described in Drosophila, including BEAF-32, dCTCF and Su(Hw). Here we find that DREF and BEAF 32 co-localize at the same genomic sites, but their enrichment shows an inverse correlation. Furthermore, DREF co-localizes in the genome with other insulator proteins, suggesting that the function of this protein may require components of Drosophila insulators. This is supported by the finding that mutations in insulator proteins modulate DREF-induced cell proliferation. DREF persists bound to chromatin during mitosis at a subset of sites where it also co-localizes with dCTCF, BEAF-32 and CP190. These sites are highly enriched for sites where Orc2 and Mcm2 are present during interphase and at the borders of topological domains of chromosomes defined by Hi-C. The results suggest that DREF and insulator proteins may help maintain chromosome organization during the cell cycle and mark a subset of genomic sites for the assembly of pre-replication complexes and gene bookmarking during the M/G1 transition. PMID- 23624841 TI - Deletion of p21/Cdkn1a confers protective effect against prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate model. AB - Cyclin-dependent kinase inhibitors (CDKIs) p21(Cip1/Waf1) (p21) and p27(Kip1) (p27) play a determining role in cell cycle progression by regulating CDK activity; however, p21 role in prostate cancer (PCa) is controversial. Whereas p21 upregulation by anticancer agents causes cell cycle arrest in various PCa cell lines, elevated p21 levels have been associated with higher Gleason score, poor survival and increased PCa recurrence. These conflicting findings suggest that more studies are needed to examine p21 role in PCa. Herein, employing genetic approach, transgenic mice harboring p21/Cdkn1a homozygous deletion (p21( /-)) were crossed with the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice to characterize in vivo consequences of p21 deletion on prostate tumorigenesis. Lower urogenital tract weight of p21(-/-)/TRAMP mice was significantly lower than those of p21(+/-)/TRAMP and TRAMP mice. Histopathology further supported these observations, showing less aggressiveness in prostates of p21(-/-)/TRAMP. Furthermore, a significantly higher incidence of low-grade prostatic intraepithelial lesions (PIN) with a concomitant reduction in adenocarcinoma incidence was observed in p21(-/-)/TRAMP mice compared with TRAMP mice. In addition, whereas TRAMP mice showed the presence of poorly differentiated adenocarcinoma lesions, no such lesions were observed in p21/TRAMP transgenic mice. Specifically, there was a significant reduction in the severity of lesions in both p21(-/-)/TRAMP and p21(+/-)/TRAMP mice compared with TRAMP mice. Together, our data showed that p21 deletion reduces prostate tumorigenesis by slowing-down progression of PIN (pre-malignant) to adenocarcinoma (malignant), suggesting that intact p21 expression is associated with PCa aggressiveness, while its decreased levels may in fact confer protection against prostate tumorigenesis. PMID- 23624842 TI - Centromere fragmentation is a common mitotic defect of S and G2 checkpoint override. AB - DNA damaging agents, including those used in the clinic, activate cell cycle checkpoints, which blocks entry into mitosis. Given that checkpoint override results in cell death via mitotic catastrophe, inhibitors of the DNA damage checkpoint are actively being pursued as chemosensitization agents. Here we explored the effects of gemcitabine in combination with Chk1 inhibitors in a panel of pancreatic cancer cell lines and found variable abilities to override the S phase checkpoint. In cells that were able to enter mitosis, the chromatin was extensively fragmented, as assessed by metaphase spreads and Comet assay. Notably, electron microscopy and high-resolution light microscopy showed that the kinetochores and centromeres appeared to be detached from the chromatin mass, in a manner reminiscent of mitosis with unreplicated genomes (MUGs). Cell lines that were unable to override the S phase checkpoint were able to override a G2 arrest induced by the alkylator MMS or the topoisomerase II inhibitors doxorubicin or etoposide. Interestingly, checkpoint override from the topoisomerase II inhibitors generated fragmented kinetochores (MUGs) due to unreplicated centromeres. Our studies show that kinetochore and centromere fragmentation is a defining feature of checkpoint override and suggests that loss of cell viability is due in part to acentric genomes. Furthermore, given the greater efficacy of forcing cells into premature mitosis from topoisomerase II-mediated arrest as compared with gemcitabine-mediated arrest, topoisomerase II inhibitors maybe more suitable when used in combination with checkpoint inhibitors. PMID- 23624843 TI - p53 regulates nuclear GSK-3 levels through miR-34-mediated Axin2 suppression in colorectal cancer cells. AB - p53 is a bona fide tumor suppressor gene whose loss of function marks the most common genetic alteration in human malignancy. Although the causal link between loss of p53 function and tumorigenesis has been clearly demonstrated, the mechanistic links by which loss of p53 potentiates oncogenic signaling are not fully understood. Recent evidence indicates that the microRNA-34 (miR-34) family, a transcriptional target of the p53, directly suppresses a set of canonical Wnt genes and Snail, resulting in p53-mediated suppression of Wnt signaling and the EMT process. In this study, we report that p53 regulates GSK-3beta nuclear localization via miR-34-mediated suppression of Axin2 in colorectal cancer. Exogenous miR-34a decreases Axin2 UTR-reporter activity through multiple binding sites within the 5' and 3' UTR of Axin2. Suppression of Axin2 by p53 or miR-34 increases nuclear GSK-3beta abundance and leads to decreased Snail expression in colorectal cancer cells. Conversely, expression of the non-coding UTR of Axin2 causes depletion of endogenous miR-34 via the miR-sponge effect together with increased Axin2 function, supporting that the RNA-RNA interactions with Axin2 transcripts act as an endogenous decoy for miR-34. Further, RNA transcripts of miR-34 target were correlated with Axin2 in clinical data set of colorectal cancer patients. Although the biological relevance of nuclear GSK-3 level has not been fully studied, our results demonstrate that the tumor suppressor p53/miR-34 axis plays a role in regulating nuclear GSK-3 levels and Wnt signaling through the non-coding UTR of Axin2 in colorectal cancer. PMID- 23624844 TI - Gene expression is highly correlated on the chromosome level in urinary bladder cancer. AB - OBJECTIVE: Chromosome correlation maps display correlations between gene expression patterns on the same chromosome. Our goal was to map the genes on chromosome regions and to identify correlations through their location on chromosome regions. MATERIALS AND METHODS: Following microarray analysis we used Ingenuity Pathway Analysis (IPA) to construct gene networks of the co-deregulated genes in bladder cancer. Chromosome mapping, mathematical modeling and data simulations were performed using the WebGestalt and Matlab((r)) softwares. RESULTS: The top deregulated molecules among 129 bladder cancer samples were implicated in the PI3K/AKT signaling, cell cycle, Myc-mediated apoptosis signaling and ERK5 signaling pathways. Their most prominent molecular and cellular functions were related to cell cycle, cell death, gene expression, molecular transport and cellular growth and proliferation. Chromosome correlation maps allowed us to detect significantly co-expressed genes along the chromosomes. We identified strong correlations among tumors of Talpha-grade 1, as well as for those of Talpha-grade 2, in chromosomes 1, 2, 3, 7, 12 and 19. Chromosomal domains of gene co-expression were revealed for the normal tissues, as well. The expression data were further simulated, exhibiting an excellent fit (0.7 < R(2) < 0.9). The simulations revealed that along the different samples, genes on same chromosomes are expressed in a similar manner. CONCLUSIONS: Gene expression is highly correlated on the chromosome level. Chromosome correlation maps of gene expression signatures can provide further information on gene regulatory mechanisms. Gene expression data can be simulated using polynomial functions. PMID- 23624845 TI - Improvement of mannitol production by Lactobacillus brevis mutant 3-A5 based on dual-stage pH control and fed-batch fermentations. AB - Lactobacillus brevis 3-A5 was isolated and expected to produce mannitol efficiently by regulating pH in batch and fed-batch fermentations. In 48 h batch fermentations with free and constant pH, the optimal pH for cell growth and mannitol production in the first 24 h of incubation was 5.5, whereas that for mannitol production in the second 24 h of incubation was 4.5. To achieve high cell density and mannitol yield simultaneously, a dual-stage pH control strategy was proposed based on the kinetic analysis of mannitol production. The pH value was controlled at 5.5 for the first 12 h of fermentation and subsequently shifted to 4.5 until the fermentation was completed. Under dual-stage pH control fermentation, a 103 g/L yield of mannitol with a volumetric production rate of 3.7 g/L/h was achieved after 28 h. The dual-stage pH control fed-batch fermentation strategy was further developed to improve mannitol yield, wherein the yield increased by 109 % to 215 g/L after 98 h of fermentation. This value is the highest yield of mannitol ever reported using L. brevis. PMID- 23624846 TI - Bone formation within the articular cartilage of the lateral compartment of varus osteoarthritic knees. AB - BACKGROUND: One of the causes of failure after unicompartmental knee arthroplasty (UKA) for varus osteoarthritis is the progression of osteoarthritis in the lateral compartment. Bone formation within the articular cartilage has been reported as a possible cause of the deterioration of the osteoarthritis. However, its prevalence and histology are still uncertain. The purpose of the current study is to investigate bone pieces obtained from the lateral compartment of the knee during total knee arthroplasty (TKA) radiographically and histopathologically, and to examine the bone formation within the articular cartilage in detail. METHODS: Thirty-four consecutive patients, who underwent TKA for varus osteoarthritis of the knee, were included in this study. There were 6 males and 28 females and the mean age at the surgery was 74 years (range 63-85 years). Fifty-seven and 99 sagittal slabs were acquired from the resected bone pieces of the distal lateral femoral condyle and lateral tibial plateau, respectively. These slabs were investigated by soft X-ray radiographs and histopathological analyses stained with hematoxylin-eosin and elastica-Masson. RESULTS: On soft X-ray radiographs, bone formation (in which bone trabeculae were clearly detected) within the articular cartilage was observed in 8 (14.0%) of 57 femoral slabs and 7 (7.1%) of 99 tibial slabs. Histopathological analyses revealed that the bone which had formed comprised normal trabeculae and fatty marrow. There was rich vascularity in the cartilage around the formed bone. CONCLUSIONS: The current study is the first to describe the prevalence, location, and histopathological findings of bone formation within the articular cartilage of the lateral compartment of varus osteoarthritic knees. Since the thickness of the cartilage covering the bone formation is less than that without it, it may result in the deterioration of the lateral compartment after UKA. PMID- 23624847 TI - In-vivo transfection of the proopiomelanocortin gene, precursor of endogenous endorphin, by use of radial shock waves alleviates neuropathic pain. AB - BACKGROUND: Neuropathic pain is difficult to control and patient response to current treatment is often inadequate. Opioids have been widely used to treat a variety of pain states, but have several side effects. Endogenous opioids are clinically safe, but are not used for treatment because of rapid metabolism. However, in-vivo transfection of endogenous opioid genes could have a powerful and safe analgesic effect. The purpose of this study was to investigate the efficacy of proopiomelanocortin (POMC, a precursor of the endogenous opioid peptide beta-endorphin) gene transfer by use of radial shock waves (RSWs) in a rat neuropathic pain model. METHODS: As a neuropathic pain model, we used the Bennett chronic constriction injury (CCI) method. Immediately after CCI induction, POMC plasmid was injected into the rats' gastrocnemius muscle followed by exposure to RSW. Mechanical allodynia was measured for 4 weeks and dorsal root ganglion (DRG) neurons were sectioned and immunostained. RESULTS: beta-Endorphin blood levels and the number of beta-endorphin-immunoreactive (IR) muscle fibers increased over 28 days. beta-Endorphin overexpression caused a decrease in the number of calcitonin gene-related peptide (CGRP)-IR DRG neurons and suppressed neuropathic pain induced by CCI without causing adverse side effects. The size distribution pattern of CGRP-IR DRG neurons shifted from small to large cells in the CCI group; however, the number of both small and large CGRP-IR cells decreased in the POMC group. CONCLUSION: POMC gene transfection alleviated allodynia and reduced CGRP expression in DRG neurons without adverse effects. CGRP is not produced in large neurons under physiologic conditions; however, in this study CGRP expression was shifted to large neurons after nerve injury. This change in cell-size distribution suggests that CGRP expression in large neurons is related to neuropathic pain. These findings suggest that POMC gene transfection using RSWs is a safe and effective treatment for neuropathic pain. PMID- 23624848 TI - Uninsurance, underinsurance, and health care utilization in Mexico by US border residents. AB - Using data from the 2008 Cross-Border Utilization of Health Care Survey, we examined the relationship between United States (US) health insurance coverage plans and the use of health care services in Mexico by US residents of the US Mexico border region. We found immigrants were far more likely to be uninsured than their native-born counterparts (63 vs. 27.8 %). Adults without health insurance coverage were more likely to purchase medications or visit physicians in Mexico compared to insured adults. However, adults with Medicaid coverage were more likely to visit dentists in Mexico compared to uninsured adults. Improving health care access for US residents in the southwestern border region of the country will require initiatives that target not only providing coverage to the large uninsured population but also improving access to health care services for the large underinsured population. PMID- 23624849 TI - Exploring HIV knowledge, risk and protective factors among west African forced migrants in New York City. AB - Because of ongoing political and social instability throughout the continent, many Africans have become forced migrants. Unlike immigrants who choose to migrate, forced migrants flee their countries in search of safety and often endure multiple traumatic events during their migration. They are often unprepared for new risks in their adopted country. There is a high incidence of newly-diagnosed HIV cases among West African immigrants in the New York City metropolitan area, but little research to date to understand why this might occur. In order to gain insight, the current pilot study explored HIV knowledge, risk and protective behaviors among 52 West African-born forced migrants in New York City. HIV risk behavior came primarily from unprotected heterosexual activities. While most participants were very knowledgeable about HIV transmission and risk factors, almost half reported that they had not used condoms during sexual activities in the past 6 months. Women were more knowledgeable about HIV transmission, yet reported significantly more STDs than men. Many participants did not know about HIV/AIDS treatments and could not identify HIV/AIDS services and resources within their immigrant communities. Factors influencing HIV risk and protective behaviors among this population are identified and discussed. Suggestions for future research and strategies to reduce risky behaviors while enhancing protective ones among forced West African migrants are highlighted. PMID- 23624850 TI - Structural modifications of (Z)-3-(2-aminoethyl)-5-(4 ethoxybenzylidene)thiazolidine-2,4-dione that improve selectivity for inhibiting the proliferation of melanoma cells containing active ERK signaling. AB - We herein report on the pharmacophore determination of the ERK docking domain inhibitor (Z)-3-(2-aminoethyl)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione, which has led to the discovery of compounds with greater selectivities for inhibiting the proliferation of melanoma cells containing active ERK signaling. PMID- 23624851 TI - Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients. AB - First-generation, E1-deleted adenovirus subtype 5 (Ad5)-based vectors, although promising platforms for use as cancer vaccines, are impeded in activity by naturally occurring or induced Ad-specific neutralizing antibodies. Ad5-based vectors with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), the latter encoding the DNA polymerase and the pre-terminal protein, by virtue of diminished late phase viral protein expression, were hypothesized to avoid immunological clearance and induce more potent immune responses against the encoded tumor antigen transgene in Ad-immune hosts. Indeed, multiple homologous immunizations with Ad5 [E1-, E2b-]-CEA(6D), encoding the tumor antigen carcinoembryonic antigen (CEA), induced CEA-specific cell-mediated immune (CMI) responses with antitumor activity in mice despite the presence of preexisting or induced Ad5-neutralizing antibody. In the present phase I/II study, cohorts of patients with advanced colorectal cancer were immunized with escalating doses of Ad5 [E1-, E2b-]-CEA(6D). CEA-specific CMI responses were observed despite the presence of preexisting Ad5 immunity in a majority (61.3 %) of patients. Importantly, there was minimal toxicity, and overall patient survival (48 % at 12 months) was similar regardless of preexisting Ad5 neutralizing antibody titers. The results demonstrate that, in cancer patients, the novel Ad5 [E1-, E2b-] gene delivery platform generates significant CMI responses to the tumor antigen CEA in the setting of both naturally acquired and immunization-induced Ad5-specific immunity. PMID- 23624852 TI - Ventral tegmental area alpha6beta2 nicotinic acetylcholine receptors modulate phasic dopamine release in the nucleus accumbens core. AB - RATIONALE: Phasic dopamine (DA) signaling underlies reward learning. Cholinergic and glutamatergic inputs into the ventral tegmental area (VTA) are crucial for modulating burst firing activity and subsequent phasic DA release in the nucleus accumbens (NAc), but the specific VTA nicotinic receptor subtypes that regulate phasic DA release have not been identified. OBJECTIVE: The goal was to determine the role of VTA N-methyl-D-aspartate receptors (NMDARs) and specific subtypes of nicotinic acetylcholine receptors (nAChRs) in regulating phasic DA release in the NAc core. METHODS: Fast-scan cyclic voltammetry in anesthetized rats was combined with intra-VTA micro-infusion to evaluate the ability of glutamatergic and cholinergic drugs to modulate stimulated phasic DA release in the NAc core. RESULTS: VTA NMDAR blockade with AP-5 decreased, while VTA NMDAR activation with NMDA increased NAc peak phasic DA release. Intra-VTA administration of the nonspecific nAChR antagonist mecamylamine produced a persistent decrease in phasic DA release. Infusion of the alpha6-selective antagonist alpha-conotoxin MII (alpha-ctx MII) produced a robust, but transient decrease in phasic DA, whereas infusion of selective doses of either the alpha4beta2-selective antagonist, dihydro-beta-erythroidine, or the alpha7 antagonist, methyllycaconitine, had no effect. Co-infusion of AP-5 and alpha-ctx MII produced a similar phasic DA decrease as either drug alone, with no additive effect. CONCLUSIONS: The results suggest that VTA alpha6beta2 nAChRs, but not alpha4beta2 or alpha7 nAChRs, regulate phasic DA release in the NAc core and that VTA alpha6beta2 nAChRs and NMDA receptors act at a common site or target to regulate NAc phasic DA signaling. PMID- 23624853 TI - Dopamine on D2-like receptors "reboosts" dopamine D1-like receptor-mediated behavioural activation in rats licking for a isotonic NaCl solution. AB - RATIONALE: We recently suggested that dopamine on D1-like receptors is involved in the activation of goal-directed responses and the level of response activation is "reboosted" on the basis of an evaluation process involving D2-like receptors assessing "response efficacy". A main piece of evidence in support of this hypothesis was the observation of an "extinction mimicry" effect in the time course of licking bursts after dopamine D2-like receptor blockade in rats licking for sucrose. OBJECTIVES: The aim of this study was to determine whether the pattern of licking observed with sucrose as a reward could be reproduced in rats licking for a different reward (0.9% NaCl). MATERIALS AND METHODS: We investigated the effects of the dopamine D1-like receptor antagonist SCH 23390 (0.01-0.04 mg/kg) and of the dopamine D2-like receptor antagonist raclopride (0.025-0.25 mg/kg) on the microstructure of licking for a 0.9% NaCl solution in 12-h water-deprived rats in 30-min sessions. RESULTS: As previously observed with sucrose as a reward, raclopride reduced the size of licking bursts and produced on the burst number time course an "extinction mimicry" effect, while SCH 23390 reduced licking exclusively by reducing burst number. CONCLUSIONS: These results are consistent with the proposed hypothesis and provide support to the use of the study of licking microstructure as a valid model not only for the investigation of the mechanisms governing ingestive behaviour but also for the investigation of the mechanisms underlying behavioural activation and the related evaluation processes. PMID- 23624854 TI - A basic helix-loop-helix transcription factor, PtrbHLH, of Poncirus trifoliata confers cold tolerance and modulates peroxidase-mediated scavenging of hydrogen peroxide. AB - The basic helix-loop-helix (bHLH) transcription factors are involved in a variety of physiological processes. However, plant bHLHs functioning in cold tolerance and the underlying mechanisms remain poorly understood. Here, we report the identification and functional characterization of PtrbHLH isolated from trifoliate orange (Poncirus trifoliata). The transcript levels of PtrbHLH were up regulated under various abiotic stresses, particularly cold. PtrbHLH was localized in the nucleus with transactivation activity. Overexpression of PtrbHLH in tobacco (Nicotiana tabacum) or lemon (Citrus limon) conferred enhanced tolerance to cold under chilling or freezing temperatures, whereas down regulation of PtrbHLH in trifoliate orange by RNA interference (RNAi) resulted in elevated cold sensitivity. A range of stress-responsive genes was up-regulated or down-regulated in the transgenic lemon. Of special note, several peroxidase (POD) genes were induced after cold treatment. Compared with the wild type, POD activity was increased in the overexpression plants but decreased in the RNAi plants, which was inversely correlated with the hydrogen peroxide (H2O2) levels in the tested lines. Treatment of the transgenic tobacco plants with POD inhibitors elevated the H2O2 levels and greatly compromised their cold tolerance, while exogenous replenishment of POD enhanced cold tolerance of the RNAi line. In addition, transgenic tobacco and lemon plants were more tolerant to oxidative stresses. Yeast one-hybrid assay and transient expression analysis demonstrated that PtrbHLH could bind to the E-box elements in the promoter region of a POD gene. Taken together, these results demonstrate that PtrbHLH plays an important role in cold tolerance, at least in part, by positively regulating POD-mediated reactive oxygen species removal. PMID- 23624855 TI - Characterization of the complex regulation of AtALMT1 expression in response to phytohormones and other inducers. AB - In Arabidopsis (Arabidopsis thaliana), malate released into the rhizosphere has various roles, such as detoxifying rhizotoxic aluminum (Al) and recruiting beneficial rhizobacteria that induce plant immunity. ALUMINUM-ACTIVATED MALATE TRANSPORTER1 (AtALMT1) is a critical gene in these responses, but its regulatory mechanisms remain unclear. To explore the mechanism of the multiple responses of AtALMT1, we profiled its expression patterns in wild-type plants, in transgenic plants harboring various deleted promoter constructs, and in mutant plants with defects in signal transduction in response to various inducers. AtALMT1 transcription was clearly induced by indole-3-acetic acid (IAA), abscisic acid (ABA), low pH, and hydrogen peroxide, indicating that it was able to respond to multiple signals, while it was not induced by methyl jasmonate and salicylic acid. The IAA-signaling double mutant nonphototropic hypocotyls4-1; auxin responsive factor19-1 and the ABA-signaling mutant aba insensitive1-1 did not respond to auxin and ABA, respectively, but both showed an Al response comparable to that of the wild type. A synthetic microbe-associated molecular pattern peptide, flagellin22 (flg22), induced AtALMT1 transcription but did not induce the transcription of IAA- and ABA-responsive biomarker genes, indicating that both Al and flg22 responses of AtALMT1 were independent of IAA and ABA signaling. An in planta beta-glucuronidase reporter assay identified that the ABA response was regulated by a region upstream (-317 bp) from the first ATG codon, but other stress responses may share critical regulatory element(s) located between -292 and -317 bp. These results illustrate the complex regulation of AtALMT1 expression during the adaptation to abiotic and biotic stresses. PMID- 23624856 TI - Elucidation of the structure and reaction mechanism of sorghum hydroxycinnamoyltransferase and its structural relationship to other coenzyme a dependent transferases and synthases. AB - Hydroxycinnamoyltransferase (HCT) from sorghum (Sorghum bicolor) participates in an early step of the phenylpropanoid pathway, exchanging coenzyme A (CoA) esterified to p-coumaric acid with shikimic or quinic acid as intermediates in the biosynthesis of the monolignols coniferyl alcohol and sinapyl alcohol. In order to elucidate the mode of action of this enzyme, we have determined the crystal structures of SbHCT in its apo-form and ternary complex with shikimate and p-coumaroyl-CoA, which was converted to its product during crystal soaking. The structure revealed the roles of threonine-36, serine-38, tyrosine-40, histidine-162, arginine-371, and threonine-384 in catalysis and specificity. Based on the exact chemistry of p-coumaroyl-CoA and shikimic acid in the active site and an analysis of kinetic and thermodynamic data of the wild type and mutants, we propose a role for histidine-162 and threonine-36 in the catalytic mechanism of HCT. Considering the calorimetric data, substrate binding of SbHCT should occur sequentially, with p-coumaroyl-CoA binding prior to the acyl acceptor molecule. While some HCTs can use both shikimate and quinate as an acyl acceptor, SbHCT displays low activity toward quinate. Comparison of the structure of sorghum HCT with the HCT involved in chlorogenic acid synthesis in coffee (Coffea canephora) revealed many shared features. Taken together, these observations explain how CoA-dependent transferases with similar structural features can participate in different biochemical pathways across species. PMID- 23624857 TI - Reduced tonoplast fast-activating and slow-activating channel activity is essential for conferring salinity tolerance in a facultative halophyte, quinoa. AB - Halophyte species implement a "salt-including" strategy, sequestering significant amounts of Na(+) to cell vacuoles. This requires a reduction of passive Na(+) leak from the vacuole. In this work, we used quinoa (Chenopodium quinoa) to investigate the ability of halophytes to regulate Na(+)-permeable slow-activating (SV) and fast-activating (FV) tonoplast channels, linking it with Na(+) accumulation in mesophyll cells and salt bladders as well as leaf photosynthetic efficiency under salt stress. Our data indicate that young leaves rely on Na(+) exclusion to salt bladders, whereas old ones, possessing far fewer salt bladders, depend almost exclusively on Na(+) sequestration to mesophyll vacuoles. Moreover, although old leaves accumulate more Na(+), this does not compromise their leaf photochemistry. FV and SV channels are slightly more permeable for K(+) than for Na(+), and vacuoles in young leaves express less FV current and with a density unchanged in plants subjected to high (400 mm NaCl) salinity. In old leaves, with an intrinsically lower density of the FV current, FV channel density decreases about 2-fold in plants grown under high salinity. In contrast, intrinsic activity of SV channels in vacuoles from young leaves is unchanged under salt stress. In vacuoles of old leaves, however, it is 2- and 7-fold lower in older compared with young leaves in control- and salt-grown plants, respectively. We conclude that the negative control of SV and FV tonoplast channel activity in old leaves reduces Na(+) leak, thus enabling efficient sequestration of Na(+) to their vacuoles. This enables optimal photosynthetic performance, conferring salinity tolerance in quinoa species. PMID- 23624858 TI - Involvement of the sieve element cytoskeleton in electrical responses to cold shocks. AB - This study dealt with the visualization of the sieve element (SE) cytoskeleton and its involvement in electrical responses to local cold shocks, exemplifying the role of the cytoskeleton in Ca(2+)-triggered signal cascades in SEs. High affinity fluorescent phalloidin as well as immunocytochemistry using anti-actin antibodies demonstrated a fully developed parietal actin meshwork in SEs. The involvement of the cytoskeleton in electrical responses and forisome conformation changes as indicators of Ca(2+) influx was investigated by the application of cold shocks in the presence of diverse actin disruptors (latrunculin A and cytochalasin D). Under control conditions, cold shocks elicited a graded initial voltage transient, DeltaV1, reduced by external La(3+) in keeping with the involvement of Ca(2+) channels, and a second voltage transient, DeltaV2. Cytochalasin D had no effect on DeltaV1, while DeltaV1 was significantly reduced with 500 nm latrunculin A. Forisome dispersion was triggered by cold shocks of 4 degrees C or greater, which was indicative of an all-or-none behavior. Forisome dispersion was suppressed by incubation with latrunculin A. In conclusion, the cytoskeleton controls cold shock-induced Ca(2+) influx into SEs, leading to forisome dispersion and sieve plate occlusion in fava bean (Vicia faba). PMID- 23624859 TI - The microtubule-associated tau protein has intrinsic acetyltransferase activity. AB - Tau proteins are the building blocks of neurofibrillary tangles (NFTs) found in a range of neurodegenerative tauopathies, including Alzheimer's disease. Recently, we demonstrated that tau is extensively post-translationally modified by lysine acetylation, which impairs normal tau function and promotes pathological aggregation. Identifying the enzymes that mediate tau acetylation could provide targets for future therapies aimed at reducing the burden of acetylated tau. Here, we report that mammalian tau proteins possess intrinsic enzymatic activity capable of catalyzing self-acetylation. Functional mapping of tau acetyltransferase activity followed by biochemical analysis revealed that tau uses catalytic cysteine residues in the microtubule-binding domain to facilitate tau lysine acetylation, thus suggesting a mechanism similar to that employed by MYST-family acetyltransferases. The identification of tau as an acetyltransferase provides a framework to further understand tau pathogenesis and highlights tau enzymatic activity as a potential therapeutic target. PMID- 23624860 TI - Substrate-specific structural rearrangements of human Dicer. AB - Dicer has a central role in RNA-interference pathways by cleaving double-stranded RNAs (dsRNAs) to produce small regulatory RNAs. Human Dicer can process long double-stranded and hairpin precursor RNAs to yield short interfering RNAs (siRNAs) and microRNAs (miRNAs), respectively. Previous studies have shown that pre-miRNAs are cleaved more rapidly than pre-siRNAs in vitro and are the predominant natural Dicer substrates. We have used EM and single-particle analysis of Dicer-RNA complexes to gain insight into the structural basis for human Dicer's substrate preference. Our studies show that Dicer traps pre-siRNAs in a nonproductive conformation, whereas interactions of Dicer with pre-miRNAs and dsRNA-binding proteins induce structural changes in the enzyme that enable productive substrate recognition in the central catalytic channel. These findings implicate RNA structure and cofactors in determining substrate recognition and processing efficiency by human Dicer. PMID- 23624861 TI - Structural basis for substrate transport in the GLUT-homology family of monosaccharide transporters. AB - Here we present two structures of the major facilitator (MFS) xylose transporter XylE from Escherichia coli in inward open and partially occluded inward open conformations. These structures provide key information about the transport cycle of XylE and the closely related human GLUT transporters. This is, to our knowledge, the first MFS transporter structure determined in more than one conformational state, which may establish XylE as an important MFS model protein. PMID- 23624863 TI - Foraging behavior delays mechanically-stimulated escape responses in fish. AB - Foraging and the evasion of predators are fundamental for the survival of organisms, but they impose contrasting demands that can influence performance in each behavior. Previous studies suggested that foraging organisms may experience decreased vigilance to attacks by predators; however, little is known about the effect of foraging on escape performance with respect to the kinematics and the timing of the response. This study tested the hypothesis that engaging in foraging activities affected escape performance by comparing fast-start escape responses of silver-spotted sculpins Blepsias cirrhosus under three conditions: (1) control (no foraging involved), (2) while targeting prey, and (3) immediately after capture of prey. Escape response variables (non-locomotor and locomotor) were analyzed from high-speed videos. Responsiveness was lower immediately after capturing a prey item compared with the other two treatments, and latency of performance was higher in the control treatment than in the other two. Locomotor variables such as maximum speed, maximum acceleration, and turning rates did not show statistical differences among the three groups. Our results demonstrate that foraging can negatively affect two fundamental components of the escape response: (1) responsiveness and (2) latency of escape, suggesting that engaging in foraging may decrease an individual's ability to successfully evade predators. PMID- 23624862 TI - Coordinated conformational and compositional dynamics drive ribosome translocation. AB - During translation elongation, the ribosome compositional factors elongation factor G (EF-G; encoded by fusA) and tRNA alternately bind to the ribosome to direct protein synthesis and regulate the conformation of the ribosome. Here, we use single-molecule fluorescence with zero-mode waveguides to directly correlate ribosome conformation and composition during multiple rounds of elongation at high factor concentrations in Escherichia coli. Our results show that EF-G bound to GTP (EF-G-GTP) continuously samples both rotational states of the ribosome, binding with higher affinity to the rotated state. Upon successful accommodation into the rotated ribosome, the EF-G-ribosome complex evolves through several rate limiting conformational changes and the hydrolysis of GTP, which results in a transition back to the nonrotated state and in turn drives translocation and facilitates release of both EF-G-GDP and E-site tRNA. These experiments highlight the power of tracking single-molecule conformation and composition simultaneously in real time. PMID- 23624864 TI - Historical perspectives on the evolution of tetrapodomorph movement. AB - Over the past century, various modern analogs have been used to infer the evolution of locomotor performance in stem tetrapods and their fish ancestors, with varying success. Here, we conduct a phylogenetic review of these modern analogs, from chondrichthyans to mammals, highlighting the broad spectrum of vertebrate clades and locomotor behaviors. The pros and cons behind utilizing modern analogs for the early stages of the transition from water to land also are discussed. In particular, it is noted that any hypothesis about locomotion not only must be supported by evidence from living animals but must also be consistent with character transformations in the fossil record. A "total evidence" approach that emphasizes what extinct taxa could not do, rather than focusing on the specifics of how they functioned, is thus recommended. An example of this approach, which investigates mobility of the limb joints in modern semi aquatic animals and in the Devonian stem tetrapod Ichthyostega, is detailed. We propose that various locomotion behaviors of modern quadrupeds can be ruled out for Ichthyostega, but that forelimb "crutching" motions, as seen in living mudskippers, may have been possible. The potential for movement in other known Devonian stem tetrapods is assessed through an anatomical comparison of limb joint morphology-and associated mobility-with Ichthyostega, and deemed to have been quite similar. PMID- 23624865 TI - Kinematics of terrestrial capture of prey by the eel-catfish Channallabes apus. AB - In contrast to numerous studies on the function of the locomotor system used by fishes when moving between water and land, little knowledge is available about the biomechanical requirements to the capture and transport of food by fish in a terrestrial situation. This study focuses on the kinematics of terrestrial capture of prey by the eel-catfish (Channallabes apus: Clariidae), a behavior that was only recently discovered for this species. The analyses show that C. apus inclines its head downward at a significantly steeper angle during terrestrial feeding compared with benthic aquatic feeding. This suggests that placing the jaws above ground-based prey is important for successful prehension by the jaws. The increased inclination of the head resulted from accumulated dorsoventral flexion of the body more than one head-length behind the skull. Alternatively, this posture of the head was assumed by rolling to one side while bending the body laterally. The speed of buccopharyngeal expansion in air versus in water matched the predicted increase by a factor of 3, under the assumption that the velocity of muscular contraction for maximal output of power by C. apus is optimized to operate under a specific hydrodynamic loading, and shifts to an unloaded contraction regime when operating in air. Combining these insights with future studies on other extant amphibious fish species that perform terrestrial feeding may eventually allow us to pinpoint the adaptations to the feeding system that have led to the evolution of a terrestrial lifestyle in tetrapods. PMID- 23624866 TI - The deep homology of the autopod: insights from hox gene regulation. AB - The evolution of tetrapod limbs from fish fins was a significant functional and morphological shift, but how significant was it in terms of the underlying genetic mechanisms? The fossil record provides insight into the morphological changes. However, to understand the underlying mechanisms, we must peer into the gene regulatory networks of living vertebrates. Analysis of HoxA/D expression in a basal actinopterygian, the North American paddlefish, Polyodon spathula, reveals patterns of expression long considered to be a unique developmental signature of the autopod (hands/feet, digits) and shown in tetrapods to be controlled by a "digit enhancer" regulatory landscape. These data, along with recent interspecific transgenic experiments, expression results from chondrichthyans, and data from fossils support the notion that the autopod shares a deep homology with the distal endoskeleton of the fin (distal radials) of other gnathostomes. PMID- 23624867 TI - Plasticity in learning causes immediate and trans-generational changes in allocation of resources. AB - Plasticity in the development and expression of behavior may allow organisms to cope with novel and rapidly changing environments. However, plasticity itself may depend on the developmental experiences of an individual. For instance, individuals reared in complex, enriched environments develop enhanced cognitive abilities as a result of increased synaptic connections and neurogenesis. This suggests that costs associated with behavioral plasticity-in particular, increased investment in "self" at the expense of reproduction-may also be flexible. Using butterflies as a system, this work tests whether allocation of resources changes as a result of experiences in "difficult" environments that require more investment in learning. We contrast allocation of resources among butterflies with experience in environments that vary in the need for learning. Butterflies with experience searching for novel (i.e., red) hosts, or searching in complex non-host environments, allocate more resources (protein and carbohydrate reserves) to their own flight muscle. In addition, butterflies with experience in these more difficult environments allocate more resources per individual offspring (i.e., egg size and/or lipid reserves). This results in a mother's experience having significant effects on the growth of her offspring (i.e., dry mass and wing length). A separate study showed this re-allocation of resources comes at the expense of lifetime fecundity. These results suggest that investment in learning, and associated changes in life history, can be adjusted depending on an individual's current need, and their offspring's future needs, for learning. PMID- 23624868 TI - Phylogenetic novelties and geographic anomalies among tropical Verongida. AB - Exploring marine sponges from shallow tropical reefs of the Caribbean and western Central Pacific, as part of large biodiversity (Moorea Biocode Project) and evolutionary (Porifera Tree of Life) research projects, we encountered 13 skeleton-less specimens, initially divided in two morphological groups, which had patterns of coloration and oxidation typical of taxa of the order Verongida (Demospongiae). The first group of samples inhabited open and cryptic habitats of shallow (15-20 m) Caribbean reefs at Bocas del Toro Archipelago, Panama. The second group inhabited schiophilous (e.g., inner coral framework and crevices) habitats on shallow reefs (0.5-20 m deep) in Moorea Island, French Polynesia. We applied an integrative approach by combining analyses of external morphology, histological observations, 18S rDNA, and mtCOI to determine the identity and the relationships of these unknown taxa within the order Verongida. Molecular analyses revealed that none of the species studied belonged to Hexadella (Ianthellidae, Verongida), the only fibreless genus of the Order Verongida currently recognized. The species from the Caribbean locality of Bocas del Toro (Panama) belong to the family Ianthellidae and is closely related to the Pacific genera Ianthella and Anomoianthella, both with well-developed fiber reticulations. We suggest the erection of a new generic denomination to include this novel eurypylous, fibreless ianthellid. The species collected in Moorea were all diplodal verongid taxa, with high affinities to a clade containing Pseudoceratina, Verongula, and Aiolochroia, a Pacific and two Caribbean genera, respectively. These unknown species represented at least three different taxa distinguished by DNA sequence analysis and morphological characteristics. Two new genera and a new species of Pseudoceratina are here proposed to accommodate these novel biological discoveries. The evolutionary and ecological meaning of having or lacking a fiber skeleton within Verongida is challenged under the evidence of the existence of fibreless genera within various verongid clades. Furthermore, the discovery of a fibreless Peudoceratina suggests that the possession of a spongin-chitin fiber reticulation is an "ecological" plastic trait that might be lost under certain conditions, such us growing within another organism's skeletal framework. These results raise new questions about the ecological and evolutionary significance of the development of a fiber skeleton and of sponges' adaptability to various environmental conditions. PMID- 23624869 TI - Downregulation of miR-124 promotes the growth and invasiveness of glioblastoma cells involving upregulation of PPP1R13L. AB - microRNA-124 (miR-124) plays an important role in regulating growth, invasiveness, stem-like traits, differentiation and apoptosis of glioblastoma cells. PPP1R3L, an inhibitory member of the apoptosis-stimulating protein of p53 family (IASPP), is also able to affect growth, cell cycle progression, metastasis and apoptosis of various types of cancer. To investigate the regulation of PPP1R13L expression by miR-124 and their effects on proliferation, cell cycle transition and invasion in glioblastoma cells, U251 and U373 glioblastoma cells were transfected with miR-124 mimics, its negative control (NC) or an inhibitor. We found that miR-124 was downregulated in glioblastoma tissues, and inversely regulated PPP1R13L expression in U251 and U373 glioblastoma cells. PPP1R13L was found to be a direct target of miR-124 in glioblastoma cells. Overexpression of miR-124 inhibited proliferation, G1/S transition and invasiveness in glioblastoma cells. miR-124 downregulation-mediated malignant progression of glioblastoma was partly attributed to increased PPP1R13L expression. Consequently, our findings provide a molecular basis for the role of miR-124/PPP1R13L in the progression of human glioblastoma and suggest a novel target for the treatment of glioblastoma. PMID- 23624870 TI - Combination of GHRH antagonists and docetaxel shows experimental effectiveness for the treatment of triple-negative breast cancers. AB - In preclinical studies, antagonists of growth hormone-releasing hormone (GHRH) have demonstrated inhibitory effects on the growth of various types of cancers expressing the pituitary type of GHRH receptors (pGHRH-R) and/or its active splice variant 1 (SV1). In this study, we investigated the effectiveness of the treatment of MDA-MB-231 human triple-negative breast cancer (TNBC) with GHRH antagonist JMR-132 alone or in combination with docetaxel. Receptor expression in the MDA-MB-231 human breast cancer cell line was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Cell viability assays were performed on MDA-MB-231 cells treated with JMR-132, docetaxel or in combination. For studies in vivo, a subcutaneous nude mouse xenograft model was used. JMR-132 was administered s.c. at a dose of 10 ug/day and docetaxel at a dose of 10 mg/kg i.p. given on day 1 and 5. Similar regimens were used for the combination of both substances. At the end of the experiment, an mRNA-based human cancer pathway array including 84 major genes was performed on the tumor tissue of mice treated with JMR-132 to elucidate the mechanism of action of GHRH antagonists in vivo. The in vitro proliferation studies revealed that JMR-132 and docetaxel decreased the cell viability in a dose-dependent manner. The combination of both treatments produced a significantly greater inhibition of cell viability compared to the single agents. Treatment of nude mice bearing MDA-MB-231 xenografts with JMR-132 and docetaxel significantly (p<0.05) inhibited tumor growth by 46 and 50%, respectively. Treatment with the combination of JMR-132 and docetaxel led to an inhibition of tumor volume by 71.6% (p<0.001). Polymerase chain reaction array analysis revealed that JMR-132 interacts with signal transduction pathways involved in proliferation, apoptosis and angiogenesis. Our results suggest that GHRH antagonists in combination with taxanes may enhance the efficacy of treatment for patients with TNBC expressing the SV1 and/or the pGHRH receptor. PMID- 23624871 TI - Bilineal inheritance of PKD1 abnormalities mimicking autosomal recessive polycystic disease. AB - BACKGROUND: Dominant polycystic kidney disease is common and usually presents clinically in adulthood. Recessive polycystic kidney disease is much less common and frequently presents antenatally or in the neonatal period with severe renal involvement. These are usually thought of as clinically distinct entities but diagnostic confusion is not infrequent. CASE-DIAGNOSIS/TREATMENT: We describe an infant with antenatally diagnosed massive renal enlargement and oligohydramnios with no resolvable cysts on ultrasound scanning. He underwent bilateral nephrectomy because of respiratory compromise and poor renal function but died subsequently of overwhelming sepsis. Genetic analysis revealed that he had bilineal inheritance of abnormalities of PKD1 and no demonstrable abnormalities of PKD2 or PKHD1. CONCLUSIONS: Biallelic inheritance of abnormalities of PKD1 may causextremely severe disease resembling autosomal recessive polycystic kidney disease (ARPKD) which can result indiagnostic confusion. Accurate diagnosis is essential forgenetic counseling [corrected]. PMID- 23624872 TI - Eculizumab therapy for atypical haemolytic uraemic syndrome due to a gain-of function mutation of complement factor B. AB - BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is caused by dysregulated complement activation. A humanised anti-C5 monoclonal antibody has recently become available for treatment of this condition CASE-DIAGNOSIS/TREATMENT: We present the first description of an infant with an activating mutation of complement factor B successfully treated with eculizumab. On standard doses she had evidence of ongoing C5 cleavage despite a good clinical response. CONCLUSIONS: Eculizumab is effective therapy for aHUS associated with factor B mutations, but recommended doses may not be adequate for all patients. PMID- 23624873 TI - Large variation between hospitals in follow-up for colorectal cancer in southern Netherlands. AB - PURPOSE: The aims of the study were to describe the follow-up of colorectal cancer (CRC) patients in southern Netherlands and examine their overall and disease-free survival. METHODS: Patients newly diagnosed with CRC in 2003-2005 and 2008 with a survival of at least 1 year after diagnosis and recorded in the retrospective Eindhoven Cancer Registry were included (n = 579). Follow-up was defined as at least one liver imaging and at least two carcinoembryonic antigen (CEA) measurements. Logistic regression analyses were conducted to assess determinants of follow-up. Proportions of patients undergoing colonoscopy, CEA measurements and liver and chest imaging were calculated. Overall and disease free survival were calculated. RESULTS: Patients >=75 years (odds ratio (OR) 0.5 (95% confidence interval (CI) 0.3-0.7)) were less likely to receive follow-up, contrasting patients <50 years (OR 3.1 (95% CI 1.3-7.4)). In 2008, follow-up intensity increased (OR 2.3 (95% CI 1.2-4.3)), especially for liver imaging and CEA measurements. There were large differences in follow-up intensity and activities between hospitals, which were unaffected by comorbidity: ranges for colonoscopy 15-73 %, CEA measurement 46-91 % and imaging of the liver 22-70 % between hospitals. No effect of follow-up intensity was found on 5-year disease free survival for patients aged <75 years (64 vs. 68 %; p = 0.6). Similarly, no effect of follow-up intensity on 5-year overall survival was found in these patients (77 vs. 82 %; p = 0.07). CONCLUSION: Large variation in follow-up was found for patients with CRC, mainly declining with age and hospital of follow-up. Over time, follow-up became more intensive, especially with respect to liver imaging and CEA measurements. However, follow-up consisting of at least one liver imaging and at least two CEA measurements did not improve overall and disease free survival. PMID- 23624874 TI - Intake of whole grains from different cereal and food sources and incidence of colorectal cancer in the Scandinavian HELGA cohort. AB - PURPOSE: A high intake of whole grains has been associated with a lower incidence of colorectal cancer, but few studies are available on the association with whole grains from different cereals, for example, wheat, rye and oats, and none has addressed these separately. The objective of this study was to investigate the association between whole-grain intake and colorectal cancer. METHOD: We used data from the large population-based Scandinavian cohort HELGA consisting of 108,000 Danish, Swedish, and Norwegian persons, of whom 1,123 developed colorectal cancer during a median of 11 years of follow-up. Detailed information on daily intake of whole-grain products, including whole-grain bread, crispbread, and breakfast cereals, was available, and intakes of total whole grains and specific whole-grain species (wheat, rye, and oats) were estimated. Associations between these whole-grain variables and the incidence of colorectal cancer were investigated using Cox proportional hazards models. Intake of whole-grain products was associated with a lower incidence of colorectal cancer per 50-g increment (incidence rate ratio [IRR], 0.94; 95% confidence interval [CI], 0.89, 0.99), and the same tendency was found for total whole-grain intake (IRR pr. 25-g increment, 0.94; 95% CI, 0.88, 1.01). Intake of whole-grain wheat was associated with a lower incidence of colorectal cancer (IRR for highest versus lowest quartile of intake, 0.66; 95% CI, 0.51, 0.85), but no statistical significant linear trend was observed (p for trend: 0.18). No significant association was found for whole-grain rye or oats. CONCLUSION: Whole-grain intake was associated with a lower incidence of colorectal cancer. PMID- 23624876 TI - 4-Hydroxybenzyl alcohol confers neuroprotection through up-regulation of antioxidant protein expression. AB - An herb-derived phenolic compound, 4-hydroxybenzyl alcohol (4-HBA), exhibits beneficial effects in cerebral ischemic injury. However, the molecular mechanisms underlying this observation remain unclear. Here we used an in vitro ischemic model of oxygen-glucose deprivation followed by reperfusion (OGD/R) and an in vivo ischemic model of middle cerebral artery occlusion to investigate the relevant neuroprotective mechanisms. We demonstrated that 4-HBA reduced the neuronal injury, LDH release, and up-regulation of 8-hydroxydeoxyguanosine (8 OHdG) induced by OGD/R. Furthermore, 4-HBA reduced the cerebral infarct size and improved the behavioral parameters after cerebral ischemia. These neuroprotective effects may be conferred by the 4-HBA mediated upregulation of the transcription factor nuclear factor E2-related factor 2 (Nrf2), peroxiredoxin 6 (Prdx6) and protein disulfide isomerase (PDI) by the use of 4-HBA. Interestingly, LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, blocked the increase in phosphorylation of Akt and abolished the neuroprotection associated with 4-HBA. Our results suggested that 4-HBA protects neurons against cerebral ischemic injury, and this neuroprotection may occur through upregulation of Nrf2, Prdx6, and PDI expression via the PI3K/Akt pathway. PMID- 23624877 TI - Critical role of PD-1/PD-L1 pathway in generation and function of follicular regulatory T cells. PMID- 23624878 TI - Types of tolerance seen in autoreactive phosphocholine-specific B cells are dependent on the idiotype of the receptors expressed. AB - Phosphocholine (PC) is the immunodominant epitope found on the surface of a number of microorganisms, including Streptococcus pneumoniae (SPn), and is thought to play a vital role in the pathogenesis of SPn. B cells expressing M167Hkappa24L immunoglobulin receptors specific for PC have been shown to be autoreactive in that they undergo clonal deletion in both X-linked immune deficient and Rag(-/-) mice. We have now shown that B cells expressing M603Hkappa8L PC-specific receptors also delete in Rag(-/-) mice, whereas those expressing T15Hkappa22L transgenes do not delete. However, T15Hkappa22L B cells are lost in normal heterozygous transgenic mice because they cannot compete with normal B cells. These data indicate that M167Hkappa24L and M603Hkappa8L PC specific B cells are recognizing an autoantigen expressed on membranes which causes them to downregulate their receptors and clonally delete, while T15Hkappa22L B cells are tolerized by a soluble form of PC-antigen which results in their being trapped in the spleen. Thus, the types of tolerance seen in autoreactive PC-specific B cells are dependent on the idiotype of the receptors expressed. PMID- 23624879 TI - Brief report: suitability of the Social Skills Performance Assessment (SSPA) for the assessment of social skills in adults with autism spectrum disorders. AB - The present study aims at examining whether the 'Social Skills Performance Assessment' (SSPA; Patterson et al. in Schizophr Res 48(2-3):351-360, 2001) is a suitable performance-based measure to assess social skills in adults with autism spectrum disorders (ASD). For this purpose, social skills of individuals with ASD and non-ASD participants were assessed through the SSPA role plays. Results of this study suggest that the SSPA is suitable for the assessment of social skills in adults with ASD. The SSPA discriminates between individuals with ASD and non ASD individuals, with the ASD group scoring significantly lower. Although no evidence was found for convergent validity of the SSPA in participants with ASD, divergent validity of the SSPA and interrater reliability among adults with ASD were good. PMID- 23624880 TI - Factors influencing outcomes in laparoscopic adrenal surgery. AB - PURPOSE: This study aims to recognize factors affecting operative and postoperative outcomes in patients undergoing unilateral laparoscopic adrenalectomy performed by using the transabdominal approach. METHODS: From a prospectively collected adrenal database, we performed a retrospective analysis of all patients undergoing unilateral adrenalectomy from July 2002 to December 2011. The outcome measures considered were the following: conversion rate, intra- and postoperative complications, duration of surgery, length of hospital stay, and return-to-work time. Demographic data, American Society of Anesthesiologists score, characteristics of adrenal tumor, and operative and postoperative variables were analyzed to assess their influence on the outcome variables. RESULTS: A total of 163 laparoscopic adrenalectomies were included. Intraoperative complications, conversion to laparotomy, and postoperative complications were observed in 6.7, 6.1, and 1.8 % of cases, respectively. Conversion to open surgery, intraoperative complications, metastasis, and pheochromocytoma were found to be predictive factors for operative time of >140 min. An operative duration of >140 min was associated with intraoperative complications. Tumor size, intraoperative complications, and adrenalectomy for metastasis significantly increased conversion rate. Hospital stay was extended by operative time of >140 min, conversion to laparotomy, and postoperative complications. CONCLUSION: Our study highlights that simple clinical variables, long procedures, and operative complications have a negative impact on procedural outcomes. Based on this, it may be possible to predict cases requiring collaboration with experienced surgeons in order to minimize perioperative morbidity. PMID- 23624882 TI - Nuclease and anti-proliferative activities of copper(II) complexes of N3O tripodal ligands involving a sterically hindered phenolate. AB - Copper(II) complexes 1(2+)-6 of a series of tripodal ligands involving a N3O donor set, namely 2-[(bis-pyridin-2-ylmethyl-amino)-methyl]-4-methoxy-phenol (1L), 2-tert-butyl-4-methoxy-6-[bis-pyridin-2-ylmethyl-amino)-methyl]-phenol (2L), 2-tert-butyl-4-methoxy-6-{[(2-pyridin-2-yl-ethyl)-pyridin-2-ylmethyl-amino] methyl}-phenol (3L), 2-tert-butyl-4-methoxy-6-{[(6-methyl-pyridin-2-ylmethyl) pyridin-2-ylmethyl-amino]-methyl}-phenol (4L), 2-tert-butyl-4-fluoro-6-{[(6 methyl-pyridin-2-ylmethyl)-pyridin-2-ylmethyl-amino]-methyl}-phenol (5L) and 2 tert-butyl-4-methoxy-6-{bis[(6-methyl-pyridin-2-ylmethyl)-amino]-methyl}-phenol (6L), respectively, were synthesized. Complexes 1(2+), 3(+) and 4(+) were structurally characterized by X-ray diffraction. The structure of 1(2+) is dimeric, with an essentially trigonal bipyramidal geometry around the copper(II) ions and two bridging deprotonated phenolate moieties. The mononuclear complexes 3(+) and 4(+) contain a square pyramidal copper ion, coordinated in axial position by the phenol moiety. In the water-DMF (90 : 10) mixture at pH 7.3 all the copper(II) complexes are mononuclear, mainly under their phenolate neutral form (except 3(+)), with a coordinated solvent molecule. The DNA cleavage activity of the complexes was tested towards the phiX174 DNA plasmid. In the absence of an exogenous agent 1(2+) does not show any cleavage activity, 2(+) and 3(+) are moderately active, while 4(+), 5(+) and 6(+) exhibit a high nuclease activity. Experiments in the presence of various scavengers reveal that reactive oxygen species (ROS) are not involved in the strand scission mechanism. The cytotoxicity of the complexes was evaluated on bladder cancer cell lines sensitive or resistant to cisplatin. The IC50 values of the complexes 2(+), 4(+), 5(+) and 6(+) are lower than that of cisplatin (range from 6.3 to 3.1 MUM against 9.1 MUM for cisplatin). Furthermore, complexes 2(+), 4(+), 5(+) and 6(+) are able to circumvent cisplatin cellular resistance. PMID- 23624881 TI - Stem cells and the developing mammary gland. AB - The mammary gland undergoes dynamic changes throughout life. In the mouse, these begin with initial morphogenesis of the gland in the mid-gestation embryo followed by hormonally regulated changes during puberty and later in adulthood. The adult mammary gland contains a hierarchy of cell types with varying potentials for self-maintenance and differentiation. These include cells able to produce complete, functional mammary glands in vivo and that contain daughter cells with the same remarkable regenerative potential, as well as cells with more limited clonogenic activity in vitro. Here we review how applying in vitro and in vivo methods for quantifying these cells in adult mammary tissue to fetal mammary cells has enabled the first cells fulfilling the functional criteria of transplantable, isolated mammary stem cells to be identified a few days before birth. Thereafter, the number of these cells increases rapidly. Populations containing these fetal stem cells display growth and gene expression programs that differ from their adult counterparts but share signatures characteristic of certain types of breast cancer. Such observations reinforce growing evidence of important differences between tissue-specific fetal and adult cells with stem cell properties and emphasize the merits of investigating their molecular basis. PMID- 23624883 TI - Experimental study of vibrations of gerbil tympanic membrane with closed middle ear cavity. AB - The purpose of the present work is to investigate the spatial vibration pattern of the gerbil tympanic membrane (TM) as a function of frequency. In vivo vibration measurements were done at several locations on the pars flaccida and pars tensa, and along the manubrium, on surgically exposed gerbil TMs with closed middle ear cavities. A laser Doppler vibrometer was used to measure motions in response to audio frequency sine sweeps in the ear canal. Data are presented for two different pars flaccida conditions: naturally flat and retracted into the middle ear cavity. Resonance of the flat pars flaccida causes a minimum and a shallow maximum in the displacement magnitude of the manubrium and pars tensa at low frequencies. Compared with a flat pars flaccida, a retracted pars flaccida has much lower displacement magnitudes at low frequencies and does not affect the responses of the other points. All manubrial and pars tensa points show a broad resonance in the range of 1.6 to 2 kHz. Above this resonance, the displacement magnitudes of manubrial points, including the umbo, roll off with substantial irregularities. The manubrial points show an increasing displacement magnitude from the lateral process toward the umbo. Above 5 kHz, phase differences between points along the manubrium start to become more evident, which may indicate flexing of the tip of the manubrium or a change in the vibration mode of the malleus. At low frequencies, points on the posterior side of the pars tensa tend to show larger displacements than those on the anterior side. The simple low frequency vibration pattern of the pars tensa becomes more complex at higher frequencies, with the breakup occurring at between 1.8 and 2.8 kHz. These observations will be important for the development and validation of middle ear finite-element models for the gerbil. PMID- 23624884 TI - Experiences of fecal incontinence in people with inflammatory bowel disease: self reported experiences among a community sample. AB - BACKGROUND: Poor bowel control is a major concern of people with inflammatory bowel disease (IBD). Previous research demonstrates the impact of fecal incontinence (FI) on adults in the non-IBD population; there are no previous reports on the experience of IBD-related FI. METHODS: We randomly sampled 10,000 members of Crohn's & Colitis UK to receive a questionnaire to collect demographic information, medical history, continence status, quality of life, and free-text responses to questions about FI. Respondents could also choose to be interviewed about their experiences of living with IBD-related FI. This article presents findings from the free-text paper questionnaire responses and the interviews. Following transcription, data were sorted and analyzed using a pragmatic thematic approach. RESULTS: We received 3264 eligible replies (32.6%). Twenty-eight interviews and 583 sets of questionnaire data were transcribed, continuing with the latter until no new themes emerged. The remaining questionnaires (n = 2681) were read to check that no issues had been missed. Several core themes emerged: emotional and psychological impact, feelings of stigma, limited lives, symptoms, practical coping mechanisms, access to facilities, and fear of incontinence. DISCUSSION: Incontinence, and fear of it, limits social, working, and personal lives, impacting on people with IBD in complex ways. Key strategies, including situation avoidance and dietary restrictions, are used to cope. Incontinence is degrading and humiliating for most people, although a small number approach their situation positively. CONCLUSIONS: IBD-related FI, and fear of incontinence, causes multiple difficulties. People with IBD-related FI need help in accessing professional support. PMID- 23624885 TI - Contemporary outcomes for ulcerative colitis inpatients admitted to pediatric hospitals in the United Kingdom. AB - BACKGROUND: Pediatric ulcerative colitis (UC) care is variable with a lack of appropriate guidelines to guide practice until recently. METHODS: UC inpatients <17 years old admitted to 23 U.K. pediatric hospitals had clinical details collected between September 2010 and 2011. Comparative data for 248 patients were available from a previous audit in 2008. RESULTS: One hundred and seventy-six patients (98 males) of median age 13 years (interquartile range, 10-13) were analyzed; 23 were elective surgical admissions, 47 new diagnoses, and 106 needed acute medical care for established UC. Median length of stay was 6 days (interquartile range, 3-10) with no deaths. Eighty-eight of 126 patients (70%) with active disease had standard stool cultures performed (3 [2%] were positive), and 57 (45%) had Clostridium difficile toxin tested (none positive). Twenty-five of 66 (38%) emergency admissions had an abdominal x-ray on admission, and 13 of 66 patients (20%) had a Pediatric Ulcerative Colitis Activity Index score. There were 3 cases of toxic megacolon and 2 thromboses. Eighty-one of 116 patients (71%) responded to steroids. Nineteen patients who did not respond adequately to steroids received rescue therapy (7 infliximab, 11 ciclosporin, and 1 both) with overall response rate of 90%; 7 patients needed surgery acutely, 5 without previous rescue therapy. Compared with the 2008 data, stool culture rates improved significantly (86 of 121 [71%] versus 76 of 147 [52%], P = 0.001) as did heparinization rates (15 of 150 [10%] versus 5 of 215 [2%], P = 0.002) and rescue therapy usage (17 of 33 [52%] versus 10 of 38 [26%], P = 0.03). CONCLUSIONS: There were signs of improving UC care with significantly increased rates of stool culture and rescue therapy. The majority of sites, however, did not use Pediatric Ulcerative Colitis Activity Index scores. PMID- 23624886 TI - Risk of inflammatory bowel disease following Bacille Calmette-Guerin and smallpox vaccination: a population-based Danish case-cohort study. AB - BACKGROUND: Childhood immunology has been suggested to play a role in development of inflammatory bowel disease (IBD) based on the studies of childhood vaccinations, infections, and treatment with antibiotics. Bacille Calmette-Guerin (BCG) and smallpox vaccinations were gradually phased-out in Denmark for children born between 1965 and 1976, hence allowing the study of subsequent risk of Crohn's disease and ulcerative colitis in a unique prospective design. METHODS: The Copenhagen School Health Records Register contains detailed documentation of vaccination. Among the background cohort of individuals born between 1965 and 1976 (N = 47,622), cases with Crohn's disease (n = 218) and ulcerative colitis (n = 256) were identified through linkage to the Danish National Patient Registry. The vaccination status of the cases was compared with that of a subcohort (n = 5741) of the background cohort and analyzed in a case-cohort design. RESULTS: No difference in risk of IBD was observed between individuals vaccinated and unvaccinated with BCG (hazard ratio = 0.95; 95% confidence interval, 0.75-1.19) or smallpox vaccine (hazard ratio = 1.01; 95% confidence interval, 0.77-1.32). This was also the case for Crohn's disease and ulcerative colitis separately. However, BCG given before 4 months of age may decrease the risk of IBD (hazard ratio = 0.43; 95% confidence interval, 0.20-0.93). CONCLUSIONS: This prospective long-term case-cohort study shows that BCG and smallpox vaccination do not cause IBD later in life. These findings are important for the etiological understanding of IBD and of clinical importance because BCG is still one of the most commonly used childhood vaccinations, smallpox vaccine has been reintroduced in the U.S. military, and both vaccines may be used as vectors in new vaccines. PMID- 23624887 TI - A review of mortality and surgery in ulcerative colitis: milestones of the seriousness of the disease. AB - Standardized mortality rates in ulcerative colitis (UC) are no different than that in the general population. Patients who are older and have more comorbidities have increased mortality. Emergent colectomy still carries 30-day mortality rates of approximately 5%. In more recent studies, UC surgery rates at 10 years from diagnosis are nearly 3% in Hungary, <10% in referral center studies from Asia, approximately 10% in Norway, the European Cohort Study of Inflammatory Bowel Diseases and Manitoba, Canada, and nearly 17% in Olmsted County, Minnesota. These rates are for the most part lower than reported colectomy rates from studies completed before 1990. Short-term colectomy rates in severe hospitalized UC have remained stable at 27% for several years. Generally, children seem to have higher rates of extensive colitis at diagnosis than adults. There also seems to be higher rates of colectomy in children than in adults (i.e., at least 20% at 10 years), and perhaps, this reflects a higher rate of extensive disease. Acute severe colitis in patients with UC still represents a condition with a high early colectomy rate and a measurable mortality rate. PMID- 23624888 TI - Patient perceptions of fecal microbiota transplantation for ulcerative colitis. AB - BACKGROUND: Fecal microbiota transplantation (FMT), the delivery of stool from a healthy prescreened donor to an individual with disease, is gaining increasing recognition as a potential treatment for inflammatory bowel diseases. Our objective was to describe patient interest in and social concerns around FMT. METHODS: We conducted a survey of adults with ulcerative colitis (UC) seen in outpatient clinic at the University of Chicago IBD Center. All English-speaking patients >=18 years of age were eligible. Subjects completed a written survey in clinic. Ninety-five participants, median age 39 years, 53% female, were enrolled in the study. RESULTS: Forty-four percent and 49% reported excellent or good/satisfactory medical management of their UC, respectively. Forty-six percent participants were willing to undergo FMT as a treatment of UC, 43% were unsure, and 11% were unwilling to undergo FMT. Subjects who had been hospitalized were more willing to undergo FMT, 54% versus 34%, P = 0.035. Primary concerns included the following: adequate screening for infections (41%), cleanliness (24%), and potential to worsen UC (18%); 21% reported no specific concerns. For donor selection, an equal number of participants (46%) preferred whomever their doctor recommended or family member/spouse. CONCLUSIONS: In our center despite reporting satisfactory to excellent disease control with their treatments, the vast majority of patients with UC are interested in or willing to consider FMT. Proof of safety and effectiveness, and failure of other medical therapies are key issues in considering FMT. Strong interest in this as-yet unproven therapy warrants attention and is a pressing priority for clinical research and education. PMID- 23624889 TI - Hair loss in patients with inflammatory bowel disease. AB - BACKGROUND: Little is known about the prevalence, causes, and management of hair loss in patients with inflammatory bowel disease (IBD). Despite the fact that there are relatively few case reports describing hair loss in IBD, anecdotally, it is a common clinical problem. Hair loss is associated with both acute and chronic illness, with nutritional deficiencies, and with adverse drug reactions, all of which are relevant to IBD. METHODS: A literature search was performed using PubMed from 1966 to July 2012 to identify all articles describing cases of and/or the cause of hair loss in patients with IBD. RESULTS: There is relatively little data describing the prevalence, cause, or course of hair loss in people with IBD. Because there are many potential reasons for hair loss in people with IBD, identifying the cause is not always possible. Telogen effluvium associated with acute or chronic flares of IBD is probably the commonest cause of disease related hair loss, although the prevalence of this is unknown. Other causes include drug side effects and nutritional deficiencies. More recently shared genetic risk factors with alopecia areata and IBD have been identified. CONCLUSIONS: The potential causes of hair loss in IBD are protean, although its prevalence is unknown. A practical guide to assessing and managing patients with hair loss in IBD is presented. PMID- 23624890 TI - Comparison of QD and TID oral mesalazine for maintenance of remission in quiescent ulcerative colitis: a double-blind, double-dummy, randomized multicenter study. AB - BACKGROUND: Mesalazine preparations are widely used to treat mild to moderately severe ulcerative colitis (UC). We compared once-daily administration of oral mesalazine in patients with quiescent UC with the established 3-times-daily prescription, assessing the efficacy and safety of each method in maintaining remission for 52 weeks. METHODS: This was a double-blind, double-dummy, randomized, multicenter noninferiority study in which 301 patients with quiescent UC were randomly assigned to treatment groups and administered prolonged-release oral mesalazine at doses of 1.5 to 2.25 g/d once daily (QD) or 3 times daily (TID) for 52 weeks. The primary endpoint was whether remission was maintained after 52 weeks of administration or until the time of discontinuation, as represented by the Ulcerative Colitis Disease Activity Index score. RESULTS: The proportion of patients still in remission after 52 weeks of administration was 79.4% in the QD group and 71.6% in the TID group. The between-group difference was 7.8% (2-tailed 95% confidence interval [CI]: -2.2% to 17.8%), and the noninferiority of QD administration to TID administration was verified with a noninferiority margin of -10%. In the safety analysis, the incidence of adverse events in each group was 72.4% for the QD group and 76.5% for the TID group, showing no statistically significant difference between the 2 groups (P = 0.4305). CONCLUSIONS: This double-blind parallel-group comparison verified for the first time the noninferiority of QD administration of oral mesalazine 1.5 to 2.25 g/d to TID administration in terms of maintaining remission in patients with UC. PMID- 23624891 TI - The role of disulfide bond in hyperthermophilic endocellulase. AB - The hyperthermophilic endocellulase, EGPh (glycosyl hydrolase family 5) from Pyrococcus horikoshii possesses 4 cysteine residues forming 2 disulfide bonds, as identified by structural analysis. One of the disulfide bonds is located at the proximal region of the active site in EGPh, which exhibits a distinct pattern from that of the thermophilic endocellulase EGAc (glycosyl hydrolase family 5) of Acidothermus cellulolyticus despite the structural similarity between the two endocellulases. The structural similarity between EGPh and EGAc suggests that EGPh possesses a structure suitable for changing the position of the disulfide bond corresponding to that in EGAc. Introduction of this alternative disulfide bond in EGPh, while removing the original disulfide bond, did not result in a loss of enzymatic activity but the EGPh was no longer hyperthermostable. These results suggest that the contribution of disulfide bond to hyperthermostability at temperature higher than 100 degrees C is restrictive, and that its impact is dependent on the specific structural environment of the hyperthermophilic proteins. The data suggest that the structural position and environment of the disulfide bond has a greater effect on high-temperature thermostability of the enzyme than on the potential energy of the dihedral angle that contributes to disulfide bond cleavage. PMID- 23624892 TI - Ion channels and regulation of insulin secretion in human beta-cells: a computational systems analysis. AB - In mammals an increase in glucose leads to block of ATP dependent potassium channels in pancreatic beta cells leading to membrane depolarization. This leads to the repetitive firing of action potentials that increases calcium influx and triggers insulin granule exocytosis. Several important differences between species in this process suggest that a dedicated human-oriented approach is advantageous as extrapolating from rodent data may be misleading in several respects. We examined depolarization-induced spike activity in pancreatic human islet-attached beta-cells employing whole-cell patch-clamp methods. We also reviewed the literature concerning regulation of insulin secretion by channel activity and constructed a data-based computer model of human beta cell function. The model couples the Hodgkin-Huxley-type ionic equations to the equations describing intracellular Ca2+ homeostasis and insulin release. On the basis of this model we employed computational simulations to better understand the behavior of action potentials, calcium handling and insulin secretion in human beta cells under a wide range of experimental conditions. This computational system approach provides a framework to analyze the mechanisms of human beta cell insulin secretion. PMID- 23624893 TI - Signaling pathways mediating adhesion and spreading through extracellular ADP and the P2Y12 receptor: presented by Maria P. Abbracchio. PMID- 23624894 TI - A 3-year-old girl with frequent nose bleeds. PMID- 23624895 TI - Commentary. PMID- 23624896 TI - Commentary. PMID- 23624897 TI - Eleftherios P. Diamandis. PMID- 23624898 TI - A patient with undetectable hemoglobin A(1c). PMID- 23624899 TI - Micromanipulation through chemical play. PMID- 23624902 TI - Neoclassicism in the industrial context. PMID- 23624903 TI - Knockdown of copper chaperone antioxidant-1 by RNA interference inhibits copper stimulated proliferation of non-small cell lung carcinoma cells. AB - Copper is required for cell proliferation and tumor angiogenesis. Cellular copper metabolism is regulated by a network of copper transporters and chaperones. Antioxidant-1 (ATOX1) is a cytosolic copper chaperone important for intracellular copper transport, which plays a role in the regulation of cell proliferation by functioning as a transcription factor in cell growth signal-transduction pathways. The present study aimed to explore the role of ATOX1 in the copper related regulation of lung cancer cell proliferation by immunohistochemical (IHC) analysis of ATOX1 expression in non-small cell lung cancer (NSCLC) tissue samples and by assessing the effects of RNA interference (RNAi)-mediated knockdown of ATOX1 on copper-stimulated proliferation of NSCLC cells. Overexpression of ATOX1 was detected in NSCLC by IHC analysis of the tissue samples from patients diagnosed with NSCLC when compared with expression of ATOX1 in non-malignant lung tissue samples. Knockdown of ATOX1 in the NSCLC cells transduced by a lentiviral vector encoding short hairpin RNA (shRNA) specific for ATOX1 was associated with reduction in copper-stimulated cell proliferation. These findings suggest that ATOX1 plays an important role in copper-stimulated proliferation of NSCLC cells and ATOX1 holds potential as a therapeutic target for lung cancer therapy targeting copper metabolism. PMID- 23624904 TI - Multiplexed tyrosine kinase activity detection in cancer cells using a hydrogel immobilized substrate. AB - Kinases play a key role in cellular signaling, and the overactivation or overexpression of these kinases has been linked to a variety of cancers. Tyrosine kinase inhibitors treat the mechanism of these cancers by targeting the specific kinases that are overactive. Some patients, however, do not respond to these inhibitors or develop resistance to these inhibitors during treatment. Additionally, even within cancers of the same tissue type, different kinases may be overactive in different patients. For example, some lung cancers overexpress epidermal growth factor receptor (EGFR) and respond to EGFR inhibitors, whereas other lung cancers do not overexpress EGFR and receive no benefit from this treatment. Even among patients exhibiting EGFR overexpression, some do not respond to EGFR kinase inhibitors because other kinases, such as Met kinase, are also overactivated. Here we describe a quantitative and specific multiplexed microfluidic assay using a hydrogel immobilized substrate for measuring the kinase activity of Met and Abl kinase from cancer cells. We immobilized kinase specific substrates on macroporous hydrogel micropillars in microchannels. These microchannels were incubated with 6 MUl of a kinase reaction solution containing cancer cell lysate, and we measured kinase activity via fluorescence detection of a phosphotyrosine antibody. We showed that the assay can specifically measure the activity of both Met and Abl kinase within one microchannel and has the potential to measure the activity of as many as five kinases within one microchannel. The assay also detected Met kinase inhibition from lysates of cancer cells grown in the Met kinase inhibitor PHA665752. PMID- 23624906 TI - A plantar closing wedge osteotomy of the medial cuneiform for residual forefoot supination in flatfoot reconstruction. AB - BACKGROUND: Residual forefoot supination is commonly encountered during a flatfoot reconstruction, and a new technique for its treatment is described. Contrary to the standard Cotton osteotomy, a plantar closing wedge osteotomy of the medial cuneiform (PCWOMC) was performed, which has a number of advantages. METHODS: We followed 10 feet in 9 patients who had a PCWOMC performed as the last step of a standard flatfoot reconstruction for the correction of residual forefoot supination. These patients were evaluated pre- and postoperatively by standardized radiographic parameters, Short Form-12 (SF-12), and Foot and Ankle Outcome Score (FAOS). RESULTS: Patients were followed for an average of 25.8 months with final radiographic analysis performed at an average of 9.9 months. A significant difference (P < .001) between pre- and postoperative parameters was demonstrated for both lateral talus-first metatarsal angle and medial-cuneiform to-ground distance. Likewise, there was a statistically significant improvement in the SF-12 score and 4 out of 5 components of the FAOS. One patient developed internal hardware-related symptoms, which were relieved following implant removal. All osteotomies healed uneventfully. CONCLUSION: A PCWOMC can be considered an alternative to the Cotton osteotomy for the treatment of forefoot supination deformity in adult flatfoot reconstruction. The main advantage of this technique over the Cotton osteotomy was simplicity, as an additional dorsal incision and bone graft were not required. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 23624907 TI - Characteristics of male adolescent-onset hallux valgus. AB - BACKGROUND: Several studies show that hallux valgus has a female preponderance and that approximately 50% of patients have an adolescent onset of deformity. However, little is known about male adolescent-onset hallux valgus. We evaluated the radiologic characteristics and the result of deformity correction in male adolescent-onset hallux valgus (MAHV). METHODS: We evaluated 31 feet with MAHV that received corrective osteotomies (16 scarf, 11 distal chevron, 4 proximal chevron, and 21 Akin). The patients' mean age was 22 years. Using standard weight bearing radiographs, we measured hallux valgus angle (HVA), intermetatarsal angle (IMA), distal metatarsal articular angle (DMAA), proximal phalangeal angle (PPA), metatarsus adductus angle (MAA), and congruency, preoperatively and at an average of 21 months after surgery. We assessed the clinical outcome at follow-up with regard to patient satisfaction using the American Orthopedic Foot & Ankle Society (AOFAS) Hallux Metatarsophalangeal-Interphalangeal score. RESULTS: The mean HVA, IMA, DMAA, and PPA decreased from 28.8, 12.0, 11.9, and 6.5 degrees to 10.9, 4.2, 9.7, and 6.3 degrees, respectively (P < .05). Preoperative congruency was 68% (21 of 31 feet). All feet had metatarsus adductus, and the mean MAA was 26.7 degrees. The mean AOFAS score increased from 64.3 to 92.7. Excellent and good satisfaction rate was 94% (29 of 31 feet). We had 2 complications: 1 patient with acute deep infection and 1 patient with complex regional pain syndrome type II accompanying neuralgia of the hallux. CONCLUSIONS: Most of the patients with MAHV had congruent first metatarsophalangeal joints consistent with increased MAA and DMAA. They also had high PPA and relatively lower IMA. Metatarsal osteotomy with lateral translation and phalangeal corrective osteotomy for MAHV was a reliable technique with successful outcomes and low complication rates. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 23624908 TI - Surgical correction of the ball and socket ankle joint in the adult associated with a talonavicular tarsal coalition. AB - BACKGROUND: Ball and socket ankle (BASA) deformity is a rare condition. Little is known about outcomes and treatments in the adult population. METHODS: Retrospective comparative review was performed of 13 patients treated for BASA with a minimum follow-up of 2.5 years. Evaluation included clinical and radiographic review, outcome scores, a questionnaire, and a subjective satisfaction survey. RESULTS: Nine patients with correctable valgus deformity not associated with arthritis of the ankle joint underwent a supramalleolar osteotomy (SMO). Four patients underwent arthrodesis-2 a tibiotalocalcaneal (TTC) arthrodesis and 2 a pantalar arthrodesis. AOFAS scores improved from 30.1 to 77.6 (range, 16-82) (P < .05) in the SMO group. AOFAS scores improved from 24 to 60.5 (range, 16-66) (P < .05) in the arthrodesis group. Arthritis grade in the SMO patients was unchanged in 4 patients at final follow-up and worsened in 5 patients by only 1 grade. Nine patients reported good results (all 4 arthrodesis patients, 5 SMO patients) and 4 reported fair results (all SMO patients). CONCLUSIONS: BASA deformity and dysfunction can be improved with corrective surgery. LEVEL OF EVIDENCE: Level III, prospective comparative study. PMID- 23624909 TI - Operative treatment of chronic irreparable Achilles tendon ruptures with large flexor hallucis longus tendon transfers. AB - BACKGROUND: Transfer of the flexor hallucis longus (FHL) tendon aims to restore function and relieve pain in chronic Achilles tendon (AT) disease. The goal of the present study was to investigate the clinical and radiographic outcomes of FHL transfer to the AT and to compare the transtendinous technique to the transosseous technique. We hypothesized that the type of technique would have a notable impact on outcome. METHODS: Forty patients (42 ankles) were retrospectively reviewed and divided into group 1 (transtendinous technique, 22 patients/24 ankles) and group 2 (transosseous technique, 18 patients/18 ankles). Outcome parameters included the American Orthopaedic Foot & Ankle Society (AOFAS) hindfoot score, Victorian Institute of Sports Assessment-Achilles (VISA-A) score, Foot Function Index (FFI), and Short Form-36 (SF-36) scores. Magnetic resonance imaging of the lower leg was performed preoperatively to assess muscle quality and fatty infiltration. Postoperatively, isokinetic plantar flexion strength was assessed using a Con-Trex dynamometer. RESULTS: In group 1 (follow-up, 73 months; age, 52 years), the AOFAS score improved from 66 points to 89 points (P < .001) with average values for the VISA-A of 76 points, FFI-D pain 15%, and FFI-D function 22%. In group 2 (follow-up, 35 months; age, 56 years), the AOFAS score increased from 59 points to 85 points (P < .001) with mean values for the VISA-A 76 points, FFI-D pain 25%, and FFI-D function 24%. At follow-up, the average SF 36 score in group 1 was 66% and in group 2 was 77%. Isokinetic testing at 30 deg/s in group 1 revealed notable weakness in the operated ankle averaging 54.7 N.m (75% of normal), and in group 2 the average was 58.2 N.m (77% of normal). No statistically significant differences were found between the groups. CONCLUSION: The hypothesis was disproved. Both techniques for FHL transfer to AT, intratendinous and transosseous, provided good to excellent clinical and functional outcome in the treatment of irreparable AT disease. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 23624910 TI - Two-stage procedure in anterior cruciate ligament revision surgery: a five-year follow-up prospective study. AB - PURPOSE: The purpose of this study was to show that this two-stage procedure for ACL (anterior cruciate ligament) revision surgery could be straight-forward and provide satisfactory clinical and functional outcomes. MATERIALS: This is a five year prospective analysis of clinical and functional data on 30 patients (19 men and 11 women; average age 29.1 +/- 5.4) who underwent a two-stage ACL revision procedure after traumatic re-rupture of the ACL. Diagnosis was on Lachman and pivot-shift tests, arthrometer 30-lb KT-1000 side-to-side findings, and on MRI and arthroscopic assessments. RESULTS: Postoperative IKDC and Lysholm scores were significantly improved compared to baseline values (P < 0.001). At the last follow up, 20 of 30 patients (66.7%) had returned to preoperative sport activity level (nine elite athletes, 11 county level), seven had changed to lower sport levels, and three had given up any sport activity. At the same appointment, 11 patients had degenerative changes. All these patients reported significantly lower Lysholm scores compared to patients without any degenerative change (p < 0.001). CONCLUSIONS: In ACL revision surgery, when the first femoral tunnel has been correctly placed, this procedure allows safe filling of large bony defects, with no donor site comorbidities. It provides comfortable clinical, functional and imaging outcomes. PMID- 23624911 TI - Effect of a novel bladder preservation therapy, BOAI-CDDP-radiation (OMC regimen). AB - We have developed a novel form of bladder preservation therapy [OMC (Osaka Medical College)-regimen] involving balloon-occluded-arterial-infusion (BOAI) of an anticancer agent (cisplatin/gemcitabine), used concomitantly with hemodialysis, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects, along with concurrent radiation. We previously reported that the OMC-regimen elicited a complete response (CR) in >90% of patients with organ confined tumors, while LN(+), T4 tumors and a non-UC histological type were statistically significant risk factors for treatment failure and patient survival. In this study, we investigated the effects of the OMC-regimen in patients with organ confined urothelial cancer tumors and the outcomes were compared to those with total cystectomy. Three hundred and one patients were assigned to receive either the OMC-regimen (n=162) or total cystectomy (n=139). Patients in the OMC-regimen group who failed to achieve CR underwent cystectomy, or secondary BOAI with an increased amount of CDDP or gemcitabine (1600 mg). The OMC-regimen yielded 98.1% of clinical response; CR in 93.8% (152/162) of patients; PR in 4.3% (7/162). More than 96% of the CR patients (146/152) were alive with no evidence of recurrence after a mean follow-up of 166 (range 23-960) weeks. No patients suffered grade III toxicity; all patients successfully completed this therapy. The patient survival was significantly better compared to the cystectomy group; the overall 5-, 10- and 15 year survival rates were 87.3, 79.6 and 59.7%, respectively. Moreover, the 5-, 10 and 15-year bladder intact survival rates, the most important issue for bladder preservation therapy, were 85.7, 78.4 and 58.8%, respectively. In conclusion, the OMC-regimen is a useful bladder-preservation strategy, not only in those for whom cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment and for whom palliation would otherwise seem the only option. PMID- 23624912 TI - Inhibitor of growth 4 induces NFkappaB/p65 ubiquitin-dependent degradation. AB - As a tumor suppressor protein, the inhibitor of growth 4 (ING4) has an important role in many cellular processes including cell cycle progression, proliferation, apoptosis, DNA damage response, tumor angiogenesis and contact inhibition. Here, we report that ING4 functions as an E3 ubiquitin ligase to induce nuclear factor kappaB (NFkappaB)/p65 degradation. The plant homeodomain finger of ING4 interacted with p65 to undergo robust ubiquitination and degradation. ING4 bound to p65 and delivered the Lys-48-linked polyubiquitin to Lys-62 residue of p65, leading to ubiquitination of p65 and degradation. Lys-62 residue of p65 was required for ING4-mediated ubiquitination of p65 and degradation. Further analysis shows that C239 of ING4 was critical for ING4-induced p65 degradation. These findings demonstrate that ING4 acts as an E3 ubiquitin ligase to induce ubiquitination of p65 and degradation, which is critical to terminate NFkappaB activation. PMID- 23624913 TI - SCFs in the new millennium. AB - Substrate-specific degradation is a key feature of the ubiquitin proteasome system. Substrate specificity is typically directed by the E3 or ubiquitin ligase; such specificity can be conferred either by ligase modification or expression or conversely via modification of substrates that permit their recognition by a specific E3 ligase. The most well-known example of such complexes are the Cullin-RING ligases (CRLs). CRLs are composed of one of seven cullin-family scaffold proteins; the CRL serves as a scaffold that interacts directly with a RING-domain enzyme (Rbx1/2) through an extensive protein-protein interface within the globular C-terminal domain. At the N terminus, the cullin associates with an adaptor protein through cullin-repeat motifs. This adaptor, in turn, facilitates recruitment of a substrate-specifying factor that recruits the target to be ubiquitylated. The prototypical CRL is the cul1-containing complex, commonly referred to as the Skp1-Cul1-Fbox (SCF) ligase. SCF ligases contribute to the timely destruction of numerous substrates thereby ensuring normal cell growth. The importance of SCF function is highlighted by cancer-specific alterations in either the expression or the function of select F-box substrate specific adaptors that results in neoplastic conversion. Herein, we discuss the current understanding of SCF function and contribution to cell biology. PMID- 23624914 TI - ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer. AB - The mitogen-activated extracellular signal-regulated kinase/extracellular signal regulated kinase (MEK/ERK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways are often concurrently activated by separate genetic alterations in colorectal cancer (CRC), which is associated with CRC progression and poor survival. However, how activating both pathways is required for CRC metastatic progression remains unclear. Our recent study showed that both ERK and AKT signaling are required to activate eukaryotic translation initiation factor 4E (eIF4E) initiated cap-dependent translation via convergent regulation of the translational repressor 4E-binding protein 1 (4E-BP1) for maintaining CRC transformation. Here, we identified that the activation of cap-dependent translation by cooperative ERK and AKT signaling is critical for promotion of CRC motility and metastasis. In CRC cells with coexistent mutational activation of ERK and AKT pathways, inhibition of either MEK or AKT alone showed limited activity in inhibiting cell migration and invasion, but combined inhibition resulted in profound effects. Genetic blockade of the translation initiation complex by eIF4E knockdown or expression of a dominant active 4E-BP1 mutant effectively inhibited migration, invasion and metastasis of CRC cells, whereas overexpression of eIF4E or knockdown of 4E-BP1 had the opposite effect and markedly reduced their dependence on ERK and AKT signaling for cell motility. Mechanistically, we found that these effects were largely dependent on the increase in mammalian target of rapamycin complex 1 (mTORC1)-mediated survivin translation by ERK and AKT signaling. Despite the modest effect of survivin knockdown on tumor growth, reduction of the translationally regulated survivin profoundly inhibited motility and metastasis of CRC. These findings reveal a critical mechanism underlying the translational regulation of CRC metastatic progression, and suggest that targeting cap-dependent translation may provide a promising treatment strategy for advanced CRC. PMID- 23624915 TI - LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK SPHK1 signaling and extracellular matrix remodeling. AB - EGFR overexpression and chromosome 3p deletion are two frequent events in head and neck cancers. We previously mapped the smallest region of recurrent copy number loss at 3p12.2-p14.1. LRIG1, a negative regulator of EGFR, was found at 3p14, and its copy-number loss correlated with poor clinical outcome. Inducible expression of LRIG1 in head and neck cancer TW01 cells, a line with low LRIG1 levels, suppressed cell proliferation in vitro and tumor growth in vivo. Gene expression profiling, quantitative RT-PCR, chromatin immunoprecipitation, and western blot analysis demonstrated that LRIG1 modulated extracellular matrix (ECM) remodeling and EGFR-MAPK-SPHK1 transduction pathway by suppressing expression of EGFR ligands/activators, MMPs and SPHK1. In addition, LRIG1 induction triggered cell morphology changes and integrin inactivation, which coupled with reduced SNAI2 expression. By contrast, knockdown of endogenous LRIG1 in TW06 cells, a line with normal LRIG1 levels, significantly enhanced cell proliferation, migration and invasiveness. Such tumor-promoting effects could be abolished by specific MAPK or SPHK1 inhibitors. Our data suggest LRIG1 as a tumor suppressor for head and neck cancers; LRIG1 downregulation in cancer cells enhances EGFR-MAPK-SPHK1 signaling and ECM remodeling activity, leading to malignant phenotypes of head and neck cancers. PMID- 23624916 TI - Dual roles of hemidesmosomal proteins in the pancreatic epithelium: the phosphoinositide 3-kinase decides. AB - Given the failure of chemo- and biotherapies to fight advanced pancreatic cancer, one major challenge is to identify critical events that initiate invasion. One priming step in epithelia carcinogenesis is the disruption of epithelial cell anchorage to the basement membrane which can be provided by hemidesmosomes (HDs). However, the existence of HDs in pancreatic ductal epithelium and their role in carcinogenesis remain unexplored. HDs have been explored in normal and cancer pancreatic cells, and patient samples. Unique cancer cell models where HD assembly can be pharmacologically manipulated by somatostatin/sst2 signaling have been then used to investigate the role and molecular mechanisms of dynamic HD during pancreatic carcinogenesis. We surprisingly report the presence of mature type-1 HDs comprising the integrin alpha6beta4 and bullous pemphigoid antigen BP180 in the human pancreatic ductal epithelium. Importantly, HDs are shown to disassemble during pancreatic carcinogenesis. HD breakdown requires phosphoinositide 3-kinase (PI3K)-dependent induction of the matrix metalloprotease MMP-9, which cleaves BP180. Consequently, integrin alpha6beta4 delocalizes to the cell-leading edges where it paradoxically promotes cell migration and invasion through S100A4 activation. As S100A4 in turn stimulates MMP-9 expression, a vicious cycle maintains BP180 cleavage. Inactivation of this PI3K-MMP-9-S100A4 signaling loop conversely blocks BP180 cleavage, induces HD reassembly and inhibits cell invasion. We conclude that mature type-1 HDs are critical anchoring structures for the pancreatic ductal epithelium whose disruption, upon PI3K activation during carcinogenesis, provokes pancreatic cancer cell migration and invasion. PMID- 23624917 TI - Mammary epithelial cell interactions with fibronectin stimulate epithelial mesenchymal transition. AB - In the mammary gland, the stromal extracellular matrix (ECM) undergoes dramatic changes during development and in tumorigenesis. For example, normal adult breast tissue is largely devoid of the ECM protein fibronectin (FN) whereas high FN levels have been detected in the stroma of breast tumors. FN is an established marker for epithelial-mesenchymal transition (EMT), which occurs during development and has been linked to cancer. During EMT, epithelial cell adhesion switches from cell-cell contacts to mainly cell-ECM interactions, raising the possibility that FN may have a role in promoting this transition. Using MCF-10A mammary epithelial cells, we show that exposure to exogenous FN induces an EMT response including upregulation of the EMT markers FN, Snail, N-cadherin, vimentin, the matrix metalloprotease MMP2, alpha-smooth muscle actin and phospho Smad2, as well as acquisition of cell migratory behavior. FN-induced EMT depends on Src kinase and extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase signaling but not on the immediate early gene EGR-1. FN initiates EMT under serum-free conditions; this response is partially reversed by a transforming growth factor (TGF)beta-neutralizing antibody, suggesting that FN enhances the effect of endogenous TGFbeta. EMT marker expression is upregulated in cells on a fragment of FN containing the integrin-binding domain but not other domains. Differences in gene expression between FN and Matrigel are maintained with addition of a subthreshold level of TGFbeta1. Together, these results show that cells interacting with FN are primed to respond to TGFbeta. The ability of FN to induce EMT shows an active role for the stromal ECM in this process and supports the notion that the increased levels of FN observed in breast tumors facilitate tumorigenesis. PMID- 23624918 TI - The molecular and cell biology of pediatric low-grade gliomas. AB - Pilocytic astrocytoma (PA) is the most common glial cell tumor arising in children. Sporadic cases are associated with KIAA1549:BRAF fusion rearrangements, while 15-20% of children develop PA in the context of the neurofibromatosis 1 (NF1) inherited tumor predisposition syndrome. The unique predilection of these tumors to form within the optic pathway and brainstem (NF1-PA) and cerebellum (sporadic PA) raises the possibility that gliomagenesis requires more than biallelic inactivation of the NF1 tumor suppressor gene or expression of the KIAA1549:BRAF transcript. Several etiologic explanations include differential susceptibilities of preneoplastic neuroglial cell types in different brain regions to these glioma-causing genetic changes, contributions from non neoplastic cells and signals in the tumor microenvironment, and genomic modifiers that confer glioma risk. As clinically-faithful rodent models of sporadic PA are currently under development, Nf1 genetically-engineered mouse (GEM) models have served as tractable systems to study the role of the cell of origin, deregulated intracellular signaling, non-neoplastic cells in the tumor microenvironment and genomic modifiers in gliomagenesis. In this report, we highlight advances in Nf1 GEM modeling and review new experimental evidence that supports the emerging concept that Nf1- and KIAA1549:BRAF-induced gliomas arise from specific cell types in particular brain locations. PMID- 23624919 TI - MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. AB - Elevated activity of the mitogen-activated protein kinase (MAPK) signaling cascade is found in the majority of human melanomas and is known to regulate proliferation, survival and invasion. Current targeted therapies focus on decreasing the activity of this pathway; however, we do not fully understand how these therapies impact tumor biology, especially given that melanoma is a heterogeneous disease. Using a three-dimensional (3D), collagen-embedded spheroid melanoma model, we observed that MEK and BRAF inhibitors can increase the invasive potential of ~20% of human melanoma cell lines. The invasive cell lines displayed increased receptor tyrosine kinase (RTK) activity and activation of the Src/FAK/signal transducers and activators of transcription-3 (STAT3) signaling axis, also associated with increased cell-to-cell adhesion and cadherin engagement following MEK inhibition. Targeting various RTKs, Src, FAK and STAT3 with small molecule inhibitors in combination with a MEK inhibitor prevented the invasive phenotype, but only STAT3 inhibition caused cell death in the 3D context. We further show that STAT3 signaling is induced in BRAF-inhibitor resistant cells. Our findings suggest that MEK and BRAF inhibitors can induce STAT3 signaling, causing potential adverse effects such as increased invasion. We also provide the rationale for the combined targeting of the MAPK pathway along with inhibitors of RTKs, SRC or STAT3 to counteract STAT3-mediated resistance phenotypes. PMID- 23624920 TI - Overexpression of Cdk6 and Ccnd1 in chondrocytes inhibited chondrocyte maturation and caused p53-dependent apoptosis without enhancing proliferation. AB - Cell proliferation and differentiation are closely coupled. However, we previously showed that overexpression of cyclin-dependent kinase (Cdk6) blocks chondrocyte differentiation without affecting cell-cycle progression in vitro. To investigate whether Cdk6 inhibits chondrocyte differentiation in vivo, we generated chondrocyte-specific Cdk6 transgenic mice using Col2a1 promoter. Unexpectedly, differentiation and cell-cycle progression of chondrocytes in the Cdk6 transgenic mice were similar to those in wild-type mice. Then, we generated chondrocyte-specific Ccnd1 transgenic mice and Cdk6/Ccnd1 double transgenic mice to investigate the possibility that Cdk6 inhibits chondrocyte differentiation through E2f activation. Bromodeoxyuridine (BrdU)-positive chondrocytes and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive chondrocytes were increased in number, and chondrocyte maturation was inhibited only in Cdk6/Ccnd1 transgenic mice (K6(H)/D1(H) mice), which showed dwarfism. Retinoblastoma protein (pRb) was highly phosphorylated but p107 was upregulated, and the expression of E2f target genes was dysregulated as shown by upregulation of Cdc6 but downregulation of cyclin E, dihydrofolate reductase (dhfr), Cdc25a and B-Myb in chondrocytes of K6(H)/D1(H) mice. Similarly, overexpression of Cdk6/Ccnd1 in a chondrogenic cell line ATDC5 highly phosphorylated pRb, upregulated p107, induced apoptosis, upregulated Cdc6 and downregulated cyclin E, dhfr and B-Myb and p107 small interfering RNA reversed the expression of downregulated genes. Further, introduction of kinase-negative Cdk6 and cyclin D1 abolished all effects by Cdk6/cyclin D1 in ATDC5 cells, indicating the requirement of the kinase activity on these effects. p53 deletion partially restored the size of the skeleton and almost completely rescued chondrocyte apoptosis, but failed to enhance chondrocyte proliferation in K6(H)/D1(H) mice. These findings indicated that Cdk6/Ccnd1 overexpression inhibited chondrocyte maturation and enhanced G1/S cell-cycle transition by phosphorylating pRb, but the chondrocytes failed to accomplish the cell cycle, and underwent p53-dependent apoptosis probably due to the dysregulation of E2f target genes. Our findings also indicated that p53 deletion in addition to the inactivation of Rb was not sufficient to accelerate chondrocyte proliferation, suggesting the resistance of chondrocytes to sarcomagenesis. PMID- 23624921 TI - Activation of NFAT signaling establishes a tumorigenic microenvironment through cell autonomous and non-cell autonomous mechanisms. AB - NFAT (the nuclear factor of activated T cells) upregulation has been linked to cellular transformation intrinsically, but it is unclear whether and how tissue cells with NFAT activation change the local environment for tumor initiation and progression. Direct evidence showing NFAT activation initiates primary tumor formation in vivo is also lacking. Using inducible transgenic mouse systems, we show that tumors form in a subset of, but not all, tissues with NFATc1 activation, indicating that NFAT oncogenic effects depend on cell types and tissue contexts. In NFATc1-induced skin and ovarian tumors, both cells with NFATc1 activation and neighboring cells without NFATc1 activation have significant upregulation of c-Myc and activation of Stat3. Besides known and suspected NFATc1 targets, such as Spp1 and Osm, we have revealed the early upregulation of a number of cytokines and cytokine receptors, as key molecular components of an inflammatory microenvironment that promotes both NFATc1(+) and NFATc1(-) cells to participate in tumor formation. Cultured cells derived from NFATc1-induced tumors were able to establish a tumorigenic microenvironment, similar to that of the primary tumors, in an NFATc1-dependent manner in nude mice with T-cell deficiency, revealing an addiction of these tumors to NFATc1 activation and downplaying a role for T cells in the NFATc1-induced tumorigenic microenvironment. These findings collectively suggest that beyond the cell autonomous effects on the upregulation of oncogenic proteins, NFATc1 activation has non-cell autonomous effects through the establishment of a promitogenic microenvironment for tumor growth. This study provides direct evidence for the ability of NFATc1 in inducing primary tumor formation in vivo and supports targeting NFAT signaling in anti-tumor therapy. PMID- 23624923 TI - Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in (V600D/E)BRAF mutant melanoma depends on JNK and TNF-alpha signaling. AB - Melanoma is an aggressive skin cancer that carries an extremely poor prognosis when local invasion, nodal spread or systemic metastasis has occurred. Recent advances in melanoma biology have revealed that RAS-RAF-MEK-ERK signaling has a pivotal role in governing disease progression and treatment resistance. Proof-of concept clinical studies have shown that direct BRAF inhibition yields impressive responses in advanced disease but these are short-lived as treatment resistance rapidly emerges. Therefore, there is a pressing need to develop new targeted strategies for BRAF mutant melanoma. As such, oncolytic viruses represent a promising cancer-specific approach with significant activity in melanoma. This study investigated interactions between genetically-modified vaccinia virus (GLV 1h68) and radiotherapy in melanoma cell lines with BRAF mutant, Ras mutant or wild-type genotype. Preclinical studies revealed that GLV-1h68 combined with radiotherapy significantly increased cytotoxicity and apoptosis relative to either single agent in (V600D)BRAF/(V600E)BRAF mutant melanoma in vitro and in vivo. The mechanism of enhanced cytotoxicity with GLV-1h68/radiation (RT) was independent of viral replication and due to attenuation of JNK, p38 and ERK MAPK phosphorylation specifically in BRAF mutant cells. Further studies showed that JNK pathway inhibition sensitized BRAF mutant cells to GLV-1h68-mediated cell death, mimicking the effect of RT. GLV-1h68 infection activated MAPK signaling in (V600D)BRAF/(V600E)BRAF mutant cell lines and this was associated with TNF-alpha secretion which, in turn, provided a prosurvival signal. Combination GLV-1h68/RT (or GLV-1h68/JNK inhibition) caused abrogation of TNF-alpha secretion. These data provide a strong rationale for combining GLV-1h68 with irradiation in (V600D/E)BRAF mutant tumors. PMID- 23624922 TI - SPROUTY2 is a beta-catenin and FOXO3a target gene indicative of poor prognosis in colon cancer. AB - SPROUTY2 (SPRY2) is an intracellular regulator of receptor tyrosine kinase signaling involved in cell growth, differentiation and tumorigenesis. Here, we show that SPRY2 is a target gene of the Wnt/beta-catenin pathway that is abnormally activated in more than 90% of colon carcinomas. In human colon cancer cells, SPRY2 expression is induced by beta-catenin in co-operation with the transcription factor FOXO3a instead of lymphoid enhancer factor/T-cell factor proteins. We found binding of beta-catenin to the SPRY2 promoter at FOXO3a response elements. In vivo, cells marked by nuclear beta-catenin and FOXO3a express SPRY2 in proliferative epithelial tissues, such as intestinal mucosa and epidermis. Consistently, inducible beta-catenin deletion in mice reduced Spry2 expression in the small intestine. Moreover, SPRY2 protein expression correlated with nuclear beta-catenin and FOXO3a colocalization in human colon carcinomas. Importantly, the amount of SPRY2 protein correlated with shorter overall survival of colon cancer patients. Our data reveal SPRY2 as a novel Wnt/beta-catenin and FOXO3a target gene indicative of poor prognosis in colon cancer. PMID- 23624924 TI - Toward a predictive understanding of the fitness costs of heterospecific pollen receipt and its importance in co-flowering communities. AB - PREMISE OF THE STUDY: While we have a good understanding of how co-flowering plants interact via pollinator foraging, we still know very little about how plants interact via heterospecific pollen (HP) receipt. To fill this gap, we sought to illuminate the extent of HP receipt and quantitatively evaluate the fitness consequences of HP receipt. We consider plant traits that could mediate the fitness costs of HP receipt in an effort to better understand the potential consequences of pollinator sharing in natural communities. * METHODS: We survey the literature for occurrence of HP receipt and assess variation in the fitness effects of a standard HP treatment. We develop a conceptual framework for understanding variation in fitness consequences of HP receipt. * KEY RESULTS: We find evidence for variation in HP receipt and its costs. Our framework predicts that certain traits (self-incompatibility, small, highly aperaturate or allelopathic pollen) will lead to detrimental HP donors, whereas others (self compatibility, small or wet stigmas, short styles) will lead to vulnerable HP recipients. We also predict that detrimental effects of HP receipt will increase with decreasing phylogenetic distance between donor and recipient. * CONCLUSIONS: Our framework can guide much needed additional work so that we can evaluate whether and which plant traits contribute to the variation in the effects of HP receipt. This will be a step toward predicting the consequences of HP receipt in natural communities, and ultimately transform our understanding of the role of postpollination interactions in floral trait evolution and pollinator sharing. PMID- 23624925 TI - Seed development in Trimenia (Trimeniaceae) and its bearing on the evolution of embryo-nourishing strategies in early flowering plant lineages. AB - PREMISE OF THE STUDY: Seeds of most families in the ancient angiosperm lineage Austrobaileyales produce a full-fledged genetically biparental embryo-nourishing endosperm. However, seeds of fossil and extant Trimeniaceae have been described as having a perisperm, a maternal nutrient-storing and embryo-nourishing tissue derived from the nucellus of the ovule. Because perisperm is also found in Nymphaeales, another ancient angiosperm clade, the presence of a perisperm in Trimeniaceae, if confirmed, would be congruent with the hypothesis that the first angiosperms used a perisperm in addition to a minute (nutrient-transferring) endosperm. * METHODS: Seed development was studied from fertilization through maturity/dormancy in Trimenia moorei and in maturing fruits of T. neocaledonica. * KEY RESULTS: A persistent layer of nucellar tissue surrounds the endosperm but does not contain stored nutrients and does not function as a perisperm. The nutrient-storing and embryo-nourishing tissue in Trimenia seeds is an endosperm, as is the case in all other members of the Austrobaileyales studied to date. * CONCLUSION: The absence of a perisperm and the presence of a typical nutrient storing and embryo-nourishing endosperm in Trimeniaceae may represent the ancestral condition for angiosperms. However, the combination of a copious nutrient-storing and embryo-nourishing perisperm with a minute endosperm, as in Nymphaeales, remains a plausible plesiomorphic condition for angiosperms as a whole. In either case, the developmental and functional biology of the diploid endosperm of Trimenia (and other Austrobaileyales) differs markedly from the diploid endosperm of Nymphaeales, and is fundamentally similar to the triploid endosperms of most other angiosperms. PMID- 23624926 TI - Developmental plasticity, genetic assimilation, and the evolutionary diversification of sexual expression in Solanum. AB - PREMISE OF THE STUDY: For over a century, it has been hypothesized that selection can convert an environmentally induced phenotype (i.e., plasticity) into a fixed (constitutively produced) phenotype, a process known as genetic assimilation. While evidence of assimilation is accumulating, the role of plasticity generally and assimilation specifically in evolutionary diversification has rarely been examined from a comparative phylogenetic perspective. * METHODS: We combined experimental analyses of plasticity with ancestral state reconstructions to examine the evolutionary dynamics of sexual expression in two well-characterized sections (Acanthophora and Lasiocarpa) in Solanum subgenus Leptostemonum. We examined sexual expression phenotypes and the proportion of staminate flowers produced under contrasting resource conditions in 10 species and combined these data with previous studies. * KEY RESULTS: Staminate flower production was phenotypically plastic for nine of 14 species and unaffected by treatment in five species. Two of the nonplastic species bore few staminate flowers, and three constitutively produced large numbers of staminate flowers. For individuals and species producing staminate flowers, these flowers occurred in a distinctive architectural pattern that was qualitatively the same in both plastic and nonplastic species. Parsimony and Bayesian reconstructions demonstrate that plasticity is ancestral among the species studied. * CONCLUSIONS: Plasticity has been lost independently in sections Acanthophora and Lasiocarpa, and the consequence of its loss results in evolutionary diversification of sexual expression. In section Acanthophora, loss of plasticity represents a reversion to production of predominantly hermaphroditic flowers. In contrast, the fixed production of staminate flowers in Lasiocarpa has the hallmarks of evolution via genetic assimilation. PMID- 23624927 TI - Reconstructing the evolution and biogeographic history of tribe Cardueae (Compositae). AB - PREMISE OF THE STUDY: Tribe Cardueae (thistles) forms one of the largest tribes in the family Compositae (2400 species), with representatives in almost every continent. The greatest species richness of Cardueae occurs in the Mediterranean region where it forms an important element of its flora. New fossil evidence and a nearly resolved phylogeny of Cardueae are used here to reconstruct the spatiotemporal evolution of this group. * METHODS: We performed maximum parsimony and Bayesian phylogenetic inference based on nuclear ribosomal DNA and chloroplast DNA markers. Divergence times and ancestral area reconstructions for main lineages were estimated using penalized likelihood and dispersal-vicariance analyses, respectively, and integrated over the posterior distribution of the phylogeny from the Bayesian Markov chain Monte Carlo analysis to accommodate uncertainty in phylogenetic relationships. * KEY RESULTS: The phylogeny shows that subtribe Cardopatiinae is sister to the remaining subtribes, and subtribes Carlininae and Echinopsinae appear as consecutive sister-clades to the Carduinae/Centaureinae. Tribe Cardueae is inferred to have originated around the Mid Eocene in West Asia, which is also the ancestral area of most subtribes within Cardueae. Diversification within each subtribe began during the Oligocene Miocene period. * CONCLUSIONS: Most diversification events within Cardueae are related to the continuous cycles of area connection and division between the Anatolian microplate and the western Mediterranean Basin during the Oligocene Miocene and with the uplift of the Himalayan range from the Miocene onward. From these two regions, thistles dispersed and colonized the rest of the continents (e.g., the New World, Africa, and Australia), most likely during the colder Pliocene-Pleistocene period. PMID- 23624928 TI - Atypical laterality of resting gamma oscillations in autism spectrum disorders. AB - Abnormal brain oscillatory activity has been found in autism spectrum disorders (ASD) and proposed as a potential biomarker. While several studies have investigated gamma oscillations in ASD, none have examined resting gamma power across multiple brain regions. This study investigated resting gamma power using EEG in 15 boys with ASD and 18 age and intelligence quotient matched typically developing controls. We found a decrease in resting gamma power at right lateral electrodes in ASD. We further explored associations between gamma and ASD severity as measured by the Social Responsiveness Scale (SRS) and found a negative correlation between SRS and gamma power. We believe that our findings give further support of gamma oscillations as a potential biomarker for ASD. PMID- 23624929 TI - Relationship between amount of cigarette smoking and coronary atherosclerosis on coronary CTA in asymptomatic individuals. AB - Current smoking is a powerful independent predictor of coronary atherosclerosis in asymptomatic individuals. Many researchers have suggested a cigarette dose response relationship between smoking and subclinical coronary atherosclerosis. Our study purposes were (a) to investigate the prevalence and plaque characteristics of coronary atherosclerosis in asymptomatic smokers and (b) to assess the cigarette dose-response relationship between smoking and subclinical coronary atherosclerosis using coronary CT angiography (CTA). We consecutively enrolled 7,104 self-referred asymptomatic subjects who underwent coronary CTA as part of a general health evaluation. Current smokers (n = 1,784) were categorized according to total pack years (TPY) with four grades (A, 0.1-10; B, 10-20; C, 20 30; D, >30), smoking duration (SD, years) with four grades (A, 0.1-10; B, 10-20; C, 20-30; D, >30), and number of cigarettes per day (CPD) with four grades (A, 1 20; B, 10-20; C, 20-40; D, >40). After adjusting for other cardiovascular risk factors, adjusted odds ratios for current smokers versus never-smokers as a control group were estimated for the presence of plaques, significant stenosis, and non-calcified plaques (NCP). Current smokers had a statistically significant higher prevalence of any plaque, significant stenosis, NCP, and coronary artery calcium score >100 than never-smokers. According to each categorization of TPY, SD, and CPD, the subclinical coronary atherosclerosis risk increased as grades increased in asymptomatic current smokers relative to never-smokers after adjusting for variable clinical and chemical risk factors. Our study suggests a cigarette dose-response relationship between current smoking and coronary atherosclerosis in asymptomatic individuals. PMID- 23624930 TI - Cardiac magnetic resonance imaging safety following percutaneous coronary intervention. AB - In the first 8 weeks after percutaneous coronary intervention (PCI), possible negative interactions exist between the cardiac magnetic resonance (CMR) imaging environment and the weakly ferromagnetic material in coronary stents. There are circumstances when CMR would be indicated shortly following PCI, such as acute myocardial infarction (AMI). The purpose of this study is to demonstrate CMR safety shortly following stent PCI in AMI patients. We performed a retrospective analysis of safety data in AMI patients with recently placed coronary artery stents enrolled in a multi-center phase II trial for gadoversetamide. Patients underwent 1.5 T CMR within 16 days of PCI. Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) and ECGs were taken pre-CMR, 1, 2, and 24 h post-CMR. Any major adverse cardiac event (MACE) or other serious adverse events in the first 24 h after MRI were recorded. There were 258 stents in 211 AMI patients. The mean delay to CMR following PCI was 6.5 +/- 4 days, with 62 patients (29 %) receiving CMR within 3 days and 132 patients (63 %) within 1 week. Patients showed no significant vital sign changes following CMR. Ten patients (4.7 %) showed mild, transient ECG changes. Within the 24-h follow-up group, 4 patients (1.9 %) had moderate to severe events, including chest pain (1) and elevated cardiac enzymes (1), resolving in 24 h; heart failure (1) and ischemic stroke (1). There were no deaths. This study demonstrates fewer MACE in AMI patients undergoing 1.5 T CMR within 16 days of stent placement in comparison to post-stent event rate reported in the literature. This study adds to the CMR after stent PCI safety profile suggested by previous studies and is the largest and first study that uses multicenter data to assess stent safety following CMR examination. PMID- 23624931 TI - The chromodomain helicase Chd4 is required for Polycomb-mediated inhibition of astroglial differentiation. AB - Polycomb group (PcG) proteins form transcriptional repressor complexes with well established functions during cell-fate determination. Yet, the mechanisms underlying their regulation remain poorly understood. Here, we extend the role of Polycomb complexes in the temporal control of neural progenitor cell (NPC) commitment by demonstrating that the PcG protein Ezh2 is necessary to prevent the premature onset of gliogenesis. In addition, we identify the chromodomain helicase DNA-binding protein 4 (Chd4) as a critical interaction partner of Ezh2 required specifically for PcG-mediated suppression of the key astrogenic marker gene GFAP. Accordingly, in vivo depletion of Chd4 in the developing neocortex promotes astrogenesis. Collectively, these results demonstrate that PcG proteins operate in a highly dynamic, developmental stage-dependent fashion during neural differentiation and suggest that target gene-specific mechanisms regulate Polycomb function during sequential cell-fate decisions. PMID- 23624932 TI - Regulation of cerebral cortex size and folding by expansion of basal progenitors. AB - Size and folding of the cerebral cortex increased massively during mammalian evolution leading to the current diversity of brain morphologies. Various subtypes of neural stem and progenitor cells have been proposed to contribute differently in regulating thickness or folding of the cerebral cortex during development, but their specific roles have not been demonstrated. We report that the controlled expansion of unipotent basal progenitors in mouse embryos led to megalencephaly, with increased surface area of the cerebral cortex, but not to cortical folding. In contrast, expansion of multipotent basal progenitors in the naturally gyrencephalic ferret was sufficient to drive the formation of additional folds and fissures. In both models, changes occurred while preserving a structurally normal, six-layered cortex. Our results are the first experimental demonstration of specific and distinct roles for basal progenitor subtypes in regulating cerebral cortex size and folding during development underlying the superior intellectual capability acquired by higher mammals during evolution. PMID- 23624933 TI - Real-time observation of the conformational dynamics of mitochondrial Hsp70 by spFRET. AB - The numerous functions of the important class of molecular chaperones, heat shock proteins 70 (Hsp70), rely on cycles of intricate conformational changes driven by ATP-hydrolysis and regulated by cochaperones and substrates. Here, we used Forster resonance energy transfer to study the conformational dynamics of individual molecules of Ssc1, a mitochondrial Hsp70, in real time. The intrinsic dynamics of the substrate-binding domain of Ssc1 was observed to be uncoupled from the dynamic interactions between substrate- and nucleotide-binding domains. Analysis of the fluctuations in the interdomain separation revealed frequent transitions to a nucleotide-free state. The nucleotide-exchange factor Mge1 did not induce ADP release, as expected, but rather facilitated binding of ATP. These results indicate that the conformational cycle of Ssc1 is more elaborate than previously thought and provide insight into how the Hsp70s can perform a wide variety of functions. PMID- 23624934 TI - Arginine methylation of the c-Jun coactivator RACO-1 is required for c-Jun/AP-1 activation. AB - c-Jun, the major component of the AP-1 transcription factor complex, has important functions in cellular proliferation and oncogenic transformation. The RING domain-containing protein RACO-1 functions as a c-Jun coactivator that molecularly links growth factor signalling to AP-1 transactivation. Here we demonstrate that RACO-1 is present as a nuclear dimer and that c-Jun specifically interacts with dimeric RACO-1. Moreover, RACO-1 is identified as a substrate of the arginine methyltransferase PRMT1, which methylates RACO-1 on two arginine residues. Arginine methylation of RACO-1 promotes a conformational change that stabilises RACO-1 by facilitating K63-linked ubiquitin chain formation, and enables RACO-1 dimerisation and c-Jun interaction. Abrogation of PRMT1 function impairs AP-1 activity and results in decreased expression of a large percentage of c-Jun target genes. These results demonstrate that arginine methylation of RACO-1 is required for efficient transcriptional activation by c-Jun/AP-1 and thus identify PRMT1 as an important regulator of c-Jun/AP-1 function. PMID- 23624935 TI - BRCA1 is a negative modulator of the PRC2 complex. AB - The Polycomb-repressive complex 2 (PRC2) is important for maintenance of stem cell pluripotency and suppression of cell differentiation by promoting histone H3 lysine 27 trimethylation (H3K27me3) and transcriptional repression of differentiation genes. Here we show that the tumour-suppressor protein BRCA1 interacts with the Polycomb protein EZH2 in mouse embryonic stem (ES) and human breast cancer cells. The BRCA1-binding region in EZH2 overlaps with the noncoding RNA (ncRNA)-binding domain, and BRCA1 expression inhibits the binding of EZH2 to the HOTAIR ncRNA. Decreased expression of BRCA1 causes genome-wide EZH2 re targeting and elevates H3K27me3 levels at PRC2 target loci in both mouse ES and human breast cancer cells. BRCA1 deficiency blocks ES cell differentiation and enhances breast cancer migration and invasion in an EZH2-dependent manner. These results reveal that BRCA1 is a key negative modulator of PRC2 and that loss of BRCA1 inhibits ES cell differentiation and enhances an aggressive breast cancer phenotype by affecting PRC2 function. PMID- 23624936 TI - The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer. AB - TBX2 and TBX3, closely related members of the T-box family of transcription factor genes, are expressed in mammary tissue in both humans and mice. Ulnar mammary syndrome (UMS), an autosomal dominant disorder caused by mutations in TBX3, underscores the importance of TBX3 in human breast development, while abnormal mammary gland development in Tbx2 or Tbx3 mutant mice provides models for experimental investigation. In addition to their roles in mammary development, aberrant expression of TBX2 and TBX3 is associated with breast cancer. TBX2 is preferentially amplified in BRCA1/2-associated breast cancers and TBX3 overexpression has been associated with advanced stage disease and estrogen receptor-positive breast tumors. The regulation of Tbx2 and Tbx3 and the downstream targets of these genes in development and disease are not as yet fully elucidated. However, it is clear that the two genes play unique, context dependent roles both in mammary gland development and in mammary tumorigenesis. PMID- 23624937 TI - Alteration of flavonoid accumulation patterns in transparent testa mutants disturbs auxin transport, gravity responses, and imparts long-term effects on root and shoot architecture. AB - Flavonoids have broad cross-kingdom biological activity. In Arabidopsis, flavonoid accumulation in specific tissues, notably the root elongation zone and root/shoot junction modulate auxin transport, affect root gravitropism, and influence overall plant architecture. The relative contribution made by aglycones and their glycosides remains undetermined, and the longer-term phenotypic effects of altered flavonoid accumulation are not fully assessed. We tested Arabidopsis thaliana mutants that accumulate different flavonoids to determine which flavonoids were causing these affects. Tandem mass spectrometry and in situ fluorescence localisation were used to determine the in vivo levels of aglycones in specific tissues of 11 transparent testa mutants. We measured rootward and shootward auxin transport, gravitropic responses, and identified the long-term changes to root and shoot architecture. Unexpected aglycone species accumulated in vivo in several flavonoid-pathway mutants, and lower aglycone levels occurred in transcription factor mutants. Mutants accumulating more quercetin and quercetin-glycosides changed the greatest in auxin transport, gravitropism, and aerial tissue growth. Early flavonoid-pathway mutants showed aberrant lateral root initiation patterns including clustered lateral root initiations at a single site. Transcription factor mutants had multiple phenotypes including shallow root systems. These results confirm that aglycones are present at very low levels, show that lateral root initiation is perturbed in early flavonoid-pathway mutants, and indicate that altered flavonoid accumulation affects multiple aspects of plant architecture. PMID- 23624939 TI - Development and validation of a new radiographic scoring system to evaluate bone and cartilage destruction and healing of large joints with rheumatoid arthritis: ARASHI (Assessment of rheumatoid arthritis by scoring of large joint destruction and healing in radiographic imaging) study. AB - OBJECTIVE: To assess the reliability and sensitivity of a novel scoring method to evaluate the radiographic appearance of and longitudinal changes including joint remodeling in large joints with early and established rheumatoid arthritis (RA). METHODS: The ARASHI study group devised new radiographic scoring systems (Status score; range 0-16 points, and Change score; range -11 to 12 points) for evaluation of large joints with RA. Radiographs showing anterior/posterior views of large joints (shoulder, elbow, hip, knee, and ankle joints) taken at two time points (mean interval 2.3 years) were collected from 25 patients with established RA (5 patients for each of the 5 joints, 50 films in total), and an additional 5 films of each joint with severe joint destruction were collected from 5 different sets of RA patients. After consensus on the definition of each component and reader training, images were evaluated using the Larsen's grading system and the ARASHI Status and Change score by 9 independent senior orthopedic surgeons. The reliability was estimated by intra-class correlation coefficients (ICCs) and measurement error by 95% confidence intervals of minimum detectable change (MDC95). RESULTS: ARASHI Status score and Change score significantly correlated with Larsen's grade (r = 0.89, P < 0.0001) and follow-up-baseline differences in Larsen's grade (r = 0.83, P < 0.0001), respectively. Inter-reader ICCs were very high for both Status score (0.88, 95% confidence interval [CI], 0.83-0.92, P < 0.001) and Change score (0.92, 95% CI, 0.87-0.96, P < 0.001). Intra-reader ICCs were also very high for both Status score (0.92, 95% CI, 0.71-0.98, P < 0.001) and Change score (0.97, 95% CI, 0.91-0.99, P < 0.001). The MDC95 for inter-reader agreement were 4.18 (25% of maximum obtainable score, MOS) and 4.99 (21% of MOS) for Status score and Change score, respectively. The MDC95 for intra-reader agreement was acceptable with 2.82 (17% of MOS) and 3.02 (13% of MOS) for Status score and Change score, respectively. CONCLUSION: The ARASHI scoring method showed good inter-/intra-reader reliability with high ICCs and acceptable MDC95 with respect to each large joint and the components of both Status and Change scores. The results suggest that the ARASHI scoring method might be useful for the assessment of status, as well as longitudinal monitoring of destruction and remodeling of large joints with RA. PMID- 23624938 TI - The dynamics of histone H3 modifications is species-specific in plant meiosis. AB - Different histone modifications often modify DNA-histone interactions affecting both local and global structure of chromatin, thereby providing a vast potential for functional responses. Most studies have focused on the role of several modifications in gene transcription regulation, being scarce on other aspects of eukaryotic chromosome structure during cell division, mainly in meiosis. To solve this issue we have performed a cytological analysis to determine the chromosomal distribution of several histone H3 modifications throughout all phases of both mitosis and meiosis in different plant species. We have chosen Aegilops sp. and Secale cereale (monocots) and Arabidopsis thaliana (dicots) because they differ in their phylogenetic affiliation as well as in content and distribution of constitutive heterochromatin. In the species analyzed, the patterns of H3 acetylation and methylation were held constant through mitosis, including modifications associated with "open chromatin". Likewise, the immunolabeling patterns of H3 methylation remained invariable throughout meiosis in all cases. On the contrary, there was a total loss of acetylated H3 immunosignals on condensed chromosomes in both meiotic divisions, but only in monocot species. Regarding the phosphorylation of histone H3 at Ser10, present on condensed chromosomes, although we did not observe any difference in the dynamics, we found slight differences between the chromosomal distribution of this modification between Arabidopsis and cereals (Aegilops sp. and rye). Thus far, in plants chromosome condensation throughout cell division appears to be associated with a particular combination of H3 modifications. Moreover, the distribution and dynamics of these modifications seem to be species-specific and even differ between mitosis and meiosis in the same species. PMID- 23624940 TI - The clinical characteristics of juvenile-onset systemic sclerosis in Japanese patients. PMID- 23624941 TI - Syntheses, structures and magnetic properties of two unprecedented hybrid compounds constructed from open Wells-Dawson anions and high-nuclear transition metal clusters. AB - Two new inorganic-organic hybrid compounds Na2(C3N2H12)4{[Ni5(OH)3(H2O)4(CH3CO2)][Si2W18O66]}.12.5H2O (1) and (C3N2H12)3{[Co(II)2Co(III)4(OH)5(H2O)2(CH3CO2)][Si2W18O66]}.6H2O.(C3N2H10) (2), based on lacunary polyoxometalates and high-nuclear transition-metal clusters, have been synthesized by a new method (solvothermal method). Single crystal XRD, magnetic measurements, nonlinear-optical (NLO) measurements, thermogravimetric (TG) measurements, and IR spectra were performed to analyze the structures and properties of 1 and 2. XRD analyses reveal that compound 1 consists of an open Wells-Dawson anion [Si2W18O66](16-), a five-nuclear cationic cluster [Ni5(OH)3(H2O)4(CH3CO2)](6+), free Na(+) cations, and protonated 1,3 diaminopropanes. Compound 2 has a similar structure to 1, while a six-nuclear cationic cluster [Co(II)2Co(III)4(OH)5(H2O)2(CH3CO2)](10+) replaces the five nuclear cationic cluster [Ni5(OH)3(H2O)4(CH3CO2)](6+) in 1. Magnetic susceptibility measurements indicate antiferromagnetic interactions in 1, and the chirality of compound 2 may bring potential properties of catalysis and optical nonlinearity. PMID- 23624942 TI - Differential expression of micro-heterogeneous LewisX-type glycans in the stem cell compartment of the developing mouse spinal cord. AB - Complex glycan structures and their respective carrier molecules are often expressed in a cell type specific manner. Thus, glycans can be used for the enrichment of specific cell types such as neural precursor cells (NPCs). We have recently shown that the monoclonal antibodies 487(LeX) and 5750(LeX) differentially detect the LewisX (LeX) glycan on NPCs in the developing mouse forebrain. Here, we analysed the staining pattern of both antibodies during late embryonic mouse spinal cord development. At E13.5 both antibodies strongly label the central canal region. Along these lines they detect the LeX glycan primarily on Nestin-positive NPCs at that age. Moreover, we show that spinal cord NPCs cultured as free floating neurospheres display a high immunoreactivity to both antibodies. In that context, we also demonstrate that the 487(LeX) antibody can be used to deplete a subpopulation of neurosphere forming NPCs from a mixed E13.5 spinal cord cell suspension. Towards the end of embryogenesis the overall immunoreactivity to both antibodies increases and the staining appears very diffuse. However, the 5750(LeX) antibody still labels the central canal region. The increase in immunoreactivity correlates with an expression increase of the extracellular matrix molecules Tenascin C and Receptor Protein Tyrosine Phosphatase beta/zeta, two potential LeX carrier proteins. In line with this, immunoprecipitation analyses confirmed Tenascin C as a LeX carrier protein in the embryonic mouse spinal cord. However, the immunoreactivity to both antibodies appears only to be marginally affected in the absence of Tenascin C, arguing against Tenascin C being the major LeX carrier. In conclusion our study gives some novel insights into the complex expression of LeX glycans and potential carrier proteins during the development of the mouse spinal cord. PMID- 23624944 TI - Study of a bifuran vs. bithiophene unit for the rational design of pi-conjugated systems. What have we learned? AB - A comparative study of two structural isomers highlights the advantages of bifuran vs. bithiophene units in conjugated systems, such as higher fluorescence, solubility, and increased stability of the oxidized species. Importantly, we have found that the small bifuran unit bestows the advantages found in longer oligofurans, and should be considered in the rational design of pi-conjugated systems. PMID- 23624943 TI - Prenatal stress produces social behavior deficits and alters the number of oxytocin and vasopressin neurons in adult rats. AB - The present study investigated the long-lasting effects of prenatal repeated restraint stress on social behavior and anxiety, as well as its repercussions on oxytocin (OT) and vasopressin (VP)-positive neurons of the paraventricular (PVN) and supraoptic (SON) nuclei from stressed pups in adulthood. Female Wistar rats were exposed to restraint stress in the last 7 days of pregnancy. At birth, pups were cross-fostered and assigned to the following groups: prenatally non-stressed offspring raised by prenatally non-stressed mothers (NS:NS), prenatally non stressed offspring raised by prenatally stressed mothers (S:NS), prenatally stressed offspring raised by prenatally non-stressed mothers (NS:S), prenatally stressed offspring raised by prenatally stressed mothers (S:S). As adults, male prenatally stressed offspring raised both by stressed mothers (S:S group) and non stressed ones (NS:S group) showed impaired social memory and interaction. In addition, when both adverse conditions coexisted (S:S group), increased anxiety like behavior and aggressiveness was observed in association with a decrease in the number of OT-positive magnocellular neurons, VP-positive magnocellular and parvocellular neurons of the PVN. The NS:S group exhibited a reduction in the amount of VP-positive magnocellular neurons compared to the S:NS. Thus, the social behavior deficits observed in the S:S and NS:S groups may be only partially associated with these alterations to the peptidergic systems. No changes were shown in the OT and VP cellular composition of the SON nucleus. Nevertheless, it is clear that a special attention should be given to the gestational period, since stressful events during this time may be related to the emergence of behavioral impairments in adulthood. PMID- 23624945 TI - Trafficking to the thymus. AB - The continuous production of T lymphocytes requires that hematopoietic progenitors developing in the bone marrow migrate to the thymus. Rare progenitors egress from the bone marrow into the circulation, then traffic via the blood to the thymus. It is now evident that thymic settling is tightly regulated by selectin ligands, chemokine receptors, and integrins, among other factors. Identification of these signals has enabled progress in identifying specific populations of hematopoietic progenitors that can settle the thymus. Understanding the nature of progenitor cells and the molecular mechanisms involved in thymic settling may allow for therapeutic manipulation of this process, and improve regeneration of the T lineage in patients with impaired T cell numbers. PMID- 23624946 TI - The Protein Model Portal--a comprehensive resource for protein structure and model information. AB - The Protein Model Portal (PMP) has been developed to foster effective use of 3D molecular models in biomedical research by providing convenient and comprehensive access to structural information for proteins. Both experimental structures and theoretical models for a given protein can be searched simultaneously and analyzed for structural variability. By providing a comprehensive view on structural information, PMP offers the opportunity to apply consistent assessment and validation criteria to the complete set of structural models available for proteins. PMP is an open project so that new methods developed by the community can contribute to PMP, for example, new modeling servers for creating homology models and model quality estimation servers for model validation. The accuracy of participating modeling servers is continuously evaluated by the Continuous Automated Model EvaluatiOn (CAMEO) project. The PMP offers a unique interface to visualize structural coverage of a protein combining both theoretical models and experimental structures, allowing straightforward assessment of the model quality and hence their utility. The portal is updated regularly and actively developed to include latest methods in the field of computational structural biology. Database URL: http://www.proteinmodelportal.org. PMID- 23624947 TI - Characterization of ZC3H15 as a potential TRAF-2-interacting protein implicated in the NFkappaB pathway and overexpressed in AML. AB - The gene product of the zinc finger CCCH-type containing 15 (ZC3H15) gene, an immediate early erythropoietin response gene (synonymous: LEREPO4), was further characterized. ZC3H15 was expressed ubiquitously in all human tissues tested by northern blotting and showed mainly a diffuse cytoplasmic distribution by immune fluorescence microscopy and western blotting of subcellular protein fractions. The expression of ZC3H15 was downregulated effectively in HeLa cells to <=13% of the control by transfection of specific small interfering RNA (siRNA). Subsequent Affymetrix microarray analysis revealed 202 differentially expressed genes including 114 induced (>=3-fold) genes and 88 suppressed (<=0.3-fold) genes. The gene ontology (GO) categories containing an over-representation of differentially expressed genes comprised cell growth, transcription, cell adhesion, regulation of NF-kappaB, regulation of MAPK, cell cycle arrest and immune response. ZC3H15 interacted with the signaling adapter protein tumor necrosis factor receptor associated factor 2 (TRAF-2) as shown by co-immunoprecipitation. ZC3H15 expression was found to be significantly increased in acute myeloid leukemia (AML) samples compared to MDS, CML, ALL and normal bone marrow samples using the Leukemia Gene Atlas (LGA) database. Based on these data, it is hypothesized that ZC3H15 may interact with TRAF-2 functionally within the NF-kappaB pathway, and may be explored as a potential target in AML. PMID- 23624948 TI - Development and screening of contrast agents for in vivo imaging of Parkinson's disease. AB - PURPOSE: The goal was to identify molecular imaging probes that would enter the brain, selectively bind to Parkinson's disease (PD) pathology, and be detectable with one or more imaging modalities. PROCEDURE: A library of organic compounds was screened for the ability to bind hallmark pathology in human Parkinson's and Alzheimer's disease tissue, alpha-synuclein oligomers and inclusions in two cell culture models, and alpha-synuclein aggregates in cortical neurons of a transgenic mouse model. Finally, compounds were tested for blood-brain barrier permeability using intravital microscopy. RESULTS: Several lead compounds were identified that bound the human PD pathology, and some showed selectivity over Alzheimer's pathology. The cell culture models and transgenic mouse models that exhibit alpha-synuclein aggregation did not prove predictive for ligand binding. The compounds had favorable physicochemical properties, and several were brain permeable. CONCLUSIONS: Future experiments will focus on more extensive evaluation of the lead compounds as PET ligands for clinical imaging of PD pathology. PMID- 23624949 TI - Direct, quantitative, and noninvasive imaging of the transport of active agents through intact brain with positron emission tomography. AB - PURPOSE: Our goal was to use positron emission tomography (PET) to analyze the movement of radiolabeled agents in tissue to enable direct measurement of drug delivery to the brain. PROCEDURES: Various (11)C- and (18) F-labeled compounds were delivered directly to an agarose phantom or rat striatum. Concentration profiles were extracted for analysis and fitted to diffusion models. RESULTS: Diffusion coefficients ranged from 0.075 +/- 0.0026 mm(2)/min ([(18) F]fluoride ion, 18 Da) to 0.0016 +/- 0.0018 mm(2)/min ([(18) F]NPB4-avidin, 68 kDa) and matched well with predictions based on molecular weight (R (2) = 0.965). The tortuosity of the brain extracellular space was estimated to be 1.56, with the tissue clearance halftime of each tracer in the brain varying from 19 to 41 min. CONCLUSIONS: PET is an effective modality to directly quantify the movement of locally delivered drugs or drug carriers. This continuous, noninvasive assessment of delivery will aid the design of better drug delivery methods. PMID- 23624950 TI - Electrochemical investigation of the interaction between lysozyme-shelled microbubbles and vitamin C. AB - We report loading of vitamin C (ascorbic acid) on to lysozyme-shelled microbubbles. The interaction between lysozyme-shelled microbubbles and vitamin C was studied by use of cyclic and differential pulse voltammetry, zeta potential measurements, and scanning electron microscopy. The effect of microbubbles on electrochemical measurement of ascorbic acid was evaluated. The linear range for ascorbic acid obtained for differential pulse measurement in the presence of 1 mg mL(-1) microbubbles was 1-50 MUmol L(-1) (y = 0.067x + 0.130, r(2) = 0.995), with a detection limit of 0.5 MUmol L(-1). The experimental conditions, i.e., pH and ionic strength, were optimized to improve the interaction between ascorbic acid and lysozyme-shelled microbubbles. The results were satisfactory when the interaction was performed for 1 h in aqueous solution at pH 6. The amount of vitamin C loaded on the microbubbles (90% of the analyte added, RSD(inter-expt.) = 3%, n = 6) and the stability of microbubbles-ascorbic acid complex (until 72 h at 25 degrees C) were also evaluated by use of differential pulse voltammetry and zeta potential measurements. PMID- 23624951 TI - Molecular imaging of paper cross sections by FT-IR spectroscopy and principal component analysis. AB - The molecular imaging of paper cross sections containing the wet-strength additive poly(amidoamine)-epichlorohydrin (PAE) was effected by Fourier transform infrared (FT-IR) spectroscopic imaging. Thin cross sections of laboratory sheet samples were prepared and transferred onto CaF2 substrates. A laboratory sheet sample without PAE acted as a reference. Principal component analysis (PCA) was applied to identify and to reveal the distribution of PAE across the section. Differences in the loading plots of the fourth and fifth principal components for the sheets with and without PAE were found in the region of the amide I, amide II, and amine bands within a variance of 0.4-0.8%. The score images of the PCA reveal inhomogeneous distribution of PAE. Small areas of higher concentration of PAE occur across the cross section. The aim of this study was to demonstrate that FT-IR spectroscopic imaging provides spatially resolved quantitative information about the chemical composition of paper, which was successfully achieved. PMID- 23624952 TI - Size and charge characterization of polymeric drug delivery systems by Taylor dispersion analysis and capillary electrophoresis. AB - In this work, Taylor dispersion analysis and capillary electrophoresis were used to characterize the size and charge of polymeric drug delivery nanogels based on polyglutamate chains grafted with hydrophobic groups of vitamin E. The hydrophobic vitamin E groups self-associate in water to form small hydrophobic nanodomains that can incorporate small drugs or therapeutic proteins. Taylor dispersion analysis is well suited to determine the weight average hydrodynamic radius of nanomaterials and to get information on the size polydispersity of polymeric samples. The effective charge was determined either from electrophoretic mobility and hydrodynamic radius using electrophoretic modeling (three different approaches were compared), or by indirect UV detection in capillary electrophoresis. The influence of vitamin E hydrophobicity on the polymer effective charge has been studied. The presence of vitamin E leads to a drastic decrease in polymer effective charge in comparison to non-modified polyglutamate. Finally, the electrophoretic behavior of polyglutamate backbone grafted with hydrophobic vitamin E (pGVE) nanogels according to the ionic strength was investigated using the recently proposed slope plot approach. It was deduced that the pGVE nanogels behave electrophoretically as polyelectrolytes which is in good agreement with the high water content of the nanogels. PMID- 23624953 TI - The influence of stationary phase on pressure-induced retention, selectivity and resolution changes in RP-LC. AB - This paper reports the influence of a diverse range of stationary phases and differing mobile phase modifiers on pressure-induced retention changes in reversed-phase liquid chromatography (RP-LC). The practical implications of these effects in the Tanaka column characterization using ultra high-performance liquid chromatography (UHPLC) conditions, and implications for HPLC to UHPLC translations in order to increase productivity and resolution are investigated. The stationary and mobile phase combinations responded to a similar degree to elevated pressure; hence, the authors believe that reliable column characterization parameters should be obtainable when UHPLC format columns are evaluated using the Tanaka approach. Analytes exhibited differing pressure induced retention changes even for only modest increases in pressure (i.e. DeltaP(total) 85 bar as shown when one transfers from a 3- to 2-MUm particle). The degree of pressure-induced retention changes correlated with the analyte's molar volume and refractivity. The hydrophobicity of the analytes, as measured by logD, only exhibited a weak correlation. Hence, translating a RP-LC methodology from large to smaller particle size material of the same type may result in an increased or decreased selectivity and hence resolution between two analytes depending on their differing response to the pressure-induced retention changes. This potentially has a major impact on LC method development/optimization strategies and LC method translations. PMID- 23624954 TI - Ionization of pesticides using a far-ultraviolet femtosecond laser in gas chromatography/time-of-flight mass spectrometry. AB - The fourth harmonic emission (200 nm) of a femtosecond Ti:sapphire laser (35 fs) was generated and used in the multiphoton ionization of 49 pesticides in gas chromatography/time-of-flight mass spectrometry. The limit of detection was improved when the ionization source from the third harmonic emission (267 nm) was replaced with the fourth harmonic emission for several pesticide molecules that contained no conjugated double bonds since their absorption bands are located in the far-ultraviolet region. This analytical instrument was used in the analysis of a series of real samples including potatoes, carrots, and cabbage, and a signal suspected to arise from di-allate was observed for the potato sample. ? PMID- 23624955 TI - Differential linear scan voltammetry: analytical performance in comparison with pulsed voltammetry techniques. AB - We report here on differential linear scan voltammetry, DLSV, that combines the working principles of linear scan voltammetry, LSV, and the numerous existing pulsed voltammetry techniques. DLSV preserves the information from continuous interrogation in voltage and high accuracy that LSV provides about electrochemical processes, and the much better sensitivity of differential pulsed techniques. DLSV also minimizes the background current compared to both LSV and pulsed voltammetry. An early version of DLSV, derivative stationary electrode polarography, DSEP, had been proposed in the 1960s but soon abandoned in favor of the emerging differential pulsed techniques. Relative to DSEP, DLSV takes advantage of the flexibility of discrete smoothing differentiation that was not available to early investigators. Also, DSEP had been explored in pure solutions and with reversible electrochemical reactions. DLSV is tested in this work in more challenging experimental contexts: the measurement of oxygen with a carbon fiber microelectrode in buffer, and with a gold microdisc electrode exposed to a live biological preparation. This work compares the analytical performance of DLSV and square wave voltammetry, the most popular pulsed voltammetry technique. PMID- 23624956 TI - Rituximab in adult patients with multi-relapsing/steroid-dependent minimal change disease and focal segmental glomerulosclerosis: a report of 5 cases. AB - BACKGROUND: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are common causes of nephrotic syndrome in children and adults. However, frequent relapses, steroid dependence, steroid resistance, and side effects of immunosuppressive therapy remain a therapeutic challenge. Rituximab (RTX) has evolved as an efficacious alternative in childhood MCD/FSGS. We report the effect of RTX in 5 adult patients with multirelapsing/steroid-dependent nephrotic syndrome due to MCD or FSGS. RESULTS: All five patients treated with RTX achieved sustained complete remission and additional immunosuppression was withdrawn. One patient had a relapse after 23 months, which was successfully treated with a further series of RTX infusion without reinitiation of steroid therapy. Serious adverse events related to RTX therapy were not observed in our patients. CONCLUSIONS: Our results indicate that RTX is effective and cessation of additional immunosuppressants could be achieved in all patients reported in this study. RTX may be an effective alternative therapy in adult patients with multirelapsing/steroid-dependent nephrotic syndrome due to MCD or FSGS. PMID- 23624957 TI - Holocarboxylase synthetase synergizes with methyl CpG binding protein 2 and DNA methyltransferase 1 in the transcriptional repression of long-terminal repeats. AB - Holocarboxylase synthetase (HLCS) is a chromatin protein that facilitates the creation of histone H3 lysine 9-methylation (H3K9me) gene repression marks through physical interactions with the histone methyltransferase EHMT-1. HLCS knockdown causes a depletion of H3K9me marks in mammalian cell cultures and severe phenotypes such as short lifespan and low stress resistance in Drosophila melanogaster. HLCS displays a punctuate distribution pattern in chromatin despite lacking a strong DNA-binding domain. Previous studies suggest that the binding of HLCS to chromatin depends on DNA methylation. We tested the hypothesis that HLCS interacts physically with the DNA methyltransferase DNMT1 and the methyl CpG binding protein MeCP2 to facilitate the binding of HLCS to chromatin, and that these interactions contribute toward the repression of long-terminal repeats (LTRs) by H3K9me marks. Co-immunoprecipitation and limited proteolysis assays provided evidence suggesting that HLCS interacts physically with both DNMT1 and MeCP2. The abundance of H3K9me marks was 207% greater in the LTR15 locus in HLCS overexpression human embryonic kidney HEK293 cells compared with controls. This gain in H3K9me was inversely linked with a 87% decrease in mRNA coding for LTRs. Effects of HLCS abundance on LTR expression were abolished when DNA methylation marks were erased by treating cells with 5-azacytidine. We conclude that interactions between DNA methylation and HLCS are crucial for mediating gene repression by H3K9me, thereby providing evidence for epigenetic synergies between the protein biotin ligase HLCS and dietary methyl donors. PMID- 23624958 TI - Image quality of low-dose CCTA in obese patients: impact of high-definition computed tomography and adaptive statistical iterative reconstruction. AB - The accuracy of coronary computed tomography angiography (CCTA) in obese persons is compromised by increased image noise. We investigated CCTA image quality acquired on a high-definition 64-slice CT scanner using modern adaptive statistical iterative reconstruction (ASIR). Seventy overweight and obese patients (24 males; mean age 57 years, mean body mass index 33 kg/m(2)) were studied with clinically-indicated contrast enhanced CCTA. Thirty-five patients underwent a standard definition protocol with filtered backprojection reconstruction (SD-FBP) while 35 patients matched for gender, age, body mass index and coronary artery calcifications underwent a novel high definition protocol with ASIR (HD-ASIR). Segment by segment image quality was assessed using a four-point scale (1 = excellent, 2 = good, 3 = moderate, 4 = non-diagnostic) and revealed better scores for HD-ASIR compared to SD-FBP (1.5 +/- 0.43 vs. 1.8 +/- 0.48; p < 0.05). The smallest detectable vessel diameter was also improved, 1.0 +/- 0.5 mm for HD-ASIR as compared to 1.4 +/- 0.4 mm for SD-FBP (p < 0.001). Average vessel attenuation was higher for HD-ASIR (388.3 +/- 109.6 versus 350.6 +/- 90.3 Hounsfield Units, HU; p < 0.05), while image noise, signal-to-noise ratio and contrast-to noise ratio did not differ significantly between reconstruction protocols (p = NS). The estimated effective radiation doses were similar, 2.3 +/- 0.1 and 2.5 +/- 0.1 mSv (HD-ASIR vs. SD-ASIR respectively). Compared to a standard definition backprojection protocol (SD-FBP), a newer high definition scan protocol in combination with ASIR (HD-ASIR) incrementally improved image quality and visualization of distal coronary artery segments in overweight and obese individuals, without increasing image noise and radiation dose. PMID- 23624959 TI - Identifying a high risk cardiovascular phenotype by carotid MRI-depicted intraplaque hemorrhage. AB - Intraplaque hemorrhage (IPH), a component of late-stage complicated plaque, identified within carotid endarterectomy surgical specimens has been recently demonstrated to predict cardiovascular (CV) events. MRI is able to depict carotid IPH. We investigated the ability of carotid MR-depicted IPH (MR-IPH) to identify high-risk CV patients. From January 2008 to April 2011, 216 patients (mean age, 67.5 years; range 31-100) referred for neurovascular MRI at an academic tertiary care centre, underwent 3T carotid MRI with adjunct 3D high-spatial-resolution coronal imaging to detect MR-IPH. Five experienced neuroradiologists made a binary decision on the presence or absence of MR-IPH. Patients' charts were reviewed blindly for demographic and CV outcomes data. Of the patients with and without MR-IPH, 62.5 % (15/24) and 19.8 % (38/192) had a composite CV event (defined as a past myocardial infarction, coronary intervention (i.e., angioplasty, stenting or bypass graft) and/or peripheral vascular disease), respectively. The odds ratio (OR) of a composite CV event in the MR-IPH group was 6.75 (Bivariable analysis, 95 % CI 2.75-16.6, p < 0.0001) and 3.25 (Multivariable regression analysis, 1.14-9.37, p = 0.028). MR-IPH had the highest OR of a prior CV event compared to other variables including age, sex, hypertension and stenosis. The OR of individual CV events was also significant: MI (3.35, 95 % CI 2.11-14.2, p < 0.01), coronary stenting (26.4, 95 % CI 8.80-79.4, p < 0.01), coronary angioplasty (21, 95 % CI 4.84-91.1, p < 0.01), and PVD (3.35, 95 % CI 1.09-10.3, p < 0.05). MR-IPH is independently associated with prior CV events in patients who are evaluated for neurovascular disease. Carotid MR-IPH, employed easily in routine clinical practice, is emerging as an indicator of systemic vascular disease and may potentially be a useful surrogate marker of CV risk including in those already undergoing neurovascular imaging. PMID- 23624961 TI - Regioselective di- and tetra-functionalisation of gamma-cyclodextrin using capping methodology. AB - Alkylation of gamma-cyclodextrin with 3 equiv. of 1,3-bis[bis(4-tert butylphenyl)chloromethyl]benzene, followed by permethylation afforded selectively a singly capped (A,B), as well as two doubly capped (A,B:D,E and A,B:E,F) methylated gamma-CDs. Deprotection with HBF4 gave quantitatively the corresponding diols and tetrols, which constitute valuable starting compounds for further functionalisation. PMID- 23624960 TI - Intra-procedural imaging of the left atrium and pulmonary veins with rotational angiography: a comparison of anatomy obtained by pre-procedural cardiac computed tomography and trans-thoracic echocardiography. AB - This study evaluated the feasibility and accuracy of three-dimensional rotational angiography (3DRA) to determine the anatomy of the left atrium (LA) and pulmonary veins (PVs) compared with cardiac computed tomography (CCT) and trans-thoracic echocardiography (TTE). One hundred two patients (56.1 +/- 9.9 years, 86 males) with an indication for atrial fibrillation ablation were prospectively enrolled. Intra-procedural 3DRA was performed with power injected contrast medium (20 cc/s for 4 s, 240 degrees ) in the LA. 3DRA images of the LA and PVs were assessed qualitatively and then compared quantitatively. LA volume measured by 3DRA, CCT and TTE were compared. The majority of 3DRA acquisitions were optimal in delineating the right-side LA-PV (95 % for right superior PV and 96 % for right inferior PV) and left inferior PV anatomy (91 %), whereas it was optimal in only 63 % of left superior PV and 73 % of the LA appendage. The circumferences of PV ostia identified by 3DRA and CCT were correlated in four PVs (r = 0.57 for right superior PV, r = 0.67 for right inferior PV, r = 0.60 for left superior PV, and r = 0.52 for left inferior PV, p < 0.001). The mean LA volume measured by 3DRA (120 +/- 32 mL) was greater than that found by CCT (109 +/- 35 mL) or TTE (64 +/- 23 mL), but the 3DRA LA volume measurements correlated well with those of CCT (r = 0.83, p < 0.001) and TTE (r = 0.69, p < 0.001). Intra-procedural 3DRA provided anatomical accuracy of LA and PVs comparable to those of CCT. However, optimal delineation of the left superior PV and LA appendage was limited. The LA volume determined by 3DRA was well correlated with those of CCT and TTE, despite different absolute values of each. PMID- 23624962 TI - Reducing fetal alcohol exposure in the United States. AB - Fetal alcohol exposure is the leading preventable cause of birth and developmental defects in the United States. Despite a growing body of knowledge about the spectrum of disorders resulting from fetal alcohol exposure, 1 in 9 pregnant women continues to drink alcohol during pregnancy, and a small percentage of pregnant women continues to binge drink. Health care providers do not consistently screen pregnant women for alcohol use, nor do health professionals necessarily know how to counsel pregnant women effectively about the risks of fetal alcohol exposure. In this article, we review the epidemiology of fetal alcohol exposure and discuss current strategies for screening and prevention of fetal alcohol exposure. We also explore the multiple barriers that exist toward reducing alcohol-exposed pregnancies from the patient, provider, and systems perspectives. Finally, we make recommendations for improved clinical and public health strategies to eliminate fetal alcohol exposure in the United States. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians. LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to describe rates of fetal alcohol exposure in the United States, describe the demographic characteristics of women at highest risk for fetal alcohol exposure, counsel patients appropriately regarding the risk of poor fetal outcomes in association with fetal alcohol exposure, and understand the barriers to effective counseling about fetal alcohol exposure. PMID- 23624963 TI - Emergency cerclage: literature review. AB - This article reviews the use and effectiveness of emergency cerclage for women who present with a dilated cervix in the second trimester of pregnancy and seeks to identify predictors of favorable emergency cerclage outcomes. We searched PubMed and the Cochrane Library for the period January 1995 to April 2012 and used the terms "emergency cerclage," "emergency stitch," "rescue cerclage," and "rescue stitch." Thirty-four studies in which transvaginal emergency cervical cerclage was performed in women with a dilated cervix were identified and included. Predictors of poor outcome were prolapsed membranes, evidence of intra amniotic or systemic infection, symptomatic presentation, cervical dilatation greater than 3 cm, or cerclage after 22 weeks. According to observational and limited randomized controlled trials, the cerclage group did significantly better than the bed-rest group in mean randomization-to-delivery interval, preterm delivery before 34 weeks, and compound neonatal morbidity. The current data suggest that emergency cerclage is associated with a longer latency period and, most often, with better pregnancy outcomes when compared with bed rest. Many of the predictors of adverse outcomes appear to be associated with evidence of inflammation or infection. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to review the use and evaluate the effectiveness of emergency cerclage for women who present with a dilated cervix in the second trimester, to identify predictors of favorable emergency cerclage outcomes, and to compare emergency cerclage versus bed rest. PMID- 23624964 TI - Obesity in pregnancy: a big problem and getting bigger. AB - Obesity has increased dramatically in the United States over the last several decades, with approximately 40% of women now considered overweight or obese. Obesity has been shown to be associated with poor pregnancy outcomes, including increased rates of cesarean delivery, preeclampsia, gestational diabetes, fetal macrosomia, stillbirth, and postterm pregnancy. In this review, we discuss the association of obesity with maternal, fetal, and pregnancy outcomes as well as the recommendations for care of the obese gravida. TARGET AUDIENCE: Obstetricians and gynecologists and family physicians. LEARNING OBJECTIVES: After completing the CME activity, physicians should be better able to describe the maternal, neonatal, and intrapartum complications associated with obesity in pregnancy and implement additional changes to prenatal care appropriate for the obese gravida. PMID- 23624965 TI - Saving vs creating: perceptions of intensive care at different ages and the potential for injustice. PMID- 23624966 TI - Prenatal diagnosis of Potocki-Lupski syndrome in a fetus with hypoplastic left heart and aberrant right subclavian artery. AB - Potocki-Lupski syndrome (PTLS) is a rare genetic disorder associated with neurodevelopmental delay and heart defects. We report the first case of prenatal diagnosis of PTLS in a fetus with hypoplastic left heart and aberrant right subclavian artery. Detection of a fetal heart defect should be followed by chromosomal and genetic studies in order to rule out fetal aneuploidy and/or associated genetic syndromes with significant implications for the treatment of children with PTLS. PMID- 23624967 TI - A case of isolated bilateral pulmonary arterial calcification diagnosed in utero. AB - We report a very rare case of isolated multiple pulmonary arterial calcification with severe bilateral peripheral pulmonary arterial stenosis diagnosed in utero. Despite treatment with bisphosphonate for 6 months, systolic right ventricular pressure increased persistently and surpassed left ventricular pressure. After successful bilateral pulmonary arterioplasty at 13 months of age, the patient showed decreased systolic right ventricular pressure with normal interventricular septal configuration. This is the first case report for an isolated pulmonary artery calcification without other arterial calcification proven by non-contrast computed tomography of a living patient. PMID- 23624968 TI - Alveolar capillary dysplasia with misalignment of pulmonary [corrected] veins: concordance between pathological and molecular diagnosis. AB - We report the case of a newborn with alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), a rare condition of unknown etiology presenting in the neonatal period with significant persistent pulmonary hypertension. The diagnosis was made by lung biopsy and confirmed at autopsy. Specific genetic analysis demonstrated defects in the FOXF1 gene. The diagnosis of ACD/MPV requires a high level of suspicion and is made by lung biopsy or necropsy examination by a pediatric pathologist with experience in this condition. The availability of genetic testing has led to increasing diagnosis of patients with this lethal disorder and can influence their management, specifically by indicating the need for lung biopsy in a critically ill newborn. PMID- 23624969 TI - A neonate with Coombs-negative hemolytic jaundice with spherocytes but normal erythrocyte indices: a rare case of autosomal-recessive hereditary spherocytosis due to alpha-spectrin deficiency. AB - The diagnosis of hereditary spherocytosis (HS) in a newborn infant is generally made on the basis of a positive family history, spherocytes on blood film and Coombs-negative hemolytic jaundice of variable severity with an elevated mean corpuscular hemoglobin concentration (MCHC) and a low mean corpuscular volume (MCV). In general, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) quantification of erythrocyte membrane proteins is not needed to make the clinical diagnosis of HS. However, we observed that a neonate with no family history of HS, but with abundant spherocytosis on repeated blood films, Coombs negative hemolytic jaundice and normal MCHC and MCV measurements, where SDS-PAGE revealed alpha-spectrin deficiency, a rare autosomal-recessive variety of HS that generally has a severe clinical phenotype. PMID- 23624970 TI - Absent left common and left external iliac artery presenting in a neonate. PMID- 23624971 TI - Letter regarding 'Utilizing a line maintenance team to reduce central-line associated bloodstream infections in a neonatal intensive care unit'. PMID- 23624972 TI - Reply: utilizing a line maintenance team to reduce central-line-associated bloodstream infections in a neonatal intensive care unit. PMID- 23624973 TI - Awaiting evidence of neuroprotective effects of recombinant erythropoietin in very preterm infants. PMID- 23624974 TI - Response to dr C dame. PMID- 23624976 TI - Quantitative transcriptomics using designed primer-based amplification. AB - We developed a novel Designed Primer-based RNA-sequencing strategy (DP-seq) that uses a defined set of heptamer primers to amplify the majority of expressed transcripts from limiting amounts of mRNA, while preserving their relative abundance. Our strategy reproducibly yielded high levels of amplification from as low as 50 picograms of mRNA while offering a dynamic range of over five orders of magnitude in RNA concentrations. We also demonstrated the potential of DP-seq to selectively suppress the amplification of the highly expressing ribosomal transcripts by more than 70% in our sequencing library. Using lineage segregation in embryonic stem cell cultures as a model of early mammalian embryogenesis, DP seq revealed novel sets of low abundant transcripts, some corresponding to the identity of cellular progeny before they arise, reflecting the specification of cell fate prior to actual germ layer segregation. PMID- 23624978 TI - Genomic characterization, molecular cloning and expression analysis of two terpene synthases from Thymus caespititius (Lamiaceae). AB - The identification, isolation and functional characterization of two genes encoding two monoterpene synthases-gamma-terpinene synthase (Tctps2) and alpha terpineol synthase (Tctps5)-from three chemically distinct Thymus caespititius (Lamiaceae) genotypes were performed. Genomic exon-intron structure was also determined for both terpene synthase genes, revealing an organization with seven exons and six introns. The cDNA of Tctps2 was 2,308 bp long and had an open reading frame of 1,794 bp encoding for a protein with 598 amino acids. Tctps5 was longer, mainly due to intron sequences, and presented high intraspecific variability on the plants analyzed. It encoded for a protein of 602 amino acids from an open reading frame of 1,806 bp comprising a total of 2,507 bp genomic sequence. The amino acid sequence of these two active Tctps genes shared 74 % pairwise identity, ranging between 42 and 94 % similarity with about 50 known terpene synthases of other Lamiaceae species. Gene expression revealed a multi product Tctps2 and Tctps5 enzymes, producing gamma-terpinene and alpha-terpineol as major components, respectively. These enzymatic results were consistent with the monoterpene profile present in T. caespititius field plants, suggesting a transcriptional regulation in leaves. Herewith reported for the first time for this species, these two newly characterized Tctps genes improve the understanding of the molecular mechanisms of reaction responsible for terpene biosynthesis and chemical diversity found in T. caespititius. PMID- 23624977 TI - Alternative splicing of transcription factors in plant responses to low temperature stress: mechanisms and functions. AB - Transcription factors play a central role in the gene regulatory networks that mediate various aspects of plant developmental processes and responses to environmental changes. Therefore, their activities are elaborately regulated at multiple steps. In particular, accumulating evidence illustrates that post transcriptional control of mRNA metabolism is a key molecular scheme that modulates the transcription factor activities in plant responses to temperature fluctuations. Transcription factors have a modular structure consisting of distinct protein domains essential for DNA binding, dimerization, and transcriptional regulation. Alternative splicing produces multiple proteins having different structural domain compositions from a single transcription factor gene. Recent studies have shown that alternative splicing of some transcription factor genes generates small interfering peptides (siPEPs) that negatively regulate the target transcription factors via peptide interference (PEPi), constituting self-regulatory circuits in plant cold stress response. A number of splicing factors, which are involved in RNA binding, splice site selection, and spliceosome assembly, are also affected by temperature fluctuations, supporting the close association of alternative splicing of transcription factors with plant responses to low temperatures. In this review, we summarize recent progress on the temperature-responsive alternative splicing of transcription factors in plants with emphasis on the siPEP-mediated PEPi mechanism. PMID- 23624979 TI - Improved occupational performance of young adults with a physical disability after a vocational rehabilitation intervention. AB - PURPOSE: The purpose of this study was to investigate into more detail how occupational performance of participants of a 1-year multidisciplinary vocational rehabilitation intervention changed over time, using a broad focus on three areas of occupational performance, addressing work, as well as self-care and leisure. In addition, we explored differences between employed and unemployed persons. METHODS: In a pre-post-intervention design, changes in occupational performance, addressing work, self-care and leisure, were evaluated using the Canadian Occupational Performance Measure (COPM) and the Occupational Performance History Interview (OPHI-II). RESULTS: Eleven young adults (median 22 years) with physical disabilities participated. Post-intervention, participants experienced fewer problems and showed improved occupational performance in work, as well as self care and leisure, and improved satisfaction with performance. Participants also showed improved occupational identity and occupational competence, and total scores on OPHI-II. Participants who did not achieve employment did not differ in demographic characteristics. They experienced problems in all three areas of occupational performance at pre-intervention, and more difficulty in interacting in occupational settings (environment). Post-intervention, their levels of occupational identity, competence and settings were similar to those of employed persons. CONCLUSIONS: Participants showed improved occupational performance after the intervention. The goal of employment and the broad integrated approach of the intervention seemed to motivate participants to resolve problems in work, as well as self-care and leisure. Unemployed persons faced problems in all three areas of occupational performance at start. Although they seemed to catch up during the intervention, they did not achieve employment within 1 year. PMID- 23624980 TI - In-depth study of the workers' perspectives to enhance sustainable working life: comparison between workers with and without a chronic health condition. AB - PURPOSE: To gain in-depth understanding of the number and type of experienced ageing problems, obstacles to perform work tasks, retention factors to maintain work and support needs to continue working life in the next years among workers aged 45 years and older with and without a chronic health condition. METHODS: A survey of workers' perspectives on problems, obstacles, retention factors and needs due to ageing was carried out in 3,008 workers aged 45 years and older in nine different companies. To classify the open-ended questions we used the International Classification of Functioning and disability (ICF). RESULTS: Older workers with a chronic health condition reported more problems due to ageing (56 vs 34 %; p < .001), more obstacles (42 vs 16 %; p < .001) and more needs (51 vs 31 %; p < .001) compared to those without a chronic health condition. No relevant differences were found on type of experienced problems, obstacles, retention factors and needs between both groups. Problems and obstacles were found on physiological and psychological functions. Retention factors and needs to enhance sustainable working life were particularly reported on work-related environmental factors. CONCLUSION: Because workers with a chronic health condition experienced more problems, obstacles and needs, the largest gain of occupational intervention can be achieved in these workers. However, our findings suggest that interventions aimed to enhance sustainable working life of older workers can be similar in content for persons with and without chronic health conditions and should have a central focus on work-related factors. PMID- 23624981 TI - Invasiveness in cardiac surgery: a question of age. AB - A survey was conducted among 1644 cardiac surgeons on the surgical strategy regarding the invasiveness of the procedure they would prefer as a patient in a number of simple clinical scenarios. A total of 380 (23%) replies were received. Only in the case of aortic valve surgery, a notable preference of minimally invasive strategy was registered, as transcatheter aortic valve implantation was indicated by 49% of the respondents. Regarding the size of the incision for mitral valve surgery, there was a substantial equality between preferences of standard surgery and minimally invasive option (port access: 42%; standard surgery with full sternotomy: 40%). With regard to the use of extracorporeal circulation for coronary surgery, the traditional option received more preferences than the less-invasive one (on-pump CABG: 42%; off-pump CABG: 31%). When respondents' age was taken into account, surgeons aged<50 years preferred mini-thoracotomy (P=0.03) and transcathether approaches (P=0.008) to have their mitral and aortic valve surgeries performed, whereas more senior ones would choose more traditional techniques. In conclusion, the findings of this survey suggest that the surgeon's age may play an important role in the preference for less-invasive techniques. PMID- 23624982 TI - External aortic root support: a histological and mechanical study in sheep. AB - OBJECTIVES: Personalized external aortic root support has completed initial evaluation and has technology appraisal in the UK for patients with Marfan syndrome for use as an alternative to root replacement. Its long-term success in preventing aortic dissection remains uncertain. Here, we report a study in sheep to establish whether the externally supporting mesh, as used clinically, is biologically incorporated. The strength of the resulting mesh/artery composite has been tested. METHODS: The carotid artery of growing sheep (n=6) was enclosed in a mesh sleeve made of a polymer, polyethylene terephthalate. After a predefined interval of 4-6 months, a length of the artery was excised, including the sleeved and unsleeved portions, and was stress tested and examined histologically. RESULTS: One animal died of pneumonia 7 days after implantation. Comparing sleeved with normal segments, the overall thickness was increased and there was a fibrotic sheet in the periarterial space. The overall vessel wall architecture was preserved in all specimens. Although media thickness of ensleeved arteries was smaller and in one animal mild oedema was found in one quadrant of the outer part of the media. There was a significant increase in stiffness and maximum tensile strength of the supported segments compared with normal arterial tissue. CONCLUSIONS: Polyethylene terephthalate mesh, as used for the external support of the dilated aortic root in Marfan syndrome, becomes incorporated in the periadventitial tissue of the carotid artery of sheep. Limited thinning of the media, without any signs of inflammation or medial necrosis, was visible. There was a significantly greater tensile strength in the carotid artery/mesh composite compared with the unsleeved carotid artery. PMID- 23624983 TI - A new cable-tie-based sternal closure device: infectious considerations. AB - OBJECTIVES: To determine the difference in sternal infection and other infectious events between conventional wire and cable-tie-based closure techniques post sternotomy in a collective of patients after cardiac surgery. METHODS: The sternal ZipFixTM (ZF) system consists of a biocompatible poly-ether-ether-ketone (PEEK) cable-tie that surrounds the sternum through the intercostal space and provides a large implant-to-bone contact. Between 1 February 2011 and 31 January 2012, 680 cardiac operations were performed via sternotomy at our institution. After the exclusion of operations for active endocarditis and early mortality within 7 days, 95 patients were exclusively closed with ZF and could be compared with 498 who were closed with conventional wires (CWs) during the same period. A multivariable logistic regression analysis, including body mass index, renal impairment and emergency as suspected confounders and inverse propensity weights was performed on the infection rate. RESULTS: Total infection rate was 6.1%, with a total of 36 diagnosed sternal infections (5 in ZF and 31 in CW). Comparing ZF with CW with regard to sternal infection, there is no statistically significant difference related to the device (odds ratio: 0.067, confidence interval: 0.04 9.16, P=0.72). The propensity modelling provided excellent overlap and the mean propensity was almost the same in both groups. Thus, we have observed no difference in receiving either ZF or CW. No sternal instability was observed with the ZF device, unlike 4/31 patients in the CW group. The overall operation time is reduced by 11 min in the ZF group with identical perfusion and clamping times. CONCLUSIONS: Our study underlines a neutral effect of the sternal ZipFixTM system in patients regarding sternal infection. Postoperative complications are similar in both sternal closure methods. The cable-tie-based system is fast, easy to use, reliable and safe. PMID- 23624984 TI - Virtual segmentectomy based on high-quality three-dimensional lung modelling from computed tomography images. AB - OBJECTIVES: The aim of this study was to demonstrate the feasibility and efficacy of a novel simulation software called, virtual segmentectomy. METHODS: We developed the segmentectomy simulation system, which was programmed to analyse the detailed 3D bronchovascular structure and to predict the appropriate segmental surface and surgical margin, based on lung modelling from CT images. RESULTS: We have attempted this novel technique for 3 cases of pulmonary metastases and 1 case of multiple lung cancer. For validation, the predicted resection margin was compared with the actual resected specimen. The surgical surface, as estimated by the simulation, was compared with the surface of the specimen and a surgical video. To test its feasibility, the operation time, blood loss, durations of chest tube placement and hospitalization as well as pathological findings were assessed. CONCLUSIONS: Preoperative simulation and intraoperative guidance by virtual segmentectomy could contribute significantly to determining the most appropriate anatomical segmentectomy and curative resection. PMID- 23624986 TI - Tales of a spermatological variety--finding Master Right. PMID- 23624985 TI - Maternal origin of 47,XXY and confined placental mosaicism 47,XXY/48,XXY,+13 in an infant conceived through IVF. PMID- 23624987 TI - Temperature-sensitive phenotype caused by natural mutation in Capsicum latescent in two tropical regions. AB - Plants in tropical regions experience temperature fluctuation only in non-extreme ambient temperatures. Thus, moderate changes in temperatures, which they never experience in their local environments, might be sufficient to manifest the locally hidden phenotype caused by natural mutation. To validate this hypothesis, temperature-treating experiments were performed on Capsicum accessions collected from tropical regions. Thirty-six Capsicum accessions, collected from Caribbean countries, were screened for temperature sensitivity. Similarities in their temperature sensitivities were compared with Sy-2 (C. chinense) from Seychelles, which was previously found to be a temperature-sensitive accession. Tr-13 from Trinidad & Tobago exhibited developmental abnormalities at temperatures below 24 degrees C. Expression of defense-related genes was induced, and salicylic acid, which is a key molecule in the plant's defense response, accumulated in Tr-13 at temperatures below 24 degrees C. Tr-13 and Sy-2 appeared normal when they were grown at temperatures simulating those in Trinidad and Seychelles, respectively. Crossing Tr-13 with No. 3341 or Sy-2 revealed that the temperature-sensitive phenotype of Tr-13 was caused by a genetic mutation in the same locus as Sy-2. Plants having a temperature-sensitive phenotype that is caused by natural mutations evade artificial selection and exist as crops in specific environments, such as tropical regions. PMID- 23624988 TI - Twenty-two years of HIV-related consultations in Dutch general practice: a dynamic cohort study. AB - OBJECTIVES: To examine the role of general practitioners (GPs) in HIV counselling and testing over a 22-year period. DESIGN: A dynamic cohort study. SETTING: General practices (N=42) participating in the Dutch Sentinel General Practice Network at Nivel with a nationally representative patient population by age, gender, regional distribution and population density. OUTCOME MEASURES: HIV related consultations from 1988 to 2009 were recorded using a questionnaire in which patient's characteristics, interventions and test results were recorded. Trends over time and effects of urbanisation (3 categories) were assessed by multilevel analysis to control for clustering of observations within general practices. RESULTS: Time trend analyses show an increasing trend in HIV-related consultations and in the total number of HIV tests per 10 000 registered patients from 1988 to 1996, followed by a declining period and an increase again in the period 2007-2009. Over the whole period, the number of HIV-related consultations was highest in the urban areas with a maximum of 18 per 10 000 patients in 1996. The proportion of people high at risk, men who have sex with men, decreased. The proportion of HIV-related consultations initiated by the GPs increased from 11% in 1988 to 23% in 2009. CONCLUSION: In this 22-year period, HIV-related consultations and provider-initiated HIV testing in the Dutch general practice have increased. More attention for sexual health in general practice is required that focuses on high-risk groups and on more routine testing in high prevalence areas. PMID- 23624989 TI - Medicines information needs during pregnancy: a multinational comparison. AB - OBJECTIVES: The aim was to assess the perceived needs of medicines information and information sources for pregnant women in various countries. DESIGN: Cross sectional internet-based study. SETTING: Multinational. PARTICIPANTS: Pregnant women and women with children less than 25 weeks. PRIMARY AND SECONDARY OUTCOME MEASURES: The need for information about medicines was assessed by a question: 'Did you need information about medicines during the course of your pregnancy?' A list of commonly used sources of information was given to explore those that are used. RESULTS: Altogether, 7092 eligible women responded to the survey (5090 pregnant women and 2002 women with a child less than 25 weeks). Of the respondents, 57% (n=4054, range between different countries 46-77%) indicated a need for information about medicines during their pregnancy. On average, respondents used three different information sources. The most commonly used information sources were healthcare professionals-physicians (73%), pharmacy personnel (46%) and midwifes or nurses (33%)-and the internet (60%). There were distinct differences in the information needs and information sources used in different countries. CONCLUSIONS: A large proportion of pregnant women have perceived information needs about medicines during pregnancy, and they rely on healthcare professionals. The internet is also a widely used information source. Further studies are needed to evaluate the use of the internet as a medicines information source by pregnant women. PMID- 23624990 TI - Long-term clinical results after cataract surgery with and without capsular tension ring in patients with retinitis pigmentosa: a retrospective study. AB - OBJECTIVES: To describe the long-term clinical outcomes after cataract surgery with and without capsular tension ring (CTR) in a group of patients with retinitis pigmentosa (RP). DESIGN: A retrospective study. SETTING: Tertiary referral centre. PARTICIPANTS: 52 eyes (46 patients) with RP. INTERVENTIONS: Cataract surgery was undertaken between October 2002 and May 2010. PRIMARY AND SECONDARY OUTCOME MEASURES: Visual acuity, secondary cataract, capsular contraction syndrome (CCS), intraocular pressure, cystoid macular edema (CME), intraocular lens dislocation and endophthalmitis. RESULTS: The mean age at surgery was about 53 years and the overall mean follow-up was 26 months (range 3 60 months). The mean preoperative logarithm of the minimal angle of resolution of the best corrected visual acuity (LogMAR BCVA) in the entire group was 1.45+/ 0.85 (95% CI 1.21 to 1.69) and had increased to 1.32+/-0.95 (95% CI 1.06 to 1.58, p=0.02). The mean preoperative and the mean postoperative LogMAR BCVA in the non CTR group (group 1) improved from 1.16+/-0.8 (95% CI 0.83 to 1.48) to 0.98+/-0.88 (95% CI 0.62 to 1.33, p=0.02) and in the CTR group (group 2) from 1.74+/-0.81 (95% CI 1.42 to 2.07) to 1.66+/-0.90 (95% CI 1.3 to 2.03, p=0.31), respectively. Secondary cataract was observed in a total of 23 eyes (44%), of which 13 (50%) were belonged to group 1 and 10 (38%) to group 2. CCS was seen in a total of two eyes (4%) all under group 1. CME was noted in two eyes (4%), of which one belonged to group 1 and a second one to group 2. Endophthalmitis was not observed in any group. CONCLUSIONS: Both surgical approaches were beneficial to the RP patients. Eyes under group 2 showed less long-term postoperative complications. This includes secondary cataract and CCS. Eyes under group 1 performed significantly better in respect of visual acuity. Further research would include insights into the genetic subsets. PMID- 23624991 TI - Suicide following the death of a sibling: a nationwide follow-up study from Sweden. AB - OBJECTIVES: The death of a sibling can trigger grief and depression. Sibling deaths from external causes may be particularly detrimental, since they are often sudden. We aimed to examine the association between the death of an adult sibling from external causes and the risk of suicide among surviving siblings up to 18 years after bereavement. We adjusted for intrafamily correlation in death risks, which might occur because of shared genetics and shared early-life experiences of siblings in the same family. DESIGN: A follow-up study between 1981 and 2002 based on the total population. SETTING: Sweden. PARTICIPANTS: Swedes aged 25-64 years (n=1 748 069). PRIMARY AND SECONDARY OUTCOME MEASURES: Suicide from the Swedish cause of death register. RESULTS: An increased risk of mortality from suicide was found among persons who had experienced the death of a sibling. In women, the suicide risk was 1.55 times that of non-bereaved persons (95% CI 0.99 to 2.44), and in men it was 1.28 times higher (95% CI 0.93 to 1.77). If one sibling committed suicide, the risk of the remaining sibling also committing suicide was 3.19 (95% CI 1.23 to 8.25) among women and 2.44 (95% CI 1.34 to 4.45) among men. Associations with other main causes of death-such as external other than suicide, cardiovascular diseases or cancer-were generally much smaller and statistically not significant in either sex. We found no clear support for a specific time pattern according to time since a sibling's death. CONCLUSIONS: Our study provided evidence for suicide risk associated with the death of a sibling at adult age, revealing that bereaved persons' risk of suicide is higher when siblings die from suicide, even when adjusting for intrafamily correlation in death risks. PMID- 23624992 TI - Does cognitive behaviour therapy have an enduring effect that is superior to keeping patients on continuation pharmacotherapy? A meta-analysis. AB - OBJECTIVES: Although cognitive behaviour therapy (CBT) and pharmacotherapy are equally effective in the acute treatment of adult depression, it is not known how they compare across the longer term. In this meta-analysis, we compared the effects of acute phase CBT without any subsequent treatment with the effects of pharmacotherapy that either were continued or discontinued across 6-18 months of follow-up. DESIGN: We conducted systematic searches in bibliographical databases to identify relevant studies, and conducted a meta-analysis of studies meeting inclusion criteria. SETTING: Mental healthcare. PARTICIPANTS: Patients with depressive disorders. INTERVENTIONS: CBT and pharmacotherapy for depression. OUTCOME MEASURES: Relapse rates at long-term follow-up. RESULTS: 9 studies with 506 patients were included. The quality was relatively high. Short-term outcomes of CBT and pharmacotherapy were comparable, although drop out from treatment was significantly lower in CBT. Acute phase CBT was compared with pharmacotherapy discontinuation during follow-up in eight studies. Patients who received acute phase CBT were significantly less likely to relapse than patients who were withdrawn from pharmacotherapy (OR=2.61, 95% CI 1.58 to 4.31, p<0.001; numbers needed-to-be-treated, NNT=5). The acute phase CBT was compared with continued pharmacotherapy at follow-up in five studies. There was no significant difference between acute phase CBT and continued pharmacotherapy, although there was a trend (p<0.1) indicating that patients who received acute phase CBT may be less likely to relapse following acute treatment termination than patients who were continued on pharmacotherapy (OR=1.62, 95% CI 0.97 to 2.72; NNT=10). CONCLUSIONS: We found that CBT has an enduring effect following termination of the acute treatment. We found no significant difference in relapse after the acute phase CBT versus continuation of pharmacotherapy after remission. Given the small number of studies, this finding should be interpreted with caution pending replication. PMID- 23624993 TI - Safety and efficacy of liraglutide in patients with type 2 diabetes and end-stage renal disease: protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded, parallel intervention study. AB - INTRODUCTION: Diabetes is the leading cause of end-stage renal disease (ESRD). Owing to renal clearance, several antidiabetic agents cannot be used in patients with ESRD. The present protocol describes an investigator-initiated trial aiming to test safety and efficacy of treatment with the glucagon-like peptide-1 receptor agonist liraglutide in patients with type 2 diabetes and dialysis dependent ESRD. METHODS AND ANALYSIS: Twenty patients with type 2 diabetes and ESRD will be compared with 20 matched patients with type 2 diabetes and normal kidney function in a randomised, parallel, placebo-controlled (1 : 1), double blinded setting. All participants will receive 12 weeks of daily treatment with liraglutide/placebo in an individually titrated dose of 0.6, 1.2 or 1.8 mg. Over nine visits, plasma liraglutide, glycaemic control, beta-cell response, cardiovascular parameters, various biomarkers and adverse events will be assessed. The primary endpoint will be evaluated from dose-corrected plasma trough liraglutide concentration at the final trial visit to determine potential accumulation in the ESRD group. ETHICS AND DISSEMINATION: The study has been approved by the Danish Medicines Agency, the Scientific-Ethical Committee of the Capital Region of Denmark and the Danish Data Protection Agency. An external monitoring committee (The Good Clinical Practice Unit at Copenhagen University Hospitals) will oversee the study. The results of the study will be presented at national and international scientific meetings, and publications will be submitted to peer-reviewed journals. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01394341. PMID- 23624994 TI - Application of the ELOHA framework to regulated rivers in the Upper Tennessee River Basin: a case study. AB - In order for habitat restoration in regulated rivers to be effective at large scales, broadly applicable frameworks are needed that provide measurable objectives and contexts for management. The Ecological Limits of Hydrologic Alteration (ELOHA) framework was created as a template to assess hydrologic alterations, develop relationships between altered streamflow and ecology, and establish environmental flow standards. We tested the utility of ELOHA in informing flow restoration applications for fish and riparian communities in regulated rivers in the Upper Tennessee River Basin (UTRB). We followed the steps of ELOHA to generate univariate relationships between altered flows and ecology within the UTRB. By comparison, we constructed multivariate models to determine improvements in predictive capacity with the addition of non-flow variables. We then determined whether those relationships could predict fish and riparian responses to flow restoration in the Cheoah River, a regulated system within the UTRB. Although ELOHA provided a robust template to construct hydrologic information and predict hydrology for ungaged locations, our results do not suggest that univariate relationships between flow and ecology (step 4, ELOHA process) can produce results sufficient to guide flow restoration in regulated rivers. After constructing multivariate models, we successfully developed predictive relationships between flow alterations and fish/riparian responses. In accordance with model predictions, riparian encroachment displayed consistent decreases with increases in flow magnitude in the Cheoah River; however, fish richness did not increase as predicted 4 years after restoration. Our results suggest that altered temperature and substrate and the current disturbance regime may have reduced opportunities for fish species colonization. Our case study highlights the need for interdisciplinary science in defining environmental flows for regulated rivers and the need for adaptive management approaches once flows are restored. PMID- 23624995 TI - Thromboembolic complications in burn patients and associated risk factors. AB - Early mobilization and deep venous thrombosis (DVT) prophylaxis have been shown to reduce the incidence of DVT and pulmonary embolism among hospitalized patients, yet thromboembolic complications remain a great concern, especially to those who remain immobilized for an extended period of time. There are many risk factors associated with the development of thromboembolism, especially DVT. The main objective of this retrospective study is to estimate the occurrence of DVT in burn patients and to investigate some burn-related risk factors. A retrospective examination of DVT cases was conducted among the acute burn patients admitted to our Regional Burn Center during 2008. The analysis included the demographic factors, preexisting medical conditions, ventilator support, number of surgeries and blood transfusions, and use of central line. There was a total of 97 diagnosed patients with DVT and among them 86 were adult acute burn patients. There were 113 diagnosed with DVTs in 86 burn patients, including 22 patients diagnosed with DVT at multiple sites either in one screening or in subsequent screenings. Incidence of DVT at the center was 5.92 per 100 adult acute burn admissions. Men had more DVT than women (6.87 vs. 3.34%, relative risk 2.05, P < .05). The average percentage of %TBSA was smaller in the patients who were more than 50 years of age compared with the patients who were 49 years or younger (21.97 vs. 34.77%, P < .05). Among the patients with DVT, 80 (93%) had a central venous catheter before DVT developed and the other six never had a central venous catheter. The most common site for DVT development was common femoral vein site 89%. The average number of procedures before DVT was 7.84 +/- 8.36, and blood transfusions were 39.55 +/- 108.37 units. Six patients (7%) died in the hospital within these study cohorts and there was no indication that pulmonary embolism was the cause of the deaths. The study showed that the incidence of DVT in the burn center was comparable with the incidences reported in the literature. Being of male sex, a smoker, an alcoholic, high-age group, high %TBSA, use of central line, increased number of surgeries, and increased number of blood transfusions are identified as possible predisposing factors for DVTs. Further meaningful evaluation to determine the incidence of DVT in burn patients and its associated risk factors will require large multicenter, well controlled, prospective designed study. PMID- 23624996 TI - Immediate burn excision fails to reduce injury progression. AB - The contact thermal injury model in the pig was used to determine whether immediate burn excision could alter the extent of injury progression. It was hypothesized that immediate excision of burns would prevent or reduce tissue necrosis in the uninjured interspaces. Four comb burns were created on the back of each animal, using a brass comb preheated in hot water (100 degrees C) for 5 minutes. This brass comb produced four distinctive burns sites separated by three "interspaces" of unburned skin, which were to undergo progressive injury. Immediately after burn creation, half of the full-thickness burns were excised leaving the unburned interspaces intact. Two full-thickness excisional wounds per pig with the dimensions identical to the comb burns were included as controls. Burn injury progression was microscopically assessed and reported as the percentage of unburned interspaces that progressed to full-thickness necrosis 7 days after injury. Scar formation was grossly evaluated on day 28 after injury and reported as the total surface area (in square centimeters) of the scar. A total of 24 combs with 72 interspaces were evenly distributed among the three groups. The unburned interspaces of both comb burns and excised comb burns had undergone progressive injury and were 100% dead (24/24; i.e., necrotic and/or apoptotic) 7 days postinjury (95% confidence interval, 86-100%) for both. However, interspaces of the control excisional wounds maintained complete viability, that is, no necrosis or apoptosis (0/24 [0%]; 95% confidence interval, 0-14%; P < .001). There was no significant difference in both surface area and depth of scar resulting from excised and nonexcised comb burns. Immediate burn excision neither prevented nor limited burn injury progression. PMID- 23624997 TI - Key role of hydrazine to the interaction between oxaloacetic against phosphoenolpyruvic carboxykinase (PEPCK): ONIOM calculations. AB - The interactions between oxaloacetic (OAA) and phosphoenolpyruvic carboxykinase (PEPCK) binding pocket in the presence and absence of hydrazine were carried out using quantum chemical calculations, based on the two-layered ONIOM (ONIOM2) approach. The complexes were partially optimized by ONIOM2 (B3LYP/6-31G(d):PM6) method while the interaction energies between OAA and individual residues surrounding the pocket were performed at the MP2/6-31G(d,p) level of theory. The calculated interaction energies (INT) indicated that Arg87, Gly237, Ser286, and Arg405 are key residues for binding to OAA with the INT values of -1.93, -2.06, 2.47, and -3.16 kcal mol(-1), respectively. The interactions are mainly due to the formation of hydrogen bonding interactions with OAA. Moreover, using ONIOM2 (B3LYP/6-31G(d):PM6) applied on the PEPCKHS complex, two proton transfers were observed; first, the proton was transferred from the carboxylic group of OAA to hydrazine while the second one was from Asp311 to Lys244. Such reactions cause the generation of binding strength of OAA to the pocket via electrostatic interaction. The orientations of Lys243, Lys244, His264, Asp311, Phe333, and Arg405 were greatly deviated after hydrazine incorporation. These indicate that hydrazine plays an important role in terms of not only changing the conformation of the binding pocket, but is also tightly bound to OAA resulting in its conformation change in the pocket. The understanding of such interaction can be useful for the design of hydrazine-based inhibitor for antichachexia agents. PMID- 23624998 TI - Heart rate before ICU discharge: a simple and readily available predictor of short- and long-term mortality from critical illness. AB - PURPOSE: A heart rate >90 bpm serves as one of four characteristics defining the systemic inflammatory response syndrome and is used in scoring systems to predict in-hospital mortality of intensive care unit (ICU) patients. Despite its central role in critical illness, specific data regarding the relationship between heart rate and outcome are rare. METHODS: In this post hoc analysis of a prospectively collected database, we analyzed the value of heart rate averaged from four predefined time points during the last 24 h before ICU discharge as a predictor of post-ICU in-hospital and post-hospital mortality in medical ICU patients. Furthermore, the relationship between heart rate and inflammation, as well as the influence of rate control medications on the association between heart rate and outcome were identified. RESULTS: Among the 702 ICU patients discharged from the ICU, 7.1 % died before hospital discharge. At 4 years of follow-up, post-hospital mortality was 14.4 %. Multivariate Cox proportional hazards models revealed heart rate before ICU discharge (HR 5.95; 95 % CI 1.24-28.63; p = 0.03) as an independent predictor of post-ICU in-hospital mortality. Both heart rate (HR 2.56; 95 % CI, 1.05-6.34; p = 0.04) and the C-reactive protein serum concentration before ICU discharge (HR, 1.26; 95 % CI, 1.09-1.46; p = 0.002) were independently associated with post-hospital mortality. Heart rate control therapy reduced the risk of post-ICU in-hospital (HR 0.38; 95 % CI, 0.18-0.81; p = 0.01) and post-hospital (HR, 0.47; 95 % CI, 0.22-1.00; p = 0.05) mortality. CONCLUSION: Heart rate evaluated 24 h before ICU discharge was independently associated with post-ICU in-hospital and post-hospital mortality. Pharmacological interventions to control heart rate may beneficially influence post-ICU mortality. PMID- 23624999 TI - Reproductive factors and kidney cancer risk in 2 US cohort studies, 1993-2010. AB - Clinical and experimental findings suggest that female hormonal and reproductive factors could influence kidney cancer development. To evaluate this association, we conducted analyses in 2 large prospective cohorts (the National Institutes of Health-AARP Diet and Health Study (NIH-AARP), 1995-2006, and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), 1993-2010). Cohort-specific and aggregated hazard ratios and 95% confidence intervals relating reproductive factors and kidney cancer risk were computed by Cox regression. The analysis included 792 incident kidney cancer cases among 283,952 postmenopausal women. Women who had undergone a hysterectomy were at a significantly elevated kidney cancer risk in both NIH-AARP (hazard ratio = 1.28, 95% confidence interval: 1.09, 1.50) and PLCO (hazard ratio = 1.41, 95% confidence interval: 1.06, 1.88). Similar results were observed for both cohorts after analyses were restricted to women who had undergone a hysterectomy with or without an oophorectomy. For the NIH-AARP cohort, an inverse association was observed with increasing age at menarche (P for trend = 0.02) and increasing years of oral contraceptive use (P for trend = 0.02). No clear evidence of an association with parity or other reproductive factors was found. Our results suggest that hysterectomy is associated with increased risk of kidney cancer. The observed associations with age at menarche and oral contraceptive use warrant further investigation. PMID- 23625006 TI - Preparation of potentially porous, chiral organometallic materials through spontaneous resolution of pincer palladium conformers. AB - Understanding the mechanism by which advanced materials assemble is essential for the design of new materials with desired properties. Here, we report a method to form chiral, potentially porous materials through spontaneous resolution of conformers of a PCP pincer palladium complex ({2,6-bis[(di-t butylphosphino)methyl]phenyl}palladium(II)halide). The crystallisation is controlled by weak hydrogen bonding giving rise to chiral qtz-nets and channel structures, as shown by 16 such crystal structures for X = Cl and Br with various solvents like pentane and bromobutane. The fourth ligand (in addition to the pincer ligand) on palladium plays a crucial role; the chloride and the bromide primarily form hexagonal crystals with large 1D channels, whereas the iodide (presumably due to its inferior hydrogen bonding capacity) forms monoclinic crystals without channels. The hexagonal channels are completely hydrophobic and filled with disordered solvent molecules. Upon heating, loss of the solvent occurs and the hexagonal crystals transform into other non-porous polymorphs. Also by introducing a strong acid, the crystallisation process can be directed to a different course, giving several different non-porous polymorphs. In conclusion, a number of rules can be formulated dictating the formation of hexagonal channel structures based on pincer palladium complexes. Such rules are important for a rational design of future self-assembling materials with applications in storage and molecular recognition. PMID- 23625007 TI - On Ramanujan's definition of mock theta function. AB - In his famous "deathbed" letter, Ramanujan "defined" the notion of a mock theta function and offered some examples of functions he believed satisfied his definition. Very recently, Griffin et al. established for the first time that Ramanujan's mock theta functions actually satisfy his own definition. On the other hand, Zwegers' 2002 doctoral thesis [Zwegers S (2002) Mock theta functions. PhD thesis (Univ Utrecht, Utrecht, The Netherlands)] showed that all of Ramanujan's examples are holomorphic parts of harmonic Maass forms. This has led to an alternate definition of a mock theta function. This paper shows that Ramanujan's definition of mock theta function is not equivalent to the modern definition. PMID- 23625008 TI - Nogo-A is a negative regulator of CNS angiogenesis. AB - Nogo-A is an important axonal growth inhibitor in the adult and developing CNS. In vitro, Nogo-A has been shown to inhibit migration and cell spreading of neuronal and nonneuronal cell types. Here, we studied in vivo and in vitro effects of Nogo-A on vascular endothelial cells during angiogenesis of the early postnatal brain and retina in which Nogo-A is expressed by many types of neurons. Genetic ablation or virus-mediated knock down of Nogo-A or neutralization of Nogo A with an antibody caused a marked increase in the blood vessel density in vivo. In culture, Nogo-A inhibited spreading, migration, and sprouting of primary brain microvascular endothelial cells (MVECs) in a dose-dependent manner and induced the retraction of MVEC lamellipodia and filopodia. Mechanistically, we show that only the Nogo-A-specific Delta 20 domain exerts inhibitory effects on MVECs, but the Nogo-66 fragment, an inhibitory domain common to Nogo-A, -B, and -C, does not. Furthermore, the action of Nogo-A Delta 20 on MVECs required the intracellular activation of the Ras homolog gene family, member A (Rho-A) associated, coiled-coil containing protein kinase (ROCK)-Myosin II pathway. The inhibitory effects of early postnatal brain membranes or cultured neurons on MVECs were relieved significantly by anti-Nogo-A antibodies. These findings identify Nogo-A as an important negative regulator of developmental angiogenesis in the CNS. They may have important implications in CNS pathologies involving angiogenesis such as stroke, brain tumors, and retinopathies. PMID- 23625009 TI - Latency of Epstein-Barr virus is disrupted by gain-of-function mutant cellular AP 1 proteins that preferentially bind methylated DNA. AB - ZEBReplication Activator (ZEBRA), a viral basic zipper protein that initiates the Epstein-Barr viral lytic cycle, binds to DNA and activates transcription through heptamer ZEBRA response elements (ZREs) related to AP-1 sites. A component of the biologic action of ZEBRA is attributable to binding methylated CpGs in ZREs present in the promoters of viral lytic cycle genes. Residue S186 of ZEBRA, Z(S186), which is absolutely required for disruption of latency, participates in the recognition of methylated DNA. We find that mutant cellular AP-1 proteins, Jun(A266S) and Fos(A151S), with alanine-to-serine substitutions homologous to Z(S186), exhibit altered DNA-binding affinity and preferentially bind methylated ZREs. These mutant AP-1 proteins acquire functions of ZEBRA; they activate expression of many viral early lytic cycle gene transcripts in cells harboring latent EBV but are selectively defective in activating expression of some viral proteins and are unable to promote viral DNA replication. Transcriptional activation by mutant c-Jun and c-Fos that have acquired the capacity to bind methylated CpG challenges the paradigm that DNA methylation represses gene expression. PMID- 23625010 TI - Role of the host stroma in cancer and its therapeutic significance. AB - Current cancer research focuses mainly upon the cancer cells in malignant tumours and is providing a growing database about aberrations in their genetic composition. However, tumours also contain non-cancerous host tissue, referred to as the stroma, which plays an active and indispensable role in tumour growth and influences the virulence of the neoplasm towards the host. Many cell types inhabit the stroma, amidst apparently inert fibrous and viscous matrix material, composed of complex polysaccharides, proteins and other molecules. Actually, all of these elements are in constant turnover, causing unpredictable evolution in the properties of the community. This article provides pathologic observations and data on reciprocal interactions between these stromal and neoplastic components of tumours and how they change during the course of the disease. Malignant progression depends upon dauntingly intricate communications between different specialised lineages within the cellular society, which enable rapid adaptation to changing circumstances. Opportunistic misuse of such communication networks enables tumour cells to recruit and incorporate adjacent normal stroma into their midst, so that they may grow, infiltrate and parasitise the host. The absolute dependency of primary tumours and metastases on their diverse stromal components for survival and their insatiable need to continuously recruit more stroma to support expansion, renders them vulnerable to strategies capable of disrupting the cellular interactions involved. This dependency is of critical importance for cancer therapy research, and proposed methods for turning this parasitic behaviour of tumours against themselves are suggested below. PMID- 23625011 TI - Ethical debate: the ethics of not performing extended lymphadenectomy in patients with gastrointestinal cancer. AB - The ethical debate about performing-or not-extended lymphadenectomy in patients with a gastrointestinal malignancy is approached in this work. It offers a thorough overview of the ethical principles. Problem-solving tools are provided to assist in framing the issues and resolving the conflicts. PMID- 23625012 TI - Extended lymphadenectomy in esophageal cancer is crucial. AB - Surgery with lymphadenectomy remains the mainstay of treatment for esophageal cancer. The optimal extent of nodal dissection is controversial. Evidence is accumulating, however, that could demonstrate the benefits of extended lymphadenectomy, which include more accurate disease staging, better locoregional disease control, and improved survival. Except in very early disease where nodal metastases are rare, extended lymphadenectomy is indicated. Data from a randomized controlled trial comparing transhiatal and transthoracic resection have shown better survival in patients with limited nodal burden. Other investigations on en bloc resection, three-field lymphadenectomy, and large-scale international collaborative studies have all provided evidence for the more extensive approach to enhance cure for esophageal cancer. The more extended surgery does lead to potentially higher morbidity rates, and thus surgeons should be versatile in applying such techniques in carefully selected patients, so that postoperative survival and quality of life of patients are not compromised. The challenge in the future is how to tailor surgical strategies for individual patients in order to achieve the best outcome. PMID- 23625013 TI - Extended lymphadenectomy in gastric cancer is crucial. PMID- 23625014 TI - On your histone mark, SET, methylate! AB - Lysine methylation of histones and non-histone proteins has emerged in recent years as a posttranslational modification with wide-ranging cellular implications beyond epigenetic regulation. The molecular interactions between lysine methyltransferases and their substrates appear to be regulated by posttranslational modifications surrounding the lysine methyl acceptor. Two very interesting examples of this cross-talk between methyl-lysine sites are found in the SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain-containing lysine methyltransferases SET7 and SETDB1, whereby the histone H3 trimethylated on lysine 4 (H3K4 (me3) ) modification prevents methylation by SETDB1 on H3 lysine 9 (H3K9) and the histone H3 trimethylated on lysine 9 (H3K9 (me3) ) modification prevents methylation by SET7 on H3K4. A similar cross-talk between posttranslational modifications regulates the functions of non-histone proteins such as the tumor suppressor p53 and the DNA methyltransferase DNMT1. Herein, in cis effects of acetylation, phosphorylation, as well as arginine and lysine methylation on lysine methylation events will be discussed. PMID- 23625015 TI - Drought-induced H2O 2 accumulation in subsidiary cells is involved in regulatory signaling of stomatal closure in maize leaves. AB - Increasing H2O2 levels in guard cells in response to environmental stimuli are recently considered a general messenger involved in the signaling cascade for the induction of stomatal closure. But little is known as to whether subsidiary cells participate in the H2O2-mediated stomatal closure of grass plants. In the present study, 2-week-old seedlings of maize (Zea mays) were exposed to different degrees of soil water deficit for 3 weeks. The effects of soil water contents on leaf ABA and H2O2 levels and stomatal aperture were investigated using physiological, biochemical, and histochemical approaches. The results showed that even under well-watered conditions, significant amounts of H2O2 were observed in guard cells, whereas H2O2 concentrations in the subsidiary cells were negligible. Decreasing soil water contents led to a significant increase in leaf ABA levels associated with significantly enhanced O2 (-) and H2O2 contents, consistent with reduced degrees of stomatal conductance and aperture. The significant increase in H2O2 appeared in both guard cells and subsidiary cells of the stomatal complex, and H2O2 levels increased with decreasing soil water contents. Drought-induced increase in the activity of antioxidative enzymes could not counteract the significant increase in H2O2 levels in guard cells and subsidiary cells. These results indicate that subsidiary cells participate in H2O2-mediated stomatal closure, and drought-induced H2O2 accumulation in subsidiary cells is involved in the signaling cascade regulating stomatal aperture of grass plants such as maize. PMID- 23625016 TI - Increase in ACC oxidase levels and activities during paradormancy release of leafy spurge (Euphorbia esula) buds. AB - The plant hormone ethylene is known to affect various developmental processes including dormancy and growth. Yet, little information is available about the role of ethylene during paradormancy release in underground adventitious buds of leafy spurge. In this study, we examined changes in ethylene evolution and the ethylene biosynthetic enzyme ACC oxidase following paradormancy release (growth induction). Our results did not show an obvious increase in ethylene during bud growth. However, when buds were incubated with 1 mM ACC, ethylene levels were higher in growing than non-growing buds, suggesting that the levels of ACC oxidase increased in growing buds. Real-time qPCR indicated that the transcript of a Euphorbia esula ACC oxidase (Ee-ACO) increased up to threefold following growth induction. In addition, a 2.5- to 4-fold increase in ACO activity was observed 4 days after decapitation, and the Ee-ACO accounted for 40 % of the total ACO activity. Immunoblot analyses identified a 36-kD Ee-ACO protein that increased in expression during bud growth. This protein was highly expressed in leaves, moderately expressed in crown buds, stems and meristems, and weakly expressed in roots and flowers. Immunolocalization of Ee-ACO on growing bud sections revealed strong labeling of the nucleus and cytoplasm in cells at the shoot apical meristem and leaf primordia. An exception to this pattern occurred in cells undergoing mitosis, where labeling of Ee-ACO was negligible. Taken together, our results indicated an increase in the levels of Ee-ACO during paradormancy release of leafy spurge that was not correlated with an increase in ethylene synthesis. PMID- 23625017 TI - The utility of hyperbaric oxygen therapy to treat recurrent acute bowel obstruction after previous pelvic radiotherapy: a case series. AB - BACKGROUND AND OBJECTIVE: Repeated episodes of acute bowel obstruction is a potential complication following pelvic radiation therapy. It has been previously thought that hyperbaric oxygen therapy (HBOT) may not be useful for treatment of such obstructive episodes. We report our experience with the use of HBOT for recurrent radiation-induced acute bowel obstruction. METHODS: This is a retrospective case series. Radiological imaging had excluded the presence of recurrent or new cancer. Possible predisposing causes for acute obstruction had been treated and had not led to resolution of symptoms or had been excluded. RESULTS: During 2007-2010, five patients with recurrent episodes of acute obstructive bowel symptoms following previous therapeutic pelvic irradiation were referred for HBOT (four females and one male; median age 56; range 48-72). The primary tumours sites were the endometrium (n = 2), ovary, cervix and prostate (n = 1 each), and patients were treated 2-17 (median 9) years previously with radiotherapy. Before HBOT, patients were experiencing acute obstructive bowel symptoms at 1-6 weekly intervals. Four patients had progressive weight loss. Patients received 100 % oxygen in a multiplace hyperbaric chamber at a pressure of 2.4 atm absolute for up to 90 min once a day, 5 to 7 days weekly. All patients were initially referred for 40 sessions of HBOT. Three patients required a further extra 20 sessions for complete resolution of bowel symptoms. HBOT was well tolerated with no side effects. Patients have remained well after 6-24 months of follow-up. CONCLUSIONS: HBOT may be an effective treatment of radiation induced bowel obstruction and deserves prospective evaluation. PMID- 23625018 TI - A prospective study of characteristics and outcomes of bacteremia in patients with solid organ or hematologic malignancies. AB - OBJECTIVE: To study the epidemiology and outcomes of bacteremia in patients with hematologic or solid organ malignancies cared for at the University Hospital of Heraklion, Greece. METHODS: This prospective study was conducted during a 4-year period (2007-2011). Patients with bacterial and fungal blood stream infections were followed until discharge. Mortality was the primary outcome, while duration of hospitalization, relapses, time to relapse, and defervescence were the secondary outcomes. RESULTS: Ninety-nine patients with neoplasia (104 episodes) were included. Bacteremia developed mainly in patients with hematologic malignancies (56%). Secondary bacteremias due to respiratory and urinary tract infections were most commonly identified. Gram-negative bacteria were the predominantly isolated pathogens (65%); Pseudomonas spp. was the most common cause (19%), followed closely by E. coli (18%) and Klebsiella pneumoniae (17%). In-hospital mortality was 26.2%. No differences in mortality were seen among patients in different subgroups according to isolated bacteria (according to Gram's stain, species, or number of isolated bacteria in positive cultures), hematologic or solid organ malignancy, neutropenia, and primary or secondary bacteremia. However, patients with bacteremia due to extensively drug resistant bacteria had higher mortality than patients with bacteremia due to multidrug resistant or susceptible pathogens. Patients required a prolonged period of hospitalization (21.8 +/- 14.9 days), which was complicated with relapses or reinfections in another body site in 27 % of them. CONCLUSION: Gram-negative bacteria were the predominantly isolated pathogens from patients with cancer in our population. The overall mortality remains high. PMID- 23625019 TI - Unmet needs in immigrant cancer survivors: a cross-sectional population-based study. AB - PURPOSE: Social suffering, language difficulties, and cultural factors may all make the cancer experience more difficult for immigrants. This study aimed to document unmet needs, and variables associated with these, in a population-based sample of first-generation immigrants and Anglo-Australians who had survived cancer. METHODS: Participants were recruited via Australian cancer registries. Eligible cancer survivors had a new diagnosis 1-6 years earlier and were aged between 18 and 80 years at diagnosis. Eligible immigrant participants and parents were born in a country where Arabic, Chinese (Mandarin, Cantonese, and other dialects), or Greek is spoken, and they spoke one of these languages. A random sample of English-speaking Anglo-Australian-born controls was recruited. RESULTS: Five hundred ninety-six patients (277 immigrants) were recruited to the study (response rate, 26%). Compared to Anglo-Australians, the adjusted odds ratio of Chinese immigrants for at least one unmet information/support need was 5.1 (95% CI 3.1, 8.3) and for any unmet physical need was 3.1 (95% CI 1.9, 5.1). For Greek, these were 2.0 (95% CI 1.1, 4.0) and 2.7 (95% CI 1.4, 5.2). Arabic patients had elevated, but not statistically significant, odds ratios compared to Anglo-Australians. Written information and having a specialist, support services, and other health professionals who spoke their language were in the top ten unmet needs amongst immigrants. CONCLUSION: Immigrant cancer survivors, several years after initial diagnosis, are more likely to have an unmet need for information or for help with a physical problem than Anglo-Australians. They strongly desire information and support in their own language. PMID- 23625021 TI - Four-component assembly in the crystalline state driven by amidinium-carboxylate salt bridge formation from an aqueous solution. AB - A series of diamidine dihydrochlorides was prepared utilizing a spacer unit to control the distance between the two amidinium groups. The introduction of two amidinium groups to the 1,8-position of each spacer unit (i.e., 9,10 dihydroanthracene, anthracene, biphenylene) can control the direction of formation of a self-assembled structure. The fine-tuning of the distances between the two amidinium groups in the spacer units can help control the stabilizing interactions of two carboxylic acid units (intermolecular attraction) after the four-component assembly (see ). Based on this concept, we succeeded in the formation of a four-component box-like assembled structure using amidinium carboxylate salt bridge formation in the crystalline state from aqueous solutions. PMID- 23625020 TI - Association between hope and burden reported by family caregivers of patients with advanced cancer. AB - PURPOSE: The aim of this study, in a sample of family caregivers (FCs) of patients with advanced cancer, was to describe the level of FC burden using the Caregiver Reaction Assessment (CRA). In addition, the effects of select FC and patient characteristics on each of the CRA subscales were evaluated. METHODS: FCs and patients (n = 112) completed a demographic questionnaire, and Herth Hope Index, and the Hospital Anxiety and Depression Scale. FCs completed the CRA. Data were analyzed using multiple linear regression analyses. RESULTS: For three of the five CRA subscales (i.e., "impact on finances", "impact on daily schedule", and "impact on health"), the mean scores were comparable to a Norwegian sample of FCs caring for patients in the late palliative phase. The variance in each of the CRA subscales was explained by different factors. Total explained variance ranged from 5.5% ("lack of family support") to 31.8% ("impact on daily schedule"). FC characteristics, such as being female and lower educational level, distress regarding the patient's pain, anxiety, depression, and level of hope, as well as the patients' number of comorbidities, depression, and hope contributed to an increase in various domains of FC burden. FCs' level of hope was a significant predictor for three of the CRA subscales (i.e., "self-esteem", "lack of family support", and "impact on health"). CONCLUSIONS: Findings suggest that FCs' and patients' level of hope are important determinants of caregiver burden and that FCs with lower levels of hope represent a high-risk group for higher levels of caregiver burden. PMID- 23625022 TI - Relationship between cardiovascular resting state and visual attention. AB - INTRODUCTION: Cardiovascular features seem to modulate performance in attention tasks. METHODS: We investigated the relationship between blood pressure, resting heart rate and heart rate variability (HRV) and performance in a visuospatial attention task comparing normotensive and hypotensive young adults. CONCLUSIONS: We found an association between resting HRV and visual attention performance only in the normotensive group. In addition, we provided a further evidence of attention impairment in hypotensive individuals. PMID- 23625023 TI - 5-HT1A receptor pharmacophores to screen for off-target activity of alpha1 adrenoceptor antagonists. AB - The alpha1-adrenoceptors (alpha1-ARs), in particular the alpha1A-AR subtype, are current therapeutic targets of choice for the treatment of urogenital conditions, such as benign prostatic hyperplasia (BPH). Due to the similarity between the transmembrane domains of the alpha1-AR subtypes, and the serotonin receptor subtype 1A (5-HT1A-R), currently used alpha1-AR subtype-selective drugs to treat BPH display considerable off-target affinity for the 5-HT1A-R, leading to side effects. We describe the construction and validation of pharmacophores for 5-HT1A R agonists and antagonists. Through the structural diversity of the training sets used in their development, these pharmacophores define the properties of a compound needed to bind to 5-HT1A receptors. Using these and previously published pharmacophores in virtual screening and profiling, we have identified unique chemical compounds (hits) that fit the requirements to bind to our target, the alpha1A-AR, selectively over the off-target, the 5-HT1A-R. Selected hits have been obtained and their affinities for alpha1A-AR, alpha1B-AR and 5-HT1A-R determined in radioligand binding assays, using membrane preparations which contain human receptors expressed individually. Three of the tested hits demonstrate statistically significant selectivity for alpha1A-AR over 5-HT1A-R. All seven tested hits bind to alpha1A-AR, with two compounds displaying K i values below 1 MUM, and a further two K i values of around 10 MUM. The insights and knowledge gained through the development of the new 5-HT1A-R pharmacophores will greatly aid in the design and synthesis of derivatives of our lead compound, and allow the generation of more efficacious and selective ligands. PMID- 23625024 TI - Identification of novel small molecule TGF-beta antagonists using structure-based drug design. AB - Aberrant transforming growth factor-beta (TGF-beta) signalling has been associated with a number of disease pathologies, such as the development of fibrosis in the heart, lung and liver, cardiovascular disease and cancer, hence the TGF-beta pathway represents a promising target for a variety of diseases. However, highly specific ways to inhibit TGF-beta signalling need to be developed to prevent cross-talk with related receptors and minimise unwanted side effects. We have used used virtual screening and molecular docking to identify small molecule inhibitors of TGF-beta binding to TbetaRII. The crystal structure of TGF beta3 in complex with the extracellular domain of the type II TGF-beta receptor was taken as a starting point for molecular docking and we developed a structure based pharmacophore model to identify compounds that competitively inhibit the binding of TGF-beta to TbetaRII and antogonize TGF-beta signalling. We have experimentally tested 67 molecules suggested by in silico screening and similarity searching for their ability to inhibit TGF-beta signalling in TGF-beta dependent luciferase assays in vitro and the molecule with the strongest inhibition had an IC50 of 18 MUM. These compounds were selected to bind to the SS1 subsite (composed of F30, C31, D32, I50, T51 S52, I53, C54 and E55) of TbetaRII and all share the general property of being aromatic and fairly flat. Molecular dynamics simulations confirmed that this was the most likely binding mode. The computational methods used and the hits identified in this study provide an excellent guide to medicinal chemistry efforts to design tighter binding molecules to disrupt the TGF-beta/TbetaRII interaction. PMID- 23625025 TI - Adverse events associated with complementary and alternative medicine use in ovarian cancer patients. AB - INTRODUCTION: Many women with ovarian cancer are choosing to include complementary and alternative medicine (CAM) substances in conjunction with their conventional treatment for ovarian cancer. Many oncologists express concern that the adjunct use of CAM substances may be detrimental to the achievement of therapeutic levels of chemotherapy leading to increases in drug toxicity, under treatment of disease or other adverse events. In an effort to ascertain the extent of the potential problem with simultaneous use of CAM with conventional treatment we undertook comprehensive systematic review of published case reports describing CAM-related adverse events among ovarian cancer patients. STUDY DESIGN: This article describes a systematic literature review. METHODS: The Natural Medicines Comprehensive Database (NMCD). PubMed, EMBASE(r) and the Cochrane Central Register of Controlled Trials (CCTR) were systematically reviewed for research articles pertaining to case reports describing adverse events in patients, and clinical trials which examined the effects of herbs and supplements used during cancer treatment. RESULTS: Only one case report and one clinical trial were identified which met our inclusion criteria and were relevant to the current investigation. CONCLUSION: Although there are concerns about the potential for adverse events related to concurrent use of CAM substances during conventional treatment we found few case reports and clinical trials in the literature which support this. PMID- 23625026 TI - We and they in the house of healing: debate among Arab complementary medicine practitioners on an integrative versus alternative approach to supportive cancer care. AB - PURPOSE: Complementary and traditional medicine (CTM) plays an important role in culture-centered care for cancer patients in the Middle East. In this article, we have studied the attitudes of Arab CTM therapists concerning integration of complementary medicine within the conventional supportive cancer care of Arab patients in northern Israel. METHODS: Semistructured interviews were held with 27 Arab therapists who use medicinal herbs, the Quran, and various CTM modalities, with the aim of characterizing their treatment practices and learning about their perspectives regarding conventional cancer care. RESULTS: We first summarized the different characteristics of the various CTM therapists, including training, typical practice, and so on. Thematic analysis revealed that folk healers and complementary medicine therapists describe their role as supportive and secondary to that of physicians. Their goal was not to cure patients with cancer but rather to enhance their quality of life by reducing the severity of both the disease symptoms and the side effects of cancer treatment. Religious healers, by contrast, purport to cure the disease. While folk healers opt for parallel alternative care and complementary therapists support integrative care, religious healers claimed that they offer an alternative to conventional medicine in terms of both etiology and practice. CONCLUSIONS: The majority of Arab CTM therapists support integration of their treatments with the conventional system, but in practice, they are not sure how to bring about this change or create a parallel model in which 2 different systems are active, but not integrated. Our findings emphasized the need to promote doctor-CTM practitioner communication based on structured referral and bidirectional consultation. Moreover, we recommend intensifying research on the efficacy and safety of CTM in the Middle East and the potential role in promoting culture-based supportive care. PMID- 23625027 TI - The impact of music interventions on anxiety for adult cancer patients: a meta analysis and systematic review. AB - INTRODUCTION: Listening to music can positively benefit neurophysiological and emotional responses as well as promote relaxation, which may be especially beneficial for cancer patients undergoing painful and anxiety inducing treatments. The purpose of the present study was to conduct an evidenced-based systematic review and meta-analysis of randomized controlled trials of music interventions to reduce anxiety for adult cancer patients undergoing medical treatment. METHODS: A systematic literature search was conducted and data were abstracted from all eligible studies. Studies were included if they tested a music therapy randomized controlled trial in adult cancer patients (in active treatment), assessed anxiety postintervention using a validated measure, were published in English (or were translatable), and accessible in full text. Studies were qualitatively reviewed by the first author and 2 raters independently assessed each study using the PEDro scale. Standardized mean differences between experimental and control groups were calculated for studies meeting a specified methodological rigor score with accessible means and standard deviations postintervention. Heterogeneity and publication bias were explored. RESULTS: Thirteen randomized controlled trials were included with 4 eligible for meta analysis. Studies varied in intervention methodology and utilization of anxiety measures. Almost all studies reported either a significant difference in anxiety between groups postintervention or a significant decrease in anxiety over time in the music intervention group. Meta-analytic results of 4 studies (4/13) demonstrated that differences in anxiety between experimental and control groups were not significant in the main analysis or subgroup analysis. Studies demonstrated heterogeneity in anxiety results. Publication bias was not evident. CONCLUSION: The meta-analytic results failed to demonstrate a positive effect on anxiety among adult cancer patients in treatment but may in part be attributed to the small sample size. These findings are in contrast to a prior meta-analysis that analyzed all studies regardless of methodological rigor. More research is needed to ascertain the most optimal intervention methodology and which cancer populations or treatment modalities are appropriate for such an intervention. PMID- 23625029 TI - Introduction to the special section: sustainability of work with chronic health conditions. AB - BACKGROUND: The increasing prevalence of older workers and chronic health conditions represents a growing occupational health concern. More research is needed to understand risk factors, apply and adapt theories, and test workplace focused interventions that might prevent work disability and disengagement among chronically ill workers. METHODS: A 2-h roundtable symposium involving 28 participants was held at an international conference (Second Scientific Conference on Work Disability Prevention & Integration, Groningen, The Netherlands) in October 2012. In that symposium, small groups of participants were invited to discuss theoretical, methodological, and implementation considerations for studying workplace function and well-being among workers with chronic health conditions. As a follow-up to the symposium, the organizers invited authors to submit original articles to a Special Section of the Journal of Occupational Rehabilitation for peer review and publication. RESULTS: Results of the symposium reflected the need to address social, not just physical, aspects of the workplace, to include both individual-level and organizational interventions, and to integrate employer perspectives and operational models. Contributions to the Special Issue focus on outcome measurement, symptom self management at work, job accommodations, prognostic factors for disability escalation, and the perceived needs of affected workers. CONCLUSIONS: The content of the Special Section reflects an evolving body of research that continues to grapple with basic issues around choice of outcome measures, level of intervention, and the optimal ways to meet the needs of workers with chronic health conditions, including supporting efforts to manage symptoms and function at work. Future research should focus on integrating organizational and individual-level interventions. PMID- 23625030 TI - Resveratrol reduces acute lung injury in a LPS-induced sepsis mouse model via activation of Sirt1. AB - The development of acute lung injury (ALI) during sepsis almost doubles the mortality rate of patients. The efficacy of current treatment strategies is low as treatment is usually initiated following the onset of symptoms. Inflammation is one of the main mechanisms of autoimmune disorders and is a common feature of sepsis. The suppression of inflammation is therefore an important mechanism for the treatment of sepsis. Sirtuin 1 (Sirt1) has been demonstrated to play a role in the regulation of inflammation. Resveratrol, a potent Sirt1 activator, exhibits anti-inflammatory properties. However, the role of resveratrol for the treatment of ALI during sepsis is not fully understood. In the present study, the anti-inflammatory role of Sirt1 in the lipopolysaccharide (LPS)-induced TC-1 cell line and its therapeutic role in ALI was investigated in a mouse model of sepsis. The upregulation of matrix metalloproteinase-9, interleukin (IL)-1beta, IL-6 and inducible nitric oxide synthase was induced by LPS in the mouse model of sepsis and the TC-1 cell line, and resveratrol suppressed the overexpression of these proinflammatory molecules in a dose-dependent manner. Resveratrol decreased pulmonary edema in the mouse model of sepsis induced by LPS. In addition, resveratrol improved lung function and reduced pathological alterations in the mouse model of sepsis. Knockdown of Sirt1 by RNA interference resulted in an increased susceptibility of TC-1 cells to LPS stimulation and diminished the anti inflammatory effect of resveratrol. These results demonstrated that resveratrol inhibits LPS-induced ALI and inflammation via Sirt1, and indicated that Sirt1 is an efficient target for the regulation of LPS-induced ALI and inflammation. The present study provides insights into the treatment of ALI during sepsis. PMID- 23625031 TI - Synthesis and biological evaluation of cationic fullerene quinazolinone conjugates and their binding mode with modeled Mycobacterium tuberculosis hypoxanthine-guanine phosphoribosyltransferase enzyme. AB - The present work reports a series of novel cationic fullerene derivatives bearing a substituted-quinazolinone moiety as a side arm. Fullerene-quinazolinone conjugates synthesized using the 1,3-dipolar cycloaddition reaction of C60 with azomethine ylides generated from the corresponding Schiff bases of substituted quinazolinone were characterized by elemental analysis, FT-IR, (1)H NMR, (13)C NMR and ESI-MS and screened for their antibacterial activity against Mycobacterium tuberculosis (H 37 Rv strain). All the compounds exhibited significant activity with the most effective having MIC in the range of 1.562 3.125 MUg/mL. Compound 9f exhibited good biological activity compared to standard drugs. We developed a computational strategy based on the modeled M. tuberculosis hypoxanthine-guanine phosphoribosyltransferase (HGPRT) using homology modeling techniques and studied its binding pattern with synthesized fullerene derivatives. We then explored the surface geometry of the protein to place the cage adjacent to the active site while optimizing its quinazolinone side arm to establish H bonding with active site residues. PMID- 23625032 TI - Understanding the antioxidant behavior of some vitamin molecules: a first principles density functional approach. AB - The structures, energetics, vertical and adiabatic ionization potentials, electron affinities, and global reactivity descriptors of antioxidant vitamins (both water- and fat-soluble) in neutral, positively charged, and negatively charged states were investigated theoretically. We worked within the framework of first-principles density functional theory (DFT), using the B3LYP functional and both localized (6-311G+(d,p) and plane-wave basis sets. Solvent effects were modeled via the polarizable continuum model (PCM), using the integral equation formalism variant (IEFPCM). From the computed structural parameters, ionization potentials, electron affinities, and spin densities, we deduced that these vitamins prefer to lose electrons to neutral reactive oxygen species (.OH and .OOH), making them good antioxidants. Conceptual DFT was used to determine global chemical reactivity parameters. The computed chemical hardnesses showed that these antioxidant vitamins are more reactive than neutral reactive oxygen species (ROS), thus supporting their antioxidant character towards these species. However, in the neutral state, these vitamins do not act as antioxidants for [Formula: see text]. The reactivity of vitamins towards ROS depends on the nature of the solvent. Amongst the ROS, .OH has the greatest propensity to attract electrons from a generic donor. The reactivities of fat-soluble vitamins towards neutral reactive oxygen species were found to be larger than those of water soluble vitamins towards these species, showing that the former are better antioxidants. PMID- 23625034 TI - Effect of flexible bis-pyridyl-bis-amide ligands and dicarboxylates on the assembly and properties of multifunctional Cu(II) metal-organic coordination polymers. AB - A series of multifunctional Cu(II) metal-organic coordination polymers based on three flexible bis-pyridyl-bis-amide ligands and four aromatic dicarboxylates, namely [Cu(3-dpye)(3-NPA)(H2O)].3H2O (1), [Cu(3-dpye)0.5(5-AIP)(H2O)] (2), [Cu(3 dpye)(1,3-BDC)].3H2O (3), [Cu3(3-dpye)(1,2-BDC)2(MU2-OH)2] (4), [Cu3(3-dpyb)(1,2 BDC)2(MU2-OH)2] (5), [Cu(3-dpyh)0.5(1,2-BDC)].H2O (6), [Cu(3-dpyh)0.5(5 AIP)(H2O)] (7) [3-dpye = N,N'-bis(3-pyridinecarboxamide)-1,2-ethane, 3-dpyb = N,N'-bis(3-pyridinecarboxamide)-1,4-butane, 3-dpyh = N,N'-bis(3 pyridinecarboxamide)-1,6-hexane, 3-H2NPA = 3-nitrophthalic acid, 5-H2AIP = 5 aminoisophthalic acid, 1,3-H2BDC = 1,3-benzenedicarboxylic acid, 1,2-H2BDC = 1,2 benzenedicarboxylic acid], have been hydrothermally synthesized and structurally characterized by elemental analyses, IR, PXRD, TG and single crystal X-ray diffraction. X-ray analyses reveal that the seven Cu(II) complexes show three kinds of different 2D layer structures (for complexes 1, 2, 3, 6 and 7) and a 3D coordination framework (for complexes 4 and 5), exhibiting the (4(4).6(2)) topology for 1, (4(2).6(3).8)(4(2).6) topology for isostructural complexes 2 and 7, (4(2).6(7).8)(4(2).6) topology for complex 3, (3.4.5)2(3.4(2).5.8(6))2(3(2).8.9(2).10)(4(2).8(2).10(2)) topology for isostructural complexes 4 and 5, and the (4(2).6(3).8)(4(2).6) topology for complex 6, respectively. In complexes 1-7, the bis-pyridyl-bis-amide ligands adopt a MU2-bridging mode in 1, 2, 3, 6 and 7 (via ligation of two pyridyl nitrogen atoms) and a MU4-bridging coordination mode in 4 and 5 (via ligation of two pyridyl nitrogen atoms and two carbonyl oxygen atoms), which play an important role in determining the dimensionality of the title complexes. The aromatic dicarboxylates serve as a linker (for 1) and three-connected nodes (for 2-7) to bridge the adjacent Cu(II) ions, respectively, leading to the formation of various topological structures, which indicate both the substitute group and position of carboxyl group of the dicarboxylates play significant roles in the construction of the title complexes. The fluorescent, electrochemical and photocatalytic properties of complexes 1-7 have also been investigated. PMID- 23625033 TI - Thermodynamic computational approach to capture molecular recognition in the binding of different inhibitors to the DNA gyrase B subunit from Escherichia coli. AB - DNA gyrase subunit B, that catalyzes the hydrolysis of ATP, is an attractive target for the development of antibacterial drugs. This work is intended to rationalize molecular recognition at DNA gyrase B enzyme - inhibitor binding interface through the evaluation of different scoring functions in finding the correct pose and scoring properly 50 Escherichia coli DNA Gyrase B inhibitors belonging to five different classes. Improving the binding free energy calculation accuracy is further attempted by using rescoring schemes after short molecular dynamic simulations of the obtained docked complexes. These data are then compared with the corresponding experimental enzyme activity data. The results are analyzed from a structural point of view emphasizing the strengths and limitations of the techniques applied in the study. PMID- 23625035 TI - Social grooming among wild bonobos (Pan paniscus) at Wamba in the Luo Scientific Reserve, DR Congo, with special reference to the formation of grooming gatherings. AB - Chimpanzees (Pan troglodytes) groom in gatherings in which many individuals may be connected via multiple chains of grooming and they often exchange partners with each other. They sometimes groom another while receiving grooming; that is, one animal can play two roles (i.e., groomer and groomee) simultaneously. Although this feature of chimpanzees is notable from the viewpoint of the evolution of human sociality, information on our other closest living relative, the bonobo (Pan paniscus), is still lacking. In this study, I describe grooming interactions of bonobos at Wamba in the Luo Scientific Reserve, Democratic Republic of the Congo (DR Congo), with a particular focus on the formation of grooming gatherings. Like chimpanzees, the bonobos also performed mutual grooming (two individuals grooming each other simultaneously) and polyadic grooming (three or more individuals). However, unlike chimpanzees, these sessions lasted for only a short time. Bonobos rarely groomed another while receiving grooming. Because social grooming occurred not only in trees but also in open spaces, including treefall gaps, the conditions did not necessarily limit the opportunity to make multiple chains of grooming. However, bonobos also engaged in social grooming in different ways from chimpanzees; That is, many individuals were involved simultaneously at a site, in which they separated for dyadic grooming. Some cases clearly showed that bonobos preferred a third party not to join while grooming in a dyad, suggesting that bonobos have a preference for grooming in dyads and that immature individuals formed the preference that was shared among adults while growing up. Most members of the study group ranged together during the majority of the study period. Although bonobos show a fission-fusion grouping pattern, when group members frequently encounter one another on a daily basis, they may not be motivated to form multiple grooming chains at this site, as do chimpanzees. PMID- 23625036 TI - Exciplexes and conical intersections lead to fluorescence quenching in pi-stacked dimers of 2-aminopurine with natural purine nucleobases. AB - Fluorescent analogues of the natural DNA bases are useful in the study of nucleic acids' structure and dynamics. 2-Aminopurine (2AP) is a widely used analogue with environmentally sensitive fluorescence behavior. The quantum yield of 2AP has been found to be significantly decreased when engaged in pi-stacking interactions with the native bases. We present a theoretical study on fluorescence quenching mechanisms in dimers of 2AP pi-stacked with adenine or guanine as in natural DNA. Relaxation pathways on the potential energy surfaces of the first excited states have been computed and reveal the importance of exciplexes and conical intersections in the fluorescence quenching process. PMID- 23625037 TI - Heart rate differentiates urgency and emergency in hypertensive crisis. AB - OBJECTIVE: To study the clinical significance of presenting blood pressure parameters and heart rate in patients with hypertensive crisis. METHODS: In patients admitted with hypertensive crisis between January 2011 and May 2011, demography, mode of presentation, co-morbidities, blood pressure readings, and heart rate at presentation were documented. Further clustering of hypertensive crisis into emergency or urgency was based on the presence or absence of target organ involvement. The relationship between blood pressure parameters, heart rate, and other variables was analyzed. RESULTS: 189 patients in sinus rhythm were enrolled in this pilot study. The rate of hypertensive urgency was 56 %, whereas the rate of hypertensive emergency was 44 %, respectively. Subjects with hypertensive emergency had a higher mean heart rate (93 +/- 22.7 bpm) than those with urgency (81 +/- 11.5 bpm) (P = 0.015). Women had higher heart rates (92 +/- 18.5 bpm) than men (86 +/- 17.6 bpm) (P = 0.014). Heart rates below 100 bpm had a specificity of 94 %, classifying patients as hypertensive urgency. Tachycardia had a powerful statistical association with hypertensive left ventricular failure (P < 0.0001). Other hemodynamic parameters, including systolic blood pressure, diastolic blood pressure, pulse pressure, and mean blood pressure relates neither to urgency nor to emergency. Diabetic patients with HBA1c levels of more than 53 mmol/mol had a heart rate of more than 100 bpm (P = 0.015) during hypertensive crisis. CONCLUSIONS: Normal heart rate is characteristic of hypertensive urgency. Tachycardia in this setting is an ominous sign and denotes hypertensive complications in particular left ventricular failure. Among diabetics, elevated heart rate is associated with poor glycemic control. PMID- 23625038 TI - Life is a self-organizing machine driven by the informational cycle of Brillouin. AB - Acquiring information is indisputably energy-consuming and conversely, the availability of information permits greater efficiency. Strangely, the scientific community long remained reluctant to establish a physical equivalence between the abstract notion of information and sensible thermodynamics. However, certain physicists such as Szilard and Brillouin proposed: (i) to give to information the status of a genuine thermodynamic entity (k B T ln2 joules/bit) and (ii) to link the capacity of storing information inferred from correlated systems, to that of indefinitely increasing organization. This positive feedback coupled to the self templating molecular potential could provide a universal basis for the spontaneous rise of highly organized structures, typified by the emergence of life from a prebiotic chemical soup. Once established, this mechanism ensures the longevity and robustness of life envisioned as a general system, by allowing it to accumulate and optimize microstate-reducing recipes, thereby giving rise to strong nonlinearity, decisional capacity and multistability. Mechanisms possibly involved in priming this cycle are proposed. PMID- 23625039 TI - Survivability and abiotic reactions of selected amino acids in different hydrothermal system simulators. AB - We tested the stability and reaction of several amino acids using hydrothermal system simulators: an autoclave and two kinds of flow reactors at 200-250 degrees C. This study generally showed that there is a variation in the individual amino acids survivability in the simulators. This is mainly attributed to the following factors; heat time, cold quenching exposure, metal ions and also silica. We observed that, in a rapid heating flow reactor, high aggregation and/or condensation of amino acids could occur even during a heat exposure of 2 min. We also monitored their stability in a reflow-type of simulator for 120 min at 20 min intervals. The non-hydrolyzed and hydrolyzed samples for this system showed a similar degradation only in the absence of metal ions. PMID- 23625040 TI - Calvarial diploic venous channels: an anatomic study using high-resolution magnetic resonance imaging. AB - BACKGROUND: The calvarial diploic venous channels (CDVCs) are well-known intraosseous structures, but their distribution and anatomofunctional implications are not fully understood. OBJECTIVE: To investigate the architecture of CDVCs using high-resolution magnetic resonance (MR) imaging. METHOD: This prospective study enrolled 43 male and 37 female outpatients who underwent a 3.0 T MR imaging equipped by a 32-channel head coil. T1-weighted imaging covering the whole cranial vault was performed after gadolinium injection. In addition, one piece orbitozygomatic craniotomy was performed in three cadaveric heads to observe the interruption of the CDVCs. RESULTS: The CDVCs showed irregular contours and peculiar branching patterns with four common major pathways: the pteriofrontparietal (PFP), frontoorbital (FO), occipitoparietal (OP), and occipitocervical (OC) routes. The proximal PFP coursed as a single trunk and divided into several branches at the level of the frontal eminence. The orbital part of the FO continued to the subcutaneous vein via the supraorbital rim. The PFP and the pterional part of the FO fused proximally with the sphenoparietal sinus and descended as the middle meningeal vein. The OP coursed in the superoinferior direction and connected the junction part of the transverse sigmoid sinus to the parietal superior sagittal sinus. The OC occurred as a single trunk in the median occipital bone, drained extracranially, and joined the suboccipital venous channels. CONCLUSIONS: The CDVCs seem to be a relatively consistent network functioning not only as conduits connecting the intracranial dural sinuses but also as pathways to the extracranial venous systems. High resolution MR imaging is useful for investigating the CDVCs. PMID- 23625041 TI - ATRP synthesis of poly(2-(methacryloyloxy)ethyl choline phosphate): a multivalent universal biomembrane adhesive. AB - A new monomer, 2-(methacryloyloxy)ethyl choline phosphate, and its direct polymerization into a polyvalent choline phosphate are described, providing a universal biomembrane adhesive exhibiting rapid, strong attachment to any mammalian cell membrane and fast internalization, properties of great value in applications such as tissue engineering and drug delivery. PMID- 23625042 TI - Dynamic changes of peritoneal macrophages and subpopulations during ulcerative colitis to metastasis of colorectal carcinoma in a mouse model. AB - OBJECTIVE AND DESIGN: Patients with ulcerative colitis have increased risk of colorectal carcinoma, but little is known about how peritoneal macrophages are involved in ulcerative colitis-associated carcinogenesis. We investigated the alteration of peritoneal macrophages and M1/M2 subpopulations during ulcerative colitis-associated carcinogenesis. MATERIALS AND METHODS: Expression and functional changes in peritoneal macrophages and M1/M2 subpopulations were investigated by histopathology, flow cytometry, immunofluorescence, cytokines expression by ELISA and QRT-PCR in an azoxymethane (AOM)- and dextran sodium sulfate (DSS)-induced chemical colitis-associated carcinoma mouse model using male Crj:CD-1 (ICR) mice. RESULTS: Striking evidence observed in histopathology, flow cytometry, cytokine detection, and gene expression analysis all revealed that inflammation-associated cytokines (IL-1beta, IL-10, IL-12, IL-6, TNF-alpha) and migration/invasion-associated factors (G-CSF, GM-CSF, CXCR4, VEGF, TGF-beta, ICAM-1) induced by peritoneal M2 macrophages increased significantly during the progression from inflammatory hyperplasia to carcinoma and metastasis. Similar functional changes occurred during peritoneal metastasis in M1 macrophages without changed polarization. CONCLUSIONS: These results suggested that peritoneal M2 macrophages played a critical role in ulcerative colitis-associated carcinogenesis, including unbalanced pro-inflammatory and anti-inflammatory axis and enhanced expression of migration/invasion-associated factors. Furthermore, functional changes of M1 macrophages occurred without changed polarization during carcinogenesis and metastasis. PMID- 23625043 TI - Periodic vs constant high glucose in inducing pro-inflammatory cytokine expression in human coronary artery endothelial cells. AB - OBJECTIVE AND DESIGN: Fluctuating hyperglycemia exerts a more deleterious effect than constant hyperglycemia on cardiovascular outcome in diabetic patients. We investigated the inflammatory responses of human coronary artery endothelial cells (HCAECs) to constant and periodic high glucose in vitro. MATERIAL AND TREATMENT: HCAECs were incubated for 72 h continuously either in normal glucose (5.5 mmol/L), constant high glucose (25 mmol/L glucose), periodic high glucose (5.5 and 25 mmol/L glucose alternating every 6 h) or mannitol. METHODS: Concentrations of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and intercellular adhesion molecule (ICAM)-1 in the supernatants of cell culture were measured using ELISA kits. The mRNAs of IL-6, TNF-alpha and ICAM-1 were evaluated by real-time quantitative PCR. RESULTS: Periodic high glucose caused a more intense inflammatory response than normal glucose and constant high glucose in HCAECs, with a marked increase in IL-6, TNF-alpha and ICAM-1 in supernatants of cell culture (P < 0.05). The concentrations of the three pro-inflammatory cytokine mRNAs were higher in cells exposed to periodic high glucose than those exposed to constant high glucose and normal glucose (P < 0.05). CONCLUSION: In cultured HCAECs, periodic high glucose evoked a more intense inflammatory response than constant high glucose. PMID- 23625044 TI - Synthesis of substituted hydantoins in low melting mixtures. AB - A novel domino synthesis of 1,3,5-trisubstituted hydantoin derivatives has been developed in low melting L-(+)-tartaric acid-DMU melt mixtures. The functionalized hydantoins are obtained in good yields from beta,gamma-unsaturated ketoacids and urea under environmentally benign and simple reaction conditions. PMID- 23625045 TI - The orthographic sensitivity to written Chinese in the occipital-temporal cortex. AB - Previous studies have identified an area in the left lateral fusiform cortex that is highly responsive to written words and has been named the visual word form area (VWFA). However, there is disagreement on the specific functional role of this area in word recognition. Chinese characters, which are dramatically different from Roman alphabets in the visual form and in the form to phonological mapping, provide a unique opportunity to investigate the properties of the VWFA. Specifically, to clarify the orthographic sensitivity in the mid-fusiform cortex, we compared fMRI response amplitudes (Exp. 1) as well as the spatial patterns of response across multiple voxels (Exp. 2) between Chinese characters and stimuli derived from Chinese characters with different orthographic properties. The fMRI response amplitude results suggest the existence of orthographic sensitivity in the VWFA. The results from multi-voxel pattern analysis indicate that spatial distribution of the responses across voxels in the occipitotemporal cortex contained discriminative information between the different types of character related stimuli. These results together suggest that the orthographic rules are likely represented in a distributed neural network with the VWFA containing the most specific information regarding a stimulus' orthographic regularity. PMID- 23625046 TI - Force feedback facilitates multisensory integration during robotic tool use. AB - The present study investigated the effects of force feedback in relation to tool use on the multisensory integration of visuo-tactile information. Participants learned to control a robotic tool through a surgical robotic interface. Following tool-use training, participants performed a crossmodal congruency task, by responding to tactile vibrations applied to their hands, while ignoring visual distractors superimposed on the robotic tools. In the first experiment it was found that tool-use training with force feedback facilitates multisensory integration of signals from the tool, as reflected in a stronger crossmodal congruency effect with the force feedback training compared to training without force feedback and to no training. The second experiment extends these findings by showing that training with realistic online force feedback resulted in a stronger crossmodal congruency effect compared to training in which force feedback was delayed. The present study highlights the importance of haptic information for multisensory integration and extends findings from classical tool use studies to the domain of robotic tools. We argue that such crossmodal congruency effects are an objective measure of robotic tool integration and propose some potential applications in surgical robotics, robotic tools, and human-tool interaction. PMID- 23625047 TI - Postural control and head stability during natural gaze behaviour in 6- to 12 year-old children. AB - We investigated how the influence of natural exploratory gaze behaviour on postural control develops from childhood into adulthood. In a cross-sectional design, we compared four age groups: 6-, 9-, 12-year-olds and young adults. Two experimental trials were performed: quiet stance with a fixed gaze (fixed) and quiet stance with natural exploratory gaze behaviour (exploratory). The latter was elicited by having participants watch an animated short film on a large screen in front of them. 3D head rotations in space and centre of pressure (COP) excursions on the ground plane were measured. Across conditions, both head rotation and COP displacement decreased with increasing age. Head movement was greater in the exploratory condition in all age groups. In all children-but not in adults-COP displacement was markedly greater in the exploratory condition. Bivariate correlations across groups showed highly significant positive correlations between COP displacement in ML direction and head rotation in yaw, roll, and pitch in both conditions. The regularity of COP displacements did not show a clear developmental trend, which indicates that COP dynamics were qualitatively similar across age groups. Together, the results suggest that the contribution of head movement to eye-head saccades decreases with age and that head instability-in part resulting from such gaze-related head movements-is an important limiting factor in children's postural control. The lack of head stabilisation might particularly affect children in everyday activities in which both postural control and visual exploration are required. PMID- 23625048 TI - A molecular level prototype for mechanoelectrical transducer in mammalian hair cells. AB - The mechanoelectrical transducer (MET) is a crucial component of mammalian auditory system. The gating mechanism of the MET channel remains a puzzling issue, though there are many speculations, due to the lack of essential molecular building blocks. To understand the working principle of mammalian MET, we propose a molecular level prototype which constitutes a charged blocker, a realistic ion channel and its surrounding membrane. To validate the proposed prototype, we make use of a well-established ion channel theory, the Poisson-Nernst-Planck equations, for three-dimensional (3D) numerical simulations. A wide variety of model parameters, including bulk ion concentration, applied external voltage, blocker charge and blocker displacement, are explored to understand the basic function of the proposed MET prototype. We show that our prototype prediction of channel open probability in response to blocker relative displacement is in remarkable accordance with experimental observation of rat cochlea outer hair cells. Our results appear to suggest that tip links which connect hair bundles gate MET channels. PMID- 23625050 TI - Distribution coefficients of potentially toxic elements in soils from the eastern Amazon. AB - The solid-solution distribution or partition coefficient (Kd) is a measure of affinity of potentially toxic elements (PTE) for soil colloids. Kd plays a key role in several models for defining PTE guideline values in soils and for assessing environmental risks, and its value depends on edaphic and climatic conditions of the sites where the soils occur. This study quantified Kd values for Cd, Co, Cr, Cu, Hg, Ni, Pb, and Zn from representative soil samples from Brazil's eastern Amazon region, which measures 1.2 million km(2). The Kd values obtained were lower than those set by both international and Brazilian environmental agencies and were correlated with the pH, Fe and Mn oxide content, and cationic exchange capacity of the soils. The following order of decreasing affinity was observed: Pb>Cu>Hg>Cr>Cd~Co>Ni>Zn. PMID- 23625051 TI - Dynamics and mitigation of six pesticides in a "Wet" forest buffer zone. AB - Pesticide pollution is one of the main current threats on water quality. This paper presents the potential and functioning principles of a "Wet" forest buffer zone for reducing concentrations and loads of glyphosate, isoproturon, metazachlor, azoxystrobin, epoxiconazole, and cyproconazole. A tracer injection experiment was conducted in the field in a forest buffer zone at Bray (France). A fine time-scale sampling enabled to illustrate that interactions between pesticides and forest buffer substrates (soil and organic-rich litter layer), had a retarding effect on molecule transfer. Low concentrations were observed for all pesticides at the forest buffer outlet thus demonstrating the efficiency of "Wet" forest buffer zone for pesticide dissipation. Pesticide masses injected in the forest buffer inlet directly determined concentration peaks observed at the outlet. Rapid and partially reversible adsorption was likely the major process affecting pesticide transfer for short retention times (a few hours to a few days). Remobilization of metazachlor, isoproturon, desmethylisoproturon, and AMPA was observed when non-contaminated water flows passed through the forest buffer. Our data suggest that pesticide sorption properties alone could not explain the complex reaction mechanisms that affected pesticide transfer in the forest buffer. Nevertheless, the thick layer of organic matter litter on the top of the forest soil was a key parameter, which enhanced partially reversible sorption of pesticide, thus retarded their transfer, decreased concentration peaks, and likely increased degradation of the pesticides. Consequently, to limit pesticide pollution transported by surface water, the use of already existing forest areas as buffer zones should be equally considered as the most commonly implemented grass buffer strips. PMID- 23625052 TI - Abundance of denitrification genes under different peizometer depths in four Irish agricultural groundwater sites. AB - This study examined the relationship between the abundance of bacterial denitrifiers in groundwater at four sites, differing with respect to overlaying land management and peizometer depth. Groundwater was sourced from 36 multilevel piezometers, which were installed to target different groundwater zones: (1) subsoil, (2) subsoil to bedrock interface, and (3) bedrock. The gene copy concentrations (GCCs), as gene copies per liter, for bacterial 16S rRNA genes and the denitrifying functional genes, nirK, nirS, and nosZ, were determined using quantitative polymerase chain reaction assays. The results were related to gaseous nitrogen emissions and to the physicochemical properties of the four sites. Overall, nirK and nirS abundance appeared to show no significant correlation to N2O production (P = 0.9989; P = 0.3188); and no significant correlation was observed between nosZ and excess N2 concentrations (P = 0.0793). In the majority of piezometers investigated, the variation of nirK and nirS gene copy concentrations was considered significant (P < 0.0001). Dissolved organic carbon (DOC) decreased with aquifer depth and ranged from 1.0-4.0 mg l(-1), 0.9 2.4 mg l(-1), and 0.8-2.4 mg l(-1) within piezometers located in the subsoil, subsoil/bedrock interface, and bedrock depths, respectively. The availability of increasing DOC and the depth of the water table were positively correlated with increasing nir and nosZ GCCs (P = 0.0012). A significant temporal correlation was noted between nirS and piezometer depth (P < 0.001). Interestingly, the nirK, nirS, and nosZ GCCs varied between piezometer depths within specific sites, while GCCs remained relatively constant from site to site, thus indicating no direct impact of agricultural land management strategies investigated on denitrifier abundance. PMID- 23625054 TI - A portable device for measuring donor corneal transparency in eye banks. AB - To develop a portable device for measuring the donor corneal transparency and validate its efficacy for corneal evaluation in the eye-banks and for research. The transparency device (TD) has a light source, a detachable system for corneal insertion and a base for light transmission. The probe detects the transmitted light which is measured by a lux-meter. A contact lens was set as 'control' to reduce the light scattering concern, an empty petri-plate as 'blank' and the cornea as 'sample'. Two experts and non-experts (masked) observed the corneas for subjective analysis which was then compared using the TD. The parameters observed were scars, foreign-body, stromal-deformities, folds, thickness and opacity which were then converted to a relative overall percentage by the observer. Twenty corneas were evaluated for correlation, five tissues to obtain standard-deviation and twenty-four pairs for a comparative study. Experts mimicked the eye-banks with long-term experience while non-experts mimicked the emerging eye-banks. Subjective values by the experts closely resembled the measurements by TD. The average correlation between the experts and the non-experts to TD was 0.985 and 0.960 respectively. TD showed higher reproducibility than experts followed by the non-experts. The comparative study showed that increase in thickness reduces the transparency. TD is portable, easy, efficient, maintains sterility and less expensive hence the emerging eye-banks and researchers can use to raise their standards and evaluate the transparency for in vitro tests and comparative studies. The suitable transparency for the cornea deemed for clinical applications was found to be >75 %. PMID- 23625055 TI - Overview of active cesium contamination of freshwater fish in Fukushima and Eastern Japan. AB - This paper focuses on an overview of radioactive cesium 137 (quasi-Cs137 included Cs134) contamination of freshwater fish in Fukushima and eastern Japan based on the data published by the Fisheries Agency of the Japanese Government in 2011. In the area north and west of the Fukushima Nuclear plant, freshwater fish have been highly contaminated. For example, the mean of active cesium (quasi-Cs137) contamination of Ayu (Plecoglossus altivelis) is 2,657 Bq/kg at Mano River, 20-40 km north-west from the plant. Bioaccumulation is observed in the Agano river basin in Aizu sub-region, 70-150 km west from the plant. The active cesium (quasi Cs137) contamination of carnivorous Salmondae is around 2 times higher than herbivorous Ayu. The extent of active cesium (quasi-Cs137) contamination of Ayu is observed in the entire eastern Japan. The some level of the contamination is recognized even in Shizuoka prefecture, 400 km south-west from the plant. PMID- 23625056 TI - Italian cardiological guidelines for sports eligibility in athletes with heart disease: part 2. AB - In Italy the existence of a law on health protection of competitive sports since 1982 has favored the creation and the revision of these cardiological guidelines (called COCIS), which have reached their fourth edition (1989-2009). The present article is the second English version, which has summarized the larger version in Italian. The experience of the experts consulted in the course of these past 20 years has facilitated the application and the compatibility of issues related to clinical cardiology to the sports medicine field. Such prolonged experience has allowed the clinical cardiologist to acquire knowledge of the applied physiology of exercise and, on the other hand, has improved the ability of sports physicians in cardiological diagnostics. All this work has produced these guidelines related to the judgment of eligibility for competitive sports in the individual clinical situations and in the different cardiovascular abnormalities and/or heart disease. Numerous arguments are debated, such as interpretation of the athlete's ECG, the utility of a preparticipation screening, arrhythmias, congenital heart disease, cardiomyopathies, arterial hypertension, ischemic heart disease and other particular issues. PMID- 23625058 TI - Clinical study in patients with ocular ischemic diseases treated with enhanced external counterpulsation combined with drugs. AB - The aim of this study was to evaluate the clinical effect in patients with ocular ischemic diseases treated with enhanced external counterpulsation (EECP) combined with drugs. A total of 65 patients with carotid artery stenosis were included in this study. Group A consisted of 31 patients (43 eyes) treated with EECP and medication, and group B consisted of 34 patients (49 eyes) treated with medication alone. The clinical effect was analyzed by comparing the visual acuity, visual fields and optical hemodynamics between the two groups of patients. Ocular ischemic diseases mainly included ischemic optic neuropathy, central (branch) retinal artery occlusion, ophthalmoplegia externa and ocular ischemic syndrome. Significant improvement of visual acuity, visual fields and optical hemodynamics was observed in the patients of group A, and statistically significant differences were found between groups A and B (chi2=4.935, 7.124 and 5.478, respectively; P<0.05). In conclusion, ophthalmologists should observe for ocular ischemic diseases. The symptoms of the disease and the vision of the patient could be effectively improved by EECP, which has no evident complications. PMID- 23625059 TI - Purification and characterization of neurotoxin complex from a dual toxin gene containing Clostridium Botulinum Strain PS-5. AB - Botulinum neurotoxins are produced as a toxin complex (TC) which consists of neurotoxin (NT) and neurotoxin associated proteins. The characterization of NT in its native state is an essential step for developing diagnostics and therapeutic countermeasures against botulism. The presence of NT genes was validated by PCR amplification of toxin specific fragments from genomic DNA of Clostridium botulinum strain PS-5 which indicated the presence of both serotype A and B genes on PS-5 genome. Further, TC was purified and characterized by Western blotting, Digoxin-enzyme linked immunosorbent assay, endopeptidase activity assay, and Liquid chromatography-Mass spectrometry. The data showed the presence of serotype A specific neurotoxin. Based on the analysis of neurotoxin genes and characterization of TC, PS-5 strain appears as a serotype A (B) strain of C. botulinum which produces only serotype A specific TC in the cell culture medium. PMID- 23625060 TI - A novel medial collateral ligament reconstruction procedure using semitendinosus tendon autograft in patients with multiligamentous knee injuries: clinical outcomes. AB - BACKGROUND: Several new procedures for medial collateral ligament (MCL) reconstruction using a hamstring tendon graft have been reported in the 2000s. However, the midterm and long-term clinical outcomes of these procedures have not been reported. HYPOTHESIS: Postoperative medial stability of the knee that underwent our MCL reconstruction may not be significantly different from that of the noninjured knee. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 37 patients who sustained multiligamentous knee injuries underwent combined MCL and cruciate ligament reconstruction at our institution between 1994 and 2007. Thirty of the 37 patients were clinically evaluated at least 2 years after surgery. Sixteen had combined MCL and anterior cruciate ligament (ACL) reconstruction, 5 had combined MCL and posterior cruciate ligament (PCL) reconstruction, and 9 had combined MCL, ACL, and PCL reconstruction. The International Knee Documentation Committee (IKDC) evaluation form and Lysholm score were used to evaluate postoperative knee function. Anteroposterior knee laxity was examined with a KT-2000 arthrometer. To assess objective medial instability, we performed a stress radiograph examination under valgus stress with the knee at 20 degrees of flexion. RESULTS: At the final follow-up, 1 patient showed a loss of knee extension of more than 3 degrees . Five patients revealed a loss of knee flexion of 6 degrees to 15 degrees and 2 patients of 16 degrees to 25 degrees . Lysholm scores averaged 94.8 points. In the IKDC evaluation, 9 patients were graded as A, 17 were graded as B, 3 were graded as C, and 1 was graded as D. In the stress radiograph examination, the mean medial joint opening was 8.5 +/- 1.6 mm in the reconstructed knee and 8.0 +/- 1.2 mm in the healthy opposite knee. There was no significant difference in the medial joint opening between reconstructed and intact knees. CONCLUSION: Medial collateral ligament reconstruction for chronic combined knee instabilities can be safely performed using hamstring tendon autografts, and the clinical outcome with a minimum 2-year follow-up was favorable with satisfactory stability. PMID- 23625061 TI - Severe nigrostriatal degeneration without clinical parkinsonism in patients with polymerase gamma mutations. AB - The role of mitochondria in the pathogenesis of neurodegeneration is an area of intense study. It is known that defects in proteins involved in mitochondrial quality control can cause Parkinson's disease, and there is increasing evidence linking mitochondrial dysfunction, and particularly mitochondrial DNA abnormalities, to neuronal loss in the substantia nigra. Mutations in the catalytic subunit of polymerase gamma are among the most common causes of mitochondrial disease and owing to its role in mitochondrial DNA homeostasis, polymerase gamma defects are often considered a paradigm for mitochondrial diseases generally. Yet, despite this, parkinsonism is uncommon with polymerase gamma defects. In this study, we investigated structural and functional changes in the substantia nigra of 11 patients with polymerase gamma encephalopathy. We characterized the mitochondrial DNA abnormalities and examined the respiratory chain in neurons of the substantia nigra. We also investigated nigrostriatal integrity and function using a combination of post-mortem and in vivo functional studies with dopamine transporter imaging and positron emission tomography. At the cellular level, dopaminergic nigral neurons of patients with polymerase gamma encephalopathy contained a significantly lower copy number of mitochondrial DNA (depletion) and higher levels of deletions than normal control subjects. A selective and progressive complex I deficiency was seen and this was associated with a severe and progressive loss of the dopaminergic neurons of the pars compacta. Dopamine transporter imaging and positron emission tomography showed that the degree of nigral neuronal loss and nigrostriatal depletion were severe and appeared greater even than that seen in idiopathic Parkinson's disease. Despite this, however, none of our patients showed any signs of parkinsonism. The additional presence of both thalamic and cerebellar dysfunction in our patients suggested that these may play a role in counteracting the effects of basal ganglia dysfunction and prevent the development of clinical parkinsonism. PMID- 23625062 TI - Brain communication in the locked-in state. AB - Patients in the completely locked-in state have no means of communication and they represent the target population for brain-computer interface research in the last 15 years. Although different paradigms have been tested and different physiological signals used, to date no sufficiently documented completely locked in state patient was able to control a brain-computer interface over an extended time period. We introduce Pavlovian semantic conditioning to enable basic communication in completely locked-in state. This novel paradigm is based on semantic conditioning for online classification of neuroelectric or any other physiological signals to discriminate between covert (cognitive) 'yes' and 'no' responses. The paradigm comprised the presentation of affirmative and negative statements used as conditioned stimuli, while the unconditioned stimulus consisted of electrical stimulation of the skin paired with affirmative statements. Three patients with advanced amyotrophic lateral sclerosis participated over an extended time period, one of which was in a completely locked-in state, the other two in the locked-in state. The patients' level of vigilance was assessed through auditory oddball procedures to study the correlation between vigilance level and the classifier's performance. The average online classification accuracies of slow cortical components of electroencephalographic signals were around chance level for all the patients. The use of a non-linear classifier in the offline classification procedure resulted in a substantial improvement of the accuracy in one locked-in state patient achieving 70% correct classification. A reliable level of performance in the completely locked-in state patient was not achieved uniformly throughout the 37 sessions despite intact cognitive processing capacity, but in some sessions communication accuracies up to 70% were achieved. Paradigm modifications are proposed. Rapid drop of vigilance was detected suggesting attentional variations or variations of circadian period as important factors in brain-computer interface communication with locked-in state and completely locked-in state. PMID- 23625063 TI - Three-arm phase III trial comparing cisplatin plus 5-FU (CF) versus docetaxel, cisplatin plus 5-FU (DCF) versus radiotherapy with CF (CF-RT) as preoperative therapy for locally advanced esophageal cancer (JCOG1109, NExT study). AB - A three-arm Phase III trial was started in November 2012. Preoperative chemotherapy with cisplatin plus 5-fluorouracil is the current standard treatment for locally advanced esophageal cancer in Japan, while preoperative chemoradiotherapy with cisplatin plus 5-fluorouracil is the standard in Western countries. Preoperative chemotherapy with docetaxel, cisplatin plus 5 fluorouracil is another promising regimen. The purpose of this study is to confirm the superiority of docetaxel, cisplatin plus 5-fluorouracil over cisplatin plus 5-fluorouracil and the superiority of cisplatin plus 5 fluorouracil with chemoradiotherapy over cisplatin plus 5-fluorouracil as preoperative therapy for squamous cell carcinoma of esophagus. A total of 501 patients will be accrued from 41 Japanese institutions within 6.25 years. The primary endpoint is overall survival and the secondary endpoints include progression-free survival, %R0 resection, response rate, pathologic complete response rate and adverse events. PMID- 23625064 TI - Patients with hepatitis C infection and normal liver function: an evaluation of cognitive function. AB - PURPOSE OF THE STUDY: Hepatitis C virus (HCV) is associated with neuropsychiatric complaints. Previous studies have associated cognitive alterations with HCV infection but have often included confounding factors in their samples. This study compares the cognitive performance between patients with HCV infection (HCV patients) and a control group while excluding other factors that may cause cognitive impairment. STUDY DESIGN: This cross-sectional study was conducted from March 2010 through June 2011. HCV infected patients and healthy individuals between the ages of 18 and 80 years were considered eligible. The exclusion criteria included well established causes of cognitive impairment such as depression and cirrhosis. Study participants underwent neuropsychological testing involving measures of attention, memory, abstraction, visuoconstructive abilities, and executive function. RESULTS: Of 138 initial patients, 47 were excluded because of their medical records, three refused to participate, 23 did not attend the consultation, and 32 were excluded because of having Beck Depression Inventory (BDI) scores >11. In all, 33 patients underwent neuropsychological testing; however, three were excluded because of having hypothyroidism, and one was excluded because of having a cobalamin deficiency. For the control group, of the 33 healthy individuals that were selected, four were excluded because of having BDI scores >11. Thus, the final analysis included 29 HCV patients and 29 control participants. The groups did not differ in education, age, or gender. No statistically significant differences were found between the groups regarding cognitive performance. CONCLUSIONS: In this study using strict selection criteria, there was no evidence of an association between HCV infection and cognitive impairment. PMID- 23625065 TI - Topical contrast agents to improve soft-tissue contrast in the upper airway using cone beam CT: a pilot study. AB - The purpose of this study is to explore the topical use of radiographic contrast agents to enhance soft-tissue contrast on cone beam CT (CBCT) images. Different barium sulphate concentrations were first tested using an airway phantom. Different methods of barium sulphate application (nasal drops, syringe, spray and sinus wash) were then tested on four volunteers, and nebulized iodine was tested in one volunteer. CBCT images were performed and then assessed subjectively by two examiners for contrast agent uniformity and lack of streak artefact. 25.0% barium sulphate presented adequate viscosity and radiodensity. Barium sulphate administered via nasal drops and sprays showed non-uniform collection at the nostrils, along the inferior and/or middle nasal meatuses and posterior nasal choana. The syringe and sinus wash showed similar results with larger volumes collecting in the naso-oropharynx. Nebulized iodine failed to distribute into the nasal cavity and scarcely collected at the nostrils. All methods of nasal application failed to adequately reach or uniformly coat the nasal cavity beyond the inferior nasal meatuses. The key factors to consider for optimum topical radiographic contrast in the nasal airway are particle size, flow velocity and radio-opacity. PMID- 23625066 TI - Evaluation of condylar morphology following orthognathic surgery on digital panoramic radiographs. Could methodology influence the range of "normality" in condylar changes? AB - OBJECTIVES: To evaluate the morphological condylar changes following orthognathic surgery by using a rapid and reliable computational method on panoramic radiographs. METHODS: Digital panoramic radiographs of 45 patients who underwent bilateral sagittal split osteotomy (alone or associated with a Le Fort I osteotomy) between 2007 and 2010 were analysed. Calculation of the area, perimeter and height of 90 condyles was performed by using a specific computational method. Measurements were taken before surgery (m1), 1 day after surgery (m2) and 1 year after surgery (m3). The evolution of each index was analysed using paired t-tests between measures before and 1 day after surgery (m1 - m2) and measures before and 1 year after surgery (m1 - m3). The changes in the condylar area, perimeter and height were examined using the Bland and Altman plotting method. RESULTS: There were no statistically significant changes in the mean condylar area, perimeter or height between m1 and m2 or between m1 and m3. The Bland and Altman plots for each index showed that a very limited number of condyles increased or decreased in area, perimeter and/or height outside the boundaries of the measurement error. Given the impossibility for a condyle to increase in size, these results are considered to represent the limits of the computational method used. CONCLUSIONS: This study demonstrated that there were no significant morphological condylar changes at the 1-year follow-up following surgery and that the range of normality in condylar changes could be influenced by the methodology used. PMID- 23625067 TI - Comparison of cone beam CT scans with enhanced photostimulated phosphor plate images in the detection of root fracture of endodontically treated teeth. AB - OBJECTIVES: Two-dimensional intraoral radiography is the most common tool for diagnosing root fractures (RFs). Cone beam CT (CBCT) is widely used to depict RFs in endodontically treated teeth. Beam hardening and other artefacts caused by gutta percha may result in an incorrect diagnosis when using CBCT only. A comparison of two CBCT machines with photostimulated phosphor (PSP) plate images enhanced with the equalization tool was carried out to detect RFs in endodontically treated teeth. METHODS: 66 roots were collected, decoronated and treated endodontically using the same technique with gutta percha. 33 of these roots were randomly selected and fractured; the 2 root fragments were glued together with 1 layer of methyl methacrylate and placed randomly in 8 prepared beef rib fragments. Large fields of view (FOVs) were acquired with one CBCT unit and small FOVs with the second CBCT unit. Periapical radiographs (using intraoral PSP plates) were also acquired. A contrast enhancement tool was used when evaluating the PSP plate images. RESULTS: Small FOV images had significantly higher accuracy (area under the receiver operating characteristic curve) and sensitivity in detecting RFs than PSP plates and large FOV images. The specificity of the enhanced PSP images was higher than, although not significantly higher than, the small FOV images and was significantly higher than the large FOV images. CONCLUSIONS: CBCT small FOVs should be acquired for depicting RFs of endodontically treated teeth. Images obtained using PSP plates had the lowest rate of false-positive results and their use can save the patient a radiation dose. PMID- 23625068 TI - Free fatty acid receptors and their role in regulation of energy metabolism. AB - The free fatty acid receptor (FFAR) is a G protein-coupled receptor (GPCR) activated by free fatty acids (FFAs), which play important roles not only as essential nutritional components but also as signaling molecules in numerous physiological processes. In the last decade, FFARs have been identified by the GPCR deorphanization strategy derived from the human genome database. To date, several FFARs have been identified and characterized as critical components in various physiological processes. FFARs are categorized according to the chain length of FFA ligands that activate each FFAR; FFA2 and FFA3 are activated by short chain FFAs, GPR84 is activated by medium-chain FFAs, whereas FFA1 and GPR120 are activated by medium- or long-chain FFAs. FFARs appear to act as physiological sensors for food-derived FFAs and digestion products in the gastrointestinal tract. Moreover, they are considered to be involved in the regulation of energy metabolism mediated by the secretion of insulin and incretin hormones and by the regulation of the sympathetic nerve systems, taste preferences, and inflammatory responses related to insulin resistance. Therefore, because FFARs can be considered to play important roles in physiological processes and various pathophysiological processes, FFARs have been targeted in therapeutic strategies for the treatment of metabolic disorders including type 2 diabetes and metabolic syndrome. In this review, we present a summary of recent progress regarding the understanding of their physiological roles in the regulation of energy metabolism and their potential as therapeutic targets. PMID- 23625069 TI - [Is less than 100 Euro sufficient for a capillary microscope?]. PMID- 23625070 TI - Morphometric measurements and sexual dimorphism of the piriform aperture in adults. AB - PURPOSE: The aim of this study was to evaluate the dimensions (maximal width and length), the size and the shape of the PA and their sexual dimorphism. METHODS: Using 3D-CT scan reconstructions and landmarks positioning around the piriform aperture and on the face, a collective of 170 non-pathologic subjects (79 female, 91 male) from Marseille (France) was examined in classical and geometric morphometrics methods. RESULTS: The mean width of the piriform aperture was 24.00 mm in females and 25.32 mm in males, the mean length was 32.54 mm in females and 36.35 mm in males. The difference between males and females was significant, and our data correlates well with the previously data acquired from humans skulls. Facial measurements also showed a statistically significant dimorphism. In morphometric geometrics, the correlation between the centroid size and PC1 in the shape space was weak, while this correlation was strong in the size and shape space. Visualization of shape differences was achieved on 2D wireframes. CONCLUSION: Shape and size analysis of the piriform aperture showed the existence of a significant sexual dimorphism. These results encourage us to go further with functional and imaging correlations. PMID- 23625071 TI - The correlation between muscles insertions and topography of break lines in pertrochanteric fractures: a comprehensive anatomical approach of complex proximal femur injuries. AB - PURPOSE: The purpose of our work was to verify the hypothesis that muscle insertions and ligament attachments have an impact on the course of typical break lines in the area of the trochanteric massif, i.e., to provide a more detailed description of the origins and insertions of the musculo-ligamentous apparatus on the surface of the proximal femur, and to find a potential morphological correlate between muscle insertions and ligament attachments to the proximal femur and the course of the break line in a typical pertrochanteric fracture. METHODS: A detailed dissection of areas of trochanter major et minor, linea et crista intertrochanterica was performed in 50 anatomical preparations of the proximal femur, and the insertions of the muscular-ligamentous structures were described. The set of 600 radiographs were used to obtain projections of typical break lines on the proximal femur, and corresponding areas of exposed bone surface were identified in the anatomical preparations based on the projections and on 15 real specimens of patients after the pertrochanteric fracture osteosynthesis. RESULTS AND CONCLUSION: Bone covered only with the periosteum, with no reinforcing elements of the origin or insertions of muscles or attachments of ligaments, represents the locus minoris resistentiae for beginning of fractures. Variability in the sizes and shapes of pertrochanteric fracture fragments also depends on variability of the locations and sizes of soft tissue attachment areas at specified sites on the proximal femur. PMID- 23625072 TI - Transversal craniofacial growth evaluated on children dry skulls using V2 and V 3 canal openings as references. AB - PURPOSE: The aim of this study was to investigate the transversal relationships between two cephalometric landmarks and lines on the face using ovale, rotundum, greater palatine and infra-orbital foramina as references. METHOD: Thirty-four children dry skulls, 19 males and 15 females aged 0-6 years, were examined by computed tomography scanning by using constructed tomographic axial and frontal planes. The cephalometric transversal dimensions of the face skull were measured between the right and left landmarks from the orbital lateral wall and from the zygomatic arch. The cephalometric transversal dimensions of the base skull were measured between the right and left ovale, rotundum, greater palatine and infra orbital foramina. RESULTS: Statistical analysis using partial correlations, regardless of the age, showed strong relationships (p < 0.05) among transversal measurements with nerve canal openings and transversal distances of skull face. CONCLUSION: We showed that the cranial base transversal growth was very strongly related to facial transversal growth from the postnatal period up to 6 years of age. PMID- 23625074 TI - Unprecedented gallium-nitrogen anions: synthesis and characterization of [(Cl3Ga)3N]3- and [(Cl3Ga)2NSnMe3]2-. AB - The [(Cl3Ga)3N](3-) (1) anion, which is the sole example of a discrete chemical species containing a MU3-N atom bound only to gallium, was isolated from the reaction of Cl3Ga.N(SnMe3)3 with [GaCl4](1-). The analogous reaction of [GaCl4](1 ) with (Me3Sn)3N afforded [(Cl3Ga)2NSnMe3](2-) (2), which is also an unprecedented anion containing a single MU3-N atom bound to only gallium and tin. PMID- 23625075 TI - The learning of isometric force time scales is differentially influenced by constant and variable practice. AB - This experiment was set up to investigate the influence of constant and variable practice on performance accuracy and the time- and frequency-dependent structure of the force output dynamics in the learning of an irregular isometric force pattern. Traditional approaches to the variability of practice hypothesis have demonstrated benefits of task-induced variability at the outcome level of behavior, but there have been limited investigations of the effect of practice conditions on movement execution and particularly the multiple time scale processes of force output. During the practice phase, variability was induced along the force-time dimension of the target pattern for the variable practice condition (different wave forms), but the wave forms exhibited the same distributional properties of the frequency content (1/f noise: beta = -1.5) as the constant practice condition. The results showed that both practice conditions exhibited similar reductions in task error as a function of practice. However, constant practice produced greater changes in the time- and frequency-dependent properties of force output than variable practice, including a higher relative change in the contribution from faster (4-12 Hz) time scale mechanisms. Generalization tests to novel target patterns revealed that the task dynamics had a greater influence than the effect of practice conditions. Collectively, the findings support the adaptive nature of force output structure and the perspective that practice conditions can produce differential effects on the outcome and execution levels of motor behavior. PMID- 23625076 TI - The organization of digit contact timing during grasping. AB - While the process of hand preshaping during grasping has been studied for over a decade, there is relatively little information regarding the organization of digit contact timing (DCT). This dearth of information may be due to the assumption that DCT while grasping exhibits few regularities or to the difficulty in obtaining information through traditional movement recording techniques. In this study, we employed a novel technique to determine the time of digit contacts with the target object at a high precision rate in normal healthy participants. Our results indicate that, under our task conditions, subjects tend to employ a radial to ulnar pattern of DCT which may be modulated by the shape of the target object. Moreover, a number of parameters, such as the total contact time, the frequency of first contacts by the thumb and index fingers and the number of simultaneous contacts, are affected by the relative complexity of the target object. Our data support the notion that a great deal of information about the object's physical features is obtained during the early moments of the grasp. PMID- 23625073 TI - Interleukin 7 and thymic stromal lymphopoietin: from immunity to leukemia. AB - Cancer is often caused by deregulation of normal developmental processes. Here, we review recent research on the aberrant activation of two hematopoietic cytokine receptors in acute lymphoid leukemias. Somatic events in the genes for thymic stromal lymphopoietin and Interleukin 7 receptors as well as in their downstream JAK kinases result in constitutive ligand-independent activation of survival and proliferation in B and T lymphoid precursors. Drugs targeting these receptors or the signaling pathways might provide effective therapies of these leukemias. PMID- 23625077 TI - Grip-force modulation in multi-finger prehension during wrist flexion and extension. AB - Extrinsic digit muscles contribute to both fingertip forces and wrist movements (FDP and FPL-flexion, EDC-extension). Hence, it is expected that finger forces depend on the wrist movement and position. We investigated the relation between grip force and wrist kinematics to examine whether and how the force (1) scales with wrist flexion-extension (FE) angle and (2) can be predicted from accelerations induced during FE movement. In one experiment, subjects naturally held an instrumented handle using a prismatic grasp and performed very slow FE movements. In another experiment, the same movement was performed cyclically at three prescribed frequencies. In quasistatic conditions, the grip force remained constant over the majority of the wrist range of motion. During the cyclic movements, the grip force changed. The changes were described with a linear regression model that represents the thumb and virtual finger (VF = four fingers combined) normal forces as the sum of the effects of the object's tangential and radial accelerations and an object-weight-dependent constant term. The model explained 99 % of the variability in the data. The independence of the grip force from wrist position agrees with the theory that the thumb and VF forces are controlled with two neural variables that encode referent coordinates for each digit while accounting for changes in the position dependence of muscle forces, rather than a single neural variable like referent aperture. The results of the cyclical movement study extend the principle of superposition (some complex actions can be decomposed into independently controlled elemental actions) for a motor task involving simultaneous grip-force exertion and wrist motion with significant length changes of the grip-force-producing muscles. PMID- 23625078 TI - The neural correlates of incidental self-processing induced by handwritten negative words. AB - Behavioral studies revealed that people were less likely to endorse negative information as self-descriptive. Neuroimaging studies have tapped on the neural mechanism underlying intentional self-processing of negative information using self-reflection tasks. Given that human self-processing occurring in our daily life is more likely to be captured by tasks involving incidental self-processing (automatic associations between the self- and external stimuli), rather than tasks involving intentional self-processing, it could be presumed that the relationship between self- and negative emotion might be better reflected during incidental self-processing. The present functional magnetic resonance imaging study aimed to explore incidental self-processing of negative information. To induce participants' incidental self-processing, we adopted negative and neutral words written by themselves or others as materials. They were scanned during judging whether the handwritten words were negative or neutral (additional non self-task). Results revealed that incidental self-processing of negative information relied on the activation of left anterior insula, whereas medial prefrontal cortex activity was associated with incidental self-processing of neutral information. PMID- 23625079 TI - Cryopreservation for the 'in perpetuity' conservation of yam and cassava genetic resources. AB - Cryopreservation via droplet vitrification showed high efficiency for cassava meristems (79 pecent average recovery) when these were excised from in vitro seedlings. The efficiency of the process dropped considerably (to > 23 percent) when meristems were excised from field-grown plants, thus precluding the use of such explants for routine cryobanking. In yam, large disparities were observed in the ability of meristems to produce a shoot after cryopreservation ranging from 0 to 60 percent, depending on the accession. Overall, better recovery was observed for Dioscorea rotundata than for D. alata, the two main species tested. Using a probabilistic decision support tool and taking into consideration our cryoprocessing capacity, we conclude that processing 100 meristems per accession and retrieving 30 to estimate the recovery rate of the batch are a good compromise for the cryobanking routine. PMID- 23625080 TI - RAPD and phytochemical analysis of Thymus moroderi plantlets after cryopreservation. AB - Cryopreservation is at present the most reliable strategy to preserve plant germplasm. When aromatic plants are the object of conservation it is necessary to assess not only the genetic but also the phytochemical stability to ensure that plant material maintains its qualities after storage. In this work we present molecular and phytochemical stability data related to a previously described vitrification-based cryopreservation protocol for Thymus moroderi Pau ex Martinez. RAPD markers have been used to assess the genetic stability of T. moroderi explants and revealed 0.34 percent of variation in the cryopreserved material studied. Phytochemical data collected from GC-MS analysis of dichloromethane extracts from cryopreserved plantlets rendered a profile in which 1,8-cineole (14.5 percent), camphor (5.9 percent) and borneol (5.2 percent) were the major components. Both data confirmed the suitability of the cryopreservation protocol applied. PMID- 23625081 TI - Genetic stability assessment of wWasabi plants regenerated from long-term cryopreserved shoot tips using morphological, biochemical and molecular analysis. AB - This study compared the effect of cryopreserved storage duration of wasabi shoot tips, which derived from the same in vitro mother-plant. We compared the survival of shoot tips and the genetic stability of regenerated plants originating from four experimental groups: shoot tips stored in a -150 degrees C deep-freezer for 10 years; shoot tips stored in liquid nitrogen for 2 h; shoot tips treated with PVS2 vitrification solution; and untreated controls. No significant difference in survival was observed between the four experimental groups. Survival ranged between 93 and 100%. Genetic stability of plants regenerated from cryopreserved shoot tips was assessed over a period of 24 months using morphological, biochemical and molecular markers. While glucose, fructose and glutamic acid concentrations differed slightly between experimental groups after 16 months, these differences disappeared after 24 months. No significant differences were noted for the morphological markers studied (petiole length, shoot number and leaf index). No differences were observed in RAPD profiles obtained with the six primers tested. PMID- 23625082 TI - The ice nucleation activity of extremophilic algae. AB - Differences in the level of cold acclimation and cryoprotection estimated as ice nucleation activity in snow algae (Chlamydomonas cf. nivalis and Chloromonas nivalis), lichen symbiotic algae (Trebouxia asymmetrica, Trebouxia erici and Trebouxia glomerata), and a mesophilic strain (Chlamydomonas reinhardti) were evaluated. Ice nucleation activity was measured using the freezing droplet method. Measurements were performed using suspensions of cells of A750 (absorbance at 750 nm) ~ 1, 0.1, 0.01 and 0.001 dilutions for each strain. The algae had lower ice nucleation activity, with the exception of Chloromonas nivalis contaminated by bacteria. The supercooling points of the snow algae were higher than those of lichen photobionts. The supercooling points of both, mesophilic and snow Chlamydomonas strains were similar. The lower freezing temperatures of the lichen algae may reflect either the more extreme and more variable environmental conditions of the original localities or the different cellular structure of the strains examined. PMID- 23625083 TI - Production of yam mosaic virus (ymv)-free Dioscorea opposita plants by cryotherapy of shoot-tips. AB - In the present study, Yam mosaic virus (YMV) could be efficiently eliminated by cryotherapy in Dioscorea opposita. Shoot apices were precultured for 16 h with 0.3 M sucrose, encapsulated in sodium alginate and dehydrated for 4 h prior to direct immersion in liquid nitrogen. Up to 90 percent of the plants regenerated from cryopreserved shoot tips were YMV-free, whereas only 40% of those regenerated using meristem culture were YMV-free. YMV-free yam plantlets could be propagated in vitro through nodal stem culture, with sequential subculturing at 6 week intervals on medium containing 0.5 mg per liter kinetin. The microtubers formed at the bottom and axil of the explants, incubated at 30 degreeC after being chilled (4 degree C) for 3 months, could be sprouted successfully under in vivo conditions. Healthy plants were established without any damaging symptoms of the virus. Thus, cryotherapy provides an alternative method for efficient elimination of yam viruses, and could be simultaneously used for long-term storage of yam germplasm and for the production of virus-free plants. PMID- 23625084 TI - How important are internal temperature gradients in french straws during freezing of bovine sperm in nitrogen vapor? AB - The subject of present work was to predict internal temperature gradients developed during freezing of bovine sperm diluted in extender, packaged in 0.5 ml French plastic straws and suspended in static liquid nitrogen vapor at -100 degree C. For this purpose, a mathematical heat transfer model previously developed to predict freezing times (phase change was considered) of semen/extender packaged in straw was extended to predict internal temperature gradients during the cooling/freezing process. Results showed maximum temperature differences between the centre and the periphery of semen/extender "liquid" column was 1.5 degree C for an external heat transfer coefficient, h = 15 W per (m(2) K), and only 0.5 degree C for h = 5 W per (m(2) K). It is concluded that if a thermocouple wire were inserted in a 0.5 ml plastic straw to monitor the freezing process in nitrogen vapor, its radial position would have little importance since expected internal gradients may be safely neglected. This finding facilitates the interpretation of freezing rates in 0.5 ml plastic straws immersed in nitrogen vapor over liquid nitrogen, a widely used method for cryopreservation of bovine spermatozoa. PMID- 23625085 TI - Effect of temperature and glycerol on the hydrogen-bond dynamics of water. AB - The effect of glycerol, water and glycerol-water binary mixtures on the structure and dynamics of biomolecules has been well studied. However, a lot remains to be learned about the effect of varying glycerol concentration and temperature on the dynamics of water. We have studied the effect of concentration and temperature on the hydrogen bonded network formed by water molecules. A strong correlation between the relaxation time of the network and average number of hydrogen bonds per water molecules was found. The radial distribution function of water oxygen and hydrogen atoms clarifies the effect of concentration on the structure and clustering of water. PMID- 23625086 TI - The expression pattern of the genes engrailed, pax6, otd and six3 with special respect to head and eye development in Euperipatoides kanangrensis Reid 1996 (Onychophora: Peripatopsidae). AB - The genes otd/otx, six3, pax6 and engrailed are involved in eye patterning in many animals. Here, we describe the expression pattern of the homologs to otd/otx, six3, pax6 and engrailed in the developing Euperipatoides kanangrensis embryos. Special reference is given to the expression in the protocerebral/ocular region. E. kanangrensis otd is expressed in the posterior part of the protocerebral/ocular segment before, during and after eye invagination. E. kanangrensis otd is also expressed segmentally in the developing ventral nerve cord. The E. kanangrensis six3 is located at the extreme anterior part of the protocerebral/ocular segment and not at the location of the developing eyes. Pax6 is expressed in a broad zone at the posterior part of the protocerebral/ocular segment but only weak expression can be seen at the early onset of eye invagination. In late stages of development, the expression in the eye is upregulated. Pax6 is also expressed in the invaginating hypocerebral organs, thus supporting earlier suggestions that the hypocerebral organs in onychophorans are glands. Pax6 transcripts are also present in the developing ventral nerve cord. The segment polarity gene engrailed is expressed at the dorsal side of the developing eye including only a subset of the cells of the invaginating eye vesicle. We show that engrailed is not expressed in the neuroectoderm of the protocerebral/ocular segment as in the other segments. In addition, we discuss other aspect of otd, six3 and pax6 expression that are relevant to our understanding of evolutionary changes in morphology and function in arthropods. PMID- 23625087 TI - Macro creatine kinase type 1: a cause of spuriously elevated serum creatine kinase associated with leukoencephalopathy in a child. AB - Macro creatine kinase type 1 is a complex formed by the creatine kinase isoenzyme BB and monoclonal IgG and occurs in about 1% of patients studied. First identified as a cause of spurious elevation of the total serum creatine kinase in patients suspected of myocardial infarction, the test has been largely replaced by the measurement of troponin levels. We present a child with delayed milestones and persistently elevated total serum creatine kinase measurements (~ 1000-4000 IU) normal electromyogram and brisk myotatic reflexes. Creatine kinase isoenzymes and brain imaging showed the presence of macro creatine kinase type 1 and extensive signal abnormality of the cerebral white matter. Macro creatine kinase type 1 has been associated with several conditions though it has not been described in association with leukoencephalopathy or in patients this young. Macro creatine kinase type 1 can be a cause of elevated total creatine kinase in patients without primary muscle disease. The significance of the relationship of the macro creatine kinase to the leukoencephalopathy in this patient is unknown. PMID- 23625088 TI - Lissencephaly with brainstem and cerebellar hypoplasia and congenital cataracts. AB - Classical lissencephaly may be associated with cerebellar hypoplasia and when significant cerebellar abnormalities occur, defects in proteins encoded by TUBA1A, RELN, and very-low-density lipoprotein receptor (VLDLR) genes have been reported. We present a neonate with a severe neurologic phenotype associated with hypotonia, oropharyngeal incoordination that required a gastric tube for feeding, intractable epilepsy, and congenital cataracts. Her brain magnetic resonance imaging (MRI) showed classical lissencephaly, ventriculomegaly, absent corpus callosum, globular and vertical hippocampi, and severe cerebellar and brainstem hypoplasia. She died at 6 weeks of age. No specific molecular diagnosis was made. This likely represents a previously undescribed genetic lissencephaly syndrome. PMID- 23625089 TI - Gene silencing of c-Met leads to brain metastasis inhibitory effects. AB - An unfortunate consequence of improvements in the treatments of advanced primary cancers is the concurrent increase of metastatic brain tumors. Despite of unfavorable clinical prognosis, radiation therapy is still the only viable treatment option for brain metastases. Expression of c-Met induces cell migration and invasion in many cancers, which are indispensable steps for metastasis. Accordingly, we examined the effects of gene silencing of c-Met on brain metastasis to evaluate the possibility of c-Met as a potential target. MDA-MB-435 cells were transfected with c-Met targeting short hairpin RNAs (shRNAs). Effects of c-Met shRNAs on the expression of epithelial mesenchymal transition (EMT) related proteins, in vitro migration, and in vivo brain metastasis were examined. Expression of mesenchymal markers and in vitro migration of MDA-MB-435 cells were significantly inhibited by introduction of c-Met shRNAs. When c-Met-silenced MDA MB-435 cells were stereotactically implanted into the brains of immune compromised mice or injected into the right internal carotid arteries, c-Met silenced MDA-MB-435 cells produced significantly smaller tumor masses or survival time was significantly prolonged, respectively, compared with MDA-MB-435 cells transfected with control shRNA. The data reveal the novel function of c-Met in the process of brain metastasis and its potential as a preventive and/or therapeutic target in this disease. PMID- 23625090 TI - Cardiac hemodynamics and proinflammatory cytokines during biatrial and right atrial appendage pacing in patients with interatrial block. AB - PURPOSE: Interatrial block (IAB) frequently coexists with sinus node disease and is considered a risk factor of left atrial dysfunction, atrial arrhythmias, and heart failure development. Conventional right atrial appendage (RAA) pacing impairs intra- and interatrial conductions and consequently prolongs P wave duration. Biatrial (BiA) pacing helps correct IAB, but its advantageous influence remains controversial. The aim of the study was to compare the effects of BiA and RAA pacing on cardiac hemodynamics and serum concentrations of inflammatory markers and neuropeptides. METHODS: Twenty-eight patients with IAB and preserved atrio-ventricular conduction treated with BiA pacing were studied. Standard invasive hemodynamic measurements were performed during BiA and RAA pacings. Furthermore, the influence of 1 week of BiA and RAA pacing on neuropeptides: atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and markers of inflammation: high sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL 6), and neopterin was examined. RESULTS: BiA pacing resulted in significant increase of cardiac output (CO) and reduction of pulmonary capillary wedge pressure. We demonstrated significantly lower concentrations of ANP, hs-CRP, IL 6, and neopterin after 1 week of BiA in comparison to RAA pacing. BNP levels remained unchanged. CONCLUSIONS: BiA pacing in comparison to RAA pacing improves hemodynamic performance in patients with IAB and preserved atrio-ventricular conduction. BiA pacing is associated with reduction of ANP and markers of inflammation (hs-CRP, IL-6, and neopterin). PMID- 23625091 TI - Continuous warfarin versus periprocedural dabigatran to reduce stroke and systemic embolism in patients undergoing catheter ablation for atrial fibrillation or left atrial flutter. AB - PURPOSE: Left atrial catheter ablation for patients with atrial fibrillation (AF) requires periprocedural anticoagulation to minimize thromboembolic complications. High rates of major bleeding complications using dabigatran etexilate for periprocedural anticoagulation have been reported, raising concerns regarding its safety during left atrial catheter ablation. We sought to evaluate the safety and efficacy of a dabigatran use strategy versus warfarin, at a single high-volume AF ablation center. METHODS: We performed a retrospective analysis on consecutive patients undergoing left atrial ablation at Vanderbilt Medical Center from January 2011 through August 2012 with a minimum follow-up of 3 months. Patient cohorts were divided into two groups, those utilizing dabigatran etexilate pre- and post-ablation and those undergoing ablation on dose-adjusted warfarin, with or without low-molecular-weight heparin bridging. Dabigatran was held 24-30 h pre procedure and restarted 4-6 h after hemostasis was achieved. We evaluated all thromboembolic and bleeding complications at 3 months post-ablation. RESULTS: A total of 254 patients underwent left atrial catheter ablation for atrial fibrillation or left atrial flutter. Periprocedural anticoagulation utilized dabigatran in 122 patients and warfarin in 135 patients. Three late thromboembolic complications occurred in the dabigatran group (2.5 %), compared with one (0.7 %) in the warfarin group (p = 0.28). The dabigatran group had similar minor bleeding (2.5 vs. 7.4 %, p = 0.07), major bleeding (1.6 vs. 0.7 %, p = 0.51), and composite of bleeding and thromboembolic complications (6.6 vs. 8.9 %, p = 0.49) when compared to warfarin. There were no acute thromboembolic complications in either group (<24 h post-ablation). CONCLUSIONS: In patients undergoing left atrial catheter ablation for AF or left atrial flutter, use of periprocedural dabigatran etexilate provides a safe and effective anticoagulation strategy compared to warfarin. A prospective randomized study is warranted. PMID- 23625092 TI - The reliability of cardiogenic impedance and correlation with echocardiographic and plethysmographic parameters for predicting CRT time intervals post implantation. AB - AIMS: Encouraging data have been reported on the use of cardiogenic impedance (CI) in cardiac resynchronization therapy (CRT) optimization. The purposes of this study were to: evaluate the stability of certain CI vectors 24 h postimplantation, study the correlation between these CI signals and selected echocardiographic parameters, and examine the possibility of non-invasive calibration of the patient-specific impedance-based prediction model. METHODS AND RESULTS: Thirteen patients received a CRT-defibrillator device with monitor capability of the dynamic impedance between several electrodes. At implantation, a patient-specific impedance-based prediction model was created for identification of optimal atrioventricular and interventricular (VV) delays and calibrated on invasive measurements of left ventricular contractility (LV dP/dtmax). Simultaneously, non-invasive measurements of LV dP/dtmax and stroke volume (SV) were obtained using a finger plethysmograph. Patients were re evaluated with echocardiography and new CI measurements the day after implantation. The hemodynamic benefit achieved by optimal VV setting according to the patient-specific impedance-based prediction model at follow-up was not as large as the one obtained at implantation. In a multivariate partial least square regression analysis, a correlation was found between aortic velocity time integral (VTI) and a generic linear combination of CI features (P < 0,005). No correlation was found between the patient-specific impedance-based prediction models and the non-invasive measurements of LV dP/dtmax and SV. CONCLUSION: Cardiogenic impedance signals can be used to optimize CRT settings but seem less feasible as an ambulatory tool since calibration is required. The positive correlation between aortic VTI and CI measurements seems promising, although a larger cohort is required to create an echocardiography-based patient-specific model. PMID- 23625094 TI - Relative kinetic reactivity of boronic acid and boronate ion towards Tiron, 2,2' biphenol, and propylene glycol. AB - Reaction systems of boronic acid (RB(OH2), R = phenyl or 3-fluorophenyl) with diols and no proton ambiguity were elaborately set up, and kinetic measurements were conducted to elucidate the relative reactivities of RB(OH)2 and RB(OH)3(-). In the reactions of phenylboronic and 3-fluorophenylboronic acids with propylene glycol, the reactivity order was: RB(OH)2 >> RB(OH)3(-), whereas in the reactions of 3-pyridylboronic acid with Tiron and 2,2'-biphenol, the reactivity of RB(OH)2 was comparable to that of RB(OH)3(-). These results are in contrast to those that have been previously reported, and widely accepted for over thirty years, that concluded that the reactivity of RB(OH)3(-) is several orders of magnitude higher than that of RB(OH)2. The reactivity of Tiron with 3-pyridylboronic acid is affected by the protonation of one of its sulfonate groups. PMID- 23625093 TI - Medium-term results of cryoballoon ablation of the pulmonary veins in patients with paroxysmal and persistent atrial fibrillation. First experience of a Spanish center. AB - PURPOSE: Cryoballoon ablation of the pulmonary veins (CAPV) is a new technique that could have similar results to radiofrequency procedures, but with fewer complications. We analyzed the outcomes and safety of this technique in a consecutive cohort of patients with atrial fibrillation (AF). METHODS: A total of 63 patients with paroxysmal (n = 40) or persistent (n = 23) AF were studied. Patient follow-up was performed at 3 months and then every 6 months with 72-h continuous electrocardiographic recordings. RESULTS: A total of 262 pulmonary veins were treated; 60.3 % of the cases presented normal pulmonary vein drainage with 4 pulmonary veins, and 23.8 % of the cases presented a common left-sided antrum. Complete isolation of all veins was achieved in 95.2 % of cases with 10.3 +/- 2.8 (mean +/- standard deviation) applications per patient. Transient right phrenic nerve injury was the most common complication (4.7 %). Median follow-up was 5.5 months. The probability of being free of recurrence at 1 and 2 years was, respectively, 86.2 and 72.2 % for paroxysmal AF and 49 and 36.4 % for persistent AF (P = 0.012). Patients with structural heart disease experienced recurrence more often than patients with a normal heart (62.5 versus 24.5 %; P = 0.03). CONCLUSIONS: CAPV appears to be a safe and effective procedure for the treatment of patients with AF, particularly those with paroxysmal AF and no structural heart disease. PMID- 23625098 TI - Preventing the first cesarean. PMID- 23625096 TI - Imaging the cytosolic drug delivery mechanism of HDL-like nanoparticles. AB - PURPOSE: Molecular therapeutics often require an effective nanoparticle-based delivery strategy to transport them to cytosolic organelles to be functional. Recently, a cytosolic delivery strategy based on the scavenger receptor class B type I (SR-BI) mediated pathway has shown great potential for the effective delivery of theranostics agents into the cytoplasm of cells without detrimental endosomal entrapment. This study elucidates this unique delivery mechanism for improving cytosolic drug delivery. METHODS: Multifluorophore-labeled HDL mimicking peptide phospholipid scaffold (HPPS) nanoparticles were developed. Fluorescence imaging was utilized to examine HPPS transporting payloads into cells step by step through sequential inhibition studies. RESULTS: HPPS specifically recognizes and binds to SR-BI, then interacts with SR-BI, which results in direct transport of payload molecules into the cell cytoplasm without entire particles internalization. The cytosolic transport of payloads occurred through a temperature- and energy-independent pathway, and was also different from actin- and clathrin-mediated endocytosis. Furthermore, this transport was significantly inhibited by disruption of lipid rafts using filipin or methyl-beta cyclodextrin. CONCLUSIONS: The cytosolic delivery of payloads by HPPS via SR-BI targeting is predominately mediated through a lipid rafts/caveolae-like pathway. This cytosolic delivery strategy can be utilized for transporting molecular therapeutics that require their action sites to be within cytosolic organelles to enhance therapeutic effect. PMID- 23625099 TI - Should healthcare workers be required to be vaccinated against influenza? PMID- 23625095 TI - Nanoparticles in the brain: a potential therapeutic system targeted to an early defect observed in many neurodegenerative diseases. AB - Currently, there are no effective treatments or cures for many neurodegenerative diseases affecting an aging baby-boomer generation. The ongoing problem with many of the current therapeutic treatments is that most are aimed at dissolving or dissociating aggregates and preventing cell death, common neuropathology often seen towards the end stage of disease. Often such treatments have secondary effects that are more devastating than the disease itself. Thus, effective therapeutics must be focused on directly targeting early events such that global deleterious effects of drugs are minimized while beneficial therapeutic effects are maximized. Recent work indicates that in many neurodegenerative diseases long distance axonal transport is perturbed, leading to axonal blockages. Axonal blockages are observed before pathological or behavioral phenotypes are seen indicating that this pathway is perturbed early in disease. Thus, developing novel therapeutic treatments to an early defect is critical in curing disease. Here I review neurodegenerative disease and current treatment strategies, and discuss a novel nanotechnology based approach that is aimed at targeting an early pathway, with the rationale that restoring an early problem will prevent deleterious downstream effects. To accomplish this, knowledge exchange between biologists, chemists, and engineers will be required to manufacture effective novel biomaterials for medical use. PMID- 23625100 TI - Influence of holding practice on preterm infant development. AB - PURPOSE: The purpose of this randomized, controlled trial was to determine if nurse-supported kangaroo holding of healthy preterm infants in the first 8 weeks of the infant's life facilitates early behavioral organization and development. METHODS: We randomized 87 infants born between 32 and 35 weeks gestation and their mothers to one of three holding groups: kangaroo (skin-to-skin between mother's breasts), blanket (held in mother's arms), or control (no holding restrictions). Nurse-supported groups (kangaroo and blanket) received 8 weekly visits from a registered nurse who encouraged holding and provided education about infant development. The control group received brief social visits. Mothers recorded time held in a daily diary. The Assessment of Preterm Infant Behavior was administered when infants were 40 to 44 weeks postconceptional age. RESULTS: Total holding time averaged 4 to 5 hr/day and did not differ among groups. Mothers held kangaroo style an average of 59 min/day in the kangaroo group, and 5 and 9 min/day in the blanket and control groups, respectively (p < .001). Infants in the kangaroo and blanket groups had more optimal scores than the control group in Robust Crying (p = .015) indicating that they could arouse to vigorous crying and calm. Scores, except for Attention and State Regulation, were at least as high as those of full-term infants. CLINICAL IMPLICATIONS: When kangaroo holding is compared to blanket holding, both methods may provide equal early behavioral organization and developmental benefit to the infant. PMID- 23625101 TI - Reducing anxiety among children born preterm and their young mothers. AB - PURPOSE: To examine the efficacy of COPE on maternal and child anxiety associated with younger mothers of premature infants. The COPE program provides instruction and practice in parenting behaviors specific to the NICU, in combination with information that reduces ambiguity about their infant's appearance and behaviors. STUDY DESIGN AND METHODS: Secondary data analysis was conducted on data obtained from a larger randomized controlled trial with 253 mothers of low birthweight premature infants to examine the efficacy of the Creating Opportunities for Parent Empowerment (COPE) program, an educational-behavioral parent intervention in the NICU, on maternal and child anxiety based on maternal age. For these analyses, child and maternal anxiety were assessed using the Child Behavior Checklist for Ages 2 to 3 and the State-Trait Anxiety Inventory collected at 24 months and 2 to 4 days postintervention, respectively. To test study hypotheses, we conducted multiple regression models using the structural equation modeling approach to path analysis. RESULTS: Multiple regression results for the full model indicated that there was a significant COPE * mothers' age interaction effect on both mothers' anxiety and child anxiety. Participation in the COPE program significantly predicted lower levels of mothers' anxiety at postintervention as well as lower levels of child anxiety at 24 months for younger mothers (18-21 years old), but not for mothers over 21 years old. CLINICAL IMPLICATIONS: Participating in COPE was associated with more favorable mental health outcomes for younger mothers and their children than mothers over 21 years old. Participation in the COPE program may help close the health disparities gap by improving behaviors in infants of younger mothers to rates similar to those of children of mothers over 21 years old. PMID- 23625102 TI - Are birth plans associated with improved maternal or neonatal outcomes? AB - PURPOSE: The purpose of this study was to determine whether birth plans are associated with improved obstetric and neonatal outcomes. STUDY AND DESIGN: This retrospective case-control study (N = 182) was conducted at a hospital in Cordoba, Spain, between August 2008 and September 2011. Obstetric and neonatal outcomes were compared between groups (women with and without birth plans). Chi square statistics and Student's t-tests were used for statistical analysis. RESULTS: Women with birth plans were older and had a higher academic background than the control group. There were no significant differences between groups for any of the obstetric outcomes or 5-minute Apgar scores; however, there was a significant difference in umbilical artery cord blood pH values (p = .019). The percent of babies with umbilical cord blood pH < 7.24 among nulliparous women with birth plans (14.7%, n = 5) was lower than among babies of nulliparous women without birth plans (37.5%, n = 26). CLINICAL IMPLICATIONS: Findings of this study provide evidence that birth plans may be helpful and are not associated with any negative obstetric or neonatal outcomes. Mothers with birth plans and their babies have at least as good outcomes as those without a birth plan. Babies of nulliparous women with birth plans had better umbilical cord blood pH values than babies of nulliparous women without birth plans. Healthcare professionals can promote the use of birth plans as a resource to enhance communication of women's desires for labor and birth. PMID- 23625103 TI - Obstetric float nurse role redesign in a small rural community hospital. AB - PURPOSE: The purpose of this process improvement project in a rural community hospital with a small volume perinatal service was to foster a cooperative working environment between the obstetric and medical-surgical nursing teams and promote quality nursing care by evaluating, revising, and clearly defining the obstetric float nurse role. SCOPE OF THE PROBLEM: Members of the obstetric and medical-surgical nursing team were convened to evaluate the obstetric float nurse role and develop plans for improvement. Nurses from both units participated in a written survey before and after the project was completed. Based on issues identified from review of the surveys and group discussion, a guideline was developed that defined the expectations and responsibilities of the obstetric float nurse on the medical-surgical unit. RESULT: The redesigned obstetric float nurse role helped nurses of both units understand the expectations and responsibilities of the obstetric float nurse and promoted better working relationships. An additional benefit was improved communication regarding care and needs of the medical-surgical patients. CLINICAL IMPLICATIONS: Clearly defined obstetric float nurse guidelines were successful in our small rural community hospital and may be of benefit to other similar volume perinatal units. PMID- 23625105 TI - Psychological birth trauma in adolescents experiencing an early birth. AB - PURPOSE: To explore and compare associations among demographics, childbirth related stressors, depressive symptoms, gestational age, and psychological birth trauma (PBT) among adolescents. STUDY DESIGN AND METHODS: : This cross-sectional, descriptive, comparative study compared two groups of adolescents for PBT. From a larger study dataset, we identified all adolescents delivering prior to 38 weeks (n = 30) and randomly selected 30 adolescents delivering between 38 and 42 weeks gestation for comparison. PBT was defined via birth appraisal, assessed by a one item rating scale, and trauma impact, assessed via the Impact of Event Scale. Surveys, including the Center for Epidemiological Studies-Depression Scale, were completed within 72 hours of birth. We used frequencies and percentages to describe the sample and Chi square, Spearman Rank-Order Correlation, and Pearson's Product Moment Correlation to determine relationships between variables. Chi square and ANOVA statistical tests determined group differences. RESULTS: Adolescents were primarily Latina, single, primigravidas, and over 16 years of age. Adolescents delivering before 38 weeks experiencing cesarean births reported symptoms of depression and were highest risk for PBT. Additionally adolescents delivering before 38 weeks reported lack of pain control and unsupportive caregivers in labor. CLINICAL IMPLICATIONS: Healthcare professionals cognizant of the potential risk factors for PBT can help vulnerable adolescents through caregiver support, adequate pain control in labor, education, and screening and treatment of depressive symptoms. Follow-up postdischarge, especially for high-risk adolescents, should be arranged to monitor for continued, delayed, or remitting symptoms of depression and PBT. PMID- 23625107 TI - Sugar-sweetened beverages: why the fuss? PMID- 23625108 TI - Clinical databases: electronic health records and repositories. PMID- 23625109 TI - Silent suffering: the tragedy of obstetric fistula. PMID- 23625111 TI - Perinatal acuity tool. PMID- 23625112 TI - Blood pressure levels and risk of cardiovascular events and mortality in type-2 diabetes: cohort study of 34 009 primary care patients. AB - OBJECTIVE: The optimal blood pressure (BP) in persons with type-2 diabetes is debated. We investigated shapes of the associations of SBP and DBP levels with risk of cardiovascular events and mortality in a large primary care-based sample of diabetic patients. METHODS: We investigated all 34 009 consecutive cardiovascular disease-free type-2 diabetes patients aged 35 years or older (mean age 64 years) at 84 primary care centers in central Sweden between 1999 and 2008. We followed this cohort until the end of 2009 in national registries for the incidence of major cardiovascular events (a composite endpoint of myocardial infarction, stroke, heart failure, or cardiovascular mortality) or total mortality. RESULTS: During up to 11 years of follow-up, 6344 patients (18.7%) had a first cardiovascular event, and 6235 died (18.3%). The associations of annually updated SBP and DBP with risk of major cardiovascular events were U-shaped. The lowest risk of cardiovascular events was observed at a SBP of 135-139 mmHg and a DBP of 74-76 mmHg, and the lowest mortality risk at a SBP of 142-150 mmHg and a DBP of 78-79 mmHg, in both antihypertensive drug-untreated and drug-treated persons. CONCLUSION: In a large primary care-based sample of patients with type-2 diabetes, associations of SBP and DBP with risk of major cardiovascular events and mortality were U-shaped. This may have implications for risk stratification of persons with diabetes. PMID- 23625113 TI - Inhibition of the renin-angiotensin system does not reduce platelet activity at rest or during stress in hypertension. AB - OBJECTIVES: We investigated the influence of angiotensin receptor blockade and angiotensin-converting enzyme inhibition on stress-induced platelet activation in hypertensive patients. Secondary aims were effects on inflammation, coagulation, and endothelial function. METHODS: Following a 4-week placebo period, 25 hypertensive patients entered a double-blind, crossover study comparing enalapril (20 mg once daily) and losartan (100 mg once daily) treatment (each for 8 weeks). Patients were studied at rest and after a standardized exercise test. RESULTS: Mean arterial pressure was reduced from 119 +/- 2 to 104 +/- 2 (enalapril) and 106 +/- 2 (losartan) mmHg (both P <0.001). Plasma angiotensin II decreased from 2.4 +/- 0.4 to 0.5 +/- 0.1 pmol/l with enalapril, and increased to 7.2 +/- 1.3 pmol/l with losartan (both P <0.001). Exercise-evoked platelet activation, as evidenced by increased numbers of P-selectin-positive platelets (P <0.01), elevated circulating platelet-platelet aggregates (P <0.01) and soluble P selectin levels (P <0.001), and increased platelet responsiveness to adenosine diphosphate and thrombin (both P <0.05). Neither drug influenced these markers of platelet activation at rest or following exercise. Markers of inflammation (high sensitivity C reactive protein, interleukin-6, tissue necrosis factor-alpha), coagulation (tissue plasminogen activator antigen, prothrombin fragment F1+2), and endothelial function (von Willebrand factor, soluble vascular cellular adhesion molecule-1, and intercellular adhesion molecule-1) were also uninfluenced by treatment. CONCLUSION: Enalapril and losartan failed to reduce platelet activity both at rest and during exercise in hypertensive patients. Markers of inflammation, coagulation, and endothelial function were similarly unaffected. Inhibition of the renin-angiotensin system promotes its beneficial effects in hypertension through mechanisms other than platelet inhibition. PMID- 23625114 TI - Relationships between three different tests to evaluate endothelium-dependent vasodilation and cardiovascular risk in a middle-aged sample. AB - OBJECTIVE: For a couple of decades, flow-mediated vasodilation in the brachial artery (FMD) and acetylcholine-mediated vasodilation in the forearm (EDV) have been used to assess endothelium-dependent vasodilation. During recent years a third technique, peripheral artery tonometry (PAT) using EndoPat, has been introduced. We now aimed to investigate the relationships between these techniques, and their relation to cardiovascular risk. METHODS: In the population based Prospective investigation of Obesity, Energy and Metabolism (POEM) study conducted in individuals all aged 50 years (50% women), EDV, FMD and the reactive hyperemia index were measured in the first 222 individuals. Cardiovascular risk was assessed by the Framingham risk score. RESULTS: No significant relationships were seen between the three different tests to evaluate endothelium-dependent vasodilation. EDV (r = -0.21, P = 0.004) and FMD (r = -0.19, P = 0.004), but not PAT were significantly related to the Framingham score in an inverse way. Also sodium nitroprusside-mediated vasodilation in the forearm, reflecting endothelium independent vasodilation (EIDV), was related to the Framingham score in an inverse way (r = -0.30, P < 0.0001). CONCLUSION: No close relationships were seen between the three tests of endothelium-dependent vasodilation, suggesting that they each contribute with unique information on vasoreactivity. EDV, EIDV and FMD, but not PAT, were related to the Framingham score, suggesting that vasoreactivity in some vascular beds are related to cardiovascular risk in middle aged individuals. PMID- 23625115 TI - Targeting oncogene expression to endothelial cells induces proliferation of the myelo-erythroid lineage by repressing the Notch pathway. AB - Human oncogenes involved in the development of hematological malignancies have been widely used to model experimental leukemia. However, models of myeloid leukemia rarely reproduce the human disease in full, due to genetic complexity or to difficulties in targeting leukemia initiating cells. Here, we used a zebrafish genetic model to induce the expression of oncogenic RAS in endothelial cells, including the hemogenic endothelium of the dorsal aorta that generates hematopoietic cells, and observed the development of a myelo-erythroid proliferative disorder. In larvae, the phenotype is characterized by disruption of the vascular system and prominent expansion of the caudal hematopoietic tissue. In few surviving juveniles, increased number of immature hematopoietic cells and arrest of myeloid maturation was found in kidney marrow. Peripheral blood showed increased erythroblasts and myeloid progenitors. We found that the abnormal phenotype is associated with a downregulation of the Notch pathway, whereas overexpressing an activated form of Notch together with the oncogene prevents the expansion of the myelo-erythroid compartment. This study identifies the downregulation of the Notch pathway following an oncogenic event in the hemogenic endothelium as an important step in the pathogenesis of myelo-erythroid disorders and describes a number of potential effectors of this transformation. PMID- 23625116 TI - Fish oil suppresses bone resorption by inhibiting osteoclastogenesis through decreased expression of M-CSF, PU.1, MITF and RANK in ovariectomized rats. AB - Previous studies have identified a positive correlation between the intake of n-3 fatty acids and bone mineral density in postmenopausal women. The aim of the present study was to determine the effects of fish oil on bone metabolism and to investigate the underlying mechanism using ovariectomized rats. Ovariectomized or sham-operated (sham) female rats were fed AIN-76A-based diets containing 5% corn or fish oil for 2 weeks. Fish oil was found to decrease the plasma levels of arachidonic and linoleic acids, but increased the levels of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. Fish oil reversed the increased activity and number of osteoclasts, and decreased calcium (Ca) and hydroxyproline (Hyp) content of the proximal tibia to sham values without affecting the activity or number of osteoblasts. In addition, fish oil suppressed increases in the mRNA and protein levels of macrophage colony-stimulating factor (M-CSF), PU.1, microphthalmia-associated transcription factor (MITF), receptor for activation of NFkappaB (RANK) and RANK ligand (RANKL) and serum levels of tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6) and prostaglandin E2 (PGE2). Fish oil was also found to suppress NFkappaB activation induced by ovariectomy. These results indicate that increases in plasma n-3 fatty acid levels by fish oil led to the suppression of NFkappaB activation and subsequent downregulation of TNFalpha, followed by suppression of M-CSF and RANKL. Dietary fish oil suppressed ovariectomy-stimulated osteoclastogenesis by inhibiting the expression of M-CSF, PU.1, MITF and RANK in the early stages of osteoclastogenesis, upstream of RANKL signaling. PMID- 23625118 TI - Preliminaries on pollution risk factors related to mining and ore processing in the Cu-rich pollymetallic belt of Eastern Carpathians, Romania. AB - The present study focuses on the mineralogical and geochemical patterns of mining and ore-processing wastes from some occurrences in the Eastern Carpathians; its aim is to identify the main factors and processes that could lead to the pollution of the environment. In this respect, the following types of solid waste were investigated: efflorescent salts developed on the surface of rock blocks from a quarry, ore-processing waste from two tailings ponds, and salt crusts developed at the surface of a tailings pond. The potential risks emphasized by these preliminary investigations are the following: (1) the risk of wind-driven removal and transport of the waste from the surface of tailings ponds, given that fine grains prevail (up to 80%); (2) the risk of tailings removal through mechanical transport by water, during heavy rainfall; (3) the appearance of hydrated sulfates on the rock fragments from the mining waste, sulfates which are highly susceptible to the generation of acid mine drainage (pH<4); (4) the high amount of toxic elements (Pb, Cd, Cu, Zn, As, etc.) that acid mine drainage leachates contain; and (5) the development of a salt crust on the flat, horizontal surfaces of the waste deposit, due to this very shape. Statistical data regarding the amount of both major and minor elements in the tailings have revealed two statistical populations for nearly all the toxic metals. This suggests that, beyond the effect that the tailings have upon the environment through their mere presence in a given area, there are alleged additional factors and processes which intensify the pollution: the location of the waste deposit relative to the topography of the area; the shape of the waste deposit; the development of low areas on the surface of the deposit, areas which favor the appearance of salt crusts; and the mineralogy of efflorescent aggregates. PMID- 23625117 TI - Blood nickel and chromium levels in association with smoking and occupational exposure among head and neck cancer patients in Tunisia. AB - Chronic exposure to chromium (Cr) and nickel (Ni) has long been recognized as being capable to increase head and neck cancer (HNC) incidence among exposed human populations. This study represents the first biomonitoring of Cr and Ni exposure in Tunisia and focuses on a possible association with HNC risk. The aim of the present study was to evaluate the concentrations of Cr and Ni in the blood of HNC patients and controls. Metals blood levels of 169 HNC patients and 351 controls were determined using a Perkin-Elmer Analyst 800 Atomic Absorption Spectrometer. Mean blood levels of Cr and Ni in HNC cases (52.15 and 111.60 MUg/L, respectively) were significantly higher than those of controls (37.04 and 30.50 MUg/L, respectively). Cases' blood levels of Cr and Ni were significantly higher than those of controls after controlling for the other risk factors of HNC, including smoking, shisha consumption, occupational exposure, and nearby environment (P<0.05). Among these risk factors, smoking and occupational exposure presented the most significant association with HNC (odds ratio (OR)=6.54 and 7.66, respectively, P<0.001). Cr and Ni levels in blood sample of cases and controls that are smoker/occupationally exposed were higher than that of non smoker/non-occupationally exposed (P<0.05). Smokers who are occupationally exposed present the most significant association with HNC (OR=25.08, P<0.0001). High levels of blood Cr (OR=2.09) and high levels of blood Ni (OR=8.87) were strongly associated with HNC after other potential confounders were controlled (P=0.004 and P<0.0001, respectively). This study suggested a potential role of Cr and Ni in the mechanism of HNC development. PMID- 23625119 TI - Residential proximity to gasoline service stations and preterm birth. AB - Preterm birth (PTB) is a growing public health problem potentially associated with ambient air pollution. Gasoline service stations can emit atmospheric pollutants, including volatile organic compounds potentially implicated in PTB. The objective of this study was to evaluate the relationship between residential proximity to gasoline service stations and PTB. Singleton live births on the Island of Montreal from 1994 to 2006 were obtained (n=267,478). Gasoline service station locations, presence of heavy-traffic roads, and neighborhood socioeconomic status (SES) were determined using a geographic information system. Multivariable logistic regression was used to analyze the association between PTB and residential proximity to gasoline service stations (50, 100, 150, 200, 250, and 500 m), accounting for maternal covariates, neighborhood SES, and heavy traffic roads. For all distance categories beyond 50 m, presence of service stations was associated with a greater odds of PTB. Associations were robust to adjustment for maternal covariates for distance categories of 150 and 200 m but were nullified when adjusting for neighborhood SES. In analyses accounting for the number of service stations, the likelihood of PTB within 250 m was statistically significant in unadjusted models. Associations were, however, nullified in models accounting for maternal covariates or neighborhood SES. Our results suggest that there is no clear association between residential proximity to gasoline service stations in Montreal and PTB. Given the correlation between proximity of gasoline service stations and SES, it is difficult to delineate the role of these factors in PTB. PMID- 23625121 TI - Prospects in straw disintegration for biogas production. AB - The pretreatment methods for enhancing biogas production from oat straw under study include hot maceration, steam explosion, and pressure shockwaves. The micropore area (9, 55, and 64 m(2) g(-1)) inhibitor formations (0, 15, and 0 mL L(-1)) as well as the overall methane yields (67, 179, and 255 CH4 VS t(-1)) were robustly analyzed. It was confirmed that the operating conditions of the steam explosion must be precisely tailored to the substrate. Furthermore, it was beneficial to prepend the hot maceration before the steam explosion and the pressure shockwaves. The second alternative may give increased methane yields (246 in comparison to 273 CH4 VS t(-1)); however, the application of pressure shockwaves still faces limitations for deployment on a commercial scale. PMID- 23625120 TI - 5-Aminolevulinic acid ameliorates cadmium-induced morphological, biochemical, and ultrastructural changes in seedlings of oilseed rape. AB - Due to its prolific growth, oilseed rape (Brassica napus L.) can be grown successfully for phytoremediation of cadmium (Cd)-contaminated soils. Nowadays, use of plant growth regulators against heavy metals stress is one of the major objectives of researchers. The present study evaluates the ameliorate effects of 5-aminolevulinic acid (ALA, 0, 0.4, 2, and 10 mg/l) on the growth of oilseed rape (B. napus L. cv. ZS 758) seedlings under Cd stress (0, 100, and 500 MUM). Results have shown that Cd stress hampered the seedling growth by decreasing the radical and hypocotyls length, shoot and root biomass, chlorophyll content, and antioxidants enzymes. On the other hand, Cd stress increased the level of malondialdehyde (MDA) and production of H2O2 and accumulation of Cd in the shoots. The microscopic study of leaf mesophyll cells showed that toxicity of Cd totally destroyed the whole cell structure, and accumulation of Cd also appeared in micrographs. Application of ALA at lower dosage (2 mg/l) enhanced the seedling growth and biomass. The results showed that 2 mg/l ALA significantly improved chlorophyll content under Cd stress and decreased the level of Cd contents in shoots. Application of ALA reduced the MDA and H2O2 levels in the cotyledons. The antioxidants enzymes (ascorbate peroxidase, peroxidase, catalase, glutathione reductase, and superoxide dismutase) enhanced their activities significantly with the application of 2 mg/l ALA under Cd stress. This study also indicated that higher dosage of ALA (10 mg/l) imposed the negative effect on the growth of oilseed rape. Microscopic study showed that application of ALA alleviated the toxic effects of Cd in the mesophyll cell and improved the cell structure. Use of 2 mg/l ALA under 500 MUM Cd was found to be more effective, and under this dosage, cell structure was clear, with obvious cell wall and cell membrane as well as a big nucleus, which was found with well-developed two or more nucleoli. Chloroplast was almost round in shape and contained thylakoids membranes and grana, but starch grains were not found in chloroplast comparatively to other treatments. On the basis of our results, we can conclude that ALA has a promotive effect which could improve plant survival under Cd stress. PMID- 23625122 TI - Misuse of null hypothesis significance testing: would estimation of positive and negative predictive values improve certainty of chemical risk assessment? AB - Although generally misunderstood, the p value is the probability of the test results or more extreme results given H0 is true: it is not the probability of H0 being true given the results. To obtain directly useful insight about H0, the positive predictive value (PPV) and the negative predictive value (NPV) may be useful extensions of null hypothesis significance testing (NHST). They provide information about the probability of statistically significant and non significant test outcomes being true based on an a priori defined biologically meaningful effect size. The present study explores the utility of PPV and NPV in an ecotoxicological context by using the frequently applied Daphnia magna reproduction test (OECD guideline 211) and the chemical stressor lindane as a model system. The results indicate that especially the NPV deviates meaningfully between a test design strictly following the guideline and an experimental procedure controlling for alpha and beta at the level of 0.05. Consequently, PPV and NPV may be useful supplements to NHST that inform the researcher about the level of confidence warranted by both statistically significant and non significant test results. This approach also reinforces the value of considering alpha, beta, and a biologically meaningful effect size a priori. PMID- 23625125 TI - To have life, and have it abundantly! Health and well-being in biblical perspective. AB - Epidemiological studies researching the impact of participation in religious activities on the overall health and well-being of individuals suggest that having faith and practicing religion is good since they represent expense free, non-medical coping mechanisms accessible to everyone. Faith and religion, thus, can serve for a large number of people as potential reservoirs for cultivating well-being and maintaining health, thereby cutting health-care costs significantly. This begs the question if such pragmatic instrumentalization does do justice to faith and religion in the first place. The article investigates this question taking the Christian biblical tradition as an example by, first, identifying texts speaking of 'health' across different Bible versions (I), second, by sketching related concepts of 'health' (II) and, finally, by assessing the actual extent to which biblical tradition supports the quest for health and well-being (III). PMID- 23625123 TI - Predictive modeling of an azo metal complex dye sorption by pumpkin husk. AB - Effective disposal of pumpkin husk (PH) as a redundant waste is a significant work for environmental protection and full utilization of resource. Predictive modeling of sorption of Lanaset Red (LR) G on PH was investigated in a batch system as functions of particle size, adsorbent dose, pH, temperature, and initial dye concentration. Fourier transform infrared spectroscopy attenuated total reflectance spectra of PH powders before and after the sorption of LR G were determined. Sorption process was found to be dependent on particle size, adsorbent dose, pH, temperature, initial dye concentration, and contact time. Amine and amide groups of PH had significant effect on the sorption process. The pHzpc of PH was found as 6.4. Sorption process was very fast initially and reached equilibrium within 60 min. Dynamic behavior of sorption was well represented by logistic and Avrami models. The sorption of LR G on PH was excellently described by Langmuir model, indicating a homogeneous phenomenon. Monolayer sorption capacity decreased from 440.78 to 436.28 mg g(-1) with increasing temperature. Activation energy, thermodynamic, and desorption studies showed that this process was physical character, exothermic, and spontaneous. This study confirmed that PH as an effective and low-cost adsorbent had a great potential for the removal of LR G as an alternative eco-friendly process. PMID- 23625126 TI - Perspectives of Indian traditional and allopathic professionals on religion/spirituality and its role in medicine: basis for developing an integrative medicine program. AB - Allopathic medical professionals in developed nations have started to collaborate with traditional, complementary, and alternative medicine (TCAM) to enquire on the role of religion/spirituality (r/s) in patient care. There is scant evidence of such movement in the Indian medical community. We aim to understand the perspectives of Indian TCAM and allopathic professionals on the influence of r/s in health. Using RSMPP (Religion, Spirituality and Medicine, Physician Perspectives) questionnaire, a cross-sectional survey was conducted at seven (five TCAM and two allopathic) pre-selected tertiary care medical institutes in India. Findings of TCAM and allopathic groups were compared. Majority in both groups (75% of TCAM and 84.6% of allopathic practitioners) believed that patients' spiritual focus increases with illness. Up to 58% of TCAM and allopathic respondents report patients receiving support from their religious communities; 87% of TCAM and 73% of allopaths believed spiritual healing to be beneficial and complementary to allopathic medical care. Only 11% of allopaths, as against 40% of TCAM, had reportedly received 'formal' training in r/s. Both TCAM (81.8%) and allopathic (63.7%) professionals agree that spirituality as an academic subject merits inclusion in health education programs (p = 0.0003). Inclusion of spirituality in the health care system is a need for Indian medical professionals as well as their patients, and it could form the basis for integrating TCAM and allopathic medical systems in India. PMID- 23625127 TI - Spirituality and optimism: a holistic approach to component-based, self management treatment for HIV. AB - For people living with HIV (PLWH), spirituality and optimism have a positive influence on their health, can slow HIV disease progression, and can improve quality of life. Our aim was to describe longitudinal changes in spirituality and optimism after participation in the SystemCHANGETM-HIV intervention. Upon completion of the intervention, participants experienced an 11.5 point increase in overall spiritual well-being (p = 0.036), a 6.3 point increase in religious well-being (p = 0.030), a 4.8 point increase in existential well-being (p = 0.125), and a 0.8 point increase in total optimism (p = 0.268) relative to controls. Our data suggest a group-based self-management intervention increases spiritual well-being in PLWH. PMID- 23625128 TI - Current approaches for mitigating acid mine drainage. AB - AMD is one of the critical environmental problems that causes acidification and metal contamination of surface and ground water bodies when mine materials and/or over burden-containing metal sulfides are exposed to oxidizing conditions. The best option to limit AMD is early avoidance of sulfide oxidation. Several techniques are available to achieve this. In this paper, we review all of the major methods now used to limit sulfide oxidation. These fall into five categories: (1) physical barriers,(2) bacterial inhibition, (3) chemical passivation, ( 4) electrochemical, and (5) desulfurization.We describe the processes underlying each method by category and then address aspects relating to effectiveness, cost, and environmental impact. This paper may help researchers and environmental engineers to select suitable methods for addressing site specific AMD problems.Irrespective of the mechanism by which each method works, all share one common feature, i.e., they delay or prevent oxidation. In addition, all have limitations.Physical barriers such as wet or dry cover have retarded sulfide oxidation in several studies; however, both wet and dry barriers exhibit only short-term effectiveness.Wet cover is suitable at specific sites where complete inundation is established, but this approach requires high maintenance costs. When employing dry cover, plastic liners are expensive and rarely used for large volumes of waste. Bactericides can suppress oxidation, but are only effective on fresh tailings and short-lived, and do not serve as a permanent solution to AMD. In addition, application of bactericides may be toxic to aquatic organisms.Encapsulation or passivation of sulfide surfaces (applying organic and/or inorganic coatings) is simple and effective in preventing AMD. Among inorganic coatings,silica is the most promising, stable, acid-resistant and long lasting, as compared to phosphate and other inorganic coatings. Permanganate passivation is also promising because it creates an inert coating on the sulfide surface, but the mechanism by which this method works is still unclear, especially the role of pH. Coatings of Fe-oxyhydroxide, which can be obtained from locally available fly ash are receiving attention because of its low cost, self-healing character, and high cementation capacity. Among organic coatings, lipids and natural compounds such as humic acid appear to be encouraging because they are effective, and have a low environmental impact and cost. Common advantages of organic vs. inorganic coatings are that they work best at low pH and can prevent both chemical and biological oxidation.However, organic coatings are more expensive than inorganic coatings. Furthermore,while organic coatings are effective under laboratory conditions, they often fail under field conditions or require large amounts of reagents to insure effectiveness.Electrochemical cover technology may become a suitable technique to prevent AMD, but the mechanism by which this technique operates is still under investigation.Limitations of this method include the initial capital cost and ongoing costs of anodes and cathodes.Desulfurization is an alternative process for managing large-scale sulfide wastes/tailings. This process can separate sulfide minerals into a low-volume stream, leaving mainly waste with low sulfur content that will be non-acid-generating. The attractiveness of desulfurization is that it is simple and economic.Our review has clearly disclosed that more information is needed for most of the AMD-mitigation techniques available. Silica passivation has shown promise, butmore extensive field-testing is needed to reduce it to commercial viability. Silica is the dominant element in fly ash, and therefore, its use as a low-cost, easily accessible coating should be evaluated. Permanganate passivation also requires further study to understand the role of pH. The secondary formation of Fe-oxyhydroxide minerals from Fe-oxyhydroxides, from the standpoint of their phase transformation,stability and effectiveness, should be assessed over longer experimental periods. All inorganic coatings are designed to inhibit abiotic oxidation of pyrite; however, their effect on biotic pyrite oxidation is not well known and should be further studied.Currently, there is no information available on longer-term field application of organic reagents. Such information is needed to evaluate their lifetime environmental and performance effects. Future studies require spectroscopic analyses of all coating types to achieve a better understanding of their surface chemistry. In addition,a thorough mineralogical and geochemical characterization of waste materialsis essential to understand the acid generating potential, which can indeed help to select better prevention measures.From having performed this review, we have concluded that no single method is technologically mature, although the majority of methods employed are promising for some applications, or at specific sites. Combining techniques can help ac~Ie:eAMD containment in some cases. For example, applying dry cover (e.g., sml) mcombination with liming material or a bactericide, or applying inorganic coatings(e.g., silica) along with organic reagents (e.g., lipids or humic acid) may be moreeffective than utilizing any single technique alone. PMID- 23625129 TI - Urban vs. rural factors that affect adult asthma. AB - In this review, our aim was to examine the influence of geographic variations on asthma prevalence and morbidity among adults, which is important for improving our understanding, identifying the burden, and for developing and implementing interventions aimed at reducing asthma morbidity. Asthma is a complex inflammatory disease of multifactorial origin, and is influenced by both environmental and genetic factors. The disparities in asthma prevalence and morbidity among the world's geographic locations are more likely to be associated with environmental exposures than genetic differences. In writing this article, we found that the indoor factors most consistently associated with asthma and asthma-related symptoms in adults included fuel combustion, mold growth, and environmental tobacco smoke in both urban and rural areas. Asthma and asthma related symptoms occurred more frequently in urban than in rural areas, and that difference correlated with environmental risk exposures, SES, and healthcare access. Environmental risk factors to which urban adults were more frequently exposed than rural adults were dust mites,high levels of vehicle emissions, and a westernized lifestyle.Exposure to indoor biological contaminants in the urban environment is common.The main risk factors for developing asthma in urban areas are atopy and allergy to house dust mites, followed by allergens from animal dander. House dust mite exposure may potentially explain differences in diagnosis of asthma prevalence and morbidity among adults in urban vs. rural areas. In addition, the prevalence of asthma morbidity increases with urbanization. High levels of vehicle emissions,Western lifestyles and degree of urbanization itself, may affect outdoor and thereby indoor air quality. In urban areas, biomass fuels have been widely replaced by cleaner energy sources at home, such as gas and electricity, but in most developing countries, coal is still a major source of fuel for cooking and heating, particularly in winter. Moreover, exposure to ETS is common at home or at work in urban areas.There is evidence that asthma prevalence and morbidity is less common in rural than in urban areas. The possible reasons are that rural residents are exposed early in life to stables and to farm milk production, and such exposures are protective against developing asthma morbidity. Even so, asthma morbidity is disproportionately high among poor inner-city residents and in rural populations. A higher proportion of adult residents of nonmetropolitan areas were characterized as follows:aged 55 years or older, no previous college admission, low household income, no health insurance coverage, and could not see a doctor due to healthcare service availability, etc. In rural areas, biomass fuels meet more than 70% of the rural energy needs. Progress in adopting modern energy sources in rural areas has been slow. The most direct health impact comes from household energy use among the poor, who depend almost entirely on burning biomass fuels in simple cooking devices that are placed in inadequately ventilated spaces. Prospective studies are needed to assess the long-term effects of biomass smoke on lung health among adults in rural areas.Geographic differences in asthma susceptibility exist around the world. The reason for the differences in asthma prevalence in rural and urban areas may be due to the fact that populations have different lifestyles and cultures, as well as different environmental exposures and different genetic backgrounds. Identifying geographic disparities in asthma hospitalizations is critical to implementing prevention strategies,reducing morbidity, and improving healthcare financing for clinical asthma treatment. Although evidence shows that differences in the prevalence of asthma do exist between urban and rural dwellers in many parts of the world, including in developed countries, data are inadequate to evaluate the extent to which different pollutant exposures contribute to asthma morbidity and severity of asthma between urban and rural areas. PMID- 23625130 TI - Mercury in the atmospheric and coastal environments of Mexico. AB - In Mexico, published studies relating to the occurrence of Hg in the environment are limited. Among the main sources of Hg in Mexico are mining and refining of Auand Hg, chloralkali plants, Cu smelting, residential combustion of wood, carbo electric plants, and oil refineries. Hg levels are highly variable in the atmospheric compartment because of the atmospheric dynamics and ongoing metal exchange with the terrestrial surface. In atmospheric studies, Hg levels are usually reported as total gaseous Hg (TGM). In Mexico, TGM values ranged from 1.32 ng m-3 in Hidalgo state (a rural agricultural area) to 71.82 ng m-3 in Zacatecas state (an area where brick manufacturers use mining wastes as a raw material).Published information on mercury levels in the coastal environment comprise 21 studies, representing 21 areas, in which sediments constituted the substrate that was analyzed for Hg. In addition, water samples were analyzed for Hg in nine studies.Few studies exist on Hg levels in the Caribbean and in the southwest of the country where tourism is rapidly increasing. Hence, there is a need for establishing baseline levels of mercury in these increasingly visited areas. In regions where studies have been undertaken, Hg levels in sediments were highly variable. Variations in Hg sediment levels mainly result from geological factors and the varying degree of anthropogenic impacts in the studied areas. In areas that still have pristine or nearly pristine environments (e.g., coast, Baja California, Todos Santos Bay, and La Paz lagoon), sediment Hg levels ranged from <0.006 to 0.35 j.lg g-1 on a dry wt basis.When higher levels exist (0.34-57.94 j.lg g-1 on a dry wt basis), the environment generally shows the influence of inputs from mining, oil processing, agriculture,geothermal events, or harmful algal bloom events (e.g., Guaymas Bay and Coatzacoalcos estuary). From chronological studies performed in selected coastal lagoons in NW Mexico, it is clear that Hg fluxes to sediments have increased from2- to 15-fold in recent years. Since the 1940s, historical increases of Hg fluxes have resulted from higher agricultural waste releases and exhaust from the thermo electric plants. The levels of Hg in water reveal a moderate to elevated contamination of some Mexican coastal sites. In Urias lagoon (NW Mexico), moderate to high levels were found in the dissolved and suspended fraction, and these are related to shipping, the fishing industry, domestic effluents, and the presence of a thermoelectric plant. In Coatzacoalcos (SE Mexico), extremely elevated Hg levels were found during the decade of the 1970s. Low to moderate levels of Hg were measured in waters from the Alvarado lagoon (SE Mexico); those concentrations appear to be associated with river waters that became enriched with organic matter and suspended solids inthe brackish mixing zone.Regarding the Hg content in invertebrates, the use of bivalves (oysters and mussels)as biomonitors must be established along the coastal zones of Mexico, because some coastal lagoons have not been previously monitored. In addition, more research is needed to investigate shrimp farms that are associated with agricultural basins and receive effluents from several anthropogenic sources (e.g., mining activity and urban discharges). Hg residues in several vertebrate groups collected in Mexico have been studied.These include mammals, birds, reptiles, and fish. In elasmobranch species, the highest Hg concentration (27.2 flg g-1 dry wt) was found in the muscle of the smooth hammer head shark (Sphyrna zygaena). Teleost fish are the vertebrate group that has been most studied, with regard to Hg residue content; the highest value (5.67 11g g-1dry wt) was detected in the striped marlin (T. audax). Among reptiles, only marine turtles were studied; Hg levels found ranged from 0.795 in the liver to 0.0006flg g-1dry wt in the blood of L. olivacea. In birds, the highest Hg concentration (5.08 flg g-1dry wt) detected was in the liver of the olivaceous cormorant (P. olivaceous).Specimens from stranded marine mammals were also analyzed; levels of Hg ranged from 70.35 flg g-1 dry wt in the liver of stranded spinner dolphin (S. longirostris ), to0.145 flg g-1 dry wt in the muscle of gray whale (E. robustus). The presence of Hgin these marine animals is not thought to have caused the stranding of the animals.Other organisms like macroalgae and vestimentiferan tube worms were used to monitor the occurrence of Hg in the aquatic environment; levels were comparable to data reported on similar organisms from other areas of the world. Few investigation shave been carried out concerning the mercury content in human organs/tissues in Mexico. Considering the potential deleterious effects of Hg on kidney, lung, and the central nervous system, more information about human exposure to organic and inorganic forms of mercury and their effects is needed, both in Mexico and elsewhere. PMID- 23625131 TI - Do Cd, Cu, Ni, Pb, and Zn biomagnify in aquatic ecosystems? AB - In this review, we sought to assess from a study of the literature whether five in organic metals (viz., cadmium, copper, lead, nickel, and zinc) bio magnify in aquatic food webs. We also examined whether accumulated metals were toxic to consumers/predators and whether the essential metals (Cu and Zn and possibly Ni) behaved differently from non-essential ones (Cd and Pb). Biomagnification potential was indexed by the magnitude of single and multiple trophic transfers in food chains. In this analysis, we used three lines of evidence-laboratory empirical, biokinetic modeling, and field studies-to make assessments. Trophic transfer factors, calculatedfrom lab studies, field studies, and biokinetic modeling, were generally congruent.Results indicated that Cd, Cu, Pb, and Zn generally do not biomagnify in food chains consisting of primary producers, macro invertebrate consumers, and fish occupying TL 3 and higher. However, bio magnification of Zn (TTFs of 1-2) is possible for circumstances in which dietary Zn concentrations are below those required for metabolism. Cd, Cu, Ni, and Zn may biomagnify in specific marine food chains consisting of bivalves, herbivorous gastropods, and barnacles at TL2 and carnivorous gastropods at TL3. There was an inverse relationship between TTF and exposure concentration for Cd, Cu, Pb, and Zn, a finding that is consistent with previous reviews of bioconcentration factors and bioaccumulation factors for metals. Our analysis also failed to demonstrate a relationship between the magnitude of TTFsand dietary toxicity to consumer organisms. Consequently, we conclude that TTFs for the metals examined are not an inherently useful predictor of potential hazard(i.e., toxic potential) to aquatic organisms. This review identified several uncertainties or data gaps, such as the relatively limited data available for nickel, reliance upon highly structured food chains in laboratory studies compared to the unstructured food webs found in nature, and variability in TTFs between the organisms found in different habitats, and years sampled. PMID- 23625132 TI - Performance of a new pulse contour method for continuous cardiac output monitoring: validation in critically ill patients. AB - BACKGROUND: A new calibrated pulse wave analysis method (VolumeViewTM/EV1000TM, Edwards Lifesciences, Irvine, CA, USA) has been developed to continuously monitor cardiac output (CO). The aim of this study was to compare the performance of the VolumeView method, and of the PiCCO2TM pulse contour method (Pulsion Medical Systems, Munich, Germany), with reference transpulmonary thermodilution (TPTD) CO measurements. METHODS: This was a prospective, multicentre observational study performed in the surgical and interdisciplinary intensive care units of four tertiary hospitals. Seventy-two critically ill patients were monitored with a central venous catheter, and a thermistor-tipped femoral arterial VolumeViewTM catheter connected to the EV1000TM monitor. After initial calibration by TPTD CO was continuously assessed using the VolumeView-CCO software (CCO(VolumeView)) during a 72 h period. TPTD was performed in order to obtain reference CO values (COREF). TPTD and arterial wave signals were transmitted to a PiCCO2TM monitor in order to obtain CCO(PiCCO) values. CCO(VolumeView) and CCO(PiCCO) were recorded over a 5 min interval before assessment of CO(TPTD). Bland-Altman analysis, %(errors), and concordance (trend analysis) were calculated. RESULTS: A total of 338 matched sets of data were available for comparison. Bias for CCO(VolumeView) CO(REF) was -0.07 litre min(-1) and for CCO(PiCCO)-CO(REF) +0.03 litre min(-1). Corresponding limits of agreement were 2.00 and 2.48 litre min(-1) (P<0.01), %(errors) 29 and 37%, respectively. Trending capabilities were comparable for both techniques. CONCLUSIONS: The performance of the new VolumeViewTM-CCO method is as reliable as the PiCCO2TM-CCO pulse wave analysis in critically ill patients. However, an improved precision was observed with the VolumeViewTM technique. CLINICALTRIALS.GOV IDENTIFIER: NCT01405040. PMID- 23625133 TI - Young children's screen habits are associated with consumption of sweetened beverages independently of parental norms. AB - OBJECTIVES: This study investigated the associations between children's screen habits and their consumption of sweetened beverages. Because parents might be disposed to regulate their child's screen and dietary habits in a similar direction, our specific aim was to examine whether these associations were independent of parental norms. METHODS: In the Swedish sample of the European Identification and prevention of dietary and lifestyle-induced health effects in children and infants (IDEFICS) study, parents filled in questionnaires about their 2 to 9-year-old children's (n = 1,733) lifestyle and diets. RESULTS: Associations between screen habits and sweetened beverage consumption were found independent of parental norms regarding sweetened beverages. A longitudinal analysis revealed that sweetened beverage consumption at 2-year follow-up was predicted by exposure to commercial TV at baseline (OR 1.4, 95 % CI 1.1-1.9). Cross-sectional analysis showed that the likelihood of consuming sweetened beverages at least 1-3 times per week increased for each hour/day watching television (OR 1.5, 95 % CI 1.2-1.9), and for being exposed to commercials (OR 1.6, 95 % CI 1.3-2.1). TV viewing time and commercial exposure contributed to the associations independently of each other. CONCLUSIONS: The results strengthen the assumption that it is possible to influence children's dietary habits through their TV habits. PMID- 23625134 TI - An atypical manifestation of acquired von Willebrand syndrome (AVWS) associated with systemic lupus erythematosus (SLE). PMID- 23625135 TI - A novel redox-responsive pillar[6]arene-based inclusion complex with a ferrocenium guest. AB - A novel and highly stable inclusion complex was formed between per-butylated pillar[6]arene and a ferrocenium cation, while the reduced form ferrocene only showed extremely weak binding affinity with per-butylated pillar[6]arene in organic solvents. PMID- 23625136 TI - Homocysteine, antioxidant micronutrients and late onset dementia. AB - PURPOSE: To distinguish between contributions to dementia made by homocysteine, folate, B12 and antioxidant micronutrients. METHODS: This is a follow-up study of a sample reported in 2002. Homocysteine was measured at baseline in 201 individuals born in 1921 and without dementia at age 77 years and followed up to age 88 years. Baseline macro- and micronutrient status was estimated from BMI, the MONICA food frequency questionnaire, plasma folate, B12 and, in a subgroup (N = 173), plasma antioxidant micronutrients. Time to dementia onset during follow up was compared between participants grouped by homocysteine concentration using Cox regression. Model 1 adjusted for age, sex, childhood IQ, education, socioeconomic deprivation, presence of heart disease, hypertension, plasma folate and B12. In model 2 plasma, antioxidants were added to these covariables. RESULTS: During a mean follow-up of about 5 years, there were 39 incident dementia cases among 201 participants. In model 1, being in the highest homocysteine group (>14 MUmol/L) was associated with a 234 % increased risk (HR 3.34, 95 % CI 1.16-9.57) of any dementia. After inclusion of plasma antioxidants in model 2, there were 32 incident dementia cases from a subsample (N = 173). Homocysteine >14 MUmol was associated with a 272 % increased dementia risk (HR = 3.72, 95 % CI 1.06-13.08). CONCLUSIONS: High homocysteine increases the risk of dementia. The association between tHcy and dementia is independent of plasma folate, B12 and antioxidant micronutrient status. PMID- 23625137 TI - Comparison of cardiovascular aquaporin-1 changes during water restriction between 25- and 50-day-old rats. AB - PURPOSE: Aquaporin-1 (AQP1) is the predominant water channel in the heart, linked to cardiovascular homeostasis. Our aim was to study cardiovascular AQP1 distribution and protein levels during osmotic stress and subsequent hydration during postnatal growth. METHODS: Rats aged 25 and 50 days were divided in: 3d WR: water restriction 3 days; 3d-WAL: water ad libitum 3 days; 6d-WR+ORS: water restriction 3 days + oral rehydration solution (ORS) 3 days; and 6d-WAL: water ad libitum 6 days. AQP1 was evaluated by immunohistochemistry and western blot in left ventricle, right atrium and thoracic aorta. RESULTS: Water restriction induced a hypohydration state in both age groups (40 and 25 % loss of body weight in 25- and 50-day-old rats, respectively), reversible with ORS therapy. Cardiac AQP1 was localized in the endocardium and endothelium in both age groups, being evident in cardiomyocytes membrane only in 50-day-old 3d-WR group, which presented increased protein levels of AQP1; no changes were observed in the ventricle of pups. In vascular tissue, AQP1 was present in the smooth muscle of pups; in the oldest group, it was found in the endothelium, increasing after rehydration in smooth muscle. No differences were observed between control groups 3d-WAL and 6d-WAL of both ages. CONCLUSION: Our findings suggest that cardiovascular AQP1 can be differentially regulated in response to hydration status in vivo, being this response dependent on postnatal growth. The lack of adaptive mechanisms of mature animals in young pups may indicate an important role of this water channel in maintaining fluid balance during hypovolemic state. PMID- 23625138 TI - Relationship between bifenthrin sediment toxic units and benthic community metrics in urban California streams. AB - The objective of this study was to use ecologically relevant field measurements for determining the relationship between bifenthrin sediment toxic units (TUs) (environmental concentrations/Hyalella acute LC50 value) and 15 benthic metrics in four urban California streams sampled from 2006 to 2011. Data from the following four California streams were used in the analysis: Kirker Creek (2006, 2007), Pleasant Grove Creek (2006, 2007, and 2008), Arcade Creek (2009, 2010, and 2011), and Salinas streams (2009, 2010, and 2011). The results from univariate analysis of benthic metrics versus bifenthrin TU calculations for the four California streams with multiple-year datasets combined by stream showed that there were either nonsignificant relationships or lack of metric data for 93 % of cases. For 7 % of the data (4 cases) where significant relationships were reported between benthic metrics and bifenthrin TUs, these relationships were ecologically meaningful. Three of these significant direct relationships were an expression of tolerant benthic taxa (either % tolerant taxa or tolerance values, which are similar metrics), which would be expected to increase in a stressed environment. These direct significant tolerance relationships were reported for Kirker Creek, Pleasant Grove Creek, and Arcade Creek. The fourth significant relationship was an inverse relationship between taxa richness and bifenthrin TUs for the 3-year Pleasant Grove Creek dataset. In summary, only a small percent of the benthic metric * bifenthrin TU relationships were significant for the four California streams. Therefore, the general summary conclusion from this analysis is that there is no strong case for showing consistent meaningful relationships between various benthic metrics used to characterize the status of benthic communities and bifenthrin TUs for these four California streams. PMID- 23625139 TI - China's new mental health law: reframing involuntary treatment. PMID- 23625141 TI - Staging stage IV colorectal cancer. PMID- 23625140 TI - An implementation evaluation of the community engagement and planning intervention in the CPIC Depression Care Improvement Trial. AB - The goal of this paper is to document and evaluate the process of implementing an evidence-based depression intervention in community settings through the use of community-academic partnered approaches. We discuss how and to what extent the goals of community engagement and collaborative planning were achieved in the intervention arm of the Community Partners in Care study that aimed to adapt evidence-based depression care toolkits for diverse agencies in Hollywood and South Los Angeles. We find that partnered research strategies have a potential to effectively engage community members around depression and involve them in intervention planning activities. Our results suggest that successful collaboration among diverse agencies requires that they understand what is expected of them, are comfortable with the role they choose to perform, and have organizational support to contribute to the project. To facilitate the development of collaborative relationships, time and effort should be devoted to explaining how collaboration among diverse agencies may take place. PMID- 23625142 TI - Lymph node harvest in esophageal cancer after neoadjuvant chemoradiotherapy. AB - BACKGROUND: This study was designed to determine the effects of lymph node (LN) harvest on survival in esophageal cancer after neoadjuvant chemoradiation (nCRT). METHODS: An analysis of surgically resected esophageal cancer patients after nCRT was performed to determine an association between the number of LNs resected and survival. Overall survival (OS) and disease-free survival (DFS) curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis (MVA) was performed by the Cox proportional hazard model. RESULTS: We identified 358 patients with a mean follow-up of 27.3 months. The number of LN removed was not impacted by the type of surgical procedure. The number of LNs removed (<10 vs. >=10, <12 vs. >=12, and <15 vs. >=15) did not impact OS or DFS. We found a significant difference in OS and DFS by pathologic response. The median and 5-year OS for patients with complete, partial, and no response was 65.6 months and 52.7%, 29.7 months and 30.4%, and 17.7 months and 25.4% (p=0.0002). However, the number of LN harvested did not impact OS and DFS when patients were stratified by pathologic response. MVA also revealed that the number of lymph nodes removed was not prognostic for OS or DFS. Higher age, higher stage, and less than a complete response were associated with a decreased OS. Higher stage and less than a complete response were prognostic for worse DFS. CONCLUSIONS: The number of LNs harvested during esophagectomy does not impact survival after nCRT. Stage and pathologic response continue to be the strongest prognostic factors for survival in esophageal cancer after nCRT. PMID- 23625143 TI - Clinical testing of visual fields using a laser pointer and a wall. PMID- 23625144 TI - Cotton bracts are adapted to a microenvironment of concentrated CO2 produced by rapid fruit respiration. AB - BACKGROUND AND AIMS: Elucidation of the mechanisms by which plants adapt to elevated CO2 is needed; however, most studies of the mechanisms investigated the response of plants adapted to current atmospheric CO2. The rapid respiration rate of cotton (Gossypium hirsutum) fruits (bolls) produces a concentrated CO2 microenvironment around the bolls and bracts. It has been observed that the intercellular CO2 concentration of a whole fruit (bract and boll) ranges from 500 to 1300 umol mol(-1) depending on the irradiance, even in ambient air. Arguably, this CO2 microenvironment has existed for at least 1.1 million years since the appearance of tetraploid cotton. Therefore, it was hypothesized that the mechanisms by which cotton bracts have adapted to elevated CO2 will indicate how plants will adapt to future increased atmospheric CO2 concentration. Specifically, it is hypothesized that with elevated CO2 the capacity to regenerate ribulose-1,5-bisphosphate (RuBP) will increase relative to RuBP carboxylation. METHODS: To test this hypothesis, the morphological and physiological traits of bracts and leaves of cotton were measured, including stomatal density, gas exchange and protein contents. KEY RESULTS: Compared with leaves, bracts showed significantly lower stomatal conductance which resulted in a significantly higher water use efficiency. Both gas exchange and protein content showed a significantly greater RuBP regeneration/RuBP carboxylation capacity ratio (Jmax/Vcmax) in bracts than in leaves. CONCLUSIONS: These results agree with the theoretical prediction that adaptation of photosynthesis to elevated CO2 requires increased RuBP regeneration. Cotton bracts are readily available material for studying adaption to elevated CO2. PMID- 23625145 TI - Higher dose L-methylfolate may be an effective adjunctive therapy for adults with major depression who have inadequate response to SSRIs. PMID- 23625148 TI - Facile synthesis of Ti(4+)-immobilized Fe3O4@polydopamine core-shell microspheres for highly selective enrichment of phosphopeptides. AB - In this work, for the first time, Ti(4+)-Fe3O4@polydopamine microspheres were designed and synthesized for efficient and selective enrichment of phosphopeptides in biological samples. PMID- 23625146 TI - Sex-specific gray matter volume differences in females with developmental dyslexia. AB - Developmental dyslexia, characterized by unexpected reading difficulty, is associated with anomalous brain anatomy and function. Previous structural neuroimaging studies have converged in reports of less gray matter volume (GMV) in dyslexics within left hemisphere regions known to subserve language. Due to the higher prevalence of dyslexia in males, these studies are heavily weighted towards males, raising the question whether studies of dyslexia in females only and using the same techniques, would generate the same findings. In a replication study of men, we obtained the same findings of less GMV in dyslexics in left middle/inferior temporal gyri and right postcentral/supramarginal gyri as reported in the literature. However, comparisons in women with and without dyslexia did not yield left hemisphere differences, and instead, we found less GMV in right precuneus and paracentral lobule/medial frontal gyrus. In boys, we found less GMV in left inferior parietal cortex (supramarginal/angular gyri), again consistent with previous work, while in girls differences were within right central sulcus, spanning adjacent gyri, and left primary visual cortex. Our investigation into anatomical variants in dyslexia replicates existing studies in males, but at the same time shows that dyslexia in females is not characterized by involvement of left hemisphere language regions but rather early sensory and motor cortices (i.e., motor and premotor cortex, primary visual cortex). Our findings suggest that models on the brain basis of dyslexia, primarily developed through the study of males, may not be appropriate for females and suggest a need for more sex-specific investigations into dyslexia. PMID- 23625149 TI - Transformation of vibration signals in rotary blood pumps: the diagnostic potential of pump failure. AB - Although non-destructive and continuous monitoring is indispensable for long-term circulatory support with rotary blood pumps, a practical monitoring system has not yet been developed. The objective of this study was to investigate the possibility of detecting pump failure caused by thrombus formation through the monitoring of vibration signals. The data acquisition equipment included vibration pickups, a charge amplifier, vibration analysis systems, and exclusive hardware. A pivot-bearing centrifugal pump with a mock circuit was investigated for vibration analysis. To simulate the four common areas of thrombus formation, we used a piece of silicon attached to each of the following four locations: the total area of the bottom of the impeller, an eccentric shape on the bottom of the impeller, a circular shape around the shaft top, and an eccentric shape on the top of the impeller. Vibration signals were picked up, and the power spectrum density analysis was performed at pump rotational speeds of 2100, 2400, and 3000 rpm. In this study, pump failure could be detected, and the types of imitation thrombi could be determined. We conclude that vibration detection with a computerized analysis system is a potentially valuable diagnostic tool for long term circulatory support with rotary blood pumps. PMID- 23625147 TI - Striatal patch compartment lesions alter methamphetamine-induced behavior and immediate early gene expression in the striatum, substantia nigra and frontal cortex. AB - Methamphetamine (METH) induces stereotypy, which is characterized as inflexible, repetitive behavior. Enhanced activation of the patch compartment of the striatum has been correlated with stereotypy, suggesting that stereotypy may be related to preferential activation of this region. However, the specific contribution of the patch compartment to METH-induced stereotypy is not clear. To elucidate the involvement of the patch compartment to the development of METH-induced stereotypy, we determined if destruction of this sub-region altered METH-induced behaviors. Animals were bilaterally infused in the striatum with the neurotoxin dermorphin-saporin (DERM-SAP; 17 ng/MUl) to specifically ablate the neurons of the patch compartment. Eight days later, animals were treated with METH (7.5 mg/kg), placed in activity chambers, observed for 2 h and killed. DERM-SAP pretreatment significantly reduced the number and total area of mu-labeled patches in the striatum. DERM-SAP pretreatment significantly reduced the intensity of METH-induced stereotypy and the spatial immobility typically observed with METH-induced stereotypy. In support of this observation, DERM-SAP pretreatment also significantly increased locomotor activity in METH-treated animals. In the striatum, DERM-SAP pretreatment attenuated METH-induced c-Fos expression in the patch compartment, while enhancing METH-induced c-Fos expression in the matrix compartment. DERM-SAP pretreatment followed by METH administration augmented c-Fos expression in the SNpc and reduced METH-induced c Fos expression in the SNpr. In the medial prefrontal, but not sensorimotor cortex, c-Fos and zif/268 expression was increased following METH treatment in animals pre-treated with DERM-SAP. These data indicate that the patch compartment is necessary for the expression of repetitive behaviors and suggests that alterations in activity in the basal ganglia may contribute to this phenomenon. PMID- 23625150 TI - Synthesis and crystal structure of Fe6Ca2(SeO3)9Cl4--a porous oxohalide. AB - A porous oxohalide, Fe6Ca2(SeO3)9Cl4, has been synthesized by solid state reactions using concentrated HCl as the Cl-source. It crystallizes in the hexagonal space group P63/m with unit cell parameters a = 12.118(2) A, c = 12.703(4) A, Z = 2. The crystal structure is an open framework having one dimensional channels extending along [001] that the chlorine atoms and lone pairs on Se(4+) are facing. The channels in this framework structure are unusually large compared to other oxohalide compounds and also accessible to guest molecules. Water vapor sorption measurements show an uptake of 9 wt% at 293 K. PMID- 23625151 TI - Mitral valve endocarditis in a patient with Ehlers-Danlos syndrome. AB - We report a patient with Ehlers-Danlos syndrome and mitral valve endocarditis. The case was complicated due to the initial septic status of the patient and the fragility of the mitral valve both of which required further early operative intervention. The patient also had pre-existing pulmonary septic emboli, the significance of which was missed prior to the admission to our Unit. Two peripheral arterial aneurysms were identified and corrected surgically on same admission. Possible complications of the syndrome and surgical implications are discussed along with review of the literature. PMID- 23625152 TI - Extending the socio-sexual brain: arginine-vasopressin immunoreactive circuits in the telencephalon of mice. AB - Quantitative analysis of the immunoreactivity for arginine-vasopressin (AVP-ir) in the telencephalon of male (intact and castrated) and female CD1 mice allows us to precisely locate two sexually dimorphic (more abundant in intact than castrated males and females) AVP-ir cell groups in the posterior bed nucleus of the stria terminalis (BST) and the amygdala. Chemoarchitecture (NADPH diaphorase) reveals that the intraamygdaloid AVP-ir cells are located in the intra-amygdaloid BST (BSTIA) rather than the medial amygdala (Me), as previously thought. Then, we have used for the first time tract tracing (combined with AVP immunofluorescence) and fiber-sparing lesions of the BST to analyze the projections of the telencephalic AVP-ir cell groups. The results demonstrate that the posterior BST originates the sexually dimorphic innervation of the lateral septum, the posterodorsal Me and a substance P-negative area in the medioventral striato pallidum (mvStP).The BSTIA may also contribute to some of these terminal fields. Our material also reveals non-dimorphic AVP-ir processes in two locations of the amygdala. First, the ventral Me shows dendrite-like AVP-ir processes apparently belonging supraoptic neurons, whose possible functions are discussed. Second, the Ce shows sparse, thick AVP-ir axons with high individual variability in density and distribution, whose possible influence on stress coping in relation to the affiliative or agonistic behaviors mediated by the Me are discussed. Finally, we propose that the region of the mvStP showing sexually dimorphic AVP-ir innervation is part of the brain network for socio-sexual behavior, in which it would mediate motivational aspects of chemosensory-guided social interactions. PMID- 23625153 TI - Cortico-subthalamic connection predicts individual differences in value-driven choice bias. AB - It has been suggested that a connection between the STN and value-sensitive areas of the prefrontal cortex might mediate value-based actions in perceptual decision making. In this study, we first seek to quantify a structural connection between the STN and a cortical region that was associated with mechanisms underlying bias in choice behavior (vmPFC). Next, we tested whether individual differences in the probabilistic tract-strength of this connection were predictive for individual differences in the magnitude of bias in a perceptual decision-making task. Probabilistic tractography was used to measure the tract-strength between the STN and the vmPFC. Bias was quantified using an accumulation-to-bound model where a shift in the starting point of the accumulation of sensory evidence causes faster and more choices for an alternative that is more likely or more valuable. Results show that vmPFC is structurally connected with the STN and that the strength of this connection is predictive for choice bias towards an alternative that is more valuable, but not for choice bias towards an alternative that is more likely. These findings confirm the involvement of the cortico-subthalamic circuit in mechanisms underlying value-based actions in perceptual decision making. PMID- 23625154 TI - Age differences in suprathreshold sensory function. AB - While there is general agreement that vision and audition decline with aging, observations for the somatosensory senses and taste are less clear. The purpose of this study was to assess age differences in multimodal sensory perception in healthy, community-dwelling participants. Participants (100 females and 78 males aged 20-89 years) judged the magnitudes of sensations associated with graded levels of thermal, tactile, and taste stimuli in separate testing sessions using a cross-modality matching (CMM) procedure. During each testing session, participants also rated words that describe magnitudes of percepts associated with differing-level sensory stimuli. The words provided contextual anchors for the sensory ratings, and the word-rating task served as a control for the CMM. The mean sensory ratings were used as dependent variables in a MANOVA for each sensory domain, with age and sex as between-subject variables. These analyses were repeated with the grand means for the word ratings as a covariate to control for the rating task. The results of this study suggest that there are modest age differences for somatosensory and taste domains. While the magnitudes of these differences are mediated somewhat by age differences in the rating task, differences in warm temperature, tactile, and salty taste persist. PMID- 23625155 TI - Nicotine induces resistance to epidermal growth factor receptor tyrosine kinase inhibitor by alpha1 nicotinic acetylcholine receptor-mediated activation in PC9 cells. AB - INTRODUCTION: Nicotine, the major component among the 4000 identified chemicals in cigarette smoke, binds to nicotinic acetylcholine receptors (nAChRs) on non small-cell lung cancer (NSCLC) cells and regulates cellular proliferation by activating mitogen-activated protein kinases [AQ: MAPK has been expanded to mitogen-activated protein kinases. Please approve.]and PI3K/Akt pathways. In patients with smoking-related lung cancer who continue smoking, the anticancer effect of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is weaker than that in nonsmokers; however, the precise reason for this difference remains unclear. We investigated the role of alpha1 nAChR subunit in this phenomenon. METHODS: We screened for alpha1 nAChR mRNA in three NSCLC cell lines and analyzed the protein in resected primary NSCLC tissues. We used Western blot and RNA interference (siRNA) methodology to confirm the results. RESULTS: We determined that alpha1 nAChR plays an essential role in nicotine-induced cell signaling and nicotine-induced resistance to EGFR-TKI. In addition, we showed that silencing of alpha1 nAChR subunit in NSCLC may suppress the nicotine-induced resistance to EGFR-TKI. CONCLUSIONS: These results further implicate nicotine in lung carcinogenesis, and suggest that alpha1 nAChR may be a biomarker for EGFR TKI treatment and also a personalizing target molecule for patients with smoking related lung cancer. PMID- 23625156 TI - Detection of ALK rearrangement by immunohistochemistry in lung adenocarcinoma and the identification of a novel EML4-ALK variant. AB - INTRODUCTION: The echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion gene has been identified as a potent oncogenic driver in non-small-cell lung cancer, in particular adenocarcinoma (ADC). It defines a unique subgroup of lung ADC, which may be responsive to ALK inhibitors. Detection of ALK rearrangement by fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR) is considered to be the standard procedure, but each with its own limitation. We evaluated the practical usefulness of immunohistochemistry (IHC) to detect ALK expression as a reliable detection method of ALK rearrangement in lung ADC. METHODS: We tested 373 lung ADCs for ALK rearrangement by IHC and FISH. Multiplex RT-PCR was performed to confirm the fusion variants. RESULTS: Twenty-two of 373 lung ACs (5.9%) were positive for ALK immunoreactivity. ALK-positive tumor cells demonstrated strong and diffused granular staining in the cytoplasm. All the ALK IHC-positive cases were confirmed to harbor ALK rearrangement, either by FISH, or RT-PCR. Two cases with positive ALK protein expression, but negative for breakapart FISH signal were shown to harbor EML4-ALK variant 1 by RT-PCR. None of the ALK IHC-negative cases were FISH-positive. In addition, we identified a novel EML4-ALK fusion variant (E3:ins53A20), and its potent transformation potential has been confirmed by in vivo tumorigenicity assay. CONCLUSION: IHC can effectively detect ALK rearrangement in lung cancer. It might provide a reliable and cost-effective diagnostic approach in routine pathologic laboratories for the identification of suitable candidates for ALK-targeted therapy. PMID- 23625159 TI - Does soil water saturation mobilize metals from riparian soils to adjacent surface water? A field monitoring study in a metal contaminated region. AB - In the Noorderkempen (NW Belgium), a large area (about 280 km(2)) is contaminated with cadmium (Cd) and zinc (Zn) due to historical pollution by the Zn smelters. Direct aquatic emissions of metals have diminished over time, however the surface water metal concentration largely exceeds quality standards, mainly during winter periods. Monitoring data were analyzed to reveal whether these fluctuations are related to seasonal redox reactions in associated contaminated riparian soils that drain into the rivers. A field survey was set up with soil pore-water and groundwater monitored for three years in transects of soil monitoring points perpendicular to rivers at contaminated and non-contaminated sites. Site averaged surface water concentrations of a 15 year dataset exceeded local quality standards 4 to 200-fold. Winter averaged metal concentrations significantly exceeded the corresponding summer values 1.3-1.8 (Zn) and 1.5-2.4 fold (Cd). Zinc and Cd concentrations in water were positively related to Fe and Mn but not to Ca, K or Na suggesting that redox reactions and not dilution processes are involved. In ground- and pore-water of the associated riparian soils, the concentrations of Zn fluctuate by the same order of magnitude as in surface water but were generally smaller than in the corresponding contaminated rivers. In addition, correlations of dissolved Zn with Fe and Mn were lacking. This analysis suggests that redox reactions in streams, and not in riparian soils, explain the seasonal trends of Zn and Cd in surface water. Hence, river sediments and not riparian soils may be the cause of the winter peaks of Zn and Cd in these rivers. PMID- 23625158 TI - Peripheral blood gene expression signature differentiates children with autism from unaffected siblings. AB - Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental disorders with high heritability, yet a majority of genetic contribution to pathophysiology is not known. Siblings of individuals with ASD are at increased risk for ASD and autistic traits, but the genetic contribution for simplex families is estimated to be less when compared to multiplex families. To explore the genomic (dis-) similarity between proband and unaffected sibling in simplex families, we used genome-wide gene expression profiles of blood from 20 proband unaffected sibling pairs and 18 unrelated control individuals. The global gene expression profiles of unaffected siblings were more similar to those from probands as they shared genetic and environmental background. A total of 189 genes were significantly differentially expressed between proband-sib pairs (nominal p < 0.01) after controlling for age, sex, and family effects. Probands and siblings were distinguished into two groups by cluster analysis with these genes. Overall, unaffected siblings were equally distant from the centroid of probands and from that of unrelated controls with the differentially expressed genes. Interestingly, five of 20 siblings had gene expression profiles that were more similar to unrelated controls than to their matched probands. In summary, we found a set of genes that distinguished probands from the unaffected siblings, and a subgroup of unaffected siblings who were more similar to probands. The pathways that characterized probands compared to siblings using peripheral blood gene expression profiles were the up-regulation of ribosomal, spliceosomal, and mitochondrial pathways, and the down-regulation of neuroreceptor-ligand, immune response and calcium signaling pathways. Further integrative study with structural genetic variations such as de novo mutations, rare variants, and copy number variations would clarify whether these transcriptomic changes are structural or environmental in origin. PMID- 23625157 TI - The EKZ/AMC childhood cancer survivor cohort: methodology, clinical characteristics, and data availability. AB - PURPOSE: Childhood cancer survivors are at high risk of late adverse effects of cancer treatment, but there are still many gaps in evidence about these late effects. We described the methodology, clinical characteristics, data availability, and outcomes of our cohort study of childhood cancer survivors. METHODS: The Emma Children's Hospital/Academic Medical Center (EKZ/AMC) childhood cancer survivor cohort is an ongoing single-center cohort study of >=5-year childhood cancer survivors, which started in 1996 simultaneously with regular structured medical outcome assessments at our outpatient clinic. RESULTS: From 1966 to 2003, 3,183 eligible children received primary cancer treatment in the EKZ/AMC, of which 1,822 (57.2 %) survived >=5 years since diagnosis. Follow-up time ranged from 5.0 to 42.5 years (median, 17.7). Baseline primary cancer treatment characteristics were complete for 1,781 (97.7 %) survivors, and 1,452 (79.7 %) survivors visited our outpatient clinic. Baseline characteristics of survivors who visited the clinic did not differ from those without follow-up. Within our cohort, 54 studies have been conducted studying a wide range of late treatment-related effects. CONCLUSIONS: The EKZ/AMC childhood cancer survivor cohort provides a strong structure for ongoing research on the late effects of childhood cancer treatment and will continuously contribute in reducing evidence gaps concerning risks and risk groups within this vulnerable population. IMPLICATIONS FOR CANCER SURVIVORS: Our large cohort study of childhood cancer survivors with complete baseline characteristics and unique, long-term medical follow-up decreases gaps in evidence about specific risks of late effects and high-risk groups, with the ultimate goal of improving the quality of care for childhood cancer survivors. PMID- 23625160 TI - The acute and chronic effects of monosodium L-glutamate on serum iron and total iron-binding capacity in the jugular artery and vein of pigs. AB - We analyzed the effects of acute and chronic oral administration of monosodium L glutamate (MSG) on serum iron (Fe) levels and total iron-binding capacity (TIBC) in piglets. In the first experiment, 12 piglets were randomly assigned to two groups: one fed a standard diet (SD) and the other fed an SD containing MSG (10 g/kg). On day 30, serum, liver, kidney, and spleen samples were collected to determine the Fe levels. In the second experiment, six pigs were surgically fitted with a catheter in the jugular artery and vein to investigate the dynamic changes of serum Fe and TIBC. Blood samples were taken from each pig via the catheter every 30 min, for a period of 4 h. The results show that MSG increases Fe levels in the spleen (P < 0.05) and in serum obtained from the jugular artery (P < 0.01). In addition, TIBC in serum obtained from the jugular artery demonstrated an increasing trend in pigs fed the MSG diet; however, this trend was not observed in the jugular vein. In conclusion, MSG increases Fe retention by enhancing TIBC in serum. PMID- 23625161 TI - Hyperbaric oxygen did not improve symptoms in children with cerebral palsy. PMID- 23625162 TI - Acknowledging and researching treatment uncertainties in paediatric practice: an ethical imperative. PMID- 23625164 TI - Abstracts of the Irish Society for Rheumatology Autumn Meeting 2012. September 20 21, 2012. Belfast, Northern Ireland. PMID- 23625163 TI - Plasma vitamin D levels, menopause, and risk of breast cancer: dose-response meta analysis of prospective studies. AB - Previous evidence suggests that higher circulating 25-hydroxyvitamin D (25[OH]D) levels are variably associated with lower breast cancer risk; however, prospective studies and clinical trials have been inconsistent, particularly between older and younger women of differing menopausal status. We conducted a quantitative nonlinear dose-response meta-analysis of prospective studies evaluating the association between circulating 25(OH)D and breast cancer risk, stratified by menopause. A systematic search of MEDLINE and EMBASE included studies published through May 2011. We reviewed references from retrieved articles and contacted relevant investigators for additional data from prospective studies on circulating 25(OH)D levels and incident breast cancers. Prospective studies of circulating vitamin D and breast cancer risk were reviewed, and no language restrictions were imposed. Information on study population, menopausal status, 25(OH)D levels, and relative risk (RR) estimates were extracted using a standardized protocol.A total of 9 prospective studies were included, comprising 5206 cases and 6450 controls. Data were pooled using dose-response random-effects meta-regression models. Identifying nonlinear effects, spline models were optimized for thresholds. The relationship between circulating 25(OH)D and breast cancer risk differed by menopausal status (p = 0.05 for effect modification). While no association was found in premenopausal women, dose-response modeling revealed a nonlinear inverse association among postmenopausal women. Notably, a flat association was observed in the lowest range of 25(OH)D levels <27 ng/mL (RR = 1.01 per 5 ng/mL; 95% confidence interval [CI], 0.98-1.04). In contrast, postmenopausal breast cancer risk decreased with 25(OH)D levels 27-<35 ng/mL (p = 0.02 for nonlinear risk change), where a 5 ng/mL increase in 25(OH)D was associated with a 12% lower risk of breast cancer (RR = 0.88 per 5 ng/mL; 95% CI, 0.79-0.97), with suggestive flattening at higher doses >35 ng/mL. The significant inverse association did not appear to vary across strata of invasive/in-situ cases, body mass index adjustment, region, postmenopausal hormone use, or assay method.In summary, this dose-response meta analysis of prospective studies of plasma 25(OH)D suggested a breast cancer risk differential by menopause, whereby a step-wise inverse association was observed beyond a threshold of 27 ng/mL, but with flattening of effects above 35 ng/mL, in postmenopausal women. These findings help resolve prior inconsistent findings and may carry important clinical and public health implications. PMID- 23625165 TI - Helicobacter pylori resistance rates for levofloxacin, tetracycline and rifabutin among Irish isolates at a reference centre. AB - INTRODUCTION: Helicobacter pylori eradication rates using conventional triple therapies are falling, making viable second-line and rescue regimens necessary. Levofloxacin, tetracycline and rifabutin are three efficacious antibiotics for rescue therapy. AIM: We aimed to assess the resistance rates for H. pylori against these antibiotics in an Irish cohort. METHODS: Gastric biopsies were collected from 85 patients infected with H. pylori (mean age 46 years) in the Adelaide and Meath Hospital, Dublin in 2008 and 2009. Susceptibility to antibiotics was tested using the Etest. Clinical information was obtained from endoscopy reports and chart review. RESULTS: 50.6 % of patients were females. Mean age was 47 years. Ten had prior attempts at eradication therapy with amoxicillin-clarithromycin-PPI, two had levofloxacin-based second-line therapy. 11.7 % [95 % CI (6.5-20.3 %)] (N = 10) had strains resistant to levofloxacin. There were no strains resistant to rifabutin or tetracycline. Levofloxacin resistance in the under 45 age group was 2.6 % (1/38) compared to 19.1 % (9/47) of above 45 age group (p = 0.02). DISCUSSION: The levofloxacin rates illustrated in this study are relatively low by European standards and in line with other studies from the United Kingdom and Germany, with younger patients having very low levels of resistance. Levofloxacin, tetracycline and rifabutin are all valid options for H. pylori eradication in Irish patients but the importance of compliance cannot be underestimated. PMID- 23625166 TI - Epigenetic signature of early cardiac regulatory genes in native human adipose derived stem cells. AB - Adipose-derived stem cells (ADSCs) are stromal mesenchymal stem cells isolated from lipoaspirates, and they display a broad potential to differentiate toward different lineages. The role of epigenetics in regulating the expression of their lineage-specific genes is under evaluation, however till date virtually nothing is known about the relative significance of cardiac-specific transcription factor genes in human ADSCs. The aim of this study was to investigate DNA promoter methylation and relevant histone modifications involving MEF-2C, GATA-4, and Nkx2.5 in native human ADSCs. CpG sites at the transcription start in their promoters were found unmethylated using methylation-specific PCR. Chromatin immunoprecipitation assay showed low levels of total acetylated H3 histone (acH3) and high levels of trimethylated lysine 27 in H3 histone (H3K27me3) which were associated with both GATA-4 and Nkx2.5 promoters, indicating their transcriptional repressive chromatin arrangement. On the other hand, the opposite was apparent for MEF-2C promoter. Accordingly, MEF-2C-but not GATA-4 and Nkx2.5 transcripts were evidenced in native human ADSCs. These results suggest that the chromatin arrangement of these early cardiac regulatory genes could be explored as a level of intervention to address the differentiation of human ADSCs toward the cardiac lineage. PMID- 23625167 TI - Enrichment, detection and clinical significance of circulating tumor cells. AB - Circulating Tumor Cells (CTCs) are shed from primary or secondary tumors into blood circulation. Accessing and analyzing these cells provides a non-invasive alternative to tissue biopsy. CTCs are estimated to be as few as 1 cell among a few million WBCs and few billion RBCs in 1 ml of patient blood and are rarely found in healthy individuals. CTCs are FDA approved for prognosis of the major cancers, namely, Breast, Colon and Prostate. Currently, more than 400 clinical trials are ongoing to establish their clinical significance beyond prognosis, such as, therapy selection and companion diagnostics. Understanding the clinical relevance of CTCs typically involves isolation, detection and molecular characterization of cells, ideally at single cell level. The need for highly reliable, standardized and robust methodologies for isolating and analyzing CTCs has been widely expressed by clinical thought leaders. In the last decade, numerous academic and commercial technology platforms for isolation and analysis of CTCs have been reported. A recent market report highlighted the presence of more than 100 companies offering products and services related to CTCs. This review aims to capture the state of the art and examines the technical merits and limitations of contemporary technologies for clinical use. PMID- 23625168 TI - Occurrence of piperidine alkaloids in Piper species collected in different areas. AB - A simple and convenient method was established for simultaneous quantitative determination of piperine and piperlonguminine in dried fruits of Piper longum and allied plants. The average content of piperine in P. longum (18.26 mg/g, range 12.05-33.23 mg/g) was about one half that of P. nigrum (40.09 mg/g, range 29.57-54.23 mg/g), but the content of piperlonguminine in P. longum was in the range of 0.42-1.82 mg/g, and the average content of piperlonguminne (0.91 mg/g) was about seven times higher than that in P. nigrum (0.13 mg/g). A sample of P. longum from Vietnam and a sample of P. retrofractum collected in Ishigaki, Japan, showed high contents of piperine and piperlonguminine. On the other hand, a sample of P. betle collected in Taiwan showed low content of piperine, and piperlonguminine was not detected. PMID- 23625171 TI - Exploring the spiritual/religious dimension of patients: a timely opportunity for personal and professional reflection for graduating medical students. AB - Teaching about spirituality in medical school training is lacking. Spirituality is a dimension of humanity that can put experiences of health and illness into a meaningful context. Medical students might benefit from understanding how spirituality is an important element in learning to care for patients. Spirituality also provides a context for medical students to explore their own motivations for doctoring. This article describes a longitudinal senior elective course at the end of their medical school training to delve into matters of religion/spirituality surrounding patient care. The authors pose their own perspectives on what both students and faculty gained from the experience. PMID- 23625170 TI - MiRAuto: an automated user-friendly microRNA prediction tool utilizing plant small RNA sequencing data. AB - MicroRNAs (miRNAs) are a class of small RNAs that post-transcriptionally regulate gene expression in animals and plants. The recent rapid advancement in miRNA biology, including high-throughput sequencing of small RNA libraries, inspired the development of a bioinformatics software, miRAuto, which predicts putative miRNAs in model plant genomes computationally. Furthermore, miRAuto enables users to identify miRNAs in non-model plant species whose genomes have yet to be fully sequenced. miRAuto analyzes the expression of the 5'-end position of mapped small RNAs in reference sequences to prevent the possibility of mRNA fragments being included as candidate miRNAs. We validated the utility of miRAuto on a small RNA dataset, and the results were compared to other publicly available miRNA prediction programs. In conclusion, miRAuto is a fully automated user-friendly tool for predicting miRNAs from small RNA sequencing data in both model and non model plant species. miRAuto is available at http://nature.snu.ac.kr/software/miRAuto.htm. PMID- 23625172 TI - Near-death experiences and spiritual well-being. AB - People who have near-death experiences often report a subsequently increased sense of spirituality and a connection with their inner self and the world around them. In this study, we examined spiritual well-being, using Paloutzian and Ellison's Spiritual Well-Being Scale, among 224 persons who had come close to death. Participants who reported having near-death experiences reported greater spiritual well-being than those who did not, and depth of spiritual well-being was positively correlated with depth of near-death experience. We discussed the implications of these findings in light of other reported aftereffects of near death experiences and of spiritual well-being among other populations. PMID- 23625169 TI - Molecular epidemiology and genetic diversity of human rhinovirus affecting hospitalized children in Rome. AB - Human rhinoviruses (HRV) have been re-classified into three species (A-C), but the recently discovered HRV-C strains are not fully characterized yet. This study aimed to undertake a molecular and epidemiological characterization of HRV strains infecting children hospitalized over one year in two large research hospitals in Rome. Nasal washings from single HRV infections were retrospectively subjected to phylogenetic analysis on two genomic regions: the central part of the 5'Untranslated Region (5'UTR) and the Viral Protein (VP) 4 gene with the 5' portion of the VP2 gene (VP4/2). Forty-five different strains were identified in 73 HRV-positive children: 55 % of the cases were HRV-A, 38 % HRV-C and only 7 % HRV-B. HRV-C cases were less frequent than HRV-A during summer months and more frequent in cases presenting wheezing with respect to HRV-A. Species distribution was similar with respect to patient age, and seasonality differed during summer months with fewer HRV-C than HRV-A cases. On admission, a significantly higher number of HRV-C cases presented with wheezing with respect to HRV-A. The inter- and intra-genotype variability in VP4/2 was higher than in 5'UTR; in particular, HRV-A patient VP4/2 sequences were highly divergent (8-14 %) at the nucleotide level from those of their reference strains, but VP4 amino acid sequence was highly conserved. In HRV-C isolates, the region preceding the initiator AUG, the amino acids involved in VP4 myristoylation, the VP4-VP2 cleavage site and the cis acting replication element were highly conserved. Differently, VP4 amino acid conservation was significantly lower in HRV-C than in HRV-A strains, especially in the transiently exposed VP4 N-terminus. This study confirmed the high number of different HRV genotypes infecting hospitalized children over one year and reveals a greater than expected variability in HRV-C VP4 protein, potentially suggestive of differences in replication. PMID- 23625173 TI - Religiousness and religious coping in a secular society: the gender perspective. AB - Women are found to be more religious than men and more likely to use religious coping. Only few studies have explored religious gender differences in more secular societies. This population-based study comprised 3,000 Danish men and women (response rate 45 %) between 20 and 40 years of age. Information about demographics, religiousness and religious coping was obtained through a web-based questionnaire. We organized religiousness in the three dimensions: Cognition, Practice and Importance, and we assessed religious coping using the brief RCOPE questionnaire. We found substantial gender differences in both religiousness and religious coping. Nearly, 60 % of the women believed in some sort of spirit or in God compared to 40 % of the men. Generally, both men and women scored low on the RCOPE scale. However, for respondents reporting high levels of religiousness, the proportion of men who scored high in the RCOPE exceeded the proportion of women in using positive and especially negative coping strategies. Also, in a secular society, women are found to be more religious than men, but in a subset of the most religious respondents, men were more inclined to use religious coping. Further studies on religious coping in secular societies are required. PMID- 23625174 TI - Anti-inflammatory and analgesic activities of the hydrolyzed sasanquasaponins from the defatted seeds of Camellia oleifera. AB - The defatted seeds of Camellia oleifera (Abel.) are used for stopping itching and pain in old days, the effective compounds need to be investigated. Sasanquasaponin as a rich fraction was extracted with 70% ethanol, purified by AB 8 macro-reticular resin, crystallized in 80% ethanol, and further hydrolyzed by 4% hydroxyl potassium or 2 M hydrochloride. Anti-inflammatory activities of the extracts were measured by carrageenan-induced paw edema in rats and croton oil induced ear inflammation in mice; the analgesic activities were analyzed by hot plate test, acetic acid induced writhing in mice; the levels of pain mediators of IL-1beta, TNF-alpha and PGE2 were determined; the antioxidative activities in vivo were evaluated by MDA, SOD and GSH-Px in serum of rats. The extracts showed significant (p < 0.01) anti-inflammatory and analgesic activities, remarkably (p < 0.01) inhibited production of pro-inflammatory cytokines and PGE2, decreased MDA and increased SOD and GSH-Px in serum. Inhibition of IL-1beta, TNF-alpha and PGE2 may contribute to their anti-inflammatory and analgesic effects; elimination of free radicals is also involved. The sapogenin and acid hydrolyzed product have better anti-inflammatory, analgesic effects, and stronger antioxidative activity than sasanquasaponin and alkaline hydrolyzed product, and they are better candidate medicines for inflammation and pain. PMID- 23625175 TI - The value of expression of M2-PK and VEGF in patients with advanced gastric cancer. AB - Glycolytic pyruvate kinase isoenzyme type M2 (M2-PK) plays a key role in tumor metabolism and energy production. Vascular endothelial growth factor (VEGF) is critical in regulating angiogenesis which is an essential process required for tumor growth and metastasis. These two genes may function in accordance with tumor development. The purpose of this study was to investigate the relationship between the expression of M2-PK and VEGF, and their association with clinicopathological features in patients with advanced gastric cancer. Expression of M2-PK and VEGF were examined in 142 cases of paraffin-embedded tissue blocks from patients with advanced gastric cancer. M2-PK expression was found to strongly correlate with that of VEGF (r = 0.718). In addition, expression of M2 PK and VEGF correlates with tumor size (p = 0.0001, and p = 0.0017, respectively), depth of invasion (p = 0.0024, and p = 0.0261, respectively), and lymph node metastasis (p = 0.036, and p = 0.028, respectively). The high expression levels of M2-PK and VEGF may indicate poor prognosis in patients with advanced gastric cancer. PMID- 23625176 TI - Protein phosphatases but not reactive oxygen species play functional role in acute amphetamine-mediated dopamine release. AB - Drug abuse-induced neurodegeneration can be triggered by elevated production of reactive oxygen species (ROS). Involvement of oxidative stress in acute amphetamine (AMPH)-mediated dopamine (DA) release, however, has not been completely understood yet. In order to elucidate the dopaminergic response of PC12 cells to a single dose of 10 MUM AMPH, ROS production was measured as related to the extracellular DA level. Due to the spontaneous oxidation of peroxide-sensitive fluorophore 2',7'-dichlorofluorescin diacetate (DCFH-DA) to 2',7'-dichlorofluorescein (DCF), the increase in fluorescence could not be unambiguously attributed to AMPH-triggered ROS production. Based on Amplex Red fluorescence, no ROS production was detected after acute AMPH application. Our data strongly suggest that ROS development was not the main triggering factor for immediate DA release after acute AMPH treatment. On the other hand, AMPH-induced elevation of DA levels in rat brain striatal slices was quenched by the water soluble antioxidant, N-acetylcysteine (NAC) at 10 mM. In this study, we also investigated the contribution of protein phosphatases to the AMPH-induced rat brain striatal dopaminergic response. The experimental protocol, double AMPH challenge was applied for screening the effect of NAC and cantharidin on AMPH mediated DA release. Here we show that AMPH-mediated DA release increased nearly twofold in striatal rat brain slices pretreated for 30 min with 1000 MUM cantharidin, a selective PP1 and PP2A inhibitor. These findings prove the lack of ROS inhibitory action on protein phosphatase activity in acute AMPH-mediated DA efflux. PMID- 23625178 TI - Agammaglobulinemia and lack of immunization protection in exudative atopic dermatitis. AB - Atopic dermatitis is very frequent in the first 6 months of life, and the severe exudative form of this skin disorder is by no means rare. Failure to achieve immunization protection is a potentially life-threatening complication of exudative atopic dermatitis that may go unrecognized. We report the case of a 6 month-old infant with severe exudative atopic dermatitis in whom hypoproteinemia and agammaglobulinemia were attributed to the massive exudation after exclusion of other possible causes. The patient failed to respond to standard immunization, and adequate protection with a good antibody response could be achieved only after exudation from the skin lesions had been treated by intensive topical skin therapy and multiple intravenous immunoglobulin substitution. Two otherwise similar earlier case reports did not investigate the immune status. Therefore, to the best of our knowledge, this is the first report to draw attention to absence of immunization protection in exudative atopic dermatitis. CONCLUSION: We hope that our case report will motivate pediatricians to check the immunization status of patients with exudative atopic dermatitis and take the necessary steps to improve their care. PMID- 23625177 TI - Intrathecal soluble HLA-E correlates with disease activity in patients with multiple sclerosis and may cooperate with soluble HLA-G in the resolution of neuroinflammation. AB - Expression and function of the immunoregulatory molecule HLA-E was investigated in patients with relapsing-remitting (RR) multiple sclerosis (MS). Serum and cerebrospinal fluid (CSF) soluble (s)HLA-E and -G levels were measured by ELISA in 80 RRMS patients. Controls were patients with other inflammatory neurological disorders (OIND, n = 81) and noninflammatory neurological disorders (NIND, n = 86). Serum sHLA-E concentrations were higher in RRMS than in NIND patients only. CSF sHLA-E concentrations were higher in RRMS than controls. Increased CSF sHLA-E levels were detected in MRI inactive and clinically stable RRMS patients. sHLA-E intrathecal synthesis (ITS) was higher in RRMS than controls, and the number of patients with sHLA-E ITS above cut-off was higher i) in MS than controls, and ii) in clinically stable than clinically active MS patients. sHLA-E CSF levels and ITS correlated with i) the same sHLA-G parameters, and ii) disease duration. HLA E expression and co-expression with CD markers were investigated in MS plaques from three different cases by immunohistochemistry and confocal microscopy, respectively. Infiltrating T lymphocytes and macrophages, as well as resident microglial cells and astrocytes expressed HLA-E. CSF samples from MS patients were finally tested for inhibitory activity of in vitro CTL and NK cell mediated cytotoxicity. sHLA-E+ were more effective than sHLA-E- CSF samples in such inhibition. Maximum inhibition was achieved with sHLA-E+/sHLA-G+ CSF samples In conclusion, increased sHLA-E CSF levels may play an immunomodulatory role in MS, contributing to the inhibition of intrathecal inflammatory response. The potential of sHLA-E as biomarker of MS activity warrants further investigation. PMID- 23625180 TI - Etiology and therapeutic management of erythema nodosum during pregnancy: an update. AB - Erythema nodosum (EN) is the most common form of panniculitis. It is characterized by erythematous, raised, tender nodules that usually occur bilaterally on the extensor surfaces of the lower extremities. EN is associated with many underlying conditions including infection, sarcoidosis, malignancy, and pregnancy. Its underlying etiology, however, is unknown in up to half of cases. Pregnancy is thought to create an optimal background for EN to develop, although the exact mechanisms are unclear. Immune complexes may play a role in the pathogenesis of EN during pregnancy, or EN may be a hypersensitivity reaction to either estrogens or progesterone. EN is a self-limiting process, and non pharmacologic means such as bed rest and elastic web bandages may be sufficient to control the symptoms. Potassium iodide, systemic and intralesional corticosteroids, non-steroidal anti-inflammatory drugs, salicylates, tumor necrosis factor-alpha inhibitors, hydroxychloroquine, colchicine, and dapsone are other treatment options available, but some of these drugs are contraindicated in pregnancy while others are considered safe. Before prescribing one of these treatments to a pregnant patient, the patient's obstetrician should be consulted, and a careful risk-benefit analysis should be performed. PMID- 23625179 TI - Use of cyclosporine A and tacrolimus in treatment of vernal keratoconjunctivitis. AB - Vernal keratoconjunctivitis is a sight-threatening inflammatory disease of conjunctiva and cornea. It is frequently observed in young children with the onset usually occurring in the first decade of life. Mild cases of VKC tend to remit with nonspecific and supportive therapy. In contrast, severe cases are usually more protracted with remission/relapse occurring for a prolonged period of time. Although VKC is classified as an allergic eye condition, the role of allergens as an inciting factor is not clear. Pathogenesis of VKC involves roles for IgE, cytokines, chemokines, and inflammatory cells (T and B lymphocytes, mast cells, basophils, neutrophils, and eosinophils) with the release of their granular proteins, proliferation of fibroblasts, and laying down exuberant amounts of collagen fibers in the conjunctival tissue. In severe VKC cases-often of tarsal VKC-diagnostic giant papilla are classically observed on the upper tarsal plate, giving the classic 'cobble-stone' appearance. Corneal ulcer can occur from the effect of eosinophilic granular proteins on corneal epithelium and by physical trauma by intense eye rubbing. Topical corticosteroids, often required for controlling symptoms and signs in severe VKC, can lead to serious ocular complications. Immunomodulators that have been investigated for VKC treatment include topical ocular preparations of cyclosporine A and tacrolimus. Severe VKC responds promptly to topical cyclosporine A and tacrolimus, mostly within 1 month of therapy. Prolonged use of cyclosporine A and tacrolimus in VKC is safe and is tolerated by most patients without significant side effects. Recent investigations on the use of these two agents in VKC are the main purpose of this review. The use of cyclosporine A and tacrolimus are a major breakthrough in treatment for severe VKC, a debilitating allergic eye disease in children. PMID- 23625181 TI - Emotional reactivity and exposure to household stress in childhood predict psychological problems in adolescence. AB - In recent years, research has examined the role of heightened emotional reactivity and poor regulation on maladjustment during childhood and adolescence. Although much of this research has shown a direct link between high emotional reactivity and maladjustment, there is less research on the ways in which reactivity interacts with contextual factors. Using data from the National Institute of Child Health & Human Development Study of Early Child Care and Youth Development (SECCYD), the current study asks how emotional reactivity in childhood, household chaos, and household income impact changes in emotional and behavioral problems between childhood and adolescence. Participants in the SECCYD were followed from birth until adolescence. Of these, 958 youth (52 % male; 80 % Caucasian, 13 % African American, 2 % Asian, and 5 % Other) who completed measures at age 15 were included in the current study. Results indicate that emotional reactivity and low household income during childhood directly predict higher levels of emotional and behavioral problems in adolescence. In contrast, the impact of household chaos on adolescent mental health depends on the child's emotional reactivity. Specifically, the adverse impact of household chaos on emotional problems was observed among adolescents who were highly emotionally reactive as children, but not among their less reactive counterparts. Taken together, the relationship between an individual's childhood context and temperament are important aspects in the prediction of outcomes in adolescents. PMID- 23625182 TI - The remodeling of alveolar bone supporting the mandibular first molar with different levels of periodontal attachment. AB - The objective of this study was to investigate alveolar bone remodeling of the mandibular first molar with differing levels of periodontal attachment under mastication loading. Three-dimensional finite element models of the mandibular first molar with differing levels of periodontal attachment were established. The stress distributions and bone density changes were analyzed under mastication loading to simulate the remodeling process of mandibular bone based on the theory of strain energy density. The results showed that the alveolar buccal, lingual ridges and root apex areas experienced higher stresses. The stresses and densities of the alveolar bone increased proportionally to increased mastication loading. Decrease in alveolar bone density under extreme loading indicated bone resorption. The remodeling rate was continual with gradual loading. Periodontal ligament support marginally decreased with an increased remodeling rate under extreme loading. Changes in alveolar bone density can reflect the remodeling process of periodontal tissue under mastication loading. The relationship between the change in density and mastication loading during remodeling can provide useful indicators into clinical treatment and diagnosis of the periodontal disease. PMID- 23625183 TI - Experimental and model-based analysis of differences in perception of cutaneous electrical stimulation across the sole of the foot. AB - During electrocutaneous stimulations, variation in skin properties across locations can lead to differences in neural activation. However, little focus has been given to the effect of different skin thicknesses on neural activation. Electrical stimulation was applied to six sites across the sole of the foot. The intensities used were two and four times perception threshold. The subjects (n = 8) rated the perception quality and intensity using the McGill Pain Questionnaire and a visual analog scale (VAS). A finite element model was developed and combined with the activation function (AF) to estimate neural activation. Electrical stimulation was perceived as significantly less sharp at the heel compared to all other sites, except one site in the forefoot (logistic regression, p < 0.05). The VAS scores were significantly higher in the arch than at the heel (RM ANOVA, p < 0.05). The model showed that the AF was between 91 and 231 % higher at the five other sites than at the heel. The differences in perception across the sole of the foot indicated that the CNS received different inputs depending on the stimulus site. The lower AF at the heel indicated that the skin thicknesses could contribute to the perceived differences. PMID- 23625185 TI - Bidirectional associations between valued activities and adolescent positive adjustment in a longitudinal study: positive mood as a mediator. AB - Although activity involvement has been linked to positive youth development, the value that adolescents place on these activities (i.e., how much they enjoy the activities, find them important, and spend time on them) has received less attention. The purpose of the present study was to examine the bidirectional longitudinal association between engagement in valued activities and adolescent positive adjustment (optimism, purpose in life, and self-esteem), as well as investigate a possible underlying mechanism for this link. High school students (N = 2,270, 48.7% female) from Ontario, Canada completed questionnaires annually in grades 10, 11, and 12. Auto-regressive cross-lagged path analyses were conducted over time, controlling for gender, parental education, and academic grades. Greater engagement in valued activities predicted higher optimism, purpose, and self-esteem over time. Importantly, the results did not support an alternate hypothesis of selection effects, in that adolescents who were better adjusted were not more likely than their peers to engage in valued activities over time. We also found that the longitudinal associations between valued activities and positive adjustment may be due partly to an underlying effect of increased positive mood. Thus, engagement in valued activities appears to be important for adolescent positive adjustment, and may help to foster thriving. Communities, educators, and parents should actively support and encourage adolescents to develop valued activities, and seek to ensure that there are ample opportunities and resources available for them to do so. PMID- 23625184 TI - Long-term outcomes of primary ocular adnexal lymphoma treatment with intraorbital rituximab injections. AB - PURPOSE: We recently reported on the efficacy of intralesional rituximab for treating primary ocular adnexal lymphoma in a pilot study. After treatment, a complete response was observed in two of five patients, a partial response in one patient, and lesion recurrence in two patients. In this study, we evaluate the long-term follow-up of the five previously treated patients as well as the response of two new patients to an augmented dose of rituximab. METHODS: We followed up the five patients who were treated with rituximab during the initial pilot study. Two additional patients were also enrolled and treated with four intraorbital injections of 10 mg rituximab once a week for 1 month (total dose of 40 mg). Median follow-up period was 4 years for the first five patients and 1 year for the last two patients. RESULTS: Lymphoma did not relapse in the two patients who originally responded immediately to treatment. Of the initial partial responders, one became disease-free after additional rituximab treatment, and one experienced a standardized uptake value reduction, as measured with positron emission tomography-CT. One patient who experienced abdominal and pulmonary localization 7 months later showed no local recurrence. The two newly enrolled patients had complete remission after the first cycle of treatment and no disease recurrence eight and 11 months later, respectively. CONCLUSIONS: This study suggests that intralesional administration of rituximab for treating localized ocular adnexal CD20+ lymphomas could be an effective front-line therapeutic option with negligible side effects and a good response rate and duration. PMID- 23625187 TI - New stent retriever devices. AB - Acute ischemic stroke (AIS) is among the leading causes of adult death and number one cause of severe disability in the United States. In 1995 physicians had their first available Food and Drug Administration (FDA) approved treatment for AIS in the form of intravenous tissue plasminogen activator (IV-tPA). Since then, there has been an explosion of interest into endovascular mechanical thrombectomy as a potential treatment of stroke. Beginning in 2004 with the Merci Retriever, there have been multiple devices tested for this purpose. In 2012, the FDA approved two new devices-the Trevo Pro and Solitaire stent retrievers-after they were shown to have superior rates of recanalization when compared to the Merci device. In this article we will highlight the similarities and differences in the devices themselves, and the trials that brought them into use. Lastly, we will briefly touch on the future of mechanical embolectomy and considerations for future trial designs and patient selection. PMID- 23625188 TI - Role of cytochrome p450 isoenzymes 3A and 2D6 in the in vivo metabolism of mirabegron, a beta3-adrenoceptor agonist. AB - BACKGROUND: Mirabegron is a beta3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6. OBJECTIVE: To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism. METHODS: Two open-label, randomized, one-sequence crossover drug-drug interaction studies in healthy subjects were conducted to assess the effect of ketoconazole and rifampicin on the pharmacokinetics of mirabegron and two parallel-group studies in healthy subjects with either known confirmed or predicted CYP2D6 phenotype. RESULTS: Co-administration of multiple dosages of 400 mg/day ketoconazole with a single 100 mg mirabegron oral controlled absorption system (OCAS) dose increased mirabegron maximum concentration (C(max)) and area under the curve extrapolated to infinity (AUCinfinity) to 145 % (90 % confidence interval [CI] 123-172 %] and 181 % (90 % CI 163-201 %), respectively. Co-administration of multiple dosages of 600 mg/day rifampicin with a single 100 mg mirabegron OCAS dose decreased mirabegron C max and AUCinfinity to 65 % (90 % CI 50-86 %) and 56 % (90 % CI 49-65 %), respectively, without an effect on terminal elimination half-life (t(1/2)). The urinary excretion of mirabegron was increased by ketoconazole and decreased by rifampicin, reflecting the AUC changes, whereas renal clearance was not affected. Ketoconazole decreased mirabegron t 1/2 from 50.9 to 37.6 h suggesting that volume of distribution as well as first-pass effect decreased. Rifampicin did not affect mirabegron t 1/2, suggesting that it affects first pass through the intestinal wall or liver. Rifampicin greatly increased the ratio to parent drug of the presumed CYP-mediated mirabegron metabolites M8 and M15 by 777 and 646 %. Steady-state mirabegron pharmacokinetic parameters (50 and 100 mg mirabegron OCAS) were similar in 13 CYP2D6 poor, 40 intermediate, and 99 extensive metabolizers, whereas C max and AUC under the dosing interval tau of 24 h (AUCtau) were 30-47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C(max) was 14 % and AUCinfinity 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t 1/2. All treatments were well tolerated. CONCLUSIONS: Mirabegron is metabolized by CYP3A and to a minor extent by CYP2D6 in humans. Mirabegron is not considered a sensitive substrate of CYP3A in vivo, as ketoconazole increased mirabegron exposure by less than 2-fold. The effect of CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance. PMID- 23625189 TI - Tbx3 and Nr5alpha2 play important roles in pig pluripotent stem cells. AB - Pigs are valuable animal models in pre-clinical research due to their anatomical and similarity to human-beings. Little is known about porcine embryonic development and porcine pluripotent stem cells. Recently, porcine-induced pluripotent stem cells (piPSCs) have been generated with Oct4 (Pou5f1), Sox2, Klf4 and c-Myc (termed OSKM, 4 F). Here, we found two other factors (Tbx3 and Nr5alpha2, termed TN), with important roles in piPSCs induction. They could improve the generation of piPSCs by supplementing these two factors on the basis of OSKM (OSKMTN, 6 F) orientated to mouse ESCs-like. Surprisingly, Nr5alpha2 alone could induce piPSCs formation in the presence or absence of c-Myc. These results suggested that Tbx3 and Nr5alpha2 may have vital roles in Sus scrofa and proposed new insights into pig pluripotent stem cells. PMID- 23625190 TI - Human pluripotent stem cell differentiation into authentic striatal projection neurons. AB - Here we present the principles and steps of a protocol that we have recently developed for the differentiation of hES/iPS cells into the authentic human striatal projection medium spiny neurons (MSNs) that die in Huntington's Disease (HD). Authenticity is judged by the convergence of multiple features within individual cells. Our procedure lasts 80 days and couples neural induction via BMP/TGF-beta inhibition with exposure to the developmental factors sonic hedgehog (SHH) and dickkopf1 (DKK-1) to drive ventral telencephalic specification, followed by terminal differentiation [1]. Authenticity of the resulting neuronal population is monitored by the appearance of FOXG1(+)/GSX2(+) progenitor cells of the lateral ganglionic eminence (LGE) at day 15-25 of differentiation, followed by appearance of CTIP2-, FOXP1- and FOXP2-positive cells at day 45. These precursor cells then mature into MAP2(+)/GABA(+) neurons with 20 % of them ultimately co-expressing the DARPP-32 and CTIP2 diagnostic markers and carrying electrophysiological properties expected for fully functional MSNs.The protocol is characterized by its replicability in at least three human pluripotent cell lines. Altogether this protocol defines a useful platform for in vitro developmental neurobiology studies, drug screening, and regenerative medicine approaches. PMID- 23625191 TI - An analysis of the treatment effect of panitumumab on overall survival from a phase 3, randomized, controlled, multicenter trial (20020408) in patients with chemotherapy refractory metastatic colorectal cancer. AB - Panitumumab is a fully human monoclonal antibody that targets the epidermal growth factor receptor. Results from the primary analysis of a phase 3, randomized, controlled study showed a statistically significant improvement in progression-free survival for patients receiving panitumumab; however, overall survival was confounded by best supportive care (BSC) patients that crossed over to panitumumab therapy after disease progression. Three post hoc analyses are presented that approximate the panitumumab overall survival treatment effect in both the all-randomized and wild-type (WT) KRAS populations by using the BSC patients with mutant (MT) KRAS as the comparator group to discount the effect of crossover from BSC to panitumumab. The primary post hoc analysis showed a median overall survival of 6.4 months for all KRAS-evaluable patients randomized to panitumumab versus 4.4 months for patients with MT KRAS tumors randomized to BSC, yielding an adjusted hazard ratio (95 % CI) of 0.764 (0.598-0.977). Similar results were observed for the two secondary post hoc analyses. These analyses suggest a positive treatment effect of panitumumab in both the overall and WT KRAS patient populations consistent with an improvement in overall survival relative to BSC. PMID- 23625192 TI - The effect of wait times on oncological outcomes from periampullary adenocarcinomas. AB - BACKGROUND: Overall few patients presenting with periampullary adenocarcinomas have resectable lesions. We postulated that rapid diagnosis and treatment would enhance the likelihood of successful resection, improving survival. METHODS: A retrospective analysis of patients undergoing surgery for resection of a pancreatic or periampullary lesion was conducted. Resection rate, disease stage and survival were evaluated as a function of wait times. RESULTS: Pancreatic resections were booked in 355 patients. Of 193 patients with periampullary adenocarcinomas, 119 patients (61.7%) had resectable disease. There was no difference in median time from initial physician consultation to surgery in patients with resectable and unresectable disease (61 days vs. 64 days, respectively). The likelihood of successful resection was virtually identical in patients with wait times <= 30 and > 30 days (from surgical consultation to procedure). There was a trend toward a higher T-stage in patients who waited >30 days for surgery (P = 0.055). However, there was no difference in survival as a function of wait time. CONCLUSIONS: This series does not demonstrate an advantage for rapid diagnosis and surgery, in terms of resection rate and survival. However, further study is required in a larger cohort of patients, to confirm these findings. PMID- 23625193 TI - VEGF and GM-CSF levels in nodular thyroid diseases. AB - VEGF is a specific mitogen for endothelial cells. GM-CSF is a key player in the regulation of steady-state functions. The aim of this study was to evaluate VEGF and GM-CSF levels in thyroid nodules >1 cm, which are negative for malignancy with fine needle aspiration biopsy. Age, serum VEGF, GM-CSF, TSH, fT3, fT4, anti TG, anti-TPO, thyroid size, and thyroid volume were compared between 41 female patients and 20 healthy female volunteers. This study was performed with 41 female patients who were euthyroid and whose nodules were benign. Twenty healthy female volunteers were enrolled as the control group. VEGF and GM-CSF were assayed by ELISA; TSH, fT3, and fT4 were detected by electrochemiluminescence method and anti-TPO and anti-TG were detected by competitive immunoassay method. Only thyroid volume and anti-TG levels were significantly different between the two groups (p < 0.007 and p < 0.026, respectively). Other parameters including VEGF and GM-CSF were not significantly different. VEGF has a weak positive correlation only with anti-TPO levels in the patient group (r = 0.325, p = 0.036). There was a weak positive correlation between anti-TPO and anti-TG (r = 0.388, p = 0.007). There was a positive correlation between nodule size and thyroid volume (r = 0.464, p = 0.015). GM-CSF was not correlated with any parameters. VEGF and GM-CSF were not found to be increased in euthyroid patients with benign nodules and they do not seem to play a role in development of simple nodular goiter. PMID- 23625194 TI - Lifestyle intervention and anti-obesity therapies in the polycystic ovary syndrome: impact on metabolism and fertility. AB - Obesity is frequently present in patients with polycystic ovary syndrome (PCOS) and plays an important role in the pathogenesis of the metabolic, endocrine, and reproductive abnormalities associated with this syndrome. We aimed to summarize the effects of lifestyle changes and anti-obesity pharmacotherapy in patients with PCOS. We reviewed the literature regarding the effects of lifestyle changes and anti-obesity agents on the metabolic and endocrine abnormalities of PCOS. Lifestyle changes, including diet, exercise, and behavioral modification, appear to improve the metabolic and reproductive abnormalities of overweight and obese patients with PCOS. Therefore, lifestyle changes appear to represent the first line management for all overweight and obese patients with PCOS. However, the optimal composition of diet and the optimal type of exercise in these patients are unknown. Anti-obesity agents that have been studied in PCOS include orlistat, sibutramine, and rimonabant. However, the latter two agents have been withdrawn from the market because of side effects. Long-term studies with orlistat in overweight and obese diabetic patients showed greater weight loss and metabolic and cardiovascular benefits than those achieved with lifestyle changes alone. However, there are limited data on the efficacy of orlistat in women with PCOS. In conclusion, lifestyle changes (diet, exercise and behavioral modification), particularly when combined with anti-obesity agents, exert beneficial effects on the endocrine abnormalities of obese patients with PCOS and improve metabolic parameters. PMID- 23625195 TI - Effect of iridoid glucoside on plasma lipid profile, tissue fatty acid changes, inflammatory cytokines, and GLUT4 expression in skeletal muscle of streptozotocin induced diabetic rats. AB - The present study was designed to examine the antihyperlipidaemic potential of iridoid glucoside isolated from Vitex negundo leaves in STZ-induced diabetic rats. The levels of cholesterol (TC), triglycerides, lipoproteins, free fatty acids, phospholipids, fatty acid composition, proinflammatory cytokines, muscle glycogen content, and glucose transporter 4 (GLUT4) expression were estimated in control and diabetic rats. Oral administration of iridoid glucoside at a dose of 50 mg/kg body weight per day to STZ-induced diabetic rats for a period of 30 days resulted in a significant reduction in plasma and tissue (liver and kidney) cholesterol, triglycerides, free fatty acids, and phospholipids. In addition, the decreased plasma levels of high-density lipoprotein-cholesterol and increased plasma levels of low density lipoprotein- and very low density lipoprotein cholesterol in diabetic rats were restored to near normal levels following treatment with iridoid glucoside. The fatty acid composition of the liver and kidney was analyzed by gas chromatography. The altered fatty acid composition in the liver and kidney of diabetic rats was also restored upon treatment with iridoid glucoside. Moreover, the elevated plasma levels of proinflammatory cytokines and decreased levels of muscle glycogen and GLUT4 expression in the skeletal muscle of diabetic rats were reinstated to their normal levels via enhanced secretion of insulin from the remnant beta cells of pancreas by the administration of iridoid glucoside. The effect produced by iridoid glucoside on various parameters was comparable with that of glibenclamide, a well-known antihyperglycemic drug. PMID- 23625196 TI - The Q192R polymorphism of the paraoxonase 1 gene is a risk factor for coronary artery disease in Saudi subjects. AB - Paraoxonase-1 (PON1) is a HDL-bound antioxidant enzyme that protects LDL from oxidative modification. Discovery of the antioxidant properties of PON1 led to extensive research on its role in the initiation and progression of atherosclerosis. The Q192R (rs662; A/G) polymorphism, which results in the glutamine to arginine substitution at position 192, of the PON1 gene has been linked to increased atherosclerosis risk in several but not all population studies. Besides genetic factors, environmental variables and ethnicity have been implicated as factors responsible for the ambiguity in relating the PON1 gene with atherosclerotic risk. Here, we tested the association of the Q192R polymorphism with coronary artery disease (CAD) in Saudi ethnic subjects taking environmental factors into consideration. The genomic DNA samples from 121 angiographically confirmed CAD cases and 108 normal healthy control subjects were genotyped by PCR-RFLP analysis. The distribution of QQ, QR, and RR genotypes was significantly different between cases and controls (p < 0.005). The RR genotype was associated with CAD risk independently of several established risk factors including age, gender, smoking, obesity, and diabetes (OR 2.2, 1.4-7.4, p < 0.01). Genotype-based stratification of demographic and biochemical data revealed that the RR genotype has proatherogenic properties. This study, thus, identifies the Q192R polymorphism as an additional risk factor for CAD in the Saudi population and suggests that it may have prognostic value. The negative effect of this genetic variant is presumably due to the diminished ability of the RR variant genotype of PON1 to blunt LDL oxidation. PMID- 23625197 TI - The future of thiazolidinedione therapy in the management of type 2 diabetes mellitus. AB - Since their approval, thiazolidinediones (TZDs) have been used extensively as insulin-sensitizers for the management of type 2 diabetes mellitus (T2DM). Activation of peroxisomal proliferator-activated receptor gamma (PPARgamma) nuclear receptors by TZDs leads to a vast spectrum of metabolic and antiinflammatory effects. In the past decade, clinicians and scientists across the fields of metabolism, diabetes, liver disease (NAFLD), atherosclerosis, inflammation, infertility, and even cancer have had high hopes about the potential for TZDs to treat many of these diseases. However, an increasing awareness about undesirable "off-target" effects of TZDs have made us rethink their role and be more cautious about the long-term benefits and risks related to their use. This review examines the most relevant work on the benefits and risks associated with TZD treatment, with a focus on the only PPARgamma agonist currently available (pioglitazone), aiming to offer the reader a balanced overview about the current and future role of TZDs in the management of insulin resistant states and T2DM. PMID- 23625199 TI - What's your age again? Determination of human neutrophil half-lives revisited. AB - Neutrophils are the most abundant white blood cells and are indispensable for host defense. Recently, they have also been implicated in immune regulation and suppression. The latter functions seem hard to reconcile with the widely held view that neutrophils are very short-lived, with a circulatory half-life of <7 h. To reopen the discussion on the average neutrophil half-life, we review and discuss experiments performed in the 1950s, 1960s, and 1970s, as well as recent in vivo labeling experiments. We reappraise the current knowledge on neutrophil half-lives, including their production in the bone marrow, their residency in the circulation and marginated pool, and their exit from the circulation. PMID- 23625198 TI - At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. AB - Tumors can avoid immune surveillance by stimulating immune inhibitory receptors that function to turn off established immune responses. By blocking the ability of tumors to stimulate inhibitory receptors on T cells, sustained, anti-tumor immune responses can be generated in animals. Thus, therapeutic blockade of immune inhibitory checkpoints provides a potential method to boost anti-tumor immunity. The CTLA-4 and PD-1Rs represent two T cell-inhibitory receptors with independent mechanisms of action. Preclinical investigations revealed that CTLA-4 enforces an activation threshold and attenuates proliferation of tumor-specific T lymphocytes. In contrast, PD-1 functions primarily as a stop signal that limits T cell effector function within a tumor. The unique mechanisms and sites of action of CTLA-4 and PD-1 suggest that although blockade of either has the potential to promote anti-tumor immune responses, combined blockade of both might offer even more potent anti-tumor activity. See related review At the Bedside: CTLA-4 and PD 1 blocking antibodies in cancer immunotherapy. PMID- 23625200 TI - Alcohol-induced IL-1beta in the brain is mediated by NLRP3/ASC inflammasome activation that amplifies neuroinflammation. AB - Alcohol-induced neuroinflammation is mediated by proinflammatory cytokines, including IL-1beta. IL-1beta production requires caspase-1 activation by inflammasomes-multiprotein complexes that are assembled in response to danger signals. We hypothesized that alcohol-induced inflammasome activation contributes to increased IL-1beta in the brain. WT and TLR4-, NLRP3-, and ASC-deficient (KO) mice received an ethanol-containing or isocaloric control diet for 5 weeks, and some received the rIL-1ra, anakinra, or saline treatment. Inflammasome activation, proinflammatory cytokines, endotoxin, and HMGB1 were measured in the cerebellum. Expression of inflammasome components (NLRP1, NLRP3, ASC) and proinflammatory cytokines (TNF-alpha, MCP-1) was increased in brains of alcohol fed compared with control mice. Increased caspase-1 activity and IL-1beta protein in ethanol-fed mice indicated inflammasome activation. TLR4 deficiency protected from TNF-alpha, MCP-1, and attenuated alcohol-induced IL-1beta increases. The TLR4 ligand, LPS, was not increased in the cerebellum. However, we found up regulation of acetylated and phosphorylated HMGB1 and increased expression of the HMGB1 receptors (TLR2, TLR4, TLR9, RAGE) in alcohol-fed mice. NLRP3- or ASC deficient mice were protected from caspase-1 activation and alcohol-induced IL 1beta increase in the brain. Furthermore, in vivo treatment with rIL-1ra prevented alcohol-induced inflammasome activation and IL-1beta, TNF-alpha, and acetylated HMGB1 increases in the cerebellum. Conversely, intracranial IL-1beta administration induced TNF-alpha and MCP-1 in the cerebellum. In conclusion, alcohol up-regulates and activates the NLRP3/ASC inflammasome, leading to caspase 1 activation and IL-1beta increase in the cerebellum. IL-1beta amplifies neuroinflammation, and disruption of IL-1/IL-1R signaling prevents alcohol induced inflammasome activation and neuroinflammation. Increased levels of acetylated and phosphorylated HMGB1 may contribute to alcoholic neuroinflammation. PMID- 23625201 TI - PGI2 signaling inhibits antigen uptake and increases migration of immature dendritic cells. AB - PGI2 signaling through IP inhibits allergen-induced inflammatory responses in mice. We reported previously that PGI2 analogs decreased proinflammatory cytokine and chemokine production by mature BMDCs. However, whether PGI2 modulates the function of immature DCs has not been investigated. We hypothesized that PGI2 negatively regulates immature DC function and investigated the effect of PGI2 analogs on immature BMDC antigen uptake and migration in vitro and in vivo. Immature BMDCs were obtained from WT and IPKO mice, both on a C57BL/6 background. The PGI2 analog cicaprost decreased FITC-OVA uptake by immature BMDCs. In addition, cicaprost increased immature BMDC podosome dissolution, pro-MMP-9 production, cell surface CCR7 expression, and chemotactic migration toward CCL19 and CCL21, as well as chemokinesis, in an IP-specific fashion. These in vitro results suggested that cicaprost promotes migration of immature DCs from mucosal surface to draining LNs. This concept was supported by the finding that migration of immature GFP+ BMDCs to draining LNs was enhanced by pretreatment with cicaprost. Further, migration of immature lung DCs labeled with PKH26 was enhanced by intranasal cicaprost administration. Our results suggest PGI2-IP signaling increases immature DC migration to the draining LNs and may represent a novel mechanism by which this eicosanoid inhibits immune responses. PMID- 23625202 TI - Colorectal cancer in a monoallelic MYH mutation carrier. AB - Although the literature describes mutY homolog gene (MYH) polyposis as an autosomal recessive syndrome, we report a case of colorectal cancer in a carrier of MYH polyposis. Biallelic mutations in the MYH gene have been shown to increase the risk of colorectal cancer over the lifetime of the mutation carrier.1,2 However, there is no clear consensus in the literature as whether a monoallelic mutation increases the risk for colorectal cancer.3 In this report, we postulate that a single mutation is sufficient to increase the risk of colorectal cancer. We also propose that the G382D MYH mutation may play a dominant rather than a recessive role in polyposis and cancer development. PMID- 23625203 TI - BRAF and RAS mutations in follicular variants of papillary thyroid carcinoma. AB - Follicular variants of papillary thyroid carcinoma (FVPTC), particularly the encapsulated subtype, often cause a diagnostic dilemma. Therefore, many FVPTCs are interpreted as "indeterminate" in preoperative fine-needle aspiration (FNA). The aim of this study was to analyze the genotypic changes in BRAF codons 600 and 601, as well as the N, H, and KRAS codons 12, 13, and 61 in FVPTCs and investigate the usefulness of preoperative BRAF and RAS mutation analysis as an adjunct diagnostic tool along with routine FNA. Surgically resected thyroid nodules were reviewed to establish the histological diagnosis of FVPTC. All preoperative FNA diagnoses were categorized according to the Bethesda Reporting System. Mutations in BRAF codons 600 and 601, and N, H, KRAS codons 12, 13, and 61 were analyzed by pyrosequencing. Of 132 cases, 81 (61.4 %) had a point mutation in one of the BRAF V600E, BRAF K601E, or RAS oncogenes; BRAF V600E in 43(32.6 %), BRAF K601E in three (2.3 %), and RAS in 35 (26.5 %) cases. All mutations were mutually exclusive. Of 78 cases with an FNA indeterminate category diagnosis, 51 (65.4 %) were positive for mutations: 24 for BRAF V600E, 3 for BRAF K601E, and 24 for the RAS gene. The KRAS mutation was more frequently found than the HRAS mutation, comprising 22.9 % of the RAS mutations, and all KRAS mutations were located at codon 61. This study demonstrated that either BRAF or RAS mutations were present in two thirds of FVPTCs and these mutations were mutually exclusive. PMID- 23625204 TI - Molecular cloning, sequence characterization, SNP detection, and tissue expression analysis of duck FMO3 gene. AB - Flavin-containing monooxygenase 3 (FMO3) is an important monooxygenase for catalytic oxygenation of many harmful xenobiotics. Mutations in the FMO3 gene have been identified as causing trimethylaminuria in human and fishy off-flavor in cow milk and chicken eggs. In this study, the full-length cDNA sequence of Pekin duck FMO3 gene was cloned, sequenced, and characterized. The full-length cDNA sequence consisted of 1,846 bp and contained a 1,599 bp open-reading frame encoding 532 amino acids. Duck FMO3 gene shared a similar nine exon-eight intron structure with chicken and human. The duck FMO3 putative protein sequence showed high identity with that of chicken (82 %), and relative low identity with those of mammals (61-66 %). We also found that the duck FMO3 gene was dramatically expressed in liver, lung, and kidney compared to that in other tissues in the ducks, indicating the possible roles the FMO3 gene could play in the three tissues. By bidirectional sequencing, we also found one nonsense mutation, 5 nonsynonymous, and 21 synonymous mutations in the coding region of the FMO3 gene in 11 duck breeds and some of them were predicted to be potentially associated with the activities of FMO3 protein. PMID- 23625205 TI - ADAM17 mediates hypoxia-induced drug resistance in hepatocellular carcinoma cells through activation of EGFR/PI3K/Akt pathway. AB - A disintegrin and metalloproteinase-17 (ADAM17) is a member of the metalloproteinase superfamily and involved in the cleavage of ectodomain of many transmembrane proteins. ADAM17 is overexpressed in a variety of human tumors, which is associated with tumor development and progression. In the present study, we sought to investigate the expression and function of ADAM17 in hypoxia-treated hepatocellular carcinoma (HCC) cells. Western blot analysis was used to measure the expression of ADAM17 in HCC cell lines (Hep3B and HepG2 cells). Annexin V/PI double staining was performed to analyze the effects of ADAM17 on hypoxia mediated cisplatin resistance. ADAM17 expression was upregulated by hypoxia treatment in HCC cells at both mRNA and protein levels. Overexpression of ADAM17 reduced cisplatin-induced apoptosis in HCC cells, accompanies by less cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP). Forced expression of ADAM17 enhanced the phosphorylation of epidermal growth factor receptor (EGFR) and Akt without affecting the expression of total EGFR and Akt. Pretreatment with EGFR inhibitor AG1478 or phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 rescued ADAM17-mediated cisplatin resistance of HCC cells. ADAM17 silencing attenuated hypoxia-induced cisplatin resistance and enhanced the accumulation of cleaved caspase-3 and PARP. Western blot analysis showed that overexpression of hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor, upregulated the expression of ADAM17 and HIF-1alpha silencing downregulated the expression of ADAM17 in hypoxia-treated HCC cells, indicating the regulation of ADAM17 by HIF 1alpha. Taken together, our results indicated that ADAM17 is upregulated by hypoxia and contributes to hypoxia-induced cisplatin resistance via EGFR/PI3K/Akt pathway. PMID- 23625206 TI - Effect of estrogen and tamoxifen on the expression pattern of AP-1 factors in MCF 7 cells: role of c-Jun, c-Fos, and Fra-1 in cell cycle regulation. AB - The activated transcription factor ERalpha plays an important role in the breast development and progression of cancer. In a non-classical pathway ER interacts with other transcription factors AP-1, NFkB, SP1, etc. AP-1 transcription factors control rapid responses of mammalian cells to stimuli that impact proliferation, differentiation, and transformation. AP-1 factors are leucine zipper proteins belonging to members of the Jun family (c-Jun, JunB, and JunD) and Fos family (c Fos, FosB, Fra-1, and Fra-2) proteins. Although AP-1 factors are well characterized, not much is known about the expression pattern of the AP-1 factors in breast cancer cells. Hence to determine which AP-1 factors are expressed and regulated by estrogen, we used human breast cancer MCF-7 cells as in vitro model system. The MCF-7 cells were treated with or without estradiol-17beta (E2) or antiestrogen tamoxifen (TMX) and the cell proliferation and viability was assessed by MTT assay. The expression of different AP-1 factors was analyzed by semi-quantitative RT-PCR. The cells treated with E2 found to increase the cell proliferation by more than 35 % and TMX an antiestrogen decreased by 29 % compared to control. The E2 found to induce the expression of c-Jun, Fra-1, and c Fos, while TMX decreased the expression. In addition TMX also decreased the mRNA levels of Jun-D and Fra-2. These results suggest that the AP-1 factors c-Jun, c Fos, and Fra-1 may be involved in the proliferation and transformation of MCF-7 cells. E2 also found to induce cyclin D1 and cyclin E1 mRNA transcripts of cell cycle regulators while TMX significantly decreased compared to control. Further E2 induced the anti-apoptotic Bcl-2 and TMX decreased mRNA transcripts. The data presented here support the E2-ERalpha-mediated MCF-7 cell proliferation and confirms the role of AP-1 factors in cell cycle regulation. PMID- 23625207 TI - The role of home blood pressure telemonitoring in managing hypertensive populations. AB - Hypertension is a common chronic disease affecting nearly one-third of the United States population. Many interventions have been designed to help patients manage their hypertension. With the evolving climate of healthcare, rapidly developing technology, and emphasis on delivering patient-centered care, home-based blood pressure telemonitoring is a promising tool to help patients achieve optimal blood pressure (BP) control. Home-based blood pressure telemonitoring is associated with reductions in blood pressure values and increased patient satisfaction. However, additional research is needed to understand cost effectiveness and long-term clinical outcomes of home-based BP monitoring. We review key interventional trials involving home based BP monitoring, with special emphasis placed on studies involving additionally behavioral modification and/or medication management. Furthermore, we discuss the role of home-based blood pressure telemonitoring within the context of the patient-centered medical home and the evolving role of technology. PMID- 23625209 TI - EHRA practical guide on the use of new oral anticoagulants in patients with non valvular atrial fibrillation: executive summary. AB - New oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with non-valvular atrial fibrillation (AF). Both physicians and patients will have to learn how to use these drugs effectively and safely in specific clinical situations. This text is an executive summary of a practical guide that the European Heart Rhythm Association (EHRA) has assembled to help physicians in the use of the different NOACs. The full text is being published in EP Europace. Practical answers have been formulated for 15 concrete clinical scenarios: (i) practical start-up and follow-up scheme for patients on NOACs; (ii) how to measure the anticoagulant effect of NOACs; (iii) drug-drug interactions and pharmacokinetics of NOACs; (iv) switching between anticoagulant regimens; (v) ensuring compliance of NOAC intake; (vi) how to deal with dosing errors; (vii) patients with chronic kidney disease; (viii) what to do if there is a (suspected) overdose without bleeding, or a clotting test is indicating a risk of bleeding?; (ix) management of bleeding complications; (x) patients undergoing a planned surgical intervention or ablation; (xi) patients undergoing an urgent surgical intervention; (xii) patients with AF and coronary artery disease; (xiii) cardioversion in a NOAC-treated patient; (xiv) patients presenting with acute stroke while on NOACs; (xv) NOACs vs. VKAs in AF patients with a malignancy. Since new information is becoming available at a rapid pace, an EHRA web site with the latest updated information accompanies the guide (www.NOACforAF.eu). It also contains links to the ESC AF Guidelines, a key message pocket booklet, print-ready files for a proposed universal NOAC anticoagulation card, and feedback possibilities. PMID- 23625210 TI - Sequential coronary angiograms unveil the progression of an acquired coronary aneurysm. PMID- 23625211 TI - Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II. AB - In part II of this review, we describe the epidemiology and clinical consequences of vascular disease in patients with diabetes, and discuss the efficacy of risk factor modification and antiplatelet treatment. Specifically, evidence-based cardiovascular therapies are discussed through novel clinical insights on management of hyperglycaemia, hypertension, dyslipidaemia as well as platelet dysfunction. Recent trends in the incidence and outcomes of vascular disease in diabetes suggest that timely and effective implementation of therapies is making a favourable impact. PMID- 23625213 TI - The unique metabolism of SAR11 aquatic bacteria. AB - The deeply branching clade of abundant, globally distributed aquatic alpha Proteobacteria known as "SAR11", are adapted to nutrient-poor environments such as the surface waters of the open ocean. Unknown prior to 1990, uncultured until 2002, members of the SAR11 clade can now be cultured in artificial, defined media to densities three orders of magnitude higher than in unamended natural media. Cultivation in natural and defined media has confirmed genomic and metagenomic predictions such as an inability to reduce sulfate to sulfide, a requirement for pyruvate, an ability to oxidize a wide variety of methylated and one-carbon compounds for energy, and an unusual form of conditional glycine auxotrophy. Here we describe the metabolism of the SAR11 type strain Candidatus "Pelagibacter ubique" str. HTCC1062, as revealed by genome-assisted studies of laboratory cultures. We also describe the discovery of SAR11 and field studies that have been done on natural populations. PMID- 23625214 TI - The alpha-barrel tip region of Escherichia coli TolC homologs of Vibrio vulnificus interacts with the MacA protein to form the functional macrolide specific efflux pump MacAB-TolC. AB - TolC and its homologous family of proteins are outer membrane factors that are essential for exporting small molecules and toxins across the outer membrane in Gram-negative bacteria. Two open reading frames in the Vibrio vulnificus genome that encode proteins homologous to Escherichia coli TolC, designated TolCV1 and TolCV2, have 51.3% and 29.6% amino acid identity to TolC, respectively. In this study, we show that TolCV1 and TolCV2 functionally and physically interacted with the membrane fusion protein, MacA, a component of the macrolide-specific MacAB TolC pump of E. coli. We further show that the conserved residues located at the aperture tip region of the alpha-hairpin of TolCV1 and TolCV2 played an essential role in the formation of the functional MacAB-TolC pump using site-directed mutational analyses. Our findings suggest that these outer membrane factors have conserved tip-to-tip interaction with the MacA membrane fusion protein for action of the drug efflux pump in Gram-negative bacteria. PMID- 23625215 TI - Prevalence of amino acid changes in the yvqF, vraSR, graSR, and tcaRAB genes from vancomycin intermediate resistant Staphylococcus aureus. AB - Vancomycin intermediate Staphylococcus aureus (VISA) strains are increasingly prevalent in the hospital setting, and are of major concern in the treatment of methicillin-resistant S. aureus infections. Multiple mutations in vancomycin susceptible S. aureus (VSSA) strains likely led to the emergence of VISA, and point mutations in the agr, orf1, yvqF, vraSR, graSR, and tcaRAB genes of VISA strains have been shown to contribute to glycopeptide resistance. Therefore, we investigated point mutations in these genes from 87 VISA and 27 VSSA clinical strains isolated from Korean hospitals. All strains were assigned an agr type (I, II, or III) on the basis of multiplex PCR, with the majority of VISA strains belonging to agr groups I and II. Sequencing revealed amino acid changes in vraS from VISA strains which were not present in the VSSA strains. The E59D substitution in the vraR gene occurred in 36.3% of VSSA/agrI and 92.7% of VISA/agrI strains, suggesting that this mutation associated with emergence of VISA/agrI strains. VISA strains were classified into 31 mutation patterns according to mutations in the yvqF, vraSR, graSR, and tcaRAB genes. In addition, the mutation patterns were correlated with agr and sequence type (ST). The most prevalent pattern included agr type I (ST 72) strains with E59D (vraR), L26F and T224I (graS), D148Q (graR), and L218P, R283H and G312D (tcaA) amino acid substitutions. The minimum inhibitory concentration (MIC) range of mutation pattern 5 toward oxacillin and imipenem was much lower than that of patterns 6 and 24. These results improve our understanding of emergence of VISA strains. PMID- 23625216 TI - Construction of a Streptomyces lydicus A01 transformant with a chit42 gene from Trichoderma harzianum P1 and evaluation of its biocontrol activity against Botrytis cinerea. AB - Streptomyces lydicus A01 and Trichoderma harzianum P1 are potential biocontrol agents of fungal diseases in plants. S. lydicus A01 produces natamycin to bind the ergosterol of the fungal cell membrane and inhibits the growth of Botrytis cinerea. T. harzianum P1, on the other hand, features high chitinase activity and decomposes the chitin in the cell wall of B. cinerea. To obtain the synergistic biocontrol effects of chitinase and natamycin on Botrytis cinerea, this study transformed the chit42 gene from T. harzianum P1 to S. lydicus A01. The conjugal transformant (CT) of S. lydicus A01 with the chit42 gene was detected using polymerase chain reaction (PCR). Associated chitinase activity and natamycin production were examined using the 3, 5-dinitrosalicylic acid (DNS) method and ultraviolet spectrophotometry, respectively. The S. lydicus A01-chit42 CT showed substantially higher chitinase activity and natamycin production than its wild type strain (WT). Consequently, the biocontrol effects of S. lydicus A01-chit42 CT on B. cinerea, including inhibition to spore germination and mycelial growth, were highly improved compared with those of the WT. Our research indicates that the biocontrol effect of Streptomyces can be highly improved by transforming the exogenous resistance gene, i.e. chit42 from Trichoderma, which not only enhances the production of antibiotics, but also provides a supplementary function by degrading the cell walls of the pathogens. PMID- 23625217 TI - Cloning, annotation and expression analysis of mycoparasitism-related genes in Trichoderma harzianum 88. AB - Trichoderma harzianum 88, a filamentous soil fungus, is an effective biocontrol agent against several plant pathogens. High-throughput sequencing was used here to study the mycoparasitism mechanisms of T. harzianum 88. Plate confrontation tests of T. harzianum 88 against plant pathogens were conducted, and a cDNA library was constructed from T. harzianum 88 mycelia in the presence of plant pathogen cell walls. Randomly selected transcripts from the cDNA library were compared with eukaryotic plant and fungal genomes. Of the 1,386 transcripts sequenced, the most abundant Gene Ontology (GO) classification group was "physiological process". Differential expression of 19 genes was confirmed by real-time RT-PCR at different mycoparasitism stages against plant pathogens. Gene expression analysis revealed the transcription of various genes involved in mycoparasitism of T. harzianum 88. Our study provides helpful insights into the mechanisms of T. harzianum 88-plant pathogen interactions. PMID- 23625218 TI - Lactobacillus salivarius strain FDB89 induced longevity in Caenorhabditis elegans by dietary restriction. AB - In this study, we utilized the nematode Caenorhabditis elegans to assess potential life-expanding effect of Lactobacillus salivarius strain FDB89 (FDB89) isolated from feces of centenarians in Bama County (Guangxi, China). This study showed that feeding FDB89 extended the mean life span in C. elegans by up to 11.9% compared to that of control nematodes. The reduced reproductive capacities, pharyngeal pumping rate, growth, and increased superoxide dismutase (SOD) activity and XTT reduction capacity were also observed in FDB89 feeding worms. To probe the anti-aging mechanism further, we incorporated a food gradient feeding assay and assayed the life span of eat-2 mutant. The results demonstrated that the maximal life span of C. elegans fed on FDB89 was achieved at the concentration of 1.0 mg bacterial cells/plate, which was 10-fold greater than that of C. elegans fed on E. coli OP50 (0.1 mg bacterial cells/plate). However, feeding FDB89 could not further extend the life span of eat-2 mutant. These results indicated that FDB89 modulated the longevity of C. elegans in a dietary restriction-dependent manner and expanded the understanding of anti-aging effect of probiotics. PMID- 23625219 TI - Biochemical characterization of chitinase 2 expressed during the autolytic phase of the inky cap, Coprinellus congregatus. AB - Fungal cell walls consist of various glucans and chitin. The inky cap, Coprinellus congregatus, produces mushrooms at 25 degrees C in a regime of 15 h light/9 h dark, and then the mushroom is autolyzed rapidly to generate black liquid droplets in which no cell walls are detected by microscopy. Chitinase cDNA from the mature mushroom tissues of C. congregatus, which consisted of 1,622 nucleotides (chi2), was successfully cloned using the rapid amplification of cDNA ends polymerase chain reaction technique. The deduced 498 amino acid sequence of Chi2 had a conserved catalytic domain as in other fungal chitinase family 18 enzymes. The Chi2 enzyme was purified from the Pichia pastoris expression system, and its estimated molecular weight was 68 kDa. The optimum pH and temperature of Chi2 was pH 4.0 and 35 degrees C, respectively when 4-nitrophenyl N,N'-diacetyl beta-D-chitobioside was used as the substrate. The K m value and V max for the substrate A, 4-nitrophenyl N,N'-diacetyl-beta-D-chitobioside, was 0.175 mM and 0.16 OD min(-1)unit(-1), respectively. PMID- 23625220 TI - Pneumolysin-mediated expression of beta-defensin 2 is coordinated by p38 MAP kinase-MKP1 in human airway cells. AB - Antimicrobial peptides act as important innate immune defense mediators against invading microbes such as Streptococcus pneumoniae. Among a number of antimicrobial peptides, beta-defensin 2 (BD2) has strong antimicrobial activity against S. pneumoniae. However, little is known about the molecular signaling mechanisms leading to the BD2 expression. Here, we report that BD2 is strongly induced by S. pneumoniae in human airway cells including human middle-ear cells. Among diverse pneumococcal virulence factors, pneumolysin is required for inducing BD2 whose expression is under the control of p38 mitogen-activated protein kinase (MAPK). Pneumolysin also selectively regulates the expression of MAPK phosphatase 1 (MKP1), which inhibits the p38 signaling pathway, thereby leading to upregulation of BD2 to mount an effective defense against S. pneumoniae infection. These results provide novel insights into the molecular mechanisms underlying the coordinative regulation of BD2 expression via p38-MKP1 in the pathogenesis of airway infectious diseases. PMID- 23625221 TI - The intracellular mechanism of action on Escherichia coli of BF2-A/C, two analogues of the antimicrobial peptide Buforin 2. AB - In the present study, the antimicrobial peptides BF2-A and BF2-C, two analogues of Buforin 2, were chemically synthesized and the activities were assayed. To elucidate the bactericidal mechanism of BF2-A/C and their different antimicrobial activities, the influence of peptides to E. coli cell membrane and targets of intracellular action were researched. Obviously, BF2-A and BF2-C did not induce the influx of PI into the E. coli cells, indicating nonmemebrane permeabilizing killing action. The FITC-labeled BF2-A/C could penetrate the E. coli cell membrane and BF2-C penetrated the cells more efficiently. Furthermore, BF2-A/C could bind to DNA and RNA respectively, and the affinity of BF2-C to DNA was powerful at least over 4 times than that of BF2-A. The present results implied that BF2-A and BF2-C inhibited the cellular functions by binding to DNA and RNA of cells after penetrating the cell membranes, resulting in the rapid cell death. The structure-activity relationship analysis of BF2-A/C revealed that the cell penetrating efficiency and the affinity ability to DNA were critical factors for determining the antimicrobial potency of both peptides. The more efficient cell penetrating and stronger affinity to DNA caused that BF2-C displayed more excellent antimicrobial activity and rapid killing kinetics than BF2-A. PMID- 23625222 TI - An aqueous extract of Yunnan Baiyao inhibits the quorum-sensing-related virulence of Pseudomonas aeruginosa. AB - Yunnan Baiyao is a famous Chinese medicine that has long been directly applied to wounds to reduce bleeding, pain, and swelling without causing infection. However, little is known about its ability to prevent infection. The present study aimed to assess in vitro the anti-virulence activity of an aqueous extract of Yunnan Baiyao (YBX) using Pseudomonas aeruginosa as a pathogenic model. We found that a sub-MIC (2.5 mg/ml) of YBX can efficiently interfere with the quorum-sensing (QS) signaling circuit. Real-time polymerase chain reaction analysis showed that a sub MIC of YBX down-regulated the transcriptions of lasR, lasI, rhlR, and rhlI, which resulted in global attenuation of QS-regulated virulence activities, such as biofilm formation, and secretion of LasA protease, LasB elastase and pyocyanin. Further, YBX reduced the motility of P. aeruginosa related to QS, and impaired the formation of biofilms. These results suggest that YBX may possess global inhibitory activity against the virulence of P. aeruginosa and that YBX may also exhibit antimicrobial activity in vivo. The present study suggests that Yunnan Baiyao represents a potential source for isolating novel, safe, and efficacious antimicrobial agents. PMID- 23625223 TI - Low-scale expression and purification of an active putative iduronate 2-sulfate sulfatase-Like enzyme from Escherichia coli K12. AB - The sulfatase family involves a group of enzymes with a large degree of similarity. Until now, sixteen human sulfatases have been identified, most of them found in lysosomes. Human deficiency of sulfatases generates various genetic disorders characterized by abnormal accumulation of sulfated intermediate compounds. Mucopolysaccharidosis type II is characterized by the deficiency of iduronate 2-sulfate sulfatase (IDS), causing the lysosomal accumulation of heparan and dermatan sulfates. Currently, there are several cases of genetic diseases treated with enzyme replacement therapy, which have generated a great interest in the development of systems for recombinant protein expression. In this work we expressed the human recombinant IDS-Like enzyme (hrIDS-Like) in Escherichia coli DH5alpha. The enzyme concentration revealed by ELISA varied from 78.13 to 94.35 ng/ml and the specific activity varied from 34.20 to 25.97 nmol/h/mg. Western blotting done after affinity chromatography purification showed a single band of approximately 40 kDa, which was recognized by an IgY polyclonal antibody that was developed against the specific peptide of the native protein. Our 100 ml-shake-flask assays allowed us to improve the enzyme activity seven fold, compared to the E. coli JM109/pUC13-hrIDS-Like system. Additionally, the results obtained in the present study were equal to those obtained with the Pichia pastoris GS1115/pPIC-9-hrIDS-Like system (3 L bioreactor scale). The system used in this work (E. coli DH5alpha/pGEX-3X-hrIDS-Like) emerges as a strategy for improving protein expression and purification, aimed at recombinant protein chemical characterization, future laboratory assays for enzyme replacement therapy, and as new evidence of active putative sulfatase production in E. coli. PMID- 23625224 TI - Expression, purification, and biochemical properties of arginase from Bacillus subtilis 168. AB - The arginine-degrading and ornithine-producing enzymes arginase has been used to treat arginine-dependent cancers. This study was carried out to obtain the microbial arginase from Bacillus subtilis, one of major microorganisms found in fermented foods such as Cheonggukjang. The gene encoding arginase was isolated from B. subtilis 168 and cloned into E. coli expression plasmid pET32a. The enzyme activity was detected in the supernatant of the transformed and IPTG induced cell-extract. Arginase was purified for homogeneity from the supernatant by affinity chromatography. The specific activity of the purified arginase was 150 U/mg protein. SDS-PAGE analysis revealed the molecular size to be 49 kDa (Trix.Tag, 6*His.Tag added size). The optimum pH and temperature of the purified enzyme with arginine as the substrate were pH 8.4 and 45 degrees C, respectively. The Km and Vmax values of arginine for the enzyme were 4.6 mM and 133.0 mM/min/mg protein respectively. These findings can contribute in the development of functional fermented foods such as Cheonggukjang with an enhanced level of ornithine and pharmaceutical products by providing the key enzyme in arginine degradation and ornithine-production. PMID- 23625225 TI - A real-time qPCR assay to quantify Ophiocordyceps sinensis biomass in Thitarodes larvae. AB - Ophiocordyceps sinensis, an entomogenous fungus parasitic in the larvae of moths (Lepidoptera), is one of the most valuable medicinal fungi, and it only distributed naturally on the Tibetan Plateau. The parasitical amount of O. sinensis in various tissues of the host Thitarodes larvae has an important role in study the occurrence and developmental mechanisms of O. sinensis, but there no an effective method to detect the fungal anamorph. A real-time quantitative PCR (qPCR) system, including a pair of species-specific ITS primers and its related program, was developed for O. sinensis assay with high reliability and efficiency. A calibration curve was established and exhibited a very good linear correlation between the fungal biomass and the C T values (R (2)=0.999419) by the qPCR system. Based on this method, O. sinensis was detected rapidly in four tissues of its host caterpillars, and the results were shown as following: the maximum content of O. sinensis parasitized in the fat-body, and next came body wall; both of them were much larger than that observed in the haemolymph and intestinal-wall. Taken together, these results show that qPCR assays may become useful tools for study on developmental mechanism of O. sinensis. PMID- 23625226 TI - Secretion of truncated recombinant rabies virus glycoprotein with preserved antigenic properties using a co-expression system in Hansenula polymorpha. AB - Rabies virus infection remains a serious public health threat in the developing world, where cost-concerns make wide-scale public health interventions impractical. The development of novel and inexpensive ELISA diagnostic antigens is critical in early detection and prevention of complications. The transmembrane glycoprotein (G) of rabies virus (RV) contains an external domain capable of inducing the synthesis of anti-rabies, virus-neutralizing antibodies, in infected or immunized hosts. In our study, the external G domain was synthesized and fused in-frame with a polyhistidine-tag coding sequence present in the expression plasmid. Soluble truncated recombinant G was secreted in Hansenula polymorpha (H. polymorpha) using H. polymorpha-derived calnexin (HpCNE1) overproduction and found to be correctly N-glycosylated. The truncated recombinant G was purified from cell culture supernatant by Ni-agarose affinity chromatography and when compared with the full-length glycoprotein, found to be similarly immunogenic in vaccinated rabbits. These results subsequently led us to explore the potential of truncated recombinant G as a diagnostic antigen in ELISA. Our results show that the truncated recombinant G can detect antibodies directed to both whole virion and native glycoprotein. More sophisticated applications of truncated recombinant G would profit from the correctly N-glycosylated and soluble monomer. PMID- 23625227 TI - Allelic MHC class I chain related B (MICB) molecules affect the binding to the human cytomegalovirus (HCMV) unique long 16 (UL16) protein: implications for immune surveillance. AB - Unique long 16 (UL16) is a viral glycoprotein produced in a host cell infected with human cytomegalovirus (HCMV). It down regulates surface expression of MICB, one of the NKG2D ligands, by forming stable intracellular complexes and retained in the endoplasmic reticulum. Down expression of MICB renders cells less susceptible to NK cell lysis via the NKG2D receptor. Diverse UL16 sequences were identified from different strains of HCMV. MICB is known to be polymorphic. It is not known whether these polymorphisms affect the interactions between these molecules leading to alteration of the immune surveillance of HCMV. The soluble Fc fusion variant UL16 proteins from four laboratory and clinical isolates (AD169, Toledo, PH, and TR) were produced. Four allelic MICB alleles (008, 003, 004, and 00502) were cloned and stable cell lines expressing these MICB alleles were produced. The binding activities of variant UL16 to allelic MICB proteins were determined by flow cytometry. The variants of UL16 proteins did not affect the binding activities to allelic MICB proteins. However, diverse MICB alleles differentially bound UL16. We found that MICB*008 which contains methionine and asparagine at the amino acid positions 98 and 113, respectively, in the alpha 2 domain showed decreased binding activities to UL16 when compared to MICB*003, 004, and MICB*00502 containing isoleucine and aspartic acid, respectively. This finding may imply that MICB*008 is a protective allele and involved in the immune surveillance of HCMV infected patients. PMID- 23625228 TI - Phenotypic characteristics of natural killer cells in acute hepatitis. AB - Natural killer (NK) cells are the principal effector cell population in innate immune defense against many types of infections. These cells are enriched in the liver, where they comprise approximately 40% to 60% of the intrahepatic lymphocyte pool compared to the peripheral blood compartment. In chronic HBV and HCV infection, NK cells were reported to be partially dysfunctional due to impaired IFN-Gamma secretion. Few studies have examined phenotypic features of NK cells in acute hepatitis. We identified NK (CD56+CD3-) cell populations in patients with acute hepatitis by examining the expressions of phenotypic NK cell markers (CD16, NKG2A, and NKG2D). Peripheral blood mononuclear cells were isolated from patients with acute hepatitis A (7) and patients with non-viral acute toxic hepatitis (6) during the symptomatic and convalescent phases. Expressions of NK (CD56+CD3-) cell markers, CD16, NKG2A, and NKG2D, were measured by flow cytometry. Symptomatic acute hepatitis including non-viral hepatitis and HAV infection showed significant increases of NKG2A expression compared to healthy controls. Interestingly, there was a direct correlation between the proportion of NK cell populations and liver function parameters (AST, ALT) in HAV infection. The strong correlation was also observed between the expression of NKG2A+NK cells and ALT, which suggests that most of NK cells in severe phase of disease express high level of NKG2A on their surface. In addition, decreased number of NK cells (CD56+CD3-) in symptomatic phase began to increase in the convalescent phase of acute hepatitis A. However, the expression of NKG2A tended to be reduced, which indicates that NKG2A, the inhibitory receptor on NK cells, can be a severity parameter in acute hepatitis. PMID- 23625229 TI - Development and evaluation of multiplex real-time RT-PCR assays for seasonal, pandemic A/H1pdm09 and avian A/H5 influenza viruses detection. AB - Since the pandemic influenza A (H1N1) 2009 ((H1N1)pdm09) virus spread all over the world, the (H1N1)pdm09 virus has been circulating with seasonal influenza viruses. We developed rapid and sensitive one-step multiplex real-time RT-PCR assays (rRT-PCR) for simultaneous detection of influenza viruses currently circulating in humans, and the avian A/H5 virus. The detection limit of each assay was 4.8 to 1 copies per reaction and no cross-reactivity with other major respiratory pathogens was found. Analytical positive predictive value (PPV), negative predictive value (NPV) sensitivity and specificity were 100%, 94.1%, 93.7% and 100%, respectively. Clinical evaluation revealed that 1,976 (16.5%) of 11,963 throat swabs from patients with respiratory symptoms were confirmed as 1,651 (83.6%) A/H1pdm09, 308 (15.6%) A/H3 and 17 (0.8%) B virus during the 2010 2011 influenza season. Collectively, the multiplex rRT-PCR assays described here provide a practical tool for reliable implementation of influenza surveillance and diagnosis. PMID- 23625230 TI - Rhodanobacter umsongensis sp. nov., isolated from a Korean ginseng field. AB - A bacterial isolate designated GR24-2(T) was isolated from Korean soil used for cultivating ginseng (Panax ginseng C. A. Meyer). The strain was aerobic, Gram negative, motile, and rod-shaped. It grew optimally at 28-30 degrees C, pH 7.0, and in a range of 0-1% NaCl. Phylogenetically, the strain clustered with members of the genus Rhodanobacter. The strain exhibited the highest sequence similarities (>98%) with R. panaciterrae LnR5-47(T) (98.4%), R. soli DCY45(T) (98.2%), and R. ginsengisoli GR17-7(T) (98.0%). However, it also showed high sequence similarities (>97%) with some other Rhodanobacter and Dyella species. The strain contained Q-8 as the predominant respiratory quinone. The major fatty acids (greater than 10% of the total fatty acids) were iso-C17:1 omega9c (24.5%), iso-C16:0 (22.8%), anteiso-C15:0 (10.5%), and iso-C15:0 (10.1%). Its major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, and an unknown aminophospholipid. The DNA G+C content of strain GR24-2(T) was 65.6 mol%. The strain showed less than 70% DNA relatedness values between the closely related Rhodanobacter and Dyella species. The phylogeny, phenotype, DNA-DNA hybridization, and chemotaxonomic data generated in this study reveal that the isolate is a novel species of the genus Rhodanobacter. The name proposed for this strain is Rhodanobacter umsongensis sp. nov. (type strain GR24-2(T) =KACC 12917(T) =DSM 21300(T)). PMID- 23625231 TI - Paraherbaspirillum soli gen. nov., sp. nov. isolated from soil. AB - A bacterial strain, designated JS5-2(T), was isolated from soil collected from Jeju Island, Republic of Korea. The cells of the strain were Gram-negative, nonspore forming, catalase- and oxidase-positive, aerobic, nonmotile and rod shaped. Strain JS5-2(T) exhibited 96.2-97.2, 95.1-96.3, and 95.4-95.8% 16S rRNA gene sequence similarities to the genera Herbaspirillum, Oxalicibacterium, and Herminiimonas, respectively. The highest sequence similarities were with Herbaspirillum autotrophicum IAM 14942(T) (97.2%) and Herbaspirillum frisingense GSF30(T) (97.1%). The major fatty acids of strain JS5-2(T) were C16:0 (35.0%), C17:0 cyclo (19.9%), C18:1 omega7c (11.4%), and summed feature 3 (C16:1 omega7c/C15:0 iso 2-OH) (15.2%), and the major polar lipids of strain JS5-2(T) were diphosphatidylglycerol and an unknown aminophospholipid. The strain contained Q-8 as the predominant ubiquinone. DNA-DNA relatedness values between strain JS5-2(T) and H. autotrophicum IAM 14942(T), and H. frisingense GSF30(T) were 32 and 35%, respectively. The DNA G+C content of strain JS5-2(T) was 59.0 mol%. On the basis of phenotypic, genotypic, and physiological evidence, strain JS5-2(T) represents a novel species of a new genus, for which the name Paraherbaspirillum soli gen. nov., sp. nov. is proposed. The type strain JS5-2(T) (=KACC 12633(T) =NBRC 106496(T)) is proposed. PMID- 23625232 TI - Rummeliibacillus suwonensis sp. nov., isolated from soil collected in a mountain area of South Korea. AB - A Gram-positive, facultatively aerobic, rod-shaped, non-motile, terminal spore forming bacterium, designated strain G20(T), was isolated from soil collected in a mountain region of Suwon, South Korea. On the basis of 16S rRNA gene sequence similarity, this strain was shown to be related to Rummeliibacillus pycnus NBRC 101231(T) (97.4%) and Rummeliibacillus stabekisii KSC-SF6g(T) (95.7%). DNA-DNA hybridization studies showed 42% and 50% similarity of strain G20(T) with R. pycnus NBRC 101231(T) and R. stabekisii KSC-SF6g(T), respectively. The DNA G content of G20(T) was 37.8 mol%, the major cellular fatty acids were iso-C15:0 and anteiso-C15:0, and the predominant menaquinones were MK-7 and MK-8. On the basis of phylogenetic, chemotaxonomic, and phenotypic characteristics, we propose this strain to be a novel species and the third member of genus Rummeliibacillus. We suggest the name Rummeliibacillus suwonensis sp. nov. The type strain is G20(T) (KACC 17316(T) =KEMB 9005-003(T) =JCM 19065(T)). PMID- 23625233 TI - Retraction. Identification and characterization of a novel antibacterial peptide, avian beta-defensin 2 from ducks: Journal of Microbiology (2009, 47: 610-8). PMID- 23625234 TI - Government defends its dog control proposals. PMID- 23625235 TI - Ups and downs in zoonotic disease trends in Europe. PMID- 23625237 TI - First case of Schmallenberg disease confirmed in Scotland. PMID- 23625238 TI - World Veterinary Day highlights the value of vaccination. PMID- 23625239 TI - International Sheep Veterinary Association recognises lifetimes of service. PMID- 23625240 TI - Raising awareness of the realities of veterinary practice. PMID- 23625242 TI - AHVLA workshop reviews validity and credibility of scientific models. PMID- 23625243 TI - Standardising approaches to nutrition and pain in companion animals. PMID- 23625244 TI - Cardiac disease in dogs and cats: is breed screening the answer? PMID- 23625246 TI - The art and the science of equine surgery. PMID- 23625247 TI - Bovine viral diarrhoea virus: biology, diagnosis and control. PMID- 23625248 TI - Osteochondrosis in foals. PMID- 23625249 TI - Transmission of classical scrapie via goat milk. PMID- 23625250 TI - Osteochondrosis in foals. PMID- 23625252 TI - Survey on analgesia in small animals. PMID- 23625251 TI - Salmonella septicaemia in a smooth snake. PMID- 23625253 TI - Tetrapisispora taiwanensis sp. nov. and Tetrapisispora pingtungensis sp. nov., two ascosporogenous yeast species isolated from soil. AB - Two novel yeast species, Tetrapisispora taiwanensis sp. nov. and Tetrapisispora pingtungensis sp. nov., belonging to the Saccharomycetaceae within the Saccharomycetales, are proposed to accommodate six strains isolated from samples of Taiwanese forest soil between 2005 and 2010. Sequence analysis of the internal transcribed spacer (ITS) and the D1/D2 domains of the large-subunit (LSU) rRNA gene revealed that the two species are phylogenetically closely related to species of the genus Tetrapisispora. Moreover, the assimilation spectrum of carbon and nitrogen sources and morphological characteristics are very similar to those of other Tetrapisispora species. The molecular, morphological and physiological characteristics described above indicate that these two species should be classified as members of the genus Tetrapisispora. The two species can be differentiated from each other and from other Tetrapisispora species based on their LSU D1/D2 rRNA gene and ITS sequences. Thus, the two species could be regarded as novel species of the genus Tetrapisispora, and the names Tetrapisispora taiwanensis sp. nov. (type strain SJ6S04(T) =CBS 10586(T) =NBRC 102652(T) =BCRC 23090(T)) and Tetrapisispora pingtungensis sp. nov. (type strain NC2S06(T) =CBS 12780(T) =BCRC 23409(T)) are proposed. The type strains of the two species were isolated from forest soil in Leinhuatsu Park, Nantou, in 2006 and from Hungchun, Pingtung, in 2009, respectively. PMID- 23625254 TI - Sugiyamaella xylanicola sp. nov., a xylan-degrading yeast species isolated from rotting wood. AB - Four strains of a novel yeast species were isolated from rotting-wood samples in an Atlantic rainforest site in the state of Minas Gerais, Brazil. These yeasts were obtained from enrichments using yeast nitrogen base (YNB)-d-xylose or YNB xylan media. The novel yeast species produces bacilliform ascospores typical of the genus Sugiyamaella, and its closest described relative in terms of sequence similarity is Candida (iter. nom. Sugiyamaella) marionensis. The yeast is able to grow in medium with xylan as sole carbon source and produces extracellular enzymes with xylanolytic activities. The novel species Sugiyamaella xylanicola sp. nov. is proposed to accommodate these isolates. The type strain is UFMG-CA 32.1(T) (=CBS 12683(T) =CBMAI 1467(T)). PMID- 23625255 TI - Gillisia marina sp. nov., from seashore sand, and emended description of the genus Gillisia. AB - A Gram-staining-negative, strictly aerobic, rod-shaped bacterium, designated CBA3202(T), was isolated from seashore sand on Jeju Island, Republic of Korea. Based on the 16S rRNA gene sequence analysis, strain CBA3202(T) was allocated to the genus Gillisia (family Flavobacteriaceae) and was most closely related to the type strain of Gillisia mitskevichiae (99.0 % 16S rRNA gene sequence similarity). Optimal growth occurred at 25 degrees C and with 3 % NaCl. The only isoprenoid quinone was menaquinone-6 (MK-6), the predominant fatty acids were C16 : 0, iso C15 : 1 G, iso-C16 : 0 and summed feature 3 (comprising C16 : 1omega6c and/or C16 : 1omega7c), and the DNA G+C content was 34.9 mol%. The polar lipids were phosphatidylethanolamine, two unidentified aminolipids and several unidentified polar lipids. Based on phylogenetic inference and phenotypic data, we conclude that strain CBA3202(T) represents a novel species of the genus Gillisia, for which the name Gillisia marina sp. nov. is proposed. The type strain is CBA3202(T) ( = KACC 16693(T) = KCTC 32030(T) = JCM 18402(T)). An emended description of the genus Gillisia is also provided. PMID- 23625256 TI - Paenibacillus taihuensis sp. nov., isolated from an eutrophic lake. AB - Two Gram-stain-negative, facultatively anaerobic and endospore-forming rod-shaped bacterial strains, THMBG22(T) and R24, were isolated from decomposing algal scum. Phylogenetic analysis of 16S rRNA gene sequences showed that the two strains were closely related to each other (99.7 % similarity) and that they were also closely related to Paenibacillus sacheonensis DSM 23054(T) (97-97.1 %) and Paenibacillus phyllosphaerae DSM 17399(T) (96.1-96.4 %). This affiliation was also supported by rpoB-based phylogenetic analyses. Growth was observed at 20-40 degrees C (optimum, 30-37 degrees C) and at pH 5.0-9.0 (optimum, pH 6.0-7.0). The cells contained MK-7 as the sole respiratory quinone and anteiso-C15 : 0 as the major cellular fatty acid. Their cellular polar lipids were composed of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine and 12 unidentified polar lipids. The diamino acid of their cell-wall peptidoglycan was meso-diaminopimelic acid. The DNA-DNA hybridization value between THMBG22(T) and R24 was 84 %, and DNA-DNA relatedness to the most closely related species with a validly published name (P. sacheonensis) was 35-37 %. These results supported the assignment of the new isolates to the genus Paenibacillus and also distinguished them from the previously described species of the genus Paenibacillus. Hence, it is proposed that strains THMBG22(T) and R24 represent a novel species of the genus Paenibacillus, with the name Paenibacillus taihuensis sp. nov. The type strain is THMBG22(T) ( = CGMCC 1.10966(T) = NBRC 108766(T)). PMID- 23625257 TI - Seleniivibrio woodruffii gen. nov., sp. nov., a selenate- and arsenate-respiring bacterium in the Deferribacteraceae. AB - A Gram-type-negative, obligately anaerobic, selenate-respiring bacterium, strain S4(T), was isolated from activated sludge of a wastewater treatment plant in New Jersey after enrichment with 10 mM selenate as the sole electron acceptor. In addition to its selenate-respiring capability, strain S4(T) also respired arsenate with acetate as carbon source and electron donor. Fermentative growth was not observed. The optimum growth temperature was 37 degrees C and optimum pH was pH 7. Phylogenetic analysis of the 16S rRNA gene sequence revealed that strain S4(T) is a novel member of the family Deferribacteraceae, with the type strain of Denitrovibrio acetiphilus as its closest cultivated relative, with 91.5 % sequence similarity. The cellular fatty acid profile was composed predominantly of straight-chain fatty acids C14 : 0, C15 : 0, C16 : 0, C17 : 0 and C18 : 0, which distinguishes this organism from its closest relatives. The DNA G+C content was 47.7 mol%. Together, these findings support the conclusion that strain S4(T) represents a novel genus and species, for which the name Seleniivibrio woodruffii gen. nov., sp. nov. is proposed. The type strain of Seleniivibrio woodruffii is S4(T) ( = DSM 24984(T) = ATCC BAA-2290(T)). PMID- 23625258 TI - Oceanobacillus chungangensis sp. nov., isolated from a sand dune. AB - A Gram-stain-positive, spore-forming, rod-shaped, motile, strictly aerobic bacterial strain, designated CAU 1051(T), was isolated from a sand dune and its taxonomic position was investigated using a polyphasic approach. Strain CAU 1051(T) grew optimally at pH 5.0 and 30 degrees C. NaCl was not required for growth but up to 10.0 % (w/v) NaCl was tolerated. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CAU 1051(T) formed a distinct lineage within the genus Oceanobacillus and was most closely related to Oceanobacillus profundus CL-MP28(T), Oceanobacillus caeni S-11(T), and Oceanobacillus picturae LMG 19492(T) (96.8 %, 95.6 % and 95.3 % similarity, respectively). DNA-DNA reassociation analysis showed that strain CAU 1051(T) displayed 28.2+/-0.7 % relatedness to O. profundus KCTC 13625(T). Strain CAU 1051(T) contained MK-7 as the only isoprenoid quinone and anteiso-C15 : 0 as the major fatty acid. The cell wall peptidoglycan of strain CAU 1051(T) contained meso-diaminopimelic acid. The polar lipids were composed of diphosphatidylglycerol, phosphatidylglycerol, six unidentified phospholipids, an unidentified glycolipid, and six unidentified polar lipids. The major whole-cell sugars were glucose and ribose. The DNA G+C content was 36.3 mol%. On the basis of phenotypic data and phylogenetic inference, strain CAU 1051(T) represents a novel species of the genus Oceanobacillus for which the name Oceanobacillus chungangensis sp. nov. is proposed. The type strain is CAU 1051(T) ( = KCTC 33035(T) = CCUG 63270(T)). PMID- 23625259 TI - Bacillus thermotolerans sp. nov., a thermophilic bacterium capable of reducing humus. AB - A novel thermotolerant bacterium, designated SgZ-8(T), was isolated from a compost sample. Cells were non-motile, endospore-forming, Gram-staining positive, oxidase-negative and catalase-positive. The isolate was able to grow at 20-65 degrees C (optimum 50 degrees C) and pH 6.0-9.0 (optimum 6.5-7.0), and tolerate up to 9.0 % NaCl (w/v) under aerobic conditions. Anaerobic growth occurred with anthraquinone-2,6-disulphonate (AQDS), fumarate and NO3(-) as electron acceptors. Phylogenetic analysis based on the16S rRNA and gyrB genes grouped strain SgZ-8(T) into the genus Bacillus, with the highest similarity to Bacillus badius JCM 12228(T) (96.2 % for 16S rRNA gene sequence and 83.5 % for gyrB gene sequence) among all recognized species in the genus Bacillus. The G+C content of the genomic DNA was 49.3 mol%. The major isoprenoid quinone was menaquinone 7 (MK-7) and the polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and an unidentified phospholipid. The major cellular fatty acid was iso-C16 : 0. On the basis of its phenotypic and phylogenetic properties, chemotaxonomic analysis and the results of physiological and biochemical tests, strain SgZ-8(T) ( = CCTCC AB 2012108(T) = KACC 16706(T)) was designated the type strain of a novel species of the genus Bacillus, for which the name Bacillus thermotolerans sp. nov. is proposed. PMID- 23625260 TI - Aminivibrio pyruvatiphilus gen. nov., sp. nov., an anaerobic, amino-acid degrading bacterium from soil of a Japanese rice field. AB - A novel anaerobic bacterium that could ferment amino acids and organic acids was isolated from an anaerobic, propionate-oxidizing enrichment culture originating from soil of a rice field in Japan. Cells of the isolate, designated strain 4F6E(T), were Gram-staining-negative, oxidase- and catalase-negative, non-spore forming, vibrio-shaped, motile rods (0.8*2.0-2.5 um) with two or three lateral flagella. Growth occurred at 20-42 degrees C (optimum at 37-40 degrees C), at pH 6.4-8.4 (optimum at pH 7.3) and at 0-1.5 % (w/v) NaCl (optimum at 0-0.5 %). Good growth occurred on glycine, serine, cysteine, pyruvate and citrate, whereas poor growth was observed on threonine, glutamine, L-malate, alpha-ketoglutarate, peptone and Casamino acids. In co-culture with the hydrogen-utilizing methanogen Methanobacterium formicicum JCM 10132(T), strain 4F6E(T) oxidized alanine, valine, leucine, isoleucine, methionine, aspartate, glutamate, histidine, asparagine and fumarate. Yeast extract was required for growth. The G+C content of genomic DNA was 61.9 mol%. A phylogenetic analysis based on comparison of the 16S rRNA gene sequence showed that the type strains of Fretibacterium fastidiosum, Aminobacterium colombiense and Aminobacterium mobile, members of the family Synergistaceae, were the closest relatives of strain 4F6E(T), with low sequence similarities (89.3, 89.5 and 86.2 %, respectively). Strain 4F6E(T) contained iso-C13 : 0 (24.43 %), iso-C15 : 0 (16.47 %) and C19 : 1omega11c/C19 : 1omega9c (16.32 %) as the major fatty acids, which differed from those of F. fastidiosum, Aminobacterium colombiense and Aminobacterium mobile. On the basis of phenotypic, chemotaxonomic and phylogenetic differences between strain 4F6E(T) and the type strains of F. fastidiosum and Aminobacterium species, we propose that strain 4F6E(T) represents a novel genus and species, Aminivibrio pyruvatiphilus gen. nov., sp. nov. The type strain of Aminivibrio pyruvatiphilus is strain 4F6E(T) ( = JCM 18417(T) = DSM 25964(T)). PMID- 23625261 TI - Janibacter cremeus sp. nov., an actinobacterium isolated from sea sediment. AB - A novel Gram-stain-positive actinobacterium, designated HR08-44(T), was isolated from a sea-sediment sample collected from the foreshore of Rishiri Island, Japan, and its taxonomic position was investigated by a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that strain HR08-44(T) was closely related to the members of the genus Janibacter, with pairwise sequence similarities of 97.3-98.8 %. Strain HR08-44(T) had peptidoglycan type A1gamma, with meso-diaminopimelic acid as the diagnostic diamino acid. The predominant menaquinone was MK-8(H4) and the major fatty acids were iso-C16 : 0, C17 : 1omega8c, C17 : 0 and C18 : 1omega9c. These data supported the affiliation of the novel strain to the genus Janibacter. Meanwhile, the results of DNA-DNA hybridization and physiological and biochemical tests indicated that strain HR08-44(T) can be distinguished from recognized species of the genus Janibacter. Therefore, strain HR08-44(T) represents a novel species of the genus Janibacter, for which the name Janibacter cremeus sp. nov. is proposed; the type strain is HR08-44(T) ( = NBRC 107693(T) = DSM 26154(T)). PMID- 23625262 TI - Vibrio hemicentroti sp. nov., an alginate lyase-producing bacterium, isolated from the gut microflora of sea urchin (Hemicentrotus pulcherrimus). AB - An alginate lyase-producing bacterium, designated AlyHP32(T), was isolated from the gut of sea urchin (Hemicentrotus pulcherrimus) obtained from the South Sea, Republic of Korea. Cells of strain AlyHP32(T) were Gram-reaction-negative and motile with a single polar flagellum. The strain grew with 1-6 % (w/v) NaCl (optimum 2-4 %) and at 4-30 degrees C (optimum 15-25 degrees C). Phylogenetic analysis based on sequences of the 16S rRNA gene and five housekeeping genes (atpA, pyrH, recA, rpoA and rpoD) revealed that strain AlyHP32(T) belonged to the genus Vibrio and formed a compact clade with the Vibrio splendidus group. However, DNA-DNA hybridization and fingerprints using the repetitive primers BOX and REP indicated that strain AlyHP32(T) was distinct from closely related species of the genus Vibrio. The major fatty acids were summed feature 3 (C16:1omega7c and/or C16:1omega6c) and C16:0. The DNA G+C content was 44.1 mol%. The predominant quinone was ubiquinone Q-8. Based on genotypic, phenotypic and DNA-DNA hybridization analysis, strain AlyHP32(T) represents a novel species of the genus Vibrio; the name Vibrio hemicentroti sp. nov. (type strain AlyHP32(T) = KCTC 32085(T) = DSM 26178(T)) is proposed for this novel taxon. PMID- 23625263 TI - Fabibacter pacificus sp. nov., a moderately halophilic bacterium isolated from seawater. AB - A Gram-stain-negative, aerobic, moderately halophilic bacterium, strain DY53(T), was isolated from a deep-seawater sample collected from the eastern Pacific Ocean. This isolate grew in the presence of 0.5-10.0 % (w/v) NaCl, at pH 6.5-8.5 and at 15-40 degrees C. The optimum NaCl concentration for growth of DY53(T) was 2 % (w/v) at 35 degrees C. Chemotaxonomic analysis showed MK-7 as the predominant menaquinone and iso-C15 : 0, summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1omega7c), iso-C15 : 1 G, iso-C15 : 0 3-OH and iso-C17 : 0 3-OH as major cellular fatty acids. The genomic DNA G+C content was 40.8 mol%. Phylogenetic trees based on 16S rRNA gene sequences revealed that Fabibacter halotolerans UST030701-097(T) was the closest neighbour, with 96.7 % sequence similarity. Based on phylogenetic, chemotaxonomic and phenotypic data, we propose that strain DY53(T) represents a novel species of the genus Fabibacter, for which the name Fabibacter pacificus sp. nov. is proposed. The type strain is DY53(T)( = CGMCC 1.12402(T) = JCM 18885(T)). PMID- 23625264 TI - Algibacter undariae sp. nov., isolated from a brown algae reservoir. AB - A Gram-stain-negative, non-flagellated, rod-shaped bacterial strain able to move by gliding, designated WS-MY9(T), was isolated from a brown algae reservoir in South Korea. Strain WS-MY9(T) grew optimally at 25 degrees C, at pH 7.0-8.0 and in the presence of 2 % (w/v) NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences showed that strain WS-MY9(T) clustered with the type strain of Algibacter lectus with a bootstrap resampling value of 100 %. Strain WS MY9(T) exhibited 16S rRNA gene sequence similarity values of 98.5 and 96.7 % to the type strains of A. lectus and Algibacter mikhailovii, respectively, and less than 96.1 % sequence similarity to other members of the family Flavobacteriaceae. Strain WS-MY9(T) contained MK-6 as the predominant menaquinone and anteiso-C15 : 0, iso-C17 : 0 3-OH, iso-C15 : 1 G and iso-C15 : 0 as the major fatty acids. The major polar lipids of strain WS-MY9(T) were phosphatidylethanolamine and two unidentified lipids. The DNA G+C content of strain WS-MY9(T) was 35.0 mol% and its DNA-DNA relatedness value with A. lectus KCTC 12103(T) was 15 %. The phylogenetic and genetic distinctiveness and differential phenotypic properties revealed that strain WS-MY9(T) is separate from the two recognized species of the genus Algibacter. On the basis of the data presented, strain WS-MY9(T) represents a novel species of the genus Algibacter, for which the name Algibacter undariae sp. nov. is proposed. The type strain is WS-MY9(T) ( = KCTC 32259(T) = CCUG 63684(T)). PMID- 23625265 TI - Hansschlegelia beijingensis sp. nov., an aerobic, pink-pigmented, facultatively methylotrophic bacterium isolated from watermelon rhizosphere soil. AB - A novel Gram-stain-negative, aerobic, rod-shaped strain designated PG04(T) was isolated from the rhizosphere of watermelon plants cultivated in Beijing, China. A polyphasic taxonomic study was performed on the new isolate. On the basis of 16S rRNA gene sequence similarity studies, isolate PG04(T) belonged clearly to the genus Hansschlegelia and was most closely related to Hansschlegelia zhihuaiae (97.3 % similarity to the type strain). The predominant respiratory quinone was ubiquinone 10 (Q-10) and the polar lipid profile was composed of the major lipids diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylcholine. The major fatty acids were C18 : 1omega7c (41.3 %), C19 : 0 cyclo omega8c (30.6 %) and C16 : 0 (19.1 %). The G+C content of the DNA was about 64.4 mol%. DNA-DNA hybridization experiments showed 34.4 % relatedness between strain PG04(T) and H. zhihuaiae DSM 18984(T). The results of physiological and biochemical tests and differences in fatty acid profiles allowed clear phenotypic differentiation of strain PG04(T) from the most closely related species in the genus, H. zhihuaiae. Strain PG04(T) therefore represents a novel species within the genus Hansschlegelia, for which the name Hansschlegelia beijingensis sp. nov. is proposed, with the type strain PG04(T) ( = DSM 25481(T) = ACCC 05759(T)). PMID- 23625266 TI - Fusicatenibacter saccharivorans gen. nov., sp. nov., isolated from human faeces. AB - Three Gram-stain-positive, obligately anaerobic, non-motile, non-spore-forming, spindle-shaped bacterial strains (HT03-11(T), KO-38 and TT-111), isolated from human faeces were characterized by phenotypic and molecular taxonomic methods. Comparative 16S rRNA gene sequencing showed that the strains were highly related to each other genetically (displaying >99 % sequence similarity) and represented a previously unknown subline within the Blautia coccoides rRNA group of organisms (cluster XIVa). The closest phylogenetic neighbours of strain HT03-11(T) were Clostridium bolteae WAL 16351(T) (93.7 % 16S rRNA gene sequence similarity) and Clostridium saccharolyticum WM1(T) (93.7 % similarity). All isolates produced lactic acid, formic acid, acetic acid and succinic acid as fermentation end products from glucose. Their chemotaxonomic properties included lysine as the cell wall diamino acid and C16 : 0, C18 : 1omega7c DMA and C16 : 0 DMA as the major fatty acids. The G+C contents of the genomic DNA were 46.9-47.2 mol% (HPLC). Several phenotypic and chemotaxonomic characteristics could be readily used to differentiate the isolates from phylogenetically related clostridia. Therefore, strains HT03-11(T), KO-38 and TT-111 represent a novel species in a new genus of the family Lachnospiraceae, for which the name Fusicatenibacter saccharivorans gen. nov., sp. nov. is proposed. The type strain of the type species is HT03-11(T) ( = YIT 12554(T) = JCM 18507(T) = DSM 26062(T)). PMID- 23625267 TI - Pitfalls with smartphones in medicine. PMID- 23625268 TI - Electronic health records and ambulatory quality. PMID- 23625269 TI - Spironolactone inhibits apoptosis in rat mesangial cells under hyperglycaemic conditions via the Wnt signalling pathway. AB - Mesangial cells (MCs) play a crucial role in maintaining structure and function of glomerular tufts, providing structural support for capillary loops and modulating glomerular filtration by their contractility. MCs apoptosis occurs in experimental diabetic nephropathy, and this correlates with worsening albuminuria. Accumulating evidence suggests that mineralocorticoid receptor (MR) blockade effectively reduces proteinuria in diabetic nephropathy; however, it is rarely known whether spironolactone (SPI), a nonspecific MR antagonist, inhibits apoptosis in MCs under hyperglycaemic conditions. The objectives of this study are to determine the relationship between SPI and apoptosis, and investigate the cell signalling pathway by which SPI inhibits apoptosis. Rat MCs were treated with 30 mM D-glucose and 10(-8), 10(-7) or 10(-6) M aldosterone (ALD) for 24 h. In some experiments, MCs were pretreated with 10(-7) M SPI or 10 mM LiCl for 1 h. Apoptosis was evaluated by cell nucleus staining and flow cytometric analyses, and caspase-3 activity was assayed. Gene and protein expression were quantified using quantitative real-time PCR and Western blotting, respectively. SPI directly inhibited high glucose and ALD-induced MCs apoptosis in a caspase-dependent manner. Importantly, SPI inhibited MCs apoptosis via the Wnt signalling pathway. SPI promoted activation of the Wnt signalling pathway in MCs, leading to upregulation of Wnt4 and Wnt5a mRNA expression, decreased GSK-3beta protein expression and increased beta-catenin protein expression. As a conclusion, this study suggests that SPI may inhibit apoptosis in MCs during hyperglycaemic conditions via the Wnt signalling pathway. Blockade of the ALD system may represent a novel therapeutic strategy to prevent MCs injury under hyperglycaemic conditions. PMID- 23625271 TI - Pharmacologic treatment options for obesity: what is old is new again. AB - After a long period of failure in development, two new medications (phentermine/topiramate ER - QsymiaTM and lorcaserin - Belviq(r)) have been approved by the US Food and Drug Administration for long-term weight management in persons with obesity (BMI >= 30 kg/m(2)) or in overweight persons (BMI >= 27 kg/m(2)) with comorbidities. Another medication, bupropion/naltrexone, is undertaking a cardiovascular outcomes trial and an analysis in 2014 will determine its approval and release. The most widely prescribed drug for obesity, phentermine, used since 1959 for short-term weight management, has been released in a new formulation. This paper reviews these new medications, and other important events in the landscape for management of obesity, with an eye to the interests of physicians who manage hypertension. All the new drugs under discussion are re-fittings of old agents or fresh approaches to old targets; thus, what is old is new again in the pharmacotherapy of obesity. PMID- 23625270 TI - PACAP protects against salsolinol-induced toxicity in dopaminergic SH-SY5Y cells: implication for Parkinson's disease. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous 38 amino acid containing neuropeptide with various cytoprotective functions including neuroprotection. Administration of PACAP has been shown to reduce damage induced by ischemia, trauma, or exogenous toxic substances. Moreover, mice deficient in PACAP are more vulnerable to damaging insults. In this study, we sought to determine whether PACAP may also be protective against salsolinol induced toxicity in SH-SY5Y cells and, if so, elucidate its mechanism(s) of action. Salsolinol (SALS) is an endogenous dopamine metabolite with selective toxicity to nigral dopaminergic neurons, which are directly implicated in Parkinson's disease (PD). SH-SY5Y cells, derived from human neuroblastoma cells, express high levels of dopaminergic activity and are used extensively as a model to study these neurons. Exposure of SH-SY5Y cells to 400 MUM SALS for 24 h resulted in approximately 50 % cell death that was mediated by apoptosis as determined by cell flow cytometry and increases in caspase-3 levels. Cellular toxicity was also associated with reductions in brain-derived neurotrophic factor and phosphorylated cyclic AMP response element-binding protein. Pretreatment with PACAP dose-dependently attenuated SALS-induced toxicity and the associated apoptosis and the chemical changes. PACAP receptor antagonist PACAP6-38, in turn, dose-dependently blocked the effects of PACAP. Neither PACAP nor PACAP antagonist had any effect of its own on cellular viability. These results suggest the protective effects of PACAP in a cellular model of PD. Hence, PACAP or its agonists could be of therapeutic benefit in PD. PMID- 23625272 TI - Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a systematic review of recent evidence. AB - BACKGROUND: Several alternative treatment regimens for Helicobacter pylori eradication have been proposed since the efficacy of standard triple therapy has declined over time, and sequential therapy is one of them. The purpose of this systematic review is to analyze and compare the efficacy, adverse effects and cost of sequential therapy with that of standard triple therapy for H. pylori infection. METHODS: MEDLINE, EMBASE, Google Scholar and Cochrane databases were used to retrieve all relevant articles published in the English language over the last 5 years (January 2008-October 2012). Eligibility criteria were randomized controlled trials (RCTs) comparing sequential and standard triple therapies in patients with documented H. pylori infection. Eligibility and quality of the trials were assessed independently by two reviewers, and the data regarding eradication rate, adverse effects and the cost of therapy were extracted. RESULTS: Of the 17 RCTs included in the analysis (Asia 13, Europe 3, Latin America, 1), 12 reported better eradication rates with the sequential therapy, four did not find a significant difference between the two treatment regimens, and one reported a better eradication rate with standard triple therapy. All except one RCT reported no significant difference in the incidence of adverse effects between standard triple therapy and sequential therapy. Sequential therapy was cheaper than standard triple therapy in all three RCTs where a cost analysis was performed. The limitations of the RCTs included in the systematic review were that the sequential therapy regimen and the duration of standard triple therapy were not uniform. Antibiotic susceptibility tests were performed in only three RCTs. CONCLUSIONS: While the majority of the RCTs have shown superior eradication rates with sequential therapy, the largest RCT from Latin America did not find a significant difference between the two treatment regimens. Sequential therapy has good efficacy; however, further trials other than those from Asia and Italy are required to assess its superiority over existing regimens before recommending sequential therapy as the first line of treatment for H. pylori infection. PMID- 23625274 TI - Heart failure in China: a review of the literature. AB - Heart failure (HF) is a serious disease associated with high morbidity and mortality. In China, as in other countries, it is a common cause for hospital admission; however, as yet there are few data documenting the epidemiology and management of HF in China, or quality of life-related considerations in this population. This review aims to identify relevant Chinese and English language publications that discuss the causes, risks, treatment, and health outcomes (costs, health-related quality of life) of HF in China (excluding Taiwan and Hong Kong). The prevalence of HF in China appears to be lower than that reported in many Western countries, including the US. Hypertension and coronary heart disease are the leading causes of HF in China, as they are in many Western nations, potentially highlighting the improvement in socioeconomic conditions in China. Evidence suggests that use of newer pharmacological agents for the treatment of HF is increasing; however, it is still believed that there is a lack of physician knowledge regarding newer, more effective treatment options, with rural (poor) areas appearing to be the most reliant on older, less expensive, medications. Interest in Chinese quality of life measures for HF has risen recently, with the development of valid and reliable rating scales in the Chinese population. Although the amount of available literature on HF in China is improving, there remain significant gaps in our understanding of the issue, and further research is needed to provide a reliable Chinese evidence base for the improvement of clinical practice. PMID- 23625273 TI - Hyperphosphataemia: treatment options. AB - Hyperphosphataemia can be induced by three main conditions: a massive acute phosphate load, a primary increase in renal phosphate reabsorption, and an impaired renal phosphate excretion due to acute or chronic renal insufficiency. Renal excretion is so efficient in normal subjects that balance can be maintained with only a minimal rise in serum phosphorus concentration even for a large phosphorus load. Therefore, acute hyperphosphataemia usually resolves within few hours if renal function is intact. The most frequent cause of chronic hyperphosphataemia is chronic renal failure. Hyperphosphataemia in chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. Lowering the phosphate load and maintaining serum phosphorus levels within the normal range are considered important therapeutic goals to improve clinical outcomes in CKD patients. Treatment consists of diminishing intestinal phosphate absorption by a low phosphate diet and phosphate binders. In CKD patients on dialysis an efficient dialysis removal of phosphate should be ensured. Dietary restriction of phosphorus while maintaining adequate protein intake is not sufficient to control serum phosphate levels in most CKD patients; therefore, the prescription of a phosphate binder is required. Aluminium containing agents are efficient but no longer widely used because of their toxicity. Calcium-based salts are inexpensive, effective and most widely used, but there is now concern about their association with hypercalcaemia, parathyroid gland suppression, adynamic bone disease, and vascular and extraosseous calcification. The average daily dose of calcium acetate or carbonate prescribed in the randomised controlled trials to control hyperphosphataemia in dialysis patients ranges between 1.2 and 2.3 g of elemental calcium. Such doses are greater than the recommended dietary calcium intake and can lead to a positive calcium balance. Although large amounts of calcium salts should probably be avoided, modest doses (<1 g of elemental calcium) may represent a reasonable initial approach to reduced serum phosphorus levels. A non-calcium-based binder can then be added when large doses of binder are required. At present, there are three types of non-calcium-based phosphate binders available: sevelamer, lanthanum carbonate and magnesium salts. Each of these compounds is as effective as calcium salts in lowering serum phosphorus levels depending on an adequate prescribed dose and adherence of the patient to treatment. Sevelamer is the only non-calcium-containing phosphate binder that does not have potential for systemic accumulation and presents pleiotropic effects that may impact on cardiovascular disease. In contrast, lanthanum carbonate and magnesium salts are absorbed in the gut and their route of excretion is biliary for lanthanum and urinary for magnesium. There are insufficient data to establish the comparative superiority of non-calcium binding agents over calcium salts for such important patient-level outcomes as all-cause mortality and cardiovascular end points. Moreover, full adoption of sevelamer and lanthanum by government drug reimbursement agencies in place of calcium salts would lead to a large increase in health-care expenditure. Therefore, the choice of phosphate binder should be individualised, considering the clinical context, the costs, and the individual tolerability the concomitant effects on other parameters of mineral metabolism, such as serum calcium and parathyroid hormone, besides those on serum phosphorus. PMID- 23625276 TI - Breast cancer screening and the changing population pyramid of Japan. AB - BACKGROUND: Breast cancer has been the most prevalent cancer in Japan since the 1990s. The mortality from breast cancer is increasing in Japan, whereas in other industrialized countries it has been decreasing since 1990. On the other hand, Japan faces unparalleled growth in its aging population. The aim of this study was to report the mammography screening among Japanese women and the related upcoming changes in the population pyramid of Japan. DATA SOURCES AND METHODS: The reference data for our study were obtained from the Center for Cancer Control and Information Services, Japan Ministry of Internal Affairs and Communications, Ministry of Health, Labour and Welfare, the Japanese Cancer Society, and the National Institute of Population and Social Security. The survey data were obtained from breast cancer and mammography screenings in the Tokyo Prefecture in 2008. The following parameters were analyzed: annual breast cancer incidence, current screening rates, average life-span, and predicted demographic statistics. RESULTS: Our results showed that breast cancer incidence and mortality have been increasing annually in Japan. The average age of breast cancer patients increased to 58.40 years in 2010. The incidence of breast cancer in women aged 65 years and older increased from 25.3 to 32.9 % in the last 10 years and is expected to continue to increase in the future. The check-up rate was 16.0-20.0 % for women aged 65-74 years and 43.0-46.0 % for women aged 40-54 years. According to our questionnaire survey, concerns about breast cancer and mammography screening were high in the young and low in the elderly women. The Japanese population aged 65 years and older was 30,740 (24.1 %) in 2012 and is estimated to increase by 40 % over the next 20 years despite Japan's declining population size. CONCLUSION: Breast cancer incidence has increased in Japan, even among patients aged 65 years and older. Breast cancer has become increasingly prevalent in older Japanese women. As the population pyramid of Japan changes, women aged 65 years and older, who think that there is no longer need to receive mammography screening and are not educated regarding self-examinations, should be encouraged to receive regular check-ups for breast cancer. PMID- 23625275 TI - Catheter ablation for atrial fibrillation results in greater improvement in cardiac function in patients with low versus normal left ventricular ejection fraction. AB - PURPOSE: It is still unknown whether left ventricular ejection fraction (LVEF) might affect the magnitude of improvement after atrial fibrillation (AF) ablation on cardiac function in persistent or longstanding persistent AF (CAF) patients. METHOD: We performed echocardiography in 35 patients with CAF before and after catheter ablation (CA). Patients were stratified by LVEF into two groups prior to CA-normal LVEF (>=50 % LVEF, N group, n = 24) and a low LVEF group (<50 % LVEF, L group, n = 11). Patients were followed at 1 month, 3 months, 6 months, 1 year, and 2 years after ablation. RESULTS: After 15.8 +/- 7.4 months follow-up, the L group showed greater improvement in LVEF and left atrial ejection fraction (LAEF; N group vs L group: LVEF difference (%), 5 +/-8 vs 20+/- 13, p < 0.01; LAEF difference (%), 11 +/- 12 vs 21 +/- 10, p < 0.05). LA maximal volume and E/e' showed the same tendency after ablation, although the extent of improvement was not statistically significant. Both groups showed almost the same time course of improvement up to 2 years, although the L group showed earlier recovery in LVEF. CONCLUSION: The greater improvement in several cardiac functions was seen in patients with greater LV dysfunction, after the CA for CAF. PMID- 23625277 TI - Lack of genomic rearrangements involving the aromatase gene CYP19A1 in breast cancer. AB - Increased intratumoral expression of aromatase, the key enzyme for estrogen biosynthesis, is predicted to be of critical importance in the development of breast cancer. Recently, several germline rearrangements at 15q21 have been shown to cause overexpression of the aromatase gene CYP19A1 and resulting aromatase excess syndrome. To determine whether submicroscopic genomic rearrangements at 15q21 are involved in aromatase overexpression in breast cancer tissues, we investigated copy-number alterations in genomic DNA obtained from 44 tumor samples. Comparative genomic hybridization analysis identified no deletion or duplication at 15q21 in the 44 samples. These results, in conjunction with previous data, indicate that aromatase overexpression in breast cancer tissues is likely to result from a promoter switch of CYP19A1 and/or accumulation of CYP19A1 expressing cells, rather than from cryptic transactivation of CYP19A1 because of genomic rearrangements at 15q21. PMID- 23625279 TI - Thrombocytopenia associated with 5-aminosalicylate prodrug, olsalazine: is the devil still there? AB - CASE DESCRIPTION: We present a case of a 63-year-old Chinese female who developed severe thrombocytopenia after receiving olsalazine 1.5 g daily for 3 months, and eventually culminated in hospital admission. According to a Medline search, this is the first case report of olsalazine-associated thrombocytopenia in Asia. CONCLUSION: Olsalazine, similar to other 5-aminosalicylates, can also cause thrombocytopenia. Clinicians should be aware of this potential adverse drug reaction. Future studies should focus on the trigger mechanism and possible cross reaction between olsalazine and other aminosalicylates. PMID- 23625280 TI - What sources do adolescents turn to for information about their health concerns? AB - BACKGROUND: Adolescents are developmentally normatively interested in information about sexuality and other health-related issues. In the absence of available health programming, identifying the sources of information that youth are currently accessing will help adolescent health researchers understand where youth 'are,' thereby informing where and how future interventions can be targeted. This is particularly important in resource-limited settings, such as Iran, where funding for public health programming is scant. This study aimed to examine primary and preferred sources of adolescents' health information queries and identify health topics in which they are most interested. METHODS: In 2011, a random sample of 915 adolescents, aged 14-18 years, completed anonymous, self administered questionnaires. RESULTS: Mothers (51.11%) and same-sex friends (40.11%) were both the primary as well as the preferred source of health information for adolescents. More than one in three adolescents identified media information sources, including books (39.6%) and the Internet (37.9%), as their primary and preferred sources. The most common topic adolescents sought information about was sexuality issues. Younger adolescents preferred receiving information from parents, whereas older adolescents preferred friends as sources for information [X2=9.3, p=0.009]. No age differences were noted in using media sources (p>0.05). CONCLUSIONS: These findings indicate future interventions should integrate some if not all of these sources [both people (mothers, same-sex friends) and media (books, the Internet)] to deliver evidenced-based health information. PMID- 23625281 TI - Expression of estrogen receptors (alpha, beta), cyclooxygenase-2 and aromatase in normal endometrium and endometrioid cancer of uterus. AB - PURPOSE: Endometrial cancer (EC) is one of the most common malignancies of the female genital tract, but the etiology, especially its metabolism is still investigated. The aim of this study was to evaluate the presence and relative expression of Estrogen Receptors (alpha, beta), Cyclooxygenase-2 and Aromatase in both endometrial cancer and normal mucosa. MATERIAL/METHODS: Two groups of women were selected for the study: 1) patients with endometrioid endometrial cancer (FIGO I; G1 - G3) (n=35) and 2) subjects with normal endometrial tissue (control group, n=29). The expression of Estrogen Receptors (ERalpha, beta), Cyclooxygenase-2 (COX-2), Aromatase were estimated by Western blot analysis. Furthermore, the associations between FIGO classification (stage: Ia, Ib), tumor grade (G) and expression of ERalpha, beta, COX-2, aromatase proteins were evaluated. Overall and disease-free survival curves were generated according to the Kaplan-Meier method. Median follow-up time of the patients examined in this study was 39 months. RESULTS: The relative expression of each examined protein was markedly higher in the endometrial cancer tissue as compared to the healthy endometrium. The trends towards greater expression along with a tumor progression was noticed (FIGO stage: Ia vs. Ib). Analysis of endometrial cancer risk factors and their influence on survival curves showed only an inverse significant correlations between obesity (BMI: 36.2; n=21) and disease-free survival in EC group (p=0.00872), but there was no significant association between obesity and overall survival (p=0.358). CONCLUSIONS: Endometrioid endometrial cancer shows relatively higher expression of either ER, COX-2 and aromatase comparing to healthy mucosa, suggesting their involvement in tumor development and progression. PMID- 23625282 TI - Effect of fumonisin B1 on the cell cycle of normal human liver cells. AB - Fumonisin B1 (FB1) is a well-known liver and kidney carcinogen in rodents and humans. The aim of the present study was to investigate the effect of FB1 on the proliferation and cell cycle of the normal human liver cell line HL-7702 and to explore the underlying molecular mechanisms of action. The cells were treated with FB1 (0.0, 0.1, 1.0, 10.0 and 100.0 umol/l) for 24, 48, 72 and 96 h. Cell proliferation was assessed by colorimetric assay. Cell cycle analysis was performed by flow cytometry. The mRNA and protein expression of cyclin E and P21 were determined by RT-PCR and western blot analysis, respectively. FB1 was initially demonstrated to significantly inhibit the proliferation of HL-7702 cells; however, cell proliferation increased with increasing treatment time. The percentage of cells in the G0/G1 phase was significantly increased by FB1; however, significantly decreased with an increasing concentration of FB1. The mRNA expression of cyclin E was upregulated and then gradually downregulated with increasing treatment time. The mRNA expression of P21 was significantly increased following treatment with 0.1 umol/l FB1, and decreased following treatment with 10.0 and 100.0 umol/l FB1 for different treatment durations. Western blot analysis showed that FB1 significantly increased the protein expression of cyclin E and significantly decreased the protein expression of P21 at various concentrations and treatment durations. Our results demonstrated that FB1 affects the cell cycle of normal human liver cells and that the underlying mechanism of action is associated with alterations in the expression levels of cyclin E and P21 induced by FB1. PMID- 23625283 TI - Analysis of the genome-wide DNA methylation profile of side population cells in hepatocellular carcinoma. AB - BACKGROUND: DNA methylation plays an important role in maintaining pluripotency and regulating the differentiation of stem cells, but the DNA methylation profile of stem cells in hepatocellular carcinoma (HCC) remains unclear. AIMS: To investigate the genome-wide DNA methylation profile of side population (SP) cells of HCC, a special subpopulation of cells enriched with cancer stem cells, by DNA methylation microarray analysis and to analyze the functions and signal pathways of the aberrantly methylated genes in SP cells. METHODS: Side population cells were isolated from HCC cell lines Huh7 and PLC/PRF/5 using flow cytometry, and the tumorigenicity of these SP cells was assessed in NOD/SCID mice. The genome wide DNA methylation status of SP cells and non-SP (NSP) cells was detected and compared by DNA methylation microarray analysis. Genes with differential methylation between SP and NSP cells were further analyzed for their functions and roles in related signaling pathways. RESULTS: Subcutaneous inoculation of 1 * 10(3) SP cells yielded tumors in 60 % NOD/SCID mice, whereas no tumor was developed after the inoculation of 1 * 10(6) NSP cells. Genome-wide DNA methylation microarray analysis showed that 72 and 181 genes were hypermethylated and hypomethylated, respectively, in both Huh7 and PLC/PRF/5 SP cells as compared with their corresponding NSP cells. Analyses of signaling pathways revealed that hypermethylated and hypomethylated genes were related to four and eight pathways, respectively. CONCLUSIONS: Hepatocellular carcinoma SP cells possessed a differential DNA methylation status compared with NSP cells, and the differentially methylated genes in SP cells were involved in 12 signaling pathways. Our results provide valuable clues for further investigations in elucidating the importance of epigenetic regulation in sustaining HCC SP cells and tumorigenesis. PMID- 23625284 TI - Granulomas of intestinal tuberculosis and Crohn's disease can be differentiated by CD73 cell surface marker expression: a pilot study. AB - BACKGROUND: Intestinal tuberculosis (ITB) and Crohn's disease are similar granulomatous disorders. Granulomas are present in both and difficult to differentiate on histopathology alone. A recent study demonstrated recruitment of mesenchymal cells (MSCs) at the periphery of granulomas in lymph node tuberculosis which suppressed T cell responses. We hypothesized that granulomas of ITB would also recruit MSCs to evade host immune response. AIM: The purpose of this study was to demonstrate MSC markers in granulomas of ITB and evaluate whether distribution of MSC markers could differentiate between granulomas of Crohn's and ITB. METHODS: We initially retrospectively enrolled 17 patients with confirmed ITB (8) or Crohn's (9) with granulomas on histopathology. Tissues were evaluated by immunofluorescence for MSC markers CD29, CD90, CD73 and absence of haematopoietic markers CD31, CD34, CD45 and CD14. Double-staining was done to confirm presence of MSCs. Subsequently, 23 postoperative specimens of Crohn's (18) and ITB (5) were analyzed for validation. RESULTS: Overall, 27 Crohn's and 13 ITB cases were assessed. CD29 and CD90 positive cells were noted around both ITB and Crohn's granulomas. MSC marker CD73 was expressed around the granulomas of ITB alone and was completely absent in the Crohn's. The subsequent assessment of granulomas in postoperative specimens of Crohn's and ITB also showed similar results. CONCLUSION: Granulomas of ITB and Crohn's disease can be differentiated by CD73 MSC surface marker expression. The differential CD73 expression around ITB granuloma indicates that Mycobacterium tuberculosis evades host immunity by recruiting MSCs with CD73 expression. MSCs with increased CD73 expression could be the future for therapeutic intervention in Crohn's. PMID- 23625285 TI - Use of ImPACT to diagnose minimal hepatic encephalopathy: an accurate, practical, user-friendly internet-based neuropsychological test battery. AB - BACKGROUND AND AIMS: An effective, user-friendly neurocognitive test to diagnose minimal hepatic encephalopathy (MHE) is needed. Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) is a brief, validated, Web-based, neuropsychological test battery resulting in four composite scores [Verbal Memory (VrbM), Visual Memory, Visual Motor Speed (VMS), Reaction Time (RT)]. We compared ImPACT to traditional paper-and-pencil tests in patients at risk for MHE versus controls. METHODS: Ninety cirrhotic patients with no history of overt hepatic encephalopathy were compared with 131 controls on standard psychometric tests (SPT) [Trail Making Test-A, Trail Making Test-B, Digit Symbol Test], 4 ImPACT composite scores, and the Sickness Impact Profile (SIP). MHE+ was defined by a score 2 SD below the normative mean on at least one of the SPT. ImPACT (ImP+) scores of patients were defined as 2 SD from the control mean. RESULTS: Cirrhotic patients scored more poorly than controls on 3/4 of ImPACT scores: VrbM (78.88 vs. 71.37, p<0.001), VMS (26.47 vs. 22.68, p<0.001) and RT (0.89 vs. 1.00, p<0.01), as well as on all 3 SPT. Of the 90 cirrhotics, 16 (18%) were MHE+, who performed more poorly (p<0.001) than patients without MHE on VrbM (58.13 vs. 74.19), VMS (16.77 vs. 23.95) and RT (1.24 vs. 0.95). Of the 90 cirrhotics, 25 (27.8%) were ImP+. MHE+ and ImP+ patients had increased SIP scores versus controls (p<0.001). CONCLUSIONS: Compared to paper-and-pencil testing, ImPACT provides a brief, user-friendly, neuropsychological evaluation of MHE. ImPACT could become a new standard for MHE diagnosis. PMID- 23625286 TI - Colonic 15-PGDH levels are stable across distance and time and are not perturbed by aspirin intervention. AB - BACKGROUND AND AIMS: 15-Hydroxprostaglandin dehydrogenase (15-PGDH) mediates a colon neoplasia suppressor pathway, acting through metabolic antagonism of cyclooxygenase-mediated colon carcinogenesis. To determine whether the colon tumor prevention activity of 15-PGDH acts as a constant or variable effect among individuals, we determined whether 15-PGDH levels remain stable over subsite and time in the human colon, determined the extent of differences in 15-PGDH levels between different individuals, and determined whether 15-PGDH modulation mediates any part of the anti-colon tumor effect of aspirin. METHODS: Using real-time PCR, we measured 15-PGDH mRNA to determine the correlation of 15-PGDH level in replicate colon biopsies, in biopsies from throughout the length of the colon, in repeat biopsies taken 4 months apart, and in paired biopsies of individuals taken before and after aspirin treatment, and by Western-blot for 15-PGDH protein in mice. RESULTS: Colonic 15-PGDH levels varied 4.4-fold across the human population. Within individuals, 15-PGDH levels proved highly reproducible (r=0.81 in duplicate biopsies) and stable along the length of the colon, with average 15 PGDH levels deviating by only 17% from rectum to cecum. An individual's 15-PGDH levels are also highly stable over time, with a median coefficient of variation over a 4-month interval of only 12%. Last, colonic 15-PGDH levels proved resistant to alteration by aspirin, with only a 10% difference in 15-PGDH levels measured before and after aspirin treatment. CONCLUSIONS: 15-PGDH levels vary across the population in a stable and reproducible manner, and are resistant to alteration by aspirin. 15-PGDH represents an independent target for modulation by candidate colon tumor chemopreventive agents. PMID- 23625287 TI - Bilateral metal stents for hilar biliary obstruction using a 6Fr delivery system: outcomes following bilateral and side-by-side stent deployment. AB - BACKGROUND AND STUDY AIM: Controversy exists on optimal endoscopic management for palliation of malignant hilar obstruction, with advocates for metal "side-by side" (SBS) and "stent-in-stent" (SIS) techniques. We sought to evaluate the technical feasibility, efficacy, and outcomes of bilateral biliary self-expanding metal stents (SEMS) for treatment of malignant hilar obstruction using a stent with a 6Fr delivery system. PATIENTS AND METHODS: This was a single-center, retrospective review of all patients who underwent bilateral placement of Zilver(r) biliary SEMS for malignant hilar obstruction from January 2010 to August 2012. Patients underwent endoscopic retrograde cholangiopancreatography with placement of stents using either the SIS or SBS stent techniques. RESULTS: Twenty-four patients (19 men, mean age 63 years) underwent bilateral stenting for malignant hilar obstruction during the study period. Seventeen and seven patients underwent the SBS and SIS technique, respectively. Cholangiocarcinoma (n=14) was the most common cause of hilar obstruction. Initial technical success was achieved in 24/24 (100%) of patients; however, 12 (50%) patients required re intervention during the study period (median 98 days). Comparison of the SBS and SIS groups revealed no statistical difference with respect to need for re intervention (P=0.31), successful re-intervention (P=0.60), or procedural length (P=0.89). CONCLUSIONS: Use of bilateral Zilver(r) SEMS in either the SBS or SIS configuration is safe, technically feasible, and effective for drainage of malignant hilar obstruction; however, duration of stent patency and procedure free survival remain variable. PMID- 23625288 TI - The pathogenesis of eosinophilic esophagitis: beyond the eosinophil. PMID- 23625289 TI - Activity of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase in different stages of colorectal carcinoma. AB - BACKGROUND: Reactive oxygen species are involved in the pathogenesis of colorectal carcinoma. Clarification of oxidative/antioxidant specificities of different stages of colorectal carcinoma is of special importance. AIM: To determine oxidative/antioxidant status in plasma of patients with different stages of colorectal carcinoma using malondialdehyde concentration, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities and distribution of superoxide dismutase isoforms. METHODS: Lipid peroxidation and antioxidant enzymes activity were estimated using spectrophotometric methods. Reverse zymography was applied for characterization of superoxide dismutase isoforms. RESULTS: Lipid peroxidation is increased in all groups compared to the control, but without differences between different stages of colorectal carcinoma. Total superoxide dismutase activity is lower in all colorectal carcinoma groups than in control, and there is a significant increase in tumor stage IV when compared with tumor stage II. Manganese superoxide dismutase isoform is dominant in all groups and its relative activities are significantly higher than activities of a copper/zinc isoform. Total peroxidase potential reflected in catalase and glutathione peroxidase activity is increased when compared to the control, but without any significant differences between colorectal carcinoma groups. Glutathione reductase activity is lower in all colorectal carcinoma groups than in control, and a significant decrease in glutathione reductase activity was obtained between patients in tumor stage II and III compared to tumor stage IV. CONCLUSIONS: Colorectal carcinoma is characterized by increased oxidative stress and antioxidant disbalance. Progression of disease is followed by an increase in redox disbalance. PMID- 23625290 TI - Estrogens and gastroparesis: a clinical relevance. PMID- 23625291 TI - Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses. AB - PURPOSE: Plecanatide, an analogue of uroguanylin, activates the guanylate cyclase C (GC-C) receptor found on the GI mucosal epithelial cells, leading to secretion of fluid, facilitating bowel movements. Plecanatide is being investigated as a potential treatment for constipating GI disorders. The aim of this investigation was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single doses of plecanatide in healthy volunteers. METHODS: A total of 72 healthy volunteers at a single site were randomized in 9 cohorts to receive oral plecanatide or placebo from 0.1 to 48.6 mg. Plasma PK samples were collected pre-dose and post-dose. PD assessments included time to first stool, stool frequency, and stool consistency using the Bristol Stool Form Scale. All adverse events were documented. RESULTS: Plecanatide was safe and well tolerated at all dose levels. A total of 17 of 71 subjects (23.9%) reported 25 treatment-emergent adverse events (TEAEs) during the study. The number of TEAEs reported by subjects who received plecanatide or placebo was comparable (24.5 vs. 22.2%, respectively). There were no dose-related increases in TEAEs or any SAEs reported. No measurable systemic absorption of oral plecanatide was observed at any of the oral doses studied, utilizing an assay sensitive down to 1 ng/mL. CONCLUSIONS: Plecanatide, an oral GC-C agonist, acting locally within the GI tract without measurable systemic exposure, was safe and well-tolerated in single doses up to 48.6 mg. The study was not powered for statistical analyses, but trends in PD parameters supported continued clinical development. PMID- 23625292 TI - Angiotensin II induces endothelin-1 expression in human hepatic stellate cells. AB - BACKGROUND: Both angiotensin (Ang)-II and endothelin-1 (ET-1) are involved in the pathogenesis of liver fibrosis. Activated hepatic stellate cells (HSCs) are considered a key effector of liver fibrosis. AIMS: To explore the effect of Ang II on ET-1 expression in cultured human HSCs and the underlying mechanisms. METHODS: Human HSCs were treated with Ang-II in different concentrations (0.1, 0.5, 1, 5, or 10 nM) for different lengths of time (0.5, 1, 2, 4, or 6 h) with or without transcription inhibitor actinomycin D, Ang-II type 1 (AT1) receptor blocker losartan, AT2 receptor blocker PD123177, or different kinase inhibitors. RESULTS: Ang-II increased the ET-1 mRNA level in a statistically significant dose and time-dependent manner within 4 h, which led to dose-dependent up-regulation of the ET-1 protein level. Actinomycin D (1 mg/ml), losartan (50 MUM), and phosphatidylinositol-3 kinase inhibitor LY294002 (50 MUM) abolished the promoting effect of Ang-II on ET-1 expression. Ang-II (10 nM) significantly increased the expression of alpha-smooth muscle actin and type I collagen in HSCs, which was abolished by losartan, LY294002, ET A receptor blocker BQ123, and ET-1 siRNA, but not PD123177 and ET B receptor blocker BQ788. CONCLUSIONS: Ang-II induces ET-1 expression in human HSCs via the AT1 receptor by the PI3 K/Akt signaling pathway. The ET-1/ET A receptor axis could mediate the promoting effects of Ang-II on HSCs' transdifferentiation into myofibroblast-like cells. This is the first evidence of crosstalk between the Ang-II/AT1 axis and the ET-1 system in regard to the pathogenesis of liver fibrosis. PMID- 23625293 TI - Catechins in dietary supplements and hepatotoxicity. AB - BACKGROUND: Many herbal dietary supplements (HDS) contain green tea extract (GTE) and its component catechins, although their presence may not always be indicated on the product label. PURPOSE: Because GTE and catechins have been implicated in human hepatotoxicity in several case reports, our objective was to determine whether catechins were present in HDS that were implicated in hepatotoxicity, even if not identified among the labeled ingredients, and whether these compounds could be associated with liver injury. METHODS: We assayed 97 HDS implicated in human hepatotoxicity for catechins. RESULTS: We found that 29 of 73 HDS (39.7%) that did not identify GTE or any of its component catechins on their label contained catechins. Among patients with confirmed hepatotoxicity, there was no statistically significant association between the presence of catechin or the dose consumed and liver injury causality score, severity, or pattern of liver injury. Catechin levels tended to be highest in products used for weight loss, although catechin concentrations were low in most products. CONCLUSIONS: Many HDS commonly contain catechins that are implicated in hepatotoxicity, although their presence may not be indicated on the product label. Although our results did not establish an association between GTE or catechins with hepatotoxicity, they highlight some of the many complexities and uncertainties that surround the attribution of drug-induced liver injury (DILI) to HDS. PMID- 23625294 TI - Parallel TIPS for treatment of refractory ascites and hepatic hydrothorax. PMID- 23625295 TI - Increased alpha-tubulin1b expression indicates poor prognosis and resistance to chemotherapy in hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. It is important to understand molecular mechanisms of HCC progression and to develop clinically useful biomarkers for the disease. AIM: We aimed to investigate the possible involvement of alpha-tubulin1b (TUBA1B) in HCC pathology. METHODS: Tissue specimens were obtained from 114 HCC patients during hepatectomy. Immunohistochemistry and western blot analysis were used to detect TUBA1B expression in HCC tissues and cell lines. TUBA1B was knocked down in HCC cells by siRNA transfection. CCK-8 assay and flow cytometry were applied to determine cell proliferation and cell cycle progression, respectively. The efficacy of paclitaxel chemotherapy was evaluated by plate colony formation assay. RESULTS: TUBA1B was higher expressed in HCC tumor tissues than in adjacent nontumor tissues. TUBA1B and Ki-67 expressions were positively related to each other, and both their expressions were significantly associated with histological grade of HCC patients. Univariate and multivariate survival analyses revealed that TUBA1B was a significant predictor for overall survival of HCC patients. TUBA1B expression was increased in HCC cells during the G1- to S-phase transition. TUBA1B knockout in HCC cells inhibited cell proliferation, and attenuated resistance to paclitaxel. CONCLUSIONS: Our results indicated that TUBA1B expression was upregulated in HCC tumor tissues and proliferating HCC cells, and an increased TUBA1B expression was associated with poor overall survival and resistance to paclitaxel of HCC patients. PMID- 23625296 TI - The effect of diabetes mellitus and end-stage renal disease on the number of CD34+ cells in the blood. AB - The aim of this study was to investigate the effect of end-stage renal disease (ESRD) and diabetes mellitus (DM) on the number of stem cells in the peripheral blood. Sixty-two patients diagnosed with ESRD who had not received dialysis previously, 25 patients with a diagnosis of DM without nephropathy, and 21 healthy volunteers were included in the study. The group diagnosed with ESRD was divided into two groups. The first group (DM-CRD) consisted of 28 patients with DM who had developed chronic renal disease (CRD). The second group (NON-DM-CRD) consisted of 34 patients without DM who had CRD by etiology. The routine complete blood count, renal function, and number of CD34+ cells were determined for all of those involved in the study. The microalbumin/creatinine levels were measured, and glomerular filtration rates were calculated in all patients. The number of CD34+ cells was found to be significantly lower in the DM control group and DM CRD group compared with the healthy group. No statistically significant difference was found between the NON-DM-CRD and the healthy control group. There was a moderate negative correlation between the ratio of microalbumin/creatinine and the number of CD34+ cells. A significant reduction in the number of CD34+ cells was shown in subjects with DM and ESRD caused by diabetic nephropathy. PMID- 23625297 TI - Addition of clarithromycin to lenalidomide/low-dose dexamethasone was effective in a case of relapsed myeloma after long-term use of lenalidomide. PMID- 23625298 TI - Improved tolerability by a modified intermittent treatment schedule of dasatinib for patients with chronic myeloid leukemia resistant or intolerant to imatinib. AB - Intermittent dosing of dasatinib with a once daily regimen has been shown to reduce side effects while preserving clinical efficacy in early and advanced phase chronic myeloid leukemia (CML). Yet, hematologic toxicity and fluid retention demand a dose modification or treatment discontinuation in selected patients. Patients resistant or intolerant to imatinib were retrospectively evaluated based on the toxicity-guided administration of a dose-reduced dasatinib regimen. Patients were treated with an on/off regimen (3 to 5 days on, 2 to 4 days off) to allow regression of dasatinib-dependent off-target toxicity. Patients were followed up by routine hematologic and cytogenetic assessment and molecular monitoring to safeguard clinical response to the altered drug schedule. Thirty-three CML patients primarily in chronic phase with imatinib intolerance (n = 11) or resistance (n = 22) were investigated. Nonexclusive reasons for dose reduction were hematologic toxicity (17/33, 51%) and pleural effusions (18/33, 55%). On/off treatment with a weekend drug holiday significantly reduced pleural effusions and hematologic toxicity. Eighteen of 31 (58%) patients showed effective disease control despite reduced total weekly dasatinib doses, either demonstrated by achieving an improved response level (12/31) or keeping the response level achieved by conventional continuous dosing (6/31). Of note, 10/12 patients with subsequently improved response have been treated for a minimum of 6 months with continuous dosing dasatinib regimens without having achieved the response level achieved after allowing drug holiday. Weekend treatment interruption of dasatinib allows continuation of dasatinib treatment for patients suffering from side effects. These data mandate prospective investigation of alternative intermittent targeting regimens. PMID- 23625299 TI - Impact of ischemia and scar on therapeutic benefit of myocardial revascularization. AB - The question of how to optimally manage coronary artery disease (CAD) has been a challenge for the cardiology community. The results of early, large randomized clinical trials (RCTs) comparing strategies of medical therapy alone versus revascularization plus medical therapy in patients with stable CAD suggested a survival advantage for a revascularization strategy in the setting of more advanced, higher-risk CAD (left main, three-vessel CAD), but a superiority of medical therapy in patients with more limited, relatively lower-risk CAD (one vessel, limited two-vessel CAD). The results of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) and Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trials redefined the management of CAD, supporting the concept that the impact of aggressively applied modern "medical therapy" on patient survival and patient-reported outcomes is not further improved by the addition of percutaneous intervention. On the other hand, RCTs incorporating fractional flow reserve have shown that this physiologic metric can help identify which patients will benefit from a revascularization strategy. This paradigm has been extended to the use of myocardial perfusion imaging-identified ischemia to determine which patients may have enhanced survival with early revascularization versus medical therapy. Although data from a series of observational studies suggest that inducible ischemia on myocardial perfusion scintigraphy can identify revascularization candidates, several studies, including substudies from major RCTs, do not support this idea. Until RCTs comparing revascularization with medical therapy strategies are performed, many questions remain open. The correct thresholds for treatment, the metric to guide treatment, and how revascularization should be performed are as yet undefined. PMID- 23625300 TI - Cardiogenic shock due to a large VSD after myocardial infarction. Time for a new strategy? PMID- 23625301 TI - Network characteristic analysis of ADR-related proteins and identification of ADR ADR associations. AB - Adverse drug reactions (ADRs) are caused by interactions between drugs or their metabolites and specific proteins. Knowledge of these proteins is important for facilitating mechanistic research of ADRs and new drug discovery. Here, we identified 41 network modules from an ADR-protein network; analysed the function of each module; revealed the potential accompanying actions of the ADRs and the new ADR-related proteins (ADRPs) to a unique ADR and studied the characteristics of composition, subcellular location and tissue distribution of these ADRPs by comparing them with drug-related proteins (DRPs). The results indicated that ADRs are mainly caused by risk drug-related proteins (RDRPs) and that drug off-target effects are a secondary cause. Biological processes that enzymes involve are the main reason for the occurrence of ADRs. However, drug-related transporters have a higher risk of inducing ADRs than drug-related enzymes do, and ADRPs locating in the cell membrane tend to induce multiple ADRs. PMID- 23625304 TI - Abstracts of the 36th Annual Meeting of the Society of General Internal Medicine. April 24-27, 2013. Denver, Colorado, USA. PMID- 23625302 TI - Phasic genioglossus and palatoglossus muscle activity during recovery from sevoflurane anesthesia: a prospective observational study in children. AB - BACKGROUND: Inhalational anesthetic effects on upper airway muscle activity in children are largely unknown. The authors tested the hypothesis that phasic inspiratory genioglossus and palatoglossus activity increases during recovery from sevoflurane anesthesia in a dose-dependent manner in children. METHODS: Sixteen children, aged 2.0 to 6.9 yr, scheduled for elective urological surgery were studied. Electromyogram recordings were acquired using intramuscular needle electrodes during spontaneous ventilation. After a 15-min period of equilibration, electromyogram activity was recorded over 30 s at each of three end-tidal concentrations, 1.5, 1.0, and 0.5 minimum alveolar concentration (MAC), administered in sequence. RESULTS: Phasic genioglossus activity was noted in four children at 1.5 MAC, five at 1.0 MAC, and six children at 0.5 MAC sevoflurane. Phasic palatoglossus activity was noted in 4 children at 1.5 MAC, 6 at 1.0 MAC, and 10 children at 0.5 MAC sevoflurane. Both the proportion of children exhibiting phasic activity, and the magnitude of phasic activity increased during recovery from anesthesia. For the genioglossus, decreasing the depth of sevoflurane anesthesia from 1.5 to 1.0 MAC increased phasic activity by approximately 35% and a further decrease to 0.5 MAC more than doubled activity (median [range] at 1.5 and 0.5 MAC: 2.7 MUV [0 to 4.0 MUV] and 8.6 MUV [3.2 to 17.6], respectively; P = 0.029). A similar dose-related increase was recorded at the palatoglossus (P = 0.0002). CONCLUSIONS: Genioglossus and palatoglossus activity increases during recovery from sevoflurane anesthesia in a dose dependent manner over the clinical range of sevoflurane concentrations in children. PMID- 23625305 TI - Investigation of the lipid-modifying and antiinflammatory effects of Cornus mas L. supplementation on dyslipidemic children and adolescents. AB - Cornus mas L. (CM) fruits are rich in anthocyanins and possess both antiinflammatory and antioxidant activities. The current study was conducted to investigate whether supplementation with CM could ameliorate lipid profile and vascular inflammation in dyslipidemic children and adolescents. In this randomized clinical trial, 40 dyslipidemic children and adolescents ages 9 to 16 years were assigned to receive 50 g of CM twice a day after lunch and dinner (n = 20, case group) or to continue their normal diet (n = 20, control group). The serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apo A-I, apo B, intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), C-reactive protein (CRP), and anthropometric indices were determined at baseline and then after weeks 3 and 6 of the trial. After week 6 of the trial, the TC, TG, LDL-C, apo B, ICAM-1, and VCAM-1 levels in the CM group were significantly lower and the HDL-C and apo A-I levels higher than at baseline. After week 6 of the trial, none of these parameters in the control group, except for ICAM-1, was significantly altered from baseline. However, between-group comparison showed a significant difference only for apo A-I (p = 0.016) and a borderline significant difference for ICAM-1 (p = 0.076). No significant difference in body mass index, waist-to-hip ratio, or C-reactive protein was observed between the studied groups. The present findings revealed a trend toward amelioration of lipid profile and vascular inflammation following addition of CM to the daily diet of dyslipidemic children and adolescents but this needs to be verified by larger scale trials. PMID- 23625306 TI - Percutaneous interspinous spacer versus open decompression: a 2-year follow-up of clinical outcome and quality of life. AB - PURPOSE: Percutaneous interspinous stand-alone spacers offer a simple and effective technique to treat lumbar spinal stenosis with neurogenic claudication. Nonetheless, open decompressive surgery remains the standard of care. This study compares the effectiveness of both techniques and the validity of percutaneous interspinous spacer use. METHODS: Forty-five patients were included in this open prospective non-randomized study, and treated either with percutaneous interspinous stand-alone spacers (Aperius((r))) or bilateral open microsurgical decompression at L3/4 or L4/5. Patient data, operative data, COMI, SF-36, PCS and MCS, ODI, and walking distance were collected 6 weeks, 3, 6, 9, 12, and 24 months post-surgery. RESULTS: Group 1 (n = 12) underwent spacer implantation, group 2 (n = 33) open decompression. Five patients from group 1 required implant removal and open decompression during follow-up (FU); one patient was lost to FU. From group 2, seven patients were lost to FU. Remaining patients were assessed as above. After 2 years, back pain, leg pain, ODI, and quality of life improved significantly for group 2. Remaining group 1 patients (n = 6) reported worse results. Walking distance improved for both groups. CONCLUSION: Decompression proved superior to percutaneous stand-alone spacer implantation in our two observational cohorts. Therapeutic failure was too high for interspinous spacers. PMID- 23625307 TI - First regiocontrolled synthesis of procyanidin B6, a catechin dimer with rare connectivity: a halo-capping strategy for formation of 4,6-interflavan bonds. AB - The first regiocontrolled synthesis of procyanidin B6, a dimer with a rare 4,6 interflavan linkage, is described. Regioselective linking was achieved by the halo-capping strategy followed by removal of all the benzyl protecting groups and the halo-caps by one-pot hydrogenolysis. PMID- 23625308 TI - In vivo lung microvasculature visualized in three dimensions using fiber-optic color Doppler optical coherence tomography. AB - For the first time, the use of fiber-optic color Doppler optical coherence tomography (CDOCT) to map in vivo the three-dimensional (3-D) vascular network of airway segments in human lungs is demonstrated. Visualizing the 3-D vascular network in the lungs may provide new opportunities for detecting and monitoring lung diseases such as asthma, chronic obstructive pulmonary disease, and lung cancer. Our CDOCT instrument employs a rotary fiber-optic probe that provides simultaneous two-dimensional (2-D) real-time structural optical coherence tomography (OCT) and CDOCT imaging at frame rates up to 12.5 frames per second. Controlled pullback of the probe allows 3-D vascular mapping in airway segments up to 50 mm in length in a single acquisition. We demonstrate the ability of CDOCT to map both small and large vessels. In one example, CDOCT imaging allows assignment of a feature in the structural OCT image as a large (~1 mm diameter) blood vessel. In a second example, a smaller vessel (~80 MUm diameter) that is indistinguishable in the structural OCT image is fully visualized in 3-D using CDOCT. PMID- 23625309 TI - [Catheter ablation of persistent and long-standing persistent atrial fibrillation. Strategies and results]. AB - Catheter ablation for paroxysmal atrial fibrillation is a meanwhile established therapy option, which is most frequently performed using radiofrequency ablation. Mid-term success rate of 70 % are achievable with a single ablation procedure. However, the mechanistics of persistent atrial fibrillation are less well understood and catheter ablation is a far more challenging procedure. Different ablation approaches are being performed to treat persistent atrial fibrillation ranging from sole pulmonary vein isolation to additional ablation of fractionated electrograms aiming for termination of atrial fibrillation. Thus far, it has not been investigated which strategy is most successful in treating persistent atrial fibrillation. After extended ablation of atrial fibrillation, occurrence of organized atrial arrhythmias is not uncommon and can be successfully ablated. These consecutive arrhythmias can be considered as a next step towards stable sinus rhythm after repeat ablation. Improvement of mapping methods as well as a better understanding of mechanisms of atrial fibrillation may increase success rate of catheter ablation of persistent atrial fibrillation and may also help to improve success rate of these complex procedures. PMID- 23625311 TI - Licochalcone E present in licorice suppresses lung metastasis in the 4T1 mammary orthotopic cancer model. AB - We investigated whether licochalcone E (LicE), a phenolic constituent of licorice, inhibits mammary tumor growth and metastasis using animal and cell culture models. 4T1 mammary carcinoma cells were injected into the mammary fat pads of syngeneic BALB/c mice. Starting 7 days after the injection, the mice received LicE (7 or 14 mg/kg body weight/day) via oral gavage for 25 days. LicE suppressed solid tumor growth and lung metastasis, but did not exhibit kidney or liver toxicity. In tumor tissues, LicE treatment induced a reduction in the expression of Ki67, cyclins, and cyclin-dependent kinases and stimulated apoptosis with increased expression of Bax and cleaved caspase-3 but decreased expression of Bcl-2. In addition, LicE decreased expression of CD31, vascular endothelial growth factor (VEGF)-A and C, VEGF-receptor 2, lymphatic vessel endothelial receptor-1, CD45, cyclooxygenase-2, inducible nitric oxide synthase, and hypoxia inducible factor-1alpha in tumor tissues. In lung tissues, LicE reduced the levels of proinflammatory cytokines and angiogenesis/metastasis related proteins. In mammary cancer cell cultures, LicE (5-20 MUmol/L) dose dependently inhibited cell migration and invasion. LicE inhibited secretion of matrix metalloproteinase-9, urokinase-type plasminogen activator and VEGF-A, and stimulated secretion of tissue inhibitor of metalloproteinase-2 in MDA-MB-231 cells. In addition, LicE inhibited tube formation of vascular endothelial cells. We show that LicE administration suppressed tumor growth and lung metastasis in the mouse model in conjunction with LicE inhibition of cell migration, invasion, and tube formation in vitro. Reduced tumor growth and metastasis in LicE-treated mice may be, at least in part, attributed to reduced inflammation and tumor angiogenesis. PMID- 23625310 TI - [Patient selection for the implantation of a left atrial appendage occluder in primary and secondary prevention of cardioembolic stroke in atrial fibrillation]. AB - The implantation of a left atrial appendage (LAA) occluder has evolved into an established non-pharmacological alternative to oral anticoagulation (OAC) in the prevention of cardioembolic stroke in patients with atrial fibrillation. While 2 randomized trials investigated the LAA occluder as an alternative treatment in patients who can also undergo OAC, current guidelines recommend the LAA occluder rather as a second line therapy if permanent OAC is not possible due to contraindications. This is in line with current practice where an LAA occluder is usually only implanted if OAC is contraindicated or stopped due to bleeding. The LAA occluder seems most promising for patients with a high risk for both, stroke without OAC and severe bleeding with OAC. After patient informed consent, the LAA occluder may also represent an option for patients who are unwilling to undergo OAC. Since a large proportion of patients do not receive OAC despite an indication (because of contraindications or mere fear of bleeding) and since the majority of patients have to stop OAC during the course of 2 years, mostly due to bleeding, the LAA occluder may play an important role in the long-term prophylaxis of cardioembolic stroke due to atrial fibrillation. PMID- 23625312 TI - Flotillin-1 mediates PrPc endocytosis in the cultured cells during Cu2+ stimulation through molecular interaction. AB - Flotillins are membrane association proteins consisting of two homologous members, flotillin-1 (Flot-1) and flotillin-2 (Flot-2). They define a clathrin independent endocytic pathway in mammal cells, which are also distinct from some other endocytosis mechanisms. The implicated cargoes of the flotillin-dependent pathway are mainly some GPI-anchored proteins, such as CD59 and Thy-1, which positionally colocalize with flotillins at the plasma membrane microdomains. To see whether flotillins are involved in the endocytosis of PrP(C), the potential molecular interaction between PrP(C) and flotillins in a neuroblastoma cell line SK-N-SH was analyzed. Co-immunoprecipitation assays did not reveal a detectable complex in the cell lysates of a normal feeding situation. After stimulation of Cu(2+), PrP(C) formed a clear complex with Flot-1, but not with Flot-2. Immunofluorescent assays illustrated that PrP(C) colocalized well with Flot-1, and the complexes of PrP(C)-Flot-1 shifted from the cell membrane to the cytoplasm along with the treatment of Cu(2+). Down-regulating the expression of Flot-1 in SK-N-SH cells by Flot-1-specific RNAi obviously abolished the Cu(2+) stimulated endocytosis process of PrP(C). Moreover, we also found that in the cell line human embryonic kidney 293 (HEK293) without detectable PrP(C) expression, the distribution of cellular Flot-1 maintained almost unchanged during Cu(2+) treatment. Cu(2+)-induced PrP(C)-Flot-1 molecular interaction and endocytosis in HEK293 cells were obtained when expressing wild-type human PrP (PrP(PG5)), but not in the preparation expressing octarepeat-deleted PrP (PrP(PG0)). Our data here provide direct evidences for the molecular interaction and endocytosis of PrP(C) with Flot-1 in the presence of copper ions, and the octarepeat region of PrP(C) is critical for this process, which strongly indicates that the Flot-1-dependent endocytic pathway seems to mediate the endocytosis process of PrP(C) in the special situation. PMID- 23625313 TI - Abortive cell cycle events in the brains of scrapie-infected hamsters with remarkable decreases of PLK3/Cdc25C and increases of PLK1/cyclin B1. AB - Polo-like kinases (PLKs) consist of a family of kinases which play critical roles during multiple stages of cell cycle progression. Increase of PLK1 and decrease of PLK3 are associated with the developments and metastases of many types of human malignant tumors; however, the situations of PLKs in prion diseases are less understood. Using Western blots and immunohistochemical and immunofluorescent assays, marked increase of PLK1 and decrease of PLK3 were observed in the brains of scrapie strain 263K-infected hamsters, presenting obviously a time-dependent phenomenon along with disease progression. Similar alterations of PLKs were also detected in a scrapie infectious cell line SMB-S15. Both PLK1 and PLK3 were observed in neurons by confocal microscopy. Accompanying with the changes of PLKs in the brains of 263K-infected hamsters, Cdc25C and its phosphorylated forms (p-Cdc25C-Ser198 and p-Cdc25C-Ser216) were significantly down-regulated, whereas Cyclin B1 and PCNA were obviously up-regulated, while phospho-histone H3 remained almost unchanged. Moreover, exposure of the cytotoxic peptide PrP106-126 on the primary cultured cortical neuron cells induced similar changes of cellular PLKs and some cell cycle-related proteins, such as Cdc25C and its phosphorylated forms, phospho-histone H3. Those results illustrate obviously aberrant expressions of cell cycle regulatory proteins in the prion-infected neurons, which may lead to the cell cycle arrest at M phase. Possibly due to the ill-regulation of some key cell cycle events during prion infection, together with the fact that neurons are unable to complete mitosis, the cell cycle reentry in prion-infected neurons is definitely abortive, which may lead to neuron apoptosis and neuron degeneration. PMID- 23625314 TI - Autophagy modulation for Alzheimer's disease therapy. AB - Autophagy is an essential and conserved lysosomal degradation pathway that controls the quality of cytoplasm by eliminating the intracellular aggregated proteins and damaged organelles. Autophagy works in mammalian target of rapamycin (mTOR)-dependent pathway or mTOR-independent pathway to keep the neuronal homeostasis. Mounting evidence has implicated the importance of defective autophagy in the pathogenesis of aging and neurodegenerative diseases, especially in Alzheimer's disease (AD). It has also demonstrated a neuroprotective role of autophagy in mediating the degradation of amyloid beta and tau which are major factors of AD. Amounts of molecules function in either mTOR-dependent pathway or mTOR-independent pathway to induce autophagy, which maybe a potential treatment for AD. In this review, we summarize the latest studies concerning the role of autophagy in AD and explore autophagy modulation as a potential therapeutic strategy for AD. However, to date, little of the researches on autophagy have been performed to investigate the modulation in AD; more investigations need to be confirmed in the future. PMID- 23625316 TI - Freezing of gait in Parkinson's disease: where are we now? AB - Freezing of gait (FOG) is defined as a brief, episodic absence or marked reduction of forward progression of the feet despite the intention to walk. It is one of the most debilitating motor symptoms in patients with Parkinson's disease (PD) as it may lead to falls and a loss of independence. The pathophysiology of FOG seems to differ from the cardinal features of PD and is still largely unknown. In the present paper, we review the studies that were performed since 2011 on methods to provoke and assess FOG and discuss new insights into behavioral and neural mechanisms underlying this clinical phenomenon. We conclude that most of the work reviewed confirms that gait pattern generation disturbances are central to FOG. The finding that FOG reflects a combined motor and cognitive de-automatization deficit, which may not be sufficiently offset by executive control, probably acts as parallel mechanism. PMID- 23625315 TI - LXR agonists: new potential therapeutic drug for neurodegenerative diseases. AB - Liver X receptors (LXRs) are nuclear receptors involved in the regulation of lipid metabolism and inflammatory responses in the central nervous system. Defects in cholesterol homeostasis contribute to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. Inflammatory responses could enhance the neurodegenerative process or act independently. The natural and synthetic LXR agonists induce the transcriptional activity of LXR target genes, thus attenuate the imbalance of cholesterol metabolism and overactivation of microglia and astrocytes in inflammation and are widely used in a variety of neurodegenerative diseases animal models. By developing more specific, potent, penetrable, and functional LXR agonist may lead to a better curative effect for neurodegenerative diseases and avoidance of potentially deleterious side effects. Here, we focus on recent advances in our understanding of the role of LXRs and their agonists in cholesterol homeostasis, inflammation, and the potential therapeutic effects in neurodegenerative diseases. PMID- 23625317 TI - Preparation, characterization and in vitro release properties of morphine-loaded PLLA-PEG-PLLA microparticles via solution enhanced dispersion by supercritical fluids. AB - Morphine-loaded poly(L-lactide)-poly(ethylene glycol)-poly(L-lactide) (PLLA-PEG PLLA) microparticles were prepared using solution enhanced dispersion by supercritical CO2 (SEDS). The effects of process variables on the morphology, particles size, drug loading (DL), encapsulation efficiency and release properties of the microparticles were investigated. All particles showed spherical or ellipsoidal shape with the mean diameter of 2.04-5.73 MUm. The highest DL of 17.92 % was obtained when the dosage ratio of morphine to PLLA-PEG PLLA reached 1:5, and the encapsulation efficiency can be as high as 87.31 % under appropriate conditions. Morphine-loaded PLLA-PEG-PLLA microparticles displayed short-term release with burst release followed by sustained release within days or long-term release lasted for weeks. The degradation test of the particles showed that the degradation rate of PLLA-PEG-PLLA microparticles was faster than that of PLLA microparticles. The results collectively suggest that PLLA-PEG-PLLA can be a promising candidate polymer for the controlled release system. PMID- 23625318 TI - PolyNaSS grafting on titanium surfaces enhances osteoblast differentiation and inhibits Staphylococcus aureus adhesion. AB - Titanium surface modifications to simultaneously prevent bacterial adhesion but promote bone-cell functions could be highly beneficial for improving implant osseointegration. In the present in vitro study, the effect of sulfonate groups on titanium surfaces was investigated with respect to both S. aureus adhesion and osteoblast functions pertinent to new bone formation. Commercial pure titanium (cpTi) squares were oxydized (Tiox), grafted with poly(sodium styrene sulfonate) groups (Tigraft) by covalent bonding using radical polymerization, and were characterized by infrared spectroscopy (HATR-FTIR) and colorimetry. Bacterial adhesion study showed that Tigraft exhibited high inhibition of S. aureus adhesion S at levels >90 %, when compared to cpTi (P < 0.05). In contrast osteoblasts adhesion was similar on all three titanium surfaces. While the kinetics of cell proliferation were similar on the three titanium surfaces, Alkaline phosphatase-specific activity of osteoblasts cultured on Tigraft surfaces was twofold higher than that observed on either on Tiox or cpTi surfaces (P < 0.01). More importantly, the amount and the distribution of calcium containing nodules was different. The total area covered by calcium-containing nodules was 2.2-fold higher on the Tigraft as compared to either Tiox or cpTi surfaces (P < 0.01). These results provide evidence that poly(sodium styrene sulfonate) groups grafting on cpTi simultaneously inhibits bacteria adhesion but promote osteoblast function pertinent to new bone formation. Such modified titanium surfaces offer a promising strategy for preventing biofilm-related infections and enhancing osteointegration of implants in orthopaedic and dental applications. PMID- 23625319 TI - A novel porous scaffold fabrication technique for epithelial and endothelial tissue engineering. AB - Porous scaffolds have the ability to minimize transport barriers for both two- (2D) and three-dimensional tissue engineering. However, current porous scaffolds may be non-ideal for 2D tissues such as epithelium due to inherent fabrication based characteristics. While 2D tissues require porosity to support molecular transport, pores must be small enough to prevent cell migration into the scaffold in order to avoid non-epithelial tissue architecture and compromised function. Though electrospun meshes are the most popular porous scaffolds used today, their heterogeneous pore size and intense topography may be poorly-suited for epithelium. Porous scaffolds produced using other methods have similar unavoidable limitations, frequently involving insufficient pore resolution and control, which make them incompatible with 2D tissues. In addition, many of these techniques require an entirely new round of process development in order to change material or pore size. Herein we describe "pore casting," a fabrication method that produces flat scaffolds with deterministic pore shape, size, and location that can be easily altered to accommodate new materials or pore dimensions. As proof-of-concept, pore-cast poly(epsilon-caprolactone) (PCL) scaffolds were fabricated and compared to electrospun PCL in vitro using canine kidney epithelium, human colon epithelium, and human umbilical vein endothelium. All cell types demonstrated improved morphology and function on pore-cast scaffolds, likely due to reduced topography and universally small pore size. These results suggest that pore casting is an attractive option for creating 2D tissue engineering scaffolds, especially when the application may benefit from well-controlled pore size or architecture. PMID- 23625320 TI - Influence of acid-etching after grit-blasted on osseointegration of titanium dental implants: in vitro and in vivo studies. AB - Rough implant surfaces have shown improved osseointegration rates. In a majority of dental implants, the microrough surfaces are obtained by grit blasting and/or acid-etching. The aim of this contribution was to evaluate the effects of acid etching, after the grit-blasted treatment in titanium dental implants, on surface wettability, surface energy, osteoblast responses and its osseointegration behavior. Four surfaces were studied: as-machined, acid-etched, micro-rough by grit-blasting and the combination grit-blasted surface with acid-etched. The surfaces with increasing roughness show more osteoblastic adhered cells. This effect was most pronounced on samples blasted and blasted with acid-etching. The roughness obtained by grit-blasting is the main factor in comparison with the acid etching treatment in the biological response. These results were confirmed in vivo tests and histological analysis. The results demonstrated that the combination of the grit-blasted and acid-etched accelerated lightly bone regeneration at the different periods of implantation in comparison with the grit blasted implants. PMID- 23625321 TI - Elastin and collagen enhances electrospun aligned polyurethane as scaffolds for vascular graft. AB - Mismatch in mechanical properties between synthetic vascular graft and arteries contribute to graft failure. The viscoelastic properties of arteries are conferred by elastin and collagen. In this study, the mechanical properties and cellular interactions of aligned nanofibrous polyurethane (PU) scaffolds blended with elastin, collagen or a mixture of both proteins were examined. Elastin softened PU to a peak stress and strain of 7.86 MPa and 112.28 % respectively, which are similar to those observed in blood vessels. Collagen-blended PU increased in peak stress to 28.14 MPa. The growth of smooth muscle cells (SMCs) on both collagen-blended and elastin/collagen-blended scaffold increased by 283 and 224 % respectively when compared to PU. Smooth muscle myosin staining indicated that the cells are contractile SMCs which are favored in vascular tissue engineering. Elastin and collagen are beneficial for creating compliant synthetic vascular grafts as elastin provided the necessary viscoelastic properties while collagen enhanced the cellular interactions. PMID- 23625322 TI - Bevacizumab versus ranibizumab: why are we not playing the joker? PMID- 23625323 TI - Cognitive assessment of patients with minimal hepatic encephalopathy in Brazil. AB - Minimal hepatic encephalopathy is a syndrome caused by liver cirrhosis and accompanied by a broad spectrum of cognitive symptoms. The objective of the present study was to describe the prevalence of minimal hepatic encephalopathy in cirrhotic patients and to compare their cognitive performance with controls using standardized tests. Patients receiving medication or experiencing comorbidities associated with cognitive disorders were excluded. The final cohort was compared with a control-matched group using the Mini-Mental State Examination (MMSE), as well as Simple Drawing, Clock Drawing, Rey Auditory-Verbal Learning Test (RAVLT), Random Letter, Stroop, Trail-Making Test (TMT) A and B, Boston Naming, Category Verbal Fluency, Digit Span, Constructional Praxis, Processing Speed, and Similarities Tests. The results indicated no differences in the prevalence of cognitive complaints spontaneously reported by 29 patients with cirrhosis versus 22 healthy controls. The most affected tests included: MMSE (26.3 +/- 2 vs. 28.1 +/- 1.8 points; p = 0.004), learning (35.4 +/- 9 vs. 41 +/- 9.1 points; p = 0.041), retroactive interference (0.67 +/- 0.22 vs. 0.84 +/- 0.16 points; p = 0.004), and recognition (8.7 +/- 2.6 vs. 11.2 +/- 4.1 points; p = 0.024) in RAVLT, TMT-A (63.2 +/- 29.3 vs. 47.6 +/- 16.5 s; p = 0.029) and TMT-B (197.9 +/- 88.1 vs. 146.8 +/- 76.5 s; p = 0.03). No differences were observed with respect to age, gender, and education. In conclusion, MMSE proved to be a useful tool for detecting global cognitive impairment experienced by cirrhosis patients. Moreover, the most impaired cognitive functions were verbal episodic memory and information processing speed. These findings suggest that minimal hepatic encephalopathy represents a disorder that affects the medial temporal system and, possibly, the prefrontal cortex, and this requires further study. PMID- 23625324 TI - [Anticoagulation]. AB - Anticoagulant drugs belong to the group of antithrombotic agents and are successfully used in the prophylaxis and treatment of thromboembolic disorders. The use of anticoagulants in the prevention of deep venous thrombosis has significantly lowered the risk of venous thrombosis and fatal pulmonary embolisms even in high-risk situations such as orthopedic surgery. Anticoagulants play a central role in the treatment of acute venous thrombosis and in the prevention of recurrent events. Long-term anticoagulation therapy with orally active anticoagulants significantly reduces the risk of thromboembolic complications in patients showing cardiac arrhythmias. Whereas a few years ago heparins and vitamin K antagonists were the dominant anticoagulants, today a wide range of anticoagulants with improved pharmacological profiles are available. It remains an open question whether these new anticoagulants will improve the efficacy, safety, and acceptance of anticoagulant treatment approaches. PMID- 23625325 TI - Composition and characteristics of distinct macrophage subpopulations in the mouse thymus. AB - The aim of the present study was to investigate the composition, morphology, characteristics, distribution and function of distinct macrophage subpopulations in the mouse thymus. Apoptosis of mouse thymocytes was induced by glucocorticoids and three monoclonal antibodies against Mac-2, F4/80 and ED1 were used for immunofluorescence staining and immunohistochemical analysis. The morphology of thymic macrophages was examined by transmission electron microscopy. Four subpopulations of mouse thymic macrophages were identified. Dendritic macrophages were identified using anti-Mac-2 and anti-F4/80 antibodies, and were demonstrated to be distributed in the entire thymus. Phagocytes were also observed. In addition, plate-shaped macrophages, identified using the anti-F4/80 antibody, were distributed under the thymic cortex capsule. Small oval macrophages, identified using the anti-Mac-2 antibody, were distributed in the thymic medulla and corticomedullary region (CMR), while phagocytes were not observed in these types of cell. ED1+ thymic macrophages with irregular forms were distributed in the CMR. All of the four subpopulations of mouse thymic macrophages described above exhibited acid phosphate activity. This study indicated the existence of macrophage subpopulations with different shapes, distribution and functions in the mouse thymus. PMID- 23625326 TI - Triple therapy with darbepoetin alfa, idebenone, and riboflavin in Friedreich's ataxia: an open-label trial. AB - Minimal objective evidence exists regarding management of Friedreich's ataxia (FRDA). Antioxidant and recombinant human erythropoietin therapies have been considered potential treatments to slow progression of FRDA in a small number of studies. The primary objective of the current study was to test the efficacy, safety, and tolerability of triple therapy-darbepoetin alfa, idebenone, and riboflavin-in FRDA in a clinical pilot study. Patients included in this study were nine females, 16 to 45 years of age (average 28 +/- 8), diagnosed with FRDA with confirmed GAA repeat expansion mutations in the FXN gene and a GAA repeat >=400 on the shorter allele. Patients had a baseline score between 8 and 28.5 (average 20.7 +/- 8.3) on the scale for the assessment and rating of ataxia and 94.3 +/- 27.2 g/m(2) in left ventricular mass index (LVMI). Patients had been treated with triple therapy with 150 MUg darbepoetin alfa every 2 or 3 weeks, 10 20 mg/kg/day idebenone, and 10-15 mg/kg/day riboflavin for 32 +/- 19.4 months (range of 8-56 months). Triple therapy was tolerated. Although not statistically significant, improvement of ataxia was observed during the first six 4-month periods of the study. Furthermore, a small decrease in disease progression during the first 2 years of treatment was observed. Long-term statistically nonsignificant improvement of LVMI and stability of the echocardiographic parameters could be considered. Triple therapy may slow disease progression of FRDA. PMID- 23625327 TI - Cerebellar TMS in treatment of a patient with cerebellar ataxia: evidence from clinical, biomechanics and neurophysiological assessments. AB - We describe a patient with a probable diagnosis of idiopathic late-onset cerebellar atrophy who shows improvement of limb coordination, speech, and gait following 21 days of transcranial magnetic stimulation (TMS) applied to scalp regions presumably corresponding to the cerebellum. This case study provides, for the first time, a quantitative assessment of gait improvement in response to TMS therapy in ataxia, as well as neurophysiological evidence in support of modification of cerebellar-cortical interaction that may underlie some of the improvements. PMID- 23625328 TI - Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study. AB - PURPOSE: Some targeted anticancer agents are associated with serious ventricular tachyarrhythmias, which may be predicted by electrocardiographic evaluation of drug-related QT prolongation. We studied the effects of nintedanib (BIBF 1120; an oral, triple angiokinase inhibitor targeting vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors) on the QT interval in patients with renal cell carcinoma (RCC) participating in an open label phase II trial. METHODS: Treatment-naive, adult patients with unresectable/metastatic, clear cell RCC received nintedanib 200 mg twice daily. QT intervals were evaluated at baseline (day -1), on day 1 (after the first dose), and on day 15 (steady state) by 12-lead electrocardiograms (ECGs) performed in triplicate. Pharmacokinetic sampling was also undertaken. RESULTS: Among 64 evaluable patients, the upper limits of the 2-sided 90 % confidence intervals for the adjusted mean time-matched changes in QTcF interval (corrected for heart rate by Fridericia's method) from baseline to day 1 and 15 (primary ECG endpoint) were well below the regulatory threshold of 10 ms at all times. No relationship between nintedanib exposure and change from baseline in QTcF was seen. Nintedanib was generally well tolerated with no drug-related cardiovascular adverse events. CONCLUSION: Nintedanib administered at 200 mg twice daily was not associated with clinically relevant QT prolongation. PMID- 23625329 TI - Design of multishell sampling schemes with uniform coverage in diffusion MRI. AB - PURPOSE: In diffusion MRI, a technique known as diffusion spectrum imaging reconstructs the propagator with a discrete Fourier transform, from a Cartesian sampling of the diffusion signal. Alternatively, it is possible to directly reconstruct the orientation distribution function in q-ball imaging, providing so called high angular resolution diffusion imaging. In between these two techniques, acquisitions on several spheres in q-space offer an interesting trade off between the angular resolution and the radial information gathered in diffusion MRI. A careful design is central in the success of multishell acquisition and reconstruction techniques. METHODS: The design of acquisition in multishell is still an open and active field of research, however. In this work, we provide a general method to design multishell acquisition with uniform angular coverage. This method is based on a generalization of electrostatic repulsion to multishell. RESULTS: We evaluate the impact of our method using simulations, on the angular resolution in one and two bundles of fiber configurations. Compared to more commonly used radial sampling, we show that our method improves the angular resolution, as well as fiber crossing discrimination. DISCUSSION: We propose a novel method to design sampling schemes with optimal angular coverage and show the positive impact on angular resolution in diffusion MRI. PMID- 23625330 TI - Sirenomelia: a review on embryogenic enviromental theories, novel three dimensional ultrasound imaging and first trimester diagnosis in a case of mosaic 69,XXX/46,XX fetus. AB - PURPOSE: Sirenomelia is caused by atrophy of the lower extremities that is commonly associated with gastrointestinal and urogenital malformations. METHODS: Embryogenic environmental theories and systematic review of the literature are reported. RESULTS: Genetic basis of the condition has been demonstrated in the animal model. In humans, association with de novo balanced translocation has only recently been documented. CONCLUSIONS: A case of triploidy mosaic fetus with sirenomelia and posterior fossa anomaly diagnosed at first trimester using novel three-dimensional ultrasound imaging techniques is presented. PMID- 23625331 TI - The effect of oral evening primrose oil on menopausal hot flashes: a randomized clinical trial. AB - PURPOSE: Hot flashes are common experience for menopausal women, and for many, are severe enough to significantly compromise their overall sense of well being and quality of life. The aim of this study was to compare the efficacy of evening primrose with placebo in improvement of menopausal hot flashes. METHODS: In a 6 week randomized clinical trial, a total of 56 menopausal women aged 45-59 years were participated in this study. The patients were asked for their hot flashes characteristics and responded to HFRDIS (hot flash related daily interference scale) questionnaire before and after the intervention. The participants were randomly assigned to take two capsules per day (totally 90 capsules for 6 weeks) of placebo or evening primrose (500 mg) for continuous 6 weeks. Then, the improvement in hot flashes was compared between two groups. RESULTS: The percent of improvement in hot flash frequency, severity and duration were 39, 42 and 19 %, in evening primrose group compared with 32, 32 and 18 % in placebo group, respectively. Although all three characters of hot flash was ameliorated in evening primrose arm, only its severity was significantly better in this arm compared with placebo group (P < 0.05). All HFRDIS score were significantly improved in two groups, but the percentage of improvement in social activities, relations with others, and sexuality was significantly superior to placebo group (P < 0.05). CONCLUSIONS: The application of oral evening primrose oil compared with placebo for controlling hot flashes may decrease more the intensity of attacks as well as ameliorating the HFRDIS score. PMID- 23625332 TI - Metabolic dysfunctions in Nigerian pre-eclamptics. AB - AIM: The patho-physiology of pre-eclampsia is not fully understood. This study determined the plasma levels of markers of oxidative stress, thyroid hormones, nitric oxide, C-reactive protein, and nutritional profiles in pre-eclamptic patients. METHODS: Thirty-two pregnant women with pre-eclampsia and 40 women with normal pregnancy (controls) participated in this study. The pre-eclamptics were recruited after 20 weeks of gestation. They presented with hypertension (systolic pressure = 169 +/- 26.0 mmHg, diastolic pressure = 102 +/- 11.0 mmHg), significant proteinuria (368 +/- 39 mg/24 h), severe headache, abdominal pain and vomiting. The plasma levels of total antioxidant potential (TAP), total plasma peroxides (TPP), total cholesterol (TC), total protein (TP), albumin, globulin, nitric oxide (NO), C-reactive protein (CRP), total tri-iodotyronine (TT3) and thyroid stimulating hormone (TSH) were determined in them using spectrophotometry, radial immunodiffusion and enzyme linked immunosorbent assay (ELISA) methods, respectively. Oxidative stress index (OSI) was calculated as the percent ratio of TPP and TAP. RESULTS: The weight and body mass index of pre eclamptics increased significantly (p < 0.05) when compared with the controls. The mean systolic and diastolic blood pressure increased significantly (p < 0.001) in pre-eclamptics when compared with the controls. Plasma mean values of TAP, NO, albumin, TP and TT3 decreased significantly (p < 0.05) in pre-eclamptics when compared with the controls. The plasma mean values of TSH, TPP, OSI, CRP, and TC increased significantly (p < 0.05) in pre-eclamptics when compared with the controls. There was no significant change in the plasma value of globulin when compared with the controls. TT3 correlated positively with plasma TP and globulin in the pre-eclamptics. CONCLUSION: It could be concluded that hypothyroidism, hypercholesterolemia, oxidative stress and deranged inflammatory responses are possible features of pre-eclampsia. PMID- 23625333 TI - LigaSure vessel sealing system in vaginal hysterectomy: safety, efficacy and limitations. AB - PURPOSE: The aim of this study is to compare vaginal hysterectomy performed with standard technique versus the one performed with LigaSure. METHODS: Observational longitudinal-cohort study on 42 women candidates to vaginal hysterectomy because of benign uterine pathology. Outcome variables, methods of analysis, inclusion and exclusion criteria were determined prospectively. Eligible patients were subdivided in Group-A (LigaSure-21 patients), or in Group-B (classical-21 patients). Group-A was divided into Subgroup-A1 (10 patients) and Subgroup-A2 (11 patients), depending on the point where the stump of the uterosacral-ligament was transfixed: Subgroup-A1 at cervical portion, Subgroup-A2 at intermediate portion. For all patients were reported: pre-post surgery haemoglobin and hematocrit, number of sutures, duration of intervention and blood loss, NRS-score on first/third post-operative days. All patients underwent gynaecological examination 30 and 180 days after surgery. RESULTS: General characteristics did not show significant differences between the two groups. Statistically significant differences emerged from the comparison between Group-A versus Group B in terms of: intraoperative bleeding, post-operative value of haemoglobin, Delta-Hb, number of sutures, surgical time, pain at first and third post operative day. The 180 days follow-up demonstrated four cases of vaginal vault prolapse, only in the Subgroup-A1 related to thermal damage of the uterosacral ligament. CONCLUSION: LigaSure vessel sealing system is a safe alternative for securing pedicles in vaginal hysterectomy with significant improvement in patients outcome. Following vaginal vault prolapse, we determined the optimal fixation-site to perform the colposuspension in the intermediate portion of the uterosacral-ligament, especially if the cervical portion received a thermal damage, as occurs during the LigaSure use. PMID- 23625334 TI - Influence of prophylactic oophorectomy on mood and sexual function in women of menopausal transition or postmenopausal period. AB - AIM: To evaluate the impact of prophylactic oophorectomy on mood and sexual function in women at menopausal transition or postmenopausal period. METHODS: Patients who underwent operations due to benign diseases of uterus and ovaries were included and were stratified into two groups, namely Group A with 256 patients undergoing hysterectomy and prophylactic oophorectomy and Group B with 337 patients undergoing simple hysterectomy. Follow-ups included demographic data, Self-Rating Zung Depression Scale (ZDS), Self-Rating Zung Anxiety Scale (ZAS), and Female Sexual Function of Index (FSFI). RESULTS: Five hundred and ninety-three patients were successfully followed. 69.27 % of patients at menopausal transition period chose ovary conservation whilst 79.22 % of postmenopausal women chose oophorectomy due to fear of potential cancer and economy issue. Ovarian cancer was not found in this cohort. Incidence of distress was higher in Group A (P = 0.001). No difference was obtained in ZAS scores between the two groups (P = 0.110). Incidence of anxiety was higher in Group A (P = 0.010). Percentage of patients scoring above 20 in FSFI was significantly higher in Group B (P = 0.003). Oophorectomy and marital status were independent factors for depression (P = 0.009 and <0.001, respectively). CONCLUSION: Adverse influence on mental and sexual status was severer in women undergoing prophylactic oophorectomy at menopausal transition or postmenopausal period. Comprehensive evaluation may contribute to better ovary conservation strategy for women with benign morbidities. PMID- 23625335 TI - Nitric oxide, oxidant status and antioxidant response in morbidly obese patients: the impact of 1-year surgical weight loss. AB - BACKGROUND: The aims of this study were to evaluate nitric oxide (NO) metabolites (nitrite/nitrate NO x ) as proinflammatory parameter and total oxidant status (TOS) as well as total antioxidant response (TAR) as oxidative stress (OS) markers in morbidly obese (MO) patients in comparison with normal-weight healthy (NWH) subjects and to determine the post-bariatric surgery changes of NO x and OS indicators in relation with weight loss. METHODS: We examined serum NO x , TOS, and TAR in a bariatric group of MO patients and a NWH control group (n = 23 each group). In the NWH group, serum was examined once, while in the MO group, serum was examined before and at 3, 6, and 12 months after silastic ring vertical gastroplasty (SRVG). RESULTS: Serum NO x and TOS values were higher (p < 0.001), while TAR level was lower (p < 0.001) in MO patients as compared to the NWH group. No significant changes occurred at 12 months after surgery in the MO group as far as the NO x (p = 0.93), TOS (p = 0.11), and TAR (p = 0.15) levels were concerned as compared to baseline values. However, NO x increased at 6 months after surgery (p < 0.008) and then decreased by the 12th month after SRVG (p < 0.008), reaching almost baseline values. CONCLUSIONS: At baseline, there was a high production of proinflammatory and OS markers in MO patients. SRVG surgical weight loss was not accompanied by significant changes of these parameters at 1 year after surgery. PMID- 23625336 TI - Investigation of coupled bending of the lumbar spine during dynamic axial rotation of the body. AB - PURPOSE: Little is known about the coupled motions of the spine during functional dynamic motion of the body. This study investigated the in vivo characteristic motion patterns of the human lumbar spine during a dynamic axial rotation of the body. Specifically, the contribution of each motion segment to the lumbar axial rotation and the coupled bending of the vertebrae during the dynamic axial rotation of the body were analyzed. METHODS: Eight asymptomatic subjects (M/F, 7/1; age, 40-60 years) were recruited. The lumbar segment of each subject was MRI scanned for construction of 3D models of the vertebrae from L2 to S1. The lumbar spine was then imaged using a dual fluoroscopic system while the subject performed a dynamic axial rotation from maximal left to maximal right in a standing position. The 3D vertebral models and the fluoroscopic images were used to reproduce the in vivo vertebral motion. In this study, we analyzed the primary left-right axial rotation, the coupled left-right bending of each vertebral segment from L2 to S1 levels. RESULTS: The primary axial rotations of all segments (L2-S1) followed the direction of the body axial rotation. Contributions of each to the overall segment axial rotation were 6.7 degrees +/- 3.0 degrees (27.9 %) for the L2-L3, 4.4 degrees +/- 1.2 degrees (18.5 %) for the L3-L4, 6.4 degrees +/- 2.2 degrees (26.7 %) for the L4-L5, and 6.4 degrees +/- 2.6 degrees (27.0 %) for the L5-S1 vertebral motion segments. The upper segments of L2-L3 and L3-L4 demonstrated a coupled contralateral bending towards the opposite direction of the axial rotation, while the lower segments of L4-L5 and L5-S1 demonstrated a coupled ipsilateral bending motion towards the same direction of the axial rotation. Strong correlation between the primary axial rotation and the coupled bending was found at each vertebral level. We did not observe patterns of coupled flexion/extension rotation with the primary axial rotation. CONCLUSIONS: This study demonstrated that a dynamic lumbar axial rotation coupling with lateral bendings is segment-dependent and can create a coordinated dynamic coupling to maintain the global dynamic balance of the body. The results could improve our understanding of the normal physiologic lumbar axial rotation and to establish guidelines for diagnosing pathological lumbar motion. PMID- 23625337 TI - Severe sprains of the sub-axial cervical spine in adolescents: a diagnostic and therapeutic challenge: a report of three cases. AB - BACKGROUND: Sub-axial cervical spine(C spine) distraction flexion injuries, known as cervical sprains, have been divided into either "benign" or "severe" sprains depending on the integrity of the posterior longitudinal ligament (PLL) of the spinal column. It is a very uncommon injury and rarely reported in the literature. Most of the reports in the literature discuss this injury in the adult age group and so the adolescent age group was also considered to follow the same model of progression of mechanical instability depending on the degree and extent of structures injured, including the PLL as a cutoff factor between a "stable" and an "unstable" injury. PATIENTS AND METHODS: We report three cases of adolescents with severe cervical sprains at the C2-C3 level and argue the integrity of PLL as a determinant factor in the sagittal stability of the C spine in this age group. PMID- 23625338 TI - Finding and fixing mistakes: do checklists work for clinicians with different levels of experience? AB - Checklists that focus attention on key variables might allow clinicians to find and fix their mistakes. However, whether this approach can be applied to clinicians of varying degrees of expertise is unclear. Novice and expert clinicians vary in their predominant reasoning processes and in the types of errors they commit. We studied 44 clinicians with a range of electrocardiography (ECG) interpretation expertise: novice, intermediate and expert. Clinicians were asked to interpret 10 ECGs, self-report their predominant reasoning strategy and then check their interpretation with a checklist. We found that clinicians of all levels of expertise were able to use the checklist to find and fix mistakes. However, novice clinicians disproportionately benefited. Interestingly, while clinicians varied in their self-reported reasoning strategy, there was no relationship between reasoning strategy and checklist benefit. PMID- 23625339 TI - Development of an Epstein-Barr virus-associated lymphoproliferative disorder in a patient treated with azacitidine for chronic myelomonocytic leukaemia. AB - Some chemotherapeutic agents can cause iatrogenic lymphoproliferative disorders. In analogy to what has been observed with other nucleoside analogues such as cladribine and fludarabine, we document the first case of an Epstein-Barr virus positive, iatrogenic immunodeficiency-associated, lymphoproliferative disease, formally resembling polymorphic post-transplant lymphoproliferative disease in a patient treated with azacitidine (Vidaza) for chronic myelomonocytic leukaemia (CMML). A 78-year-old female patient was diagnosed with CMML in January 2012, and treatment with azacitidine was initiated, which lasted for five cycles from February until June 2012. The patient was hospitalized in June 2012 under the suspicion of pneumonia. Transformation of the CMML was suspected at that time too. During hospitalization, a generalized enlargement of the lymph nodes and the spleen was noticed. The patient rapidly deteriorated and finally died of respiratory insufficiency. At autopsy, an Epstein-Barr virus-associated lymphoproliferative disorder, resembling polymorphic post-transplant lymphoproliferative disease with involvement of the lymph nodes, the spleen and the lung and causing necrotizing pneumonia, was diagnosed. Diagnostic criteria for diffuse large B-cell lymphoma or infectious mononucleosis-like lymphoproliferative disease were not met. This is the first documented case of an azacitidine-associated lymphoproliferative disease, raising awareness for possible not yet known side effects of this drug, which should be kept in mind by oncologists and pathologists. PMID- 23625341 TI - Natura non facit saltus in anti-ganglioside antibody-mediated neuropathies. AB - Natura non facit saltus (Latin for "nature does not make jumps") is a maxim expressing the idea that natural things and properties change gradually, in a continuum, rather than suddenly. In biomedical sciences, for taxonomic purposes, we make jumps that emphasize differences more than similarities. Among the dysimmune neuropathies, 2 disorders, characterized by the presence of antibodies to gangliosides GM1 and GD1a and a peculiar, exclusive motor involvement, have been identified: acute motor axonal neuropathy (AMAN) and multifocal motor neuropathy (MMN). However, anti-GM1 or -GD1a antibodies are also associated with acute motor and sensory axonal motor neuropathy (AMSAN). We review the results of recent clinical and experimental studies showing that AMAN and MMN are not exclusively motor. We discuss the possible explanations for the greater resistance of sensory fibers to antibody attack to finally suggest that AMAN, AMSAN, and MMN belong to a continuous spectrum with a common pathophysiological mechanism. PMID- 23625342 TI - Surgical outcome of desmoid tumors: adjuvant radiotherapy delayed the recurrence, but did not affect long-term outcomes. AB - BACKGROUND: We retrospectively reviewed the outcomes of desmoid tumor (DT) patients treated by surgical excision. METHODS: Among 155 consecutive patients, 119 patients satisfied our inclusion criteria. The mean follow-up duration was 82 months. Age, gender, location, size, depth, resection margin, adjuvant radiotherapy, and excision history were analyzed for the outcomes. RESULTS: The recurrence-free survival (RFS) rates were 75% at 5 years and 72% at 10 years. Twenty-seven (93.1%) out of 29 recurrences were detected within 5 years. In multivariate analysis, positive resection margin and excision history were independently associated with the RFS. In the comparison between the propensity score matched groups, adjuvant radiotherapy was not significantly associated with the RFS. The mean time interval from surgery to recurrence was 30.0 +/- 28.7 months (median, 20 months; range, 4-123 months). This interval was significantly longer for patients who received adjuvant radiotherapy than for those who received surgical resection only, both in all recurrences and in recurrences in matched cases. CONCLUSIONS: Surgical excision appears to be a reliable treatment option for DTs. However, positive outcomes require a clear resection margin. Adjuvant radiotherapy may delay the recurrence of the tumor, although it seems to have no effect on the ultimate relapse rate. PMID- 23625340 TI - Current progress for the use of miRNAs in glioblastoma treatment. AB - Glioblastoma (GBM) is a highly aggressive brain cancer with the worst prognosis of any central nervous system disease despite intensive multimodal therapy. Inevitably, glioblastoma is fatal, with recurrence of treatment-resistant tumour growth at distal sites leading to an extremely low median survival rate of 12-15 months from the time of initial diagnosis. With the advent of microarray and gene profiling technology, researchers have investigated trends in genetic alterations and, in this regard, the role of dysregulated microRNAs (highly conserved endogenous small RNA molecules) in glioblastoma has been studied with a view to identifying novel mechanisms of acquired drug resistance and allow for development of microRNA (miRNA)-based therapeutics for GBM patients. Considering the development of miRNA research from initial association to GBM to commercial development of miR-based therapeutics in less than a decade, it is not beyond reasonable doubt to anticipate significant advancements in this field of study, hopefully with the ultimate conclusion of improved patient outcome. This review discusses the recent advancements in miRNA-based therapeutic development for use in glioblastoma treatment and the challenges faced with respect to in vivo and clinical application. PMID- 23625343 TI - 'Dystextia': onset of difficultly writing mobile phone texts determines the time of acute ischaemic stroke allowing thrombolysis. PMID- 23625344 TI - The anatomy of the hip abductor muscles. AB - The anatomy of the hip abductors has not been comprehensively examined, yet is important to understanding function and pathology in the gluteal region. For example, pathology of the hip abductor muscle-tendon complexes can cause greater trochanteric pain syndrome, and may be associated with gluteal atrophy and fatty infiltration. The purpose of this study was to investigate the detailed morphology of gluteus medius (GMed), gluteus minimus (GMin), and tensor fascia lata (TFL), and determine whether the muscles comprised anatomical compartments. The gluteal region from 12 cadavers was dissected and data collected on attachment sites, volume, fascicular and tendinous anatomy, and innervation. Three sites of GMed origin were identified (gluteal fossa, gluteal aponeurosis, and posteroinferior edge of the iliac crest) and the distal tendon had lateral and posterior parts. GMed was the largest in volume (27.6 +/- 11.6 cm(3); GMin 14.1 +/- 11.1 cm(3); TFL 1.8 +/- 0.8 cm(3)). Fascicles of GMin originated from the gluteal fossa, inserting onto the deep surface of its distal tendon and the hip joint capsule. TFL was encapsulated in the fascia lata, having no bony attachment. Primary innervation patterns varied for GMed, with three or four branches supplying different regions of muscle. Distinct secondary nerve branches entered four regions of GMin; no differential innervation was observed for TFL. On the basis of architectural parameters and innervation, GMed, and GMin each comprise of four compartments but TFL is a homogenous muscle. It is anticipated that these data will be useful for future clinical and functional studies of the hip abductors. PMID- 23625345 TI - The role of radiation therapy in small cell lung cancer. AB - Radiotherapy (RT) is fundamental to the care of patients diagnosed with small cell lung cancer (SCLC). In the setting of limited stage disease (LS-SCLC), the addition of thoracic RT to chemotherapy (CHT) improves survival and local control, as demonstrated in decades-worth of randomized clinical trials and subsequent meta-analyses. In extensive stage disease (ES-SCLC), thoracic RT is invaluable in the palliation of chest symptoms but there are suggestions that its use in selected patients may potentially improve overall survival . Prophylactic cranial irradiation (PCI) also improves outcomes in SCLC. For LS-SCLC patients, it reduces brain metastases rates by half and improves overall survival with minimal impact on quality-of-life. Recently, favorable results for PCI with respect to survival and prevention of symptomatic brain disease have been observed for ES-SCLC patients with any response to CHT. Current phase III trials in SCLC RT include studies looking at the optimal dose and target for limited disease and the role of thoracic RT in extensive disease. PMID- 23625346 TI - Comparative proteomics and physiological characterization of Arabidopsis thaliana seedlings in responses to Ochratoxin A. AB - Ochratoxin A (OTA) is a mycotoxin that is primarily produced by Aspergillus ochraceus and Penicillium verrucosum. This mycotoxin is a contaminant of food and feedstock worldwide and may induce cell death in plants. To investigate the dynamic growth process of Arabidopsis seedlings in response to OTA stress and to obtain a better understanding of the mechanism of OTA toxicity towards Arabidopsis, a comparative proteomics study using 2-DE and MALDI-TOF/TOF MS/MS was performed. Mass spectrometry analysis identified 59 and 51 differentially expressed proteins in seedlings exposed to 25 and 45 MUM OTA for 7 days, respectively. OTA treatment decreased root elongation and leaf area, increased anthocyanin accumulation, damaged the photosynthetic apparatus and inhibited photosynthesis. Treatment of the seedlings with 25 MUM OTA enhanced energy metabolism, whereas higher concentration of OTA (45 MUM) inhibited energy metabolism in the seedlings. OTA treatment caused an increase of ROS, an enhancement of antioxidant enzyme defense responses, disturbance of redox homeostasis and activation of lipid oxidation. Glutamine and S-adenosylmethionine metabolism may also play important roles in the response to OTA. In conclusion, our study provided novel insights regarding the response of Arabidopsis to OTA at the level of the proteome. These results are expected to be highly useful for understanding the physiological responses and dissecting the OTA response pathways in higher plants. PMID- 23625347 TI - Efficient and specific cardiac IK1 inhibition by a new pentamidine analogue. AB - AIMS: In excitable cells, KIR2.x ion-channel-carried inward rectifier current (IK1) is thought to set the negative and stable resting membrane potential, and contributes to action potential repolarization. Loss- or gain-of-function mutations correlate with cardiac arrhythmias and pathological remodelling affects normal KIR2.x protein levels. No specific IK1 inhibitor is currently available for in vivo use, which severely hampers studies on the precise role of IK1 in normal cardiac physiology and pathophysiology. The diamine antiprotozoal drug pentamidine (P) acutely inhibits IK1 by plugging the cytoplasmic pore region of the channel. We aim to develop more efficient and specific IK1 inhibitors based on the P structure. METHODS AND RESULTS: We analysed seven pentamidine analogues (PA-1 to PA-7) for IK1 blocking potency at 200 nM using inside-out patches from KIR2.1 expressing HEK-293 cells. PA-6 showed the highest potency and was tested further. PA-6 blocked KIR2.x currents of human and mouse with low IC50 values (12 15 nM). Modelling indicated that PA-6 had less electrostatic but more lipophilic interactions with the cytoplasmic channel pore than P, resulting in a higher channel affinity for PA-6 (DeltaG -44.1 kJ/Mol) than for P (DeltaG -31.7 kJ/Mol). The involvement of acidic amino acid residues E224 and E299 in drug-channel interaction was confirmed experimentally. PA-6 did not affect INav1.5, ICa-L, IKv4.3, IKv11.1, and IKv7.1/minK currents at 200 nM. PA-6 inhibited the inward (50 nM 40%; 100 nM 59%; 200 nM 77%) and outward (50 nM 40%; 100 nM 76%; 200 nM 100%) components of IK1 in isolated canine adult-ventricular cardiomyocytes (CMs). PA-6 prolonged action potential duration of CMs by 8 (n = 9), 26 (n = 5), and 34% (n = 11) at 50, 100, and 200 nM, respectively. Unlike P, PA-6 had no effect on KIR2.1 channel expression at concentrations from 0.1 to 3 MUM. However, PA-6 at 10 MUM increased KIR2.1 expression levels. Also, PA-6 did not affect the maturation of hERG, except when applied at 10 MUM. CONCLUSION: PA-6 has higher efficiency and specificity to KIR2.x-mediated current than P, lengthens action potential duration, and does not affect channel trafficking at concentrations relevant for complete IK1 block. PMID- 23625348 TI - Nanocrystalline spherical hydroxyapatite granules for bone repair: in vitro evaluation with osteoblast-like cells and osteoclasts. AB - Conventionally sintered hydroxyapatite-based materials for bone repair show poor resorbability due to the loss of nanocrystallinity. The present study describes a method to establish nanocrystalline hydroxyapatite granules. The material was prepared by ionotropic gelation of an alginate sol containing hydroxyapatite (HA) powder. Subsequent thermal elimination of alginate at 650 degrees C yielded non sintered, but unexpectedly stable hydroxyapatite granules. By adding stearic acid as an organic filler to the alginate/HA suspension, the granules exhibited macropores after thermal treatment. A third type of material was achieved by additional coating of the granules with silica particles. Microstructure and specific surface area of the different materials were characterized in comparison to the already established granular calcium phosphate material Cerasorb M((r)). Cytocompatibility and potential for bone regeneration of the materials was evaluated by in vitro examinations with osteosarcoma cells and osteoclasts. Osteoblast-like SaOS-2 cells proliferated on all examined materials and showed the typical increase of alkaline phosphatase (ALP) activity during cultivation. Expression of bone-related genes coding for ALP, osteonectin, osteopontin, osteocalcin and bone sialoprotein II on the materials was proven by RT-PCR. Human monocytes were seeded onto the different granules and osteoclastogenesis was examined by activity measurement of tartrate-specific acid phosphatase (TRAP). Gene expression analysis after 23 days of cultivation revealed an increased expression of osteoclast-related genes TRAP, vitronectin receptor and cathepsin K, which was on the same level for all examined materials. These results indicate, that the nanocrystalline granular materials are of clinical interest, especially for bone regeneration. PMID- 23625350 TI - Detection of saccades and postsaccadic oscillations in the presence of smooth pursuit. AB - A novel algorithm for detection of saccades and postsaccadic oscillations in the presence of smooth pursuit movements is proposed. The method combines saccade detection in the acceleration domain with specialized on- and offset criteria for saccades and postsaccadic oscillations. The performance of the algorithm is evaluated by comparing the detection results to those of an existing velocity based adaptive algorithm and a manually annotated database. The results show that there is a good agreement between the events detected by the proposed algorithm and those in the annotated database with Cohen's kappa around 0.8 for both a development and a test database. In conclusion, the proposed algorithm accurately detects saccades and postsaccadic oscillations as well as intervals of disturbances. PMID- 23625349 TI - A new approach for resolution of complex tissue impedance spectra in hearts. AB - This study was designed to test the feasibility of using sinusoidal approximation in combination with a new instrumentation approach to resolve complex impedance (uCI) spectra from heart preparations. To assess that feasibility, we applied stimuli in the 10-4000 Hz range and recorded potential differences (uPDs) in a four-electrode configuration that allowed identification of probe constants (Kp) during calibration that were in turn used to measure total tissue resistivity rhot from rabbit ventricular epicardium. Simultaneous acquisition of a signal proportional to the supplied current (Vstim) with uPD allowed identification of the V- I ratio needed for rhot measurement, as well as the phase shift from Vstim to uPD needed for uCI spectra resolution. Performance with components integrated to reduce noise in cardiac electrophysiologic experiments, in particular, and provide accurate electrometer-based measurements, in general, was first characterized in tests using passive loads. Load tests showed accurate uCI recovery with mean uPD SNRs between 10 (1) and 10 (3) measured with supplied currents as low as 10 nA. Comparable performance characteristics were identified during calibration of nine arrays built with 250 MUm Ag/AgCl electrodes, with uCIs that matched analytic predictions and no apparent effect of frequency ( F = 0.12, P = 0.99). The potential ability of parasitic capacitance in the presence of the electrode-electrolyte interface associated with the small sensors to influence the uCI spectra was therefore limited by the instrumentation. Resolution of uCI spectra in rabbit ventricle allowed measurement of rhot = 134 +/- 53 Omega. cm. The rapid identification available with this strategy provides an opportunity for new interpretations of the uCI spectra to improve quantification of disease-, region-, tissue-, and species-dependent intercellular uncoupling in hearts. PMID- 23625351 TI - Assessment of tumor blood flow distribution by dynamic contrast-enhanced CT. AB - A distinct feature of the tumor vasculature is its tortuosity and irregular branching of vessels, which can translate to a wider dispersion and higher variability of blood flow in the tumor. To enable tumor blood flow variability to be assessed in vivo by imaging, a tracer kinetic model that accounts for flow dispersion is developed for use with dynamic contrast-enhanced (DCE) CT. The proposed model adopts a multiple-pathway approach and allows for the quantification of relative dispersion in the blood flow distribution, which reflects flow variability in the tumor vasculature. Monte Carlo simulation experiments were performed to study the possibility of reducing the number of model parameters based on the Akaike information criterion approach and to explore possible noise and tissue conditions in which the model might be applicable. The model was used for region-of-interest analysis and to generate perfusion parameter maps for three patient DCE CT cases with cerebral tumors, to illustrate clinical applicability. PMID- 23625352 TI - Heat wave hazard classification and risk assessment using artificial intelligence fuzzy logic. AB - The average summer temperatures as well as the frequency and intensity of hot days and heat waves are expected to increase due to climate change. Motivated by this consequence, we propose a methodology to evaluate the monthly heat wave hazard and risk and its spatial distribution within large cities. A simple urban climate model with assimilated satellite-derived land surface temperature images was used to generate a historic database of urban air temperature fields. Heat wave hazard was then estimated from the analysis of these hourly air temperatures distributed at a 1-km grid over Athens, Greece, by identifying the areas that are more likely to suffer higher temperatures in the case of a heat wave event. Innovation lies in the artificial intelligence fuzzy logic model that was used to classify the heat waves from mild to extreme by taking into consideration their duration, intensity and time of occurrence. The monthly hazard was subsequently estimated as the cumulative effect from the individual heat waves that occurred at each grid cell during a month. Finally, monthly heat wave risk maps were produced integrating geospatial information on the population vulnerability to heat waves calculated from socio-economic variables. PMID- 23625353 TI - Changes in urinary catecholamines in response to noise exposure in workers at Sarcheshmeh Copper Complex, Kerman, Iran. AB - Noise is one of the most harmful agents in the workplace. In addition to the adverse effects of noise on the auditory system, as a stressor it may cause increased blood pressure, cardiovascular disease, anxiety, and impaired secretion of hormones. The purpose of this study was to evaluate changes in urinary catecholamines in workers exposed to industrial noise. This is an experimental study of the workers at the smelter section of Sarcheshmeh Copper Industries done on two separate days. During the first day, urine samples from 20 workers who did not use any hearing protection device, were collected during an 8-h work shift and on the second day the same was done but they were asked to use earplugs. Also 20 people were selected as a control group from people who were not exposed to noise at work. Urinary catecholamine levels were measured with ELISA kits. The mean urinary epinephrine and norepinephrine levels in the workers (without earplugs) was respectively 8.69 and 35.56 MUg/8h on the first day and on the second day (with earplugs) dropped to 6.45 and 30.95 MUg/8h. Noise reduction by earplugs led to almost significant reductions in urinary epinephrine (p = 0.05) and significant reductions in norepinephrine (p = 0.02). The results showed that with noise reduction the urinary excretion of stress hormones, especially norepinephrine significantly decreases and workers are probably less prone to stress-related disorders. PMID- 23625354 TI - Ultra-sensitive quantification of copper in food and water samples by electrochemical adsorptive stripping voltammetry. AB - A new electrochemical adsorptive stripping voltammetry method was developed for the determination of trace amounts of copper in food and water samples. The study of electrochemical behavior of Cu ion indicated that Cu(II) and Schiff base formed a complex in H3BO4-NaOH buffer solution (pH = 7.25). An accumulation potential of -100 mV (vs Ag/AgCl) was applied while the solution was stirred for 60 s. The response curve was recorded by scanning the potential, and the peak current of -0.31 V (vs Ag/AgCl) was recorded. The peak current and concentration of copper accorded with linear relationship in the range of 0.04-120 ng mL(-1). The relative standard deviation (for 12 ng mL(-1) of copper) was 1.73%, and the detection limit was 0.007 ng mL(-1). The possible interference of some common ions was studied. The proposed method was applied to the determination of copper in water, rice, wheat, tea, milk, and tomato with satisfactory results. PMID- 23625355 TI - Weather variability permitted within amphibian monitoring protocol and affects on calling Hylidae. AB - Anuran populations are sensitive to changing environmental conditions and act as useful indicators. Presently, much information collected concerning frog populations comes from volunteers following the North American Amphibian Monitoring Protocol. Does weather variability allowed within protocol affect the abundance of calling frogs? For 10 years, Credit Valley Conservation (Ontario, Canada) has been collecting anuran data concerning nine frog species employing three frog monitoring runs. Records include frog abundance by protocol code and five weather variables. Antecedent precipitation and temperature were determined from the nearest weather station. Locations with large source populations of two Hylidae species were selected (spring peeper calling in April and gray tree frog in May). Spearman correlations suggested there were no significant relationships between calling abundance of Hylidae species and ambient wind speed or humidity. However, gray tree frogs were temperature sensitive and calling was significantly related to increased water and air temperatures as well as day time high temperatures over the previous 2 weeks. Both species of calling Hylidae were affected by the volume and timing of precipitation (though, in different ways). Gray tree frogs seem to prefer drier conditions (when temperatures are significantly warmer) while spring peepers prefer to call during, or closely following, precipitation. Monitors targeting gray tree frog should track local weather conditions and focus on evenings when it is (a) warmer than the minimum temperatures and (b) drier than suggested by the protocol. It is recommended that an additional monitoring run could be added to reduce detection variability of this species. PMID- 23625356 TI - Dilemmas encountered while dealing a pregnancy complicated by pelvic Hydatid disease. PMID- 23625357 TI - A rapid assay to quantify the cleavage efficiency of custom-designed nucleases in planta. AB - Custom-designed nucleases are a promising technology for genome editing through the catalysis of double-strand DNA breaks within target loci and subsequent repair by the host cell, which can result in targeted mutagenesis or gene replacement. Implementing this new technology requires a rapid means to determine the cleavage efficiency of these custom-designed proteins in planta. Here we present such an assay that is based on cleavage-dependent luciferase gene correction as part of a transient dual-luciferase((r)) reporter (Promega) expression system. This assay consists of co-infiltrating Nicotiana benthamiana leaves with two Agrobacterium tumefaciens strains: one contains the target sequence embedded within a luciferase reporter gene and the second strain contains the custom-designed nuclease gene(s). We compared repair following site specific nuclease digestion through non-homologous DNA end-joining, as opposed to single strand DNA annealing, as a means to restore an out-of-frame luciferase gene cleavage-reporter construct. We show, using luminometer measurements and bioluminescence imaging, that the assay for non-homologous end-joining is sensitive, quantitative, reproducible and rapid in estimating custom-designed nucleases' cleavage efficiency. We detected cleavage by two out of three transcription activator-like effector nucleases that we custom-designed for targets in the Arabidopsis CRUCIFERIN3 gene, and we compared with the well established 'QQR' zinc-finger nuclease. The assay we report requires only standard equipment and basic plant molecular biology techniques, and it can be carried out within a few days. Different types of custom-designed nucleases can be preliminarily tested in our assay system before their downstream application in plant genome editing. PMID- 23625359 TI - Poly(ADP-ribose)polymerases are involved in microhomology mediated back-up non homologous end joining in Arabidopsis thaliana. AB - Besides the KU-dependent classical non-homologous end-joining (C-NHEJ) pathway, an alternative NHEJ pathway first identified in mammalian systems, which is often called the back-up NHEJ (B-NHEJ) pathway, was also found in plants. In mammalian systems PARP was found to be one of the essential components in B-NHEJ. Here we investigated whether PARP1 and PARP2 were also involved in B-NHEJ in Arabidopsis. To this end Arabidopsis parp1, parp2 and parp1parp2 (p1p2) mutants were isolated and functionally characterized. The p1p2 double mutant was crossed with the C NHEJ ku80 mutant resulting in the parp1parp2ku80 (p1p2k80) triple mutant. As expected, because of their role in single strand break repair (SSBR) and base excision repair (BER), the p1p2 and p1p2k80 mutants were shown to be sensitive to treatment with the DNA damaging agent MMS. End-joining assays in cell-free leaf protein extracts of the different mutants using linear DNA substrates with different ends reflecting a variety of double strand breaks were performed. The results showed that compatible 5'-overhangs were accurately joined in all mutants, that KU80 protected the ends preventing the formation of large deletions and that PARP proteins were involved in microhomology mediated end joining (MMEJ), one of the characteristics of B-NHEJ. PMID- 23625358 TI - Functional characterization of an abiotic stress-inducible transcription factor AtERF53 in Arabidopsis thaliana. AB - AP2/ERF proteins play crucial roles in plant growth and development and in responses to biotic and abiotic stresses. ETHYLENE RESPONSE FACTOR 53 (AtERF53) belongs to group 1 in the ERF family and is induced in the early hours of dehydration and salt treatment. The functional study of AtERF53 is hampered because its protein expression in Arabidopsis is vulnerable to degradation in overexpressed transgenic lines. Taking advantage of the RING domain ligase1/RING domain ligase2 (rglg1rglg2) double mutant in which the AtERF53 can express stably, we investigate the physiological function of AtERF53. In this study, we demonstrate that expression of AtERF53 in wild-type Arabidopsis was responsive to heat and abscisic acid (ABA) treatment. From results of the cotransfection experiment, we concluded that AtERF53 has positive transactivation activity. Overexpression of AtERF53 in the rglg1rglg2 double mutant conferred better heat stress tolerance and had resulted in higher endogenous ABA and proline levels compared to rglg1rglg2 double mutants. AtERF53 also has a function to regulate guard-cell movement because the stomatal aperture of AtERF53 overexpressed in rglg1rglg2 double mutant was smaller than that in the rglg1rglg2 double mutant under ABA treatment. In a global gene expression study, we found higher expressions of many stress-related genes, such as DREB1A, COR15A, COR15B, PLC, P5CS1, cpHSC70 s and proline and ABA metabolic-related genes. Furthermore, we identified several downstream target genes of AtERF53 by chromatin immunoprecipitation assay. In conclusion, the genetic, molecular and biochemical result might explain how AtERF53 serving as a transcription factor contributes to abiotic stress tolerance in Arabidopsis. PMID- 23625360 TI - Do acetylcholine receptor and striated muscle antibodies predict the presence of thymoma in patients with myasthenia gravis? AB - INTRODUCTION: Acetylcholine receptor (AChR) and striated muscle antibodies (StrAbs) are found frequently in myasthenia gravis (MG) patients with thymoma. In this study we aimed to determine the positive predictive value (PPV) and negative predictive value (NPV) of these antibodies for thymoma in patients with MG. METHODS: Antibody findings, thymic histology, and onset age were reviewed for 1141 patients with MG. PPV and NPV of these antibodies for thymoma were determined. RESULTS: The PPV of AChR binding antibodies plus StrAbs was highest (50.0%) with onset before the age of 40 years. The PPV of all antibodies was low (<9%) after age 40. Higher StrAb levels did not increase the PPV. The NPV of AChR binding antibodies was high (99.7%) for all ages. CONCLUSIONS: Patients without AChR binding antibody are not likely to have a thymoma. StrAbs and AChR binding antibodies are not diagnostic for thymoma, but in early-onset MG their presence should raise the clinical suspicion for thymoma. PMID- 23625361 TI - 125I brachytherapy alone for recurrent or locally advanced adenoid cystic carcinoma of the oral and maxillofacial region. AB - BACKGROUND AND PURPOSE: This retrospective study was to evaluate the local control and survival of (125)I brachytherapy for recurrent and/or locally advanced adenoid cystic carcinoma (ACC) of the oral and maxillofacial region. PATIENTS AND METHODS: A total of 38 patients with recurrent and/or locally advanced ACC of the oral and maxillofacial region received (125)I brachytherapy alone from 2001-2010. Twenty-nine were recurrent cases following previous surgery and radiation therapy. The other 9 cases involved primary tumors. Overall, 12 tumors were located in the major salivary glands, 12 in the minor salivary glands, and 14 in the paranasal region, the nasal cavity or the skull base. The prescribed dose was 100-160 Gy. RESULTS: Patients were followed for 12-122 months (median 51 months). The 2-, 5-, and 10-year local tumor control rates were 86.3, 59, and 31.5 %, respectively. The 2-, 5-, and 10-year overall survival rates were 92.1, 65 and 34.1 %, respectively. Tumors > 6 cm had significantly lower local control and survival rates. No severe complications were observed during follow up. CONCLUSION: (125)I brachytherapy is a feasible and effective modality for the treatment of locally advanced unresectable or recurrent ACC. PMID- 23625363 TI - ATP-binding cassette transporters and cholesterol translocation. AB - Cholesterol, a major component of mammalian cell membranes, plays important structural and functional roles. However, accumulation of excessive cholesterol is toxic to cells. Aberrant cholesterol trafficking and accumulation is the molecular basis for many diseases, such as atherosclerotic cardiovascular disease and Tangier's disease. Accumulation of excessive cholesterol is also believed to contribute to the early onset of Alzheimer's disease. Thus, cellular cholesterol homeostasis is tightly regulated by uptake, de novo synthesis, and efflux. Any surplus of cholesterol must either be stored in the cytosol in the form of esters or released from the cell. Recently, several ATP-binding cassette (ABC) transporters, such as ABCA1, ABCG1, ABCG5, and ABCG8 have been shown to play important roles in the regulation of cellular cholesterol homeostasis by mediating cholesterol efflux. Mutations in ABC transporters are associated with several human diseases. In this review, we discuss the physiological roles of ABC transporters and the underlying mechanisms by which they mediate cholesterol translocation. (c) 2013 IUBMB Life, 2013. PMID- 23625362 TI - Short-course radiotherapy in elderly patients with glioblastoma: feasibility and efficacy of results from a single centre. AB - BACKGROUND: The incidence of glioblastoma (GBM) in the elderly population is currently increasing, with a peak seen between 65 and 84 years. The optimal treatment in terms of both efficacy and quality of life still remains a relevant and debated issue today. The purpose of our study was to evaluate the feasibility of short-course hypofractionated accelerated radiotherapy (HART) in GBM patients aged over 70 years and with a good Karnofsky performance score (KPS). METHODS: A review of medical records at the "Istituto Neurologico C. Besta" was undertaken; patients aged >= 70 years who had undergone adjuvant HART for GBM between January 2000 and January 2004 were included in the study. HART was administered to a total dose of 45 Gy, 2.5 Gy/fraction, in three daily fractions for three consecutive days/cycle fractions each, delivered in two cycles (split 15 days). RESULTS: A total of 33 patients were evaluable for the current analysis. Median follow-up was 10 months. According to CTCAE (version 3.0) criteria, none of the patients developed radiation-induced neurological status deterioration or necrosis. KPS evaluation after HART was found to be stable in 73 % of patients, improved in 24 %, and worse in 3 %. The median overall survival time of the entire study population was 8 months (range 2-24). CONCLUSIONS: Our findings suggest that a hypofractionated accelerated schedule can be a safe and effective option in the treatment of GBM in the elderly. PMID- 23625364 TI - Practical use of chemical shift databases for protein solid-state NMR: 2D chemical shift maps and amino-acid assignment with secondary-structure information. AB - We introduce a Python-based program that utilizes the large database of (13)C and (15)N chemical shifts in the Biological Magnetic Resonance Bank to rapidly predict the amino acid type and secondary structure from correlated chemical shifts. The program, called PACSYlite Unified Query (PLUQ), is designed to help assign peaks obtained from 2D (13)C-(13)C, (15)N-(13)C, or 3D (15)N-(13)C-(13)C magic-angle-spinning correlation spectra. We show secondary-structure specific 2D (13)C-(13)C correlation maps of all twenty amino acids, constructed from a chemical shift database of 262,209 residues. The maps reveal interesting conformation-dependent chemical shift distributions and facilitate searching of correlation peaks during amino-acid type assignment. Based on these correlations, PLUQ outputs the most likely amino acid types and the associated secondary structures from inputs of experimental chemical shifts. We test the assignment accuracy using four high-quality protein structures. Based on only the Calpha and Cbeta chemical shifts, the highest-ranked PLUQ assignments were 40-60 % correct in both the amino-acid type and the secondary structure. For three input chemical shifts (CO-Calpha-Cbeta or N-Calpha-Cbeta), the first-ranked assignments were correct for 60 % of the residues, while within the top three predictions, the correct assignments were found for 80 % of the residues. PLUQ and the chemical shift maps are expected to be useful at the first stage of sequential assignment, for combination with automated sequential assignment programs, and for highly disordered proteins for which secondary structure analysis is the main goal of structure determination. PMID- 23625365 TI - Long-term starvation in cave salamander effects on liver ultrastructure and energy reserve mobilization. AB - The morphological alterations of hepatocytes of cave-dwelling salamander Proteus anguinus anguinus after food deprivation periods of one and 18 months were investigated and the concentrations of glycogen, lipids, and proteins in the liver were determined. Quantitative analyses of the hepatocyte size, the lipid droplets, the number of mitochondria, and volume densities of M and P in the hepatocytes were completed. After one month of food deprivation, the cytological changes in the hepatocytes are mainly related to the distribution and amount of glycogen, which was dispersed in the cytoplasm and failed to form clumps typical of normal liver tissue. After 18 months of food deprivation hepatocytes were reduced in size, lipid droplets were less numerous, peroxisomes formed clusters with small, spherical mitochondria, and specific mitochondria increased in size and lost cristae. Lysosomes, autophagic vacuoles, and clear vacuoles were numerous. The liver integrity was apparently maintained, no significant loss of cytoplasmic constituents have been observed. Biochemical analysis revealed the utilization of stored metabolic reserves in the liver during food deprivation. Glycogen is rapidly utilized at the beginning of the starvation period, whereas lipids and proteins are utilized subsequently, during prolonged food deprivation. In the Proteus liver carbohydrates are maintained in appreciable amounts and this constitutes a very important energy depot, invaluable in the subterranean environment. PMID- 23625366 TI - Botulinum toxin-what urologic uses does the data support? AB - Botulinum toxin-A (BTX-A) is well established in the management of various aspects of lower urinary tract dysfunction (LUTD). One formulation, OnabotulinumtoxinA has recently been licensed in many parts of the world for use in neurogenic detrusor overactivity (NDO), and in the US for idiopathic overactive bladder (OAB), in patient's refractory to antimuscarinics. This review article looks at recent clinical publications that examine the use of BTX-A for the treatment of LUTD with a focus on OAB, detrusor overactivity (DO), benign prostatic hyperplasia (BPH) and Painful bladder syndrome / interstitial cystitis (PBS / IC). A literature review was conducted using the PubMed database and studies that were published within the time frame of January 2011 to present were included. Large randomised placebo controlled trials and a pooled analysis of patients with multiple sclerosis / spinal cord injury and NDO has suggested that BTX-A improved urinary incontinence (UI) episodes, urodynamic parameters and QoL in these patients. 200 U of OnabotulinumtoxinA appeared equivalent to 300 U. In patients with OAB, lower doses of 100 U OnabotulinumtoxinA, appear efficacious and with an acceptable adverse event profile. In one large phase III trial, de novo clean intermittent catheterisation rates were 6.1 %. Repeated injections in DO appear efficacious. Results from BPH studies are mixed, and the largest randomised study in this setting has shown significant improvements in a number of parameters for a variety of OnabotulinumtoxinA doses, but none of the doses were statistically better than placebo. Few studies have been conducted in PBS / IC and larger scale randomised placebo controlled trials are required to validate its use in this setting. PMID- 23625367 TI - Homeostatic housecleaning effect of selenium: evidence that noncytotoxic oxidant induced damage sensitizes prostate cancer cells to organic selenium-triggered apoptosis. AB - The anti-cancer activity of organic selenium has been most consistently documented at supra-nutritional levels at which selenium-dependent, antioxidant enzymes are maximized in both expression and activity. Thus, there is a strong imperative to identify mechanisms other than antioxidant protection to account for selenium's anti-cancer activity. In vivo work in dogs showed that dietary selenium supplementation decreased DNA damage but increased apoptosis in the prostate, leading to a new hypothesis: Organic selenium exerts its cancer preventive effect by selectively increasing apoptosis in DNA-damaged cells. Here, we test whether organic selenium (methylseleninic acid; MSA) triggers more apoptosis in human and canine prostate cancer cells that have more DNA damage (strand breaks) created by hydrogen-peroxide (H2O2) at noncytotoxic doses prior to MSA exposure. Apoptosis triggered by MSA was significantly higher in H2O2 damaged cells. A supra-additive effect was observed--the extent of MSA-triggered apoptosis in H2O2-damaged cells exceeded the sum of apoptosis induced by MSA or H2O2 alone. However, neither the persistence of H2O2-induced DNA damage, nor the activation of mitogen-activated protein kinases was required to sensitize cells to MSA-triggered apoptosis. Our results document that selenium can exert a "homeostatic housecleaning" effect--a preferential elimination of DNA-damaged cells. This work introduces a new and potentially important perspective on the anti-cancer action of selenium in the aging prostate that is independent of its role in antioxidant protection. PMID- 23625369 TI - Research on the drought index of irrigation district with multi-time scales. AB - The empirical mode decomposition method is applied to analyze fluctuating periods and local features of the annual drought index and the drought index in the irrigation and non-irrigation periods from 1956 to 2010 in the Yinchuan irrigation district. In order to understand the uncertainty between these variables, the set pair analysis method is used to present the identity, discrepancy, and contrary of the drought index with multi-time scales. The results reveal that the annual drought index and the drought index in the irrigation and non-irrigation periods have a complex relationship which may be related to El Nino, the air-sea intersection, and the long period of solar activity. The drought index in the irrigation and non-irrigation periods presents mainly the contrary and the discrepancy; the fluctuating shapes of the annual drought index and drought index in the irrigation period are the same on their different period levels. The original annual drought index and its intrinsic mode function components have a certain connection degree; they mainly present the discrepancy. PMID- 23625368 TI - Polycyclic aromatic hydrocarbons in soils along the coastal and estuarine areas of the northern Bohai and Yellow Seas, China. AB - Polycyclic aromatic hydrocarbons (PAHs) and their health risks in surface soils (n = 31) collected from coastal and estuarine areas of the northern Bohai and Yellow Seas (CEANBYS), China, were investigated. Total concentrations of PAHs ranged from 6.6 * 10(1) to 9.2 * 10(2) ng g(-1) dry weight, with an average of 3.1 * 10(2) ng g(-1) dw. The locations where greater concentrations of PAHs were observed were all near factories emitting black smoke or on the edge of the urban areas. These observations are consistent with concentrations of PAHs in soils being influenced by human activities, especially industrialization and urbanization. Concentrations of PAHs were significantly correlated with concentrations of organic carbon in soils. The patterns of relative concentrations and types of PAHs observed as well as knowledge of the potential sources were consistent with the primary sources of PAHs in soils of the CEANBYS being derived from the pyrolytic processes such as combustion of fossil fuel. The incremental lifetime cancer risks of exposing to PAHs for child, youth, and adult were 1.6 * 10(-6), 1.2 * 10(-6), and 1.9 * 10(-6). PMID- 23625370 TI - One-step synthesis of 6-acetamido-3-(N-(2-(dimethylamino) ethyl) sulfamoyl) naphthalene-1-yl 7-acetamido-4-hydroxynaphthalene-2-sulfonate and its characterization with 1D and 2D NMR techniques. AB - A one-step method was reported for the synthesis of 6-acetamido-3-(N-(2 (dimethylamino) ethyl) sulfamoyl) naphthalene-1-yl 7-acetamido-4 hydroxynaphthalene-2-sulfonate by treating 7-acetamido-4-hydroxy-2 naphthalenesulfonyl chloride with equal moles of N, N-dimethylethylenediamine in acetonitrile in the presence of K2CO3. The chemical structure of the obtained compounds was characterized by MS, FTIR, (1)H NMR, (13)C NMR, gCOSY, TOCSY, gHSQC, and gHMBC. The chemical shift differences of (1)H and (13)C being delta 0.04 and 0.2, respectively, were unambiguously differentiated. PMID- 23625371 TI - Fetal asphyxia induces acute and persisting changes in the ceramide metabolism in rat brain. AB - Fetal asphyctic preconditioning, induced by a brief episode of experimental hypoxia-ischemia, offers neuroprotection to a subsequent more severe asphyctic insult at birth. Extensive cell stress and apoptosis are important contributing factors of damage in the asphyctic neonatal brain. Because ceramide acts as a second messenger for multiple apoptotic stimuli, including hypoxia/ischemia, we sought to investigate the possible involvement of the ceramide pathway in endogenous neuroprotection induced by fetal asphyctic preconditioning. Global fetal asphyxia was induced in rats by clamping both uterine and ovarian vasculature for 30 min. Fetal asphyxia resulted in acute changes in brain ceramide/sphingomyelin metabolic enzymes, ceramide synthase 1, 2, and 5, acid sphingomyelinase, sphingosine-1-phosphate phosphatase, and the ceramide transporter. This observation correlated with an increase in neuronal apoptosis and in astrocyte number. After birth, ceramide and sphingomyelin levels remained high in fetal asphyxia brains, suggesting that a long-term regulation of the ceramide pathway may be involved in the mechanism of tolerance to a subsequent, otherwise lethal, asphyctic event. PMID- 23625373 TI - Novel EDA p.Ile260Ser mutation linked to non-syndromic hypodontia. AB - Hypodontia, a tooth developmental disease, can affect chewing and pronunciation. Mutations in the ectodysplasin-A (EDA) gene can lead to both X-linked hypohidrotic ectodermal dysplasia (XLHED) and non-syndromic hypodontia (NSH). However, the mechanism by which these 2 related but different disorders are caused by the distinct mutations in EDA is unknown. In this study, we identified a novel missense mutation (c.779 T>G) in a Chinese family with NSH via a direct sequencing approach. This mutation results in an Ile260Ser substitution in the tumor necrosis factor (TNF) homology domain. Homology modeling suggests that this alteration may induce a conformational change in the hydrophobic center of the TNF homology domain. Furthermore, by exploring systematic 3D conformation analysis and calculation of residue relative solvent accessibility (RSA) for all the reported mutated amino acid sites on EDA's TNF homology domain, we found that the site mutations at the interior may be linked to XLHED, while those at the surface are more likely to be associated with NSH. These findings may aid in the discovery of unidentified functionally significant mutation sites in the EDA gene and provide a new way to clarify the mechanisms by which the XLHED and NSH phenotypes arise from mutations in the same gene. PMID- 23625372 TI - Retinol and retinyl esters: biochemistry and physiology. AB - By definition, a vitamin is a substance that must be obtained regularly from the diet. Vitamin A must be acquired from the diet, but unlike most vitamins, it can also be stored within the body in relatively high levels. For humans living in developed nations or animals living in present-day vivariums, stored vitamin A concentrations can become relatively high, reaching levels that can protect against the adverse effects of insufficient vitamin A dietary intake for six months, or even much longer. The ability to accumulate vitamin A stores lessens the need for routinely consuming vitamin A in the diet, and this provides a selective advantage to the organism. The molecular processes that underlie this selective advantage include efficient mechanisms to acquire vitamin A from the diet, efficient and overlapping mechanisms for the transport of vitamin A in the circulation, a specific mechanism allowing for vitamin A storage, and a mechanism for mobilizing vitamin A from these stores in response to tissue needs. These processes are considered in this review. PMID- 23625374 TI - Expression and function of enamel-related gene products in calvarial development. AB - Enamel-related gene products (ERPs) are detected in non-enamel tissues such as bone. We hypothesized that, if functional, ERP expression corresponds with distinct events during osteoblast differentiation and affects bone development and mineralization. In mouse calvariae and MC3T3 cells, expression profiles of enamel-related gene products (ERPs) correlated with key events in post-natal calvarial development and MC3T3 cell mineralization. Developing skulls from both Amel- and Ambn-deficient animals were approximately 15% shorter when compared with those of wild-type controls, and their sutures remained patent for a longer period of time. Analysis of Amel- and Ambn-deficient calvariae and calvarial osteoblast cultures revealed a dramatic reduction in mineralized nodules, a significant reduction in Runx2, Sp7, Ibsp, and Msx2 expression, and a reduction in Alx4 in Amel-deficient calvariae vs. an increase in Alx4 in Ambn-deficient calvariae. Analysis of these data indicates that ERP expression follows defined developmental profiles and affects osteoblast differentiation, mineralization, and calvarial bone development. We propose that, in parallel to their role in the developing enamel matrix, ERPs have retained an evolutionary conserved function related to the biomineralization of bones. PMID- 23625376 TI - Homozygous and compound heterozygous MMP20 mutations in amelogenesis imperfecta. AB - In this article, we focus on hypomaturation autosomal-recessive-type amelogenesis imperfecta (type IIA2) and describe 2 new causal Matrix metalloproteinase 20 (MMP20) mutations validated in two unrelated families: a missense mutation p.T130I at the expected homozygous state, and a compound heterozygous mutation having the same mutation combined with a nucleotide deletion, leading to a premature stop codon (p.N120fz*2). We characterized the enamel structure of the latter case using scanning electron microscopy analysis and microanalysis (Energy dispersive X-ray Spectroscopy, EDX) and confirmed the hypomaturation-type amelogenesis imperfecta as identified in the clinical diagnosis. The mineralized content was slightly decreased, with magnesium substituting for calcium in the crystal structure. The anomalies affected enamel with minimal inter-rod enamel present and apatite crystals perpendicular to the enamel prisms, suggesting a possible new role for MMP20 in enamel formation. PMID- 23625375 TI - Mobile microbiome: oral bacteria in extra-oral infections and inflammation. AB - The link between oral infections and adverse systemic conditions has attracted much attention in the research community. Several mechanisms have been proposed, including spread of the oral infection due to transient bacteremia resulting in bacterial colonization in extra-oral sites, systemic injury by free toxins of oral pathogens, and systemic inflammation caused by soluble antigens of oral pathogens. Mounting evidence supports a major role of the systemic spread of oral commensals and pathogens to distant body sites causing extra-oral infections and inflammation. We review here the most recent findings on systemic infections and inflammation complicated by oral bacteria, including cardiovascular disease, adverse pregnancy outcomes, rheumatoid arthritis, inflammatory bowel disease and colorectal cancer, respiratory tract infections, and organ inflammations and abscesses. The recently identified virulence mechanisms of oral species Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Campylobacter rectus are also reviewed. A pattern emerges indicating that only select subtype(s) of a given species, e.g., F. nucleatum subspecies animalis and polymorphum and S. mutans non-c serotypes, are prone to extra-oral translocation. These findings advocate the importance of identification and quantification of potential pathogens at the subtype levels for accurate prediction of disease potential. PMID- 23625377 TI - Thoracoscopic resection of a giant mediastinal parathyroid cyst. AB - Parathyroid cysts are a rare situation, unusually in the mediastinum. The preoperative diagnosis could be more difficult in some atypical topographies and imaging characteristics in particular in case of huge mediastinal cyst. In the following years traditionally, in case of intrathoracic parathyroid cysts, sternotomy or thoracotomy have been the preferred approaches. We report a case of an older patient with a huge mediastinal parathyroid cyst removed successfully using videothoracoscopy. PMID- 23625378 TI - Noradrenergic neurotransmission within the bed nucleus of the stria terminalis modulates the retention of immobility in the rat forced swimming test. AB - The bed nucleus of the stria terminalis (BNST) is a limbic structure that has a direct influence on the autonomic, neuroendocrine, and behavioral responses to stress. It was recently reported that reversible inactivation of synaptic transmission within this structure causes antidepressant-like effects, indicating that activation of the BNST during stressful situations would facilitate the development of behavioral changes related to the neurobiology of depression. Moreover, noradrenergic neurotransmission is abundant in the BNST and has an important role in the regulation of emotional processes related to the stress response. Thus, this study aimed to test the hypothesis that activation of adrenoceptors within the BNST facilitates the development of behavioral consequences of stress. To investigate this hypothesis, male Wistar rats were stressed (forced swimming, 15 min) and 24 h later received intra-BNST injections of vehicle, WB4101, RX821002, CGP20712, or ICI118,551, which are selective alpha(1), alpha(2), beta(1), and beta(2) adrenoceptor antagonists, respectively, 10 min before a 5-min forced swimming test. It was observed that administration of WB4101 (10 and 15 nmol), CGP20712 (5 and 10 nmol), or ICI118,551 (5 nmol) into the BNST reduced the immobility time of rats subjected to forced swimming test, indicating an antidepressant-like effect. These findings suggest that activation of alpha(1), beta(1), and beta(2) adrenoceptors in the BNST could be involved in the development of the behavioral consequences of stress. PMID- 23625379 TI - Evaluation of functional relationship between mouse hippocampal cholinergic and nitrergic systems in anxiogenic-like behavior. AB - Although a body of evidence shows the crucial role of hippocampal nitrergic and cholinergic systems in the modulation of anxiety, little is known about their functional relationship with regard to anxiety. The present study investigated the relationship between intra-CA1 administration of a nicotinic acetylcholine receptor antagonist (mecamylamine) and a nitric oxide synthase inhibitor [Nomega nitro-L-arginine methyl ester (L-NAME)] or its precursor (L-arginine) in anxiety related behaviors. Mice received bilateral intra-CA1 injections of either L-NAME or L-arginine in the presence of mecamylamine and were subsequently tested in the elevated plus maze. A dose of 0.5 MUg/0.5 MUl mecamylamine bilaterally administered into CA1 did not change the percentage of open arm time (%OAT) or the percentage of open arm entries (%OAE) in the elevated plus maze task and thus was considered as a subeffective dose. Intra-CA1 administration of either L arginine (1 and 1.5 MUg/0.5 MUl, bilaterally) or L-NAME (at 60 ng/0.5 MUl, bilaterally) decreased %OAT, which represents an anxiogenic-like effect. Coadministration of the subeffective dose of mecamylamine together with the lower doses of L-NAME (10 and 30 ng/0.5 MUl, bilaterally) or L-arginine (0.5 MUg/0.5 MUl, bilaterally) led to a decrease in %OAT and %OAE. Thus, both L-NAME and L arginine showed anxiogenic-like effects, but the effects of mecamylamine were too small to support a functional relationship between the hippocampal cholinergic and nitrergic systems. PMID- 23625380 TI - Patients' experiences following local-regional recurrence of thyroid cancer: a qualitative study. AB - BACKGROUND AND OBJECTIVE: The psychosocial impact of local-regional thyroid cancer recurrence is not known. The aim of this study was to explore thyroid cancer patients' experiences relating to diagnosis and treatment of local regional disease recurrence. METHODS: We conducted 15 semi-structured interviews with survivors of differentiated thyroid cancer who underwent neck reoperation for recurrent disease. Participants were recruited from the clinical practices of thyroid surgeons and endocrinologists at University Health Network and Mount Sinai Hospitals in Toronto, Ontario. Participant interviews were audio-recorded, transcribed verbatim, and analyzed using qualitative methods. Saturation of themes was achieved. RESULTS: Local-regional recurrence of thyroid cancer was associated with significant psychological distress. Confidence in healthcare providers as well as psychosocial support from family or social relations, were helpful in coping with disease recurrence. After recovery from treatment, post traumatic growth was reported. However, questions and worry about the risk for future recurrence lingered at follow-up. CONCLUSIONS: Local-regional recurrence of thyroid cancer has a significant psychosocial impact on patients, and support needs are heightened throughout the experience. Healthcare providers should strive to ensure that medical information and psychosocial needs of such patients are met, throughout the treatment experience, as well as at follow-up. PMID- 23625381 TI - Neuromuscular electrical stimulation alters gene expression and delays quadriceps muscle atrophy of rats after anterior cruciate ligament transection. AB - INTRODUCTION: Neuromuscular electrical stimulation (NMES) is used to improve quadriceps mass after anterior cruciate ligament (ACL) injury. We studied the effect of NMES on mRNA levels of atrophy genes in the quadriceps muscle of rats after ACL transection. METHODS: mRNA levels of atrogin-1, MuRF-1, and myostatin were assessed by quantitative PCR and the polyubiquitinated proteins by Western blot at 1, 2, 3, 7, and 15 days postinjury. RESULTS: NMES minimized the accumulation of atrogenes and myostatin according to time period. NMES also prevented reduction in muscle mass in all muscles of the ACLES group at 3 days. CONCLUSIONS: Use of NMES decreased the accumulation of atrogenes and myostatin mRNA in the quadriceps muscles, inhibiting early atrophy at 3 days, although it did not prevent atrophy at 7 and 15 days after ACL transection. This study highlights the importance of therapeutic NMES interventions in the acute phase after ACL transection. PMID- 23625383 TI - Stimulating the cerebellum affects visuomotor adaptation but not intermanual transfer of learning. AB - When systematic movement errors occur, the brain responds with a systematic change in motor behavior. This type of adaptive motor learning can transfer intermanually; adaptation of movements of the right hand in response to training with a perturbed visual signal (visuomotor adaptation) may carry over to the left hand. While visuomotor adaptation has been studied extensively, it is unclear whether the cerebellum, a structure involved in adaptation, is important for intermanual transfer as well. We addressed this question with three experiments in which subjects reached with their right hands as a 30 degrees visuomotor rotation was introduced. Subjects received anodal or sham transcranial direct current stimulation on the trained (experiment 1) or untrained (experiment 2) hemisphere of the cerebellum, or, for comparison, motor cortex (M1). After the training period, subjects reached with their left hand, without visual feedback, to assess intermanual transfer of learning aftereffects. Stimulation of the right cerebellum caused faster adaptation, but none of the stimulation sites affected transfer. To ascertain whether cerebellar stimulation would increase transfer if subjects learned faster as well as a larger amount, in experiment 3 anodal and sham cerebellar groups experienced a shortened training block such that the anodal group learned more than sham. Despite the difference in adaptation magnitude, transfer was similar across these groups, although smaller than in experiment 1. Our results suggest that intermanual transfer of visuomotor learning does not depend on cerebellar activity and that the number of movements performed at plateau is an important predictor of transfer. PMID- 23625384 TI - WiLLOW: reaching HIV-positive African-American women through a computer-delivered intervention. AB - WiLLOW is an evidence-based, group level HIV prevention program for African American women living with HIV. This study evaluated the efficacy of a multimedia adaptation of WiLLOW in enhancing protective sexual behaviors and psychosocial mediators associated with HIV risk reduction. Using a randomized controlled design, 168 participants completed baseline, satisfaction, and three-month follow up assessments. At follow-up intervention participants reported higher proportions of condom protected sex acts (p = .002) with both HIV-negative (p = .040) and HIV-positive (p = .003) partners. They were also more likely to report 100 % condom use (OR = 9.67; p = .03); fewer unprotected vaginal and anal sex acts (p = .002); significantly greater sexual communication self-efficacy (p = .004); and less stress (p = .012). Participants rated Multimedia WiLLOW favorably in four satisfaction categories-enjoyment (p < .001); information utility (p = .018); information clarity (p = .015) and held attention (p = .01). PMID- 23625385 TI - Labelling of diathermy consoles when multiple systems are used: should this be part of the WHO checklist? PMID- 23625382 TI - Relationships between regional cerebellar volume and sensorimotor and cognitive function in young and older adults. AB - The cerebellum has been implicated in both sensorimotor and cognitive function, but is known to undergo volumetric declines with advanced age. Individual differences in regional cerebellar volume may therefore provide insight into performance variability across the lifespan, as has been shown with other brain structures and behaviors. Here, we investigated whether there are regional age differences in cerebellar volume in young and older adults, and whether these volumes explain, in part, individual differences in sensorimotor and cognitive task performance. We found that older adults had smaller cerebellar volume than young adults; specifically, lobules in the anterior cerebellum were more impacted by age. Multiple regression analyses for both age groups revealed associations between sensorimotor task performance in several domains (balance, choice reaction time, and timing) and regional cerebellar volume. There were also relationships with working memory, but none with measures of general cognitive or executive function. Follow-up analyses revealed several differential relationships with age between regional volume and sensorimotor performance. These relationships were predominantly selective to cerebellar regions that have been implicated in cognitive functions. Therefore, it may be the cognitive aspects of sensorimotor task performance that are best explained by individual differences in regional cerebellar volumes. In sum, our results demonstrate the importance of regional cerebellar volume with respect to both sensorimotor and cognitive performance, and we provide additional insight into the role of the cerebellum in age-related performance declines. PMID- 23625386 TI - Natural evolution of an eardrum bridge in patients with a traumatic eardrum perforation. AB - Although the "eardrum bridge" of traumatic tympanic membrane perforations (TMPs) is very little seen, the underlying natural evolution during the healing process are still unknown.The aim of this retrospective study was to evaluate the natural evolution of the "eardrum bridge" of TMPs. The data for 36 patients with barotrauma-associated traumatic TMPs with an "eardrum bridge" between January 2006 and December 2007 were retrieved. The eardrum bridge was completely liquefied due to infection in one patient. The bridge gradually became necrotic and incorporated into the new eardrum in four patients, and the healed eardrum formed a retraction pocket. In nine patients, epithelial hyperplasia occurred on both sides of the eardrum bridge at the edges, and the bridge became incorporated into the new eardrum, which became very thin over time. However, in 22 patients, the eardrum bridge gradually became necrotic, finally forming a yellow crust-like substance and migrating to the external auditory canal (EAC); it was not incorporated into the new eardrum. The closure of the perforation depended on stratified epithelial migration at the perforation edges near the eardrum bridge, resulting in a normal morphology of the healed eardrum. The present study shows that the eardrum bridge has a different natural evolution during the healing process in patients with a TMP. Most eardrum bridges gradually became necrotic and migrated toward the EAC, and stratified epithelial migration occurred at the perforation edges near the eardrum bridge and closed the perforation. However, a few eardrum bridges gradually became necrotic or developed epithelial hyperplasia, then became incorporated into the new eardrum, resulting in the formation of a retraction pocket and the development of atrophy. Thus, long-term follow-up and histological examination of a larger sample is necessary. PMID- 23625387 TI - Increased expression of aldehyde dehydrogenase 1 A1 in nasopharyngeal carcinoma is associated with enhanced invasiveness. AB - Increased expression of aldehyde dehydrogenase 1 (ALDH1) has recently been reported in several cancers. However, whether member A1 of aldehyde dehydrogenase 1 (ALDH1A1) is involved in the formation of nasopharyngeal carcinoma (NPC) remains unknown. To investigate the expression of ALDH1A1 in NPC and its association with the tumorigenesis of NPC, we examined the expression of ALDH1A1 in NPC specimens using immunohistochemistry (IHC), quantitative RT-PCR (qRT-PCR) and Western blot. Moreover, we sorted ALDH1A1(high) cells from NPC cell line CNE 2 by flow cytometry and examined the expression of primitive embryonic stem cell markers OCT4, SOX2 and Nanog. Finally, we investigated the capacities of growth, proliferation, colony- formation and tumorigenesis of ALDH1A1(high) cells in vitro and in vivo. We found ALDH1A1 was significantly increased in human NPC samples via IHC, qRT-PCR and Western blot (p < 0.05). ALDH1A1(high) cells sorted from NPC cell line CNE-2 by flow cytometry had higher expression of primitive embryonic stem cell markers OCT4, SOX2 and Nanog, and showed enhanced capacities of growth, proliferation, colony formation and tumorigenesis in vitro and in vivo when compared with ALDH1A1(low) cells (p < 0.05). Our findings indicated that increased expression of ALDH1A1 in NPC was associated with enhanced invasiveness. PMID- 23625388 TI - Dynamic contrast-enhanced ultrasound for differential diagnosis of submandibular gland disease. AB - Intensity-time gradients (ITGs) of contrast-enhanced ultrasound (CEUS) can be used for non-invasive monitoring of gland-preserving treatment effects in sialolithiasis-related chronic sialadenitis as well as for imaging vascularization in tumors. The aim of this clinical trial was to evaluate feasibility to distinguish different entities of submandibular gland disease including inflammatory alterations of the submandibular gland as well as benign and malignant tumors. In this prospective clinical study, ITGs in 30 patients with sialolithiasis-related chronic sialadenitis or an unilateral submandibular mass and 18 disease-free submandibular gland controls were quantitatively analyzed by CEUS using the contrast agent SonoVue. In addition, clinical complaints according to visual analog scales (VAS) were documented. VAS data documented significantly less complaints only in benign tumors compared with the other pathologies of the submandibular gland. In parallel, CEUS-derived ITGs revealed significantly reduced ITGs only in benign tumors (n = 5) compared to the controls (n = 18). Despite of comparably reduced wash-in velocities in malignant lesions (n = 3) statistical significance was not reached. Chronic sialadenitis (n = 18) and its sclerosing variant (Kuttner tumor, n = 4) revealed comparable ITGs as controls. Tumors of the submandibular gland present with reduced functional microcirculatory networks comparing with healthy gland controls and chronically inflamed submandibular glands. Thus, dynamic CEUS-derived ITGs in combination with conventional clinical measures--for example VAS--appear as a safe and promising strategy for non-invasive diagnostic workup of submandibular lesions and warrant further validation in a larger set of patients. PMID- 23625390 TI - Affinity depletion of plasma and serum for mass spectrometry-based proteome analysis. AB - Protein biomarker discovery in blood plasma and serum is severely hampered by the vast dynamic range of the proteome. With protein concentrations spanning 12 orders of magnitude, conventional mass spectrometric analysis allows for detection of only a few low-abundance proteins. Prior depletion of high-abundant proteins from the sample can increase analytical depth considerably and has become a widely used practice. We describe in detail an affinity depletion method that selectively removes 14 of the most abundant proteins in plasma and serum. PMID- 23625389 TI - Early oral intake after total laryngectomy does not increase pharyngocutaneous fistulization. AB - Timing of oral intake after total laryngectomy (TLE) is mostly delayed until postoperative day 10-12, under the assumption that this limits the incidence of pharyngocutaneous fistulization (PCF). However, early oral intake could be advantageous and could reduce costs, providing that it does not lead to increased PCF. Comparison of PCF incidence in traditional 'late' oral intake protocol (start at postoperative day 10-12; LOI) and in early oral intake protocol (start at postoperative day 2-4; EOI). Retrospective cohort study comparing two different oral intake protocols in 247 consecutive patients laryngectomized between early 2000 until mid 2006 (LOI; N = 140), and mid 2006 until mid 2012 (EOI; N = 107). Both groups were comparable in terms of sex, age, origin of tumor, and TLE indication, except for the American Society of Anesthesiologists score (ASA), which was slightly more favorable in the LOI group (p = 0.047). Compliance with the oral intake protocols during both periods was good: the median day of starting oral intake was day 11 (range 6-103) in the LOI group vs. day 3 (range 2-84) in the EOI group (p = 0.001). The incidence of PCF was not significantly different between the two groups (25% for LOI and 32% for EOI; Fisher's exact: p = 0.255). In addition, no association was observed between the timing of oral intake and PCF (HR = 0.995; CI 0.98-1.01; p = 0.364). This study suggests that early oral intake is safe and does not increase pharyngocutaneous fistulization. PMID- 23625391 TI - Tissue sample preparation for biomarker discovery. AB - Global protein expression studies, an approach known as "proteomics," can offer important clues for understanding tumor biology that cannot be obtained by other approaches. Proteomic studies have provided protein expression profiles of tumors that can be used to develop novel diagnostic and therapeutic biomarkers. In this chapter, we describe the strategy and design of proteomic studies, as well as the protocols for tissue sample collection and preparation for biomarker discovery, especially tumor biomarkers, followed by a few examples of our recent proteomic studies. PMID- 23625392 TI - Subcellular fractionation for identification of biomarkers: serial detergent extraction by subcellular accessibility and solubility. AB - Cellular localization of proteins is one of the most valuable sources of information regarding spatiotemporal biological events involved in human disease. This information is sometimes enhanced by carrying out protein isolation using a process known as subcellular fractionation. This involves the sequential extraction of proteins from specific compartments and/or organelles within the cell. Additionally, subcellular fractionation for biomarker discovery enables the in-depth analysis of biomolecules by reducing the complexity of the protein mixture. In this chapter, four custom fractionation approaches and one commercial kit are compared for their efficacy and compatibility with subsequent proteomic analysis. PMID- 23625393 TI - Analysis of secreted proteins. AB - Most biological processes including growth, proliferation, differentiation, and apoptosis are coordinated by tightly regulated signaling pathways, which also involve secreted proteins acting in an autocrine and/or paracrine manner. In addition, extracellular signaling molecules affect local niche biology and influence the cross-talking with the surrounding tissues. The understanding of this molecular language may provide an integrated and broader view of cellular regulatory networks under physiological and pathological conditions. In this context, the profiling at a global level of cell secretomes (i.e., the subpopulations of a proteome secreted from the cell) has become an active area of research. The current interest in secretome research also deals with its high potential for the biomarker discovery and the identification of new targets for therapeutic strategies. Several proteomic and mass spectrometry platforms and methodologies have been applied to secretome profiling of conditioned media of cultured cell lines and primary cells. Nevertheless, the analysis of secreted proteins is still a very challenging task, because of the technical difficulties that may hamper the subsequent mass spectrometry analysis. This chapter describes a typical workflow for the analysis of proteins secreted by cultured cells. Crucial issues related to cell culture conditions for the collection of conditioned media, secretome preparation, and mass spectrometry analysis are discussed. Furthermore, an overview of quantitative LC-MS-based approaches, computational tools for data analysis, and strategies for validation of potential secretome biomarkers is also presented. PMID- 23625394 TI - Preparation of human cerebrospinal fluid for proteomics biomarker analysis. AB - The analysis of the cerebrospinal fluid (CSF) proteome in recent years has resulted in a valuable repository of data for targeting and diagnosing a variety of diseases, such as Parkinson's disease, Alzheimer's disease, traumatic brain injury, and amyotrophic lateral sclerosis. Human ventricular CSF contains numerous proteins that are unique to CSF due in part to the interaction of the biofluid with the brain. This allows researchers to obtain information from a region that would otherwise be inaccessible except through invasive surgery or during autopsy. Characterization of the CSF proteome requires that strict care be taken so that sample integrity and fidelity are maintained to ensure data reproducibility. Standardized methods in sample collection, storage, preparation, analysis, and data mining must be used for meaningful information to be obtained. The following method describes a simple and robust approach for preparing CSF samples for analysis via reversed-phase liquid chromatography (RPLC) and mass spectrometry (MS). PMID- 23625395 TI - Proteomic analysis of frozen tissue samples using laser capture microdissection. AB - The discovery of effective cancer biomarkers is essential for the development of both advanced molecular diagnostics and new therapies/medications. Finding and exploiting useful clinical biomarkers for cancer patients is fundamentally linked to improving outcomes. Towards these aims, the heterogeneous nature of tumors represents a significant problem. Thus, methods establishing an effective functional linkage between laser capture microdissection (LCM) and mass spectrometry (MS) provides for an enhanced molecular profiling of homogenous, specifically targeted cell populations from solid tumors. Utilizing frozen tissue avoids molecular degradation and bias that can be induced by other preservation techniques. Since clinical samples are often of a small quantity, tissue losses must be minimized. Therefore, all steps are carried out in the same single tube. Proteins are identified through peptide sequencing and subsequent matching against a specific proteomic database. Using such an approach enhances clinical biomarker discovery in the following ways. First, LCM allows for the complexity of a solid tumor to be reduced. Second, MS provides for the profiling of proteins, which are the ultimate bio-effectors. Third, by selecting for tumor proper or microenvironment-specific cells from clinical samples, the heterogeneity of individual solid tumors is directly addressed. Finally, since proteins are the targets of most pharmaceuticals, the enriched protein data streams can then be further analyzed for potential biomarkers, drug targets, pathway elucidation, as well as an enhanced understanding of the various pathologic processes under study. Within this context, the following method illustrates in detail a synergy between LCM and MS for an enhanced molecular profiling of solid tumors and clinical biomarker discovery. PMID- 23625396 TI - Use of formalin-fixed, paraffin-embedded tissue for proteomic biomarker discovery. AB - Application of mass spectrometry to proteomic analysis of tissue is a highly desirable approach to discovery of disease biomarkers due to a direct correlation of findings to tissue/disease histology and in many respects obviating the need for model systems of disease. Both frozen and formalin-fixed, paraffin-embedded (FFPE) tissue can be interrogated; however, worldwide access to vastly larger numbers of highly characterized FFPE tissue collections derived from both human and model organisms makes this form of tissue more advantageous. Here, an approach to large-scale, global proteomic analysis of FFPE tissue is described that can be employed to discover differentially expressed proteins between different histological tissue types and thus discover novel protein biomarkers of disease. PMID- 23625397 TI - Phosphopeptide enrichment using offline titanium dioxide columns for phosphoproteomics. AB - Identification of phosphoproteins or phosphopeptides as cancer biomarkers is an emerging field in phosphoproteomics. Owing to the low stoichiometric nature of protein phosphorylation, phosphoproteins or phosphopeptides must be enriched prior to downstream mass spectrometry analysis. Titanium dioxide (TiO2) has been prevalently used to enrich phosphopeptides from complex proteome samples due to its high affinity for phosphopeptides, and the method is straightforward. In this protocol, an offline phosphopeptide enrichment procedure using TiO2 columns is described. Peptides from a proteome lysate are loaded onto a TiO2 column in an acidic environment, followed by column washing with aqueous, organic, and ammonium glutamate (NH4Glu) buffers at acidic conditions. Phosphopeptides are eluted using an ammonia solution at high pH. Use of NH4Glu significantly reduces nonspecific bindings while a high recovery rate (84 %) of phosphopeptides is retained. The method is optimized for large-scale phosphoproteomic analysis and phosphoprotein biomarker discovery starting from sub-milligram or milligrams of proteome samples. PMID- 23625398 TI - iTRAQ-labeling for biomarker discovery. AB - Various mass-tagging approaches have been developed over the last few years that have enabled mass spectrometry-based relative and absolute quantification of proteins from complex samples. This, in turn, has facilitated proteomics research to address issues ranging from alterations in the proteome of various model systems in response to various stimuli to biomarker discovery studies. Here we describe the use of one such mass-tagging approach, viz., iTRAQ labeling, as applied to cancer biomarker discovery. When applied to a cohort of tens of clinical samples, this technology can provide useful leads that serve as a basis for a more targeted validation-scale study. PMID- 23625399 TI - Analysis of glycoproteins for biomarker discovery. AB - Glycoproteins play an important role in cell signaling and cell-cell interaction. The alterations of glycoproteins are often relevant to progression of diseases, and these changed glycoproteins can be important biomarkers. The lectin-based glycoproteomic technology has extensively been used for high-throughput screening of potential glycoprotein biomarkers. Here we describe a multi-lectin affinity chromatography and label-free quantitative glycoproteomic approach for discovery of glycoprotein biomarkers relevant to differentiation of glioblastoma stem cells. PMID- 23625400 TI - SILAC in biomarker discovery. AB - Stable isotope labeling with amino acids in cell culture (SILAC) has become an extremely valuable tool in quantitative proteomics and in biomarker discovery. Incorporation of SILAC labels occurs when cells are passaged multiple times in media where the endogenous amino acids are replaced with the heavy isotope ones. During a typical experiment, cells from heavy and light strains are combined in equal ratios and all steps of protein extraction and digestion occur on these cells together, minimizing the number of external variables introduced during sample processing. Potential biomarkers are revealed during liquid chromatography tandem mass spectrometry analysis by peptides that differ considerably in intensity between the two strains as revealed by the mass shift from the incorporated SILAC label. The protocol presented here describes how to perform a typical experiment using the SILAC technology for the search for biomarkers as revealed by differences in protein expression levels, as well as by phosphorylation, a common posttranslational modification. PMID- 23625401 TI - Trypsin-mediated 18O/16O labeling for biomarker discovery. AB - Differential (18)O/(16)O stable isotopic labeling that relies on post-digestion (18)O exchange is a simple and efficient method for the relative quantitation of proteins in complex mixtures. This method incorporates two (18)O atoms onto the C termini of proteolytic peptides resulting in a 4 Da mass-tag difference between (18)O- and (16)O-labeled peptides. This allows for wide-range relative quantitation of proteins in complex mixtures using shotgun proteomics. Because of minimal sample consumption and unrestricted peptide tagging, the post-digestion (18)O exchange is suitable for labeling of low-abundance membrane proteins enriched from cancer cell lines or clinical specimens, including tissues and body fluids. This chapter describes a protocol that applies post-digestion (18)O labeling to elucidate putative endogenous tumor hypoxia markers in the plasma membrane fraction enriched from a hypoxia-adapted malignant melanoma cell line. Plasma membrane proteins from hypoxic and normoxic cells were differentially tagged using (18)O/(16)O stable isotopic labeling. The initial tryptic digestion and solubilization of membrane proteins were carried out in a buffer containing 60 % methanol followed by post-digestion (18)O exchange/labeling in buffered 20 % methanol. The differentially labeled peptides were mixed in a 1:1 ratio and fractionated using off-line strong cation exchange (SCX) liquid chromatography followed by on-line reversed-phase nano-flow RPLC-MS identification and quantitation of peptides/proteins in respective SCX fractions. The present protocol illustrates the utility of (18)O/(16)O stable isotope labeling in the context of quantitative shotgun proteomics that provides a basis for the discovery of hypoxia-induced membrane protein markers in malignant melanoma cell lines. PMID- 23625402 TI - Two-dimensional SDS-PAGE fractionation of biological samples for biomarker discovery. AB - Two-dimensional electrophoresis is still a very valuable tool in proteomics, due to its reproducibility and its ability to analyze complete proteins. However, due to its sensitivity to dynamic range issues, its most suitable use in the frame of biomarker discovery is not on very complex fluids such as plasma, but rather on more proximal, simpler fluids such as CSF, urine, or secretome samples. Here, we describe the complete workflow for the analysis of such dilute samples by two dimensional electrophoresis, starting from sample concentration, then the two dimensional electrophoresis step per se, ending with the protein detection by fluorescence. PMID- 23625403 TI - Informatics of protein and posttranslational modification detection via shotgun proteomics. AB - Frequently, proteomic LC-MS/MS data may contain sets of modifications that evade identification during standard database search. For many laboratories, the standard technique to seek posttranslational modifications (PTMs) adds a short list of specified mass shifts to database search configuration. This technique provides information for only the specified PTMs, takes substantial time to run, and drives false discoveries upward through an exponential expansion of search space. This protocol describes a more structured approach to blind PTM discovery through reducing protein lists, targeting attention to a data-driven list of mass shifts, and seeking the resulting short list of modifications through targeted search. PMID- 23625404 TI - Quantitation of Met tyrosine phosphorylation using MRM-MS. AB - Phosphorylation has long been accepted as a key cellular regulator of cell signaling pathways. The recent development of multiple-reaction monitoring mass spectrometry (MRM-MS) provides a useful tool for measuring the absolute quantity of phosphorylation occupancy at pivotal sites within signaling proteins, even when the phosphorylation sites are in close proximity. Here, we described a targeted quantitation approach to measure the absolute phosphorylation occupancy at Y1234 and Y1235 of Met. The approach is utilized to obtain absolute occupancy of the two phosphorylation sites in the full-length recombinant Met. It is further applied to quantitate the phosphorylation state of these two sites in SNU 5 cells treated with a Met inhibitor. PMID- 23625405 TI - Preparation of human serum for prolactin measurement by multiple reaction monitoring mass spectrometry. AB - The measurement of the protein hormone prolactin (PRL) in biological samples has developed over the years into a routine clinical assay aiding the diagnosis of multiple medical conditions. PRL is known to exist in multiple isoforms circulating throughout the body. Current methodologies for measuring the PRL levels typically involve a variety of immunoassays. However, most of these tests are not capable of distinguishing between the different isoforms. To address this need, we have developed a highly specialized method employing multiple reaction monitoring mass spectrometry (MRM-MS) capable of monitoring seven distinct peptides from two of the most common prolactin isoforms (the 23 kDa PRL and its 16 kDa N-terminal cleavage product). Since serum is the main source of clinical specimen for the measurement of prolactin isoforms, the method described in this chapter is focused on the approach to processing whole serum samples for prolactin analysis via reversed-phase liquid chromatography (RPLC) and MRM-MS. PMID- 23625406 TI - Label-free quantitative shotgun proteomics using normalized spectral abundance factors. AB - In this chapter we describe the workflow used in our laboratory for label-free quantitative shotgun proteomics based on spectral counting. The main tools used are a series of R modules known collectively as the Scrappy program. We describe how to go from peptide to spectrum matching in a shotgun proteomics experiment using the XTandem algorithm, to simultaneous quantification of up to thousands of proteins, using normalized spectral abundance factors. The outputs of the software are described in detail, with illustrative examples provided for some of the graphical images generated. While it is not strictly within the scope of this chapter, some consideration is given to how best to extract meaningful biological information from quantitative shotgun proteomics data outputs. PMID- 23625407 TI - Employment of complementary dissociation techniques for body fluid characterization and biomarker discovery. AB - Proteomic analysis of biological fluids has become the de facto method for biomarker discovery over the past half decade. Mass spectrometry, in particular, has emerged as the premier technology to perform such analysis. This shift in the prevailing choice of analytical method is primarily due to the rapid evolution of mass spectrometry technology, with advances in acquisition speed, increased resolving power and mass accuracy, and the development of novel fragmentation methods. The benefits of using one of these new fragmentation methods, electron transfer dissociation, as a complement to the traditional dissociation technique (i.e., collision-activated dissociation) have been thoroughly illustrated. Detailed here is a method for proteomic analysis of a readily obtainable and often investigated biological fluid, blood plasma, which takes advantage of these complementary dissociation techniques and employs the most recent advances in mass spectrometry technology. PMID- 23625408 TI - Phosphopeptide microarrays for comparative proteomic profiling of cellular lysates. AB - Protein phosphorylation is one of the most important and well-studied posttranslational modifications. Aberrant phosphorylation causes a wide spectrum of diseases, including cancers. As a result, many of the proteins involved in these pathways are seen as vital drug targets and biomarkers in treatment and diagnosis. The availability of broad-based platforms that identify changes across cellular states is critical in understanding unique disease characteristics and changes at the proteomic level. To highlight how microarrays can be applied in this regard, we describe here a comparative proteomic profiling method using two color sample labeling and application on phosphopeptide microarrays, followed by a pull-down strategy and MS-based protein identification. This strategy has been applied to uncover candidate biomarkers in breast cancer and colon cancer cell lines. Apart from the synthesis of the phosphopeptide libraries and growth/isolation of cellular lysates, the protocol takes approximately 15 days to complete, once key steps have been optimized, and can be readily extended to other similarly complex biological specimens/samples. PMID- 23625409 TI - Tissue preparation for MALDI-MS imaging of protein and peptides. AB - Matrix-assisted laser desorption/ionization (MALDI) imaging is rapidly gaining importance in the -biomarkers field because it is able to detect several analytes at the same time and to assign to each one of them not only an m/z value but also spatial distribution. Here we present the detailed description of sample preparation for protein and peptide MALDI imaging assays. This chapter describes the microtomy performed in a cryostat to produce tissue slides mounted onto glass slides suitable for MALDI. Sample preparation will include matrix coating procedure with a sensor-controlled aerosol. Finally, we will show some examples of how data can be visualized to suit the purposes of the research. PMID- 23625410 TI - Plant proteogenomics: from protein extraction to improved gene predictions. AB - Historically many genome annotation strategies have lacked experimental evidence at the protein level, which and have instead relied heavily on ab initio gene prediction tools, which consequently resulted in many incorrectly annotated genomic sequences. Proteogenomics aims to address these issues using mass spectrometry (MS)-based proteomics, genomic mapping, and providing statistical significance measures such as false discovery rates (FDRs) to validate the mapped peptides. Presented here is a tool capable of meeting this goal, the UCSD proteogenomic pipeline, which maps peptide-spectrum matches (PSMs) to the genome using the Inspect MS/MS database search tool and assigns a statistical significance to the match using a target-decoy search approach to assign estimated FDRs. This pipeline also provides the option of using a more reliable approach to proteogenomics by determining the precise false-positive rates (FPRs) and p-values of each PSM by calculating their spectral probabilities and rescoring each PSM accordingly. In addition to the protein prediction challenges in the rapidly growing number of sequenced plant genomes, it is difficult to extract high-quality protein samples from many plant species. For that reason, this chapter contains methods for protein extraction and trypsin digestion that reliably produce samples suitable for proteogenomic analysis. PMID- 23625411 TI - Label-free differential analysis of murine postsynaptic densities. AB - This chapter provides detailed methodology for the enrichment and label-free differential analysis of postsynaptic density (PSD) proteins. Methods discussed will include tissue homogenization, subcellular fractionation, protein digestion, and label-free differential analysis after liquid chromatography-tandem mass spectrometry. When combined, these protocols facilitate the identification of receptors and signal transducers that comprise the PSD and provide an optimized workflow for the differential analysis of PSD proteomes. This strategy supports a utility for coupling fractionation with proteomics analysis to enrich for low abundant proteins in cellular localizations that would otherwise be lost in a global tissue context. PMID- 23625412 TI - Fractionation of peptides by strong cation-exchange liquid chromatography. AB - Chromatography in all its formats plays an important role in proteomics research. The search for protein biomarkers for different diseases has been an active area of research. The dynamic concentration range and the large number of proteins in a proteome require the development of multidimensional separation strategies to allow for the identification of the largest number of proteins. Strong cation exchange chromatography (SCX) has been used extensively for the fractionation of proteins and peptides. This chapter provides a detailed description for the SCX fractionation of complex proteome samples. PMID- 23625413 TI - Camphor modulates TRPV3 cation channels activity by interacting with critical pore-region cysteine residues. AB - TRPV3 ion channels mediate thermo-transduction, nociception, inflammation and dermatitis in mammals. TRPV1-4 proteins have been shown to have conserved cysteine-residues in the pore-forming regions. These residues participate in channel activation via S-nitrosylation of channel proteins. Camphor is a commonly used ligand for TRPV3 channels. Thus the knowledge about the potential binding/interacting site(s) for camphor will help to design effective and potent analgesic compounds. In an overlap-extension PCR method, following primer-pairs were used to mutate conserved cysteine-residues in the pore-region of TRPV3 channels; GATTGAGAATcCTCCAAGGACAAAAAGGAC, TRPV3-C612S-Fw and GTCCTTGGAGgACTTCTCAATCAGTCAGTGAGG, TRPV3-C612S-Rv primers pair. And for TRPV3 C619S: GGACTCcAGTTCCTATGGCCAGC, TRPV3-C619S-Fw and GCTGGCCATAgGAACTGGAGTCC, TRPV3 C619S-Rv respectively. All cDNA constructs were confirmed by DNA-sequencing and used to make cRNAs. Oocytes expressing mTRPV3-C619S and mTRPV3-C612S mutant channels were challenged with 2-APB (1 mM), camphor (10 mM) and dihydrocarveol (10 mM) either at -40 mV or +40 mV holding potentials in voltage-clamp experiments. Responses of both mutants to 2-APB were similar to wild-type mTRPV3. Interestingly, responses to camphor were totally lost in mTRPV3-C619S mutant, while responses to dihydrocarveol remained intact. In contrast mTRPV3-C612S displayed slightly altered (16+/-2 % reduction) phenotype with respect to camphor sensitivity. It is concluded that pore-region cysteines play critical role in camphor sensitivity of TRPV3 ion channels. PMID- 23625414 TI - Physico-chemical comparison of famotidine tablets prepared via dry granulation and direct compression techniques. AB - Famotidine is generally employed for the treatment of gastric ulcer. The present study was conducted to fabricate famotidine tablets using various diluents. The binder was incorporated to the formulations in different proportions. Both the dry granulation and direct compression techniques were employed to develop the tablets. Physical evaluation of tablets i.e. tablets hardness, friability, weight variation, thickness and diameter was determined. In vitro dissolution studies of the prepared tablets were carried out for 60 min using the USP apparatus II and 900 ml 0.1 M HCl stirred at 37 +/- 0.5 degrees C with a speed of 50 rpm. Physical analysis of tablets prepared via direct compression showed satisfactory results regarding the weight variation, hardness and friability, since their respective values were within the BP limits. All the prepared famotidine tablets exhibited diffusion based mode of drug release. 100% release of drug occurred in less than 60 min. The drug release from all the formulated tablets has elaborated the involvement of diffusion (Higuchian drug release). This comparative study exhibited that physical parameters of tablets are affected by the technique of tabletting. PMID- 23625415 TI - In vivo antioxidant and biochemical evaluation of Sphenocentrum jollyanum leaf extract in P. berghei infected mice. AB - Recent approach in treatment and drug development suggested that the control of oxidative stress in malarial infected patients may be an added advantage. In this study, effect of methanolic leaf extract of Sphenocentrum jollyanum pier (S. jollyanum) on liver damage, markers of oxidative stress and alteration in lipid profile in P. berghei infected mice was assessed. Oxidative stress was induced by intravenously inoculation of mice with 1 * 107 sporozoites P. berghei. Treatment of parasitized mice with leaf extract of S. jollyanum had a significant (p<0.05) reductions in elevated levels of total protein, globulin, AST, ALT, ALP, GGT and total bilirubin, serum, kidney and liver malondialdehyde (MDA) concentrations, but caused a significant (p<0.05) increased in the activities of serum and liver catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH) level when compared with parasitized non-treated group (PNT). The extract treated group also showed significant (p<0.05) improvement in the levels of HDLc, total cholesterol, LDL and reduction in triglyceride compared with parasitized non treated group. Our results revealed that the protective capacity and antioxidant activity of the extract is dose dependant. The findings suggest that antioxidant property of Sphenocentrum jollyanum leave extract might be an added advantage to it anti malarial activity. PMID- 23625416 TI - Anti-inflammatory activity of the topical preparation of Valeriana wallichii and Achyranthes aspera leaves. AB - In vivo and in vitro screening of anti inflammatory activity of Valeriana wallichii and Achyranthes aspera leaves crude extract was performed, using standardized procedures. Methanolic crude extract topical formulation (cream) of Valeriana wallichii and Achyranthes aspera leaves (Family Valerianaceae and Amaranthaceae respectively), were screened for their anti-inflammatory activity, through "Carrageenan induced hind paw edema" test, for their effect on the acute and chronic phase inflammation models in male Wistar rats. Methanolic extract and its fractions were also evaluated for their in vitro anti-inflammatory activity using lipoxygenase inhibition assay. Leaves of Valeriana wallichii showed significant (P<0.001), dose dependant anti inflammatory activity, comparable with that of the standard, in animal model. The ethyl acetate fraction of Valeriana wallichii also showed considerable (IC 50=73 +/- 0.36) in vitro anti-inflammatory activity as compared to standard (6.11 +/- 0.02). Similarly Achyranthes aspera leaves showed relatively weak (p>0.05) in vivo anti-inflammatory activity. However, its activity was comparable with that of standard at 10% concentration after 5 hrs of carrageenan injection. This activity was present in ethyl acetate fraction during in vitro screening (IC 50=76 +/- 0.14) as compared to that of standard (IC 50=6.11 +/- 0.02). The combined in vitro and in vivo Anti inflammatory screening shows that the ethyl acetate fraction of the crude extract of Valeriana wallichii and Achyranthes aspera can be used for the isolation of new Anti-inflammatory lead compounds. PMID- 23625417 TI - Synthesis, characterization and biological screening of N-substituted derivatives of 5-benzyl-1,3,4-oxadiazole-2yl-2"-sulfanyl acetamide. AB - A series of new N-substituted derivatives of 5-benzyl-1, 3, 4-oxadiazole-2yl-2" sulfanyl acetamide (6a-n) were synthesized in three phases. The first phase involved the sequentially converting phenyl acetic acid into ester, hydrazide and finally cyclized in the presence of CS2 to afford 5-benzyl-1, 3, 4-oxadiazole-2 thiol. In the second phase N-substituted-2-bromoacetamides were prepared by reacting substituted amines with bromoacetyl bromide in basic media. In the third phase, 5-benzyl-1,3,4-oxadiazole-2-thiol was stirred with N-substituted-2 bromoacetamides in the presence of N,N-dimethyl formamide (DMF) and sodium hydride (NaH) to get the target compounds. Spectral techniques were used to confirm the structures of synthesized compounds. Synthesized compounds were screened against butyrylcho linesterase (BChE), acetylcholinesterase (AChE), and lipoxygenase enzymes (LOX) and were found to be relatively more active against acetylcholinesterase. PMID- 23625418 TI - Development and validation of high performance liquid chromatographic method for analysis of clozapine. AB - In this study a rapid, simple and sensitive assay to quantify clozapine in human plasma by using reverse phase high performance liquid chromatographic method has been developed. Clozapine was extracted from human plasma using a mixture of chloroform: n-hexane 50:50 employing liquid-liquid extraction method. The calibration curve was found to be linear in the concentration range of 25-800 ng/ml. The inter day and intra day assay accuracy and precision fulfilled the criteria specified by USFDA, Guidance for industry: bioanalytical method validation. Clozapine was found to be stable in human plasma after 6 h incubation at room temperature, 50 days storage at -27 degrees C and freeze thaw cycles, as well as after reconstitution with mobile phase after 24 h of storage in refrigerator. The validated method offers the advantage of using minimum injection volume (25MUl) and plasma sample volume (300MUl). The extraction method is simple and single step with no back extraction step, thus, making this method applicable to determination of pharmacokinetic profiles and parameters. PMID- 23625419 TI - Bioautography-guided isolation of antibacterial compounds of essential oils from Thai spices against histamine-producing bacteria. AB - The outbreak of histamine fish poisoning has been being an issue in food safety and international trade. The growth of contaminated bacterial species including Morganella morganii which produce histidine decarboxylase causes histamine formation in fish during storage. Histamine, the main toxin, causes mild to severe allergic reaction. At present, there is no well-established solution for histamine fish poisoning. This study was performed to determine the antibacterial activity of essential oils from Thai spices against histamine-producing bacteria. Among the essential oils tested, clove, lemongrass and sweet basil oils were found to possess the antibacterial activity. Clove oil showed the strongest inhibitory activity against Morganella morganii, followed by lemongrass and sweet basil oils. The results indicated that clove, lemongrass and sweet basil oils could be useful for the control of histamine-producing bacteria. The attempt to identify the active components using preparative TLC and GC/MS found eugenol, citral and methyl chavicol as the active components of clove, lemongrass and sweet basil oils, respectively. The information from this study would be useful in the research and development for the control of histamine-producing bacteria in fish or seafood products to reduce the incidence of histamine fish poisoning. PMID- 23625420 TI - Synthesis of biologically active O-substituted derivatives of 1-[(3, 5-dichloro-2 hydroxyphenyl)sulfonyl]piperidine. AB - In the present work, a series of 2-O-substituted derivatives of 1-[(3,5-dichloro 2-hydroxy phenyl) sulfonyl]piperidine (5a-j) were synthesized. These derivatives were geared up by the coupling of 3,5-dichloro-2-hydroxy benzenesulfonyl chloride (1) with piperidine (2) under dynamic pH control in aqueous media to form parent compound 1-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]piperidine (3), followed by the substitution at oxygen atom with different electrophiles (4a-j) in the presence of sodium hydride (NaH) and dimethyl formamide (DMF) to give a series of O-substituted derivatives of sulfonamides bearing piperidine nucleus 5a-j. The synthesized O-substituted sulfonamides were spectrally characterized. The bioactivity of all the synthesized compounds were evaluated against lipoxygenase (LOX), acetylcholinesterae (AChE) and butyrylcholinesterase (BChE) enzymes and found to be having talented activity against butyrylcholinesterase enzyme. PMID- 23625421 TI - Computational study on the geometry optimization and excited - state properties of riboflavin by ArgusLab 4.0.1. AB - Riboflavin (vitamin B2) belongs to a group of respiratory enzymes that occur widely in animals and plants participating in vital oxidation- reduction processes in the body. A computational study was conducted on riboflavin by ArgusLab 4.0.1 to obtain the most active conformation of riboflavin and to analyze its excited-state properties. The best conformation of riboflavin was found to be -199.2173 kcal/mol which is the minimum potential energy calculated by geometry convergence function by ArgusLab software; performed according to Hartree-Fock calculation method. Electronic transition states (ground and excited), were also calculated and visualized by semi-empirical ZINDO method by ArgusLab from which molecular properties such as energies, wave function and dipole moments were established. All the results obtained from geometry optimization and excited-state properties lead us to delineate the active sites with charged groups of riboflavin to interact with the receptors. Such types of investigations are significant for drug-receptor interactions. PMID- 23625422 TI - Dissolution improvement of poorly water-soluble drug by cogrinding method using jar mill. AB - As a representative proton pump inhibitor, Lansoprazole was poorly soluble in water which caused the low oral bioavailability. The present study was carried out to enhance the dissolution of lansoprazole by cogrinding with some commonly used hydrophilic polymers (beta-CD, PVP, HPMC, L-HPC, CS, PEG and PVPP) in the weight ratio of 1:1 for 2 h in the jar mill. Samples of coground mixture, micronised drug, and physical mixture were characterized by XRPD, and DSC, the results showed that the drug crystallinity reduced in the coground process. The amount of drug released from the coground mixtures in PBS (pH 6.8, 37 degrees C) in 30 min was 100% approximately (except the coground mixtures prepared with VPP or PEG) while released from the micronised drug was just about 20%. Increasing the hydrophilicity and diminishing the size of drug particles by cogrinding were the main causes for enhancing the dissolution of the drug. The results of the stability study of lansoprazole in coground mixture showed that there were no significant changes in the drug content and dissolution characteristics 6 months later. It is clear that the cogrinding method described in the article is very effective for enhancing the dissolution of the poorly soluble drugs, and it is easy for industrialization, showing a strong potential for future applications. PMID- 23625423 TI - Oil, protein, antioxidants and free radical scavenging activity of stone from wild olive trees (Olea europaea L.). AB - The wild olive trees or oleaster (var. sylvestris) and the cultivated olive trees (var. europaea) constitute the two botanical varieties of Olea europaea L. from Mediterranean. In this study, a partial chemical profile was conducted including the total lipids, the fatty acid profiles, soluble proteins, polyphenols, flavanoids contents and antioxidants activities of stone from six oleaster trees. The comparison was made by two olive cultivars cultivated in the same region. The oleaster and cultivar stones were richer in oil content having an average of 8.99 and 7.38 % dry weight basis (DW), respectively. Qualitatively, all studied oils have the same fatty acids profile with the oleic acid C18:1n-9 as the major fatty acid. The oleaster stone oils were richer in monounsaturated fatty acids having an average of 64.87%. They, also, richer in protein content with an average of 198.86 mg/g DW.The globulin is the major fraction, followed by the albumin, the prolamin and the glutemin fractions. The oleaster stone extracts contain polyphenols, flavonoids with an average of 151.14 and 11.91 mg gallic acid equivalent/100g of DW, respectively. The studied extracts showed antioxidant activity using the free radical scavenging activity determined by DPPH and ABTS. The unexploited oleaster stone seems to be a source of oil with good fatty acids balance, in protein and antioxidants metabolites and would be useful for the formulation of supplements and/or pharmaceutical ingredients. PMID- 23625424 TI - Neurochemical and behavioral effects of green tea (Camellia sinensis): a model study. AB - Being rich in polyphenolic compounds such as flavonoids, green tea is suggested to be a potential candidate for the treatment of obesity, stress, depression, Parkinson's and other disorders. Since serotonin has an important role in the pathophysiology of these disorders, present study was designed to monitor the effects of green tea in rats. Green tea extract was provided to the male Albino Wistar rats for 5 weeks, and effects on behaviors were monitored. Results show a decrease in food intake after 5th week but not before. An increase in locomotive activities of the animals was observed, as monitored in novel as well as in familiar environment. Anxiolytic effects were observed in elevated plus maze but not in light dark activity box. An increase in dopamine and serotonin turnover was observed. Our results suggest that beneficial effects of green tea drinking might be due to alteration of serotonin and/or dopamine metabolism. We thereby propose that in further experiments, green tea should be administered in animal model of learned helplessness and effects on the development of adaptation to stress should be monitored. Neurochemical estimations of catecholamine and indoleamine in these animal models of stress exposed to green tea would help in understanding the anxiolytic effects of green tea. PMID- 23625425 TI - Synthesis and cytotoxic activity of some derivatives of alkyl piperidine. AB - Synthesis of novel phenacyl derivatives of alkyl piperidine as cytotoxic agents via simple and single step reaction procedure is going to be reported here. Twelve new compounds were successfully synthesized in moderate yield and in solid form. Their synthesis was confirmed by TLC, melting point, CHN analysis and through different spectral studies such as UV, IR, Mass and proton NMR. The advantages of this synthetic route are simple operation, mild reaction conditions and good yields. These newly synthesized derivatives were extensively explored for their cytotoxicity by brine shrimp lethality assay. PMID- 23625426 TI - Characterization and optimization of lyophilization and storage conditions of Leech saliva extract from the tropical leech Hirudinaria manillensis. AB - The medicinal Malaysian leeches have been used in traditional medicine to treat many different ailments. In this study, leech saliva extract (LSE) was collected from the medicinal Malaysian leech Hirudinaria manillensis. Gel electrophoresis of LSE was carried out to estimate the peptide and protein molecular weights of its content. Results showed that LSE contains more than 60 peptides and proteins with molecular masses ranging from 1.9-250kDa. Thrombin time assay in vitro was employed to assess the collected LSE antithrombin activity. First, to study its stability, LSE was lyophilized under the following different conditions: pre freezing temperature, type of container and lyophilization cycle. Pre-freezed LSE sample at -20 degrees C and lyophilized for 24 hours retained about 100-95% of its original biological activities. Second, the LSE antithrombin activity was monitored for a period of six months. Storage temperature, type of the container and photosensitivity effects on antithrombin activity of the lyophilized (solid state) and non-lyophilized (liquid state) were investigated. Results showed that storage temperature drastically affected the biological activity of LSE with -20 degrees C as the optimum temperature. Samples stored at ambient temperature and +4 degrees C were light photosensitive and adversely affected when stored in polypropylene tubes. Lyophilized samples were more stable than non-lyophilized ones over the period of study. To sum up, in order to have a biologically active stock of LSE, it has to be lyophilized for no more than 24 hours following freezing at -20 degrees C and has to be stored at -20 degrees C in glass tubes protected from light. PMID- 23625427 TI - In vivo and in vitro anti-natriuretic activity of twigs fraction from Dorstenia picta: a possible mechanism. AB - The present study examine the in vivo effects of Dorstenia Picta (D. picta) on urinary volume and sodium excretion in streptozotocin-induced diabetic rats, and determine a possible mechanism by which the extract increased sodium transport in A6 cells monolayers. Administration of the plant extract at the dose of 150 mg/kg during two weeks decreased urinary volume and sodium excretion. In vitro study showed that, apical application of the plant extract at the dose of 100 ug/mL does not significantly increase sodium transport, whereas basolateral administration provoked a significant (P<0.05) increase of sodium transport in a concentration-dependent manner. The plant extract increases the sodium transport by 69.93% versus 55.41% for insulin and 78.44% for adenosine after 30 min. Preincubation of A6 cells monolayers with inhibitor of all adenosine receptors completely suppressed adenosine and plant extract stimulated sodium transport. Interesting is that, the A1 inhibitor receptor (DPCPX), at 100 nM completely abolished the effect of plant extract. The plant extract increased sodium transport by increase PI3-kinase activity and this effect is strongly inhibited by LY-294002. These data also suggest that, the twigs methanol fraction from Dorstenia picta increase sodium transport via PI 3-kinase pathway and requires A1 adenosine receptor. PMID- 23625428 TI - Preparation and evaluation of (99m)Tc-DMSA lyophilized kit for renal imaging. AB - Dimercaptosuccinic acid (DMSA) has been evaluated and used with technetium 99m ((99m)Tc) in imaging of kidneys. DMSA lyophilized kits were prepared and radiolabelled with (99m)Tc. Paper and thin-layer chromatography have been employed using various eluent systems for the radiochemical analysis, percentage labeling and binding capacity of (99m)Tc-DMSA. Female albino rabbits were used for this study. Biological data obtained after intravenous injection of radiolabelled DMSA to female albino rabbits revealed 32.42% uptake and long retention time in the kidneys. On the basis of animal biodistribution data, it is suggested that DMSA when labeled with (99m)Tc is useful complex for renal imaging and can be successfully applied as a diagnostic tool in nuclear medicine. Clinical biodistribution and radiation dosimetry studies are planned in future. PMID- 23625429 TI - Study of phenolic content and urease and alpha-amylase inhibitory activities of methanolic extract of Rumex acetosella roots and its sub-fractions in different solvents. AB - The present study aimed to establish relationship between urease and alpha amylase inhibitory activities on the one hand and on the other between anti enzymatic activities and total phenolic contents of the methanolic extract of roots of Rumex acetosella and its fractions in various solvents. The methanolic extract and its fractions in chloroform, ethyl acetate, n-butanol and water showed remarkable inhibitory activities against both urease and alpha-amylase, there was a close correspondence between urease and alpha-amylase inhibitory activities of the plant samples. The n-butanol fraction which had the highest total phenolic content (252.19 +/- 2.32 ug of Gallic Acid Equivalents/mg of dry mass of the sample) showed prominent activity against both urease and alpha amylase indicating a possible role of phenolics in inhibiting the activities of these enzymes. The samples displayed enzyme inhibitory activities in a dose dependent manner and their effectiveness was comparable with that of the standards, thiourea (for urease) and acarbose (for alpha-amylase). The samples were manifold more effective against urease than alpha-amylase; 2.8 mg/mL of MeOH extract produced about 81% inhibition in alpha-amylase activity, while only 10 ug/mL of the extract was required to create the same inhibition in urease activity. The IC50 values of methanolic, chloroform, ethyl acetate, n-butanolic, aqueous and standard solutions were 1.29, 1.31, 1.90, 1.38, 0.85 and 1.20 (mg/mL) respectively against alpha-amylase and 0.99, 3.89, 1.76, 0.91, 0.85 and 0.97 (MUg/mL) respectively against urease. The total phenolic content in MeOH, hexane, chloroform, ethyl acetate, n-butanol and water fractions was 108.88 +/- 2.65, 43.70 +/- 1.90, 34.44 +/- 2.30, 230.71 +/- 1.78, 252.19 +/- 2.32 and 94.07 +/- 2.25 respectively. PMID- 23625430 TI - Larvicidal effect of aqueous and ethanolic extracts of Senna alata on Anopheles gambiae, Culex quinquefasciatus and Aedes aegypti. AB - Senna alata is locally used in South Eastern Nigeria in the treatment of several infections which include ringworm and other parasitic skin diseases.The larvicidal activities of aqueous and ethanolic leaf and stem extracts of S. alata were evaluated in static bioassays, on fourth instar larvae of Anopheles gambiae, Culex quinquefasciatus and Aedes aegypti, at extract concentrations of 0.15, 0.30, 0.45, 0.60 and 0.75% w/v, for 72 hours. Mortality of larvae exposed to the different extracts increased with increase in extract concentration and time of exposure. This study revealed a differential potency of the extracts used and a difference in susceptibility of larvae to the extracts as evident by the 72hLC50 values obtained. The leaf extract proved to be more lethal to the larvae than the stem extract as judged by the 72hLC50 values obtained both for the aqueous as well as the ethanolic extracts assayed. Phytochemical screening of the plant parts investigated revealed the presence of some plant metabolites, which have been reported in separate studies to be lethal to mosquito larvae. Results obtained from this study suggest that the leaf and stem extracts of S. alata possess a promising larvicidal potential which can be exploited in mosquito vector control. PMID- 23625431 TI - Protective effects of Sonchus asper (L.) against KBrO3-induced oxidative stress in rat testis. AB - Sonchus asper is used traditionally in the treatment of kidney inflammation, hormonal imbalance and impotency. Sonchus asper methanolic extract (SAME) was investigated for its possible preventive effect against potassium bromate (KBrO3) induced oxidative damages in male rats using biochemical, molecular and histopathological markers in this study. 5 groups, each group of 6 rats were taken kept under standard conditions. Group 1 remained untreated while Group II was given 20 mg/kg KBrO3 orally (in aqueous saline) and Group III, and IV were treated with 100; 200 mg/kg b.w., of SAME after 48 h of KBrO3 treatment. KBrO3 administration in rats significantly altered (P<0.01) the serum level of reproductive hormones, activities of antioxidant enzymes and glutathione contents (GSH), which was significantly reversed P<0.001) by co-treatment of 100 mg/kg and 200 mg/kg b.w., SAME. Administration of SAME in rats also significantly P<0.001) reversed the lipid peroxidation induced by KBrO3 in rats, which could be due to the presence of some plant bioactive constituents. PMID- 23625432 TI - Assessment of Cedrus deodara root oil on the histopathological changes in the gastrointestinal tissues in rats. AB - The present study was designed to investigate the effect of Cedrus deodara root oil on the histopathology of different gastrointestinal organs of Wistar rats. This oil was used traditionally as an anti-ulcer agent in the Indus Unic System and extracted from the plant root by destructive distillation method. A total of 90 rats were taken and divided into groups A, B and C, each comprising of 30 animals. The animals of group B and C were given 0.5 ml/kg and 2.5 ml/kg of C. deodara oil respectively while group A served as control and administered vehicle only. The treatment was given to the animals ones only for 24 hours. All animals were sacrificed and the organs like esophagus, stomach and ileum were taken out. Tissue processing and staining procedure was then carried out for any pathological changes in the animal tissues during microscopic examination. The results indicated that Cedurs deodara root oil at both doses 0.5ml/ kg and 2.5 ml/kg exhibited some adverse effects such as erosion of epithelium, edema on sub mucosal and mucosal layers, congestion of blood vessels as well as presence of inflammatory cells on esophagus, stomach and ileum were seen. Moreover shortening of villi was also seen at both doses. A study conducted on mammalian toxicity previously on rats revealed that the C. deodara root oil used is not very toxic and comes under least toxic group as standardized by toxicologists. Based on the results obtained it was concluded that C. deodara root oil produced some adverse changes in the tissues of GIT when given at 0.5 ml/kg and 2.5 ml/kg doses but the effects were not lethal therapeutically at this dose LC50 16.5 ml/kg. The plant oil showed some toxicity and needs further detailed studies to assess its potential toxicity and therapeutic status before using this material as drug. PMID- 23625433 TI - Effect of pitavastatin in different SLCO1B1 backgrounds on repaglinide pharmacokinetics and pharmacodynamics in healthy Chinese males. AB - The effect of pitavastatin and SLCO1B1 genetic background on the pharmacokinetic and pharmacodynamic properties of repaglinide was investigated. In this randomized, placebo-controlled, crossover study, twelve healthy Chinese males were administered with pitavastatin 4 mg/d or the placebo for 5 d followed by repaglinide 4 mg given orally on d 5. Plasma repaglinide and glucose levels were measured by liquid chromatography-tandem mass spectrometry (LC/MS/MS) and the glucose oxidase method, respectively. Treatment with pitavastatin significantly increased the peak plasma concentration (Cmax) of repaglinide (P=0.003) in SLCO1B1*1b homozygotes (P=0.015) and SLCO1B1*15 carriers (P=0.031). Treatment with pitavastatin led to a marginal increase in the area under plasma concentration-time curve from 0 h to infinity (AUC0=>infinity) of repaglinide (P=0.091). There was no significant difference in pharmacokinetic parameters or hypoglycemic effects of repaglinide among SLCO1B1 genotypes in either the pitavastatin or control group. Pitavastatin increased the Cmax of the plasma concentration of repaglinide in an SLCO1B1 genotype dependent manner, but had no apparent effect on the pharmacodynamics of repaglinide in healthy volunteers. The p values for this statement were not reported. PMID- 23625434 TI - Gemmomodification: an emerging source of natural antioxidants from Silybum marianum. AB - Gemmomodification is a form of herbal medicine in which young freshly growing buds of plants are used. At germinating stage, plants metabolic activities are maximum and various nutrients, hormones enzymes and bioactive phytoconstituents are released and available at this stage. Plants may be promising source of natural antioxidants at growing stage. Oxidative stress leads to many chronic and degenerative diseases. Antioxidants are very essential for human body; they can protect the body from damage caused by free radical induced oxidative stress. This research project had been designed to investigate the antioxidant potential of gemmo modified and native (dry leaves) extract of Silybum marianum. Total phenolic contents was calculated by using Folin-Ciocalteu reagent and antioxidant potential was evaluated by using four radical assays (DPPH, ABTS, Super oxide and nitric oxide), reducing power assay and lipid peroxidation assay spectrophotometrically. Gemmo modified extract showed significantly higher (p<0.050) TPC (830 mg GAE/g of plant extract) as compared to native extract (800 mg GAE/g.) Results of this study revealed that gemmo modified extract demonstrated better antioxidant potential than natively used parts of Silybum marianum. PMID- 23625435 TI - Relationship between serum nitric oxide and sialic acid in coexisted diabetes, hypertension and nephropathy. AB - This study was designed to study the relationship between serum nitric oxide and sialic acid in patients of diabetic nephropathy. Total 210 diabetic patients including 115 males and 95 females, suffering from diabetes and nephropathy (DN) were selected followed by informed consent and approval from institutional ethical committee. Equal number of age and sex matched normal healthy subjects were selected without any known history of hyperglycemia, hypertension and renal insufficiency as controls. Fasting blood samples from patients and controls were collected and analyzed for serum nitric oxide, sialic acid, fasting blood glucose (FBG), serum urea, creatinine, HbA1c and golmerular filtration rate (GFR). The raised levels (p<0.05) of systolic and diastolic blood pressures, BMI, FBG, HbA1c, serum urea, creatinine and sialic acid were noted in DN patients as compared to controls. Significantly lower levels of GFR and serum nitric oxide (p<0.05) were observed in DN patients as compared to controls. Strong negative correlation was found between serum sialic acid and nitric oxide levels in patients diabetic nephropathy (p<0.05). The relationship between the levels of serum nitric oxide and sialic acid may be considered as a strong biochemical indicator for micro and macro vascular complications of diabetes such as hypertension and nephropathy. These parameters should be taken into account during screening procedures regarding identifications of the diabetic patients to get them rid of progressive renal impairment to ESRD. PMID- 23625436 TI - Biological activities and chemical composition of the stems and roots of Helichrysum oligocephalum DC grown in Iran. AB - Helichrysum has long been used medicinally, proving to be beneficial in treatment of acne, asthma, bronchitis and circulatory problems, and lymphatic system diseases. The objective of this research was to study the antioxidant and antibacterial activities and chemical composition of the compounds derived from the stems and roots of cultivated H. oligocephalum using gas chromatography (GC) and gas chromatography-mass spectroscopy (GC-MS). The primary components found in the stem oil were ortho-vanillin (51.0%) and carvacrol (16.0%), and those found in the root oil were 1,8-cineole (30.6%) and isobornyl acetate (13.9%). Stem and root oils of H. oligocephalum demonstrated antibacterial activity, particularly in relation to Gram-positive bacteria. In a beta-carotene/linoleic acid bleaching assay, the root oil of H. oligocephalum demonstrated an antioxidant effect. Antioxidant capacity measured with 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was 1205.0 for the stem oil and 722.8 MUg/ml for the root oil. PMID- 23625437 TI - Rho GTPase activating protein 15 (arhGAP15) siRNA effect apoptosis-induced by ethanol in bovine fibroblast cells. AB - The Rho GTPases are the sub-group of Ras super family and identified in all eukaryotes. The Rho GTPases effect different cellular signaling pathways involved in a number of diseases such as cancer, neurological and cardiovascular disorders. Members of Rho GTPases including RhoA, RhoC and Rac1 play a major role in regulation of apoptosis in different kind of stress conditions. Here we investigated the Rho GTPase activating protein 15 (ArhGAP15) gene knock-down effect on apoptosis induced by ethanol in bovine fibroblast cells. The bovine Fibroblast cells were treated and transfected with two different concentrations (50 and 100 nM) of ArhGAP15 siRNA for 48 h respectively. Both concentrations of siRNA were effective and the results of RT-PCR revealed an efficient knock-down of ArhGAP15 mRNA in fibroblast cells. Further, the normal cells exposed to a 100 mM ethanol concentration showed a reduction in cell viability and induced the ratio of apoptosis related Bax/Bcl-2 proteins compared with ArhGAP15 siRNA transfected ethanol treated cells. Ethanol also increased caspase-3 expression in normal fibroblast cells compared with transfected cells. The ArhGAP15 knock-down cells treated with ethanol decreased Bax/Bcl-2 ratio and lower caspase-3 protein levels in ArhGAP15 knocked-down cells. Our results suggest that apoptosis induced by ethanol involves the activation of Rho GTPase activating protein 15 and silencing of the said gene protects apoptosis. PMID- 23625438 TI - Effect of missense mutations on structure and interaction of anaplastic Lymphoma kinase (ALK) in neuroblastom. AB - Neuroblastoma is a cancer of the sympathetic nervous system, accounting for upto 15% of childhood cancer mortality. It can occur in many areas but most of them begin in the abdomen in the adrenal gland and can spread to the bones and other areas. http://en.wikipedia.org/wiki/Neuroblastoma-cite_note-pmid19383347-3. Unfortunately, like other cancers, its causes are still poorly understood. Anaplastic lymphoma kinase (ALK), a membrane associated tyrosine kinase was recently found to be mutated in neuroblastoma. Protein sequence of ALK was retrieved from UniProt and the seven identified mutations were substituted in native sequence to get its mutant proteins. Significant changes were explored in the mutant secondary structures when compared with the native protein. Changes were also observed in the physiochemical properties and it can therefore be inferred that, these changes may be translated in the tertiary structures due to their effects on the folding pattern. Tertiary structure of the protein modeled after refinement and validation was submitted to Protein Model Database (PMDB) and was assigned with the PMDB ID P0077827. RMSD values of the mutant structures were observed deviated from the native structure when compared with probability < 0.05. It was observed that there are a total of 15 Disordered Regions in the protein having a total of 290 Disordered Residues. Protein-ligand interaction analysis was performed to investigate the effects of mutations damaging its interactions and it was observed that the mutations understudy affects its interactions with ATP which ultimately results in causing neuroblastoma. This study was based on the in silico mutation analysis of Seven missense mutations of anaplastic lymphoma kinase which can better explain why missense mutations in ALK protein cause neuroblastoma. Structure and sequence based computations were systematically and comprehensively evaluated applied to the mutants in anaplastic lymphoma kinase and on the basis of our observations a detailed structural explanations have been developed for the measured and predicted impact of these missense substitutions. PMID- 23625439 TI - Formulation and in vitro evaluation of clotrimazole gel containing almond oil and tween 80 as penetration enhancer for topical application. AB - Achieving a desirable percutaneous absorption of drug molecule is a major concern in formulating dermal and transdermal products. The use of penetration enhancers could provide a successful mean for this purpose. The aim of this study was to develop Clotrimazole gel and to evaluate the effect of almond oil and tween 80 (in different concentrations), on the permeation of drug through rabbit skin in vitro. In order to investigate the effect of penetration enhancers used in this study on the permeation of Clotrimazole through sections of excised rabbit skin, Franz diffusion cell was employed. Sample solution was withdrawn at specific time interval up to 24 h. Significant difference in permeation among the eight formulations was seen in the study. The permeation profile of various formulations also showed that the added enhancers in individual batches affected the permeation of the drug. Drug permeation increased with increased concentration of Tween 80 and decreased concentration of almond oil. Furthermore, almond oil combined with tween 80 showed synergistic effect. The clotrimazole gels were successfully formulated and could be beneficial for topical use. PMID- 23625440 TI - Variation in bioactive principles of Artemisia amygdalina Decne. in wild and tissue culture regenerants. AB - Wild and tissue culture raised regenerants of Artemisia amygdalina, a critically endangered and endemic plant of Kashmir and North West Frontier Provinces of Pakistan were screened for the amount of bioactive principles and in particular antimalarial compound artemesinin. Phytochemical screening of extracts revealed the presence of terpenes, alkaloids, phenolics, tannins (polyphenolics), cardiac glycosides and steroids in wild (aerial, inflorescence) and tissue culture regenerants (in vitro grown plant, callus and green house acclimatized plants). HPLC of Artemisia amygdalina revealed the presence of artemesinin in petroleum ether extracts of wild aerial part, tissue culture raised plant and green house acclimatized plants. Acetonitrile and water in 70:30 ratios at flow rate of 1ml/min was standardised as mobile phase. Retention time for standard chromatogram was 6.7. Wild inflorescences and callus does not produce artemesinin. This is the first report of phytochemical screening and artemesinin estimation of wild and tissue culture raised regenerants of Artemisia amygdalina. PMID- 23625441 TI - Preparation, characterization and tableting of cilnidipine solid dispersions. AB - Solid dispersion technique has been developed many years for improving solubility of water-insoluble drugs, aiming to achieve a better oral bioavailability. However, this technique exhibits many inconveniences when used for large-scale tableting procedures. The objective of current research work was to develop cilnidipine solid dispersions (SDs) to improve the dissolution behaviors of this water-insoluble drug. Moreover, an innovative granulation method was designed to simplify the traditional tableting technology used in solid dispersion technique. Three different kinds of polymers, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) and poloxamer, were used as carriers to prepare solid dispersions. The interactions in the solid state were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and FT IR spectroscopy. The designed granulation method was employed to prepare solid dispersion tablets and the formulation was optimized through investigating the dissolution behaviors. The results indicated PEG solid dispersion showed the best effect both on physical characterizations and dissolution studies. Furthermore, all type of solid dispersions significantly improved the dissolution rates when compared to pure drug and its corresponding physical mixture (PM). The solid dispersion tablets prepared in simplified tableting method exhibited better operability, stability and dissolution behavior than the tablets prepared in traditional ways, which brought more opportunities to solid dispersion technique for industrial production. PMID- 23625442 TI - Report: Fatal toxic epidermal necrolysis induced by sodium valproate. AB - A 26 years old manual labourer from Azad Jammu Kashmir presented with four days history of an extensive exfoliation of skin involving the entire body. Histology of the lesion showed epidermal necrolysis. The patient was a recently diagnosed case of epilepsy and had been started on therapy with sodium valproate three weeks ago. Following admission in our center, intensive care and wound care were instituted according to standard protocols. Despite all therapeutic measures the patient kept on deteriorating and developed multi-organ failure with pneumonia. He died on 7th day of hospitalization. PMID- 23625443 TI - Report: Simultaneous determination of naphazoline hydrochloride, chlorpheniramine maleate and methylene blue in their ternary mixture. AB - Validated spectrophotometric and chemometric methods were developed for determination of Naphazoline Hydrochloride (NAP), Chlorpheniramine maleate (CLO) and Methylene blue (MB) in their ternary mixture. Method A was a spectrophotometric method, where NAP and MB were determined using second derivative (D2) spectrophoto metric method using the peak amplitudes at 299 nm and 337 nm for NAP and MB respectively , while CLO was determined using second derivative ratio (DD2) spectrophotometric method using the peak amplitude at 276.6 nm. Method B used the chemometric techniques; principal component regression (PCR) and partial least squares (PLS) for determination of NAP, CLO and MB using the information contained in the absorption spectra of their ternary mixture solutions. The proposed methods have been successfully applied for the analysis of NAP, CLO and MB in their pharmaceutical formulation and the obtained results were statistically compared with the reported methods. PMID- 23625444 TI - Report: seroprevalence of corynebacterium diphtheriae among vaccinated population of Rawalpindi/Islamabad, Pakistan. AB - Diphtheria is a communicable disease of global significance, and its outbreaks have to be reported to the world community under the International Health Regulations (IHR). A pilot seroepidemiological survey was conducted to assess immunity status of diphtheria among healthy individuals of Rawalpindi/Islamabad (Pakistan), who had been administered at least one dose of the vaccine against the disease, as part of childhood vaccination. The study group comprised of 128 healthy subjects, grouped according to the decade representing their age. Antidiphtheria IgG levels were measured by Enzyme Linked Immunosorbent Assay (ELISA) method. The studied sample showed 100% prevalence of diphtheria antitoxin, confirming prior vaccination; however 49.2% exhibited only minimal protection against diphtheria. Full protection was observed in a significantly higher (p=0.013) percentage of males (54.45%) as compared to female subjects (33.33%). Maximum level of serum antibodies were seen in 1-10 year age group (0.195+0.031 IU/mL), which was significantly higher than that recorded in the age group of 11-20 (p=0.024) and above 30 years (p=0.0064). The present results emphasize the need for periodical booster immunization in adolescents and adults, after primary childhood immunization. PMID- 23625446 TI - [The technique of sleeve resection on the bronchial and pulmonary vascular tree]. AB - Sleeve resections of the lungs have affected the oncologic radicality, parenchyma and lung function-saving resections and extended the indications for operations in thoracic surgery. Whenever lung amputations can be avoided by bronchoplastic and/or angioplastic procedures with the same radicality, sleeve resection should be performed. In centrally located distinct malignomas, intraluminal tumor growth (T3) infiltrations of peribronchial or extrabronchial areas, the lobular ostia and the pulmonary artery (T2/T3) as well as lymph node involvement (N1/N2), these procedures give a better qualitative survival and lower morbidity and mortality rates. Broncoscope-guided localization of a double lumen tube and routine anesthesia monitoring are mandatory. Before performing sleeve resections a complete lymph node dissection should be done without denuding the area of the anastomosis and sparing the bronchial arteries. Preoperative endoscopic biopsies, knowledge of the topography and mobilization of the vascular and bronchial tree, subtile operation techniques, perioperative and postoperative videobronchoscopic guidance as well as intraoperative frozen sections and a tension-free and smooth anastomosis, avoid postoperative complications. Depending on the blood supply of the bronchial tree a vascularized flap is indicated. Operability can therefore be achieved in elderly patients with limited pulmonary function, particularly those under adjuvant or neoadjuvant therapy who are no longer suitable for pneumonectomy. PMID- 23625445 TI - Cotton PRP5 gene encoding a proline-rich protein is involved in fiber development. AB - Proline-rich proteins contribute to cell wall structure of specific cell types and are involved in plant growth and development. In this study, a fiber-specific gene, GhPRP5, encoding a proline-rich protein was functionally characterized in cotton. GhPRP5 promoter directed GUS expression only in trichomes of both transgenic Arabidopsis and tobacco plants. The transgenic Arabidopsis plants with overexpressing GhPRP5 displayed reduced cell growth, resulting in smaller cell size and consequently plant dwarfs, in comparison with wild type plants. In contrast, knock-down of GhPRP5 expression by RNA interference in cotton enhanced fiber development. The fiber length of transgenic cotton plants was longer than that of wild type. In addition, some genes involved in fiber elongation and wall biosynthesis of cotton were up-regulated or down-regulated in the transgenic cotton plants owing to suppression of GhPRP5. Collectively, these data suggested that GhPRP5 protein as a negative regulator participates in modulating fiber development of cotton. PMID- 23625447 TI - [Ileojejunal neuroendocrine tumors: remember!]. PMID- 23625449 TI - Very early repair of tetralogy of Fallot: we can, but should we? PMID- 23625448 TI - An artificial fusion protein between bone morphogenetic protein 2 and titanium binding peptide is functional in vivo. AB - The purpose of this study was to investigate osteogenesis using an artificial fusion protein (AFP) composed of modified bone morphogenetic protein 2 (BMP-2) with a titanium (Ti)-binding peptide (TBP) motif on a Ti surface in vivo. In the in vivostudy, 5-MUm thick Ti was coated with electron cyclotron resonance sputtering on a porous carbon scaffold which was then dipped in one of three different mixtures of collagen gel: (1) collagen gel only, (2) collagen gel with TBP, and (3) collagen gel with the AFP between BMP-2 and the TBP motif (AFP-TBP BMP-2). These scaffolds were then implanted into rat abdominal muscles and were studied histologically at various times and the expression of several bone related protein messenger RNAs (mRNAs) was also analyzed. The Ti-coated scaffold of the collagen gel with AFP-TBP-BMP-2 produced cartilage in the muscle and the expression of alkaline phosphatase, bone sialoprotein, and runt-related gene 2 mRNAs was significantly increased. These results suggest that the scaffold of the collagen gel with AFP-TBP-BMP-2 accelerates osteogenesis in vivo. PMID- 23625450 TI - All anterior and bileaflet mitral valve prolapses are repairable in the modern era of reconstructive surgery. AB - OBJECTIVE: Although mitral valve repair is the preferred treatment for degenerative mitral valve disease, valve replacement still remains prevalent, particularly in the setting of anterior leaflet prolapse. We sought to determine the feasibility and mid-term durability of a lesion-based surgical strategy applied systematically in a consecutive and nonexclusionary (all comers) series of patients with degenerative mitral valve disease and either isolated anterior leaflet or bileaflet prolapse. METHODS: From January 2002 to December 2010, 188 consecutive patients [mean age 56 +/- 14 years (range 12-86), 31% female, mean left ventricular ejection fraction 55 +/- 9%] underwent surgery for degenerative anterior mitral leaflet prolapse [isolated (n = 42, 22%) or bileaflet prolapse (n = 146, 78%)]. Degenerative aetiology was Barlow's disease in 110 (58%) patients and fibroelastic deficiency in 78 (42%). RESULTS: Patients with anterior leaflet prolapse were significantly more symptomatic (New York Heart Association functional Class III-IV) than those with bileaflet prolapse (28.6 vs 9.6%; P = 0.003) at the time of surgery. All patients underwent mitral valve repair and ring annuloplasty. There was 1 immediate valve replacement due to atrioventricular groove bleeding and consequent haematoma in an elderly female patient (99.5% repair rate). Predominant repair techniques were polytetrafluoroethylene neochordoplasty (or loop technique) in 93 (49%) patients, chordal transfer in 86 (46%) and posterior leaflet flip technique in 21 (11%). Median length of stay was 6 (interquartile 5-8) days. In-hospital mortality was 1% (n = 2). Predischarge transthoracic echocardiography showed none to trace mitral regurgitation in 91% of the patients and mild mitral regurgitation in 9%. The Kaplan-Meier estimates for cumulative survival at 1 and 7 years were 98.4 +/- 0.9 and 88.7 +/- 2.2%, respectively. Freedom from >= moderate mitral regurgitation was 100% at 1 year, 93.7 +/- 2.2% at 4 years and 90.3 +/- 3.7% at 7 years. When the interval-censored estimator was used, freedom from >= moderate mitral regurgitation at 1, 4 and 7 years was 100, 96 and 92%, respectively. CONCLUSION: A lesion-based surgical approach with an intention to repair all degenerative valves with anterior leaflet prolapse was applied to a consecutive series of patients with degenerative mitral valve disease. We were able to achieve a near-100% repair rate. Repair of all degenerative valves may be feasible with good mid-term durability, regardless of valve morphology, patient age or comorbidities. PMID- 23625451 TI - Recurrent supraclavicular hydatid cyst. PMID- 23625452 TI - Surgical repair of truncal valve regurgitation. AB - OBJECTIVES: Truncal valve regurgitation remains a short- and long-term risk factor for patients with truncus arteriosus. There are limited data available on techniques and outcomes of truncal valve repair (TVR). The aim of this study was to report our experience with TVR in patients of all ages. METHODS: From 1997 to 2012, 36 patients (13 neonates, 30 children and 3 adults) underwent TVR for significant regurgitation. RESULTS: There were 3 early deaths (8%), all of which were in neonates. Twenty-two patients had a quadricuspid, 13 a tricuspid and 1 a bicuspid truncal valve before repair. Valve repair improved regurgitation in 31 of 36 repairs. The median regurgitation decreased from moderate-severe to mild (P < 0.001). During a mean follow-up of 38.3 +/- 44.9 months (range 1 month-15 years), there was 1 late death, 16 patients required reoperation on the truncal valve and 1 required a second reoperation. Freedom from reoperation was 91.4 +/- 4.8% at 1 year, 55.0 +/- 10.4% at 5 and 22.9 +/- 12.2% at 10 years. A quadricuspid valve after repair tended to worsen freedom from reoperation (P = 0.15), and tricuspidization tended to improve freedom from reoperation (P = 0.19). Neonatal repair (hazards ratio (HR) 4.1, P = 0.03) and leaflet thinning (HR 22.5, P = 0.002) were independent predictors of reoperation. CONCLUSIONS: Valve repair for truncal valve regurgitation is feasible, with good results. Surgical creation of a tricuspid truncal valve seems to provide the best outcomes in this challenging population. PMID- 23625453 TI - The Ross procedure in endocarditis: a report of 28 cases. AB - OBJECTIVES: The Ross procedure has received increasing interest as an attractive alternative to a prosthetic aortic valve. Given its presumably greater resistance to infection, the pulmonary autograft is theoretically preferable for active endocarditis. The objective of this retrospective study was to present our experience in aortic valve endocarditis treated using the Ross procedure. METHODS: Between May 1997 and February 2011, the Ross procedure was performed on 142 patients in our institution. Twenty-eight patients had aortic valve endocarditis at the time of operation. Fourteen patients had urgent or emergency procedures, and 13 had active disease at the time of surgery. Twelve patients were alcoholics and/or drug addicts. Eight patients had an abscess of the aortic annulus. Clinical follow-up was complete. RESULTS: Hospital mortality was 10.7%. Overall patient survival (+/- standard deviation) was 47 +/- 13% at 10 years with no cardiac-related death during the mean follow-up of 6.4 +/- 4.2 years. There were 3 cases of recurrent endocarditis including anterior mitral leaflets endocarditis and right-sided endocarditis to another germ in a drug addict. Four patients required further surgery, 2 on the pulmonary autograft; 18 of the 19 survivors were in New York Heart Association class I. At the final investigation, all patients had no or grade I autograft regurgitation. The mean pressure gradient across the homograft was 9 +/- 7.5, 11 +/- 9.5 and 15 +/- 9.5 mmHg, respectively, for patients between 0-3, 4-9 and >9 years. CONCLUSIONS: Endocarditis can be treated with good results using the Ross procedure, with a very low rate of recurrence of endocarditis. PMID- 23625454 TI - 4D experiments measured with APSY for automated backbone resonance assignments of large proteins. AB - Detailed structural and functional characterization of proteins by solution NMR requires sequence-specific resonance assignment. We present a set of transverse relaxation optimization (TROSY) based four-dimensional automated projection spectroscopy (APSY) experiments which are designed for resonance assignments of proteins with a size up to 40 kDa, namely HNCACO, HNCOCA, HNCACB and HN(CO)CACB. These higher-dimensional experiments include several sensitivity-optimizing features such as multiple quantum parallel evolution in a 'just-in-time' manner, aliased off-resonance evolution, evolution-time optimized APSY acquisition, selective water-handling and TROSY. The experiments were acquired within the concept of APSY, but they can also be used within the framework of sparsely sampled experiments. The multidimensional peak lists derived with APSY provided chemical shifts with an approximately 20 times higher precision than conventional methods usually do, and allowed the assignment of 90 % of the backbone resonances of the perdeuterated primase-polymerase ORF904, which contains 331 amino acid residues and has a molecular weight of 38.4 kDa. PMID- 23625455 TI - Solvated protein-DNA docking using HADDOCK. AB - Interfacial water molecules play an important role in many aspects of protein-DNA specificity and recognition. Yet they have been mostly neglected in the computational modeling of these complexes. We present here a solvated docking protocol that allows explicit inclusion of water molecules in the docking of protein-DNA complexes and demonstrate its feasibility on a benchmark of 30 high resolution protein-DNA complexes containing crystallographically-determined water molecules at their interfaces. Our protocol is capable of reproducing the solvation pattern at the interface and recovers hydrogen-bonded water-mediated contacts in many of the benchmark cases. Solvated docking leads to an overall improvement in the quality of the generated protein-DNA models for cases with limited conformational change of the partners upon complex formation. The applicability of this approach is demonstrated on real cases by docking a representative set of 6 complexes using unbound protein coordinates, model-built DNA and knowledge-based restraints. As HADDOCK supports the inclusion of a variety of NMR restraints, solvated docking is also applicable for NMR-based structure calculations of protein-DNA complexes. PMID- 23625456 TI - Promoting Alternative Thinking Strategies (PATHS) and elementary school aged children's aggression: results from a cluster randomized trial. AB - This study reports on aggressive outcomes from a cluster randomized trial of the Promoting Alternative Thinking Strategies (PATHS) curriculum. Fourteen elementary schools were randomly assigned to intervention or control condition and third grade students were followed through the fifth grade. Teacher and self-reports of student aggression, conduct problems, delinquency, acting out problems, and social information processing (SIP) variables were collected. Linear change for each of the SIP variables was noted with control students demonstrating increased normative beliefs about aggression, increased aggressive social problem solving, increased hostile attribution bias, and increased aggressive interpersonal negotiation strategies over time while PATHS students remained relatively stable. Teachers reported significant curvilinear change in student aggression, conduct problems, and acting out behavior problems; all favoring PATHS students. PMID- 23625457 TI - Recurrent gene fusions in prostate cancer: their clinical implications and uses. AB - Gene fusions, resulting from chromosomal rearrangements, have been attributed to leukaemias and soft tissue sarcomas. The recent discovery of a recurrent gene fusion TMPRSS2-ERG in approximately half of the prostate cancers tested indicates that gene fusions also play a role in the onset of common epithelial cancers. Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the Western male population. It is a heterogeneous disease, both in terms of pathology and clinical presentation. Since the discovery of the TMPRSS2-ERG fusion, other gene fusions have been reported, most of which result in the androgen-regulated over-expression of the oncogene ERG or other ETS transcription factors. The high prevalence of these gene fusions represents a distinct class of tumours, which may give more insight in the heterogeneity of the disease. These gene fusions are of interest as biomarkers for diagnosis of prostate cancer, and some of them could be useful in predicting the presence of aggressive disease. This review focuses on the biological significance and clinical implementation of gene fusions, and particularly the most commonly reported TMPRSS2-ERG fusion, in prostate cancer. PMID- 23625458 TI - Length of left anterior descending coronary artery determines prognosis in acute anterior wall myocardial infarction. AB - BACKGROUND: The left anterior descending artery (LAD) supplies blood to a large part of the myocardium. However, the amount of myocardium supplied varies depending on the length of the LAD and as a result, occlusion of its proximal portion may influence outcome. We investigated the prognosis of patients with anterior wall myocardial infarction as the initial presentation of coronary disease who underwent primary percutaneous coronary intervention (PPCI) in our institution due to isolated proximal LAD occlusion. METHODS: We retrospectively analyzed all patients that underwent PPCI in our institution from 2002 to June 2012. The individuals who fulfilled the above criteria constituted the study group. We recorded demographic, clinical, and angiographic data as well as mortality during the study period. RESULTS: Of 2,532 patients undergoing PPCI, 196 had isolated proximal LAD occlusion. In 112 of them (57%), the LAD wrapped around the apex (group A) and in the remaining 84 (43%), the LAD terminated at or before the apex (group B). At univariate analysis, patients in group A were found to be older (P = 0.04). Over the study period, 28% of patients in group A died in comparison to 2.4% in group B (P < 0.01). When differentiating between cardiac and non-cardiac death, both were also significantly higher in group A (P < 0.01). At multivariate analysis, the strongest predictor of death was long LAD versus shorter LAD (HR 9.1, 95% CI 1.1-76, P = 0.04). CONCLUSION: Wrap-around LAD is a strong predictor of prognosis in patients with anterior wall MI undergoing PPCI to isolated proximal LAD occlusion. In addition, those with a shorter LAD have an excellent prognosis. PMID- 23625459 TI - 1H-HRMAS NMR study of cold smoked Atlantic salmon (Salmo salar) treated with E beam. AB - (1)H High resolution magic angle spinning (HRMAS) NMR spectroscopic data in combination with principal components analysis and analysis of variance were used to differentiate between irradiated and non-irradiated cold-smoked Atlantic salmon (Salmo salar). NMR profiling was obtained, with a spectral acquisition time of less than 8 min, from a small sample size of intact white salmon muscle, by non-destructive analysis that includes a very simple and rapid sample preparation step. Results obtained enable the use of creatine, trimethylamine oxide and the sum of phosphorylcholine and glycerophosphorylcholine as diagnostic compounds to detect irradiation treatment. This study shows the potential of (1)H HRMAS to be a rapid method for investigating compositional changes due to food processing as well as to confirm the presence or absence of some bioactive compounds in irradiated samples. PMID- 23625460 TI - Heterometallic mixed-valence copper(I,II) cyanides that were tuned by using the chelate effect: discovery of famous Cairo pentagonal tiling and unprecedented (3,4)-connected {8(3)}2{8(6)} topological 3D net. AB - By using environmentally friendly [Ni(CN)4](2-) as a cyanide source, three new heterometallic cyano-bridged mixed-valence Cu(I)/Cu(II) coordination polymers with three different electronic configurations (d(8)-d(10)), that is, [Cu2Ni(CN)5(H2O)3] (1), [Cu2Ni(CN)5(pn)H2O] (2), and [Cu3Ni(CN)6(pn)2] (3, pn = 1,2-propane diamine) have been synthesized by gradually increasing the amount of pn. Compound 1, which was hydrothermally synthesized in the absence of pn ligand, exhibits the famous 2D Cairo pentagonal tiling, in which the Cu(I), Cu(II), and Ni(II) atoms act as trigonal, T-shaped, and square-planar nodes, respectively. Notably, there are three water molecules located at the meridianal positions of the octahedrally coordinated Cu(II) atom in compound 1. A similar reaction, except for the addition of a small amount of pn, generated a similar Cairo pentagonal tiling layer in which two of the water molecules that were located at the meridianal positions of the octahedrally coordinated Cu(II) atom were replaced by a chelating pn group. Another similar hydrothermal reaction, with the addition of a larger amount of pn, yielded compound 3, which showed a related two fold-interpenetrated (3,4)-connected 3D framework with an unprecedented {8(3)}2{8(6)} topology in which the Cu(II) atom was chelated by two pn groups. These structural changes between compounds 1-3 can be explained by the chelating effect of the pn group. The replacement of two meridianally coordinated water molecules on the octahedral Cu(II) atom in compound 1 by a pn group gives compound 2, which shows similar Cairo tiling, and a further increase in the amount of pn results in the formation of the [Cu(NC)2(pn)2] unit and the two-fold interpenetrated 3D framework of compound 3. The mixed-valence properties of compounds 1, 2, and 3 were confirmed by variable-temperature magnetic susceptibility measurements. PMID- 23625461 TI - Muscular adaptations and insulin-like growth factor-1 responses to resistance training are stretch-mediated. AB - INTRODUCTION: Modulation of muscle characteristics was attempted through altering muscle stretch during resistance training. We hypothesized that stretch would enhance muscle responses. METHODS: Participants trained for 8 weeks, loading the quadriceps in a shortened (SL, 0-50 degrees knee flexion; n=10) or lengthened (LL, 40-90 degrees ; n=11) position, followed by 4 weeks of detraining. Controls (CON; n=10) were untrained. Quadriceps strength, vastus lateralis architecture, anatomical cross-sectional area (aCSA), and serum insulin-like growth factor-1 (IGF-1) were measured at weeks 0, 8, 10, and 12. RESULTS: Increases in fascicle length (29+/-4% vs. 14+/-4%), distal aCSA (53+/-12% vs. 18+/-8%), strength (26+/ 6% vs. 7+/-3%), and IGF-1 (31+/-6% vs. 7+/-6%) were greater in LL compared with SL muscles (P<0.05). No changes occurred in CON. Detraining decrements in strength and aCSA were greater in SL than LL muscles (P<0.05). CONCLUSIONS: Enhanced muscle in vivo (and somewhat IGF-1) adaptations to resistance training are concurrent with muscle stretch, which warrants its inclusion within training. PMID- 23625462 TI - MicroRNA-1 enhances the angiogenic differentiation of human cardiomyocyte progenitor cells. AB - Instigated by the discovery of adult cardiac progenitor cells, cell replacement therapy has become a promising option for myocardial repair in the past decade. We have previously shown that human-derived cardiomyocyte progenitor cells (hCMPCs) can differentiate into cardiomyocyte-, endothelial-, and smooth muscle like cells in vitro, and in vivo after transplantation in a mouse model of myocardial infarction, resulting in preservation of cardiac function. However, to allow successful repopulation of the injured myocardium, it is of key importance to restore myocardial perfusion by the formation of new vasculature. Several studies have shown that microRNAs regulate vascular differentiation of different stem/progenitor cells. Here, we show that miR-1 is upregulated in hCMPCs during angiogenic differentiation. Upregulation of miR-1 enhanced the formation of vascular tubes on Matrigel and within a collagen matrix, and also increased hCMPC motility, as shown by planar and transwell migration assays. By western blot, qRT PCR and luciferase reporter assays, miR-1 was found to directly target and inhibit the expression of sprouty-related EVH1 domain-containing protein 1 (Spred1). Knocking down Spred1 phenocopies the functional effect seen for miR-1 upregulation. Using a systems biology approach, we found that in hCMPCs, miR-1 is proposed to control a network of genes predominantly involved in angiogenesis related processes, including the Spred1 pathway. Our data shows that by upregulation of miR-1, the angiogenic differentiation of hCMPCs can be enhanced, which may be used as a new therapeutic approach to improve the efficiency of cell based therapy for cardiac regeneration by enhancing the formation of new vasculature. PMID- 23625463 TI - Gene expression profiling and association studies implicate the neuregulin signaling pathway in Behcet's disease susceptibility. AB - Behcet's disease (BD) is a complex disease with genetic and environmental risk factors implicated in its etiology; however, its pathophysiology is poorly understood. To decipher BD's genetic underpinnings, we combined gene expression profiling with pathway analysis and association studies. We compared the gene expression profiles in peripheral blood mononuclear cells (PBMCs) of 15 patients and 14 matched controls using Affymetrix microarrays and found that the neuregulin signaling pathway was over-represented among the differentially expressed genes. The Epiregulin (EREG), Amphiregulin (AREG), and Neuregulin-1 (NRG1) genes of this pathway stand out as they are also among the top differentially expressed genes. Twelve haplotype tagging SNPs at the EREG-AREG locus and 15 SNPs in NRG1 found associated in at least one published BD genome wide association study were tested for association with BD in a dataset of 976 Iranian patients and 839 controls. We found a novel association with BD for the rs6845297 SNP located downstream of EREG, and replicated three associations at NRG1 (rs4489285, rs383632, and rs1462891). Multifactor dimensionality reduction analysis indicated the existence of epistatic interactions between EREG and NRG1 variants. EREG-AREG and NRG1, which are members of the epidermal growth factor (EGF) family, seem to modulate BD susceptibility through main effects and gene gene interactions. These association findings support a role for the EGF/ErbB signaling pathway in BD pathogenesis that warrants further investigation and highlight the importance of combining genetic and genomic approaches to dissect the genetic architecture of complex diseases. PMID- 23625465 TI - The entotympanic in late fetal Artiodactyla (Mammalia). AB - The entotympanic is a neomorphic component of the bulla tympanica of placental mammals. Ontogenetically, its rostral component seems to be derived from the tubal cartilage, whereas its caudal component is normally connected with the sheath of the tympanohyal; the present study indicates additional sources of the caudal entotympanic. The entotympanics develop in late fetal or early postnatal life as cartilaginous structures, but in most taxa they ossifiy endochondrally as "os bullae". This skeletal element is absent only in a few placental orders, among them the Artiodactyla. Because it is present in their sister taxa within the Scrotifera, it is likely to be reduced secondarily in the even-toed mammals. The study of histological serial sections of late fetal stages of several artiodactyl species shows that vestigial cartilaginous homologues of the entotympanics are invariably present, contrary to statements in the literature. In a few perinatal stages even secondary ossifications or calcifications of the entotympanic cartilages can be observed. The tubal cartilage of artiodactyls also continues into an anterior tegmen tympani (new term) that forms the floor of the fossa muscularis major. PMID- 23625466 TI - Tunable delivery of bioactive peptides from hydroxyapatite biomaterials and allograft bone using variable-length polyglutamate domains. AB - Hydroxyapatite (HA) biomaterials and allograft bone are common alternatives to autogenous grafts; however, these materials lack the strong osteoinductive potential of autologous bone. Previous studies have established that polyglutamate domains, which bind selectively to HA, can be engineered onto bioactive peptides as a mechanism for coupling osteoinductive signals onto HA and allograft. In the current investigation, we adapted the polyglutamate approach to tailor delivery of a model collagen-derived peptide, Asp-Gly-Glu-Ala (DGEA), by manipulating the number of glutamates in the HA binding domain. Specifically, DGEA was modified with diglutamate (E2-DGEA), tetraglutamate (E4-DGEA), or heptaglutamate (E7-DGEA), and it was found that initial peptide binding to HA and allograft was significantly enhanced as the number of glutamates increased. We also determined that the rate of release of polyglutamate-DGEA from substrates over a 5-day interval increased proportionally as the number of glutamate residues was decreased. Additionally, we tuned the peptide release rate by creating mixtures of E2-DGEA, E4-DGEA, and E7-DGEA, and observed that release kinetics of the mixtures were distinct from pure solutions of each respective peptide. These collective results suggest that variable-length polyglutamate domains provide an effective mechanism for controlled delivery of osteoregenerative peptides on HA-containing bone graft materials. PMID- 23625467 TI - The schizoaffective disorder diagnosis: a conundrum in the clinical setting. AB - The term schizoaffective was introduced to describe the co-occurrence of both psychotic and affective symptoms. Overtime, as the diagnosis schizoaffective disorder was added to diagnostic manuals, significant concerns were raised as to the reliability and clinical utility of the diagnosis. We recruited 134 psychiatrically hospitalized subjects who had received a diagnosis of schizophrenia, schizoaffective disorder or bipolar disorder with psychotic features by their treating clinician. The subjects were also diagnosed by trained research personnel with the Structured Clinical Interview of the DSM-IV-TR, employing an explicit time threshold for criterion C of the schizoaffective disorder diagnosis. We found significant differences between the clinical and research diagnoses. Clinicians diagnosed 48 patients (36%) with schizophrenia, 50 patients (37%) with schizoaffective disorder and 36 patients (27%) with psychotic bipolar disorder. In contrast, researchers diagnosed 64 patients (48%) with schizophrenia, 38 patients (28%) with schizoaffective disorder and 32 patients (24%) with psychotic bipolar disorder. This was a statistically significant disagreement between the research and clinical diagnoses (p = 0.003) and indicates that clinicians choose the less severe diagnosis for psychotic patients. We conclude that a more stringent criterion C for the schizoaffective disorder diagnosis will address an implicit bias in clinical practice and will affect the prevalence of the psychotic disorder diagnoses. PMID- 23625468 TI - How to treat relapsed acute lymphoblastic leukemia: transplant vs. conventional chemotherapy. AB - Management of relapsed acute lymphoblastic leukemia (ALL) is challenging and far from satisfactory. The treatment approaches are often varied and controversial. The duration of first remission, site of relapse, immunophenotypic and molecular characteristics of relapsed disease and response to therapy influence treatment outcome. There are three main therapeutic options i.e., chemotherapy alone, induction chemotherapy followed by HLA matched allogeneic transplant and palliation. These may be chosen based on the above mentioned factors. The response to therapy may be evaluated morphologically or by minimal residual disease (MRD). Persistence of MRD, as assessed by molecular techniques or through flowcytometry, clearly influences prognosis in children with relapsed ALL. It not only helps in identifying the subset of patients likely to benefit from allogeneic bone marrow transplant (ABMT) but also in determining the timing of transplant. Patients with non-T phenotype, with late relapsing disease and good response to re-induction therapy have been shown to do equally well with chemotherapy alone. On the other hand patients with early relapse and poor initial response are selected for ABMT. With the improvement in supportive care, better selection of HLA match donors and better immunosuppressive therapies, transplant related mortality has decreased considerably. Despite all of these overall salvage rates are still poor and novel agents are being tested in various trials to establish their role in relapsed ALL therapy. PMID- 23625469 TI - Palatal perforation due to late congenital syphilis. PMID- 23625470 TI - Rituximab for opsoclonus myoclonus ataxia syndrome associated with neuroblastoma. PMID- 23625471 TI - Tubercular ventriculitis: an uncommon entity. AB - Although tubercular meningitis is common in children, tubercular ventriculitis is uncommon. The authors report a 3-mo-old infant who had tubercular ventriculitis secondary to disseminated tuberculosis. PMID- 23625472 TI - Ratiometric analysis in hyperpolarized NMR (I): test of the two-site exchange model and the quantification of reaction rate constants. AB - Conventional methods for the analysis of in vivo hyperpolarized (13) C NMR data from the lactate dehydrogenase (LDH) reaction usually make assumptions on the stability of rate constants and/or the validity of the two-site exchange model. In this study, we developed a framework to test the validity of the assumption of stable reaction rate constants and the two-site exchange model in vivo via ratiometric fitting of the time courses of the signal ratio L(t)/P(t). Our analysis provided evidence that the LDH enzymatic kinetics observed by hyperpolarized NMR are in near-equilibrium and satisfy the two-site exchange model for only a specific time window. In addition, we quantified both the forward and reverse exchange rate constants of the LDH reaction for the transgenic and mouse xenograft models of breast cancer using the ratio fitting method developed, which includes only two modeling parameters and is less sensitive to the influence of instrument settings/protocols, such as flip angles, degree of polarization and tracer dosage. We further compared the ratio fitting method with a conventional two-site exchange modeling method, i.e. the differential equation fitting method, using both the experimental and simulated hyperpolarized NMR data. The ratio fitting method appeared to fit better than the differential equation fitting method for the reverse rate constant on the mouse tumor data, with less relative errors on average, whereas the differential equation fitting method also resulted in a negative reverse rate constant for one tumor. The simulation results indicated that the accuracy of both methods depends on the width of the transport function, noise level and rate constant ratio; one method may be more accurate than the other based on the experimental/biological conditions aforementioned. We were able to categorize our tumor models into specific conditions of the computer simulation and to estimate the errors of rate quantification. We also discussed possible approaches to the development of more accurate rate quantification methods for hyperpolarized NMR. PMID- 23625473 TI - Spirituality and religion in oncology. AB - Despite the difficulty in clearly defining and measuring spirituality, a growing literature describes its importance in oncology and survivorship. Religious/spiritual beliefs influence patients' decision-making with respect to both complementary therapies and aggressive care at the end of life. Measures of spirituality and spiritual well-being correlate with quality of life in cancer patients, cancer survivors, and caregivers. Spiritual needs, reflective of existential concerns in several domains, are a source of significant distress, and care for these needs has been correlated with better psychological and spiritual adjustment as well as with less aggressive care at the end of life. Studies show that while clinicians such as nurses and physicians regard some spiritual care as an appropriate aspect of their role, patients report that they provide it infrequently. Many clinicians report that their religious/spiritual beliefs influence their practice, and practices such as mindfulness have been shown to enhance clinician self-care and equanimity. Challenges remain in the areas of conceptualizing and measuring spirituality, developing and implementing training for spiritual care, and coordinating and partnering with chaplains and religious communities. PMID- 23625474 TI - Surgery on a patient with iatrogenic aortic valve leaflet perforation after repair of a congenital ventricular septal defect. AB - Aortic valve regurgitation caused by a leaflet perforation occurs most often with infective endocarditis involving the aortic valve. Although rare, leaflet perforation can be caused by suture-related injury during cardiac operations, such as mitral valve replacement, ventricular septal defect (VSD) repair, and repair of an ostium primum atrial septal defect. Few reports have described this form of iatrogenic aortic valve leaflet perforation. We used a pericardial patch in a successful repair of an iatrogenic perforation in an aortic valve leaflet that occurred after simple VSD repair. PMID- 23625475 TI - Graft flow unaffected by full occlusion of left anterior descending artery during coronary artery bypass grafting in a porcine model. AB - BACKGROUND: We investigated in a porcine model whether measuring both the flow distal to an anastomosis and the graft transit time flow (TTF) gives a more accurate picture of the true blood flow in the left anterior descending artery (LAD) than graft TTF measurement alone. METHODS: We performed off-pump coronary artery bypass grafting (CABG)-left internal mammary artery (LIMA) to the LAD-on 5 Yorkshire-Landrace pigs. Snares were placed both proximal and distal to the anastomosis. Flow was measured with ultrasound and TTF. This was carried out on the LIMA and at 2 locations on the LAD. Measurements were performed at the following times: baseline, during proximal snaring, after proximal snare loosening, during distal snaring, after distal snare loosening, and during both proximal and distal snaring. RESULTS: During distal snaring, the TTF dropped (P = .047), and the pulsatile index (PI) increased (P = .025), while the ultrasound flow in the LAD dropped (P = .002). During proximal and distal snaring, the ultrasound flow dropped (P = .005), but the TTF value did not change significantly, compared with baseline. CONCLUSION: A high flow and a low PI were seen in the graft, both proximal and distal to the anastomosis, despite a fully occluded LAD. This result suggests that graft TTF measurement alone is not sufficient when performing CABG, and measurement of flow distal to the anastomosis is also necessary to determine the true blood flow in the LAD. PMID- 23625476 TI - Serpentine left circumflex coronary artery aneurysm as a rare cause of angina with contrast-enhanced multislice computed tomographic evaluation. AB - Left circumflex coronary artery anomalies are rare causes of cardiac symptoms, especially in the adult population. Herein we describe a case of a 40-year-old man presenting with stable angina who was found to have aneurysmal formation and fistulization of the left circumflex coronary artery to the coronary sinus. Contrast-enhanced multislice computed tomography was very useful in our case for the diagnosis of such anomalies. PMID- 23625477 TI - Simultaneous beating heart coronary artery bypass surgery and modified radical mastectomy. AB - Concomitant surgeries for unrelated diseases can be performed to minimize the risks associated with surgery and general anesthesia. In treating a male patient with breast cancer and severe coronary artery disease, we used the beating heart technique for a coronary artery bypass graft to avoid the negative effects of on pump bypass on the possible acceleration of tumor growth. In this report, we present a unique case of concomitant off-pump coronary artery bypass graft surgery and modified radical mastectomy in a 56-year-old man. PMID- 23625478 TI - Safety and efficacy of cangrelor, an intravenous, short-acting platelet inhibitor in patients requiring coronary artery bypass surgery. AB - OBJECTIVE: Oral P2Y12 platelet receptor inhibitors are a cornerstone of reducing complications in patients with acute coronary syndromes or coronary stents. Guidelines advocate discontinuing treatment with P2Y12 platelet receptor inhibitors before surgery. Cangrelor, a short-acting, reversible, intravenously administered P2Y12 platelet inhibitor is effective in achieving appropriate platelet inhibition in patients who are awaiting coronary artery bypass grafting (CABG) and require P2Y12 inhibition. The objective of this study was to assess the effects of preoperative cangrelor on the incidence of perioperative complications, which are currently unknown. METHODS: Patients (n = 210) requiring preoperative clinical administration of thienopyridine therapy were randomized in a multicenter, double-blinded study to receive cangrelor or placebo while awaiting CABG after discontinuation of the thienopyridine. Optimal platelet reactivity, which was defined as <240 P2Y12 platelet reaction units, was measured with serial point-of-care testing (VerifyNow). Pre- and postoperative outcomes, bleeding values, and transfusion rates were compared. To quantify potential risk factors for bleeding, we developed a multivariate logistic model. RESULTS: The differences between the groups in bleeding and perioperative transfusion rates were not significantly different. The rate of CABG-related bleeding was 11.8% (12/102) in cangrelor-treated patients and 10.4% (10/96) in the placebo group (P = .763). Transfusion rates for the groups were similar. Serious postoperative adverse events for the cangrelor and placebo groups were 7.8% (8/102) and 5.2% (5/96), respectively (P = .454). CONCLUSIONS: Compared with placebo, bridging patients with cangrelor prior to CABG effectively maintains platelet inhibition without increasing post-CABG complications, including bleeding and the need for transfusions. These data suggest cangrelor treatment is a potential strategy for bridging patients requiring P2Y12 receptor inhibition while they await surgery. PMID- 23625479 TI - Bleeding outcomes associated with coronary artery bypass graft surgery and recent clopidogrel exposure. AB - BACKGROUND: Guidelines recommend discontinuing clopidogrel for at least 5 days before elective coronary artery bypass graft surgery (CABG) to limit blood transfusions and for at least 24 hours before urgent CABG to reduce major bleeding complications. Studies have produced conflicting results regarding whether recent exposure to clopidogrel increases bleeding, the need for intraoperative and postoperative blood products, postoperative complications, and hospital length of stay. We evaluated the effect of clopidogrel exposure on major bleeding at our institution within 5 days of CABG. METHODS: We conducted a retrospective review of patients who underwent CABG at a tertiary academic medical center. The primary outcome was major bleeding, defined as transfusion of 4 units of packed red blood cells (PRBCs) and/or a need for reexploration. Secondary outcomes included non-life-threatening bleeding, defined as transfusion of 2 units but <4 units of PRBCs; postoperative complications; hospital length of stay; readmission within 30 days of the procedure; and hospital mortality. Major bleeding events were analyzed with a logistic regression model that adjusted for covariates of bleeding risk factors. RESULTS: Of the 715 patients we reviewed, 169 patients received clopidogrel within 5 days before CABG, and 546 patients did not. A significantly higher incidence of major bleeding was observed in the clopidogrel group compared with the group not exposed to clopidogrel (32% versus 17%, P = .002). After adjusting for covariates, patients exposed to clopidogrel had significantly higher odds of major bleeding (odds ratio, 2.1; 95% confidence interval, 1.3-3.4; P = .003). The groups were similar with respect to postoperative complications, except for infection. The clopidogrel-exposed group had a significantly higher rate of leg site infections (3% versus 0.2%, P = .003). CONCLUSIONS: Clopidogrel exposure within 5 days of CABG is associated with an increased risk of major bleeding. PMID- 23625480 TI - Evaluation of positive inotropic drug effects on thyroid hormone levels after open heart surgery. AB - OBJECTIVE: The aim of this study was to examine the effects of positive inotropic drugs, including adrenaline, dopamine, and dobutamine on thyroid hormone levels following open heart surgery. METHODS: We analyzed free thyroid hormones (FT3 and FT4) and thyroid-stimulating hormones (TSH) in 200 consecutive patients undergoing open heart surgery. Patients were divided into 5 groups according to the inotropic drug administration as follows: Group A (n = 46) received dopamine alone; Group B (n = 40), dopamine and dobutamine; Group C (n = 36), dopamine, dobutamine, and adrenaline; Group D (n = 32), adrenaline alone; and Group E (n = 46), placebo. Procedural factors affecting thyroid hormones were recorded and included cardiopulmonary bypass (CPB) time, cross-clamping time, degree of hypothermia, and the duration and doses of positive inotropic drugs. Blood samples for hormone assays were collected before initiation of inotropic drug therapy (baseline) and postoperatively at 24, 72, and 120 hours after drug therapy. RESULTS: FT3, FT4, and TSH levels at baseline were similar in all groups. Although there was a trend showing very slight increases in thyroid hormone levels from baseline to the 24th, 72nd, and 120th postoperative hours after drug therapy, these changes were not significant, and there were also no significant differences between the groups. There was also no significant statistical difference in CPB time, cross-clamping time, degree of hypothermia, and duration and doses of positive inotropic drugs between groups. CONCLUSION: Although thyroid hormone levels were affected by positive inotropic drug usage after open heart surgery, this effect was not significant and thyroid hormone levels remained within normal ranges. PMID- 23625481 TI - Key-lock type mini-sternotomy: an alternative approach for adult cardiac operations. AB - An alternative technique for minimally invasive aortic valve replacement and atrial septal defect repair is described. After a 5-cm skin incision, a key-lock type sternotomy is made. Excellent exposure of the right atrium and aortic valve was achieved. The configuration of the mini-sternotomy (or the lock) limits the movement of the sternal surfaces (or the key) on the lateral and craniocaudal directions. PMID- 23625482 TI - Long-term results of the single-patch repair technique for sinus venosus atrial septal defects. AB - BACKGROUND: Anomalous pulmonary venous drainage commonly accompanies sinus venosus atrial septal defects (SVASDs). Many techniques have been reported for avoiding postoperative complications, such as narrowing of the superior vena cava (SVC) or the pulmonary system, and arrhythmia. We perform a single V-Y pericardial patch plasty repair technique for SVASDs. The purpose of this study is to report on the long-term results of this surgical technique. METHODS: We retrospectively analyzed patients who had a diagnosis of ASD and who underwent their operations between 2000 and 2010 at the Gulhane Military Medical Academy Haydarpasa Training Hospital. Thirty-nine of the patients had an anomalous pulmonary return, and the single pericardial patch technique had been performed in 32 of these patients. RESULTS: The mean (+/-SD) postoperative extubation time was 5 +/- 1.6 hours. The mean drainage volume was 384 +/- 137 mL. All patients were discharged from the hospital at a mean of 4.6 +/- 1.1 days after their operation and were prescribed anticoagulants for 3 months. No perioperative or late-term mortality was observed. Patients were followed up for 6 months to 2 years. There were no residual shunts and no stenosis-related findings in the pulmonary venous system or the SVC. CONCLUSION: Use of the single pericardial patch plasty technique might lower complication rates in patients with SVASD, especially those who have not completed their growth. PMID- 23625483 TI - Relationship between patient income level and mitral valve repair utilization. AB - BACKGROUND: The superiority of mitral valve (MV) repair is well established with respect to long-term survival, preservation of ventricular function, and valve related complications. The relationship between patient income level and the selection of MV procedure (repair versus replacement) has not been studied. METHODS: The 2005 to 2007 Nationwide Inpatient Sample database was searched for patients >= 30 years old with MV repair or replacement; patients with ischemic and congenital MV disease were excluded. Patients were stratified into quartiles according to income level (quartile 1, lowest; quartile 4, highest). We used univariate and multivariate models to compare patients with respect to baseline characteristics, selection of MV procedure, and hospital mortality. RESULTS: The preoperative profiles of the income quartiles differed significantly, with more risk factors occurring in the lower income quartiles. Unadjusted hospital mortality decreased with increasing income quartile. The percentage of patients receiving MV repair increased with increasing income (35.6%, 39.6%, 48.2%, and 55.8% for quartiles 1, 2, 3, and 4, respectively; P = .0001). Following adjustment for age, race, sex, urban residency, admission status, primary payer, Charlson comorbidity index, and hospital location and teaching status, the income quartiles had similar hospital death rates, whereas the highly significant relationship between valve repair and income level persisted (P = .0008). CONCLUSIONS: Significant disparity exists among patients in the different income quartiles with respect to the likelihood of receiving MV repair. MV repair is performed less frequently in patients with lower incomes, even after adjustment for differences in baseline characteristics. The higher unadjusted mortality rate for less affluent patients appears mostly related to their worse preoperative profiles. PMID- 23625484 TI - Valve-in-valve in the tricuspid position for a stenosed bioprosthesis. AB - The strategy of transcatheter valve-in-valve implantation into failing mitral and aortic bioprosthetic valves is a documented approach. It allows one to avoid performing a high-risk repeat cardiac surgery in elderly patients with multiple comorbidities. Tricuspid valve-in-valve implantation has been documented only a few times in the literature. We report the case of a 65-year-old woman with a failing bioprosthetic tricuspid valve who had undergone 3 prior open heart operations. We attempted a transatrial transcatheter approach and successfully deployed a 29-mm Edwards Sapien balloon-expandable bioprosthesis into a severely stenotic tricuspid bioprosthesis. This case demonstrates the technical feasibility and safety of this approach. PMID- 23625485 TI - Temporary tricuspid valve detachment for ventricular septal defect closure: is it worth doing it? AB - BACKGROUND: Tricuspid valve detachment (TVD) may improve the access for closing certain ventricular septal defects (VSDs), but it has some potential risks. We aimed to study the benefits and drawbacks of this technique. METHODS: The midterm outcomes of all 20 patients who underwent a TVD closure for VSD were reviewed and compared with a control group of 15 patients with VSD closure without TVD. RESULTS: There was no significant residual shunt in either group at the last actuarial follow-up. Tricuspid regurgitation occurred in both groups (45% in the TVD group and 27% in the control group, P = .48). These lesions were considered insignificant in all patients. There were no atrioventricular blocks, and all patients were in sinus rhythm. The cardiopulmonary bypass times were significantly higher in the TVD group than in the control group (91.6 +/- 17.2 minutes versus 68.3 +/- 15.7 minutes, P <= .01), as were the aortic cross clamping times (50.7 +/- 12.1 minutes versus 35.9 +/- 14.4 minutes, P <= .01). CONCLUSION: Our results, along with results from other series, suggest that TVD can be used effectively and safely for closure of certain VSDs. PMID- 23625486 TI - Impact of Sodium Chloride, Sucrose and Milk on Heat Stability of the Murine Norovirus and the MS2 Phage. AB - Until now, little is known about the influence of food additives on heat inactivation of noroviruses. Only a few studies have shown a protective or inhibiting effect on virus infectivity caused by the food matrix. Therefore, the aim of this study was to examine the influence of sodium chloride, sucrose and milk on heat stability of the surrogates murine norovirus (MNV) and MS2 phage at 60 degrees C for 1-5 min in PBS for MNV and for 5-120 min in suspension medium buffer for MS2 phage. Different concentrations of sodium chloride (5, 10 %) and sucrose (5, 50 %) were added to the respective buffers. In addition, commercially available milk with different fat concentrations (0.3, 1.5, 3.5 %) was investigated in this study. In general, a linear titre reduction for MNV and MS2 phage could be observed, except for the heat treatment of MNV in PBS with 50 % sucrose. A protective effect of PBS with 50 % sucrose and of the matrix milk on MNV could be concluded. All other tested conditions did not show any influence on virus inactivation. However, MS2 phage did show a higher heat resistance throughout the experiments compared to MNV. In future investigations, it should be tested, whether the achieved data may be considered in risk assessments of heat-treated food products with high concentrations of sugar. Furthermore, it should be clarified, whether these results can also be referred to complex food matrices. PMID- 23625487 TI - The frequency response of a floating piezoelectric microphone for the implantable middle ear microphone. AB - OBJECTIVES/HYPOTHESIS: A piezoelectric sensor, floating piezoelectric microphone, driven by acoustic vibration of the ossicles, is one possible design for a microphone for a totally implantable cochlear implant. The purpose of the article was to study the frequency response of the floating piezoelectric microphone and to identify the ideal feasible position in the ossicular chain. STUDY DESIGN: Basic Research. METHODS: The frequency response of the floating piezoelectric microphone was analyzed by finite-element modeling and in vitro testing of fresh cadaveric heads. The floating piezoelectric microphone, 5.0 mm in length and 1.5 mm by 1.2 mm in rectangular cross section, as a piezoelectric microphone, was placed at various locations on the ossicular chain and stimulated by pure tones of different frequencies. RESULTS: The floating piezoelectric microphone can pick up the vibration of the ossicular chain and effectively convert it into the electronic signals effectively both in the long process of incus and in the malleus. The average sensitivity of the FPM is -44.22 dB rms ref 1V at 1000 Hz in the long process of incus, -53.33 dB rms ref 1V at 1000 Hz in the malleus, and 108.59 dB rms ref 1V at 1000 Hz in the tympanic cavity. CONCLUSIONS: The floating piezoelectric microphone is expected to be used as an implantable middle ear microphone for the totally implantable cochlear implant. PMID- 23625488 TI - The inhibitors of antioxidant cell enzymes induce permeability transition in yeast mitochondria. AB - In this study we investigated the effects of exogenous and endogenous oxidative stress on mitochondrial membrane permeability transition in yeast cells. E. magnusii yeast was used in the study as it is the only yeast strain possessing a natural high-capacity Sa2+ transport system. The key reactive oxygen species (ROS) detoxifying enzymes in the yeast cells--catalases (CATs) and superoxide dismutases (SODs)--were fully characterized. At least five isoforms of SODs and only one isoform of CATs were found in the E. magnusii mitochondria. The assessment of the main properties of mitochondrial non-specific permeability under physiological conditions such as dynamics of the membrane potential (?Psi) and swelling in mitochondria showed that under physiological conditions classical inhibitors of CATs (ATZ--3-amino-1, 2, 4-triazole) and of SODs (DDC- diethyldithiocarbamate) caused irreversible decline in ?Psi in the yeast mitochondria. This decline was accelerated in the presence of 500 MUM Sa2+. The combined action of the inhibitors (ATZ + DDC) promoted moderate swelling in the isotonic medium, which was confirmed by transmission electron microscopy. Mitochondrial swelling in the cells exposed to antioxidant system inhibitors was accompanied by typical signs of early apoptosis, namely by chromatin margination and condensation, vacuolization of the cytosol, and damage of the plasma membrane. Here we showed, at both cellular and mitochondrial levels, that the deregulation of oxidant-scavenging enzymes directly leads to the opening of the mPTP, followed by induction of apoptotic markers in the whole yeast cells. Our studies are the first to clarify the highly contradictory data in the literature on mPTP in yeast mitochondria. PMID- 23625490 TI - Chemokine-dependent signaling pathways in the peripheral nervous system. AB - Chemokines and their G-protein-coupled receptors play important roles in development, homeostasis, and the innate and adaptive immune response. Pathologic chemokine signaling pathways in the peripheral nervous system can be studied in peripheral nerves using human in vitro models of the blood-nerve barrier (BNB) and a reliable model of acute peripheral nerve inflammation called severe murine experimental autoimmune neuritis (EAN). This chapter describes a flow-dependent human leukocyte-BNB trafficking assay and the reliable induction of EAN in female SJL/J mice as tools to study pro-inflammatory chemokine-dependent signaling in peripheral nerves. PMID- 23625489 TI - The fine balance of chemokines during disease: trafficking, inflammation, and homeostasis. AB - The action of chemokines (or "chemotactic cytokines") is recognized as an integral part of inflammatory and regulatory processes. Leukocyte mobilization during physiological conditions, trafficking of various cell types during pathological conditions, cell activation, and angiogenesis are among the target functions exerted by chemokines upon signaling via their specific receptors. Current research is focused in analyzing changes in chemokine/chemokine receptor patterns during various diseases with the aim to modulate pathological trafficking of cells, or to attract particular cell types to specific tissues. This review focuses on defining the role(s) of certain chemokine ligands and receptors in inflammatory neurological conditions such as multiple sclerosis. In addition, the role(s) of chemokines in neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease is also described, as well as the contribution of chemokines to the pathogenesis of cancer, diabetes, and cardiovascular disease. PMID- 23625491 TI - Multispectral imaging and automated laser capture microdissection of human cortical neurons: a quantitative study of CXCR4 expression. AB - Quantifying protein and RNA expression within specific cell populations in vivo is an essential step in unraveling the complex mechanisms of neurological disease. The challenges associated with studying human brain tissue are commonly compounded by variations in postmortem interval, formalin fixation time, and tissue processing methods among others. The result is a sample population that is inherently heterogeneous, implying the need for reliable protocols that are sensitive to low levels of antigen while minimizing background and nonspecific staining. Here, we describe a single immunohistochemistry protocol on formalin fixed, paraffin-embedded human cortex which can be adapted to (1) quantify the relative protein expression of the chemokine receptor, CXCR4, using multispectral image or (2) isolate neuronal RNA through automated laser capture microdissection. PMID- 23625492 TI - Chemokine receptors and neural stem cells. AB - Neural stem cells (NSCs) represent a limited population of progenitor cells in the central nervous system that sustain their self-renewal and multipotency from early development to adulthood. Recent evidence suggests that chemokine receptors are constitutively expressed by NSCs and are directly involved in stem cell biology. As cell surface receptors, chemokine receptors also provide an important avenue to enrich these cells and further identify the potential molecular pathways required to maintain their biological functions. Here, I describe in vitro methods that have been widely applied to sort, culture, maintain, and differentiate NSCs. PMID- 23625493 TI - Chemokine receptor interactions with virus-like particles. AB - Virus-like particles (VLPs) presenting conformational envelope proteins on their surface represent an invaluable tool to study molecular interactions between viruses and cellular receptors/co-receptors, eliminating biological risks associated with working with live native viruses. The availability of target cells expressing specific chemokine receptors facilitates the dissection of specific interactions between human immunodeficiency virus (HIV) viral envelope proteins and these receptors in the laboratory. Here, we describe a method to evaluate HIV-VLP binding to cellular chemokine co-receptors, by carboxyfluorescein succinimidyl ester labeling and cellular uptake. PMID- 23625494 TI - Chemokine receptor antagonist development. AB - This chapter describes assays that focus on the characterization of compounds identified in high--throughput screening campaigns, and the subsequent medicinal chemistry programs. They cover methods to determine potency in buffer, the effect of whole blood on the compounds' activity and finally the pharmacokinetic (PK)/pharmacodynamic (PD) -relationship of the compounds in a rodent species. PMID- 23625496 TI - Unraveling chemokine and chemokine receptor expression patterns using genetically engineered mice. AB - Over the past 25 years, genetically engineered mouse models have become an integral and invaluable research tool to develop our understanding of mammalian physiology and pathology. This unit describes methods for generating transgenic mice, focusing on reporter animals relevant to chemokine receptor and ligand expression. Specifically, we describe the use of bacterial artificial chromosome (BAC) engineering and embryonic stem cell manipulation to generate "knock in" and transgenic mice. PMID- 23625495 TI - A novel approach to quantify G-protein-coupled receptor dimerization equilibrium using bioluminescence resonance energy transfer. AB - Along with other resonance energy transfer techniques, bioluminescence resonance energy transfer (BRET) has emerged as an important method for demonstrating protein-protein interactions in cells. In the field of G-protein-coupled receptors, including chemokine receptors, BRET has been widely used to investigate homo- and heterodimerization, a feature of their interactions that is emerging as integral to function and regulation. While demonstrating the existence of dimers for a given receptor proved to be fairly straightforward, quantitative comparisons of different receptors or mutants are nontrivial because of inevitable variations in the expression of receptor constructs. The uncontrollable parameters of the cellular expression machinery make amounts of transfected DNA extremely poor predictors for the expression levels of BRET donor and acceptor receptor constructs, even in relative terms. In this chapter, we show that properly accounting for receptor expression levels is critical for quantitative interpretation of BRET data. We also provide a comprehensive account of expected responses in all types of BRET experiments and propose a framework for uniform and accurate quantitative treatment of these responses. The framework allows analysis of both homodimer and heterodimer BRET data. The important caveats and obstacles for quantitative treatment are outlined, and the utility of the approach is illustrated by its application to the homodimerization of wild type (WT) and mutant forms of the chemokine receptor CXCR4. PMID- 23625497 TI - Zebrafish as a model to study chemokine function. AB - Zebrafish have emerged as a powerful model organism to study embryo morphogenesis. Due to their optical clarity, they are uniquely suited for time lapse imaging studies, providing insights into the dynamic processes underlying tissue formation and cell migration. These studies have been tremendously facilitated by the availability of transgenic zebrafish lines, labelling distinct embryonic structures, individual cells, or even subcellular structures, such as the nucleus. Zebrafish studies have revealed that the migration of several different cell types in the embryo is controlled by chemokines, small vertebrate specific proteins. Here, we report methods to analyze the expression pattern of a given chemokine and its receptor in transgenic zebrafish using fluorescent in situ hybridization in combination with an anti-green fluorescent protein (GFP) antibody staining. We furthermore illustrate how to image migrating cell populations using time-lapse microscopy in double-transgenic embryos. We show how to investigate cell number and direction of migration by using a nuclear localized GFP. The combination of this transgene with a membrane-targeted red fluorescent protein allows for the simultaneous determination of changes in cell shape, such as the formation of filopodial extensions. We exemplify this by describing how a mutation in the chemokine receptor cxcr4a affects endothelial cell migration and blood vessel formation. Finally, we provide a method to perform fluorescent angiography to monitor blood vessel perfusion in chemokine receptor mutants. PMID- 23625498 TI - Inflammatory macrophage migration in experimental autoimmune encephalomyelitis. AB - Experimental autoimmune encephalomyelitis (EAE) is a CD4 T cell-mediated demyelinating disease of the central nervous system (CNS) where macrophages are the end-stage effector cell. EAE serves as a model for multiple sclerosis where it has been instructive in delineating the autoimmune cellular response in the CNS for the purpose of developing more effective therapies. Understanding the nature of how cytokine and chemokine networks regulate the migration of leukocytes to the CNS requires the ability to track subpopulations of those cells in vivo. We describe a flow cytometric technique to monitor the migration of macrophages during EAE development. PMID- 23625499 TI - Visualizing chemokine-dependent T cell activation and migration in response to central nervous system infection. AB - In response to central nervous system (CNS) injury and infection, astrocytes, neurons, and CNS vasculature express several chemokines, including CCL21. Quantitative polymerase chain reaction (qPCR), western blot, and immunohistochemical methods can quantify mRNA and protein expression. However, these methods do not quantify chemokine bioavailability and bioactivity, variables modified by many environmental factors including composition of the extracellular matrix (ECM). Here we illustrate how two-photon microscopy and carboxyfluorescein succinimidyl ester (CFSE or CFDA SE) labeling of T cells coupled with flow cytometry can be used as tools to assess chemokine-mediated regulation of T cell proliferation, activation, and migration. PMID- 23625500 TI - Epigenetic regulation of chemokine/chemokine receptor expression. AB - Epigenetic regulation of gene expression is an important event for normal cellular homeostasis. Gene expression may be "switched" on or "turned" off via epigenetic means through adjustments in DNA architecture. These structural alterations result from changes to the DNA methylation status in addition to histone posttranslational modifications such as acetylation and methylation. Drugs which can alter the status of these epigenetic markers are currently undergoing clinical trials in a wide variety of diseases, including cancer.We illustrate the treatment of cell lines with histone deacetylase (HDi) and DNA methyltransferase inhibitors and the subsequent RNA isolation and reverse transcriptase polymerase chain reaction for several members of the CXC (ELR(+)) chemokine family. In addition we describe a chromatin immunoprecipitation assay to determine the association between chromatin transcription markers and DNA following pretreatment of cell cultures with an HDi, Trichostatin A (TSA). This assay allows us to determine whether treatment with TSA dynamically remodels the promoter region of our selected genes, as judged by the differences in the PCR product between our treated and untreated samples. PMID- 23625501 TI - Using fluorescent chemokine uptake to detect chemokine receptors by fluorescent activated cell sorting. AB - Fluorescent activated cell sorting (FACS) is a powerful technique that allows rapid quantitative cell-by-cell analysis of the expression of multiple distinct proteins and the isolation of specific cell types from complex cellular mixtures. FACS-based detection of chemokine receptors is typically achieved using chemokine receptor-specific antibodies. However, this approach has some limitations, and, in our experience, many anti-chemokine receptor antibodies have poor signal-to noise ratios and thus low sensitivity and reliability in FACS. Moreover, antibodies against some chemokine receptors are not commercially available, particularly in nonhuman species, and generating good antibodies against chemokine receptors is challenging and expensive. Here, we describe a simple alternative method of detecting chemokine receptors by FACS that relies on cellular internalization of fluorescently labelled chemokines. This approach detects chemokine receptors with high sensitivity, specificity, and reliability, and consistently outperforms antibody-based detection methods when applied to the analysis of mouse cells in our experience. It can also be used to study receptor specificity on primary cells and, since chemokines from one species often bind to receptors from other species, a single fluorescently labelled chemokine should allow reliable chemokine receptor detection and analysis across a range of species. PMID- 23625502 TI - Live cell imaging of chemotactic dendritic cell migration in explanted mouse ear preparations. AB - Leukocyte migration through the interstitial space is crucial for the maintenance of tolerance and immunity. The main cues for leukocyte trafficking are chemokines thought to directionally guide these cells towards their targets. However, model systems that facilitate quantification of chemokine-guided leukocyte migration in vivo are uncommon. Here we describe an ex vivo crawl-in assay using explanted mouse ears that allows the visualization of chemokine-dependent dendritic cell (DC) motility in the dermal interstitium in real time. We present methods for the preparation of mouse ear sheets and their use in multidimensional confocal imaging experiments to monitor and analyze the directional migration of fluorescently labelled DCs through the dermis and into afferent lymphatic vessels. The assay provides a more physiological approach to study leukocyte migration than in vitro three-dimensional (3D) or 2-dimensional (2D) migration assays such as collagen gels and transwell assays. PMID- 23625503 TI - Studying extracellular signaling utilizing a glycoproteomic approach: lectin blot surveys, a first and important step. AB - Successful innovative proteomic analysis is highly dependent on molecular biology techniques at the -surveying and validation stage. This is because mass spectrometry (MS) analyses of complex samples are limited by their dynamic range for detection-so careful front-end sample preparation, fractionation, and enrichment are crucial to find biologically relevant signals in an extremely complex extracellular environment. Here, we share a very useful and simple front end surveying methodology-lectin blotting-for proteomic analysis of glycosylation patterns-the most abundant posttranslational modification in extracellular signaling.Lectin blotting is an effective biochemical technique based on lectin glycan interactions. It is used to detect and characterize carbohydrate epitopes on protein or lipids. Depending on lectin patterns, specific lectins can be used as tags to enrich glycoproteins for further proteomic analysis. In this method, proteins or lipids are resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred electrophoretically to adsorbent membranes such as nitrocellulose or polyvinylidene difluoride (PVDF) membrane first. Transferred proteins or lipids are subsequently analyzed by probes including labeled lectins. In this chapter, we provide a detailed methodology of lectin blotting for glycol-proteomic analysis. This method is robust and can be used for complex cell lysates, conditioned media, or human samples to monitor glycosylation pattern following extracellular signal transduction. Here, we will use patient plasma samples post hypothermic therapy-an extremely complex medium as a tool to describe in detail the technique of lectin blotting for proteomic analysis. PMID- 23625504 TI - Protein film voltammetry and co-factor electron transfer dynamics in spinach photosystem II core complex. AB - Direct protein film voltammetry (PFV) was used to investigate the redox properties of the photosystem II (PSII) core complex from spinach. The complex was isolated using an improved protocol not used previously for PFV. The PSII core complex had high oxygen-evolving capacity and was incorporated into thin lipid and polyion films. Three well-defined reversible pairs of reduction and oxidation voltammetry peaks were observed at 4 degrees C in the dark. Results were similar in both types of films, indicating that the environment of the PSII bound cofactors was not influenced by film type. Based on comparison with various control samples including Mn-depleted PSII, peaks were assigned to chlorophyll a (Chl a) (Em = -0.47 V, all vs. NHE, at pH 6), quinones (-0.12 V), and the manganese (Mn) cluster (Em = 0.18 V). PFV of purified iron heme protein cytochrome b-559 (Cyt b-559), a component of PSII, gave a partly reversible peak pair at 0.004 V that did not have a potential similar to any peaks observed from the intact PSII core complex. The closest peak in PSII to 0.004 V is the 0.18 V peak that was found to be associated with a two-electron process, and thus is inconsistent with iron heme protein voltammetry. The -0.47 V peak had a peak potential and peak potential-pH dependence similar to that found for purified Chl a incorporated into DMPC films. The midpoint potentials reported here may differ to various extents from previously reported redox titration data due to the influence of electrode double-layer effects. Heterogeneous electron transfer (hET) rate constants were estimated by theoretical fitting and digital simulations for the -0.47 and 0.18 V peaks. Data for the Chl a peaks were best fit to a one-electron model, while the peak assigned to the Mn cluster was best fit by a two-electron/one-proton model. PMID- 23625505 TI - Morphological and cytochemical changes in synganglion of Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae) female ticks from exposure of andiroba oil (Carapa guianensis). AB - Actually, the most used method to control ticks is synthetic acaricides with neurotoxic action. However, the use of these methods presents inconveniences, such as the contamination of the environment and risks to the host's health due to the residual effects. Thus, several studies have been developed aiming to find alternative ways to control these ectoparasites, such as the use of natural compounds with active ingredients, which act controlling some species of plagues in addition to presenting medicinal properties that are beneficial to humans. The present study aimed to analyze the action of andiroba oil (Carapa guianensis) on the synganglion of Rhipicephalus sanguineus semiengorged females through morphological and cytochemical techniques aiming to verify if this natural product have neurotoxic action as the numerous synthetic acaricides. The results showed that andiroba oil interferes in the synganglion through structural and enzymatic changes, which lead the nervous tissue to apoptotic death involving autophagy. Among these changes was observed the emergence of large empty spaces between the perineurium and the cortical region, vacuolated cortex cells and with cell swelling, neural cells with picnotic nuclei or in initial stage of chromatin margination and neuropile with high structural disorganization. Considering these data, it can be concluded that andiroba seed oil can be used as an alternative method in the control of R. sanguineus ticks due to its neurotoxic action. PMID- 23625506 TI - Novel convergence-oriented approach for evaluation and optimization of workflow in single-particle two-dimensional averaging of electron microscope images. AB - Three-dimensional (3D) protein structures facilitate the understanding of their biological functions and provide valuable information for developing medicines. Single-particle analysis (SPA) from electron microscopy (EM) is a structure determination method suitable for macromolecules. To achieve a high resolution using combinations of several SPA software packages, 'workflow' optimization and comparative evaluation by scoring results are essential. Two-dimensional (2D) averaging is a key step for 3D reconstruction. The integrated convergence evaluation oriented system (IC-EOS) proposed here provides an effective tool for customizing 2D averaging. This assesses the behavior and characteristics of workflows and evaluates the convergence of iteration steps without human intervention. We chose five base measurements for quantifying convergence: resolution, variance, similarity, shift-distance and rotation-angle. Curve fitting to history graphs scored their stability. We call this score 'fluctuation'. The number of particle images discarded from the library and the number of classification groups were examined to see their effects on optimization levels and fluctuation of measurements, allowing the IC-EOS to select the most appropriate workflow for the target. A case study using a bacterial sodium channel and a simulation study using GroEL showed that resolution of 2D averaging improved with relatively stricter particle selection. With fewer groups, resolutions of class averages improved, but similarities between class-averages and their constituent particle images degraded. Fluctuation was useful for selecting adequate conditions, even when achieved values alone were not conclusive. The vote method, using fluctuation, was robust against noise and enabled a decision without exhaustive search trials. Thus, the IC-EOS is a step toward full automation of SPA. PMID- 23625507 TI - Raster scan waveform compensation control for enhancing the orthogonality of images in SEM. AB - Electron microscopy is used to determine the form and size of samples from images. Consequently, distortion or error in the images produces incorrect data. This study developed an algorithm to enhance the scanner signal in order to improve the orthogonality of the image. The results of images with poor orthogonality, when observed from the central axis standard, are analogous to those of rotationally transformed images. Therefore, we believe that transmitting enhanced signals with rotationally transformed images will improve the quality of the data. PMID- 23625508 TI - Assessing the impact of heart failure therapeutics on quality of life and functional capacity. AB - OPINION STATEMENT: Chronic heart failure (CHF) is an increasingly common disorder with major impact on morbidity and mortality. Goals of therapy include improving survival, attenuating progression of disease, improving functional capacity, and improving health-related quality of life (HRQL). Although there are multiple HRQL instruments that are psychometrically valid, concerns exist on the ability to reliably measure HRQL concepts. Nevertheless, there has been an emphasis on improving HRQL and thus novel therapies and clinical trials have included HRQL assessment routinely. Nonpharmacologic interventions have made a greater impact on HRQL, including the use of transcutaneous aortic valve replacement, left ventricular assist devices, and cardiac resynchronization devices. Pharmacologic therapies have resulted in modest improvements in HRQL and these improvements are often not clinically meaningful to the patient and not lasting beyond 6 months. As novel therapies are developed for CHF patients, researchers must: (a) identify mechanisms that may meaningfully improve HRQL, (b) develop better instruments to measure HRQL, and (c) target the right population with enough impairment in their sense of well-being to enable an intervention to work. The recent publication of the Food and Drug Administration Draft Guidance for Use of Patient-Reported Outcome measures in clinical trials has served as the foundation for more robust trial design using these HRQL measures. PMID- 23625509 TI - Cross-sectional study of the characteristics, healthcare usage, morbidity and mortality of injecting drug users attending an inner city emergency department. AB - BACKGROUND: The affliction of injecting drug use (IDU) has resulted in the emergence of a subgroup of people with a unique set of medical issues. We aimed to describe the emergency department (ED) presentations of IDUs. METHODS: In a prospective observational study over a 3-month period, we identified characteristics of patients with a history of active IDU presenting to the ED. RESULTS: From 1 January 2010 to 31 March 2010, 146 patients with a history of IDU were identified. These contributed to 222 acute presentations to the ED. Baseline characteristics revealed that patients were predominantly male, of Irish nationality, with high levels of homelessness, unemployment and lack of stable family or intimate partner relationships. 45% of presentations occurred as a result of infection (95% CI 38.5% to 51.5%). Trauma, pure toxicological issues, thromboembolic phenomena and psychiatric issues comprised the other common acute diagnoses. The burden of comorbid medical illness was substantial with high rates of hepatitis C infection (74%) and HIV infection (13.8%). Healthcare utilisation indices for this cohort are extreme on multiple measures. We found an ED attendance rate of 445 per 100 patient-years, an admission rate of 68.8 per 100 patient-years and mortality rate of 4.86 per 100 patient-years. CONCLUSIONS: Our study characterises the emergency presentations of active IDUs. We describe considerable acute and chronic medical consequences and high healthcare utilisation associated with IDU. This study is of particular relevance to any institution that provides acute medical care to this group of patients. PMID- 23625510 TI - High rates of head injury among homeless and low-income housed men: a retrospective cohort study. AB - OBJECTIVE: To examine the predictors and temporal patterns of head injury (HI) presentation in the emergency department among cohorts of homeless and low-income housed men. METHODS: Retrospective review and logistic regression of HIs found in emergency department records for three groups of men, those: (1) who were chronically homeless with drinking problems (CHDP) (n=50), (2) in the general homeless population (GH) (n=60) and (3) in low-income housing (LIH) (n=59). RESULTS: The proportion of individuals with non-minimal HIs documented in the previous year were 28%, 3% and 5% with annual rates of 0.47, 0.017 and 0.037 among the CHDP, GH and LIH groups (p<0.0001). In the multivariate model, independent associations with having an HI included: an HI in the previous year (OR 11.8, 95% CI 3.83 to 36.4), drug dependence (OR 3.67, 95% CI 1.11 to 12.13) and seizures (OR 3.50, 95% CI 1.13 to 10.90), while mood-disorders were protective. Homelessness had a crude risk increase of HI (OR 3.15, 95% CI 1.21 to 8.23) but was not significant in the multivariate model. Among those with HIs, chronic homelessness with drinking problems was associated with a higher rate of HI. With each successive HI, the time interval to another HI was 12 days shorter (p=0.0004). The chronic subdural haematoma incidence in the under-65-year-old CHDP group was 11 per 1000 (95% CI 2.8 to 45). CONCLUSIONS: Having an HI is better predicted by previous head injuries, drug dependence or a seizure disorder than a history of homelessness or alcohol dependence. HIs may become more frequent with time. PMID- 23625511 TI - Operculum ultrastructure in leech cocoons. AB - Clitellate annelids (i.e., oligochaetes including leeches) secrete cocoons as part of their normal reproductive cycle. Typically, the cocoon sheath is passed over the head of the leech and sealed at both ends by opercula (i.e., glue-like material secreted by the clitellum). Both the fibrous cocoon wall (CW) and opercula are chemically-related biomaterials that share unusual physiochemical properties, including thermal and chemical resiliency. To explore the underlying morphology of the operculum, we examined cocoons from four leech species (i.e., Myzobdella lugubris, Theromyzon tessulatum, Erpobdella obscura, and Erpobdella punctata) by transmission (TEM) and scanning electron microscopy (SEM). Transmission electron micrographs of all opercula revealed a common, ultrastructural pattern comprising an electron-dense mosaic of ordered polygons that surrounded interspersed cavities. The long axes of cavities were often oriented directionally, suggesting that operculum material is pliable prior to solidification and distorted as a consequence of cocoon deposition. Concomitantly, the operculum permeates jagged edges of the cocoon sheath sealing the cocoon, which provides a mechanically strong CW/operculum boundary. SEM of leech opercula revealed globular nanoparticles comparable to that observed in bioadhesives from disparate animal phyla (e.g., mussel, barnacle, sea star), suggesting a convergent mechanism of bioadhesion among animals. PMID- 23625512 TI - DDQ-induced dehydrogenation of heterocycles for C-C double bond formation: synthesis of 2-thiazoles and 2-oxazoles. AB - Strong as an Ox: 2-Thiazoles and 2-oxazoles are formed by oxidation of 2 thiazolines and 2-oxazolines without requiring substituents at the C4 and C5 positions. DDQ plays an important role as the oxidant in this transformation and metal is unnecessary. This general procedure shows good functional group tolerance and provides a wide variety of 2-thiazoles and 2-oxazoles in moderate to excellent yields. PMID- 23625513 TI - Schwann cells seeded in acellular nerve grafts improve functional recovery. AB - INTRODUCTION: This study evaluated whether Schwann cells (SCs) from different nerve sources transplanted into cold-preserved acellular nerve grafts (CP-ANGs) would improve functional regeneration compared with nerve isografts. METHODS: SCs isolated and expanded from motor and sensory branches of rat femoral and sciatic nerves were seeded into 14mm CP-ANGs. Growth factor expression, axonal regeneration, and functional recovery were evaluated in a 14-mm rat sciatic injury model and compared with isografts. RESULTS: At 14 days, motor or sensory derived SCs increased expression of growth factors in CP-ANGs versus isografts. After 42 days, histomorphometric analysis found CP-ANGs with SCs and isografts had similar numbers of regenerating nerve fibers. At 84 days, muscle force generation was similar for CP-ANGs with SCs and isografts. SC source did not affect nerve fiber counts or muscle force generation. CONCLUSIONS: SCs transplanted into CP-ANGs increase functional regeneration to isograft levels; however SC nerve source did not have an effect. PMID- 23625515 TI - Loss of T-cadherin (CDH-13) regulates AKT signaling and desensitizes cells to apoptosis in melanoma. AB - An understanding of signaling pathways is a basic requirement for the treatment of melanoma. Currently, kinases are at the center of melanoma therapies. According to our research, additional alternative molecules are equally important for development of melanoma. In this regard, cancer progression is, among other factors, driven by an altered adhesion via cadherins. For instance, the de regulated expression of the adhesion molecule T-cadherin is found in various cancer types, including melanoma, and influences migration and invasion. T cadherin is thought to affect cellular function largely through its signaling and not its adhesion properties because the molecule is anchored into the cell membrane by a glycosylphosphatidylinositol (GPI) moiety. However, detailed knowledge about the consequences of the loss of T-cadherin in melanoma is currently lacking. For this reason, we were interested in assessing which signaling pathways are initiated by T-cadherin. The tumor growth of subcutaneously injected T-cadherin-positive melanoma cells was diminished compared with T-cadherin-negative cells in nude mice. The difference in tumor volume was not due to decreased proliferation but rather due to increased apoptosis. After the expression of T-cadherin was induced, we detected V-AKT murine thymoma viral oncogene homolog (AKT) and FoxO3a hypophosphorylation accompanied by the downregulation of the antiapoptotic molecules BCL-2, BCL-x and Clusterin. Furthermore, we detected a diminished transcriptional activity of CREB and AP-1. We demonstrated that T-cadherin functions as a pro-apoptotic tumor suppressor that antagonizes AKT/CREB/AP-1/FoxO3a signaling, whereas NFkappaB, TCF/LEF and mTOR are not part of the T-cadherin signaling pathway. Notably, we found that the restoration of T-cadherin in melanoma cells causes sensitization to apoptosis induced by CD95/Fas antibody CH-11. PMID- 23625514 TI - Effects of CT-Xp gene knock down in melanoma cell lines. AB - Cancer/testis (CT) genes are encoded by genes that are normally expressed only in the human germ line but which are activated in various malignancies. CT proteins are frequently immunogenic in cancer patients and their expression is highly restricted to tumors. They are thus important targets for anticancer immunotherapy. In several different tumor types, the expression of CT-X genes is associated with advanced disease and poor outcome, indicating that their expression might contribute to tumorigenesis. CT-X genes encoding members of the MAGE protein family on Xq28 have been shown to potentially influence the tumorigenic phenotype. We used small interfering RNA (siRNA) to investigate whether CT-X mapping to the short arm of the X-chromosome might also have tumorigenic properties and therefore be potentially targeted by functional inhibitors in a therapeutic setting. siRNAs specific to GAGE, SSX and XAGE1 were used in cell proliferation, migration and cell survival assays using cell lines derived from melanoma, a tumor type known to present high frequencies of expression of CT antigens. We found that of these, those specific to GAGE and XAGE1 most significantly impeded melanoma cell migration and invasion and those specific to SSX4 and XAGE1 decreased the clonogenic survival of melanoma cells. Our results suggest that GAGE, XAGE1 and SSX4 might each have a role in tumor progression and are possible therapeutic targets for the treatment of melanoma and other malignancies. PMID- 23625516 TI - Elongation of textile pelvic floor implants under load is related to complete loss of effective porosity, thereby favoring incorporation in scar plates. AB - Use of textile structures for reinforcement of pelvic floor structures has to consider mechanical forces to the implant, which are quite different to the tension free conditions of the abdominal wall. Thus, biomechanical analysis of textile devices has to include the impact of strain on stretchability and effective porosity. Prolift((r)) and Prolift + M((r)), developed for tension free conditions, were tested by measuring stretchability and effective porosity applying mechanical strain. For comparison, we used Dynamesh-PR4((r)), which was designed for pelvic floor repair to withstand mechanical strain. Prolift((r)) at rest showed moderate porosity with little stretchability but complete loss of effective porosity at strain of 4.9 N/cm. Prolift + M((r)) revealed an increased porosity at rest, but at strain showed high stretchability, with subsequent loss of effective porosity at strain of 2.5 N/cm. Dynamesh PR4((r)) preserved its high porosity even under strain, but as consequence of limited stretchability. Though in tension free conditions Prolift((r)) and Prolift + M((r)) can be considered as large pore class I meshes, application of mechanical strain rapidly lead to collapse of pores. The loss of porosity at mechanical stress can be prevented by constructions with high structural stability. Assessment of porosity under strain was found helpful to define requirements for pelvic floor devices. Clinical studies have to prove whether devices with high porosity as well as high structural stability can improve the patients' outcome. PMID- 23625517 TI - A new fossil thryonomyid from the Late Miocene of the United Arab Emirates and the origin of African cane rats. AB - Cane rats (Thryonomyidae) are represented today by two species inhabiting sub Saharan Africa. Their fossil record is predominately African, but includes several Miocene species from Arabia and continental Asia that represent dispersal events from Africa. For example, Paraulacodus indicus, known from the Miocene of Pakistan, is closely related to living Thryonomys. Here we describe a new thryonomyid, Protohummus dango, gen. et sp. nov., from the late Miocene Baynunah Formation of the United Arab Emirates. The new thryonomyid is less derived than "Thryonomys" asakomae from the latest Miocene of Ethiopia and clarifies the origin of crown Thryonomys and the evolutionary transition from Paraulacodus. A phylogenetic analysis shows Protohummus dango to be morphologically intermediate between Paraulacodus spp. and extinct and living Thryonomys spp. The morphological grade and phylogenetic position of Protohummus dango further supports previous biochronological estimates of the age of the Baynunah Formation (ca. 6-8 Ma). PMID- 23625518 TI - Effect of post-fire resprouting on leaf fluctuating asymmetry, extrafloral nectar quality, and ant-plant-herbivore interactions. AB - Fires in the Cerrado savanna are a severe form of disturbance, but some species are capable of resprouting afterwards. It is unknown, however, how and whether post-fire resprouting represents a stressful condition to plants and how their rapid re-growth influences both the production of biochemical compounds, and interactions with mutualistic ants. In this study, we examined the influence of post-fire resprouting on biotic interactions (ant-plant-herbivore relationships) and on plant stress. The study was performed on two groups of the extrafloral nectaried shrub Banisteriopsis campestris (Malpighiaceae); one group was recovering from fire while the other acted as control. With respect to biotic interactions, we examined whether resprouting influenced extrafloral nectar concentration (milligrams per microliter), the abundance of the ant Camponotus crassus and leaf herbivory rates. Plant stress was assessed via fluctuating asymmetry (FA) analysis, which refers to deviations from perfect symmetry in bilaterally symmetrical traits (e.g., leaves) and indicates whether species are under stress. Results revealed that FA, sugar concentration, and ant abundance were 51.7 %, 35.7 % and 21.7 % higher in resprouting plants. Furthermore, C. crassus was significantly associated with low herbivory rates, but only in resprouting plants. This study showed that post-fire resprouting induced high levels of plant stress and influenced extrafloral nectar quality and ant herbivore relationships in B. campestris. Therefore, despite being a stressful condition to the plant, post-fire resprouting individuals had concentrated extrafloral nectar and sustained more ants, thus strengthening the outcomes of ant-plant mutualism. PMID- 23625519 TI - The influence of adjuvant radiotherapy dose on overall survival in patients with resected pancreatic adenocarcinoma. AB - BACKGROUND: Adjuvant radiotherapy (A-RT) for patients with resected pancreatic adenocarcinoma (PAC) is controversial. In the current study, the authors aim to determine whether there is an association between overall survival (OS) and A-RT dose. METHODS: National Cancer Data Base (NCDB) data were obtained for all patients who received A-RT for resected PAC from 1998 through 2002. Univariate and multivariate survival analyses were performed along with Kaplan-Meier estimates for A-RT levels < 40 grays (Gy), 40 Gy to < 50 Gy, 50 Gy to < 55 Gy, and >= 55 Gy. RESULTS: A total of 1385 patients met the inclusion criteria. The median age of the patients was 64 years (range, 29 years-87 years). All patients underwent surgical resection and A-RT with or without chemotherapy. A total of 231 patients were diagnosed with stage I disease, 273 were diagnosed with stage II disease, 734 were diagnosed with stage III disease, and 126 were diagnosed with stage IVA disease (according to the fifth edition of the American Joint Committee on Cancer); 21 were found to have an unknown stage of disease. The median A-RT dose was 45 Gy (range, 1.63 Gy-69 Gy). The median OS was 21 months (95% confidence interval [95% CI], 19 months-23 months). On multivariate analysis, an A-RT dose < 40 Gy (hazards ratio [HR], 1.30 [95% CI, 1.03-1.66]; P = .031), an A-RT dose of 40 Gy to < 50 Gy (HR, 1.17 [95% CI, 1.00-1.37]; P = .05), and an A-RT dose >= 55 Gy (HR, 1.44 [95% CI, 1.08-1.93]; P = .013) predicted worse OS compared with the reference category of 50 Gy to < 55 Gy. CONCLUSIONS: A RT doses of < 40 Gy, 40 Gy to < 50 Gy, and >= 55 Gy were found to be associated with an inferior OS. The dose of A-RT delivered appears to influence OS and a prospective study evaluating the addition of optimally delivered A-RT for patients with resected PAC is needed. PMID- 23625521 TI - Religion in meaning making and boundary work: theoretical explorations. AB - Based on the articles brought together for this special issue, this article proposes a transversal analysis and theoretical elaboration of the question of the uses of religious elements for meaning making and boundary work. In order to do so, we will first propose a sociocultural psychological perspective to examine meaning making dynamics. Second, we will apply a boundary work perspective, as recently developed in the social sciences, on the organization of religious differences. The first considers religious elements as resources that can be used by people to orient themselves in time and the social space, to interpret and guide action, and to create new forms of life. The second approach proposes an analysis of uses of religious stuff in order to understand how boundaries between groups are created, transgressed or dissolved as well as to explore the link between religion and power. Our argument is that the articulation of these two approaches can itself offer a rich theoretical frame to apprehend religions in contemporary society. PMID- 23625520 TI - A novel translocation event leads to a recombinant stable chromosome with interrupted centromeric domains in rice. AB - Rice (Oryza sativa L.) centromeres are composed of 155-bp satellite repeats (CentO), centromere-specific retrotransposon (CRR), and a variety of other repeats. Previous studies have shown that CentO and CRR elements are both parts of the functional centromere/kinetochore complex. In this study, a naturally occurring karyotype rearrangement involving a reciprocal translocation between chromosomes 9 and 11 in an indica rice Zhongxian 3037 has been identified. The recombinant centromere in Chr11L.9L has two CentO tandem arrays, separated by a long array of 5S rDNAs. Chromatin immunoprecipitation and immunostaining showed that centromere-specific histone H3 (cenH3) variant was bound to the two flanking CentO arrays, but not to the 5S rDNAs residing between the CentO repeats. No obvious difference was detected in H3K4me2 and H3K9ac modification of the 5S rDNAs between the wild type and the mutant. Therefore, the translocation results in a recombinant stable chromosome with interrupted centromeric domains. A lack of cenH3 binding in 5S rDNA sequences residing within the centromeric core suggests that not all centromeric sequences confer centromere identity in rice. PMID- 23625522 TI - Regenerative process of tracheal epithelium using a collagen vitrigel sponge scaffold. AB - OBJECTIVES/HYPOTHESIS: Our group has developed a collagen vitrigel sponge scaffold containing basic fibroblast growth factor (b-FGF) for tracheal reconstruction. In this study, we have investigated the regenerative process of tracheal epithelium histologically and morphologically. STUDY DESIGN: A preliminary animal experiment. METHODS: A collagen vitrigel sponge scaffold was fabricated with simultaneous addition of 100 ng b-FGF. Tracheotomies were performed, and collagen vitrigel sponge scaffolds were implanted on tracheal defects in rats. At 5, 7, and 14 days after implantation, the intraluminal surface of the regenerated tracheae was observed using endoscope. Histological examination of the intraluminal regenerated trachea was performed using light microscope and scanning electron microscope. RESULTS: Endoscopic images showed epithelial regeneration at 7 days after implantation. Light microscopic examination detected stratified epithelium at 5 days, columnar cells at 7 days, and ciliated cells at 14 days after implantation. Scanning electron microscopy images showed regenerated epithelial cells at 5 and 7 days, and ciliated cells at 14 days after implantation. CONCLUSIONS: The horizontal section and luminal area of the regenerated epithelium were investigated. The epithelium was formed at 5 days, and mature cilia were found at 14 days after implantation. Epithelium of equality equivalent to normal trachea was regenerated in a rat model with collagen vitrigel-scaffold containing b-FGF at 14 days. PMID- 23625524 TI - Optimization of dispersive liquid-liquid microextraction with central composite design for preconcentration of chlordiazepoxide drug and its determination by HPLC-UV. AB - A simple, rapid, and sensitive method based on dispersive liquid-liquid microextraction combined with HPLC-UV detection applied for the quantification of chlordiazepoxide in some real samples. The effect of different extraction conditions on the extraction efficiency of the chlordiazepoxide drug was investigated and optimized using central composite design as a conventional efficient tool. Optimum extraction condition values of variables were set as 210 MUL chloroform, 1.8 mL methanol, 1.0 min extraction time, 5.0 min centrifugation at 5000 rpm min(-1), neutral pH, 7.0% w/v NaCl. The separation was reached in less than 8.0 min using a C18 column using isocratic binary mobile phase (acetonitrile/water (60:40, v/v)) with flow rate of 1.0 mL min(-1) The linear response (r(2) > 0.998) was achieved in the range of 0.005-10 MUg mL(-1) with detection limit 0.0005 MUg mL(-1) The applicability of this method for simultaneous extraction and determination of chlordiazepoxide in four different matrices (water, urine, plasma, and chlordiazepoxide tablet) were investigated using standard addition method. Average recoveries at two spiking levels were over the range of 91.3-102.5% with RSD < 5.0% (n = 3). The obtained results show that dispersive liquid-liquid microextraction combined with HPLC-UV is a fast and simple method for the determination of chlordiazepoxide in real samples. PMID- 23625523 TI - Emulsified isoflurane postconditioning produces cardioprotection against myocardial ischemia-reperfusion injury in rats. AB - Emulsified isoflurane (EIso) preconditioning can induce cardioprotection. We investigated whether EIso application after ischemia protects hearts against reperfusion injury and whether it is mediated by the inhibition of apoptosis. Rats were subjected to 30-min coronary occlusion followed by 180-min reperfusion. At the onset of reperfusion, rats were intravenously administered saline (sham, control group), 30 % intralipid (IL group) or 2 ml kg(-1) EIso (EIso group) for 30 min. After reperfusion, infarct sizes, myocardial apoptosis and expression of Bcl-2, Bax and caspase-3 proteins were determined. Hemodynamic parameters were not different among groups. Compared with control and intralipid group, EIso limited infarct size, inhibited apoptosis, increased the expression of Bcl-2, decreased the expression of Bax, cleaved caspase-3, and enhanced Bcl-2/Bax ratio. EIso protects hearts against reperfusion injury when administered at the onset of reperfusion, which may be mediated by the inhibition of apoptosis via modulation of the expression of pro- and anti-apoptotic proteins. PMID- 23625525 TI - Nisin adsorption on hydrophilic and hydrophobic surfaces: evidence of its interactions and antibacterial activity. AB - Study of peptides adsorption on surfaces remains a current challenge in literature. A complementary approach, combining X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used to investigate the antimicrobial peptide nisin adsorption on hydrophilic and hydrophobic surfaces. The native low density polyethylene was used as hydrophobic support and it was grafted with acrylic acid to render it hydrophilic. XPS permitted to confirm nisin adsorption and to determine its amount on the surfaces. ToF-SIMS permitted to identify the adsorbed bacteriocin type and to observe its distribution and orientation behavior on both types of surfaces. Nisin was more oriented by its hydrophobic side to the hydrophobic substrate and by its hydrophilic side to the outer layers of the adsorbed peptide, in contrast to what was observed on the hydrophilic substrate. A correlation was found between XPS and ToF-SIMS results, the types of interactions on both surfaces and the observed antibacterial activity. Such interfacial studies are crucial for better understanding the peptides interactions and adsorption on surfaces and must be considered when setting up antimicrobial surfaces. PMID- 23625527 TI - An unusual case of pituitary apoplexy. PMID- 23625526 TI - Anti-amyloid beta autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies. AB - OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by vasogenic edema and multiple cortical/subcortical microbleeds, sharing several aspects with the recently defined amyloid-related imaging abnormalities (ARIA) reported in Alzheimer's disease (AD) passive immunization therapies. Herein, we investigated the role of anti-amyloid beta (Abeta) autoantibodies in the acute and remission phases of CAA-ri. METHODS: We used a novel ultrasensitive technique on patients from a retrospective multicenter case control study, and evaluated the anti-Abeta autoantibody concentration in the cerebrospinal fluid (CSF) of 10 CAA-ri, 8 CAA, 14 multiple sclerosis, and 25 control subjects. Levels of soluble Abeta40, Abeta42, tau, P-181 tau, and APOE genotype were also investigated. RESULTS: During the acute phase of CAA-ri, anti Abeta autoantibodies were specifically increased and directly correlated with Abeta mobilization, together with augmented tau and P-181 tau. Following clinical and radiological remission, autoantibodies progressively returned to control levels, and both soluble Abeta and axonal degeneration markers decreased in parallel. INTERPRETATION: Our data support the hypothesis that the pathogenesis of CAA-ri may be mediated by a selective autoimmune reaction against cerebrovascular Abeta, directly related to autoantibody concentration and soluble Abeta. The CSF dosage of anti-Abeta autoantibodies with the technique here described can thus be proposed as a valid alternative tool for the diagnosis of CAA-ri. Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Abeta autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA. PMID- 23625528 TI - The novel use of commonly captured data to assess a district's diabetes service that encompasses both primary and secondary care. AB - AIM: To identify commonly captured data in the UK to look at the performance of a district's diabetes care that encompasses both primary and secondary care. METHODS: Primary care quality outcomes framework (QOF) measures for diabetes, referral rates for first appointment for specialist secondary care and emergency admission rates for diabetes (Dr Foster/HES) were used to produce a performance index scoring system. Illustrative measures from QOF were total diabetes points, DM23 attainment of HbA1c <7% (53 mmol/mol) and its exemption rate (number of patients excluded from analysis). The performance index was used to study the effectiveness of the Medway district diabetes service and this was compared to another district (Guildford) within the same Strategic Health Authority and nationally. RESULTS: Medway has the highest prevalence of Diabetes (6.1%) of the 8 Primary Care Trusts examined, the lowest achievement of diabetes QOF points (96.1%) and the lowest achievement of an HbA1c level <7% (53 mmol/mol) (54.3%). Exemption reporting was the 3rd highest. SAR for first diabetes out-patient appointment to the hospital was low at 281 (predicted 576) 48% of expected. The emergency admission rate was high at 225 (predicted 168) 133% of expected. Thus primary care diabetes needs to raise performance and implement a lower threshold for OPD referral to prevent emergency admissions. CONCLUSION: It is possible to produce an assessment of diabetes care that transcends primary/secondary care that gives a true reflection of a district's performance which will be useful to plan future health service provision. PMID- 23625529 TI - Finding horse meat in beef products--a global problem. AB - The Food Safety Authority of Ireland (FSAI) oversees the implementation of food safety controls in Ireland which are set out in EU and Irish law. The FSAI, a science-based consumer protection organization, has nurtured a close relationship with the scientific community allowing it to utilize the best scientific advice available to underpin risk assessments. In early 2013, a 2-month long investigation in to the authenticity of beef products culminated in the publication of results that demonstrated the presence of horse meat in a frozen burger produced in Ireland. The events that followed revealed a pan-European food fraud which will likely result in significant changes in the way this small section of the meat industry will be regulated in the future in the EU. Although revelations of implicated products and food businesses have relented, the EU-wide investigation is continuing in an effort to determine how a food fraud of this scale could have occurred in such a highly regulated industry and who was involved. The FSAI initially received some criticism after publication of the results, but was also commended for its scientific approach as well as its openness and transparency. The end result of this incident is likely to be that the complexity of the food chain will be addressed again and DNA-based or similar methods will become a regular feature in verifying the authenticity of meat-based foods. PMID- 23625530 TI - Haematuria and the nutcracker syndrome. PMID- 23625531 TI - A double-blind trial of the effect of docosahexaenoic acid and vitamin and mineral supplementation on aggression, impulsivity, and stress. AB - OBJECTIVES: Although a series of well-designed studies have reported that supplementation with vitamins/minerals and omega-3 fatty acids reduces the incidence of aggressive behavior, to date, the relative contribution and interaction between these nutrients has not been examined. The aim was therefore to consider the relative contribution of supplementation with multivitamins/minerals and/or docosahexaenoic acid (DHA) on laboratory-based measures of aggression, impulsivity, and stress. METHODS: In a double-blind randomized trial, four groups of young adult men without a history of aggressive or impulsive behavior received a placebo (n = 42), multivitamins/minerals (n = 43), DHA (n = 47) or both (n = 41) for 3 months. RESULTS: With the Picture Frustration Task, DHA decreased the display of aggressive behavior. DHA also decreased impulsivity as measured using the GoStop Impulsivity Paradigm that examines the ability to inhibit already initiated behavior. Although a multivitamin and mineral supplement did not influence these measures, it did decrease perceived stress. CONCLUSIONS: The influence of supplementation on aggression and impulsivity can be conveniently studied in a sample without a history of antisocial behavior, using laboratory-based measures. No evidence was found of a synergistic interaction between vitamins/minerals and DHA. PMID- 23625532 TI - Inhibition of CO2 fixation by iodoacetamide stimulates cyclic electron flow and non-photochemical quenching upon far-red illumination. AB - The Benson-Calvin cycle enzymes are activated in vivo when disulfide bonds are opened by reduction via the ferredoxin-thioredoxin system in chloroplasts. Iodoacetamide reacts irreversibly with free -SH groups of cysteine residues and inhibits the enzymes responsible for CO2 fixation. Here, we investigate the effect of iodoacetamide on electron transport, when infiltrated into spinach leaves. Using fluorescence and absorption spectroscopy, we show that (i) iodoacetamide very efficiently blocks linear electron flow upon illumination of both photosystems (decrease in the photochemical yield of photosystem II) and (ii) iodoacetamide favors cyclic electron flow upon light excitation specific to PSI. These effects account for an NPQ formation even faster in iodoacetamide under far-red illumination than in the control under saturating light. Such an increase in NPQ is dependent upon the proton gradient across the thylakoid membrane (uncoupled by nigericin addition) and PGR5 (absent in Arabidopsis pgr5 mutant). Iodoacetamide very tightly insulates the electron current at the level of the thylakoid membrane from any electron leaks toward carbon metabolism, therefore, providing choice conditions for the study of cyclic electron flow around PSI. PMID- 23625533 TI - Mitochondrial Infantile Liver Disease due to TRMU Gene Mutations: Three New Cases. AB - Combined respiratory chain defect is a common feature in mitochondrial liver disease during early infancy. Mitochondrial DNA depletions, induced by mutations of the nuclear genes POLG, DGUOK, and MPV17, are the major causes of these combined deficiencies. More recently, mutations in TRMU gene encoding the mitochondrial tRNA-specific 2-thiouridylase were found in infantile hepatopathy related to mitochondrial translation defect. It is characterized by a combined defect of respiratory chain complexes without mitochondrial DNA depletion.We report here clinical, biochemical, and genetic findings from three unrelated children presenting with hepatopathy associated with hyperlactatemia and respiratory chain defect due to bi-allelic mutations in TRMU gene. Two patients recovered spontaneously in a few months, whereas the other one died of acute liver failure. Spontaneous remission is a rare feature in mitochondrial liver diseases, and early identification of TRMU mutations could impact on clinical management. Our results extend the small number of TRMU mutations reported in mitochondrial liver disorders and allowed accumulating data for genotype phenotype correlation. PMID- 23625534 TI - Functional implications of impaired control of submaximal hip flexion following stroke. AB - INTRODUCTION: We quantified submaximal torque regulation during low to moderate intensity isometric hip flexion contractions in individuals with stroke and the associations with leg function. METHODS: Ten participants with chronic stroke and 10 controls performed isometric hip flexion contractions at 5%, 10%, 15%, 20%, and 40% of maximal voluntary contraction (MVC) in paretic, nonparetic, and control legs. RESULTS: Participants with stroke had larger torque fluctuations (coefficient of variation, CV), for both the paretic and nonparetic legs, than controls (P < 0.05) with the largest CV at 5% MVC in the paretic leg (P < 0.05). The paretic CV correlated with walking speed (r2 = 0.54) and Berg Balance Score (r2 = 0.40). At 5% MVC, there were larger torque fluctuations in the contralateral leg during paretic contractions compared with the control leg. CONCLUSIONS: Impaired low-force regulation of paretic leg hip flexion can be functionally relevant and related to control versus strength deficits poststroke. PMID- 23625536 TI - The value of observer performance studies in dose optimization: a focus on free response receiver operating characteristic methods. AB - Receiver operating characteristic (ROC) analysis has been successfully used in radiology to help determine the combined success of system and observer. There is great value in these methods for assessing new and existing techniques to see if diagnostic accuracy can be improved. Within all aspects of radiology there should be compliance with the as-low-as-reasonably-achievable principle, which requires optimization of the diagnostic suitability of the image. Physical measures of image quality have long been used in the assessment of system performance, but these alone are not sufficient to assess diagnostic capability. It is imperative that the observer be included in any assessment of diagnostic performance. The free-response ROC paradigm has been developed as a statistically powerful advancement of traditional ROC analysis that allows a precise interpretation of complex images by adding location information to the level of observer confidence. The following review of free-response ROC methodology will explain how observer performance methods can be valuable in image optimization, including examples of how these have already been successful in hybrid imaging. PMID- 23625537 TI - Energy constraints. AB - Building on research in anthropology and philosophy, one can make a distinction between type I and type II energy ethics as a framework for advancing public debate about energy. Type I holds energy production and use as a fundamental good and is grounded in the assumption that increases in energy production and consumption result in increases in human wellbeing. Conversely, type II questions the linear relationship between energy production and progress by examining questions of equity and human happiness. The type I versus type II framework helps to advance public debates about energy that address broad questions of profitability, regulation, and the environment, and in the process poses fundamental questions about the reverence for energy growth in advanced technological societies. PMID- 23625535 TI - Obesity-related dysregulation of the tryptophan-kynurenine metabolism: role of age and parameters of the metabolic syndrome. AB - OBJECTIVE: Obesity-related immune mediated systemic inflammation was associated with the development of the metabolic syndrome by induction of the tryptophan (TRP)-kynurenine (KYN) pathway. The study aimed to assess whether this holds true across the lifespan from juvenility to adulthood. DESIGN AND METHODS: Five hundred twenty-seven participants aged between 10 and 65 years were analyzed. Standard anthropometric measures, carotid ultrasound, and laboratory analysis including interleukin-6, ultra-sensitive C-reactive protein, lipids, glucose metabolism, neopterin, TRP, KYN levels, and the KYN/TRP ratio were performed. RESULTS: Overweight/obese (ow/ob) adults had significantly increased KYN serum levels and a significantly increased KYN/TRP ratio. In sharp contrast, ow/ob juvenile males aged <=18 years showed decreased, females similar KYN and KYN/TRP ratio in comparison to their control counterparts. Also, adult ow/ob subjects with metabolic syndrome showed markedly increased KYN/TRP ratios contrary to decreased KYN/TRP ratios in ow/ob juveniles. Abdominal fat content, characterized by age normalized waist circumference, and not body mass index, had the strongest effect for an increase of the KYN/TRP ratio in adults. CONCLUSIONS: TRP metabolism and obesity-related immune mediated inflammation differs markedly between juveniles and adults. While childhood obesity seems to be dominated by a Th2-driven activation, an accelerated production of Th1-type cytokines may pave the way for later atherosclerotic endpoints. PMID- 23625538 TI - Galectin-3: a possible complementary marker to the PSA blood test. AB - The prostate-specific antigen (PSA) test has served as a blood marker of prostate cancer (PCa), and for monitoring recurrence/metastasis in patients after therapeutic intervention. However, the applicability/reliability of the PSA test was recently questioned as it is not without challenges, in particular in men who have PCa without an elevated PSA (false negative), or in men who are disease-free with elevated levels of PSA (false positive). Galectin-3 is a tumor-associated protein; present in the seminal fluid and is a substrate for the PSA enzyme e.g., a chymotrypsin-like serine protease. We hypothesized that the cleavage status and level of galectin-3 in the prostate tissue and sera are associated with PCa. Thus, we compared galectin-3 levels obtained from sera of non-cancer urology patients to those of metastatic PCa patients. The data were confirmed by analyzing PCa tissue arrays. Here, we report that galectin-3 levels in the sera of patients with metastatic PCa were uniformly higher as compared to the non cancer patient controls. The data suggest that galectin-3 serum level may be a useful serum complementary marker to the PSA blood test to be used for initial and follow-up PSA complimentary diagnostic/prognostic tool for recurrence in PCa patients. PMID- 23625539 TI - FLIP: molecular switch between apoptosis and necroptosis. AB - Cancerous growth is one of the most difficult diseases to target as there is no one clear cause, and targeting only one pathway does not generally produce quantifiable improvement. For a truly effective cancer therapy, multiple pathways must be targeted at the same time. One way to do this is to find a gene that is associated with several pathways; this approach expands the possibilities for disease targeting and enables multiple points of attack rather than one fixed point, which does not allow treatment to evolve over time as cancer does. Inducing programmed cell death (PCD) is a promising method to prevent or inhibit the progression of tumor cells. Intricate cross talk among various programmed cell death pathways including cell death by apoptosis, necroptosis or autophagy plays a critical role in the regulation of PCD. In addition, the complex and overlapping patterns of signaling and lack of understanding of such networks between these pathways generate hurdles for developing effective therapeutic approaches. This review article focuses on targeting FLIP (Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein) signaling as a bridge between various PCD processes as an effective approach for cancer management. PMID- 23625540 TI - Which strategies reduce breast cancer mortality most? Collaborative modeling of optimal screening, treatment, and obesity prevention. AB - BACKGROUND: US breast cancer mortality is declining, but thousands of women still die each year. METHODS: Two established simulation models examine 6 strategies that include increased screening and/or treatment or elimination of obesity versus continuation of current patterns. The models use common national data on incidence and obesity prevalence, competing causes of death, mammography characteristics, treatment effects, and survival/cure. Parameters are modified based on obesity (defined as BMI >= 30 kg/m(2) ). Outcomes are presented for the year 2025 among women aged 25+ and include numbers of cases, deaths, mammograms and false-positives; age-adjusted incidence and mortality; breast cancer mortality reduction and deaths averted; and probability of dying of breast cancer. RESULTS: If current patterns continue, the models project that there would be about 50,100-57,400 (range across models) annual breast cancer deaths in 2025. If 90% of women were screened annually from ages 40 to 54 and biennially from ages 55 to 99 (or death), then 5100-6100 fewer deaths would occur versus current patterns, but incidence, mammograms, and false-positives would increase. If all women received the indicated systemic treatment (with no screening change), then 11,400-14,500 more deaths would be averted versus current patterns, but increased toxicity could occur. If 100% received screening plus indicated therapy, there would be 18,100-20,400 fewer deaths. Eliminating obesity yields 3300-5700 fewer breast cancer deaths versus continuation of current obesity levels. CONCLUSIONS: Maximal reductions in breast cancer deaths could be achieved through optimizing treatment use, followed by increasing screening use and obesity prevention. PMID- 23625541 TI - Sentinel lymph node status is the most important prognostic factor in patients with melanoma of the scalp. AB - OBJECTIVES/HYPOTHESIS: To compare clinicopathologic and prognostic factors associated with scalp melanomas and nonscalp melanomas of the head and neck (H&N). STUDY DESIGN: Post hoc analysis of the database from a multi institutional, prospective, randomized study. METHODS: Clinicopathologic factors were assessed and correlated with survival and recurrence. Univariate and multivariate analysis of prognostic factors affecting disease-free survival and overall survival were performed. RESULTS: Of 405 patients with H&N melanomas >=1.0 mm Breslow thickness, 109 patients had melanoma of the scalp. All were Caucasian (100%), with most being male (79.5%) with a mean age of 49.8 years. The mean Breslow thickness was 2.4 mm; 25% had signs of ulceration. Sentinel lymph node (SLN) positivity was seen in 20.9% of scalp melanoma patients, and was more likely in younger patients (44.7 vs. 50.8 years, P = .04) and in those with a Breslow thickness of 2 to 4 mm (P = .005). The incidence of locoregional and distant recurrence were similar. Overall survival for scalp melanoma patients was significantly impacted by SLN positivity (P = .03), whereas Breslow thickness and ulceration status predicted poorer survival in nonscalp melanoma patients (P = .005, P < .0001, respectively). CONCLUSIONS: In the Sunbelt Melanoma Trial, SLN status was the strongest predictor of overall survival in scalp melanoma. Tumor thickness and ulceration correlated with poorer overall survival in nonscalp H&N melanoma. The prognostic significance of SLN status in the H&N may vary with the melanoma site. PMID- 23625542 TI - Imagination as expansion of experience. AB - This paper proposes a developmental view on imagination: from this perspective, imagination can be seen as triggered by some disrupting event, which generates a disjunction from the person's unfolding experience of the "real" world, and as unfolding as a loop, which eventually comes back to the actual experience. Examining recent and classical theorization of imagination in psychology, the paper opposes a deficitary view of imagination to an expansive notion of imagination. The paper explores Piaget, Vygotsky, Harris and Pelaprat & Cole consider: 1) What does provoke a "rupture" or disjunction? 2) What are the psychological processes involved in the imaginary loop? 3) What nourishes such processes? 4) What are the consequences of such imaginary loop, or what does it enable doing? The paper proposes to adopt an expansive view of imagination, as Vygotsky proposed-a perspective that has been under-explored empirically since his seminal work. To stimulate such sociocultural psychology of imagination, two empirical examples are provided, one showing how children make sense of metaphor in an experimental setting, the other showing a young person using a novel met at school as symbolic resource. PMID- 23625543 TI - Up-regulation of the fetal baboon hypothalamo-pituitary-adrenal axis in intrauterine growth restriction: coincidence with hypothalamic glucocorticoid receptor insensitivity and leptin receptor down-regulation. AB - Intrauterine growth restriction (IUGR) is an important fetal developmental problem resulting from 2 broad causes: maternal undernutrition and/or decreased fetal nutrient delivery to the fetus via placental insufficiency. IUGR is often accompanied by up-regulation of the hypothalamo-pituitary-adrenal axis (HPAA). Sheep studies show fetal HPAA autonomy in late gestation. We hypothesized that IUGR, resulting from poor fetal nutrient delivery, up-regulates the fetal baboon HPAA in late gestation, driven by hypothalamo-pituitary glucocorticoid receptor (GR) insensitivity and decreased fetal leptin in peripheral plasma. Maternal baboons were fed as ad libitum controls or nutrient restricted to produce IUGR (fed 70% of the control diet) from 0.16 to 0.9 gestation. Peripheral ACTH, cortisol, and leptin were measured by immunoassays. CRH, arginine vasopressin (AVP), GR, leptin receptor (ObRb), and pro-opiomelanocortin peptide expression were determined immunohistochemically. IUGR fetal peripheral cortisol and ACTH, but not leptin, were increased (P < .05). IUGR increased CRH peptide expression, but not AVP, in the fetal hypothalamic paraventricular nucleus (PVN) and median eminence (P < .05). PVN ObRb peptide expression, but not GR, was decreased (P < .05) with IUGR. ObRb and pro-opiomelanocortin were robustly expressed in the anterior pituitary gland, but ~1% of cells showed colocalization. We conclude that (1) CRH, not AVP, is the major releasing hormone driving ACTH and cortisol secretion during primate IUGR, (2) fetal HPAA activation was aided by GR insensitivity and decreased ObRb expression in the PVN, and (3) the anterior pituitary is not a site for ObRb effects on the HPAA. PMID- 23625544 TI - Perceived unfairness at work, social and personal resources, and resting blood pressure. AB - By drawing from theoretical perspectives suggesting that unfair conditions threaten fundamental psychological needs, perceived unfairness at work was proposed and tested as a predictor of resting blood pressure. As part of the Midlife Development in the United States Biomarkers project, participants completed questionnaires measuring perceived unfairness, self-esteem and coworker support. Resting blood pressure readings were also recorded as part of a larger physical examination. Results indicate that perceived unfairness at work was associated with higher resting diastolic and systolic blood pressure. Perceived unfairness was most strongly related to diastolic and systolic blood pressure among women with low levels of coworker support. Contrary to predictions, self esteem did not moderate the association between perceived unfairness and blood pressure. These results suggest that high blood pressure may be a mechanism linking unfairness to negative health outcomes and point to coworker support as a moderator of the perceived unfairness-blood pressure relationship among women. Further research is needed exploring the mediating mechanisms linking unfair treatment at work to blood pressure and health. PMID- 23625545 TI - Residual paralysis: a real problem or did we invent a new disease? AB - PURPOSE: Over the past three decades, many studies have shown a high proportion of patients in the recovery room with residual neuromuscular blockade after anesthesia. The purpose of this Continuing Professional Development module is to present the physiological consequences of residual paralysis, estimate the extent of the problem, and suggest solutions to prevent its occurrence. PRINCIPAL FINDINGS: Residual paralysis is defined as a train-of-four ratio (TOFR) < 0.9 at the adductor pollicis. While tidal volume and, to a lesser extent, vital capacity are well preserved as the intensity of blockade increases, the probability of airway obstruction, impaired swallowing, and pulmonary aspiration increases markedly as TOFR decreases. In recent studies, incidences of residual paralysis from 4-57% have been reported, but surveys indicate that anesthesiologists estimate the incidence of the problem at 1% or less. The decision to administer neostigmine or sugammadex should be based on the degree of spontaneous recovery at the adductor pollicis muscle (thumb), not on recovery at the corrugator supercilii (eyebrow). The most important drawback of neostigmine is its inability to reverse profound blockade, which is a consequence of its ceiling effect. When spontaneous recovery reaches the point where TOFR > 0.4 or four equal twitch responses are seen, reduced doses of neostigmine may be given. The dose of sugammadex required in a given situation depends on the intensity of blockade. CONCLUSION: Careful monitoring and delaying the administration of neostigmine until four twitches are observed at the adductor pollicis can decrease the incidence of residual paralysis. The clinical and pharmacoeconomic effects of unrestricted sugammadex use are unknown at this time. PMID- 23625546 TI - Retraction note to: Effect of xenon on diaphragmatic contractility in dogs. PMID- 23625547 TI - Retraction note to: Ramosetron vs granisetron for the prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy. PMID- 23625548 TI - Retraction note to: High-dose colforsin daropate increases diaphragmatic contractility in dogs. PMID- 23625549 TI - From concept to publication: celebrating mentorship and knowledge generation through research during postgraduate residency training. PMID- 23625550 TI - Retraction note to: Combined diltiazem and lidocaine reduces cardiovascular responses to tracheal extubation and anesthesia emergence in hypertensive patients. PMID- 23625551 TI - Negotiating a labyrinth: experiences of assessment and diagnostic journey in cognitive impairment and dementia. AB - OBJECTIVES: There has been a global push towards the earlier diagnosis of dementia, but there is little understanding of the transitions along the assessment and diagnostic pathway from the perspective of people affected by memory problems, cognitive impairment and early dementia. This study explores the experience of the assessment and diagnostic pathway for people with cognitive impairment and their family carers. METHODS: Qualitative interviews with 27 people with cognitive impairment and 26 carers (20 dyads) using four memory services before and after diagnosis disclosure were conducted. Interview transcripts were subject to constant comparative analysis and interpretations subject to discussion at regular 'analysis clinics'. RESULTS: Twelve sub-themes were identified along four points on the assessment journey. Feelings of confusion, uncertainty and anxiety over interminable waiting times dominated. Participants often felt without support to manage their uncertainties, emotions and did not know where to turn for support. Some were highly critical of the systemic process of assessment and diagnosis disclosure but were generally positive of the practice of individual professionals. CONCLUSIONS: Service providers should review the process of assessment and diagnosis disclosure for people with cognitive impairment and their carers. They should develop a process that is person centred and accommodates the individualised preferences. The development of service systems to provide continuous relevant information and clarity to service users needs to involve all stakeholders, including people with cognitive impairment and their carers. PMID- 23625552 TI - Mucosal biomarkers of colorectal cancer risk do not increase at 6 months following sleeve gastrectomy, unlike gastric bypass. AB - OBJECTIVE: The hypothesis that sleeve gastrectomy (SG) is not associated with an increase in mucosal colorectal cancer (CRC) biomarkers, unlike Roux-en-Y gastric bypass (RYGB), was tested. DESIGN AND METHODS: Rectal mucosa, blood, and urine were obtained from morbidly obese patients (n = 23) before and after (median 28 months) SG, as well as from nonobese controls (n = 20). Rectal epithelial cell mitosis and apoptosis, crypt size/fission, and pro-inflammatory gene expression were measured, as well as systemic inflammatory biomarkers, including C-reactive protein (CRP). RESULTS: The mean pre-operative body mass index in SG patients was 65.7 kg/m2 (24.7 kg/m2 in controls). Mean excess weight loss post-SG was 38.2%. There was a significant increase in mitosis frequency, crypt size, and crypt fission (all P < 0.01) in SG patients versus controls, as well as evidence of a chronic inflammatory state (raised CRP and mononuclear cell p65 NFkappaB binding), but there was no significant change in these biomarkers after SG, except CRP reduction. Macrophage migration inhibitory factor mRNA levels were increased by 39% post-SG (P = 0.038). CONCLUSIONS: Mucosal biomarkers of CRC risk do not increase at 6 months following SG, unlike RYGB. Biomarkers of rectal crypt proliferation and systemic inflammation are increased in morbidly obese patients compared with controls. PMID- 23625553 TI - The use of traits-based approaches and eco(toxico)logical models to advance the ecological risk assessment framework for chemicals. AB - This article presents a framework to diagnose and predict the effects of chemicals, integrating 2 promising tools to incorporate more ecology into ecological risk assessment, namely traits-based approaches and ecological modeling. Traits-based approaches are used increasingly to derive correlations between the occurrence of species traits and chemical exposure from biological and chemical monitoring data. This assessment can also be used in a diagnostic way, i.e., to identify the chemicals probably posing the highest risks to the aquatic ecosystems. The article also describes how ecological models can be used to explore how traits govern the species-substance interactions and to predict effects at the individual, population, and community and ecosystem level, i.e., from the receptor to the landscape level. This can be done by developing models describing the toxicokinetics and toxicodynamics of the chemical in the individual, the life-history of species and the connectivity of populations, determining their recovery, and the food web relations at the community and ecosystem level that determine the indirect effects. Special attention is given on how spatial aspects can be included in the ecological risk assessments using ecological models. The components of the framework are introduced and critically discussed. We describe how the different tools and data generated through experimentation (laboratory and semifield) and biomonitoring can be integrated. The article uses examples from the aquatic compartment, but the concepts that are used, and their integration within the framework, can be generalized to other environmental compartments. PMID- 23625554 TI - The sertraline versus electrical current therapy for treating depression clinical study (select-TDCS): results of the crossover and follow-up phases. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a promising nonpharmacological therapy for major depression. In the Sertraline versus Electrical Current Therapy for Treating Depression Clinical Trial (SELECT-TDCS) trial, phase-I (Brunoni et al., JAMA Psychiatry, 2013) we found that tDCS is effective for the acute episode. Here, we describe tDCS effects during phases II (crossover) and III (follow-up) of this trial (NCTs: 01149889 and 01149213). METHODS: Phase II (n = 25) was the open-label, crossover phase in which phase-I nonresponders who had received sham-tDCS received a 10-day course of active-tDCS. In phase-III (n = 42), all active-tDCS responders (>50% Montgomery-Asberg Depression Rating Scale (MADRS) improvement or MADRS <= 12) were enrolled to a 24 week, follow-up phase in which a maximum of nine tDCS sessions were performed every other week for 3 months and, thereafter, once a month for the subsequent 3 months-sessions would be interrupted earlier whether the subject relapsed. TDCS was applied at 2 mA/30 min, with the anode over the left and the cathode over the right dorsolateral prefrontal cortex. Relapse was the outcome measure. RESULTS: In phase-II, 52% of completers responded to tDCS. In phase-III, the mean response duration was 11.7 weeks. The survival rate per Kaplan-Meier analysis was 47%. Patients with treatment-resistant depression presented a much lower 24-week survival rate as compared to nonrefractory patients (10% vs. 77%, OR = 5.52; P < .01). Antidepressant use (sertraline 50 mg/day, eight patients) was not a predictor of relapse. TDCS was well tolerated and with few side effects. CONCLUSION: Continuation tDCS protocols should be optimized as to prevent relapse among tDCS responders, particularly for patients with baseline treatment resistant depression. PMID- 23625555 TI - Reduced fasting plasma levels of diazepam-binding inhibitor in adolescents with anorexia nervosa. AB - OBJECTIVE: Altered expression and/or function, both peripherally and centrally, of various neuropeptides is involved in the neurophysiology of anorexia nervosa (AN). Diazepam-binding inhibitor (DBI) is an interesting peptide for understanding this crosstalk. The aim of this work was to assess fasting plasma levels of DBI and leptin in patients with AN. METHOD: Twenty-four AN adolescents were recruited together with 10 age-comparable healthy controls. Neuropeptide determinations were performed on plasma samples by enzyme-linked immunosorbent assays. Patients with AN were further characterized for the presence of a depressive state or anxiety by using, respectively, the Children's Depression Inventory or the State-Trait Anxiety Inventory form Y. RESULTS: Levels of both plasma DBI and leptin were reduced in patients with AN (~40 and ~70%, respectively). DBI levels displayed a tendency to increase in the presence of a depressive state, although not with anxiety, whereas leptin levels correlated exclusively with body mass index. DISCUSSION: These data further extend our knowledge of neuropeptide dysfunction in AN, and plasma DBI may represent a marker for this disease, in particular considering its correlation with comorbid mood disorders. PMID- 23625556 TI - Caffeine and adenosine A(2A) receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado-Joseph disease. AB - OBJECTIVE: Machado-Joseph disease (MJD) is a neurodegenerative disorder associated with an abnormal CAG expansion, which translates into an expanded polyglutamine tract within ataxin-3. There is no therapy to prevent or modify disease progression. Because caffeine (a nonselective adenosine receptor antagonist) and selective adenosine A2A receptor (A2A R) blockade alleviate neurodegeneration in different brain diseases, namely at early stages of another polyglutamine-related disorder such as Huntington's disease, we now tested their ability to control MJD-associated neurodegeneration. METHODS: MJD was modeled by transducing the striatum of male adult C57Bl/6 mice with lentiviral vectors encoding mutant ataxin-3 in one hemisphere and wild-type ataxin-3 in the other hemisphere (as internal control). Caffeine (1g/L) was applied through the drinking water. Mice were killed at different time points (from 2 to 12 weeks) to probe for the appearance of different morphological changes using immunohistochemical analysis. RESULTS: Mutant ataxin-3 caused an evolving neuronal dysfunction (loss of DARPP-32 staining) leading to neurodegeneration (cresyl violet and neuronal nuclei staining) associated with increased number of mutant ataxin-3 inclusions in the basal ganglia. Notably, mutant ataxin-3 triggered early synaptotoxicity (decreased synaptophysin and microtubule associated protein-2 staining) and reactive gliosis (glial fibrillary acidic protein and CD11b staining), which predated neuronal dysfunction and damage. Caffeine reduced the appearance of all these morphological modifications, which were also abrogated in mice with a global A2A R inactivation (knockout). INTERPRETATION: Our findings provide a demonstration that synaptotoxicity and gliosis are precocious events in MJD and that caffeine and A2A R inactivation decrease MJD-associated striatal pathology, which paves the way to consider A2A Rs as novel therapeutic targets to manage MJD. PMID- 23625557 TI - An exponential decay model for mediation. AB - Mediation analysis is often used to investigate mechanisms of change in prevention research. Results finding mediation are strengthened when longitudinal data are used because of the need for temporal precedence. Current longitudinal mediation models have focused mainly on linear change, but many variables in prevention change nonlinearly across time. The most common solution to nonlinearity is to add a quadratic term to the linear model, but this can lead to the use of the quadratic function to explain all nonlinearity, regardless of theory and the characteristics of the variables in the model. The current study describes the problems that arise when quadratic functions are used to describe all nonlinearity and how the use of nonlinear functions, such as exponential decay, address many of these problems. In addition, nonlinear models provide several advantages over polynomial models including usefulness of parameters, parsimony, and generalizability. The effects of using nonlinear functions for mediation analysis are then discussed and a nonlinear growth curve model for mediation is presented. An empirical example using data from a randomized intervention study is then provided to illustrate the estimation and interpretation of the model. Implications, limitations, and future directions are also discussed. PMID- 23625558 TI - Kinematics of the thoracoabdominal contents under various loading scenarios. AB - High-speed biplane x-ray was used to investigate relative kinematics of the thoracoabdominal organs in response to blunt loading. Four post-mortem human surrogates instrumented with radiopaque markers were subjected to eight crash- specific loading scenarios, including frontal chest and abdominal impacts, as well as driver-shoulder seatbelt loading. Testing was conducted with each surrogate perfused, ventilated, and positioned in an inverted, fixed-back configuration. Displacement of radiopaque markers recorded with high-speed x-ray in two perspectives was tracked using motion analysis software and projected into calibrated three-dimensional coordinates. Internal organ kinematics in response to blunt impact were quantified for the pericardium, lungs, diaphragm, liver, spleen, stomach, mesentery, and bony structures. These data can be used to better understand the interaction of anatomical structures during impact and the associated injury mechanisms, and for the development or validation of human body finite element models. PMID- 23625559 TI - Thoraco-abdominal deflection responses of post mortem human surrogates in side impacts. AB - The objective of the present study was to determine the thorax and abdomen deflections sustained by post mortem human surrogate (PMHS) in oblique side impact sled tests and compare the responses and injuries with pure lateral tests. Oblique impact tests were conducted using modular and non-modular load-wall designs, with the former capable of accommodating varying anthropometry. Tests were conducted at 6.7 m/s velocity. Deflection responses from chestbands were analyzed from 15 PMHS tests: five each from modular load-wall oblique, non modular load-wall oblique and non-modular load- wall pure lateral impacts. The thorax and abdomen peak deflections were greater in non-modular load-wall oblique than pure lateral tests. Peak abdomen deflections were statistically significantly different while the upper thorax deflections demonstrated a trend towards significance. Deflection angulations were statistically significantly different between pure lateral and oblique tests at all regions indicating that it is important to characterize not only the amplitude but also the angle of the vector. Injuries were confined to skeletal regions in pure lateral tests and this was in contrast to the occurrence of both skeletal and soft tissue/organ injury in oblique loading tests, again emphasizing the role of obliqueness in side impacts. Furthermore, injuries in oblique tests were primarily unilateral, paralleling real-world trauma and confirming the applicability of the experimental design to field environments. Potential injury mechanisms are discussed based on anatomical considerations. These findings, albeit from a limited sample size, underscore the need for additional studies to derive human injury tolerance and criteria in oblique side impacts. PMID- 23625560 TI - Dynamic properties of the upper thoracic spine-pectoral girdle (UTS-PG) system and corresponding kinematics in PMHS sled tests. AB - Anthropomorphic test devices (ATDs) should accurately depict head kinematics in crash tests, and thoracic spine properties have been demonstrated to affect those kinematics. To investigate the relationships between thoracic spine system dynamics and upper thoracic kinematics in crash-level scenarios, three adult post mortem human subjects (PMHS) were tested in both Isolated Segment Manipulation (ISM) and sled configurations. In frontal sled tests, the T6-T8 vertebrae of the PMHS were coupled through a novel fixation technique to a rigid seat to directly measure thoracic spine loading. Mid-thoracic spine and belt loads along with head, spine, and pectoral girdle (PG) displacements were measured in 12 sled tests conducted with the three PMHS (3-pt lap-shoulder belted/unbelted at velocities from 3.8 - 7.0 m/s applied directly through T6-T8). The sled pulse, ISM- derived characteristic properties of that PMHS, and externally applied forces due to head-neck inertia and shoulder belt constraint were used to predict kinematic time histories of the T1-T6 spine segment. The experimental impulse applied to the upper thorax was normalized to be consistent with a T6 force/sled acceleration sinusoidal profile, and the result was an improvement in the prediction of T3 X-axis displacements with ISM properties. Differences between experimental and model-predicted displacement-time history increases were quantified with respect to speed. These discrepancies were attributed to the lack of rotational inertia of the head-neck late in the event as well as restricted kyphosis and viscoelasticity of spine constitutive structures through costovertebral interactions and mid-spine fixation. The results indicate that system dynamic properties from sub-injurious ISM testing could be useful for characterizing forward trajectories of the upper thoracic spine in higher energy crash simulations, leading to improved biofidelity for both ATDs and finite element models. PMID- 23625561 TI - Biomechanical responses of PMHS in moderate-speed rear impacts and development of response targets for evaluating the internal and external biofidelity of ATDS. AB - The objectives of this study were to obtain biomechanical responses of post mortem human subjects (PMHS) by subjecting them to two moderate-speed rear impact sled test conditions (8.5g, 17 km/h; 10.5g, 24 km/h) while positioned in an experimental seat system, and to create biomechanical targets for internal and external biofidelity evaluation of rear impact ATDs. The experimental seat was designed to measure external loads on the head restraint (4 load cells), seat back (6 load cells), and seat pan (4 load cells) such that subject dynamic interaction with the seat could be evaluated. This seat system was capable of simulating the dynamic characteristics of modern vehicle seat backs by considering the moment-rotation properties of a typical passenger vehicle, thus providing a more realistic test environment than using a rigid seat with a non rotating seat back as done in previous studies. Instrumentation used to measure biomechanical responses of the PMHS included both accelerometers and angular rate sensors (ARS). A total of fourteen sled tests using eight PMHS (males 175.8 +/- 6.2 cm of stature and 78.4 +/- 7.2 kg of weight) provided data sets of seven PMHS for both test conditions. The biomechanical responses are described at both speeds, and cervical spine injuries are documented. Biomechanical targets are also created for internal and external biofidelity evaluation of rear impact anthropomorphic test devices (ATDs). PMID- 23625562 TI - Evaluation of the internal and external biofidelity of current rear impact ATDs to response targets developed from moderate-speed rear impacts of PMHS. AB - The goal of this study is to evaluate both the internal and external biofidelity of existing rear impact anthropomorphic test devices (BioRID II, RID3D, Hybrid III 50th) in two moderate-speed rear impact sled test conditions (8.5g, 17 km/h; 10.5g, 24 km/h) by quantitatively comparing the ATD responses to biomechanical response targets developed from PMHS testing in a corresponding study. The ATDs and PMHS were tested in an experimental seat system that is capable of simulating the dynamic seat back rotation response of production seats. The experimental seat contains a total of fourteen load cells installed such that external loads from the ATDs and PMHS can be measured to evaluate external biofidelity. The PMHS were instrumented to correspond to the instrumentation contained in the ATDs so that direct comparison between ATDs and PMHS could be made to evaluate internal biofidelity. The NHTSA Biofidelity Ranking system was used to quantitatively evaluate the biofidelity of the ATDs and an additional tool was introduced and utilized which allows for the biofidelity score to be partitioned into components of amplitude, phase, and shape. For internal biofidelity, the BioRID II and RID3D were more biofidelic than the Hybrid III in the 17 km/h test, and the BioRID II was most biofidelic in the 24 km/h test. For external biofidelity, the BioRID II was most biofidelic in the 17 km/h test, while both the BioRID II and the RID3D were more biofidelic than the Hybrid III in the 24 km/h test. Overall, the BioRID II demonstrated the best biofidelity in both the 17 km/h and 24 km/h tests. PMID- 23625563 TI - Development of a human body finite element model with multiple muscles and their controller for estimating occupant motions and impact responses in frontal crash situations. AB - A few reports suggest differences in injury outcomes between cadaver tests and real-world accidents under almost similar conditions. This study hypothesized that muscle activity could primarily cause the differences, and then developed a human body finite element (FE) model with individual muscles. Each muscle was modeled as a hybrid model of bar elements with active properties and solid elements with passive properties. The model without muscle activation was firstly validated against five series of cadaver test data on impact responses in the anterior-posterior direction. The model with muscle activation levels estimated based on electromyography (EMG) data was secondly validated against four series of volunteer test data on bracing effects for stiffness and thickness of an upper arm muscle, and braced driver's responses under a static environment and a brake deceleration. A muscle controller using reinforcement learning (RL), which is a mathematical model of learning process in the basal ganglia associated with human postural controls, were newly proposed to estimate muscle activity in various occupant conditions including inattentive and attentive conditions. Control of individual muscles predicted by RL reproduced more human like head-neck motions than conventional control of two groups of agonist and antagonist muscles. The model and the controller demonstrated that head-neck motions of an occupant under an impact deceleration of frontal crash were different in between a bracing condition with maximal braking force and an occupant condition predicted by RL. The model and the controller have the potential to investigate muscular effects in various occupant conditions during frontal crashes. PMID- 23625564 TI - Research of the relationship of pedestrian injury to collision speed, car-type, impact location and pedestrian sizes using human FE model (THUMS Version 4). AB - Injuries in car to pedestrian collisions are affected by various factors such as the vehicle body type, pedestrian body size and impact location as well as the collision speed. This study aimed to investigate the influence of such factors taking a Finite Element (FE) approach. A total of 72 collision cases were simulated using three different vehicle FE models (Sedan, SUV, Mini-Van), three different pedestrian FE models (AM50, AF05, AM95), assuming two different impact locations (center and the corner of the bumper) and at four different collision speeds (20, 30, 40 and 50 km/h). The impact kinematics and the responses of the pedestrian model were validated against those in the literature prior to the simulations. The relationship between the collision speed and the predicted occurrence of head and chest injuries was examined for each case, analyzing the impact kinematics of the pedestrian against the vehicle body and resultant loading to the head and the chest. Strain based indicators were used in the simulation model to estimate skeletal injury (bony fracture) and soft tissue (brain and internal organs) injury. The study results primarily showed that the injury risk became higher with the collision speed, but was also affected by the combination of the factors such as the pedestrian size and the impact location. The study also discussed the injury patterns and trends with respect to the factors examined. In all of the simulated conditions, the model did not predict any severe injury at a collision speed of 20 km/h. PMID- 23625565 TI - Injury risk curves for the WorldSID 50th male dummy. AB - The development of the WorldSID 50th percentile male dummy was initiated in 1997 by the International Organisation for Standardisation (ISO/TC22/SC12/WG5) with the objective of developing a more biofidelic side impact dummy and supporting the adoption of a harmonised dummy into regulations. The dummy is currently under evaluation at the Working Party on Passive Safety (GRSP) in order to be included in the pole side impact global technical regulation (GTR). Injury risk curves dedicated to this dummy and built on behalf of ISO/TC22/SC12/WG6 were proposed in order to assess the occupant safety performance (Petitjean et al. 2009). At that time, there was no recommendation yet on the injury criteria and no consensus on the most accurate statistical method to be used. Since 2009, ISO/TC22/SC12/WG6 reached a consensus on the definition of guidelines to build injury risk curves, including the use of the survival analysis, the distribution assessment and quality checks. These guidelines were applied to the WorldSID 50th results published in 2009 in order to be able to provide a final set of injury risk curves recommended by ISO/TC22/SC12/WG6. The paper presents the different steps of the guidelines as well as the recommended injury risk curves dedicated to the WorldSID 50th for lateral shoulder load, thoracic rib deflection, abdomen rib deflection and pubic force. PMID- 23625566 TI - How few? Bayesian statistics in injury biomechanics. AB - In injury biomechanics, there are currently no general a priori estimates of how few specimens are necessary to obtain sufficiently accurate injury risk curves for a given underlying distribution. Further, several methods are available for constructing these curves, and recent methods include Bayesian survival analysis. This study used statistical simulations to evaluate the fidelity of different injury risk methods using limited sample sizes across four different underlying distributions. Five risk curve techniques were evaluated, including Bayesian techniques. For the Bayesian analyses, various prior distributions were assessed, each incorporating more accurate information. Simulated subject injury and biomechanical input values were randomly sampled from each underlying distribution, and injury status was determined by comparing these values. Injury risk curves were developed for this data using each technique for various small sample sizes; for each, analyses on 2000 simulated data sets were performed. Resulting median predicted risk values and confidence intervals were compared with the underlying distributions. Across conditions, the standard and Bayesian survival analyses better represented the underlying distributions included in this study, especially for extreme (1, 10, and 90%) risk. This study demonstrates that the value of the Bayesian analysis is the use of informed priors. As the mean of the prior approaches the actual value, the sample size necessary for good reproduction of the underlying distribution with small confidence intervals can be as small as 2. This study provides estimates of confidence intervals and number of samples to allow the selection of the most appropriate sample sizes given known information. PMID- 23625567 TI - Abdominal Twin Pressure Sensors for the assessment of abdominal injuries in Q dummies: in-dummy evaluation and performance in accident reconstructions. AB - The Abdominal Pressure Twin Sensors (APTS) for Q3 and Q6 dummies are composed of soft polyurethane bladders filled with fluid and equipped with pressure sensors. Implanted within the abdominal insert of child dummies, they can be used to detect abdominal loading due to the belt during frontal collisions. In the present study - which is part of the EC funded CASPER project - two versions of APTS (V1 and V2) were evaluated in abdominal belt compression tests, torso flexion test (V1 only) and two series of sled tests with degraded restraint conditions. The results suggest that the two versions have similar responses, and that the pressure sensitivity to torso flexion is limited. The APTS ability to detect abdominal loading in sled tests was also confirmed, with peak pressures typically below 1 bar when the belt loaded only the pelvis and the thorax (appropriate restraint) and values above that level when the abdomen was loaded directly (inappropriate restraint). Then, accident reconstructions performed as part of CASPER and previous EC funded projects were reanalyzed. Selected data from 19 dummies (12 Q6 and 7 Q3) were used to plot injury risk curves. Maximum pressure, maximum pressure rate and their product were all found to be injury predictors. Maximum pressure levels for a 50% risk of AIS3+ were consistent with the levels separating appropriate and inappropriate restraint in the sled tests (e.g. 50% risk of AIS3+ at 1.09 bar for pressure filtered CFC180). Further work is needed to refine the scaling techniques between ages and confirm the risk curves. PMID- 23625568 TI - Kinematics and dynamics of the pelvis in the process of submarining using PMHS sled tests. AB - This study focused on a better understanding and characterization of the submarining phenomenon that occurs in frontal crashes when the lap belt slides over the anterior superi or iliac spine. Submarining is the consequence of the pelvis kinematics relative to the lap belt, driven by the equilibrium of forces and moments applied to the pelvis. The study had two primary purposes; the first was to provide new PMHS data in submarining test configurations, the second was to investigate the Hybrid II and Hybrid III dummies biofidelity regarding submarining. Several Post Mortem Human Subject (PMHS) studies have been published on this subject. However, the lack of information about the occupant initial positioning and the use of car seats make it difficult to reconstruct these tests. Furthermore, the two dummies are rarely compared to PMHS in submarining test configurations. A fifteen frontal sled test campaign was carried out on two Anthropomorphic Test Devices (ATDs) and nine PMHS. The test environment was designed to be reproducible. It consisted of a rigid seat, a 2-poi nts shoulder belt and a 2-points lap belt instrumented to record their 3D forces at anchorage. The subjects were instrumented with angular sensors at the sacrum, T1 and T12 levels to record their initial angles. Kinematics was measured at these three levels by means of three accelerometers and angular velocity sensors. A PMHS positioning procedure was developed to ensure repeatability. A pre-test was performed on each subject to characterize its lumbar spine static behavior. All the subjects were CT-scanned from head to toe prior to the test. The campaign was divided into three test configurations leading to different surrogates' interaction with the environment and different kinematics. This resulted in a wider range of behaviors for the dummies evaluation. The deceleration pulse, initial lap belt angle, lap belt slack, seat pan angle and footrest position varied. The Hybrid II and Hybrid III dummies and three PMHS were tested in each configuration. Forces and kinematics time history corridors based on the PMHS responses are provided for each configuration. The dummies' responses are evaluated against these targets. For the first configuration (40 km/h), the peak lap belt tension for both sides was between 3,000 N and 6,385 N for the three PMHS while it was around 4,700 N and 6,200 N in average for Hybrid II and Hybrid III respectively. The maximum pelvic rotation ranged from 41 degrees to 80 degrees for the PMHS and reached approximately 45 degrees for the two dummies. For the other two configurations (50 km/h), the peak lap belt tension varied from 3,660 N to 7,180 N for the PMHS and was between 5,400 N and 6,100 N for Hybrid II and between 7,145 N and 7,900 N for Hybrid III. The maximum pelvic rotation ranged from 43 degrees to 73 degrees for the PMHS, while it reached approximately 54 degrees and 46 degrees for Hybrid II and Hybrid III respectively. PMID- 23625569 TI - The effect of pretensioning and age on torso rollout in restrained human volunteers in far-side lateral and oblique loading. AB - Far-side side impact loading of a seat belt restrained occupant has been shown to lead to torso slip out of the shoulder belt. A pretensioned seat belt may provide an effective countermeasure to torso rollout; however the effectiveness may vary with age due to increased flexibility of the pediatric spine compared to adults. To explore this effect, low-speed lateral (90 degrees ) and oblique (60 degrees ) sled tests were conducted using male human volunteers (20 subjects: 9-14 years old, 10 subjects: 18-30 years old), in which the crash pulse safety envelope was defined from an amusement park bumper-car impact. Each subject was restrained by a lap and shoulder belt system equipped with an electromechanical motorized seat belt retractor (EMSR) and photo- reflective targets were attached to a tight fitting headpiece or adhered to the skin overlying key skeletal landmarks. Each subject was randomly assigned to either the 60 degrees or 90 degrees direction and was exposed to 4 test conditions - arms up (with hands on their knees) with EMSR on, arms down (with hands low on the hips) with EMSR on, arms up with EMSR off, arms down with EMSR off. The effect of age and pretensioning on the following outcomes was quantified: 1) lateral and forward displacement of the torso, 2) torso rollout angle projected onto three orthogonal planes, and 3) resultant belt-sternal distance. The effect of pretensioning on torso containment within the shoulder belt was strong in both impact directions across all metrics evaluated. EMSR activation significantly reduced lateral displacement of the suprasternal notch (~100 mm, p<0.0001), coronal projection of the torso rollout angle (~15 degrees , p<0.0001), and belt sternal distance when the arms were down (~50 mm, p<0.05). The benefit of pretensioning was achieved by early engagement of the torso by the shoulder belt. An added benefit of pretensioning was the ability to make similar the torso kinematics across a range of anthropometries as assessed within and across age groups. These results can serve as a data set for validating the responses of restrained ATDs and computational human models to low severity far side collisions, in particular the interaction between the torso and the shoulder belt. PMID- 23625570 TI - An integrated helmet and neck support (iHANS) for racing car drivers: a biomechanical feasibility study. AB - A new form of head and neck protection for racing car drivers is examined. The concept is one whereby the helmet portion of the system is attached, by way of a quick release clamp, to a collar-like platform which is supported on the driver's shoulders. The collar, which encircles the back and sides of the driver's neck, is held in place by way of the on-board restraint belts. The interior of the helmet portion of the assembly is large enough to provide adequate volitional head motion. The overall objective of the design is to remove the helmet from the wearer's head and thereby to mitigate the deleterious features of helmet wearing such as neck fatigue, poor ventilation and aerodynamic buffeting. Just as importantly, by transferring the weight of the helmet and all attendant reaction forces associated with inertial and impact loads to the shoulder complex (instead of to the neck), reduced head and neck injury probability should be achievable. This paper describes the concept development and the evolution of various prototype designs. Prototypes have been evaluated on track and sled tested in accordance with contemporary head neck restraint systems practice. Also discussed is a series of direct impact tests. In addition, low mass high velocity ballistic tests have been conducted and are reviewed herein. It is concluded that this new concept indeed does address most of the drawbacks of the customary helmet and that it generally can reduce the probability of head and neck injury. PMID- 23625571 TI - From crash test speed to performance in real world conditions: a conceptual model and its application to underhood clearance in pedestrian head tests. AB - Current safety testing protocols typically evaluate performance at a single test speed, which may have undesirable side effects if vehicles are optimised to perform at that speed without consideration to performance at other speeds. One way of overcoming this problem is by using an evaluation that incorporates the distribution of speeds that would be encountered in real crashes, the relationship between test speed and test performance, and the relationship between test performance and injury risk. Such an evaluation is presented in this paper and is applied to pedestrian headform testing. The applicable distribution of pedestrian impact speeds was compiled from in-depth crash data. Values of the Head Injury Criterion across the speed distribution were imputed from a single test result, taking into account the potential for 'bottoming out' on harder structures beneath the hood. Two different risk functions were used: skull fracture risk and fatal head injury risk. Eight example test locations were evaluated; each had an underhood clearance such that it would perform worse at higher speeds than suggested by its original test result. When the effect of bottoming out was included in the evaluation, the calculated average injury risk was generally higher than it was if bottoming out was ignored. The average risk of fatal head injury was more affected by the inclusion of bottoming out than the average skull fracture risk. The methodology presented in this paper may be extended to other forms of impact testing, although the input functions may be more difficult to derive for more complex tests. PMID- 23625572 TI - A new method to evaluate future impact of vehicle safety technology in Sweden. AB - In the design of a safe road transport system there is a need to better understand the safety challenges lying ahead. One way of doing that is to evaluate safety technology with retrospective analysis of crashes. However, by using retros- pective data there is the risk of adapting safety innovations to scenarios irrelevant in the future. Also, challenges arise as safety interventions do not act alone but are rather interacting components in a complex road transport system. The objective of this study was therefore to facilitate the prioritizing of road safety measures by developing and applying a new method to consider possible impact of future vehicle safety technology. The key point was to project the chain of events leading to a crash today into the crashes for a given time in the future. Assumptions on implementation on safety technologies were made and these assump- tions were applied on the crashes of today. It was estimated which crashes would be prevented and the residual was analyzed to identify the characteristics of future crashes. The Swedish Transport Administration's in-depth studies of fatal crashes from 2010 involving car passengers (n=156) were used. This study estimated that the number of killed car occupant would be reduced with 53 percent from the year 2010 to 2020. Through this new method, valuable information regarding the characteristic of the future crashes was found. The results of this study showed that it was possible to evaluate future impact of vehicle safety technology if detailed and representative crash data is available. PMID- 23625573 TI - A common and functional gene variant in the vascular endothelial growth factor a predicts clinical outcome in early-stage breast cancer. AB - Angiogenesis and cell cycle control play critical roles in breast cancer susceptibility and clinical outcome and are mainly controlled by vascular endothelial growth factor (VEGF) and cyclin-dependent kinases, respectively. Functional germline polymorphisms in these genes alter the function, thereby causing inter-individual differences in breast cancer risk and clinical outcome. In this study, we investigated the influence of the functional polymorphisms VEGF A rs3025039 C > T and CCND1 rs9344 G > A on risk and clinical outcome in early stage breast cancer. DNA of 539 female patients with histologically confirmed early-stage breast cancer and 804 control subjects was genotyped for these polymorphisms. Genotypes were tested for associations with breast cancer risk and clinical outcome. There was no significant association between the polymorphisms and breast cancer risk. However, the minor allele of VEGF-A rs3025039 C > T was significantly associated with decreased recurrence-free survival (HR 1.845; 95% confidence interval [CI] 1.035-3.290; P = 0.038) and remained significant in multivariate analysis (HR 1.880; 95% CI 1.020-3.465; P = 0.043). Patients carrying at least one A-allele in CCND1 rs9344 G > A showed a trend towards decreased recurrence-free survival in univariate analysis (HR 2.379; 95% CI 0.841 6.728; P = 0.068). This study provides evidence that the functional VEGF-A rs3025039 C > T polymorphism influences recurrence-free survival in early-stage breast cancer. PMID- 23625574 TI - Nongenomic actions of progesterone and 17beta-estradiol on the chloride conductance of skeletal muscle. AB - INTRODUCTION: Myotonia congenita, caused by mutations in ClC-1, tends to be more severe in men and is often exacerbated by pregnancy. METHODS: We performed whole cell patch clamp of mouse muscle chloride currents in the absence/presence of 100 MUM progesterone or 17beta-estradiol. RESULTS: 100 MUM progesterone rapidly and reversibly shifted the ClC-1 activation curve of mouse skeletal muscle (V50 changed from -52.6 +/- 9.3 to +35.5 +/- 6.7; P < 0.01) and markedly reduced chloride currents at depolarized potentials. 17beta-estradiol at the same concentration had a similar but smaller effect (V50 change from -57.2 +/- 7.6 to 40.5 +/- 9.8; P < 0.05). 1 MUM progesterone produced no significant effect. CONCLUSIONS: Although the data support the existence of a nongenomic mechanism in mammalian skeletal muscle through which sex hormones at high concentration can rapidly modulate ClC-1, the influence of hormones on muscle excitability in vivo remains an open question. PMID- 23625575 TI - Trends in all-cause mortality among patients with chronic myeloid leukemia: a Surveillance, Epidemiology, and End Results database analysis. AB - BACKGROUND: Outcomes for patients with chronic myeloid leukemia (CML) have improved after the advent of tyrosine kinase inhibitors (TKIs), which target the BCR/ABL fusion gene product. Nonetheless, differences in survival persist between age groups. The authors performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database to assess 5-year overall survival (OS) in various patient age groups. METHODS: Patients who had a diagnosis of CML were identified using the SEER 19 registries database. Patients who were included had SEER diagnosis codes for CML not otherwise specified (code 9863) and BCR/ABL-positive CML (code 9875) diagnosed between January 2000 and December 2005. Patients were divided into cohorts based on age at diagnosis: ages 15 to 44 years, 45 to 64 years, 65 to 74 years, and 75 to 84 years. OS was estimated using the Kaplan-Meier method, and Cox regression was used to estimate predictors of patient survival. RESULTS: In total, 5138 patients with a new CML diagnosis were identified. Five-year OS improved for all patients between the years 2000 and 2005. Compared with patients who were diagnosed in 2000, 5-year survival improved among patients ages 15 to 44 years (hazard ratio [HR] for mortality, 0.424; P < .0001), ages 45 to 64 years (HR, 0.716; P = .0315), and ages 65 to 74 years (HR, 0.692; P = .0126); and patients ages 75 to 84 years had an increased 5-year OS rate from 19.2% in 2000 to 36.4% in 2005 (HR, 0.568; P < .0001). CONCLUSIONS: OS at 5 years improved among all patients, including those ages 75 to 84 years, a group with historically poor outcomes. However, older age retained an association with worse survival, suggesting opportunities for further progress. PMID- 23625576 TI - Biographical sketch: Harald Tscherne, MD (1933-present). AB - This biographical sketch on Prof. Harald Tscherne corresponds to the historic text, The Classic: Der Strabetaenunfall [Traffic Accidents]. Wien Med Wochenschr. 1966;116:105-108 (Translated by Dr. Roman Pfeifer), available at DOI 10.1007/s11999-013-3012-9. PMID- 23625577 TI - Health policy implications of outcomes measurement in orthopaedics. AB - BACKGROUND: An emphasis on "value" over volume in health care is driving new healthcare measurement, delivery, and payment models. Orthopaedic surgery is a major contributor to healthcare spending and, as such, is the focus of many of these new models. WHERE ARE WE NOW?: An evaluation of "value" in orthopaedics requires information that has not traditionally been collected as part of routine clinical practice. If value is defined as patient outcomes in relation to healthcare costs, we need to collect information about both. In orthopaedics, patient-reported functional status is not routinely measured, and a poor understanding of the costs associated with the provision of musculoskeletal care limits our ability to quantify and report on financial measures. WHERE DO WE NEED TO GO?: To improve the value of musculoskeletal care, we need to focus on both improving outcomes and controlling costs. To improve outcomes, orthopaedists must agree on a set of outcome measures for appropriate care and advocate for their collection through the use of registries. Orthopaedic registries in several countries provide best practices for this information collection and sharing. In the United States, we should make comparable investments in registries to measure patient-reported outcomes. To address escalating costs, we need to improve the accuracy of cost data by applying modern cost accounting processes. HOW DO WE GET THERE?: Orthopaedists should take a leadership position in the promotion and implementation of value-based health care by advocating for the use of registries to measure risk-adjusted patient specific outcomes, negotiating with payors for value-based payment incentives and applying modern cost accounting processes to control costs rather than waiting for public and private payors to define components of the value equation that will affect how orthopaedic surgeons are evaluated and compensated in the future. PMID- 23625578 TI - Primary embryonal rhabdomyosarcoma of the anterior neck and thyroid: report of a new case with review of the literature. AB - Primary embryonal rhabdomyosarcoma of anterior neck involving the thyroid is extremely rare. This report is only the second of its kind that describes this form of nonorbital nonparameningeal rhabdomyosarcoma in a 7-year-old boy and adds to a new, seldom-reported variant of rhabdomyosarcoma in the head-neck region. The child presented with a huge anterior neck swelling that clinically resembled a thyroid mass. Computed tomography scan showed a heterogeneous mass in the anterior neck replacing the entire right lobe of thyroid. Fine-needle aspiration cytology was nondiagnostic. Right hemithyroidectomy with selective neck dissection suggested embryonal rhabdomyosarcoma by histopathology; the diagnosis was confirmed by positive reactions to desmin and myogenin. The child was subsequently treated with chemotherapy. Repeat chemotherapy with radiotherapy was required when recurrences were detected in the mediastinum and cervical lymph nodes at 13-month follow-up. PMID- 23625579 TI - Adrenal-to-liver SUV ratio is the best parameter for differentiation of adrenal metastases from adenomas using 18F-FDG PET/CT. AB - PURPOSE: To investigate the best standardized uptake value (SUV) index for differentiation of adrenal metastases from adrenocortical adenomas using 18F fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT). MATERIALS AND METHODS: A total of 129 patients (82 males and 47 females; mean age 65.4 years) with extra-adrenal primary malignancies who had known or suspected adrenal lesions underwent FDG PET/CT examinations for detection, staging, re staging, or recurrence of tumor. Among these patients, 45 adrenal lesions (22 adenomas and 23 metastases) in 41 patients were evaluated. The maximum SUVs for adrenal lesions (adrenal SUVmax) and mean liver and spleen SUVs were recorded, and the ratio of the adrenal SUVmax to the mean liver SUV (adrenal-to-liver SUV ratio) and that of the adrenal SUVmax to the mean spleen SUV (adrenal-to-spleen SUV ratio) were obtained. Diagnostic performances for the adrenal SUVmax, adrenal to-liver SUV ratio, and adrenal-to-spleen SUV ratio were compared. RESULTS: The mean adrenal SUVmax, adrenal-to-liver SUV ratio, and adrenal-to-spleen SUV ratio were higher for adrenal metastases (8.4 +/- 3.8, 3.0 +/- 1.3, and 4.0 +/- 1.9, respectively) than for adrenocortical adenomas (2.9 +/- 1.0, 0.9 +/- 0.3, and 1.3 +/- 0.3, respectively) (P < 0.001). The area under the curve was higher for the adrenal-to-liver SUV ratio (0.99) than for the adrenal SUVmax (0.96) and adrenal to-spleen SUV ratio (0.98). In the differentiation of adrenocortical adenomas and adrenal metastases, an adrenal-to-liver SUV ratio cutoff value of 1.37 yielded a sensitivity of 96% and specificity of 100%. CONCLUSION: In FDG PET/CT analysis, the adrenal-to-liver SUV ratio had a greater ability to differentiate adrenocortical adenomas and adrenal metastases than did the adrenal SUVmax or adrenal-to-spleen SUV ratio. PMID- 23625580 TI - Induction of avian beta-defensins by CpG oligodeoxynucleotides and proinflammatory cytokines in hen vaginal cells in vitro. AB - Immune function in the vagina of hen oviduct is essential to prevent infection by microorganisms colonizing in the cloaca. The aim of this study was to determine whether CpG oligodeoxynucleotides (CpG-ODN) stimulate the expression of avian beta-defensins (AvBDs) in hen vaginal cells. Specific questions were whether CpG ODN affects the expression of AvBDs and proinflammatory cytokines and whether the cytokines affect AvBDs expression in vaginal cells. The dispersed vaginal cells of White Leghorn laying hens were cultured and stimulated by different doses of lipopolysaccharide (LPS), CpG-ODN, interleukin 1beta (IL1B), or IL6. The cultured cell population contained epithelial cells, fibroblast-like cells, and CD45 positive leukocytes. The immunoreactive AvBD3, -10, and -12 were localized in the mucosal epithelium in the section of the vagina. The expression of AvBDs, IL1B, and IL6 was analyzed by quantitative RT-PCR. RT-PCR analysis showed the expression of AvBD1, -3, -4, -5, -10, and -12 in the cultured vaginal cells without stimulation. Toll-like receptors (TLRs) 4 and 21, which recognize LPS and CpG-ODN respectively and IL1 and IL6 receptors (IL1R1 and IL6R) were also expressed in them. The expression of IL1B, IL6, and AvBD10 and -12 was upregulated by LPS, whereas only IL1B and IL6 were upregulated by CpG-ODN. IL1B stimulation upregulated AvBD1 and -3 expression, whereas IL6 stimulation did not cause changes in AvBDs expression. These results suggest that CpG-ODN derived from microbes upregulates the expression of IL1B and IL6 by interaction with TLR21 and then IL1B induces AvBD1 and -3 to prevent infection in the vagina. PMID- 23625582 TI - Placental growth factor (PlGF)-specific uptake in tumor microenvironment of 89Zr labeled PlGF antibody RO5323441. AB - Placental growth factor (PlGF) is a member of the proangiogenic vascular endothelial growth factor family, which is upregulated in many tumors. RO5323441, a humanized monoclonal antibody against PlGF, showed antitumor activity in human tumor xenografts. We therefore aimed to radiolabel RO5323441 and preclinically validate this tracer to study drug tumor uptake and organ distribution by PET imaging. (89)Zr-RO5323441 was tested for stability and immunoreactivity in vitro. METHODS: The tumor uptake and organ distribution for 10, 50, and 500 MUg of (89)Zr-RO5323441 was assessed in mice bearing human PlGF-expressing hepatocellular cancer (Huh7) xenografts or human renal cell carcinoma (ACHN) xenografts without detectable human PlGF expression. The effect of pretreatment with RO5323441 (20 mg/kg) on (89)Zr-RO5323441 tumor uptake was analyzed in Huh7 xenografts. (111)In-IgG served as a control for nonspecific tumor uptake and organ distribution. Cy5-RO5323441 was injected to study the intratumor distribution of RO5323441 with fluorescence microscopy. RESULTS: (89)Zr-RO5323441 showed a time- and dose-dependent tumor accumulation. Uptake in Huh7 xenografts at 10 MUg of (89)Zr-RO5323441 was 8.2% +/- 1.7% injected dose (ID)/cm(3) at 144 h after injection, and in ACHN xenografts it was 5.5 +/- 0.3 %ID/cm(3) (P = 0.03). RO5323441 pretreatment of Huh7 xenograft-bearing mice reduced (89)Zr-RO5323441 tumor uptake to the level of nonspecific (111)In-IgG uptake. Cy5-RO5323441 was present in the tumors mainly in the microenvironment. CONCLUSION: The findings show that RO5323441 tumor uptake is PlGF-specific and time- and dose-dependent. PMID- 23625583 TI - Quality of life, health status and caregiver burden in Parkinson's disease: relationship to executive functioning. AB - OBJECTIVE: High-quality person-centred care for people with Parkinson's disease (PwPD) and their families relies on identifying and addressing factors that specifically impact on quality of life (QoL). Deficits in executive functions (EF) are common in Parkinson's disease, but their impact on PwPD and their caregivers is not well understood. The present study evaluated how EF contributes to QoL and health status for the PwPD and caregiver burden. METHODS: Sixty-five PwPD completed measures of QoL, health status and EF, and 50 caregivers rated the EF of the PwPD and their own burden. Multiple regression analyses examined predictors of QoL (general life, health and movement disorders domains), health status and caregiver burden. RESULTS: Quality of life in the health and movement disorders domains was best explained by caregiver-rated EF, whereas QoL in the general life domain was best explained by level of depression. Health status was predicted by self-rated EF, with an objective EF measure also included in the regression model. Caregiver burden was best explained by caregiver-rated EF and disease severity, with general cognition and other factors also included in the regression model. CONCLUSIONS: Executive functions-related behavioural problems may contribute to QoL and health status in PwPD and affect caregiver burden. The findings support the view that the concepts of subjective QoL and self-assessed health status are only partially related and should not be seen as identical. Adequate strategies to reduce the impact of EF deficits are needed as this may have the potential to improve QoL in PwPD. PMID- 23625581 TI - The effect of lipoic acid on cyanate toxicity in different structures of the rat brain. AB - Cyanate is formed mostly during nonenzymatic urea biodegradation. Its active form isocyanate reacts with protein -NH2 and -SH groups, which changes their structure and function. The present studies aimed to investigate the effect of cyanate on activity of the enzymes, which possess -SH groups in the active centers and are implicated in anaerobic cysteine transformation and cyanide detoxification, as well as on glutathione level and peroxidative processes in different brain structures of the rat: cortex, striatum, hippocampus, and substantia nigra. In addition, we examined whether a concomitant treatment with lipoate, a dithiol that may act as a target of S-carbamoylation, can prevent these changes. Cyanate inhibited sulfurtransferase activities and lowered sulfide level, which was accompanied by a decrease in glutathione concentration and elevation of reactive oxygen species level in almost all rat brain structures. Lipoate administered in combination with cyanate was able to prevent the above-mentioned negative cyanate induced changes in a majority of the examined brain structures. These observations can be promising for chronic renal failure patients since lipoate can play a double role in these patients contributing to efficient antioxidant defense and protection against cyanate and cyanide toxicity. PMID- 23625584 TI - An efficient analysis of covariance model for crossover thorough QT studies with period-specific baseline days. AB - Baseline adjustment is an important consideration in thorough QT studies for nonantiarrhythmic drugs. For crossover studies with period-specific baseline days, we propose an analysis of covariance model with change from time-matched baseline as response, time-matched baseline for the current treatment, day averaged baseline for the current treatment, time-matched baseline averaged across treatments, and day-averaged baseline averaged across treatments as covariates. This model adjusts for within-subject diurnal effects for each treatment and is more efficient than commonly used models for treatment comparisons. We illustrate the benefit using real clinical trial data. PMID- 23625585 TI - Toxicokinetics and toxicodynamics of nickel in Enchytraeus crypticus. AB - Metal toxicity is usually determined at a fixed time point, which may bias the assessment of risks associated with varied exposure time. Time-dependent accumulation and toxicity of nickel in the potworm Enchytraeus crypticus were investigated in solutions embedded in an inert quartz sand matrix. Internal Ni concentration and mortality were determined at 7 different time intervals and interpreted from the perspective of toxicokinetics and toxicodynamics. A 1 compartment model was used to describe the uptake and elimination kinetics of Ni. At each exposure concentration, Ni concentration in the organisms increased with increasing exposure time, reaching equilibrium after approximately 14 d. Median lethal concentration (LC50) decreased with time and reached an ultimate value of 0.182 mg/L. The LC50 values expressed as internal Ni concentrations (LC50inter) were almost constant (16.7 mg/kg body dry wt) at each exposure time. The LC50inter was independent of exposure time, suggesting that internal concentration was a better indicator of Ni toxicity than external concentration. The uptake rate constant was 11.9 L/kg/d, and elimination rate constants were 0.325/d (based on internal concentration) and 0.070/d (based on survival), indicating that not all internal Ni contributes to toxicity. The present study highlights the importance of taking time into account in future toxicity testing and risk assessment practices. PMID- 23625586 TI - Polymer monolithic capillary microextraction combined on-line with inductively coupled plasma MS for the determination of trace rare earth elements in biological samples. AB - A rapid and sensitive method based on polymer monolithic capillary microextraction combined on-line with microconcentric nebulization inductively coupled plasma MS has been developed for the determination of trace/ultratrace rare earth elements in biological samples. For this purpose, the iminodiacetic acid modified poly(glycidyl methacrylate-trimethylolpropane trimethacrylate) monolithic capillary was prepared and characterized by SEM and FTIR spectroscopy. Factors affecting the extraction efficiency, such as sample pH, sample flow rate, sample/eluent volume, and coexisting ions were investigated in detail. Under the optimal conditions, the LODs for rare earth elements were in the range of 0.08 (Er) to 0.97 ng/L (Nd) with a sampling frequency of 8.5 h(-1), and the RSDs were between 1.5% (Sm) and 7.4% (Nd) (c = 20 ng/L, n = 7). The proposed method was successfully applied to the analysis of trace/ultratrace rare earth elements in human urine and serum samples, and the recoveries for the spiked samples were in the range of 82-105%. The developed method was simple, rapid, sensitive, and favorable for the analysis of trace/ultratrace rare earth elements in biological samples with limited sample volume. PMID- 23625587 TI - Improved memory function two years after bariatric surgery. AB - OBJECTIVE: Obesity is as an independent risk factor for poor neurocognitive outcomes, including Alzheimer's disease. Bariatric surgery has recently been shown to result in improved memory at 12-weeks postoperatively. However, the long term effects of bariatric surgery on cognitive function remain unclear. DESIGN AND METHODS: Eighty-six individuals (63 bariatric surgery patients, 23 obese controls) were recruited from a prospective study examining the neurocognitive effects of bariatric surgery. All participants completed self-report measurements and a computerized cognitive test battery prior to surgery and at 12-week and 24 month follow-up; obese controls completed measures at equivalent time points. RESULTS: Bariatric surgery patients exhibited high rates of pre-operative cognitive impairments in attention, executive function, memory, and language. Relative to obese controls, repeated measures ANOVA showed improvements in memory from baseline to 12-weeks and 24-months postoperatively (P < 0.05). Regression analyses controlling for baseline factors revealed that a lower BMI at 24-months demonstrated a trend toward significance for improved memory (beta = -.30, P = 0.075). CONCLUSION: These findings suggest that cognitive benefits of bariatric surgery may extend to 24-months postoperatively. Larger prospective studies with extended follow-up periods are needed to elucidate whether bariatric surgery decreases risk for cognitive decline and possibly the development of dementia. PMID- 23625588 TI - Differential effects on lung cancer cell proliferation by agonists of glucocorticoid and PPARalpha receptors. AB - Glucocorticoids (GCs) are well-known anti-inflammatory compounds, but they also inhibit cell proliferation depending on cell type. Similarly, peroxisome proliferator-activated receptors (PPARalpha, PPARdelta, and PPARgamma) also possess anti-proliferation properties beyond their canonical roles as metabolic mediators. In the present study, we investigated the potential additive or synergistic inhibitory effects on cancer cell proliferation by simultaneous application of fenofibrate and budesonide, agonists for PPARalpha and glucocorticoid receptor, respectively. We observed differential effects on cell proliferation in A549 and SK-MES-1 lung cancer cells by budesonide and fenofibrate. Fenofibrate inhibited cell proliferation in both TP53 wild type and deficient lung cancer cells. The anti-proliferation effect of budesonide in TP53 wild type A549 cells was abolished in SK-MES-1 cells that do not have wild type TP53 protein. An additive effect against cell proliferation by budesonide and fenofibrate combination was observed only in TP53 wild type A549 cancer cells. Analysis of cell cycle distribution and cyclin profile indicated that the inhibition of cell proliferation was associated with G1 cell cycle arrest. The suppression of NF-kappaB activity and ERK signaling may contribute to the inhibition of cell proliferation by budesonide and or fenofibrate. The additive inhibitory effect on cell proliferation by budesonide and fenofibrate combination suggests that the same or greater therapeutic effect could be achieved with reduced dosage and side effects when the two compounds are applied simultaneously. PMID- 23625589 TI - Eating disorder risk behavior and dental implications among adolescents. AB - OBJECTIVE: To compare the occurrence of tooth erosion (TE) and dental caries (DC) in adolescents with and without risk behavior for eating disorders (EDs). METHOD: A controlled cross-sectional study involving 1,203 randomly selected female students aged 15-18 years was conducted in Brazil. Risk behavior for EDs was evaluated through the Bulimic Investigatory Test of Edinburgh and dental examinations were performed. RESULTS: The prevalence of risk behavior for EDs was 6%. Twenty adolescents (1.7%) were identified with severe risk behavior for EDs and matched to 80 adolescents without such risk. Among the severe risk group, 45% of adolescents were affected by TE and 80% by DC compared with 8.8 and 51.3%, respectively, in the matched group. Adolescents with severe risk had higher chances for TE (OR = 10.04; 95% CI = 2.5-39.4). DISCUSSION: In this study, a severe risk behavior for EDs was significantly associated with TE, but not with DC. PMID- 23625590 TI - More ecological ERA: incorporating natural environmental factors and animal behavior. AB - We discuss the importance of selected natural abiotic and biotic factors in ecological risk assessment based on simplistic laboratory bioassays. Although it is impossible to include all possible natural factors in standard lower-tier ecotoxicological testing, neglecting them is not an option. Therefore, we try to identify the most important factors and advocate redesigning standard testing procedures to include theoretically most potent interactions. We also point out a few potentially important factors that have not been studied enough so far. The available data allowed us to identify temperature and O2 depletion as the most critical factors that should be included in ecotoxicity testing as soon as possible. Temporal limitations and fluctuations in food availability also appear important, but at this point more fundamental research in this area is necessary before making decisions on their inclusion in risk assessment procedures. We propose using specific experimental designs, such as Box-Behnken or Central Composite, which allow for simultaneous testing of 3 or more factors for their individual and interactive effects with greater precision and without increasing the effort and costs of tests dramatically. Factorial design can lead to more powerful tests and help to extend the validity of conclusions. Finally, ecological risk assessment procedures should include information on animal behavior, especially feeding patterns. This requires more basic studies, but already at this point adequate mechanistic effect models can be developed for some species. PMID- 23625591 TI - Utility of the PedsQLTM family impact module: assessing the psychometric properties in a community sample. AB - PURPOSE: Research on families coping with pediatric chronic illnesses has established that children and parents are affected by the illness. Therefore, optimal assessment of parent and family functioning is clinically important. The PedsQLTM family impact module (FIM) assesses parents' health-related quality of life (HRQOL) and family functioning. While the FIM has been shown to be reliable and valid in multiple chronic illness groups, there is little data on its use in non-clinical groups. The study's objective was to assess the reliability, validity, and factor structure of the FIM in a community sample. METHODS: Nine hundred and twenty-nine community parents of children 2-17 years old completed an anonymous online survey. The mean age of the participants was 37.6 years (SD = 8.6), and the majority were mothers (63.6 %), white (82.9 %), and married (74.8 %). The mean age of the children being reported on was 8.8 years (SD = 3.9), and the majority were female (52.3 %) and 41.2 % were reported as having at least one chronic condition. RESULTS: All of the FIM's scales demonstrated excellent internal consistency reliability. Confirmatory factor analysis of the measure supported the current structure. The measure correlated in the expected direction with validated measures of anxiety, depression, child HRQOL, and number of chronic conditions endorsed. Independent t tests indicated that the measure has discriminant validity between parents who reported having a child with a chronic condition to those who did not. CONCLUSION: The results of this study suggest the FIM is a reliable and valid measure of parent HRQOL and family functioning within a community sample, and facilitate its use in comparative studies. PMID- 23625592 TI - A brief cognitive-behavioral intervention for treating depression and panic disorder in patients with noncardiac chest pain: a 24-week randomized controlled trial. AB - BACKGROUND: Most patients with noncardiac chest pain experience anxiety and depressive symptoms. Commonly they are reassured and referred back to primary care, leaving them undiagnosed and untreated. Some small studies have suggested efficacy of 12 cognitive behavioral therapy (CBT) sessions. Our aim was to examine efficacy of brief CBT in reducing anxiety and depressive symptoms in patients with noncardiac chest pain and comorbid panic and/or depressive disorders. METHODS: In this 24-week randomized controlled trial comparing CBT (n = 60) versus treatment as usual (TAU, n = 53), we included all adults who presented at the cardiac emergency unit of a university hospital with noncardiac chest pain, scored >=8 on the hospital anxiety and depression scale (HADS) and were diagnosed with a comorbid panic and/or depressive disorder with the Mini International Neuropsychiatric Interview. CBT consisted of six individual sessions. Main outcome was disease severity assessed with the clinical global inventory (CGI) by a blinded independent rater. RESULTS: ANCOVA in the intention to-treat and completer sample showed that CBT was superior to TAU after 24 weeks in reducing disease severity assessed with CGI (P < .001). Secondary outcomes on anxiety (HADS-anxiety, state trait anxiety inventory (STAI)-trait) and depressive symptoms (Hamilton depression rating scale) were in line with these results except for HADS-depression (P = .10), fear questionnaire (P = .13), and STAI state (P = .11). CONCLUSIONS: Brief CBT significantly reduces anxiety and depressive symptoms in patients with noncardiac chest pain who are diagnosed with panic and/or depressive disorders. Patients presenting with noncardiac chest pain should be screened for psychopathology and if positive, CBT should be considered. PMID- 23625593 TI - Prognostic comparison of the proliferation markers (mitotic activity index, phosphohistone H3, Ki67), steroid receptors, HER2, high molecular weight cytokeratins and classical prognostic factors in T1-2N0M0 breast cancer. AB - The proliferation factors: mitotic activity index (MAI), phosphohistone H3 (PPH3) and Ki67 have strong prognostic value in early breast cancer but their independent value to each other and other prognostic factors has not been evaluated. In 237 T1-2N0M0 breast cancers without systemic adjuvant treatment, formalized MAI assessment and strictly standardized, fully automated quantitative immunohistochemistry (IHC) for Ki67, PPH3, estrogen (ER) and progesterone receptor (PR), HER2, cytokeratins-5/6 and -14, and automated digital image analysis (DIA) for measuring PPH3 and Ki67 were performed. Section thickness was measured to further control IHC measurements. All features were measured in the periphery of tumors. The different proliferation assessments and other well established clinicopathological and biomarker prognostic factors were compared. DIA-Ki67 added prognostically to PPH3. None of the other biomarkers or clinicopathological variables added prognostically to this PPH3/Ki67 combination. However, when PPH3 is replaced by MAI the prognostic value is nearly the same. In early operable node negative breast cancer without adjuvant systemic treatment, Ki67 with a threshold of 6.5% assessed by digital image analysis in the periphery of the tumor is prognostically strong. The combination of either PPH3/Ki67 or MAI/Ki67 overshadowed the prognostic value of all other features including Ki67 alone. PMID- 23625594 TI - Active transport of RB protein from the nucleus to the cytoplasm as one of the development mechanisms of HER2-positive breast cancer. AB - HER2-positive breast cancer (HER2+) occurs in approximately 15-20% of all breast cancers. Biologically this cancer subtype is characterized by an aggressive clinical course (often spread to regional lymph nodes at the time of diagnosis), and after successful treatment high risk of recurrence. Deregulation of the cell cycle is the basis for cancer aggressiveness. The RB protein is one of the key regulators of the cell cycle. There are only a few published studies on the expression and localization of RB protein in the cells of HER2-positive breast cancer. The aim of this study was to determine whether there are differences in the expression and localization of RB protein in HER2-positive breast cancers compared to breast cancers showing no expression of HER2. We used 50 tissue samples from HER2 positive breast cancer and 21 tissue samples derived from patients with HER2 negative breast cancer. The RB protein expression was measured by immunohistochemical techniques in tissue microarray format. Cytoplasmic RB expression was observed in 29 out of 50 (58%) HER2 positive breast cancers. In this group only cytoplasmic expression was observed. There was no case with nuclear expression. In contrast, in the HER2-negative breast cancer control group, in no case RB expression was observed in the cytoplasm (0/21, 0%). All 21 samples (100%) showed expression of RB protein in the nucleus (p < 0.0001). We can speculate that lack of expression suggests alternative mechanisms in the development of HER2 positive breast cancer. We hypothesize that HER2 overexpression is in some way associated with active transport of RB protein from the nucleus to the cytoplasm. This may be an indirect mechanism of inactivation of tumor suppressor protein in breast cancer exhibiting overexpression of HER2. PMID- 23625595 TI - PTEN expression profiles in colorectal adenocarcinoma and its precancerous lesions. AB - The aim of the study was to determine expression of the PTEN suppressor gene in colorectal adenocarcinoma and its precancerous lesions (adenomatous polyps) in correlation with common clinical and histopathological features. Forty-four patients with adenomatous polyps and 32 with primary adenocarcinoma of the colon or rectum were enrolled in the study. They underwent endoscopic removal of polyps or major surgery and postoperative adjuvant chemo- and radiotherapy depending on staging of the disease. No patient had received chemotherapy and/or radiotherapy before the surgery. PTEN expression was evaluated using immunohistochemical staining on paraffin-embedded specimens and compared to clinicopathological features of tumors. In colorectal cancers, PTEN expression was found to be significantly lower than in normal intestinal mucosa and adenomatous polyps. That was associated with complete loss of PTEN expression observed more frequently in colorectal cancer, contrary to reduction of PTEN expression occurring mostly in polyps. A correlation between polyp diameter and loss of PTEN was demonstrated as well as between tumor size and TNM advanced stage and PTEN expression. The obtained results suggest that the PTEN/PI3K/Akt pathway may play an important role in early stages of sporadic colorectal carcinogenesis and reduced PTEN expression in late oncogenesis is associated with some adverse clinical and pathological features. PMID- 23625596 TI - A cocktail of MCM2 and TOP2A, p16INK4a and Ki-67 as biomarkers for the improved diagnosis of cervical intraepithelial lesion. AB - The purpose of this paper was to explore the immunohistochemistry (IHC) results for a cocktail of minichromosome maintenance protein 2 (MCM2) and topoisomerase II? (TOP2A), p16INK4a and Ki-67 as biomarkers for the diagnosis of cervical intraepithelial neoplasia (CIN), improving the routine interpretation of cervical histopathology. 133 cases of CIN were collected from the archival data. All routine hematoxylin and eosin (HE)-stained slides of the subjects were re examined independently by three senior pathologists, to provide a "consensus diagnosis". Immunohistochemistry for the three biomarkers was performed, and the results were reviewed independently of the corresponding archival diagnosis to make a "diagnosis assisted by IHC" by the original pathological practitioners. The diagnosis accordance rate of the archival original diagnosis with the "consensus diagnosis" and the "diagnosis assisted by IHC" with the "consensus diagnosis" were verified by Fisher's exact test. The results showed that raw agreement between the original HE diagnosis and the "consensus diagnosis" was 88.55%, and raw agreement between the "diagnosis assisted by IHC" and the "consensus diagnosis" was 95.78%. The latter was significantly higher than the former (Fisher's exact test, p = 0.023). In conclusion, the three biomarkers had a high degree of sensitivity and specificity, and appear to be a useful and reliable diagnostic adjunct to improve the routine diagnosis, and reduce inter observer variability in cervical biopsy specimens. PMID- 23625597 TI - Expression of AEG-1 and p53 and their clinicopathological significance in malignant lesions of renal cell carcinomas: a microarray study. AB - The aim of this study was to investigate the relationship of AEG-1 and p53 with the prognostic parameters of renal cell carcinoma (RCC). In this study, 50 paraffin blocks were histopathologically diagnosed at the Department of Pathology of the Medical Hospital of Duzce University, between 2005 and 2011. The cases consisted of 24 clear cell (CC) and 26 non-clear cell (NCC) RCC subtypes as follows: 24 (48%) clear cell RCC, 12 (24%) papillary RCC, 4 (8%) multilocular cystic RCC and 10 (20%) chromophobe RCC; none had sarcomatoid changes. By immunohistochemical analysis we investigated AEG-1 and p53 expression in carcinomas of the kidney, and by statistical analysis determined their relationship with clinicopathological parameters. Significant relationships were found between increasing tumor diameter and the increase of p53 (p = 0.028). In addition, p53 was significantly related to renal sinus invasion (p = 0.05) and Fuhrman grade (p = 0.026). There was a significant relationship between increased AEG-1 staining scores and CC and NCC carcinoma subtypes (p = 0.032), tumor capsule invasion (p = 0.01) and lymphovascular invasion (p = 0.015). There was also a significant correlation between tumor size and capsule and lymphovascular invasion (p = 0.02). We concluded that high AEG-1 and p53 expression correlates with the prognostic parameters in RCC patients, and in addition may be associated with tumor progression. PMID- 23625598 TI - Microvessel density and expression of vascular endothelial growth factor in clinically localized prostate cancer. AB - Identifying biological differences between benign lesions and malignant prostatic cancer (PC) may facilitate precise indication for more aggressive post-operative treatment. Therefore, we examined immunohistochemically histological specimens from 140 PC patients treated with radical surgery. The mean age of the patients was 62.9 +/-6.2 (range 49.0-77.0) years. There were 13 (9.3%) at pTNM stage 1, 78 (55.7%) at stage 2, 40 (28.6%) at stage 3 and 9 (6.4%) at stage 4. In the analysed group there were 75 (53.6%) well-differentiated, 53 (37.8 %) moderately differentiated and 12 (8.6%) poorly differentiated tumours. The mean pre operative prostate-specific antigen (PSA) level was 9.9 +/-0.5 ng/ml. Concentration of serum PSA was significantly increased with pTNM stage (p = 0.011), Gleason score (p = 0.011) and tumour grade (p = 0.003). In 34 (24.3%) tumours vascular endothelial growth factor (VEGF) expression was not shown. In the analysed group of tumours the mean percentage of positive VEGF cells was 14.8 +/-1.4% and was not correlated with tumour grade (p = 0.648) or Gleason score (p = 0.697). However, significantly higher values for the protein were observed in pTNM 3 (p = 0.035) and pTNM 4 (P = 0.037) than in pTNM stage 1. In the whole series of tumours the mean microvessel density (MVD) was 97.5 +/-2.4 /mm2. A non significant decrease in the number of microvessels was observed in the highest pathological tumour volume (P = 0.631), Gleason score (p = 0.368) and tumour grade (p = 0.233). Prostate-specific antigen level was not associated statistically with either MVD (p = 0.466) or VEGF expression (p = 0.188). There was also no correlation between the immunohistochemical expression of VEGF and MVD (p = 0.925). PMID- 23625599 TI - RAD51 genotype and triple-negative breast cancer (TNBC) risk in Polish women. AB - The most lethal damage for the cell among all damage is double-strand breaks (DSB) of DNA. DSB cause development of cancer diseases including the triple negative molecular subtype of breast cancer. The aim of this work was to evaluate the single nucleotide polymorphism -135G>C (rs1801320) of the RAD51 gene encoding DNA repair proteins by homologous recombination (HR) in triple-negative breast cancer (TNBC). We assessed the RAD51 -135G>C polymorphism in 50 women with triple negative breast cancer and in 50 women from the control group. RAD51 polymorphism was analysed by the PCR-RFLP (restriction fragment length polymorphism) technique. Our results demonstrated a significant positive association between the RAD51 C/C genotype and TNBC, with an adjusted odds ratio (OR) of 5.95 (p = 0.002). The homozygous C/C genotype was found in 68% of breast cancer cases and 20% of controls. The variant 135C allele of RAD51 increased TNBC risk. This is the first study linking single nucleotide polymorphisms of the RAD51 gene with TNBC incidence in the population of Polish women. In conclusion, RAD51 polymorphisms may be regarded as predictive factors of triple-negative breast cancer in the female population. Large studies are needed to confirm our findings. PMID- 23625600 TI - Clinicopathological significance of DNA fragmentation factor 45 and thyroid transcription factor 1 expression in benign and malignant lesions of the gallbladder. AB - Gallbladder cancer (GBC) is one of the most aggressive tumors; we examined the expression level of DNA fragmentation factor 45 (DFF45) and thyroid transcription factor 1 (TTF-1) in benign and malignant lesions of the gallbladder by immunohistochemistry. The results were correlated with clinicopathological features and prognosis. DNA fragmentation factor 45 and TTF-1 expression was significantly higher in gallbladder adenocarcinomas than in the corresponding peritumoral tissues (chi2DFF45 = 6.92, chi2TTF-1 = 8.68, ps < 0.01), polyps (chi2DFF45 = 4.49, chi2TTF-1 = 5.35, ps < 0.05), and chronic cholecystitis (chi2DFF45 = 12.98, chi2TTF-1 = 17.74, ps < 0.01). Negative expression of DFF45 and TTF-1 was significantly associated with tumor differentiation, tumor mass, lymph node metastasis and invasion of adenocarcinomas (p < 0.05). Univariate Kaplan-Meier analysis showed that elevated expression levels of DFF45 and TTF-1 (p < 0.05) were closely associated with increased overall survival. In addition, the average survival time of patients with DFF45(+) TTF-1(+) tumors was significantly higher than those with DFF45(-) TTF-1(-) tumors (p < 0.05). Finally, multivariate Cox regression analysis showed that negative expression of DFF45 and TTF-1 was an independent prognostic predictor in gallbladder adenocarcinoma (p < 0.05). The expression of DFF45 and/or TTF-1 is closely related to the carcinogenesis, progression, clinical behavior and prognosis of gallbladder adenocarcinomas. DNA fragmentation factor 45 and TTF-1 could be progression-associated genes correlating with good prognosis in GBC. PMID- 23625601 TI - Pure tocotrienol concentrate protected rat gastric mucosa from acute stress induced injury by a non-antioxidant mechanism. AB - Stress has been implicated as a risk factor of various major health problems, such as stress-induced gastric mucosal injury. This study was performed to investigate the action of a pure preparation of tocotrienol (T3) concentrate, made up of 90% delta-tocotrienol and 10% gamma-tocotrienol, on gastric injury of rats induced by water-immersion restraint stress (WIRS). Fourteen male Sprague Dawley rats (200-250 g) were divided into two equal groups: a control group and a treated group. The treatment group received T3 concentrate at 60 mg/kg body weight daily for 28 days. The body weights of rats were recorded daily before the treatment was given. At the end of the treatment period, all rats were subjected to WIRS for 3.5 hours, following which the rats were euthanized. The stomachs were isolated and opened along the greater curvature for the examination of lesions and measurements of gastric malondialdehyde (MDA) and prostaglandin E2 (PGE2) contents. The mean gastric mucosal lesion index in the treated rats was significantly lower than that in the control rats. This suggests that the T3 concentrate has the ability to confer protection to the gastric mucosa against gastric injury induced by acute stress. No significant difference was observed for changes in body weight before and after the treatment. The gastric PGE2 content in both groups was comparable. However, the gastric MDA content was significantly higher in the treated group compared to the control group, indicating that the T3 supplementation was not able to reduce the lipid peroxidation process. This study concludes that the T3 concentrate has the ability to protect the gastric mucosa from stress-induced injury by a non antioxidant mechanism. PMID- 23625602 TI - Primary leiomyosarcoma of the mesentery in two sisters: clinical and molecular characteristics. AB - Mesenteric leiomyosarcoma (LMS) is a very rare malignancy whose familiar occurrence has not yet been reported. We present two sisters who developed intestinal LMS. Pathological analysis of the tumor samples, including evaluation of smooth muscle actin+, desmin+, Myf4-, DOG-1-, S100-, CD34- and CD117- confirmed LMS diagnosis. Molecular analysis of the lesions, both primary tumors and a liver metastasis, revealed several genomic imbalances, with recurrent chromosomal aberration: interstitial gain at chromosome 17p11.2-13.1 with the minimal overlapping region of 9.2 Mb. Our study provides further evidence for the significant role of the genes located in this region in the early stage of carcinogenesis. PMID- 23625603 TI - Malignant transformation in the course of a dentigerous cyst: a problem for a clinician and a pathologist. Considerations based on a case report. AB - Primary intraosseous squamous cell carcinoma (PIOSCC) is a rarely reported neoplasm resulting from malignant transformation of a dentigerous cyst of the mandible or maxilla. Until 2010, only 116 cases had been described. The diagnosis of PIOSCC is difficult because of non-specific symptoms. A case of a 66-year-old patient with PIOSCC arising from a dentigerous cyst of the mandible is presented. Both pathologists and clinicians should be aware of the probability of malignant transformation of dentigerous cysts during the two-stage treatment. The patient should be subject to regular clinical and radiographic examination. PMID- 23625604 TI - MDM2 SNP309 and risk of endometrial cancer. PMID- 23625605 TI - Letter to the editor reply. PMID- 23625606 TI - Canalicular adenoma of the upper lip. Metachronous (multifocal) canalicular adenoma of the upper lip: a case report of an unusual finding. AB - We report a peculiar case of canalicular adenoma of the upper lip in a 57-year old woman, presenting as two distinct asymptomatic nodules diagnosed and treated surgically within a 2-year period. PMID- 23625607 TI - Activity enhancement of Candida antarctica lipase B by flexibility modulation in helix region surrounding the active site. AB - The activity of Candida antarctica lipase B was improved by mutation of the area surrounding the active site. We changed the edges of four helices surrounding the active site to flexible amino acids. Two mutants, V139E and I255E, obtained as a result of Pichia pastoris expression, showed enhanced specific activity of 9.9 and 8.1 U/mg while that of wild type was 2.3 U/mg for p-nitrophenyl caprylate hydrolysis. It was nearly 5.4-fold and 3.5-fold, respectively. The stability of both mutants on organic solvent was slightly decreased but almost similar with that of wild type. In the kinetic assay, k(cat) values were shown as dominant factor for the enhancement of catalytic efficiency, k(cat)/K(m), since it was 4.1 fold and 3.8-fold, respectively. PMID- 23625608 TI - Zingipain, a ginger protease with acetylcholinesterase inhibitory activity. AB - In order to search for new acetylcholinesterase inhibitors (AChEIs), 15 Zingiberaceae plants were tested for AChEI activity in rhizome extracts. The crude homogenate and ammonium sulfate cut fraction of Zingiber officinale contained a significant AChEI activity. Eighty percent saturation ammonium sulfate precipitation and diethylaminoethyl cellulose ion exchange chromatography (unbound fraction) enriched the protein to a single band on nondenaturing and reducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (approximately 33.5 kDa). Gelatin-degrading zymography showed that the AChEI-containing band also contained cysteine protease activity. The AChEI activity was largely stable between -20 and 60 degrees C (at least over 120 min) and over a broad pH range (2-12). The AChEI activity was stimulated strongly by Mn(2+) and Cu(2+) at 1-10 mM and weakly by Ca(2+), Fe(2+), Mg(2+), and Zn(2+) at 1 mM, but was inhibited at 10 mM. In contrast, Hg(2+) and ethylenediaminetetraacetic acid were very and moderately strongly inhibitory, respectively. In-gel tryptic digestion with liquid chromatography-tandem mass spectroscopy resolution revealed two heterogeneous peptides, a 16-amino-acid-long fragment with 100 % similarity to zingipain-1, which is a cysteine protease from Z. officinale, and a 9-amino-acid long fragment that was 100 % identical to actinidin Act 2a, suggesting that the preparation was heterogeneous. AChEI exhibited noncompetitive inhibition of AChE for the hydrolysis of acetylthiocholine iodide with a K(i) value of 9.31 mg/ml. PMID- 23625610 TI - All that glitters is not gold: differential diagnosis of clover-leaf lymphocytes. PMID- 23625609 TI - Genotypic and phenotypic features of Japanese patients with mild to moderate hemophilia A. AB - Hemophilia A is the most common inherited bleeding disorder. To better understand the genotypic and phenotypic features of Japanese patients with mild to moderate hemophilia A, we studied 29 unrelated patients with more than 1 % FVIII activity (FVIII:C). Differences were observed in nine of 21 patients in measured FVIII:C levels between the one-stage clotting and chromogenic assays. We identified a mutation in F8 in 28 of the 29 patients. Mutations in two amino acids, Y492 and R550, were detected at a much higher frequency in our patients than in the international hemophilia A mutation database. We demonstrated that all five patients with the Y492C mutation have an identical F8 haplotype that is unique to them, suggesting that the mutation may have originated from a common ancestor. Because non-severe, moderate to mild, hemophilia patients have a longer lifespan, mutations that cause non-severe phenotypes tend to persist in the population. We believe that the Y492C mutation is a distinctive feature of Japanese patients with mild hemophilia A. The identification of a high frequency of R550 mutation that underlies the discrepancies in FVIII:C measurements in the present study suggests that Japanese patients with mild hemophilia may require careful characterization. PMID- 23625611 TI - Voluntary rate of torque development is impaired after a voluntary versus tetanic conditioning contraction. AB - INTRODUCTION: Both voluntary and evoked conditioning contractions will potentiate muscle twitch contractile properties. The response of a voluntary contraction to each condition type is not well understood but it may be a more functional model than evoked twitch potentiation. METHODS: Baseline measurements from tibialis anterior included: maximal isometric twitch torque and rate of torque development (RTD); maximal evoked 50-Hz torque; and maximal voluntary ballistic RTD. Potentiation was induced by a 10-s voluntary or tetanic contraction (?78% MVC), followed by 2 twitches and 2 ballistic contractions. RESULTS: Twitch properties (torque and RTD) were potentiated equally after each conditioning contraction. Ballistic RTD was greater post-tetanus (390.2 +/- 59.3 Nm/s) than post-voluntary (356.4 +/- 69.1 Nm/s), but both were reduced from baseline (422.0 +/- 88.9 Nm/s). CONCLUSIONS: Twitch potentiation was similar between conditioning contraction types, but ballistic RTD was lower after post-tetanus than post-voluntary. The results indicate central inhibition or fatigue concurrent with peripheral potentiation. PMID- 23625612 TI - Long-term outcome of centrally located low-grade glioma in children. AB - BACKGROUND: Optimal management of children with centrally located low-grade glioma (LGG) is unclear. Initial interventions in most children are chemotherapy in younger and radiation therapy (RT) in older children. A better understanding of the inherent risk factors along with the effects of interventions on long-term outcome can lead to reassessment of the current approaches to minimize long-term morbidity. METHODS: To reassess the current treatment strategies of centrally located LGG, we compared the long-term survival and morbidity of different treatment regimens. Medical records of patients primarily treated at Texas Children's Cancer and Hematology Centers between 1987 and 2008 were reviewed. RESULTS: Forty-seven patients with a median follow-up of 79 months were included in the analysis. The 5-year overall survival and progression-free survival (PFS) for all patients were 96% and 53%, respectively. The 5-year PFS for those treated initially with RT (12 patients; median age, 11 years [range, 3-15 years]) and with chemotherapy (28 patients; median age, 2 years [range 0-8 years]) were 76% and 37%, respectively (log-rank test P = .02). Among children who progressed after chemotherapy, the 5-year PFS after salvage RT was 55%. Patients diagnosed at a younger age (<5 years) were more likely to experience endocrine abnormalities (Fisher exact test; P<.00001). CONCLUSIONS: Effective and durable tumor control was obtained with RT as initial treatment. In younger patients, chemotherapy can delay the use of RT; however, frequent progression and long-term morbidity are common. More effective and less toxic therapies are required in these patients, the majority of whom are long-term survivors. PMID- 23625613 TI - Prostate cancer genomics by high-throughput technologies: genome-wide association study and sequencing analysis. AB - Prostate cancer (PC) is the most common malignancy in males. It is evident that genetic factors at both germline and somatic levels play critical roles in prostate carcinogenesis. Recently, genome-wide association studies (GWAS) by high throughput genotyping technology have identified more than 70 germline variants of various genes or chromosome loci that are significantly associated with PC susceptibility. They include multiple 8q24 loci, prostate-specific genes, and metabolism-related genes. Somatic alterations in PC genomes have been explored by high-throughput sequencing technologies such as whole-genome sequencing and RNA sequencing, which have identified a variety of androgen-responsive events and fusion transcripts represented by E26 transformation-specific (ETS) gene fusions. Recent innovations in high-throughput genomic technologies have enabled us to analyze PC genomics more comprehensively, more precisely, and on a larger scale in multiple ethnic groups to increase our understanding of PC genomics and biology in germline and somatic studies, which can ultimately lead to personalized medicine for PC diagnosis, prevention, and therapy. However, these data indicate that the PC genome is more complex and heterogeneous than we expected from GWAS and sequencing analyses. PMID- 23625615 TI - Is impaired emmetropization related to foveal hypoplasia or is it specific to albinism? PMID- 23625616 TI - Snoring intensity after a first session of soft palate radiofrequency: predictive value of the final result. AB - OBJECTIVES/HYPOTHESIS: To determine whether snoring sound intensity measured after a first soft palate radiofrequency (RF) session for simple snoring helps predict the final result of the treatment. STUDY DESIGN: Observational retrospective study. METHODS: We conducted a retrospective review of 105 subjects presenting with simple snoring or mild sleep apnea. All patients underwent two to three sessions of RF-assisted stiffening of the soft palate. In addition, uvulectomy was performed in case of a long uvula, and two paramedian trenches were created in the presence of palatal webbing. Snoring sound intensity was evaluated by the bed partner after each session. RESULTS: Eighty-six men and 19 women were included in the study. Mean age was 51.7 +/- 9.8 years, and mean body mass index was 24.7 +/- 4.4 kg/m(2) . The mean apnea/hypopnea index was 6.6 +/- 4.2/h. The mean snoring sound intensity, as evaluated on a 10-cm visual analog scale (VAS), decreased from 8.2 +/- 1.5 to 3.5 +/- 2.2 after all sessions (P < .0001). A score of 3 was determined as being a score that satisfied the bed partner. Two groups were formed according to the final snoring sound intensity, using 3 as a threshold. Both groups had similar preoperative characteristics, but the snoring sound intensity was significantly lower after the first session in the group with final score <3 (P = .01). Similarly, a VAS score >7 after the first session was associated with a final score <3 in 30% of the cases. CONCLUSIONS: Snoring sound intensity after the first RF session helps predict the final outcome of RF-assisted stiffening of the soft palate for simple snoring. PMID- 23625614 TI - Aromatase inhibition 2013: clinical state of the art and questions that remain to be solved. AB - Following their successful implementation for the treatment of metastatic breast cancer, the 'third-generation' aromatase inhibitors (anastrozole, letrozole, and exemestane) have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancers. These drugs are characterized by potent aromatase inhibition, causing >98% inhibition of estrogen synthesis in vivo. A recent meta-analysis found no difference in anti-tumor efficacy between these three compounds. As of today, aromatase inhibitor monotherapy and sequential treatment using tamoxifen followed by an aromatase inhibitor for a total of 5 years are considered equipotent treatment options. However, current trials are addressing the potential benefit of extending treatment duration beyond 5 years. Regarding side effects, aromatase inhibitors are not found associated with enhanced risk of cardiovascular disease, and enhanced bone loss is prevented by adding bisphosphonates in concert for those at danger of developing osteoporosis. However, arthralgia and carpal tunnel syndrome preclude drug administration among a few patients. While recent findings have questioned the use of aromatase inhibitors among overweight and, in particular, obese patients, this problem seems to focus on premenopausal patients treated with an aromatase inhibitor and an LH-RH analog in concert, questioning the efficacy of LH-RH analogs rather than aromatase inhibitors among overweight patients. Finally, recent findings revealing a benefit from adding the mTOR inhibitor everolimus to endocrine treatment indicate targeted therapy against defined growth factor pathways to be a way forward, by reversing acquired resistance to endocrine therapy. PMID- 23625617 TI - Safety and feasibility of high-dose administration of nicorandil before reperfusion therapy in acute myocardial infarction. AB - The efficacy and safety of high-dose nicorandil therapy in acute myocardial infarction (AMI) have not yet been clarified. This is a prospective study including 30 patients who received nicorandil at 0.06 mg/kg/h [standard dose nicorandil (SDN) group] and 32 patients who received a bolus injection of nicorandil 0.2 mg/kg followed by a continuous infusion at 0.2 mg/kg/h [high-dose nicorandil (HDN) group]. The benefits and adverse events were assessed during acute phase and 12-month follow-up period. There were no significant differences between the groups in blood pressure, heart rate or urine volume 2, 6 and 24 h after drug administration, although blood pressure decreased during acute phase. The percentages of patients who required dose reduction or discontinuation of nicorandil were 34.4 and 16.7 % in HDN and SDN groups, respectively (p = 0.11). In HDN group, subgroup analysis revealed that the TIMI frame count (TFC) was significantly lower in patients in whom the treatment was started within 12 h compared to those more than 12 h (17.0 vs. 21.0, p = 0.017) and in patients with baseline WBC elevation compared to those without it (16.5 vs. 22.0, p = 0.029). A TFC of >20 was significantly associated with being in HDN group [odds ratio (OR) 0.27; 95 % confidence interval, CI 0.07-0.89], onset-to-balloon time (OR 1.06; 95 % CI 1.01-1.16), and ?creatine kinase (OR 7.27; 95 % CI 1.40-57.83). There were no significant differences in incidences of cardiovascular death, rehospitalization, and target lesion revascularization between the groups. HDN therapy may improve coronary microcirculation in patients with AMI. PMID- 23625619 TI - An outline of the history of family nursing in Japan and the Japanese Association for Research in Family Nursing (JARFN). PMID- 23625620 TI - History lesson: how a little girl and her family moved mountains to change care and policy to help children with special health care needs go home. PMID- 23625623 TI - Impact of diet and exercise training-induced weight loss on myocardial mechanics in severely obese adolescents. AB - OBJECTIVE: Recent findings indicated silent incipient myocardial dysfunction in juvenile obesity despite normal global cardiac function. The present study investigated whether lifestyle intervention is able to favorably impact these obesity-related myocardial abnormalities and whether improvements are related to changes in insulin resistance and cardiac remodeling. DESIGN AND METHODS: Twenty eight severe obese adolescents (OB) participated in a 9 month lifestyle intervention program (LIP) based on aerobic exercise and diet. Twenty healthy adolescents (CG) served as controls. Conventional echocardiography and myocardial mechanics were obtained at baseline and follow-up along with insulin resistance. RESULTS: Insulin sensitivity improved (P < 0.001) and body weight decreased (P < 0.001) consecutive to LIP. At baseline, OB had depressed longitudinal (L) strain (CG: -18.3 +/- 2.6, OB: -14.2 +/- 3.6%, P < 0.001) and enhanced twist compared to controls. The LIP in OB restored L strain to normal values (-16.9 +/- 3.5%, NS), whereas it did not affect twist mechanics. From stepwise multiple regression analysis, only baseline L strain and changes in BMI Z-score (r(2) -adjusted = 0.49, P < 0.001) emerged as independent predictors of L strain changes. CONCLUSIONS: Juvenile obesity is associated with myocardial mechanic abnormalities that can be partly corrected by lifestyle intervention. Restoration of longitudinal myocardial function occurs in the absence of left ventricular remodeling changes and is not associated with insulin resistance improvements. PMID- 23625624 TI - Effects of the insecticide fipronil on reproductive endocrinology in the fathead minnow. AB - Gamma-aminobutyric acid (GABA) and GABA receptors play an important role in neuroendocrine regulation in fish. Disruption of the GABAergic system by environmental contaminants could interfere with normal regulation of the hypothalamic-pituitary-gonadal axis, leading to impaired fish reproduction. The present study used a 21-d fathead minnow (Pimephales promelas) reproduction assay to investigate the reproductive toxicity of fipronil (FIP), a broad-spectrum phenylpyrazole insecticide that acts as a noncompetitive blocker of GABA receptor gated chloride channels. Continuous exposure up to 5 ug FIP/L had no significant effect on most of the endpoints measured, including fecundity, secondary sexual characteristics, plasma steroid and vitellogenin concentrations, ex vivo steroid production, and targeted gene expression in gonads or brain. The gonad mass, gonadosomatic index, and histological stage of the gonad were all significantly different in females exposed to 0.5 ug FIP/L compared with those exposed to 5.0 ug FIP/L; however, there were no other significant effects on these measurements in the controls or any of the other treatments in either males and females. Overall, the results do not support a hypothesized adverse outcome pathway linking FIP antagonism of the GABA receptor(s) to reproductive impairment in fish. PMID- 23625625 TI - Use of new scientific developments in regulatory risk assessments: challenges and opportunities. AB - Since the 1990s, science based ecological risk assessments constitute an essential tool for supporting decision making in the regulatory context. Using the European REACH Regulation as example, this article presents the challenges and opportunities for new scientific developments within the area of chemical control and environmental protection. These challenges can be sorted out in 3 main related topics (sets). In the short term, the challenges are directly associated with the regulatory requirements, required for facilitating a scientifically sound implementation of the different obligations for industry and authorities. It is important to mention that although the actual tools are different due to the regulatory requirements, the basic needs are still the same as those addressed in the early 1990s: understanding the ecological relevance of the predicted effects, including the uncertainty, and facilitating the link with the socio-economic assessment. The second set of challenges covers the opportunities for getting an added value from the regulatory efforts. The information compiled through REACH registration and notification processes is analyzed as source for new integrative developments for assessing the combined chemical risk at the regional level. Finally, the article discusses the challenge of inverting the process and developing risk assessment methods focusing on the receptor, the individual or ecosystem, instead of on the stressor or source. These approaches were limited in the past due to the lack of information, but the identification and dissemination of standard information, including uses, manufacturing sites, physical-chemical, environmental, ecotoxicological, and toxicological properties as well as operational conditions and risk management measures for thousands of chemicals, combined by the knowledge gathered through large scale monitoring programs and spatial information systems is generating new opportunities. The challenge is liking predictions and measured data in an integral "-omic type" approach, considering collectively data from different sources and offering a complete assessment of the chemical risk of individuals and ecosystems, with new conceptual approaches that could be defined as "risk omics based" paradigms and models. PMID- 23625626 TI - Survival of pediatric patients after relapsed osteosarcoma: the St. Jude Children's Research Hospital experience. AB - BACKGROUND: Chemotherapy has improved the outcome of patients with newly diagnosed osteosarcoma, but its role in relapsed disease is unclear. METHODS: We reviewed the records of all patients who were treated for relapsed high-grade osteosarcoma at our institution between 1970 and 2004. Postrelapse event-free survival (PREFS) and postrelapse survival (PRS) were estimated, and outcome comparisons were made using an exact log-rank test. RESULTS: The 10-year PREFS and PRS of the 110 patients were 11.8% +/- 3.5% and 17.0% +/- 4.3%, respectively. Metastasis at initial diagnosis (14%), and relapse in lung only (75%) were not significantly associated with PREFS or PRS. Time from initial diagnosis to first relapse (RL1) >=18 months (43%), surgery at RL1 (76%), and ability to achieve second complete remission (CR2, 56%) were favorably associated with PREFS and PRS (P <= 0.0002). In patients without CR2, chemotherapy at RL1 was favorably associated with PREFS (P = 0.01) but not with PRS. In patients with lung relapse only, unilateral relapse and number of nodules ( <= 3) were associated with better PREFS and PRS (P <= 0.0005); no patients with bilateral relapse survived 10 years. The median PREFS after treatment with cisplatin, doxorubicin, methotrexate, and ifosfamide was 3.5 months (95% confidence interval, 2.1-5.2), and the median PRS was 8.2 months (95% confidence interval, 5.2-15.1). CONCLUSIONS: Late relapse, surgical resection, and unilateral involvement (in lung relapse only) favorably impact outcome after relapse. Surgery is essential for survival; chemotherapy may slow disease progression in patients without CR2. These data are useful for designing clinical trials that evaluate novel agents. PMID- 23625627 TI - Forkhead box protein A1 inhibits the expression of uncoupling protein 2 in hydrogen peroxide-induced A549 cell line. AB - Forkhead box protein A1 (FoxA1) is a transcription factor that is involved in embryonic development and cell differentiation. In this study, we show that hydrogen peroxide (H2O2) treatment upregulated expression of FoxA1 and UCP2 in the A549 cell line. Overexpression of FoxA1 by full-length complementary DNA reduced UCP2 expression, while silencing of FoxA1 expression by small interfering RNA significantly increased UCP2 levels. FoxA1 binds to a site from -919 to -913 bp relative to the UCP2 transcription start site. The overexpression of FoxA1 promoted the DNA binding activity and attenuated the transcription of UCP2 promoter as shown by electromobility shift, chromatin immunoprecipitation assays, and luciferase reporter assay. These data indicate an important role of FoxA1 in regulating expression of UCP2. PMID- 23625628 TI - Is outpatient cognitive remediation therapy feasible to use in randomized clinical trials for anorexia nervosa? AB - OBJECTIVE: There are limited data supporting specific treatments for adults with anorexia nervosa (AN). Randomized clinical trials (RCTs) for adults with AN are characterized by high attrition limiting the feasibility of conducting and interpreting existing studies. High dropout rates may be related to the inflexible and obsessional cognitive style of patients with AN. This study evaluated the feasibility of using cognitive remediation therapy (CRT) to reduce attrition in RCTs for AN. METHOD: Forty-six participants (mean age of 22.7 years and mean duration of AN of 6.4 years) were randomized to receive eight sessions of either CRT or cognitive behavioral therapy (CBT) over 2 months followed by 16 sessions of CBT for 4 months. RESULTS: During the 2-month CRT vs. CBT treatment, rates of attrition were lower in CRT (13%) compared with that of CBT (33%). There were greater improvements in cognitive inefficiencies in the CRT compared with that of the CBT group at the end of 2 months. There were no differences in other outcomes. DISCUSSION: These results suggest that CRT is acceptable and feasible for use in RCTs for outpatient treatment of AN. CRT may reduce attrition in the short term. Adequately powered future studies are needed to examine CRT as an outpatient treatment for AN. PMID- 23625629 TI - Efficient optimization of ultra-high- performance supercritical fluid chromatographic separation of Rosa sericea by response surface methodology. AB - An approach for rapid optimization of ultra-high-performance supercritical fluid chromatographic (UHPSFC) gradient by response surface methodology was developed for fast separation of complex crude extracts of the leaves of Rosa sericea. The optimization was performed with Box-Behnken designs and the multicriteria response variables were described using Derringer's desirability. Based on factorial design experiments, five factors were selected for Box-Behnken designs to optimize the UHPSFC conditions, which led to 46 experiments being performed within 8 h. An evaporative light-scattering detector (ELSD) was used, and quantitative analysis of main components in R. sericea samples was employed to evaluate the statistical significance of the parameters on UHPSFC-ELSD analytes response. The results indicated that the optimized UHPSFC-ELSD method is very sensitive with LODs and LOQs below 1.19 and 4.55 MUg/mL, respectively. The overall intra- and interday variations were less than 3.91 and 6.41%, respectively. The recovery of the method ranged from 95.66 to 104.22%, with RSD < 5.91%. This newly developed UHPSFC-ELSD method was demonstrated to be fast and sensitive in analyzing complex herbal extracts of Traditional Chinese Medicines. PMID- 23625630 TI - [Endocrine abnormalities in a young patient with metastatic cancer - case 3/2013]. AB - HISTORY AND ADMISSION FINDINGS: We report on a 24-year-old male patient who presented with worsening of the general condition and abdominal pain. INVESTIGATIONS: On physical examination, gynecomastia was noted. Laboratory tests showed manifest hyperthyroidism. The beta-hCG levels were markedly increased. By ultrasound, the thyroid gland was hyperperfused without thyroid nodules. Several large echo mixed lesions were found in the liver. The testes appeared normal. DIAGNOSIS: In light of the typical laboratory findings, a non-seminomatous extragonadal germ cell tumor was diagnosed. Hyperthyroidism was most probably HCG induced. TREATMENT AND COURSE: Initially the patient was treated with thyreostatic drugs. After initiation of chemotherapy and a marked decrease in beta-hCG, thyreostatic therapy could be terminated. CONCLUSIONS: Germ cell tumors may cause an increase in beta-hCG concentration. By cross-reacting with the TSH receptor this could induce hyperthyroidism. Germ cell tumors are therefore a rare differential diagnosis of hyperthyreoidism. PMID- 23625631 TI - Surgical and postpartum hereditary brachial plexus attacks and prophylactic immunotherapy. PMID- 23625633 TI - A Bayesian non-inferiority test for two independent binomial proportions. AB - In drug development, non-inferiority tests are often employed to determine the difference between two independent binomial proportions. Many test statistics for non-inferiority are based on the frequentist framework. However, research on non inferiority in the Bayesian framework is limited. In this paper, we suggest a new Bayesian index tau = P(pi1 > pi2-Delta0|X1, X2), where X1 and X2 denote binomial random variables for trials n1 and n2, and parameters pi1 and pi2 , respectively, and the non-inferiority margin is Delta0> 0. We show two calculation methods for tau, an approximate method that uses normal approximation and an exact method that uses an exact posterior PDF. We compare the approximate probability with the exact probability for tau. Finally, we present the results of actual clinical trials to show the utility of index tau. PMID- 23625632 TI - Role of PTEN in basal cell derived lung carcinogenesis. AB - Lung adenocarcinoma (AdC) and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes, however, most genetic mouse models of lung cancer produce predominantly, if not exclusively, AdC. Whether this is secondary to targeting mutations to the distal airway cells or to the use of activating Kras mutations that drive AdC formation is unknown. We previously showed that targeting Kras(G12D) activation and transforming growth factor beta receptor type II (TGFbetaRII) deletion to airway basal cells via a keratin promoter induced formation of both lung AdC and SCC. In this study we assessed if targeting phosphatase and tensin homologue (PTEN) deletion to airway basal cells could initiate lung tumor formation or increase lung SCC formation. We found that PTEN deletion is capable of initiating both lung AdC and SCC formation when targeted to basal cells and although PTEN deletion is a weaker tumor initiator than Kras(G12D) with low tumor multiplicity and long latency, tumors initiated by PTEN deletion were larger and displayed more malignant conversion than Kras(G12D) initiated tumors. That PTEN deletion did not increase lung SCC formation compared to Kras(G12D) activation, suggests that the initiating genetic event does not dictate tumor histology when genetic alterations are targeted to a specific cell. These studies also confirm that basal cells of the conducting airway are capable of giving rise to multiple NSCLC tumor types. PMID- 23625634 TI - Biotransformation of chloro-substituted indoles to indigoids by phenol hydroxylase from Arthrobacter sp. W1. AB - Recombinant Escherichia coli cells expressing phenol hydroxylase (designated as strain PH(IND)) were used to synthesize chloro-substituted indigoids by the transformation of indoles. The optimal conditions for the biotransformation of 4- and 7-chloroindole were determined by response surface methodology. Biotransformation kinetic assays revealed that strain PH(IND) showed high catalytic efficiency for 4- and 7-chloroindole. The formation rate of 7,7' dichloroindigo (1.35 unit/mg cell dry weight) by strain PH(IND) was 1.14-fold higher than that of 4,4'-dichloroindigo. The intermediates of 7-chloroindole biotransformation were identified by high-performance liquid chromatography-mass spectroscopy, and the biotransformation mechanism was also proposed. These results suggested that there was a potential application of strain PH(IND) in the biotransformation of chloro-substituted indoles to valuable indigoids. PMID- 23625635 TI - Psychosocial problems associated with depression at 18 months poststroke. AB - OBJECTIVE: With a prevalence that varies between 20% and 65%, poststroke depression (PSD) is a frequent sequel of stroke. The aim of this study was to determine incidence and risk factors for PSD 18 months after stroke. METHODS: As part of the Middelheim Interdisciplinary Stroke Study, patients were followed up for 18 months in this prospective and longitudinal epidemiological study. Clinically significant signs and symptoms of PSD were quantified by means of the Cornell Scale for Depression (CSD) and the Montgomery and Asberg Depression Rating Scale. Activities, including social activities, were measured with the Stroke Impact Scale (SIS). Relational problems since stroke onset were defined by a questionnaire. RESULTS: Data analysis was performed on 125 patients who completed follow-up assessments. Depression (CSD score >=8) was diagnosed in 28% of the patients. Patients with PSD were more dependent for activities of daily living and displayed more physical and cognitive impairment than patients without PSD. The risk to become depressed decreased with 5% when the patient's activities increased with one unit on the SIS (odds ratio (OR) = 0.95; 95% confidence interval (CI) = 0.93-0.97). Patients with persistent relational problems since stroke onset had approximately four and a half times greater risk of becoming depressed than patients without (OR = 4.48; 95%CI = 1.17-16.87). CONCLUSIONS: Multiple regression models indicated that the most determining features for developing PSD at 18 months poststroke include reduced activity and relationship problems due to stroke. Further studies on risk factors for PSD are essential, including psychosocial aspects, given its negative impact on rehabilitation and quality of life. PMID- 23625636 TI - Studies on the toxic interaction mechanism between 2-naphthylamine and herring sperm DNA. AB - The toxic interaction between 2-naphthylamine (2-NA) and herring sperm deoxyribonucleic acid (hs-DNA) has been thoroughly investigated by UV absorption, fluorescence, and circular dichroism (CD) spectroscopic methods. UV absorption result indicates that 2-NA may intercalate into the stack base pairs of DNA during the toxic interaction of 2-NA with DNA. A fluorescence quenching study shows that DNA quenches the intrinsic fluorescence of 2-NA via a static pathway. The studies on effects of ionic strength and anionic quenching rule out electrostatic and groove bindings as the dominant binding modes. Further studies on denatured DNA fluorescence quenching and thermal melting studies confirm that the dominant binding mode of 2-NA-DNA is intercalative binding. A CD spectral study shows that the binding interaction of 2-NA with DNA leads to the disorganization of the neat double-helical structure of hs-DNA. PMID- 23625637 TI - Serine substitution of proline at codon 151 of TP53 confers gain of function activity leading to anoikis resistance and tumor progression of head and neck cancer cells. AB - OBJECTIVES/HYPOTHESIS: Mutation of the TP53 gene occurs in more than half of cases of head and neck squamous cell carcinoma (HNSCC). However, little is known about how specific TP53 mutations affect tumor progression. The objective of this study is to determine the gain of function of mutant p53 with a proline-to-serine substitution at codon 151. STUDY DESIGN: Laboratory-based study. METHODS: A panel of HNSCC cell lines was determined with anoikis assays, and orthotopic mouse experiments were performed. TP53 was sequenced. The shRNA knockdown and overexpression approaches were used for testing mutant p53 functions. The crystal structure of the p53 protein was analyzed using an in silico approach. RESULTS: An anoikis-resistant cell line, Tu138, was found to have a proline-to-serine substitution at codon 151 of TP53, which results in loss of wild-type p53 transcriptional activity. Moreover, the mutant p53 was shown to promote anoikis resistance and soft agar growth. Using an in silico approach based on the crystal structure of wild-type p53 protein, substitution of proline by serine at position 151 would create a cavity in a hydrophobic pocket, the loss of van der Waals contacts, and the thermodynamically unfavorable placement of a polar group, the hydroxyl oxygen atom of the serine, within a hydrophobic region, all of which likely cause a locally altered structure. CONCLUSIONS: Our data suggest that mutation at position 151 leads to a structural alteration, which results in significant functional changes in the p53 protein that impact tumor progression. PMID- 23625638 TI - High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia. AB - OBJECTIVES: Thrombocytopenia is sometimes observed during linezolid therapy. Here, we aimed to investigate the factors affecting linezolid-induced thrombocytopenia. METHODS: A prospective observational study was performed between October 2009 and February 2011; 30 patients were included. Plasma linezolid trough concentrations were measured on days 3, 7 and 14 after initial drug administration. Platelet counts and haemoglobin levels were also monitored. RESULTS: Thrombocytopenia occurred in 17 patients (56.7%). Median linezolid trough concentrations on day 3 were significantly higher in patients with renal impairment (creatinine clearance <60 mL/min) than in patients without renal impairment (14.7 versus 4.8 mg/L; P < 0.0001). Median linezolid trough concentrations on day 3 in patients who developed thrombocytopenia were also significantly higher than those in patients who did not (13.4 versus 4.3 mg/L, P < 0.0001). Development of thrombocytopenia occurred significantly more frequently in patients with linezolid trough concentration >7.5 mg/L (OR, 90.0; P < 0.0001) and renal impairment (OR, 39.0; P = 0.0002). The Kaplan-Meier plot showed that the median time from the initiation of therapy to development of thrombocytopenia was 11 days. CONCLUSIONS: Patients with renal impairment are more likely to have a high plasma linezolid concentration. In addition, a high plasma linezolid concentration and renal impairment significantly affected the development of linezolid-induced thrombocytopenia. Further studies are required to evaluate whether therapeutic drug monitoring-guided dosage adjustment of linezolid decreases the adverse effects while maintaining treatment efficacy in patients with renal dysfunction. PMID- 23625640 TI - Health promotion in adolescent and young adult cancer survivors: mobilizing compliance in a multifaceted risk profile. AB - With rising cure rates of childhood cancer, nurse practitioners have an increased chance of encountering a large survivor cohort in practice. A variety of late effects programs exist; however, funding is limited for these programs and is not accessible for all patients. Primary providers may increasingly act as a medical home for childhood cancer survivors (CCS). Understanding the inherent risks of cytotoxic treatment and the progressive consequences of late effects is vital to limit morbidity and mortality. Adolescent and young adult survivors (AYA) are particularly apt to make health behavior decisions that create risks for comorbidities. Developmentally appropriate experimentation with drug, alcohol, or tobacco use and increased ultraviolet ray exposure intensifies the risk for secondary malignancies and novel diseases. The paucity of evidence-based surveillance guidelines and survivor-specific health promotion programs cumulatively widen the gap in noncompliance and misinformation. This article overviews the risk profile of CCS. It explores health practices, as well as emerging health promotion techniques, within the AYA survivor population and the role nurse practitioners have in enhancing health maintenance. PMID- 23625639 TI - Hypoglycemic and hepatoprotective activity of Rosmarinus officinalis extract in diabetic rats. AB - The present study examined the effect of water extract (200 mg/kg body weight) of Rosmarinus officinalis L. in streptozotocin (STZ)-induced diabetic rats for 21 days. The hepatoprotective effects were investigated in the liver tissues sections. There was a significant increase in serum liver biochemical parameters (aspartate aminotransferase, alanine transaminase, and alkaline phosphatase), accompanied by a significant decrease in the level of total protein and albumin in the STZ-induced rats when compared with that of the normal group. The high dose treatment group (200 mg/kg body wt) significantly restored the elevated liver function enzymes near to normal. This study revealed that rosemary extracts exerted a hepatoprotective effect. The results indicate that the extract exhibits the protective effect on tissues and prove its potentials as an antidiabetic agent. PMID- 23625641 TI - Musculoskeletal deterioration in men accompanies increases in body fat. AB - OBJECTIVE: To examine body fat and musculoskeletal changes in men over 5 years. METHODS: Body composition was evaluated for men in the Geelong Osteoporosis Study using whole body dual energy X-ray absorptiometry (DXA) during two time-periods. DXA was performed for 1329 men (25-96 years) during 2001-2006 and for 900 men (25 98 years), 2006-2011. The masses of fat, lean, and bone were expressed relative to the square of height (kg/m2). Each compartment was also expressed as a percentage relative to body weight (%fat, %lean, %bone). RESULTS: Mean BMI increased from 26.9 kg/m2 in 2001-2006, to 27.2 kg/m2 in 2006-2011 (P = 0.04). Mean fat mass increased by 9.0% from 6.98 kg/m2 (95% CI 6.84-7.11) in 2001-2006, to 7.60 kg/m2 (7.44-7.77) in 2006-2011 (P < 0.001); mean lean mass decreased by 0.9%, from 18.92 kg/m2 (18.83-19.01) to 18.75 kg/m2 (18.64-18.86) (P = 0.02), and mean bone mass decreased 1.6% from 1.041 kg/m2 (1.034-1.047), to 1.024 kg/m2 (1.016-1.032). Mean %fat increased from 23.4% to 25.2%, mean %lean decreased from 72.6% to 70.9% and mean %bone decreased from 4.0% to 3.9% (all P < 0.05). CONCLUSIONS: An increase in BMI, which reflects a substantial increase in body fat mass and declines in both lean and bone mass was reported. This may have implications for future development of bone fragility, sarcopenia, and sarcopenic obesity. PMID- 23625642 TI - Development of short, acute exposure hazard estimates: a tool for assessing the effects of chemical spills in aquatic environments. AB - Management decisions aimed at protecting aquatic resources following accidental chemical spills into rivers and coastal estuaries require estimates of toxic thresholds derived from realistic spill conditions: acute pulse exposures of short duration (h), information which often is unavailable. Most existing toxicity data (median lethal concentration or median effective concentration) come from tests performed under constant exposure concentrations and exposure durations in the 24-h to 96-h range, conditions not typical of most chemical spills. Short-exposure hazard concentration estimates were derived for selected chemicals using empirical toxicity data. Chemical-specific 5th percentile hazard concentrations (HC5) of species sensitivity distributions (SSD) from individual exposure durations (6-96 h) were derived via bootstrap resampling and were plotted against their original exposure durations to estimate HC5s and 95% confidence intervals (CIs) at shorter exposures (1, 2, and 4 h). This approach allowed the development of short-exposure HC5s for 12 chemicals. Model verification showed agreement between observed and estimated short-exposure HC5s (r(2) adjusted = 0.95, p < 0.0001), and comparison of estimated short-exposure HC5s with empirical toxicity data indicated generally conservative hazard estimates. This approach, applied to 2 real spill incidents, indicated hazard estimates above expected environmental concentrations (acrylonitrile), and suggested that environmental concentrations likely exceeded short-exposure hazard estimates (furfural). Although estimates generated through this approach were likely overprotective, these were derived from environmentally realistic exposure durations, providing risk-assessors with a tool to manage field decisions. Environ Toxicol Chem 2013;32:1918-1927. (c) 2013 SETAC. PMID- 23625643 TI - A sex difference in interference between identity and expression judgments with static but not dynamic faces. AB - Facial motion cues facilitate identity and expression processing (Pilz, Thornton, & Bulthoff, 2006). To explore this dynamic advantage, we used Garner's speeded classification task (Garner, 1976) to investigate whether adding dynamic cues alters the interactions between the processing of identity and expression. We also examined whether facial motion affected women and men differently, given that women show an advantage for several aspects of static face processing (McClure, 2000). Participants made speeded identity or expression judgments while the irrelevant cue was held constant or varied. Significant interference occurred with both tasks when static stimuli were used (as in Ganel & Goshen-Gottstein, 2004), but interference was minimal with dynamic displays. This suggests that adult viewers are either better able to selectively attend to relevant cues, or better able to integrate multiple facial cues, when viewing moving as opposed to static faces. These gains, however, come with a cost in processing time. Only women showed asymmetrical interference with static faces, with variations in identity affecting expression judgments more than the opposite. This finding may reflect sex differences in global-local processing biases (Godard & Fiori, 2012). Our findings stress the importance of using dynamic displays and of considering sex distributions when characterizing typical face processing mechanisms. PMID- 23625644 TI - Unconscious priming by illusory figures: the role of the salient region. AB - In this study we provide evidence that unconscious priming can be obtained as a result of the processing of the salient region (SR) of illusory figures and without that of illusory contours (ICs). We used a metacontrast masking paradigm where illusory figures were masked by real figures. In Experiment 1 we found a clear priming effect when participants were asked to discriminate between square and diamond masks preceded by congruent or incongruent illusory square or diamond primes. It is likely that metacontrast impairs the processing of ICs but not of the SR; therefore the above result strongly suggests that the priming effect was specifically related to the processing of the SR. In Experiment 2 participants were tested in the same task as in Experiment 1 with additional primes in which the inducers were presented in the same locations but their shapes were changed so as to modify the global configuration. We termed these primes High, Low, and No Salient Region (HSR, LSR, and NSR, respectively). The HSR condition replicated Experiment 1, whereas in the LSR and NSR conditions the priming effect got progressively smaller. The results of Experiment 1 were replicated with the priming effect significantly larger in the HSR than in all other conditions. It was also larger in the HSR than in LSR condition and smallest but still present in the NSR condition. Taken together, these results indicate that the unconscious processing of only the SR yields a priming effect and that a reduction of the saliency of the SR leads to a reduction of the priming effect, while its elimination does not abolish it. PMID- 23625646 TI - Separation of chlorogenic acid and concentration of trace caffeic acid from natural products by pH-zone-refining countercurrent chromatography. AB - Chlorogenic acid and caffeic acid were selected as test samples for separation by the pH-zone-refining countercurrent chromatography (CCC). The separation of these test samples was performed with a two-phase solvent system composed of methyl tert-butyl-ether/acetonitrile/water at a volume ratio of 4:1:5 v/v/v where trifluoroacetic acid (TFA; 8 mM) was added to the organic stationary phase as a retainer and NH4 OH (10 mM) to the aqueous mobile phase as an eluter. Chlorogenic acid was successfully separated from Flaveria bidentis (L.) Kuntze (F. bidentis) and Lonicerae Flos by pH-zone-refining CCC, a slightly polar two-phase solvent system composed of methyl-tert-butyl-ether/acetonitrile/n-butanol/water at a volume ratio of 4:1:1:5 v/v/v/v was selected where TFA (3 mM) was added to the organic stationary phase as a retainer and NH4 OH (3 mM) to the aqueous mobile phase as an eluter. A 16.2 mg amount of chlorogenic acid with the purity of 92% from 1.4 g of F. bidentis, and 134 mg of chlorogenic acid at the purity of 99% from 1.3 g of crude extract of Lonicerae Flos have been obtained. These results suggest that pH-zone-refining CCC is suitable for the isolation of the chlorogenic acid from the crude extracts of F. bidentis and Lonicerae Flos. PMID- 23625645 TI - Indole-3-carbinol protects against pressure overload induced cardiac remodeling via activating AMPK-alpha. AB - SCOPE: Indole-3-carbinol (I3C), a monomer component extracted from leaves and stems of cruciferous vegetables, has inhibitory effects on tumors, obesity, and liver fibrosis, but its effects on the development of cardiac remodeling remain completely unknown. We determined the effects of I3C on cardiac remodeling and heart function using an aortic banding (AB) mouse model. METHODS AND RESULTS: Male 8- to10-wk-old wild-type and 5' adenosine monophosphate-activated protein kinase (AMPK)-alpha2 knockout mice fed with or without I3C were subjected to AB or a sham operation and were phenotyped, accordingly. I3C both prevented and reversed cardiac remodeling induced by AB, as assessed by heart weight/body weight, lung weight/body weight, and heart weight/tibia length ratios, echocardiographic and hemodynamic parameters, histological analysis, and gene expression of hypertrophic and fibrotic markers. The inhibitory effect of I3C on cardiac remodeling was mediated by AMPK-alpha and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling. Moreover, AMPK-alpha2 gene deficiency completely blocked the inhibitory effects of I3C on cardiac remodeling, preventing the improvements in heart weight/body weight, lung weight/body weight, heart weight/tibia length, cardiac function, gene expression of hypertrophic and fibrotic markers, and phosphorylation of mammalian target of rapamycin and ERK1/2 signaling components. CONCLUSION: I3C both prevents and reverses cardiac remodeling by activating AMPK-alpha signaling. I3C is a potential therapeutic drug for heart failure. PMID- 23625647 TI - Sex differences in binge eating patterns in male and female adult rats. AB - OBJECTIVE: Several efforts are underway to model binge eating in animals in order to advance neurobiological models of risk. However, knowledge of sex differences in these models is currently lacking. The goal of the present study was to examine sex differences in binge eating phenotypes using a well-established rodent model (i.e., the binge eating resistant/binge eating prone model). METHOD: Thirty male and 30 female adult Sprague-Dawley rats were exposed to feeding tests consisting of intermittent access to palatable food (PF). Rats were then categorized as binge eating prone (BEP) based on the amount and consistency of PF consumption across tests. RESULTS: Across multiple methods for BEP classification, rates of BEP phenotypes were two to six times higher in female than male rats. DISCUSSION: Findings provide support for sex differences in rodent models of binge eating and highlight the promise of the BER/BEP model for understanding neurobiological mechanisms underlying sex differences in risk. PMID- 23625648 TI - Reply: To PMID 23042485. PMID- 23625649 TI - Clinical, virologic, and immunologic outcomes in lymphoma survivors and in cancer free, HIV-1-infected patients: a matched cohort study. AB - BACKGROUND: The objective of this study was to compare immunologic, virologic, and clinical outcomes between living human immunodeficiency virus (HIV)-infected individuals who had a diagnosis of lymphoma versus outcomes in a control group of cancer-free, HIV-infected patients. METHODS: In this matched cohort study, patients in the case group were survivors of incident lymphomas that occurred between 1997 and June 2010. Controls were living, cancer-free, HIV-infected patients who were matched to cases at a 4:1 ratio by age, sex, nadir CD4 cell count, and year of HIV diagnosis. The date of lymphoma diagnosis served as the baseline in cases and in the corresponding controls. RESULTS: In total, 62 patients (cases) who had lymphoma (20 with Hodgkin disease [HD] and 42 with non Hodgkin lymphoma [NHL]) were compared with 211 controls. The overall median follow-up was 4.8 years (interquartile range, 2.0-7.9 years). The CD4 cell count at baseline was 278 cells/mm3 (interquartile range, 122-419 cells/mm3) in cases versus 421 cells/mm3 (interquartile range, 222-574 cells/mm3) in controls (P = .003). At the last available visit, the CD4 cell count was 412 cells/mm3 (range, 269-694 cells/mm3) in cases versus 518 cells/mm3 (interquartile range, 350-661 cells/mm3) in controls (P = .087). The proportion of patients who achieved virologic success increased from 30% at baseline to 74% at the last available visit in cases (P = .008) and from 51% to 81% in controls (P = .0286). Patients with HD reached higher CD4 cell counts at their last visit than patients with NHL (589 cells/mm3 [range, 400-841 cells/mm3] vs 332 cells/mm3 [interquartile range, 220-530 cells/mm3], respectively; P = .003). Virologic success was similar between patients with HD and patients with NHL at the last visit. Forty cases (65%) and 76 controls (36%) experienced at least 1 clinical event after baseline (P < .0001); cases were associated with a shorter time to occurrence of the first clinical event compared with controls (P < .0001). CONCLUSIONS: HIV-infected lymphoma survivors experienced more clinical events than controls, especially during the first year of follow-up, but they reached similar long-term immunologic and virologic outcomes. PMID- 23625650 TI - The role of ERK2 in colorectal carcinogenesis is partly regulated by TRAPPC4. AB - The extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK) pathway is an important cell proliferation pathway. We previously reported that the transport protein particle complex 4 (TRAPPC4), ERK2 interaction may activate ERK1/2, modulate pERK2 nuclear localization and regulate proliferation and apoptosis in colorectal cancer (CRC) cells. The present study further investigated the function of the TRAPPC4-ERK2 interaction in CRC in vitro and in vivo. Silencing of TRAPPC4 induced G0/G1 phase cell cycle arrest, upregulated p21 and downregulated cyclin B1 in CRC cells. Overexpression of TRAPPC4 after ERK2 silencing decreased the percentage of G0/G1 phase cells, increased the percentage of G2/M and S phase cells, downregulated p21, upregulated cyclin B1, and enhanced CRC cell viability. Immunohistochemical staining revealed that knockdown of TRAPPC4 downregulated pERK2, whereas overexpression of TRAPPC4 upregulated pERK2. Epidermal growth factor (EGF) stimulated upregulation of TRAPPC4 and pERK2 in SW1116 cells; EGF stimulation or overexpression of TRAPPC4 induced pERK2 nuclear translocation. Silencing of TRAPPC4 reduced SW1116 xenograft tumor growth in vivo, whereas overexpression of TRAPPC4 increased tumor growth, compared to control tumors. Moreover, modulation of TRAPPC4 expression in vivo affected the levels of pERK2 in the cytoplasm and nucleus and expression of p21. These results conclusively demonstrate that TRAPPC4 regulates ERK2 activation and also affects the distribution of activated pERK2 in CRC cells. The ability of ERK2 to play a role in colorectal carcinogenesis depends, at least in part, on TRAPPC4. PMID- 23625651 TI - Binding interactions of naringenin and naringin with calf thymus DNA and the role of beta-cyclodextrin in the binding. AB - The interaction of naringenin (Nar) and its neohesperidoside, naringin (Narn), with calf thymus deoxyribonucleic acid (ctDNA) in the absence and the presence of beta-cyclodextrin (beta-CD) was investigated. The interaction of Nar and Narn with beta-CD/ctDNA was analyzed by using absorption, fluorescence, and molecular modeling techniques. Docking studies showed the existence of hydrogen bonding, electrostatic and phobic interaction of Nar and Narn with beta-CD/DNA. 1:2 stoichiometric inclusion complexes were observed for Nar and Narn with beta-CD. With the addition of ctDNA, Nar and Narn resulted into the fluorescence quenching phenomenon in the aqueous solution and beta-CD solution. The binding constant K(b) and the number of binding sites were found to be different for Nar and Narn bindings with DNA in aqueous and beta-CD solution. The difference is attributed to the structural difference between Nar and Narn with neohesperidoside moiety present in Narn. PMID- 23625652 TI - Solid lipid nanoparticles as effective reservoir systems for long-term preservation of multidose formulations. AB - Cosmetic multidose preparations, as well as pharmaceutical ones, are at risk of contamination by microorganisms, due to their high water content. Besides the risk of contamination during manufacturing, multidose cosmetic preparations may be contaminated by consumers during their use. In this paper, the results of the utilization of nanoparticles as reservoir systems of parabens, the most used class of preservatives, were reported. Two different systems, solid lipid nanoparticles (SLN) made of pure precirol and nanostructured lipid carriers (NLC) made of precirol and almond oil, containing three parabens as single molecules or as a mixture, were prepared and tested. All the systems were characterized for size, polydispersion index, zeta potential and encapsulation efficiency. Release experiments, carried out in steady state and sink conditions, allowed to evidence that both SLN and NLC were able to act as reservoir systems. The antimicrobial activity of the systems was tested against Candida albicans ATCC 10231 with repeat insult tests. The results of the release experiments and the antimicrobial tests showed very low water concentration of parabens still maintaining their antimicrobial activity. PMID- 23625653 TI - Postoperative management in the prevention of complications after septoplasty: a systematic review. AB - OBJECTIVES/HYPOTHESIS: The purpose of this article is to assess the relative rates of septal hematomas, synechiae, and septal perforations associated with methods commonly used to manage the nasal septum after septoplasty. As a secondary objective, we assessed the relative contribution of each method of septal management with respect to pain and patient discomfort. STUDY DESIGN: Systematic review. METHODS: A systematic literature search was performed for all relevant English randomized controlled, cohort, or case-control trials. Inclusion criteria included any study that assessed postoperative septal hematoma, perforation, or synechiae formation and reported on these outcomes regardless of method of septoplasty. Two authors independently extracted study information and analyzed all included articles for bias. RESULTS: A total of 279 studies were identified, with 17 meeting the inclusion criteria. The majority of the studies had a high risk of bias that prevented the performance of a meta-analysis. Eight studies provided data on postoperative pain associated with different techniques, and quilting sutures were found to be significantly less painful than both nasal packing and septal splints. CONCLUSIONS: Due to the low level of evidence and the high bias of the studies, the results of this systematic review fail to demonstrate a clear benefit among any of the postseptoplasty treatment techniques. However, the results do demonstrate that septal sutures are associated with less postoperative pain versus the other methods of septal management in this review. PMID- 23625654 TI - Serum miR-21 and miR-92a as biomarkers in the diagnosis and prognosis of colorectal cancer. AB - Previous studies from our laboratory identified a number of miRNAs that were aberrantly expressed in colorectal cancer (CRC) tissue. However, their diagnostic and prognostic value in serum has not been fully evaluated. In the present study, we measured the levels of five miRNAs (miR-21, miR-31, miR-92a, miR-18a, and miR 106a) in serum samples from 200 CRC patients, 50 advanced adenoma patients, and 80 healthy controls by real-time quantitative polymerase chain reaction (RT-PCR). In our study, the levels of miR-21 and miR-92a in patients with CRC and advanced adenoma were significantly higher than those in healthy controls (all P < 0.05). MiR-21 yielded an area under the receiver-operating characteristics (ROC) curve (AUC) of 0.802 and miR-92a yielded an AUC of 0.786 in discriminating CRCs from the controls. Additionally, miR-21 and miR-92a yielded an AUC of 0.709 and 0.701, respectively, in discriminating advanced adenomas from the controls. Combined ROC analyses using both miRNAs, revealed an elevated AUC of 0.847 in discriminating CRCs, and an AUC of 0.722 in discriminating advanced adenomas from the controls. In the multivariate Cox proportional hazards analysis, high miR-92a expression in CRC was independently associated with poor survival (P = 0.03; hazard ratio 4.36; 95 % confidence interval = 1.64-11.57). No significant difference was observed in the levels of miR-18a, miR-31, and miR-106a among CRC, advanced adenoma, and control samples. In summary, our data indicate that miR-21 and miR-92a serum levels have potential value for early detection of CRC. Furthermore, miR-92a has prognostic value in CRC patients. PMID- 23625655 TI - Are high initial CEA and CA 19-9 levels associated with the presence of K-ras mutation in patients with metastatic colorectal cancer? AB - In certain cell culture studies, significant CEA expression was observed in K-ras mutant cells. However, the relationship between high CEA levels and K-ras status has not been sufficiently investigated. In the present study, we aimed to determine the prognostic role of initial CEA and CA 19-9 values in metastatic colorectal cancer patients according to the status of K-ras. Between 2000 and 2010, a total of 215 patients with metastatic colorectal cancer who were treated and followed up in our oncology center were analyzed. Smokers were excluded from the study. The clinicopathological findings and initial CEA and CA19-9 values were determined. K-ras mutation analysis was performed using quantitative PCR evaluation of the DNA from the tumor tissues. Eighty-two patients (38.1 %) were female and 133 (61.9 %) were male, with a median age of 59 years (range 27-83). Based on tumor localization, 127 patients (59 %) were classified as colon cancer patients and 88 patients (41 %) were classified as rectal cancer patients. The majority of patients (83.3 %) had pure adenocarcinoma histology, while 36 cases (16.7 %) had mucinous adenocarcinoma. The initial CEA levels were detected to be high (>5 ng/mL) in 108 of the patients (50.2 %), while high levels of initial CA 19-9 (>37 ng/mL) were found in 90 patients (41.8 %). K-ras mutations were detected in 99 of the patients (46 %). K-ras was found to be wild type in 116 patients (54 %). Significant differences were detected between the K-ras wild type and mutant groups with respect to age and the initial serum CEA levels. Patients with K-ras mutations were younger (p = 0.04) and had higher initial CEA levels (p = 0.02) compared to patients with K-ras wild type. The median overall survival (OS) time and 3-year OS rate for patients with a high initial CEA level (>5 ng/mL) were significantly shorter than those of patients with a low initial CEA level (<5 ng/mL) (50.5 months and 61.8 % vs. 78.6 months and 79.1 %, p = 0.014). Furthermore, the patients with low initial CA 19-9 levels (<37 ng/mL) had a significant better median OS interval and 3-year OS rate (76.1 months and 80.1 %) compared to patients with high initial CA 19-9 levels (>37 ng/mL) (37.6 months and 55.7 %, p = 0.04). Multivariate analysis indicated that stage at the time of diagnosis (p < 0.001) and low initial serum CEA level (p = 0.037) were independent prognostic factors of OS. For K-ras mutant patients, the stage at diagnosis (p = 0.017), low initial serum CEA level (p = 0.001), and low initial serum CA 19-9 level were found to be independent prognostic indicators of OS. Our findings demonstrate for the first time that the presence of a K-ras mutation correlated with high initial CEA and CA 19-9 levels in patients with metastatic colorectal cancer. Patients with high initial CEA and CA 19-9 levels may potentially predict the presence of a K-ras mutation, and this prediction may guide targeted therapies in these patients. PMID- 23625656 TI - Glutathione S-transferase M1 null genotype contributes to increased risk of esophageal carcinoma in Chinese population. AB - Glutathione S-transferases (GSTs) play important roles in the detoxification of electrophilic carcinogens, and GSTM1 null genotype is associated with the dysfunction of GSTs. Previous studies investigating the association between GSTM1 null genotype and risk of esophageal carcinoma in Chinese provided inconsistent findings. To provide a more precise estimation on the association between GSTM1 null genotype and risk of esophageal carcinoma in Chinese population, a meta analysis was performed. Eligible studies were searched in PubMed, Embase, and China National Knowledge Infrastructure databases. Odds ratio (OR) with the corresponding 95 % confidence interval (95 %CI) was used to assess the association. A total of 18 case-control studies involving 1,947 cases and 3,506 controls were finally included in the meta-analysis. Meta-analysis of those 18 studies showed that GSTM1 null genotype was associated with an increased risk of esophageal carcinoma in Chinese (random effect model OR = 1.49, 95 %CI = 1.11 2.00, P = 0.008). The findings from cumulative meta-analysis showed that the association was more obvious as the data increased by publication year. There was no risk of publication bias in the meta-analysis. Therefore, the findings from our meta-analysis provide a strong evidence for the association between GSTM1 null genotype and risk of esophageal carcinoma in Chinese population, and GSTM1 null genotype contributes to increased risk of esophageal carcinoma in Chinese. PMID- 23625657 TI - Upregulated hPuf-A promotes breast cancer tumorigenesis. AB - hPuf-A is a member of RNA-binding PUF family that regulates mRNA translation. Redistribution of hPuf-A from the nucleolus to the nucleoplasm upon genotoxic stress modulates the poly(ADP-ribosyl)ation activity of PARP-1. Here, we report a novel function of hPuf-A involved in promoting breast cancer progression. Immunohistochemical studies showed higher expression levels of hPuf-A in stage I, II, III, and IV breast cancer specimens in contrast with those of hPuf-A in ductal carcinoma in situ. The presence of hPuf-A is highly associated with colony formation capacities in breast cancer T47D and MDA-MB-231 cells. Xenograft growth of hPuf-A-silenced and hPuf-A overexpressing MDA-MB-231 cells in nude mice was substantially in concert with colony formation capacities. This promoting effect of hPuf-A in tumorigenesis might be correlated with the regulation of its associated mRNAs, such as RbAp48 and DDX3. Collectively, hPuf-A may have diagnostic values in breast cancer progression. PMID- 23625660 TI - Bayesian design and analysis of composite endpoints in clinical trials with multiple dependent binary outcomes. AB - The author considers studies with multiple dependent primary endpoints. Testing hypotheses with multiple primary endpoints may require unmanageably large populations. Composite endpoints consisting of several binary events may be used to reduce a trial to a manageable size. The primary difficulties with composite endpoints are that different endpoints may have different clinical importance and that higher-frequency variables may overwhelm effects of smaller, but equally important, primary outcomes. To compensate for these inconsistencies, we weight each type of event, and the total number of weighted events is counted. To reflect the mutual dependency of primary endpoints and to make the weighting method effective in small clinical trials, we use the Bayesian approach. We assume a multinomial distribution of multiple endpoints with Dirichlet priors and apply the Bayesian test of noninferiority to the calculation of weighting parameters. We use composite endpoints to test hypotheses of superiority in single-arm and two-arm clinical trials. The composite endpoints have a beta distribution. We illustrate this technique with an example. The results provide a statistical procedure for creating composite endpoints. PMID- 23625658 TI - DLC1 as a regulator of proliferation, invasion, cell cycle, and apoptosis in cutaneous squamous cell carcinoma. AB - Increasing evidence has demonstrated that the tumor suppressor gene deleted in liver cancer-1 (DLC1) is tightly implicated in the development and progression of tumors and is verified to be downregulated in a variety of tumors. However, the roles and precise molecular mechanisms of DLC1 in cutaneous squamous cell carcinoma (cutaneous SCC) remain to be elucidated. In the present study, we confirmed the reduced level in cutaneous SCC tissues and cells, and DLC1 mRNA relative level in cutaneous SCC tissues with lymph node metastasis (0.801 +/- 0.079) was markedly lower than those without lymph node metastasis (1.245 +/- 0.071) (P < 0.0001). Importantly, the survival rates of patients with low DLC1 level were lower than those with high DLC1 level (P = 0.0051). Further investigation revealed that DLC1 overexpression inhibited proliferation and arrested cell cycle at G0/G1 phase in A431 cells, which may be tightly associated with upregulation of p21 protein and downregulation of cyclin D1 and cdk2 proteins. Moreover, the decreases of FAK and p-FAK as well as the increase of E cadherin level mediated by elevated DLC1 level suppressed invasion in A431 cells. Additionally, DLC1 overexpression induced apoptosis coupled with elevations of Bax level and caspase-3 activity and decrease of Bcl-2 level in A431 cells. Taken altogether, our data presented herein suggest that DLC1 plays a pivotal role in the development and progression of cutaneous SCC, which may be in part achieved by regulating the signaling pathway related to proliferation, invasion, cell cycle, and apoptosis in cutaneous SCC cells. PMID- 23625659 TI - Ascent to altitude as a weight loss method: the good and bad of hypoxia inducible factor activation. AB - OBJECTIVE: Given the epidemic of obesity worldwide there is a need for more novel and effective weight loss methods. Altitude is well known to be associated with weight loss and has actually been used as a method of weight reduction in obese subjects. This review demonstrates the critical role of hypoxia inducible factor (HIF) in bringing about reductions in appetite and increases in energy expenditure characteristic of hypobaric hypoxia DESIGN AND METHODS: A MEDLINE search of English language articles through February 2013 identified publications associating altitude or hypobaric hypoxia with key words to include HIF, weight loss, appetite, basal metabolic rate, leptin, cellular energetics, and obesity. The data from these articles were synthesized to formulate a unique and novel mechanism by which HIF activation leads to alterations in appetite, basal metabolic rate, and reductions in body adiposity. RESULTS: A synthesis of previously published literature revealed mechanisms by which altitude induces activation of HIF, thereby suggesting this transcription factor regulates changes in cellular metabolism/energetics, activation of the central nervous system, as well as peripheral pathways leading to reductions in food intake and increases in energy expenditure. CONCLUSIONS: Here a unifying hypothesis is present suggesting that activation of HIF under conditions of altitude potentially leads to metabolic benefits that are dose dependent, gender and genetic specific, and results in adverse effects if the exposure is extreme. PMID- 23625661 TI - Deriving bio-equivalents from in vitro bioassays: assessment of existing uncertainties and strategies to improve accuracy and reporting. AB - Bio-equivalents (e.g., 17beta-estradiol or dioxin equivalents) are commonly employed to quantify the in vitro effects of complex human or environmental samples. However, there is no generally accepted data analysis strategy for estimating and reporting bio-equivalents. Therefore, the aims of the present study are to 1) identify common mathematical models for the derivation of bio equivalents from the literature, 2) assess the ability of those models to correctly predict bio-equivalents, and 3) propose measures to reduce uncertainty in their calculation and reporting. We compiled a database of 234 publications that report bio-equivalents. From the database, we extracted 3 data analysis strategies commonly used to estimate bio-equivalents. These models are based on linear or nonlinear interpolation, and the comparison of effect concentrations (ECX ). To assess their accuracy, we employed simulated data sets in different scenarios. The results indicate that all models lead to a considerable misestimation of bio-equivalents if certain mathematical assumptions (e.g., goodness of fit, parallelism of dose-response curves) are violated. However, nonlinear interpolation is most suitable to predict bio-equivalents from single point estimates. Regardless of the model, subsequent linear extrapolation of bio equivalents generates additional inaccuracy if the prerequisite of parallel dose response curves is not met. When all these factors are taken into consideration, it becomes clear that data analysis introduces considerable uncertainty in the derived bio-equivalents. To improve accuracy and transparency of bio-equivalents, we propose a novel data analysis strategy and a checklist for reporting Minimum Information about Bio-equivalent ESTimates (MIBEST). PMID- 23625663 TI - Modelling the effects of climate change on the distribution and production of marine fishes: accounting for trophic interactions in a dynamic bioclimate envelope model. AB - Climate change has already altered the distribution of marine fishes. Future predictions of fish distributions and catches based on bioclimate envelope models are available, but to date they have not considered interspecific interactions. We address this by combining the species-based Dynamic Bioclimate Envelope Model (DBEM) with a size-based trophic model. The new approach provides spatially and temporally resolved predictions of changes in species' size, abundance and catch potential that account for the effects of ecological interactions. Predicted latitudinal shifts are, on average, reduced by 20% when species interactions are incorporated, compared to DBEM predictions, with pelagic species showing the greatest reductions. Goodness-of-fit of biomass data from fish stock assessments in the North Atlantic between 1991 and 2003 is improved slightly by including species interactions. The differences between predictions from the two models may be relatively modest because, at the North Atlantic basin scale, (i) predators and competitors may respond to climate change together; (ii) existing parameterization of the DBEM might implicitly incorporate trophic interactions; and/or (iii) trophic interactions might not be the main driver of responses to climate. Future analyses using ecologically explicit models and data will improve understanding of the effects of inter-specific interactions on responses to climate change, and better inform managers about plausible ecological and fishery consequences of a changing environment. PMID- 23625664 TI - Multistakeholder perspectives on composite measures of ambulatory care quality: a qualitative descriptive study. AB - The development of composite measures of ambulatory care quality is an area of growing practice and policy interest. Using 29 semistructured interviews, this study describes the opinions of stakeholders related to the use and development of composite measures in a multistakeholder setting. Research experts working in multistakeholder settings need to understand the perspective of various stakeholders, many of whom have varying levels of research expertise, in order to develop useful and acceptable composite measures. Findings from this study suggest that to achieve maximal stakeholder buy-in, research experts should focus on clinical area-specific composites that are designed and constructed in a simple and transparent manner. However, composite measures are not a panacea for improving the utility of public reporting. Performance measure and report card creators should continue to investigate other ways to improve the user friendliness of their reports and to address other barriers that prevent more extensive use of reports. PMID- 23625662 TI - A transcriptome-proteome integrated network identifies endoplasmic reticulum thiol oxidoreductase (ERp57) as a hub that mediates bone metastasis. AB - Bone metastasis is the most common distant relapse in breast cancer. The identification of key proteins involved in the osteotropic phenotype would represent a major step toward the development of new prognostic markers and therapeutic improvements. The aim of this study was to characterize functional phenotypes that favor bone metastasis in human breast cancer. We used the human breast cancer cell line MDA-MB-231 and its osteotropic BO2 subclone to identify crucial proteins in bone metastatic growth. We identified 31 proteins, 15 underexpressed and 16 overexpressed, in BO2 cells compared with parental cells. We employed a network-modeling approach in which these 31 candidate proteins were prioritized with respect to their potential in metastasis formation, based on the topology of the protein-protein interaction network and differential expression. The protein-protein interaction network provided a framework to study the functional relationships between biological molecules by attributing functions to genes whose functions had not been characterized. The combination of expression profiles and protein interactions revealed an endoplasmic reticulum-thiol oxidoreductase, ERp57, functioning as a hub that retained four down-regulated nodes involved in antigen presentation associated with the human major histocompatibility complex class I molecules, including HLA-A, HLA-B, HLA-E, and HLA-F. Further analysis of the interaction network revealed an inverse correlation between ERp57 and vimentin, which influences cytoskeleton reorganization. Moreover, knockdown of ERp57 in BO2 cells confirmed its bone organ-specific prometastatic role. Altogether, ERp57 appears as a multifunctional chaperone that can regulate diverse biological processes to maintain the homeostasis of breast cancer cells and promote the development of bone metastasis. PMID- 23625665 TI - Management of mandibular deviation after mandibulectomy by simplified approach. AB - Unfavourable sequelae from mandibular surgeries include malocclusion and temporomandibular joint dysfunction. The management of the situation before these complications arise is largely based on experience. This report presents a case where mandibular deviation is decreased through an additional row of teeth in the maxillary removable partial denture, and by decreasing scar contracture in the surgical site by means of a simple exercise. PMID- 23625666 TI - Necrotising pancreatitis presenting as a painful mass in the groin and sepsis. AB - Acute pancreatitis is typically associated with classical clinical and radiological features. The sensitivity of CT to diagnose acute pancreatitis depends on the severity of the attack and ranges from 77% to 92% with a specificity approaching 100%. Despite the fact this is a common disease, there are myriad clinical presentations of acute pancreatitis. We report herein an especially rare presentation where severe acute necrotising pancreatitis presented with a tender inguinoscrotal swelling with a normal pancreas on CT imaging. PMID- 23625667 TI - Chronic eosinophilic pneumonia: a paediatric case. AB - Chronic eosinophilic pneumonia (CEP) is a rare disorder in children, characterised by respiratory and systemic symptoms, with a generally good prognosis. A 11-year-old asthmatic girl was admitted to our clinic with a 3-month history of progressive cough, dyspnoea, weight loss and asthenia. Peripheral blood eosinophilia, multiple bilateral pulmonary infiltrates to the x-ray, multiple nodules with a surrounding ground-glass halo and peripheral predominance to the chest CT suggested the diagnosis of eosinophilic lung disease (ELD). Further investigations ruled out other ELD and supported diagnosis of CEP. The response to oral corticosteroids was dramatic, no relapses were reported in 2 year follow-up while the patient was under inhaled corticosteroids for pre existing asthma. PMID- 23625668 TI - Vesicocutaneous fistula following adjuvant radiotherapy for prostate cancer. AB - Vesicocutaneous fistulas (VCF) are a rare complication of radical radiotherapy to the pelvis. Timely diagnosis and management are often difficult and complex. We report the unusual case of a 64-year-old gentleman who presented to the emergency department with worsening sepsis and profuse discharge from a cutaneous opening in the left groin. This presentation was 6 weeks following the completion of external beam radiotherapy for apical margin-positive prostate cancer (pT3a). A diagnosis of a VCF was confirmed after CT scanning of the abdomen and pelvis with contrast. Urinary diversion was achieved by a temporary urethral catheter insertion. Full resolution of this gentleman's symptoms was accomplished. In this article, we present a non-invasive approach to the management of VCF. This case raises intricate management issues in the atypical development of an early urinary tract fistula postradiotherapy. PMID- 23625669 TI - Splenic abcess owing to brucellosis. AB - Brucellosis, caused by aerobic Gram-negative coccabacilli, is prevalent worldwide. It occurs mainly because of the consumption of unpasteurised milk and contact with animals. The disease is particularly hyperendemic in the Mediterranean region and Arabian Peninsula. Its high prevalence in the UAE continues to be a major health problem, causing significant morbidity and mortality. According to the Ministry of Health, 119 cases were reported in 2010, and most of those cases were patients aged over 45. Even though an effective treatment is available for this disease, treatment failure frequently occurs owing to delay in diagnosis, relapses and its prolonged clinical course. We present a 33-year-old man who was admitted to our internal medicine teaching unit service with non-specific symptoms. A workup revealed Brucella in the blood cultures. An abdominal ultrasound showed multiple splenic abscesses. After treatment with triple therapy, the patient has remained asymptomatic at 2 years follow-up. PMID- 23625670 TI - Traumatic carotid-cavernous fistula combined with pseudoaneurysm requires immediate treatment. PMID- 23625671 TI - alpha1-Antitrypsin deficiency in a patient diagnosed with granulomatosis with polyangiitis. AB - Granulomatosis with polyangiitis is a rare type of vasculitis that affects small sized and medium-sized vessels. Any organ system can become affected, but it most commonly affects the upper airways, lungs and kidneys. The alpha1-antitrypsin deficiency is another rare disease that involves a genetic deficiency in the enzyme antitrypsin, which is produced in the liver and protects the lung against proteinases. The simultaneous occurrence of these two diseases is very rare and has been described. We present a case of granulomatosis with polyangiitis limited to the upper airways, and alpha1-antitrypsin deficiency occurring in the same patient. The patient presented with recurrent upper airway infections. The patient was treated with steroids and azathioprine which prevented recurrence of symptoms. High clinical suspicion of the concomitant occurrence of alpha1 antitrypsin deficiency in patients with vasculitis is essential to provide patients with adequate screening and treatment. PMID- 23625672 TI - Rapidly progressive osteoarthritis presenting as acute limb shortening. PMID- 23625673 TI - Cryptococcal sternal osteomyelitis in a healthy woman: a review of Cryptococcus neoformans. AB - Cryptococcus, an opportunistic yeast, known to afflict immune-compromised patients is often overlooked in immune-competent patients. This has led to increasing morbidity and mortality worldwide. We present a case of Cryptococcus causing sternal osteomyelitis in an immune-competent individual. Till date no case of Cryptococcus causing sternal osteomyelitis in an immune-competent patient has been reported in the English literature since 1946-2011. With the rising incidence of Cryptococcus infection it should be included among the list of infections causing osteomyelitis. Early detection and prompt treatment can decrease both morbidity and mortality. PMID- 23625674 TI - Pneumothorax necessitans in a patient with trapped lung and rheumatoid arthritis. AB - The authors report the case of a patient with a background of trapped lung following thoracocentesis who developed an anterolateral intercostal pneumothoracocele resulting in a pneumothorax necessitans (PN). Our purpose is to highlight the pathophysiology and interesting radiological features associated with PN in trapped lung. Our case is particularly unique due to the subacute nature of its presentation in a patient with rheumatoid arthritis and unusual pre existing lung pathology. PMID- 23625675 TI - Successful treatment of acute hereditary angioedema attacks with self administered icatibant in patients with venous access problems. AB - Hereditary angioedema is a rare and potentially fatal autosomal dominant disorder characterised by unpredictable skin, gastrointestinal tract or respiratory tract oedema. Plasma-derived C1-esterase inhibitors are effective in the prophylaxis or treatment of hereditary angioedema type I and II attacks, but must be administered intravenously. This may be problematic in patients with venous access difficulties. Icatibant, a bradykinin B2-receptor antagonist, is administered subcutaneously. In July 2008 icatibant received approval for healthcare professional-administered treatment of hereditary angioedema attacks in adults. In 2011 it received European Medicines Agency and US Food and Drug Administration licences for patient-administered treatment of hereditary angioedema attacks. Given these approvals, and with the appropriate training, icatibant could provide the opportunity for patients to self-administer treatment. This is one of the first long-term follow-up reports of patients with hereditary angioedema using self-administered icatibant. During follow-up, icatibant remained effective and patient satisfaction was high. PMID- 23625676 TI - Nevirapine-induced Stevens-Johnson syndrome following HIV postexposure prophylaxis. AB - A 25-year-old Caucasian heterosexual man with a recent history of unprotected sex in Vietnam while on a holiday was prescribed HIV postexposure prophylaxis by a local doctor; nevirapine, stavudine and lamivudine. He was subsequently admitted to a UK hospital with sore throat, bilateral conjunctivitis, genital ulceration and severe widespread maculo-papular rash. Extensive investigations for infective causes were negative and he was subsequently recovered with conservative therapy. PMID- 23625677 TI - A rare cause of epigastric pain in a middle-aged man. AB - A 50-year-old man presents to the emergency department with epigastric pain and is found to have severe hypertension on clinical examination. After admission to hospital, further investigation with CT imaging reveals the patient has an uncomplicated splenic artery dissection. Conservative management is chosen as advised by a vascular surgery team and the patient was subsequently discharged from hospital with warfarin anticoagulation and antihypertensive medicines. This case report aims to build a profile of a patient who may present with splenic artery dissection and details our recommended management plan. PMID- 23625678 TI - A simplified technique for bend backs in lingual orthodontics. PMID- 23625679 TI - Giant plexiform neurofibroma causing asymptomatic cervical spinal cord compression in a child with neurofibromatosis type 1. PMID- 23625680 TI - Resolution of trigeminal neuralgia by coil embolization of a persistent primitive trigeminal artery aneurysm. AB - The persistent primitive trigeminal artery (PTA) is a rare anastomosis between the carotid artery and basilar artery. While most PTAs are asymptomatic, lateral variants can occasionally compress the trigeminal nerve and precipitate trigeminal neuralgia. Aneurysms of the PTA are exceptionally rare in the literature and have not previously been associated with trigeminal neuralgia. We present the first case of an aneurysm of the PTA causing trigeminal neuralgia. The patient underwent coil embolization of the aneurysm which relieved her symptoms. We propose embolization as a viable therapeutic option for the resolution of trigeminal neuralgia when the condition is secondary to irritation by the high velocity pulsatile flow of an aneurysm. PMID- 23625681 TI - Bioavailability of the major bioactive diterpenoids in a rosemary extract: metabolic profile in the intestine, liver, plasma, and brain of Zucker rats. AB - SCOPE: Carnosic acid (CA) and derived diterpenes abundant in rosemary extracts (REs) exert anti-obesity effects. The aim of this study was to investigate the bioavailability of these compounds in a rat model of obesity. METHODS AND RESULTS: A total of 26 compounds were tentatively identified based on accurate mass information and the isotopic pattern provided by TOF-MS analyzer. The main metabolites detected in the gut content, liver, and plasma were the glucuronide conjugates of CA, carnosol, and rosmanol. Two other metabolites were also identified: CA 12-methyl ether and 5,6,7,10-tetrahydro-7-hydroxyrosmariquinone. All the metabolites were detected as early as 25 min following oral administration. Most of the compounds remained in the intestine, liver, and (or) plasma at substantial concentrations for several hours supporting their potential health benefits in these tissues. We also corroborated the presence of small quantities of CA and detected trace quantities of the main CA metabolites in the brain. Notably, we did not find significant differences in the metabolic profile between lean and obese rats. CONCLUSION: We report for the first time a comprehensive profile of metabolites in various organs following the oral consumption of an RE enriched in CA and contribute to establish the potential bioactive molecules. PMID- 23625682 TI - Severe anemia in 3 toddlers with gastric lactobezoar. AB - BACKGROUND: Anemia in toddlers may result from many disorders including excessive feeding with cow's milk. Another sequel of age-inadequate cow's milk nutrition may be gastric lactobezoar (GLB), a dense lump of coagulated milk and mucus in the stomach. PATIENTS: 3 toddlers presented with a history of excessive intake of full cream cow's milk, abdominal distension, vomiting, dehydration, fatigue, marked pallor and tachycardia. DIAGNOSTIC WORKUP: Diagnostic imaging revea-led large GLBs as the likely origin of the abdominal symptoms. Laboratory evaluation showed severe anemia with depleted iron stores and signs of protein catabolism. Non-cow's milk-induced causes of anemia including defects of erythropoiesis, hemoglobin structure, RBC-enzymes and blood coagulation, hemolysis, immune disorders, infection, inflammation, extraintestinal hemorrhage, nephropathy were according to the available data - unlikely to cause the anemia in our patients. Thus their anemia is thought to be due to age-inadequate cow's milk nutrition leading to 1) low intake, decreased absorption/bioavailability and increased intestinal loss of iron, and 2) GLB which induced blood loss following mechanical irritation of the gastric mucosa and vomiting causing high gastric pH and decrease in duodenal iron absorption. CONCLUSION: The anemia in our patients is due to both exaggerated feeding with cow's milk and adverse effects of GLBs. This hypothesis is supported by the finding that, after erythrocyte transfusion, iron substitution, age-adapted nutrition and GLB-dissolution, the anemia did not recur. We propose to include GLB in the differential diagnosis of anemia in cow's milk fed small children. PMID- 23625683 TI - Normalized transcranial Doppler velocities, stroke prevention and improved pulmonary function after stem cell transplantation in children with sickle cell anemia. AB - BACKGROUND: Abnormal transcranial Doppler velocities (TCD) indicate an increased risk of stroke in patients with sickle cell anemia (SCA) and require regular blood transfusions. Hematopoietic stem cell transplantation (HSCT) is under discussion as an alternative to chronic transfusion in these patients. PATIENTS AND METHODS: This retrospective analysis includes 9 patients with SCA undergoing HSCT at a single center in Germany. Special focus was given to the neurologic follow-up and to the results of TCD studies. RESULTS: High risk of stroke or previous stroke was an HSCT-indication in 8 of 9 patients, although most patients had more than one indication for HSCT. TCD was normalized in all 5 patients after HSCT in whom this test was available. None of the patients developed a stroke after HSCT. No further strokes occurred even in patients that experienced recurrent strokes during chronic transfusion before HSCT. 2 of the 9 patients received a 10/10 HLA-matched unrelated donor graft, the others matched related grafts.All patients were alive, free of SCA symptoms and transfusion-independent with stable chimerism 3-11 years after HSCT. Pulmonary function tests normalized in 1 patient with severe sickle cell lung disease. CONCLUSION: HSCT is able to prevent stroke in patients with SCA. Its perspectives and limitations should be discussed early during the treatment of a patient with complicated SCA. PMID- 23625684 TI - DICER1 syndrome: a new cancer syndrome. AB - Recently, germline mutations of DICER1 have been identified in patients with rare neoplasms suggesting the existence of a newly discovered cancer prone syndrome. Initially, DICER1 mutations were identified in patients with familial pleuropulmonary blastoma. Subsequently, additional manifestations of the syndrome have been identified including cystic nephroma, medulloepithelioma, Sertoli Leydig cell tumor and others. The DICER1 gene encodes an enzyme that is involved in the biogenesis of microRNAs. The entire tumor spectrum and the respective tumor risks are unknown. We are in the process of launching a natural history study aimed at identifying more information on this new cancer syndrome. PMID- 23625685 TI - Molecular targeted therapies for rhabdomyosarcoma: focus on hedgehog and apoptosis signaling. AB - Dysfunction of cell death and proliferation pathways can contribute to rhabdomyosarcomagenesis, tumor progression and treatment resistance. Therefore, the identification of key signaling hubs and molecules that govern the decision between life and death of a cancer cell is expected to open new perspectives for drug discovery. For example, programmed cell death pathways can be engaged in rhabdomyosarcoma (RMS) cells by recombinant soluble proteins, monoclonal antibodies or small-molecule inhibitors. In addition, the hedgehog (Hh) cascade is often aberrantly activated in RMS and represents a promising target for therapeutic intervention. The development of molecular targeted cancer therapeutics will likely lead to more effective treatment options for patients with RMS. PMID- 23625686 TI - Acute promyelocytic leukemia complicated by massive intracerebral hemorrhage: safety and efficacy of replacing conventional chemotherapy with arsenic trioxide in an adolescent. PMID- 23625688 TI - Crystal structure of deltarhodopsin-3 from Haloterrigena thermotolerans. AB - Deltarhodopsin, a new member of the microbial rhodopsin family, functions as a light-driven proton pump. Here, we report the three-dimensional structure of deltarhodopsin (dR3) from Haloterrigena thermotolerans at 2.7 A resolution. A crystal belonging to space group R32 (a, b = 111.71 A, c = 198.25 A) was obtained by the membrane fusion method. In this crystal, dR3 forms a trimeric structure as observed for bacteriorhodopsin (bR). Structural comparison of dR with bR showed that the inner part (the proton release and uptake pathways) is highly conserved. Meanwhile, residues in the protein-protein contact region are largely altered so that the diameter of the trimeric structure at the cytoplasmic side is noticeably larger in dR3. Unlike bR, dR3 possesses a helical segment at the C-terminal region that fills the space between the AB and EF loops. A significant difference is also seen in the FG loop, which is one residue longer in dR3. Another peculiar property of dR3 is a highly crowded distribution of positively charged residues on the cytoplasmic surface, which may be relevant to a specific interaction with some cytoplasmic component. PMID- 23625687 TI - Taste intensity in the Beaver Dam Offspring Study. AB - OBJECTIVES/HYPOTHESIS: To determine the distribution of the perceived intensity of salt, sweet, sour, and bitter in a large population and to investigate factors associated with perceived taste intensity. STUDY DESIGN: Cross-sectional population. METHODS: Subjects (n = 2,374; mean age, 48.8 years) were participants in the Beaver Dam Offspring Study examined during 2005 to 2008. Perceived taste intensity was measured using paper disks and a general labeled magnitude scale. Multiple linear regression was performed. RESULTS: Mean intensity ratings were: salt = 27.2 (standard deviation [SD] = 18.5), sweet = 20.4 (SD = 15.0), sour = 35.7 (SD = 21.4), and bitter = 49.6 (SD = 23.3). Females and those with less than a college degree education rated tastes stronger. With adjustment for age, sex, and education, stronger perceived sour and bitter intensities were related to current smoking (sour: B = 2.8, 95% confidence interval [CI], 0.4 to 5.2; bitter: B = 2.8, 95% CI, 0.3 to 5.4) and lipid-lowering medications (sour: B = 5.1, 95% CI, 2.5 to 7.6; bitter: B = 3.2, 95% CI, 0.6 to 5.8). Alcohol consumption in the past year was related to weaker salt (B = -2.8, 95% CI, -5.3 to -0.3) and sweet intensity ratings (B = -2.3, 95% CI, -4.3 to -0.3), whereas olfactory impairment was associated with higher sweet ratings (B = 4.7, 95% CI, 1.4 to 7.9). CONCLUSIONS: Perceived intensities were strongest for bitter and weakest for sweet. Sex and education were associated with each taste, whereas age did not demonstrate a consistent relationship. Associations with other factors differed by tastants, with current smoking and alcohol consumption being related to some tastes. PMID- 23625690 TI - A novel sorbent for chromatographic separations: a silica matrix modified with non-covalently bonded tetrakis(beta-cyclodextrin)-porphyrin conjugates. AB - We prepared new phases for LC that consisted of silica modified with non covalently bonded tetrakis(beta-cyclodextrin)-porphyrin (where cyclodextrin is CD) conjugates. The effects of the porphyrin core, type of spacer and beta-CD moieties on the behaviours of the modified phases for the separation of aromatic compounds (benzene, toluene, ethylbenzene, propylbenzene, butylbenzene, pentylbenzene, o-terphenyl, triphenylene, phenol and caffeine) and fluorinated aromatic compounds (pentafluorobenzonitrile, pentafluoronitrobenzene and hexafluorobenzene) were studied using the Tanaka test. The results indicate that the non-covalent substitution of silica with CD-based macromolecules that have a porphyrin core can be a very effective method for preparing novel sorbents with specific chromatographic properties for applications in LC. PMID- 23625689 TI - The Ah receptor regulates growth factor expression in head and neck squamous cell carcinoma cell lines. AB - Previous studies in head and neck squamous cell carcinoma (HNSCC) cell lines have revealed that the Ah receptor (AHR) plays a significant role in mediating the "aggressive" phenotype of these cells, which includes enhanced inflammatory signaling (e.g., IL6) and migratory potential. Here we sought to identify putative novel targets of the AHR associated with enhanced tumor invasiveness. Global gene expression analysis identified a number of genes that are repressed upon treatment of OSC-19 or HN30 cells with an AHR antagonist. Three growth factors were targets of AHR activity; amphiregulin (AREG), epiregulin (EREG), and platelet-derived growth factor A (PDGFA) were repressed by an AHR antagonist and further examined. Quantitative PCR analysis, ELISA, and siRNA-mediated knock down of AHR revealed an attenuation of basal and/or induced levels of expression of these growth factors in two HNSCC lines, following AHR antagonism. In silico analysis revealed that these growth factors possess dioxin-like response elements. Two other AHR ligands, 6-formylindolo[3,2-b]carbazole and benzo(a)pyrene (BP) also elicited similar responses. In conclusion, this study identified AREG, EREG, and PDGFA as growth factor targets of AHR activity associated with metastatic phenotype of HNSCC cells, suggesting that attenuation of AHR activity may be a therapeutic strategy. PMID- 23625691 TI - The evolution of simulation techniques for dynamic bone tissue engineering in bioreactors. AB - Bone tissue engineering aims to overcome the drawbacks of current bone regeneration techniques in orthopaedics. Bioreactors are widely used in the field of bone tissue engineering, as they help support efficient nutrition of cultured cells with the possible combination of applying mechanical stimuli. Beneficial influencing parameters of in vitro cultures are difficult to find and are mostly determined by trial and error, which is associated with significant time and money spent. Mathematical simulations can support the finding of optimal parameters. Simulations have evolved over the last 20 years from simple analytical models to complex and detailed computational models. They allow researchers to simulate the mechanical as well as the biological environment experienced by cells seeded on scaffolds in a bioreactor. Based on the simulation results, it is possible to give recommendations about specific parameters for bone bioreactor cultures, such as scaffold geometries, scaffold mechanical properties, the level of applied mechanical loading or nutrient concentrations. This article reviews the evolution in simulating various aspects of dynamic bone culture in bioreactors and reveals future research directions. PMID- 23625693 TI - The cost-effectiveness of oral direct factor Xa inhibitors compared with low molecular-weight heparin for the prevention of venous thromboembolism prophylaxis in total hip or knee replacement surgery. AB - INTRODUCTION: Major orthopedic surgery is associated with a high risk of venous thromboembolism (VTE). Anticoagulants are recommended to prevent VTE, and recently an oral direct factor Xa inhibitor (FXaI) was approved for this indication. We compared the cost-effectiveness of FXaIs with low-molecular-weight heparin (LMWH) in patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery. DESIGN: A decision-tree model was developed to compare the cost-effectiveness of oral direct FXaIs (rivaroxaban, apixaban, and edoxaban) to subcutaneous LMWHs (enoxaparin and dalteparin), with separate models for THR and TKR. The analysis was conducted over a 180-day postoperative time horizon from the U.S. Medicare perspective. The model was developed using TreeAge Pro 2011 (TreeAge Software Inc., Williamstown, MA, USA). METHODS: Efficacy and safety data (probabilities of distal and proximal deep vein thrombosis, symptomatic pulmonary embolism, and major bleeding) were derived from a systematic review and meta-analysis of phase II and III clinical trials. Costs and quality-adjusted life-years (QALYs) are reported. One-way and probabilistic sensitivity analyses were performed to evaluate parameter uncertainty. RESULTS: In the THR model, the average costs per patient for FXaIs and LMWHs were $18,762 and $18,897, respectively, and the QALYs were 0.938 and 0.932. In the TKR model, the average cost per patient for FXaIs and LMWHs were $18,804 and $18,991, respectively, and the QALYs were 0.935 and 0.931. In both models, FXaIs dominated LMWH (less costly and more efficacious). Neither model was sensitive to changes in any of the variables in the one-way sensitivity analyses. Probabilistic sensitivity analysis indicated that FXaIs were cost-effective in more than 99% of iterations in the THR population and in 98% of iterations in the TKR population assuming a willingness-to-pay threshold of $50,000/QALY. CONCLUSION: Oral direct FXaIs may be an economically dominant strategy compared with LMWHs for VTE prophylaxis in patients undergoing either THR or TKR surgery. PMID- 23625692 TI - Targeting the PI3K/AKT/mTOR signaling pathway in glioblastoma: novel therapeutic agents and advances in understanding. AB - Glioblastoma multiforme (GBM) is a grade IV astrocytoma with a median survival of 12 months despite current multi-modal treatment options. GBM is distinguished clinicopathologically into primary and secondary subtypes. Mutations of phosphatase and tensin homolog, and subsequent upregulation of the downstream protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway, are commonly seen in primary GBM and less predominantly in secondary GBM. While investigations into targeted treatments of mTOR have been attempted, feedback regulation within the mTOR signaling pathway may account for therapeutic resistance. Currently, rapamycin analogs, dual-targeted mTOR complex 1 and 2 agents as well as dual mTOR and phosphatidylinositol-3 kinase-targeted agents are being investigated experimentally and in clinical trials. This review will discuss the experimental potential of these agents in the treatment of GBM and their current stage in the GBM drug pipeline. Knowledge obtained from the application of these agents can help in understanding the pathogenesis of GBM as well as delineating subsequent treatment strategies. PMID- 23625694 TI - Lipase in aqueous-polar organic solvents: activity, structure, and stability. AB - Studying alterations in biophysical and biochemical behavior of enzymes in the presence of organic solvents and the underlying cause(s) has important implications in biotechnology. We investigated the effects of aqueous solutions of polar organic solvents on ester hydrolytic activity, structure and stability of a lipase. Relative activity of the lipase monotonically decreased with increasing concentration of acetone, acetonitrile, and DMF but increased at lower concentrations (upto ~20% v/v) of dimethylsulfoxide, isopropanol, and methanol. None of the organic solvents caused any appreciable structural change as evident from circular dichorism and NMR studies, thus do not support any significant role of enzyme denaturation in activity change. Change in 2D [15N, 1H]-HSQC chemical shifts suggested that all the organic solvents preferentially localize to a hydrophobic patch in the active-site vicinity and no chemical shift perturbation was observed for residues present in protein's core. This suggests that activity alteration might be directly linked to change in active site environment only. All organic solvents decreased the apparent binding of substrate to the enzyme (increased Km ); however significantly enhanced the kcat . Melting temperature (Tm ) of lipase, measured by circular dichroism and differential scanning calorimetry, altered in all solvents, albeit to a variable extent. Interestingly, although the effect of all organic solvents on various properties on lipase is qualitatively similar, our study suggest that magnitudes of effects do not appear to follow bulk solvent properties like polarity and the solvent effects are apparently dictated by specific and local interactions of solvent molecule(s) with the protein. PMID- 23625695 TI - Effects of soil trace elements on longevity population in China. AB - Based on background concentrations of elements in soils and the sixth population census data of China, this study discussed the distribution characteristics of soil elements and longevity population at province level in China. Percentages of the aging population are high in Southwest China and the eastern coastal region but low in western and northwestern regions. Provinces in South and Southwest China gain a high level of longevity, while the northern part of China has a low level of longevity. The background concentration of Se in soil has a significant positive correlation with longevity index, while Ba and Ni have a significant negative correlation with longevity indexes. By regression analysis, longevity index C/100,000 can be expressed as C/100,000 = 1.679-0.205 Ni + 0.413 Co + 0.006 Se (with R (2) = 0.402 and p < 0.01), C/65+ can be expressed as C/65+=3.425-0.262 Ni + 0.435 Co + 0.006 Se (with R (2) = 0.369 and p < 0.01). PMID- 23625696 TI - Antidiabetic and pancreas-protective effects of zinc threoninate chelate in diabetic rats may be associated with its antioxidative stress ability. AB - Zinc exerts a wide range of important biological roles. The present study was carried out to investigate the effects of zinc threoninate chelate in blood glucose levels, lipid peroxidation, activities of antioxidant defense systems and nitrite concentration, and histology of the pancreas in diabetic rats. Wistar rats were intravenously injected with a single dose of streptozotocin to induce diabetes. Then, diabetic rats were administrated orally with zinc threoninate chelate (3, 6, and 9 mg/kg body weight) once daily for 7 weeks. Fasting blood glucose was monitored weekly. At the end of the experimental period, the diabetic rats were killed, and levels of serum insulin, malondialdehyde, and nitric oxide, activities of glutathione peroxidase, total superoxide dismutase, copper/zinc superoxide dismutase, and nitric oxide synthase were determined; pancreas was examined histopathologically as well. Zinc threoninate chelate significantly reduced the blood glucose levels and significantly increased the serum insulin levels in diabetic rats. In addition, zinc threoninate chelate caused a significant increase in activities of antioxidant enzymes and significant decrease in nitrite concentration and malondialdehyde formation in the pancreas and serum of diabetic rats. These biochemical observations were supplemented by histopathological examination of the pancreas. These results suggested that the antidiabetic effect of zinc threoninate chelate may be related to its antioxidative stress ability in diabetic rats. PMID- 23625697 TI - Alteration in glutathione homeostasis and oxidative stress during the sequelae of trimethyltin syndrome in rat brain. AB - Trimethyltin (TMT), a by-product of tin, is used in a wide variety of industrial and agricultural purposes which serves as a model neurotoxicant in hippocampal neurodegeneration, and this could, in turn, be exploited for various therapeutic compounds essential for hippocampal neurodegeneration. Therefore, the present investigation explores the sequential changes in behavior, oxidative burden, and apoptosis following TMT administration in rat hippocampus. Male SD rats weighing 250 g were given single dose of 8.5 mg/kg TMT (i.p.) that resulted in "TMT syndrome" which begins at the third post-TMT exposure and continued till 21 days posttreatment. This resulted in behavioral alteration (aggression and spontaneous seizures), cognitive impairment as assessed by plus maze, and passive avoidance resulting in short-term memory deficits. These behavioral alterations were associated with an increase in oxidative stress. The levels of malondialdehyde, reactive oxygen species, and protein carbonyl were significantly increased (p < 0.001) in the TMT-treated rats after the third day of exposure and were maximum at day 14 postexposure. The glutathione system was not able to adapt rapidly in response to oxidative stress which resulted in imbalance in redox status. The imbalance in the redox state resulted in the death of neurons as seen by a significant increase in caspase activation at gene as well as protein level after TMT exposure on day 14, quoting an extent of changes. Therefore, it is proposed that behavioral deficits could be accounted by the impairment of endogenous glutathione homeostasis which resulted in death of neurons in the hippocampal region. PMID- 23625698 TI - Determination of lead in biological samples of children with different physiological consequences using cloud point extraction method. AB - In present study, lead (Pb) level in biological samples of children with physiological disorders (liver, bone, and gastrointestinal; age ranged 1-10 years) have been assessed. For comparison purpose, age-matched healthy children were also selected. Cloud point extraction (CPE) was employed for preconcentration of Pb in acid-digested biological samples prior to its determination by flame atomic absorption spectrometry (FAAS). Dithizone (diphenylthiocarbazone) and nonionic surfactant Triton X-114 (TX-114) were used as complexing reagent and extractant, respectively. The effects of several experimental variables on proposed CPE were evaluated. Under the optimum experimental conditions, the observed detection limit (LOD) and the enhancement factor (EF) were 0.08 MUg L(-1) and 53, respectively. Relative standard deviation (RSD) of 10 MUg L(-1) Pb was 3.4 %. It was observed that children with liver-, bone-, and gastrointestinal-related disorders had three- to fourfold higher Pb level in blood and scalp hair samples. PMID- 23625699 TI - Reverse relationship between blood boron level and body mass index in humans: does it matter for obesity? AB - The exact role of boron in humans is not known although its supplementation causes several important metabolic and inflammatory changes. The objective of this study is to evaluate the possibility of an association between blood boron level and obesity in normal, overweight, obese, and morbidly obese subjects. A total number of 80 subjects, categorized into four groups based on their body mass index as normal, overweight, obese, and morbidly obese, were enrolled in this study. Age, sex, body mass index, and blood boron levels were recorded for each subject. Although the distribution of female and male subjects and blood boron levels were similar between groups, the mean age of normal subjects was significantly lower than the others (p = 0.002). There was a significant relationship between age and quantitative values of body mass index for each subject (beta = 0.24; p = 0.003). In addition, between blood boron levels and quantitative values of body mass index for each subject, a significant reverse relationship was detected (beta = -0.16; p = 0.043). Although age seemed to be an important variable for blood boron level and body mass index, blood boron levels were shown to be lower in obese subjects in comparison to non-obese subjects. PMID- 23625700 TI - High burden of metastases and poor outcome in pelvic PNET. AB - Data on prognostic factors in pelvic PNET are minimal. We analyzed patients with pelvic PNET treated between June 2003 and November 2011 for prognostic factors. Forty-eight (13%) of 374 patients with PNET were pelvic PNET with median age 14.5 years (range: 5-33); 31 (65%) had metastases. After median follow-up of 20.4 months (range: 1.3-64.9), 3-year EFS, OS, and local-control-rate were 13.5 +/- 5.5%, 15.4 +/- 9%, and 41.3 +/- 14.9%, respectively. Hypoalbuminemia (<=3.4 g/dl) predicted inferior EFS and OS for both entire cohort and metastatic group. All patients with hypoalbuminemia (n = 10) had low BMI as compared to 23/38 without hypoalbuminemia (P = 0.02). PMID- 23625701 TI - Salinity and copper interactive effects on Perez's frog Pelophylax perezi. AB - The present study was intended to assess the influence of salinity on the effects of copper on 2 life stages of Pelophylax perezi. Single and combined effects of salinity (NaCl) and Cu on survival, malformations, body length, and biochemical markers (catalase [CAT], cholinesterases, lactate dehidrogenase [LDH], and glutathione S-transferase) of individuals were evaluated in a multifactorial design. Two experiments were performed, 1 with embryos and the other with tadpoles. Each of these life stages was exposed to individual and combinations of Cu (0.0-7.4 mg/L and 0.0-2.4 mg/L, respectively) and NaCl (0.0-10.2 g/L and 0.0 7.4 g/L, respectively) concentrations. Copper alone had a higher lethal toxicity to tadpoles (90%; 2.4 mg/L) than to embryos (65%; 7.4 mg/L). Conversely, NaCl alone had a higher lethal toxicity to embryos (100%; 6.9 g/L) than to tadpoles (50%; 7.4 g/L). The 4 lowest tested NaCl concentrations decreased the lethal effects of Cu to embryos and the incidence of malformations, but the same outcome was not observed for tadpoles. Regarding enzymatic activities, although significant interactions between Cu and NaCl were observed for the activity of CAT and LDH in embryo and tadpole, a consistent pattern of NaCl and Cu interactive effects was not observed. The authors' results suggest a life-stage dependence on the effects of exposure to the individual substances or their combination. Also, it was observed that moderate salinity might have a shield effect against Cu lethal toxicity for embryos of P. perezi. These results highlight the need within ecological risk evaluations to characterize the sensitivity of different amphibian life stages to individual chemicals but also their combination with other environmental conditions resulting from climate changes. PMID- 23625702 TI - Quantification of total thyroxine in plasma from Xenopus laevis. AB - There is evidence that the endocrine systems of certain fish and wildlife can be affected by chemical contaminants, possibly resulting in developmental and reproductive problems. Perturbations in the hypothalamus-pituitary-thyroid (HPT) axis, in particular, can be detrimental during early development. Because the rate of amphibian metamorphosis is controlled by circulating thyroid hormones, tadpoles undergoing metamorphosis have been selected as relevant test organisms for evaluating the potential effects of a substance on the HPT axis in vertebrates. An indicative measure of HPT functioning in these assays is the concentration of the thyroid hormone, thyroxine (T4), in frog plasma. Therefore, there is a need for a validated method to measure T4 in plasma during amphibian metamorphosis. This study describes a method involving mixed-mode strong cation exchange solid-phase extraction (SPE) with ultrahigh-performance liquid chromatography and isotope dilution tandem mass spectrometry (UPLC-ID-MS-MS) to quantify total T4 in a small volume (10 uL) of plasma from Xenopus laevis (African clawed frog). The SPE procedure, together with MS detection, produced the required selectivity for the analysis of both T4 and the T4 internal standard. The limit of detection of the method was determined to be 0.2 ng/mL, whereas the lower limit of quantification was 0.5 ng/mL. The intra-day and inter day precision values were less than +/- 5 and +/-10%, respectively. Concentrations of total T4 in the plasma of X. laevis tadpoles at metamorphic peak were calculated to be 10.7 +/- 0.8 ng/mL, which is comparable to the results from radioimmunoassay. This validated UPLC-ID-MS-MS method for the determination of total T4 in plasma has demonstrated good accuracy and precision, with low susceptibility to interferences with the utilization of multiple reaction monitoring and ID. PMID- 23625703 TI - Validation of a novel immunoassay for the detection of synthetic cannabinoids and metabolites in urine specimens. AB - Synthetic cannabinoid drugs do not cross react on traditional marijuana immunoassay tests, preventing their use in large scale drug screening programs. This paper describes the validation and performance characteristics of two enzyme linked immunosorbent assays designed to detect the use of two common synthetic cannabinoids in urine, JWH-018 and JWH-250. The JWH-018 assay has significant cross-reactivity with several synthetic cannabinoids and their metabolites, whereas the JWH-250 assay has limited cross-reactivity. The assays are calibrated at 5 ng/mL with the 5-OH metabolite of JWH-018 and the 4-OH metabolite of JWH 250. The method was validated with 114 urine samples for JHW-018 and 84 urine samples for JWH-250 and confirmed by using liquid chromatography tandem mass spectrometry, which tests for metabolites of JWH-018, JWH-019, JWH-073, JWH-250 and AM-2201. The accuracy was determined to be 98% with greater than 95% sensitivity and specificity for both assays. PMID- 23625704 TI - Histologic comparison of vocal fold microflap healing with sutures and glue. AB - OBJECTIVES/HYPOTHESIS: Improved voice quality is the expected outcome of microphonosurgery. To this end, the complex vibratory movement of the vocal folds must be preserved. Scarring of the vocal folds may compromise vocal outcome and is one of the most difficult to treat conditions. To minimize scar formation, a consensus exists on the need for maximum preservation of the epithelium and superficial lamina propria, and minimal exposure of vocal ligament. However, the need to cover the microflap defect is controversial. The aim of this study was to compare healing characteristics of microflap technique when the microflap is left to heal by second intention, when the defect is closed with sutures, and when it is covered with glue. STUDY DESIGN: Experimental animal study. MATERIAL AND METHODS: An experimental study comparing the three techniques was carried out on 37 New Zealand rabbits. Vocal fold healing was evaluated 7, 30, and 90 days after surgical intervention. Collagen concentration, inflammatory reaction, epithelium, and lamina propria thickness were evaluated. RESULTS: Collagen concentration significantly increased in all groups. After 7 days, epithelium thickness significantly increased and lamina propria thickness was not significantly altered. At 90 days, only the suture group showed no significant alteration in epithelium thickness. After 90 days, lamina propria thickness decreased, except in the fibrin glue group. No difference was seen in the number of inflammatory cells among the techniques. CONCLUSIONS: The use of microsutures or fibrin glue to close microflap defects did not consistently improve vocal fold healing nor produce better scarring results when compared to healing by second intention. PMID- 23625706 TI - Optimization of programmed-temperature vaporization injection preparative capillary GC for compound specific radiocarbon analysis. AB - Preparative capillary GC (PCGC) is a powerful tool for the separation and purification of compounds from any complex matrix, which can be used for compound specific radiocarbon analysis. However, the effect of PCGC parameters on the trapping efficiency is not well understood. Here, we present a comprehensive study on the optimization of parameters based on 11 reference compounds with different physicochemical properties. Under the optimum conditions, the trapping efficiencies of these 11 compounds (including high-boiling-point n-hentriacontane and methyl lignocerate) are about 80% (60-89%). The isolation of target compounds from standard solutions, plant and soil samples demonstrates that our optimized method is applicable for different classes of compounds including n-alkanes, fatty acid esters, long-chain fatty alcohol esters, polycyclic aromatic hydrocarbons (PAHs) and steranes. By injecting 25 MUL in large volume injection mode, over 100 MUg, high purity (>90%) target compounds are harvested within 24 h. The recovery ranges of two real samples are about 70% (59.9-83.8%) and about 83% (77.2-88.5%), respectively. Compared to previous studies, our study makes significant improvement in the recovery of PCGC, which is important for its wide application in biogeochemistry, environmental sciences, and archaeology. PMID- 23625705 TI - Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors. AB - BACKGROUND: It has been previously shown that CB1 cannabinoid receptor agonism using cannabis extracts alleviates spasticity in both a mouse experimental autoimmune encephalomyelitis (EAE) model and multiple sclerosis (MS) in humans. However, this action can be associated with dose-limiting side effects. OBJECTIVE: We hypothesised that blockade of anandamide (endocannabinoid) degradation would inhibit spasticity, whilst avoiding overt cannabimimetic effects. METHODS: Spasticity eventually developed following the induction of EAE in either wild-type or congenic fatty acid amide hydrolase (FAAH)-deficient Biozzi ABH mice. These animals were treated with a variety of different FAAH inhibitors and the effect on the degree of limb stiffness was assessed using a strain gauge. RESULTS: Control of spasticity was achieved using FAAH inhibitors CAY100400, CAY100402 and URB597, which was sustained following repeated administrations. Therapeutic activity occurred in the absence of overt cannabimimetic effects. Importantly, the therapeutic value of the target could be definitively validated as the treatment activity was lost in FAAH-deficient mice. Spasticity was also controlled by a selective monoacyl glycerol lipase inhibitor, JZL184. CONCLUSIONS: This study demonstrates definitively that FAAH inhibitors provide a new class of anti-spastic agents that may have utility in treating spasticity in MS and avoid the dose-limiting side effects associated with cannabis use. PMID- 23625707 TI - Soil invertebrate fauna affect N2 O emissions from soil. AB - Nitrous oxide (N2 O) emissions from soils contribute significantly to global warming. Mitigation of N2 O emissions is severely hampered by a lack of understanding of its main controls. Fluxes can only partly be predicted from soil abiotic factors and microbial analyses - a possible role for soil fauna has until now largely been overlooked. We studied the effect of six groups of soil invertebrate fauna and tested the hypothesis that all of them increase N2 O emissions, although to different extents. We conducted three microcosm experiments with sandy soil and hay residue. Faunal groups included in our experiments were as follows: fungal-feeding nematodes, mites, springtails, potworms, earthworms and isopods. In experiment I, involving all six faunal groups, N2 O emissions declined with earthworms and potworms from 78.4 (control) to 37.0 (earthworms) or 53.5 (potworms) mg N2 O-N m(-2) . In experiment II, with a higher soil-to-hay ratio and mites, springtails and potworms as faunal treatments, N2 O emissions increased with potworms from 51.9 (control) to 123.5 mg N2 O-N m(-2) . Experiment III studied the effect of potworm density; we found that higher densities of potworms accelerated the peak of the N2 O emissions by 5 days (P < 0.001), but the cumulative N2 O emissions remained unaffected. We propose that increased soil aeration by the soil fauna reduced N2 O emissions in experiment I, whereas in experiment II N2 O emissions were driven by increased nitrogen and carbon availability. In experiment III, higher densities of potworms accelerated nitrogen and carbon availability and N2 O emissions, but did not increase them. Overall, our data show that soil fauna can suppress, increase, delay or accelerate N2 O emissions from soil and should therefore be an integral part of future N2 O studies. PMID- 23625708 TI - [Briefing and accusation of medical malpractice--the second victim]. AB - In June 2012, the German Medical Association (Bundesarztekammer) published the statistics of medical malpractice for 2011 [1]. Still ENT-specific accusations of medical malpractice are by far the fewest in the field of hospitals and actually even in the outpatient context. Clearly most of the unforeseen incidents still occur in the disciplines of trauma surgery and orthopedics. In total, however, an increasing number of errors in treatment can be noticed on the multidisciplinary level: in 25.5% of the registered cases, an error in treatment was found to be the origin of damage to health justifying a claim for compensation of the patient. In the year before, it was only 24.7%. The reasons may be manifold, but the medical system itself certainly plays a major role in this context: the recent developments related to health policy lead to a continuous economisation of medical care. Rationing and limited remuneration more and more result in the fact that therapeutic decisions are not exclusively made for the benefit of the patient but that they are oriented at economic or bureaucratic aspects. Thus, in the long term, practising medicine undergoes a change. According to the SS 1, 3 of the professional code of conduct for doctors (Musterberufsordnung fur Arzte; MBO-A) medical practice as liberal profession is principally incompatible with the pursuit of profit, however, even doctors have to earn money which more and more makes him play the role of a businessman. Lack of personnel and staff savings lead to excessive workloads of physicians, caregivers, and nurses, which also favour errors. The quality and even the confidential relationship between doctor and patient, which is important for the treatment success, are necessarily affected by the cost pressure. The victims in this context are not only the patients but also the physicians find themselves in the continuous conflict between ethical requirements of their profession and the actual requirements of the realities in the healthcare field. But also the technical and scientific progress bear new risks beside the therapeutic successes, further especially bigger hospitals require high efforts regarding organisation favouring errors in cases of deficiencies. Even the increasing juridification of the medicine that is expected to achieve a provisional highlight with the planned law of patients' rights leads to an important focus on the quality of medical care [2]. The explicit legal regulation of patients' rights, which have never been out of question up to now, confirms the impression of patients who have to be protected from their doctors. This development favours a natural mistrust in the quality of the treatment and the desire of legal verification in cases of treatment failures. A totally perfect and error-free treatment, however, will never occur. Already this fact leads to the obligation to do everything possible to reduce the risk to an absolute minimum. The risks that might arise from a relation of treatment are manifold. Not only may the patient undergo risks that arise in particular from lacking or insufficient briefing, complications, or medical malpractice. Also the doctor has to fear legal consequences if he does not stick clearly to the increasing requirements that jurisdiction and legislation impose - not least by the planned law of patients' rights. In the following, the basic principles and particularities will be described that apply for the patients' briefing. Further the different types of medical malpractice will be explained in relation to the resulting procedural consequences. Finally some current problematic fields will be described with regard to other possible liabilities or responsibilities of physicians in hospitals or doctor's offices. PMID- 23625709 TI - [Comprehensive review on danger points, complications and medico-legal aspects in endoscopic sinus surgery]. AB - Endoscopic endonasal sinus surgery represents the overall accepted type of surgical treatment for chronic rhinosinusitis. Notwithstanding raised and still evolving quality standards, surgeons performing routine endoscopic interventions are faced with minor complications in 5% and major complications in 0.5-1%.A comprehensive review on all minor and major complications of endoscopic surgery of the paranasal sinuses and also on the anterior skull base is presented listing the actual scientific literature. The pathogenesis, signs and symptoms of each complication are reviewed and therapeutic regimens are discussed in detail relating to actual publication references. Potential medico-legal aspects are explicated and recent algorithms of avoidance are mentioned taking into account options in surgical training and education. PMID- 23625710 TI - [Complications and pitfalls in surgery of the ear/lateral skull base]. AB - Surgery of the ear and the lateral skull base is a fascinating, yet challenging field in otorhinolaryngology. A thorough knowledge of the associated complications and pitfalls is indispensable for the surgeon, not only to provide the best possible care to his patients, but also to further improve his surgical skills.Following a summary about general aspects in pre-, intra- and postoperative care of patients with disorders of the ear/lateral skull base, this article covers the most common pitfalls and complications in stapes surgery, cochlear implantation, surgery of vestibular schwannomas, and jugulotympanal paragangliomas. Based on these exemplary procedures, basic "do's and don'ts" of skull base surgery are explained, which the reader can easily transfer to other disorders. Special emphasis is laid on functional aspects, such as hearing, balance and facial nerve function. Furthermore, the topics of infection, bleeding, skull base defects, quality of life and indication for revision surgery are discussed.An open communication about complications and pitfalls in ear/lateral skull base surgery among surgeons is a prerequisite for the further advancement of this fascinating field in ENT surgery. This article is meant to be a contribution to this process. PMID- 23625711 TI - [Surgical errors and risks--the head and neck cancer patient]. AB - Head and neck surgery is one of the basic principles of head and neck cancer therapy. Surgical errors and malpractice can have fatal consequences for the treated patients. This can lead into functional impairment and even have impact in future chances for disease related survival. There are many risks for head and neck surgeons which can cause errors and malpractice. To avoid surgical errors, thorough preoperative management of patients is demanded for. Such is ensuring operability, cautious evaluation of preoperative diagnostics and operative planning. Moreover knowledge of anatomical structures of the head and neck, of medical studies and data as well as qualifications in modern surgical techniques and the surgeons ability for critical self assessment are basic but important prerequisites for head and neck surgeons in order to prevent from mistakes. Moreover it is important to have profound knowledge in nutrition management of cancer patients, wound healing and to realize and be capable of dealing with complications, when they occur.Despite all preventive precaution and surgical care, mistakes cannot always be avoided. For that it is important to be able to deal with errors and to establish an appropriate and clear communication and management for such events. The manuscript comments on recognition and prevention of risks and mistakes in the preoperative, operative and postoperative phase of head and neck cancer surgery. PMID- 23625712 TI - [Errors and hazards in oncology: radiation oncology]. AB - Adverse effects and hazards which have their origin from radiation using conventional techniques like 3-D conformal radiotherapy and total radiation doses are well known. However little is known about the sprectum of especially late toxicity after radiation using new technologies like intensity modulated radiotherapy (IMRT) combined with novel target volume and dose concepts. Since IMRT allows for selective protection of the large salivary glands this technique improves the intermediate term quality of life and is the standard of care despite many details need further prospective evaluation. Combining cytotoxic drugs and radiotherapy yield improved survival in well-defined high risk patients. However morbidity and mortality of these protocols are high and deserve special expertise and supportive therapy. EGF-receptor antibodies have gained well defined indications, albeit specific toxicities in combination with irradiation deserve prospective studies and special attention. PMID- 23625713 TI - [Management of patients with risk factors]. AB - This review deals with concomitant diseases and risk factors in patients treated for otorhinolaryngologic disease in outpatient and hospital services. Besides heart disease, lung disease, liver disease and kidney disease this article also covers disorders of coagulation (including the therapy with new anticoagulant drugs) of electrolyte hemostasis. Special attention is paid to prophylaxis, diagnosis and treatment of delirium. Also information is provided to optimize preparation of surgical procedures and pharmacotherapy. PMID- 23625714 TI - [Safe patient care: safety culture and risk management in otorhinolaryngology]. AB - Safety culture is positioned at the heart of an organisation's vulnerability to error because of its role in framing organizational awareness to risk and in providing and sustaining effective strategies of risk management. Safety related attitudes of leadership and management play a crucial role in the development of a mature safety culture ("top-down process"). A type marker for organizational culture and thus a predictor for an organizations maturity in respect to safety is information flow and in particular an organization's general way of coping with information that suggests anomaly. As all values and beliefs, relationships, learning, and other aspects of organizational safety culture are about sharing and processing information, safety culture has been termed "informed culture". An informed culture is free of blame and open for information provided by incidents. "Incident reporting systems" are the backbone of a reporting culture, where good information flow is likely to support and encourage other kinds of cooperative behavior, such as problem solving, innovation, and inter-departmental bridging. Another facet of an informed culture is the free flow of information during perioperative patient care. The World Health Organisation's "safe surgery checklist" is the most prevalent example of a standardized information exchange aimed at preventing patient harm due to information deficit. In routine tasks mandatory standard operating procedures have gained widespread acceptance in guaranteeing the highest possible process quality.Technical and non-technical skills of healthcare professionals are the decisive human resource for an efficient and safe delivery of patient care and the avoidance of errors. The systematic enhancement of staff qualification by providing training opportunities can be a major investment in patient safety. In recent years several otorhinolaryngology departments have started to incorporate simulation based team trainings into their curriculum. PMID- 23625715 TI - [Diagnostic and therapeutic pitfalls in benign vocal fold diseases]. AB - More than half of patients who present with the symptom of hoarseness show benign vocal fold changes. The clinician should be familiar with modern diagnostic and therapeutic possibilities of benign vocal fold changes in order to ensure an optimal and individualized attention to voice patients. Basic knowledge of the etiology are provided for targeted phonosurgical or conservative therapy. This review article focuses on the diagnostic and therapeutic limitations and difficulties of treatment of benign vocal fold tumors, the management and prophylaxis of scarred vocal fold changes and the issue of unilateral vocal fold paralysis. PMID- 23625716 TI - [Faults and failure of tonsil surgery and other standard procedures in otorhinolaryngology]. AB - Septoplasty, tonsillectomy (with and without adenoidectomy) and cervical lymph node excision are amongst the most common 50 inpatient operations in Germany. Intracapsular tonsillectomies (i.e., tonsillotomies) are increasingly performed. The aim of this study was to evaluate alleged medical malpractice, technical traps and pitfalls associated with tonsillectomy (TE), adenoidectomy (AE), tonsillotomy (TT), septoplasty (SP) and cervical lymph node excision (LN).A questionnaire was sent to the Regional Medical Conciliation Boards, Medical Services of the Health Insurance Companies (MDK) and Regional Institutes of Forensic Medicine in Germany to collect anonymized cases of complications or medico legal implications following TE, TT, AE, LN and SP. The results were discussed in the light of the contemporary medical literature and published verdicts in Germany.The response rate of our survey was 55.9%. The Institutes of Forensic Medicine contributed 9 cases, 49 cases were submitted by the Regional Conciliation Boards and none by MDK. All forensic cases were associated with exsanguinations following tonsillectomy including 2 children (5 and 8 years of age) and 7 adults (aged 20-69 years). The fatal post-tonsillectomy hemorrhage (PTH) had occurred 8.7 days on average; 4 patients experienced the bleeding episode at home (day 5, 8, 9 and 17, respectively). Repeated episodes of bleeding requiring surgical intervention had occurred in 6 patients. 3 Conciliation Boards submitted expert opinions concerning cases TT (1), AE (4), LN (3), SP (16) and TE (25). Cases with lethal outcome were not registered. Only 3 of the 49 cases were assessed as surgical malpractice (6.1%) including lesion of the spinal accessory nerve, wrong indication for TE and dental lesion after insertion of the mouth gag. The review of the medico legal literature yielded 71 published verdicts after AE and TE (29), LN (28) and SP (14) of which 37 resulted in compensation of malpractice after LN (16; 57%), TE (11; 41%), SP (8; 57%) and AE (2; 100%). There were 16 cases of PTH amongst 27 trials after TE resulting either in death (5) or apallic syndrome (5). Bleeding complications had occurred on the day of surgery in only 2 patients. 16 trials were based on malpractice claims following SP encompassing lack of informed consent (6), anosmia (4), septal perforation (2), frontobasal injury (2) and dry nose (2). Trials based on LN were associated exclusively with a lesion of the spinal accessory nerve (28), including lack of informed consent in 19 cases. 49 cases (69%) were decided for the defendant, 22 (31%) were decided for the plaintiff with monetary compensation in 7 of 29 AE/TE trials, 9 of 28 LN-trials and 6 of 14 SP-trials. Lack of informed consent was not registered for AE/TE but LN (11) and SP (2).Complicated cases following TE, TT, ATE, SP and LN are not systematically collected in Germany. It can be assumed, that not every complicated case is published in the medical literature or law journals and therefore not obtainable for scientific research. Alleged medical malpracice is proven for less than 6% before trial stage. Approximately half of all cases result in a plaintiff verdict or settlement at court. Proper documentation of a thorough counselling, examination, indication, informed consent and follow-up assists the surgeon in litigation. An adequate complication management of PTH is essential, including instructions for the patients/parents, instructions for the medical staff, readily available surgical instruments and appropriate airway management in an interdisciplinary approach. Electrosurgical tonsillectomy techniques were repeatedly labeled as a risk factor for bleeding complications following TE. Institutions should analyse the individual PTH rate on a yearly basis. Contradictory expert opinions and verdicts of the courts concerning spinal accesory nerve lesions following LN are due to a lack of a surgical standard. PMID- 23625717 TI - [Faults and failure: aesthetic rhinoplasty plus brow, eyelid and conchal surgery]. AB - Within the last years aesthetic surgery enjoys greater popularity and acceptance. One of the most frequently asked operations has been the aesthetic rhinoplasty. Hardly any other field of surgery is exposed to such a critical analysis than aesthetic rhinoplasty because the results are so obvious. According to the "International Society of Aesthetic Surgery" (ISAPS) over 980 000 cosmetic rhinoplasties have been performed in 2010. This corresponds to 10.4% of all registered aesthetic procedures worldwide. Complications can not be eliminated in such a large number of nasal operations. Up to 15% of all patients re-consult a doctor for a revision because they are dissatisfied with their final rhinoplasty result. Findings of the tip followed by functional problems and irregularities of the nasal dorsum are named most frequently. The responsible rhinosurgeon has to regard all anatomical and physiological details and to consider ethical and psychological aspects in the preselection and postoperative care of the patient. Aesthetic surgeons should be acquainted with terms and definitions like body image, dysmorphophobia or Thersites complex. Acronyms, like "SIMON" or "SYLVIA", support the physician additionally to analyze and assess the patient. The following article describes the most frequent faults, complications and pitfalls after aesthetic rhinoplasty listed by the anatomical structure. Results will be analyzed, strategies and techniques will be suggested to correct the faults and to prevent them in the future. Furthermore psychologic, social and psychiatric aspects will be discussed and handling with aesthetic patients explained. PMID- 23625718 TI - Attenuation of monocyte chemotaxis--a novel anti-inflammatory mechanism of action for the cardio-protective hormone B-type natriuretic peptide. AB - B-type natriuretic peptide (BNP) is a prognostic and diagnostic marker for heart failure (HF). An anti-inflammatory, cardio-protective role for BNP was proposed. In cardiovascular diseases including pressure overload-induced HF, perivascular inflammation and cardiac fibrosis are, in part, mediated by monocyte chemoattractant protein (MCP)1-driven monocyte migration. We aimed to determine the role of BNP in monocyte motility to MCP1. A functional BNP receptor, natriuretic peptide receptor-A (NPRA) was identified in human monocytes. BNP treatment inhibited MCP1-induced THP1 (monocytic leukemia cells) and primary monocyte chemotaxis (70 and 50 %, respectively). BNP did not interfere with MCP1 receptor expression or with calcium. BNP inhibited activation of the cytoskeletal protein RhoA in MCP1-stimulated THP1 (70 %). Finally, BNP failed to inhibit MCP1 directed motility of monocytes from patients with hypertension (n = 10) and HF (n = 6) suggesting attenuation of this anti-inflammatory mechanism in chronic heart disease. We provide novel evidence for a direct role of BNP/NPRA in opposing human monocyte migration and support a role for BNP as a cardio-protective hormone up-regulated as part of an adaptive compensatory response to combat excess inflammation. PMID- 23625719 TI - Harnessing graphics processing units for improved neuroimaging statistics. AB - Simple models and algorithms based on restrictive assumptions are often used in the field of neuroimaging for studies involving functional magnetic resonance imaging, voxel based morphometry, and diffusion tensor imaging. Nonparametric statistical methods or flexible Bayesian models can be applied rather easily to yield more trustworthy results. The spatial normalization step required for multisubject studies can also be improved by taking advantage of more robust algorithms for image registration. A common drawback of algorithms based on weaker assumptions, however, is the increase in computational complexity. In this short overview, we will therefore present some examples of how inexpensive PC graphics hardware, normally used for demanding computer games, can be used to enable practical use of more realistic models and accurate algorithms, such that the outcome of neuroimaging studies really can be trusted. PMID- 23625720 TI - I suffer more from your pain when you act like me: being imitated enhances affective responses to seeing someone else in pain. AB - Social-psychological research has suggested that being imitated changes the way that we experience others: We like someone who imitates us more, and the interaction with this person runs more smoothly. Whether being imitated also affects basic social reactions, such as empathy for pain, is an open question. Empathy for pain refers to the observation that perceiving another person in pain results in pain-related brain activation in the observer. The aim of the present study was to combine the two lines of research, to investigate whether being imitated can influence empathy for pain. To this end, we developed an experimental approach combining an imitation task with a pain perception task. Subjective reports, as well as physiological responses, indicated that being imitated enhances affective responses to seeing someone else in pain. Furthermore, using rubber hand illusion measures, we provided evidence for the role of shared representations in the sensory and motor domains as a core underlying mechanism. In this way, our study integrated social-psychological research on being imitated with cognitive research on empathy for pain. This has broad implications, since imitation plays a crucial role in our daily social interactions, and our study provides insights into a basic cognitive mechanism that might underlie these social situations. PMID- 23625721 TI - Epicatechin regulation of mitochondrial structure and function is opioid receptor dependent. AB - SCOPE: The flavanol (-)-epicatechin (Epi), a component of cacao, has cardiac protective benefits in humans. Our previous study demonstrated Epi has delta opioid receptor (DOR) binding activity and promotes cardiac protection. Here we examined the effects of 10 days of Epi treatment on: cardiac mitochondrial respiration, reactive oxygen species production, calcium swelling, and mitochondrial membrane fluidity. METHODS AND RESULTS: Mice were randomized into four groups: (i) control (saline), (ii) naltrindole (Nalt; DOR antagonist), (iii) Epi, and (iv) Epi + Nalt and received 1 mg/kg Epi or water via oral gavage. Nalt groups received 5 mg/kg ip per day for 10 days. Significant increases in mitochondrial respiration and enhanced free radical production during state 3 respiration were observed with Epi. Additionally, we observed significant increases in rigidity of mitochondrial membranes and resistance to calcium induced mitochondrial swelling with Epi treatment. Blocking the DOR with Nalt resulted in decreases in all of the observed parameters by Epi treatment. CONCLUSION: These findings indicate that Epi induces an integrated response that includes metabolic and structural changes in cardiac mitochondria resulting in greater functional capacity via DOR. Mitochondrial targeted effects of epicatechin may explain the physiologic benefit observed on cardiac protection and support epicatechin's potential clinical application as a cardiac protective mimetic. PMID- 23625722 TI - Carnitine and acetylcarnitine modulate mesenchymal differentiation of adult stem cells. AB - Cellular metabolic activity, especially mitochondrial metabolism, plays a vital role in regulating cell proliferation and differentiation. Metabolism could therefore be an important factor to consider when using engineering technologies to stimulate tissue development and repair. The small metabolite carnitine and its derivative acetylcarnitine affect the activities of several pathways in mitochondrial metabolism, but their influence on cell differentiation has not yet been thoroughly studied. To elucidate the effects of these two small molecules on mesenchymal tissue engineering, we used adult stem cells as a platform in both monolayer and 3D hydrogel culture systems. We investigated the impact of these two small molecules on the differentiation of adult stem cells and analysed gene expression, cell proliferation and extracellular matrix deposition. We found that the molecules reduced adipogenesis but stimulated osteogenesis and chondrogenesis in both culture systems. Our results suggest that carnitine and acetylcarnitine could affect the differentiation rate of adult stem cells by regulating mitochondrial metabolism. The effects of these two small molecules give rise to the possibility of employing such metabolites in tissue-engineering systems to enhance cell differentiation and tissue development. PMID- 23625723 TI - Antitumor T cell responses in bladder cancer are directed against a limited set of antigens and are modulated by regulatory T cells and routine treatment approaches. AB - Regulatory T cells (Tregs) play a key role in cancer immune escape. We identified target antigens of spontaneous tumor-specific T cell responses in urothelial carcinoma (UC) and evaluated their modulation by treatment and Treg. We determined Treg target antigens in UC. Fifty-six UC and 13 control patients were prospectively enrolled. Blood was drawn before and after routine treatment. Changes in Treg frequency were measured by fluorescence cytometry and the T effector cell (Teff) response against a set of nine tumor-associated antigens (TAAs) was monitored with an interferon-gamma ELISpot. Antigen specificity of Treg was determined by their increased capacity to inhibit after TAA-specific activation the proliferation of an autologous T cell population. The highest difference in the overall response rate for the total T cell population was observed for epidermal growth factor receptor (EGFR) (UC: 23% and controls: 0%). After depleting Treg, also new york esophageal (NYES)O1 (19 and 0%) and MUC20 (27 and 0%) were more frequently recognized in UC patients. In metastasized patients, the TAA-directed T cell response was augmented by Treg depletion. Tumor resection seemed to diminish Treg suppression of TAA-specific immunity, whereas chemotherapy had no effect. We demonstrated the existence of TAA-specific Treg in UC, which share antigen specificities with Teff. The coexistence of TAA-specific Treg and Teff was very rare. Treg frequencies in the peripheral blood were not changed by therapy. In summary, we identified potentially immunologically relevant TAA in UC. TAA-specific T cell responses against these antigens are suppressed by Treg. We identified TAA-specific Treg in UC patients, which do not cooccur with TAA-specific Teff. PMID- 23625724 TI - In vitro and in vivo characterization of designed immunogens derived from the CD helix of the stem of influenza hemagglutinin. AB - The conserved "stem" domain of influenza virus hemagglutinin (HA) is a target for broadly neutralizing antibodies and a potential vaccine antigen for induction of hetero-subtypic protection. The epitope of 12D1, a previously reported bnAb neutralizing several H3 subtype influenza strains, was putatively mapped to residues 76-106 of the CD-helix, also referred to as long alpha helix (LAH) of the HA stem. A peptide derivative consisting of wt-LAH residues 76-130 conjugated to keyhole limpet hemocyanin was previously shown to confer robust protection in mice against challenge with influenza strains of subtypes H3, H1, and H5 which motivated the present study. We report the design of multiple peptide derivatives of LAH with or without heterologous trimerization sequences and show that several of these are better folded than wt-LAH. However, in contrast to the previous study immunization of mice with wt-LAH resulted in negligible protection against a lethal homologous virus challenge, while some of the newly designed immunogens could confer weak protection. Combined with structural analysis of HA, our data suggest that in addition to LAH, other regions of HA are likely to significantly contribute to the epitope for 12D1 and will be required to elicit robust protection. In addition, a dynamic, flexible conformation of isolated LAH peptide may be required for eliciting a functional anti-viral response. PMID- 23625725 TI - Post-functionalization of polymers via orthogonal ligation chemistry. AB - The establishment of advanced living/controlled polymerization protocols allows for engineering synthetic polymers in a precise fashion. Combining advanced living/controlled polymerization techniques with highly efficient coupling chemistries facilitates quantitative, modular, and orthogonal functionalization of synthetic polymer strands at their chain termini as well as side-chain functionalization. The review highlights the current status of selected post functionalization techniques of polymers via orthogonal ligation chemistries, major characteristics of the specific transformation chemistry, as well as the characterization of the products. PMID- 23625727 TI - Linking survival and biomarker responses over time. AB - The practical usefulness of biomarkers is limited by the complexity of linking their responses to life-history traits of the organisms (e.g., survival, growth, reproduction) over time. Here the authors present a first attempt to model biomarker responses and survival over time simultaneously with a toxicokinetic toxicodynamic approach. Even though more work is clearly needed, the present study provides a novel direction for interpreting biomarker responses and dynamically linking them to life-history traits. PMID- 23625726 TI - Up-regulated cten by FGF2 contributes to FGF2-mediated cell migration. AB - Cten is a focal adhesion molecule that is expressed at very low levels in most normal tissues. Nonetheless, its expression has been found to increase dramatically in many types of cancer including colorectal, breast, gastric, and pancreatic cancer, suggesting that cten may play a critical role during tumorigenesis. To study the mechanisms that induce cten expression and the function of up-regulated cten, we examined the effects of several cancer associated growth factors and cytokines on cten expression. We found that EGF, FGF2, NGF, PDGF, TGF-beta, IGF-1, IL-6, and IL-13 were able to induce cten expression in a dose- and time-dependent manner. The Mek-Erk and PI3K-Akt pathways were two main signaling cascades responsible for cten up-regulation, whereas the Jak-Stat pathway could contribute to the increase in some conditions. Since many of these factors are known to promote cell migration, we hypothesized that up-regulated cten might contribute to this process. This hypothesis was investigated in FGF2-mediated cell migration. Silencing of cten not only reduced regular cell motility but also FGF2-mediated cell migration. Overexpression of cten promoted cell migration and FGF2 treatment failed to further enhance cell migration. Our findings that (1) cten is a common downstream molecule of these cancer-associated growth factors and cytokines; and that (2) up-regulated cten modulates cell migration induced by FGF2 and likely other growth factors as well, strongly suggest that cten could be a potential downstream therapeutic target for treating cancers associated with aberrant signaling of these growth factors and cytokines. PMID- 23625728 TI - Bactericidal activity of lachrymal secretion and complement system in copper deficient bovines. AB - Copper deficiency in humans and animals has been related to increased susceptibility to infections. Neutrophils are one of the most studied components of the immune response; however, to the best of our knowledge, other defenses of the innate immune system have not been analyzed in copper-deficient animals. Our previous studies in copper-deficient bovines have shown increased susceptibility to infectious keratoconjunctivitis, an ocular disease caused by Moraxella bovis. The objective of this work was to evaluate the bactericidal activity of lachrymal secretion and complement system, two main mechanisms of the innate immune response against M. bovis, in copper-deficient cattle. Our results indicate that copper deficiency has no effect on bactericidal activity of complement system and lachrymal secretion against M. bovis in calves. Other components of local and systemic ocular defense mechanisms that could explain the increased susceptibility to infectious keratoconjunctivitis observed in copper-deficient bovines should be investigated. PMID- 23625729 TI - Simvastatin treatment ameliorates injury of rat testes induced by cadmium toxicity. AB - Cadmium-induced testicular toxicity is mediated through oxidative stress and inflammation which eventually lead to cell death. Simvastatin, the antihyperlipidemic agent, exhibits additional antioxidant and anti-inflammatory activities. The aim of the present work was to investigate the protective effect of simvastatin against cadmium-induced testicular toxicity in rats. The rats received a single intraperitoneal (i.p.) injection of cadmium chloride (2 mg/kg). Simvastatin treatment (5 mg/kg/day, i.p.) was applied for three consecutive days, starting 1 day before cadmium administration. Cadmium significantly decreased serum testosterone, and testicular reduced glutathione and catalase activity, and significantly increased testicular malondialdehyde, nitric oxide, and cadmium ion levels. Simvastatin significantly ameliorated the biochemical changes induced by cadmium. Cadmium-induced testicular tissue injury observed by histopathological examination was attenuated by simvastatin. In addition, simvastatin significantly decreased the expression of inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-alpha, nuclear factor-kappaB, and caspase-3, and increased heme oxygenase-1 expression in testicular tissue of rats exposed to cadmium toxicity. It was concluded that simvastatin, through its antioxidant and anti inflammatory activities, provided a significant protective effect against cadmium induced testicular toxicity in rats. However, starting treatment with simvastatin before cadmium exposure, as done in the present work, is not clinically applicable. Therefore, other investigations are needed to assess the protective effect of simvastatin treatment following induction of cadmium testicular toxicity. PMID- 23625730 TI - Feasibility of breast cancer screening by PIXE analysis of hair. AB - To reveal the role of key elements present in the hair of breast cancer patients on cancer development, the levels of a number of elements in scalp hair samples of 82 people including healthy individuals, people suffering from benign breast disease, and breast cancer patients were measured by PIXE analysis. Pellets of hair samples were prepared and bombarded by 2.2 MeV proton beam of a 3-MV Van de Graaff accelerator. The number of incident ions hitting the sample was indirectly measured using the RBS spectrum of a thin Ag film placed in the beam path. The concentrations of S, Cl, K, Ca, Fe, and Cu in the hair of healthy individuals were in agreement with those observed in the hair of hyperplasia and cancer patients within standard deviations. However, a lower average level of zinc was found in samples from hyperplasia and breast cancer patients. Strong positive correlations were found between iron and potassium as well as between calcium and potassium in the cancer patients. These results could be of significance in the screening for breast cancer. PMID- 23625731 TI - Psychologic disorders and statin use: a propensity score-matched analysis. AB - STUDY OBJECTIVE: To evaluate the association between statin therapy and the risk of psychologic disorders including schizophrenia, psychosis, major depression, and bipolar disorder in a military population. DESIGN: Retrospective, observational, population-based, propensity score-matched, cohort study. SETTING: Database of a patient population enrolled in the San Antonio Military Multi Market Area as Tricare Prime or Plus. PATIENTS: Medical records were reviewed from 46,249 patients aged 30-85 years who were continuously enrolled in the San Antonio Military Multi-Market Area as Tricare Prime or Plus from October 1, 2003 March 1, 2010. Data were obtained from the Military Health System Management Analysis and Reporting Tool (M2). Based on drug fills during fiscal year 2005, patients were stratified as statin users (13,626 patients received at least 90 days supply of statin) or nonusers (32,623 patients never received a statin during the study period). A propensity score-matched cohort of 6972 statin users and 6972 nonusers from this population was created. MEASUREMENTS AND MAIN RESULTS: The occurrence of psychologic disorders between October 1, 2005, and March 1, 2010, was determined using prespecified groups of ICD-9-CM, Psych1: schizophrenia, schizoaffective disorders, and other psychosis; Psych2: major depression and bipolar disorder; Psych3: all psychologic disorders as identified by the Agency for Health Research and Quality-Clinical Classifications (except for categories of childhood or developmental psychiatric disorders). Between matched pairs of statin users and nonusers, the odds ratios and 95% confidence intervals were as follows: Psych1 (0.9, 0.75-1.05), Psych2 (1.02, 0.94-1.11), and Psych3 (1.02, 0.96-1.1), respectively. CONCLUSION: The risk of developing psychologic disorders was similar in this cohort of propensity score-matched statin users and nonusers. PMID- 23625732 TI - The meaning of receiving help from home nursing care. AB - The aim of this study was to illuminate the meaning of receiving help from home nursing care for the chronically ill, elderly persons living in their homes. The study was carried out in Norway. Data were collected by narrative interviews and analysed by phenomenological hermeneutic interpretations. Receiving help from home nursing care sometimes meant 'Being ill and dependent on help'. Other times it meant 'Being at the mercy of help'. It could also mean 'Feeling inferior as a human being'. Sometimes help was given by nurses who were respectful and proficient at caring for an elderly person, while at other times nurses seemed to be incompetent and worked with a paternalistic attitude without respect for privacy. Receiving help also meant elderly persons wanted to be regarded and approached as equal human beings, supported in the courage to meet challenges in life. PMID- 23625733 TI - Update on pediatric cancer predisposition syndromes. AB - Hereditary cancer syndromes in children and adolescents are becoming more recognized in the field of pediatric hematology/oncology. A recent workshop held at the American Society of Pediatric Hematology/Oncology (ASPHO) 2012 Annual Meeting included several interactive sessions related to specific familial cancer syndromes, genetic testing and screening, and ethical issues in caring for families with inherited cancer risk. This review highlights the workshop presentations, including a brief background about pediatric cancer predisposition syndromes and the importance of learning about them for the practicing pediatric hematologists/oncologists. This is followed by a brief summary of the newly described cancer predisposition syndromes including Rhabdoid Tumor Predisposition Syndrome, Hereditary Paragangliomas and Pheochromocytoma Syndrome, and Familial Pleuropulmonaryblastoma Tumor Predisposition (DICER1) Syndrome. The next section covers genetic testing and screening for pediatric cancer predisposition syndromes. Ethical issues are also discussed including preimplantation genetic diagnosis or testing (PGD/PGT), suspicious lesions found on tumor screening, and incidental mutations discovered by whole genome sequencing. Finally, the perspective of a family with Li-Fraumeni Syndrome is shared. PMID- 23625734 TI - Keeping management effects separate from environmental effects in terrestrial carbon accounting. AB - This study proposes that carbon fluxes identified as being from land use and land cover change (LULCC) include only that component of a flux that can be attributed to LULCC, exclusive of the effects of environmental change (CO2 , climate, N, etc.). This proposal seems too obvious to need saying, but published estimates of the LULCC flux are widely variable for reasons that have more to do with modeling environmental effects than with LULCC. PMID- 23625735 TI - Should we continue treatment for M? The benefits of living. AB - Wilkinson and Savulescu did not agree with the court's decision to continue M's treatment and suggested in their recent commentary that the magnitude of benefits of being alive for M is small compared with the potential use of health resources for other patients. We argue that the benefits of being sensate to the surroundings for an otherwise unconscious person are not necessarily small. One cannot assess on behalf of another person the magnitude of benefits of being alive according to the intensity or the duration of negative experiences. Denying life-sustaining treatment to patients in a minimally conscious state solely on the grounds that they are less capable of enjoying the benefits represents grave discrimination against disabled persons. For patients in a minimally conscious state who have not delegated a surrogate or made any advance decision about their medical treatment, the duty of doctors is to preserve their right to self determination and maximise their capacity to enjoy their life. M should live on, and life-sustaining treatment should not be withdrawn. PMID- 23625736 TI - Embryonic viability, parental care and the pro-life thesis: a defence of Bovens. AB - On the basis of three empirical assumptions about the rhythm method and the viability of embryos, Bovens concludes that the pro-life position regarding empbryos implies that it is prima facie wrong to use the rhythm method. Pruss objects to Bovens's philosophical presuppositions and Kennedy to his empirical premises. This essay defends two revised versions of Bovens's argument. These arguments revise Bovens's empirical assumptions in response to Kennedy and, in response to Pruss, supplement Bovens's argument with what I call 'the principle of parental care'. PMID- 23625737 TI - Cultural sensitivity in paediatrics. AB - In a recent Journal of Medical Ethics article, 'Should Religious Beliefs Be Allowed to Stonewall a Secular Approach to Withdrawing and Withholding Treatment in Children?', Joe Brierley, Jim Linthicum and Andy Petros argue for rapid intervention in cases of futile life-sustaining treatment. In their experience, when discussions of futility are initiated with parents, parents often appeal to religion to 'stonewall' attempts to disconnect their children from life support. However, I will argue that the intervention that the authors propose is culturally insensitive. PMID- 23625738 TI - The duty to be well-informed: the case of depression. AB - It is now an ethical dictum that patients should be informed by physicians about their diagnosis, prognosis and treatment options. In this paper, I ask: 'How informed are the 'informers' in clinical practice?' Physicians have a duty to be 'well-informed': patient well-being depends not just in conveying adequate information to patients, it also depends on physicians keeping up-to-date about: (1) popular misunderstandings of illnesses and treatments; and (2) the importance of patient psychology in affecting prognosis. Taking the case of depression as an entry point, this paper argues that medical researchers and physicians need to pay serious attention to the explanations given to patients regarding their diagnosis. Studies on lay understanding of depression show that there is a common belief that depression is wholly caused by a 'chemical imbalance' (such as 'low serotonin') that can be restored by chemically restorative antidepresssants, a claim that has entered 'folk wisdom'. However, these beliefs oversimplify and misrepresent the current scientific understanding of the causes of depression: first, there is consensus in the scientific community that the causes of depression include social as well as psychological triggers (and not just biochemical ones); second, there is significant dissensus in the scientific community over exactly what lower level, biological or biochemical processes are involved in causing depression; third, there is no established consensus about how antidepressants work at a biochemical level; fourth, there is evidence that patients are negatively affected if they believe their depression is wholly explained by (the vague descriptor) of 'biochemical imbalance'. I argue that the medical community has a duty, to provide patients with adequate information and to be aware of the negative health impact of prevalent oversimplifications whatever their origins. PMID- 23625739 TI - Graphene nanomesh promises extremely efficient in vivo photothermal therapy. AB - Reduced graphene oxide nanomesh (rGONM), as one of the recent structures of graphene with a surprisingly strong near-infrared (NIR) absorption, is used for achieving ultraefficient photothermal therapy. First, by using TiO2 nanoparticles, graphene oxide nanoplatelets (GONPs) are transformed into GONMs through photocatalytic degradation. Then rGONMs functionalized by polyethylene glycol (PEG), arginine-glycine-aspartic acid (RGD)-based peptide, and cyanine 7 (Cy7) are utilized for in vivo tumor targeting and fluorescence imaging of human glioblastoma U87MG tumors having alphanu beta3 integrin receptors, in mouse models. The rGONM-PEG suspension (1 MUg mL(-1) ) exhibits about 4.2- and 22.4 fold higher NIR absorption at 808 nm than rGONP-PEG and graphene oxide (GO) with lateral dimensions of ~60 nm and ~2 MUm. In vivo fluorescence imaging demonstrates high selective tumor uptake of rGONM-PEG-Cy7-RGD in mice bearing U87MG cells. The excellent NIR absorbance and tumor targeting of rGONM-PEG-Cy7 RGD results in an ultraefficient photothermal therapy (100% tumor elimination 48 h after intravenous injection of an ultralow concentration (10 MUg mL(-1) ) of rGONM-PEG-Cy7-RGD followed by irradiation with an ultralow laser power (0.1 W cm( 2) ) for 7 min), whereas the corresponding rGO- and rGONP-based composites do not present remarkable treatments under the same conditions. All the mice treated by rGONM-PEG-Cy7-RGD survived over 100 days, whereas the mice treated by other usual rGO-based composites were dead before 38 days. The results introduce rGONM as one of the most promising nanomaterials in developing highly desired ultraefficient photothermal therapy. PMID- 23625740 TI - Interspecific variations of inner ear structure in the deep-sea fish family melamphaidae. AB - Inner ear structures are compared among three major genera of the deep-sea fish family Melamphaidae (bigscales and ridgeheads). Substantial interspecific variation is found in the saccular otoliths, including the presence of a unique otolithic "spur" in the genera Melamphaes and Poromitra. The variation in the saccular otolith is correlated with an increase in the number of hair bundle orientation groups on the sensory epithelia from the genera Scopelogadus to Poromitra to Melamphaes. The diverse structural variations found in the saccule may reflect the evolutionary history of these species. The sensory hair cell bundles in this family have the most variable shapes yet encountered in fish ears. In the saccule, most of the hair bundles are 15-20 MUm high, an exceptional height for fish otolithic end organs. These bundles have large numbers of stereovilli, including some that reach the length of the kinocilium. In the utricle, the striolar region separates into two unusually shaped areas that have not been described in any other vertebrates. The brains in all species have a relatively small olfactory bulb and optic tectum, as well as an enlarged posterior cerebellar region that is likely to be involved in inner ear and lateral line (octavolateral) functions. Data from melamphaids support the hypothesis that specialized anatomical structures are found in the ears of some (if not most) deep-sea fishes, presumably enhancing their hearing sensitivity. PMID- 23625741 TI - Posterror slowing predicts rule-based but not information-integration category learning. AB - We examined whether error monitoring, operationalized as the degree to which individuals slow down after committing an error (i.e., posterror slowing), is differentially important in the learning of rule-based versus information integration category structures. Rule-based categories are most efficiently solved through the application of an explicit verbal strategy (e.g., "sort by color"). In contrast, information-integration categories are believed to be learned in a trial-by-trial, associative manner. Our results indicated that posterror slowing predicts enhanced rule-based but not information-integration category learning. Implications for multiple category-learning systems are discussed. PMID- 23625742 TI - Toxic, cytotoxic, and genotoxic effects of a glyphosate formulation (Roundup(r)SL Cosmoflux(r)411F) in the direct-developing frog Eleutherodactylus johnstonei. AB - The aerial spraying of glyphosate formulations in Colombia to eradicate illegal crops has generated great concern about its possible impact on nontarget organisms, particularly amphibians. This study evaluated the toxic, cytotoxic, and genotoxic effects of a glyphosate formulation (Roundup(r)SL-Cosmoflux(r)411F) in the direct-developing frog Eleutherodactylus johnstonei by estimating the median lethal application rate (LC50 ), median hemolytic application rate (HD50 ), and extent of DNA damage using the in vitro and in vivo Comet assays. Toxicity results indicated that the application rate [37.4 ug acid equivalent (a.e.)/cm(2) ] equivalent to that used in aerial spraying (3.74 kg a.e./ha) is not lethal in male and female adult frogs, whereas neonates are highly sensitive. Glyphosate formulation at application rates above 5.4 ug a.e./cm(2) (in vivo) and concentrations above 95 ug a.e./mL (in vitro) showed clear evidence of cytotoxicity. In vivo and in vitro exposure of E. johnstonei erythrocytes to the glyphosate formulation induced DNA breaks in a dose-dependent manner with statistically significant values (P < 0.05) at all doses tested. DNA damage initially increased with the duration of exposure and then decreased, suggesting that DNA repair events were occurring during in vivo and in vitro exposures. These results are discussed from the perspective of possible ecotoxicological risks to anuran species from exposure to glyphosate formulation. PMID- 23625743 TI - New activities for the anti-tumor agent trabectedin: taking two birds with one stone. PMID- 23625744 TI - Pharmacokinetics of nebivolol in the rat: low oral absorption, loss in the gut and systemic stereoselectivity. AB - Nebivolol is a third-generation beta1-adrenoceptor blocker with beta3 agonistic properties (AR). It has a low oral bioavailability that is speculated to be due to its hepatic first-pass metabolism. Inflammation is known to suppress the clearance of drugs with efficient hepatic metabolism. However, inflammation does not influence nebivolol clearance. Therefore, we looked into the mechanism involved in the drug's low bioavailability and stereoselectivity. Single 1 mg/kg i.v. or intraperitoneal (i.p.) or 2 mg/kg oral doses were administered to male Sprague-Dawley rats and the plasma nebivolol concentration was measured using chiral and achiral assays. The passage of nebivolol enantiomers through the gut was also measured using everted rat sacs. The serum protein binding of the enantiomers was studied in vitro using the ultrafiltration method. Plasma nebivolol concentrations were significantly lower after p.o., but not after i.p., compared with i.v. doses suggesting the gut as the site of pre-systemic loss. Approximately 50% of the enantiomers were lost during 90 min incubation in the presence of gut. Only 0.1% of the added drug crossed the gut wall with no evidence of stereoselectivity. Thus stereoselectivity in the pharmacokinetics of nebivolol (+ > -) is likely at the level of plasma protein binding. The low nebivolol bioavailability is due to its loss in the gut as well as its limited permeability through the intestinal wall. PMID- 23625745 TI - Effectiveness of a pharmacy care management program for veterans with dyslipidemia. AB - OBJECTIVE: To evaluate the effectiveness of a care management program provided by clinical pharmacists for veterans with dyslipidemia. DESIGN: Retrospective cohort design. SETTING: Two primary care clinics at a Veterans Affairs Medical Center. PATIENTS: An intervention (IT) cohort of 213 patients referred for management of dyslipidemia by clinical pharmacists and a control cohort of 219 patients with dyslipidemia receiving usual care (UC). METHODS: Data were obtained from electronic medical records regarding drug therapy, lipid levels, and patient characteristics. Using multivariable regression models to adjust for baseline characteristics, the primary analyses compared mean final measured values of low density lipoprotein (LDL) cholesterol, total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglycerides (TGs) among the IT and UC cohorts at the final follow-up visits. Secondary analyses compared the proportion of patients achieving National Cholesterol Education Program/Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP/ATPIII) concordant LDL goals and the time to achieve LDL goals between the two groups. RESULTS: Compared with the UC cohort, the adjusted difference in the mean final measured LDL for the IT cohort was -10.4 mg/dl (95% confidence interval [CI] -16.1 to -4.6, p < 0.001) and TC was -12.7 (95% CI -21.3 to -4.1, p=0.004). There were no significant differences in the adjusted mean final measured HDL or TGs between the two groups. The NCEP/ATPIII goal LDL was met in 80.3% of patients in the IT cohort and 65.3% of patients in the UC cohort (odds ratio [OR], 2.6; 95% CI 1.6-4.3, p<0.001). Time to achieve goal LDL was significantly shorter for the IT cohort compared with the UC cohort (risk ratio, 1.8; 95% CI 1.2-2.8, log-rank p=0.002). CONCLUSION: Veterans referred to a clinical pharmacist for treatment of dyslipidemia achieved significant reductions in TC and LDL. A greater proportion of patients achieved NCEP/ATPIII goal LDL, and the time to attainment of LDL goals was shorter in the pharmacist-managed cohort, supporting a continued role for pharmacy care management in the treatment of patients with dyslipidemia. PMID- 23625746 TI - Convergent responses of nitrogen and phosphorus resorption to nitrogen inputs in a semiarid grassland. AB - Human activities have significantly altered nitrogen (N) availability in most terrestrial ecosystems, with consequences for community composition and ecosystem functioning. Although studies of how changes in N availability affect biodiversity and community composition are relatively common, much less remains known about the effects of N inputs on the coupled biogeochemical cycling of N and phosphorus (P), and still fewer data exist regarding how increased N inputs affect the internal cycling of these two elements in plants. Nutrient resorption is an important driver of plant nutrient economies and of the quality of litter plants produce. Accordingly, resorption patterns have marked ecological implications for plant population and community fitness, as well as for ecosystem nutrient cycling. In a semiarid grassland in northern China, we studied the effects of a wide range of N inputs on foliar nutrient resorption of two dominant grasses, Leymus chinensis and Stipa grandis. After 4 years of treatments, N and P availability in soil and N and P concentrations in green and senesced grass leaves increased with increasing rates of N addition. Foliar N and P resorption significantly decreased along the N addition gradient, implying a resorption mediated, positive plant-soil feedback induced by N inputs. Furthermore, N : P resorption ratios were negatively correlated with the rates of N addition, indicating the sensitivity of plant N and P stoichiometry to N inputs. Taken together, the results demonstrate that N additions accelerate ecosystem uptake and turnover of both N and P in the temperate steppe and that N and P cycles are coupled in dynamic ways. The convergence of N and P resorption in response to N inputs emphasizes the importance of nutrient resorption as a pathway by which plants and ecosystems adjust in the face of increasing N availability. PMID- 23625747 TI - Challenges with defining response to antitumor agents in pediatric neuro oncology: a report from the response assessment in pediatric neuro-oncology (RAPNO) working group. AB - Criteria for new drug approval include demonstration of efficacy. In neuro oncology, this is determined radiographically utilizing tumor measurements on MRI scans. Limitations of this method have been identified where drug activity is not reflected in decreased tumor size. The RANO (Response Assessment in Neuro Oncology) working group was established to address limitations in defining endpoints for clinical trials in adult neuro-oncology and to develop standardized response criteria. RAPNO was subsequently established to address unique issues in pediatric neuro-oncology. The aim of this paper is to delineate response criteria issues in pediatric clinical trials as a basis for subsequent recommendations. PMID- 23625748 TI - Biotransformation model of neutral and weakly polar organic compounds in fish incorporating internal partitioning. AB - A model for whole-body in vivo biotransformation of neutral and weakly polar organic chemicals in fish is presented. It considers internal chemical partitioning and uses Abraham solvation parameters as reactivity descriptors. It assumes that only chemicals freely dissolved in the body fluid may bind with enzymes and subsequently undergo biotransformation reactions. Consequently, the whole-body biotransformation rate of a chemical is retarded by the extent of its distribution in different biological compartments. Using a randomly generated training set (n = 64), the biotransformation model is found to be: log (HLphifish ) = 2.2 (+/-0.3)B - 2.1 (+/-0.2)V - 0.6 (+/-0.3) (root mean square error of prediction [RMSE] = 0.71), where HL is the whole-body biotransformation half-life in days, phifish is the freely dissolved fraction in body fluid, and B and V are the chemical's H-bond acceptance capacity and molecular volume. Abraham-type linear free energy equations were also developed for lipid-water (Klipidw ) and protein-water (Kprotw ) partition coefficients needed for the computation of phifish from independent determinations. These were found to be 1) log Klipidw = 0.77E - 1.10S - 0.47A - 3.52B + 3.37V + 0.84 (in Lwat /kglipid ; n = 248, RMSE = 0.57) and 2) log Kprotw = 0.74E - 0.37S - 0.13A - 1.37B + 1.06V - 0.88 (in Lwat /kgprot ; n = 69, RMSE = 0.38), where E, S, and A quantify dispersive/polarization, dipolar, and H-bond-donating interactions, respectively. The biotransformation model performs well in the validation of HL (n = 424, RMSE = 0.71). The predicted rate constants do not exceed the transport limit due to circulatory flow. Furthermore, the model adequately captures variation in biotransformation rate between chemicals with varying log octanol-water partitioning coefficient, B, and V and exhibits high degree of independence from the choice of training chemicals. The present study suggests a new framework for modeling chemical reactivity in biological systems. PMID- 23625749 TI - Polyaniline-polypyrrole composites with enhanced hydrogen storage capacities. AB - A facile method for the synthesis of polyaniline-polypyrrole composite materials with network morphology is developed based on polyaniline nanofibers covered by a thin layer of polypyrrole via vapor phase polymerization. The hydrogen storage capacity of the composites is evaluated at room temperature exhibits a twofold increase in hydrogen storage capacity. The HCl-doped polyaniline nanofibers exhibit a storage capacity of 0.46 wt%, whereas the polyaniline-polypyrrole composites could store 0.91 wt% of hydrogen gas. In addition, the effect of the dopant type, counteranion size, and the doping with palladium nanoparticles on the storage properties are also investigated. PMID- 23625750 TI - The effects of the adenosine A3 receptor agonist IB-MECA on sodium taurocholate induced experimental acute pancreatitis. AB - The role of adenosine A3 receptors and their distribution in the gastrointestinal tract have been widely investigated. Most of the reports discuss their role in intestinal inflammations. However, the role of adenosine A3 receptor agonist in pancreatitis has not been well established. The aim of this study is [corrected] to evaluate the effects of the adenosine A3 receptor agonist on the course of sodium taurocholate-induced experimental acute pancreatitis (EAP). The experiments were performed on 80 male Wistar rats, 58 of which survived, subdivided into 3 groups: C--control rats, I--EAP group, and II--EAP group treated with the adenosine A3 receptor agonist IB-MECA (1-deoxy-1-6[[(3 iodophenyl) methyl]amino]-9H-purin-9-yl)-N-methyl-B-D-ribofuronamide at a dose of 0.75 mg/kg b.w. i.p. at 48, 24, 12 and 1 h before and 1 h after the injection of 5% sodium taurocholate solution into the biliary-pancreatic duct. Serum for alpha amylase and lipase determinations and tissue samples for morphological examinations were collected at 2, 6, and 24 h of the experiment. In the IB-MECA group, alpha-amylase activity was decreased with statistically high significance compared to group I. The activity of lipase was not significantly different among the experimental groups but higher than in the control group. The administration of IB-MECA attenuated the histological parameters of inflammation as compared to untreated animals. The use of A3 receptor agonist IB-MECA attenuates EAP. Our findings suggest that stimulation of adenosine A3 receptors plays a positive role in the sodium taurocholate-induced EAP in rats. PMID- 23625751 TI - Downregulation of MED23 promoted the tumorigenecity of esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common tumors in the world. It is very urgent to develop new therapeutic strategies. MED23, a component of the mediator complex, is known as a hub to integrate various signaling pathways. However, the function of MED23 in ESCC remains unknown. Here, we found that the expression of MED23 was downregulated in the clinical ESCC samples and the expression of MED23 reversely correlated with tumor size and clinical stage. Moreover, overexpression of MED23 in ESCC cells inhibited cell growth dramatically, while downregulation of MED23 promoted the tumorigenecity of ESCC cells in vitro and in vivo. Mechanistically, knockdown the expression of MED23 inhibited cell apoptosis by downregulation of Bax, activated Caspase 3, activated Caspase 9 and upregulation of cyclinD1 and Bcl2. Taken together, our study revealed the suppressive role of MED23 in ESCC and MED23 might be an important therapeutic target in ESCC. PMID- 23625752 TI - Blood type B antigen modulates cell migration through regulating cdc42 expression and activity in HaCaT cells. AB - ABO blood group is determined by carbohydrate antigens, called ABH antigens. It has been known that the change of carbohydrate antigen expression, including ABH antigens, has correlation with the tumor metastasis and survival; however, the exact mechanism remains to be elucidated. ABH antigens are expressed not only in blood cells but also in several tissues. In epidermis, ABH antigen is expressed in the uppermost spinous and granular layer. We investigated the role of ABH antigens on the cell migration of HaCaT keratinocytes, which express B antigen. Knock-down of B antigen expression by small interference RNA of FUT1 inhibited HaCaT cell migration. At that time, we found that lamellipodia and actin fiber were also reduced by knock-down of B antigen expression. The transcription of cdc42, a kind of Rho GTPase which plays a key role in actin polymerization, was reduced by down-regulated B antigen expression. Furthermore, the reduced B antigen expression also inhibited the interaction of cdc42 and N-WASP. Collectively, our data provide a clue how ABH antigens regulate the cell migration mechanism. PMID- 23625753 TI - Dynamics of amino acid utilization in Phaeobacter inhibens DSM 17395. AB - Time-resolved utilization of multiple amino acids by Phaeobacter inhibens DSM 17395 was studied during growth with casamino acids. The 15 detected amino acids could be grouped according to depletion rate into four different categories, i.e. from rapid (category I) to nondepletion (category IV). Upon entry into stationary growth phase, amino acids of category I (e.g. glutamate) were (almost) completely depleted, while those of categories II (e.g. leucine) and III (e.g. serine) were further consumed at varying rates and to different extents. Thus, cultures entered stationary growth phase despite the ample presence of organic nutrients, i.e. under nonlimiting conditions. Integrated proteomic and metabolomic analysis identified 1747 proteins and 94 intracellular metabolites. Of these, 180 proteins and 86 metabolites displayed altered abundance levels during growth. Most strikingly, abundance and activity profiles of alanine dehydrogenase concomitantly increased with the onset of enhanced alanine utilization during transition into stationary growth phase. Most enzymes of amino acid and central metabolism, however, displayed unaltered abundances across exponential and stationary growth phases. In contrast, metabolites of the Entner-Doudoroff pathway and gluconeogenesis as well as cellular fatty acids increased markedly in abundance in early stationary growth phase. PMID- 23625754 TI - Thrombosis in nephrotic syndrome. AB - Nephrotic syndrome (NS) is characterized by heavy proteinuria, edema, hypoalbuminemia, and hyperlipidemia and the most frequent causes are glomerular diseases. An uncommon presentation is iatrogenic NS, an adverse effect of some drugs administration. In the clinical course of NS, a typical feature is dysregulated coagulation state, promoted by the breakdown of permselectivity barrier of the glomerular capillary wall, resulting in the leakage of high molecular-mass proteins, at least the size of albumin. This hypercoagulable condition is supported by several factors, such as abnormalities in platelet activation and an imbalance between anticoagulation/antithrombosis and procoagulant/prothrombotic mechanisms. Thus, NS and the risk of developing thromboses are strictly related. Thrombotic events affect the venous system rather than arterial vessels with different features and frequencies. Deep venous system of the lower extremities and renal veins are the most frequent source of pulmonary embolism, the most dangerous NS complication. Prophylactic anticoagulation and thrombosis treatment are not clearly established because large randomized trials and guidelines are lacking. The management of NS and the decision of when and how to anticoagulate the patient represent a teamwork challenge for physicians. PMID- 23625755 TI - Role of obesity in the etiology of deep vein thrombosis and pulmonary embolism: current epidemiological insights. AB - The number of overweight and obese individuals in the population has increased dramatically in the past few decades, and the rising prevalence of obesity is a major public health concern. Growing evidence has accrued for obesity as a risk factor for venous thrombosis. The risk of venous thrombosis increases in a dose dependent manner with increasing body mass index and is also associated with the majority of other anthropometric measures of overweight and obesity, such as waist circumference, hip circumference, and waist-to-hip ratio. An increased relative risk of both unprovoked and provoked venous thrombosis has been shown in obese compared with normal-weight subjects. However, encountering obesity as a causal factor for venous thrombosis is problematic due to the ill-defined concept of obesity. In this review, we will examine the current epidemiological evidence for an association between obesity and venous thrombosis. We will comment on the problem of causal interpretation of obesity per se and discuss how individual components that define obesity can serve as potential biological mechanisms for the observed association between obesity and venous thrombosis. PMID- 23625756 TI - Sepsis and thrombosis. AB - Activation of coagulation frequently occurs in severe infection and sepsis and may contribute to the development of thrombosis. Coagulation abnormalities in sepsis range from a small decrease in platelet count and subclinical prolongation of global clotting times to fulminant disseminated intravascular coagulation (DIC), characterized by simultaneous widespread microvascular thrombosis and profuse bleeding from various sites. Septic patients with severe forms of DIC may present with manifest thromboembolic disease or clinically less apparent microvascular fibrin deposition, which predominantly presents as multiple organ dysfunction. Thrombophilia is associated with a prohemostatic state and consequently with an increased tendency to develop thrombosis. Hypothetically, patients with thrombophilia may suffer from more severe coagulopathy in case of severe infection or sepsis, which may result in a more serious clinical course and an unfavorable outcome. On the basis of the knowledge of the pathogenesis of thrombosis in severe inflammation and sepsis, strategies aimed at the inhibition of coagulation activation have been developed and have been found favorable in experimental and clinical studies. PMID- 23625757 TI - Regulation of mechanical stress by mammary epithelial tissue structure controls breast cancer cell invasion. PMID- 23625758 TI - Reference values for nerve ultrasonography in the upper extremity. AB - INTRODUCTION: The aims of this study were to identify factors affecting the measurement of nerve cross-sectional area (CSA) and to establish normal reference values for nerve ultrasonography of the upper extremity. METHODS: Ninety-seven age-matched, healthy individuals were enrolled. Ultrasonographic tests were performed by tracing nerves from the axilla to the distal arm. CSA was measured at the following locations: median nerve (carpal tunnel inlet, forearm, antecubital fossa, midhumerus); ulnar nerve (wrist, 2 cm proximal to the wrist, forearm, cubital tunnel outlet and inlet, midhumerus); radial nerve (spiral groove, antecubital fossa); and musculocutaneous nerve (proximal humerus). RESULTS: The CSA reference values differed between the measured points along the path of each nerve. Nerve CSA correlated significantly with weight, body mass index, height, and gender; however, the CSA ratio (distal/proximal) did not correlate with demographic factors. CONCLUSIONS: The normal reference values may be helpful in diagnosis of pathologies involving these nerves. PMID- 23625759 TI - Passive sampling for target and nontarget analyses of moderately polar and nonpolar substances in water. AB - The applicability of silicone rubber and low-density polyethylene (LDPE) as passive sampling materials for target and nontarget analyses of moderately polar and nonpolar substances was assessed through a field deployment of samplers along a small, polluted stream in Oslo, Norway. Silicone and LDPE samplers of identical surface area (but different volumes) were deployed at 6 sites in the River Alna for 49 d. Quantitative target analysis by gas chromatography-mass spectrometry (quadrupole, single-ion monitoring mode) demonstrated that masses of polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and organochlorine compounds absorbed in the 2 polymeric materials were consistent with the current understanding of the control and mode of accumulation in these sampler materials. Some deviation was observed for decabromodiphenyl ether (BDE-209) and may be linked to the large molecular size of this substance, resulting in lower diffusivity in the LDPE. Target and nontarget analyses with gas chromatography coupled to high resolution time-of-flight mass spectrometry allowed the identification of a wide range of chemicals, including organophosphate compounds (OPCs) and musk compounds (galaxolide and tonalid). Semiquantitative analysis revealed enhanced quantities of the OPCs in silicone material, indicating some limitation in the absorption and diffusion of these substances in LDPE. Overall, silicone allows nontarget screening analysis for compounds with a wider range of log octanol-water partition coefficient values than what can be achieved with LDPE. PMID- 23625760 TI - Ecological niche modeling of coastal dune plants and future potential distribution in response to climate change and sea level rise. AB - Climate change (CC) and sea level rise (SLR) are phenomena that could have severe impacts on the distribution of coastal dune vegetation. To explore this we modeled the climatic niches of six coastal dunes plant species that grow along the shoreline of the Gulf of Mexico and the Yucatan Peninsula, and projected climatic niches to future potential distributions based on two CC scenarios and SLR projections. Our analyses suggest that distribution of coastal plants will be severely limited, and more so in the case of local endemics (Chamaecrista chamaecristoides, Palafoxia lindenii, Cakile edentula). The possibilities of inland migration to the potential 'new shoreline' will be limited by human infrastructure and ecosystem alteration that will lead to a 'coastal squeeze' of the coastal habitats. Finally, we identified areas as future potential refuges for the six species in central Gulf of Mexico, and northern Yucatan Peninsula especially under CC and SLR scenarios. PMID- 23625761 TI - Routine testing of fetal Rhesus D status in Rhesus D negative women using cell free fetal DNA: an investigation into the preferences and information needs of women. AB - OBJECTIVE: The goal of this study is to investigate women's preferences and information needs for routine implementation of fetal Rhesus D (RhD) typing using cell-free fetal DNA. METHODS: A questionnaire was developed following focus groups and interviews with both health professionals and RhD negative (RhD-) women offered fetal RhD genotyping within a research study and distributed to RhD women attending routine antenatal appointments in four National Health Service hospitals. Current knowledge of blood types, anti-D administration, fetal RhD genotyping and future practices were explored. RESULTS: A total of 19 respondents participated in interviews and focus groups, and 270 respondents completed the questionnaires. Questionnaire respondents overwhelmingly felt that the test should be offered to all RhD- women (92.1%), and 75.9% said that they would accept this test. Most were happy to have the test even if it involved extra blood tests (89.3%) or appointments (79%). The knowledge of blood groups was poor. Although 90.7% knew that the baby could have a different blood group from themselves, only 34% knew that blood groups are inherited from both parents. More than 40% were not aware that anti-D would not be required if their baby was RhD-. CONCLUSIONS: Women would welcome the introduction of routine fetal RhD genotyping. Information leaflets and training of midwives will be essential for implementation to ensure good understanding regarding testing. PMID- 23625762 TI - Bioinformatic progress and applications in metaproteogenomics for bridging the gap between genomic sequences and metabolic functions in microbial communities. AB - Metaproteomics of microbial communities promises to add functional information to the blueprint of genes derived from metagenomics. Right from its beginning, the achievements and developments in metaproteomics were closely interlinked with metagenomics. In addition, the evaluation, visualization, and interpretation of metaproteome data demanded for the developments in bioinformatics. This review will give an overview about recent strategies to use genomic data either from public databases or organismal specific genomes/metagenomes to increase the number of identified proteins obtained by mass spectrometric measurements. We will review different published metaproteogenomic approaches in respect to the used MS pipeline and to the used protein identification workflow. Furthermore, different approaches of data visualization and strategies for phylogenetic interpretation of metaproteome data are discussed as well as approaches for functional mapping of the results to the investigated biological systems. This information will in the end allow a comprehensive analysis of interactions and interdependencies within microbial communities. PMID- 23625763 TI - Ontogeny of the vertebral column of Eleutherodactylus johnstonei (Anura: Eleutherodactylidae) reveals heterochronies relative to metamorphic frogs. AB - Over the last century, the morphogenesis of the vertebral column has been considered as a highly conserved process among anurans. This statement is based on the study of few metamorphic taxa, ignoring the role of developmental mechanisms underlying the evolution of specialized life-histories. Direct development in anurans has been regarded as evolutionarily derived and involves developmental recapitulation and repatterning at different levels in all amphibian taxa studied so far. Herein, we analyze the vertebral column morphogenesis of the direct-developing frog Eleutherodactylus johnstonei, describing the sequence of chondrification and ossification, based on cleared and double-stained specimens from early stage embryos to adults. In general, our results show that the morphogenesis of the vertebral column in E. johnstonei recapitulates the ancestral tadpole-like pattern of development. However, the analysis of the sequence of events using heterochrony plots shows important heterocronies relative to metamorphic species, such as a delay in the chondrification of the vertebral centra and in osteogenesis. These ontogenetic peculiarities may represent derived traits in direct-developing frogs and are possibly correlated with its unusual life history. In addition, several features of the vertebral column of E. johnstonei are highly variable from its typical morphology. We report some malformations and small deviations, which do not seem to affect the survival of individuals. These anomalies have also been found in other frogs, and include many vertebral defects, such as vertebral fusion, and vertebral preclusion and/or induction. PMID- 23625764 TI - [Editorial]. PMID- 23625765 TI - [Hyperglycaemia and preterm infants: a chapter of its own]. AB - Antenatally, glucose maintenance takes place via transplacental transfer from mother to fetus. In the third trimester, the amount of glucose transported increases, while glycogen and fat stores are developed. After delivery a continuous and sufficient glucose supply for vital organs and brain is essential. In term infants hormonal and metabolic adaption is well-coordinated, involving adrenal gland, pancreas and liver. However, in preterm infants, mainly during first week of life, there is a high risk of abnormalities in glucose homeostasis. Due to limited glycogen and fat stores, hypoglycaemia may occur which is avoided by continuous glucose infusion. An underestimated risk is hyperglycaemia due to a combination of relative insulin deficiency and insulin resistance, associated with increased mortality and morbidity. Management of hyperglycaemia is one of the topics in neonatology and is still being discussed controversially. This review approaches different therapeutic strategies and gives an overview about the current recommendations in the literature. PMID- 23625766 TI - [Results of surveillance cultures on a neonatal intensive care unit: a retrospective analysis]. AB - BACKGROUND: Microbiological screening (MS) is standard on neonatal intensive care units (NICU). Objectives are the collection of information regarding bacterial pathogens of the individual patient as well as of the NICU, especially of multidrug-resistant pathogens (MRE). The role of microbiological screening for preterm infants <=32 weeks of gestational age has not been fully evaluated. PATIENTS AND METHODS: For preterm infants <=32 weeks of gestational age admitted during a 41-month period the results of microbiological screening during the first 2 weeks of life were analysed retrospectively. The results were associated with documented septic episodes. RESULTS: Bacteria were isolated in 215/972 of postnatal and 416/862 of later swabs. Detection of bacteria in the initial MS was associated with vaginal birth, low gestational age, low APGAR values at 5 and 10 min and mechanical ventilation. The proportion of patients with positive microbiological screening in subsequent swabs was not influenced by gestational age, birth weight, sex, mode of delivery and APGAR score. During the observation period 52 cases of sepsis (28 clinic, 24 microbiological) occurred. The sepsis rate was increased in patients with positive postnatal swabs, low gestational age, low birth weight, low 5 min APGAR score, male sex or need for mechanical ventilation. CONCLUSIONS: Microbiological screening provides an overview of the NICU-specific pathogens but is of limited value in the prediction of septicaemias in preterm infants <=32 weeks gestational age. PMID- 23625767 TI - [Relevance of parents as source for contamination of neonates with multiresistant Gram-negative pathogens (MRGN)]. AB - BACKGROUND: There is an increase in nosocomial contamination and infection with multi-resistant bacteria among NICU patients. In 2011 we had to deal with an outbreak from multi-resistant Klebsiella pneumoniae in our NICU. Analysing the situation, we found 3 different clonal tribes. We presume that there are different sources for the contamination with multiresistant Gram-negative pathogens (MRGN) and we suspect that parents of NICU children may be of some importance. We studied in a one-year setting whether the incidence of nosocomial contaminations and infections may be prevented in a setting of barrier nursing and surveillance of the NICU patients and their parents. Our study was prospective and justified by a vote of support from the ethics committee of the 'Hamburger Arztekammer' as well as additional funding from the Asklepios-Hamburg Pro-Research for the laboratory expenses. MATERIAL AND METHODS: In a one-year study we undertook a programme of barrier nursing for all children admitted to our NICU with bacteriological surveillance on their entry into the NICU for children and their parents with anal and pharyngeal-nasal swabs. As long as there were no results, barrier-nursing for the children, their parents and staff was maintained. Where negative results were found, barrier-nursing was interrupted and children were nursed under normal hygienic conditions. Surveillance cultures from the children were taken once a week until being released. In cases of detection of MRGN bacteria, barrier-nursing was implemented together with room isolation. RESULTS: We detected 23 families carrying MRGN bacteria pre-existent before hospitalisation. In cases of MRGN findings, barrier-nursing and room isolation were maintained. Under these circumstances, there were 6 cases of contamination of NICU children, 4 after vaginal delivery and secondary admittance in the NICU. The circumstances for the 2 others are discussed. CONCLUSION: Parents are an important source for MRGN bacteria in the NICU. The early detection of those carriers is important for the avoidance of outbreaks in an NICU. In most cases, contamination and infection can be prevented. PMID- 23625769 TI - A 7-year case of furosemide-induced immune thrombocytopenia. AB - Immune thrombocytopenia has been attributed to many causes. Several drugs have been implicated as culprits in causing drug-induced thrombocytopenia. Although the mechanism for this type of thrombocytopenia is not well understood, at least three types of antibodies appear to be involved: drug-dependent antibodies, hapten-dependent antibodies, and drug-induced platelet-reactive autoantibodies. In this report, we describe a case in which furosemide was identified as the probable cause of drug-induced thrombocytopenia in an 84-year-old man with chronic symptomatic idiopathic thrombocytopenia for seven years before discovery. The patient's platelet count and daily furosemide dose, both intravenous and oral, were documented throughout his medical history. A dose-dependent change in platelet count was observed in association with the furosemide dose. His platelet count increased on discontinuation of furosemide and beginning of torsemide. Several months after discontinuation of furosemide, his platelet count increased to a 9-year high of 206 * 103/mm3 from a low of 36 * 103/mm3 while receiving furosemide therapy. Based on the observations of this case report, clinicians should more readily consider furosemide as a potential cause of thrombocytopenia. PMID- 23625768 TI - [Neurodevelopmental outcome of very low birth weight infants born at the Perinatal Centre in Ulm, Germany]. AB - BACKGROUND: Since 2006 an assessment of the neurodevelopmental outcome of very low birth weight infants (VLBWI) at a corrected age of 2 years is mandatory for every perinatal centre in Germany. The aim of our study was to check how complete these assessments were performed in our population of infants born at our perinatal centre and receiving treatment within our local neonatal network. Furthermore, the data obtained will be used for prenatal consultations. Another objective was to identify risk factors for adverse neurodevelopmental outcomes. METHODS: All VLBWI were invited for a follow-up exam using the Bayley Scales of Infant Development II (BSID-II) or III (BSID-III), or Griffiths Mental Developmental Scales) at 2 years corrected age. The results of children assessed by other institutions were collected. RESULTS: 142 (69.3%) of the 205 VLBWI, born and finally discharged alive at the perinatal centre in Ulm were assessed at a median (minimum - maximum) corrected age of 23 (18-27) months. The BSID-II Psychomotor Development Index (PDI) 91 was (< 50-128) (n=115), the BSID-II Mental Development Index (MDI) was 87 (< 50-134) (n=96), BSID-III MDI 95 (60-112) (n=29) and the Griffiths Score was 93 (67-140) (n=17). Severe disability was diagnosed in 36 (25.4%) of the children studied. Gestational age and higher grade intraventricular haemorrhage were associated independently with severe disability. CONCLUSIONS: It is very difficult to achieve a high rate of follow-up examinations in preterm infants <1,500 g in a neonatal network. Severe impairment in VLBWI is not rare. Improving neurodevelopmental outcome remains a challenge. PMID- 23625770 TI - Smart molecularly imprinted polymers: recent developments and applications. AB - The use of the molecular imprinting technique to produce polymers with high specificity for a given "molecular template" has undergone a rapid and expansive evolution since the inception of the idea over half a century ago. It was only a matter of time before the seemingly inevitable "marriage" of this concept with another modern research obsession, the generation of "smart" polymers, capable of reacting quickly, accurately and reproducibly to changes in their environment. Many advances have since been made, concerning the quality and diversity of these systems and polymers responsive to temperature, pH and a host of other environmental cues now exist. This article provides a succinct overview of the process and outcomes of "smart" molecular imprinting, followed by a detailed assessment of recent developments and applications in such field. PMID- 23625771 TI - Protective effect of female gender-related factors on muscle force-generating capacity and fragility in the dystrophic mdx mouse. AB - INTRODUCTION: The dystrophic features in hindlimb skeletal muscles of female mdx mice are unclear. METHODS: We analyzed force-generating capacity and force decline after lengthening contraction-induced damage (fragility). RESULTS: Young (6-month-old) female mdx mice displayed reduced force-generating capacity (-18%) and higher fragility (23% force decline) compared with female age-matched wild type mice. These 2 dystrophic features were less accentuated in young female than in young male mdx mice (-32% and 42% force drop). With advancing age, force generating capacity decreased and fragility increased in old (20 month) female mdx mice (-21% and 57% force decline), but they were unchanged in old male mdx mice. Moreover, estradiol treatment had no effect in old female mdx mice. CONCLUSIONS: Female gender-related factors mitigate dystrophic features in young but not old mdx mice. Further studies are warranted to identify the beneficial gender-related factor in dystrophic muscle. PMID- 23625772 TI - Strain differences influence timing and magnitude of both acute and late inflammatory reactions after intratracheal instillation of an alkylating agent in rats. AB - The acute pulmonary responses after exposure to sulfur and nitrogen mustards are well documented whereas the late pulmonary effects are not. With a novel focus on the immune system this paper investigate whether late phase pulmonary effects developed in rats exposed to the nitrogen mustard melphalan are linked to the acute responses and whether the reactions are genetically regulated. The DA rat strain was used to establish a lung exposure model. Five other inbred rat strains (PVG, PVG.1AV1, LEW, WF and F344) were compared within the model at selected time points. All rat strains displayed a biphasic pattern of leukocyte infiltration in the lungs, dominated by neutrophils 2 days after exposure and a second peak dominated by macrophages 29 days after exposure. The number of macrophages was higher in the DA rat compared with the other strains. The infiltration of lymphocytes in the lungs varied in both time of appearance and magnitude between strains. The quantity of collagen deposition in the lungs varied between strains at day 90; LEW and WF displayed high collagen content which coincided with an increased level of cytotoxic T cells. LEW further displayed an increased number of T helper cells and natural killer (NK) T cells in the lungs. The results in this study suggest there is a link between the development of lung fibrosis and high cytotoxic cell responses and that there is a genetic influence, as there are variations in acute and late adverse reactions between rat strains in both timing and magnitude. PMID- 23625773 TI - Use of zoledronic acid for treatment of chemotherapy related osteonecrosis in children and adolescents: a retrospective analysis. AB - BACKGROUND: Osteonecrosis (ON) is a disabling complication of chemotherapy, especially steroids in children and adolescents. There are few reports in the literature of non-surgical management of ON. Patients with chemotherapy related ON, treated with zoledronic acid (ZA) were analyzed for clinical and radiological outcome. METHODS: Retrospective chart review. Serial joint radiographs were performed to assess response and graded according to Association Research Circulation Osseous (ARCO) system. All patients were evaluated for bone turnover and bone mineral density (BMD) at set intervals. RESULTS: Twenty children with ON were treated with ZA for median duration of 13 months (range 5-25) with median number of doses being 6 (2, 8). Five (25%) patients were pain free at the end of treatment and had minimal joint destruction on X-ray (ARCO score II); 5 (25%) underwent arthroplasty due to severe joint destruction and pain limiting activity (ARCO score III/IV); 10 (50%) reported ongoing pain with activity, none on regular analgesia. BMD analysis showed increase in lumbosacral BMD after 1 year of treatment. Compared to patients with ON of the knees, majority of patients with ON of the hips had radiological progression. CONCLUSION: ZA was well tolerated and improved joint pain in the majority of patients. Despite treatment with ZA, most patients with ON of hips had progressive joint destruction requiring arthroplasty. Patients with ON of the knees appeared to have radiological stabilization. Novel treatment strategies should be considered to prevent this debilitating complication in survivors of childhood cancer. PMID- 23625774 TI - MicroRNA-302a sensitizes testicular embryonal carcinoma cells to cisplatin induced cell death. AB - Cisplatin is a commonly used chemotherapeutic agent for the treatment of several human malignancies, such as testicular germ cell tumors (TGCT). The toxic effects persist and those that are present long after chemotherapy affect the overall quality of life of patients. MicroRNAs (miRNAs) play important roles in the responses of cancer cells to chemotherapy and have been shown to modulate cell sensitivity to chemotherapeutic drugs. However, the relationship between miRNA expression and cisplatin sensitivity of TGCT has not been fully explored. In this study, the effects of miR-302a on cisplatin cytotoxicity in TGCT-derived cell line NTERA-2 (NT2) were evaluated. We found that expression levels of miR-302a were increased in cisplatin-treated NT2 cells. Up-regulation of miR-302a significantly increased the sensitivity of NT2 cells to cisplatin by enhancing cisplatin-induced G2/M phase arrest and the subsequent progression to apoptosis. MiR-302a also increased the killing effects of cisplatin by lowering the apoptotic threshold; the same result was also observed in another TGCT-derived cell line, NCCIT. Furthermore, miR-302a-enhanced cisplatin sensitivity was partially mediated through the down-regulation of p21 in NT2 cells. MiR-302a induced apoptosis was further enhanced by silencing of p53 in NT2 cells. p53 levels were inversely associated with the expression of Oct4, Sox2, and Nanog in response to cisplatin. Thus, targeting miR-302a may offer new therapeutic interventions in TGCT. PMID- 23625775 TI - Transit phenomena in organic field-effect transistors through Kelvin-probe force microscopy. AB - The temporal evolution of the surface-potential distribution in the channel of pentacene based field-effect transistors is investigated during the charge reversal from the electron to the hole dominated operation. This measurement allows the determination of the carrier density and electric field dependent hole mobility in the sub-threshold regime of the transistor. PMID- 23625776 TI - Diffusion tensor imaging (DTI) in the detection of white matter lesions in patients with mild cognitive impairment (MCI). AB - Mild cognitive impairment (MCI) is recognized as a precursor to dementia. The amnestic MCI progresses usually to Alzheimer disease. Amnestic MCI multiple domain (md-MCI) seems to progress more rapidly than amnestic MCI single domain (a MCI). In an attempt to identify patients at risk, we examined white matter changes in MCI subtypes using diffusion tensor imaging (DTI). We also tried to correlate DTI findings to neuropsychological tests. Forty-four amnestic single domain (a-MCI) patients, 19 amnestic multi domain (md-MCI), and 25 cognitively normal (NC) controls were included in the present study. All participants were assessed clinically using a battery of cognitive tests. DTI was performed to measure fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Areas studied were corpus callosum, posterior cingulum (PC), anterior cingulum (AC), and superior longitudinal fasciculus (SLF). ADC and FA of the above areas were related to the scores of certain neuropsychological tests that evaluate visual and verbal memory. No difference in DTI measurements was found between the two MCI subtypes. ADC in MCI cases was increased in comparison with NC in the genu, PC, right SLF, and left AC. FA was spared. Verbal memory was related to ADC of the genu, PC, right AC and right SLF, and to FA of the left SLF. Visual memory was related to ADC of the genu, PC, right AC, and SLF. The strongest correlation found was between the visual memory and the ADC of the right PC (Spearman rho = 0.45, p < 0.001). DTI revealed that ADC was increased in certain brain areas in MCI patients. No difference in DTI measurements was found between the two MCI subtypes. DTI indices correlate with cognitive performance. PMID- 23625777 TI - Puerperal cerebral sinus venous thrombosis and acute hyperthyroidism in Graves' disease. PMID- 23625778 TI - Concomitant neuromyelitis optica and cytomegalovirus-associated retinitis in an immunocompetent female. PMID- 23625779 TI - Mesoporous silica nanoparticles act as a self-adjuvant for ovalbumin model antigen in mice. AB - Immunization to the model protein antigen ovalbumin (OVA) is investigated using MCM-41 mesoporous silica nanoparticles as a novel vaccine delivery vehicle and adjuvant system in mice. The effects of amino surface functionalization and adsorption time on OVA adsorption to nanoparticles are assessed. Amino functionalized MCM-41 (AM-41) shows an effect on the amount of OVA binding, with 2.5-fold increase in binding capacity (72 mg OVA/g AM-41) compared to nonfunctionalized MCM-41 (29 mg OVA/g MCM-41). Immunization studies in mice with a 10 MUg dose of OVA adsorbed to AM-41 elicits both antibody and cell-mediated immune responses following three subcutaneous injections. Immunizations at a lower 2 MUg dose of OVA adsorbed to AM-41 particles results in an antibody response but not cell-mediated immunity. The level of antibody responses following immunization with nanoformulations containing either 2 MUg or 10 MUg of OVA are only slightly lower than that in mice which receive 50 MUg OVA adjuvanted with QuilA, a crude mixture of saponins extracted from the bark of the Quillaja saponaria Molina tree. This is a significant result, since it demonstrates that AM-41 nanoparticles are self-adjuvanting and elicit immune responses at reduced antigen doses in vivo compared to a conventional delivery system. Importantly, there are no local or systemic negative effects in animals injected with AM-41. Histopathological studies of a range of tissue organs show no changes in histopathology of the animals receiving nanoparticles over a six week period. These results establish the biocompatible MCM-41 silica nanoparticles as a new method for vaccine delivery which incorporates a self-adjuvant effect. PMID- 23625780 TI - Chronic ozone exacerbates the reduction in photosynthesis and acceleration of senescence caused by limited N availability in Nicotiana sylvestris. AB - Both elevated ozone (O(3)) and limiting soil nitrogen (N) availability negatively affect crop performance. However, less is known about how the combination of elevated O(3) and limiting N affect crop growth and metabolism. In this study, we grew tobacco (Nicotiana sylvestris) in ambient and elevated O(3) at two N levels (limiting and sufficient). Results at the whole plant, leaf, and cellular level showed that primary metabolism was reduced by growth in limiting N, and that reduction was exacerbated by exposure to elevated O(3). Limiting N reduced the rates of photosynthetic CO(2) uptake by 40.8% in ambient O(3)-exposed plants, and by 58.6% in elevated O(3)-exposed plants, compared with plants grown with sufficient N. Reductions in photosynthesis compounded to cause large differences in leaf and whole plant parameters including leaf number, leaf area, and leaf and root biomass. These results were consistent with our meta-analysis of all published studies of plant responses to elevated O(3) and N availability. In tobacco, N uptake and allocation was also affected by growth in limiting N and elevated O(3), and there was an O(3)-induced compensatory response that resulted in increased N recycling from senescing leaves. In addition, transcript-based markers were used to track the progress through senescence, and indicated that limiting N and elevated O(3), separately and in combination, caused an acceleration of senescence. These results suggest that reductions in crop productivity in growing regions with poor soil fertility will be exacerbated by rising background O(3). PMID- 23625781 TI - Reduced prevalence of obesity in children with primary fructose malabsorption: a multicentre, retrospective cohort study. AB - BACKGROUND: Studies in animals and in man have demonstrated that excessive consumption of fructose can cause all components of the metabolic syndrome. OBJECTIVE: To investigate the impact of a condition resulting in decreased absorption of fructose, on obesity. METHODS: In a multicentre study, we analyzed a cohort of paediatric patients with suspected primary fructose malabsorption (FM). Patients with chronic intestinal diseases were excluded. The final cohort comprised 628 patients. RESULTS: 302 patients were diagnosed with primary FM (48.1%). The proportion of obese patients was lower among FM patients, compared to non-FM patients (2.3 vs. 6.1%, P = 0.029). Logistic regression analysis with inclusion of various covariates showed that FM was negatively associated with obesity (OR 0.35, 95% CI [0.13; 0.97]). We discuss several mechanisms involving the metabolic, endocrine and gastrointestinal system. CONCLUSIONS: Our data indicate that primary FM is negatively associated with childhood obesity. PMID- 23625782 TI - Endocrine disruption by di-(2-ethylhexyl)-phthalate in Chinese rare minnow (Gobiocypris rarus). AB - Great concern has been raised over the potential impact of environmental contaminants on fish populations that inhabit the Three Gorge Reservoir. The present study investigated the endocrine-disrupting effects of di-(2-ethylhexyl) phthalate (DEHP) on the Chinese rare minnow (Gobiocypris rarus), an endemic fish distributed in upstream waters in the Yangtze River. Adult rare minnow were exposed to environmentally relevant concentrations of DEHP (0 ug/L, 3.6 ug/L, 12.8 ug/L, 39.4 ug/L, and 117.6 ug/L) for a 21-d period. Then, concentrations of sex hormones in the plasma and relative transcription of various associated genes were measured in the hypothalamic-pituitary-gonadal (HPG) axis and liver of the fish. Exposure to DEHP resulted in greater circulating concentrations of testosterone (T) and lower concentrations of estradiol (E2), which were accompanied by upregulation of Cyp17 mRNA and downregulation of Cyp19a mRNA in the gonads of females. In males, increases of T and E2 levels were consistent with upregulation of Cyp17 and Cyp19a in the gonads. Furthermore, the T/E2 ratio was increased in females but reduced in males. A significant increase in the levels of hepatic vitellogenin (VTG) gene transcription was observed in both females and males. The present study showed that waterborne exposure to DEHP altered plasma sex hormone levels and modulated gene transcription profiles of associated genes in the HPG axis and liver, occurring mostly at higher concentrations (>39.4 ug/L), which suggests that environmental concentration of DEHP (5.4 ug/L) alone might not disturb the endocrine system of the rare minnow in the TGR. PMID- 23625783 TI - Diethylhexyl phthalate exposure impairs follicular development and affects oocyte maturation in the mouse. AB - Diethylhexyl phthalate (DEHP) is an estrogen-like compound widely used as a commercial plasticizer and present in medical devices, tubing, food containers and packaging. It is considered an endocrine disruptor and studies on experimental animals showed that exposure to DEHP can alter the function of several organs including liver, kidneys, lungs and reproductive system, particularly the developing testes of prenatal and neonatal males. Exposure to DEHP has been proposed as a potential human health hazard. This study assessed the effects of DEHP on folliculogenesis and oocyte maturation using the mouse as the experimental model. Newborn female mice were hypodermically injected with DEHP at doses of 20 and 40 MUg/kg per body weight following different exposure regimens during the weaning period. We found that DEHP altered both folliculogenesis and oocyte development. In particular, DEHP exposure significantly decreased the number of the primordial follicles at pubertal and adult age by possibly accelerating the rate of follicle recruitment dynamics, reduced and/or delayed the level of imprinted gene methylation in the oocytes and increased metaphase II spindle abnormalities in oocytes matured in vitro. Furthermore, the weight of pups and litter size of mothers exposed to DEHP were significantly lower than controls. Finally, the number of primordial follicles appeared significantly reduced also in the F1 offspring at the adult age. These results show that DEHP may have a number of adverse effects on oogenesis, especially when exposure occurs during early postnatal age, arising concerns about the exposure of human female infants and children to this compound. PMID- 23625784 TI - [Treatment strategies for spinal metastases]. AB - Spinal metastases occur in 10 % of all carcinoma patients in the course of their oncologic disease. Spinal metastasis is a manifestation of a systemic oncologic disease. The treatment of the metastasis does not influence the overall oncological outcome. Treatment decision is depending from the primary tumor, presence of neurological symptoms, stability of the spine, extent of visceral and osseous dissemination, general state of the patient and his life expectancy. Therapy should focus on the patient's needs and be correlated with the expectations and prognosis of the patient. There exist a number of valid prognostic scores to support and objectify the decision. There has been a change of paradigmata with regard to surgical treatment, supported by an improvement in oncosurgical and anesthesiological fields. Surgery is indicated in case of instability or neurological compromise, in respect of the general state and life expectancy and can be performed from a ventral, dorsal or combined approach. Alternative or complimentary treatment methods are radiotherapy, chemotherapy, hormonotherapy, stereotactic radiosurgery and additive therapies like sequential embolization, antiresorptive medication or corticoid therapy. Therapy should be established by a multidisciplinary tumor board. Main issue for treatment decisions is palliation and optimizing the patient's quality of life. PMID- 23625785 TI - The contribution of proteomics to the unveiling of the survival strategies used by Pseudomonas putida in changing and hostile environments. AB - Pseudomonas putida is a ubiquitous, metabolically very versatile, Gram-negative bacterium adapted to habitats as diverse as soil, water and the rhizosphere. Most strains are nonpathogenic, many are used as experimental models, and many others have biotechnological applications in the areas of agriculture, bioremediation, biocatalysis, and the production of bioplastics. This review summarizes the contribution of proteomic technologies to our understanding of how P. putida responds to different carbon sources, how it adapts to living at suboptimal temperatures or attached to surfaces, and how it responds to the presence of toxic compounds such as aromatic molecules and heavy metals. The examples described illustrate the value of proteomics in furthering our knowledge of the physiology and behavior of bacteria, knowledge that is important for understanding how they behave in their natural habitats and for optimizing their behavior in biotechnological applications. PMID- 23625787 TI - Risk factors for excessive anticoagulation among hospitalized adults receiving warfarin therapy using a pharmacist-managed dosing protocol. AB - STUDY OBJECTIVE: To identify specific risk factors for excessive anticoagulation, defined as an international normalized ratio (INR) higher than 5, in hospitalized adults receiving warfarin therapy using a pharmacist-managed dosing protocol. DESIGN: Retrospective nested case-control study. SETTING: Large academic tertiary care medical center. PATIENTS: Hospitalized nonsurgical patients 18 years or older who received at least one dose of warfarin according to the pharmacist managed protocol from January 1, 2009, to January 31, 2012, were included. Patients who experienced an INR higher than 5 were designated as case patients; those who received warfarin for at least as many days as the case patients but who did not experience an INR more than 5 were deemed control patients. Controls were matched to cases in a 2:1 ratio by age, sex, INR goal, and type of warfarin therapy (new start or continuation). MEASUREMENTS AND MAIN RESULTS: A total of 87 case patients were matched to 174 controls. Ten different hypothesized risk factors were examined. Two variables, severity of illness score (odds ratio [OR] 4.89, p<0.001) and poor nutritional status (OR 4.27, p<0.001), demonstrated strong independent associations with risk of excessive anticoagulation. Administration of interacting drugs that highly potentiate warfarin's effect (OR 2.26, p=0.011) and concurrent diarrheal illness (OR 4.75, p<0.001) also displayed a statistically significant risk for excessive anticoagulation. CONCLUSION: Even in a highly standardized system for warfarin dosing by a pharmacist-managed protocol, higher disease severity and poor nutritional status placed hospitalized patients at greater risk of experiencing excessive anticoagulation. In addition, administration of interacting drugs that highly potentiate warfarin's effect or the occurrence of diarrheal illness may predict increased risk. PMID- 23625789 TI - Two-dimensional ultrasound imaging of the diaphragm: quantitative values in normal subjects. AB - INTRODUCTION: Real time ultrasound imaging of the diaphragm is an under-used tool in the evaluation of patients with unexplained dyspnea or respiratory failure. METHODS: We measured diaphragm thickness and the change in thickness that occurs with maximal inspiration in 150 normal subjects, with results stratified for age, gender, body mass index, and smoking history. RESULTS: The lower limit of normal diaphragm thickness at end expiration or functional residual capacity is 0.15 cm, and an increase of at least 20% in diaphragm thickness from functional residual capacity to total lung capacity is normal. A side to side difference in thickness at end expiration of > 0.33 cm is abnormal. Diaphragm thickness and contractility are minimally affected by age, gender, body habitus, or smoking history. CONCLUSIONS: This study confirms previous findings in much smaller groups of normal controls for quantitative ultrasound of the diaphragm and provides data that can be applied widely to the general population. PMID- 23625790 TI - Structural variations, the regulatory landscape of the genome and their alteration in human disease. AB - High-throughput genomic technologies are revolutionizing human genetics. So far the focus has been on the 1.5% of the genome, which is coding, in spite of the fact that the great majority of genomic variants fall outside the coding regions. Recent efforts to annotate the non-coding sequence show that over 80% of the genome is biochemically active. The genome is divided into regulatory domains consisting of sequence regions that enhance and/or silence the expression of nearby genes and are, in some cases, separated by boundaries with insulator activity. In this paper, we review the recent advances in the identification of variations that influence gene regulation and their consequences for human disease. We hypothesize that structural variations outside of the coding genome can interfere with normal gene regulation by disrupting the regulatory landscape. Therefore, the regulatory landscape of the genome has also to be taken into consideration when investigating the pathology of human disease. PMID- 23625788 TI - Aspergillus vertebral osteomyelitis in immunocompetent subjects: case report and review of the literature. AB - Aspergillus spondylodiscitis (AS) is rare in immunocompetent (IC) patients. A 65 year-old diabetic IC male subject presented with cervical AS 18 months after otomycosis. Two serological tests, mastoidectomy and biopsy of the sphenoid bone, were negative. A prevertebral biopsy identified A. flavus. The patient was successfully treated with voriconazole. Forty-three cases of AS in IC patients have been published. A predisposition was found in 84 % of cases. Fever was reported in 20 % of cases, whereas neurological defects were present in 41 %. Serology was inconsistently positive (5/7) and diagnosis was confirmed by biopsy or surgery. A. fumigatus was the most frequently isolated species (74 %). All episodes were medically treated, associated with surgery in 57 % of cases, and 73 % of patients fully recovered. AS must be discussed in IC patients presenting with risk factors, including diabetes mellitus. Biopsy is necessary to confirm diagnosis, since serology offers low sensitivity. Nevertheless, the prognosis is good. PMID- 23625791 TI - Pore-functionalized nanoporous materials derived from block copolymers. AB - This review deals with nanoporous materials made from the self-assembly of block copolymers with a special interest in the chemical functions covering the surface of their nanopores. A detailed overview of the existing methods and strategies to generate well-defined organic functional groups covering the surface of the pore walls is provided. This further enables to finely tune the affinity of the pore walls and to perform well-defined chemical reactions onto them, which is essential for further dedicated applications. PMID- 23625792 TI - Exciton dynamics in semiconductor nanocrystals. AB - This review article provides an overview of recent advances in the study and understanding of dynamics of excitons in semiconductor nanocrystals (NCs) or quantum dots (QDs). Emphasis is placed on the relationship between exciton dynamics and optical properties, both linear and nonlinear. We also focus on the unique aspects of exciton dynamics in semiconductor NCs as compared to those in bulk crystals. Various experimental techniques for probing exciton dynamics, particularly time-resolved laser methods, are reviewed. Relevant models and computational studies are also briefly presented. By comparing different materials systems, a unifying picture is proposed to account for the major dynamic features of excitons in semiconductor QDs. While the specific dynamic processes involved are material-dependent, key processes can be identified for all the materials that include electronic dephasing, intraband relaxation, trapping, and interband recombination of free and trapped charge carriers (electron and hole). Exciton dynamics play a critical role in the fundamental properties and functionalities of nanomaterials of interest for a variety of applications including optical detectors, solar energy conversion, lasers, and sensors. A better understanding of exciton dynamics in nanomaterials is thus important both fundamentally and technologically. PMID- 23625793 TI - Pericytes, stem-cell-like cells, but not mesenchymal stem cells are recruited to support microvascular tube stabilization. AB - An experimental model is introduced for the induction of endothelial cell (EC) tubulogenesis after 24 h of incubation on micropatterned polymer surfaces. Pericytes or mesenchymal stem cells are added separately to this system to evaluate their effect on tubular stabilization. In the absence of additional cells, the tubular structures are lost after 36 h. Addition of only pericytes, however, stabilizes the EC vasculogenic tubes. PMID- 23625794 TI - FUS/TLS assembles into stress granules and is a prosurvival factor during hyperosmolar stress. AB - FUsed in Sarcoma/Translocated in LipoSarcoma (FUS/TLS or FUS) has been linked to several biological processes involving DNA and RNA processing, and has been associated with multiple diseases, including myxoid liposarcoma and amyotrophic lateral sclerosis (ALS). ALS-associated mutations cause FUS to associate with stalled translational complexes called stress granules under conditions of stress. However, little is known regarding the normal role of endogenous (non disease linked) FUS in cellular stress response. Here, we demonstrate that endogenous FUS exerts a robust response to hyperosmolar stress induced by sorbitol. Hyperosmolar stress causes an immediate re-distribution of nuclear FUS to the cytoplasm, where it incorporates into stress granules. The redistribution of FUS to the cytoplasm is modulated by methyltransferase activity, whereas the inhibition of methyltransferase activity does not affect the incorporation of FUS into stress granules. The response to hyperosmolar stress is specific, since endogenous FUS does not redistribute to the cytoplasm in response to sodium arsenite, hydrogen peroxide, thapsigargin, or heat shock, all of which induce stress granule assembly. Intriguingly, cells with reduced expression of FUS exhibit a loss of cell viability in response to sorbitol, indicating a prosurvival role for endogenous FUS in the cellular response to hyperosmolar stress. PMID- 23625795 TI - Correlation of tumor marker expression with nodal disease burden in metastatic head and neck cancer. AB - OBJECTIVES: To investigate the correlation between the percentage of metastatic tumor present in lymph nodes resected from patients with squamous cell carcinoma of the head and neck (HNSCC) and level of expression of 3 marker genes: pemphigus vulgaris antigen (PVA), parathyroid hormone-related peptide (PTHrP), and tumor associated calcium signal transducer 1 (TACSTD1). In addition, we investigated whether the level of expression of these 3 markers was associated with clinical outcomes for patients with HNSCC. STUDY DESIGN: Retrospective analysis of previously harvested patient samples. SETTING: The University of Pittsburgh. SUBJECTS AND METHODS: A total of 448 lymph nodes from 92 patients with HNSCC were evaluated for expression of the gene markers PVA, PTHrP, and TACSTD1 using real time polymerase chain reaction. Confirmation of metastasis was determined by histologic examination. The expression level of these markers versus tumor percentage was analyzed. RESULTS: All 3 markers were studied independently and were associated with tumor percentage in metastatic lymph nodes. PVA had the strongest correlation, followed by PTHrP and then TACSTD1. PVA levels had a trend toward association with clinical outcome, specifically time to death caused by cancer, but this was confounded by tumor stage. CONCLUSION: All 3 tumor gene markers were associated with percentage of tumor cells in metastatic lymph nodes. PVA had the strongest correlation. PVA may add prognostic utility beyond pathologic staging, but this requires analysis of a larger cohort. Prospective studies of tumor volume in metastatic nodes should determine a lower limit threshold of molecular marker detection. PMID- 23625796 TI - Practical guide to understanding the need for clinical practice guidelines. AB - With recent changes in the landscape of health care, clinical practice guidelines (CPGs) have proliferated. Attitudes about guidelines differ considerably, forming 2 competing viewpoints with considerable tension between them. Some feel CPGs are unneeded or are efforts to create automated "cookie cutter" medical practice; at best, they are perceived as suggestions that may be altered by experience. Others feel they are mandates that must be followed to the letter. This article attempts to explain how and why we have arrived at this point and to explain the origins of the differing viewpoints. We begin by describing the 2 viewpoints and proceed to define the origin of medicine as a profession and to chronicle the evolution of health insurance, medical education, and scientific methods for evaluating evidence. PMID- 23625797 TI - Secondary onlay free flap reconstruction of glossectomy defects following initial successful flap restoration. AB - Patients who undergo tongue reconstruction over time may develop gradual worsening of dysarthria and dysphagia secondary to flap atrophy. At our institution, these patients undergo a secondary flap onlay procedure for augmentation of the neotongue. We review a total of 11 patients with total glossectomy defect who underwent secondary tongue augmentation with secondary onlay free flap consisting of radial forearm free flap (n = 6) and rectus free flap (n = 5). There was improvement in swallowing in 7 of 11 patients. Five (45.4%) patients achieved gastric tube independence. Seven (63.6%) patients achieved a varying degree of oral intake. All patients achieved tracheostomy independence. Dysarthria was improved in all patients. There were no flap failures. Therefore, a secondary onlay flap technique is feasible and may improve dysphagia and dysarthria to achieve gastric tube and tracheostomy independence in total glossectomy patients with delayed tongue atrophy. PMID- 23625798 TI - Calorie-sweetened beverages and fructose: what have we learned 10 years later. AB - BACKGROUND: Sugar-sweetened drinks and the fructose they provide are associated with several health problems. METHODS: Data from the Nielsen Homescan and product content were analysed for sweetener type using the Gladson Nutrition Database. Meta-analyses and randomized clinical trials were used to evaluate outcomes of beverage and fructose intake. RESULTS: Over 70% of all foods contain some amounts of added sugar, and consumption of soft drinks has increased fivefold since 1950. Meta-analyses suggest that consumption of sugar-sweetened beverages is related to the risk of diabetes, the metabolic syndrome and cardiovascular disease in adults and in children. Drinking two sugar-sweetened beverages per day for 6 months induced features of the metabolic syndrome and fatty liver. Randomized, controlled trials in children and adults lasting from 6 months to 2 years have shown that lowering the intake of soft drinks reduced weight gain. Genetic factors influence the weight gain when drinking soft drinks. CONCLUSION: Consumption of calorie-sweetened beverages and the fructose they contain has continued to increase and may play a role in the epidemic of obesity, the metabolic syndrome and fatty liver disease. Reducing intake of soft drinks is associated with less weight gain and metabolic improvement as well. PMID- 23625799 TI - "Yes, I have sometimes stolen bikes": blindness for norm-violating behaviors and implications for suspect interrogations. AB - Across two experiments, we studied a phenomenon akin to choice blindness in the context of participants' accounts of their own history of norm-violating behaviors. In Experiment 1, N = 67 participants filled in an 18-item questionnaire about their history of norm-violating behaviors (QHNVB). Subsequently, they were questioned about four of their answers, two of which had covertly been manipulated by the experimenter. Of the 134 manipulations, 20 (14.9%) remained undetected concurrently and 13 were accepted in retrospect (9.7%). In Experiment 2 (N = 37), we inserted a one-week interval between questionnaire and interview. Twenty-seven (36.5%) of the 74 manipulations remained undetected concurrently and three were accepted in retrospect (8.1%). Data obtained in a four-week follow-up indicated that our manipulations may have long-term effects on participants' perception of their own history of norm violating behaviors. Implications for the occurrence of false confessions during the course of an interrogation are discussed. PMID- 23625800 TI - Congenital amegakaryocytic thrombocytopenia (CAMT) presenting as severe pancytopenia in the first month of life. AB - Congenital amegakaryocytic thrombocytopenia (CAMT) is characterised by neonatal thrombocytopenia, with reduced or absent bone marrow megakaryocytes, leading eventually to pancytopenia. The mean age for progression to bone marrow failure is four years, with the earliest reported being six months. We describe a CAMT patient with compound heterozygous mutations of the causative MPL gene (one being a previously unreported splice site mutation in intron 11) who developed pancytopenia within the first month of life. This report emphasises the importance of considering CAMT in the differential diagnosis of congenital aplastic anaemia or idiopathic aplastic anaemia in babies. PMID- 23625801 TI - Making sense of OMICS data in population-based environmental health studies. AB - Although experience from the application of OMICS technologies in population based environmental health studies is still relatively limited, the accumulated evidence shows that it can allow the identification of features (genes, proteins, and metabolites), or sets of such features, which are targeted by particular exposures or correlate with disease risk. Such features or profiles can therefore serve as biomarkers of exposure or disease risk. Blood-based OMIC profiles appear to reflect to some extent events occurring in target tissues and are associated with toxicity or disease and therefore have the potential to facilitate the elucidation of exposure-disease relationships. Further progress in this direction requires better understanding of the significance of exposure-induced network perturbations for disease initiation and progression and the development of a framework that combines agnostic searches with the utilization of prior knowledge, taking account of particular elements which characterize the structure and evolution of complex systems and brings in principles of systems biology. PMID- 23625802 TI - Impact of dermatologic adverse events on quality of life in 283 cancer patients: a questionnaire study in a dermatology referral clinic. AB - BACKGROUND: Anticancer therapies cause a wide range of dermatologic adverse events (AE). Although the frequency and severity of these events have been described, their effects on health-related quality of life (QoL) remain poorly understood, and the ones having a greater impact have not been ascertained. OBJECTIVE: To assess QoL in patients on conventional versus targeted anti-cancer therapies using a dermatology-specific questionnaire. METHODS: Patients (n = 283) completed the Skindex-16, a QoL questionnaire measuring the effects on three domains: symptoms, emotions, and function. Patients were grouped into two categories according to the types of oncology treatments received: (1) targeted therapies and (2) non-targeted therapies. Correlations of Skindex-16 scores with type of anti-cancer therapy, number of AEs, and specific dermatologic AEs were investigated. RESULTS: Significant differences between patients treated with targeted versus non-targeted therapy with regards to total Skindex-16 (p = 0.02) and emotion subdomain (p = 0.02) scores were observed. Additionally, patients on targeted therapies experienced a significantly greater number of AEs (p < 0.001) compared with patients on non-targeted therapies. Patients who exhibited epidermal growth factor receptor (EGFR) inhibitor-induced rash had higher Skindex 16 scores (p = 0.009) and higher scores in the symptom (p < 0.001), emotion (p = 0.01), and function (p = 0.001) subdomains than patients without this AE. Similar results were observed for pruritus. All p values were two sided. CONCLUSIONS: Dermatologic AEs are associated with a diminished QoL. Targeted therapies are associated with a significantly increased number of AEs and worse total and emotion Skindex-16 scores in comparison with non-targeted therapies. EGFR inhibitor rash and pruritus produced the greatest negative impact. PMID- 23625803 TI - The association between controlled interpersonal affect regulation and resource depletion. AB - BACKGROUND: This investigation focuses on what occurs to individuals' self regulatory resource during controlled Interpersonal Affect Regulation (IAR) which is the process of deliberately influencing the internal feeling states of others. Combining the strength model of self-regulation and the resources conservation model, the investigation tested whether: (1) IAR behaviors are positively related to ego-depletion because goal-directed behaviors demand self-regulatory processes, and (2) the use of affect-improving strategies benefits from a source of resource-recovery because it initiates positive feedback from targets, as proposed from a resource-conservation perspective. METHOD: To test this, a lab study based on an experimental dual-task paradigm using a sample of pairs of friends in the UK and a longitudinal field study of a sample of healthcare workers in Spain were conducted. RESULTS: The experimental study showed a depleting effect of interpersonal affect-improving IAR on a subsequent self regulation task. The field study showed that while interpersonal affect-worsening was positively associated with depletion, as indicated by the level of emotional exhaustion, interpersonal affect-improving was only associated with depletion after controlling for the effect of positive feedback from clients. CONCLUSION: The findings indicate that IAR does have implications for resource depletion, but that social reactions play a role in the outcome. PMID- 23625804 TI - Mechanistic aspects of hSOD1 maturation from the solution structure of Cu(I) loaded hCCS domain 1 and analysis of disulfide-free hSOD1 mutants. AB - Superoxide dismutase 1 (SOD1) maturation within the cell is mainly accomplished with the SOD1-specific chaperone, CCS, a dimeric protein with three distinct domains in each monomer. We recently showed that the first domain of human CCS (hCCSD1) is responsible for copper transfer to its protein partner, human SOD1 (hSOD1). The NMR solution structure of the copper(I)-loaded form of hCCSD1 reported here contributes further to characterization of the copper-transfer mechanism to hSOD1. NMR spectroscopy was also used to examine the hSOD1 mutants C57A, C146A, and C57A/C146A, which are unable to form the structurally conserved disulfide bond in SOD1, in order to investigate the role of these cysteines during hSOD1 copper acquisition. Together, the information on both hCCS and hSOD1, along with a sequence analysis of eukaryotic CCSD1, allows us to propose important mechanistic aspects regarding the copper-transfer process from hCCS to hSOD1. PMID- 23625808 TI - Semitendinosus muscle fatty infiltration following tendon harvest in rabbits. AB - The hamstring tendon autograft is one of the most commonly used graft choices in Anterior cruciate ligament (ACL) reconstruction. There are conflicting results regarding postoperative hamstring strength deficits in patients who have had a hamstring graft. The semitendinosus tendon has been shown to regenerate after harvesting for ACL autograft, suggesting that the muscle has the potential to regain normal function. However, no studies have been performed to define the microstructural changes that occur in the semitendinosus muscle after tendon resection. In this study, we hypothesized that fatty infiltration of the semitendinosus muscle after tendon harvest in New Zealand White rabbits increases postoperatively and remains constant or increases during the first year of repair. The semitendinosus tendon was unilaterally detached and harvested from 15 rabbits. Five rabbits were sacrificed at 3-, 6-, and 12-month intervals, and the semitendinosus muscle-tendon units were analyzed. The contralateral unoperated limb served as the control. The gross tendon and muscle dimensions and histologic percentage of fatty infiltration were measured. We found no significant difference in fatty infiltration at any time point between the control muscle and test specimens and that there was no progression of fatty infiltration over time. If these results hold true in humans, natural repair of the hamstring muscle following tendon harvest during ACL autograft reconstruction is not inhibited by fatty infiltration. PMID- 23625805 TI - Studying protein-reconstituted proteoliposome fusion with content indicators in vitro. AB - In vitro reconstitution assays are commonly used to study biological membrane fusion. However, to date, most ensemble and single-vesicle experiments involving SNARE proteins have been performed only with lipid-mixing, but not content-mixing indicators. Through simultaneous detection of lipid and small content-mixing indicators, we found that lipid mixing often occurs seconds prior to content mixing, or without any content mixing at all, during a 50-seconds observation period, for Ca(2+) -triggered fusion with SNAREs, full-length synaptotagmin-1, and complexin. Our results illustrate the caveats of commonly used bulk lipid mixing fusion experiments. We recommend that proteoliposome fusion experiments should always employ content-mixing indicators in addition to, or in place of, lipid-mixing indicators. PMID- 23625809 TI - Arsonium-containing lipophosphoramides, poly-functional nano-carriers for simultaneous antibacterial action and eukaryotic cell transfection. AB - Gene therapy of diseases like cystic fibrosis (CF) would consist of delivering a gene medicine towards the lungs via the respiratory tract into the target epithelial cells. Accordingly, poly-functional nano-carriers are required in order to overcome the various successive barriers of such a complex environment, such as airway colonization with bacterial strains. In this work, the antibacterial effectiveness of a series of cationic lipids is investigated before evaluating its compatibility with gene transfer into human bronchial epithelial cells. Among the various compounds considered, some bearing a trimethyl-arsonium headgroup demonstrate very potent biocide effects towards clinically relevant bacterial strains. In contrast to cationic lipids exhibiting no or insufficient antibacterial potency, arsonium-containing lipophosphoramides can simultaneously inhibit bacteria while delivering DNA into eukaryotic cells, as efficiently and safely as in absence of bacteria. Moreover, such vectors can demonstrate antibacterial activity in vitro while retaining high gene transfection efficiency to the nasal epithelium as well as to the lungs in mice in vivo. Arsonium containing amphiphiles are the first synthetic compounds shown to achieve efficient gene delivery in the presence of bacteria, a property particularly suitable for gene therapy strategies under infected conditions such as within the airways of CF patients. PMID- 23625810 TI - Functional role of Runx3 in the regulation of aggrecan expression during cartilage development. AB - Runx2 and Runx3 are known to be expressed in the growth plate during endochondral bone formation. Here we addressed the functional role of Runx3 as distinct from Runx2 by using two models of postnatal bone repair: fracture healing that proceeds by an endochondral process and marrow ablation that proceeds by only an intramembranous process. Both Runx2 and Runx3 mRNAs were differentially up regulated during fracture healing. In contrast, only Runx2 showed increased expression after marrow ablation. During fracture healing, Runx3 was expressed earlier than Runx2, was concurrent with the period of chondrogenesis, and coincident with maximal aggrecan expression a protein associated with proliferating and permanent cartilage. Immunohistological analysis showed Runx3 protein was also expressed by chondrocytes in vivo. In contrast, Runx2 was expressed later during chondrocyte hypertrophy, and primary bone formation. The functional activities of Runx3 during chondrocyte differentiation were assessed by examining its regulatory actions on aggrecan gene expression. Aggrecan mRNA levels and aggrecan promoter activity were enhanced in response to the over expression of either Runx2 and Runx3 in ATDC5 chondrogenic cell line, while sh RNA knocked down of each Runx protein showed that only Runx3 knock down specifically suppressed aggrecan mRNA expression and promoter activity. ChIP assay demonstrated that Runx3 interactions were selective to sites within the aggrecan promoter and were only observed during early periods of chondrogenesis before hypertrophy. Our studies suggest that Runx3 positively regulates aggrecan expression and suggest that its function is more limited to cartilage development than to bone. In aggregate these data further suggest that the various members of the Runx transcription factors are involved in the coordination of chondrocyte development, maturation, and hypertrophy during endochondral bone formation. PMID- 23625811 TI - Sonographic incidence of ulnar nerve (sub)luxation and its associated clinical and electrodiagnostic characteristics. AB - INTRODUCTION: The aim of this study was to assess the presence of (sub)luxation of the ulnar nerve in patients with ulnar neuropathy at the elbow (UNE) compared with healthy controls (HC). We assessed its clinical patterns, electrodiagnostic, and sonographic characteristics. METHODS: Using high-resolution sonography, we studied the incidence of (sub)luxation in a cohort of 342 patients and 70 HC. RESULTS: Subluxation occurred in 14% and luxation in 6.7% of the UNE patients versus 5.7% and 5.7%, respectively, in HC (no significant differences). Pain at the elbow occurred more often in patients with (sub)luxation (P = 0.007). Electrodiagnostic and sonographic findings did not differ between patients with or without (sub)luxation. CONCLUSIONS: The incidence of ulnar nerve (sub)luxation between patients with UNE and HC does not differ. UNE patients with (sub)luxation do not have specific clinical or electrodiagnostic findings, apart from experiencing pain at the elbow more often. PMID- 23625812 TI - Transcranial Doppler velocity and brain MRI/MRA changes in children with sickle cell anemia on chronic transfusions to prevent primary stroke. AB - BACKGROUND: Chronic transfusions help prevent primary stroke in children with sickle cell anemia (SCA) and abnormal transcranial Doppler (TCD) velocities. However, the effects of transfusions on TCD velocities and brain MRI/MRA findings are incompletely described. PROCEDURE: We reviewed TCD and brain MRI/MRA results in 27 children with SCA and abnormal TCD velocities receiving transfusions to prevent primary stroke. All TCDs were performed by a single examiner, immediately prior to a scheduled transfusion. We also examined the effects of laboratory and clinical parameters on TCD responses to transfusion therapy. RESULTS: For the whole cohort, the average pre-transfusion HbS on transfusions was 31.7 +/- 12.3%. The most significant decline in TCD velocities occurred within 10 months of starting transfusions. Follow-up TCD values trended upward with increasing pre transfusion %HbS levels while on treatment. Half of the children had persistent conditional/abnormal TCD velocities despite transfusions and 28% had new/progressive stenosis on MRA, but none had primary stroke during 73 patient years of follow-up. CONCLUSIONS: For children with SCA and abnormal TCD velocities, transfusions lower TCD velocities and help prevent stroke, but do not always result in normal velocities or protect against progression of cerebral vasculopathy. Improved adherence to transfusion goals may improve on-treatment TCD velocities. PMID- 23625814 TI - Triple junction polymer solar cells for photoelectrochemical water splitting. AB - A triple junction polymer solar cell in a novel 1 + 2 type configuration provides photoelectrochemical water splitting in its maximum power point at V ~ 1.70 V with an estimated solar to hydrogen energy conversion efficiency of 3.1%. The triple junction cell consists of a wide bandgap front cell and two identical small bandgap middle and back cells. PMID- 23625813 TI - Glomerular filtration rate equations overestimate creatinine clearance in older individuals enrolled in the Baltimore Longitudinal Study on Aging: impact on renal drug dosing. AB - OBJECTIVES: To evaluate the performance of kidney function estimation equations and to determine the frequency of drug dose discordance in an older population. DESIGN: Cross-sectional analysis of data from community-dwelling volunteers randomly selected from the Baltimore Longitudinal Study of Aging from January 1, 2005, to December 31, 2010. SUBJECTS: A total of 269 men and women with a mean +/ SD age of 81 +/- 6 years, mean serum creatinine concentration (Scr ) of 1.1 +/- 0.4 mg/dl, and mean 24-hour measured creatinine clearance (mClcr ) of 53 +/- 13 ml/minute. MEASUREMENTS AND MAIN RESULTS: Kidney function was estimated by using the following equations: Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The performance of each equation was assessed by measuring bias and precision relative to mClcr . Dose calculation errors (discordance) were determined for 10 drugs requiring renal dosage adjustments to avoid toxicity when compared with the dosages approved by the Food and Drug Administration. The CG equation was the least biased estimate of mClcr . The MDRD and CKD-EPI equations were significantly positively biased compared with CG (mean +/- SD 34 +/- 20% and 22 +/- 15%, respectively, p<0.001) and mClcr (29 +/- 47% and 18 +/- 40%, respectively, p<0.001). Rounding low Scr values (less than 1.0 mg/dl) up to an arbitrary value of 1.0 mg/dl resulted in CG values (44 +/- 10 ml/minute) that were significantly lower than mClcr (56 +/- 12 ml/minute, p<0.001) and CG (56 +/- 15 ml/minute, p<0.001). The MDRD and CKD-EPI equations had median dose discordance rates of 28.6% and 22.9%, respectively. CONCLUSION: The MDRD and CKD EPI equations significantly overestimated creatinine clearance (mClcr and CG) in elderly individuals. This leads to dose calculation errors for many drugs, particularly in individuals with severe renal impairment. Thus equations estimating glomerular filtration rate should not be substituted in place of the CG equation in older adults for the purpose of renal dosage adjustments. In addition, the common practice of rounding or replacing low Scr values with an arbitrary value of 1.0 mg/dl for use in the CG equation should be avoided. Additional studies that evaluate alternative eGFR equations in the older populations that incorporate pharmacokinetic and pharmacodynamic outcomes measures are needed. PMID- 23625815 TI - Bright far-red/near-infrared conjugated polymer nanoparticles for in vivo bioimaging. AB - A highly emissive far-red/near-infrared (FR/NIR) fluorescent conjugated polymer (CP), poly[(9,9-dihexylfluorene)-co-2,1,3-benzothiadiazole-co-4,7-di(thiophen-2 yl)-2,1,3-benzothiadiazole] (PFBTDBT10) is designed and synthesized via Suzuki polymerization. Formulation of PFBTDBT10 using 1,2-distearoyl-sn-glycero-3 phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000 ) and DSPE-PEG5000-folate as the encapsulation matrix yielded CP-loaded DSPE-PEG-folic acid nanoparticles (CPDP-FA NPs) with bright FR/NIR fluorescence (27% quantum yield) and a large Stoke's shift of 233 nm in aqueous solution. CPDP-FA NPs show improved thermal/photostabilities and larger Stoke's shifts as compared to commercially available quantum dots (Qdot 655) and organic dyes such as Alexa Fluor 555 and Rhodamine 6G. In vivo studies of CPDP-FA NPs on a hepatoma H22 tumor-bearing mouse model reveal that they could serve as an efficient FR/NIR fluorescent probe for targeted in vivo fluorescence imaging and cancer detection in a high contrast and specific manner. Together with the negligible in vivo toxicity, CPDP-FA NPs are promising FR/NIR fluorescent probes for future in vivo applications. PMID- 23625816 TI - Diameter and density control of single-walled carbon nanotube forests by modulating Ostwald ripening through decoupling the catalyst formation and growth processes. AB - A continuous and wide range control of the diameter (1.9-3.2 nm) and density (0.03-0.11 g cm(-3) ) of single-walled carbon nanotube (SWNT) forests is demonstrated by decoupling the catalyst formation and SWNT growth processes. Specifically, by managing the catalyst formation temperature and H2 exposure, the redistribution of the Fe catalyst thin film into nanoparticles is controlled while a fixed growth condition preserved the growth yield. The diameter and density are inversely correlated, where low/high density forests would consist of large/small diameter SWNTs, which is proposed as a general rule for the structural control of SWNT forests. The catalyst formation process is modeled by considering the competing processes, Ostwald ripening, and subsurface diffusion, where the dominant mechanism is found to be Ostwald ripening. Specifically, H2 exposure increases catalyst surface energy and decreases diameter, while increased temperature leads to increased diffusion on the surface and an increase in diameter. PMID- 23625818 TI - An assessment of the genetic toxicology of novel boron-containing therapeutic agents. AB - Boron-containing compounds are being studied as potential therapeutic agents. As part of the safety assessment of these therapeutic agents, a battery of genetic toxicology studies was conducted. The battery included a bacterial reverse mutation (Ames) assay, an in vitro chromosome aberration assay in peripheral human lymphocytes, and an in vivo rat micronucleus study. The following compounds represent some of the boron-containing compounds that have been advanced to human clinical trials in various therapeutic areas. The borinic picolinate, AN0128, is an antibacterial compound with anti-inflammatory activity that has been studied in clinical trials for acne and the treatment of mild to moderate atopic dermatitis. AN2690 (tavaborole) is a benzoxaborole in Phase 3 clinical trials for the topical treatment of onychomycosis, a fungal infection of the toenails and fingernails. Another benzoxaborole derivative, AN2728, a phosphodiesterase-4 (PDE4) inhibitor, is in Phase 2 clinical trials for the treatment of atopic dermatitis. AN2898, also a PDE4 inhibitor, has been studied in clinical trials for atopic dermatitis and psoriasis. AN3365 is a leucyl-tRNA synthetase inhibitor that has been in clinical development for the treatment of various Gram-negative bacterial infections. These five representative compounds were negative in the three genotoxicity assays. Furthermore, AN2690 has been studied in mouse and rat 2-year bioassays and was not found to have any carcinogenic potential. These results demonstrate that it is possible to design boron-based therapeutic agents with no genetic toxicology liabilities. PMID- 23625817 TI - Multiple site-selective insertions of noncanonical amino acids into sequence repetitive polypeptides. AB - A simple and efficient method is described for the introduction of noncanonical amino acids at multiple, defined sites within recombinant polypeptide sequences. Escherichia coli MRA30, a bacterial host strain with attenuated activity of release factor 1 (RF1), was assessed for its ability to support incorporation of a diverse range of noncanonical amino acids in response to multiple encoded amber (TAG) codons within genes derived from superfolder GFP and an elastin-mimetic protein polymer. Suppression efficiency and protein yield depended on the identity of the orthogonal aminoacyl-tRNA synthetase/tRNA(CUA) pair and the noncanonical amino acid. Elastin-mimetic protein polymers were prepared in which noncanonical amino acid derivatives were incorporated at up to 22 specific sites within the polypeptide sequence with high substitution efficiency. The identities and positions of the variant residues were confirmed by mass spectrometric analysis of the full-length polypeptides and proteolytic cleavage fragments from thermolysin digestion. The data suggest that this multisite suppression approach permits the preparation of protein-based materials in which novel chemical functionalities can be introduced at precisely defined positions within the polypeptide sequence. PMID- 23625819 TI - Botulinum toxin modulates cortical maladaptation in post-stroke spasticity. AB - INTRODUCTION: Maladaptive plasticity involving the unaffected hemisphere (UH) in stroke patients may contribute to post-stroke deficits, including spasticity. We investigated the central and peripheral effects of botulinum toxin in post-stroke spasticity to determine whether there is modulation of cortical processes in the UH. METHODS: Transcranial magnetic stimulation and peripheral nerve excitability studies were undertaken in 5 stroke patients with upper limb spasticity before (T1) and 6 weeks after (T2) botulinum injection. RESULTS: Transcranial magnetic stimulation demonstrated inexcitable motor cortices of the affected hemisphere at T1 and T2, and short-interval intracortical inhibition (SICI) in the UH was significantly reduced at T1. At T2, SICI in the UH increased significantly compared with T1, normalizing to controls, and was found to be associated with clinical improvements in spasticity. Peripheral excitability parameters were unchanged after injection. CONCLUSION: Cortical excitability changes were demonstrated in UH, suggesting that the clinical benefits of botulinum toxin relate to modulation of abnormal central reorganization (maladaptive plasticity) in post-stroke spasticity. PMID- 23625820 TI - Does social support really help to eat a low-fat diet? Main effects and gender differences of received social support within the Health Action Process Approach. AB - BACKGROUND: Most theories of health-behavior change focus exclusively on individual self-regulation without taking social factors, such as social support, into account. This study's first aim was to systematically test the added value of received instrumental and emotional social support within the Health Action Process Approach (HAPA) in the context of dietary change. In the social support literature, gender effects emerge with regard to the effectiveness of social support. Thus, a second aim was the examination of gender differences in the association of social support with dietary behavior. METHODS: Participants were 252 overweight and obese individuals. At baseline and 12 months later, participants completed questionnaires on HAPA variables; diet-specific received social support and low-fat diet. RESULTS: For the prediction of intentions 12 months later, instrumental support was more beneficial for men than for women over and above individual self-regulation. In terms of dietary behavior at T2, a moderate main effect of instrumental support emerged. Moreover, received emotional social support was beneficial for men, but not for women in terms of a low-fat diet 12 months later. CONCLUSIONS: Effects of received instrumental social support found in this study provide new evidence for the added value of integrating social support into the HAPA. PMID- 23625821 TI - The benefits of photodynamic therapy on vertebral bone are maintained and enhanced by combination treatment with bisphosphonates and radiation therapy. AB - Photodynamic therapy (PDT) has been shown to ablate tumors within vertebral bone and yield short-term improvements in vertebral architecture and biomechanical strength, in particular when combined with bisphosphonate (BP) treatment. Longer term outcomes of PDT combined with current treatments for skeletal metastases are essential to understand its therapeutic potential. The objective of this study is to evaluate the response of vertebrae to PDT after a longer (6-week) time period, alone and combined with previous BP or radiation treatment (RT). Sixty-three female rnu/rnu rats were randomized to six treatment groups: untreated control, BP-only, RT-only, PDT-only, combined BP + PDT and combined RT + PDT. L2 vertebrae were structurally analyzed through uCT-based analysis, axial compressive load-to failure testing and histological analysis of morphology, osteoid formation and osteoclast activity. Combined BP + PDT treatment yielded the largest improvements in bone architecture with combined RT + PDT treatment yielding similar findings, but of a lesser magnitude. Mechanically, ultimate force and stress were correlated to stereological parameters that demonstrated a positive structural effect from combinatory treatment. Increased osteoid formation was observed in both combination therapies without any significant differences in osteoclast activity. Overall, multimodality treatment demonstrated a sustained positive effect on vertebral structural integrity, motivating PDT as a minimally-invasive adjuvant treatment for spinal metastases. PMID- 23625822 TI - X-chromosome-encoded microRNA-19 and -18 are possible modulators of female immunity. PMID- 23625823 TI - Board of Regents commentary. Qualifications of pharmacists who provide direct patient care: perspectives on the need for residency training and board certification. AB - In 2006, the American College of Clinical Pharmacy (ACCP) released a position statement and a white paper to provide the College's viewpoints on the importance of postgraduate pharmacy residency training as a prerequisite for direct patient care practice and the vision that future clinical pharmacists engaged in direct patient care would be certified by the Board of Pharmacy Specialties (BPS). Since the release of these papers, some members of the pharmacy profession have interpreted ACCP's position as maintaining that all pharmacists-regardless of the focus of their professional practice activities-should complete formal postgraduate residency training and be board-certified specialists. That interpretation is not accurate. In this commentary, ACCP further defines "direct patient care" and states that it believes that clinical pharmacists engaged in direct patient care should be board certified (i.e., and residency-trained or otherwise board eligible) and have established a valid collaborative drug therapy management (CDTM) agreement or have been formally granted clinical privileges. The rationale for this viewpoint is presented in detail. The pharmacy profession has appropriately invested substantial resources to ensure the quality of its accredited residency training programs and board certification processes. ACCP believes that these training and certification programs are essential steps in preparing clinical pharmacists to provide direct patient care. PMID- 23625824 TI - An all-optical, non-volatile, bidirectional, phase-change meta-switch. AB - Non-volatile, bidirectional, all-optical switching in a phase-change metamaterial delivers high-contrast transmission and reflection modulation at near- to mid infrared wavelengths in device structures down to ~1/27 of a wavelength thick. PMID- 23625825 TI - pH-dependent anticancer drug release from silk nanoparticles. AB - Silk has traditionally been used as a suture material because of its excellent mechanical properties and biocompatibility. These properties have led to the development of different silk-based material formats for tissue engineering and regenerative medicine. Although there have been a small number of studies about the use of silk particles for drug delivery, none of these studies have assessed the potential of silk to act as a stimulus-responsive anticancer nanomedicine. This report demonstrates that an acetone precipitation of silk allows the formation of uniform silk nanoparticles (98 nm diameter, polydispersity index 0.109), with an overall negative surface charge (-33.6 +/- 5.8 mV), in a single step. Silk nanoparticles are readily loaded with doxorubicin (40 ng doxorubicin/MUg silk) and show pH-dependent release (pH 4.5? 6.0 > 7.4). In vitro studies with human breast cancer cell lines demonstrates that the silk nanoparticles are not cytotoxic (IC50 > 120 MUg mL(-1) ) and that doxorubicin loaded silk nanoparticles are able to overcome drug resistance mechanisms. Live cell fluorescence microscopy studies show endocytic uptake and lysosomal accumulation of silk nanoparticles. In summary, the pH-dependent drug release and lysosomal accumulation of silk nanoparticles demonstrate the ability of drug loaded silk nanoparticles to serve as a lysosomotropic anticancer nanomedicine. PMID- 23625826 TI - Inhibitory role of Smad7 in hepatocarcinogenesis in mice and in vitro. AB - Smad7 is a principal inhibitor of the TGFbeta-Smad signalling pathway. We have investigated the functional significance of Smad7 in hepatocellular carcinoma (HCC). Smad7 knockout (KO) and wild-type (WT) mice were injected with diethylnitrosamine (DEN) to induce HCC. The effects of Smad7 on cellular features were examined in HCC cells, using a Smad7 over-expression or deletion approach. Signalling pathway components modulated by Smad7 in HCC were evaluated using luciferase reporter assay and co-immunoprecipitation. Smad7 was down-regulated in human HCCs compared with the adjacent normal tissues (p < 0.001). Smad7 KO mice were more susceptible to DEN-induced HCC than WT mice (78% versus 22%, p < 0.05). HCCs from KO mice displayed a greater proliferation activity (p < 0.05) and a reduced apoptotic index compared with WT littermates (p < 0.05). Deletion of Smad7 promoted cell proliferation in primary cultured HCC cells. In addition, over-expression of Smad7 in HCC cell lines markedly suppressed cell growth (p < 0.0001) and colony formation (p < 0.01). Cell cycle analysis revealed an increase in the G1 phase and a reduction in the S-phase populations, accompanied by up regulation of p27(Kip1) and down-regulation of cyclin D1. Smad7 increased cell apoptosis (p < 0.01) by mediating an intrinsic [caspase-9, caspase-3 and poly(ADP ribose) polymerase] apoptotic pathway. Moreover, Smad7 inhibited NF-kappaB signalling by interacting with TAB2, an upstream activator of NF-kappaB, and inhibited TGFbeta signalling by suppressing phosphorylation of Smad3. In conclusion, loss of Smad7 enhances susceptibility to HCC. Smad7 suppresses HCC cell growth by inhibiting proliferation and G1 -S phase transition and inducing apoptosis through attenuation of NF-kappaB and TGFbeta signalling. Smad7 acts as a potential tumour suppressor in liver. PMID- 23625827 TI - A comparative study of the influence of three pure titanium plates with different micro- and nanotopographic surfaces on preosteoblast behaviors. AB - There is a great demand for dental implants with the ability to accelerate periimplant bone regeneration. Modification of surface micro- and nanotopographies has been revealed to affect bone cell metabolism. In this study, we utilized dielectric barrier discharge (DBD) technology to modify commercially pure titanium (Ti-tr) surfaces and then investigated the cytocompability of DBD modified Ti surface when compared with machined (Ti-m) and polished (Ti-p) Ti surfaces. These three kinds of Ti plates exhibited different surface energies and topographies at the micro- and nanoscale levels. The DBD-treated pure Ti surface significantly enhances cell adhesion, spread, and proliferation of MC3T3-E1 preosteoblast cells compared with the Ti-p and Ti-m surfaces, suggesting that Ti tr has better cytocompatibility compared with the other two surfaces. Preosteoblast cells on Ti-m surface exhibited higher alkaline phosphatase activity than cells on Ti-tr and Ti-p surfaces 14 days after seeding. No significant difference in alkaline phosphatase activity was observed between cells grown on Ti-tr and Ti-p surfaces. Our study demonstrated that DBD modification significantly enhanced cell adhesion, spread, and proliferation of preosteoblasts with no negative effects on cell differentiation. Microtopography and nanotopography of the surfaces of different materials and chemical/energetic properties have a synergistic effect on cell attachment, proliferation, and differentiation. PMID- 23625828 TI - Induced adaptation of Bacillus sp. to antimicrobial nanosilver. AB - The natural ability of Bacillus sp. to adapt to nanosilver cytotoxicity upon prolonged exposure is reported for the first time. The combined adaptive effects of nanosilver resistance and enhanced growth are induced under various intensities of nanosilver-stimulated cellular oxidative stress, ranging from only minimal cellular redox imbalance to the lethal levels of cellular ROS stimulation. An important implication of the present work is that such adaptive effects lead to the ultimate domination of nanosilver-resistant Bacillus sp. in the microbiota, to which nanosilver cytotoxicity is continuously applied. PMID- 23625831 TI - Trajectory-based nonadiabatic dynamics with time-dependent density functional theory. AB - Understanding the fate of an electronically excited molecule constitutes an important task for theoretical chemistry, and practical implications range from the interpretation of atto- and femtosecond spectroscopy to the development of light-driven molecular machines, the control of photochemical reactions, and the possibility of capturing sunlight energy. However, many challenging conceptual and technical problems are involved in the description of these phenomena such as 1) the failure of the well-known Born-Oppenheimer approximation; 2) the need for accurate electronic properties such as potential energy surfaces, excited nuclear forces, or nonadiabatic coupling terms; and 3) the necessity of describing the dynamics of the photoexcited nuclear wavepacket. This review provides an overview of the current methods to address points 1) and 3) and shows how time-dependent density functional theory (TDDFT) and its linear-response extension can be used for point 2). First, the derivation of Ehrenfest dynamics and nonadiabatic Bohmian dynamics is discussed and linked to Tully's trajectory surface hopping. Second, the coupling of these trajectory-based nonadiabatic schemes with TDDFT is described in detail with special emphasis on the derivation of the required electronic structure properties. PMID- 23625832 TI - Pulse-train photoelectron spectroscopy of electronic and nuclear dynamics in molecules. AB - We theoretically study the application of a femtosecond pulse train to simultaneously probe the electronic excitation dynamics and nuclear vibrational motion in the excited-state LiH molecule by means of time-resolved photoelectron spectroscopy. The step-like population transfers caused by continual interaction with a sequence of pulses and refractory periods are shown to give rise to time evolution of the photoelectron kinetic energy distribution as the history of molecular electronic and vibrational states. Such a signal should lead to a novel and direct way to investigate electronic and nuclear simultaneous dynamics involving multiple excited states. PMID- 23625833 TI - NFATc3 promotes Ca(2+) -dependent MMP3 expression in astroglial cells. AB - Increase in intracellular calcium ([Ca(2+) ]i ) is a key mediator of astrocyte signaling, important for activation of the calcineurin (CN)/nuclear factor of activated T cells (NFAT) pathway, a central mediator of inflammatory events. We analyzed the expression of matrix metalloproteinase 3 (Mmp3) in response to increases in [Ca(2+) ]i and the role of the CN/NFAT pathway in this regulation. Astrocyte Mmp3 expression was induced by overexpression of a constitutively active form of NFATc3, whereas other MMPs and tissue inhibitor of metalloproteinases (TIMP) were unaffected. Mmp3 mRNA and protein expression was also induced by calcium ionophore (Io) and 2'(3')-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate (Bz-ATP) and Mmp3 upregulation was prevented by the CN inhibitor cyclosporin A (CsA). Ca(2+) -dependent astrocyte Mmp3 expression was also inhibited by actinomycin D, and a Mmp3 promoter luciferase reporter was efficiently activated by increased [Ca(2+) ]i , indicating regulation at the transcriptional level. Furthermore, Ca(2+) /CN/NFAT dependent Mmp3 expression was confirmed in pure astrocyte cultures derived from neural stem cells (Ast-NSC), demonstrating that the induced Mmp3 expression occurs in astrocytes, and not microglial cells. In an in vivo stab-wound model of brain injury, MMP3 expression was detected in NFATc3-positive scar-forming astrocytes. Because [Ca(2+) ]i increase is an early event in most brain injuries, these data support an important role for Ca(2+) /CN/NFAT-induced astrocyte MMP3 expression in the early neuroinflammatory response. Understanding the molecular pathways involved in this regulation could provide novel therapeutic targets and approaches to promoting recovery of the injured brain. PMID- 23625834 TI - Bioreactor design for clinical-grade expansion of stem cells. AB - The many clinical trials currently in progress will likely lead to the widespread use of stem cell-based therapies for an extensive variety of diseases, either in autologous or allogeneic settings. With the current pace of progress, in a few years' time, the field of stem cell-based therapy should be able to respond to the market demand for safe, robust and clinically efficient stem cell-based therapeutics. Due to the limited number of stem cells that can be obtained from a single donor, one of the major challenges on the roadmap for regulatory approval of such medicinal products is the expansion of stem cells using Good Manufacturing Practices (GMP)-compliant culture systems. In fact, manufacturing costs, which include production and quality control procedures, may be the main hurdle for developing cost-effective stem cell therapies. Bioreactors provide a viable alternative to the traditional static culture systems in that bioreactors provide the required scalability, incorporate monitoring and control tools, and possess the operational flexibility to be adapted to the differing requirements imposed by various clinical applications. Bioreactor systems face a number of issues when incorporated into stem cell expansion protocols, both during development at the research level and when bioreactors are used in on-going clinical trials. This review provides an overview of the issues that must be confronted during the development of GMP-compliant bioreactors systems used to support the various clinical applications employing stem cells. PMID- 23625835 TI - Asymptomatic/pauci-symptomatic creatine kinase elevations (hyperckemia). AB - Neuromuscular clinicians are frequently asked to evaluate patients referred for asymptomatic elevations in creatine kinase (CK), a catalytic enzyme that combines creatine and ATP to form phosphocreatine and ADP. This reaction is crucial for cellular energy generation and metabolism. This laboratory finding, often referred to in simplified lexicon as asymptomatic hyperCKemia, continues to generate controversy at several levels, including definition, the extent of evaluation, and the yield of diagnostic testing. In this review, we summarize the literature based on series of patients with asymptomatic hyperCKemia and provide a rational clinical approach to reveal identifiable underlying causes. PMID- 23625836 TI - Turning performance in persons with a dysvascular transtibial amputation. AB - BACKGROUND AND AIM: Turning is an inherent problem in all lower limb amputees and more so in older dysvascular amputees. This study aimed to compare the turning performance of dysvascular amputees with that of the traumatic amputees. TECHNIQUE: Six dysvascular transtibial amputees (69.83 +/- 6.3 years) and six traumatic transtibial amputees (68.3 +/- 6.6 years) completed the Step Quick Turn test of the NeuroCom((r)) Balance Master and the Timed Up and Go Test. The measures used for comparison were as follows: turn time and turn sway of Step Quick Turn test, turning 180 degrees to both the prosthetic and sound side and time taken to complete the Timed Up and Go Test. DISCUSSION: The Mann-Whitney U test demonstrated a significant difference (p < 0.05) between the dysvascular and traumatic groups in turn sway to the prosthetic (70.7 +/- 14.2 and 43.3 +/- 9.7) and sound sides (72.5 +/- 16.1 and 43.5 +/- 8.2). Similar results were observed in turn time to the prosthetic (4.1 +/- 1.4 and 1.7 +/- 0.46) and sound sides (4.0 +/- 1.3 and 2.1 +/- 0.5). No significant difference was observed for the Timed Up and Go Test. CLINICAL RELEVANCE: The observed differences suggest that dysvascular amputees are less able to adapt to the challenges associated with turning. More attention is required in the rehabilitation of dysvascular amputees in turning tasks particularly towards the prosthetic side. PMID- 23625837 TI - Keep moving forward: a new energy returning prosthetic device with low installation height after Syme or Pirogoff amputation. AB - BACKGROUND: The incidence of foot amputations increased in the Netherlands to 3.3/100,000 people up to 1994. Despite these numbers, only a few basic prosthetic and orthotic devices are available, and all lack functionality to restore ankle and foot mobility. OBJECTIVES: The aim of this explorative study was to design and test a unique prosthesis for Syme or Pirogoff amputees with the necessary low installation height but restoring ankle and foot mobility. STUDY DESIGN: A case study was performed. METHODS: The new prosthesis was designed and numerically analyzed on aspects concerning strength and deformation. A prototype was tested in a case study to assess the biomechanical behavior of the new foot. As a reference, six Syme/Pirogoff amputees were measured. Additionally, all volunteers filled out a questionnaire to evaluate their prosthetic feet. RESULTS: The self selected and maximum walking speed of the case subject at 0 degrees and 5 degrees slopes was higher using the new foot (0.36 m/s and 0.53 m/s, respectively) comparing to the Low Rider (Otto Bock HealthCare) (0.31 m/s and 0.31 m/s, respectively). Using the new foot, a more symmetrical walking pattern was achieved. CONCLUSION: The case study shows that this new prosthetic foot could be an improvement compared to existing prosthetic feet. CLINICAL RELEVANCE: Foot amputees with low available installation height still experience daily the inconvenience of missing ankle and foot mobility. Their low velocity and cosmetically poor walking pattern influence on their sound leg and overall walking functionality. A more functional prosthesis would have a great impact on their daily activities. PMID- 23625838 TI - Prosthetic management of mid-facial defect with magnet-retained silicone prosthesis. AB - BACKGROUND AND AIM: Mid-facial defect is one of the most disfiguring and impairing defects. A design of prosthesis that is aesthetic and stable can be precious to a patient who has lost part of his face due to surgical excision. Prosthesis can restore the patients' self-esteem and confidence, which affects the patients and their life style. The aim of this case report is to describe a technique of mid-facial silicone prosthesis fabrication. TECHNIQUE: To provide an aesthetic and stable facial prosthesis, the extra-oral prosthesis was fabricated using silicone material, while the intra-oral defect was restored with obturator prosthesis, and then both prostheses were connected and attached to each other using magnets. DISCUSSION: This clinical report describes the rehabilitation of a large mid-facial defect with a two-piece prosthesis. The silicone facial prosthesis was made hollow and lighter by using an acrylic framework. Two acrylic channels were included within the facial prosthesis to provide the patient with clean and patent airways. CLINICAL RELEVANCE: A sectional mid-facial prosthesis was made and retained in place by using magnets, which resulted in a significant improvement in the aesthetical and functional outcome without the need for plastic surgery. Silicone prostheses are reliable alternatives to surgery and should be considered in selected cases. PMID- 23625839 TI - Functional testing provides unique insights into the pathomechanics of femoroacetabular impingement and an objective basis for evaluating treatment outcome. AB - Femoroacetabular impingement (FAI) has been recognized as a significant clinical problem. While hip reshaping surgery for treating FAI has had positive clinical outcomes, there remains a need for objective functional outcomes of FAI treatment. We tested the hypothesis that during walking and stair climbing significant changes in hip kinematics would occur following hip reshaping surgery that indicate restoration of normal function post-operatively. Hip and pelvic kinematics were collected for 17 FAI patients pre- and 1 year post-operatively and compared to 17 healthy matched controls. Prior to surgery, FAI patients had significantly reduced hip internal rotation and hip sagittal plane range of motion during walking (p = 0.01, p < 0.001, respectively) and stair climbing (p = 0.01, p < 0.001, respectively) as compared with controls. Post-operatively, these motions were restored to normal during walking (p = 0.70, p = 0.46, respectively), but remained significantly reduced in the FAI patients during stair climbing (p = 0.03, p < 0.001, respectively). These results have important implications for understanding the functional pathomechanics of FAI and providing an objective basis for evaluating treatment outcome. The stair climbing results indicate that problems still exist in the hip joint for activities requiring higher ranges of hip motion and suggest a basis for exploring future improvements for the treatment of FAI. PMID- 23625840 TI - Goodness-of-fit test for proportional subdistribution hazards model. AB - This paper concerns using modified weighted Schoenfeld residuals to test the proportionality of subdistribution hazards for the Fine-Gray model, similar to the tests proposed by Grambsch and Therneau for independently censored data. We develop a score test for the time-varying coefficients based on the modified Schoenfeld residuals derived assuming a certain form of non-proportionality. The methods perform well in simulations and a real data analysis of breast cancer data, where the treatment effect exhibits non-proportional hazards. PMID- 23625841 TI - Stress-induced outer membrane vesicle production by Pseudomonas aeruginosa. AB - As an opportunistic Gram-negative pathogen, Pseudomonas aeruginosa must be able to adapt and survive changes and stressors in its environment during the course of infection. To aid survival in the hostile host environment, P. aeruginosa has evolved defense mechanisms, including the production of an exopolysaccharide capsule and the secretion of a myriad of degradative proteases and lipases. The production of outer membrane-derived vesicles (OMVs) serves as a secretion mechanism for virulence factors as well as a general bacterial response to envelope-acting stressors. This study investigated the effect of sublethal physiological stressors on OMV production by P. aeruginosa and whether the Pseudomonas quinolone signal (PQS) and the MucD periplasmic protease are critical mechanistic factors in this response. Exposure to some environmental stressors was determined to increase the level of OMV production as well as the activity of AlgU, the sigma factor that controls MucD expression. Overexpression of AlgU was shown to be sufficient to induce OMV production; however, stress-induced OMV production was not dependent on activation of AlgU, since stress caused increased vesiculation in strains lacking algU. We further determined that MucD levels were not an indicator of OMV production under acute stress, and PQS was not required for OMV production under stress or unstressed conditions. Finally, an investigation of the response of P. aeruginosa to oxidative stress revealed that peroxide-induced OMV production requires the presence of B-band but not A-band lipopolysaccharide. Together, these results demonstrate that distinct mechanisms exist for stress-induced OMV production in P. aeruginosa. PMID- 23625842 TI - Constitutively Opa-expressing and Opa-deficient neisseria gonorrhoeae strains differentially stimulate and survive exposure to human neutrophils. AB - The Neisseria gonorrhoeae (the gonococcus [Gc]) opacity-associated (Opa) proteins mediate bacterial binding and internalization by human epithelial cells and neutrophils (polymorphonuclear leukocytes [PMNs]). Investigating the contribution of Opa proteins to gonococcal pathogenesis is complicated by high-frequency phase variation of the opa genes. We therefore engineered a derivative of Gc strain FA1090 in which all opa genes were deleted in frame, termed Opaless. Opaless Gc remained uniformly Opa negative (Opa(-)), whereas cultures of predominantly Opa( ) parental Gc and an intermediate lacking the "translucent" subset of opa genes (DeltaopaBEGK) stochastically gave rise to Opa-positive (Opa(+)) bacterial colonies. Loss of Opa expression did not affect Gc growth. Opaless Gc survived exposure to primary human PMNs and suppressed the PMN oxidative burst akin to parental, Opa(-) bacteria. Notably, unopsonized Opaless Gc was internalized by adherent, chemokine-primed, primary human PMNs, by an actin-dependent process. When a non-phase-variable, in-frame allele of FA1090 opaD was reintroduced into Opaless Gc, the bacteria induced the PMN oxidative burst, and OpaD(+) Gc survived less well after exposure to PMNs compared to Opa(-) bacteria. These derivatives provide a robust system for assessing the role of Opa proteins in Gc biology. PMID- 23625843 TI - Mutations in the Escherichia coli ribosomal protein L22 selectively suppress the expression of a secreted bacterial virulence factor. AB - Mutations in the ribosomal protein L22 that impair peptide-mediated translation arrest in Escherichia coli have been shown to reduce the expression of several genes, including secA, which encodes an ATPase that drives protein export via the Sec pathway. Here, we used a comparative proteomic approach to obtain insight into the global effects of the L22(Delta82-84) mutation on gene expression and protein synthesis. While the mutation did not affect or modestly affected the level of most soluble proteins, it dramatically reduced the level of antigen 43 (Ag43), a secreted virulence factor that promotes autoaggregation. The reduced protein concentration correlated with a sharp decrease in the abundance and stability of Ag43 mRNA. We found that the overexpression of secA or the inactivation of genes that encode presecretory and membrane proteins restored Ag43 production in the L22 mutant strain. Furthermore, impairment of the Sec pathway in a wild-type strain reduced Ag43 production but did not significantly affect the synthesis of other presecretory proteins. Taken together, these results indicate that Ag43 gene expression is exquisitely sensitive to the status of the Sec machinery and strongly suggest that the L22 mutation decreases the Ag43 concentration indirectly by reducing secA expression. Our results imply the existence of a novel regulatory mechanism in which the efficiency of protein export is coupled to gene expression and help to explain the modulation of SecA synthesis that has been observed in response to secretion stress. PMID- 23625844 TI - Functional properties and structural requirements of the plasmid pMV158-encoded MobM relaxase domain. AB - A crucial element in the horizontal transfer of mobilizable and conjugative plasmids is the relaxase, a single-stranded endonuclease that nicks the origin of transfer (oriT) of the plasmid DNA. The relaxase of the pMV158 mobilizable plasmid is MobM (494 residues). In solution, MobM forms a dimer through its C terminal domain, which is proposed to anchor the protein to the cell membrane and to participate in type 4 secretion system (T4SS) protein-protein interactions. In order to gain a deeper insight into the structural MobM requirements for efficient DNA catalysis, we studied two endonuclease domain variants that include the first 199 or 243 amino acid residues (MobMN199 and MobMN243, respectively). Our results confirmed that the two proteins behaved as monomers in solution. Interestingly, MobMN243 relaxed supercoiled DNA and cleaved single-stranded oligonucleotides harboring oriTpMV158, whereas MobMN199 was active only on supercoiled DNA. Protein stability studies using gel electrophoresis and mass spectrometry showed increased susceptibility to degradation at the domain boundary between the N- and C-terminal domains, suggesting that the domains change their relative orientation upon DNA binding. Overall, these results demonstrate that MobMN243 is capable of nicking the DNA substrate independently of its topology and that the amino acids 200 to 243 modulate substrate specificity but not the nicking activity per se. These findings suggest that these amino acids are involved in positioning the DNA for the nuclease reaction rather than in the nicking mechanism itself. PMID- 23625845 TI - A putative transmembrane leucine zipper of agrobacterium VirB10 is essential for t-pilus biogenesis but not type IV secretion. AB - The Agrobacterium tumefaciens VirB/VirD4 type IV secretion system is composed of a translocation channel and an extracellular T pilus. Bitopic VirB10, the VirB7 lipoprotein, and VirB9 interact to form a cell envelope-spanning structural scaffold termed the "core complex" that is required for the assembly of both structures. The related pKM101-encoded core complex is composed of 14 copies each of these VirB homologs, and the transmembrane (TM) alpha helices of VirB10-like TraF form a 55-A-diameter ring at the inner membrane. Here, we report that the VirB10 TM helix possesses two types of putative dimerization motifs, a GxxxA (GA4) motif and two leucine (Leu1, Leu2) zippers. Mutations in the Leu1 motif disrupted T-pilus biogenesis, but these or other mutations in the GA4 or Leu2 motif did not abolish substrate transfer. Replacement of the VirB10 TM domain with a nondimerizing poly-Leu/Ala TM domain sequence also blocked pilus production but not substrate transfer or formation of immunoprecipitable complexes with the core subunits VirB7 and VirB9 and the substrate receptor VirD4. The VirB10 TM helix formed weak homodimers in Escherichia coli, as determined with the TOXCAT assay, whereas replacement of the VirB10 TM helix with the strongly dimerizing TM helix from glycophorin A blocked T-pilus biogenesis in A. tumefaciens. Our findings support a model in which VirB10's TM helix contributes to the assembly or activity of the translocation channel as a weakly self-interacting membrane anchor but establishes a heteromeric TM-TM helix interaction via its Leu1 motif that is critical for T-pilus biogenesis. PMID- 23625847 TI - Biofilms 2012: new discoveries and significant wrinkles in a dynamic field. AB - The ASM 6th Conference on Biofilms was held in Miami, Florida, 29 September to 4 October, 2012. The conference provided an opportunity for the exchange of new findings and ideas with regard to biofilm research. A wide range of findings, spanning applied biology, evolution, ecology, physiology, and molecular biology, were presented at the conference. This review summarizes the presentations with regard to emerging biofilm-related themes. PMID- 23625846 TI - Identification of new proteins that modulate the germination of spores of bacillus species. AB - A number of operons encoding the nutrient germinant receptors (GRs) in dormant spores of Bacillus megaterium and Bacillus subtilis species have small open reading frames (ORFs) of unknown function within or immediately adjacent to the operons. Inactivation of the genes in these ORFs, encoding proteins now termed D proteins, either significantly increased or decreased spore germination via the associated GR but had no effects on germination via non-GR-dependent germinants. These effects on GR-dependent germination were complemented by ectopic expression of the appropriate D gene (gene encoding D protein). However, substitution of noncognate D genes in two GR operons resulted in inhibition of germination via the GR manipulated, although ectopic overexpression of a D gene had no effect on overall GR-dependent germination. The various D genes studied were expressed in the forespore during sporulation in parallel with the associated GR operon, and transcription of a B. subtilis D gene was controlled by RNA polymerase sigma factor sigma(G). These results indicate that proteins encoded by small ORFs within or adjacent to operons encoding GRs play major roles in modulating GR function in spores of Bacillus species. In B. subtilis, deletion of a D gene (B. subtilis gerKD [gerKDbs]) adjacent to the gerK operon encoding the GerK GR or ectopic expression or overexpression of gerKDbs had no major effect on the levels of GR subunits or of two other germination proteins. PMID- 23625848 TI - Investigating the functional hierarchy of Bacillus megaterium PV361 spore germinant receptors. AB - Spores of Bacillus megaterium QM B1551 germinate rapidly when exposed to a number of single-trigger germinant compounds, including glucose, proline, leucine, and certain inorganic salts. However, spores of strain PV361, a plasmidless QM B1551 derivative that lacks the GerU germinant receptor (GR) responsible for mediating germination in response to single-trigger compounds, can germinate efficiently when incubated in nutritionally rich media, presumably via activation of additional germinant receptors. In this work, we have identified five chromosomally encoded GRs and attempted to characterize, by mutational analysis, germinant recognition profiles associated with the respective receptors in strain PV361. Of strains engineered with single GR insertion-deletions, only GerK-null spores displayed significant defective germination phenotypes when incubated in 5% (wt/vol) beef extract or plated on rich solid medium. Cumulative decreases in viability were observed in GerK-null spores that also lacked GerA or GerA2, indicating that these GRs, which exerted little effect on spore germination when disrupted individually, have a degree of functionality. Unexpectedly, an efficient germination response to combinations of germinants was restored in GerA(+) spores, which lack all other functional GRs, providing evidence for negative cooperativity between some GRs within the spore. Tetrazolium-based germinative assays conducted with purified spores indicated that these newly characterized B. megaterium GRs are cognate for a wide and chemically diverse range of germinant molecules, but unlike GerU, can only be induced to trigger germination when stimulated by at least two different germinants. PMID- 23625850 TI - GaP-ZnS solid solutions: Semiconductors for efficient visible light absorption and emission. AB - GaP-ZnS solid solutions and multilayered structures have a tunable direct band gap in the energy range for absorption and emission of visible light. A direct band gap of around 2.0 eV, the optimum for photocatalysis of water splitting, is readily accessible with these systems. PMID- 23625849 TI - Inactivation of the Pta-AckA pathway causes cell death in Staphylococcus aureus. AB - During growth under conditions of glucose and oxygen excess, Staphylococcus aureus predominantly accumulates acetate in the culture medium, suggesting that the phosphotransacetylase-acetate kinase (Pta-AckA) pathway plays a crucial role in bacterial fitness. Previous studies demonstrated that these conditions also induce the S. aureus CidR regulon involved in the control of cell death. Interestingly, the CidR regulon is comprised of only two operons, both encoding pyruvate catabolic enzymes, suggesting an intimate relationship between pyruvate metabolism and cell death. To examine this relationship, we introduced ackA and pta mutations in S. aureus and tested their effects on bacterial growth, carbon and energy metabolism, cid expression, and cell death. Inactivation of the Pta AckA pathway showed a drastic inhibitory effect on growth and caused accumulation of dead cells in both pta and ackA mutants. Surprisingly, inactivation of the Pta AckA pathway did not lead to a decrease in the energy status of bacteria, as the intracellular concentrations of ATP, NAD(+), and NADH were higher in the mutants. However, inactivation of this pathway increased the rate of glucose consumption, led to a metabolic block at the pyruvate node, and enhanced carbon flux through both glycolysis and the tricarboxylic acid (TCA) cycle. Intriguingly, disruption of the Pta-AckA pathway also induced the CidR regulon, suggesting that activation of alternative pyruvate catabolic pathways could be an important survival strategy for the mutants. Collectively, the results of this study demonstrate the indispensable role of the Pta-AckA pathway in S. aureus for maintaining energy and metabolic homeostasis during overflow metabolism. PMID- 23625851 TI - Micro-flow imaging and resonant mass measurement (Archimedes)--complementary methods to quantitatively differentiate protein particles and silicone oil droplets. AB - Our study aimed to comparatively evaluate Micro-Flow Imaging (MFI) and the recently introduced technique of resonant mass measurement (Archimedes, RMM) as orthogonal methods for the quantitative differentiation of silicone oil droplets and protein particles. This distinction in the submicron and micron size range is highly relevant for the development of biopharmaceuticals, in particular for products in prefilled syringes. Samples of artificially generated silicone oil droplets and protein particles were quantified individually and in defined mixtures to assess the performance of the two techniques. The built-in MFI software solution proved to be suitable to discriminate between droplets and particles for sizes above 2 MUm at moderate droplet/particle ratios (70:30 30:70). A customized filter developed specifically for this study greatly improved the results and enabled reliable discrimination also for more extreme mixing ratios (95:5-15:85). RMM showed highly accurate discrimination in the size range of about 0.5-2 MUm independent of the ratio, provided that a sufficient number of particles (>50 counted particles) were counted. We recommend applying both techniques for a comprehensive analysis of biotherapeutics potentially containing silicone oil droplets and protein particles in the submicron and micron size range. PMID- 23625853 TI - Synergistic effect between bioactive glass foam and a perfusion bioreactor on osteogenic differentiation of human adipose stem cells. AB - Tissue engineering is a multidisciplinary science that combines a structural scaffold and cells to form a construct able to promote regeneration of injured tissue. Bioactive glass foam produced by sol-gel is an osteoinductive material with a network of interconnected macropores necessary for cell colonization. The use of human adipose-derived stem cell (hASC) presents advantages as the potential for a large number of cells, rapid expansion in vitro and the capability of differentiating into osteoblasts. The use of a bioreactor in three dimensional cell culture enables greater efficiency for cell nutrition and application of mechanical forces, important modulators of bone physiology. The hASC seeded in a bioactive glass scaffold and cultured in osteogenic Leibovitz L 15 medium in a bioreactor with a flow rate of 0.1 mL min(-1) demonstrated a significant increase in cell proliferation and viability and alkaline phosphatase (ALP) activity peak after 14 days. The immunofluorescence assay revealed an expression of osteopontin, osteocalcin and type I collagen from 7 to 21 days after culture. The cells changed from a spindle shape to a cuboidal morphology characteristic of osteoblasts. The polymerase chain reaction assay confirmed that osteopontin, osteocalcin, and ALP genes were expressed. These results indicate that hASCs differentiated into an osteogenic phenotype when cultured in bioactive glass scaffold, osteogenic Leibovitz L-15 medium and a perfusion bioreactor. Therefore, these results highlight the synergism between a bioactive glass scaffold and the effect of perfusion on cells and indicate the differentiation into an osteogenic phenotype. PMID- 23625854 TI - Off-resonance insensitive complementary SPAtial Modulation of Magnetization (ORI CSPAMM) for quantification of left ventricular twist. AB - PURPOSE: To evaluate Off Resonance Insensitive Complementary SPAtial Modulation of Magnetization (ORI-CSPAMM) and Fourier Analysis of STimulated echoes (FAST) for the quantification of left ventricular (LV) systolic and diastolic function and compare it with the previously validated FAST+SPAMM technique. MATERIALS AND METHODS: LV short-axis tagged images were acquired with ORI-CSPAMM and SPAMM in healthy volunteers (n = 13). The FAST method was used to automatically estimate LV systolic and diastolic twist parameters from rotation of the stimulated echo and stimulated anti-echo about the middle of k-space subsequent to ~3 min of user interaction. RESULTS: There was no significant difference between measures obtained for FAST+ORI-CSPAMM and FAST+SPAMM for mean peak twist (12.9 +/- 3.4 degrees versus 11.9 +/- 4.0 degrees ; P = 0.4), torsion (3.3 +/- 0.9 degrees /cm versus 2.9 +/- 1.0 degrees /cm, P = 0.3), circumferential-longitudinal shear angle (9.1 +/- 3.0 degrees versus 8.2 +/- 3.4 degrees , P = 0.3), twisting rate (79.6 +/- 20.2 degrees /s versus 68.2 +/- 23.4 degrees /s, P = 0.1), untwisting rate (-117.5 +/- 31.4 degrees /s versus -106.6 +/- 32.4 degrees /s, P = 0.3), normalized untwisting rate (-9.3 +/- 2.0/s versus -9.9 +/- 4.4/s, P = 0.7), and time of peak twist (281 +/- 18 ms versus 293 +/- 25 ms, P = 0.04). FAST+ORI CSPAMM also provided measures of duration of untwisting (148 +/- 21 ms) and the ratio of rapid untwisting to peak twist (0.9 +/- 0.3). Bland-Altman analysis of FAST+ORI-CSPAMM and FAST+SPAMM twist data demonstrates excellent agreement with a bias of -0.1 degrees and 95% confidence intervals of (-1.0 degrees , 3.2 degrees ). CONCLUSION: FAST+ORI-CSPAMM is a semi-automated method that provides a quick and quantitative assessment of LV systolic and diastolic twist and torsion. ORI CSPAMM corrects off-resonance accrued during tagging preparation and readout and visibly removes chemical shift from the tagging pattern, which confers greater robustness to the derived quantitative measures. PMID- 23625855 TI - Meeting report: 8(th) HIC/RPC Bioseparation Conference. AB - The 8(th) HIC/RPC Bioseparation Conference was held from March 3-7, 2013 at the Westin Savannah Harbor Resort in Savannah, Georgia, USA. Read this meeting report to find out more on the latest developments in chromatography for bioprocess applications. PMID- 23625856 TI - Do you teach the way you learn? PMID- 23625857 TI - Classical and unconventional pathways of vesicular release in microglia. AB - Emerging evidence indicates that activation of microglia, the immune cells of the brain, is strictly associated to both secretion of soluble molecules and release of extracellular membrane vesicles (EMVs) into the pericellular space. Through these processes, microglia heavily influence brain cell functions, either propagating inflammation and causing damage to neurons or playing a supportive, neuroprotective role. In this review, we highlight the emerging concepts related to vesicular mechanisms of secretion operating in microglial cells, with the aim of dissecting how microglia communicate with other cell types within the brain microenvironment in health and disease. PMID- 23625858 TI - Fabrication of layer-by-layer assembled biomimetic nanochannels for highly sensitive acetylcholine sensing. AB - Channel tunneling: We have prepared functional biomimetic nanochannels in polyethylene terephthalate (PET) polymer films (see illustration). We used p sulfonatocalix[4]arene to modify the channel surface by flexible layer-by-layer electrostatic assembly. Using this method we were able to detect acetylcholine with high sensitivity. PMID- 23625859 TI - Biodegradable weft-knitted intestinal stents: fabrication and physical changes investigation in vitro degradation. AB - Biodegradable stents can alleviate intestinal obstruction and stenosis in patients. The objective of this study was to develop a biodegradable polydioxanone (PDO) stent using weft-knitting technology and then investigate its biodegradation behaviors in vitro. PDO monofilament with linear density of 100 +/ 10 tex was knitted into a tubular stent using a tubular weft-knitting machine. The physical and mechanical properties were evaluated according to the British standard BS EN 13895:2003 and ISO 7198:1998. The biodegradation behaviors of PDO weft-knitted stent in a phosphate buffer solution (pH = 6.8 +/- 0.2, 37 +/- 0.5 degrees C) were then investigated. The results showed that the stent maintained more than 60% of its original radial force above 12 weeks. During the 16 weeks of degradation, weight, crystallization, and pH change indicated the degradation medium was diffused into the chain segments of low molecular weight due to the rupture of ester bonds in the monofilament. Fourier transform infrared spectroscopy results demonstrated that the chemical structure of PDO polymer is stable during the in vitro degradation. In conclusion, this biodegradable stent can find valuable applications in treatment of intestinal obstruction and stenosis clinically. PMID- 23625861 TI - Improving the physical stability of freeze-dried amorphous sugar matrices by compression at several hundreds MPa. AB - Amorphous matrices, composed of sugars, are markedly plasticized by moisture uptake, which results in physical instability. Our previous studies, in the compression pressure range <=443 MPa, indicated that when a matrix is compressed, the amount of sorbed water at given relative humidities (RHs) decreases, whereas the glass transition temperature (T(g)) remains constant. Herein, the effect of higher compression pressures than those used previously was explored to investigate the feasibility of using compression to improve the physical stability of amorphous sugar matrix against water uptake and subsequent collapse. Amorphous sugar samples were prepared by freeze-drying and then compressed at 0 665 MPa, followed by rehumidification at given RHs. The physical stability of the amorphous sugar sample was evaluated by measuring T(g) and crystallization temperature (T(cry)). The amounts of sorbed water, different in the interaction state, were determined using an FTIR technique. It was found that the compression at pressures of >=443 MPa decreased the amount of sorbed water, which is a major factor in plasticization and crystallization, and thus markedly increased the T(g) and T(cry) relative to that for the uncompressed sample. Hence, the compression at several hundreds MPa appears to be feasible for improving the physical stability of amorphous sugar matrix. PMID- 23625862 TI - Large-scale parametric survival analysis. AB - Survival analysis has been a topic of active statistical research in the past few decades with applications spread across several areas. Traditional applications usually consider data with only a small numbers of predictors with a few hundreds or thousands of observations. Recent advances in data acquisition techniques and computation power have led to considerable interest in analyzing very-high dimensional data where the number of predictor variables and the number of observations range between 10(4) and 10(6). In this paper, we present a tool for performing large-scale regularized parametric survival analysis using a variant of the cyclic coordinate descent method. Through our experiments on two real data sets, we show that application of regularized models to high-dimensional data avoids overfitting and can provide improved predictive performance and calibration over corresponding low-dimensional models. PMID- 23625863 TI - Biosynthesis of gamma-linolenic acid and beta-carotene by Zygomycetes fungi. AB - Due to increasing demand for natural sources of both polyunsaturated fatty acids (PUFAs) and beta-carotene, 28 Zygomycetes fungal soil isolates were screened for their potential to synthesize these biologically active compounds. Although all fungi produced C18 PUFAs, only nine strains also formed beta-carotene. Although Actinomucor elegans CCF 3218 was the best producer of gamma-linolenic acid (GLA) (251 mg/L), Umbelopsis isabellina CCF 2412 was found to be the most valuable fungus because of the dual production of GLA (217 mg/L) and beta-carotene (40.7 mg/L). The calculated ratio of formed PUFAs provided new insight into activities of individual fatty acid desaturases involved in biosynthetic pathways for various types of PUFAs. The maximal activity of delta-9 desaturase was accompanied by high accumulation of storage lipids in fungal cells. On the other hand, maximal activity of delta-15 desaturase was found in strains synthesizing low amounts of oleic acid due to diminished delta-9 desaturase. Activities of delta-6 desaturase showed competition for fatty acids engaged in n3, n6, and n9 biosynthetic pathways. Such knowledge about fatty acid desaturase activities provides new challenges for the regulation of biotechnological production of PUFAs by Zygomycetes fungi. PMID- 23625864 TI - Brand name or generic? What are the health professionals prescribed for treating diabetes? A longitudinal analysis of the National Health Insurance reimbursement database. AB - OBJECTIVE: This study aimed to explore whether physicians prescribe more brand name oral hypoglycemic agents (OHA) for diabetic patients with medical training background (MP) than for general patients (GP). RESEARCH DESIGN AND METHODS: A longitudinal analysis of 1,000,000 National Health Insurance cohorts of 1998-2008 was conducted. Univariate and multivariate models were performed to assess the associations of the outcome (the ratio of brand-name/generic odds in the MP group to that in the GP group) and the covariates, including patient medical training background, characteristics of patient, prescriber, and medical settings, and market competition. A generalized estimating equation method was used to control the dependency of longitudinal data. RESULTS: A total of 46,850 diabetic patients were prescribed with 2,703,149 OHA prescriptions during the study period. Compared with GP, MP had 1.37 times greater odds of being prescribed with brand name instead of generic OHA, among whom pharmacists and physicians had the highest odds ratios of 2.78 (95%CI, 1.05-7.36) and 1.68 (95%CI, 0.99-2.85), respectively. Patients' diabetes severity, prescribers' level of experience, medical settings that were publicly owned, had a higher accreditation level, and were located in a higher urbanized area, lower market competition, and earlier dates of prescription were positively associated with brand-name prescription. Among all medical sub-specialties, cardiologists were more likely to prescribe brand-name OHA. CONCLUSIONS: This study is the first to demonstrate how a patients' medical training background, in addition to the characteristics of patients, prescribers, and medical settings, and market competition might influence physicians' prescribing choice of brand-name or generic OHA. PMID- 23625865 TI - Molecular tools for cryptic Candida species identification with applications in a clinical laboratory. AB - Candida spp. includes more than 160 species but only 20 species pose clinical problems. C. albicans and C. parapsilosis account for more than 75% of all the fungemias worldwide. In 1995 and 2005, one C. albicans and two C. parapsilosis related species were described, respectively. Using phenotypic traits, the identification of these newly described species is inconclusive or impossible. Thus, molecular-based procedures are mandatory. In the proposed educational experiment we have adapted different basic molecular biology techniques designed to identify these species including PCR, multiplex PCR, PCR-based restriction endonuclease analysis and nuclear ribosomal RNA amplification. During the classes, students acquired the ability to search and align gene sequences, design primers, and use bioinformatics software. Also, in the performed experiments, fungal molecular taxonomy concepts were introduced and the obtained results demonstrated that classic identification (phenotypic) in some cases needs to be complemented with molecular-based techniques. As a conclusion we can state that we present an inexpensive and well accepted group of classes involving important concepts that can be recreated in any laboratory. PMID- 23625866 TI - The long pentraxin PTX3: a candidate anti-inflammatory mediator in cardiac surgery. AB - Coronary artery bypass grafting (CABG) is performed with the use of cardiopulmonary bypass (CPB) and cardioplegic arrest (CA) of the heart. The advantage of this technique, alternatively referred to as "on-pump" surgery, resides, for the surgeon, in relatively easy access to and manipulation with the non-beating, bloodless heart. However, the advantage that is, thereby, gained by the patient is paid off by an increased susceptibility to postoperative systemic inflammatory response syndrome (SIRS). Under unfavorable conditions, the inflammatory syndrome may develop into life-threatening forms of MODS (multiple organ dysfunction syndrome) or even MOFS (multiple organ failure syndrome). Deliberate avoidance of CPB, also known as "off-pump" surgery, attenuates early postoperative inflammation throughout its trajectory of SIRS->MODS->MOFS, but, in the long run, there appears to be no substantial difference in the overall mortality rates. In the last years, our knowledge of the pathophysiology of surgical inflammation has increased considerably. Recent findings, highlighting the as yet rather obscure role of pentraxin 3 (PTX3) in these processes, are discussed in this review article. PMID- 23625867 TI - Immediate effects of individualized heparin and protamine management on hemostatic activation and platelet function in adult patients undergoing cardiac surgery with tranexamic acid antifibrinolytic therapy. AB - OBJECTIVE: This randomized prospective study was initiated to clarify whether individualized heparin and protamine dosing has immediate effects on hemostatic activation and platelet function in adult cardiac surgery. METHODS: Sixty adults undergoing elective coronary artery bypass grafting (CABG) were assigned to receive individualized heparin and protamine (HMS group, n= 29) or a standard dose (ACT group, n=24). Measures of thrombin generation and Multiplate (Verum Diagnostica, Munich, Germany) platelet function tests were performed before and after cardiopulmonary bypass (CPB). RESULTS: HMS patients received higher heparin (p = 0.006) and lower protamine (p<0.001) doses. Post-CPB, HMS managed patients showed significantly lower thrombin generation (thrombin-antithrombin (TAT) p<0.02) than the ACT group. Moreover, HMS managed patients had a better preservation of platelet function (COL p = 0.013; ADP p = 0.04; TRAP p = 0.04). CONCLUSION: An individualized and stable heparin concentration and appropriate dosing of protamine can reduce thrombin generation and preserve platelet function, even in short-time CPB. PMID- 23625869 TI - Materials discovery and crystal growth of zeolite A type zeolitic-imidazolate frameworks revealed by atomic force microscopy. AB - A new zeolitic-imidazolate framework (ZIF), [Zn(imidazolate)2 x(benzimidazolate)x], that has the zeolite A (LTA) framework topology and contains relatively inexpensive organic linkers has been revealed using in situ atomic force microscopy. The new material was grown on the structure-directing surface of [Zn(imidazolate)1.5(5-chlorobenzimidazolate)0.5] (ZIF-76) crystals, a metal-organic framework (MOF) that also possesses the LTA framework topology. The crystal growth processes for both [Zn(imidazolate)2-x(benzimidazolate)x] and ZIF 76 were observed using in situ atomic force microscopy; it is the first time the growth process of a nanoporous material with the complex zeolite A (LTA) framework topology has been monitored temporally at the nanoscale. The results reveal the crystal growth mechanisms and possible surface terminations on the {100} and {111} facets of the materials under low supersaturation conditions. Surface growth of these structurally complex materials was found to proceed through both "birth-and-spread" and spiral crystal-growth mechanisms, with the former occurring through the nucleation and spreading of metastable and stable sub-layers reliant on the presence of non-framework species to bridge the framework during formation. These results support the notion that the latter process may be a general mechanism of surface crystal growth applicable to numerous crystalline nanoporous materials of differing complexity and demonstrate that the methodology of seeded crystal growth can be used to discover previously unobtainable ZIFs and MOFs with desirable framework compositions. PMID- 23625868 TI - Human astrocytes express a novel NLRP2 inflammasome. AB - Central nervous system (CNS) trauma involves extensive cellular damage that is due, in part, to an innate inflammatory response induced by extracellular ATP. The innate immune response is regulated by pattern recognition receptors (PRRs), which include NOD-like receptors (NLRs). The PRRs and signaling cascades that regulate innate glial responses to CNS injury remain largely undefined. In this report, we show that human astrocytes express the NLR protein 2 (NLRP2) inflammasome that is activated by the danger associated molecular pattern (DAMP) ATP. The NLRP2 inflammasome is a multiprotein complex that consists of NLRP2, the adaptor protein apoptosis-speck-like protein containing a caspase recruitment domain (ASC) and caspase-1. NLRP2 also interacts with the P2X7 receptor and the pannexin 1 channel. Stimulation of human astrocytes with ATP resulted in activation of the NLRP2 inflammasome leading to the processing of inflammatory caspase-1 and interleukin-1beta (IL-1beta). ATP-induced activation of the NLRP2 inflammasome was inhibited by the pannexin 1 inhibitor probenecid and by the P2X7 receptor antagonist Brilliant Blue G (BBG). siRNA knockdown of NLRP2 significantly decreased NLRP2 levels and caspase-1 processing in human astrocytes in response to ATP. Our findings suggest that the astrocytic NLRP2 inflammasome is an important component of the CNS inflammatory response and that the NLRP2 inflammasome may be a therapeutic target to inhibit inflammation induced by CNS injury. PMID- 23625870 TI - Translucent titanium coating altered the composition of focal adhesions and promoted migration of osteoblast-like MG-63 cells on glass. AB - "TiGlass" was designed and was known to promote initial adhesion and increase migration of rat calvarial osteoblats. In this article, migration study and a series of epifluorescence microscopic studies were conducted to find out the composition of focal adhesion on titanium surface. The translucent titanium surface was applied in random migration analysis and immunofluorescence cell staining. In the immunofluorescent double staining, phosphorylated focal adhesion kinase was tested with vinculin. Various integrin subunits were then tested with vinculin to study the composition of activated focal adhesions. Integrin subunit alpha5 and alphaV were tested against beta3; integrin subunits alpha5, alphaV, beta3, and alphaVbeta3 were tested with F-actin, respectively. The MG-63 cells began migration earlier and migrated faster on "TiGlass." Immunofluorescent double staining revealed that all focal adhesion kinase in the focal adhesions were activated on both the surfaces. The osteoblast was inferred to made adhesion to titanium and glass through integrins. The focal adhesions on glass were found to be composed of integrin subunits alphaV and beta3. However, on "TiGlass," integrin subunits alpha5 might have supplemented the adhesion to titanium. Results from double staining of integrin subunits alpha5, alphaV, beta3, and alphaVbeta3 with F-actin also supported integrin subunits alpha5 might have involved in adhesion of titanium. PMID- 23625871 TI - Editorial: Molecular Endocrinology articles in the spotlight for May 2013. PMID- 23625873 TI - Inverse probability weighted estimating equations for randomized trials in transfusion medicine. AB - Thrombocytopenia is a condition characterized by extremely low platelet counts, which puts patients at elevated risk of morbidity and mortality because of bleeding. Trials in transfusion medicine are routinely designed to assess the effect of experimental platelet products on patients' platelet counts. In such trials, patients may receive multiple platelet transfusions over a predefined period of treatment, and a response is available from each such administration. The resulting data comprised multiple responses per patient, and although it is natural to want to use this data in testing for treatment effects, naive analyses of the multiple responses can yield biased estimates of the probability of response and associated treatment effects. These biases arise because only subsets of the patients randomized contribute response data on the second and subsequent administrations of therapy and the balance between treatment groups with respect to potential confounding factors is lost. We discuss the design and analysis issues involved in this setting and make recommendations for the design of future platelet transfusion trials. PMID- 23625874 TI - Facile preparation of well-defined near-monodisperse chitosan/sodium alginate polyelectrolyte complex nanoparticles (CS/SAL NPs) via ionotropic gelification: a suitable technique for drug delivery systems. AB - Polymeric nanoparticles have emerged as a promising approach for drug delivery systems. We prepared chitosan (CS)/sodium alginate (SAL) polyelectrolyte complex nanoparticles (CS/SAL NPs) via a simple and mild ionic gelation method by adding a CS solution to a SAL solution, and investigated the effects of molecular weight of the added CS, and the SAL:CS mass ratio on the formation of the polyelectrolyte complex nanoparticles. The well-defined CS/SAL NPs with near monodisperse particle size of about 160 nm exhibited a pH stable structure, and pH responsive properties with a negatively or positively charged surface. The so called "electrostatic sponge" structure of the polyelectrolyte complex nanoparticles enhanced their drug-loading capacity towards the differently charged model drug molecules, and favored controlled release. We also found that the drug-loading capacity was influenced by the nature of the drugs and the drug loading media, while drug release was affected by the solubility of the drugs in the drug-releasing media. The biocompatibility and biodegradability of the polyelectrolytes in the polyelectrolyte complex nanoparticles were maintained by ionic interactions. These results indicate that CS/SAL NPs can represent a useful technique for pH-responsive drug delivery systems. PMID- 23625875 TI - A simulation study to compare three self-controlled case series approaches: correction for violation of assumption and evaluation of bias. AB - PURPOSE: The assumption that the occurrence of outcome event must not alter subsequent exposure probability is critical for preserving the validity of the self-controlled case series (SCCS) method. This assumption is violated in scenarios in which the event constitutes a contraindication for exposure. In this simulation study, we compared the performance of the standard SCCS approach and two alternative approaches when the event-independent exposure assumption was violated. METHODS: Using the 2009 H1N1 and seasonal influenza vaccines and Guillain-Barre syndrome as a model, we simulated a scenario in which an individual may encounter multiple unordered exposures and each exposure may be contraindicated by the occurrence of outcome event. The degree of contraindication was varied at 0%, 50%, and 100%. The first alternative approach used only cases occurring after exposure with follow-up time starting from exposure. The second used a pseudo-likelihood method. RESULTS: When the event independent exposure assumption was satisfied, the standard SCCS approach produced nearly unbiased relative incidence estimates. When this assumption was partially or completely violated, two alternative SCCS approaches could be used. While the post-exposure cases only approach could handle only one exposure, the pseudo-likelihood approach was able to correct bias for both exposures. CONCLUSIONS: Violation of the event-independent exposure assumption leads to an overestimation of relative incidence which could be corrected by alternative SCCS approaches. In multiple exposure situations, the pseudo-likelihood approach is optimal; the post-exposure cases only approach is limited in handling a second exposure and may introduce additional bias, thus should be used with caution. PMID- 23625876 TI - Synthesis of a [26]hexaphyrin bis-Pd(II) complex with a characteristic aromatic circuit. AB - Not one, but two: Metalation of a mono-Pd(II) hexaphyrin (1) with [Pd(OCOCF3)2] gave a bis-Pd(II) complex (2), which possesses a characteristic 26 pi-aromatic circuit with two outer amino-pyrroles within a rectangular molecular framework. Complex 2 was readily deprotonated to afford a dianion, which was regioselectively methylated to give a methyl derivative. A similar methylation reaction of 1 produced a skeletally rearranged product that contained an N confused pyrrole. PMID- 23625877 TI - Applied spectrophotometry: analysis of a biochemical mixture. AB - Spectrophotometric analysis is essential for determining biomolecule concentration of a solution and is employed ubiquitously in biochemistry and molecular biology. The application of the Beer-Lambert-Bouguer Lawis routinely used to determine the concentration of DNA, RNA or protein. There is however a significant difference in determining the concentration of a given species (RNA, DNA, protein) in isolation (a contrived circumstance) as opposed to determining that concentration in the presence of other species (a more realistic situation). To present the student with a more realistic laboratory experience and also to fill a hole that we believe exists in student experience prior to reaching a biochemistry course, we have devised a three week laboratory experience designed so that students learn to: connect laboratory practice with theory, apply the Beer-Lambert-Bougert Law to biochemical analyses, demonstrate the utility and limitations of example quantitative colorimetric assays, demonstrate the utility and limitations of UV analyses for biomolecules, develop strategies for analysis of a solution of unknown biomolecular composition, use digital micropipettors to make accurate and precise measurements, and apply graphing software. PMID- 23625878 TI - The effect of plasma-nitrided titanium surfaces on osteoblastic cell adhesion, proliferation, and differentiation. AB - In this study, we evaluated the effect of new plasma-nitrided Ti surfaces on the progression of osteoblast cultures, including cell adhesion, proliferation and differentiation. Ti surfaces were treated using two plasma-nitriding protocols, hollow cathode for 3 h (HC 3 h) and 1 h (HC 1 h) and planar for 1 h. Untreated Ti surfaces were used as control. Cells derived from human alveolar and rat calvarial bones were cultured on Ti surfaces for periods of up to 14 days and the following parameters were evaluated: cell morphology, adhesion, spreading and proliferation, alkaline phosphatase (ALP) activity, extracellular matrix mineralization, and gene expression of key osteoblast markers. Plasma-nitriding treatments resulted in Ti surfaces with distinct physicochemical characteristics. The cell adhesion and ALP activity were higher on plasma-nitrided Ti surfaces compared with untreated one, whereas cell proliferation and extracellular matrix mineralization were not affected by the treatments. In addition, the plasma nitrided Ti surfaces increased the ALP, reduced the osteocalcin and did not affect the Runx2 gene expression. We have shown that HC 3 h and planar Ti surfaces slightly favored the osteoblast differentiation process, and then these surfaces should be considered for further investigation using preclinical models. PMID- 23625879 TI - Education enhances the acuity of the nonverbal approximate number system. AB - All humans share a universal, evolutionarily ancient approximate number system (ANS) that estimates and combines the numbers of objects in sets with ratio limited precision. Interindividual variability in the acuity of the ANS correlates with mathematical achievement, but the causes of this correlation have never been established. We acquired psychophysical measures of ANS acuity in child and adult members of an indigene group in the Amazon, the Mundurucu, who have a very restricted numerical lexicon and highly variable access to mathematics education. By comparing Mundurucu subjects with and without access to schooling, we found that education significantly enhances the acuity with which sets of concrete objects are estimated. These results indicate that culture and education have an important effect on basic number perception. We hypothesize that symbolic and nonsymbolic numerical thinking mutually enhance one another over the course of mathematics instruction. PMID- 23625881 TI - Global gene expression analysis of Saccharomyces cerevisiae grown under redox potential-controlled very-high-gravity conditions. AB - Redox potential (ORP) plays a pivotal role in yeast viability and ethanol production during very-high-gravity (VHG) ethanol fermentation. In order to identify the correlation between redox potential profiles and gene expression patterns, global gene expression of Saccharomyces cerevisiae was investigated. Results indicated that significant changes in gene expression occurred at the periods of 0 - 6 h and 30 - 36 h, respectively. Changes noted in the period of 0 6 h were mainly related to carbohydrate metabolism. In contrast, gene expression variation at 30 - 36 h could be attributed primarily to stress response. Although CDC19 was down-regulated, expression of PYK2, PDC6 and ADH2 correlated inversely with ORP. Meanwhile, expression of GPD1 decreased due to the depletion of dissolved oxygen in the fermentation broth, but expression of GPD2 correlated with ORP. Transcription of genes encoding heat shock proteins was characterized by uphill, downhill, valley and plateau expression profiles, accordingly to specific function in stress response. These results highlight the role of ORP in modulating yeast physiology and metabolism under VHG conditions. PMID- 23625880 TI - Cost-effectiveness of the introduction of specialized oral care with laser therapy in hematopoietic stem cell transplantation. AB - Oral mucositis (OM) is one of the side effects of hematopoietic stem cell transplantation (HSCT), resulting in major morbidity. The aim of this study was to determine the cost-effectiveness of the introduction of a specialized oral care program including laser therapy in the care of patients receiving HSCT with regard to morbidity associated with OM. Clinical information was gathered on 167 patients undergoing HSCT and divided according to the presence (n = 91) or absence (n = 76) of laser therapy and oral care. Cost analysis included daily hospital fees, parenteral nutrition (PN) and prescription of opioids. It was observed that the group without laser therapy (group II) showed a higher frequency of severe degrees of OM (relative risk = 16.8, 95% confidence interval 5.8 to 48.9, p < 0.001), with a significant association between this severity and the use of PN (p = 0.001), prescription of opioids (p < 0.001), pain in the oral cavity (p = 0.003) and fever > 37.8 degrees C (p = 0.005). Hospitalization costs in this group were up to 30% higher. The introduction of oral care by a multidisciplinary staff including laser therapy helps reduce morbidity resulting from OM and, consequently, helps minimize hospitalization costs associated with HSCT, even considering therapy costs. PMID- 23625882 TI - Synthesis of arylacetates from benzylic alcohols and oxalate esters through decarboxylative coupling. AB - Follow that dream: By combining a reversible transesterification between benzylic alcohols and dialkyl oxalates with catalytic decarboxylation of the resulting esters, a regiospecific C-C-bond-forming reaction to give alpha-arylacetates was achieved. In the overall process, CO2 and a volatile alcohol are the only byproducts. Various alpha-arylacetates were thus synthesized in high yields from easily accessible starting materials in the presence of catalytic amounts of Pd(OAc)2, dppp, and DABCO (see scheme). PMID- 23625883 TI - Construction of a functional silk-based biomaterial complex with immortalized chondrocytes in vivo. AB - To explore the feasibility of constructing a functional biomaterial complex with regenerated silk fibroin membrane and immortalized chondrocytes in vivo. Rat auricular chondrocytes (RACs) were transfected with the lentivirus vector pGC-FU hTERT-3FLAG or pGC-FU-GFP-3FLAG, encoding the human telomerase reverse transcriptase (hTERT) or GFP gene. The effects of regenerated silk fibroin film on the adhesion, growth of immortalized chondrocytes and expression of collagen II in vitro were analyzed with immunofluorescent histochemistry. Immortalized RACs were transformed. Induction by nutrient medium promoted higher expression levels of collagen II in transformed chondrocytes. The regenerated silk fibroin film was not cytotoxic to immortalized chondrocytes and had no adverse influence on their adhesion. Collagen II expression was good in the immortalized chondrocytes in vivo. The construction of a silk-based biomaterial complex with immortalized chondrocytes may provide a feasible kind of functional biomaterial for the repair of cartilage defects in clinical applications. PMID- 23625884 TI - A novel, general-purpose, MR-compatible, manually actuated robotic manipulation system for minimally invasive interventions under direct MRI guidance. AB - BACKGROUND: Performing minimally invasive interventions under direct MRI guidance offers significant advantages. Required accessibility to the patient inside the MRI scanner is fairly limited, and employment of robotic assistance has been proposed. The development of MR-compatible robotic systems entails engineering challenges related to geometric constraints and the magnetic nature of the scanning environment. METHODS: A novel, general-purpose, MR-compatible robotic manipulation system has been developed for the performance of minimally invasive interventions inside a cylindrical scanner under direct MRI guidance. The system is endowed with five degrees of freedom (DOF), is characterized by a unique kinematics structure and is manually actuated. RESULTS: The prototype system was shown to exhibit the required MR-compatibility characteristics and a task-space positioning ability of approximately 5 mm. Needle targeting testing demonstrated a 93% success rate in acquiring a 5 mm spherical target. Phantom testing was performed inside a 3 T scanner and results are reported for an experimental study simulating MRI-guided, manipulator-assisted, MR arthrography. CONCLUSIONS: Robotic assistance provided by the developed manipulator may effectively facilitate the performance of various MRI-guided, minimally invasive interventions inside a cylindrical scanner. PMID- 23625885 TI - Piper nigrum and piperine: an update. AB - Black pepper (Piper nigrum L.) is a very widely used spice, known for its pungent constituent piperine. However, in addition to its culinary uses, pepper has important medicinal and preservative properties, and, more recently, piperine has been shown to have fundamental effects on p-glycoprotein and many enzyme systems, leading to biotransformative effects including chemoprevention, detoxification, and enhancement of the absorption and bioavailability of herbal and conventional drugs. Based on modern cell, animal, and human studies, piperine has been found to have immunomodulatory, anti-oxidant, anti-asthmatic, anti-carcinogenic, anti inflammatory, anti-ulcer, and anti-amoebic properties. In this review, the chemical constituents, biological activities, effects of processing, and future potential of black pepper and piperine have been discussed thoroughly. PMID- 23625886 TI - Decellularized liver scaffolds effectively support the proliferation and differentiation of mouse fetal hepatic progenitors. AB - Decellularized whole organs represent ideal scaffolds for engineering new organs and/or cell transplantation. Here, we investigate whether decellularized liver scaffolds provide cell-friendly biocompatible three-dimensional (3-D) environment to support the proliferation and differentiation of hepatic progenitor cells. Mouse liver tissues are efficiently decellularized through portal vein perfusion. Using the reversibly immortalized mouse fetal hepatic progenitor cells (iHPCs), we are able to effectively recellularize the decellularized liver scaffolds. The perfused iHPCs survive and proliferate in the 3-D scaffolds in vitro for 2 weeks. When the recellularized scaffolds are implanted into the kidney capsule of athymic nude mice, cell survival and proliferation of the implanted scaffolds are readily detected by whole body imaging for 10 days. Furthermore, epidermal growth factor (EGF) is shown to significantly promote the proliferation and differentiation of the implanted iHPCs. Histologic and immunochemical analyzes indicate that iHPCs are able to proliferate and differentiate to mature hepatocytes upon EGF stimulation in the scaffolds. The recellularization of the biomaterial scaffolds is accompanied with vascularization. Taken together, these results indicate that decullarized liver scaffolds effectively support the proliferation and differentiation of iHPCs, suggesting that decellularized liver matrix may be used as ideal biocompatible scaffolds for hepatocyte transplantation. PMID- 23625887 TI - 5'-Trityl-substituted thymidine derivatives as a novel class of antileishmanial agents: Leishmania infantum EndoG as a potential target. AB - Two series of 5'-triphenylmethyl (trityl)-substituted thymidine derivatives were synthesized and tested against Leishmania infantum axenic promastigotes and amastigotes. Several of these compounds show significant antileishmanial activity, with IC50 values in the low micromolar range. Among these, 3'-O (isoleucylisoleucyl)-5'-O-(3,3,3-triphenylpropanoyl)thymidine displays particularly good activity against intracellular amastigotes. Assays performed to characterize the nature of parasite cell death in the presence of the tritylthymidines indicated significant alterations in mitochondrial transmembrane potential, an increase in superoxide concentrations, and also significant decreases in DNA degradation during the cell death process. Results point to the mitochondrial nuclease LiEndoG as a target for the action of this family of compounds. PMID- 23625888 TI - Accelerated evolution after gene duplication: a time-dependent process affecting just one copy. AB - Gene duplication is widely regarded as a major mechanism modeling genome evolution and function. However, the mechanisms that drive the evolution of the two, initially redundant, gene copies are still ill defined. Many gene duplicates experience evolutionary rate acceleration, but the relative contribution of positive selection and random drift to the retention and subsequent evolution of gene duplicates, and for how long the molecular clock may be distorted by these processes, remains unclear. Focusing on rodent genes that duplicated before and after the mouse and rat split, we find significantly increased sequence divergence after duplication in only one of the copies, which in nearly all cases corresponds to the novel daughter copy, independent of the mechanism of duplication. We observe that the evolutionary rate of the accelerated copy, measured as the ratio of nonsynonymous to synonymous substitutions, is on average 5-fold higher in the period spanning 4-12 My after the duplication than it was before the duplication. This increase can be explained, at least in part, by the action of positive selection according to the results of the maximum likelihood based branch-site test. Subsequently, the rate decelerates until purifying selection completely returns to preduplication levels. Reversion to the original rates has already been accomplished 40.5 My after the duplication event, corresponding to a genetic distance of about 0.28 synonymous substitutions per site. Differences in tissue gene expression patterns parallel those of substitution rates, reinforcing the role of neofunctionalization in explaining the evolution of young gene duplicates. PMID- 23625889 TI - Evidence for polygenic adaptation to pathogens in the human genome. AB - Most approaches aiming at finding genes involved in adaptive events have focused on the detection of outlier loci, which resulted in the discovery of individually "significant" genes with strong effects. However, a collection of small effect mutations could have a large effect on a given biological pathway that includes many genes, and such a polygenic mode of adaptation has not been systematically investigated in humans. We propose here to evidence polygenic selection by detecting signals of adaptation at the pathway or gene set level instead of analyzing single independent genes. Using a gene-set enrichment test to identify genome-wide signals of adaptation among human populations, we find that most pathways globally enriched for signals of positive selection are either directly or indirectly involved in immune response. We also find evidence for long distance genotypic linkage disequilibrium, suggesting functional epistatic interactions between members of the same pathway. Our results show that past interactions with pathogens have elicited widespread and coordinated genomic responses, and suggest that adaptation to pathogens can be considered as a primary example of polygenic selection. PMID- 23625892 TI - Editor's commentary. PMID- 23625890 TI - Analysis of piRNA-mediated silencing of active TEs in Drosophila melanogaster suggests limits on the evolution of host genome defense. AB - The Piwi-interacting RNA (piRNA) pathway defends animal genomes against the harmful consequences of transposable element (TE) infection by imposing small-RNA mediated silencing. Because silencing is targeted by TE-derived piRNAs, piRNA production is posited to be central to the evolution of genome defense. We harnessed genomic data sets from Drosophila melanogaster, including genome-wide measures of piRNA, mRNA, and genomic abundance, along with estimates of age structure and risk of ectopic recombination, to address fundamental questions about the functional and evolutionary relationships between TE families and their regulatory piRNAs. We demonstrate that mRNA transcript abundance, robustness of "ping-pong" amplification, and representation in piRNA clusters together explain the majority of variation in piRNA abundance between TE families, providing the first robust statistical support for the prevailing model of piRNA biogenesis. Intriguingly, we also discover that the most transpositionally active TE families, with the greatest capacity to induce harmful mutations or disrupt gametogenesis, are not necessarily the most abundant among piRNAs. Rather, the level of piRNA targeting is largely independent of recent transposition rate for active TE families, but is rapidly lost for inactive TEs. These observations are consistent with population genetic theory that suggests a limited selective advantage for host repression of transposition. Additionally, we find no evidence that piRNA targeting responds to selection against a second major cost of TE infection: ectopic recombination between TE insertions. Our observations confirm the pivotal role of piRNA-mediated silencing in defending the genome against selfish transposition, yet also suggest limits to the optimization of host genome defense. PMID- 23625893 TI - Extended utilization of noninvasive ventilation for acute respiratory failure and its clinical outcomes. AB - BACKGROUND: Noninvasive ventilation (NIV) has increasingly been used for the treatment of acute respiratory failure. Despite recommendations supporting its utilization in a limited group of patients, NIV is frequently relied on as a first line treatment. We conducted a retrospective study to assess whether the extended use of NIV is associated with worse clinical outcomes. METHODS: This was a retrospective review of a data set consisting of patients admitted with respiratory failure and treated with NIV. Based on guidelines, we grouped the patients on whether they had indications and/or contraindications for NIV: NIV indicated and not contraindicated; NIV indicated and contraindicated; NIV not indicated and not contraindicated; NIV not indicated and contraindicated. The need for endotracheal intubation, hospital mortality, and stay were compared between these 4 groups. RESULTS: Demographic data were not significantly different between the groups. Within the group of subjects with no contraindication for NIV, those with indication and with no indication intubation rates were 28% and 17%, respectively (P = .39). Among the group of subjects with indications for NIV, the rate of intubation was 28% for those with no contraindication and 56% in those with it (P = .13). In the group of subjects with no indication for NIV, the presence of contraindications was associated with higher rate of intubation, compared with those without contraindications (70% vs 17%, P = .002). CONCLUSIONS: This study supports the extended utilization of NIV for subjects without contraindications, and for subjects with indications despite the presence or absence of contraindications. PMID- 23625894 TI - Evaluation of interpretation strategies and substantial bronchodilator response in pediatric patients with normal baseline spirometry. AB - BACKGROUND: Controversy exists regarding the best method to interpret pediatric spirometry. There is also controversy regarding the benefit of performing post bronchodilator spirometry after normal baseline spirometry. This study compares the use of lower limit of normal (LLN) against percent of predicted (PP) in the interpretation of spirometry. We also investigate the occurrence of a substantial bronchodilator response for patients who received post-bronchodilator spirometry. METHODS: Spirometric tests performed in the pediatric clinic at San Antonio Military Medical Center were retrospectively reviewed. Results of spirometry were compared using LLN and PP for interpretation. Abnormal spirometry was defined as a low FEV1 or low FEV1/FVC, indicating evidence of airway obstruction. The presence of a substantial bronchodilator response was recorded and the results were analyzed. RESULTS: Of 242 tests, 212 normal and 30 abnormal tests were reported using the LLN interpretation strategy. Using the PP interpretation strategy, there was a significant difference in the number of normal (183) and abnormal (59) tests, when compared to the LLN (P < .001). No significant difference between LLN versus PP interpretation strategies was noted in the number of baseline tests, normal or abnormal, that demonstrated a substantial response to bronchodilator. Of the subjects with normal baseline spirometry, 10% (PP) and 12% (LLN) had a substantial bronchodilator response. An abnormal baseline spirometry was more likely to have a substantial response to bronchodilator, compared to normal baseline spirometry (P < .001). CONCLUSIONS: The use of LLN for interpretation is more likely to report a test as normal, when compared to the PP interpretation strategy. Although a substantial bronchodilator response is more likely to occur following abnormal baseline spirometry, 10-12% of subjects with normal baseline spirometry showed a substantial bronchodilator response. This suggests that normal baseline spirometry may miss reversible airway obstruction, which is a hallmark of asthma. PMID- 23625895 TI - High frequency oscillatory ventilation versus conventional ventilation in a newborn piglet model with acute lung injury. AB - BACKGROUND: High frequency oscillatory ventilation (HFOV) is considered a protective strategy for human lungs. This study was designed to define microscopic structural features of lung injury following HFOV with a high lung volume strategy in newborn piglets with acute lung injury. METHODS: After acute lung injury with saline lavage, newborn piglets were randomly assigned to 5 study groups (6 in each group): control (no mechanical ventilation), conventional mechanical ventilation for 24 hours, conventional ventilation for 48 hours, HFOV for 24 hours, and HFOV for 48 hours. The right upper lung tissue was divided into the gravitation-dependent and gravitation-nondependent regions after the completion of mechanical ventilation. Under light microscopy, the numbers of polymorphonuclear leukocytes (PMNLs), alveolar macrophages, red blood cells, and hyaline membrane/alveolar edema were assessed in all lung tissues. Oxygenation index was continuously monitored. RESULTS: Our results showed that the degree of histopathologic lung damage in the gravitation-dependent region was greater than that in the gravitation-nondependent region. Compared with the control group, PMNLs, red blood cells and hyaline membrane/alveolar edemas were significantly increased and alveolar macrophages were significantly decreased in lung tissues of conventional ventilation and HFOV piglets. In HFOV with high lung volume strategy piglets, lung tissues had significantly fewer PMNLs, red blood cells, and hyaline membrane/alveolar edemas, and oxygenation was improved significantly, compared to those of the conventional ventilation piglets. CONCLUSIONS: Histopathologic lung damage in newborn piglets with lung injury was more severe in the gravitation-dependent region than in the gravitation-nondependent region. HFOV with high lung volume strategy reduced pulmonary PMNL infiltration, hemorrhage, alveolar edema, and hyaline membrane formation with improved oxygenation. PMID- 23625896 TI - Respiratory care year in review 2012: Asthma and sleep-disordered breathing. AB - Asthma has long been recognized as a common respiratory disease, and the recognition of sleep-disordered breathing is becoming more prevalent. Patients with these disorders are commonly seen by clinicians caring for patients with respiratory disease. There is also much academic interest in asthma and sleep disordered breathing. The purpose of this paper is to review the recent literature related to asthma and sleep-disordered breathing in a manner that is most likely to have interest to the readers of Respiratory Care. PMID- 23625897 TI - Neurally adjusted ventilatory assist: insufficient evidence of broad clinical outcomes. PMID- 23625898 TI - Decremental PEEP titration: a step away from the table. PMID- 23625899 TI - Mentoring and respiratory care. PMID- 23625900 TI - Complications following pulmonary lobectomy: the role of helmet noninvasive ventilation. PMID- 23625902 TI - High-flow nasal cannula oxygen therapy in the emergency department: welcome, but selection should be the first step. PMID- 23625901 TI - Noninvasive mechanical ventilation and helmet after lung resection: oxygenation improvement: a small step or a large step? PMID- 23625903 TI - Study of variations of radiofrequency power density from mobile phone base stations with distance. AB - The variations of radiofrequency (RF) radiation power density with distance around some mobile phone base stations (BTSs), in ten randomly selected locations in Ibadan, western Nigeria, were studied. Measurements were made with a calibrated hand-held spectrum analyser. The maximum Global System of Mobile (GSM) communication 1800 signal power density was 323.91 uW m(-2) at 250 m radius of a BTS and that of GSM 900 was 1119.00 uW m(-2) at 200 m radius of another BTS. The estimated total maximum power density was 2972.00 uW m(-2) at 50 m radius of a different BTS. This study shows that the maximum carrier signal power density and the total maximum power density from a BTS may be observed averagely at 200 and 50 m of its radius, respectively. The result of this study demonstrates that exposure of people to RF radiation from phone BTSs in Ibadan city is far less than the recommended limits by International scientific bodies. PMID- 23625904 TI - Lifestyle and dietary factors in relation to risk of chronic myeloid leukemia in the NIH-AARP Diet and Health Study. AB - BACKGROUND: Aside from exposure to ionizing radiation and benzene, little is known about lifestyle risk factors for chronic myeloid leukemia (CML) in the general population. METHODS: We examined the relation between lifestyle and dietary risk factors for CML in 493,188 participants (294,271 males and 198,917 females) aged 50 to 71 years who completed a baseline questionnaire in the National Institutes of Health-AARP Diet and Health Study in 1995 to 1996. Over a median of 10.5 years of follow-up, 178 incident cases of CML (139 males and 39 females) were ascertained from state registries. We used Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals for exposures of interest, adjusting for potential confounding variables. RESULTS: In multivariable analysis of all participants combined, female sex, years of education, and vigorous physical activity (HR for >=3 times/week vs. <1 time/week 0.70; 95% CI, 0.49-0.99) were inversely associated with risk of CML, whereas smoking intensity (HR for smokers of >=20 cigarettes per day vs. never smokers: 1.53; 95% CI, 1.03-2.27) and body mass (HR for BMI >= 30 vs. <25 kg/m(2) 1.46; 95% CI, 0.95-2.23) were associated with increased risk. A range of dietary factors was not associated with disease. CONCLUSIONS: This study adds to the sparse information about lifestyle factors, which affect the risk of CML in the general population. IMPACT: If these findings are confirmed, it would suggest that CML may be amenable to preventive strategies. PMID- 23625905 TI - Effect of chromium (VI) exposure on antioxidant defense status and trace element homeostasis in acute experiment in rat. AB - Occupational exposure to hexavalent chromium (Cr(VI)) compounds is of concern in many Cr-related industries and their surrounding environment. Cr(VI) is a proven toxin and carcinogen. The Cr(VI) compounds are easily absorbed, can diffuse across cell membranes, and have strong oxidative potential. Despite intensive studies of Cr(VI) pro-oxidative effects, limited data exist on the influence of Cr(VI) on selenoenzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx)-important components of antioxidant defense system. This study investigates the effect of Cr(VI) exposure on antioxidant defense status, with focus on these selenoenzymes, and on trace element homeostasis in an acute experiment in rat. Male Wistar rats (130-140g) were assigned to two groups of 8 animals: I. control; and II. Cr(VI) treated. The animals in Cr(VI) group were administered a single dose of K2Cr2O7 (20 mg /kg, intraperitoneally (ip)). The control group received saline solution. After 24 h, the animals were sacrificed and the liver and kidneys were examined for lipid peroxidation (LP; thiobarbituric acid reactive substances (TBARS) concentration), the level of reduced glutathione (GSH) and the activities of GPx-1, TrxR-1, and glutathione reductase (GR). Samples of tissues were also used to estimate Cr accumulation and alterations in zinc, copper, and iron levels. The acute Cr(VI) exposure caused an increase in both hepatic and renal LP (by 70%, p < 0.01 and by 15%, p < 0.05, respectively), increased hepatic GSH level and GPx-1 activity, and decreased renal GPx-1 activity. The activity of GR was not changed. A significant inhibitory effect of Cr(VI) was found on TrxR-1 activity in both the liver and the kidneys. The ability of Cr(VI) to cause TrxR inhibition could contribute to its cytotoxic effects. Further investigation of oxidative responses in different in vivo models may enable the development of strategies to protect against Cr(VI) oxidative damage. PMID- 23625906 TI - Studying the effect of antioxidants on cytogenetic manifestations of solvent exposure in the paint industry. AB - OBJECTIVE: To investigate the antioxidant role in reversing cytogenetic changes caused by solvent exposure in paint industry. SUBJECTS AND METHODS: A prospective controlled clinical trial was performed on 39 workers exposed to solvents and 39 workers not exposed to solvents by supplying a mixture of antioxidant vitamins (A, C, E and selenium) and the after effects of such regimen were analyzed. Environmental monitoring was carried out for air concentrations of different solvents at workplace. Exposed group was cytogenetically tested before and after giving the mixture of antioxidant vitamins for 1 month duration. RESULTS: Frequency of chromosomal aberrations (CAs) and the mean of sister chromatid exchanges (SCEs) were statistically significantly higher among exposed workers than among controls. After the supplementation of antioxidants, there was a statistically significant decrease in the frequency of CAs, and 88% abnormal levels of SCEs were back to normal levels. CONCLUSION: Antioxidant supplementation decreases the frequency of CAs and SCEs among exposed workers. PMID- 23625907 TI - Pirimicarb-based formulation-induced genotoxicity and cytotoxicity in the freshwater fish Cnesterodon decemmaculatus (Jenyns, 1842) (Pisces, Poeciliidae). AB - We analyzed the aspects of lethality, genotoxicity, and cytotoxicity in the ten spotted live-bearer exposed under laboratory conditions to the pirimicarb-based formulation Patton Flow(r) (50% active ingredient (a.i.)). Acute effects were evaluated using different end points for lethality, genotoxicity, and cytotoxicity. Median lethal concentration (LC50) estimation was employed as a bioassay for lethality, whereas micronucleus (MN) induction and alterations in erythrocyte/erythroblast frequency were used as end points for genotoxicity and cytotoxicity, respectively. Results demonstrated an LC5096h value of 88 mg/L. Patton Flow(r) increased the MN frequency in fish erythrocytes after 48 h of exposure at a concentration of 66 mg/L, whereas a concentration range of 22-66 mg/L was able to exert the same genotoxic effect at 96 h of treatment. Furthermore, cytotoxicity was also observed by alterations in erythrocyte/erythroblast frequencies within the concentration range of 22-66 mg/L, regardless of the exposure time. Our current observations provide evidence that Patton Flow(r) (50% a.i.) should be considered a clear lethal, cytotoxic, and genotoxic agent on Cnesterodon decemmaculatus. Thus, repeated applications of this carbamic insecticide can enter the aquatic environment and exert deleterious effects on aquatic organisms other than the evaluated species C. decemmaculatus. PMID- 23625908 TI - 1,1-Diphenyl,2-picrylhydrazyl free radical scavenging, bactericidal, fungicidal and leishmanicidal properties of Teucrium stocksianum. AB - In the present study, we evaluated the pharmacological and toxicological effects of Teucrium stocksianum. The crude extract of T. stocksianum (Ts.Cr) and its subsequent organic fractions: n-hexane (Ts.Hex), chloroform (Ts.CHCl3) and ethyl acetate (Ts.EtAc) exhibited 1,1-diphenyl,2-picrylhydrazyl free radical scavenging activity with different potencies. Ts.EtAc was found to be most potent. Ts.Cr, Ts.Hex, Ts.CHCl3 and Ts.EtAc showed significant bactericidal activity against Escherichia coli, Staphylococcus aureus, Salmonella typhi, Shigella flexneri and Bacillus subtilis at their extent. Ts.Cr, Ts.Hex, Ts.CHCl3 and Ts.EtAc displayed fungicidal action against Aspergillus niger, Aspergillus flavus, Aspergillus fumigatus and Fusarium solani at various minimum inhibitory concentrations. Ts.Cr and Ts.EtAc exhibited marked inhibition of Leishmania tropica growth, observed after 48 and 96 hrs of treatment. These data indicate that the T. stocksianum methanolic extract and its resultant fractions possess antioxidant, antibacterial, antifungal and antileishmanial activities. Thus, the present research unearths the scientific base for T. stocksianum medicinal application as antioxidant and antimicrobial agents. PMID- 23625909 TI - Optimization of conventional water treatment plant using dynamic programming. AB - In this research, the mathematical models, indicating the capability of various units, such as rapid mixing, coagulation and flocculation, sedimentation, and the rapid sand filtration are used. Moreover, cost functions were used for the formulation of conventional water and wastewater treatment plant by applying Clark's formula (Clark, 1982). Also, by applying dynamic programming algorithm, it is easy to design a conventional treatment system with minimal cost. The application of the model for a case reduced the annual cost. This reduction was approximately in the range of 4.5-9.5% considering variable limitations. Sensitivity analysis and prediction of system's feedbacks were performed for different alterations in proportion from parameters optimized amounts. The results indicated (1) that the objective function is more sensitive to design flow rate (Q), (2) the variations in the alum dosage (A), and (3) the sand filter head loss (H). Increasing the inflow by 20%, the total annual cost would increase to about 12.6%, while 20% reduction in inflow leads to 15.2% decrease in the total annual cost. Similarly, 20% increase in alum dosage causes 7.1% increase in the total annual cost, while 20% decrease results in 7.9% decrease in the total annual cost. Furthermore, the pressure decrease causes 2.95 and 3.39% increase and decrease in total annual cost of treatment plants. PMID- 23625910 TI - Effect of paraoxonase 1 192 Q/R polymorphism on paraoxonase and acetylcholinesterase enzyme activities in a Turkish population exposed to organophosphate. AB - Organophosphate (OP) compounds are the most commonly used pesticide groups and they are commercially used in the market for local and industrial purposes. Paraoxonase 1 (PON1) enzyme plays an important role in biotransformation of OP compounds, which shows toxic effects via inhibiting the acetylcholinesterase (AChE). The aim of this study was to determine the effects of PON1 gene polymorphism and its effects on PON and AChE enzyme activities in individuals who were exposed to organophosphorus insecticides due to occupational reasons, and to profile the probability of susceptibility to organophosphorus compounds. For this purpose, 54 individuals who were exposed to OPs and 54 healthy unrelated controls were studied. First, PON1 and AChE enzyme activities were measured. Second, PON1 192 Q/R polymorphism was determined by standard polymerase chain reaction restriction fragment length polymorphism technique. When the PON1 192 Q/R polymorphism was compared with PON1 enzyme activities, statistically significant association was found in both OP-exposed and control groups (p < 0.05). PON1 192 R(+) (QR + RR genotypes) genotype carriers had higher PON1 activities than 192 R( ) (QQ) genotype carriers. On the other hand, results were statistically analyzed in terms of AChE enzyme activities and there were statistically significant differences only in the OP-exposed group (p < 0.05). The mean AChE concentration in the OP-exposed group was determined as 33.79 +/- 6.84 U/g haemoglobin (Hb) for PON1 192 R(+) carriers and 30.37 +/- 7.62 U/g Hb for PON1 192 R(+) carriers. As a conclusion, PON1 and AChE activities were increasing according to the genotypes found in individuals having been exposed to OPs at a chronic level; 192 R(+) > 192 R(-), respectively. PMID- 23625911 TI - Metoprolol and diltiazem ameliorate ziprasidone-induced prolonged corrected QT interval in rats. AB - Ziprasidone, an atypical antipsychotic agent, has been shown to increase the corrected QT (QTc) interval in some patients. The aim of this study was to reveal the effects of metoprolol and diltiazem on ziprasidone drug-induced prolonged QTc interval. A total of 24 rats were equally divided into the following four groups: the first group was used as the control and received 1 mL/kg saline; 3 mg/kg ziprasidone and saline were administered to the second group; 3 mg/kg ziprasidone and 1 mg/kg metoprolol were administered to the third group and 3 mg/kg ziprasidone and 2 mg/kg diltiazem were administered to the fourth group. Two hours following application of the drugs, the QTc was calculated by performing electrocardiography in derivation (D)I. The duration of QTc interval was compared among the four groups. The mean QTc intervals were significantly increased in the third and fourth groups compared with the second group (p < 0.0005 and p < 0.0001, respectively). The study demonstrated the effectiveness of metoprolol and diltiazem in the prevention of ziprasidone-induced elongation in the QTc interval. Both metoprolol and diltiazem may be considered in the prophylactic therapy of high-risk patients who are using ziprasidone. PMID- 23625912 TI - Effects of aluminum chloride on some trace elements and erythrocyte osmotic fragility in rats. AB - Aluminum (Al) is a nonessential, toxic element to which humans are constantly exposed as a result of an increase in industrialization and improving technology practices. The aim of the study was to investigate the effects of different durations and doses of Al exposure on serum and tissue element levels and erythrocyte osmotic fragility in rats. A total of 40 male Wistar Albino rats were divided into five groups: control, group I (3 weeks, 8 mg/kg), group II (6 weeks, 8 mg/kg), group III (3 weeks, 16 mg/kg), and group IV (6 weeks, 16 mg/kg). Al chloride (AlCl3) was injected intraperitoneally (i.p.) five times a week. At the end of the experimental period, levels of Al, iron (Fe), copper (Cu), and zinc (Zn) in serum, liver, and kidney tissues were measured using inductively coupled plasma optical emission spectrometry. Osmotic fragility was determined using a spectrophotometer. The results of the experiment indicate that Al induced a statistically significant increase in Al and Fe concentrations in liver and serum as well as in Cu in the kidney. The Fe concentration in serum and kidney tissues was significantly lower in all the groups. As a result of our study, it may be concluded that tissue Al accumulation may lead to an increase in osmotic fragility of erythrocytes and abnormal trace element levels. PMID- 23625913 TI - A pilot test of videoconferencing to improve access to a stroke risk-reduction programme for Veterans. AB - We conducted a pilot study to determine the feasibility of using videoconferencing for a programme of self-management to prevent stroke (V-STOP). A total of 37 Veterans with a history of stroke, or with multiple risk factors for stroke, were enrolled in the study from two rural sites. The V-STOP intervention consisted of 6 weekly sessions of self-management classes and clinic visits delivered via videoconferencing, with one or two individual telephone counselling sessions. Participants' mean satisfaction scores were 4.7 out of 5, indicating very high approval of the programme. Attendance was 87%, almost twice as high as at an equivalent in-person programme. Access was improved as participants saved, on average, 160 km by travelling to a community centre instead of the main Veterans Administration facility. Stroke risk knowledge and self-management behaviours such as communication with healthcare providers significantly improved from baseline. Overall, videoconferencing is feasible for delivering self-management classes and clinic visits and the V-STOP programme shows promise as a method for delivery of self-management education and preventive care services to reduce stroke risk. PMID- 23625914 TI - Determination of cotinine by LC-MS-MS with automated solid-phase extraction. AB - Cotinine is the primary metabolite of nicotine and the preferred biomarker for assessing cigarette smoke exposure. Several liquid chromatography-tandem mass spectrometry (LC-MS-MS) methods have been described for measuring cotinine in biological fluids. Sample preparation typically involves manual solvent evaporation and reconstitution steps. This study describes a novel LC-MS-MS method for the quantification of cotinine by using electrospray ionization with multiple reaction monitoring and cotinine-d3 as internal standard, coupled with an automated solid-phase extraction (SPE) procedure. The assay was linear over the analytical range of 0.5-1,000 ng/mL. The limits of detection and quantification were 0.13 and 0.20 ng/mL, respectively. Intra-assay and inter assay imprecision of cotinine in all samples was <5 and <10% (coefficient of variation), respectively. The analytical recovery of cotinine spiked into plasma was >95-100%. Matrix effects in serum and plasma were <10%. A rapid, sensitive and specific LC-MS-MS method was developed and validated for the determination of cotinine in human plasma, using a straightforward automated SPE protocol. The application of this method to an epidemiological study has demonstrated its utility for batch analyses of a large sample set (>500 samples). PMID- 23625915 TI - Store-operated Ca2+ entry (SOCE) induced by protease-activated receptor-1 mediates STIM1 protein phosphorylation to inhibit SOCE in endothelial cells through AMP-activated protein kinase and p38beta mitogen-activated protein kinase. AB - The Ca(2+) sensor STIM1 is crucial for activation of store-operated Ca(2+) entry (SOCE) through transient receptor potential canonical and Orai channels. STIM1 phosphorylation serves as an "off switch" for SOCE. However, the signaling pathway for STIM1 phosphorylation is unknown. Here, we show that SOCE activates AMP-activated protein kinase (AMPK); its effector p38beta mitogen-activated protein kinase (p38beta MAPK) phosphorylates STIM1, thus inhibiting SOCE in human lung microvascular endothelial cells. Activation of AMPK using 5-aminoimidazole-4 carboxamide-1-beta-d-ribofuranoside (AICAR) resulted in STIM1 phosphorylation on serine residues and prevented protease-activated receptor-1 (PAR-1)-induced Ca(2+) entry. Furthermore, AICAR pretreatment blocked PAR-1-induced increase in the permeability of mouse lung microvessels. Activation of SOCE with thrombin caused phosphorylation of isoform alpha1 but not alpha2 of the AMPK catalytic subunit. Moreover, knockdown of AMPKalpha1 augmented SOCE induced by thrombin. Interestingly, SB203580, a selective inhibitor of p38 MAPK, blocked STIM1 phosphorylation and led to sustained STIM1-puncta formation and Ca(2+) entry. Of the three p38 MAPK isoforms expressed in endothelial cells, p38beta knockdown prevented PAR-1-mediated STIM1 phosphorylation and potentiated SOCE. In addition, inhibition of the SOCE downstream target CaM kinase kinase beta (CaMKKbeta) or knockdown of AMPKalpha1 suppressed PAR-1-mediated phosphorylation of p38beta and hence STIM1. Thus, our findings demonstrate that SOCE activates CaMKKbeta AMPKalpha1-p38beta MAPK signaling to phosphorylate STIM1, thereby suppressing endothelial SOCE and permeability responses. PMID- 23625916 TI - Structures of Mycobacterium tuberculosis FadD10 protein reveal a new type of adenylate-forming enzyme. AB - Mycobacterium tuberculosis has a group of 34 FadD proteins that belong to the adenylate-forming superfamily. They are classified as either fatty acyl-AMP ligases (FAALs) or fatty acyl-CoA ligases based on sequence analysis. FadD10, involved in the synthesis of a virulence-related lipopeptide, was mis-annotated as a fatty acyl-CoA ligase; however, it is in fact a FAAL that transfers fatty acids to an acyl carrier protein (Rv0100). In this study, we have determined the structures of FadD10 in both the apo-form and the complexed form with dodecanoyl AMP, where we see for the first time an adenylate-forming enzyme that does not adopt a closed conformation for catalysis. Indeed, this novel conformation of FadD10, facilitated by its unique inter-domain and intermolecular interactions, is critical for the enzyme to carry out the acyl transfer onto Rv0100 rather than coenzyme A. This contradicts the existing model of FAALs that rely on an insertion motif for the acyltransferase specificity and thus makes FadD10 a new type of FAAL. We have also characterized the fatty acid preference of FadD10 through biological and structural analyses, and the data indicate long chain saturated fatty acids as the biological substrates of the enzyme. PMID- 23625917 TI - Role of phosphatidylethanolamine in the biogenesis of mitochondrial outer membrane proteins. AB - The mitochondrial outer membrane contains proteinaceous machineries for the import and assembly of proteins, including TOM (translocase of the outer membrane) and SAM (sorting and assembly machinery). It has been shown that the dimeric phospholipid cardiolipin is required for the stability of TOM and SAM complexes and thus for the efficient import and assembly of beta-barrel proteins and some alpha-helical proteins of the outer membrane. Here, we report that mitochondria deficient in phosphatidylethanolamine (PE), the second non-bilayer forming phospholipid, are impaired in the biogenesis of beta-barrel proteins, but not of alpha-helical outer membrane proteins. The stability of TOM and SAM complexes is not disturbed by the lack of PE. By dissecting the import steps of beta-barrel proteins, we show that an early import stage involving translocation through the TOM complex is affected. In PE-depleted mitochondria, the TOM complex binds precursor proteins with reduced efficiency. We conclude that PE is required for the proper function of the TOM complex. PMID- 23625918 TI - Helix unfolding/refolding characterizes the functional dynamics of Staphylococcus aureus Clp protease. AB - The ATP-dependent Clp protease (ClpP) plays an essential role not only in the control of protein quality but also in the regulation of bacterial pathogen virulence, making it an attractive target for antibacterial treatment. We have previously determined the crystal structures of Staphylococcus aureus ClpP (SaClpP) in two different states, extended and compressed. To investigate the dynamic switching of ClpP between these states, we performed a series of molecular dynamics simulations. During the structural transition, the long and straight helix E in the extended SaClpP monomer underwent an unfolding/refolding process, resulting in a kinked helix very similar to that in the compressed monomer. As a stable intermediate in the molecular dynamics simulation, the compact state was suggested and subsequently identified in x-ray crystallographic experiment. Our combined studies also determined that Ala(140) acted as a "hinge" during the transition between the extended and compressed states, and Glu(137) was essential for stabilizing the compressed state. Overall, this study provides molecular insights into the dynamics and mechanism of the functional conformation changes of SaClpP. Given the highly conserved sequences of ClpP proteins among different species, these findings potentially reflect a switching mechanism for the dynamic process shared in the whole ClpP family in general and thus aid in better understand the principles of Clp protease assembly and function. PMID- 23625919 TI - The evolutionary rewiring of the ribosomal protein transcription pathway modifies the interaction of transcription factor heteromer Ifh1-Fhl1 (interacts with forkhead 1-forkhead-like 1) with the DNA-binding specificity element. AB - The genes encoding the ribosomal proteins of fungi form a regulon whose expression is enhanced under good growth conditions and down-regulated under starvation conditions. The fungal pathogen Candida albicans contains an evolutionarily ancient control circuit for this regulon where a heteromer made up of the transcription regulators Ifh1 (interacts with Forkhead 1) and Fhl1 (Forkhead-like 1) is targeted to the ribosomal protein genes by the DNA binding factor Tbf1. In the more recently evolved circuit in the model yeast Saccharomyces cerevisiae (Sc), the generalist repressor-activator protein Rap1 now directs the Ifh1-Fhl1 module to the ribosomal protein genes. Even though overall sequence similarity is low for the respective Fhl1 and Ifh1 subunits, in both species, the Ifh1 protein links to the Forkhead-associated domain of Fhl1 through its FHB domain. Intriguingly, correlated with the transition to the Rap1 regulated circuit, the Sc-Ifh1 contains a Rap1 binding domain that is not present in the C. albicans protein. Because no extensive common sequences are found in Tbf1 and Rap1, it appears that these targeting proteins must connect to the Ifh1 Fhl1 module in distinct ways. Two-hybrid and co-immunoprecipitation analysis has been used to show that in C. albicans Tbf1 is linked to the heterodimer through direct association with Fhl1. By contrast, in S. cerevisiae, the linkage of the heteromer to Rap1 occurs through Ifh1. Thus, in the ascomycetes, the Ifh1-Fhl1 heterodimer has reconfigured its protein associations to remain connected to the ribosomal protein regulon despite rewiring of the targeting transcription factor from Tbf1 to Rap1. PMID- 23625920 TI - MicroRNA-33a mediates the regulation of high mobility group AT-hook 2 gene (HMGA2) by thyroid transcription factor 1 (TTF-1/NKX2-1). AB - In lung cancers, TTF-1 displays seemingly paradoxical activities. Although TTF-1 is amplified in primary human lung cancers, it inhibits primary lung tumors from metastasizing in a mouse model system. It was reported that the oncogenic proepithelial mesenchymal transition (EMT) high mobility group AT-hook 2 gene (HMGA2) mediates the antimetastatic function of TTF-1. To gain mechanistic insight into the metastasis-critical signaling axis of TTF-1 to HMGA2, we used both reverse and forward strategies and discovered that microRNA-33a (miR-33a) is under direct positive regulation of TTF-1. By chromatin immunoprecipitation, we determined that TTF-1 binds to the promoter of SREBF2, the host gene of miR-33a. The 3'-untranslated region (UTR) of HMGA2 contains three predicted binding sites of miR-33a. We showed that the first two highly conserved sites are conducive to HMGA2 repression by miR-33a, establishing HMGA2 as a genuine target of miR-33a. Functional studies revealed that enforced expression of miR-33a inhibits the motility of lung cancer cells, and this inhibition can be rescued by overexpression of the form of HMGA2 without the 3'-UTR, suggesting that TTF-1 keeps the prometastasis gene HMGA2 in check via up-regulating miR-33a. This study reports the first miRNAs directly regulated by TTF-1 and clarifies how TTF-1 controls HMGA2 expression. Moreover, the documented importance of SREBF2 and miR 33a in regulating cholesterol metabolism suggests that TTF-1 may be a modulator of cholesterol homeostasis in the lung. Future studies will be dedicated to understanding how miRNAs influence the oncogenic activity of TTF-1 and the role of TTF-1 in cholesterol metabolism. PMID- 23625921 TI - Epigenetic switching by the metabolism-sensing factors in the generation of orexin neurons from mouse embryonic stem cells. AB - The orexin system plays a central role in the integration of sleep/wake and feeding behaviors in a broad spectrum of neural-metabolic physiology. Orexin-A and orexin-B are produced by the cleavage of prepro-orexin, which is encoded on the Hcrt gene. To date, methods for generating other peptide neurons could not induce orexin neurons from pluripotent stem cells. Considering that the metabolic status affects orexin expression, we supplemented the culture medium with a nutrient factor, ManNAc, and succeeded in generating functional orexin neurons from mouse ES cells. Because DNA methylation inhibitors and histone deacetylase inhibitors could induce Hcrt expression in mouse ES cells, the epigenetic mechanism may be involved in this orexin neurogenesis. DNA methylation analysis showed the presence of a tissue-dependent differentially methylated region (T DMR) around the transcription start site of the Hcrt gene. In the orexin neurons induced by supplementation of ManNAc, the T-DMR of the Hcrt gene was hypomethylated in association with higher H3/H4 acetylation. Concomitantly, the histone acetyltransferases p300, CREB-binding protein (CBP), and Mgea5 (also called O-GlcNAcase) were localized to the T-DMR in the orexin neurons. In non orexin-expressing cells, H3/H4 hypoacetylation and hyper-O-GlcNAc modification were observed at the T-DMRs occupied by O-GlcNAc transferase and Sirt1. Therefore, the results of the present study suggest that the glucose metabolite, ManNAc, induces switching from the inactive state by Ogt-Sirt1 to the active state by Mgea5, p300, and CBP at the Hcrt gene locus. PMID- 23625922 TI - Bifunctional lipocalin ameliorates murine immune complex-induced acute lung injury. AB - Molecules that simultaneously inhibit independent or co-dependent proinflammatory pathways may have advantages over conventional monotherapeutics. OmCI is a bifunctional protein derived from blood-feeding ticks that specifically prevents complement (C)-mediated C5 activation and also sequesters leukotriene B4 (LTB4) within an internal binding pocket. Here, we examined the effect of LTB4 binding on OmCI structure and function and investigated the relative importance of C mediated C5 activation and LTB4 in a mouse model of immune complex-induced acute lung injury (IC-ALI). We describe two crystal structures of bacterially expressed OmCI: one binding a C16 fatty acid and the other binding LTB4 (C20). We show that the C5 and LTB4 binding activities of the molecule are independent of each other and that OmCI is a potent inhibitor of experimental IC-ALI, equally dependent on both C5 inhibition and LTB4 binding for full activity. The data highlight the importance of LTB4 in IC-ALI and activation of C5 by the complement pathway C5 convertase rather than by non-C proteases. The findings suggest that dual inhibition of C5 and LTB4 may be useful for treatment of human immune complex dependent diseases. PMID- 23625923 TI - Tiered assembly of the yeast Far3-7-8-9-10-11 complex at the endoplasmic reticulum. AB - Target of rapamycin signaling is a conserved, essential pathway integrating nutritional cues with cell growth and proliferation. The target of rapamycin kinase exists in two distinct complexes, TORC1 and TORC2. It has been reported that protein phosphatase 2A (PP2A) and the Far3-7-8-9-10-11 complex (Far complex) negatively regulate TORC2 signaling in yeast. The Far complex, originally identified as factors required for pheromone-induced cell cycle arrest, and PP2A form the yeast counterpart of the STRIPAK complex, which was first isolated in mammals. The cellular localization of the Far complex has yet to be fully characterized. Here, we show that the Far complex localizes to the endoplasmic reticulum (ER) by analyzing functional GFP-tagged Far proteins in vivo. We found that Far9 and Far10, two homologous proteins each with a tail-anchor domain, localize to the ER in mutant cells lacking the other Far complex components. Far3, Far7, and Far8 form a subcomplex, which is recruited to the ER by Far9/10. The Far3-7-8- complex in turn recruits Far11 to the ER. Finally, we show that the tail-anchor domain of Far9 is required for its optimal function in TORC2 signaling. Our study reveals tiered assembly of the yeast Far complex at the ER and a function for Far complex's ER localization in TORC2 signaling. PMID- 23625924 TI - IgG1 thioether bond formation in vivo. AB - During either production or storage, the LC214-HC220 disulfide in therapeutic antibodies can convert to a thioether bond. Here we report that a thioether forms at the same position on antibodies in vivo. An IgG1kappa therapeutic antibody dosed in humans formed a thioether at this position at a rate of about 0.1%/day while circulating in blood. Thioether modifications were also found at this position in endogenous antibodies isolated from healthy human subjects, at levels consistent with this conversion rate. For both endogenous antibodies and recombinant antibodies studied in vivo, thioether conversion rates were faster for IgG1 antibodies containing lambda light chains than those containing kappa light chains. These light chain reaction rate differences were replicated in vitro. Additional mechanistic studies showed that base-catalyzed thioether formation through the light chain dehydrogenation was more preferred on antibodies with lambda light chains, which may help explain the observed reaction rate differences. PMID- 23625925 TI - Reduced immunosuppressive properties of axitinib in comparison with other tyrosine kinase inhibitors. AB - The multikinase inhibitors sunitinib, sorafenib, and axitinib have an impact not only on tumor growth and angiogenesis, but also on the activity and function of immune effector cells. In this study, a comparative analysis of the growth inhibitory properties and apoptosis induction potentials of tyrosine kinase inhibitors on T cells was performed. Tyrosine kinase inhibitor treatment resulted in a dramatic decrease in T cell proliferation along with distinct impacts on the cell cycle progression. This was at least partially associated with an enhanced induction of apoptosis although triggered by distinct apoptotic mechanisms. In contrast to sunitinib and sorafenib, axitinib did not affect the mitochondrial membrane potential (Deltapsim) but resulted in an induction or stabilization of the induced myeloid leukemia cell differentiation protein (Mcl-1), leading to an irreversible arrest in the G2/M cell cycle phase and delayed apoptosis. Furthermore, the sorafenib-mediated suppression of immune effector cells, in particular the reduction of the CD8(+) T cell subset along with the down regulation of key immune cell markers such as chemokine CC motif receptor 7 (CCR7), CD26, CD69, CD25, and CXCR3, was not observed in axitinib-treated immune effector cells. Therefore, axitinib rather than sorafenib seems to be suitable for implementation in complex treatment regimens of cancer patients including immunotherapy. PMID- 23625926 TI - Thermal stability of rhodopsin and progression of retinitis pigmentosa: comparison of S186W and D190N rhodopsin mutants. AB - Over 100 point mutations in the rhodopsin gene have been associated with retinitis pigmentosa (RP), a family of inherited visual disorders. Among these, we focused on characterizing the S186W mutation. We compared the thermal properties of the S186W mutant with another RP-causing mutant, D190N, and with WT rhodopsin. To assess thermal stability, we measured the rate of two thermal reactions contributing to the thermal decay of rhodopsin as follows: thermal isomerization of 11-cis-retinal and hydrolysis of the protonated Schiff base linkage between the 11-cis-retinal chromophore and opsin protein. We used UV visible spectroscopy and HPLC to examine the kinetics of these reactions at 37 and 55 degrees C for WT and mutant rhodopsin purified from HEK293 cells. Compared with WT rhodopsin and the D190N mutant, the S186W mutation dramatically increases the rates of both thermal isomerization and dark state hydrolysis of the Schiff base by 1-2 orders of magnitude. The results suggest that the S186W mutant thermally destabilizes rhodopsin by disrupting a hydrogen bond network at the receptor's active site. The decrease in the thermal stability of dark state rhodopsin is likely to be associated with higher levels of dark noise that undermine the sensitivity of rhodopsin, potentially accounting for night blindness in the early stages of RP. Further studies of the thermal stability of additional pathogenic rhodopsin mutations in conjunction with clinical studies are expected to provide insight into the molecular mechanism of RP and test the correlation between rhodopsin's thermal stability and RP progression in patients. PMID- 23625927 TI - WDR26 functions as a scaffolding protein to promote Gbetagamma-mediated phospholipase C beta2 (PLCbeta2) activation in leukocytes. AB - We have recently identified WDR26 as a novel WD40 repeat protein that binds Gbetagamma and promotes Gbetagamma signaling during leukocyte migration. Here, we have determined the mechanism by which WDR26 enhances Gbetagamma-mediated phospholipase C beta2 (PLCbeta2) activation in leukocytes. We show that WDR26 not only directly bound Gbetagamma but also PLCbeta2. The binding sites of WDR26 and PLCbeta2 on Gbeta1gamma2 were overlapping but not identical. WDR26 used the same domains for binding Gbetagamma and PLCbeta but still formed a signaling complex with Gbetagamma and PLCbeta2 probably due to the fact that WDR26 formed a higher order oligomer through its Lis homology and C-terminal to LisH (LisH-CTLH) and WD40 domains. Additional studies indicated that the formation of higher order oligomers was required for WDR26 to promote PLCbeta2 interaction with and activation by Gbetagamma. Moreover, WDR26 was required for PLCbeta2 translocation from the cytosol to the membrane in polarized leukocytes, and the translocation of PLCbeta2 was sufficient to cause partial activation of PLCbeta2. Collectively, our data indicate that WDR26 functions as a scaffolding protein to promote PLCbeta2 membrane translocation and interaction with Gbetagamma, thereby enhancing PLCbeta2 activation in leukocytes. These findings have identified a novel mechanism of regulating Gbetagamma signaling through a scaffolding protein. PMID- 23625928 TI - JosD1, a membrane-targeted deubiquitinating enzyme, is activated by ubiquitination and regulates membrane dynamics, cell motility, and endocytosis. AB - The functional diversity of deubiquitinating enzymes (DUBs) is not well understood. The MJD family of DUBs consists of four cysteine proteases that share a catalytic "Josephin" domain. The family is named after the DUB ATXN3, which causes the neurodegenerative disease Machado-Joseph disease. The two closely related Josephin domain-containing (JosD) proteins 1 and 2 consist of little more than the Josephin domain. To gain insight into the properties of Josephin domains, we investigated JosD1 and JosD2. JosD1 and JosD2 were found to differ fundamentally in many respects. In vitro, only JosD2 can cleave ubiquitin chains. In contrast, JosD1 cleaves ubiquitin chains only after it is monoubiquitinated, a form of posttranslational-dependent regulation shared with ATXN3. A significant fraction of JosD1 is monoubiquitinated in diverse mouse tissues. In cell-based studies, JosD2 localizes to the cytoplasm whereas JosD1 preferentially localizes to the plasma membrane, particularly when ubiquitinated. The membrane occupancy by JosD1 suggests that it could participate in membrane-dependent events such as cell motility and endocytosis. Indeed, time-lapse imaging revealed that JosD1 enhances membrane dynamics and cell motility. JosD1 also influences endocytosis in cultured cells by increasing the uptake of endocytic markers of macropinocytosis while decreasing those for clathrin- and caveolae-mediated endocytosis. Our results establish that two closely related DUBs differ markedly in activity and function and that JosD1, a membrane-associated DUB whose activity is regulated by ubiquitination, helps regulate membrane dynamics, cell motility, and endocytosis. PMID- 23625929 TI - Engineering A-kinase anchoring protein (AKAP)-selective regulatory subunits of protein kinase A (PKA) through structure-based phage selection. AB - PKA is retained within distinct subcellular environments by the association of its regulatory type II (RII) subunits with A-kinase anchoring proteins (AKAPs). Conventional reagents that universally disrupt PKA anchoring are patterned after a conserved AKAP motif. We introduce a phage selection procedure that exploits high-resolution structural information to engineer RII mutants that are selective for a particular AKAP. Selective RII (RSelect) sequences were obtained for eight AKAPs following competitive selection screening. Biochemical and cell-based experiments validated the efficacy of RSelect proteins for AKAP2 and AKAP18. These engineered proteins represent a new class of reagents that can be used to dissect the contributions of different AKAP-targeted pools of PKA. Molecular modeling and high-throughput sequencing analyses revealed the molecular basis of AKAP-selective interactions and shed new light on native RII-AKAP interactions. We propose that this structure-directed evolution strategy might be generally applicable for the investigation of other protein interaction surfaces. PMID- 23625931 TI - Complementary and alternative medicine utilization in Texas hospices: prevalence, importance, and challenges. AB - The purpose of this study was to describe the prevalence, importance, and challenges of complementary and alternative medicine (CAM) utilization in Texas hospices. Mail surveys were sent to 369 hospices in Texas, and 110 useful surveys were returned. Results showed that a majority (n = 62, 56.4%) of hospices offer CAM to their clients, with the most popularly offered CAMs being massage, music, and relaxation therapies. Despite the availability of CAM services in most hospices, and that the utilization of CAM has the potential to improve overall quality of life of patients, our results showed that a sizeable proportion of patients in these hospices are not utilizing the provided CAMs. Funding and personnel constraints were substantial obstacles to offering CAM. PMID- 23625930 TI - Identification of the beta-lactamase inhibitor protein-II (BLIP-II) interface residues essential for binding affinity and specificity for class A beta lactamases. AB - The interactions between beta-lactamase inhibitory proteins (BLIPs) and beta lactamases have been used as model systems to understand the principles of affinity and specificity in protein-protein interactions. The most extensively studied tight binding inhibitor, BLIP, has been characterized with respect to amino acid determinants of affinity and specificity for binding beta-lactamases. BLIP-II, however, shares no sequence or structural homology to BLIP and is a femtomolar to picomolar potency inhibitor, and the amino acid determinants of binding affinity and specificity are unknown. In this study, alanine scanning mutagenesis was used in combination with determinations of on and off rates for each mutant to define the contribution of residues on the BLIP-II binding surface to both affinity and specificity toward four beta-lactamases of diverse sequence. The residues making the largest contribution to binding energy are heavily biased toward aromatic amino acids near the center of the binding surface. In addition, substitutions that reduce binding energy do so by increasing off rates without impacting on rates. Also, residues with large contributions to binding energy generally exhibit low temperature factors in the structures of complexes. Finally, with the exception of D206A, BLIP-II alanine substitutions exhibit a similar trend of effect for all beta-lactamases, i.e., a substitution that reduces affinity for one beta-lactamase usually reduces affinity for all beta lactamases tested. PMID- 23625932 TI - Completion of advance directives among low-income older adults: does race/ethnicity matter? AB - This study examined the prevalence of completion of advance directives (ADs) and the effects of race/ethnicity on AD completion using a cross-sectional design. Low-income older adults (n = 256) who were residents of supportive housing facilities or members of a senior center were interviewed in person. About 20% of the participants had completed ADs. Knowledge and attitudes toward ADs, income, and previous experience in an intensive care unit significantly predicted the completion of ADs after controlling for other factors. Those with higher levels of knowledge, positive attitudes, or those with higher incomes were more likely to complete ADs than their counterparts. Findings suggest that as a proxy for multiple socioeconomic, social and cultural factors, race, and ethnicity need to be considered in planning end-of-life care. PMID- 23625933 TI - Psychiatrists and GPs: diagnostic decision making, personality profiles and attitudes toward depression and anxiety. AB - OBJECTIVES: The objective of this article is to explore diagnostic decision making around psychological symptoms presenting to general practitioners (GPs) and psychiatrists, identify attitudinal and personality factors of possible relevance in these decisions, and compare GPs and psychiatrists to help identify potential educational targets. METHODS: GPs and psychiatrists attended separate peer-facilitated workshops in which two case presentations were discussed. Decision making was explored by structured questions embedded in the workshop, with responses recorded by electronic keypad technology. Participants completed demographic questionnaires and measures of personality and attitudes to depression. RESULTS: GPs and psychiatrists accorded emphasis to different elements of the history, and assigned different diagnoses based on the same set of symptoms. Both groups relied on non-pharmacological management for milder psychological symptoms; GPs were less likely to make a diagnosis of bipolar disorder. Traits of Extraversion and Agreeableness were associated with greater ease in treating depression. CONCLUSIONS: Differences in diagnostic decision making likely reflect the different contexts of specialist and generalist practice. Educational targets may include information about key symptoms to assist in diagnostic precision, but further information is needed to determine the best match between diagnostic processes, context and outcome. An awareness of the role of personality factors may help when designing education and support programs. PMID- 23625934 TI - Escaping the behavioural 'spin' of evidence-based psychiatry: Merleau-Ponty's ontology of truth. AB - OBJECTIVE: To explore the limitations of the concept of 'truth' in the ontology of evidence-based psychiatry and to provide expanded ontological foundations for psychiatric practice based instead on the ontology of the French existential phenomenologist, Maurice Merleau-Ponty. CONCLUSIONS: Evidence-based medicine is founded on a 'scientific' ontology of 'causality', which equates 'truth' with effecting statistically-significant changes in objective measures of disease by a specified treatment. Because of the absence of biological markers of disease in psychiatry, evidence-based psychiatry equates 'truth' with effecting changes in observable psychometric measures of behaviour. This is the same ontology underlying marketing 'spin' and all attempts to effect pre-determined behavioural change. In contrast, Merleau-Ponty's ontology rejects causality and mind/body duality, and views 'truth' as the expression of our deepest embodied feeling and perception of the world, which establishes all our thinking, and on which all our thinking relies, including 'scientific' thinking. Merleau-Ponty's ontology is therefore a preferable foundation for psychiatric practice, because it allows psychiatrists to consider the 'truth' of clinically important, but non measurable, aspects of psychiatry while not excluding 'scientific' thinking, but recognising its limitations and potential for misuse. PMID- 23625936 TI - Reply to Gonzalez-Serna et al. PMID- 23625935 TI - Small-molecule inhibitors of acetyltransferase p300 identified by high-throughput screening are potent anticancer agents. AB - Acetyltransferase p300 (KAT3B) plays key roles in signaling cascades that support cancer cell survival and sustained proliferation. Thus, p300 represents a potential anticancer therapeutic target. To discover novel anticancer agents that target p300, we conducted a high-throughput screening campaign. A library of 622,079 compounds was assayed for cytotoxicity to the triple-negative breast cancer (TNBC) cell line MDA-MB-231 but not to the human mammary epithelial cells. The resulting compounds were tested in a biochemical assay for inhibiting the enzymatic activity of p300. One compound (L002, NSC764414) displayed an IC50 of 1.98 MUmol/L against p300 in vitro, inhibited acetylation of histones and p53, and suppressed STAT3 activation in cell-based assays. L002 could be docked to the active site of the p300 catalytic domain. Biochemical tests of a series of related compounds revealed functional groups that may impact inhibitory potency of L002 against p300. Interestingly, these analogs showed inhibitory activities against the cellular paralog of p300 (CBP), p300/CBP-associated factor, and GCN5, but not to other acetyltransferases (KAT5, KAT6B, and KAT7), histone deacetylases, and histone methyltransferases. Among the NCI-60 panel of cancer cell lines, leukemia and lymphoma cell lines were extremely sensitive to L002, whereas it is toxic to only a limited number of cell lines derived from solid tumors. Notably, breast cancer cell lines, especially those derived from TNBC, were highly susceptible to L002. In vivo, it potently suppressed tumor growth and histone acetylation of MDA-MB-468 xenografts. Thus, these new acetyltransferase inhibitors are potential anticancer therapeutics. PMID- 23625937 TI - "Test-and-treat" strategy for control of HIV and AIDS can lead to a decrease, not an increase, of multidrug-resistant viruses. PMID- 23625940 TI - Health technology assessment on catheter ablation of atrial fibrillation in Belgium. PMID- 23625939 TI - Critical role of hyaluronidase-2 during preimplantation embryo development. AB - Biological functions of hyaluronan (HA) depend on its molecular size. Small size HAs are known to regulate cell proliferation; however, the expression of HA synthases (HASs) and hyaluronidase-2 (HYAL2) and their role during early embryo development have not been previously identified. In this paper, we have shown by immunostaining that HA is produced by bovine in vitro-produced embryos at all stages of early development to blastocyst. Addition of HA-synthesis inhibitor (4 methylumbelliferone; 4MU) to in vitro embryo culture inhibited blastocyst formation. HASs HAS2 and HAS3 mRNA were expressed at all stages of embryo development; however, relative mRNA expression of HAS2 was significantly reduced as the embryos develop to the blastocyst stage. HAS1 was detected during 2- and 4 cell stages but was barely detectable in subsequent stages. HYAL2 mRNA expression was detected in oviducts at the early luteal phase but was only detected in the embryos at morula and blastocyst stages (Day 6 and 7 post-fertilization). Addition of HYAL2 to embryo culture media at Day 2 post-fertilization increased phosphorylated mitogen-activated protein kinases (MAPK1 and 3) in the embryos and improved development to the blastocyst stage and increased embryo cell numbers. Addition of an anti-CD44 antibody or an MAPK inhibitor (U0126) abrogated the positive effects of HYAL2 on blastocyst rates. In conclusion, we demonstrate that the expression of different HAS genes and HYAL2 in bovine embryos varies according to the stage of development and that the supplementation of HYAL2 in vitro mimics oviductal conditions and is shown to improve the blastocyst rate and embryo quality, an effect which requires CD44 activity and MAPK signalling. PMID- 23625938 TI - Staphylococcus aureus small-colony variants are independently associated with worse lung disease in children with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) lung disease is associated with diverse bacteria chronically infecting the airways. Slow-growing, antibiotic-resistant mutants of Staphylococcus aureus known as small-colony variants (SCVs) have been isolated from respiratory secretions from European adults and children with CF lung disease using specific but infrequently used culture techniques. Staphylococcus aureus SCVs can be selected either by exposure to specific antibiotics or by growth with another CF pathogen, Pseudomonas aeruginosa. We sought to determine the prevalence, clinical significance, and likely mechanisms of selection of S. aureus SCVs among a US cohort of children with CF. METHODS: We performed a 2-year study of 100 children with CF using culture techniques sensitive for S. aureus SCVs, and evaluated associations with clinical characteristics using multivariable regression models. RESULTS: Staphylococcus aureus SCV infection was detected among 24% of participants and was significantly associated with a greater drop in lung function during the study (P = .007, adjusted for age and lung function at enrollment). This association persisted after adjusting for infection with other known CF pathogens, including P. aeruginosa and methicillin resistant S. aureus. Evidence indicated that S. aureus SCVs were likely selected in vivo by treatment with the antibiotic trimethoprim-sulfamethoxazole and possibly by coinfection with P. aeruginosa. CONCLUSIONS: Infection with SCV S. aureus was independently associated with worse CF respiratory outcomes in this pediatric cohort. As many clinical microbiology laboratories do not specifically detect S. aureus SCVs, validation and extension of these findings would require widespread changes in the usual laboratory and clinical approaches to these bacteria. PMID- 23625941 TI - Impact of energy titration in endoscopic pulmonary vein isolation. PMID- 23625942 TI - European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. AB - New oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with non-valvular atrial fibrillation (AF). Both physicians and patients will have to learn how to use these drugs effectively and safely in clinical practice. Many unresolved questions on how to optimally use these drugs in specific clinical situations remain. The European Heart Rhythm Association set out to coordinate a unified way of informing physicians on the use of the different NOACs. A writing group listed 15 topics of concrete clinical scenarios and formulated as practical answers as possible based on available evidence. The 15 topics are: (1) Practical start-up and follow-up scheme for patients on NOACs; (2) How to measure the anticoagulant effect of NOACs; (3) Drug-drug interactions and pharmacokinetics of NOACs; (4) Switching between anticoagulant regimens; (5) Ensuring compliance of NOAC intake; (6) How to deal with dosing errors; (7) Patients with chronic kidney disease; (8) What to do if there is a (suspected) overdose without bleeding, or a clotting test is indicating a risk of bleeding? (9) Management of bleeding complications; (10) Patients undergoing a planned surgical intervention or ablation; (11) Patients undergoing an urgent surgical intervention; (12) Patients with AF and coronary artery disease; (13) Cardioversion in a NOAC-treated patient; (14) Patients presenting with acute stroke while on NOACs; (15) NOACs vs. VKAs in AF patients with a malignancy. Since new information is becoming available at a rapid pace, an EHRA Web site with the latest updated information accompanies this text (www.NOACforAF.eu). PMID- 23625943 TI - An update and current expert opinions on percutaneous left atrial appendage occlusion for stroke prevention in atrial fibrillation. AB - Oral anticoagulation (OAC) remains the mainstream therapy for ischaemic stroke prevention in patients with atrial fibrillation (AF). However, for patients contraindicated to OAC and those who experienced a stroke while on therapeutic OAC, no reasonable pharmacotherapy is available. Although surgical left atrial appendage (LAA) excision offers a non-pharmacological alternative, effective stroke prevention by this treatment is not demonstrated by randomized clinical studies. Percutaneous occlusion of the LAA may be an alternative therapy for selected AF patients. Recently reported results confirm the technical feasibility of this technique and its effectiveness in preventing ischaemic stroke. With increasing operator experience, successful and event-free device implantation is achieved in typically 97% of the cases. Moreover, in non-randomized cohorts implanted with LAA occlusion devices, stroke rates are markedly reduced compared with rates predicted by risk stratification schemes such as CHADS2 and CHA2DS2 VASc. This paper summarizes recently published results from clinical studies on percutaneous LAA occlusion and current expert opinions with respect to patients who may be suitable for this therapy. In addition, several aspects regarding the safety of device implantation for LAA occlusion and follow-up of patients are discussed. PMID- 23625944 TI - Current strategy for treatment of patients with Wolff-Parkinson-White syndrome and asymptomatic preexcitation in Europe: European Heart Rhythm Association survey. AB - The aims of this survey was to provide insight into treatment activity, the strategy of treatment, and risk stratification of patients with asymptomatic and symptomatic ventricular pre-excitation across Europe. Fifty-eight centres, members of the European Heart Rhythm Association EP research network, covering 20 countries answered the survey questions. All centres were high-volume ablation centres. A younger person with asymptomatic Wolff-Parkinson-White (WPW) pattern has a higher likelihood of being risk-stratified or receiving ablation therapy compared with an older subject. Two-thirds of centres report that they have observed a decline in the number of patients ablated for an accessory pathway during the last 10 years. Pre-excited atrial fibrillation is rarely seen. Discontinuation of a scheduled WPW ablation due to close vicinity of the accessory pathway to the AV node happens very rarely. Patients with a first episode of pre-excited atrial fibrillation would immediately be referred for catheter ablation to be performed within weeks by 80.4% of the centres. A significant proportion of responders (50.9%) would use electrical cardioversion to restore sinus rhythm in a patient with pre-excited atrial fibrillation. With respect to the choice of antiarrhythmic medication for a patient with pre-excited AF, the majority (80.0%) would choose class 1C antiarrhytmic drugs while waiting for a catheter ablation. A patient seen in the emergency room with a second episode of orthodromic atrioventricular reentry tachycardia would be referred for immediate ablation by 79.2-90.6% of centres depending on the presence of pre excitation. The volume of paediatric ablations performed on children younger than 12 years was low (46.4%: 0 patients per year; 46.4%: 1-9 patients per year). The majority of responding centres (61-69%) report that their country lack national guidelines dealing with clinical strategies related to WPW. There is a need for national guidelines dealing with clinical strategy in patients with WPW syndrome. Older individuals with asymptomatic WPW pattern have a higher risk of not receiving risk stratification or curative therapy with ablation compared with younger patients, despite the higher risk of developing atrial fibrillation. PMID- 23625945 TI - Clinical benefit of eplerenone in patients with mild symptoms of systolic heart failure already receiving optimal best practice background drug therapy: analysis of the EMPHASIS-HF study. AB - BACKGROUND: In EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), eplerenone significantly reduced major cardiovascular events versus placebo in 2737 patients with mild symptoms of heart failure and an ejection fraction of <35%, in addition to recommended therapy. However, it is not known whether such benefits were preserved in patients receiving optimal background drug therapy, that is, high doses of angiotensin converting enzyme inhibitor (ACEi, or angiotensin receptor blocker), beta blocker, or both drug classes. METHODS AND RESULTS: We further analyzed EMPHASIS HF according to the use and dose of these background drug classes. Patients receiving >= 50% of target dose were considered to be receiving high doses; patients on <50% or no drug comprised the low-dose group. The primary end point of the study (cardiovascular death/heart failure hospitalization), as well as all cause mortality, was evaluated in this way. The beneficial clinical effects of eplerenone (as observed in the main study) were preserved for the EMPHASIS-HF primary end point in patients receiving higher doses of ACEi or angiotensin receptor blocker, beta-blocker, or both (hazard ratio for eplerenone versus placebo, ACEi/angiotensin receptor blocker: high dose, 0.67; low dose, 0.65; beta blockers: high dose, 0.55; low dose, 0.72; both ACEi/angiotensin receptor blocker and beta-blocker: high dose, 0.59; low dose, 0.68; P value for interaction 0.80, 0.15, and 0.53, respectively), as well as for all-cause mortality. There were no major safety issues, except a borderline increased risk of hypotension with eplerenone in those on high-dose ACEi or ACEi/beta-blocker. CONCLUSIONS: Eplerenone provides substantial benefit on major events (with an acceptable safety profile) in patients with mild symptoms of systolic heart failure, even in those already receiving high doses of standard background therapies. PMID- 23625946 TI - Physical health status measures predict all-cause mortality in patients with heart failure. AB - BACKGROUND: Physical health status measures have been shown to predict death in heart failure (HF); however, few studies found significant associations after adjustment for confounders, and most were not representative of all HF patients. METHODS AND RESULTS: HF patients from southeastern MN were prospectively enrolled between 10/2007 and 12/2010, completed a 12-item Short Form Health Survey (SF-12) and a 6-minute walk, and were followed through 2011 for death from any cause. Scores <= 25 on the SF-12 physical component indicated low self-reported physical functioning, and the first question of the SF-12 measured self-rated general health. Low functional exercise capacity was defined as <= 300 m walked during a 6-minute walk. Over a mean follow-up of 2.3 years, 86 deaths occurred among the 352 participants. A 1.6-fold (95% confidence interval, 1.0-2.7) and 1.8-fold (95% confidence interval, 1.1-2.9) increased risk of death was observed among patients with low self-reported physical functioning and low functional exercise capacity, respectively. Poor self-rated general health corresponded to a 2.7-fold (95% confidence interval, 1.5-4.9) increased risk of death compared with good to excellent general health. All measures equally discriminated between who would die and who would survive (C-statistics: 0.729, 0.750, and 0.740 for self reported physical functioning, self-rated general health, and functional exercise capacity, respectively). CONCLUSIONS: Three physical health status measures, captured by the SF-12 and a 6-minute walk, equally predict death among community HF patients. Therefore, the first question of the SF-12, which is the least burdensome to administer, may be sufficient to identify HF patients at greatest risk of death. PMID- 23625948 TI - The nuclear factor kappaB family member RelB facilitates apoptosis of renal epithelial cells caused by cisplatin/tumor necrosis factor alpha synergy by suppressing an epithelial to mesenchymal transition-like phenotypic switch. AB - Cis-diamminedichloroplatinum(II) (cisplatin)-induced renal proximal tubular apoptosis is known to be preceded by actin cytoskeleton reorganization, in conjunction with disruption of cell-matrix and cell-cell adhesion. In the present study, we show that the proinflammatory cytokine tumor necrosis factor alpha (TNF alpha) aggravated these cisplatin-induced F-actin and cell adhesion changes, which was associated with enhanced cisplatin-induced apoptosis of immortalized proximal tubular epithelial cells. TNF-alpha-induced RelB expression and lentiviral small hairpin RNA (shRNA)-mediated knockdown of RelB, but not other nuclear factor kappaB members, abrogated the synergistic apoptosis observed with cisplatin/TNF-alpha treatment to the level of cisplatin-induced apoptosis. This protective effect was associated with increased stress fiber formation, cell matrix, and cell-cell adhesion in the shRNARelB (shRelB) cells during cisplatin/TNF-alpha treatment, mimicking an epithelial-to-mesenchymal phenotypic switch. Indeed, gene array analysis revealed that knockdown of RelB was associated with upregulation of several actin regulatory genes, including Snai2 and the Rho GTPase proteins Rhophilin and Rho guanine nucleotide exchange factor 3 (ARHGEF3). Pharmacological inhibition of Rho kinase signaling re-established the synergistic apoptosis induced by combined cisplatin/TNF-alpha treatment of shRelB cells. In conclusion, our study shows for the first time that RelB is required for the cisplatin/TNF-alpha-induced cytoskeletal reorganization and apoptosis in renal cells by controlling a Rho kinase-dependent signaling network. PMID- 23625947 TI - Structural determinants of agonist efficacy at the glutamate binding site of N methyl-D-aspartate receptors. AB - N-methyl-d-aspartate (NMDA) receptors are ligand-gated ion channels assembled from GluN1 and GluN2 subunits. We used a series of N-hydroxypyrazole-5-glycine (NHP5G) partial agonists at the GluN2 glutamate binding site as tools to study activation of GluN1/GluN2A and GluN1/GluN2D NMDA receptor subtypes. Using two electrode voltage-clamp electrophysiology, fast-application patch-clamp, and single-channel recordings, we show that propyl- and ethyl-substituted NHP5G agonists have a broad range of agonist efficacies relative to the full agonist glutamate (<1-72%). Crystal structures of the agonist binding domains (ABDs) of GluN2A and GluN2D do not reveal any differences in the overall domain conformation induced by binding of the full agonist glutamate or the partial agonist propyl-NHP5G, which is strikingly different from ABD structures of 2 amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoate (AMPA) and kainate receptors bound to full and partial agonists. Subsequent evaluation of relative NHP5G agonist efficacy at GluN2A-GluN2D chimeric subunits implicates the amino-terminal domain (ATD) as a strong determinant of agonist efficacy, suggesting that interdomain interactions between the ABD and the ATD may be a central element in controlling the manner by which agonist binding leads to channel opening. We propose that variation in the overall receptor conformation, which is strongly influenced by the nature of interdomain interactions in resting and active states, mediates differences in agonist efficacy and partial agonism at the GluN2 subunits. PMID- 23625949 TI - Response to Pomozi et al's research commentary. PMID- 23625950 TI - Regulation of cardiac microRNAs by cardiac microRNAs. AB - RATIONALE: MicroRNAs modestly suppress their direct mRNA targets, and these direct effects are amplified by modulation of gene transcription pathways. Consequently, indirect mRNA modulatory effects of microRNAs to increase or decrease mRNAs greatly outnumber direct target suppressions. Because microRNAs are products of transcription, the potential exists for microRNAs that regulate transcription to regulate other microRNAs. OBJECTIVE: Determine whether cardiac expressed microRNAs regulate expression of other cardiac microRNAs, and measure the impact of microRNA-mediated microRNA regulation on indirect regulation of nontarget mRNAs. METHODS AND RESULTS: Transgenic expression of pre-microRNAs was used to generate mouse hearts expressing 6- to 16-fold normal levels of microRNA (miR)-143, miR-378, and miR-499. Genome-wide mRNA and microRNA signatures were established using deep sequencing; expression profiles provoked by each microRNA were defined. miR-143 suppressed its direct cardiac mRNA target hexokinase 2, but exhibited little indirect target regulation and did not regulate other cardiac microRNAs. Both miR-378 and miR-499 indirectly regulated hundreds of cardiac mRNAs and 15 to 30 cardiac microRNAs. MicroRNA overexpression did not alter normal processing of either transgenic or endogenous cardiac microRNAs, and microRNA-mediated regulation of other microRNAs encoded within parent genes occurred in tandem with parent mRNAs. MicroRNA regulation by miR-378 and miR-499 was stimulus specific, and contributed to observed mRNA downregulation. CONCLUSIONS: MicroRNAs that modulate cardiac transcription can indirectly regulate other microRNAs. Transcriptional modulation by microRNAs, and microRNA mediated microRNA regulation, help explain how small direct effects of microRNAs are amplified to generate striking phenotypes. PMID- 23625952 TI - Primary school teachers' attitudes about children with attention deficit/hyperactivity disorder and the role of pharmacological treatment. AB - BACKGROUND: Clinical experience and research suggest that teachers' attitudes about attention deficit/hyperactivity disorder (ADHD) are an important factor influencing access to specialist assessment and treatment, including medication. METHODS: We performed a thematic analysis of comments written by primary school teachers who participated in a case-vignette study investigating the ability of teachers to recognise ADHD. Teachers read one of four types of vignette describing the behaviour of a nine-year-old child who met diagnostic criteria for ADHD (either a boy or a girl with inattentive or combined subtype of ADHD). They answered questions (identical for all types of vignette) about their views regarding the problems and their management. Teachers were invited to add their own comments. RESULTS: Altogether 496 teachers from 110 schools completed the questionnaire: 250 (50%) teachers from 94 schools wrote at least one comment, adding up to 341 comments. Regarding their views on the need to refer the child to specialist services, 32 teachers made comments that reflected caution. The most frequent comments were that it was too early to say whether a referral was necessary, the problems were not severe enough or the main support would come from school. Teachers also reported a lack of knowledge about specialist services or criticised them. When asked whether medication might be beneficial for the child, 125 teachers expressed hesitant or negative views: that it was premature to express an opinion about medication or too soon to give medication to the child; that medication was not necessary or should not be used at all; or that the problems were not severe enough or were emotional in nature. Only five teachers reported having a positive experience of the effect of medication. CONCLUSION: Teachers' comments suggested a strong preference in using within school strategies for the management of children with ADHD. Teachers were reluctant to endorse medication for DHD and expressed negative views about its use. Health services should support teachers' management of ADHD-related behaviours in school and provide information to increase teachers' ability to identify the need for a referral to specialist health services. PMID- 23625951 TI - ABCC6 is a basolateral plasma membrane protein. AB - RATIONALE: ABCC6 plays a crucial role in ectopic calcification; mutations of the gene cause pseudoxanthoma elasticum and general arterial calcification of infancy. To elucidate the role of ABCC6 in cellular physiology and disease, it is crucial to establish the exact subcellular localization of the native ABCC6 protein. OBJECTIVE: In a recent article in Circulation Research, ABCC6 was reported to localize to the mitochondria-associated membrane and not the plasma membrane. As the suggested mitochondrial localization is inconsistent with published data and the presumed role of ABCC6, we performed experiments to determine the cellular localization of ABCC6 in its physiological environment. METHODS AND RESULTS: We performed immunofluorescent labeling of frozen mouse and human liver sections, as well as primary hepatocytes. We used several different antibodies recognizing human and mouse ABCC6. Our results unequivocally show that ABCC6 is in the basolateral membrane of hepatocytes and is not associated with the mitochondria, mitochondria-associated membrane, or the endoplasmic reticulum. CONCLUSIONS: Our findings support the model that ABCC6 is in the basolateral membrane, mediating the sinusoidal efflux of a metabolite from the hepatocytes to systemic circulation. PMID- 23625953 TI - Cardiorespiratory coupling of sympathetic outflow in humans: a comparison of respiratory and cardiac modulation of sympathetic nerve activity to skin and muscle. AB - NEW FINDINGS: What is the central question of this study?Muscle sympathetic nerve activity (MSNA) is well known to be modulated by the arterial baroreceptors and respiration, but what are the magnitudes of cardiac and respiratory modulation of skin sympathetic nerve activity (SSNA), which primarily subserves thermoregulation?What is the main finding and what is its importance?Using direct microelectrode recordings of MSNA and SSNA in awake humans, we show that the magnitude of respiratory modulation of SSNA is identical to that of MSNA, the primary difference between the two sources of sympathetic outflow being the greater cardiac modulation of MSNA. This emphasises the role of the baroreceptors in entraining sympathetic outflow to muscle. It is well known that microelectrode recordings of skin sympathetic nerve activity (SSNA) in awake human subjects reveal spontaneous bursts of activity with no overt modulation by changes in blood pressure or respiration, in contrast to the clear cardiac and respiratory modulation of muscle sympathetic nerve activity (MSNA). However, cross correlation analysis has revealed that, like individual muscle vasoconstrictor neurones, the firing of individual cutaneous vasoconstrictor neurones is temporally coupled to both the cardiac and respiratory rhythms during cold induced cutaneous vasoconstriction, and the same is true of single sudomotor neurones during heat-induced sweating. Here, we used cross-correlation analysis to determine whether SSNA exhibits cardiac and respiratory modulation in thermoneutral conditions and to compare respiratory and cardiac modulation of SSNA with that of MSNA. Oligounitary recordings of spontaneous SSNA (n = 20) and MSNA (n = 18) were obtained during quiet, unrestrained breathing. Respiration was recorded by a strain-gauge transducer around the chest and ECG recorded by surface electrodes. Respiratory and cardiac modulation of SSNA and MSNA were quantified by fitting polynomial equations to the cross-correlation histograms constructed between the sympathetic spikes and respiration or ECG. The amplitude of the respiratory modulation (52.5 +/- 3.4%) of SSNA was not significantly different from the amplitude of the cardiac modulation (46.6 +/- 3.2%). Both were comparable to the respiratory modulation of MSNA (47.7 +/- 4.2%), while cardiac modulation of MSNA was significantly higher (89.8 +/- 1.5%). We conclude that SSNA and MSNA share similar levels of respiratory modulation, the primary difference between the two sources of sympathetic outflow being the marked cardiac modulation of MSNA provided by the baroreceptors. PMID- 23625954 TI - Mitochondrial dysfunction and therapeutic approaches in respiratory and limb muscles of cancer cachectic mice. AB - NEW FINDINGS: What is the central question of this study? We explored whether experimental cancer-induced cachexia may alter mitochondrial respiratory chain (MRC) complexes and oxygen uptake in respiratory and peripheral muscles,and whether signalling pathways, proteasome and oxidative stress influence that process. What is the main finding and what is its importance? In cancer cachectic mice, MRC complexes and oxygen consumption were decreased in the diaphragm and gastrocnemius. Blockade of nuclear factor-kappaB and mitogen-activated protein kinase actions partly restored the muscle mass and force and corrected the MRC dysfunction,while concomitantly reducing tumour burden. Antioxidants improved mitochondrial oxygen consumption without eliciting effects on the loss of muscle mass and force or the tumour size,whereas bortezomib reduced tumour burden without influencing muscle mass and strength or MRC function. Abnormalities in mitochondrial content, morphology and function have been reported in several muscle-wasting conditions. We specifically explored whether experimental cancer induced cachexia may alter mitochondrial respiratory chain (MRC) complexes and oxygen uptake in respiratory and peripheral muscles, and whether signalling pathways, proteasomes and oxidative stress may influence that process. We evaluated complex I, II and IV enzyme activities (specific activity assays) and MRC oxygen consumption (polarographic measurements) in diaphragm and gastrocnemius of cachectic mice bearing the LP07 lung tumour, with and without treatment with N-acetylcysteine, bortezomib and nuclear factor-kappaB (sulfasalazine) and mitogen-activated protein kinases (MAPK, U0126) inhibitors (n = 10 per group for all groups). Whole-body and muscle weights and limb muscle force were also assessed in all rodents at baseline and after 1 month. Compared with control animals, cancer cachectic mice showed a significant reduction in body weight gain, smaller sizes of the diaphragm and gastrocnemius, lower muscle strength, decreased activity of complexes I, II and IV and decreased oxygen consumption in both muscles. Blockade of nuclear factor-kappaB and MAPK actions restored muscle mass and force and corrected the MRC dysfunction in both muscles, while partly reducing tumour burden. Antioxidants improved mitochondrial oxygen uptake without eliciting significant effects on the loss of muscle mass and force or tumour size, whereas the proteasome inhibitor reduced tumour burden without significantly influencing muscle mass and strength or mitochondrial function. In conclusion, nuclear factor-kappaB and MAPK signalling pathways modulate muscle mass and performance and MRC function of respiratory and limb muscles in this model of experimental cancer cachexia, thus offering targets for therapeutic intervention. PMID- 23625955 TI - The influence of gender on the development of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a progressive disease in which increased pulmonary arterial pressure and remodelling eventually lead to right heart failure and death. Idiopathic and familial PAH occur far more frequently in women than in men. Historically, investigations into this gender bias have been impeded because female gender and oestrogens paradoxically protect against PAH in commonly used rodent models. However, recent descriptions of female gender specific murine models of PAH have led to an increased understanding of the role of oestrogens in disease development. Specifically, oestrogen metabolism has been highlighted as playing an important role in disease development, and the oestrogen-metabolizing enzyme CYP1B1 may represent a novel therapeutic target. In addition, emerging evidence suggests that sex hormones may have direct effects on the right ventricle independent of haemodynamic effects. This review discusses our current understanding of the role of sex hormones in the development of PAH. PMID- 23625956 TI - Pulmonary hypertension and the right ventricle in hypoxia. AB - Hypoxia causes pulmonary vasoconstriction. Regional hypoxic vasoconstriction improves the matching of perfusion to alveolar ventilation. Global hypoxic vasoconstriction increases right ventricular afterload. The hypoxic pulmonary pressor response is universal in mammals and in birds, but with considerable interspecies and interindividual variability. Chronic hypoxia induces pulmonary hypertension in proportion to initial vasoconstriction. Prolonged hypoxic exposure is also associated with an increase in red blood cell mass, which aggravates pulmonary hypertension by an increase in blood viscosity. Hypoxic pulmonary hypertension in humans is usually mild to moderate, but pulmonary vascular pressure-flow relationships are steep, which corresponds to a substantial afterload on the right ventricle during exercise. A partial recovery of 10-25% of the hypoxia-induced decrease in maximal oxygen uptake has been reported with intake-specific pulmonary vasodilating interventions. Hypoxia has been reported to decrease myocardial fibre contractility in vitro. However, the acutely hypoxic right ventricle remains able to preserve the coupling of its contractility to increased afterload in intact animals. Echocardiographic studies of the right ventricle in healthy hypoxic human subjects show altered diastolic function, but systolic function that is preserved or even increased acutely and slightly depressed chronically. These findings are more pronounced in patients with chronic mountain sickness. Their clinical significance remains incompletely understood. Almost no imaging studies of right ventricular function have been reported in a minority of subjects who develop severe pulmonary hypertension and clinical right ventricular failure in hypoxia. No imaging studies of right ventricular function during hypoxic exercise in normal subjects are yet available. Thus, while it is plausible that the right ventricle limits exercise capacity in hypoxia, this still needs to be firmly established. PMID- 23625957 TI - MiR-378 controls cardiac hypertrophy by combined repression of mitogen-activated protein kinase pathway factors. AB - BACKGROUND: Several microRNAs (miRs) have been shown to regulate gene expression in the heart, and dysregulation of their expression has been linked to cardiac disease. miR-378 is strongly expressed in the mammalian heart but so far has been studied predominantly in cancer, in which it regulates cell survival and tumor growth. METHODS AND RESULTS: Here, we report tight control of cardiomyocyte hypertrophy through miR-378. In isolated primary cardiomyocytes, miR-378 was found to be both necessary and sufficient to repress cardiomyocyte hypertrophy. Bioinformatic prediction suggested that factors of the mitogen-activated protein kinase (MAPK) pathway are enriched among miR-378 targets. Using mRNA and protein expression analysis along with luciferase assays, we validated 4 key components of the MAPK pathway as targets of miR-378: MAPK1 itself, insulin-like growth factor receptor 1, growth factor receptor-bound protein 2, and kinase suppressor of ras 1. RNA interference with these targets prevented the prohypertrophic effect of antimiR-378, suggesting their functional relation with miR-378. Because miR-378 significantly decreases in cardiac disease, we sought to compensate for its loss through adeno-associated virus-mediated, cardiomyocyte-targeted expression of miR-378 in an in vivo model of cardiac hypertrophy (pressure overload by thoracic aortic constriction). Restoration of miR-378 levels significantly attenuated thoracic aortic constriction-induced cardiac hypertrophy and improved cardiac function. CONCLUSIONS: Our data identify miR-378 as a regulator of cardiomyocyte hypertrophy, which exerts its activity by suppressing the MAPK signaling pathway on several distinct levels. Restoration of disease associated loss of miR-378 through cardiomyocyte-targeted adeno-associated virus miR-378 may prove to be an effective therapeutic strategy in myocardial disease. PMID- 23625958 TI - Defining miRNA targets: balancing simplicity with complexity. PMID- 23625959 TI - Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. AB - BACKGROUND: Adiponectin is an adipokine with potentially important roles in human cardiovascular disease states. We studied the role of adiponectin in the cross talk between adipose tissue and vascular redox state in patients with atherosclerosis. METHODS AND RESULTS: The study included 677 patients undergoing coronary artery bypass graft surgery. Endothelial function was evaluated by flow mediated dilation of the brachial artery in vivo and by vasomotor studies in saphenous vein segments ex vivo. Vascular superoxide (O2(-)) and endothelial nitric oxide synthase (eNOS) uncoupling were quantified in saphenous vein and internal mammary artery segments. Local adiponectin gene expression and ex vivo release were quantified in perivascular (saphenous vein and internal mammary artery) subcutaneous and mesothoracic adipose tissue from 248 patients. Circulating adiponectin was independently associated with nitric oxide bioavailability and O2(-) production/eNOS uncoupling in both arteries and veins. These findings were supported by a similar association between functional polymorphisms in the adiponectin gene and vascular redox state. In contrast, local adiponectin gene expression/release in perivascular adipose tissue was positively correlated with O2(-) and eNOS uncoupling in the underlying vessels. In ex vivo experiments with human saphenous veins and internal mammary arteries, adiponectin induced Akt-mediated eNOS phosphorylation and increased tetrahydrobiopterin bioavailability, improving eNOS coupling. In ex vivo experiments with human saphenous veins/internal mammary arteries and adipose tissue, we demonstrated that peroxidation products produced in the vascular wall (ie, 4-hydroxynonenal) upregulate adiponectin gene expression in perivascular adipose tissue via a peroxisome proliferator-activated receptor-gamma-dependent mechanism. CONCLUSIONS: We demonstrate for the first time that adiponectin improves the redox state in human vessels by restoring eNOS coupling, and we identify a novel role of vascular oxidative stress in the regulation of adiponectin expression in human perivascular adipose tissue. PMID- 23625960 TI - Analysis of an innovative one-stop, hospital-based, outpatient acute gynaecology clinic: model for taking the service to community. PMID- 23625961 TI - What is the actual cost of providing the intrauterine system for contraception in a UK community sexual and reproductive health setting? AB - BACKGROUND: The anticipated increase in uptake of intrauterine system (IUS) fittings is slower than predicted by the National Institute for Health and Clinical Excellence (NICE). There is evidence to suggest that this is because of a high perceived cost of providing this contraceptive method. Whereas studies to date have all guessed at these costs, we calculated the actual costs of providing the IUS. METHODS: We tracked the notes of 283 women who had an IUS fitted in our community sexual and reproductive health service for 5 years. We recorded duration of use, measured the actual cost of all appointments and interventions over the lifespan of the device, and compared our findings with NICE predicted costs. RESULTS: With 70% complete follow-up, the average duration of use of the IUS was 3.44 years compared to NICE's prediction of 3.32. The average annual cost of providing an IUS for contraception in community clinics was L54.55 per woman; this compares with L70.49 modelled by NICE for provision in primary care. Most (80%) of the cost is incurred in the first year. The cost of managing problems is small. CONCLUSIONS: Providing the IUS for contraception was 23% cheaper in the present study than that predicted by NICE and cheaper than providing combined oral contraception in our service. Fitting IUSs in community clinics may be cheaper than in primary care. Streamlining the patient pathway will reduce costs further. Restricting access to the IUS because of initial cost is a false economy. PMID- 23625962 TI - Recognition of two distinct elements in the RNA substrate by the RNA-binding domain of the T. thermophilus DEAD box helicase Hera. AB - DEAD box helicases catalyze the ATP-dependent destabilization of RNA duplexes. Whereas duplex separation is mediated by the helicase core shared by all members of the family, flanking domains often contribute to binding of the RNA substrate. The Thermus thermophilus DEAD-box helicase Hera (for "heat-resistant RNA-binding ATPase") contains a C-terminal RNA-binding domain (RBD). We have analyzed RNA binding to the Hera RBD by a combination of mutational analyses, nuclear magnetic resonance and X-ray crystallography, and identify residues on helix alpha1 and the C-terminus as the main determinants for high-affinity RNA binding. A crystal structure of the RBD in complex with a single-stranded RNA resolves the RNA protein interactions in the RBD core region around helix alpha1. Differences in RNA binding to the Hera RBD and to the structurally similar RBD of the Bacillus subtilis DEAD box helicase YxiN illustrate the versatility of RNA recognition motifs as RNA-binding platforms. Comparison of chemical shift perturbation patterns elicited by different RNAs, and the effect of sequence changes in the RNA on binding and unwinding show that the RBD binds a single-stranded RNA region at the core and simultaneously contacts double-stranded RNA through its C terminal tail. The helicase core then unwinds an adjacent RNA duplex. Overall, the mode of RNA binding by Hera is consistent with a possible function as a general RNA chaperone. PMID- 23625963 TI - Megakaryocytic leukemia 1 (MKL1) ties the epigenetic machinery to hypoxia-induced transactivation of endothelin-1. AB - Increased synthesis of endothelin-1 (ET-1) by human vascular endothelial cells (HVECs) in response to hypoxia underscores persistent vasoconstriction observed in patients with pulmonary hypertension. The molecular mechanism whereby hypoxia stimulates ET-1 gene transcription is not well understood. Here we report that megakaryocytic leukemia 1 (MKL1) potentiated hypoxia-induced ET-1 transactivation in HVECs. Disruption of MKL1 activity by either a dominant negative mutant or small interfering RNA mediated knockdown dampened ET-1 synthesis. MKL1 was recruited to the proximal ET-1 promoter region (-81/+150) in HVECs challenged with hypoxic stress by the sequence-specific transcription factor serum response factor (SRF). Depletion of SRF blocked MKL1 recruitment and blunted ET-1 transactivation by hypoxia. Chromatin immunoprecipitation analysis of the ET-1 promoter revealed that MKL1 loss-of-function erased histone modifications consistent with transcriptional activation. In addition, MKL1 was indispensable for the occupancy of Brg1 and Brm, key components of the chromatin remodeling complex, on the ET-1 promoter. Brg1 and Brm modulated ET-1 transactivation by impacting histone modifications. In conclusion, our data have delineated a MKL1 centered complex that links epigenetic maneuverings to ET-1 transactivation in HVECs under hypoxic conditions. PMID- 23625964 TI - Multi-chromatic control of mammalian gene expression and signaling. AB - The emergence and future of mammalian synthetic biology depends on technologies for orchestrating and custom tailoring complementary gene expression and signaling processes in a predictable manner. Here, we demonstrate for the first time multi-chromatic expression control in mammalian cells by differentially inducing up to three genes in a single cell culture in response to light of different wavelengths. To this end, we developed an ultraviolet B (UVB)-inducible expression system by designing a UVB-responsive split transcription factor based on the Arabidopsis thaliana UVB receptor UVR8 and the WD40 domain of COP1. The system allowed high (up to 800-fold) UVB-induced gene expression in human, monkey, hamster and mouse cells. Based on a quantitative model, we determined critical system parameters. By combining this UVB-responsive system with blue and red light-inducible gene control technology, we demonstrate multi-chromatic multi gene control by differentially expressing three genes in a single cell culture in mammalian cells, and we apply this system for the multi-chromatic control of angiogenic signaling processes. This portfolio of optogenetic tools enables the design and implementation of synthetic biological networks showing unmatched spatiotemporal precision for future research and biomedical applications. PMID- 23625965 TI - ValiDichro: a website for validating and quality control of protein circular dichroism spectra. AB - Circular dichroism (CD) spectroscopy is widely used in structural biology as a technique for examining the structure, folding and conformational changes of proteins. A new server, ValiDichro, has been developed for checking the quality and validity of CD spectral data and metadata, both as an aid to data collection and processing and as a validation procedure for spectra to be included in publications. ValiDichro currently includes 25 tests for data completeness, consistency and quality. For each test that is done, not only is a validation report produced, but the user is also provided with suggestions for correcting or improving the data. The ValiDichro server is freely available at http://valispec.cryst.bbk.ac.uk/circularDichroism/ValiDichro/upload.html. PMID- 23625966 TI - Transient RNA structure features are evolutionarily conserved and can be computationally predicted. AB - Functional RNA structures tend to be conserved during evolution. This finding is, for example, exploited by comparative methods for RNA secondary structure prediction that currently provide the state-of-art in terms of prediction accuracy. We here provide strong evidence that homologous RNA genes not only fold into similar final RNA structures, but that their folding pathways also share common transient structural features that have been evolutionarily conserved. For this, we compile and investigate a non-redundant data set of 32 sequences with known transient and final RNA secondary structures and devise a dedicated computational analysis pipeline. PMID- 23625967 TI - Microfluidic affinity and ChIP-seq analyses converge on a conserved FOXP2-binding motif in chimp and human, which enables the detection of evolutionarily novel targets. AB - The transcription factor forkhead box P2 (FOXP2) is believed to be important in the evolution of human speech. A mutation in its DNA-binding domain causes severe speech impairment. Humans have acquired two coding changes relative to the conserved mammalian sequence. Despite intense interest in FOXP2, it has remained an open question whether the human protein's DNA-binding specificity and chromatin localization are conserved. Previous in vitro and ChIP-chip studies have provided conflicting consensus sequences for the FOXP2-binding site. Using MITOMI 2.0 microfluidic affinity assays, we describe the binding site of FOXP2 and its affinity profile in base-specific detail for all substitutions of the strongest binding site. We find that human and chimp FOXP2 have similar binding sites that are distinct from previously suggested consensus binding sites. Additionally, through analysis of FOXP2 ChIP-seq data from cultured neurons, we find strong overrepresentation of a motif that matches our in vitro results and identifies a set of genes with FOXP2 binding sites. The FOXP2-binding sites tend to be conserved, yet we identified 38 instances of evolutionarily novel sites in humans. Combined, these data present a comprehensive portrait of FOXP2's-binding properties and imply that although its sequence specificity has been conserved, some of its genomic binding sites are newly evolved. PMID- 23625968 TI - Double-strand DNA end-binding and sliding of the toroidal CRISPR-associated protein Csn2. AB - The adaptive immunity of bacteria against foreign nucleic acids, mediated by CRISPR (clustered regularly interspaced short palindromic repeats), relies on the specific incorporation of short pieces of the invading foreign DNA into a special genomic locus, termed CRISPR array. The stored sequences (spacers) are subsequently used in the form of small RNAs (crRNAs) to interfere with the target nucleic acid. We explored the DNA-binding mechanism of the immunization protein Csn2 from the human pathogen Streptococcus agalactiae using different biochemical techniques, atomic force microscopic imaging and molecular dynamics simulations. The results demonstrate that the ring-shaped Csn2 tetramer binds DNA ends through its central hole and slides inward, likely by a screw motion along the helical path of the enclosed DNA. The presented data indicate an accessory function of Csn2 during integration of exogenous DNA by end-joining. PMID- 23625970 TI - Pathophysiology and treatment options of chronic renal allograft damage. AB - Chronic rejection is a poorly understood entity albeit a frequent cause of graft failure. Despite the advent of new immunosuppressive agents, neither the slope of graft destruction nor the frequency is ameliorated. There are a number of hypothesis which try to explain the conundrum of chronic graft destruction: ongoing rejection, antibody-mediated rejection, poor choice of organs, hyperfiltration, calcineurin inhibitors (CNI) nephrotoxicity and non-compliance among them. None of these hypotheses can explain all features of the process, thus, it is likely that they act in combination. What seems to be clear is a beneficial effect of early angiotensin-converting enzyme (ACE)/AT1 blocker treatment. It is less clear, however, whether a reduction or a switch from CNIs to other immunosuppressants prolongs graft survival. This review highlights the pathophysiological aspects that are important for the development of chronic allograft damage in the context of possible treatment options. PMID- 23625969 TI - MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma. AB - MYCN is a master regulator controlling many processes necessary for tumor cell survival. Here, we unravel a microRNA network that causes tumor suppressive effects in MYCN-amplified neuroblastoma cells. In profiling studies, histone deacetylase (HDAC) inhibitor treatment most strongly induced miR-183. Enforced miR-183 expression triggered apoptosis, and inhibited anchorage-independent colony formation in vitro and xenograft growth in mice. Furthermore, the mechanism of miR-183 induction was found to contribute to the cell death phenotype induced by HDAC inhibitors. Experiments to identify the HDAC(s) involved in miR-183 transcriptional regulation showed that HDAC2 depletion induced miR-183. HDAC2 overexpression reduced miR-183 levels and counteracted the induction caused by HDAC2 depletion or HDAC inhibitor treatment. MYCN was found to recruit HDAC2 in the same complexes to the miR-183 promoter, and HDAC2 depletion enhanced promoter-associated histone H4 pan-acetylation, suggesting epigenetic changes preceded transcriptional activation. These data reveal miR-183 tumor suppressive properties in neuroblastoma that are jointly repressed by MYCN and HDAC2, and suggest a novel way to bypass MYCN function. PMID- 23625972 TI - Uraemic sarcopenia: aetiology and implications. AB - The term uraemic myopathy has been used loosely to describe the skeletal muscle abnormalities in uraemic patients. However, it does not fully explain the observed abnormalities as recent research has documented a normal skeletal muscle physiology in the presence of reduced muscle force, selective structural changes and significant muscle wasting. Ageing is associated with sarcopenia (muscle wasting) and an increase in the prevalence of chronic kidney disease (CKD), which accelerates the normal physiological muscle wasting. Similar to sarcopenia, muscle wasting in uraemic patients appears to be the hallmark of the disease and its aetiology is multifactorial with hormonal, immunologic and myocellular changes, metabolic acidosis, reduced protein intake and physical inactivity. Uraemic sarcopenia presents a high probability for morbidity and mortality and consequently a high priority for muscle wasting prevention and treatment in these patients. Perhaps, the use of the term 'uraemic sarcopenia' would provide recognition by the renal community for this devastating problem. The purpose of this review is to relate the findings of the recent publications that describe abnormalities in uraemic skeletal muscle to the possible pathogenesis of muscle wasting and its consequences in patients with CKD. PMID- 23625973 TI - Neonatal RIFLE. AB - A standardized classification of acute kidney injury (AKI) has recently been proposed with the RIFLE (Risk, Injury, Failure, Loss of function, End-stage kidney disease) score. Such definition/classification has been applied both in adult and in paediatric patients. Neonatal definition of AKI likely results as a challenging task due to the peculiar renal pathophysiology of newborn critically ill patients. Their so-called 'immature kidneys' require careful management and neonatal AKI is frequently complicated by unfavourable outcomes. A recent attempt to implement the RIFLE score with a neonatal modification might lead to improvement on the knowledge of AKI incidence and epidemiology. PMID- 23625971 TI - Fibroblast growth factor-23: what we know, what we don't know, and what we need to know. AB - Traditional risk factors of cardiovascular morbidity and mortality such as hypertension, hypercholesterolemia and obesity are paradoxically associated with better outcomes in dialysis patients, and the few trials of interventions targeting modifiable traditional risk factors have yielded disappointing results in this patient population. Non-traditional risk factors such as inflammation, anemia and abnormalities in bone and mineral metabolism have been proposed as potential explanations for the excess mortality seen in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), but without clear understanding of what the most important pathophysiologic mechanisms of these risk factors are, which ones might be ideal treatment targets and which therapeutic interventions may be effective and safe in targeting them. Among the novel risk factors, fibroblast growth factor-23 (FGF23) has recently emerged as one of the most powerful predictors of adverse outcomes in patients with CKD and ESRD. FGF23 is a hormone produced by osteoblasts/osteocytes in bone that acts on the kidney to regulate phosphate and vitamin D metabolism through activation of FGF receptor/alpha-Klotho co-receptor complexes. It is possible that elevated FGF23 may exert its negative impact through distinct mechanisms of action independent from its role as a regulator of phosphorus homeostasis. Elevated circulating FGF23 concentrations have been associated with left ventricular hypertrophy (LVH), and it has been suggested that FGF23 exerts a direct effect on the myocardium. While it is possible that 'off target' effects of FGF23 present in very high concentrations could induce LVH, this possibility is controversial, since alpha-klotho is not expressed in the myocardium. Another possibility is that FGF23's effect on the heart is mediated indirectly, via 'on target' activation of other humoral pathways. We will review the physiology and pathophysiology of FGF23, the outcomes associated with elevated FGF23 levels, and describe putative mechanisms of action responsible for its negative effects and potential therapeutic strategies to treat these. PMID- 23625974 TI - Targeted therapies and the treatment of non-clear cell renal cell carcinoma. AB - BACKGROUND: Targeted therapies have shown profound effects on the outcome of patients with advanced renal cell carcinoma (RCC). However, the optimal treatment for RCC of non-clear cell histology (nccRCC)-typically excluded from trials of targeted agents-remains uncertain. MATERIALS AND METHODS: By carrying out extensive searches of PubMed and ASCO databases, we identified and summarised research into the biological characteristics, clinical behaviour and treatment of different histological subtypes of nccRCC, focusing on targeted therapy. RESULTS: The available data suggest that treatments currently approved for RCC are active in ncc subtypes, although the overall clinical benefit may be less than for clear cell RCC. Temsirolimus has proven benefit over interferon-alfa (IFN-alpha) in patients with nccRCC, based on phase III data, while everolimus, sunitinib and sorafenib have all demonstrated some degree of activity in nccRCC in expanded access trials. No clear picture has emerged of whether individual histological subtypes are particularly responsive to any individual treatment. CONCLUSIONS: Further molecular studies into the pathogenesis of RCC histological subtypes will help direct the development of novel, appropriate targeted agents. Clinical trials specifically designed to evaluate the role of targeted agents in nccRCC are ongoing, and data from trials with sunitinib and everolimus will be reported soon. PMID- 23625975 TI - Circulating plasmablasts/plasmacells as a source of anticitrullinated protein antibodies in patients with rheumatoid arthritis. AB - OBJECTIVE: To study the characteristics and phenotype of anticitrullinated protein antibody (ACPA)-specific B cells in peripheral blood of patients with rheumatoid arthritis (RA). METHODS: Peripheral blood B cells from ACPA-positive patients with RA were cultured with or without stimulating factors. Following culture, supernatants were assessed for the presence of ACPA-IgG and non-specific total IgG by ELISA. RESULTS: Following stimulation, ACPA were detectable in up to 100% of culture wells. Of interest, ACPA were also produced spontaneously by unstimulated peripheral blood mononuclear cells. In both cases, the average ACPA titre per culture well correlated with ACPA serum titres. No ACPA production was detectable in B cell cultures from ACPA-negative patients with RA or healthy controls. Importantly, FACS-sorting experiments located spontaneous ACPA production to the CD20 negative B cell population corresponding to circulating plasmablasts/cells. CONCLUSIONS: ACPA-specific peripheral blood B cells are not confined to the CD20 positive memory pool, as circulating plasmablasts/cells spontaneously producing ACPA are also readily detectable. The latter points to an ongoing B cell immune response against citrullinated proteins and contrasts conventional immune responses against, for example, vaccines, where antigen specific plasmablasts appear in peripheral blood only shortly after vaccination. These circulating, ACPA-specific plasmablasts/cells might represent targets for novel therapeutic interventions. PMID- 23625976 TI - Anaemia to predict radiographic progression in rheumatoid arthritis. PMID- 23625977 TI - Osteoarthritis development is induced by increased dietary cholesterol and can be inhibited by atorvastatin in APOE*3Leiden.CETP mice--a translational model for atherosclerosis. AB - OBJECTIVE: Hypercholesterolaemia, a risk factor for atherosclerosis (ATH), has been suggested to have a role in the development of osteoarthritis (OA). To test this hypothesis, the effect of cholesterol and different cholesterol-lowering treatments on OA was investigated in a mouse model resembling human lipoprotein metabolism. METHODS: Female ApolipoproteinE*3Leiden.human Cholesteryl Ester Transfer Protein mice received a western-type diet with 0.1% (w/w) cholesterol (LC), 0.3% (w/w) cholesterol alone (HC) or treated with 3 mg/kg/day atorvastatin or 0.3 mg/kg/day ezetimibe. One group remained on chow (control). After 39 weeks, OA grades of the knees and the extent of ATH were determined. Plasma cholesterol levels were measured throughout the study. RESULTS: LC and HC groups developed significantly more OA at the medial side than the control group in a dose dependent manner. Atorvastatin but not ezetimibe treatment significantly suppressed OA development. As expected, features of ATH were significantly increased in the LC and HC groups compared with the control group and suppressed by atorvastatin (48%) and ezetimibe (55%) treatment. There were significant correlations between the development of OA on the medial side of the joint and cholesterol exposure (r=0.4) or ATH features (r=0.3). CONCLUSIONS: Dietary cholesterol and accordingly increased plasma levels play a role in the development of OA. The correlation found between OA, cholesterol and ATH demonstrates that these variables are connected, but indicates the contribution of other ongoing processes in the development of OA. The suppressive effect on OA development of atorvastatin but not of ezetimibe, which had similar cholesterol exposure levels, corroborates these findings. PMID- 23625978 TI - Expression of aberrant HLA-B27 molecules is dependent on B27 dosage and peptide supply. AB - OBJECTIVES: Cellular expression of non-classical forms of human leukocyte antigen (HLA)-B27 (NC-B27) may be involved in spondyloarthritis (SpA) pathogenesis. We used a novel B27-specific monoclonal antibody, HD6, to ask if B27 transgenic (TG) rat splenocytes express these NC-B27 molecules. We also investigated whether B27 binding peptides could affect the expression and functional immune recognition of HD6-reactive B27 molecules. METHODS: Splenocytes from B27-TG, B7-TG and non transgenic rats, and HLA-B27+ cell lines were stained with monoclonal antibodies recognising classical (ME-1, HLA-ABC-m1) and non-classical (HD6, HC10) B27. Cells were further cultured in the presence of HLA-B27-binding peptides, or subjected to brief low pH treatment prior to mAb staining and/or immunoprecipitation or co culture with KIR3DL2-CD3epsilon-expressing Jurkat reporter cells. RESULTS: HD6 reactive molecules were detected in the majority of adult B27-TG rat splenocyte cell subsets, increasing with age and concomitant increased B27 expression. HD6 staining was inhibited by incubation with B27-binding peptides and induced by low pH treatment. HD6 staining correlated with KIR3DL2-CD3epsilon-expressing Jurkat reporter cell activity. Thus, IL-2 production was decreased when B27-expressing antigen-presenting cells were preincubated with B27-binding peptides, but increased following pretreatment with low pH buffer. CONCLUSIONS: Surface expression of HD6-reactive B27 molecules on B27-TG rat splenocytes is consistent with a pathogenic role for NC-B27 in SpA. Interaction of NC-B27 with innate immune receptors could be critical in SpA pathogenesis, and we show that this may be influenced by the availability and composition of the B27-binding peptide pool. PMID- 23625979 TI - Novel targeted therapies: the future of rheumatoid arthritis? Mavrilumab and tabalumab as examples. PMID- 23625980 TI - Osteitis and synovitis, but not bone erosion, is associated with proteoglycan loss and microstructure damage in the cartilage of patients with rheumatoid arthritis. AB - OBJECTIVES: To investigate the relation between anatomic changes of the synovium, the bone, the bone marrow and the cartilage to biochemical properties of the cartilage in patients with rheumatoid arthritis (RA). METHODS: 33 patients with RA received 3-T MRI scans of the metacarpophalangeal joints. Two independent methods, (A) the delayed gadolinium enhanced MRI of the cartilage (dGEMRIC, T2 mapping), which was used to assess the biochemical properties of the cartilage; (B) synovitis, osteitis and bone erosions were quantified according to the RA MRI scoring (RAMRIS) method and cartilage thickness (CT), interbone joint space (IBJS, distance between proximal and distal bone surface) and intercartilage joint space (ICJS, distance between proximal and distal cartilage surface) were measured. RESULTS: Biochemical changes of the cartilage, corresponding to low dGEMRIC and high T2 values, were more likely to be seen in joints with decreased IBJS and ICJS as well as decreased CT. For instance, dGEMRIC was directly correlated to the IBJS (p=0.001) and ICJS (p=0.001), whereas T2 mapping was inversely correlated to IBJS and ICJS (both p=0.017). Moreover, the degree of osteitis, and to some extent synovitis, was correlated to biochemical cartilage changes as measured by dGEMRIC (p=0.003) or the T2 mapping (p=0.013). By contrast, bone erosions did not correlate to the degree of biochemical cartilage changes. DISCUSSION: These data support the concept that synovitis and osteitis may be two main triggers for cartilage damage. Thus, the actual inflammatory state of a joint, but not so much the degree of bone erosion, appears to influence cartilage properties in RA. PMID- 23625981 TI - Cigarette smoking has a dose-dependent impact on progression of structural damage in the spine in patients with axial spondyloarthritis: results from the GErman SPondyloarthritis Inception Cohort (GESPIC). PMID- 23625982 TI - Efficacy of oral prednisolone in active ankylosing spondylitis: results of a double-blind, randomised, placebo-controlled short-term trial. AB - BACKGROUND: The efficacy of oral prednisolone in patients with active ankylosing spondylitis (AS) has not been studied to date. METHODS: In this double-blind, randomised, placebo-controlled trial, patients with AS with active disease despite taking non-steroidal antirheumatic drugs were randomised to three groups in which they were either treated with 20 mg (n=13) or 50 mg (n=12) of prednisolone, or placebo (n=14), administered orally every day for a total of 2 weeks. The primary endpoint was defined as a 50% improvement of the Bath AS Disease Activity Index (BASDAI) at week 2. RESULTS: The primary endpoint was reached in 33% and 27% of the patients treated with 50 and 20 mg of prednisolone, respectively, versus only 8% on placebo (p=0.16 and p=0.30). However, the mean improvement of BASDAI score was significantly higher in the 50 mg prednisolone compared to the placebo group (2.39+/-0.5 vs 0.66+/-0.49, p=0.03), while there was only a small change in the 20 mg group (1.19+/-0.53; p=0.41). The results for other outcome parameters were similar. CONCLUSIONS: Oral prednisolone 50 mg per day, but not low dose prednisolone, showed a short-term response that was significantly higher than placebo. The clinical significance and the duration of this effect warrant further study. PMID- 23625983 TI - Anakinra treatment in patients with refractory inflammatory myopathies and possible predictive response biomarkers: a mechanistic study with 12 months follow-up. AB - OBJECTIVE: To perform a mechanistic study on the effect of interleukin (IL)-1 blockade by anakinra in patients with refractory myositis and to explore possible predictive biomarkers. METHODS: Fifteen patients with refractory myositis were treated with anakinra for 12 months. Clinical response was assessed by the six item core set measures of disease activity International Myositis Assessment and Clinical Studies (IMACS) and functional index (FI). Repeated muscle biopsies were investigated for cellular infiltrates, IL-1alpha, IL-1beta, IL-1Ra and major histocompatibility complex-class I by immunohistochemistry. Serum levels of IL 1Ra and granulocyte colony-stimulating factor (G-CSF) were measured by ELISA. T cell phenotype and functional assays were investigated by multicolour flow cytometry. RESULTS: Seven patients had clinical response according to IMACS, four of them also showed improved FI. Responders had higher baseline extramuscular score compared with non-responders. In muscle biopsies, baseline CD163 macrophages and IL-1alpha expression were inversely correlated with muscle performance after 6 months treatment; all responders had IL-1Ra expression in the post-treatment biopsies but only 3/8 non-responders. In serum, IL-1Ra levels were increased and G-CSF was decreased after 6 months treatment, but their levels and changes were not related to clinical response. For T cells, an inverse correlation between baseline frequency of CD4 activated/memory T cells and decreased creatine kinase levels was observed. Five of six patients demonstrated less IL-17A and more IFN-gamma secreting CD4 T cells after 6 months treatment. Moreover, anakinra reduced IL-17A secretion in vitro. CONCLUSIONS: Patients with myositis may respond to anakinra. Extramuscular score, muscle CD163 macrophages and IL-1alpha expression, blood CD4 activated/memory T cells might associate with anakinra treatment response. Blocking the IL-1 receptor disfavoured Th17 cell differentiation both in vivo and in vitro. PMID- 23625984 TI - Changes in biomarkers after therapeutic intervention in temporal arteries cultured in Matrigel: a new model for preclinical studies in giant-cell arteritis. AB - BACKGROUND: Search for therapeutic targets in giant-cell arteritis (GCA) is hampered by the scarcity of functional systems. We developed a new model consisting of temporal artery culture in tri-dimensional matrix and assessed changes in biomarkers induced by glucocorticoid treatment. METHODS: Temporal artery sections from 28 patients with GCA and 22 controls were cultured in Matrigel for 5 days in the presence or the absence of dexamethasone. Tissue mRNA concentrations of pro-inflammatory mediators and vascular remodelling molecules was assessed by real-time RT-PCR. Soluble molecules were measured in the supernatant fluid by immunoassay. RESULTS: Histopathological features were exquisitely preserved in cultured arteries. mRNA concentrations of pro inflammatory cytokines (particularly IL-1beta and IFNgamma), chemokines (CCL3/MIP 1alpha, CCL4/MIP-1beta, CCL5/RANTES) and MMP-9 as well as IL-1beta and MMP-9 protein concentrations in the supernatants were significantly higher in cultured arteries from patients compared with control arteries. The culture system itself upregulated expression of cytokines and vascular remodelling factors in control arteries. This minimised differences between patients and controls but underlines the relevance of changes observed. Dexamethasone downregulated pro-inflammatory mediator (IL-1beta, IL-6, TNFalpha, IFNgamma, MMP-9, TIMP-1, CCL3 and CXCL8) mRNAs but did not modify expression of vascular remodelling factors (platelet derived growth factor, MMP-2 and collagens I and III). CONCLUSIONS: Differences in gene expression in temporal arteries from patients and controls are preserved during temporal artery culture in tri-dimensional matrix. Changes in biomarkers elicited by glucocorticoid treatment satisfactorily parallel results obtained in vivo. This may be a suitable model to explore pathogenetic pathways and to perform preclinical studies with new therapeutic agents. PMID- 23625985 TI - Sleep disturbance in childhood epilepsy: clinical implications, assessment and treatment. AB - The ways in which sleep can affect epilepsy, and epilepsy can influence sleep and wakefulness, are described. Different forms of sleep disturbance have been reported in patients with epilepsy, depending on the type of seizure disorder. Confusions between epilepsy and non-epileptic parasomnias can be a particular diagnostic problem but they can be avoided. Untreated sleep disturbance is likely to have harmful psychological, physical and family effects. Screening for sleep disturbance should be routine, and leading, if indicated, to precise diagnosis of the underlying sleep disorder on which choice of advice and treatment depends. PMID- 23625986 TI - The utility of sildenafil in pulmonary hypertension: a focus on bronchopulmonary dysplasia. AB - The treatment of pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants has evolved in recent years, improving both quality of life and survival for patients. One of the potential agents for this condition is sildenafil, a phosphodiesterase-V inhibitor with proven efficacy within the idiopathic PH population. However, only limited evidence exists for its use as either monotherapy or part of a combination approach towards the management of PH in BPD. This review summarises the evidence base for sildenafil alone and in combination with other recognised therapeutic agents for ameliorating paediatric PH in the presence of BPD. It also examines the suitability for current practice with the aim of clarifying regimens that produce improved patient outcomes. We conclude that sildenafil is both safe and effective in this utility. Doses should be started at 0.5 mg/kg every 8 h before titrating up towards 2 mg/kg every 6 h to effect reductions in pulmonary vascular resistance and arterial pressure. Evidence suggests that if continued until PH resolution, this improves survival from 61% to 81% at 12 months. Furthermore, there are also data suggesting that in treatment refractory PH cases, the addition of endothelin antagonists and prostacyclin analogues to sildenafil therapy can also be considered. PMID- 23625987 TI - Genetic testing in children with surfactant dysfunction. AB - OBJECTIVES: To present the UK experience in genetic diagnoses of surfactant protein dysfunction disorders and develop a referral algorithm for neonates and children with persistent respiratory problems. MATERIALS AND METHODS: Between 2006 and 2011, 427 cases were referred for surfactant mutation analyses to the North East Thames Regional Molecular Genetics Laboratory at Great Ormond Street Hospital, London. The results were reviewed and referring physicians of mutation positive cases contacted to complete a questionnaire providing clinical, radiological, histological and outcome information. RESULTS: 25 new cases were found to have genetic mutations for surfactant dysfunction disorders (7.5%), with six resulting in surfactant protein B dysfunction, seven surfactant protein C dysfunction and 12 ATP-binding cassette subfamily A member 3 (ABCA3) dysfunction. The referrals were from 15 different paediatric centres. In addition, three affected surfactant protein B (SFTPB) cases were prenatal diagnoses, following the birth of previously affected children. The majority of the confirmed cases (23 of 25) were born after 37 weeks gestation. All children with SFTPB dysfunction and the majority of ABCA3 patients presented with respiratory distress at birth. All SFTPB cases died from intractable respiratory failure. The outcome for ABCA3 mutations was variable with seven survivors. The clinical and radiological presentation of surfactant protein C (SFTPC) patients suggested mainly interstitial lung process with the majority surviving on medication. CONCLUSIONS: Surfactant mutation analysis is now well established in the UK and allows better genetic diagnosis and counselling. The rarity of the condition makes it difficult to develop a validated algorithm for genetic evaluation with a need for international networking. Referrals need to be rationalised for the service to be time and cost effective. PMID- 23625988 TI - The importance of a preschool booster for children born to hepatitis B-positive mothers. PMID- 23625989 TI - Neurodevelopment outcome of newborns with cerebral subependymal pseudocysts at 18 and 46 months: a prospective study. AB - OBJECTIVES: Subependymal pseudocysts (SEPC) are cerebral periventricular cysts located on the floor of the lateral ventricle and result from regression of the germinal matrix. They are increasingly diagnosed on neonatal cranial ultrasound. While associated pathologies are reported, information about long-term prognosis is missing, and we aimed to investigate long-term follow-up of these patients. STUDY DESIGN: Newborns diagnosed with SEPC were enrolled for follow-up. Neurodevelopment outcome was assessed at 6, 18 and 46 months of age. RESULTS: 74 newborns were recruited: we found a high rate of antenatal events (63%), premature infants (66% <37 weeks, 31% <32 weeks) and twins (30%). MRI was performed in 31 patients, and cystic periventricular leukomalacia (c-PVL) was primarily falsely diagnosed in 9 of them. Underlying disease was diagnosed in 17 patients, 8 with congenital cytomegalovirus (CMV) infection, 5 with genetic and 4 with metabolic disease. Neurological examination (NE) at birth was normal for patients with SEPCs and no underlying disease, except one. Mean Developmental Quotient and IQ of these patients was 98.2 (+/-9.6SD; range 77-121), 94.6 (+/ 14.2SD; 71-120) and 99.6 (+/-12.3SD; 76-120) at 6, 18 and 46 months of age, respectively, with no differences between the subtypes of SEPC. A subset analysis showed no outcome differences between preterm infants with or without SEPC, or between preterm of <32 GA and >=32 GA. CONCLUSIONS: Neurodevelopment of newborns with SEPC was normal when no underlying disease was present. This study suggests that if NE is normal at birth and congenital CMV infection can be excluded, then no further investigations are needed. Moreover, it is crucial to differentiate SEPC from c-PVL which carries a poor prognosis. PMID- 23625990 TI - The importance of currency in data trends. PMID- 23625995 TI - Explaining microbial phenotypes on a genomic scale: GWAS for microbes. AB - There is an increasing availability of complete or draft genome sequences for microbial organisms. These data form a potentially valuable resource for genotype phenotype association and gene function prediction, provided that phenotypes are consistently annotated for all the sequenced strains. In this review, we address the requirements for successful gene-trait matching. We outline a basic protocol for microbial functional genomics, including genome assembly, annotation of genotypes (including single nucleotide polymorphisms, orthologous groups and prophages), data pre-processing, genotype-phenotype association, visualization and interpretation of results. The methodologies for association described herein can be applied to other data types, opening up possibilities to analyze transcriptome-phenotype associations, and correlate microbial population structure or activity, as measured by metagenomics, to environmental parameters. PMID- 23625997 TI - Emerging roles of recycling endosomes. AB - Cells internalize extracellular solutes, ligands and proteins and lipids in the plasma membrane (PM) by endocytosis. The removal of membrane from the PM is counteracted by endosomal recycling pathways that return the endocytosed proteins and lipids back to the PM. Recycling to the PM can occur from early endosomes. However, many cells have a distinct subpopulation of endosomes that have a mildly acidic pH of 6.5 and are involved in the endosomal recycling. These endosomes are dubbed recycling endosomes (REs). In recent years, studies have begun to reveal that function of REs is not limited to the endosomal recycling. In this review, I summarize the nature of membrane trafficking pathways that pass through REs and the cell biological roles of these pathways. PMID- 23625996 TI - TET proteins: on the frenetic hunt for new cytosine modifications. AB - Epigenetic genome marking and chromatin regulation are central to establishing tissue-specific gene expression programs, and hence to several biological processes. Until recently, the only known epigenetic mark on DNA in mammals was 5 methylcytosine, established and propagated by DNA methyltransferases and generally associated with gene repression. All of a sudden, a host of new actors novel cytosine modifications and the ten eleven translocation (TET) enzymes-has appeared on the scene, sparking great interest. The challenge is now to uncover the roles they play and how they relate to DNA demethylation. Knowledge is accumulating at a frantic pace, linking these new players to essential biological processes (e.g. cell pluripotency and development) and also to cancerogenesis. Here, we review the recent progress in this exciting field, highlighting the TET enzymes as epigenetic DNA modifiers, their physiological roles, and their functions in health and disease. We also discuss the need to find relevant TET interactants and the newly discovered TET-O-linked N-acetylglucosamine transferase (OGT) pathway. PMID- 23625998 TI - The heparin-binding growth factor midkine: the biological activities and candidate receptors. AB - The heparin-binding growth factor midkine (MK) comprises a family with pleiotrophin/heparin-binding growth-associated molecule. The biological phenomena in which MK is involved can be categorized into five areas: (i) cancer, (ii) inflammation/immunity, (iii) blood pressure, (iv) development and (v) tissue protection. The phenotypes are clear in vivo, but the mechanisms by which MK exerts these actions are not fully understood. Candidate receptors for MK include anaplastic lymphoma kinase, protein tyrosine phosphatase zeta, Notch2, LDL receptor-related protein 1, integrins and proteoglycans. Some physical associations between these candidate receptors are also known. Because of the striking in vivo phenotypes after manipulation of MK, MK could be an important molecular target for the treatment of various diseases. To this end, it will be important to pursue studies to fully understand the mechanisms of MK action. PMID- 23625999 TI - NetworkTrail--a web service for identifying and visualizing deregulated subnetworks. AB - The deregulation of biochemical pathways plays a central role in many diseases like cancer or Parkinsons's disease. In silico tools for calculating these deregulated pathways may help to gain new insights into pathogenic mechanisms and may open novel avenues for therapy stratification in the sense of personalized medicine. Here, we present NetworkTrail, a web service for the detection of deregulated pathways and subgraphs in biological networks. NetworkTrail uses a state-of-the-art integer linear programming-based approach for this task and offers interfaces to the Biological Network Analyzer (BiNA) and Cytoscape Web for visualizing the resulting subnetworks. By providing an accessible interface to otherwise hard-to-use command line tools, the new web service enables non-experts to quickly and reliably carry out this type of network analyses. AVAILABILITY AND IMPLEMENTATION: NetworkTrail is a JavaServer Pages-based web service. The algorithm for finding deregulated subnetworks has been implemented in C++. NetworkTrail is available at http://networktrail.bioinf.uni-sb.de/. PMID- 23626000 TI - OCSANA: optimal combinations of interventions from network analysis. AB - Targeted therapies interfering with specifically one protein activity are promising strategies in the treatment of diseases like cancer. However, accumulated empirical experience has shown that targeting multiple proteins in signaling networks involved in the disease is often necessary. Thus, one important problem in biomedical research is the design and prioritization of optimal combinations of interventions to repress a pathological behavior, while minimizing side-effects. OCSANA (optimal combinations of interventions from network analysis) is a new software designed to identify and prioritize optimal and minimal combinations of interventions to disrupt the paths between source nodes and target nodes. When specified by the user, OCSANA seeks to additionally minimize the side effects that a combination of interventions can cause on specified off-target nodes. With the crucial ability to cope with very large networks, OCSANA includes an exact solution and a novel selective enumeration approach for the combinatorial interventions' problem. AVAILABILITY: The latest version of OCSANA, implemented as a plugin for Cytoscape and distributed under LGPL license, is available together with source code at http://bioinfo.curie.fr/projects/ocsana. PMID- 23626001 TI - Incorporating key position and amino acid residue features to identify general and species-specific Ubiquitin conjugation sites. AB - MOTIVATION: Systematic dissection of the ubiquitylation proteome is emerging as an appealing but challenging research topic because of the significant roles ubiquitylation play not only in protein degradation but also in many other cellular functions. High-throughput experimental studies using mass spectrometry have identified many ubiquitylation sites, primarily from eukaryotes. However, the vast majority of ubiquitylation sites remain undiscovered, even in well studied systems. Because mass spectrometry-based experimental approaches for identifying ubiquitylation events are costly, time-consuming and biased toward abundant proteins and proteotypic peptides, in silico prediction of ubiquitylation sites is a potentially useful alternative strategy for whole proteome annotation. Because of various limitations, current ubiquitylation site prediction tools were not well designed to comprehensively assess proteomes. RESULTS: We present a novel tool known as UbiProber, specifically designed for large-scale predictions of both general and species-specific ubiquitylation sites. We collected proteomics data for ubiquitylation from multiple species from several reliable sources and used them to train prediction models by a comprehensive machine-learning approach that integrates the information from key positions and key amino acid residues. Cross-validation tests reveal that UbiProber achieves some improvement over existing tools in predicting species specific ubiquitylation sites. Moreover, independent tests show that UbiProber improves the areas under receiver operating characteristic curves by ~15% by using the Combined model. AVAILABILITY: The UbiProber server is freely available on the web at http://bioinfo.ncu.edu.cn/UbiProber.aspx. The software system of UbiProber can be downloaded at the same site. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23626002 TI - KGVDB: a population-based genomic map of CNVs tagged by SNPs in Koreans. AB - SUMMARY: Despite a growing interest in a correlation between copy number variations (CNVs) and flanking single nucleotide polymorphisms, few databases provide such information. In particular, most information on CNV available so far was obtained in Caucasian and Yoruba populations, and little is known about CNV in Asian populations. This article presents a database that provides CNV regions tagged by single nucleotide polymorphisms in about 4700 Koreans, which were detected under strict quality control, manually curated and experimentally validated. AVAILABILITY: KGVDB is freely available for non-commercial use at http://biomi.cdc.go.kr/KGVDB. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23626003 TI - Circulating levels of FGF-21 in obese youth: associations with liver fat content and markers of liver damage. AB - OBJECTIVE: Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates glucose and lipid metabolism in rodents. The effects of obesity and fatty liver on circulating FGF-21 levels have been described mainly in adults. Herein, we measured plasma FGF-21 levels in lean and obese adolescents with low and high hepatic fat content (HFF% <5.5% and HFF% >= 5.5%, respectively) and explored their relationship with hepatic fat content, measures of hepatic apoptosis, and insulin sensitivity. METHODS: A total of 217 lean and obese adolescents with both low and high HFF% (lean = 31; obese low HFF% = 107; and obese high HFF% = 79) underwent an oral glucose tolerance test, a fast gradient magnetic resonance imaging to measure the %HFF and abdominal fat distribution. Cytokeratin 18 levels were measured as a biomarker of liver apoptosis. A subset of adolescents underwent a 2-step hyperinsulinemic-euglycemic clamp, and a liver biopsy (N = 14), to assess insulin sensitivity and steatohepatitis, respectively. RESULTS: Compared to controls, FGF-21 levels were higher in obese youth, especially in those with high HFF (P < .001). FGF-21 significantly correlated with adiposity indexes (P < .001), visceral fat (r2 = 0.240, P < .001), hepatic fat content (r2 = 0.278, P < .001), cytokeratin 18 (r2 = 0.217, P < .001), and alanine aminotransferase (r2 = .164, P < .001). In subjects with steatoheaptitis, FGF-21 levels significantly correlated with the nonalcoholic fatty liver disease activity score (r2 = 0.27, P = .04). Stepwise regression analysis indicated that these relationships are independent of body mass index, visceral fat, and insulin sensitivity. An inverse correlation was documented with insulin, hepatic resistance indexes, and adipose resistance indexes, which disappeared after adjusting for hepatic fat content. CONCLUSIONS: Plasma FGF-21 levels are increased in obese adolescents, particularly in those with fatty liver. FGF-21 concentrations significantly and independently correlate with hepatic fat content and markers of hepatic apoptosis in obese youths. PMID- 23626004 TI - Sex steroid hormone levels and body composition in men. AB - BACKGROUND: Previous studies indicate that testosterone (T) is positively correlated with lean mass and inversely correlated with fat mass in men; however, the directionality of these associations, as well as the association with other hormones including estradiol (E2) and SHBG, is unclear. METHODS: We examined cross-sectional and longitudinal associations of E2, T, SHBG, and E2/T ratio with body composition among men ages 30 to 79 in the Boston Area Community Health/Bone Survey. Total, trunk, and appendicular lean and fat mass were measured by dual energy x-ray absorptiometry at baseline, and weight and waist/hip circumference were measured at baseline and follow-up. Partial Pearson correlation coefficients were used to estimate the linear relationship between each body composition measure and log-transformed hormone variable. RESULTS: In cross-sectional analyses of 821 men, T, calculated free T, and SHBG were inversely correlated with fat mass, weight, body mass index, waist/hip circumference, and waist-to-hip ratio, with multivariable-adjusted correlations ranging from -0.13 to -0.37. Calculated free E2 was positively correlated with percentage total (r = .13) and trunk (r = .15) fat mass, and E2/T was positively correlated with all measures examined (r = .13-.40). There were no significant multivariable-adjusted longitudinal associations between baseline hormone levels and change in weight, body mass index, waist/hip circumference, or waist-to-hip ratio after an average follow-up of 4.8 years. CONCLUSIONS: We observed significant cross-sectional associations between hormone levels, including E2, T, and E2/T, and body composition measures in men. Longitudinal analyses showing no influence of baseline hormone levels on change in anthropometric measures imply that body composition affects hormone levels and not the reverse. PMID- 23626005 TI - Patients with differentiated thyroid cancer who underwent radioiodine thyroid remnant ablation with low-activity 131I after either recombinant human TSH or thyroid hormone therapy withdrawal showed the same outcome after a 10-year follow up. AB - BACKGROUND: No long-term follow-up data are available for differentiated thyroid carcinoma (DTC) patients prepared with either exogenous or endogenous TSH and treated with low-activity (1.1 GBq [30 mCi]) radioiodine (131I). AIM: The aim of this study was to evaluate the 10-year follow-up of DTC patients who underwent remnant ablation with 1.1 GBq 131I after l-T4 withdrawal, recombinant human TSH (rhTSH) administration, or both. PATIENTS: A total of 159 DTC patients treated with total thyroidectomy and 1.1 GBq (30 mCi) of 131I for remnant ablation and stimulated with rhTSH and/or endogenous TSH were separated into ablated (n = 115) and not ablated (n = 44) patients and prospectively followed-up for at least 10 years. In addition, we evaluated several features that could correlate with the final status of patients. RESULTS: During the follow-up, 4 of 115 (3.5%) ablated patients showed a recurrence and 1 was successfully cured. Among not ablated patients, 16 of 44 (36.4%) had a persistent disease. At the end of the 10-year follow-up, 140 of 159 (88.1%) patients were disease-free, whereas 19 of 159 (11.9%) remained affected. No correlation was found with the type of TSH stimulation, and no other clinical and pathological features showed any correlation with the final status. However, low levels of stimulated serum thyroglobulin (<5.4 ng/mL) at first control after remnant ablation identified a subgroup of not ablated patients who became spontaneously cured. CONCLUSIONS: Long-term outcomes are similar in DTC patients treated with 1.1 GBq (30 mCi) 131I and prepared either with rhTSH or endogenous TSH. It is of interest that serum thyroglobulin at first control after ablation can have a prognostic role. PMID- 23626006 TI - Effects of recombinant human growth hormone for 1 year on body composition and muscle strength in children on long-term steroid therapy: randomized controlled, delayed-start study. AB - CONTEXT: Recombinant human GH (rhGH) improves growth and body composition in glucocorticoid-treated children. Its effects on muscle strength are poorly evaluated. OBJECTIVES: Our objective was to evaluate rhGH effects on muscle strength in children receiving long-term glucocorticoid therapy; effects on height SD score (SDS) and body composition were assessed also. DESIGN AND SETTING: A randomized, controlled, delayed-start study of rhGH for 12 months was started after randomization (baseline) or 6 months later (M6). PATIENTS: Patients included 30 children with various diagnoses. INTERVENTION: rhGH was administered at 0.065 mg/kg/d for 6 months and then in the dosage maintaining serum IGF-I levels below +2 SDS for chronological age. MAIN OUTCOME MEASURES: The primary criterion was the between-group difference in composite index of muscle strength (CIMS) change at M6. Secondary criteria included between-group differences in CIMS SDS(height), lean mass (LM), thigh muscle area (MA), and height SDS changes at M6; these parameters were also assessed in the overall population after 1 year of rhGH therapy. RESULTS: At M6, rhGH therapy did not significantly affect changes in CIMS or CIMS SDS(height) (+17.6% vs +7.5% and +0.14 +/- 0.38 vs +0.11 +/- 0.62, respectively); the rhGH-treated group had significantly larger changes in height SDS (+0.2 [0.3] vs -0.2 [0.3]; P = 0.003), LM (+7.3% [+3.7%; +21.6%] vs 0% [-4.7%; +3.2%]; P = 0.002), and MA (+8.8% [+5%; +15.6%] vs. -0.6% [-6.3%; +7.7%]; P = 0.01) compared with the untreated group. After 1 year of rhGH, height SDS, LM, and MA increased significantly, CIMS increased by 24.7% (+5.8%; +34.2%), and CIMS SDS(height) remained within the normal range. CONCLUSIONS: rhGH increased height, LM, and MA. However, muscle strength did not improve significantly. PMID- 23626007 TI - Gene of the month: KRAS. AB - This is a general overview of KRAS, its structure and role in pertinent cancers. Also its role in determining adjuvant therapy is discussed. PMID- 23626008 TI - p63 and p53 expression in extranodal NK/T cell lymphoma, nasal type. AB - OBJECTIVES: To investigate the pathological and clinical meaning of p63 in extranodal nasal type NK/T cell lymphoma (NKTCL). METHODS: We detected p63 and p53 expression using immunohistochemistry staining in 84 cases of NKTCL from Southern of China, an area with a well known high incidence of nasopharyngeal carcinoma, which is closely associated with Epstein-Barr virus infection. Moreover, we analysed the relationship between p63 and p53 expression and the clinicopathological features of NKTCL. RESULTS: Our results first showed that p63 expression was found in 14.3% (12/84) of NKTCL compared with 6.6% (2/30) in reactive lymphoid hyperplasia of nasopharynx. p63 Expression rate in NKTCL was significantly higher than that in reactive lymphoid hyperplasia of nasopharynx (p=0.016). NKTCL patients with p63 positivity had poorer 5-year overall survival rate (29.2%) than that (49.9%) of p63 negativity. p53 expression was found in 33.3% (28/84) of NKTCL. Our data showed that p53 expression was significantly associated with tumour stage (p=0.016) and international prognostic index (p=0.026) in patients with NKTCL. Cox regression test showed that p53 expression rate and international prognostic index score were statistically independent prognostic factors for NKTCL patients (p=0.002 and p=0.016, respectively). Our results suggest that p63 and p53 might play a role in pathogenesis of NKTCL. PMID- 23626009 TI - Smoking-related interstitial fibrosis (SRIF): pathologic findings and distinction from other chronic fibrosing lung diseases. AB - Smoking-related interstitial fibrosis (SRIF) is a common, histologically striking finding in smokers that must be distinguished from the idiopathic interstitial pneumonias and other chronic interstitial fibrosing lesions. It is characterised by marked thickening of alveolar septa by fibrosis composed of thick collagen bundles that have a distinctive hyalinised quality and often are admixed with variable numbers of hyperplastic smooth muscle fibres. There is minimal accompanying inflammation. This fibrosis is usually most prominent in subpleural and centrilobular parenchyma, but can be present elsewhere as well. It is accompanied by emphysema and respiratory bronchiolitis. Most patients are asymptomatic or only mildly symptomatic, and the clinical course is stable in most. This paper reviews the pathologic features of SRIF in detail, its differentiation from more ominous interstitial fibrosing processes, and the clinical implications of its diagnosis. PMID- 23626010 TI - Aggressive variants of follicular cell derived thyroid carcinoma; the so called 'real thyroid carcinomas'. AB - The pathological diagnoses and classification schemes for thyroid carcinoma have changed over the past 20 years and continue to do so. New entities have been described and molecular analyses have suggested better characterisation and grouping of certain tumours. Because some of the lesions have been named differently by different authors, clinicians and patients may be confused as to what a specific patient's lesion represents. In this review, we discuss the thyroid tumours of follicular origin which are clinically unusual but important to recognise as their behaviour may be aggressive, they may not respond to radioiodine treatment and they may cause significant mortality. This paper describes these important but rare lesions, their pathological features, important clinicopathological correlations, molecular correlates and prognostic implications. PMID- 23626011 TI - Estradiol promotes functional responses in inflammatory and steady-state dendritic cells through differential requirement for activation function-1 of estrogen receptor alpha. AB - 17beta-Estradiol (E2) has been shown to regulate GM-CSF- or Flt3 ligand-driven dendritic cell (DC) development through estrogen receptor (ER) alpha signaling in myeloid progenitors. ERalpha regulates transcription of target genes through two distinct activation functions (AFs), AF-1 and AF-2, whose respective involvement varies in a cell type- or tissue-specific manner. In this study, we investigated the role of ERalpha AFs in the development and effector functions of inflammatory DCs, steady-state conventional DCs, and plasmacytoid DCs (pDC), using mouse lacking either AF-1 or AF-2. In agreement with previous works, we showed that E2 fostered the differentiation and effector functions of inflammatory DCs through ERalpha-dependent upregulation of IFN regulatory factor (IRF)-4 in GM-CSF stimulated myeloid progenitors. Interestingly, whereas AF-1 was required for early IRF-4 upregulation in DC precursors, it was dispensable to enhance IRF-4 expression in differentiated DCs to a level compatible with the development of the more functional Ly6C(-) CD11b(+) DC subset. Presence of E2 had no effect on progenitors from either knock-in mice with 7-aa deletion in helix 12 of ERalpha, lacking AF-2, or ERalpha(-/-) mice. By contrast, in Flt3 ligand-driven DC differentiation, activation of AF-1 domain was required to promote the development of more functionally competent conventional DCs and pDCs. Moreover, lack of ERalpha AF-1 blunted the TLR7-mediated IFN-alpha response of female pDCs in vivo. Thus, our study demonstrates that ERalpha uses AF-1 differently in steady-state and inflammatory DC lineages to regulate their innate functions, suggesting that selective ER modulators could be used to target specific DC subsets. PMID- 23626012 TI - Imprinting of lymphocytes with melanoma antigens acquired by trogocytosis facilitates identification of tumor-reactive T cells. AB - Trogocytosis is a contact-dependent intercellular transfer of membrane fragments and associated molecules from APCs to effector lymphocytes. We previously demonstrated that trogocytosis also occurs between tumor target and cognate melanoma Ag-specific cytotoxic T cells (CTL). In this study, we show that, following trogocytosis, immune effector cells acquire molecular components of the tumor, including surface Ags, which are detectable by specific mAbs. We demonstrate that CD8(+) and CD4(+) T cells from melanoma patients' PBMC and tumor infiltrating lymphocytes (TIL) capture melanoma Ags, enabling identification of trogocytosing lymphocytes by staining with Ag-specific Abs. This finding circumvents the necessity of tumor prelabeling, which in the past was mandatory to detect membrane-capturing T cells. Through the detection of melanoma Ags on TIL, we sorted trogocytosing T cells and verified their preferential reactivity and cytotoxicity. Furthermore, tumor Ag-imprinted T cells were detected at low frequency in fresh TIL cultures shortly after extraction from the tumor. Thus, T cell imprinting by tumor Ags may allow the enrichment of melanoma Ag-specific T cells for research and potentially even for the adoptive immunotherapy of patients with cancer. PMID- 23626013 TI - gammadelta T cells are essential effectors of type 1 diabetes in the nonobese diabetic mouse model. AB - gammadelta T cells, a lineage of innate-like lymphocytes, are distinguished from conventional alphabeta T cells in their Ag recognition, cell activation requirements, and effector functions. gammadelta T cells have been implicated in the pathology of several human autoimmune and inflammatory diseases and their corresponding mouse models, but their specific roles in these diseases have not been elucidated. We report that gammadelta TCR(+) cells, including both the CD27( )CD44(hi) and CD27(+)CD44(lo) subsets, infiltrate islets of prediabetic NOD mice. Moreover, NOD CD27(-)CD44(hi) and CD27(+)CD44(lo) gammadelta T cells were preprogrammed to secrete IL-17, or IFN-gamma upon activation. Adoptive transfer of type 1 diabetes (T1D) to T and B lymphocyte-deficient NOD recipients was greatly potentiated when gammadelta T cells, and specifically the CD27(-) gammadelta T cell subset, were included compared with transfer of alphabeta T cells alone. Ab-mediated blockade of IL-17 prevented T1D transfer in this setting. Moreover, introgression of genetic Tcrd deficiency onto the NOD background provided robust T1D protection, supporting a nonredundant, pathogenic role of gammadelta T cells in this model. The potent contributions of CD27(-) gammadelta T cells and IL-17 to islet inflammation and diabetes reported in this study suggest that these mechanisms may also underlie human T1D. PMID- 23626371 TI - A tale of two community initiatives for promoting aging in place: similarities and differences in the national implementation of NORC programs and villages. AB - PURPOSE: Villages and Naturally Occurring Retirement Community (NORC) Supportive Service Programs (NORC programs) are among the most prominent community-based models for promoting aging in place. To advance systematic understanding of their development, this study examined how these models have been implemented nationally and the models' similarities and differences. DESIGN AND METHODS: A survey of program leaders representing 69 Villages and 62 NORC programs was conducted from January to June of 2012. Bivariate analyses compared measures of the initiatives' services/activities, beneficiaries, service delivery processes, and funding sources. RESULTS: Village members were reportedly more likely than NORC program participants to be younger, to be less functionally impaired, to be more economically secure, and to reside in higher socioeconomic communities. Reflecting these differences in populations served, NORC programs reported offering more traditional health and social services, had more paid staff, and relied more on government funding than Villages. IMPLICATIONS: Findings indicate that Villages and NORC programs both aim to promote aging in place by offering a diverse range of supports and services to older adults within a locally defined geographic area. Nevertheless, key differences were found in the means through which they seek to achieve these aims, as well as the populations likely to benefit from their efforts. These differences raise questions regarding the models' inclusivity, sustainability, expansion, and effectiveness and have implications for community aging in place initiatives more broadly. PMID- 23626014 TI - Mammalian target of rapamycin regulates IL-10 and resistance to Pseudomonas aeruginosa corneal infection. AB - IL-10 is important in the resistance response of BALB/c mice to experimental Pseudomonas aeruginosa corneal infection. However, the cellular mechanisms by which this anti-inflammatory cytokine is regulated remain unknown. Because the mammalian target of rapamycin (mTOR) regulates IL-10 in other disease models, the present study tested its role in bacterial keratitis. After infection, corneas of rapamycin versus control-treated BALB/c mice showed worsened disease, and real time RT-PCR confirmed that mTOR mRNA levels were significantly decreased. Rapamycin treatment also increased clinical score, polymorphonuclear neutrophil (PMN) infiltration (determined by myeloperoxidase assay), and bacterial load, but it diminished PMN bactericidal activity. Inhibition of mTOR also led to elevated mRNA and protein levels of IL-12p40, matrix metalloproteinase 9, and inducible NO synthase, whereas mRNA and protein levels of IL-10, its regulator/effector STAT 3, and suppressor of cytokine signaling 3 (a proinflammatory cytokine regulator) were decreased. Furthermore, mTOR inhibition reduced levels of proapoptotic caspase-3 and increased levels of B cell lymphoma-2 (antiapoptotic), indicative of delayed apoptosis. mTOR inhibition also altered genes related to TLR signaling, including elevation of TLR4, TLR5, and IL-1R1, with decreases in IL-1R associated kinase 1 and an inhibitor of NF-kappaB, NF-kappaB inhibitor-like 1. Rapamycin treatment also increased levels of IFN-gamma and CCAAT/enhancer binding protein, beta, a gene that regulates expression of preprotachykinin-A (the precursor of substance P). Collectively, these data, as well as a rescue experiment using rIL-10 together with rapamycin, which decreased PMN in cornea, provide concrete evidence that mTOR regulates IL-10 in P. aeruginosa-induced bacterial keratitis and is critical to balancing pro- and anti-inflammatory events, resulting in better disease outcome. PMID- 23626372 TI - Voices on relocation and aging in place in very old age--a complex and ambivalent matter. AB - PURPOSE: This cross-national qualitative study explores how very old people reflect upon relocation and aging in place. DESIGN AND METHODS: Swedish and German data are utilized in this study. About 80 community-living participants, 80-89 years of age, were interviewed with open-ended questions at home by trained interviewers. The interviews were analyzed by using conventional qualitative content analyses. RESULTS: Reasoning about relocation or aging in place in very old age is a complex and ambivalent matter. A variety of reflections, emotions, and behaviors for and against a move are revealed. Reasons to move reflect the urge to maintain independence, to stay in control, and to avoid loneliness. This is mainly expressed reactively. Reasons not to move reflect a strong attachment to the home and neighborhood. Moreover, reasons not to move reflect practical aspect such as economy and strain, as well as fear of losing continuity of habits and routines. IMPLICATIONS: There is a need for society to develop counseling systems to meet very old people's ambivalence and practical considerations to move or not to move. Thus, the ambivalence to stay put or to relocate needs to be further explored from an applied perspective by also taking nonmovers into account. PMID- 23626374 TI - An examination of spatial concentrations of sex exchange and sex exchange norms among drug users in Baltimore, Maryland. AB - Baltimore, Maryland consistently ranks highest nationally in rates of sexually transmitted diseases and HIV infection. Prior studies have identified geographic areas where STI and HIV infection in the city is most prevalent. It is well established that sex exchange behavior is associated with HIV and STIs, yet it is not well understood how sex exchangers are spatially distributed within the high risk areas. We sought to examine the spatial distribution of individuals who report sex exchange compared to those who do not exchange. Additionally we examined the spatial context of perceived norms about sex exchange. Data for the study came from a baseline sample of predominately injection drug users (n=842). Of these, 21% reported sex exchange in the prior 90 days. All valid baseline residential addresses of participants living within Baltimore city boundaries were geocoded. The Multi-Distance Spatial Cluster Analysis (Ripley's K-function) was used to separately calculate the K-functions for the addresses of participants reporting sex exchange or non-sex exchange, relative to the recruited population. Evidence of spatial clustering of sex exchangers was observed and norms aligned with these clusters. Of particular interest was the high density of sex exchangers in one specific housing complex of East Baltimore, which happens to be the oldest in Baltimore. These findings can inform targeted efforts for screening and testing for HIV and STIs and placement of both individual and structural level interventions that focus on increasing access to risk reduction materials and changing norms about risk behaviors. PMID- 23626375 TI - Comparison of N-acetylmethionine reactivity between oxaliplatin and an oxaliplatin derivative with chiral (S,S) amine nitrogen atoms. AB - We have synthesized an oxaliplatin derivative using N,N'-dimethyl-1,2 diaminocyclohexane (Me2dach) as the diamine ligand. The complex (S,R,R,S) Pt(Me2dach)(oxalate), where S,R,R,S represents the chiralities at N,C,C,N, respectively, was prepared and characterized by 1H NMR spectroscopy, COSY, NOESY, and HMQC. Oxaliplatin reacts with N-acetylmethionine (N-AcMet) to form [Pt(dach)(N-AcMet-S)2] and [Pt(dach)(N-AcMet-S,N)], with the former favored at higher molar ratios of N-AcMet. In contrast, Pt(Me2dach)(oxalate) reacts to form [Pt(Me2dach)(N-AcMet-S,O)]+ even in the presence of excess N-AcMet. Molecular mechanics calculations are consistent with significant steric clashes in models of [Pt(Me2dach)(N-AcMet-S)2]. When N-AcMet was reacted with an excess of each platinum complex, the rate of N-AcMet decrease was very similar for both complexes. Thus, the methyl groups at the nitrogen atoms had little to no effect on the addition of the sulfur atom of a single N-acetylmethionine, but they prevented chelation of the amide nitrogen or coordination of a second N acetylmethionine residue. PMID- 23626373 TI - Crohn's disease complicated by strictures: a systematic review. AB - The occurrence of strictures as a complication of Crohn's disease is a significant clinical problem. No specific antifibrotic therapies are available. This systematic review comprehensively addresses the pathogenesis, epidemiology, prediction, diagnosis and therapy of this disease complication. We also provide specific recommendations for clinical practice and summarise areas that require future investigation. PMID- 23626377 TI - FRACTIONAL PEARSON DIFFUSIONS. AB - Pearson diffusions are governed by diffusion equations with polynomial coefficients. Fractional Pearson diffusions are governed by the corresponding time-fractional diffusion equation. They are useful for modeling sub-diffusive phenomena, caused by particle sticking and trapping. This paper provides explicit strong solutions for fractional Pearson diffusions, using spectral methods. It also presents stochastic solutions, using a non-Markovian inverse stable time change. PMID- 23626376 TI - Photoimmunotherapy and irradiance modulation reduce chemotherapy cycles and toxicity in a murine model for ovarian carcinomatosis: perspective and results. AB - Significant toxicities from multiple cycles of chemotherapy often cause delays or early termination of treatment, leading to poor outcomes in ovarian cancer patients. Complementary modalities that potentiate the efficacy of traditional agents with fewer cycles and less toxicity are needed. Photodynamic therapy is a mechanistically-distinct modality that synergizes with chemo and biologic agents. A combination regimen with a clinically relevant chemotherapy cocktail (cisplatin + paclitaxel) and anti-EGFR targeted photoimmunotherapy (PIT) is evaluated in a murine model for ovarian carcinomatosis. Mice received either 1 or 2 chemotherapy cycles followed by PIT with a chlorine6-Erbitux photoimmunoconjugate and 25 J/cm2 light. PIT + 1 cycle of chemotherapy significantly reduced tumor burden, comparable to multiple chemotherapy cycles. Relative to 1 cycle of chemotherapy, the addition of PIT did not cause significant mouse weight loss, whereas 2 cycles of chemotherapy led to a significant reduction in weight. Irradiance-dependence on PIT efficacy was a function of the conjugation chemistry, providing an additional variable for optimization of PIT outcome. PMID- 23626379 TI - A strategy toward the synthesis of C13-oxidized cembrenolides. AB - An efficient strategy for the construction of C13-oxidized cembrenolides is reported. Central to this strategy is the installation of the C13 hydroxyl group prior to cembrane macrocyclization (via formation of the C1-C2 bond), allowing access to both C13 alcohol epimers. The orientation of the C13 alcohol was found to influence the cyclization mode of the cembranolide scaffold upon furan oxidation, leading to motifs reminiscent to bipinnatolide F, bielschowskysin, and verrillin. PMID- 23626378 TI - Dripping and jetting in microfluidic multiphase flows applied to particle and fiber synthesis. AB - Dripping and jetting regimes in microfluidic multiphase flows have been investigated extensively, and this review summarizes the main observations and physical understandings in this field to date for three common device geometries: coaxial, flow-focusing and T-junction. The format of the presentation allows for simple and direct comparison of the different conditions for drop and jet formation, as well as the relative ease and utility of forming either drops or jets among the three geometries. The emphasis is on the use of drops and jets as templates for microparticle and microfiber syntheses, and a description is given of the more common methods of solidification and strategies for achieving complex multicomponent microparticles and microfibers. PMID- 23626380 TI - An efficient framework for optimization and parameter sensitivity analysis in arterial growth and remodeling computations. AB - Computational models for vascular growth and remodeling (G&R) are used to predict the long-term response of vessels to changes in pressure, flow, and other mechanical loading conditions. Accurate predictions of these responses are essential for understanding numerous disease processes. Such models require reliable inputs of numerous parameters, including material properties and growth rates, which are often experimentally derived, and inherently uncertain. While earlier methods have used a brute force approach, systematic uncertainty quantification in G&R models promises to provide much better information. In this work, we introduce an efficient framework for uncertainty quantification and optimal parameter selection, and illustrate it via several examples. First, an adaptive sparse grid stochastic collocation scheme is implemented in an established G&R solver to quantify parameter sensitivities, and near-linear scaling with the number of parameters is demonstrated. This non-intrusive and parallelizable algorithm is compared with standard sampling algorithms such as Monte-Carlo. Second, we determine optimal arterial wall material properties by applying robust optimization. We couple the G&R simulator with an adaptive sparse grid collocation approach and a derivative-free optimization algorithm. We show that an artery can achieve optimal homeostatic conditions over a range of alterations in pressure and flow; robustness of the solution is enforced by including uncertainty in loading conditions in the objective function. We then show that homeostatic intramural and wall shear stress is maintained for a wide range of material properties, though the time it takes to achieve this state varies. We also show that the intramural stress is robust and lies within 5% of its mean value for realistic variability of the material parameters. We observe that prestretch of elastin and collagen are most critical to maintaining homeostasis, while values of the material properties are most critical in determining response time. Finally, we outline several challenges to the G&R community for future work. We suggest that these tools provide the first systematic and efficient framework to quantify uncertainties and optimally identify G&R model parameters. PMID- 23626381 TI - Hierarchical structure in a self-created communication system: Building nominal constituents in homesign. AB - Deaf children whose hearing losses are so severe that they cannot acquire spoken language and whose hearing parents have not exposed them to sign language nevertheless use gestures, called homesigns, to communicate. Homesigners have been shown to refer to entities by pointing at that entity (a demonstrative, that). They also use iconic gestures and category points that refer, not to a particular entity, but to its class (a noun, bird). We used longitudinal data from a homesigner called David to test the hypothesis that these different types of gestures are combined to form larger, multi-gesture nominal constituents (that bird). We verified this hypothesis by showing that David's multi-gesture combinations served the same semantic and syntactic functions as demonstrative gestures or noun gestures used on their own. In other words, the larger unit substituted for the smaller units and, in this way, functioned as a nominal constituent. Children are thus able to refer to entities using multi-gesture units that contain both nouns and demonstratives, even when they do not have a conventional language to provide a model for this type of hierarchical constituent structure. PMID- 23626382 TI - Land Transitions in the American Plains: Multilevel Modeling of Drivers of Grassland Conversion (1950 to 2000). AB - This paper examines drivers of land-cover change in the U.S. Great Plains in the last half of the twentieth century. Its central aim is to evaluate the dynamics of grassland preservation and conversion, across the region, and to identify areas of grassland that were never plowed during the period. The research compares land-cover data from 400 sample areas, selected from and nested within 50 counties, to aggregate data from the agricultural and population censuses. The spatially explicit land-cover data were interpreted from aerial photographs taken at three time points (1950s, 1970s and 2000s). Sample areas were chosen using a stratified random design based on the Public Land Survey grid with in the target counties, in several clusters across the region. We modeled the sequences and magnitudes of changes in the interpreted air photo data in a multi-level panel model that included soil quality and slope of sample areas and agricultural activities and employment reported in the U.S. Censuses of Agriculture and Population. We conclude that land retirement programs and production subsidies have worked at cross purposes, destabilizing micro-level patterns of land use in recent decades, increasing levels of switching between cropland and grassland and reducing the size of remaining areas of native grassland in the U.S. Great Plains. PMID- 23626383 TI - Mechanism(s) Involved in Carbon Monoxide-releasing Molecule-2-mediated Cardioprotection During Ischaemia-reperfusion Injury in Isolated Rat Heart. AB - The purpose of the present study was to determine the mechanism(s) involved in carbon monoxide-releasing molecule-2, carbon monoxide-releasing molecule-2 induced cardioprotection. We used the transition metal carbonyl compound carbon monoxide-releasing molecule-2 that can act as carbon monoxide donor in cardiac ischaemia-reperfusion injury model using isolated rat heart preparation. Langendorff's perfused rat hearts when treated with carbon monoxide-releasing molecule-2 (50 MUM) for 10 min before global ischaemia exhibited significant reduction in postischaemic levels of myocardial injury markers, creatine kinase and lactate dehydrogenase in coronary effluent. Similarly, pretreatment with carbon monoxide-releasing molecule-2 showed significantly improved postischaemic recovery of heart rate, coronary flow rate, cardiodynamic parameters and reduced infarct size as compared to vehicle control hearts. Perfusion with p38 mitogen activated protein kinase inhibitor, SB203580, a specific inhibitor of alpha and beta isoform, before and concomitantly with carbon monoxide-releasing molecule-2 treatment abolished carbon monoxide-releasing molecule-2-induced cardioprotection. However, p38 mitogen-activated protein kinase alpha inhibitor, SCIO-469, was unable to inhibit the cardioprotective effect of carbon monoxide releasing molecule-2. Furthermore, protective effect of carbon monoxide-releasing molecule-2 was significantly inhibited by the protein kinase C inhibitor, chelerythrine, when added before and concomitantly with carbon monoxide-releasing molecule-2. It was also observed that, perfusion with phosphatidylinositol 3 kinase inhibitor, wortmannin, before and concomitantly with carbon monoxide releasing molecule-2 was not able to inhibit carbon monoxide-releasing molecule-2 induced cardioprotection. Interestingly, we observed that wortmannin perfusion before ischaemia and continued till reperfusion significantly inhibited carbon monoxide-releasing molecule-2-mediated cardioprotection. Our findings suggest that the carbon monoxide-releasing molecule-2 treatment may activate the p38 mitogen-activated protein kinase beta and protein kinase C pathways before ischaemia and phosphatidylinositol 3-kinase pathway during reperfusion which may be responsible for the carbon monoxide-releasing molecule-2-mediated cardioprotective effect. PMID- 23626384 TI - Use of propranolol-magnesium aluminium silicate intercalated complexes as drug reservoirs in polymeric matrix tablets. AB - The objective of the present study was to investigate the use of propranolol magnesium aluminium silicate intercalated complexes as drug reservoirs in hydroxypropylmethylcellulose tablets. The matrix tablets containing the complexes were prepared and characterised with respect to propranolol release and were subsequently compared with those loading propranolol or a propranolol-magnesium aluminium silicate physical mixture. Additionally, the effects of varying viscosity grades of hydroxypropyl methylcellulose, compression pressures and calcium acetate incorporation on the drug release characteristics of the complex loaded tablets were also examined. The results showed that the complex-loaded tablets have higher tablet hardness than those containing propranolol or a physical mixture. The drug release from the complex-loaded tablets followed a zero-order release kinetic, whereas an anomalous transport was found in the propranolol or physical mixture tablets. The drug release rate of the complex tablet significantly decreased with increasing hydroxypropylmethylcellulose viscosity grade. Increase in the compression pressure caused a decrease in the drug release rate of the tablets. Furthermore, the incorporation of calcium ions could accelerate propranolol release, particularly in acidic medium, because calcium ions could be exchanged with propranolol molecules intercalated in the silicate layers of magnesium aluminium silicate. These findings suggest that propranolol-magnesium aluminium silicate intercalated complexes show strong potential for use as drug reservoirs in matrix tablets intended for modifying drug release. PMID- 23626385 TI - Statistical Design of Experiments on Fabrication of Bilayer Tablet of Narrow Absorption Window Drug: Development and In vitro characterisation. AB - The current study involves the fabrication of oral bioadhesive bilayer matrices of narrow absorption window drug baclofen and the optimisation of their in vitro drug release and characterisation. Statistical design of experiments, a computer aided optimisation technique, was used to identify critical factors, their interactions and ideal process conditions that accomplish the targeted response(s). A central composite design was employed to systematically optimise the drug delivery containing a polymer, filler and compression force. The values of ratio of different grades of hydroxypropyl methylcellulose, microcrystalline cellulose and compression force were varied to be fitted in design. Drug release at 1 h (Q1), 4 h (Q4), 8 h (Q8), 12 h (Q12), and hardness were taken as responses. Tablets were prepared by direct compression methods. The compressed tablets were evaluated for their hardness, weight variation, friability, content uniformity and diameter. Counter plots were drawn and optimum formulation was selected by desirability function. The formulations were checked for their ex vivo mucoadhesion. The experimental value of Q1, Q4, Q8, Q12 and hardness for check-point batch was found to be 31.64, 45.82, 73.27, 98.95% and 4.4 kg/cm(2), respectively. The release profile indicates Highuchi kinetics (Fickian transport) mechanism. The results of the statistical analysis of the data demonstrated significant interactions amongst the formulation variables, and the desirability function was demonstrated to be a powerful tool to predict the optimal formulation for the bilayer tablet. PMID- 23626386 TI - Comparative Studies on the Dissolution Profiles of Oral Ibuprofen Suspension and Commercial Tablets using Biopharmaceutical Classification System Criteria. AB - In vitro dissolution studies for solid oral dosage forms have recently widened the scope to a variety of special dosage forms such as suspensions. For class II drugs, like Ibuprofen, it is very important to have discriminative methods for different formulations in physiological conditions of the gastrointestinal tract, which will identify different problems that compromise the drug bioavailability. In the present work, two agitation speeds have been performed in order to study ibuprofen suspension dissolution. The suspensions have been characterised relatively to particle size, density and solubility. The dissolution study was conducted using the following media: buffer pH 7.2, pH 6.8, 4.5 and 0.1 M HCl. For quantitative analysis, the UV/Vis spectrophotometry was used because this methodology had been adequately validated. The results show that 50 rpm was the adequate condition to discriminate the dissolution profile. The suspension kinetic release was found to be dependent on pH and was different compared to tablet release profile at the same experimental conditions. The ibuprofen release at pH 1.0 was the slowest. PMID- 23626387 TI - Microencapsulation Approach for Orally Extended Delivery of Glipizide: In vitro and in vivo Evaluation. AB - Glipizide is an effective antidiabetic agent, however, it suffers from relatively short biological half-life. To solve this encumbrance, it is a prospective candidate for fabricating glipizide extended release microcapsules. Microencapsulation of glipizde with a coat of alginate alone or in combination with chitosan or carbomer 934P was prepared employing ionotropic gelation process. The prepared microcapsules were evaluated in vitro by microscopical examination, determination of the particle size, yield and microencapsulation efficiency. The filled capsules were assessed for content uniformity and drug release characteristics. Stability study of the optimised formulas was carried out at three different temperatures over 12 weeks. In vivo bioavailability study and hypoglycemic activity of C9 microcapsules were done on albino rabbits. All formulas achieved high yield, microencapsulation efficiency and extended t 1/2. C9 and C19 microcapsules attained the most optimised results in all tests and complied with the dissolution requirements for extended release dosage forms. These two formulas were selected for stability studies. C9 exhibited longer shelf life and hence was chosen for in vivo studies. C9 microcapsules showed an improvement in the drug bioavailability and significant hypoglycemic activity compared to immediate release tablets (Minidiab((r)) 5 mg). The optimised microcapsule formulation developed was found to produce extended antidiabetic activity. PMID- 23626388 TI - Antibacterial activity of halophilic bacterial bionts from marine invertebrates of mandapam-India. AB - Marine ecosystem and its organisms, particularly the invertebrates are recent targets of bioprospecting and mining for a large group of structurally unique natural products encompassing a wide variety of chemical classes such as terpenes, polyketides, acetogenins, peptides and alkaloids of varying structures, having pronounced pharmacological activities. In view of the limited reports on the antibacterials produced by bacteria, isolated from marine sponges, corals and bivalves of Indian origin, the present study is aimed at investigating the antagonistic activities of 100 heterotrophic, halophilic bacterial bionts isolated from 9 sponges, 5 corals and one bivalve. Culture broths of 46 of these bionts were active against human pathogenic bacteria namely Staphylococcus citreus, Proteus vulgaris, Serratio marcesans, Salmonella typhi, Aerobacter aerogenes and Escherichia coli. Further, the ethyl acetate extracts of cell free supernatant confirmed the presence of extracellular bioactive factor, by agar cup diffusion method. Interestingly, highest number of bionts having activity was isolated from corals followed by sponges and bivalve. The study clearly demonstrates that bacterial bionts of marine invertebrates are a rich source of bioactive secondary metabolites against human bacterial pathogens. PMID- 23626389 TI - Characterisation of Polyphenols in Terminalia arjuna Bark Extract. AB - The bark of Terminalia arjuna is known for its heart-health benefits in ayurvedic literature. This has been further supported by in vivo studies on animal and human volunteers. But there is no detailed study on identification of the active ingredients such as polyphenols. Polyphenols possesses antioxidant properties and are well-known health actives, it is important to characterise polyphenols in Terminalia arjuna. Aqueous extract of Terminalia arjuna bark was analysed for its composition and molecular weight distribution by dialysis. Compositional analysis revealed that it has 44% polyphenols and dialysis study showed that 70% of the polyphenols have molecular weight greater than 3.5 kDa. High performance liquid chromatography and liquid chromatography-mass spectrometry analysis of Terminalia arjuna, confirmed that it contains flavon-3-ols such as (+)-catechin, (+) gallocatechin and (-)-epigallocatechin. Phenolic acids such as gallic acid, ellagic acid and its derivatives were also found in Terminalia arjuna extract. Ellagic acid derivatives were isolated and their spectral studies indicated that isolated compounds were 3-O-methyl-ellagic acid 4-O-beta-D-xylopyranoside, ellagic acid and 3-O-methyl ellagic acid 3-O-rhamnoside. Hydrolysis and thiolysis studies of high molecular weight polyphenols indicated that they are proanthocyanidins. Given these results, it may be possible to attribute the heart health effects of Terminalia arjuna to these polyphenols which may be responsible for the endothelial benefit functions like tea. PMID- 23626390 TI - Antibacterial Activity of Mangrove Leaf Extracts against Human Pathogens. AB - The antibacterial activity of leaf extract of mangroves, namely, Rhizophora mucronata, Sonneratia alba and Exoecaria agallocha from Chorao island, Goa was investigated against human bacterial pathogens Staphylococcus aureus, Streptococcus sp., Salmonella typhi, Proteus vulgaris and Proteus mirabilis. As compared to aqueous, ethanol extract showed broad-spectrum activity. The multidrug-resistant (MDR) bacteria Salmonella typhi was inhibited by the ethanol extract of S. alba leaf whereas the other two resistant bacteria Staphylococcus aureus and Streptococcus sp. were inhibited by the ethanol extract of leaves of all the species. The aqueous extract of S. alba and E. agallocha showed their activity against P. vulgaris and P. mirabilis, respectively. Phytochemical analysis revealed the presence of saponins, glycosides, tannins, flavonoids, phenol and volatile oils in the leaves of mangroves. Further studies using different solvents for extraction are necessary to confirm that mangroves are a better source for the development of novel antibiotics. PMID- 23626391 TI - Procyanidin b2 cytotoxicity to mcf-7 human breast adenocarcinoma cells. AB - Procyanidins have attracted some attention due to their demonstrated chemopreventive action, a relatively new and promising strategy to prevent cancer. Breast cancer is one of the leading causes of death in women worldwide and its treatment needs improvements. The aim of this work was to verify the procyanidin dimmer B2 cytotoxic effect to MCF-7 human breast cancer cells. MCF-7 cells were cultured in RPMI medium, containing 20% fetal bovine serum and antibiotics in a CO2 chamber. The cells were treated with different concentrations of B2 and its cytotoxic potential was assessed by the sulforhodamine B assay, morphologically through haematoxylin-eosin staining and by DNA fragmentation analysis. The significance of differences between experimental conditions was determined using the ANOVA test, followed by the Tukey test when P<0.05. Cell proliferation decreased in a concentration and time dependent manner upon procyanidin dimmer B2 treatment, being 19.20 MUM the IC50. Procyanidin dimmer B2 treatment displayed concentration and time-dependent decline in MCF-7 cells compared to control and also induced morphological alterations compatible with cell-death induction. Cell condensation and cell diameter decreased (3.5 folds compared to control cells), after 48 h cell exposure to 50 MUM procyanidin dimmer B2, but the DNA ladder formation was not observed. In conclusion, our results demonstrated that procyanidin dimmer B2 exhibits cytotoxic activity to MCF-7 cells and it could be a potential antineoplastic agent. Further studies are necessary to clarify the procyanidin dimmer B2 mechanism of action. The evaluation of biological efficacy of individual components is an important step towards drug discovery and development. PMID- 23626392 TI - Biochemical Activities of Iranian Cymbopogon olivieri (Boiss) Bor. Essential Oil. AB - Cymbopogon olivieri essential oil from aerial parts was analyzed by gas chromotography and gas chromatography-mass spectrometry and led to the identification of 38 compounds. Piperitone (72.8%), 4-carene (11.8%) and beta himachalene (7.6%) were found as the major components of the oil. The antimicrobial activity was achieved using disc-diffusion and microbroth dilution assays and microbicidal kinetics of oil was screened against different microorganisms. The possible antioxidant activity of oil was evaluated by diphenylpicrylhydrazyl free-radical scavenging system. The oil had excellent antimicrobial activity against Bacillus cereus, Staphylococcus epidermidis and Streptococcus pneumoniae. The oil exhibited inhibitory effect against Bacillus subtilis and fungi. Dvalues of oil were 12.5, 10 and 2.4 min for Escherichia coli, Staphylococcus aureus and Candida albicans, respectively. The IC50 value of Cymbopogon olivieri oil was 35 mg/ml and its antioxidant activity was lower than that of butylated hydroxytoluene. Cymbopogon olivieri oil possesses compounds with antimicrobial properties that can be used as antimicrobial agents. PMID- 23626393 TI - Rapid and sensitive high performance liquid chromatographic determination of zonisamide in human serum application to a pharmacokinetic study. AB - An accurate and very rapid method for determination of zonisamide an antiepileptic drug, in human serum is described. The analytical procedure involves liquid-liquid extraction of the analyte and an internal standard (vanillin) from human serum by ethyl acetate as extracting solvent. Chromatographic separation was achieved using a monolithic C18 analytical column and a mixture of 0.05 M phosphate buffer containing triethylamine (1 ml/l; pH 2.7) and methanol (83:17 v/v) was used as the mobile phase. The detection wavelength was set at 240 nm. The calibration curve was linear over a concentration range of 0.015-6.4 MUg/ml of zonisamide in human serum. The total run time of analysis was 3.5 min and the lower limits of detection and quantification were 0.005 and 0.015 MUg/ml, respectively. The method validation was carried out in terms of specificity, sensitivity, linearity, precision, accuracy and stability. The validated method was applied in a randomised crossover bioequivalence study of two different zonisamide preparations in 24 healthy volunteers, and the assay was sensitive enough to measure drug levels up to 8 days following a single dose administration of zonisamide. PMID- 23626394 TI - Spectrophotometric estimation of azithromycin in tablets. AB - The present manuscript describes a simple, sensitive, accurate, precise and economical visible spectrophotometric method for the estimation of azithromycin from tablet formulation. The method is based on the reduction of potassium permanganate in alkaline medium with azithromycin. The measurement of decrease in absorbance of potassium permanganate at 547 nm was done, as it decolourises upon reduction by azithromycin. The method was used to determine between 2 and 20 MUg/ml of azithromycin in the final measured solution. There is no interference from the ingredients commonly found in azithromycin tablets with this method. The results for the determination of azithromycin in tablets were in good agreement with the labelled quantities and related analytical parameters are calculated. PMID- 23626395 TI - Analgesic, Antibacterial and Antiviral Activities of 2-(5-Alkyl-1,3,4-oxadiazol-2 yl)-3H-benzo[f]chromen-3-ones. AB - A novel series of 2-(5-alkyl-1,3,4-oxadiazol-2-yl)-3H-benzo[f]chromen-3-ones (4a e) have been evaluated for analgesic, antibacterial and antiviral activities. Analgesic activity was carried out using acetic acid-induced writhing method in Swiss albino male mice. The antibacterial activity was performed against Gram positive and Gram-negative clinical strains by agar well diffusion method. The in vitro antiviral activity was carried out against camelpox and buffalopox viruses. The analgesic activity exhibited by the compounds 4a, 4c and 4d were found to be more significant compared to the standard. The bacterial activity was determined by the inhibition of growth of the organism by the drugs at different concentrations. All the compounds showed significant activity when compared with the drug ciprofloxacin. The in vitro antiviral activity of the compound 4b tested against camelpox and buffalopox viruses revealed no activity when tested at concentrations of 250 MUg. The compound 4b did not alter the titres of both the viruses and the titres remain, respectively, 10(6.5) TCID50 and 10(6.74) TCID50 per ml for camelpox vaccine virus and buffalopox vaccine virus. However, the compounds 4a-e showed significant analgesic and antibacterial activities. PMID- 23626396 TI - Production of Cyclosporine A by Submerged Fermentation from a Local Isolate of Penicillium fellutanum. AB - Six locally isolated strains of Penicillium were checked for their potential to produce cyclosporine A through submerged fermentation. The medium used for drug production was composed of glucose, 5%; peptone, 1%; KH2PO4, 0.5% and KCl, 0.25% (w/v). Butyl acetate was used to extract the fermentation medium for cyclosporine 'A' analysis. The confirmation analysis was done through high performance liquid chromatography and the chromatograms obtained were compared with that of Sandimmun Neoral ((r))capsule (Novartis) containing 100 mg of cyclosporine and with the external standard cyclosporine A 98.5% pure. Only chromatogram of Penicillium fellutanum (FCBP 937) isolated from Guava fruit showed a peak at 2.768, which was comparable with both the standards. The amount of drug calculated was 16.18 MUg/ml. PMID- 23626397 TI - The Study of Anticancer and Antifungal Activities of Pistacia integerrima Extract in vitro. AB - Pistacia integerrima Stew. ex Brand (Anacardiaceae) is an ethanobotanically important plant species traditionally used in the treatment of chronic wounds, jaundice, dysentery, etc. The crude extract from Pistacia integerrima and its fractions were tested for cytotoxic activity against Michigan Cancer Foundation-7 human breast cancer cell line. We have also investigated that crude stem extract of this plant also exhibits the antitumour as well as antifungal potential activities. Moreover, we have also studied that the crude extract inhibited Michigan Cancer Foundation-7 cell viability in a dose-dependent manner; the poor toxicity (1.6%) at 10 MUg/ml to moderate toxicity (55.4%) at 100 MUg/ml. The IC50 values calculated were 90.9 MUg/ml. The ethyl acetate and chloroform fractions at a concentration of 200 MUg/ml showed ~100 and 97.4% inhibition against Michigan Cancer Foundation-7 cell line, respectively. The crude methanol extract also showed good antitumour (IC50 125 ppm) activity, but weak antifungal activity. These findings reveal that the ethyl acetate and chloroform fractions of Pistacia integerrima are potent cytotoxic fractions, and could be an alternate candidate for the development of novel biologically active compounds. PMID- 23626398 TI - Recombinant Expression, Isotope Labeling and Purification of the Vitamin D Receptor Binding Peptide. AB - The vitamin D receptor binding peptide, VDRBP, was overexpressed as a fused form with the ubiquitin molecule in Rosetta(DE3)pLysS, a protein production strain of Escherichia coli harboring an induction controller plasmid. The fusion protein was bound to the immobilized metal ions, and the denaturation and renaturation of the fusion protein were performed as a part of the purification procedure. After the elution of the fusion protein, the peptide hormone was released from its fusion partner by using yeast ubiquitin hydrolase (YUH), and subsequently purified by reverse phase chromatography. The purity of the resulting peptide fragment was checked by MALDI-TOF mass and NMR spectroscopy. The final yields of the target peptide were around 5 and 2 mg per liter of LB and minimal media, respectively. The recombinant expression and purification of this peptide will enable structural and functional studies using multidimensional NMR spectroscopy and X-ray crystallography. PMID- 23626399 TI - National Board Certification and Developmentally Appropriate Practices: Perceptions of Impact. AB - The study investigated a relationship between National Board certification and perceived use of developmentally appropriate practices (DAP). A self-developed survey, the Early-childhood Teacher Inventory of Practices, was e-mailed to participants. Participants included 246 non-National Board-certified (non-NBCT) and 135 National Board-certified (NBCT) early childhood teachers. Descriptives were reported for age, years of teaching experience, grade level currently teaching, ethnicity, degree type, certification type, and degree level. Inferential statistics were used to understand the differences between perceived use of DAP. NBCTs scored significantly higher than non-NBCTs in three of the four target areas and on the total of the scale. Pearson product-moment corelations were used to determine a relationship between years of experience or level of education and NBCTs' perceived use of DAP. Years of experience were significantly related, but level of education was not. The findings indicate that NBCT teachers perceive they incorporate more developmentally appropriate practices into their teaching than do non-NBCT teachers. PMID- 23626400 TI - Novel pentablock copolymer (PLA-PCL-PEG-PCL-PLA) based nanoparticles for controlled drug delivery: Effect of copolymer compositions on the crystallinity of copolymers and in vitro drug release profile from nanoparticles. AB - The purpose of this investigation was to design novel pentablock copolymers (polylatide-polycaprolactone-polyethylene glycol- polycaprolactone-polylatide) (PLA-PCL-PEG-PCL-PLA) to prepare nanoparticle formulations which provide continuous delivery of steroids over a longer duration with minimal burst effect. Another purpose was to evaluate the effect of poly (L-lactide) (PLLA) or poly (D, L-lactide) (PDLLA) incorporation on crystallinity of pentablock copolymers and in vitro release profile of triamcinolone acetonide (selected as model drug) from nanoparticles. PLA-PCL-PEG-PCL-PLA copolymers with different block ratio of PCL/PLA segment were synthesized. Release of triamcinolone acetonide from nanoparticles was significantly affected by crystallinity of the copolymers. Burst release of triamcinolone acetonide from nanoparticles was significantly minimized with incorporation of proper ratio of PDLLA in the existing triblock (PCL-PEG-PCL) copolymer. Moreover, pentablock copolymer based nanoparticles exhibited continuous release of triamcinolone acetonide. Pentablock copolymer based nanoparticles can be utilized to achieve continuous near zero-order delivery of corticosteroids from nanoparticles without any burst effect. PMID- 23626401 TI - Migration Decision-Making among Mexican Youth: Individual, Family, and Community Influences. AB - We explored migration decisions using in-depth, semi-structured interviews with male and female youth ages 14 to 24 (n=47) from two Mexican communities, one with high and one with low U.S. migration density. Half were return migrants and half were non-migrants with relatives in the U.S. Migrant and non-migrant youth expressed different preferences, especially in terms of education and their ability to wait for financial gain. Reasons for migration were mostly similar across the two communities; however, the perceived risk of the migration journey was higher in the low density migration community while perceived opportunities in Mexico were higher in the high density migration community. Reasons for return were related to youths' initial social and economic motivations for migration. A greater understanding of factors influencing migration decisions may provide insight into the vulnerability of immigrant youth along the journey, their adaptation process in the U.S., and their reintegration in Mexico. PMID- 23626402 TI - MODERN REGRESSION METHODS THAT CAN SUBSTANTIALLY INCREASE POWER AND PROVIDE A MORE ACCURATE UNDERSTANDING OF ASSOCIATIONS. AB - During the last half century hundreds of papers published in statistical journals have documented general conditions where reliance on least squares regression and Pearson's correlation can result in missing even strong associations between variables. Moreover, highly misleading conclusions can be made, even when the sample size is large. There are, in fact, several fundamental concerns related to non-normality, outliers, heteroscedasticity, and curvature that can result in missing a strong association. Simultaneously, a vast array of new methods have been derived for effectively dealing with these concerns. The paper (1) reviews why least squares regression and classic inferential methods can fail, (2) provides an overview of the many modern strategies for dealing with known problems, including some recent advances, and (3) illustrates that modern robust methods can make a practical difference in our understanding of data. Included are some general recommendations regarding how modern methods might be used. PMID- 23626403 TI - GENDER, DEBT, AND DROPPING OUT OF COLLEGE. AB - For many young Americans, access to credit has become critical to completing a college education and embarking on a successful career path. Young people increasingly face the trade-off of taking on debt to complete college or foregoing college and taking their chances in the labor market without a college degree. These trade-offs are gendered by differences in college preparation and support and by the different labor market opportunities women and men face that affect the value of a college degree and future difficulties they may face in repaying college debt. We examine these new realities by studying gender differences in the role of debt in the pivotal event of graduating from college using the 1997 cohort of the national longitudinal Survey of youth. In this article, we find that women and men both experience slowing and even diminishing probabilities of graduating when carrying high levels of debt, but that men drop out at lower levels of debt than do women. We conclude by theorizing that high levels of debt are one of the mechanisms that sort women and men into different positions in the social stratification system. PMID- 23626404 TI - A functional deficit in the sensorimotor interface component as revealed by oral reading in Thai conduction aphasia. AB - The contemporary view is that a disruption in phonological encoding underlies the speech production deficit in conduction aphasia. We therefore expect to observe a commonality in phonological errors regardless of task - speaking, reading, or writing. A case report is presented of an oral reading task performed by a Thai conduction aphasic with evidence of localized damage in the left temporoparietal zone. He was instructed to read aloud selections from elementary school materials printed in Thai script at his own pace. A phonological analysis of substitution errors revealed that syllable-initial consonants were more vulnerable to disruption than vowels or tones. Tonal errors were seen to be a secondary consequence of a substitution error involving the syllable-initial consonant. His impaired performance is interpreted as evidence in support of a sensorimotor interface system that converts phonological representations derived from visual orthographic input into articulatory motor representations for speech output. PMID- 23626405 TI - Effects of a phonological awareness program on English reading and spelling among Hong Kong Chinese ESL children. AB - This study investigated the effects of a 12-week language-enriched phonological awareness instruction on 76 Hong Kong young children who were learning English as a second language. The children were assigned randomly to receive the instruction on phonological awareness skills embedded in vocabulary learning activities or comparison instruction which consisted of vocabulary learning and writing tasks but no direct instruction in phonological awareness skills. They were tested on receptive and expressive vocabulary, phonological awareness at the syllable, rhyme and phoneme levels, reading, and spelling in English before and after the program implementation. The results indicated that children who received the phonological awareness instruction performed significantly better than the comparison group on English word reading, spelling, phonological awareness at all levels and expressive vocabulary on the posttest when age, general intelligence and the pretest scores were controlled statistically. The findings suggest that phonological awareness instruction embedded in vocabulary learning activities might be beneficial to kindergarteners learning English as a second language. PMID- 23626406 TI - Dielectric Resonator for Ka-Band Pulsed EPR Measurements at Cryogenic Temperatures: Probehead Construction and Applications. AB - The construction and performance of a Ka-band pulsed electron paramagnetic resonance (EPR) cryogenic probehead that incorporates dielectric resonator (DR) is presented. We demonstrate that the use of DR allows one to optimize pulsed double electron-electron resonance (DEER) measurements utilizing large resonator bandwidth and large amplitude of the microwave field B1 . In DEER measurements of Gd-based spin labels, use of this probe finally allows one to implement the potentials of Gd-based labels in distance measurements. Evidently, this DR is well suited to any applications requiring large B1-fields and resonator bandwidths, such as electron spin echo envelope modulation spectroscopy of nuclei having low magnetic moments and strong hyperfine interactions and double quantum coherence dipolar spectroscopy as was recently demonstrated in the application of a similar probe based on an loop-gap resonator and reported by Forrer et al. (J Magn Reson 190:280, 2008). PMID- 23626407 TI - Predicting Stress Related to Basic Needs and Safety in Darfur Refugee Camps: A Structural and Social Ecological Analysis. AB - The research on the determinants of mental health among refugees has been largely limited to traumatic events, but recent work has indicated that the daily hassles of living in refugee camps also play a large role. Using hierarchical linear modelling to account for refugees nested within camp blocks, this exploratory study attempted to model stress surrounding safety and acquiring basic needs and functional impairment among refugees from Darfur living in Chad, using individual level demographics (e.g., gender, age, presence of a debilitating injury), structural factors (e.g., distance from block to distribution centre), and social ecological variables (e.g., percentage of single women within a block). We found that stress concerning safety concerns, daily hassles, and functional impairment were associated with several individual-level demographic factors (e.g., gender), but also with interactions between block-level and individual-level factors as well (e.g., injury and distance to distribution centre). Findings are discussed in terms of monitoring and evaluation of refugee services. PMID- 23626408 TI - The invention of the psychosocial: An introduction. AB - Although the compound adjective 'psychosocial' was first used by academic psychologists in the 1890s, it was only in the interwar period that psychiatrists, psychologists and social workers began to develop detailed models of the psychosocial domain. These models marked a significant departure from earlier ideas of the relationship between society and human nature. Whereas Freudians and Darwinians had described an antagonistic relationship between biological instincts and social forces, interwar authors insisted that individual personality was made possible through collective organization. This argument was advanced by dissenting psychoanalysts such as Ian Suttie and Karen Horney; biologists including Julian Huxley and Hans Selye; philosophers (e.g. Olaf Stapledon), anthropologists (e.g. Margaret Mead) and physicians (e.g John Ryle and James Halliday). This introduction and the essays that follow sketch out the emergence of the psycho-social by examining the methods, tools and concepts through which it was articulated. New statistical technologies and physiological theories allowed individual pathology to be read as an index of broader social problems and placed medical expertise at the centre of new political programmes. In these arguments the intangible structure of social relationships was made visible and provided a template for the development of healthy and effective forms of social organization. By examining the range of techniques deployed in the construction of the psychosocial (from surveys of civilian neurosis, techniques of family observation through to animal models of psychotic breakdown) a critical genealogy of the biopolitical basis of modern society is developed. PMID- 23626409 TI - War on fear: Solly Zuckerman and civilian nerve in the Second World War. AB - This article examines the processes through which civilian fear was turned into a practicable investigative object in the inter-war period and the opening stages of the Second World War, and how it was invested with significance at the level of science and of public policy. Its focus is on a single historical actor, Solly Zuckerman, and on his early war work for the Ministry of Home Security-funded Extra Mural Unit based in Oxford's Department of Anatomy (OEMU). It examines the process by which Zuckerman forged a working relationship with fear in the 1930s, and how he translated this work to questions of home front anxiety in his role as an operational research officer. In doing so it demonstrates the persistent work applied to the problem: by highlighting it as an ongoing research project, and suggesting links between seemingly disparate research objects (e.g. the phenomenon of 'blast' exposure as physical and physiological trauma), the article aims to show how civilian 'nerve' emerged from within a highly specific analytical and operational matrix which itself had complex foundations. PMID- 23626410 TI - An Evolutionary Fitness Enhancement Conferred by the Circadian System in Cyanobacteria. AB - Circadian clocks are found in a wide variety of organisms from cyanobacteria to mammals. Many believe that the circadian clock system evolved as an adaption to the daily cycles in light and temperature driven by the rotation of the earth. Studies on the cyanobacterium, Synechococcus elongatus PCC 7942, have confirmed that the circadian clock in resonance with environmental cycles confers an adaptive advantage to cyanobacterial strains with different clock properties when grown in competition under light-dark cycles. The results thus far suggest that in a cyclic environment, the cyanobacterial strains whose free running periods are closest to the environmental period are the most fit and the strains lacking a functional circadian clock are at a competitive disadvantage relative to strains with a functional clock. In contrast, the circadian system provides little or no advantage to cyanobacteria grown in competition in constant light. To explain the potential mechanism of this clock-mediated enhancement in fitness in cyanobacteria, several models have been proposed; these include the limiting resource model, the diffusible inhibitor model and the cell-to-cell communication model. None of these models have been excluded by the currently available experimental data and the mechanistic basis of clock-mediated fitness enhancement remains elusive. PMID- 23626411 TI - Journal of Minimal Access Surgery: Looking back and looking ahead. PMID- 23626412 TI - Long-term experience on laparoscopic incontinent urinary diversion unrelated to cystectomy in radiated or recurrent pelvic malignancies. AB - BACKGROUND: There are few reports describing series of cases about development on laparoscopic urinary diversions no related to cystectomy. The aim of this paper is to show the experience of our reference institutions for treatment of pelvic malignancies when laparoscopic techniques were applied to perform only urinary diversion without cystectomy or pelvic exenteration. MATERIALS AND METHODS: We included retrospectively 12 cases of cutaneous ureterostomy and 21 cases with a reservoir (16 ileal conduits, 2 colonic conduits and 3 wet colostomies) treated in our institute from 2004 to 2010. It was evaluated operative time, blood loss, intraoperative complications, conversion rate, length of large incision, post operative complications, analgesic consumption, time to food intake, hospital stay, time to recovery to normal activities. Mean time to follow-up was 3(2-7) years. RESULTS: All procedures were completed without conversions. In the cutaneous ureterostomy group the mean surgical time. PMID- 23626413 TI - Single port laparoscopic repair of paediatric inguinal hernias: Our experience at a secondary care centre. AB - BACKGROUND: Congenital inguinal hernias are a common paediatric surgical problem and herniotomy through a groin incision is the gold standard. Over the last 2 decades minimally invasive surgery (MIS) has challenged this conventional surgery. Over a period, MIS techniques have evolved to making it more minimally invasive - from 3 to 2 and now single port technique. All studies using single port technique are from tertiary care centres. We used a modification of the technique described by Ozgediz et al. and reviewed the clinical outcome of this novel procedure and put forth our experience at a secondary level hospital. MATERIALS AND METHODS: Prospective review of 37 hernias in 31 children (29 male and 2 female) (8 months - 13 years) performed laparoscopically by a single surgeon at a single centre between September 2007 and June 2010. Under laparoscopic guidance, the internal ring was encircled extraperitoneally using a 2-0 non-absorbable suture and knotted extraperitoneally. Data analyzed included operating time, ease of procedure, occult patent processus vaginalis (PPV), complications, and cosmesis. RESULTS: Sixteen right (52%), 14 left (45%) and 1 bilateral hernia (3%) were repaired. Five unilateral hernias (16.66%), all left, had a contralateral PPV that was repaired (P = 0.033). Mean operative time for a unilateral and bilateral repair were 13.20 (8-25) and 20.66 min (17 -27 min) respectively. Only one of the repairs (2.7%) recurred and another had a post operative hydrocoele (2.7%). One case (2.7%) needed an additional port placement due to inability to reduce the contents of hernia completely. There were no stitch abscess/granulomas, obvious spermatic cord injuries, testicular atrophy, or nerve injuries. CONCLUSION: Single port laparoscopic inguinal hernia repair can be safely done in the paediatric population. It permits extension of benefits of minimal access surgery to patients being managed at secondary level hospitals with limited resources. The advantage of minimal instrumentation and avoidance of intracorporeal knotting makes it a feasible technique for a secondary care centre. PMID- 23626414 TI - Feasibility of single-incision laparoscopic surgery for appendicitis in abnormal anatomical locations: A single surgeon's initial experience. AB - BACKGROUND: Single-incision laparoscopic surgery is considered as a more technically demanding procedure than the standard laparoscopic surgery. Based on an initial and early experience, single-incision laparoscopic appendectomy (LA) was found to be technically advantageous for dealing with appendicitis in unusual anatomical locations. This study aims to highlight the technical advantages of single-incision laparoscopic surgery in dealing with the abnormally located appendixes and furthermore report a case of acute appendicitis occurring in a sub gastric position, which is probably the first such case to be reported in English literature. MATERIALS AND METHODS: A retrospective analysis of the first 10 cases of single-incision LA which were performed by a single surgeon is presented here. RESULTS: There were seven females and three males. The mean age of the patients was 30.6 (range 18-52) years, mean BMI was 22.7 (range 17-28) kg/m(2) and the mean operative time was 85.5 (range 45-150) min. The mean postoperative stay was 3.6 (range 1-7) days. The commonest position of the appendix was retro-caecal (50%) followed by pelvic (30%). In three cases the appendix was found to be in abnormal locations namely sub-hepatic, sub-gastric and deep pelvic or para vesical or para-rectal. All these cases could be managed with this technique without any conversions. CONCLUSION: Single-incision laparoscopic surgery appears to be a feasible and safe technique for dealing with appendicitis in rare anatomical locations. Appendectomy may be a suitable procedure for the initial training in single-incision laparoscopic surgery. PMID- 23626415 TI - Minimal access surgery in newborns and small infants; five years experience. AB - AIMS AND OBJECTIVES: The aim of this study was to assess and present the outcome (initial experience and lessons learnt) of minimally invasive surgery for various indications in neonates and small infants (< 5 kg) at a single medical centre. MATERIALS AND METHODS: A retrospective analysis was performed on 65 patients (age day 2 to 10 months) managed with minimal access surgery (MAS) for various indications, between 2005 and 2010. We analyzed demographic information, procedures, complications, outcomes, and follow-up and overall feasibility of the procedure. RESULTS: No serious complications except one death in congenital diaphragmatic hernia (CDH) (due to other comorbidities) occurred. Intra operative hypercarbia and hypoxia were observed more frequently in thoracoscopic procedures. Intra operative hypothermia was not common and was well tolerated. Conversion to open procedure (n = 5), post operative ileus (n = 3), port site infection (n = 5) were other complications. CONCLUSION: MAS in neonates and small infants is a technically demanding but a feasible choice available. Some prior experience in older children is required for safe and effective outcome. Good quality optics, video equipments and instruments are required for safe and effective procedure. Intra operative measurement of oxygen saturation and temperature, and diligent post operative ICU care are mandatory for safe and successful outcome. PMID- 23626416 TI - Bronchogenic cyst: Clinical course from antenatal diagnosis to postnatal thoracoscopic resection. AB - PURPOSE: The purpose of this study was to describe an approach to surgical management of bronchogenic cysts based on the natural course observed from the time of antenatal screening to surgical resection in patients treated at our institution and reported in the literature. MATERIALS AND METHODS: We retrospectively reviewed the clinical features of all children presenting bronchogenic cyst diagnosed antenatally from 2007 to 2010. A total of six children were included. RESULTS: Antenatal diagnosis was accurate in 62.5% of cases. In the first year of life, the size of the cyst remained stable in four patients, doubled in one, and increased 30% within six months in one. The indication for surgery was emphysema of the left bronchus in two patients and rapid growth in two patients. One patient is still awaiting surgery. CONCLUSION: Bronchogenic cysts grow slowly in the first months of life, but growth is exponential even in the absence of complications. We recommend complete resection before the age of two years to prevent infectious complications and facilitate surgery. PMID- 23626417 TI - Retained surgical sponge mimicking GIST: Laparoscopic diagnosis and removal 34 years after original surgery. AB - The term gossypiboma denotes a cotton foreign body retained inside the patient during surgery, a rare surgical complication. The symptoms following this entity are non-specific, such as pain, palpable mass and fever, which make clinical diagnosis difficult. The computerized tomography (CT) scan is the most useful method for diagnosis; however, sometimes the preoperative diagnosis remains uncertain even after the imaging exam. In that case, laparoscopy arises as a valuable diagnostic tool, as well as a prompt treatment option. However, when diagnosis is made years after the original surgery, the laparoscopic approach becomes harder. Our patient presented without clear symptoms, remaining asymptomatic for 34 years. The CT scan presumptive diagnosis was a gastrointestinal stromal tumour, and laparoscopy was performed providing an accurate diagnosis and treatment in the same surgical time. PMID- 23626418 TI - Lower gastrointestinal bleeding due to hepatic artery pseudoaneurysm following laparoscopic cholecystectomy. AB - Pseudoaneurysm of hepatic artery is a rare but known complication of laparoscopic cholecystectomy (LC). Such pseudoaneurysms may bleed in biliary tree, upper gastrointestinal (GI) tract or peritoneal cavity leading to life-threatening internal haemorrhage. It is very rare for them to present as lower GI bleeding. We report an unusual case of Right hepatic artery pseudoaneurysm developed following LC, which ruptured into hepatic flexure of colon resulting in catastrophic lower GI bleeding. This was associated with partial celiac artery occlusion due to thrombosis. Due to failure of therapeutic embolisation, the patient was subjected to exploratory laparotomy to control haemorrhage. Postoperatively, patient recovered well and was discharged on postoperative day 10. A strong index of suspicion is necessary for early diagnosis of such condition and to limit resultant morbidity. Angioembolisation is the first-line treatment and surgery is indicated in selected cases. PMID- 23626419 TI - Laparoscopic excision of intra-abdominal oesophageal duplication cyst in a child. AB - Duplication cysts are congenital cystic malformation of the alimentary tract consisting of a duplication of the segment to which it is adjacent. It can occur anywhere from mouth to anus. Oesophageal duplication cysts comprise 4% of the same. Of these, total intra-abdominal oesophageal duplication cysts are extremely rare. On review of literature, only 3 case reports of total intra-abdominal oesophageal duplication managed laparoscopically are found. All these cases were adults. We report the first paediatric case of intra-abdominal oesophageal duplication cyst excised laparoscopically. PMID- 23626420 TI - Laparoscopic excision of mesenteric cyst of sigmoid mesocolon. AB - Mesenteric cysts are rare abdominal tumours. They are found in the mesentery of small bowel (66%) and mesentery of large intestine (33%), usually in the right colon. Very few cases have been reported of tumours found in mesentery of descending colon, sigmoid or rectum. Mesenteric cysts do not show classical clinical findings and are detected incidentally during imaging due to absent or non-specific clinical presentation or during management of one of their complications. Ultrasonography (USG)/computed tomography (CT)/ magnetic resonance imaging (MRI) are used in diagnosing mesenteric cyst but they cannot determine the origin of cyst. Laparoscopy not only helps in diagnosing the site and origin of the mesenteric cyst but also has a therapeutic role. Laparoscopic treatment of mesenteric cyst is a safe, preferred method of treatment and is a less-invasive surgical technique. Here, we present an unusual case of mesenteric cyst arising from the sigmoid mesocolon treated by laparoscopic excision. PMID- 23626421 TI - Polypropelene mesh eroding transverse colon following laparoscopic ventral hernia repair. AB - Polypropylene mesh when used in laparoscopic ventral hernia repair can produce the worst complication such as enterocutaneous fistula. We report an interesting case of incisional hernia operated with laparoscopic polypropylene mesh hernioplasty who subsequently developed an enterocutaneous fistula 1 month after surgery. A fistulogram showed dye entering into the transverse colon. On exploration, the culprit polypropylene mesh was found to have eroded into the mid transverse colon causing the fistula. Resection and end-to-end anastomosis of the colon were done with the removal of the mesh. On literature review, polypropylene mesh erosion in to transverse colon is rare. PMID- 23626422 TI - A modified minimally invasive technique for the surgical management of large trichobezoars. AB - BACKGROUND: Trichobezoar which were traditionally managed by open surgical retrieval are now often managed by minimally invasive surgical approach. Removal of a large trichobezoar by laparoscopy, however, needs an incision (usually 4-5 cm in size) for specimen removal and has the risk of intra-peritoneal spillage of hair and inspissated secretions. MATERIALS AND METHODS: The present paper describes a modified laparoscopy-assisted technique with temporary gastrocutaneopexy for the effective removal of a large trichobezoar using a camera port and a 4-5 cm incision (which is similar to that needed for specimen removal during laparoscopy). RESULTS: Three patients with large trichobezoar were managed with the described technique. The average duration of surgery was 45 (30 60) min and the intraoperative blood loss was minimal. There was no peritoneal spillage and the trichobezoar could be retrieved through a 4-5 cm incision in all patients. All had an uneventful recovery and at a median followup of 6 months had excellent cosmetic and functional results. CONCLUSION: The described technique is a minimally invasive alternative for trichobezoar removal. There is no risk of peritoneal contamination and the technical ease and short operative time in addition to an incision limited to size required for the specimen removal, makes it an attractive option. PMID- 23626423 TI - The "BASE FIRST" technique in laparoscopic appendectomy. PMID- 23626424 TI - Authors' reply. PMID- 23626426 TI - Learning from Bristol - National database for congenital heart disease in India? PMID- 23626425 TI - Auditing our 'selves'. PMID- 23626427 TI - Stage one Norwood procedure in an emerging economy:Initial experience in a single center. AB - OBJECTIVE: The evolution of surgical skills and advances in pediatric cardiac intensive care has resulted in Norwood procedure being increasingly performed in emerging economies. We reviewed the feasibility and logistics of performing stage one Norwood operation in a limited-resource environment based on a retrospective analysis of patients who underwent this procedure in our institution. METHODS: Retrospective review of medical records of seven neonates who underwent Norwood procedure at our institute from October 2010 to August 2012. RESULTS: The median age at surgery was 9 days (range 5-16 days). All cases were done under deep hypothermic cardiopulmonary bypass and selective antegrade cerebral perfusion. The median cardiopulmonary bypass (CPB) time was 240 min (range 193-439 min) and aortic cross-clamp time was 130 min (range 99-159 min). A modified Blalock Taussig (BT) shunt was used to provide pulmonary blood flow in all cases. There were two deaths, one in the early postoperative period. The median duration of mechanical ventilation was 117 h (range 71-243 h) and the median intensive care unit (ICU) stay was 12 days (range 5-16 days). Median hospital stay was 30.5 days (range 10-36 days). Blood stream sepsis was reported in four patients. Two patients had preoperative sepsis. One patient required laparotomy for intestinal obstruction. CONCLUSIONS: Stage one Norwood is feasible in a limited-resource environment if supported by a dedicated postoperative intensive care and protocolized nursing management. Preoperative optimization and prevention of infections are major challenges in addition to preventing early circulatory collapse. PMID- 23626428 TI - Treating hypoplastic left heart syndrome in emerging economies: Heading the wrong way? PMID- 23626429 TI - Conotruncal anomalies in the fetus: Referral patterns and pregnancy outcomes in a dedicated fetal cardiology unit in South India. AB - OBJECTIVE: To describe the referral patterns and pregnancy outcomes of fetuses with conotruncal anomalies (CTA) from a fetal cardiology unit in South India. METHODS: Records of 68 women identified to have diagnosis of CTA on fetal echocardiography (mean gestational age 26.8 +/- 5.9 weeks; range 17-38 weeks) during the period 2008-2011 were reviewed. RESULTS: The most common indication for referral was suspected congenital heart disease during routine antenatal scan (89.7%). The various CTA diagnosed included Tetralogy of Fallot (TOF, 44.1%), Double outlet right ventricle (DORV, 27.9%), Transposition of great vessels (TGA, 8.8%), TOF with pulmonary atresia (TOF-PA, 8.8%), TOF absent pulmonary valve (TOF APV, 7.4%) and truncus arteriosus (TA, 2.9%). Extra cardiac anomalies were reported in 4 fetuses (7.1%). Pregnancy outcomes included pregnancies not culminating in live-birth (54.4%), delivery at term (41.2%) with 3 patients (4.4%) being lost to follow-up. Proportion of pregnancies not culminating in live birth lesion wise include: TOF (53.3%), DORV (52.6%), TGA (50%), TOF -APV (80%), TOF-PA (50%), and TA (50%). Twenty-four babies (35.3%) received post-natal cardiac care with 5 (7.4%) undergoing neonatal surgical procedures. Seven babies (10.3%) died in neonatal period, including 2 who underwent surgery. The accuracy of fetal echo was 96.4% for primary lesion and 67.9% for complete segmental diagnosis. CONCLUSIONS: Pre-natal diagnosis of CTA, despite a high diagnostic accuracy, prompted utilization of post-natal tertiary cardiac care in a limited proportion of patients, including those with reparable lesions. Focus in developing countries should shift towards earlier referral, improving awareness about treatment options and a comprehensive evaluation for associated anomalies. PMID- 23626430 TI - Does fetal echo help the fetus? PMID- 23626431 TI - Asymptomatic right ventricular dysfunction in surgically repaired adult tetralogy of fallot patients. AB - BACKGROUND: Right ventricular (RV) dysfunction after surgical repair of Tetralogy of Fallot (TOF) is often asymptomatic and may be detected by tissue Doppler imaging (TDI). The severity of RV dysfunction is more after intracardiac repair with transannular patch (TAP). METHODS: One hundred seventy-three adult patients who have undergone surgical repair for TOF were prospectively analyzed for RV function using 2D echocardiography and TDI. RV function was compared between patients who have undergone intracardiac repair with and without TAP. RESULTS: In both the patient sub-groups, TDI derived myocardial performance index (MPI) and myocardial velocities were abnormal even when 2D echocardiography derived RV functional area change was normal. TDI derived MPI was significantly higher (0.5 +/- 0.1 vs. 0.4 +/- 0 P < 0.001) and Systolic tricuspid annular velocity (Sa) (9.2 +/- 1.3 vs. 10.8 +/- 1.6 P < 0.001) was significantly lower in the TAP group. Older age at surgery and severity of pulmonary regurgitation on follow-up were among the significant predictors of TDI derived MPI. CONCLUSIONS: Asymptomatic RV dysfunction in surgically repaired adult TOF atients can be detected by TDI. Extent of RV dysfunction was significantly greater with patients requiring TAP, in those operated at older age, and in patients with severe pulmonary regurgitation. PMID- 23626432 TI - Stenosis of the branches of the neopulmonary artery after the arterial switch operation: A cardiac magnetic resonance imaging study. AB - BACKGROUND: The neonatal arterial switch operation (ASO) is now the standard of care for children born with transposition of the great arteries. Stenosis of the neopulmonary artery on long-term follow up is a known complication. METHODS: We performed a retrospective analysis of eleven patients who underwent a cardiac magnetic resonance imaging (MRI) due to echocardiographic evidence suggestive of stenosis of the neopulmonary artery or its branches (mean estimated Doppler gradient 48 mmHg, min 30 mmHg, max 70 mmHg). A comprehensive evaluation of anatomy and perfusion was done by cardiac MRI. RESULTS: The branches of the neopulmonary artery (neo PA) showed decreased caliber in three patients unilaterally and in two patients, bilaterally. Magnetic resonance (MR) perfusion studies showed concomitant decreased flow, with discrepancy between the two lungs of 35/65% or worse, only in the three patients with unilateral obstruction, by two different MR perfusion methods. CONCLUSIONS: Cardiac MR can be used as a comprehensive non-invasive imaging technique to diagnose stenosis of the branches of the neopulmonary after the ASO, allowing evaluation of anatomy and function of the neoPA, its branches, and the differential perfusion to each lung, thus facilitating clinical decision making. PMID- 23626433 TI - Complete heart block due to diphtheritic myocarditis in the present era. AB - Diphtheria continues to be reported from many parts of the world. Complete heart block is rare but often fatal complication of diphtheric myocarditis. We report six children with diphtheric myocarditis who presented with complete heart block. Three patients survived, one with persistent complete heart block. Aggressive supportive management including transvenous pacing may result in complete recovery in a significant number of children with diphtheric myocarditis. PMID- 23626434 TI - Rhythm disturbances in childhood obstructive sleep apnea during apnea-hypopnea episodes. AB - BACKGROUND: Obstructive sleep apnoea (OSA) can result in cardiovascular complications. Nocturnal arrhythmias are reported up to 50% of adult OSA patients. Arrhythmias and heart rate variability in children with OSA have not been well studied. AIMS: We sought to study rhythm disturbances in childhood OSA and also to analyze the relationship of heart rate variability to the severity of OSA in children. METHODS: In a retrospective cross sectional study, records of children aged < 15 years with history of snoring and suspected OSA, who had undergone polysomnography (PSG) for first time were analyzed. The cardiac rhythm and heart rate variability were studied during PSG. RESULTS: A total of 124 patients diagnosed with OSA were grouped into mild (n = 52), moderate (n = 30), and severe (n = 42) OSA. During PSG, all had sinus arrhythmias and only three patients had premature atrial contractions (PACs). The standard deviation of heart rate (SD-HR) during rapid eye movement (REM) sleep in severe OSA (9.1 +/- 2.4) was significantly higher than SD-HR in mild OSA (7.5 +/- 1.3, P < 0.0001). The maximum heart rate (max-HR) during REM-sleep in severe OSA (132.1 +/- 22.1) was significantly higher than the max-HR in mild OSA (121.3 +/- 12.6 bpm, P = 0.016). CONCLUSIONS: There was no significant arrhythmia in children with OSA during their sleep. Heart rate variability correlated with the severity of OSA. PMID- 23626435 TI - Intraoperative hybrid left pulmonary artery stenting. PMID- 23626436 TI - Pacing in children. AB - The implantation of cardiac pacing devices in children and young adults can be challenging and different from the adult population due to their smaller size, their longer life expectancy, and anatomical variations associated with congenital heart defects. A knowledge of indications, pacing leads and devices, anatomical variations, and the technical skills are important for those who implant and care for children with pacemakers. In this review we attempt to discuss these specific points of cardiac pacing in children and young adults. PMID- 23626437 TI - Pathology of Takayasu arteritis: A brief review. AB - Takayasu arteritis (TA) is a chronic idiopathic and granulomatous vasculitis, manifesting mainly as a panaortitis. Autoimmune cell-mediated immunity is probably responsible for the disease. The inflammation commences from the adventitia and progresses to the intima and leads to, both in adults and children, segmental stenosis, occlusion, dilatation, and/or aneurysm formation. This review focuses briefly on the etiopathogenesis, and describes the pathological and clinical features in adults and children. PMID- 23626438 TI - Anti-platelet agents in pediatric cardiac practice. AB - Pediatric patients with a variety of congenital and acquired cardiac conditions receive antithrombotic therapy. Many of the indications are empirical, and have either not been proven in controlled studies or are extrapolated from adult studies. This article reviews the current available literature regarding the use of anti-platelet drugs in the pediatric cardiac population. PMID- 23626439 TI - Right superior vena cava draining in the left atrium associated with tetralogy of Fallot and pulmonary atresia. AB - We report a case of an anomalous drainage of the right superior vena cava to the left atrium with intact atrial septum associated with Tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries. PMID- 23626440 TI - Idiopathic giant right atrial aneurysm. AB - A 2-year-old boy with an incidental finding of massive cardiomegaly on a chest X ray was diagnosed with a giant right atrial aneurysm upon further investigation with echocardiography. The patient underwent successful surgical reduction of the right atrium and closure of the patent foramen ovale to prevent thromboembolic complications and to lower the risk of atrial arrhythmias. The resected atrium had paper-thin walls and pathological features of interstitial fibrosis with endocardial thickening. PMID- 23626441 TI - One-stage total repair of anomalous origin of right pulmonary artery from aorta by the double-flap technique, followed by coarctation repair using extended end to-end arch reconstruction. AB - The anomalous origin of the right pulmonary artery from the ascending aorta combined with coarctation of aorta is a rare congenital malformation. The method chosen for performing a prompt surgery to correct the multiple disease lesions is important. Here we report one-stage surgical strategy which involved a double flap technique alongside an extended end-to-end arch reconstruction in a newborn baby. PMID- 23626442 TI - Persistent electrocardiographic ST segment elevation from previous myocarditis. AB - Various conditions may present with an electrocardiographic pattern of ST segment elevation simulating myocardial infarction. We present an asymptomatic 16-year old male patient, whose ECG showed persistent anterolateral ST segment elevation and magnetic resonance imaging showed wall motion abnormalities from previous myocarditis but no evidence of inflammation. PMID- 23626443 TI - Pre-excitation induced left ventricular dysfunction: A less known cause of cardiomyopathy in children. AB - A 7-year-old boy was diagnosed to have dilated cardiomyopathy with severe left ventricular (LV) dysfunction at 1 year of age. Although well compensated, his LV function remained impaired over the follow-up years. His electrocardiogram (ECG) was initially misinterpreted as left bundle branch block. However, on follow-up, it was recognized as a pre-excited ECG. The accessory pathway causing pre excitation was implicated as the cause of LV dysfunction and dysynchrony as the mechanism. Radiofrequency ablation was done. His LV function and dimensions improved significantly over 6 months follow up. PMID- 23626444 TI - Pseudoaneurysm of mitral-aortic intervalvular fibrosa in a child: Demonstration by MDCT and MRI. AB - Subaortic left ventricular outflow tract pseudoaneurysms are rare lesions that are associated with aortic valve diseases, infective endocarditis, trauma or surgery. We present dynamic multidetector computerized tomography and cine magnetic resonance imaging features of a case of subaortic aneurysm arising from interaortic-mitral valvular region in a child with past history of infective endocarditis. PMID- 23626445 TI - Functional pulmonary atresia in newborn with normal intracardiac anatomy: Successful treatment with inhaled nitric oxide and pulmonary vasodilators. AB - Functional pulmonary atresia is characterized by a structurally normal pulmonary valve that does not open during right ventricular ejection. It is usually associated with Ebstein's anomaly, Uhl's anomaly, neonatal Marfan syndrome and tricuspid valve dysplasia. However, functional pulmonary atresia is rarely reported in newborn with anatomically normal heart. We report a newborn with functional pulmonary atresia who had normal intracardiac anatomy, who responded to treatment with nitric oxide and other vasodilator therapy successfully. PMID- 23626446 TI - Unusual association of aortic valve stenosis with ventricular septal defect and pulmonary atresia: Differentiation from truncus arteriosus with truncal valve stenosis. AB - Stenosis of systemic semilunar valve in cyanotic congenital heart defects is rare. It can happen in truncus arteriosus with truncal valve stenosis and the very rare anomaly of tetralogy of fallot with aortic valve stenosis. Here we describe a neonate with pulmonary atresia, ventricular septal defect and associated aortic valve stenosis and discuss the points of differentiation from truncus arteriosus. PMID- 23626447 TI - Holt-oram syndrome associated with double outlet right ventricle: A rare association. AB - Holt-Oram syndrome is a rare inherited disorder that causes abnormalities of the hands, arms, and the heart. Most commonly, there are defects in the carpal bones of the wrist and in the bones of the thumb along with cardiac defects such as atrial or ventricular septal defects. We report a case of Holt-Oram syndrome with a rare association of double outlet right ventricle. PMID- 23626448 TI - Syncope in a child. AB - Acute rheumatic fever (ARF) is a well-characterized illness. However, syncope in ARF due to advanced heart block is very rare. A 10-year-old boy was admitted with recurrent syncope for 12 h. The patient was diagnosed as ARF because of arthritis, elevated acute phase reactants, advanced heart block, high antistreptolysin O titer, and echocardiographic evidence of mitral regurgitation. On the 9(th) day of hospitalization, the electrocardiogram revealed normal sinus rhythm. PMID- 23626449 TI - Pulsatile neck mass: A rare cause. AB - A 20-year-old female presented with a pulsatile neck mass. On evaluation, she was found to have right cervical aortic arch, which is a rare anomaly. We highlight the conventional and Computed tomography angiography features of this vascular anomaly. PMID- 23626450 TI - Differential diagnosis of vascular structures in relation to upper ascending aorta: The retro-aortic innominate vein. AB - The retroaortic course of left innominate vein is a rare entity which can be misinterpreted during echocardiography for other abnormal vascular structures under the arch of aorta. We report the case of a 2 month old infant where the suprasternal window showed 2 vascular structures beneath the aortic arch, one of which was traced to be a retroaortic innominate vein. PMID- 23626451 TI - Staged pacemaker implantation in a preterm with hydrops fetalis due to complete heart block. PMID- 23626452 TI - Selected summaries. PMID- 23626453 TI - Electrochemical Activation of the Natural Catalytic Cycle of Cytochrome P450s in Human Liver Microsomes. AB - The natural catalytic cycle of cytochrome (cyt) P450 enzymes in human liver microsome (HLM) films was activated electrochemically via the electron transfer sequence electrode->cyt P450 reductase (CPR)->cyt P450. Cyclic voltammograms for HLM films had midpoint potentials of -0.50 V vs. SCE at pH 7.4 characteristic of CPR, not cyt P450s. HLM and CPR microsomes without cyt P450s did not electrocatalytically reduce H2O2, and did not shift midpoint potential when CO was added, also indicating that the peaks do not correspond to iron heme cyt P450 enzymes. Electrochemical activation of the natural cyt P450 cycle for substrate conversion via CPR in HLM films was confirmed by catalytic electrolysis in an electrochemical microfluidic array designed to generate and detect reactive metabolites by measuring their reactivity with DNA. PMID- 23626454 TI - Measures of Mentoring, Department Climate, and Graduate Student Preparedness in the Responsible Conduct of Psychological Research. AB - Drawing upon two independent national samples of 201 and 241 psychology graduate students, this article describes the development and psychometric evaluation of 4 web-based student self-report scales tapping student socialization in the responsible conduct of research (RCR) with human participants. The Mentoring the Responsible Conduct of Research Scale (MRCR) is composed of 2 subscales assessing RCR instruction and modeling by research mentors. The 2 subscales of the RCR Department Climate Scale (RCR-DC) assess RCR department policies and faculty and student RCR practices. The RCR-Preparedness Scale (RCR-P) and the RCR Field Integrity scale (RCR-FI) measure respectively students' confidence in their ability to conduct research responsibly and their belief in the RCR integrity of psychology as a discipline. Factor analysis, coefficient alphas, correlations and multiple regression analyses demonstrated each of the scales had good internal consistency and concurrent and construct validity. PMID- 23626455 TI - Effect of the Ruffled Porphyrin Ring on Electronic Structures: Structure and Characterization of [Fe(TalkylP)(OClO3)] and [Fe(TPrP)(THF)2]ClO4 (alkyl = Ethyl, Et and n-Propyl, Pr). AB - We report the synthesis of Fe(TalkylP)(OClO3)] (alkyl = ethyl and propyl) and [Fe(TPrP)(THF)2]ClO4, which are characterized by UV-vis, EPR, X-ray crystallography, and solid-state magnetic susceptibilities. The macrocycles of all three complexes are ruffled, all of the structural features for [Fe(TEtP(OClO3)] and [Fe(TPrP)(OClO3)] are characteristic of the nearly pure S = 3/2 state, while the structural parameters for [Fe(TPrP)(THF)2]ClO4 feature a pure intermediate-spin (S = 3/2) state, which are all consistent with EPR and magnetic data. It is clear from these studies that the ruffled conformation plays a significant role in affecting the extent of S = 3/2 character. PMID- 23626457 TI - Long-term retinal nerve fiber layer changes following nonarteritic anterior ischemic optic neuropathy. AB - BACKGROUND: In cases of nonarteritic anterior ischemic optic neuropathy (NAION), retinal nerve fiber layer (RNFL) thickness changes have been described during the first 12 months following the acute event. The purpose of this study was to report on the long-term RNFL changes in these eyes beyond the first year following onset of NAION. METHODS: Fourteen eyes of 13 patients with NAION were analyzed in this retrospective observational case series study. Uninvolved eyes served as controls. All patients underwent a complete neuro-ophthalmological examination and repeat measurements of peripapillary RNFL thickness using Stratus optical coherence tomography. RESULTS: On optical coherence tomography scan performed on average 6 months following onset of NAION, the mean global RNFL thickness (59.8 +/- 11.8 MUm) was significantly thinner (P < 0.001) compared with uninvolved eyes (95.1 +/- 13.9 MUm). In a second optical coherence tomography scan performed on average 13 (range 12-23) months later, the mean global RNFL thickness (58.9 +/- 6.5 MUm) was not significantly different (P = 0.702) from the first scan. CONCLUSION: There appears to be no further RNFL loss beyond the first 6 months following an acute event of NAION. PMID- 23626456 TI - Multivariate genetic analysis of learning and early reading development. AB - The genetic factor structure of a range of learning measures was explored in twin children, recruited in preschool and followed to Grade 2 (total N = 2084). Measures of orthographic learning and word reading were included in the analyses to determine how these patterned with the learning processes. An exploratory factor analysis of the genetic correlations among the variables indicated a three factor model. Vocabulary tests loaded on the first factor, the Grade 2 measures of word reading and orthographic learning, plus preschool letter knowledge, loaded on the second, and the third was characterized by tests of verbal short term memory. The three genetic factors correlated, with the second (print) factor showing the most specificity. We conclude that genetically-influenced learning processes underlying print-speech integration, foreshadowed by preschool letter knowledge, have a degree of independence from genetic factors affecting spoken language. We also argue that the psychology and genetics of associative learning be afforded a more central place in studies of reading (dis)ability, and suggest some links to molecular studies of the genetics of learning. PMID- 23626458 TI - Corneal sensitivity after topical bromfenac sodium eye-drop instillation. AB - PURPOSE: To evaluate the safety of bromfenac sodium eye drops from the standpoint of corneal sensitivity and tear secretion in healthy controls following instillation for 1 month. METHODS: A prospective single-blind parallel clinical study was conducted in 20 eyes of ten healthy volunteers with no history of ocular or systemic allergic disease, dry eye, contact lens wear, or ocular surgery. Participants were instructed to instill either bromfenac sodium or artificial tears in each eye twice daily for 28 days. Corneal sensitivity tested using a Cochet-Bonnet esthesiometer was evaluated before and immediately after instillation at 7, 14, and 28 days after the initiation of treatment. Tear secretion was also evaluated by Schirmer's eye test before and at 28 days. RESULTS: No significant difference in mean corneal sensitivity and tear-secretion rate was observed between the bromfenac and artificial-tear treatment groups at any time. CONCLUSION: These results indicate that bromfenac sodium eye drops are safe with respect to corneal sensitivity and tear secretion in subjects with a normal ocular surface condition. Further evaluation is still necessary to determine whether bromfenac is safe in pathological conditions, such as inflammatory disorders and postsurgical cases. PMID- 23626459 TI - Efficacy of autologous platelets in macular hole surgery. AB - The introduction of optical coherence tomography has allowed accurate measurement of the size of macular holes. A retrospective consecutive review was performed of 21 patients undergoing macular hole repair with vitrectomy, gas tamponade, and autologous platelet injection and we assessed the effect of macular hole parameters on anatomic and functional outcomes. We looked at the demographic features, final visual outcome, and anatomical closure. Twenty-one patients were included in the study. They underwent routine vitrectomy with gas tamponade (C3F8) and injection of autologous platelets. All patients were advised to maintain a facedown posture for 2 weeks. Anatomical closure was confirmed in all cases and 20 out of 21 of patients had improved postoperative visual acuity by two or more lines. In our series, the macular hole dimensions did not have much effect on the final results. The use of autologous platelets and strict facedown posture seems to be the deciding factor in good anatomical and visual outcome irrespective of macular hole dimensions. PMID- 23626460 TI - Three-dimensional foveal shape changes after asymptomatic macular posterior vitreous detachment. AB - PURPOSE: To show a case in which the shape of the fovea changed after an asymptomatic macular posterior vitreous detachment (PVD). METHODS: The foveal shape was determined from the spectral-domain optical coherence tomography (OCT) images before and after a spontaneous macular PVD. RESULTS: A 66-year-old man with a unilateral macular hole in the right eye presented with a perifoveal PVD in the asymptomatic left eye. One year later, the left eye developed a macular PVD, and OCT measurements showed a 16.7% decrease in the central foveal thickness, and increases in the pit depth by 20.5%, foveola diameter by 14.7%, and pit volume by 19.4%. The thicknesses of the macular subfields of the Early Treatment Diabetic Retinopathy Study were decreased by 13.0% in the central subfield and by 1.4%-6.6% in the other subfields. CONCLUSION: The deepening and widening of the fovea after a macular PVD indicate that a PVD can alter the shape of the fovea. PMID- 23626461 TI - Tolerability and efficacy of glycemic control with saxagliptin in older patients (aged >= 65 years) with inadequately controlled type 2 diabetes mellitus. AB - PURPOSE: To assess safety and efficacy of saxagliptin in older patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: This was a post hoc analysis of pooled data from older patients (>=65 years of age) from five 24-week phase III trials: three studies of saxagliptin versus placebo as an add-on therapy to metformin, glyburide, or a thiazolidinedione; and two studies of saxagliptin versus placebo as monotherapy in drug-naive patients. Separate analyses were conducted on one study of initial combination therapy with saxagliptin plus metformin versus metformin monotherapy in drug-naive patients. The safety analysis population for the five-study pool included 428 patients >= 65 years of age with baseline glycated hemoglobin (HbA(1c)) 7.0% to 10.5% who received saxagliptin 2.5 or 5 mg or placebo, and for the study of initial combination therapy included 69 patients >= 65 years of age with baseline HbA(1c) 8.0% to 12.0% who received saxagliptin 5 mg in combination with metformin or metformin monotherapy. The primary efficacy endpoint was change from baseline HbA(1c). RESULTS: In the five-study pool, the differences in the adjusted mean change from baseline HbA(1c) among older patients receiving saxagliptin versus placebo were 0.60% (95% confidence interval [CI], -0.99% to -0.21%) for saxagliptin 2.5 mg and -0.55% (-0.97% to -0.14%) for saxagliptin 5 mg; in the initial combination study, the difference was -1.22% (-2.27% to -0.17%) among older patients receiving saxagliptin 5 mg plus metformin versus metformin monotherapy. The results were generally similar in older and younger patients. Saxagliptin was well tolerated; the incidence and types of adverse events were similar for saxagliptin and comparators. Hypoglycemia was reported in 3.0% to 9.4% of patients receiving saxagliptin (0%-8.0% for comparators) and was confirmed (finger stick glucose <= 50 mg/dL, with associated symptoms) in 0% to 0.7% (0%-0.7% for comparators); hypoglycemic episodes did not vary by age category and did not require medical intervention. CONCLUSION: Saxagliptin was effective and well tolerated, with a low risk of hypoglycemia, when used as monotherapy, add-on therapy, or initial combination therapy with metformin in older patients with T2DM. PMID- 23626463 TI - Optimal management of renal cell carcinoma in the elderly: a review. AB - Both the aging population and the incidence of renal cell carcinoma (RCC) are growing, making the question of tumor management in the elderly a real challenge. Doctors should be aware of the importance of assessing this specific subpopulation. An aggressive therapeutic approach may be balanced by the benefit of the treatment - care or cure - and the life expectancy and willingness of the patient. The treatment for local disease can be surgery (radical or partial nephrectomy) or ablative therapies (radiofrequency, cryotherapy). Even if in most cases surgery is safe, complications such as alteration of renal function may occur, especially in the elderly, with physiological renal impairment at baseline. More recently, another option has been developed as an alternative: active surveillance. In the past decade, new drugs have been approved in the metastatic setting. All the phase 3 trials have included patients without a limit on age. Nevertheless, data concerning the elderly are still poor and concern only a very selective subpopulation. The toxicity profile of targeted agents may interfere with pre-existent comorbidities. Furthermore, the metabolism of several agents via cytochrome P450 can cause drug interaction. The importance of quality of life is a major factor with regard to management of therapy. Finally, to date, there is no recommendation of systematic a priori dose reduction in the elderly. In this review we describe the various possibilities of treatment for localized RCC or metastatic RCC in an aging population. PMID- 23626464 TI - Sweeper's lung disease: a cross-sectional study of an overlooked illness among sweepers of Pakistan. AB - BACKGROUND: Sweepers are prone to develop chronic obstructive pulmonary disease even without tobacco smoking. PURPOSE: To investigate roadside dust as a cause of air flow obstruction among sweepers, and the role of spirometry in its preclinical diagnosis. MATERIAL AND METHODS: One-hundred nonsmoking sweepers (aged 30-60 years) of both sexes sweeping on roads for 8-12 hours a day for the Capital Development Authority of Islamabad, Pakistan were used as study participants (Group A). One-hundred healthy nonsmokers (aged 30-60 years) in the same socioeconomic group and living in the same environment represented the nonsweeper group (Group B). After proper clinical evaluation and chest X-rays, spirometric evaluation was carried out in both groups. Comparisons were drawn between various spirometric parameters. RESULTS: Pulmonary function tests showed that the mean forced vital capacity was 78 +/- 1.40 in the sweeper group (Group A) and 83 +/- 0.86 in the nonsweeper group (Group B). Mean forced expiratory volume in 1 second was 66 +/- 1.67 in Group A and 85 +/- 0.85 in Group B (P < 0.05), a difference of 19%. The forced midexpiratory flow was 41% lower in Group A than in Group B (P < 0.0001). The pattern of pulmonary function obstruction was shown to be proportional to the duration of exposure to dust caused by sweeping. CONCLUSION: Occupational exposure to dust leads to an obstructive pattern among sweepers. Spirometry is the simplest, noninvasive technique to detect preclinical disease. PMID- 23626465 TI - Hemostatic absorbable gelatin sponge loaded with 5-fluorouracil for treatment of tumors. AB - BACKGROUND: Surgical tumor resection is the main treatment for tumors however the treatment process often results in massive bleeding and tumor cell residue. The main aim of this research was to address problems such as bleeding, systemic chemotherapy side effects while enhancing quality of life, and increasing drug concentrations at the tumor site by developing a novel formulation with local long-term efficacy for treatment of tumors and to stop bleeding. METHODS: 5 Fluorouracil (5-FU) was suspended in an ethyl acetate solution of poly D,L lactide-co-glycolic acid (PLGA) and a vacuum drying method was applied. The hemostatic gelatin sponge loaded with 5-FU was prepared by absorption of the suspension. The in vitro and in vivo characteristics of the hemostatic gelatin sponge loaded with 5-FU (5-FU-HAGS) were investigated. RESULTS: 5-FU-HAGS (hemostatic absorbable gelatin sponge loaded with 5-fluorouracil) was successfully produced with controlled release of the content and was reproducibly suitable for local tumor treatment as an implant to stop bleeding. The encapsulation efficiency of 5-FU-HAGS was above 98%. The in vitro 5-FU release kinetic profile matched a near zero-order equation for 20 days. The in vivo 5-FU plasma concentration was at a more stable level than when 5-FU solution was administered by subcutaneous injection. Bleeding can be stopped more effectively by coating a piece of blank gelatin sponge. The survival ratio of tumor-bearing mice using a 5-FU-HAGS subcutaneous implant was higher when compared to mice given a subcutaneous injection of 5-FU solution. CONCLUSION: The 5-FU-HAGS system is a potential and effective way of enhancing the survival ratio and improving the quality of life of tumor-bearing mice. PMID- 23626466 TI - Nanostructured self-assembling peptides as a defined extracellular matrix for long-term functional maintenance of primary hepatocytes in a bioartificial liver modular device. AB - Much effort has been directed towards the optimization of the capture of in vivo hepatocytes from their microenvironment. Some methods of capture include an ex vivo cellular model in a bioreactor based liver module, a micropatterned module, a microfluidic 3D chip, coated plates, and other innovative approaches for the functional maintenance of primary hepatocytes. However, none of the above methods meet US Food and Drug Administration (FDA) guidelines, which recommend and encourage that the duration of a toxicity assay of a drug should be a minimum of 14 days, to a maximum of 90 days for a general toxicity assay. Existing innovative reports have used undefined extracellular matrices like matrigel, rigid collagen, or serum supplementations, which are often problematic, unacceptable in preclinical and clinical applications, and can even interfere with experimental outcomes. We have overcome these challenges by using integrated nanostructured self-assembling peptides and a special combination of growth factors and cytokines to establish a proof of concept to mimic the in vivo hepatocyte microenvironment pattern in vitro for predicting the in vivo drug hepatotoxicity in a scalable bioartificial liver module. Hepatocyte functionality (albumin, urea) was measured at days 10, 30, 60, and 90 and we observed stable albumin secretion and urea function throughout the culture period. In parallel, drug metabolizing enzyme biomarkers such as ethoxyresorufin-O-deethylase, the methylthiazol tetrazolium test, and the lactate dehydrogenase test were carried out at days 10, 30, 60, and 90. We noticed excellent mitochondrial status and membrane stability at 90 days of culture. Since alpha glutathione S-transferase (GST) is highly sensitive and a specific marker of hepatocyte injury, we observed significantly low alpha GST levels on all measured days (10, 30, 60, and 90). Finally, we performed the image analysis of mitochondria-cultured hepatocytes at day 90 in different biophysical parameters using confocal microscopy. We applied an automatic algorithm-based method for 3D visualization to show the classic representation of the mitochondrial distribution in double hepatocytes. An automated morphological measurement was conducted on the mitochondrial distribution in the cultured hepatocytes. Our proof of concept of a scalable bioartificial liver modular device meets FDA guidelines and may function as an alternative model of animal experimentation for pharmacological and toxicological studies involving drug metabolism, enzyme induction, transplantation, viral hepatitis, hepatocyte regeneration, and can also be used in other existing bioreactor modules for long-term culture for up to 90 days or more. PMID- 23626467 TI - A novel small peptide as an epidermal growth factor receptor targeting ligand for nanodelivery in vitro. AB - The epidermal growth factor receptor (EGFR) serves an important function in the proliferation of tumors in humans and is an effective target for the treatment of cancer. In this paper, we studied the targeting characteristics of small peptides (AEYLR, EYINQ, and PDYQQD) that were derived from three major autophosphorylation sites of the EGFR C-terminus domain in vitro. These small peptides were labeled with fluorescein isothiocyanate (FITC) and used the peptide LARLLT as a positive control, which bound to putative EGFR selected from a virtual peptide library by computer-aided design, and the independent peptide RALEL as a negative control. Analyses with flow cytometry and an internalization assay using NCI-H1299 and K562 with high EGFR and no EGFR expression, respectively, indicated that FITC AEYLR had high EGFR targeting activity. Biotin-AEYLR that was specifically bound to human EGFR proteins demonstrated a high affinity for human non-small-cell lung tumors. We found that AEYLR peptide-conjugated, nanostructured lipid carriers enhanced specific cellular uptake in vitro during a process that was apparently mediated by tumor cells with high-expression EGFR. Analysis of the MTT assay indicated that the AEYLR peptide did not significantly stimulate or inhibit the growth activity of the cells. These findings suggest that, when mediated by EGFR, AEYLR may be a potentially safe and efficient delivery ligand for targeted chemotherapy, radiotherapy, and gene therapy. PMID- 23626468 TI - The inhibitory effect of small interference RNA protein kinase C-alpha on the experimental proliferative vitreoretinopathy induced by dispase in mice. AB - AIM: To evaluate the effects of small interference RNA protein kinase C-alpha (siRNA-PKCalpha) on experimental proliferative vitreoretinopathy (PVR) induced by dispase in mice. METHODS: C57BL/6 mice PVR models (4-6 weeks old) were induced by intravitreal injection of dispase and then equally divided into six groups. After 1 week, the five treatment groups received 2 MUL, intravitreal injections of siRNA-PKCalpha at a concentration of 250 nM, 500 nM, 750 nM, 1000 nM, and 1500 nM, respectively, while the negative control group received 2 MUL of 500 nM no silencing siRNA. SiRNA-PKCalpha was transfected by a square wave electroporator. Postoperative ophthalmic observations of lens clarity and the fundus of the eyes were performed periodically. The eyeballs of the mice were enucleated and imbedded in optimal cutting temperature to perform histological and immunofluorescence analysis at the end of a 4-week observation period. RESULTS: Four weeks after the siRNA-PKCalpha injections, there are 100% lens dissolution and 100% PVR in the 250 nM group and 70%, 70%, 70%, and 50% PVR in the 500 nM, 750 nM, 1000 nM, and 1500 nM groups, respectively, which is significantly different from the negative group. Abnormalities in fundus appearance were related to the concentrations of siRNA-PKCalpha; a higher concentration of siRNA PKCalpha resulted in a more normal fundus. Histological sections by hematoxylin eosin staining of the eyes support the clinical observation. Immunofluorescence analysis showed that RPE65, glutamine synthase, glial acidic fibrillary protein, and alpha-smooth muscle actin were increasing in the retina with the decreasing concentration of siRNA-PKCalpha, indicating that intraocular siRNA-PKCalpha can partly inhibit changes of markers for glia cells, fibroblast cells, retinal pigment epithelium cells, and Muller cells in the process of PVR. CONCLUSION: Gene therapy with siRNA-PKCalpha could effectively inhibit PVR in mice and provide us with a novel therapeutic target on PVR. PMID- 23626469 TI - Stress-induced cardiomyopathy (Takotsubo)--broken heart and mind? AB - Stress-induced cardiomyopathy (SIC), also known as Takotsubo cardiomyopathy, is characterized by severe but potentially reversible regional left ventricular wall motion abnormalities, ie, akinesia, in the absence of explanatory angiographic evidence of a coronary occlusion. The typical pattern is that of an akinetic apex with preserved contractions in the base, but other variants are also common, including basal or midmyocardial akinesia with preserved apical function. The pathophysiology of SIC remains largely unknown but catecholamines are believed to play a pivotal role. The diverse array of triggering events that have been linked to SIC are arbitrarily categorized as either emotional or somatic stressors. These categories can be considered as different elements of a continuous spectrum, linked through the interface of neurology and psychiatry. This paper reviews our current knowledge of SIC, with focus on the intimate relationship between the brain and the heart. PMID- 23626470 TI - Update on the management of cirrhosis - focus on cost-effective preventative strategies. AB - Cirrhosis is a chronic liver disease stage that encompasses a variety of etiologies resulting in liver damage. This damage may induce secondary complications such as portal hypertension, esophageal variceal bleeding, spontaneous bacterial peritonitis, and hepatic encephalopathy. Screening for and management of these complications incurs substantial health care costs; thus, determining the most economical and beneficial treatment strategies is essential. This article reviews the economic impact of a variety of prophylactic and treatment regimens employed for cirrhosis-related complications. Prophylactic use of beta-adrenergic blockers for portal hypertension and variceal bleeding appears to be cost-effective, but the most economical regimen for treatment of initial bleeding is unclear given that cost comparisons of pharmacologic and surgical regimens are lacking. In contrast, prophylaxis for spontaneous bacterial peritonitis cannot be recommended. Standard therapy for spontaneous bacterial peritonitis includes antibiotics, and the overall economic impact of these medications depends largely on their direct cost. However, the potential development of bacterial antibiotic resistance and resulting clinical failure should also be considered. Nonabsorbable disaccharides are standard therapies for hepatic encephalopathy; however, given their questionable efficacy, the nonsystemic antibiotic rifaximin may be a more cost-effective, long-term treatment for hepatic encephalopathy, despite its increased direct cost, because of its demonstrated efficacy and prevention of hospitalization. Further studies evaluating the cost burden of cirrhosis and cirrhosis-related complications, including screening costs, the cost of treatment and maintenance therapy, conveyance to liver transplantation, liver transplantation success, and health related quality of life after transplantation, are essential for evaluation of the economic burden of hepatic encephalopathy and all cirrhosis-related complications. PMID- 23626471 TI - Intrapleural hemorrhage due to alteplase use in a 6-year-old boy with pleural effusion. AB - BACKGROUND: Intrapleural fibrinolytics have been used successfully worldwide for the management of complicated pleural effusions and empyema. Bleeding complications are usually mentioned as rare side effects, but there is no clear information in the literature addressing the alarming outcome that might result following the use of alteplase as a fibrinolytic in the management of complicated parapneumonic effusions. We present a rare, if not unique, case of intrapleural hemorrhage requiring transfusion after alteplase use as a fibrinolytic in a 6 year-old male with complicated parapneumonic effusion. METHODS: A SEARCH OF THE PUBMED DATABASE WAS CARRIED OUT, USING A COMBINATION OF THE FOLLOWING TERMS: alteplase, fibrinolytic, intrapleural hemorrhage, and side effects. RESULTS: The majority of studies found in the search concentrated on the efficacy of intrapleural fibrinolytics in the management of pleural effusion, but very few of the reports addressed the bleeding complications which may be caused by the treatment. CONCLUSION: Although intrapleural and systemic hemorrhage are rare side effects of intrapleural fibrinolytic use, the health care provider must be watchful for these potentially life-threatening complications. Further studies are needed to understand not only the efficacy of fibrinolytics but also their safety, especially in children. PMID- 23626473 TI - Ginsenosides Have a Suppressive Effect on c-Fos Expression in Brain and Reduce Cardiovascular Responses Increased by Noxious Stimulation to the Rat Tooth. AB - The purpose of this study is to investigate the antinociceptive effects of ginsenosides on toothache. c-Fos immunoreactive (IR) neurons were examined after noxious intrapulpal stimulation (NS) by intrapulpal injection of 2 M KCl into upper and lower incisor pulps exposed by bone cutter in Sprague Dawley rats. The number of Fos-IR neurons was increased in the trigeminal subnucleus caudalis (Vc) and the transitional region between Vc and subnucleus interpolaris (Vi) by NS to tooth. The intradental NS raised arterial blood pressure (BP) and heart rate (HR). The number of Fos-IR neurons was also enhanced in thalamic ventral posteromedial nucleus (VPMN) and centrolateral nucleus (CLN) by NS to tooth. The intradental NS increased the number of Fos-IR neurons in the nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM), hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN), central cardiovascular regulation centers. Ginsenosides reduced the number of c-Fos-IR increased by NS to tooth in the trigeminal Vc and thalamic VPMN and CLN. Naloxone, an opioid antagonist, did not block the effect of ginsenoside on the number of Fos-IR neurons enhanced by NS to tooth in the trigeminal Vc and thalamic VPMN and CLN. Ginsenosides ameliorated arterial BP and HR raised by NS to tooth and reduced the number of Fos-IR neurons increased by NS to tooth in the NTS, RVLM, hypothalamic SON, and PVN. These results suggest that ginsenosides have an antinociceptive effect on toothache through non-opioid system and attenuates BP and HR increased by NS to tooth. PMID- 23626472 TI - Prolyl 4 hydroxylase: a critical target in the pathophysiology of diseases. AB - Prolyl 4 hydroxylases (P4H) are iron- and 2-oxoglutamate-dependent dioxygenase enzymes and hypoxia-inducible transcription factor (HIF)-P4Hs play a critical role in the regulating oxygen homeostasis in the local tissues as well in the systemic circulation. Over a period of time, a number of prolyl hydroxylase inhibitors and activators have been developed. By employing the pharmacological tools and transgenic knock out animals, the critical role of these enzymes has been established in the pathophysiology of number of diseases including myocardial infarction, congestive heart failure, stroke, neurodegeneration, inflammatory disease, respiratory diseases, retinopathy and others. The present review discusses the different aspects of these enzymes including their pathophysiological role in disease development. PMID- 23626474 TI - Inhibitory Effects of Ginsenoside Metabolites, Compound K and Protopanaxatriol, on GABAC Receptor-Mediated Ion Currents. AB - Ginsenosides, one of the active ingredients of Panax ginseng, show various pharmacological and physiological effects, and they are converted into compound K (CK) or protopanaxatriol (M4) by intestinal microorganisms. CK is a metabolite derived from protopanaxadiol (PD) ginsenosides, whereas M4 is a metabolite derived from protopanaxatriol (PT) ginsenosides. The gamma-aminobutyric acid receptorC (GABAC) is primarily expressed in retinal bipolar cells and several regions of the brain. However, little is known of the effects of ginsenoside metabolites on GABAC receptor channel activity. In the present study, we examined the effects of CK and M4 on the activity of human recombinant GABAC receptor (rho1) channels expressed in Xenopus oocytes by using a 2-electrode voltage clamp technique. In oocytes expressing GABAC receptor cRNA, we found that CK or M4 alone had no effect in oocytes. However, co-application of either CK or M4 with GABA inhibited the GABA-induced inward peak current (IGABA ). Interestingly, pre application of M4 inhibited IGABA more potently than CK in a dose-dependent and reversible manner. The half-inhibitory concentration (IC50) values of CK and M4 were 52.1+/-2.3 and 45.7+/-3.9 uM, respectively. Inhibition of IGABA by CK and M4 was voltage-independent and non-competitive. This study implies that ginsenoside metabolites may regulate GABAC receptor channel activity in the brain, including in the eyes. PMID- 23626475 TI - Ginsenoside rg2 inhibits lipopolysaccharide-induced adhesion molecule expression in human umbilical vein endothelial cell. AB - Vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), P- and E-selectin play a pivotal role for initiation of atherosclerosis. Ginsenoside, a class of steroid glycosides, is abundant in Panax ginseng root, which has been used for prevention of illness in Korea. In this study, we investigated the mechanism(s) by which ginsenoside Rg2 may inhibit VCAM 1 and ICAM-1 expressions stimulated with lipopolysaccharide (LPS) in human umbilical vein endothelial cell (HUVEC). LPS increased VCAM-1 and ICAM-1 expression. Ginsenoside Rg2 prevented LPS-mediated increase of VCAM-1 and ICAM-1 expression. On the other hand, JSH, a nuclear factor kappa B (NF-kappaB) inhibitor, reduced both VCAM-1 and ICAM-1 expression stimulated with LPS. SB202190, inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), and wortmannin, phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, reduced LPS mediated VCAM-1 but not ICAM-1 expression. PD98059, inhibitor of mitogen activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) did not affect VCAM-1 and ICAM-1 expression stimulated with LPS. SP600125, inhibitor of c-Jun N-terminal kinase (JNK), reduced LPS-mediated ICAM-1 but not VCAM-1 expression. LPS reduced IkappaBalpha (IkappaBalpha) expression, in a time dependent manner within 1 hr. Ginsenoside Rg2 prevented the decrease of IkappaBalpha expression stimulated with LPS. Moreover, ginsenoside Rg2 reduced LPS-mediated THP-1 monocyte adhesion to HUVEC, in a concentration-dependent manner. These data provide a novel mechanism where the ginsenoside Rg2 may provide direct vascular benefits with inhibition of leukocyte adhesion into vascular wall thereby providing protection against vascular inflammatory disease. PMID- 23626476 TI - Signaling pathway of lysophosphatidic Acid-induced contraction in feline esophageal smooth muscle cells. AB - Lysolipids such as LPA, S1P and SPC have diverse biological activities including cell proliferation, differentiation, and migration. We investigated signaling pathways of LPA-induced contraction in feline esophageal smooth muscle cells. We used freshly isolated smooth muscle cells and permeabilized cells from cat esophagus to measure the length of cells. Maximal contraction occurred at 10(-6) M and the response peaked at 30s. To identify LPA receptor subtypes in cells, western blot analysis was performed with antibodies to LPA receptor subtypes. LPA1 and LPA3 receptor were detected at 50 kDa and 44 kDa. LPA-induced contraction was almost completely blocked by LPA receptor (1/3) antagonist KI16425. Pertussis toxin (PTX) inhibited the contraction induced by LPA, suggesting that the contraction is mediated by a PTX-sensitive G protein. Phospholipase C (PLC) inhibitors U73122 and neomycin, and protein kinase C (PKC) inhibitor GF109203X also reduced the contraction. The PKC-mediated contraction may be isozyme-specific since only PKCepsilon antibody inhibited the contraction. MEK inhibitor PD98059 and JNK inhibitor SP600125 blocked the contraction. However, there is no synergistic effect of PKC and MAPK on the LPA-induced contraction. In addition, RhoA inhibitor C3 exoenzyme and ROCK inhibitor Y27632 significantly, but not completely, reduced the contraction. The present study demonstrated that LPA-induced contraction seems to be mediated by LPA receptors (1/3), coupled to PTX-sensitive G protein, resulting in activation of PLC, PKC epsilon pathway, which subsequently mediates activation of ERK and JNK. The data also suggest that RhoA/ROCK are involved in the LPA-induced contraction. PMID- 23626477 TI - Effects of histamine on cultured interstitial cells of cajal in murine small intestine. AB - Interstitial cells of Cajal (ICCs) are the pacemaker cells in the gastrointestinal tract, and histamine is known to regulate neuronal activity, control vascular tone, alter endothelial permeability, and modulate gastric acid secretion. However, the action mechanisms of histamine in mouse small intestinal ICCs have not been previously investigated, and thus, in the present study, we investigated the effects of histamine on mouse small intestinal ICCs, and sought to identify the receptors involved. Enzymatic digestions were used to dissociate ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record potentials (in current clamp mode) from cultured ICCs. Histamine was found to depolarize resting membrane potentials concentration dependently, and whereas 2-PEA (a selective H1 receptor agonist) induced membrane depolarizations, Dimaprit (a selective H2-agonist), R-alpha-methylhistamine (R-alpha-MeHa; a selective H3-agonist), and 4-methylhistamine (4-MH; a selective H4-agonist) did not. Pretreatment with Ca(2+)-free solution or thapsigargin (a Ca(2+)-ATPase inhibitor in endoplasmic reticulum) abolished the generation of pacemaker potentials and suppressed histamine-induced membrane depolarization. Furthermore, treatments with U-73122 (a phospholipase C inhibitor) or 5-fluoro-2-indolyl des chlorohalopemide (FIPI; a phospholipase D inhibitor) blocked histamine-induced membrane depolarizations in ICCs. On the other hand, KT5720 (a protein kinase A inhibitor) did not block histamine-induced membrane depolarization. These results suggest that histamine modulates pacemaker potentials through H1 receptor mediated pathways via external Ca(2+) influx and Ca(2+) release from internal stores in a PLC and PLD dependent manner. PMID- 23626478 TI - Insulin Like Growth Factor Binding Protein-5 Regulates Excessive Vascular Smooth Muscle Cell Proliferation in Spontaneously Hypertensive Rats via ERK 1/2 Phosphorylation. AB - Insulin-like growth factor binding proteins (IGFBPs) are important components of insulin growth factor (IGF) signaling pathways. One of the binding proteins, IGFBP-5, enhances the actions of IGF-1, which include the enhanced proliferation of smooth muscle cells. In the present study, we examined the expression and the biological effects of IGFBP-5 in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). The levels of IGFBP-5 mRNA and protein were found to be higher in the VSMC from SHR than in those from WKY. Treatment with recombinant IGFBP-5-stimulated VSMC proliferation in WKY to the levels observed in SHR. In the VSMCs of WKY, incubation with angiotensin (Ang) II or IGF-1 dose dependently increased IGFBP-5 protein levels. Transfection with IGFBP-5 siRNA reduced VSMC proliferation in SHR to the levels exhibited in WKY. In addition, recombinant IGFBP-5 significantly up-regulated ERK1/2 phosphorylation in the VSMCs of WKY as much as those of SHR. Concurrent treatment with the MEK1/2 inhibitors, PD98059 or U0126 completely inhibited recombinant IGFBP-5-induced VSMC proliferation in WKY, while concurrent treatment with the phosphatidylinositol-3 kinase inhibitor, LY294002, had no effect. Furthermore, knockdown with IGFBP-5 siRNA inhibited ERK1/2 phosphorylation in VSMC of SHR. These results suggest that IGFBP-5 plays a role in the regulation of VSMC proliferation via ERK1/2 MAPK signaling in hypertensive rats. PMID- 23626479 TI - Effect of cholera toxin administered supraspinally or spinally on the blood glucose level in pain and d-glucose fed animal models. AB - In the present study, the effect of intrathecal (i.t.) or intracerebroventricular (i.c.v.) administration with cholera toxin (CTX) on the blood glucose level was examined in ICR mice. The i.t. treatment with CTX alone for 24 h dose-dependently increased the blood glucose level. However, i.c.v. treatment with CTX for 24 h did not affect the blood glucose level. When mice were orally fed with D-glucose (2 g/kg), the blood glucose level reached to a maximum level at 30 min and almost returned to the control level at 120 min after D-glucose feeding. I.c.v. pretreatment with CTX increased the blood glucose level in a potentiative manner, whereas i.t. pretreatment with CTX increased the blood glucose level in an additive manner in a D-glucose fed group. In addition, the blood glucose level was increased in formalin-induced pain animal model. I.c.v. pretreatment with CTX enhanced the blood glucose level in a potentiative manner in formalin-induced pain animal model. On the other hand, i.t. pretreatment with CTX increased the blood glucose level in an additive manner in formalin-induced pain animal model. Our results suggest that CTX administered supraspinally or spinally differentially modulates the regulation of the blood glucose level in D-glucose fed model as well as in formalin-induced pain model. PMID- 23626480 TI - Oxytocin ameliorates remote liver injury induced by renal ischemia-reperfusion in rats. AB - Renal ischemia-reperfusion (IR) causes remote liver damage. Oxytocin has anti inflammatory and antioxidant effects. The main purpose of this study was to evaluate the protective function of oxytocin (OT) in remote liver damage triggered by renal IR in rats. Twenty four rats were randomly divided into four different groups, each containing 8 rats. The groups were as follows: (1) Sham operated group; (2) Sham operated+OT group (3) Renal IR group; (4) Renal IR+OT group. OT (500ug/kg) was administered subcutaneously 12 and 24 hours before and immediately after ischemia. At the end of experimental procedure, the rats were sacrificed, and liver specimens were taken for histological assessment or determination of malondialdehyde (MDA), total oxidant status (TOS), total antioxidant status (TAS), paraoxonase (PON-1) activity and nitric oxide (NO). The results showed that renal IR injury constituted a notable elevation in MDA, TOS, Oxidative stress index (OSI) and significantly decreased TAS, PON-1 actvity and NO in liver tissue (p<0.05). Additionally renal IR provoked significant augmentation in hepatic microscopic damage scores. However, alterations in these biochemical and histopathological indices due to IR injury were attenuated by OT treatment (p<0.05). These findings show that OT ameliorates remote liver damage triggered by renal ischemia-reperfusion and this preservation involves suppression of inflammation and regulation of oxidant-antioxidant status. PMID- 23626481 TI - Resveratrol Inhibits GABAC rho Receptor-Mediated Ion Currents Expressed in Xenopus Oocytes. AB - Resveratrol is a phytoalexin found in grapes, red wine, and berries. Resveratrol has been known to have many beneficial health effects, such as anti-cancer, neuroprotective, anti-inflammatory, and life-prolonging effects. However, relatively little is known about the effects of resveratrol on the regulation of ligand-gated ion channels. We have previously reported that resveratrol regulates subsets of homomeric ligand-gated ion channels such as those of 5-HT3A receptors. The gamma-aminobutyric acidC (GABAC) receptor is mainly expressed in retinal bipolar cells and plays an important role in visual processing. In the present study, we examined the effects of resveratrol on the channel activity of homomeric GABAC receptor expressed in Xenopus oocytes injected with cRNA encoding human GABAC rho subunits. Our data show that the application of GABA elicits an inward peak current (IGABA ) in oocytes that express the GABAC receptor. Resveratrol treatment had no effect on oocytes injected with H2O or with GABAC receptor cRNA. Co-treatment with resveratrol and GABA inhibited IGABA in oocytes with GABAC receptors. The inhibition of IGABA by resveratrol was in a reversible and concentration-dependent manner. The IC50 of resveratrol was 28.9+/-2.8 uM in oocytes expressing GABAC receptor. The inhibition of IGABA by resveratrol was in voltage-independent and non-competitive manner. These results indicate that resveratrol might regulate GABAC receptor expression and that this regulation might be one of the pharmacological actions of resveratrol on the nervous system. PMID- 23626482 TI - Resolving conflicting views: Gaze and arrow cues do not trigger rapid reflexive shifts of attention. AB - It has become widely accepted that the direction of another individual's eye gaze induces rapid, automatic, attentional orienting, due to it being such a vital cue as to where in our environment we should attend. This automatic orienting has also been associated with the directional-arrow cues used in studies of spatial attention. Here, we present evidence that the response-time cueing effects reported for spatially non-predictive gaze and arrow cues are not the result of rapid, automatic shifts of attention. For both cue types, response-time effects were observed only for long-duration cue and target stimuli that overlapped temporally, were largest when the cues were presented simultaneously with the response-relevant target, and were driven by a slowing of responses for invalidly cued targets rather than speeding for validly cued ones. These results argue against automatic attention-orienting accounts and support a novel spatial incongruency explanation for a whole class of rapid behavioral cueing effects. PMID- 23626483 TI - The Adaptation of the Immigrant Second Generation in America: Theoretical Overview and Recent Evidence. AB - This paper summarises a research program on the new immigrant second generation initiated in the early 1990s and completed in 2006. The four field waves of the Children of Immigrants Longitudinal Study (CILS) are described and the main theoretical models emerging from it are presented and graphically summarised. After considering critical views of this theory, we present the most recent results from this longitudinal research program in the forum of quantitative models predicting downward assimilation in early adulthood and qualitative interviews identifying ways to escape it by disadvantaged children of immigrants. Quantitative results strongly support the predicted effects of exogenous variables identified by segmented assimilation theory and identify the intervening factors during adolescence that mediate their influence on adult outcomes. Qualitative evidence gathered during the last stage of the study points to three factors that can lead to exceptional educational achievement among disadvantaged youths. All three indicate the positive influence of selective acculturation. Implications of these findings for theory and policy are discussed. PMID- 23626484 TI - Synthesis, Characterization, and in vitro Testing of a Bacteria-Targeted MR Contrast Agent. AB - A bacteria-targeted MR contrast agent, Zn-1, consisting of two Zn-dipicolylamine (Zn-dpa) groups conjugated to a GdIII chelate has been synthesized and characterized. In vitro studies with S. aureus and E. coli show that Zn-1 exhibits a significant improvement in bacteria labeling efficiency vs. control. Studies with a structural analogue, Zn-2, indicate that removal of one Zn-dpa moiety dramatically reduces the agent's affinity for bacteria. The ability of Zn 1 to significantly reduce the T1 of labeled vs. unlabeled bacteria, resulting in enhanced MR image contrast, demonstrates its potential for visualizing bacterial infections in vivo. PMID- 23626485 TI - From desires to behavior: Moderating factors in a fertility transition. AB - BACKGROUND: Extensive research in both developed and developing countries has shown that preferences and intentions for future childbearing predict behavior. However, very little of this research has examined high-fertility contexts in sub Saharan Africa. In particular, the factors that increase or decrease correspondence between fertility desires and behavior in these settings are not well understood. OBJECTIVE: This article documents the degree to which the desire to stop childbearing predicts fertility behavior over the short term among married women in rural southern Mozambique, a context where fertility transition is still in the early stages. Analyses test the moderating powers of individual, household, and community characteristics. METHODS: Analyses use data from a longitudinal survey of married women of reproductive age (N=1678) carried out in 2006 and 2009 in rural areas of southern Mozambique. Logistic regression models are estimated to predict childbearing between 2006 and 2009 based on desires to stop childbearing and characteristics measured in 2006. RESULTS: As expected, the desire to stop childbearing is strongly predictive of fertility behavior. Household wealth, local adult AIDS mortality, and being married to an unsuccessful labor migrant are associated with higher correspondence between reported desire to stop childbearing and fertility behavior. CONCLUSIONS: Both factors related to the ability to carry out desires to stop childbearing and factors related to the strength and consistency of these desires moderate the association between desires and behaviors. Future research should expand measurement of fertility preferences to incorporate their strength and consistency as well as direction. PMID- 23626486 TI - Predictors of Unsafe Sex among At-Risk Heterosexual Women. AB - Despite widespread intervention efforts to curtail the spread of HIV, heterosexual transmission of HIV continues to drive the HIV/AIDS epidemic in the United States, especially among women. Research has shown that knowledge about HIV and AIDS is relatively great, even among persons who engage in high rates of risky sexual behaviors. This begs the question: What characteristics underlie and are predictive of involvement in unprotected sex? The objective of this paper is to examine the factors that are associated with engaging in unprotected sex in a population of urban, at-risk, heterosexually-active women. Conceptually, the research is guided by the notion of understanding risk and, theoretically, by the Theory of Gender and Power. Face-to-face structured interviews were conducted with 178 sexually active adult at-risk heterosexual women in Atlanta, Georgia. Street outreach efforts were used to identify potential study participants, and ethnographic mapping and targeted sampling procedures guided the recruitment process. Using a multivariate path analysis approach, three factors-marital status, having two drug-abusing parents, and negative attitudes toward condom use were identified as predictors of unsafe sex. Further exploration of the latter measure yielded two factors that were statistically-significant multivariate predictors of attitudes toward using condoms: age and self-esteem level. Structural equation modeling was used to assess the fit of a risk-prediction model containing all of these measures, and it was shown to be supported quite strongly by the data. PMID- 23626487 TI - Emphasizing Social Features in Information Portals: Effects on New Member Engagement. AB - Many information portals are adding social features with hopes of enhancing the overall user experience. Invitations to join and welcome pages that highlight these social features are expected to encourage use and participation. While this approach is widespread and seems plausible, the effect of providing and highlighting social features remains to be tested. We studied the effects of emphasizing social features on users' response to invitations, their decisions to join, their willingness to provide profile information, and their engagement with the portal's social features. The results of a quasi-experiment found no significant effect of social emphasis in invitations on receivers' responsiveness. However, users receiving invitations highlighting social benefits were less likely to join the portal and provide profile information. Social emphasis in the initial welcome page for the site also was found to have a significant effect on whether individuals joined the portal, how much profile information they provided and shared, and how much they engaged with social features on the site. Unexpectedly, users who were welcomed in a social manner were less likely to join and provided less profile information; they also were less likely to engage with social features of the portal. This suggests that even in online contexts where social activity is an increasingly common feature, highlighting the presence of social features may not always be the optimal presentation strategy. PMID- 23626488 TI - Strategies for Fostering Synergy between Neuroscience Programs and Chemistry Departments. AB - The successful model of the Neuroscience Program at Concordia College is used as a source of illustrative examples in a presentation of strategies to foster synergy between neuroscience programs and chemistry departments. Chemistry is an increasing voice in the dialog of modern neuroscience. To be well-prepared to engage in this dialog, students must have strong chemistry training and be comfortable applying it to situations in neuroscience. The strategies presented here are designed to stimulate thought and discussion in the undergraduate neuroscience education community. Hopefully this will lead to greater interaction between chemistry and neuroscience at the undergraduate level in other institutions. PMID- 23626489 TI - The use of "non-fiction novels" in a sensation and perception course. AB - Scientific material can be difficult to relate to everyday knowledge. Textbook facts can be abstract. This Study of Teaching and Learning project examined the use of "non-fiction novels" (biographies and other books that read like novels but are true) in an undergraduate Sensation and Perception course in order to increase the concreteness of the reading material and to give the students a story on which to hang the facts learned in lecture. In Phase I (Fall 2009) non fiction novels were used for half of the units and a standard textbook for the other half. In Phase II (Fall 2010) only non-fiction novels were used. The Fall 2009 class was very positive about the use of non-fiction novels, but exam scores did not mirror this enthusiasm, either on semester exam scores or on a four-month re-take of the cumulative final exam. In contrast, the Fall 2010 class missed having a textbook, but exam performance significantly improved over prior semesters, and performance on the four-month re-take of the cumulative final exam showed performance equivalent to the Fall 2009 class's four-month performance on questions from textbook units. In both semesters, the effectiveness of the instructor in stimulating student interest was significantly higher than in prior years where only the textbook was used. In addition, 68% of the students said that reading the non-fiction novels made them want to learn more about our sensory systems. PMID- 23626490 TI - Human Brains Engaged in Rat Brains: Student-driven Neuroanatomy Research in an Introductory Biology Lab Course. AB - Inquiry-based laboratory instruction has been shown to actively engage students in the content and skills being taught. These courses are further intended to teach students not only what is known, but also the process by which investigators come to know it. We sought to take this approach one step further and incorporate novel research questions into an inquiry-based laboratory model early in the undergraduate course of study. In this research-based introductory laboratory course, first-year students acquired basic lab skills not just for their own sake, but rather within the context of a research question of a member of the faculty. Student projects investigated potential neuroanatomical changes in animal models of dyslexia and aging and included measurements of neuron numbers and levels and distribution of neuronal proteins. Students played an active role in designing and implementing an experimental plan, explored data analysis techniques, and reflected on the results that they obtained in scholarly forms such as research papers and a departmental poster session. Student feedback on this approach has been extremely positive, and the data collected were research quality preliminary data that are being actively pursued for further study. Based on our encouraging experiences, we conclude that designing an introductory course around novel research, including some assessments modeled after scholarly practices, provides motivation and excitement for the students, instills good scientific habits, and can potentially benefit departmental research. PMID- 23626491 TI - Decreasing neuroscience anxiety in an introductory neuroscience course: an analysis using data from a modified science anxiety scale. AB - To determine whether participation in a neuroscience course reduced neuroscience anxiety, a modified version of the Science Anxiety Scale was administered to students at the beginning and end of an introductory course. Neuroscience anxiety scores were significantly reduced at the end of the course and correlated with higher final grades. Reduced neuroscience anxiety did not correlate with reduced science anxiety, suggesting that neuroscience anxiety is a distinct subtype of anxiety. PMID- 23626492 TI - Integrating community outreach into the undergraduate neuroscience classroom. AB - While both federal agencies and professional associations emphasize the importance of neuroscience outreach, this goal seldom reaches the undergraduate neuroscience classroom. However, incorporating outreach into undergraduate neuroscience classes is an efficient means to reach not only future scientists, but also the future practitioners (K-12 teachers, social service workers, etc.) with whom neuroscientists hope to communicate. It also provides a vehicle for faculty members to engage in outreach activities that are typically un- or under rewarded in faculty reviews. In this article, a Neuroscience Community Outreach Project (NCOP) is described. The project has been used in three offerings of a Cognitive Neuroscience course at a small liberal arts college, shared and applied at a large state university, and presented at a regional Society for Neuroscience meeting as an example of outreach opportunities for faculty. The NCOP assignment is a student-driven, modular activity that can be easily incorporated into existing neuroscience course frameworks. The assignment builds on student interests and connections in the community, providing a way for faculty at institutions without formal outreach programs to incorporate neuroscience outreach into the classroom and connect students to online resources. Several sample student projects are described across three broad domains (K-12 outreach, presentations to social service organizations, and media / popular press presentations). The article ends with a set of suggestions addressing common faculty concerns about incorporating community outreach into the undergraduate neuroscience classroom. PMID- 23626493 TI - "Writing in neuroscience": a course designed for neuroscience undergraduate students. AB - Although neuroscience students may learn to write in a generic fashion through university writing courses, they receive little training in writing in their field. Here I describe a course that was created at the request of a Neuroscience Department with the intent to teach neuroscience students how to write well in their discipline. I explain the purpose for creating the "Writing in Neuroscience" course and offer a brief overview of the course curriculum, including pertinent pedagogical outcomes for such a course. I describe in depth the major assignment for the course, the literature review, and provide examples of paper titles that students wrote to fulfill the assignment. I briefly describe other relevant course assignments. I evaluate the course and include an overview of who should teach such a course, what support might be helpful, and what can be learned from formative assessment of the course. Using these insights can help others determine whether such a course is a good fit for them. PMID- 23626494 TI - Practical Experience with Age-related Dementia: Implementation and Outcomes of a Semester-long Service Learning Project in Neuropsychology. AB - Most neuroscience faculty share the common goal of maximizing student understanding of course material and increasing student excitement for the discipline. There is evidence that educational practices such as service learning, which is characterized by the fact that it both addresses a need in the community and meets key learning objectives in a course, can help accomplish these goals in an impactful way. This article describes the implementation of a service learning project at an assisted-living facility in an upper-level neuropsychology course. In addition, results of student self-evaluations indicate that students self-report higher understanding of course content and skills associated with working with people with disabilities. Lastly, a discussion of some benefits of implementation is provided along with advice to others wishing to implement a similar service learning project. This advice will help ensure a positive experience for students in the course as well as for residents at the assisted-living facility. PMID- 23626495 TI - Use of personal EEG monitors in a behavioral neuroscience course to investigate natural setting sleep patterns and the factors affecting them in college students. AB - Sleep is often a topic of avid interest to college students, yet it is one that does not yield itself well to hands-on, interactive learning modules. Supplementing classroom learning with interactive "real world" laboratory activities provides students with a deeper understanding of behavior and its neural control. The project described here was designed to supplement the teaching of EEGs, sleep and circadian rhythms and involved students in the empirical process from hypothesizing about the factors that affect sleep, to personal data collection, data analysis and writing in the style of a peer reviewed manuscript. Students enrolled in Behavioral Neuroscience at Connecticut College were provided with a home-based personal EEG monitor used to collect sleep data in their natural sleep setting. Participants recorded sleep data with the use of the ZEO(r) Personal Sleep Coach system and completed a nightly sleep journal questionnaire for seven nights. The ZEO(r) system uses EEG patterns to define sleep stages including wakefulness, light, deep and REM sleep. The journal included questions about factors known to affect sleep such as stress, caffeine, academic activity, exercise and alcohol. A class data set was compiled and used by students to perform univariate correlations examining the relationships between ZEO(r) variables and sleep journal variables. The data set allowed students to choose specific variables to investigate, analyze and write a peer reviewed style manuscript. Significant class-wide correlations were found between specific sleep stages and behavioral variables suggesting that the ZEO(r) system is sophisticated yet inexpensive enough to be used as an effective tool in the classroom setting. Overall student feedback on the exercise was positive with many students indicating that it significantly enhanced their understanding of sleep architecture and made them keenly aware of the factors that affect quality of sleep. PMID- 23626496 TI - A conceptual framework for interdisciplinary curriculum design: a case study in neuroscience. AB - Teaching of interdisciplinary fields of study poses a challenge to course organizers. Often interdisciplinary courses are taught by different departments, and hence, at best provide a multidisciplinary overview. Scientific progress in neuroscience, for instance, is thought to depend heavily on interdisciplinary investigations. If students are only taught to think in particular disciplines without integrating these into a coherent framework to study the nervous system, it is unlikely that they will truly develop interdisciplinary thinking. Yet, it is this interdisciplinary thinking that is at the heart of a holistic understanding of the brain. It is, therefore, important to develop a conceptual framework in which students can be taught interdisciplinary, rather than multidisciplinary, thinking. It is also important to recognize that not all teaching needs to be interdisciplinary, but that the type of curriculum design is dependent on the aims of the course, as well as on the background of the students. A rational curriculum design that aligns learning and teaching objectives is, therefore, advocated. PMID- 23626497 TI - Design plans for an inexpensive tail flick analgesia meter. AB - While the pedagogical benefits of incorporating inquiry driven labs into an undergraduate curriculum are well established, often the prohibitive costs of providing equipment for such labs limits the types of experiences that can be offered. For example, the lab portion of Advanced Neuroscience at Centenary College of Louisiana consists of a semester-long research project developed by the students. Frequently, these junior- and senior-level students generate interesting research questions that must be culled or scaled back simply due to a lack of appropriate equipment. In the most recent iteration of the class, the students wanted to examine analgesia using the tail flick test, a measure of spinal nociception. In this test a rodent subject is restrained; its tail is exposed to a heat source; and the latency to flick its tail away from the noxious stimuli is recorded. As commercial devices were far beyond the lab budget, we sought to develop an inexpensive tail flick analgesia meter that was easy to use and generated reliable data. The prototype device was tested by students in the above-mentioned class and was found to consistently produce reliable data in agreement with the literature. Here we present plans for a tail flick analgesia meter that can be constructed for $50-75, roughly 100 times cheaper than commercial devices. PMID- 23626498 TI - A Modified Golgi-Cox Procedure for use in Undergraduate Courses. AB - The Golgi staining method has a long history in the field of neuroscience, and remains an important teaching tool in undergraduate laboratory settings. The ability to visualize a cell with all the processes makes the method useful when teaching introductory neuroscience courses. However, the amount of time required for post-stain tissue processing makes it a difficult procedure to use when teaching laboratory classes. We detail a modified Golgi-Cox method with a short incubation period and minimal post-stain processing that produces well differentiated cells, making it ideal for use in an undergraduate laboratory. PMID- 23626500 TI - Unquenchable neuroscience. PMID- 23626499 TI - A mechanism for multidisciplinary dialogue: the memory & ... series. AB - Neuroscientists have long explored the mechanisms of memory from molecular, physiological, cognitive, and social perspectives. Scholars from other disciplines such as history, sociology, literature, and cultural studies, that do not traditionally cross-pollinate ideas with neuroscientists, also study memory from a variety of angles. In this article, we describe the founding of a multidisciplinary discussion series in which faculty and staff from the arts, humanities, social sciences, and natural sciences come together to explain how memory is integral to their scholarship and teaching. After panelists from different disciplines present opening comments, the floor is open for discussion with the audience that includes students, staff, and community members, as well as other faculty. Each year the series is anchored by a keynote address by an eminent scholar engaged in cross-disciplinary memory research. We outline the benefits of such thematic discussion series, highlighting the synchrony with the academy's increasing focus on interdisciplinarity, and on the need to train scholars to speak clearly about their work beyond their own disciplinary boundaries. More specifically, we focus on the need to train scientists to communicate with non-scientists. We have experienced success with this series and believe that the format could be adapted to a wide range of issues that cross disciplines (e.g., development, language, music, environmental studies). PMID- 23626501 TI - Input-output: The Role of Undergraduate Curriculum in Successful Graduate Training in the Neurosciences. AB - This article was motivated by the 2010 SfN session on Undergraduate Curricula and Graduate Expectations. To prepare for my role as panelist, I examined the background of Washington University Neuroscience Ph.D. students. Current students with a declared thesis lab were queried, and records from past graduates were reviewed to determine the characteristics that contribute to graduate success. This pilot research suggests that no specific undergraduate curriculum element or quantitative undergraduate achievement metric predicts success at the graduate level, measured by graduate GPA, years to degree, or number of publications. I extrapolate these results to suggest that students from non-typical backgrounds should not be deterred from applying to Ph.D. programs in Neuroscience. I speculate that less tangible traits may be most important for graduate success. These include critical thinking skills and independent research experience. PMID- 23626502 TI - Enhanced modeling via network theory: Adaptive sampling of Markov state models. AB - Computer simulations can complement experiments by providing insight into molecular kinetics with atomic resolution. Unfortunately, even the most powerful supercomputers can only simulate small systems for short timescales, leaving modeling of most biologically relevant systems and timescales intractable. In this work, however, we show that molecular simulations driven by adaptive sampling of networks called Markov State Models (MSMs) can yield tremendous time and resource savings, allowing previously intractable calculations to be performed on a routine basis on existing hardware. We also introduce a distance metric (based on the relative entropy) for comparing MSMs. We primarily employ this metric to judge the convergence of various sampling schemes but it could also be employed to assess the effects of perturbations to a system (e.g. determining how changing the temperature or making a mutation changes a system's dynamics). PMID- 23626503 TI - Sexual victimization and health-related indicators among sexual minority men. AB - This study reports rates of childhood and adult sexual victimization among a community sample of 634 gay and bisexual-identified men, and examines how men with differing sexual victimization histories compare on a number of health related outcomes. Results indicate that men with histories of childhood and adult sexual victimization are more likely to report substance use, more lifetime STIs, higher sexual compulsivity scores, and greater gay-related stigma scores than men with no histories of sexual victimization. Few differences are found in comparisons of health outcomes based on age at first sexual victimization (childhood vs. adulthood). Furthermore, men with histories of sexual victimization report healthier coping skills than men with no histories of sexual victimization, but no significant group differences are found in social support or stress-related growth. Findings underscore the importance of assessing lifetime sexual victimization among sexual minority men during counseling, with special attention given to the enhancement of protective factors among those at risk for harmful behaviors and subsequent poor health outcomes. PMID- 23626504 TI - Psychosocial Functioning Among Inmates in Prison-Based Drug Treatment: Results from Project BRITE. AB - OBJECTIVE: To assess the impact of a positive behavioral reinforcement intervention on psychosocial functioning of inmates over the course of treatment and on post-treatment self-reported measures of treatment participation, progress, and satisfaction. METHOD: Male (n = 187) and female (n = 143) inmates participating in 12-week prison-based Intensive Outpatient (IOP) drug treatment were randomly assigned to receive standard treatment (ST) or standard treatment plus positive behavioral reinforcement (BR) for engaging in targeted activities and behaviors. Participants were assessed for psychosocial functioning at baseline and at the conclusion of treatment (post-treatment). Self-reported measures of treatment participation, treatment progress, and treatment satisfaction were also captured at post-treatment. RESULTS: The intervention affected female and male subjects differently and not always in a way that favored BR subjects, as compared to the ST subjects, most notably on measures of depression and criminal thinking. CONCLUSIONS: Possible explanations for the results include differences in the male and female custody environments combined with the procedures that study participants had to follow to earn and/or receive positive reinforcement at the two study sites, as well as baseline differences between the genders and a possible floor effect among females on measures of criminality. Limitations of the study included the inability to make study participants blind to the study conditions and the possible over-branding of the study, which may have influenced the results. PMID- 23626505 TI - Pediatric gastric volvulus: diagnostic and clinical approach. AB - Gastric volvulus is a significant, rare cause of non-bilious vomiting and consists of a pathological rotation of the stomach of more than 180 degrees around the axis without obstruction of the gastrointestinal tract. A definitive diagnosis is made with upper radiological gastrointestinal studies. Treatment may be conservative or surgical with anterior and fundal gastropexy in patients with ingravescent symptoms. We describe the case of a 16-month-old female admitted to our hospital for recurrent and postprandial vomiting episodes which had started at 11 months of age. A history of gastroesophageal reflux was present until 1 year of age, in association with recurrent respiratory infections. The basic metabolic panel was normal. Barium study showed stomach rotation along a horizontal plane stomach. Esophagogastroduodenoscopy showed no mucosal alterations. The diagnosis was chronic organoaxial gastric volvulus. In our patient, the surgical procedure of gastropexy, both anterior and fundal, without fundoplication was performed. She showed good improvement after surgery, with resolution of symptoms and weight gain. PMID- 23626506 TI - Synchronous sporadic gastrointestinal stromal tumors in the stomach and jejunum: report of a case. AB - This report describes a patient with synchronous sporadic gastrointestinal stromal tumors (GISTs) in the stomach and jejunum. A 71-year-old Japanese male presented with a 2-year history of occasional melena and general fatigue. Computed tomography of the abdomen demonstrated an enhanced extramural gastric tumor, 4 cm in diameter. Endoscopic examination revealed a jejunal submucosal tumor. He was referred to the surgical outpatient clinic for surgical treatment of an extramural gastric tumor and a jejunal submucosal tumor. Laparotomy allowed the identification of a nut-sized extramural tumor at the stomach and a thumb's head-sized tumor on the jejunum. Partial resections of the stomach and jejunum were performed. Histopathological and immunohistochemical examination revealed that these tumors were GISTs. Although no molecular analysis was performed, the immunohistochemical staining patterns of these two tumors were different from each other. Therefore, the final diagnosis was synchronous sporadic GISTs in the stomach and jejunum. This patient has survived without recurrence for approximately 12 years since complete resection. PMID- 23626507 TI - Transileocolic vein obliteration for bleeding rectal varices with portal thrombus. AB - We report a case of rectal varices treated successfully with transileocolic vein obliteration (TIO). A 70-year-old man was admitted to our hospital for evaluation of fresh bloody stools in January 2011. Emergent colonoscopy revealed fresh blood in the rectum and tortuous rectal varices. Three-dimensional computed tomography was used as a non-invasive method for the identification of rectal varices and thrombus in the extrahepatic portal vein. Angiography demonstrated that rectal varices were supplied with backward blood flow by the inferior mesenteric vein. Transileocolic variceal obliteration was performed using coils and 5% ethanolamine oleate with iopamidol. Complete hemostasis was achieved without complications. We conclude that TIO is a safe and effective hemostatic measure for ruptured rectal varices with portal thrombus. PMID- 23626508 TI - Pulmonary embolism in a patient with eosinophilic esophagitis: causal or coincidental? AB - Eosinophilic esophagitis is a chronic immune-mediated disease characterized by infiltration of the esophageal mucosa with eosinophils and concomitant esophageal dysfunction. Though there are well-described associations between certain chronic inflammatory conditions and venous thromboembolism, there have been no reports of venous thromboembolism occurring in eosinophilic esophagitis. We report the case of a 33-year-old man with severe eosinophilic esophagitis resulting in recurrent esophageal strictures who was unresponsive to oral viscous budesonide therapy, and who developed an isolated pulmonary embolism in the absence of risk factors for venous thromboembolism. We then discuss potential mechanisms for venous thromboembolism in eosinophilic esophagitis, such as inflammation-mediated hypercoagulability, hypereosinophilia, and immunoglobulin E-mediated platelet activation. PMID- 23626509 TI - Treatment of esophageal variceal hemorrhage with self-expanding metal stents as a rescue maneuver in a swiss multicentric cohort. AB - Acute esophageal variceal bleeding in patients with portal hypertension remains a complication with a high mortality today. In cases refractory to standard therapy including endoscopic band ligation and pharmacological therapy, traditionally balloon tamponade has been used as salvage therapy. However, these techniques show several important limitations. Self-expanding metal stents (SEMS) have been proposed as an alternative rescue treatment. The use of variceal stenting in 7 patients with a total of 9 bleeding episodes in three different Swiss hospitals is demonstrated. While immediate bleeding control is achieved in a high percentage of cases, the 5-day and 6-week mortality rate remain high. Mortality is strongly influenced by the severity of the underlying liver disease. Accordingly, our data represent a high-risk patient collective. Thanks to their safety and easy handling, SEMS are an interesting alternative to balloon tamponade as a bridging intervention to definitive therapy including the pre hospital setting. PMID- 23626510 TI - Metastatic breast carcinoma presenting as a sigmoid stricture: report of a case and review of the literature. AB - Metastatic spread of breast carcinoma to the colon and rectum is rare. We report the case of a patient treated for lobular breast carcinoma presenting 17 years later with metastatic breast cancer of the colon. A 63-year-old lady with a past history of right-sided invasive lobular carcinoma of the breast presented with persistent diarrhoea. Colonoscopy with biopsies revealed a benign-looking stricture at the rectosigmoid junction. A CT scan of the abdomen and pelvis revealed a benign-looking stricture in keeping with a probable diverticular stricture. A Hartmann procedure was performed and histology revealed a metastatic lobular carcinoma with oestrogen and progesterone receptor-positive status. Treatment was commenced with letrozole and the patient remains well under clinical surveillance. In a patient with a history of breast carcinoma who presents with gastrointestinal symptoms the possibility of gastrointestinal tract spread should always be considered. Endoscopic diagnosis may be misleading with pathological diagnosis only being made following surgical resection. A history of breast carcinoma must be declared to the histopathologist following surgical resection so that an accurate diagnosis is made and appropriate treatment is commenced. PMID- 23626511 TI - Synchronous occurrence of advanced neuroendocrine carcinoma and tubular adenocarcinoma of the rectum. AB - This report presents a rare case with the synchronous occurrence of advanced neuroendocrine carcinoma (NEC) and tubular adenocarcinoma of the rectum. A 52 year-old Japanese male presented with general fatigue and bloody stool. Endoscopic examination showed an ulcerated lesion of the lower rectum. The pathological diagnosis of biopsy specimens from this lesion indicated moderately differentiated adenocarcinoma. He was referred to the surgical outpatient clinic with advanced rectal cancer. Barium enema indicated two lesions in the upper and lower rectum. Computed tomography revealed multiple hepatic metastases. A low anterior resection was performed with lymph node dissection. The resected specimen indicated an elevated lesion with ulceration in the upper rectum and an ulcerated lesion in the lower rectum. Histopathological and immunohistochemical analyses revealed NEC from the upper rectum and moderately differentiated tubular adenocarcinoma from the lower rectum. These two lesions were completely separated from each other. Therefore, this case demonstrates the synchronous occurrence of advanced NEC and tubular adenocarcinoma in the rectum. PMID- 23626512 TI - Effective Treatment of Intestinal Behcet's Disease with Long-Term, Low-Dose Clarithromycin. AB - A 51-year-old man was referred for body weight loss and lower right abdominal pain. Total colonoscopy revealed discrete and round ulceration at the ileocecal valve, and he was diagnosed with intestinal Behcet's disease (BD). By treatment with glucocorticoid, colchicine and salazosulfapyridine, the symptoms and ulceration were improved, but cessation of glucocorticoid resulted in relapse of ulceration at the terminal ileum. Long-term, low-dose treatment with clarithromycin (CAM) was implemented for chronic respiratory infections. Furthermore, we expected that this CAM treatment would also be effective in BD. During this long-term, low-dose treatment with CAM, discrete ulceration at the terminal ileum was never revealed by follow-up total colonoscopy once or twice per year for 7 years. No reports have described the effectiveness of this treatment in patients with intestinal BD; however, we confirm that long-term treatment with low-dose CAM might have clinical benefits for patients with intestinal BD. PMID- 23626513 TI - Lymphoepithelioma-like carcinoma of the colon. AB - A 70-year-old female underwent follow-up colonoscopy after colonic polypectomy. The colonoscopy revealed the presence of a 7-mm submucosal tumor in the sigmoid colon. The tumor surface was smooth and covered with normal mucosa. It was diagnosed as a submucosal tumor, and polypectomy was performed. Histopathological examination of the resected specimen revealed moderately to poorly differentiated adenocarcinoma measuring 2 * 5 * 3 mm with marked peritumoral lymphocytic infiltration and lymphoid follicle formation. It was diagnosed as carcinoma with lymphoid stroma (lymphoepithelioma-like carcinoma), SM (1,800 MUm), ly2, v0, budding; grade 1. We confirmed the indication for noncurative additional surgical resection and performed laparoscopic sigmoid colectomy. No metastases were observed in the dissected lymph nodes. PMID- 23626514 TI - Secondary Sclerosing Cholangitis due to Gallbladder Adenocarcinoma. AB - Sclerosing cholangitis is a chronic cholestatic liver disease defined by both inflammatory and fibrotic changes of the biliary tract leading to diffuse stricture formation. This entity exists in both a primary and secondary form. Here we present a rare case of secondary sclerosing cholangitis due to direct metastasis from a gallbladder adenocarcinoma. A 55-year-old morbidly obese male presented electively with a 2-week history of low back pain and scleral icterus for 2 days. He also described severe epigastric pain that worsened postprandially and a 13 kg weight loss over the previous month. The patient denied any personal or familial history of malignancy or prior liver disease. Laboratory evaluation revealed mild elevation of transaminases with moderately elevated alkaline phosphatase and total bilirubin. Imaging included ultrasound and contrast enhanced computed tomography of the abdomen and pelvis showing multiple large gallstones and a large tissue density mass within the fundus of the gallbladder. Subsequent endoscopic ultrasound was performed revealing celiac and portal lymphadenopathy with fine needle aspirations demonstrating adenocarcinoma. Over the next 15 days, bilirubin progressively increased. Magnetic resonance cholangiopancreatography was unremarkable. Liver biopsy, performed to exclude other etiologies of liver failure, demonstrated biliary cholestasis. Endoscopic retrograde cholangiopancreatography was then performed and an occlusion cholangiogram revealed diffuse multifocal stricturing of the intrahepatic bile ducts and moderate stenosis of the common bile duct without proximal ductal dilatation. Thus secondary sclerosing cholangitis due to gallbladder adenocarcinoma was diagnosed. PMID- 23626515 TI - Management considerations for purported spontaneous regression of hepatocellular carcinoma: a case report. AB - Spontaneous regression of hepatocellular carcinoma (HCC) is an extraordinary phenomenon that occurs rarely. While more than 80 cases have been described, most have been established via radiological findings or examination of biopsy tissues rather than via pathological examination of a resected specimen. The present report describes a purported case of spontaneous regression of HCC as indicated by radiological examination. Subsequent immunostaining of surgically resected specimens revealed viable cancer cells, though only necrotic tissues were seen on hematoxylin and eosin staining. These data indicate that viable cancer cells may still be present even if imaging findings suggest spontaneous regression of HCC. Therefore, these patients should receive aggressive treatment similar to that used for patients with established HCC. PMID- 23626516 TI - Primary intestinal lymphangiectasia: is it always bad? Two cases with different outcome. AB - Primary intestinal lymphangiectasia (PIL) or Waldmann's disease is a rare protein losing gastroenteropathy of unknown etiology. Less than 200 cases have been reported globally. Patients may be asymptomatic or present edema, lymphedema, diarrhea, ascites and other manifestations. We report two pediatric cases with PIL with extremely different outcome in a 3-year follow-up period. The first patient presented with persistent diarrhea, hypoalbuminemia and failure to thrive, while the second patient presented with an abrupt eyelid edema. Hypoproteinemia was the common laboratory finding for the two patients and upper gastrointestinal endoscopy established the diagnosis. The first patient relapsed five times during the follow-up period after the diagnosis had been made and required intravenous albumin administration and micronutrient supplementation. The second patient revealed normal gastrointestinal endoscopy 4 months after the diagnosis had been established; he followed an unrestricted diet and remained asymptomatic throughout the follow-up period. PIL can be either severe, affecting the entire small bowel, leading to lifetime disease, or sometimes affects part of the small bowel, leading to transient disorder. PMID- 23626517 TI - Diverticular Choledochal Cyst with a Large Impacted Stone Masquerading as Mirizzi's Syndrome. AB - Choledochal cysts are congenital anomalies of the biliary tract manifested by cystic dilatation of the extrahepatic and intrahepatic bile ducts. Choledochal cyst is not rare in far-East Asian countries. Type II choledochal cysts account for 2% of all such cysts. They are true diverticula of the extrahepatic bile duct and communicate with the bile duct through a narrow stalk. This condition is associated with significant complications, such as ductal strictures, stone formation, cholangitis, rupture and secondary biliary cirrhosis. We describe a case of a huge impacted stone in a diverticular choledochal cyst which masqueraded as an unusual cystic duct stone causing Mirizzi's syndrome. PMID- 23626518 TI - Hepatocellular Carcinoma with Sarcomatoid Change without Anticancer Therapies. AB - Hepatocellular carcinoma (HCC) with sarcomatoid change is a rare neoplasm of the liver, and recurrent therapies for HCC such as transcatheter arterial chemoembolization and percutaneous ablation therapy are presumed to promote sarcomatoid change. A 73-year-old man was admitted to our hospital diagnosed as having liver cancer originating from hepatitis C-related cirrhosis without any previous treatment for HCC. Ultrasonography showed that the tumor was hypoechoic, 3 cm in diameter, with unclear margins. Computed tomography demonstrated a low density lesion with ring enhancement on delayed phase. Under a diagnosis of poorly differentiated HCC the patient underwent liver resection. Histologically, the tumor consisted of proliferation of spindle-shaped sarcomatoid carcinoma cells with unclear trabecular and pseudoglandular structures including a nodule of typical moderately differentiated HCC, which was observed to shift mutually in one region. Here, we report a case of sarcomatoid HCC with a review of the literature. PMID- 23626519 TI - Salvage total pelvic exenteration with bilateral v-y advancement flap reconstruction for locally recurrent rectal cancer. AB - Total pelvic exenteration for locally recurrent rectal cancer typically requires extensive excision of the pelvic floor with perineal skin. Due to the extensiveness of the procedure and its non-curative nature, it is controversial as purely palliative therapy. A 66-year-old male patient who had undergone abdominoperineal resection at another hospital 8 years prior was admitted to our hospital. During radiation and chemotherapy for 2 years, he complained of perineal pain, discharge, cacosmia and bleeding from a recurrent tumor. The 10 * 8 cm recurrent tumor was exposed on the perineum and the patient suffered from serious discomfort in his daily life during walking or sitting. We performed total pelvic exenteration with partial sacrectomy, after which the large perineal defect was reconstructed with a bilateral V-Y gluteus maximus advancement flap in approximately 120 min. The patient's postoperative course was satisfactory and his quality of life markedly improved. PMID- 23626520 TI - Successful resection of intracranial metastasis of hepatocellular carcinoma. AB - Intracranial metastasis of hepatocellular carcinoma (HCC) is rare, but has an extremely poor prognosis. We report a case with successful surgical removal of intracranial metastasis of HCC. A 32-year-old man was admitted to our hospital with severe vomiting. He had been followed for liver cirrhosis due to hepatitis B virus infection and received a right hepatic trisectionectomy for HCC 1 year earlier. For the recurrence of HCC, sorafenib had been administered 6 months before admission. On admission, he exhibited consciousness disturbance, which gradually worsened. Two days later, both computed tomography and magnetic resonance imaging revealed an intra-axial tumor with perifocal edema and hemorrhage in the left frontal lobe. The tumor was successfully removed by craniotomy and pathological examination revealed that it was composed of moderately differentiated HCC cells. The day after surgical resection of the tumor, his consciousness returned to normal. Subsequently, he was treated with hepatic arterial infusion chemotherapy with 5-fluorouracil and cisplatin using an implanted port-catheter system. Surgical resection of intracranial metastasis of HCC would be important and meaningful in some cases. PMID- 23626521 TI - Prefrontal dopamine and behavioral flexibility: shifting from an "inverted-U" toward a family of functions. AB - Studies on prefrontal cortex (PFC) dopamine (DA) function have revealed its essential role in mediating a variety of cognitive and executive functions. A general principle that has emerged (primarily from studies on working memory) is that PFC DA, acting on D1 receptors, regulates cognition in accordance to an "inverted-U" shaped function, so that too little or too much activity has detrimental effects on performance. However, contemporary studies have indicated that the receptor mechanisms through which mesocortical DA regulates different aspects of behavioral flexibility can vary considerably across different DA receptors and cognitive operations. This article will review psychopharmacological and neurochemical data comparing and contrasting the cognitive effects of antagonism and stimulation of different DA receptors in the medial PFC. Thus, set-shifting is dependent on a co-operative interaction between PFC D1 and D2 receptors, yet, supranormal stimulation of these receptors does not appear to have detrimental effects on this function. On the other hand, modification of cost/benefit decision biases in situations involving reward uncertainty is regulated in complex and sometimes opposing ways by PFC D1 vs. D2 receptors. When viewed collectively, these findings suggest that the "inverted-U" shaped dose-response curve underlying D1 receptor modulation of working memory is not a one-size-fits-all function. Rather, it appears that mesocortical DA exerts its effects via a family of functions, wherein reduced or excessive DA activity can have a variety of effects across different cognitive domains. PMID- 23626523 TI - Neural interactions in unilateral colliculus and between bilateral colliculi modulate auditory signal processing. AB - In the auditory pathway, the inferior colliculus (IC) is a major center for temporal and spectral integration of auditory information. There are widespread neural interactions in unilateral (one) IC and between bilateral (two) ICs that could modulate auditory signal processing such as the amplitude and frequency selectivity of IC neurons. These neural interactions are either inhibitory or excitatory, and are mostly mediated by gamma-aminobutyric acid (GABA) and glutamate, respectively. However, the majority of interactions are inhibitory while excitatory interactions are in the minority. Such unbalanced properties between excitatory and inhibitory projections have an important role in the formation of unilateral auditory dominance and sound location, and the neural interaction in one IC and between two ICs provide an adjustable and plastic modulation pattern for auditory signal processing. PMID- 23626522 TI - Neurotransmitter signaling in the pathophysiology of microglia. AB - Microglial cells are the resident immune cells of the central nervous system. In the resting state, microglia are highly dynamic and control the environment by rapidly extending and retracting motile processes. Microglia are closely associated with astrocytes and neurons, particularly at the synapses, and more recent data indicate that neurotransmission plays a role in regulating the morphology and function of surveying/resting microglia, as they are endowed with receptors for most known neurotransmitters. In particular, microglia express receptors for ATP and glutamate, which regulate microglial motility. After local damage, the release of ATP induces microgliosis and activated microglial cells migrate to the site of injury, proliferate, and phagocytose cells, and cellular compartments. However, excessive activation of microglia could contribute to the progression of chronic neurodegenerative diseases, though the underlying mechanisms are still unclear. Microglia have the capacity to release a large number of substances that can be detrimental to the surrounding neurons, including glutamate, ATP, and reactive oxygen species. However, how altered neurotransmission following acute insults or chronic neurodegenerative conditions modulates microglial functions is still poorly understood. This review summarizes the relevant data regarding the role of neurotransmitter receptors in microglial physiology and pathology. PMID- 23626525 TI - Three-dimensional reconstruction of electron micrographs reveals intrabulbar circuit differences between accessory and main olfactory bulbs. AB - Three-dimensional (3D) reconstruction of synaptic arrangement on a particular dendrite provides essential information regarding neuronal properties and neural microcircuits. Unconventional synapses are particularly good candidates for such steric attribution. In main and accessory olfactory bulbs (MOBs and AOBs), there are dendrodendritic reciprocal synapses (RSs) between excitatory projection neurons and inhibitory interneurons. Although the fine structure and configuration of these synapses have been investigated in MOB, their characteristics in AOB were unknown. In this study, we performed 3D AOB reconstruction using serial section transmission electron microscopy. We found numerous RSs on primary dendrites from glomeruli to mitral/tufted (MT) cell somas. These synapses formed between dendritic shafts of MT cells and large dendritic spines, or so-called gemmules, of granule (Gr) cells. This indicates that chemical signals received by a glomerulus are regulated in the primary dendrite of an MT cell before reaching its soma. In MOB, RSs are located on secondary dendrites and act as lateral and self-inhibiting following mitral cell depolarization. Our results indicate that AOB intrabulbar microcircuitry is quite different from that in the MOB. PMID- 23626524 TI - In and out of the loop: external and internal modulation of the olivo-cerebellar loop. AB - Cerebellar anatomy is known for its crystal like structure, where neurons and connections are precisely and repeatedly organized with minor variations across the Cerebellar Cortex. The olivo-cerebellar loop, denoting the connections between the Cerebellar cortex, Inferior Olive and Cerebellar Nuclei (CN), is also modularly organized to form what is known as the cerebellar module. In contrast to the relatively organized and static anatomy, the cerebellum is innervated by a wide variety of neuromodulator carrying axons that are heterogeneously distributed along the olivo-cerebellar loop, providing heterogeneity to the static structure. In this manuscript we review modulatory processes in the olivo cerebellar loop. We start by discussing the relationship between neuromodulators and the animal behavioral states. This is followed with an overview of the cerebellar neuromodulatory signals and a short discussion of why and when the cerebellar activity should be modulated. We then devote a section for three types of neurons where we briefly review its properties and propose possible neuromodulation scenarios. PMID- 23626527 TI - Rhythm and timing in autism: learning to dance. AB - In recent years, a significant body of research has focused on challenges to neural connectivity as a key to understanding autism. In contrast to attempts to identify a single static, primarily brain-based deficit, children and adults diagnosed with autism are increasingly perceived as out of sync with their internal and external environments in dynamic ways that must also involve operations of the peripheral nervous systems. The noisiness that seems to occur in both directions of neural flow may help explain challenges to movement and sensing, and ultimately to entrainment with circadian rhythms and social interactions across the autism spectrum, profound differences in the rhythm and timing of movement have been tracked to infancy. Difficulties with self-synchrony inhibit praxis, and can disrupt the "dance of relationship" through which caregiver and child build meaning. Different sensory aspects of a situation may fail to match up; ultimately, intentions and actions themselves may be uncoupled. This uncoupling may help explain the expressions of alienation from the actions of one's body which recur in the autobiographical autism literature. Multi modal/cross-modal coordination of different types of sensory information into coherent events may be difficult to achieve because amodal properties (e.g., rhythm and tempo) that help unite perceptions are unreliable. One question posed to the connectivity research concerns the role of rhythm and timing in this operation, and whether these can be mobilized to reduce overload and enhance performance. A case is made for developmental research addressing how people with autism actively explore and make sense of their environments. The parent/author recommends investigating approaches such as scaffolding interactions via rhythm, following the person's lead, slowing the pace, discriminating between intentional communication and "stray" motor patterns, and organizing information through one sensory mode at a time. PMID- 23626528 TI - Excitotoxic lesions in the central nucleus of the amygdala attenuate stress induced anxiety behavior. AB - The extended amygdala, composed by the amygdaloid nuclei and the bed nucleus of the stria terminalis (BNST), plays a critical role in anxiety behavior. In particular, the link between the central nucleus of the amygdala (CeA) and the BNST seems to be critical to the formation of anxiety-like behavior. Chronic unpredictable stress (CUS) exposure is recognized as a validated animal model of anxiety and is known to trigger significant morphofunctional changes in the extended amygdala. Quite surprisingly, no study has ever analyzed the role of the CeA in the onset of stress-induced anxiety and fear conditioning behaviors; thus, in the present study we induced a bilateral excitotoxic lesion in the CeA of rats that were subsequently exposed to a chronic stress protocol. Data shows that the lesion in the CeA induces different results in anxiety and fear-behaviors. More specifically, lesioned animals display attenuation of the stress response and of stress-induced anxiety-like behavior measured in the elevated-plus maze (EPM) when compared with stressed animals with sham lesions. This attenuation was paralleled by a decrease of stress-induced corticosterone levels. In contrast, we did not observe any significant effect of the lesion in the acoustic startle paradigm. As expected, lesion of the CeA precluded the appearance of fear behavior in a fear-potentiated startle paradigm in both non-stressed and stressed rats. These results confirm the implication of the CeA in fear conditioning behavior and unravel the relevance of this brain region in the regulation of the HPA axis activity and in the onset of anxiety behavior triggered by stress. PMID- 23626526 TI - Serotonin modulation of cortical neurons and networks. AB - The serotonergic pathways originating in the dorsal and median raphe nuclei (DR and MnR, respectively) are critically involved in cortical function. Serotonin (5 HT), acting on postsynaptic and presynaptic receptors, is involved in cognition, mood, impulse control and motor functions by (1) modulating the activity of different neuronal types, and (2) varying the release of other neurotransmitters, such as glutamate, GABA, acetylcholine and dopamine. Also, 5-HT seems to play an important role in cortical development. Of all cortical regions, the frontal lobe is the area most enriched in serotonergic axons and 5-HT receptors. 5-HT and selective receptor agonists modulate the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT3 subtypes play a major role. Little is known, however, on the role of other excitatory receptors moderately expressed in cortical areas, such as 5-HT2C, 5-HT4, 5-HT6, and 5-HT7. In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC). The activation of 5-HT1A receptors in mPFC hyperpolarizes pyramidal neurons whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization and increase of excitatory postsynaptic currents (EPSCs) and of discharge rate. 5-HT can also stimulate excitatory (5-HT2A and 5-HT3) and inhibitory (5-HT1A) receptors in GABA interneurons to modulate synaptic GABA inputs onto pyramidal neurons. Likewise, the pharmacological manipulation of various 5-HT receptors alters oscillatory activity in PFC, suggesting that 5-HT is also involved in the control of cortical network activity. A better understanding of the actions of 5-HT in PFC may help to develop treatments for mood and cognitive disorders associated with an abnormal function of the frontal lobe. PMID- 23626529 TI - Regional personalized electrodes to select transcranial current stimulation target. AB - RATIONALE: Personalizing transcranial stimulations promises to enhance beneficial effects for individual patients. OBJECTIVE: To stimulate specific cortical regions by developing a procedure to bend and position custom shaped electrodes; to probe the effects on cortical excitability produced when the properly customized electrode is targeting different cortical areas. METHOD: An ad hoc neuronavigation procedure was developed to accurately shape and place the personalized electrodes on the basis of individual brain magnetic resonance images (MRI) on bilateral primary motor (M1) and somatosensory (S1) cortices. The transcranial alternating current stimulation (tACS) protocol published by Feurra et al. (2011b) was used to test the effects on cortical excitability of the personalized electrode when targeting S1 or M1. RESULTS: Neuronal excitability as evaluated by tACS was different when targeting M1 or S1, with the General Estimating Equation model indicating a clear tCS Effect (p < 0.001), and post hoc comparisons showing solely M1 20 Hz tACS to reduce M1 excitability with respect to baseline and other tACS conditions. CONCLUSIONS: The present work indicates that specific cortical regions can be targeted by tCS properly shaping and positioning the stimulating electrode. SIGNIFICANCE: Through multimodal brain investigations continuous efforts in understanding the neuronal changes related to specific neurological or psychiatric diseases become more relevant as our ability to build the compensating interventions improves. An important step forward on this path is the ability to target the specific cortical area of interest, as shown in the present pilot work. PMID- 23626530 TI - Transcranial direct current stimulation: a remediation tool for the treatment of childhood congenital dyslexia? PMID- 23626531 TI - The role of the dorsoanterior striatum in implicit motivation: the case of the need for power. AB - Implicit motives like the need for power (nPower) scale affective responses to need-specific rewards or punishments and thereby influence activity in motivational-brain structures. In this paper, we review evidence specifically supporting a role of the striatum in nPower. Individual differences in nPower predict (1) enhanced implicit learning accuracy, but not speed, on serial response tasks that are reinforced by power-related incentives (e.g., winning or losing a contest; dominant or submissive emotional expressions) in behavioral studies and (2) activation of the anterior caudate in response to dominant emotional expressions in brain imaging research. We interpret these findings on the basis of Hikosaka et al.'s (2002a) model of central mechanisms of motor skill learning. The model assigns a critical role to the dorsoanterior striatum in dopamine-driven learning of spatial stimulus sequences. Based on this model, we suggest that the dorsoanterior striatum is the locus of nPower-dependent reinforcement. However, given the centrality of this structure in a wide range of motivational pursuits, we also propose that activity in the dorsoanterior striatum may not only reflect individual differences in nPower, but also in other implicit motives, like the need for achievement or the need for affiliation, provided that the proper incentives for these motives are present during reinforcement learning. We discuss evidence in support of such a general role of the dorsoanterior striatum in implicit motivation. PMID- 23626532 TI - From ear to hand: the role of the auditory-motor loop in pointing to an auditory source. AB - Studies of the nature of the neural mechanisms involved in goal-directed movements tend to concentrate on the role of vision. We present here an attempt to address the mechanisms whereby an auditory input is transformed into a motor command. The spatial and temporal organization of hand movements were studied in normal human subjects as they pointed toward unseen auditory targets located in a horizontal plane in front of them. Positions and movements of the hand were measured by a six infrared camera tracking system. In one condition, we assessed the role of auditory information about target position in correcting the trajectory of the hand. To accomplish this, the duration of the target presentation was varied. In another condition, subjects received continuous auditory feedback of their hand movement while pointing to the auditory targets. Online auditory control of the direction of pointing movements was assessed by evaluating how subjects reacted to shifts in heard hand position. Localization errors were exacerbated by short duration of target presentation but not modified by auditory feedback of hand position. Long duration of target presentation gave rise to a higher level of accuracy and was accompanied by early automatic head orienting movements consistently related to target direction. These results highlight the efficiency of auditory feedback processing in online motor control and suggest that the auditory system takes advantages of dynamic changes of the acoustic cues due to changes in head orientation in order to process online motor control. How to design an informative acoustic feedback needs to be carefully studied to demonstrate that auditory feedback of the hand could assist the monitoring of movements directed at objects in auditory space. PMID- 23626533 TI - Interaction of short-term depression and firing dynamics in shaping single neuron encoding. AB - We investigated how the two properties short-term synaptic depression of afferent input and postsynaptic firing dynamics combine to determine the operating mode of a neuron. While several computational roles have been ascribed to either, their interaction has not been studied. We considered two types of short-term synaptic dynamics (release-dependent and release-independent depression) and two classes of firing dynamics (regular firing and firing with spike-frequency adaptation). The input-output transformation of the four possible combinations of pre- and post-synaptic dynamics was characterized. Adapting neurons receiving input from release-dependent synapses functioned largely as coincidence detectors. The other three configurations showed properties consistent with integrators, each with distinct features. These results suggest that the operating mode of a neuron is determined by both the pre- and post-synaptic dynamics and that studying them together is necessary to understand emergent properties and their implications for neuronal coding. PMID- 23626534 TI - Control of reaching movements by muscle synergy combinations. AB - Controlling the movement of the arm to achieve a goal, such as reaching for an object, is challenging because it requires coordinating many muscles acting on many joints. The central nervous system (CNS) might simplify the control of reaching by directly mapping initial states and goals into muscle activations through the combination of muscle synergies, coordinated recruitment of groups of muscles with specific activation profiles. Here we review recent results from the analysis of reaching muscle patterns supporting such a control strategy. Muscle patterns for point-to-point movements can be reconstructed by the combination of a small number of time-varying muscle synergies, modulated in amplitude and timing according to movement directions and speeds. Moreover, the modulation and superposition of the synergies identified from point-to-point movements captures the muscle patterns underlying multi-phasic movements, such as reaching through a via-point or to a target whose location changes after movement initiation. Thus, the sequencing of time-varying muscle synergies might implement an intermittent controller which would allow the construction of complex movements from simple building blocks. PMID- 23626535 TI - Muscle synergies in neuroscience and robotics: from input-space to task-space perspectives. AB - In this paper we review the works related to muscle synergies that have been carried-out in neuroscience and control engineering. In particular, we refer to the hypothesis that the central nervous system (CNS) generates desired muscle contractions by combining a small number of predefined modules, called muscle synergies. We provide an overview of the methods that have been employed to test the validity of this scheme, and we show how the concept of muscle synergy has been generalized for the control of artificial agents. The comparison between these two lines of research, in particular their different goals and approaches, is instrumental to explain the computational implications of the hypothesized modular organization. Moreover, it clarifies the importance of assessing the functional role of muscle synergies: although these basic modules are defined at the level of muscle activations (input-space), they should result in the effective accomplishment of the desired task. This requirement is not always explicitly considered in experimental neuroscience, as muscle synergies are often estimated solely by analyzing recorded muscle activities. We suggest that synergy extraction methods should explicitly take into account task execution variables, thus moving from a perspective purely based on input-space to one grounded on task-space as well. PMID- 23626539 TI - Possible nagashima-type palmoplantar keratosis in two siblings. AB - Nagashima-type palmoplantar keratosis (PPK) is an autosomal recessive, transgressive and non-progressive form of PPK. It was once described as a mild form of mal de Meleda, but it is now proposed as a novel entity of PPK. Since its pathogenesis remains unclear, it is important to clarify the mode of inheritance. Here, we present a case of possible Nagashima-type PPK in 2 siblings. The siblings had non-affected parents, suggesting that the mode of inheritance was autosomal recessive. At present, reports on PPK in the English literature are limited, and thus the clinical features of Nagashima-type PPK may not be well appreciated in Western countries. More reports and concise clinical observations with genetic studies are required to establish this new entity of PPK. PMID- 23626536 TI - Theoretical models of synaptic short term plasticity. AB - Short term plasticity is a highly abundant form of rapid, activity-dependent modulation of synaptic efficacy. A shared set of mechanisms can cause both depression and enhancement of the postsynaptic response at different synapses, with important consequences for information processing. Mathematical models have been extensively used to study the mechanisms and roles of short term plasticity. This review provides an overview of existing models and their biological basis, and of their main properties. Special attention will be given to slow processes such as calcium channel inactivation and the effect of activation of presynaptic autoreceptors. PMID- 23626540 TI - Normal immunostaining pattern for aquaporin-5 in the lesions of palmoplantar hyperhidrosis. AB - Aquaporin-5 (AQP-5) is a water-transporting protein expressed in mammal sweat glands. It has been reported that the expression of AQP-5 is involved in sweating of mice, rats, and horses. However, the physiological function of human AQP-5 is still uncertain. In this report, we examined the expression pattern of AQP-5 in the skin lesions of palmoplantar hyperhidrosis in patients with Nagashima-type palmoplantar hyperkeratosis (PPK). We found that there was no significant difference in AQP-5 expression in the palmoplantar skin of healthy subjects and patients with palmoplantar hyperhidrosis. Our findings suggest that a mechanism other than AQP-5 may be involved in the pathogenesis of hyperhidrosis in PPK. PMID- 23626541 TI - Basal cell carcinoma arising from xeroderma pigmentosum: a case report and an immunohistochemical study. AB - We describe a 26-year-old Japanese patient with basal cell carcinoma arising from xeroderma pigmentosum (XP). Immunohistochemical staining revealed dense infiltration of CD163(+) M2 macrophages, together with Foxp3(+) regulatory T cells. Interestingly, MMP9, which was reported as one of the functional markers for immunosuppressive macrophages, was also detected in the CD163(+) M2 macrophage-infiltrated areas. Our case suggests the immunological background of tumor development in a patient with XP. PMID- 23626542 TI - Eruptive Nevi Mimicking Wart-Like Lesions under Selective BRAF Inhibition in a 37 Year-Old Female Melanoma Patient. AB - BACKGROUND: The BRAF inhibitor vemurafenib is state of the art in therapy of patients with malignant melanoma in non-resectable stage III or stage IV and evidence of oncogenetic BRAF mutation. Multiple cutaneous side effects like rash and keratoacanthoma-like lesions have been described so far. CASE REPORT: We report a patient who presented multiple wart-like lesions under therapy with vemurafenib. Histologically we have seen multiple melanocytic nevi with a wart like appearance. One melanoma in situ developed on the left forearm. CONCLUSIONS: Eruptive nevi and induction of melanoma may be a further side effect in patients undergoing a therapy with BRAF inhibitors. PMID- 23626543 TI - Three cases of sacral pressure ulcers presenting primary dermatoporosis on the forearms. AB - The relatively new term dermatoporosis refers to chronic deficiencies in the skin's functions in the elderly population due to aging. This syndrome is marked by chronic cutaneous fragility clinically represented by skin atrophy, senile purpura, stellate pseudoscars, skin laceration, and dissecting hematoma of the skin. In this paper, we report three cases of sacral pressure ulcers presenting primary dermatoporosis on the forearms. Case 1 was a 74-year-old male who presented with a stage IV sacral pressure ulcer. The signs of dermatoporosis appeared on the forearms. Histopathology of the lesions revealed epidermal thinning with loss of rete ridges. Azan and Elastica van Gieson staining demonstrated the degeneration of the dermal collagen fibers and elastic fibers, respectively. In spite of 6 months of treatment, the ulcer failed to heal sufficiently. Case 2 was a 74-year-old male and Case 3 was a 97-year-old female. Both cases presented with a stage II sacral pressure ulcer and dermatoporosis on the forearms. Histopathological examinations and the clinical course of the wound could not be ascertained in Cases 2 and 3. None of the patients had previously used corticosteroids. The presence of a primary dermatoporosis on the forearms in these cases may be associated with the increased risk of pressure ulcer development. PMID- 23626544 TI - Successful treatment of plasmacytosis circumorificialis with topical tacrolimus: two case reports and an immunohistochemical study. AB - Plasmacytosis circumorificialis (PLC), a benign chronic inflammatory disease with an unknown pathogenesis, is characterized by erythema, erosion nodules and ulcers around the openings of the human body. In this report, we describe two cases of PLC successfully treated with topical tacrolimus. Interestingly, immunohistochemical staining revealed that prominent CD163(+) proinflammatory macrophages and IL-17-producing cells were infiltrating around plasma cells, which might suggest the reason for the therapeutic effect of topical tacrolimus on PLC. PMID- 23626545 TI - A case of lichen planus pemphigoides successfully treated with a combination of cyclosporine a and prednisolone. AB - Lichen planus pemphigoides (LPP) is a rare clinical variant of bullous pemphigoid (BP). A 35-year-old female patient presented to our hospital complaining of pruritic violaceous-colored plaques or papules on the extremities. Tense vesicles were also seen on the soles. Skin biopsies from the papules and vesicles demonstrated lichen planus and BP, respectively. Direct immunofluorescence demonstrated linear IgG and C3 deposition on the basement membrane zone. Indirect immunofluorescence on 1 M NaCl split skin detected IgG reactivity with the epidermal side. Enzyme-linked immunosorbent assay also detected anti-BP180 antibodies. After treatment with oral prednisolone alone had failed, low-dose cyclosporine A (CyA) was added. The clinical symptoms immediately improved and the titer of the anti-BP180 antibodies decreased. Although there is little information about the treatment of recalcitrant LPP, additional CyA appeared to be beneficial. PMID- 23626546 TI - Profiles of cytotoxic T lymphocytes in cutaneous lymphoid hyperplasia of the face. AB - Cutaneous lymphoid hyperplasia (CLH) is difficult to differentiate from primary malignant cutaneous lymphomas that may present as solitary nodules, and sometimes it requires much time to achieve a final diagnosis. A recent report [Park et al.: Acta Haematol 2011;126:79-86] suggested that the expression of granulysin correlates with the prognosis of cancer patients, even in hematological disorders. In this report, we immunohistochemically examine the expression of cytotoxic molecules (e.g. granulysin, TIA-1 and perforin) in tumor-infiltrating lymphocytes of 10 patients with CLH and 3 patients with cutaneous diffuse large B cell lymphoma, not otherwise specified (CDLBCL-NOS) of the face. In the patients with CLH, the number of granulysin-bearing cells was higher than in the patients with CDLBCL-NOS. In contrast, there was no difference in the number of TIA-1(+) or perforin(+) cells. The present study attempts to explain the different biological behaviors of these two hematological disorders and suggests granulysin as a possible diagnostic tool for CLH and CDLBCL-NOS of the face. PMID- 23626547 TI - Granulysin-Bearing Cells in the Skin Lesions of Acute Graft-versus-Host Disease: Possible Mechanisms for Hypohidrosis in Graft-versus-Host Disease. AB - Graft-versus-host disease (GVHD) is an important complication of bone marrow transplantation and is known to induce sweat gland abnormalities. We employed immunohistochemical staining for granulysin, dermcidin as well as IL-17 and Foxp3 in the lesional skin of 7 patients with acute GVHD. Granulysin-bearing cells were distributed in the epidermis, basal membrane zone of the dermis, and superficial perivascular lesion of the dermis. Interestingly, granulysin-bearing cells were also detected around the secretory portion of the eccrine glands, which might be related to the downregulation of the expression of dermcidin on the secretory portion of the eccrine glands. Differing from a mouse model, in human acute GVHD, IL-17-producing cells and Foxp3(+) cells were not prominent. Our present observation sheds light on the contribution of granulysin-bearing cells to the decrease of the sweat in patients with acute GVHD. Though we did not assess the function of these infiltrating lymphocytes directly, further analysis of the mechanism of this phenomenon would offer fundamental insight into the establishment of acute GVHD. PMID- 23626548 TI - Cyclosporine in the management of impetigo herpetiformis: a case report and review of the literature. AB - A 27-year-old female, gravida 1, para 0, in week 22 of pregnancy, presented with an eruption consisting of annular erythematosquamous plaques with an active polycyclic elevated border comprised of superficial micropustules. Clinical and histological features were typical of impetigo herpetiformis (IH). Systemic steroids resulted in an unstable condition, with no resolution of lesions. Resistance to the above therapeutic scheme served as a stimulus to discuss the use of cyclosporine as a therapeutic option in this condition. Reviewing the limited literature, cyclosporine seems to serve not as a monotherapy in the management of IH but as an additional medication, in order to achieve a stable course of the disease and avoid high doses of systemic steroids. PMID- 23626549 TI - Congenital Erythropoietic Porphyria: Mutation of the Uroporphyrinogen III Cosynthase Gene in a Vietnamese Patient. AB - Congenital erythropoietic porphyria (CEP) arises from an autosomal recessive inherited disorder of the porphyrin metabolism, which leads to the accumulation of uroporphyrinogen I in bone marrow, skin and several other tissues by a deficiency of uroporphyrinogen III cosynthase (UROS). We studied a Vietnamese patient and her family suffering from severe cutaneous photosensitivity with skin fragility, bullous lesions and hypertrichosis on light-exposed areas. A missense mutation in the UROS gene was identified as a transversion of G to T at nucleotide 11,776, resulting in a substitution of valine by phenylalanine at codon 3 of exon 2. The patient showed a homozygous mutant profile, and the heterozygous state was observed in the parents. The activity of mutated UROS expressed in Escherichia coli was less than 16.1% that of the control, indicating that the markedly reduced activity of UROS is responsible for CEP. We described for the first time a mutation in the UROS gene in a Southeast Asian patient and a molecular diagnosis for the identification of clinically asymptomatic heterozygous mutation carriers and families with CEP. PMID- 23626550 TI - Erythema a computatro. AB - Historically, erythema ab igne (EAI) was commonly seen on the shins of individuals working in front of coal stoves or sitting close to a fireplace. In the more recent past, this condition has been primarily observed after repeated application of heating pads. Today, unintentional and unperceived exposure to heat from laptop computers needs to be considered as a potential trigger. A rising number of laptop-induced cases of EAI have been reported recently. For this modern-age version of classic EAI, we propose thus the more accurate neo Latin term erythema a computatro. PMID- 23626551 TI - Targeting VEGF-VEGFR Pathway by Sunitinib in Peripheral Primitive Neuroectodermal Tumor, Paraganglioma and Epithelioid Hemangioendothelioma: Three Case Reports. AB - Sunitinib malate (Sutent(TM); Pfizer Inc., New York, N.Y., USA) is a small molecule kinase inhibitor with activity against a number of tyrosine kinase receptors, including vascular endothelial growth factor receptors, stem-cell factor receptor, and platelet-derived growth factor receptors alpha and beta. Sunitinib, registered for the treatment of renal cell carcinoma and gastrointestinal stromal tumors, has recently been approved for the treatment of patients with advanced pancreatic neuroendocrine tumors. Peripheral primitive neuroectodermal tumor (pPNET), paraganglioma (PGL) and epithelioid hemangioendothelioma (EHE) are rare tumors in which there is an overexpression of pro-angiogenic factors and in which a high intratumoral microvessel density is a significant poor prognostic factor. On the basis of this preclinical rationale and the lack of effective treatments in pre-treated advanced stages of these rare diseases, we report our interesting experience of pPNET, PGL and EHE treatment with sunitinib. PMID- 23626552 TI - Advanced hepatocellular carcinoma in adolescence associated with congenital cholestasis: a case description. AB - This case describes the clinical course and treatment of a 17-year-old male patient with advanced hepatocellular carcinoma (HCC) arising in a non-cirrhotic liver. The disease was thought to be caused by a congenital cholestatic syndrome associated with intermittent oedema in childhood, resembling the rare Aagenaes syndrome. Treatment choices in advanced HCC arising in adolescence are discussed. PMID- 23626553 TI - Diagnosis and management of primary umbilical melanoma with omphalitis features. AB - We report on a 62-year-old Chinese male patient who presented with a pigmented lesion in the umbilical area and who was treated for omphalitis in a local hospital for 1 month. Biopsy pathological examination revealed that the lesion was a melanoma. The Breslow depth was estimated at 3 mm, and Clark's level was IV. Ultrasonography showed no suspicious pathological lymph nodes, and no metastases were detected in the lung, liver or brain through CT scans. Reexcision was performed with lateral marginsd >2 cm from the original scar down to the peritoneum, including the umbilicus, round ligament of the liver and urachus. No adjuvant therapy was suggested, and the patient was still alive without recurrences or metastases after 36 months. PMID- 23626554 TI - Thirty-five-year-old woman with signet ring cell gastric carcinoma secondary to the chernobyl nuclear accident: a case report. AB - The 1986 Chernobyl nuclear accident resulted in radiation exposures throughout much of Europe, with the highest exposures within the city of Pripyat, Ukraine, where the accident occurred. We report a woman who was exposed to the Chernobyl accident at age 13. Beginning in her early thirties, she experienced several years of upper abdominal pain that became progressively more severe. At age 35, she underwent upper endoscopy and gastric biopsy. Histological examination revealed a signet ring cell (SRC) gastric carcinoma. The tumor was discovered at an advanced stage and proved unresectable. She died 3 months following her diagnosis. The mean age for SRC gastric carcinoma diagnosis is about 62 years; the median survival following diagnosis is 13 months. The early appearance and aggressive clinical course of this malignancy in relation to the Chernobyl nuclear accident is discussed. PMID- 23626555 TI - Metachronous gastrointestinal stromal tumor and acute leukemia after liver transplantation for cholangiocellular carcinoma: is there a link? AB - The synchronous or metachronous coexistence of gastrointestinal stromal tumors (GISTs) with solid and hematologic neoplasms has been addressed in a non transplant population. However, the association with primary hepatic neoplasms and leukemias is uncommon. Scarce data exist considering association of GISTs and other neoplasms in a transplant population where long-term immunosuppression carries the additional burden of de novo malignancy. We present a case of posttransplant metachronous GIST and acute biphenotypic leukemia in a patient transplanted for intrahepatic cholangiocellular carcinoma, emphasizing the possible link between mechanisms of carcinogenesis and influence of other factors upon their development. PMID- 23626556 TI - The use of high dosages of transdermal buprenorphine for pain management in palliative cancer patients: a case study. AB - Pain is a prevalent condition in patients with cancer, particularly in advanced stages of cancer. Although strong opioids are the mainstay of cancer pain management protocols, patients are often undertreated. Transdermal buprenorphine is currently available for the treatment of moderate to severe cancer pain and severe pain which does not respond to nonopioid analgesics; patch doses of 35, 52.5 and 70 ug/h are available (applied for up to 96 h), with no more than 2 transdermal patches at the same time, regardless of the strength. To date, there are no published reports in the literature of the use of high-dose transdermal buprenorphine (>140 ug/h). Herein, we present 2 cases of palliative cancer patients who received transdermal buprenorphine at doses titrated up to 210 and 175 ug/h, respectively, for the management of pain. Transdermal buprenorphine titrated to doses >140 ug/h provided adequate pain control and was well tolerated. Future studies to confirm these initial observations are warranted. PMID- 23626557 TI - Systemic mastocytosis presenting as acute appendicitis: a case report and review of the literature. AB - Systemic mastocytosis is characterized by abnormal growth and accumulation of mast cells in various organs. Gastrointestinal (GI) symptoms are common disease manifestations in this disease and can significantly impair the quality of life. Signs of GI systemic mastocytosis include steatorrhea, malabsorption, hepatomegaly, splenomegaly, portal hypertension, and ascites. Acute appendicitis as a presenting feature in systemic mastocytosis has not been reported in the literature previously. In this report, we discuss the case of a female patient with systemic mastocytosis (c-KIT D816V (+)) who was admitted for right-sided acute abdominal pain. Laboratory study revealed an normal white blood cell count with eosinophilia and an elevated serum tryptase level of 23 MUg/l. CT of the abdomen and pelvis showed an enlarged appendix of 12 mm in diameter, with minimal wall enhancement. Laparoscopic appendectomy was performed. The appendix was found to be hyperemic and firm, and it was densely adherent to the posterior cecum, the surrounding peritoneal wall, and the overlying mesenteric fat. Pathology revealed acute appendicitis with greater than 30 mast cells per high-power field by immunoperoxidase studies with mast cell tryptase and CD117. The patient subsequently improved and was discharged home. This case is the first reported case with a histological diagnosis of acute appendicitis resulting from mast cell infiltration. Physicians should be aware of acute appendicitis as a manifestation of systemic mastocytosis. Prompt diagnosis and management may prevent potentially fatal complications of appendiceal perforation and peritonitis. PMID- 23626558 TI - Spontaneous Regression of Hepatocellular Carcinoma due to Disruption of the Feeding Artery. AB - We present an unusual case of spontaneous regression of hepatocellular carcinoma (HCC). A 77-year-old man with alcoholic liver cirrhosis presented with a 50-mm tumor in the Couinaud's segment 8 (S8) of the liver, a 15-mm tumor in the S8-7 and 10-mm tumors in the other segments (S4, S6). The tumors were diagnosed as HCC by typical imaging findings and elevated serum alpha-fetoprotein (AFP, 1,825.0 ng/ml) and protein induced by vitamin K absence II (PIVKA II, 3,043 mAU/ml). One month later, AFP and PIVKA II decreased to 51.1 ng/ml and 411 mAU/ml, respectively, and the 50-mm tumor in the S8 became small and completely necrotic on angiography and computed tomography arteriography without any treatment. On the other hand, the 15-mm tumor in the S8-7 decreased in size to 10 mm and received blood supply from the right posterior superior arteries (A7). The other 10-mm tumors remained. Ischemia of the tumors due to disruption of the feeding artery (A8) might have induced tumor regression in the present case. PMID- 23626559 TI - Adenocarcinoma in colonic interposition. AB - A 59-year-old female with dysphagia presented to our clinic. In childhood, she underwent colonic interposition due to anastomotic stricture after a previous proximal gastrectomy for gastric ulcer perforation. Imaging studies revealed a space-occupying lesion obstructing the distal interposed colon. At surgery, completion gastrectomy with segmental colectomy was carried out, and Roux-en-Y coloenterostomy and enteroenterostomy were performed. PMID- 23626560 TI - Long-Term Treatment with Erlotinib for EGFR Wild-Type Non-Small Cell Lung Cancer: A Case Report. AB - The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib are known to have greater efficacy in EGFR mutation positive non-small cell lung cancer (NSCLC), although erlotinib also has activity in wild-type disease. We report the successful long-term maintenance treatment of a patient with EGFR wild-type NSCLC with gefitinib and later erlotinib. The patient (male; 44 years old; smoker) was diagnosed with EGFR wild-type NSCLC after computer tomography had revealed a mediastinal mass, and histology and mutation testing had identified the tumor as an EGFR wild-type grade 3 adenocarcinoma. The patient received multiple rounds of chemotherapy, followed by gefitinib maintenance (3 years). Later on, he received erlotinib maintenance and developed a persistent rash (grade 1/2) that lasted throughout the treatment. The patient's condition has remained stable on erlotinib for more than 5 years, with no evidence of progression. We describe the patient's disease course and treatment in the context of EGFR TKI therapy and the prognostic factors for long term clinical outcomes of NSCLC, including the development of erlotinib-induced rash. PMID- 23626561 TI - Treatment of a frail older patient with diffuse large B-cell lymphoma on maintenance dialysis: attenuated immunochemotherapy and adapted care plan. AB - PURPOSE OF THE STUDY: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy worldwide. Its incidence increases with age and about 40% of cases occur in patients over 70 years. Herein, we describe a case of a frail elderly patient with renal insufficiency and DLBCL treated with R-mini-CHOP. CASE REPORT: A 77-year-old man on maintenance hemodialysis started experiencing persistent fatigue. He was diagnosed with a large mass on the left lobe of the lung. Biopsy demonstrated a DLBCL, CD20 positive. The patient was assigned clinical stage IIBX, with a high age-adjusted international prognosis index. A proper geriatric assessment revealed a frail patient. Thus, an adapted chemotherapy regimen was proposed which consisted of R-mini-CHOP every 21 days, with a reduction of 10% in the doses of doxorubicin and cyclophosphamide. During the treatment, the patient went through regular dialysis sessions, 3 times per week, with an extra session performed 12 h after each chemotherapy administration. The patient experienced no adverse events or grade 3/4 toxicities. After 6 cycles of R-mini-CHOP, the patient achieved unconfirmed complete remission, and consolidation radiotherapy was performed. At the last follow-up, he was still in unconfirmed complete remission, with a progression free survival of 11.3 months. CONCLUSIONS: R-mini-CHOP represented a reasonable treatment option for this patient with renal failure. The oncogeriatric approach led to a successful management of this frail patient, highlighting that an adapted plan of care is a key issue to improve the outcomes of elderly cancer patients. PMID- 23626562 TI - Posterior reversible leukoencephalopathy syndrome associated with pazopanib. AB - A 62-year-old female patient with metastatic renal cell carcinoma under third line treatment with pazopanib for 8 weeks suddenly developed severe headaches, grand mal seizures and paresis of the left arm in combination with gait instability as well as nausea and vomiting during her vacation abroad. The emergency physician measured systolic blood pressure values over 300 mm Hg and suspected a stroke. The CT imaging without contrast agent in a local hospital did not show any pathologic findings despite bone metastases. The colleagues suspected cerebral metastases or meningeosis carcinomatosa and referred the patient to our department for further diagnostics and treatment planning. An MRI scan ruled out the suspected cerebral metastases or meningeosis carcinomatosa, but showed signs of reversible posterior leukoencephalopathy syndrome (RPLS) in the form of band-like hyperintensities as a sign of cytotoxic edema in the gray and white matter of the left parietal lobe. The patient then reported that similar blood pressure values had been measured shortly after the start of a first-line therapy with sunitinib, so that we discontinued the current treatment with pazopanib. Within 6 days the neurologic symptoms vanished and the patient was discharged. An intermittent hypertension persisted. A follow-up MRI 3 weeks later showed an RPLS-typical cortical infarction in the affected area. RPLS should be considered as the actual reason for neurologic findings in hypertensive patients with known metastatic cancers under tyrosine kinase inhibitor therapy. PMID- 23626563 TI - Long-term management of a patient with well-differentiated pulmonary neuroendocrine carcinoma: a case report. AB - Pulmonary neuroendocrine tumors (NET) are rare, and very few published reports have described the long-term treatment of patients with this disease. Current treatment options for patients with metastatic well-differentiated pulmonary NET are limited. This case report details the long-term treatment of a 62-year-old female patient with well-differentiated pulmonary NET and multiple liver metastases. The heavily pretreated patient achieved radiographic stability in measurable disease, improvement in nonmeasurable disease, and symptomatic improvement over 3 years while receiving the combination of everolimus and octreotide long-acting repeatable (LAR). Treatment was well tolerated without mucositis, rash, or pneumonitis. This case report suggests that the combination of everolimus and octreotide LAR may be a novel treatment option for heavily pretreated patients with metastatic well-differentiated pulmonary NET, but these findings require further analysis in clinical trials. PMID- 23626564 TI - Estrogen receptor- and progesterone receptor-positive diffuse sclerosing variant of papillary thyroid carcinoma: a case report. AB - The diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) is a relatively rare tumor. We herein report the case of young woman with DSV-PTC who developed cervical lymph node recurrence 7 years after the initial surgery. A 15 year-old female patient with no medical or family history of thyroid tumors developed a thyroid neoplasm in the right lobe. Right thyroidectomy and regional lymphadenectomy were performed, and the tumor was diagnosed as DSV-PTC. She was followed up as an outpatient. Seven years after the surgery, cervical lymph node recurrence developed. On microscopic examination, the thyroid tumor showed a papillary growth pattern with numerous psammoma bodies and distinct fibrosis. Immunohistochemically, the tumor cells were estrogen receptor and progesterone receptor positive with reduced membranous expression of E-cadherin and were intermingled with S-100-positive dendritic/Langerhans cells. DSV-PTC is characterized by a strong tendency for invasion and metastasis. Thus, accurate diagnosis is clinically important, and a morphological and immunohistochemical understanding of DSV-PTC is necessary. PMID- 23626565 TI - Are steroids a beneficial adjunctive therapy in the immunosuppressed patient with herpes simplex virus encephalitis? AB - Few reports describe the reactivation of latent herpes simplex virus causing encephalitis (HSVE) in patients undergoing brain radiation therapy and a concomitant steroid regimen. The role for steroid use in the treatment of patients with HSVE has not been fully elucidated. We report the case of a female patient immunosuppressed by steroids and brain radiation who developed HSVE and responded to acyclovir and dexamethasone. PMID- 23626566 TI - Thrombolysis in a stroke patient on dabigatran anticoagulation: case report and synopsis of published cases. AB - We present the case of an aphasic 77-year-old stroke patient with left distal M1 occlusion who received rt-PA for thrombolysis while on oral anticoagulant treatment with dabigatran (150 mg b.i.d.). Coagulation parameters were normal (thrombin time 20 s, aPTT 20 s, INR 1.08) and the patient improved from an NIHSS of 15 to 5 within 24 h with sonographic evidence of M1 recanalization. She did not develop intracranial bleeding complications but showed unusually large diffuse skin ecchymoses. In our report, we give an overview of all reported cases of thrombolysis under dabigatran anticoagulation and discuss the questions of medication adherence under novel oral anticoagulants (NOA) and the safety of NOA in terms of secondary intracerebral hemorrhage after stroke. PMID- 23626567 TI - Cochleovestibular Deficit as First Manifestation of Syphilis in a HIV-Infected Patient. AB - We report the detailed documented case of a 57-year-old homosexual HIV-positive man with bilateral cochleovestibular deficits as a first symptom of syphilis infection in early stage II disease. As a morphological substrate, a strong enhancement of both inner ears and vestibulocochlear nerves were found on gadolinium-enhanced MR scans. The serological tests identified an active infection with Treponema pallidum. After a high-dose treatment with penicillin G and prednisolone, the auditory and vestibular functions and the MR morphology of the vestibulocochlear nerves and inner ears on both sides returned to normal. PMID- 23626568 TI - Amelioration of persistent, non-ketotic hyperglycemia-induced hemichorea by repetitive transcranial magnetic stimulation. AB - Diabetic hemichorea-hemiballism with non-ketotic hyperglycemia is usually a benign syndrome. Here, we report a 78-year-old woman with persistent hemichorea (HC) for longer than 1 year with a recurrence after rapid correction of hyperglycemia. Following the disappearance of the characteristic T1 hyperintensity at 3 months after onset, an MRI demonstrated T2* hypointensity and atrophic changes in the contralateral striatum, suggesting irreversible neuronal loss and some vascular proliferation. The electrophysiological examination using transcranial magnetic stimulation revealed significantly shorter cortical silent periods (CSPs) on the contralateral primary motor cortex (M1), possibly in relation to cortical hyperexcitability. We have applied 10 daily sessions of low frequency repetitive transcranial magnetic stimulation (rTMS) over the contralateral M1 to reduce the hyperexcitability. The HC was suppressed during and for several minutes after rTMS with prolongation of CSPs. After rehabilitation therapy, the patient was able to walk independently with a walker. We suggest that the combination of low-frequency rTMS and rehabilitation therapy may be a possible choice in medically refractory involuntary movements. PMID- 23626569 TI - Joint Modeling of Longitudinal Change and Survival: An Investigation of the Association Between Change in Memory Scores and Death. AB - Joint longitudinal-survival models are useful when repeated measures and event time data are available and possibly associated. The application of this joint model in aging research is relatively rare, albeit particularly useful, when there is the potential for nonrandom dropout. In this article we illustrate the method and discuss some issues that may arise when fitting joint models of this type. Using prose recall scores from the Swedish OCTO-Twin Longitudinal Study of Aging, we fitted a joint longitudinal-survival model to investigate the association between risk of mortality and individual differences in rates of change in memory. A model describing change in memory scores as following an accelerating decline trajectory and a Weibull survival model was identified as the best fitting. This model adjusted for random effects representing individual variation in initial memory performance and change in rate of decline as linking terms between the longitudinal and survival models. Memory performance and change in rate of memory decline were significant predictors of proximity to death. Joint longitudinal-survival models permit researchers to gain a better understanding of the association between change functions and risk of particular events, such as disease diagnosis or death. Careful consideration of computational issues may be required because of the complexities of joint modeling methodologies. PMID- 23626570 TI - A Case of Branch Retinal Artery Occlusion following Uneventful Phacoemulsification. AB - We would like to present a case of branch retinal artery occlusion following uneventful phacoemulsification, possibly caused by sub-Tenon's anaesthesia. There were no predisposing general health problems. There are two possible mechanisms: (1) mechanical effect of the bolus anaesthetic; (2) pharmacologically mediated changes in the vascular calibre. The latter mechanism is much more probable, because of the vasoconstrictive properties of both medications used. This is the first reported case of branch retinal artery occlusion after sub-Tenon's anaesthesia with preservative-free medications. PMID- 23626571 TI - Four years old, one eye, pars planitis and cataract: surgical challenges give challenging surprises. AB - Pars planitis (PP) is an intermediate form of uveitis, which, if left untreated, can result in vision loss. Although phacoemulsification with IOL implantation in eyes with PP often results in improved vision, it represents a surgical challenge due to inflammatory sequelae and the possibility of postoperative complications. This case report describes a 4-year-old male who was admitted for poor visual acuity and severe photophobia. The patient previously received vitreo-retinal surgery on his right eye due to an 'unknown disease'. Ophthalmological evaluation revealed NLP, pupillary seclusion and band keratopathy in the right eye; echographic scans revealed funnel retinal detachment. The left eye had a visual acuity of CF at 1 foot, minimal band keratopathy, posterior synechiae and the following echographic findings: abundant vitreous opacities and increased chorioretinal thickness (1.6 mm). Complete medical and laboratory assessments found no infectious pathologies. The patient was diagnosed with PP. Anti inflammatory and immunological therapy was given in order to control inflammation. Within four months, the inflammation was controlled. Slow motion phacoemulsification with iris-retractors was performed. During the surgery, an unexpected challenge was identified: an opaque-vascular retrolental membrane. The membrane was cauterized with diathermy. Primary posterior capsulotomy and membranectomy were performed, followed by a limited anterior vitrectomy. An in the-bag IOL was implanted successfully, with no postoperative complications, and visual acuity improved to 20/200. PMID- 23626572 TI - Acute-Onset Endophthalmitis Caused by Alloiococcus otitidis following a Dexamethasone Intravitreal Implant. AB - PURPOSE: To report the first case of acute endophthalmitis caused by Alloiococcus otitidis after a dexamethasone intravitreal implant. METHODS: A 74-year-old female was treated with intravitreal Ozurdex((r)) in her left eye for central retinal vein occlusion (CRVO). Best-corrected visual acuity (BCVA) in the eye was 4/20. Intravitreal injection was uneventful. At 48 h after injection, she developed ocular pain and visual acuity had dropped to light perception. Endophthalmitis associated with intravitreal injection was suspected. RESULTS: The patient did not show a favorable clinical response following systemic, intravitreal, and topical fortified antibiotics. We then performed a vitreous biopsy and removed the Ozurdex implant by pars plana vitrectomy. A vitreous culture was positive for A. otitidis. At the 2-month follow up, no inflammation was observed, but due to CRVO and probably aggravated by endophthalmitis, the fundus showed macular fibrosis. The final BCVA was finger counting at 30 cm in her left eye. CONCLUSIONS: In cases of an intravitreal implant associated with endophthalmitis, we recommend removal of the device because it may act as a permanent reservoir of organisms if it remains in the vitreous cavity. PMID- 23626573 TI - Enterobacter cloacae Postsurgical Endophthalmitis: Report of a Positive Outcome. AB - We report a positive outcome of postcataract endophthalmitis caused by Enterobacter cloacae, which has previously resulted in poor outcomes in endophthalmitis. A 67-year-old man underwent uncomplicated cataract surgery. On the morning of postoperative day (POD) #1, he had significant anterior chamber inflammation without pain, hypopyon, or vitritis but then rapidly developed hypopyon and worsening visual acuity. He underwent a tap and inject with vancomycin and ceftazidime and was prescribed topical steroids and antibiotics as well as oral levofloxacin. On POD #3, cultures of the vitreous and aqueous returned positive for E. cloacae. By POD #6, his hypopyon had resolved with improved vitritis, decreased inflammation, and visual acuity of 20/200. Two weeks after surgery, his best-corrected visual acuity was 20/60. Contrary to prior reports, we demonstrate that it is possible to achieve a good outcome in cases of E. cloacae endophthalmitis treated early with appropriate antibiotics and anti inflammatory agents. PMID- 23626574 TI - A Case of Bilateral Descemet's Membrane and Subepithelial Opacity: In vivo Laser Confocal Microscopic Study. AB - PURPOSE: To report the in vivo laser confocal microscopy findings from a patient with Descemet's membrane and subepithelial opacity OU. CASE REPORT: A healthy 41 year-old male with Descemet's membrane and subepithelial opacity OU was studied. Routine ophthalmic examination, standard slit-lamp biomicroscopy, and in vivo laser confocal microscopic analysis of the entire corneal layer were performed. Slit-lamp biomicroscopy revealed subepithelial opacity in the mid-peripheral to peripheral cornea and numerous opacities located at the level of Descemet's membrane. It was difficult to distinguish the precise histological location of the opacity. In vivo laser confocal microscopy showed numerous hyperreflective particles in the subepithelium to superficial stroma and hyperreflectivity of Descemet's membrane. No abnormalities could be detected in the epithelial cell layer, midstromal layer, deep stromal layer, or endothelial cell layer. CONCLUSION: Although the origin of the corneal opacities was unclear, in vivo laser confocal microscopy was useful for observing microstructural abnormalities in a case of Descemet's membrane and subepithelial opacity. PMID- 23626575 TI - The impact of cancer therapy on cognition in the elderly. AB - Cancer and cancer therapy-related cognitive impairment (formerly known as chemobrain or chemo-fog) are often described in the literature. In the past, studies have failed to prove the existence of cancer therapy-related cognitive dysfunction. However, more recently, prospective trials have shown that patients undergoing chemotherapy do display impairment in specific cognitive domains. Aging confers an increased risk of developing cancer, as well as cognitive impairment. The Geriatric Oncology clinic of the Segal Cancer Centre, Jewish General Hospital in Montreal was founded in 2006 to address the unique needs of older cancer patients. We will describe two cases of cancer therapy-related cognitive impairment from our Geriatric Oncology clinic. The first case is that of a 75 year old male diagnosed with stage III non-small cell lung carcinoma who complained of forgetfulness since starting carboplatin-paclitaxel. The second case is that of a 65 year old female diagnosed with stage I, estrogen-receptor positive breast cancer who had undergone lumpectomy followed by adjuvant cyclophosphamide, methotrexate and fluorouracil chemotherapy, radiation therapy and was on exemestane when she was evaluated. We will also briefly review the literature of cancer therapy-related cognitive impairment. PMID- 23626576 TI - After the chemotherapy: potential mechanisms for chemotherapy-induced delayed skeletal muscle dysfunction in survivors of acute lymphoblastic leukaemia in childhood. AB - There is evidence that survivors of childhood cancers, such as acute lymphoblastic leukemia (ALL), have increased rates of long-term skeletal muscle dysfunction. This places them at higher risk of physical restriction and functional impairment as well as potentially contributing to observed increases in cardiovascular disease and insulin resistance in later life. The mechanisms underlying these changes in skeletal muscle are unknown but chemotherapy drugs used in treatment for ALL are strongly implicated. Normal skeletal muscle growth, development, and function are dependent on correctly functioning muscle satellite cells, muscle motor neurons, and muscle mitochondria. Each of these key components is potentially susceptible to damage by chemotherapy in childhood, particularly prolonged courses including repeated administration of combination chemotherapy. If this chemotherapy-induced damage is not fully reversible, impairment of satellite cells, muscle motor innervation, and mitochondria could, either singly or together, lead to the emergence of delayed or persistent skeletal muscle dysfunction many years later. The known effects of individual drugs used in the treatment of ALL are outlined and the need for specific targeted studies to investigate the mechanisms underlying persistent muscle dysfunction in survivors of ALL and other childhood cancers is highlighted. PMID- 23626577 TI - Mitochondrial dysfunction, alternans, and arrhythmias. PMID- 23626578 TI - Time scales in cognitive neuroscience. AB - Cognitive neuroscience boils down to describing the ways in which cognitive function results from brain activity. In turn, brain activity shows complex fluctuations, with structure at many spatio-temporal scales. Exactly how cognitive function inherits the physical dimensions of neural activity, though, is highly non-trivial, and so are generally the corresponding dimensions of cognitive phenomena. As for any physical phenomenon, when studying cognitive function, the first conceptual step should be that of establishing its dimensions. Here, we provide a systematic presentation of the temporal aspects of task-related brain activity, from the smallest scale of the brain imaging technique's resolution, to the observation time of a given experiment, through the characteristic time scales of the process under study. We first review some standard assumptions on the temporal scales of cognitive function. In spite of their general use, these assumptions hold true to a high degree of approximation for many cognitive (viz. fast perceptual) processes, but have their limitations for other ones (e.g., thinking or reasoning). We define in a rigorous way the temporal quantifiers of cognition at all scales, and illustrate how they qualitatively vary as a function of the properties of the cognitive process under study. We propose that each phenomenon should be approached with its own set of theoretical, methodological and analytical tools. In particular, we show that when treating cognitive processes such as thinking or reasoning, complex properties of ongoing brain activity, which can be drastically simplified when considering fast (e.g., perceptual) processes, start playing a major role, and not only characterize the temporal properties of task-related brain activity, but also determine the conditions for proper observation of the phenomena. Finally, some implications on the design of experiments, data analyses, and the choice of recording parameters are discussed. PMID- 23626579 TI - Neurocognitive impairment in childhood chronic fatigue syndrome. AB - Neurocognitive impairment is a feature of childhood chronic fatigue syndrome (CCFS). Several studies have demonstrated reduced attention control in CCFS patients in switching and divided attention tasks. In students, the extent of deterioration in task performance depends on the level of fatigue. Poor performance in switching and divided attention is common in both fatigued students and CCFS patients. Additionally, attentional functions show dramatic development from childhood to adolescence, suggesting that abnormal development of switching and divided attention may be induced by chronic fatigue. The brain structures associated with attentional control are situated in the frontal and parietal cortices, which are the last to mature, suggesting that severe fatigue in CCFS patients and students may inhibit normal structural and functional development in these regions. A combination of treatment with cognitive behavioral therapy and antidepressant medication is effective to improve attentional control processing in CCFS patients. Studies identifying the features of neurocognitive impairment in CCFS have improved our current understanding of the neurophysiological mechanisms of CCFS. PMID- 23626580 TI - Perceptual decision making "through the eyes" of a large-scale neural model of v1. AB - Sparse coding has been posited as an efficient information processing strategy employed by sensory systems, particularly visual cortex. Substantial theoretical and experimental work has focused on the issue of sparse encoding, namely how the early visual system maps the scene into a sparse representation. In this paper we investigate the complementary issue of sparse decoding, for example given activity generated by a realistic mapping of the visual scene to neuronal spike trains, how do downstream neurons best utilize this representation to generate a "decision." Specifically we consider both sparse (L1-regularized) and non-sparse (L2 regularized) linear decoding for mapping the neural dynamics of a large-scale spiking neuron model of primary visual cortex (V1) to a two alternative forced choice (2-AFC) perceptual decision. We show that while both sparse and non-sparse linear decoding yield discrimination results quantitatively consistent with human psychophysics, sparse linear decoding is more efficient in terms of the number of selected informative dimension. PMID- 23626581 TI - Illusory motion and mislocalization of temporally offset target in apparent motion display. AB - When a visual target briefly appears in a display containing visual motion information, the perceived position of the target is mislocalized forward along its direction of motion. This phenomenon is assumed to be caused by the interaction between the transient onset signal of the target and motion information. However, while transient onset and offset signals are important for the establishment of our perceptual awareness, it has not been examined whether transient offset signals could be also effective for target mislocalization. Here, we demonstrate that shifts in perceived position occurred for a visual target containing a temporally transient offset signal in an apparent motion (AM) display. First, with horizontal AM, we found that illusory motion was perceived when a static target transiently and repeatedly blinked at a fixed position. The perceived direction of the illusory motion was in counter-phase with that of the AM stimuli. Further, we confirmed that illusory motion was frequently perceived when (1) the eccentricity of the target was larger, (2) offset duration was longer, and (3) smoother AM was perceived. Illusory motion was not perceived unless AM stimuli were presented after the offset signal, while illusory motion still occurred when the AM stimuli disappeared before the offset signal. In addition, we found that mislocalization of the target's perceived position actually occurred in a direction opposite to AM. These findings suggest that a transient offset signal could trigger perceptual mislocalization of static visual stimuli by interacting with motion information in a postdictive manner. PMID- 23626582 TI - Metaphor in embodied cognition is more than just combining two related concepts: a comment on Wilson and Golonka (2013). PMID- 23626583 TI - Balancing on a Slackline: 8-Year-Olds vs. Adults. AB - Children are less stable than adults during static upright stance. We investigated whether the same holds true for a task that was novel for both children and adults and highly dynamic: single-legged stance on a slackline. We compared 8-year-olds with young adults and assessed the following outcome measures: time on the slackline, stability on the slackline (calculated from slackline reaction force), gaze movement, head-in-space rotation and translation, trunk-in-space rotation, and head-on-trunk rotation. Eight-year-olds fell off the slackline quicker and were generally less stable on the slackline than adults. Eight-year-olds also showed more head-in-space rotation and translation, and more gaze variability around a visual anchor point they were instructed to fixate. Trunk-in-space and head-on-trunk rotations did not differ between groups. The results imply that the lower postural stability of 8-year-olds compared to adults - as found in simple upright stance - holds true for dynamic, novel tasks in which adults lack the advantage of more practice. They also suggest that the lack of head and gaze stability constitutes an important limiting factor in children's ability to master such tasks. PMID- 23626584 TI - Structure and Function of Parkin, PINK1, and DJ-1, the Three Musketeers of Neuroprotection. AB - Autosomal recessive forms of Parkinson's disease are caused by mutations in three genes: Parkin, PINK1, and DJ-1. These genes encode for proteins with distinct enzymatic activities that may work together to confer neuroprotection. Parkin is an E3 ubiquitin ligase that has been shown to ubiquitinate substrates and to trigger proteasome-dependent degradation or autophagy, two crucial homeostatic processes in neurons. PINK1 is a mitochondrial protein kinase whose activity is required for Parkin-dependent mitophagy, a process that has been linked to neurodegeneration. Finally, DJ-1 is a protein homologous to a broad class of bacterial enzymes that may function as a sensor and modulator of reactive oxygen species, which have been implicated in neurodegenerative diseases. Here, we review the literature on the structure and biochemical functions of these three proteins. PMID- 23626585 TI - The role of melanin-concentrating hormone and its receptors in energy homeostasis. AB - Extensive studies in rodents with melanin-concentrating hormone (MCH) have demonstrated that the neuropeptide hormone is a potent orexigen. Acutely, MCH causes an increase in food intake, while chronically it leads to increased weight gain, primarily as an increase in fat mass. Multiple knockout mice models have confirmed the importance of MCH in modulating energy homeostasis. Animals lacking MCH, MCH-containing neurons, or the MCH receptor all are resistant to diet induced obesity. These genetic and pharmacologic studies have prompted a large effort to identify potent and selective MCH receptor antagonists, initially as tool compounds to probe pharmacology in models of obesity, with an ultimate goal to identify novel anti-obesity drugs. In animal models, MCH antagonists have consistently shown efficacy in reducing food intake acutely and inhibiting body weight gain when given chronically. Five compounds have proceeded into clinical testing. Although they were reported as well-tolerated, none has advanced to long term efficacy and safety studies. PMID- 23626586 TI - Metagenomic evidence for sulfur lithotrophy by Epsilonproteobacteria as the major energy source for primary productivity in a sub-aerial arctic glacial deposit, Borup Fiord Pass. AB - We combined free enenergy calculations and metagenomic analyses of an elemental sulfur (S(0)) deposit on the surface of Borup Fiord Pass Glacier in the Canadian High Arctic to investigate whether the energy available from different redox reactions in an environment predicts microbial metabolism. Many S, C, Fe, As, Mn, and [Formula: see text] oxidation reactions were predicted to be energetically feasible in the deposit, and aerobic oxidation of S(0) was the most abundant chemical energy source. Small subunit ribosomal RNA (SSU rRNA) gene sequence data showed that the dominant phylotypes were Sulfurovum and Sulfuricurvum, both Epsilonproteobacteria known to be capable of sulfur lithotrophy. Sulfur redox genes were abundant in the metagenome, but sox genes were significantly more abundant than reverse dsr (dissimilatory sulfite reductase)genes. Interestingly, there appeared to be habitable niches that were unoccupied at the depth of genome coverage obtained. Photosynthesis and [Formula: see text] oxidation should both be energetically favorable, but we found few or no functional genes for oxygenic or anoxygenic photosynthesis, or for [Formula: see text] oxidation by either oxygen (nitrification) or nitrite (anammox). The free energy, SSU rRNA gene and quantitative functional gene data are all consistent with the hypothesis that sulfur-based chemolithoautotrophy by Epsilonproteobacteria (Sulfurovum and Sulfuricurvum) is the main form of primary productivity at this site, instead of photosynthesis. This is despite the presence of 24-h sunlight, and the fact that photosynthesis is not known to be inhibited by any of the environmental conditions present. This is the first time that Sulfurovum and Sulfuricurvum have been shown to dominate a sub-aerial environment, rather than anoxic or sulfidic settings. We also found that Flavobacteria dominate the surface of the sulfur deposits. We hypothesize that this aerobic heterotroph uses enough oxygen to create a microoxic environment in the sulfur below, where the Epsilonproteobacteria can flourish. PMID- 23626587 TI - Characteristics of microbial communities in crustal fluids in a deep-sea hydrothermal field of the suiyo seamount. AB - To directly access the sub-seafloor microbial communities, seafloor drilling has been done in a deep-sea hydrothermal field of the Suiyo Seamount, Izu-Bonin Arc, Western Pacific. In the present study, crustal fluids were collected from the boreholes, and the bacterial and archaeal communities in the fluids were investigated by culture-independent molecular analysis based on 16S rRNA gene sequences. Bottom seawater, sands, rocks, sulfide mound, and chimneys were also collected around the boreholes and analyzed for comparisons. Comprehensive analysis revealed the characteristics of the microbial community composition in the crustal fluids. Phylotypes closely related to cultured species, e.g., Alteromonas, Halomonas, Marinobacter, were relatively abundant in some crustal fluid samples, whereas the phylotypes related to Pelagibacter and the SUP05-group were relatively abundant in the seawater samples. Phylotypes related to other uncultured environmental clones in Alphaproteobacteria and Gammaproteobacteria were relatively abundant in the sand, rock, sulfide mound, and chimney samples. Furthermore, comparative analysis with previous studies of the Suiyo Seamount crustal fluids indicates the change in the microbial community composition for 3 years. Our results provide novel insights into the characteristics of the microbial communities in crustal fluids beneath a deep-sea hydrothermal field. PMID- 23626588 TI - Design and development of synthetic microbial platform cells for bioenergy. AB - The finite reservation of fossil fuels accelerates the necessity of development of renewable energy sources. Recent advances in synthetic biology encompassing systems biology and metabolic engineering enable us to engineer and/or create tailor made microorganisms to produce alternative biofuels for the future bio era. For the efficient transformation of biomass to bioenergy, microbial cells need to be designed and engineered to maximize the performance of cellular metabolisms for the production of biofuels during energy flow. Toward this end, two different conceptual approaches have been applied for the development of platform cell factories: forward minimization and reverse engineering. From the context of naturally minimized genomes,non-essential energy-consuming pathways and/or related gene clusters could be progressively deleted to optimize cellular energy status for bioenergy production. Alternatively, incorporation of non indigenous parts and/or modules including biomass-degrading enzymes, carbon uptake transporters, photosynthesis, CO2 fixation, and etc. into chassis microorganisms allows the platform cells to gain novel metabolic functions for bioenergy. This review focuses on the current progress in synthetic biology-aided pathway engineering in microbial cells and discusses its impact on the production of sustainable bioenergy. PMID- 23626589 TI - Endogenous Acute Phase Serum Amyloid A Lacks Pro-Inflammatory Activity, Contrasting the Two Recombinant Variants That Activate Human Neutrophils through Different Receptors. AB - Most notable among the acute phase proteins is serum amyloid A (SAA), levels of which can increase 1000-fold during infections, aseptic inflammation, and/or trauma. Chronically elevated SAA levels are associated with a wide variety of pathological conditions, including obesity and rheumatic diseases. Using a recombinant hybrid of the two human SAA isoforms (SAA1 and 2) that does not exist in vivo, numerous in vitro studies have given rise to the notion that acute phase SAA is a pro-inflammatory molecule with cytokine-like properties. It is however unclear whether endogenous acute phase SAA per se mediates pro-inflammatory effects. We tested this in samples from patients with inflammatory arthritis and in a transgenic mouse model that expresses human SAA1. Endogenous human SAA did not drive production of pro-inflammatory IL-8/KC in either of these settings. Human neutrophils derived from arthritis patients displayed no signs of activation, despite being exposed to severely elevated SAA levels in circulation, and SAA-rich sera also failed to activate cells in vitro. In contrast, two recombinant SAA variants (the hybrid SAA and SAA1) both activated human neutrophils, inducing L-selectin shedding, production of reactive oxygen species, and production of IL-8. The hybrid SAA was approximately 100-fold more potent than recombinant SAA1. Recombinant hybrid SAA and SAA1 activated neutrophils through different receptors, with recombinant SAA1 being a ligand for formyl peptide receptor 2 (FPR2). We conclude that even though recombinant SAAs can be valuable tools for studying neutrophil activation, they do not reflect the nature of the endogenous protein. PMID- 23626590 TI - The Regulation of Immune Responses by DC Derived Type I IFN. AB - Our immune system bears the tremendous task of mounting effective anti-microbial responses whilst maintaining immunoregulatory functions to avoid autoimmunity. In order to quickly respond to pathogens, Dendritic cells (DC) are armed with pattern recognition receptors (PRRs), allowing them to recognize highly conserved pathogen-associated molecular patterns (PAMPs) that are uniquely expressed by invading microbes. PRR activation can trigger DCs to release the pleiotropic cytokine, Type I interferons (IFN), which facilitates various biological functions in different immune cell types. In this review, we will discuss the classical PRR-induced Type I IFN response in DCs as well as describe a novel mechanism for Type I IFN induction by the tumor-necrosis factor receptor superfamily (TNFRSF) members, TNFR-1 and lymphotoxin-beta receptor (LTbetaR). While PRR activation during viral infection, produces large amounts of Type I IFN in a relative short period of time, TNFRSF-induced Type I IFN expression is modest with gradual kinetics. Type I IFN can exert pro-inflammatory effects, but in some cases it also facilitates immune-regulatory functions. Therefore, DCs are important regulators of immune responses by carefully modulating Type I IFN expression. PMID- 23626592 TI - Nitrogen recycling and flowering time in perennial bioenergy crops. AB - Perennials have a number of traits important for profitability and sustainability of a biofuel crop. Perennialism is generally defined as the ability to grow and reproduce in multiple years. In temperate climates, many perennial plants enter dormancy during winter and recycle nutrients, such as nitrogen, to below ground structures for the next growing season. Nitrogen is expensive to produce and application of nitrogen increases the potent greenhouse gas NO x . Perennial bioenergy crops have been evaluated for biomass yields with nitrogen fertilization, location, year, and genotype as variables. Flowering time and dormancy are closely related to the N recycling program. Substantial variation for flowering time and dormancy has been identified in the switchgrass (Panicum virgatum L.) species, which provides a source to identify the genetic components of N recycling, and for use in breeding programs. Some studies have addressed recycling specifically, but flowering time and developmental differences were largely ignored, complicating interpretation of the results. Future studies on recycling need to appreciate plant developmental stage to allow comparison between experiments. A perennial/annual model(s) and more environmentally controlled experiments would be useful to determine the genetic components of nitrogen recycling. Increasing biomass yield per unit of nitrogen by maximizing recycling might mean the difference for profitability of a biofuel crop and has the added benefit of minimizing negative environmental effects from agriculture. PMID- 23626591 TI - Modeling the Mycobacterium tuberculosis Granuloma - the Critical Battlefield in Host Immunity and Disease. AB - Granulomas are the hallmark of Mycobacterium tuberculosis (M.tb) infection and thus sit at the center of tuberculosis (TB) immunopathogenesis. TB can result from either early progression of a primary granuloma during the infection process or reactivation of an established granuloma in a latently infected person. Granulomas are compact, organized aggregates of immune cells consisting of blood derived infected and uninfected macrophages, foamy macrophages, epithelioid cells (uniquely differentiated macrophages), and multinucleated giant cells (Langerhans cells) surrounded by a ring of lymphocytes. The granuloma's main function is to localize and contain M.tb while concentrating the immune response to a limited area. However, complete eradication does not occur since M.tb has its own strategies to persist within the granuloma and to reactivate and escape under certain conditions. Thus M.tb-containing granulomas represent a unique battlefield for dictating both the host immune and bacterial response. The architecture, composition, function, and maintenance of granulomas are key aspects to study since they are expected to have a profound influence on M.tb physiology in this niche. Granulomas are not only present in mycobacterial infections; they can be found in many other infectious and non-infectious diseases and play a crucial role in immunity and disease. Here we review the models currently available to study the granulomatous response to M.tb. PMID- 23626593 TI - Mass spectrometry based imaging techniques for spatially resolved analysis of molecules. AB - Higher plants are composed of a multitude of tissues with specific functions, reflected by distinct profiles for transcripts, proteins, and metabolites. Comprehensive analysis of metabolites and proteins has advanced tremendously within recent years, and this progress has been driven by the rapid development of sophisticated mass spectrometric techniques. In most of the current "omics" studies, analysis is performed on whole organ or whole plant extracts, rendering to the loss of spatial information. Mass spectrometry imaging (MSI) techniques have opened a new avenue to obtain information on the spatial distribution of metabolites and of proteins. Pioneered in the field of medicine, the approaches are now applied to study the spatial profiles of molecules in plant systems. A range of different plant organs and tissues have been successfully analyzed by MSI, and patterns of various classes of metabolites from primary and secondary metabolism could be obtained. It can be envisaged that MSI approaches will substantially contribute to build spatially resolved biochemical networks. PMID- 23626594 TI - A prospective study on the prevalence and risk factors of poststroke depression. AB - BACKGROUND AND PURPOSE: Poststroke depression (PSD) is common. Early detection of depressive symptoms and identification of patients at risk for PSD are important as PSD negatively affects stroke outcome and costs of medical care. Therefore, the aim of this study was to determine incidence and risk factors for PSD at 3 months after stroke. METHODS: We conducted a prospective, longitudinal epidemiological study aiming to determine incidence and risk factors for PSD at 1, 3, 6, 12 and 18 months poststroke. The present data analysis covers the convalescent phase of 3 months poststroke. Participants in this study were inpatients, admitted to a stroke unit with first or recurrent stroke. Demographic data and vascular risk factors were collected and patients were evaluated at baseline and 3 months poststroke for functional and cognitive deficits, stroke characteristics, stroke severity and stroke outcome. Signs and symptoms of depression were quantified by means of the Cornell Scale for Depression (CSD) and Montgomery and Asberg Depression Rating Scale (MADRS). Significantly associated variables from univariate analysis were analyzed by using multiple linear and logistic regression methods. RESULTS: Data analysis was performed in 135 patients who completed follow-up assessments at 3 months poststroke. Depression (CSD score >=8) was diagnosed in 28.1% of the patients. Patients with PSD were significantly more dependent with regard to activities of daily living (ADL) and displayed more severe physical and cognitive impairment than patients without PSD. A higher prevalence of speech and language dysfunction and apraxia were observed in patients with PSD (36.8 and 34.3%, respectively) compared to non-depressed stroke patients (19.6 and 12.4%; p = 0.036 and p = 0.004, respectively). Applying multiple linear regressions, cognitive impairment and reduced mobility as part of the Stroke Impact Scale were independently associated with PSD, as scored using CSD and MADRS (r(2) = 0.269 and r(2) = 0.474, respectively). CONCLUSIONS: The risk of developing PSD is increased in patients with more functional and cognitive impairment, greater dependency with regard to ADL functions and with occurrence of speech and language dysfunctions and apraxia. Multiple regression models indicated that the most determining features for depression risk in the convalescent phase after stroke include reduced mobility and cognitive impairment. Further studies on risk factors for PSD are essential, given its negative impact on rehabilitation and quality of life. Identification of risk factors for PSD may allow more efficacious preventive measures and early implementation of adequate antidepressive treatment. PMID- 23626595 TI - Chronic portal-systemic shunt encephalopathy in a hemodialysis patient treated with balloon-occluded retrograde transvenous obliteration. AB - We report a case of chronic portal-systemic shunt encephalopathy in a 79-year-old female hemodialysis patient with end-stage renal disease. Approximately 1 month before admission, she occasionally had a discrepant conversation. It was considered that hepatic encephalopathy was caused by an increase in the ammonia level in the blood flow of the shunt, which had been diagnosed 7 years previously between the splenic vein and the left renal vein. On admission, disturbed consciousness and an elevated serum ammonia level (221 MUg/dl) were observed. No change in the shunt diameter was noted. Consciousness improved with conservative treatment, whereas hyperammonemia remained. Balloon-occluded retrograde transvenous obliteration (B-RTO) was performed on the shunt. As a result, hyperammonemia resolved immediately, and the level of ammonia was maintained at approximately 60 MUg/dl. The patient often complained of drug-induced constipation; therefore, an increase in the intra-abdominal pressure in addition to ammonia production in the intestinal tract was suspected as the cause of encephalopathy. More than 23 months have passed since the B-RTO therapy, and no symptoms of encephalopathy have been observed yet. PMID- 23626596 TI - Secondary membranous nephropathy associated with guillain-barre syndrome. AB - Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome (NS) in adults. It may be primary, usually mediated by IgG4 anti phospholipase A2 autoantibodies or secondary to various other conditions. Guillain- Barre syndrome (GBS) has been associated with MN, but a cause and effect relation has not been proven. We present a case of concurrent development of GBS and severe NS, with renal biopsy demonstrating MN. IgG4 stain was negative, indicating that most likely, the MN was secondary and probably caused by the underlying GBS. PMID- 23626597 TI - Interferon-alpha Treatment for Growing Teratoma Syndrome of the Testis. AB - A 23-year-old man with a right scrotal mass and back pain was referred for further treatment after right radical orchiectomy for testicular cancer. CT scans brought by the patient showed extensive metastasis to the retroperitoneal lymph nodes with no lung involvement. alpha-Fetoprotein and human chorionic gonadotropin were elevated preoperatively (384 ng/ml and 112 mIU/ml, respectively). Confirmation of the histopathologic examination revealed a mixed germ cell tumor (95% immature teratoma and 5% embryonal carcinoma). We started the patient on chemotherapy with bleomycin, etoposide, and cisplatin (BEP). After a single course, tumor markers began to normalize, but there was radiologic evidence of continued growth of the retroperitoneal mass and new metastases in the lung. The patient was given 2 courses of salvage chemotherapy with etoposide, ifosfamide, and cisplatin (VIP). However, the mass and lung metastases continued to progress, and the patient was growing rapidly intolerant of the side effects of treatment (i.e., nausea, appetite loss, and pancytopenia). After thorough discussion with the patient and his family, we decided to start the patient on interferon (IFN)-alpha therapy. Natural, nonrecombinant IFN-alpha (OIF, Otsuka, Japan) 5,000,000 IU was administered twice weekly with approval of the ethics committee of our institution. The patient responded moderately with marked deceleration of tumor growth and stabilization of the lung metastases. He is alive and well at 16 months on IFN-alpha therapy. PMID- 23626598 TI - Cell-free microRNAs: potential biomarkers in need of standardized reporting. AB - MicroRNAs are abundantly present and surprisingly stable in multiple biological fluids. These findings have been followed by numerous reverse transcription real time quantitative PCR (RT-qPCR)-based reports revealing the clinical potential of using microRNA levels in body fluids as a biomarker of disease. Despite a rapidly increasing body of literature, the field has failed to adopt a set of standardized criteria for reporting the methodology used in the quantification of cell-free microRNAs. Not only do many studies based on RT-qPCR fail to address the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) criteria but frequently there is also a distinct lack of detail in descriptions of sample source and RNA isolation. As a direct result, it is often impossible to compare the results of different studies, which in turn, hinders progress in the field. To address this point, we propose a simple set of criteria to be used in conjunction with MIQE to reveal the true potential of cell-free microRNAs as biomarkers. PMID- 23626599 TI - Down Syndrome Related Muscle Hypotonia: Association with COL6A3 Functional SNP rs2270669. AB - Down syndrome (DS), the principal cause for intellectual disability, is also associated with hormonal, immunological, and gastrointestinal abnormalities. Muscle hypotonia (MH) and congenital heart diseases (CHD) are also frequently observed. Collagen molecules are essential components for maintaining muscle integrity and are formed by the assembly of three chains, alpha 1-3. The type VI collagen is crucial for cardiac as well as skeletal muscles. The COL alpha1 (VI) and alpha2 (VI) chains are encoded by genes located at the 21st chromosome and are expected to have higher dosage in individuals with DS. The alpha 3 (VI) chain is encoded by the COL6A3 located at the chromosome 2. We hypothesized that apart from COL6A1 and COL6A2, COL6A3 may also have some role in the MH of subjects with DS. To find out the relevance of COL6A3 in DS associated MH and CHD, we genotyped two SNPs in COL6A3, rs2270669 and rs2270668, in individuals with DS. Subjects with DS were recruited based on the Diagnostic and Statistical Manual for Mental Disorders-IV and having trisomy of the 21st chromosome. Parents of individuals with DS and ethnically matched controls were enrolled for comparison. Informed written consent was obtained for participation. Peripheral blood was used for isolation of genomic DNA. Target genetic loci were studied by DNA sequence analysis. Data obtained was subjected to population - as well as family-based statistical analysis. rs2270668 was found to be non-polymorphic in the studied population. rs2270669 showed significant association of the "C" allele and "CC" genotype with DS probands having MH (P = 0.02). Computational analysis showed that rs2270669 may induce structural and functional alterations in the COL alpha3 (VI). Interaction of COLalpha3 (VI) with different proteins, crucial for muscle integrity, was also noticed by computational methods. This pioneering study on COL6A3 with DS related MH thus indicates that rs2270669 "C" could be considered as a risk factor for DS related MH. PMID- 23626600 TI - Employing MCMC under the PPL framework to analyze sequence data in large pedigrees. AB - The increased feasibility of whole-genome (or whole-exome) sequencing has led to renewed interest in using family data to find disease mutations. For clinical phenotypes that lend themselves to study in large families, this approach can be particularly effective, because it may be possible to obtain strong evidence of a causal mutation segregating in a single pedigree even under conditions of extreme locus and/or allelic heterogeneity at the population level. In this paper, we extend our capacity to carry out positional mapping in large pedigrees, using a combination of linkage analysis and within-pedigree linkage trait-variant disequilibrium analysis to fine map down to the level of individual sequence variants. To do this, we develop a novel hybrid approach to the linkage portion, combining the non-stochastic approach to integration over the trait model implemented in the software package Kelvin, with Markov chain Monte Carlo-based approximation of the marker likelihood using blocked Gibbs sampling as implemented in the McSample program in the JPSGCS package. We illustrate both the positional mapping template, as well as the efficacy of the hybrid algorithm, in application to a single large pedigree with phenotypes simulated under a two locus trait model. PMID- 23626602 TI - Understanding pH Effects on Trichloroethylene and Perchloroethylene Adsorption to Iron in Permeable Reactive Barriers for Groundwater Remediation. AB - Metallic iron filings are becoming increasing used in permeable reactive barriers for remediating groundwater contaminated by chlorinated solvents. Understanding solution pH effects on rates of reductive dechlorination in permeable reactive barriers is essential for designing remediation systems that can meet treatment objectives under conditions of varying groundwater properties. The objective of this research was to investigate how the solution pH value affects adsorption of trichloroethylene (TCE) and perchloroethylene (PCE) on metallic iron surfaces. Because adsorption is first required before reductive dechlorination can occur, pH effects on halocarbon adsorption energies may explain pH effects on dechlorination rates. Adsorption energies for TCE and PCE were calculated via molecular mechanics simulations using the Universal force field and a self consistent reaction field charge equilibration scheme. A range in solution pH values was simulated by varying the amount of atomic hydrogen adsorbed on the iron. The potential energies associated TCE and PCE complexes were dominated by electrostatic interactions, and complex formation with the surface was found to result in significant electron transfer from the iron to the adsorbed halocarbons. Adsorbed atomic hydrogen was found to lower the energies of TCE complexes more than those for PCE. Attractions between atomic hydrogen and iron atoms were more favorable when TCE versus PCE was adsorbed to the iron surface. These two findings are consistent with the experimental observation that changes in solution pH affect TCE reaction rates more than those for PCE. PMID- 23626603 TI - Does L-carnitine improve endothelial function in hemodialysis patients? AB - BACKGROUND: Atherosclerosis is the leading cause of death in hemodialysis patients. These patients are also very prone to L-carnitine deficiency due to kidney disease. In this clinical trial, we investigated the effect of oral L carnitine on endothelial function of these patients. MATERIALS AND METHODS: [corrected] We studied 31 adult chronic hemodialysis patients in our center and divided them into two groups. The first group (n = 20) received 1500 mg/dialysis interval (every other day) oral L-carnitine. The control group (n = 11) received placebo for one month. Ultrasonographic measurements of flow mediated dilation and carotid intima-media thickness were performed before and after one month of L carnitine and placebo therapy. RESULTS: This study showed that after one month of L-carnitine or placebo therapy there was no significant improvement in flow mediated dilation (p = 0.80 and p = 0.59, respectively) or decrease in carotid intima-media thickness (p = 0.12 and p = 0.50, respectively). CONCLUSIONS: Our study revealed that one month of oral L-carnitine therapy did not improve endothelial function in hemodialysis patients. Long-term studies with large sample size using intravenous form and higher doses of the drug are required to clarify the questionable role of L-carnitine in hemodialysis patients. PMID- 23626604 TI - Intravenous pamidronate for refractory rheumatoid arthritis. AB - BACKGROUND: Patients with rheumatoid arthritis may be resistant to conventional treatment with disease-modifying antirheumatic drugs (DMARDs). On the other hand, biologic therapy is costly and may be inconvenient for many patients. Pamidronate is a potent bisphosphonate with the capacity of modifying the biological activity of the immune system cells. It may thus be used as an anti-inflammatory agent in patients with inflammatory joint diseases. MATERIALS AND METHODS: To assess the effectiveness of pamidronate in the management of rheumatoid arthritis, we selected 38 patients with rheumatoid arthritis to enroll in a pilot study to receive pamidronate and conventional treatment with prednisolone and DMARDs in combination. These patients received 60 mg of pamidronate for 3 consecutive months and were followed for 6 months since the first infusion. RESULTS: The mean visual analogue score (VAS) and disease activity score (DAS28) fell steadily until one month after the third infusion. However, no improvements were observed during the 3 months after the last infusion of the drug. All patients, except one, reported decreased pain in response to 3 consecutive pulses of pamidronate and most had improvements in the assessed laboratory and clinical indices. The drug was tolerated well in our patients. CONCLUSION: Pamidronate infusions had beneficial effects on various clinical and laboratory parameters of patients, but alleviation of symptoms were temporary and did not last for more than 6 months. This treatment option can be a choice for difficult cases of rheumatoid arthritis with severe pain and osteoporosis. PMID- 23626605 TI - Potential diagnostic value of P16 expression in premalignant and malignant cervical lesions. AB - BACKGROUND: The goal of this study was to evaluate the results of the expression of p16INK4a in normal uterine cervical epithelium, low-grade cervical intraepithelial neoplasia (CIN), high-grade CIN, squamous cell carcinoma (SCC), and adenocarcinoma of the cervix, in order to help draw a distinction between low risk and high risk patients with cervical lesions. MATERIALS AND METHODS: [corrected] P16INK4a expression was evaluated by immunohistochemistry in 78 paraffin-embedded tissue samples including 39 normal cervical tissues, 11 low grade CINs, 11 high-grade CINs, 22 cervical SCCs and 8 cervical adenocarcinomas. Two parameters in immunohistochemical p16 expression were evaluated: percentage of p16-positive cells, and reaction intensity. RESULTS: The p16INK4a expression rate was 81.8% in low-grade CINs, 91% in high-grade CINs, 90% in SCCs and 75% in cervical adenocarcinomas. 10% of normal cervical samples expressed p16. Moreover, there was a significant relationship between the histological diagnoses and percentage of positive cells and reaction intensity of p16 (p < 0.005). The intensity of the reaction was the best parameter to evaluate the positivity of p16. CONCLUSIONS: Over-expression of the p16INK4a was typical for dysplastic and neoplastic epithelia of the uterine cervix. However, p16INK4a-negative CINs and carcinomas did exist. Although negative p16INK4a expression does not definitely exclude the patient with cervical lesion from the high-risk group, immunohistochemical study for p16INK4a may be used as a supplementary test for an early diagnosis of cervical cancers. PMID- 23626606 TI - The relationship between occupational radiation exposure and thyroid nodules. AB - BACKGROUND: Considering that thyroid nodules and thyroid cancer occur more frequently in people chronically exposed to radiation, the aim of this study was to evaluate the prevalence of thyroid nodules in a population occupationally exposed to radiation in hospitals of Isfahan, Iran. MATERIALS AND METHODS: In this case-control study, the prevalence of thyroid nodules in staff members occupationally exposed to radiation was determined by ultrasonography. The results were compared with the results of another study among the adult population of Isfahan which selected by cluster random sampling method. The 2 studied groups were matched according to sex and age. RESULTS: The case and control groups included 124 and 471 persons, respectively. The prevalence of thyroid nodules in the case and control groups was 22.6% and 24.6%, respectively (p > 0.05). Although thyroid nodules were significantly more prevalent in females in the control group, no such difference was observed between females and males of the case group (p > 0.05). The number of thyroid nodules (single or multiple) and calcification were not different between the two groups (p > 0.05). In addition, hypoechogenicity of thyroid nodules was not different between the two groups for (p > 0.05). CONCLUSION: In our study, there was not any correlation between chronic occupational exposure to low dose of radiation and the risk of developing thyroid nodules. Further studies with larger sample sizes, at different doses of radiation, and considering iodine status and thyroid function are thus required. PMID- 23626607 TI - The effect of Aloe vera leaf gel on fatty streak formation in hypercholesterolemic rabbits. AB - BACKGROUND: Atherosclerosis is a complex disease that is associated with a variety of etiologic factors such as hyperlipidemia and inflammation. Aloe vera (Liliaceae family) has been used traditionally as an anti-inflammatory drug. The aims of this survey were to define the beneficial effects of Aloe vera leaf gel on some of the atherosclerosis risk factors, and also fatty streak formation in hypercholesterolemic rabbits. MATERIALS AND METHODS: [corrected] 32 white male rabbits were randomly divided into four experimental groups (n = 8, each). During the study, the animals had a standard diet (control group), high cholesterol diet (HC group), high cholesterol diet with Aloe vera leaf gel (3.2%v/v) (HC+ Aloe group) and Aloe vera leaf gel (Aloe group) for 30 days. Fasting blood samples were collected from all animals at the beginning and end of the study. Then total cholesterol (TC), fasting blood sugar (FBS), triglyceride (TG) and CRP were measured before and after experimental periods. By the end of the study, the aortas were removed and investigated for atherosclerosis plaque formation. RESULTS: Significant differences were observed in TC and CRP levels of the high cholesterol diet with Aloe vera and the high-cholesterol diet alone (p < 0.05). The formation of fatty streaks in the aorta was also significantly lower in the same animals under the influence of dietary Aloe vera(p < 0.05). The control and Aloe group did not show any evidence of atherosclerosis. No significant difference was found between the groups in TG and FBS. CONCLUSIONS: The data suggests that Aloe vera has beneficial effects on the prevention of fatty streak development; it may reduce the development of atherosclerosis through modification of risk factors. However, further studies are needed to understand the mechanisms whereby this plant exerts its anti-atherosclerotic effects. PMID- 23626608 TI - Relation of resistin with obesity and some cardiovascular risk factors in hypertensive women. AB - BACKGROUND: Hypertension and obesity are risk factors of cardiovascular disease. The association between C-reactive protein, homocysteine, microalbuminuria and cardiovascular risk have been debated for decades. Resistin is a newly discovered adipocyte derived cytokine. In the current study we planned to investigate the relation of resistin to these probable cardiovascular risk factors and obesity in hypertensive patients. MATERIALS AND METHODS: The study population consisted of 42 non-obese and 42 obese hypertensive females. After making comparisons between C-reactive protein, homocysteine, microalbuminuria and resistin in the two groups, we also sought correlations between all parameters in non-obese and obese groups. RESULTS: In our obese hypertensive group, resistin levels were higher than in the non-obese hypertensive group (p < 0.001), but we did not find any difference in other parameters. We found a positive correlation between resistin and C-reactive protein in both non-obese and obese hypertensive groups (in non obese hypertensives p < 0.05, and in obese hypertensives p < 0.001). CONCLUSIONS: We showed that in female obese hypertensive patients resistin levels were higher than in the non-obese patients. We also think that resistin may be associated with C-reactive protein levels but not with homocysteine or microalbuminuria in both non-obese and obese hypertensive patients. PMID- 23626609 TI - The relationship between consanguineous marriage and death in fetus and infants. AB - BACKGROUND: Given the high prevalence of consanguineous marriages in rural and urban areas of Iran, the aim of this study was to identify its role in increasing fetal and infant deaths. MATERIALS AND METHODS: This was a cross-sectional study in which 494 mothers with more than one exceptional child (mentally retarded and physically-dynamically disabled) or with normal children were selected based on multi-stage random sampling method. Data was gathered using the features of parents with more than one exceptional child questionnaire. The validity and reliability of this questionnaire was acceptable. Hierarchical log-linear method was used for statistical analysis. RESULTS: Consanguineous marriage significantly increased the number of births of exceptional children. Moreover, there was a significant relation between the history of fetal/infant death and belonging to the group. There was a significant relation between consanguineous marriage and the history of fetal/infant death which means consanguineous marriage increased the prevalence of fetal/infant death in parents with exceptional children rather than in parents with normal children. CONCLUSIONS: The rate of fetal/infant death in exceptional births of consanguineous marriages was higher than that of non consanguineous marriages. PMID- 23626610 TI - The relationship between MDM2 expression and tumor thickness and invasion in primary cutaneous malignant melanoma. AB - BACKGROUND: Malignant melanoma is the most invasive cutaneous tumor which is associated with an incredibly high mortality rate. The most reliable histological factors associated with melanoma prognosis are tumor thickness- measured by the Breslow index- and invasion depth- measured by Clark level. Murine double minute 2 (MDM2) gene inhibits p53-dependent apoptosis. An increase in MDM2 expression has been found in many tumors. This study aimed to investigate MDM2 expression and its correlation with tumor thickness and invasion level in malignant melanoma. MATERIALS AND METHODS: This study evaluated paraffin blocks from 43 randomly selected patients with primary cutaneous melanoma who referred to the main university pathology center in Isfahan, Iran. MDM2 expression rate was assessed via immunohistochemical techniques and hematoxylin and eosin staining to determine tumor thickness and invasion level. Correlations between MDM2 expression and tumor thickness and invasion were analyzed using Spearman's correlation coefficient in SPSS17. RESULTS: The mean age of patients was 61.2 +/- 15 years. Men and women constituted 55.8% and 44.2% of the participants, respectively. The rate of MDM2 positivity was 28.9%. MDM2 expression was directly associated with tumor thickness (r = 0.425; p = 0.002) and weakly with invasion level (r = 0.343; p = 0.01). CONCLUSIONS: Despite the low MDM2 expression rate observed in this study, direct relationships between MDM2 positivity and tumor thickness and invasion level were identified. MDM2 expression can thus be suggested as a potential new predictive prognostic factor. PMID- 23626611 TI - Evaluation of in vitro sperm nuclear chromatin decondensation among different subgroups of infertile males in Mysore, India. AB - BACKGROUND: Infertility is a condition associated with multiple etiologies. Sperm nuclear chromatin decondensation is one of the important events that occur during fertilization. Abnormal spermatogenesis leads to improper protamine package and chromatin condensation. The aim of the study was to analyze and understand the levels of fertilization capacity and nuclear stability of the spermatozoa in different infertile subgroups. MATERIAL AND METHODS: A total of 65 infertile males and 24 fertile males were employed in the study. Infertile subjects were classified into different groups according to the World Health Organization (WHO) protocol. In this study, in vitro nuclear chromatin decondensation status was assessed in different subgroups of infertile males. The obtained data was then statistically analyzed. RESULTS: Decreased sperm chromatin decondensation was observed in different infertile subgroups compared to the control group (p < 0.05). Spermatozoa with swollen head indicated a positive response and unswollen head indicated a negative response. CONCLUSION: This study asserts that abnormal nuclear decondensation is a potential factor that diminishes the fertilizing capacity of the sperms among different subgroups of infertile males. PMID- 23626612 TI - Introduction of a potent single-donor fibrin glue for vascular anastomosis: An animal study. AB - BACKGROUND: Vascular anastomosis is considered as a difficult surgical procedure. Although different alternative methods have been tried to tackle these difficulties, none were found to be successful. Commercial fibrin glue has recently been used for vascular anastomosis. However, it did not gain popularity due to some limitations such as low tensile strength, rapid removal by the immune system, and risk of transmission of blood-borne viral infections. In this article, we presented a novel method for producing single-donor human fibrin glue and determined its success rate for vascular anastomosis in an animal model. MATERIALS AND METHODS: [corrected] In this study, 3 mL of single-donor fibrin sealant was prepared from 150 mL of whole blood containing 50-70 mg/mL of fibrinogen. The study was performed on 10 dogs and 5 cats. After transection of the carotid artery, both ends were anastomosed by means of 3-4 sutures (Prolene 8 0). The suture line was then sealed with one layer of the new fibrin sealant. After 3-8 weeks, the site of anastomosis was evaluated angiographically and morphologically for healing and possible complications such as thrombosis or aneurysm. RESULTS: In evaluations 3 weeks after the surgery, all arterial anastomoses were patent in dogs, but some degree of subintimal hyperplasia was noted. After 8 weeks, all anastomoses were patent and the degree of subintimal hyperplasia was decreased. In cats on the other hand, after 4 weeks, all anastomoses were patent and subintimal hyperplasia was absent. CONCLUSIONS: Single-donor fibrin glue was a quite reliable and practical alternative to minimize suturing and therefore operative time in our animal model. This sealant can easily be obtained from the patient's whole blood. Its application in humans would require further studies. PMID- 23626613 TI - The association of non-O blood group and severity of liver fibrosis in patients with chronic hepatitis C infection. AB - BACKGROUND: The progression rate of liver fibrosis is variable among patients with hepatitis C virus (HCV) infection. It is affected by environmental and genetic factors. We determined the association between ABO blood groups and the severity of liver fibrosis in HCV patients. MATERIALS AND METHODS: This cross sectional study was conducted on adult patients with chronic HCV infection who referred to university clinics in Isfahan, Iran in 2009-10. Patients with positive hepatitis B surface antigen (HBS Ag), human immunodeficiency virus antibody (HIV Ab), or other liver disorders, as well as those who had received anti-HCV treatments were not included. Blood type was determined and liver biopsy was obtained from all patients. The severity of hepatic fibrosis was graded from F0 to F4 based on METAVIR system. RESULTS: Non-O blood groups were present in 53.8%, 72.3%, 75%, 87.5%, and 90.4% of the patients with F0-F4 grades of liver fibrosis, respectively (p = 0.019). There was no relationship between the severity of hepatic fibrosis and age or gender. In ordinal regression analysis, only the viral load (p = 0.028) and non-O blood group (p = 0.001) were associated with the severity of hepatic fibrosis. CONCLUSION: Non-O blood group is a genetic risk factor for progression of liver fibrosis in patients with HCV infection. It can play an important role in determining the prognosis and appropriate treatment among these patients. The association between blood group and liver fibrosis is probably due to the increased risk of venous thrombosis. Such relation can be the goal of preventive/treatment strategies. PMID- 23626614 TI - Toxicity effects of methamphetamine on embryonic stem cell-derived neuron. AB - BACKGROUND: Methamphetamine (MA) is the most popular recreational drug. According to potential neurotoxicity of this agent, it can cause deleterious effects on neural differentiation of embryo, if MA is used during the child bearing period. In recent decades, undifferentiated pluripotent embryo-derived stem cell lines, resembling early embryonic stages, have been used to analyze the toxic effects of components in vitro. Thus, this study aims at assessing toxic effects of MA on embryonic stem cell (ESC)-derived neuronal cells during differentiation in a pharmacological model. MATERIALS AND METHODS: ESC line Royan was used throughout this study. The effect of MA on neural differentiation was assessed during two periods, group 1: MA (10, 100, 200,500, 750, 1000 MUM concentrations) was added during EB formation, group 2: MA (10, 50, 70, 100, 200, 500 MUM concentrations) was added after the generation of neural precursors. Then cells were evaluated for neuronal markers by immunocytochemistry and RT-PCR. One way ANOVA followed by the post hoc test was used to analyze data. RESULTS: The declining in outgrowth of dendrites was observed in neural morphology in a dose dependent manner. The ID50 (Inhibition of neuronal differentiation) of groups 1 and 2 were 130 and 400 MUM, respectively. By using RT-PCR, in comparison with MAP2, no significant change was observed in Nestin expression. CONCLUSIONS: Our data on neuronal toxicity were consistent with in vivo and in vitro studies. We concluded that ESCs can be used as an efficient model to assess the toxicity of drugs. PMID- 23626615 TI - Touch imprint and crash preparation intra operative cytology versus frozen section in thyroid nodule. AB - BACKGROUND: Intra operative cytology (IC), including touch imprint (TI) and crash preparations (CP), in general has been demonstrated to be a diagnostic tool for many organs but its validity and reliability for diagnosis of thyroid nodules remain controversial. We evaluate the diagnostic value of frozen section, touch imprint, crash preparation and the combination of touch imprint and crash preparation and the combination of frozen section, touch imprint and crash preparation. MATERIALS AND METHODS: [corrected] 55 intra operative specimens from patients with thyroid nodules who underwent thyroidectomy were evaluated at Alzahra and vali-Asr hospital laboratories. For all of the patients frozen section (FS), touch imprint (TI) and crash preparation (CP) was obtained and reviewed by two pathologists at the same time. Serial TI and CP, and FS, TI and CP were reviewed by the same pathologists. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and accuracy were calculated according to the permanent section as the gold standard test. RESULTS: In our study sensitivity, specificity and accuracy for FS was 100%, 97.6% and 98.1% respectively; for TI they were 78.6%, 95% and 92.4%; for CP they were 78.6%, 92.7% and 89.9%; for serial TI and CP they were 85.7%, 92.7% and 90.9%; and for the combination of FS and TI and CP they were 100%, 97.6% and 98.18% respectively. CONCLUSIONS: Intra operative cytology (including TI and CP) seems to be a useful, valuable and inexpensive method in clinics, which do not have equipment for frozen sections. Intra operative cytology combined with FS increased the overall accuracy of diagnosis. Further studies are needed to validate the obtained results of this study. PMID- 23626616 TI - Research priorities in the field of HIV and AIDS in Iran. AB - BACKGROUND: HIV is a multidimensional problem. Therefore, prioritization of research topics in this field is a serious challenge. We decided to prioritize the major areas of research on HIV/AIDS in Iran. MATERIALS AND METHODS: In a brain-storming session with the main national and provincial stakeholders and experts from different relevant fields, the direct and indirect dimensions of HIV/AIDS and its related research issues were explored. Afterward, using the Delphi method, we sent questionnaires to 20 experts (13 respondents) from different sectors. In this electronic based questioner, we requested experts to evaluate main topics and their subtopics. The ranges of scores were between 0 and 100. RESULTS: The score of priorities of main themes were preventive activities (43.2), large scale planning (25.4), the estimation of the HIV/AIDS burden (20.9), and basic scientific research (10.5). The most important priority in each main theme was education particularly in high risk groups (52.5), developing the national strategy to address the epidemic (31.8), estimation of the incidence and prevalence among high-risk groups (59.5) and developing new preventive methods (66.7), respectively. CONCLUSIONS: The most important priorities of researches on HIV/AIDS were preventive activities and developing national strategy. As high risk groups are the most involved people in the epidemic, and they are also the most hard-to-reach sub-populations, a national well designated comprehensive strategy is essential. However, we believe with a very specific and directed scheme, special attention to research in basic sciences is necessary, at least in limited number of institutes. PMID- 23626617 TI - Primary gastrointestinal lymphoma. AB - BACKGROUND: Extranodal lymphoma may arise anywhere outside lymph nodes mostly in the gastrointestinal (GI) tract as non-Hodgkin's disease. We reviewed the clinicopathological features and treatment results of patients with primary GI lymphoma. MATERIALS AND METHODS: A total number of 30 cases with primary GI lymphoma were included in this study. Patients referred to the Radiation Oncology Department of Omid Hospital (Mashhad, Iran) during a 5-year period (2006-11). Clinical, paraclinical, and radiological data was collected from medical records of the patients. RESULTS: Out of the 30 patients with primary GI lymphoma in the study, 12 were female (40%) and 18 were male (60%) (male to female ratio: 3/2). B symptoms were present in 27 patients (90%). Antidiuretic hormone (LDH) levels were elevated in 9 patients (32.1%). The most common primary site was stomach in 14 cases (46.7%). Other common sites included small intestine and colon each in 8 patients (26.7%). All patients had histopathologically proven non-Hodgkin's lymphoma. The most common histologic subtype was diffuse large B-cell lymphoma (DLBL) in 16 patients (53.3%). In addition, 28 patients (93.3%) received chemotherapy with cyclophosphamide, vincristine, doxorubicin, prednisolone (CHOP regimen). The median course of chemotherapy was 6 cources. Moreover, 8 patients (26.7%) received radiotherapy with cobalt 60. The median follow-up time was 26 months. The overall 5-year survival rate was 53% and the median survival time was 60 months. CONCLUSION: Primary GI lymphoma is commonly seen in stomach and small intestine and mostly is DLBCL or mucosa-associated lymphoid tissue (MALT) lymphoma. PMID- 23626618 TI - Fetus in fetu: A rare case report. AB - BACKGROUND: Fetus in fetu is a rare congenital anomaly in which malformed fetus grows within the body of its twin. It is almost always detected as an abdominal mass in infancy. It is a parasitic twin of a diamniotic, monozygotic twin. It should be differentiated from teratoma which has no axial arrangement and has got definite malignant potential. Herein, we present a case of a two-month old female infant and review the literature. Although fetus in fetu is a rare condition, correct diagnosis using imaging can be made before surgery. It should be considered as a differential diagnosis for lump abdomen especially in infants. Complete excision is curative. PMID- 23626619 TI - Childhood tongue squamous cell carcinoma. AB - BACKGROUND: Tongue squamous cell carcinoma is a very rare disease in children with only a few cases reported in the literature. A case of 15 year old female tongue squamous cell carcinoma (SCC) with review of reported cases is presented. Pediatricians and family physicians should also be aware of the possibility of this disease entity occurring at an earlier age to decrease delay in diagnosis and initiation of treatment. PMID- 23626620 TI - Synchronous bilateral adrenalectomy by midline incision: A reliable method for treatment of hypercortisolism. PMID- 23626621 TI - Spirituality and medical education in India: Are we ready? PMID- 23626622 TI - Introduction of midwifery ruler. PMID- 23626623 TI - A comparison of intraocular pressure and hemodynamic responses to insertion of laryngeal mask airway or endotracheal tube using anesthesia with propofol and remifentanil in cataract surgery. AB - BACKGROUND: The aim of this study was to evaluate intraocular pressure (IOP) and hemodynamic responses following insertion of laryngeal mask airway (LMA) or endotracheal tube (ETT) after anesthesia induction with propofol and remifentanil in cataract surgery. MATERIALS AND METHODS: In a randomized controlled study, 50 adults scheduled for elective cataract extraction procedure under general anesthesia were allocated to LMA insertion (n = 25) or ETT (n = 25) groups. IOP, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were measured after insertion of the airway device every minute up to 5 min. RESULTS: There were no significant differences between LMA and ETT groups in SBP, DBP, HR, and IOP immediately after airway instrumentation up to 5 min, except in 4th min in DBP, 2nd min in HR, and 5th min in IOP (7.9 +/- 2.3 mmHg in LMA and 9.4 +/- 2.5 mmHg in ETT group; P = 0.030). There was good surgeon satisfaction for providing acceptable surgical field in both groups (88% in LMA and 80% in ETT group; P = 0.702). CONCLUSION: Propofol combined with remifentanil provides good and excellent conditions for insertion of LMA or ETT with minimal hemodynamic disturbances in cataract surgery. Considering LMA insertion is less traumatic than ETT, using LMA may be better than ETT for airway securing in these patients. PMID- 23626624 TI - Association between allergic rhinitis and migraine. AB - BACKGROUND: Migraine and allergic rhinitis (AR) are two common causes of headache and facial pain that inflammatory mediators with vasoactive function play important roles in both of them. The aim of this research was to determine the prevalence of migraine in AR patients. MATERIALS AND METHODS: In a cross sectional comparative study performed from June to December 2010 in patients with AR sign and symptoms referred to ear, nose, throat (ENT) clinic of a university hospital in Iran-Rasht, 46 patients with positive skin prick test were compared with 60 subject without AR signs and symptoms and with negative skin test. In both the groups, history of migraine according to IHS (International Headache Society ) criteria were investigated. Analysis of data was performed by chi sqaure and Fisher exact test by using SPSS16. Odds ratio were estimated for determining the chance of migraine in AR. RESULTS: In case group (14 male, 37 female; mean age: 31.17 +/- 8.31 years) and control group (23 male, 32 female; mean age: 37.58 +/- 12.63 years), the prevalence of migraine was 37% and 5%, respectively. The differences in prevalence of migraine and migraine without aura between cases and controls were significant (P = 0.001). The chance of migraine in AR was 8.227 folds (95% CI: 2.38-28.42). In subjects older than 40 years old, the difference of prevalence of migraine was significant, contrary to subjects younger than 30 years old and between 30 and 39 years old. CONCLUSIONS: There is a correlation between migraine especially without aura and AR and this correlation is more powerful with increasing age. PMID- 23626625 TI - Regulatory T-cell profile in early and late lesions of cutaneous leishmaniasis due to Leishmania major. AB - CONTEXT: Cutaneous leishmaniasis (CL) is a public health problem in several endemic countries. Recent studies on mouse model and also a few clinical experiments showed that the type of immune response generated at the site of infection and especially balance between regulatory and effector T-cells determines the outcome of the disease toward self-limiting or long-lasting lesions. AIMS: The aim of this study was to evaluate the role of natural regulatory T cells (nTregs) in early and late cutaneous lesions of human Leishmania major (L. major) infection. SETTINGS AND DESIGN: Skin biopsies were collected from parasitologically proven lesions of 28 CL patients, divided into two groups of early and late lesions. The causative agents were identified to be L. major. MATERIALS AND METHODS: Quantitative real-time reverse transcription polymerase chain reaction (PCR) and immunofluorescent staining of biopsies were used to assess the Foxp3 mRNA expression and frequency of nTregs in two groups. Mann-Whitney U test was used to determine the significance of deference between the two groups. RESULTS: Mean relative expressions of Foxp3 mRNA were 0.53 +/- 0.23 and 1.26 +/- 0.99 in early and late lesions, respectively, which was significantly upper in chronic lesions (P = 0.007). Parallel results were obtained in tissue staining method. CONCLUSIONS: Increased in gene expression and protein staining of nTreg markers in chronic biopsy samples indicates a role for these cells in chronic L. major induced leishmaniasis and supports the effectiveness of regulatory T cell-based immunotherapy for treatment of chronic CL. PMID- 23626626 TI - Is Friedewald formula a good estimation for low density lipoprotein level in Iranian population? AB - OBJECTIVE: Serum low density lipoprotein (LDL) level is an important biomarker for coronary artery disease (CAD). As direct LDL measurement is expensive and not cost effective, especially in a large population, it is estimated by Friedewald formula. Therefore, we decided to compare the direct LDL measurement method with LDL measured by Friedewald formula in a large general population for the first time in Iran. Furthermore, we examined the association of total cholesterol (TCh), triglyceride (TG), and high density lipoprotein (HDL) with LDL. SUBJECTS AND METHODS: This study was conducted on the subjects, aged 11-97 years, in the third phase of Isfahan Healthy Heart Program (IHHP) from three cities: Isfahan, Najafabad, and Arak. A fasting blood sample was taken from all subjects and referred to Isfahan Cardiovascular Research Center (ICRC) laboratory (central laboratory of IHHP) to assess TCh, TG, HDL, and LDL directly. Also, the LDL level was calculated by Friedewald formula, in addition. RESULTS: The mean level of LDL by direct method was lower than that calculated by Friedewald formula. The mean difference between the two methods was significant, which was 6.6 +/- 15.5 mg/dl difference (t = -42.925, P < 0.0001). There was strong correlation between direct and calculated LDL levels (adjusted R(2) = 80.4%). Using regression model, a new formula was found for the estimation of LDL. CONCLUSION: It is concluded that the Friedewald formula overestimates the LDL level compared to the direct method in general Iranian population. It is suggested that LDL measurement be carried out directly, especially in high-risk people. If a formula is necessary for LDL estimation, it is better to obtain an especial formula for each population. PMID- 23626627 TI - Cognitive schemas among mental health professionals: Adaptive or maladaptive? AB - OBJECTIVES: Maladaptive cognitive schemas can lead to biases during clinical assessment or psychotherapeutic interventions. This study aimed to explore the cognitive schemas among mental health professionals. MATERIALS AND METHODS: 100 mental health professionals, of both genders, equally divided between psychiatrists, psychologists, social workers, and psychiatric nurses, were approached and administered the Young Schema Questionnaire - Short Form after written informed consent. RESULTS: Males had higher maladaptive schemas than female respondents across all schema domains, viz., disconnection/rejection, impaired autonomy, impaired limits, other-directedness, and overvigilance (P <= 0.05). Psychiatrists had higher maladaptive schemas than psychologists (P <= 0.05). Age was weakly but positively corelated with the schemas of self-sacrifice (P = 0.038) and unrelenting standards (P = 0.002). CONCLUSIONS: Mental health professionals also may have maladaptive schemas, which needs to be addressed through schema therapy. PMID- 23626628 TI - Response rates to HB vaccine in CKD stages 3-4 and hemodialysis patients. AB - BACKGROUND: Hepatitis-B virus (HBV) infection is a big problem in chronic kidney disease (CKD) population. We attempted to compare the response rate to HB vaccine in CKD stages3-4 patients with that in hemodialysis (CKD stage-5; HD patients) and medical staff. MATERIALS AND METHODS: Three hundred and three participants were enrolled into the study to test the seroconversion rate after vaccination. Participants formed three groups: Group-A:HD patients, Group-B: diagnosed with CKD stages 3-4, and Group-C: healthy medical staff. CKD stages 3-4 participants were vaccinated from February to November 2010. HD patients were vaccinated at the time of initial HD. While the medical staffs were vaccinated at the time they started working at the hospital. Group-A, Group-B and Group-C received four 40MUg (in 0,1,2 and 6 months), three 40MUg (0, 1 and 6 months) and three 20MUg (0, 1and 6 months) doses of HB vaccine, respectively. Three months after completion of the vaccination schedule, seroconversion and seroprotection rates in each group were investigated. RESULTS: Seroconversion rates were 44.3%, 89.7%, and 96.2% for groups A, B and C, respectively. CKD stages 3-4 patients showed higher response rate than dialysis patients [chi(2)(1):30.6, P <0.001]. But a significant difference in the seroconversion rate between CKD stages 3-4 patients and medical staffs was not observed [chi(2)(1):3.4, P = 0.064]. Multivariate analyses showed patients with more advanced CKD and who were older had less seroconversion rates [odds ratio: 0.09(95%CI: 0.04 - 0.25) and [odds ratio: 0.39(95% CI: 0.18-0.85)], respectively. But sex was not associated with seroconversion (P>0.05). CONCLUSION: Stages 3-4 patients with higher dosages of routine HB vaccine had higher seroconversion rate than HD patients. Future studies should evaluate the recommended dosage of HB vaccine among these patients. PMID- 23626629 TI - The role of VEGF in melanoma progression. AB - BACKGROUND: Melanoma is the most serious skin cancer. There is an established correlation between thickness and aggressiveness of the tumor. Nevertheless, the potential value of vascular endothelial growth factor (VEGF) in correlation with tumor progression remains unresolved. MATERIALS AND METHODS: Thirty seven paraffin blocks of cutaneous melanoma were obtained from Pathology department of Al-zahra hospital between 2005 and 2010. The sections were stained with monoclonal mouse antibodies (mAbs) against vascular endothelial growth factor A and evaluated by distribution of expression of VEGF in tumor cells as 0, 0%; 1, 1%--25%; 2, 25%--50%; 3, >50% and the staining intensity from 0 (negative) to 3 (strong). The sum of intensity score and distribution score was then calculated as the VEGF index. The relationship between VEGF expression (distribution, intensity, and index) and tumor progression (vertical and radial growth, Clark's level, and Breslow's depth) was studied. SPSS software was used to analyze the data by ANOVA, and chi-square tests. RESULTS: 51.4% of the patients showed vertical growth pattern. Mean Breslow's depth was 1.84 +/- 1.79 mm. There was a significant association between growth pattern and VEGF distribution, intensity and index (P = 0.006, P = 0.005, and P = 0.001 respectively). VEGF distribution, intensity, and index all had correlation with Breslow's depth as well (ANOVA test: P = 0.003, P < 0.001, and P < 0.001 respectively) VEGF index had also correlation with Clark's level, but this was not seen for VEGF distribution and intensity. CONCLUSION: VEGF expression (both VEGF distribution and intensity) is associated with progression of malignant melanoma. VEGF index can explain this association better. PMID- 23626630 TI - Mortality in esophageal atresia: Assessment of probable risk factors (10 years' experience). AB - BACKGROUND: Esophageal atresia (EA) is a common congenital anomaly. In this study, we evaluated the mortality and its risk factors in patients born with esophageal atresia. METHODS AND MATERIALS: A database of 206 consecutive patients treated for EA was developed in ST-Zahra hospital of Isfahan between 1994 and 2004. RESULTS: In this study, 206 patients were evaluated. The most common type of EA was type C (86.4%). Mortality rate was 56%; it was more common in patients with congenital malformation, in late operation and in low birth weight and premature babies. Sepsis was the most common cause of death. CONCLUSIONS: For improvement of EA survival, we should improve operation techniques, supportive care, and ICU management. It is also important to operate these patients as soon as possible. PMID- 23626631 TI - Type D personality is associated with hyperlipidemia in patients with myocardial infarction. AB - OBJECTIVE: There are many studies indicating the role of psychological factors in the pathogenesis of cardiovascular disorders. Type D as a new personality construct has been proposed by Denollet, characterized by the joint global traits including negative affectivity and social inhibition. The purpose of this study was to examine the link between type D personality and hyperlipidemia in patients with myocardial infarction (MI). MATERIALS AND METHODS: One hundred and seventy six consecutive patients admitted to the cardiac care unit (CCU) wards of nine hospitals in Isfahan, Iran, following MI, were selected based on the inclusive and exclusive criteria. The patients completed demographic questionnaire and Type D Personality Scale (DS14). Their medical data were obtained from medical records. Chi-squared test, Student's t-test, and multivariate logistic regression were used to analyze the data. RESULTS: Of the 176 subjects, 63 patients (35.8%) were type D. In univariate analysis, hyperlipidemia was the only significant variable (56% vs. 40%, P = 0.041) found to be associated with type D. Also, by multivariable logistic regression analysis, hyperlipidemia [Odds Ratio (OR) 0.374; 95% confidence interval (CI) 0.175-0.796] was the only independently significant variable found to be linked with type D personality. No other statistically significant differences were found between the two groups on demographic and medical factors characteristics. CONCLUSION: The type D personality was associated with hyperlipidemia. Thus, personality factors may make people vulnerable to metabolic syndromes. PMID- 23626632 TI - Plasma osmolality in acute spontanious intra-cerebral hemorrhage: Does it influence hematoma volume and clinical outcome? AB - BACKGROUND: Neurological deterioration in acute spontaneous intra cerebral hemorrhage (ICH) may depend on hematoma volume, electrolyte imbalances, hydration status and other physiological parameters. Plasma osmolality is a marker of hydration. This study has examined the relationship of plasma osmolality with hematoma volume and clinical outcome. MATERIALS AND METHODS: This is a prospective observational study included 75 patients with non-traumatic acute spontaneous ICH. Plasma osmolality, hematoma volume and clinical outcome in National Institute Health stroke scale (NIHSS) were measured on admission and on day 7 after treatment. Mean plasma osmolality was compared between those who died before day 7 and those who died after day 7. Plasma osmolality was also compared between patients with NIHSS score >20 and patients with NIHSS score <=20. Paired t test, Pearson correlation coefficient and independent sample t test were done using SPSS software (version 17 for Windows). RESULT: There is no significant correlation between hematoma volume and plasma osmolality. Higher admission plasma osmolality was associated with early death [312.0 (+/-16.0) mOsm/kg for those who died before day 7 versus 297.0 (+/-14.7) mOsm/kg for those who died after day 7, P value =0.031]. Higher admission plasma osmolality was associated with very severe stroke [311.5 (+/-14.1) mOsm/Kg for patients with NIHSS score >20 versus 293.6 (+/-11.3) mOsm/kg for patients with NIHSS score <=20, P value =0.000). CONCLUSION: High plasma osmolality is a predictor of early mortality. Hematoma volume is not influenced by plasma osmolality. PMID- 23626633 TI - Developing a reliable and valid instrument to assess health-affecting aspects of neighborhoods in Tehran. AB - BACKGROUND: Residence characteristics can affect health of residents. This paper reports the development of an instrument assessing these aspects of neighborhoods. MATERIALS AND METHODS: Literature search and focus group discussions with residents were carried out and relevant items were extracted. Five experts reviewed and commented on the items. An observation instrument with 54 items was composed and completed by two independent observers in 20 randomly selected locations. Due to lack of acceptable reliability in some items, the checklist was revised. The new 22-items checklist in four categories (general characteristics, public green area characteristics, access to services and undesirable features) was completed by two independent trained observers in 28 randomly selected locations. RESULTS: The items in the final checklist had kappa statistics ranging from 0.63 to 1, with an exception of the item assessing "presence of beggars, homeless or working/street children", with kappa as low as 0.27 due to variability of their presence in different times. Average Kappa statistics was 0.78 for general characteristics, 0.79 for public green area characteristics, 0.84 for access to services, and 0.54 for undesirable features. CONCLUSION: Neighborhood and health observation instrument seems to have good reliability in city of Tehran. It can probably be used in other large cities of Iran and similar cities elsewhere. PMID- 23626634 TI - The contributing factors to poor sleep experiences in according to the university students: A cross-sectional study. AB - BACKGROUND: Sleep problems among university students are common; however, the contributing factors to poor sleep experiences are still unclear. The purpose of this study is to examine the contributing factors to poor sleep experiences in university students. MATERIALS AND METHODS: The study was cross-sectional, and the students completed self-report, anonymous questionnaires provided during an in-class survey. This is a single center study. A descriptive survey was conducted randomly on 256 university students in Turkey. The instruments for data collection consisted of the demographic data, and the contributing factors to poor sleep. RESULTS: The most frequent self-reported cause to poor sleep experiences in according to the university students were exposure psychological problems (67.2%), stress (64.8%), exposure to tobacco smoke in the sleeping room (63,7%), pain (62,9%), having family problems (62,5%), being patient (55,1%), air quality of the room (55,1%), strenuous physical activity (53,9%), fatigue (53,5%), sadness (53,1%), noise that caused by other people in the room (52.0%), room scents (sweat, perfume, humidity, naphthalene, etc.) (53.1%), depression (51, 6 %), anxiety, and tension (51, 1%). CONCLUSION: Students should be encouraged to solve psychological problems, to suitable stress-relieving measures, to follow sleep hygiene practice and adequate time management for academic and social activities. PMID- 23626635 TI - The role of developing breast cancer in alteration of serum lipid profile. AB - AIMS: The major aim of this study is to examine the role of alterations in lipid profile in women developing breast cancer. This study was carried out between May 2009 and December 2010. BACKGROUND: The relationship between lipids and breast cancer is undistinguished. Until now, conflicting results have been reported on the association between lipids and risk of breast cancer development in women. MATERIALS AND METHODS: Plasma lipids (i.e., total cholesterol [TC], high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglycerides [TG] were analyzed from 60 controls and 120 untreated breast cancer patients with clinical and histopathological evidence, under aseptic conditions. Venous blood was drawn from the cases and controls and estimations of lipid profile were done utilizing the standard procedures. STATISTICAL ANALYSIS USED: Independent sample t-test to compare the mean serum levels of lipid profile and TC/HDL ratio between patients and controls. RESULTS: A significant rise in serum total cholesterol, low-density lipoprotein cholesterol, and ratio of total cholesterol: high density lipoprotein cholesterol values, whereas high density lipoprotein cholesterol and very low density lipoprotein cholesterol were not affected significantly by the breast cancer. CONCLUSIONS: The developing breast cancer might be considered as one of the factors in alterations in lipid profile levels. PMID- 23626636 TI - The relationship of antisocial personality disorder and history of conduct disorder with crime incidence in schizophrenia. AB - BACKGROUND: Commission of crime and hostility and their forensic consequences in a patient with schizophrenia can worsen the patient's condition and disturb his family, society, and even the psychiatrist. Based on previous research, patients with schizophrenia are at a higher risk for crime. It is not clear whether this is due to the nature of schizophrenia, comorbidity of antisocial personality disorder, or the history of conduct disorder in childhood. In this study, we investigated this hypothesis. MATERIALS AND METHODS: In this case-control study, 30 criminal and 30 non-criminal patients with schizophrenia, who had been referred by the court to the Forensic Medicine Center of Isfahan, were evaluated for antisocial personality disorder, history of conduct disorder, and psychopathy checklist-revise (PCL-R) score. RESULTS: Frequency distribution of antisocial personality disorder (73.3%), history of conduct disorder in childhood (86.7%), and score of PCL-R >=25 (indicating high probability of hostility) in patients (40%) were significantly higher in criminal patients than in non-criminals (10%, 30% and 0%, respectively; P < 0.001). CONCLUSIONS: More prevalence of antisocial personality disorder, history of conduct disorder, and high score of PCL-R (>=25) in criminal schizophrenic patients may indicate that in order to control the hostility and for prevention of crime, besides treating acute symptoms of psychosis, patients might receive treatment and rehabilitation for comorbidities too. PMID- 23626637 TI - Molecular and cytogenetic characterization of two patients with recurrent miscarriages and X-autosome translocation. AB - AIM: To report two patients with recurrent miscarriages and unique reciprocal X autosomal translocation. MATERIALS AND METHODS: Cytogenetic analysis was performed using G-banding and Molecular cytogenetic analysis by Fluorescence in situ hybridization to confirm the breakpoint regions. RESULTS: The chromosomal analysis of the two cases revealed a karyotype of 46,X,t(X;22)(p11.21;q13.3) in the first patient and 46,X,t(X;2)(q22;q13) in second patient. Both the cases were confirmed by using whole chromosome paint probes. CONCLUSIONS: This is the rare report of X-autosomal translocations with unique breakpoint regions and their association with recurrent miscarriages. The translocation breakpoint in case 2 on Xq22 and on Xp11.21 in case 1 might be a risk factor for recurrent miscarriages. Here the impact of the X-autosomal translocations is discussed. PMID- 23626638 TI - Sinonasal teratocarcinosarcoma of the ethmoid and paranasal sinus: A rare neoplasm. AB - Sinonasal teratocarcinosarcoma (SNTCS) is a very rare and aggressive malignant neoplasm histologically characterized by the combination of one or many components of epithelial and mesenchymal elements. Here, we report a SNTCS in a 60-year-old man involving posterior nasal and nasopharyngeal wall extending into left ethmoidal sinus. The patient complained of bleeding from nose, nasal obstruction, and generalized weakness for last two months. Tumor was completely removed by Caldwell-Luc operation and postoperative radiation therapy was given. The follow-up of the patient for two years has shown no evidence of recurrence or metastasis. PMID- 23626640 TI - Visual recovery from optic atrophy following acute optic neuropathy in the fellow eye. AB - The left eye of a 65-year-old male was blind due to optic atrophy and only seeing eye had also dry type age-related macular degeneration. An anterior ischemic optic neuropathy developed in the better seeing eye. Vision recovered in the blind eye in a short time after losing the better eye. Gaining some vision in a blind eye may be an adaptation of visual pathway in such patients. PMID- 23626639 TI - Catfish stings: A report of two cases. AB - Venomous catfish stings are a common environment hazard worldwide. Although these stings are often innocuous, significant morbidity may result from stings, including severe pain, retained foreign bodies, infection, respiratory compromise, arterial hypotension, and cardiac dysrhythmias. Treatment included hot water immersion, analgesia, wound exploration, and prophylactic antibiotics. In this article, two cases of stings by catfish referred to the poison center of Noor Hospital, Isfahan University of Medical Sciences and their treatments have been reported. PMID- 23626641 TI - Paraphenylenediamine: Blackening more than just hair. AB - Paraphenylenediamine is an important constituent of hair dye toxicity of which one could herald fatal complications such as rhabdomyolysis, renal failure, angioneurotic edema, and respiratory failure. We present a case of hair dye poisoning that presented with respiratory distress due to laryngeal edema and later developed trismus, subclinical tetany, apnea, and conduction abnormality on electrocardiogram. This case report highlights the need for a thorough toxicological review of the components of any ingested substance. PMID- 23626642 TI - Human experimental pain models: A review of standardized methods in drug development. AB - Human experimental pain models are essential in understanding the pain mechanisms and appear to be ideally suited to test analgesic compounds. The challenge that confronts both the clinician and the scientist is to match specific treatments to different pain-generating mechanisms and hence reach a pain treatment tailored to each individual patient. Experimental pain models offer the possibility to explore the pain system under controlled settings. Standardized stimuli of different modalities (i.e., mechanical, thermal, electrical, or chemical) can be applied to the skin, muscles, and viscera for a differentiated and comprehensive assessment of various pain pathways and mechanisms. Using a multimodel multistructure testing, the nociception arising from different body structures can be explored and modulation of specific biomarkers by new and existing analgesic drugs can be profiled. The value of human experimental pain models is to link animal and clinical pain studies, providing new possibilities for designing successful clinical trials. Spontaneous pain, the main compliant of the neuropathic patients, but currently there is no human model available that would mimic chronic pain. Therefore, current human pain models cannot replace patient studies for studying efficacy of analgesic compounds, although being helpful for proof-of-concept studies and dose finding. PMID- 23626643 TI - The puzzling case of hyperexcitability in amyotrophic lateral sclerosis. AB - The development of hyperexcitability in amyotrophic lateral sclerosis (ALS) is a well-known phenomenon. Despite controversy as to the underlying mechanisms, cortical hyperexcitability appears to be closely related to the interplay between excitatory corticomotoneurons and inhibitory interneurons. Hyperexcitability is not a static phenomenon but rather shows a pattern of progression in a spatiotemporal aspect. Cortical hyperexcitability may serve as a trigger to the development of anterior horn cell degeneration through a 'dying forward' process. Hyperexcitability appears to develop during the early disease stages and gradually disappears in the advanced stages of the disease, linked to the destruction of corticomotorneuronal pathways. As such, a more precise interpretation of these unique processes may provide new insight regarding the pathophysiology of ALS and its clinical features. Recently developed technologies such as threshold tracking transcranial magnetic stimulation and automated nerve excitability tests have provided some clues about underlying pathophysiological processes linked to hyperexcitability. Additionally, these novel techniques have enabled clinicians to use the specific finding of hyperexcitability as a useful diagnostic biomarker, enabling clarification of various ALS-mimic syndromes, and the prediction of disease development in pre-symptomatic carriers of familial ALS. In terms of nerve excitability tests for peripheral nerves, an increase in persistent Na(+) conductances has been identified as a major determinant of peripheral hyperexcitability in ALS, inversely correlated with the survival in ALS. As such, the present Review will focus primarily on the puzzling theory of hyperexcitability in ALS and summarize clinical and pathophysiological implications for current and future ALS research. PMID- 23626644 TI - Cortico-cortical modulation induced by 1-Hz repetitive transcranial magnetic stimulation of the temporal cortex. AB - BACKGROUND AND PURPOSE: Repetitive transcranial magnetic stimulation (rTMS) has potential as a noninvasive neuromodulation treatment method for various neuropsychiatric disorders, and repeated sessions of rTMS are more likely to enhance the therapeutic efficacy. This study investigated neurophysiologic and spatiodynamic changes induced by repeated 1-Hz rTMS of the temporal cortex using transcranial magnetic stimulation (TMS) indices and fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS: Twenty-seven healthy subjects underwent daily 1-Hz active or sham rTMS of the right temporal cortex for 5 consecutive days. TMS indices of motor cortical excitability were measured in both hemispheres daily before and after each rTMS session, and 2 weeks after the last stimulation. FDG-PET was performed at baseline and after the 5 days of rTMS sessions. RESULTS: All subjects tolerated all of the sessions well, with only three of them (11.1%) reporting mild transient side effects (i.e., headache, tinnitus, or local irritation). One-Hz rTMS decreased motor evoked potential amplitudes and delayed cortical silent periods in the stimulated hemisphere. Statistical parametric mapping of FDG-PET data revealed a focal reduction of glucose metabolism in the stimulated temporal area and an increase in the bilateral precentral, ipsilateral superior and middle frontal, prefrontal and cingulate gyri. CONCLUSIONS: Repeated rTMS sessions for 5 consecutive days were tolerated in all subjects, with only occasional minor side effects. Focal 1-Hz rTMS of the temporal cortex induces cortico-cortical modulation with widespread functional changes in brain neural networks via long-range neural connections. PMID- 23626645 TI - Follow-up of 58 traumatic carotid-cavernous fistulas after endovascular detachable-balloon embolization at a single center. AB - BACKGROUND AND PURPOSE: This study evaluated the clinical value of detachable balloon embolization for traumatic carotid-cavernous fistula (TCCF), focusing on the frequency, risk factors, and retreatment of recurrence. METHODS: Fifty-eight patients with TCCF underwent transarterial detachable-balloon embolization between October 2004 and March 2011. The clinical follow-up was performed every 3 months until up to 3 years postprocedure. Each patient was placed in either the recurrence group or the nonrecurrence group according to whether a recurrence developed after the first procedure. The relevant factors including gender, fistula location, interval between trauma and the interventional procedure, blood flow in the carotid-cavernous fistula, number of balloons, and whether the internal carotid artery (ICA) was sacrificed were evaluated. RESULTS: All 58 TCCFs were successfully treated with transarterial balloon embolization, including 7 patients with ICA sacrifice. Recurrent fistulas occurred in seven patients during the follow-up period. Univariate analysis indicated that the interval between trauma and the interventional procedure (p=0.006) might be the main factor related to the recurrence of TCCF. The second treatments involved ICA sacrifice in two patients, fistula embolization with balloons in four patients, and placement of a covered stent in one patient. CONCLUSIONS: Detachable balloons can still serve as the first-line treatment for TCCFs and recurrent TCCFs despite having a nonnegligible recurrence rate. Shortening the interval between trauma and the interventional procedure may reduce the risk of recurrence. PMID- 23626646 TI - A comparison of stent-assisted mechanical thrombectomy and conventional intra arterial thrombolysis for acute cerebral infarction. AB - BACKGROUND AND PURPOSE: We evaluated whether stent-assisted thrombectomy (SAT) is safer or more clinically beneficial than aggressive mechanical clot disruption (AMCD) for patients with acute intracranial artery occlusion. METHODS: We retrospectively analyzed the clinical data of 72 patients (33 with SAT and 39 with AMCD) who underwent intra-arterial thrombolysis for acute intracranial artery occlusions. Procedure parameters, clinical outcomes, and incidence of complications were compared between the SAT and AMCD groups. RESULTS: The time interval to recanalization was shorter in SAT patients (69.2+/-39.6 minutes, mean+/-standard deviation) than in AMCD patients (94.4+/-48.0 minutes, p<0.05). Recanalization was achieved in more SAT patients (91%) than AMCD patients (80%), but with no statistically significance. Urokinase was used less frequently in SAT patients (21%) than in AMCD patients (92%, p<0.05), and the incidence of symptomatic hemorrhages was lower in SAT patients (3%) than in AMCD patients (18%, p<0.05). Device-related complications in SAT patients comprised two cases of stent fracture and one case of distal migration of a captured thrombus. The proportion of patients with good outcomes, defined as scores from 0 to 3 on the modified Rankin Scale, was similar in the two groups at discharge (SAT, 46%; AMCD, 39%), but significantly higher in the SAT group than in the AMCD group at 3 months (64% vs. 40%, p<0.05) and 6 months (67% vs. 42%, p<0.05) after discharge. CONCLUSIONS: The outcomes and clinical parameters were better for SAT during thrombolytic procedures for acute intracranial artery occlusions than for AMCD for up to 6 months. However, some device-related complications occurred during stent interventions. PMID- 23626647 TI - Hemispheric differences in ischemic stroke: is left-hemisphere stroke more common? AB - BACKGROUND AND PURPOSE: Understanding the mechanisms underlying stroke can aid the development of therapies and improve the final outcome. The purposes of this study were to establish whether there are characteristic mechanistic differences in the frequency, severity, functional outcome, and mortality between left- and right-hemisphere ischemic stroke and, given the velocity differences in the carotid circulation and direct branching of the left common carotid artery from the aorta, whether large-vessel ischemia (including cardioembolism) is more common in the territory of the left middle cerebral artery. METHODS: Trial cohorts were combined into a data set of 476 samples. Using Trial of Org 10172 in Acute Stroke Treatment criteria, ischemic strokes in a total 317 patients were included in the analysis. Hemorrhagic stroke, stroke of undetermined etiology, cryptogenic stroke, and bilateral ischemic strokes were excluded. Laterality and vascular distribution were correlated with outcomes using a logistic regression model. The etiologies of the large-vessel strokes were atherosclerosis and cardioembolism. RESULTS: The overall event frequency, mortality, National Institutes of Health Stroke Scale (NIHSS) score, Glasgow Coma Scale score, and rate of mechanical thrombectomy interventions differed significantly between the hemispheres. Left-hemispheric strokes (54%) were more common than right hemispheric strokes (46%; p=0.0073), and had higher admission NIHSS scores (p=0.011), increased mortality (p=0.0339), and higher endovascular intervention rates (p<=0.0001). ischemic strokes were more frequent in the distribution of the left middle cerebral artery (122 vs. 97; p=0.0003) due to the higher incidence of large-vessel ischemic stroke in this area (p=0.0011). CONCLUSIONS: Left hemispheric ischemic strokes appear to be more frequent and often have a worse outcome than their right-hemispheric counterparts. The incidence of large-vessel ischemic strokes is higher in the left middle cerebral artery distribution, contributing to these hemispheric differences. The hemispheric differences exhibit a nonsignificant trend when strokes in the middle cerebral artery distribution are excluded from the analysis. PMID- 23626649 TI - Reliability and validity of the short form of the literacy-independent cognitive assessment in the elderly. AB - BACKGROUND AND PURPOSE: The Literacy-Independent Cognitive Assessment (LICA) has been developed for a diagnosis of dementia and is a useful neuropsychological test battery for illiterate populations as well as literate populations. The objective of this study was to develop the short form of the LICA (S-LICA) and to evaluate the reliability and validity of the S-LICA. METHODS: The subtests of the S-LICA were selected based on the factor analysis and validation study results of the LICA. Patients with dementia (n=101) and normal elderly controls (n=185) participated in this study. RESULTS: Cronbach's coefficient alpha of the S-LICA was 0.92 for illiterate subjects and 0.94 for literate subjects, and the item total correlation ranged from 0.63 to 0.81 (p<.01).The test-retest reliability of the S-LICA total score was high (r=0.94, p<.001), and the subtests had high test retest reliabilities (r=0.68-0.87, p<.01). The correlation between the K-MMSE and S-LICA total scores were substantial in both the illiterate subjects (r=0.837, p<.001) and the literate subjects(r=0.802, p<.001). The correlation between the S LICA and LICA was very high (r=0.989, p<.001). The area under the curve of the receiver operating characteristic was 0.999 for the literate subjects and 0.985 for the illiterate subjects. The sensitivity and specificity of the S-LICA for a diagnosis of dementia were 97% and 96% at the cutoff point of 72 for the literate subjects, and 96% and 93% at the cutoff point of 68 for the illiterate subjects, respectively. CONCLUSIONS: Our results indicate that the S-LICA is a reliable and valid instrument for quick evaluation of patients with dementia in both illiterate and literate elderly populations. PMID- 23626648 TI - Juxtacortical spots on fluid-attenuated inversion recovery images in cryptogenic transient ischemic attack. AB - BACKGROUND AND PURPOSE: Juxtacortical spots are detected frequently on fluid attenuated inversion recovery (FLAIR) images, but have not been extensively researched in patients with transient ischemic attack (TIA). We hypothesized that juxtacortical spots on FLAIR images are partly associated with right-to-left shunt (RLS) in TIA without clear etiology. The possibility of an association between the presence of RLS and juxtacortical spots on FLAIR images in patients with TIA without clear etiology was investigated, and the imaging findings of patients with and without RLS were compared. METHODS: This was a retrospective study of TIA patients who visited our tertiary stroke center consecutively within 72 hours of TIA onset. Cryptogenic TIA was defined as no clear etiology despite a routine diagnostic workup. The presence of RLS was examined by transcranial Doppler with an agitated saline test or transesophageal echocardiography. Juxtacortical spots were defined as small and round hyperintensities in the juxtacortex on FLAIR images, excluding white-matter hyperintensities. RESULTS: Of the 132 patients with cryptogenic TIA examined for this study, 70 (53.0%) had RLS. Juxtacortical spots on FLAIR images were detected more frequently in patients with RLS than in those without. The independent factors for the presence of juxtacortical spots were RLS [odds ratio (OR)=3.802, 95% confidence interval (95% CI)=1.74-8.2; p=0.001] and age (OR=1.058, 95% CI=1.01-1.10; p=0.004) by multivariate analysis. The number of juxtacortical spots was significantly higher among patients with a moderate-to-large RLS than in those with a small or no RLS. CONCLUSIONS: The findings of the present study demonstrate a significant association between the presence of RLS and the occurrence of juxtacortical spots on FLAIR images in patients with cryptogenic TIA. PMID- 23626650 TI - Is High IQ Protective Against Cognitive Dysfunction in Narcoleptic Patients? AB - BACKGROUND AND PURPOSE: The aims of this study were to elucidate the cognitive functions of narcoleptics and determine whether intelligence protects against cognitive dysfunction and depressive mood in these patients. METHODS: Sixty-six subjects (33 narcoleptics, 33 controls) were administered a battery of neuropsychological tests and an individual standardized intelligence test. The cognitive functions of the narcoleptic patients and the healthy controls were compared, as were those of high-IQ and mid-to-low-IQ narcoleptic patients. RESULTS: Narcoleptics exhibited significantly lower scores in the Corsi Block Tapping Test forward and backward, and the digit symbol tests, and significantly higher Beck Depression Inventory scores than the controls. However, verbal attention, verbal-visual long-term memory, and executive function task scores did not differ significantly between patients and controls. The mid-to-low-IQ patient group had lower mean digit span backward test, phonemic and semantic fluency Controlled Oral Word Association Test and Korean version of the Boston Naming Test scores, and a higher total score and general depressive symptoms subscales Beck Depression Inventory score than the high-IQ patient group. However, controls exhibited no IQ-related differences in cognitive performance or depressive mood. Patients in the high-IQ group exhibited impaired visual attention and working memory as compared with controls. CONCLUSIONS: The findings of the present study show that narcolepsy patients have deficits in visual attention and visual working memory, and tend to feel more general depressive symptoms but not somatic symptoms than their control, nonnarcoleptic counterparts. In addition, it appears that higher intelligence protects against cognitive dysfunction and depressive mood. PMID- 23626651 TI - Hypolipidemia in patients with amyotrophic lateral sclerosis: a possible gender difference? AB - BACKGROUND AND PURPOSE: We compared the levels of serum lipid, protein, and glucose between patients with amyotrophic lateral sclerosis (ALS) and healthy controls. METHODS: The serum levels of lipids [including triglycerides, cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL)], protein, and glucose of 95 patients with ALS (60 men) were compared with those of 99 age- and sex-matched healthy controls (64 men). Both groups had normal dietary intakes. RESULTS: Total cholesterol (p=0.004), LDL (p=0.040), triglyceride (p=0.025), and protein (p=0.010) levels, and LDL/HDL ratios (p<0.001) in men with ALS were significantly lower than those in their control counterparts. There were no such significant differences in these parameters between female patients with ALS and female controls. CONCLUSIONS: The serum levels of lipid and protein were significantly lower in male patients with ALS than in the male controls. Since we controlled for the confounding effects of dietary intake, hypolipidemia in ALS might be associated with the pathophysiology of the disease rather than being the result of the decreased dietary intake in ALS patients. Metabolic demand might increase in ALS, and it may be affected by gender. PMID- 23626652 TI - The coexistence of myasthenia gravis and myotonic dystrophy type 2 in a single patient. AB - BACKGROUND: Myasthenia gravis (MG) and myotonic dystrophy type 2 (DM2) are rare disorders individually, and their coexistence in the same patient is very rare. We present a patient in which these two diseases coexisted. CASE REPORT: The patient complained of diplopia, fluctuating limb weakness, and difficulties in swallowing and speaking. A neurological examination revealed diplopia, facial, weakness of the neck and proximal limb muscles, dysphagia, dysphonia, and myotonia. The patient's mother had DM2 and her maternal grandfather had cataracts. MG was confirmed in our patient by positive results for neostigmine and a repetitive nerve stimulation test, and elevated serum anti-acetylcholine receptor antibodies, while DM2 was confirmed by electromyography and genetic testing. The patient improved remarkably after treatment with anticholinesterases, corticosteroids, and azathioprine. CONCLUSIONS: This is the second reported case of the coexistence of DM2 and MG in the same patient. Since the symptoms of these two diseases overlap it is very important to keep in mind the possibility of their coexistence, so that MG is not overlooked in patients with a family history of myotonic dystrophy. PMID- 23626653 TI - A case of frontotemporal dementia with amyotrophic lateral sclerosis presenting with pathological gambling. AB - BACKGROUND: Pathological gambling (PG), which is characterized by consistent, repetitive gambling and unsuccessful quitting attempts, is classified as an impulse control disorder. PG has also been reported in patients with Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. CASE REPORT: A 53-year-old male visited the outpatient clinic due to excessive gambling and personality changes. Based on electrophysiological findings and neuropsychiatric assessment, he was diagnosed as frontotemporal dementia-amyotrophic lateral sclerosis. CONCLUSIONS: This case report underlines that PG can also be seen in patients with neurological disorders involving the orbitofrontal cortex. PMID- 23626654 TI - Reducing sexual risk taking behaviors among adolescents who engage in transactional sex in post-conflict Liberia. AB - Transactional sex (TS) has been correlated with HIV/STD infection, pregnancy, early marriage, and sexual violence in sub-Saharan Africa (SSA). Few Western based HIV prevention programs adapted for SSA have examined intervention impacts for this group. This article examines whether an HIV prevention intervention, delivered to sixth-grade students in Liberia (age range 14-17) and found to increase condom use and other mediators for the larger sample, significantly impacted sexual behaviors and mediators for those who engaged in TS. Using an attention-matched, group-randomized controlled design, four matched pairs of elementary schools in Monrovia, Liberia, were randomly assigned to an adapted eight-module HIV prevention or a general health curriculum. Nine-month impacts of the intervention on sexual risk behaviors and mediators for those who engaged in TS, when compared with other study participants, are presented. Twelve percent of our sample of sixth graders (n = 714) ever engaged in TS. The majority of females reported being promised something in exchange for sex (52%), whereas the majority of males (52%) reported being both the giver and recipient of gifts in exchange for sex. Compared with other students, those who engaged in TS reported greater increases in the number of sex partners, reported greater frequency of sexual intercourse, were more likely to try to get pregnant or someone else pregnant, and reported greater reductions in protective sexual attitudes and HIV risk perception at the nine month follow-up, in both the intervention and the control groups. Our intervention, although successful for the general in-school adolescent sample, did not impact risk behaviors or mediators for adolescents who engaged in TS. Future research should explore the complex sexual economy in which TS is embedded and consider adapting HIV prevention interventions to the needs of this high-risk group. PMID- 23626655 TI - Latest trends in drugs of abuse - HIV infection and neuroAIDS. AB - Drug abuse and co-occurring infections are associated with significant morbidity and mortality. In particular, HIV infection is associated with serious neurological complications, including neuroAIDS. Therefore, on 13-15 September 2012, the OMICS Group (USA) and Shailendra K Saxena (Centre for Cellular and Molecular Biology, India) hosted a symposium titled: 'Drugs of Abuse - HIV Infection and NeuroAIDS: A Global Perspective' that was cochaired by Jag H Khalsa and Jeymohan Joseph of the NIH, MD, USA, at the 3rd World Congress on Biotechnology, in Hyderabad, India. Renowned scientists from India and the USA highlighted a number of issues, including the epidemiology, causes and underlying pathophysiological mechanisms of neuroAIDS, impact on health, and designing new treatment modalities (e.g., nanotherapeutics) for the treatment of neurological disorders. PMID- 23626657 TI - Ambulatory Autonomic Activity Monitoring Among At-Risk Adolescent Mothers. AB - BACKGROUND: Many adolescent mothers experience significant challenges in regulating emotions due to adverse life experiences, which can place adolescent mothers and their children at risk for poor developmental outcomes. Ambulatory monitoring of stress that also provides immediate feedback using wearable biosensors has the potential to enhance clinician-delivered parenting interventions and help young mothers develop emotion regulatory skills. METHODS: We conducted a pilot study to assess the acceptability, ease of use, and preliminary efficacy of a wearable biosensor, the iCalm sensor band, among a sample of four mothers, ages 15-18 years. Mothers wore the biosensor for a period of 24-36 hours while engaging in normal, daily tasks (e.g. caring for their child, attending school). Both quantitative electrodermal activity (EDA) data (via the iCalm sensor band) and qualitative data (via individual semi-structured interviews) were collected. RESULTS: The adolescent mothers were able to comfortably use and wear the iCalm sensor band. EDA data were collected and corresponded with stressful daily life events described by the mothers during qualitative interviews. CONCLUSION: The iCalm biosensor is acceptable to use among high-risk adolescent mothers and appears to help mothers with the development of emotion regulatory skills. PMID- 23626656 TI - A review of experimental and natural infections of animals with monkeypox virus between 1958 and 2012. AB - Monkeypox virus (MPXV) was discovered in 1958 during an outbreak in an animal facility in Copenhagen, Denmark. Since its discovery, MPXV has revealed a propensity to infect and induce disease in a large number of animals within the mammalia class from pan-geographical locations. This finding has impeded the elucidation of the natural host, although the strongest candidates are African squirrels and/or other rodents. Experimentally, MPXV can infect animals via a variety of multiple different inoculation routes; however, the natural route of transmission is unknown and is likely to be somewhat species specific. In this review we have attempted to compile and discuss all published articles that describe experimental or natural infections with MPXV, dating from the initial discovery of the virus through to the year 2012. We further discuss the comparative disease courses and pathologies of the host species. PMID- 23626658 TI - Hyperglycemia alters mitochondrial fission and fusion proteins in mice subjected to cerebral ischemia and reperfusion. AB - Preischemic hyperglycemia exacerbates brain damage caused by cerebral ischemia. In the present experiment, we studied the effects of preischemic hyperglycemia on protein markers that are related to mitochondrial fission and fusion, mitochondrial biogenesis, and autophagy in mice subjected to 30-min transient focal ischemia. The fission proteins dynamin-related protein 1 (Drp1) and fission 1 (Fis1), fusion proteins optic atrophy 1 (Opa1) and mitofusin 2 (Mfn2), mitochondrial biogenesis regulators nuclear respiratory factor 1 (NRF1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC 1alpha), and autophagy marker beclin 1 and microtubule-associated protein light chain 3 (LC3) were analyzed in control, 30 min middle cerebral artery occlusion (MCAO) plus 6-, 24-, and 72 h of reperfusion in normo- and hyperglycemic conditions. Cerebral ischemia increased the levels of Drp1 and decreased Fis1 after reperfusion. Preischemic hyperglycemia further augmented the increase of Drp1 and induced elevation in Fis1. Ischemia inhibited the levels of Opa1 and Mfn2 and hyperglycemia further decreased the level of Opa1. Further, NRF1 increased after reperfusion in both normo- and hyperglycemic animals. However, such increase was caused by reperfusion rather than glucose level. Finally, ischemia increased beclin 1 level at 6 and 24 h of reperfusion and hyperglycemia further increased the beclin 1 level and caused LC3-II increase as well. Hyperglycemia enhances the ischemia-induced mitochondrial dynamic imbalance towards fission that may favor mitochondrial fragmentation and subsequent damage. Hyperglycemia elevated autophagy markers may represent an adapting reaction to the severe damage incurred in hyperglycemic animals or a third pathway of cell death. PMID- 23626659 TI - Splenic immune cells in experimental neonatal hypoxia-ischemia. AB - Neuroimmune processes contribute to hypoxic-ischemic damage in the immature brain and may play a role in the progression of particular variants of neonatal encephalopathy. The present study was designed to elucidate molecular mediators of interactions between astrocytes, neurons and infiltrating peripheral immune cells after experimental neonatal hypoxia-ischemia (HI). Splenectomy was performed on postnatal day-7 Sprague-Dawley rats 3 days prior to HI surgery; in which the right common carotid artery was permanently ligated followed by 2 hours of hypoxia (8% O2). Quantitative analysis showed that natural killer (NK) and T cell expression was reduced in spleen but increased in the brain following HI. Elevations in cyclooxygenase-2 (COX-2) expression after HI by immune cells promoted interleukin-15 expression in astrocytes and infiltration of inflammatory cells to site of injury; additionally, down-regulated the pro-survival protein, phosphoinositide-3-kinase, resulting in caspase-3 mediated neuronal death. The removal of the largest pool of peripheral immune cells in the body by splenectomy, COX-2 inhibitors, as well as rendering NK cells inactive by CD161 knockdown, significantly ameliorated cerebral infarct volume at 72 hours, diminished body weight loss and brain and systemic organ atrophy, and reduced neurobehavioral deficits at 3 weeks. Herein we demonstrate with the use of surgical approach (splenectomy), with pharmacological loss-gain function approach using COX-2 inhibitors/agonists, as well as with NK cell-type specific siRNA that after neonatal HI, the infiltrating peripheral immune cells may modulate downstream targets of cell death and neuroinflammation by COX-2 regulated signals. PMID- 23626661 TI - AAPL: Assessing Association between P-value Lists. AB - Joint analyses of high-throughput datasets generate the need to assess the association between two long lists of p-values. In such p-value lists, the vast majority of the features are insignificant. Ideally contributions of features that are null in both tests should be minimized. However, by random chance their p-values are uniformly distributed between zero and one, and weak correlations of the p-values may exist due to inherent biases in the high-throughput technology used to generate the multiple datasets. Rank-based agreement test may capture such unwanted effects. Testing contingency tables generated using hard cutoffs may be sensitive to arbitrary threshold choice. We develop a novel method based on feature-level concordance using local false discovery rate. The association score enjoys straight-forward interpretation. The method shows higher statistical power to detect association between p-value lists in simulation. We demonstrate its utility using real data analysis. The R implementation of the method is available at http://userwww.service.emory.edu/~tyu8/AAPL/. PMID- 23626660 TI - Air pollution and circulating biomarkers of oxidative stress. AB - Chemical components of air pollutant exposures that induce oxidative stress and subsequent inflammation may be partly responsible for associations of cardiovascular morbidity and mortality with airborne particulate matter and combustion-related pollutant gasses. However, epidemiologic evidence regarding this is limited. An exposure-assessment approach is to measure the oxidative potential of particle mixtures because it is likely that hundreds of correlated chemicals are involved in overall effects of air pollution on health. Oxidative potential likely depends on particle composition and size distribution, especially ultrafine particle concentration, and on transition metals and certain semivolatile and volatile organic chemicals. For health effects, measuring systemic oxidative stress in the blood is one feasible approach, but there is no universal biomarker of oxidative stress and there are many potential target molecules (lipids, proteins, DNA, nitric oxide, etc.), which may be more or less suitable for specific study goals. Concurrent with the measurement of oxidative stress, it is important to measure gene and/or protein expression of endogenous antioxidant enzymes because they can modify relations between oxidative stress biomarkers and air pollutants. Conversely, the expression and activities of these enzymes are modified by oxidative stress. This interplay will likely determine the observed effects of air pollutants on systemic inflammatory and thrombotic mediators and related clinical outcomes. Studies are needed to assess the reliability and validity of oxidative stress biomarkers, evaluate differences in associations between oxidative stress biomarkers and various pollutant measurements (mass, chemical components, and oxidative potential), and evaluate impacts of antioxidant responses on these relations. PMID- 23626666 TI - ATM deficiency results in accumulation of DNA-topoisomerase I covalent intermediates in neural cells. AB - Accumulation of peptide-linked DNA breaks contributes to neurodegeration in humans. This is typified by defects in tyrosyl DNA phosphodiesterase 1 (TDP1) and human hereditary ataxia. TDP1 primarily operates at single-strand breaks (SSBs) created by oxidative stress or by collision of transcription machinery with topoisomerase I intermediates (Top1-CCs). Cellular and cell-free studies have shown that Top1 at stalled Top1-CCs is first degraded to a small peptide resulting in Top1-SSBs, which are the primary substrates for TDP1. Here we established an assay to directly compare Top1-SSBs and Top1-CCs. We subsequently employed this assay to reveal an increased steady state level of Top1-CCs in neural cells lacking Atm; the protein mutated in ataxia telangiectasia. Our data suggest that the accumulation of endogenous Top1-CCs in Atm-/- neural cells is primarily due to elevated levels of reactive oxygen species. Biochemical purification of Top1-CCs from neural cell extract and the use of Top1 poisons further confirmed a role for Atm during the formation/resolution of Top1-CCs. Finally, we report that global transcription is reduced in Atm-/- neural cells and fails to recover to normal levels following Top1-mediated DNA damage. Together, these data identify a distinct role for ATM during the formation/resolution of neural Top1-CCs and suggest that their accumulation contributes to the neuropathology of ataxia telangiectasia. PMID- 23626667 TI - Quantitative characterization of glycan-receptor binding of H9N2 influenza A virus hemagglutinin. AB - Avian influenza subtypes such as H5, H7 and H9 are yet to adapt to the human host so as to establish airborne transmission between humans. However, lab-generated reassorted viruses possessing hemagglutinin (HA) and neuraminidase (NA) genes from an avian H9 isolate and other genes from a human-adapted (H3 or H1) subtype acquired two amino acid changes in HA and a single amino acid change in NA that confer respiratory droplet transmission in ferrets. We previously demonstrated for human-adapted H1, H2 and H3 subtypes that quantitative binding affinity of their HA to alpha2->6 sialylated glycan receptors correlates with respiratory droplet transmissibility of the virus in ferrets. Such a relationship remains to be established for H9 HA. In this study, we performed a quantitative biochemical characterization of glycan receptor binding properties of wild-type and mutant forms of representative H9 HAs that were previously used in context of reassorted viruses in ferret transmission studies. We demonstrate here that distinct molecular interactions in the glycan receptor-binding site of different H9 HAs affect the glycan-binding specificity and affinity. Further we show that alpha2 >6 glycan receptor-binding affinity of a mutant H9 HA carrying Thr-189->Ala amino acid change correlates with the respiratory droplet transmission in ferrets conferred by this change. Our findings contribute to a framework for monitoring the evolution of H9 HA by understanding effects of molecular changes in HA on glycan receptor-binding properties. PMID- 23626668 TI - Limited population structure, genetic drift and bottlenecks characterise an endangered bird species in a dynamic, fire-prone ecosystem. AB - Fire is a major disturbance process in many ecosystems world-wide, resulting in spatially and temporally dynamic landscapes. For populations occupying such environments, fire-induced landscape change is likely to influence population processes, and genetic patterns and structure among populations. The Mallee Emu wren Stipiturus mallee is an endangered passerine whose global distribution is confined to fire-prone, semi-arid mallee shrublands in south-eastern Australia. This species, with poor capacity for dispersal, has undergone a precipitous reduction in distribution and numbers in recent decades. We used genetic analyses of 11 length-variable, nuclear loci to examine population structure and processes within this species, across its global range. Populations of the Mallee Emu-wren exhibited a low to moderate level of genetic diversity, and evidence of bottlenecks and genetic drift. Bayesian clustering methods revealed weak genetic population structure across the species' range. The direct effects of large fires, together with associated changes in the spatial and temporal patterns of suitable habitat, have the potential to cause population bottlenecks, serial local extinctions and subsequent recolonisation, all of which may interact to erode and homogenise genetic diversity in this species. Movement among temporally and spatially shifting habitat, appears to maintain long-term genetic connectivity. A plausible explanation for the observed genetic patterns is that, following extensive fires, recolonisation exceeds in-situ survival as the primary driver of population recovery in this species. These findings suggest that dynamic, fire-dominated landscapes can drive genetic homogenisation of populations of species with low-mobility and specialised habitat that otherwise would be expected to show strongly structured populations. Such effects must be considered when formulating management actions to conserve species in fire-prone systems. PMID- 23626669 TI - Designed ankyrin repeat proteins: a new approach to mimic complex antigens for diagnostic purposes? AB - Inhibitory antibodies directed against coagulation factor VIII (FVIII) can be found in patients with acquired and congenital hemophilia A. Such FVIII inhibiting antibodies are routinely detected by the functional Bethesda Assay. However, this assay has a low sensitivity and shows a high inter-laboratory variability. Another method to detect antibodies recognizing FVIII is ELISA, but this test does not allow the distinction between inhibitory and non-inhibitory antibodies. Therefore, we aimed at replacing the intricate antigen FVIII by Designed Ankyrin Repeat Proteins (DARPins) mimicking the epitopes of FVIII inhibitors. As a model we used the well-described inhibitory human monoclonal anti-FVIII antibody, Bo2C11, for the selection on DARPin libraries. Two DARPins were selected binding to the antigen-binding site of Bo2C11, which mimic thus a functional epitope on FVIII. These DARPins inhibited the binding of the antibody to its antigen and restored FVIII activity as determined in the Bethesda assay. Furthermore, the specific DARPins were able to recognize the target antibody in human plasma and could therefore be used to test for the presence of Bo2C11-like antibodies in a large set of hemophilia A patients. These data suggest, that our approach might be used to isolate epitopes from different sets of anti-FVIII antibodies in order to develop an ELISA-based screening assay allowing the distinction of inhibitory and non-inhibitory anti-FVIII antibodies according to their antibody signatures. PMID- 23626670 TI - Comparison of prognostic genomic predictors in colorectal cancer. AB - BACKGROUND: Although several prognostic genomic predictors have been identified from independent studies, it remains unclear whether these predictors are actually concordant with respect to their predictions for individual patients and which predictor performs best. We compared five prognostic genomic predictors, the V7RHS, the ColoGuideEx, the Meta163, the OncoDX, and the MDA114, in terms of predicting disease-free survival in two independent cohorts of patients with colorectal cancer. STUDY DESIGN: Using original classification algorithms, we tested the predictions of five genomic predictors for disease-free survival in two cohorts of patients with colorectal cancer (n = 229 and n = 168) and evaluated concordance of predictors in predicting outcomes for individual patients. RESULTS: We found that only two predictors, OncoDX and MDA114, demonstrated robust performance in identifying patients with poor prognosis in 2 independent cohorts. These two predictors also had modest but significant concordance of predicted outcome (r>0.3, P<0.001 in both cohorts). CONCLUSIONS: Further validation of developed genomic predictors is necessary. Despite the limited number of genes shared by OncoDX and MDA114, individual-patient outcomes predicted by these two predictors were significantly concordant. PMID- 23626671 TI - Tumour necrosis factor alpha, interferon gamma and substance P are novel modulators of extrapituitary prolactin expression in human skin. AB - Human scalp skin and hair follicles (HFs) are extra-pituitary sources of prolactin (PRL). However, the intracutaneous regulation of PRL remains poorly understood. Therefore we investigated whether well-recognized regulators of pituitary PRL expression, which also impact on human skin physiology and pathology, regulate expression of PRL and its receptor (PRLR) in situ. This was studied in serum-free organ cultures of microdissected human scalp HFs and skin, i.e. excluding pituitary, neural and vascular inputs. Prolactin expression was confirmed at the gene and protein level in human truncal skin, where its expression significantly increased (p = 0.049) during organ culture. There was, however, no evidence of PRL secretion into the culture medium as measured by ELISA. PRL immunoreactivity (IR) in female human epidermis was decreased by substance P (p = 0.009), while neither the classical pituitary PRL inhibitor, dopamine, nor corticotropin-releasing hormone significantly modulated PRL IR in HFs or skin respectively. Interferon (IFN) gamma increased PRL IR in the epithelium of human HFs (p = 0.044) while tumour necrosis factor (TNF) alpha decreased both PRL and PRLR IR. This study identifies substance P, TNFalpha and IFNgamma as novel modulators of PRL and PRLR expression in human skin, and suggests that intracutaneous PRL expression is not under dopaminergic control. Given the importance of PRL in human hair growth regulation and its possible role in the pathogenesis of several common skin diseases, targeting intracutaneous PRL production via these newly identified regulatory pathways may point towards novel therapeutic options for inflammatory dermatoses. PMID- 23626672 TI - Systematic analysis of experimental phenotype data reveals gene functions. AB - High-throughput phenotyping projects in model organisms have the potential to improve our understanding of gene functions and their role in living organisms. We have developed a computational, knowledge-based approach to automatically infer gene functions from phenotypic manifestations and applied this approach to yeast (Saccharomyces cerevisiae), nematode worm (Caenorhabditis elegans), zebrafish (Danio rerio), fruitfly (Drosophila melanogaster) and mouse (Mus musculus) phenotypes. Our approach is based on the assumption that, if a mutation in a gene [Formula: see text] leads to a phenotypic abnormality in a process [Formula: see text], then [Formula: see text] must have been involved in [Formula: see text], either directly or indirectly. We systematically analyze recorded phenotypes in animal models using the formal definitions created for phenotype ontologies. We evaluate the validity of the inferred functions manually and by demonstrating a significant improvement in predicting genetic interactions and protein-protein interactions based on functional similarity. Our knowledge based approach is generally applicable to phenotypes recorded in model organism databases, including phenotypes from large-scale, high throughput community projects whose primary mode of dissemination is direct publication on-line rather than in the literature. PMID- 23626674 TI - Studying gene expression system regulation at the program level. AB - Understanding how gene expression systems influence biological outcomes is an important goal for diverse areas of research. Gene expression profiling allows for the simultaneous measurement of expression levels for thousands of genes and the opportunity to use this information to increase biological understanding. Yet, the best way to relate this immense amount of information to biological outcomes is far from clear. Here, a novel approach to gene expression systems research is presented that focuses on understanding gene expression systems at the level of gene expression program regulation. It is suggested that such an approach has important advantages over current techniques and may provide novel insights into how gene expression systems are regulated to shape biological outcomes such as the development of disease or response to treatment. PMID- 23626673 TI - Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study. AB - Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos. PMID- 23626675 TI - The first prokaryotic trehalose synthase complex identified in the hyperthermophilic crenarchaeon Thermoproteus tenax. AB - The role of the disaccharide trehalose, its biosynthesis pathways and their regulation in Archaea are still ambiguous. In Thermoproteus tenax a fused trehalose-6-phosphate synthase/phosphatase (TPSP), consisting of an N-terminal trehalose-6-phosphate synthase (TPS) and a C-terminal trehalose-6-phosphate phosphatase (TPP) domain, was identified. The tpsp gene is organized in an operon with a putative glycosyltransferase (GT) and a putative mechanosensitive channel (MSC). The T. tenax TPSP exhibits high phosphatase activity, but requires activation by the co-expressed GT for bifunctional synthase-phosphatase activity. The GT mediated activation of TPS activity relies on the fusion of both, TPS and TPP domain, in the TPSP enzyme. Activation is mediated by complex-formation in vivo as indicated by yeast two-hybrid and crude extract analysis. In combination with first evidence for MSC activity the results suggest a sophisticated stress response involving TPSP, GT and MSC in T. tenax and probably in other Thermoproteales species. The monophyletic prokaryotic TPSP proteins likely originated via a single fusion event in the Bacteroidetes with subsequent horizontal gene transfers to other Bacteria and Archaea. Furthermore, evidence for the origin of eukaryotic TPSP fusions via HGT from prokaryotes and therefore a monophyletic origin of eukaryotic and prokaryotic fused TPSPs is presented. This is the first report of a prokaryotic, archaeal trehalose synthase complex exhibiting a much more simple composition than the eukaryotic complex described in yeast. Thus, complex formation and a complex-associated regulatory potential might represent a more general feature of trehalose synthesizing proteins. PMID- 23626676 TI - Human neutrophil cytoskeletal dynamics and contractility actively contribute to trans-endothelial migration. AB - Transmigration through the endothelium is a key step in the immune response. In our recent work, the mechanical properties of the subendothelial matrix and biophysical state of the endothelium have been identified as key modulators of leukocyte trans-endothelial migration. Here, we demonstrated that neutrophil contractile forces and cytoskeletal dynamics also play an active biophysical role during transmigration through endothelial cell-cell junctions. Using our previously-established model for leukocyte transmigration, we first discovered that >93% of human neutrophils preferentially exploit the paracellular mode of transmigration in our in vitro model, and that is independent of subendothelial matrix stiffness. We demonstrated that inhibition of actin polymerization or depolymerization completely blocks transmigration, thus establishing a critical role for neutrophil actin dynamics in transmigration. Next, inhibition of neutrophil myosin II-mediated contractile forces renders 44% of neutrophils incapable of retracting their trailing edge under the endothelium for several minutes after the majority of the neutrophil transmigrates. Meanwhile, inhibition of neutrophil contractile forces or stabilization of microtubules doubles the time to complete transmigration for the first neutrophils to cross the endothelium. Notably, the time to complete transmigration is significantly reduced for subsequent neutrophils that cross through the same path as a previous neutrophil and is less dependent on neutrophil contractile forces and microtubule dynamics. These results suggest that the first neutrophil induces a gap in endothelial cell-cell adhesions, which "opens the door" in the endothelium and facilitates transmigration of subsequent neutrophils through the same hole. Collectively, this work demonstrates that neutrophils play an active biophysical role during the transmigration step of the immune response. PMID- 23626677 TI - Characterization of novel precursor miRNAs using next generation sequencing and prediction of miRNA targets in Atlantic halibut. AB - BACKGROUND: microRNAs (miRNAs) are implicated in regulation of many cellular processes. miRNAs are processed to their mature functional form in a step-wise manner by multiple proteins and cofactors in the nucleus and cytoplasm. Many miRNAs are conserved across vertebrates. Mature miRNAs have recently been characterized in Atlantic halibut (Hippoglossus hippoglossus L.). The aim of this study was to identify and characterize precursor miRNA (pre-miRNAs) and miRNA targets in this non-model flatfish. Discovery of miRNA precursor forms and targets in non-model organisms is difficult because of limited source information available. Therefore, we have developed a methodology to overcome this limitation. METHODS: Genomic DNA and small transcriptome of Atlantic halibut were sequenced using Roche 454 pyrosequencing and SOLiD next generation sequencing (NGS), respectively. Identified pre- miRNAs were further validated with reverse transcription PCR. miRNA targets were identified using miRanda and RNAhybrid target prediction tools using sequences from public databases. Some of miRNA targets were also identified using RACE-PCR. miRNA binding sites were validated with luciferase assay using the RTS34st cell line. RESULTS: We obtained more than 1.3 M and 92 M sequence reads from 454 genomic DNA sequencing and SOLiD small RNA sequencing, respectively. We identified 34 known and 9 novel pre-miRNAs. We predicted a number of miRNA target genes involved in various biological pathways. miR-24 binding to kisspeptin 1 receptor-2 (kiss1-r2) was confirmed using luciferase assay. CONCLUSION: This study demonstrates that identification of conserved and novel pre-miRNAs in a non-model vertebrate lacking substantial genomic resources can be performed by combining different next generation sequencing technologies. Our results indicate a wide conservation of miRNA precursors and involvement of miRNA in multiple regulatory pathways, and provide resources for further research on miRNA in non-model animals. PMID- 23626678 TI - Impact of vitamin D on chronic kidney diseases in non-dialysis patients: a meta analysis of randomized controlled trials. AB - BACKGROUND AND OBJECTIVES: Recent studies have supported a role for both newer and more established vitamin D compounds in improving proteinuria, although systematic evaluation is lacking. Furthermore, concerns remain regarding the influence of vitamin D on the progression of renal function. We analyzed the efficacy and safety of vitamin D in non-dialysis patients and compared the use of newer versus established vitamin D compounds by performing a meta-analysis of randomized controlled trials. DESIGN: A literature search of PubMed (1975 to September, 2012), EMBASE.com (1966 to September, 2012) and Ovid EBM Reviews (through September, 2012) was conducted. RESULTS: Eighteen studies were eligible for final inclusion; of these, six explored the effects of vitamin D on proteinuria, twelve studied the effects of supplementation on renal function, and fifteen discussed the incidence of hypercalcemia. Compared to the placebo or no interference, both the newer and established vitamin D sterols reduced proteinuria to a similar extent (RR, 2.00; 95% CI, 1.42 to 2.81). No decrease in the glomerular filter rate was observed (SMD, -0.10; 95%CI, -0.24 to 0.03), and the risk for dialysis initiation was 1.48 (95% CI, 0.54 to 4.03) with vitamin D treatment. Additionally, there was an increased risk of hypercalcemia for patients treated with either newer or established vitamin D compounds as compared with the controls (RR, 4.78; 95% CI, 2.20 to 10.37). The head-to-head studies showed no differences in the effects of either newer or established compounds on proteinuria or the risk of hypercalcemia. No serious adverse events were associated with the administration of vitamin D. CONCLUSIONS: Vitamin D therapy appears to decrease proteinuria and have no negative influence on renal function in non-dialysis patients. But the occurrence of hypercalcemia should be evaluated when vitamin D is provided. No superiority for newer versus established vitamin D analogue is found. PMID- 23626679 TI - Ecrg4 attenuates the inflammatory proliferative response of mucosal epithelial cells to infection. AB - We report an inverse relationship between expression of the orphan candidate tumor suppressor gene esophageal cancer related gene 4 (Ecrg4), and the mucosal epithelial cell response to infection in the middle ear (ME). First, we found constitutive Ecrg4 mRNA expression in normal, quiescent ME mucosa that was confirmed by immunostainning of mucosal epithelial cells and immunoblotting of tissue lysates for the 14 kDa Ecrg4 protein. Upon experimental ME infection, Ecrg4 gene expression rapidly decreased by over 80%, between 3 to 48 hrs, post infection. When explants of this infected mucosa were placed in culture and transduced with an adenovirus (AD) encoding Ecrg4 gene (ADEcrg4), the proliferative and migratory responses of mucosal cells were significantly inhibited. ADEcrg4 transduction of control explants from uninfected MEs had no effect on basal growth and migration. Over-expression of Ecrg4 in vivo, by pre injecting MEs with ADEcrg4 48 hrs prior to infection, prevented the natural down regulation of Ecrg4, reduced mucosal proliferation and prevented inflammatory cell infiltration normally observed after infection. Taken together, these data support a hypothesis that Ecrg4 plays a role in coordinating the inflammatory and proliferative response to infection of mucosal epithelium suggesting a possible mechanism for its putative anti-tumor activity. PMID- 23626680 TI - Resistance to DDT in an urban setting: common mechanisms implicated in both M and S forms of Anopheles gambiae in the city of Yaounde Cameroon. AB - BACKGROUND: In the city of Yaounde in Cameroon malaria is predominately transmitted by the M and S molecular forms of Anopheles gambiae and both are resistant to the pyrethroid insecticides and DDT. Mutations in the target site of these insecticides, present at a high frequency in malaria vectors in this city, contribute to this resistance profile. To identify additional resistance mechanisms, the expression profile of multiple DDT-resistant field populations of M and S molecular forms was compared to laboratory-susceptible populations. METHODOLOGY/PRINCIPAL FINDINGS: The prevalence of DDT resistance was highest in the S form population originating from the cultivated site of Nkolondom (mortality after WHO bioassay = 4%). A high prevalence of DDT resistance was also found in two urban M form populations, Messa from a pristine unpolluted environment (DDT mortality = 54%), and Gare, where the breeding sites are heavily polluted with organic matter (DDT mortality = 38%). Microarray analysis showed that several transcripts coding for detoxification enzymes (P450s, GSTs and UDPGTs) and ABC transporters were upregulated in the three populations. Despite the presence of multiple detoxification genes over expressed in the DDT-resistant subset of these field populations, only three were commonly over expressed in resistant populations from all three environments. Two of these genes, CYP6M2 and GSTD1-6, encode enzymes that have been previously shown to metabolize DDT. CONCLUSION/SIGNIFICANCE: Analogous to target site resistance, genes involved in metabolic resistance to DDT are also shared between the M and S forms of An gambiae. Alternative explanations for this occurrence are explored. PMID- 23626681 TI - High fat diet feeding exaggerates perfluorooctanoic acid-induced liver injury in mice via modulating multiple metabolic pathways. AB - High fat diet (HFD) is closely linked to a variety of health issues including fatty liver. Exposure to perfluorooctanoic acid (PFOA), a synthetic perfluorinated carboxylic acid, also causes liver injury. The present study investigated the possible interactions between high fat diet and PFOA in induction of liver injury. Mice were pair-fed a high-fat diet (HFD) or low fat control with or without PFOA administration at 5 mg/kg/day for 3 weeks. Exposure to PFOA alone caused elevated plasma alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels and increased liver weight along with reduced body weight and adipose tissue mass. HFD alone did not cause liver damage, but exaggerated PFOA-induced hepatotoxicity as indicated by higher plasma ALT and AST levels, and more severe pathological changes including hepatocyte hypertrophy, lipid droplet accumulation and necrosis as well as inflammatory cell infiltration. These additive effects of HFD on PFOA-induced hepatotoxicity correlated with metabolic disturbance in liver and blood as well as up-regulation of hepatic proinflammatory cytokine genes. Metabolomic analysis demonstrated that both serum and hepatic metabolite profiles of PFOA, HFD, or HFD-PFOA group were clearly differentiated from that of controls. PFOA affected more hepatic metabolites than HFD, but HFD showed positive interaction with PFOA on fatty acid metabolites including long chain fatty acids and acylcarnitines. Taken together, dietary high fat potentiates PFOA-induced hepatic lipid accumulation, inflammation and necrotic cell death by disturbing hepatic metabolism and inducing inflammation. This study demonstrated, for the first time, that HFD increases the risk of PFOA in induction of hepatotoxicity. PMID- 23626682 TI - Prognostic value of metastatic axillary lymph node ratio for Chinese breast cancer patients. AB - OBJECTIVE: The prevalence of breast cancer varies among countries and regions. This retrospective study investigated the prognostic value of the lymph node ratio (LNR) compared with the number of positive lymph nodes (pN) in Chinese breast cancer patients. METHODS: The medical records of female breast cancer patients (N = 2591) were retrospectively evaluated. The association of LNR and TMN staging system were compared with respect to overall, disease-free, and distant metastasis-free survival. RESULTS: Out of 2591 patients, 2495 underwent modified radical surgery and 96 received breast conserving surgery. All patients had adjuvant chemotherapy following surgery. The median follow up period 66.9 months (range 5-168 months). The 5-year and 10-year overall survival rates were 89.3% and 78.8%, respectively, and 5-year disease-free survival and distant metastasis-free survival rates were 81.6% and 83.5%, respectively. Univariate analysis indicated that in general T, pN, LNR, as well as tumor expression of the estrogen receptor, progesterone receptor, and HER2 were associated with overall, disease-free, and distant metastasis-free survival (all P-values <0.05). Mutlivariate analysis found pN stage and LNR were independent predictors of overall, disease-free, and distant metastasis-free survival (all P-values <0.001). If pN stage and LNR were both included in a multivariate analysis, LNR was still an independent prognostic factor for overall, disease-free, and distant metastasis-free survival (all P-values <0.001). CONCLUSION: Our findings support the use of LNR as a predictor of survival in Chinese patients with breast cancer, and that LNR is superior to pN stage in determining disease prognosis. PMID- 23626683 TI - Construction of a single lentiviral vector containing tetracycline-inducible Alb uPA for transduction of uPA expression in murine hepatocytes. AB - The SCID-beige/Alb-uPA mouse model is currently the best small animal model available for viral hepatitis infection studies [1]. But the construction procedure is often costly and time-consuming due to logistic and technical difficulties. Thus, the widespread application of these chimeric mice has been hampered [2]. In order to optimize the procedure, we constructed a single lentiviral vector containing modified tetracycline-regulated system to control Alb-uPA gene expression in the cultured hepatocytes. The modified albumin promoter controlled by tetracycline (Tet)-dependent transactivator rtTA2S-M2 was integrated into a lentiviral vector. The full-length uPA cDNA was inserted into another lentiviral vector containing PTight, a modified Tet-responsive promoter. Two vectors were then digested by specific enzymes and ligated by DNA ligase 4. The ligated DNA fragment was inserted into a modified pLKO.1 cloning vector and the final lentiviral vector was then successfully constructed. H2.35 cell, Lewis lung carcinoma, primary kidney, primary hepatic interstitial and CT26 cells were infected with recombinant lentivirus at selected MOI. The expression of uPA induced by DOX was detectable only in the infected H2.35 cells, which was confirmed by real-time PCR and Western blot analysis. Moreover, DOX induced uPA expression on the infected H2.35 cells in a dose-dependent manner. The constructed single lentiviral vector has many biological advantages, including that the interested gene expression under "Tet-on/off" system is controlled by DOX in a dose-depending fashion only in murine liver cells, which provides an advantage for simplifying generation of conditional transgenic animals. PMID- 23626684 TI - Biomimicry enhances sequential reactions of tethered glycolytic enzymes, TPI and GAPDHS. AB - Maintaining activity of enzymes tethered to solid interfaces remains a major challenge in developing hybrid organic-inorganic devices. In nature, mammalian spermatozoa have overcome this design challenge by having glycolytic enzymes with specialized targeting domains that enable them to function while tethered to a cytoskeletal element. As a step toward designing a hybrid organic-inorganic ATP generating system, we implemented a biomimetic site-specific immobilization strategy to tether two glycolytic enzymes representing different functional enzyme families: triose phosphoisomerase (TPI; an isomerase) and glyceraldehyde 3 phosphate dehydrogenase (GAPDHS; an oxidoreductase). We then evaluated the activities of these enzymes in comparison to when they were tethered via classical carboxyl-amine crosslinking. Both enzymes show similar surface binding regardless of immobilization method. Remarkably, specific activities for both enzymes were significantly higher when tethered using the biomimetic, site specific immobilization approach. Using this biomimetic approach, we tethered both enzymes to a single surface and demonstrated their function in series in both forward and reverse directions. Again, the activities in series were significantly higher in both directions when the enzymes were coupled using this biomimetic approach versus carboxyl-amine binding. Our results suggest that biomimetic, site-specific immobilization can provide important functional advantages over chemically specific, but non-oriented attachment, an important strategic insight given the growing interest in recapitulating entire biological pathways on hybrid organic-inorganic devices. PMID- 23626685 TI - A real-time PCR-based semi-quantitative breakpoint to aid in molecular identification of urinary tract infections. AB - This study presents a novel approach to aid in diagnosis of urinary tract infections (UTIs). A real-time PCR assay was used to screen for culture-positive urinary specimens and to identify the causative uropathogen. Semi-quantitative breakpoints were used to screen for significant bacteriuria (presence of >= 10(5) CFU/ml of uropathogens) or low-level bacteriuria (containing between 10(3) and 10(4) CFU/ml of uropathogens). The 16S rDNA-based assay could identify the most prevalent uropathogens using probes for Escherichia coli, Pseudomonas species, Pseudomonas aeruginosa, Staphylococcus species, Staphylococcus aureus, Enterococcus species and Streptococcus species. 330 urinary specimens were analysed and results were compared with conventional urine culture. Using a PCR Ct value of 25 as semi-quantitative breakpoint for significant bacteriuria resulted in a sensitivity and specificity of 97% and 80%, respectively. In 78% of the samples with monomicrobial infections the assay contained probes to detect the bacteria present in the urine specimens and 99% of these uropathogens was correctly identified. Concluding, this proof-of-concept approach demonstrates that the assay can distinguish bacteriuria from no bacteriuria as well as detect the involved uropathogen within 4 hours after sampling, allowing adequate therapy decisions within the same day as well as drastically reduce consequent urine culturing. PMID- 23626686 TI - Reconstitution of the anti-apoptotic Bcl-2 protein into lipid membranes and biophysical evidence for its detergent-driven association with the pro-apoptotic Bax protein. AB - The anti-apoptotic B-cell CLL/lymphoma-2 (Bcl-2) protein and its counterpart, the pro-apoptotic Bcl-2-associated X protein (Bax), are key players in the regulation of the mitochondrial pathway of apoptosis. However, how they interact at the mitochondrial outer membrane (MOM) and there determine whether the cell will live or be sentenced to death remains unknown. Competing models have been presented that describe how Bcl-2 inhibits the cell-killing activity of Bax, which is common in treatment-resistant tumors where Bcl-2 is overexpressed. Some studies suggest that Bcl-2 binds directly to and sequesters Bax, while others suggest an indirect process whereby Bcl-2 blocks BH3-only proteins and prevents them from activating Bax. Here we present the results of a biophysical study in which we investigated the putative interaction of solubilized full-length human Bcl-2 with Bax and the scope for incorporating the former into a native-like lipid environment. Far-UV circular dichroism (CD) spectroscopy was used to detect direct Bcl-2-Bax-interactions in the presence of polyoxyethylene-(23)-lauryl ether (Brij-35) detergent at a level below its critical micelle concentration (CMC). Additional surface plasmon resonance (SPR) measurements confirmed this observation and revealed a high affinity between the Bax and Bcl-2 proteins. Upon formation of this protein-protein complex, Bax also prevented the binding of antimycin A2 (a known inhibitory ligand of Bcl-2) to the Bcl-2 protein, as fluorescence spectroscopy experiments showed. In addition, Bcl-2 was able to form mixed micelles with Triton X-100 solubilized neutral phospholipids in the presence of high concentrations of Brij-35 (above its CMC). Following detergent removal, the integral membrane protein was found to have been fully reconstituted into a native-like membrane environment, as confirmed by ultracentrifugation and subsequent SDS-PAGE experiments. PMID- 23626687 TI - Lithium inhibits tumorigenic potential of PDA cells through targeting hedgehog GLI signaling pathway. AB - Hedgehog signaling pathway plays a critical role in the initiation and development of pancreatic ductal adenocarcinoma (PDA) and represents an attractive target for PDA treatment. Lithium, a clinical mood stabilizer for mental disorders, potently inhibits the activity of glycogen synthase kinase 3beta (GSK3beta) that promotes the ubiquitin-dependent proteasome degradation of GLI1, an important downstream component of hedgehog signaling. Herein, we report that lithium inhibits cell proliferation, blocks G1/S cell-cycle progression, induces cell apoptosis and suppresses tumorigenic potential of PDA cells through down-regulation of the expression and activity of GLI1. Moreover, lithium synergistically enhances the anti-cancer effect of gemcitabine. These findings further our knowledge of mechanisms of action for lithium and provide a potentially new therapeutic strategy for PDA through targeting GLI1. PMID- 23626688 TI - Shedding light on the microbial community of the macropod foregut using 454 amplicon pyrosequencing. AB - Twenty macropods from five locations in Queensland, Australia, grazing on a variety of native pastures were surveyed and the bacterial community of the foregut was examined using 454-amplicon pyrosequencing. Specifically, the V3/V4 region of 16S rRNA gene was examined. A total of 5040 OTUs were identified in the data set (post filtering). Thirty-two OTUs were identified as 'shared' OTUS (i.e. present in all samples) belonging to either Firmicutes or Bacteroidetes (Clostridiales/Bacteroidales). These phyla predominated the general microbial community in all macropods. Genera represented within the shared OTUs included: unclassified Ruminococcaceae, unclassified Lachnospiraceae, unclassified Clostridiales, Peptococcus sp. Coprococcus spp., Streptococcus spp., Blautia sp., Ruminoccocus sp., Eubacterium sp., Dorea sp., Oscillospira sp. and Butyrivibrio sp. The composition of the bacterial community of the foregut samples of each the host species (Macropus rufus, Macropus giganteus and Macropus robustus) was significantly different allowing differentiation between the host species based on alpha and beta diversity measures. Specifically, eleven dominant OTUs that separated the three host species were identified and classified as: unclassified Ruminococcaceae, unclassified Bacteroidales, Prevotella spp. and a Syntrophococcus sucromutans. Putative reductive acetogens and fibrolytic bacteria were also identified in samples. Future work will investigate the presence and role of fibrolytics and acetogens in these ecosystems. Ideally, the isolation and characterization of these organisms will be used for enhanced feed efficiency in cattle, methane mitigation and potentially for other industries such as the biofuel industry. PMID- 23626689 TI - MTHFR Glu429Ala and ERCC5 His46His polymorphisms are associated with prognosis in colorectal cancer patients: analysis of two independent cohorts from Newfoundland. AB - INTRODUCTION: In this study, 27 genetic polymorphisms that were previously reported to be associated with clinical outcomes in colorectal cancer patients were investigated in relation to overall survival (OS) and disease free survival (DFS) in colorectal cancer patients from Newfoundland. METHODS: The discovery and validation cohorts comprised of 532 and 252 patients, respectively. Genotypes of 27 polymorphisms were first obtained in the discovery cohort and survival analyses were performed assuming the co-dominant genetic model. Polymorphisms associated with disease outcomes in the discovery cohort were then investigated in the validation cohort. RESULTS: When adjusted for sex, age, tumor stage and microsatellite instability (MSI) status, four polymorphisms were independent predictors of OS in the discovery cohort MTHFR Glu429Ala (HR: 1.72, 95%CI: 1.04 2.84, p = 0.036), ERCC5 His46His (HR: 1.78, 95%CI: 1.15-2.76, p = 0.01), SERPINE1 -675indelG (HR: 0.52, 95%CI: 0.32-0.84, p = 0.008), and the homozygous deletion of GSTM1 gene (HR: 1.4, 95%CI: 1.03-1.92, p = 0.033). In the validation cohort, the MTHFR Glu429Ala polymorphism was associated with shorter OS (HR: 1.71, 95%CI: 1.18-2.49, p = 0.005), although with a different genotype than the discovery cohort (CC genotype in the discovery cohort and AC genotype in the validation cohort). When stratified based on treatment with 5-Fluorouracil (5-FU)-based regimens, this polymorphism was associated with reduced OS only in patients not treated with 5-FU. In the DFS analysis, when adjusted for other variables, the TT genotype of the ERCC5 His46His polymorphism was associated with shorter DFS in both cohorts (discovery cohort: HR: 1.54, 95%CI: 1.04-2.29, p = 0.032 and replication cohort: HR: 1.81, 95%CI: 1.11-2.94, p = 0.018). CONCLUSIONS: In this study, associations of the MTHFR Glu429Ala polymorphism with OS and the ERCC5 His46His polymorphism with DFS were identified in two colorectal cancer patient cohorts. Our results also suggest that the MTHFR Glu429Ala polymorphism may be an adverse prognostic marker in patients not treated with 5-FU. PMID- 23626690 TI - A Chlamydomonas-derived Human Papillomavirus 16 E7 vaccine induces specific tumor protection. AB - BACKGROUND: The E7 protein of the Human Papillomavirus (HPV) type 16, being involved in malignant cellular transformation, represents a key antigen for developing therapeutic vaccines against HPV-related lesions and cancers. Recombinant production of this vaccine antigen in an active form and in compliance with good manufacturing practices (GMP) plays a crucial role for developing effective vaccines. E7-based therapeutic vaccines produced in plants have been shown to be active in tumor regression and protection in pre-clinical models. However, some drawbacks of in whole-plant vaccine production encouraged us to explore the production of the E7-based therapeutic vaccine in Chlamydomonas reinhardtii, an organism easy to grow and transform and fully amenable to GMP guidelines. METHODOLOGY/PRINCIPAL FINDINGS: An expression cassette encoding E7GGG, a mutated, attenuated form of the E7 oncoprotein, alone or as a fusion with affinity tags (His6 or FLAG), under the control of the C. reinhardtii chloroplast psbD 5' UTR and the psbA 3' UTR, was introduced into the C. reinhardtii chloroplast genome by homologous recombination. The protein was mostly soluble and reached 0.12% of total soluble proteins. Affinity purification was optimized and performed for both tagged forms. Induction of specific anti-E7 IgGs and E7-specific T-cell proliferation were detected in C57BL/6 mice vaccinated with total Chlamydomonas extract and with affinity-purified protein. High levels of tumor protection were achieved after challenge with a tumor cell line expressing the E7 protein. CONCLUSIONS: The C. reinhardtii chloroplast is a suitable expression system for the production of the E7GGG protein, in a soluble, immunogenic form. The production in contained and sterile conditions highlights the potential of microalgae as alternative platforms for the production of vaccines for human uses. PMID- 23626691 TI - Genes of the mitochondrial apoptotic pathway in Mytilus galloprovincialis. AB - Bivalves play vital roles in marine, brackish, freshwater and terrestrial habitats. In recent years, these ecosystems have become affected through anthropogenic activities. The ecological success of marine bivalves is based on the ability to modify their physiological functions in response to environmental changes. One of the most important mechanisms involved in adaptive responses to environmental and biological stresses is apoptosis, which has been scarcely studied in mollusks, although the final consequence of this process, DNA fragmentation, has been frequently used for pollution monitoring. Environmental stressors induce apoptosis in molluscan cells via an intrinsic pathway. Many of the proteins involved in vertebrate apoptosis have been recognized in model invertebrates; however, this process might not be universally conserved. Mytilus galloprovincialis is presented here as a new model to study the linkage between molecular mechanisms that mediate apoptosis and marine bivalve ecological adaptations. Therefore, it is strictly necessary to identify the key elements involved in bivalve apoptosis. In the present study, six mitochondrial apoptotic related genes were characterized, and their gene expression profiles following UV irradiation were evaluated. This is the first step for the development of potential biomarkers to assess the biological responses of marine organisms to stress. The results confirmed that apoptosis and, more specifically, the expression of the genes involved in this process can be used to assess the biological responses of marine organisms to stress. PMID- 23626692 TI - Divergent roles of amino acid residues inside and outside the BB loop affect human Toll-like receptor (TLR)2/2, TLR2/1 and TLR2/6 responsiveness. AB - TLR2 specifically recognizes a wide range of ligands by homodimerizing or heterodimerizing with TLR1 or TLR6. However, the molecular basis of the specific signalling transduction induced by TLR2 homodimerization or heterodimerization with TLR1 or TLR6 is largely unknown. In this study, we found three amino acid residues, two (663L and 688N) outside and one (681P) inside the BB loop, which were conserved in all of the TLRs, except for the TLR3 toll/IL-1R(TIR) domain. The responsiveness of human TLR2/2, TLR2/1 or TLR2/6 was completely lost when 663L and 688N were replaced with the corresponding amino acid residues in the TLR3 TIR domain, respectively. However, the response of TLR2 (P681A) to the high concentration of TLR2/TLR6 agonist was almost intact, but the activity of TLR2 (P681A) was greatly reduced when stimulated with the TLR2/1 agonist or the TLR2/2 agonist. Although the surface expression of TLR2 (L663E) was sharply reduced, both the intracellular distribution and the surface expression of all of the other TLR2 mutants were unchanged. The ability of all three TLR2 mutants to recruit MyD88, was consistent with their responsivenesses. Computer modelling indicated that the surface negative charge of all of the TLR2 mutants' BB loops was reduced. Thus, our data demonstrated that the 663L and 688N residues outside of the BB loop were essential for the responsiveness of TLR2/2, TLR2/1 and TLR2/6, but the 681P residue inside of the BB loop exhibited divergent roles in TLR2/2, TLR2/1 and TLR2/6 signalling transduction, thereby providing clues regarding the specific signalling transduction of TLR2/2, TLR2/1 and TLR2/6. PMID- 23626693 TI - Novel binding partners and differentially regulated phosphorylation sites clarify Eps8 as a multi-functional adaptor. AB - Eps8 is involved in both cell signalling and receptor trafficking. It is a known phosphorylation substrate for two proteins involved in the fibroblast growth factor receptor (FGFR) signalling pathway: the receptor itself and Src. Here we report a differential proteomic analysis of Eps8 aimed to identify specific FGFR and Src family kinase dependent phosphosites and co-associated phosphodependent binding partners. This study reveals a total of 22 Eps8 pTyr and pSer/Thr phosphorylation sites, including those that are dependent on Src family and FGFR kinase activity. Peptide affinity purification of proteins that bind to a selection of the pTyr phosphosites has identified a range of novel Eps8 binding partners including members of the intracellular vesicle trafficking machinery (clathrin and AP-2), proteins which have been shown to regulate activated receptor trafficking (NBR1 and Vav2), and proteins involved in receptor signalling (IRS4 and Shp2). Collectively this study significantly extends the understanding of Eps8 post-translational modification by regulated phosphorylation, identifies novel Eps8 binding partners implicated in receptor trafficking and signalling, and confirms the functions of Eps8 at the nexus of receptor signalling and vesicular trafficking. PMID- 23626694 TI - Intraplaque stretch in carotid atherosclerotic plaque--an effective biomechanical predictor for subsequent cerebrovascular ischemic events. AB - BACKGROUND: Stretch is a mechanical parameter, which has been proposed previously to affect the biological activities in different tissues. This study explored its utility in determining plaque vulnerability. METHODS: One hundred and six patients with mild to moderate carotid stenosis were recruited in this study (53 symptomatic and 53 asymptomatic). High resolution, multi-sequence magnetic resonance (MR) imaging was performed to delineate various plaque components. Finite element method was used to predict high stretch concentration within the plaque. RESULTS: During a two-year follow-up, 11 patients in symptomatic group and 3 in asymptomatic group experienced recurrent cerebrovascular events. Plaque stretch at systole and stretch variation during one cardiac cycle was greater in symptomatic group than those in the asymptomatic. Within the symptomatic group, a similar trend was observed in patients with recurrent events compared to those without. CONCLUSION: Plaques with high stretch concentration and large stretch variation are associated with increased risk of future cerebrovascular events. PMID- 23626695 TI - Comparative genomic analysis of the genus Nocardiopsis provides new insights into its genetic mechanisms of environmental adaptability. AB - The genus Nocardiopsis, a widespread group in phylum Actinobacteria, has received much attention owing to its ecological versatility, pathogenicity, and ability to produce a rich array of bioactive metabolites. Its high environmental adaptability might be attributable to its genome dynamics, which can be estimated through comparative genomic analysis targeting microorganisms with close phylogenetic relationships but different phenotypes. To shed light on speciation, gene content evolution, and environmental adaptation in these unique actinobacteria, we sequenced draft genomes for 16 representative species of the genus and compared them with that of the type species N. dassonvillei subsp. dassonvillei DSM 43111(T). The core genome of 1,993 orthologous and paralogous gene clusters was identified, and the pan-genomic reservoir was found not only to accommodate more than 22,000 genes, but also to be open. The top ten paralogous genes in terms of copy number could be referred to three functional categories: transcription regulators, transporters, and synthases related to bioactive metabolites. Based on phylogenomic reconstruction, we inferred past evolutionary events, such as gene gains and losses, and identified a list of clade-specific genes implicated in environmental adaptation. These results provided insights into the genetic causes of environmental adaptability in this cosmopolitan actinobacterial group and the contributions made by its inherent features, including genome dynamics and the constituents of core and accessory proteins. PMID- 23626696 TI - CNNcon: improved protein contact maps prediction using cascaded neural networks. AB - BACKGROUNDS: Despite continuing progress in X-ray crystallography and high-field NMR spectroscopy for determination of three-dimensional protein structures, the number of unsolved and newly discovered sequences grows much faster than that of determined structures. Protein modeling methods can possibly bridge this huge sequence-structure gap with the development of computational science. A grand challenging problem is to predict three-dimensional protein structure from its primary structure (residues sequence) alone. However, predicting residue contact maps is a crucial and promising intermediate step towards final three-dimensional structure prediction. Better predictions of local and non-local contacts between residues can transform protein sequence alignment to structure alignment, which can finally improve template based three-dimensional protein structure predictors greatly. METHODS: CNNcon, an improved multiple neural networks based contact map predictor using six sub-networks and one final cascade-network, was developed in this paper. Both the sub-networks and the final cascade-network were trained and tested with their corresponding data sets. While for testing, the target protein was first coded and then input to its corresponding sub-networks for prediction. After that, the intermediate results were input to the cascade-network to finish the final prediction. RESULTS: The CNNcon can accurately predict 58.86% in average of contacts at a distance cutoff of 8 A for proteins with lengths ranging from 51 to 450. The comparison results show that the present method performs better than the compared state-of-the-art predictors. Particularly, the prediction accuracy keeps steady with the increase of protein sequence length. It indicates that the CNNcon overcomes the thin density problem, with which other current predictors have trouble. This advantage makes the method valuable to the prediction of long length proteins. As a result, the effective prediction of long length proteins could be possible by the CNNcon. PMID- 23626697 TI - Multi-country evaluation of affective experience: validation of an abbreviated version of the day reconstruction method in seven countries. AB - BACKGROUND: The Day Reconstruction Method (DRM) was developed to assess affective states as measures of experienced well-being. The present study aimed to validate an abbreviated version of the DRM in a representative sample of the population in seven countries (China, Ghana, India, Mexico, Russia, South Africa, and Spain), and to examine whether there are country differences in affect and in the relationships among the activities based on the similarity of the affect associated with each of them. METHODS: Interviews were conducted with 47,222 non institutionalized adults from seven countries, using an abbreviated version of the DRM. A cluster analysis was carried out to classify activities on the basis of the similarity of the associated affect. In each country, the factorial structure of the affect adjectives was tested through Confirmatory Factor Analysis. Internal consistency and construct validity were also assessed. Moreover, the differences in affect across countries and the diurnal cycles of affect were evaluated. RESULTS: The DRM showed adequate psychometric properties regarding reliability and construct validity in all countries. Respondents from Ghana and South Africa reported more positive net affect whereas Indian respondents reported less positive net affect. Most of the countries showed a similar diurnal variation of affect, which tended to improve throughout the day. CONCLUSIONS: The results show that this abbreviated version of the DRM is a useful tool for multi-country evaluation of experienced well-being. PMID- 23626698 TI - Efficient and reproducible myogenic differentiation from human iPS cells: prospects for modeling Miyoshi Myopathy in vitro. AB - The establishment of human induced pluripotent stem cells (hiPSCs) has enabled the production of in vitro, patient-specific cell models of human disease. In vitro recreation of disease pathology from patient-derived hiPSCs depends on efficient differentiation protocols producing relevant adult cell types. However, myogenic differentiation of hiPSCs has faced obstacles, namely, low efficiency and/or poor reproducibility. Here, we report the rapid, efficient, and reproducible differentiation of hiPSCs into mature myocytes. We demonstrated that inducible expression of myogenic differentiation1 (MYOD1) in immature hiPSCs for at least 5 days drives cells along the myogenic lineage, with efficiencies reaching 70-90%. Myogenic differentiation driven by MYOD1 occurred even in immature, almost completely undifferentiated hiPSCs, without mesodermal transition. Myocytes induced in this manner reach maturity within 2 weeks of differentiation as assessed by marker gene expression and functional properties, including in vitro and in vivo cell fusion and twitching in response to electrical stimulation. Miyoshi Myopathy (MM) is a congenital distal myopathy caused by defective muscle membrane repair due to mutations in DYSFERLIN. Using our induced differentiation technique, we successfully recreated the pathological condition of MM in vitro, demonstrating defective membrane repair in hiPSC derived myotubes from an MM patient and phenotypic rescue by expression of full length DYSFERLIN (DYSF). These findings not only facilitate the pathological investigation of MM, but could potentially be applied in modeling of other human muscular diseases by using patient-derived hiPSCs. PMID- 23626699 TI - Surprisal analysis of transcripts expression levels in the presence of noise: a reliable determination of the onset of a tumor phenotype. AB - Towards a reliable identification of the onset in time of a cancer phenotype, changes in transcription levels in cell models were tested. Surprisal analysis, an information-theoretic approach grounded in thermodynamics, was used to characterize the expression level of mRNAs as time changed. Surprisal Analysis provides a very compact representation for the measured expression levels of many thousands of mRNAs in terms of very few - three, four - transcription patterns. The patterns, that are a collection of transcripts that respond together, can be assigned definite biological phenotypic role. We identify a transcription pattern that is a clear marker of eventual malignancy. The weight of each transcription pattern is determined by surprisal analysis. The weight of this pattern changes with time; it is never strictly zero but it is very low at early times and then rises rather suddenly. We suggest that the low weights at early time points are primarily due to experimental noise. We develop the necessary formalism to determine at what point in time the value of that pattern becomes reliable. Beyond the point in time when a pattern is deemed reliable the data shows that the pattern remain reliable. We suggest that this allows a determination of the presence of a cancer forewarning. We apply the same formalism to the weight of the transcription patterns that account for healthy cell pathways, such as apoptosis, that need to be switched off in cancer cells. We show that their weight eventually falls below the threshold. Lastly we discuss patient heterogeneity as an additional source of fluctuation and show how to incorporate it within the developed formalism. PMID- 23626700 TI - Two's a crowd: phenotypic adjustments and prophylaxis in Anticarsia gemmatalis larvae are triggered by the presence of conspecifics. AB - Defence from parasites and pathogens involves a cost. Thus, it is expected that organisms use this only at high population densities, where the risk of pathogen transmission may be high, as proposed by the "density-dependent prophylaxis" (DDP) hypothesis. These predictions have been tested in a wide range of insects, both in comparative and experimental studies. We think it pertinent to consider a continuum between solitarious and gregarious living insects, wherein: (1) solitarious insects are those that are constitutively solitary and do not express any phenotypic plasticity, (2) the middle of the continuum is represented by insects that are subject to fluctuations in local density and show a range of facultative and plastic changes; and (3) constitutively gregarious forms live gregariously and show the gregarious phenotype even in the absence of crowding stimuli. We aimed to chart some of the intermediary continuum with an insect that presents solitarious aspects, but that is subject to fluctuations in density. Thus, Anticarsia gemmatalis (Lepidoptera: Noctuidae) larvae reared at higher densities showed changes in coloration, a greater degree of encapsulation, had higher hemocyte densities and were more resistant to Baculovirus anticarsia, but not to Bacillus thuringiensis. Meanwhile, with increased rearing density there was reduced capsule melanization. Hemocyte density was the only variable that did not vary according to larval phenotype. The observed responses were not a continuous function of larval density, but an all-or-nothing response to the presence of a conspecific. As A. gemmatalis is not known for gregarious living, yet shows these density-dependent changes, it thus seems that this plastic phenotypic adjustment may be a broader phenomenon than previously thought. PMID- 23626701 TI - Novel fluorescein angiography-based computer-aided algorithm for assessment of retinal vessel permeability. AB - PURPOSE: To present a novel method for quantitative assessment of retinal vessel permeability using a fluorescein angiography-based computer algorithm. METHODS: Twenty-one subjects (13 with diabetic retinopathy, 8 healthy volunteers) underwent fluorescein angiography (FA). Image pre-processing included removal of non-retinal and noisy images and registration to achieve spatial and temporal pixel-based analysis. Permeability was assessed for each pixel by computing intensity kinetics normalized to arterial values. A linear curve was fitted and the slope value was assigned, color-coded and displayed. The initial FA studies and the computed permeability maps were interpreted in a masked and randomized manner by three experienced ophthalmologists for statistical validation of diagnosis accuracy and efficacy. RESULTS: Permeability maps were successfully generated for all subjects. For healthy volunteers permeability values showed a normal distribution with a comparable range between subjects. Based on the mean cumulative histogram for the healthy population a threshold (99.5%) for pathological permeability was determined. Clear differences were found between patients and healthy subjects in the number and spatial distribution of pixels with pathological vascular leakage. The computed maps improved the discrimination between patients and healthy subjects, achieved sensitivity and specificity of 0.974 and 0.833 respectively, and significantly improved the consensus among raters for the localization of pathological regions. CONCLUSION: The new algorithm allows quantification of retinal vessel permeability and provides objective, more sensitive and accurate evaluation than the present subjective clinical diagnosis. Future studies with a larger patients' cohort and different retinal pathologies are awaited to further validate this new approach and its role in diagnosis and treatment follow-up. Successful evaluation of vasculature permeability may be used for the early diagnosis of brain microvascular pathology and potentially predict associated neurological sequelae. Finally, the algorithm could be implemented for intraoperative evaluation of micovascular integrity in other organs or during animal experiments. PMID- 23626702 TI - Pre-treatment with amifostine protects against cyclophosphamide-induced disruption of taste in mice. AB - Cyclophosphamide (CYP), a commonly prescribed chemotherapy drug, has multiple adverse side effects including alteration of taste. The effects on taste are a cause of concern for patients as changes in taste are often associated with loss of appetite, malnutrition, poor recovery and reduced quality of life. Amifostine is a cytoprotective agent that was previously shown to be effective in preventing chemotherapy-induced mucositis and nephrotoxicity. Here we determined its ability to protect against chemotherapy-induced damage to taste buds using a mouse model of CYP injury. We conducted detection threshold tests to measure changes in sucrose taste sensitivity and found that administration of amifostine 30 mins prior to CYP injection protected against CYP-induced loss in taste sensitivity. Morphological studies showed that pre-treatment with amifostine prevented CYP induced reduction in the number of fungiform taste papillae and increased the number of taste buds. Immunohistochemical assays for markers of the cell cycle showed that amifostine administration prevented CYP-induced inhibition of cell proliferation and also protected against loss of mature taste cells after CYP exposure. Our results indicate that treatment of cancer patients with amifostine prior to chemotherapy may improve their sensitivity for taste stimuli and protect the taste system from the detrimental effects of chemotherapy. PMID- 23626703 TI - Novel alpha-MSH peptide analogues with broad spectrum antimicrobial activity. AB - Previous investigations indicate that alpha-melanocyte-stimulating hormone (alpha MSH) and certain synthetic analogues of it exert antimicrobial effects against bacteria and yeasts. However, these molecules have weak activity in standard microbiology conditions and this hampers a realistic clinical use. The aim in the present study was to identify novel peptides with broad-spectrum antimicrobial activity in growth medium. To this purpose, the Gly10 residue in the [DNal(2')-7, Phe-12]-MSH(6-13) sequence was replaced with conventional and unconventional amino acids with different degrees of conformational rigidity. Two derivatives in which Gly10 was replaced by the residues Aic and Cha, respectively, had substantial activity against Candida strains, including C. albicans, C. glabrata, and C. krusei and against gram-positive and gram-negative bacteria. Conformational analysis indicated that the helical structure along residues 8-13 is a key factor in antimicrobial activity. Synthetic analogues of alpha-MSH can be valuable agents to treat infections in humans. The structural preferences associated with antimicrobial activity identified in this research can help further development of synthetic melanocortins with enhanced biological activity. PMID- 23626704 TI - Ecological specialization to fluctuating resources prevents long-distance migratory raptors from becoming sedentary on islands. AB - BACKGROUND: The adaptive transition between behavioral strategies, such as the shift from migratoriness to sedentariness, remains an outstanding question in evolutionary ecology. Density-dependent variation in the age of first breeding has been proposed as a feasible mechanism through which long-lived migratory birds with deferred sexual maturity should become sedentary to persist on islands. Although this pattern seems to hold for most raptors and herons, a few exceptions have been identified. One of these exceptions is the Eleonora's falcon, a long-distance migratory bird, which shows one of the most peculiar adaptations in the timing of reproduction and food requirements among raptors. METHODOLOGY/PRINCIPAL FINDINGS: Here, we compiled data concerning demography, banding recoveries and satellite tracking of Eleonora's falcons to discuss likely explanations for the exceptional behavior of this insular long-distance migratory species. CONCLUSIONS/SIGNIFICANCE: New data reveal that Eleonora's falcons do return to the natal colonies in their first year and young birds are able to breed. However, in contrast to previous hypothesis, the highly specialized strategy of this and other ecologically similar species, as well as the virtual lack of food during winter at breeding areas prevent them from becoming sedentary on islands. Although the ultimate mechanisms underlying the process of sedentarization remain poorly understood, the evidence provided reveal the existence of important trade-offs associated with ecological specialization that may become particularly relevant in the present context of global change. PMID- 23626705 TI - The cytokine ciliary neurotrophic factor (CNTF) activates hypothalamic urocortin expressing neurons both in vitro and in vivo. AB - Ciliary neurotrophic factor (CNTF) induces neurogenesis, reduces feeding, and induces weight loss. However, the central mechanisms by which CNTF acts are vague. We employed the mHypoE-20/2 line that endogenously expresses the CNTF receptor to examine the direct effects of CNTF on mRNA levels of urocortin-1, urocortin-2, agouti-related peptide, brain-derived neurotrophic factor, and neurotensin. We found that treatment of 10 ng/ml CNTF significantly increased only urocortin-1 mRNA by 1.84-fold at 48 h. We then performed intracerebroventricular injections of 0.5 mg/mL CNTF into mice, and examined its effects on urocortin-1 neurons post-exposure. Through double-label immunohistochemistry using specific antibodies against c-Fos and urocortin-1, we showed that central CNTF administration significantly activated urocortin-1 neurons in specific areas of the hypothalamus. Taken together, our studies point to a potential role for CNTF in regulating hypothalamic urocortin-1-expressing neurons to mediate its recognized effects on energy homeostasis, neuronal proliferaton/survival, and/or neurogenesis. PMID- 23626706 TI - Boosted beta regression. AB - Regression analysis with a bounded outcome is a common problem in applied statistics. Typical examples include regression models for percentage outcomes and the analysis of ratings that are measured on a bounded scale. In this paper, we consider beta regression, which is a generalization of logit models to situations where the response is continuous on the interval (0,1). Consequently, beta regression is a convenient tool for analyzing percentage responses. The classical approach to fit a beta regression model is to use maximum likelihood estimation with subsequent AIC-based variable selection. As an alternative to this established - yet unstable - approach, we propose a new estimation technique called boosted beta regression. With boosted beta regression estimation and variable selection can be carried out simultaneously in a highly efficient way. Additionally, both the mean and the variance of a percentage response can be modeled using flexible nonlinear covariate effects. As a consequence, the new method accounts for common problems such as overdispersion and non-binomial variance structures. PMID- 23626707 TI - Peripherally administered nanoparticles target monocytic myeloid cells, secondary lymphoid organs and tumors in mice. AB - Nanoparticles have been extensively developed for therapeutic and diagnostic applications. While the focus of nanoparticle trafficking in vivo has traditionally been on drug delivery and organ-level biodistribution and clearance, recent work in cancer biology and infectious disease suggests that targeting different cells within a given organ can substantially affect the quality of the immunological response. Here, we examine the cell-level biodistribution kinetics after administering ultrasmall Pluronic-stabilized poly(propylene sulfide) nanoparticles in the mouse. These nanoparticles depend on lymphatic drainage to reach the lymph nodes and blood, and then enter the spleen rather than the liver, where they interact with monocytes, macrophages and myeloid dendritic cells. They were more readily taken up into lymphatics after intradermal (i.d.) compared to intramuscular administration, leading to ~50% increased bioavailability in blood. When administered i.d., their distribution favored antigen-presenting cells, with especially strong targeting to myeloid cells. In tumor-bearing mice, the monocytic and the polymorphonuclear myeloid derived suppressor cell compartments were efficiently and preferentially targeted, rendering this nanoparticulate formulation potentially useful for reversing the highly suppressive activity of these cells in the tumor stroma. PMID- 23626708 TI - Identification of metabolic engineering targets through analysis of optimal and sub-optimal routes. AB - Identification of optimal genetic manipulation strategies for redirecting substrate uptake towards a desired product is a challenging task owing to the complexity of metabolic networks, esp. in terms of large number of routes leading to the desired product. Algorithms that can exploit the whole range of optimal and suboptimal routes for product formation while respecting the biological objective of the cell are therefore much needed. Towards addressing this need, we here introduce the notion of structural flux, which is derived from the enumeration of all pathways in the metabolic network in question and accounts for the contribution towards a given biological objective function. We show that the theoretically estimated structural fluxes are good predictors of experimentally measured intra-cellular fluxes in two model organisms, namely, Escherichia coli and Saccharomyces cerevisiae. For a small number of fluxes for which the predictions were poor, the corresponding enzyme-coding transcripts were also found to be distinctly regulated, showing the ability of structural fluxes in capturing the underlying regulatory principles. Exploiting the observed correspondence between in vivo fluxes and structural fluxes, we propose an in silico metabolic engineering approach, iStruF, which enables the identification of gene deletion strategies that couple the cellular biological objective with the product flux while considering optimal as well as sub-optimal routes and their efficiency. PMID- 23626709 TI - Regulation of neurite growth by inorganic pyrophosphatase 1 via JNK dephosphorylation. AB - Neural cell differentiation during development is controlled by multiple signaling pathways, in which protein phosphorylation and dephosphorylation play an important role. In this study, we examined the role of pyrophosphatase1 (PPA1) in neuronal differentiation using the loss and gain of function analysis. Neuronal differentiation induced by external factors was studied using a mouse neuroblastoma cell line (N1E115). The neuronal like differentiation in N1E115 cells was determined by morphological analysis based on neurite growth length. In order to analyze the loss of the PPA1 function in N1E115, si-RNA specifically targeting PPA1 was generated. To study the effect of PPA1 overexpression, an adenoviral gene vector containing the PPA1 gene was utilized to infect N1E115 cells. To address the need for pyrophosphatase activity in PPA1, D117A PPA1, which has inactive pyrophosphatase, was overexpressed in N1E115 cells. We used valproic acid (VPA) as a neuronal differentiator to examine the effect of PPA1 in actively differentiated N1E115 cells. Si-PPA1 treatment reduced the PPA1 protein level and led to enhanced neurite growth in N1E115 cells. In contrast, PPA1 overexpression suppressed neurite growth in N1E115 cells treated with VPA, whereas this effect was abolished in D117A PPA1. PPA1 knockdown enhanced the JNK phosphorylation level, and PPA1 overexpression suppressed it in N1E115 cells. It seems that recombinant PPA1 can dephosphorylate JNK while no alteration of JNK phosphorylation level was seen after treatment with recombinant PPA1 D117A. Enhanced neurite growth by PPA1 knockdown was also observed in rat cortical neurons. Thus, PPA1 may play a role in neuronal differentiation via JNK dephosphorylation. PMID- 23626710 TI - Suppressing multi-channel ultra-low-field MRI measurement noise using data consistency and image sparsity. AB - Ultra-low-field (ULF) MRI (B 0 = 10-100 uT) typically suffers from a low signal to-noise ratio (SNR). While SNR can be improved by pre-polarization and signal detection using highly sensitive superconducting quantum interference device (SQUID) sensors, we propose to use the inter-dependency of the k-space data from highly parallel detection with up to tens of sensors readily available in the ULF MRI in order to suppress the noise. Furthermore, the prior information that an image can be sparsely represented can be integrated with this data consistency constraint to further improve the SNR. Simulations and experimental data using 47 SQUID sensors demonstrate the effectiveness of this data consistency constraint and sparsity prior in ULF-MRI reconstruction. PMID- 23626711 TI - Global and ocular hypothermic preconditioning protect the rat retina from ischemic damage. AB - Retinal ischemia could provoke blindness. At present, there is no effective treatment against retinal ischemic damage. Strong evidence supports that glutamate is implicated in retinal ischemic damage. We investigated whether a brief period of global or ocular hypothermia applied 24 h before ischemia (i.e. hypothermic preconditioning, HPC) protects the retina from ischemia/reperfusion damage, and the involvement of glutamate in the retinal protection induced by HPC. For this purpose, ischemia was induced by increasing intraocular pressure to 120 mm Hg for 40 min. One day before ischemia, animals were submitted to global or ocular hypothermia (33 degrees C and 32 degrees C for 20 min, respectively) and fourteen days after ischemia, animals were subjected to electroretinography and histological analysis. Global or ocular HPC afforded significant functional (electroretinographic) protection in eyes exposed to ischemia/reperfusion injury. A marked alteration of the retinal structure and a decrease in retinal ganglion cell number were observed in ischemic retinas, whereas global or ocular HPC significantly preserved retinal structure and ganglion cell count. Three days after ischemia, a significant decrease in retinal glutamate uptake and glutamine synthetase activity was observed, whereas ocular HPC prevented the effect of ischemia on these parameters. The intravitreal injection of supraphysiological levels of glutamate induced alterations in retinal function and histology which were significantly prevented by ocular HPC. These results support that global or ocular HPC significantly protected retinal function and histology from ischemia/reperfusion injury, probably through a glutamate-dependent mechanism. PMID- 23626712 TI - Alcohol use and subsequent sex among HIV-infected patients in an ethnic minority area of Yunnan Province, China. AB - OBJECTIVE: To examine alcohol use and subsequent HIV risky behaviors among a sample of predominately ethnic minority people living with HIV/AIDS (PLWHA) in a rural community in Yunnan Province, China. METHOD: A cross-sectional study with a face-to-face questionnaire interview was conducted among eligible participants. RESULTS: In total, 455 (94.4%) out of 482 eligible HIV patients participated in the study. Of them, 82.6% were ethnic minorities; 15.4% were never married; 96.5% were sexually experienced; 55.4% had used drugs, 67% were receiving antiretroviral therapy (ART). Over 65% were ever drinkers; of whom 61.5% were current drinkers. Among current drinkers, 32.4% drank daily and 41.2% were hazardous drinkers. Chinese white wine was the preferred choice. Higher level of alcohol use among drinkers in the preceding month was positively associated with being males (OR = 2.76, 95%CI: 1.03-7.43), ethnic minorities (OR Jingpo = 2.21, 95%CI: 1.06-4.59; OR other minorities = 3.20, 95%CI: 1.34-7.62), higher education (OR1-6 = 1.98, 95%CI: 0.99-3.96; OR>=7 = 2.35, 95%CI: 1.09-5.06) and being ART naive (OR = 2.69, 95%CI: 1.67-4.32). About 39% of ever drinkers reported having engaged in sex after drinking since HIV diagnosis. Those who were younger than 46 years (OR16-25 = 7.77, 95%CI: 1.22-49.60, OR26-35 = 2.79, 95%CI: 1.06-7.35, OR36 45 = 2.96, 95%CI: 1.57-7.58), hazardous drinkers (OR = 1.99, 95%CI: 1.00-3.97) and drug users (OR = 3.01, 95%CI: 1.19-7.58) were more likely to have had sex after drinking. Approximately 56% of drug users had used drugs after drinking. CONCLUSIONS: High prevalence of alcohol use and subsequent risky behaviors including sexual engagement and drug use among HIV patients in rural Yunnan require tremendous and integrated efforts for prevention and control of alcohol and drug abuse and HIV spreading. PMID- 23626714 TI - Characterization and localization of insoluble organic matrices associated with diatom cell walls: insight into their roles during cell wall formation. AB - Organic components associated with diatom cell wall silica are important for the formation, integrity, and function of the cell wall. Polysaccharides are associated with the silica, however their localization, structure, and function remain poorly understood. We used imaging and biochemical approaches to describe in detail characteristics of insoluble organic components associated with the cell wall in 5 different diatom species. Results show that an insoluble organic matrix enriched in mannose, likely the diatotepum, is localized on the proximal surface of the silica cell wall. We did not identify any organic matrix embedded within the silica. We also identified a distinct material consisting of glucose polymer with variable localization depending on the species. In some species this component was directly involved in the morphogenesis of silica structure while in others it appeared to be only a structural component of the cell wall. A novel glucose-rich structure located between daughter cells during division was also identified. This work for the first time correlates the structure, composition, and localization of insoluble organic matrices associated with diatom cell walls. Additionally we identified a novel glucose polymer and characterized its role during silica structure formation. PMID- 23626713 TI - The motor protein KIF14 inhibits tumor growth and cancer metastasis in lung adenocarcinoma. AB - The motor protein kinesin superfamily proteins (KIFs) are involved in cancer progression. The depletion of one of the KIFs, KIF14, might delay the metaphase to-anaphase transition, resulting in a binucleated status, which enhances tumor progression; however, the exact correlation between KIF14 and cancer progression remains ambiguous. In this study, using loss of heterozygosity and array comparative genomic hybridization analyses, we observed a 30% loss in the regions surrounding KIF14 on chromosome 1q in lung adenocarcinomas. In addition, the protein expression levels of KIF14 in 122 lung adenocarcinomas also indicated that approximately 30% of adenocarcinomas showed KIF14 down-regulation compared with the expression in the bronchial epithelial cells of adjacent normal counterparts. In addition, the reduced expression of KIF14 mRNA or proteins was correlated with poor overall survival (P = 0.0158 and <0.0001, respectively), and the protein levels were also inversely correlated with metastasis (P<0.0001). The overexpression of KIF14 in lung adenocarcinoma cells inhibited anchorage independent growth in vitro and xenograft tumor growth in vivo. The overexpression and silencing of KIF14 also inhibited or enhanced cancer cell migration, invasion and adhesion to the extracellular matrix proteins laminin and collagen IV. Furthermore, we detected the adhesion molecules cadherin 11 (CDH11) and melanoma cell adhesion molecule (MCAM) as cargo on KIF14. The overexpression and silencing of KIF14 enhanced or reduced the recruitment of CDH11 in the membrane fraction, suggesting that KIF14 might act through recruiting adhesion molecules to the cell membrane and modulating cell adhesive, migratory and invasive properties. Thus, KIF14 might inhibit tumor growth and cancer metastasis in lung adenocarcinomas. PMID- 23626715 TI - Cryptochrome 1 overexpression correlates with tumor progression and poor prognosis in patients with colorectal cancer. AB - BACKGROUND: Clock genes drive about 5-15% of genome-wide mRNA expression, and disruption of the circadian clock may deregulate the cell's normal biological functions. Cryptochrome 1 is a key regulator of the circadian feedback loop and plays an important role in organisms. The present study was conducted to investigate the expression of Cry1 and its prognostic significance in colorectal cancer (CRC). In addition, the function of Cry1 in human CRC was investigated in cell culture models. METHODS: Real-time quantitative PCR, Western blot analysis and immunohistochemistry were used to explore Cry1 expression in CRC cell lines and primary CRC clinical specimens. MTT and colony formation assays were used to determine effects on cellular proliferation ability. The animal model was used to explore the Cry1 impact on the tumor cellular proliferation ability in vivo. Transwell assays were performed to detect the migration ability of the cell lines. Statistical analyzes were applied to evaluate the diagnostic value and the associations of Cry1 expression with clinical parameters. RESULTS: Cry1 expression was up regulated in the majority of the CRC cell lines and 168 primary CRC clinical specimens at the protein level. Clinical pathological analysis showed that Cry1 expression was significantly correlated with lymph node metastasis (p = 0.004) and the TNM stage (p = 0.003). High Cry1 expression was associated with poor overall survival in CRC patients (p = 0.010). Experimentally, we found that up-regulation of Cry1 promoted the proliferation and migration of HCT116 cells, while down-regulation of Cry1 inhibited the colony formation and migration of SW480 cells. CONCLUSIONS: These results suggest that Cry1 likely plays important roles in CRC development and progression andCry1 may be a prognostic biomarker and a promising therapeutic target for CRC. PMID- 23626716 TI - Role of tachykinin 1 and 4 gene-derived neuropeptides and the neurokinin 1 receptor in adjuvant-induced chronic arthritis of the mouse. AB - OBJECTIVE: Substance P, encoded by the Tac1 gene, is involved in neurogenic inflammation and hyperalgesia via neurokinin 1 (NK1) receptor activation. Its non neuronal counterpart, hemokinin-1, which is derived from the Tac4 gene, is also a potent NK1 agonist. Although hemokinin-1 has been described as a tachykinin of distinct origin and function compared to SP, its role in inflammatory and pain processes has not yet been elucidated in such detail. In this study, we analysed the involvement of tachykinins derived from the Tac1 and Tac4 genes, as well as the NK1 receptor in chronic arthritis of the mouse. METHODS: Complete Freund's Adjuvant was injected intraplantarly and into the tail of Tac1(-/-), Tac4(-/-), Tacr1(-/-) (NK1 receptor deficient) and Tac1(-/-/)Tac4(-/-) mice. Paw volume was measured by plethysmometry and mechanosensitivity using dynamic plantar aesthesiometry over a time period of 21 days. Semiquantitative histopathological scoring and ELISA measurement of IL-1beta concentrations of the tibiotarsal joints were performed. RESULTS: Mechanical hyperalgesia was significantly reduced from day 11 in Tac4(-/-) and Tacr1(-/-) animals, while paw swelling was not altered in any strain. Inflammatory histopathological alterations (synovial swelling, leukocyte infiltration, cartilage destruction, bone damage) and IL 1beta concentration in the joint homogenates were significantly smaller in Tac4( /-) and Tac1(-/-/)Tac4(-/-) mice. CONCLUSIONS: Hemokinin-1, but not substance P increases inflammation and hyperalgesia in the late phase of adjuvant-induced arthritis. While NK1 receptors mediate its antihyperalgesic actions, the involvement of another receptor in histopathological changes and IL-1beta production is suggested. PMID- 23626717 TI - In vitro effects of a small-molecule antagonist of the Tcf/beta-catenin complex on endometrial and endometriotic cells of patients with endometriosis. AB - BACKGROUND: Our previous studies suggested that aberrant activation of Wnt/beta catenin signaling might be involved in the pathophysiology of endometriosis. We hypothesized that inhibition of Wnt/beta-catenin signaling might result in inhibition of cell proliferation, migration, and/or invasion of endometrial and endometriotic epithelial and stromal cells of patients with endometriosis. OBJECTIVES: The aim of the present study was to evaluate the effects of a small molecule antagonist of the Tcf/beta-catenin complex (PKF 115-584) on cell proliferation, migration, and invasion of endometrial and endometriotic epithelial and stromal cells. METHODS: One hundred twenty-six patients (78 with and 48 without endometriosis) with normal menstrual cycles were recruited. In vitro effects of PKF 115-584 on cell proliferation, migration, and invasion and on the Tcf/beta-catenin target genes were evaluated in endometrial epithelial and stromal cells of patients with and without endometriosis, and in endometrial and endometriotic epithelial and stromal cells of the same patients. RESULTS: The inhibitory effects of PKF 115-584 on cell migration and invasion in endometrial epithelial and stromal cells of patients with endometriosis prepared from the menstrual phase were significantly higher than those of patients without endometriosis. Levels of total and active forms of MMP-9 were significantly higher in epithelial and stromal cells prepared from menstrual endometrium in patients with endometriosis compared to patients without endometriosis. Treatment with PKF 115-584 inhibited MMP-9 activity to undetectable levels in both menstrual endometrial epithelial and stromal cells of patients with endometriosis. The number of invasive cells was significantly higher in epithelial and stromal cells of endometriotic tissue compared with matched eutopic endometrium of the same patients. Treatment with PKF 115-584 decreased the number of invasive endometriotic epithelial cells by 73% and stromal cells by 75%. CONCLUSIONS: The present findings demonstrated that cellular mechanisms known to be involved in endometriotic lesion development are inhibited by targeting the Wnt/beta-catenin pathway. PMID- 23626718 TI - Separating movement and gravity components in an acceleration signal and implications for the assessment of human daily physical activity. AB - INTRODUCTION: Human body acceleration is often used as an indicator of daily physical activity in epidemiological research. Raw acceleration signals contain three basic components: movement, gravity, and noise. Separation of these becomes increasingly difficult during rotational movements. We aimed to evaluate five different methods (metrics) of processing acceleration signals on their ability to remove the gravitational component of acceleration during standardised mechanical movements and the implications for human daily physical activity assessment. METHODS: An industrial robot rotated accelerometers in the vertical plane. Radius, frequency, and angular range of motion were systematically varied. Three metrics (Euclidian norm minus one [ENMO], Euclidian norm of the high-pass filtered signals [HFEN], and HFEN plus Euclidean norm of low-pass filtered signals minus 1 g [HFEN+]) were derived for each experimental condition and compared against the reference acceleration (forward kinematics) of the robot arm. We then compared metrics derived from human acceleration signals from the wrist and hip in 97 adults (22-65 yr), and wrist in 63 women (20-35 yr) in whom daily activity-related energy expenditure (PAEE) was available. RESULTS: In the robot experiment, HFEN+ had lowest error during (vertical plane) rotations at an oscillating frequency higher than the filter cut-off frequency while for lower frequencies ENMO performed better. In the human experiments, metrics HFEN and ENMO on hip were most discrepant (within- and between-individual explained variance of 0.90 and 0.46, respectively). ENMO, HFEN and HFEN+ explained 34%, 30% and 36% of the variance in daily PAEE, respectively, compared to 26% for a metric which did not attempt to remove the gravitational component (metric EN). CONCLUSION: In conclusion, none of the metrics as evaluated systematically outperformed all other metrics across a wide range of standardised kinematic conditions. However, choice of metric explains different degrees of variance in daily human physical activity. PMID- 23626719 TI - Mapping of MN1 sequences necessary for myeloid transformation. AB - The MN1 oncogene is deregulated in human acute myeloid leukemia and its overexpression induces proliferation and represses myeloid differentiation of primitive human and mouse hematopoietic cells, leading to myeloid leukemia in mouse models. To delineate the sequences within MN1 necessary for MN1-induced leukemia, we tested the transforming capacity of in-frame deletion mutants, using retroviral transduction of mouse bone marrow. We found that integrity of the regions between amino acids 12 to 458 and 1119 to 1273 are required for MN1's in vivo transforming activity, generating myeloid leukemia with some mutants also producing T-cell lympho-leukemia and megakaryocytic leukemia. Although both full length MN1 and a mutant that lacks the residues between 12-228 (Delta12-228 mutant) repressed myeloid differentiation and increased myeloproliferative activity in vitro, the mutant lost its transforming activity in vivo. Both MN1 and Delta12-228 increased the frequency of common myeloid progentiors (CMP) in vitro and microarray comparisons of purified MN1-CMP and Delta12-228-CMP cells showed many differentially expressed genes including Hoxa9, Meis1, Myb, Runx2, Cebpa, Cebpb and Cebpd. This collection of immediate MN1-responsive candidate genes distinguishes the leukemic activity from the in vitro myeloproliferative capacity of this oncoprotein. PMID- 23626721 TI - A flattest constrained envelope approach for empirical mode decomposition. AB - Empirical mode decomposition (EMD) is an adaptive method for nonlinear, non stationary signal analysis. However, the upper and lower envelopes fitted by cubic spline interpolation (CSI) may often occur overshoots. In this paper, a new envelope fitting method based on the flattest constrained interpolation is proposed. The proposed method effectively integrates the difference between extremes into the cost function, and applies a chaos particle swarm optimization method to optimize the derivatives of the interpolation nodes. The proposed method was tested on three different types of data: ascertain signal, random signals and real electrocardiogram signals. The experimental results show that: (1) The proposed flattest envelope effectively solves the overshoots caused by CSI method and the artificial bends caused by piecewise parabola interpolation (PPI) method. (2) The index of orthogonality of the intrinsic mode functions (IMFs) based on the proposed method is 0.04054, 0.02222 +/- 0.01468 and 0.04013 +/- 0.03953 for the ascertain signal, random signals and electrocardiogram signals, respectively, which is lower than the CSI method and the PPI method, and means the IMFs are more orthogonal. (3) The index of energy conversation of the IMFs based on the proposed method is 0.96193, 0.93501 +/- 0.03290 and 0.93041 +/- 0.00429 for the ascertain signal, random signals and electrocardiogram signals, respectively, which is closer to 1 than the other two methods and indicates the total energy deviation amongst the components is smaller. (4) The comparisons of the Hilbert spectrums show that the proposed method overcomes the mode mixing problems very well, and make the instantaneous frequency more physically meaningful. PMID- 23626720 TI - Characterization of peanut germin-like proteins, AhGLPs in plant development and defense. AB - BACKGROUND: Germin-like superfamily members are ubiquitously expressed in various plant species and play important roles in plant development and defense. Although several GLPs have been identified in peanut (Arachis hypogaea L.), their roles in development and defense remain unknown. In this research, we study the spatiotemporal expression of AhGLPs in peanut and their functions in plant defense. RESULTS: We have identified three new AhGLP members (AhGLP3b, AhGLP5b and AhGLP7b) that have distinct but very closely related DNA sequences. The spatial and temporal expression profiles revealed that each peanut GLP gene has its distinct expression pattern in various tissues and developmental stages. This suggests that these genes all have their distinct roles in peanut development. Subcellular location analysis demonstrated that AhGLP2 and 5 undergo a protein transport process after synthesis. The expression of all AhGLPs increased in responding to Aspergillus flavus infection, suggesting AhGLPs' ubiquitous roles in defense to A. flavus. Each AhGLP gene had its unique response to various abiotic stresses (including salt, H2O2 stress and wound), biotic stresses (including leaf spot, mosaic and rust) and plant hormone stimulations (including SA and ABA treatments). These results indicate that AhGLPs have their distinct roles in plant defense. Moreover, in vivo study of AhGLP transgenic Arabidopsis showed that both AhGLP2 and 3 had salt tolerance, which made transgenic Arabidopsis grow well under 100 mM NaCl stress. CONCLUSIONS: For the first time, our study analyzes the AhGLP gene expression profiles in peanut and reveals their roles under various stresses. These results provide an insight into the developmental and defensive roles of GLP gene family in peanut. PMID- 23626722 TI - Inbuilt potential of YEM medium and its constituents to generate Ag/Ag2O nanoparticles. AB - We discovered that Yeast Extract Mannitol (YEM) medium possessed immense potential to generate silver nanoparticles from AgNO3 upon autoclaving, which was evident from (i) alteration in color of the medium; (ii) peak at ~410 nm in UV Vis spectrum due to surface plasmon resonance specific to silver nanoparticles; and (iii) TEM investigations. TEM coupled with EDX confirmed that distinct nanoparticles were composed of silver. Yeast extract and mannitol were key components of YEM medium responsible for the formation of nanoparticles. PXRD analysis indicated crystalline geometry and Ag/Ag2O phases in nanoparticles generated with YEM medium, yeast extract and mannitol. Our investigations also revealed that both mannitol and yeast extract possessed potential to convert ~80% of silver ions in 0.5 mM AgNO3 to nanoparticles, on autoclaving for 30 min at 121 degrees C under a pressure of 1.06 kg/cm(2). Addition of filter sterilized AgNO3 under ambient conditions to pre-autoclaved YEM medium and yeast extract brought about color change due to the formation of silver nanoparticles, but required prolonged duration. In general, even after 72 h intensity of color was significantly less than that recorded following autoclaving. Silver nanoparticles formed at room temperature were more heterogeneous compared to that obtained upon autoclaving. In summary, our findings demonstrated that (i) YEM medium and its constituents promote synthesis of silver nanoparticles; and (ii) autoclaving enhances rapid synthesis of silver nanoparticles by YEM medium, yeast extract and mannitol. PMID- 23626723 TI - An alkylphenol mix promotes seminoma derived cell proliferation through an ERalpha36-mediated mechanism. AB - Long chain alkylphenols are man-made compounds still present in industrial and agricultural processes. Their main use is domestic and they are widespread in household products, cleansers and cosmetics, leading to a global environmental and human contamination. These molecules are known to exert estrogen-like activities through binding to classical estrogen receptors. In vitro, they can also interact with the G-protein coupled estrogen receptor. Testicular germ cell tumor etiology and progression are proposed to be stimulated by lifelong estrogeno-mimetic exposure. We studied the transduction signaling pathways through which an alkyphenol mixture triggers testicular cancer cell proliferation in vitro and in vivo. Proliferation assays were monitored after exposure to a realistic mixture of 4-tert-octylphenol and 4-nonylphenol of either TCam-2 seminoma derived cells, NT2/D1 embryonal carcinoma cells or testis tumor in xenografted nude mice. Specific pharmacological inhibitors and gene-silencing strategies were used in TCam-2 cells in order to demonstrate that the alkylphenol mix triggers CREB-phosphorylation through a rapid, ERalpha36-PI3kinase non genomic pathway. Microarray analysis of the mixture target genes revealed that this pathway can modulate the expression of the DNA-methyltransferase-3 (Dnmt3) gene family which is involved in DNA methylation control. Our results highlight a key role for ERalpha36 in alkylphenol non genomic signaling in testicular germ cell tumors. Hence, ERalpha36-dependent control of the epigenetic status opens the way for the understanding of the link between endocrine disruptor exposure and the burden of hormone sensitive cancers. PMID- 23626724 TI - The calmodulin-binding, short linear motif, NSCaTE is conserved in L-type channel ancestors of vertebrate Cav1.2 and Cav1.3 channels. AB - NSCaTE is a short linear motif of (xWxxx(I or L)xxxx), composed of residues with a high helix-forming propensity within a mostly disordered N-terminus that is conserved in L-type calcium channels from protostome invertebrates to humans. NSCaTE is an optional, lower affinity and calcium-sensitive binding site for calmodulin (CaM) which competes for CaM binding with a more ancient, C-terminal IQ domain on L-type channels. CaM bound to N- and C- terminal tails serve as dual detectors to changing intracellular Ca(2+) concentrations, promoting calcium dependent inactivation of L-type calcium channels. NSCaTE is absent in some arthropod species, and is also lacking in vertebrate L-type isoforms, Cav1.1 and Cav1.4 channels. The pervasiveness of a methionine just downstream from NSCaTE suggests that L-type channels could generate alternative N-termini lacking NSCaTE through the choice of translational start sites. Long N-terminus with an NSCaTE motif in L-type calcium channel homolog LCav1 from pond snail Lymnaea stagnalis has a faster calcium-dependent inactivation than a shortened N-termini lacking NSCaTE. NSCaTE effects are present in low concentrations of internal buffer (0.5 mM EGTA), but disappears in high buffer conditions (10 mM EGTA). Snail and mammalian NSCaTE have an alpha-helical propensity upon binding Ca(2+)-CaM and can saturate both CaM N-terminal and C-terminal domains in the absence of a competing IQ motif. NSCaTE evolved in ancestors of the first animals with internal organs for promoting a more rapid, calcium-sensitive inactivation of L-type channels. PMID- 23626725 TI - Filter characteristics influencing circulating tumor cell enrichment from whole blood. AB - A variety of filters assays have been described to enrich circulating tumor cells (CTC) based on differences in physical characteristics of blood cells and CTC. In this study we evaluate different filter types to derive the properties of the ideal filter for CTC enrichment. Between 0.1 and 10 mL of whole blood spiked with cells from tumor cell lines were passed through silicon nitride microsieves, polymer track-etched filters and metal TEM grids with various pore sizes. The recovery and size of 9 different culture cell lines was determined and compared to the size of EpCAM+CK+CD45-DNA+ CTC from patients with metastatic breast, colorectal and prostate cancer. The 8 um track-etched filter and the 5 um microsieve had the best performance on MDA-231, PC3-9 and SKBR-3 cells, enriching >80% of cells from whole blood. TEM grids had poor recovery of ~25%. Median diameter of cell lines ranged from 10.9-19.0 um, compared to 13.1, 10.7, and 11.0 um for breast, prostate and colorectal CTC, respectively. The 11.4 um COLO-320 cell line had the lowest recovery of 17%. The ideal filter for CTC enrichment is constructed of a stiff, flat material, is inert to blood cells, has at least 100,000 regularly spaced 5 um pores for 1 ml of blood with a <=10% porosity. While cell size is an important factor in determining recovery, other factors must be involved as well. To evaluate a filtration procedure, cell lines with a median size of 11-13 um should be used to challenge the system. PMID- 23626726 TI - Population-based 5-year follow-up study in Taiwan of dementia and risk of stroke. AB - BACKGROUND: This study estimates the risk of stroke within 5 years of newly diagnosed dementia among elderly persons aged 65 and above. We examined the relationship between antipsychotic usage and development of stroke in patients with dementia. METHODS: We conducted a nationwide 5-year population-based study using data retrieved from the Longitudinal Health Insurance Database 2005 (LHID2005) in Taiwan. The study cohort comprised 2243 patients with dementia aged >=65 years who had at least one inpatient service claim or at least 2 ambulatory care claims, whereas the comparison cohort consisted of 6714 randomly selected subjects (3 for every dementia patient) and were matched with the study group according to sex, age, and index year. We further classified dementia patients into 2 groups based on their history of antipsychotic usage. A total of 1450 patients were classified into the antipsychotic usage group and the remaining 793 patients were classified into the non-antipsychotic usage group. Cox proportional hazards regressions were performed to compute the 5-year stroke-free survival rates after adjusting for potentially confounding factors. RESULTS: The dementia patients have a 2-fold greater risk of developing stroke within 5 years of diagnosis compared to non-dementia age- and sex-matched subjects, after adjusting for other risk factors (95% confidence interval (CI) = 2.58-3.08; P<.001). Antipsychotic usage among patients with dementia increases risk of stroke 1.17 fold compared to patients without antipsychotic treatment (95% CI = 1.01-1.40; P<.05). CONCLUSIONS: Dementia may be an independent risk factor for stroke, and the use of antipsychotics may further increase the risk of stroke in dementia patients. PMID- 23626727 TI - Ecological stoichiometry and density responses of plant-arthropod communities on cormorant nesting islands. AB - Seabirds deposit large amounts of nutrient rich guano on their nesting islands. The increased nutrient availability strongly affects plants and consumers. Consumer response differs among taxonomic groups, but mechanisms causing these differences are poorly understood. Ecological stoichiometry might provide tools to understand these mechanisms. ES suggests that nutrient rich taxa are more likely to be nutrient limited than nutrient poorer taxa and are more favored under nutrient enrichment. Here, we quantified differences in the elemental composition of soil, plants, and consumers between islands with and without nesting cormorant colonies and tested predictions made based on ES by relating the elemental composition and the eventual mismatch between consumer and resource stoichiometry to observed density differences among the island categories. We found that nesting cormorants radically changed the soil nutrient content and thereby indirectly plant nutrient content and resource quality to herbivores. In contrast, consumers showed only small differences in their elemental composition among the island categories. While we cannot evaluate the cause of the apparent homeostasis of invertebrates without additional data, we can conclude that from the perspective of the next trophic level, there is no difference in diet quality (in terms of N and P content) between island categories. Thus, bottom-up effects seemed mainly be mediated via changes in resource quantity not quality. Despite a large potential trophic mismatch we were unable to observe any relation between the invertebrate stoichiometry and their density response to nesting cormorant colonies. We conclude that in our system stoichiometry is not a useful predictor of arthropod responses to variation in resource nutrient content. Furthermore, we found no strong evidence that resource quality was a prime determinant of invertebrate densities. Other factors like resource quantity, habitat structure and species interactions might be more important or masked stoichiometric effects. PMID- 23626728 TI - Vaccination against influenza with recombinant hemagglutinin expressed by Schizochytrium sp. confers protective immunity. AB - For the rapid production of influenza vaccine antigens in unlimited quantities, a transition from conventional egg-based production to cell-based and recombinant systems is required. The need for higher-yield, lower-cost, and faster production processes is critical to provide adequate supplies of influenza vaccine to counter global pandemic threats. In this study, recombinant hemagglutinin proteins of influenza virus were expressed in the microalga Schizochytrium sp., an established, fermentable organism grown in large scale for the manufacture of polyunsaturated fatty acids for animal and human health applications. Schizochytrium was capable of exporting the full-length membrane-bound proteins in a secreted form suitable for vaccine formulation. One recombinant hemagglutinin (rHA) protein derived from A/Puerto Rico/8/34 (H1N1) influenza virus was evaluated as a vaccine in a murine challenge model. Protective immunity from lethal challenge with homologous virus was elicited by a single dose of 1.7, 5 or 15 ug rHA with or without adjuvant at survival rates between 80-100%. Full protection (100%) was established at all dose levels with or without adjuvant when mice were given a second vaccination. These data demonstrate the potential of Schizochytrium sp. as a platform for the production of recombinant antigens useful for vaccination against influenza. PMID- 23626729 TI - Xenobiotic-induced hepatocyte proliferation associated with constitutive active/androstane receptor (CAR) or peroxisome proliferator-activated receptor alpha (PPARalpha) is enhanced by pregnane X receptor (PXR) activation in mice. AB - Xenobiotic-responsive nuclear receptors pregnane X receptor (PXR), constitutive active/androstane receptor (CAR) and peroxisome proliferator-activated receptor alpha (PPARalpha) play pivotal roles in the metabolic functions of the liver such as xenobiotics detoxification and energy metabolism. While CAR or PPARalpha activation induces hepatocyte proliferation and hepatocarcinogenesis in rodent models, it remains unclear whether PXR activation also shows such effects. In the present study, we have investigated the role of PXR in the xenobiotic-induced hepatocyte proliferation with or without CAR activation by 1,4-bis[2-(3,5 dichloropyridyloxy)]benzene (TCPOBOP) and phenobarbital, or PPARalpha activation by Wy-14643 in mice. Treatment with TCPOBOP or phenobarbital increased the percentage of Ki-67-positive nuclei as well as mRNA levels of cell proliferation related genes in livers as expected. On the other hand, treatment with the PXR activator pregnenolone 16alpha-carbonitrile (PCN) alone showed no such effects. Surprisingly, PCN co-treatment significantly augmented the hepatocyte proliferation induced by CAR activation with TCPOBOP or phenobarbital in wild type mice but not in PXR-deficient mice. Intriguingly, PXR activation also augmented the hepatocyte proliferation induced by Wy-14643 treatment. Moreover, PCN treatment increased the RNA content of hepatocytes, suggesting the induction of G0/G1 transition, and reduced mRNA levels of Cdkn1b and Rbl2, encoding suppressors of cell cycle initiation. Our present findings indicate that xenobiotic-induced hepatocyte proliferation mediated by CAR or PPARalpha is enhanced by PXR co-activation despite that PXR activation alone does not cause the cell proliferation in mouse livers. Thus PXR may play a novel and unique role in the hepatocyte/liver hyperplasia upon exposure to xenobiotics. PMID- 23626730 TI - Influence of non-alcoholic fatty liver disease on autonomic changes evaluated by the time domain, frequency domain, and symbolic dynamics of heart rate variability. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular atherosclerosis independent of classical risk factors. This study investigated the influence of NAFLD on autonomic changes, which is currently unknown. METHODS: Subjects without an overt history of cardiovascular disease were enrolled during health checkups. The subjects diagnosed for NAFLD using ultrasonography underwent 5-min heart rate variability (HRV) measurements that was analyzed using the following indices: (1) the time domain with the standard deviation of N-N (SDNN) intervals and root mean square of successive differences between adjacent N-N intervals (rMSSD); (2) the frequency domain with low frequency (LF) and high frequency (HF) components; and (3) symbolic dynamics analysis. Routine blood biochemistry data and serum leptin levels were analyzed. Homeostasis model assessment of insulin resistance (HOMA-IR) was measured. RESULTS: Of the 497 subjects (mean age, 46.2 years), 176 (35.4%) had NAFLD. The HRV indices (Ln SDNN, Ln rMSSD, Ln LF, and Ln HF) were significantly decreased in the NAFLD group (3.51 vs 3.62 ms, 3.06 vs 3.22 ms, 5.26 vs 5.49 ms(2), 4.49 vs 5.21 ms(2), respectively, all P<0.05). Ln SDNN was significantly lower in the NAFLD group after adjustment for age, sex, hypertension, dyslipidemia, metabolic syndrome, body mass index, smoking, estimated glomerular filtration rate, HOMA IR, and leptin (P<0.05). In the symbolic dynamic analysis, 0 V percentage was significantly higher in the NAFLD group (33.8% vs 28.7%, P = 0.001) and significantly correlated with linear HRV indices (Ln SDNN, Ln rMSSD, and Ln HF). CONCLUSIONS: NAFLD is associated with decreased Ln SDNN and increased 0 V percentage. The former association was independent of conventional cardiovascular risk factors and serum biomarkers (insulin resistance and leptin). Further risk stratification of autonomic dysfunction with falls or cardiovascular diseases by these HRV parameters is required in patients with NAFLD. PMID- 23626731 TI - Children's use of communicative intent in the selection of cooperative partners. AB - Within the animal kingdom, human cooperation represents an outlier. As such, there has been great interest across a number of fields in identifying the factors that support the complex and flexible variety of cooperation that is uniquely human. The ability to identify and preferentially interact with better social partners (partner choice) is proposed to be a major factor in maintaining costly cooperation between individuals. Here we show that the ability to engage in flexible and effective partner choice behavior can be traced back to early childhood. Specifically, across two studies, we demonstrate that by 3 years of age, children identify effective communication as "helpful" (Experiments 1 & 2), reward good communicators with information (Experiment 1), and selectively reciprocate communication with diverse cooperative acts (Experiment 2). Taken together, these results suggest that even in early childhood, humans take advantage of cooperative benefits, while mitigating free-rider risks, through appropriate partner choice behavior. PMID- 23626732 TI - Effects of Tai Chi in patients with chronic obstructive pulmonary disease: preliminary evidence. AB - BACKGROUND: Currently, several studies assessed the role of Tai Chi (TC) in management of chronic obstructive pulmonary disease, but these studies have wide variation of sample and convey inconclusive results. We therefore undertook a meta-analysis to assess the effects of TC. METHODS: A computerized search through electronic databases was performed to obtain sample studies. The primary outcomes were 6-min walking distance (6MWD) and dyspnea. Secondary outcomes included health-related quality of life and pre-bronchodilator spirometry. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and heterogeneity was assessed with the I(2) test. A random-effects meta-analysis model was applied. RESULTS: Eight randomized controlled trials involving 544 patients met the inclusion criteria. The pooled WMDs were 34.22 m (95% CI 21.25 47.20, P<0.00001) for 6 MWD, -0.86 units (95% CI -1.44--0.28, P = 0.004) for dyspnea, 70 ml (95% CI 0.02-0.13, P = 0.01) for FEV1, 120 ml (95% CI 0.00-0.23, P = 0.04) for FVC. TC significantly improved the Chronic Respiratory Disease Questionnaire total score, and the St George's Respiratory Questionnaire score except impact score. CONCLUSIONS: Findings suggest that TC may provide an effective alternative means to achieve results similar to those reported following participation in pulmonary rehabilitation programs. Further studies are needed to substantiate the preliminary findings and investigate the long-term effects of TC. PMID- 23626733 TI - An image analysis algorithm for malaria parasite stage classification and viability quantification. AB - With more than 40% of the world's population at risk, 200-300 million infections each year, and an estimated 1.2 million deaths annually, malaria remains one of the most important public health problems of mankind today. With the propensity of malaria parasites to rapidly develop resistance to newly developed therapies, and the recent failures of artemisinin-based drugs in Southeast Asia, there is an urgent need for new antimalarial compounds with novel mechanisms of action to be developed against multidrug resistant malaria. We present here a novel image analysis algorithm for the quantitative detection and classification of Plasmodium lifecycle stages in culture as well as discriminating between viable and dead parasites in drug-treated samples. This new algorithm reliably estimates the number of red blood cells (isolated or clustered) per fluorescence image field, and accurately identifies parasitized erythrocytes on the basis of high intensity DAPI-stained parasite nuclei spots and Mitotracker-stained mitochondrial in viable parasites. We validated the performance of the algorithm by manual counting of the infected and non-infected red blood cells in multiple image fields, and the quantitative analyses of the different parasite stages (early rings, rings, trophozoites, schizonts) at various time-point post merozoite invasion, in tightly synchronized cultures. Additionally, the developed algorithm provided parasitological effective concentration 50 (EC50) values for both chloroquine and artemisinin, that were similar to known growth inhibitory EC50 values for these compounds as determined using conventional SYBR Green I and lactate dehydrogenase-based assays. PMID- 23626734 TI - The mitochondrial genome of Elodia flavipalpis Aldrich (Diptera: Tachinidae) and the evolutionary timescale of Tachinid flies. AB - Tachinid flies are natural enemies of many lepidopteran and coleopteran pests of forests, crops, and fruit trees. In order to address the lack of genetic data in this economically important group, we sequenced the complete mitochondrial genome of the Palaearctic tachinid fly Elodia flavipalpis Aldrich, 1933. Usually found in Northern China and Japan, this species is one of the primary natural enemies of the leaf-roller moths (Tortricidae), which are major pests of various fruit trees. The 14,932-bp mitochondrial genome was typical of Diptera, with 13 protein coding genes, 22 tRNA genes, and 2 rRNA genes. However, its control region is only 105 bp in length, which is the shortest found so far in flies. In order to estimate dipteran evolutionary relationships, we conducted a phylogenetic analysis of 58 mitochondrial genomes from 23 families. Maximum-likelihood and Bayesian methods supported the monophyly of both Tachinidae and superfamily Oestroidea. Within the subsection Calyptratae, Muscidae was inferred as the sister group to Oestroidea. Within Oestroidea, Calliphoridae and Sarcophagidae formed a sister clade to Oestridae and Tachinidae. Using a Bayesian relaxed clock calibrated with fossil data, we estimated that Tachinidae originated in the middle Eocene. PMID- 23626735 TI - Identification of the control region of pancreatic expression of Bmp4 in vitro and in vivo. AB - Bone morphogenetic protein 4 (Bmp4) was recently shown to be related to glucose homeostasis in mouse adult pancreas through the regulation of insulin production. We previously revealed the predominant expression of Bmp4 in adult pancreas by in vivo imaging of transgenic mice. However, the control regions for predominant Bmp4 expression in the adult pancreas are unclear. In this study, we established transgenic (Tg) mice that allow real time in vivo bioluminescence imaging of the enhancer/promoter activity of the Bmp4 gene. Tg mice expressing firefly luciferase with a 7 kb upstream region and 5'-non-coding sequence (three exons and two introns) of the Bmp4 gene showed pancreatic expression of bioluminescence, while the Tg mice bearing luciferase with the 7 kb upstream region alone did not show pancreatic expression of the reporter gene. Interestingly, pancreatic expression of bioluminescence was also present in Tg mice harboring the truncated promoter without exon IA and IB, indicating the presence of a cryptic promoter in front of exon II. Furthermore, the bioluminescence signal was not detected in embryonic pancreas, but increasing signals were observed in neonatal and infantile Tg mice depending on the genotypes observed. These results suggested that a novel mechanism of transcription is involved in pancreatic expression of the Bmp4 gene. PMID- 23626736 TI - Human S100A9 protein is stabilized by inflammatory stimuli via the formation of proteolytically-resistant homodimers. AB - S100A8 and S100A9 are Ca(2+)-binding proteins that are associated with acute and chronic inflammation and cancer. They form predominantly heterodimers even if there are data supporting homodimer formation. We investigated the stability of the heterodimer in myeloid and S100A8/S100A9 over-expressing COS cells. In both cases, S100A8 and S100A9 proteins were not completely degraded even 48 hrs after blocking protein synthesis. In contrast, in single transfected cells, S100A8 protein was completely degraded after 24 h, while S100A9 was completely unstable. However, S100A9 protein expression was rescued upon S100A8 co-expression or inhibition of proteasomal activity. Furthermore, S100A9, but not S100A8, could be stabilized by LPS, IL-1beta and TNFalpha treatment. Interestingly, stimulation of S100A9-transfected COS cells with proteasomal inhibitor or IL-1beta lead to the formation of protease resistant S100A9 homodimers. In summary, our data indicated that S100A9 protein is extremely unstable but can be rescued upon co-expression with S100A8 protein or inflammatory stimuli, via proteolytically resistant homodimer formation. The formation of S100A9 homodimers by this mechanism may constitute an amplification step during an inflammatory reaction. PMID- 23626737 TI - The roles of dehumanization and moral outrage in retributive justice. AB - When innocents are intentionally harmed, people are motivated to see that offenders get their "just deserts". The severity of the punishment they seek is driven by the perceived magnitude of the harm and moral outrage. The present research extended this model of retributive justice by incorporating the role of offender dehumanization. In three experiments relying on survey methodology in Australia and the United States, participants read about different crimes that varied by type (child molestation, violent, or white collar - Studies 1 and 2) or severity (Study 3). The findings demonstrated that both moral outrage and dehumanization predicted punishment independently of the effects of crime type or crime severity. Both moral outrage and dehumanization mediated the relationship between perceived harm and severity of punishment. These findings highlight the role of offender dehumanization in punishment decisions and extend our understanding of processes implicated in retributive justice. PMID- 23626738 TI - Low voltage activation of KCa1.1 current by Cav3-KCa1.1 complexes. AB - Calcium-activated potassium channels of the KCa1.1 class are known to regulate repolarization of action potential discharge through a molecular association with high voltage-activated calcium channels. The current study examined the potential for low voltage-activated Cav3 (T-type) calcium channels to interact with KCa1.1 when expressed in tsA-201 cells and in rat medial vestibular neurons (MVN) in vitro. Expression of the channel alpha-subunits alone in tsA-201 cells was sufficient to enable Cav3 activation of KCa1.1 current. Cav3 calcium influx induced a 50 mV negative shift in KCa1.1 voltage for activation, an interaction that was blocked by Cav3 or KCa1.1 channel blockers, or high internal EGTA. Cav3 and KCa1.1 channels coimmunoprecipitated from lysates of either tsA-201 cells or rat brain, with Cav3 channels associating with the transmembrane S0 segment of the KCa1.1 N-terminus. KCa1.1 channel activation was closely aligned with Cav3 calcium conductance in that KCa1.1 current shared the same low voltage dependence of Cav3 activation, and was blocked by voltage-dependent inactivation of Cav3 channels or by coexpressing a non calcium-conducting Cav3 channel pore mutant. The Cav3-KCa1.1 interaction was found to function highly effectively in a subset of MVN neurons by activating near -50 mV to contribute to spike repolarization and gain of firing. Modelling data indicate that multiple neighboring Cav3-KCa1.1 complexes must act cooperatively to raise calcium to sufficiently high levels to permit KCa1.1 activation. Together the results identify a novel Cav3-KCa1.1 signaling complex where Cav3-mediated calcium entry enables KCa1.1 activation over a wide range of membrane potentials according to the unique voltage profile of Cav3 calcium channels, greatly extending the roles for KCa1.1 potassium channels in controlling membrane excitability. PMID- 23626739 TI - Localisation of RNAs into the germ plasm of vitellogenic Xenopus oocytes. AB - We have studied the localisation of mRNAs in full-grown Xenopus laevis oocytes by injecting fluorescent RNAs, followed by confocal microscopy of the oocyte cortex. Concentrating on RNA encoding the Xenopus Nanos homologue, nanos1 (formerly Xcat2), we find that it consistently localised into aggregated germ plasm ribonucleoprotein (RNP) particles, independently of cytoskeletal integrity. This implies that a diffusion/entrapment-mediated mechanism is active, as previously reported for previtellogenic oocytes. Sometimes this was accompanied by localisation into scattered particles of the "late", Vg1/VegT pathway; occasionally only late pathway localisation was seen. The Xpat RNA behaved in an identical fashion and for neither RNA was the localisation changed by any culture conditions tested. The identity of the labelled RNP aggregates as definitive germ plasm was confirmed by their inclusion of abundant mitochondria and co localisation with the germ plasm protein Hermes. Further, the nanos1/Hermes RNP particles are interspersed with those containing the germ plasm protein Xpat. These aggregates may be followed into the germ plasm of unfertilized eggs, but with a notable reduction in its quantity, both in terms of injected molecules and endogenous structures. Our results conflict with previous reports that there is no RNA localisation in large oocytes, and that during mid-oogenesis even germ plasm RNAs localise exclusively by the late pathway. We find that in mid oogenesis nanos1 RNA also localises to germ plasm but also by the late pathway. Late pathway RNAs, Vg1 and VegT, also may localise into germ plasm. Our results support the view that mechanistically the two modes of localisation are extremely similar, and that in an injection experiment RNAs might utilise either pathway, the distinction in fates being very subtle and subject to variation. We discuss these results in relation to their biological significance and the results of others. PMID- 23626740 TI - Lifestyle behaviors of African American breast cancer survivors: a Sisters Network, Inc. study. AB - INTRODUCTION: African American breast cancer survivors experience poor cancer outcomes that may, in part, be remedied by healthy lifestyle choices. Few studies have evaluated the health and lifestyle behaviors of this population. The purpose of this study was to characterize the health and lifestyle habits of African American breast cancer survivors and evaluate the socio-demographic and medical correlates of these behaviors. METHODS: A total of 470 African American breast cancer survivors (mean age = 54 years) participated in an online survey. All participants completed measures assessing medical and demographic characteristics, physical activity, and sedentary behavior. Chi-square tests for association, nonparametric tests, and logistic regression models were used to assess associations. All statistical tests were two sided. RESULTS: Almost half (47%) of the women met the current guidelines for physical activity, almost half (47%) were obese, and many reported having high blood pressure (53%) or diabetes (21%). The prevalence of high blood pressure, diabetes, and high cholesterol increased by age (P<0.001), and obese women had a higher prevalence of high blood pressure (63% vs. 44%) and diabetes (21% vs. 12%) than did non-obese women (all P<0.05). Obese women participated in significantly fewer total minutes of physical activity per week (100 minutes/week) than did non-obese women (150 minutes/week; P<0.05). The number of comorbid conditions was associated with increased odds for physical inactivity (odds ratio = 1.40) and obesity (odds ratio = 2.22). CONCLUSION: Many African American breast cancer survivors had chronic conditions that may be exacerbated by poor lifestyle choices. Our results also provide evidence that healthy lifestyle interventions among obese African American breast cancer survivors are urgently needed. PMID- 23626741 TI - Syntaxin 16 regulates lumen formation during epithelial morphogenesis. AB - The formation and maintenance of cell-cell junctions, both under physiological and pathological conditions, requires the targeting and trafficking of junctional proteins. Proteins of the syntaxin (Stx)-family localize to a variety of subcellular membranes and contribute to intracellular transport of cargo by regulating vesicle fusion events at these sites. Unlike plasma membrane localized Stxs, the roles of endosome- and Golgi-localized stx proteins in epithelial morphogenesis are less understood. Here we show that Stx16- an endosome- and Golgi-localized target-membrane soluble N-ethylmaleimide attachment protein receptor (t-SNARE) that plays a role in membrane trafficking between these compartments - is essential for lumen development. In cultured Madin Darby Canine Kidney (MDCK) cells, Stx16 was selectively upregulated as sparsely plated cells attained confluency. Stx16-depleted confluent monolayers consistently showed lower transepithelial resistance than control monolayers, and failed to maintain endogenous and ectopically expressed E-cadherin at the adherens junctions due to decreased recycling. We further found that whereas cysts formed by MDCK cells cultured in Matrigel have a single hollow lumen, those formed by stx16-depleted counterparts had multiple lumens, due to abnormal orientiation of the mitotic spindle. Finally, a similar role for stx16 function in vivo is indicated by our analysis of pronephric-duct development in zebrafish expressing the claudinB:lynGFP transgene; lack of stx16 function in this structure (in stx16 morphant embryos) led to the development of enlarged, torturous pronephric ducts with more than one lumen. Taken together, our in vitro and in vivo studies establish a role for Stx16 in maintaining the integrity of cell-cell junctions, and thereby in morphogenesis of the kidney epithelial lumen. PMID- 23626742 TI - Prevalence of transmitted HIV drug resistance in Iran between 2010 and 2011. AB - OBJECTIVE: Drug-resistant (DR) HIV emerges during combined antiretroviral treatment (cART), creating concern about widespread transmission of DR-HIV as cART is expanded in resource-limited countries. The aim of this study was to determine the predominant HIV-1 subtypes and prevalence of transmitted DR mutations among antiretroviral-naive patients in Iran. DESIGN: To monitor transmission of DR HIV, a threshold surveillance based on the world health organization (WHO) guidelines was implemented in Iran. METHODS: For this HIVDR threshold surveillance study, blood samples were collected from 50 antiretroviral naive HIV-1-infected patients. Antiretroviral-resistant mutations were determined by sequencing HIV-1 protease, reverse transcriptase and integrase regions. The HIV-1 subtype was determined by sequencing the p17 and C2-V5 regions of the gag and env genes, respectively. RESULTS: Phylogenetic analyses of the sequenced regions revealed that 45 (95.7%) of 47 samples that were successfully obtained were CRF35_AD. The remaining two cases were subtype B (2.1%) and CRF01_AE (2.1%). Consistent results were obtained also from Env and Gag sequences. Regarding prevalence of transmitted DR viruses, two cases were found to harbor reverse transcriptase-inhibitor-resistant mutations (4.3%). In addition, although not in the WHO list for surveillance of transmitted mutations, 13 minor protease inhibitor-resistant mutations listed in the International AIDS Society-USA panel of drug resistance mutations were found. No DR mutations were detected in the integrase region. CONCLUSIONS: Our study clarified that CRF35_AD is the major subtype among HIV-1-infected patients in Iran. According to the WHO categorization method of HIVDR threshold survey, the prevalence of transmitted drug resistant HIV in Iran was estimated as moderate (5-15%). PMID- 23626743 TI - Heritability of subcortical volumetric traits in mesial temporal lobe epilepsy. AB - OBJECTIVES: We aimed to 1) determine if subcortical volume deficits are common to mesial temporal lobe epilepsy (MTLE) patients and their unaffected siblings 2) assess the suitability of subcortical volumetric traits as endophenotypes for MTLE. METHODS: MRI-based volume measurements of the hippocampus, amygdala, thalamus, caudate, putamen and pallidium were generated using an automated brain reconstruction method (FreeSurfer) for 101 unrelated 'sporadic' MTLE patients [70 with hippocampal sclerosis (MTLE+HS), 31 with MRI-negative TLE], 83 unaffected full siblings of patients and 86 healthy control subjects. Changes in the volume of subcortical structures in patients and their unaffected siblings were determined by comparison with healthy controls. Narrow sense heritability was estimated ipsilateral and contralateral to the side of seizure activity. RESULTS: MTLE+HS patients displayed significant volume deficits across the hippocampus, amygdala and thalamus ipsilaterally. In addition, volume loss was detected in the putamen bilaterally. These volume deficits were not present in the unaffected siblings of MTLE+HS patients. Ipsilaterally, the heritability estimates were dramatically reduced for the volume of the hippocampus, thalamus and putamen but remained in the expected range for the amygdala. MRI-negative TLE patients and their unaffected siblings showed no significant volume changes across the same structures and heritability estimates were comparable with calculations from a healthy population. CONCLUSIONS: The findings indicate that volume deficits for many subcortical structures in 'sporadic' MTLE+HS are not heritable and likely related to acquired factors. Therefore, they do not represent suitable endophenotypes for MTLE+HS. The findings also support the view that, at a neuroanatomical level, MTLE+HS and MRI-negative TLE represent two distinct forms of MTLE. PMID- 23626744 TI - Characterization of stratum corneum molecular dynamics by natural-abundance 13C solid-state NMR. AB - Despite the enormous potential for pharmaceutical applications, there is still a lack of understanding of the molecular details that can contribute to increased permeability of the stratum corneum (SC). To investigate the influence of hydration and heating on the SC, we record the natural-abundance (13)C signal of SC using polarization transfer solid-state NMR methods. Resonance lines from all major SC components are assigned. Comparison of the signal intensities obtained with the INEPT and CP pulse sequences gives information on the molecular dynamics of SC components. The majority of the lipids are rigid at 32 degrees C, and those lipids co-exist with a small pool of mobile lipids. The ratio between mobile and rigid lipids increases with hydration. An abrupt change of keratin filament dynamics occurs at RH = 80-85%, from completely rigid to a structure with rigid backbone and mobile protruding terminals. Heating has a strong effect on the lipid mobility, but only a weak influence on the keratin filaments. The results provide novel molecular insight into how the SC constituents are affected by hydration and heating, and improve the understanding of enhanced SC permeability, which is associated with elevated temperatures and SC hydration. PMID- 23626745 TI - Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity. AB - Several chemotherapeutics exert immunomodulatory effects. One of these is the nucleoside analogue gemcitabine, which is widely used in patients with lung cancer, ovarian cancer, breast cancer, mesothelioma and several other types of cancer, but with limited efficacy. We hypothesized that the immunopotentiating effects of this drug are partly restrained by the inhibitory T cell molecule CTLA 4 and thus could be augmented by combining it with a blocking antibody against CTLA-4, which on its own has recently shown beneficial clinical effects in the treatment of patients with metastatic melanoma. Here we show, using two non immunogenic murine tumor models, that treatment with gemcitabine chemotherapy in combination with CTLA-4 blockade results in the induction of a potent anti-tumor immune response. Depletion experiments demonstrated that both CD4(+) and CD8(+) T cells are required for optimal therapeutic effect. Mice treated with the combination exhibited tumor regression and long-term protective immunity. In addition, we show that the efficacy of the combination is moderated by the timing of administration of the two agents. Our results show that immune checkpoint blockade and cytotoxic chemotherapy can have a synergistic effect in the treatment of cancer. These results provide a basis to pursue combination therapies with anti-CTLA-4 and immunopotentiating chemotherapy and have important implications for future studies in cancer patients. Since both drugs are approved for use in patients our data can be immediately translated into clinical trials. PMID- 23626746 TI - Generating porcine chimeras using inner cell mass cells and parthenogenetic preimplantation embryos. AB - BACKGROUND: The development and validation of stem cell therapies using induced pluripotent stem (iPS) cells can be optimized through translational research using pigs as large animal models, because pigs have the closest characteristics to humans among non-primate animals. As the recent investigations have been heading for establishment of the human iPS cells with naive type characteristics, it is an indispensable challenge to develop naive type porcine iPS cells. The pluripotency of the porcine iPS cells can be evaluated using their abilities to form chimeras. Here, we describe a simple aggregation method using parthenogenetic host embryos that offers a reliable and effective means of determining the chimera formation ability of pluripotent porcine cells. METHODOLOGY/SIGNIFICANT PRINCIPAL FINDINGS: In this study, we show that a high yield of chimeric blastocysts can be achieved by aggregating the inner cell mass (ICM) from porcine blastocysts with parthenogenetic porcine embryos. ICMs cultured with morulae or 4-8 cell-stage parthenogenetic embryos derived from in vitro-matured (IVM) oocytes can aggregate to form chimeric blastocysts that can develop into chimeric fetuses after transfer. The rate of production of chimeric blastocysts after aggregation with host morulae (20/24, 83.3%) was similar to that after the injection of ICMs into morulae (24/29, 82.8%). We also found that 4-8 cell-stage embryos could be used; chimeric blastocysts were produced with a similar efficiency (17/26, 65.4%). After transfer into recipients, these blastocysts yielded chimeric fetuses at frequencies of 36.0% and 13.6%, respectively. CONCLUSION/SIGNIFICANCE: Our findings indicate that the aggregation method using parthenogenetic morulae or 4-8 cell-stage embryos offers a highly reproducible approach for producing chimeric fetuses from porcine pluripotent cells. This method provides a practical and highly accurate system for evaluating pluripotency of undifferentiated cells, such as iPS cells, based on their ability to form chimeras. PMID- 23626747 TI - Penetrating cations enhance uncoupling activity of anionic protonophores in mitochondria. AB - Protonophorous uncouplers causing a partial decrease in mitochondrial membrane potential are promising candidates for therapeutic applications. Here we showed that hydrophobic penetrating cations specifically targeted to mitochondria in a membrane potential-driven fashion increased proton-translocating activity of the anionic uncouplers 2,4-dinitrophenol (DNP) and carbonylcyanide-p trifluorophenylhydrazone (FCCP). In planar bilayer lipid membranes (BLM) separating two compartments with different pH values, DNP-mediated diffusion potential of H(+) ions was enhanced in the presence of dodecyltriphenylphosphonium cation (C12TPP). The mitochondria-targeted penetrating cations strongly increased DNP- and carbonylcyanide m chlorophenylhydrazone (CCCP)-mediated steady-state current through BLM when a transmembrane electrical potential difference was applied. Carboxyfluorescein efflux from liposomes initiated by the plastoquinone-containing penetrating cation SkQ1 was inhibited by both DNP and FCCP. Formation of complexes between the cation and CCCP was observed spectophotometrically. In contrast to the less hydrophobic tetraphenylphosphonium cation (TPP), SkQ1 and C12TPP promoted the uncoupling action of DNP and FCCP on isolated mitochondria. C12TPP and FCCP exhibited a synergistic effect decreasing the membrane potential of mitochondria in yeast cells. The stimulating action of penetrating cations on the protonophore mediated uncoupling is assumed to be useful for medical applications of low (non toxic) concentrations of protonophores. PMID- 23626748 TI - Immunopathogenesis of severe acute respiratory disease in Zaire ebolavirus infected pigs. AB - Ebola viruses (EBOV) are filamentous single-stranded RNA viruses of the family Filoviridae. Zaire ebolavirus (ZEBOV) causes severe haemorrhagic fever in humans, great apes and non-human primates (NHPs) with high fatality rates. In contrast, Reston ebolavirus (REBOV), the only species found outside Africa, is lethal to some NHPs but has never been linked to clinical disease in humans despite documented exposure. REBOV was isolated from pigs in the Philippines and subsequent experiments confirmed the susceptibility of pigs to both REBOV and ZEBOV with predilection for the lungs. However, only ZEBOV caused severe lung pathology in 5-6 weeks old pigs leading to respiratory distress. To further elucidate the mechanisms for lung pathology, microarray analysis of changes in gene expression was performed on lung tissue from ZEBOV-infected pigs. Furthermore, systemic effects were monitored by looking at changes in peripheral blood leukocyte subsets and systemic cytokine responses. Following oro-nasal challenge, ZEBOV replicated mainly in the respiratory tract, causing severe inflammation of the lungs and consequently rapid and difficult breathing. Neutrophils and macrophages infiltrated the lungs but only the latter were positive for ZEBOV antigen. Genes for proinflammatory cytokines, chemokines and acute phase proteins, known to attract immune cells to sites of infection, were upregulated in the lungs, causing the heavy influx of cells into this site. Systemic effects included a decline in the proportion of monocyte/dendritic and B cells and a mild proinflammatory cytokine response. Serum IgM was detected on day 5 and 6 post infection. In conclusion, a dysregulation/over-activation of the pulmonary proinflammatory response may play a crucial role in the pathogenesis of ZEBOV infection in 5-6 weeks old pigs by attracting inflammatory cells to the lungs. PMID- 23626749 TI - Myosin-Va-dependent cell-to-cell transfer of RNA from Schwann cells to axons. AB - To better understand the role of protein synthesis in axons, we have identified the source of a portion of axonal RNA. We show that proximal segments of transected sciatic nerves accumulate newly-synthesized RNA in axons. This RNA is synthesized in Schwann cells because the RNA was labeled in the complete absence of neuronal cell bodies both in vitro and in vivo. We also demonstrate that the transfer is prevented by disruption of actin and that it fails to occur in the absence of myosin-Va. Our results demonstrate cell-to-cell transfer of RNA and identify part of the mechanism required for transfer. The induction of cell-to cell RNA transfer by injury suggests that interventions following injury or degeneration, particularly gene therapy, may be accomplished by applying them to nearby glial cells (or implanted stem cells) at the site of injury to promote regeneration. PMID- 23626750 TI - Fruit and seed anatomy of Chenopodium and related genera (Chenopodioideae, Chenopodiaceae/Amaranthaceae): implications for evolution and taxonomy. AB - A comparative carpological study of 96 species of all clades formerly considered as the tribe Chenopodieae has been conducted for the first time. The results show important differences in the anatomical structure of the pericarp and seed coat between representatives of terminal clades including Chenopodium s.str.+Chenopodiastrum and the recently recognized genera Blitum, Oxybasis and Dysphania. Within Chenopodium the most significant changes in fruit and seed structure are found in members of C. sect. Skottsbergia. The genera Rhagodia and Einadia differ insignificantly from Chenopodium. The evolution of heterospermy in Chenopodium is discussed. Almost all representatives of the tribe Dysphanieae are clearly separated from other Chenopodioideae on the basis of a diverse set of characteristics, including the small dimensions of the fruits (especially in Australian taxa), their subglobose shape (excl. Teloxys and Suckleya), and peculiarities of the pericarp indumentum. The set of fruit and seed characters evolved within the subfamily Chenopodioideae is described. A recent phylogenetic hypothesis is employed to examine the evolution of three (out of a total of 21) characters, namely seed color, testa-cell protoplast characteristics and embryo orientation. PMID- 23626751 TI - P.Arg82Leu von Hippel-Lindau (VHL) gene mutation among three members of a family with familial bilateral pheochromocytoma in India: molecular analysis and in silico characterization. AB - Various missense mutations in the VHL gene have been reported among patients with familial bilateral pheochromocytoma. However, the p.Arg82Leu mutation in the VHL gene described here among patients with familial bilateral pheochromocytoma, has never been reported previously in a germline configuration. Interestingly, long term follow-up of these patients indicated that the mutation might have had little impact on the normal function of the VHL gene, since all of them have remained asymptomatic. We further attempted to correlate this information with the results obtained by in silico analysis of this mutation using SIFT, PhD-SNP SVM profile, MutPred, PolyPhen2, and SNPs&GO prediction tools. To gain, new mechanistic insight into the structural effect, we mapped the mutation on to 3D structure (PDB ID 1LM8). Further, we analyzed the structural level changes in time scale level with respect to native and mutant protein complexes by using 12 ns molecular dynamics simulation method. Though these methods predict the mutation to have a pathogenic potential, it remains to be seen if these patients will eventually develop symptomatic disease. PMID- 23626752 TI - Characterisation of patients receiving moxifloxacin for acute bacterial rhinosinusitis in clinical practice: results from an international, observational cohort study. AB - We conducted a prospective, non-controlled, multi-centre Phase IV observational cohort study of patients with acute bacterial rhinosinusitis who were treated with moxifloxacin in clinical practice in 19 countries in Asia Pacific, Europe and the Middle East. With the data collected we evaluated the presentation and course of the current disease episode, particularly in terms of the principal clinical signs and symptoms of acute rhinosinusitis and diagnostic procedures. A final assessment of moxifloxacin therapy was made to evaluate the impact of the sinusitis episode on activities of daily life and on sleep disturbance, and to evaluate the clinical outcome of treatment. A total of 7,090 patients were enrolled, of whom 3909 (57.6%) were included in the valid for clinical outcome and safety population. Regional differences were observed in the main symptoms of acute rhinosinusitis and, according to several characteristics, disease episodes appeared to be more severe in patients in Europe than in the Asia Pacific or Middle East regions. The sinusitis episode impacted on daily living for mean (SD) periods of 3.6 (3.2), 4.6 (3.9) and 3.1 (3.0) days and disturbed sleep for 3.6 (3.2), 4.6 (3.9) and 3.1 (3.0) nights in the Asia Pacific, Europe and Middle East regions, respectively. With moxifloxacin treatment, the mean (SD) time to improvement of symptoms was 3.0 (1.5), 3.4 (1.6) and 3.2 (1.5) days, and the time to resolution of symptoms was 4.8 (2.6) days, 5.7 (2.4) days and 5.5 (2.5) days, in the Asia Pacific, Europe and Middle East regions, respectively. In conclusion, acute rhinosinusitis remains a substantial health burden with significant impact on patients' quality of life, and there are differences between global regions in the clinical presentation, diagnosis and clinical course of disease episodes. Moxifloxacin was an effective and well-tolerated treatment option in the overall population. REGISTRATION: ClinicalTrials.gov Identifier: NCT00930488. PMID- 23626753 TI - Suture pull-through insertion techniques for Descemet stripping automated endothelial keratoplasty in Chinese phakic eyes: outcomes and complications. AB - PURPOSE: To investigate the outcomes and complications of suture pull-through insertion techniques for Descemet stripping automated endothelial keratoplasty (DSAEK) in Chinese phakic eyes. PATIENTS AND METHODS: Retrospective case series. Included in the study were all Chinese patients with phakic eyes who underwent DSAEK at Peking University Third Hospital from August 2008 to August 2011. All ocular diseases of the patients were recorded. Distance visual acuity (DVA), near visual acuity (NVA), intraocular pressure (IOP), anterior chamber depth (ACD), central corneal thickness (CCT), and corneal endothelial cell density (ECD) were compared prior to and 12 months after DSAEK. The DSAEK success rate, endothelial cell loss (ECL), complications, and prognosis were analyzed. All patients had at least 12 months of follow up. RESULTS: Twenty-one eyes of 16 patients were included (11 males and 5 females). Ages ranged from 2 to 47 years with an average age of 29.8 years. The average follow up was 15.4 months (ranging from 12 to 36 months). Diagnoses included 7 eyes (4 patients) with corneal endothelial dystrophy and 14 eyes (12 patients) with bullous keratopathy. Presurgical DVA and NVA (LogMAR) were 1.7 +/- 0.7 and 1.2 +/- 0.4; postsurgical DVA and NVA were 0.8 +/- 0.6 and 0.7 +/- 0.5; Z = -3.517, -2.764; P<0.001 and P = 0.006 respectively. Presurgical IOP was 15.8 +/- 3.7 mm Hg; postsurgical IOP was 15.2 +/- 2.6 mm Hg; Z = -0.505, P = 0.614. Presurgical ACD was 3.00 +/- 0.74 mm; postsurgical ACD was 2.72 +/- 0.59 mm; Z = -0.524, P = 0.600. Donor ECD was 2992 +/- 163 cells/mm(2), ECD was 1836 +/- 412 cells/mm(2) with a 12-month postsurgical ECL of 39%. Success rate was 86%. Surgery complications included pupillary block-induced hypertension in 5 eyes (24%), graft detachment in 3 eyes (14%), and graft dislocation in 1 eye (5%). CONCLUSIONS: DSAEK on Chinese phakic eyes can significantly improve DVA and NVA by preserving the patient's own crystalline lens. DSAEK is an optional surgery for patients who need to preserve accommodative function. More attention should be given to postsurgical pupillary block-induced hypertension. PMID- 23626754 TI - Predicting mortality of incident dialysis patients in Taiwan--a longitudinal population-based study. AB - BACKGROUND: Comorbid conditions are highly prevalent among patients with end stage renal disease (ESRD) and index score is a predictor of mortality in dialysis patients. The aim of this study is to perform a population-based cohort study to investigate the survival rate by age and Charlson comorbidity index (CCI) in incident dialysis patients. METHODS: Using the catastrophic illness registration of the Taiwan National Health Insurance Research Database for all patients from 1 January 1998 to 31 December 2008, individuals newly diagnosed with ESRD and receiving dialysis for more than 90 days were eligible for our study. Individuals younger than 18 years or renal transplantation patients either before or after dialysis were excluded. We calculated the CCI, age-weighted CCI by Deyo-Charlson method according to ICD-9 code and categorized CCI into six groups as index scores <3, 4-6, 7-9, 10-12, 13-15, >15. Cox regression models were used to analyze the association between age, CCI and survival, and the risk markers of survival. RESULTS: There were 79,645 incident dialysis patients, whose mean age (+/- SD) was 60.96 (+/-13.92) years; 51.43% of patients were women and 51.2% were diabetic. In cox proportional hazard models and stratifying by age, older patients had significantly higher mortality than younger patients. The mortality risk was higher in persons with higher CCI as compared with low CCI. Mortality increased steadily with higher age or comorbidity both for unadjusted and for adjusted models. For all age groups, mortality rates increased in different CCI groups with the highest rates occurring in the oldest age groups. CONCLUSIONS: Age and CCI are both strong predictors of survival in Taiwan. The older age or higher comorbidity index in incident dialysis patient is associated with lower long-term survival rates. These population-based estimates may assist clinicians who make decisions when patients need long-term dialysis. PMID- 23626755 TI - RASSF6 expression in adipocytes is down-regulated by interaction with macrophages. AB - Macrophage infiltration into adipose tissue is associated with obesity and the crosstalk between adipocytes and infiltrated macrophages has been investigated as an important pathological phenomenon during adipose tissue inflammation. Here, we sought to identify adipocyte mRNAs that are regulated by interaction with infiltrated macrophages in vivo. An anti-inflammatory vitamin, vitamin B6, suppressed macrophage infiltration into white adipose tissue and altered mRNA expression. We identified >3500 genes whose expression is significantly altered during the development of obesity in db/db mice, and compared them to the adipose tissue mRNA expression profile of mice supplemented with vitamin B6. We identified PTX3 and MMP3 as candidate genes regulated by macrophage infiltration. PTX3 and MMP3 mRNA expression in 3T3-L1 adipocytes was up-regulated by activated RAW264.7 cells and these mRNA levels were positively correlated with macrophage number in adipose tissue in vivo. Next, we screened adipose genes down-regulated by the interaction with macrophages, and isolated RASSF6 (Ras association domain family 6). RASSF6 mRNA in adipocytes was decreased by culture medium conditioned by activated RAW264.7 cells, and RASSF6 mRNA level was negatively correlated with macrophage number in adipose tissue, suggesting that adipocyte RASSF6 mRNA expression is down-regulated by infiltrated macrophages in vivo. Finally, this study also showed that decreased RASSF6 expression up-regulates mRNA expression of several genes, such as CD44 and high mobility group protein HMGA2. These data provide novel insights into the biological significance of interactions between adipocytes and macrophages in adipose tissue during the development of obesity. PMID- 23626756 TI - A novel method testing the ability to imitate composite emotional expressions reveals an association with empathy. AB - Social communication relies on intentional control of emotional expression. Its variability across cultures suggests important roles for imitation in developing control over enactment of subtly different facial expressions and therefore skills in emotional communication. Both empathy and the imitation of an emotionally communicative expression may rely on a capacity to share both the experience of an emotion and the intention or motor plan associated with its expression. Therefore, we predicted that facial imitation ability would correlate with empathic traits. We built arrays of visual stimuli by systematically blending three basic emotional expressions in controlled proportions. Raters then assessed accuracy of imitation by reconstructing the same arrays using photographs of participants' attempts at imitations of the stimuli. Accuracy was measured as the mean proximity of the participant photographs to the target stimuli in the array. Levels of performance were high, and rating was highly reliable. More empathic participants, as measured by the empathy quotient (EQ), were better facial imitators and, in particular, performed better on the more complex, blended stimuli. This preliminary study offers a simple method for the measurement of facial imitation accuracy and supports the hypothesis that empathic functioning may utilise motor control mechanisms which are also used for emotional expression. PMID- 23626757 TI - Development of GMDR-GPU for gene-gene interaction analysis and its application to WTCCC GWAS data for type 2 diabetes. AB - Although genome-wide association studies (GWAS) have identified a significant number of single-nucleotide polymorphisms (SNPs) associated with many complex human traits, the susceptibility loci identified so far can explain only a small fraction of the genetic risk. Among other possible explanations, the lack of a comprehensive examination of gene-gene interaction (G*G) is often considered a source of the missing heritability. Previously, we reported a model-free Generalized Multifactor Dimensionality Reduction (GMDR) approach for detecting G*G in both dichotomous and quantitative phenotypes. However, the computational burden and less efficient implementation of the original programs make them impossible to use for GWAS. In this study, we developed a graphics processing unit (GPU)-based GMDR program (named GWAS-GPU), which is able not only to analyze GWAS data but also to run much faster than the earlier version of the GMDR program. As a demonstration of the program, we used the GMDR-GPU software to analyze a publicly available GWAS dataset on type 2 diabetes (T2D) from the Wellcome Trust Case Control Consortium. Through an exhaustive search of pair-wise interactions and a selected search of three- to five-way interactions conditioned on significant pair-wise results, we identified 24 core SNPs in six genes (FTO: rs9939973, rs9940128, rs9922047, rs1121980, rs9939609, rs9930506; TSPAN8: rs1495377; TCF7L2: rs4074720, rs7901695, rs4506565, rs4132670, rs10787472, rs11196205, rs10885409, rs11196208; L3MBTL3: rs10485400, rs4897366; CELF4: rs2852373, rs608489; RUNX1: rs445984, rs1040328, rs990074, rs2223046, rs2834970) that appear to be important for T2D. Of these core SNPs, 11 in FTO, TSPAN8, and TCF7L2 have been reported to be associated with T2D, obesity, or both, providing an independent replication of previously reported SNPs. Importantly, we identified three new susceptibility genes; i.e., L3MBTL3, CELF4, and RUNX1, for T2D, a finding that warrants further investigation with independent samples. PMID- 23626758 TI - Proteomic profiling in Drosophila reveals potential Dube3a regulation of the actin cytoskeleton and neuronal homeostasis. AB - The molecular defects associated with Angelman syndrome (AS) and 15q duplication autism are directly correlated to expression levels of the E3 ubiquitin ligase protein UBE3A. Here we used Drosophila melanogaster to screen for the targets of this ubiquitin ligase under conditions of both decreased (as in AS) or increased (as in dup(15)) levels of the fly Dube3a or human UBE3A proteins. Using liquid phase isoelectric focusing of proteins from whole fly head extracts we identified a total of 50 proteins that show changes in protein, and in some cases transcriptional levels, when Dube3a fluctuates. We analyzed head extracts from cytoplasmic, nuclear and membrane fractions for Dube3a regulated proteins. Our results indicate that Dube3a is involved in the regulation of cellular functions related to ATP synthesis/metabolism, actin cytoskeletal integrity, both catabolism and carbohydrate metabolism as well as nervous system development and function. Sixty-two percent of the proteins were >50% identical to homologous human proteins and 8 have previously be shown to be ubiquitinated in the fly nervous system. Eight proteins may be regulated by Dube3a at the transcript level through the transcriptional co-activation function of Dube3a. We investigated one autism-associated protein, ATPalpha, and found that it can be ubiquitinated in a Dube3a dependent manner. We also found that Dube3a mutants have significantly less filamentous actin than wild type larvae consistent with the identification of actin targets regulated by Dube3a. The identification of UBE3A targets is the first step in unraveling the molecular etiology of AS and duplication 15q autism. PMID- 23626759 TI - Antagonizing effects and mechanisms of afzelin against UVB-induced cell damage. AB - Ultraviolet (UV) radiation induces DNA damage, oxidative stress, and inflammatory processes in human keratinocytes, resulting in skin inflammation, photoaging, and photocarcinogenesis. Adequate protection of skin against the harmful effects of UV irradiation is essential. Therefore, in this study, we investigated the protective effects of afzelin, one of the flavonoids, against UV irradiation in human keratinocytes and epidermal equivalent models. Spectrophotometric measurements revealed that the afzelin extinction maxima were in the UVB and UVA range, and UV transmission below 376 nm was <10%, indicating UV-absorbing activity of afzelin. In the phototoxicity assay using the 3T3 NRU phototoxicity test (3T3-NRU-PT), afzelin presented a tendency to no phototoxic potential. In addition, in order to investigate cellular functions of afzelin itself, cells were treated with afzelin after UVB irradiation. In human keratinocyte, afzelin effectively inhibited the UVB-mediated increase in lipid peroxidation and the formation of cyclobutane pyrimidine dimers. Afzelin also inhibited UVB-induced cell death in human keratinocytes by inhibiting intrinsic apoptotic signaling. Furthermore, afzelin showed inhibitory effects on UVB-induced release of pro inflammatory mediators such as interleukin-6, tumor necrosis factor-alpha, and prostaglandin-E2 in human keratinocytes by interfering with the p38 kinase pathway. Using an epidermal equivalent model exposed to UVB radiation, anti apoptotic activity of afzelin was also confirmed together with a photoprotective effect at the morphological level. Taken together, our results suggest that afzelin has several cellular activities such as DNA-protective, antioxidant, and anti-inflammatory as well as UV-absorbing activity and may protect human skin from UVB-induced damage by a combination of UV-absorbing and cellular activities. PMID- 23626760 TI - Severe liver cirrhosis markedly reduces AhR-mediated induction of cytochrome P450 in rats by decreasing the transcription of target genes. AB - Although the induction of cytochrome P450 (CYP) has long been investigated in patients with cirrhosis, the question whether liver dysfunction impairs the response to CYP inducers still remains unresolved. Moreover, the mechanism underlying the possible effect of cirrhosis on induction has not been investigated. Since ethical constraints do not permit methodologically rigorous studies in humans, this question was addressed by investigating the effect of the prototypical inducer benzo[a]pyrene (BP) on CYP1A1 and CYP1A2 in cirrhotic rats stratified according to the severity of liver dysfunction. We simultaneously assessed mRNA level, protein expression and enzymatic activity of the CYP1A enzymes, as well as mRNA and protein expressions of the aryl hydrocarbon receptor (AhR), which mediates the BP effect. Basal mRNA and protein expressions of CYP1A1 were virtually absent in both healthy and cirrhotic rats. On the contrary, CYP1A2 mRNA, protein and enzyme activity were constitutively present in healthy rats and decreased significantly as liver function worsened. BP treatment markedly increased the concentrations of mRNA and immunodetectable protein, and the enzymatic activities of both CYP1A enzymes to similar levels in healthy and non ascitic cirrhotic rats. Induced mRNA levels, protein expressions and enzymatic activities of both CYPs were much lower in ascitic rats and were proportionally reduced. Both constitutive and induced protein expressions of AhR were significantly lower in ascitic than in healthy rats. These results indicate that the inducibility of CYP1A enzymes is well preserved in compensated cirrhosis, whereas it is markedly reduced when liver dysfunction becomes severe. Induction appears to be impaired at the transcriptional level, due to the reduced expression of AhR, which controls the transcription of CYP1A genes. PMID- 23626761 TI - Reducing AsA leads to leaf lesion and defence response in knock-down of the AsA biosynthetic enzyme GDP-D-mannose pyrophosphorylase gene in tomato plant. AB - As a vital antioxidant, L-ascorbic acid (AsA) affects diverse biological processes in higher plants. Lack of AsA in cell impairs plant development. In the present study, we manipulated a gene of GDP-mannose pyrophosphorylase which catalyzes the conversion of D-mannose-1-P to GDP-D-mannose in AsA biosynthetic pathway and found out the phenotype alteration of tomato. In the tomato genome, there are four members of GMP gene family and they constitutively expressed in various tissues in distinct expression patterns. As expected, over-expression of SlGMP3 increased total AsA contents and enhanced the tolerance to oxidative stress in tomato. On the contrary, knock-down of SlGMP3 significantly decreased AsA contents below the threshold level and altered the phenotype of tomato plants with lesions and further senescence. Further analysis indicated the causes for this symptom could result from failing to instantly deplete the reactive oxygen species (ROS) as decline of free radical scavenging activity. More ROS accumulated in the leaves and then triggered expressions of defence-related genes and mimic symptom occurred on the leaves similar to hypersensitive responses against pathogens. Consequently, the photosynthesis of leaves was dramatically fallen. These results suggested the vital roles of AsA as an antioxidant in leaf function and defence response of tomato. PMID- 23626762 TI - The use of combining ability analysis to identify elite parents for Artemisia annua F1 hybrid production. AB - Artemisia annua is an important medicinal crop used for the production of the anti-malarial compound artemisinin. In order to assist in the production of affordable high quality artemisinin we have carried out an A. annua breeding programme aimed at improving artemisinin concentration and biomass. Here we report on a combining ability analysis of a diallel cross to identify robust parental lines for hybrid breeding. The parental lines were selected based on a range of phenotypic traits to encourage heterosis. The general combining ability (GCA) values for the diallel parental lines correlated to the positive alleles of quantitative trait loci (QTL) in the same parents indicating the presence of beneficial alleles that contribute to parental performance. Hybrids generated from crossing specific parental lines with good GCA were identified as having an increase in both artemisinin concentration and biomass when grown either in glasshouse or experimental field trials and compared to controls. This study demonstrates that combining ability as determined by a diallel cross can be used to identify elite parents for the production of improved A. annua hybrids. Furthermore, the selection of material for breeding using this approach was found to be consistent with our QTL-based molecular breeding approach. PMID- 23626763 TI - Mitochondrial peroxiredoxin 3 regulates sensory cell survival in the cochlea. AB - This study delineates the role of peroxiredoxin 3 (Prx3) in hair cell death induced by several etiologies of acquired hearing loss (noise trauma, aminoglycoside treatment, age). In vivo, Prx3 transiently increased in mouse cochlear hair cells after traumatic noise exposure, kanamycin treatment, or with progressing age before any cell loss occurred; when Prx3 declined, hair cell loss began. Maintenance of high Prx3 levels via treatment with the radical scavenger 2,3-dihydroxybenzoate prevented kanamycin-induced hair cell death. Conversely, reducing Prx3 levels with Prx3 siRNA increased the severity of noise-induced trauma. In mouse organ of Corti explants, reactive oxygen species and levels of Prx3 mRNA and protein increased concomitantly at early times of drug challenge. When Prx3 levels declined after prolonged treatment, hair cells began to die. The radical scavenger p-phenylenediamine maintained Prx3 levels and attenuated gentamicin-induced hair cell death. Our results suggest that Prx3 is up-regulated in response to oxidative stress and that maintenance of Prx3 levels in hair cells is a critical factor in their susceptibility to acquired hearing loss. PMID- 23626764 TI - CD271 defines a stem cell-like population in hypopharyngeal cancer. AB - Cancer stem cells contribute to the malignant phenotypes of a variety of cancers, but markers to identify human hypopharyngeal cancer (HPC) stem cells remain poorly understood. Here, we report that the CD271(+) population sorted from xenotransplanted HPCs possesses an enhanced tumor-initiating capability in immunodeficient mice. Tumors generated from the CD271(+) cells contained both CD271(+) and CD271(-) cells, indicating that the population could undergo differentiation. Immunohistological analyses of the tumors revealed that the CD271(+) cells localized to a perivascular niche near CD34(+) vasculature, to invasive fronts, and to the basal layer. In accordance with these characteristics, a stemness marker, Nanog, and matrix metalloproteinases (MMPs), which are implicated in cancer invasion, were significantly up-regulated in the CD271(+) compared to the CD271 (-) cell population. Furthermore, using primary HPC specimens, we demonstrated that high CD271 expression was correlated with a poor prognosis for patients. Taken together, our findings indicate that CD271 is a novel marker for HPC stem-like cells and for HPC prognosis. PMID- 23626765 TI - Vitellogenins are new high molecular weight components and allergens (Api m 12 and Ves v 6) of Apis mellifera and Vespula vulgaris venom. AB - BACKGROUND/OBJECTIVES: Anaphylaxis due to hymenoptera stings is one of the most severe clinical outcomes of IgE-mediated hypersensitivity reactions. Although allergic reactions to hymenoptera stings are often considered as a general model for the underlying principles of allergic disease, venom immunotherapy is still hampered by severe systemic side effects and incomplete protection. The identification and detailed characterization of all allergens of hymenoptera venoms might result in an improvement in this field and promote the detailed understanding of the allergological mechanism. Our aim was the identification and detailed immunochemical and allergological characterization of the low abundant IgE-reactive 200 kDa proteins of Apis mellifera and Vespula vulgaris venom. METHODS/PRINCIPAL FINDINGS: Tandem mass spectrometry-based sequencing of a 200 kDa venom protein yielded peptides that could be assigned to honeybee vitellogenin. The coding regions of the honeybee protein as well as of the homologue from yellow jacket venom were cloned from venom gland cDNA. The newly identified 200 kDa proteins share a sequence identity on protein level of 40% and belong to the family of vitellogenins, present in all oviparous animals, and are the first vitellogenins identified as components of venom. Both vitellogenins could be recombinantly produced as soluble proteins in insect cells and assessed for their specific IgE reactivity. The particular vitellogenins were recognized by approximately 40% of sera of venom-allergic patients even in the absence of cross-reactive carbohydrate determinants. CONCLUSION: With the vitellogenins of Apis mellifera and Vespula vulgaris venom a new homologous pair of venom allergens was identified and becomes available for future applications. Due to their allergenic properties the honeybee and the yellow jacket venom vitellogenin were designated as allergens Api m 12 and Ves v 6, respectively. PMID- 23626766 TI - Crystal structure of Sus scrofa quinolinate phosphoribosyltransferase in complex with nicotinate mononucleotide. AB - We have determined the crystal structure of porcine quinolinate phosphoribosyltransferase (QAPRTase) in complex with nicotinate mononucleotide (NAMN), which is the first crystal structure of a mammalian QAPRTase with its reaction product. The structure was determined from protein obtained from the porcine kidney. Because the full protein sequence of porcine QAPRTase was not available in either protein or nucleotide databases, cDNA was synthesized using reverse transcriptase-polymerase chain reaction to determine the porcine QAPRTase amino acid sequence. The crystal structure revealed that porcine QAPRTases have a hexameric structure that is similar to other eukaryotic QAPRTases, such as the human and yeast enzymes. However, the interaction between NAMN and porcine QAPRTase was different from the interaction found in prokaryotic enzymes, such as those of Helicobacter pylori and Mycobacterium tuberculosis. The crystal structure of porcine QAPRTase in complex with NAMN provides a structural framework for understanding the unique properties of the mammalian QAPRTase active site and designing new antibiotics that are selective for the QAPRTases of pathogenic bacteria, such as H. pylori and M. tuberculosis. PMID- 23626767 TI - Calcitriol imparts neuroprotection in vitro to midbrain dopaminergic neurons by upregulating GDNF expression. AB - During development a tightly controlled signaling cascade dictates the differentiation, maturation and survival of developing neurons. Understanding this signaling mechanism is important for developing therapies for neurodegenerative illnesses. In previous work we have sought to understand the complex signaling pathways responsible for the development of midbrain dopamine neurons using a proteomic approach. One protein we have identified as being expressed in developing midbrain tissue is the vitamin D receptor. Therefore we investigated the effect of the biologically active vitamin D3 metabolite, calcitriol, on primary fetal ventral mesencephalic cultures of dopamine neurons. We observed a dose responsive increase in numbers of rat primary dopamine neurons when calcitriol was added to culture media. Western blot data showed that calcitriol upregulated the expression of glial derived neurotrophic factor (GDNF). Blocking GDNF signaling could prevent calcitriol's ability to increase numbers of dopamine neurons. An apoptosis assay and cell birth dating experiment revealed that calcitriol increases the number of dopamine neurons through neuroprotection and not increased differentiation. This could have implications for future neuroprotective PD therapies. PMID- 23626768 TI - Cerebellar soluble mutant ataxin-3 level decreases during disease progression in Spinocerebellar Ataxia Type 3 mice. AB - Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominantly inherited neurodegenerative disease caused by an expanded polyglutamine stretch in the ataxin-3 protein. A pathological hallmark of the disease is cerebellar and brainstem atrophy, which correlates with the formation of intranuclear aggregates in a specific subset of neurons. Several studies have demonstrated that the formation of aggregates depends on the generation of aggregation-prone and toxic intracellular ataxin-3 fragments after proteolytic cleavage of the full-length protein. Despite this observed increase in aggregated mutant ataxin-3, information on soluble mutant ataxin-3 levels in brain tissue is lacking. A quantitative method to analyze soluble levels will be a useful tool to characterize disease progression or to screen and identify therapeutic compounds modulating the level of toxic soluble ataxin-3. In the present study we describe the development and application of a quantitative and easily applicable immunoassay for quantification of soluble mutant ataxin-3 in human cell lines and brain samples of transgenic SCA3 mice. Consistent with observations in Huntington disease, transgenic SCA3 mice reveal a tendency for decrease of soluble mutant ataxin-3 during disease progression in fractions of the cerebellum, which is inversely correlated with aggregate formation and phenotypic aggravation. Our analyses demonstrate that the time-resolved Forster resonance energy transfer immunoassay is a highly sensitive and easy method to measure the level of soluble mutant ataxin-3 in biological samples. Of interest, we observed a tendency for decrease of soluble mutant ataxin-3 only in the cerebellum of transgenic SCA3 mice, one of the most affected brain regions in Spinocerebellar Ataxia Type 3 but not in whole brain tissue, indicative of a brain region selective change in mutant ataxin-3 protein homeostasis. PMID- 23626769 TI - Amelioration of experimental autoimmune uveitis by leflunomide in Lewis rats. AB - PURPOSE: To investigate the efficacy of leflunomide in experimental autoimmune uveitis (EAU) in rats. METHODS: Lewis rats were immunized with interphotoreceptor retinoid-binding peptide (IRBP) in order to generate EAU. Rats received three dose of leflunomide through intragastric administration (prevention or treatment protocols) after immunization at three separate doses (3 mg/kg/d; 6 mg/kg/d; 12 mg/kg/d). Cyclosporin A was administered as a positive) control. Rats were euthanized during peak disease activity (day 14 or 15). Treatment effectiveness was evaluated in vivo using clinical EAU scoring (d14) and histopathological evaluation of enucleated eyes after experimental termination. The expression levels of inflammatory cytokines in the serum were quantified by ELISA. Eyeball of rats were harvested and mRNA expression of interleukin 17 (IL17) and IFN-gamma were quantified through RT-PCR. Intracellular expression of interleukin (IL)-17 in the activated CD4(+) T cells was assessed by flow cytometry. The effects of leflunomide inhibition on immune responses in rats were investigated in isolated lymphocytes. RESULTS: Histopathological and clinical data revealed severe intraocular inflammation in the immunized rat. Inflammation reached its peak on day 14 in this EAU model. Treatment with leflunomide significantly prevented and treated EAU-induced ocular inflammation and decreased clinical and pathological scores compared to vehicle-treated eyes. Gene expression of IL17 and IFN-gamma was markedly reduced in leflunomide-treated eyes. Leflunomide significantly decreased the serum levels of IL17 and IFN-gamma. The study of IL17+ T cells in peripheral blood and spleen by flow cytometry showed a decreased number of Th17 cell in rats of leflunomide prevented group. Lymphocytes from animals treated with leflunomide had decreased antigen-specific proliferation in vitro compared with lymphocytes from untreated animals. CONCLUSIONS: Oral administration of leflunomide effectively suppressed IRBP-induced uveitis in rats. These results suggest that leflunomide may be potentially clinical application in uveitis. PMID- 23626770 TI - Imperfect isolation: factors and filters shaping Madagascar's extant vertebrate fauna. AB - Analyses of phylogenetic topology and estimates of divergence timing have facilitated a reconstruction of Madagascar's colonization events by vertebrate animals, but that information alone does not reveal the major factors shaping the island's biogeographic history. Here, we examine profiles of Malagasy vertebrate clades through time within the context of the island's paleogeographical evolution to determine how particular events influenced the arrival of the island's extant groups. First we compare vertebrate profiles on Madagascar before and after selected events; then we compare tetrapod profiles on Madagascar to contemporary tetrapod compositions globally. We show that changes from the Mesozoic to the Cenozoic in the proportions of Madagascar's tetrapod clades (particularly its increase in the representation of birds and mammals) are tied to changes in their relative proportions elsewhere on the globe. Differences in the representation of vertebrate classes from the Mesozoic to the Cenozoic reflect the effects of extinction (i.e., the non-random susceptibility of the different vertebrate clades to purported catastrophic global events 65 million years ago), and new evolutionary opportunities for a subset of vertebrates with the relatively high potential for transoceanic dispersal potential. In comparison, changes in vertebrate class representation during the Cenozoic are minor. Despite the fact that the island's isolation has resulted in high vertebrate endemism and a unique and taxonomically imbalanced extant vertebrate assemblage (both hailed as testimony to its long isolation), that isolation was never complete. Indeed, Madagascar's extant tetrapod fauna owes more to colonization during the Cenozoic than to earlier arrivals. Madagascar's unusual vertebrate assemblage needs to be understood with reference to the basal character of clades originating prior to the K-T extinction, as well as to the differential transoceanic dispersal advantage of other, more recently arriving clades. Thus, the composition of Madagascar's endemic vertebrate assemblage itself provides evidence of the island's paleogeographic history. PMID- 23626771 TI - ROCK inhibitor enhances adhesion and wound healing of human corneal endothelial cells. AB - Maintenance of corneal transparency is crucial for vision and depends mainly on the endothelium, a non-proliferative monolayer of cells covering the inner part of the cornea. When endothelial cell density falls below a critical threshold, the barrier and "pump" functions of the endothelium are compromised which results in corneal oedema and loss of visual acuity. The conventional treatment for such severe disorder is corneal graft. Unfortunately, there is a worldwide shortage of donor corneas, necessitating amelioration of tissue survival and storage after harvesting. Recently it was reported that the ROCK inhibitor Y-27632 promotes adhesion, inhibits apoptosis, increases the number of proliferating monkey corneal endothelial cells in vitro and enhance corneal endothelial wound healing both in vitro and in vivo in animal models. Using organ culture human cornea (N = 34), the effect of ROCK inhibitor was evaluated in vitro and ex vivo. Toxicity, corneal endothelial cell density, cell proliferation, apoptosis, cell morphometry, adhesion and wound healing process were evaluated by live/dead assay standard cell counting method, EdU labelling, Ki67, Caspase3, Zo-1 and Actin immunostaining. We demonstrated for the first time in human corneal endothelial cells ex vivo and in vitro, that ROCK inhibitor did not induce any toxicity effect and did not alter cell viability. ROCK inhibitor treatment did not induce human corneal endothelial cells proliferation. However, ROCK inhibitor significantly enhanced adhesion and wound healing. The present study shows that the selective ROCK inhibitor Y-27632 has no effect on human corneal endothelial cells proliferative capacities, but alters cellular behaviours. It induces changes in cell shape, increases cell adhesion and enhances wound healing ex vivo and in vitro. Its absence of toxicity, as demonstrated herein, is relevant for its use in human therapy. PMID- 23626772 TI - Parents of adolescents with type 1 diabetes--their views on information and communication needs and internet use. A qualitative study. AB - BACKGROUND: Little is known about parents' views on the use of online resources for information, education and support regarding childhood type 1 diabetes (T1DM). Considering the rapidly evolving new communication practices, parents' perspectives need to be explored. The main purpose of this paper was to explore parents' perceptions of their information-seeking, Internet use, and social networking online. This applied to their everyday life, including the contexts of T1DM and contact with peers. A second aim was to identify implications for future development of Internet use in this respect. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-seven parents of 24 young persons aged 10-17 with T1DM participated in eight focus group interviews during their regular visits to a county hospital. Focus group discussions were video/audio-taped, transcribed and analysed using inductive qualitative content analysis. Self-reported demographic and medical information was also collected. A main theme was Finding things out, including two sub-themes, Trust and Suitability. The latter were key factors affecting parents' perceptions of online resources. Parents' choice of information source was related to the situation, previous experiences and knowledge about sources and, most importantly, the level of trust in the source. A constantly present background theme was Life situation, including two sub-themes, Roles and functions and Emotions and needs. Parents' information-seeking regarding T1DM varied greatly, and was closely associated with their life situation, the adolescents development phases and the disease trajectory. CONCLUSIONS/SIGNIFICANCE: Health practitioners and system developers need to focus on creating trust and suitability for users' needs. They should understand the children's diverse needs, which depend on their life situation, on the children's development, and on the disease trajectory. To enhance trust in online health information and support services, the participation of local practitioners is crucial. PMID- 23626773 TI - Identification and characterization of pheromone receptors and interplay between receptors and pheromone binding proteins in the diamondback moth, Plutella xyllostella. AB - Moths depend on olfactory cues such as sex pheromones to find and recognize mating partners. Pheromone receptors (PRs) and Pheromone binding proteins (PBPs) are thought to be associated with olfactory signal transduction of pheromonal compounds in peripheral olfactory reception. Here six candidate pheromone receptor genes in the diamondback moth, Plutella xyllostella were identified and cloned. All of the six candidate PR genes display male-biased expression, which is a typical characteristic of pheromone receptors. In the Xenopus-based functional study and in situ hybridization, PxylOR4 is defined as another pheromone receptor in addition to the previously characterized PxylOR1. In the study of interaction between PRs and PBPs, PxylPBPs could increase the sensitivity of the complex expressing oocyte cells to the ligand pheromone component while decreasing the sensitivity to pheromone analogs. We deduce that activating pheromone receptors in olfactory receptor neurons requires some role of PBPs to pheromone/PBP complex. If the chemical signal is not the pheromone component, but instead, a pheromone analog with a similar structure, the complex would have a decreased ability to activate downstream pheromone receptors. PMID- 23626774 TI - Blood levels of glial fibrillary acidic protein (GFAP) in patients with neurological diseases. AB - BACKGROUND AND PURPOSE: The brain-specific astroglial protein GFAP is a blood biomarker candidate indicative of intracerebral hemorrhage in patients with symptoms suspicious of acute stroke. Comparably little, however, is known about GFAP release in other neurological disorders. In order to identify potential "specificity gaps" of a future GFAP test used to diagnose intracerebral hemorrhage, we measured GFAP in the blood of a large and rather unselected collective of patients with neurological diseases. METHODS: Within a one-year period, we randomly selected in-patients of our university hospital for study inclusion. Patients with ischemic stroke, transient ischemic attack and intracerebral hemorrhage were excluded. Primary endpoint was the ICD-10 coded diagnosis reached at discharge. During hospital stay, blood was collected, and GFAP plasma levels were determined using an advanced prototype immunoassay at Roche Diagnostics. RESULTS: A total of 331 patients were included, covering a broad spectrum of neurological diseases. GFAP levels were low in the vast majority of patients, with 98.5% of cases lying below the cut-off that was previously defined for the differentiation of intracerebral hemorrhage and ischemic stroke. No diagnosis or group of diagnoses was identified that showed consistently increased GFAP values. No association with age and sex was found. CONCLUSION: Most acute and chronic neurological diseases, including typical stroke mimics, are not associated with detectable GFAP levels in the bloodstream. Our findings underline the hypothesis that rapid astroglial destruction as in acute intracerebral hemorrhage is mandatory for GFAP increase. A future GFAP blood test applied to identify patients with intracerebral hemorrhage is likely to have a high specificity. PMID- 23626775 TI - Rapid diagnosis of bloodstream infections with PCR followed by mass spectrometry. AB - Achieving a rapid microbiological diagnosis is crucial for decreasing morbidity and mortality of patients with a bloodstream infection, as it leads to the administration of an appropriate empiric antimicrobial therapy. Molecular methods may offer a rapid alternative to conventional microbiological diagnosis involving blood culture. In this study, the performance of a new technology that uses broad spectrum PCR coupled with mass spectrometry (PCR/ESI-MS) was evaluated for the detection of microorganisms directly from whole blood. A total of 247 whole blood samples and paired blood cultures were prospectively obtained from 175 patients with a suspicion of sepsis. Both sample types were analyzed using the PCR/ESI-MS technology, and the results were compared with those obtained by conventional identification methods. The overall agreement between conventional methods and PCR/ESI-MS performed in blood culture aliquots was 94.2% with 96.8% sensitivity and 98.5% specificity for the molecular method. When comparing conventional methods with PCR/ESI-MS performed in whole blood specimens, the overall agreement was 77.1% with 50% sensitivity and 93.8% specificity for the molecular method. Interestingly, the PCR/ESI-MS technology led to the additional identification of 13 pathogens that were not found by conventional methods. Using the PCR/ESI-MS technology the microbiological diagnosis of bloodstream infections could be anticipated in about half of the patients in our setting, including a small but significant proportion of patients newly diagnosed. Thus, this promising technology could be very useful for the rapid diagnosis of sepsis in combination with traditional methods. PMID- 23626776 TI - Expression and cellular distribution of ubiquitin in response to injury in the developing spinal cord of Monodelphis domestica. AB - Ubiquitin, an 8.5 kDa protein associated with the proteasome degradation pathway has been recently identified as differentially expressed in segment of cord caudal to site of injury in developing spinal cord. Here we describe ubiquitin expression and cellular distribution in spinal cord up to postnatal day P35 in control opossums (Monodelphis domestica) and in response to complete spinal transection (T10) at P7, when axonal growth through site of injury occurs, and P28 when this is no longer possible. Cords were collected 1 or 7 days after injury, with age-matched controls and segments rostral to lesion were studied. Following spinal injury ubiquitin levels (western blotting) appeared reduced compared to controls especially one day after injury at P28. In contrast, after injury mRNA expression (qRT-PCR) was slightly increased at P7 but decreased at P28. Changes in isoelectric point of separated ubiquitin indicated possible post translational modifications. Cellular distribution demonstrated a developmental shift between earliest (P8) and latest (P35) ages examined, from a predominantly cytoplasmic immunoreactivity to a nuclear expression; staining level and shift to nuclear staining was more pronounced following injury, except 7 days after transection at P28. After injury at P7 immunostaining increased in neurons and additionally in oligodendrocytes at P28. Mass spectrometry showed two ubiquitin bands; the heavier was identified as a fusion product, likely to be an ubiquitin precursor. Apparent changes in ubiquitin expression and cellular distribution in development and response to spinal injury suggest an intricate regulatory system that modulates these responses which, when better understood, may lead to potential therapeutic targets. PMID- 23626777 TI - Association between tumorigenic potential and the fate of cancer cells in a syngeneic melanoma model. AB - The self-renewal potential of a cancer cell can be estimated by using particular assays, which include xenotransplantation in immunocompromised animals or culturing in non-adherent serum-free stem-cells media (SCM). However, whether cells with self-renewal potential actually contribute to disease is unknown. Here we investigated the tumorigenic potential and fate of cancer cells in an in-vivo melanoma model. We examined cell lines which were derived from the same parental line: a non-metastatic cell line (K1735/16), a metastatic cell line (K1735/M4) and a cell line which was selected in non-adherent conditions (K1735/16S). All cell lines exhibited similar proliferation kinetics when grown on culture plates. K1735/16 cells grown in soft agar or in suspension non-adherent conditions failed to form colonies or spheroids, whereas the other cell lines showed prominent colonogenicity and spheroid formation capacity. By using sphere limiting dilution analysis (SLDA) in serum-free media, K1735/16S and K1735/M4 cells grown in suspension were capable of forming spheroids even in low frequencies of concentrations, as opposed to K1735/16 cells. The tumorigenic potential of the cell lines was determined in SCID mice using intra footpad injections. Palpable tumors were evident in all mice. In agreement with the in-vitro studies, the K1735/M4 cell line exhibited the highest growth kinetics, followed by the K1735/16S cell line, whereas the K1735/16 cell line had the lowest tumor growth potential (P<0.001). In contrast, when we repeated the experiments in syngeneic C3H/HeN mice, the K1735/16 cell line produced macroscopic tumors 30-100 days after injection, whereas K1735/M4 and K1735/16S derived tumors regressed spontaneously in 90-100% of mice. TUNEL analysis revealed significantly higher number of apoptotic cells in K1735/16S and K1735/M4 cell line-derived tumors compared to K1735/16 tumors (P<0.001). The models we have examined here raised the possibility, that cells with high-tumorigenic activity may be more immunogenic and hence are more susceptible to immune-regulation. PMID- 23626778 TI - Insulin regulates hypoxia-inducible factor-1alpha transcription by reactive oxygen species sensitive activation of Sp1 in 3T3-L1 preadipocyte. AB - Oxygen sensing transcription factor HIF-1 is activated due to accumulation of regulatory subunit HIF-1alpha by posttranslational stability mechanism during hypoxia or by several other stimuli even in normoxia. HIF-1alpha is also regulated by NF-kB mediated transcription mechanism. Reactive oxygen species (ROS) act as an important regulator of HIF-1 either by affecting prolyl hydroxylase activity, the critical determinant of HIF-1alpha stabilization or by activating NF-kB to promote HIF-1alpha transcription. Insulin is known to activate HIF-1 by a ROS dependent mechanism but the molecular mechanism of HIF 1alpha regulation is not known so far. Here we show that insulin regulates HIF 1alpha by a novel transcriptional mechanism by a ROS-sensitive activation of Sp1 in 3T3-L1 preadipocyte. Insulin shows little effect on HIF-1alpha protein stability, but increases HIF-1alpha promoter activity. Mutation analyses, electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirm the role of Sp1 in HIF-1alpha transcription. We further demonstrate that insulin-induced ROS generation initiates signaling pathway involving phosphatidylinositol 3-kinase and protein kinase C for Sp1 mediated HIF-1alpha transcription. In summary, we reveal that insulin regulates HIF-1alpha by a novel transcriptional mechanism involving Sp1. PMID- 23626779 TI - Transgenic mouse models enabling photolabeling of individual neurons in vivo. AB - One of the biggest tasks in neuroscience is to explain activity patterns of individual neurons during behavior by their cellular characteristics and their connectivity within the neuronal network. To greatly facilitate linking in vivo experiments with a more detailed molecular or physiological analysis in vitro, we have generated and characterized genetically modified mice expressing photoactivatable GFP (PA-GFP) that allow conditional photolabeling of individual neurons. Repeated photolabeling at the soma reveals basic morphological features due to diffusion of activated PA-GFP into the dendrites. Neurons photolabeled in vivo can be re-identified in acute brain slices and targeted for electrophysiological recordings. We demonstrate the advantages of PA-GFP expressing mice by the correlation of in vivo firing rates of individual neurons with their expression levels of the immediate early gene c-fos. Generally, the mouse models described in this study enable the combination of various analytical approaches to characterize living cells, also beyond the neurosciences. PMID- 23626780 TI - Identification of functional mutations in GATA4 in patients with congenital heart disease. AB - Congenital heart disease (CHD) is one of the most prevalent developmental anomalies and the leading cause of noninfectious morbidity and mortality in newborns. Despite its prevalence and clinical significance, the etiology of CHD remains largely unknown. GATA4 is a highly conserved transcription factor that regulates a variety of physiological processes and has been extensively studied, particularly on its role in heart development. With the combination of TBX5 and MEF2C, GATA4 can reprogram postnatal fibroblasts into functional cardiomyocytes directly. In the past decade, a variety of GATA4 mutations were identified and these findings originally came from familial CHD pedigree studies. Given that familial and sporadic CHD cases allegedly share a basic genetic basis, we explore the GATA4 mutations in different types of CHD. In this study, via direct sequencing of the GATA4 coding region and exon-intron boundaries in 384 sporadic Chinese CHD patients, we identified 12 heterozygous non-synonymous mutations, among which 8 mutations were only found in CHD patients when compared with 957 controls. Six of these non-synonymous mutations have not been previously reported. Subsequent functional analyses revealed that the transcriptional activity, subcellular localization and DNA binding affinity of some mutant GATA4 proteins were significantly altered. Our results expand the spectrum of GATA4 mutations linked to cardiac defects. Together with the newly reported mutations, approximately 110 non-synonymous mutations have currently been identified in GATA4. Our future analysis will explore why the evolutionarily conserved GATA4 appears to be hypermutable. PMID- 23626781 TI - Evidence of airborne excretion of Pneumocystis carinii during infection in immunocompetent rats. Lung involvement and antibody response. AB - To better understand the role of immunocompetent hosts in the diffusion of Pneumocystis in the environment, airborne shedding of Pneumocystis carinii in the surrounding air of experimentally infected Sprague Dawley rats was quantified by means of a real-time PCR assay, in parallel with the kinetics of P. carinii loads in lungs and specific serum antibody titres. Pneumocystis-free Sprague Dawley rats were intratracheally inoculated at day 0 (d0) and then followed for 60 days. P. carinii DNA was detected in lungs until d29 in two separate experiments and thereafter remained undetectable. A transient air excretion of Pneumocystis DNA was observed between d14 and d22 in the first experiment and between d9 and d19 in the second experiment; it was related to the peak of infection in lungs. IgM and IgG anti-P. carinii antibody increase preceded clearance of P. carinii in the lungs and cessation of airborne excretion. In rats receiving a second challenge 3 months after the first inoculation, Pneumocystis was only detected at a low level in the lungs of 2 of 3 rats at d2 post challenge and was never detected in air samples. Anti-Pneumocystis antibody determinations showed a typical secondary IgG antibody response. This study provides the first direct evidence that immunocompetent hosts can excrete Pneumocystis following a primary acquired infection. Lung infection was apparently controlled by the immune response since fungal burdens decreased to become undetectable as specific antibodies reached high titres in serum. This immune response was apparently protective against reinfection 3 months later. PMID- 23626782 TI - Clostridium difficile is an autotrophic bacterial pathogen. AB - During the last decade, Clostridium difficile infection showed a dramatic increase in incidence and virulence in the Northern hemisphere. This incessantly challenging disease is the leading cause of antibiotic-associated and nosocomial infectious diarrhea and became life-threatening especially among elderly people. It is generally assumed that all human bacterial pathogens are heterotrophic organisms, being either saccharolytic or proteolytic. So far, this has not been questioned as colonization of the human gut gives access to an environment, rich in organic nutrients. Here, we present data that C. difficile (both clinical and rumen isolates) is also able to grow on CO2+H2 as sole carbon and energy source, thus representing the first identified autotrophic bacterial pathogen. Comparison of several different strains revealed high conservation of genes for autotrophic growth and showed that the ability to use gas mixtures for growth decreases or is lost upon prolonged culturing under heterotrophic conditions. The metabolic flexibility of C. difficile (heterotrophic growth on various substrates as well as autotrophy) could allow the organism in the gut to avoid competition by niche differentiation and contribute to its survival when stressed or in unfavorable conditions that cause death to other bacteria. This may be an important trait for the pathogenicity of C. difficile. PMID- 23626783 TI - Differential expression of candidate virus receptors in human T lymphocytes prone or resistant to infection with patient-derived hepatitis C virus. AB - Accumulated evidence implies that hepatitis C virus (HCV) infects not only the liver but also the immune system. A lymphocyte-specific CD5 molecule was recently identified as essential for infection of T cells with native, patient-derived HCV. To assess whether the proposed hepatocyte receptors may also contribute to HCV lymphotropism, expression of scavenger receptor-class B type 1 (SR-B1), claudin-1 (CLDN-1), claudin-6 (CLDN-6), occludin (OCLN), CD5 and CD81 was examined by real-time RT-PCR and the respective proteins quantified by immunoblotting in HCV-prone and resistant T cell lines, peripheral blood mononuclear cells (PBMC), primary T cells and their subsets, and compared to hepatoma Huh7.5 and HepG2 cells. SR-B1 protein was found in T and hepatoma cell lines but not in PBMC or primary T lymphocytes, CLDN-1 in HCV-resistant PM1 T cell line and hepatoma cells only, while CLDN-6 equally in the cells investigated. OCLN protein occurred in HCV-susceptible Molt4 and Jurkat T cells and its traces in primary T cells, but not in PBMC. CD5 was displayed by HCV prone T cell lines, primary T cells and PBMC, but not by non-susceptible T and hepatoma cell lines, while CD81 in all cell types except HepG2. Knocking-down OCLN in virus-prone T cell line inhibited HCV infection, while de novo infection downregulated OCLN and CD81, and upregulated CD5 without modifying SR-B1 expression. Overall, while no association between SR-B1, CLDN-1 or CLDN-6 and the susceptibility to HCV was found, CD5 and CD81 expression coincided with virus lymphotropism and that of OCLN with permissiveness of T cell lines but unlikely primary T cells. This study narrowed the range of factors potentially utilized by HCV to infect T lymphocytes amongst those uncovered using laboratory HCV and Huh7.5 cells. Together with the demonstrated role for CD5 in HCV lymphotropism, the findings indicate that virus utilizes different molecules to enter hepatocytes and lymphocytes. PMID- 23626784 TI - Prognostic significance of twist and N-cadherin expression in NSCLC. AB - BACKGROUND: Metastasis is the most common cause of disease failure and mortality for non-small cell lung cancer after surgical resection. Twist has been recently identified as a putative oncogene and a key regulator of carcinoma metastasis. N cadherin is associated with a more aggressive behavior of cell lines and tumors. The aim of this study was to evaluate the clinical relevance of Twist and N cadherin expression in NSCLC, and the effects of Twist1 knockdown on lung cancer cells. METHODS: We examined the expressions of Twist and N-cadherin by immunohistochemistry in 120 cases of non-small cell lung cancer (including 68 cases with follow-up records). We also analyzed Twist1 and N-cadherin mRNA expression in 30 non-small cell lung cancer tissues using quantitative reverse transcription polymerase chain reaction. The functional roles of Twist1 in lung cancer cell lines were evaluated by small interfering RNA-mediated depletion of the protein followed by analyses of cell apoptosis and invasion. RESULTS: In lung cancer tissues, the overexpression rate of Twist was 38.3% in lung cancer tissues. Overexpression of N-cadherin was shown in 40.83% of primary tumors. Moreover, Twist1 mRNA expression levels correlated with N-cadherin mRNA levels. Furthermore, overexpression of Twist1 or N-cadherin in primary non-small cell lung cancers was associated with a shorter overall survival (P<0.01, P<0.01, respectively). Depleting Twist expression inhibited cell invasion and increased apoptosis in lung cancer cell lines. CONCLUSIONS: The overexpression of Twist and N-cadherin could be considered as useful biomarkers for predicting the prognosis of NSCLC. Twist1 could inhibit apoptosis and promote the invasion of lung cancer cells, and depletion of Twist1 in lung cancer cells led to inhibition of N cadherin expression. PMID- 23626785 TI - Novel anticoagulants for stroke prevention in atrial fibrillation: a systematic review of cost-effectiveness models. AB - OBJECTIVE: To conduct a systematic review of economic models of newer anticoagulants for stroke prevention in atrial fibrillation (SPAF). PATIENTS AND METHODS: We searched Medline, Embase, NHSEED and HTA databases and the Tuft's Registry from January 1, 2008 through October 10, 2012 to identify economic (Markov or discrete event simulation) models of newer agents for SPAF. RESULTS: Eighteen models were identified. Each was based on a lone randomized trial/new agent, and these trials were clinically and methodologically heterogeneous. Dabigatran 150 mg, 110 mg and sequentially-dosed were assessed in 9, 8, and 9 models, rivaroxaban in 4 and apixaban in 4. Warfarin was a first-line comparator in 94% of models. Models were conducted from United States (44%), European (39%) and Canadian (17%) perspectives. Models typically assumed patients between 65-73 years old at moderate-risk of stroke initiated anticoagulation for/near a lifetime. All models reported cost/quality-adjusted life-year, 22% reported using a societal perspective, but none included indirect costs. Four models reported an incremental cost-effectiveness ratio (ICER) for a newer anticoagulant (dabigatran 110 mg (n = 4)/150 mg (n = 2); rivaroxaban (n = 1)) vs. warfarin above commonly reported willingness-to-pay thresholds. ICERs vs. warfarin ranged from $3,547 $86,000 for dabigatran 150 mg, $20,713-$150,000 for dabigatran 110 mg, $4,084 $21,466 for sequentially-dosed dabigatran and $23,065-$57,470 for rivaroxaban. Apixaban was found economically-dominant to aspirin, and dominant or cost effective ($11,400-$25,059) vs. warfarin. Indirect comparisons from 3 models suggested conflicting comparative cost-effectiveness results. CONCLUSIONS: Cost effectiveness models frequently found newer anticoagulants cost-effective, but the lack of head-to-head trials and the heterogeneous characteristics of underlying trials and modeling methods make it difficult to determine the most cost-effective agent. PMID- 23626786 TI - Lipopolysaccharide disrupts the milk-blood barrier by modulating claudins in mammary alveolar tight junctions. AB - Mastitis, inflammation of the mammary gland, is the most costly common disease in the dairy industry, and is caused by mammary pathogenic bacteria, including Escherichia coli. The bacteria invade the mammary alveolar lumen and disrupt the blood-milk barrier. In normal mammary gland, alveolar epithelial tight junctions (TJs) contribute the blood-milk barrier of alveolar epithelium by blocking the leakage of milk components from the luminal side into the blood serum. In this study, we focused on claudin subtypes that participate in the alveolar epithelial TJs, because the composition of claudins is an important factor that affects TJ permeability. In normal mouse lactating mammary glands, alveolar TJs consist of claudin-3 without claudin-1, -4, and -7. In lipopolysaccharide (LPS)-induced mastitis, alveolar TJs showed 2-staged compositional changes in claudins. First, a qualitative change in claudin-3, presumably caused by phosphorylation and participation of claudin-7 in alveolar TJs, was recognized in parallel with the leakage of fluorescein isothiocyanate-conjugated albumin (FITC-albumin) via the alveolar epithelium. Second, claudin-4 participated in alveolar TJs with claudin 3 and claudin-7 12 h after LPS injection. The partial localization of claudin-1 was also observed by immunostaining. Coinciding with the second change of alveolar TJs, the severe disruption of the blood-milk barrier was recognized by ectopic localization of beta-casein and much leakage of FITC-albumin. Furthermore, the localization of toll-like receptor 4 (TLR4) on the luminal side and NFkappaB activation by LPS was observed in the alveolar epithelial cells. We suggest that the weakening and disruption of the blood-milk barrier are caused by compositional changes of claudins in alveolar epithelial TJs through LPS/TLR4 signaling. PMID- 23626787 TI - ATM influences the efficiency of TCRbeta rearrangement, subsequent TCRbeta dependent T cell development, and generation of the pre-selection TCRbeta CDR3 repertoire. AB - Generation and resolution of DNA double-strand breaks is required to assemble antigen-specific receptors from the genes encoding V, D, and J gene segments during recombination. The present report investigates the requirement for ataxia telangiectasia-mutated (ATM) kinase, a component of DNA double-strand break repair, during TCRbeta recombination and in subsequent TCRbeta-dependent repertoire generation and thymocyte development. CD4(-)CD8(-) double negative stage 2/3 thymocytes from ATM-deficient mice have both an increased frequency of cells with DNA break foci at TCRbeta loci and reduced Vbeta-DJbeta rearrangement. Sequencing of TCRbeta complementarity-determining region 3 demonstrates that ATM deficient CD4(+)CD8(+) double positive thymocytes and peripheral T cells have altered processing of coding ends for both in-frame and out-of-frame TCRbeta rearrangements, providing the unique demonstration that ATM deficiency alters the expressed TCRbeta repertoire by a selection-independent mechanism. ATMKO thymi exhibit a partial developmental block in DN cells as they negotiate the beta selection checkpoint to become double negative stage 4 and CD4(+)CD8(+) thymocytes, resulting in reduced numbers of CD4(+)CD8(+) cells. Importantly, expression of a rearranged TCRbeta transgene substantially reverses this defect in CD4(+)CD8(+) cells, directly linking a requirement for ATM during endogenous TCRbeta rearrangement to subsequent TCRbeta-dependent stages of development. These results demonstrate that ATM plays an important role in TCRbeta rearrangement, generation of the TCRbeta CDR3 repertoire, and efficient TCRbeta dependent T cell development. PMID- 23626789 TI - Methylation state of the EDA gene promoter in Chinese X-linked hypohidrotic ectodermal dysplasia carriers. AB - INTRODUCTION: Hypodontia, hypohidrosis, sparse hair and characteristic faces are the main characters of X-linked hypohidrotic ectodermal dysplasia (XLHED) which is caused by genetic ectodysplasin A (EDA) deficiency. Heterozygous female carriers tend to have mild to moderate XLHED phenotype, even though 30% of them present no obvious symptom. METHODS: A large Chinese XLHED family was reported and the entire coding region and exon-intron boundaries of EDA gene were sequenced. To elucidate the mechanism for carriers' tempered phenotype, we analyzed the methylation level on four sites of the promoter of EDA by the pyrosequencing system. RESULTS: A known frameshift mutation (c.573-574 insT) was found in this pedigree. Combined with the pedigrees we reported before, 120 samples comprised of 23 carrier females from 11 families and 97 healthy females were analyzed for the methylation state of EDA promoter. Within 95% confidence interval (CI), 18 (78.26%) carriers were hypermethylated at these 4 sites. CONCLUSION: Chinese XLHED carriers often have a hypermethylated EDA promoter. PMID- 23626788 TI - Prox1 directly interacts with LSD1 and recruits the LSD1/NuRD complex to epigenetically co-repress CYP7A1 transcription. AB - Cholesterol 7alpha-hydroxylase (CYP7A1) catalyzes the first and rate-limiting step in the classical pathway of bile acids synthesis in liver and is crucial for maintaining lipid homeostasis. Hepatocyte nuclear factor 4alpha (HNF4alpha) and alpha1-fetoprotein transcription factor (FTF) are two major transcription factors driving CYP7A1 promoter activity in hepatocytes. Previous researches have shown that Prospero-related homeobox (Prox1) directly interacts with both HNF4alpha and FTF and potently co-represses CYP7A1 transcription and bile acid synthesis through unidentified mechanisms. In this work, mechanisms involved in Prox1 mediated co-repression were explored by identifying Prox1-associated proteins using immunoprecipitation followed by mass spectrometry (IP-MS) methodology. Multiple components of the epigenetically repressive lysine-specific demethylase 1 (LSD1)/nucleosome remodeling and histone deacetylase (NuRD) complex, most notably LSD1 and histone deacetylase 2 (HDAC2), were found to be associated with Prox1 and GST pulldown assay demonstrated that Prox1 directly interacts with LSD1. Sequential chromatin immunoprecipitation (ChIP) assays showed that Prox1 co localizes with HNF4alpha, LSD1 and HDAC2 on CYP7A1 promoter in HepG2 cells. Furthermore, by using ChIP assay on HepG2 cells with endogenous Prox1 knocked down by RNA interference, Prox1 was shown to recruit LSD1 and HDAC2 onto CYP7A1 promoter and cause increased H3K4 demethylation. Finally, bile acids treatment of HepG2 cells, which significantly repressed CYP7A1 transcription, resulted in increased Prox1 and LSD1/NuRD complex occupancy on CYP7A1 promoter with a concurrent increase in H3K4 demethylation and H3/H4 deacetylation. These results showed that Prox1 interacts with LSD1 to recruit the repressive LSD1/NuRD complex to CYP7A1 promoter and co-represses transcription through epigenetic mechanisms. In addition, such Prox1-mediated epigenetic repression is involved in the physiologically essential negative feedback inhibition of CYP7A1 transcription by bile acids. PMID- 23626790 TI - Response of soil respiration to acid rain in forests of different maturity in southern China. AB - The response of soil respiration to acid rain in forests, especially in forests of different maturity, is poorly understood in southern China despite the fact that acid rain has become a serious environmental threat in this region in recent years. Here, we investigated this issue in three subtropical forests of different maturity [i.e. a young pine forest (PF), a transitional mixed conifer and broadleaf forest (MF) and an old-growth broadleaved forest (BF)] in southern China. Soil respiration was measured over two years under four simulated acid rain (SAR) treatments (CK, the local lake water, pH 4.5; T1, water pH 4.0; T2, water pH 3.5; and T3, water pH 3.0). Results indicated that SAR did not significantly affect soil respiration in the PF, whereas it significantly reduced soil respiration in the MF and the BF. The depressed effects on both forests occurred mostly in the warm-wet seasons and were correlated with a decrease in soil microbial activity and in fine root biomass caused by soil acidification under SAR. The sensitivity of the response of soil respiration to SAR showed an increasing trend with the progressive maturity of the three forests, which may result from their differences in acid buffering ability in soil and in litter layer. These results indicated that the depressed effect of acid rain on soil respiration in southern China may be more pronounced in the future in light of the projected change in forest maturity. However, due to the nature of this field study with chronosequence design and the related pseudoreplication for forest types, this inference should be read with caution. Further studies are needed to draw rigorous conclusions regarding the response differences among forests of different maturity using replicated forest types. PMID- 23626791 TI - Low rates of repeat HIV testing despite increased availability of antiretroviral therapy in rural Tanzania: findings from 2003-2010. AB - BACKGROUND: HIV counselling and testing (HCT) services can play an important role in HIV prevention by encouraging safe sexual behaviours and linking HIV-infected clients to antiretroviral therapy (ART). However, regular repeat testing by high risk HIV-negative individuals is important for timely initiation of ART as part of the 'treatment as prevention' approach. AIM: To investigate HCT use during a round of HIV serological surveillance in northwest Tanzania in 2010, and to explore rates of repeat testing between 2003 and 2010. METHODS: HCT services were provided during the fourth, fifth and sixth rounds of serological surveillance in 2003-2004 (Sero-4), 2006-2007 (Sero-5) and 2010 (Sero-6). HCT services have also been available at a government-run health centre and at other clinics in the study area since 2005. Questionnaires administered during sero-surveys collected information on socio-demographic characteristics, sexual behaviour and reported previous use of HCT services. RESULTS: The proportion of participants using HCT increased from 9.4% at Sero-4 to 16.6% at Sero-5 and 25.5% at Sero-6. Among participants attending all three sero-survey rounds (n = 2,010), the proportions using HCT twice or more were low, with 11.1% using the HCT service offered at sero-surveys twice or more, and 25.3% having tested twice or more if reported use of HCT outside of sero-surveys was taken into account. In multivariable analyses, individuals testing HIV-positive were less likely to repeat test than individuals testing HIV-negative (aOR 0.17, 95% CI 0.006-0.52). DISCUSSION/CONCLUSIONS: Although HCT service use increased over time, it was disappointing that the proportions ever testing and ever repeat-testing were not even larger, considering the increasing availability of HCT and ART in the study area. There was some evidence that HIV-negative people with higher risk sexual behaviours were most likely to repeat test, which was encouraging in terms of the potential to pick-up those at greatest risk of HIV-infection. PMID- 23626792 TI - Prevalence of cryptococcal antigenemia and cost-effectiveness of a cryptococcal antigen screening program--Vietnam. AB - BACKGROUND: An estimated 120,000 HIV-associated cryptococcal meningitis (CM) cases occur each year in South and Southeast Asia; early treatment may improve outcomes. The World Health Organization (WHO) recently recommended screening HIV infected adults with CD4<100 cells/mm(3) for serum cryptococcal antigen (CrAg), a marker of early cryptococcal infection, in areas of high CrAg prevalence. We evaluated CrAg prevalence and cost-effectiveness of this screening strategy in HIV-infected adults in northern and southern Vietnam. METHODS: Serum samples were collected and stored during 2009-2012 in Hanoi and Ho Chi Minh City, Vietnam, from HIV-infected, ART-naive patients presenting to care in 12 clinics. All specimens from patients with CD4<100 cells/mm(3) were tested using the CrAg lateral flow assay. We obtained cost estimates from laboratory staff, clinicians and hospital administrators in Vietnam, and evaluated cost-effectiveness using WHO guidelines. RESULTS: Sera from 226 patients [104 (46%) from North Vietnam and 122 (54%) from the South] with CD4<100 cells/mm(3) were available for CrAg testing. Median CD4 count was 40 (range 0-99) cells/mm(3). Nine (4%; 95% CI 2-7%) specimens were CrAg-positive. CrAg prevalence was higher in South Vietnam (6%; 95% CI 3-11%) than in North Vietnam (2%; 95% CI 0-6%) (p = 0.18). Cost per life year gained under a screening scenario was $190, $137, and $119 at CrAg prevalences of 2%, 4% and 6%, respectively. CONCLUSION: CrAg prevalence was higher in southern compared with northern Vietnam; however, CrAg screening would be considered cost-effective by WHO criteria in both regions. Public health officials in Vietnam should consider adding cryptococcal screening to existing national guidelines for HIV/AIDS care. PMID- 23626793 TI - A high throughput screen for RGS proteins using steady state monitoring of free phosphate formation. AB - G-protein coupled receptors are a diverse group that are the target of over 50% of marketed drugs. Activation of these receptors results in the exchange of bound GDP for GTP in the Galpha subunit of the heterotrimeric G-protein. The Galpha subunit dissociates from the beta/gamma subunits and both proceed to affect downstream signaling targets. The signal terminates by the hydrolysis of GTP to GDP and is temporally regulated by Regulators of G-protein Signaling (RGS) proteins that act as GTPase Activating Proteins (GAPs). This makes RGS proteins potentially desirable targets for "tuning" the effects of current therapies as well as developing novel pharmacotherapies. Current methods for evaluating RGS activity depend on laborious and/or expensive techniques. In this study we developed a simple and inexpensive assay for the steady state analysis of RGS protein GAP activity, using RGS4, RGS8 and RGS17 as models. Additionally, we report the use of RGS4 as a model for high throughput assay development. After initial setup, this assay can be conducted in a highly parallel fashion with a read time of less than 8 minutes for a 1536-well plate. The assay exhibited a robust Z-factor of 0.6 in a 1536-well plate. We conducted a pilot screen for inhibitors using a small, 2320 compound library. From this screen, 13 compounds were identified as compounds for further analysis. The successful development of this assay for high-throughput screening provides a low cost, high speed, simple method for assessing RGS protein activity. PMID- 23626794 TI - Crystal structures of a plant trypsin inhibitor from Enterolobium contortisiliquum (EcTI) and of its complex with bovine trypsin. AB - A serine protease inhibitor from Enterolobium contortisiliquum (EcTI) belongs to the Kunitz family of plant inhibitors, common in plant seeds. It was shown that EcTI inhibits the invasion of gastric cancer cells through alterations in integrin-dependent cell signaling pathway. We determined high-resolution crystal structures of free EcTI (at 1.75 A) and complexed with bovine trypsin (at 2 A). High quality of the resulting electron density maps and the redundancy of structural information indicated that the sequence of the crystallized isoform contained 176 residues and differed from the one published previously. The structure of the complex confirmed the standard inhibitory mechanism in which the reactive loop of the inhibitor is docked into trypsin active site with the side chains of Arg64 and Ile65 occupying the S1 and S1' pockets, respectively. The overall conformation of the reactive loop undergoes only minor adjustments upon binding to trypsin. Larger deviations are seen in the vicinity of Arg64, driven by the needs to satisfy specificity requirements. A comparison of the EcTI trypsin complex with the complexes of related Kunitz inhibitors has shown that rigid body rotation of the inhibitors by as much as 15 degrees is required for accurate juxtaposition of the reactive loop with the active site while preserving its conformation. Modeling of the putative complexes of EcTI with several serine proteases and a comparison with equivalent models for other Kunitz inhibitors elucidated the structural basis for the fine differences in their specificity, providing tools that might allow modification of their potency towards the individual enzymes. PMID- 23626795 TI - Interactions among quorum sensing inhibitors. AB - Many pathogenic bacteria use quorum sensing (QS) systems to regulate the expression of virulence genes in a density-dependent manner. In one widespread QS paradigm the enzyme LuxI generates a small diffusible molecule of the acyl homoserine lactone (AHL) family; high cell densities lead to high AHL levels; AHL binds the transcription factor LuxR, triggering it to activate gene expression at a virulence promoter. The emergence of antibiotic resistance has generated interest in alternative anti-microbial therapies that target QS. Inhibitors of LuxI and LuxR have been developed and tested in vivo, and can act at various levels: inhibiting the synthesis of AHL by LuxI, competitively or non competitively inhibiting LuxR, or increasing the turnover of LuxI, LuxR, or AHL. Here use an experimentally validated computational model of LuxI/LuxR QS to study the effects of using inhibitors individually and in combination. The model includes the effect of transcriptional feedback, which generates highly non linear responses as inhibitor levels are increased. For the ubiquitous LuxI feedback virulence systems, inhibitors of LuxI are more effective than those of LuxR when used individually. Paradoxically, we find that LuxR competitive inhibitors, either individually or in combination with other inhibitors, can sometimes increase virulence by weakly activating LuxR. For both LuxI-feedback and LuxR-feedback systems, a combination of LuxR non-competitive inhibitors and LuxI inhibitors act multiplicatively over a broad parameter range. In our analysis, this final strategy emerges as the only robust therapeutic option. PMID- 23626796 TI - TOM40 mediates mitochondrial dysfunction induced by alpha-synuclein accumulation in Parkinson's disease. AB - Alpha-synuclein (alpha-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery--TOM40--might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype alpha-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in alpha-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in alpha-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in alpha-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in alpha Synucleinopathies. PMID- 23626797 TI - Molecular clone and expression of a NAD+-dependent glycerol-3-phosphate dehydrogenase isozyme gene from the halotolerant alga Dunaliella salina. AB - Glycerol is an important osmotically compatible solute in Dunaliella. Glycerol-3 phosphate dehydrogenase (G3PDH) is a key enzyme in the pathway of glycerol synthesis, which converts dihydroxyacetone phosphate (DHAP) to glycerol-3 phosphate. Generally, the glycerol-DHAP cycle pathway, which is driven by G3PDH, is considered as the rate-limiting enzyme to regulate the glycerol level under osmotic shocks. Considering the peculiarity in osmoregulation, the cDNA of a NAD(+)-dependent G3PDH was isolated from D. salina using RACE and RT-PCR approaches in this study. Results indicated that the length of the cDNA sequence of G3PDH was 2,100 bp encoding a 699 amino acid deduced polypeptide whose computational molecular weight was 76.6 kDa. Conserved domain analysis revealed that the G3PDH protein has two independent functional domains, SerB and G3PDH domains. It was predicted that the G3PDH was a nonsecretory protein and may be located in the chloroplast of D. salina. Phylogenetic analysis demonstrated that the D. salina G3PDH had a closer relationship with the G3PDHs from the Dunaliella genus than with those from other species. In addition, the cDNA was subsequently subcloned in the pET-32a(+) vector and was transformed into E. coli strain BL21 (DE3), a expression protein with 100 kDa was identified, which was consistent with the theoretical value. PMID- 23626798 TI - Partner violence and psychosocial distress among female sex workers in China. AB - BACKGROUND: Despite recognized vulnerability of female sex workers (FSW), most data on this population are focused on their HIV and STI prevalence; studies on their experience of partner violence and psychosocial distress are limited, especially FSW in China. METHODS AND FINDINGS: A cross-sectional survey was administered among 1,022 FSW recruited from 9 different types of commercial sex venues in Southwest China. Partner violence scales were adapted from WHO's Women's Health and Domestic Violence scale and psychosocial distress was measured by five indicators, including alcohol intoxication, drug use, suicidal behavior, depression, and loneliness. Random effects modeling was used to control for cluster effects. FINDINGS: About 58% of FSW ever experienced violence from their stable partners, and 45% suffered it from their clients. Partner violence was strongly associated with each of the five measures of psychosocial distress, even after controlling for potential confounders. CONCLUSION: This study is one of the first to examine the association between partner violence and psychosocial distress among FSW in China. The high prevalence of violence experience and distress in this population suggests urgency for intervention. The public health programs targeting FSW should go beyond the focus on HIV/STI prevention and care for the fundamental health and human rights of millions of FSW in China. PMID- 23626799 TI - Next-generation sequencing of the Chrysanthemum nankingense (Asteraceae) transcriptome permits large-scale unigene assembly and SSR marker discovery. AB - BACKGROUND: Simple sequence repeats (SSRs) are ubiquitous in eukaryotic genomes. Chrysanthemum is one of the largest genera in the Asteraceae family. Only few Chrysanthemum expressed sequence tag (EST) sequences have been acquired to date, so the number of available EST-SSR markers is very low. METHODOLOGY/PRINCIPAL FINDINGS: Illumina paired-end sequencing technology produced over 53 million sequencing reads from C. nankingense mRNA. The subsequent de novo assembly yielded 70,895 unigenes, of which 45,789 (64.59%) unigenes showed similarity to the sequences in NCBI database. Out of 45,789 sequences, 107 have hits to the Chrysanthemum Nr protein database; 679 and 277 sequences have hits to the database of Helianthus and Lactuca species, respectively. MISA software identified a large number of putative EST-SSRs, allowing 1,788 primer pairs to be designed from the de novo transcriptome sequence and a further 363 from archival EST sequence. Among 100 primer pairs randomly chosen, 81 markers have amplicons and 20 are polymorphic for genotypes analysis in Chrysanthemum. The results showed that most (but not all) of the assays were transferable across species and that they exposed a significant amount of allelic diversity. CONCLUSIONS/SIGNIFICANCE: SSR markers acquired by transcriptome sequencing are potentially useful for marker-assisted breeding and genetic analysis in the genus Chrysanthemum and its related genera. PMID- 23626800 TI - Electrocardiographic changes associated with smoking and smoking cessation: outcomes from a randomized controlled trial. AB - INTRODUCTION: Cardiovascular disease (CVD) can be detected and quantified by analysis of the electrocardiogram (ECG); however the effects of smoking and smoking cessation on the ECG have not been characterized. METHODS: Standard 12 lead ECGs were performed at baseline and 3 years after subjects enrolled in a prospective, randomized, placebo-controlled clinical trial of smoking cessation pharmacotherapies. ECGs were interpreted using the Minnesota Code ECG Classification. The effects of (i) smoking burden on the prevalence of ECG findings at baseline, and (ii) smoking and smoking cessation on ECG changes after 3 years were investigated by multivariable and multinomial regression analyses. RESULTS: At baseline, 532 smokers were (mean [SD]) 43.3 (11.5) years old, smoked 20.6 (7.9) cigarettes/day, with a smoking burden of 26.7 (18.6) pack-years. Major and minor ECG criteria were identified in 87 (16.4%) and 131 (24.6%) of subjects, respectively. After adjusting for demographic data and known CVD risk factors, higher pack-years was associated with major ECG abnormalities (p = 0.02), but current cigarettes/day (p = 0.23) was not. After 3 years, 42.9% of subjects were abstinent from smoking. New major and minor ECG criteria were observed in 7.2% and 15.6% of subjects respectively, but in similar numbers of abstinent subjects and continuing smokers (p>0.2 for both). Continuing smokers showed significant reduction in current smoking (-8.4 [8.8] cigarettes/day, p<0.001) compared to baseline. CONCLUSIONS: In conclusion, major ECG abnormalities are independently associated with lifetime smoking burden. After 3 years, smoking cessation was not associated with a decrease in ECG abnormalities, although cigarettes smoked/day decreased among continuing smokers. PMID- 23626801 TI - Stress modulates instrumental learning performances in horses (Equus caballus) in interaction with temperament. AB - The present study investigates how the temperament of the animal affects the influence of acute stress on the acquisition and reacquisition processes of a learning task. After temperament was assessed, horses were subjected to a stressor before or after the acquisition session of an instrumental task. Eight days later, horses were subjected to a reacquisition session without any stressor. Stress before acquisition tended to enhance the number of successes at the beginning of the acquisition session. Eight days later, during the reacquisition session, contrary to non-stressed animals, horses stressed after acquisition, and, to a lesser extent, horses stressed before acquisition, did not improve their performance between acquisition and reacquisition sessions. Temperament influenced learning performances in stressed horses only. Particularly, locomotor activity improved performances whereas fearfulness impaired them under stressful conditions. Results suggest that direct exposure to a stressor tended to increase acquisition performances, whereas a state of stress induced by the memory of a stressor, because it has been previously associated with the learning context, impaired reacquisition performances. The negative effect of a state of stress on reacquisition performances appeared to be stronger when exposure to the stressor occurred after rather than before the acquisition session. Temperament had an impact on both acquisition and reacquisition processes, but under stressful conditions only. These results suggest that stress is necessary to reveal the influence of temperament on cognitive performances. PMID- 23626802 TI - Mouse transplant models for evaluating the oncogenic risk of a self-inactivating XSCID lentiviral vector. AB - Hematopoietic stem cell gene therapy requires the use of integrating retroviral vectors in order to stably transmit a therapeutic gene to mature blood cells. Human clinical trials have shown that some vector integration events lead to disrupted regulation of proto-oncogenes resulting in disordered hematopoiesis including T-cell leukemia. Newer vectors have been designed to decrease the incidence of these adverse events but require appropriate pre-clinical assays to demonstrate safety. We have used two distinct mouse serial transplant assays to evaluate the safety of a self-inactivating lentiviral vector intended for use in X-linked severe combined immunodeficiency (XSCID) gene therapy trials. These experiments entailed 28 months of total follow-up and included 386 mice. There were no cases in which the XSCID lentiviral vector clearly caused hematopoietic malignancies, although a single case of B cell malignancy was observed that contained the lentiviral vector as a likely passenger event. In contrast, a SFFV DsRed gamma-retroviral vector resulted in clonal transformation events in multiple secondary recipients. Non-specific pathology not related to vector insertions was noted including T cell leukemias arising from irradiated recipient cells. Overall, this comprehensive study of mouse transplant safety assays demonstrate the relative safety of the XSCID lentiviral vector but also highlight the limitations of these assays. PMID- 23626803 TI - Reduced expression of miR-200 family members contributes to antiestrogen resistance in LY2 human breast cancer cells. AB - INTRODUCTION: The role of miRNAs in acquired endocrine-resistant breast cancer is not fully understood. One hallmark of tumor progression is epithelial-to mesenchymal transition (EMT), characterized by a loss of cell adhesion resulting from reduced E-cadherin and increased cell mobility. miR-200 family members regulate EMT by suppressing expression of transcriptional repressors ZEB1/2. Previously we reported that the expression of miR-200a, miR-200b, and miR-200c was lower in LY2 endocrine-resistant, mesenchymal breast cancer cells compared to parental, endocrine sensitive, epithelial MCF-7 breast cancer cells. Here we investigated the regulation of miR-200 family members and their role in endocrine sensitivity in breast cancer cells. RESULTS: miR-200 family expression was progressively reduced in a breast cancer cell line model of advancing endocrine/tamoxifen (TAM) resistance. Concomitant with miR-200 decrease, there was an increase in ZEB1 mRNA expression. Overexpression of miR-200b or miR-200c in LY2 cells altered cell morphology to a more epithelial appearance and inhibited cell migration. Further, miR-200b and miR-200c overexpression sensitized LY2 cells to growth inhibition by estrogen receptor (ER) antagonists TAM and fulvestrant. Knockdown of ZEB1 in LY2 cells recapitulated the effect of miR-200b and miR-200c overexpression resulting in inhibition of LY2 cell proliferation by TAM and fulvestrant, but not the aromatase inhibitor exemestane. Demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) in combination with histone deacetylase inhibitor trichostatin A (TSA) increased miR-200b and miR-200c in LY2 cells. Concomitant with the increase in miR-200b and miR-200c, ZEB1 expression was decreased and cells appeared more epithelial in morphology and were sensitized to TAM and fulvestrant inhibition. Likewise, knockdown of ZEB1 increased antiestrogen sensitivity of LY2 cells resulting in inhibition of cell proliferation. CONCLUSIONS: Our data indicate that reduced miRNA-200b and miR 200c expression contributes to endocrine resistance in breast cancer cells and that the reduced expression of these miR-200 family members in endocrine resistant cells can be reversed by 5-aza-dC+TSA. PMID- 23626804 TI - Treatment of colorectal cancer using a combination of liposomal irinotecan (Irinophore CTM) and 5-fluorouracil. AB - PURPOSE: To investigate the use of liposomal irinotecan (Irinophore CTM) plus or minus 5-fluorouracil (5-FU) for the treatment of colorectal cancer. EXPERIMENTAL DESIGN: The effect of irinotecan (IRI) and/or 5-FU exposure times on cytotoxicity was assessed in vitro against HT-29 or LS174T human colon carcinoma cells. The pharmacokinetics and biodistribution of Irinophore CTM (IrCTM) and 5-FU, administered alone or in combination, were compared in vivo. A subcutaneous model of HT-29 human colorectal cancer in Rag2-M mice was utilized to assess the efficacy of IrCTM alone, and in combination with 5-FU. RESULTS: The cytotoxicity of IRI and 5-FU were strongly dependent on exposure time. Synergistic interactions were observed following prolonged exposure to IRI/5-FU combinations. Pharmacokinetics/biodistribution studies demonstrated that the 5-FU elimination rate was decreased significantly when 5-FU was co-administered intravenously with IrCTM, versus alone. Significant decreases in 5-FU elimination were also observed in plasma, with an associated increase of 5-FU in some tissues when 5-FU was given by intraperitoneal injection and IrCTM was given intravenously. The elimination of IrCTM was not significantly different when administered alone or in combination with 5-FU. Therapeutic studies demonstrated that single agent IrCTM was significantly more effective than the combination of IRI/5-FU; surprisingly, IrCTM/5-FU combinations were no more effective than IrCTM alone. The administration of combinations of 5-FU (16 mg/kg) and IrCTM (60 mg IRI/kg) showed increased toxicity when compared to IrCTM alone. Treatment with IrCTM alone (60 mg IRI/kg) delayed the time required for a 5-fold increase in initial tumor volume to day 49, compared to day 23 for controls. When IrCTM (40 mg IRI/kg) was used in combination with 5-FU (16 mg/kg), the time to increase tumor volume 5-fold was 43 days, which was comparable to that achieved when using IrCTM alone (40 mg IRI/kg). CONCLUSIONS: Single agent IrCTM was well tolerated and has significant therapeutic potential. IrCTM may be a suitable replacement for IRI treatment, but its use with free 5-FU is complicated by IrCTM-engendered changes in 5-FU pharmacokinetics/biodistribution which are associated with increased toxicity when using the combination. PMID- 23626805 TI - Proinflammatory cytokines are elevated in serum of patients with multiple system atrophy. AB - BACKGROUND: Despite several lines of evidence from preclinical and post-mortem studies suggesting that inflammation is involved in Multiple System Atrophy (MSA), no previous studies have measured peripheral indices of inflammation in MSA patients. METHODS: We measured C-reactive protein, interleukin (IL)-6, soluble IL-2 receptor and tumor necrosis factor (TNF)-alpha in blood samples from MSA patients (n = 14) and healthy controls (n = 40). RESULTS: IL-6 and TNF-alpha were significantly elevated in MSA patients compared to healthy controls. After controlling for the potentially confounding effects of age, gender, and somatic co-morbidities, a diagnosis of MSA was still significantly associated with high levels of TNF-alpha. Higher TNF-alpha levels were associated with less severe motor symptoms and earlier disease stage. CONCLUSIONS: Our findings are in line with the hypothesis that inflammation might be involved at an early stage of MSA pathophysiology. PMID- 23626806 TI - Contrast water therapy and exercise induced muscle damage: a systematic review and meta-analysis. AB - The aim of this systematic review was to examine the effect of Contrast Water Therapy (CWT) on recovery following exercise induced muscle damage. Controlled trials were identified from computerized literature searching and citation tracking performed up to February 2013. Eighteen trials met the inclusion criteria; all had a high risk of bias. Pooled data from 13 studies showed that CWT resulted in significantly greater improvements in muscle soreness at the five follow-up time points (<6, 24, 48, 72 and 96 hours) in comparison to passive recovery. Pooled data also showed that CWT significantly reduced muscle strength loss at each follow-up time (<6, 24, 48, 72 and 96 hours) in comparison to passive recovery. Despite comparing CWT to a large number of other recovery interventions, including cold water immersion, warm water immersion, compression, active recovery and stretching, there was little evidence for a superior treatment intervention. The current evidence base shows that CWT is superior to using passive recovery or rest after exercise; the magnitudes of these effects may be most relevant to an elite sporting population. There seems to be little difference in recovery outcome between CWT and other popular recovery interventions. PMID- 23626807 TI - Internalization of Met requires the co-receptor CD44v6 and its link to ERM proteins. AB - Receptor Tyrosine Kinases (RTKs) are involved in many cellular processes and play a major role in the control of cell fate. For these reasons, RTK activation is maintained under tight control. Met is an essential RTK that induces proliferation, differentiation, migration, survival and branching morphogenesis. Deregulation of Met by overexpression, amplification or lack of effective degradation leads to cancer and metastasis. We have shown that Met relies on CD44v6 for its activation and for signaling in several cancer cell lines and also in primary cells. In this paper, we show that internalization of Met is dependent on CD44v6 and the binding of Ezrin to the CD44v6 cytoplasmic domain. Both CD44v6 and Met are co-internalized upon Hepatocyte Growth Factor induction suggesting that Met-induced signaling from the endosomes relies on its collaboration with CD44v6 and the link to the cytoskeleton provided by ERM proteins. PMID- 23626808 TI - Factors associated with self-reported repeat HIV testing after a negative result in Durban, South Africa. AB - BACKGROUND: Routine screening for HIV infection leads to early detection and treatment. We examined patient characteristics associated with repeated screening in a high prevalence country. METHODS: We analyzed data from a cohort of 5,229 adults presenting for rapid HIV testing in the outpatient departments of 2 South African hospitals from November 2006 to August 2010. Patients were eligible if they were >=18 years, reported no previous diagnosis with HIV infection, and not pregnant. Before testing, participants completed a questionnaire including gender, age, HIV testing history, health status, and knowledge about HIV and acquaintances with HIV. Enrollment HIV test results and CD4 counts were abstracted from the medical record. We present prevalence of HIV infection and median CD4 counts by HIV testing history (first-time vs. repeat). We estimated adjusted relative risks (ARR's) for repeat testing by demographics, health status, and knowledge of HIV and others with HIV in a generalized linear model. RESULTS: Of 4,877 participants with HIV test results available, 26% (N = 1258) were repeat testers. Repeat testers were less likely than first-time testers to be HIV-infected (34% vs. 54%, p<0.001). Median CD4 count was higher among repeat than first-time testers (201/uL vs. 147/uL, p<0.001). Among those HIV negative at enrollment (N = 2,499), repeat testing was more common among those with family or friends living with HIV (ARR 1.50, 95% CI: 1.33-1.68), women (ARR: 1.24, 95% CI: 1.11-1.40), and those self-reporting very good health (ARR: 1.28, 95% CI: 1.12 1.45). CONCLUSIONS: In this high prevalence setting, repeat testing was common among those undergoing HIV screening, and was associated with female sex, lower prevalence of HIV infection, and higher CD4 counts at diagnosis. PMID- 23626809 TI - Interferon-beta induces distinct gene expression response patterns in human monocytes versus T cells. AB - BACKGROUND: Monocytes, which are key players in innate immunity, are outnumbered by neutrophils and lymphocytes among peripheral white blood cells. The cytokine interferon-beta (IFN-beta) is widely used as an immunomodulatory drug for multiple sclerosis and its functional pathways in peripheral blood mononuclear cells (PBMCs) have been previously described. The aim of the present study was to identify novel, cell-specific IFN-beta functions and pathways in tumor necrosis factor (TNF)-alpha-activated monocytes that may have been missed in studies using PBMCs. METHODOLOGY/PRINCIPAL FINDINGS: Whole genome gene expression profiles of human monocytes and T cells were compared following in vitro priming to TNF-alpha and overnight exposure to IFN-beta. Statistical analyses of the gene expression data revealed a cell-type-specific change of 699 transcripts, 667 monocyte specific transcripts, 21 T cell-specific transcripts and 11 transcripts with either a difference in the response direction or a difference in the magnitude of response. RT-PCR revealed a set of differentially expressed genes (DEGs), exhibiting responses to IFN-beta that are modulated by TNF-alpha in monocytes, such as RIPK2 and CD83, but not in T cells or PBMCs. Known IFN-beta promoter response elements, such as ISRE, were enriched in T cell DEGs but not in monocyte DEGs. The overall directionality of the gene expression regulation by IFN-beta was different in T cells and monocytes, with up-regulation more prevalent in T cells, and a similar extent of up and down-regulation recorded in monocytes. CONCLUSIONS: By focusing on the response of distinct cell types and by evaluating the combined effects of two cytokines with pro and anti-inflammatory activities, we were able to present two new findings First, new IFN-beta response pathways and genes, some of which were monocytes specific; second, a cell-specific modulation of the IFN-beta response transcriptome by TNF-alpha. PMID- 23626810 TI - Aft2, a novel transcription regulator, is required for iron metabolism, oxidative stress, surface adhesion and hyphal development in Candida albicans. AB - Morphological transition and iron metabolism are closely relevant to Candida albicans pathogenicity and virulence. In our previous study, we demonstrated that C. albicans Aft2 plays an important role in ferric reductase activity and virulence. Here, we further explored the roles of C. albicans Aft2 in numerous cellular processes. We found that C. albicans Aft2 exhibited an important role in iron metabolism through bi-directional regulation effects on iron-regulon expression. Deletion of AFT2 reduced cellular iron accumulation under iron deficient conditions. Furthermore, both reactive oxygen species (ROS) generation and superoxide dismutase (SOD) activity were remarkably increased in the aft2Delta/Delta mutant, which were thought to be responsible for the defective responses to oxidative stress. However, we found that over-expression of C. albicans AFT2 under the regulation of the strong PGK1 promoter could not effectively rescue Saccharomyces cerevisiae aft1Delta mutant defects in some cellular processes, such as cell-wall assembly, ion homeostasis and alkaline resistance, suggesting a possibility that C. albicans Aft2 weakened its functional role of regulating some cellular metabolism during the evolutionary process. Interestingly, deletion of AFT2 in C. albicans increased cell surface hydrophobicity, cell flocculation and the ability of adhesion to polystyrene surfaces. In addition, our results also revealed that C. albicans Aft2 played a dual role in regulating hypha-specific genes under solid and liquid hyphal inducing conditions. Deletion of AFT2 caused an impaired invasive growth in solid medium, but an increased filamentous aggregation and growth in liquid conditions. Moreover, iron deficiency and environmental cues induced nuclear import of Aft2, providing additional evidence for the roles of Aft2 in transcriptional regulation. PMID- 23626811 TI - Spermine and citrate as metabolic biomarkers for assessing prostate cancer aggressiveness. AB - Separating indolent from aggressive prostate cancer is an important clinical challenge for identifying patients eligible for active surveillance, thereby reducing the risk of overtreatment. The purpose of this study was to assess prostate cancer aggressiveness by metabolic profiling of prostatectomy tissue and to identify specific metabolites as biomarkers for aggressiveness. Prostate tissue samples (n = 158, 48 patients) with a high cancer content (mean: 61.8%) were obtained using a new harvesting method, and metabolic profiles of samples representing different Gleason scores (GS) were acquired by high resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS). Multivariate analysis (PLS, PLS-DA) and absolute quantification (LCModel) were used to examine the ability to predict cancer aggressiveness by comparing low grade (GS = 6, n = 30) and high grade (GS>=7, n = 81) cancer with normal adjacent tissue (n = 47). High grade cancer tissue was distinguished from low grade cancer tissue by decreased concentrations of spermine (p = 0.0044) and citrate (p = 7.73.10(-4)), and an increase in the clinically applied (total choline+creatine+polyamines)/citrate (CCP/C) ratio (p = 2.17.10(-4)). The metabolic profiles were significantly correlated to the GS obtained from each tissue sample (r = 0.71), and cancer tissue could be distinguished from normal tissue with sensitivity 86.9% and specificity 85.2%. Overall, our findings show that metabolic profiling can separate aggressive from indolent prostate cancer. This holds promise for the benefit of applying in vivo magnetic resonance spectroscopy (MRS) within clinical MR imaging investigations, and HR-MAS analysis of transrectal ultrasound-guided biopsies has a potential as an additional diagnostic tool. PMID- 23626812 TI - Top-down modulation on perceptual decision with balanced inhibition through feedforward and feedback inhibitory neurons. AB - Recent physiological studies have shown that neurons in various regions of the central nervous systems continuously receive noisy excitatory and inhibitory synaptic inputs in a balanced and covaried fashion. While this balanced synaptic input (BSI) is typically described in terms of maintaining the stability of neural circuits, a number of experimental and theoretical studies have suggested that BSI plays a proactive role in brain functions such as top-down modulation for executive control. Two issues have remained unclear in this picture. First, given the noisy nature of neuronal activities in neural circuits, how do the modulatory effects change if the top-down control implements BSI with different ratios between inhibition and excitation? Second, how is a top-down BSI realized via only excitatory long-range projections in the neocortex? To address the first issue, we systematically tested how the inhibition/excitation ratio affects the accuracy and reaction times of a spiking neural circuit model of perceptual decision. We defined an energy function to characterize the network dynamics, and found that different ratios modulate the energy function of the circuit differently and form two distinct functional modes. To address the second issue, we tested BSI with long-distance projection to inhibitory neurons that are either feedforward or feedback, depending on whether these inhibitory neurons do or do not receive inputs from local excitatory cells, respectively. We found that BSI occurs in both cases. Furthermore, when relying on feedback inhibitory neurons, through the recurrent interactions inside the circuit, BSI dynamically and automatically speeds up the decision by gradually reducing its inhibitory component in the course of a trial when a decision process takes too long. PMID- 23626813 TI - Genetic variation in vitamin B-12 content of bovine milk and its association with SNP along the bovine genome. AB - Vitamin B-12 (also called cobalamin) is essential for human health and current intake levels of vitamin B-12 are considered to be too low. Natural enrichment of the vitamin B-12 content in milk, an important dietary source of vitamin B-12, may help to increase vitamin B-12 intake. Natural enrichment of the milk vitamin B-12 content could be achieved through genetic selection, provided there is genetic variation between cows with respect to the vitamin B-12 content in their milk. A substantial amount of genetic variation in vitamin B-12 content was detected among raw milk samples of 544 first-lactation Dutch Holstein Friesian cows. The presence of genetic variation between animals in vitamin B-12 content in milk indicates that the genotype of the cow affects the amount of vitamin B-12 that ends up in her milk and, consequently, that the average milk vitamin B-12 content of the cow population can be increased by genetic selection. A genome wide association study revealed significant association between 68 SNP and vitamin B-12 content in raw milk of 487 first-lactation Dutch Holstein Friesian cows. This knowledge facilitates genetic selection for milk vitamin B-12 content. It also contributes to the understanding of the biological mechanism responsible for the observed genetic variation in vitamin B-12 content in milk. None of the 68 significantly associated SNP were in or near known candidate genes involved in transport of vitamin B-12 through the gastrointestinal tract, uptake by ileum epithelial cells, export from ileal cells, transport through the blood, uptake from the blood, intracellular processing, or reabsorption by the kidneys. Probably, associations relate to genes involved in alternative pathways of well studied processes or to genes involved in less well-studied processes such as ruminal production of vitamin B-12 or secretion of vitamin B-12 by the mammary gland. PMID- 23626814 TI - Increased cytokines response in patients with tuberculosis complicated with chronic obstructive pulmonary disease. AB - OBJECTIVES: To explore the change and its significance of cytokines in patients with pulmonary tuberculosis complicated with COPD. METHODS: The immune function of 152 cases of pulmonary tuberculosis with COPD was detected to compare with 150 cases of patients with pulmonary tuberculosis, 157 cases of patients with COPD and 50 cases of healthy volunteers who were in the hospital during the same period. T lymphocyte cell population in peripheral blood was detected by flow cytometry. The serum levels of sIL-2R, IL-6, IFN-gamma, TNF-alpha were measured using ELISA. RESULTS: The percentage of CD4+ T cells in TB patients with or without COPD and COPD patients without TB was significantly lower than that in control group. The percentage of CD4+ T cells in patients with TB and COPD was significantly lower than that in the non-COPD TB patients. The percentage of CD8+ T cells was higher in the TB patients group than that in control group. The CD4+/CD8+ ratio in the TB patients group was significantly lower than that in control group. The concentrations of sIL-2R, IL-6, TNF-alpha, IFN-gamma in TB patients with or without COPD and COPD patients without TB were significantly higher than those in control group. In addition, sIL-2R, IL-6, TNF-alpha concentrations in the patients with TB and COPD were higher than those in the non COPD TB patients. The concentrations of sIL-2R, IL-6, TNF-alpha, IFN-gamma in COPD patients with TB were significantly higher than those in COPD patients without TB. There was a significant negative correlation between serum levels of TNF-alpha, IL-6 and FEV1 (%, predicted) in COPD without TB group. CONCLUSIONS: The patients with pulmonary tuberculosis complicated with COPD were impaired in cellular immunity, and its extent of immune impairment is more serious than those of the patients with pulmonary tuberculosis and the patients with COPD. PMID- 23626815 TI - Coupled dynamics of iron and phosphorus in sediments of an oligotrophic coastal basin and the impact of anaerobic oxidation of methane. AB - Studies of phosphorus (P) dynamics in surface sediments of lakes and coastal seas typically emphasize the role of coupled iron (Fe), sulfur (S) and P cycling for sediment P burial and release. Here, we show that anaerobic oxidation of methane (AOM) also may impact sediment P cycling in such systems. Using porewater and sediment profiles for sites in an oligotrophic coastal basin (Bothnian Sea), we provide evidence for the formation of Fe-bound P (possibly vivianite; Fe3(PO4)2(.)8H2O) below the zone of AOM with sulfate. Here, dissolved Fe(2+) released from oxides is no longer scavenged by sulfide and high concentrations of both dissolved Fe(2+) (>1 mM) and PO4 in the porewater allow supersaturation with respect to vivianite to be reached. Besides formation of Fe(II)-P, preservation of Fe-oxide bound P likely also contributes to permanent burial of P in Bothnian Sea sediments. Preliminary budget calculations suggest that the burial of Fe bound P allows these sediments to act as a major sink for P from the adjacent eutrophic Baltic Proper. PMID- 23626816 TI - Induction of viable but nonculturable Escherichia coli O157:H7 by high pressure CO2 and its characteristics. AB - The viable but nonculturable (VBNC) state is a survival strategy adopted by many pathogens when exposed to harsh environmental stresses. In this study, we investigated for the first time that whether high pressure CO2 (HPCD), one of the nonthermal pasteurization techniques, can induce Escherichia coli O157:H7 into the VBNC state. By measuring plate counts, viable cell counts and total cell counts, E. coli O157:H7 in 0.85% NaCl solution (pH 7.0) was able to enter the VBNC state by HPCD treatment at 5 MPa and four temperatures (25 degrees C, 31 degrees C, 34 degrees C and 37 degrees C). Meanwhile, with the improvement of treatment temperature, the time required for E. coli O157:H7 to enter VBNC state would shorten. Enzymatic activities in these VBNC cells were lower than those in the exponential-phase cells by using API ZYM kit, which were also reduced with increasing the treatment temperature, but the mechanical resistance of the VBNC cells to sonication was enhanced. These results further confirmed VBNC state was a self-protection mechanism for some bacteria, which minimized cellular energetic requirements and increased the cell resistance. When incubated in tryptic soy broth at 37 degrees C, the VBNC cells induced by HPCD treatment at 25 degrees C, 31 degrees C and 34 degrees C achieved resuscitation, but their resuscitation capabilities decreased with increasing the treatment temperature. Furthermore, electron microscopy revealed changes in the morphology and interior structure of the VBNC cells and the resuscitated cells. These results demonstrated that HPCD could induce E. coli O157:H7 into the VBNC state. Therefore, it is necessary to detect if there exist VBNC microorganisms in HPCD-treated products by molecular based methods for food safety. PMID- 23626817 TI - The PI3K/AKT/mTOR signaling pathway is overactivated in primary aldosteronism. AB - BACKGROUND: To date, the available non-invasive remedies for primary aldosteronism are not satisfactory in clinical practice. The phosphoinositide 3 kinase (PI3Ks)/protein kinase B (PKB or AKT)/mammalian target of rapamycin (mTOR) signaling pathway is essential for tumorigenesis and metastasis in many types of human tumors, including renal cancer, adrenal carcinoma and pheochromocytoma. The possibility that this pathway is also necessary for the pathogenesis of primary aldosteronism has not yet been explored. To answer this question, we investigated the activity of the PI3K/AKT/mTOR signaling pathway in normal adrenal glands (NAGs), primary aldosteronism (PA) patients and NCI-H295R cells. METHODOLOGY/PRINCIPAL FINDINGS: Between January 2005 and December 2011, we retrospectively reviewed the records of 45 patients with PA. We compared clinical characteristics (age, gender and biochemical data) and the expression of phospho AKT (p-AKT), phospho-mTOR (p-mTOR), phospho-S6 (p-S6) and vascular endothelial growth factor (VEGF) by immunohistochemical staining and western blotting, analyzing 30 aldosterone-producing adenomas (APAs), 15 idiopathic hyperaldosteronism (IHA) tissues and 12 NAGs following nephrectomy for renal tumors (control group). Compared with the control group, most of the PA patients presented with polydipsia, polyuria, resistant hypertension, profound hypokalemia, hyperaldosteronemia and decreased plasma renin activity. Compared with normal zona glomerulosa, the levels of p-AKT, p-mTOR, p-S6 and VEGF were significantly upregulated in APA and IHA. No significant differences were found between APA and IHA in the expression of these proteins. Additionally, positive correlations existed between the plasma aldosterone levels and the expression of p-AKT and p-mTOR. In vitro studies showed that mTOR inhibitor rapamycin could inhibit cell proliferation in NCI-H295R cells in a dose- and time-dependent manner. Furthermore, this inhibitor also decreased aldosterone secretion. CONCLUSIONS: Our data suggest that the PI3K/AKT/mTOR signaling pathway, which was overactivated in APA and IHA compared with normal zona glomerulosa, may mediate aldosterone hypersecretion and participate in the development of PA. PMID- 23626818 TI - Cell surface localization of alpha3beta4 nicotinic acetylcholine receptors is regulated by N-cadherin homotypic binding and actomyosin contractility. AB - Neuronal nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central and peripheral nervous system and are localized at synaptic and extrasynaptic sites of the cell membrane. However, the mechanisms regulating the localization of nicotinic receptors in distinct domains of the cell membrane are not well understood. N-cadherin is a cell adhesion molecule that mediates homotypic binding between apposed cell membranes and regulates the actin cytoskeleton through protein interactions with the cytoplasmic domain. At synaptic contacts, N-cadherin is commonly localized adjacent to the active zone and the postsynaptic density, suggesting that N-cadherin contributes to the assembly of the synaptic complex. To examine whether N-cadherin homotypic binding regulates the cell surface localization of nicotinic receptors, this study used heterologous expression of N-cadherin and alpha3beta4 nAChR subunits C-terminally fused to a myc-tag epitope in Chinese hamster ovary cells. Expression levels of alpha3beta4 nAChRs at cell-cell contacts and at contact-free cell membrane were analyzed by confocal microscopy. alpha3beta4 nAChRs were found distributed over the entire surface of contacting cells lacking N-cadherin. In contrast, N cadherin-mediated cell-cell contacts were devoid of alpha3beta4 nAChRs. Cell-cell contacts mediated by N-cadherin-deleted proteins lacking the beta-catenin binding region or the entire cytoplasmic domain showed control levels of alpha3beta4 nAChRs expression. Inhibition of actin polymerization with latrunculin A and cytochalasin D did not affect alpha3beta4 nAChRs localization within N-cadherin mediated cell-cell contacts. However, treatment with the Rho associated kinase inhibitor Y27632 resulted in a significant increase in alpha3beta4 nAChR levels within N-cadherin-mediated cell-cell contacts. Analysis of alpha3beta4 nAChRs localization in polarized Caco-2 cells showed specific expression on the apical cell membrane and colocalization with apical F-actin and the actin nucleator Arp3. These results indicate that actomyosin contractility downstream of N cadherin homotypic binding regulates the cell surface localization of alpha3beta4 nAChRs presumably through interactions with a particular pool of F-actin. PMID- 23626819 TI - Is mislocalization during saccades related to the position of the saccade target within the image or to the gaze position at the end of the saccade? AB - A stimulus that is flashed around the time of a saccade tends to be mislocalized in the direction of the saccade target. Our question is whether the mislocalization is related to the position of the saccade target within the image or to the gaze position at the end of the saccade. We separated the two with a visual illusion that influences the perceived distance to the target of the saccade and thus saccade endpoint without affecting the perceived position of the saccade target within the image. We asked participants to make horizontal saccades from the left to the right end of the shaft of a Muller-Lyer figure. Around the time of the saccade, we flashed a bar at one of five possible positions and asked participants to indicate its location by touching the screen. As expected, participants made shorter saccades along the fins-in (<->) configuration than along the fins-out (>-<) configuration of the figure. The illusion also influenced the mislocalization pattern during saccades, with flashes presented with the fins-out configuration being perceived beyond flashes presented with the fins-in configuration. The difference between the patterns of mislocalization for bars flashed during the saccade for the two configurations corresponded quantitatively with a prediction based on compression towards the saccade endpoint considering the magnitude of the effect of the illusion on saccade amplitude. We conclude that mislocalization is related to the eye position at the end of the saccade, rather than to the position of the saccade target within the image. PMID- 23626820 TI - Children's phthalate intakes and resultant cumulative exposures estimated from urine compared with estimates from dust ingestion, inhalation and dermal absorption in their homes and daycare centers. AB - Total daily intakes of diethyl phthalate (DEP), di(n-butyl) phthalate (DnBP), di(isobutyl) phthalate (DiBP), butyl benzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP) were calculated from phthalate metabolite levels measured in the urine of 431 Danish children between 3 and 6 years of age. For each child the intake attributable to exposures in the indoor environment via dust ingestion, inhalation and dermal absorption were estimated from the phthalate levels in the dust collected from the child's home and daycare center. Based on the urine samples, DEHP had the highest total daily intake (median: 4.42 ug/d/kg-bw) and BBzP the lowest (median: 0.49 ug/d/kg-bw). For DEP, DnBP and DiBP, exposures to air and dust in the indoor environment accounted for approximately 100%, 15% and 50% of the total intake, respectively, with dermal absorption from the gas-phase being the major exposure pathway. More than 90% of the total intake of BBzP and DEHP came from sources other than indoor air and dust. Daily intake of DnBP and DiBP from all exposure pathways, based on levels of metabolites in urine samples, exceeded the Tolerable Daily Intake (TDI) for 22 and 23 children, respectively. Indoor exposures resulted in an average daily DiBP intake that exceeded the TDI for 14 children. Using the concept of relative cumulative Tolerable Daily Intake (TDI(cum)), which is applicable for phthalates that have established TDIs based on the same health endpoint, we examined the cumulative total exposure to DnBP, DiBP and DEHP from all pathways; it exceeded the tolerable levels for 30% of the children. From the three indoor pathways alone, several children had a cumulative intake that exceeded TDI(cum). Exposures to phthalates present in the air and dust indoors meaningfully contribute to a child's total intake of certain phthalates. Such exposures, by themselves, may lead to intakes exceeding current limit values. PMID- 23626822 TI - Methamphetamine and dopamine receptor D1 regulate entrainment of murine circadian oscillators. AB - We investigated the effect of methamphetamine (MA) injections on the circadian organization of behavior and individual tissues in the mouse. Scheduled, daily injections of MA resulted in anticipatory activity, with an increase in locomotor activity immediately prior to the time of injection. Daily MA also shifted the peak time of PER2 expression in the liver, pituitary, and salivary glands. It has been suggested that reward pathways, and dopamine signaling in particular, may underlie the effects of MA on the circadian system. To test this hypothesis, we examined the effect of the D1 receptor antagonist SCH23390 (SCH) on circadian rhythms. The MA-induced shift in the phase of pituitary and salivary glands was attenuated by pretreatment with the D1 antagonist SCH23390 (SCH). Interestingly, daily SCH, administered alone, also affected some circadian oscillators. The livers and lungs (but not pituitaries or salivary glands) of mice treated with daily injections of SCH displayed disrupted rhythms of PER2 expression, suggesting that D1 receptor signaling is important for entrainment of these organs. From these results, we conclude that MA has widespread effects within the circadian system, and that these effects are mediated, at least in part, by the dopaminergic system. This study also identifies a role for dopamine signaling in normal entrainment of circadian oscillators. PMID- 23626821 TI - The focal adhesion: a regulated component of aortic stiffness. AB - Increased aortic stiffness is an acknowledged predictor and cause of cardiovascular disease. The sources and mechanisms of vascular stiffness are not well understood, although the extracellular matrix (ECM) has been assumed to be a major component. We tested here the hypothesis that the focal adhesions (FAs) connecting the cortical cytoskeleton of vascular smooth muscle cells (VSMCs) to the matrix in the aortic wall are a component of aortic stiffness and that this component is dynamically regulated. First, we examined a model system in which magnetic tweezers could be used to monitor cellular cortical stiffness, serum starved A7r5 aortic smooth muscle cells. Lysophosphatidic acid (LPA), an activator of myosin that increases cell contractility, increased cortical stiffness. A small molecule inhibitor of Src-dependent FA recycling, PP2, was found to significantly inhibit LPA-induced increases in cortical stiffness, as well as tension-induced increases in FA size. To directly test the applicability of these results to force and stiffness development at the level of vascular tissue, we monitored mouse aorta ring stiffness with small sinusoidal length oscillations during agonist-induced contraction. The alpha-agonist phenylephrine, which also increases myosin activation and contractility, increased tissue stress and stiffness in a PP2- and FAK inhibitor 14-attenuated manner. Subsequent phosphotyrosine screening and follow-up with phosphosite-specific antibodies confirmed that the effects of PP2 and FAK inhibitor 14 in vascular tissue involve FA proteins, including FAK, CAS, and paxillin. Thus, in the present study we identify, for the first time, the FA of the VSMC, in particular the FAK-Src signaling complex, as a significant subcellular regulator of aortic stiffness and stress. PMID- 23626823 TI - Mannose-binding lectin blunts macrophage polarization and ameliorates lupus nephritis. AB - BACKGROUND: Deficiency in clearance of self nuclear antigens, including DNA, is the hallmark of systemic lupus erythematosus (SLE), a chronic autoimmnue disease characterized by the production of various autoantibodies, immune complex deposition and severe organ damage. Our previous studies revealed that administration of syngeneic BALB/c mice with activated lymphocyte-derived DNA (ALD-DNA) could induce SLE disease. Mannose-binding lectin (MBL), a secreted pattern recognition receptor with binding activity to DNA, has been proved to be a modulator of inflammation, but whether MBL takes responsibility for DNA clearance, modulates the DNA-mediated immune responses, and is involved in the development of DNA-induced SLE disease remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: The levels of serum MBL significantly decreased in lupus mice induced by ALD-DNA and were negatively correlated with SLE disease. MBL blunted macrophage M2b polarization by inhibiting the MAPK and NF-kappaB signaling while enhancing the activation of CREB. Furthermore, MBL suppressed the ability of ALD-DNA-stimulated macrophages to polarize T cells toward Th1 cells and Th17 cells. Importantly, MBL supplement in vivo could ameliorate lupus nephritis. CONCLUSION/SIGNIFICANCE: These results suggest MBL supplement could alleviate SLE disease and might imply a potential therapeutic strategy for DNA induced SLE, which would further our understanding of the protective role of MBL in SLE disease. PMID- 23626824 TI - Large number discrimination in newborn fish. AB - Quantitative abilities have been reported in a wide range of species, including fish. Recent studies have shown that adult guppies (Poecilia reticulata) can spontaneously select the larger number of conspecifics. In particular the evidence collected in literature suggest the existence of two distinct systems of number representation: a precise system up to 4 units, and an approximate system for larger numbers. Spontaneous numerical abilities, however, seem to be limited to 4 units at birth and it is currently unclear whether or not the large number system is absent during the first days of life. In the present study, we investigated whether newborn guppies can be trained to discriminate between large quantities. Subjects were required to discriminate between groups of dots with a 0.50 ratio (e.g., 7 vs. 14) in order to obtain a food reward. To dissociate the roles of number and continuous quantities that co-vary with numerical information (such as cumulative surface area, space and density), three different experiments were set up: in Exp. 1 number and continuous quantities were simultaneously available. In Exp. 2 we controlled for continuous quantities and only numerical information was available; in Exp. 3 numerical information was made irrelevant and only continuous quantities were available. Subjects successfully solved the tasks in Exp. 1 and 2, providing the first evidence of large number discrimination in newborn fish. No discrimination was found in experiment 3, meaning that number acuity is better than spatial acuity. A comparison with the onset of numerical abilities observed in shoal-choice tests suggests that training procedures can promote the development of numerical abilities in guppies. PMID- 23626825 TI - FDG PET and MRI in logopenic primary progressive aphasia versus dementia of the Alzheimer's type. AB - OBJECTIVES: The logopenic variant of primary progressive aphasia is an atypical clinical variant of Alzheimer's disease which is typically characterized by left temporoparietal atrophy on magnetic resonance imaging and hypometabolism on F-18 fluorodeoxyglucose positron emission tomography. We aimed to characterize and compare patterns of atrophy and hypometabolism in logopenic primary progressive aphasia, and determine which brain regions and imaging modality best differentiates logopenic primary progressive aphasia from typical dementia of the Alzheimer's type. METHODS: A total of 27 logopenic primary progressive aphasia subjects underwent fluorodeoxyglucose positron emission tomography and volumetric magnetic resonance imaging. These subjects were matched to 27 controls and 27 subjects with dementia of the Alzheimer's type. Patterns of atrophy and hypometabolism were assessed at the voxel and region-level using Statistical Parametric Mapping. Penalized logistic regression analysis was used to determine what combinations of regions best discriminate between groups. RESULTS: Atrophy and hypometabolism was observed in lateral temporoparietal and medial parietal lobes, left greater than right, and left frontal lobe in the logopenic group. The logopenic group showed greater left inferior, middle and superior lateral temporal atrophy (inferior p = 0.02; middle p = 0.007, superior p = 0.002) and hypometabolism (inferior p = 0.006, middle p = 0.002, superior p = 0.001), and less right medial temporal atrophy (p = 0.02) and hypometabolism (p<0.001), and right posterior cingulate hypometabolism (p<0.001) than dementia of the Alzheimer's type. An age-adjusted penalized logistic model incorporating atrophy and hypometabolism achieved excellent discrimination (area under the receiver operator characteristic curve = 0.89) between logopenic and dementia of the Alzheimer's type subjects, with optimal discrimination achieved using right medial temporal and posterior cingulate hypometabolism, left inferior, middle and superior temporal hypometabolism, and left superior temporal volume. CONCLUSIONS: Patterns of atrophy and hypometabolism both differ between logopenic primary progressive aphasia and dementia of the Alzheimer's type and both modalities provide excellent discrimination between groups. PMID- 23626826 TI - Differential contributions of vision, touch and muscle proprioception to the coding of hand movements. AB - To further elucidate the mechanisms underlying multisensory integration, this study examines the controversial issue of whether congruent inputs from three different sensory sources can enhance the perception of hand movement. Illusory sensations of clockwise rotations of the right hand were induced by either separately or simultaneously stimulating visual, tactile and muscle proprioceptive channels at various intensity levels. For this purpose, mechanical vibrations were applied to the pollicis longus muscle group in the subjects' wrists, and a textured disk was rotated under the palmar skin of the subjects' right hands while a background visual scene was projected onto the rotating disk. The elicited kinaesthetic illusions were copied by the subjects in real time and the EMG activity in the adductor and abductor wrist muscles was recorded. The results show that the velocity of the perceived movements and the amplitude of the corresponding motor responses were modulated by the nature and intensity of the stimulation. Combining two sensory modalities resulted in faster movement illusions, except for the case of visuo-tactile co-stimulation. When a third sensory input was added to the bimodal combinations, the perceptual responses increased only when a muscle proprioceptive stimulation was added to a visuo tactile combination. Otherwise, trisensory stimulation did not override bimodal conditions that already included a muscle proprioceptive stimulation. We confirmed that vision or touch alone can encode the kinematic parameters of hand movement, as is known for muscle proprioception. When these three sensory modalities are available, they contribute unequally to kinaesthesia. In addition to muscle proprioception, the complementary kinaesthetic content of visual or tactile inputs may optimize the velocity estimation of an on-going movement, whereas the redundant kinaesthetic content of the visual and tactile inputs may rather enhance the latency of the perception. PMID- 23626827 TI - Reduced threshold for induction of LTP by activation of dopamine D1/D5 receptors at hippocampal CA1-subiculum synapses. AB - The phasic release of dopamine in the hippocampal formation has been shown to facilitate the encoding of novel information. There is evidence that the subiculum operates as a detector and distributor of sensory information, which incorporates the novelty and relevance of signals received from CA1. The subiculum acts as the final hippocampal relay station for outgoing information. Subicular pyramidal cells have been classified as regular- and burst-spiking neurons. The goal of the present study was to study the effect of dopamine D1/D5 receptor activation on synaptic transmission and plasticity in the subicular regular-spiking neurons of 4-6 week old Wistar rats. We demonstrate that prior activation of D1/D5 receptors reduces the threshold for the induction of long term potentiation (LTP) in subicular regular-spiking neurons. Our results indicate that D1/D5 receptor activation facilitates a postsynaptic form of LTP in subicular regular-spiking cells that is NMDA receptor-dependent, relies on postsynaptic Ca(2+) signaling, and requires the activation of protein kinase A. The enhanced propensity of subicular regular-spiking cells to express postsynaptic LTP after activation of D1/D5 receptors provides an intriguing mechanism for the encoding of hippocampal output information. PMID- 23626828 TI - Function and expression of cystic fibrosis transmembrane conductance regulator after small intestinal transplantation in mice. AB - The secretion function of intestinal graft is one of the most important factors for successful intestinal transplantation. Cystic fibrosis transmembrane conductance regulator (CFTR) mediates HCO3(-) and Cl(-) secretions in intestinal epithelial cells. In this study, we made investigation on the expression and function of CFTR in an experimental model of murine small intestinal transplantation. Heterotopic intestinal transplantations were performed in syngeneic mice. The mRNA and protein expressions of CFTR were analyzed by real time PCR and western blot. Murine intestinal mucosal HCO3(-) and Cl(-) secretions were examined in vitro in Ussing chambers by the pH stat and short circuit current (I(sc)) techniques. The results showed that forskolin, an activator of CFTR, stimulated jejunal mucosal epithelial HCO3(-) and Cl(-) secretions in mice, but forskolin-stimulated HCO3(-) and Cl(-) secretions in donor and recipient jejunal mucosae of mice after heterotopic jejunal transplantation were markedly decreased, compared with controls (P<0.001). The mRNA and protein expression levels of CFTR in donor and recipient jejunal mucosae of mice were also markedly lower than those in controls (P<0.001), and the mRNA and protein expression levels of tumor necrosis factor alpha (TNFalpha) were markedly increased in donor jejunal mucosae of mice (P<0.001), compared with controls. Further experiments showed that TNFalpha down-regulated the expression of CFTR mRNA in murine jejunal mucosa. In conclusion, after intestinal transplantation, the function of CFTR was impaired, and its mRNA and protein expressions were down-regulated, which may be induced by TNFalpha. PMID- 23626829 TI - Distinct modulation of event-related potentials during motor preparation in patients with motor conversion disorder. AB - OBJECTIVE: Conversion paresis patients and healthy people feigning weakness both exhibit weak voluntary movement without detectable neuropathology. Uniquely, conversion patients lack a sense of conscious awareness of the origin of their impairment. We investigated whether conversion paresis patients show distinct electroencephalographic (EEG) markers associated with their unconscious movement deficits. METHODS: Six unilateral upper limb conversion paresis patients, 12 feigning participants asked to mimic weakness and 12 control participants performed a precued reaction time task, requiring movements of either hand, depending on precue information. Performance measures (force, reaction and movement time), and event-related EEG potentials (ERP) were compared, between groups and across hands or hemisphere, using linear mixed models. RESULTS: Feigners generated the same inter-hand difference in reaction and movement time as expressed by patients, even though no specific targets were set nor feedback given on these measures. We found novel ERP signatures specific to patients. When the symptomatic hand was precued, the P3 ERP component accompanying the precue was dramatically larger in patients than in feigning participants. Additionally, in patients the earlier N1 ERP component was diminished when the precue signalled either the symptomatic or asymptomatic hand. CONCLUSIONS: These results are consistent with previous suggestions that lack of awareness of the origin of their symptoms in conversion disorder patients may result from suppression of brain activity normally related to self-agency. In patients the diminished N1 to all precues is consistent with a generalised reduction in cognitive processing of movement-related precues. The P3 enhancement in patients is unlikely to simply reflect changes required for generation of impaired movements, because it was not seen in feigners showing the same behavioural deficits. Rather, this P3 enhancement in patients may represent a neural biomarker of unconscious processes, including additional emotional loading, related to active suppression of brain circuits involved in the attribution of self-agency. PMID- 23626830 TI - A method to prioritize quantitative traits and individuals for sequencing in family-based studies. AB - Owing to recent advances in DNA sequencing, it is now technically feasible to evaluate the contribution of rare variation to complex traits and diseases. However, it is still cost prohibitive to sequence the whole genome (or exome) of all individuals in each study. For quantitative traits, one strategy to reduce cost is to sequence individuals in the tails of the trait distribution. However, the next challenge becomes how to prioritize traits and individuals for sequencing since individuals are often characterized for dozens of medically relevant traits. In this article, we describe a new method, the Rare Variant Kinship Test (RVKT), which leverages relationship information in family-based studies to identify quantitative traits that are likely influenced by rare variants. Conditional on nuclear families and extended pedigrees, we evaluate the power of the RVKT via simulation. Not unexpectedly, the power of our method depends strongly on effect size, and to a lesser extent, on the frequency of the rare variant and the number and type of relationships in the sample. As an illustration, we also apply our method to data from two genetic studies in the Old Order Amish, a founder population with extensive genealogical records. Remarkably, we implicate the presence of a rare variant that lowers fasting triglyceride levels in the Heredity and Phenotype Intervention (HAPI) Heart study (p = 0.044), consistent with the presence of a previously identified null mutation in the APOC3 gene that lowers fasting triglyceride levels in HAPI Heart study participants. PMID- 23626831 TI - Differential virulence gene expression of group A Streptococcus serotype M3 in response to co-culture with Moraxella catarrhalis. AB - Streptococcus pyogenes (group A Streptococcus, GAS) and Moraxella catarrhalis are important colonizers and (opportunistic) pathogens of the human respiratory tract. However, current knowledge regarding colonization and pathogenic potential of these two pathogens is based on work involving single bacterial species, even though the interplay between respiratory bacterial species is increasingly important in niche occupation and the development of disease. Therefore, to further define and understand polymicrobial species interactions, we investigated whether gene expression (and hence virulence potential) of GAS would be affected upon co-culture with M. catarrhalis. For co-culture experiments, GAS and M. catarrhalis were cultured in Todd-Hewitt broth supplemented with 0.2% yeast extract (THY) at 37 degrees C with 5% CO2 aeration. Each strain was grown in triplicate so that triplicate experiments could be performed. Bacterial RNA was isolated, cDNA synthesized, and microarray transcriptome expression analysis performed. We observed significantly increased (>=4-fold) expression for genes playing a role in GAS virulence such as hyaluronan synthase (hasA), streptococcal mitogenic exotoxin Z (smeZ) and IgG endopeptidase (ideS). In contrast, significantly decreased (>=4-fold) expression was observed in genes involved in energy metabolism and in 12 conserved GAS two-component regulatory systems. This study provides the first evidence that M. catarrhalis increases GAS virulence gene expression during co-culture, and again shows the importance of polymicrobial infections in directing bacterial virulence. PMID- 23626832 TI - Bumblebee venom serine protease increases fungal insecticidal virulence by inducing insect melanization. AB - Insect-killing (entomopathogenic) fungi have high potential for controlling agriculturally harmful pests. However, their pathogenicity is slow, and this is one reason for their poor acceptance as a fungal insecticide. The expression of bumblebee, Bombus ignitus, venom serine protease (VSP) by Beauveria bassiana (ERL1170) induced melanization of yellow spotted longicorn beetles (Psacothea hilaris) as an over-reactive immune response, and caused substantially earlier mortality in beet armyworm (Spodopetra exigua) larvae when compared to the wild type. No fungal outgrowth or sporulation was observed on the melanized insects, thus suggesting a self-restriction of the dispersal of the genetically modified fungus in the environment. The research is the first use of a multi-functional bumblebee VSP to significantly increase the speed of fungal pathogenicity, while minimizing the dispersal of the fungal transformant in the environment. PMID- 23626833 TI - Estradiol represses the G(D3) synthase gene ST8SIA1 expression in human breast cancer cells by preventing NFkappaB binding to ST8SIA1 promoter. AB - Recent data have underlined a possible role of G(D3) synthase (GD3S) and complex gangliosides in Estrogen Receptor (ER) negative breast cancer progression. Here, we describe the main transcript of the GD3S coding gene ST8SIA1 expressed in breast tumors. We characterized the corresponding core promoter in Hs578T breast cancer cells and showed that estradiol decreases ST8SIA1 mRNA expression in ER positive MCF-7 cells and ERalpha-transfected ER-negative Hs578T cells. The activity of the core promoter sequence of ST8SIA1 is also repressed by estradiol. The core promoter of ST8SIA1 contains two putative Estrogen Response Elements (ERE) that were not found to be involved in the promoter activity pathway. However, NFkappaB was shown to be involved in ST8SIA1 transcriptional activation and we demonstrated that estradiol prevents NFkappaB to bind to ST8SIA1 core promoter in ERalpha expressing breast cancer cells by inhibiting p65 and p50 nucleus localization. The activation of NFkappaB pathway in ER-negative tumors, due to the absence of estradiol signaling, might explain the overexpression of G(D3) synthase in this tumor subtype. PMID- 23626834 TI - Human metapneumovirus glycoprotein G disrupts mitochondrial signaling in airway epithelial cells. AB - Human metapneumovirus (hMPV) is a recently identified RNA virus belonging to the Paramyxoviridae family. It is a common cause of respiratory tract infections in children, adults, and immunocompromised patients, for which no specific treatment or vaccine is available. Recent investigations in our lab identified hMPV glycoprotein G as an important virulence factor, as a recombinant virus lacking the G protein (rhMPV-DeltaG) exhibited enhanced production of important immune and antiviral mediators, such as cytokines, chemokines and type I interferon (IFN) in airway epithelial cells, and expression of G protein alone inhibits cellular signaling dependent on retinoic induced gene (RIG)-I, a RNA helicase with a fundamental role in initiating hMPV-induced cellular responses. In this study, we have further investigated the mechanism underlying the inhibitory role of hMPV G protein on RIG-I-dependent signaling. We found that the interaction of hMPV G with RIG-I occurs primarily through the CARD domains of RIG-I N-terminus, preventing RIG-I association with the adaptor protein MAVS (mitochondrial antiviral signaling protein), recruitment of RIG-I to mitochondria, as well as the interaction between mitochondria and mitochondria-associated membrane (MAM) component of the endoplasmic reticulum (ER), which contains STINGS, an important part of the viral-induced RIG-I/MAVS signaling pathway, leading in the end to the inhibition of cytokine, chemokine and type I IFN expression. Mutagenesis analysis showed that hMPV G protein cytoplasmic domain played a major role in the observed inhibitory activity, and recombinant viruses expressing a G protein with amino acid substitution in position 2 and 3 recapitulated most of the phenotype observed with rhMPV-DeltaG mutant upon infection of airway epithelial cells. PMID- 23626835 TI - Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration. AB - Fragile X associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder caused by aberrant expansion of CGG repeats in 5' UTR of FMR1 gene. The elevated mRNA confers a toxic gain-of-function thought to be the critical event of pathogenesis. Expressing rCGG90 repeats of the human FMR1 5'UTR in Drosophila is sufficient to induce neurodegeneration. Rapamycin has been demonstrated to attenuate neurotoxicity by inducing autophagy in various animal models of neurodegenerative diseases. Surprisingly, we observed rapamycin exacerbated rCGG90-induced neurodegenerative phenotypes through an autophagy independent mechanism. CGG90 expression levels of FXTAS flies exposed to rapamycin presented no significant differences. We further demonstrated that activation of the mammalian target of rapamycin (mTOR) signaling could suppress neurodegeneration of FXTAS. These findings indicate that rapamycin will exacerbate neurodegeneration, and that enhancing autophagy is insufficient to alleviate neurotoxicity in FXTAS. Moreover, these results suggest mTOR and its downstream molecules as new therapeutic targets for FXTAS by showing significant protection against neurodegeneration. PMID- 23626836 TI - Anthrax lethal toxin downregulates claudin-5 expression in human endothelial tight junctions. AB - Vascular leakage pathologies such as pleural effusion and hemorrhage are hallmarks of anthrax pathogenesis. We previously reported that anthrax lethal toxin (LT), the major virulence factor of anthrax, reduces barrier function in cultured primary human microvascular endothelial cells. Here, we show that LT induced barrier dysfunction is accompanied by the reduced expression of the endothelial tight junction (TJ) protein claudin-5 but no change in the expression of other TJ components occludin, ZO-1, ZO-2, or the adherens junction (AJ) protein VE-cadherin. The downregulation of claudin-5 correlated temporally and dose-dependently with the reduction of transendothelial electrical resistance. LT induced loss of claudin-5 was independent of cell death and preceded the appearance of actin stress fibers and altered AJ morphology. Pharmacological inhibition of MEK-1/2, two kinases that are proteolytically inactivated by LT, showed a similar reduction in claudin-5 expression. We found that LT reduced claudin-5 mRNA levels but did not accelerate the rate of claudin-5 degradation. Mice challenged with LT also showed significant reduction in claudin-5 expression. Together, these findings support a possible role for LT disruption of endothelial TJs in the vascular leakage pathologies of anthrax. PMID- 23626837 TI - Sox9-regulated miRNA-574-3p inhibits chondrogenic differentiation of mesenchymal stem cells. AB - The aim of this study was to identify new microRNAs (miRNAs) that are modulated during the differentiation of mesenchymal stem cells (MSCs) toward chondrocytes. Using large scale miRNA arrays, we compared the expression of miRNAs in MSCs (day 0) and at early time points (day 0.5 and 3) after chondrogenesis induction. Transfection of premiRNA or antagomiRNA was performed on MSCs before chondrogenesis induction and expression of miRNAs and chondrocyte markers was evaluated at different time points during differentiation by RT-qPCR. Among miRNAs that were modulated during chondrogenesis, we identified miR-574-3p as an early up-regulated miRNA. We found that miR-574-3p up-regulation is mediated via direct binding of Sox9 to its promoter region and demonstrated by reporter assay that retinoid X receptor (RXR)alpha is one gene specifically targeted by the miRNA. In vitro transfection of MSCs with premiR-574-3p resulted in the inhibition of chondrogenesis demonstrating its role during the commitment of MSCs towards chondrocytes. In vivo, however, both up- and down-regulation of miR-574 3p expression inhibited differentiation toward cartilage and bone in a model of heterotopic ossification. In conclusion, we demonstrated that Sox9-dependent up regulation of miR-574-3p results in RXRalpha down-regulation. Manipulating miR 574-3p levels both in vitro and in vivo inhibited chondrogenesis suggesting that miR-574-3p might be required for chondrocyte lineage maintenance but also that of MSC multipotency. PMID- 23626838 TI - Toxocara infection in psychiatric inpatients: a case control seroprevalence study. AB - BACKGROUND: There is poor knowledge about the epidemiology of toxocariasis in psychiatric patients. AIMS: Determine the seroepidemiology of Toxocara infection in psychiatric patients. METHODS: Through a case-control seroprevalence study, 128 psychiatric inpatients and 276 control subjects were compared for the presence of anti-Toxocara IgG antibodies in Durango, Mexico. Socio-demographic, clinical, and behavioral characteristics of inpatients associated with toxocariasis were also investigated. RESULTS: Six of the 128 (4.7%) psychiatric inpatients, and 3 (1.1%) of the 276 controls were positive for anti-Toxocara IgG antibodies (P = 0.03). Stratification by age showed that Toxocara seroprevalence was significantly (P = 0.02) higher in patients aged <=50 years old (6/90?6.7%) than controls of the same age (2/163?1.2%). While Toxocara seroprevalence was similar in patients and controls aged >50 years old. Stratification by gender showed that Toxocara seroprevalence was significantly (P = 0.03) higher in female patients (2/37?5.4%) than in female controls (0/166?0%). No statistically significant associations between Toxocara seropositivity and clinical characteristics were found. In contrast, Toxocara seropositivity was associated with consumption of goat meat and raw sea snail. CONCLUSIONS: This is the first report of toxocariasis in psychiatric inpatients in Mexico. Further studies with larger sample sizes are needed to elucidate the association of toxocariasis with psychiatric diseases. The role of the consumption of goat meat and raw sea snail in the transmission of Toxocara deserve further investigation. PMID- 23626839 TI - HDAC inhibition induces increased choline uptake and elevated phosphocholine levels in MCF7 breast cancer cells. AB - Histone deacetylase (HDAC) inhibitors have emerged as effective antineoplastic agents in the clinic. Studies from our lab and others have reported that magnetic resonance spectroscopy (MRS)-detectable phosphocholine (PC) is elevated following SAHA treatment, providing a potential noninvasive biomarker of response. Typically, elevated PC is associated with cancer while a decrease in PC accompanies response to antineoplastic treatment. The goal of this study was therefore to elucidate the underlying biochemical mechanism by which HDAC inhibition leads to elevated PC. We investigated the effect of SAHA on MCF-7 breast cancer cells using (13)C MRS to monitor [1,2-(13)C] choline uptake and phosphorylation to PC. We found that PC synthesis was significantly higher in treated cells, representing 154+/-19% of control. This was within standard deviation of the increase in total PC levels detected by (31)P MRS (129+/-7% of control). Furthermore, cellular choline kinase activity was elevated (177+/-31%), while cytidylyltransferase activity was unchanged. Expression of the intermediate affinity choline transporter SLC44A1 and choline kinase alpha increased (144% and 161%, respectively) relative to control, as determined by mRNA microarray analysis with protein-level confirmation by Western blotting. Taken together, our findings indicate that the increase in PC levels following SAHA treatment results from its elevated synthesis. Additionally, the concentration of glycerophosphocholine (GPC) increased significantly with treatment to 210+/-45%. This is likely due to the upregulated expression of several phospholipase A2 (PLA2) isoforms, resulting in increased PLA2 activity (162+/-18%) in SAHA-treated cells. Importantly, the levels of total choline (tCho)-containing metabolites, comprised of choline, PC and GPC, are readily detectable clinically using (1)H MRS. Our findings thus provide an important step in validating clinically translatable non-invasive imaging methods for follow-up diagnostics of HDAC inhibitor treatment. PMID- 23626840 TI - Generation of inducible immortalized dendritic cells with proper immune function in vitro and in vivo. AB - Dendritic cells are the professional antigen presenting cells of innate immunity and key players in maintaining the balance of immune responses. Studies with dendritic cells are mainly limited by their low numbers in vivo and their difficult maintenance in vitro. We differentiated bone marrow cells from transgenic mice expressing an inducible SV40 large T-antigen into dendritic cells. When immortalized by dexamethasone and doxycycline, these cells were stable in long-term culture. In the absence of dexamethasone and doxycycline (de induction), dendritic cells displayed properties of primary cells, characterized by expression of classical dendritic cell surface markers CD11c, CD11b, MHCII, CD40 and CD86. Furthermore, de-induced lipopolysaccharide activated dendritic cells secreted IL-1beta, IL-6, TNFalpha and IL-12. De-induced, Ovalbumin-loaded dendritic cells polarize CD4(+) T cells into Th1, Th17 and Th2 cells, indicating their correct antigen presenting property. Consistent with intratracheal application of Ovalbumin-loaded primary dendritic cells into mice, the application of de-induced dendritic cells resulted in recruitment of lymphocytes to the lungs. In summary, we successfully expanded dendritic cells using conditional immortalization. The generated dendritic cells demonstrate the characteristic immunophenotype of primary dendritic cells and will facilitate further studies on immunomodulatory properties of dendritic cells. PMID- 23626841 TI - Impacts of nitrate and nitrite on physiology of Shewanella oneidensis. AB - Shewanella oneidensis exhibits a remarkable versatility in anaerobic respiration, which largely relies on its diverse respiratory pathways. Some of these are expressed in response to the existence of their corresponding electron acceptors (EAs) under aerobic conditions. However, little is known about respiration and the impact of non-oxygen EAs on the physiology of the microorganism when oxygen is present. Here we undertook a study to elucidate the basis for nitrate and nitrite inhibition of growth under aerobic conditions. We discovered that nitrate in the form of NaNO3 exerts its inhibitory effects as a precursor to nitrite at low concentrations and as an osmotic-stress provider (Na(+)) at high concentrations. In contrast, nitrite is extremely toxic, with 25 mM abolishing growth completely. We subsequently found that oxygen represses utilization of all EAs but nitrate. To order to utilize EAs with less positive redox potential, such as nitrite and fumarate, S. oneidensis must enter the stationary phase, when oxygen respiration becomes unfavorable. In addition, we demonstrated that during aerobic respiration the cytochrome bd oxidase confers S. oneidensis resistance to nitrite, which likely functions via nitric oxide (NO). PMID- 23626842 TI - Multicellular tumor spheroids for evaluation of cytotoxicity and tumor growth inhibitory effects of nanomedicines in vitro: a comparison of docetaxel-loaded block copolymer micelles and Taxotere(r). AB - While 3-D tissue models have received increasing attention over the past several decades in the development of traditional anti-cancer therapies, their potential application for the evaluation of advanced drug delivery systems such as nanomedicines has been largely overlooked. In particular, new insight into drug resistance associated with the 3-D tumor microenvironment has called into question the validity of 2-D models for prediction of in vivo anti-tumor activity. In this work, a series of complementary assays was established for evaluating the in vitro efficacy of docetaxel (DTX) -loaded block copolymer micelles (BCM+DTX) and Taxotere(r) in 3-D multicellular tumor spheroid (MCTS) cultures. Spheroids were found to be significantly more resistant to treatment than monolayer cultures in a cell line dependent manner. Limitations in treatment efficacy were attributed to mechanisms of resistance associated with properties of the spheroid microenvironment. DTX-loaded micelles demonstrated greater therapeutic effect in both monolayer and spheroid cultures in comparison to Taxotere(r). Overall, this work demonstrates the use of spheroids as a viable platform for the evaluation of nanomedicines in conditions which more closely reflect the in vivo tumor microenvironment relative to traditional monolayer cultures. By adaptation of traditional cell-based assays, spheroids have the potential to serve as intermediaries between traditional in vitro and in vivo models for high-throughput assessment of therapeutic candidates. PMID- 23626843 TI - Gain-of-function mutations in the K(ATP) channel (KCNJ11) impair coordinated hand eye tracking. AB - BACKGROUND: Gain-of-function mutations in the ATP-sensitive potassium channel can cause permanent neonatal diabetes mellitus (PNDM) or neonatal diabetes accompanied by a constellation of neurological symptoms (iDEND syndrome). Studies of a mouse model of iDEND syndrome revealed that cerebellar Purkinje cell electrical activity was impaired and that the mice exhibited poor motor coordination. In this study, we probed the hand-eye coordination of PNDM and iDEND patients using visual tracking tasks to see if poor motor coordination is also a feature of the human disease. METHODS: Control participants (n = 14), patients with iDEND syndrome (n = 6 or 7), and patients with PNDM (n = 7) completed three computer-based tasks in which a moving target was tracked with a joystick-controlled cursor. Patients with PNDM and iDEND were being treated with sulphonylurea drugs at the time of testing. RESULTS: No differences were seen between PNDM patients and controls. Patients with iDEND syndrome were significantly less accurate than controls in two of the three tasks. The greatest differences were seen when iDEND patients tracked blanked targets, i.e. when predictive tracking was required. In this task, iDEND patients incurred more discrepancy errors (p = 0.009) and more velocity errors (p= 0.009) than controls. CONCLUSIONS: These results identify impaired hand-eye coordination as a new clinical feature of iDEND. The aetiology of this feature is likely to involve cerebellar dysfunction. The data further suggest that sulphonylurea doses that control the diabetes of these patients may be insufficient to fully correct their neurological symptoms. PMID- 23626844 TI - Hypothalamic inhibition of acetyl-CoA carboxylase stimulates hepatic counter regulatory response independent of AMPK activation in rats. AB - BACKGROUND: Hypothalamic AMPK acts as a cell energy sensor and can modulate food intake, glucose homeostasis, and fatty acid biosynthesis. Intrahypothalamic fatty acid injection is known to suppress liver glucose production, mainly by activation of hypothalamic ATP-sensitive potassium (K(ATP)) channels. Since all models employed seem to involve malonyl-CoA biosynthesis, we hypothesized that acetyl-CoA carboxylase can modulate the counter-regulatory response independent of nutrient availability. METHODOLOGY/PRINCIPAL FINDINGS: In this study employing immunoblot, real-time PCR, ELISA, and biochemical measurements, we showed that reduction of the hypothalamic expression of acetyl-CoA carboxylase by antisense oligonucleotide after intraventricular injection increased food intake and NPY mRNA, and diminished the expression of CART, CRH, and TRH mRNA. Additionally, as in fasted rats, in antisense oligonucleotide-treated rats, serum glucagon and ketone bodies increased, while the levels of serum insulin and hepatic glycogen diminished. The reduction of hypothalamic acetyl-CoA carboxylase also increased PEPCK expression, AMPK phosphorylation, and glucose production in the liver. Interestingly, these effects were observed without modification of hypothalamic AMPK phosphorylation. CONCLUSION/SIGNIFICANCE: Hypothalamic ACC inhibition can activate hepatic counter-regulatory response independent of hypothalamic AMPK activation. PMID- 23626845 TI - Strain field mapping of dislocations in a Ge/Si heterostructure. AB - Ge/Si heterostructure with fully strain-relaxed Ge film was grown on a Si (001) substrate by using a two-step process by ultra-high vacuum chemical vapor deposition. The dislocations in the Ge/Si heterostructure were experimentally investigated by high-resolution transmission electron microscopy (HRTEM). The dislocations at the Ge/Si interface were identified to be 90 degrees full-edge dislocations, which are the most efficient way for obtaining a fully relaxed Ge film. The only defect found in the Ge epitaxial film was a 60 degrees dislocation. The nanoscale strain field of the dislocations was mapped by geometric phase analysis technique from the HRTEM image. The strain field around the edge component of the 60 degrees dislocation core was compared with those of the Peierls-Nabarro and Foreman dislocation models. Comparison results show that the Foreman model with a = 1.5 can describe appropriately the strain field around the edge component of a 60 degrees dislocation core in a relaxed Ge film on a Si substrate. PMID- 23626846 TI - Induction of broadly neutralising HCV antibodies in mice by integration-deficient lentiviral vector-based pseudotyped particles. AB - INTRODUCTION: Integration-deficient lentiviral vectors (IDLVs) are a promising platform for immunisation to elicit both humoral immunity and cellular mediated immunity (CMI). Here, we compared the specific immunity in mice immunised via different regimens (homologous and cocktail) with IDLV-based HCV pseudoparticles (HCVpps) carrying pseudotyped glycoproteins E1E2 and bearing the HCV NS3 gene. Humoral and cell-mediated immune responses were also evaluated after IDLV-HCVpp immunisation combined with heterologous rAd5-CE1E2 priming protocols. Sera from the mice effectively elicited anti-E1, -E2, and -NS3 antibody responses, and neutralised various HCVpp subtypes (1a, 1b, 2a, 3a and 5a). No significant CMI was detected in the groups immunised with IDLV-based HCVpps. In contrast, the combination of rAd5-CE1E2 priming and IDLV-based HCVpp boosting induced significant CMI against multiple antigens (E1, E2, and NS3). CONCLUSION: IDLV based HCVpps are a promising vaccination platform and the combination of rAd5 CE1E2 and IDLV-based HCVpp prime-boost strategy should be further explored for the development of a cross-protective HCV vaccine. PMID- 23626847 TI - Loss of the inducible Hsp70 delays the inflammatory response to skeletal muscle injury and severely impairs muscle regeneration. AB - Skeletal muscle regeneration following injury is a highly coordinated process that involves transient muscle inflammation, removal of necrotic cellular debris and subsequent replacement of damaged myofibers through secondary myogenesis. However, the molecular mechanisms which coordinate these events are only beginning to be defined. In the current study we demonstrate that Heat shock protein 70 (Hsp70) is increased following muscle injury, and is necessary for the normal sequence of events following severe injury induced by cardiotoxin, and physiological injury induced by modified muscle use. Indeed, Hsp70 ablated mice showed a significantly delayed inflammatory response to muscle injury induced by cardiotoxin, with nearly undetected levels of both neutrophil and macrophage markers 24 hours post-injury. At later time points, Hsp70 ablated mice showed sustained muscle inflammation and necrosis, calcium deposition and impaired fiber regeneration that persisted several weeks post-injury. Through rescue experiments reintroducing Hsp70 intracellular expression plasmids into muscles of Hsp70 ablated mice either prior to injury or post-injury, we confirm that Hsp70 optimally promotes muscle regeneration when expressed during both the inflammatory phase that predominates in the first four days following severe injury and the regenerative phase that predominates thereafter. Additional rescue experiments reintroducing Hsp70 protein into the extracellular microenvironment of injured muscles at the onset of injury provides further evidence that Hsp70 released from damaged muscle may drive the early inflammatory response to injury. Importantly, following induction of physiological injury through muscle reloading following a period of muscle disuse, reduced inflammation in 3-day reloaded muscles of Hsp70 ablated mice was associated with preservation of myofibers, and increased muscle force production at later time points compared to WT. Collectively our findings indicate that depending on the nature and severity of muscle injury, therapeutics which differentially target both intracellular and extracellular localized Hsp70 may optimally preserve muscle tissue and promote muscle functional recovery. PMID- 23626848 TI - From epidemiology to daily life: linking daily life stress reactivity to persistence of psychotic experiences in a longitudinal general population study. AB - Subclinical psychotic experiences at the level of the general population are common, forming an extended psychosis phenotype with clinical psychosis. Persistence of subclinical experiences is associated with transition to later mental disorder. Increased daily life stress reactivity is considered an endophenotype for psychotic disorders. We examined, in a longitudinal framework, whether baseline momentary assessment markers of stress reactivity would predict persistence of subclinical psychotic experiences over time. In a general population sample of female twins (N = 566), the Experience Sampling Method (ESM; repetitive random sampling of momentary emotions, psychotic experiences and context) was used to assess (emotional and psychotic) daily life stress reactivity. Persistence of subclinical psychotic experiences was based on the Community Assessment of Psychic Experiences (CAPE), assessed three times over 14 months post-baseline. It was investigated whether baseline daily life emotional and psychotic stress reactivity predicted persistence of psychotic experiences over time. Higher levels of emotional stress reactivity (a decrease in positive and an increase in negative affect in response to stress), and increased psychotic reactivity to daily stress was found in individuals with persistent psychotic experiences over time compared to individuals with transient psychotic experiences. The results suggest that markers of daily life stress reactivity may predict "macro-level" persistence of normally transient expression of psychotic liability over time. Linking daily life markers of altered reactivity in terms of emotions and psychotic experiences to longitudinal persistence of psychotic experiences, associated with increased risk of transition to overt mental disorder, may contribute to earlier and more accurate diagnosis of risk. PMID- 23626849 TI - Extreme variations of pCO2 and pH in a macrophyte meadow of the Baltic Sea in summer: evidence of the effect of photosynthesis and local upwelling. AB - The impact of ocean acidification on benthic habitats is a major preoccupation of the scientific community. However, the natural variability of pCO2 and pH in those habitats remains understudied, especially in temperate areas. In this study we investigated temporal variations of the carbonate system in nearshore macrophyte meadows of the western Baltic Sea. These are key benthic ecosystems, providing spawning and nursery areas as well as food to numerous commercially important species. In situ pCO2, pH (total scale), salinity and PAR irradiance were measured with a continuous recording sensor package dropped in a shallow macrophyte meadow (Eckernforde bay, western Baltic Sea) during three different weeks in July (pCO2 and PAR only), August and September 2011.The mean (+/- SD) pCO2 in July was 383+/-117 uatm. The mean (+/- SD) pCO2 and pH(tot) in August were 239+/-20 uatm and 8.22+/-0.1, respectively. The mean (+/- SD) pCO2 and pH(tot) in September were 1082+/-711 uatm and 7.83+/-0.40, respectively. Daily variations of pCO2 due to photosynthesis and respiration (difference between daily maximum and minimum) were of the same order of magnitude: 281+/-88 uatm, 219+/-89 MUatm and 1488+/-574 uatm in July, August and September respectively. The observed variations of pCO2 were explained through a statistical model considering wind direction and speed together with PAR irradiance. At a time scale of days to weeks, local upwelling of elevated pCO2 water masses with offshore winds drives the variation. Within days, primary production is responsible. The results demonstrate the high variability of the carbonate system in nearshore macrophyte meadows depending on meteorology and biological activities. We highlight the need to incorporate these variations in future pCO2 scenarios and experimental designs for nearshore habitats. PMID- 23626850 TI - Linking injury to outcome in acute kidney injury: a matter of sensitivity. AB - Current consensus definitions of Acute Kidney Injury (AKI) utilise thresholds of change in serum or plasma creatinine and urine output. Biomarkers of renal injury have been validated against these definitions. These biomarkers have also been shown to be independently associated with mortality and need for dialysis. For AKI definitions to include these structural biomarkers, there is a need for an independent outcome against which to judge both markers of functional change and structural markers of injury. We illustrate how sensitivity to need for dialysis and death can be used to link functional and structural (biomarker) based definitions of AKI. We demonstrated the methodology in a representative cohort of critically ill patients, in which an increase of plasma creatinine of >26.4 umol/L in 48 hours or >50% in 7 days (Functional-AKI) had a sensitivity of 62% for death or dialysis within 30 days. In a development sub-cohort the urinary neutrophil-gelatinase-associated-lipocalin threshold with a 62% sensitivity for death or dialysis was 140 ng/ml (Structural-AKI). Using these thresholds in a validation sub-cohort, the risk of death or dialysis relative to those with no AKI by either definition was, for combined Structural-AKI and Functional-AKI 3.11 (95% Confidence interval: 2.53 to 3.55), for those with Structural-AKI but not Functional-AKI 1.51 (1.26 to 1.62), and for those with Functional-AKI but not Structural-AKI 1.34 (1.16 to 1.42). Linking functional and structural biomarkers via sensitivity for death and dialysis is a viable method by which to define thresholds for novel biomarkers of AKI. PMID- 23626852 TI - Interlimb coordination during forward and backward walking in primary school-aged children. AB - Previous studies comparing forward (FW) and backward (BW) walking suggested that the leg kinematics in BW were essentially those of FW in reverse. This led to the proposition that in adults the neural control of FW and BW originates from the same basic neural circuitry. One aspect that has not received much attention is to what extent development plays a role in the maturation of neural control of gait in different directions. BW has been examined either in adults or infants younger than one year. Therefore, we questioned which changes occur in the intermediate phases (i.e. in primary school-aged children). Furthermore, previous research focused on the lower limbs, thereby raising the question whether upper limb kinematics are also simply reversed from FW to BW. Therefore, in the current study the emphasis was put both on upper and lower limb movements, and the coordination between the limbs. Total body 3D gait analysis was performed in primary school-aged children (N = 24, aged five to twelve years) at a preferred walking speed to record angular displacements of upper arm, lower arm, upper leg, lower leg, and foot with respect to the vertical (i.e. elevation angle). Kinematics and interlimb coordination were compared between FW and BW. Additionally, elevation angle traces of BW were reversed in time (revBW) and correlated to FW traces. Results showed that upper and lower limb kinematics of FW correlated highly to revBW kinematics in children, which appears to be consistent with the proposal that control of FW and BW may be similar. In addition, age was found to mildly alter lower limb kinematic patterns. In contrast, interlimb coordination was similar across all children, but was different compared to adults, measured for comparison. It is concluded that development plays a role in the fine-tuning of neural control of FW and BW. PMID- 23626851 TI - High concentrations of L-ascorbic acid specifically inhibit the growth of human leukemic cells via downregulation of HIF-1alpha transcription. AB - We examined the antileukemic effects of high concentrations of L-ascorbic acid (high AA) on human leukemic cells. In vitro, high AA markedly induced apoptosis in various leukemic cell lines by generating hydrogen peroxide (H2O2) but not in normal hematopoietic stem/progenitor cells. High AA significantly repressed leukemic cell proliferation as well as neoangiogenesis in immunodeficient mice. We then noted that in leukemic cells, HIF-1alpha transcription was strongly suppressed by high AA and correlated with the transcription of VEGF. Our data indicate that exposure to high AA markedly increased the intracellular AA content of leukemic cells and inhibited the nuclear translocation of NF-kappaB, which mediates expression of HIF-1alpha. We next generated K562 cells that overexpressed HIF-1alpha (K562-HIF1alpha cells) and assessed the mechanistic relationship between inhibition of HIF-1alpha transcription and the antileukemic effect of high AA. The ability of high AA to induce apoptosis was significantly lower in K562-HIF1alpha cells than in K562 cells in vitro. We found that expression of HIF-1alpha-regulated antiapoptotic proteins of the Bcl-2 family, such as Mcl-1, Bcl-xL, and Bcl-2, was significantly suppressed by high AA in K562 cells, but was sustained at higher levels in K562-HIF1alpha cells, regardless of high AA exposure. Moreover, repression of cell proliferation and neoangiogenesis by high AA was completely abrogated in mice receiving transplants of K562 HIF1alpha cells. These results indicate that, along with H2O2 generation, downregulation of HIF-1alpha transcription plays a crucial role in growth inhibition of human leukemic cells by high AA. PMID- 23626853 TI - ISS--an electronic syndromic surveillance system for infectious disease in rural China. AB - BACKGROUND: Syndromic surveillance system has great advantages in promoting the early detection of epidemics and reducing the necessities of disease confirmation, and it is especially effective for surveillance in resource poor settings. However, most current syndromic surveillance systems are established in developed countries, and there are very few reports on the development of an electronic syndromic surveillance system in resource-constrained settings. OBJECTIVE: This study describes the design and pilot implementation of an electronic surveillance system (ISS) for the early detection of infectious disease epidemics in rural China, complementing the conventional case report surveillance system. METHODS: ISS was developed based on an existing platform 'Crisis Information Sharing Platform' (CRISP), combining with modern communication and GIS technology. ISS has four interconnected functions: 1) work group and communication group; 2) data source and collection; 3) data visualization; and 4) outbreak detection and alerting. RESULTS: As of Jan. 31(st) 2012, ISS has been installed and pilot tested for six months in four counties in rural China. 95 health facilities, 14 pharmacies and 24 primary schools participated in the pilot study, entering respectively 74,256, 79,701, and 2330 daily records into the central database. More than 90% of surveillance units at the study sites are able to send daily information into the system. In the paper, we also presented the pilot data from health facilities in the two counties, which showed the ISS system had the potential to identify the change of disease patterns at the community level. CONCLUSIONS: The ISS platform may facilitate the early detection of infectious disease epidemic as it provides near real-time syndromic data collection, interactive visualization, and automated aberration detection. However, several constraints and challenges were encountered during the pilot implementation of ISS in rural China. PMID- 23626854 TI - Stac3 is a novel regulator of skeletal muscle development in mice. AB - The goal of this study was to identify novel factors that mediate skeletal muscle development or function. We began the study by searching the gene expression databases for genes that have no known functions but are preferentially expressed in skeletal muscle. This search led to the identification of the Src homology three (SH3) domain and cysteine rich (C1) domain 3 (Stac3) gene. We experimentally confirmed that Stac3 mRNA was predominantly expressed in skeletal muscle. We determined if Stac3 plays a role in skeletal muscle development or function by generating Stac3 knockout mice. All Stac3 homozygous mutant mice were found dead at birth, were never seen move, and had a curved body and dropping forelimbs. These mice had marked abnormalities in skeletal muscles throughout the body, including central location of myonuclei, decreased number but increased cross-sectional area of myofibers, decreased number and size of myofibrils, disarrayed myofibrils, and streaming Z-lines. These phenotypes demonstrate that the Stac3 gene plays a critical role in skeletal muscle development and function in mice. PMID- 23626855 TI - Comparative analysis of the peanut witches'-broom phytoplasma genome reveals horizontal transfer of potential mobile units and effectors. AB - Phytoplasmas are a group of bacteria that are associated with hundreds of plant diseases. Due to their economical importance and the difficulties involved in the experimental study of these obligate pathogens, genome sequencing and comparative analysis have been utilized as powerful tools to understand phytoplasma biology. To date four complete phytoplasma genome sequences have been published. However, these four strains represent limited phylogenetic diversity. In this study, we report the shotgun sequencing and evolutionary analysis of a peanut witches' broom (PnWB) phytoplasma genome. The availability of this genome provides the first representative of the 16SrII group and substantially improves the taxon sampling to investigate genome evolution. The draft genome assembly contains 13 chromosomal contigs with a total size of 562,473 bp, covering ~90% of the chromosome. Additionally, a complete plasmid sequence is included. Comparisons among the five available phytoplasma genomes reveal the differentiations in gene content and metabolic capacity. Notably, phylogenetic inferences of the potential mobile units (PMUs) in these genomes indicate that horizontal transfer may have occurred between divergent phytoplasma lineages. Because many effectors are associated with PMUs, the horizontal transfer of these transposon-like elements can contribute to the adaptation and diversification of these pathogens. In summary, the findings from this study highlight the importance of improving taxon sampling when investigating genome evolution. Moreover, the currently available sequences are inadequate to fully characterize the pan-genome of phytoplasmas. Future genome sequencing efforts to expand phylogenetic diversity are essential in improving our understanding of phytoplasma evolution. PMID- 23626856 TI - Environmental and ontogenetic effects on intraspecific trait variation of a macrophyte species across five ecological scales. AB - Although functional trait variability is increasingly used in community ecology, the scale- and size-dependent aspects of trait variation are usually disregarded. Here we quantified the spatial structure of shoot height, branch length, root/shoot ratio and leaf number in a macrophyte species Potamogeton maackianus, and then disentangled the environmental and ontogenetic effects on these traits. Using a hierarchical nested design, we measured the four traits from 681 individuals across five ecological scales: lake, transect, depth stratus, quadrat and individual. A notable high trait variation (coefficient variation: 48-112%) was observed within species. These traits differed in the spatial structure, depending on environmental factors of different scales. Shoot height and branch length were most responsive to lake, transect and depth stratus scales, while root/shoot ratio and leaf number to quadrat and individual scales. The trait variations caused by environment are nearly three times higher than that caused by ontogeny, with ontogenetic variance ranging from 21% (leaf number) to 33% (branch length) of total variance. Remarkably, these traits showed non-negligible ontogenetic variation (0-60%) in each ecological scale, and significant shifts in allometric trajectories at lake and depth stratus scales. Our results highlight that environmental filtering processes can sort individuals within species with traits values adaptive to environmental changes and ontogenetic variation of functional traits was non-negligible across the five ecological scales. PMID- 23626857 TI - A novel two-component response regulator links rpf with biofilm formation and virulence of Xanthomonas axonopodis pv. citri. AB - Citrus bacterial canker caused by Xanthomonas axonopodis pv. citri is a serious disease that impacts citrus production worldwide, and X. axonopodis pv. citri is listed as a quarantine pest in certain countries. Biofilm formation is important for the successful development of a pathogenic relationship between various bacteria and their host(s). To understand the mechanisms of biofilm formation by X. axonopodis pv. citri strain XW19, the strain was subjected to transposon mutagenesis. One mutant with a mutation in a two-component response regulator gene that was deficient in biofilm formation on a polystyrene microplate was selected for further study. The protein was designated as BfdR for biofilm formation defective regulator. BfdR from strain XW19 shares 100% amino acid sequence identity with XAC1284 of X. axonopodis pv. citri strain 306 and 30-100% identity with two-component response regulators in various pathogens and environmental microorganisms. The bfdR mutant strain exhibited significantly decreased biofilm formation on the leaf surfaces of Mexican lime compared with the wild type strain. The bfdR mutant was also compromised in its ability to cause canker lesions. The wild-type phenotype was restored by providing pbfdR in trans in the bfdR mutant. Our data indicated that BfdR did not regulate the production of virulence-related extracellular enzymes including amylase, lipase, protease, and lecithinase or the expression of hrpG, rfbC, and katE; however, BfdR controlled the expression of rpfF in XVM2 medium, which mimics cytoplasmic fluids in planta. In conclusion, biofilm formation on leaf surfaces of citrus is important for canker development in X. axonopodis pv. citri XW19. The process is controlled by the two-component response regulator BfdR via regulation of rpfF, which is required for the biosynthesis of a diffusible signal factor. PMID- 23626858 TI - Economic valuation of health care services in public health systems: a study about Willingness to Pay (WTP) for nursing consultations. AB - BACKGROUND: Identifying the economic value assigned by users to a particular health service is of principal interest in planning the service. The aim of this study was to evaluate the perception of economic value of nursing consultation in primary care (PC) by its users. METHODS AND RESULTS: Economic study using contingent valuation methodology. A total of 662 users of nursing consultation from 23 health centers were included. Data on demographic and socioeconomic characteristics, health needs, pattern of usage, and satisfaction with provided service were compiled. The validity of the response was evaluated by an explanatory mixed-effects multilevel model in order to assess the factors associated with the response according to the welfare theory. Response reliability was also evaluated. Subjects included in the study indicated an average Willingness to Pay (WTP) of ?14.4 (CI 95%: ?13.2-15.5; median ?10) and an average Willingness to Accept [Compensation] (WTA) of ?20.9 (CI 95%: ?19.6-22.2; median ?20). Average area income, personal income, consultation duration, home visit, and education level correlated with greater WTP. Women and older subjects showed lower WTP. Fixed parameters explained 8.41% of the residual variability, and response clustering in different health centers explained 4-6% of the total variability. The influence of income on WTP was different in each center. The responses for WTP and WTA in a subgroup of subjects were consistent when reassessed after 2 weeks (intraclass correlation coefficients 0.952 and 0.893, respectively). CONCLUSIONS: The economic value of nursing services provided within PC in a public health system is clearly perceived by its user. The perception of this value is influenced by socioeconomic and demographic characteristics of the subjects and their environment, and by the unique characteristics of the evaluated service. The method of contingent valuation is useful for making explicit this perception of value of health services. PMID- 23626859 TI - Decreased pattern recognition receptor signaling, interferon-signature, and bactericidal/permeability-increasing protein gene expression in cord blood of term low birth weight human newborns. AB - BACKGROUND: Morbidity and mortality rates of low birth weight (LBW) newborns at term are higher than rates in normal birth weight (NBW) newborns. LBW newborns are at greater risk to acquire recurrent bacterial and viral infections during their first few weeks of life possibly as an outcome of compromised innate immune functions. As adaptive immunity is in a naive state, increased risk of infection of LBW as compared to NBW newborns may reflect impairments in innate immunity. METHODOLOGY: To characterize the increased susceptibility to infections in LBW newborns we used microarray technology to identify differences in gene expression in LBW newborns (n = 8) compared to NBW newborns (n = 4) using cord blood. The results obtained from the microarray study were validated on a larger number of samples using real time RT-PCR (LBW = 22, NBW = 18) and western blotting (LBW = 12, NBW = 12). The Interferome database was used to identify interferon (IFN) signature genes and ingenuity pathway analysis identified canonical pathways and biological functions associated with the differentially expressed genes in LBW newborns. ELISAs for IFNs and bactericidal/permeability-increasing protein were performed in both LBW and NBW newborns and in adults (LBW = 18, NBW = 18, Adults= 8). PRINCIPAL FINDINGS: Upon microarray analysis, we identified 1,391 differentially expressed genes, of which, 1,065 genes were down-regulated and 326 genes were up-regulated in the LBW compared to NBW newborns. Of note, 70 IFN signature genes were found to be significantly down-regulated in LBW compared to NBW newborns. Ingenuity pathway analysis revealed pattern recognition receptors signaling including Toll-Like Receptors (TLRs) -1, -5, and -8 genes and IFN signaling as the most significantly impacted pathways. Respiratory infectious diseases were the most significantly affected bio-functions in LBW newborns. CONCLUSION AND SIGNIFICANCE: Diminished PRRs, IFN-signature, and BPI gene expression raises the possibility that impairments in these pathways contribute to the susceptibility of LBW term infants to infection. PMID- 23626860 TI - IL-22-producing RORgammat-dependent innate lymphoid cells play a novel protective role in murine acute hepatitis. AB - Retinoid-related orphan receptor (ROR) gammat is known to be related to the development and function of various immunological compartments in the liver, such as Th17 cells, natural killer T (NKT) cells, and innate lymphoid cells (ILCs). We evaluated the roles of RORgammat-expressing cells in mouse acute hepatitis model using RORgammat deficient (RORgammat(-/-)) mice and RAG-2 and RORgammat double deficient (RAG-2(-/-) * RORgammat(-/-)) mice. Acute hepatitis was induced in mice by injection with carbon tetrachloride (CCl4), to investigate the regulation of liver inflammation by RORgammat-expressing cells. We detected RORC expression in three compartments, CD4(+) T cells, NKT cells, and lineage marker-negative SCA 1(+)Thy1(high) ILCs, of the liver of wild type (WT) mice. CCl4-treated RORgammat( /-) mice developed liver damage in spite of lack of RORgammat-dependent cells, but with reduced infiltration of macrophages compared with WT mice. In this regard, ILCs were significantly decreased in RAG-2(-/-) * RORgammat(-/-) mice that lacked T and NKT cells. Surprisingly, RAG-2(-/-) * RORgammat(-/-) mice developed significantly severer CCl4-induced hepatitis compared with RAG-2(-/-) mice, in accordance with the fact that hepatic ILCs failed to produce IL-22. Lastly, anti-Thy1 monoclonal antibody (mAb), but not anti-NK1.1 mAb or anti asialo GM1 Ab administration exacerbated liver damage in RAG-2(-/-) mice with the depletion of liver ILCs. Collectively, hepatic RORgammat-dependent ILCs play a part of protective roles in hepatic immune response in mice. PMID- 23626861 TI - Severity of anemia among children under 36 months old in rural western China. AB - OBJECTIVE: To describe severity of anemia and explore its determinants among children under 36 months old in rural western China. STUDY DESIGN: The family information of 6711 children was collected and their hemoglobin was measured in 2005. A generalized estimated equation (GEE) linear model was used to identify the determinants of severity of childhood anemia. RESULTS: The prevalence of mild, moderate and severe anemia among these children was 27.4%, 21.9% and 3.2% respectively. GEE model analysis showed that province-level region and severity of maternal anemia affected the severity of childhood anemia not only in 0-5 months but also beyond 5 months. In addition, children aged 0-5 months in families using iron pot (coefficient = -0.26 95%CI -0.41,-0.12) had seldom more severe anemia, and children aged 6-36 months in families more than 4 members (coefficient = -0.03 95%CI -0.06,-0.01) or of Han ethnicity (coefficient = -0.08 95%CI -0.13,-0.04) seldom had more severe anemia but boys (coefficient = 0.03 95%CI 0.01,0.06) or younger children (6-11 month vs 30-36 month: coefficient = 0.23 95%CI 0.17, 0.28; 12-17 month vs 30-36 month: coefficient = 0.19 95%CI 0.15,0.24; 18-23 vs 30-36 month: coefficient = 0.09 95%CI 0.04,0.13) had more severe anemia. CONCLUSION: The prevalence of moderate-to-severe anemia in these children was about 25%. Province-level region, iron pot use, family size, ethnicity, age and gender of children and severity of maternal anemia were important determinants of the severity of childhood anemia. These findings have some important implications for health policy decision for childhood anemia in rural western China. PMID- 23626862 TI - A comprehensive search for recombinogenic motifs in the human genome. AB - The patterns of male and female recombination vary greatly on a macro scale. A unique motif in each gender, triggering a double strand break at its location, much in the way Chi sites operate in E. coli, could logically explain this difference. As such, we have undertaken a comprehensive search of all small motifs in an attempt to identify one or more that match to the available data. In the end, we conclude that no such motifs appear to exist in the human genome. PMID- 23626863 TI - Synthesis, Photophysics, Electrochemistry and Electrogenerated Chemiluminescence of PEG-Modified BODIPY dyes in Organic and Aqueous Solutions. AB - A set polyethylene glycol (PEG) appended BODIPY architectures (BOPEG1 - BOPEG3) have been prepared and studied in CH2Cl2, H2O:CH3CN (1:1) and aqueous solutions. BOPEG1 and BOPEG2 both contain a short PEG chain and differ in substitution about the BODIPY framework. BOPEG3 is comprised of a fully substituted BODIPY moiety linked to a PEG polymer that is roughly 13 units in length. The photophysics and electrochemical properties of these compounds have been thoroughly characterized in CH2Cl2 and aqueous CH3CN solutions. The behavior of BOPEG1 - BOPEG3 correlates with established rules of BODIPY stability based on substitution about the BODIPY moiety. ECL for each of these compounds was also monitored. BOPEG1, which is unsubstituted at the 2- and 6-positions dimerized upon electrochemical oxidation while BOPEG2, which contains ethyl groups at the 2- and 6-positions, was much more robust and served as an excellent ECL luminophore. BOPEG3 is highly soluble in water due to the long PEG tether and demonstrated modest ECL activity in aqueous solutions using tri-n-propylamine (TPrA) as a coreactant. As such, BOPEG3 represents the first BODIPY derivative that has been shown to display ECL in water without the need for an organic cosolvent, and marks an important step in the development of BODIPY based ECL probes for various biosensing applications. PMID- 23626864 TI - Deploying RNA and DNA with Functionalized Carbon Nanotubes. AB - Carbon nanotubes internalize into cells and are potential molecular platforms for siRNA and DNA delivery. A comprehensive understanding of the identity and stability of ammoniumfunctionalized carbon nanotube (f-CNT)-based nucleic acid constructs is critical to deploying them in vivo as gene delivery vehicles. This work explored the capability of f-CNT to bind single- and double-strand oligonucleotides by determining the thermodynamics and kinetics of assembly and the stoichiometric composition in aqueous solution. Surprisingly, the binding affinity of f-CNT and short oligonucleotide sequences was in the nanomolar range, kinetics of complexation were extremely rapid, and from one to five sequences were loaded per nanotube platform. Mechanistic evidence for an assembly process that involved electrostatic, hydrogen-bonding and pi-stacking bonding interactions was obtained by varying nanotube functionalities, oligonucleotides, and reaction conditions. 31P-NMR and spectrophotometric fluorescence emission data described the conditions required to assemble and stably bind a DNA or RNA cargo for delivery in vivo and the amount of oligonucleotide that could be transported. The soluble oligonucleic acid-f-CNT supramolecular assemblies were suitable for use in vivo. Importantly, key evidence in support of an elegant mechanism by which the bound nucleic acid material can be 'off-loaded' from the f CNT was discovered. PMID- 23626865 TI - Cardiac CT: Imaging of and Through Cardiac Devices. AB - For patients with cardiac devices, cardiac computed tomography (CT) remains the mainstay for imaging due to its superior resolution as compared with echocardiography and nuclear studies and no contraindication to metal as with cardiac magnetic resonance imaging. This review focuses on the evaluation and pitfalls of coronary arterial imaging in patients with devices, such as pacemakers, implantable defibrillators, cardiac resynchronization therapy (CRT), as well as complications such as lead perforation and safety concerns of CT interference. We discuss both pre- and post-procedural CRT assessment for coronary venous imaging and pre-procedural myocardial scar assessment to localize regions of scar and peri-infarct zone to facilitate ventricular tachycardia ablation in patients with devices. We describe potential new research on dyssynchrony and integration with myocardial scar and site of latest activation for patients with or being considered for CRT. We detail the utility of CT for the assessment of proper function and complications in patients with left ventricular assist device implantation. PMID- 23626866 TI - Optimum Design of Disease-modifying Trials on Alzheimer's Disease. AB - Randomized start and withdrawal designs have been recently proposed to test the disease-modifying agents on Alzheimer's disease (AD). This article provides methods to determine the optimum parameters for these designs. A general linear mixed effects model is proposed. This model employs a piecewise linear growth pattern for those in the delayed treatment or early withdrawal arm, and incorporates a potential correlation on the rates of change on efficacy outcome before and after the treatment switch. Based on this model, we formulate the disease-modifying hypothesis by comparing the rate of change on efficacy outcome between treatment arms with and without a treatment switch, and develop a methodology to optimally determine the sample size allocations to different treatment arms as well as the time of treatment switch for subjects whose treatment is changed. We then propose an intersection-union test (IUT) to assess the disease-modifying efficacy, and study the size and the power of the IUT. Finally, we employ two recently published symptomatic trials on AD to obtain pilot estimates to model parameters, and provide the optimum design parameters including total and individual sample size to different arms as well as the time of treatment switch for future disease-modifying trials on AD. PMID- 23626867 TI - USE OF FUSED CIRCULATIONS TO INVESTIGATE THE ROLE OF APOLIPOPROTEIN E AS AMYLOID CATALYST AND PERIPHERAL SINK IN ALZHEIMER'S DISEASE. AB - Apolipoprotein E (apoE) synthesized in liver and brain plays a key role in both cholesterol transport and Alzheimer's disease (AD): apoE-knockout mice develop hypercholesterolemia and atherosclerosis and cannot support AD amyloid deposition. The ApoE4 allele is the strongest genetic risk factor for late-onset AD, and apoE4 protein preferentially catalyzes amyloid-beta (Abeta) peptide fibrillization in vitro and amyloid plaque deposition in vivo. Circulating apoE may also have the potential to draw Abeta from the brain and reduce amyloid deposition. We used parabiosis to determine how circulating apoE impacts brain amyloid deposition and blood cholesterol levels in transgenic mice carrying AD promoting APP and PS1 human transgenes-either with or without the endogenous mouse apoE gene. ApoE transferred through the joined circulations from WT to parabiosed APP+/+,PS1+/-,apoE-KO mice prevented hypercholesterolemia and reduced already low brain amyloid deposition. The findings indicate that apoE synthesis in the brain itself is necessary for amyloid accumulation. Furthermore, plasma apoE can both normalize cholesterol levels in apoE-KO mice and act as a peripheral sink to induce net efflux of Abeta peptide from the brain. The therapeutic implication is that inhibiting Alzheimer's disease neuropathology may be accomplished by either reducing apoE in the brain or increasing apoE in the blood. PMID- 23626868 TI - Milk processing as a tool to reduce cow's milk allergenicity: a mini-review. AB - Milk processing technologies for the control of cow's milk protein allergens are reviewed in this paper. Cow's milk is a high nutritious food; however, it is also one of the most common food allergens. The major allergens from cow's milk have been found to be beta-lactoglobulin, alpha-lactalbumin and caseins. Strategies for destroying or modifying these allergens to eliminate milk allergy are being sought by scientists all over the world. In this paper, the main processing technologies used to prevent and eliminate cow's milk allergy are presented and discussed, including heat treatment, glycation reaction, high pressure, enzymatic hydrolysis and lactic acid fermentation. Additionally, how regulating and optimizing the processing conditions can help reduce cow's milk protein allergenicity is being investigated. These strategies should provide valuable support for the development of hypoallergenic milk products in the future. PMID- 23626869 TI - Predicting criminality from child maltreatment typologies and posttraumatic stress symptoms. AB - BACKGROUND: The associations between childhood abuse and subsequent criminality and posttraumatic stress disorder (PTSD) are well known. However, a major limitation of research related to childhood abuse and its effects is the focus on one particular type of abuse at the expense of others. Recent work has established that childhood abuse rarely occurs as a unidimensional phenomenon. Therefore, a number of studies have investigated the existence of abuse typologies. METHODS: The study is based on a Danish stratified random probability survey including 2980 interviews of 24-year-old people. The sample was constructed to include an oversampling of child protection cases. Building on a previous latent class analysis of four types of childhood maltreatment, three maltreatment typologies were used in the current analyses. A criminality scale was constructed based on seven types of criminal behavior. PTSD symptoms were assessed by the PC-PTSD Screen. RESULTS: Significant differences were found between the two genders with males reporting heightened rates of criminality. Furthermore, all three maltreatment typologies were associated with criminal behavior with odds ratios (ORs) from 2.90 to 5.32. Female gender had an OR of 0.53 and possible PTSD an OR of 1.84. CONCLUSION: The independent association of participants at risk for PTSD and three types of maltreatment with criminality should be studied to determine if it can be replicated, and considered in social policy and prevention and rehabilitation interventions. PMID- 23626870 TI - Editorial. PMID- 23626871 TI - Constructing a Mouse Oct4 Promoter/EGFP Vector, as a Whole-Cellular Reporter to Monitor the Pluripotent State of Cells. AB - BACKGROUND: The transcription factor Oct-4, is an important marker of undifferentiating level and a key regulating factor for maintenance of pluripotency in cells. Establishment of an Oct-4 promoter-based reporter system is an appropriate tool for monitoring the differentiation of embryonic stem cells both in vivo and in vitro. METHODS: In the present study, we report construction of a recombinant vector, pDB2 Oct4 promoter/EGFP, in which expression of Enhanced Green Fluorescent Protein (EGFP) was controlled by the mouse Oct-4 promoter. RESULTS: In transfected mouse embryonic stem cells with this vector, EGFP was predicted to be specifically expressed in pluripotency state. After transfection, high-level expression of EGFP under the control of Oct-4 promoter was observed in manipulated embryonic stem cells. CONCLUSION: Thus, our new cellular reporter showed that both the properties of embryonic cells and expression the EGFP could be of great help in studying the differentiating and reprogramming mechanisms of mESCs. PMID- 23626872 TI - RORC2 gene silencing in human Th17 cells by siRNA: design and evaluation of highly efficient siRNA. AB - BACKGROUND: RNA interference-based gene silencing has recently been applied as an efficient tool for functional gene analysis. RORC2 is the key transcription factor orchestrating Th17 cells differentiation, the cells that are known as the pathogenic elements in various autoimmune diseases. The aim of this study was to design efficient siRNAs specific for RORC2 and to evaluate different criteria affecting their functionality. METHODS: Three siRNA duplexes specific for RORC2 mRNA were designed. Th17 cells were produced from IL-6 and IL-1 treated cord blood CD4(+) T cells. The T cells were transfected with three different designed siRNAs against RORC2 and the expression of RORC2 gene was measured using quantitative real time PCR. RESULTS: Different levels of RORC2 down regulation were observed in the presence of each of the designed siRNAs. Efficient siRNA with 91.1% silencing activity met the majority of the established bioinformatics criteria while the one with 46.6% silencing activity had more deviations from these criteria. CONCLUSION: The more bioinformatics criteria are considered, the more functionality were observed for silencing RORC2. However, the importance of the type of criteria per se should not be neglected. Although all recommended criteria are important for designing siRNA but their value is not the same. PMID- 23626873 TI - Expression, Purification and Characterization of Three Overlapping Immunodominant Recombinant Fragments from Bordetella pertussis Filamentous Hemagglutinin. AB - BACKGROUND: Filamentous hemagglutinin (FHA) is one of the most important immunoprotective antigens of Bordetella pertussis (B. pertussis) and a major component of the acellular pertussis vaccine. In the present study, three overlapping recombinant fragments from the immunodominant region of FHA were produced and their immunogenicity was investigated. METHODS: Three overlapping coding sequences of FHA antigen were amplified from B. pertussis genomic DNA by PCR. Amplified fragments were expressed in Escherichia coli (E. coli) BL21(DE3) strain and purified through His-tag using Nickel-based chromatography. Purified fragments were characterized by SDS-PAGE and Western blotting techniques. In vitro peripheral blood mononuclear cells (PBMC) proliferation and IFN-gamma production were assessed in a limited number of healthy adults vaccinated with a commercial acellular pertussis vaccine in response to all purified FHA fragments by H3-Thymidine incorporation and ELISA, respectively. RESULTS: Recombinant FHA segments were successfully cloned and produced at high levels in E. coli BL21(DE3). SDS-PAGE and Western blot analyses confirmed their purity and reactivity. All three recombinant fragments together with a commercial native FHA were able to induce in vitro PBMC proliferation and IFN-gamma production. CONCLUSION: Our preliminary results suggest that these overlapping recombinant FHA fragments are immunogenic and may prove to be immuno-protective. PMID- 23626874 TI - Generation of a Uracil Auxotroph Strain of the Probiotic Yeast Saccharomyces boulardii as a Host for the Recombinant Protein Production. AB - BACKGROUND: Saccharomyces boulardii (S. boulardii) is the best known probiotic yeast. The genetic engineering of this probiotic strain requires the availability of appropriate mutants to accept various gene constructs carrying different selection markers. As the auxotrophy selection markers are under focus, we have generated a ura3 auxotroph mutant of S. boulardii for use in further genetic manipulations. METHODS: Classical UV mutagenesis was used for the generation of auxotroph mutants. The mutants were selected in the presence of 5-FOA (5 Fluoroorotic acid), uracil and uridine. Uracil auxotrophy phenotype was confirmed by the ability of mutants to grow in the presence of uracil and the lack of growth in the absence of this compound. To test whether the uracil auxotrophy phenotype is due to the inactivation of URA3, the mutants were transformed with a plasmid carrying the gene. An in vitro assay was used for the analysis of acid and bile resistance capacity of these mutants. RESULTS: Three mutants were found to be ura3 auxotroph as they were able to grow only in the presence of uracil. When the URA3 gene was added, these mutants were able to grow normally in the absence of uracil. Further in vitro analysis showed that the acid and bile resistance capacity of one of these mutants is intact and similar to the wild type. CONCLUSION: A uracil auxotroph mutant of the probiotic yeast, S. boulardii, was generated and characterized. This auxotroph strain may have potential applications in the production and delivery of the recombinant pharmacuetics into the intestinal lumen. PMID- 23626875 TI - Cloning and Expression of Gumboro VP2 Antigen in Aspergillus niger. AB - BACKGROUND: Infectious Bursal Disease Virus (IBDV) causes a highly immunosuppressive disease in chickens and is a pathogen of major economic importance to the poultry industry worldwide. The VP2 protein is the major host protective immunogen of IBDV and has been considered as a potential subunit vaccine against the disease. VP2 coding sequence was cloned in an inducible fungal vector and the protein was expressed in Aspergillus niger (A. niger). METHODS: Aiming at a high level of expression, a multicopy AMA1-pyrG-based episomal construct driven by a strong inducible promoter, glaA, was prepared and used in transformation of A. niger pyrG-protoplasts. SDS-PAGE and western blot analysis was carried out to confirm the expression of the protein. RESULTS: A number of pyrG (+) positive transformants were isolated and the presence of expression cassette was confirmed. Western blot analysis of one of these recombinant strains using monospecific anti-VP2 antibodies demonstrated the successful expression of the protein. The recombinant protein was also detected by serum obtained from immunized chicken. CONCLUSION: In the present study, we have generated a recombinant A. niger strain expressing VP2 protein intracellulary. This recombinant strain of A. niger may have potential applications in oral vaccination against IBDV in poultry industry. PMID- 23626876 TI - Antifungal indole and pyrrolidine-2,4-Dione derivative peptidomimetic lead design based on in silico study of bioactive Peptide families. AB - BACKGROUND: The rise of opportunistic fungal infections highlights the need for development of new antimicrobial agents. Antimicrobial Peptides (AMPs) and Antifungal Peptides (AFPs) are among the agents with minimal resistance being developed against them, therefore they can be used as structural templates for design of new antimicrobial agents. METHODS: In the present study four antifungal peptidomimetic structures named C1 to C4 were designed based on plant defensin of Pisum sativum. Minimum inhibitory concentrations (MICs) for these structures were determined against Aspergillus niger N402, Candida albicans ATCC 10231, and Saccharomyces cerevisiae PTCC 5052. RESULTS: C1 and C2 showed more potent antifungal activity against these fungal strains compared to C3 and C4. The structure C2 demonstrated a potent antifungal activity among them and could be used as a template for future study on antifungal peptidomemetics design. Sequences alignments led to identifying antifungal decapeptide (KTCENLADTY) named KTC-Y, which its MIC was determined on fungal protoplast showing 25 (ug/ml) against Aspergillus fumigatus Af293. CONCLUSION: The present approach to reach the antifungal molecules seems to be a powerful approach in design of bioactive agents based on AMP mimetic identification. PMID- 23626877 TI - Isolation and culture of human spermatogonial stem cells derived from testis biopsy. AB - BACKGROUND: In cancer patients, chemo and radiotherapy can cause infertility by damaging spermatogenesis process. This process is based on self-renewal and differentiation of a rare population of the testicular cells called Spermatogonial Stem Cells (SSCs). Scientists have tried to isolate, enrich and culture Human spermatogonial stem cells, hoping to resolve infertility problems in cancer recovered patients in the future. METHODS: Spermatogonial stem cells were isolated and purified from human testicular biopsies sample consisting of at least 500,000 and at most 2,000,000 cells. Two enzymatic digestion steps were performed. Enriching methods, differential plating, and specific culture in serum free medium with added growth factors: human GDNF, bFGF, EGF and LIF was performed on coated dishes. RESULTS: Human spermatogonial stem cell clusters were observed after 7 to 10 days in specific culture, then after several passages and successful expanding duration of 52 days, the cells were evaluated by three layer immunocytochemistry test (LSAB) to stain GPR125 protein as a surface marker in human spermatogonial stem cells. CONCLUSION: In current study human spermatogonial stem cell were isolated and expanded with the least manipulations in comparison with the other usual isolation methods like florescent or magnetic activated cell sorting. In contrast to the other SSCs isolation and culture methods, this system is based on the testicular biopsies against large samples, thus suggested method in this study is closer to clinical usage in the future. PMID- 23626878 TI - A technique for facile and precise transfer of mouse embryos. AB - BACKGROUND: Successful Embryo Transfer (ET) technique is a fateful step of all efforts to achieve live births from in vitro produced embryos in assisted reproductive techniques or in knockout, transgenic or cloned animal projects. Small reproductive tract of mice and limitation of current techniques may not well satisfy the requirements for mass production of genetically modified mice. Genetic abnormalities of embryos, receptivity and uterine contractions, expulsion of embryos, blood, mucus or bacterial contamination on the transfer pipette tip, technical problems and even animal strain may affect embryo transfer outcome. METHODS: In this study, two techniques of embryo transfer in mice were compared. In conventional technique the oviduct wall was punctured with a 30-gauge needle and the loaded Pasteur pipette with embryos and medium was inserted into the hole. In new technique, embryos that were loaded in modified micropipette with minimal medium were transferred directly to the oviduct by manual piston micro pump easily. Embryo viability was evaluated considering the percentage of live healthy newborns. RESULTS: Results of the two techniques were compared by t-test within the NPAR1WAY procedure of SAS software (ver. 9.2). The average live birth rates in the novel methods was significantly higher (42.4%) than the conventional method (21.7%, p<0.05). CONCLUSION: In conclusion, using new embryo transfer technique improved birth rate by preventing embryos expulsion from the oviduct, saving time and easy transfer of embryos with minimum volume of medium. PMID- 23626879 TI - Importance of water and water-borne diseases: on the occasion of the world water day (march 22, 2013). PMID- 23626880 TI - Sleep disorders as a cause of motor vehicle collisions. AB - Studies have shown that a large proportion of traffic accidents around the world are related to inadequate or disordered sleep. Recent surveys have linked driver fatigue to 16% to 20% of serious highway accidents in the UK, Australia, and Brazil. Fatigue as a result of sleep disorders (especially obstructive sleep apnea), excessive workload and lack of physical and mental rest, have been shown to be major contributing factors in motor vehicle accidents. A number of behavioral, physiological, and psychometric tests are being used increasingly to evaluate the impact of fatigue on driver performance. These include the oculography, polysomnography, actigraphy, the maintenance of wakefulness test, and others. Various strategies have been proposed for preventing or reducing the impact of fatigue on motor vehicle accidents. These have included: Educational programs emphasizing the importance of restorative sleep and the need for drivers to recognize the presence of fatigue symptoms, and to determine when to stop to sleep; The use of exercise to increase alertness and to promote restorative sleep; The use of substances or drugs to promote sleep or alertness (i.e. caffeine, modafinil, melatonin and others), as well as specific sleep disorders treatment; The use of CPAP therapy for reducing excessive sleepiness among drivers who have been diagnosed with obstructive sleep apnea. The evidence cited in this review justifies the call for all efforts to be undertaken that may increase awareness of inadequate sleep as a cause of traffic accidents. It is strongly recommended that, for the purpose of promoting highway safety and saving lives, all disorders that cause excessive sleepiness should be investigated and monitored. PMID- 23626881 TI - Efficacy of Co-administration of Garlic Extract and Metformin for Prevention of Gentamicin-Renal Toxicity in Wistar Rats: A Biochemical Study. AB - BACKGROUND: Gentamicin (GM) nephrotoxicity has been related to oxidative stress. Garlic and metformin (MF) have anti-oxadant activity and therefore, this study was aimed to evaluate the preventive and curative effects of garlic, MF and their combination on GM indeced tubular toxicity in Wistar rats. METHODS: In a pre clinical study, 70 male Wistar rats were randomly designated into 7 groups of 10 and treated as follows: Group 1: Received saline for 20 days. Group 2: Were injected 100 mg/kg/d of GM intraperitoneally (ip), for 10 days and saline for 10 more days. Group 3: Received GM for 10 days then 20 mg/kg garlic ip for the next 10 days. Group 4: Received GM for 10 days and MF (100 mg/kg) orally for the next 10 days. Group 5: Received GM for 10 days and a combination of MF and garlic for the next 10 days (100 and 20 mg/kg, respectively). Group 6: The same as group 5but with half-doses of MF and Garlic. Group 7: Received GM for 10 days together with a combination ofMF and garlic. On 20(th) day of the experiment the serum blood urea nitrogen (BUN) and creatinine (Cr) were measured and compared in different groups. RESULTS: GM injection significantly increased the serum BUN and Cr (P < 0.05). Administration of MF, garlic or their combination with or after injection of GM (high doses) could atenuate BUN and Cr. CONCLUSIONS: The results indicate that MF and garlic or their combination have curative and protective activity against GM nephrotoxicity. PMID- 23626882 TI - Mortality inequality in 1-59 months children across Iranian provinces: referring system and determinants of death based on hospital records. AB - BACKGROUND: To determine inequality in mortality in 1-59 months children across Iranian provinces focusing on referring system and determinants of death. METHODS: After designing and examining a national questionnaire for mortality data collection of children 1-59 months, 40 medical universities have been asked to fill in the questionnaires and return to the main researcher in the health ministry in 2009. RESULTS: Mortality in 1-59 months children was unequally distributed across provinces (universities). The recommended refer was 3466 but only 1620 patients were referred. The first five important determinants of death were congenital (671 children or 20.9%), accident (547 children or 17.1%), pulmonary diseases (370 children or 11.5%), cardiovascular (266 children or less than 8.3%), central nervous system (263 children or 8.2%), and infectious and parasitic diseases (245 children or 7.6%), respectively. CONCLUSIONS: Our results suggest that inequality in 1-59 months mortality based on the hospital records, and specially referring system, needs more attention in Iran. In addition, it is advisable to conduct provincially representative surveys to provide recent estimates of hospital access inequalities and to allow monitoring over time. PMID- 23626883 TI - Tooth brushing and cardiometabolic risk factors in adolescents: Is there an association? The CASPIAN-III study. AB - BACKGROUND: A growing body of evidence supports an association between oral health and cardiovascular diseases and diabetes in adults. This study aimed to investigate the relationship between tooth brushing frequency and cardiometabolic risk factors in adolescents. METHODS: This nationwide population-based study was conducted among 5258 Iranian students, aged 10-18 years, living in urban and rural areas of 27 provinces in Iran. The association of tooth brushing frequency was assessed with anthropometric indexes and cardiometabolic risk factors after adjustment for potential confounders. RESULTS: Higher frequency of tooth brushing was associated with lower mean levels of low-density lipoprotein cholesterol (LDL C) in both genders (P < 0.0001) and lower frequency of elevated LDL-C in girls (P = 0.03). The frequency of elevated blood pressure decreased with higher tooth brushing frequency in boys (P = 0.03). After adjustment for many potential cofounders such as age, gender, anthropometric indexes, screen time, socioeconomic status, and family history of non-communicable diseases, participants who washed their teeth at least once a day had lower risk of high LDL-C and low high-density lipoprotein cholesterol (HDL-C) levels in comparison to those who reported lower frequency of tooth brushing; some different associations were observed among girls and boys. CONCLUSIONS: Our findings suggest an independent and protective role of teeth brushing frequency for some cardiometabolic risk factors in adolescents. Increasing both the general health awareness and improving oral health should be considered in primordial and primary prevention of non-communicable diseases. PMID- 23626884 TI - Skew-symmetric Random Effect Models with Application to a Preventive Cohort Study: Improving Outcomes in Low Back Pain Patients. AB - BACKGROUND: To investigate the respective contribution of various biologic and psychosocial factors, especially Health Related Quality of Life (HRQOL) as a main outcome, in the natural history of acute low back pain (LBP) and to evaluate the impact of this condition on HRQOL. METHODS: In a prospective cohort study For 24 weeks, 150 patients were assessed at an outpatient clinic in Korea consulting for low back and confirmed disc herniation duration at inclusion and treated with treatment package comprised of herbal medicines, acupuncture, bee venom acupuncture, and a Korean version of spinal manipulation (Chuna). Study participants were evaluated at baseline and every 4 weeks for 24 weeks. Low back intensity levels were measured on a visual analog scale (0-10), back function was evaluated with the Oswestry Disability Index (0-100), disability assessed by HRQOL assessed by the short form 36 health survey (0-100 in 8 different sub categories). RESULTS: Out of 150 patients, 128 completed the 24 weeks of traditional therapy. Patients reported improvements SF-36 outcome measures. At the completion of the study, low back pain scores improved by a mean of 3.3 (95% CI = 2.8 to 3.8). According to the results of our modeling, low back intensity level, back function and BMI measures had significant effects on quality of life during study. Interpreting the coefficients of modeling, the impact of the decreasing acute LBP episode on HRQOL by VAS and ODI outcomes, was high and important. CONCLUSIONS: This study highlights the large contribution of integrative package therapy as an effective preventive method for improving LBP patient's HRQOL. PMID- 23626885 TI - Protective Role of Silymarin and Deferoxamine Against Iron Dextran-induced Renal Iron Deposition in Male Rats. AB - BACKGROUND: Kidney iron deposition (KID) is caused by iron overload that is observed in kidney diseases and anemia. The protective effects of deferoxamine (DF) and silymarin (SM) were studied against iron overload-induced KID in rat model. METHODS: Rats received iron dextran (200 mg/kg) for a period of 4 weeks every other day, but at the beginning of week 3, they also were subjected to a 2 week (every other day) treatment with vehicle (group 2, positive control), SM (200 mg/kg; group 3), DF (50 mg/kg; group 4), SM (400 mg/kg; group 5), and combination of SM and DF (200 and 50 mg/kg, respectively; group 6). Group 1, as the negative control, received saline alone during the study. The levels of serum creatinine (Cr), blood urea nitrogen (BUN), iron, ferritin, and nitrite were determined, and the kidney was removed for histopathological investigations. RESULTS: Before treatment, the serum levels of iron and ferritin in all iron dextran receiver groups were significantly higher than those of the negative control group (P < 0.05). However, the serum levels of BUN, Cr, and nitrite were not different between the groups. No statistical differences were detected in kidney weight and the serum levels of BUN, Cr, iron, ferritin, and nitrite after 2 weeks of treatment with SM, DF, or combination of both. The SM and DF treatments reduced the intensity of the KID, but only in the SM (200 mg/kg) group, a significant reduction in KID was observed (P < 0.05). CONCLUSION: It seems that SM is a nephroprotectant agent against KID in acute iron overload animal models. PMID- 23626886 TI - Physical and Psychological Well-being of University Students: Survey of Eleven Faculties in Egypt. AB - BACKGROUND: We examined perceived health status and physical and psychological well-being of 3,271 undergraduate students attending eleven faculties in a university in Egypt. METHODS: During 2009-2010, participants completed a self administered questionnaire that gathered socio-demographic, physical and psychological health data. Body mass index (BMI) was calculated from students' measured height and weight. Differences across these variables were computed by gender and participating faculties. RESULTS: Whilst more females watched and rated their health favorably, they were more likely to feel psychosomatic/physical health problems, to have seen a medical practitioner or been ill that they had to stay in bed. Females were consistently more likely to feel burdened overall, and across several aspects apart from financial problems. Less females had 'normal' BMI, were satisfied with current weight, perceived their body image as 'just right', or were not worried about their shape. More males rated their quality of life favorably. About 25% of males and 32% of females were either overweight/obese. Exams, presentations, and the lack of time for studies were the frequently-reported burdens. Comparisons of health/well being indicators across the participating faculties suggested some evidence of 'clustering': Favorable indicators would cluster at some faculties; and conversely, less favorable variables would cluster at other faculties. CONCLUSIONS: Generally, the levels of some health complaints and psychological problems/burdens are higher than in other countries. Increased vigilance of university administrators and leaders to monitoring the health and well-being of their students, as well as their health needs is required if policy makers are to operate from a valid evidence base platform. Given cultural factors prevalent in the Eastern Mediterranean region generally, female students might require particular attention. The clustering effects suggest the need for local (faculty specific) health and well-being profiles as basis and guidance for relevant health promotion programs in faculty/university settings. PMID- 23626887 TI - Angiotensin 1-7 Receptor and Angiotensin II Receptor 2 Blockades Prevent the Increased Serum and Kidney Nitric Oxide Levels in Response to Angiotensin II Administration: Gender-Related Difference. AB - BACKGROUND: The angiotensin II (Ang II) receptor 2 (AT2R) and angiotensin 1-7 receptor (masR) expression in the kidney are gender-related. We attempted to compare the response of nitric oxide (NO) production to Ang II administration, with and without AT2R and masR blockades, using A-779 and PD123319 in male and female rats. METHODS: Anesthetized and catheterized male and female Wistar rats were subjected to one-hour continuous infusion of Ang II (~20 MUg/kg/hour), with and without masR and AT2R blockades. The level of the NO metabolite (nitrite) was measured before and after the experiment in rat serum and in the homogenized kidney tissue. RESULTS: The basal data indicated that no sex difference in the serum level of nitrite could be detected before Ang II infusion. However, administration of Ang II in male and female rats caused a gender difference in the nitrite level, which resulted in the serum level of the nitrite significantly increasing in males (P < 0.05) when compared with the females. In addition, masR blockade or co-blockade of masR and AT2R in male rats abolished the gender difference related to the effect of Ang II on nitrite production. In the presence of masR and AT2R, or when masR alone was blocked, the level of nitrite in the kidney, in response to the Ang II infusion was not significantly different between the two sexes. On the contrary, masR and AT2R co-blockades significantly decreased the kidney nitrite concentration response to Ang II administration in both male and female rats (P < 0.05), but no sex difference was detected. CONCLUSIONS: The renal vasculature of male rats may provide more response to Ang II administration-induced NO, which is dependent on masR and AT2R. During dual masR + AT2R blockades, the kidney NO formation wasreduced in a non-gender related manner. PMID- 23626889 TI - Is there any difference between preeclamptic and healthy pregnant women regarding the presence of periopathogenic bacteria in the placenta? AB - BACKGROUND: Preeclampsia is an important cause of maternal morbidity and mortality with unclear cause. It is believed that inflammation plays an important role in the pathogenesis of preeclampsia. Periodontal disease is a chronic inflammatory infectious condition which commonly involves humans. Recently, chronic infection was linked to atherosclerosis. Atherosclerosis shares some histopathologic features with uteroplacental atherosis of preeclamptic women. This study was aimed to investigate the presence of periopathogenic bacteria in the placental tissue of preeclamptic women, and compare it with women with normal pregnancy. METHODS: Samples were obtained from 23 placentas of preeclamptic women and from 23 age-matched healthy pregnant women. Qualitative polymerase chain reaction was performed to detect the presence of five periopathogenic bacteria. RESULTS: There was no significant difference between the two groups regarding the relative frequency of women with different types of periopathogenic bacterial infection of the placenta. In addition, there was no significant difference in the number of women with any type of infection of the placenta (regardless of the type of periopathogenic bacteria) [14 (61%) mothers with placental infection in the case group vs. 18 (78%) mothers in the control group, P value = 0.16]. CONCLUSIONS: This study did not show any significant difference between preeclamptic women and healthy women with normal pregnancy regarding the periopathogenic bacterial profile of the placenta. PMID- 23626888 TI - Preventive and curative effects of ginger extract against histopathologic changes of gentamicin-induced tubular toxicity in rats. AB - BACKGROUND: Gentamicin (GM) is a commonly used aminoglycoside, however, renal toxicity has limited its usage. This study was designed to evaluate the curative and protective effects of Zingiber officinale (ginger) against gentamicin tubular toxicity in rats. The phenolic and flavonoid components and antioxidant activity of ginger were also evaluated. METHODS: In a preclinical study, 50 male Wistar rats were designated into 5 groups of 10 and treated as follows: Group I: vehicle. Group II: 200 mg/kg/d of ginger for 3 days then, GM (80 mg/kg) for 7 days. Group III: 200 mg/kg ginger orally for 3 days, then ginger plus GM for 7 days. Group IV: GM for 7 days. Group V: GM for 10 days. Group VI: GM for 7 days, then 200 mg/kg ginger orally for 10 days. At the end of the study, the animals were sacrificed and their kidneys were histologically evaluated. RESULTS: Ginger could prevent degeneration of the renal cells and reduce the severity of tubular damage caused by gentamicin. However, it could not regenerate the GM degeneration. CONCLUSIONS: The results indicate that ginger is effective as a prophylaxis agent, but has not curative effect. PMID- 23626890 TI - Comparison of newborn outcomes in women with gestational diabetes mellitus treated with metformin or insulin: a randomised blinded trial. AB - BACKGROUND: Few studies have been done on the use of metformin in pregnancy and their results were not similar, therefore this research is performed to compare neonatal outcomes of metformin and insulin in the treatment of gestational diabetes. METHODS: In this prospective randomized trial, 200 pregnant women within their 24(th) to 34(th) weeks of gestation with gestational diabetes, single fetus pregnancy, and in need of hyperglycemia treatment were entered and grouped as either metformin or insulin. Data related to maternal and neonatal outcomes were recorded and analyzed. RESULTS: Considering data recorded of HbA1c at the beginning of pregnancy, pregnancy induced hypertension, preeclampsia, birth weight, dystocia, first and 5(th) min APGAR, neonatal sepsis, rout of delivery, liver function tests of neonate, hypoglycemia, anomaly, and still birth, there were no significant statistical differences between groups. The end pregnancy HbA1c, maternal weight gain during pregnancy, preterm labor, neonatal jaundice, respiratory distress and hospitalization of infants were higher in insulin group. CONCLUSIONS: Considering data from this study, metformin is efficient to control hyperglycemia in pregnancy. It is suggested performing more studies to evaluate long term side effects of metformin in pregnancy with higher sample size and longer follow-up of newborns. PMID- 23626891 TI - Validation of the persian version of berlin sleep questionnaire for diagnosing obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common but usually under-diagnosed sleep disorder. Objective diagnosis is based on polysomnography, which is an expensive test. We assessed the reliability and diagnostic accuracy of the Berlin questionnaire (BQ) in diagnosis of OSA in Iranian sleep clinic patients. METHODS: A cross-sectional linguistic validation study was conducted on consecutive Iranian patients with Persian language attending one sleep clinic in Isfahan (Iran) were studied. Patients completed the Persian BQ (contains 10 questions in 3 categories), developed by forward-backward translation method. The patients underwent an overnight polysomnographic study at the clinic. Apneas/hypopnea index of >5/Hour was considered for diagnosis of OSA. RESULTS: One hundred and fifty seven patients (55.4% male, mean age = 52.3 +/- 13.6 years) were evaluated. Sleep study confirmed OSA diagnosis in 91.7% of the studied patients. The reliability analysis of the BQ categories showed alpha Cronbach's as 0.70 and 0.50 for category 1 and category 2, respectively. BQ categories 1-3 were positive respectively in 88.5%, 67.5%, and 66.9% of the patients. The BQ and sleep study were in agreement for 82.1% of the cases. The sensitivity, specificity, positive and negative predictive values, and positive, and negative likelihood ratio of the BQ were calculated as 84.0%, 61.5%, 96.0%, 25.8%, 2.18%, and 0.26% respectively. CONCLUSIONS: BQ is useful as a screening test for diagnosing OSA in Iranian patients with sleep complaints; however, the test cannot be used for rolling out the OSA. Further studies on editing, modifying, and applying the BQ in a larger sample of patients are warranted in our society. PMID- 23626892 TI - Barriers of clinical practice guidelines development and implementation in developing countries: a case study in iran. AB - BACKGROUND: Knowledge products such as clinical practice guidelines (CPG) are vitally required for evidence-based medicine (EBM). Although the EBM, to some extent, has been attended during recent years, no result has achieved thus far. The current qualitative study is to identify the barriers to establishing development system and implementation of CPGs in Iran. METHODS: Twelve semi structured, in-depth interviews were conducted with a purposive sample of health policy and decision makers, the experts of development and or adaptation of CPGs, and the experts of EBM education and development. In addition, 11 policy-makers, decision-makers, and managers of the health system participated in a focus group discussion. The analysis of the study data was undertaken by thematic framework approach. RESULT: Six themes emerged in order of their frequency include practice environment, evidence-based health care system, individual professional, politician and political context, innovation (CPG) and patients. Most of the indications in the treatment environment focused on such sub-themes as regulations and rules, economical factors, organizational context, and social context. While the barriers related to the conditions of treatment environment, service provider and the features of innovation and patients had been identified before in other studies, very little attention has been paid to the evidence based health care system and politician and political context. CONCLUSION: The lack of an evidence-based healthcare system and a political macro support are mentioned as the key barriers in Iran as a developing country. The establishment of a system of development and implementation of CPGs as the evidence-based practice tools will not be possible, unless the barriers are removed. PMID- 23626893 TI - Only One Third of Tehran's Physicians are Familiar with 'Evidence-Based Clinical Guidelines'. AB - BACKGROUND: Clinical guidelines have increasingly been used as tools for applying new knowledge and research findings. Although, efforts have been made to produce clinical guidelines in Iran, it is not clear whether they have been used by physicians and what factors are associated with them?. METHODS: Four hundred and forty three practicing physicians in Tehran were selected from private clinics through weighted random sampling. The data collection tool was a questionnaire on familiarity and attitude toward clinical guidelines. The descriptive and analytical findings were analyzed with t-tests, Chi(2), logistic and linear multivariate regression by SPSS, version 16. RESULTS: 31.8% of physicians were familiar with clinical guidelines. Based on the logistic regression model physicians' familiarity with clinical guidelines was positively and significantly associated with 'working experience in a health service delivery point' OR = 2.13 (95% CI, 1.17-3.90), 'familiarity with therapeutic protocols' OR = 2.09 (95% CI, 1.22-3.57) and 'holding a specialty degree' OR = 2.51 (95% CI, 1.24-5.07). The mean overall attitude scores in the 'usefulness', 'reliability', and 'problems and barriers' domains were, respectively, 78.9 (SD = 16.5), 78.9 (SD = 19.7) and 50.4 (SD = 15.9) out of a total of 100 scores in each domain. No significant association was observed between attitude domains and other independent variables using multivariate linear regression. CONCLUSIONS: Little familiarity with clinical guidelines may represent weakness in of production and distribution of domestic evidence. Although, physicians considered guidelines as useful and reliable tools, but problems such as difficult access to guidelines and lack of facilities to apply them were stated as well. PMID- 23626894 TI - Family-based intervention for controlling childhood obesity: an experience among Iranian children. AB - BACKGROUND: Treatment of childhood obesity is difficult, and successful management may differ in various areas with different cultural backgrounds. The present study was conducted to assess the effect of lifestyle modification family based intervention in young Iranian children. METHODS: This field trial study was conducted in 2011 among 156 obese children in Tehran, Iran. They were randomly assigned to intervention and control groups. At baseline, anthropometric measurements and biochemical analysis were performed. The second and third phases consisted of training sessions for parents of the intervention group. At the fourth phase, there was no training program. In all four phases, questionnaires on demographic characteristics, lifestyle and food frequency were completed by interviewing with mothers, and biochemical analysis was repeated at the end of the study. RESULTS: During the second and third phases of the study, weight and height increased significantly in both groups, although weight increased more slowly, and waist and hip circumferences was decreased in the intervention group. Serum triglycerides and cholesterol decreased significantly in the intervention group (P < 0.05). Analysis of food group consumption showed that in the intervention group, not only consumption of milk, dairy and nuts group increased significantly but also the corresponding figure decreased for bread and cereals, sugar and confectionery ingredients; moreover, the family's oil and fat consumption decreased significantly (P < 0.05). Watching TV and playing on the computer decreased significantly in the intervention group; however, walking time increased significantly in both groups (P < 0.05). CONCLUSIONS: The family-based lifestyle program had limited but desirable effects on anthropometric and metabolic outcomes of the obese children. We suggest that a longer period of intervention may have more favorable results. PMID- 23626895 TI - Incidence of Nosocomial Infections in a Big University Affiliated Hospital in Shiraz, Iran: A Six-month Experience. AB - BACKGROUND: Nosocomial infections (NIs) are one of the most important health issues, particularly in developing countries, because these infections cause high mortality and morbidity, and economic and human resource loss as a consequence. To date, most surveillance studies have been conducted in developed countries, and only a few have been performed in Iran. All of the few Iranian studies have been performed using paper-based collection forms, and none was conducted with the aid of an electronic patient data retrieving and collecting tool. The aim of this study is to determine the incidence of NIs in a big university hospital of Shiraz, with the help of specifically programmed surveillance software merging electronically the available patient data and the infection results input manually. METHODS: The study was conducted prospectively through 6 months from 21(st) March up to 22(nd) September 2006, in a 374-bedded educational hospital. All patients admitted during this period were included in the study and examined everyday for detecting four types of NIs: surgical site infection (SSI), urinary tract infection (UTI), pneumonia (PNEU), and blood stream infection (BSI). Centres for Disease Control and Prevention National Nosocomial Infection Surveillance system criteria were applied. RESULTS: 4013 patients were admitted in the hospital. The overall infection rate was 4.14, and UTI, SSI, BSI, and PNEU rates were 1.82, 1.22, 0.5, and 0.5, respectively, per 1000 patient days of admission. CONCLUSIONS: The results of this study showed that the frequency of NI in the investigated hospital was not higher than in many other reported surveillance results from other countries. This, however, might be a bias as the administration of antibiotics was very high in this study and the quality of microbiological investigation might have influenced significantly, resulting in more false-negative results than expected. Overall, the use of the Iranian National Nosocomial Infection Surveillance System Software proved to be useful and allowed both rapid data collection and detailed data analysis. PMID- 23626896 TI - Prevention of diabetic foot ulcer. PMID- 23626897 TI - Telemedicine in primary health care: the road ahead. PMID- 23626898 TI - Effects of cinnamon consumption on glycemic status, lipid profile and body composition in type 2 diabetic patients. PMID- 23626899 TI - Early cohort mortality predicts the rate of aging in the cohort: a historical analysis. AB - Early environmental influences on later-life health and mortality are well recognized in the doubling of life expectancy since 1800. To further define these relationships, we analyzed the associations between early-life mortality and both the estimated mortality level at age 40 and the exponential acceleration in mortality rates with age characterized by the Gompertz model. Using mortality data from 630 cohorts born throughout the 19th and early 20th century in nine European countries, we developed a multilevel model that accounts for cohort and period effects in later-life mortality. We show that early-life mortality, which is linked to exposure to infection and poor nutrition, predicts both the estimated cohort mortality level at age 40 and the subsequent Gompertz rate of mortality acceleration during aging. After controlling for effects of country and period, the model accounts for the majority of variance in the Gompertz parameters (about 90% of variation in the estimated level of mortality at age 40 and about 78% of variation in the Gompertz slope). The gains in cohort survival to older ages are entirely due to large declines in adult mortality level, because the rates of mortality acceleration at older ages became faster. These findings apply to cohorts born in both the 19th century and the early 20th century. This analysis defines new links in the developmental origins of adult health and disease in which effects of early-life circumstances, such as exposure to infections or poor nutrition, persist into mid-adulthood and remain evident in the cohort mortality rates from ages 40 to 90. PMID- 23626900 TI - Kinetics and Mechanisms of Oxidative Cleavage of HIV RRE RNA by Rev-Coupled Transition Metal Chelates. AB - Catalytic metallodrugs were used to oxidatively cleave HIV-1 Rev Response Element RNA (RRE RNA), and the mechanisms of RNA cleavage were studied using a combination of matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), fluorescence spectroscopy, and gel electrophoresis. The metallodrugs, which contained combinations of the transition metals Fe2+, Co2+, Ni2+, and Cu2+ and the Rev-coupled chelators DOTA, DTPA, EDTA, NTA, tripeptide GGH, and tetrapeptide KGHK, bind to and cleave HIV RRE RNA through heretofore unknown oxidative mechanisms. The broad spectrum of metal catalysts and co-reagents provided a means for systematic variation of oxidative reactivity without significant perturbation of binding between catalyst and RNA. Detailed MS analyses were used to monitor formation of RNA fragments containing terminal 2',3'-cyclic phosphate (2',3'-cPO4), 3'-phosphate (3'-PO4), 3'-phosphoglycolate (3'-PG), 5'- hydroxyl (5'-OH), 5'- phosphate (5'-PO4) and other nascent overhangs at sites of cleavage. The distinct overhangs corresponded to distinct mechanisms of oxidative hydrogen-abstraction (H abstraction), hydrolysis, and/or endonucleolysis, allowing a dissection of the contributions of various mechanisms of oxidative cleavage. Rapid co-reactant- and catalyst-dependent formation of fragments containing terminal 3'-PG, 3'-PO4 and 5'-PO4 overhangs appeared to be initiated primarily by H abstraction events. The standard thiobarbituric acid (TBA) assay was employed herein in a novel usage to monitor the formation of base 2-hydroxypropenal products produced by 4'-H abstraction in RNA. Formation of an adduct with TBA was monitored by fluorescence, and its quantification correlated with the formation of 3'-PG monitored by MALDI-TOF MS, confirming oxidative 4'-H abstraction as a major mechanism of rapid catalyst-mediated cleavage of RRE RNA. Rapid formation of 3'-PO4 overhangs was most likely a result of 5'-H abstraction. Apparent rates of formation of 3'-PG (a unique product of 4'-H abstraction) at differing nucleotide positions within the RNA were used to triangulate probable 3D positions of metal centers and establish the distance-dependence of 4'-H abstraction for certain catalytic metallodrugs. PMID- 23626901 TI - Comparative evaluation of short-term biomarker response to treatment for growth hormone deficiency in Chinese children with growth hormone deficiency born small for or appropriate for gestational age: a randomized phase IV open-label study. AB - OBJECTIVES: To compare the response between Chinese children with growth hormone deficiency (GHD) born either small for gestational age (SGA) or appropriate for gestational age (AGA) after 4 weeks of recombinant human growth hormone (r-hGH) therapy. METHODS: This was a phase IV, open-label, multicenter, interventional study (NCT01187550). Prepubertal children with GHD received open-label treatment with daily r-hGH (0.033 mg/kg) for 4 weeks. Serum levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor-binding protein 3 (IGFBP3), and metabolic markers (including fasting glucose, insulin, total cholesterol, and homeostasis model assessment of insulin resistance) were assessed at baseline and after 4 weeks of treatment, and were analyzed according to patient subgroup (SGA or AGA). RESULTS: A total of 205 children with GHD (mean age 10.4 years; 175 AGA, 30 SGA) were included in the analysis. Mean baseline serum IGF-I and IGFBP3 standard deviation scores (SDS) across the whole patient population were lower than the population norms (mean values: -2.1 SDS for IGF-I and -1.2 SDS for IGFBP3), with no significant differences between the two patient subgroups. After 4 weeks, IGF-I and IGFBP3 levels increased by 1.0 SDS (p < 0.001) and 0.34 SDS (p < 0.001), respectively, but no significant differences were found between the two patient subgroups for growth-related or metabolic markers. CONCLUSIONS: For children with GHD born SGA, IGF-I and IGFBP3 are short-term biomarkers of responsiveness to treatment with growth hormone, as for children with GHD born AGA. PMID- 23626902 TI - The importance of local criteria in the diagnosis of metabolic syndrome in Saudi Arabia. AB - The clustering of risk factors predisposing an individual to cardiovascular morbidity and mortality are usually referred to as the 'metabolic syndrome' (MS). Several definitions exist, causing confusion to practicing clinicians. A consensus definition was reached by several major organizations stating that the presence of any three of five risk factors (abdominal obesity, elevated triglyceride, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting glucose) constitutes a diagnosis. Cutoff points for each of the risk factors were defined, taking into account ethnicity in case of abdominal obesity. The prevalence of MS has been reported to be on the rise globally, and was mainly attributed to changes in diet and lifestyle, in addition to genetic factors and metabolic susceptibility. The risk of cardiovascular disease (CVD) has almost doubled and the risk of developing type 2 diabetes mellitus (T2DM) has increased fivefold in individuals diagnosed with MS. The prevalence T2DM in Saudi Arabia is increasing, making it an epidemic health hazard. Intervention programs to decrease the risk of progression from MS to full T2DM, and later CVD have been successful in many countries. Therefore, diagnosing MS is important to address risk factors and to prevent progression to the more serious chronic conditions. The prevalence of MS in Saudi adults varies from 16% to 40% depending on the definition used and the study location. Use of the consensus definition might decrease the number of missed cases. However, in the absence of local cutoff points for various risk factors for MS, the use of ratios such as waist/hip ratio and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio, and family history of diabetes and CVD might aid diagnosis. Priority should be given to establishing national normal ranges, screening programs for hyperglycemia and hypertension, and community-directed programs to combat obesity and inactivity. PMID- 23626903 TI - Optimal treatment of diabetic retinopathy. AB - Diabetic retinopathy (DRP) is a common complication caused by multiple biochemical abnormalities of the underlying metabolic disease. While the incidence of DRP appears to decline due to evidence-based changes in diabetes management, the predicted increase in patients affected in particular by type 2 diabetes may outweigh the positive trend. The diagnosis is based on the alterations of the vessels, usually indicating abnormalities of the blood-retinal barrier and increased vasoregression, but the neuroglial elements appear equally vulnerable to the diabetic condition. Control of blood glucose, blood pressure and timely identification of coincident nephropathy are important to prevent progression to vision-threatening stages. Guidelines give specific indications for laser photocoagulation, in particular when euglycemia is no longer effective in preventing progression to advanced stages. Intravitreal administration of antibodies directed against the single best characterized propagator of clinically significant macular edema, vascular endothelial growth factor (VEGF), has become popular despite uncertainty about the patient subgroups which benefit best and the optimum administration schedule. Multifactorial intervention beyond glycemic control includes antihypertensive, lipid-lowering and antiaggregatory and is effective in type 2 diabetic patients with high-risk profiles, in particular coincident nephropathy. PMID- 23626905 TI - The impact of advance care planning of place of death, a hospice retrospective cohort study. AB - OBJECTIVES: There is limited evidence of the impact of advance care planning (ACP) on outcomes. We conducted a retrospective cohort study on deaths of all patients known to a hospice in a 2.5-year period to see if use of ACP affected actual place of death, hospital use and cost of hospital care in the last year. RESULTS: 969 patients were included. 550 (57%) people completed ACP. 414 (75%) achieved their choice of place of death. For those who chose home, 34 (11.3%) died in hospital; a care home 2 (1.7%) died in hospital; a hospice 14 (11.2%) died in hospital and 6 (86%) who chose to die in hospital did so. 112 (26.5%) of people without ACP died in hospital. Mean number of days in hospital in the last year of life was 18.1 in the ACP group and 26.5 in the non-ACP group(p<0.001). Mean cost of hospital treatment during the last year of life for those who died in hospital was L11,299, those dying outside of hospital L7,730 (p<0.001). Mean number of emergency admissions for those who died in hospital was 2.2 and who died elsewhere was 1.7 (p<0.001). CONCLUSIONS: ACP can be used routinely in a hospice setting. Those who used ACP spent less time in hospital in their last year. ACP is associated with a reduction in the number of days in hospital in the last year of life with less hospital costs, supporting the assumptions made in the End of Life Care Strategy 2008. PMID- 23626906 TI - Development and evaluation of an aged care specific Advance Care Plan. AB - OBJECTIVES: To report on the quality of advance care planning (ACP) documents in use in residential aged care facilities (RACF) in areas of Victoria Australia prior to a systematic intervention; to report on the development and performance of an aged care specific Advance Care Plan template used during the intervention. DESIGN: An audit of the quality of pre-existing documentation used to record resident treatment preferences and end-of-life wishes at participating RACFs; development and pilot of an aged care specific Advance Care Plan template; an audit of the completeness and quality of Advance Care Plans completed on the new template during a systematic ACP intervention. PARTICIPANTS AND SETTING: 19 selected RACFs (managed by 12 aged care organisations) in metropolitan and regional areas of Victoria. RESULTS: Documentation in use at facilities prior to the ACP intervention most commonly recorded preferences regarding hospital transfer, life prolonging treatment and personal/cultural/religious wishes. However, 7 of 12 document sets failed to adequately and clearly specify the resident's preferences as regards life prolonging medical treatment. The newly developed aged care specific Advance Care Plan template was met with approval by participating RACFs. Of 203 Advance Care Plans completed on the template throughout the project period, 49% included the appointment of a Medical Enduring Power of Attorney. Requests concerning medical treatment were specified in almost all completed documents (97%), with 73% nominating the option of refusal of life prolonging treatment. Over 90% of plans included information concerning residents' values and beliefs, and future health situations that the resident would find to be unacceptable were specified in 78% of completed plans. CONCLUSIONS: Standardised procedures and documentation are needed to improve the quality of processes, documents and outcomes of ACP in the residential aged care sector. PMID- 23626904 TI - Pulmonary Arterial Hypertension-A Deadly Complication of Systemic Sclerosis. AB - Pulmonary arterial hypertension (PAH) is a devastating disease with limited therapeutic options. Moreover, when PAH occurs in patients diagnosed with systemic sclerosis, worse outcomes are observed. The purpose of this review is to discuss the etiologies of PAH found in the systemic sclerosis patient, limitations of current medical therapies, and, finally, potential therapies for patients with this combination. PMID- 23626907 TI - Effect of antioxidants on enzyme-catalysed biodegradation of carbon nanotubes. AB - The growing applications of carbon nanotubes (CNTs) inevitably increase the risk of exposure to this potentially toxic nanomaterial. In an attempt to address this issue, research has been implemented to study the biodegradation of CNTs. In particular, myeloperoxidase (MPO), an enzyme expressed by inflammatory cells of animals including humans, catalyse the degradation of oxidized carbon nanomaterials. While reactive intermediates generated by MPO efficiently degrade oxidized single-walled carbon nanotubes (o-SWCNTs); the exact mechanism of enzyme catalysed biodegradation remains ambiguous. In this work, we tried to explain enzymatic oxidation in terms of redox potentials by employing competitive substrates for MPO such as chloride, which is oxidized by MPO to form a strong oxidant (hypochlorite), and antioxidants that have lower redox potentials than CNTs. Employing transmission electron microscopy, Raman spectroscopy, and vis-NIR absorption spectroscopy, we demonstrate that the addition of antioxidants, L ascorbic acid and L-glutathione, with or without chloride significantly mitigates MPO-catalysed biodegradation of o-SWCNTs. This study focuses on a fundamental understanding of the mechanisms of enzymatic biodegradation of CNTs and the impact of antioxidants on these pathways. PMID- 23626908 TI - Microscale Strategies for Generating Cell-Encapsulating Hydrogels. AB - Hydrogels in which cells are encapsulated are of great potential interest for tissue engineering applications. These gels provide a structure inside which cells can spread and proliferate. Such structures benefit from controlled microarchitectures that can affect the behavior of the enclosed cells. Microfabrication-based techniques are emerging as powerful approaches to generate such cell-encapsulating hydrogel structures. In this paper we introduce common hydrogels and their crosslinking methods and review the latest microscale approaches for generation of cell containing gel particles. We specifically focus on microfluidics-based methods and on techniques such as micromolding and electrospinning. PMID- 23626909 TI - The potential for resident lung mesenchymal stem cells to promote functional tissue regeneration: understanding microenvironmental cues. AB - Tissue resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Bone marrow derived mesenchymal stem cells (BM-MSCs) and endothelial progenitor cells (EPC) are currently being considered and tested in clinical trials as a potential therapy in patients with such inflammatory lung diseases including, but not limited to, chronic lung disease, pulmonary arterial hypertension (PAH), pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD)/emphysema and asthma. However, our current understanding of tissue resident lung MSCs remains limited. This review addresses how environmental cues impact on the phenotype and function of this endogenous stem cell pool. In addition, it examines how these local factors influence the efficacy of cell-based treatments for lung diseases. PMID- 23626911 TI - Certification for physicians in biomedical informatics. PMID- 23626912 TI - Achieving Holistic Health for the Individual through Person-Centered Collaborative Care Supported by Informatics. AB - OBJECTIVES: This article seeks to describe the current state of informatics supported collaborative care and to point out areas of future research in this highly interdisciplinary field. METHODS: In this article, person-centered collaborative care is seen as a concept addressing both the provision of care over organizational borders between health and social care, and within care teams as well as the changed patient/client-care provider relationship characterized by increased patient/client involvement. RESULTS: From a health systems perspective, there are several attempts to describe the conceptual and theoretical basis for collaborative care indicating that agreement on core concepts and terminology is difficult. From an informatics perspective, focus is on standardization of clinical content models and terminology to achieve interoperability of information technology systems and to support standardized care pathways. Few examples look into how ad-hoc collaborative care processes can be supported using information technology and informatics standards. Nevertheless, promising examples do exist showing that integrational Information Communication Technology services can be supportive for collaborative care developments. However, the current landscape consists of many fragmented, often technology-driven eHealth solutions targeting specific diagnostic groups in geographically and/or organizationally restricted settings. CONCLUSIONS: A systematic approach incorporating organizational, clinical, informatics and social science knowledge is needed to perform further research in areas such as virtual team partnerships, new paradigms of care delivery, data and knowledge management as well as its secure sharing. Also organizational and legal aspects need to be further researched in order to facilitate the coordinated provision of health and social care to citizens including self-management, utilizing informatics support in a societal context. PMID- 23626913 TI - Informatics as tool for quality improvement: rapid implementation of guidance for the management of chronic kidney disease in England as an exemplar. AB - OBJECTIVES: Chronic kidney disease (CKD) is an important cause of excess cardiovascular mortality and morbidity; as well as being associated with progression to end stage renal disease. This condition was largely unheard of in English primary care prior to the introduction of pay-for-performance targets for management in 2006. A realist review of how informatics has been a mechanism for national implementation of guidance for the improved management of CKD. METHODS: Realist review of context, the English National Health Service with a drive to implement explicit national quality standards; mechanism, the informatics infrastructure and its alignment with policy objectives; and outcomes are describe at the micro-data and messaging, meso-patient care and quality improvement initiatives, and marco-national policy levels. RESULTS: At the micro level computerised medical records can be used to reliably identify people with CKD; though differences in creatinine assays, fluctuation in renal function, and errors in diabetes coding were less well understood. At the meso-level more aggressive management of blood pressure (BP) in individual patients appears to slow or reverse decline in renal function; technology can support case finding and quality improvement at the general practice level. At the macro-level informaticians can help ensure that leverage from informatics is incorporated in policy, and ecological investigations inform if there is any association with improved health outcomes. CONCLUSIONS: In the right policy context informatics appears to be an enabler of rapid quality improvement. However, a causal relationship or generalisability of these findings has not been demonstrated. PMID- 23626914 TI - Comparison of machine learning algorithms for classification of the sentences in three clinical practice guidelines. AB - OBJECTIVES: Clinical Practice Guidelines (CPGs) are an effective tool for minimizing the gap between a physician's clinical decision and medical evidence and for modeling the systematic and standardized pathway used to provide better medical treatment to patients. METHODS: In this study, sentences within the clinical guidelines are categorized according to a classification system. We used three clinical guidelines that incorporated knowledge from medical experts in the field of family medicine. These were the seventh report of the Joint National Committee (JNC7) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure from the National Heart, Lung, and Blood Institute; the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults from the same institution; and the Standards of Medical Care in Diabetes 2010 report from the American Diabetes Association. Three annotators each tagged 346 sentences hand-chosen from these three clinical guidelines. The three annotators then carried out cross-validations of the tagged corpus. We also used various machine learning-based classifiers for sentence classification. RESULTS: We conducted experiments using real-valued features and token units, as well as a Boolean feature. The results showed that the combination of maximum entropy-based learning and information gain-based feature extraction gave the best classification performance (over 98% f-measure) in four sentence categories. CONCLUSIONS: This result confirmed the contribution of the feature reduction algorithm and optimal technique for very sparse feature spaces, such as the sentence classification problem in the clinical guideline document. PMID- 23626910 TI - Developmental neurobiology of the rat attachment system and its modulation by stress. AB - Stress is a powerful modulator of brain structure and function. While stress is beneficial for survival, inappropriate stress dramatically increases the risk of physical and mental health problems, particularly when experienced during early developmental periods. Here we focus on the neurobiology of the infant rat's odor learning system that enables neonates to learn and approach the maternal odor and describe the unique role of the stress hormone corticosterone in modulating this odor approach learning across development. During the first nine postnatal days, this odor approach learning of infant rats is supported by a wide range of sensory stimuli and ensures attachment to the mother's odor, even when interactions with her are occasionally associated with pain. With maturation and the emergence of a stress- or pain-induced corticosterone response, this odor approach learning terminates and a more adult-like amygdala-dependent fear/avoidance learning emerges. Strikingly, the odor approach and attenuated fear learning of older pups can be re-established by the presence of the mother, due to her ability to suppress her pups' corticosterone release and amygdala activity. This suggests that developmental changes in stress responsiveness and the stimuli that produce a stress response might be critically involved in optimally adapting the pup's attachment system to its respective ecological niche. PMID- 23626915 TI - Association rules to identify complications of cerebral infarction in patients with atrial fibrillation. AB - OBJECTIVES: The purpose of this study was to find risk factors that are associated with complications of cerebral infarction in patients with atrial fibrillation (AF) and to discover useful association rules among these factors. METHODS: The risk factors with respect to cerebral infarction were selected using logistic regression analysis with the Wald's forward selection approach. The rules to identify the complications of cerebral infarction were obtained by using the association rule mining (ARM) approach. RESULTS: We observed that 4 independent factors, namely, age, hypertension, initial electrocardiographic rhythm, and initial echocardiographic left atrial dimension (LAD), were strong predictors of cerebral infarction in patients with AF. After the application of ARM, we obtained 4 useful rules to identify complications of cerebral infarction: age (>63 years) and hypertension (Yes) and initial ECG rhythm (AF) and initial Echo LAD (>4.06 cm); age (>63 years) and hypertension (Yes) and initial Echo LAD (>4.06 cm); hypertension (Yes) and initial ECG rhythm (AF) and initial Echo LAD (>4.06 cm); age (>63 years) and hypertension (Yes) and initial ECG rhythm (AF). CONCLUSIONS: Among the induced rules, 3 factors (the initial ECG rhythm [i.e., AF], initial Echo LAD, and age) were strongly associated with each other. PMID- 23626916 TI - Predictors of medication adherence in elderly patients with chronic diseases using support vector machine models. AB - OBJECTIVES: The aim of this study was to establish a prediction model of medication adherence in elderly patients with chronic diseases and to identify variables showing the highest classification accuracy of medication adherence in elderly patients with chronic diseases using support vector machine (SVM) and conventional statistical methods, such as logistic regression (LR). METHODS: We included 293 chronic disease patients older than 65 years treated at one tertiary hospital. For the medication adherence, Morisky's self-report was used. Data were collected through face-to-face interviews. The mean age of the patients was 73.8 years. The classification process was performed with LR (SPSS ver. 20.0) and SVM (MATLAB ver. 7.12) method. RESULTS: Taking into account 16 variables as predictors, the result of applying LR and SVM classification accuracy was 71.1% and 97.3%, respectively. We listed the top nine variables selected by SVM, and the accuracy using a single variable, self-efficacy, was 72.4%. The results suggest that self-efficacy is a key factor to medication adherence among a Korean elderly population both in LR and SVM. CONCLUSIONS: Medication non-adherence was strongly associated with self-efficacy. Also, modifiable factors such as depression, health literacy, and medication knowledge associated with medication non-adherence were identified. Since SVM builds an optimal classifier to minimize empirical classification errors in discriminating between patient samples, it could achieve a higher accuracy with the smaller number of variables than the number of variables used in LR. Further applications of our approach in areas of complex diseases, treatment will provide uncharted potentials to researchers in the domains. PMID- 23626917 TI - Discovery of outpatient care process of a tertiary university hospital using process mining. AB - OBJECTIVES: There is a need for effective processes in healthcare clinics, especially in tertiary hospitals, that consist of a set of complex steps for outpatient care, in order to provide high quality care and reduce the time cost. This study aimed to discover the potential of a process mining technique to determine an outpatient care process that can be utilized for further improvements. METHODS: The outpatient event log was defined, and the log data for a month was extracted from the hospital information system of a tertiary university hospital. That data was used in process mining to discover an outpatient care process model, and then the machine-driven model was compared with a domain expert-driven process model in terms of the accuracy of the matching rate. RESULTS: From a total of 698,158 event logs, the most frequent pattern was found to be "Consultation registration > Consultation > Consultation scheduling > Payment > Outside-hospital prescription printing" (11.05% from a total cases). The matching rate between the expert-driven process model and the machine-driven model was found to be approximately 89.01%, and most of the processes occurred with relative accuracy in accordance with the expert-driven process model. CONCLUSIONS: Knowledge regarding the process that occurs most frequently in the pattern is expected to be useful for hospital resource assignments. Through this research, we confirmed that process mining techniques can be applied in the healthcare area, and through detailed and customized analysis in the future, it can be expected to be used to improve actual outpatient care processes. PMID- 23626918 TI - AnsNGS: An Annotation System to Sequence Variations of Next Generation Sequencing Data for Disease-Related Phenotypes. AB - OBJECTIVES: Next-generation sequencing (NGS) data in the identification of disease-causing genes provides a promising opportunity in the diagnosis of disease. Beyond the previous efforts for NGS data alignment, variant detection, and visualization, developing a comprehensive annotation system supported by multiple layers of disease phenotype-related databases is essential for deciphering the human genome. To satisfy the impending need to decipher the human genome, it is essential to develop a comprehensive annotation system supported by multiple layers of disease phenotype-related databases. METHODS: AnsNGS (Annotation system of sequence variations for next-generation sequencing data) is a tool for contextualizing variants related to diseases and examining their functional consequences. The AnsNGS integrates a variety of annotation databases to attain multiple levels of annotation. RESULTS: The AnsNGS assigns biological functions to variants, and provides gene (or disease)-centric queries for finding disease-causing variants. The AnsNGS also connects those genes harbouring variants and the corresponding expression probes for downstream analysis using expression microarrays. Here, we demonstrate its ability to identify disease related variants in the human genome. CONCLUSIONS: The AnsNGS can give a key insight into which of these variants is already known to be involved in a disease related phenotype or located in or near a known regulatory site. The AnsNGS is available free of charge to academic users and can be obtained from http://snubi.org/software/AnsNGS/. PMID- 23626919 TI - Measure of clinical information technology adoption. AB - OBJECTIVES: The objective of this study was to create a new measure for clinical information technology (IT) adoption as a proxy variable of clinical IT use. METHODS: Healthcare Information and Management Systems Society (HIMSS) data for 2004 were used. The 18 clinical IT applications were analyzed across 3,637 acute care hospitals in the United States. After factor analysis was conducted, the clinical IT adoption score was created and evaluated. RESULTS: Basic clinical IT systems, such as laboratory, order communication/results, pharmacy, radiology, and surgery information systems had different adoption patterns from advanced IT systems, such as cardiology, radio picture archiving, and communication, as well as computerized practitioner order-entry. This clinical IT score varied across hospital characteristics. CONCLUSIONS: Different IT applications have different adoption patterns. In creating a measure of IT use among various IT components in hospitals, the characteristics of each type of system should be reflected. Aggregated IT adoption should be used to explain technology acquisition and utilization in hospitals. PMID- 23626920 TI - The Effect of Premarital Sex on Sexually Transmitted Infections (STIs) and High Risk Behaviors in Women. AB - This research aimed to study the effect of premarital sex on sexually transmitted infections (STIs) and high risk behaviors among women in sub-Saharan Africa. It included 1393 women randomly selected from the Moshi urban district of northern Tanzania. Participants' demographic and socio-demographic characteristics, alcohol use, condom use, number of partners, symptoms of STIs and age at first sex and marriage were obtained. Moreover, blood and urine samples were tested for HIV-1, HSV-2, syphilis, chlamydia, gonorrhea, trichomonas and Mycoplasma genitalium infections. The average duration of premarital sex in the study participants was 1.66 years (SD of 2.61 years). Women with longer duration of premarital sex had higher odds of HIV-1, HSV-2 and other STIs. Moreover, women with longer duration of premarital sex were more likely to report multiple sexual partners. These findings highlight the importance of a lengthy period of premarital sex as a public health issue. STIs prevention programs in sub-Saharan Africa should address factors leading to a longer period of premarital sex in women. PMID- 23626921 TI - Exposure to Different Types of Violence and Subsequent Sexual Risk Behavior among Female STD Clinic Patients: A Latent Class Analysis. AB - OBJECTIVE: Diverse forms of violence, including childhood maltreatment (CM), intimate partner violence (IPV), and exposure to community violence (ECV), have been linked separately with sexual risk behaviors. However, few studies have explored multiple experiences of violence simultaneously in relation to sexual risk-taking, especially in women who are most vulnerable to violent experiences. METHODS: Participants were 481 women (66% African American, Mage = 27 years) attending a publicly-funded STD clinic who reported on their past and current experiences with violence and their current sexual risk behavior. We identified patterns of experience with violence using latent class analysis (LCA) and investigated which combinations of experiences were associated with the riskiest sexual outcomes. RESULTS: Four classes of women with different experiences of violence were identified: Low Violence (39%), Predominantly ECV (20%), Predominantly CM (23%), and Multiply Victimized (18%). Women in the Multiply Victimized and Predominantly ECV classes reported the highest levels of sexual risk behavior, including more lifetime sexual partners and a greater likelihood of receiving STD treatment and using substances before sex. CONCLUSIONS: Women with different patterns of violent experiences differed in their sexual risk behavior. Interventions to reduce sexual risk should address violence against women, focusing on experiences with multiple types of violence and experiences specifically with ECV. Additional research is needed to determine the best ways to address violence in sexual risk reduction interventions. PMID- 23626922 TI - From the Large Scale Expression Analysis of Lupus Nephritis to Targeted Molecular Medicine. AB - Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus (SLE). Current treatments for LN lack sufficient efficacy as they do not necessarily target the LN responsible pathways and therapeutic responses vary widely in the patient population. LN mouse models have been useful in delineating disease pathogenesis and for testing novel therapies, but they do not entirely represent the events happening in human LN. This review describes how recently developed systems biology technologies can help to integrate current knowledge with large scale experimental data to generate new hypotheses and insight into the regulatory events occurring in LN. PMID- 23626923 TI - Role of TH-17 cells in rheumatic and other autoimmune diseases. AB - In humans multiple pathways can induce TH-17 cell differentiation, whereas in mice this process is mostly modulated by IL-6 and TGF-beta. IL-17 produced by TH 17 cells has been associated with a number of inflammatory autoimmune diseases including psoriasis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. In this review, we have primarily focused on the role of TH-17 cells/IL-17 in the pathogenesis of rheumatoid arthritis and experimental arthritis. The potential role of TH-17 cells in rheumatoid arthritis progression has been demonstrated by correlating the percent TH-17 cells or levels of IL-17 with rheumatoid arthritis disease activity score and C-reactive protein levels. Further, previous studies suggest that IL-17 mediated vascularization may lay the foundation for rheumatoid arthritis joint neutrophil and monocyte recruitment as well as cartilage and bone destruction. The profound role of IL-17 in the pathogenesis of experimental arthritis may be due to its synergistic effect with TNF-alpha and IL-1beta. Although the initial clinical trial employing anti-IL-17 antibody has been promising for rheumatoid arthritis, future studies in humans will shed more light on how anti-IL-17 therapy affects rheumatoid arthritis and other autoimmune disease pathogenesis. PMID- 23626924 TI - The Nature of Macular Damage in Glaucoma as Revealed by Averaging Optical Coherence Tomography Data. AB - PURPOSE: To better understand the nature of glaucomatous damage, especially to the macula, the inner retinal thickness maps obtained with frequency domain optical coherence tomography (fdOCT) were averaged. METHODS: Frequency domain optical coherence tomography macular and optic disc cube scans were obtained from 54 healthy eyes and 156 eyes with glaucomatous optic neuropathy. A manually corrected algorithm was used for layer segmentation. Patients' eyes were grouped both by mean deviation (MD) and hemifield classification using standard categories and 24-2 (6 degrees grid) visual fields (VFs). To obtain average difference maps, the thickness of retinal nerve fiber (RNF) and retinal ganglion cell plus inner plexiform (RGC+) layers were averaged and subtracted from the average control values. RESULTS: On the average difference maps, RGC+ and RNF layer thinning was seen in the patient groups with VFs classified as normal. The pattern of the thinning was the same, but the degree of thinning increased with decreased MD and with classification category (from normal to arcuate). This RGC+ thinning was largely within the central four points of the 24-2 (6 degrees grid) field, after correcting for RGC displacement. CONCLUSION: 1. VF categories represent different degrees of the same pattern of RGC+ and RNFL layer thinning. 2. RGC+ damage occurs in the central macula even in patients with VFs classified as normal. 3. The 6 degrees grid (24-2) pattern is not optimally designed to detect macular damage. 4. A schematic model of RGC projections is proposed to explain the pattern of macular loss, including the greater vulnerability of the inferior retinal region. TRANSLATIONAL RELEVANCE: The 24-2 is not an optimal test pattern for detecting or following glaucomatous damage. Further, we suggest clinical fdOCT reports include RGC+ and RNFL probability plots combined with VF information. PMID- 23626926 TI - Traction esophageal diverticulum: a rare cause of gastro-intestinal bleeding. AB - Esophageal diverticula are uncommon lesions that are usually classified according to their location (cervical, thoracic, or epiphrenic), or underlying pathogenesis (pulsion or traction), and their morphology (true or false).The majority of esophageal diverticula are acquired lesions that occur predominantly in elderly adults. Pulsion, or false, diverticula are the most commonly encountered type of esophageal diverticula noticed at the level of cricopharyngeus muscle, occur as a localized outpouchings that lacks a muscular coat, and as such their wall is formed entirely by mucosa and submucosa. True, or traction, esophageal diverticulum (TED) is seen in the middle one third of the thoracic esophagus in a peribronchial location, occurs secondary to mediastinal inflammatory lesions such as tuberculosis or histoplasmosis. The resultant desmoplastic reaction in the paraesophageal tissue causes full thickness pinching on the esophageal wall, producing a conical, broad-mouthed true diverticulum. They often project to the right side because subcarinal lymph nodes in this area are closely associated with the right anterior wall of the esophagus. TED usually presents with symptoms such as dysphagia, postural regurgitation, belching, retrosternal pain, heartburn, and epigastric pain. As in patients with pharyngoesophageal (Zenker's) diverticula, pulmonary symptoms are often present but underestimated in TED patients. These symptoms range from mild nocturnal cough to life-threatening massive aspiration. In this particular report we describe a rare case of TED presenting as a symptomatic upper gastrointestinal bleeding. Diagnostic evaluation of TED includes chest X-ray, barium esophagogram and manometry. A significant proportion of lower esophageal diverticula are associated with motility disorders. Management of TED include treating the underlying cause sometimes a surgical resection of diverticulum along with esophageal myotomy is necessitated in symptomatic patients. PMID- 23626925 TI - Low-level laser (light) therapy (LLLT) on muscle tissue: performance, fatigue and repair benefited by the power of light. AB - The use of low level laser (light) therapy (LLLT) has recently expanded to cover areas of medicine that were not previously thought of as the usual applications such as wound healing and inflammatory orthopedic conditions. One of these novel application areas is LLLT for muscle fatigue and muscle injury. Since it is becoming agreed that mitochondria are the principal photoacceptors present inside cells, and it is known that muscle cells are exceptionally rich in mitochondria, this suggests that LLLT should be highly beneficial in muscle injuries. The ability of LLLT to stimulate stem cells and progenitor cells means that muscle satellite cells may respond well to LLLT and help muscle repair. Furthermore the ability of LLLT to reduce inflammation and lessen oxidative stress is also beneficial in cases of muscle fatigue and injury. This review covers the literature relating to LLLT and muscles in both preclinical animal experiments and human clinical studies. Athletes, people with injured muscles, and patients with Duchenne muscular dystrophy may all benefit. PMID- 23626927 TI - Sudden weaning of angel fish pterophyllum scalare (Lichtenstein) (Pisces; Cichlidae) larvae from brine shrimp (Artemia sp) nauplii to formulated larval feed. AB - This study investigated the effects of sudden weaning of angel fish larvae (Pteraphylum scalari) from Artemia nauplii to commercial larval feed. Four days post hatch (DPH) larvae were reared in four different weaning protocols (TR1-TR4) with triplicates in a complete randomize design. Larvae in TR1 and TR4 were exclusively fed Artemia nauplii and dry feed respectively. In TR2 and TR3, larvae were initially fed Artemia nauplii and suddenly wean to formulated feed on 14 DPH and 7 DPH respectively. The experiment was lasted for 28 days. At the end of the experiment, final mean weight (FW), total length (FL), height (FH), Daily Weight Gain (DWG), Specific Growth Rate (SGR), survival and stress index were compared. Significantly highest (P < 0.05) FW, DWG and SGR were observed in TR1 and TR2 while former values of TR3 were not significantly different from TR1. Highest FL observed in TR1 and TR2 while FL of TR2 was statistically similar to that of TR3. The poorest growth was observed in larvae solely fed formulated feed. Survival and the stress index were independent from weaning methods. Although sudden weaning is possible on 7 DPH, larvae showed comparatively higher growth when switch off to formulate feed on 14 DPH. PMID- 23626928 TI - Production and partial characterization of extracellular amylase enzyme from Bacillus amyloliquefaciens P-001. AB - Amylases are one of the most important enzymes in present-day biotechnology. The present study was concerned with the production and partial characterization of extracellular amylase from Bacillus amyloliquefaciens P-001. The effect of various fermentation conditions on amylase production through shake-flask culture was investigated. Enzyme production was induced by a variety of starchy substrate but corn flour was found to be a suitable natural source for maximum production. Tryptone and ammonium nitrate (0.2%) as nitrogen sources gave higher yield compared to other nitrogen sources. Maximum enzyme production was obtained after 48 hrs of incubation in a fermentation medium with initial pH 9.0 at 42 degrees C under continuous agitation at 150 rpm. The size of inoculum was also optimized which was found to be 1% (v/v). Enzyme production was 2.43 times higher after optimizing the production conditions as compared to the basal media. Studies on crude amylase revealed that optimum pH, temperature and reaction time of enzyme activity was 6.5, 60 degrees C and 40 minutes respectively. About 73% of the activity retained after heating the crude enzyme solution at 50 degrees C for 30 min. The enzyme was activated by Ca(2+) (relative activity 146.25%). It was strongly inhibited by Mn(2+), Zn(2+) and Cu(2+), but less affected by Mg(2+) and Fe(2+). PMID- 23626929 TI - An updated global picture of cigarette smoking persistence among adults. AB - BACKGROUND: Cross-national variance in smoking prevalence is relatively well documented. The aim of this study is to estimate levels of smoking persistence across 21 countries with a hypothesized inverse relationship between country income level and smoking persistence. METHODS: Data from the World Health Organization World Mental Health Survey Initiative were used to estimate cross national differences in smoking persistence--the proportion of adults who started to smoke and persisted in smoking by the date of the survey. RESULTS: There is large variation in smoking persistence from 25% (Nigeria) to 85% (China), with a random-effects meta-analytic summary estimate of 55% with considerable cross national variation. (Cochran's heterogeneity Q statistic = 6845; p < 0.001). Meta regressions indicated that observed differences are not attributable to differences in country's income level, age distribution of smokers, or how recent the onset of smoking began within each country. CONCLUSION: While smoking should remain an important public health issue in any country where smokers are present, this report identifies several countries with higher levels of smoking persistence (namely, China and India). PMID- 23626930 TI - NF-kappaB pathway in colitis-associated cancers. AB - Colitis-associated cancer is the subtype of colorectal cancer that is associated with inflammatory bowel diseases including ulcerative colitis and Crohn's disease. Colorectal cancer is one of the most commonly diagnosed cancers, and is the third leading cause of cancer death in developed countries. Of the signaling pathways involved in colonic inflammation, that triggered by NF-kappaB plays a key role. A relationship between inflammation and cancer is now well documented. Moreover, the association between NF-kappaB activity and cancer development has been intensively investigated. The present review focuses on the activity of the NF-kappaB signaling pathway in colitis-associated carcinogenesis. The pivotal roles played by this pathway in apoptosis, tumor promotion, and tumor maintenance strongly suggest that inhibitors of the pathway would be powerful anti-cancer agents. PMID- 23626931 TI - Evaluation of preincubation time interval in testicular biopsy to obtain optimum sperm parameters. AB - OBJECTIVE: In sever oligospermia; one of the paths used for surgical sperm retrieval (SSR) is to extract sperm via a testicular biopsy. The aim of our study is to determine the reliable time interval between testicular biopsy and intracytoplasmic sperm injection (ICSI) procedure in order to obtain optimumsperm parameters (count, motility and normal morphology). MATERIALS AND METHODS: This cohort study was carried out on 30 patients which were candidates for ICSI. After collection and keeping the samples obtained from the testicular biopsy in Ham's F10 environment, the concentration, motility and morphology of the sperm in each sample was evaluated immediately as well as 2 and 4 hours after processing. The Data were then compared with each other. For the statistical analysis, Friedman, Willcoxon and Cochran tests were used. RESULTS: The mean of sperm concentration was 5.69 +/- 6.14 million and the motility was10.83 +/- 12.63% at 2 hours following biopsy which was significantly higher than those obtained after 0 and 4 hours of the biopsy (p <0.05). CONCLUSION: The reliable preincubation time which resulted in the highest rate of spermatozoa parameters after testicular biopsy and before incubation was 2 hours. PMID- 23626932 TI - Pyocyanine Biosynthetic Genes in Clinical and Environmental Isolates of Pseudomonas aeruginosa and Detection of Pyocyanine's Antimicrobial Effects with or without Colloidal Silver Nanoparticles. AB - OBJECTIVE: Pyocyanine plays an important role in the pathogenesis of Pseudomonas aeruginosa, (P. aeruginosa) and is known to have inhibitory and bactericidal effects. This study has aimed to detect the phenazine biosynthetic operon (phz ABCDEFG) and two phenazine modifying genes (phzM and phzS) by polymerase chain reaction (PCR) and detection of its possible protein bands by sodium dodecyl sulfate - polyacrylamide gel electrophoresis (SDS-PAGE). The antimicrobial effects of pyocyanine alone and mixed with colloidal silver nanoparticles were studied. MATERIALS AND METHODS: In this descriptive study, clinical and environmental species of P. aeruginosa were isolated by thioglycollate medium culture and cetrimide agar, respectively. The existence of a phenazine biosynthetic operon and two phenazine modifying genes as well as their protein products were confirmed by PCR and SDS-PAGE, respectively. Pyocyanine was extracted with chloroform and its antimicrobial effects against bacteria such as; Escherichia coli (E. coli), P. aeruginosaand Staphylococcus aureus (S. aureus) bacteria and yeast Candida albicans (C. albicans) were tested using well, spot and disk diffusion methods. RESULTS: In this study, 3 out of 48 clinical strains were unable to produce pyocyanine on cetrimide and Mueller Hinton (MH) agar. Two strains did not have phenazine modifying gene bands. Another strain did not have the possible protein band of the phzM gene. Pyocyanine had antimicrobial effects against the microbial strains, which increased in the presence of silver nanoparticles. CONCLUSION: According to the results of the present study, some P. aeruginosa strains are unable to produce pyocyanine due to the absence of the phzM or phzS genes. Therefore, these genes have an important role in pyocyanine production in P. aeruginosa. Pyocyanine shows synergistic antimicrobial effects in the presence of silver nanoparticles against microbial strains. PMID- 23626933 TI - Evaluation of Methylation Status in the 5'UTR Promoter Region of the DBC2 Gene as a Biomarker in Sporadic Breast Cancer. AB - OBJECTIVE: Breast cancer is one of the most common malignancies in women worldwide. It is caused by a number of genetic and epigenetic factors. Aberrant hypermethylation of the promoter regions in specific genes is a key event in the formation and progression of breast cancers as well as the DBC2 gene, as a tumor suppressor gene. Different studies show that the DBC2 gene is inactivated through epigenetic mechanisms such as methylation in its promoter region. In this study, authors have tried to analyze methylation status in the promoter region of DBC2 gene in affected women and healthy controls. MATERIALS AND METHODS: In this experimental study, we evaluated the methylation status of DBC2 gene with nested methylation-specific PCR (MSPCR) using specific methylated and unmethylated primer sets, in three separate PCR reactions. We used 50 tissue and blood samples of patients with breast cancer, 5 normal tissues and also 30 normal blood samples. Results were evaluated by the Mann-Whitney test, SPSS 16.0 statistical software. RESULTS: Nested MSPCR results demonstrated that the frequency of the DBC2 promoter region methylation status in tumor and blood samples of the affected patients was significantly higher than that of the corresponding normal controls. CONCLUSION: DBC2 gene inactivation by methylation of CpG islands in the promoter region probably is a crucial step in the process of cell proliferation and susceptibility to different cancers, including breast cancer. Our study provides new evidence that aberrant methylation of the DBC2 gene is involved in the tumorigenesis of breast cancer. DNA methylation in this gene is proven to be a potential marker for tumor diagnosis and prognosis, as well as a novel therapeutic target. PMID- 23626934 TI - DNA Damage Induced in Glioblastoma Cells by I-131: A Comparison between Experimental Data and Monte Carlo Simulation. AB - OBJECTIVE: The passage of ionizing radiation in living cells creates clusters of damaged nucleotides in DNA. In this study, DNA strand breaks induced by the beta particle of iodine-131 (I-131), have been determined experimentally and compared to Monte Carlo simulation results as a theoretical method of determining(131)I damage. MATERIALS AND METHODS: In this experimental study, in order to create single strand breaks (SSB) and double strand breaks (DSB) in the DNA, glioblastoma (GBM) cells were exposed to 10 mCi I-131, at a dose of 2 Gy. Damage of irradiated cells were evaluated quantitatively by the Fast Micromethod assay. The energy spectrum of electrons released in cells were obtained by the macroscopic Monte Carlo code (MCNP4c) and used as an input of the micro Monte Carlo code (MCDS). The percent of damage induced in cells was analyzed by Mann Whitney test. RESULTS: A significant reduction (p<0.05) in fluorescence intensity in irradiated cells compared to control cells as determined by the Fast Micromethod assay represented induced SSB and DSB damages in the DNA of irradiated cells. Comparison of experimental and theoretical results showed that the difference between the percentages of SSB per Gy was about 7.4% and DSB was about 1% per Gy. CONCLUSION: The differences in experimental and theoretical results may be due to the algorithm of applied codes. Since the Fast Micromethod and other experimental techniques do not provide information about the amount of detailed and complex damages of DNA-like base damages, the applied Monte Carlo codes, due to their capability to predict the amount of detailed damages that occur in the DNA of irradiated cells, can be used in in vitro experiments and radiation protection areas. PMID- 23626935 TI - The effect of aligned and random electrospun fibrous scaffolds on rat mesenchymal stem cell proliferation. AB - OBJECTIVE: The development of combining mesenchymal stem cells (MSCs) with surface modified three-dimensional (3D) biomaterial scaffold provides a desirable alternative for replacement of damaged and diseased tissue. Nanofibrous scaffolds serve as suitable environment for cell attachment and proliferation due to their similarity to the physical dimension of the natural extracellular matrix. In this study the properties of plasma treated poly-C-caprolactone nanofiber scaffolds (p PCL) and unaltered PCL scaffolds were compared, and then p-PCL scaffolds were evaluated for MSC culture. MATERIALS AND METHODS: Aligned and random PCL nanofibrus scaffolds were fabricated by electrospining and their surface modified with O2 plasma treatment to enhance MSC proliferation, adhesion and interaction. Chemical and mechanical characterizations were carried out using scanning electron microscopy (SEM), water contact angle and tensile testing. Cell adhesion and morphology were evaluated using SEM 1 day after culture. Statistical analysis was carried out using one way analysis of variance (ANOVA). RESULTS: The proliferation of MSCs were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5 Diphenyltetrazolium Bromide(MTT) assay on day 1, 3, and 5 after cell culture. Results showed that the numbers of cells that had grown on PCL nanofibrous scaffolds were significantly higher than those of control surfaces without nanofibers. Furthermore, the proliferation of MSCs on random nanofiber was significantly higher compared to that on aligned nanofiber. CONCLUSION: This study showed that while both aligned and random plasma treated PCL nanofibrous scaffold are more suitable substrates for MSC growth than tissue culture plates, random nanofiber best supported the proliferation of MSCs. PMID- 23626936 TI - The effects of schwann and bone marrow stromal stem cells on sciatic nerve injury in rat: a comparison of functional recovery. AB - OBJECTIVE: Transplantation of bone marrow stromal cells (BMSCs) or Schwann cells (SCs) can facilitate axonal regeneration in peripheral nerve injuries. The aim of this study was to compare the effects of transplantation of BMSCs and SCs on functional recovery after injury to the sciatic nerve in the rat. MATERIALS AND METHODS: In this experimental research, adult male Wistar rats (n=24, 250-300 g) were used, BMSCs and SCs were cultured, and SCs were confirmed with anti S100 antibody. Rats were randomly divided into 3 groups (n=8 in each group): 1; control group: silicon tube filled with fibrin gel without the cells, 2; BMSCs group: silicon tube filled with fibrin gel seeded with BMSCs and 3; SCs group: silicon tube filled with fibrin gel seeded with SCs. The left sciatic nerve was exposed, a 10 mm segment removed, and a silicone tube interposed into this nerve gap. BMSCs and SCs were separately transplanted into the gap in the two experimental groups and were labeled with anti BrdU and DiI respectively. After 12 weeks electrophysiological and functional assessments were performed and analyzed by one-way analysis of variance (ANOVA). RESULTS: Electrophysiological and functional assessments showed a significant difference between the experimental groups compared with the control group. Electrophysiological measures were significantly better in the SCs transplantation group compared with the BMSCs treatment group (p <0.05). Functional assessments showed no statistically significant difference between the BMSCs and SCs groups (p <0.05). CONCLUSION: Although both BMSCs and SCs have the potential to produce functional recovery after injury to the sciatic nerve in rats, electrophysiological evaluation confirms that the improvement after SCs transplantation is greater than that after BMSCs transplantation. PMID- 23626937 TI - Effect of the Hydroalcoholic Extract of Heracleum persicum (Golpar) on Folliculogenesis in Female Wistar Rats. AB - OBJECTIVE: Medicinal plants are widely used throughout the world. Since these plants are known to have minimal side effects, many people embrace them. The golpar plant, scientifically known as Heracleum persicum (H. persicum), is a common Asian and Iranian medicinal plant. The use of golpar is recommended in traditional medicine as a contraceptive medication for females; however, no scientifically documented evidence has been reported. This study investigates the effects of the golpar plant on ovarian tissue and folliculogenesis. MATERIALS AND METHODS: In this experimental study, H. persicum hydroalcoholic extract (HPHE) was used at 400 mg/kg and 1600 mg/kg doses. Adult female rats were divided into three groups: control, sham, and experimental(I, II). The control group did not receive any injection, the sham group received saline solution, and the experimental group received IP injections of HPHE for 21 days, once every other day, during the sexual cycle. At the end of the injection period, ovarian samples were harvested for histological studies. The FSH assay was performed according to the chemiluminescence immunoassay (CLIA) method. Data were statistically analyzed by the Instat3 program and one-way ANOVA. A p value of <0.05 was considered significant. RESULTS: In the experimental group the numbers of primordial and primary follicles increased (p <0.001), while the number of preantral and antral follicles decreased (p <0.01). The atretic follicles decreased in the experimental group, but this decrease was not significant. There was no statistical difference in FSH concentration when compared with the control group. CONCLUSION: This report gives primary information on the in vivo effects of the HPHE on the ovarian follicles of the female Wistar rat. The results suggest that administration of HPHE may have inhibitory effects on folliculogenesis and cause infertility in females. PMID- 23626938 TI - Effect of Neem Leaf Extract (Azadirachta indica) on c-Myc Oncogene Expression in 4T1 Breast Cancer Cells of BALB/c Mice. AB - OBJECTIVE: Breast cancer is the most common cause of cancer-related deaths in women both worldwide and in Malaysia. Azadirachta indica (A. Juss), commonly known as neem, is one of the most versatile medicinal plants that has gained worldwide prominence due to its medicinal properties. However, the anticancer effect of ethanolic neem leaf extract against breast cancer has not been documented. The purpose of the present study is to investigate the effect of neem leaf extract on c-Myc oncogene expression in 4T1 breast cancer BALB/c mice. MATERIALS AND METHODS: In this experimental study, A total of 48 female BALB/c mice were divided randomly into four groups of 12 mice per group: i.cancer control (CC) treated with 0.5% Tween 20 in PBS, ii. 0.5 ug/mL tamoxifen citrate (CT), iii. 250 mg/kg neem leaf extract (C250), and iv. 500 mg/kg neem leaf extract (C500). in situ reverse transcription polymerase chain reaction (in situ RT-PCR) was applied to evaluate suppression of c-Myc oncogene expression in breast cancer tissue. RESULTS: The C500 group showed significant (p<0.05) suppression of c-Myc oncogene expression compared to the CC group. CONCLUSION: c Myc was found to be down regulated under the effect of 500 mg/kg ethanolic neem leaf extract. PMID- 23626939 TI - Construction of an Expression Vector Containing Mtb72F of Mycobacterium tuberculosis. AB - OBJECTIVE: Despite using the Bacille Calmette Guerin (BCG) vaccine, tuberculosis (TB) is still a worldwide disease that kills 2-3 million people each year. Developing a new and more effective vaccine is one way to possibly reduce the morbidity and mortality of TB. The Mtb72F vaccine is one of the important subunit vaccines applied in human clinical trials. In this study, we have constructed an expression vector that contains the Mtb72F fragment with some new modifications. MATERIALS AND METHODS: In this experimental study, Mtb32N and Mtb39 fragments were amplified by polymerase chain reaction (PCR) using specific primers and inserted into pET21b?Mtb32C. Colony-PCR, restriction enzyme analysis, and DNA sequencing were used to confirm the accuracy of the cloning. We used Western blot to verify the desired protein expression. RESULTS: The amplified fragments showed the desired size in PCR and digestion methods, and protein expression was confirmed using a monoclonal antibody. CONCLUSION: Our modification made it possible to insert another gene or gene fragments into the Mtb72F vector for developing new constructs. In addition, our data has shown that the placement of the histidine tag in the carboxyl- (C-) or amino- (N-) terminal part of a protein may influence protein expression and/or stability. PMID- 23626941 TI - Interdisciplinary Researches in Iran II. PMID- 23626940 TI - Lipoprotein Lipase HindIII Intronic Polymorphism in a Subset of Iranian Patients with Late-Onset Alzheimer's Disease. AB - OBJECTIVE: Lipid metabolism is involved in the pathogenesis of late-onset Alzheimer's disease (LOAD). Lipoprotein lipase (LPL) is a multifunctional enzyme that plays a major role in lipid metabolism; its abnormal function seems to be related, either directly or indirectly, to the pathogenesis of many diseases such as atherosclerosis, coronary artery disease (CAD) and Alzheimer's disease (AD) . HindIII polymorphism is a common LPL genetic variant shown to increase the risk of LOAD. The present research investigates whether this polymorphism is involved in the pathogenesis of Iranian LOAD patients. MATERIALS AND METHODS: In this case control study ,allele and genotype frequencies for the HindIII polymorphism of the LPL gene in 100 patients affected with LOAD and 100 healthy controls were determined by reaction-restriction fragment length polymorphism (PCR-RFLP) and compared using the chi-square and Fisher's exact tests. RESULTS: LPL H+H+ genotype frequency in LOAD patients was 58%, which was significantly higher than controls (44%). There was a 1.75-fold increased risk for the development of LOAD in carriers of the H+H+ genotype compared to non-carriers (OR=1.75; 95%CI: 1.00 3.07; p=0.048). When adjusted for sex, the H+H+ genotype was more frequent in patients than controls; this difference was more remarkable in males (OR: 1.90; 95% CI: 1.08-3.34; p=0.024). The mean age of disease onset did not differ in patients with the LPL H+H+ genotype compared to unaffected individuals. CONCLUSION: This study confirms the association between the H+H+ genotype with LOAD and supports the correlation of this genotype of the LPL gene with risk of developing LOAD in Iranian patients with AD. PMID- 23626942 TI - Fuzzy-based Medical X-Ray Image Classification. AB - In this paper, a novel fuzzy scheme for medical X-ray image classification is presented. In this method, each image is partitioned into 25 overlapping subimages and then, we extracted the shape-texture features from shape and directional information of each subimage. In the classification step, we apply a fuzzy membership to each subimage considering the Euclidean distance between feature vector of each subimage and average of feature vectors of training subimages. At last, a hard classification of the test image can be obtained by performing a max operation on the summation of fuzzy memberships. The proposed method is evaluated for image classification on 2655 radiographic images from IRMA dataset with 300 training samples and 2355 test samples. Classification accuracy rates obtained by fuzzy classifier are higher than that of obtained by multilayer perceptron or even SVM classifier. PMID- 23626943 TI - Assessment of human random number generation for biometric verification. AB - Random number generation is one of the human abilities. It is proven that the sequence of random numbers generated by people do not follow full randomness criteria. These numbers produced by brain activity seem to be completely nonstationary. In this paper, we show that there is a distinction between the random numbers generated by different people who provide the discrimination capability, and can be used as a biometric signature. We considered these numbers as a signal, and their complexity for various time-frequency sections was calculated. Then with a proper structure of a support vector machine, we classify the features. The error rate, obtained in this study, shows high discrimination capabilities for this biometric characteristic. PMID- 23626944 TI - Accurate localization of chromosome centromere based on concave points. AB - Analyzing the features of the chromosomes can be very useful for diagnosis of many genetic disorders or prediction of possible abnormalities that may occur in the future generations. For this purpose, karyotype is often used, for which to be made, it is necessary to identify each one of the 24 chromosomes from the microscopic images. Definition and extraction of the morphological and band pattern-based features for each chromosome is the first step to identify them. Centromere location is an important morphological feature. In this paper, a novel algorithm for centromere localization is presented. The procedure is based on the calculation and analyzing the concavity degree of the chromosome's boundary pixels. In this method, the centerline of the chromosome is computed and the score of each pixel on the centerline is considered as the sum of the concavity degree of two pixels on the chromosome's boundary that are perpendicular to it. Finally, location of the centromere is estimated as one pixel on the centerline which is corresponding to the maximum score. When applied the proposed algorithm on 50 images, an average error of 2.25 pixels for centromere localization is achieved. PMID- 23626945 TI - Breast cancer recognition using a novel hybrid intelligent method. AB - Breast cancer is the second largest cause of cancer deaths among women. At the same time, it is also among the most curable cancer types if it can be diagnosed early. This paper presents a novel hybrid intelligent method for recognition of breast cancer tumors. The proposed method includes three main modules: the feature extraction module, the classifier module, and the optimization module. In the feature extraction module, fuzzy features are proposed as the efficient characteristic of the patterns. In the classifier module, because of the promising generalization capability of support vector machines (SVM), a SVM-based classifier is proposed. In support vector machine training, the hyperparameters have very important roles for its recognition accuracy. Therefore, in the optimization module, the bees algorithm (BA) is proposed for selecting appropriate parameters of the classifier. The proposed system is tested on Wisconsin Breast Cancer database and simulation results show that the recommended system has a high accuracy. PMID- 23626946 TI - Circular symmetric laplacian mixture model in wavelet diffusion for dental image denoising. AB - In this paper, we try to find a particular combination of wavelet shrinkage and nonlinear diffusion for noise removal in dental images. We selected the wavelet diffusion and modified its automatic threshold selection by proposing new models for speckle-related modulus. The Laplacian mixture model, Rayleigh mixture model, and circular symmetric Laplacian mixture models were evaluated and, as it could be expected, the latter provided a better model because of its compatibility with heavy tailed structure of the wavelet coefficients besides their interscale dependence. The numerical evaluation of contrast-to-noise ratio (CNR) along with simple observation of the results showed reasonably acceptable improvement of CNR from 2.9149 to 38.8813 in anterior--posterior images, from 41.6131 to 86.3141 in cephal-lateral images, from 13.6414 to 43.4711 in intraoral pictures, and from 6.0102 to 31.8771 in panoramic datasets. Furthermore, technical ability of the proposed filtering method in retaining the possible cavities on dental images was evaluated in two datasets with natural and artificially applied cavities. PMID- 23626947 TI - Is stretching and folding feature of chaotic trajectories useful in adaptive local projection? PMID- 23626948 TI - Designing and Constructing an Optical Monitoring System of Blood Supply to Tissues under Pressure. AB - Reduced blood flow due to obstruction is in most cases a primary factor in pressure ulcer formation and creation of bedsores. The aim of this study is to design and manufacture a care system for tissue under pressure, based on variations in blood flow at different depths of tissue. In the manufacture of the system two infrared light transmitters and receivers were located between 5 and 10 mm depth to measure the flow of blood at different in the under- pressure heel tissue. In addition, blood flow was evaluated in an unloaded and loaded condition, with 30 mmHg and 60.0 mmHg. A total of 15 people participated with a mean age of 50. Of these 15; 9 (60%) were men and 6 (40%) were women. Primary measurement results showed different individual differences in variation of blood flow in the tissue. To study signal amplitude changes significantly influenced by external pressure the PPG, P-value was measured. It was noted that there were significant changes in PPG signal amplitude during loading both pressures of 30 and 60 mmHg. Further development of this system would be possible with the use of a more flexible probe and by using a stronger optical receiver and transmitter to access more depth. PMID- 23626949 TI - In vitro Natural Killer Cell Immunotherapy for Medulloblastoma. AB - How the immune system attacks medulloblastoma (MB) tumors effectively is unclear, although natural killer (NK) cells play an important role in immune defense against tumor cells. Interactions between receptors on NK cells and ligands expressed by tumor cells are critical for tumor control by immunotherapy. In this study, we analyzed tumor samples from 54 MB patients for expression of major histocompatibility complex class I-related chains A (MICA) and UL16 binding protein (ULPB-2), which are ligands for the NK group 2 member D activatory receptor (NKG2D). The percentage of MICA and ULBP-2 positive cells was higher than 25% in 68% and 6% of MB patients, respectively. A moderate-high intensity of MICA cytoplasmic staining was observed in 46% MB patients and weak ULBP-2 staining was observed in 8% MB patients. No correlation between MICA/ULBP-2 expression and patient outcome was found. We observed that HTB-186, a MB cell line, was moderately resistant to NK cell cytotoxicity in vitro. Blocking MICA/ULBP-2 on HTB-186, and NKG2D receptor on NK cells increased resistance to NK cell lysis in vitro. However, HLA class I blocking on HTB-186 and overnight incubation with IL-15 stimulated NK cells efficiently killed tumor cells in vitro. We conclude that although NKG2D/MICA-ULBP-2 interactions have a role in NK cell cytotoxicity against MB, high expression of HLA class I can protect MB from NK cell cytotoxicity. Even so, our in vitro data indicate that if NK cells are appropriately stimulated, they may have the potential to target MB in vivo. PMID- 23626950 TI - Emerging microfluidic tools for functional cellular immunophenotyping: a new potential paradigm for immune status characterization. AB - Rapid, accurate, and quantitative characterization of immune status of patients is of utmost importance for disease diagnosis and prognosis, evaluating efficacy of immunotherapeutics and tailoring drug treatments. Immune status of patients is often dynamic and patient-specific, and such complex heterogeneity has made accurate, real-time measurements of patient immune status challenging in the clinical setting. Recent advances in microfluidics have demonstrated promising applications of the technology for immune monitoring with minimum sample requirements and rapid functional immunophenotyping capability. This review will highlight recent developments of microfluidic platforms that can perform rapid and accurate cellular functional assays on patient immune cells. We will also discuss the future potential of integrated microfluidics to perform rapid, accurate, and sensitive cellular functional assays at a single-cell resolution on different types or subpopulations of immune cells, to provide an unprecedented level of information depth on the distribution of immune cell functionalities. We envision that such microfluidic immunophenotyping tools will allow for comprehensive and systems-level immunomonitoring, unlocking the potential to transform experimental clinical immunology into an information-rich science. PMID- 23626951 TI - Bone morphogenetic proteins: periodontal regeneration. AB - Periodontitis is an infectious inflammatory disease that results in attachment loss and bone loss. Regeneration of the periodontal tissues entails de novo formation of cementum, periodontal ligament, and alveolar bone. Several different approaches are currently being explored to achieve complete, reliable, and reproducible regeneration of periodontal tissues. The therapeutic management of new bone formation is one of the key issues in successful periodontal regeneration. Bone morphogenetic proteins form a unique group of proteins within the transforming growth factor superfamily of genes and have a vital role in the regulation in the bone induction and maintenance. The activity of bone morphogenetic proteins was first identified in the 1960s, but the proteins responsible for bone induction were unknown until the purification and cloning of human bone morphogenetic proteins in the 1980s, because of their osteoinductive potential. Bone morphogenetic proteins have gained a lot of interest as therapeutic agents for treating periodontal defects. A systematic search for data related to the use of bone morphogenetic proteins for the regeneration of periodontal defects was performed to recognize studies on animals and human (PUBMED, MEDLINE, COCHRANE, and Google search). All the studies included showed noticeable regeneration of periodontal tissues with the use of BMP. PMID- 23626953 TI - Prenatal screening methods for aneuploidies. AB - Aneuploidies are a major cause of perinatal morbidity and mortality. Therefore, it is the most common indication for invasive prenatal diagnosis. Initially, screening for aneuploidies started with maternal age risk estimation. Later on, serum testing for biochemical markers and ultrasound markers were added. Women detected to be at high-risk for aneuploidies were offered invasive testing. New research is now focusing on non-invasive prenatal testing using cell-free fetal DNA in maternal circulation. The advantage of this technique is the ability to reduce the risk of miscarriage associated with invasive diagnostic procedures. However, this new technique has its own set of technical limitations and ethical issues at present and careful consideration is required before broad implementation. PMID- 23626952 TI - Chlamydophila pneumoniae infection and cardiovascular disease. AB - Atherosclerosis is a multifactorial vascular inflammatory process; however, the inciting cause for inflammation remains unclear. Two decades ago, Chlamydophila pneumoniae (formerly Chlamydia pneumoniae) infection was proposed as a putative etiologic agent. We performed a PubMed search using the keywords Chlamydia and atherosclerosis in a Boolean query to identify published studies on C. pneumoniae and its role in atherogenesis, and to understand research interest in this topic. We found 1,652 published articles on this topic between 1991 and 2011. We analyzed relevant published studies and found various serological, molecular, and animal modeling studies in the early period. Encouraged by positive results from these studies, more than a dozen antibiotic clinical-trials were subsequently conducted, which did not find clinical benefits of anti-Chlamydophila drug therapy. While many researchers believe that the organism is still important, negative clinical trials had a similar impact on overall research interest. With many novel mechanisms identified for atherogenesis, there is a need for newer paradigms in Chlamydophila-atherosclerosis research. PMID- 23626954 TI - New guidelines for diagnosis of gestational diabetes: pathology-based impact assessment. AB - BACKGROUND: A recent study indicated an average of 19.5% abnormal oral glucose tolerance in antenatal clients per year. AIM: The purpose of this study was to determine the impact on gestational diabetes cases due to new guidelines for diagnosis and classification of hyperglycaemia in pregnancy. MATERIALS AND METHODS: This study reviewed the archived clinical pathology data on oral glucose tolerance tests performed between January 1999 and December 2008 on antenatal clients (N = 615). The cases were reviewed to determine changes if any in percentage of gestational diabetes due to new guidelines. RESULTS: Over the 10 years period, a yearly average of additional 10.8% antenatal cases suggestive of gestational diabetes was observed due to the new recommended thresholds. Further, the average yearly incidence would have increased from 8.8 cases to 16.2 cases, which translates to almost 46% increase in the prospective numbers of gestational diabetes. CONCLUSIONS: This report presents the extent of how the new recommended guidelines for diagnosis and classification of hyperglycaemia in pregnancy could increase the prevalence of gestational diabetes. It also provides pathology-based evidence for the epidemiology of gestational diabetes mellitus and allows for planning the costs that would be attendant to the full implementation of the new guidelines. PMID- 23626955 TI - Hypertension association with serum lipoproteins, insulin, insulin resistance and C-Peptide: unexplored forte of cardiovascular risk in hypothyroidism. AB - BACKGROUND: There is a gross dearth of correlative data for cardiovascular diseases. AIM: We aimed to explore the association of systolic and diastolic blood pressure with anthropometric and biochemical parameters of hypothyroid patients in order to establish any correlation that may exist and be useful in an early diagnosis and management against cardiovascular risk. MATERIALS AND METHODS: The study included 100 healthy controls and 150 newly diagnosed hypothyroid patients. Subjects were evaluated anthropometrically and biochemically for fasting blood sugar, triiodothyronine, thyroxine, thyroid stimulating hormone, Insulin, C-peptide, lipid profile, apo-B and apo-A1. The results were statistically analysed using unpaired t-test and Spearman's coefficient of Correlation. RESULTS: The hypothyroids had a female preponderance (73.3%) however; their biochemical profiles were comparable with those of male counterparts. They had raised Body Mass Index, hypertension, hyperinsulinemia, insulin resistance, raised C-peptide, dyslipidaemia with raised apo-B and reduced apo-A1 and strong association of systolic and diastolic blood pressure with insulin, insulin resistance, C-peptide and Total cholesterol/HDLc (TC/HDLc). CONCLUSION: Strong association of hypertension with serum insulin, IR, C-peptide and TC/HDLc hints significant contribution towards cardiovascular risk in hypothyroid adults of Jodhpur. PMID- 23626956 TI - Allele Frequencies of the Epidermal Growth Factor Receptors Polymorphism R521K in Colorectal Cancer Patients and Healthy Subjects Indicate a Risk-Reducing Effect of K521 in Syrian Population. AB - BACKGROUND: Colorectal cancer contributes heavily to cancer morbidity and mortality worldwide. Numerous therapies are currently in use, including monoclonal antibodies against cellular components involved in tumorigenesis such as epidermal growth factor receptors (EGFRs). Studies showed the polymorphism [R521K] GaA in the EGFR gene to be involved in both colorectal cancer susceptibility and clinical response to therapeutics (e.g., Cetuximab). AIM: We aimed at uncovering allele frequencies of this polymorphism among Syrian colorectal cancer patients and healthy individuals. MATERIALS AND METHODS: Forty seven patients with colorectal cancer were included in a case-control study along with 48 healthy subjects, all native Syrians. Individuals were genotyped using PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) and results were statistically analyzed to elucidate significant differences between the two groups. RESULTS: Allele frequencies were 40.4% (G/G), 57.4% (G/A) and 2.1% (A/A) in colorectal cancer patients and 41.6% (G/G), 43.7% (G/A) and 14.5% (A/A) in healthy subjects. The A/A genotype was significantly lower in colorectal cancer patients than in the control group. CONCLUSIONS: Homozygosity for the A allele is linked to reducing the risk of developing colorectal cancer in Syrian patients. The lower prevalence of (A/A) locally may predict sub-optimal rates of clinical response to Cetuximab compared with populations with higher frequencies of the A allele. Larger scale investigations are needed for a stronger conclusion. PMID- 23626957 TI - Immunomodulatory activity of aged garlic extract against implanted fibrosarcoma tumor in mice. AB - BACKGROUND: Garlic is known as a medicinal herb with broad therapeutic properties ranging from antibacterial to anticancer and even anticoagulant. AIM: Current study was designed to evaluate antitumor effects of aged garlic extract (AGE) on fibrosarcoma tumor in BALB/c mice. MATERIALS AND METHODS: WEHI-164 fibrosarcoma cells were implanted subcutaneously on day zero into right flank of 40 BALB/c mice aged eight weeks. Mice were randomly categorized in two separate groups: 1(st) received AGE (100 mg/kg, intraperitoneally), 2(nd) group as control received phosphate buffered saline, (PBS). Treatments were done three times per week. Tumor growth was measured and morbidity was recorded. Subpopulations of CD4+/CD8+ T cells were determined using flow cytometry. WEHI-164 cell specific cytotoxicity of splenocytes and in vitro production of gamma-interferon, (IFN gamma) and Interleukin-4, (IL-4) cytokines were measured. RESULTS: The mice received AGE had significantly longer survival time compared to control mice. The inhibitory effect on tumor growth was seen in AGE treated mice. The CD4+/CD8+ ratio and in vitro IFN-gamma production of splenocytes were significantly increased in AGE group. CONCLUSIONS: Administration of AGE resulted in improved immune responses against experimentally implanted fibrosarcoma tumors in BALB/c mice. AGE showed significant effects on inhibition of tumor growth and longevity of survival times. PMID- 23626958 TI - Antioxidant Enzymes and Lipid Peroxidation in Type 2 Diabetes Mellitus Patients with and without Nephropathy. AB - BACKGROUND: Oxidative stress has been considered to be a pathogenic factor of diabetic complications including nephropathy. There are many controversies and limited studies regarding the antioxidant enzymes in diabetic nephropathy. AIM: This study was to evaluate the levels of antioxidant enzymes and lipid peroxidation in Type-2 Diabetes Mellitus (DM) patients with and without nephropathy. MATERIALS AND METHODS: The study included 90 age and sex matched subjects. Blood samples of all subjects were analyzed for all biochemical and oxidative stress parameters. RESULTS: The malondialdehyde (MDA) levels and catalase (CAT) activity were significantly increased and reduced glutathione (GSH) levels and activities of glutathione peroxidase (GPx) and glutathione reductase (GR) were significantly decreased in Type-2 DM with and without nephropathy as compared to controls and also in Type-2 DM with nephropathy as compared to Type-2 DM without nephropathy. There were an excellent positive correlation of glycohemoglobin (HbA1c) with MDA and a good negative correlation of GPx with GSH in controls. There were positive correlations of GR, CAT, and superoxide dismutase (SOD) with MDA in Type-2 diabetes patients with nephropathy. CONCLUSIONS: Intensity of oxidative stress in Type-2 diabetic patients with nephropathy is greater when compared with Type-2 diabetic patients without nephropathy as compared to the controls. PMID- 23626959 TI - Adherence to Antiretroviral Therapy Among People Living with HIV. AB - BACKGROUND: Acquired immune deficiency syndrome (AIDS) is now considered as a manageable chronic illness. There has been a dramatic reduction in human immunodeficiency virus (HIV) related morbidity and mortality due to antiretroviral therapy. A high level of adherence (>95%) is required for antiretroviral therapy to be effective. There are many barriers to adherence in both developed and developing countries. AIM: The aim of our study was to determine adherence levels and factors influencing adherence to antiretroviral therapy among people living with HIV. MATERIALS AND METHODS: Using a cross sectional study design, 116 HIV positive patients receiving antiretroviral therapy for at least 1 year were interviewed using a semi structured questionnaire. The collected data was analyzed using Statistical Product and Service Solutions (SPSS) version 11.5. Chi-square test was done. A P value of < 0.05 was considered statistically significant. RESULTS: Of 116 participants, 63.7% reported adherence >= 95%. Mean adherence index was 91.25%. Financial constraints, forgetting to take medication, lack of family care, depression, alcohol use, social stigma and side effects to antiretroviral therapy were barriers for adherence in our study. CONCLUSION: Adherence to antiretroviral therapy in south India is suboptimal. Intensive adherence counseling should be provided to all patients before initiation ofantiretroviral therapy. Health care providers must identify possible barriers to adherence at the earliest and provide appropriate solutions. PMID- 23626960 TI - Socio-demographic Characteristics of Transsexuals Referred to the Forensic Medicine Center in Southwest of Iran. AB - BACKGROUND: Transsexualism or gender identity disorder affects person's gender identity. AIM: This study was to describe socio-demographic characteristics in a population of transsexuals. MATERIALS AND METHODS: We studied 44 persons of both sexes with diagnostic criteria of gender identity disorder who were referred to the Legal Medicine Organization of Fars, southwest of Iran during the time period 2005-2010. The general practitioners examined the following socio-demographic characteristics and then recorded them in a semi-structured questionnaire, which was developed by the Forensic Medicine Center in Shiraz: Sex, age, educational level, place of residence, marital status, duration of treatment, and employment status. RESULTS: A total of 44 persons (18 (40.9%) males versus 26 (59.1%) females) were referred for sex change during the study period. The sex ratio was 0.69:1. The mean age was 27.6 +/- 2.9 years. The majority of patients were diploma and higher diploma education (77.3%), lived in urban areas (81.8%), were employed (56.9%), were single (93.1%), and were under six months of hormonal treatment (61.4%). CONCLUSIONS: It seems that social acceptance is lower for male to female transsexuals, since these patients have lower employment and literacy statuses. Further studies should be designed to evaluate and deeper analyze more socio-demographic, clinical, and psychiatric variables about transsexual patients. PMID- 23626961 TI - Carotid Intima Media Thickness as a Reflection of Generalized Atherosclerosis is Related to Body Mass Index in Ischemic Stroke Patients. AB - BACKGROUND: Carotid artery intima media thickness reflects the ongoing process of atherosclerosis in the body. The pathologic process occurring in the obese patients in the vascular system is atherosclerosis which is an important cause of ischemic stroke. Body mass index is an indirect measure of obesity in general population. AIM: The study was to assess the role of carotid artery intima media thickness as a marker of atherosclerosis and its relation with body mass index in ischemic stroke patients. MATERIALS AND METHODS: Body mass index of the all stroke patients was calculated by using formula body mass in kilograms divided by the square of height in meters. The patients were classified in four groups of body mass index according to Indian standards. Carotid sonography was done to assess the common carotid artery intima media thickness in millimeters by using high resolution 7.5 MHz sonography technique. RESULTS: The average Carotid intima media thickness in this study was 9.23mm. There was a significant association found between increasing carotid artery intima media thickness and groups of body mass index (P- <0.05) in ischemic stroke patients. CONCLUSIONS: Body mass index as an indicator of obesity and carotid intima media thickness both are very important risk factors for ischemic stroke and are associated with each other. PMID- 23626962 TI - Acute Renal Failure and/or Rhabdomyolysis due to Multiple Bee Stings: A Retrospective Study. PMID- 23626963 TI - Pyogenic renal abscess masquerading as malignancy. PMID- 23626964 TI - Hydatid cyst of liver complicated with budd-Chiari syndrome and portal vein thrombosis. PMID- 23626965 TI - Dengue hemorrhagic Fever and acute compartment syndrome. PMID- 23626967 TI - Chasing Eosinophilia in Loeffler's Syndrome: A Case of Strongyloidiasis in Upstate New York. PMID- 23626966 TI - Amlodipine-induced subacute cutaneous lupus. PMID- 23626968 TI - Assessment of knowledge, attitude, and practice in health care delivery. PMID- 23626969 TI - Stent dislodgement: a rare complication of subclavian artery aangioplasty and stenting. PMID- 23626970 TI - Sister Mary Joseph's Nodule: What Lies Beneath? PMID- 23626971 TI - Hematologic Recovery of Pancytopenia after Treatment of Hashimoto's Thyroiditis and Primary Adrenal Insufficiency. PMID- 23626972 TI - An interview with Donald Kepron on the occasion of his real retirement. Interview by Douglas Chaytor. PMID- 23626973 TI - Understanding Kaplan-Meier and survival statistics. AB - PURPOSE: This paper aims to explore the mathematics of Kaplan-Meier and survival statistics, explain how the mathematics are relevant for prosthodontic treatment planning, and provide advice for future presentation of such data. MATERIALS AND METHODS: The mathematics of the Kaplan-Meier and related survival statistic formulas were explored with hypothetical data consisting of 100 prostheses, reviewed yearly for 10 years. The hypothetical impact of failures (n = 1, 2, 9, or 0) and censored data (n = 5, 9, or 10) were reviewed across three life tables and survival curves. Actual published data of 304 porcelain veneers, reviewed regularly for 16 years, were similarly utilized. The impact of changing the number of failures and censored data on the estimated cumulative survival (ECS) and the standard error (SE) was reviewed across two life tables and survival curves. RESULTS: The ECS and SE are calculated from two data figures: the number of failures that occurred during an interval and the number of prostheses at risk during that same interval. The ECS reduces and its SE enlarges when prostheses fail. These results can also change if prostheses are lost from the study (censored). However, the number of failures is in the numerator of the equation. Therefore, if no failures occur, loss of prostheses from the study cannot change the ECS or the SE. This can dramatically affect the calculated ECS and SE if a prosthesis becomes lost to follow-up rather than presenting as a failure. The hypothetical and actual data were used to explore these concepts. CONCLUSION: Current techniques for analysis of time-to-event data are imperfect and can be misleading. It therefore behooves authors to strive to improve reporting transparency, journals to support such industry, and readers to remain mindful that the cumulative survival is an estimate, ie, a reflection of reality. PMID- 23626974 TI - Palatal rugae: a potential reference to determine key anterior maxilla dimensions and tooth positions. AB - Palatal rugae have been suggested as a stable landmark and potential biometric guide for positioning anterior maxillary teeth. This study aimed to evaluate the use of palatal rugae as a biomarker by establishing mathematical correlations with anterior maxillary dental arch geometry and tooth positions. One hundred dental casts were obtained from fully dentate individuals with normal occlusal relationships. Thirteen reference points were analyzed. Significant correlations were found between measurements in the anterior dental segment and palatal rugae measurements. Those correlation coefficients were, however, low. Although some correlation values obtained were statistically significant, they are not likely to have significant clinical predictive value. PMID- 23626975 TI - The efficacy of glass-ceramic onlays in the restoration of morphologically compromised and endodontically treated molars. AB - PURPOSE: This study evaluated the 4-year clinical performance of IPS Empress II ceramic onlay restorations on extensively restored, endodontically treated molars. MATERIALS AND METHODS: A sample of 53 morphologically compromised and endodontically treated molar teeth were restored with IPS Empress II ceramic onlays cemented with a dual cured luting composite. The molars were evaluated by two experienced clinicians in accordance with the modified United States Public Health Service criteria at baseline and 6-month recalls up to a 4-year observation period. The analyses were carried out using the Wilcoxon signed-rank test and the Kaplan-Meier product limit method. RESULTS: Four failures were noted. Two onlays debonded; one was reinserted and reluted while the other resulted in lost coronal hard tissue and was restored with a fiber reinforced post-and-core system followed by a full ceramic crown restoration. The third failure resulted from secondary caries and fracture of the remaining enamel and was restored with a full ceramic crown. The fourth failure was extracted. None of the onlays exhibited wear, fracture of antagonist teeth, or dimensional change at proximal contacts. CONCLUSION: Within the limitations of this study's design and short 4-year observation period, IPS Empress II ceramic onlay restorations demonstrated promising results with a 92.5% success rate. PMID- 23626976 TI - Strain comparisons for splinted and nonsplinted cement-retained implant crowns. AB - The aim of this study was to compare strains generated by splinted and nonsplinted cement-retained implant crowns for two implants. A stereolithic resin cast was printed using computed tomography scan data from a patient. Two 4 * 6-mm implants were placed in the posterior left side of the cast. Splinted and nonsplinted cement retained crowns were made. The three-dimensional image correlation technique was used for the measurement of strains as crowns were loaded up to 400 N in vertical and oblique directions with an Instron machine. Patterns and magnitudes of strain for splinted and nonsplinted crowns were similar. Results of this in vitro study suggest that splinting has a minimal effect on the load sharing of adjacent cement retained crowns. PMID- 23626977 TI - Prediction of sleep bruxism events by increased heart rate. AB - PURPOSE: To investigate the hypothesis that sleep bruxism (SB) events could be predicted by an increase in heart rate. MATERIALS AND METHODS: Fourteen sleep bruxers were recruited. Each participant recorded his or her own electromyography (EMG) and electrocardiography (ECG) at home for 2 consecutive nights using a portable telemetry system. Ten heartbeats before (B10 to B1) and three heartbeats after (A1 to A3) the onset of SB events were analyzed, and the threshold for the prediction of an SB event was determined. The validity of the threshold was tested by EMG and ECG recorded in the same manner for an additional night. The prediction accuracy of SB events was evaluated for sensitivity and specificity. RESULTS: A gradual increase in heart rate was observed before an SB event, and B1, A1, A2, and A3 were significantly higher than B10 (P < .01). The threshold value was set at 110% when the mean of all heart rates of the second night of recording was set at 100%. A total of 324 SB events were observed and 299 were preceded by increased heart rate that exceeded the threshold (sensitivity, 92.3%). The total number of increased heart rate events was 1,239, and the total number of threshold applications was estimated to be 120,000. The specificity was 99.2%. CONCLUSION: Over 90% of SB events could be predicted by an increasing heart rate of 110%. Since the sensitivity and specificity were extremely high, the hypothesis that SB events could be predicted by increased heart rate was positively verified. PMID- 23626978 TI - A 10-year retrospective clinical evaluation of immediately loaded tapered maxillary implants. AB - PURPOSE: The aim of this study was to compare the effects of immediate loading (IL) and delayed loading (DL) on peri-implant crestal bone loss around maxillary implants after long-term functioning. MATERIALS AND METHODS: A retrospective chart review was conducted to assess the outcomes of 110 tapered, multithreaded implants placed for the treatment of one or more missing and/or unsalvageable teeth in the maxilla of 23 patients. Implants were assigned to either the DL or IL database according to loading time. Marginal bone changes were calculated using standardized radiographs taken at implant placement (baseline) and during annual follow-ups. RESULTS: One implant failed in the DL group. After a mean follow-up of 111 months in the DL group and 119 months in the IL group, cumulative implant survival was 99.09% (DL = 98.11%, IL = 100%). No observable bone loss was evident in 83.49% of the surviving implants. Cumulative success rates were 100% for the IL group and 98.11% for the DL group. CONCLUSIONS: Immediately loaded maxillary implants showed long-term results comparable to delayed loaded maxillary implants. PMID- 23626979 TI - The Burdens in Prosthetic Dentistry Questionnaire (BiPD-Q): development and validation of a patient-based measure for process-related quality of care in prosthetic dentistry. AB - PURPOSE: To develop and validate an instrument for the assessment of patient based measures of process-related quality of care in prosthodontic patients. MATERIALS AND METHODS: In this nonrandomized study, the new Burdens in Prosthetic Dentistry Questionnaire (BiPD-Q) was developed in two steps using a total of 128 prosthodontic patients in a mixed-method approach, combining quantitative qualitative methodologies. First, the item pool for the instrument was created using semistructured interviews and a group of experts in prosthodontics. This resulted in a preliminary version of the questionnaire. Second, an assessment of redundancy, completion rates, face validity, difficulty, and distribution of the core set of the items was performed. The final version of the BiPD-Q had psychometric core properties (reliability and validity) evaluated. RESULTS: The BiPD-Q consisted of 25 items. Reliability was satisfactory (Cronbach's alpha = .87). The mean score of all items of the BiPD-Q was significantly correlated with mean perceived burdens during treatment as rated by the clinician (r = 0.26; P < .01) and with overall satisfaction with the treatment procedures as rated by patients (r = .31; P < .01), indicating sufficient convergent validity. CONCLUSION: A reliable and valid instrument for the assessment of patient-based process-related quality of care in prosthodontics has been developed. The BiPD-Q allows comparisons of different dental procedures within a treatment course and of different treatment providers. The use of this type of questionnaire appears to be a valuable tool for dental health care research. The outcomes of research using the BiPD-Q may result in a more pleasant treatment experience for future patients. PMID- 23626980 TI - A retrospective comparative 8-year study of cumulative complications in teeth adjacent to both natural and implant-supported fixed partial dentures. AB - PURPOSE: To compare the complication rate of natural teeth adjacent to implant supported dentures (IFDs) with that of teeth serving as abutments for fixed partial dentures (FPDs). The second goal was to assess the risk factors for complications in teeth adjacent to bounded edentulous spaces. MATERIALS AND METHODS: The study subjects were selected from patients who received prosthodontic treatment for their bounded edentulous space not exceeding two missing teeth between February 1990 and March 2007. Sixty-one patients were included in the IFD group and 66 patients were included in the FPD group. Tooth complications were defined as tooth extraction, periodontal lesion, periapical lesion, and loss of prosthesis and were assessed by one examiner based on dental records. RESULTS: The 8-year cumulative complication rate for the IFD group (7.9%) was significantly lower than for the FPD group (40.7%). Additionally, the 8-year cumulative complication rate of vital teeth (6%) was significantly lower than that of nonvital teeth (45.9%). A cox proportional hazard analysis revealed that nonvitality of dental pulp was a significant risk factor for tooth complications, whereas treatment modality was not. CONCLUSIONS: Teeth adjacent to IFD-treated edentulous spaces presented fewer complications than natural teeth serving as abutments for FPDs. Conservation of teeth adjacent to edentulous spaces as vital teeth was the key finding to limit further tooth loss. PMID- 23626981 TI - Development of stable peri-implant soft tissue and mentolabial sulcus depth with an implant-retained soft tissue conformer after osteocutaneous flap reconstruction. AB - Excessive soft tissue bulk, movement, chronic inflammation, and hypertrophy in periimplant areas pose challenges for long-term management of peri-implant soft tissues surrounding osteocutaneous flap reconstructions. A case history report is presented on the predictable establishment of stable peri-implant soft tissue and improved mentolabial sulcus depth in a patient treated for high-grade osteosarcoma of the mandible. Following surgical resection, reconstruction with osteocutaneous fibula free flap, and endosseous implant placement, a combined surgical and prosthetic approach was used through a lip switch vestibuloplasty and an implant-retained soft tissue conformer. PMID- 23626982 TI - Numeric simulation of the upper airway structure and airflow dynamic characteristics after unilateral complete maxillary resection. AB - This study investigated upper airway aerodynamic characteristics of patients who underwent maxillectomy using three-dimensional reconstruction and computational fluid dynamics. The results revealed the generation of low-velocity vortices throughout the entire maxillary defect during respiration. The nasal structure on the nonsurgical side changed postsurgically, possibly due to the pressure gradient between the defective and healthy side. The bilateral disturbed airflow patterns are believed to be the cause of common symptoms. The numeric simulation technique could be used as a potential method to understand upper airway morphology changes and respiratory functions, thus guiding the fabrication of prostheses. PMID- 23626983 TI - Complication and survival of Mark II restorations: 4-year clinical follow-up. AB - A total of 163 monolithic restorations made from Vitablocs Mark II and luted adhesively or with resin cement were followed up for 3 to 70 months. Recall consisted of an evaluation of complete dental and hygiene status as well as quality assessment. Seven of 35 patients were lost to follow-up. Ninety-one percent of the 37 crowns, 23 partial crowns, and 89 inlays evaluated were in the posterior region. Combined survival estimate was 0.92 at the 48-month median observation time. Inlays and partial crowns performed well. Prevalence of complication and failure was highest for crowns (CP = 37.8%, FP = 21.6%). The results demonstrate that success relates to patient factors and restoration type, not luting protocol. PMID- 23626984 TI - Zirconia implants supporting overdentures: a pilot study with novel prosthodontic designs. AB - Limited clinical research identifies prosthodontic perspectives of novel designs for zirconia implants supporting overdentures. Four pilot study participants were selected before a planned randomized clinical trial on zirconia implants supporting overdentures. Novel designs for maxillary four-implant overdentures (quadrilateral design) and mandibular three-implant overdentures (tripodal design) were used with 28 implants (maxilla, n = 16; mandible, n = 12). Four implants failed to achieve osseointegration prior to loading. At the 1-year follow-up appointment, all implants were surviving, the overdentures were in function, and there were no clinical signs of wear of the attachment system. A proof-of-principle for prosthodontic perspectives of a novel design using one piece zirconia implants supporting maxillary and mandibular implant overdentures was achieved. PMID- 23626985 TI - Dimensional and occlusal accuracy of a novel three-dimensional digital model of articulated dental arches. AB - PURPOSE: To develop a method for capturing the three-dimensional (3D) shapes of dental arches in a position relative to that of maximum intercuspation and to evaluate its dimensional and occlusal accuracy. MATERIALS AND METHODS: The conventional custom-tray impression technique was used to capture detailed and dimensionally accurate impressions of individual teeth, and a modified bite registration technique was used to register the relative positions of the maxillary and mandibular teeth in maximum intercuspation. It was hypothesized that this procedure may help to eliminate the occlusal inaccuracy caused by mouth opening-induced mandibular flexion. Two types of rigid frames (buccal and palatal) were used to prevent deformation of the interocclusal record. Their effects were tested on an articulated full-arch master cast and compared in terms of dimensional accuracy. In addition, the procedure was applied to a healthy volunteer to visually evaluate occlusal accuracy based on the form and distribution of the occlusal contacts. RESULTS: The mean decrements of the dental arch width were 0.037 +/- 0.017 mm and 0.269 +/- 0.114 mm when using the palatal and buccal frames, respectively. The dimensional accuracy of the palatal frame was comparable to that of the custom-tray impression technique. The form and distribution of the occlusal contacts between the 3D dental arches were similar to those observed in the transilluminated image of the interocclusal record, indicating the occlusal accuracy of this method. CONCLUSION: The dimensional and occlusal accuracy of the method proposed here is suitable for clinical application when used in combination with the palatal frame. PMID- 23626986 TI - Disassembly mediated fluorescence recovery of gold nanodots for selective sulfide sensing. AB - We report a one-pot, two-step strategy to synthesize fluorescent gold nanodots (AuNDs) co-modified with 1-(10-mercaptodecyl)-5-methylpyrimidine-2,4-dione (TSH) and 11-mercaptoundecanoic acid (MUA) through a ligand exchange reaction and demonstrate their capability of selective sulfide sensing in aqueous media on the basis of fluorescence recovery. PMID- 23626987 TI - Biological and biomedical (14)C-accelerator mass spectrometry and graphitization of carbonaceous samples. AB - Accelerator mass spectrometry (AMS) is the ultimate technique for measuring rare isotopes in small samples. Biological and biomedical applications of (14)C-AMS (bio-(14)C-AMS) commenced in the early 1990s and are now widely used in many research fields including pharmacology, toxicology, food, and nutrition. For accurate, precise, and reproducible bio-(14)C-AMS analysis, the graphitization step in sample preparation is the most critical step. So, various sample preparation methods for a process called graphitization have been reported for specific applications. Catalytic graphitization using either a flame-sealed borosilicate tube or a septa-sealed vial is a popular sample preparation method for bio-(14)C-AMS. In this review, we introduce the AMS system, especially for bio-(14)C-AMS. In addition, we also review the graphitization method for bio (14)C-AMS to promote further understanding and improvement of sample preparation for this technique. Examples of catalytic graphitization methods over the past two decades are described. PMID- 23626989 TI - Screening of peptides recognizing simple polycyclic aromatic hydrocarbons. AB - Peptides that specifically bind to the simplest polycyclic aromatic hydrocarbon, naphthalene, were obtained by affinity-based screening using a phage-displayed peptide library. The identified peptide with a beta-turn structure showed specific binding to naphthalene present not only on substrates but also in aqueous solutions. PMID- 23626988 TI - An AC electrokinetics facilitated biosensor cassette for rapid pathogen identification. AB - To develop a portable point-of-care system based on biosensors for common infectious diseases such as urinary tract infection, the sensing process needs to be implemented within an enclosed fluidic system. On chip sample preparation of clinical samples remains a significant obstacle to achieving robust sensor performance. Herein AC electrokinetics is applied in an electrochemical biosensor cassette to enhance molecular convection and hybridization efficiency through electrokinetics induced fluid motion and Joule heating induced temperature elevation. Using E. coli as an exemplary pathogen, we determined the optimal electrokinetic parameters for detecting bacterial 16S rRNA in the biosensor cassette based on the current output, signal-to-noise ratio, and limit of detection. In addition, a panel of six probe sets targeting common uropathogenic bacteria was demonstrated. The optimized parameters were also validated using patient-derived clinical urine samples. The effectiveness of electrokinetics for on chip sample preparation will facilitate the implementation of point-of-care diagnosis of urinary tract infection in the future. PMID- 23626990 TI - [The problem is the basic framework!]. PMID- 23626991 TI - [Rights of the contract physician - retrospective correction of physician accounts]. PMID- 23626992 TI - [Practice management - for the greatest satisfaction - reading applications properly]. PMID- 23626993 TI - Introduction to special section on grand challenges in engineering life sciences and medicine. PMID- 23626994 TI - Author reply: To PMID 21261242. PMID- 23626995 TI - Immunotherapy for hymenoptera venom allergy: too expensive for European health care? PMID- 23626996 TI - Educational interventions to raise men's awareness of bladder and bowel health. AB - Urinary incontinence is a common health problem that carries with it a significant burden. Nearly twice as many men suffer from this problem than women, and studies have demonstrated that help-seeking behavior is more challenging for men. This information sheet is based on a systematic review and focuses on the best-available evidence regarding educational interventions to raise men's awareness of bladder and bowel health. It also provides recommendations for practice. PMID- 23626997 TI - Interdisciplinarity: Artistic merit. PMID- 23626998 TI - Root cause analysis for young engineers. AB - Root Cause Analysis, an IBI prize-winning module, requires students to use a systematic approach to analyze complex problems. PMID- 23626999 TI - Response to letter regarding article, "Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction". PMID- 23627001 TI - Positive surgical margins at radical prostatectomy: much ado about nothing? PMID- 23627000 TI - Clinical applications of multiparametric MRI within the prostate cancer diagnostic pathway. PMID- 23627003 TI - Across the divide. PMID- 23627002 TI - The fight against bird flu. PMID- 23627004 TI - What's your diagnosis? Aniridic epitheliopathy associated with hereditary aniridia (PAX6+/-). PMID- 23627005 TI - [Reply]. PMID- 23627006 TI - Motivation: the missing link in performance. PMID- 23627008 TI - Findings of research misconduct. PMID- 23627007 TI - Role of scavenger receptors in the pathophysiology of chronic liver diseases. AB - Scavenger receptors comprise a large family of structurally diverse proteins that are involved in many homeostatic functions. They recognize a wide range of ligands, from pathogen-associated molecular patterns (PAMPs) to endogenous, as well as modified host-derived molecules (DAMPs). The liver deals with blood micro organisms and DAMPs released from injured organs, thus performing vital metabolic and clearance functions that require the uptake of nutrients and toxins. Many liver cell types, including hepatocytes and Kupffer cells, express scavenger receptors that play key roles in hepatitis C virus entry, lipid uptake, and macrophage activation, among others. Chronic liver disease causes high morbidity and mortality worldwide. Hepatitis virus infection, alcohol abuse, and non alcoholic fatty liver are the main etiologies associated with this disease. In this context, continuous inflammation as a result of liver damage leads to hepatic fibrosis, which frequently brings about cirrhosis and ultimately hepatocellular carcinoma. In this review, we will summarize the role of scavenger receptors in the pathophysiology of chronic liver diseases. We will also emphasize their potential as biomarkers of advanced liver disease, including cirrhosis and cancer. PMID- 23627010 TI - Bibliography. Current world literature. Trauma. PMID- 23627011 TI - Bibliography. Current world literature. Ethical, legal and organizational issues in the ICU. PMID- 23627009 TI - VA Prosthetic and Sensory Aids Service-65 years of progress. PMID- 23627012 TI - Twenty years of progress. . . an editorial. PMID- 23627013 TI - [Molecular detection assays for 2012 identified novel human coronavirus (HCoV) and probe modification with locked nucleic acid (LNA)]. AB - OBJECTIVE: To develop and optimize the molecular detection assays for recently identified human coronavirus (HCoV) infection. METHODS: Based on the 208 base pair(bp) sequence of novel HCoV reported by HPA of UK, we designed and obtained several pairs of primer (F-1, R-1; F-2, R-2) and Taqman probes (TZ1,TZ2) for detection of novel HCoV. Two of probes were modified with LNA (LNA-TZ1, LNA-TZ2). Then, RT-PCR and various real time RT-PCR assays were developed and optimized in this study. We also compared our assays with the real time RT-PCR assays reported recently by Europe team based on upE or ORF1b target. RESULTS: The RT-PCR or real time RT-PCR assays for novel HCoV were developed without cross-reactivity with other HCoV and several common respiratory viruses using clinical specimen panel. The analytical sensitivity of assays were less than 50-500 copies per reaction and the detection was improved when Taqman probe modified with LNA-tagged, compared to no LNA-tagged in real time RT-PCR assays. The upE and LNA-TZ1 based assays were better than others. CONCLUSION: The molecular detection sensitivity and specificity of TaqMan-based real time PCR assay could be improved when probe tagged with LNA. The upE or LNA-TZ1 based real time RT-PCR assay was recommend for detection of novel HCoV. This study laid a foundation for improving the performance of novel HCoV detection. PMID- 23627014 TI - [Prior infected influenza virus could protect mice from challenge of lethal influenza virus]. AB - OBJECTIVE: To determine whether it could protect mice from challenge of lethal influenza virus which group prior infected A(H1N1) pdm09 and H9N2 virus respectively. METHODS: 150 BALB/c mice are divided into three groups. Mice are infected A(H1N1) pdm09 virus (pCA07) and poultry H9N2 virus (GZ333) respectively. Infected mice are challenged with 10 times of lethal dose virus (PR8) then compare the viral load, antibody and survival of the two group mice before and after challenged. RESULTS: Both experimental group mice survived after challenge of lethal influenza virus and lung viral load are lower than that of the first infection. Antibodies derived from the infective virus and challenge virus. CONCLUSION: Prior infected A(H1N1) pdm09 and H9N2 virus could protect mice from challenge of lethal influenza virus. PMID- 23627015 TI - [The detection and clinical feature of HcoV-nL63 in children with acute respiratory tract infection in Lanzhou city]. AB - OBJECTIVE: To investigate the prevalence and clinical characterization of HCoV NL63 (NL63) in children with acute respiratory tract infections (ARTIs) in Lanzhou with other respiratory viruses. The prevalence of HBoV1 in ALRTI was obviously city,China. METHOD: From November 2006 to October 2009,1169 nasopharyngeal aspirates (NPA) were collected from children under 14 years old with ARTIs. Samples were screened for NL63 using a reverse transcription polymerase chain reaction (RT-PCR) and sequencing. Demography and clinical information were recorded. RESULT: NL63 was detected in 35 (2.99%) of the 1169 children. The peak of the positive rate were in August, September 2007, July, August 2008 (23.53%,17.65%, 50%, 33.33% separately). There are no NL63 positive samples was detected in December, 2007 to February 2009. 25 (25/35, 71.43%) were co-infected with other respiratory viruses, and human rhinovirus (HRV) were the most common additional respiratory virus. No significant differences of infective rate of NL63 was found between < or = 3 years age group and > 3 years age group. Bronchiolitis and pneumonia were the most frequent diagnoses in NL63 positive patients and the major symptoms were fever and cough in our study. Between the monoinfection group and the coinfection group of NL63-positive patients, no differences were found in symptoms and clinical diagnoses except symptoms of gastrointestinal. CONCLUSION: HCoV-NL63 is an important pathogen of acute respiratory tract infection in children in Lanzhou city. The peak of HCoV-NL63 infections was in summer. There were annual differences in the prevalence of HCoV NL63. HCoV-NL63 infections existed a high rate of mixed infection, and mixed infection does not increase the severity of the disease. PMID- 23627016 TI - [Etiological analysis of influenza surveillance data in Xuzhou from 2005 to 2011]. AB - OBJECTIVE: To investigate the prevalence and subtypes of influenza viruses in Xuzhou city from 2005 to 2011 and to provide the scientific supports for influenza prevention and control in this religion. METHODS: The throat swab samples were collected from the influenza-like cases from national influenza like illness sentinel hospital in Xuzhou. The samples were used for influenza virus isolation and identification, sent on the national flu center to confirm according to the "national influenza surveillance program" and "influenza virus and experimental technology". RESULTS: From Oct. 2005 to Dec. 2011, a total of 9561 swab specimens were collected in which 1152 strains were identified for influenza viruses with total isolated rate of 12.0%. Among these strains, 708 strains were A1 (H1N1) subtype (14.2%), 466 strains were A3 (H3N2) subtype (40.5%), 78 strains were new H1N1 subtype (6.8%), 362 strains were BV (Victoia) subtype (31.4%) and 82 strains were BY (Yamagate) subtype (7.1%). The top detection rate (25.9%) arose in 2007, secondary detection rate (17.4%) occurred at 2009 and the lowest one (2.3%) appeared in 2011. From the winter of 2005 to the spring of 2006 A1 (H1N1) subtype had appeared as predominant strains but in the winter of 2006 the predominant strains were BV subtype. It changed to A3 subtype in 2007 to 2009 and the other three dominant strains were A1, BV and BY in 2008. In the winter of 2009, both A3 (H3N2) and new H1N1 subtype were predominant strains. BV subtype was predominant strains in 2010 to 2011. The prevalence of A3 subtype appeared in all the year while prevalence of BV only arose in the spring and winter. So the detection rate was high in January (34.4%) but low in August (2.2%). The influenza population is correlated with age, the highest detection rate arose in 5-age group and the lowest detection rate appeared in 25-age group. CONCLUSION: Influenza subtype A1, A3, New H1N1 are all appeared as predominant strains in Xuzhou city from 2005 to 2010. Besides, the prevalence of BV subtype is stronger in recently. PMID- 23627017 TI - [The influence of representative herbs of clearing and detoxifying drugs effect on inflammatory cytokines expression of mice lung homogenate infected by influenza virus FM1]. AB - OBJECTIVE: In order to screen out a certain kind of traditional medicine which has a better role in immune regulatory, the influence of representatives of heat clearing and detoxicating herb on inflammatory cytokines protein expression of mice lung homogenate infected by FM1 have been observed. METHOD: Modeling mice infected by FM1. On the first, third, fifth and seventh day after FM1 infection, tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL 6), interleukin-10 (IL-10), and gamma-interferon (IFN-gamma) expression in mice lung homogenate of normal control group, model control group, scutellari group, isatidis group, pulsatilla group, polygonum cuspidatum group and oldenlandia group have been tested by ELISA method. RESULT: The expression of TNF-alpha, IL 6, IFN-gamma and IL-10 in mice lung homogenate reaches its peak on the third day after FM1 infection, significantly higher than the control group (P < 0.05). Scutellari and isatidis are two representatives of heat clearing and detoxicating herb, which can decrease the expression of TNF-alpha, IL-6 and IL-1 and increase the expression of IL-10, IFN-gamma. The effect are more pronounced and statistically significant (P < 0.05) on the third and fifth day after infection, pulsatilla, polygonum cuspidatum and oldenlandia can also regulate the inflammatory cytokines, but the effect are not so obvious as scutellari and isatidis. CONCLUSION: Scutellari and isatidis, two representatives of heat clearing and detoxicating herb, have a good intervention on immune damage caused by influenza virus through adjusting the balance of inflammatory cytokines and anti-inflammatory cytokines. PMID- 23627018 TI - [Analysis on pathogen detection for 53 influenza outbreaks]. AB - OBJECTIVE: In order to provide a scientific basis for influenza prevention and control, analyzing the epidemic characteristics and laws of influenza outbreaks in Xuzhou area during 2005-2011. METHOD: Using fluorescent-PCR method to detect influenza virus nucleic acid on Nasopharyngeal swab specimens collected from influenza outbreak cases during 2005-2011 and fast classifying influenza virus A1 (H1N1), A3 (H3N2), new H1N1 BV (Victoria) and BY (Yamagate) on subtypes. At the same time, isolating the influenza virus with MDCK cells, and sending them to the National Influenza Center for review, after the preliminary identification of the isolated influenza virus. RESULTS: During 2005-2011, there are 53 influenza outbreaks in Xuzhou area, which caused by influenza virus subtype BV accounting for 26.42% (14/53), A3 accounting for 49.1% (26/53), A3 and A1 mixture accounting for 3.77% (2/53) and the new H1N1 accounting for 20.75% (11/53). The outbreaks in 2007 and 2009 mainly caused by A3, and show that the winter spring (January) and summer autumn (September) as two popular peaks during 2005-2011; BV mainly causes the outbreaks from Feb. to Jun. CONCLUSION: In Xuzhou area, since the winter of 2005, influenza virus subtype BV, the A3, and new H1N1 has alternately as mainly predominant strain, caused local influenza outbreaks. In which BV has increased trend year by year during 2005-2011. The students in primary and secondary schools are the major crowd of influenza outbreaks. Fluorescent-PCR detection methods could be a preferred method for reliable and rapid diagnostic of epidemic influenza outbreaks. PMID- 23627019 TI - [The genetic stability of recombinant adenovirus expressing human rotavirus VP6 gene which used Ad41 as vector]. AB - OBJECTIVE: To investigate the genetic stability of non-replicating recombinant adenovirus which used Ad41 as vector and could express VP6 gene of group A rotavirus during continous passage, in order to develop the vaccine of rotavirus. METHODS: The recombinant adenovirus rvAd41-VP6 (o) was prepared by our laboratory early, it then was continuously propagated on 293TE7 cells for 14 passages. After that samples of the infected cells were collected at every 2 passages for the detection of the integration of the VP6 gene by PCR, and the expression of the target protein was detected by Western Blot analysis. RESULTS: Analysis by PCR revealed that, there was stable integration of specific VP6 gene in the rvAd41 VP6 (o), Western Blot analysis confirmed that rvAd41-VP6 (o) could stably expressed the group-specific antigen structural protein VP6 (o), and it had preferable genetic stability. CONCLUSION: The recombinant adenovirus rvAd41-VP6 (o) which could stably express the VP6 (o) gene had favorable biological property in vitro, and it has provided a basis for further research of animal immunization. PMID- 23627020 TI - [Transmission and prevalence patterns of C4a evolutionary lineage of human enterovirus 71 circulating in mainland China, 2008-2010]. AB - OBJECTIVE: To understand the evolutionary relationship between the C4a evolutionary lineage of human enterovirus 71 (HEV71) strains circulating in mainland of China during 2008-2010 and 2008 Fuyang strains and study the prevalence and transmission patterns of 2008 Fuyang strains. METHODS: Download all the complete VP1 ( > or = 891 bp) or approximate complete VP1 (> or = 876 bp) gene nucleotide sequences from GenBank of HEV71 strains circulating in Mainland of China during 2008-2010. And analyze the phylogenetic relationship between Fuyang strains and other provinces' strains using the MEGA software, version 5.0. RESULTS: All of the HEV71 isolates circulating in Mainland of China during 2008 2010 were clustered into evolutionary lineage C4a except for eight strains grouped in the genotype A and one isolate belongs to evolutionary lineage C4b; the homology analysis showed there were 96.5%-100% identity between C4a viruses circulating in mainland China during 2008-2010 and 2008 Fuyang strains, and they were evolved from C4b viruses of 1998. The transmission chains of Fuyang strains were mainly transmitted in Guangdong, Jiangsu, Shanghai, Hunan, Shandong provinces. CONCLUSION: The predominant viruses circulating in Mainland of China during 2008-2010 were evolutionary lineage C4a of human Enterovirus 71; Fuyang transmission chains mainly distributed in southern of China and the Central China around Anhui provinces. PMID- 23627021 TI - [Association of HLA-G 14bp gene polymorphisms and plasma sHLA-G level with susceptibility to EV71 infection in children]. AB - OBJECTIVE: Explore the relationship between the HLA-G 14bp insertion/deletion polymorphism and the infection of Enterovirus 71 (EV71) for children. METHODS: We genotyped HLA-G 14bp insertion/deletion polymorphism of 125 severe HFMD children infected with EV71 and 133 normal controls by PCR-PAGE;detected the plasma sHLA-G level of 66 heavy type and 15 critical type and 133 normal controls by ELISA. RESULTS: Frequencies of the genotype 14 bp - / - ,14 bp + / - and 14 bp + / + were 49.6% , 42.4% and 8.0% for the severe HFMD children infected with EV71, and 34.6%, 48.9% and 16.5% for the normal controls, respectively. A significant difference was observed for the frequencies of the HLA-G 14bp genotype between the two groups(chi2 = 7.850, P = 0.020). And for the allele frequencies. The plasma sHLA-G levels in heavy type were dramatically higher than that in normal controls (Z = -9.692, P = 0.000). The plasma sHLA-G levels in children with critical HFMD were dramatically higher than that with heavy type (Z = -2.420, P = 0.016). CONCLUSION: There was a relationship between the HLA-G 14 bp insertion/deletion polymorphism and the susceptibility to the severe HFMD children infected with EV71 and the plasma sHLA-G might be considered as a index for auxiliary diagnosis the severe HFMD infected with EV71. PMID- 23627022 TI - [Epidemiological study of rotavirus diarrhea in Beijing area from 2010 to 2012]. AB - OBJECTIVE: To investigate the epidemic of diarrhea caused by rotavirus infection among children treated at the Beijing Friendship Hospital in a period of 2 years. METHODS: Stool samples were collected from 972 diarrheic children from January 2010 to January 2012. The antigen of rotavirus was detected by the gold imunochromatography assay (GICA). RESULT: Among the samples studied, 370 out of 972 cases (38.1%) were positive for rotavirus antigen. The ratio of infected boys and girls was 2.14:1. Most infected children (91.4%) were under the age of two. The viral infection takes place all year round but breaks out mainly within a cold season that lasts from October through March, with a peak in November and December. Even in the spring and summer, however, its prevalence rates were quite significant among the children with diarrhea, ranging from 11.1% to 41.7%. CONCLUSION: In Beijing area, rotavirus is the major etiologic cause of diarrhea in children, especially in those under the age of 2. The peak prevalence occurs at any given time during the late fall and early spring seasons. It is necessary, therefore, to strengthen the surveillance of rotavirus infection in the spring and summer seasons in order not only to predict and prevent a potential outbreak in the end of the year, but also collect and provide more dynamic data for the further epidemiologic research of rotavirus diarrhea in the children. PMID- 23627023 TI - [Study on the correlation between membrane protein Flotillin-1 and PrPc endocytosis]. AB - OBJECTIVE: To explore whether the membrane-associated protein Flotillin-1 has relationship with endocytosis of PrPc. METHODS: The expression of Flotillin-1 in different cell lines was detected with the method of Western Blot; the interaction between Flotillin-1 and PrPc in Cells which were treated with copper ions was observed using immunoprecipitation method. RESULTS: (1) Flotillin-1 was widely expressed in many cell lines without significant difference in the amounts of expression level; (2) Only in the appearance of copper ions, the protein complexes of PrPc and Flotillin-1 can be detected with the method of IP, which were related to copper ions concentration and processing time. CONCLUSION: The membrane-associated protein Flotillin-1 has the relationship with the endocytosis of PrPc. PMID- 23627024 TI - [Recombinant adeno-associated virus type 8 mediated dual-luciferase gene expression in mouse]. AB - OBJECTIVE: Recombinant adeno-associated virus type 8 (rAAV8) mediating transgene expression in mice was investigated using co-expressed report gene of secreted Gaussia princeps luciferase (Gluc) and non-secreted firefly luciferase(Fluc). METHODS: rAAV8-Gluc/Fluc was prepared and infected HEK293 cells to test its performance in vitro. BALB/c mice were received rAAV8-Gluc/Fluc at different doses by intravenous injection (iv) or intramuscular injection (im). Then Glue activities in blood were measured,the whole-body images for Flue activities were performed and Flue activities of tissue lysate were also detected. RESULTS: rAAV8 Gluc/Fluc was successfully prepared and could infected HEK293 cells. The Glue was mainly detected in the culture media while the Flue was mainly detected within cells. The blood Glue activities of mice received rAAV8-Gluc/Fluc by iv or im peaked at 10-20 d post injection and persisted for at least 120d. The blood Gluc activities increased at the rAAV8-Gluc/Fluc dose-dependent manner. For mice received rAAV8 by iv, Fluc mainly expressed in liver and minor Fluc expression was also found in cardiac muscle and skeletal muscle. For mice received rAAV8 Gluc/Fluc by im, Fluc mainly expressed in local skeletal muscle and secondly in liver. CONCLUSION: rAAV8-Gluc/Fluc has been prepared successfully and its mediating transgene expression in mice has been investigated. This research will facilitate preclinical studies for rAAV8-mediated gene therapy. PMID- 23627025 TI - [The comparison between HIV-infected patients' Vdelta2 T cells expansion efficiencies by zoledronic acid and gammadelta TCR monoclonal antibody in vitro]. AB - OBJECTIVE: To find out the more efficient induction method through investigating the expansion efficiencies of HIV-infected patients' Vdelta2 T cells induced by zoledronic acid (Zol) or gammadelta TCR monoclonal antibody (mAb). METHODS: 38 healthy control subjects (HC group) and 65 HIV infected patients (HIV group) were enrolled in this research. Peripheral blood mononuclear cells (PBMCs) of individuals were stimulated by Zol or gammadelta TCR mAb respectively for 14 days at 2.0 x 10(7) cells/ well, and then gammadelta T cells and Vdelta2 subsets frequencies were measured by flow cytometry (FCM) on 0, 7 and 14 day. The absolute numbers of Vdelta2 T cells were calculated and the Vdelta2 T cell expansion efficiencies by these two methods were compared. RESULTS: The absolute numbers and frequencies of Vdelta2 T cell of HIV groups were lower than those of HC groups significantly on 0 day. After 14 days, the frequencies of Vdelta2 T cell of HIV group and HC group were(17.6 +/- 19.8)% and(64.3 +/- 4.5)% respectively, and the expansion indexes of Vdelta2 T cell were 54 +/- 40 and 74 +/- 29 respectively by induction of gammadelta TCR mAb. However, the frequencies of Vgammadelta2 T cell of HIV group and HC group were (69.6 +/- 21.2)% and (97.3 +/- 1.7)% respectively, and the Vgammadelta2 T cell expansion indexes were 538 +/ 11 and 5984 +/- 721 respectively by induction of Zol. CONCLUSION: Zol could induce the vast expansion of Vgammadelta2 T cells of HIV infected patients. The expansion efficiency by Zol was better than that by the gammadelta TCR mAb. PMID- 23627026 TI - [Effect of kurarinol on peripheral blood CTL surface PD-1 expression of patients with chronic hepatitis B]. AB - OBJECTIVE: To explore the anti-viral mechanism of kurarinol through studying its influence on cytotoxic T lymphocyte (CTL) surface program death receptor-1 (PD-1) expression of patients with chronic hepatitis B (CHB). METHODS: 69 cases of CHB, HBV DNA > or = 10(4) copies/ml, HBeAg positive, human leukocyte antigen (HLA)-A2 positive, alanine aminotransferase (ALT) > 2 x upper limit of normal value(ULN).69 cases were randomly divided into two groups:34 cases in treatment group,600 mg of kurarinol glucose injection was used for intravenous dripping, once a day, one month later, 200 mg of kurarinol capsule was used orally,three times a day and 200 mg of silybin meglumine tablet was used orally, three times a day. 35 cases in control group, only silibin meglumine tablet was used, method and dosage were the same as those of treatment group. Three months later, their peripheral blood HBV specific CTL surface PD-1 expression, non-specific CTL surface PD-1 expression and level of HBV specific CTL,HBV DNA and HBeAg negative rate and liver functions were analyzed and compared. RESULTS: 3 months after treatment, peripheral blood HBV specific CTL surface PD-1 expression of the treatment group decreased compared with that before treatment (t = 2.39, P < 0.05), it also decreased compared with that of the control group 3 months after treatment (t = 2.26, P < 0.05), HBV specific CTL increased compared with that before treatment( t = 3.01, P < 0.01), it also increased compared with that of the control group after treatment (t = 2.65, P < 0.05). There was no significant difference of non-specific CTL surface PD-1 expression compared with that before treatment (P > 0.05), and there was no significant difference compared with that of the control group after treatment (P > 0.05). HBV DNA of 11 cases (32.5%) turned negative ( HBV DNA < 500 copies/ ml), higher than that of the control group after treatment (2 cases, 5.71%) chi2 = 7.99, P < 0.01, HBeAg of 9 cases (26.47%) turned negative, higher than that of the control group after treatment (1 case, 2.86%), chi2 = 7.75, P < 0.01. CONCLUSION: Kurarinol can increase level of HBV specific CTL by down-regulating peripheral blood HBV specific CTL surface PD-1 expression of CHB patients, which may be one of the possible mechanisms that kurarinol can remove or inhibit HBV of CHB patients. PMID- 23627027 TI - [Evaluation of the effect of chronic virus infection on laboratory tests results in patients with osteoarticular tuberculosis]. AB - OBJECTIVE: To evaluate the effect of chronic virus infection on laboratory tests results in patients with osteoarticular tuberculosis. METHODS: A total of 121 patients with osteoarticular tuberculosis, who were hospitalized in Shenzhen Third People's Hospital during June 2008 to June 2012, were recruited for analysis. Clinical laboratory tests results were collected for comparison between patients with or without chronic co-infection with virus. RESULTS: Among the 121 patients, thirty patients were co-infected with hepatitis B virus (HBV), two were with Human immunodeficiency virus (HIV), and one was co-infected with HBV, HIV and hepatitis C virus (HCV). Compared to patients with osteoarticular tuberculosis without HBV/HCV/HIV infection, patients with chronic HBV/HCV/HIV virus infection had similar positive rate of laboratory tests including tissue smear acid-fast bacilli (AFB) staining, tissue Mycobacterium tuberculosis (Mtb) culture, tissue Mtb DNA detection, serological test of antibodies against Mtb, and Mtb. antigen-specific interferon-gamma release assay. Similar results were also found for erythrocyte sedimentation rate, C-reative protein level and liver function including Alanine aminotransferase and Aspartate Aminotransferase. CONCLUSION: Chronic infection with HBV/HCV in patients with have no obvious effect on clinical laboratory tests related to tuberculosis. PMID- 23627028 TI - [Mutation analysis of the HBV reverse transcriptase in nucleos(t)ide-treated patients with chronic HBV infection]. AB - OBJECTIVE: To characterize genotypic resistance within HBV RT region in chronic hepatitis B (CHB) patients with nucleos(t)ide analogue (NA) treatment. METHODS: Serum samples of 229 CHB patients with NA treatment were obtained. Full-length HBV RT sequences were amplified, sequenced and analyzed, on the following NA resistant (NAr) mutations belonging to different NAr pathways. RESULTS: Among 229 HBV isolates, 14.41% (33/229) and 85.59% (196/229) were genotype B and C, respectively; and the patients with HBV genotype C may be more susceptible to develope resistant mutations than patients with HBV genotype B(chi2 = 2.95, P < 0.05). NAr mutations were detected in 63 CHB patients. Mutations were not found at rtI169, rtT184, rtA194 or rtS202. RtM204 mutations were detected at the highest frequency among 63 mutants (40/63, 63.49%) and found to display 11 combination mutation patterns, in which rtM204I were associated with rtL80I/V and rtL180M, and rtM204V were associated with rtL1l80M, respectively. Conclusions There are complicated mutation patterns in the HBV RT region for chronic hepatitis B (CHB) patients with nucleos(t)ide analogue (NA) treatment. RtM204V/I mutation was the highest. PMID- 23627029 TI - [Hepatitis A virus mimotope mapping by phage display peptide library]. AB - OBJECTIVE: A 12 mer phage display peptide library was used to identify hepatitis A virus mimotopes of antigenic determinants, to provide the feasibility of virus epitope mapping by using this approach. METHODS: Using purified anti-hepatitis A virus monoclonal antibody as affinity selective molecule, phage display peptide library was biopanned and positive clones were selected by ELISA, competition assay and DNA sequencing. RESULTS: 10 ELISA positive clones were chosen for DNA sequencing, and the displayed peptide sequences were deduced. 9 of them showed identical nucleotide sequence, and similarity in their amino acid sequence with VP1 of HAV HM175 was found, but no sequence homology was found between the other phage clone and the capsid proteins of HAV. Those peptides may behave as mimotopes of HAV. CONCLUSION: The mimotope of HAV was selected by using phage display peptide library screening. The results provide the potential of this method to search for the mimotopes of the virus. PMID- 23627030 TI - [Subtype and sequence analysis of the gag genes for HIV-1 strains isolated in Hubei province]. AB - OBJECTIVE: To investigate the characteristic of subtypes and genetic diversity of HIV-1 circulating in Hubei province and its molecular epidemiological linkages with regard to risk factors of viral transmission. METHODS: plasma samples of 80 diagnosed individuals was characterized. The gene fragments of gag were amplified by reverse transcriptase polymerase chain reaction (RT-PCR) and HIV-1 genotypes were determined based on the nucleotide sequences of gag region. RESULTS: Seven HIV-1 group M subtypes or CRF including B, B', G, CRF01-AE, CRF07-BC, CRF08-BC and CRF15-01B were identified. CRF01-AE was found to be the most dominant subtype (48.4%) followed by CRF7-BC (22.6%) and B' (12.9%). CONCLUSION: The data from this study indicate the existence of multiple HIV-1 subtypes or CRFs in Hubei province and the surveillance of HIV-1 gene variation should be paid more attention to. PMID- 23627031 TI - [Expression and purification of a novel thermophilic bacterial single-stranded DNA-binding protein and enhancement the synthesis of DNA and cDNA]. AB - OBJECTIVE: Express a novel species of single-stranded DNA-binding protein (SSB) derived from Thermococcus kodakarensis KOD1, abbreviated kod-ssb. And evaluate the effect of kod-ssb on PCR-based DNA amplification and reverse transcription. METHODS: We express kod-ssb with the Transrtta (DE3), and kod-ssb was purified by affinity chromatography on a Ni2+ Sepharose column, detected by SDS-PAGE. To evaluate the effect of kod-ssb on PCR-based DNA amplification, the human beta globin gene was used as template to amplify a 5-kb, 9-kb and 13-kb. And to detect the effect of kod-ssb on reverse transcription, we used RNA from flu cell culture supernatant extraction as templates to implement qRT-PCR reaction. RESULTS: The plasmid pET11a-kod was transformed into Transetta (DE3) and the recombinant strain Transetta (pET11 a-kod) was obtained. The kod-ssb was highly expressed when the recombinant strain Transetta(pET11a-kod) was induced by IPTG. The specific protein was detected by SDS-PAGE. To confirm that kod-ssb can enhance target DNA synthesis and reduce PCR by-products, 5-, 9-, and 13-kb human beta globin gene fragments were used as templates for PCR. When PCR reactions did not include SSB proteins, the specific PCR product was contaminated with non-specific products. When kod -ssb was added, kod-ssb significantly enhanced amplification of the 5-, 9-and 13-kb target product and minimised the non-specific PCR products. To confirm that kod-ssb can enhance target cDNA synthesis, RNA from flu cell culture supernatant extraction was used as templates for qRT-PCR reaction. The results was that when kod-ssb was added, kod-ssb significantly enhanced the synthesis of cDNA, average Ct value is 19.42, and the average Ct value without kod-ssb is 22.15. CONCLUSIONS: kod-ssb may in future be used to enhance DNA and cDNA amplification. PMID- 23627032 TI - [Analysis of the related risk factors of diabetic peripheral neuropathy]. AB - OBJECTIVE: To explore the risk factors of diabetic peripheral neuropathy (DPN) and the relationship between DPN and diabetic retinopathy (DR). METHODS: The data of the in-patients with type 2 diabetes mellitus (T2 DM) were retrospectively studied. A total of 200 T2 DM patients were divided into DPN group (n = 136) and non-DPN group (n = 64) according to peripheral neuropathy. The basic clinical data and the incidence rate of DR were compared between two groups. Logistic regression analysis was used to study the risk factors of DPN. RESULTS: The course of disease, the level of BMI, glycosylated hemoglobin (HbA1c), 2 hour postprandial blood glucose (2 hPG), 2 hour glucose C peptide (2 hC-P) and the incidence rate of the DR were significantly different between two groups (P < 0.01). Logistic regression analysis showed that significant differences were observed in T2 DM complicated by DR (P = 0.023), the course of disease (P = 0.008), the level of HbA1c (P = 0.006), BMI (P = 0.000) and 2 hC-P (P = 0.065). CONCLUSION: Diabetic retinopathy, the course of disease, the level of BMI,HbA1c and 2 hC-P are the risk factors for type 2 diabetic peripheral neuropathy. Diabetic peripheral neuropathy is positive correlated with diabetic retinopathy. PMID- 23627033 TI - [FibroScan can be used to diagnose the size of oesophageal varices in patients with HBV-related cirrhosis]. AB - OBJECTIVE: To study ability of FibroScan (FS) in diagnosing the size of oesophageal varices (OV) in patients with HBV-related cirrhosis. METHODS: A total of 158 patients with HBV-related liver cirrhosis were enrolled in the study. The relation between the presence of OV assessed by endoscopy, and liver stiffness measurement by Fibroscan was studied, and ROC curves were drawn to assess the diagnostic ability of FS value. RESULTS: For the patients without OV, mild OV, moderate OV, and severe OV, their corresponding FS values were (21.7 +/- 9.9) kPa, (32.1 +/- 13.6) kPa, (42.3 +/- 20.0) kPa and (54.5 +/- 16.2) kPa, respectively. Significant difference was found among the groups (P < 0.001) and also between any two groups (P < 0.05). ROC curve for the diagnosis of with vs. without OV, moderate OV, and < severe vs. severe OV were 0.798 (95% CI: 73.1%-86.5%), 0.823 (95% CI: 74.5%-90.0%) and 0.879 (95% CI: 80.8% 95.0%), respectively, with corresponding FS cut-off value of 23.3 kPa, 31.5 kPa and 34.6 kPa. CONCLUSION: Liver stiffness measurement allows to predict the sizes of oesophageal varices in patients with HBV-related cirrhosis. PMID- 23627034 TI - [Genotypes and evolution characteristics of three patients with poor response to initial treatment of Lamivudine and Adefovir dipivoxil for hepatitis]. AB - OBJECTIVE: To understand the genotype characteristics and its evolution of patients with poor response to initial combined treatment of Lamivudine and Adefovir dipivoxil for chronic hepatitis B. METHODS: We detected the HBV genotypes of three patients-S1, S2, S3, who with poor response to initial treatment of Lamivudine and Adefovir dipivoxil for chronic hepatitis B over 12 months by the application of cloning and sequencing method at the time point of baseline,4 weeks after treatment, 12 weeks, 24 weeks, 48 weeks, 60 weeks. 25 clones were randomly selected to identify and sequence at each time point. RESULTS: The total number of clones from 3 patients with poor response to initial combined treatment of Lamivudine and Adefovir dipivoxil for chronic hepatitis B at each time point was 398. About patient S1 at baseline, genotype C accounting for 8.3%, genotype B, for 91.7%, so genotype B was in dominant (22/24). But genotype C has gradually developed to 100% after treatment for 60 weeks. About patient S2 and S3, genotype B was the only type at baseline. However type B has gradually "drift" to type C during treatment. When treatment for 60 weeks, type C has taken the absolute advantage 75% for S2, and 100% for S3. CONCLUSIONS: The cloning and sequencing can represent the overall genotype level better. HBV genotype has performed the evolution trend that genotype has drifted from B to C during long-term drug pressure, which is the main reason for poor response to initial combined treatment of Lamivudine and Adefovir dipivoxil for chronic hepatitis B. PMID- 23627035 TI - [Interleukin-21 expression in serum of patients with acute-on-chronic liver failure and its significance]. AB - OBJECTIVE: To investigate the level of the serum IL-21 and its correlation with serum biochemical indices of liver function test in patients with acute-on chronic liver failure. METHODS: Sixty patients with acute-on-chronic liver failure (severe hepatitis group) and 18 normal cases (control group) were enrolled in the study. Peripheral blood lymphocytes were isolated and total RNA of lymphocytes was extracted by using Trizol. Real-time PCR was used to assay IL 21 mRNA level. The serum IL-21 expression level was detected by ELISA method. The correlation between IL-21 and ALT, AST, TBiL, ALB was analyzed using Pearson's correlation analysis, respectively. RESULTS: Serum IL-21 expression level in severe hepatitis group was higher than that of control group. Moreover, the difference between them was statistically significant (P < 0.05). Serum IL-21 level was positively correlated with serum ALT, AST, TBil, respectively (P < 0.05), but was negatively correlated with ALB, respectively (P < 0.05). CONCLUSION: Serum IL-21 expression level was increased in patients with acute-on chronic liver failure and was associated with the severe of inflammation. We, therefore, believe that IL-21 might be involved in the pathogenesis of acute-on chronic liver failure and might be an index of the severity of liver inflammation. PMID- 23627036 TI - [Diagnostic value and clinical significance of the Golgi protein-73 in hepatocellular carcinoma]. AB - OBJECTIVE: By the detection of hepatocellular carcinoma in patients with GP73 content to explore its significance for liver cancer diagnosis and clinical treatment. METHODS: Up-converting phosphor immunochromatography methods was used for detection of serum GP73 in 302 cases of liver cancer, chronic hepatitis, cirrhosis patients and normal control, application electrochemiluminescence detection of AFP as a comparison. And ROC curve analysis of its diagnostic performance, and patients with HCC before and after treatment GP73 periodic testing of the treatment effect. RESULTS: GP73 content of liver cancer patients was (160.83 +/- 37.24) ng/ml, significantly higher than the chronic hepatitis, cirrhosis patients and normal controls. The area under ROC curve for GP73 diagonosis of hepatocellular carcinoma and chronic hepatitis and cirrhosis was 0. 907 which higher than the area under the ROC curve of AFP was 0. 727. Determine 110 ng/ml most of its critical value, the sensitivity was 84.7%, specificity was 75.8%; liver cancer patients with AFP < 400 ng/ml, detection rate of GP73 was 71.15%; the GP73 content after treatment showing an overall downward trend. CONCLUSION: GP73 has a high sensitivity for the diagnosis of HCC can add to the AFP's lack of sensitivity that can be used to monitor liver cancer treatment. PMID- 23627037 TI - [Detection of hepatitis A virus RNA with an improved loop-mediated isothermal amplification assay]. AB - OBJECTIVE: To establish a novel improved loop-mediated isothermal amplification (LAMP) technique to detect hepatitis A virus (HAV). METHODS: A novel improved LAMP assay based on the addition of an acceleration primer was developed for hepatitis A virus nucleotide acid detection. RESULTS: Precision and reproducibility analysis proved its high stability and reliability. Comparison between the improved and conventional LAMP assays revealed that the former was more sensitive with a detection limit of 5 TCID50/ml. The novel detection method displayed 100% consistency with the TaqMan real-time PCR assay when applied to clinical specimens collected from patients with confirmed acute HAV infection. CONCLUSION: This novel technique is widely applicable as a simple diagnostic tool in the clinical field as well as for the surveillance and investigation of the infectious disease in developing countries where HAV is endemic. PMID- 23627038 TI - [Establishment and application of TaqMan real-time RT-PCR for the detection of hepatitis E virus]. AB - OBJECTIVE: To establish a specific TaqMan-based Real-time PCR assay for the detection of hepatitis E virus (HEV). METHODS: According to the references, primers-probe sets which were located in ORF2, the conservative part of HEV genome were designed and therefore we established a HEV TaqMan real-time RT-PCR assay with great performance of specificity, sensitivity and reproducibility. And then it was used in the detection of HEV RNA in clinical samples. RESULTS: The HEV Real-time RT-PCR assay established in this study were able to detect HEV RNA with a detection limit of 10 copies/reaction. When the detection of a same sample was repeated for several times, coefficients of variation (CV) was all less than 1.53%. Our data also suggested that there were 1.87 x 10(6)-8.12 x 10(9) RNA copies in 1 ml of the clinical samples. CONCLUSION: The TaqMan-based Real-time PCR assay established in this study was specific and precise for the rapid detection of HEV RNA. It was applied successfully in the pathogen detection of clinical samples. PMID- 23627039 TI - [Development and evaluation of a quantitative double antibodies sandwich ELISA assay for rIFN-alpha1b]. AB - OBJECTIVE: To develop a double antibody sandwich ELISA assay for quantitative determination of recombinant human interferon alpha1b. METHODS: Mouse monoclonal antibodies with different binding site on rIFN-alpha1b were screened to select optimized candidates as coating and HRP-labeled index antibodies respectively. And a double antibodies sandwich ELISA was assembled; the reliable lower detection limit, specificity, accuracy and reproducibility were evaluated and validated. RESULTS: The quantitative sandwich ELISA had a reliable lower detection limit of 10 ng/ml, with a liner detection range 10-100 ng/ml (R2 = 0.992), variation coefficient inter-plates is less than 10%. CONCLUSION: The developed sandwich ELISA was a sensitive and specific, accuracy and reproducibility method for quantitative determination of recombinant human interferon alpha1b in final product. PMID- 23627040 TI - [Comparison of two different methods to detect HIV antibodies]. AB - OBJECTIVE: Evaluated the chemiluminescence and enzyme-linked immunosorbent assay (ELISA) to detect HIV antibodies, and compared the results, to provide a reference for the selection and clinical application of HIV screening. METHODS: 3000 cases of our hospital patients were measured by enzyme-linked immunosorbent assay and chemiluminescence immunoassay, using comfirmming experimental results as gold standards. Comparing sensitivity, specificity and other Indicators. RESULTS: In the diagnosis of HIV infection, enzyme-linked immunosorbent assay and chemiluminescence immunoassay had no significant difference. The positive rate of enzyme-linked immunosorbent assay was 0.93%, while the sensitivity and specificity were 89.66%, 99.93%, the positive rate of chemiluminescence immunoassay was 1.03%, while the sensitivity and specificity were 100%, 99.93%, respectively. CONCLUSION: Both methods are suitable for screening of HIV, having high specificity, and chemiluminescence has greater sensitivity than ELISA. PMID- 23627042 TI - Preparation and characterization of SiO2-Au nanoshells: in vivo study of its photo-heat conversion. AB - In the event of cancer treatment, photothermal therapy has met successful cancerous cells damage with highly reduced toxicity to normal cells. The prepared GNSs samples have been characterized using transmission electron microscope (TEM), dynamic light scattering, zeta potential and UV-VIS absorption spectroscopy. In-vivo photo-heat conversion of GNSs accumulated in Ehrlich tumor cells inoculated in female balb mice was monitored by measuring tumor tissue temperature as a function of NIR laser exposure time. Resultant heating and therapeutic efficacy were assessed by monitoring tumor growth/regression and tumor cells necrotic percentage. Histopathological examinations for treated and control tumors using light microscope and transmission electron microscopes (TEM) were performed to evaluate the treatment effects. Passively targeted pegylated gold nanoshells were found to have localized photo-heat conversion sufficient to selectively destruct tumor cells. This has been emphasized by the significant decrease in Ehrlich tumor volume for treated groups that administrated either intratumorly (IT) or intravenously (IV) with GNSs. Light microscope examinations revealed high necrotic percentages for both administration routes. TEM images showed degenerated cell membrane and nuclear envelop as well as the appearance of nucleus debris and other cell organelles. This non-invasive protocol showed great promise as a technique for selective cancer photo-thermal therapy. PMID- 23627041 TI - Micelles of methoxy poly(ethylene glycol)-poly(epsilon-caprolactone) as a novel drug delivery vehicle for tacrolimus. AB - As a traditional immunosuppressive drug, tacrolimus showed the potency in treating ulcerative colitis. In this study, a novel drug delivery vehicle achieved by self-assembly was applied to tacrolimus. During the preparation, amphiphilic copolymer MPEG-PCL was chosen to form the unique core-shell structure, and tacrolimus was loaded into the hydrophobic core due to its great hydrophobicity. After several relevant tests, MPEG-PCL (2000-2000) was selected to be the most suitable and safest copolymer for drug carrier. For the tacrolimus loaded MPEG-PCL (2000-2000) micelles, the mean particle size and drug entrapment efficiency were ca. 25 +/- 5 nm and 98.47 +/- 0.43% respectively. The micelles could be stored for quite a long time even at room temperature after freeze drying, and the freeze-drying process didn't affect the monodispersity of micelles. Transmission electron microscope (TEM) image emerged the spherical shape of micelles. Both Differential Scanning Calorimetric (DSC) and X-ray Diffractometer (XRD) assays demonstrated that tacrolimus was relatively completely incorporated into the core-shell structure. In vitro release profiles showed the apparent sustained release behavior compared with tacrolimus solution. Above all, animal treatment showed the most satisfactory therapeutic effect of tacrolimus loaded micelles, which means the micelles possess the ability to treat ulcerative colitis induced by dextran sulfate sodium (DSS) in mice. Therefore, micelles of MPEG-PCL could be a very promising novel vehicle for tacrolimus. PMID- 23627043 TI - In vitro cell culture evaluation and in vivo efficacy of amphiphilic chitosan for oral insulin delivery. AB - The overall goal of this paper was to enhance the bioavailability of orally delivered insulin. A mucoadhesive amphiphilic chitosan derivative, lauroyl sulphated chitosan (LSCS) was used as the oral carrier for insulin. Trans epithelial electrical resistance experiment was performed on Caco-2 cell monolayers and observed a reduction of TEER after the incubation with the particles. The insulin transport experiment was done with excised rat intestinal tissue using an Ussing chamber and observed an enhanced transport of insulin due to the effect of LSCS. Following oral administration of FITC-insulin loaded LSCS in SD rats; the qualitative biodistribution of the administered drug was investigated using a fluorescence microscopy. The results showed the time dependent distribution of insulin through gastro intestinal tract (GIT). The efficacy of insulin-loaded LSCS sub micro particles (LSCS-ins) was investigated in diabetic rats by measuring the blood glucose level and found to be an effective reduction of the blood glucose level after oral administration of LSCS ins. The pharmacological availability was found to be 2.5-fold and had a longer pharmacological activity compared with that of native insulin via oral and subcutaneous (sc) routes. The enhanced oral bioavailability of insulin may be associated with a higher release rate in the intestinal juice, enhanced absorption by improved permeability and increased residence time in the intestinal cavity. Thus, encapsulating insulin in LSCS matrix is a promising carrier for sustained and controlled drug delivery with improved bioavailability of insulin for diabetic patients. PMID- 23627044 TI - Polyethylene glycol-modified gelatin/polylactic acid nanoparticles for enhanced photodynamic efficacy of a hypocrellin derivative in vitro. AB - The present study focused on the development of a novel biodegradable nanoparticle system based on polyethyleneglycol-modified gelatin (PEG-GEL) and polylactic acid (PLA) biopolymers for improving the photodynamic efficacy of cyclohexane-1,2-diamino hypocrellin B (CHA2HB), a potent photodynamic therapeutic (PDT) agent. The CHA2HB-loaded PEG-GEL/PLA nanoparticles showed near-spherical morphology with an average size of 190 nm at a PLA to PEG-GEL ratio of 1:3. The drug loading was sufficient enough to produce potentially toxic reactive oxygen species (ROS) needed for photodynamic therapy (PDT). Slow and controlled drug release was observed in normal conditions, whereas enzyme assistance resulted in a relatively fast release due to partial disintegration of CHA2HB-loaded PEG GEL/PLA nanoparticles. In vitro experiments indicated that CHA2HB-loaded PEG-GEL PLA nanoparticles are efficiently taken up by cancer cells such as human breast adenocarcinoma (MCF-7), human gastric sarcoma (AGS) and mice specific Dalton's lymphoma (DLA) in a time dependent manner. Further, CHA2HB-loaded PEG-GEL/PLA nanoparticles evoked superior phototoxicity compared to free-CHA2HB towards all the three cell lines investigated. Interestingly, PDT effectiveness was different for the different cell type studied. CHA2HB-loaded PEG-GEL/PLA nanoparticles induced both apoptotic and necrotic cell death as a result of photoirradiation. Thus, our data suggest that PEG-GEL/PLA nanoparticles are highly effective in delivery and phototoxic enhancement of CHA2HB against model cancer cells in vitro. PMID- 23627045 TI - Improvement in bone properties by using risedronate adsorbed hydroxyapatite novel nanoparticle based formulation in a rat model of osteoporosis. AB - A superior drug formulation capable of achieving efficient osteogenesis is in imperative demand for the treatment of osteoporosis. In the present study we investigated the potential of using novel risedronate-hydroxyapatite (HA) nanoparticle based formulation in an animal model of established osteoporosis. Nanoparticles of HA loaded with risedronate (NHLR) of various sizes (80-130 nm) were generated for bone targeted drug delivery. Three months after ovariectomy, 36 ovariectomized (OVX) rats were divided into 6 equal groups and treated with various doses of NHLR (500, 350 and 250 microg/kg intravenous single dose) and sodium risedronate (500 microg/kg, intravenous single dose). Untreated OVX and sham OVX served as controls. One month after drug administration, the left tibia and femur were tested for bone mechanical properties and histology, respectively. In the right femur, bone density was measured by method based on Archimedes principle and bone porosity analyses were performed using X-ray imaging. NHLR (250 microg/kg) showed a significant increase in bone density and reduced bone porosity when compared with OVX control. Moreover, NHLR (250 microg/kg) significantly increased bone mechanical properties and bone quality when compared with OVX control. The results strongly suggest that the NHLR, which is a novel nanoparticle based formulation, has a therapeutic advantage over risedronate sodium monotherapy for the treatment of osteoporosis in a rat model of postmenopausal osteoporosis. PMID- 23627046 TI - Factors affecting the production of nanostructure lipid carriers of valproic acid. AB - The objective of this study was to optimize a nano-lipid carrier (NLCs) of valproic acid for nasal delivery using statistical methods. NLCs were prepared by solvent diffusion method followed by ultrasonication. After a preliminary screening study using Taguchi design, the Box-Behnken statistical model using desirability function was applied to evaluate variables affecting key specifications (minimum particle size, maximum drug loading and optimum release) of nano-lipid carriers of valproic acid. Each variable was assessed at three levels of surfactant concentration, acetone/ethanol volume ratio and organic/aqueous phase volume ratio. The best predicted model for particle size and drug release was quadratic model, while for drug loading, 2 factor interaction model fitted better. The measured results for the optimized formulation were a mean size of 154 nm, 47% payload and 75% of drug content released within 21 days. The optimum formulation was obtained using 1% of Poloxamer-188 as surfactant, organic/aqueous phase volume ratio of 1/5 and acetone/ethanol volume ratio of 3/1. Overall, the results show that entrapment of valproic acid in nano-lipid carriers was achieved. Such carriers might be a promising delivery system in the treatment of seizures via the nasal route of administration. PMID- 23627047 TI - Pegylated dendrimer and its effect in fluorouracil loading and release for enhancing antitumor activity. AB - Dendrimer, a new class of hyper-branched polymer with predetermined molecular weight, is being received much attention in nano biomedical applications such as anticancer drug delivery, gene therapy, disease diagnosis and etc. In this study, polyamidoamine (PAMAM)-based dendrimer generation 3.0 (G 3.0) was synthesized and subsequently pegylated. Obtained results showed that pegylation degree of the dendrimer was around 31% for its external amine groups. TEM image of the pegylated dendrimer exhibited spherical shape and nano sizes ranging from 30 to 40 nm. The fluorouracil (5-FU)-loaded pegylated dendrimer showed a slow release profile of the drug. In vitro study, at the primary screening concentration of 100 microg/mL, the PAMAM dendrimer presented higher toxicity in MCF-7 cells as compared to its pegylated counterpart. Meanwhile, the (5-FU)-loaded pegylated dendrimer exhibited the antiproliferative activity against the cell line with the IC50 of 9.92 +/- 0.19 microg/mL. In vivo tumor xenograft study, we succeeded in generating MCF-7 cells-derived cancer tumors on mice that was well-confirmed by using flow cytometer assay. The 5-FU encapsulated pegylated dendrimer exhibited a significant decrement in volume of the tumors which was generated by MCF-7 cancer cells. PMID- 23627048 TI - Nanobiotechnological approaches to delivery of DNA vaccine against fungal infection. AB - Vaccines play an essential role in keeping humans healthy. Innovative approaches to their use include the utilization of plasmid DNA encoding sequences to express foreign antigens. DNAhsp65 from Mycobacterium leprae is suitable for this purpose due to its ability to elicit a powerful immune response. Controlled release systems represent a promising approach to delivering vaccines. In this work, we used liposomes or PLGA systems to deliver DNAhsp65 to treat the pulmonary fungal infection Paracoccidioidomycosis. Both formulations modulated a protective immune response and reduced the pulmonary fungal burden even in the groups receiving less than four times the amount of the DNAhps65 entrapped within the nanoparticles. Although both systems had the same effective therapeutic results, the advantage of the liposome formulation was that it was administered intranasally, which may be more easily accepted by patients. These systems are a great alternative to be considered as adjuvant vaccine therapy for systemic mycosis. PMID- 23627049 TI - Application of poly(ethylene glycol)-b-poly(epsilon-caprolactone) copolymers with different Poly(ethylene glycol) contents for the preparation of PEG-coated nanoparticles. AB - This work used one poly(ethylene glycol)-b-poly(epsilon-caprolactone) (PEG-b-PCL) copolymer with low PEG content as matrix material and the copolymers with high PEG content as emulsifier to prepare PEG-coated nanoparticles for controlled release of paclitaxel by solvent evaporation technique. The copolymers were synthesized by ring-opening polymerization and characterized by 1H NMR and gel permeation chromatography (GPC). The effects of the composition and concentration of the copolymers used as emulsifier on the diameters and encapsulation efficiency of nanoparticles were investigated. The mean hydrodynamic diameters of the nanoparticles measured by dynamic light scattering ranged from 70 to 160 nm. The higher PEG content of emulsifier led to bigger diameter of nanoparticles and the emulsifier concentration (0.1%-1.0%) had no obvious influence on the diameters. The paclitaxel-loaded nanoparticles could achieve a sustained drug release for 7 days. When 2%-30% (w/v) of inulin was used as cryoprotectant during freeze drying process, the lyophilized nanoparticles could be well reconstituted into aqueous solution and the hydrodynamic diameter was not obviously changed. PMID- 23627050 TI - Lipid nanocarriers containing ester prodrugs of flurbiprofen preparation, physical-chemical characterization and biological studies. AB - In this paper, the preparation, chemical-physical, technological and in vitro characterization of nanostructured lipid carriers (NLC) carrying R-flurbiprofen ester prodrugs, were analyzed for a potential pharmaceutical application. R flurbiprofen was chosen as a model drug because it has been found to play an effective role in counteracting secretases involved in neurodegenerative diseases, although it does not cross the Blood Brain Barrier (BBB). In this study, two R-flurbiprofen ester prodrugs (ethyl and hexyl) were successfully synthesized and entrapped into non-pegylated and pegylated NLC. The obtained systems showed average diameters in the colloidal size range, negative zeta potential values and a good loading capacity. Drug release studies in physiological media on all drug-loaded samples showed a controlled drug release both at at pH 7.4 (containing esterase or not) and in human plasma of each ester prodrug, with a complete hydrolysis to R-flurbiprofen in media containing esterase. Empty and ethyl prodrug-loaded NLC were also demonstrated to have no cytotoxicity on human neuroblastoma (LAN5) cells, while hexyl prodrug-loaded NLC caused a reduction of cell viability probably due to a better capability of prodrug-loaded NLC to cross the cell membrane than the free compounds. These data were confirmed by microscopical observation, in which only the cells treated with hexyl prodrug-loaded NLC showed morphological changes. Outcoming data suggest that NLC could be potential carriers for parenteral administration of ethyl ester of R-flurbiprofen in the treatment of neurodegenerative diseases such as Alzheimer's. PMID- 23627051 TI - High throughput SNP detection system based on magnetic nanoparticles separation. AB - Single-nucleotide polymorphism (SNP) was one-base variations in DNA sequence that can often be helpful to find genes associations for hereditary disease, communicable disease and so on. We developed a high throughput SNP detection system based on magnetic nanoparticles (MNPs) separation and dual-color hybridization or single base extension. This system includes a magnetic separation unit for sample separation, three high precision robot arms for pipetting and microtiter plate transferring respectively, an accurate temperature control unit for PCR and DNA hybridization and a high accurate and sensitive optical signal detection unit for fluorescence detection. The cyclooxygenase-2 gene promoter region--65G > C polymorphism locus SNP genotyping experiment for 48 samples from the northern Jiangsu area has been done to verify that if this system can simplify manual operation of the researchers, save time and improve efficiency in SNP genotyping experiments. It can realize sample preparation, target sequence amplification, signal detection and data analysis automatically and can be used in clinical molecule diagnosis and high throughput fluorescence immunological detection and so on. PMID- 23627052 TI - Mercaptoethanol capped CdSe quantum dots and CdSe/ZnS core/shell: synthesis, characterization and cytotoxicity evaluation. AB - CdSe Quantum dots (Q-dots) and CdSe/ZnS core/shell have been synthesized by wet chemical route using mercaptoethanol (ME) as cappant. The synthesized Q-dots and core/shell were characterized using X-ray diffraction (XRD), Transmission electron microscopy (TEM), Energy dispersive X-ray analysis (EDS), Dynamic Light Scattering (DLS), Optical absorption and luminescence spectroscopy. The core/shell formation was confirmed by both XRD and TEM analysis. The luminescence was shown to be considerably enhanced in the core/shell sample. Effect of dialysis process on the optical properties of the Q-dots and core/shell has also been discussed. Cytotoxicity studies have been carried out for Q-dots and core/shell. CdSe/ZnS core/shell was found to be non-cytotoxic as compared to CdSe Q-dots up to a certain concentration range. Polyethylene glycol (PEG) coating enhances the non-cytotoxic nature of CdSe/ZnS core/shell when compared with bare core/shell. PMID- 23627053 TI - Chemiluminescence analysis for HBV-DNA hybridization detection with magnetic nanoparticles based DNA extraction from positive whole blood samples. AB - Molecular detection of HBV has a significant impact on prognosis and therapy of the disease. In this paper, a sensitive nucleic acid detection method of HBV was established taking advantage of magnetic nanoparticles (MNPs), chemiluminescence (CL) and polymerase chain reaction (PCR). HBV-DNA was extracted from hepatitis B positive human blood samples using MNPs adsorption method and biotin was labeled on the DNA segment after base insertion of bintin-dUTP in PCR. The biotinylated DNA segment was captured by amino probe immobilized on carboxyl MNPs and was detected by the chemiluminescence system of alkaline phosphatase catalyzing 3-(2' spiroadamantane)-4-methoxy-4-(3"-phosphoryloxy) phenyl-1, 2-dioxetane. Different concentrations of HBV-DNA were detected under the optimized experiment conditions and the relevant CL intensity were obtained, which provided a novel research or clinic diagnosis method for the quantification detection of HBV-DNA. PMID- 23627054 TI - In vivo monitoring the process of tumor growth, metastasis and bacterial infection expressing GFP via real-time optical imaging. AB - Noninvasive molecular fluorescence imaging in vivo which combines Optical imaging with genetic marker technology can real time monitor the development of tumor, through the use of human adenoid cystic carcinoma cell (ACC-M) and lung carcinoma cells SPC-A1 were thansfected by green fluorescent protein (GFP). This study established three types of model: Experimental metastases by tail vein injection of ACC-M-EGFP, spontaneous metastases by abdomen subcutaneous injection of SPC-A1 EGFP and subcutaneous tumor growth by subcutaneous injection of SPC-A1-EGFP. Tumor-bearing mice were viewed with whole-body fluorescent imaging system. The results showed that growth and metastasis of tumor were visualized clearly with this system. While this simple, nonintrusive technique can show in great detail the temporal behavior of the infectious process of red fluorescent protein (DsRed2)-expressing bacteria from outside intact infected animals. Therefore, this study provides a platform for monitoring tumor growth and metastasis and evaluating efficacy of antitumor drugs in vivo. PMID- 23627055 TI - Manipulating cell adhesions with optical tweezers for study of cell-to-cell interactions. AB - This paper presents an approach to manipulating cell adhesions using optical tweezers for cell-to-cell interactions at single cell level. A case study of investigating the adhesions between leukemia cells and bone marrow stromal cells is reported. First, the trapping force imposed on the cell is calibrated and the viability of leukemia cells after optical trapping is tested and verified. This is for demonstrating the feasibility of the proposed optical manipulation method. Second, properties of adhesions of leukemia cells K562 on stromal cells M210B4 from mouse and HS5 from human are characterized. Based on characterization results, we classify adhesions into three categories namely tightly adherent, loosely adherent or free suspending. Finally, the adhesion abilities of K562 on M210B4 and HS5 are changed by adding heparin into culture medium, which demonstrates the specificity of the adhesion. The important contribution of this paper lies in development of a dexterous cell manipulation method to characterize cell adhesion properties, which helps create a new opportunity to investigate cell-to-cell interactions at single cell level. PMID- 23627056 TI - Real-time monitoring in vitro cellular cytotoxicity of silica nanotubes using electric cell-substrate impedance sensing (ECIS). AB - An electrical measurement known as Electric Cell-substrate Impedance Sensing (ECIS) has become increasingly applied to the study of cellular viability, proliferation and cytotoxicity with the advantages of label-free, non-invasion and real-time monitoring capability in comparison with other conventional methods (MTS, MTT). With this technique, cells are grown on the micro-sized gold electrodes where the micro-ampere alternative current is applied to measure the impedance changes due to the physiological changes caused by internal or external stimuli. In another field, Silica Nanotubes (SNTs) are a novel class of inorganic structures with promising potentials in bio-separation, drug delivery, imaging and other biomedical applications. In this study, by using ECIS-based self fabricated cell chip, Cells were cultured on the working electrodes and separately exposure to the 0, 2 microm, 2 microm and 10 microm long at the varying concentrations of SNTs to evaluate the cellular responses such as viability, multiplication time and cytotoxicity. Final results were additionally compared with the MTS method as a reference to review the reliability PMID- 23627057 TI - Dye-doped silica nanoparticle with HIV-1 TAT peptide for bioimaging. AB - Multifunctional silica nanoparticles for bioimaging and drug delivery have progressively been developed as novel modalities for cancer diagnosis and treatment. In this study, we synthesized fluorescein isothiocyanate (FITC) doped silica nanoparticle coated with 3-aminopropyl trimethoxysilane (APTS). Additionally, the surface of this silica nanoparticle was modified with HIV-1 trans-activating transcriptional activator (HIV-1 TAT) peptide. The HIV-1 TAT peptide (cell-penetrating peptide) is able to deliver cargos such as oligonucleotides and proteins across the plasma membrane of living cells. This study demonstrates the feasibility of TAT peptide coated silica nanoparticle as a potential carrier for bioimaging and drug delivery. PMID- 23627058 TI - Development of multi scale structured Al/AI2O3 nanowires for controlled cell guidance. AB - Cell responses to surface and contact cell guidance are of great interest in bio applications especially on nano- and micro scale features. Recently we showed selective cell responses on Al/Al2O3, bi-phasic nanowires (NWs). In this context, Al/Al2O3 NWs were synthesized by the chemical vapor deposition of (tBuOAIH2)2. Afterwards, linear periodic nano- and micro structured NWs were formed using laser interference lithography (LIL) technique to study the contact guidance of neurons from rat dorsal root ganglion (DRG), human umbilical vein smooth muscle cells (HUVSMC), human umbilical vein endothelial cells (HUVEC) and human osteoblast (HOB). LIL treatment did not alter surface chemistry of NWs. From our preliminary research LIL patterned NWs lead to alignment of axons contrary to non patterned NWs. Morphology of HUVSMC changed from poly- to linear shapes and strong alignment was observed while HUVEC and HOB were not affected. PMID- 23627059 TI - Combination effect of paclitaxel and hyaluronic acid on cancer stem-like side population cells. AB - Cancer recurrence is the main cause of chemotherapeutic treatment failure. The mechanisms driving cancer recurrence may be due to very rare subpopulation cells, cancer stem-like cells (CSCs). Therefore, the early detection and better treatment of cancer stem-like cells are of great interest. In this study, we investigated how to eliminate the side population cells (SP), which have the characteristics of cancer stem-like cells, and also show chemotherapy resistance. Fluorescence-activated cell sorting (FACS) were used to sort SP and non-SP cells from human liver cancers, Huh-7 Hyaluronic acid (HA), which is an abundant component in the extracellular matrix, is known to involve in proliferation of normal and cancer cells. Herein, we investigated the effect of HA component on chemotherapy against SP cells. Cell growth inhibitory effects of the paclitaxel (PTX) chemotherapy combined with the HA component on SP cells of Huh-7 was determined using the trypan blue dye exclusion test. PTX combined with HA was found to show more increased inhibition of cell growth in both SP and non-SP cells, compared to free PTX treatment. In conclusion, SP cells of Huh-7 shows chemotherapeutic drug resistance due to the over-expressed efflux pumps. HA proposed one of possibilities to overcome the limitation of chemotherapy against cancer stem-like cells. PMID- 23627060 TI - Evaluation of various electrode materials for detection of oxidized low-density lipoproteins. AB - Measurement of oxidized low-density lipoprotein (LDL) generated by oxidative stress of various kinds might be useful for evaluating the risk of cardiovascular disease. We evaluated some electrode materials to detect oxidized LDL electrochemically. Some carbon nanotube dispersions were studied as electrode materials. Native LDL was isolated from normal human serum using ultracentrifugation. Oxidized LDL was prepared by treating the native LDL with CuSO4. Electrodes were fabricated by depositing the nanotube dispersion on a gold electrode, with subsequent drying. The potential change of the electrode against a reference electrode was monitored before and after adding native LDL or oxidized LDL. Only acid-treated carbon nanotubes were able to discriminate both LDL preparations, perhaps because of the carboxylic acid groups introduced on the nanotube by acid treatment. PMID- 23627061 TI - Nanoscale film fabrication of various peptides on neural stem cell chip. AB - Modification of peptide on the electrode surface is very important issue for achieving valuable information from cell chip. In this study, various kinds of cysteine-containing peptide were fabricated on the electrode surface to enhance the electrochemical signals, cell spreading, and proliferation of rat neural stem cells. Different kinds of lysine-rich and RGD peptides were self-assembled on the gold nanoparticle modified ITO surfaces via strong Au-S chemical bond, followed by seeding neural stem cells (NE-4C) on its surface. As a result, K-MAP-C peptide consists of the quadruple branches of lysine chains and cysteine terminal showed outstanding characteristics respect to the improvement of redox signals, cell spreading and proliferation on electrode surface. Hence, our stem cell chip composed of lysine-rich peptide modified electrode can be usefully applied as efficient stem cell research tool. PMID- 23627062 TI - Preparation of functional magnetic nanoparticles mediated with PEG-4000 and application in Pseudomonas aeruginosa rapid detection. AB - A rapid detection method of Pseudomonas aeruginosa based on magnetic separation and chemiluminescence was developed in this paper. Magnetic nanoparticles (MNPs) were prepared by solvothermal method with PEG-4000 as a surfactant, and then were modified. The prepared MNPs present a uniform morphology and good dispersion. The sizes of MNPs can be controlled by adjusting the dosage of FeCl3 x 6H2O. The obtained particles were characterized with Scanning electron microscope (SEM), Transmission electronic microscopy (TEM) and Fourier transform infrared (FTIR). The biotin-dUTP-labeled DNA fragments of gyrB gene were amplified by polymerase chain reaction (PCR), and Pseudomonas aeruginosa was successfully detected with detection limit as low as 7.5 fM of gyrB fragments. PMID- 23627063 TI - Preparation and electrochemical behavior of L-glutamate electrochemical biosensor. AB - Using the nano-porous pseudo carbon paste electrode (Nano-PPCPE) as the working electrode, mixing L-glutamate oxidase (L-GLOD), catalase (Cat) and bovine serum albumin (BSA) with phosphate buffer (PB, pH = 7.4), followed by cross-linking with glutaraldehyde, a novel L-glutamate electrochemical biosensor was successfully formed. It was demonstrated that the modified nano-PPCPE exhibits a high selectivity and sensitivity in comparison with the modified CPE. The L glutamate biosensor showed a linear range from 5 x 10(-7) M to 1 x 10(-5) M with the detection limit of 2.5 x 10(-7) M. PMID- 23627065 TI - Enhancement of human oral bioavailability and in vitro antitumor activity of rosuvastatin via spray dried self-nanoemulsifying drug delivery system. AB - The purpose of this study was to develop spray dried self-nanoemulsifying drug delivery system (SNEDDS) tablets of rosuvastatin using mannitol as a carrier. SNEDDS were prepared using Capryol 90, poloxamer 407 and Transcutol P or triacetin as oil, surfactant and cosurfactants, respectively. The prepared systems were characterized and their cytotoxicity was evaluated using Caco-2 cell lines. A comparative bioavailability study was performed in human volunteers relative to the conventional commercial product. Results showed better self nanoemulsifying ability of systems containing triacetin compared to Transcutol P. SNEDDS formed uni-modal nanoemulsion droplet size distributions with droplet size less than 50 nm and polydispersity index values ranging from 0.127 to 0.275. The solubilizing capacity of rosuvastatin was affected by both surfactant and cosurfactant concentrations. Upon spray drying, systems prepared using Transcutol P tended to be soft and tacky and were sticking to the walls of the dryer. The redispersion of rosuvastatin from solid SNEDDS was very fast (100% within 5 minutes). Optimized SNEDDS prepared with triacetin were safe with no cytotoxic effect on Caco-2 cells. The anticancer effect of rosuvastatin was enhanced when incorporated in SNEDDS (IC50 value decreased from 4 to 3 microg/ml) due to the increase in penetration of SNEDDS inside the cells. The relative bioavailability for SNEDDS tablets compared to the commercial tablets was 167%. The effective solubilization, penetration and enhancement in bioavailability of SNEDDS tablets proves their potential as a safe, and effective drug delivery system for poorly soluble drugs. PMID- 23627066 TI - Proteomic analysis of molecular biocompatibility of gold nanoparticles to human dermal fibroblasts-fetal. AB - The aim of the present study is to investigate the molecular effects of Gold nanoparticles (GNPs) on the human dermal fibroblasts-fetal (HDF-f) at the level of protein expression. 20-nm GNPs were prepared using chemical reduction method. After HDF-f were treated with 200 microM GNPs for 1, 4 and 8 h, protein expression profiles were obtained using two-dimensional difference gel electrophoresis (2D-DIGE) and mass spectra (MS) analysis. The obtained differential expressed proteins were analyzed by clustering, gene microarray pathway profiler (GenMAPP) and Ingenuity pathway analysis (IPA) analysis, and verified by western blot. 40 protein spots were filtered with different expression in abundance in all three-culture periods and 24 unique proteins were identified. Bioinformatics analysis results indicated that GNPs might have an influence on the HDF-f in the aspects of signal transduction, actin cytoskeleton, energy metabolism, oxidative stress cell transcription factor, etc. Compared with the gene expression effects induced by GNPs in our previous research, certain relationships at molecular level after HDF-f treated with GNPs were identified. The proteomic analysis used here would also be a useful tool to improve the mechanistic understanding of nanomaterials biocompatibility. PMID- 23627064 TI - Biomedical detection via macro- and nano-sensors fabricated with metallic and semiconducting oxides. AB - Originally developed as gas sensors, the benefits of metallic and semiconducting oxide materials are now being realized in other areas of sensing, such as chemical, environmental, and biomedical monitoring and detection. Metallic and semiconducting oxides have continuously expanded their roles to date, and have also established their significance in biosensing by utilizing a variety of modes for signal generation and detection mechanism. These sensors are typically based either on their optical, electrochemical, electrical, gravimetric, acoustic, and magnetic properties for signal transduction. This article reviews such biosensors that employ metallic and semiconducting oxides as active sensing elements to detect nucleic acids, proteins, cells, and a variety of important biomarkers, both in thin film and one-dimensional forms. Specific oxide materials (M(x)O(y)) examined comprehensively in this article include M = Fe, Cu, Si, Zn, Sn, In. The derivatives of these oxide materials resulting from incorporation of dopants are examined as well. The crystalline structures and unique properties that may be exploited for various biosensing applications are discussed, and recent efforts investigating the feasibility of using these oxide materials in biosensor technology are described. Key biosensor characteristics resulting from reduced dimensionality are overviewed under the motif of planar and one-dimensional sensors. This article also provides insight into current challenges facing biosensor applications for metallic and semiconducting oxides. In addition, future outlook in this particular field as well as different impacts on biology and medicine are addressed. PMID- 23627067 TI - Highly H2O2-sensitive electrospun quantum dots nanocomposite films for fluorescent biosensor. AB - Bright CdSe quantum dots (QDs)/polycaprolactone (PCL) nanocomposite fluorescent films were fabricated by electronspinning. By using chloroform and N,N dimethylformamide as electronspinning solvent, the oil-soluble CdSe QDs were uniformly distributed in PCL fibers, and were directly employed as optical probe without any modification processing. The fluorescences of CdSe QDs/PCL nanocomposite films were quickly quenched when the films were contacted with H2O2, solution. In the presence of glucose oxidase (GOD), the fluorescence intensities of these fluorescent films exhibit a liner change with the concentrations of glucose. The H2O2-sensitive electrospun QDs nanocomposite films are highly uniform and repeatable, demonstrating the potential to fabricate stable, sensitive and recyclable fluorescent biosensor for the detection different H2O2-generating oxidases and their substrates. PMID- 23627068 TI - Gold nanoparticles decorated by amphiphilic block copolymer as efficient system for drug delivery. AB - A drug delivery system based on gold nanoparticles (Au NPs) stabilized by an thiol-functionalized amphiphilic diblock copolymer was developed. The copolymer, poly(ethylene glycol)-b-poly(n-butyl acrylate) (MPEG-b-PBA), was synthesized by Reversible Addition-Fragmentation Transfer (RAFT) polymerization and the thiocarbonylthio group at the end of the hydrophobic block PBA was further reduced to thiol group. Pyrene, used as a model molecule for the hydrophobic drugs, was loaded in the hydrophobic interior of the shell around Au NPs by physical entrapment. The analysis performed by UV-Vis spectrophotometer show that the obtained Au NPs-pyrene nanocomposites have good stability in the aqueous solution and high drug loading capacity in comparison with Au NPs decorated with small molecular ligands. In addition, both their loading capacity and release behavior were found closely related to the chain length of hydrophobic block. In conclusion, we report here a versatile and simple procedure to fabricate Au NP polymer hybrids that is applicable to various amphiphilic copolymers synthesized by RAFT polymerization and useful to produce efficient Au NP based drug carriers. PMID- 23627069 TI - Selectively enhanced antibacterial effects and ultraviolet activation of antibiotics with ZnO nanorods against Escherichia coli. AB - In this paper, the selectively enhanced antibacterial effects of ZnO nanorods with several kinds of conventional medical antibiotics are investigated. Compares to gentamicin, clarithromycin and ofloxacin, ZnO nanorods could obviously achieve synergistic antibacterial effects with ceftriaxone against Escherichia coli (E. coli). Meanwhile, ultraviolet (UV) activation is adopted to induce higher antibacterial activity of ceftriaxone-ZnO nanorods than that of pure ceftriaxone or ZnO nanorods. The results of colony-forming capability test, infrared ray (IR) spectrum, and detection of reactive oxygen species (ROS) indicated that ceftriaxone may the facilitate the entry of ZnO nanorods into bacterial cell, and this effect would play an important role in mechanisms of such antibacterial behavior under the conditions of this study. PMID- 23627070 TI - Broad based tissue uptake of polycationic near-infrared polymeric nanoparticles in living mice. AB - A near infrared (NIR) fluorescent polymeric nanoparticle, commercialized under the name X-Sight 761 (X761), was tested for compatibility with pre-clinical in vivo imaging applications. In one experiment, an optical clearance profile was obtained by performing whole animal fluorescence imaging over the course of 48 hours on mice injected intravenously with X761. In a second trial, a temporal biodistribution was assessed by conducting necropsy and ex vivo analysis of X761 tissue accumulation at selected time points over a 48 hours period after i.v. injection. Taken together, the data demonstrate a sustained distribution of X761 into all major tissues over the time course, with an extremely low net clearance from the animal. This unique behavior is attributed to cell uptake mediated by the polycationic surface of X761. These properties negate the use of X761 as a reporter within a classical targeted molecular probe construct, in which selective concentration at a target site and rapid clearance from background tissues are needed to develop contrast. Nevertheless, the brightness and stability of X761 is well suited for a range of other applications, ranging from broad based in vivo drug delivery to in vitro fluorescence assays. PMID- 23627071 TI - Functional responses of human adipose tissue-derived mesenchymal stem cells to metal oxide nanoparticles in vitro. AB - Nanoparticles (NPs) are frequently applied in biomedical applications. The use of human mesenchymal stem cells (hMSC) in biomedicine is pivotal, especially in oncology and tissue engineering. Titanium dioxide (TiO2) and zinc oxide (ZnO) NPs are interesting agents in experimental oncology and stem cells are discussed to be a potential vehicle for NPs to tumor sites. However, little is known about hazardous effects of NPs in hMSC. The aim of the present study was to analyze functional impairment of hMSC by ZnO- and TiO2-NPs. Cytotoxic effects of NPs were evaluated by the MTT-assay. Furthermore, multi-differentiation capacity, spheroid formation and migration were assessed. The immunophenotype was observed by flow cytometry. Cytotoxic effects were observed at 625 nM ZnO-NPs whereas no cytotoxicity was seen in hMSC by TiO2-NPs. The differentiation capacity of hMSC into osteogenic and adipose lineages was unchanged. A long-term period cultivation of hMSC for 3 weeks after NP exposure revealed a persistence of NPs in the cytoplasm. The migration capability was impaired whereas the ability to form spheroids was not affected. Flow cytometric analysis revealed distinct alteration of cell surface markers CD 90 and CD 73. Major functional properties of hMSC were unaffected by TiO2- and ZnO-NPs. However, restricted migration might critically influence wound healing capacity. Further information is needed to assess the clinical impact of these findings. PMID- 23627072 TI - Folic acid conjugated guar gum nanoparticles for targeting methotrexate to colon cancer. AB - It was envisaged to develop surface modified Guar Gum Nanoparticles (GGNP) with Folic acid (FA) charged with methotrexate (MTX) to target the colon specifically. The MTX loaded FA functionalized GGNP (MTX-FA-GGNP) have been prepared by emulsion crosslinking method. These surface modified nanoparticles were compared with unmodified MTX loaded GGNP (MTX-GGNP). The developed formulations were evaluated for size and size distribution, zeta potential, Differential Scanning Calorimetry (DSC), release profile and uptake studies. The nanoparticles have been found to have average size of 325 nm in diameter having polydispersity index (PDI) 0.177 indicating mono-disperse particles. The zeta potential of the particles was found to be -36.9 mV. The percent growth inhibition of Caco 2 cells with MTX-FA-GGNP was found to be better than MTX-GGNP indicating folate receptor mediated uptake. The MTX-GGNP protects the release of MTX in upper gastrointestinal tract while maximum release of MTX occurred in simulated colonic fluids of pH 6.8. The in vivo uptake studies revealed preferential uptake of nanoparticles formulation in the colon. These studies provide evidences that MTX FA-GGNP holds promise to address colorectal cancer over-expressing folate receptors. This prototype formulation enjoys dual advantage of having propensity to release the drug in the colon and in the conditions of colorectal carcinoma; it could be better localized and targeted with improved therapy due to over expression of folate receptors. PMID- 23627073 TI - Development and evaluation of porous chitosan nanoparticles for treatment of enterotoxigenic Escherichia coil infection. AB - Enterotoxigenic Escherichia coil (ETEC) infections result in large mortality rate and usually a frequent cause of diarrhea in infants and a major cause of economic losses in the swine industry. To prevent enterotoxigenic Escherichia coli infections animal needs an active mucosal immunity at the moment of weaning. In the present study, F4 loaded porous chitosan nanoparticles were prepared by spray drying method for oral vaccination. In order to prevent the release the antigen in upper GI tract and to release it at target site nanoparticles were coated with Eudragit L100 which protect the antigen against the detrimental effects in the gastro-intestinal tract. Average size of prepared nanoparticles varied between 548 +/- 2.3 to 98 +/- 1.1 nm with a polydispersity index ranging from 0.767 +/- 0.023 to 0.209 +/- 0.021. Zeta potential for prepared nanoparticles was found to be in range from +18.3 +/- 2.5 to +29.5 +/- 2.8 mV. SEM studies completely revealed that the drug loaded nanoparticles were found to be distinct, spherical in shape with pores formed. Practicability of NPs was compared to vaccination with F4 fimbriae in solution. Mucosal immune response study revealed that, immune response were elicited in solution was well as in NPs group but colonization of the small intestine by F4+ ETEC upon oral solution challenge could not be prevented. However animals vaccinated with porous NPs group reveal a significant reduction in excretion of F4+ E. coli. Studies indicate that a solid vaccine formulation will be more efficient as compared to oral solutions. These systems can contribute to the development of oral vaccines in veterinary as well as in human medicines. PMID- 23627074 TI - Fabrication and bioproperties of raspberry-type hybrid nanoparticles of Au thioethyl pendant ligand@chitosan. AB - Synthesis of nanoparticles with desired size/morphology has enormous importance, especially in the compelling field of nanotechnology. In this case, a novel kind of raspberry-type hybrid nanoparticles was prepared by hybridization of chitosan (CS) with thioethyl pendant ligand (TPL) modified Au nanoparticles (Au-TPL@CS NPs). Such method was based on ionic gelation using sodium tripolyphosphate as a counterion. The blood compatibility of Au-TPL@CS NPs was characterized by coagulation tests, plasma recalcification time, hemolysis assay, morphological changes of red blood cells (RBCs) and complement activation in vitro. The results showed that Au-TPL@CS NPs exhibited good blood compatibility. The possible underlying mechanism was also present. Finally, the direct electron transfer reactivity of the Hemoglobin/Au-TPL@CS NPs/multi-walled carbon nanotubes/glassy carbon electrode was investigated with cyclic voltammetry measurements. The biosensor exhibited a good electrocatalytic activity to the reduction of H2O2. Such new type of Au-TPL@CS NPs provides a promising platform of biological system for early illness detection and treatment in future. PMID- 23627076 TI - Calcium phosphate nanoparticles for transcutaneous vaccine delivery. AB - The main objective of this study was to investigate the potential of calcium phosphate (CAP) nanoparticles for transcutaneous vaccine delivery. CAP nanoparticles were prepared by nanoprecipitation method followed by sequential adsorption of sugars and ovalbumin. Nanoparticles were characterized using dynamic light scattering, XRD, ATR-FTIR, and microscopy methods. In-vitro release of ovalbumin from nanoparticles was studied in phosphate buffer (pH 7.4). In-vivo immunization studies were carried out in Balb/C mice. The size and zeta potential of ovalbumin-sugar adsorbed CAP nanoparticles was 350 +/- 22.5 nm and -12.93 +/- 1.02 mV respectively. Around 60% ovalbumin was released from nanoparticles within 24 hrs. To test the feasibility for transcutaneous vaccine delivery, the nanoparticles were applied in mice after removing the stratum corneum by tape stripping. In the positive control group, the nanoparticles were administered by intradermal injection. Ovalbumin-sugar coated CAP nanoparticles showed significantly higher antibody titers (Total IgG and IgG1) compared to ovalbumin alone. IgG2a antibodies were only seen with intradermal injection. Both topical and intradermal treatment groups showed splenocyte proliferation when re stimulated with ovalbumin. The results from this study demonstrate the potential of using CAP nanoparticles for transcutaneous vaccine delivery. PMID- 23627075 TI - Development and characterization of pilocarpine loaded Eudragit nanosuspensions for ocular drug delivery. AB - With aim of improving the availability of drug at intraocular level and to reduce the frequency of drug administration, pilocarpine nitrate nanosuspensions were made from inert polymer resin (Eudragit RL 100) with varying drug to polymer ratios using Lutrol F68 solution in various concentration. Nanosuspensions were successfully prepared by solvent displacement method. Size of nanoparticles varied between 121.5 +/- 2.28 to 291.5 +/- 1.28 nm, a polydispersity index ranging from 0.218 +/- 0.003 to 0.658 +/- 0.035 with zeta potential ranging +14.1 +/- 0.7 to +19.8 +/- 2.3 mV. Differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) studies clearly suggest the compatibility of the drug with the polymer used. Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM) studies completely revealed that the drug loaded nanoparticles were found to be distinct, spherical in shape having a smooth surface and the drug is molecularly dispersed uniformly throughout the whole polymer matrix. PRL4 was successfully able to sustain the drug release for 24 hr as compared to other batches of formulated nanosuspensions. No significant change in average particle size and zeta potential were observed after conducting stability studies. Results of the studies clearly suggest the suitability of Eudragit RL 100 as a promising potential drug delivery adjuvant for ocular drug administration. PMID- 23627077 TI - A new quantitative method to determine the uptake of SPIONs in animal tissue and its application to determine the quantity of nanoparticles in the liver and lung of Balb-c mice exposed to the SPIONs. AB - We propose a new method for determining the quantity of superparamagnetic iron oxide nanoparticles (Fe3O4, SPIONs) embedded in animal tissue using magnetization measurements. With this method, the smallest detectable quantity of magnetite nanoparticles in a tissue sample is -1 microg. We showed that this method has proved being efficient. In this study, we focused in determining the quantity of SPION confined in lung and liver tissue of mice injected with -13 nm magnetite superparamagnetic nanoparticles. Furthermore, the method allowed us to detect the magnetite nanoparticles present in animal tissues without letting the natural iron ions present in the tissue or blood interfere with the measurements. PMID- 23627078 TI - [Study on germination characteristics of Disporum cantoniense]. AB - OBJECTIVE: To study the seed germination characteristic and optimal germination condition of wild Disporum cantoniense. METHODS: Used wild Disporum cantoniense seed as the test materials, the rate of water absorption of the seed was determined. The germination rates under different conditions, along a temperature gradient (15, 20, 25 and 30 degres C), in light or dark, on top or between wet filter papers, and keeping or removing the seed coat, were determined respectively using petri dish method. At the same time germination trends were observed. RESULTS: The thousand seed weight was 33.24 g, and the seed water absorbing reached saturation pot after soaking for 30 h. Higher germination rates were respectively recorded at 25 degrees C, between filter papers, and in dark after 24 h soaking in the pretreatment solution. CONCLUSION: The optimal condition for the germination of the seed of wild Disporum cantoniense is as follow: keeping testa, seed soaking for 24 h in seed germination agent and being incubated between wet filter papers in dark at 25 degrees C. PMID- 23627079 TI - [Prime study of Gekko gecko in HPLC fingerprint]. AB - OBJECTIVE: To establish HPLC fingerprint of Gekko gecko. METHODS: The relative retention time and relative peak area of exteacts of Gekko gecko were determine by HPLC to confirm proper chromatographic condition and obtain the data. RESULTS: Better distribution of relative retention time and relative peak area were shown under the chromatographic condition and the HPLC fingerprint was established. CONCLUSION: The established HPLC fingerprints of Gekko gecko can be used to identify Gekko gecko and its quality control. PMID- 23627080 TI - [Study on the dynamic variations of Z-ligustilide and n-butylidenephthalide content in essential oil of radix angelicae sinensis from different growth period]. AB - OBJECTIVE: To study the variation of the biomass of the root and active components of Angelica sinensis during different growth periods. METHODS: 27 batches of Angelica sinensis were harvested from different growth periods, and the biomass of underground parts were determined; The Gas Chromatography-Mass Spectrometry (GC-MS) was used for determining the contents of Z-ligustilide and n Butylidenephthalide in essential oil of Radix Angelicae Sinensis. RESULTS: The average contents of n-Butylidenephthalide and Z-ligustilide were more than 1% and 40% in the total essential oil of Radix Angelicae sinensis respectively. Their contents showed larger difference during different growth period. CONCLUSION: The contents of Z-ligustilide and n-Butylidenephthalide of Radix Angelicae Sinensis is closely related to their growth period. PMID- 23627081 TI - [Study on quality evaluation of Angelica sinensis by grey incidence degree method]. AB - OBJECTIVE: To evaluate the quality of Angelica sinensis based on Grey incidence degree method. METHODS: Grey model was set up by determining four main compositions contained in the samples. RESULTS: The result of quality evaluation on 21 samples by this model was as same as that of genuine medicinal materials. CONCLUSION: Grey incidence degree method and the model can be used to evaluate the quality of Angelica sinensis. PMID- 23627082 TI - [Determination of the content of the main components of flavonoids compounds in raw malt, torrefied malt and ustulate malt]. AB - OBJECTIVE: To determine the content of Catechin, Myricetin, Quercetin and Kaempferol in barley grain, raw malt, torrefied malt and ustulate malt based on different barley cultivars. METHODS: HPLC method was used. Analysis was performed on Agilent ZORBAXSB-C18 (150 mm x 4. 6 mm, 3.5 microm) column with acetonitrile 0.1% acetic acid as mobile phase. The detection wavelength was 280 nm, flow rate was 0.8 mL/min, and the column temperature was 30 degrees C. RESULTS: Catechin was the main component of barley seeds and its processed products. Slight reduction of catechin was observed in processed and sprouting seeds. Sprouting significantly increased the content of myricetin. Both barley seeds and the processed products were lack of quercetin. The amounts of kaempferol in seed were higher than that in barley grain, but similar to that in ustulate malt. CONCLUSION: The content of flavonoids in raw malt and torrefied malt are significantly affected by sprouting and processing, and significance differences are presented among different varieties. PMID- 23627083 TI - [RP-HPLC fingerprint of milk Stellera chamaejasme]. AB - OBJECTIVE: To establish a RP-HPLC fingerprint of milk Stellera chamaejasme. METHODS: The gradient elution mode was applied in chromatographic separation, and data were analysed by "Computer Aided Similarity Evaluation" software to compare the quality of milk Stellera chamaejasme samples from different habitats. RESULTS: Samples from different habitats were of high similarity, and analysied milk Stellera chamaejasme chromone and E15 in the atlas. CONCLUSION: The method is repeatable, and can be used in quality assessment of milk Stellera chamaejasme. PMID- 23627084 TI - [Species differentiation and quality assessment of Ziziphus jujuba var. spinosa based on the HPLC fingerprint and quantitative analysis]. AB - OBJECTIVE: To establish an HPLC method of a characteristical chemical fingerprint analysis in combination with simultaneous determination of four bioactive components for species differentiation and quality assessment of Ziziphus jujuba var. spinosa. METHODS: The chromatographic separation was performed on an Agilent TC-C18 BDS (250 mm x 4.6 mm, 5 microm) column. The mobile phase consisted of acetonitrile and water in a linear gradient elution procedure. The evaporator tube temperature of ELSD was set at 110.5 degrees C with the nebulizing gas flow rate of 3.1 mL/min and the flow rate of mobile phase was 1.0 mL/min. The column was maintained at 30 degrees C. The injection volume was 20 microL. RESULTS: HPLC methodology for both chemical fingerprint analysis and quantitative determination of four active ingredients were validated, respectively. According to the contents of the four ingredients and the chemical fingerprints of Ziziphus jujuba var. spinosa using principal component analysis, Ziziphus jujuba var. spinosa was different from the fake derived from the seeds of Ziziphus mauritiana. CONCLUSION: The developed HPLC method is exclusive and repetitive for the species identification and quality evaluation of Ziziphus jujuba var. spinosa. PMID- 23627085 TI - [Identification characters of leaf morphological and venation pattern of Houttuynia cordata with its confused herb Gymnotheca chinensis]. AB - OBJECTIVE: To study the identification characters of Houttuynia cordata and its confused herb Gymnotheca chinensis and establish an identification method. METHODS: LMVP (leaf morphological-venation pattern for identification Chinese herbs), and QAERM (quantitatively analyze and evaluate reliability for the method of identification Chinese herbs) were applied for the study. RESULTS: Both venations were brochidodromous-acrodromous and arising from the mid-petiole or the upper section of petiole. The main characteristic of the leaf of Houttuynia cordata: surface with small gray-white stoma protuberances; Ligulate process of stipule-petiole sheath were clear; Primary veins 7 or 5; The innermost pair of primary vein closed up the top of the sinus at blade base or above sinus, and the section of closed vein was straight; Emitted a smell of fish when fresh leaf was kneaded into pieces. The main feature of the leaf of Gymnotheca chinensis: no small gray-white stoma protuberances; Ligulate process of stipule-petiole sheath were not clear; Primary veins 5; The innermost pair of primary vein closed into the sinus at blade base, and the section of closed vein was slightly curve; No smell of fish. With the mentioned key differences, the both plants could be successfully identified from each other. The accuracy of identification results (AC) was 100%, the repeatability of identification results: agreement rate for observation (ARO) was 100% and Kappa value was 1.00. CONCLUSION: The established method is simple, rapid, economic and reliable. PMID- 23627086 TI - [Study on the chemical constituents of Elephantopus mollis]. AB - OBJECTIVE: To investigate the chemical constituents of Elephantopus mollis. METHODS: Compounds were separated and purified by various column chromatographies including macroporous resin, ODS, Sephadex LH-20 and silica gel columns. The structures were identified by their physicochemical properties and spectroscopic data. RESULTS: Nine compounds were identified as 2beta-deethoxy-2 hydroxyphantomolin (1), 2beta-methoxy-2-deethoxyphantomolin (2), 2beta-methoxy-2 deethoxy-8-O-deacylphantomolin-8-O-tigli-nate (3), molephantinin (4), betulinic acid (5), magnolol (6), honokiol (7), dibutly phthalate (8) and tricin (9). CONCLUSION: Compounds 5-9 are isolated from this plant for the first time. PMID- 23627087 TI - [Study on the chemical constituents in Pouzolzia zeylanica]. AB - OBJECTIVE: To study the chemical constituents of Pouzolzia zeylanica. METHODS: Many chromatography means were used in separation and purification, and the structures of all compounds were identified by the means of spectroscopic analysis and physicochemical properties. RESULTS: 14 compounds were elucidated as: beta-sitosterol (1), daucosterol (2), oleanolic acid (3), epicatechin (4), alpha-amyrin (5), eugenyl-beta-rutinoside (6), 2alpha, 3alpha, 19alpha trihydroxyurs-12-en-28-oic (7), scopolin (8), scutellarein-7-O-alpha-L-rhamnoside (9), scopoletin (10), quercetin (11), quercetin-3-O-beta-D-glucoside (12), apigenin (13), 2alpha-hydroxyursolic acid (14). CONCLUSION: All compounds are obtained from this plant for the first time. PMID- 23627088 TI - [Study on the chemical constituents from the leaf of Hydnocarpus hainanensis]. AB - OBJECTIVE: To study the chemical constituents from the leaf of Hydnocarpus hainanensis. METHODS: Compounds were isolated and purified by silica gel and Sephadex LH-20 column chromatography, their structures were identified by spectroscopic analysis. RESULTS: Nine compounds were isolated and identified as glutinol (I), fernenol (II), lupeol (III), a-armyrin (IV), 2, 9-dimethyldeca-2, 8 diene (V), phytenal (VI), phytol (VII), 3, 7, 11,15-tetramethylhexadecane-1,2 diol ( VI), 3, 5-dimethoxy-4-hydroxybenzaldehyde (IX). CONCLUSION: All the compounds are isolated from this plant for the first time. PMID- 23627089 TI - [Study on the coumarin glucosides of Angelica dahurica]. AB - OBJECTIVE: To study the coumarin glucosides of Angelica dahurica. METHODS: Fresh roots and rhizomes of Angelica dahurica were extracted with ethanol at room temperature. Repeated column chromatography and preparative HPLC were used to isolate and purify the compounds. Their structures were elucidated on the basis of chemical evidence and spectral analysis. RESULTS: Twenty-six coumarin glucosides were isolated from Angelica dahurica, while here we reported 7 of them: sec.-O-beta-D-Galactopyranosyl-(R)-byakangelicin (I);8-O-beta-D Galactopyranosyl-xanthotoxol (II); 7-O-beta-D-Apiofuranosyl-(1-->6)-beta-D Glucopyranosyl-peucedanol (III); (R)-peucedanol-7-O-beta-D-Glucopyranoside (IV); sec.-O-beta-D-Glucopyranosyl-(R)-Oxypeucedaninhydrate (V); 7-O-beta-D Galactopyranosyl-Sco-poletin( VI); Aesculin (VII). CONCLUSION: Compound V is a new compound, Compound VII is isolated from Umbellifera for the first time, compounds III, IV are isolated from Angelica for the first time,while compound I, II and VI are isolated from this plant for the first time. PMID- 23627090 TI - [Chemical constituents of Dipsacus asper]. AB - OBJECTIVE: To study the chemical constituents of Dipsacus asper. METHODS: Column chromatography on Silica gel and RP-C18 were applied for isolation and purification of the constituents. Their structures were identified by spectral and chemical methods. RESULTS: From the crude MeOH fraction of Dipsacus asper, 12 compounds were isolated and identified as Sucrose (1), beta-sitosterol (2), Oleanic acid (3), Triplostoside A (4), Loganin (5), Loganin acid (6), Sweroside (7), Epi-vogeloside ( 8), Vogeloside (9), Akebiasaponin D(10), Cauloside A(11),7 Deoxyloganic acid (12). CONCLUSION: Compounds 8, 9, 12 are isolated from this plant for the first time. PMID- 23627091 TI - [Study on the chemical constituents of Lonicera similes]. AB - OBJECTIVE: To study the chemical constituents of flower buds of Lonicera similes. METHODS: The chemical constituents were isolated and purified with macroporous resin, silica gel column chromatography, gel chromatography, ect. The structures were elucidated according to the references combined with the application of spectrum techniques such as 1H-NMR, 13C-NMR ect. RESULTS: Nine compounds were isolated and their structures were identified as 5-hydroxyl-7,4'-dimethoxyflavone (I), rutin (II), quercetin (III), amentoflavone (IV), aesculetin (V), beta sitosterol (VI), 5-hydroxyl-7,3', 4'-trimethoxyflavone (VIII), oleanolic acid (VIII), beta-daucosterin (IX). CONCLUSION: Among the nine isolated compounds, compounds I, II, III, IV, V, are flavonoids. Compounds I , IV, V, VII, VIII, IX are isolated from this plant for the first time. PMID- 23627092 TI - [Study on chemical constituents of root bark of Discocleidion rufescens]. AB - OBJECTIVE: To study the chemical constituents from root bark of Discocleidion rufescens. METHODS: Column chromatography and spectral analysis were used to isolate and identify the constituents. RESULTS: Ten compounds were obtained and identified from root bark of Discocleidion rufescens including beta-sitosterol (I), scopoletin (II), daucosterol (III), ricinine (IV), chrysophanol (V), aphyscion (VI), taraxerol (VII), pigenin (VIII), luteolin (IX), gallic acid (X). CONCLUSION: Ten compounds are isolated for the first time from root bark of Discocleidion rufescens. The monomer of Compounds II is isolated from this genus for the first time. PMID- 23627093 TI - [Research the extraction and detection method of gastrodin content in Gastrodia elata]. AB - OBJECTIVE: To improve an extraction and determination method for gastrodin in Gastrodia elata. METHODS: On the basis of single factor experiment, used the method of hot water reflux extraction and applied the response surface methodology to determine the best conditions for extracting gastrodin and using HPLC test. RESULTS: Under the boiling water condition, pure water as solvent, the solid-liquid ratio was 1:37,extraction 2 times and extraction time 126 min per times,the content of gastrodin was 0.377%. Comparison with the 2010 edition of the China pharmacopoeia of gastrodin extracted in Gastrodia elata, the result showed the gastrodin content was increased by 2. 12 times. CONCLUSION: This extraction method of gastrodin dissolution rate is high and can reflect the real content of gastrodin of Gastrodia elata. PMID- 23627094 TI - [The effect of PNS on the content and activity of alpha-secretase in the brains of SAMP8 mice with alzheimer's disease]. AB - OBJECTIVE: To explore the effects of PNS on the content and activity of alpha secretase in the brains of SAMP8 mice with Alzheimer's disease. METHODS: SAMP8 mice were randomly divided into four groups: PNS high-dosage group, PNS low dosage group, huperzine A group and control group. The high-dosage group and low dosage group were treated with 200 and 100 mg/kg PNS respectively per day and the huperzine A group was treated with 0.3 mg/kg huperzine A per day, all by intragastric administration for 8 consecutive weeks. The same volume of double distilled water was given to the control group. The activity of a-secretase was assayed by direct immunofluorescent method(DIF). Western blot was used to detect the content of alpha-secretase including ADAM9, ADAM10 and ADAM17 proteins. RESULTS: The Relative Fluorescence Units (RFU) of PNS high-dosage and low-dosage groups were higher than that of control group (P < 0.01). The results of western blot showed that the level of ADAM9 protein expression in PNS high-dosage, low dosage and huperzine A groups was significantly higher than that of control group (P < 0.05) while the levels of ADAM10 protein expression in PNS high-dosage, low dosage and huperzine A groups was significantly lower than that of control group (P < 0.05), while level of ADAM17 of huperzine A group was higher than that of control group (P < 0.05). CONCLUSION: PNS can increase activity of alpha secretase in the brain of SAMP8 mouse via increasing the level of ADAM9 protein expression. PMID- 23627095 TI - [Effect of Huangqi gegen decoction (HGD) on TGF-beta1/Smad3 pathway in diabetic cardiomyopathy rats]. AB - OBJECTIVE: To study the effect of HGD on diabetic cardiomyopathy and its mechanism. METHODS: The T2-DM rats model was established by combining high fat diet with STZ. The blood glucose, insulin, myocardial fibrosis and TGF beta1/Smad3 signaling pathway were observed; TGF-beta1 and Smad3 mRNA expression were detected by RT-PCR method, protein expression detected by immunohistochemical method. RESULTS: HGD obviously reduced fasting blood glucose, insulin, improved insulin resistance, reduced myocardial hydroxyproline contents, lowered cardiac index, significantly inhibited over-expression of TGF-beta1/SMAD3 mRNA and protein in diabetic rats cardiac. CONCLUSION: HGD can obviously prevent experimental diabetic myocardial fibrosis through the regulation effect on TGFbeta1/Smad3 signaling pathway. PMID- 23627096 TI - [The inhibition effect of protocatechuic acid on the mRNA expression of APP on M146L cell]. AB - OBJECTIVE: To investigate the effect of protocatechuic acid on the mRNA expression of APP in double transfected (human APP gene and presenlin-1 gene) Chinese hamster ovary (CHO) cells (M146L). METHODS: Abeta42 overexpressing cell model was established in vitro by culturing Chinese hamster ovary cells stably expressing amyloid beta-protein precursor and mutant presenilin (M146L). The MTT assay was used to test cytotoxicity of protocatechuic acid, and reverse transcription polymerase chain reaction (RT-PCR) was carried out to determine the mRNA expression level of APP. RESULTS: The MTT assay showed that protocatechuic acid at suitable concentrations didn't have cytotoxicity on M146L cell survival. Protocatechuic acid at the concentration of 0.25 mmol/L, 0.5 mmol/L and 1.0 mmol/L significantly inhibited the mRNA expression of APP. CONCLUSION: The study suggests that the suitable dose of protocatechuic acid could inhibit the mRNA expression of APP in M146L cell,and its mechanism needs further study. PMID- 23627097 TI - [Effect of subchronic realgar exposure on Glu and Gln in infant rat brain]. AB - OBJECTIVE: To study the effect of realgar on Glu and Gln on rat brain tissues. METHODS: Forty-eight Wistar rats were divided into 4 groups randomly:control group,low dosage group, moderate dosage group and high dosage group. The treatment groups were treated with realgar by gastric perfusion at a dosage of 0.3 g/kg, 0.9 g/kg, 2.7 g/kg and the control group ones were orally given the same volume of 0.5% sodium carboxymethylcellulose (CMC-Na) for 6 weeks. The contents of inorganic arsenic, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in brain tissues were measured by hydride generation-atomic absorption (HG-AAS) method. The contents of amino acid neurotransmitters in brain tissues of rats were determined by means of high performance liquid chromatography with precolumn derivatization. RESULTS: The levels of MMA and DMA in brain increased as the dosage of realgar increased, while the second methylation index declined. Compared with control group,the levels of Glu was significantly decreased in realgar treated group (P < 0.05); Gln also tended to decrease and that of low dosage group was obviously decreased compared with controls. CONCLUSION: Realgar exposure can cause accumulation of MMA and DMA,declination of second methylation index and the reduction of Glu and Gln in brain tissue. PMID- 23627098 TI - [Effects of drug serum of plantaginis semen on bone formation function of rat osteoblast in vitro]. AB - OBJECTIVE: To study the influence of Plantaginis Semen on cell proliferation, differentiation and function of rat osteoblasts, and investigate the regulation effects of rat osteoblast epithelial sodium channel (ENaC) on bone formation. METHODS: The animal serum was prepared by serum pharmacology means. The cells were got by separating and inducing the SD neonatal rat's skull bone. Cell proliferation and differentiation were evaluated by CCK-8 assay kit and AKP assay kit respectively. Regulation effects on mRNA expression of ENaC and osteogenesis gene were investigated by semi-quantitative PCR. RESULTS: Plantaginis Semen stimulated the osteoblasts proliferation and differentiation,the difference between treatment group and control group had statistical significance (P < 0.01) in a dose-dependent manner. The effects of Plantaginis Semen serum on alpha-ENaC gene expression paralleled those on osteogenic gene (OC, ALP, OP) expression level. CONCLUSION: Plantaginis Semen stimulates proliferation, differentiation and the mRNA expression of ENaC and osteogenesis gene in rat osteoblasts. Our results suggest that ENaC participate in the effects of Plantaginis Semen serum on osteoblast bone formation. Regulation of ENaC channel expression and function may provide a new clue for research on treatment of osteoporosis with traditional Chinese medicine. PMID- 23627099 TI - [The application of cation exchange resins in the separation of total flavonoids and alkaloids from seed embryo of Nelumbo nucifera]. AB - OBJECTIVE: To explore the optimal separation condition of the total flavonoids and alkaloids from seed embryo of Nelumbo nucifera. METHODS: Types of cation exchange resins, concentration of extract liquid, solution volume, velocity of adsorption and eluent were evaluated in separating efficiency with measuring the adsorption ratio and eluent ratio. RESULTS: D152 resin was finally chosen. After enrichment and purification with it, the purity of flavonoids and alkaloids were significantly increased by 27.08 and 7.86 times, respectively. CONCLUSION: This method is simple, feasible and suitable for the separation of total flavonoids and alkaloids from seed embryo of Nelumbo nucifera. PMID- 23627100 TI - [Study on nano-CaCO3 applicated in Xin Yue Shu Capsules preliminarily]. AB - OBJECTIVE: To investigate the characteristics of nano-CaCO3 applicated in Xin Yue Shu Capsules. METHODS: Studied the effect of different dosages of aerosil or nano CaCO3 on fluidity, bulk density, moisture absorption of Xin Yue Shu capsules spray drying powder. In vitro dissolution and ferulic acid stability of Xin Yue Shu capsules was observed. RESULTS: It significantly improved powder fluidity and bulk density of Xin Yue Shu spray drying powder when aerosil or nano-CaCO3 was added. But there was no significant effect on powder moisture absorption, ferulic acid in vitro dissolution and ferulic acid stability. CONCLUSION: The effect of Nano-CaCO3 on improving powder fluidity and bulk density applicated in the spray drying powder of traditional Chinese medicine deserves studying further. PMID- 23627101 TI - [Technical study of vinpocetine micelles prepared by thin-film hydration method]. AB - OBJECTIVE: To prepare PEG-PLA polymeric micelles loaded with vinpocetine (VP). METHODS: VP micelles were prepared by thin-film hydration method, single factors affecting drug loading content, encapsulation efficiency, productivity, particle size and polydispersity index (PDI) such as dosage, type of organic solvent, quantity of organic solvent, hydration temperature, hydration speed, amount of hydration water, hydration time were investigated, and the optimum technology was obtained. The mean particle size and PDI were determined by DLS. The drug loading content, encapsulation efficiency, productivity of VP micelles were investigated by UV. RESULTS: The drug loading content and particle size of VP micelles were 20.35% and 118.3 nm, respectively. CONCLUSION: The technology of VP micelles prepared by thin-film hydration method is practical and simple. It's valuable to be further studied. PMID- 23627102 TI - [HPLC fingerprint of compound xueshuantong capsule]. AB - OBJECTIVE: To establish the HPLC fingerprint of Compound Xueshuantong Capsule. METHODS: Dionex Acclaim 120 C18 column (4.6 mm x 150 mm, 3 microm) was used with acetonitrile (A) and 0.05% phosphoric acid (B) in gradient elution mode. The elution profile was:0-50 min (15%-->34% A), 50-95 min (34%-->75% A); The detective wavelength was 203 nm and 270 nm. The column temperature was set at 25 degrees C and the flow rate was 1.0 mL/min. RESULTS: In the established fingerprint,42 common peaks covering 4 medicinal materials were detected, and 23 chemical compounds were identified by RRLC/MS/MS and DAD spetra. CONCLUSION: The method can be used for quality control of Compound Xueshuantong Capsule with great precision, accuracy and good reproducibility. PMID- 23627103 TI - [Kdo2-lipid A modification in gram-negative bacteria--a review]. AB - In most Gram-negative bacteria, the Kdo2-lipid A moiety of lipopolysaccharide forms the outer monolayer of the outer membrane. Diverse covalent modifications of Kdo2-lipid A may occur in bacteria to survive different environmental conditions. Kdo2-lipid A is usually synthesized on the cytoplasmic surface of the inner membrane. After the core oligosaccharide is attached to Kdo2-lipid A, the molecule is flipped to the outer surface of the inner membrane, where the O antigen repeats are attached to form lipopolysaccharide. Kdo2-lipid A could activate the innate immune system through TLR4. Therefore, researches on the structure modification of Kdo2-lipid A would be useful for developing new vaccines and adjuvants. PMID- 23627104 TI - [Effect of retS gene on biosynthesis of 2, 4-diacetyl-phloroglucinol in Pseudomonas fluorescens 2P24]. AB - Regulator of exopolysaccharide and type III secretion (RetS) is a hybrid sensor kinase/response regulator protein located on bacterial membrane, and essential for expression of numerous genes. In Pseudomonas aeruginosa, RetS modulates the phosphorylation state of another kinase GacS via a direct interaction. OBJECTIVE: The goal of this study is to study the effect of retS on the antibiotic 2,4 diacetyl-phloroglucinol (2,4-DAPG) production in P. fluorescens 2P24. METHODS: Production of 2,4-DAPG in strain 2P24 and its mutants was quantified by HPLC. To determine the effect of RetS on the Gac/Rsm pathway, the promoters of the small RNA genes rsmX/rsmY/rsmZ and regulatory genes rsmA/rsmE in the Rsm pathway were fused with a promoterless lacZ, and the promoter activities were measured in 2P24 and the retS-deficient mutants. RESULTS: Genetic inactivation of the retS in strain 2P24 increased the production of an uncharacterized red pigment and the antibiotic 2,4-DAPG. RetS negatively regulated the transcription of the small RNAs RsmX and RsmZ. In the retS and gacS double mutant or the retS and gacA double mutant, all the phenotypic changes caused by the retS deletion were reversed to the level of gacS or gacA single gene mutant. CONCLUSION: In P. fluorescens 2P24, RetS negatively regulates the production of antibiotic 2,4-DAPG through the Gac/Rsm pathway. PMID- 23627105 TI - [Positive regulation in expression of the phenazine-producing operon phz2 mediated by pip in Pseudomonas aeruginosa PAO1]. AB - Pseudomonas aeruginosa PAO1, an opportunistic pathogenic bacterium, produces phenazine and its derivatives which play a critical role in pathogen-host interaction during its infection. In a biological control strain P. chlororaphis PCL1391, Pip positively regulates PCN production. OBJECTIVE: Our aim is to identify the function and regulation of an ORF of PA0243 (the homolog of Pip) in Pseudomonas aeruginosa PAO1. METHODS: We first cloned the fragment of the pip gene from the chromosomal DNA of P. aeruginosa PAO1 and constructed the pip defect mutant PA-PG with the insertion of gentamycin resistance cassette (aacC1). With construction and introduction of pME10P (containing the whole pip gene region) , complementation of the pip was then carried out. With creation of the mutants PA-PD-Z1G and PA-PG-Z2K, phenazine-1-carboxylic acid and pyocyanin were measured in GA medium in relative mutants, respectively. RESULTS: In GA medium, production of phenazine-1-carboxylic acid and pyocyanin in the mutant PA-PG decreased dramatically in comparison with that produced in the wild type strain PAO1. The amounts of phenazine-1-carboxylic acid and pyocyanin, however, were recovered with complementation of the derivative PA-PG bearing pME10P. The production of phenazine-1-carboxylic acid and pyocyanin in mutant PA-PG-Z2K were same to those in parental strain PA-Z2K. Phenazine-1-carboxylic acid and pyocyanin produced by the mutant PA-PD-Z1G were lower than those in the original strain PA-Z1G. CONCLUSION: With these results, it is suggested that Pip exerts positively regulation in phenazine biosynthesis by specifically modulating expression of the phz2 operon, not by mediating expression of the phzl operon in P. aeruginosa PAO1. PMID- 23627106 TI - [Superoxide dismutase, malondialdehyde and proline as new quality criteria for Schizochytrium sp. fermentation]. AB - OBJECTIVE: The aim of our study was to find a novel method to evaluate the strain quality of Schizochytrium sp. HX-308. METHODS: An acclimatized strain and an original strain were cultivated under normal condition. Meanwhile, the same acclimatized strain was cultured under two different conditions, the optimum condition and the harsh condition. We detected the activity of superoxide dismutase and the contents of malondialdehyde and proline by WST-1 method, thiobarbituric acid test and colorimetry, respectively. The relationship between the three criteria and the fermentation performance of Schizochytrium sp. HX-308 was studied. RESULTS: The acclimatized strain cultured under the optimal fermentation condition had the lowest superoxide dismutase activity (0.025 U/g protein), malondialdehyde (26.20 mmol/g x Fw) and proline contents (0.098 mg/g x Fw). In contrast, the superoxide dismutase activity of the original strain cultured in the harsh conditions was 5 times higher than that of the acclimatized strain, the malondialdehyde and proline contents were both 2 times as high as the acclimatized strain. CONCLUSION: The three criteria were correlated negatively with the fermentation performance. Thus, they could be used to evaluate quality and fermentation performance of Schizochytrium sp. PMID- 23627107 TI - [Expression and secretion regulation of Bacillus naganoensis pullulanase in recombinant Escherichia coli]. AB - OBJECTIVE: To increase extracellular productivityof pullulanase, pullulanase gene from Bacillus naganoensis JNB-1 was expressed in recombinant Escherichia coli, followed by optimizing induction conditions and applying chemical additives. METHODS: We amplified pullulanase gene pul from B. naganoensis genome by PCR and constructed recombinant E. coli BL21/pET-20b-pul. Optimal induction conditions and additive parameters of glycine and Na+ were determined by measuring the extracellular pullulanase activity. RESULTS: Pullulanase was expressed in E. coli with the molecular weight of 119 kDa. Under optimal induction conditions, i. e. induction was initiated with 0.4 mmol/L isopropyl beta-D-1-Thiogalactopyranoside (IPTG) at 20 degrees C when OD600 of bacteria culture reached 1.2, total pullulanase activity including intracellular and extracellular enzyme reached 10.8 U/mL. Addition of glycine and Na+ enhanced the secretion of pullulanase. With the supplementation of 0.08 mol/L glycine and 0.2 mol/L Na+, extracellular pullulanase activity was increased up to 8.1 U/mL, 10.3 times of that without additives. CONCLUSION: A promising resource of pullulanase was achieved by construction of recombinant E. coli for industrial production of pullulanase, and additionally the efficient regulation method with chemical additives was developed for pullulanase secretion, which would also be useful for high-level extracellular production of recombinant enzymes. PMID- 23627108 TI - [Quantitative proteomic analysis of streptomycin resistant and sensitive clinical isolates of Mycobacterium tuberculosis]. AB - OBJECTIVE: To identify specific antigens related to streptomycin resistant (SMr) Mycobacterium tuberculosis. METHODS: Cellular proteins were extracted from SMr clinical isolate 01108, SM-sensitive clinical isolate 01105 and H37Rv. Differential expression proteins were identified with isobaric tags for relative and absolute quantitation (iTRAQ) combined with Nano LC-MS/MS technology. RESULTS: Approximately 194 and 146 differential expression proteins were identified in 01108 strain compared with the proteomic profiles of 01105 strain and H37Rv, respectively, and 121 proteins were identified in 01108 strain compared with the proteomic profiles of both 01105 strain and H37Rv. Identified proteins showed a pI (isoelectric point) variation between 3.74-12.48 and a molecular mass (M) range between 7.63 and 326.2 kDa. Differential expression proteins were mainly associated with metabolism (involved in intermediary metabolism, respiration, and lipid metabolism) and took part in catalysis and binding function. Seven ribosomal proteins (Rv0056, Rv0641, Rv0652, Rv0701, Rv1630, Rv2442c and Rv2785c) and seven proteins (the ratios > 1.20 or < 0.55) were commonly down-regulated in 01108 strain compared with both 01105 strain and H37Rv, i. e. the thiol peroxidase (Rv1932), acyl carrier protein dehydrogenase (Rv0824c), 30S ribosomal protein S15 (Rv2785c), acetone acid dehydrogenase E2 part (Rv2215), two-component transcriptional regulatory protein (Rv3133c) and Hypothetical protein (Rv2466e and Rv2626c). CONCLUSION: Differential expression proteins were found in SMr strain compared with both SM-sensitive strain and H37Rv. Further studies are needed to assess the role of these differential expression proteins in SM resistance. PMID- 23627109 TI - [Phylogenetic and physiological diversity of cold-adapted bacteria producing protease from sediments of the bottom layer of the glacier no. 1 in the Tianshan mountains]. AB - OBJECTIVE: We characterized proteolytic bacteria isolates from sediments of the bottom layer of the Glacier No. 1 in the Tianshan Mountains, China. Physiological test and phylogenetic analysis were undertaken to expand our knowledge on diversity and ecological distribution of psycrotrophic and psycrophlic bacteria populations. METHODS: Using the screening media containing skim milk, we screened cold-adapted strains producing protease. Taxonomic identity and genetic variability of strains isolated was determined by partial 16S rRNA gene sequences and repetitive-element PCR fingerprint. RESULTS: Of the total 125 cold-adapted bacterial isolates, high levels of protease activity were observed from 27 isolates at optimal growth temperatures ranging from 15 to 24 degrees C in plate assay. Among 27 protease-producing strains, only 6 isolates were psychrophilic. The 16S rRNA gene phylogenetic analysis revealed that protease-producing isolates belonged to 5 phyum, namely alpha, beta and gamma of Proteobacteria, Actinobacteria and Cytophaga-Flexibacter-Bacteroides. They are affiliated to the genera Pseudomonas, Polaromonas, Brevundimonas, Rholococces, Cryobacterium, Kocuria, Arthrobacter, Chryseobacterium and Flavobacterium. The populations of the predominant cultivated protease-producing bacteria are the Pseudomonas spp. (40.7%). CONCLUSION: The results enriched our knowledge on the phylogenetic and physiological diversity of cold-adapted strains producing protease in cold environments. PMID- 23627110 TI - [Next generation sequencing and stable isotope probing of active microorganisms responsible for aerobic methane oxidation in red paddy soils]. AB - OBJECTIVE: This study is aimed to establish an unbiased profiling strategy for investigating the microorganisms responsible for aerobic methane oxidation by pyrosequencing the total soil microbial communities at DNA and RNA levels, and to link aerobic methane oxidation activity with taxonomic identity of active microorganisms by DNA/RNA SIP in red paddy soils. METHODS: Three red paddy soils derived from quaternary red clay were collected from Gushi and Taoyuan cities of Hunan province and Leizhou city of Guangdong province, were incubated with the labeled 13CH4 or 12CH4 for determination of aerobic methane oxidation kinetics. Pyrosequencing of the 16S rRNA andl6S rRNA gene at the whole microbial community levels were performed over the course of aerobic methane oxidation in soil microcosms. 13C-DNA and 13C-RNA were obtained through ultracentrifugation of the total soil DNA and RNA extracts, respectively. Clone library of pmoA genes in 13C DNA and 16S rRNA genes in 13C-RNA were constructed. RESULTS: Pyrosequencing of the total microbial communities revealed significant increase in the relative abundance of aerobic methanotrophs in soil microcosms upon the completion of aerobic methane consumption. The proportional increase of aerobic methanotrophs was significantly higher at RNA than DNA levels. Type I and II aerobic methanotrophs significantly increased in Gushi soil, while the significant increase of type II aerobic methanotrophs was observed in Taoyuan soil. In the meantime, type I aerobic methanotrophs appeared to be stimulated exclusively in Leizhou soil. Sequencing analysis of the 13C-labeled pmoA genes and 16S rRNA further demonstrate that phylogenetically distinct methanotrophs dominated aerobic methane oxidation activity in paddy soils of Gushi (Type I and II), Taoyuan (Type II) and Leizhou (Type I). CONCLUSION: High-throughput pyrosequencing at the whole community level of 16S rRNA genes provides an almost unbiased profiling stragety for measuring characteristic changes in relative proportions of aerobic methanotrophs responsible for aerobic methane oxidation activity in red paddy soils, and higher sensitivity was observed at RNA than DNA levels. DNA/RNA-SIP can accurately reveal the active microorganisms responsible for aerobic methane oxidation in read soil, being largely consistent to pyrosequencing-based fingerprinting analysis of the total microbial communities. PMID- 23627111 TI - [Bacterial diversity within different sections of summer sea-ice samples from the Prydz Bay, Antarctica]. AB - OBJECTIVE: In order to assess bacterial abundance and diversity within three different sections of summer sea-ice samples collected from the Prydz Bay, Antarctica. METHODS: Fluorescence in situ hybridization was applied to determine the proportions of Bacteria in sea-ice. Bacterial community composition within sea ice was analyzed by 16S rRNA gene clone library construction. Correlation analysis was performed between the physicochemical parameters and the bacterial diversity and abundance within sea ice. RESULTS: The result of fluorescence in situ hybridization shows that bacteria were abundant in the bottom section, and the concentration of total organic carbon, total organic nitrogen and phosphate may be the main factors for bacterial abundance. In bacterial 16S rRNA gene libraries of sea-ice, nearly complete 16S rRNA gene sequences were grouped into three distinct lineages of Bacteria (gamma-Proteobacteria, alpha-Proteobacteria and Bacteroidetes). Most clone sequences were related to cultured bacterial isolates from the marine environment, arctic and Antarctic sea-ice with high similarity. The member of Bacteroidetes was not detected in the bottom section of sea-ice. The bacterial communities within sea-ice were little heterogeneous at the genus-level between different sections, and the concentration of NH4+ may cause this distribution. CONCLUSION: The number of bacteria was abundant in the bottom section of sea-ice. Gamma-proteobacteria was the dominant bacterial lineage in sea-ice. PMID- 23627112 TI - [Metagenomics-based detection of swine viruses]. AB - Extreme varieties of viruses exist in the environment and animals, some of which are unknown. However, many unknown viruses are barely detected by means of conventional virus isolation and PCR assay. OBJECTIVE: To develop a technology platform for detecting unknown viruses. METHODS: We established the technology based on viral metagenomics in combination with novel molecular diagnostics. The technology is consisted of removal of host nucleic acid, random PCR amplification, large-scale sequencing, and bioinformatics. RESULTS: The technology was applied to detect classical swine fever virus (CSFV)-infected cells and a tissue sample of a pig infected with porcine circovirus type 2 (PCV2). We amplified 13.7% sequences of CSFV genome and 47.2% those of PCV2 genome, respectively. Moreover, we amplified 16.4% sequences of the simian parainfluenza virus type 5 genome from an unknown virus cell culture using the developed method. In addition, using the developed method combined with the high throughput sequencing, we detected 1.1% virus sequences, including CSFV, PCV2, torque teno sus virus (TTSuV), porcine bocavirus (PBoV) and human adenovirus type 6 (Ad6) from 7 clinical swine samples of unknown causative agents. CONCLUSION: The developed metagenomics-based method showed good sensitivity for detection of both DNA and RNA viruses from diverse swine samples, and has potential for universal detection of known and unknown viruses. It might facilitate the diagnosis of emerging viral diseases. PMID- 23627113 TI - [Mutagenesis of cysteine residues in dptC from Salmonella enteric serovar Cerro 87 and its effects on DNA phosphorothioate modification]. AB - OBJECTIVE: DNA phosphorothioate modification (DNA sulfur modification, a non bridging oxygen swapped with a sulfur) exists in diverse bacteria. Salmonella enterica serovar Cerro 87 is one of the bacteria that harbor the DNA sulfur modification. The modification is carried out by the products of a four-membered gene cluster, dptBCDE. Transformation of Escherichia coli DH10B with the dptBCDE gene cluster endows the strain with DNA sulfur modification capability. Deletion of dptC abolished the modification. Here, we studied the function of dptC in DNA sulfur modification. METHODS: Six cysteine residues in dptC were mutated individually within the dptBCDE gene cluster. Mutants were then tested for DNA sulfur modification. RESULTS: Among the 6 cysteine mutations (C39, C146, C262, C273, C280, and C283), 5 abolished DNA modification except for C39, suggesting that C146, C262, C273, C280, and C283 are essential for DNA sulfur modification. Sequence alignment shows that these five cysteine residues are conserved among different strains. CONCLUSION: Mutation at anyone of C146, C262, C273, C280 and C283 of dptC abolished DNA modification. Our results shed light on further study of DNA sulfur modification biochemical pathway. PMID- 23627114 TI - [Characterization of daptomycin-resistance in environmental actinomycetes]. AB - OBJECTIVE: Daptomycin-resistance in environmental actinomycetes was studied to provide warning systems for emerging clinical resistance. METHODS: In total 49 soil and 10 endophytic acitnomycetes were used in this study. The daptomycin resistant strains were identified by measuring daptomycin resistance profile. Subsequently, daptomycin inactivating assay was preformed to distinguish resistance from other nondestructive mechanisms. Then, the strains of interest were determined by morphology and 16S rRNA gene sequence analysis. Finally, PCR analysis was used to detect the daptomycin acylase gene (dpa) encoding daptomycin acylase in those strains. RESULTS: All strains tested in this study were resistant towards daptomycin. Of them 24 soil acitnomycetes and 4 endophytic actinomycetes had the ability to inactivate daptomycin, while the remaining strains used other measures to confer resistance. Sequence analysis demonstrated that strains inactivating daptomycin were Streptomyces, Micromonospora and Norcadia. PCR analysis shows that 17.9% strains contained the dpa. CONCLUSION: There is very high percentage of resistance in environmental actinomycetes and inactivating daptomycin is one of the main resistant mechanisms. PMID- 23627115 TI - [Comparative study of growth potential on hardwood cutting of Lycium barbarum strains]. AB - OBJECTIVE: To lay foundation of strains selection through primary selection of 44 strains of Lycium barbarum. METHODS: Used the single plant selection. RESULTS: Screened out 22 strains of Lycium barbarum by preliminary determination of germination rates and seeding rates of hardwood cutting, the growth potential of 2009-26, 2009-21, 2009-17, 2009-29, 2009-2 were better than those of others strains. CONCLUSION: 2009-26 has better growth potential except the length of root, the result provides a basis for further screening can focus on research for 2009-26. PMID- 23627116 TI - [Study on the pollen viability and stigma receptivity of Chrysanthemum morifolium 'Fubaiju']. AB - OBJECTIVE: To study the blooming habits, pollen viability and stigma receptivity of Chrysanthemum morifolium and provide theoretical basis for its breeding. METHODS: Explored the blooming habits by dynamic observation on the process of blossom, evaluated the pollen viability by germination in vitro culture method and estimated stigma receptivity by benzidine-hydrogen peroxide method. RESULTS: About the pollen viability, there were no significant differences between the flowers which in the same round of the capitulum; Tubular flowers in the center of a capitulum were significantly higher than that on the edge; In the morning pollen vitality gradually raised, during 11: 00 - 14: 00 maintained the highest, and then gradually decreased; Tubular flower began to loose powder on the third day, during 4th - 6th day the pollen viability was highest, respectively was 35.12%, 39.89%, 38.12%, then gradually decreased, on the 15th day was only 7.41%, finally turned into wither. Regard to the stigma receptivity, the center of a capitulum were significantly higher than that on the edge, outer edge ligulate flower had no receptivity; Revealed the strongest during 13: 00 - 14:00 in one day; During the 5th - 7th day was the strongest after flowering. The regulation of the stigma secreted mucus existed great consistency with the stigma receptivity, namely the stigma receptivity usually was strong when it secreted large number mucus. CONCLUSION: Understand the blossom habits of Chrysanthemun morifolium, as well as the dynamic changes regulation of pollen viability and stigma receptivity during its blossom, which could be used to select the flowers in a capitulum which are on the more suitable period and position for artificial pollination and hybridization breeding research. PMID- 23627117 TI - [Relation between soil nutrient of artificially cultivated area and rhizome quality of Paris polyphylla var. yunnanensis]. AB - OBJECTIVE: To explore the relation between the quality of the Herb-Paris and their cultivation of soil nutritional status. METHODS: The soil nutrient status (0 - 30 cm) of Paris polyphylla var. yunnanensis, artificially cultivated areas were determined in 2009 and their rhizome qualities harvested in 2010 were evaluated respectively. Determination of 0 - 30cm depth soil ingredients status with soil conventional five nutritional analysis method of 29 artificial cultivation area, 9 Prefectures of Yunnan Province. RESULTS: Soil nutrient has effect on quality of Herb-Paris medicinal ingredients. CONCLUSION: The multiple linear stepwise regression analysis reveals that among a certain range, the steroidal saponin VII content is positively correlated with the content of soil organic matter and pH. Steroidal saponin H content is positively correlated with the content of soil organic matter, available P and pH. Steroidal saponin I is positively correlated with the content of available K, but negatively correlated with the content of available Herb-Paris, and steroidal saponin II is positively correlated with the content of soil organic matter and available K. PMID- 23627118 TI - [Research on the effect of Aconitum soongaricum and its processed products on AA rat]. AB - OBJECTIVE: To observe the effect of Aconitum soongaricum and its processed products on adjuvant arthritis (AA) rat and its mechanism. METHODS: Rats were radomly divided into normal group, model group, positive group, Aconitum soongaricum and its processed products (including Pharmacopoeia method, document method, Kazak method three processed products), which divided into high dose, middle dose, low dose groups (30.65, 15.32, 7.66 mg/kg); Except normal group, prepared AA rat model by using Freund's complete Adjuvant (FCA) for the rest groups; Each group was administered for 23 days after the rat model was established, observed rats ankle swelling degree and arthritis index. Determined content of interleukin-1beta (IL-1beta) and cortisol (Cort) in serum by ELISA method. RESULTS: (1) The swelling degree of model group was higher than that of normal group (P < 0.01). Compared with model group, the swelling degree and AI of Aconitum soongaricum and all of its processed products groups were lower (P < 0.01 or P < 0.05). (2) The content of IL-1beta and Cort in serum of model group was higher than that of normal group (P < 0.01). Compared with model group, the content of Cort in serum of positive group, Aconitum soongaricum groups (high dose, middle dose, low dose), its Pharmacopoeia method processed product groups (high dose, middle dose) and its document method processed product groups (high dose) were lower (P < 0.01); Compared with model group, the content of IL-1beta in serum of positive group, Aconitum soongaricum groups (high dose, middle dose, low dose), its Pharmacopoeia method processed product groups (high dose, middle dose, low dose) its document method processed product group (high dose) and its Kazak method processed product group (middle dose) were lower (P < 0.01 or P < 0.05). CONCLUSION: Aconitum soongaricum and all of its processed products groups are proved with anti-inflammatory effect, which possible mechanism would be restraining inflammation cell factor such as IL-1beta and Cort in serum of AA rat. PMID- 23627119 TI - [Research on the HPLC fingerprint of stir-baked rhizoma curcumae with vinegar]. AB - OBJECTIVE: To establish the HPLC fingerprint for stir-baked Rhizoma curcumae with vinegar. METHODS: Gradient elut was performed by the mobile phase consisted of acetonitrile-water. The detecting wave length was set at 216 nm. The computer aided similarity evaluation system was used for the similarity analysis of fingerprint. RESULTS: Fingerprints chromatograms were obtained which could be used for the evaluation of the stir-baked Rhizoma Curcumae with vinegar, 16 common peaks were confirmed in fingerprints chromatograms. CONCLUSION: The method is convenient and reliability which can be used for quality control of the stir baked Rhizoma Curcumae with vinegar and can provide the scientific foundation for the processing mechanism. PMID- 23627120 TI - [Study on the infrared fingerprint of Evodia rutaecarpa based on the methods of sequential analysis of dual-indexes]. AB - OBJECTIVE: To establish a method to identify the different origins of herba Evodia rutaecarpa by IR and provide a new technique for their identification and quality evaluation. METHODS: The herba materials were extracted by chloroform and absolute alcohol, the powder and the extracts of Evodia rutaecarpa were mixed and pelleted with KBr. The slides were detected within 4000 - 400 cm(-1) by FIR spectrophotometry. The Difference of samples was studied. RESULTS: The infrared spectrums of Evodia rutaecarpa extracted by chloroform were obviously different. CONCLUSION: The method can be used to identify and appraise the different origins of herba Evodia rutaecarpa. PMID- 23627121 TI - [Identification study of raw oyster and calcined ostreae concha]. AB - OBJECTIVE: To identify the differences in characteristics of raw oyster and oysters calcined under different temperatures. METHODS: Identified raw oyster, oysters calcined under different temperatures and calcium carbonate, calcium oxide by differential thermal analysis, infrared spectroscopy and X-ray diffraction analysis. RESULTS: Composition of calcined oysters was closer to calcium carbonate than raw oyster. CONCLUSION: The fingerprints are established and identify raw oyster and calcined oysters. PMID- 23627122 TI - [Chemical constituents of the fruits of Lycium ruthenicum]. AB - OBJECTIVE: To study the chemical constituents of the fruits of Lycium ruthenicum Murr.. METHODS: Isolation and purification were carried out on macroporous resin column, Sephadex LH-20 and HPLC. The structures of the compounds were identified by physicochemical properties and spectral analysis. RESULTS: Nine compounds were isolated and identified as N-mono-cinnamoyl-putrescine (1), petunidin-3-trans-p coumaroylrutinoside-5-glucoside (2), 4-(p-cumaroyl) -methyl-L-rhamnoside (3), p coumarinic acid (4), ferulic acid (5), rutin (6), quercetin (7), protocatechuric acid (8), malvidin (9). CONCLUSION: Compound 1 - 9 are obtained from Lycium ruthenicum for the first time. PMID- 23627123 TI - [Chemical constituents from Pleione bulbocodioides]. AB - OBJECTIVE: To study the chemical constituents of Pleione bulbocodioides. METHODS: The compounds were isolated by repeated column chromatography with silica gel, Sephadex LH-20 and ODS-HPLC. The structures were elucidated by analysis of spectroscopic data (1H-NMR, 13C-NMR). RESULTS: Nine compounds were isolated from the EtOAc extract in the rhizoma of Pleione bulbocodioides. Their structures were identified as amentoflavone(I), kayaflavone(II), gymconopin D(III), methyl(4-OH) phenylacetate (IV), p-hydroxy benzaldehyde(V), p-hydroxybenzcic acid (VI), 4 oxopentanoic acid (VII), p-dihydroxy benzene (VIII), gastrodine (IX). CONCLUSION: Compounds I - IX are isolated from this plant for the first time. PMID- 23627124 TI - [Study on chemical constituents from flowers of Ailanthus altissima]. AB - OBJECTIVE: To isolate and identify the chemical constituents from the flowers of Ailanthus altissima. METHODS: Macroporous adsorptive resins (DM130), Silica gel, Sephadex LH-20, ODS were employed for the isolation and purification of chemical constituents. The structures were identified on the basis of spectral data and physicochemical examination. RESULTS: Eight compounds were isolated and identified as follows: brevifolin (1), brevifolin carboxylic acid (2), methyl brevifolin carboxylate (3), ellagic acid (4), diethyl-2,2',3,3',4,4'- hexahydroxybiphenyl-6,6'-dicarboxylate (5), rutin (6), gallic acid (7), ethyl gallate (8). CONCLUSION: Compounds 1 -5 are isolated from this genus for the first time. PMID- 23627125 TI - [Study on chemical constituents from the roots and rhizomes of Sinopodophyllum emodi]. AB - OBJECTIVE: To investigate the chemical constituents in the roots and rhizomes of Sinopodophyllum emodi. METHODS: The compounds were isolated by many different chromatographic methods such as silica gel, Sephadex LH-20, and ODS column. Their structures were identified by their physicochemical properties and spectrascopic data. RESULTS: Nine compounds were isolated and identified as isopicrodeoxypodophyllotoxin(I), 3beta-hydroxy-7alpha-methoxy-24beta-ethyl cholest-5-ene(II), 5alpha, 8alpha-epidioxy-(22E,24R)-erg-osta-6,22-dien-3beta ol(III), 7beta-hydroxysitosterol (IV), beta-sitosterol (V), daucosterol (VI), alpha-glyceryl palmitate (VII), alpha-D-glucose (VIII), 5-hydromethyl furaldehyde (IX). CONCLUSION: Compounds I - IV, VII - IX are obtained from this genus for the first time. PMID- 23627126 TI - [Study on chemical composition of ethylacetate fraction from Polygonum amplexicaule var. sinense]. AB - OBJECTIVE: To study chemical composition of ethylacetate fraction from Polygonoum amplexicaule D. Don var. sinense Forb. METHODS: TLC, Normal-phase silica gel column, reveres-phase silica gel column, Sephadex-LH, semi-preparative HPLC column were used to isolate chemical compositions of ethylacetate fraction from Polygonoum var. sinense. RESULTS: Eight compounds were identified as: 1. P Hydroxybenzoic acid, 2. P-Hydroxybenzoic ethanol, 3. Diisobutyl phthalate, 4. Vanillin, 5. Isovanillic acid, 6.3,4,5-trihydroxy-benzoic acid-butyl ester, 7. 4 hydroxy-3-methoxycinnamic acid, 8. 7-hydroxy-6-methoxycoumarin. CONCLUSION: Except of Diisobutyl phthalate, the others are isolated for the first from this plant, moreover, Vanillin, Isovanillic acid and P-hydro -xyphenethyl alcohol are gained from genus for the first time. PMID- 23627127 TI - [Chemical constituents from the flower of Juglans regia]. AB - OBJECTIVE: To study the chemical constituents from the flower Juglans regia. METHODS: All compounds were isolated and purified by normal column chromatograph and polyamide chromatograph, the chemical strucures were mainly elucidated by ESI MS and NMR spectra. RESULTS: Seven compounds were identified as follows: 4,5,8 trihydroxy-alpha-tetralone 5-O-beta-D-glucopyranoside(1),4,5-dihydroxy-alpha tetralone4-O-beta-D-glucopyranoside(2), 5-hydroxy-4-methoxytetralone (3), 5 hydroxy-1, 4-naphthoquinone (4), rutin (5), vanillin (6), tetracosanoic acid 2,3 dihydroxypropyl ester (7). CONCLUSION: All compounds are isolated from this plant for the first time. PMID- 23627128 TI - [Study on chemical constituents of Carthamus tinctorius]. AB - OBJECTIVE: To investigate the chemical constituents in water-soluble fraction of Carthamus tinctorius. METHODS: Compounds were isolated and purified by macroporus resin, silica gel, Sephadex LH-20 column chromatography and preparative HPLC. The structures were identified by spectral analysis. RESULTS: Twelve compounds were isolated and identified as 4-Hydroxybenzaldehyde (1); E-1-(4'-hydroxypheny) -but 1-en-3-one (2); 3-Formylindole (3); 2-Acetyl-5-hydroxymethylfuran (4); p Hydroxycinnamic acid (5); (6R, 7E, 9R) -9-hydroxy-4,7-megastigmandien-3-one (6); 4-hydroxyacetophenone (7); 5-(hydroxymethyl) -2-furaldehyde (8); 4-Hydroxybenzoic acid (9); Stigmasterol-3-O-beta-D-glucopyranoside (10); Daucosterol (11); beta sitosterol (12). CONCLUSION: Compounds 1 - 4, 6, 7, 10 are isolated from this plant for the first time. PMID- 23627129 TI - [Study on chemical constituents from petroleum ether-soluble parts of cones of Platycladus orientalis]. AB - OBJECTIVE: To study chemical constituents from petroleum ether-soluble parts of cones of Platycladus orientalis. METHODS: The compound were isolaeed by repeated column chromatography of silica gel and Sephadex LH-20. The structures were elucidated by physicochemical properties and spectrum analysis. RESULTS: Seven constituents were isolated and identified as sandaracopimaric acid (1), 6alpha hydroxy sandaracopimaric acid (2), ent-isopimara-8 (14), 15-dien-3beta, 19-diol (3), ent-isopimara-8 (9), 15-dien-3beta-ol (4), ent-isopimara-8 (14),15- dien 3beta-ol (5), isocupressic acid (6) and 15-acetylisocupressic acid (7). CONCLUSION: Compounds 2 and 7 are isolated from this genus for the first time. PMID- 23627130 TI - [Preliminary analysis of quality of Antrodia camphorata powder]. AB - OBJECTIVE: To proceed a preliminary analysis of the quality of Antrodia camphorata powder. METHODS: The contents of water-soluble extract were detected according to the standards stated in Chinese Pharmacopoeia. UV-VIS was used to analyze total polysaccharide and triterpenoid. HPLC method was applied for the analysis of adenosine in Antrodia. camphorata. Besides, volatile compounds were analyzed by HSGC-MS. RESULTS: The contents of water-soluble extract (37.26% - 40.98%), total polysaccharide (5.45% - 8.08%), total triterpenoid (2.44% - 2.87%) and adenosine (0.0470% - 0.0604%) were obtained respectively. 49 volatile compounds were identified in Antrodia camphorata powder. CONCLUSION: The established method can be used for the quality control of Antrodia camphorata powder. PMID- 23627132 TI - [Effect of chitosan oligosacharide on the inhibition and apoptosis of ovarian carcinoma SKOV-3 cells]. AB - OBJECTIVE: To explore the effect and mechanism of inhibition and apoptosis of SKOV-3 cells induced by Chitosan oligosaccharide. METHODS: Human ovarian cancer SKOV-3 cells were treated by various concentrations of Chitosan oligosaccharide. The inhibition of cell proliferation was tested by MTT. Apoptosis induced by Chitosan oligosaccharide was analysed by flow cytometry and agarose gel SKOV-3 cells DNA ladder electrophoresis. RESULTS: Chitosan oligosaccharide could efficiently inhibit SKOV-3 cells proliferation in a dose-dependent manner. Also, the significantly apoptosis of SKOV-3 cells induced by Chitosan oligosaccharide was confirmed through flew cytometry with Annexin V/PI double labels and agarose gel DNA ladder electrophoresis. CONCLUSION: Chitosan oligosaccharide can efficiently inhibit SKOV-3 cells proliferation and induce its obviously apoptosis. PMID- 23627131 TI - [Study on regulation of tanshinone II(A) on GFAP and ATPase and PDI of cerebral ischemia reperfusion injury in rats]. AB - OBJECTIVE: To observe the neuroprotective effect of tanshinone II(A) (Tan II(A)) on the expression of brain tissue glial fibrillary acidic protein (GFAP) and adenosine triphosphatase (ATPase) and protein disulfide isomerase (PDI) of cerebral ischemia reperfusion (I/R) injury of different time in rats, and investigate the neuroprotective and its molecular mechanism of Tan II(A) on brain injury. METHODS: Sixty-four male Sprague-Dawley rats were randomly devided into eight groups (n = 8 per group): Group 1, sham-operated animals without I/R; Group 2, animals with I/R of 3 days; Group 3, animals with I/R of 7 days; Group 4, animals with I/R of 7 days and treatment with low doses of Tan II(A); Group 5, animals with IR of 7 days, treated with high doses of Tan II(A); Group 6, animals with I/R of 15 days; Group 7, animals with IR of 15 days and low doses of Tan II(A) treatment; Group 8, animals with I/R of 15 days, treated with high doses of Tan II(A). The model of focal middle cerebral artery occlusion (MCAO) was established by suture-occluded method. After Tan II(A) treatment, pathological changes of brain tissue in all groups were observed by hematoxylin-eosin staining (HE) and the expression levels of GFAP, ATP and PDI by immunohistochemistry staining. RESULTS: (1) The pathological changes of ischemic injury in low and high dose of Tan II(A) treatment groups were lighter than those in I/R groups, and so were in high dose of Tan II(A) treatment group than in low dose Tan II(A) treatment group. (2) Compared with sham-operated group, expression levels of GFAP in the three different I/R groups increased evidently, while the levels in high dose of Tan II(A) treatment groups were relatively low (P < 0.05). There was no statistically difference between high dose of Tan II(A) treatment group and low dose of Tan II(A) treatment group in either 7 or 15 days treatment groups (P > 0.05). (3) Compared with sham-operated group, expression levels of ATPase and PDI in the three different I/R groups all decreased clearly; Compared with I/R groups, expression levels of ATPase and PDI in Tan II(A) treatment groups increased in the ischemic territory obviously (P < 0.05). CONCLUSIONS: Tan II(A) may have a neuroprotective effect on ischemia-reperfusion injury by inhibiting the production of GFAP to reduce the excessive inflammatory response produced by glial cells in brain and up-regulating the activities of ATPase and PDI in neurons to improve the balance of energy metabolism and maintain the intracellular homeostasis. PMID- 23627133 TI - [Effect of banxia xiexin decoction on leptin and endothelin-1 of gastric ulcer rat and the optimal combination screening of active components]. AB - OBJECTIVE: To select the optimal combination of five active component of Banxia Xiexin Decoction on gastric ulcer rat, and observe its effect on Leptin and ET-1. METHODS: Eighty-seven SD rats were randomly divided into normal group, sham operated group and acetic acid-induced gastric ulcer group, omeprazole group as a positive control, five active components (glycyrrhetic acid, beta-sitosterol, berberine, baicalin and ginsenoside) of Banxia Xiexin Decoction were divided into groups by L16 orthogonal design. The ulcer area, and the content of Leptin and ET 1, and the mRNA expression level of both were detected. RESULTS: Among the sixteen orthogonal design groups, the ulcer area of these groups using both beta sitosterol and berberine was the smallest (P < 0.05), the content of Leptin of these groups using both glycyrrhetic acid and ginsenoside was the highest in blood serum (P < 0.05), the group using glycyrrhetic acid had the minimum concentration of ET-1 in blood plasma. Compared with model group, berberine could raise the mRNA expression level of Leptin (P < 0.01), and beta-sitosterol could lower the mRNA expression level of ET-1 (P < 0.01). CONCLUSION: The pathogenesis of gastric ulcer may be related with the down-regulation of concentration and mRNA expression level of Leptin, and upregulation of concentration and mRNA expression level of ET-1, the active components in Banxia Xiexin Decoction may upregulated Leptin and inhibit ET-1 to accelerate the healing of gastric ulcer. PMID- 23627134 TI - [Research on EGCG improving the degenerative changes of the brain in AD model mice induced with chemical drugs]. AB - OBJECTIVE: To study the effect and mechanism of (-)-Epigallocatechin-3-gallate (EGCG) on the degeneretive changes of the brain in Alzheimer's disease (AD) model mice induced with chemical drugs. METHODS: AD model mice were established by subcutaneously injecting with 3% D-gal at the dose of 150 mg/kg body weight once daily for 6 weeks. From the third week, the mice of D-gal + V(E) 280 U/kg group, D-gal + EGCG 2 mg/(kg x d) group and D-gal + EGCG 6 mg/(kg x d) group were intragastricly given with 5.6% V(E) at the dose of 280 IU/kg and EGCG at the dose of 2 mg/kg x d or 6 mg/kg x d respectively after injection of D-gal. The mice of control group, D-gal + dd H2O group and D-gal + oil group were administered with same volume vehicle distilled water and soybean oil respectively. The pathological changes of the brain in AD model mice were observed by HE staining analysis, the immunohistochemical analysis of beta-amyloid (Abeta) and evaluating the expression of amyloid precursor protein (APP) in the hippocampus of mice by Western blot analysis. RESULTS: EGCG 2 mg/(kg x d) or 6 mg/(kg x d) 4 weeks, ig evidently released neuronal injury in the hippocampus of the AD mice induced by D gal, and significantly reduced the express of Abeta and APP in the hippocampus of AD model mice induced by D-gal (P < 0.01). CONCLUSION: EGCG has a protective effect on AD model mice induced by D-gal by decreasing the expression of APP and beta-Amyloid in the hippocampus of mice. PMID- 23627135 TI - [Pharmacological researches of curcumin solid dispersions in treatment of cancer]. AB - OBJECTIVE: To investigate the anticancer effect of curcumin Solid Dispersions (SDs). METHODS: Curcumin SDs were prepared by patent technology. The anticancer effect of curcumin SDs were investigated by vivo and vitro tests of SCG-7901, BEL 7402, S-180 and Ehrlich ascites tumor models. RESULTS: The results showed that Curcumin SDs had markedly anticancer effect and could improve the anticancer effect of cisplatin. CONCLUSION: Curcumin SDs could be developed into one kind of adjuvant drug for anticancer, as it has markedly anticancer effect, and could improve the anticancer effects of cisplatin. PMID- 23627136 TI - [Optimization of enzymolysis extraction of total anthraquinones from wild rhubarb (Rheum palmatum) via response surface methodology]. AB - OBJECTIVE: To optimize the technology of enzymolysis extraction of total anthraquinones. METHODS: Used the total anthraquinone concentration extracted from rhubarb (Rheum palmatum, L) via enzymolysis as experimental assess index, effect of enzyme dose, enzyme solution temperature, enzyme solution time and pH on total anthraquinone extraction were investigated respectively based on single factor variance analysis. Furthermore, its extraction process was optimized based on response surface methodology. RESULTS: The yield of total anthraquinones demonstrated the top (3.1730 +/- 0.1023 mg/L) while the enzyme dose was up to 0.12 g, besides, for the enzyme solution time, the total anthraquinones yield exhibited a trend of increase with the increase of enzyme solution time and the top concentration of total anthraquinones was up to 2.1410 +/- 0.1252 mg/L while it was 48 h; Moreover, the top field of total anthraquinones were up to 2.2777 +/ 0.2133 mg/L and 4.1360 +/- 0.3877 mg/L while the pH and enzyme solution temperature were up to 4.8 and 50 degrees C in respectively. Finally, the most optimum enzymolysis extraction processing technology via response surface methodology was as follows: pH: 4.59, enzyme dose: 0.1 g as well as enzyme solution temperature: 45.86 degrees C. CONCLUSION: The condition of extraction processing technology is easily-controlled, simple and lower cost, and the final extraction concentration of total anthraquinone is up to 4.3231 mg/L under the processing technology above. PMID- 23627137 TI - [Preparation of sustained release microspheres containing oxymatrine and their release characteristics in vitro]. AB - OBJECTIVE: To prepare poly(lactide-co-glycolide) (PLGA) microspheres containing Oxymatrine (OMT-PLGA-MS) and study their release characteristics in vitro. METHODS: OMT-PLGA-MS was prepared with PLGA as carriers using double emulsion solvent evaporation method (W/O/W). The preparation technology of microspheres was optimized by orthogonal design, and the microspheres were characterized in terms of morphology, the rate of drug loading, encapsulation efficiency, and in vitro drug release. RESULTS: The formed microspheres were spherical with smooth surfaces and the average size was (98.3 +/- 3.4) microm. The encapsulation efficiency and rate of drug loading were (70.14 +/- 3.47)% and (21.59 +/- 1.07)%, respectively. In vitro release study revealed that 84.63% of OMT was released from OMT-PLGA-MS in 240 hours, and the Higuchi model fitted OMT release pattern best. CONCLUSION: OMT-PLGA-MS is prepared successfully and shows good sustained release characteristics. PMID- 23627138 TI - [Extraction technology and antioxidant activity of total flavonoids and total triterpenoids from Tetrastigma planicaule]. AB - OBJECTIVE: To study the optimum extraction technology of total flavonoids and total triterpenoids from Tetrastigma planicaule and their antioxidant activity. METHODS: Optimized the extraction of total flavonoids and total triterpenoids using an L9 (3(4)) orthogonal array design, and the antioxidant activity was extimated by FRAP assay, salicylicl acid assay and ABTS assay. RESULTS: The best extraction conditions for total flavonoids from Tetrastigma planicaule were as follows: 70 degrees C of 70% ethanol ultrasound-assisted extracting for 1 h and extracting three times, and total triterpenoids was:70 degrees C of 60% ethanol microwave extracting for 5 min and extracting two times. Compared with the positive control samples VC and tea polyphenol, the activity of reducing Fe3+ antioxidant and scavenging ABTS + * of flavonoids from Tetrastigma planicaule was higher than that of tea polyphenol, but scavenging OH * was lower than theirs; CONCLUSION: The method of using ultrasound-assisted extraction to extract total flavonoids and microwave extraction to extract total triterpenoids is the best, the extracts of Tetrastigma planicaule also shows certain antioxidative activity. PMID- 23627139 TI - [Classification and treatment of thoracolumbar fractures]. PMID- 23627140 TI - [Comparison between bipedicular approach and uni-extrapedicular approach in application of vertebroplasty]. AB - OBJECTIVE: To analyze the advantages and disadvantages of bipedicular approach and uni-extrapedicular approach of vertebroplasty in treating osteoporotic vertebral compression fractures (OVCFs). METHODS: From January 2008 to December 2010,53 patients with OVCFs were retrospectively analyzed. There were 24 males, 30 females with an average age of 66.9 years (ranged,59 to 88 years). Among them, 26 cases were treated with bipedicular approach, 28 cases were treated with uni extrapedicular approach. The data of bone cement injection, radiology exposure times, operation time, bone cement leakage and vessels nerve complications were observed. Cobb angle, vertebral compression ration were observed by imaging data, and evaluate recovery of deformity. RESULTS: The data of bone cement injection, radiology exposure times, operation time, VAS score were (6.6 +/- 0.8) ml and (6.8 +/- 1.5) ml, (21.7 +/- 4.0) times and (17.9 +/- 3.6) times, (40.5 +/- 5.5) min and (31.6 +/- 9.1) min, (2.8 +/- 0.6) scores and (3.1 +/- 0.5) scores respectively. Cobb angle,vertebral compression ration were (7.6 +/- 2.0) degrees and (6.9 +/- 2.6) degrees, (18.1 +/- 5.8)% and (16.5 +/- 6.1)%. There were no vascular nerve complications occurred. For bone cement leakage, 3 cases (11%) in bipedicular approach and 3 cases (11%)in uni-extrapedicular approach. There was no significant differences between two groups in VAS score, recovery of vetebral body, Cobb angle, bone cement injection and bone cement leakage, but had significant differences in radiology exposure times and operation time (P<0.05). CONCLUSION: Both of two approaches can treat OVCFs well, especially extropedicle approach which could reduce operation time and radiation shoot frequency. PMID- 23627141 TI - [Surgical treatment of thoracolumbar burst fractures through Wiltse paraspinal approach]. AB - OBJECTIVE: To investigate clinical effects and advantages of Wiltse paraspinal approach to thoracolumbar burst fractures. METHODS: From June 2008 to June 2010, the data of 53 patients with thoracolumbar burst fractures with no obviously nerve injury were retrospectively analyzed, including 43 males and 10 females with an average age of 41 years ( ranged, 19 to 62 years). For segmental distribution, 6 cases were T11, 11 cases were T12, 22 cases were L1 and 14 cases were L2. Among them, 28 cases were treated with Wiltse paraspinal approach, and 25 cases with postmiddle approach. The operation time, blood loss, postoperative drainage,VAS score of back, Cobb angle of injured cord, changes of collapse of vertebral and median sagittal diameter of injured vertebral were observed. RESULTS: Compared with two methods, there were advantages in improving operation time, blood loss, postoperative drainage and VAS score of back, but there were no significant differences in improving Cobb angle of injuried cord, changes of collapse of vertebral and median sagittal diameter of injuried vertebral. CONCLUSION: Wiltse paraspinal approach to thoracolumbar burst fractures can achieve the same reduction with postmiddle approach,and has advantages of minimally invasive, less blood, simple operation and rapid recovery, and worth popularizing. PMID- 23627142 TI - [Pedicle fixation without bone fusion for the treatement of thoracolumbar fractures through paraspinal approach]. AB - OBJECTIVE: To evaluate clinical effects of pedicle fixation without bone fusion in treating thoracolumbar fractures through paraspinal approach. METHODS: From January 2006 to January 2009, 25 patients (15 males and 10 females) with thoracolumbar fractures were treated. The average age was 39.3 years,ranged from 17 to 49 years. According to classification, flexion fracture in 7 cases, brust fracture in 18 cases. There were no nervous injury, and radiology information showed the angle of sagittal vertebral body >20 degrees or collapse of vertebral body >40%,without vertebral injury. The operation were performed at 3 to 7 days after injury (mean 5 day). Internal fixation implants were removed at 8 to 12 months after operation. The height, kyphosis angle were measured before operation, 1 week and 24 months after operation,and Oswestry disability index (ODI) were compared before and after operation. RESULTS: All patients were followed up for 24 months. Among them, 1 case was followed up at 30 months after operation. The operation time ranged from 70 to 110 (mean 90) minutes, the blood loss was 120 to 280 (mean 200) ml. The height of vertebral body and kyphosis angle were obviously corrected, and had significant differences between postoperation immediately and at the final follow-up (P<0.05). There were no differences after remove of internal fixation (P>0.05). The final ODI was (5.36 +/- 1.21)%, had statistical differences compared with preoperation (P<0.05). CONCLUSION: For flexion and burst thoracolumbar fractures without nervous injury, pedicle fixation without bone fusion is a good method,which has advantages of minimally invasive, rapid recovery, and maintain spinal motion segment. PMID- 23627143 TI - [Posterior reduction and interbody fusion for the treatment of thoracolumbar fractures and dislocations]. AB - OBJECTIVE: To explore efficacy of posterior reduction and interbody fusion in treating thoracolumbar fractures and dislocations. METHODS: From August 2004 to May 2009, 24 patients (18 males and 6 females with an average of 38.2 years, ranged 24 to 56 years old) were treated. Among them, 14 cases were by traffic accident,6 cases were falling down, 2 cases were heavy hit, 2 cases were transverse crush. According to AO classification, 12 cases were type B1, 5 cases B2, 2 cases B3,3 cases C1, 2 cases C2. One cases in T(10,11), 2 cases in T(11,12), 5 cases in T12L1, 8 cases in L(1,2), 2 cases in L(2,3), 4 cases in L(3,4), 2 cases in L4/5. Acoording to Frankle classification,5 cases in grade A, 9 cases in grade B, 8 cases in grade C and 2 cases in grade D. The reduction, graft healing and recovery of nervous function were followed up. RESULTS: All patients were followed up from 8 to 33 months with an average of 16 months. The operation time was for 3.0 to 5.8 hours, meaned 3.7 h, and mean blood loss was 860 ml (ranged, 500 to 1800 ml). Cobb angle improved from preoperative (32.6 +/- 3.7) degrees to postoperative (13.7 +/- 2.4) degrees. The anterior high of fractured vertebrae increased from preoperative (41.0 +/- 11.6)% to postoperative (87.6 +/- 2.3)% .Three cases of 5 cases with Frankle A were not recovery, 1 case changed to grade B, 1 case changed to grade C; Five cases of 9 cases with Frankle B were changed to grade C, 3 cases to grade D, 1 case changed to grade E; Five cases of 8 cases with Frankle C were changed to Grade D, 3 cases to Grade E; Two cases with Frankle D were recoved to normal. Planting bone surface got bone fusion, and no internal fixation lossen, dislocation occurred. CONCLUSION: Posterior reduction and rigid interbody fusion for the treatment of thoracolumbar fractures and dislocations can receive satisfactory fusion based on recovering normal spinal sequence PMID- 23627144 TI - [Modified funnel method transpedicular bone graft in the treatment of thoracolumbar vertebral fractures]. AB - OBJECTIVE: To explore efficacy of modified funnel method for transpedicular bone grafting in treating thoracolumbar vertebras fracture. METHODS: From May 2006 to November 2011, 35 patients (19 males and 16 females, ranged in age from 21 to 66 years with an average of 34.6 years) with thoracolumbar vertebras fracture were treated by posterior pedicle screw fixation, reduction and modified funnel method for transpedicular autogenous iliac bone grafting. Of the 35 cases, 9 cases were severe compression fracture and 26 cases were burst fracture. The anterior body height and Cobb's angle of injured vertebral were measured by X-ray; the effect of implantation bone and CT value were assessed by radiograph CT scan; Nerve function were evaluated according to Frankel's neurological function classification and back pain were evaluated by visual analogue scale (VAS). RESULTS: Thirty-two patients were followed up from 18 to 37 months with an average of 19.7 months. No nerve injuries aggravated, and 11 patients with partial nerve injuires preoperatively were improved at least 1 level recovery postoperatively; Breakage or loosen of screws were not found. Vertebral bone grafting filled well, bone fusion were got after 6 months' treatment and without cavity gap in grafting bone area. The anterior vertebral height was improved respectively from preoperative (50.17 +/- 8.26)% to postoperative (90.79 +/- 4.85)%, and (90.34 +/- 4.03)% at the final follow-up. The Cobb's angle improved from preoperative (28.7 +/- 6.24) degrees to postoperative (7.26 +/- 3.79) degrees, with (7.34 +/- 4.05) degrees at the final follow-up. CT value of injured vertebras at the final follow-up were significantly higher than adjacent vertebras'. The average VAS was 1.06. CONCLUSION: Posterior pedicle screw fixation, reduction and modified funnel method for transpedicular autogenous iliac bone grafting is a feasible and safe method for the treatment of thoracolumbar vertebras fracture. It can effectively prevent bone loss of injured vertebral height, progressive deformity of kyphosis, and keep spinal movement function at the maximum. PMID- 23627145 TI - [Pedicle screw at the fracture level and vertebroplasty via paraspinal approach for the treatment of old thoracolumbar fractures]. AB - OBJECTIVE: To investigate the feasibility and safety of the treatment for thoracolumbar fractures with pedicle screw at the fracture level and vertebroplasty via paraspinal approach. METHODS: From August 2007 to August 2010, 22 old patients with thoracolumbar fractures were treated with pedicle screw at the fracture level and vertebroplasty via paraspinal approach. There were 14 males and 8 females, ranging in age from 60 to 71 years (mean, 64.6 years). The time from injury to surgery varied from 1 to 4 d (mean,2.7 d). All the patients suffered from single thoracolumbar fractures and located at T11 in 2 cases, at T12 in 5 cases, at L1 in 11 cases and at L2 in 4 cases. According to the Denis fracture classification, there were 6 compression fractures and 16 burst fractures. The mean preoperative load-sharing classification of spine fractures was 5.4 score. The mean preoperative thoracolumbar injury classification and scoring was 5.2. Based on the ASIA neurologic grading system, preoperative neurological function was grade B in 2 cases,grade C in 3 cases, grade D in 7 cases and grade E in 10 cases. The neurological function, vertebral central and anterior height, kyphotic angle of the vertebral fractures by radiographs and visual analog scale were calculated pre-operatively, post-operatively and at the last follow-up. RESULTS: Median operating time was 60.8 min (ranged from 50 to 95 min) and median blood loss was 84 ml (ranged from 50 to 130 ml). The operative incisions were healed well. The duration of follow-up averaged 21.6 months (ranged from 12 to 48 months). The anterior vertebral body height was corrected from preoperative (52.3 +/- 10.3) % to postoperative (6.1 +/- 4.2) % and (6.8 +/- 5.4) % at the last follow-up. The central vertebral body height was corrected from preoperative (38.9 +/- 11.2) % to postoperative (8.3 +/- 4.7) % and (9.4 +/- 4.5)% at the last follow-up. The Cobbs angle of the injured vertebral segment was corrected from preoperative (19.5 +/- 9.5) degrees to postoperative (4.3 +/- 4.1) degrees and (6.2 +/- 4.7) degrees at the last follow-up. The VAS scores reduced from preoperative 8.56 +/- 0.88 to post-operative 3.48 +/- 0.91 and 3.20 +/- 0.92 at the last follow-up. The postoperative neurologic function of all 22 patients improved 1 to 2 degrees except 10 patients of grade E. There were no instances of instrumentation failure and no patient had persistent postoperative back pain. CONCLUSION: The pedicle screw at the fracture level and vertebroplasty via paraspinal approach has the advantages of less invasive and blood loss, and could prevent the development of kyphosis and offers improvement of the spinal cord function. Furthermore, it could decrease the risks of postoperative back pain and the failure of instrumentation. PMID- 23627146 TI - [Three nonparallel screws for the treatment of femoral neck fractures]. AB - OBJECTIVE: To explore clinical effects of three nonparallel screws in treating femoral neck fractures. METHODS: From September 2008 and May 2009, 29 patients were treated, including 12 males and 17 females with an average age of 52 years (ranged from 27 to 62 years). Before operation, according to Garden classification system, 2 cases were Garden type II (undisplaced fracture), 18 cases were Garden type III (partial displaced fracture) and 9 cases were Garden type IV (complete displaced fracture). After fracture reduction in operation, Pauwels classification system was used to classify the type, and 12 cases were type II, 17 cases were type III Closed reduction and internal fixation with three non-parallel screws were used to treat. The surgery X-ray and follow-up X-ray were compared to observe whether femoral neck abbreviate and screw exit appeare. Harris scoring was used to evaluate function. RESULTS: All patients were followed up from 34 to 44 months with an average of 38 months. The mean time of bone union was 7 (ranged, 3 to 12) months. Nonunion occured in 4 cases with Garden IV, and femoral head necrosis occurred in 2 cases. For Harris scoring, two cases with nondisplaced fracture were 100. Among 27 cases with displaced fractures, 23 cases achieved bone union without femoral head necrosis, average Harris scale was 91.35 +/- 8.00, and the average Harris scale of 4 cases with bone nonunion was 61.23 +/ 5.12. For all but one, there was no femoral neck crispation after bone union. CONCLUSION: Nonparallel screws for femoral neck fractures can effectively control abbreviation and screw tail exit after fracture healing. PMID- 23627147 TI - [Comparison of screw' inserting angle through the 11th and 12th rib anterior approaches for L1 burst fracture]. AB - OBJECTIVE: To compare screw's inserting angle through the 11th and 12th rib in treating L1 burst fracture, explore effects on inserting screw and postoperative angle. METHODS: From October 2007 to October 2010, 108 patients with L1 brust fracture treated through anterior approach were analyzed,including 68 males and 40 females, aged from 21 to 64 years (mean 38.22 years). All patients were divided into the 11th (A, 51 cases) and 12th (B, 57 cases) approach. The data of operation time,blood loss, duration of incision pain, JOA score, Oswestry score, VAS score, quality of life (SF-36), recovery of nervous function, coronal Cobb angle, included angle between screw and plate were observed. RESULTS: All patients were followed up for 9 to 37 months, mean 23 months. The operation time, blood loss, duration of incision pain, in group A were lower than group B (P<0.05), JOA score, Oswestry score, VAS score, SF-36, recovery of nervous function had no significant differences (P>0.05). There were no differences in Cobb angle before operation, but had significance after operation (P=0.000). There were statistically significance between two group in angle between screw and plate (P=0.000, P=0.003). CONCLUSION: The 11th rib approach for the treatment of L1 burst fracture has less effects on screw, less trauma and less angle between screw and plate. PMID- 23627148 TI - [Experimental study on Yougui recipe in preventing osteolysis surrounding artificial prosthesis]. AB - OBJECTIVE: To explore effects of Yougui recipe (see text) and salmon calcitonin acetate in preventing osteolysis surrounding artificial prosthesis. METHODS: Thirty-two SD male rats with weighted (250 +/- 20) g, aged 8 weeks, were randomly divided into four groups: blank group, model group, salmon calcitonin acetate group and Yougui recipe (see text) group, and 8 rats in each group. Blank group did not undergo any process, other 24 rats underwent anesthesia by chloral hydrate, their knee joints were exposed through medial patellar side,drilling from fermoral condyle nest to marrow cavity,high density of polythlene particles were injected into hole, titanium nail were put into, bone wax closed the window, then suturing step by step. After the molding, saline were used to gavaged in blank group and model group, Yougui recipe (see text) for Yougui recipe (see text) group, salmon calcitonin maximus injection for calcitonin group. After 10 weeks' mediation, rats were executed, and arterial blood and bilateral femoral organization were collected to biochemical, imaging morphology, tissue pathology and molecular biology detection. RESULTS: The key gene expression of activiting osteoclast were inhibited in Yougui recipe (see text) group and calcitonin group. The level of OPG, Ca, ALP in Yougui recipe group were higher than calcitonin group (P<0.01); the content of RANKL were lower (P<0.01). There were no significance meaning in RANK, Trap5b, P between two groups. CONCLUSION: Both of Yougui recipe (see text) and calcitonin can slow and treat surrounding osteolysis of artificial joint prosthesis, and Yougui recipe (see text) has better effect in promoting bone formation. The effect of Yougui recipe (see text) in promoting bone formation, inhibiting osteoclasts to provide a new method to treating surrounding osteolysis of artificial joint prosthesis. PMID- 23627149 TI - [Effects of tanshinone- II A sulfonate on expression of nuclear factor-kappaB, vascular cell adhesion molecule-1 and hemorrheology during spinal cord ischemia reperfusion injury]. AB - OBJECTIVE: To observe effects of Tanshinone- II A sulfonate on expression of Nuclear factor-kappaB (NF-kappaB), Vascular Cell Adhesion Molecule-1 (VCAM-1) and hemorrheology during spinal cord ischemia reperfusion injury,and explore the function and mechnism. METHODS: Fifty-four New Zealand rabbits (aged 3 months,weighted 2.0 +/- 0.2 kg) were randomly divided into 6 in sham group (lumbar artery were separated in operation,0.8 ml/kg saline were injected at 0.5 h before and after operation), 24 in ischemia group ( lumbar artery were clipped after seperation, and the same dose of saline), 24 in Tanshinone group (lumbar artery were clipped after seperation, and the same dose of Tanshinone- II A sulfonate) . Abdomincal aorta blood were drawed after treatment respectively at 0.5 h, 1 h, 4 h and 8 h, and tesetd whole blood viscosity [high cut (mpa.s)/150(l/s), middle cut (mpa.s)/60(l/s) and low cut (mpa.s)/10(l/s)], capillary plasma viscosity, red cell aggregation index, rigid index, deformation index and electrophoresis index. Spinal cord tissues were divided into two sections,one fixed in 4% paraformaldehyde, another stored in liquid nitrogen. Immunohistochemical method and ELISA were used to test change of content of NF kappaB and VCAM-1. RESULTS: 1) The expression of NF-kappaB in Tanshinone group were lowest, and in ischemia group were highest. 2) Compared with sham group, VCAM-1 in ischemia group at different time were obviously increased,especially at 0.5, 1 and 4 h (P<0.01), and had meaning at 8 h (P<0.05). Compare between Tanshinone group and ischemia group, VCAM-1 at 0.5 h were obviously decreased (P<0.01), and had meaning at 1 h, 4 h and 8 h (P<0.05). 3) There were no postive vasvular expression in sham group, and at 0.5 h in Tanshinone group and ischemia group. The highest postive vasvular expression in ischemia group were at 1 h, 4 h and 8 h, and had significant meaning at 1 h and 4 h between ischemia group and Tanshinone group (P<0.05), and 8 h were obviously most. 4) The whole blood viscosity in ischemia group at 10 s(-1), 60 s(-1), 150 s(-1) were highest, and capillary viscosity increased (P<0.05 or P<0.01). While capillary viscosity, red cell aggregation index, figid index, deformation index in Tanshinone group decreased obviously (P<0.01). CONCLUSION: Tanshinone-II A sulfonate can relieve spinal cord ischemia reperfusion injury by regulating expression of NF-kappaB, VCAM-1, decreasing whole blood viscosity, capillary plasma viscosity, red cell aggregation index, rigid index, and improve hemorhelogy. PMID- 23627150 TI - [Simple osteotomy for correct hallux valgus with increased I, II intermetatarsal angle]. AB - OBJECTIVE: To investigate efficacy of simple osteotomy for correct hallux valgus,and explore its scope and condition. METHODS: From December 2009 to April 2011, 20 patients (32 feet) with hallux valgus were treated by simple osteotomy. There were 1 male (1 foot), 19 females (31 feet) with an average age of 40 years (ranged, 22 to 64 years). The course of disease ranged from 2 to 31 years(mean 12 years). Among them, 6 feet were mild, 20 feet were moderate, 6 feet were serious. Patients had symptoms of metatarsophalangeal joint pain, but tensity of lateral soft tissue were normal. Hallux Valgus Angle (HVA) and Intermetatarsal Angle (IMA) were examined before and after treatment. The criteria of hallux valgus was used to evaluate the effects from valgus deformity, activity of metatarsophalangeal joint, satisfaction of patients. RESULTS: Twenty patients were followed up from 6 to 18 months with an average of 8.5 months. The wounds were healed well, no infection and metatarsal head necrosis occurred, 95.1% of patients were satisfied with the efficacy. Average AOFAS score increased from preoperative (53.1 +/- 7.5) points to the final follow-up (93.1 +/- l.9) points (P<0.05), the average correct HVA increased from preoperative (33.4 +/- 7.8) degrees to postoperative (11.9 +/- 3.6) degrees (P<0.05), the average IMA were decreased from preoperative (12.3 +/- 3.0) degrees to postoperative (6.3 +/- 1.9) degrees (P<0.05), tibial sesamoid position improved from 1.9 to 0.9 (P<0.05). CONCLUSION: the main pathological changes of hallux valgus patients with normal tension of lateral soft tissue is metatarsal adduction, simple osteotomy can get satisfactory results, no need to cut adductor muscle. PMID- 23627151 TI - [Clinical diagnosis and treatment of giant cell tumor of tendon sheath in finger (70 cases report)]. AB - OBJECTIVE: To investigate surgical methods and therapeutic effects of giant cell tumor of tendon sheath in finger. METHODS: From July 2002 to December 2010,70 patients with giant cell tumor of tendon sheath in finger which confirmed by operation and pathology,were retrospectively analyzed. There were 29 males,41 females with an average of 42 years (ranged, 16 to 61), and the course of disease ranged form 4 months to 6 years (mean 11 months). The method of surgery and anesthesia were observed. RESULTS: All wounds were got stage I healing,no necrosis occurred. Vascular crisis occurred in 6 cases (8.6%), inconformity of diagnosis in 18 cases (25.7%), changing of anesthesia due to situation of tumor in operation in 17 cases (24.3%). The patients were followed up from 2.2 to 10.5 years. Among them, 8 cases (11.4%) recurred, and diagnosied by the second operation without malignant change. CONCLUSION: The best anesthesia for giant cell tumor in finger should choose brachial plexus to fully expose,complete resection and less harmful damage; while the operation should complete resection at the stage I, and followed up actively, the second operation can be carried out for recorrenced. PMID- 23627152 TI - [Pigmented villonodular synovitis of knee joint combined with femoral defect: a case report]. PMID- 23627153 TI - [Radiological studies on the best entry point and trajectory of anterior cervical pedicle screw in the lower cervical spine]. AB - OBJECTIVE: To explore the best entry point and trajectory of anterior cervical screw in the cervical screw by radiological studies, and provide reference for clincal application. METHODS: From January 2008 to December 2010,50 patients were scanned by cervical CT and confirmed no obvious defect of lower cervical spine. Of them, 27 cases were males and 23 were females, ranged the age from 38 to 83 years ( mean 58.5 years). On horizontal axis, the camber angle of C3-C7 anterior lower cervical pedicle of vertebral arch axis (alpha) and distance between (axial length, AL) of anterior cervical pedicle axial line was measured from C3 to C7. Vertebral were divided into four areas, and from measured side of pedicle of vertebral began to record, orderly 1 to 4, the area of pedicle vertebral arch intersert into vertebral were recorded. On sagittal view, the head or tail angle (beta) and length (sagittal length, SL) of anterior cervical pedicle axial line was also measured from C3 to C7. Vertebral were divided into four areas, and from measured side of pedicle of vertebral began to record, orderly 1 to 4, the area of pedicle vertebral arch arch intersert into vertebral were recorded. The above data were statistically analyzed to find the best entry point and trajectory of anterior cervical screw in the cervical screw and insert pedicle screw. RESULTS: The lateral angle of lower cervical spine was 38 degrees to 45 degrees on transverse plane, C3 to C5 increasing gradually, C5 to C7 decreasing. On sagittal view, C3,C4 pedicle were head tulting, C5 were basic level, C6,C7 were tail. C3 to C5 decreasing gradually, C5 to C7 increasing gradually. C3 to C7 in AL and SL increased gradually. On horizontal axis, the intersection of C3,C4 and C5 were in the second area, the number of C6 in the second and third area were the same, but C7 were in the third area. The intersection in the first and forth area were less. On sagittal view,the intersection of C3,C4 and C5 were in the first area,the number of C6 in third and forth area were less. Six pedicle screws of 3 cases were insert into lower cervical spine, and obtained good effects, no complications occurred. CONCLUSION: The best entry point of C3,C4 and C5 were located in the center line and slightly to opposite vertebral body side and upper 1/4 area; C7 were located the vertebral body side and upper 2/4 area; C6 were located between them. The best insertion point were extraversion 38 degrees to 45 degrees, C3 to C5 increased graduallly, C5 to C7 decreased on horizontal axis; On sagittal view, C3,C4 for head 5 degrees to 10 degrees, C5 were basic level, C6,C7 for tail 5 degrees to 10 degrees. The anterior cervical pedicle screw for lower cervial spine is a good and feasible internal fixation. PMID- 23627154 TI - [Case-control study on stiletto needle and Dichofenac Diethylammon for the treatment of knee osteoarthritis pain]. AB - OBJECTIVE: To investigate therapeutic effects of stiletto needle and Dichofenac Diethylammon in treating knee osteoarthritis pain at early and medium-term. METHODS: Sixty-seven patients with early and medium-term knee osteoarthritis were randomly divided into two groups, 34 cases in stiletto needle group (treatment group) and 33 cases in Dichofenac Diethylammon (control group). Among them, 60 patients finished treatment and followed-up for 1 months (7 cases fall off totally, 4 cases in treatment group and 3 cases in control group). In treatment group, there were 5 males and 25 females with a mean age of (55.90 +/- 9.34) years (ranged, 40 to 68 years), the course of disease for 0.25 to 1 year, mean (0.87 +/- 0.34) years, treated by stiletto needle once a week, and 3 weeks were a course. In control group, there were 6 males and 24 females with a mean age of (58.67 +/- 7.39) years (ranged, 40 to 70 years), the course of disease for 0.25 to 2 years, mean (0.93 +/- 0.60) years, treated by Dichofenac Diethylammon, three times a day for 3 weeks. Soft tissue displacement and banana area were tested by soft tissue tension tester, pressure value were measured by pressure measuring instrument, VAS score were recorded by pain visual analog scale record, HSS scoring and effects were used to evaluated and statistical analyzed. RESULTS: There were significant differences in tissue displacement, banana area, pressure value, VAS scoring and HSS scoring between two groups before and after treatment, and tissue displacement, pressure value, HSS scoring in treatment group were higher than control group, while banana area and VAS scoring were lower than control group. According to HSS scoring and VAS scoring, 3 cases were healed, 8 cases were markedly improved, 18 cases were effective and 1 case was effectiveless in treatment group;while 1 case was healed, 4 cases were markedly improved, 20 cases were effective and 5 cases were effectiveless in control group. There was no significant meaning in therapeutic effects. CONCLUSION: Stiletto needle for knee osteoarthritis pain can effectively reduce high tension of local soft tissue ,alleviate symptom of pain, and improve knee function. PMID- 23627155 TI - [Therapeutic effects of cannulated compression screws for treating femoral neck fractures]. AB - OBJECTIVE: To explore the relevant factor of cannulated compression screws in treating femoral neck fractures. METHODS: From January 2004 to January 2011, 190 patients with femoral neck fractures treated by cannulated compression screws were analyzed retrospectively. In all of the 190 cases, there were 104 males and 86 females with an average of 65 years (ranged, 21 to 83 years). According to Garden classification system, 25 cases were type I, 51 cases were type II, 58 cases were type II and 56 cases were type IV. The time from injury to operation was 15 h to 10 d (mean 3.5 d). The gender,age, trauma type, fracture type, osteoporosis, emergency operation, fracture reduction, relation between open reduction and nonunion were observed and analyzed. RESULTS: All patients were followed-up for 12 to 84 months, with a mean of 38 months. All incisions obtained stage I healing. There were 23 patients with bone nonunion. The rate of nonunion was 12.1%. Single factor analysis showed that there were significant differences in age, trauma type, fracture type, fracture reduction and osteoporosis (P<0.05), but no meaning in gender, emergency operation, relation between open reduction and nonunion (P>0.05). CONCLUSION: Cannulated compression screws for femoral neck fractures can obtain good outcomes, and age, trauma type, fracture type, fracture reduction and osteoporosis are main factors. PMID- 23627156 TI - [Closed reduction and percutaneous hollow screw fixation with prototypical retractor for the treatment of calcaneal fracture]. AB - OBJECTIVE: To evaluate efficacy of closed reduction and percutaneous hollow screw fixation with prototypical retractor in treating calcaneal fracture. METHODS: From January 2009 to June 2011, 39 patients (43 feet) with calcaneal fracture were treated by closed reduction and percutaneous hollow screw fixation with prototypical retractor. There were 33 males and 6 females, aged from 19 to 61 years with an average of 36.7 years. According to type of Sanders, type II were in 19 feet, type III were in 24 feet. Preoperative and postoperative X-ray were estimated, the data of height, width, Bolher angle, Gissane angle of calcaneous were collected, and ankle function were estimated according to AOFAS system. RESULTS: All patients were followed up from 6 to 36 months with an average of (15.4 +/- 3.1) months. All wounds were healed well, no skin edge necrosis and infections occurred. Before operation, the height of calcaneous was average of (32.45 +/- 3.51) mm, width was (41.60 +/- 2.42) mm, Bolher angle was (8.64 +/- 13.2) degrees and Gissan angle was (136.35 +/- 15.23) degrees; while after operation, the height of calcaneous was average of (43.62 +/- 1.02) mm, width was (38.02 +/- 1.28) mm, Bolher angle was (26.87 +/- 5.32) degrees and Gissan angle was (120.78 +/- 5.34) degrees, and had significanty differences between preoperative and postoperative treatment (P<0.05). AOFAS score was improved from preoperative (35.64 +/- 11.23) to postoperative (76.18 +/- 9.87), and 29 cases got excellent results, 11 good and 3 fair. COMCLUSION: Closed reduction and percutaneous hollow screw fixation auxiliary by the retractor for the treatment is a good way, which has advantages of simple operation, satisfactory reduction fixation, reliable fixation, minimally invasive, less complications and rapid recovery. PMID- 23627157 TI - [Treatment of type C3 distal femoral fractures with double-plating fixation via anteriormiddle approach]. AB - OBJECTIVE: To investigate clinical efficacy and feasibility of double-plating fixation via anteriormiddle approach in treating type C3 distal femoral fractures. METHODS: From August 2008 to August 2011, 12 cases with type C3 distal femoral fractures were treated, including 5 open fractures and 7 closed fractures. Among them, there were 8 males, 4 females with an average of 40 years (ranged, 25 to 55 years). There were 7 in left side, 5 in right side. Nine cases were caused by car accident, 3 cases by falling down. The duration from injury to hospital was form 20 minutes to 5 days (mean 135 min). After tibia bone traction for 5 to 8 days, the operation were performed by double-plating fixation via anteriormiddle approach, and autograft of iliac bone or allograft bone grafting were given to bone defect. Knee joint function was evaluated according to Merchanetal criteria. RESULTS: The operation time was from 110 to 160 min, with an average of 135 min, the blood loss was from 300 ml to 500 ml,with an average of 400 ml. Post-operative wound were stage I healing. All patients were followed up from 16 to 36 months (mean 24 months). No infection, reduction loss, nonunion, deep vein thrombosis occurred. Bone healing time was for 18 to 24 weeks with an average of 21 weeks. According to the Merchanetal criteria, 4 cases got excellent results, 6 good, 1 fair and 1 poor. CONCLUSION: Double-plating fixation via anteriormiddle approach for type C3 distal femoral fractures is an effective way, which has advantages of obvious exposure, simple manipulation, anatomical reduction, stable fixation. However,operation indications and operating instructions should be strictly followed. PMID- 23627158 TI - [New research progress on atrophic nonunion]. AB - Occurance of atrophic nonunion is a complex process. Previous studies suggested that atrophic nonunion was mainly due to lack of blood supply of fracture fragments, but recent studies found that blood supply was not deficiency in middle and late stages, indicating that decreased osteogenic factors and blood supply in early stages might play an important role in morbidity. Current effective treatment measures for atrophic nonunion mainly include bone graft and fixation,physical therapy, local injection therapy. All-round preventive could reduce incidence of atrophic nonunion. Atrophic nonunion is still a troublesome complication of fractures in orthopaedics, and more attention should be paid for its effective prevention and treatment. The paper summarized recent original articles about atrophic nonunion and reviewed the occurrence mechanisms, diagnosis, prevention and treatment measures of this disease. PMID- 23627159 TI - [Percutaneous transforaminal endoscopic discectomy through different approaches for lumbar disc herniation]. AB - Compared with open surgery, percutaneous transforaminal endoscopic discectomy (PTED) for lumbar disc herniation (LDH) has advantages of minamilly invasive, little impact on stability of spine and rapid recovery. However, PTED by transforaminal approach has relatively limited indications and can not completely replace open surgery, due to different location of migrated herniated fragment, the level of pathological segment or presence of a high iliac crest. Development of new approach and ancillary equipment have become the focus and future direction of PTED. In recent years, interlaminar and transiliac approach extended the indications of PTED greatly. However, not-standard manipulation, improper selection of indications or surgical approach has been attributed to the main reason for failure in PTED surgery. In view of this, the paper summaries indications, different approaches and methods, clinical efficacy and complications of PTED. PMID- 23627160 TI - [Application of bioinformatics in study of Chinese medicine resources]. AB - In the late 20th century, the rapid development of life sciences resulted masses of biological data, in which laws of life sciences urgently needed to be excavated. Together with the progress of computer science and technology, bioinformatics was born. Chinese medicinal resources, especially the plant resources, are the basis for the development of the Chinese pharmaceutical industry. As a new discipline and important life science research tools, bioinformatics applied rapidly in the study of Chinese medicine resources and involved in different aspects of genomics in recent years. Bioinformatics provides a new research approach to reveal the biological principles, methods and techniques and powerful tools of excavation, at the same time it is speeding researches in the field of Chinese medicine resources and the development of the industry. This article summarizes a comprehensive collection of bioinformatics application data in the study of Chinese medicine resources, prospects the application in Chinese medicine resources, and provides a basis bioinformatics information for the study of Chinese medicine resources. PMID- 23627161 TI - [Influencing factors on culture of medicinal plants adventitious roots]. AB - With the modernization of traditional Chinese medicine, medicinal plants resources cannot meet the request of Chinese medicine industry. Medicinal plants adventitious roots culture in a large scale is an important way to achieve Chinese medicine industrialization. However, how to establish good adventitious roots culture system is its key, such as plant hormones, explant, sucrose, innoculum and salt strength. PMID- 23627162 TI - [Review of traditional Chinese medicine processed by fermentation]. AB - The fermentation processing of traditional Chinese medicines (TCMs), as an important processing method for TCM, originated from the ancient brewing technology. It has a long history in China. Fermented TCMs (FTCMs) are widely applied among folks for preventing and treating many diseases. There are many kinds of TCM processed by spontaneous fermentation, including Massa Medicata Fermentata, Rhizoma Pinelliae Fermentata, Red fermented rice, Semen Sojae Praepaaratum, Mass Galla chinesis et camelliae Fermentata and Pien Tze Huang. This essay summarizes historical origin, main varieties, the effect of microbial strains, current processing techniques and existing problems of FTCM, and look into the prospect of modern development of FTCMs. PMID- 23627163 TI - [Screening of endophytic fungi from Huperzia serrata for acetylcholinesterase inhibitory activity and its taxonomic identification]. AB - OBJECTIVE: To screen out fungus strains with acetylcholinesterase inhibitory activity from Huperzia serrata. METHOD: Endophytic fungi fermentation products from 59 H. serrata strains were stained with acetylcholinesterase hydrolyzed alpha-naphthaleneacetic ethyl ester and fast blue B salt, and screened for acetylcholinesterase inhibitory activity with thin-layer chromatography bioautography. Target strains were classified and identified through the sequence analysis on 18s rDNA and 5.8s rDNA combined with morphological characteristics. RESULT: Fungus strain LQ2F01 from H. serrata showed positive color reaction in the screening for acetylcholinesterase inhibitory activity. The sequence analysis on 18s rDNA and 5.8s rDNA combined with morphological characteristics showed the strain LQ2F01 belonged to Acremonium. CONCLUSION: Endophytic Fungi LQ2F01 from H. serrata shows identical acetylcholinesterase inhibitory activity with the host plant, which is of great significance to the development of natural medicines and the studies on the relationship between the endophytic gungi and the host plant. PMID- 23627165 TI - [Optimizing expression of recombinant jasmonate ZIM-domain protein from Salvia miltiorrhiza]. AB - OBJECTIVE: Accumulation of tanshinton in Salvia miltiorrhiza are enhanced by exogenous application of jasmonates. The core JA signaling module COI1/JAZ/MYC2 play a central role on control of downstream gene expression in the JA pathway. To obtained the antibody of SmJAZ, SmJAZ recombinant protein was expressed in Escherichia coli and optimal expression was performed. METHOD: The full-length SmJAZ1 ORF was sub-cloned in a prokaryotic expression vector pET32a. The recombinant fusion protein had high expression level in BL21 (DE3) strain of E. coli, and SDS-PAGE analysis showed its molecular weight was about 24 kDa. RESULT: The induction of E. coli [pET32-JAZ1] in different temperature, induction time, IPTG concentrations and IPTG adding time of E. coli were performed. The induction time and the induction temperature are positively related trends with SmJAZ1 protein expression, and IPTG concentration had no significant impact in protein expression, whereas IPTG adding time had significant impact on protein expression. CONCLUSION: Shaking the culture at 30 degrees C until the A600 is approximately 0.9 (2 h in LB), and add IPTG to a final concentration of 0.1 mmol x L(-1), and then the optimal expression of SmJAZ1 recombinant protein were accumulated after the induction time of 20 h. PMID- 23627164 TI - [Cultivation of Panax ginseng adventitious roots in bubble bioreactors]. AB - OBJECTIVE: To study cultivation of Panax ginseng adventitious roots in bubble bioreactors. METHOD: The adventitious roots were obtained through tissue culture different types of bioreactors. The contents of ginsenosides Re, Rb1 and Rg1 were determined by HPLC while the contents of polysaccharides were determined by ultraviolet spectrophotometry. RESULT: The results showed that of the three types tested, the most efficient bioreactor for cultivation of the ginseng adventitious roots was the cone-type bioreactors (with the 120 degrees ), in which, the growth curve of adventitious roots was S-shaped. The maximum biomass was obtained on the 40th day, with the fresh weight, dry weight and growth rate reaching the maximum, which were 113.15 g, 9.62 g and 63.13 times respectively, and the concomitant contents of polysaccharide and ginsenoside were 2.73% and 2.25 mg x g(-1). CONCLUSION: The results showed that the most efficient bioreactor for cultivation of the ginseng adventitious roots was the cone-type bioreactors (with the 120 degrees). These results provide a theoretical reference for developing an efficient production process of active metabolites of ginseng in the scale-up cultivation. PMID- 23627166 TI - [Proteome analysis on interaction between Anoectochilus roxburghii and Mycorrhizal fungus]. AB - OBJECTIVE: To study the mechanism of plant growing promoted by Mycorrhizal fungus through the difference of proteomes. METHOD: The differential proteomes between uninoculated and inoculated endophytic fungi, Epulorhiza sp. on Anoectochilus roxburghii were analyzed by two-dimensional gel electrophoresis and MALDI-TOF/TOF mass spectrum. RESULT AND CONCLUSION: Twenty-seven protein spots were analyzed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Twenty-two candidate proteins were identified by database comparisons. The function of these proteins mostly involved in signal transduction, metabolic regulation, as well as photosynthesis and substance metabolism. The results indicate that the regulator control system of plant is influenced by fungi action, and the positive regulation improves substance metabolism and photosynthesis, which results in strong plant and higher resistance. It is also deduced that silent genes may exist in endosymbiosis plants. PMID- 23627167 TI - [Tissue cultivation of tiller buds of Epimedium wushanense]. AB - OBJECTIVE: To established the rapid tissue propagation system of Epimedium wushanense, in order to provide theoretical basis for industrialized seed cultivation. METHOD: Tiller buds E. wushanense were used as explants, with MS, B5, WPM as basic media, and added with different concentrations of plant growth regulators such as 6-BA, NAA and GA3, in order to conduct a systematic study on induction and propagation conditions for tiller buds. RESULT: The suitable method for sterilizing bud was to disinfect with 75% ethanol for 30 s, and then treated with 0.1% HgCl2 for (4 + 2) min for consecutively twice, which could control the pollution rate below 5% and the survival rate above 75%. The optimal medium for bud induction was WPM + 6-BA 2.0 mg x L(-1) + NAA 0.1 mg x L(-1) + GA3 0.5 mg x L(-1), with the induction rate of 75.5%; meanwhile, the basic medium and 6-BA showed significant effect on the induction rate. The propagation medium suitable for buds was MS +6-BA 2.0 mg x L(-1) + NAA 0.5 mg x L(-1), with the propagation rate of 3.3. The optimal growth of rooting medium was 1/2 WPM + IBA 0.5 mg x L( 1) + activated carbon which (0.05%), with the rooting rate of 90%, three to six strong seedlings in each plant. CONCLUSION: The disinfection method suitable for tiller buds and the medium combination suitable for induction, propagation and rooting of adventitious buds are screened out to establish the rapid cultivation system for tiller buds of E. wushanense. PMID- 23627168 TI - [Identification of EST-SSRs in Taxus cuspidata based on high-throughput sequencing]. AB - OBJECTIVE: Taxus species are highly valued for the production of taxol. Based on high-throughput sequenceing, EST-SSRs were explored and studied in the transcriptome of Taxus cuspidata. METHOD: T cuspidata leaf cDNA was extracted and sequenced by 454 GS FLX Titanium. High-quality sequences were assembled using Newbler Assembler Software, which produced unique sequences. SSRs motif was explored using simple sequence repeat identification tool (Perl Script). Primers were designed using PRIMER3. RESULT: A total of 81 148 high-quality reads from the needles of T. cuspidata were produced using the Roche GS FLX Titanium system. A total of 20 557 unique sequences were obtained. There were 753 simple sequence repeat motifs identified. Primers of PCR were obtained for 519 EST-SSRs, randomly selected cloning sequencing revealed that 87.5% of ESTs were the same as the results of Sanger sequencing. CONCLUSION: The results provide the first EST-SSRs collection in Taxus and are essential for future efforts of gene discovery, functional genomics, and genome annotation in related species. PMID- 23627169 TI - [Chemical constituents from cell suspension cultures of Cudrania tricuspidata]. AB - Ten compounds were isolated and purified from cell suspension cultures of Cudrania tricuspidata with silica-gel column chromatography, semi-preparative HPLC and Sephadex LH-20. On the base of their physicochemical properties and spectral data, their structures were identified as 1, 3, 5-trihydroxy4-(3, 3 dimethylallyl) xanthone (1), wighteone (2), 6-prenylapigenin (3), licoflavone C(4), cudraflavanone C(5), erythrivarone A (6), derrone (7), carthamidin (8), genistein (9) and aromadendrin (10). Among them, compounds 2-10 were flavonoids, and compound 1 was a xanthone which was isolated from the plant for the first time. PMID- 23627170 TI - [Chemical constituents from cell cultures of Morus alba]. AB - The column chromatography on silica gel, Sephadex LH-20 and semi-preparative HPLC were used to separate and purify the compounds from the EtOAc extract of medium and MeOH extract of cell cultures of Morus alba. Eight compounds were isolated. Based on physico-chemical properties and spectroscopic data, their structures were identified as isobavachalcone (1), genistein (2), norartocarpetin (3), albanin A (4), guangsangon E (5), mulberrofuran F (6), chalcomoracin (7), kuwanon J (8). Compounds 3-6 were isolated from the cell cultures of M. alba for the first time. PMID- 23627171 TI - [Studies on metabolism of total terpene ketones from Swertia mussotii with human intestinal bacteria]. AB - OBJECTIVE: To study the metabolism of total terpene ketones from Swertia mussotii with human intestinal bacteria. METHOD: Total terpene ketones were incubated with human intestinal bacteria under an anaerobic environment and at 37 degrees C. The metabolites were extracted by ethyl acetate processing, detected by HPLC-DAD method. A qualitative analysis was made for its metabolites by HPLC-MS. RESULT: Eight metabolites were detected from total terpene ketones from S. mussotii with human intestinal bacteria, and two of them were preliminarily identified as gentianine and mangiferin aglycon. CONCLUSION: Total terpene ketones can be metabolized with human intestinal bacteria, which provides basis for experiments on the metabolism process total terpene ketones from S. mussotii with human intestinal bacteria. PMID- 23627172 TI - [PCR-SSCP molecular identification of Panax ginseng and P. quinquefolius based on ITS2 bar coding SNPs]. AB - OBJECTIVE: To establish a method for identifying Panax ginseng and P. quinquefolius with PCR-SSCP, on the basis of specific SNP identification sites of their ITS2 bar codes. METHOD: ITS2 sequences of P. ginseng and P. quinquefolius recorded in GenBank were searched to conduct a comparative analysis and screen out specific SNP identification sites of their ITS2 bar codes. Based on that, the Polymerase Chain Reaction-Single Strand Conformation Polymorphism (PCR-SSCP) method was adopted for analyzing 11 P. ginseng samples and 10 P. quinquefolius samples and verifying sequencing of their PCR products. RESULT: The P. ginseng and P. quinquefolius samples had the same agarose mages of PCR-SSCP with the standard medicines. There were significant differences between the PCR-SSCP agarose mages of P. ginseng and P. quinquefolius, with identifical identification results between PCR-SSCP and sequencing. CONCLUSION: Compared with the sequencing method, PCR-SSCP is so rapid and accurate that it can be used for identifying P. ginseng and P. quinquefolius medicines. PMID- 23627173 TI - [Authentication of Lonicera japonica using bidirectional PCR amplification of specific alleles]. AB - OBJECTIVE: To identify SNP in flos Lonicerae, and authenticate Lonicera japonica from its adulterants and the mixture by using bidirectional PCR amplification of specific alleles (Bi-PASA). METHOD: SNP of L. japonica and its adulterants was identified by using ClustulW to align trnL-trnF sequences of the Lonicera genus from GenBank database. Bi-PASA primer was designed and the PCR reaction systems including annealing temperature optimized. Optimized result was performed in 84 samples to authenticate L. japonica, its adulterants and the mixture. RESULT: When the annealing temperature was 61 degrees C, DNA from L. japonica would be amplified 468 bp whereas PCR products from all of the 9 adulterants were 324 bp. The established method also can detect 5% of intentional adulteration DNA into L. japonica. CONCLUSION: The Bi-SPASA could authenticate L. japonica from its adulterants and the mixture. PMID- 23627174 TI - [Genetic transformation of Pinellia ternata with Agrobacterium tumefaciens mediated sHSP genes]. AB - OBJECTIVE: To establish an efficient genetic transformation system of Pinellia ternata. METHOD: With petioles from test-tube seedlings of P. ternata as explants, Agrobacterium tumefaciens mediation method was adopted to explore the effect of phenolic substances, A. tumefaciens's concentration, infection time, pre-incubation time and co-cultivation time on genetic transformation efficiency of P. ternata. RESULT AND CONCLUSION: The genetic transformation efficiency could be effectively enhanced by infecting in A. tumefaciens culture containing AS 40 mg x L(-1) for 15 min for three days. The petioles were put into the differentiation medium containing 150 mg x L(-1) Kan and 350 mg x L(-1) Carb to screening and cultivation. After around 30 days, microtubers could be observed at both sides of the petioles. Gus staining and PCR verification on the regenerated plants showed that the exogenous gene sHSP had been integrated into genome of P. ternata. PMID- 23627175 TI - [Cultivation of protocorms of Dendrobium candidum in air-lift bioreactors]. AB - OBJECTIVE: To explore the factors affecting the growth of protocorms of Dendrobium candidum and substance synthesis in a reactor, in order to provide a new method for mass production of raw materials of D. candidum. METHOD: Protocorms in vitro were used as experimental materials to study the effect of inoculum volume, light intensity and air volume on the growth of protocorms of D. candidum and the accumulation of polysaccharide and dendrobine in a 3 L-air lift balloon type bioreactor. RESULT: After 30 days of cultivation in a bioreactor, protocorms became dark green and grew well at the inoculum volume of 10 g x L( 1). The polysaccharide content in protocorms showed no difference at various inoculum volumes; whereas the dendrobine content showed differences (with the highest treatment at the inoculum volume of 10 g x L(-1)), particularly the productions of polysaccharide and alkaloid reached the maximum at the inoculum volume of 10 g x L(-1). The condition of 1 600 lx of light intensity was the most favorable for the growth of protocorms. Though light played a role of improving the accumulation of polysaccharide in protocorms of D. candidum, it could inhibit the accumulation of dendrobine. Polysaccharide content and production were better under light conditions of 1 600 and 2 400 lx than dark conditions. Despite the maximum dendrobine content in dark conditions, the dendrobine production showed the maximum in the light condition of 1 600 lx due to poor growth of protocorms. Protocorms grew well and became dark green at the air volume of 0.2 vvm (air volume culture volume per minute) , which was better than at 0.1 and 0.3, with maximum polysaccharide and dendrobine contents and productions. CONCLUSION: In a 3 L-air lift balloon type bioreactor with a working volume of 2 L, the conditions of 10 inoculum volume, 1 600 lx light intensity and 0.2 air volume were favorable for the growth of protocorms and the production of dendrobine. This demonstrates that the cultivation of D. candidum and substance synthesis in a reactor is an effectie approach for mass production of polysaccharide and dendrobine. PMID- 23627176 TI - [Induction of adventitious roots of Echinacea pallida and accumulation of caffeic acid derivatives]. AB - OBJECTIVE: To investigate the effect of auxins 2,4-D,IAA,IBA,NAA on induction of adventitious roots as well as that of IBA concentrations on the growth of adventitious roots and the accumulation of caffeic acid derivatives, with test tube seedling leaves Echinacea pallida as the explant, and cultivate adventitious roots in bioreactors. RESULT: 1.0 mg x L(-1) IBA was found the best for the induction of adventitious roots, with the numer of induced adventitious roots up to 22. 5 in each culture dish. Among different concentrations for suspension cultivation of IBA tested, 1.0 mg x L(-1) IBA was found the most suitable for the growth of adventitious roots and the accumulation of caffeic acid derivatives. In a 5 L balloon type bubble bioreactor, 8.98 g x L(-1) dry weight was achieved after one month, which was 2.05 times of 4.38 g x L(-1) dry weight cultivated in a triangular flask. The content of echinacoside cultivated in a bioreactor was 14.08 mg x g(-1) DW, which was 2.4 times of cultivated roots. The contents of chlorogenic acid, chicoric acid and total caffeic acid derivatives were 4.0-25.6 times of ultivated roots. CONCLUSION: The study can provide high-quality biomedical drugs containing such caffeic acid derivatives as echinacoside for mass production of Echinacea purpurea medicines. PMID- 23627177 TI - [Molecular identification of astragali radix and its adulterants by ITS sequences]. AB - OBJECTIVE: To explore a new method for identification Astragali Radix from its adulterants by using ITS sequence. METHOD: Thirteen samples of the different Astragali Radix materials and 6 samples of the adulterants of the roots of Hedysarum polybotrys, Medicago sativa and Althaea rosea were collected. ITS sequence was amplified by PCR and sequenced unidirectionally. The interspecific K 2-P distances of Astragali Radix and its adulterants were calculated, and NJ tree and UPGMA tree were constructed by MEGA 4. RESULT: ITS sequences were obtained from 19 samples respectively, there were Astragali Radix 646-650 bp, H. polybotrys 664 bp, Medicago sativa 659 bp, Althaea rosea 728 bp, which were registered in the GenBank. Phylogeny trees reconstruction using NJ and UPGMA analysis based on ITS nucleotide sequences can effectively distinguish Astragali Radix from adulterants. CONCLUSION: ITS sequence can be used to identify Astragali Radix from its adulterants successfully and is an efficient molecular marker for authentication of Astragali Radix and its adulterants. PMID- 23627178 TI - [Researches on influence of squalene synthase gene polymorphism on catalytic efficiency of its encode enzyme in Glycyrrhiza uralensis]. AB - OBJECTIVE: To analyse the polymorphism of squalene synthase gene and reveal the influence of squalene synthase (SQS) gene polymorphism on the catalytic efficiency of its encode enzyme in Glycyrrhiza uralensi. METHOD: The total RNA was extracted. PCR was used to amplify the coding sequences of squalene synthase gene, which were sequenced and analysed. The expression vectors containing different SQS gene sequences, including SQS1C, SQS1F, SQS2A, SQS2B, were constructed and transformed into Escherichia coli BL21. The fusion protein was induced to express by IPTG, then was isolated, purified and used to carry out the enzymatic reaction in vitro. GC-MS was used to analyse the production. RESULT: There were three kinds of gene polymorphism existing in SQS1 gene of G. uralensis, including single nucleotide polymorphism (SNPs), insertion/deletion length polymorphism (InDels) and level of amino acid, the proportion of conservative replace of SQS1 was 53.94%, and there were 2 mutational sites in structural domains. The proportion of conservative replace of SQS2 was 60%, and there was 1 mutational site in structural domains. The production squalene could be detected by GC-MS in all the 4 kinds of enzymatic reactions. The capacity of accumulating squalene of SQS1F was higher than other SQS genes. CONCLUSION: The polymorphism of SQS gene was quite abundant in G. uralensis, which maybe the molecular foundation of the formation of high-quality liquorice. PMID- 23627179 TI - [Researches on the influence of 3-hydroxy-3-methylglutary-coenzyme A reductase gene polymorphism on catalytic efficiency of its encode enzyme in Glycyrrhiza uralensis]. AB - OBJECTIVE: To analyse the effect of expression proteins containing different escherichia coli of 3-hydroxy-3-methylglutary-coenzyme A reductase(HMGR) genic mutation on the conversion efficiency of MVA with GC-MS method, in order to lay a foundation for revealing the function of HMGR gene polymorphism of Glycyrrhiza uralensis in the production of high-quality G. uralensis medicines. METHOD: The expression carrier was established from four HMGR genic mutation types cloned from G. uralensis and transformed into Escherichia coli BL21. The protein was induced to express, detected and purified. The purified protein was adopted for in vitro enzymatic reaction. TLC and GC-MS were used for qualitative and quantitative analysis on reaction products. RESULT: The catalytic activity of L/V genotype(-HSL and -HSV) was similar, and so was the catalytic activity of the genotype with GA insertion (GALLV and GALSV), but the catalytic activity of the latter was around 2 times higher than that of the former. CONCLUSION: The functional gene polymorphism of G. uralensis may be the molecular foundation for the production of high-quality G. uralensi medicines. PMID- 23627180 TI - [Analysis on correlation between 3-hydroxy-3-methylglutary-coenzyme A reductase gene polymorphism of Glycyrrhiza uralensis and content of glycyrrhizic acid]. AB - OBJECTIVE: To reveal the 3-hydroxy-3-methylglutary-coenzyme A reductase (HMGR) gene polymorphism of Glycyrrhiza uralensis, and the correlation between HMGR gene polymorphism and the content of glycyrrhizic acid. METHOD: Liquorice plants containing different content of glycyrrhizic acid were used as materials. RT-PCR was used to amplify their HMGR gene sequences, which were connected with vector pMD19-T for clone sequencing. Multiple alignments were performed to analyse HMGR gene polymorphism of G. uralensis. Then the correlation between HMGR gene polymorphism and the content of glycyrrhizic acid was revealed. RESULT: HMGR gene sequences polymorphism included codon mutation, base substitution mutation, copy number polymorphism and allele heterozygosity. There were 4 types of mutations in HMGR gene coding amino acid sequences, namely -HSL, -HSV, GALLV, GALSV. Among them, -HSV type was common in liquorice plants, -HSL type only existed in liquorice plants with low content of glycyrrhizic acid, and GALSV type only existed in liquorice plants with high content of glycyrrhizic acid. CONCLUSION: HMGR gene sequences of G. uralensis are highly polymorphic and related to the content of glycyrrhizic acid. PMID- 23627181 TI - [Effect of different developmental stage on plant growth and active compounds in Scutellaria baicalensis]. AB - OBJECTIVE: To study the developmental phase on the growth and active compounds in Scutellaria baicalensis. METHOD: Seeds of wild plants were collected from Laiwu and sowed in Fangshan (Beijing) and Laiwu (Shandong). Samples of aerial and underground parts were collected in five growth periods of sprouts, seedlings, flowering, seed drop and withered periods respectively. The length of taproot, fresh weight of root, diameter of taproot and the length of stem were determined. The content of active compounds and total flavonoids were determined by HPLC and ultraviolet spectrophotometry respectively. The transcripted level of PAL1, PAL2, PAL3, C4H, 4CL, CHS, GUS and UBGAT were analyzed with RT-PCR. RESULT: The results showed that the aerial part of S. baicalensis grew quickly before flowering stage, and the underground part grew mostly between the periods of flowering and withered. In the whole growing developmental periods, the content of total flavonoids was not changed significantly, the content of baicalin was increased gradually and the content of baicalein was decreased gradually. Expression level of PAL and 4CL was the highest in withered period, CHS was increased between flowering and seed drop and decreased in withered period. CONCLUSION: Seedlings and withered periods may be the key phase affecting the growth and active compounds in S. baicalensis. PMID- 23627182 TI - [Effect on different concentrations of exogenous hormones on baicalin in Scutellaria baicalensis callus]. AB - OBJECTIVE: To determine the content of baicalin in Scutellaria baicalensis callus induced by different doncentrations of exogenous hormones. METHOD: HPLC system was adopted to determine baicalin in S. baicalensis callus. Chromatographic conditions: ODS column was adopted, with methanol-water-phosphate (47: 53: 0.2) as the mobile phase. The flow velocity was 1 mL x min(-1), the detective wavelength was 280 nm, and the temperature of column was room temperature. RESULT: S. baicalensis callus induced by 6-BA 1.0 mg x L(-1) + NAA 0.5 mg x L(-1) showed the highest baicalin content, up to 49.78 mg x g(-1). CONCLUSION: The experiment is such a simple, rapid and stable method for determining the baicalin content that it can be used for determining the baicalin content in S. baicalensis callus. PMID- 23627183 TI - [Study on tissue cultivation of adventitious roots of Pseudostellaria heterophylla]. AB - OBJECTIVE: To systematically optimize the cultivation conditions of adventitious roots of Pseudostellaria heterophylla. METHOD: Tissue cultivation technology and ultraviolet spectrophotometry were adopted to observe the effect of inoculum volume, sucrose concentration, inorganic salt concentration, number of cultivation days, gradual scale-up cultivation and bubble different angles of bioreactor on the growth of adventitious roots of P. heterophylla, and determine the content of constituents such as saponin, polysaccharide and amino acid. RESULT: The propagation multiple of adventitious roots reached the maximum when the inoculum was 6 g in a 1 L culture shake flask. With the increase in sucrose concentration, the dry weight propagation multiples of adventitious roots followed an up and down trend. The inorganic salt concentration in a cultivation dish had a greater effect on the growth of adventitious roots, particularly 3/4 MS was the most favorable for the growth of adventitious roots. The growth curve of P. heterophylla was "S", with the biomass reaching the maximum at the 28th day. CONCLUSION: The inoculum volume, sucrose concentration, inorganic salt concentration, gradual scale-up cultivation and angles of bubble bioreactor had a significant effect on the growth of adventitious roots of P. heterophylla. The contents of saponin and amino acid in adventitious roots were higher than that in cultivated P. heterophylla, whereas the polysaccharide content were lower than that in cultivated P. heterophylla. PMID- 23627184 TI - [Preliminary study on cultivation of adventitious roots of Hypericum perforatum in bioreactors]. AB - OBJECTIVE: To cultivate adventitious roots of Hypericum perforatum in bioreactors, in order to seek for suitable conditions for adventitious growth. METHOD: The effect of IBA concentration, sugar type and concentration, inoculum volume and air volume of adventitious roots on the cultivation of adventitious roots of H. perforatum was observed in a 5 L air-lift bioreactor. RESULT: Adventitious roots of H. perforatum were cultivated in a MS culture dish. With the increase of IBA concentration, the propagation coefficient of adventitious roots of H. perforatum was on the rise. The IBA concentration ranging between 1.25-1.75 mg x L(-1) was suitable for the growth of adventitious roots. Adventitious roots grew best with sucrose in MS medium, with the propagation coefficient up to 22.15. When sucrose concentration was 30 g x L(-1), fresh weight, dry weight and propagation coefficient reached the maximum value. An adventitious root reactor with an inoculum volume of 20 g was favorable for the growth of adventitious roots. The air volume of reactors of 0.075 vvm (air volume/culture volume per minute) was favorable for the growth of adventitious roots, with the significant increase in the propagation coefficient of adventitious roots. In the amplification experiment, we found that the cultivation conditions of adventitious roots in a 5 L bioreactor was completely applicable to that in 10 and 20 L bioreactors, and adventitious roots grew well in a large bioreactor. CONCLUSION: IBA concentration, sugar type and concentration, inoculum volume and air volume had a significant effect on the growth of adventitious roots. PMID- 23627185 TI - [Study on optimization of induction system of test-tube tuberous roots from leaves of Rehmannia glutinosa]. AB - OBJECTIVE: To study the effect of sucrose and plant growth substances of different concentrations on the induction of test-tube tuberous roots of Rehmannia glutinosa, in order to establish an efficient system for the induction of test-tube tuberous roots from leaves of R. glutinosa. METHOD: Leaves from test tube seedlings of 85-5 R. glutinosa were used as explants. After rooting induction, they were transferred to medium with orthogonal design for inducing test-tube tuberous roots of R. glutinosa. RESULT AND CONCLUSION: NAA played a significant role in induction of test-tube tuberous roots of R. glutinosa, followed by sucrose and 6-BA. With leaves from test-tube seedlings as the explants, the optimal medium for inducing test-tube tuberous roots of R. glutinosa was MS + BA 3.0 mg x L(-1) + NAA 0.1 mg x L(-1) + sucrose 7%. The study provides an efficient induction system for studies on artificial seeds and secondary metabolism with test-tube tuberous roots of R. glutinosa. PMID- 23627186 TI - [Study on optimization of SRAP-PCR reaction system for Pinellia ternata in Suzhou]. AB - OBJECTIVE: To investigate the optimization system of SRAP-PCR molecular marker technology in the analysis on Pinellia ternata. METHOD: SRAP-PCR reaction system for P. ternata was optimized by L16 (5(4)) orthogonal design with five elements (dNTPs, Mg2+, the template DNA, primers, Taq enzyme) and four standards. RESULT: The most suitable forward primer for SRAP for Pinellia ternata was 5' TGAGTCCAAACCGGAAG-3', while the reverse primer was 5'-GACTGCGTACGAATTACG-3'. The optimized reaction system contained 70 ng DNA template, 0.9 micromol x L(-1) primer, 0.20 mmol x L(-1) dNTP s, 1.5 - 2.0 mmol x L(-1) Mg2+, and 2 U Taq enzyme. CONCLUSION: SRAP-PCR system for P. ternata is established to lay a foundation for future construction of SRAP genetic map of P. ternata. PMID- 23627187 TI - Use of out-of-hours services: the patient's point of view on co-payment a mixed methods approach. AB - INTRODUCTION: In many countries out of hours (OOH) care is offered by different health care services. General practitioners (GP) tend to offer services in competition with emergency departments (ED). Patients behaviour depends on a number of factors. In this study, we highlight the knowledge and ideas of patients concerning the co-payment system. METHODS: We used a mixed methods design, combining quantitative and qualitative research. During two weekends in January 2005, all patients using the ED or the GP OOH service, were invited for an interview with a structured questionnaire. A stratified random sample of patients participated in a semi-structured interview. Both methods add complementary data to answer the research questions. RESULTS: Most mentioned reasons for seeking help at the ED are: accessibility (15.0%), proximity (6.4%) and competence of the staff (5.6%). Reasons for choosing the GP are: GP is easy to find, minor medical problem or anxiety and confidence in the GP. The odds of not knowing the co-payment system are significantly higher in patients visiting the ED (OR 1.783; 95% CI: 1.493-2.129). Mostly GP users recognize the problem of ED overuse. They suggested especially to provide clear information about the tasks of the different services and about the payment system, to reduce ED overuse. CONCLUSION AND DISCUSSION: When intending to shift from ED to GP services for minor medical problems, aiming at just one measure is no option. Information campaigns aiming to address the entire population, can clarify the role of each player in out-of-hours care. PMID- 23627188 TI - Complement factor H functional assay may help to monitor atypical haemolytic uraemic syndrome: a pilot study. AB - BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) results from uncontrolled complement system activation. Complement factor H gene mutations are common causes of aHUS. Plasmatherapy, including plasma infusions and/or plasma exchanges, has been tried in this setting with various successes. At present, we lack a specific marker to monitor functional factor H deficiency-related aHUS. METHODS: We report the use of factor H functional assay in three patients with atypical haemolytic uraemic syndrome. This assay is based on the requirement of soluble complement regulators that bind sheep red cells to prevent haemolysis. As factor H is highly abundant in the plasma, its defect results in haemolysis. Factor H activity was also measured among plasma donors. RESULTS: One patient suffered from a plasma-dependent form of atypical haemolytic uraemic syndrome. Plasma exchanges restored higher factor H activity and were associated with a 15 months disease-free period. In the two other patients, one with a failing renal graft and the other on chronic dialysis, a bout of thrombotic microangiopathy was preceded by a drop of haemolytic activity below normal values. Plasma from healthy donors (N=65) showed only minimal variations of Factor H activity (mean activity: 98.3%, SD=4.0). CONCLUSION: These preliminary data suggest that factor H activity could be of interest in both the diagnosis and the treatment by plasmatherapy of factor H-related aHUS. PMID- 23627189 TI - Drug interactions and adverse drug reactions in the older patients admitted to the emergency department. AB - PURPOSE: The aim of this study was to prospectively evaluate drug interactions and adverse drug reactions (ADRs) in the older patients admitted to the emergency department (ED) and to characterize risk factors. METHODS: In 80 patients aged 65 years and older medication history and ED drug administration were analysed. Medical records were analysed for ADRs by an expert panel which also evaluated their avoidability and causality. An interaction program was used to search for potential drug interactions followed by assessment for clinical significance. Data were analysed using a logistic regression model. The significance level was set at alpha=0.05. RESULTS: Eighty seven ADRs were identified in 37 patients; 18 were the result of an interaction (15 patients). Causality was assessed as definite (n=11), probable (n=62) and possible (n=24). The reason for admission was definitely and probably related to an ADR in 6 and 18 patients respectively. Only 17 (20%) of the ADRs were assessed as unavoidable, while 23 (26%) and 47 (54%) were classified as definitely and possibly avoidable, respectively. ADRs were related with female gender (p=0.023) and number of drugs (p=0.004), but not with high age (p=0.151). Clinically relevant interactions were related with older age (p=0.032) and number of drugs (p=0.003), but not with gender (p=0.380). None of the interactions with ED initiated medications were considered unjustified. CONCLUSIONS: ADRs frequently occur in the older patients admitted to the ED and are an important cause of hospital admissions with a substantial contribution of adverse drug interactions. PMID- 23627190 TI - Time course of iron metabolism in critically ill patients. AB - BACKGROUND: Altered iron metabolism plays a central role in the development of anaemia in critically ill patients but the time course of iron status in septic and non-septic critically ill patients has not been well defined. METHODS: Prospective study in a 34-bed medico-surgical ICU. The complete blood count, iron, ferritin, transferrin, and transferrin receptor concentrations, transferrin saturation and C-reactive protein (CRP) concentrations were measured on days 1, 3 and 5 of the ICU stay in 95 consecutive ICU patients (33 with sepsis and 62 without). RESULTS: Despite an identical complete blood count on day 1, septic patients had significantly lower iron concentrations (21 [13-34] vs 50[28-75] microg/dL, p<0.001), transferrin concentrations (169[121-215] vs 214[173-247] mg/dL; p=0.003), and transferrin saturation (11[7-15] vs 19[11-25]%; p= 0.004), and higher ferritin concentrations (432[184-773] vs 204[78-354] ng/mL; p=0.002) than non-septic patients. These alterations were associated with a lower reticulocyte count (42[29-61] vs 58[48-77] x 10(3)/mm3; p=0.028). On day 1, CRP concentrations, which were higher in septic than in non-septic patients (20.0[13.5-27.5] vs 2.3[0.7-5.9] mg/dL; p<0.001), were directly correlated with ferritin concentrations (rho=0.55, p<0.001) and inversely correlated with transferrin concentrations (rho=-0.49, p=0.0001) and transferrin saturation (rho= 0.49, p=0.0001). After 3 days, iron and transferrin concentrations were identical in septic and non-septic patients. Iron metabolism remained altered in both populations until the 5th day. CONCLUSIONS: Iron status is rapidly altered in critically ill patients, especially in septic patients. These alterations persist during the course of the disease and are associated with decreased erythropoiesis. PMID- 23627191 TI - Switching from premixed insulin to basal-bolus insulin glargine plus rapid-acting insulin: the ATLANTIC study. AB - INTRODUCTION: Data on switching from premixed insulin to a basal-bolus regimen in routine clinical practice are sparse. The aim was to evaluate the efficacy and safety of switching from twice-daily premixed insulin to basal glargine plus rapid-acting insulin in a "real-world" clinical practice setting in Belgium and The Netherlands. METHODS: This prospective, 6-month, noninterventional, observational study was conducted in 37 centres in Belgium and 19 centres in The Netherlands. Adults (> or =18 years of age) with type 2 diabetes were eligible if they were not taking oral antihyperglycaemic drugs or only taking metformin. The primary objective was the proportion of patients attaining glycated haemoglobin (HbA1c) <7% at months 3 and 6. Secondary objectives included changes in HbA1c, weight, body mass index (BMI), insulin doses, hypoglycaemic events, and treatment satisfaction. RESULTS: There were 214 patients from Belgium and The Netherlands enrolled. Mean age was 64.6 years, weight was 89.5 kg, BMI was 31.4 kg/m2, and duration of diabetes was 12.1 years. At month 6, the percentage of patients with HbA1c <7% increased from 3.3% to 24.9% (p<0.001). Mean HbA1c at baseline was 8.9%; mean change from baseline was -1.5% (p<0.001). Glargine and prandial insulin doses increased (p<0.001, each), while body weight and BMI were unchanged. Hypoglycaemic events did not increase. Overall treatment satisfaction improved significantly (p<0.001). CONCLUSIONS: In a Belgian and Dutch clinical practice setting, patients with type 2 diabetes that is poorly controlled on premixed insulin experienced significant improvements in glycaemic control, without a concomitant increase in hypoglycaemic events or weight, when switched from premixed insulin to basal-bolus glargine plus rapid-acting insulin. As a result, treatment satisfaction significantly improved. PMID- 23627192 TI - Cutaneous metastatic tuberculous abcess in a patient with cervico-mediastinal lymphatic tuberculosis. AB - Metastatic tuberculous abcess or tuberculous gumma is a rare form of cutaneous tuberculosis resulting from haematogenous spread from a non-cutaneous tuberculous focus. A 26-year old patient of Pakistani origin presented at our clinic with an abcess on his right thigh that had slowly grown over a period of two months to a total size of 30 cm. Based on clinical findings, microbiology, CT thigh and CT chest, our patient was diagnosed with a tuberculous abcess and cervico mediastinal tuberculous lymphadenitis. Antituberculosis drugs were initiated. Cutaneous tuberculosis should be included in the differential diagnosis of chronic cutaneous abcesses, especially in patients from tuberculosis endemic nations. PMID- 23627193 TI - Predictors of quit success in Belgian participants of a varenicline observational smoking cessation study. AB - BACKGROUND: We evaluated efficacy, predictors of quitting success and the safety profile of varenicline for smoking cessation in the Belgian participants in an observational, "real world" study. METHODS: In this post-hoc analysis of a prospective, observational, non-comparative study, participants were adult smokers who were motivated to quit and were prescribed varenicline in accordance with the recommendations of the European Summary of Product Characteristics. The 7-day point prevalence of abstinence at Weeks 12 and 24 was determined based on patient reporting, and these data were further analysed by time to first cigarette on waking and by the use of behavioural support. The safety profile of varenicline was also assessed. RESULTS: Overall, 61.1% of participants (n= 226) successfully quit smoking by the end of Week 12. There was a significant association between abstinence and time to first cigarette on waking (Week 12: OR, 0.69 [95% CI, 0.50-0.94], p = 0.02; Week 24: OR, 0.70 [95% CI, 0.52-0.94], p=0.02) and the use of behavioural support (Week 12: OR, 6.18 [95% CI, 3.41 11.2], p<0.01; Week 24: OR, 5.37 [95% CI, 2.89-9.98], p<0.01). The most frequent treatment-emergent adverse event was nausea (9.3%). CONCLUSIONS: In this post-hoc analysis, varenicline was an effective smoking cessation aid with an acceptable safety profile in real world clinical practice in Belgian smokers. Significant predictors of abstinence were time to first cigarette on waking and use of behavioural support. PMID- 23627194 TI - The attitude of Flemish paediatricians regarding informed consent of adolescents. AB - BACKGROUND: Since 2002 the Belgian law requires an informed consent of the patient before each medical intervention. This provision applies also for adolescent patients on condition that the physician considers the young patient as competent to autonomously participate in the decision making process. AIM: The purpose of this study is to evaluate to what extent Belgian paediatricians from the Flemish part of the country have implemented the legal requirements for informed consent of adolescent patients, in particular when they consult alone. METHODS: In the frame of a larger study regarding the relation between paediatricians and their patients, a questionnaire was sent via regular mail to 570 Flemish paediatricians, evaluating how and how often they obtain an informed consent of the adolescent when consulting a physician unaccompanied. RESULTS: In only 1% of all consultations an adolescent consulted the physician alone and agreed to a medical intervention on his/her own. The information given by the paediatrician did not differ if the adolescent consulted alone or was accompanied by (one of) his/her parents for the following items: purpose and type of treatment (100% vs 100%), duration of treatment (92% vs 94%) and aftercare (89% vs 93%). However, the information differed with regard to alternatives to the treatment (65% vs 76%), degree of urgency (89% vs 95% ), treatment related risks (82% vs 90%) and cost (21% vs 45%). 18.6% of the paediatricians consider age as the single criterion to evaluate the competence of the adolescent to provide an informed consent; other criteria that are considered: experience (92%), insight into and factual understanding of the clinical picture (84%). To fulfil the tasks of providing information and asking for consent, paediatricians rarely had recourse to prior established protocols (14%), they preferred to rely on proper experience and expertise (81%). Fifty percent appealed to the opinion of other health care providers. CONCLUSIONS: Although the Belgian law stipulates regulations that should be complied with by the physician during the decision making process about any medical intervention on adolescents, this legislation has rarely been put into practice, as the adolescents used their right to autonomously consent in barely 1% of all paediatric consultations. For the majority of the respondents other criteria than age were taken into account to consider an adolescent as able to provide informed consent. PMID- 23627195 TI - Four-year analysis of microbial aetiology and antimicrobial sensitivity patterns of peritoneal-dialysis related peritonitis in a tertiary care facility. AB - Peritonitis related to peritoneal dialysis increases morbidity and mortality and is the main reason for switching to haemodialysis. In this study, we analysed the dialysate of 164 peritoneal dialysis patients that was sent to our laboratory between January 2005 and August 2009. There were 196 peritonitis episodes identified in 78 patients. For all episodes, microbial aetiologies and in-vitro antimicrobial sensitivities were determined in addition to parameters such as the leukocyte count (WBC) and the result of the Gram stain. Results in children were analysed separately because of previously described differences in aetiology. In both groups, Gram positives were most commonly isolated, followed by Gram negatives and fungi or yeasts. In children, the proportion of coagulase-negative staphylococci compared to S. aureus is smaller than in adults. Gram stain showed predominant morphotypes concordant with culture results in 28% of episodes. A significant difference in WBC count was found between culture-positive (mean=3117 x 10(9)/L) and culture-negative (mean=981 x 10(9)/L) episodes in adults (p=0.001). The WBC count in episodes caused exclusively by CNS (mean=1502x10(9)/L) was also on average significantly lower (p=0.001) compared to all culture positive episodes. Resistance to methicillin was registered in 33% of cultures, positive for staphylococci. All Gram-positives were sensitive to vancomycin. Coverage of Gram-negatives by ceftazidim and quinolones was excellent (89%). Based on local sensitivity data and known characteristics of antimicrobials, a first-line empirical combination of intraperitoneal vancomycin with orally administered ciprofloxacin seems indicated in our population. Pathogens of positive aerobic cultures were sensitive in-vitro to their combined antimicrobial effect in 90% of cases. PMID- 23627196 TI - Favourable outcome in a patient bitten by a rabid bat infected with the European bat lyssavirus-1. AB - The classic rabies virus (genotype 1) has been eliminated in Western Europe, but related lyssaviruses still circulate in local bats. In August 2010, a Belgian photographer was bitten upon provocation of a disoriented Eptesicus serotinus bat in Spain. The bat was infected with European bat lyssavirus-1 (genotype 5). The isolate proved highly neurovirulent in mice. The patient had received preventive rabies immunisations years before the incident and received two boosters with the HDCV rabies vaccine afterwards. Available vaccines are based on the classic rabies virus, which is significantly divergent from the European bat lyssavirus 1. Fortunately, the patient's serological immune response demonstrated satisfactory neutralisation of the 2010 EBLV-1 isolate, using an intracerebral challenge model in mice. Most likely, the patient's life was saved thanks to vaccination with the classic rabies vaccine, which proved sufficiently protective against European bat lyssavirus-1. This case highlights the need for preventive rabies vaccination in people, who come in contact with bats and to seek medical council after a scratch or bite from a bat. PMID- 23627197 TI - Bilateral orbital metastases from small cell lung cancer: a case report. AB - A 46-year-old man with a history of heavy smoking for last 20 years presented with coughing. Computed tomography (CT) scan of the thorax showed a mass in right lung tissue. A fine needle aspiration biopsy (FNAB) confirmed the diagnosis of small cell lung cancer (SCLC), with limited stage at presentation. CT scan and MRI of the orbits demonstrated that the solid masses separately invaded the posterior orbita bilaterally. Then, we made a diagnosis of bilateral posterior orbital metastases from SCLC. Simulation CT imaging was obtained, using head mask. Both of the orbital masses were contoured as the planning target volume. A palliative radiotherapy of 30 Gy was planned, with 3D conformal technique using 12-15 MeV electrons. I presented the case of rare bilateral posterior orbital metastasis due to SCLC. PMID- 23627198 TI - Intraabdominal abscess related fungaemia caused by Rhodotorula glutinis in a non neutropenic cancer patient. AB - Rhodotorula glutinis is a rare fungal infection that is especially observed in immune-compromised patients. It is common in the skin, faeces, nails, sputum, gastrointestinal system and adenoid tissue. However, the incidence of Rhodotorula glutinis is increased in both local and systemic infections in recent years. Presented here is a case of Rhodotorula glutinis fungaemia that isolated from subhepatic abscess formation and blood in a patient who was operated with Roux-en Y technique due to gastric adenocarcinoma. Fungal sepsis is an important cause of fever resistant to antibiotic therapy that is often taken into marginal account. It should instead be particularly considered in patients with a history of intraabdominal surgery and non-neutropenic cancer patients. The case described illustrates an episode of systemic infection by Rhodotorula glutinis, correlated with the presence of intraabdominal abscess and without central venous catheters. This is the first case of fungaemia by Rhodotorula glutinis with an intraabdominal abscess source reported from Turkey. PMID- 23627199 TI - Methyltestosterone-induced transient hyperthyroidism in a hypothyroid patient. AB - In this paper we report different effects of methyltestosterone administration on thyroid function in two twin brothers, one of whom suffered from hypothyroidism, while the other was apparently healthy. Methyltestosterone, which is a non aromatisable androgen, resulted in a marked reduction of thyroxine-binding globulin (TBG), irrespectively of the patient's hormonal status, while the impact on free thyroid hormones depended on baseline thyroid function. Our research shows that a possibility of the use of non-aromatisable androgens or other drugs affecting TBG levels should be taken into consideration in all hypothyroid patients receiving levothyroxine, in whom thyroid hormone status suddenly changes without any apparent reason. PMID- 23627200 TI - A rare cause of severe recurrent abdominal pain. AB - Recurrent abdominal pain may be enigmatic to solve. We report three cases, presenting after a protracted history of severe recurrent bouts of epigastric pain, impeding daily activities. In all cases, serology for strongyloidiasis stercoralis proved positive. In one case, stool examination was positive for larvae. Treatment with ivermectin or albendazole resulted in complete resolution of abdominal symptoms without recurrence in all three cases. PMID- 23627201 TI - Acute renal failure due to diffuse extramedullary plasmocytoma. PMID- 23627202 TI - Medullary sponge kidney and von Meyenburg complex. PMID- 23627204 TI - The spies who sabotaged global health. PMID- 23627203 TI - Bilateral synchronous multifocal renal clear-cell carcinoma. PMID- 23627205 TI - Wisdom in numbers. PMID- 23627206 TI - Beyond symptoms. PMID- 23627208 TI - Tadpoles in space. PMID- 23627207 TI - The tiniest bites. PMID- 23627209 TI - Ant invasion! PMID- 23627210 TI - Anybody home? PMID- 23627211 TI - Preventing the next Chelyabinsk. PMID- 23627213 TI - The strange magic of micro movies. PMID- 23627212 TI - Good bacteria for bad breath. PMID- 23627214 TI - How to make the next big thing. PMID- 23627215 TI - My boss the robot. PMID- 23627216 TI - Future stuff. PMID- 23627217 TI - To print the impossible. PMID- 23627218 TI - Rise of the nano machines. PMID- 23627219 TI - Assembled in code. PMID- 23627221 TI - Mars in motion. PMID- 23627220 TI - Seeds of dementia. PMID- 23627222 TI - Human hybrids. PMID- 23627223 TI - How kitty is killing the dolphins. PMID- 23627224 TI - Mirror molecules. PMID- 23627225 TI - Gun science. PMID- 23627226 TI - Gender gaps. PMID- 23627227 TI - Future forecast. PMID- 23627228 TI - Whackers. PMID- 23627229 TI - Teeter-totter. PMID- 23627230 TI - 'Not acting right'. PMID- 23627231 TI - Wave of the future. PMID- 23627232 TI - Tunnel vision. AB - Since 2000, many studies of advanced emergency airway management have appeared in the medical literature. Although most described patients in the operating room, intensive care unit or emergency department, studies of video laryngoscopy in the field are in progress and beginning to appear in the literature. Video laryngoscopy provides better views of the glottis, and it permits more successful intubations with fewer attempts. Price reductions as more devices, some specifically intended for EMS, enter the market will lower the entry costs for adoption. It is my prediction that in five years, video laryngoscopy will be the method of choice for endotracheal intubation in the field. PMID- 23627233 TI - Putting the 'rap' in 'rapport'. PMID- 23627234 TI - Revolutionary multi-tool. PMID- 23627235 TI - Occupational medicine ABCs. PMID- 23627236 TI - Update on 360 degree data. PMID- 23627238 TI - Can EMS still party? PMID- 23627237 TI - Keeping it cool. PMID- 23627239 TI - How many pharmacies compound and what do they compound? PMID- 23627240 TI - Looking for solutions. PMID- 23627241 TI - Pediatric health care: an introduction. AB - Pediatric healthcare, to include compounded medications, is a challenge for healthcare providers. Although current studies have provided important new information about drug safety and effectiveness for children, carrying out studies in children is difficult. Age-appropriate equipment and medical techniques, along with specialists who are sensitive to a child's concerns, are a must. Therefore, experts must build a foundation and resources that are needed to conduct studies involving pediatric patients. Compounding pharmacists welcome reliable data from which to use when compounding medications for such an elite group of patients. PMID- 23627242 TI - Compounding slow-release capsules: a comprehensive review and an Excel spreadsheet for faster calculations of excipients. AB - Compounding pharmacists throughout the world are compounding a special type of capsule called "slow-release." This type of capsule is a compounding pharmacy application of the commercial hydrophilic matrix tablets. It is a relatively simple system that allows formulating a robust, reliable, and consistent drug system based on 30% w/w to 40% w/w of specific types of hydroxypropyl methylcellulose. The main purpose of these capsules is to attenuate the drug release when there is a clinical need and no commercial medication exists. Five in vitro trials verified and proved this kind of preparation can be compounded by specialized pharmacists achieving substantial attenuation of drug release that resembles the pharmacokinetic profiles of commercial slow-release medications. An in-depth explanation of the mechanism of action of the slow-release capsules is provided. Since the pharmaceutical calculations needed to compound this preparation are time consuming, a suggestion of a faster way to perform these calculations by using a special Excel spreadsheet is provided. The article demonstrates a special table with a comparison between the specifications, results, and conclusions of the five in vitro trials that evaluated the pharmacokinetic rates of compounded slow-release capsules. The regulatory aspect of compounding slow-release capsules is also discussed. PMID- 23627243 TI - Treatment of canine pulmonary arterial hypertension: is tadalafil an appropriate alternative to sildenafil? AB - The drugs tadalafil and sildenafil share the same mechanism. Although more research is necessary to solidify the recommendation of the routine use of tadalafil, human and dog data combined with pharmacokinetic data suggest that dogs may be safely treated for canine pulmonary arterial hypertension with tadalafil for the convenience of less frequent dosing, with effects similar to sildenafil. While more costly, the use of tadalafil has positive implications in improving compliance and, therefore, therapeutic outcomes in canine pulmonary arterial hypertension. This article explores the data for the use of tadalafil in canine pulmonary arterial hypertension and provides example compounded preparations. PMID- 23627244 TI - Treatment options for male hypogonadism. AB - Male hypogonadism is a common condition widely associated with the aging process. Understanding of this condition is continuing to grow as new information is available. Pharmacists are in a very unique position to work with patients and physicians in achieving better diagnosis and treatment plans for the hundreds of thousands of men in the U.S. who are hypogonadal. This article discusses various methods that can be employed to restore testosterone in men and the varying expectations associated with each treatment methods. PMID- 23627245 TI - Adrenal fatigue. AB - This article discusses the function of the adrenal gland and adrenal fatigue, to include the symptoms, possible causes, and treatment of adrenal fatigue. Compounding pharmacists can prepare formulations to assist the patient who is suffering from this syndrome. Included with this article are formulations which require a physician's prescription, as well as nonprescription nutritional supplements. PMID- 23627246 TI - International Academy of Compounding Pharmacists' recommendations for state-based legislative and regulatory initiatives. PMID- 23627247 TI - Calibration of equipment and calibration curves. AB - Calibration involves a comparison of measurements; one of known magnitude of correctness that is compared to another measurement made in as similar a way as possible with a second device. The device with the known or assigned correctness is called the standard. The second device is the test instrument or any of several other names for the device being calibrated. Some of the topics that are briefly discussed in this article are: the definition of calibration, the history of calibration, the basic calibration process, calibration process success factors, how to improve the quality of calibrations, instrument calibrations, the types of measurement error, etc. PMID- 23627248 TI - Basic of compounding: Repackaging, Part 1. AB - This article on the topic of sterile and nonsterile repackaging is based on the content of United States Pharmacopeia 35-National Formulary 30 and how the respective official chapters of the publication relate to pharmacy compounding and practice. The article differentiates between commercial repackagers and pharmacists that repackage in their pharmacy for their patients. It also discusses the standards for packaging and the beyond-use dates that should be assigned. PMID- 23627249 TI - The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women. AB - Menopause impacts 25 million women world wide each year, and the World Health Organization estimates 1.2 billion women will be postmenopausal by 2030. Menopause has been associated with symptoms of hot flashes, night sweats, dysphoric mood, sleep disturbance, and conditions of cardiovascular disease, depression, osteoporosis, osteoarthritis, depression, dementia, and frailty. Conventional hormone replacement therapy results in increased thrombotic events, and an increased risk of breast cancer and dementia as evidenced in large prospective clinical trials including Heart and Estrogen/Progestin Replacement Study I and the Women's Health Initiative. A possible mechanism for these adverse events is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on the hemostatic balance and inflammatory and immune factors. Physiologic sex steroid therapy with transdermal delivery for peri/postmenopausal women may offer a different risk/benefit profile, yet long term studies of this treatment model are lacking. The objective of this study was to examine the long-term effects of compounded bioidentical transdermal sex steroid therapy including estriol, estradiol, progesterone, DHEA, and testosterone on cardiovascular biomarkers, hemostatic, inflammatory, immune signaling factors; quality-of-life measures; and health outcomes in peri/postmenopausal women within the context of a hormone restoration model of care. A prospective, cohort, closed-label study received approval from the Human Subjects Committee. Recruitment from outpatient clinics at an academic medical center and the community at large resulted in three hundred women giving signed consent. Seventy-five women who met strict inclusion/exclusion criteria were enrolled. Baseline hormone evaluation was performed along with baseline experimental measures. Following this, women received compounded transdermal bioidentical hormone therapy of BiEst (80%Estriol/20%Estradiol), and/or Progesterone for eight weeks to meet established physiologic reference ranges for the luteal phase in premenopausal women. The luteal phase hormone ratios were selected based on animal and epidemiologic studies demonstrating favorable outcomes related to traumatic, ischemic, or neuronal injury. Follow-up testing was performed at eight weeks and adjustment to hormone regimens were made including addition of androgens of DHEA and Testosterone if indicated. Experimental subjects were monitored for 36 months. Baseline, 2-month, and annual values were obtained for: blood pressure, body mass index, fasting glucose, Homeostasis Metabolic Assessment of Insulin Resistance (HOMA-IR), fasting triglycerides, total Factor VII, Factor VIII, fibrinogen, Antithrombin III, Plasminogen Activator Inhibitor1(PAL-1), C-reactive protein (CRP), Interleukin-6 (IL-6), Matrix Metalloproteinase-9 (MMP-9), Tumor Necrosis Factor-alpha (TNF), Insulin-like Growth Factor (IGF-1), and sex steroid levels. Psychosocial measures included: Greene Climacteric Scale, Visual Analog Pain Scale, Hamilton Anxiety Scale, Hamilton Depression Scale, Holmes Rahe Stress Scale, Job Strain, and Home Strain. Health outcome measures included the number of prescribed medications used, number of co-morbidities, and endometrial thickness in postmenopausal women with intact uteri. Subjects receiving compounded transdermal bioidentical hormone therapy showed significant favorable changes in: Greene Climacteric Scale scores, Hamilton Anxiety Scale, Hamilton Depression Scale, Visual Analog Pain Scale, fasting glucose, fasting triglycerides, MMP-9, C-reactive Protein, fibrinogen, Factor VII, Factor VIII, Insulin-Like Growth Factor 1, and health outcomes of co morbidities and a number of prescribed medications. Antithrombin III levels were significantly decreased at 36 months. All other measures did not exhibit significant effects. Administration of compounded transdermal bioidentical hormone therapy in doses targeted to physiologic reference ranges administered in a daily dose significantly relieved menopausal symptoms in peri/postmenopausal women. Cardiovascular biomarkers, inflammatory factors, immune signaling factors, and health outcomes were favorably impacted, despite very high life stress, and home and work strain in study subjects. The therapy did not adversely alter the net prothrombotic potential, and there were no associated adverse events. This model of care warrants consideration as an effective and safe clinical therapy for peri/postmenopausal women especially in populations with high perceived stress and a history of stressful life events prior to, or during the menopausal transition. PMID- 23627250 TI - GMPs and GCPs: a topical comparison. PMID- 23627251 TI - Rapid reversible superhydrophobicity-to-superhydrophilicity transition on alternating current etched brass. AB - Reversible surface wetting behavior is a hot topic of research because of the potential engineering applications. In the present work, a hierarchical micro/nanostructure is fabricated on brass by alternate current (AC) etching. The superhydrophilic as-prepared etched brass (EB) turns into superhydrophobic after the modification of stearic acid for 1 min. After annealing at 350 degrees C for 5 min, the superhydrophobic modified EB surface becomes superhydrophilic again. Furthermore, the annealed EB can restore the superhydrophobicity with the remodification of stearic acid. The wetting transition is realized by stearic acid modification and annealing rapidly in 6 min. The wetting transition mechanism is discussed based on the surface chemical analysis. This method is facile and suitable for the construction of large-scale and complex brass surfaces with tunable wetting behaviors. PMID- 23627252 TI - Self-assembly and near perfect macroscopic alignment of fluorescent triangulenium salt in spin-cast thin films on PTFE. AB - Highly fluorescent, discotic trioxatriangulenium dyes were aligned by simple spin casting on substrates with friction transferred PTFE layers. The fluorescent crystalline thin films show near perfect macroscopic alignment on centimeter large areas directly from spin-casting. Gracing Incidence X-ray Diffraction (GIXD) unambiguously allowed the determination of a long-range order unit cell as well as its orientation with respect to the PTFE fibers. Further analysis of the X-ray data, in conjunction with polarized absorption spectroscopy, suggest a lamellar packing model with alternating layers of alkyl chains and ionic dyes oriented parallel to the substrate. This structure results in a highly anisotropic electrostatic potential around the cationic chromophore, causing significant shifts in energy and orientation of the optical transitions. Thus, the optical properties of the material are, to a large extent, controlled by the position of the otherwise inert PF6(-) counterions. The bright fluorescence from the films is also polarized parallel to the PTFE alignment layer. Doping of the thin films with fluorescent energy acceptor traps shows that efficient exciton migration takes place in the thin films. The excellent exciton transfer capabilities, in conjunction with the perfect alignment, might be of interest in future applications in solar energy harvesting or as thin film sensors. PMID- 23627253 TI - The treatment of lacrimal gland prolapse in blepharoplasty by repositioning the glands. AB - Prolapse of the lacrimal gland is an unusual condition. An appearance of bilateral dermatochalasis was observed in the medical examination of a 30-year old female patient with bilateral upper eyelid edema.The patient underwent bilateral blepharopylasty. During the surgery, it was noticed that in the temporal portions of the eyelids, there was a prolabed tissue-like lacrimal gland. We did incisional biopsy from the prolabed tissue that was thought to be orbital lobe of the lacrimal gland and carried out reposition of the orbital rim with 5-0 polyester suture and closed the orbital septum. Lacrimal gland reposition is a procedure which entails the separation of such anatomic structures as orbital septum, adipose tissue, and levator complex. However, failure to recognize a prolapsed lacrimal gland may mistreat by simple excision, and will lead to important alterations in ocular lubrication. In our case, repositioning of the glands was successfully performed during upper-lid blepharoplasty. PMID- 23627254 TI - Thermostated Hamiltonian dynamics with log oscillators. AB - With this work, we present two new methods for the generation of thermostatted, manifestly Hamiltonian dynamics and provide corresponding illustrations. The basis for this new class of thermostats is the peculiar thermodynamics as exhibited by logarithmic oscillators. These two schemes are best suited when applied to systems with a small number of degrees of freedom. PMID- 23627255 TI - Calcitonin measurement in aspiration needle washout fluids has higher sensitivity than cytology in detecting medullary thyroid cancer: a retrospective multicentre study. AB - OBJECTIVE: Only few studies analysed the capability of cytology in detecting medullary thyroid cancer (MTC), and they reported a low accuracy of this diagnostic technique. Recently, calcitonin (CT) measurement in aspiration needle washout (FNA-CT) of thyroid and neck lesions has been reported as a sensitive tool for MTC. The aim of this study is to compare the sensitivity of FNA-CT and cytology in detecting MTC and to assess a cut-off value of FNA-CT for clinical practice. PATIENTS: Thirty-eight MTC lesions from 36 patients were retrospectively studied, diagnosed and treated in four different centres. Furthermore, 52 nonmedullary lesions from subjects undergone biopsy following increased serum CT were collected as a control group. RESULTS: Cytology detected MTC in 21/37 lesions with 56.8% sensitivity. The median FNA-CT value was 2000 pg/ml (range 58-10 000 pg/ml) in MTC and 2.7 pg/ml (range <2-13 pg/ml) in controls (P < 0.001). Using a cut-off of 39.6 pg/ml, MTC lesions could be identified with 100% sensitivity and specificity. As the most important finding, 14 histologically proved MTC lesions could be detected by FNA-CT, despite they were cytologically diagnosed as benign or nonconclusive. CONCLUSIONS: This study shows, as the first in a multicentre series, that FNA-CT sensitivity is higher than that of cytology in diagnosing MTC. To avoid false-negative MTC by cytology, CT measurement in aspiration needle washout is to be performed in all patients undergoing biopsy following high serum CT. PMID- 23627256 TI - On ballistic parameters of less lethal projectiles influencing the severity of thoracic blunt impacts. AB - The development and safety certification of less lethal projectiles require an understanding of the influence of projectile parameters on projectile-chest interaction and on the resulting terminal effect. Several energy-based criteria have been developed for chest injury assessment. Many studies consider kinetic energy (KE) or energy density as the only projectile parameter influencing terminal effect. In a common KE range (100-160 J), analysis of the firing tests of two 40 mm projectiles of different masses on animal surrogates has been made in order to investigate the severity of the injuries in the thoracic region. Experimental results have shown that KE and calibre are not sufficient to discriminate between the two projectiles as regards their injury potential. Parameters, such as momentum, shape and impedance, influence the projectile-chest interaction and terminal effect. A simplified finite element model of projectile structure interaction confirms the experimental tendencies. Within the range of ballistic parameters used, it has been demonstrated that maximum thoracic deflection is a useful parameter to predict the skeletal level of injury, and it largely depends on the projectile pre-impact momentum. However, numerical simulations show that these results are merely valid for the experimental conditions used and cannot be generalised. Nevertheless, the transmitted impulse seems to be a more general factor governing the thorax deflection. PMID- 23627257 TI - An asymmetric Michael addition of alpha,alpha-disubstituted aldehydes to maleimides leading to a one-pot enantioselective synthesis of lactones catalyzed by amino acids. AB - A cheap and fast construction of both enantiomers of substituted succinimides is reported. alpha- or beta-amino acids, such as beta-phenylalanine and alpha-tert butyl aspartate, were found to be efficient organocatalysts for the reaction between alpha,alpha-disubstituted aldehydes and maleimides. Products containing contiguous quaternary-tertiary stereogenic centers are obtained in high to quantitative yields and excellent selectivities utilizing low catalyst loadings (0.5-3.5%). Finally, a one-pot efficient asymmetric synthesis of lactones is described. PMID- 23627258 TI - Public awareness of three major infectious diseases in rural Zhejiang province, China: a cross-sectional study. AB - BACKGROUND: This study aimed to investigate the level of awareness of and factors associated with major infectious diseases in rural China and to provide the most recent baseline data for the prevention and control of these diseases. METHODS: This cross-sectional study was carried out in Zhejiang province between December 2010 and April 2011. Participants were recruited from 36 villages and interviewed by doctors from the community health service using a structured questionnaire. RESULTS: The study sample consisted of 36,377 subjects aged 15 to 80 years old. Study results showed that knowledge of HIV was adequate in 44.21% of rural residents; knowledge of TB was adequate in 52.66% of respondents; and knowledge of HBV was adequate in 60.18% of respondents. People in older age groups and with lower education levels were more likely to have low levels of awareness of these three infectious diseases. Participants in the farming industry had poorer awareness of HIV and HBV, while students and factory workers knew little of TB. The proportions of people reporting being fully satisfied with the control policies for HIV, TB and HBV were 37.70%, 34.25% and 36.12%, respectively. CONCLUSIONS: The level of awareness of HIV, TB and HBV is still low among rural residents. Further national disease control plans for major infectious diseases should emphasise effective and comprehensive health education campaigns to increase public awareness of these diseases in rural areas of China. PMID- 23627259 TI - The indirect effect of attention bias on memory via interpretation bias: evidence for the combined cognitive bias hypothesis in subclinical depression. AB - Little research has investigated functional relations among attention, interpretation, and memory biases in depressed samples. The present study tested the indirect effect of attention bias on memory through interpretation bias as an intervening variable in a mixed sample of non-depressed and subclinically depressed individuals. Subclinically depressed and non-depressed individuals completed a spatial cueing task (to measure attention bias), followed by a scrambled sentences test (to measure interpretation bias), and an incidental free recall task (to measure memory bias). Bias-corrected bootstrapping yielded evidence for the hypothesised indirect effect model, in that an emotional bias in attention is related to a congruent bias in interpretative choices which are in turn reflected in memory. These findings extend previous research and provide further support for the combined cognitive bias hypothesis in depression. Theoretical and clinical implications of our findings are discussed. PMID- 23627261 TI - A class of temporal boundaries derived by quantifying the sense of separation. AB - The perception of moment-to-moment environmental flux as being composed of meaningful events requires that memory processes coordinate with cues that signify beginnings and endings. We have constructed a technique that allows this coordination to be monitored indirectly. This technique works by embedding a sequential priming task into the event under study. Memory and perception must be coordinated to resolve temporal flux into scenes. The implicit memory processes inherent in sequential priming are able to effectively shadow then mirror scene forming processes. Certain temporal boundaries are found to weaken the strength of irrelevant feature priming, a signal which can then be used in more ambiguous cases to infer how people segment time. Over the course of 13 independent studies, we were able to calibrate the technique and then use it to measure the strength of event segmentation in several instructive contexts that involved both visual and auditory modalities. The signal generated by sequential priming may permit the sense of separation between events to be measured as an extensive psychophysical quantity. PMID- 23627260 TI - Pheochromocytoma of the urinary bladder: a systematic review of the contemporary literature. AB - BACKGROUND: Pheochromocytoma (paraganglioma) of the urinary bladder is a rare tumor. Herein we sought to review the contemporary literature on pheochromocytomas of the urinary bladder in order to further illustrate the presentation, treatment options and outcomes of patients diagnosed with these tumors. METHODS: A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed database and using the search terms "paraganglioma, pheochromocytoma, bladder." This search resulted in the identification of 186 articles published between January 1980 and April 2012 of which 80 articles were ultimately included in our analysis. RESULTS: Pheochromocytomas usually occurred in young adult Caucasians (mean age, 43.3 years; range,11-84 years). According to the literature, the most common symptoms and signs of pheochromocytomas of the urinary bladder were hypertension, headache, and hematuria. Of the 77 cases that commented on catecholamine production, 65 patients had biochemically functional tumors. Approximately 20% of patients were treated by transurethral resection alone, 70% by partial cystectomy and 10% by radical cystectomy. The 75 patients with follow-up information had a mean follow-up of 35 months. At the time of last follow-up, 15 (14.2%) had disease recurrence, 10 (9.4%) had metastasis, and 65 (61.3%) were alive. CONCLUSIONS: Pheochromocytomas of the urinary bladder tend to be functional and occur mostly in young adult Caucasians. Patients with localized tumors have an extremely favorable prognosis and may be managed by less aggressive modalities, whereas patients with metastatic disease have a significant reduction in survival rates despite aggressive treatment. PMID- 23627262 TI - Are metabolic syndrome antecedents in prepubertal children associated with being born idiopathic large for gestational age? AB - INTRODUCTION: Being born large for gestational age (LGA) is a risk factor for development of metabolic syndrome (MS) in adolescents and adults. OBJECTIVE: To evaluate prepubertal children born idiopathic LGA to non-obese mothers without gestational diabetes or glucosuria with respect to the presence of MS antecedents. PATIENTS AND METHODS: We conducted a cross-sectional study to compare 40 (19 F) LGA-born prepubertal children of a mean age of 6.1 +/- 2.5 yr and 49 (25 F) appropriate for gestational age (AGA)-born body mass index (BMI) matched peers of a mean age of 5.4 +/- 1.8 yr with respect to their anthropometric data, blood pressure measurements, fasting serum glucose and insulin levels, homeostasis model assessment-insulin resistance (HOMA-IR), and lipids and atherogenic index (AI) [triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C)]. HOMA-IR > 2.5 was used to define IR. HDL-C <= 40 mg/dL and TG >= 110 mg/dL were used to define dyslipidemia. Both groups were further divided into subgroups as obese and non-obese according to their BMI percentiles and the analyses were repeated. RESULTS: Non-obese LGA children had higher waist circumference (WC) standard deviation scores (SDSs) than BMI-matched AGA-born peers (p = 0.024). There were no significant differences between pooled, obese and non-obese subgroups of LGA-born children and their AGA counterparts with respect to dyslipidemia and IR. AI was higher in non-obese LGA children than in AGA counterparts (p = 0.028). CONCLUSIONS: Non-obese idiopathic LGA-born children have higher AIs than AGA-born counterparts in the absence of IR. WC seems to be a good clinical screening tool in identifying at risk of non-obese LGA children. Further studies are needed to evaluate MS antecedents in idiopathic LGA-born children. PMID- 23627263 TI - Hybrid technique for muscular ventricular septal defect closure. AB - Since 2008 we have performed 10 hybrid procedures for perventricular muscular ventricular septal defects (mVSD) closure. The mean age was 8.5 months (range 2.7 to 17.8), the mean diameter of mVSD was 6.3 mm (range 4 to 10 mm). The postoperative course was uncomplicated and complete closure of the mVSD was accomplished in all patients. There was neither in-hospital nor late mortality, and the longest follow-up now exceeds three years (range 2 months to 3.1 years). PMID- 23627264 TI - Perceptions of voice disorders: a survey of Arab adults. AB - A disordered voice may lead to social stigma as well as reduced occupational opportunities. Much of the research on this topic has investigated the effects of voice disorders from a Western perspective. The societal attitudes of international populations toward people with voice disorders (PWVD) are less well known. The purpose of this study was to investigate the attitudes of adults living in Kuwait toward PWVD. Participants completed a questionnaire that addressed social, educational, and occupational aspects of life for PWVD. The results indicated that while Kuwaiti adults hold generally positive attitudes toward PWVD, they may also perceive PWVD as more likely to be emotionally disturbed, have difficulty making friends or getting married, and experience trouble in finding a good job. PMID- 23627266 TI - Theoretical study of torsional disorder in poly(3-alkylthiophene) single chains: intramolecular charge-transfer character and implications for photovoltaic properties. AB - The role of polymer chain morphology on the optoelectronic properties of polythiophenes is an ongoing investigation with the promise of improving organic photovoltaic performance. Chain morphology is predominantly affected by torsional disorder, which causes localization of holes and electrons in the conjugated backbone. Using the model compound oligo(3-methylthiophene), torsionally disordered oligomers were created to compare with a trans-planar oligomer such as found in crystalline poly(3-hexylthiophene). Low lying electronic excitations are calculated using TD-HF and TD-DFT with various long-range corrected functionals. Probability densities of electron and hole were constructed from natural transition orbitals, giving insight into localization and electron-hole overlap. Overlap is found to be substantially higher in disordered oligomers, indicating a stronger Coulombic interaction between electron and hole. Results suggest that improved photovoltaic performance with increased crystallinity is partially explained by stronger light absorption in crystalline polymers and a higher barrier to charge separation in disordered polymers. PMID- 23627265 TI - Efficacious cyclic N-acyl O-amino phenol duocarmycin prodrugs. AB - Two novel cyclic N-acyl O-amino phenol prodrugs are reported as new members of a unique class of reductively cleaved prodrugs of the duocarmycin family of natural products. These prodrugs were explored with the expectation that they may be cleaved selectively within hypoxic tumor environments that have intrinsically higher concentrations of reducing nucleophiles and were designed to liberate the free drug without the release of an extraneous group. In vivo evaluation of the prodrug 6 showed that it exhibits extraordinary efficacy (T/C > 1500, L1210; 6/10 one year survivors), substantially exceeding that of the free drug, that its therapeutic window of activity is much larger, permitting a dosing >= 40-fold higher than the free drug, and yet that it displays a potency in vivo that approaches the free drug (within 3-fold). Clearly, the prodrug 6 benefits from either its controlled slow release of the free drug or its preferential intracellular reductive cleavage. PMID- 23627267 TI - Novel protease-based diagnostic devices for detection of wound infection. AB - A gelatinase-based device for fast detection of wound infection was developed. Collective gelatinolytic activity in infected wounds was 23 times higher (p <= 0.001) than in noninfected wounds and blisters according to the clinical and microbiological description of the wounds. Enzyme activities of critical wounds showed 12-fold elevated enzyme activities compared with noninfected wounds and blisters. Upon incubation of gelatin-based devices with infected wound fluids, an incubation time of 30 minutes led to a clearly visible dye release. A 32-fold color increase was measured after 60 minutes. Both matrix metalloproteinases and elastases contributed to collective gelatinolytic enzyme activity as shown by zymography and inhibition experiments. The metalloproteinase inhibitor 1,10 phenanthroline (targeting matrix metalloproteinases) and the serine protease inhibitor phenylmethlysulfonyl fluoride (targeting human neutrophil elastase) inhibited gelatinolytic activity in infected wound fluid samples by 11-37% and 60 95%, respectively. Staphylococcus aureus and Pseudomonas aeruginosa, both known for gelatinase production, were isolated in infected wound samples. PMID- 23627268 TI - Mixed Si/Ge nine-atom Zintl clusters: ESI mass spectrometric investigations and single-crystal structure determination of paramagnetic [Si(9-x)Ge(x)]3-. AB - Mixed Si/Ge compounds are of special interest as potential materials for photovoltaic applications. In order to evaluate the usage of soluble precursor compounds, we investigated the synthesis of heteroatomic nine-atom clusters that consist of Si and Ge atoms through dissolution of the ternary Zintl phases K12Si(17-x)Ge(x) (x = 9, 12) and Rb12Si(17-x)Ge(x) (x = 9). Electrospray ionization (ESI) mass spectrometry demonstrates the presence of mixed Si(9 x)Ge(x) clusters in acetonitrile solution. From ammonia solutions of the ternary phases, four compounds that contain 3-fold negatively charged [Si(9-x)Ge(x)](3-) clusters are obtained. The paramagnetic behavior is confirmed by EPR spectroscopy. [E9](3-) Zintl clusters are considered as intermediate structures in the stepwise oxidation of [E9](4-) clusters to novel element allotropes (E = Si-Pb). The structure of Rb[Rb-crypt]2[Si2.3(1)Ge6.7(1)](NH3)7 and the isostructural structures of [Rb-crypt]3[Si2.2(1)Ge6.8(1)](NH3)8, [K crypt]3[Si2.4(1)Ge6.6(1)](NH3)8.5, and [K-crypt]3[Si4.6(1)Ge4.4(1)](NH3)8.5 are investigated by single-crystal X-ray diffraction (crypt = 4,7,13,16,21,24-hexaoxa 1,10-diazabicyclo[8.8.8]-hexacosane). The Si/Ge ratio of the products correlates with the composition of the ternary precursor phases. PMID- 23627269 TI - Differences in energy and nutrient-intake among Greek children between 1992/93 and 2006/07. AB - BACKGROUND: There is lack of data in Greece on the trends in energy and nutrient intake. The present study aimed to examine differences in these parameters among first-grade children of Crete, Greece, between 1992/93 and 2006/07. METHODS: Children (aged 5.7-7.6 years) from two-representative cross-sectional samples participated during 1992/93 (n = 245) and 2006/07 (n = 257). Nutrient and food intakes were assessed using estimated 3-day-food records. Nutrient intakes were estimated as amounts per 4185 kJ (1000 kcal) of energy intake (EI), whereas macronutrients were estimated as percentage of total EI. RESULTS: Between 1992/93 and 2006/07, respectively, significant increases (P < 0.05) were observed in the intake of energy (boys: 7996 versus 8646 kJ; girls: 7265 versus 7963 kJ), calcium (boys: 488 versus 587 mg; girls: 464 versus 594 mg), iron (boys: 5.8 versus 7.3 mg; girls: 5.7 versus 7.4 mg) and vitamins B2 (boys: 1.01 versus 1.17 mg; girls: 1.0 versus 1.16 mg) and B6 (boys: 0.80 versus 0.87 mg; girls: 0.75 versus 0.95 mg), for boys and girls, respectively. Among boys, the intake of protein (13.6 versus 14.6% of EI) and total trans fatty acids (TTFA) (0.84 versus 0.99 g) was also significantly lower in 1992/93 (P < 0.016). Between 1992/93 and 2006/07, total fat (boys: 42.9% versus 42.8%, girls: 42% versus 43.1%) and saturated fat (boys: 15.5% versus 15.4%, girls: 15% versus 15.3%) exceeded the 30-35% and <10% dietary recommendations, respectively, A significantly higher proportion of children in 2006/07, compared to 1992/93, had a higher intake of total energy (>120% of the recommended energy allowance). CONCLUSIONS: The intake of several macronutrients (protein, TTFA, total and saturated fat) in this sample of children did not meet the recommended intakes in either time period. PMID- 23627270 TI - The use of nitrous oxide as an adjuvant for inhalation inductions with sevoflurane: a pro-con debate. PMID- 23627271 TI - An expedient synthesis and screening for antiacetylcholinesterase activity of piperidine embedded novel pentacyclic cage compounds. AB - The aim of this study was to synthesize and evaluate diazapentacyclic analogs for their acetylcholinesterase (AChE) inhibitory activity. The pentacyclic analogs were synthesized by one-pot three-component domino reactions in a microwave synthesizer. Most of the compounds exhibited moderate to good AChE inhibitory activity, compound 5i showed potent inhibitory activity with IC50 1.12 +/- 0.01 uM and this may provide a new lead for developing potential inhibitors for Alzheimer's disease. PMID- 23627272 TI - A quantitative structure-activity relationship study on a series of selective non zinc binding inhibitors of MMP13. AB - Two novel series of potent and selective matrix metalloproteinase (MMP) inhibitors, involving unique binding mode at the active site and not interacting with the catalytic zinc, were collectively investigated to quantify their inhibition actions in relation with chemometric descriptors. Significant correlations, between their MMP13 inhibition activity and 2D-descriptors, were obtained through the combinatorial protocol in multiple linear regression (CP MLR) computational procedure. The derived bi-variant models, validated internally and externally, were able to account for 86.5% of variance in the observed MMP13 inhibition activities. The filtered descriptors, from CP-MLR, satisfactorily explained the biological phenomenon under investigation. However the descriptors, MPC10, N-075 and C-030 accounting, respectively, for molecular path (bond) count of order 10, the structural fragments CH--N--CH and N--CH--N of aromatic ring remained prime to address the MMP13 inhibition actions of the compounds. From the highest significant correlations, it appeared that the higher value of MPC10 and absence of these aromatic ring fragments, are conducive in further improvement of MMP13 inhibition activity of a compound. The partial least squares (PLS) analysis has further confirmed the dominance of the identified descriptors. In the analysis, two-components remained optimum for these descriptors which are able to explain 89.3% of variances. Applicability domain (AD) analysis revealed that the suggested models have acceptable predictability. All the compounds remained within the AD of the proposed models and were evaluated correctly. Based on the inferences drawn from the study, some new analogues were suggested for further exploration. Their predicted MMP13 inhibition activities were much higher than the highest active congener of the original series. PMID- 23627273 TI - Synthesis and anti-tumor activity evaluation of gallic acid-mangiferin hybrid molecule. AB - To improve the anti-tumor effects of gallic acid and mangiferin, a gallic acid mangiferin hybrid molecule (GAMA) was synthesized from gallic acid with mangiferin in the presence of ionic liquid ChC1(choline chloride).2SnC12. Chemical and spectroscopic methods, such as (1)H and (13)C NMR spectroscopy, and HR-ESIMS were used for the structure identification of GA-MA. Using the cell counting kit-8 (CCK-8) assay, the in vitro anti-tumor effects were compared between GA-MA, gallic acid and mangiferin on human hepatoma HepG2, human nasopharyngeal carcinoma CNE, human lung cancer NCI-H460, human ovarian cancer SK OV-3, and human cervical cancer Hela cells. The results showed that the half inhibitory concentration (IC50) of GA-MA on HepG2, CNE, NCI-H460, SK-OV-3, and Hela cells was significantly lower than that of gallic acid or mangiferin. This showed that GA-MA has a better in vitro anti-tumor effect than gallic acid and mangi-ferin. PMID- 23627274 TI - Studies on novel pyridine and 2-pyridone derivatives of N-arylpiperazine as alpha adrenoceptor ligands. AB - This paper describes the synthesis of a series of new N-arylpiperazine derivatives of pyridine and 2-pyridone. The in vitro pharmacological study indicated that all of the compounds possess affinity towards alpha1 adrenoceptors, with exception of 6d, and are selective over alpha2 receptor. The most potent compound 5f displayed 62-fold alpha2/alpha1 selectivity with Ki value of 27.3 nM for alpha1 receptor. Selectivity of other ligands ranged from 6 to more than 146-fold. Hydrochlorides of selected compounds with the best alpha1 adrenoceptor affinity (7b, 7e, 7f, 8b) were tested in vivo (hypotensive activity test in rats) and the results proved their alpha-adrenoreceptor antagonistic activity. Furthermore, the lipophilicity of the investigated compounds has been assessed experimentally and in silico. PMID- 23627275 TI - Dual-responsive capsules with tunable low critical solution temperatures and their loading and release behavior. AB - Dual-responsive capsules sensitive to pH and temperature changes were successfully prepared by grafting random copolymer brushes of 2-(2 methoxyethoxy)ethyl methacrylate (MEO2MA) and oligo(ethylene glycol) methacrylate (OEGMA) from polydopamine (Pdop)-coated SiO2 via a surface-initiated atom transfer radical polymerization (SI-ATRP) method with subsequent removal of the SiO2 core. The uptake and release properties of the resulting capsules are highly affected by changes in the pH values and temperature of the solution. The capsules can take up cationic dye rhodamine 6G (Rh6G) at high pH and T < LCST but not at low pH and T > LCST. In contrast, the capsules can release Rh6G at pH < 7 and temperature below the LCST, but release is less efficient under the opposite conditions. This dual-responsive property was also observed for the anionic dye methyl orange. PMID- 23627276 TI - UV-enhanced NO2 gas sensing properties of SnO2-core/ZnO-shell nanowires at room temperature. AB - SnO2-core/ZnO-shell nanowires were synthesized using a two-step process: the synthesis of SnO2 nanowires by the thermal evaporation of Sn powders followed by the atomic layer deposition of ZnO. The room temperature NO2 gas sensing properties of the nanowires under ultraviolet (UV) illumination were examined. The cores and shells of the nanowires were primitive tetragonal-structured single crystal SnO2 and wurtzite-structured single crystal ZnO, respectively. The responses of multiple networked SnO2 nanowire sensors were increased 2-3-fold at NO2 concentrations ranging from 1 to 5 ppm by encapsulating the nanowires with ZnO. The SnO2-core/ZnO-shell nanowire sensors showed a remarkably enhanced response under UV illumination. The sensing mechanism of the core/shell nanowires under UV illumination is also discussed. PMID- 23627277 TI - Theoretical insights into photoinduced charge transfer and catalysis at oxide interfaces. PMID- 23627278 TI - Polycarbonates derived from glucose via an organocatalytic approach. AB - An organocatalyzed ring-opening polymerization methodology was developed for the preparation of polycarbonates derived from glucose as a natural product starting material. The cyclic 4,6-carbonate monomer of glucose having the 1, 2, and 3 positions methyl-protected was prepared in three steps from a commercially available glucose derivative, and the structure was confirmed by means of NMR and IR spectroscopies, electrospray ionization mass spectrometry (MS), and single crystal X-ray analysis. Polymerization of the monomer, initiated by 4 methylbenzyl alcohol in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene as the organocatalyst, proceeded effectively in a controlled fashion to afford the polycarbonate with a tunable degree of polymerization, narrow molecular weight distribution, and well-defined end groups, as confirmed by a combination of NMR spectroscopy, gel-permeation chromatography, and MALDI-TOF MS. A distribution of head-to-head, head-to-tail, and tail-to-tail regiochemistries was determined by NMR spectroscopy and tandem MS analysis by electron transfer dissociation. These polycarbonates are of interest as engineering materials because of their origination from renewable resources combined with their amorphous character and relatively high glass transition temperatures as determined by X-ray diffraction and differential scanning calorimetry studies. PMID- 23627279 TI - Cyanide detection using a triazolopyridinium salt. AB - A triazolopyridinium salt chemodosimeter has been developed that displays a 60 fold enhancement in fluorescence upon reaction with cyanide. The novel, fast, selective and sensitive reaction-based indicator relies on the pseudopericyclic ring opening of the bridgehead nitrogen-containing detector. PMID- 23627280 TI - Binding mechanism of inositol stereoisomers to monomers and aggregates of Abeta(16-22). AB - Alzheimer's disease (AD) is a severe neurodegenerative disease with no cure. A potential therapeutic approach is to prevent or reverse the amyloid formation of Abeta42, a key pathological hallmark of AD. We examine the molecular basis for stereochemistry-dependent inhibition of the formation of Abeta fibrils in vitro by a polyol, scyllo-inositol. We present molecular dynamics simulations of the monomeric, disordered aggregate, and protofibrillar states of Abeta(16-22), an amyloid-forming peptide fragment of full-length Abeta, successively with and without scyllo-inositol and its inactive stereoisomer chiro-inositol. Both stereoisomers bind monomers and disordered aggregates with similar affinities of 10-120 mM, whereas binding to beta-sheet-containing protofibrils yields affinities of 0.2-0.5 mM commensurate with in vitro inhibitory concentrations of scyllo-inositol. Moreover, scyllo-inositol displays a higher binding specificity for phenylalanine-lined grooves on the protofibril surface, suggesting that scyllo-inositol coats the surface of Abeta protofibrils and disrupts their lateral stacking into amyloid fibrils. PMID- 23627281 TI - Using dual-task methodology to dissociate automatic from nonautomatic processes involved in artificial grammar learning. AB - Previous studies have suggested that both automatic and intentional processes contribute to the learning of grammar and fragment knowledge in artificial grammar learning (AGL) tasks. To explore the relative contribution of automatic and intentional processes to knowledge gained in AGL, we utilized dual-task methodology to dissociate automatic and intentional grammar- and fragment-based knowledge in AGL at both acquisition and at test. Both experiments used a balanced chunk strength grammar to assure an equal proportion of fragment cues (i.e., chunks) in grammatical and nongrammatical test items. In Experiment 1, participants engaged in a working memory dual-task either during acquisition, test, or both acquisition and test. The results showed that participants performing the dual-task during acquisition learned the artificial grammar as well as the single-task group, presumably by relying on automatic learning mechanisms. A working memory dual-task at test resulted in attenuated grammar performance, suggesting a role for intentional processes for the expression of grammatical learning at test. Experiment 2 explored the importance of perceptual cues by changing letters between the acquisition and test phase; unlike Experiment 1, there was no significant learning of grammatical information for participants under dual-task conditions in Experiment 2, suggesting that intentional processing is necessary for successful acquisition and expression of grammar-based knowledge under transfer conditions. In sum, it appears that some aspects of learning in AGL are indeed relatively automatic, although the expression of grammatical information and the learning of grammatical patterns when perceptual similarity is eliminated both appear to require explicit resources. PMID- 23627282 TI - Development and therapeutic implications of selective histone deacetylase 6 inhibitors. AB - This Perspective provides an in depth look at the numerous disease states in which histone deacetylase 6 (HDAC6) has been implicated. The physiological pathways, protein-protein interactions, and non-histone substrates relating to different pathological conditions are discussed with regard to HDAC6. Furthermore, the compounds and methods used to modulate HDAC6 activity are profiled. The latter half of this Perspective analyzes reported HDAC6 selective inhibitors in terms of structure, potency, and selectivity over the other HDAC isoforms with the intent of providing a comprehensive overview of the molecular tools available. Potential obstacles and future directions of HDAC6 research are also presented. PMID- 23627283 TI - Industrially applicable strategies for mitigating acrylamide, furan, and 5 hydroxymethylfurfural in food. AB - Acrylamide and furanic compounds, such as furan and 5-hydroxymethylfurfural (HMF), are formed in a variety of heat-treated commercial foods. They are known to be toxic and, according to the International Agency for Research on Cancer, "possibly carcinogenic to humans". As this gave rise to concern, research was carried out to study their metabolism and toxicity and elucidate the mechanistic pathways of formation. So far, many papers have been published on acrylamide, furan, and HMF occurrence, precursors and mechanisms of formation, toxicity, and detection methods, as well as on possible routes to reduce their levels in food and, thus, consumer intake. This paper reviews the interventions suggested in the literature to mitigate the presence of acrylamide and furanic compounds in food. In particular, some technological measures potentially exploitable at the industrial level are discussed extensively. These are (i) preventive strategies based on the use of asparaginase and thermal input reduction (i.e., low temperature-long time dehydration; dielectric heating) and (ii) removal intervention by means of vacuum treatment, aimed to remove the already formed acrylamide and furanic compounds from the finished product. PMID- 23627284 TI - Pyridinophane platform for stable lanthanide(III) complexation. AB - A detailed investigation of the solid state and solution structures of lanthanide(III) complexes with the macrocyclic ligand 2,11,20 triaza[3.3.3](2,6)pyridinophane (TPP) is reported. The solid state structures of 14 different Ln(3+) complexes have been determined using X-ray crystallography. The ligand is coordinating to the Ln(3+) ion by using its six nitrogen atoms, while nitrate or triflate anions and water molecules complete the metal coordination environments. The structure of the complexes in solution has been investigated by (1)H and (13)C NMR spectroscopy, as well as by DFT calculations (TPSSh model) performed in aqueous solution. The structures obtained from these calculations for the complexes with the lightest Ln(3+) ions (La-Sm) are in very good agreement with those determined by the analysis of the Ln(3+)-induced paramagnetic shifts. A structural change occurs across the lanthanide series at Sm(3+); the complexes of the large Ln(3+) ions (La-Nd) are chiral due to the nonplanar conformation of the macrocycle, and present effective C3v symmetries in solution as a consequence of a fast interconversion of two enantiomeric forms with C3 symmetry. The activation free energy for this enantiomerization process, as estimated by using DFT calculations, amounts to 33.0 kJ.mol(-1). The TPP ligand in the complexes of the heaviest Ln(3+) ions (Eu-Lu) presents a half-chair conformation, which results in C(s) symmetries in solution. PMID- 23627285 TI - Polarity control for nonthiolated DNA adsorption onto gold nanoparticles. AB - Gold nanoparticles (AuNPs) functionalized with thiolated DNA have enabled many studies in nanoscience. The strong thiol/gold affinity and the nanoscale curvature of AuNPs allow the attached DNA to adapt an upright conformation favorable for hybridization. Recently, it has been shown that nonthiolated DNA can also be attached via DNA base adsorption. Without a thiol label, both ends of the DNA and even internal bases could be adsorbed, decreasing the specificity of subsequent molecular recognition reactions. In this work, we employed a modular sequence design approach to systematically study the effect of DNA sequence on adsorption polarity. A block of poly adenine (poly-A) could be used to achieve a high density of DNA attachment. When the poly-A block length is short (e.g., below 5-7), the loading was independent of the block length, and the conjugate cannot hybridize to its cDNA effectively, suggesting a random attachment controlled by adsorption kinetics. Increasing the block length leads to reduced capacity but improved hybridization, suggesting that more DNA with the desired conformation was adsorbed due to the thermodynamic effects of poly-A binding. The design can be further improved by including capping sequences rich in T or G. Finally, a more general double-stranded DNA approach was described to be suitable for DNA that cannot satisfy the above-mentioned design requirements. PMID- 23627286 TI - Cation-specific effects on enzymatic catalysis driven by interactions at the tunnel mouth. AB - Cationic specificity which follows the Hofmeister series has been established for the catalytic efficiency of haloalkane dehalogenase LinB by a combination of molecular dynamics simulations and enzyme kinetic experiments. Simulations provided a detailed molecular picture of cation interactions with negatively charged residues on the protein surface, particularly at the tunnel mouth leading to the enzyme active site. On the basis of the binding affinities, cations were ordered as Na(+) > K(+) > Rb(+) > Cs(+). In agreement with this result, a steady state kinetic analysis disclosed that the smaller alkali cations influence formation and productivity of enzyme-substrate complexes more efficiently than the larger ones. A subsequent systematic investigation of two LinB mutants with engineered charge in the cation-binding site revealed that the observed cation affinities are enhanced by increasing the number of negatively charged residues at the tunnel mouth, and vice versa, reduced by decreasing this number. However, the cation-specific effects are overwhelmed by strong electrostatic interactions in the former case. Interestingly, the substrate inhibition of the mutant LinB L177D in the presence of chloride salts was 7 times lower than that of LinB wild type in glycine buffer. Our work provides new insight into the mechanisms of specific cation effects on enzyme activity and suggests a potential strategy for suppression of substrate inhibition by the combination of protein and medium engineering. PMID- 23627288 TI - Nematicidal activity of allylisothiocyanate from horseradish (Armoracia rusticana) roots against Meloidogyne incognita. AB - In recent years, there has been a great development in the search for new natural pesticides for crop protection aiming a partial or total replacement of currently used chemical nematicides. Glucosinolate breakdown products are volatile and are therefore good candidates for nematodes fumigants. In this article, the methanol aqueous extract (1:1, w/v) of horseradish (Armoracia rusticana) fresh roots (MAH) was in vitro tested for nematicidal activity against second stage (J2) Meloidogyne incognita. The EC50 of MAH after 3 days of J2 immersion in test solutions was 251 +/- 46 mg/L. The chemical composition analysis of the extract carried out by the GC-MS technique showed that allylisothicyanate was the most abundant compound. This pure compound induced J2 paralysis with an EC50 of 52.6 +/- 45.6 and 6.6 +/- 3.4 mg/L after 1 h and 3 days of incubation. The use of LC MS/MS showed for the first time that horseradish root is rich in polyphenols. The study of isothiocyanate degradation in soil showed that allylisothiocyanate was the most quickly degradable compound (half-life <10 min), whereas no significant differences in half-life time were noted between degradation in regular and autoclaved soil. PMID- 23627289 TI - Local provision of percutaneous coronary intervention increases stenting rates and reduces length of hospital stay in remote regional centre. AB - INTRODUCTION: An early invasive strategy with follow-on percutaneous coronary intervention (PCI) is recommended in the management of high risk acute coronary syndromes (ACS). This article aimed to assess the impact of a new PCI service in a remote population. METHOD: The study compared patient treatment pre- and post introduction of the PCI service in a remote regional centre. Patients were identified using ICD discharge code during two 12 week periods ('pre' and 'post' introduction of the new PCI service). Further data was obtained from a catheter laboratory database, electronic patient management systems and clinical notes. Non-parametric statistical tests were used. RESULTS: There were 182 patients in the pre-PCI group and 204 in the post-PCI group. There were no demographic differences between the groups. Patients admitted post service introduction who required active treatment were more likely to have PCI rather than an angiogram only (p = 0.046). Furthermore, patients admitted after the introduction of the PCI service had a shorter period of time from admission to PCI (p = 0.002), were less likely to be transferred to another hospital (p < 0.001), and on average had a shorter hospital stay (p = 0.017). CONCLUSION: A local PCI service in a remote regional centre increased efficiency in the management of patients with ACS with increased rates of PCI, shorter waiting times, reduced requirement for hospital transfer, and shorter length of stay. Nevertheless, many patients still required transfer to other centres. Therefore, maintaining links with other regional centres with clear patient pathways are necessary to provide optimal ACS care to all patients in a rural area. PMID- 23627290 TI - Annealing of P3HT:PCBM blend film--the effect on its optical properties. AB - Annealing is a common method to improve the efficiency of polymer photovoltaic cells. Annealing changes the microphase separation in a polymer blend film and typically also results in a change in its optical properties. We investigated the optical properties of poly(3-hexylthiophene) (P3HT):[6,6]-phenyl C61 butyric acid methyl ester (PCBM) before and after thermal annealing using spectroscopic ellipsometry and transmission measurements, with simultaneous fitting of samples with different thicknesses to ensure reliability of extracted index of refraction values. We found that, after annealing, it is necessary to consider an anisotropic model to describe the properties of P3HT:PCBM blend films, which reflects the increased order of P3HT chains as a result of annealing. Different fitting models (simple anisotropic layer, graded isotropic, graded anisotropic model, generalized oscillator, and oscillator model including Huang-Rhys vibronic envelope) have been compared and discussed. The effect of the number of samples used for fitting and surface roughness corrections is also discussed. PMID- 23627291 TI - Dipole moment surfaces of the CH4 + *X -> CH3* + HX (X = F, Cl) reactions from atomic dipole moment surfaces, and the origins of the sharp extrema of the dipole moments near the transition states. AB - The partitioning of the dipole moment of an isolated molecule or that of a reacting system is reviewed and applied to a dynamic reacting system whereby the system's dipole moment surface is constructed in parallel to its potential energy surface. The dipole moment surface is then decomposed into two origin-independent surfaces: (1) an atomic polarization (AP) surface and a charge transfer (CT) surface. The dipole moment surface as well as its two composing AP and CT surfaces are all further broken down into atomic and/or group contributions with the aid of the quantum theory of atoms in molecules (QTAIM). This approach is applied to the title's laser-induced chemical reactions [CH4 + (*)X -> CH3(*) + HX (X = F, Cl)] previously studied by Bandrauk et al. [ J. Chem. Phys. 2004 , 121 , 7764 - 7775 ], and which were found to exhibit marked peaks in the dipole moment and in the polarizability tensor component at (or near) the transition state. These peaks afford a means to control the kinetics of these reactions with the proper adjustment of an external laser field intensity and phase. The entrance channel potentials of these reactions have recently been probed by photodetachment spectroscopy by Bowman and collaborators [ J. Chem. Phys. 2011 , 134 , 191102_1 - 4 ]. The understanding of the origin of the peaks in the dipole moment can provide, eventually, an additional layer of control in the design of reactions tunable by external fields through the proper selection of the reactants to maximize the field-molecule interaction. PMID- 23627292 TI - Molybdenum 17- and 18-electron bis- and tris(butadiene) complexes: electronic structures, spectroscopic properties, and oxidative ligand substitution reactions. AB - New results on the electronic structures, spectroscopic properties, and reactivities of the molybdenum tris(butadiene) and tris(2,3-dimethylbutadiene) complexes [Mo(bd)3] (1(bd)) and [Mo(dmbd)3] (1(dmbd)), respectively, are reported. Importantly, the metal ligand bonding interaction can be weakened by oxidizing the metal center with ferrocenium salts. The addition of the bidentate phosphine ligand 1,2-bis(diphenylphosphino)ethane then leads to a new type of stable 17-electron complex, [Mo(dmbd)2(dppe)](X) (2; X = BF4(-), PF6(-), BPh4( )), where one of the butadiene ligands is exchanged by a chelating phosphine. Reduction of the cationic complexes 2 generates the corresponding 18-electron complex [Mo(dmbd)2(dppe)] (3), thus establishing a new strategy for ligand substitution reactions in [Mo(bd)3] complexes via one-electron oxidized intermediates. The new heteroleptic molybdenum complexes are characterized by X ray structure analysis; vibrational, NMR, and EPR spectroscopy; and electrochemistry. DFT calculations are performed to explain the structural and specroscopic trends observed experimentally. For compound 1(bd), a normal coordinate analysis is presented, providing additional information on the bonding situation in this type of complex. PMID- 23627293 TI - Synthesis of a highly functionalized core of verrillin. AB - An efficient stereoselective synthesis of furanoverrillin (5), a highly functionalized core of verrillin (1), is reported. The synthetic strategy is based on constructing bicyclic lactone 17 prior to the 10-membered ring macrocyclization. The effect of the C4 methyl group on the furan reactivity is also discussed. PMID- 23627294 TI - Temperature effects on electrophoresis. AB - We present a model capturing the important contributors to the effects of temperature on the observable electrophoretic mobilities of small ions, and on solution conductivity and pH. Our temperature model includes relations for temperature-dependent viscosity, ionic strength corrections, degree of ionization (pK), and ion solvation effects on mobility. We incorporate thermophysical data for water viscosity, temperature-dependence of the Onsager-Fuoss model for finite ionic strength effects on mobility, temperature-dependence of the extended Debye Huckel theory for correction of ionic activity, the Clarke-Glew approach and tabulated thermodynamic quantities of ionization reaction for acid dissociation constants as a function of temperature, and species-specific, empirically evaluated correction terms for temperature-dependence of Stokes' radii. We incorporated our model into a MATLAB-based simulation tool we named Simulation of Temperature Effects on ElectroPhoresis (STEEP). We validated our model using conductivity and pH measurements across a temperature variation of 25-70 degrees C for a set of electrolytes routinely used in electrophoresis. The model accurately captures electrolyte solution pH and conductivity, including important effects not captured by simple Walden-type relations. PMID- 23627295 TI - CROSS: an efficient workflow for reaction-driven rescaffolding and side-chain optimization using robust chemical reactions and available reagents. AB - A novel procedure (CROSS: Computational Rescaffolding and Optimization using Synthetic Schemes) for in silico rescaffolding and side-chain optimization is reported with explicit consideration of the route of synthesis and availability of compatible chemical reagents. We have defined a set of retrosynthetic disconnections representing robust reactions, amenable for combinatorial chemistry. This rule set is used to generate virtual fragment databases from available reagents. Each reactive center is annotated with its compatibility with regard to the chemical reactions. The rule set is then applied to a new molecule to obtain separate query subunits for rescaffolding by 3D similarity searching in specific reagent-derived fragment databases. Thus, only fragments compatible with the chemistry and shape of the corresponding query moiety are investigated further. The identified fragment hits directly indicate (1) available chemical reagents that can replace the query moiety in the starting molecule and (2) the route for the synthesis of the proposed molecules. PMID- 23627296 TI - Syntheses and antimycobacterial activities of [(2S,3R)-2-(amino)-4 (arenesulfonamido)-3-hydroxy-1-phenylbutane derivatives. AB - The syntheses of hydroxyethylsulfonamides, (2S,3R)-tert-butyl N-[4-(N-benzyl-4-R phenylsulfonamido)-3- hydroxy-1-phenylbutan-2-yl]carbamates and (5) (2S,3R)-2 amino-4-[N-benzyl-4-R-benzenesulfonamido]-3-hydroxy-1- phenylbutane hydrochlorides (6), derived from (2S,3S)-Boc-phenylalanine epoxide, are reported. None of the compounds, containing the Boc group, showed activity against M. tuberculosis ATTC 27294, while compounds 6 did, with the most active compounds having R = p-Cl, p-Br and p-Me. Results indicate that the presence of a free amino group at C2 and the sulphonamide moiety are important for biological activity. The antimycobacterial activity of compounds 6 correlated well with the calculated lipophilicities, but not with the electronic effects of the substituents, R. All compounds 6 were highly cytotoxic against the hepatoma cell lineage Hep G2 A16. The X-ray crystal structure of compound [(6: R = Me).H2O] is also reported. In the propeller-like conformation adopted by the cation, the amino and hydroxy groups have a cis arrangement, and thus are suitably placed to form 5- membered chelates. PMID- 23627297 TI - 2D QSAR studies on series of human beta-secretase (BACE-1) inhibitors. AB - beta-secretase (BACE-1) plays a pivotal role in the beta-Amyloid plaques formation, which is responsible for progressive cognitive and memory loss commonly found in Alzheimer disease patients. As a consequence, it has been considered as a good target for drug development efforts. Early work focused on the synthesis of peptidomimetics, but poor pharmacokinetics profile prevented advancing lead compounds to clinical trials. As an alternative, aminoimidazoles, aminohydantoins and aminopyridines derivatives that inhibit BACE-1 were designed. Herein we report statistically sound descriptor- based (r(2) = 0.87, q(2) = 0.85, 6 PCs) and fragment-based (r(2) = 0.91, q(2) = 0.84, 6 PCs) QSAR models, that show high predictive ability (r(2)pred = 0.84, averaged r(2)m=0.78) and underscore polar interactions that are important for BACE-1 inhibition. PMID- 23627298 TI - Anti-neoplastic activity of 1,3-diaza-2-functionalized-adamantan-6-one compounds against melanoma cells. AB - Four series of 1,3-diaza-2-functionalized-adamantan-6-one derivatives, bearing at the 2 position SO, SO2, POCl and PO2H functional groups, were synthesized via a key quadruple Mannich reaction, followed by transformation of an aminal functionality into the final 2-thia- and 2-phospha compounds. The compounds were tested for cytotoxic activity against the mouse B16-F10 melanoma cell line. Malignant melanoma is notorious for its high resistance to chemotherapy, and new anti-melanoma drugs are urgently needed. The 2-thia compounds exhibited poor proliferation inhibition activity, but the 2-phospha derivatives showed significant activity, with IC50 values of 10-60 uM. The compounds induced cell death by G2/M cell cycle arrest, which led to apoptosis, as determined by Annexin V-FITC/PI staining, mitochondrial membrane potential changes assessed by the JC-1 reagent, caspases 3 and 7 activation, and morphological changes. PMID- 23627299 TI - IRMPD spectroscopic study of microsolvated [Na(GlyAla)]+ and [Ca(GlyAla-H)]+ and the blue shifting of the hydrogen-bonded amide stretch with each water addition. AB - In this study, the structures of [Na(GlyAla)(H2O)](+) and [Ca(GlyAla H)(H2O)n](+), (n = 1-3) solvated ion-molecule complexes (as well as the AlaGly isomers) were investigated using infrared multiple photon dissociation (IRMPD) spectroscopy and with computational methods. Calculations showed that in the calcium clusters, the lowest-energy complex is the one in which the peptide is deprotonated at the carboxylic acid end and that Ca(2+) binds to both carboxylate oxygen atoms as well as the amide carbonyl oxygen. For the microsolvated structures, all three water molecules also bind directly to Ca(2+). For the singly, doubly, and triply solvated complexes, these structures are supported by experimental IRMPD spectra. For the [Na(GlyAla)(H2O)](+) complex, both carbonyl oxygen atoms, one from the intact carboxylic acid and one from the amide group, as well as the water molecule were found to be bound to the Na(+). In all of the spectra, a strong band is observed between 3300 and 3400 cm(-1) and is assigned to the amide N-H stretch, which is red-shifted due to hydrogen bonding with the amine nitrogen. The position of the hydrogen-bonded amide N-H stretch is experimentally and theoretically found to be sensitive to the number of water molecules; it is shown to blue shift upon successive hydrations. PMID- 23627300 TI - Different beers with different hops. Relevant compounds for their aroma characteristics. AB - Hop-derived aroma characteristics in beer are very important for the quality of beer. This study compared the differences of hop aroma characteristics and the compounds contained in beer by changing the variety of hops applying the idea of "food metabolomics" on the GC*GC/TOF-MS analysis data, to clarify which aroma compounds contribute to the differences of hop aroma profiles indicated by sensory descriptors. As a result, by focusing only on hop-derived compounds, 67 compounds were strongly correlated with one or more of the sensory descriptors. Furthermore, the odor descriptions of each key compound corresponded well to each sensory descriptor. Thus, these compounds are likely to be the key compounds explaining the differences of hop aroma characteristics in beer. This study led to the suggestion that understanding the relationship between the comprehensive nontarget analysis by GC*GC-TOF/MS and organoleptic evaluation using PCA is effective in estimating the key compounds. PMID- 23627301 TI - Structure and magnetic properties of Cu3Ni2SbO6 and Cu3Co2SbO6 Delafossites with honeycomb lattices. AB - The crystal structures of two Delafossites, Cu3Ni2SbO6 and Cu3Co2SbO6, are determined by high-resolution synchrotron powder X-ray diffraction. The Ni and Co are ordered with respect to Sb in the layer of edge sharing octahedra, forming magnetic layers with honeycomb geometry. High-resolution electron microscopy confirms ordering, and selected-area electron diffraction patterns identify examples of the stacking polytypes. Low temperature synthetic treatments result in disordered stacking of the layers, but heating just below their melting points results in nearly fully ordered stacking variants. The major variant in both cases is a monoclinic distortion of a 6-layer Delafossite polytype, but a significant amount of a 2-layer polytype is also present for the Ni case. The antiferromagnetic ordering with transitions, at 22.3 and 18.5 K for Ni and Co variants, respectively, is investigated by temperature and field dependent magnetization, as well as specific heat. The sharp magnetic transitions support the presence of well developed 2:1 ordering of the Co:Sb or Ni:Sb ions in the honeycomb layers. Neutron diffraction measurements at 4 K are used to determine the magnetic structures. For both the Ni and Co phases, the propagation vector is k = [100], and can be described as alternating ferromagnetic chains in the metal oxide plane giving an overall antiferromagntic "zigzag" alignment. While orientation of the magnetic moments of the Co is along the b-axis, the Ni moments are in the ac plane, approximately parallel to the stacking direction. Bulk magnetization properties are discussed in terms of their magnetic structures. PMID- 23627302 TI - Enhanced electrochemical performance of FeWO4 by coating nitrogen-doped carbon. AB - FeWO4 (FWO) nanocrystals were prepared at 180 degrees C by a simple hydrothermal method, and carbon-coated FWO (FWO/C) was obtained at 550 degrees C using pyrrole as a carbon source. The FWO/C obtained from the product hydrothermally treated for 5 h exhibits reversible capacities of 771.6, 743.8, 670.6, 532.6, 342.2, and 184.0 mAh g(-1) at the current densities of 100, 200, 400, 800, 1600, and 3200 mA g(-1), respectively, whereas that from the product treated for 0.5 h achieves a reversible capacity of 205.9 mAh g(-1) after cycling 200 times at a current density of 800 mA g(-1). The excellent electrochemical performance of the FWO/C results from the combination of the nanocrystals with good electron transport performance and the nitrogen-doped carbon coating. PMID- 23627304 TI - Feasibility and acceptability of a text messaging-based smoking cessation program in ankara, Turkey. AB - Data from high-income countries suggest that cell phone-based smoking cessation programs have the potential to affect cessation rates. There is a paucity of research, however, about the feasibility of cell phone-based smoking cessation programs in lower income countries that have higher smoking prevalence rates. A one-arm feasibility and acceptability pilot study of SMS Turkey, a text messaging based smoking cessation program, was conducted in Ankara, the capital of Turkey. The authors recruited 75 daily smokers who were seriously thinking about quitting in the subsequent 30 days into the 6-week SMS Turkey program. Recruitment was completed in 4 months. Participant retention was high: Almost all (96%) completed the program, and 84% provided 12-week follow-up data. Most (89%) of the respondents who completed the 4-week follow-up measures (n = 38, 51%) said that the text messages were easy to understand and referred to what they were experiencing and feeling during the quitting process (78%). On the basis of intention to treat, 13% of participants (n = 10) reported, at 12-week follow-up, continuous abstinence since their quit date, confirmed by carbon monoxide readings. The cell phone text messaging-based smoking cessation intervention appears feasible and acceptable in Ankara, Turkey. PMID- 23627303 TI - Serum amyloid A promotes lung neutrophilia by increasing IL-17A levels in the mucosa and gammadelta T cells. AB - RATIONALE: Neutrophilic inflammation is an important pathologic feature of chronic obstructive pulmonary disease (COPD) and infectious exacerbations of COPD. Serum amyloid A (SAA) promotes neutrophilic inflammation by its interaction with lung mucosal ALX/FPR2 receptors. However, little is known about how this endogenous mediator regulates IL-17A immunity. OBJECTIVES: To determine whether SAA causes neutrophilic inflammation by IL-17A-dependent mechanisms. METHODS: The relationship between SAA and neutrophils was investigated in lung sections from patients with COPD and a chronic mouse model of SAA exposure. A neutralizing antibody to IL-17A was used to block SAA responses in vivo, and a cell-sorting strategy was used to identify cellular sources. MEASUREMENTS AND MAIN RESULTS: SAA mRNA expression was positively associated with tissue neutrophils in COPD (P < 0.05). SAA predominately promoted expression of the TH17 polarizing cytokine IL 6, which was opposed by 15-epi-lipoxin A4, a counter-regulatory mediator, and ALX/FPR2 ligand. SAA-induced inflammation was markedly reduced by a neutralizing antibody to IL-17A in vivo. Cellular sources of IL-17A induced by SAA include CD4(+) T cells, gammadelta T cells, and an Epcam(+)CD45(-) population enriched for epithelial cells. SAA promotes expression of IL-17A in gammadelta T cells and this innate cell proportionally expressed higher levels of IL-17A transcript than CD4(+) T cells or epithelial cells. CONCLUSIONS: The SAA-IL-17A axis represents an important innate defense network that may underlie persistent neutrophilic airway inflammation in COPD and modulating the ALX/FPR2 receptor represents a novel approach to targeting aberrant IL-17A-mediated lung immunity. PMID- 23627305 TI - Dual infection by streptococcus and atypical mycobacteria following Ahmed glaucoma valve surgery. AB - PURPOSE: To report a case of late postoperative endophthalmitis caused by Streptococcus pneumoniae and conjunctival necrosis by Streptococcus pneumoniae and Mycobacterium fortuitum following Ahmed glaucoma valve (AGV) surgery in a young patient. METHODS: Case report of a 13-year-old boy with purulent exudates and extensive conjunctival necrosis two months following amniotic membrane graft and conjunctival closure (for conjunctival retraction post AGV for secondary glaucoma). RESULTS: The conjunctiva showed extensive necrosis causing exposure of the tube and plate associated with frank exudates in the area adjoining the plate and anterior chamber mandating explantation of the plate along with intravitreal antibiotics. The vitreous aspirate grew Streptococcus pneumoniae while Streptococcus pneumoniae with Mycobacterium fortuitum was isolated from the explanted plate. Despite adequate control of infection following surgery, the final visual outcome was poor owing to disc pallor. CONCLUSION: Conjunctival necrosis and retraction post-AGV can cause late postoperative co-infections by fulminant and slow-growing organisms. A close follow-up is therefore essential in these cases to prevent sight-threatening complications. PMID- 23627306 TI - Uncommon crown-root fracture treated with adhesive tooth fragment reattachment: 7 years of follow-up. AB - Crown-root fractures account for 5% of all fractures in permanent teeth and can involve enamel, dentin, and cementum. Depending on whether there is pulpal involvement, these problems may be classified as complicated (which are more common) or noncomplicated. The treatment depends on the level of the fracture line, root length and/or morphology, and esthetic needs. Several treatment strategies are available for esthetic and functional rehabilitation in crown-root fractures. Adhesive tooth fragment reattachment is the most conservative restorative option when the tooth fragment is available and the biological width has no or minimal violation. This article reports a case of an uncomplicated crown-root fracture in the permanent maxillary right central incisor of a young patient who received treatment with adhesive tooth fragment reattachment, preserving the anatomic characteristics of the fractured tooth after periodontal intervention. The fracture line of the fragment had an unusual shape, starting on the palatal side and extending to the buccal side subgingivally. After 7 years, the attached coronal fragment remained in position with good esthetics, as well as clinical and radiographic signs of pulpal vitality, periodontal health, and root integrity, thus indicating success. PMID- 23627307 TI - Partial rehabilitation of the posterior edentulous maxilla using axial and tilted implants in immediate function to avoid bone grafting. AB - There is a need to create rehabilitation solutions for partial edentulism in the posterior maxilla, thereby reducing the need for grafting in these areas. The purpose of this study was to report the results of partial edentulism rehabilitation in the posterior maxilla with a three- to four-unit bridge supported by two implants: anterior implant placed in axial position and posterior implant tilted distally. A theoretical analysis of the concept including a biomechanical discussion is also provided. MATERIALS AND METHODS: The clinical study included 35 patients (21 women, 14 men) with an age range of 37 to 80 years (mean = 55.5 years), rehabilitated with an implant-supported partial bridge, followed between 4 months and 8 years, with a mean follow-up time of 53 months. ASSESSMENT DATA:The success criteria included clinical parameters (ie, implant fulfilled its purported function as support for reconstruction; was stable when individually and manually tested; had absence of infection; demonstrated a good esthetic outcome of the rehabilitation; allowed fabrication of the implant-supported fixed prosthesis, which provided patient comfort and hygiene) and radiographic parameters (ie, implant probability of long-term stability, as judged by annual bone loss). The implant survival estimate was computed using the Kaplan-Meier product limit estimator. Data were analyzed with descriptive and inferential analyses. RESULTS: The survival rates were 97.1% and 98.8% at 8 years (Kaplan-Meier), using the patient and implant as units of analysis, respectively. The overall average marginal bone resorption was 1.05 mm (SD = 0.65 mm) at 1-year follow-up, and 1.47 mm (SD = 0.37 mm) at 5-year follow up, with no significant differences between axial and tilted implants in the 1 year (P = 0.107) and 5-year (P = 0.211) evaluations. DISCUSSION OF RESULTS:The results indicate that within the limitations of this preliminary study the present protocol is valid for the rehabilitation of partial edentulism in the posterior maxilla. The clinical results confirmed the theoretical analysis on biomechanics and load distribution, with high survival and success rates in the long-term, low implant marginal bone resorption, and low frequencies of complications. PMID- 23627308 TI - Alveolar ridge augmentation: comparison of two socket graft materials in implant cases. AB - With the variety of bone grafting materials available and their use around both natural teeth and dental implants, clinicians need to understand not only basic bone biology but also characteristics of different bone grafting materials to make a proper choice when selecting a material for alveolar bone augmentation and implant treatment. The grafting materials used in the maxillofacial region include autogenous bone, allografts, xenografts, alloplastic or synthetic products, and composite grafts (combination of different materials). This case report describes two frequenly used bone graft materials for socket preservation immediately after extraction: Puros(r) (Zimmer Dental Inc, www.zimmerdental.com) (allogeneic) and Bio-Oss(r)(Osteohealth Co, www.osteohealth.comwww.osteohealth.com) (xenogeneic). In the case presented, the authors perform biologic, clinical, radiologic, and histologic analysis of the two grafting materials by placing them side-by-side in the same patient during implant reconstruction. Implant-related phases of bone augmentation are proposed, and an overview of bone grafting materials, specifically Bio-Oss and Puros, is presented. PMID- 23627309 TI - Use of antioxidants in oral healthcare. AB - There is increasing attention to the potential benefit from the use of antioxidants in the field of dental medicine. In general, antioxidants may be available through oral ingestion, diet or vitamin supplements, and in nutraceuticals. In addition, treatment of oral and dental health problems may include drug-free, natural antioxidant remedies that are available in topical oral applications such as mouth rinse, gel, paste, gum, or lozenge compositions. These topical antioxidant remedies help reduce free-radical or reactive-oxygen species, which are causative inflammatory factors in the progression of gingival and periodontal maladies. This review focuses on relationships between antioxidants and free-radical/reactive-oxygen species in the oral environment. PMID- 23627310 TI - Wettability of supercritical carbon dioxide/water/quartz systems: simultaneous measurement of contact angle and interfacial tension at reservoir conditions. AB - Injection of carbon dioxide in deep saline aquifers is considered as a method of carbon sequestration. The efficiency of this process is dependent on the fluid fluid and rock-fluid interactions inside the porous media. For instance, the final storage capacity and total amount of capillary-trapped CO2 inside an aquifer are affected by the interfacial tension between the fluids and the contact angle between the fluids and the rock mineral surface. A thorough study of these parameters and their variations with temperature and pressure will provide a better understanding of the carbon sequestration process and thus improve predictions of the sequestration efficiency. In this study, the controversial concept of wettability alteration of quartz surfaces in the presence of supercritical carbon dioxide (sc-CO2) was investigated. A novel apparatus for measuring interfacial tension and contact angle at high temperatures and pressures based on Axisymmetric Drop Shape Analysis with no-Apex (ADSA-NA) method was developed and validated with a simple system. Densities, interfacial tensions, and dynamic contact angles of CO2/water/quartz systems were determined for a wide range of pressures and temperatures relevant to geological sequestration of CO2 in the subcritical and supercritical states. Image analysis was performed with ADSA-NA method that allows the determination of both interfacial tensions and contact angles with high accuracy. The results show that supercritical CO2 alters the wettability of quartz surface toward less water-wet conditions compared to subcritical CO2. Also we observed an increase in the water advancing contact angles with increasing temperature indicating less water-wet quartz surfaces at higher temperatures. PMID- 23627312 TI - Behaviour of orthotropic surgical implant in hernia repair due to the material orientation and abdomen surface deformation. AB - Surgical implants used in hernia repair reveal isotropic as well as orthotropic properties. In particular, its orthotropy, in relation to the different range of typical deformations observed in different directions and zones of abdomen surface due to the patients' life activities, has a significant influence on the extreme junction forces in the mesh-tissue connections and hence the repair persistence. The finite element model of the orthotropic implant was developed, and the junction forces in the connections of tissue and mesh were studied. The kinematical extortions representing the abdomen surface deformations identified in specific zones of hernia placement were applied to the model. The sensitive analysis was applied to specify the influence of the orthotropy (implant orientation) direction to the repair persistence. Due to the anisotropy of the human abdomen and also the different range of deformations observed in different areas of abdomen surface, the behaviour of the implant differs significantly depending on the hernia placement and the implant orientation. Especially, it is observed in the values of the implant-tissue junction forces which determinate considerably the repair persistence. The provided results and conclusions may be useful in some clinical recommendations for implantation of orthotropic surgical mesh specifying the hernia placement as well as the orthotropic implant orientation. This can also be considered in the design of new synthetic implants with more physiologic tissue-like properties also taking into account the human abdomen anisotropy. PMID- 23627311 TI - Synthesis and structure activity relationship of tetrahydroisoquinoline-based potentiators of GluN2C and GluN2D containing N-methyl-D-aspartate receptors. AB - We describe here the synthesis and evaluation of a series of tetrahydroisoquinolines that show subunit-selective potentiation of NMDA receptors containing the GluN2C or GluN2D subunits. Bischler-Napieralski conditions were employed in the key step for the conversion of acyclic amides to the corresponding tetrahydroisoquinoline-containing analogs. Compounds were evaluated using both two-electrode voltage clamp recordings from Xenopus laevis oocytes and imaging of mammalian BHK cells loaded with Ca(2+)-sensitive dyes. The most potent analogues had EC50 values of 300 nM and showed over 2-fold potentiation of the response to maximally effective concentrations of glutamate and glycine but had no effect on responses from NMDA receptors containing the GluN2A or GluN2B subunits AMPA, kainate, and GABA or glycine receptors or a variety of other potential targets. These compounds represent a potent class of small molecule subunit-selective potentiators of NMDA receptors. PMID- 23627313 TI - The mitochondrial tRNA(Met) 4454T > C variant may not be associated with essential hypertension in Han Chinese population. PMID- 23627314 TI - Complete mitochondrial genome of the anadromous river pufferfish, Takifugu obscurus (Tetraodontiformes: Tetraodontidae). AB - The complete mitochondrial genome was sequenced from the anadromous river pufferfish, Takifugu obscurus. The genome sequence was 16,446 bp in size, and the gene order and contents were identical with those of congeneric species in the genus Takifugu. Of 13 protein-coding genes (PGCs), 2 genes (CO2 and ND4) had incomplete stop codons as shown in T. obscurus. Furthermore, the stop codon of CO1 and ND6 genes was AGG. The base composition of T. obscurus mitogenome showed anti-G bias (13.2% and 6.4%) on the second and third positions of protein-coding genes (PCGs), respectively. PMID- 23627315 TI - Social identity salience shapes group-based emotions through group-based appraisals. AB - Group-based emotions have been conceptualised as being rooted in perceivers' social identity. Consistent with this idea, previous research has shown that social identity salience affects group-based emotions, but no research to date has directly examined the role of group-based appraisals in comparison with individual appraisals. In the present studies, we measured group-based appraisals through a thought-listing procedure. In Experiment 1, we explicitly reminded people of their group identity, which led to the predicted change in group-based anger. This effect was mediated by group-based appraisals. In Experiment 2, participants either discussed a group-relevant scenario in small groups or a related topic irrelevant to the group. The group-relevant condition not only led to stronger indignation but the perceived presence of group-based appraisals was also related to participants' reports of indignation. These results provide further evidence for the importance of group-based appraisals as components of group-based emotions. PMID- 23627316 TI - Role of hydrophobic interactions in the encounter complex formation of the plastocyanin and cytochrome f complex revealed by paramagnetic NMR spectroscopy. AB - Protein complex formation is thought to be at least a two-step process, in which the active complex is preceded by the formation of an encounter complex. The interactions in the encounter complex are usually dominated by electrostatic forces, whereas the active complex is also stabilized by noncovalent short-range forces. Here, the complex of cytochrome f and plastocyanin, electron-transfer proteins involved in photosynthesis, was studied using paramagnetic relaxation NMR spectroscopy. Spin labels were attached to cytochrome f, and the relaxation enhancements of plastocyanin nuclei were measured, demonstrating that a large part of the cytochrome f surface area is sampled by plastocyanin. In contrast, plastocyanin is always oriented with its hydrophobic patch toward cytochrome f. The complex was visualized using ensemble docking, showing that the encounter complex is stabilized by hydrophobic as well as electrostatic interactions. The results suggest a model of electrostatic preorientation before the proteins make contact, followed by the formation of an encounter complex that rapidly leads to electron-transfer active conformations by gradual increase of the overlap of nonpolar surface areas on cytochrome f and plastocyanin. In this model the distinction between the encounter and active complexes vanishes, at least in the case of electron-transfer complexes, which do not require a high degree of specificity. PMID- 23627317 TI - Design, synthesis and PASS assisted evaluation of novel 2-substituted benzimidazole derivatives as potent anthelimintics. AB - Two series of compounds (AB and APB) bearing substituted phenoxy groups at 2 position of benzimidazole nucleus through amino or phenyleneamino were synthesized and evaluated through PASS software for predicting the activity spectrum of each compound. All compounds of both the series were predicted to have potent anthelmintic activity. The activity of each compound was evaluated experimentally at the concentrations of 0.1, 0.2 and 0.5% in terms of mortality time and paralysis time of the helminthes and was found to comply with the PASS predicted activity. In general, all compounds of APB series were more potent than those of AB series probably due to the additional hydrophobic interactions of the spacer phenyl ring in the APB series. The activity of all compounds was found to increase with increasing concentration. The compound with p-chlorophenoxy moiety was the most active from the APB series (mortality time 5.7+/-0.4 min and paralysis time 3.1+/-0.3 min) and equipotent to albendazole (mortality time 5.4+/ 0.1 min and paralysis time 2.8+/-0.2 min) at concentration of 0.2%. The o chlorophenoxy analogs in both the series were found to be the least active of all. Based on these results, a substituent capable of binding with the receptor through van der Waals and/or electronic interactions at 4-position of the phenoxy ring in the compound is suggested to increase binding interaction leading to potent anthelmintic activity. PMID- 23627318 TI - Surface modification of Al30 Keggin-type polyaluminum molecular clusters. AB - Keggin-type molecular clusters formed from the partial hydrolysis of aluminum in aqueous solutions have the capacity to adsorb a variety of inorganic and organic contaminants. The adsorptive capability of Keggin-type polyaluminum species, such as Al13 and Al30, lead to their wide usage as precursors for heterogeneous catalysts and clarifying agents for water purification applications, but a molecular-level understanding of adsorption process is lacking. Two model Al30 clusters, whose surface has been modified with chelated metals (Al(3+) and Zn(2+)) have been synthesized and structurally characterized by single-crystal X ray diffraction. Al32IDA [(Al(IDA)H2O)2(Al30O8(OH)60(H2O)22)](2,6 NDS)4(SO4)2Cl4(H2O)40, IDA = iminodiacetic acid, 2,6-NDS = 2,6 napthalene disulfonate) crystallize in the triclinic space group, P1 with a = 13.952(2) A, b = 16.319(3) A, c = 23.056(4) A, alpha = 93.31(1) degrees , beta = 105.27(1) degrees , and gamma = 105.52(1) degrees . Zn2Al32 [(Zn(NTA)H2O)2(Al(NTA)(OH)2)2(Al30(OH)60(O)8(H2O)20](2,6-NDS)5(H2O)64, (NTA = nitrilotriacetic acid), also crystallizes in P1 with unit cell parameter refined as a = 16.733(7) A, b = 18.034(10) A, c = 21.925(11) A, alpha = 82.82(2) degrees , beta = 70.96(2) degrees , and gamma = 65.36(2) degrees . The chelated metal centers adsorb to the surface of the Al30 clusters through hydroxyl bridges located at the central belt region of the molecule. The observed binding sites for the metal centers mirror the reactivity predicted by previously reported molecular dynamic simulations and can be identified by the acidity and hydration factor of the water group that participates in the adsorption process. PMID- 23627319 TI - A diffusion tensor-based finite element model of microdialysis in the deep brain. AB - Microdialysis of the basal ganglia was recently used to study neurotransmitter levels in relation to deep brain stimulation. In order to estimate the anatomical origin of the obtained data, the maximum tissue volume of influence (TVImax) for a microdialysis catheter was simulated using the finite element method. This study investigates the impact of brain heterogeneity and anisotropy on the TVImax using diffusion tensor imaging (DTI) to create a second-order tensor model of the basal ganglia. Descriptive statistics showed that the maximum migration distance for neurotransmitters varied by up to 55% (n = 98,444) for DTI-based simulations compared with an isotropic reference model, and the anisotropy differed between different targets in accordance with theory. The size of the TVImax was relevant in relation to the size of the anatomical structures of interest, and local tissue properties should be accounted for when relating microdialysis data to their anatomical targets. PMID- 23627320 TI - Temperature dependent photoluminescence of size-purified silicon nanocrystals. AB - The photoluminescence (PL) of size-purified silicon nanocrystals is measured as a function of temperature and nanoparticle size for pure nanocrystal films and polydimethylsiloxane (PDMS) nanocomposites. The temperature dependence of the bandgap is the same for both sample types, being measurably different from that of bulk silicon because of quantum confinement. Our results also suggest weaker interparticle and environmental coupling in the nanocomposites, with enhanced PL and an unexpected dependence of lifetime on size for the pure nanocrystal films at low temperatures. We interpret these results through differences in the low temperature size dependence of the ensemble nonradiative equilibrium constants. The response of the PDMS nanocomposites provides a consistent measure of local temperature through intensity, lifetime, and wavelength in a polymer-dispersed morphology suitable for biomedical applications, and we exploit this to fabricate a small-footprint fiber-optic cryothermometer. A comparison of the two sample types offers fundamental insight into the photoluminescent behavior of silicon nanocrystal ensembles. PMID- 23627321 TI - Infection and inflammatory mechanisms. AB - This introductory article examines the potential mechanisms that may play a role in the associations between periodontitis and the systemic conditions being considered in the EFP/AAP Workshop in Segovia, Spain. Three basic mechanisms have been postulated to play a role in these interactions; metastatic infections, inflammation and inflammatory injury, and adaptive immunity. The potential role of each alone and together is considered in in vitro and animal studies and in human studies when available. This is not a systematic or critical review, but rather an overview of the field to set the stage for the critical reviews in each of the working groups. PMID- 23627322 TI - Diabetes and periodontal diseases: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. AB - BACKGROUND: Diabetes and periodontitis are complex chronic diseases with an established bidirectional relationship. There is long-established evidence that hyperglycaemia in diabetes is associated with adverse periodontal outcomes. However, given the ubiquity of periodontal diseases and the emerging global diabetes epidemic, the complications of which contribute to significant morbidity and premature mortality, it is timely to review the role of periodontitis in diabetes. AIMS: To report the epidemiological evidence from cross-sectional, prospective and intervention studies for the impact of periodontal disease on diabetes incidence, control and complications and to identify potential underpinning mechanisms. EPIDEMIOLOGY: Over the last 20 years, consistent and robust evidence has emerged that severe periodontitis adversely affects glycaemic control in diabetes and glycaemia in non-diabetes subjects. In diabetes patients, there is a direct and dose-dependent relationship between periodontitis severity and diabetes complications. Emerging evidence supports an increased risk for diabetes onset in patients with severe periodontitis. BIOLOGICAL MECHANISMS: Type 2 diabetes is preceded by systemic inflammation, leading to reduced pancreatic beta-cell function, apoptosis and insulin resistance. Increasing evidence supports elevated systemic inflammation (acute-phase and oxidative stress biomarkers) resulting from the entry of periodontal organisms and their virulence factors into the circulation, providing biological plausibility for the effects of periodontitis on diabetes. AGE (Advanced Glycation Endproducts)-RAGE (Receptor for AGEs) interactions and oxidative-stress-mediated pathways provide plausible mechanistic links in the diabetes to periodontitis direction. INTERVENTIONS: Randomized controlled trials (RCTs) consistently demonstrate that mechanical periodontal therapy associates with approximately a 0.4% reduction in HbA1C at 3 months, a clinical impact equivalent to adding a second drug to a pharmacological regime for diabetes. RCTs are needed with larger numbers of subjects and longer term follow-up, and if results are substantiated, adjunctive periodontal therapies subsequently need to be evaluated. There is no current evidence to support adjunctive use of antimicrobials for periodontal management of diabetes patients. GUIDELINES: Given the current evidence, it is timely to provide guidelines for periodontal care in diabetes patients for medical and dental professionals and recommendations for patients/the public. PMID- 23627323 TI - A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes. AB - AIMS: To review the evidence for the molecular and cellular processes that may potentially link periodontal disease and diabetes. The pathogenic roles of cytokines and metabolic molecules (e.g. glucose, lipids) are explored and the role of periodontal bacteria is also addressed. Paradigms for bidirectional relationships between periodontitis and diabetes are discussed and opportunities for elaborating these models are considered. METHODS: Database searches were performed using MeSH terms, keywords, and title words. Studies were evaluated and summarized in a narrative review. RESULTS: Periodontal microbiota appears unaltered by diabetes and there is little evidence that it may influence glycaemic control. Small-scale clinical studies and experiments in animal models suggest that IL-1beta, TNF-alpha, IL-6, OPG and RANKL may mediate periodontitis in diabetes. The AGE-RAGE axis is likely an important pathway of tissue destruction and impaired repair in diabetes-associated periodontitis. A role for locally activated pro-inflammatory factors in the periodontium, which subsequently impact on diabetes, remains speculative. CONCLUSION: There is substantial information on potential mechanistic pathways which support a close association between diabetes and periodontitis, but there is a real need for longitudinal clinical studies using larger patient groups, integrated with studies of animal models and cells/tissues in vitro. PMID- 23627324 TI - Effect of periodontal disease on diabetes: systematic review of epidemiologic observational evidence. AB - BACKGROUND: Periodontal disease and diabetes mellitus are common, chronic diseases worldwide. Epidemiologic and biologic evidence suggest periodontal disease may affect diabetes. OBJECTIVE: To systematically review non experimental, epidemiologic evidence for effects of periodontal disease on diabetes control, complications and incidence. DATA SOURCES: Electronic bibliographic databases, supplemented by hand searches of recent and future issues of relevant journals. STUDY ELIGIBILITY CRITERIA AND PARTICIPANTS: Longitudinal and cross-sectional epidemiologic, non-interventional studies that permit determination of directionality of observed effects were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Four reviewers evaluated pair-wise each study. Review findings regarding study results and quality were summarized in tables by topic, using the PRISMA Statement for reporting and the Newcastle-Ottawa System for quality assessment, respectively. From 2246 citations identified and available abstracts screened, 114 full-text reports were assessed and 17 included in the review. RESULTS: A small body of evidence supports significant, adverse effects of periodontal disease on glycaemic control, diabetes complications, and development of type 2 (and possibly gestational) diabetes. LIMITATIONS: There were only a limited number of eligible studies, several of which included small sample sizes. Exposure and outcome parameters varied, and the generalizability of their results was limited. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Current evidence suggests that periodontal disease adversely affects diabetes outcomes, and that further longitudinal studies are warranted. PMID- 23627325 TI - Evidence that periodontal treatment improves diabetes outcomes: a systematic review and meta-analysis. AB - CONTEXT: The effect of periodontal therapy on diabetes outcomes has not been established. OBJECTIVE: This update examines the effect of periodontal treatment on diabetes outcomes. DATA SOURCES: Literature since October 2009 using MEDLINE. STUDY ELIGIBILITY CRITERIA: Published RCTs including periodontal therapy for diabetic subjects, a metabolic outcome, an untreated control group, and follow-up of 3 months. DATA EXTRACTION: Pre-defined data fields, including study quality indicators were used. DATA SYNTHESIS: A search revealed 56 publications of which 9 met inclusion criteria. Mean change of HbA1c from baseline was compared across treatment groups. Pooled analysis was based on random effects models. RESULTS: A meta-analysis indicated a mean treatment effect of -0.36% HbA1c (CI -0.54, -0.19) compared to no treatment after periodontal therapy (p < 0.0001). Heterogeneity tests revealed only minimal evidence of publication bias (I(2 ) = 9%). LIMITATIONS: Small sample size and high risk of bias remain problematic for studies of this type. Periodontal therapy varied considerably. CONCLUSION: The modest reduction in HbA1c observed as a result of periodontal therapy in subjects with type 2 diabetes is consistent with previous systematic reviews. Despite this finding, there is limited confidence in the conclusion due to a lack of multi centre trials of sufficient sample size are lacking. PMID- 23627326 TI - Periodontitis and adverse pregnancy outcomes: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. AB - BACKGROUND: Pregnancy sometimes has adverse outcomes including low birthweight (<2500 g), pre-term birth (<37 weeks), growth restriction, pre-eclampsia, miscarriage and/or stillbirth. Maternal periodontitis directly and/or indirectly have potential to influence the health of the foetal-maternal unit. AIMS: To assess the epidemiological evidence for the impact of periodontal disease on adverse pregnancy outcomes and to identify potential underpinning mechanisms. EPIDEMIOLOGY: Low birthweight, pre-term birth and pre-eclampsia have been associated with maternal periodontitis exposure. However, the strength of the observed associations is modest and seems to vary according to the population studied, the means of periodontal assessment and the periodontal disease classification employed. BIOLOGICAL MECHANISMS: Two major pathways have been identified, One direct, in which oral microorganisms and/or their components reach the foetal-placental unit and one indirect, in which Inflammatory mediators circulate and impact the foetal-placental unit. INTERVENTIONS: Although periodontal therapy has been shown to be safe and leads to improved periodontal conditions in pregnant women, case-related periodontal therapy, with or without systemic antibiotics does not reduce overall rates of pre-term birth and low birthweight. GUIDELINES: Given the current evidence, various treatment strategies could be evaluated that consider specific target populations, as well as timing and intensity of treatment. PMID- 23627327 TI - Adverse pregnancy outcomes (APOs) and periodontal disease: pathogenic mechanisms. AB - AIM: To evaluate the evidence on potential biological pathways underlying the possible association between periodontal disease (PD) and adverse pregnancy outcomes (APOs). MATERIAL & METHODS: Human, experimental and in vitro studies were evaluated. RESULTS: Periodontal pathogens/byproducts may reach the placenta and spread to the foetal circulation and amniotic fluid. Their presence in the foeto-placental compartment can stimulate a foetal immune/inflammatory response characterized by the production of IgM antibodies against the pathogens and the secretion of elevated levels of inflammatory mediators, which in turn may cause miscarriage or premature birth. Moreover, infection/inflammation may cause placental structural changes leading to pre-eclampsia and impaired nutrient transport causing low birthweight. Foetal exposure may also result in tissue damage, increasing the risk for perinatal mortality/morbidity. Finally, the elicited systemic inflammatory response may exacerbate local inflammatory responses at the foeto-placental unit and further increase the risk for APOs. CONCLUSIONS: Further investigation is still necessary to fully translate the findings of basic research into clinical studies and practice. Understanding the systemic virulence potential of the individual's oral microbiome and immune response may be a distinctly different issue from categorizing the nature of the challenge using clinical signs of PD. Therefore, a more personalized targeted therapy could be a more predictive answer to the current "one-size-fits-all" interventions. PMID- 23627328 TI - Epidemiology of association between maternal periodontal disease and adverse pregnancy outcomes--systematic review. AB - BACKGROUND AND OBJECTIVES: There is still debate regarding potential relationships between maternal periodontitis during pregnancy and adverse pregnancy outcomes. The aim of this systematic review was to synthesize the available epidemiological evidence on this association. DATA SOURCES: Combined electronic and hand search of MEDLINE, EMBASE, WEB OF SCIENCE and Cochrane Central Register databases. STUDY ELIGIBILITY CRITERIA: Original publications reporting data from cross-sectional, case-control or prospective cohort epidemiological studies on the association between periodontal status and preterm birth, low birthweight (LBW) or pre-eclampsia. The search was not limited to publications in English. All selected studies provided data based on professional assessments of periodontal status, and outcome variables, including preterm birth (<37 weeks gestation), LBW (<2500 g), gestational age, small for gestational age, birthweight, pregnancy loss or miscarriage, or pre-eclampsia. PARTICIPANTS: Pregnant women with or without periodontal disease, and with or without adverse pregnancy outcomes, assessed either during pregnancy or postpartum. No intervention studies were included. Study appraisal and synthesis methods - Publications were assessed based on predefined screening criteria including type of periodontal assessment, consistency in the timing of the periodontal assessment with respect to gestational age, examiner masking and consideration of additional exposures and confounders. RESULTS: Maternal periodontitis is modestly but significantly associated with LBW and preterm birth, but the use of a categorical or a continuous exposure definition of periodontitis appears to impact the findings: Although significant associations emerge from case-control and cross-sectional studies using periodontitis "case definitions," these were substantially attenuated in studies assessing periodontitis as a continuous variable. Data from prospective studies followed a similar pattern, but associations were generally weaker. Maternal periodontitis was significantly associated with pre-eclampsia. LIMITATIONS: There is a high degree of variability in study populations, recruitment and assessment, as well as differences in how data are recorded and handled. As a result, studies included in meta-analyses show a high degree of heterogeneity. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Maternal periodontitis is modestly but independently associated with adverse pregnancy outcomes, but the findings are impacted by periodontitis case definitions. It is suggested that future studies employ both continuous and categorical assessments of periodontal status. Further use of the composite outcome preterm LBW is not encouraged. PMID- 23627329 TI - The effects of periodontal treatment on pregnancy outcomes. AB - BACKGROUND: Preterm infants are at greater risk than term infants for physical and developmental disorders. Morbidity and mortality increases as gestational age at delivery decreases. Observational studies indicate an association between poor periodontal health and risk for preterm birth or low birthweight, making periodontitis a potentially modifiable risk factor for prematurity. AIM: To identify randomized controlled trials (RCTs) published between January 2011 and July 2012 and discuss all published RCTs testing whether periodontal therapy reduces rates of preterm birth and low birthweight. METHODS: Search of databases including PubMed, ISI Web of Science and Cochrane Library. RESULTS: The single RCT identified showed no significant effect of periodontal treatment on birth outcomes. DISCUSSION: All published trials included non-surgical periodontal therapy; only two included systemic antimicrobials as part of test therapy. The trials varied substantially in terms of sample size, obstetric histories of subjects, study preterm birth rates and the periodontal treatment response. The largest trials - also judged to be high-quality and at low risk of bias - have yielded consistent results, and indicate that treatment does not alter rates of adverse pregnancy outcomes. CONCLUSION: Non-surgical periodontal therapy, scaling and root planing, does not improve birth outcomes in pregnant women with periodontitis. PMID- 23627330 TI - Periodontitis and systemic diseases: a record of discussions of working group 4 of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. AB - BACKGROUND: There has been an explosion in research into possible associations between periodontitis and various systemic diseases and conditions. AIM: To review the evidence for associations between periodontitis and various systemic diseases and conditions, including chronic obstructive pulmonary disease (COPD), pneumonia, chronic kidney disease, rheumatoid arthritis, cognitive impairment, obesity, metabolic syndrome and cancer, and to document headline discussions of the state of each field. Periodontal associations with diabetes, cardiovascular disease and adverse pregnancy outcomes were not discussed by working group 4. RESULTS: Working group 4 recognized that the studies performed to date were largely cross-sectional or case-control with few prospective cohort studies and no randomized clinical trials. The best current evidence suggests that periodontitis is characterized by both infection and pro-inflammatory events, which variously manifest within the systemic diseases and disorders discussed. Diseases with at least minimal evidence of an association with periodontitis include COPD, pneumonia, chronic kidney disease, rheumatoid arthritis, cognitive impairment, obesity, metabolic syndrome and cancer. The working group agreed that there is insufficient evidence to date to infer causal relationships with the exception that organisms originating in the oral microbiome can cause lung infections. CONCLUSIONS: The group was unanimous in their opinion that the reported associations do not imply causality, and establishment of causality will require new studies that fulfil the Bradford Hill or equivalent criteria. Precise and community-agreed case definitions of periodontal disease states must be implemented systematically to enable consistent and clearer interpretations of studies of the relationship to systemic diseases. The members of the working group were unanimous in their opinion that to develop data that best inform clinicians, investigators and the public, studies should focus on robust disease outcomes and avoid surrogate endpoints. It was concluded that because of the relative immaturity of the body of evidence for each of the purported relationships, the field is wide open and the gaps in knowledge are large. PMID- 23627332 TI - Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. AB - BACKGROUND: This consensus report is concerned with the association between periodontitis and atherosclerotic cardiovascular disease (ACVD). Periodontitis is a chronic multifactorial inflammatory disease caused by microorganisms and characterized by progressive destruction of the tooth supporting apparatus leading to tooth loss; as such, it is a major public health issue. AIMS: This report examined biological plausibility, epidemiology and early results from intervention trials. PLAUSIBILITY: Periodontitis leads to entry of bacteria in the blood stream. The bacteria activate the host inflammatory response by multiple mechanisms. The host immune response favors atheroma formation, maturation and exacerbation. EPIDEMIOLOGY: In longitudinal studies assessing incident cardiovascular events, statistically significant excess risk for ACVD was reported in individuals with periodontitis. This was independent of established cardiovascular risk factors. The amount of the adjusted excess risk varies by type of cardiovascular outcome and across populations by age and gender. Given the high prevalence of periodontitis, even low to moderate excess risk is important from a public health perspective. INTERVENTION: There is moderate evidence that periodontal treatment: (i) reduces systemic inflammation as evidenced by reduction in C-reactive protein (CRP) and improvement of both clinical and surrogate measures of endothelial function; but (ii) there is no effect on lipid profiles - supporting specificity. Limited evidence shows improvements in coagulation, biomarkers of endothelial cell activation, arterial blood pressure and subclinical atherosclerosis after periodontal therapy. The available evidence is consistent and speaks for a contributory role of periodontitis to ACVD. There are no periodontal intervention studies on primary ACVD prevention and there is only one feasibility study on secondary ACVD prevention. CONCLUSIONS: It was concluded that: (i) there is consistent and strong epidemiologic evidence that periodontitis imparts increased risk for future cardiovascular disease; and (ii) while in vitro, animal and clinical studies do support the interaction and biological mechanism, intervention trials to date are not adequate to draw further conclusions. Well-designed intervention trials on the impact of periodontal treatment on prevention of ACVD hard clinical outcomes are needed. PMID- 23627333 TI - Periodontal bacterial invasion and infection: contribution to atherosclerotic pathology. AB - OBJECTIVE: The objective of this review was to perform a systematic evaluation of the literature reporting current scientific evidence for periodontal bacteria as contributors to atherosclerosis. METHODS: Literature from epidemiological, clinical and experimental studies concerning periodontal bacteria and atherosclerosis were reviewed. Gathered data were categorized into seven "proofs" of evidence that periodontal bacteria: 1) disseminate from the oral cavity and reach systemic vascular tissues; 2) can be found in the affected tissues; 3) live within the affected site; 4) invade affected cell types in vitro; 5) induce atherosclerosis in animal models of disease; 6) non-invasive mutants of periodontal bacteria cause significantly reduced pathology in vitro and in vivo; and 7) periodontal isolates from human atheromas can cause disease in animal models of infection. RESULTS: Substantial evidence for proofs 1 to 6 was found. However, proof 7 has not yet been fulfilled. CONCLUSIONS: Despite the lack of evidence that periodontal bacteria obtained from human atheromas can cause atherosclerosis in animal models of infection, attainment of proofs 1 to 6 provides support that periodontal pathogens can contribute to atherosclerosis. PMID- 23627336 TI - Periodontal systemic associations: review of the evidence. AB - AIM: To critically appraise recent research into associations between periodontal disease and systemic diseases and conditions specifically respiratory disease, chronic kidney disease, rheumatoid arthritis, cognitive impairment, obesity, metabolic syndrome and cancer. METHODS: A MEDLINE literature search of papers published between 2002 and April 2012 was conducted. Studies that included periodontitis as an exposure were identified. Cross-sectional epidemiological investigations on large samples, prospective studies and systematic reviews formed the basis of the narrative review. A threshold set for the identification of periodontitis was used to identify those studies that contributed to the conclusions of the review. RESULTS: Many of the investigations were cross sectional secondary analyses of existing data sets in particular the NHANES studies. There were a small number of systematic reviews and prospective studies. There was substantial variability in the definitions of exposure to periodontitis. A small number of studies met the threshold set for periodontitis and supported associations; however, in some of the chronic diseases there were no such studies. There was strong evidence from randomized controlled trials that interventions, which improve oral hygiene have positive effects on the prevention of nosocomial pneumonias. CONCLUSIONS: There was substantial heterogeneity in the definitions used to identify periodontitis and very few studies met a stringent threshold for periodontitis. Published evidence supports modest associations between periodontitis and some, although not all, of the diseases and conditions reviewed. There is a need to reach a consensus on what constitutes periodontitis for future studies of putative associations with systemic diseases. PMID- 23627335 TI - The epidemiological evidence behind the association between periodontitis and incident atherosclerotic cardiovascular disease. AB - OBJECTIVES: The objective of this study was to systematically review the epidemiological evidence for an association between periodontitis (PD) and incident atherosclerotic cardiovascular disease (ACVD), including coronary heart disease (CHD), cerebrovascular disease and peripheral arterial disease. METHODS: Systematic review of cohort and case-control studies on the association of clinically or radiographically diagnosed PD and ACVD. RESULTS: Overall, 12 studies were included in this study (six studies on CHD, three studies on cerebrovascular disease, two studies on both coronary heart and cerebrovascular disease mortality and one study on peripheral arterial disease). All but one study reported positive associations between various periodontal disease measures and the incidence of ACVD, at least in specific subgroups. The association was stronger in younger adults and there was no evidence for an association between PD and incident CHD in subjects older than 65 years. Only one study evaluated the association between PD and secondary cardiovascular events. CONCLUSIONS: There is evidence for an increased risk of ACVD in patients with PD compared to patients without. However, this may not apply to all groups of the population. There is insufficient evidence for an association between PD and the incidence of secondary cardiovascular events. PMID- 23627337 TI - Evidence that periodontal treatment improves biomarkers and CVD outcomes. AB - AIM: The aim of this review was to critically appraise the evidence on the impact of periodontal treatment of cardiovascular diseases (CVDs) biomarkers and outcomes. METHODS: A systematic search was performed in Cinhal, Cochrane, Embase and Medline for relevant articles up to July 2012. Duplicate screening and reference hand searching were performed. Data were then summarized and evidence graded in tables. RESULTS: The search resulted in: (a) no evidence on the effects of periodontal therapy on subclinical atherosclerosis, serum levels of CD40 ligand, serum amyloid A and monocyte chemoattractant protein-1, (b) limited evidence on the effects of periodontal therapy on arterial blood pressure, leucocyte counts, fibrinogen, tissue necrosis factor-alpha, sE-selectin, von Willebrand factors, d-dimers, matrix metalloproteinases, oxidative stress and CVD events, and (c) moderate evidence suggesting a negligible effect of periodontal therapy in reducing interleukin-6 and lipids levels, whilst a positive effect in reducing serum C-reactive protein levels and improving endothelial function. CONCLUSIONS: Periodontal therapy triggers a short-term inflammatory response followed by (a) a progressive and consistent reduction of systemic inflammation and (b) an improvement in endothelial function. There is however limited evidence that these acute and chronic changes will either increase or reduce CVD burden of individuals suffering from periodontitis in the long term. PMID- 23627334 TI - Inflammatory mechanisms linking periodontal diseases to cardiovascular diseases. AB - AIMS: In this article, inflammatory mechanisms that link periodontal diseases to cardiovascular diseases are reviewed. METHODS: This article is a literature review. RESULTS: Studies in the literature implicate a number of possible mechanisms that could be responsible for increased inflammatory responses in atheromatous lesions due to periodontal infections. These include increased systemic levels of inflammatory mediators stimulated by bacteria and their products at sites distant from the oral cavity, elevated thrombotic and hemostatic markers that promote a prothrombotic state and inflammation, cross reactive systemic antibodies that promote inflammation and interact with the atheroma, promotion of dyslipidemia with consequent increases in pro-inflammatory lipid classes and subclasses, and common genetic susceptibility factors present in both disease leading to increased inflammatory responses. CONCLUSIONS: Such mechanisms may be thought to act in concert to increase systemic inflammation in periodontal disease and to promote or exacerbate atherogenesis. However, proof that the increase in systemic inflammation attributable to periodontitis impacts inflammatory responses during atheroma development, thrombotic events or myocardial infarction or stroke is lacking. PMID- 23627338 TI - Proton displacements coupled to primary electron transfer in the Rhodobacter sphaeroides reaction center. AB - Using first-principles molecular dynamics (AIMD) and constrained density functional theory (CDFT) we identify the pathway of primary electron transfer in the R. Sphaeroides reaction center from the special pair excited state (P*) to the accessory bacteriochlorophyll (BA). Previous AIMD simulations on the special pair (PLPM) predicted a charge-transfer intermediate formation through the excited-state relaxation along a reaction coordinate characterized by the rotation of an axial histidine (HisM202). To account for the full electron transfer we extend the model to include the primary acceptor BA. In this extended model, the LUMO is primarily localized on the acceptor BA and extends over an interstitial water (water A) that is known to influence the rate of electron transfer (Potter et al. Biochemistry 2005 280, 27155-27164). A vibrational analysis of the dynamical trajectories gives a frequency of 30-35 cm(-1) for a molecular motion involving the hydrogen-bond network around water A, in good agreement with experimental findings (Yakovlev et al. Biochemistry, 2003, 68, 603 610). In its binding pocket water A can act as a switch by breaking and forming hydrogen bonds. With CDFT we calculate the energy required to the formation of the charge-separated state and find it to decrease along the predicted anisotropic reaction coordinate. Furthermore, we observe an increased coupling between the ground and charge-separated state. Water A adapts its hydrogen bonding network along this reaction coordinate and weakens the hydrogen bond with HisM202. We also present AIMD simulations on the radical cation (P(*+)) showing a weakening of the hydrogen bond between HisL168 and the 3(1)-acetyl of PL. This work demonstrates how proton displacements are crucially coupled to the primary electron transfer and characterizes the reaction coordinate of the initial photoproduct formation. PMID- 23627339 TI - Underlying motivation in the approach and avoidance goals of depressed and non depressed individuals. AB - Neurobiological theories predict decreased approach motivation and increased avoidance motivation in depression, but the results of previous studies have been equivocal. This study addressed a key limitation of previous research by assessing participants' underlying motivation for adopting their goals. Depressed (N=26) and non-depressed (N=33) participants listed approach and avoidance goals and wrote down their underlying reasons for adopting those goals. The groups did not differ on either the number of goals or underlying reasons but when underlying reasons were coded for approach or avoidance motivation depressed participants, compared to controls, showed less approach motivation and more avoidance motivation in relation to their approach goals. There were no effects related to avoidance goals. The results suggest that while the goals of depressed persons appear to be similar to those who are not depressed there are important differences at the level of underlying motivation. PMID- 23627340 TI - Combined disc methods for the detection of KPC- and/or VIM-positive Klebsiella pneumoniae: improving reliability for the double carbapenemase producers. AB - Klebsiella pneumoniae strains co-producing klebsiella pneumoniae carbapenemase (KPC) and verona integron-encoded metallo-beta-lactamase (VIM) are frequently isolated in Greece and have also occurred in other European countries. Conventional combined disc tests exhibit low sensitivity against these emerging pathogens. We have evaluated modifications of the KPC/Metallo-beta-Lactamase Confirmation kit (ROSCO) exhibiting high diagnostic value against KPC, VIM and KPC + VIM producers. The key changes were the inclusion of additional combined tablets containing meropenem plus two inhibitors (dipicolinic acid (1000 MUg per tablet) for metallo-beta-lactamases and a boronic acid derivative for KPCs) and the replacement of aminophenylboronic acid by phenylboronic acid (400 MUg per tablet). PMID- 23627341 TI - HLA-typing, clinical, and immunological characterization of youth with type 2 diabetes mellitus phenotype from the German/Austrian DPV database. AB - AIM: To characterize the clinical and immunological features of HLA-typed youth with pediatric onset of type 2 diabetes mellitus (T2DM). METHOD: One hundred and seven patients with clinically diagnosed T2DM (aged <=20 yr at diagnosis) were examined. DNA and serum, obtained after a median diabetes duration of 2.2 (Q1-Q3: 0.8-4.6) yr, were used for centralized HLA-typing and autoantibody (GADA, IA-2A, ZnT8A) measurements. RESULTS: 64.6% of patients were female and median age at diagnosis was 13.8 (Q1-Q3: 11.6-15.4) yr. Patients were obese [median body mass index-standard deviation score (BMI-SDS): 2.6 (2.0-3.1)], 88.0% had a family history of diabetes and 40.2% a migration background. Islet autoantibodies were detected in 16 (15.0%), among which 7 (6.5%) had multiple islet autoantibodies. Autoantibody positive patients had poorer metabolic control than autoantibody negative patients [glycosylated hemoglobin A1c (HbA1c): 8.1 (6.9-10.1) % vs. 6.6 (5.9-8.0) %; p = 0.033], while patients with HLA-DR genetic risk had higher BMI SDS than those with HLA-DRXX [2.6 (2.4-3.7) vs. 2.4 (1.7-2.9); p = 0.007]. Metabolic syndrome (61.7%), microalbuminuria (13.4%), and retinopathy (3.9%) were diagnosed. Therapies used were lifestyle only (35.5%), oral anti-diabetics (OAD) only (43.3 %), insulin + OAD (15.9%) and insulin only (5.6%). Patients with beta cell autoimmunity or HLA-DR genetic risk more frequently used insulin than confirmed T2DM patients (50.0 vs. 22.0%; p = 0.037) and less often had diabetic relatives (61.1 vs. 86.0%; p = 0.030). CONCLUSION: T2DM was confirmed in about 90% of patients while about 10% with beta-cell autoimmunity or HLA-DR genetic risk likely had either T1.5DM or 'double diabetes' or an unknown diabetes type. PMID- 23627342 TI - Spontaneous posterior capsular rupture with lens dislocation in pseudoexfoliation syndrome. AB - Spontaneous posterior capsule rupture is a very rare entity and its association with lens-nucleus dislocation even more. Herein we report such a case of spontaneous posterior capsule rupture with lens dislocation in a case of Pseudoexfoliation Syndrome. PMID- 23627343 TI - Functional expression of a blood tolerant laccase in Pichia pastoris. AB - BACKGROUND: Basidiomycete high-redox potential laccases (HRPLs) working in human physiological fluids (pH 7.4, 150 mM NaCl) arise great interest in the engineering of 3D-nanobiodevices for biomedical uses. In two previous reports, we described the directed evolution of a HRPL from basidiomycete PM1 strain CECT 2971: i) to be expressed in an active, soluble and stable form in Saccharomyces cerevisiae, and ii) to be active in human blood. In spite of the fact that S. cerevisiae is suited for the directed evolution of HRPLs, the secretion levels obtained in this host are not high enough for further research and exploitation. Thus, the search for an alternative host to over-express the evolved laccases is mandatory. RESULTS: A blood-active laccase (ChU-B mutant) fused to the native/evolved alpha-factor prepro-leader was cloned under the control of two different promoters (P(AOX1) and P(GAP)) and expressed in Pichia pastoris. The most active construct, which contained the P(AOX1) and the evolved prepro-leader, was fermented in a 42-L fed-batch bioreactor yielding production levels of 43 mg/L. The recombinant laccase was purified to homogeneity and thoroughly characterized. As happened in S. cerevisiae, the laccase produced by P. pastoris presented an extra N-terminal extension (ETEAEF) generated by an alternative processing of the alpha-factor pro-leader at the Golgi compartment. The laccase mutant secreted by P. pastoris showed the same improved properties acquired after several cycles of directed evolution in S. cerevisiae for blood-tolerance: a characteristic pH-activity profile shifted to the neutral-basic range and a greatly increased resistance against inhibition by halides. Slight biochemical differences between both expression systems were found in glycosylation, thermostability and turnover numbers. CONCLUSIONS: The tandem-yeast system based on S. cerevisiae to perform directed evolution and P. pastoris to over-express the evolved laccases constitutes a promising approach for the in vitro evolution and production of these enzymes towards different biocatalytic and bioelectrochemical applications. PMID- 23627344 TI - Antibiograms from community-acquired uropathogens in Gulu, northern Uganda--a cross-sectional study. AB - BACKGROUND: Urinary tract infections (UTI) are common in clinical practice and empirical treatment is largely employed due to predictability of pathogens. However, variations in antibiotic sensitivity patterns do occur, and documentation is needed to inform local empirical therapy. The current edition of the Uganda Clinical Guidelines recommends amoxicillin or cotrimoxazole as choice drugs for empirical treatment of community-acquired UTI. From our clinical observations, we suspected that this recommendation was not effective in our setting. In order to examine validity, we sought to identify bacteria from community-acquired infections and determine their susceptibility against these antibiotics plus a range of potentially useful alternatives for treatment of UTI. METHODS: A cross-sectional study of mid-stream urine collected from 339 symptomatic patients over a three-month period at Gulu regional referral hospital. Qualitative culture and identification of bacteria and antibiotic sensitivity testing using the modified Kirby-Bauer disk diffusion method was done. Participants' demographic and clinical characteristics were collected using a standard form. Results were analyzed by simple proportions among related variables and confidence intervals computed using binomial exact distribution. RESULTS: Eighty two cultures were positive for UTI. Staphylococcus spp (46.3%) and Escherichia coli (39%) were the most common pathogens. There was high resistance to cotrimoxazole (73.2%), nalidixic acid (52.4%) and amoxicillin (51.2%). The most favorable antibiograms were obtained with gentamicin, amoxicillin-clavulanate and levofloxacin where 85.4%, 72.0%, 67.1% of isolates respectively, were either sensitive or intermediate. Only 51% of isolates were sensitive to ciprofloxacin. CONCLUSION: There was high resistance to most antibiotics tested in this study. The recommendations contained in the current edition of the Uganda Clinical Guidelines are not in tandem with antibiotic sensitivity pattern of uropathogens seen in our setting. Amoxicillin-clavulanate or gentamicin should be considered for replacement of amoxicillin and cotrimoxazole for empirical treatment of UTI in our setting. PMID- 23627345 TI - A randomized controlled trial of peripheral blood mononuclear cell depletion in experimental human lung inflammation. AB - RATIONALE: Depletion of monocytes reduces LPS-induced lung inflammation in mice, suggesting monocytes as potential therapeutic targets in acute lung injury. OBJECTIVES: To investigate whether depletion of circulating blood monocytes has beneficial effects on markers of systemic and pulmonary inflammation in a human model of acute lung inflammation. METHODS: A total of 30 healthy volunteers were enrolled in a randomized controlled trial. Volunteers inhaled LPS at baseline, and were randomized to receive active mononuclear cell depletion by leukapheresis, or sham leukapheresis, in a double-blind fashion (15 volunteers per group). Serial blood counts were measured, bronchoalveolar lavage (BAL) was performed at 9 hours, and [(18)F]fluorodeoxyglucose positron emission tomography at 24 hours. The primary endpoint was the increment in circulating neutrophils at 8 hours. MEASUREMENTS AND MAIN RESULTS: As expected, inhalation of LPS induced neutrophilia and an up-regulation of inflammatory mediators in the blood and lungs of all volunteers. There was no significant difference between the depletion and sham groups in the mean increment in blood neutrophil count at 8 hours (6.16 * 10(9)/L and 6.15 * 10(9)/L, respectively; P = 1.00). Furthermore, there were no significant differences in BAL neutrophils or protein, positron emission tomography-derived measures of global lung inflammation, or cytokine levels in plasma or BAL supernatant between the study groups. No serious adverse events occurred, and no symptoms were significantly different between the groups. CONCLUSIONS: These findings do not support a role for circulating human monocytes in the early recruitment of neutrophils during LPS-mediated acute lung inflammation in humans. PMID- 23627346 TI - Hwa-Byung among middle-aged Korean women: family relationships, gender-role attitudes, and self-esteem. AB - We surveyed 395 Korean middle-aged women and examined how their perceptions of family relationships, gender-role attitudes, and self-esteem were associated with Hwa-Byung (HB; Korean anger syndrome). Our regression analyses revealed that participants who reported worse family relationship problems experienced more HB symptoms. Having profeminist, egalitarian attitudes toward women's gender roles was also associated with more HB symptoms. Self-esteem was not significantly associated with HB. Based on the results, we suggest that what is crucial to understanding HB is not how women evaluate themselves, but rather the level of stress caused by family relationship problems and their perception of women's roles. PMID- 23627347 TI - Evaluation of a compression resistant matrix for recombinant human bone morphogenetic protein-2. AB - BACKGROUND: Previous studies document the therapeutic potential of recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge (ACS) carrier for indications in the axial and appendicular skeleton. Nevertheless, the ACS does not comprise structural integrity to adequately support bone formation for onlay indications. The objective of this study was to evaluate local bone formation and osseointegration following surgical implantation of rhBMP-2 soak-loaded onto a compression resistant matrix (CRM). METHODS: Routine, contralateral, critical-size, supraalveolar, peri-implant defects in five adult male Hound Labrador mongrel dogs received 0.8 mg rhBMP-2 soak-loaded onto either the ACS (benchmark control) or a CRM (collagen/beta TCP/hydroxyapatite) followed by submerged wound closure for primary intention healing. The animals were euthanized at 8 weeks for histologic/histometric evaluation. RESULTS: Healing was uneventful albeit considerable initial swelling was observed for either treatment. Sites receiving rhBMP-2/CRM showed significantly increased bone area (20.0 +/- 0.9 versus 12.3 +/- 2.6 mm(2) , p = 0.03) and bone density (24.1 +/- 1.4% versus 14.6 +/- 2.0%, p = 0.04) compared with those receiving rhBMP-2/ACS. There were no significant differences between treatments for new bone height and osseointegration. Woven and lamellar trabecular bone lined with abundant osteoid was observed for all sites. Inconsistent cortex formation confirmed the immature nature of the newly formed bone. Seroma formation was observed for both treatments (80-100% of the animals/implants). Sites receiving rhBMP-2/CRM showed residual ceramic granules undergoing biodegradation, including accumulation of foamy macrophages. CONCLUSIONS: rhBMP-2/CRM supports bone formation of clinically relevant geometry. Longer observation intervals as well as dose variations appear necessary to capture maturation of the newly formed bone, elimination of residual ceramic granules and resolution of seroma formation(s). PMID- 23627349 TI - Development of plasmid DNA reference material for the quantification of genetically modified common bean embrapa 5.1. AB - The genetically modified (GM) common bean Embrapa 5.1 was recently approved for commercialization. The reliable detection and quantification of GM organisms is strongly dependent on validated methods as well as calibration systems. This work presents the development of a calibrant plasmid for Embrapa 5.1 common bean detection. The reaction parameters were determined and compared for both the plasmid DNA (pDNA) and the genomic DNA (gDNA). PCR efficiencies for pDNA were 81% for the construction-specific assays and 76% for the taxon-specific assay, whereas for gDNA efficiencies were 94 and 93%, respectively. The limits of detection (LOD) in both qPCR assays were 10(2) and 10(3) copies of gDNA and pDNA per PCR reaction, respectively. This is sufficient to detect 0.067 and 0.67% of GM common bean in 100 ng of DNA, respectively, which is in agreement with detecting the 1% GM content required by the Brazilian legislation. PMID- 23627348 TI - Inhibition of protein kinase A activity depresses phrenic drive and glycinergic signalling, but not rhythmogenesis in anaesthetized rat. AB - The cAMP-protein kinase A (PKA) pathway plays a critical role in regulating neuronal activity. Yet, how PKA signalling shapes the population activity of neurons that regulate respiratory rhythm and motor patterns in vivo is poorly defined. We determined the respiratory effects of focally inhibiting endogenous PKA activity in defined classes of respiratory neurons in the ventrolateral medulla and spinal cord by microinjection of the membrane-permeable PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS) in urethane-anaesthetized adult Sprague Dawley rats. Phrenic nerve activity, end-tidal CO2 and arterial pressure were recorded. Rp-cAMPS in the preBotzinger complex (preBotC) caused powerful, dose-dependent depression of phrenic burst amplitude and inspiratory period. Rp-cAMPS powerfully depressed burst amplitude in the phrenic premotor nucleus, but had no effect at the phrenic motor nucleus, suggesting a lack of persistent PKA activity here. Surprisingly, inhibition of PKA activity in the preBotC increased phrenic burst frequency, whereas in the Botzinger complex phrenic frequency decreased. Pretreating the preBotC with strychnine, but not bicuculline, blocked the Rp-cAMPS-evoked increase in frequency, but not the depression of phrenic burst amplitude. We conclude that endogenous PKA activity in excitatory inspiratory preBotzinger neurons and phrenic premotor neurons, but not motor neurons, regulates network inspiratory drive currents that underpin the intensity of phrenic nerve discharge. We show that inhibition of PKA activity reduces tonic glycinergic transmission that normally restrains the frequency of rhythmic respiratory activity. Finally, we suggest that the maintenance of the respiratory rhythm in vivo is not dependent on endogenous cAMP-PKA signalling. PMID- 23627350 TI - Quantum stochastic dynamics in the presence of a time-periodic rapidly oscillating potential: nonadiabatic escape rate. AB - Escape from a metastable state in the presence of a high-frequency field (where the driving becomes nonadiabatic) underlies a broad range of phenomena of physics and chemistry, and thus its understanding is of paramount importance. We study the problem of intermediate-to-high-damping escape from a metastable state of a dissipative system driven by a rapidly oscillating field, one of the most important classes of nonequilibrium systems, in a broad range of field driving frequencies (omega) and amplitudes (a). We construct a Langevin equation using quantum gauge transformation in the light of Floquet theorem and exploiting a systematic perturbative expansion in powers of 1/omega using "Kapitza-Landau time window". The quantum dynamics in a high-frequency field are found to be described by an effective time-independent potential. The temperature dependence of escape rate and the change of its form with varying parameters of the field have been analyzed. It may decrease upon increasing the temperature which is contingent on the effects of intricate interplay between external modulation and dissipation. The crossover temperature between tunnelling and thermal hopping increases with an increase in external modulation so that quantum effects in the escape are relevant at higher temperatures. These observations are uncommon and counterintuitive and, therefore, of considerable interest. Our results might be valuable for the exploration of the dynamics of cold atoms in electromagnetic fields. PMID- 23627351 TI - Extensively calcified left ventricular aneurysm. PMID- 23627353 TI - Potential implication of N-acetylcysteine detoxification on adhesive endodontics. AB - Methacrylate resin-based dentin adhesives and root canal sealers used for bonding of filling materials inside the root canal system are cytotoxic and result in reduction in cell proliferation to a variable extent. An in vitro study to examine the detoxifying effects of N-acetylcysteine (NAC) on four commercial adhesive systems on adhesive-induced cytotoxicity and cell survival was conducted so that the use of methacrylate resin-based materials for filling root canals could be optimized. The finding that NAC co-treatment protected the cells from adhesive-induced toxicity by increasing cellular proliferation, attenuating cell cycle arrest, and reducing cell death suggests the null hypothesis that NAC has no effect on dentin adhesive-induced cell death and cell cycle arrest should be rejected. PMID- 23627352 TI - Design, synthesis, and molecular modeling of novel pyrido[2,3-d]pyrimidine analogues as antifolates; application of Buchwald-Hartwig aminations of heterocycles. AB - Opportunistic infections caused by Pneumocystis jirovecii (P. jirovecii, pj), Toxoplasma gondii (T. gondii, tg), and Mycobacterium avium (M. avium, ma) are the principal causes of morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). The absence of any animal models for human Pneumocystis jirovecii pneumonia and the lack of crystal structures of pjDHFR and tgDHFR make the design of inhibitors challenging. A novel series of pyrido[2,3 d]pyrimidines as selective and potent DHFR inhibitors against these opportunistic infections are presented. Buchwald-Hartwig coupling reaction of substituted anilines with pivaloyl protected 2,4-diamino-6-bromo-pyrido[2,3-d]pyrimidine was successfully explored to synthesize these analogues. Compound 26 was the most selective inhibitor with excellent potency against pjDHFR. Molecular modeling studies with a pjDHFR homology model explained the potency and selectivity of 26. Structural data are also reported for 26 with pcDHFR and 16 and 22 with variants of pcDHFR. PMID- 23627354 TI - Comprehensive oral rehabilitation of a patient with aplastic anemia by periodontal and prosthesis treatments. AB - Aplastic anemia (AA) is a rare but extremely serious disorder that results from an unexplained failure of the bone marrow to produce blood cells. Patients with AA are at high risk for infections, including periodontitis. Treatment modalities are complicated by bleeding disorders. This is a case report of the successful periodontal and prosthesis treatment in a patient with AA, chronic diffuse gingivitis, excessive tooth caries that interfered with mastication, painful oral lesions, and limited mouth opening. Physiotherapy was performed to improve the mouth opening, and the patient was examined for HBsAg, HBsAb, and HIV; white blood cell and platelet count and coagulation tests were given before every periodontal treatment. Caries removal and root canal therapy were done, hopeless teeth were extracted, and full-mouth crown lengthening was performed. Free gingival grafts were placed in areas of inadequate keratinized tissue, and full mouth rehabilitation with fixed prosthesis was completed. RESULTS: The mouth opening was improved to 31 mm, inflammation was significantly controlled especially after comprehensive periodontal treatment, the redness significantly decreased, and an acceptable condition for prosthesis reconstruction was obtained. DISCUSSION: The treatment modalities used in this case provide a new ray of hope for patients who are severely medically compromised. PMID- 23627355 TI - Diode laser offers minimal benefit for periodontal therapy. AB - Current evidence indicates that use of diode lasers in the treatment of periodontitis--either as a monotherapy or adjunctive to traditional therapy- offers minimal benefit. Further, subgingival application of the diode laser during nonsurgical periodontal therapy can result in undesired outcomes, even when using manufacturer-recommended parameters. PMID- 23627356 TI - Topical application of the lectin Artin M accelerates wound healing in rat oral mucosa by enhancing TGF-beta and VEGF production. AB - The lectin Artin M has been shown to accelerate the wound-healing process. The aims of this study were to evaluate the effects of Artin M on wound healing in the palatal mucosa of rats and to investigate the effects of Artin M on transforming growth factor beta (TGF-beta) and vascular endothelial growth factor (VEGF) secretion by rat gingival fibroblasts. A surgical wound was created on the palatal mucosa of 72 rats divided into three groups according to treatment: C- Control (nontreated), A--Artin M gel, and V--Vehicle. Eight animals per group were sacrificed at 3, 5, and 7 days postsurgery for histology, immunohistochemistry and determination of the levels of cytokines, and growth factors. Gingival fibroblasts were incubated with 2.5 MUg/mL of Artin M for 24, 48, and 72 hours. The expression of VEGF and TGF-beta was determined by enzyme linked immunosorbent assay. Histologically, at day 7, the Artin M group showed earlier reepithelialization, milder inflammatory infiltration, and increased collagen fiber formation, resulting in faster maturation of granular tissue than in the other groups (p < 0.05). Artin M-induced cell proliferation in vivo and promoted a greater expression of TGF-beta and VEGF in both experiments (p < 0.05). Artin M was effective in healing oral mucosa wounds in rats and was associated with increased TGF-beta and VEGF release, cell proliferation, reepithelialization, and collagen deposition and arrangement of fibers. PMID- 23627357 TI - Lipin1 regulates PPARgamma transcriptional activity. AB - PPARgamma (peroxisome-proliferator-activated receptor gamma) is a master transcription factor involved in adipogenesis through regulating adipocyte specific gene expression. Recently, lipin1 was found to act as a key factor for adipocyte maturation and maintenance by modulating the C/EBPalpha (CCAAT/enhancer binding protein alpha) and PPARgamma network; however, the precise mechanism by which lipin1 affects the transcriptional activity of PPARgamma is largely unknown. The results of the present study show that lipin1 activates PPARgamma by releasing co-repressors, NCoR1 (nuclear receptor co-repressor 1) and SMRT (silencing mediator of retinoid and thyroid hormone receptor), from PPARgamma in the absence of the ligand rosiglitazone. We also identified a novel lipin1 TAD (transcriptional activation domain), between residues 217 and 399, which is critical for the activation of PPARgamma, but not PPARalpha. Furthermore, this TAD is unique to lipin1 since this region does not show any homology with the other lipin isoforms, lipin2 and lipin3. The activity of the lipin1 TAD is enhanced by p300 and SRC-1 (steroid receptor co-activator 1), but not by PCAF (p300/CBP-associated factor) and PGC-1alpha (PPAR co-activator 1alpha). The physical interaction between lipin1 and PPARgamma occurs at the lipin1 C-terminal region from residues 825 to 926, and the VXXLL motif at residue 885 is critical for binding with and the activation of PPARgamma. The action of lipin1 as a co activator of PPARgamma enhanced adipocyte differentiation; the TAD and VXXLL motif played critical roles, but the catalytic activity of lipin1 was not directly involved. Collectively, these data suggest that lipin1 functions as a key regulator of PPARgamma activity through its ability to release co-repressors and recruit co-activators via a mechanism other than PPARalpha activation. PMID- 23627358 TI - The stages of reproductive aging as proposed by workshops held in 2001 and 2010 (STRAW and STRAW + 10): a commentary. PMID- 23627359 TI - DOPS assessment: a study to evaluate the experience and opinions of trainees and assessors. AB - BACKGROUND: Workplace based assessments (WBAs) have been part of UK training for the last 3 years. Carrying out procedures efficiently and safely is of paramount importance in anaesthesia. AIMS: To explore opinions and experiences of Direct Observation of Procedural Skills (DOPS) assessments in a regional anaesthetic training programme. METHODS: 19 and 20-item questionnaires were distributed to trainees and consultants respectively. RESULTS: Questionnaire response rate was 76% (90/119) for trainees and 65% (129/199) for consultants. 43% of consultants and 33% of trainees were not trained in DOPS use. Assessments were usually not planned. 50% were ad hoc and the remainder mainly retrospective. Time spent on assessment was short with DOPS and feedback achieved in <=15 minutes in the majority of cases with lack of suggestions for further improvement. Both trainees and consultants felt that DOPS was not a helpful learning tool (p = 0.001) or a reflection of trainee competency. CONCLUSIONS: DOPS assessments are currently not valued as an educational tool. Training is essential in use of this WBA tool which needs to be planned and sufficient time allocated so as to address current negative attitudes. PMID- 23627360 TI - Impact of national context and culture on curriculum change: a case study. AB - BACKGROUND: Earlier studies suggested national culture to be a potential barrier to curriculum reform in medical schools. In particular, Hofstede's cultural dimension 'uncertainty avoidance' had a significant negative relationship with the implementation rate of integrated curricula. AIMS: However, some schools succeeded to adopt curriculum changes despite their country's strong uncertainty avoidance. This raised the question: 'How did those schools overcome the barrier of uncertainty avoidance?' METHOD: Austria offered the combination of a high uncertainty avoidance score and integrated curricula in all its medical schools. Twenty-seven key change agents in four medical universities were interviewed and transcripts analysed using thematic cross-case analysis. RESULTS: Initially, strict national laws and limited autonomy of schools inhibited innovation and fostered an 'excuse culture': 'It's not our fault. It is the ministry's'. A new law increasing university autonomy stimulated reforms. However, just this law would have been insufficient as many faculty still sought to avoid change. A strong need for change, supportive and continuous leadership, and visionary change agents were also deemed essential. CONCLUSIONS: In societies with strong uncertainty avoidance strict legislation may enforce resistance to curriculum change. In those countries opposition by faculty can be overcome if national legislation encourages change, provided additional internal factors support the change process. PMID- 23627361 TI - Flow through horizontal tubes submerged in water in the absence of a pressure gradient: mechanistic considerations. AB - Self-driven flow was observed in Nafion and other hydrophilic tubes immersed in water. The intratubular flow was generated when water came in contact with the tube's hydrophilic surfaces. Flow characteristics were studied in tubes of varying size, exposed to light of different intensities and wavelengths. The results lead to the hypothesis that the flow is driven by a high concentration of protons accumulating inside the tube, creating an axial proton gradient between the inside and outside of the tube. We also demonstrate a faster flow under incident light, particularly at UV wavelengths, implying that proton generation may be driven by light. PMID- 23627362 TI - Coordination chemistry of disilylated stannylenes with group 10 d10 transition metals: silastannene vs stannylene complexation. AB - The coordination behavior of disilylated stannylenes toward zerovalent group 10 transition metal complexes was studied. This was accomplished by reactions of PEt3 adducts of disilylated stannylenes with zerovalent group 10 transition metal complexes. The thus obtained products differed between the first row example nickel and its heavier congeners. While with nickel stannylene complex formation was observed, coordination of the stannylenes to palladium and platinum compounds led to unusual silastannene complexes of these metals. A computational model study indicated that in each case metal stannylene complexes were formed first and that the disilylstannylene/silastannene rearrangement occurs only after complexation to the group 10 metal. The isomerization is a two-step process with relatively small barriers, suggesting a thermodynamic control of product formation. In addition, the results of the computational investigation revealed a subtle balance of steric and electronic effects, which determines the relative stability of the metalastannylene complex relative to its silastannene isomer. In the case of cyclic disilylstannylenes, the Pd(0) and Pt(0) silastannene complexes are found to be more stable, while with acyclic disilylstannylenes the Ni(0) stannylene complex is formed preferentially. PMID- 23627363 TI - Toughening of biodegradable polylactide/poly(butylene succinate-co-adipate) blends via in situ reactive compatibilization. AB - Polylactide and poly(butylene succinate-co-adipate) (PLA/PBSA) were melt-blended in the presence of triphenyl phosphite (TPP). An increase in the torque during melt mixing was used to monitor the changes in viscosity as compatibilization of the blends occurred. Scanning electron micrographs showed not only a reduction in the dispersed-phase size with increased TPP content but also fibrillated links between the PLA and PBSA phases, signifying compatibilization. Moreover, optimization of parameters such as the mixing sequence and time, TPP content, and PBSA concentration revealed that blends containing 30 and 10 wt % PBSA and 2 wt % TPP, which were processed for 30 min, were optimal in terms of thermomechanical properties. The impact strength increased from 6 kJ/m(2) for PLA to 11 and 16 kJ/m(2) for blends containing 30 and 10 wt % PBSA, respectively, whereas the elongation-at-break increased from 6% for PLA to 20 and 37% for blends containing 30 and 10 wt % PBSA, respectively. Upon compatibilization, the failure mode shifted from the brittle fracture of PLA to ductile deformation, effected by the debonding between the two phases. With improved phase adhesion, compatibilized blends not only were toughened but also did not significantly lose tensile strength and thermal stability. PMID- 23627364 TI - A systematic muscle model covering regions from the fast ramp stretches in the muscle fibres to the relatively slow stretches in the human triceps surae. AB - We have proposed a muscle model which consists of two Maxwell elements and a Voigt element in parallel. The muscle model was applied on the experiment of the force responses by the fast ramp stretch in muscle fibres to determine the mechanical parameters. In the simulation, the Maxwell element with a flexible spring and a long relaxation time seemed to correspond with the force-generating state of the cross-bridges. Next, we tried the muscle model to simulate the relatively slow movement. Experimentally, we have measured torque changes by the stretch responses in the human triceps surae. In the experiments, the derivation of torque by rotation angle showed two peaks P1 and P2. The first peak P1 originated from the elastic properties of engaged cross-bridges, while the second peak P2 was due to stretch reflex signals. The model of a single-joint system simulated well with the experimental results to show a good adaptability of the muscle model. PMID- 23627365 TI - Origin of abrupt rise in deuteron NMR longitudinal relaxation times of protein methyl groups below 90 K. AB - In order to examine the origin of the abrupt change in the temperature dependence of (2)H NMR longitudinal relaxation times observed previously for methyl groups of L69 in the hydrophobic core of villin headpiece protein at around 90 K (Vugmeyster et al. J. Am. Chem. Soc. 2010, 132, 4038-4039), we extended the measurements to several other methyl groups in the hydrophobic core. We show that, for all methyl groups, relaxation times experience a dramatic jump several orders of magnitude around this temperature. Theoretical modeling supports the conclusion that the origin of the apparent transition in the relaxation times is due to the existence of the distribution of conformers distinguished by their activation energy for methyl three-site hops. It is also crucial to take into account the differential contribution of individual conformers into overall signal intensity. When a particular conformer approaches the regime at which its three-site hop rate constant is on the order of the quadrupolar coupling interaction constant, the intensity of the signal due to this conformer experiences a sharp drop, thus changing the balance of the contributions of different conformers into the overall signal. As a result, the observed apparent transition in the relaxation rates can be explained without the assumption of an underlying transition in the rate constants. This work in combination with earlier results also shows that the model based on the distribution of conformers explains the relaxation behavior in the entire temperature range between 300 and 70 K. PMID- 23627366 TI - Smoking cessation practice and research in China: what's history and culture got to do with it? PMID- 23627368 TI - The architecture of Trypanosoma brucei tubulin-binding cofactor B and implications for function. AB - Tubulin-binding cofactor (TBC)-B is implicated in the presentation of alpha tubulin ready to polymerize, and at the correct levels to form microtubules. Bioinformatics analyses, including secondary structure prediction, CD, and crystallography, were combined to characterize the molecular architecture of Trypanosoma brucei TBC-B. An efficient recombinant expression system was prepared, material-purified, and characterized by CD. Extensive crystallization screening, allied with the use of limited proteolysis, led to structures of the N terminal ubiquitin-like and C-terminal cytoskeleton-associated protein with glycine-rich segment domains at 2.35-A and 1.6-A resolution, respectively. These are compact globular domains that appear to be linked by a flexible segment. The ubiquitin-like domain contains two lysines that are spatially conserved with residues known to participate in ubiquitinylation, and so may represent a module that, through covalent attachment, regulates the signalling and/or protein degradation associated with the control of microtubule assembly, catastrophe, or function. The TBC-B C-terminal cytoskeleton-associated protein with glycine-rich segment domain, a known tubulin-binding structure, is the only such domain encoded by the T. brucei genome. Interestingly, in the crystal structure, the peptide-binding groove of this domain forms intermolecular contacts with the C terminus of a symmetry-related molecule, an association that may mimic interactions with the C-terminus of alpha-tubulin or other physiologically relevant partners. The interaction of TBC-B with the alpha-tubulin C-terminus may, in particular, protect from post-translational modifications, or simply assist in the shepherding of the protein into polymerization. PMID- 23627369 TI - Factors affecting vitamin D status in different populations in the city of Sao Paulo, Brazil: the Sao PAulo vitamin D Evaluation Study (SPADES). AB - BACKGROUND: Hypovitaminosis D is a common condition among elderly individuals in temperate-climate countries, with a clear seasonal variation on 25 hydroxyvitamin D [(25(OH)D] levels, increasing after summer and decreasing after winter, but there are few data from sunny countries such as Brazil. We aimed to evaluate 25 hydroxyvitamin D concentrations and its determining factors, in individuals in the city of Sao Paulo belonging to different age groups and presenting different sun exposure habits. METHODS: 591 people were included as follows: 177 were living in institutions (NURSING HOMES, NH, 76.2 +/- 9.0 years), 243 were individuals from the community (COMMUNITY DWELLINGS, CD, 79.6 +/- 5.3 years), 99 were enrolled in physical activity program designed for the elderly (PHYSICAL ACTIVITY, PA, 67.6 +/- 5.4 years) and 72 were young (YOUNG, 23.9 +/- 2.8 years). Ionized calcium, PTH, 25(OH)D, creatinine and albumin were evaluated. ANOVA, Mann Whitney and Kruskal Wallis tests, Pearson Linear Correlation and Multiple Regression were used in the statistical analysis. RESULTS: 25(OH)D mean values during winter for the different groups were 36.1 +/- 21.2 nmol/L (NH), 44.1 +/- 24.0 nmol/L (CD), 78.9 +/- 30.9 nmol/L (PA) and 69.6 +/- 26.2 nmol/L (YOUNG) (p < 0.001) while during summer they were 42.1 +/- 25.9 nmol/L, 59.1 +/- 29.6 nmol/L, 91.6 +/- 31.7 nmol/L and 103.6 +/- 29.3 nmol/L, respectively (p < 0.001). The equation which predicts PTH values based on 25(OH)D concentration is PTH = 10 + 104.24.e-(vitD-12.5)/62.36 and the 25(OH)D value above which correlation with PTH is lost is 75.0 nmol/L. In a multiple regression analysis having 25(OH)D concentration as the depending variable, the determining factors were PTH, ionized calcium and month of the year (p < 0.05). CONCLUSIONS: Much lower 25(OH)D values were found for the older individuals when compared to younger individuals. This finding is possibly due to age and habit-related differences in sunlight exposure. The existence of seasonal effects on 25(OH)D concentration throughout the year was evident for all the groups studied, except for the nursing home group. According to our data, PTH values tend to plateau above 75 nmol/L. PMID- 23627370 TI - Comparisons of health conditions of immigrant and domestic women in Korea and China using propensity score matching. AB - We identified how the health of the growing Korean-Chinese (KC) female immigrant population differed from comparable domestic women. Using propensity score matching, we selected 227 women recruited from Korea and China; perceived health status, female cancer screening behaviors, and the Health Promoting Lifestyle Profile II were investigated. The KC women in Korea had the lowest levels of physical and mental health as well as health promoting lifestyles, but performed female cancer screenings better than other women. Considering their vulnerability, the hosting country should provide accessible health services at reasonable fees for KC women in Korea to enhance their health. PMID- 23627371 TI - Evaluation of direct immunofluorescence assay and cytological examination in comparison to polymerase chain reaction of conjunctival swabs in patients with adult inclusion conjunctivitis. AB - PURPOSE: To evaluate PCR, direct immunofluorescence assay (DIA) and cytological test of conjunctival swabs for the diagnosis of adult follicular conjunctivitis (AFC). METHODS: Eighty-three adult patients with chronic conjunctivitis and sixteen healthy individuals were included. Conjunctival scrapings underwent PCR, DIA and cytological analysis. Exams were repeated two weeks after treatment application. Sensitivity, specificity and agreement rate with PCR of DIA and Cytology were evaluated and correlated with clinical symptoms/signs. RESULTS: Cytology test was more sensitive than DIA and presented an acceptable agreement with PCR (K=0.44) in treatment-naive patients, concerning especially the combination of both conventional exams (K = 0.77). Inferior diagnostic performance of was detected post-treatment, considering the combination as well (K=0.40). Negative post-treatment PCR correlated well with significant relief of symptoms/signs. CONCLUSION: Combination of Cytology and DIA seems to be a useful diagnostic option for treatment naive AFC patients. However, PCR remains the most reliable test for post-treatment evaluation. PMID- 23627372 TI - Quantifying the impact of daily and seasonal variation in sap pH on xylem dissolved inorganic carbon estimates in plum trees. AB - In studies on internal CO2 transport, average xylem sap pH (pH(x)) is one of the factors used for calculation of the concentration of dissolved inorganic carbon in the xylem sap ([CO2 *]). Lack of detailed pH(x) measurements at high temporal resolution could be a potential source of error when evaluating [CO2*] dynamics. In this experiment, we performed continuous measurements of CO2 concentration ([CO2]) and stem temperature (T(stem)), complemented with pH(x) measurements at 30-min intervals during the day at various stages of the growing season (Day of the Year (DOY): 86 (late winter), 128 (mid-spring) and 155 (early summer)) on a plum tree (Prunus domestica L. cv. Reine Claude d'Oullins). We used the recorded pH(x) to calculate [CO2*] based on T(stem) and the corresponding measured [CO2]. No statistically significant difference was found between mean [CO2*] calculated with instantaneous pH(x) and daily average pH(x). However, using an average pH(x) value from a different part of the growing season than the measurements of [CO2] and T(stem) to estimate [CO2*] led to a statistically significant error. The error varied between 3.25 +/- 0.01% under-estimation and 3.97 +/- 0.01% over estimation, relative to the true [CO2*] data. Measured pH(x) did not show a significant daily variation, unlike [CO2], which increased during the day and declined at night. As the growing season progressed, daily average [CO2] (3.4%, 5.3%, 7.4%) increased and average pH(x) (5.43, 5.29, 5.20) decreased. Increase in [CO2] will increase its solubility in xylem sap according to Henry's law, and the dissociation of [CO2*] will negatively affect pH(x). Our results are the first quantifying the error in [CO2*] due to the interaction between [CO2] and pH(x) on a seasonal time scale. We found significant changes in pH(x) across the growing season, but overall the effect on the calculation of [CO2*] remained within an error range of 4%. However, it is possible that the error could be more substantial for other tree species, particularly if pH(x) is in the more sensitive range (pH(x) > 6.5). PMID- 23627373 TI - Speech and language development in 2-year-old children with cerebral palsy. AB - OBJECTIVE: We examined early speech and language development in children who had cerebral palsy. Questions addressed whether children could be classified into early profile groups on the basis of speech and language skills and whether there were differences on selected speech and language measures among groups. METHODS: Speech and language assessments were completed on 27 children with CP who were between the ages of 24 and 30 months (mean age 27.1 months; SD 1.8). We examined several measures of expressive and receptive language, along with speech intelligibility. RESULTS: Two-step cluster analysis was used to identify homogeneous groups of children based on their performance on the seven dependent variables characterizing speech and language performance. Three groups of children identified were those not yet talking (44% of the sample); those whose talking abilities appeared to be emerging (41% of the sample); and those who were established talkers (15% of the sample). Group differences were evident on all variables except receptive language skills. CONCLUSION: 85% of 2-year-old children with CP in this study had clinical speech and/or language delays relative to age expectations. Findings suggest that children with CP should receive speech and language assessment and treatment at or before 2 years of age. PMID- 23627374 TI - Treatment of multiple adjacent Miller class I and II gingival recessions with a Modified Coronally Advanced Tunnel (MCAT) technique and a collagen matrix or palatal connective tissue graft: a randomized, controlled clinical trial. AB - BACKGROUND: A newly developed collagen matrix (CM) of porcine origin has been shown to represent a potential alternative to palatal connective tissue grafts (CTG) for the treatment of single Miller Class I and II gingival recessions when used in conjunction with a coronally advanced flap (CAF). However, at present it remains unknown to what extent CM may represent a valuable alternative to CTG in the treatment of Miller Class I and II multiple adjacent gingival recessions (MAGR). The aim of this study was to compare the clinical outcomes following treatment of Miller Class I and II MAGR using the modified coronally advanced tunnel technique (MCAT) in conjunction with either CM or CTG. METHODS: Twenty-two patients with a total of 156 Miller Class I and II gingival recessions were included in this study. Recessions were randomly treated according to a split mouth design by means of MCAT + CM (test) or MCAT + CTG (control). The following measurements were recorded at baseline (i.e. prior to surgery) and at 12 months: Gingival Recession Depth (GRD), Probing Pocket Depth (PD), Clinical Attachment Level (CAL), Keratinized Tissue Width (KTW), Gingival Recession Width (GRW) and Gingival Thickness (GT). GT was measured 3-mm apical to the gingival margin. Patient acceptance was recorded using a Visual Analogue Scale (VAS). The primary outcome variable was Complete Root Coverage (CRC), secondary outcomes were Mean Root Coverage (MRC), change in KTW, GT, patient acceptance and duration of surgery. RESULTS: Healing was uneventful in both groups. No adverse reactions at any of the sites were observed. At 12 months, both treatments resulted in statistically significant improvements of CRC, MRC, KTW and GT compared with baseline (p < 0.05). CRC was found at 42% of test sites and at 85% of control sites respectively (p < 0.05). MRC measured 71 +/- 21% mm at test sites versus 90 +/- 18% mm at control sites (p < 0.05). Mean KTW measured 2.4 +/- 0.7 mm at test sites versus 2.7 +/- 0.8 mm at control sites (p > 0.05). At test sites, GT values changed from 0.8 +/- 0.2 to 1.0 +/- 0.3 mm, and at control sites from 0.8 +/- 0.3 to 1.3 +/- 0.4 mm (p < 0.05). Duration of surgery and patient morbidity was statistically significantly lower in the test compared with the control group respectively (p < 0.05). CONCLUSIONS: The present findings indicate that the use of CM may represent an alternative to CTG by reducing surgical time and patient morbidity, but yielded lower CRC than CTG in the treatment of Miller Class I and II MAGR when used in conjunction with MCAT. PMID- 23627378 TI - Effects of isoflurane with and without dexmedetomidine or remifentanil on heart rate variability before and after nociceptive stimulation at different multiples of minimum alveolar concentration in dogs. AB - OBJECTIVE: To evaluate the influence of 3 anesthetic protocols and multiples of minimum alveolar concentration (MAC) on heart rate variability (HRV) with and without nociceptive stimulation in dogs. ANIMALS: 6 healthy adult Beagles. PROCEDURES: Each dog was anesthetized 3 times: with isoflurane alone, with isoflurane and a constant rate infusion of dexmedetomidine (IsoD; 3 MUg/kg/h, IV), and with isoflurane and a constant rate infusion of remifentanil (IsoR; 18 MUg/kg/h, IV). Individual MAC was determined via supramaximal electrical stimulation. Sinus rhythm-derived intervals between 2 adjacent R-R intervals were exported from ECG recordings. Selected HRV time and frequency domain variables were obtained (at 2-minute intervals) and analyzed offline with signed rank tests before and after stimulation at 0.75, 1.0, and 1. 5 MAC for each anesthetic session. RESULTS: The isoflurane session had the overall lowest prestimulation SDNN (SD of all R-R intervals) values. Prestimulation SDNN values decreased significantly with increasing MAC in all sessions. For the IsoD session, SDNN (milliseconds) or high-frequency power (milliseconds(2)) was inversely correlated with MAC (Spearman rank correlation coefficient for both variables, -0.77). In the isoflurane and IsoR sessions, heart rate increased significantly after stimulation. In the IsoD session, poststimulation SDNN was increased significantly, compared with prestimulation values, at 0.75 and 1.0 MAC. CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of SDNN and high-frequency power values, anesthetic levels between 0.75 and 1.5 MAC within the same anesthetic protocol could be differentiated, but with a large overlap among protocols. Usefulness of standard HRV variables for assessment of anesthetic depth and nociception in dogs is questionable. PMID- 23627375 TI - Disrupted Cl(-) homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states. AB - The K(+) -Cl(-) cotransporter type 2 is the major Cl(-) extrusion mechanism in most adult neurons. This process in turn leads to Cl(-) influx upon activation of gamma-aminobutyric acid type A (GABAA ) receptors and the canonical hyperpolarising inhibitory postsynaptic potential. Several neurological disorders are treated with drugs that target and enhance GABAA receptor signaling, including the commonly used benzodiazepine diazepam and the anesthetic propofol. Some of these disorders are also associated with deficits in GABAA signaling and become less sensitive to therapeutic drugs that target GABAA receptors. To date, it is unknown if alterations in the neuronal Cl(-) gradient affect the efficacies of diazepam and propofol. We therefore used the in vitro model of glutamate induced hyperexcitability to test if alterations in the Cl(-) gradient affect the efficacy of GABAA modulators. We exclusively utilised the gramicidin perforated patch-clamp configuration to preserve the endogenous Cl(-) gradient in rat neurons. Brief exposure to glutamate reduced the inhibitory efficacy of diazepam within 5 min, which was caused by the collapse of the Cl(-) gradient, and not due to reductions in GABAA receptor number. Unlike diazepam, propofol retained its efficacy by shunting the membrane conductance despite the glutamate-induced appearance of depolarising GABAA -mediated currents. Similarly, pharmacological inhibition of K(+) -Cl(-) cotransporter type 2 by furosemide disrupted Cl(-) homeostasis and reduced the efficacy of diazepam but not propofol. Collectively our results suggest that pathological hyperexcitable conditions could cause the rapid accumulation of intracellular Cl(-) and the appearance of depolarising GABAA -mediated currents that would decrease the efficacy of diazepam. PMID- 23627379 TI - Cardiopulmonary effects of intravenous fentanyl infusion in dogs during isoflurane anesthesia and with concurrent acepromazine or dexmedetomidine administration during anesthetic recovery. AB - OBJECTIVE: To evaluate the cardiopulmonary effects of IV fentanyl administration in dogs during isoflurane anesthesia and during anesthetic recovery with or without dexmedetomidine or acepromazine. ANIMALS: 7 sexually intact male purpose bred hound-type dogs aged 11 to 12 months. PROCEDURES: Dogs received a loading dose of fentanyl (5 MUg/kg, IV) followed by an IV infusion (5 MUg/kg/h) for 120 minutes while anesthetized with isoflurane and for an additional 60 minutes after anesthesia was discontinued. Dogs were randomly assigned in a crossover design to receive dexmedetomidine (2.5 MUg/kg), acepromazine (0.05 mg/kg), or saline (0.9% NaCl) solution (1 mL) IV after anesthesia ceased. Cardiopulmonary data were obtained during anesthesia and for 90 minutes after treatment administration during anesthetic recovery. RESULTS: Concurrent administration of fentanyl and isoflurane resulted in significant decreases in mean arterial blood pressure, heart rate, and cardiac index and a significant increase in Paco2. All but Paco2 returned to pretreatment values before isoflurane anesthesia was discontinued. During recovery, dexmedetomidine administration resulted in significant decreases in heart rate, cardiac index, and mixed venous oxygen tension and a significant increase in arterial blood pressure, compared with values for saline solution and acepromazine treatments. Acepromazine administration resulted in significantly lower blood pressure and higher cardiac index and Po2 in mixed venous blood than did the other treatments. Dexmedetomidine treatment resulted in significantly lower values for Pao2 and arterial pH and higher Paco2 values than both other treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl resulted in transient pronounced cardiorespiratory effects when administered during isoflurane anesthesia. During anesthetic recovery, when administered concurrently with an IV fentanyl infusion, dexmedetomidine resulted in evidence of cardiopulmonary compromise and acepromazine transiently improved cardiopulmonary performance. PMID- 23627380 TI - Minimum inhibitory concentrations of cephalosporin compounds and their active metabolites for selected mastitis pathogens. AB - OBJECTIVE: To compare the minimum inhibitory concentration (MIC) of cephapirin and ceftiofur with MICs of their active metabolites (desacetylcephapirin and desfuroylceftiofur) for selected mastitis pathogens. SAMPLE: 488 mastitis pathogen isolates from clinically and subclinically affected cows in commercial dairy herds in Wisconsin. PROCEDURES: Agar dilution was used to determine MICs for Staphylococcus aureus (n = 98), coagulase-negative staphylococci (99), Streptococcus dysgalactiae (97), Streptococcus uberis (96), and Escherichia coli (98). RESULTS: All S aureus isolates were susceptible to cephapirin and ceftiofur. Most coagulase-negative staphylococci were susceptible to cephapirin and ceftiofur. For E coli, 50 (51.0%; cephapirin) and 93 (94.95%; ceftiofur) isolates were susceptible to the parent compounds, but 88 (89.8%) were not inhibited at the maximum concentration of desacetylcephapirin. All S dysgalactiae isolates were susceptible to ceftiofur and cephapirin, and consistent MICs were obtained for all compounds. Most S uberis isolates were susceptible to cephapirin and ceftiofur. Of 98 S aureus isolates classified as susceptible to ceftiofur, 42 (42.9%) and 51 (52%) were categorized as intermediate or resistant to desfuroylceftiofur, respectively. For 99 coagulase-negative staphylococci classified as susceptible to ceftiofur, 45 (45.5%) and 17 (17.2%) isolates were categorized as intermediate or resistant to desfuroylceftiofur, respectively. For all staphylococci and streptococci, 100% agreement in cross-classified susceptibility outcomes was detected between cephapirin and desacetylcephapirin. No E coli isolates were classified as susceptible to desacetylcephapirin. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in inhibition between parent compounds and their active metabolites may be responsible for some of the variation between clinical outcomes and results of in vitro susceptibility tests. PMID- 23627381 TI - Medial femoral condyle morphometrics and subchondral bone density patterns in Thoroughbred racehorses. AB - OBJECTIVE: To characterize medial femoral condyle (MFC) morphometrics and subchondral bone density patterns in Thoroughbred racehorses and to determine whether these variables differ between left and right limbs. SAMPLE: Stifle joints harvested from 6 Thoroughbred racehorses euthanized for reasons other than hind limb lameness. PROCEDURES: The distal portion of the left and right femurs of each cadaver was scanned via CT. Hounsfield units were converted to dipotassium phosphate equivalent densities through use of a phantom on each specimen. Medial femoral condyle width, length, height, and curvature; subchondral bone plate densities; and subchondral trabecular bone densities were analyzed in multiple sections in 5 frontal planes and 3 sagittal planes and were compared between left and right MFCs. RESULTS: MFC width, length, and height did not differ between left and right limbs. Regions of interest in the right caudoaxial subchondral bone plate and subchondral trabecular bone were significantly denser than their corresponding left regions of interest in the frontal and sagittal planes. A concavity in the otherwise convex articular surface of the cranial aspect of the MFC was identified in 11 of 12 specimens. CONCLUSIONS AND CLINICAL RELEVANCE: A disparity was identified between left and right subchondral bone density patterns at the caudoaxial aspect of the MFC, which could be attributable to the repetitive asymmetric cyclic loading that North American Thoroughbred racehorses undergo as they race in a counterclockwise direction. The uneven region at the cranial aspect of the MFC could be associated with the development of subchondral bone cysts in horses. PMID- 23627382 TI - Effects of serum and autologous conditioned serum on equine articular chondrocytes treated with interleukin-1beta. AB - OBJECTIVE: To compare the effects of autologous equine serum (AES) and autologous conditioned serum (ACS) on equine articular chondrocyte metabolism when stimulated with recombinant human (rh) interleukin (IL)-1beta. SAMPLE: Articular cartilage and nonconditioned and conditioned serum from 6 young adult horses. PROCEDURES: Cartilage samples were digested, and chondrocytes were isolated and formed into pellets. Chondrocyte pellets were treated with each of the following: 10% AES, 10% AES and rhIL-1beta, 20% AES and rhIL-1beta, 10% ACS and rhIL-1beta, and 20% ACS and rhIL-1beta, and various effects of these treatments were measured. RESULTS: Recombinant human IL-1beta treatment led to a decrease in chondrocyte glycosaminoglycan synthesis and collagen II mRNA expression and an increase in medium matrix metalloproteinase-3 activity and cyclooxygenase-2 mRNA expression. When results of ACS and rhIL-1beta treatment were compared with those of AES and rhIL-1beta treatment, no difference was evident in glycosaminoglycan release, total glycosaminoglycan concentration, total DNA content, or matrix metalloproteinase-3 activity. A significant increase was found in chondrocyte glycosaminoglycan synthesis with 20% AES and rhIL-1beta versus 10% ACS and rhIL 1beta. The medium from ACS and rhIL-1beta treatment had a higher concentration of IL-1beta receptor antagonist, compared with medium from AES and rhIL-1beta treatment. Treatment with 20% ACS and rhIL-1beta resulted in a higher medium insulin-like growth factor-I concentration than did treatment with 10% AES and rhIL-1beta. No difference in mRNA expression was found between ACS and rhIL-1beta treatment and AES and rhIL-1beta treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Minimal beneficial effects of ACS treatment on proteoglycan matrix metabolism in equine chonrocytes were evident, compared with the effects of AES treatment. PMID- 23627383 TI - Fecal calprotectin concentrations in adult dogs with chronic diarrhea. AB - OBJECTIVE: To evaluate fecal calprotectin concentrations in healthy dogs and dogs with chronic diarrhea, to identify cutoff values for fecal calprotectin concentrations for use in differentiating dogs with chronic diarrhea and a canine chronic enteropathy clinical activity index (CCECAI) < 12 from dogs with chronic diarrhea and a CCECAI >= 12, and to evaluate the association between histologic evidence of intestinal mucosal changes and fecal calprotectin concentrations in dogs with chronic diarrhea. SAMPLE: Fecal samples from 96 adult dogs (27 dogs with chronic diarrhea and 69 healthy control dogs). PROCEDURES: Severity of clinical signs was evaluated on the basis of the CCECAI scoring system. Endoscopy was performed in all dogs with chronic diarrhea, and mucosal biopsy specimens were evaluated histologically. Fecal calprotectin concentration was quantified via radioimmunoassay. RESULTS: Fecal calprotectin concentrations were significantly higher in dogs with chronic diarrhea than in healthy control dogs. Fecal calprotectin concentrations were also significantly higher in dogs with a CCECAI >= 12, compared with concentrations for dogs with a CCECAI between 4 and 11. Fecal calprotectin concentrations were significantly higher in dogs with chronic diarrhea associated with histologic lesions, compared with concentrations in control dogs, and were significantly correlated with the severity of histologic intestinal lesions. Among dogs with chronic diarrhea, the best cutoff fecal calprotectin concentration for predicting a CCECAI >= 12 was 48.9 MUg/g (sensitivity, 53.3%; specificity, 91.7%). CONCLUSIONS AND CLINICAL RELEVANCE: Fecal calprotectin may be a useful biomarker in dogs with chronic diarrhea, especially dogs with histologic lesions. PMID- 23627384 TI - In vitro effects of three formulations of hydroxyethyl starch solutions on coagulation and platelet function in horses. AB - OBJECTIVE: To investigate the in vitro effects of 3 hydroxyethyl starch (HES) solutions on viscoelastic coagulation testing and platelet function in horses. SAMPLE: Blood samples collected from 7 healthy adult horses. PROCEDURES: Blood samples were diluted with various crystalloid and HES solutions to approximate the dilution of blood in vivo that occurs with administration of a 10 and 20 mL/kg fluid bolus to a horse (1:8 and 1:4 dilutions, respectively). Diluted samples were analyzed through optical platelet aggregometry, platelet function analysis, thromboelastography, and dynamic viscoelastic coagulometry. Colloid osmotic pressure and concentrations of von Willebrand factor and factor VIII:C were also determined for each sample. RESULTS: For all HES products, at both dilutions, the colloid osmotic pressure was significantly higher than that in the respective carrier solutions. At the 1:4 dilution, nearly all HES solutions resulted in significant alterations in platelet function as measured via the platelet function analyzer and dynamic viscoelastic coagulometer. Significant decreases in platelet aggregation and factor concentrations were also evident. Fewer HES-associated changes were identified at the 1:8 dilutions. CONCLUSIONS AND CLINICAL RELEVANCE: Dilution of blood samples with all HES solutions resulted in changes in viscoelastic coagulation and platelet function that did not appear to be attributable to dilution alone. In vivo evaluations are necessary to understand the clinical impact of these in vitro changes. PMID- 23627385 TI - Noninvasive measurements of body composition and body water via quantitative magnetic resonance, deuterium water, and dual-energy x-ray absorptiometry in cats. AB - OBJECTIVE: To compare quantitative magnetic resonance (QMR), dual-energy x-ray absorptiometry (DXA), and deuterium oxide (D2O) dilution methods for measurement of total body water (TBW), lean body mass (LBM), and fat mass (FM) in healthy cats and to assess QMR precision and accuracy. ANIMALS: Domestic shorthair cats (58 and 32 cats for trials 1 and 2, respectively). PROCEDURES: QMR scans of awake cats performed with 2 units were followed by administration of D2O tracer (100 mg/kg, PO). Cats then were anesthetized, which was followed by QMR and DXA scans. Jugular blood samples were collected before and 120 minutes after D2O administration. RESULTS: QMR precision was similar between units (coefficient of variation < 2.9% for all measures). Fat mass, LBM, and TBW were similar for awake or sedated cats and differed by 4.0%, 3.4%, and 3.9%, respectively, depending on the unit. The QMR minimally underestimated TBW (1.4%) and LBM (4.4%) but significantly underestimated FM (29%), whereas DXA significantly underestimated LBM (9.2%) and quantitatively underestimated FM (9.3%). A significant relationship with D2O measurement was detected for all QMR (r(2) > 0.84) and DXA (r(2) > 0.84) measurements. CONCLUSIONS AND CLINICAL RELEVANCE: QMR was useful for determining body composition in cats; precision was improved over DXA. Quantitative magnetic resonance can be used to safely and rapidly acquire data without the need for anesthesia, facilitating frequent monitoring of weight changes in geriatric, extremely young, or ill pets. Compared with the D2O dilution method, QMR correction equations provided accurate data over a range of body compositions. PMID- 23627386 TI - Noninvasive measurements of body composition and body water via quantitative magnetic resonance, deuterium water, and dual-energy x-ray absorptiometry in awake and sedated dogs. AB - OBJECTIVE: To compare quantitative magnetic resonance (QMR), dual-energy x-ray absorptiometry (DXA), and deuterium oxide (D2O) methods for measurement of total body water (TBW), lean body mass (LBM), and fat mass (FM) in healthy dogs and to assess QMR accuracy. ANIMALS: 58 Beagles (9 months to 11.5 years old). PROCEDURES: QMR scans were performed on awake dogs. A D2O tracer was administered (100 mg/kg, PO) immediately before dogs were sedated, which was followed by a second QMR or DXA scan. Jugular blood samples were collected before and 120 minutes after D2O administration. RESULTS: TBW, LBM, and FM determined via QMR were not significantly different between awake or sedated dogs, and means differed by only 2.0%, 2.2%, and 4.3%, respectively. Compared with results for D2O dilution, QMR significantly underestimated TBW (10.2%), LBM (13.4%), and FM (15.4%). Similarly, DXA underestimated LBM (7.3%) and FM (8.4%). A significant relationship was detected between FM measured via D2O dilution and QMR (r(2) > 0.89) or DXA (r(2) > 0.88). Even though means of TBW and LBM differed significantly between D2O dilution and QMR or DXA, values were highly related (r(2) > 0.92). CONCLUSIONS AND CLINICAL RELEVANCE: QMR was useful for determining body composition in dogs and can be used to safely and rapidly acquire accurate data without the need for sedation or anesthesia. These benefits can facilitate frequent scans, particularly in geriatric, extremely young, or ill pets. Compared with the D2O dilution method, QMR correction equations provided accurate assessment over a range of body compositions. PMID- 23627387 TI - Evaluation of total white blood cell count as a marker for proviral load of bovine leukemia virus in dairy cattle from herds with a high seroprevalence of antibodies against bovine leukemia virus. AB - OBJECTIVE: To determine the reference interval for WBC counts in Holstein dairy cows from herds with high seroprevalence for anti-bovine leukemia virus (BLV) antibodies, analyze the correlation of total WBC counts and blood proviral load (bPVL) in BLV-infected animals, and determine whether total WBC count can be used a hematologic marker for in vivo infection. ANIMALS: 307 lactating cows from 16 dairy herds with high BLV seroprevalence. PROCEDURES: Blood samples were collected for assessment of plasma anti-BLV p24 antibody concentration (all cows), manual determination of WBC count (161 BLV-seronegative cows from 15 herds), and evaluation of bPVL (146 cows from another herd). RESULTS: The WBC count reference interval (ie, mean +/- 2 SD) for BLV-seronegative dairy cows was 2,153 to 11,493 cells/MUL. Of the 146 cows used to analyze the correlation between WBC count and bPVL, 107 (73%) had WBC counts within the reference interval; of those cows, only 21 (19.6%) had high bPVL. Most cows with high WBC counts (35/39) had high bPVL. Mean WBC count for cows with high bPVL was significantly higher than values for cows with low or undetectable bPVL. White blood cell counts and bPVL were significantly (rho = 0.71) correlated. CONCLUSIONS AND CLINICAL RELEVANCE: These data have provided an updated reference interval for WBC counts in Holstein cows from herds with high BLV seroprevalence. In dairy cattle under natural conditions, WBC count was correlated with bPVL; thus, WBC count determination could be a potential tool for monitoring BLV infection levels in attempts to control transmission. PMID- 23627388 TI - Evaluation of three approaches for performing ultrasonography-guided anesthetic blockade of the femoral nerve in calves. AB - OBJECTIVE: To develop a practical ultrasonography-guided injection approach to anesthetic blockade of the femoral nerve in calves and to assess the method's accuracy. ANIMALS: 13 cadavers of 4-week-old male Holstein Friesian calves. PROCEDURES: Detailed topographic and anatomic cross-sectional evaluation of the relevant topography in 3 cadavers was performed to identify optimal injection approaches to the femoral nerve. Three approaches (ventral paravertebral, dorsal paravertebral, and ileal) were evaluated by simulated ultrasonography-guided perineural injection of methylene blue dye in 10 cadavers. Ultrasonographic image quality, number of needle redirections required for correct needle positioning, and injection success as defined through a 3-point grading system were recorded. RESULTS: The dorsal paravertebral approach yielded the best results, compared with the ileal and ventral paravertebral approaches, to properly and adequately stain the targeted nerve. CONCLUSIONS AND CLINICAL RELEVANCE: The dorsal paravertebral injection technique appeared to be the best choice for performing a femoral nerve block in calves, although this technique will need to be further evaluated in live calves to determine its effectiveness and clinical usefulness. Diagnostic perineural anesthesia of the femoral nerve in cattle might be helpful in identifying quadriceps muscle involvement in those with complex spastic paresis. PMID- 23627389 TI - Evaluation of gait-related variables in lean and obese dogs at a trot. AB - OBJECTIVE: To assess differences in sagittal plane joint kinematics and ground reaction forces between lean and obese adult dogs of similar sizes at 2 trotting velocities. ANIMALS: 16 adult dogs. PROCEDURES: Dogs with body condition score (BCS) of 8 or 9 (obese dogs; n = 8) and dogs with BCS of 4 or 5 (lean dogs; 8) on a 9-point scale were evaluated. Sagittal plane joint kinematic and ground reaction force data were obtained from dogs trotting at 1.8 and 2.5 m/s with a 3 D motion capture system, a force platform, and 12 infrared markers placed on bony landmarks. RESULTS: Mean stride lengths for forelimbs and hind limbs at both velocities were shorter in obese than in lean dogs. Stance phase range of motion (ROM) was greater in obese dogs than in lean dogs for shoulder (28.2 degrees vs 20.6 degrees ), elbow (23.6 degrees vs 16.4 degrees ), hip (27.2 degrees vs 22.9 degrees ), and tarsal (38.9 degrees vs 27.9 degrees ) joints at both velocities. Swing phase ROM was greater in obese dogs than in lean dogs for elbow (61.2 degrees vs 53.7 degrees ) and hip (34.4 degrees vs 29.8 degrees ) joints. Increased velocity was associated with increased stance ROM in elbow joints and increased stance and swing ROM in hip joints of obese dogs. Obese dogs exerted greater peak vertical and horizontal ground reaction forces than did lean dogs. Body mass and peak vertical ground reaction force were significantly correlated. CONCLUSIONS AND CLINICAL RELEVANCE: Greater ROM detected during the stance phase and greater ground reaction forces in the gait of obese dogs, compared with lean dogs, may cause greater compressive forces within joints and could influence the development of osteoarthritis. PMID- 23627390 TI - Relationship of angiogenesis and microglial activation to seizure-induced neuronal death in the cerebral cortex of Shetland Sheepdogs with familial epilepsy. AB - OBJECTIVE: To determine whether angiogenesis and microglial activation were related to seizure-induced neuronal death in the cerebral cortex of Shetland Sheepdogs with familial epilepsy. ANIMALS: Cadavers of 10 Shetland Sheepdogs from the same family (6 dogs with seizures and 4 dogs without seizures) and 4 age matched unrelated Shetland Sheepdogs. PROCEDURES: Samples of brain tissues were collected after euthanasia and then fixed in neutral phosphate-buffered 10% formalin and routinely embedded in paraffin. The fixed samples were sectioned for H&E staining and immunohistochemical analysis. RESULTS: Evidence of seizure induced neuronal death was detected exclusively in samples of cerebral cortical tissue from the dogs with familial epilepsy in which seizures had been observed. The seizure-induced neuronal death was restricted to tissues from the cingulate cortex and sulci surrounding the cerebral cortex. In almost the same locations as where seizure-induced neuronal death was identified, microvessels appeared longer and more tortuous and the number of microvessels was greater than in the dogs without seizures and control dogs. Occasionally, the microvessels were surrounded by oval to flat cells, which had positive immunohistochemical results for von Willebrand factor. Immunohistochemical results for neurons and glial cells (astrocytes and microglia) were positive for vascular endothelial growth factor, and microglia positive for ionized calcium-binding adapter molecule 1 were activated (ie, had swollen cell bodies and long processes) in almost all the same locations as where seizure-induced neuronal death was detected. Double-label immunofluorescence techniques revealed that the activated microglia had positive results for tumor necrosis factor-alpha, interleukin-6, and vascular endothelial growth factor receptor 1. These findings were not observed in the cerebrum of dogs without seizures, whether the dogs were from the same family as those with epilepsy or were unrelated to them. CONCLUSIONS AND CLINICAL RELEVANCE: Signs of angiogenesis and microglial activation corresponded with seizure-induced neuronal death in the cerebral cortex of Shetland Sheepdogs with familial epilepsy. Microglial activation induced by vascular endothelial growth factor and associated proinflammatory cytokine production may accelerate seizure-induced neuronal death in dogs with epilepsy. PMID- 23627391 TI - Effect of bevacizumab on angiogenesis and growth of canine osteosarcoma cells xenografted in athymic mice. AB - Objective-To investigate the effects of bevacizumab, a human monoclonal antibody against vascular endothelial growth factor, on the angiogenesis and growth of canine osteosarcoma cells xenografted in mice. Animals-27 athymic nude mice. Procedures-To each mouse, highly metastasizing parent osteosarcoma cells of canine origin were injected into the left gastrocnemius muscle. Each mouse was then randomly allocated to 1 of 3 treatment groups: high-dose bevacizumab (4 mg/kg, IP), low-dose bevacizumab (2 mg/kg, IP), or control (no treatment). Tumor growth (the number of days required for the tumor to grow from 8 to 13 mm), vasculature, histomorphology, necrosis, and pulmonary metastasis were evaluated. Results-Mice in the high-dose bevacizumab group had significantly delayed tumor growth (mean +/- SD, 13.4 +/- 3.8 days; range, 9 to 21 days), compared with that for mice in the low-dose bevacizumab group (mean +/- SD, 9.4 +/- 1.5 days; range, 7 to 11 days) or control group (mean +/- SD, 7. 2 +/- 1.5 days; range, 4 to 9 days). Mice in the low-dose bevacizumab group also had significantly delayed tumor growth, compared with that for mice in the control group. Conclusions and Clinical Relevance-Results indicated that bevacizumab inhibited growth of canine osteosarcoma cells xenografted in mice, which suggested that vascular endothelial growth factor inhibitors may be clinically useful for the treatment of osteosarcoma in dogs. Impact for Human Medicine-Canine osteosarcoma is used as a research model for human osteosarcoma; therefore, bevacizumab may be clinically beneficial for the treatment of osteosarcoma in humans. PMID- 23627392 TI - Pharmacokinetics of intravenously and orally administered meloxicam in sheep. AB - OBJECTIVE: To determine the pharmacokinetics of meloxicam after IV and PO administration to 6 healthy sheep. ANIMALS: 6 healthy adult Dorset cross sheep (5 males and 1 female). PROCEDURES: Meloxicam (0.5 mg/kg, IV, or 1.0 mg/kg, PO) was administered in a randomized crossover design with a 10-day washout period. Blood samples were collected at predetermined times over 96 hours. Serum drug concentrations were determined by high-pressure liquid chromatography with mass spectrometry. Computer software was used to estimate values of pharmacokinetic parameters through noncompartmental methods. RESULTS: Following IV administration (n = 5), the geometric mean (range) elimination half-life was 14.0 hours (10.5 to 17.0 hours), volume of distribution was 0.204 L/kg (0.171 to 0.272 L/kg), and clearance was 0.17 mL/min/kg (0.12 to 0.27 mL/min/kg). Following oral administration (n = 6), maximum serum concentration was 1.72 MUg/mL (1.45 to 1.93 MUg/mL), time to maximum serum concentration was 19.0 hours (12.0 to 24.0 hours), clearance per bioavailability was 0.22 mL/min/kg (0.16 to 0.30 mL/min/kg), and terminal half-life was 15.4 hours (13.2 to 17.7 hours). Bioavailability of orally administered meloxicam was calculated as 72% (40% to 125%; n = 5). No adverse effects were evident following meloxicam administration via either route. CONCLUSIONS AND CLINICAL RELEVANCE: Meloxicam administered PO at 1.0 mg/kg has good bioavailability with slow elimination kinetics in sheep. These data suggested that meloxicam may be clinically useful, provided the safety and analgesic efficacy of meloxicam as well as feed-related influences on its pharmacokinetics are established in ruminants. PMID- 23627393 TI - Effects of hypoglossal nerve block and electrical stimulation of the thyrohyoideus muscles on position of the larynx and hyoid apparatus in healthy horses. AB - OBJECTIVE: To determine the effects of hypoglossal nerve block and electrical stimulation of the thyrohyoideus muscles on position of the larynx and hyoid apparatus in resting horses. ANIMALS: 16 healthy horses that underwent hypoglossal nerve block and 5 healthy horses that underwent electrical stimulation of the thyrohyoideus muscles. PROCEDURES: Horses underwent bilateral hypoglossal nerve block or electrical stimulation of the thyrohyoideus muscles. Positions of the basihyoid bone, ossified part of the thyroid cartilage, and articulations of the thyrohyoid bones and thyroid cartilage were determined in radiographic images obtained before and after performance of hypoglossal nerve blocks or during thyrohyoideus muscle stimulation. Radiographic images were obtained with the heads of horses in neutral (thyrohyoideus muscle stimulation) or neutral and extended (hypoglossal nerve block) positions. Radiographic images of horses obtained after performance of hypoglossal nerve blocks were also evaluated to detect dorsal displacement of the soft palate. RESULTS: Hypoglossal nerve blocks did not induce significant changes in the positions of evaluated anatomic sites in radiographic images obtained in neutral or extended head positions. Hypoglossal nerve block did not induce dorsal displacement of the soft palate in horses at rest. Bilateral thyrohyoideus muscle stimulation induced significant dorsal movement (mean +/- SD change in position, 18.7 +/- 6.8 mm) of the ossified part of the thyroid cartilage; rostral movement of evaluated anatomic structures was small and not significant after thyrohyoideus muscle stimulation. CONCLUSIONS AND CLINICAL RELEVANCE: Bilateral electrical stimulation of the thyrohyoideus muscles in horses in this study induced dorsal laryngeal movement. PMID- 23627394 TI - Characterization and osteogenic potential of equine muscle tissue- and periosteal tissue-derived mesenchymal stem cells in comparison with bone marrow- and adipose tissue-derived mesenchymal stem cells. AB - OBJECTIVE: To characterize equine muscle tissue- and periosteal tissue-derived cells as mesenchymal stem cells (MSCs) and assess their proliferation capacity and osteogenic potential in comparison with bone marrow- and adipose tissue derived MSCs. SAMPLE: Tissues from 10 equine cadavers. PROCEDURES: Cells were isolated from left semitendinosus muscle tissue, periosteal tissue from the distomedial aspect of the right tibia, bone marrow aspirates from the fourth and fifth sternebrae, and adipose tissue from the left subcutaneous region. Mesenchymal stem cells were characterized on the basis of morphology, adherence to plastic, trilineage differentiation, and detection of stem cell surface markers via immunofluorescence and flow cytometry. Mesenchymal stem cells were tested for osteogenic potential with osteocalcin gene expression via real-time PCR assay. Mesenchymal stem cell cultures were counted at 24, 48, 72, and 96 hours to determine tissue-specific MSC proliferative capacity. RESULTS: Equine muscle tissue- and periosteal tissue-derived cells were characterized as MSCs on the basis of spindle-shaped morphology, adherence to plastic, trilineage differentiation, presence of CD44 and CD90 cell surface markers, and nearly complete absence of CD45 and CD34 cell surface markers. Muscle tissue-, periosteal tissue-, and adipose tissue-derived MSCs proliferated significantly faster than did bone marrow-derived MSCs at 72 and 96 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Equine muscle and periosteum are sources of MSCs. Equine muscle- and periosteal-derived MSCs have osteogenic potential comparable to that of equine adipose- and bone marrow-derived MSCs, which could make them useful for tissue engineering applications in equine medicine. PMID- 23627395 TI - Effects of equine bone marrow aspirate volume on isolation, proliferation, and differentiation potential of mesenchymal stem cells. AB - OBJECTIVE: To compare the mesenchymal stem cell (MSC) yield and chondrogenic and osteogenic differentiation from 5- and 50-mL bone marrow aspirates from horses. ANIMALS: Six 2- to 5-year-old mixed-breed horses. Procedures-2 sequential 5-mL aspirates were drawn from 1 ilium or sternebra. A single 50-mL aspirate was drawn from the contralateral ilium, and 2 sequential 50-mL aspirates were drawn from a second sternebra. The MSC yield was determined through the culture expansion process. Chondrogenesis and osteogenesis were evaluated by means of conventional laboratory methods. RESULTS: The second of the 2 sequential 50-mL sternal aspirates yielded few to no MSCs. Independent of location, the highest density of MSCs was in the first of the 2 sequential 5-mL fractions, although with subsequent culture expansion, the overall yield was not significantly different between the first 5-mL and first 50-mL fractions. Independent of location, chondrogenesis and osteogenesis were not significantly different among fractions. Independent of fraction, the overall cell yield and chondrogenesis from the ilium were significantly higher than that from the sternum. CONCLUSIONS AND CLINICAL RELEVANCE: This study failed to detect an additional benefit of 50-mL aspirates over 5-mL aspirates for culture-expanding MSCs for equine clinical applications. Chondrogenesis was highest for MSCs from ilial aspirates, although it is not known whether chondrogenesis is indicative of activation of other proposed pathways by which MSCs heal tissues. PMID- 23627396 TI - Antifungal agents from Pseudallescheria boydii SNB-CN73 isolated from a Nasutitermes sp. termite. AB - Defense mutualisms between social insects and microorganisms have been described in the literature. The present article describes the discovery of a Pseudallescheria boydii strain isolated from Nasutitermes sp. The microbial symbiont produces two antifungal metabolites: tyroscherin and N methyltyroscherin, a compound not previously described in the literature. Methylation of tyroscherin has confirmed the structure of N-methyltyroscherin. Both compounds are effective antifungal agents with favorable selectivity indices for Candida albicans and Trichophyton rubrum. PMID- 23627397 TI - Conversion to sternotomy during sternal-sparing coronary artery surgery. AB - Conversion to a full sternotomy may complicate up to 1.8% of the sternal-sparing coronary artery surgery. Left internal mammary artery injury and anastomotic problems are the common causes. The purpose of this article is to retrospectively review the outcomes of six patients that required conversion to sternotomy during minimally invasive direct coronary artery bypass and also to point out technical aspects in order to avoid such a complication. PMID- 23627398 TI - Tumour necrosis factor antagonist and tuberculosis in patients with rheumatoid arthritis: an Asian perspective. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease in which inflammation of the joints is one of the dominant clinical abnormalities resulting in serious morbidity. Over the past decade, tumour necrosis factor (TNF) antagonist has revolutionized the treatment of RA. However, the subsequent increased risk of developing tuberculosis is one of the major drawbacks of this otherwise effective treatment. Latent tuberculosis infection (LTBI) is an asymptomatic form of tuberculosis that is confined by the host's immune system. Active tuberculosis may develop when the immune status weakens. This risk is much higher in patients receiving TNF antagonist. Traditionally, tuberculin skin test (TST) is used to diagnose LTBI. Unfortunately, TST cannot distinguish bacillus Calmette-Guerin (BCG) vaccination from tuberculosis making it difficult to use as a reliable diagnostic tool. In addition, possible anergy and interaction of the altered autoimmune status in rheumatological diseases further complicate the interpretation of TST results. Although interferon-gamma release assay (IGRA) has improved the diagnosis of LTBI in immunocompetent individuals, its respective sensitivity/specificity values are unknown in patients with autoimmune disease due to variable pretest probability and lack of confirmatory test for LTBI. Thus, the use of IGRA for screening LTBI is variable among different countries. This review explores the prevalence of tuberculosis in patients receiving TNF antagonist in countries with different tuberculosis disease burdens and the potential mechanisms for variation in the incidence of tuberculosis with different TNF antagonists, the current practice guidelines for assessing the risk of LTBI in different countries, and the possible solutions for improving diagnosis, monitoring and management of LTBI. PMID- 23627399 TI - Biochemical and biophysical characterization of four EphB kinase domains reveals contrasting thermodynamic, kinetic and inhibition profiles. AB - The Eph (erythropoietin-producing hepatocellular carcinoma) B receptors are important in a variety of cellular processes through their roles in cell-to-cell contact and signalling; their up-regulation and down-regulation has been shown to have implications in a variety of cancers. A greater understanding of the similarities and differences within this small, highly conserved family of tyrosine kinases will be essential to the identification of effective therapeutic opportunities for disease intervention. In this study, we have developed a route to production of multi-milligram quantities of highly purified, homogeneous, recombinant protein for the kinase domain of these human receptors in Escherichia coli. Analyses of these isolated catalytic fragments have revealed stark contrasts in their amenability to recombinant expression and their physical properties: e.g., a >16 degrees C variance in thermal stability, a 3-fold difference in catalytic activity and disparities in their inhibitor binding profiles. We find EphB3 to be an outlier in terms of both its intrinsic stability, and more importantly its ligand-binding properties. Our findings have led us to speculate about both their biological significance and potential routes for generating EphB isozyme-selective small-molecule inhibitors. Our comprehensive methodologies provide a template for similar in-depth studies of other kinase superfamily members. PMID- 23627400 TI - Ambivalent sexism and attitudes toward women in different stages of reproductive life: a semantic, cross-cultural approach. AB - College students in southeastern Mexico (n = 185) and the northeastern United States (n = 96) utilized a semantic differential scale to rate subtypes of women: a menstruating woman, a menopausal woman, a pregnant woman, a premenstrual woman, a woman with a hysterectomy, a teenage girl, a woman in love, and a woman with a young baby. Americans reported significantly more negative attitudes than Mexicans did toward a menstruating woman, a premenstrual woman, a teenage girl, and a pregnant woman. Participants chose more positive words to describe a teenage girl, a woman in love, a pregnant woman, and a woman with a young baby, which is suggestive of a pronatal bias. Participants also completed the Ambivalent Sexism Inventory (ASI). Men scored significantly higher than women on hostile sexism. Mexicans scored significantly higher than Americans on both hostile and benevolent sexism. Sexism scores are related to attitudes toward premenstrual, menstruating, and menopausal women; women with a hysterectomy; and women with a young baby. PMID- 23627401 TI - Clinical features and in-vivo confocal microscopic imaging of fleck corneal dystrophy. AB - PURPOSE: To evaluate the value of in-vivo confocal microscopy (CM) in the diagnosis of Fleck corneal dystrophy. METHODS: Case report and literature review. After complete eye examination of the patient, in-vivo CM was performed. The morphologies of the corneal layers were evaluated by in-vivo CM. RESULTS: Slit lamp examination revealed bilateral gray-white, oval or round discrete opacities in the stroma. Confocal microscopy showed hyper-reflective opacities in enlarged and unremarkable keratocyte nuclei throughout the stroma. The surface epithelium, subbasal nerves, and endothelium showed normal morphology. CONCLUSION: The diagnosis of rare corneal dystrophies such as Fleck corneal dystrophy should sometimes be made only after performing in-vivo confocal microscopy. PMID- 23627402 TI - Noninteracting, vicinal frustrated P/B-Lewis pair at the norbornane framework: synthesis, characterization, and reactions. AB - Hydroboration of dimesitylnorbornenylphosphane with Piers' borane [HB(C6F5)2] gave the frustrated Lewis pair (FLP) 4 in good yield. It has the -PMes2 Lewis base attached at the 2-endo position and the -B(C6F5)2 group 3-exo oriented at the norbornane framework. The vicinal FLP 4 was shown by X-ray diffraction and by spectroscopy to be a rare example of an intramolecular noninteracting pair of a Lewis acid and Lewis base functionality. The FLP 4 rapidly splits dihydrogen heterolytically at ambient temperature to yield the phosphonium/hydrido borate zwitterion 5. It adds to the carbonyl group of benzaldehyde and to carbon dioxide to yield the adducts 6 and 7, respectively. Compounds 5-7 were characterized by X ray diffraction. Compound 4 adds to the S?O function of sulfur dioxide to give a pair of diastereomeric heterocyclic six-membered ring products due to the newly formed sulfur chirality center, annulated with the norbornane skeleton, which were investigated by (31)P/(11)B single and double resonance solid state NMR experiments. Compound 8 was also characterized by X-ray diffraction. The FLP 4 undergoes a clean N,N-addition to nitric oxide (NO) to give a norbornane annulated five-membered heterocyclic persistent FLP-NO aminoxyl radical 12 (characterized, e.g., by X-ray diffraction and EPR spectroscopy). Additionally, the FLP radical was characterized by (1)H solid state NMR spectroscopy. The radical 12 undergoes a H-atom abstraction reaction with 1,4-cyclohexadiene to yield the respective diamagnetic FLP-NOH product 13, which was also characterized by X-ray diffraction and solid state NMR spectroscopy. PMID- 23627404 TI - Management of a severely malpositioned replanted avulsed tooth: a case report. AB - This case report details the treatment and follow-up of an avulsed and malrepositioned maxillary anterior tooth. Treatment of the malrepositioned tooth included re-extraction and replantation as well as root canal therapy. Initial success at 1-year post-trauma was overshadowed by the development of external root resorption and a horizontal root fracture, which occurred between 1 and 2 years after trauma. The development of external root resorption can be attributed either secondarily to the original trauma or due to active orthodontic treatment. PMID- 23627403 TI - Impact of therapy escalation on ambulatory care costs among patients with type 2 diabetes in France. AB - BACKGROUND: This study compares annual ambulatory care expenditures per patient with type 2 diabetes mellitus (T2DM) in France according to treatment phase and renal function status. METHODS: Records from patients with T2DM were extracted from a health insurance database. Patients were classified in subgroups, by treatment phase: oral/GLP1 monotherapy, double therapy, triple therapy or insulin therapy, and according to renal function status (identified using pharmacy, lab and consultation claims). Annual ambulatory expenditures were estimated from the national insurance perspective by year (from 2005 to 2010) and subgroup. RESULTS: The number of patients ranged from 9,682 to 11,772 between 2005 and 2010. The average annual expenditure per individual in 2010 ranged from ?3,017 (standard deviation: ?3,829) for monotherapy to ?3,609 +/- ?3,801 for triple therapy, and ?7,398 +/- ?5,487 with insulin (adjusted ratio insulin therapy/monotherapy: 2.36, p < 0.001). Similar differences between treatement stages were found in previous years. Additional costs for insulin were mainly related to nursing care (multiplied by 18.42, p < 0.001), medical devices and pharmacy costs. DM attributable drug costs were mainly related to antidiabetic drugs (28% for monotherapy to 71% for triple therapy), but also to cardiovascular system drugs (21% for monotherapy to 51% with insulin) and nervous system drugs (up to 8% with insulin). Declining renal function was associated with an increase in expenses by 12% to 53% according to treatment stage. CONCLUSIONS: Overall, ambulatory care expenditures increase with treatment escalation and declining renal function amongst patients with T2DM. Insulin therapy is associated with substantially increased costs, related to pharmacy, nursing care and medical device costs. PMID- 23627405 TI - Prevalence of dental erosion among young competitive swimmers: a pilot study. AB - The objective of the study presented was to determine the prevalence of oral problems--eg, dental erosion, rough surfaces, pain--among young competitive swimmers in India, because no such studies are reported. Its design was a cross sectional study with a questionnaire and clinical examination protocols. It was conducted in a community setting on those who were involved in regular swimming in pools. Questionnaires were distributed to swimmers at the 25th State Level Swimming Competition, held at Thane Municipal Corporation's Swimming Pool, India. Those who returned completed questionnaires were also clinically examined. Questionnaires were analyzed and clinical examinations focused on either the presence or absence of dental erosions and rough surfaces. Reported results were on 100 swimmers who met the inclusion criteria. They included 75 males with a mean age of 18.6 +/- 6.3 years and 25 females with a mean age of 15.3 +/- 7.02 years. Among them, 90% showed dental erosion, 94% exhibited rough surfaces, and 88% were found to be having tooth pain of varying severity. Erosion and rough surfaces were found to be directly proportional to the duration of swimming. The authors concluded that the prevalence of dental erosion, rough surfaces, and pain is found to be very common among competitive swimmers. They recommend that swimmers practice good preventive measures and clinicians evaluate them for possible swimmer's erosion. PMID- 23627406 TI - Mineral trioxide aggregate: a review of physical properties. AB - The purpose of this two-part series is to review the composition, properties, products, and clinical aspects of mineral trioxide aggregate (MTA) materials. Electronic search of scientific papers from January 1991 to May 2010 was accomplished using PubMed and MedLine search engines to include relevant scientific citations from the peer-reviewed journals published in English. MTA is a refined form of the parent compound, Portland cement (PC). It demonstrates a strong biocompatible nature owing to the high pH and its ability to form hydroxyapatite. MTA materials provide a better seal than traditional endodontic materials as observed in dye leakage, fluid filtration, protein leakage, and bacterial penetration leakage studies, and it has been recognized as a bioactive material. Currently a variety of MTA commercial products are available, including Proroot Gray MTA and White MTA both from DENTSPLY Tulsa Dental Specialties (www.DENTSPLY.com), and MTA Angelus (Angelus,www.angelus.ind.br). Although these materials are indicated for various dental uses/applications, long-term in-vivo clinical studies are still needed to claim the same. This first of this series highlights and discusses the composition, physical, and/or chemical properties of MTA. A subsequent article will offer an overview of the material aspect (commercial products) and clinical considerations for MTA materials. PMID- 23627407 TI - Optimization of a Concanavalin A-based glucose sensor using fluorescence anisotropy. AB - To date, the dependent nature of the recognition and transduction mechanisms in optical glucose sensors based upon Concanavalin A (ConA) has tended to prevent the sensors' full potential from being realized. In this paper, these mechanisms are independently optimized for a given assay configuration in order to decrease the predictive error of a ConA-based glucose sensor and to give a more accurate demonstration of its potential. To this end, we used fluorescence anisotropy as the transduction mechanism to determine the binding of ConA to 4 kDa FITC-dextran by measuring the change in the rotational correlation lifetime between the bound and unbound populations. By tracking the fluorescence anisotropy of this ligand, the ranges of ConA and 4 kDa FITC-dextran concentrations capable of being explored were not limited by the transduction mechanism. Using predetermined association constants, the binding responses to physiological glucose concentrations were predicted for different assay configurations, and experimentally collected fluorescence anisotropy data displayed the predicted trends for these assay configurations. From the experimental results, a calibration fit was generated for the optimized assay configuration to predict the glucose concentrations using the fluorescence anisotropy. This optimized assay displayed a mean standard error of prediction of 7.5 mg/dL (0-300 mg/dL), and 100% of the data points fell within clinically acceptable zones (A and B) upon the Clarke Error Grid Analysis. This indicates that, by independently optimizing the recognition and transduction mechanisms for the final assay configuration, the sensitivity of a competitive binding chemistry using ConA can be appropriately configured for continuous glucose monitoring applications. PMID- 23627408 TI - Apolipoprotein concentrations are elevated in malignant ovarian cyst fluids suggesting that lipoprotein metabolism is dysregulated in epithelial ovarian cancer. AB - SELDI-TOF MS analysis of ovarian cyst fluids revealed that peaks m/z 8696 and 8825 discriminate malignant, borderline, and benign tumors. These peaks correspond to isoforms of apoA2. ELISA demonstrates that apoA1, A2, B, C2, C3, and E cyst fluid concentrations are uncorrelated and higher in malignant ovarian tumors, but only apoA2, apoE, and age are independent classifiers of malignant ovarian tumors, yielding 55.1% sensitivity, 95% specificity, and 88.1% accuracy to discern malignant from benign and borderline tumors. These data suggest that lipoprotein metabolism is dysregulated in ovarian cancer and that apoA2 and apoE warrant further investigation as ovarian tumor biomarkers. PMID- 23627409 TI - Association of Nox1 and vinculin with colon cancer progression. AB - Nox1 mRNA, protein, and activities were compared in the paired primary and metastatic colon adenocarcinoma cell lines SW480 and SW620, and in normal colon tissues and colon cancer tissues. Our results demonstrated that Nox1 levels were higher in the primary SW480 cells than that in metastatic SW620 cells and were not associated with colon cancer progression. We further discovered that vinculin protein level in SW620 was much higher than that in SW480 cells, whereas E cadherin was lower. We conclude that vinculin and E-cadherin, but not Nox1, may serve as biomarkers for colon cancer progression. PMID- 23627410 TI - Preoperative serum C-reactive protein levels and early breast cancer by BMI and menopausal status. AB - Serum C-reactive protein (CRP), a sensitive marker of systemic inflammation, has been reported to be associated with the risk of a number of cancers including breast cancer. However, the results are inconsistent. To investigate the association between serum CRP levels and early breast cancer, we conducted a hospital-based case-control study among 506 newly diagnosed breast cancer patients and 506 controls with benign breast diseases matched by age and menopausal status. Odds ratios (ORs) were computed with unconditional logistic regression models, adjusted for major confounding factors. Relative to women with the lowest quartile of CRP level, women with the highest quartile had 1.65-fold increased breast cancer risk (OR: 1.65, 95% CI: 1.12-2.42) in a significant dose response manner (p(trend) = .011). Stratification analysis revealed a positive association only for overweight postmenopausal women (highest CRP quartile versus lowest CRP quartile: OR: 2.78, 95% CI: 1.18-6.6). Multinominal logistic regression analysis showed that only hormonal receptor (HR) positive and human epidemiological receptor 2 (HER2) negative breast cancers had elevated serum CRP levels. We observed that elevated serum CRP levels are positively associated with early breast cancer, predominantly among overweight and postmenopausal women. This study provided epidemiological evidence that chronic inflammation might mediate the association between obesity and postmenopausal breast cancer. Although a positive association between serum CRP and HR positive/HER2 negative breast cancer is intriguing, further epidemiological studies are needed to confirm such findings. PMID- 23627411 TI - Radioactive contamination of the atmosphere of Cairo, Egypt, from the Fukushima Dai-ichi nuclear plant accident. AB - Radioactive contamination in air dust particles of Cairo atmosphere from the Fukushima accident was detected by the gamma-ray spectroscopy technique. Analysis of the spectra obtained by using an High-Purity Germanium detector showed that there were some traces of (131)I and (134, 137)Cs. Estimate and study of concentration of those radionuclides were done over a period of about 5 months after the accident. Comparison with corresponding results in different countries all over the world has been performed. PMID- 23627412 TI - The art of blocking ADP-ribosyltransferases (ARTs): nanobodies as experimental and therapeutic tools to block mammalian and toxin ARTs. AB - In 1901, the first Nobel Prize in Physiology or Medicine was awarded to Emil von Behring for his ground-breaking discovery of serum therapy: serum from horses vaccinated with toxin-containing culture medium of Corynebacterium diphtheriae contained life-saving 'antitoxins'. The molecular nature of the ADP-ribosylating toxin and the neutralizing antibodies were unraveled only 50 years later. Today, von Behring's antibody therapy is being refined with a new generation of recombinant antibodies and antibody fragments. Nanobodies, which are single domain antibodies derived from the peculiar heavy-chain antibodies of llamas and other camelids, are emerging as a promising new class of highly specific enzyme inhibitors. In this review, we illustrate the potential of nanobodies as tools to block extracellular and intracellular ADP-ribosyltransferases (ARTs), using the toxin-related membrane-bound mammalian ecto-enzyme ARTC2 and the actin-ADP ribosylating Salmonella virulence plasmid factor B toxin of Salmonella enterica as examples. PMID- 23627413 TI - Characterization of a novel polysaccharide from tetraploid Gynostemma pentaphyllum makino. AB - A novel heteropolysaccharide (GPP-TL) was isolated from tetraploid Gynostemma pentaphyllum (Makino) leaf by hot water extraction and anion-exchange and gel permeation chromatography approaches. GPP-TL had a molecular weight of 9.3 * 10(3) Da and was primarily composed of glucose, galactose, and arabinose, with a molar ratio of 43:5:1, respectively. The chemical structure of GPP-TL was characterized using chemical and instrumental analyses. The results indicated the presence of (1->4)-alpha-d-glucopyranosyl, (1->4)-beta-d-galactopyranosyl, (1 >4,6)-linked-alpha-d-glucopyranosyl, and terminal 1->)-alpha-d-glucopyranosyl moieties in a molar ratio of 5.7:1:1.5:1, respectively. The results indicated that GPP-TL had glucose and galactose residues in the main chain with (1->6) linked branches at glucose residues. In addition, GPP-TL exhibited scavenging capacities against hydroxyl, peroxyl, and DPPH radicals in vitro and had a stronger bile acid-binding ability than psyllium on a same-weight basis. PMID- 23627414 TI - Toward understanding the bonding character in complexes of coinage metals with lone-pair ligands. CCSD(T) and DFT computations. AB - We present CCSD(T) interaction energies and the bonding analysis for complexes of Cu, Ag, and Au with the lone-pair ligands H2O, OF2, OMe2, NH3, NF3, NMe3, H2S, SF2, SMe2, PH3, PF3, PCl3, and PMe3 (ML complexes). Both electron correlation and relativistic effects are crucial in the bonding of all complexes. AuPH3, AuPF3, and AuPCl3 (AuPX3) complexes exhibit particularly large relativistic effects, 30 46 kJ/mol. Upon neglecting relativistic effects, the Au-P bonds almost vanish aside from weak long-range van der Waals interactions. Highest binding energies are computed for complexes with Au, followed by Cu and Ag. For all coinage metals the strongest interactions are computed for PX3 ligands followed by SX2 and NX3 OX2 ligands. Upon methylation the interaction energy rises significantly. Metal thiol complexes, particularly AuSCH3, form a separate class. Exceptional stability of gold complexes is due to large relativistic enhancement of the electron affinity of Au. Along with the electron affinity of a metal, we link the pattern of interaction energies in ML complexes with ionization potentials (IPs) of ligands. Strong interaction with P containing ligands is attributed to their lower IP and the lone pair -> metal electron donation accompanied with the back donation characteristic for P containing ligand. Energy data are accompanied with the natural bond orbital analysis. Computationally less demanding DFT computations with the PBE0 functional provide correct pattern of interaction energies when compared with benchmark CCSD(T) results. PMID- 23627415 TI - Junior doctors' perceptions of their self-efficacy in prescribing, their prescribing errors and the possible causes of errors. AB - AIMS: The aim of the study was to explore and compare junior doctors' perceptions of their self-efficacy in prescribing, their prescribing errors and the possible causes of those errors. METHODS: A cross-sectional questionnaire study was distributed to foundation doctors throughout Scotland, based on Bandura's Social Cognitive Theory and Human Error Theory (HET). RESULTS: Five hundred and forty eight questionnaires were completed (35.0% of the national cohort). F1s estimated a higher daytime error rate [median 6.7 (IQR 2-12.4)] than F2s [4.0 IQR (0-10) (P = 0.002)], calculated based on the total number of medicines prescribed. The majority of self-reported errors (250, 49.2%) resulted from unintentional actions. Interruptions and pressure from other staff were commonly cited causes of errors. F1s were more likely to report insufficient prescribing skills as a potential cause of error than F2s (P = 0.002). The prescribers did not believe that the outcomes of their errors were serious. F2s reported higher self-efficacy scores than F1s in most aspects of prescribing (P < 0.001). CONCLUSION: Foundation doctors were aware of their prescribing errors, yet were confident in their prescribing skills and apparently complacent about the potential consequences of prescribing errors. Error causation is multi-factorial often due to environmental factors, but with lack of knowledge also contributing. Therefore interventions are needed at all levels, including environmental changes, improving knowledge, providing feedback and changing attitudes towards the role of prescribing as a major influence on patient outcome. PMID- 23627417 TI - Keystone XL: pipeline to nowhere. PMID- 23627416 TI - Insulin resistance impairs cutaneous wound healing in mice. AB - Obesity is associated with significant changes in skin combined with metabolic alterations such as insulin resistance. Our aim was to investigate the effects of insulin resistance induced by a high-fat diet on cutaneous wound healing. Male C57BL/6 mice were fed standard chow (SC group) or high-fat chow (HFC group) for 30 weeks. On day 0 (28th week), an excisional wound was performed. After 14 days (30th week), the mice were euthanized. Starting from the 8th week, the HFC group had a higher body weight. The HFC group became intolerant to glucose, resistant to insulin, and presented increased plasma cholesterol and triglyceride levels. The wound area was greater in the HFC group. The inflammatory infiltrate and the amount of "fibroblast-like" cells increased in superficial regions of the lesions in the HFC group. The collagen fibers were more organized and denser in the SC group. Hydroxyproline levels were lower in the HFC group. The nitric oxide synthase-2-positive cells were higher in the HFC group. Lipid peroxidation and protein carbonyl levels were higher in the HFC group. The expression levels of alpha-smooth muscle actin and transforming growth factor-beta were higher in the HFC group. These findings support the hypothesis that insulin resistance leads to delayed cutaneous wound healing. PMID- 23627418 TI - Does EMS perceived anatomic injury predict trauma center need? AB - OBJECTIVE: Our objective was to determine the predictive value of the anatomic step of the 2011 Field Triage Decision Scheme for identifying trauma center need. METHODS: Emergency medical services (EMS) providers caring for injured adults transported to regional trauma centers in three midsized communities were interviewed over two years. Patients were included, regardless of injury severity, if they were at least 18 years old and were transported by EMS with a mechanism of injury that was an assault, motor vehicle or motorcycle crash, fall, or pedestrian or bicyclist struck. The interview was conducted upon emergency department (ED) arrival and collected physiologic condition and anatomic injury data. Patients who met the physiologic criteria were excluded. Trauma center need was defined as nonorthopedic surgery within 24 hours, intensive care unit admission, or death prior to hospital discharge. Data were analyzed by calculating descriptive statistics, including positive likelihood ratios (+LRs) with 95% confidence intervals (CIs). RESULTS: A total of 11,892 interviews were conducted. One was excluded because of missing outcome data and 1,274 were excluded because they met the physiologic step. EMS providers identified 1,167 cases that met the anatomic criteria, of which 307 (26%) needed the resources of a trauma center (38% sensitivity, 91% specificity, +LR 4.4; CI: 3.9-4.9). Criteria with a +LR >=5 were flail chest (9.0; CI: 4.1-19.4), paralysis (6.8; CI: 4.2-11.2), two or more long-bone fractures (6.3; CI: 4.5-8.9), and amputation (6.1; CI: 1.5-24.4). Criteria with a +LR >2 and <5 were penetrating injury (4.8; CI: 4.2-5.6) and skull fracture (4.8; CI: 3.0-7.7). Only pelvic fracture (1.9; CI: 1.3-2.9) had a +LR less than 2. CONCLUSIONS: The anatomic step of the Field Triage Guidelines as determined by EMS providers is a reasonable tool for determining trauma center need. Use of EMS perceived pelvic fracture as an indicator for trauma center need should be reevaluated. Key words: wounds and injury; triage; emergency medical services; emergency medical technicians. PMID- 23627419 TI - Arranged marriage in lipid signalling? The limited choices of PtdIns(4,5)P2 in finding the right partner. AB - Inositol-containing phospholipids (phosphoinositides, PIs) control numerous cellular processes in eukaryotic cells. For plants, a key involvement of PIs has been demonstrated in the regulation of membrane trafficking, cytoskeletal dynamics and in processes mediating the adaptation to changing environmental conditions. Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) mediates its cellular functions via binding to various alternative target proteins. Such downstream targets of PtdIns(4,5)P(2) are characterised by the possession of specific lipid-binding domains, and binding of the PtdIns(4,5)P(2) ligand exerts effects on their activity or localisation. The large number of potential alternative binding partners - and associated cellular processes - raises the question how alternative or even contrapuntal effects of PtdIns(4,5)P(2) are orchestrated to enable cellular function. This article aims to provide an overview of recent insights and new views on how distinct functional pools of PtdIns(4,5)P(2) are generated and maintained. The emerging picture suggests that PtdIns(4,5)P(2) species containing different fatty acids influence the lateral mobility of the lipids in the membrane, possibly enabling specific interactions of PtdIns(4,5)P(2) pools with certain downstream targets. PtdIns(4,5)P(2) pools with certain functions might also be defined by protein-protein interactions of PI4P 5-kinases, which pass PtdIns(4,5)P(2) only to certain downstream partners. Individually or in combination, PtdIns(4,5)P(2) species and specific protein protein interactions of PI4P 5-kinases might contribute to the channelling of PtdIns(4,5)P(2) signals towards specific functional effects. The dynamic nature of PI-dependent signalling complexes with specific functions is an added challenge for future studies of plant PI signalling. PMID- 23627420 TI - Mechanical stability and clinical applicability assessment of novel orthodontic mini-implant design. AB - OBJECTIVE: To compare the stability and clinical applicability of a novel orthodontic mini-implant design (N2) with the most widely used commercially available (CA) design. MATERIALS AND METHODS: Two groups of mini-implants were tested: a CA design (1.5-mm diameter, 6-mm length) and N2 (3-mm diameter, 2-mm length, tapered shape). Implants were inserted in bone blocks of cortical bone simulation with varying densities (20 pounds per cubic foot [pcf], 30 pcf, and 40 pcf). A torque test was used to measure maximum insertion torque (MIT) and maximum removal torque (MRT). Compression and tension force vectors were applied at angles of 10 degrees , 20 degrees , 30 degrees , and 40 degrees using customized load pins to determine primary stability. RESULTS: Mean MIT and MRT were higher in the N2 than the CA design at all three cortical bone densities except MRT in 20 pcf bone (not statistically significant). The mean compression force required to displace the N2 at all distances and angulations was greater for the N2 than the CA design. At all displacement distances, the highest mean tension force required for N2 displacement was at 10 degrees angulation, whereas at 30 degrees and 40 degrees , the mean tension force required to displace the CA design was greater. CONCLUSIONS: The primary stability of the N2 is superior to that of the CA design and is promising for both orthodontic and orthopedic clinical applicability, especially under compression force. The short length of the N2 reduces risk of damage to anatomic structures and root proximity during placement and orthodontic treatment. The stability of the N2 may be compromised in areas of high bone density and highly angulated tension force. PMID- 23627421 TI - Preparation and mechanics of nanotextures on adapting a low adhesive surface using local oxidation nanolithography. AB - This paper describes an application for atomic force microscopy to the fabrication of nanotextures with various features on a GaAs surface by local oxidation nanolithography (LON). By controlling the geometrical shapes and surface coverage of the nanotexture, the surface adhesion can be adjusted to a low adhesive surface. The influence of environmental conditions, such as relative humidity and temperature on adhesion behavior, was studied. An optic heater was employed to minimize thermal effect on an atomic force microscope (AFM) cantilever and PbZrTiO3 scanner. In our study, AFM is used for both fabrication and characterization. LON allows the fabricated nanotextures to be altered in situ without the need to change masks or repeat the entire fabrication process. Furthermore, the nanoadhesion characterization of nanotextures on a GaAs surface was investigated with a colloidal probe method. PMID- 23627422 TI - Integrating content and structure aspects of the self: traits, values, and self improvement. AB - Research on the structure of the self has mostly developed separately from research on its content. Taking an integrative approach, we studied two structural aspects of the self associated with self-improvement--self discrepancies and perceived mutability--by focusing on two content areas, traits and values. In Studies 1A-C, 337 students (61% female) reported self discrepancies in values and traits, with the finding that self-discrepancies in values are smaller than in traits. In Study 2 (80 students, 41% female), we experimentally induced either high or low mutability and measured perceived mutability of traits and values. We found that values are perceived as less mutable than traits. In Study 3, 99 high school students (60% female) reported their values, traits, and the extent to which they wish to change them. We found that values predict the wish to change traits, whereas traits do not predict the wish to change values. In Study 4, 172 students (47.7% female) were assigned to one of four experimental conditions in which they received feedback denoting either uniqueness or similarity to others, on either their values or their traits. The results indicated that feedback that one's values (but not traits) are unique affected self-esteem. Integrating between theories of content and structure of the self can contribute to the development of both. PMID- 23627423 TI - Five observations of a third morphologically distinct feline Demodex mite. AB - BACKGROUND: Feline demodicosis is caused by infestation with Demodex cati and/or Demodex gatoi. These two mites have distinctive morphological appearances. OBJECTIVES: To describe five observations of a morphologically distinct feline Demodex mite in 10 cats. All cats were in or adopted from an animal shelter. RESULTS: A mite with blunted ends longer than D. gatoi but shorter than D. cati was observed in one or multiple cats from animal shelters. Mean mite size was 139 +/- 4.5 MUm (n = 41 mites). Similar features among the cases included a history of recent recovery or presence of concurrent illness at the time of diagnosis. Pruritus was variable. Hairs were easily epilated in large amounts, and mites were found on either skin scrapings or hair trichograms; mites were most commonly found on the proximal third of hairs examined via trichogram. CLINICAL IMPORTANCE: Reports of this mite are uncommon but when present tend to be in cats with concurrent illnesses. Awareness of this mite morphology will hopefully provide other investigators with specimens for molecular testing to determine whether this is a third species or a variant of D. gatoi or D. cati. PMID- 23627424 TI - Successful single-stage repair of an interrupted aortic arch with a bicuspid aortic valve in a young adult. AB - Interrupted aortic arch is a rare congenital malformation. We describe the case of an interrupted aortic arch with a bicuspid aortic valve and severe aortic stenosis. The patient underwent a single-stage aortic valve replacement (AVR) and ventral aorta repair through a median sternotomy-laparotomy. PMID- 23627428 TI - Domestic abuse against elder women and perceived barriers to help-seeking. AB - The study's (n = 447) purposes were to (1) describe relationships of abuser behavior to elder women's perception of barriers to help-seeking; (2) compare fit of model to participants' levels of abuse, race-ethnicity, age, and gender and relationship of identified close other; and (3) determine extent to which the model differentiated relationship of abuser to participant and level of abuse. Analyses identified six factors contributing to the overall barrier score, accounting for 84% of total variance (chi2/df = 1.527, CFI = .989, RMSEA = .034), including three internal and two external factors and a single abuser behavior factor that were invariant across participant characteristic; however, covariances did differ. PMID- 23627427 TI - Observational study to assess pregnant women's knowledge and behaviour to prevent toxoplasmosis, listeriosis and cytomegalovirus. AB - BACKGROUND: Toxoplasmosis, listeriosis and cytomegalovirus (CMV) can negatively affect pregnancy outcomes, but can be prevented by simple precautions of pregnant women. Literature suggests that pregnant women are not always adequately informed by their care provider about preventable infectious diseases and most pregnant women have a low level of knowledge regarding these topics. There is not much information about the actual risk behaviour of pregnant women. The purpose of this study was to assess knowledge and risk behaviour related to toxoplasmosis, listeriosis and CMV infection prevention in pregnant women. METHODS: A cross sectional survey among pregnant women from twenty midwifery practices across the Netherlands that participated in the DELIVER study, between October 2010 and December 2010. The questionnaire items covered respondents' knowledge of preventive practices in general, risk behaviour, and sources of received information. RESULTS: Of the 1,097 respondents (response 66.0%), 75.3% had heard, read or seen information about toxoplasmosis, 61.7% about listeriosis and 12.5% about CMV. The majority reported having heard about these infections from their care providers or read about these in printed media or on the Internet. Respondents showed limited knowledge about preventive practices for toxoplasmosis, listeriosis or CMV infection. Regarding toxoplasmosis, risk behaviour was more prevalent among respondents who had a high level of education, had the Dutch nationality, did not take folic acid during their first trimester, and had ever worked in a children day-care setting. Regarding listeriosis, risk behaviour was more prevalent among respondents who where in their third trimester. Regarding CMV infections, risk behaviour was less prevalent among respondents who were in their third trimester of pregnancy. CONCLUSION: Of the respondents, a substantial part did not have knowledge about preventive practices to avoid listeriosis, toxoplasmosis and CMV infections during pregnancy. Many pregnant women are appropriately avoiding risk behaviour, without knowing what they are avoiding. Advising pregnant women about behaviours and life-style habits to prevent infectious diseases remains important and information about preventive practices need to be complete and adequate. However, it may be less important to give pregnant women specific infectious diseases information. More attention towards CMV is necessary. PMID- 23627426 TI - Enantioselective approach to quinolizidines: total synthesis of cermizine D and formal syntheses of senepodine G and cermizine C. AB - The formal syntheses of C5-epi-senepodine G and C5-epi-cermizine C have been accomplished through a novel diastereoselective, intramolecular amide Michael addition process. The total synthesis of cermizine D has been achieved through use of an organocatalyzed, heteroatom Michael addition to access a common intermediate. Additional key steps of this sequence include a matched, diastereoselective alkylation with an iodomethylphenyl sulfide and sulfone aldehyde coupling/reductive desulfurization sequence to combine the major subunits. The utility of a Hartwig-style C-N coupling has been explored on functionally dense coupling partners. Diastereoselective conjugate additions to alpha,beta-unsaturated sulfones have been investigated, which provided the key sulfone intermediate in just six steps from commercially available starting materials. The formal syntheses of senepodine G and cermizine C have been accomplished through an intramolecular cyclization process of a N-Boc-protected piperidine sulfone. PMID- 23627429 TI - Intimate partner violence in late life: an analysis of national news reports. AB - Intimate partner violence (IPV) in late life takes various forms including physical harm, sexual assault, and murder. Using national newspaper reports of IPV among elders, we identified the types of violence reported most frequently in media and examined how the abuse was conceptualized by reporters. We found that most cases of IPV reported involved murder, with men as perpetrators and women as victims. Caregiving stress and health problems were frequently cited as contributing factors in the cases. Interpreting these findings from a feminist perspective, we suggest implications for practitioners working with older adults. PMID- 23627430 TI - Elder abuse: what coroners know and need to know. AB - This article presents findings from a survey examining knowledge of elder abuse among Georgia's coroners. More than half of the 116 respondents indicated that they know "almost nothing" or "a little" about distinguishing signs of physical abuse from signs of aging (54%) and mandatory reporting laws and related elder abuse statutes (63%). When asked the frequency with which older adult cases were referred to the medical examiner, 49% indicated "rarely if ever." Study findings reveal specific opportunities for enhancing training efforts aimed at coroners, who play a critical role in the identification of elder abuse. PMID- 23627431 TI - How do abused elderly persons and their adult protective services caseworkers view law enforcement involvement and criminal prosecution, and what impact do these views have on case processing? AB - This study examined law enforcement and prosecution involvement in 71 cases of elder abuse where pure financial exploitation (PFE), physical abuse (PA), neglect (Neglect), or hybrid financial exploitation (HFE) (financial exploitation co occurring with physical abuse and/or neglect) occurred in a domestic setting. Victims of elder abuse and assigned Adult Protective Services (APS) caseworkers were systematically interviewed. Law enforcement officials were involved in 54% of the cases, and 18% of the cases were prosecuted. PA was significantly more likely to trigger a law enforcement response and to be prosecuted than Neglect or PFE. HFE involved prosecution for assault rather than financial exploitation. Generally, the victims of elder abuse were not receptive to criminal justice involvement, which appears to have a significant impact upon the level of this involvement. The reasons for this reluctance are discussed, as well as the challenges and limitations of criminal justice system involvement and related implications for policy and practice. PMID- 23627432 TI - Bridging the gap between localization and diagnosis of peripheral pulmonary nodules. PMID- 23627433 TI - Universal trapping mechanism in semiconductor nanocrystals. AB - Size tunability of the optical properties and inexpensive synthesis make semiconductor nanocrystals one of the most promising and versatile building blocks for many modern applications such as lasers, single-electron transistors, solar cells, and biological labels. The performance of these nanocrystal-based devices is however compromised by efficient trapping of the charge carriers. This process exhibits different features depending on the nanocrystal material, surface termination, size, and trap location, leading to the assumption that different mechanisms are at play in each situation. Here we revolutionize this fragmented picture and provide a unified interpretation of trapping dynamics in semiconductor nanocrystals by identifying the origins of this so far elusive detrimental process. Our findings pave the way for a general suppression strategy, applicable to any system, which can lead to a simultaneous efficiency enhancement in all nanocrystal-based technologies. PMID- 23627434 TI - Fetuin-A mRNA expression is elevated in NASH compared with NAFL patients. AB - Fetuin-A is a pro-inflammatory protein expressed by hepatocytes. Its course in morbidly obese patients with NAFLD (non-alcoholic fatty liver disease) following weight loss by BAS (bariatric surgery) has not been fully elucidated yet. In the present study, we prospectively examined the effects of weight loss on various metabolic factors at 4 weeks and 6 months after surgery. Blood and liver tissues were retrieved from 108 morbidly obese NAFLD patients before/during BAS, and 50 of these individuals met the criteria for NASH (non-alcoholic steatohepatitis). Fetuin-A expression was measured by qPCR (quantitative real-time PCR), Western blotting and immunohistochemistry. Hepatocyte apoptosis was quantified via M30 (caspase-cleaved cytokeratin-18 fragments). Plasma concentrations of adiponectin and fetuin-A were determined by ELISA. Serum-derived parameters were additionally taken at 4 weeks and 6 months post-operatively. In addition, primary human hepatocytes were treated with NEFA (non-esterified fatty acid) to investigate changes in fetuin-A. BMI (body mass index) decreased significantly from 53.0+/ 1.1 to 36.4+/-1.9 kg/m2 in the NAFL group and from 53.3+/-1.1 to 37.6+/-1.2 kg/m2 in the NASH group (P<0.0001) at 6 months post-surgery. This was associated with diminishing M30 and M65 (total cytokeratin-18) levels over 6 months after surgery. Adiponectin levels increased continuously in NASH patients, whereas NAFL patients plateaued at 4 weeks post-operatively. Hepatic fetuin-A mRNA and protein expression was elevated before surgery-induced weight loss. However, plasma concentrations of fetuin-A increased signficantly in NASH patients 4 weeks post operatively. Treatment of hepatocytes with NEFA led to up-regulation of fetuin-A expression. BAS probably has a beneficial effect on NAFLD, as indicated by reduced hepatocyte apoptosis and improved adipokine profiles. In addition, fetuin A expression is more prominent in NASH. PMID- 23627435 TI - Unilateral papilledema in pseudotumor cerebri. AB - PURPOSE: To report a case of a 25-year-old girl with pseudotumor cerebri who presented with unilateral swollen optic disk. METHODS: A 25-year-old obese patient admitted to our ophthalmic department complaining of headaches, tinnitus, and transient visual obscurations for the last three months. Upon ophthalmic examination, the left optic nerve was swollen with a few hemorrhages compared to the normal-appearing right optic nerve. Following lumbar puncture with opening pressure of 350 mmHg, a diagnosis of pseudotumor cerebri was made and treatment with acetazolamide was started. RESULTS: Three months later there were no episodes of visual obscurations and headache improved. CONCLUSION: Although rare, unilateral swollen disk could be a sign of unilateral papilledema due to increased intracranial pressure. PMID- 23627436 TI - Extract of Scutellaria baicalensis inhibits dengue virus replication. AB - BACKGROUND: Scutellaria baicalensis (S. baicalensis) is one of the traditional Chinese medicinal herbs that have been shown to possess many health benefits. In the present study, we evaluated the in vitro antiviral activity of aqueous extract of the roots of S. baicalensis against all the four dengue virus (DENV) serotypes. METHODS: Aqueous extract of S. baicalensis was prepared by microwave energy steam evaporation method (MEGHETM), and the anti-dengue virus replication activity was evaluated using the foci forming unit reduction assay (FFURA) in Vero cells. Quantitative real-time polymerase chain reaction (qRT-PCR) assay was used to determine the actual dengue virus RNA copy number. The presence of baicalein, a flavonoid known to inhibit dengue virus replication was determined by mass spectrometry. RESULTS: The IC(50) values for the S. baicalensis extract on Vero cells following DENV adsorption ranged from 86.59 to 95.19 MUg/mL for the different DENV serotypes. The IC(50) values decreased to 56.02 to 77.41 MUg/mL when cells were treated with the extract at the time of virus adsorption for the different DENV serotypes. The extract showed potent direct virucidal activity against extracellular infectious virus particles with IC(50) that ranged from 74.33 to 95.83 MUg/mL for all DENV serotypes. Weak prophylactic effects with IC(50) values that ranged from 269.9 to 369.8 MUg/mL were noticed when the cells were pre-treated 2 hours prior to virus inoculation. The concentration of baicalein in the S. baicalensis extract was ~1% (1.03 MUg/gm dried extract). CONCLUSIONS: Our study demonstrates the in vitro anti-dengue virus replication property of S. baicalensis against all the four DENV serotypes investigated. The extract reduced DENV infectivity and replication in Vero cells. The extract was rich in baicalein, and could be considered for potential development of anti-DENV therapeutics. PMID- 23627438 TI - Sciadopitysin: active component from Taxus chinensis for anti-Alzheimer's disease. AB - Five taxane diterpenoids derived from the 95% ethanol extract of Taxus chinensis were tested for the inhibitory activities on amyloid-beta (Abeta) peptide aggregation. Using thioflavin-T fluorescence assay, sciadopitysin was found to exhibit the most potency against Abeta aggregation and the formation of fibrils. Further cellular assay indicated that sciadopitysin increased the cell viability of SH-SY5Y cell and demonstrated neuroprotection against Abeta protein-induced insult in primary cortical neurons. According to the authors' best knowledge, this is the first report that sciadopitysin can inhibit the Abeta aggregation and reduce Abeta-induced toxicity in the primary cortical neurons. PMID- 23627437 TI - Drug uptake pathways of multidrug transporter AcrB studied by molecular simulations and site-directed mutagenesis experiments. AB - Multidrug resistance has been a critical issue in current chemotherapy. In Escherichia coli , a major efflux pump responsible for the multidrug resistance contains a transporter AcrB. Crystallographic studies and mutational assays of AcrB provided much of structural and overall functional insights, which led to the functionally rotating mechanism. However, the drug uptake pathways are somewhat controversial because at least two possible pathways, the vestibule and the cleft paths, were suggested. Here, combining molecular simulations and site directed mutagenesis experiments, we addressed the uptake mechanism finding that the drug uptake pathways can be significantly different depending on the properties of drugs. First, in the computational free energy analysis of drug movements along AcrB tunnels, we found a ligand-dependent drug uptake mechanism. With the same molecular sizes, drugs that are both strongly hydrophobic and lipophilic were preferentially taken in via the vestibule path, while other drugs favored the cleft path. Second, direct simulations realized totally about 3500 events of drug uptake by AcrB for a broad range of drug property. These simulations confirmed the ligand-dependent drug uptake and further suggested that a smaller drug favors the vestibule path, while a larger one is taken in via the cleft path. Moreover, the direct simulations identified an alternative uptake path which is not visible in the crystal structure. Third, site-directed mutagenesis of AcrB in E. coli verified that mutations of residues located along the newly identified path significantly reduced the efflux efficiency, supporting its relevance in in vivo function. PMID- 23627439 TI - Individually addressable thin-film ultramicroelectrode array for spatial measurements of single vesicle release. AB - Thin-film platinum ultramicroelectrode arrays (MEAs) with subcellular microelectrodes were developed for the spatial measurement of neurotransmitter release across single cells or clusters of single cells. MEAs consisting of 16, 25, and 36 square ultramicroelectrodes with respective widths of 4, 3, and 2 MUm were fabricated on glass substrates by photolithography, thin-film deposition, and reactive ion etching. The electrodes in each MEA are tightly defined in a 30 MUm * 30 MUm square, which is potentially useful to measure exocytosis across a single cell or clusters of single cells. These MEAs have been characterized with scanning electron microscopy and cyclic voltammetry and show excellent stability and reproducibility. Culturing PC12 cells on top of the MEAs has been achieved by modifying the array with a poly(dimethylsiloxane) chamber and coating a thin layer of collagen IV on top of the electrode surface. The electrochemical response to dopamine has been characterized after coating the surface with the cell-adhering molecules and then with cells attached. Amperometric detection demonstrates that individual exocytotic events can be recorded at these arrays with spatial resolution for dynamic electrochemical measurements near 2 MUm. In contrast to previous single-cell experiments, the effect of dopaminergic drugs on imaging single vesicle exocytotic release from PC12 cell clusters is presented at cell clusters incubated with the dopamine precursor and Parkinson's therapy agent, L-3,4-dihydroxyphenylalanine, and at cell clusters incubated with the vesicular monoamine transport inhibitor, reserpine. The results of electrochemical imaging demonstrate that the drug effect on PC12 cell clusters is consistent with previous single-cell experiments. PMID- 23627440 TI - Modified Folin-Ciocalteu antioxidant capacity assay for measuring lipophilic antioxidants. AB - The Folin-Ciocalteu (FC) method of performing a total phenolics assay, originally developed for protein determination, has recently evolved as a total antioxidant capacity assay but was found to be incapable of measuring lipophilic antioxidants due to the high affinity of the FC chromophore, that is, multivalent-charged phospho-tungsto-molybdate(V), toward water. Thus, the FC method was modified and standardized so as to enable simultaneous measurement of lipophilic and hydrophilic antioxidants in NaOH-added isobutanol-water medium. Optimal conditions were as follows: dilution ratio of aqueous FC reagent with iso-BuOH (1:2, v/v), final NaOH concentration of 3.5 * 10(-2) M, reaction time of 20 min, and maximum absorption wavelength of 665 nm. The modified procedure was successfully applied to the total antioxidant capacity assay of trolox, quercetin, ascorbic acid, gallic acid, catechin, caffeic acid, ferulic acid, rosmarinic acid, glutathione, and cysteine, as well as of lipophilic antioxidants such as alpha-tocopherol (vitamin E), butylated hydroxyanisole, butylated hydroxytoluene, tertiary butylhydroquinone, lauryl gallate, and beta-carotene. The modified FC method reliably quantified ascorbic acid, whereas the conventional method could not. The modified method was reproducible and additive in terms of total antioxidant capacity values of constituents of complex mixtures such as olive oil extract and herbal tea infusion. The trolox equivalent antioxidant capacities of the tested antioxidant compounds correlated well with those found by the Cupric Reducing Antioxidant Capacity reference method. PMID- 23627441 TI - Data mining of solubility parameters for computational prediction of drug excipient miscibility. AB - Abstract Computational data mining is of interest in the pharmaceutical arena for the analysis of massive amounts of data and to assist in the management and utilization of the data. In this study, a data mining approach was used to predict the miscibility of a drug and several excipients, using Hansen solubility parameters (HSPs) as the data set. The K-means clustering algorithm was applied to predict the miscibility of indomethacin with a set of more than 30 compounds based on their partial solubility parameters [dispersion forces (deltad), polar forces (deltap) and hydrogen bonding (deltah)]. The miscibility of the compounds was determined experimentally, using differential scanning calorimetry (DSC), in a separate study. The results of the K-means algorithm and DSC were compared to evaluate the K-means clustering prediction performance using the HSPs three dimensional parameters, the two-dimensional parameters such as volume-dependent solubility (deltav) and hydrogen bonding (deltah) and selected single (one dimensional) parameters. Using HSPs, the prediction of miscibility by the K-means algorithm correlated well with the DSC results, with an overall accuracy of 94%. The prediction accuracy was the same (94%) when the two-dimensional parameters or the hydrogen-bonding (one-dimensional) parameter were used. The hydrogen-bonding parameter was thus a determining factor in predicting miscibility in such set of compounds, whereas the dispersive and polar parameters had only a weak correlation. The results show that data mining approach is a valuable tool for predicting drug-excipient miscibility because it is easy to use, is time and cost effective, and is material sparing. PMID- 23627442 TI - Powder form and stability of Pluronic mixed micelle dispersions for drug delivery applications. AB - The aim of this work was to optimize a formulation of the Pluronic(r) F127/L121 mixed micelle system and evaluate it in terms of stability upon dilution in biologically relevant media and to explore the possibility of preparing F127/L121 micelles in a powder form that can be simply reconstituted to an initial freshly made mixed micelle formulation. The mixed F127/L121 micelles were prepared at a relatively high concentration of Pluronics (1% w/w for both Pluronics) using two different methods (direct dissolution and film rehydration) with an external input of energy. The optimal preparation of the mixed F127/L121 micelles (hydrodynamic diameter (dh) = 75 nm, polydispersity index (PDI) = 0.287) was achieved using the film rehydration method followed by ultrasonication. Stability studies of the F127/L121 micelle system were performed at 25 degrees C and 37 degrees C and upon dilution in different biologically relevant media. The F127/L121 micelles were stable in phosphate buffered saline (PBS) upon 100-fold dilution for at least 10 d and in PBS containing bovine serum albumin upon 10 and 50-fold dilution for at least 48 and 12 h, respectively. A dry powdered form of the mixed micelles was prepared by freeze-drying after slow or fast freezing process. The influence of the type and amount of cryoprotectant on the prevention of F127/L121 micelles aggregation during the freeze-drying and reconstitution processes were evaluated. The use of trehalose (5%, w/w) and sucrose (2.5%, w/w) with slow and fast freezing process, respectively, resulted in a reconstituted product with mostly similar dh and PDI values of the fresh micelle formulation. PMID- 23627443 TI - Nanocarrier-based topical drug delivery for an antifungal drug. AB - OBJECTIVE: The conventional liposomal amphotericin B causes many unwanted side effects like blood disorder, nephrotoxicity, dose-dependent side effects, highly variable oral absorption and formulation-related instability. The objective of the present investigation was to develop cost-effective nanoemulsion as nanocarreir for enhanced and sustained delivery of amphotericin B into the skin. METHODS AND CHARACTERIZATIONS: Different oil-in-water nanoemulsions were developed by varying the composition of hydrophilic (Tween((r)) 80) surfactants and co-surfactant by the spontaneous titration method. The developed formulation were characterized, optimized, evaluated and compared for the skin permeation with commercial formulation (fungisome 0.01% w/w). Optimized formulations loaded with amphotericin B were screened using varied concentrations of surfactants and co-surfactants as decided by the ternary phase diagram. RESULTS AND DISCUSSION: The maximum % transmittance obtained were 96.9 +/- 1.0%, 95.9 +/- 3.0% and 93.7 +/- 1.2% for the optimized formulations F-I, F-III and F-VI, respectively. These optimized nanoemulsions were subjected to thermodynamic stability study to get the most stable nanoemulsions (F-I). The results of the particle size and zeta potential value were found to be 67.32 +/- 0.8 nm and -3.7 +/- 1.2 mV for the final optimized nanoemulsion F-I supporting transparency and stable nanoemulsion for better skin permeation. The steady state transdermal flux for the formulations was observed between 5.89 +/- 2.06 and 18.02 +/- 4.3 ug/cm(2)/h whereas the maximum enhancement ratio were found 1.85- and 3.0-fold higher than fungisome and drug solution, respectively, for F-I. The results of the skin deposition study suggests that 231.37 +/- 3.6 ug/cm(2) drug deposited from optimized nanoemulsion F-I and 2.11-fold higher enhancement ratio as compared to fungisome. Optimized surfactants and co-surfactant combination-mediated transport of the drug through the skin was also tried and the results were shown to have facilitated drug permeation and skin perturbation (SEM). CONCLUSION: The combined results suggested that amphotericin B nanoemulsion could be a better option for localized topical drug delivery and have greater potential as an effective, efficient and safe approach. PMID- 23627444 TI - Characterization, inclusion mode, phase-solubility and in vitro release studies of inclusion binary complexes with cyclodextrins and meglumine using sulfamerazine as model drug. AB - In order to investigate the effect on the aqueous solubility and release rate of sulfamerazine (SMR) as model drug, inclusion complexes with beta-cyclodextrin (betaCD), methyl-beta-cyclodextrin (MbetaCD) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) and a binary system with meglumine (MEG) were developed. The formation of 1:1 inclusion complexes of SMR with the CDs and a SMR:MEG binary system in solution and in solid state was revealed by phase solubility studies (PSS), nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT IR), thermal analysis and X-Ray diffractometry (XRD) studies. The CDs solubilization of SMR could be improved by ionization of the drug molecule through pH adjustments. The higher apparent stability constants of SMR:CDs complexes were obtained in pH 2.00, demonstrating that CDs present more affinity for the unionized drug. The best approach for SMR solubility enhancement results from the combination of MEG and pH adjustment, with a 34-fold increment and a Smax of 54.8 mg/ml. The permeability of the drug was reduced due to the presence of betaCD, MbetaCD, HPbetaCD and MEG when used as solubilizers. The study then suggests interesting applications of CD or MEG complexes for modulating the release rate of SMR through semipermeable membranes. PMID- 23627445 TI - Statins and cancer-related mortality: an open question. PMID- 23627446 TI - Electronic structure and chemical bonding in the OTi-N2 complexes: a systematic ab initio and DFT study. AB - Two OTi-N2 complexes, experimentally observed in the TiO + N2 reaction, have been theoretically studied using several density functionals as well as ab initio approaches and various basis sets. The benchmark results calculated with coupled cluster singles, doubles, and perturbative triples CCSD(T) and sufficiently large correlation-consistent basis set were used to assess the performance of other theoretical models, especially four density functional families, pure functional, hybrid, double-hybrid, and long-range corrected ones. It has been shown that, out of twenty-three density functionals used in this work, only three functionals, namely TPSS0, LC-TPSS, and B2PLYP, are able to reproduce the CC-reference data quantitatively. Particularly, the B2PLYP double-hybrid (with or without addition of empirical dispersion) is the most promising functional, providing the closest results to the reference ones. The nature of bonding within products has been investigated using two topological techniques and a localized orbital approach. PMID- 23627448 TI - Accurate diagnosis of mesothelioma: more important than ever. PMID- 23627449 TI - Transformation of pathologists: responding in a volatile, uncertain, complex, and ambiguous environment. PMID- 23627450 TI - The College of American Pathologists' first 3 years' experience with high-risk human papillomavirus proficiency testing for cytology and other laboratories. AB - CONTEXT: The College of American Pathologists (CAP) Human Papillomavirus (High Risk) Survey for Cytopathology and Other Laboratories (CHPV) meets the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88) requirements for 5 proficiency testing challenges analyzed 3 times per year. This study reports laboratory performance for CHPV from 2008 through 2010. OBJECTIVE: To identify trends in proficiency testing performance for subscribers to the CAP CHPV. DESIGN: CHPV responses were evaluated by using a nonlinear mixed model (significance level of .05) with a 2-factor interaction term and repeated measures component, comparing year, media, method, and intended response. Media types included Digene transport, SurePath, ThinPrep media, or a mixture of media types. Proficiency testing challenges validated at 80% consensus. RESULTS: All challenges validated; 476 laboratories submitted 14 911 responses with 14 620 correct responses (98%). There were no differences between positive or negative challenges, or rate of correct responses; significant differences existed between media types by year and methods. Digene and ThinPrep media performed better than SurePath (P < .001; P = .03). There was a statistically significant difference between methods (P < .001); "other commercial kits," "other (noncommercial)" tests, and Third Wave performed more poorly than others. CONCLUSIONS: Laboratories performed well when testing for human papillomavirus in CHPV during a period of 3 years. All challenges performed to the 80% threshold. Significant differences were found between methods and media. The CAP CHPV survey provides useful information for laboratories choosing human papillomavirus testing methods. PMID- 23627451 TI - Gleason score 7 adenocarcinoma of the prostate with lymph node metastases: analysis of 184 radical prostatectomy specimens. AB - CONTEXT: Prostate cancer (PC) with lymph node metastases (LN(+)) is relatively rare, whereas it is relatively common in disease with a Gleason score (GS) 8 to 10 and virtually never seen in PC with GS 6 or less. It is most variable in GS 7 PC. OBJECTIVE: To determine clinicopathologic features associated with GS 7 PC with LN(+) compared with a control group without lymph node metastases (LN(-)). DESIGN: We analyzed 184 GS 7 radical prostatectomies with LN(+) and the same number of LN(-) Gleason-matched controls. The LN(+) cases were GS 3 + 4 = 7 (n = 64; 34.8%), GS 4 + 3 = 7 (n = 66; 35.9%), GS 3 + 4 = 7 with tertiary 5 (n = 10; 5.4%), and GS 4 + 3 = 7 with tertiary 5 (n = 44; 23.9%). RESULTS: The LN(+) cases demonstrated higher average values in preoperative prostate-specific antigen (12.2 versus 8.1 ng/mL), percentage of positive biopsy cores (59.1% versus 42.9%), prostate weight (54.4 versus 49.4 g), number of LNs submitted (12.7 versus 9.4), incidence of nonfocal extraprostatic extension (82.6% versus 63.6%), tumor volume (28.9% versus 14.8%), frequency of lymphovascular invasion (78.3% versus 38.6%), intraductal spread of carcinoma (42.4% versus 20.7%), incidence of satellite tumor foci (16.4% versus 4.3%), incidence of pT3b disease (49.5% versus 14.7%), and lymphovascular invasion in the seminal vesicles (52% versus 30%). There were differences in GS 4 patterns and cytology between LN(+) and LN(-) cases, with the former having higher volumes of cribriform and poorly formed patterns, larger nuclei and nucleoli, and more-frequent macronucleoli. All P <= .05. CONCLUSION: Gleason score 7 PC with LN(+) has features highlighting a more aggressive phenotype. These features can be assessed as prognostic markers in GS 7 disease on biopsy (eg, GS 4 pattern, intraductal spread, cytology) or at radical prostatectomies (all variables), even in men without LN dissection or LN( ) disease. PMID- 23627452 TI - Plasma cell enrichment enhances detection of high-risk cytogenomic abnormalities by fluorescence in situ hybridization and improves risk stratification of patients with plasma cell neoplasms. AB - CONTEXT: Methods for plasma cell enrichment of bone marrow (BM) specimens can increase the sensitivity of fluorescence in situ hybridization (FISH) for detecting cytogenomic abnormalities. There are no published reports using these methods to evaluate high-risk cytogenomic abnormalities in patients with plasma cell neoplasms (PCNs) after therapy. OBJECTIVE: To evaluate the utility of plasma cell enrichment combined with FISH for detection of high-risk cytogenomic abnormalities in patients with PCNs after therapy. DESIGN: Twenty-eight patients with PCNs, of whom 22 received treatment, were included in this study. Plasma cells were enriched in BM aspirates by using a magnetic cell-sorting procedure to select CD138(+) cells. Probes were chosen to assess for del(17p13/TP53), del(13q14/RB1), 1q21/CKS1B gain, IgH/FGFR3, and IgH/MAF. Clinicopathologic data were collected during clinical follow-up after plasma cell enrichment. RESULTS: Plasma cells in nonenriched BM specimens ranged from 1% to 28% (median, 8%) compared with 28% to 96% (median, 73%) in enriched BM specimens (P < .001). In a subset of treated patients in clinical remission, FISH detected high-risk cytogenomic abnormalities only in plasma cell-enriched samples. This approach also detected abnormalities in cases of solitary plasmacytoma and monoclonal gammopathy of undetermined significance. CONCLUSIONS: Plasma cell enrichment of BM specimens increases FISH sensitivity for detecting high-risk cytogenomic abnormalities, particularly in treated patients, and these results, in combination with clinical follow-up data, can be of value to improve risk stratification and patient management. PMID- 23627453 TI - p16 Deletion in sarcomatoid tumors of the lung and pleura. AB - CONTEXT: The diagnosis of sarcomatoid neoplasms of the lung and pleura can be challenging. Homozygous deletion of 9p21, the locus harboring the p16 gene, has been reported as the most common genetic alteration in malignant mesotheliomas that is of potential diagnostic and prognostic significance. OBJECTIVES: To evaluate the frequency of 9p21 deletion by fluorescence in situ hybridization in the primary sarcomatoid neoplasms of the lung and pleura and to determine its potential diagnostic utility. DESIGN: Ninety-two sarcomatoid neoplasms of the lung and pleura (32 sarcomatoid mesotheliomas, 15 sarcomatoid carcinomas, 32 solitary fibrous tumors, and 13 high-grade sarcomas) were examined for 9p21 deletion by fluorescence in situ hybridization. RESULTS: Deletion of 9p21 was most frequently seen in malignant mesotheliomas (81%), followed by sarcomatoid carcinomas (53%), sarcomas (25%), and solitary fibrous tumors (12.5%). Malignant mesotheliomas showed mostly homozygous deletion, whereas sarcomatoid carcinomas showed either homozygous or hemizygous deletion. None of the sarcomas showed homozygous deletion. There was a trend toward more frequent occurrence of 9p21 deletion in recurrent solitary fibrous tumors, but this did not reach statistical difference. CONCLUSIONS: Deletion of 9p21 is common in sarcomatoid tumors of the lung and pleura. Despite statistically significant differences in the frequency of 9p21 deletion, and because of the large overlap among the study groups, this genetic abnormality cannot be used as a reliable diagnostic tool in the assessment of sarcomatoid lesions of the lung and pleura. A potential use of p16 deletion in predicting the biology of solitary fibrous tumors should be further explored. PMID- 23627454 TI - Raising the quality of care during medical missions: a survey to assess the need for clinical and anatomic pathology services in international medical missions. AB - CONTEXT: Providing basic medical care to patients in underserved communities around the world is a valuable service and should not be compromised. Limited publicly available information on the use of pathology services during short-term medical missions (STMMs) shows a dire need for the improved quality of care being provided. OBJECTIVE: To assess the need for clinical and anatomic pathology services in international medical missions by conducting an online survey. DESIGN: A survey containing 35 questions aimed to understand the current use and availability of routine laboratory tests during STMMs, identify the need for particular tests that would improve quality of care, and determine the perceived obstacles preventing the delivery of the care to underserved communities worldwide. Answers from 21 health care providers who served on 50 medical missions were assessed. RESULTS: Survey results revealed a significant discrepancy between the availability of pathology services in the United States and during STMMs. Statistical significance (P< .001) was found in areas of routine blood work, cytopathology, and histologic evaluation, among many others. More than half of the STMMs did not have access to basic metabolic panel, rapid hepatitis B test, and microbial cultures. Another 28% of health care providers indicated that having human immunodeficiency virus testing would have improved health care quality. CONCLUSIONS: Survey results show the need for improved pathology support during STMMs. The lack of precise diagnosis and disease monitoring has a negative effect on the quality of care provided during missions and the ability to enhance global health. PMID- 23627455 TI - Increased thickness of abdominal subcutaneous adipose tissue occurs more frequently in steatohepatitis than in simple steatosis. AB - CONTEXT: The incidence of obesity is increasing and contributes to the rising incidence of fatty liver. Body mass index (BMI) is used to assess the degree of obesity but does not take into account the pattern of body fat distribution. OBJECTIVES: To confirm the increasing incidence of fatty liver in an autopsy study. We hypothesized that a standardized measurement of abdominal subcutaneous adipose tissue (ASAT) might be a good noninvasive method for differentiating steatohepatitis from steatosis. DESIGN: Consecutive complete adult postmortem cases were studied and liver sections were assessed with a steatohepatitis scoring system. Spleen weight, ASAT, and clinical information were obtained. Spleen histology was assessed in a subset of patients having splenomegaly in the absence of cirrhosis. RESULTS: Patients with human immunodeficiency virus, hepatitis C virus, and appreciable alcohol use were excluded. Of 306 cases, the frequency of fatty liver was 51.6% with 33.3% having simple steatosis and 18.3%, having steatohepatitis. Mean ASAT was 3.7 cm in the steatohepatitis group versus 2.6 cm in the steatosis group (P < .001); this difference was greater in patients with a BMI less than 25 kg/m(2) (P = .05). Fibrocongestive splenomegaly was noted in 9 of 38 patients with nonalcoholic steatohepatitis (24%) in the absence of cirrhosis. CONCLUSIONS: In this series of autopsy cases, a dramatic increase in the prevalence of fatty liver disease is demonstrated. Thicker ASAT is associated more with steatohepatitis than with simple steatosis, especially in patients with BMI below 25 kg/m(2). Fibrocongestive splenomegaly may occur in the absence of cirrhosis in the presence of steatohepatitis. PMID- 23627456 TI - Hypoxic patterns of placental injury: a review. AB - CONTEXT: In utero hypoxia is an important cause of perinatal morbidity and mortality and can be evaluated retrospectively to explain perinatal outcomes, to assess recurrence risk in subsequent pregnancies, and to investigate for medicolegal purposes by identification of many hypoxic placental lesions. Definitions of some placental hypoxic lesions have been applied relatively liberally, and many of them are frequently underreported. Objectives To present a comprehensive assessment of the criteria for diagnosing acute and chronic histologic features, patterns, and lesions of placental and fetal hypoxia and to discuss clinicopathologic associations and limitations of the use thereof. The significance of lesions that have been described relatively recently and are not yet widely used, such as laminar necrosis; excessive, extravillous trophoblasts; decidual multinucleate extravillous trophoblasts; and, most important, the patterns of diffuse chronic hypoxic preuterine, uterine, and postuterine placental injury and placental maturation defect, will be discussed. DATA SOURCES: Literature review. CONCLUSIONS: The placenta does not respond in a single way to hypoxia, and various placental hypoxic features should be explained within a clinical context. Because the placenta has a large reserve capacity, hypoxic lesions may not result in poor fetal condition or outcome. On the other hand, very acute, in utero, hypoxic events, followed by prompt delivery, may not be associated with placental pathology, and many poor perinatal outcomes can be explained by an etiology other than hypoxia. Nevertheless, assessment of placental hypoxic lesions is helpful for retrospective explanations of complications in pregnancy and in medicolegal investigation. PMID- 23627457 TI - Inflammatory fibroid polyp of the gallbladder bearing a platelet-derived growth factor receptor alpha mutation. AB - The inflammatory fibroid polyp (IFP) is a benign lesion occurring in the digestive tract, mostly in the stomach and small bowel, composed of fibrovascular tissue infiltrated by inflammatory cells including eosinophils and mastocytes. Its pathogenesis has been controversial (reactive versus neoplastic). The recent finding of mutations in platelet-derived growth factor receptor alpha (PDGFRA) in most gastric and small intestinal IFPs supported their neoplastic etiology, moreover helping in their differential diagnosis. In the only gallbladder IFP reported so far, the diagnosis was based on morphologic and immunohistochemical grounds, which in current standards would probably be considered not fully conclusive. Conversely, the gallbladder IFP we report shows typical pathologic features supported by a PDGFRA mutation, similar to its usual gastric and small intestinal counterparts, constituting the first report of an unequivocal IFP at gallbladder level. Thus, IFPs must be considered in the differential diagnosis of gallbladder mesenchymal masses, and genetic analysis of PDGFRA is a helpful tool for this purpose. PMID- 23627458 TI - Adenomyoepithelioma of the breast: a brief diagnostic review. AB - Adenomyoepithelioma of the breast is an uncommon tumor characterized by dual differentiation into luminal cells and myoepithelial cells. A spectrum of histologic patterns is observed among these tumors and even in different areas of individual tumors. These lesions can be diagnostically challenging, especially when a core needle biopsy is performed, because of the heterogeneity of adenomyoepitheliomas. Recognition of the biphasic cellular elements and the characteristic overall architecture of the tumors in combination with immunohistochemistry are essential to establish the correct diagnosis. Although most tumors have a benign clinical course, local recurrences, malignant transformations, and distant metastases have been reported. All the reported malignant adenomyoepitheliomas with metastases have shown significant cytologic atypia and brisk mitotic rates. Therefore, adequate sampling of the tumor to identify these features is necessary. A complete excision with adequate margins would lower the chance of local recurrence or potential for metastasis. PMID- 23627459 TI - Molecular characterisation of a calmodulin gene, VcCaM1, that is differentially expressed under aluminium stress in highbush blueberry. AB - Calmodulin (CaM), a small acidic protein, is one of the best characterised Ca(2+) sensors in eukaryotes. This Ca(2+) -regulated protein plays a critical role in decoding and transducing environmental stress signals by activating specific targets. Many environmental stresses elicit changes in intracellular Ca(2+) activity that could initiate adaptive responses under adverse conditions. We report the first molecular cloning and characterisation of a calmodulin gene, VcCaM1 (Vaccinium corymbosum Calmodulin 1), in the woody shrub, highbush blueberry. VcCaM1 was first identified as VCAL19, a gene induced by aluminium stress in V. corymbosum L. A full-length cDNA of VcCaM1 containing a 766-bp open reading frame (ORF) encoding 149 amino acids was cloned from root RNA. The sequence encodes four Ca(2+) -binding motifs (EF-hands) and shows high similarity (99%) with the isoform CaM 201 of Daucus carota. Expression analyses showed that following Al treatment, VcCaM1 message level decreased in roots of Brigitta, an Al-resistant cultivar, and after 48 h, was lower than in Bluegold, an Al sensitive cultivar. VcCAM1 message also decreased in leaves of both cultivars within 2 h of treatment. Message levels in leaves then increased by 24 h to control levels in Brigitta, but not in Bluegold, but then decreased again by 48 h. In conclusion, VcCaM1 does not appear to be directly involved in Al resistance, but may be involved in improved plant performance under Al toxicity conditions through regulation of Ca(2+) homeostasis and antioxidant systems in leaves. PMID- 23627460 TI - Interleukin-10 reduces scar formation in both animal and human cutaneous wounds: results of two preclinical and phase II randomized control studies. AB - Cutaneous scarring affects up to 100 million people per annum. There is no effective scar reducing/preventing therapeutic developed to date. Interleukin (IL)-10 is an anti-inflammatory and antifibrotic cytokine. In the embryo it is important for scarless wound repair. We investigated the effect on wound healing and scarring of a double deletion of the IL-10 and IL-4 genes in a knockout (KO) mouse model, and also the effect of exogenous addition of recombinant human (rh) IL-10 into rat and human cutaneous incisions. Mouse study: Two incisions were made on the dorsal skin of 20 double IL-4/IL-10 KO mice and 20 wild-type (WT) controls. Rat study: Three concentrations of rhIL-10 were investigated. Four incisions were made on the dorsal skin of 30 rats. Each rat received two concentrations. Each incision receiving a concentration of rhIL-10 was matched with a control incision, which received either placebo or standard care. Human study: Eight concentrations of rhIL-10 were investigated. Four incisions were made on each arm of 175 healthy volunteers. Four incisions received four different concentrations, which were matched with four control incisions that received either standard care or placebo. KO mice healed with poor scar histology and increased inflammation. rhIL-10-treated rat incisions healed with decreased inflammation, better scar histology, and better macroscopic scar appearance. rhIL 10-treated human incisions at low concentrations healed with better macroscopic scar appearance and less red scars. IL-10 is an important cytokine in wound healing and its suppression of inflammation and scarring is demonstrated in mice and rats with a translational effect in humans. PMID- 23627461 TI - MScDB: a mass spectrometry-centric protein sequence database for proteomics. AB - Protein sequence databases are indispensable tools for life science research including mass spectrometry (MS)-based proteomics. In current database construction processes, sequence similarity clustering is used to reduce redundancies in the source data. Albeit powerful, it ignores the peptide-centric nature of proteomic data and the fact that MS is able to distinguish similar sequences. Therefore, we introduce an approach that structures the protein sequence space at the peptide level using theoretical and empirical information from large-scale proteomic data to generate a mass spectrometry-centric protein sequence database (MScDB). The core modules of MScDB are an in-silico proteolytic digest and a peptide-centric clustering algorithm that groups protein sequences that are indistinguishable by mass spectrometry. Analysis of various MScDB uses cases against five complex human proteomes, resulting in 69 peptide identifications not present in UniProtKB as well as 79 putative single amino acid polymorphisms. MScDB retains ~99% of the identifications in comparison to common databases despite a 3-48% increase in the theoretical peptide search space (but comparable protein sequence space). In addition, MScDB enables cross-species applications such as human/mouse graft models, and our results suggest that the uncertainty in protein assignments to one species can be smaller than 20%. PMID- 23627462 TI - A survey of photodynamic therapy services in dermatology departments across Scotland. AB - There is good evidence to support the use of topical PDT for superficial nonmelanoma skin cancer and dysplasia; however, there is little information available on the structure, process and outcomes of PDT in clinical practice. We undertook a national survey to determine how PDT was being undertaken in dermatology centres in Scotland. We highlight important information on the practicalities of PDT service delivery and the types of patients and diagnoses treated, and provide preliminary information on the outcomes achieved. These data will be invaluable as a starting point to agree on minimum standards for PDT and criteria to audit against these standards. PMID- 23627463 TI - Concurrent overactivation of the cytosolic glutamine synthetase and the GABA shunt in the ABA-deficient sitiens mutant of tomato leads to resistance against Botrytis cinerea. AB - Deficiency of abscisic acid (ABA) in the sitiens mutant of tomato (Solanum lycopersicum) culminates in increased resistance to Botrytis cinerea through a rapid epidermal hypersensitive response (HR) and associated phenylpropanoid pathway-derived cell wall fortifications. This study focused on understanding the role of primary carbon : nitrogen (C : N) metabolism in the resistance response of sitiens to B. cinerea. How alterations in C : N metabolism are linked with the HR-mediated epidermal arrest of the pathogen has been also investigated. Temporal alterations in the gamma-aminobutyric acid (GABA) shunt, glutamine synthetase/glutamate synthase (GS/GOGAT) cycle and phenylpropanoid pathway were transcriptionally, enzymatically and metabolically monitored in both wild-type and sitiens plants. Virus-induced gene silencing, microscopic analyses and pharmacological assays were used to further confirm the data. Our results on the sitiens-B. cinerea interaction favor a model in which cell viability in the cells surrounding the invaded tissue is maintained by a constant replenishment of the tricarboxylic acid (TCA) cycle through overactivation of the GS/GOGAT cycle and the GABA shunt, resulting in resistance through both tightly controlling the defense-associated HR and slowing down the pathogen-induced senescence. Collectively, this study shows that maintaining cell viability via alterations in host C : N metabolism plays a vital role in the resistance response against necrotrophic pathogens. PMID- 23627464 TI - The extract of Cinnamomum cassia twigs inhibits adipocyte differentiation via activation of the insulin signaling pathway in 3T3-L1 preadipocytes. AB - CONTEXT: Obesity is associated with a number of diseases with metabolic abnormalities such as type 2 diabetes (T2D). Medicinal plants have been widely used for the treatment of obesity and related complications. OBJECTIVE: In this study, we investigated the antidiabetic properties of the extract of twigs of Cinnamomum cassia Blume (Lauraceae) (Cinnamomi Ramulus; CR) in 3T3-L1 murine preadipocytes. MATERIALS AND METHODS: 3T3-L1 cells were differentiated into adipocytes for 3 d in insulin-conditioned medium and then treated with CR extract at concentrations of 100 and 500 MUg/mL for 6 d. Adipocyte differentiation was measured by Oil Red O staining, and the expression of master transcription factors, peroxisome proliferator-activated receptor-gamma (PPARgamma), CCAAT/enhancer binding protein-alpha (C/EBPalpha), and sterol regulatory element binding protein-1c (SREBP-1c), and lipid metabolism factors were investigated by reverse transcription-polymerase chain reaction (RT-PCR). The activation of the AMP-activated protein kinase (AMPK)/insulin signaling pathway was assessed by western blot analysis. RESULTS: CR extract significantly reduced lipid accumulation and down-regulated the expression of PPARgamma, C/EBPalpha, and SREBP-1c in 3T3-L1 adipocytes. CR extract also suppressed the expression of fatty acid synthase (FAS), acyl-CoA synthase, and perilipin. Moreover, CR extract markedly up-regulated the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). In addition, CR extract effectively increased the expression levels of glucose transporter-4 (GLUT-4), phosphatidylinositol 3-kinase (PI3K), and insulin receptor substrate-1 (IRS-1) in 3T3-L1 adipocytes. DISCUSSION AND CONCLUSION: These results suggest that CR extract may have therapeutic potential as a natural agent for the improvement of T2D via regulation of the insulin-dependent signaling pathway. PMID- 23627465 TI - Comparison of protective and curative potential of Daucus carota root extract on renal ischemia reperfusion injury in rats. AB - CONTEXT: Daucus carota Linn (Apiaceae), a useful vegetable, is traditionally used in treating kidney and hepatic dysfunctions. OBJECTIVE: To evaluate the protective and curative potential of D. carota root extract on renal ischemia reperfusion injury in rats. MATERIALS AND METHODS: Wistar rats were selected with 8 + 8 groups (n = 6). Renal pedicles of rats were occluded for 45 min and allowed for reperfusion period. In protective and curative studies, 14 days prior and 14 days after the induction of ischemia/reperfusion (I/R), rats received petroleum ether extract (PEE 250 and 500 mg/kg), fractional methanol extract (FME 250 and 500 mg/kg) and direct methanol extract (DME 250 and 500 mg/kg) of Daucus carota root, orally, once daily. RESULTS: PEE at a dose of 500 mg/kg significantly (p < 0.001) reduced the levels of serum creatinine (0.853-3.090 mg/dl), uric acid (1.300-3.500 mg/dl) and urea (58.26-132.00 mg/dl) compared to disease control. FME at a dose of 500 mg/kg body weight significantly (p < 0.001) reduced the levels of serum creatinine (0.960-3.090 mg/dl), uric acid (1.700-3.500 mg/dl) and urea (77.17-132.00 mg/dl) compared to disease control. DME at a dose of 500 mg/kg body weight significantly (p < 0.001) reduced the levels of serum creatinine (1.173-3.090 mg/dl), uric acid (2.267-3.500 mg/dl) and urea (84.75-132.00 mg/dl) compared to disease control. DISCUSSION AND CONCLUSION: Findings demonstrate that postconditioning with the D. carota root extract significantly improves kidney function in I/R rats. PMID- 23627466 TI - Genistein sensitizes hepatic insulin signaling and modulates lipid regulatory genes through p70 ribosomal S6 kinase-1 inhibition in high-fat-high-fructose diet fed mice. AB - CONTEXT: Genistein reduces high-calorie diet-induced insulin resistance and fat accumulation in animals, but the mechanism is unresolved. OBJECTIVE: This study explores whether action of genistein is associated with p70 ribosomal S6 kinase-1 (S6K1) inhibition. MATERIALS AND METHODS: Adult male mice were fed either normal diet or high-fat-high-fructose diet (HFFD) for 15 days, after which animals in each dietary group were divided into two groups and administered either genistein (1 mg kg(-1) day(-1), p.o.) in 0.5 ml of 30% dimethylsulfoxide (DMSO) or 30% DMSO (0.5 ml) for the next 45 days. At the end of the study, their liver was analyzed for lipid content. Semi-quantitative RT-PCR and western blotting methods were used to analyze lipid regulatory genes and insulin signaling proteins, respectively. RESULTS: Genistein significantly (p < 0.05) lowered HFFD-induced body and liver weight gain and plasma and hepatic lipid levels. Histology showed a 2.5-fold increase of lipid in HFFD compared to control. Genistein treatment to HFFD-fed animals significantly decreased lipid accumulation (by 40%) compared to HFFD. Insulin-stimulated tyrosine phosphorylation of insulin receptor-beta and insulin receptor substrates-1 (IRS-1), IRS-1 associated phospatidylinositol 3kinase (PI3K) and Akt Ser(473) phosphorylation were improved while IRS-1 serine phosphorylation was significantly (p < 0.05) decreased by genistein in HFFD. Significant (p < 0.05) increase in adenosine monophosphate-activated protein kinase (AMPK) Thr(172) phosphorylation and decrease in S6K1 Thr(389) phosphorylation were observed in HFFD-plus genistein compared to HFFD. Genistein downregulated lipogenic genes and upregulated fatty acid oxidative genes in HFFD fed mice. CONCLUSION: Genistein improves insulin signaling and attenuates fat accumulation in liver through S6K1 inhibition. PMID- 23627467 TI - Phenolics-rich fraction of Khaya senegalensis stem bark: antitrypanosomal activity and amelioration of some parasite-induced pathological changes. AB - CONTEXT: The stem bark of Khaya senegalensis A. Juss (Meliaceae) is currently used for the treatment of trypanosomiasis by traditional practitioners in Nigeria. OBJECTIVES: The present study investigated the anti-Trypanosoma brucei brucei activity of phenolics-rich fraction of K. senegalensis (pfks) and its ameliorative effects on trypanosome-induced pathological changes. MATERIALS AND METHODS: The fraction was initially analyzed by gas chromatography-mass spectrometry (GC-MS). A 60 min time course experiment was conducted with various concentrations of the fraction using a 96-well microtiter plate technique and was further used to treat T. brucei infected rats at 100, 200 and 300 mg/kg body weight (BW). Indices of anemia as well as hepatic and renal functions were analyzed in all experimental animals at the end of the experiment. RESULTS: The GC-MS analysis of the pfks revealed that the most abundant phytochemicals are phloroglucinol (40.56%) and 3,4-(dihydroxyphenyl) acetic acid (41.76%). The fraction showed a concentration dependent in vitro antitrypanosomal activity. Interestingly, the fraction completely eliminated the parasites from the bloodstream of infected rats without relapse during the experimental period at the dose of 300 mg/kg BW and also kept the parasites consistently lower at 100 and 200 mg/kg BW than that was recorded in the untreated infected rats. Furthermore, the severity of T. brucei-induced anemia and hepatic damage was significantly (p < 0.05) ameliorated in the 300 mg/kg BW treatment group whereas the parasite-induced renal damage was significantly (p < 0.05) ameliorated in all treatment groups. CONCLUSION: Data from this study may suggest that phenolics play an important role in the antitrypanosomal activity of K. senegalensis. PMID- 23627468 TI - Direct human DNA protection by Coriolus versicolor (Yunzhi) extract. AB - CONTEXT AND OBJECTIVE: Scientific evidence has shown Coriolus versicolor (L. ex Fr.) Quel (also known as Yunzhi) has the role of immunomodulator in therapeutic effect. The aim of this in vitro study was to investigate the antioxidative effect of Yunzhi and to explore the mechanisms behind its DNA protection. MATERIALS AND METHODS: Commercial Yunzhi extract was dissolved in water and diluted in five concentrations (10(1)-10(5) MUg/L) with appropriate buffers. Lymphocytes harvested from three healthy subjects were incubated with Yunzhi extract for 30 min. Cells were then subjected to 5 min oxidant challenge by 45 MUM hydrogen peroxide. The standard alkaline comet (SAC) assay and lysed cell comet (LCC) assay were performed in parallel. DNA damage of each treatment was scored under a fluorescence microscope and compared with the cells without Yunzhi pretreatment. RESULTS: U-shaped dose-response was seen in both versions of the comet assay. Yunzhi at 10(4) MUg/L demonstrated a genoprotective effect against oxidative damage in the SAC assay (25% decrease in comet score). In the LCC assay, a trend of protection in lymphocytes was observed but it did not reach statistical significance. CONCLUSION: A direct antioxidant effect of Yunzhi against oxidant challenge on the DNA of lymphocytes was evidenced. The active component in Yunzhi was likely to be membrane permeable. PMID- 23627469 TI - Protective effect of Cnestis ferruginea and its active constituent on scopolamine induced memory impairment in mice: a behavioral and biochemical study. AB - CONTEXT: Cnestis ferruginea Vahl ex DC (Connaraceae) (CF) is used in traditional African medicine in the management of CNS disorders. The degeneration and dysfunction of cholinergic neurons is closely associated with the cognitive deficits of Alzheimer's disease (AD) and oxidative stress has been implicated in its pathogenesis. However, the influence of C. ferruginea on the cholinergic system and oxidative stress parameters has not been explored. OBJECTIVE: The present study investigates the effect of methanol root extract of C. ferruginea and its active constituent amentoflavone (CF-2) on memory, oxidative stress and acetylcholinesterase (AChE) activity in scopolamine-induced amnesia. MATERIALS AND METHODS: Mice were orally treated with CF (25-200 mg/kg), CF-2 (6.25-25 mg/kg) for three days and memory impairment was induced by intraperitoneal injection of scopolamine (3 mg/kg). Memory function was evaluated by passive avoidance and Morris water maze tests. Biochemical parameters of oxidative stress and cholinergic function were estimated in brain after the completion of behavioral studies. RESULTS: Scopolamine caused memory impairment along with increased AChE activity and oxidative stress in mice brain. Oral administration of CF and CF-2 significantly prevented scopolamine-induced memory impairment, inhibited AChE and enhanced antioxidant enzyme activity in the brain following scopolamine injection as compared to vehicle administration in scopolamine (i.p.) treated mice that were comparable to the effect of tacrine. DISCUSSION AND CONCLUSION: The study demonstrated that C. ferruginea and its constituent have significant protective effect against scopolamine-induced memory deficits in mice that can be attributed to their antioxidant and antiAChE activity. PMID- 23627470 TI - Protective effect of rutin against acute gastric mucosal lesions induced by ischemia-reperfusion. AB - CONTEXT: Rutin, a flavonoid commonly present in onions, apples and tea, has been suggested to have a variety of pharmacological activities, including immunomodulator, anti-inflammatory and antioxidant activities. OBJECTIVES: The present study was to examine the protective effects of rutin on gastric mucosal damage induced by gastric ischemia-reperfusion (I/R) in rats. MATERIALS AND METHODS: Rutin (50, 100, 200 mg/kg) was administered intragastrically for five consecutive days before ischemia. Sixty minutes after the last administration of rutin, under anesthesia, the celiac artery was clamped for 30 min, and then the clamp was removed for 60 min reperfusion. After reperfusion, the stomach was removed for biochemical and histological examinations. RESULTS: As compared with the I/R group (116.7 +/- 21.5), administration of rutin at doses of 50, 100 and 200 mg/kg significantly prevented the increase of gastric mucosal injury index induced by gastric I/R (73.4 +/- 14.8, 65.9 +/- 9.6 and 26.9 +/- 5.7, respectively). ED50 value was 138.7 mg/kg. Moreover, rutin at doses of 50, 100 and 200 mg/kg showed an inhibition on the increased myeloperoxidase (24.6, 41.3 and 53.1% reduction) activity and malondialdehyde levels (27.4, 40.3 and 50.7% reduction) in gastric mucosa. Also, the elevation of inducible NO synthase (iNOS) activity as well as the decrease of constitutive NO synthase (cNOS) in the gastric mucosa were significantly prevented by rutin pretreatment. CONCLUSION: These results suggested that rutin has a protective effect against gastric mucosal injury induced by gastric I/R and that the gastroprotection was related to the NOS/NO pathway and its antioxidant activity. PMID- 23627471 TI - Protective effects of saffron (Crocus sativus) against lethal ventricular arrhythmias induced by heart reperfusion in rat: a potential anti-arrhythmic agent. AB - CONTEXT: Saffron (Crocus sativus L.) has been used as a cuisine spice in eastern and western societies for thousands of years. In traditional medicine, saffron is recommended for the treatment of various kinds of disorders including heart palpitations. OBJECTIVE: We investigated the hypothesis of the protective effect of saffron on lethal cardiac arrhythmias induced by heart ischemia-reperfusion in rat. MATERIALS AND METHODS: Animals were divided into a control (CTL) group that received tap water, Saf50, Saf100 and Saf200 groups that were orally treated with aqueous extracts of saffron, at dosages of 50, 100 and 200 mg/kg/day, respectively, and amiodarone (Amio) group that orally received 30 mg/kg/day for seven days. On day 8, heart ischemia-reperfusion was induced by ligation and releasing of the left anterior descending coronary artery. RESULTS: During reperfusion, the numbers and durations of ventricular fibrillation (VF) decreased in all groups compared to the CTL group (p < 0.05). Ventricular tachycardia (VT)/VF numbers (3.2 +/- 1.2), durations (4.9 +/- 2.6) and also arrhythmia severity (1.9 +/- 0.35) were decreased significantly in the Saf100 group versus CTL group values (18.4 +/- 11.6, 52 +/- 31 and 3.3 +/- 0.3, respectively). The PR and QTcn intervals of ECG were significantly longer in the Saf200 group (p < 0.001 versus CTL). The other doses of saffron only significantly prolonged the QTcn interval. CONCLUSION: The results suggest that pretreatment with saffron, especially at the dosage of 100 mg/kg/day, attenuates the susceptibility and incidence of fatal ventricular arrhythmia during the reperfusion period in the rat. This protective effect is apparently mediated through reduction of electrical conductivity and prolonging the action potential duration. PMID- 23627472 TI - Correlation between polyphenol content and anti-inflammatory activity of Verbascum phlomoides (mullein). AB - CONTEXT: Verbascum phlomoides L. (Scrophulariaceae) (mullein) used in the European folk medicine due to its anti-inflammatory and soothing action on the respiratory tract is thoroughly documented in handbooks and scientific literature. Nevertheless, information regarding the influence of the polyphenol content on pharmacological activity is scarce. OBJECTIVE: This study explored the antioxidant and anti-inflammatory potential of V. phlomoides polyphenol-rich extract. MATERIALS AND METHODS: Dried mullein flowers (200 g) were subjected to water extraction (60 degrees C, 2 h, herb/solvent ratio = 1/10 m/v) and further to n-butanol partition. Total phenolics were spectrophotometrically determined and specific compounds were evaluated by HPLC. The antioxidant activity was assessed by the 2,2-di(4-tert-octylphenyl)-1-picrylhydrazyl (DPPH) assay. The anti-inflammatory potential of the extract (50-200 MUg/mL) was evaluated in vitro by ELISA measurement of ICAM-1 expression in TNF-alpha-stimulated endothelial cells and in vivo by the rat paw edema assay. RESULTS: The mullein extract contained 4.18% total polyphenols expressed as gallic acid. The main components identified by HPLC were: rosmarinic acid (14.93 mg/g), caffeic acid (39.96 mg/g), ferulic acid (29.61 mg/g) and quercetin (17.29 mg/g). Acteoside was not detected; aucubin was detected in traces (0.028 mg/g). Depending on concentration, the extract exerted scavenging activity on DPPH radical (EC50 7.09 mg/mL), significantly inhibited TNF-alpha-induced ICAM-1 expression by 55-58.8% on human umbilical vein endothelial cells at 100 and 200 MUg/mL, but failed to reduce egg white-induced rat paw edema. DISCUSSION AND CONCLUSION: Mullein polyphenols play an important role in exerting the antioxidant effect but have a weak influence on anti-inflammatory activity that is correlated, probably, to a higher content of iridoids and phenylethanoids. PMID- 23627473 TI - Antinociceptive effects of matrine on neuropathic pain induced by chronic constriction injury. AB - CONTEXT: Sophora alopecuroides L. (Leguminosae) is a commonly used Chinese herbal drug that possesses antipyretic, anti-inflammatory and analgesic effects. Among various alkaloids isolated from S. alopecuroides, matrine has been identified as the major bioactive component contributing to a variety of pharmacological effects, and studies have also shown that matrine has an analgesic effect. OBJECTIVE: To investigate the antinociceptive effects of matrine on neuropathic pain induced by chronic constriction injury (CCI) in mice. MATERIALS AND METHODS: The von Frey, plantar, cold-plate, locomotor activity and rota-rod test were performed to assess the degree of mechanical, radiant, thermal, spontaneous locomotor activity and motor coordination changes respectively, at different time intervals, i.e., one day before surgery and 7, 8, 10, 12 and 14 days post surgery. Matrine was administered from the 8th day after the surgery for seven days. RESULTS: Our present study shows that matrine at the dose of 30 mg/kg i.p. increased the paw withdrawal threshold (0.88 +/- 0.16), paw withdrawal latency (7.01 +/- 0.11) and the counts of paw withdrawal (19.7 +/- 1.15) from the day 8 for the nerve injured paw compared to the CCI group (0.18 +/- 0.04, 4.62 +/- 0.18, 44.3 +/- 2.99, respectively). Matrine, in a dose-dependent effect, was also found to produce a protective role in both plantar and cold-plate tests. The analysis of the effect supports the hypothesis that matrine is useful in neuropathic pain therapy. DISCUSSION AND CONCLUSION: The results of this study suggest that matrine could be useful in the treatment of different kinds of neuropathic pains as an adjuvant to conventional medicines. PMID- 23627474 TI - Discovery of PTPRJ agonist peptides that effectively inhibit in vitro cancer cell proliferation and tube formation. AB - PTPRJ is a receptor protein tyrosine phosphatase involved in both physiological and oncogenic pathways. We previously reported that its expression is strongly reduced in the majority of explored cancer cell lines and tumor samples; moreover, its restoration blocks in vitro cancer cell proliferation and in vivo tumor formation. By means of a phage display library screening, we recently identified two peptides able to bind and activate PTPRJ, resulting in cell growth inhibition and apoptosis of both cancer and endothelial cells. Here, on a previously discovered PTPRJ agonist peptide, PTPRJ-pep19, we synthesized and assayed a panel of nonapeptide analogues with the aim to identify specific amino acid residues responsible for peptide activity. These second-generation nonapeptides were tested on both cancer and primary endothelial cells (HeLa and HUVEC, respectively); interestingly, one of them (PTPRJ-19.4) was able to both dramatically reduce cell proliferation and effectively trigger apoptosis of both HeLa and HUVECs compared to its first-generation counterpart. Moreover, PTPRJ pep19.4 significantly inhibited in vitro tube formation on Matrigel. Intriguingly, while ERK1/2 phosphorylation and cell proliferation were both inhibited by PTPRJ-pep19.4 in breast cancer cells (MCF-7 and SKBr3), no effects were observed on primary normal human mammary endothelial cells (HMEC). We further characterized these peptides by molecular modeling and NMR experiments reporting, for the most active peptide, the possibility of self-aggregation states and highlighting new hints of structure-activity relationship. Thus, our results indicate that this nonapeptide might represent a great potential lead for the development of novel targeted anticancer drugs. PMID- 23627475 TI - How can self-regulation enhance our understanding of trauma and dissociation? PMID- 23627476 TI - Ongoing incestuous abuse during adulthood. AB - Individual cases of adult incestuous abuse have surfaced repeatedly in the lay and professional literature of the past 1.5 centuries without it occasioning systematic investigation, such as the reporting of a case series of individuals subjected to such extreme abuse. Yet substantial numbers of patients with dissociative identity disorder at the time of presentation report incestuous abuse continuing into the adult years, and for many the abuse is ongoing. Data relating to a series of 10 such incestuously abused women are presented. These patients were sexually abused from a very early age (typically from before age 3), with the manipulation of their sexual response a key component in conditioning an enduring sexualized attachment. Shame and fear were also used to ensure compliance and silence. The women, when able to speak of it, describe the induction by their paternal abuser of orgasm at an early age, typically around the age of 6. The women have high indices of self-harm and suicidality and are prone to placing themselves in dangerous reenactment scenarios. The average duration of incestuous abuse for this group of women was 31 years, and the average estimate of total episodes of sexual abuse was 3,320. Most women do not feel that they own their body and experience being "fused" to their father. Their mother was reported as an active participant in the sexual abuse or as having done nothing to protect their daughter despite seeing obvious evidence of incest. The fathers, despite a propensity to use or threaten violence, were generally outwardly productively employed, financially comfortable, and stably married and half had close church involvement. However, suicide and murder occurred within the 1st- or 2nd-degree relatives of these women at a high frequency. All 10 had been sexually abused by various groupings of individuals connected to their fathers. PMID- 23627477 TI - Detachment, compartmentalization, and schizophrenia: linking dissociation and psychosis by subtype. AB - To explain the phenomenological overlap between dissociation and schizophrenia, a dissociative subtype of schizophrenia has been proposed as a possibility. Dissociation is often believed to be organized on a continuum, although 2 qualitatively different phenomena can be distinguished in theory, research, and clinical practice: (a) states of separation from self or environment (detachment dissociation) and (b) inaccessibility of normally accessible mental contents (compartmentalization dissociation). This study used the Positive and Negative Syndrome Scale (PANSS) and the Association for Methodology and Documentation in Psychiatry module for the interview assessment of dissociation to investigate the relationships between PANSS subscales, detachment dissociation, and compartmentalization dissociation in a sample of 72 patients with schizophrenia. A confirmatory factor analysis sustained the bipartite model, yielding factors that grouped dissociative items around amnesia and depersonalization/derealization. The latter factor also contained identity disturbances and was therefore not entirely consistent with the theoretical formulations of detachment dissociation. It is important to note that the structure of those factors may be influenced by the symptoms of schizophrenia to which they were specifically linked: The factor containing depersonalization/derealization was connected to the positive symptoms subscale of the PANSS, whereas the factor containing amnesia was associated with the negative subscale. Hence, a dichotomy of dissociation is confirmed inasmuch as its subtypes are as distinguishable as PANSS subscales. This has implications on theoretical and clinical levels. PMID- 23627478 TI - Factor structure of the Cambridge Depersonalization Scale in trauma-exposed college students. AB - This study examined the factor structure of the Cambridge Depersonalization Scale (CDS; M. Sierra & G. E. Berrios, 2000 ), a 29-item self-report measure of depersonalization. The CDS was based on a conceptualization of depersonalization as a multidimensional construct, a theoretical perspective that has received limited empirical attention. Exploratory and confirmatory factor analyses were conducted on CDS item scores in a sample of 534 trauma-exposed college students. Results failed to support factor structures of the CDS previously reported in the literature and instead supported a 2-factor solution, with 1 factor representing a sense of unreality and detachment and a 2nd factor representing emotional and physical numbing. Implications regarding the structural validity of the CDS are discussed. [Supplementary material is available for this article. Go to the publisher's online edition of Journal of Trauma & Dissociation for the following resource: Four tables with the following information: inter-correlations among CDS items from Samples 1 and 2; Sierra et al. (2005 ) four-factor model and Simeon et al. (2008 ) five-factor model estimated factor loadings, covariances, and R-square in Sample 1; Factor loadings for 3-7 factor EFA models in Sample 1; and estimated factor loadings for one-factor CFA model in Sample 2.]. PMID- 23627479 TI - Dissociative symptoms and academic functioning in maltreated children: a preliminary study. AB - Research has identified numerous negative sequelae of child maltreatment that may adversely impact academic functioning (AF). There is limited research, however, on the relationship between specific trauma symptoms, such as dissociation, and poor AF. This cross-sectional study examined the association between dissociative symptoms and multi-informant reports of AF in a sample of maltreated youth with a history of out-of-home care. Participants included 149 youth and their caregivers and teachers. Dissociative symptoms were measured based on youth report, whereas AF was assessed using (a) standardized measures of academic achievement, (b) youth-report measures of school membership and perceived academic competence, (c) caregiver reports of youths' performance in school, and (d) teacher reports of student grades. Results of multiple regression analyses suggested that dissociative symptoms were generally related to poorer AF after IQ, age, gender, and the total number of school and caregiver transitions were controlled. Implications for school personnel are discussed. PMID- 23627480 TI - Development and initial validation of the Structured Interview for Self Destructive Behaviors. AB - This article describes the initial validation of the Structured Interview for Self-Destructive Behaviors (SI-SDB), a brief interview assessing suicidality, self-injury, substance abuse, disordered eating, and risky sexual behaviors. Self destructive behaviors present clinical and practical challenges for mental health treatment providers. Participants were 217 psychiatric inpatients with a wide variety of diagnoses who completed the SI-SDB and other measures of psychiatric symptoms, trauma exposure, and other childhood experiences. Internal validity analyses revealed an internally consistent measure with 2 major factors. External validity analyses indicated that the Substance Abuse and Disordered Eating scales were predictive of related psychiatric diagnoses. All scales except Substance Abuse were significantly correlated with psychiatric symptoms and childhood abuse. These findings indicate that the SI-SDB is a valid means of assessing 5 significant domains of dangerous behaviors in clinical and research settings. Further research on the reliability of reports over time, interrater consistency, and convergent validity with longer measures of the SI-SDB domains is needed. PMID- 23627481 TI - What contributes to predicting change in the treatment of dissociation: initial levels of dissociation, PTSD, or overall distress? AB - Individuals with dissociative disorders (DDs) suffer from high levels of dissociation as well as posttraumatic stress disorder (PTSD) and general distress. No research has investigated how changes in dissociation relate to changes in other symptoms over the course of treatment in patients with DD. Using a prospective, naturalistic design, we collected reports of symptoms from a sample of therapists and their patients diagnosed with dissociative identity disorder or dissociative disorder not otherwise specified who participated in the Treatment Outcome of Patients with Dissociative Disorders study. The patients completed surveys at intake (Time 1) into the study and at 30-month follow-up (Time 4). We found that dissociative symptoms, including amnesia, depersonalization/derealization, and absorption, at the initial assessment of the study ("initial") were related to initial levels of PTSD and general distress and that changes in dissociative symptoms were related to changes in PTSD and general distress. Initial dissociation was a significant predictor of change in dissociation at 30 months when we controlled for length of time for follow-up, length of time practicing therapy, and length of time treating dissociative patients. Our results suggest that a reduction in dissociative symptoms in DD patients is associated with reductions in the overall severity of dissociative, posttraumatic stress, and distress symptoms. PMID- 23627482 TI - The association among childhood maltreatment, somatic symptom intensity, depression, and somatoform dissociative symptoms in patients with fibromyalgia syndrome: a single-center cohort study. AB - Research demonstrates strong associations between childhood maltreatment and health problems that include dissociative symptoms and fibromyalgia syndrome (FMS). We assessed the associations among childhood maltreatment, somatic symptom severity, depression, and somatoform dissociative symptoms in all consecutive adult FMS patients of a tertiary referral pain medicine center between January 2010 and December 2011. Childhood maltreatment was assessed with the Childhood Trauma Questionnaire, somatoform dissociative symptoms with the Somatoform Dissociation Questionnaire, somatic symptom severity with the Patient Health Questionnaire-15 and depression by the Patient Health Questionnaire-2. A total of 117 patients (84% women) were included in the analysis, of whom 20.5% reported severe emotional abuse, 8.6% severe physical abuse, 12.8% severe sexual abuse, 25.6% severe emotional neglect, and 12.0% severe physical neglect in childhood and adolescence. On average, patients reported high levels of somatoform dissociative symptoms and moderate levels of somatic symptom severity and depression. Somatoform dissociative symptoms and emotional abuse were moderately correlated (r = .32). In hierarchical regression analysis, gender (p = .01) and somatic symptom severity (p < .0001) but not childhood maltreatment and depression were significant predictors of somatoform dissociative symptoms. Reports of somatoform dissociative symptoms by FMS patients might be attributed to their tendency to report multiple somatic symptoms. PMID- 23627486 TI - Treating peri-implantitis using a combined regenerative/resective procedure: a case report. AB - The aim of this article is to describe a combined regenerative/resective procedure used in the treatment of peri-implantitis. The following case presented with excess-cement-induced peri-implantitis and the resulting combined circumferential and buccal dehiscence defect. Surgical therapy consisted of minimal resection of interproximal peaks of bone and subsequent guided bone regeneration. The 12-month clinical result was resolution of peri-implantitis (no pathologic probing depths, bleeding on probing, suppuration), radiographic evidence of bone fill of the defect, and some recession that was clinically acceptable to the patient. PMID- 23627487 TI - Restoration variables and postoperative hypersensitivity in Class I restorations: PEARL Network findings. Part 2. AB - BACKGROUND: This study investigated postoperative hypersensitivity at 1, 4, and 13 weeks following resin-based composite restoration of occlusal caries as well as the relationship to materials and technique employed by PEARL Network Practitioner Investigators (P-Is). METHODS: PEARL P-Is (n = 45) enrolled patients with early occlusal caries lesions deemed to require treatment and placed restorations using their routine technique. Data on 485 restorations at 4 weeks included: baseline sensitivity; ranking of dentin caries activity; post preparation use of antimicrobials, liners, and dentin bonding agent; type of resin-based composite (RBC) employed; whether layer or bulk fill was used; and patient demographics. Patients anonymously reported at 1, 4, and 13 weeks any sensitivity to hot, cold, sweets, clenching, and chewing as well as quality of life (QOL) related to the restoration(s). RESULTS: Appreciable hypersensitivity (AH)--ie, sensitivity of 3 or greater on an 11-point anchored scale--was reported in 30% of all 668 eligible carious teeth at baseline. Among them, 10% of study teeth with no baseline AH had developed AH at 4 weeks post-treatment. With restoration, 63% of teeth with baseline AH no longer had AH, while the remainder had no improvement. Neither change in AH nor change in greatest sensitivity was associated with use of a liner, use of flowable or hybrid RBC, or bulk or layer technique. With use of an antimicrobial, at 1 week, there was a significant but transient effect on AH (P = 0.006), which was generally not present at 4 weeks, although it continued for one product. At 4 weeks, the change in greatest sensitivity was associated with the type of dentin bonding agent, total etch or self etch, (P = 0.004). Using similar materials and techniques, P-Is had widely differing patient-reported outcomes. CONCLUSION: Patient self-reported post restoration AH-either acquired or remaining-at 4 weeks was generally not related to the materials or techniques recorded in these small- to moderate-sized occlusal restorations. However, the change in greatest sensitivity was associated with the type of dentin bonding agent used; but the clinical significance of this difference is questionable. CLINICAL IMPLICATIONS: The post-restoration levels of AH in early and moderate-sized posterior RBC restorations provide no justification for the use of a liner (CaOH, GI/RMGI, or flowable composite) as compared to the use of a dentin-bonding agent alone. Use of an antimicrobial had an effect on AH at 1 week that was generally transient. PMID- 23627488 TI - VEGF is an important mediator of tumor angiogenesis in malignant lesions in a genetically engineered mouse model of lung adenocarcinoma. AB - BACKGROUND: VEGF is one of the key drivers of physiological or pathological angiogenesis hence several VEGF inhibitors are in different stages of clinical development. To further dissect the role of VEGF in different stages of tumor progression in lung tumors, we utilized KrasG12D-LSL GEMMs (genetically engineered mouse models). METHODS: Intranasal delivery of adenoviruses expressing cre recombinase in KrasG12D-LSL mice results in the expression of mutant Kras that leads to development of tumor lesions ranging from adenomatous hyperplasia to large adenoma and adenocarcinoma over time in lung. In the current study, we treated KrasG12D-LSL mice at 14 weeks post inhalation with three different angiogenic inhibitors including axitinib and PF-00337210 both of which are selective inhibitors of VEGFR and sunitinib which targets VEGFR, C-SF1-R, PDGFR and KIT. RESULTS: Pathology findings showed no significant difference in percentage of adenomatous hyperplastic lesions between the vehicle vs. any of the treatments suggesting that angiogenesis may not play a major role at early stages of tumorigenesis. However, each inhibitor suppressed percentage of benign adenoma lesions and almost fully inhibited growth of adenocarcinoma lesions in the recipients which was consistent with a reduction in tumor vasculature. Treatment with sunitinib which is a multi-targeted RTKI did not provide any advantage compared to selective VEGFR inhibitor further emphasizing role of VEGF in tumor angiogenesis in this model. CONCLUSION: Overall, our studies indicate significance of VEGF and angiogenesis in a spontaneous model of lung tumorigenesis and provide a proof of mechanism for anti-cancer activity of VEGF inhibitors in this model. PMID- 23627489 TI - Ambient wood smoke, traffic pollution and adult asthma prevalence and severity. AB - BACKGROUND AND OBJECTIVE: The impact of ambient wood smoke and traffic-related air pollution on adult asthma has not been well studied. This paper aims to investigate associations between exposure to ambient wood smoke, traffic-related air pollution and current asthma/asthma severity in middle age, and whether any associations are modified by atopic status. METHODS: Using data from the Tasmanian Longitudinal Health Study, associations between ambient wood smoke and two indices of traffic-related air pollution (frequency of heavy vehicles near the home and frequency of intense traffic noise) and current asthma/asthma severity were investigated. Unconditional logistic regression to examine current asthma and ordinal logistic regression to examine asthma severity was used. RESULTS: For asthmatics, both exposure to ambient wood smoke (odds ratio 1.11; 95% confidence interval 1.02-1.20) and being frequently exposed to heavy vehicles (odds ratio 1.80; 95% confidence interval 1.09-2.96) were associated with increased asthma severity. Neither association varied by atopic status. CONCLUSIONS: In middle-aged adults, ambient wood smoke and traffic pollution were associated with increased asthma severity. These findings suggest that avoiding or limiting exposure to traffic pollution and wood smoke may help to reduce asthma. Future studies to replicate this finding are recommended and should examine specific biological mechanisms for this effect. PMID- 23627490 TI - Sympathetic nervous system function and dysfunction in chronic hemodialysis patients. AB - Adequate sympathetic nervous system activation is essential for the compensatory mechanisms of blood pressure maintenance during the hemodialysis (HD) procedure. Chronic sympathetic nervous system overactivity, however, may lead to the development of hypertension and cardiovascular disease in HD patients. The present review focuses on recent findings on the sympathetic nervous system activity in these patients. Sympathetic overactivity has been demonstrated directly by muscle sympathetic nerve activity recordings (MSNA) in chronic renal disease, but only rarely in HD patients. In the latter, sympathetic activity has mostly been assessed using indirect methodology. Decreased heart rate variability, increased blood pressure variability (BPV), and suppressed baroreflex function are believed to represent chronic sympathetic overactivity in HD patients. The HD procedure and ultrafiltration are associated with enhanced sympathetic activity and baroreflex activation. During most episodes of intradialytic hypotension, the baroreflex is adequately activated; sympathetic withdrawal with bradycardia, however, has been reported during excessive hypovolemia. Sympathetic overactivity is also believed to be a mechanism associated with intradialytic hypertensive episodes and refractory hypertension. While successful renal transplantation is associated with improvement of heart rate variability (HRV), improvement and restoration of baroreflex function, persistent sympathetic overactivity has been documented in transplanted patients using MSNA recordings. Decreased HRV and baroreflex function have been reported to be associated with increased mortality and morbidity in HD patients. The predictive value of sympathetic outflow assessed by MSNA has yet to be determined. Optimization of HD treatment, pharmacological interventions, and renal sympathetic denervation are several approaches targeting sympathetic overactivity to improve cardiovascular morbidity and mortality. PMID- 23627492 TI - Scavenging amphipods: sentinels for penetration of mercury and persistent organic chemicals into food webs of the deep Arctic Ocean. AB - Archived specimens of the scavenging amphipod Eurythenes gryllus, collected from 2075 to 4250 m below the surface on five expeditions to the western and central Arctic Ocean between 1983 and 1998, were analyzed for total mercury (?Hg), methyl mercury (MeHg), polychlorinated biphenyls (PCBs) and other industrial or byproduct organochlorines (chlorobenzenes, pentachloroanisole, octachlorostyrene), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs). Median ?Hg concentrations ranged from 70 to 366 ng g(-1) wet weight (ww). MeHg concentrations (3.55 to 23.5 ng g(-1) ww) accounted for 1.7 to 20.1% (median 3.7%) of ?Hg. ?Hg and MeHg were positively and significantly correlated with ww (?Hg r(2) = 0.18, p = 0.0004, n = 63; MeHg r(2) = 0.42, p = 0.0004, n = 25), but not significantly with delta(13)C nor delta(15)N. Median concentrations of total persistent organic pollutants (POPs) ranged from 9750 to 156,000 ng g(-1) lipid weight, with order of abundance: ?TOX (chlorobornanes quantified as technical toxaphene) > ?PCBs > ?DDTs > ?chlordanes > ?mirex compounds > ?BDEs ~ ?chlorobenzenes ~ octachlorostyrene > alpha hexachlorocyclohexane ~ hexachlorobenzene ~ pentachloroanisole. Enantioselective accumulation was found for the chiral OCPs o,p'-DDT, cis- and trans-chlordane, nonachlor MC6 and oxychlordane. Lipid-normalized POPs concentrations were elevated in amphipods with lipid percentages <=10%, suggesting that utilization of lipids resulted in concentration of POPs in the remaining lipid pool. Multidimensional Scaling (MDS) analysis using log-transformed physiological variables and lipid-normalized organochlorine concentrations distinguished amphipods from the central vs western arctic stations. This distinction was also seen for PCB homologues, whereas profiles of other compound classes were more related to specific stations rather than central-west differences. PMID- 23627491 TI - Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis. AB - The molybdenum cofactor (Moco) is a redox cofactor found in all kingdoms of life, and its biosynthesis is essential for survival of many organisms, including humans. The first step of Moco biosynthesis is a unique transformation of guanosine 5'-triphosphate (GTP) into cyclic pyranopterin monophosphate (cPMP). In bacteria, MoaA and MoaC catalyze this transformation, although the specific functions of these enzymes were not fully understood. Here, we report the first isolation and structural characterization of a product of MoaA. This molecule was isolated under anaerobic conditions from a solution of MoaA incubated with GTP, S adenosyl-L-methionine, and sodium dithionite in the absence of MoaC. Structural characterization by chemical derivatization, MS, and NMR spectroscopy suggested the structure of this molecule to be (8S)-3',8-cyclo-7,8-dihydroguanosine 5' triphosphate (3',8-cH2GTP). The isolated 3',8-cH2GTP was converted to cPMP by MoaC or its human homologue, MOCS1B, with high specificities (Km < 0.060 MUM and 0.79 +/- 0.24 MUM for MoaC and MOCS1B, respectively), suggesting the physiological relevance of 3',8-cH2GTP. These observations, in combination with some mechanistic studies of MoaA, unambiguously demonstrate that MoaA catalyzes a unique radical C-C bond formation reaction and that, in contrast to previous proposals, MoaC plays a major role in the complex rearrangement to generate the pyranopterin ring. PMID- 23627493 TI - Superhydrophobic surfaces as an on-chip microfluidic toolkit for total droplet control. AB - We propose and outline a novel technique designed to utilize the unique surface repulsion present between aqueous droplets and customizable superhydrophobic surfaces for the on-chip spatial and temporal manipulation of droplets within microfluidic architectures. Through the integration of carefully designed and prepatterned superhydrophobic surfaces into polymer microfluidic chipsets, it is possible to take advantage of this enhanced surface repulsion to passively manipulate droplets on the microscale for a wide range of droplet operations, including but not limited to acceleration, deceleration, merging, and path control. This work aims to help fulfill and stimulate development based around current requirements for additional passive analytical manipulation and detection techniques in order to enable a reduction in experimental design complexity with the goal of facilitating and improving portability for Lab-on-a-chip devices. PMID- 23627494 TI - Annihilation limit of a visible-to-UV photon upconversion composition ascertained from transient absorption kinetics. AB - Noncoherent sensitized green-to-near-visible upconversion has been achieved utilizing palladium(II) octaethylporphyrin (PdOEP) as the triplet sensitizer and anthracene as the energy acceptor/annihilator in vacuum degassed toluene. Selective 547 nm excitation of PdOEP with incident irradiance as low as 600 MUW/cm(2) results in the observation of anthryl fluorescence at higher energy. Stern-Volmer analysis of the dynamic phosphorescence quenching of PdOEP by anthracene possesses an extremely large K(SV) of 810,000 M(-1), yielding a triplet-triplet energy transfer quenching constant of 3.3 * 10(9) M(-1) s(-1). Clear evidence for the subsequent triplet-triplet annihilation (TTA) of anthracene was afforded by numerous experiments, one of the most compelling was an excitation scan illustrating that the Q-band absorption features of PdOEP are solely responsible for sensitizing the anti-Stokes fluorescence. The upconverted emission intensity with respect to the excitation power was shown to vary between quadratic and linear using either coherent or noncoherent light sources, illustrating the expected kinetic limits for the light producing photochemistry under continuous wave illumination. Time-resolved experiments directly comparing the total integrated anthracene intensity/time fluorescence data produced through upconversion (lambda(ex) = 547 nm, delayed signal) and with direct excitation (lambda(ex) = 355 nm, prompt signal) under conditions where the laser pulse is completely absorbed by the sample reveal annihilation efficiencies of approximately 40%. Similarly, the delayed fluorescence kinetic analysis reported by Schmidt and co-workers (J. Phys. Chem. Lett. 2010, 1, 1795-1799) was used to reveal the maximum possible efficiency from a model red-to-yellow upconverting composition and this treatment was applied to the anthryl triplet absorption decay transients of anthracene measured for the PdOEP/anthracene composition at 430 nm. From this analysis approximately 50% of the anthryl triplets that decay by TTA produce singlet fluorescence, consistent with the notion that annihilation spin statistics does not impose efficiency limits on upconversion photochemistry. PMID- 23627496 TI - In situ observation of plasmon tuning in a single gold nanoparticle during controlled melting. AB - In this Letter we study the relations among shape, symmetry, and plasmon resonance shift in a single gold nanoparticle during laser melting. A beam of an argon ion laser is focused on a selected particle, while its optical and shape properties can be observed with the help of a combined dark field/photoluminescence microscope and an atomic force microscope, respectively. Starting from a spherical shape, radiation pressure forms the melting gold particle into an upright standing rod on a glass substrate, showing a characteristic dipole scattering pattern. A red-shift of the photoluminescence signal and the scattering spectrum is observed. The melting process can be controlled allowing the formation of different particle heights and plasmon resonance shifts. In situ tuning of the plasmon resonance of individual particles is possible with this reversible melting process. PMID- 23627497 TI - Application of label-free shotgun nUPLC-MS(E) and 2-DE approaches in the study of Botrytis cinerea mycelium. AB - The phytopathogenic fungus Botrytis cinerea infects more than different 200 plant species and causes substantial losses in numerous crops. The B05.10 and T4 wild type strain genomes have been recently sequenced, becoming a model system for necrotrophic pathogens, as well as opening up new alternatives in functional genomics, such as proteomics. We analyzed B. cinerea mycelium from these two wild type strains, introducing label-free shotgun nUPLC-MS(E) methodology to complement the 2-DE-MS-based approach. We assessed the label-free nUPLC-MS(E) methodology for protein identification and quantification using five mycelium protein dilutions. A total of 225 and 170 protein species were identified by nUPLC-MS(E) in the B05.10 and T4 strains, respectively. Moreover, 129 protein species were quantified in both strains. Significant differences in protein abundance were found in 15 more abundant and 16 less abundant protein species in the B05.10 strain compared to the T4 strain. Twenty-nine qualitative and 15 significant quantitative differences were found using 2-DE. The label-free nUPLC MS(E) was a reliable, reproducible and sensitive method for protein identification and quantification to study the B. cinerea mycelial proteome. Results obtained by gel-based and gel-free complementary approaches allow a deeper characterization of this fungus, as well as the identification of potential virulence factors. PMID- 23627495 TI - Translating stem cell therapies: the role of companion animals in regenerative medicine. AB - Veterinarians and veterinary medicine have been integral to the development of stem cell therapies. The contributions of large animal experimental models to the development and refinement of modern hematopoietic stem cell transplantation were noted nearly five decades ago. More recent advances in adult stem cell/regenerative cell therapies continue to expand knowledge of the basic biology and clinical applications of stem cells. A relatively liberal legal and ethical regulation of stem cell research in veterinary medicine has facilitated the development and in some instances clinical translation of a variety of cell based therapies involving hematopoietic stem cells and mesenchymal stem cells, as well as other adult regenerative cells and recently embryonic stem cells and induced pluripotent stem cells. In fact, many of the pioneering developments in these fields of stem cell research have been achieved through collaborations of veterinary and human scientists. This review aims to provide an overview of the contribution of large animal veterinary models in advancing stem cell therapies for both human and clinical veterinary applications. Moreover, in the context of the "One Health Initiative," the role veterinary patients may play in the future evolution of stem cell therapies for both human and animal patients will be explored. PMID- 23627498 TI - The effectiveness of a graphical presentation in addition to a frequency format in the context of familial breast cancer risk communication: a multicenter controlled trial. AB - BACKGROUND: Inadequate understanding of risk among counselees is a common problem in familial cancer clinics. It has been suggested that graphical displays can help counselees understand cancer risks and subsequent decision-making. We evaluated the effects of a graphical presentation in addition to a frequency format on counselees' understanding, psychological well-being, and preventive intentions. DESIGN: Multicenter controlled trial. SETTING: Three familial cancer clinics in the Netherlands. METHODS: PARTICIPANTS: Unaffected women with a breast cancer family history (first-time attendees). INTERVENTION: Immediately after standard genetic counseling, an additional consultation by a trained risk counselor took place where women were presented with their lifetime breast cancer risk in frequency format (X out of 100) (n = 63) or frequency format plus graphical display (10 * 10 human icons) (n = 91). MAIN OUTCOME MEASURES: understanding of risk (risk accuracy, risk perception), psychological well-being, and intentions regarding cancer prevention. Measurements were assessed using questionnaires at baseline, 2-week and 6-month follow-up. RESULTS: Baseline participant characteristics did not differ between the two groups. In both groups there was an increase in women's risk accuracy from baseline to follow-up. No significant differences were found between women who received the frequency format and those who received an additional graphical display in terms of understanding, psychological well-being and intentions regarding cancer prevention. The groups did not differ in their evaluation of the process of counseling. CONCLUSION: Women's personal risk estimation accuracy was generally high at baseline and the results suggest that an additional graphical display does not lead to a significant benefit in terms of increasing understanding of risk, psychological well-being and preventive intentions. TRIAL REGISTRATION: Current Controlled Trials http://ISRCTN14566836. PMID- 23627499 TI - Effect of a peat humic acid on morphogenesis in leaf explants of Pyrus communis and Cydonia oblonga . Metabolomic analysis at an early stage of regeneration. AB - Plant regeneration is a critical step in most in vitro breeding techniques. This paper studies the effects of a low-molecular-weight humic acid (HA) on morphogenesis from pear and quince leaf explants. Variable HA amounts [0 (control), 1, 5, 10, and 20 mg C L(-1)] were added to the regeneration media. A dose-response effect was observed in pear for root and shoot production; it was improved at HA 1 mg C L(-1) and considerably reduced at the highest amounts. HA was, instead, ineffective in quince. The (1)H HR-MAS NMR analyses of calli in the induction phase showed more evident metabolite (asparagine, alanine, and gamma aminobutyric acid) signals in quince than in pear. The assignment of overlapped signals in both genotypes was supported by the 2D NMR analyses. Spectroscopic characterization suggested also an enhancement of asparagine contents in morphogenic calli of pear with respect to the control and higher HA amount treatments. PMID- 23627500 TI - Identification of a novel microRNA (miRNA) from rice that targets an alternatively spliced transcript of the Nramp6 (Natural resistance-associated macrophage protein 6) gene involved in pathogen resistance. AB - Plants have evolved efficient defence mechanisms to defend themselves from pathogen attack. Although many studies have focused on the transcriptional regulation of defence responses, less is known about the involvement of microRNAs (miRNAs) as post-transcriptional regulators of gene expression in plant immunity. This work investigates miRNAs that are regulated by elicitors from the blast fungus Magnaporthe oryzae in rice (Oryza sativa). Small RNA libraries were constructed from rice tissues and subjected to high-throughput sequencing for the identification of elicitor-responsive miRNAs. Target gene expression was examined by microarray analysis. Transgenic lines were used for the analysis of miRNA functioning in disease resistance. Elicitor treatment is accompanied by dynamic alterations in the expression of a significant number of miRNAs, including new members of annotated miRNAs. Novel miRNAs from rice are proposed. We report a new rice miRNA, osa-miR7695, which negatively regulates an alternatively spliced transcript of OsNramp6 (Natural resistance-associated macrophage protein 6). This novel miRNA experienced natural and domestication selection events during evolution, and its overexpression in rice confers pathogen resistance. This study highlights an miRNA-mediated regulation of OsNramp6 in disease resistance, whilst illustrating the existence of a novel regulatory network that integrates miRNA function and mRNA processing in plant immunity. PMID- 23627501 TI - Plant-based foods as a source of lipotropes for human nutrition: a survey of in vivo studies. AB - Increased consumption of plant products is associated with lower chronic disease prevalence. This is attributed to the great diversity of healthy phytochemicals present in these foods. The most investigated physiological effects have been their antioxidant, anti-carcinogenic, hypolipidemic, and hypoglycemic properties. Although less studied in humans, some compounds were very early on shown to be lipotropic in animals, i.e., the capacity to hasten the removal of fat from liver and/or reduce hepatic lipid synthesis or deposits by mainly increasing phospholipid synthesis via the transmethylation pathway for triglyceride-rich lipoprotein exportation from the liver and enhanced fatty acid beta-oxidation and/or down- and up-regulation of genes involved in lipogenic and fatty acid oxidation enzyme synthesis, respectively. The main plant lipotropes are choline, betaine, myo-inositol, methionine, and carnitine. Magnesium, niacin, pantothenate, and folates also indirectly support the overall lipotropic effect. The exhaustive review of rat studies investigating phytochemical effect on hepatic lipid metabolism suggests that some fatty acids, acetic acid, melatonin, phytic acid, some fiber compounds, oligofructose, resistant starch, some phenolic acids, flavonoids, lignans, stilbenes, curcumin, saponins, coumarin, some plant extracts, and some solid foods may be lipotropic. However, this remains to be confirmed in humans, for whom intervention studies are practically non-existent. Supplemental materials are available for this article. Go to the publisher's online edition of Critical Reviews in Food Science and Nutrition(r) to view the free supplemental file. PMID- 23627502 TI - The effects of sucrose on metabolic health: a systematic review of human intervention studies in healthy adults. AB - We systematically reviewed interventions substituting sucrose for other macronutrients in apparently healthy adults to assess impact on cardiometabolic risk indicators. Multiple databases were searched to January 2012 and abstracts assessed by 2 reviewers. Twenty-five studies (29 papers) met inclusion criteria but varied in quality and duration. Weaknesses included small subject numbers, unclear reporting of allocation, unusual dietary regimes, differences in energy intake, fat composition or fibre between conditions, unhealthy subjects, heterogeneity of results, and selective reporting. Insufficient data were available to draw reliable conclusions except with regard to the substitution of sucrose for starch, where effects on plasma lipids were inconsistent, mostly explicable by other factors, or nonsignificant. Based on fewer studies, there was little evidence for significant effects on plasma glucose or insulin. Sucrose substitution for starch up to 25% energy does not appear to have adverse effects on cardiometabolic risk indicators in apparently healthy adults. Furthermore, there is no consistent evidence that restricting sucrose in an isoenergetic diet would affect risk indicators, except perhaps in people with certain preexisting metabolic abnormalities. Larger, high-quality studies, lasting several months and studying a wider range of outcomes, are needed in order to provide evidence on which to base public health initiatives. PMID- 23627503 TI - Bioactive natural constituents from food sources-potential use in hypertension prevention and treatment. AB - Prevention and management of hypertension are the major public health challenges worldwide. Uncontrolled high blood pressure may lead to a shortened life expectancy and a higher morbidity due to a high risk of cardiovascular complications such as coronary heart disease (which leads to heart attack) and stroke, congestive heart failure, heart rhythm irregularities, and kidney failure etc. In recent years, it has been recognized that many dietary constituents may contribute to human cardiovascular health. There has been an increased focus on identifying these natural components of foods, describing their physiological activities and mechanisms of actions. Grain, vegetables, fruits, milk, cheese, meat, chicken, egg, fish, soybean, tea, wine, mushrooms, and lactic acid bacteria are various food sources with potential antihypertensive effects. Their main bioactive constituents include angiotensin I-converting enzyme (ACE) inhibitory peptides, vitamins C and E, flavonoids, flavanols, cathecins, anthocyanins, phenolic acids, polyphenols, tannins, resveratrol, polysaccharides, fiber, saponin, sterols, as well as K, Ca, and P. They may reduce blood pressure by different mechanisms, such as ACE inhibition effect, antioxidant, vasodilatory, opiate-like, Ca(2+) channel blocking, and chymase inhibitory activities. These functional foods may provide new therapeutic applications for hypertension prevention and treatment, and contribute to a healthy cardiovascular population. The present review summarizes the antihypertensive food sources and their bioactive constituents, as well as physiological mechanisms of dietary products, especially focusing on ACE inhibitory activity. PMID- 23627504 TI - Do large intestinal events explain the protective effects of whole grain foods against type 2 diabetes? AB - Consumption of whole grain foods has been associated with decreased risk of type 2 diabetes. Insulin sensitivity and inflammation are key mechanisms in the development of type 2 diabetes, but the cause of the protective effects of whole grains is not known. In this review, we search for evidence to support the hypothesis of a link between whole grains, large intestinal events, and peripheral inflammation. Due to the unique structure and composition of the grain fiber complex, fermentation in the large intestine is probably an important mediator of the effects of whole grains. Fermentation of grain fiber takes place throughout the large intestine affecting beneficially the composition of gut microbiota, hence decreasing the permeability of gut barrier. Improved gut barrier function reduces leaking of endotoxic bacterial lipopolysaccharides (LPS) into the circulation. Lower concentration of LPS in blood seems to alleviate peripheral inflammation. Fermentation of grain fiber also leads to continuous supply and absorption of metabolites such as short chain fatty acids and ferulic acid derivatives which may have anti-inflammatory effects. These phenomena, mainly based on in vitro and animal studies, are associated with fermentation of grain fiber and improve insulin sensitivity, which over time may decrease the risk of type 2 diabetes. To test these mechanisms, more well-designed human studies are needed. PMID- 23627505 TI - Probiotics and its functionally valuable products-a review. AB - During the past two decades probiotic bacteria have been increasingly proposed as health promoting bacteria in variety of food system, because of its safety, functional, and technological characteristics. Commonly, Lactobacillus spp., Bifidobacterium spp., Saccharomyces boulardii, and some other microorganisms have been considered as probiotic strains. Possibly these bacterial strains exerted several beneficial effects into gastrointestinal tract of host while administered with variety of food system. Lactic acid bacteria (LAB) usually produce antimicrobial substances like bacteriocin which have broad spectrum of antagonist effect against closely related Gram positive and Gram negative pathogens. LAB strains often produce polymeric substances such as exopolysaccharides (EPS) which increase the colonization of probiotic bacteria by cell-cell interactions in gastrointestinal tract. LAB also produces biosurfactant which showed that the wide range of antimicrobial activity against bacterial pathogen as well as its antiadhesive properties reduces the adhesion of pathogens into gastric wall membrane. Furthermore, LAB strains have also been reported for production of antioxidants which are ability to scavenge the free radicals such as superoxide anions and hydroxyl radicals. For this sense, this review article is mainly focused on the ecology, biosynthesis, genetics, target sites, and applications of bacteriocins and EPS from LAB strains. Moreover, this review discusses about the production and functions of nutritive essential element folate and iron chelating agent such as siderophores from LAB. PMID- 23627524 TI - Assessing theoretical predictors of long-term medication adherence: patients' treatment-related beliefs, experiential feedback and habit development. AB - Patient non-adherence to medication is a pervasive problem that contributes to poor patient health and high healthcare costs. Basic research and interventions have focused thus far on behaviour initiation factors, such as patients' illness and treatment beliefs. This paper proposes two processes that occur after behaviour initiation that are theorised to contribute to prediction of long-term medication adherence: 'coherence' of patients' beliefs from experiences with treatment and habit development. Seventy-one hypertensive patients reported their treatment-related beliefs, experiences related to treatment efficacy and medication-taking habit strength in a baseline interview. Patients then used an electronic monitoring pill bottle for approximately one month. Patients' medication habit-strength was the strongest predictor of all adherence measures, explaining 6-27% incremental variance in adherence to that explained by patients' treatment-related beliefs. Patients' beliefs and experiences did not predict overall adherence, even for patients with 'weaker' habits. However, patients' experiences were found to predict intentional non-adherence and habit strength was found to predict unintentional adherence. Practitioners may assess patients' medication-taking habits to get an initial view of their likely adherence to long term medications. Future research should assess the current theoretical predictions in a hypertension inception sample and in populations with symptomatic conditions. PMID- 23627525 TI - In-training assessment developments in postgraduate education in Europe. AB - AIM: This paper reviews changes that are underway in postgraduate medical education in various European countries. Training in the workplace is a very effective way of learning, but it has many imperfections. Changes in in-training assessment are proposed to remedy some of these. ASSESSMENT TOOLS: The focus is on a set of assessment tools for performance in authentic work-based contexts. These tools include direct performance measures of single clinical events (mini Clinical Evaluation Exercise, Direct Observation of Practical Skills, Objective Structured Assessment of Technical Skills, Case-based Discussion, Mini-Peer Assessment Tool) and performance measures over a period of time (Multi-Source Feedback), based on judgement by one or more knowledgeable assessors (supervisor, other healthcare professional, patient, trainee himself/herself). Quantitative and qualitative information from single assessments is first and foremost used to promote learning, but also aggregated across a large sample of contexts and assessors in order to obtain an overall picture of a trainee's progress. Aggregating instruments, such as the portfolio, can be used to collect, support and assess outcomes in terms of competencies achieved. We will describe this set of instruments and provide theoretical background as well as our own practical experiences. DISCUSSION: A central message is that the utility of assessment methods lies very much in the (understanding of) the users. Therefore, our concern is more with the actual implementation of change than with the assessment technology per se. If we fail in our efforts to implement real change, postgraduate education may be at risk for bureaucratization and trivialization. We nevertheless are excited to see change happening in the right direction, but remain patient, not expecting very quick wins. PMID- 23627526 TI - Experimental and theoretical comparison of gas desorption energies on metallic and semiconducting single-walled carbon nanotubes. AB - Single-walled carbon nanotubes (SWNTs) exhibit high surface areas and precisely defined pores, making them potentially useful materials for gas adsorption and purification. A thorough understanding of the interactions between adsorbates and SWNTs is therefore critical to predicting adsorption isotherms and selectivities. Metallic (M-) and semiconducting (S-) SWNTs have extremely different polarizabilities that might be expected to significantly affect the adsorption energies of molecules. We experimentally and theoretically show that this expectation is contradicted, for both a long chain molecule (n-heptane) and atoms (Ar, Kr, and Xe). Temperature-programmed desorption experiments are combined with van der Waals corrected density functional theory, examining adsorption on interior and exterior sites of the SWNTs. Our calculations show a clear dependence of the adsorption energy on nanotube diameter but not on whether the tubes are conducting or insulating. We find no significant experimental or theoretical difference in adsorption energies for molecules adsorbed on M- and S SWNTs having the same diameter. Hence, we conclude that the differences in polarizabilities between M- and S-SWNTs have a negligible influence on gas adsorption for spherical molecules as well as for highly anisotropic molecules such as n-heptane. We expect this conclusion to apply to all types of adsorbed molecules where van der Waals interactions govern the molecular interaction with the SWNT. PMID- 23627527 TI - An evaluation of non-Luer safety connectors for neuraxial procedures. AB - We evaluated seven non-Luer spinal needles in a two-part study. In part 1, we measured the time to see and collect simulated cerebrospinal fluid. In part 2, clinicians scored needle quality using a standardised questionnaire. The mean (SD) times to see cerebrospinal fluid varied in the lateral position from 4.2 (0.3) s (Vygon) to 25.2 (1.5) s (Sarstedt), and in the sitting position from 1.7 (0.2) s (BBraun) to 6.6 (0.3) s (Sarstedt). The time to collect cerebrospinal fluid varied from 43 (2.5) s (Vygon) to 139 (9.6) s (Pajunk) and from 19 (0.4) s (BBraun) to 34 (1.7) s (Pajunk), for the lateral and sitting positions, respectively. Median (IQR [range]) satisfaction scores in 205 needle function assessments were as follows: Sarstedt 9.0 (8.0-9.3 [5.0-10.0]); BD 8.0 (7.0-9.5 [3.0-10.0]); Pajunk 9.0 (8.0-9.8 [5.0-10.0]); Neurax 8.0 (7.0-9.0 [2.0-9.0]); Smiths 8.0 (7.0-9.0 [4.0-10.0]); Vygon 8.0 (7.5-9.0 [5.0-10.0]); and BBraun 9.0 (9.0-10.0 [7.0-10.0]). The difference in satisfaction scores between the BBraun and Neurax was significant (p < 0.01). A number of recurrent problems were found during the evaluation. The variation in time to collect cerebrospinal fluid samples may have implications for non-anaesthetic practice. This evaluation provides a baseline to assist others in commencing their procurement process. PMID- 23627528 TI - The influence of orthokeratology on intraocular pressure measurements. AB - PURPOSE: Underestimation of IOP in a myopic patient may lead to misjudgment of the risk of glaucoma. This study investigated the influence of orthokeratology induced change in CCT on IOP measured by the non-contact pneumotonometer (NCT), Goldmann applanation tonometer (GAT), and Pascal dynamic contour tonometer (PDCT). METHODS: This study was conducted to examine the eyes of 34 patients who received orthokeratology for myopia. CCT and IOP were measured, and IOP was obtained with the NCT, GAT, and PDCT. The associations between changes in measured IOP and change in CCT at different orthokeratology follow-up time points were evaluated by linear regression analysis. RESULTS: Change in IOP measured by the three tonometries correlated significantly with change in CCT after one-week application of orthokeratology. The correlation was strongest for NCT followed by GAT and PDCT. The changes in measured IOP corresponding to a 10 MUm decrease in CCT were 0.7-0.9, 0.4-0.6, and 0.2-0.3 mm Hg for NCT, GAT, and PDCT, respectively. CONCLUSIONS: The IOP measured by the three methods--NCT, GAT, and PDCT--decreased as a result of the change in CCT induced by orthokeratology. The influence on NCT and GAT was greater than that on PDCT. PMID- 23627529 TI - Validation of the EUMASS Core Set for medical evaluation of work disability. AB - OBJECTIVE: To perform a content validation of the EUMASS Core Set across six European social insurance systems. The EUMASS Core Set contains 20 categories to describe the functional (in-) capacity of claimants for disability benefits. METHODS: We performed an exploratory, cross-sectional study. We used the EUMASS Core Set, added scales to rate the relevance of the 20 categories and added additional questions concerning comprehensiveness, usefulness and sufficiency of the instrument. Medical examiners from European countries filled in this instrument in 10 consecutive claim assessments. RESULTS: Forty-eight medical examiners in six different countries evaluated 446 claimants. The medical examiners used all categories to describe the claimants' functional (in-) capacity. Medical examiners missed 41 different categories, often mental functions (n = 17). They rated the instrument as useful in 68.4% and as sufficient in 63.2% of the claims. Perceived usefulness varied among countries, but not among disease groups. Perceived sufficiency varied among countries and disease groups. CONCLUSION: The EUMASS Core Set is promising for reporting about functional (in-) capacities. It contains relevant categories for disability evaluation among countries and disease groups. Adding more mental functions might make it more applicable. Medical examiners found it useful and sufficient to evaluate functional (in-) capacity. Implications for Rehabilitation In medical reports of evaluation of work disability, reporting about functional capacity is often unstructured in free text, making the reports difficult to understand. The EUMASS Core Set contains common definitions for expressing functional capacity and is expected to support taking decisions, to improve the quality of decisions and to allow national and international comparisons. Our study suggests the EUMASS core set to be comprehensive, useful and sufficient to express functional capacity in disability evaluation. PMID- 23627530 TI - Psychometric validation of the authorized Polish version of the Neck Disability Index. AB - PURPOSE: Psychometric validation of the authorized Polish version of the Neck Disability Index (NDI). METHODS: Ninety-five patients with neck pain were enrolled. Reliability was assessed through Cronbach's alpha, split-half reliability, intra-class correlation (ICC) and agreement between measures with limits of agreement using the interval of 48 hours. Validity was determined by the Pearson correlation of the NDI with VAS. Responsiveness included mainly Pearson correlations of score changes on the NDI with the Global rating of change (GRC) scale. Minimal detectable change (MDC) and factor analysis were performed. The cut-point for the change, with its sensitivity and specificity, and the area under the curve were determined with the receiver operating characteristic (ROC) curve analysis. RESULTS: Cronbach's alpha and split-half reliability were satisfactory. The ICC was 0.99. Bland and Altman analysis indicated an acceptable agreement between the measures. The correlation between the NDI and VAS was 0.55. Responsiveness estimated by the correlations between change scores of the NDI and GRC was -0.73 and -0.56. The MDC was 5.96. Factor analyses demonstrated a two factor structure. The cut-point for detecting a change was 6.5. The sensitivity was 90% and specificity was 81%. CONCLUSIONS: The Polish version of the NDI showed good psychometric properties. It can be used both in clinical and research practice. Implications for Rehabilitation The Polish version of the NDI, developed by MAPI Research Institute, was researched on a sample of 95 patients with neck pain. The psychometric properties of the adapted version of the NDI were satisfactory. The Polish version of the NDI proved to be useful in clinical practice as well as in research. PMID- 23627531 TI - Psychometric evidence of self-reported questionnaires for patellofemoral pain syndrome: a systematic review. AB - PURPOSE: To conduct a systematic review of psychometric properties of self reported questionnaires used to assess the level of symptoms and disability in individuals with patellofemoral pain syndrome (PFPS). METHODS: A structured search was conducted in four databases (Medline, Embase, CINAHL, SportDiscus). A total of 24 studies about five different self-reported questionnaires were analyzed. A pair of independent raters extracted data on validity, reliability and responsiveness to change, and performed critical appraisal (0-100%). RESULTS: Activities of Daily Living Scale (ADLS), Anterior Knee Pain Scale (AKPS), International Knee Documentation Committee (IKDC) and Lysholm Scale (LS) present excellent test-retest reliability (weighted average intraclass correlation coefficients [ICC] > 0.80), whereas Functional Index Questionnaire (FIQ) is moderately reliable (ICC = 0.61). Minimal detectable change is 8.3% for ADLS, 9.0% for AKPS, 19% for FIQ, 8.5% for IKDC and 30% for LS. ADLS, AKPS, IKDC and LS are highly responsive (effect size/standardized response mean >0.95) in individuals with PFPS, while FIQ is lowly responsive (effect size = 0.49). CONCLUSION: Based on available evidence, ADLS presents the best psychometric properties and should be preferred when evaluating patients with PFPS. AKPS and IKDC are also adequate, while FIQ and LS are not recommended for individuals with PFPS. IMPLICATIONS FOR REHABILITATION: While several questionnaires have been developed to assess symptoms and functional limitations caused by knee pain, their psychometric properties can vary depending on the condition presented by the patient. The Activities of Daily Living Scale of the Knee Outcome Survey should be preferred by clinicians when evaluating a patient with PFPS. The Anterior Knee Pain Scale and International Knee Documentation Committee Subjective knee evaluation are also adequate for use with this population. The Functional Index Questionnaire and Lysholm Scale are not recommended for PFPS. PMID- 23627532 TI - Subjective experiences of transient ischaemic attack: a repertory grid approach. AB - PURPOSE: Research on the psychosocial reactions to stroke has been used to inform rehabilitation programmes. Yet much less research has been conducted into experiences of, and reactions to, transient ischaemic attack (TIA), despite its link with secondary stroke. This study aimed to investigate the subjective psychological experiences of TIA. METHOD: Repertory grid technique was used because of its capacity to make individual implicit experiences explicit. Using the standard repertory grid protocol, 12 post-TIA patients were asked to consider how five everyday activities had been affected by TIA. Each participant generated six constructs or personal perspectives, which were analysed using proprietary (RepGrid IV) software. RESULTS: Despite the individualised nature of the responses, six themes emerged from the constructs. These included deep-seated anxiety about future uncertainties/disruption to normality, loss of confidence, frustration, TIA as a wake-up call, a sense of loss and sadness, and embarrassment. IMPLICATIONS FOR REHABILITATION: Research has shown that the patient's subjective experience and perspective are important to the rehabilitation process post-stroke. Relatively little research has been conducted into the subjective experiences of TIA patients. This study has revealed a range of subjective reactions to TIA, which could be used to inform individualised post TIA management, adaptation and rehabilitation. PMID- 23627533 TI - Personal experience of osteoarthritis and pain questionnaires: mapping items to themes. AB - PURPOSE: The aim of this study was to examine the correspondence between qualitative and quantitative methods of coding experience of pain reported by participants with osteoarthritis (OA) of the knee. METHODS: A mapping grid was produced to record the correspondence between subthemes that emerged from thematic analysis of interviews with 24 participants with knee OA, and from questionnaire items which were used in a study of 192 knee OA participants. Items were rated according to their degree of correspondence between subthemes and questionnaire items, and an overall correspondence score was produced for each subtheme and questionnaire measure. RESULTS: The subthemes that corresponded well with the questionnaire items were those that related to socio-emotional functioning, the overall experience of pain and the impact of pain on physical functioning. The questionnaire items did not relate to participants' knowledge about their condition and their experience of the medical system. CONCLUSIONS: The study indicated that many aspects of pain experience reported by patients in qualitative interviews are also assessed by commonly used questionnaire outcome measures for people with pain. However, although participants reported that knowledge about their condition and their experience of the medical system were important aspects of the overall pain experience, these are rarely used as outcome measures. Questionnaires that address these additional aspects of the pain experience could be useful to further evaluate the experience of pain and may help to address important concerns raised by patients with OA of the knee. PMID- 23627534 TI - An enriched environment increases activity in stroke patients undergoing rehabilitation in a mixed rehabilitation unit: a pilot non-randomized controlled trial. AB - PURPOSE: An enriched environment (EE) facilitates physical, cognitive and social activity in animal models of stroke. The aim of this pilot study was to determine whether enriching the environment of a mixed rehabilitation unit increased stroke patient activity. METHODS: A non- randomized controlled trial was conducted. Direct observation was used to determine the difference in change in physical, cognitive, social or any activity over 2 weeks in patients exposed to an enriched versus non-enriched environment. RESULTS: Stroke patients in the EE (n = 15) were 1.2 (95% CI 1.0-1.4) times more likely to be engaged in any activity compared with those in a non-enriched environment (n = 14). They were 1.7 (95% CI 1.1-2.5) times more likely to be engaged in cognitive activities, 1.2 (95% CI 1.0-1.5) times more likely to be engaged in social activities, 0.7 (95% CI 0.6-0.9) times as likely to be inactive and alone and 0.5 (95% CI 0.4-0.7) times as likely to be asleep than patients without enrichment. CONCLUSIONS: This preliminary trial suggests that the comprehensive model of enrichment developed for use in a rehabilitation unit was effective in increasing activity in stroke patients and reducing time spent inactive and alone. PMID- 23627535 TI - Predictors of needs for families of children with cerebral palsy. AB - BACKGROUND: This study examined child, family and service characteristics that are predictors of family needs for community, financial, family support and services needs for families of children with cerebral palsy (CP). CP is a non progressive neurological condition caused by lesions in the central nervous system resulting in limitations in motor function and associated co-morbid conditions. Children with CP often require multiple health, rehabilitation, and community services. PURPOSE: To identify risk and protective factors among predictors of needed resources and services (i.e. community, financial, family support) and to discuss implications for coordination of medical, rehabilitation, and community services for children with CP and their families. METHODS: Secondary data analysis was conducted with a national dataset (n = 441) of mothers of children with CP. The average age of children was 10.7 years (SD = 4.5) and was distributed across the various Gross Motor Function Classification System levels. Four logistic regression models were conducted to examine predictive power of child, family and current service characteristics on needed resources and services. RESULTS: Limited child gross motor function was a risk factor (odds ratio (OR): 1.30-1.70) while perception of family-centered services (FCS) was a protective factor (OR: 0.57-0.63) in having the needs met. CONCLUSION: Mothers of children with CP who are able to walk, reported strong family relationships, and perceived need-oriented and FCS expressed less needs for community, financial, family support and services' resources needs. Implications for service providers are provided. PMID- 23627536 TI - Impact of a film portrayal of a police officer with spinal cord injury on attitudes towards disability: a media effects experiment. AB - PURPOSE: The portrayal of disabled people in the media can influence the public's perception of disability in both positive and negative ways. In this article, an experimental before and after design is used to determine the effects of a short film on the attitudes of non-disabled and disabled persons concerning employment and productivity of persons with disabilities. METHOD: Three questions were posed to 480 study participants prior to and following a short film featuring a police officer with paraplegia. Linear mixed models were used to assess the effects of time point and disability status on the responses. RESULTS: The non-disabled participants' ratings of eligibility for employment of a paraplegic man and estimates of the employment rate of disabled people were significantly enhanced following the film. Nevertheless, the film had no significant effects on the ratings given by participants with disabilities in terms of eligibility, employment rate or productivity. CONCLUSIONS: This investigation highlights the potentially important influence of media portrayal and coverage of people with disabilities on attitudes of the public concerning disability. IMPLICATIONS FOR REHABILITATION: Restrictions in participation may result from an interaction of persons with impairments with an environment that is dominated by negative attitudes towards disability The portrayal of disabled people in the media can influence the public's attitudes towards disability in both positive and negative ways In this experimental study, attitudes of the general public were significantly improved following viewing a short film featuring a positive media portrayal of a police officer with paraplegia. PMID- 23627537 TI - Self-reported use of the upper limbs related to clinical tests in persons with multiple sclerosis. AB - PURPOSE: This study investigated the relationship between self-reported use of the upper limbs and clinical tests in persons with multiple sclerosis (pwMS). METHODS: This cross-sectional study involved 25 pwMS with upper limb dysfunction. The Motor Activity Log (MAL) was bilaterally applied to investigate the self reported use of both upper limbs. Clinical tests on function level were the Motricity Index (MI) and the Brunnstrom-Fugl-Meyer (BFM). On activity level, the Action Research Arm test (ARAt) was conducted. To identify the relationship between the self-reported use and the clinical tests, Spearman correlation coefficients were calculated. Subgroups of dominant and non-dominant arms were differentiated, and compared with the Wilcoxon Signed rank test. RESULTS: The highest correlations were found between the MAL and function level tests: MI (r = 0.83, p < 0.01) and BFM (r = 0.75, p < 0.01). A lower correlation was found between the MAL and the ARAt (r = 0.49, p < 0.01). For all outcome measures, the absolute scores were higher for the dominant hand. Higher correlations were found for the non-dominant compared to the dominant hand. CONCLUSION: The self-reported use of the upper limbs was highly associated with measures on function level. The association with activity level was, however, less pronounced. Magnitudes of relationships were influenced by hand dominance. Implications for Rehabilitation Self-reported use of the upper limbs in persons with MS, measured by the MAL, is highly associated with muscle strength and movement control. The ARAt (activity level of the ICF) is less associated with self-reported use compared to outcome measures at function level. The ARAt seems to be less sensitive to mild arm dysfunction. This study indicates that it is feasible and clinically relevant to apply the MAL as a self-reported outcome measure of upper limb use in MS. PMID- 23627538 TI - A comparison of two-coloured filter systems for treating visual reading difficulties. AB - PURPOSE: Visual disturbances that make it difficult to read text are often termed "visual stress". Coloured filters in spectacles may help some children overcome reading problems that are often caused by visual stress. It has been suggested that for optimal effect each child requires an individually prescribed colour for each eye, as determined in systems such as the "Harris Foundation" coloured filters. Alternatively, it has been argued that only blue or yellow filters, as used in the "Dyslexia Research Trust" (DRT) filter system, are necessary to affect the underlying physiology. METHOD: A randomised, double blind trial with 73 delayed readers, was undertaken to compare changes in reading and spelling as well as irregular and non-word reading skills after 3 months of wearing either the Harris or the DRT filters. RESULTS: Reading improved significantly after wearing either type of filter (t = -8.4, p < 0.01), with 40% of the children improving their reading age by 6 months or more during the 3 month trial. However, spelling ability (t = 2.1, p = 0.05) and non-word reading (f = 4.7, p < 0.05) improved significantly more with the DRT than with the Harris filters. CONCLUSION: Education and rehabilitation professionals should therefore, consider coloured filters as an effective intervention for delayed readers experiencing visual stress. IMPLICATIONS FOR REHABILITATION: Any disability that impacts on a child's capacity to read has serious implications for academic development as well as the ability to participate independently in activities of daily living. One reading disability, generally termed "visual stress", is related to visual disturbances that make it difficult to read text. This research demonstrates the beneficial use of coloured filters for promoting visual reading capacity for children with visual stress. Professionals who are involved in the needs of children with reading delay, may like to consider the benefits that coloured filters can afford children with visual reading problems. PMID- 23627539 TI - Continuity in care trajectories of older chronically ill patients in a battlefield of competing rationales. AB - BACKGROUND: Continuity is crucial when caring for older chronically ill patients. Research has shown that the integration of patients' own perspectives on their situation is of utmost importance for continuity and quality of care. Studies have, however, demonstrated a number of problems with health professionals' communication concerning older patients, leading to lack of continuity and integration of the patient perspective in care and treatment. In spite of these problems being well investigated, they continue to prevail. OBJECTIVES: To examine conditions for continuity and integration of the patient perspective in older, chronically ill patients' care as reflected in nursing staff's communication about the patients. DESIGN: Explorative Participatory Action Research (PAR). SETTING: An acute, general medical ward at a Danish university hospital. PARTICIPANTS: Hospital and municipality nurses (n = 29). Nursing records (n = 12). METHOD: Field studies: observations, interviews, nursing records audits and logs. Data were subject to manifest and latent content analysis. RESULTS: Participants were aware of the importance of ensuring continuity, a comprehensive approach and integration of the patient perspective in care trajectories of older, chronically ill patients. Although they adhered to these ideals, they rarely pursued them in practice. Hindering factors were: organisational values, episodic focus on patients and lack of time. They felt caught in a value conflict between nursing professional values and system values, which caused a feeling of powerlessness, maintaining status quo in their clinical practice. CONCLUSION: The prevailing episodic focus and the competing rationales on the ward constituted a barrier to continuity and integration of the patient perspective in a comprehensive way. PMID- 23627540 TI - Imiquimod 5% cream versus timolol 0.5% ophthalmic solution for treating superficial proliferating infantile haemangiomas: a retrospective study. AB - BACKGROUND: Infantile haemangiomas (IHs) are the most common vascular tumours of infancy. Topical therapies are a possible treatment for superficial IHs. AIM: To determine the efficacy and safety of topical therapy in the treatment of superficial proliferating IHs. METHODS: The medical records of all the patients with proliferating superficial IHs were reviewed. All lesions had been treated either with imiquimod 5% cream or timolol 0.5% ophthalmic solution. Lesions were classified into pairs, with one of each treatment in each pair, matched by anatomical location, colour and size. A visual analogue scale (VAS) and the Haemangioma Activity Score (HAS) were used to evaluate the efficacy of the two drugs. The paired Student t-test was used to test for differences in recovery with these two treatments. RESULTS: In total, 51 patients treated with timolol and 94 treated with imiquimod met the inclusion criteria, and 20 lesions treated with timolol were successfully matched to a lesion treated with imiquimod. The paired t-test indicated that there was no significant difference in either VAS score (P = 0.11) or HAS (P = 0.49). For the imiquimod-treated patients, crusting was the most common reaction (65.0%, 13/20). This did not cause any superficial scarring or skin pigmentation in the matched pairs; however, superficial scars (14.9%, 14/94) and skin pigmentation disorders (28.7%, 27/94) were reported for some of the unmatched cases. There were no adverse events (AEs) during the treatment with timolol. CONCLUSIONS: Both imiquimod 5% cream or timolol 0.5% ophthalmic solution showed equivalent clinical efficacy after 4 months of treatment. Timolol appeared to have fewer AEs than imiquimod in the management of superficial IHs. Larger, prospective controlled trials with long-term treatment are needed to confirm these results. PMID- 23627541 TI - Rabbit antithymocyte globulin treatment in childhood acquired severe aplastic anemia. AB - Acquired severe aplastic anemia (SAA) is a life threatening bone marrow failure characterized by pancytopenia and hypocellular bone marrow. Matched sibling donor is not available for majority of the patients and many children receive immunosuppressive therapy (IST). Although horse antithymocyte globuline (ATG) is the preferred option, our patients received rabbit ATG; since horse ATG is not available in Turkey. We reviewed the medical records of children with SAA who were treated with rabbit ATG, cyclosporine, and granulocyte colony stimulating factor (GCSF) between 2006 and 2012. Fifteen children with SAA aged between 1.5 and 17 years received rabbit ATG as first line treatment. Only two of them showed partial response and the others did not give any response at 3rd, 6th, and 12th months after the first course of IST. The second course of ATG was given to 8 of the patients; Rabbit ATG at the same dosage was used for 3 of them, and others were given horse ATG. None of the patients responded to the second course of ATG. Invasive fungal infection (IFI) which was seen in 80% of the patients was the most significant problem. Overall survival rate was 60%. The median time between the diagnosis and initiation of IST was 57 (range; 29-144) days. This delay might be significantly contributed to unresponsiveness. In our series, the use of rabbit ATG was not effective for these patients as first line treatment modality. Response rate was very low and the incidence of fungal infections was very high in the SAA patients who received rabbit ATG. PMID- 23627542 TI - Can selenium levels act as a marker of colorectal cancer risk? AB - BACKGROUND: Selenium has attracted attention because of its antioxidant properties. Antioxidants protects cells from damage. Certain breakdown products of selenium are believed to prevent tumor growth by enhancing the immune cell activity and suppressing the development of tumor blood vessels. In this observational study, selenium level was measured in a series of patients from Poland and Estonia to determine a correlation between levels of this microelement and colorectal cancer risk. METHODS: A total of 169 colorectal cancer patients and 169 healthy controls were enrolled in the study after obtaining their informed consent. Selenium level in the blood serum was measured using Graphite Furnace Atomic Absorption Spectrometry (GFAAS). The statistical analysis was performed by Fisher's exact test. RESULTS: The threshold point of selenium level was 55 MUg/l and 65 MUg/l for Poland and Estonia respectively, for an increase in cancer risk. The lower levels of selenium were associated with greater risk of colorectal cancer. CONCLUSIONS: The result reveals a significant strong association between low selenium level and the colorectal cancer risk in both Estonian and Polish populations. PMID- 23627543 TI - Comparison of the in vitro and in vivo metabolism of Cladribine (Leustatin, Movectro) in animals and human. AB - New insight into the in vitro and in vivo metabolism of Cladribine (2-chloro-2' deoxyadenosine, [2-CdA]) are presented. Following incubation of [(14)C]-2-CdA in mouse, rat, rabbit, dog, monkey and human hepatocyte cultures, variable turnover was observed with oxidations and direct glucuronidation pathways. The oxidative cleavage to 2-chloroadenine (2-CA, M1) was only observed in rabbit and rat. Following incubation of [(14)C]-2-CdA in whole blood from mouse, monkey and human, a significant turnover was observed. The main metabolites in monkey and human were 2-chlorodeoxyinosine (M11, 16% of total radioactivity) and 2 chlorodeoxyinosine (M12, 43%). In mouse, 2-CA was the major metabolite (2-CA; M1, 73%). After single intravenous and oral administration of [(14)C]-2-CdA to mice, 2-chlorodeoxyinosine (M11) was confirmed in plasma, while 2-chlorohypoxanthine (M12) and 2-CA (M1) were found in urine. Overall, the use of [(14)C]-2-CdA both in vitro (incubations in mouse, monkey and human whole blood) and in vivo (mouse) has confirmed the existence of an additional metabolism pathway leading to the formation of 2-chlorodeoxyinosine (M11) and 2-chlorohypoxanthine (M12). Formation of these two metabolites demonstrates that Cladribine as free form is not fully resistant to adenosine deaminase as suggested earlier, an enzyme involved in its mode of action. PMID- 23627544 TI - Exploiting peptide nanostructures to construct functional artificial ion channels. AB - Natural ion channel proteins possess remarkable properties that researchers could exploit to develop nanochemotherapeutics and diagnostic devices. Unfortunately, the poor stability, limited availability, and complexity of these structures have precluded their use in practical devices. One solution to these limitations is to develop simpler molecular systems through chemical synthesis that mimic the salient properties of artificial ion channels. Inspired by natural channel proteins, our group has developed a family of peptide nanostructures thatcreate channels for ions by aligning crown ethers on top of each other when they adopt an alpha-helical conformation. Advantages to this crown ether/peptide framework approach include the ease of synthesis, the predictability of their conformations, and the ability to fine-tune and engineer their properties. We have synthesized these structures using solid phase methods from artificial crown ether amino acids made from L-DOPA. Circular dichroism and FTIR spectroscopy studies in different media confirmed that the nanostructures adopt the predicted alpha-helical conformation. Fluorescence studies verified the crown ether stacking arrangement. We confirmed the channel activity by single-channel measurements using a modified patch-clamp technique, planar lipid bilayer (PLB) assays, and various vesicle experiments. From the results, we estimate that a 6 A distance between two relays is ideal for sodium cation transport, but relatively efficient ion transport can still occur with an 11 A distance between two crown ethers. Biophysical studies demonstrated that peptide channels operate as monomers in an equilibrium between adsorption at the surface and an active, transmembrane orientation. Toward practical applications of these systems, we have prepared channel analogs that bear a biotin moiety, and we have used them as nanotransducers successfully to detect avidin. Analogs of channel peptide nanostructures showed cytotoxicity against breast and leukemia cancer cells. Overall, we have prepared well-defined nanostructures with designed properties, demonstrated their transport abilities, and described their mechanism of action. We have also illustrated the advantages and the versatility of polypeptides for the construction of functional nanoscale artificial ion channels. PMID- 23627545 TI - Multidrug-resistant organisms in dialysis patients. AB - Multidrug-resistant organisms (MDROs) have emerged as important causes of healthcare-associated infections (HAIs), and these infections are associated with significant morbidity and mortality. Dialysis patients have been particularly affected by these pathogens, with colonization and infection rates often exceeding those seen in persons with other types of healthcare exposure. The infection control practices that are currently recommended for use in dialysis facilities and other healthcare settings have the potential to eliminate, or at least substantially reduce transmission of and infection with MDROs. Unfortunately, recent data suggest that these recommended practices are not consistently implemented. Additional efforts and research are needed to increase healthcare workers' awareness of and adherence to infection prevention measures, to develop new and more effective prevention strategies, and to determine cost effective approaches to MDRO prevention to optimize the safety and quality of care provided to dialysis patients. PMID- 23627546 TI - Severe vitamin D deficiency is associated with non-tuberculous mycobacterial lung disease: a case-control study. AB - BACKGROUND AND OBJECTIVE: Previous studies have found evidence of an association between tuberculosis and vitamin D deficiency (VDD). However, the association between VDD and infection caused by non-tuberculous mycobacteria (NTM) has never been studied. This study evaluated the prevalence and severity of VDD in NTM lung disease and attempted to identify predictive factors. METHODS: Age- and sex matched case-control study was conducted to assess the prevalence and severity of VDD in patients with NTM lung disease. RESULTS: After adjusting for potential confounding factors, the adjusted mean serum level of 25-hydroxyvitamin D (25(OH)D) levels was lower in 104 patients with NTM lung disease (10.7 ng/mL, 95% confidence interval (CI) 4.5-16.8 ng/mL) than that of 312 controls (13.7 ng/mL, 95% CI 7.4-19.5 ng/mL) (P = 0.012). Although the prevalence of VDD defined as serum 25(OH)D level <20 ng/mL was not different, severe VDD defined as serum 25(OH)D level <10 ng/mL was more prevalent in patients (P < 0.001). In multivariate analysis, severe (but not mild) VDD was independently associated with NTM lung disease (adjusted odds ratio 3.9, 95% CI 1.9-8.5, P < 0.001). CONCLUSIONS: Patients with NTM lung disease have a high prevalence of severe VDD and VDD was independently associated with NTM lung disease. Further studies are needed to examine causality. PMID- 23627547 TI - Valence-bond determination of diradical character of polycyclic aromatic hydrocarbons: from acenes to rectangular benzenoids. AB - The number of Kekule resonance structures in a conjugated hydrocarbon is a measure of its singlet ground state, and its number of Dewar resonance structures is a measure of the triplet contribution to its ground state. We present a 2 dimensional organized study of rectangular benzenoids having both armchair and zigzag edges that play an important role in the electronic properties of nanographene patches and strips. Analytical expressions for the number of Dewar resonance structures (DS) for select series of rectangular benzenoid hydrocarbons are presented for the first time. An index of biradical character present (BRC) in polycyclic aromatic hydrocarbons is defined and illustrated. Biradical character is strongly influenced by zigzag edges and the presence of a diradical excised internal structure in polycyclic aromatic hydrocarbons. PMID- 23627548 TI - Siah2-deficient mice show impaired skin wound repair. AB - Hypoxia is associated with the dermal wound healing process and hypoxia signaling is presumed to be crucial for normal wound repair. The Siah2 ubiquitin ligase controls the abundance of hypoxia-inducible factor-1 alpha, and loss of Siah2 results in destabilization of hypoxia-inducible factor-1 alpha under hypoxia. Utilizing Siah2(-/-) mice we demonstrate that cutaneous wound healing is impaired in these mice. Wounds in Siah2(-/-) mice heal slower and are associated with delayed induction of myofibroblast infiltration and reduced collagen deposition. This coincides with delayed angiogenesis and reduced macrophage infiltration into the wounds of Siah2(-/-) mice. We furthermore demonstrate that primary Siah2(-/-) dermal fibroblasts have reduced migratory capacities and produce less collagen than wild-type fibroblasts. Additionally, Siah2(-/-) fibroblasts showed conserved responses to transforming growth factor-beta at the receptor level (pSmad 2C activation) but reduced responses downstream. Together, our data show, for the first time, that Siah2 is involved as a positive regulator in the wound healing response. Understanding the role of hypoxia signaling in tissue repair and fibrosis and interference with the hypoxia signaling pathway via regulation of Siah2 may provide new targets for clinical regulation of fibrosis and scarring. PMID- 23627549 TI - Effects of ethanol on vehicle energy efficiency and implications on ethanol life cycle greenhouse gas analysis. AB - Bioethanol is the world's largest-produced alternative to petroleum-derived transportation fuels due to its compatibility within existing spark-ignition engines and its relatively mature production technology. Despite its success, questions remain over the greenhouse gas (GHG) implications of fuel ethanol use with many studies showing significant impacts of differences in land use, feedstock, and refinery operation. While most efforts to quantify life-cycle GHG impacts have focused on the production stage, a few recent studies have acknowledged the effect of ethanol on engine performance and incorporated these effects into the fuel life cycle. These studies have broadly asserted that vehicle efficiency increases with ethanol use to justify reducing the GHG impact of ethanol. These results seem to conflict with the general notion that ethanol decreases the fuel efficiency (or increases the fuel consumption) of vehicles due to the lower volumetric energy content of ethanol when compared to gasoline. Here we argue that due to the increased emphasis on alternative fuels with drastically differing energy densities, vehicle efficiency should be evaluated based on energy rather than volume. When done so, we show that efficiency of existing vehicles can be affected by ethanol content, but these impacts can serve to have both positive and negative effects and are highly uncertain (ranging from -15% to +24%). As a result, uncertainties in the net GHG effect of ethanol, particularly when used in a low-level blend with gasoline, are considerably larger than previously estimated (standard deviations increase by >10% and >200% when used in high and low blends, respectively). Technical options exist to improve vehicle efficiency through smarter use of ethanol though changes to the vehicle fleets and fuel infrastructure would be required. Future biofuel policies should promote synergies between the vehicle and fuel industries in order to maximize the society-wise benefits or minimize the risks of adverse impacts of ethanol. PMID- 23627551 TI - Justification and implications of the introduction of an expanded Close Marking System for the Fellowship Examination. AB - Critical review of the close marking system used in the Fellowship Examination revealed that minor modifications to the way in which it was employed could significantly improve the quality (reliability and validity) of the examination. In addition, it could provide better information for the specialty courts to use during their discussion of the borderline candidate at their mini-court meetings. An expanded close marking system (ECMS) probably has little impact on the overall pass rate, but it does improve the ability to determine the marginal candidate. In addition, it has the capacity to provide feedback on examiner performance and provides the specialty courts with a tool to assess the quality of their questions. Analysis of data collected during several 'live trials' of ECMS has shown that the implementation of the ECMS represents a further improvement in the processes around the Fellowship Examination. PMID- 23627550 TI - Design of a randomized controlled trial to assess the comparative effectiveness of a multifaceted intervention to improve adherence to colorectal cancer screening among patients cared for in a community health center. AB - BACKGROUND: Colorectal cancer (CRC) is common and leads to significant morbidity and mortality. Although screening with fecal occult blood testing (FOBT) or endoscopy has been shown to decrease CRC mortality, screening rates remain suboptimal. Screening rates are particularly low for people with low incomes and members of underrepresented minority groups. FOBT should be done annually to detect CRC early and to reduce CRC mortality, but this often does not occur. This paper describes the design of a multifaceted intervention to increase long-term adherence to FOBT among poor, predominantly Latino patients, and the design of a randomized controlled trial (RCT) to test the efficacy of this intervention compared to usual care. METHODS: In this RCT, patients who are due for repeat FOBT are identified in the electronic health record (EHR) and randomized to receive either usual care or a multifaceted intervention. The usual care group includes multiple point-of-care interventions (e.g., standing orders, EHR reminders), performance measurement, and financial incentives to improve CRC screening rates. The intervention augments usual care through mailed CRC screening test kits, low literacy patient education materials, automated phone and text message reminders, in-person follow up calls from a CRC Screening Coordinator, and communication of results to patients along with a reminder card highlighting when the patient is next due for screening. The primary outcome is completion of FOBT within 6 months of becoming due. DISCUSSION: The main goal of the study is to determine the comparative effectiveness of the intervention compared to usual care. Additionally, we want to assess whether or not it is possible to achieve high rates of adherence to CRC screening with annual FOBT, which is necessary for reducing CRC mortality. The intervention relies on technology that is increasingly widespread and declining in cost, including EHR systems, automated phone and text messaging, and FOBTs for CRC screening. We took this approach to ensure generalizability and allow us to rapidly disseminate the intervention through networks of community health centers (CHCs) if the RCT shows the intervention to be superior to usual care. TRIAL REGISTRATION: ClinicalTrials.gov NCT01453894. PMID- 23627552 TI - Toxicokinetics of isoeugenol in F344 rats and B6C3F1 mice. AB - 1. Isoeugenol (IEG) has been tested for toxicity and carcinogenicity due to high potential for human exposure and the structural resemblance to known carcinogenic allylbenzenes. In order to support the interpretation of toxicity and carcinogenecity study outcomes, a toxicokinetic study was performed in which both sexes of F344 rats and B6C3F1 mice were given IEG as a single intravenous (IV) or gavage administration. 2. Following IV administration, IEG was rapidly eliminated from systemic circulation in both species and sexes. Gavage administration revealed a rapid absorption of IEG with tmax values <=20 min for both species and sexes. In rats, AUC increased in a greater than dose-proportional manner and Clapp values decreased with increasing dose in both sexes suggesting saturation of IEG metabolism. On the other hand, Clapp values in male mice increased with increasing dose suggesting induction of IEG metabolism although this was not evident in the females. 3. Absolute bioavailability was greater in female rats (19%) than male rats (10%) (p < 0.0001), but was not different between the sexes for mice (28% males; 31% females) (p = 0.2437). The collective toxicokinetic data supported that low bioavailability following administration of IEG was the result of extensive first-pass metabolism. PMID- 23627554 TI - Single molecule force spectroscopy reveals that iron is released from the active site of rubredoxin by a stochastic mechanism. AB - Metal centers in metalloproteins involve multiple metal-ligand bonds. The release of metal ions from metalloproteins can have significant biological consequences, so understanding of the mechanisms by which metal ion dissociates has broad implications. By definition, the release of metal ions from metalloproteins involves the disruption of multiple metal-ligand bonds, and this process is often accompanied by unfolding of the protein. Detailed pathways for metal ion release from metalloproteins have been difficult to elucidate by classical ensemble techniques. Here, we combine single molecule force spectroscopy and protein engineering techniques to investigate the mechanical dissociation mechanism of iron from the active site of the simplest iron-sulfur protein, rubredoxin, at the single molecule level. Our results reveal that the mechanical rupture of this simplest iron center is stochastic and follows multiple, complex pathways that include concurrent rupture of multiple ferric-thiolate bonds as well as sequential rupture of ferric-thiolate bonds that lead to the formation of intermediate species. Our results uncover the surprising complexity of the rupture process of the seemingly simple iron center in rubredoxin and provide the first unambiguous experimental evidence concerning the detailed mechanism of mechanical disruption of a metal center in its native protein environment in aqueous solution. This study opens up a new avenue to investigating the rupture mechanism of metal centers in metalloproteins with unprecedented resolution by using single molecule force spectroscopy techniques. PMID- 23627555 TI - The relation between persistent coma and brain ischemia after severe brain injury. AB - AIM: To investigate the relation between brain ischemia and persistent vegetative state after severe traumatic brain injury. METHODS: The 66 patients with severe brain injury were divided into two groups: The persistent coma group (coma duration >=10 d) included 51 patients who had an admission Glasgow Coma Scale (GCS) of 5-8 and were unconscious for more than 10 d. There were 15 patients in the control group, their admission GCS was 5-8, and were unconscious for less than 10 d. The brain areas, including frontal, parietal, temporal, occipital lobes and thalamus, were measured by Single Photon Emission Computed Tomography (SPECT). RESULTS: In the first SPECT scan, multiple areas of cerebral ischemia were documented in all patients in both groups, whereas bilateral thalamic ischemia were presented in all patients in the persistent coma group and were absented in the control group. In the second SPECT scan taken during the period of analepsia, with an indication that unilateral thalamic ischemia were persisted in 28 of 41 patients in persistent coma group(28/41,68.29%). CONCLUSION: Persistent coma after severe brain injury is associated with bilateral thalamic ischemia. PMID- 23627556 TI - A simple procedure to facilitate chin implants placement via submental approach. AB - In order to facilitate chin implants placement by submental incision, the use of two threads is described. They are separately passed through the extremities of the implant and inserted into the previously created subperiosteal pocket using a grooved guide. Once the landmarks of dissection have been reached, the tip of the needle exits through the skin just a few centimetres laterally to the augmentation area and, only by pulling the free ends of the threads, the implant can easily be inserted into the pocket and the sutures cut and removed. This procedure was successfully performed in 79 patients of both sexes presenting with deficiencies in the sagittal dimension at the pogonion and in width, laterally to the symphysis. Therefore, in the authors' opinion, the before-described technique could be a useful tool that facial plastic surgeons can employ to facilitate alloplastic chin implants placement, by minimising the invasiveness of the procedure, reducing the operative time, and greatly improving the aesthetic result, without sacrificing the safety of the operation. PMID- 23627557 TI - Risk factors for complications after breast reduction surgery. AB - Women who suffer from breast hypertrophy commonly have physical symptoms such as back pain and psychosocial problems. Breast reduction surgery is performed to relieve these problems. Side-effects must be kept to a minimum. Risk factors for developing postoperative complications have not clearly been identified so far. The aim of this study was to identify risk factors that lead to complications. The medical records of 512 consecutive women (mean age 40 years) who underwent bilateral breast reduction were retrospectively studied. All complications that occurred during the first 30 days after the operation were retrieved from medical records. Complications occurred in 32% of the patients within 30 days of surgery. The most common complication was infection at the surgical site (16%) followed by delayed wound healing (10%). Fat necrosis occurred in 2.5%, partial areola necrosis in 3.1%, and total areola necrosis in 0.6% of the patients. A longer suprasternal notch to nipple distance gave significantly higher risk of postoperative infection (p < 0.001) and necrosis in the mammilla (p < 0.001). The resected specimen weight during the operation was found to significantly influence the risk of delayed wound healing (p = 0.021) and fat necrosis (p < 0.001). Smokers had twice the risk of getting a postoperative infection, RR = 2.0 (95% CI = 1.3-3.1). Diabetics had a significantly higher risk of necrosis of the areola (p = 0.003). All the above predictors were identified as independent predictors. Complications after breast reduction are common. The study has identified several risk factors for complications, some of them independent, which might be avoidable by performing a careful preoperative evaluation of the patient. PMID- 23627553 TI - A comparison of the subsecond dynamics of neurotransmission of dopamine and serotonin. AB - The neuromodulators dopamine (DA) and serotonin (5-hydroxytryptamine; 5-HT) are similar in a number of ways. Both monoamines can act by volume transmission at metabotropic receptors to modulate synaptic transmission in brain circuits. Presynaptic regulation of 5-HT and DA is governed by parallel processes, and behaviorally, both exert control over emotional processing. However, differences are also apparent: more than twice as many 5-HT receptor subtypes mediate postsynaptic effects than DA receptors and different presynaptic regulation is also emerging. Monoamines are amenable to real-time electrochemical detection using fast scan cyclic voltammetry (FSCV), which allows resolution of the subsecond dynamics of release and reuptake in response to a single action potential. This approach has greatly enriched understanding of DA transmission and has facilitated an integrated view of how DA mediates behavioral control. However, technical challenges are associated with FSCV measurement of 5-HT and understanding of 5-HT transmission at subsecond resolution has not advanced at the same rate. As a result, how the actions of 5-HT at the level of the synapse translate into behavior is poorly understood. Recent technical advances may aid the study of 5-HT in real-time. It is timely, therefore, to compare and contrast what is currently understood of the subsecond characteristics of transmission for DA and 5-HT. In doing so, a number of areas are highlighted as being worthy of exploration for 5-HT. PMID- 23627558 TI - Association between the disease severity and extraneural pressure induced by maximum elbow flexion in patients with cubital tunnel syndrome. AB - Extraneural pressure in the cubital tunnel is considered to be a major pathophysiological factor for cubital tunnel syndrome. Thus, it has been hypothesised that the higher extraneural pressure in the cubital tunnel should result in a more severe stage of cubital tunnel syndrome. Extraneural pressures in cubital tunnel at elbow maximum flexion of 41 patients with cubital tunnel syndrome were evaluated, and compared with their preoperative disease severity using McGowan's classification and Dellon's staging. Mean extraneural pressure was significantly higher in maximum elbow flexion than in maximum elbow extension (p < 0.001). However, no significant relation was seen between the severity of cubital tunnel syndrome and the extraneural pressure induced by maximum elbow flexion (McGowan's classification: p = 0.62; Dellon's staging: p = 0.92). The results suggested that the progression of disease severity of cubital tunnel syndrome may not be explained simply by dynamic pressure in the cubital tunnel, and other causative factors should also be contributing to the progression. PMID- 23627559 TI - A predictive model of risk and outcomes in tissue expander reconstruction: a multivariate analysis of 9786 patients. AB - Outcomes of tissue expander breast reconstruction show variability based on presurgical risk factors. Few comprehensive, multi-institutional risk analyses exist. Patients who underwent tissue expander reconstruction were identified in a multi-institutional registry that spans over 240 institutions with over 200 variables per patient. Bivariate analysis of preoperative variables was performed across outcomes. Multivariate logistic regression was used to adjust for confounders and identify risk factors for complications. In 9786 total tissue expander patients, 526 (5.38%) patients experienced one or more complications. Wound infection and reoperations occurred in 3.45% and 6.76% of patients, respectively. Body mass index (BMI) was found to be a significant independent risk factor for overall morbidity, reoperation, prosthesis failure, and wound infection. Overweight, obese, and morbidly obese patients were at 1.7-, 2.6-, and 5.1-times greater risk of morbidity, respectively (p < 0.001 for all). Reconstructive timing, combined surgical procedures, and neoadjuvant chemotherapy were not found to be significant predictors of morbidity. The odds of developing complications were 1.5- and 1.3-times greater in smokers and patients over the age of 50, respectively (p = 0.001 and p = 0.015). For each additional hour of surgery, the odds of morbidity increased 1.26-times (p < 0.001). Precise risk profiles garnered from multi-institutional studies can help improve patient selection and education. Overall, tissue expander reconstruction was found to be safe, with relatively few complications. Operative time, BMI, and smoking were consistently found to be independent risk factors for postoperative morbidity. PMID- 23627560 TI - Effectiveness of local anaesthetic pain catheters for abdominal donor site analgesia in patients undergoing free lower abdominal flap breast reconstruction: A meta-analysis of comparative studies. AB - The use of an infusion pain pump with local wound catheters has increased among different surgical specialities. Autologous breast reconstruction with deep inferior epigastric perforator (DIEP) and transverse rectus abdominis myocutaneous (TRAM) flaps may cause severe abdominal donor site morbidity, and infusion devices delivering local anaesthetic are suggested to improve postoperative analgesia. This study performed a meta-analysis comparing pain pump use vs control to evaluate this issue. A systematic literature search was performed. Primary outcome was the amount of opioid use. Secondary outcomes were the amount of antiemetic drugs and the length of hospital stay. Five studies involving 248 patients were retrieved and included in the present analysis. A significantly decreased use of opioids was observed after using pain pump vs control (MD = -15.13, 95% CI = -24.20, -6.06, p = 0.001). Although not statistically significant, the pooled results showed a trend toward reduction of antiemetic medicament use (MD = -0.71, 95% CI = -2.14, 0.72, p = 0.33) and hospital stay time (MD = -0.53, 95% CI = -1.18, 0.11, p = 0.10). The use of local anaesthetic pain catheters for abdominal donor sites in microsurgical breast reconstruction might be associated with a decreased use of narcotics and antiemetic medicaments and shorter hospital stay. Further studies are needed to validate this promising treatment modality. PMID- 23627561 TI - Efficacy and safety of Macrolane(TM) for breast enhancement: a 12-month follow-up study in Asian women. AB - The demand for breast enhancement has risen substantially over recent years. Stabilised hyaluronic acid of non-animal origin manufactured using NASHA(TM) technology (Q-Med, Uppsala, Sweden) is an injectable gel, which has increasingly been used as a minimally invasive, non-permanent option for breast enhancement. The aim of this study was to investigate the 12-month efficacy and safety of NASHA gel, when used for breast enhancement in Asian women. Non-pregnant, non breastfeeding women with small breasts (aged 20-50 years) were recruited into this open, prospective, non-comparative, single-centre study. Subjects received sub-glandular injections of NASHA gel. Efficacy and safety assessments were carried out at follow-up visits (1, 6, and 12 months). Physician and subject assessment of breast improvement was recorded using the Global Esthetic Improvement Scale (GEIS). Ninety-eight subjects of Asian ethnicity were enrolled; 65 subjects completed the 12-month follow-up period. Overall, a median volume of 200 mL (range 80-300 mL) NASHA gel was injected per subject. Following GEIS assessment, 79% of breasts were subject-assessed as improved, much improved, or very much improved 6 months after treatment; 48% of breasts were still considered improved after 12 months. Sub-glandular NASHA gel injection was well tolerated, eliciting no serious adverse events judged to be treatment-related. High rates of aesthetic improvement were observed for at least 6 months after NASHA gel breast enhancement. The minimally invasive injection of NASHA gel provided a treatment option, which was an attractive alternative to permanent breast implants for many women. PMID- 23627562 TI - Comparison of collagen matrix treatment impregnated with platelet rich plasma vs bone marrow. AB - This study has reported the efficacy of an autologous bone marrow-impregnated collagen matrix experimentally and clinically. Then, it reflected that platelet rich plasma (PRP) was as good a source of growth factors as bone marrow and available in a less invasive procedure. This study aimed to compare the efficacy of a PRP-impregnated collagen matrix with that of a bone marrow-impregnated collagen matrix by quantifying wound size and capillary density using genetically diabetic db/db mice. Bone marrow cells were obtained from femurs of ddy mice. Then, a small amount of collagen matrix was immersed in bone marrow suspension. This is called a bone marrow-impregnated collagen matrix. PRP was obtained from healthy human blood and a small amount of collagen matrix was immersed in PRP. This is called a PRP-impregnated collagen matrix. A bone marrow-impregnated collagen matrix and PRP-impregnated collagen matrix were applied to excisional skin wounds on a genetically healing-impaired mouse (n = 6) and wounds were evaluated 6 days after the procedure. Wounds were divided into two groups: PRP (n = 6), in which a PRP-impregnated collagen matrix was applied; and bone marrow (n = 6), in which collagen immersed in a bone marrow suspension was applied. There was no significant difference between the PRP and bone-marrow groups in the rate of vascular density increase or wound size decrease. The present study suggested that the PRP-impregnated collagen matrix promotes repair processes at least as strongly as the bone marrow-impregnated collagen matrix. Given lower invasiveness, the PRP-impregnated collagen matrix would have advantages in clinical use. PMID- 23627563 TI - Influence of continuous or intermittent negative pressure on bacterial proliferation potency in vitro. AB - Negative pressure wound therapy is helpful and effective in the treatment of intractable skin ulcers and defects, not only acute wounds. However, application of negative pressure wound therapy for an infected wound is still controversial. The authors developed an in-vitro model of negative pressure wound therapy and investigated the influence of various types of negative pressure environment on the proliferation potency of non-pathogenic Escherichia coli. E. coli in Luria Bertani liquid media was cultured at 37 degrees C under different environments, which were normal atmosphere in group 1, continuous negative pressure of 75 mmHg in group 2, intermittent negative pressure of 75 mmHg with cycle time of 1 minute aspiration and 1 minute abeyance in group 3, with the one of 3 minutes aspiration and 3 minutes abeyance in group 4. The relative amounts of E. coli in each group were investigated at different times. The proliferation potency of E. coli was higher under negative pressure than under normal atmosphere; higher under intermittent negative pressure than under continuous negative pressure; and higher under intermittent negative pressure with a short cycle than with a long cycle. It is important to consider the possibility that the intermittent and continuous mode of negative pressure wound therapy may promote proliferation of bacteria in an infected wound with no blood flow like necrotic tissue. PMID- 23627564 TI - The Abbe flap in cleft lip and palate repair. AB - The Abbe flap is a procedure where the volume of the upper lip is increased at the expense of the lower lip. This study reviewed the Abbe flaps done at Skane University Hospital during the years 1991-2006 and identified 14 patients. Data was collected from medical records. Eleven patients were deemed fit for interviews and were called to the hospital by standard mail. Six patients responded and were interviewed, examined, and photographed. One patient was interviewed over the telephone. Median age at surgery was 14 years (range = 6 22). The operation time was 152 minutes (range = 90-215). The Abbe flap was divided after 12 days (range = 11-16). All 14 flaps survived and no complications were noted. Secondary corrections were done in nine patients. Three patients experienced having their lips sutured together as difficult, and four patients described this period as easy. All patients described their lips as having better appearance after the operation and, in three of four cases, where a simultaneous columella lengthening was done, the patients described their noses as having better appearance. The scar on the lower lip was negative but also a prerequisite for the operation. All seven patients said the operation was worth all the effort and would recommend it to patients in similar situations. This data supports that the Abbe flap is a safe technique that effectively improves the appearance of the upper lip and satisfies the cleft lip and palate patients. PMID- 23627565 TI - Luers, ethics, research and service evaluation: even more shades of grey? PMID- 23627566 TI - Effect of two different treatments for reducing grape yield in Vitis vinifera cv Syrah on wine composition and quality: berry thinning versus cluster thinning. AB - The influence of two treatments for reducing grape yield, cluster thinning and berry thinning, on red wine composition and quality were studied in a Vitis vinifera cv Syrah vineyard in AOC Penedes (Spain). Cluster thinning reduced grape yield per vine by around 40% whereas berry thinning only reduced it by around 20%. Cluster thinning grapes had higher soluble solids content than control grapes, and their resultant wines have greater anthocyanin and polysaccharide concentrations than the control wine. Wine obtained from berry thinning grapes had a higher total phenolic index, greater flavonol, proanthocyanidin, and polysaccharide concentrations, and lower titratable acidity than the control wine. Wines obtained from both treatments were sufficiently different from the control wine to be significantly distinguished by a trained panel in a triangular test. Even though both treatments seem to be effective at improving the quality of wine, berry thinning has the advantage because it has less impact on crop yield reduction. PMID- 23627567 TI - Promotion of cyclic electron transport around photosystem I during the evolution of NADP-malic enzyme-type C4 photosynthesis in the genus Flaveria. AB - C4 plants display higher cyclic electron transport activity than C3 plants. This activity is suggested to be important for the production of ATPs required for C4 metabolism. To understand the process by which photosystem I (PSI) cyclic electron transport was promoted during C4 evolution, we conducted comparative analyses of the functionality of PSI cyclic electron transport among members of the genus Flaveria, which contains several C3, C3-C4 intermediate, C4-like and C4 species. The abundance of NDH-H, a subunit of NADH dehydrogenase-like complex, increased markedly in bundle sheath cells with the activity of the C4 cycle. By contrast, PROTON GRADIENT REGULATION5 (PGR5) and PGR5-LIKE1 increased in both mesophyll and bundle sheath cells in C4-like Flaveria palmeri and C4 species. Grana stacks were drastically reduced in bundle sheath chloroplasts of C4-like F. palmeri and C4 species; these species showed a marked increase in PSI cyclic electron transport activity. These results suggest that both the expression of proteins involved in PSI cyclic electron transport and changes in thylakoid structure contribute to the high activity of cyclic electron flow in NADP-malic enzyme-type C4 photosynthesis. We propose that these changes were important for the establishment of C4 photosynthesis from C3-C4 intermediate photosynthesis in Flaveria. PMID- 23627568 TI - Necrosis affinity evaluation of 131I-hypericin in a rat model of induced necrosis. AB - Cancers are often with spontaneous or therapeutic necrosis that could be utilized as a generic target for developing new treatments. The purpose of this study was to investigate the biodistribution and pharmacokinetics of radioiodinated hypericin (Hyp), a naturally occurring compound, after intravenous (i.v.) injection in a rat model of liver and muscle necrosis (n = 42), and evaluate its necrosis affinity. Hyp was labeled with (131)I with labeling efficiency >99%. After incubating in solution/rat plasma for 8 days, radiochemical purity of (131)I-Hyp remained 98.1 and 97.1%, respectively, indicating good in vitro stability. SPECT-CT images at 24 h after i.v. injection of (131)I-Hyp in rats with induced liver and muscle necrosis showed obvious tracer absorption in necrotic tissues. Biodistribution studies revealed that the percentage of the injected dose per gram of tissue (%ID/g) evolved from 1.9 %ID/g at 6 h, through a maximum 3.0 %ID/g at 12 h, to 1.0 %ID/g at 192 h in necrotic liver. Pharmacokinetics studies revealed that the terminal elimination half-life, total body clearance and area under the curve of (131)I-Hyp were 32.7 h, 9.2 L/h/kg and 1.6 MBq/L*h, respectively. These results demonstrated that (131)I-Hyp features a long blood circulation in animals and persistent retention in necrotic tissues. Therefore, (131)I-labeled Hyp could be a broad-spectrum anti-tumor agent with a cost much cheaper relative to the biological agents such as monoclonal antibodies. PMID- 23627569 TI - Renal interstitial permeability changes induced by microbubble-enhanced diagnostic ultrasound. AB - Ultrasound-targeted microbubble (MB) destruction (UTMD) has been shown to increase the glomerular permeability, providing a potential novel therapeutic approach in targeted drug release for kidney diseases. Therefore, we investigated the impact of UTMD on renal interstitial permeability using MB-mediated diagnostic ultrasound (DUS). The left kidney of Sprague-Dawley (SD) rat was insonated by UTMD with either continuous or intermittent mode for 5 min. Evans blue (EB) revealed that both modes induced renal vascular permeability increase after DUS but recovered after 24 h. Intermittent insonation caused more severe injury than continuous mode. Red blood cells leaked out of the capillaries into interstitium without glomerular capillary hemorrhage (GCH) by hematoxylin and eosin (HE) staining. Electronic microscopy revealed the disruption of focal capillary wall in interstitial tissues. Morphological results confirmed capillary wall recovered in 24 h post-treatment. Results from fluorescence-labeled MBs showed that MBs were mainly localized in the interstitial portion of the tubular region and retained at 24 h. Intriguingly, urinalysis showed no clinical proteinuria after treatment. Our results indicated that MB plus DUS specifically and reversibly enhanced the interstitial permeability without affecting glomerulus, which may be developed into a therapeutic approach for targeting drug release to individual renal compartments. PMID- 23627570 TI - Suspension bead array of the single-stranded multiplex polymerase chain reaction amplicons for enhanced identification and quantification of multiple pathogens. AB - Rapid identification of single and multiple infectious agents is vital in clinical settings and during biothreat attack. This study assesses the assay of single-stranded multiplex polymerase chain reaction (PCR) amplicons by suspension bead array (SSMP-SBA) for multiple pathogens identification in a single-tube reaction. A 15-plex assay for identification of 11 highly infectious pathogens was developed to evaluate the performance of SSMP-SBA. Pathogen-specific amplicons were obtained by sequential amplification of genomic DNAs using gene specific primers tagged with artificial unique sequences and unique primers of which the reverse primer was modified by biotin and phosphorothioate. The SSMP products generated by T7 exonuclease-mediated DNA hydrolysis were hybridized to 15 sets of beads coupled with gene-specific and control oligonucleotide probes for pathogen identification and quantification by flow cytometry. This method was validated via assessment of 57 reference strains and one clinical bacterial isolate. All 11 pathogens can be detected by the 15-plex SSMP-SBA assay, and this design significantly enhanced the signal-to-noise ratio and improved the assay performance. This assay achieves similar sensitivity to our in-house real-time PCR system with the limit of detection equivalent to 5-100 genome copies and a linear dynamic range crossing three to five logs. In the validation assay, a 100% accuracy rate was achieved when the pathogens were among the target species. Notably, the species of pathogens were accurately identified from the samples with multiple infections. SSMP-SBA presents superior performance with multiplexing capability in a single-tube reaction and provides a new approach for detection and species identification of multiple pathogen infections. PMID- 23627571 TI - Increased IL-17 expression in degenerated human discs and increased production in cultured annulus cells exposed to IL-1beta and TNF-alpha. AB - IL-17 is expressed in a number of tissues including the intervertebral disc, where it exerts strong inflammatory properties. We evaluated IL-17 using immunolocalization in herniated and non-herniated human discs, IL-17 gene expression, and the production of IL-17 by annulus cells cultured in three dimensions in the presence of IL-1beta or TNF-alpha. There was no difference in the percentage of IL-17 positive cells in annulus or nucleus in herniated vs. non herniated disc specimens. Molecular studies confirmed expression of IL-17 in disc tissue, with significantly increased expression in more degenerated discs; there was no difference in expression between herniated vs. non-herniated discs. Exposure to IL-1beta or TNF-alpha resulted in significantly greater production of IL-17. Our findings expand understanding of IL-17 production by disc cells and reveal the importance of non-canonical IL-17 production in the disc. Significantly greater expression of IL-17 in more degenerated discs adds to our understanding of the changes in disc cell function with advancing stages of disc degeneration. PMID- 23627572 TI - Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer--overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression. AB - BACKGROUND: In breast cancer, the role of epigenetic alterations including modifications of the acetylation status of histones in carcinogenesis has been an important research focus during the last years. An increased deacetylation of histones leads to increased cell proliferation, cell migration, angiogenesis and invasion. Class 1 histone deacetylases (HDAC) seem to be most important during carcinogenesis. METHODS: The immunhistochemical expression of HDAC1, 2 and 3 was analyzed on tissue microarrays (TMAs) from 238 patients with primary breast cancer. We analyzed the nuclear staining intensity (negative, weak, moderate, strong) as well as the percentage of positive tumor cells and calculated the immunoreactivity score (0-12). Expression was correlated with clinicopathological parameters and patient survival. RESULTS: In this cohort, we found a differential positive expression of HDAC1, HDAC2 and HDAC3. HDAC2 and HDAC3 expression was significantly higher in less differentiated tumors: HDAC2 (n=207), p<0.001 and HDAC3 (n=220), p<0.001 and correlated with negative hormone receptor status: HDAC2 (n=206), p=0.02 and HDAC3 (n=219), p=0.04. Additionally, a high HDAC2 expression was significantly associated with an overexpression of HER2 (n=203, p=0.005) and the presence of nodal metastasis (n=200, p=0.04).HDAC1 was highly expressed in hormone receptor positive tumors (n=203; p<0.001). CONCLUSION: As a conclusion, our results show that the class-1 HDAC isoenzymes 1, 2 and 3 are differentially expressed in breast cancer. HDAC2 and HDAC3 are strongly expressed in subgroups of tumor with features of a more aggressive tumor type. PMID- 23627574 TI - Adherence to long-term warfarin therapy remains challenging. PMID- 23627575 TI - One-year adherence to warfarin treatment for venous thromboembolism in high-risk patients and its association with long-term risk of recurrent events. AB - BACKGROUNDS: Warfarin is the predominant oral anticoagulant used for the prevention of recurrent venous thromboembolism (VTE) events. However, its long term use is complicated by the need to manage the drug within a narrow therapeutic range and by possible food and drug interactions. OBJECTIVE: To examine the association between 1-year adherence, measured through compliance with and persistence on warfarin treatment for VTE, and long-term risk of recurrent events among patients at high risk. METHODS: Medical and pharmacy claims for patients with commercial or Medicare supplemental insurance in the Thomson Reuters MarketScan database were analyzed. Adult patients with medical claims with an associated VTE diagnosis between January 1, 2006, and March 31, 2008, were identified. The index date was defined as the date of the first observed VTE claim or the date of discharge if the index event was a hospital stay. High-risk patients (patients with cancer, or noncancer patients who did not have reversible risk factors during the 3-month period prior to the index date) who filled a warfarin prescription within 2 weeks of the index date were included. Persistence was evaluated in terms of discontinuation, defined as a 90 day gap in warfarin supply during a 1-year assessment period following the index date. Compliance was measured by the proportion of days covered (PDC) over the 1 year assessment period, with PDC less than 0.8 defined as noncompliance. Recurrent VTE events were identified as hospitalizations where VTE was the primary diagnosis after the 1-year assessment period and until patients were lost to follow-up. The association between adherence to warfarin therapy and VTE recurrence was evaluated descriptively via Kaplan-Meier curves and a Cox proportional hazards model, adjusted for patient demographic and clinical characteristics. A similar analysis using the medication possession ratio (MPR) as a measure of compliance was also performed in a subset of patients who had filled at least 2 warfarin prescriptions. RESULTS: The study included 8,040 VTE patients identified as being at high risk of recurrence (mean age 61 years, 59.4% male), of whom 76.9% were not compliant with warfarin therapy based on PDC, and 51.5% discontinued therapy. Among those with at least 2 warfarin prescriptions (n = 7612), 34.1% of high-risk patients were not compliant with warfarin therapy between the first and last refills based on MPR. Kaplan-Meier curves showed that patients who were compliant or continued warfarin therapy were less likely to experience a VTE event (all P less than 0.05). Noncompliant patients had a 3 times greater risk of VTE recurrence than compliant patients, based on PDC (hazard ratio [HR] = 3.01, 95% confidence interval [CI]: 1.28-4.97). Among the subpopulation who filled at least 2 warfarin prescriptions, noncompliant patients (based on MPR) were also found to be more likely to have recurrent VTE events, compared with compliant patients (HR = 1.60, 95% CI: 1.18-2.16). Patients who discontinued warfarin were more likely to have recurrent VTE events compared with patients who did not discontinue on warfarin treatment (HR = 1.48, 95% CI: 1.09 2.01). CONCLUSION: Adherence to a year of therapy was low in patients at high risk of recurrent VTE, even though long-term therapy should be considered in this population. Noncompliance and discontinuation of warfarin treatment over a 1-year period was associated with a higher risk of recurrent VTE. Future research should investigate and differentiate between patient and provider discontinuation to develop strategies to improve compliance and persistence with appropriate anticoagulation therapy that may potentially reduce recurrent VTE. PMID- 23627576 TI - The costs of warfarin underuse and nonadherence in patients with atrial fibrillation: a commercial insurer perspective. AB - BACKGROUND: Atrial fibrillation (AF) imposes a substantial clinical and economic burden on the U.S. health care system. Despite national guidelines that recommend oral anticoagulation for stroke prevention, the literature consistently reports its underuse in AF patients with moderate to high stroke risk. OBJECTIVE: To assess the economic burden of underuse and nonadherence of warfarin therapy among patients with nonvalvular AF in a commercially insured population. METHODS: Claims data between January 2003 and December 2007 from the Thomson Reuters MarketScan Research Database were used. Patients diagnosed with nonvalvular AF who were continuously enrolled for at least 12 months prior to and 2 months following their diagnosis, who had a CHADS2 score >= 2, and were not at high risk of bleeding (ATRIA score less than 5, HEMORR2HAGE score less than 4, and HAS-BLED score less than 3) at baseline were included. Patients were followed for up to 18 months after the AF diagnosis date to assess the level of warfarin utilization. Health care resource utilization and cost during follow-up among patients with the proportion of days covered (PDC) by warfarin greater than 0.8 (high) and <= 0.8 (low) versus patients with no warfarin exposure were assessed. Multivariate negative binomial regressions and generalized linear models were used to estimate differences in resource utilization and cost, respectively. RESULTS: Of the 13,289 subjects included in this analysis, 47% had no warfarin exposure; 31.5% had low PDC; and 21.5% had high PDC. The rates of ischemic stroke and transient ischemic attack (per 100 patient-years) were significantly lower for the groups that had high and low PDCs as compared with the group with no warfarin exposure (P less than 0.001). Multivariate analysis showed that patients with high PDC were 27% less likely (P less than 0.001) to incur hospitalizations, and 16% were less likely (P = 0.019) to incur emergency room visits than patients who did not receive warfarin, but the differences between low PDC patients and no warfarin exposure were not significant. Although both low and high PDC were associated with lower all-cause inpatient cost (P less than 0.001), only high PDC was associated with a lower post-index all-cause total cost (P less than 0.001) compared with no warfarin exposure. CONCLUSION: Our results confirm that underutilization and nonadherence of warfarin among nonvalvular AF patients is both prevalent and costly. Warfarin use among patients with moderate to high stroke risk and low to moderate bleed risk demonstrated a stroke benefit without a significant increase in intracranial hemorrhage. Adherence to oral anticoagulant therapy was associated with a significant reduction in inpatient service use and total health care cost. Improving adherence to oral anticoagulation is important to attaining the clinical and economic benefits of therapy. PMID- 23627577 TI - Quality compensation programs: are they worth all the hype? A comparison of outcomes within a Medicare advantage heart failure population. AB - BACKGROUND: Quality compensation programs (QCPs), also known as pay-for performance programs, are becoming more common within managed care entities. QCPs are believed to yield better patient outcomes, yet the programs lack the evidence needed to support these claims. We evaluated a QCP offered to network primary care physicians (PCPs) within a Medicare managed care plan to determine if a positive correlation between outcomes and the program exists. OBJECTIVE: To compare outcomes of heart failure members under the care of PCPs enrolled in a Medicare Advantage Prescription Drug (MAPD) Plan QCP with those who are not affiliated with a QCP. METHODS: Retrospective analysis was conducted on the heart failure population of a MAPD in Texas. Heart failure members were identified using ICD-9-CM codes from inpatient and outpatient claims for 2010. These members must have been continuously eligible all 12 months of the year to be included in the analysis. The primary intervention was enrollment by the member's PCP into the QCP. Measurable outcomes included acute (hospital) admits, emergency room (ER) visits, appropriate laboratory tests, and prescriptions of medications that are evidence based and guideline driven. Centers for Medicare and Medicaid Services (CMS) risk scores and comorbidities were used to risk-adjust outcomes. RESULTS: A total of 4,240 members was included in the analysis. From that population, 1,225 members (28.8%) were followed by PCPs enrolled in a QCP; 3,015 members (71.1%) were followed by PCPs not enrolled in a QCP. The adjusted analysis showed that none of the drug comparisons statistically differed between the QCP and non-QCP groups, whereas all of the lab tests, including low-density lipoprotein cholesterol (LDL-C), hemoglobin A1c, creatinine, and microalbumin, as well as the acquisition of the flu vaccine, occurred more frequently in the QCP group. Acute admits and ER visits in the QCP and non-QCP groups were similar before and after adjustment. The QCP group was significantly older with a statistically significant higher prevalence of renal failure and higher CMS risk scores. CONCLUSIONS: After evaluation of our QCP's impact on the quality of care provided to our Medicare beneficiaries, we have concluded that there is potential for health care improvement through pay-for-performance programs. We have observed in our MAPD heart failure population, enrolled in a QCP during the year of 2010, an increase in age and CMS risk scores, a decline in renal function, and noted the group to have a more female presence. Yet, the outcomes of this group (hospitalizations, ER visits, acquisition of lab tests, etc.) were similar when compared with younger, healthier members not enrolled in a QCP. We feel the clinical relevance of the data indicates that, overall, the quality of care is somewhat improved for QCP-enrolled providers when compared with non-QCP providers in regards to achieving certain quality metrics. (i.e., immunizations, HgA1c, LDL C, etc.) Further research is definitely needed to determine if health care costs and clinical outcomes, in the long term, are improved for members enrolled in these QCP programs, as well as their impact upon a health plan's Medicare Star rating. PMID- 23627578 TI - Impact of clinical pharmacists' recommendations on a proton pump inhibitor taper protocol in an ambulatory care practice. AB - BACKGROUND: Previous studies have demonstrated an association between chronic proton pump inhibitor (PPI) utilization and adverse events such as fractures, infections, hypomagnesemia, and vitamin B12 deficiency. Because patients taking PPIs for an extended period of time are more susceptible to these adverse events, an approach to tapering patients off PPIs is clinically warranted. OBJECTIVE: To evaluate the impact of clinical pharmacists' recommendations to clinicians to decrease PPI use in patients when chronic therapy is not indicated. METHODS: Clinical pharmacists electronically sent PPI taper recommendations for qualifying patients to primary care providers the day before each patient's appointment. Using insurance claims data, an average pills per month (PPM) count was calculated for the 5-month period prior to initiating the PPI taper as well as for the 5-month period after the date of taper initiation. The PPM count was calculated by dividing the total number of pills a patient received by the total number of days in that period, multiplied by 30. The primary outcome for the study was the change in average PPM count from baseline (pretaper period) to follow-up (posttaper period) and was assessed using a paired t-test. Secondary outcomes included change in total annualized PPI costs to the organization, proportion of patients who began the taper protocol after primary care provider recommendation, and whether baseline characteristics were predictors of successful response. Change in annualized PPI costs to the organization was calculated by multiplying the average unit cost per pill (determined using a weighted average of the average wholesale price of the individual drugs) by the PPM change seen with the primary outcome and by the number of patients included in the study and expressed over the period of a full year. Logistic regression analysis was used to determine whether baseline variables including alcohol and tobacco use, diagnosis related to PPI use, PPI dose, dosing frequency, gender, and length of prior PPI use significantly impacted successful tapering. RESULTS: Average PPM count decreased by 8.7 pills (95% CI: 6.4, 11.1), from 25.6 at baseline (95% CI: 23.1, 28.1) to 16.9 at follow-up (95% CI: 14.3, 19.5; P less than 0.001). For the 117 evaluable patients in the study, there was an annualized PPI cost reduction of $18,151. 37.6% (44/117) of pharmacist-recommended tapers were enacted upon by primary care providers at the patient visit. Baseline patient characteristics were not found to be predictors of a successful taper response. CONCLUSION: Clinical pharmacist intervention may decrease overutilization of PPIs and associated costs in the primary care setting. While a decrease in PPI use was observed in this study, these findings do not imply improvement in clinically meaningful patient outcomes. PMID- 23627579 TI - Specialty pharmaceuticals care management in an integrated health care delivery system with electronic health records. AB - The specialty pharmaceuticals market is expanding more rapidly than the traditional pharmaceuticals market. Specialty pharmacy operations have evolved to deliver selected medications and associated clinical services. The growing role of specialty drugs requires new approaches to managing the use of these drugs. The focus, expectations, and emphasis in specialty drug management in an integrated health care delivery system such as Kaiser Permanente (KP) can vary as compared with more conventional health care systems. The KP Specialty Pharmacy (KP-SP) serves KP members across the United States. This descriptive account addresses the impetus for specialty drug management within KP, the use of tools such as an electronic health record (EHR) system and process management software, the KP-SP approach for specialty pharmacy services, and the emphasis on quality measurement of services provided. Kaiser Permanente's integrated system enables KP-SP pharmacists to coordinate the provision of specialty drugs while monitoring laboratory values, physician visits, and most other relevant elements of the patient's therapy. Process management software facilitates the counseling of patients, promotion of adherence, and interventions to resolve clinical, logistic, or pharmacy benefit issues. The integrated EHR affords KP-SP pharmacists advantages for care management that should become available to more health care systems with broadened adoption of EHRs. The KP-SP experience may help to establish models for clinical pharmacy services as health care systems and information systems become more integrated. PMID- 23627580 TI - Chronic angle-closure glaucoma related to paroxetine treatment. AB - PURPOSE: To present a unique case of a 33-year-old woman using paroxetine who presented with acute unilateral visual loss due to chronic angle-closure glaucoma. METHODS: Case report. RESULTS: A 33-year-old women who had been under paroxetine treatment for the past four months presented at the emergency room due to a sudden loss of visual acuity (VA) in the left eye (LE). Narrow anterior chamber was detected. Intraocular pressure (IOP) was 29 mmHg right eye (RE) and 42 mm Hg LE. A fundus exam revealed a cup-to-disc ratio of 0.9-1 for the LE and of 0.1-0.2 for the RE. Paroxetine treatment was suspended, and after 48 h IOP was 10 mm Hg in both eyes (BE). ND-YAG laser iridotomy was performed in BE. In the subsequent visit, IOP was 25 mm Hg in the RE and 41 mm Hg in the LE; on her own initiative the patient had resumed paroxetine treatment. After requesting the patient again to stop taking the anti-depressant, IOP was 10 mm Hg in BE in the next exam 48 h later. CONCLUSIONS: As far as we are aware, there are no other reports of chronic angle-closure glaucoma related to the use of paroxetine. We thus consider that, before initiating treatment with this drug, patients should be informed of its potential ocular risks and they should be subjected to an ophthalmologic examination before its use is authorized. PMID- 23627581 TI - Nursing, sexual health and youth with disabilities: a critical ethnography. AB - AIM: To explore the experiences of nurses providing sexual health care to adolescents with physical and/or developmental disabilities, with attention to the institutional and social discourses that shape these interactions. BACKGROUND: Previous research has shown that nurses demonstrate a lack of attention to the impact of illness or disability on sexual health. However, in their therapeutic relationship with patients and families, nurses are in an ideal position to promote sexual health. DESIGN: A critical ethnography study was conducted in an urban paediatric rehabilitative facility. METHOD: Field work occurred over 4 months (2008-2009) and data collection included interviews (n = 9), key informant discussions, collection of documentary evidence and observation of the institutional setting. FINDINGS: Four themes were identified (institutional space, professional interactions, engaging with sexuality, nursing experience), which revealed that nurse-patient interactions about sexual health were affected by a complex network of discourses. These encounters were shaped by practical discourses, such as time and space and by more complex discourses, such as professional relationships, normalization and asexuality. CONCLUSION: Nurses occupy and strive to maintain, the role of a caring agent. However, aspects of the clinical, institutional and broader social environments may undermine their ability to promote sexual health. In nurses' efforts to maintain therapeutic relationships with clients, sexual health is often medicalised to legitimize it as an appropriate topic of discussion with patients and families. Facilities serving youth with disabilities should take steps to address barriers to the delivery of sexual health promotion and several solutions are proposed. PMID- 23627582 TI - Cryoplasty for the treatment of coronary bifurcation stenoses following main vessel stenting. AB - OBJECTIVES: This retrospective study sought to assess the safety and clinical efficacy of cryoplasty for treatment of side-branch stenoses following main vessel stenting in coronary bifurcation lesions. BACKGROUND: Cryoplasty prevents restenosis by reducing smooth muscle proliferation and extracellular matrix synthesis. Clinical effectiveness has been demonstrated in the peripheral circulation. Treatment of coronary bifurcation lesions remains a challenge. We used a novel strategy of main vessel stenting combined with side-branch cryoplasty to treat high-grade stenoses following main vessel stenting. METHODS: Eighteen patients with bifurcation lesions had significant plaque shift into a side branch after main vessel intervention. Drug-eluting stents were placed in the main vessel and cryoplasty was performed on the side-branch vessel. Quantitative coronary analysis was performed on all side-branch vessels both pre- and post-main vessel stenting. All patients had clinical follow-up 3 months or more after cryoplasty including either nuclear stress testing or diagnostic coronary angiogram. RESULTS: Mean percent stenosis decreased from 80.6% post main vessel stenting to 24.8% following cryoplasty (P < 0.0001). Of the 17 patients who had pre-cryoplasty nuclear stress testing 1 patient had ischemia identified in the distribution of the treated vessel at follow-up. Five patients had follow up angiography. One patient had restenosis, the other 2 were unchanged. There was a low incidence of MACE. CONCLUSIONS: In this first report of its use in the coronary circulation, cryoplasty for bifurcation side-branch disease was safe and associated with a low rate of clinical recurrence in carefully selected patients. PMID- 23627583 TI - Facilitating the action of community representatives in a health service: the role of a community participation coordinator. AB - BACKGROUND: Commitments to community participation are common in health policy, yet ways to maximise the input and impact of community representatives in health service delivery and care remain elusive, lack empirical evidence and are under theorised. METHODS: The role of Community Participation (CP) Coordinators involved in an Australian health service were examined in a triangulated multi method, multi-site ethnographically informed three year study. Formal fieldwork involved observation of just over 42 hours of meetings together with informal interactions in the field with staff and community members and in-depth interviews and discussions with 10 Community Representatives, 19 staff and the seven CP Coordinators employed during the study period. RESULTS: Four key roles that Community Participation Coordinators undertake to support and facilitate the action of community representatives operating within a health service were identified in our analysis: 1) Building skills and confidence; 2) Engaging them in agendas for action: 3) Helping them navigate and understand the health system; and 4) Advocating to staff. A fifth role of advocating externally to outside groups and building coalitions is suggested as important, but was not strongly represented in our data. CONCLUSIONS: This study offers a new model synthesising the key roles of coordinating and facilitating community participation in health services which may be transferable to other health service settings. Our findings call attention to the need for health services to employ a facilitator who can support, engage, navigate and advocate for community representative's participation and influence in health service policy and practice. PMID- 23627584 TI - Biochemical characterization of 4-alpha-glucanotransferase from Saccharophagus degradans 2-40 and its potential role in glycogen degradation. AB - 4-alpha-Glucanotransferase, an enzyme encoded by malQ, transfers 1,4-alpha-glucan to an acceptor carbohydrate to produce long linear maltodextrins of varying lengths. To investigate the biochemical characteristics of the malQ gene (Sde0986) from Saccharophagus degradans 2-40 and to understand its physiological role in vivo, the malQ gene was cloned and expressed in Escherichia coli. The amino acid sequence of MalQ was found to be 36-47% identical to that of amylomaltases from gammaproteobacteria. MalQ is a monomeric enzyme that belongs to a family of 77 glycoside hydrolases, with a molecular mass of 104 kDa. The optimal pH and temperature for MalQ toward maltotriose were determined to be 8.5 and 35 degrees C, respectively. Furthermore, the enzyme displayed glycosyl transfer activity on maltodextrins of various sizes to yield glucose and long linear maltodextrins. MalQ, however, could be distinguished from other bacterial and archaeal amylomaltases in that it did not produce maltose and cyclic glucan. Reverse transcription PCR results showed that malQ was not induced by maltose and was highly expressed in the stationary phase. These data suggest that the main physiological role of malQ in S. degradans is in the degradation of glycogen, although the gene is commonly known to be involved in maltose metabolism in E. coli. PMID- 23627585 TI - Deep dermal fibroblast profibrotic characteristics are enhanced by bone marrow derived mesenchymal stem cells. AB - Hypertrophic scars are a significant fibroproliferative disorder complicating deep injuries to the skin. We hypothesize that activated deep dermal fibroblasts are subject to regulation by bone marrow-derived mesenchymal stem cells (BM MSCs), which leads to the development of excessive fibrosis following deep dermal injury. We found that the expression of fibrotic factors was higher in deep burn wounds compared with superficial burn wounds collected from burn patients with varying depth of skin injury. We characterized deep and superficial dermal fibroblasts, which were cultured from the deep and superficial dermal layers of normal uninjured skin obtained from abdominoplasty patients, and examined the paracrine effects of BM-MSCs on the fibrotic activities of the cells. In vitro, deep dermal fibroblasts were found higher in the messenger RNA (mRNA) levels of type 1 collagen, alpha smooth muscle actin, transforming growth factor beta, stromal cell-derived factor 1, and tissue inhibitor of metalloproteinase 1, an inhibitor of collagenase (matrix metalloproteinase 1). As well, deep dermal fibroblasts had low matrix metalloproteinase 1 mRNA, produced more collagen, and contracted collagen lattices significantly greater than superficial fibroblasts. By co-culturing layered fibroblasts with BM-MSCs in a transwell insert system, BM MSCs enhanced the fibrotic behavior of deep dermal fibroblasts, which suggests a possible involvement of BM-MSCs in the pathogenesis of hypertrophic scarring. PMID- 23627587 TI - A new parametric feature descriptor for the classification of epileptic and control EEG records in pediatric population. AB - This study evaluates the sensitivity, specificity and accuracy in associating scalp EEG to either control or epileptic patients by means of artificial neural networks (ANNs) and support vector machines (SVMs). A confluence of frequency and temporal parameters are extracted from the EEG to serve as input features to well configured ANN and SVM networks. Through these classification results, we thus can infer the occurrence of high-risk (epileptic) as well as low risk (control) patients for potential follow up procedures. PMID- 23627588 TI - Application of non-linear and wavelet based features for the automated identification of epileptic EEG signals. AB - Epilepsy, a neurological disorder, is characterized by the recurrence of seizures. Electroencephalogram (EEG) signals, which are used to detect the presence of seizures, are non-linear and dynamic in nature. Visual inspection of the EEG signals for detection of normal, interictal, and ictal activities is a strenuous and time-consuming task due to the huge volumes of EEG segments that have to be studied. Therefore, non-linear methods are being widely used to study EEG signals for the automatic monitoring of epileptic activities. The aim of our work is to develop a Computer Aided Diagnostic (CAD) technique with minimal pre processing steps that can classify all the three classes of EEG segments, namely normal, interictal, and ictal, using a small number of highly discriminating non linear features in simple classifiers. To evaluate the technique, segments of normal, interictal, and ictal EEG segments (100 segments in each class) were used. Non-linear features based on the Higher Order Spectra (HOS), two entropies, namely the Approximation Entropy (ApEn) and the Sample Entropy (SampEn), and Fractal Dimension and Hurst Exponent were extracted from the segments. Significant features were selected using the ANOVA test. After evaluating the performance of six classifiers (Decision Tree, Fuzzy Sugeno Classifier, Gaussian Mixture Model, K-Nearest Neighbor, Support Vector Machine, and Radial Basis Probabilistic Neural Network) using a combination of the selected features, we found that using a set of all the selected six features in the Fuzzy classifier resulted in 99.7% classification accuracy. We have demonstrated that our technique is capable of achieving high accuracy using a small number of features that accurately capture the subtle differences in the three different types of EEG (normal, interictal, and ictal) segments. The technique can be easily written as a software application and used by medical professionals without any extensive training and cost. Such software can evolve into an automatic seizure monitoring application in the near future and can aid the doctors in providing better and timely care for the patients suffering from epilepsy. PMID- 23627586 TI - Human RECQL5: guarding the crossroads of DNA replication and transcription and providing backup capability. AB - DNA helicases are ubiquitous enzymes that catalyze unwinding of duplex DNA and function in all metabolic processes in which access to single-stranded DNA is required, including DNA replication, repair, recombination and RNA transcription. RecQ helicases are a conserved family of DNA helicases that display highly specialized and vital roles in the maintenance of genome stability. Mutations in three of the five human RecQ helicases, BLM, WRN and RECQL4 are associated with the genetic disorders Bloom syndrome, Werner syndrome and Rothmund-Thomson syndrome that are characterized by chromosomal instability, premature aging and predisposition to cancer. The biological role of human RECQL5 is only partially understood and RECQL5 has not yet been associated with any human disease. Illegitimate recombination and replication stress are hallmarks of human cancers and common instigators for genomic instability and cell death. Recql5 knockout mice are cancer prone and show increased chromosomal instability. Recql5 deficient mouse embryonic fibroblasts are sensitive to camptothecin and display elevated levels of sister chromatid exchanges. Unlike other human RecQ helicases, RECQL5 is recruited to single-stranded DNA breaks and is also proposed to play an essential role in RNA transcription. Here, we review the established roles of RECQL5 at the cross roads of DNA replication, recombination and transcription, and propose that human RECQL5 provides important backup functions in the absence of other DNA helicases. PMID- 23627589 TI - Binding and segmentation via a neural mass model trained with Hebbian and anti Hebbian mechanisms. AB - Synchronization of neural activity in the gamma band, modulated by a slower theta rhythm, is assumed to play a significant role in binding and segmentation of multiple objects. In the present work, a recent neural mass model of a single cortical column is used to analyze the synaptic mechanisms which can warrant synchronization and desynchronization of cortical columns, during an autoassociation memory task. The model considers two distinct layers communicating via feedforward connections. The first layer receives the external input and works as an autoassociative network in the theta band, to recover a previously memorized object from incomplete information. The second realizes segmentation of different objects in the gamma band. To this end, units within both layers are connected with synapses trained on the basis of previous experience to store objects. The main model assumptions are: (i) recovery of incomplete objects is realized by excitatory synapses from pyramidal to pyramidal neurons in the same object; (ii) binding in the gamma range is realized by excitatory synapses from pyramidal neurons to fast inhibitory interneurons in the same object. These synapses (both at points i and ii) have a few ms dynamics and are trained with a Hebbian mechanism. (iii) Segmentation is realized with faster AMPA synapses, with rise times smaller than 1 ms, trained with an anti-Hebbian mechanism. Results show that the model, with the previous assumptions, can correctly reconstruct and segment three simultaneous objects, starting from incomplete knowledge. Segmentation of more objects is possible but requires an increased ratio between the theta and gamma periods. PMID- 23627590 TI - Dynamical recurrent neuro-fuzzy identification schemes employing switching parameter hopping. AB - In this paper we analyze the identification problem which consists of choosing an appropriate identification model and adjusting its parameters according to some adaptive law, such that the response of the model to an input signal (or a class of input signals), approximates the response of the real system for the same input. For identification models we use fuzzy-recurrent high order neural networks. High order networks are expansions of the first-order Hopfield and Cohen-Grossberg models that allow higher order interactions between neurons. The underlying fuzzy model is of Mamdani type assuming a standard defuzzification procedure such as the weighted average. Learning laws are proposed which ensure that the identification error converges to zero exponentially fast or to a residual set when a modeling error is applied. There are two core ideas in the proposed method: (1) Several high order neural networks are specialized to work around fuzzy centers, separating in this way the system into neuro-fuzzy subsystems, and (2) the use of a novel method called switching parameter hopping against the commonly used projection in order to restrict the weights and avoid drifting to infinity. PMID- 23627591 TI - A neural-visualization IDS for honeynet data. AB - Neural intelligent systems can provide a visualization of the network traffic for security staff, in order to reduce the widely known high false-positive rate associated with misuse-based Intrusion Detection Systems (IDSs). Unlike previous work, this study proposes an unsupervised neural models that generate an intuitive visualization of the captured traffic, rather than network statistics. These snapshots of network events are immensely useful for security personnel that monitor network behavior. The system is based on the use of different neural projection and unsupervised methods for the visual inspection of honeypot data, and may be seen as a complementary network security tool that sheds light on internal data structures through visual inspection of the traffic itself. Furthermore, it is intended to facilitate verification and assessment of Snort performance (a well-known and widely-used misuse-based IDS), through the visualization of attack patterns. Empirical verification and comparison of the proposed projection methods are performed in a real domain, where two different case studies are defined and analyzed. PMID- 23627593 TI - Host-specific salivary elicitor(s) of European corn borer induce defenses in tomato and maize. AB - Plants turn on induced defenses upon insect herbivory. In the current study, we evaluated the role of European corn borer (ECB) elicitors (molecules secreted by herbivores) that either induce/suppress defenses in Solanum lycopersicum (tomato) and Zea mays (maize), two very important crop plants that are grown for food and/or fuel throughout the world. We used a combination of molecular, biochemical, confocal and scanning electron microscopy, caterpillar spinneret ablation/cauterization, and conventional insect bioassay methods to determine the role of ECB elicitors in modulating defenses in both tomato and maize crop plants. Our results clearly demonstrate that the components present in the ECB saliva induce defense-related proteinase inhibitors in both tomato (PIN2) and maize (MPI). Presence of glucose oxidase in the ECB saliva induced defenses in tomato, but not in maize. However, ECB saliva induced genes present in the jasmonic acid biosynthesis pathway in both tomato and maize. Although ECB saliva can induce defenses in both tomato and maize, our results suggest that host specific salivary components are responsible for inducing host plant defenses. Proteomic analysis of ECB salivary elicitors and plant receptors/signaling mechanisms involved in recognizing different ECB elicitors remains to be determined. PMID- 23627594 TI - Spontaneous anterior interosseous nerve syndrome: clinical analysis of eleven surgical cases. AB - The aetiology of anterior interosseous nerve (AIN) syndrome and an optimal treatment strategy remain controversial. Eleven patients with spontaneous AIN syndrome, who were treated by surgical exploration, were reviewed at a mean of 32.5 months after the operation. Eight men and three women were included in the study. None of the patients had a history of trauma and there was no evidence of a neuropathy other than AIN syndrome. Six patients showed complete paralysis of the flexor pollicis longus (FPL) and the flexor digitorum profundus of the index finger (FDS1). Five patients had incomplete paralysis, with isolated lesions of the FPL in two and the FDP1 in three. Surgery was performed 7.8 months after the onset of paralysis. The most common structure of nerve compression was a fibrous band of the flexor digitorum sublimis muscle. However, no definitive compression site or anatomic abnormality could be found in four patients. Ten of the 11 patients had recovered muscle strength above grade 4 within 12 months of the operation. Good results were obtained in 10 patients and fair in only one at final assessment. Four patients (one man and three women) raised cosmetic concerns due to excessive scar formation on the upper forearm. Surgical exploration is recommended only in cases where AIN syndrome is apparent, no other neuronal lesions are apparent, and where there was no recovery after 6 months of conservative treatment. Careful preoperative examination is essential to avoid misdiagnosis and inappropriate operation, particularly in cases of incomplete AIN syndrome. PMID- 23627595 TI - Rupture of flexor tendons as a complication of a distal radius fracture. AB - Two cases are reported of flexor tendon rupture of ulnar side fingers as a complication after distal radius fracture. One was associated with a prominent distal volar lip of fracture site, the other with a relatively volarly displaced ulnar head due to the dorsally tilted distal radius due to malunion. These may be unique cases of flexor tendon rupture with conservatively treated patients. PMID- 23627596 TI - Two Lotus japonicus symbiosis mutants impaired at distinct steps of arbuscule development. AB - Arbuscular mycorrhiza (AM) fungi form nutrient-acquiring symbioses with the majority of higher plants. Nutrient exchange occurs via arbuscules, highly branched hyphal structures that are formed within root cortical cells. With a view to identifying host genes involved in AM development, we isolated Lotus japonicus AM-defective mutants via a microscopic screen of an ethyl methanesulfonate-mutagenized population. A standardized mapping procedure was developed that facilitated positioning of the defective loci on the genetic map of L. japonicus, and, in five cases, allowed identification of mutants of known symbiotic genes. Two additional mutants representing independent loci did not form mature arbuscules during symbiosis with two divergent AM fungal species, but exhibited signs of premature arbuscule arrest or senescence. Marker gene expression patterns indicated that the two mutants are affected in distinct steps of arbuscule development. Both mutants formed wild-type-like root nodules upon inoculation with Mesorhizobium loti, indicating that the mutated loci are essential during AM but not during root nodule symbiosis. PMID- 23627597 TI - Gold-catalyzed cycloisomerization of 1,6-diyne carbonates and esters to 2,4a dihydro-1H-fluorenes. AB - A synthetic method to prepare 2,4a-dihydro-1H-fluorenes efficiently from gold(I) catalyzed 1,2-acyloxy migration/cyclopropenation/Nazarov cyclization of 1,6-diyne carbonates and esters is described. The suggested reaction pathway provides rare examples of [2,3]-sigmatropic rearrangement in this class of compounds as well as the involvement of an in situ formed cyclopropene intermediate in gold catalysis. Experimental and ONIOM(QM:QM') [our own n-layered integrated molecular orbital and molecular mechanics(quantum mechanics:quantum mechanics')] computational studies based on the proposed Au carbenoid species provide insight into this unique selectivity. PMID- 23627598 TI - Progress in the development of animal models of acute kidney injury and its impact on drug discovery. AB - INTRODUCTION: Acute kidney injury (AKI) is a clinical syndrome characterized by the acute loss of kidney function. AKI is increasingly frequent and is associated with impaired survival and chronic kidney disease progression. Experimental AKI models have contributed to a better understanding of pathophysiological mechanisms but they have not yet resulted in routine clinical application of novel therapeutic approaches. AREAS COVERED: The authors present the advances in experimental AKI models over the last decade. Furthermore, the authors review their current and expected impact on novel drug discovery. EXPERT OPINION: New AKI models have been developed in rodents and non-rodents. Non-rodents allow the evaluation of specific aspects of AKI in both bigger animals and simpler organisms such as drosophila and zebrafish. New rodent models have recently reproduced described clinical entities, such as aristolochic and warfarin nephropathies, and have also provided better models for old entities such as thrombotic microangiopathy-induced AKI. Several therapies identified in animal models are now undergoing clinical trials in human AKI, including p53 RNAi and bone-marrow derived mesenchymal stem cells. It is conceivable that further refinement of animal models in combination with ongoing trials and novel trials based on already identified potential targets will eventually yield effective therapies for clinical AKI. PMID- 23627599 TI - Chemical composition and hypoglycemic and pancreas-protective effect of leaf essential oil from indigenous cinnamon (Cinnamomum osmophloeum Kanehira). AB - The antidiabetic effect of cinnamon has generated broad interest during the past decade. We investigated the hypoglycemic activity and pancreas-protective effect of leaf essential oil from indigenous cinnamon (CO) in diabetic rats induced with streptozotocin (STZ, iv, 65 mg/(kg bw)) and found linalool to be the major component representing 40.24% of the CO composition. In diabetics, all tested doses of CO significantly lowered fasting blood glucose and fructosamine and are concomitant with elevated plasma and pancreatic insulin levels under a fasting condition. However, during the oral glucose tolerance test (OGTT) period the effect of 25 and 50 mg/(kg bw) of CO was shown to be less effective than that of 12.5 mg/(kg bw) in ameliorating the accumulation of plasma insulin. In addition, at 12.5 mg/(kg bw), CO significantly ameliorated pancreatic values of thiobarbituric acid reactive substances and activities of superoxide dismutase and glutathione reductase in diabetics to an extent greater than that of higher CO doses. At doses 12.5 and 25 but not 50 mg/(kg bw), CO significantly ameliorated pancreatic levels of interleukin-1beta and nitric oxide. In conclusion, appropriate doses of CO of the linalool chemotype exhibited therapeutic potential in glycemic control in diabetes that was at least partially resulted from improved insulin secretion. The ameliorated oxidative stress and proinflammatory environment in the pancreas by CO may provide a protective effect on pancreatic beta cells and warrant further investigation. PMID- 23627600 TI - Axis IV--psychosocial and environmental problems--in the DSM-IV. AB - The aim of this study was to further explore the properties of axis IV in the Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV). In a naturalistic cross-sectional design, a group (n = 163) of young (18-25 years old) Swedish psychiatric outpatients was assessed according to DSM-IV. Psychosocial and environmental problems/axis IV were evaluated through structured interviewing by a social worker and by self-assessment on a questionnaire. Reliability between professional assessment and self-assessment of axis IV was examined. Concurrent validity of axis IV was also examined. Reliability between professional and self assessed axis IV was fair to almost perfect, 0.31-0.83, according to prevalence and bias-adjusted kappa. Categories of psychosocial stress and environmental problems were related to the presence of axis I disorders, co-morbidity, personality disorders and decreasing Global Assessment of Functioning (GAF) values. The revised axis IV according to DSM-IV seems to have concurrent validity, but is still hampered by limited reliability. PMID- 23627601 TI - Electrochemical method for the synthesis of disulfides of 2-(benzo[d]thiazol(or oxazol)-2-ylamino)-5-morpholinobenzenethiol. AB - Electrochemical synthesis of two new disulfides of 2-(benzo[d]thiazol(or oxazol) 2-ylamino)-5-morpholinobenzene thiols was carried out via the electrooxidation of 4-morpholinoaniline in the presence of 2-mercaptobenzothiazole and 2 mercaptobenzoxazole. Our results indicate that electrogenerated p-quinonediimine participated in a Michael-type addition reaction with 2-SH-benzazoles and after intramolecular nucleophilic substitution reaction and electrooxidative disulfide bond formation were converted to the corresponding disulfide compounds. PMID- 23627602 TI - CH2D(+), the search for the holy grail. AB - CH2D+, the singly deuterated counterpart of CH3(+), offers an alternative way to mediate formation of deuterated species at temperatures of several tens of Kelvin, as compared to the release of deuterated species from grains. We report a longstanding observational search for this molecular ion, whose rotational spectroscopy is not yet completely secure. We summarize the main spectroscopic properties of this molecule and discuss the chemical network leading to the formation of CH2D+, with explicit account of the ortho/para forms of H2, H3(+), and CH3(+). Astrochemical models support the presence of this molecular ion in moderately warm environments at a marginal level. PMID- 23627603 TI - Normotensive pseudoexfoliation glaucoma reports. PMID- 23627604 TI - When in doubt, seize the day? Security values, prosocial values, and proactivity under ambiguity. AB - Researchers have suggested that both ambiguity and values play important roles in shaping employees' proactive behaviors, but have not theoretically or empirically integrated these factors. Drawing on theories of situational strength and values, we propose that ambiguity constitutes a weak situation that strengthens the relationship between the content of employees' values and their proactivity. A field study of 204 employees and their direct supervisors in a water treatment plant provided support for this contingency perspective. Ambiguity moderated the relationship between employees' security and prosocial values and supervisor ratings of proactivity. Under high ambiguity, security values predicted lower proactivity, whereas prosocial values predicted higher proactivity. Under low ambiguity, values were not associated with proactivity. We replicated these findings in a laboratory experiment with 232 participants in which we measured proactivity objectively as initiative taken to correct errors: Participants with strong security values were less proactive, and participants with strong prosocial values were more proactive, but only when performance expectations were ambiguous. We discuss theoretical implications for research on proactivity, values, and ambiguity and uncertainty. PMID- 23627605 TI - How graphene slides: measurement and theory of strain-dependent frictional forces between graphene and SiO2. AB - Strain, bending rigidity, and adhesion are interwoven in determining how graphene responds when pulled across a substrate. Using Raman spectroscopy of circular, graphene-sealed microchambers under variable external pressure, we demonstrate that graphene is not firmly anchored to the substrate when pulled. Instead, as the suspended graphene is pushed into the chamber under pressure, the supported graphene outside the microchamber is stretched and slides, pulling in an annulus. Analyzing Raman G band line scans with a continuum model extended to include sliding, we extract the pressure dependent sliding friction between the SiO2 substrate and mono-, bi-, and trilayer graphene. The sliding friction for trilayer graphene is directly proportional to the applied load, but the friction for monolayer and bilayer graphene is inversely proportional to the strain in the graphene, which is in violation of Amontons' law. We attribute this behavior to the high surface conformation enabled by the low bending rigidity and strong adhesion of few layer graphene. PMID- 23627606 TI - Luers, ethics, research and service evaluation: more than just the sharp end. PMID- 23627607 TI - MicroRNA profile of paclitaxel-resistant serous ovarian carcinoma based on formalin-fixed paraffin-embedded samples. AB - BACKGROUND: To assess the feasibility of validating microRNA (miRNA) profile related to paclitaxel-sensitivity in formalin-fixed paraffin-embedded (FFPE) samples of serous ovarian carcinoma (OC) patients. METHODS: Deregulated miRNAs identified by miRNA microarray were further detected in 45 FFPE OC samples using Realtime PCR. Correlations between paired FFPE and frozen tumor samples were analyzed. Survival times were compared between 6 high and low miRNAs groups. Western blot and luciferase reporter assay were used for validating the target of miRNA. RESULTS: Sixteen up-regulated miRNAs and twenty-three down-regulated miRNAs were revealed in pacilitaxel-resistant ST30 cells. The up-regulated miRNAs (miR-320a, 22 and 129-5p) and down-regulated miRNAs (miR-9, 155 and 640) were confirmed in paclitaxel-resistant FFPE tumor samples, compared with paclitaxel sensitive samples. Higher miR-9 and miR-640 showed better survival time in OC patients. Expressions of miR-9, 155 and 22 in FFPE samples were closely mimicked by those in frozen tissues. RAB34 was validated as a direct target of miR-9. CONCLUSIONS: We validated miRNA profile in pacilitaxel-resistant OC using FFPE samples, which might enable treatment stratification and help us to predict outcomes in OC patients. FFPE samples are feasible materials for miRNA research. PMID- 23627608 TI - An assessment of mast cells and myofibroblasts in denture-induced fibrous hyperplasia. AB - OBJECTIVES: The pathogenesis of denture-induced fibrous hyperplasias has not been examined in detail to explain how tissue injury results in fibrous hyperplasia of the oral mucosa. PATIENTS AND METHODS: We examined the presence of mast cells and myofibroblasts in 33 denture-induced fibrous hyperplasias (DIFH) compared with 10 healthy gingival tissues. The parameters examined included mast cell numbers, tissue distribution, degranulation, and cell subtypes using immunohistochemistry. The presence of myofibroblasts and their likely origin was also examined by double immunofluorescense staining. Furthermore, we investigated the synthesis of osteopontin and TGF-beta, considered to be involved in the transformation of a fibroblast to a myofibroblast. RESULTS: The results demonstrated that the mast cell numbers are significantly increased in the DIFH compared with non-disease controls. The mast cell localization in lesions was higher in the superficial areas with inflammatory cell infiltration compared with the deep fibrotic area (P < 0.01). The number of tryptase-positive mast cells was significantly higher compared with chymase-positive ones. The TGF-beta- or osteopontin-positive cell infiltration into the lesion was found in high numbers. The presence of myofibroblasts was identified in 14 of 33 cases (42%), and some of these cells showed apoptosis when assessed by the TUNEL assay. On the survey of the origin of myofibroblasts, results showed alphaSMA and vimentin positivity indicating these transformed from fibroblasts. CONCLUSION: These results are the first to show that mast cells and myofibroblasts can be detected in DIFH, indicating important roles of these cells in the pathogenesis of this lesion. PMID- 23627609 TI - Group medical visits can deliver on patient-centred care objectives: results from a qualitative study. AB - BACKGROUND: Patient-centred care emerged in the late 1960s as a framework to guide providers and decision-makers towards the provision of more effective health care and better outcomes. An important body of literature has since emerged, reporting mixed results in terms of outcomes. To date, assessments of the effectiveness of patient-centred approaches have focused one-on-one consultations. The purpose of this article is to explore dimensions identified as key in the patient-centred literature in the context of primary health care services delivered in a group setting. Group Medical Visits (GMVs) offer a novel format for the delivery of patient-centred primary health care services, especially for patients living with complex morbidities. METHODS: Drawing on a large study of GMVs, we report on key format and process-oriented elements identified in GMVs, and on their link to improved outcomes. For the purpose of this study, we interviewed 34 providers and 29 patients who have been engaged in GMVs, delivered in rural, northern and First Nation communities in British Columbia, Canada. RESULTS: Our analysis shows that the delivery of PHC in a group format results in a shift in the role of the provider, from that of an adjudicator involved in imparting norms of self-care, to that of a facilitator who assists the group in defining norms of self-care that are based on medical knowledge but also on the broader context of patients' lived experience and on their pragmatic experience. In a group process, peer-patients take on the role of promoting these norms to other patients. This results in a significant shift in the role of the provider, increased trust, increased knowledge for the providers and the patients and better patient self-management. Our results also show increase satisfaction for patients and providers. CONCLUSIONS: GMVs offer an alternative format for the provision of PHC that brings together the benefit of a group process and of a clinical encounter. This format can successfully deliver on the promises of patient-centred care. PMID- 23627610 TI - Single-stranded DNA as a cleavable linker for bioorthogonal click chemistry-based proteomics. AB - In this communication, we report a new class of cleavable linker based on automatically synthesized, single-stranded DNAs. We incorporated a DNA oligo into an azide-functionalized biotin (biotin-DNA-N3) and used the probe to enrich for alkyne-tagged glycoproteins from mammalian cell lysates. Highly efficient and selective release of the captured proteins from streptavidin agarose resins was achieved using DNase treatment under very mild conditions. A total of 36 sialylated glycoproteins were identified from the lysates of HL60 cells, an acute human promyeloid leukemia cell line. These sialylated glycoproteins were involved in many different biological processes ranging from glycan biosynthesis to cell adhesion events. PMID- 23627611 TI - Construction of a chimeric thermoacidophilic beta-endoglucanase. AB - BACKGROUND: The archeaon Sulfolobus solfataricus P2 encodes a thermoacidophilic cellulase which shows an extreme acid and thermal stability with a pH optimum at 1.8 and a temperature optimum at 80 degrees C. This extraordinary enzyme could be useful for biotechnological exploitation but the expression and purification in expression hosts like E. coli is unsatisfactory due to the high aggregation tendency of the recombinant enzyme. The thermophilic cellulase CelA from Thermotoga maritima belongs to the same glycoside hydrolase family (GH12) but has a neutral pH optimum. In contrast to SSO1949 this enzyme is expressed partially soluble in E. coli. RESULTS: We aimed to constructed a hybrid enzyme based on these two beta-endoglucanases which should successfully combine the advantageous properties of both cellulases, i.e. recombinant expression in E. coli, acidophily and thermophily. We constructed two hybrid proteins after bioinformatic analysis: both hybrids are expressed insoluble in E. coli, but one hybrid enzyme was successfully refolded from washed inclusion bodies. CONCLUSIONS: The refolded active chimeric enzyme shows a temperature optimum of approximately 85 degrees C and a pH optimum of approximately pH 3 thus retaining the advantageous properties of the Sulfolobus parent enzyme. This study suggests that the targeted construction of chimeric enzymes is an alternative to point mutational engineering efforts as long as parent enzymes with the wanted properties are available. PMID- 23627612 TI - Association of plasma neutrophil gelatinase-associated lipocalin (NGAL) with sepsis and acute kidney dysfunction. AB - OBJECTIVE: Neutrophil gelatinase-associated lipocalin (NGAL) is secreted by injured kidney cells as well as by activated neutrophils in response to bacterial infections. We assessed the influence of acute renal dysfunction on the association between plasma NGAL and sepsis. METHODS: NGAL was measured daily in 138 critically ill patients. Simultaneous recordings of sepsis status and fluctuations in renal function were made. RESULTS: Elevated NGAL was associated with sepsis independent of level of acute renal dysfunction. A cut-off value of 98 ng/mL distinguished sepsis from systemic inflammation with high sensitivity (0.77) and specificity (0.79). CONCLUSIONS: Plasma NGAL can help clinicians to identify bacterial infections in critically ill patients. PMID- 23627613 TI - Decreased levels of circulating and tissue miR-107 in human esophageal cancer. AB - CONTEXT: Aberrant expression of miRNAs has emerged as an important hallmark of cancer. OBJECTIVES: We evaluated the clinical significance of circulating and tissue miR-107 expression in esophageal squamous cell carcinoma (ESCC) patients. MATERIALS AND METHODS: Quantitative real-time PCR was used to analyze the expression of miR-107 and its bioinformatically identified targets, PIM-1 and CDC42. RESULTS: Significant downregulation of miR-107 was observed in neoplastic and preneoplastic esophageal tissues (p = 0.004). Relative levels of circulating miR-107 significantly distinguished ESCC patients from normal subjects (p = 0.007). Significant inverse correlation was observed between miR-107 and PIM1 expression (r = -0.398; p = 0.015) suggesting PIM1 to be the downstream target of miR-107. DISCUSSION AND CONCLUSION: Our results, for the first time, document that the miR-107 levels may discriminate ESCC patients from healthy individuals emphasizing its diagnostic potential. PMID- 23627614 TI - Prognostic value of HOXB7 mRNA expression in human oesophageal squamous cell cancer. AB - OBJECTIVE: This study was to determine the role of HOXB7 in predicting outcomes of patients with oesophageal squamous cell cancer (OSCC). METHODS: Samples were collected from 179 OSCC patients. HOXB7 mRNA expression was measured by quantitative real-time polymerase chain reaction. RESULTS: HOXB7 mRNA expression was up-regulated in 85.1% of OSCC tumorous tissues, and correlated with age, pathological T and N category, as well as cancer-specific survival (CSS). However, subgroup analysis revealed its discernibility on CSS was only pronounced in early stage. CONCLUSIONS: HOXB7 mRNA expression might serve as a novel prognostic biomarker for resected OSCC patients in early stage. PMID- 23627615 TI - Trefoil factor 1 as a marker of mucosal damage of the gastrointestinal tract in children with sepsis. AB - Intestinal ischemia and reperfusion is a common pathway for many diseases in children. The objective of our study was an analysis of Trefoil factor 1 levels dynamics in patients with SIRS or septic condition during a 5-day period. Analysis of TFF1 levels dynamics revealed that TFF1 levels kept steady state during the 5-day period. TFF1 levels were similar in patients with SIRS, sepsis and severe sepsis. Significantly higher levels of TFF1 were in patients with septic shock and MODS. PMID- 23627616 TI - Plasma nitrate levels are increased in adult Down syndrome patients. PMID- 23627617 TI - Long-term stability of biomarkers of the iron status in human serum and plasma. AB - CONTEXT: In epidemiological research, it is very important to test the stability of biomarkers as function of both storage time and temperature. OBJECTIVE: In this study, the stability of biomarkers of the iron status was tested up to 1 year of storage. MATERIALS AND METHODS: The biomarkers include total iron, unsaturated iron binding capacity, ferritin, transferrin, soluble transferrin receptor, ceruloplasmin and haptoglobin. RESULTS: The concentrations of all biomarkers tested remain constant upon storage at -20, -70 and -196 degrees C. CONCLUSION: All biomarkers of the iron status were stable at the temperatures tested for 1 year. PMID- 23627618 TI - Nitric oxide levels in wound fluid may reflect the healing trajectory. AB - We analyzed nitric oxide metabolites (nitrate and nitrite, NOx) and other biomarkers in human wound fluids and correlated these markers with wound healing status (progressing or worsening) based on patient's wound history. Samples were collected pre- and postcleansing from patients with wounds of various etiologies and analyzed for NOx, matrix metalloproteinase activity, and elastase activity. A laboratory method was developed to analyze NOx which can detect at least 5 MUM in samples as small as 10 MUL. A nitrate-free sample collection device was identified to match the sensitivity of this new assay (most "nitrate-free" products tested contained nitrate levels higher than this detection limit when extracted in such a small volume). The correlation between pre- and postcleansing biomarker values, and the diagnostic potential of the biomarkers to wound progress were analyzed. Fifty wounds provided samples that were suitable for NOx analysis. The pre- and postcleansing values for NOx showed good correlation (r = 0.72); the correlation was not very strong for matrix metalloproteinase and elastase. Data analysis showed that NOx represents the best metabolite to discriminate between worsening and progressing wounds, and suggested that a two cut point diagnostic test using NOx is better than a single cut point test to identify progressing from worsening wounds. PMID- 23627619 TI - Exploiting the hydrophobic and hydrophilic binding sites for designing carbonic anhydrase inhibitors. AB - INTRODUCTION: Carbonic anhydrases (CAs, EC 4.2.1.1) exist as five genetically distinct families (alpha, beta, gamma, delta and zeta) in organisms all over the phylogenetic tree. Due to the ubiquity of such enzymes, the selective inhibition and polypharmacology of inhibitors is an important aspect of all drug design campaigns. There are several classes of CA inhibitors (CAIs): i) metal ion binders (sulfonamides and their isosteres [sulfamates/sulfamides], dithiocarbamates, mercaptans and hydroxamates); ii) compounds anchoring to the zinc-coordinated water molecule/hydroxide ion (phenols, carboxylates, polyamines, esters and sulfocoumarins) and iii) coumarins and related compounds which apparently bind even further away from the metal ion. AREAS COVERED: The authors rationalize the drug design strategies of inhibitors belonging to the first two classes, based on recent X-ray crystallographic data. More precisely, this is achieved by analyzing how the hydrophobic and hydrophilic halves of the enzyme active site interact with inhibitors. This task has been eased by the recent report of beta-CA-like enzymes possessing carbon disulfide and carbonyl sulfide hydrolase activities, respectively, allowing the authors to propose a general approach of structure-based drug design of CAIs. EXPERT OPINION: Although amazing progress has been made in the structure-based drug design of CAIs, this field is still in progress, with many constantly emerging new findings. Indeed, several new such enzymes were discovered and characterized recently and novel chemotypes were explored for finding compounds with a better inhibition profile. It is anticipated that this will continue to be one of the main frontiers in the search of pharmacologically relevant enzyme inhibitors. PMID- 23627620 TI - A methyltransferase essential for the methoxypyrazine-derived flavour of wine. AB - Methoxypyrazines are a family of potent volatile compounds of diverse biological significance. They are used by insects and plants in chemical defence, are present in many vegetables and fruit and, in particular, impart herbaceous/green/vegetal sensory attributes to wines of certain varieties, including Cabernet Sauvignon. While pathways for methoxypyrazine biosynthesis have been postulated, none of the steps have been confirmed genetically. We have used the F2 progeny of a cross between a rapid flowering grapevine dwarf mutant, which does not produce 3-isobutyl-2-methoxypyrazine (IBMP), and Cabernet Sauvignon to identify the major locus responsible for accumulation of IBMP in unripe grape berries. Two candidate methyltransferase genes within the locus were identified and one was significantly associated with berry IBMP levels using association mapping. The enzyme encoded by this gene (VvOMT3) has high affinity for hydroxypyrazine precursors of methoxypyrazines. The gene is not expressed in the fruit of Pinot varieties, which lack IBMP, but is expressed in Cabernet Sauvignon at the time of accumulation of IBMP in the fruit. The results suggest that VvOMT3 is responsible for the final step in methoxypyrazine synthesis in grape berries and is the major determinant of IBMP production. PMID- 23627621 TI - Gas-phase rate coefficients for the OH + n-, i-, s-, and t-butanol reactions measured between 220 and 380 K: non-Arrhenius behavior and site-specific reactivity. AB - Butanol (C4H9OH) is a potential biofuel alternative in fossil fuel gasoline and diesel formulations. The usage of butanol would necessarily lead to direct emissions into the atmosphere; thus, an understanding of its atmospheric processing and environmental impact is desired. Reaction with the OH radical is expected to be the predominant atmospheric removal process for the four aliphatic isomers of butanol. In this work, rate coefficients, k, for the gas-phase reaction of the n-, i-, s-, and t-butanol isomers with the OH radical were measured under pseudo-first-order conditions in OH using pulsed laser photolysis to produce OH radicals and laser induced fluorescence to monitor its temporal profile. Rate coefficients were measured over the temperature range 221-381 K at total pressures between 50 and 200 Torr (He). The reactions exhibited non Arrhenius behavior over this temperature range and no dependence on total pressure with k(296 K) values of (9.68 +/- 0.75), (9.72 +/- 0.72), (8.88 +/- 0.69), and (1.04 +/- 0.08) (in units of 10(-12) cm(3) molecule(-1) s(-1)) for n-, i-, s-, and t-butanol, respectively. The quoted uncertainties are at the 2sigma level and include estimated systematic errors. The observed non-Arrhenius behavior is interpreted here to result from a competition between the available H atom abstraction reactive sites, which have different activation energies and pre exponential factors. The present results are compared with results from previous kinetic studies, structure-activity relationships (SARs), and theoretical calculations and the discrepancies are discussed. Results from this work were combined with available high temperature (1200-1800 K) rate coefficient data and room temperature reaction end-product yields, where available, to derive a self consistent site-specific set of reaction rate coefficients of the form AT(n) exp( E/RT) for use in atmospheric and combustion chemistry modeling. PMID- 23627622 TI - A novel electrical stimulation paradigm for the suppression of epileptiform activity in an in vivo model of mesial temporal lobe status epilepticus. AB - In this study, we present a novel low-frequency electrical stimulation paradigm for mesial temporal lobe epilepsy (MTLE). The paradigm utilizes the hippocampal commissure as a unique stimulation target to simultaneously influence large portions of the bilateral hippocampal network. When applied to an acute rat model of MTLE, animals that received stimulation exhibited an 88% reduction in the signal power of the bilateral epileptiform activity relative to the control group. In addition, the stimulation entrained the hippocampal network's spontaneous epileptiform activity and disrupted its bilateral synchrony. PMID- 23627623 TI - Head-centric disparity and epipolar geometry estimation from a population of binocular energy neurons. AB - We present a hybrid neural network architecture that supports the estimation of binocular disparity in a cyclopean, head-centric coordinate system without explicitly establishing retinal correspondences. Instead the responses of binocular energy neurons are gain-modulated by oculomotor signals. The network can handle the full six degrees of freedom of binocular gaze and operates directly on image pairs of possibly varying contrast. Furthermore, we show that in the absence of an oculomotor signal the same architecture is capable of estimating the epipolar geometry directly from the population response. The increased complexity of the scenarios considered in this work provides an important step towards the application of computational models centered on gain modulation mechanisms in real-world robotic applications. The proposed network is shown to outperform a standard computer vision technique on a disparity estimation task involving real-world stereo images. PMID- 23627624 TI - Artificial neural network based approach to EEG signal simulation. AB - In this paper a new approach to the electroencephalogram (EEG) signal simulation based on the artificial neural networks (ANN) is proposed. The aim was to simulate the spontaneous human EEG background activity based solely on the experimentally acquired EEG data. Therefore, an EEG measurement campaign was conducted on a healthy awake adult in order to obtain an adequate ANN training data set. As demonstration of the performance of the ANN based approach, comparisons were made against autoregressive moving average (ARMA) filtering based method. Comprehensive quantitative and qualitative statistical analysis showed clearly that the EEG process obtained by the proposed method was in satisfactory agreement with the one obtained by measurements. PMID- 23627625 TI - An auditory brain-computer interface with accuracy prediction. AB - Fully auditory Brain-computer interfaces based on the dichotic listening task (DL BCIs) are suited for users unable to do any muscular movement, which includes gazing, exploration or coordination of their eyes looking for inputs in form of feedback, stimulation or visual support. However, one of their disadvantages, in contrast with the visual BCIs, is their lower performance that makes them not adequate in applications that require a high accuracy. To overcome this disadvantage, we employed a Bayesian approach in which the DL-BCI was modeled as a Binary phase shift keying receiver for which the accuracy can be estimated a priori as a function of the signal-to-noise ratio. The results showed the measured accuracy to match the predefined target accuracy, thus validating this model that made possible to estimate in advance the classification accuracy on a trial-by-trial basis. This constitutes a novel methodology in the design of fully auditory DL-BCIs that let us first, define the target accuracy for a specific application and second, classify when the signal-to-noise ratio guarantees that target accuracy. PMID- 23627626 TI - On the learning potential of the approximated quantron. AB - The quantron is a hybrid neuron model related to perceptrons and spiking neurons. The activation of the quantron is determined by the maximum of a sum of input signals, which is difficult to use in classical learning algorithms. Thus, training the quantron to solve classification problems requires heuristic methods such as direct search. In this paper, we present an approximation of the quantron trainable by gradient search. We show this approximation improves the classification performance of direct search solutions. We also compare the quantron and the perceptron's performance in solving the IRIS classification problem. PMID- 23627627 TI - Automated diagnosis of normal and alcoholic EEG signals. AB - Electroencephalogram (EEG) signals, which record the electrical activity in the brain, are useful for assessing the mental state of a person. Since these signals are nonlinear and non-stationary in nature, it is very difficult to decipher the useful information from them using conventional statistical and frequency domain methods. Hence, the application of nonlinear time series analysis to EEG signals could be useful to study the dynamical nature and variability of the brain signals. In this paper, we propose a Computer Aided Diagnostic (CAD) technique for the automated identification of normal and alcoholic EEG signals using nonlinear features. We first extract nonlinear features such as Approximate Entropy (ApEn), Largest Lyapunov Exponent (LLE), Sample Entropy (SampEn), and four other Higher Order Spectra (HOS) features, and then use them to train Support Vector Machine (SVM) classifier of varying kernel functions: 1st, 2nd, and 3rd order polynomials and a Radial basis function (RBF) kernel. Our results indicate that these nonlinear measures are good discriminators of normal and alcoholic EEG signals. The SVM classifier with a polynomial kernel of order 1 could distinguish the two classes with an accuracy of 91.7%, sensitivity of 90% and specificity of 93.3%. As a pre-analysis step, the EEG signals were tested for nonlinearity using surrogate data analysis and we found that there was a significant difference in the LLE measure of the actual data and the surrogate data. PMID- 23627628 TI - The use of psychological therapies by mental health nurses in Australia. AB - This paper reports on a research project which examines the feasibility of mental health nurses employing psychological therapies in the nursing care of people with severe mental illness. Attitudes towards current usage and factors influencing the adoption of psychological therapies are investigated. The paper addresses the gap in the Australian nursing literature regarding the therapeutic role of mental health nurses (MHN)s in relation to the use of evidence-based psychological therapies. This paper presents the findings from an online questionnaire survey of 528 practising MHNs in Australia. The findings demonstrate enthusiastic support among nurses towards employing psychological therapies, with 93% of respondents indicating they would like to use psychological therapies in their current practice. Correspondingly, there is strong demand for education and training in applying psychological therapies. A number of barriers to implementing psychological therapies are identified. It is noted that place of employment is a significant factor, with mental health nurses working in the public sector more likely to state institutional barriers are restricting their therapeutic potential and preventing them from implementing psychological therapies. PMID- 23627629 TI - New pathogenesis and the classification in scaphocephaly. AB - The aetiology of scaphocephaly is often described as premature fusion of the sagittal suture. This study observed wave-like deformations in abnormally long and narrow skulls typical of scaphocephaly, and these deformations were divided into two types: type I deformations (one wave) and type II deformations (two waves). However, the pathogeneses of these deformations are unknown. Computed tomographic data sets were retrospectively analyzed from 18 patients with scaphocephaly who were admitted to the hospital between 2000-2010. Using three dimensional reconstructions of the computed tomographic images, the relationship was analysed between the wave deformation types and the state of the sutures and fontanelles. The results demonstrate that the type of wave deformation was dependent on the location of the sagittal suture closure. Specifically, the premature closure of the posterior half of the sagittal suture caused a type I deformation, while total closure resulted in a type II deformation (p < 0.001). It is hypothesized that restricted growth of the fused suture causes billowing, which results in a waving deformation. The deformities that are often observed in sagittal synostosis can be explained more accurately. PMID- 23627630 TI - Early morphea mimicking acquired port-wine stain. AB - We report the case of a 2.5-year-old girl with linear morphea initially diagnosed as an acquired port-wine stain (PWS). She underwent three treatments to the right face using the pulsed dye laser (PDL) before sclerotic changes were observed and the correct diagnosis was confirmed with histopathology. Treatment using the PDL reduced the skin erythema but did not prevent subsequent sclerosis. The sclerosis became most prominent superior to the patient's right ear in an area not treated using the laser. A review of the English-language medical literature identified no cases of morphea triggered using a PDL, but there were several reports of early morphea misdiagnosed as an acquired PWS. Briefly, we review those cases, as well as morphea subtypes, and comment on how the pathophysiology of morphea may lend itself to an early underrecognized inflammatory presentation, delaying diagnosis. PMID- 23627631 TI - Glycine betaine-mediated potentiation of HSP gene expression involves calcium signaling pathways in tobacco exposed to NaCl stress. AB - Glycine betaine (GB) can enhance heat tolerance and the accumulation of heat shock protein (HSP) in plants, but the effects of GB on HSP accumulation during salt stress were not previously known. To investigate the mechanism of how GB influences the expression of HSP, wild-type tobacco (Nicotiana tabacum) seedlings pretreated with exogenous GB and BADH-transgenic tobacco plants that accumulated GB in vivo were studied during NaCl stress. A transient Ca(2+) efflux was observed in the epidermal cells of the elongation zone of tobacco roots after NaCl treatment for 1-2 min. After 24 h of NaCl treatment, an influx of Ca(2+) was observed; a low concentration of GB significantly increased NaCl-induced Ca(2+) influx. GB increased the intracellular free calcium ion concentration and enhanced the expression of the calmodulin (CaM) and heat-shock transcription factor (HSF) genes resulting in potentiated levels of HSPs. Pharmacological experiments confirmed that Ca(2+) and CaM increased HSFs and HSPs gene expression, which coincided with increased the levels of HSP70 accumulation. These results suggest a mechanism by which GB acted as a cofactor in the NaCl induction of a Ca(2+) -permeable current. A possible regulatory model of Ca(2+) CaM in the signal transduction pathway for induction of transcription and translation of the active HSPs is described. PMID- 23627632 TI - Atypical Rosai-Dorfman disease with lacrimal gland involvement. AB - PURPOSE: Rosai-Dorfman disease is a rare, benign, idiopathic histocytic proliferative disorder that typically presents in young adults with painless cervical lymphadenopathy. Here we report an atypical case of Rosai-Dorfman disease involving orbit tissue and lacrimal gland, unilaterally. CASE: A 69-year old Asian women developed a painless palpable mass with local edema over the left upper eyelid over several months. Computed tomography (CT) showed an orbital mass with homogenous soft tissue density over the left lacrimal gland and superior orbital area. The patient underwent complete excision of the orbital tumor. OBSERVATIONS: The histopathology revealed diffuse and nodular infiltrations of S 100 positive histiocytes, plasma cells and lymphocytes. Emperipolesis (lymphocytophagocytosis) was also noted. These findings were consistent with Rosai-Dorfman disease. Chest CT revealed hilar lymphadenopathy. Three months after excision of the orbital mass, the patient developed lymphadenopathy in the extremities that resolved spontaneously over a few weeks. There were no complications or recurrence without systemic treatment after the complete excision. CONCLUSIONS: Orbital Rosai-Dorfman disease is a rare disorder, especially in Asia. Though there is no consensus on therapeutic choices, including corticosteroids, chemotherapy, radiation therapy, and surgical excision, the complete surgical excision performed in this case was without complication and had a favorable outcome. PMID- 23627633 TI - Sexual selection and sex differences in the prevalence of childhood externalizing and adolescent internalizing disorders. AB - Despite the well-established sex difference in prevalence of many childhood and adolescent psychopathological conditions, no integrative metatheory of sex differences in psychopathology exists. This review attempts to provide a metatheoretical framework to guide empirical examination of sex differences in prevalence of childhood-onset "externalizing" and adolescent-onset "internalizing" disorders, based on sexual selection evolutionary theory. Sexual selection theory suggests important between-sex differences in markers, mechanisms, etiology, and developmental timing of risk and resilience relevant to psychopathology. Namely, sexual selection theory hypothesizes that disinhibition and sensation-seeking may be important proximate risk markers for childhood-onset externalizing disorders in males. The theory suggests that these male-biased markers may be a product of their higher exposure to prenatal testosterone, which makes them more susceptible to prenatal stressors with downstream effects on dopaminergic neurotransmission, especially for those with genetic alleles associated with lower dopaminergic function. In contrast, sexual selection theory hypothesizes that negative emotionality, empathy, and cognitive rumination may be important proximate risk markers for adolescent-onset internalizing disorders in females. The theory suggests that these markers are propagated by rapidly rising levels of estradiol at puberty that interact with cortisol and oxytocin. These hormones exert downstream effects on the serotonergic system in such a way as to increase females' sensitivity to interpersonal stressors particularly at puberty and especially for those with lower functional serotonergic activity. Such a metatheory can help integrate prior ideas about sex differences and can also generate new predictions of sex differences in markers, etiology, mechanisms, and developmental timing of common forms of psychopathology. PMID- 23627634 TI - A comprehensive analysis of Aurora A; transcript levels are the most reliable in association with proliferation and prognosis in breast cancer. AB - BACKGROUND: Aurora A kinase, a centrosomal serine/threonine kinase which plays an essential role in chromosome segregation during cell division, is commonly amplified and/or over expressed in human malignancies. Aurora A is suggested to be one of the proliferation parameters which is an independent prognostic factor for early invasive breast cancer patients; however the individual clinical or prognostic relevance of this gene has been a matter of debate. METHODS: A comprehensive analysis of Aurora A at the levels of gene expression, gene copy number and protein expression was performed for 278 primary invasive breast cancer patients; and the correlation with clinical outcomes were investigated. RESULTS: Aurora A gene expression level not only correlated with gene amplification, but was also significantly associated with several clinicopathological parameters and patient prognosis. Patients with higher nuclear grade, negative progesterone receptor status and higher Ki67 expressed higher levels of Aurora A mRNA, which was associated not only with poor relapse free survival (RFS) but was also found to be a significant multivariate parameter for RFS. Aurora A protein expression was also significantly associated with clinicopathological characteristics; lymph node status, nuclear grade, estrogen receptor status and Ki67, but not with prognosis. By contrast, Aurora A gene amplification correlated with tumor size, nuclear grade and Ki67, and had no prognostic value. CONCLUSION: Our data indicate that Aurora A gene expression is an effective tool, which defines both tumor proliferation potency and patient prognosis. PMID- 23627635 TI - The effects of CD44 down-regulation on stem cell properties of head and neck cancer cell lines. AB - BACKGROUND: There is now substantial evidence that only a subpopulation of cells in solid cancers is able to sustain tumour growth and to re-initiate new tumours. Various cancers and cancer-derived cell lines, including head and neck squamous cell carcinomas (HNSCC), have a subpopulation of cancer stem cells (CSCs), marked by high levels of expression of the CD44 adhesion molecule. However, it has been unclear whether, in addition to acting as a marker, CD44 has functions that directly influence stem cell properties. The aim of this study was to investigate the role of CD44 in the maintenance of the CSC population in HNSCC cell lines. METHODS: CD44 was down-regulated either by treating cultures with 1 mM sodium butyrate or by the more specific method of knockdown with siRNAs directed against CD44. Changes in CD44 expression levels were assessed at the mRNA and protein levels, and the effects of CD44 down-regulation on cell proliferation and on the fate of the CSC subpopulations were assessed. RESULTS: Reduced CD44 expression resulted in a decreased rate of population expansion, both initially and on repassage, and there was an alteration in colony morphologies indicative of stem cell loss. Down-regulation of CD44 also led to reduced expression of Oct4A, an alternative marker of CSCs. CONCLUSIONS: The results suggest that CD44 has a functional role in maintaining stem cell properties in HNSCC cell lines and provides support for the concept that therapies targeting CD44, or its related signalling pathways, may allow development of more efficient treatment strategies. PMID- 23627637 TI - Broad-range modulation of light emission in two-dimensional semiconductors by molecular physisorption gating. AB - In the monolayer limit, transition metal dichalcogenides become direct-bandgap, light-emitting semiconductors. The quantum yield of light emission is low and extremely sensitive to the substrate used, while the underlying physics remains elusive. In this work, we report over 100 times modulation of light emission efficiency of these two-dimensional semiconductors by physical adsorption of O2 and/or H2O molecules, while inert gases do not cause such effect. The O2 and/or H2O pressure acts quantitatively as an instantaneously reversible "molecular gating" force, providing orders of magnitude broader control of carrier density and light emission than conventional electric field gating. Physi-sorbed O2 and/or H2O molecules electronically deplete n-type materials such as MoS2 and MoSe2, which weakens electrostatic screening that would otherwise destabilize excitons, leading to the drastic enhancement in photoluminescence. In p-type materials such as WSe2, the molecular physisorption results in the opposite effect. Unique and universal in two-dimensional semiconductors, the effect offers a new mechanism for modulating electronic interactions and implementing optical devices. PMID- 23627638 TI - Changes in the MALT1-A20-NF-kappaB expression pattern may be related to T cell dysfunction in AML. AB - To elucidate the characteristics of T-cell receptor (TCR) signal transduction in T-cells from acute myeloid leukemia (AML), the mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1), A20, NF-kappaB and MALT1-V1 gene expression levels in CD3+ T cells sorted from the peripheral blood of patients with AML were analyzed by real-time PCR. A significantly lower MALT1 and A20 expression level was found in T cells from patients with AML compared with healthy controls (p = 0.045, p < 0.0001); however, the expression level of MALT1 V1 (variant 1) was significantly higher in the AML group than in the healthy control group (p = 0.006), and the expression level of NF-kappaB was increased in the AML group. In conclusion, the characteristics of the expression pattern of MALT1-A20-NF-kappaB and the distribution of MALT1 variants in T cells from AML were first characterized. Overall, low TCR-CD3 signaling is related to low MALT1 expression, which may related to T cell immunodeficiency, while the up-regulation of MALT1-V1 may play a role in overcoming the T cell activity by downregulating A20 in patients with AML, which may be related to a specific response to AML associated antigens. PMID- 23627639 TI - Thickness of superficial basal cell carcinoma (sBCC) predicts imiquimod efficacy: a proposal for a thickness-based definition of sBCC. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy in the white population. It is an important driver of healthcare costs and causes significant morbidity. Topical imiquimod is a good noninvasive treatment alternative for surgical excision in superficial BCC (sBCC). However, there are currently no uniform histological definitions of sBCC. A definition based on tumour thickness might be a good alternative. OBJECTIVES: To determine whether tumour thickness in sBCC is a predictor of treatment failure. METHODS: We retrospectively examined 127 histological biopsy specimens of sBCC treated primarily with imiquimod five times a week for 6 weeks. Mean follow-up was 34 months (range 3-91). Recurrence was evaluated clinically with histological verification. RESULTS: Among nonrecurrent cases the median tumour thickness was 0.26 mm (range 0.09-0.61), while for recurrent cases the median tumour thickness was 0.57 mm (range 0.41 1.41, P < 0.0001). Among lesions <= 0.40 mm in thickness, none recurred, whereas for lesions > 0.40 mm the recurrence rate was 58% (P < 0.0001). CONCLUSIONS: We recommend the use of tumour thickness to define the superficial pattern in pathology reports for BCC as this can help to determine treatment response of sBCC to imiquimod. PMID- 23627640 TI - Investigating the concordance of Gene Ontology terms reveals the intra- and inter platform reproducibility of enrichment analysis. AB - BACKGROUND: Reliability and Reproducibility of differentially expressed genes (DEGs) are essential for the biological interpretation of microarray data. The microarray quality control (MAQC) project launched by US Food and Drug Administration (FDA) elucidated that the lists of DEGs generated by intra- and inter-platform comparisons can reach a high level of concordance, which mainly depended on the statistical criteria used for ranking and selecting DEGs. Generally, it will produce reproducible lists of DEGs when combining fold change ranking with a non-stringent p-value cutoff. For further interpretation of the gene expression data, statistical methods of gene enrichment analysis provide powerful tools for associating the DEGs with prior biological knowledge, e.g. Gene Ontology (GO) terms and pathways, and are widely used in genome-wide research. Although the DEG lists generated from the same compared conditions proved to be reliable, the reproducible enrichment results are still crucial to the discovery of the underlying molecular mechanism differentiating the two conditions. Therefore, it is important to know whether the enrichment results are still reproducible, when using the lists of DEGs generated by different statistic criteria from inter-laboratory and cross-platform comparisons. In our study, we used the MAQC data sets for systematically accessing the intra- and inter platform concordance of GO terms enriched by Gene Set Enrichment Analysis (GSEA) and LRpath. RESULTS: In intra-platform comparisons, the overlapped percentage of enriched GO terms was as high as ~80% when the inputted lists of DEGs were generated by fold change ranking and Significance Analysis of Microarrays (SAM), whereas the percentages decreased about 20% when generating the lists of DEGs by using fold change ranking and t-test, or by using SAM and t-test. Similar results were found in inter-platform comparisons. CONCLUSIONS: Our results demonstrated that the lists of DEGs in a high level of concordance can ensure the high concordance of enrichment results. Importantly, based on the lists of DEGs generated by a straightforward method of combining fold change ranking with a non stringent p-value cutoff, enrichment analysis will produce reproducible enriched GO terms for the biological interpretation. PMID- 23627641 TI - Functional connectivity within the default mode network is associated with saccadic accuracy in Parkinson's disease: a resting-state FMRI and videooculographic study. AB - In addition to the skeleto-motor deficits, patients with Parkinson's disease (PD) frequently present with oculomotor dysfunctions such as impaired smooth pursuit and saccadic abnormalities. There is increasing evidence for an impaired cortical function to be responsible for oculomotor deficits that are associated with lack of inhibitory control; however, these pathomechanisms still remain poorly understood. By means of "task-free" resting-state functional magnetic resonance imaging (rs-fMRI), functional connectivity changes in PD within the default mode network (DMN) have been reported. The aim of this study was to investigate whether altered functional connectivity within the DMN was correlated with oculomotor parameter changes in PD. Twelve PD patients and 13 matched healthy controls underwent rs-fMRI at 1.5 T and videooculography (VOG) using Eye-Link System. Rs-fMRI seed-based region-to-region connectivity analysis was performed, including medial prefrontal cortex (mPFC), medial temporal lobe (MTL), posterior cingulate cortex (PCC), and hippocampal formation (HF); while VOG examination comprised ocular reactive saccades, smooth pursuit, and executive tests. Rs-fMRI analysis demonstrated a decreased region-to-region functional connectivity between mPFC and PCC as well as increased connectivity between bilateral HF in PD compared with controls. In VOG, patients and controls differed in terms of executive tests outcome, smooth pursuit eye movement, and visually guided reactive saccades but not in peak eye velocity. A significant relationship was observed between saccadic accuracy and functional connectivity strengths between MTL and PCC. These results suggest that PD-associated changes of DMN connectivity are correlated with PD-associated saccadic hypometria, in particular in the vertical direction. PMID- 23627642 TI - Heart rate variability as a measure of autonomic dysfunction in men with advanced cancer. AB - Autonomic dysfunction is common in patients with cancer and may have considerable negative effects on quality of life and mortality. This study retrospectively compared heart rate variability measured by the standard deviation of normal-to normal intervals (SDNN) to Ewing test score, a composite score from a battery of five defined autonomic tests, in detection of autonomic dysfunction in 47 men with advanced cancer. The Ewing test score has been validated for diagnosis of autonomic dysfunction but is time-consuming and requires considerable patient co operation; we hypothesised that SDNN, a much simpler test, is a useful alternative. The patients were categorised into three groups according to Ewing score: <= 2 (mild or no autonomic dysfunction), 2.5-3 (moderate) and >= 3.5 (severe). The SDNN (mean +/- SD) for the three groups were 57.1 +/- 26.9 ms 62.3 +/- 22.4 ms and 37.7 +/- 20.3 ms respectively. A significant negative correlation was found between Ewing score and SDNN (r = -0.40, P = 0.005). A SDNN of <= 40 ms had 63% sensitivity and 75% specificity in the diagnosis of severe autonomic dysfunction (i.e. Ewing score >= 3.5). The positive predictive value of SDNN <= 40 ms in predicting moderate/severe autonomic dysfunction was 89%. PMID- 23627643 TI - Comparative wound healing--are the small animal veterinarian's clinical patients an improved translational model for human wound healing research? AB - Despite intensive research efforts into understanding the pathophysiology of both chronic wounds and scar formation, and the development of wound care strategies to target both healing extremes, problematic wounds in human health care remain a formidable challenge. Although valuable fundamental information regarding the pathophysiology of problematic wounds can be gained from in vitro investigations and in vivo studies performed in laboratory animal models, the lack of concordance with human pathophysiology has been cited as a major impediment to translational research in human wound care. Therefore, the identification of superior clinical models for both chronic wounds and scarring disorders should be a high priority for scientists who work in the field of human wound healing research. To be successful, translational wound healing research should function as an intellectual ecosystem in which information flows from basic science researchers using in vitro and in vivo models to clinicians and back again from the clinical investigators to the basic scientists. Integral to the efficiency of this process is the incorporation of models which can accurately predict clinical success. The aim of this review is to describe the potential advantages and limitations of using clinical companion animals (primarily dogs and cats) as translational models for cutaneous wound healing research by describing comparative aspects of wound healing in these species, common acute and chronic cutaneous wounds in clinical canine and feline patients, and the infrastructure that currently exists in veterinary medicine which may facilitate translational studies and simultaneously benefit both veterinary and human wound care patients. PMID- 23627644 TI - Autologous fat grafting and breast cancer recurrences: retrospective analysis of a series of 100 procedures in 64 patients. AB - Autologous fat transfer (AFT) enhances the cosmetic results of breast reconstruction and corrects breast conserving operation sequelae. The question of its oncological safety remains, as in-vitro experiences have shown that adipocytes can stimulate cancer cell proliferation. This study analysed the records of patients who had AFT after breast cancer from 2004-2009. The primary end-point was cancer recurrence. The secondary end-points were AFT complications and post-AFT mammogram modifications. Sixty-four patients (100 AFT) were included. The mean follow-up for AFT was 46.44 months (SD = 21.4). Two breast cancer recurrences were recorded (3.1%). Among 55 mammograms analysed, only one patient presented radiological abnormalities. One complication of AFT (donor-site infection) was recorded. This series is in favour of the oncological safety of AFT after breast cancer. An accurate evaluation of the recurrence risk, before performing AFT, is an essential prerequisite and must lead one to postpone or avoid this procedure in high-risk patients. PMID- 23627645 TI - Validity of exploration for suitable vessels for replantation in the distal fingertip amputation in early childhood: replantation or composite graft. AB - Composite grafting, grafting without microvascular anastomoses, has been widely performed for distal fingertip amputation in children with variable results, whereas successful replantation of these amputations using microsurgical technique has been reported. However, most of these reports included a wide age range and a mix of different amputation levels. This study reviewed our cases of paediatric digital amputation, in order to verify the value of distal fingertip replantation over composite grafting, especially in early childhood. Seventeen young children (aged 3 years and 8 months on average), with single-digit fingertip amputations in Tamai zone I were reviewed from 1993-2008. Each amputation was subdivided into three types: distal, middle, and proximal. There were three distal, 13 middle, and one proximal type zone I amputations. All were crush or avulsion injuries. All three distal-type cases were reattached as primary composite grafts with one success. For middle-type cases, the survival rate of primary composite graft without exploration for possible vessels for anastomosis was 57%. On exploration, suitable vessels for anastomosis were found 50% of the time, in which all replantations were succeeded. The remaining cases were reattached as secondary composite grafts, with one success using the pocket method. Consequently, the success rate after exploration was 67%. The only one proximal-type amputation was failed in replantation. For the middle-type zone I amputation in early childhood, replantation has a high success rate if suitable vessels can be found. Therefore, exploration is recommended for amputations at this level with a view to replantation, irrespective of the mechanism of injury. PMID- 23627646 TI - Endoscopic groin lymph node dissection as a preferable technique for malignant skin neoplasms. AB - Groin lymph node dissection (GLND) remains an effective treatment for malignant neoplasms of the skin arising on the lower extremities and perineum. However, complications such as seroma, flap necrosis, and infections have been encountered. It is thought that a conventional operation using a long inguinal incision can result in those complications. To minimise the risk of such complications, endoscopic GLND (EGLND) was performed in five patients. No severe complications were found. Although EGLND is still in the developmental stage, this technique is suggested as a possible surgical option for reducing morbidity and improving aesthetic results. PMID- 23627647 TI - Influence of propylene glycol on aqueous silica dispersions and particle stabilized emulsions. AB - We have studied the influence of adding propylene glycol to both aqueous dispersions of fumed silica nanoparticles and emulsions of paraffin liquid and water stabilized by the same particles. In the absence of oil, aerating mixtures of aqueous propylene glycol and particles yields either stable dispersions, aqueous foams, climbing particle films, or liquid marbles depending on the glycol content and particle hydrophobicity. The presence of glycol in water promotes particles to behave as if they are more hydrophilic. Calculations of their contact angle at the air-aqueous propylene glycol surface are in agreement with these findings. In the presence of oil, particle-stabilized emulsions invert from water-in-oil to oil-in-water upon increasing either the inherent hydrophilicity of the particles or the glycol content in the aqueous phase. Stable multiple emulsions occur around phase inversion in systems of low glycol content, and completely stable, waterless oil-in-propylene glycol emulsions can also be prepared. Accounting for the surface energies at the respective interfaces allows estimation of the contact angle at the oil-polar phase interface; reasonable agreement between measured and calculated phase inversion conditions is found assuming no glycol adsorption on particle surfaces. PMID- 23627648 TI - A hydrophobic surface is essential to inhibit the aggregation of a tau-protein derived hexapeptide. AB - This paper seeks to understand how a macrocyclic beta-sheet peptide inhibits the aggregation of the tau-protein-derived peptide Ac-VQIVYK-NH2 (AcPHF6). Previous studies established that macrocyclic beta-sheet peptide 1 inhibits AcPHF6 aggregation, while the sequence isomer in which the lysine and leucine residues at positions R6 and R7 are swapped has little effect on AcPHF6 aggregation. The current studies find that positions R1, R3, and R7 are especially sensitive to mutations. Reducing hydrophobicity at these positions substantially diminishes inhibition. Although position R5 is not sensitive to mutations that reduce hydrophobicity, it is sensitive to mutations that increase hydrophobicity. Enhanced hydrophobicity at this position substantially enhances inhibition. These studies establish that the hydrophobic surface comprising residues R1, R3, and R7 is crucial to the inhibition process and that the residue R5, which shares this surface, is also important. Collectively, these findings demonstrate that hydrophobic surfaces between beta-sheet layers are important in inhibiting amyloid aggregation. PMID- 23627649 TI - Combinatorial growth and anisotropy control of self-assembled epitaxial ultrathin alloy nanowires. AB - Self-assembled vertical epitaxial nanostructures form a new class of heterostructured materials that has emerged in recent years. Interestingly, such kind of architectures can be grown using combinatorial processes, implying sequential deposition of distinct materials. Although opening many perspectives, this combinatorial nature has not been fully exploited yet. This work demonstrates that the combinatorial character of the growth can be further exploited in order to obtain alloy nanowires coherently embedded in a matrix. This issue is illustrated in the case of a fully epitaxial system: CoxNi1-x nanowires in CeO2/SrTiO3(001). The advantage brought by the ability to grow alloys is illustrated by the control of the magnetic anisotropy of the nanowires when passing from pure Ni wires to CoxNi1-x alloys. Further exploitation of this combinatorial approach may pave the way toward full three-dimensional heteroepitaxial architectures through axial structuring of the wires. PMID- 23627650 TI - Alprostadil infusion in patients with dry age related macular degeneration: a randomized controlled clinical trial. AB - BACKGROUND: Age-related macular degeneration is the leading cause of blindness among elderly individuals in industrialized countries. New drugs and advanced concepts for the treatment of dry AMD (dAMD) are needed. A new approach is the application of intravenous infusions of prostaglandin E1. OBJECTIVE: The aim of this study was to assess efficacy and safety of intravenous alprostadil infusion in patients with dAMD. METHODS: This was a prospective, randomized, multi-center study. Patients were treated with intravenous infusion of either 60 ug alprostadil or placebo over 3 weeks. Main efficacy outcomes were mean differences in best corrected visual acuity (BCVA) from baseline assessed in early treatment diabetic retinopathy study (ETDRS) lines immediately, 3 months and 6 months after treatment. RESULTS: In the full analysis set (FAS) a mean difference of 0.89 +/- 0.537 ETDRS lines according to analysis of variance-covariance (ANCOVA) resulted in the alprostadil group (n = 16) and a mean difference of -0.05 +/- 0.578 in the placebo group (n = 17) 3 months after end of treatment. Thus, effectiveness of alprostadil infusion was numerically superior to placebo treatment by a mean of 0.94 lines after 3 months (1.51 lines after 6 months). These findings were more pronounced in the per protocol set (PPS). Safety results were in line with the good safety profile of alprostadil. CONCLUSION: A numerical treatment effect in favor of alprostadil was visible, which lasted until the end of follow up. These results provide further evidence that alprostadil probably has a therapeutic effect in the treatment of dAMD and justify further clinical studies. PMID- 23627651 TI - Identification of genetic loci associated with fire blight resistance in Malus through combined use of QTL and association mapping. AB - Fire blight, incited by the enterobacterium Erwinia amylovora, is a destructive disease of Rosaceae, particularly of apples and pears. There are reports on the molecular mechanisms underlying E. amylovora pathogenesis and how the host activates its resistance mechanism. The host's resistance mechanism is quantitatively controlled, although some major genes might also be involved. Thus far, quantitative trait loci (QTL) mapping and differential expression studies have been used to elucidate those genes and/or genomic regions underlying quantitative resistance present in the apple genome. In this study, an effort is undertaken to dissect the genetic basis of fire blight resistance in apple using both QTL and genome-wide association mapping. On the basis of an F1 pedigree of 'Coop 16' * 'Coop 17' and a genome-wide association study (GWAS) mapping population of Malus accessions (species, old and new cultivars and selections), new QTLs and associations have been identified. A total of three QTLs for resistance to fire blight, with above 95% significant logarithm of odds threshold value of 2.5, have been identified on linkage groups (LGs) 02, 06, and 15 of the apple genome with phenotypic variation explained values of 14.7, 20.1 and 17.4, respectively. Although elevated P-values with signals for marker-trait associations are observed for some LGs, these are not found to be significant. However, a total of 34 significant associations, with P-values >=0.02, have been detected including 8 for lesion length at 7 days following inoculation (PL1), 14 for lesion length at 14 days following inoculation (PL2), and 12 for shoot length. PMID- 23627653 TI - Sexual behaviours on acute inpatient psychiatric units. AB - The purpose of the study was to assess the types and frequency of sexual behaviours displayed by patients during the first 2 weeks of admission to acute psychiatric units and what relationship these have to other challenging patient behaviours. The method used was a survey of sexual behaviours, conflict and containment events carried out by 522 patients during the first 2 weeks of admission in 84 wards in 31 hospitals in the South East of England. Incidents of sexual behaviour were common, with 13% of patients responsible for at least one incident. Although exposure was the most frequent of these behaviours, non consensual sexual touching, was instigated by 1 in 20 patients. There were no differences in the numbers of sexual events between single sex and mixed gender wards. Few associations were found with the demographic features of perpetrators, although all those engaging in public masturbation were male, and male patients were more likely to sexually touch another without their consent. Single sex wards do not seem to necessarily offer significant protection to potentially vulnerable victims. Perpetrators do not seem to be predictable in advance, nor was there any common set or pattern of disruptive behavioural events indicating that a sexual incident was about to occur. PMID- 23627652 TI - Nomothetic and idiographic symptom change trajectories in acute-phase cognitive therapy for recurrent depression. AB - OBJECTIVE: We tested nomothetic and idiographic convergence and change in 3 symptom measures during acute-phase cognitive therapy (CT) for depression and compared outcomes among patients showing different change patterns. METHOD: Outpatients (N = 362; 69% women; 85% White; age M = 43 years) with recurrent major depressive disorder according to criteria in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000) completed the Hamilton Rating Scale for Depression (Hamilton, 1960), Beck Depression Inventory (Beck, Ward, Mendelson, Mock, & Erbaugh, 1961), and Inventory for Depressive Symptomatology-Self-Report (Rush, Gullion, Basco, Jarrett, & Trivedi, 1996) on 14 occasions as well as pre/post-CT measures of social-interpersonal functioning and negative cognitive content. RESULTS: The 3 symptom measures marked the same severity and change constructs, and we offer improved formulas for intermeasure score conversions via their common factor. Pre/post-CT symptom reductions were large (ds = 1.71-1.92), and nomothetic symptom curves were log-linear (larger improvements earlier and smaller improvements later in CT). Nonetheless, only 30% of individual patients showed clear log-linear changes, whereas other patients showed linear (e.g., steady decreases; 20%), 1-step (e.g., a quick drop; 16%), and unclassified (34%) patterns. Log-linear, linear, and 1-step patients were generally similar to one another and superior to unclassified patients post-CT in symptom levels, response and stable remission rates, social-interpersonal functioning, and cognitive content (median d = 0.69). CONCLUSIONS: Reaching a low-symptom "destination" at the end of CT via any coherent "path" is more important in the short term than which path patients take. We discuss implications for theories of change, clinical monitoring of individuals' progress in CT, and the need to investigate long-term outcomes of patients with differing patterns of symptom change. PMID- 23627654 TI - Long-term follow-up after successful treatment of Pythium insidiosum keratitis in Israel. AB - The purpose of this project is to report a case of severe Pythium insidiosum keratitis confirmed by polymerase chain reaction (PCR), and its long-term cure after therapeutic penetrating keratoplasty. A 24-year-old woman with a history of contact lens wear and exposure to swimming pool water presented with a severe corneal abscess. She was treated with intensive fortified topical antibiotics and natamycin with limited response. Initial cultures suggested the presence of a septate mold, unclearly identified; therefore, both topical and intravenous voriconazole were administered. Despite the above treatment, there was worsening of the clinical picture. PCR assay revealed homology to Pythium insidiosum. Promptly, the patient underwent a large therapeutic penetrating keratoplasty. After five years of follow-up, the graft exhibits neither signs of rejection nor any recurrence of infection. We conclude that prompt identification of Pythium insidiosum keratitis and aggressive treatment by therapeutic penetrating keratoplasty may offer a cure to this disease. PMID- 23627655 TI - A multi-layer neural-mass model for learning sequences using theta/gamma oscillations. AB - A neural mass model for the memorization of sequences is presented. It exploits three layers of cortical columns that generate a theta/gamma rhythm. The first layer implements an auto-associative memory working in the theta range; the second segments objects in the gamma range; finally, the feedback interactions between the third and the second layers realize a hetero-associative memory for learning a sequence. After training with Hebbian and anti-Hebbian rules, the network recovers sequences and accounts for the phase-precession phenomenon. PMID- 23627656 TI - Automated diagnosis of epilepsy using CWT, HOS and texture parameters. AB - Epilepsy is a chronic brain disorder which manifests as recurrent seizures. Electroencephalogram (EEG) signals are generally analyzed to study the characteristics of epileptic seizures. In this work, we propose a method for the automated classification of EEG signals into normal, interictal and ictal classes using Continuous Wavelet Transform (CWT), Higher Order Spectra (HOS) and textures. First the CWT plot was obtained for the EEG signals and then the HOS and texture features were extracted from these plots. Then the statistically significant features were fed to four classifiers namely Decision Tree (DT), K Nearest Neighbor (KNN), Probabilistic Neural Network (PNN) and Support Vector Machine (SVM) to select the best classifier. We observed that the SVM classifier with Radial Basis Function (RBF) kernel function yielded the best results with an average accuracy of 96%, average sensitivity of 96.9% and average specificity of 97% for 23.6 s duration of EEG data. Our proposed technique can be used as an automatic seizure monitoring software. It can also assist the doctors to cross check the efficacy of their prescribed drugs. PMID- 23627657 TI - Adaptive and predictive control of a simulated robot arm. AB - In this work, a basic cerebellar neural layer and a machine learning engine are embedded in a recurrent loop which avoids dealing with the motor error or distal error problem. The presented approach learns the motor control based on available sensor error estimates (position, velocity, and acceleration) without explicitly knowing the motor errors. The paper focuses on how to decompose the input into different components in order to facilitate the learning process using an automatic incremental learning model (locally weighted projection regression (LWPR) algorithm). LWPR incrementally learns the forward model of the robot arm and provides the cerebellar module with optimal pre-processed signals. We present a recurrent adaptive control architecture in which an adaptive feedback (AF) controller guarantees a precise, compliant, and stable control during the manipulation of objects. Therefore, this approach efficiently integrates a bio inspired module (cerebellar circuitry) with a machine learning component (LWPR). The cerebellar-LWPR synergy makes the robot adaptable to changing conditions. We evaluate how this scheme scales for robot-arms of a high number of degrees of freedom (DOFs) using a simulated model of a robot arm of the new generation of light weight robots (LWRs). PMID- 23627658 TI - Adaptive filtering and random variables coefficient for analyzing functional magnetic resonance imaging data. AB - Functional magnetic resonance imaging (fMRI) is used to study brain functional connectivity (FC) after filtering the physiological noise (PN). Herein, we employ: adaptive filtering for removing nonstationary PN; random variables (RV) coefficient for FC analysis. Comparisons with standard techniques were performed by quantifying PN filtering and FC in neural vs. non-neural regions. As a result, adaptive filtering plus RV coefficient showed a greater suppression of PN and higher connectivity in neural regions, representing a novel effective approach to analyze fMRI data. PMID- 23627659 TI - Combination of heterogeneous EEG feature extraction methods and stacked sequential learning for sleep stage classification. AB - This work proposes a methodology for sleep stage classification based on two main approaches: the combination of features extracted from electroencephalogram (EEG) signal by different extraction methods, and the use of stacked sequential learning to incorporate predicted information from nearby sleep stages in the final classifier. The feature extraction methods used in this work include three representative ways of extracting information from EEG signals: Hjorth features, wavelet transformation and symbolic representation. Feature selection was then used to evaluate the relevance of individual features from this set of methods. Stacked sequential learning uses a second-layer classifier to improve the classification by using previous and posterior first-layer predicted stages as additional features providing information to the model. Results show that both approaches enhance the sleep stage classification accuracy rate, thus leading to a closer approximation to the experts' opinion. PMID- 23627660 TI - Design of assistive wheelchair system directly steered by human thoughts. AB - Integration of brain-computer interface (BCI) technique and assistive device is one of chief and promising applications of BCI system. With BCI technique, people with disabilities do not have to communicate with external environment through traditional and natural pathways like peripheral nerves and muscles, and could achieve it only by their brain activities. In this paper, we designed an electroencephalogram (EEG)-based wheelchair which can be steered by users' own thoughts without any other involvements. We evaluated the feasibility of BCI based wheelchair in terms of accuracies and real-world testing. The results demonstrate that our BCI wheelchair is of good performance not only in accuracy, but also in practical running testing in a real environment. This fact implies that people can steer wheelchair only by their thoughts, and may have a potential perspective in daily application for disabled people. PMID- 23627661 TI - Increased functional connectivity and brain atrophy in elderly with subjective memory complaints. AB - Subjective memory complaints (SMC) are common among elderly. Although subtle changes in memory functioning can hardly be determined using neuropsychological evaluation, neuroimaging studies indicate regionally smaller brain structures in elderly with SMC. Imaging of resting-state functional connectivity is sensitive to detect changes in neurodegenerative diseases, but is currently underexplored in SMC. Here, we investigate resting-state functional connectivity and brain structure in SMC. We analyzed magnetic resonance imaging data of 25 elderly with SMC and 29 age-matched controls (mean age of 71 years). Voxel-based morphometry and volume measurements of subcortical structures were employed on the structural scans using FSL. The dual regression method was used to analyze voxel-wise functional connectivity in relation to eight well-characterized resting-state networks. Group differences were studied with two-sample t-tests (p<0.05, Family Wise Error corrected). In addition to gray matter volume reductions (hippocampus, anterior cingulate cortex (ACC), medial prefrontal cortex, cuneus, precuneus, and precentral gyrus), elderly with SMC showed increased functional connectivity in the default mode network (hippocampus, thalamus, posterior cingulate cortex (PCC), cuneus, precuneus, and superior temporal gyrus) and the medial visual network (ACC, PCC, cuneus, and precuneus). This study is the first which demonstrates that, in addition to smaller regional brain volumes, increases in functional connectivity are present in elderly with SMC. This suggests that self reported SMC is a reflection of objective alterations in brain function. Furthermore, our results indicate that functional imaging, in addition to structural imaging, can be a useful tool to objectively determine a difference in brain integrity in SMC. PMID- 23627663 TI - Using haloperidol as an antiemetic in palliative care: informing practice through evidence from cancer treatment and postoperative contexts. AB - Nausea and vomiting are common symptoms in palliative care. Haloperidol is often used as an antiemetic in this context, although direct evidence supporting this practice is limited. To evaluate the efficacy and clinical use of haloperidol as an antiemetic in nonpalliative care contexts to inform practice, the authors conducted a rapid review of (i) published evidence to supplement existing systematic reviews, and (ii) practical aspects affecting the use of haloperidol including formulations and doses that are commonly available internationally. In nausea and vomiting related to cancer treatment, haloperidol was superior to control in two small studies. In postoperative nausea and vomiting (PONV), two randomized controlled trials found treatment with haloperidol comparable to ondansetron. In palliative care, an observational study found a complete response rate of 24% with haloperidol (one in four patients) which would be consistent with a number needed to treat (NNT) of 3 to 5 derived from PONV. There remains insufficient direct evidence to definitively support the use of haloperidol for the management of nausea and vomiting in palliative care. However, generalizing evidence from other clinical contexts may have some validity. PMID- 23627662 TI - Effects of food processing and fibre content on the digestibility, energy intake and biochemical parameters of Blue-and-gold macaws (Ara ararauna L. - Aves, Psittacidae). AB - Considering the increased incidence of obesity and metabolic diseases in caged psittacines, the effect of fibre and food processing was evaluated in the Blue and-gold macaw. Four food formulations (0%, 7%, 14% and 21% of sugarcane fibre) processed by pelleting or extrusion were studied, resulting in eight diets. To study digestibility, 48 macaws housed in pairs in cages was used in a block design. Subsequently, diets containing 0% or 21% sugarcane fibre, pelleted or extrude was fed for 4 months to evaluate energy intake and blood metabolites. A 2 * 2 * 2 (two fibre levels, two food processing methods and two genders) factorial arrangement with subplots (beginning and end) was used. When differences were detected in anova's F test, data were submitted to polynomial contrasts in the first experiment and to orthogonal contrasts in the second experiment (p < 0.05). Fibre addition reduced protein, fat and energy (p < 0.001) digestibility in both food processing. Pelleted foods presented higher dry matter digestibility and food metabolisable energy (ME) than the extruded ones (p < 0.05). Fibre addition or the type of processing did not change ME ingestion (p > 0.05). The macaws gained body weight (p < 0.05) regardless of the diet (p > 0.05), but females fed with the high-fibre diets did not gain weight (p > 0.05), suggesting a low food ME (12.5 kJ/g).The substitution of the original diet (sunflower seeds, fruits and cooked maize) by the experimental foods decreased the basal (12-h fast) concentrations of glucose, cholesterol and triglycerides (p < 0.001). The consumption of pelleted diets reduced serum glucose and cholesterol (p < 0.05). Results suggest that the pelleted diets were more beneficial and can be used to reduce blood metabolites related to metabolic disorders that are commonly observed in macaws. PMID- 23627664 TI - Pediatric pyoderma gangrenosum with splenic and pulmonary involvement. AB - An 8-year-old boy presented with ulcers on the lip and limbs, scattered pustules, fever, and general malaise. Further investigation revealed splenic and pulmonary lesions. A diagnosis of pyoderma gangrenosum with splenic and pulmonary involvement was made. The authors have not found a previous report of pediatric pyoderma with splenic involvement in the literature. PMID- 23627665 TI - Water 16-mers and hexamers: assessment of the three-body and electrostatically embedded many-body approximations of the correlation energy or the nonlocal energy as ways to include cooperative effects. AB - This work presents a new fragment method, the electrostatically embedded many body expansion of the nonlocal energy (EE-MB-NE), and shows that it, along with the previously proposed electrostatically embedded many-body expansion of the correlation energy (EE-MB-CE), produces accurate results for large systems at the level of CCSD(T) coupled cluster theory. We primarily study water 16-mers, but we also test the EE-MB-CE method on water hexamers. We analyze the distributions of two-body and three-body terms to show why the many-body expansion of the electrostatically embedded correlation energy converges faster than the many-body expansion of the entire electrostatically embedded interaction potential. The average magnitude of the dimer contributions to the pairwise additive (PA) term of the correlation energy (which neglects cooperative effects) is only one-half of that of the average dimer contribution to the PA term of the expansion of the total energy; this explains why the mean unsigned error (MUE) of the EE-PA-CE approximation is only one-half of that of the EE-PA approximation. Similarly, the average magnitude of the trimer contributions to the three-body (3B) term of the EE-3B-CE approximation is only one-fourth of that of the EE-3B approximation, and the MUE of the EE-3B-CE approximation is one-fourth that of the EE-3B approximation. Finally, we test the efficacy of two- and three-body density functional corrections. One such density functional correction method, the new EE PA-NE method, with the OLYP or the OHLYP density functional (where the OHLYP functional is the OptX exchange functional combined with the LYP correlation functional multiplied by 0.5), has the best performance-to-price ratio of any method whose computational cost scales as the third power of the number of monomers and is competitive in accuracy in the tests presented here with even the electrostatically embedded three-body approximation. PMID- 23627666 TI - Effects of selective serotonin reuptake inhibitor treatment on plasma oxytocin and cortisol in major depressive disorder. AB - BACKGROUND: Oxytocin is known for its capacity to facilitate social bonding, reduce anxiety and for its actions on the stress hypothalamopituitary adrenal (HPA) axis. Since oxytocin can physiologically suppress activity of the HPA axis, clinical applications of this neuropeptide have been proposed in conditions where the function of the HPA axis is dysregulated. One such condition is major depressive disorder (MDD). Dysregulation of the HPA system is the most prominent endocrine change seen with MDD, and normalizing the HPA axis is one of the major targets of recent treatments. The potential clinical application of oxytocin in MDD requires improved understanding of its relationship to the symptoms and underlying pathophysiology of MDD. Previous research has investigated potential correlations between oxytocin and symptoms of MDD, including a link between oxytocin and treatment related symptom reduction. The outcomes of studies investigating whether antidepressive treatment (pharmacological and non pharmacological) influences oxytocin concentrations in MDD, have produced conflicting outcomes. These outcomes suggest the need for an investigation of the influence of a single treatment class on oxytocin concentrations, to determine whether there is a relationship between oxytocin, the HPA axis (e.g., oxytocin and cortisol) and MDD. Our objective was to measure oxytocin and cortisol in patients with MDD before and following treatment with selective serotonin reuptake inhibitors, SSRI. METHOD: We sampled blood from arterial plasma. Patients with MDD were studied at the same time twice; pre- and post- 12 weeks treatment, in an unblinded sequential design (clinicaltrials.govNCT00168493). RESULTS: Results did not reveal differences in oxytocin or cortisol concentrations before relative to following SSRI treatment, and there were no significant relationships between oxytocin and cortisol, or these two physiological variables and psychological symptom scores, before or after treatment. CONCLUSIONS: These outcomes demonstrate that symptoms of MDD were reduced following effective treatment with an SSRI, and further, stress physiology was unlikely to be a key factor in this outcome. Further research is required to discriminate potential differences in underlying stress physiology for individuals with MDD who respond to antidepressant treatment, relative to those who experience treatment resistance. PMID- 23627667 TI - Steiner tree methods for optimal sub-network identification: an empirical study. AB - BACKGROUND: Analysis and interpretation of biological networks is one of the primary goals of systems biology. In this context identification of sub-networks connecting sets of seed proteins or seed genes plays a crucial role. Given that no natural node and edge weighting scheme is available retrieval of a minimum size sub-graph leads to the classical Steiner tree problem, which is known to be NP-complete. Many approximate solutions have been published and theoretically analyzed in the computer science literature, but far less is known about their practical performance in the bioinformatics field. RESULTS: Here we conducted a systematic simulation study of four different approximate and one exact algorithms on a large human protein-protein interaction network with ~14,000 nodes and ~400,000 edges. Moreover, we devised an own algorithm to retrieve a sub graph of merged Steiner trees. The application of our algorithms was demonstrated for two breast cancer signatures and a sub-network playing a role in male pattern baldness. CONCLUSION: We found a modified version of the shortest paths based approximation algorithm by Takahashi and Matsuyama to lead to accurate solutions, while at the same time being several orders of magnitude faster than the exact approach. Our devised algorithm for merged Steiner trees, which is a further development of the Takahashi and Matsuyama algorithm, proved to be useful for small seed lists. All our implemented methods are available in the R-package SteinerNet on CRAN (http://www.r-project.org) and as a supplement to this paper. PMID- 23627668 TI - In situ quantitative study of nanoscale triboelectrification and patterning. AB - By combining contact-mode atomic force microscopy (AFM) and scanning Kevin probe microscopy (SKPM), we demonstrated an in situ method for quantitative characterization of the triboelectrification process at the nanoscale. We systematically characterized the triboelectric charge distribution, multifriction effect on charge transfer, as well as subsequent charge diffusion on the dielectric surface: (i) the SiO2 surface can be either positively or negatively charged through triboelectric process using Si-based AFM probes with and without Pt coating, respectively; (ii) the triboelectric charges accumulated from multifriction and eventually reached to saturated concentrations of (-150 +/- 8) MUC/m(2) and (105 +/- 6) MUC/m(2), respectively; (iii) the charge diffusion coefficients on SiO2 surface were measured to be (1.10 +/- 0.03) * 10(-15) m(2)/s for the positive charge and (0.19 +/- 0.01) * 10(-15) m(2)/s for the negative charges. These quantifications will facilitate a fundamental understanding about the triboelectric and de-electrification process, which is important for designing high performance triboelectric nanogenerators. In addition, we demonstrated a technique for nanopatterning of surface charges without assistance of external electric field, which has a promising potential application for directed self-assembly of charged nanostructures for nanoelectronic devices. PMID- 23627669 TI - Uropathogenic Escherichia coli in Iran: serogroup distributions, virulence factors and antimicrobial resistance properties. AB - BACKGROUND: Urinary tract infections (UTIs) are one of the most common bacterial infections with global expansion. These infections are predominantly caused by uropathogenic Escherichia coli (UPEC). METHODS: Totally, 123 strains of Escherichia coli isolated from UTIs patients, using bacterial culture method were subjected to polymerase chain reactions for detection of various O- serogroups, some urovirulence factors, antibiotic resistance genes and resistance to 13 different antibiotics. RESULTS: According to data, the distribution of O1, O2, O6, O7 and O16 serogroups were 2.43%, besides O22, O75 and O83 serogroups were 1.62%. Furthermore, the distribution of O4, O8, O15, O21 and O25 serogroups were 5.69%, 3.25%, 21.13%, 4.06% and 26.01%, respectively. Overall, the fim virulence gene had the highest (86.17%) while the usp virulence gene had the lowest distributions of virulence genes in UPEC strains isolated from UTIs patients. The vat and sen virulence genes were not detected in any UPEC strains. Totally, aadA1 (52.84%), and qnr (46.34%) were the most prevalent antibiotic resistance genes while the distribution of cat1 (15.44%), cmlA (15.44%) and dfrA1 (21.95%) were the least. Resistance to penicillin (100%) and tetracycline (73.98%) had the highest while resistance to nitrofurantoin (5.69%) and trimethoprim (16.26%) had the lowest frequencies. CONCLUSIONS: This study indicated that the UPEC strains which harbored the high numbers of virulence and antibiotic resistance genes had the high ability to cause diseases that are resistant to most antibiotics. In the current situation, it seems that the administration of penicillin and tetracycline for the treatment of UTIs is vain. PMID- 23627670 TI - Conformational determinants of the activity of antiproliferative factor glycopeptide. AB - The antiproliferative factor (APF) involved in interstitial cystitis is a glycosylated nonapeptide (TVPAAVVVA) containing a sialylated core 1 alpha-O disaccharide linked to the N-terminal threonine. The chemical structure of APF was deduced using spectroscopic techniques and confirmed using total synthesis. The synthetic APF provided a platform to study amino acid modifications and their effect on APF activity, based on which a structure-activity relationship (SAR) for APF activity was previously proposed. However, this SAR model could not explain the change in activity associated with minor alterations in the peptide sequence. Presented is computational analysis of 14 APF derivatives to identify structural trends from which a more detailed SAR is obtained. The APF activity is found to be dictated by the close interplay between carbohydrate-peptide and peptide-peptide interactions. The former involves hydrogen bond and hydrophobic interactions, and the latter is dominated by hydrophobic interactions. The highly flexible hydrophobic peptide adopts collapsed conformations separated by low energy barriers. APF activity correlates with hydrophobic clustering associated with amino acids 4A, 6V, and 8V. Peptide conformations are highly sensitive to single point mutations, which explain the experimental trends. The presented SAR will act as a guide for lead optimization of more potent APF analogues of potential therapeutic utility. PMID- 23627671 TI - The short isoform of the long-type PML-RARA fusion gene in acute promyelocytic leukaemia lacks sensitivity to all-trans-retinoic acid. AB - Alternative splicing is associated with human disease. In acute promyelocytic leukaemia (APL) patients with the long (L)-type promyelocytic leukaemia-retinoic acid receptor alpha fusion gene (PML-RARA), three alternative splicing isoforms can be detected: E5(+)E6(+), E5(-)E6(+), and E5(-)E6(-). This study is the first to demonstrate that alternative splicing of L-type PML-RARA is associated with time to achieve complete remission (CR) in APL. Higher expression of the E5(-)E6( ) isoform, the short isoform, was related to longer time to achieve CR. Each isoform was constructed into recombinant lentiviral vector and transfected into U937 cells. Compared with the E5(-)E6(+) and E5(+)E6(+) groups, the U937 cells with E5(-)E6(-) showed lower sensitivity to all-trans-retinoic acid treatment. PMID- 23627672 TI - The use of a polylactide-based copolymer as a temporary skin substitute in deep dermal burns: 1-year follow-up results of a prospective clinical noninferiority trial. AB - Deep dermal burns can be covered with different kind of materials and techniques; one of them is a polylactide-based temporary skin substitute. The aim of this study was to intraindividually compare its 1-year outcome with the results obtained by use of autologous skin grafts in patients suffering from deep dermal burns. A prospective noninferiority trial was designed in order to assess skin quality and scar formation by use of subjective (Vancouver Scar Scale; Patient and Observer Scar Assessment Scale) and objective (noninvasive cutometry) burn scar assessment tools. All items of the Patient and Observer Scar Assessment Scale, except vascularity, were found to be noninferior in the areas covered with the temporary skin substitute vs. autologous skin. Results of objective scar evaluation showed comparable viscoelastic parameters without reaching noninferiority. Overall, the outcome of deep dermal burns covered with a polylactide-based temporary skin substitute revealed satisfactory results in terms of scar formation and skin quality as compared with autologous skin. This paper supports its use in deep dermal burns, where autologous skin donor sites require either to be reserved for coverage of full-thickness skin defects in severe burns or to be saved for reduction of additional morbidity in selected patient collectives. PMID- 23627673 TI - Effectiveness of a real-time clinical decision support system for computerized physician order entry of plasma orders. AB - BACKGROUND: We investigated the effect of implementing adaptive plasma ordering criteria in the computerized physician order entry (CPOE) system, with alerts that were automatically generated if the recipient's antecedent international normalized ratio (INR) did not meet the institutional criteria. STUDY DESIGN AND METHODS: In a regional health care system consisting of 11 hospitals using a common CPOE, data on the number of plasma orders and alerts that were generated were collected over a 4-month period before prescribers were required to select an indication for plasma. When adaptive ordering was implemented prescribers had to choose from prepopulated indications for plasma: INR of 1.6 or greater with bleeding, INR of 1.6 or greater before an invasive procedure, therapeutic exchange, massive transfusion, and other. Regardless of the antecedent INR the alert did not trigger if massive transfusion or plasmapheresis was selected. Information on prescribers and recipients was collected during this 5-month period. RESULTS: In the 4-month period before the adaptive alerts were implemented, 42.9% of the plasma orders generated an alert; in the 5-month period thereafter the alert rate was significantly lower at 27.9% (p < 0.0001). The percentage of heeded alerts increased during the adaptive alert period (24.3% vs. 17.1%, respectively, p = 0.004). A significant percentage (45%) of other plasma orders were for periprocedure or bleeding patients whose antecedent INR was less than 1.6. There were significant differences in prescriber specialties among those who ordered plasma using the other indication compared to all plasma orders. CONCLUSION: Electronic interventions improve compliance with plasma guidelines but as implemented are not sufficient to completely curtail non evidence-based ordering. PMID- 23627674 TI - EFNS review on the role of muscle biopsy in the investigation of myalgia. AB - BACKGROUND: Myalgia, defined as any pain perceived in muscle, is very common in the general population and a frequent cause for referral to neurologists, rheumatologists and internists in general. It is however only rarely due to primary muscle disease and often referred from ligaments, joints, bones, the peripheral and central nervous system. A muscle biopsy should only be performed if this is likely to be diagnostically useful. At present no 'guidelines' exist. METHODS: An EFNS panel of muscle specialists was set to review relevant studies from PubMed dating as far back as 1/1/1990. Only Class IV studies were available and therefore the recommendations arrived at are 'best practice recommendations' based on information harvested from the literature search and expert opinion. RESULTS: Muscle cramps should be recognized while drugs, infections, metabolic/ endocrinological and rheumatological causes of myalgia should be identified from the history and examination and pertinent laboratory tests. A muscle biopsy is more likely to be diagnostically useful if myalgia is exertional and if one or more of the following apply: i) there is myoglobinuria, (ii) there is a second wind phenomenon, (iii) there is muscle weakness, (iv) there is muscle hypertrophy /atrophy, (v) there is hyperCKemia (>2-3* normal), and (vi) there is a myopathic EMG. CONCLUSIONS: Patients presenting with myalgia can be recommended to have a biopsy based on careful history and examination and on simple laboratory screening. PMID- 23627675 TI - Parental depressive symptoms and marital intimacy at 4.5 years: joint contributions to mother-child and father-child interaction at 6.5 years. AB - Using data from a subset of 606 families who participated in the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development, we assessed emotional intimacy in the marriage as a buffer of the negative effects of parental depression on the quality of parent-child interaction. Maternal and paternal depressive symptoms and perceptions of emotional intimacy in the marriage were assessed via self-reports when children were 4.5 years old, and parental sensitive scaffolding and child task orientation were observed during mother-child and father-child interaction tasks at 4.5 years and again at 6.5 years. Path analyses indicated that marital intimacy moderated the longitudinal association between parental depressive symptoms and parent child interaction, controlling for parent or child behavior at 4.5 years. The pattern of this interaction, however, differed for mothers and fathers. Paternal depressive symptoms predicted less child task orientation with fathers when marital intimacy was low and more child task orientation when marital intimacy was high. In contrast, maternal depressive symptoms predicted less sensitive scaffolding by mothers and less child task orientation with mothers when mothers reported moderate to high levels of marital intimacy. Results are discussed with respect to the buffering role of marital intimacy for children of depressed fathers and compensatory processes that may unfold for depressed mothers. PMID- 23627676 TI - Nutritional status and quality of life in patients with acute leukaemia prior to and after induction chemotherapy in three hospitals in Tehran, Iran: a prospective study. AB - BACKGROUND: The primary objective of the present study was to assess changes in the nutritional status and quality of life in acute leukaemia patients, aged >=15 years, who had undergone induction chemotherapy. METHODS: A preliminary and post induction chemotherapy assessment of patients' nutritional status, quality of life, sociodemographic status and medical characteristics was conducted using the Patient Generated Subjective Global Assessment (PG-SGA) and the European Organization for Research and Treatment of Cancer quality of life (QOL-C30, version 3) questionnaires. The PG-SGA is a clinical nutrition assessment tool used to evaluate oncology patients. Patients with newly-diagnosed acute leukaemia, aged >=15 years, at three hospitals in Tehran (from May 2009 to March 2010), were recruited for the present study. RESULTS: Sixty-three acute leukaemia patients [65% men and 35% women with a mean (SD) age of 33 (15.4) years] participated in the present study. A total of 19.4% were found to be malnourished prior to chemotherapy. After chemotherapy, 76.1% of patients were considered moderately malnourished, whereas 6.3% were severely malnourished. After induction chemotherapy, both the nutritional status and quality of life deteriorated in the majority of patients, as demonstrated by a paired t-test. CONCLUSIONS: A deteriorated nutritional status and quality of life was the result of the side effects posed by induction chemotherapy in the patients investigated in the present study. These findings highlight the need for an appropriate nutritional support programme to improve the nutritional status and quality of life in patients with leukaemia undergoing chemotherapy. PMID- 23627677 TI - Sense of coherence, depressive feelings and life satisfaction in older persons: a closer look at the role of integrity and despair. AB - OBJECTIVES: The present study investigated the relationship between Antonovsky's sense of coherence (SOC) and well-being in a sample of Flemish elderly. In addition, the mediating role of Erikson's developmental task of integrity versus despair was examined in the relationship between SOC, depression, and life satisfaction. METHOD: Data on sociodemographic variables, SOC, depressive symptoms, life satisfaction, ego-integrity, and despair were collected. In total, 100 older persons with a mean age of 76.5 years participated. Mplus was used to test the mediating role of integrity and despair in the relationship between SOC and both life satisfaction and depression. RESULTS: A positive relationship between SOC and well-being was found. More precisely, elderly individuals with a strong SOC experienced less depressive symptoms and higher levels of satisfaction with their life. In addition, mediation analysis indicated that the relationship between SOC and depressive symptoms was partially mediated by the positive resolution of the integrity-despair crisis, whereas the relationship between SOC and life satisfaction was fully mediated by integrity and despair. CONCLUSION: Our findings indicate that SOC might be a resource for greater well-being in the elderly. Furthermore, our study offers a partial explanation for the relations found and points to the importance of finding integrity and resolving despair in this stage of life. PMID- 23627678 TI - New measure for fathers of children with developmental challenges. AB - BACKGROUND: There is a relative lack of measures tailored to the study of fathers of children with developmental challenges (DCs). The goal of the current study was to create and validate a brief measure designed to capture the perceptions and experiences of these fathers. The Fathers of Children with Developmental Challenges (FCDC) questionnaire was designed to assess fathers' perceptions of the supports for, and challenges to, their efforts to be involved in the rearing of their children. METHOD: Participants were 101 fathers of children with DCs who completed an online survey. Scale validation included tests to determine reliability, validity and factor structure. Used to establish validity were measures of parenting stress, parenting commitment, parent personality and child social-communicative skills. RESULTS: Analyses indicated that the FCDC is reliable (alpha = 0.89), demonstrates content validity, construct validity and acts in theoretically expected ways. Factor analysis on the 20-item measure yielded two sub-scales: (1) impact on parenting, and (2) involvement with child intervention. CONCLUSIONS: The FCDC fills a gap in the literature by offering an easy-to-administer self-report measure of fathers' perceptions of supports for, and barriers to, their involvement with their children with DCs. The FCDC could assist professionals in delivering support services specifically for fathers of children with DCs. PMID- 23627679 TI - Relative importance of abstinence in clients' and clinicians' perspectives of recovery from drug and alcohol abuse. AB - This study collected data on drug and alcohol workers' (n = 55) and clients' (n = 139) perspectives on what constitutes a "recovery" from substance use disorder. Data were collected during 2010 from four residential faith-based treatment programs across the east coast of Australia. Self-report surveys specifically designed for this study were administered. Responses were compared using nonparametric test. Abstinence was seen as an important component of recovery but nonabstinent factors were also seen as having an important role. Staff placed more emphasis on clients taking responsibility for their problems and on the role of spiritual development. The importance of nonabstinence components was positively associated with a person's time in treatment and recovery. Implications, limitations, and future directions are noted. PMID- 23627681 TI - Efficacy and quality of life outcomes of oxybutynin for treating palmar hyperhidrosis in children younger than 14 years old. AB - The effects of oxybutynin for treating hyperhidrosis in children are still unknown. Therefore the aim of this study was to investigate the effects of oxybutynin on improving symptoms of hyperhidrosis and quality of life (QOL) in children with palmar hyperhidrosis (PH). Forty-five children ages 7-14 years with PH were evaluated 6 weeks after protocol treatment with oxybutynin. QOL was evaluated before and after treatment using a validated clinical questionnaire. More than 85% of the children with PH treated with oxybutynin experienced moderate or greater improvement in the level of sweating and 80% experienced improvement in QOL. Children who initially presented with very poor QOL were those who benefited most from oxybutynin therapy. Side effects occurred in 25 children (55.5%) and were mainly dry mouth. Only one patient had neurologic symptoms, which was reported as drowsiness. Oxybutynin is an effective treatment option for children with PH because it improves clinical symptoms and QOL. Further studies are required to determine the long-term outcomes of treatment with oxybutynin. PMID- 23627682 TI - Cassia cinnamon as a source of coumarin in cinnamon-flavored food and food supplements in the United States. AB - Coumarin as an additive or as a constituent of tonka beans or tonka extracts is banned from food in the United States due to its potentially adverse side effects. However, coumarin in food from other natural ingredients is not regulated. "True Cinnamon" refers to the dried inner bark of Cinnamomum verum. Other cinnamon species, C. cassia, C. loureiroi, and C. burmannii, commonly known as cassia, are also sold in the U.S. as cinnamon. In the present study, coumarin and other marker compounds were analyzed in authenticated cinnamon bark samples as well as locally bought cinnamon samples, cinnamon-flavored foods, and cinnamon based food supplements using a validated UPLC-UV/MS method. The experimental results indicated that C. verum bark contained only traces of coumarin, whereas barks from all three cassia species, especially C. loureiroi and C. burmannii, contained substantial amounts of coumarin. These species could be potential sources of coumarin in cinnamon-flavored food in the U.S. Coumarin was detected in all locally bought cinnamon, cinnamon-flavored foods, and cinnamon food supplements. Their chemical profiles indicated that the cinnamon samples and the cinnamon in food supplements and flavored foods were probably Indonesian cassia, C. burmannii. PMID- 23627680 TI - A phylogeny and revised classification of Squamata, including 4161 species of lizards and snakes. AB - BACKGROUND: The extant squamates (>9400 known species of lizards and snakes) are one of the most diverse and conspicuous radiations of terrestrial vertebrates, but no studies have attempted to reconstruct a phylogeny for the group with large scale taxon sampling. Such an estimate is invaluable for comparative evolutionary studies, and to address their classification. Here, we present the first large scale phylogenetic estimate for Squamata. RESULTS: The estimated phylogeny contains 4161 species, representing all currently recognized families and subfamilies. The analysis is based on up to 12896 base pairs of sequence data per species (average = 2497 bp) from 12 genes, including seven nuclear loci (BDNF, c mos, NT3, PDC, R35, RAG-1, and RAG-2), and five mitochondrial genes (12S, 16S, cytochrome b, ND2, and ND4). The tree provides important confirmation for recent estimates of higher-level squamate phylogeny based on molecular data (but with more limited taxon sampling), estimates that are very different from previous morphology-based hypotheses. The tree also includes many relationships that differ from previous molecular estimates and many that differ from traditional taxonomy. CONCLUSIONS: We present a new large-scale phylogeny of squamate reptiles that should be a valuable resource for future comparative studies. We also present a revised classification of squamates at the family and subfamily level to bring the taxonomy more in line with the new phylogenetic hypothesis. This classification includes new, resurrected, and modified subfamilies within gymnophthalmid and scincid lizards, and boid, colubrid, and lamprophiid snakes. PMID- 23627683 TI - Vercirnon for the treatment of Crohn's disease. AB - INTRODUCTION: CCR9 antagonism is a promising new therapeutic approach for the treatment of Crohn's disease. CCR9 is expressed on the cell surface of memory/effector CD4(+) T cells and selectively binds to the small intestinal lymphocyte chemoattractant CCL25 (TECK). Blockade of the CCR9/CCL25 interaction inhibits lymphocyte homing to the intestinal mucosa, thereby limiting inflammation and disease at this site. AREAS COVERED: This review details the current research on CCR9 antagonism and summarizes available clinical trial data for vercirnon , a selective CCR9 antagonist currently under development. EXPERT OPINION: If the results of ongoing large-scale clinical trials of vercirnon are in line with preliminary reports, CCR9 antagonism may have comparable efficacy to anti-TNF therapies and a potentially superior safety profile, making it the latest addition to the growing arsenal of immunomodulatory drug therapies available to combat Crohn's disease. Moreover, since vercirnon is an oral drug, its associated costs will likely be much lower than expensive infusion-based anti TNF therapies, providing further economic benefits. PMID- 23627684 TI - A cluster-randomised, controlled trial to assess the impact of a workplace osteoporosis prevention intervention on the dietary and physical activity behaviours of working women: study protocol. AB - BACKGROUND: Osteoporosis is a debilitating disease and its risk can be reduced through adequate calcium consumption and physical activity. This protocol paper describes a workplace-based intervention targeting behaviour change in premenopausal women working in sedentary occupations. METHOD/DESIGN: A cluster randomised design was used, comparing the efficacy of a tailored intervention to standard care. Workplaces were the clusters and units of randomisation and intervention. Sample size calculations incorporated the cluster design. Final number of clusters was determined to be 16, based on a cluster size of 20 and calcium intake parameters (effect size 250 mg, ICC 0.5 and standard deviation 290 mg) as it required the highest number of clusters.Sixteen workplaces were recruited from a pool of 97 workplaces and randomly assigned to intervention and control arms (eight in each). Women meeting specified inclusion criteria were then recruited to participate. Workplaces in the intervention arm received three participatory workshops and organisation wide educational activities. Workplaces in the control/standard care arm received print resources. Intervention workshops were guided by self-efficacy theory and included participatory activities such as goal setting, problem solving, local food sampling, exercise trials, group discussion and behaviour feedback.Outcomes measures were calcium intake (milligrams/day) and physical activity level (duration: minutes/week), measured at baseline, four weeks and six months post intervention. DISCUSSION: This study addresses the current lack of evidence for behaviour change interventions focussing on osteoporosis prevention. It addresses missed opportunities of using workplaces as a platform to target high-risk individuals with sedentary occupations. The intervention was designed to modify behaviour levels to bring about risk reduction. It is the first to address dietary and physical activity components each with unique intervention strategies in the context of osteoporosis prevention. The intervention used locally relevant behavioural strategies previously shown to support good outcomes in other countries. The combination of these elements have not been incorporated in similar studies in the past, supporting the study hypothesis that the intervention will be more efficacious than standard practice in osteoporosis prevention through improvements in calcium intake and physical activity. PMID- 23627685 TI - Understanding morphology-controlled synthesis of zinc nanoparticles and their characteristics of hydrolysis reaction. AB - Two-step thermochemical water-splitting cycle based on a Zn/ZnO redox pair is considered as a potential route for carbon-free production of hydrogen because the first hydrolysis step of the cycle highly depends on the method of preparation and the resultant particle characteristics, such as size, morphology, surface state, and initial oxide content. Here, employing a conventional evaporation and condensation method, we successfully produce three types of Zn nanoparticles ranging from nanorods, mesoporous nanorods with nanospheres on their surfaces, and fully sintered nanocrystals. The achievement in morphology control is realized simply by changing the injection position of the quenching gas. We found that the resultant hydrolysis kinetics is highly dependent on the morphology and porosity of the Zn nanoparticles. Finally, a series of simple mathematical modeling is made in an effort to understand the formation mechanism of Zn nanoparticles. PMID- 23627686 TI - Race differences in the association of spiritual experiences and life satisfaction in older age. AB - OBJECTIVES: The primary objective of this study was to examine an African American 'faith advantage' in life satisfaction. Specifically, we sought to test the hypothesis that the positive relationship between spiritual experiences and life satisfaction is stronger among older African Americans than among older Whites. METHOD: The data came from 6864 community-dwelling persons aged 65+ (66% African American) who participated in the Chicago Health and Aging Project. Life satisfaction was measured using a five-item composite and we used a five-item version of the Daily Spiritual Experiences scale. RESULTS: In a regression model adjusting for age, sex, marital status, education, income and worship attendance, we found that African American race was associated with lower life satisfaction. We also found a positive association between spiritual experiences and life satisfaction. In an additional model, a significant race by spiritual experiences interaction term indicates that spiritual experiences are more positively associated with life satisfaction among African Americans. CONCLUSION: The data suggest that at higher levels of spiritual experiences, racial differences in life satisfaction are virtually non-existent. However, at lower levels of spiritual experiences, older African Americans show modestly lower levels of life satisfaction than do older Whites. This pattern suggests that spiritual experiences are a positive resource - distinct from worship attendance - that enable older African Americans to overcome decrements in life satisfaction and, in fact, that lower spiritual experiences may be especially harmful for older African American's life satisfaction. PMID- 23627687 TI - Can social support alleviate inflammation associated with childhood adversities? AB - OBJECTIVE: Childhood adversities have been linked to elevated high-sensitivity C reactive protein (hsCRP), which has been associated with increased morbidity. Low social support has been reported to worsen the prognosis in heart disease and cancer, and high social support has been linked to lower hsCRP. We hypothesized that social support could be a mediating factor between childhood adversities and hsCRP. METHODS: The sample was drawn from the data of the nationwide Health and Social Support Study (HeSSup Study) to which 25,898 Finns had responded in 1998. The cohort was stratified into groups of high and low social support, and the study group consisted of 100 women in both groups. Additionally, we invited a randomly drawn group of 50 subjects and a group of 62 women who had reported depressive symptoms. Of the 312 women, 116 participated in the study. RESULTS: Social support score (Social Support Questionnaire, SSQ) was lower when the number of adverse experiences in childhood was high (r = - 0.251, P = 0.007). hsCRP and SSQ were inversely associated (r = - 0.188, P = 0.046). In the adjusted general linear model, the level of social support was significantly associated with hsCRP and there was a statistically significant interactive effect of small effect size of childhood adversities and the level of social support on hsCRP (ES = 0.123, P = 0.004). CONCLUSION: This finding suggests that childhood adversity may affect social relationships and that high social support may attenuate the health risks caused by childhood adverse experience. PMID- 23627688 TI - Organocatalyzed asymmetric synthesis of morphans. AB - A general effective organocatalyzed synthesis of enantioenriched morphans with up to 92% ee was developed. The morphan scaffold was constructed in a one-pot tandem asymmetric organocatalyzed Michael addition followed by a domino Robinson annulation/aza-Michael intramolecular reaction sequence from easily available starting materials. PMID- 23627689 TI - Diabetes impairs adipose tissue-derived stem cell function and efficiency in promoting wound healing. AB - Adipose tissue-derived stem cells (ASCs) are gaining increasing consideration in tissue repair therapeutic application. Recent evidence indicates that ASCs enhance skin repair in animal models of impaired wound healing. To assess the therapeutic activity of autologous vs. allogeneic ASCs in the treatment of diabetic ulcers, we functionally characterized diabetic ASCs and investigated their potential to promote wound healing with respect to nondiabetic ones. Adipose tissue-derived cells from streptozotocin-induced type 1 diabetic mice were analyzed either freshly isolated as stromal vascular fraction (SVF), or following a single passage of culture (ASCs). Diabetic ASCs showed decreased proliferative potential and migration. Expression of surface markers was altered in diabetic SVF and cultured ASCs, with a reduction in stem cell marker-positive cells. ASCs from diabetic mice released lower amounts of hepatocyte growth factor, vascular endothelial growth factor (VEGF)-A, and insulin-like growth factor-1, growth factors playing important roles in skin repair. Accordingly, the supernatant of diabetic ASCs manifested reduced capability to promote keratinocyte and fibroblast proliferation and migration. Therapeutic potential of diabetic SVF administered to wounds of diabetic mice was blunted as compared with cells isolated from nondiabetic mice. Our data indicate that diabetes alters ASC intrinsic properties and impairs their function, thus affecting therapeutic potential in the autologous treatment for diabetic ulcers. PMID- 23627690 TI - The effect of estrogen in a man with Parkinson's disease and a review of its therapeutic potential. AB - Estrogen has been implicated in controlling the pathogenesis and symptoms of Parkinson's disease (PD) in women. Here, we report a 53-year-old male with PD who underwent estrogen therapy with estradiol (E2). Within a month, he exhibited increased dyskinesias. His medication was reduced by 35% from a levodopa equivalent dose (LED) of 820-535 over three months, which overall improved his motor fluctuations and dyskinesias. Therefore, E2 therapy could have therapeutic potential in males with PD. PMID- 23627691 TI - Effects of outer membrane protein TolC on the transport of Escherichia coli within saturated quartz sands. AB - The outer membrane protein (OMP) TolC is the cell surface component of several drug efflux pumps that are responsible for bacterial resistance against a variety of antibiotics. In this research, we investigated the effects of OMP TolC on E. coli transport within saturated sands through column experiments using a wild type E. coli K12 strain (with OMP TolC), as well as the corresponding transposon mutant (tolC::kan) and the markerless deletion mutant (DeltatolC). Our results showed OMP TolC could significantly enhance the transport of E. coli when the ionic strength was 20 mM NaCl or higher. The deposition rate coefficients for the wild-type E. coli strain (with OMP TolC) was usually >50% lower than those of the tolC-negative mutants. The measurements of contact angles using three probe liquids suggested that TolC altered the surface tension components of E. coli cells and lead to lower Hamaker constants for the cell-water-sand system. The interaction energy calculations using the extended Derjaguin-Landau-Verwey Overbeek (XDLVO) theory suggested that the deposition of the E. coli cell primarily occurred at the secondary energy minimum. The depth of the secondary energy minimum increased with ionic strength, and was greater for the TolC deletion strains under high ionic strength conditions. Overall, the transport behavior of three E. coli strains within saturated sands could be explained by the XDLVO calculations. Results from this research suggested that antibiotic resistant bacteria expressing OMP TolC could spread more widely within sandy aquifers. PMID- 23627692 TI - The significance of pretransplant donor-specific antibodies reactive with intact or denatured human leucocyte antigen in kidney transplantation. AB - Antibodies recognizing denatured human leucocyte antigen (HLA) can co-react with epitopes on intact HLA or recognize cryptic epitopes which are normally unaccessible to HLA antibodies. Their specificity cannot be distinguished by single antigen beads (SAB) alone, as they carry a mixture of intact and denatured HLA. In this study, we selected pretransplant sera containing donor-specific HLA class I antibodies (DSA) according to regular SAB analysis from 156 kidney transplant recipients. These sera were analysed using a SAB preparation (iBeads) which is largely devoid of denatured HLA class I, and SAB coated with denatured HLA class I antigens. A total of 241 class I DSA were found by regular SAB analysis, of which 152 (63%) were also found by iBeads, whereas 28 (11%) were caused by reactivity with denatured DNA. Patients with DSA defined either by regular SAB or iBeads showed a significantly lower graft survival rate (P = 0.007) compared to those without HLA class I DSA, whereas reactivity to exclusively denatured HLA was not associated with decreased graft survival. In addition, DSA defined by reactivity to class I SAB or class I iBeads occurred more frequently in female patients and in patients with historic HLA sensitization, whereas reactivity to denatured HLA class I was not associated with any of these parameters. Our data suggest that pretransplant donor-specific antibodies against denatured HLA are clinically irrelevant in patients already sensitized against intact HLA. PMID- 23627693 TI - Skeletal evidence for variable patterns of handedness in chimpanzees, human hunter-gatherers, and recent British populations. AB - Previous studies have shown a strong correspondence between long bone bilateral asymmetry and reported handedness. Here, we compare the pattern of asymmetry in mechanical properties of the humerus and second metacarpal of Pan troglodytes, recent British industrial and medieval populations, and a broad range of human hunter-gatherers, to test whether technological variation corresponds with lateralization in bone function. The results suggest that P. troglodytes are left lateralized in the morphology of the humerus and right-lateralized in the second metacarpal, while all human populations are predominantly right-biased in the morphology of these bones. Among human populations, the second metacarpals of 63% of hunter-gatherers show right-hand bias, a frequency similar to that found among chimpanzees. In contrast, the medieval and recent British populations show over 80% right-lateralization in the second metacarpal. The proportion of individuals displaying right-directional asymmetry is less than the expected 90% among all human groups. The variation observed suggests that the human pattern of right biased asymmetry developed in a mosaic manner throughout human history, perhaps in response to technological development. PMID- 23627694 TI - Epidemiology of Plasmodium falciparum gametocytemia in India: prevalence, age structure, risk factors and the role of a predictive score for detection. AB - OBJECTIVE: To characterise the epidemiology of Plasmodium falciparum gametocytemia and determine the prevalence, age structure and the viability of a predictive model for detection. METHODS: We collected data from 21 therapeutic efficacy trials conducted in India during 2009-2010 and estimated the contribution of each age group to the reservoir of transmission. We built a predictive model for gametocytemia and calculated the diagnostic utility of different score cut-offs from our risk score. RESULTS: Gametocytemia was present in 18% (248/1 335) of patients and decreased with age. Adults constituted 43%, school-age children 45% and under fives 12% of the reservoir for potential transmission. Our model retained age, sex, region and previous antimalarial drug intake as predictors of gametocytemia. The area under the receiver operator characteristic curve was 0.76 (95%CI:0.73,0.78), and a cut-off of 14 or more on a risk score ranging from 0 to 46 provided 91% (95%CI:88,95) sensitivity and 33% (95%CI:31,36) specificity for detecting gametocytemia. CONCLUSIONS: Gametocytemia was common in India and varied by region. Notably, adults contributed substantially to the reservoir for potential transmission. Predictive modelling to generate a clinical algorithm for detecting gametocytemia did not provide sufficient discrimination for targeting interventions. PMID- 23627696 TI - Global climate changes drive ecological specialization of mammal faunas: trends in rodent assemblages from the Iberian Plio-Pleistocene. AB - BACKGROUND: Several macroevolutionary hypotheses propose a synchrony between climatic changes and variations in the structure of faunal communities. Some of them focus on the importance of the species ecological specialization because of its effects on evolutionary processes and the resultant patterns. Particularly, Vrba's turnover pulse hypothesis and resource-use hypothesis revolve around the importance of biome inhabitation. In order to test these hypotheses, we used the Biomic Specialization Index, which is based on the number of biomes occupied by each species, and evaluated the changes in the relative importance of generalist and specialist rodents in more than forty fossil sites from the Iberian Plio Pleistocene. RESULTS: Our results indicate that there was a decrease in the specialization degree of rodent faunas during the Pliocene due to the global cooling that triggered the onset of the glacial events of the Cenozoic (around 2.75 Ma). The subsequent faunal transition after this critical paleoenvironmental event was characterized by an increase of specialization related to the adaptation to the new environmental conditions, which was mainly associated with the Pleistocene radiation of Arvicolinae (voles). CONCLUSIONS: The pattern of faunal turnover is correlated with the development of the modern glaciations in the Northern Hemisphere around 2.75 Ma, and represents a reorganization of the rodent communities, as suggested by the turnover pulse hypothesis. Our data also support the resource-use hypothesis, which presumes the role of the degree of specialization in resources specifically related to particular biomes as a driver of differential speciation and extinction rates. These results stress the intimate connection between ecological and evolutionary changes. PMID- 23627695 TI - Polymorph-specific kinetics and thermodynamics of beta-amyloid fibril growth. AB - Amyloid fibrils formed by the 40-residue beta-amyloid peptide (Abeta(1-40)) are highly polymorphic, with molecular structures that depend on the details of growth conditions. Underlying differences in physical properties are not well understood. Here, we investigate differences in growth kinetics and thermodynamic stabilities of two Abeta(1-40) fibril polymorphs for which detailed structural models are available from solid-state nuclear magnetic resonance (NMR) studies. Rates of seeded fibril elongation in the presence of excess soluble Abeta(1-40) and shrinkage in the absence of soluble Abeta(1-40) are determined with atomic force microscopy (AFM). From these rates, we derive polymorph-specific values for the soluble Abeta(1-40) concentration at quasi-equilibrium, from which relative stabilities can be derived. The AFM results are supported by direct measurements by ultraviolet absorbance, using a novel dialysis system to establish quasi equilibrium. At 24 degrees C, the two polymorphs have significantly different elongation and shrinkage kinetics but similar thermodynamic stabilities. At 37 degrees C, differences in kinetics are reduced, and thermodynamic stabilities are increased significantly. Fibril length distributions in AFM images provide support for an intermittent growth model, in which fibrils switch randomly between an "on" state (capable of elongation) and an "off" state (incapable of elongation). We also monitor interconversion between polymorphs at 24 degrees C by solid-state NMR, showing that the two-fold symmetric "agitated" (A) polymorph is more stable than the three-fold symmetric "quiescent" (Q) polymorph. Finally, we show that the two polymorphs have significantly different rates of fragmentation in the presence of shear forces, a difference that helps explain the observed predominance of the A structure when fibrils are grown in agitated solutions. PMID- 23627697 TI - Disturbed eating behaviours and associated psychographic characteristics of college students. AB - BACKGROUND: Young adulthood is a stressful transition period that may increase the risk for disturbed eating, especially for college students. The present study aimed to explore disturbed eating behaviours and a broad array of associated psychographic characteristics in a large, diverse sample of college students. METHODS: College students (n = 2604; 58% white; 63% female) enrolled at three large, public US universities in 2009 and 2010 were recruited to take an online survey. The survey included reliable and valid disturbed eating behaviour and associated psychographic characteristic measures. RESULTS: Many participants engaged in disturbed eating practices. For example, one-quarter of women and one fifth of men engaged in dietary restraint. One in seven reported regularly binge eating. One-third used inappropriate compensatory behaviours (self-induced vomiting, medicine misuse and excessive exercise) as a means for controlling weight and/or shape, with the rate of these behaviours reaching clinically significant levels for 4%, 3% and 5% of participants, respectively. Examination of psychographic characteristics revealed that one-fifth had moderate levels of depression and anxiety severity and almost half engaged in at least one obsessive compulsive disorder type behaviour. Females felt under more pressure to attain the media physical appearance standard than males. CONCLUSIONS: The findings of the present study suggest that nutrition education interventions for college students may be needed to address disturbed eating behaviours and to provide guidance on how to seek professional help. The findings also suggest that it may be prudent for healthcare professionals to routinely screen college students for disturbed eating behaviours and offer interventions early when treatment is likely to be most effective. PMID- 23627698 TI - Influence of the Surgical Education and Training programme on the Fellowship Examination. AB - Introduction of an increasingly competence-based Royal Australasian College of Surgeons (RACS) Surgical Education and Training (SET) programme has influenced the nature and conduct of the Fellowship Examination (FEX). The FEX is the final summative assessment taken near the completion of SET training, and is aligned to the other SET assessment processes. It mainly tests two of the nine RACS surgical competencies, focusing on professional judgement and the clinical application of knowledge. It is used to help determine whether candidates are safe to practise unsupervised at consultant level. There have been refinements to a number of the processes including standard setting, blueprinting, developing marking descriptors and improving the reliability and validity of the examination. An Examiners' Training Course has also been introduced. PMID- 23627699 TI - Active layer-incorporated, spectrally tuned Au/SiO2 core/shell nanorod-based light trapping for organic photovoltaics. AB - We demonstrate that incorporation of octadecyltrimethoxysilane (OTMS) functionalized, spectrally tuned, gold/silica (Au/SiO2) core/shell nanospheres and nanorods into the active layer of an organic photovoltaic (OPV) device led to an increase in photoconversion efficiency (PCE). A silica shell layer was added onto Au core nanospheres and nanorods in order to provide an electrically insulating surface that does not interfere with carrier generation and transport inside the active layer. Functionalization of the Au/SiO2 core/shell nanoparticles with the OTMS organic ligand was then necessary to transfer the Au/SiO2 core/shell nanoparticles from an ethanol solution into an OPV polymer compatible solvent, such as dichlorobenzene. The OTMS-functionalized Au/SiO2 core/shell nanorods and nanospheres were then incorporated into the active layers of two OPV polymer systems: a poly(3-hexylthiophene):[6,6]-phenyl-C61-butyric acid methyl ester (P3HT:PCB60M) OPV device and a poly[2,6-4,8-di(5 ethylhexylthienyl)benzo[1,2-b;3,4-b]dithiophene-alt-5-dibutyloctyl-3,6-bis(5 bromothiophen-2-yl)pyrrolo[3,4-c]pyrrole-1,4-dione] (PBDTT-DPP:PC60BM) OPV device. For the P3HT:PC60BM polymer with a band edge of ~700 nm, the addition of the core/shell nanorods with an aspect ratio (AR) of ~2.5 (extinction peak ~670 nm) resulted in a 7.1% improvement in PCE, while for the PBDTT-DPP:PC60BM polymer with a band edge of ~860 nm, the addition of core/shell nanorods with an AR of ~4 (extinction peak ~830 nm) resulted in a 14.4% improvement in PCE. The addition of Au/SiO2 core/shell nanospheres to the P3HT:PC60BM polymer resulted in a 2.7% improvement in PCE, while their addition to a PBDTT-DPP:PC60BM polymer resulted in a 9.1% improvement. The PCE and Jsc enhancements were consistent with external quantum efficiency (EQE) measurements, and the EQE enhancements spectrally matched the extinction spectra of Au/SiO2 nanospheres and nanorods in both OPV polymer systems. PMID- 23627702 TI - Evaluating a health behaviour model for persons with and without an intellectual disability. AB - BACKGROUND: Based on the idea of the Common Sense Model of Illness Representations by Leventhal as well as Lohaus's concepts of health and illness, a health behaviour model was designed to explain health behaviours applied by persons with intellectual disabilities (ID). The key proposal of this model is that the way someone understands the concepts of health, illness and disability influences the way they perceive themselves and what behavioural approaches to them they take. METHOD: To test this model and explain health differences between the general population and person with ID, 230 people with ID and a comparative sample of 533 persons without ID were included in this Austrian study. Data were collected on general socio-demographics, personal perceptions of illness and disability, perceptions of oneself and health-related behaviours. RESULTS: Psychometric analysis of the instruments used showed that they were valid and reliable and hence can provide a valuable tool for studying health-related issues in persons with and without ID. With respect to the testing of the suggested health model, two latent variables were defined in accordance to the theory. The general model fit was evaluated by calculating different absolute and descriptive fit indices. Most indices indicated an acceptable model fit for all samples. CONCLUSIONS: This study presents the first attempt to explore the systematic differences in health behaviour between people with and without ID based on a suggested health model. Limitations of the study as well as implications for practice and future research are discussed. PMID- 23627703 TI - Lichen nitidus with involvement of the palms. AB - A 14-year-old girl presented with hyperkeratotic, pitted, skin-colored papules on a slightly erythematous surface on her palms and erythematous and squamous papules around her ankles. She was clinically and histopathologically diagnosed with lichen nitidus, which is observed rarely on the palms. PMID- 23627704 TI - A hybrid electrospun PU/PCL scaffold satisfied the requirements of blood vessel prosthesis in terms of mechanical properties, pore size, and biocompatibility. AB - In this study, a novel hybrid polyurethane/polycaprolactone (PU/PCL) tubular scaffold was fabricated using the electrospinning process for blood vessel prosthesis applications. The detailed microstructure and material properties such as porosity, tensile and bust strength, contact angle, and biocompatibility were investigated and compared with those of monolithic PU and PCL scaffolds. The mechanical properties of the hybrid PU/PCL scaffold (tensile strength: 18 MPa, pressure strength: 590 mmHg) were found to be within the range needed for artificial blood vessel applications. The pore sizes of the PU/PCL scaffold ranged from 5-150 um in diameter, are sufficient enough to allow nutrient diffusion across the membrane. The reduced hydrophobic property of the PU/PCL scaffold was the result of the addition of relatively less hydrophobic PU compared with monolithic PCL scaffold. The biocompatibility of the PU/PCL scaffold was evaluated through cytotoxicity testing, and morphological observation by scanning electron microscopy and confocal microscopy using cow pulmonary artery endothelial cells and fibroblast like cells (L929). PMID- 23627705 TI - Neuropeptides in Alzheimer's disease: from pathophysiological mechanisms to therapeutic opportunities. AB - Neuropeptides are found throughout the entire nervous system where they can act as neurotransmitter, neuromodulator or neurohormone. In those functions, they play important roles in the regulation of cognition and behavior. In brain disorders like Alzheimer's disease (AD), where abnormal cognition and behavior are observed, the study of neuropeptides is particularly interesting since altered neuropeptides can function as biomarkers or as targets for new medication. In this article neuropeptides with relevance to AD are listed and their influence on cognitive and behavioral disturbances is discussed. Findings from human cerebrospinal fluid and brain tissue, and AD mouse models are described and related to the pathophysiology and symptomatology of the disease. In the past, clinical trials with neuropeptides have often failed due to insufficient delivery to the brain. Therefore, new strategies to target the brain with peptide drugs are also covered. PMID- 23627706 TI - Glutamate receptors in human caudate nucleus in normal aging and Alzheimer's disease. AB - Neostriatum is one of the brain areas that are not primarily affected in Alzheimer's disease, according to classic regard of the disease. However, recent data emphasize the involvement of neostriatum, especially the head of the caudate nucleus, in the emergence of characteristic symptoms of the disease. Glutamatergic neurotransmission is a key component of striatal pathways. The present study is focused on glutamate receptors of striatal neurons on human caudate nucleus in normal aging and Alzheimer's disease. Immunohistochemical studies were carried out for N-methyl-D-aspartate receptor subunit 1 (NMDAR1), alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit 2 (GluR2) and metabotropic glutamate receptor 5 (mGluR5). Ionotropic receptors (NMDAR1 and GluR2) were found to be expressed by 82% - 93% of striatal neurons with no significant alterations in aging and Alzheimer's disease. On the other hand, metabotropic receptor mGluR5 was found to be expressed by just 40% of striatal neurons in young individuals, with significant intensity variations among the neurons. This percent was increased in elderly individuals and Alzheimer's disease patients to 80% and 92% of striatal neurons, respectively. The up-regulation of mGluR5 both in normal aging and Alzheimer's disease is possibly associated with reorganization of neuronal connections, indicates the complexity of this receptor function and renders quite unpredictable the intervention and treatment of dementia with mGluR5 inhibitors or modulators. PMID- 23627707 TI - Cholinesterase inhibitors modulate autonomic function in patients with Alzheimer's disease and mixed dementia. AB - Cholinesterase inhibitors (ChEIs), the mainstay treatment for dementia, have systemic actions that can affect cardiovascular and autonomic nervous system (ANS). Thirty-nine patients with Alzheimer's disease or mixed dementia underwent a comprehensive clinical evaluation, prior to and during ChEIs therapy, including orthostatic challenge, electrocardiogram (EKG) and heart rate variability (HRV) spectral analysis through Holter recordings. ChEIs therapy determined a decrease in supine diastolic blood pressure (BP) and in both diastolic and systolic BP in orthostatic position (79.8 +/- 9.0 vs. 76.4 +/- 9.3 mmHg, p=0.012; 79.9 +/- 11.6 vs. 75.3 +/- 9.9, p=0.005 and 144.6 +/- 25.8 vs. 137.6 +/- 21.1, p=0.020, respectively). Spectral analysis revealed no difference on static HRV components, but, during orthostatic challenge, an increase in LF/HF ratio (2.2+/-2.4 vs. 4.6+/-5.9, p=0.011) and a reduction in HF component emerged (1604.3 +/- 5610.1 vs. 266.1 +/- 525.5, p=0.010). ChEIs showed no influence on EKG parameters or on the occurrence of orthostatic hypotension. Treatment with ChEIs was associated with functional improvement of the ANS behavior and to a decrease in supine DBP and in both orthostatic SBP and DBP. PMID- 23627708 TI - Efficacy and toxicity of clioquinol treatment and A-beta42 inoculation in the APP/PSI mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD), the most common human neurodegenerative disease, is characterized pathologically by numerous deposits of amyloid plaques in the brain. Systemic administration of clioquinol (CQ) and inoculation with amyloid beta42 (Abeta42) vaccines have been demonstrated to significantly inhibit deposits of amyloid in AD brains. However, each of these treatments has also been reported to be neurotoxic. The generation of transgenic mice models of AD has made it possible to study aspects of this disease employing experimental animals. In the present study, we investigated the efficacy and toxicity of CQ and Abeta42 vaccine in a transgenic AD (APP/PS1) mouse model. Our results confirmed that both CQ and Abeta42 vaccine were effective in significantly reducing the deposits of amyloid in the brains of transgenic AD mice. We also report here that systemic CQ induces myelinopathies in the dorsal lateral geniculate nucleus (DLG), which was almost devoid of amyloid plaques and is the primary site of retinal efferent projections via the optic nerve. This is the first report that systemic administration of CQ causes myelinopathies in the central nervous system (CNS) of a transgenic AD mouse model as well as wild-type mice. Inoculation with an Abeta42 vaccine was also found, for the first time, to result in a significant increase in plaque-independent astrocytic hyperplasia in the dorsal part of the lateral septal nucleus (LSD) which was also devoid of plaques, reflecting potential brain inflammatory processes. PMID- 23627711 TI - How mechanical deformations contribute to the effectiveness of negative-pressure wound therapy. AB - Negative-pressure wound therapy (NPWT) has significantly improved healing rates and patient comfort since its inception. However, a considerable number of questions have been raised regarding its mechanisms of action. Many health care workers and researchers have attempted to clarify the role of NPWT in wound healing. The purpose of this perspective article is to assemble some of the concepts that have been put forward in order to propose an integrated view of the mechanisms involved in NPWT. Particular emphasis will be placed on mechanically induced tissue deformations and their involvement in some of the key processes of wound healing, including nutrient and oxygen transport, blood vessel formation, and cellular proliferation and differentiation, mainly of myofibroblasts. PMID- 23627712 TI - Different molecular mechanisms of inhibition of bovine viral diarrhea virus and hepatitis C virus RNA-dependent RNA polymerases by a novel benzimidazole. AB - The virus-encoded RNA-dependent RNA polymerase (RdRp) has emerged as a primary target in the search for selective inhibitors of Flaviviridae. Recently, we reported on the selective inhibition, in cell-based assays, of both BVDV (EC50 = 0.80 +/- 0.06 MUM) and HCV (EC50 = 1.11 +/- 0.15 MUM) by 2-{1-[2-(2,4 dimethoxyphenyl)-1H-benzimidazol-5-yl]ethylidene}hydrazinecarbothioamide (227G). Here we show that, in enzyme assays with recombinant enzymes, 227G inhibits, in a dose-dependent manner, the RdRp of both BVDV (IC50 = 0.0020 +/- 0.0004 MUM) and HCV (IC50 = 0.40 +/- 0.04 MUM). Furthermore, we report on the selection and molecular analysis of a BVDV-resistant mutant, characterized by the presence of the I261M mutation. By applying a multilevel computational approach, we identified different 227G binding sites on the two RdRps. They were further validated by the good agreement between the calculated affinities and those extrapolated from IC50 values. Our findings suggest different molecular mechanisms of inhibition of the HCV and BVDV RdRps by 227G and indicate the importance of understanding ligand-enzyme interactions at the molecular level for the rational design of new and more potent leads. PMID- 23627709 TI - Treadmill exercise prevents learning and memory impairment in Alzheimer's disease like pathology. AB - Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by progressive memory loss. In contrast, accumulating evidence suggests a neuroprotective role of regular exercise in aging associated memory impairment. In this study, we investigated the ability of regular exercise to prevent impairments of short-term memory (STM) and early long-term potentiation (E-LTP) in area CA1 of the hippocampus in a rat model of AD (i.c.v. infusion of 250 pmol/day Abeta1-42 peptides). We utilized behavioral assessment, in vivo electrophysiological recording, and immunoblotting in 4 groups of adult Wistar rats: control, treadmill exercise (Ex), beta-amyloid-infused (Abeta), and amyloid infused/treadmill exercised (Ex/Abeta). Our findings indicated that Abeta rats made significantly more errors in the radial arm water maze (RAWM) compared to all other groups and exhibited suppressed E-LTP in area CA1, which correlated with deleterious alterations in the levels of memory and E-LTP-related signaling molecules including calcineurin (PP2B), brain derivedneurotrophic factor (BDNF) and phosphorylated CaMKII (p-CaMKII). Compared to controls, Ex and Ex/Abeta rats showed a similar behavioral performance and a normal E-LTP with no detrimental changes in the levels of PP2B, BDNF, and p- CaMKII. We conclude that treadmill exercise maybe able to prevent cognitive impairment associated with AD pathology. PMID- 23627713 TI - PCDD/Fs in plasma of individuals living near a hazardous waste incinerator. A comparison of measured levels and estimated concentrations by PBPK modeling. AB - The construction of the first and, until now, only hazardous waste incinerator (HWI) in Spain finished in 1998. To assess its potential impact on the population living in the vicinity, a surveillance program was established. It includes the periodical biomonitoring of PCDD/Fs body burden. On the basis of this program, in 2012 we determined the levels of PCDD/Fs in plasma of nonoccupationally exposed individuals living near the HWI. The results were compared with those of the baseline study, and with those of two previous surveys (2002 and 2007). A multicompartment, physiologically based pharmacokinetic (PBPK) model was also applied to estimate the levels of PCDD/Fs in plasma. The model was validated by comparing the results with our experimental data (baseline, 2002, 2007, and 2012). The current mean concentration was 6.18 pg I-TEQ/g lipid, with a range between 2.03 and 18.8 pg I-TEQ/g lipid. In 1998 (baseline), the mean concentration of PCDD/Fs in plasma was 27.0 pg I-TEQ/g lipid (reduction of 77%, p < 0.001). Significant reductions were also noted in our previous 2002 and 2007 surveys, with mean concentrations of 15.7 and 9.36 pg I-TEQ/g lipid, respectively. However, the comparison between simulated (using the PBPK model) and experimental results was very successful, as PCDD/F values in plasma were very similar (7.95 vs 6.18 pg I-TEQ/g lipid). The levels of PCDD/Fs in plasma of nonoccupationally exposed individuals living near the HWI here assessed are comparatively lower than most recently reported values. PMID- 23627714 TI - Influence of local exposure to static magnetic field on pain perception and bone turnover of osteoporotic patients with vertebral deformity - a randomized controlled trial. AB - PURPOSE: Static magnetic field (SMF) could improve pain sensation and bone turnover. In a single-center randomized double-blind placebo-controlled study we investigated the effects of SMF exposure on subjective pain and bone turnover. MATERIALS AND METHODS: Postmenopausal osteoporotic women (aged 50-70 years) with bone deformity and back pain were randomized to 10 weekly visits of 30-min SMF (n = 6) or treatment with non-magnetized pads (n = 5) on the back. Primary and secondary outcomes were changes in pain sensation on a visual analogue scale (VAS) during each visit and over 10 weeks, respectively. Tertiary outcomes were changes in osteocalcin and beta-crosslaps. SMF was inhomogeneous with 192 millitesla peak-to-peak value by 19 tesla/meter gradient of the magnetic flux density at 3 mm. RESULTS: Participants randomized to sham had higher VAS at baseline (mean difference: 2.8, 95% confidence interval (CI) 0.47-5.2 cm). Both SMF and sham similarly reduced short term pain (sham-SMF: 0.59, 95% CI - 0.31 1.49 cm, p = 0.195). VAS did not change in SMF, while it decreased in the sham group (between-group difference 0.27, 95% CI 0.04-0.50 cm/visit). Bone turnover markers remained stable. CONCLUSIONS: SMF as used in this investigation is not recommended for pain relief in postmenopausal women with vertebral deformity. The finding on long-term pain relief may relate to unbalanced randomization. PMID- 23627716 TI - Prevalence and clinical features of sexual dysfunction in male with epilepsy: the first southern Italy hospital-based study. AB - The aim of the study was to evaluate the prevalence and the etiology of sexual dysfunctions (SD) in a group of epileptic outpatients. Sixty Italian men (30 patients and 30 controls), living in Sicily, were enrolled in the study. Our diagnostic investigation included physical and neurological examination, EEG, MRI and Hamilton Depression and Anxiety Scales administration. A "semi-structured" questionnaire and the short form of the Sex relation Evaluation Schedule Assessment Monitoring were administered to the whole sample to evaluate their sexual well-being. There was no correlation between SD and type of epilepsy, EEG abnormalities and different antiepileptic drugs, while a weak correlation was observed between seizure frequency and the main SD. Forty-seven percent of the patients were affected by mild to moderate depression and 73.3% were anxious. Moreover, those patients who had uncontrolled seizures presented alteration in their social and affective area. Our findings showed a low prevalence of SD in epileptic male outpatients, especially concerning hyposexuality, and an important role of the seizure frequency in the multifactorial aetiology of sexual impairment in epilepsy. However, larger and multicenter studies are needed to better define the effects of epilepsy per se and the individual treatments on sexual function. PMID- 23627715 TI - Health economics of rubella: a systematic review to assess the value of rubella vaccination. AB - BACKGROUND: Most cases of rubella and congenital rubella syndrome (CRS) occur in low- and middle-income countries. The World Health Organization (WHO) has recently recommended that countries accelerate the uptake of rubella vaccination and the GAVI Alliance is now supporting large scale measles-rubella vaccination campaigns. We performed a review of health economic evaluations of rubella and CRS to identify gaps in the evidence base and suggest possible areas of future research to support the planned global expansion of rubella vaccination and efforts towards potential rubella elimination and eradication. METHODS: We performed a systematic search of on-line databases and identified articles published between 1970 and 2012 on costs of rubella and CRS treatment and the costs, cost-effectiveness or cost-benefit of rubella vaccination. We reviewed the studies and categorized them by the income level of the countries in which they were performed, study design, and research question answered. We analyzed their methodology, data sources, and other details. We used these data to identify gaps in the evidence and to suggest possible future areas of scientific study. RESULTS: We identified 27 studies: 11 cost analyses, 11 cost-benefit analyses, 4 cost-effectiveness analyses, and 1 cost-utility analysis. Of these, 20 studies were conducted in high-income countries, 5 in upper-middle income countries and two in lower-middle income countries. We did not find any studies conducted in low-income countries. CRS was estimated to cost (in 2012 US$) between $4,200 and $57,000 per case annually in middle-income countries and up to $140,000 over a lifetime in high-income countries. Rubella vaccination programs, including the vaccination of health workers, children, and women had favorable cost effectiveness, cost-utility, or cost-benefit ratios in high- and middle-income countries. CONCLUSIONS: Treatment of CRS is costly and rubella vaccination programs are highly cost-effective. However, in order for research to support the global expansion of rubella vaccination and the drive towards rubella elimination and eradication, additional studies are required in low-income countries, to tackle methodological limitations, and to determine the most cost-effective programmatic strategies for increased rubella vaccine coverage. PMID- 23627717 TI - Modeling of multiple equilibria in the self-aggregation of di-n decyldimethylammonium chloride/octaethylene glycol monododecyl ether/cyclodextrin ternary systems. AB - The surface tension equations of binary surfactant mixtures (di-n decyldimethylammonium chloride and octaethylene glycol monododecyl ether) are established by combining the Szyszkowski equation of surfactant solutions, the ideal or nonideal mixing theory, and the phase separation model. For surfactant mixtures, the surface tension at the air-water interface is calculated using nonideal theory due to synergism between the two adsorbed surfactant types. The incorporation of cyclodextrin complexation model to the surface tension equations gives a robust model for the description of the surface tension isotherms of binary, ternary, and more complex systems involving numerous inclusion complexes. The surface tension data obtained experimentally shows excellent agreement with the theoretical model below and above the formation of micelles. The strong synergistic effect observed between the two surfactants is disrupted by the presence of CDs, leading to ideal behavior of ternary systems. Indeed, depending on the nature of the cyclodextrin (i.e., alpha, beta, or gamma), which allows a tuning of the cavity size, the binding constants with the surfactants are modified as well as the surface properties due to strong modification of equilibria involved in the ternary mixture. PMID- 23627718 TI - Synthesis of conjugated BODIPYs via the Wittig reaction. AB - A Wittig reaction was employed to synthesize conjugated BODIPYs in high yields by treating formylated BODIPYs with alkyl/aryl ylides under simple room temperature conditions. Treatment of 3,5-diformyl BODIPYs or alpha-formyl 3-pyrrolyl BODIPY with different alkyl/aryl ylides in CH2Cl2 at room temperature for 2 h followed by straightforward column chromatographic purification on silica afforded conjugated BODIPYs in ~65-90% yields. This is an alternate method to Knoevenagel and Heck reactions which have been used to synthesize such conjugated BODIPYs. The method works very efficiently, and we prepared 12 substituted BODIPYs including cholesterol-substituted BODIPYs to demonstrate the versatility of the reaction. The spectral, electrochemical, and fluorescence properties of these conjugated BODIPYs are also described. PMID- 23627719 TI - The thrill of (absolute) victory: success among many enhances emotional payoffs. AB - The emotional value of placing in a given percentile of a competition (e.g., placing in the "top 10%") depends on how many competitors are involved. Five studies reveal that winning among larger groups is associated with more positive emotional reactions than winning among smaller groups, even when the objective chances for success are held constant. Participants thought that a runner would feel happier after placing in the top 10% in a race with many (vs. few) competitors (Experiment 1); participants who imagined placing in the top 10% of a trivia quiz predicted that they would feel happier after succeeding among many (vs. few) respondents (Experiment 2); and participants who were given randomly assigned false feedback that they placed in the top 10% of a real creativity challenge actually felt happier when the pool was described as containing many (vs. few) contestants (Experiment 3). This effect appears to be driven by participants' intuitions about the statistical law of large numbers: when people think about success among large pools, they infer that the outcome is more diagnostic of "true" abilities--that the performance must not be a fluke- compared with identical success among small pools, which provides an affective boost (Experiments 4-5). PMID- 23627720 TI - Affective states contribute to trait reports of affective well-being. AB - Asking people to provide global judgments, or trait reports, of their affective experience is a standard method for assessing trait affective well-being, with countless applications in the social sciences. Trait reports reflect numerous influences that generally go unnoticed. Although state affect is a highly plausible candidate for such influences, this source of unwanted variance does not receive much attention and is usually not controlled for in empirical studies. Using 100-day data from the COGITO study, we provide direct and strong evidence that trait reports of affect depend on how people feel at the time they provide the evaluations (i.e., their affective state). For example, participants experiencing more positive affect on a specific day relative to their individual mean also provide more positive ratings of their global affective experience. Furthermore, we found that current affect influences trait ratings in a surprisingly differentiated way--those particular facets of affect that are more/less prevalent at a certain moment are believed to occur more/less often in general. We stress the need for repeated observations within individuals to estimate state contributions to standard assessments of trait affect, to distinguish between state and trait in psychological assessment, and to achieve good indicators of affective experiences in the social and medical sciences. PMID- 23627721 TI - Attentional mechanisms in judging genuine and fake smiles: eye-movement patterns. AB - We investigated the visual attention patterns (i.e., where, when, how frequently, and how long viewers look at each face region) for faces with (a) genuine, enjoyment smiles (i.e., a smiling mouth and happy eyes with the Duchenne marker), (b) fake, nonenjoyment smiles (a smiling mouth but nonhappy eyes: neutral, surprised, fearful, sad, disgusted, or angry), or (c) no smile (and nonhappy eyes). Viewers evaluated whether the faces conveyed happiness ("felt happy") or not, while eye movements were monitored. Results indicated, first, that the smiling mouth captured the first fixation more likely and faster than the eyes, regardless of type of eyes. This reveals similar attentional orienting to genuine and fake smiles. Second, the mouth and, especially, the eyes of faces with fake smiles received more fixations and longer dwell times than those of faces with genuine smiles. This reveals attentional engagement, with a processing cost for fake smiles. Finally, when the mouth of faces with fake smiles was fixated earlier than the eyes, the face was likely to be judged as genuinely happy. This suggests that the first fixation on the smiling mouth biases the viewer to misinterpret the emotional state underlying blended expressions. PMID- 23627722 TI - Modeling the effect of mood on dimensional attention during categorization. AB - Classification is a flexible process that can be affected by mood. The goal of this paper is to evaluate the idea that mood may modulate categorization behavior through an attentional weighting mechanism in which mood changes the attention afforded to different stimulus dimensions. In two experiments, participants learn and are tested on categories while in a calm or sad mood. In Experiment 1, sad participants are faster to learn one- and two-dimensional category structures, but show no advantage on a three-dimensional category structure. In Experiment 2, the generalized context model of categorization is used to measure dimensional weighting. The results suggest that sad participants have a narrower focus of attention, but that the narrowing tends to be on diagnostic dimensions. PMID- 23627723 TI - Negative, but not positive emotional images modulate the startle response independent of conscious awareness. AB - The emotional response to a threat is influenced by the valence of other stimuli in the environment. This emotional modulation of the threat-elicited response occurs even when negative valence stimuli are not consciously perceived. Relatively little prior research has investigated whether nonconsciously perceived positive valence stimuli modify the response to a threat, and the work that has been completed is in need of additional rigorous testing of stimulus and valence perception. The current study presented images of negative, neutral, and positive valence (1,000 ms and 17 ms durations), followed by a mask. A startle probe (100 dB whitenoise) was presented during 33% of each trial type while eyeblink electromyography (EMG) and skin conductance response (SCR) were measured. During the study, participants rated the emotional content of each image to assess valence perception. Participants accurately classified the valence of 1,000 ms images, but not 17 ms images. Further, participants performed at chance levels on an independent postexperimental forced-choice perception task using 17 ms masked images, indicating they were unable to perceive the valence and content of these images. Greater EMG and SCR were elicited by the startle probe during perceived and unperceived negative images compared to perceived and unperceived positive and neutral images. In addition, perceived, but not unperceived positive images diminished startle responses. The current findings suggest that images of negative valence potentiate the startle response in the absence of conscious stimulus perception. However, the attenuation of the startle response by positive images appears to require perception of the emotional valence of an image. PMID- 23627724 TI - Validation of data-driven computational models of social perception of faces. AB - People rapidly form impressions from facial appearance, and these impressions affect social decisions. We argue that data-driven, computational models are the best available tools for identifying the source of such impressions. Here we validate seven computational models of social judgments of faces: attractiveness, competence, dominance, extroversion, likability, threat, and trustworthiness. The models manipulate both face shape and reflectance (i.e., cues such as pigmentation and skin smoothness). We show that human judgments track the models' predictions (Experiment 1) and that the models differentiate between different judgments, though this differentiation is constrained by the similarity of the models (Experiment 2). We also make the validated stimuli available for academic research: seven databases containing 25 identities manipulated in the respective model to take on seven different dimension values, ranging from -3 SD to +3 SD (175 stimuli in each database). Finally, we show how the computational models can be used to control for shared variance of the models. For example, even for highly correlated dimensions (e.g., dominance and threat), we can identify cues specific to each dimension and, consequently, generate faces that vary only on these cues. PMID- 23627725 TI - Identification of novel locus at chromosome 3p12.3-q13.31 for autosomal recessive intellectual disability in a consanguineous family. PMID- 23627726 TI - Evolution of MHC class I genes in the endangered loggerhead sea turtle (Caretta caretta) revealed by 454 amplicon sequencing. AB - BACKGROUND: In evolutionary and conservation biology, parasitism is often highlighted as a major selective pressure. To fight against parasites and pathogens, genetic diversity of the immune genes of the major histocompatibility complex (MHC) are particularly important. However, the extensive degree of polymorphism observed in these genes makes it difficult to conduct thorough population screenings. METHODS: We utilized a genotyping protocol that uses 454 amplicon sequencing to characterize the MHC class I in the endangered loggerhead sea turtle (Caretta caretta) and to investigate their evolution at multiple relevant levels of organization. RESULTS: MHC class I genes revealed signatures of trans-species polymorphism across several reptile species. In the studied loggerhead turtle individuals, it results in the maintenance of two ancient allelic lineages. We also found that individuals carrying an intermediate number of MHC class I alleles are larger than those with either a low or high number of alleles. CONCLUSIONS: Multiple modes of evolution seem to maintain MHC diversity in the loggerhead turtles, with relatively high polymorphism for an endangered species. PMID- 23627727 TI - In vivo screening of five phytochemicals/extracts and a fungal immunomodulatory protein against colibacillosis in broilers. AB - Five phytochemicals/extracts (an extract from Echinacea purpurea, a beta-glucan rich extract from Shiitake, betaine [BetainTM], curcumin from Curcuma longa [turmeric] powder, carvacrol and also a recombinant fungal immunomodulatory protein [FIP] from Ganoderma lucidum) cloned and expressed in Escherichia coli were investigated for their anticolibacillosis potential in three chicken experiments, which were conducted in floor pens. Birds that were inoculated with E. coli intratracheally were treated with the phytochemicals/extracts or the FIP and compared with doxycycline-medicated and non-medicated infected broilers. Non medicated and non-infected birds were used as negative controls. Mortality, colibacillosis lesions and body weight gains were used as parameters. Considering the sum of dead birds and chickens with generalized colibacillosis per group, there was no significant difference between the positive control groups and birds treated with phytochemicals/extracts or the FIP. In contrast, doxycycline-treated birds showed significantly lower mortality and generalized colibacillosis. Moreover, none of the phytochemicals/extracts and the FIP improved recovery from colibacillosis lesions, while all doxycycline-treated broilers recovered completely. The negative control birds and doxycycline-treated groups consistently showed the highest weight gains. Pulsed-field gel electrophoresis of reisolates showed that they were genetically indistinguishable from the inoculation strain. In conclusion, none of the tested phytochemicals/extracts and the FIP significantly reduced the E. coli-induced mortality and generalized colibacillosis, and nor did they improve recovery from colibacillosis lesions. PMID- 23627728 TI - First determination of UV filters in marine mammals. Octocrylene levels in Franciscana dolphins. AB - Most current bioexposure assessments for UV filters focus on contaminants concentrations in fish from river and lake. To date there is not information available on the occurrence of UV filters in marine mammals. This is the first study to investigate the presence of sunscreen agents in tissue liver of Franciscana dolphin (Pontoporia blainvillei), a species under special measures for conservation. Fifty six liver tissue samples were taken from dead individuals accidentally caught or found stranded along the Brazilian coastal area (six states). The extensively used octocrylene (2-ethylhexyl-2-cyano-3,3-diphenyl-2 propenoate, OCT) was frequently found in the samples investigated (21 out of 56) at concentrations in the range 89-782 ng.g(-1) lipid weight. Sao Paulo was found to be the most polluted area (70% frequency of detection). Nevertheless, the highest concentration was observed in the dolphins from Rio Grande do Sul (42% frequency of detection within that area). These findings constitute the first data reported on the occurrence of UV filters in marine mammals worldwide. PMID- 23627729 TI - The design, synthesis and validation of recoverable and readily reusable siloxane transfer agents for Pd-catalyzed cross-coupling reactions. AB - The development of competent, recoverable and reusable 1-oxa-2-silacyclopentene (siloxane) transfer agents for Pd-catalyzed cross-coupling reactions (CCRs) of organolithium reagents with aryl and alkenyl iodides has been achieved. Drawbacks of the first-generation siloxane-transfer agent (1), relating to facile recovery for potential recycling, have been addressed. PMID- 23627730 TI - Carbon use efficiency of microbial communities: stoichiometry, methodology and modelling. AB - Carbon use efficiency (CUE) is a fundamental parameter for ecological models based on the physiology of microorganisms. CUE determines energy and material flows to higher trophic levels, conversion of plant-produced carbon into microbial products and rates of ecosystem carbon storage. Thermodynamic calculations support a maximum CUE value of ~ 0.60 (CUE max). Kinetic and stoichiometric constraints on microbial growth suggest that CUE in multi-resource limited natural systems should approach ~ 0.3 (CUE max /2). However, the mean CUE values reported for aquatic and terrestrial ecosystems differ by twofold (~ 0.26 vs. ~ 0.55) because the methods used to estimate CUE in aquatic and terrestrial systems generally differ and soil estimates are less likely to capture the full maintenance costs of community metabolism given the difficulty of measurements in water-limited environments. Moreover, many simulation models lack adequate representation of energy spilling pathways and stoichiometric constraints on metabolism, which can also lead to overestimates of CUE. We recommend that broad scale models use a CUE value of 0.30, unless there is evidence for lower values as a result of pervasive nutrient limitations. Ecosystem models operating at finer scales should consider resource composition, stoichiometric constraints and biomass composition, as well as environmental drivers, to predict the CUE of microbial communities. PMID- 23627731 TI - Pathologic features of pediatric head and neck melanoma. AB - Although malignant melanoma is rare in children, its incidence is steadily increasing, and it is potentially lethal. Few studies have examined head and neck melanoma in children, and even fewer have focused on the histopathologic features of melanoma within this anatomic region. To further the understanding of this entity, we examined pathology specimens from nine subjects age 18 years and younger with an original diagnosis of head or neck melanoma. The anatomic locations of these primary melanomas were the face and nose (n = 4), scalp and neck (n = 4), and ear (n = 1). The cases included seven superficial spreading melanomas, one unclassified (possible nodular) melanoma, and one melanoma in situ. No melanomas demonstrating desmoplastic or spindle cell morphologies were noted upon review. Breslow depth ranged from 0 to 2.9 mm (mean 1.3 mm, median 0.6 mm), with Clark level ranging from I to V. Pagetoid scatter was found in eight cases. Other notable features included regression (n = 5), ulceration (n = 1), and associated melanocytic nevus (n = 4). We did not observe any small cell variants; all nine cases had an epithelioid appearance. Nor was any melanoma associated mortality observed at last follow-up (mean 60.4 mos, median 48 mos, range 2-174 mos). These histopathologic features were consistent with adult-type melanoma, which is in agreement with other histopathologic studies of melanoma in children. PMID- 23627732 TI - A Lectin-EGF antibody promotes regulatory T cells and attenuates nephrotoxic nephritis via DC-SIGN on dendritic cells. AB - BACKGROUND: Interactions between dendritic cells (DCs) and T cells play a critical role in the development of glomerulonephritis, which is a common cause of chronic kidney disease. DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), an immune-regulating molecule of the C-type lectin family, is mainly expressed on DCs and mediates DC adhesion and migration, inflammation, activation of primary T cells. DC-SIGN triggers immune responses and is involved in the immune escape of pathogens and tumours. In addition, ligation of DC-SIGN on DCs actively primes DCs to induce Tregs. Under certain conditions, DC-SIGN signalling may result in inhibition of DC maturation, by promoting regulatory T cell (Treg) function and affecting Th1/Th2 bias. METHODS: A rat model of nephrotoxic nephritis was used to investigate the therapeutic effects of an anti-lectin-epidermal growth factor (EGF) antibody on glomerulonephritis. DCs were induced by human peripheral blood mononuclear cells in vitro. The expression of DC surface antigens were detected using flow cytometry; the levels of cytokines were detected by ELISA and qPCR, respectively; the capability of DCs to stimulate T cell proliferation was examined by mixed lymphocyte reaction; PsL-EGFmAb targeting to DC-SIGN on DCs was identified by immunoprecipitation. RESULTS: Anti-Lectin-EGF antibody significantly reduced global crescent formation, tubulointerstitial injury and improved renal function impairment through inhibiting DC maturation and modulating Foxp3 expression and the Th1/Th2 cytokine balance in kidney. Binding of anti-Lectin-EGF antibody to DC SIGN on human DCs inhibited DC maturation, increased IL-10 production from DCs and enhanced CD4+CD25+ Treg functions. CONCLUSIONS: Our results suggest that treatment with anti-Lectin-EGF antibody modulates DCs to suppressive DCs and enhances Treg functions, contributing to the attenuation of renal injury in a rat model of nephrotoxic nephritis. PMID- 23627733 TI - An investigation into the association between nutritional status and quality of life in older people admitted to hospital. AB - BACKGROUND: Malnutrition is prevalent in acute hospitals and malnourished patients have an increased risk of morbidity and mortality. Studies of malnutrition and quality of life (QoL) are generally limited by both the nutritional and QoL assessment methods employed. The present study aimed to evaluate the relationship between malnutrition, as assessed using a range of nutritional assessment methods, and QoL, as measured by EuroQol-5D-3L and Short Form (SF)-36 questionnaires. METHODS: The study comprised a prospective cross sectional study of malnutrition and QoL in 149 inpatients aged 65-99 years. Exclusion criteria were: terminal illness, active malignancy, lack of capacity to consent and severe communication difficulties. Spearman's rank correlation coefficient was used to test the association between QoL indices and nutritional markers. QoL scores for those scoring above and below thresholds for nutritional risk were compared. Regression models were created to identify nutritional indices contributing to the variability of QoL. RESULTS: There were significant associations between QoL scores and the Mini Nutritional Assessment (MNA)-SF. Clear differences were evident between malnourished and well-nourished patients (on the MNA-SF), those with low and normal arm muscle circumference and those with good and poor physical function. Regression analysis showed that nutritional scores and functional status made independent contributions to the prediction of QoL. The effect on food intake, mobility and psychological stress/acute disease also had a significant influence. CONCLUSIONS: Malnutrition risk is linked to a poorer QoL in older people on admission to hospital. Functional status and eating related factors are major influencers on QoL in this group. These findings reinforce the role of nutrition as a priority with respect to achieving improvements in QoL. PMID- 23627734 TI - Assembly, activation, and substrate specificity of cyclin D1/Cdk2 complexes. AB - Previous studies have shown conflicting data regarding cyclin D1/cyclin-dependent kinase 2 (Cdk2) complexes, and considering the widespread overexpression of cyclin D1 in cancer, it is important to fully understand their relevance. While many have shown that cyclin D1 and Cdk2 form active complexes, others have failed to show activity or association. Here, using a novel p21-PCNA fusion protein as well as p21 mutant proteins, we show that p21 is a required scaffolding protein, with cyclin D1 and Cdk2 failing to complex in its absence. These p21/cyclin D1/Cdk2 complexes are active and also bind the trimeric PCNA complex, with each trimer capable of independently binding distinct cyclin/Cdk complexes. We also show that increased p21 levels due to treatment with chemotherapeutic agents result in increased formation and kinase activity of cyclin D1/Cdk2 complexes, and that cyclin D1/Cdk2 complexes are able to phosphorylate a number of substrates in addition to Rb. Nucleophosmin and Cdh1, two proteins important for centrosome replication and implicated in the chromosomal instability of cancer, are shown to be phosphorylated by cyclin D1/Cdk2 complexes. Additionally, polypyrimidine tract binding protein-associated splicing factor (PSF) is identified as a novel Cdk2 substrate, being phosphorylated by Cdk2 complexed with either cyclin E or cyclin D1, and given the many functions of PSF, it could have important implications on cellular activity. PMID- 23627736 TI - Sulfa and trimethoprim-like drugs - antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors. AB - Recent advances in microbial genomics, synthetic organic chemistry and X-ray crystallography provided opportunities to identify novel antibacterial targets for the development of new classes of antibiotics and to design more potent antimicrobial compounds derived from existing antibiotics in clinical use for decades. The antimetabolites, sulfa drugs and trimethoprim (TMP)-like agents, are inhibitors of three families of enzymes. One family belongs to the carbonic anhydrases, which catalyze a simple but physiologically relevant reaction in all life kingdoms, carbon dioxide hydration to bicarbonate and protons. The other two enzyme families are involved in the synthesis of tetrahydrofolate (THF), i.e. dihydropteroate synthase (DHPS) and dihydrofolate reductase. The antibacterial agents belonging to the THF and DHPS inhibitors were developed decades ago and present significant bacterial resistance problems. However, the molecular mechanisms of drug resistance both to sulfa drugs and TMP-like inhibitors were understood in detail only recently, when several X-ray crystal structures of such enzymes in complex with their inhibitors were reported. Here, we revue the state of the art in the field of antibacterials based on inhibitors of these three enzyme families. PMID- 23627735 TI - Working memory and corpus callosum microstructural integrity after pediatric traumatic brain injury: a diffusion tensor tractography study. AB - Deficits in working memory (WM) are a common consequence of pediatric traumatic brain injury (TBI) and are believed to contribute to difficulties in a range of cognitive and academic domains. Reduced integrity of the corpus callosum (CC) after TBI may disrupt the connectivity between bilateral frontoparietal neural networks underlying WM. In the present investigation, diffusion tensor imaging (DTI) tractography of eight callosal subregions (CC1-CC8) was examined in relation to measures of verbal and visuospatial WM in 74 children sustaining TBI and 49 typically developing comparison children. Relative to the comparison group, children with TBI demonstrated poorer visuospatial WM, but comparable verbal WM. Microstructure of the CC was significantly compromised in brain injured children, with lower fractional anisotropy (FA) and higher axial and radial diffusivity metrics in all callosal subregions. In both groups of children, lower FA and/or higher radial diffusivity in callosal subregions connecting anterior and posterior parietal cortical regions predicted poorer verbal WM, whereas higher radial diffusivity in callosal subregions connecting anterior and posterior parietal, as well as temporal, cortical regions predicted poorer visuospatial WM. DTI metrics, especially radial diffusivity, in predictive callosal subregions accounted for significant variance in WM over and above remaining callosal subregions. Reduced microstructural integrity of the CC, particularly in subregions connecting parietal and temporal cortices, may act as a neuropathological mechanism contributing to long-term WM deficits. The future clinical use of neuroanatomical biomarkers may allow for the early identification of children at highest risk for WM deficits and earlier provision of interventions for these children. PMID- 23627737 TI - Synthesis, characterization and controlled drug release from temperature responsive poly(ether-urethane) particles based on PEG-diisocyanates and aliphatic diols. AB - A series of linear amphiphilic poly(ether-urethane)s with alternative hydrophilic/hydrophobic segments based on PEG-diisocyanates and aliphatic diols is developed. The molecular structures of the copolymers were confirmed with nuclear magnetic resonance, Fourier transform infrared spectra and gel permeation chromatography. Nanoparticles prepared by self-assembly of the resulting copolymers show sharp temperature-responsive phase transition. The phase transition temperature could be easily modulated by the length of hydrophilic or hydrophobic segments of the polymer. The mechanism of the temperature-responsive behaviour is discussed. In the presence of these obtained poly(ether-urethane)s, doxorubicin (DOX) could be dispersed into aqueous solution. The ratio of DOX release from polymeric particles increased sharply above the phase transition temperature, while the release was suppressed below the phase transition temperature. A controlled drug release can be achieved by changing the environmental temperature. The easy-prepared polymeric nanoparticles, with features of biocompatibility, biodegradability and tail-made temperature responsiveness, are a kind of promising carriers for temperature-controllable drug release. PMID- 23627738 TI - Exposure to public natural space as a protective factor for emotional well-being among young people in Canada. AB - BACKGROUND: Positive emotional well-being is fundamentally important to general health status, and is linked to many favorable health outcomes. There is societal interest in understanding determinants of emotional well-being in adolescence, and the natural environment represents one potential determinant. Psychological and experimental research have each shown links between exposure to nature and both stress reduction and attention restoration. Some population studies have suggested positive effects of green space on various indicators of health. However, there are limited large-scale epidemiological studies assessing this relationship, specifically for populations of young people and in the Canadian context. The objective of this study was to examine the relationship between exposure to public natural space and positive emotional well-being among young adolescent Canadians. METHODS: This cross-sectional study was based upon the Canadian 2009/10 Health Behaviour in School-aged Children Survey with linked geographic information system (GIS) data. Following exclusions, the sample included 17 249 (grades 6 to 10, mostly ages 11 to 16) students from 317 schools. Features of the natural environment were extracted using GIS within a 5 km radius circular buffer surrounding each school. Multilevel logistic regression was used to examine the relationship between the presence of public natural space (features include green and blue spaces such as parks, wooded areas, and water bodies) and students' reports of positive emotional well-being, while controlling for salient covariates and the clustered nature of the data. RESULTS: Over half of Canadian youth reported positive emotional well-being (58.5% among boys and 51.6% among girls). Relationships between measures of natural space and positive emotional well-being were weak and lacked consistency overall, but modest protective effects were observed in small cities. Positive emotional well-being was more strongly associated with other factors including demographic characteristics, family affluence, and perceptions of neighbourhood surroundings. CONCLUSION: Exposure to natural space in youth's immediate living environment may not be a leading determinant of their emotional well-being. The relationship between natural space and positive emotional well-being may be context specific, and thus different for Canadian youth compared to adult populations and those studied in other nations. Factors of the individual context were stronger potential determinants. PMID- 23627739 TI - Novel approach to excited-state calculations of large molecules based on divide and-conquer method: application to photoactive yellow protein. AB - In this study, the divide-and-conquer (DC) method is extended to configuration interaction singles, time-dependent density functional, and symmetry-adapted cluster configuration interaction (SACCI) theories for enabling excited-state calculations of large systems. In DC-based excited-state theories, one subsystem is selected as the excitation subsystem and analyzed via excited-state calculations. Test calculations for formaldehyde in water and a conjugated aldehyde demonstrate the high accuracy and effectiveness of these methods. To demonstrate the efficiency of the method, we calculated the pi-pi* excited state of photoactive yellow protein (PYP). The numerical applications to PYP confirm that the DC-SACCI method significantly accelerates the excited-state calculations while maintaining high accuracy. PMID- 23627740 TI - Self-assembly of heterogeneously charged particles under confinement. AB - Self-assembly--the spontaneous organization of microscopic units into well defined mesoscopic structures--is a fundamental mechanism for a broad variety of nanotechnology applications in material science. The central role played by the anisotropy resulting from asymmetric shapes of the units and/or well-defined bonding sites on the particle surface has been widely investigated, highlighting the importance of properly designing the constituent entities in order to control the resulting mesoscopic structures. Anisotropy driven self-assembly can also result from the multipolar interactions characterizing many naturally occurring systems, such as proteins and viral capsids, as well as experimentally synthesized colloidal particles. Heterogeneously charged particles represent a class of multipolar units that are characterized by a competitive interplay between anisotropic attractive and repulsive interactions, due to the repulsion/attraction between charged-like/oppositely charged regions on the particle surface. In the present work, axially symmetric quadrupolar colloids are considered in a confined planar geometry; the role of both the overall particle charge and the patch extension as well as the effect of the substrate charge are studied in thermodynamic conditions such that the formation of extended structures is favored. A general tendency to form quasi-two-dimensional aggregates where particles align their symmetry axes within the plane is observed; among these planar self-assembled scenarios, a clear distinction between the formation of microcrystalline gels--branched networks consisting of purely crystalline domains--as opposed to disordered aggregates can be observed based on the specific features of the particle-particle interaction. Additionally, the possible competition of interparticle and particle-substrate interactions affects the size and the internal structure of the aggregates and can possibly inhibit the aggregation process. PMID- 23627741 TI - Taking each day as it comes: staff experiences of supporting people with Down syndrome and Alzheimer's disease in group homes. AB - BACKGROUND: Disability staff are being increasingly required to support adults with Down syndrome who develop Alzheimer's disease. They have little understanding of the nature of care required, and may lack input from aged care and dementia services, which lack knowledge of intellectual disability. The aim of this study was to report on the experiences of disability staff in group homes supporting residents with Down syndrome and Alzheimer's disease in relation to their under understanding of what was happening to these residents, their responses to them, and how they felt about their support role. METHOD: Disability support staff for nine adults with Down syndrome who had a diagnosis of Alzheimer's disease were interviewed twice, over intervals of 6-9 months. Interviews were transcribed and analysed for themes. RESULTS: Three key themes emerged - (i) struggling to understand change, (ii) taking each day as it comes, and (iii) he's got a disability and that's our job. CONCLUSIONS: Staff had only limited understanding of how Alzheimer's disease impacted the adults with Down syndrome, their responses to changes were ad hoc, and they used strategies on a trial and error basis. They were committed to providing care, but at the risk of rejecting input and support. The need for collaboration across disability, and aged and disability care was evident to facilitate aging-in-place and planned care transitions. PMID- 23627742 TI - Modelling of cell killing due to sparsely ionizing radiation in normoxic and hypoxic conditions and an extension to high LET radiation. AB - PURPOSE: An approach for describing cell killing with sparsely ionizing radiation in normoxic and hypoxic conditions based on the initial number of randomly distributed DNA double-strand breaks (DSB) is proposed. An extension of the model to high linear energy transfer (LET) radiation is also presented. MATERIALS AND METHODS: The model is based on the probabilities that a given DNA giant loop has one DSB or at least two DSB. A linear combination of these two classes of damage gives the mean number of lethal lesions. When coupled with a proper modelling of the spatial distribution of DSB from ion tracks, the formalism can be used to predict cell response to high LET radiation in aerobic conditions. RESULTS: Survival data for sparsely ionizing radiation of cell lines in normoxic/hypoxic conditions were satisfactorily fitted with the proposed parametrization. It is shown that for dose ranges up to about 10 Gy, the model describes tested experimental survival data as good as the linear-quadratic model does. The high LET extension yields a reasonable agreement with data in aerobic conditions. CONCLUSIONS: A new survival model has been introduced that is able to describe the most relevant features of cellular dose-response postulating two damage classes. PMID- 23627743 TI - Interactions between solid surfaces with preadsorbed poly(ethylenimine) (PEI) layers: effect of unadsorbed free PEI chains. AB - Poly(ethylenimine) (PEI) polyelectrolytes have been widely used to tune the stability, rheology, or adhesion properties of colloidal suspensions due to their strong tendency to adsorb to solid surfaces. They have also gained importance as gene carriers in biomedical applications, in which the anionic DNA chains are complexed and condensed to form PEI/DNA polyplexes. Some reported literatures have recently shown that the overdosed PEI chains, which are free in the solution mixture, also play a vital role in promoting the gene transfection, but the reason is unclear. In this work, we present the results of using total internal reflection microscopy (TIRM) to measure the interaction forces between a Brownian colloidal sphere and a flat glass plate in the presence of overdosed free PEI cationic chains, when both surfaces were saturated adsorbed with the PEI chains. The colloidal sphere preadsorbed with PEI chains was chosen to mimic the PEI/DNA polyplex. Results for the potential energy of interaction measured for model polyplex (e.g., PEI-coated sphere) interacting with a PEI-coated glass surface in the presence of overdosed free PEI chains at various pH values and salt concentrations were presented. As can be shown by direct force measurements, the interaction potentials in NaCl salt solution are dominated by repulsive forces originating from diffuse layer overlap and gravitational attraction. However, the presence of free PEI chains in the solution mixture produces a long-ranged (>60 nm) attractive force between two PEI-coated surfaces with the range and magnitude tunable by pH value, PEI, and salt concentrations. The possible mechanisms of this long-ranged attractive force are discussed. A better understanding of this free PEI-induced attractive force will be useful in the development of improved PEI/DNA polyplexes systems for biomedical applications. PMID- 23627744 TI - Endothelial necrosis at 1 hour postburn predicts progression of tissue injury. AB - Burn injury progression has not been well characterized at the cellular level. To define burn injury progression in terms of cell death, histopathologic spatiotemporal relationships of cellular necrosis and apoptosis were investigated in a validated porcine model of vertical burn injury progression. Cell necrosis was identified by high mobility group box 1 protein and apoptosis by Caspase 3a staining of tissue samples taken 1 hour, 24 hours, and 7 days postburn. Level of endothelial cell necrosis at 1 hour was predictive of level of apoptosis at 24 hours (Pearson's r = 0.87) and of level of tissue necrosis at 7 days (Pearson's r = 0.87). Furthermore, endothelial cell necrosis was deeper than interstitial cell necrosis at 1 hour (p < 0.001). Endothelial cell necrosis at 1 hour divided the zone of injury progression (Jackson's zone of stasis) into an upper subzone with necrotic endothelial cells and initially viable adnexal and interstitial cells at 1 hour that progressed to necrosis by 24 hours and a lower zone with initially viable endothelial cells at 1 hour but necrosis and apoptosis of all cell types by 24 hours. Importantly, this spatiotemporal series of events and rapid progression resembles myocardial infarction and stroke and implicates mechanisms of these injuries, ischemia, ischemia reperfusion, and programmed cell death in burn progression. PMID- 23627745 TI - Donor-acceptor ferrocenyl-substituted benzothiadiazoles: synthesis, structure, and properties. AB - This article reports the design, and synthesis of D-pi1-A-pi2-D unsymmetrical, and D-pi1-A-pi2-A-pi1-D symmetrical type of ferrocenyl-substituted benzothiadiazoles by the Pd-catalyzed Sonogashira, and Stille coupling reactions. The photophysical and electrochemical behavior of the ferrocenyl-substituted benzothiadiazoles show strong donor-acceptor interaction. The increase in the number of acceptor benzothiadiazole unit, results in the lowering of the energy gap, which leads to the bathochromic shift of the absorption spectrum. The single crystal X-ray structures of 3a, 5a, and 5g were obtained which show interesting supramolecular interactions. PMID- 23627746 TI - The nature and correlates of self-esteem trajectories in late life. AB - Is it possible to maintain a positive perspective on the self into very old age? Empirical research so far is rather inconclusive, with some studies reporting substantial declines in self-esteem late in life, whereas others report relative stability into old age. In this article, we examine long-term change trajectories in self-esteem in old age and very old age and link them to key correlates in the health, cognitive, self-regulatory, and social domains. To do so, we estimated growth curve models over chronological age and time-to-death using 18-year longitudinal data from the Australian Longitudinal Study of Ageing (N = 1,215; age 65-103 years at first occasion; M = 78.8 years, SD = 5.9; women: 45% of sample). Results revealed that self-esteem was, on average, fairly stable with minor declines only emerging in advanced ages and at the very end of life. Examination of the vast between-person differences revealed that lower cognitive abilities and lower perceived control independently related to lower self-esteem. Also, lower cognitive abilities were associated with steeper age-related and mortality-related self-esteem decrements. In our discussion, we consider a variety of challenges that potentially shape self-esteem late in life and highlight the need for more mechanism-oriented research to better understand the pathways underlying stability and change in self-esteem. PMID- 23627747 TI - The hobgoblin of consistency: algorithmic judgment strategies underlie inflated self-assessments of performance. AB - People often hold inflated views of their performance on intellectual tasks, with poor performers exhibiting the most inflation. What leads to such excessive confidence? We suggest that the more people approach such tasks in a "rational" (i.e., consistent, algorithmic) manner, relative to those who use more variable or ad hoc approaches, the more confident they become, irrespective of whether they are reaching correct judgments. In 6 studies, participants completed tests involving logical reasoning, intuitive physics, or financial investment. Those more consistent in their approach to the task rated their performances more positively, including those consistently pursuing the wrong rule. Indeed, completely consistent but wrong participants thought almost as highly of their performance as did completely consistent and correct participants. Participants were largely aware of the rules they followed and became more confident in their performance when induced to be more systematic in their approach, no matter how misguided that approach was. In part, the link between decision consistency and (over)confidence was mediated by a neglect of alternative solutions as participants followed a more uniform approach to a task. PMID- 23627748 TI - Paradoxical consequences of prohibitions. AB - Explanations based in attribution theory claim that strong external controls such as parental restrictiveness and punishment undermine moral internalization. In contrast, 3 studies provide evidence that parental punishment does socialize morality, but of a particular sort: a morality focused on prohibitions (i.e., proscriptive orientation) rather than positive obligations (i.e., prescriptive orientation). Study 1 found young adults' accounts of parental restrictiveness and punishment activated their sensitivity to prohibitions and predicted a proscriptive orientation. Consistent with the greater potency of temptations for proscriptively oriented children, as well as past research linking shame to proscriptive morality, Study 2 found that restrictive parenting was also associated with greater suppression of temptations. Finally, Studies 3A and 3B found that suppressing these immoral thoughts is paradoxically harder for those with strong proscriptive orientations; more specifically, priming a proscriptive (versus prescriptive) orientation and inducing mental suppression of "immoral" thoughts led to the most ego depletion for those with restrictive parents. Overall, individuals who had restrictive parents had the lowest self-regulatory ability to resist their "immoral" temptations after prohibitions were activated. In contrast to common attributional explanations, these studies suggest that harsh external control by parents does not undercut moral socialization but rather undermines individuals' ability to resist temptation. PMID- 23627749 TI - Loving freedom: concerns with promotion or prevention and the role of autonomy in relationship well-being. AB - Close relationships fulfill many important needs. However, not all of these needs are equally salient under all circumstances. This article investigated how the broad motivational context in which people evaluate relationships affects the salience of particular needs, thereby altering how the fulfillment of these needs predicts relationship well-being. Across 5 studies, participants reported how well their current romantic relationship met their needs for self-direction and autonomy, either by providing support for the fulfillment of these needs (Studies 1-3) or by allowing them to feel that they autonomously choose to remain in the relationship (Studies 4 and 5). In motivational contexts emphasizing personal growth and advancement (promotion), one's own independent priorities could become more salient, increasing the relevance of autonomy experiences when evaluating relationship well-being. However, in motivational contexts emphasizing safety and security (prevention), autonomy experiences might not be especially salient and thus might not have any special relevance when evaluating relationship well being. Both measurements and manipulations of participants' motivations for growth or security consistently supported these hypotheses. PMID- 23627750 TI - On the interaction of beta-amyloid peptides and alpha7-nicotinic acetylcholine receptors in Alzheimer's disease. AB - Deterioration of the cortical cholinergic system is a leading neurochemical feature of Alzheimer's Disease (AD). This review summarizes evidence that the homomeric alpha7- nicotinic acetylcholine receptor (nAChR) plays a crucial role in the pathogenesis of this disease, which is characterized by amyloid-beta (Abeta) accumulations and neurofibrillary tangles originating from of hyperphosphorylated tau protein. Abeta binds to alpha7-nAChRs with a high affinity, either activating or inhibiting this receptor in a concentration dependent manner. There is strong evidence that alpha7-nAChRs are neuroprotective, reducing Abeta-induced toxicity; but co-localization of alpha7- nAChRs, Abeta and amyloid plaques also points to neurodegenerative actions. Abeta induces tau phosphorylation via alpha7-nAChR activation. Abeta influences hippocampus-dependent memory and long-term potentiation in a dose-dependent way: there is evidence that enhancement by picomolar Abeta concentrations is mediated by alpha7-nAChRs, whereas inhibition by nanomolar concentrations is independent of nAChRs and probably mediated by small Abeta42 oligomers. alpha7-nAChRs located on vascular smooth muscle cells and astrocytes are also involved in the pathogenesis of AD. Although these data strongly point to an important role of alpha7-nAChRs in the development of AD, dose-dependence of the effects, rapid desensitization of the receptor and dependence of the effects on Abeta aggregation (monomers, oligomers, fibrils) make it difficult to develop simple therapeutic strategies acting upon this receptor. PMID- 23627751 TI - Neuropathological correlates of cerebral multimorbidity. AB - Age associated neurodegenerative diseases are characterized by intra- and extracellular aggregation and deposition of misfolded proteins. The neuropathological classification of neurodegenerative diseases is based on the semiquantitative assessment of these misfolded proteins, that constitute the neuropathological hallmark lesion for the respective disease: e.g. Alzheimer's disease (AD), amyloid-beta (Abeta) hyperphosphorylated tau (tau); Lewy body diseases, alpha- synuclein (alpha-syn); frontotemporal lobar degeneration, tau, TDP-43, ubiquitin or FUS. In addition, cerebrovascular lesions are assessed for the diagnosis of vascular dementia. However, in brains of elderly patients suffering from neurodegenerative diseases multiple pathologies are usually present and even in clinically characterized prospective cohorts additional pathologies are frequently found at post mortem examination. On the other hand, various amounts of AD pathology are frequently seen in brains of non-demented elderly and the threshold to cause clinical overt dementia is ill defined as additional co-morbidities (e.g., cerebrovascular lesions) might lower the threshold for clinical dementia in some cases. It becomes increasingly clear that the clinical picture of dementia in most aged patients results from a multimorbid condition in the CNS rather than from one single disease and data from animal studies suggest that Abeta, tau, and alpha-syn interact in vivo to promote the aggregation and accumulation of each other. We suggest that clinico-pathological correlative studies using a more quantitative approach in the assessment of neuropathological lesions are warranted to elucidate cerebral multimorbidity and to identify suitable targets for targeted therapeutic strategies against age associated neurodegeneration. PMID- 23627752 TI - Transcranial magnetic stimulation of degenerating brain: a comparison of normal aging, Alzheimer's, Parkinson's and Huntington's disease. AB - Although the brain's ability to change constantly in response to external and internal inputs is now well recognized the mechanisms behind it in normal aging and neurodegeneration are less well understood. To gain a better understanding, transcranial magnetic stimulation (TMS) has been used extensively to characterize non-invasively the cortical neurophysiology of the aging and degenerating brain. Furthermore, there has been a surge of studies examining whether repetitive TMS (rTMS) can be used to improve functional deficits in various conditions including normal aging, Alzheimer's and Parkinson's disease. The results of these studies in normal aging and neurodegeneration have emerged reasonably coherent in delineating the main pathology in spite of considerable technical limitations, omnipresent methodological variability, and extraordinary patient heterogeneity. Nevertheless, comparing and integrating what is known about TMS measurements of cortical excitability and plasticity in disorders that predominantly affect cortical brain structures with disorders that predominantly affect subcortical brain structures may provide better understanding of normal and abnormal brain aging fostering new. The present review provides a TMS perspective of changes in cortical neurophysiology and neurochemistry in normal aging and neurodegeneration by integrating what is revealed in individual TMS measurements of cortical excitability and plasticity in physiological aging, Alzheimer's, Parkinson's, and Huntington's, disease. The paper also reflects on current developments in utilizing TMS as a physiologic biomarker to discriminate physiologic aging from neurodegeneration and its potential as a method of therapeutic intervention. PMID- 23627753 TI - Cell clocks and neuronal networks: neuron ticking and synchronization in aging and aging-related neurodegenerative disease. AB - Body function rhythmicity has a key function for the regulation of internal timing and adaptation to the environment. A wealth of recent data has implicated endogenous biological rhythm generation and regulation in susceptibility to disease, longevity, cognitive performance. Concerning brain diseases, it has been established that many molecular pathways implicated in neurodegeneration are under circadian regulation. At the molecular level, this regulation relies on clock genes forming interconnected, self-sustained transcriptional/translational feedback loops. Cells of the master circadian pacemaker, the hypothalamic suprachiasmatic nucleus, are endowed with this molecular clockwork. Brain cells in many other regions, including those which play a key role in learning and memory, as well as peripheral cells show a circadian oscillatory behavior regulated by the same molecular clockwork. We here address the question as to whether intracellular clockwork signaling and/or the intercellular dialogue between "brain clocks" are disrupted in aging-dependent neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. The potential implications of clock genes in cognitive functions in normal conditions, clinical disturbances of circadian rhythms, and especially the sleep-wake cycle, in aging dependent neurodegenerative diseases and data in animal models are reviewed. The currently limited knowledge in this field is discussed in the context of the more extensive body of data available on cell clocks and molecular clockwork during normal aging. Hypotheses on implications of the synchronization between brain oscillators in information processing in neural networks lay ground for future studies on brain health and disease. PMID- 23627754 TI - Dynamics of nicotinic acetylcholine receptors and receptor-associated proteins at the vertebrate neuromuscular junction. AB - The mature neuromuscular junction (NMJ) is the best characterized cholinergic synapse. The maintenance of a high number and density of nicotinic acetylcholine receptors (nAChRs) at the postsynaptic membrane adjacent to the nerve terminal are crucial for NMJ function. This density is maintained by several factors, ranging from synaptic activity to postsynaptic scaffold proteins. Decreases in postsynaptic nAChR density are related to myasthenic syndromes in the peripheral NMJ, but are also associated in central synapses with neurodegenerative diseases such as Alzheimer's. In this review, we focus particularly on our increasing knowledge about the molecular dynamics of nAChR at the peripheral cholinergic NMJ and their regulation by the postsynaptic proteins of the dystrophin glycoprotein complex (DGC). PMID- 23627755 TI - Increased Alzheimer's disease neuropathology is associated with type 2 diabetes and ApoE epsilon.4 carrier status. AB - BACKGROUND: Past studies investigating the association between Alzheimer's disease (AD) pathology and diabetes mellitus type 2 (DM2) have provided conflicting results. While several studies indicate that subjects with comorbid AD and DM2 have less AD pathology, others have found no significant differences in AD pathology between the two groups. Other studies have indicated that individuals with AD and DM2 have significantly greater neuropathology than AD individuals who do not have DM2. Additional research has demonstrated that ApoE epsilon4 carriers with AD and DM2 have significantly greater pathology than ApoE epsilon4 non-carriers. METHODS: Data on clinically and pathologically diagnosed Alzheimer's disease cases (NINDS-ADRDA clinically and NIA Reagan intermediate or high pathologically) with DM2 (n= 40) and those without DM2 (n= 322) from the Banner Sun Health Research Institute Brain and Body Donation Program were obtained for this study. Plaque and tangle scores from the frontal, parietal, temporal, entorhinal and hippocampal regions were compared between the DM2+ and DM2 - groups. In addition, total plaque count, total tangle count, and Braak scores were also compared between groups. Similar analyses were conducted to determine the effect of ApoE epsilon4 carrier status on the neuropathological variables while also accounting for and DM2 status. RESULTS: The DM2+ and DM2 - groups showed no significant differences on plaque and tangle pathology. Logistic regression analyses, which accounted for the effects of ApoE .epsilon4 carrier status and age at death, found no association between total plaque [OR 1.05 (0.87, 1.27), p = 0.60] or total tangle [OR 0.97 (0.89, 1.07) p = 0.58] counts and DM2 status. ApoE epsilon4 carrier status was not significantly associated with DM2 status [.Chi2 = 0.30 (df = 1), p = 0.58]. Within the DM2+ group, significantly greater plaque and tangle pathology was found for ApoE epsilon4 carriers in relation to DM2+ ApoE epsilon4 non-carriers. CONCLUSION: Overall, the presence of DM2 does not affect plaque and tangle burden in a sample of clinically and pathologically confirmed AD cases. Among AD individuals with DM2, those who are ApoE epsilon4 carriers had significantly greater neuropathology than those who do not carry an ApoE epsilon4 allele. Positive DM2 status appears to exacerbate AD neuropathology in the presence of ApoE epsilon4. PMID- 23627756 TI - Possible protecting role of TNF-alpha in kainic acid-induced neurotoxicity via down-regulation of NFkappaB signaling pathway. AB - We have shown previously, that mice lacking tumor necrosis factor-alpha (TNF alpha) receptor 1 (TNFR1) exhibit greater hippocampal neurodegeneration, suggesting that TNFR1 may be protective in kainic acid (KA)-induced neurotoxicity. Here, we aim to clarify the role of TNF-alpha in neurodegenerative disorders and to elucidate its potential signaling pathways. TNF-alpha knockout (KO) mice and wild-type (WT) mice were treated with KA intranasally and, seizure severity measures obtained, Behavioral tests, including Elevated Plus-MazeTM, open-field, Y-maze were also performed. Five days following KA treatment, immunohistochemical methods were used to assess neuronal degeneration and glial activation. The production of nitric oxide (NO) and the expression of nuclear factor kappaB (NF-kappaB) and AKT in the hippocampus were also measured. Compared with WT mice, TNF-alpha KO mice were more susceptible to KA-induced neurotoxicity, as demonstrated by more severe seizures, measurable behavior changes, greater neuronal degeneration in hippocampus, elevated glial activation and NO production. Additionally, KA-treatment up-regulated the expression of NFkappaB in TNF-alpha KO mice to a greater degree than in KA-treated WT mice. We conclude that TNF-alpha deficiency adversely influences KA-induced neurotoxicity and that TNF-alpha may play a protective role in KA-induced neurotoxicity via the down-regulation of NFkappaB signaling pathway. PMID- 23627757 TI - Vascular risk factors and neurodegeneration in ageing related dementias: Alzheimer's disease and vascular dementia. AB - Age is the strongest risk factor for brain degeneration whether it results from vascular or neurodegenerative mechanisms or both. To evaluate the current views on the impact of vascular disease on the most common causes of dementia, most relevant articles to the selected subject headings were reviewed until November 2011 from the popularly used databases including Pubmed, Cochrane Database and Biological Abstracts. Within the past decade, there has been four-fold increased interest in the vascular basis of neurodegeneration and dementia. Vascular ageing involving arterial stiffness, endothelial changes and blood-brain barrier dysfunction affects neuronal survival by impairing several intracellular protective mechanisms leading to chronic hypoperfusion. Modifiable risk factors such as hypertension, diabetes, dyslipidaemia and adiposity linked to Alzheimer's disease and vascular dementia promote the degeneration and reduce the regenerative capacity of the vascular system. These in tandem with accumulation of abnormal proteins such as amyloid beta likely disrupt cerebral autoregulation, neurovascular coupling and perfusion of the deeper structures to variable degrees to produce white matter changes and selective brain atrophy. Brain pathological changes may be further modified by genetic factors such as the apoliopoprotein E epsilon4 allele. Lifestyle measures that maintain or improve vascular health including consumption of healthy diets, moderate use of alcohol and implementing regular physical exercise in general appear effective for reducing dementia risk. Interventions that improve vascular function are important to sustain cognitive status even during ageing whereas preventative measures that reduce risk of vascular disease are predicted to lessen the burden of dementia in the long-term. PMID- 23627758 TI - Alzheimer disease and diabetes mellitus: do they have anything in common? AB - The prevalence of diabetes mellitus (DM) continues to increase because of sedentary life style and inappropriate diet. DM is one of the most common metabolic diseases, affecting more than 240 million people worldwide. It is projected that the number of people with DM will continue to increase in the next decade. Alzheimer disease (AD) is the most common cause of dementia, and affects over 24 million people globally, mostly senior citizens. The worldwide prevalence of AD is estimated to double in the next 20 years. How are these two chronic and debilitating diseases similar? Do they have common denominators? AD is similar to DM in many ways, in that both are associated with defective insulin release and/or signalling, impaired glucose uptake, amyloidosis, increased oxidative stress, stimulation of the apoptotic pathway, angiopathy, abnormal lipid peroxidation, ageing (in type 2 DM), brain atrophy, increased formation of advanced glycation end products and tau phosphorylation, impaired lipid metabolism and mitochondrial pathology. The pathogenesis of both AD and DM has genetic as well as environmental components. Both can also cause impaired cognition and dementia. All of these common denominators indicate that AD and DM share a lot of factors in terms of pathophysiology, histopathology and clinical outcome. These similarities can be used in the search for and design of effective pharmacotherapy for AD, since potent therapeutic agents such as insulin, incretins, oral hypoglycaemic agents and antioxidants used in the management of DM may play a key role in the treatment of patients with AD. PMID- 23627759 TI - ContigScape: a Cytoscape plugin facilitating microbial genome gap closing. AB - BACKGROUND: With the emergence of next-generation sequencing, the availability of prokaryotic genome sequences is expanding rapidly. A total of 5,276 genomes have been released since 2008, yet only 1,692 genomes were complete. The final phase of microbial genome sequencing, particularly gap closing, is frequently the rate limiting step either because of complex genomic structures that cause sequence bias even with high genomic coverage, or the presence of repeat sequences that may cause gaps in assembly. RESULTS: We have developed a Cytoscape plugin to facilitate gap closing for high-throughput sequencing data from microbial genomes. This plugin is capable of interactively displaying the relationships among genomic contigs derived from various sequencing formats. The sequence contigs of plasmids and special repeats (IS elements, ribosomal RNAs, terminal repeats, etc.) can be displayed as well. CONCLUSIONS: Displaying relationships between contigs using graphs in Cytoscape rather than tables provides a more straightforward visual representation. This will facilitate a faster and more precise determination of the linkages among contigs and greatly improve the efficiency of gap closing. PMID- 23627760 TI - Water scarcity: moving beyond indexes to innovative institutions. AB - Water scarcity is a media darling often times described as a trigger of conflict in arid regions, a by-product of human influences ranging from desertification to climate change, or a combination of natural- and human-induced changes in the water cycle. A multitude of indexes have been developed over the past 20 years to define water scarcity to map the "problem" and guide international donor investment. Few indexes include groundwater within the metrics of "scarcity." Institutional communication contributes to the recognition of local or regional water scarcity. However, evaluations that neglect groundwater resources may incorrectly define conditions as scarce. In cases where there is a perception of scarcity, the incorporation of groundwater and related storage in aquifers, political willpower, new policy tools, and niche diplomacy often results in a revised status, either reducing or even eliminating the moniker locally. Imaginative conceptualization and innovative uses of aquifers are increasingly used to overcome water scarcity. PMID- 23627761 TI - Timing and route of amiodarone for prevention of postoperative atrial fibrillation after cardiac surgery: a network regression meta-analysis. AB - BACKGROUND: We attempted to evaluate if an oral-only regimen was as effective in preventing postoperative atrial fibrillation (POAF) after cardiac surgery, in comparison to a regimen that included intravenous (IV) administration using a network meta-analysis of available data, and also attempted to assess if preoperative administration at least 1 day before surgery was superior to postoperative prophylaxis (at least 1 day after surgery). METHODS: We searched PubMed, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials' databases for randomized controlled trials conducted between 1990 and 2011 that assessed rates of POAF with amiodarone. Finally an interaction odds ratio was computed to assess the efficacy of an oral-only regimen of amiodarone compared to one including IV administration and to evaluate if preoperative amiodarone was superior to postoperative prophylaxis. RESULTS: Twenty-three studies (total N = 3,950) were included. Both regimens of amiodarone improved risk of POAF; oral only risk ratio (RR) was 0.59 (95% confidence interval [CI] 0.49-0.70; P < 0.01) and regimen including IV RR was 0.57 (95% CI 0.43-0.75, P < 0.01). The interaction odds ratio was 1.17 (95% CI 0.72-1.89, P = 0.533). Both preoperative amiodarone (P < 0.01) and postoperative prophylaxis were effective (P = 0.0009), irrespective of duration. CONCLUSIONS: This systematic review suggests a regimen of both oral-only and one including IV administration, as well pre- and postoperative administration of amiodarone is effective in prevention of POAF after cardiac surgery. PMID- 23627762 TI - Widespread evidence for incipient ecological speciation: a meta-analysis of isolation-by-ecology. AB - Ecologically mediated selection has increasingly become recognised as an important driver of speciation. The correlation between neutral genetic differentiation and environmental or phenotypic divergence among populations, to which we collectively refer to as isolation-by-ecology (IBE), is an indicator of ecological speciation. In a meta-analysis framework, we determined the strength and commonality of IBE in nature. On the basis of 106 studies, we calculated a mean effect size of IBE with and without controlling for spatial autocorrelation among populations. Effect sizes were 0.34 (95% CI 0.24-0.42) and 0.26 (95% CI 0.13-0.37), respectively, indicating that an average of 5% of the neutral genetic differentiation among populations was explained purely by ecological contrast. Importantly, spatial autocorrelation reduced IBE correlations for environmental variables, but not for phenotypes. Through simulation, we showed how the influence of isolation-by-distance and spatial autocorrelation of ecological variables can result in false positives or underestimated correlations if not accounted for in the IBE model. Collectively, this meta-analysis showed that ecologically induced genetic divergence is pervasive across time-scales and taxa, and largely independent of the choice of molecular marker. We discuss the importance of these results in the context of adaptation and ecological speciation and suggest future research avenues. PMID- 23627763 TI - Where exactly do basic research findings meet the general public? PMID- 23627764 TI - The mechanism of carbon dioxide adsorption in an alkylamine-functionalized metal organic framework. AB - The mechanism of CO2 adsorption in the amine-functionalized metal-organic framework mmen-Mg2(dobpdc) (dobpdc(4-) = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate; mmen = N,N'-dimethylethylenediamine) was characterized by quantum-chemical calculations. The material was calculated to demonstrate 2:2 amine:CO2 stoichiometry with a higher capacity and weaker CO2 binding energy than for the 2:1 stoichiometry observed in most amine-functionalized adsorbents. We explain this behavior in the form of a hydrogen-bonded complex involving two carbamic acid moieties resulting from the adsorption of CO2 onto the secondary amines. PMID- 23627765 TI - Baboon-like syndrome in children. AB - Baboon syndrome is a combination of diffuse symmetrical erythema on the major flexural areas and V-shaped erythema on both upper anteromedial thighs. Infectious agents have been described as possible triggers. We describe for the first time baboon syndrome in a child induced by a coinfection with Epstein-Barr virus and cytomegalovirus. PMID- 23627766 TI - Next-generation tissue microarray (ngTMA) increases the quality of biomarker studies: an example using CD3, CD8, and CD45RO in the tumor microenvironment of six different solid tumor types. AB - BACKGROUND: Tissue microarray (TMA) technology revolutionized the investigation of potential biomarkers from paraffin-embedded tissues. However, conventional TMA construction is laborious, time-consuming and imprecise. Next-generation tissue microarrays (ngTMA) combine histological expertise with digital pathology and automated tissue microarraying. The aim of this study was to test the feasibility of ngTMA for the investigation of biomarkers within the tumor microenvironment (tumor center and invasion front) of six tumor types, using CD3, CD8 and CD45RO as an example. METHODS: Ten cases each of malignant melanoma, lung, breast, gastric, prostate and colorectal cancers were reviewed. The most representative H&E slide was scanned and uploaded onto a digital slide management platform. Slides were viewed and seven TMA annotations of 1 mm in diameter were placed directly onto the digital slide. Different colors were used to identify the exact regions in normal tissue (n=1), tumor center (n=2), tumor front (n=2), and tumor microenvironment at invasion front (n=2) for subsequent punching. Donor blocks were loaded into an automated tissue microarrayer. Images of the donor block were superimposed with annotated digital slides. Exact annotated regions were punched out of each donor block and transferred into a TMA block. 420 tissue cores created two ngTMA blocks. H&E staining and immunohistochemistry for CD3, CD8 and CD45RO were performed. RESULTS: All 60 slides were scanned automatically (total time<10 hours), uploaded and viewed. Annotation time was 1 hour. The 60 donor blocks were loaded into the tissue microarrayer, simultaneously. Alignment of donor block images and digital slides was possible in less than 2 minutes/case. Automated punching of tissue cores and transfer took 12 seconds/core. Total ngTMA construction time was 1.4 hours. Stains for H&E and CD3, CD8 and CD45RO highlighted the precision with which ngTMA could capture regions of tumor-stroma interaction of each cancer and the T-lymphocytic immune reaction within the tumor microenvironment. CONCLUSION: Based on a manual selection criteria, ngTMA is able to precisely capture histological zones or cell types of interest in a precise and accurate way, aiding the pathological study of the tumor microenvironment. This approach would be advantageous for visualizing proteins, DNA, mRNA and microRNAs in specific cell types using in situ hybridization techniques. PMID- 23627767 TI - Polychlorinated biphenyls, hexachlorocyclohexanes and hexachlorobenzene in seawater and phytoplankton from the Southern Ocean (Weddell, South Scotia, and Bellingshausen Seas). AB - The Southern Ocean is one of the most pristine environments in the world, but is nonetheless affected by inputs of persistent organic pollutants (POPs). In the present work, we report the concentrations of hexachlorocyclohexanes (HCHs), hexachlorobenzene (HCB), and 26 polychlorinated biphenyl (PCBs) congeners in seawater and phytoplankton from samples obtained during three Antarctic cruises in 2005, 2008, and 2009. The levels of PCBs, HCHs, and HCB are low in comparison to the few previous reports for this region and studies from other oceans. The long-term decline of POP concentrations in the Southern Ocean seawater since early 1980 is consistent with half-lives of 3.4 and 5.7 years for HCHs and PCBs, respectively. There is a large variability of PCBs, HCHs, and HCB concentrations in water and phytoplankton within the Bransfield Strait, South Scotia, Weddell, and Bellingshausen Seas that masks the differences between the studied Seas. However, the variability of PCBs concentrations in phytoplankton is significantly correlated with phytoplankton biomass, with lower concentrations in the most productive waters. This trend is more apparent for the more hydrophobic congeners, consistent with the role of settling fluxes of organic matter decreasing the concentrations of hydrophobic POPs in productive waters. The present work reports the most extensive data set on concentrations in seawater and phytoplankton for the Southern Ocean, and points to the important biogeochemical drivers, such as settling and degradation, influencing the occurrence of POPs in the ocean. PMID- 23627768 TI - Associations of symptoms of anxiety and depression with diabetes and cardiovascular risk factors in older people with intellectual disability. AB - BACKGROUND: Depression, anxiety, diabetes and cardiovascular risk factors are frequent health problems among older people with intellectual disability (ID). These conditions may be bidirectionally related. Depression and anxiety may have biological effects causing glucose intolerance, fat accumulation and also lifestyle changes causing metabolic syndrome. But also the effects of diabetes, metabolic syndrome and subsequent cardiovascular disease may affect mood and anxiety. This study investigated the association between depression, anxiety and diabetes and cardiovascular risk factors in older people with ID. METHODS: The healthy ageing in intellectual disability-study (HA-ID study) is a cross sectional study among people aged 50 years and over with ID, receiving formal ID care. Screening instruments for symptoms of anxiety and depression were completed and physical examination and vena-puncture were performed to establish components of the metabolic syndrome, peripheral arterial disease and c-reactive protein. RESULTS: Of the 990 people who participated, 17% had symptoms of depression and 16% had symptoms of anxiety. Type I diabetes was present in 1%, type II diabetes in 13% of the study population. Metabolic syndrome, central obesity, hypercholesterolemia and hypertension were present in 45%, 48%, 23% and 53% respectively. In a multivariate logistic regression analysis a significant association was found between increased anxiety symptoms and diabetes only (OR 2.4, 95%CI 1.2-4.9). CONCLUSIONS: Increased anxiety symptoms and diabetes are related in older people with ID. This association may be bidirectional. No other associations of depression and anxiety symptoms with cardiovascular risk factors could be proven to be significant. Therefore, more research is needed to unravel the mechanisms of stress, mood disorders and cardiovascular disease in older people with ID. To provide comprehensive care for older people with ID, screening for diabetes and components of the metabolic syndrome in people with anxiety or mood disorders, and screening for symptoms of anxiety or depression in people with diabetes is warranted. PMID- 23627769 TI - Synthesis of the C1-C21 domain of azaspiracids-1 and -3. AB - An efficient synthesis of the C1-C21 fragment of azaspiracids-1 and -3 is described. This features a Nozaki-Hiyama-Kishi reaction to couple the AB and CD ring precursors and formation of the THF-fused ABCD trioxadispiroketal system under thermodynamic conditions. PMID- 23627770 TI - Sexual risk behaviours and barriers to HIV testing among clients of female sex workers in Guatemala: a qualitative study. AB - Few interventions have targeted clients of female sex workers in Central America, despite their potential role in HIV/STI prevention. Semi-structured interviews were conducted with 30 clients of female sex workers on attitudes towards prevention of HIV/STIs, barriers to condom use and behaviour towards HIV/STI testing and treatment in Escuintla, Guatemala. Despite high knowledge of condoms as an HIV/STI preventive measure, the decision to use them was often based on the client's social judgment of the woman's sexual conduct. Regular clients reported lower condom use. Clients' risk perception diminished with the awareness of the public HIV/STI clinic addressed to female sex workers. Most preferred private clinics to increase confidentiality and were reluctant to take the HIV test for fear of a positive result. Outreach programmes offering HIV/STI counselling and testing to clients of female sex workers could increase their test uptake and health-seeking behaviour and reduce potential transmission to the general population. PMID- 23627771 TI - Nutritional screening of elderly patients: a health improvement approach to practice. AB - INTRODUCTION: Almost 60% of elderly care in-patients are at risk of malnutrition. Malnourished patients have poorer clinical outcomes and this is a key factor with respect to prolonging the length of stay. Since 2003, the Malnutrition Universal Screening Tool (MUST) has been advocated as a method for identifying these at risk patients. Screening should take place on admission; however, the Trust has set a stretch target of aiming to document the score accurately within 6 h of admission. METHODS: Three 'care of the elderly' wards participated in the project. Each month, the timeliness (within 6 h of admission) and accuracy (compared to a dietician assessment) of the MUST scores on the wards were reviewed. Plan-Do-Study-Act cycles were used to rapidly test changes in the ward areas. Tests included a study day, one-to-one ward-based nutrition training, a focus on the use of alternative anthropometric measurements, the development of a training pack and the identification of the challenges for undertaking accurate and timely assessments. RESULTS: Baseline data identified that a MUST was documented in <60% of patients within 6 h of admission and that only 70% were accurate. After implementation of the change package, all the wards achieved an improvement and documented MUST within 6 h of admission; one ward achieved 90% accuracy in the scores. CONCLUSIONS: Ward teams receiving training and monthly feedback of their results creates ownership, momentum and maintains enthusiasm for striving to reach stretch targets. The team continues to work on improving accurate nutritional screening across the Trust by using quality improvement methodologies. PMID- 23627772 TI - Microarrays of phospholipid bilayers generated by inkjet printing. AB - We report an efficient and reproducible method to generate a microarray of model biological membranes on a solid substrate by applying the inkjet printing technology. Although inkjet printing is currently widely used for industrial fabrication processes, including biological materials, printing lipid membranes remains technically challenging due to the hydrophobic nature of droplets and instability of the lipid bilayer structure against dehydration. In the present study, we printed lipids onto a glass substrate covered with a micropatterned membrane of a polymeric phospholipid bilayer. Polymeric bilayers were formed by the lithographic photopolymerization of a diacetylene-containing phospholipid, 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DiynePC). After removal of nonpolymerized DiynePC with a detergent solution, natural lipid membranes were incorporated into the polymer-free regions (corrals) by using an electric-field-based inkjet printing device that can eject subfemtoliter volume droplets. To avoid rapid dehydration and destabilization, we preprinted an aqueous solution containing agarose and trehalose onto the corrals and subsequently printed lipid suspensions ("two-step-printing method"). After rinsing, stable lipid bilayer membranes were formed in the corrals. The bilayers were continuous and fluid as confirmed by fluorescence recovery after photobleaching. We could introduce multiple bilayer patches having different lipid compositions into the neighboring corrals. The present results demonstrate that the combination of a patterned polymeric bilayer and inkjet printing technology enables efficient, reliable, and scalable generation of the model membrane microarrays having varied compositions. PMID- 23627773 TI - Time--temperature indicator for perishable products based on kinetically programmable Ag overgrowth on Au nanorods. AB - Food safety is a constant concern for humans. Besides adulteration and contamination, another major threat comes from the spontaneous spoilage of perishable products, which is basically inevitable and highly dependent on the temperature history during the custody chain. For advanced quality control and assessment, time-temperature indicators (TTIs) can be deployed to document the temperature history. However, the use of TTIs is currently limited by either relatively high cost or poor programmability. Here we describe a general, kinetically programmable, and cost-efficient TTI protocol constructed from plasmonic nanocrystals. We present proof-of-principle demonstrations that our TTI can be specifically tailored and thus used to track perishables, dynamically mimic the deteriorative processes therein, and indicate product quality through sharp-contrast multicolor changes. The flexible programmability of our TTI, combined with its substantially low cost and low toxicity, promises a general applicability to each single packaged item of a plethora of perishable products. PMID- 23627774 TI - Exposure to life events as a risk factor for psychological problems in adults with intellectual disabilities: a longitudinal design. AB - BACKGROUND: Several cross-sectional studies have shown an association between exposure to life events and psychological problems in adults with intellectual disability (ID). To establish life events as a risk factor, prospective designs are needed. METHODS: Support staff informants provided data on the psychological problems of 68 adults with ID and their recent exposure to life events. Using data collected on the same sample 3.5 to 4 years earlier, prospective analysis of the relationships between life events exposure and psychological problems over time was explored. RESULTS: Hierarchical linear regression analyses demonstrated a contribution of life events to the prediction of later psychological problems after controlling for earlier psychological problems. Exploratory analyses showed that the relationship between life events and psychological problems might be unidirectional, and non-spurious; remaining present once the impact of other correlates of psychological problems was controlled. CONCLUSIONS: These data offer support for the status of life events (with a negative valence) as a risk factor for psychological problems in adults with ID. To establish life events as a causal risk factor, research is needed to examine the mechanisms via which life events have their impact on psychological well-being. PMID- 23627776 TI - Nickel-catalyzed Suzuki-Miyaura coupling of heteroaryl ethers with arylboronic acids. AB - Nickel-catalyzed Suzuki-Miyaura coupling of heteroaryl ethers with arylboronic acids was described. Selective activation of the phenol C-O bonds was achieved by converting them into the corresponding aryl 2,4-dimethoxy-1,3,5-triazine-6-yl ethers, in which aryl C-O bond could be selectively cleaved with inexpensive, air stable NiCl2(dppf) as a catalyst. Coupling of these readily accessible heteroaryl ethers proved tolerant of extensive functional groups. PMID- 23627775 TI - Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). AB - AIMS: To compare the efficacy and safety of once-daily prandial lixisenatide with placebo in type 2 diabetes mellitus (T2DM) insufficiently controlled by pioglitazone +/- metformin. METHODS: This randomized, double-blind study included a 24-week main treatment period and a >=52-week variable extension period. Patients were randomized 2 : 1 to receive lixisenatide 20 ug once daily or placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) at week 24. RESULTS: In total, 484 patients were randomized: 323 to lixisenatide; 161 to placebo. After 24 weeks, lixisenatide once daily significantly improved HbA1c ( 0.56% vs. placebo; p < 0.0001) and increased the proportion of patients achieving HbA1c <7% compared with placebo (52.3% vs. 26.4%, respectively; p < 0.0001) and significantly improved fasting plasma glucose (-0.84 mmol/l vs. placebo; p < 0.0001). There was a small decrease in body weight with lixisenatide once daily and a small increase with placebo, with no statistically significant difference between the two groups. Overall, lixisenatide once daily was well tolerated, with a similar proportion of treatment-emergent adverse events (TEAEs) and serious TEAEs between groups (lixisenatide: 72.4% and 2.5%; placebo: 72.7% and 1.9%). Symptomatic hypoglycaemia rates were also relatively low in both groups (lixisenatide 3.4% and placebo 1.2%), with no severe episodes. Lixisenatide continued to be efficacious and well tolerated during the variable extension period. CONCLUSIONS: Lixisenatide once daily significantly improved glycaemic control with a low risk of hypoglycaemia, and was well tolerated over 24 weeks and during the long-term, double-blind extension period in patients with T2DM insufficiently controlled on pioglitazone +/- metformin. PMID- 23627777 TI - Connexin dynamics in the privileged wound healing of the buccal mucosa. AB - Wound closure is fundamental to maintaining tissue homeostasis; a plethora of processes and signals must be coordinated, and gap junctions play a critical role. Some tissues exhibit privileged healing, such as buccal mucosa, repairing more rapidly, but gap junction connexin dynamics during wound healing in such tissues have not been investigated. To determine connexin changes during this rapid healing process, incisional wounds were made in the cheeks of mice and microscopically observed. We discovered that buccal mucosa wound edge keratinocytes do not form a thin tongue of migratory cells like epidermis; instead, a wedge of cells rapidly moves into the wound. The dorsal surfaces of opposing sides of the wounds then touch and join in a "V," which subsequently fills up with cells to form a "delta" that remodels into a flat sheet. Immunostaining showed that connexin26, connexin30, and connexin43 are expressed at significantly higher levels in the buccal mucosa than the epidermis and that, unlike the skin, all three are rapidly down-regulated at the wound edge within 6 hours of wounding. This rapid down-regulation of all three connexins may in part underlie the rapid healing of the buccal mucosa. PMID- 23627778 TI - "I thought we are safe": Southern African lesbians' experiences of living with HIV. AB - HIV-prevention and service programmes have long either ignored or overlooked lesbians. The experiences of lesbians with HIV have similarly been unrecognised and unreported. This erasure has contributed to the invisibility of lesbians in relation to HIV and related health risks. This community participatory study, based on in-depth interviews with 24 self-identifying African lesbians living with HIV in South Africa, Zimbabwe and Namibia, focuses on their personal experiences and circumstances. Women's experiences shed light and challenge popular notions around lesbian risk. In particular among this group are lesbians who self-report exclusive sexual relationships with women. For these women, experiences of living with HIV are challenging as they struggle to understand the possibility of female-to-female transmission. While battling with their own perceptions of invulnerability and accepting their HIV-positive status, they have to deal also with wide-ranging misconceptions about risk. The paper argues that within the context of HIV, lesbians cannot be regarded as a 'no-risk' group. Health services and health providers are encouraged to respond to the health needs of lesbians living with HIV. PMID- 23627779 TI - DDQ-mediated direct intramolecular-dehydrogenative-coupling (IDC): expeditious approach to the tetracyclic core of ergot alkaloids. AB - An efficient route to 2-oxindoles bearing an all-carbon quaternary center at the pseudobenzylic position has been developed via a DDQ-mediated Intramolecular Dehydrogenative-Coupling (IDC). The methodology involves a one-pot C-alkylation of beta-N-arylamido esters (7) concomitant with dehydrogenative-coupling in the presence of stoichiometric amount of DDQ. A tentative mechanistic route has been proposed for the oxidative coupling. The methodology provides a two-step entry to the ergoline structure of ergot alkaloids. PMID- 23627780 TI - Lithocholic acid-induced placental tumor necrosis factor-alpha upregulation and syncytiotrophoblast cell apoptosis in intrahepatic cholestasis of pregnancy. AB - AIM: To investigate tumor necrosis factor (TNF)-alpha expression and its relationship with serum bile acids in placental trophoblasts from patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: Human placenta, including normal pregnancies (n = 10) and patients with ICP (n = 10), were collected at term and subject to TNF-alpha measurements. Bile acid-induced TNF-alpha expression and cell apoptosis were evaluated in cultured syncytiotrophoblasts in vitro. RESULTS: ICP placental trophoblasts displayed apoptotic histological abnormalities. TNF-alpha levels in ICP tissue were significantly greater than those of controls as measured by quantitative polymerase chain reaction and western blot. Levels of placental TNF-alpha mRNA were positively correlated with serum bile acid concentration in ICP patients. In vitro, lithocholic acid (LCA) significantly enhanced TNF-alpha mRNA at both doses, by 2.07-fold at 15 MUm and by 3.41-fold at 30 MUm, whereas deoxycholic acid mildly increased TNF-alpha mRNA by 1.41-fold at 100 MUm only. LCA treatment produced significantly higher percentage of caspase-3 positive cells than vehicle treatment, rescuable by the addition of a TNF-alpha inhibitor, indicative of apoptosis induced by LCA-TNF alpha pathway. CONCLUSION: This study shows that the increase of TNF-alpha expression in placental trophoblasts is strongly associated with ICP pathology and is inducible by LCA in vitro, suggesting its potential value in the clinical prevention, diagnosis and treatment of ICP. PMID- 23627781 TI - Ionizing radiation leads to the replacement and de novo production of colonic Lgr5(+) stem cells. AB - Tissue stem cells have self-renewal capability throughout their whole life, which is high enough to lead to the accumulation of DNA damage in a stem cell pool. Whether radiation-induced damage accumulates in tissue stem cells remains unknown, but could be investigated if the fate of tissue stem cells could be followed after irradiation. To realize this goal, we used an Lgr5-dependent lineage tracing system that allows the conditional in vivo labeling of Lgr5(+) intestinal stem cells and their progeny. We found that radiation induced loss of Lgr5(+) stem cells in the colon, but not in the duodenum. Interestingly, the loss of colonic Lgr5(+) cells was compensated by de novo production of Lgr5(+) cells, which increased after irradiation. These findings show that ionizing radiation effectively stimulates the turnover of colonic Lgr5(+) stem cells, implying that radiation-induced damage does not accumulate in the colonic Lgr5(+) stem cells by this mechanism. PMID- 23627782 TI - Ibogaine in the treatment of substance dependence. AB - Ibogaine is a psychoactive alkaloid derived from Tabernanthe iboga, a plant used in initiatory rituals in West Central Africa. Largely because of ibogaine's status as a Schedule I substance in the U.S., the development of ibogaine's use in the treatment of drug addiction took place outside conventional clinical and medical settings. This article reviews the history of ibogaine's use in the treatment of drug addiction, and discusses progress made towards, and obstacles blocking, the establishment of controlled clinical trials of ibogaine's efficacy. Preclinical research has generally supported anecdotal claims that ibogaine attenuates withdrawal symptoms and reduces drug cravings. Concerns about ibogaine's safety, as well as a dearth of solid data from human studies, have hampered progress in its development as an approved medication. This article outlines major findings from preclinical studies, discusses concerns about ibogaine's safety, and details previous and ongoing research on ibogaine's use as an anti-addictive treatment for humans. PMID- 23627783 TI - Studying the effects of classic hallucinogens in the treatment of alcoholism: rationale, methodology, and current research with psilocybin. AB - Recent developments in the study of classic hallucinogens, combined with a re appraisal of the older literature, have led to a renewal of interest in possible therapeutic applications for these drugs, notably their application in the treatment of addictions. This article will first provide a brief review of the research literature providing direct and indirect support for the possible therapeutic effects of classic hallucinogens such as psilocybin and lysergic acid diethylamide (LSD) in the treatment of addictions. Having provided a rationale for clinical investigation in this area, we discuss design issues in clinical trials using classic hallucinogens, some of which are unique to this class of drug. We then discuss the current status of this field of research and design considerations in future randomized trials. PMID- 23627784 TI - Ayahuasca-assisted therapy for addiction: results from a preliminary observational study in Canada. AB - INTRODUCTION: This paper reports results from a preliminary observational study of ayahuasca-assisted treatment for problematic substance use and stress delivered in a rural First Nations community in British Columbia, Canada. METHODS: The "Working with Addiction and Stress" retreats combined four days of group counselling with two expert-led ayahuasca ceremonies. This study collected pre-treatment and six months follow-up data from 12 participants on several psychological and behavioral factors related to problematic substance use, and qualitative data assessing the personal experiences of the participants six months after the retreat. FINDINGS: Statistically significant (p < 0.05) improvements were demonstrated for scales assessing hopefulness, empowerment, mindfulness, and quality of life meaning and outlook subscales. Self-reported alcohol, tobacco and cocaine use declined, although cannabis and opiate use did not; reported reductions in problematic cocaine use were statistically significant. All study participants reported positive and lasting changes from participating in the retreats. CONCLUSIONS: This form of ayahuasca-assisted therapy appears to be associated with statistically significant improvements in several factors related to problematic substance use among a rural aboriginal population. These findings suggest participants may have experienced positive psychological and behavioral changes in response to this therapeutic approach, and that more rigorous research of ayahuasca-assisted therapy for problematic substance use is warranted. PMID- 23627785 TI - Salvia divinorum: a psychopharmacological riddle and a mind-body prospect. AB - The multidisciplinary research on Salvia divinorum and its chemical principles is analyzed concerning whether the ethnobotany, phytochemistry, mental effects, and neuropharmacology of this sacred psychoactive plant and main principle clarify its experienced effects and divinatory uses. The scientific pursuit spans from the traditional practices, continues with the botanical identification, isolation of active molecules, characterization of mental and neural effects, possible therapeutic applications, and impinges upon the mind-body problem. The departure point is ethnopharmacology and therefore the traditional beliefs, ritual uses, and mental effects of this Mazatec sacred mint recorded during a 1973- 1983 field research project are described. A water potion of crushed leaves produced short lasting light-headedness, dysphoria, tactile and proprioceptive sensations, a sense of depersonalization, amplified sound perception, and an increase visual and auditory imagery, but not actual hallucinations. Similar effects were described using questionnaires and are attributable to salvinorin A, but cannot be explained solely by its specific and potent brain kappa-opioid receptor agonist activity. Some requirements for a feasible classification and mechanism of action of consciousness-altering products are proposed and include the activation of neural networks comprising several neurochemical systems. Top-down analyses should be undertaken in order to characterize such neural networks and eventually allowing to explore the differential ethnic effects. As is the case for other consciousness-altering preparations, a careful and encompassing research on this plant and principle can be consequential to endeavors ranging from the mind-body problem, a better understanding of shamanic ecstasy, to the potential generation of analgesic, antidepressant, and drug-abuse attenuating products. PMID- 23627786 TI - Can MDMA play a role in the treatment of substance abuse? AB - A wider array of treatments are needed for people with substance abuse disorders. Some psychedelic compounds have been assessed as potential substance abuse treatments with promising results. MDMA may also help treat substance abuse based on shared features with psychedelic compounds and recent reports indicating that MDMAassisted psychotherapy can reduce symptoms of PTSD. Narrative reports and data from early investigations found that some people reduced or eliminated their substance use after receiving MDMA, especially in a therapeutic setting. MDMA is a potent monoamine releaser with sympathomimetic effects that may indirectly activate 5-HT2A receptors. It increases interpersonal closeness and prosocial feelings, potentially through oxytocin release. Findings suggest that ecstasy, material represented as containing MDMA, is associated with deleterious long-term effects after heavy lifetime use, including fewer serotonin transporter sites and impaired verbal memory. Animal and human studies demonstrate moderate abuse liability for MDMA, and this effect may be of most concern to those treating substance abuse disorders. However, subjects who received MDMA-assisted psychotherapy in two recent clinical studies were not motivated to seek out ecstasy, and tested negative in random drug tests during follow-up in one study. MDMA could either directly treat neuropharmacological abnormalities associated with addiction, or it could indirectly assist with the therapeutic process or reduce symptoms of comorbid psychiatric conditions, providing a greater opportunity to address problematic substance use. Studies directly testing MDMA assisted psychotherapy in people with active substance abuse disorder may be warranted. PMID- 23627787 TI - Fabrication, gastromucoadhesivity, swelling, and degradation of zein-chitosan composite ultrafine fibers. AB - Fabrication, via electrospinning, and characterization of an ultrafine structure architected from a blend of hydrophobic zein and hydrophilic chitosan (CS) were conducted. Poly(ethylene oxide) (PEO) and nonionic surfactant, namely, Tween 40, were employed to improve the electrospinnability of the blend, while ethanol was used as a solvent for zein. The effects of ethanol (EtOH) concentration (85% and 90%) and ratio of zein/PEO/CS (95/2.5/2.5 and 87.5/10/2.5) on the fiber morphology as well as gastromucoadhesivity against porcine stomach mucosa were then investigated; polymer-mucosa adhesion was also investigated via Fourier transform infrared spectroscopy. Swelling and degradation of the composite ultrafine fibers were investigated under 2 simulated gastric conditions, namely, at pH 2 without pepsin and at pH 1.2 with pepsin. Using 85% EtOH as a solvent for zein resulted in a spider-web-like morphology; the maximum detachment force (MDF), which is an indirect indicator of the gastromucoadhesivity was nevertheless higher. Zein-based ultrafine fibers exhibited higher MDF than the zein-PEO-CS composite; however, the cohesiveness of the composite fibers was higher. FTIR spectroscopic results indicated molecular interactions between the composite fibers and mucin functional groups. Swelling of the composite ultrafine fibers in simulated gastric fluid (SGF) at pH 2 without pepsin was not different from that in SGF at pH 1.2 with pepsin. Nevertheless, degradation of the composite fibers in SGF at pH 2 without pepsin was much less than that in SGF at pH 1.2 with pepsin; only 20% degradation was noted in the former case. PMID- 23627788 TI - Ubiquinol supplementation enhances peak power production in trained athletes: a double-blind, placebo controlled study. AB - BACKGROUND: To investigate the effect of Ubiquinol supplementation on physical performance measured as maximum power output in young and healthy elite trained athletes. METHODS: In this double-blind, placebo-controlled study, 100 young German well trained athletes (53 male, 47 female, age 19.9 +/- 2.3 years) received either 300 mg Ubiquinol or placebo for 6 weeks. Athletes had to perform a maximum power output test and the performance in W/kg of bodyweight was measured at the 4 mmol lactate threshold on a cycling ergometer before the supplementation treatment (T1), after 3 weeks (T2) and after 6 weeks (T3) of treatment. In these 6 weeks all athletes trained individually in preparation for the Olympic Games in London 2012. The maximum power output was measured in Watt/kilogram body weight (W/kg bw). RESULTS: Both groups, placebo and Ubiquinol, significantly increased their physical performance measured as maximum power output over the treatment period from T1 to T3. The placebo group increased from 3.64 +/- 0.49 W/kg bw to 3.94 +/- 0.47 W/kg bw which is an increase of +0.30 +/- 0.18 W/kg bw or +8.5% (+/-5.7). The Ubiquinol group increased performance levels from 3.70 W/kg bw (+/-0.56) to 4.08 W/kg bw (+/-0.48) from time point T1 to T3 which is an increase of +0.38 +/- 0.22 W/kg bw or +11.0% (+/-8.2). The absolute difference in the enhancement of the physical performance between the placebo and the Ubiquinol group of +0.08 W/kg bodyweight was significant (p < 0.03). CONCLUSIONS: This study demonstrates that daily supplementation of 300 mg Ubiquinol for 6 weeks significantly enhanced physical performance measured as maximum power output by +0.08 W/kg bw (+2.5%) versus placebo in young healthy trained German Olympic athletes. While adherence to a training regimen itself resulted in an improvement in peak power output, as observed by improvement in placebo, the effect of Ubiquinol supplementation significantly enhanced peak power production in comparison to placebo. PMID- 23627789 TI - Driver behaviours on rural highways with and without curbs - a driving simulator based study. AB - The speed limit of 55 mph (88 km/h) is used typically on rural highways in the U.S. When curbs are installed, a lower speed limit is suggested because running into curbs at high speeds may cause significant vehicular damage and severe injuries. However, it has been argued that lowering the speed limit may cause confusion in drivers, who do not perceive the risk and tend to operate their vehicles at the same speed as before. To better understand driver behaviour on two-lane rural highways before and after curb installation, the authors conducted a series of experiments on a high-fidelity driving simulator in different posted speed limit, curb installation, lateral curb clearance, weather, visibility, and traffic conditions. Results of the study suggest that driver behaviours are influenced by the various factors in a complex and interrelated manner. It is likely that curbs have no influence on a driver's selection of speed. Drivers do perceive the risk from the curb or the opposing traffic when selecting their lane positions. The available space between the curb and the opposing traffic is crucial and has significant effects on driving behaviours. The subjective effects of drivers are found to be influential to driving behaviours. PMID- 23627790 TI - Bi-oblique dynamic proximal ulnar osteotomy in dogs: reconstructed computed tomographic assessment of radioulnar congruence over 12 weeks. AB - OBJECTIVE: To evaluate radioulnar joint modification using computed tomography (CT) after bi-oblique dynamic proximal ulnar osteotomy (BODPUO). STUDY DESIGN: Clinical study. ANIMALS: Dogs (n = 18, 26 elbows) with elbow incongruence treated by a single surgeon with BODPUO. METHODS: Radioulnar space measurements were performed on transverse, frontal, and sagittal CT projections preoperatively and after radiographically determined osteotomy healing. RESULTS: Three transverse plane measurements were statistically different than preoperatively at 12 weeks after the surgery demonstrating divergence of the lateral coronoid region of the radial incisure of the ulna from the radial head. None of the other measurements within the elbow were statistically different, but measurements of the radioulnar space at the level of the osteotomy site documented a statistically significant caudal tipping of the distal extent of the proximal ulnar segment. CONCLUSION: CT measurements documented a significant increase in radioulnar joint space at the mid-coronoid level, at the level of the base of the medial coronoid process, and at the level of the lateral coronoid process. This corresponds to cranially directed rotation of the medial coronoid process around the proximal radial epiphysis. A tendency for cranial tilting of the medial coronoid process was observed, which was confirmed by statistically significant caudal tipping of the distal extent of the proximal ulnar segment. PMID- 23627791 TI - The effectiveness of a specialised oral nutrition supplement on outcomes in patients with chronic wounds: a pragmatic randomised study. AB - BACKGROUND: Nutrition supplements enriched with immune function enhancing nutrients have been developed to aid wound-healing, although evidence regarding their effectiveness is limited and systematic reviews have lead to inconsistent recommendations. The present pragmatic, randomised, prospective open trial evaluated a wound-specific oral nutrition supplement enriched with arginine, vitamin C and zinc compared to a standard supplement with respect to outcomes in patients with chronic wounds in an acute care setting. METHODS: Twenty-four patients [11 males and 13 females; mean (SD) age: 67.8 (22.3) years] with chronic wounds (14 diabetic or venous ulcers; 10 pressure ulcers or chronic surgical wounds) were randomised to receive either a wound-specific supplement (n = 12) or standard supplement (n = 12) for 4 weeks, with ongoing best wound and nutrition care for an additional 4 weeks. At baseline, and at 4 and 8 weeks, the rate of wound-healing, nutritional status, protein and energy intake, quality of life and product satisfaction were measured. Linear mixed effects modelling with random intercepts and slopes were fitted to determine whether the wound-specific nutritional supplement had any effect. RESULTS: There was a significant improvement in wound-healing in patients receiving the standard nutrition supplement compared to a wound-specific supplement (P = 0.044), although there was no effect on nutritional status, dietary intake, quality of life and patient satisfaction. CONCLUSIONS: The results of the present study indicate that a standard oral nutrition supplement may be more effective at wound-healing than a specialised wound supplement in this clinical setting. PMID- 23627792 TI - Automated mineralogical analysis of PM10: new parameters for assessing PM toxicity. AB - This work provides the first automated mineralogical/phase assessment of urban airborne PM10 and a new method for determining particle surface mineralogy (PSM), which is a major control on PM toxicity in the lung. PM10 was analyzed on a TEOM filter (Aug.-Sept. 2006 collection) from the London Air Quality Network Bexley, East London, U.K. A cross-section of the filter was analyzed using a QEMSCAN automated mineralogical analysis system which provided 381,981 points of analysis for 14,525 particles over a period of 9 h 54 min. The method had a detection limit for individual mineral components of 0.05 ppm (by area). Particle shape and mineralogical characteristics were determined for particles in the size ranges PM(10-4), PM(4-2.5), and PM(2.5-0.8). The PM(2.5-0.8) fraction contained 2 orders of magnitude more mineral particles than the PM(10-4) and PM(4-2.5) fractions, however the PM(10-4) fraction forms 94% and 79% of the mineral mass and surface area, respectively. PSM of the PM10 was dominated by gypsum (36%), plagioclase (16%), Na sulphates (8%), and Fe-S-O phases (8%) in the PM(10-2.5), which may be important in explaining the toxicity of the coarse fraction. The wider implications of the study are discussed. PMID- 23627794 TI - Origins of amyloid-beta. AB - BACKGROUND: Amyloid-beta plaques are a defining characteristic of Alzheimer Disease. However, Amyloid-beta deposition is also found in other forms of dementia and in non-pathological contexts. Amyloid-beta deposition is variable among vertebrate species and the evolutionary emergence of the amyloidogenic property is currently unknown. Evolutionary persistence of a pathological peptide sequence may depend on the functions of the precursor gene, conservation or mutation of nucleotides or peptide domains within the precursor gene, or a species-specific physiological environment. RESULTS: In this study, we asked when amyloidogenic Amyloid-beta first arose using phylogenetic trees constructed for the Amyloid-beta Precursor Protein gene family and by modeling the potential for Amyloid-beta aggregation across species in silico. We collected the most comprehensive set of sequences for the Amyloid-beta Precursor Protein family using an automated, iterative meta-database search and constructed a highly resolved phylogeny. The analysis revealed that the ancestral gene for invertebrate and vertebrate Amyloid-beta Precursor Protein gene families arose around metazoic speciation during the Ediacaran period. Synapomorphic frequencies found domain-specific conservation of sequence. Analyses of aggregation potential showed that potentially amyloidogenic sequences are a ubiquitous feature of vertebrate Amyloid-beta Precursor Protein but are also found in echinoderm, nematode, and cephalochordate, and hymenoptera species homologues. CONCLUSIONS: The Amyloid-beta Precursor Protein gene is ancient and highly conserved. The amyloid forming Amyloid-beta domains may have been present in early deuterostomes, but more recent mutations appear to have resulted in potentially unrelated amyloid forming sequences. Our results further highlight that the species-specific physiological environment is as critical to Amyloid-beta formation as the peptide sequence. PMID- 23627795 TI - Conditioned taste aversion as instrumental punishment. AB - Conditioned taste aversion (CTA) is traditionally viewed as an instance of pavlovian conditioning. This interpretation rests on the lack of an instrumental contingency between the tastant and the gastric malaise in a standard procedure of CTA. To investigate a role for instrumental punishment in CTA, we present 2 tastants sequentially ("sucrose then NaCl" or "NaCl then sucrose") in a daily alternating and counterbalanced order to rats with an explicit positive contingency between the dosage of the lithium chloride (LiCl) administered and the amount of 1 tastant drunk on that trial. In the beginning of experiment, rats suppressed their intake of both tastants. With the increase of conditioning trials, rats gradually learned to resume the intake of noncontingent solution while selectively suppressing the intake of LiCl-contingent solution. This selective suppression in CTA is the first report indicating that rats are sensitive to the subtle cues related to the covariations between the magnitude of stimulus and the magnitude of responses in a punishment paradigm involving a long delay between the gustatory stimulus of tastant ingestion and the aversive effect of LiCl injection. PMID- 23627796 TI - Mechanisms of renewal after the extinction of instrumental behavior. AB - Four experiments with rats examined renewal of extinguished instrumental behavior when the reinforcement histories of the contexts were equated by giving complementary training and extinction of a different response (lever press and chain pull) in each context. In Experiments 1 through 3, renewal occurred when the response was tested in the acquisition context (ABA) or outside the extinction context (AAB and ABC). Further, in Experiments 1 through 3, when both responses were simultaneously available, there was a clear preference for the response that was not in its extinction context. In Experiment 4, renewal was not reduced when testing occurred in a context that had been associated with extinction of the other instrumental response. The experimental designs rule out differential context-reinforcer associations being the only contributing mechanism of renewal, and also raise questions about configural and occasion setting accounts. The results are consistent with the idea that during extinction an inhibitory association is formed between the context and the response. PMID- 23627797 TI - Extinction makes conditioning time-dependent. AB - Two experiments explored whether forgetting of an association depended on previous extinction of a different association in rats. Experiment 1 found that when rats were conditioned and extinguished with flavor X, a subsequently acquired conditioned aversion to flavor Y was reduced by a 19-day retention interval, something that did not occur when X and the US were initially presented unpaired. Experiment 2 found that when rats received training and extinction in one of two tasks (conditioned aversion to sucrose in Experiment 2a, and running for water in a straight alley in Experiment 2b), subsequent learning of the alternative task was partially forgotten over the 19-day retention interval. These results are similar to those previously found when manipulating physical and conceptual contexts in rats and humans, respectively, and suggest that the passage of time may play a role similar to the one played by the change in physical or conceptual contexts on information retrieval. PMID- 23627798 TI - Within-compound associations explain potentiation and failure to overshadow learning based on geometry by discrete landmarks. AB - In three experiments, rats were trained to locate a submerged platform in one of the base corners of a triangular arena above each of which was suspended one of two distinctive landmarks. In Experiment 1, it was established that these landmarks differed in their salience by the differential control they gained over behavior after training in compound with geometric cues. In Experiment 2, it was shown that locating the platform beneath the less salient landmark potentiated learning based on geometry compared with control rats for which landmarks provided ambiguous information about the location of the platform. The presence of the more salient landmark above the platform for another group of animals appeared to have no effect on learning based on geometry. Experiment 3 established that these landmark and geometry cues entered into within-compound associations during compound training. We argue that these within-compound associations can account for the potentiation seen in Experiment 2, as well as previous failures to demonstrate overshadowing of geometric cues. We also suggest that these within-compound associations need not be of different magnitudes, despite the different effects of each of the landmarks on learning based on geometry seen in Experiment 2. Instead, within-compound associations appear to mitigate the overshadowing effects that traditional theories of associative learning would predict. PMID- 23627799 TI - The effect of stimulus distribution form on the acquisition and rate of conditioned responding: implications for theory. AB - In four experiments rats were conditioned to an auditory conditioned stimulus (conditioned stimulus; CS) that was paired with food, and learning about the CS was compared across two conditions in which the mean duration of the CS was equated. In one, the CS was of a single, fixed duration on every trial, and in the other the CS duration was drawn from an exponential distribution, and hence changed from trial to trial. Higher rates of conditioned responding to the fixed than to the variable stimulus were observed, in both between- (Experiment 1) and within-subject designs (Experiments 2 and 3). Moreover, this difference was maintained when stimuli trained with fixed or variable durations were tested under identical conditions (i.e., with equal numbers of fixed and variable duration trials)-suggesting that the difference could not be attributed to performance effects (Experiment 3). In order to estimate the speed of acquisition of conditioned responding, the scaled cumulative distribution of a Weibull function was fitted to the trial-by-trial response rates for each rat. In the within-subject experiments specific differences in the pattern of acquisition to fixed and variable CS were shown; a somewhat different pattern was found when intertrial interval (ITI) was manipulated (Experiment 4). The implications of these findings for theories of conditioning and timing are discussed. PMID- 23627800 TI - Interval timing under variations in the relative validity of temporal cues. AB - Two groups of pigeons were trained to respond on a white center key to a fixed interval, 60-s schedule of reinforcement signaled by the onset of a side-key cue (S+ training). In additional training sessions, S+ trials alternated between S- trials in which a different side-key cue signaled nonreinforcement after 60 s (S+/S- training). For one group, S+/S- training sessions followed S+ training, and for the other group, S+/S- training preceded S+ training. Peak-time curves obtained from extended nonrewarded probe trials inserted among training trials showed loss of control by time during S+/S- training relative to S+ training. A follow-up experiment showed that this result was not caused by a difference in probability of reinforcement. We suggest that attention to time was weakened by the introduction of visual cues that were more valid predictors of trial outcomes. PMID- 23627801 TI - Differentiating models of associative learning: reorientation, superconditioning, and the role of inhibition. AB - A recent associative model (Miller, N.Y., & Shettleworth, S.J., 2007. Learning about environmental geometry: An associative model. Journal of Experimental Psychology: Animal Behavior Processes B, 33, 191-212) is an influential mathematical account of how agents behave when reorienting to previously learned locations in spatial arenas. However, it is mathematically and empirically flawed. The current article explores these flaws, including its inability to properly predict geometric superconditioning. We trace the flaws to the model's mathematical structure and how it handles inhibition. We then propose an operant artificial neural network model that solves these problems with inhibition and can correctly model both reorientation and superconditioning. PMID- 23627802 TI - Lichen planus in childhood: a series of 316 patients. AB - Lichen planus (LP) is infrequently seen in children and the clinical presentation is often atypical. We conducted a retrospective analysis of clinical features and treatment response in childhood LP to date. The clinical profile and treatment response data of patients younger than 14 years old with LP (entered in a predesigned pro forma study) from January 1997 to June 2011 were analyzed. The treatment was administered according to a predetermined departmental protocol and was comprised of topical steroids with or without oral dapsone or corticosteroids. Patients were evaluated for response, adverse effects, and relapse. The study population consisted of 316 children (166 boys, 150 girls), or 18.7% of the total registered patients in the LP clinic. The mean age was 10.28 years (range 2-14 years). Cutaneous lesions were seen in 96.2%. Involvement of the oral mucosa was detected in 18%, nails in 13.9%, scalp in 8.2%, and genitalia in 4.4%. Classic LP was most prevalent (53.8%), followed by eruptive (16.5%), hypertrophic (8.2%), linear (6.9%), and lichen planopilaris (6.3%). LP pigmentosus, annular, and atrophic variants were encountered infrequently. Topical corticosteroids were the most common treatment used in 69.5% of patients, 28.8% of whom had excellent response at 6 months, although 38.8% failed to follow up. Dapsone was prescribed in 20% and systemic steroids in 9.8% of patients. We report the largest series to date of LP in childhood, with a more varied clinical presentation than in previous series. The course and response to treatment were similar to those in adults. PMID- 23627803 TI - Poor glycaemic control and arrhythmias. AB - OBJECTIVE: To evaluate number, type, and complexity of arrhythmias in diabetics compared with controls and, among diabetics, comparing good glycaemic control (GGC) and poor glycaemic control (PGC) patients. METHODS: We compared Ambulatory Electrocardiogram recordings of 92 diabetics and 100 controls. The glycaemic profile of 50 diabetics, taken the same day as the Ambulatory ECG recording, was subdivided into GGC (gluco-stick mean values between 100 and 140 mg/dL) or PGC (gluco-stick values <=99 mg/dL in 3-of-4 daily determination or gluco-stick values >=140 mg/dL in 3-of-4 daily determination). RESULTS: Diabetics show a higher prevalence of either ventricular ectopic beats (VEBs) (93.47% vs. 82% controls, p < 0.05) and heart rate (both in sinus rhythm and in atrial fibrillation) (98.35 +/- 10 beats/min in diabetics vs. 78.10 +/- 8.1 in controls, p < 0.001). Moreover, diabetics with PGC show either a higher prevalence of VEBs (96.42% vs 77.27% in GGC, p < 0.05) and of supraventricular ectopic beats (SVEBs) (96.42% vs. 68.18 in GGC, p < 0.05); furthermore, diabetics with PGC show more severe and complex atrial and ventricular arrhythmias (SVEBs 32.14% vs 0%, p < 0.05; VEBs 39.28% vs 9.09%, p < 0.05). CONCLUSIONS: The analysis of our sample shows that the arrhythmogenic condition is not only provided from diabetic condition per se but it is enhanced in PGC. Infact PGC patients showed higher number of VEBs, often polymorphic, expression of more severe arrhythmic and cardiovascular outcome. This could be partially explained by hyperactivation of autonomic nervous system during metabolic stress (which increases mean heart rate). Moreover more severe diabetic patients may present coronary microangiopathy that can further explain their arrhythmogenic tendency. PMID- 23627805 TI - General practitioners' perspectives of education and collaboration with physiotherapists in Primary Health Care: a discourse analysis. AB - This paper explores the educational factors that underlie the poor collaboration between general practitioners (GPs) and physiotherapists (PTs) in Primary Health Care (PHC), from the GP's perspective. This study was conducted in Majorca, the Balearic Islands (Spain). Participants were nine GPs who graduated from different universities in mainland Spain. A discourse analysis study was developed employing the social-critical paradigm as theoretical framework and in-depth interviews for data collection. The perceived lack of knowledge about physiotherapy was considered by the interviewees as a major factor in the current poor communication between GPs and PTs. The individual learning during medical studies and poor interprofessional learning during clinical residency influenced their gatekeeper role, putting at risk the equity of the health system. Collaboration was considered beneficial for patients but challenging to improve in context due to multiple factors ranging from individual to systemic. The latter encompasses inadequate resources and organization for interprofessional learning. There is a need to further explore other factors influencing the poor collaboration, including PTs' views on this process. PMID- 23627804 TI - Evaluation of the in vitro cytotoxicity of cross-linked biomaterials. AB - This study evaluated the in vitro cytotoxicity of poly(propylene fumarate) (PPF). PPF is an aliphatic biodegradable polymer that has been well characterized for use in bone tissue engineering scaffolds. Four different cell types, human mesenchymal stem cells (hMSC), fibroblasts (L929), preosteoblasts (MC3T3), and canine mesenchymal stem cells (cMSC), were used to evaluate the cytotoxicity of PPF. These cell types represent the tissues that PPF would interact with in vivo as a bone tissue scaffold. The sol fraction of the PPF films was measured and then utilized to estimate cross-linking density. Cytotoxicity was evaluated using XTT assay and fluorescence imaging. Results showed that PPF supported similar cell metabolic activities of hMSC, L929, MC3T3, and cMSC compared to the noncytotoxic control, high-density polyethylene (HDPE) and were statistically different than those cultured with the cytotoxic control, a polyurethane film containing 0.1% zinc diethyldithiocarbamate (ZCF). Results showed differing cellular responses to ZCF, the cytotoxic control. The L929 cells had the lowest cell metabolic activity levels after exposure to ZCF compared to the cell metabolic activity levels of the MC3T3, hMSC, or cMSC cells. Qualitative verification of the results using fluorescence imaging demonstrated no change in cell morphology, vacuolization, or detachment when cultured with PPF compared to HDPE or blank media cultures. Overall, the cytotoxicity response of the cells to PPF was demonstrated to be similar to the cytotoxic response of cells to known noncytotoxic materials (HDPE). PMID- 23627806 TI - Superparamagnetic hollow hybrid nanogels as a potential guidable vehicle system of stimuli-mediated MR imaging and multiple cancer therapeutics. AB - Hollow hybrid nanogels were prepared first by the coassembly of the citric acid coated superparamagnetic iron oxide nanoparticles (SPIONs, 44 wt %) with the graft copolymer (56 wt %) comprising acrylic acid and 2-methacryloylethyl acrylate units as the backbone and poly(ethylene glycol) and poly(N isopropylacrylamide) as the grafts in the aqueous phase of pH 3.0 in the hybrid vesicle structure, followed by in situ covalent stabilization via the photoinitiated polymerization of MEA residues within vesicles. The resultant hollow nanogels, though slightly swollen, satisfactorily retain their structural integrity while the medium pH is adjusted to 7.4. Confining SPION clusters to such a high level (44 wt %) within the pH-responsive thin gel layer remarkably enhances the transverse relaxivity (r2) and renders the MR imaging highly pH tunable. For example, with the pH being adjusted from 4.0 to 7.4, the r2 value can be dramatically increased from 138.5 to 265.5 mM(-1) s(-1). The DOX-loaded hybrid nanogels also exhibit accelerated drug release in response to both pH reduction and temperature increase as a result of the substantial disruption of the interactions between drug molecules and copolymer components. With magnetic transport guidance toward the target and subsequent exposure to an alternating magnetic field, this DOX-loaded nanogel system possessing combined capabilities of hyperthermia and stimuli-triggered drug release showed superior in vitro cytotoxicity against HeLa cells as compared to the case with only free drug or hyperthermia alone. This work demonstrates that the hollow inorganic/organic hybrid nanogels hold great potential to serve as a multimodal theranostic vehicle functionalized with such desirable features as the guidable delivery of stimuli mediated diagnostic imaging and hyperthermia/chemotherapies. PMID- 23627808 TI - Commentary: safety and tolerability of a focused ultrasound device for treatment of adipose tissue in subjects undergoing abdominoplasty, a placebo control pilot study. PMID- 23627807 TI - Fused heteroaromatic dihydrosiloles: synthesis and double-fold modification. AB - An efficient method for the synthesis of fused heteroaromatic dihydrosiloles via Ni-catalyzed hydrosilylation/intramolecular Ir-catalyzed dehydrogenative coupling of the Si-H bond with the heteroaromatic C-H bond has been developed. The method is efficient for both electron-deficient and -rich heterocycles. It exhibits high functional group tolerance and good regioselectivity. Fused heteroaromatic dihydrosiloles can be smoothly halogenated and then oxidized or arylated. Application of these transformations allows obtaining highly functionalized heteroaromatic structures. A gram-scale synthesis of dihydropyridinosilole has also been accomplished using reduced amounts of Ni- and Ir-catalysts. PMID- 23627809 TI - Use of a special handle to control depth of recipient sites in hair transplantation. PMID- 23627810 TI - A 15-patient pilot trial of lipolysis of the hips and thighs using a phosphatidylcholine and deoxycholate formulation. PMID- 23627811 TI - The subcutaneous inverted cross mattress stitch (SICM stitch) in our experience. PMID- 23627812 TI - Innovative use of a polarized magnifier and a smart phone: a microscope in your pocket. PMID- 23627813 TI - Familial dermatofibrosarcoma protuberans: a nonfortuitous association? PMID- 23627814 TI - Adenoma, advanced adenoma and colorectal cancer prevalence in asymptomatic 40- to 49-year-old subjects with a first-degree family history of colorectal cancer. AB - AIM: First-degree relatives (FDRs) of patients with colorectal cancer (CRC) have an increased CRC risk. Few studies have addressed if adenoma and advanced adenoma risk is increased among individuals, 40-49 years of age, with a family history of CRC. Therefore, the aim of the study was to define the prevalence and location of adenoma, advanced adenoma and CRC, according to age, in asymptomatic individuals with a family history of CRC. METHOD: Retrospective study of asymptomatic FDRs, 40 to >=70 years of age undergoing first screening colonoscopy over a 3-year period, of CRC patients. RESULTS: Among 464 individuals studied, the prevalence of adenoma and advanced adenoma was 18.1% and 6.4%, respectively. According to age intervals, the prevalences of adenoma and advanced adenoma were 14% and 3.5%, respectively, in subjects 40-49 years of age; 14.4% and 6.3%, respectively, in subjects 50-59 years of age; 27% and 8%, respectively, in subjects 60-69 years of age; and 25% and 14%, respectively, in subjects >=70 years of age; no significant difference was found among the four groups. No difference in lesion location was found, with similar numbers of preneoplastic lesions being present in the right colon and the left colon. CRC was diagnosed in three (0.64%) subjects, one of whom was in the 40-49 years age group. CONCLUSION: In our population of FDRs of CRC patients, 40-49 years of age, the prevalences of adenoma and advanced adenoma were similar to those observed in older subjects with the same CRC risk. Our data support the current indication to perform screening colonoscopy earlier than 45 years of age in subjects at high CRC risk. PMID- 23627815 TI - Regeneration of chronic tympanic membrane perforation using an EGF-releasing chitosan patch. AB - Most chronic tympanic membrane (TM) perforations require surgical interventions such as tympanoplasty because, unlike with acute perforations, it is very difficult for the perforations to heal spontaneously. The purpose of this study was to develop novel therapeutic techniques and scaffolds that release growth factors to treat chronic TM perforations. We evaluated the cell proliferation effects of the epidermal growth factor (EGF) and fibroblast growth factor (FGF) on in vitro cultures of TM cells using an MTT assay. They both showed similar efficacy, so we used EGF because of its lower cost. We then constructed an EGF releasing chitosan patch scaffold (EGF-CPS) based on previous studies. We analyzed its toxicity and strength, and we studied it using scanning electron microscopy. EGF was released from the EGF-CPS for 8 weeks in an in vitro system. In animal studies, the EGF group, which was treated with EGF-CPS, showed healing in 56.5% of the animals (13/23), while the control group, which did not receive any treatment, revealed 20.8% healing (4/24) (p=0.04). Transmission electron microscopic studies of regenerated eardrums in the EGF group showed much greater preservation of histological features, and TMs of the EGF group were thinner than spontaneously healed TMs. In conclusion, this novel EGF-CPS can be used as a nonsurgical intervention technique for treatment of chronic TM perforations. PMID- 23627816 TI - Validation of self-reported cannabis dose and potency: an ecological study. AB - AIMS: To assess the reliability and validity of self-reported cannabis dose and potency measures. DESIGN: Cross-sectional study comparing self-reports with objective measures of amount of cannabis and delta-9-tetrahydrocannabinol (THC) concentration. SETTING: Ecological study with assessments at participants' homes or in a coffee shop. PARTICIPANTS: Young adult frequent cannabis users (n = 106) from the Dutch Cannabis Dependence (CanDep) study. MEASUREMENTS: The objectively measured amount of cannabis per joint (dose in grams) was compared with self reported estimates using a prompt card and average number of joints made from 1 g of cannabis. In addition, objectively assessed THC concentration in the participant's cannabis was compared with self-reported level of intoxication, subjective estimate of cannabis potency and price per gram of cannabis. FINDINGS: Objective estimates of doses per joint (0.07-0.88 g/joint) and cannabis potency (1.1-24.7%) varied widely. Self-reported measures of dose were imprecise, but at group level, average dose per joint was estimated accurately with the number of joints made from 1 g [limit of agreement (LOA) = -0.02 g, 95% confidence interval (CI) = -0.29; 0.26], whereas the prompt card resulted in serious underestimation (LOA = 0.14 g, 95% CI = -0.10; 0.37). THC concentration in cannabis was associated with subjective potency ['average' 3.77% (P = 0.002) and '(very) strong' 5.13% more THC (P < 0.001) than '(very) mild' cannabis] and with cannabis price (about 1% increase in THC concentration per euro spent on 1 g of cannabis, P < 0.001), but not with level of intoxication. CONCLUSIONS: Self-report measures relating to cannabis use appear at best to be associated weakly with objective measures. Of the self-report measures, number of joints per gram, cannabis price and subjective potency have at least some validity. PMID- 23627817 TI - Is urine the next source of stem cells? PMID- 23627818 TI - Treating muscular dystrophy by stimulating intrinsic repair. PMID- 23627821 TI - Bidirectional and mutually beneficial interactions between human mesenchymal stem cells and osteoarthritic chondrocytes in micromass co-cultures. AB - AIM: Mesenchymal stem cell (MSC)-based therapy presents a promising approach for treating osteoarthritis (OA). However, the molecular interactions between MSCs and OA chondrocytes (OACs) are not known. This study aims to investigate the bidirectional interactions between human MSCs (hMSCs) and human OACs (hOACs) in a 3D co-culture system. MATERIALS & METHODS: hMSC-collagen microspheres were cultured in hOAC-conditioned medium or co-cultured with hOAC-collagen microspheres. Growth characteristics, glycosaminoglycan (GAG) production, gene expression of major OA-associated chondrogenic markers, including SOX9, COL2A1, ACAN and MMP13, were investigated in both cell types. RESULTS: Both the conditioned medium and the co-culture induced MSC chondrogenesis with enhanced GAG production, SOX9 gene and protein expression, and gene expression of ACAN and COL2A1. Meanwhile, the co-culture also induced hOACs to partially resume the lost chondrogenic phenotype as shown by reduced proliferation, enhanced GAG production when hMSCs were chondrogenically predifferentiated, and reduced MMP13 gene expression. CONCLUSION: This work suggests that 3D co-culture of hMSCs and hOACs is mutually beneficial to each other, suggesting the potential therapeutic effect of delivering hMSC in scaffolds directly to OA defects. PMID- 23627822 TI - Human umbilical cord blood stem cells for spinal cord injury: early transplantation results in better local angiogenesis. AB - AIM: We aim to explore the repair mechanism after the transplantation of CD34(+) human umbilical cord blood cells (HUCBCs) in traumatic spinal cord injury (SCI) in rats. MATERIALS & METHODS: Wistar rats with SCI were randomly divided into three groups: DMEM injection (group A); CD34(+) HUCBC transplantation on the first day after injury (group B); and CD34(+) HUCBC transplantation on the sixth day after injury (group C). The Basso, Beattie and Bresnahan scores were used to evaluate motor behavior. At the injured site, the infarct size, blood vessel density, and survival and neural differentiation of transplanted cells were analyzed. RESULTS: It was found that the Basso, Beattie and Bresnahan score in group B was significantly higher than other groups (p < 0.05), and the infarct size and blood vessel density at the injured site were significantly different (p < 0.01). However, the transplanted cells survived at least 3 weeks at the injured site, but did not differentiate into neural cells. CONCLUSION: These results suggested transplantation of CD34(+) HUCBCs during the acute phase could promote the functional recovery better than during the subacute phase after SCI by raising blood vessel density, suggesting the possible clinical application for the treatment of spinal injury. PMID- 23627823 TI - Potentiated therapeutic angiogenesis by primed human mesenchymal stem cells in a mouse model of hindlimb ischemia. AB - BACKGROUND: Human bone marrow-derived mesenchymal stem cells (hMSCs) are advantageous for cell-based therapy to treat ischemic diseases owing to their capacity to secrete various paracrine factors with potent angiogenic activity. MATERIALS & METHODS: In this study, we describe a method to increase secreted levels of VEGF and HGF from hMSCs without genetic modification. RESULTS: We demonstrated that transplantation of primed hMSCs into ischemic limbs led to significantly greater improvements in tissue perfusion and limb salvage by increasing capillary formation compared with nonprimed hMSCs. The primed hMSCs also exhibited greater survival in vivo and secreted human VEGF and HGF in the ischemic tissue, supporting enhanced angiogenesis and cell survival. CONCLUSION: These findings indicate that priming hMSCs via methods described in this study enhances secretion of critical proangiogenic factors resulting in an enhanced therapeutic effect of cells for the treatment of ischemic diseases. PMID- 23627824 TI - Transient overexpression of Ppargamma2 and C/ebpalpha in mesenchymal stem cells induces brown adipose tissue formation. AB - BACKGROUND: Brown adipose tissue plays a pivotal role in mammal metabolism and thermogenesis. It has a great therapeutic potential in several metabolic disorders such as obesity and diabetes. Mesenchymal stem cells (MSCs) are suitable candidates for brown adipose tissue formation de novo. Ppargamma2 and C/ebpalpha are nucleic receptors known to mediate adipogenic differentiation. We hypothesized that overexpression of the Ppargamma2 and C/ebpalpha genes in MSCs would lead to the formation of adipose tissue. MATERIALS & METHODS: MSCs bearing the Luc reporter gene were transfected to overexpress Ppargamma2 and C/ebpalpha. Differentiation of nucleofected cells was evaluated in vitro and in vivo following ectopic implantation of the cells in C3H/HeN mice. RESULTS: After implantation, the engineered cells survived for 5 weeks and brown adipose-like tissue was observed in histological samples. Immunostaining and bioluminescent imaging showed new adipocytes expressing Luc and the brown adipose tissue marker, UCP1, in vitro and in vivo. CONCLUSION: We show that gene delivery of transcription factors into MSCs generates brown adipose tissue in vitro and in vivo. PMID- 23627826 TI - Limbal side population cells: a future treatment for limbal stem cell deficiency. AB - Corneal blindness carries a morbidity that affects quality of life and is often associated with an increased economic burden. In this review, we focus on the severe and painful condition of limbal stem cell deficiency, an important cause of corneal blindness. Conventional corneal transplantation usually results in graft failure and is contraindicated in this condition. Ex vivo-expanded limbal epithelial transplantation has been used as a cellular-based therapy to regenerate and reconstruct the ocular surface as a mode of treatment. Enrichment methods for stem cells are a strategy to improve the outcome of limbal stem cell transplantation. Here we discuss the side population assay as a functional assay to enrich for stem cells as an important source of limbal stem cells. The challenges in ex vivo-expanded limbal stem cell transplantation are wide and varied and will be addressed in this review with regard to improving the clinical outcomes of cultivated limbal stem cell transplantation. PMID- 23627825 TI - The potential of stem cells for the restoration of auditory function in humans. AB - Hearing loss is one of the most common disabilities, affecting approximately 10% of the population. Hair cells and spiral ganglion neurons are usually damaged in most cases of hearing loss. Currently, there is virtually no biological approach to replace damaged hearing cells. Recent developments in stem cell technology provide new opportunities for the treatment of deafness. Two major strategies have been investigated: differentiation of endogenous stem cells into new hair cells; and introduction of exogenous cells into the inner ear to substitute injured hearing neurons. Although there is still a learning curve in stem cell based replacement, the probability exists to utilize personalized stem cells to eventually provide a novel intervention for patients with deafness in future clinical research trials. PMID- 23627827 TI - Bioengineering of articular cartilage: past, present and future. AB - The treatment of cartilage defects poses a clinical challenge owing to the lack of intrinsic regenerative capacity of cartilage. The use of tissue engineering techniques to bioengineer articular cartilage is promising and may hold the key to the successful regeneration of cartilage tissue. Natural and synthetic biomaterials have been used to recreate the microarchitecture of articular cartilage through multilayered biomimetic scaffolds. Acellular scaffolds preserve the microarchitecture of articular cartilage through a process of decellularization of biological tissue. Although promising, this technique often results in poor biomechanical strength of the graft. However, biomechanical strength could be improved if biomaterials could be incorporated back into the decellularized tissue to overcome this limitation. PMID- 23627828 TI - Regenerative medicine techniques in cardiovascular disease: where is the horizon? AB - Regenerative medicine techniques to restore cardiac and vascular function are being increasingly investigated as management options for cardiovascular disease. The authors set out to identify emerging regenerative techniques in cardiovascular disease and investigate their stage of development. The relevant networks in the field in the UK were contacted and online sources for cell therapy, tissue engineering, and other regenerative techniques and products were searched for online. A total of 49 Phase II, II/III and III trials of regenerative products or techniques were identified: 13 Phase III, eight Phase II/III and 28 Phase II trials. Twelve of the Phase III trials are for myocardial ischemia and involve an intracoronary infusion or intramyocardial injection of autologous bone marrow-derived stem cells. Most of those in Phase III trials are, however, associated either with an unproven delivery technique or cellular approach. The authors conclude that translation into clinical practice and diffusion into health systems is some way off. PMID- 23627829 TI - Reassessing direct-to-consumer portrayals of unproven stem cell therapies: is it getting better? AB - AIM: To determine whether increased scrutiny of 'stem cell tourism' has resulted in changes to online claims by clinics that provide putative unproven stem cell treatments. MATERIALS & METHODS: We analyzed historical and current versions of clinics' websites. The study sample consisted of 18 websites included in a 2008 peer-reviewed study and an additional 12 clinics identified through the GoogleTM search engine. RESULTS: Our analysis revealed similarities between historical and current stem cell treatment offerings, claims, representations of risk, benefit and efficacy and attention to social, ethical and regulatory concerns. Claims and representations remain overly optimistic. Current websites provide more detailed descriptions of treatment procedures and outcomes and are more aesthetically appealing. Noteworthy trends in the movements and locations of clinics was observed. CONCLUSION: Increased scrutiny of stem cell tourism has not had much impact on the online claims of clinics that provide putative unproven stem cell treatments. PMID- 23627830 TI - Vascularization in 3D tissue using cell sheet technology. AB - Tissue engineering is a field of study unto itself, but in reality, it is a fusion of medicine, pharmacology, chemistry, cell biology, molecular biology and engineering. The field has been developing at an ever-increasing pace and already provides benefits to regenerative medicine in areas such as the skin and cornea. However, the problem facing all of these technologies is the diffusion limitation, which has impeded the fabrication of thicker 3D tissue. Overcoming this problem requires vascularization of 3D tissue, which is critical to any future advances. Here, we introduce our own cell sheet technology and compare it with other technologies for the fabrication of vascularized 3D tissue. PMID- 23627832 TI - Effects of ingestion of a commercially available thermogenic dietary supplement on resting energy expenditure, mood state and cardiovascular measures. AB - BACKGROUND: Increasing metabolism is a primary focus of many commercially available dietary supplements marketed to support weight management. Caffeine (e.g. anhydrous and herbal) and green tea are key ingredients in such products, augmenting resting energy expenditure (REE) and improving reported mood states (alertness, fatigue, focus, etc.). The purpose of this study was to evaluate the effects of a thermogenic dietary supplement (DBX) on REE, respiratory exchange ratio (RER), reported measures of alertness, focus, energy, concentration, fatigue, and hunger, as well as the general safety of the product based on electrocardiogram (ECG) and hemodynamic responses in habitual caffeine consumers. METHODS: Six male and six female subjects (mean +/- SD; 22.50 +/- 3.22 years; 76.94 +/- 14.78 kg; 22.7 +/- 9.5% body fat), physically active (>=12 months), and moderate habitual caffeine consumers (<200 mg/day) received either two capsules of DBX containing 340 mg of total caffeine plus green tea extract, yerba mate extract, carnitine tartrate and other active ingredients or a placebo (PLC) in a double-blinded, crossover design. Heart rate (HR), blood pressure (BP), REE, RER and perceived mood states were measured at baseline and then hourly for four hours after ingesting either treatment. RESULTS: Resting energy expenditure was significantly increased at all four time points and significant increases were determined for perceived alertness (p = 0.026) and focus (p = 0.05) at hour 1 and for energy at 1 and 2 hours after treatment for the DBX group (p = 0.008 and p = 0.017, respectively). Additionally, perceived fatigue was decreased at the hour 1 assessment (p = 0.010). No significant differences were seen between DBX and placebo for hunger, anxiety, HR, BP, ECG patterns or RER. CONCLUSIONS: The results of this investigation support that the proprietary blend of this thermogenic aid is capable of increasing REE for four hours post-ingestion while supporting increased focus, alertness, and energy as well as decreasing fatigue without promoting anxiety or causing significant changes in HR, BP, or ECG measurements in habitual caffeine consumers. PMID- 23627833 TI - Descriptive analysis of flavor characteristics for black walnut cultivars. AB - Seven black walnut cultivars, Brown Nugget, Davidson, Emma K, Football, Sparks 127, Sparrow, and Tomboy, were evaluated by descriptive sensory analysis. Seven trained panelists developed a lexicon for the black walnuts and scored the intensities of the samples for 22 flavor attributes. Results showed that the 7 samples differed significantly (P <= 0.05) on 13 of the attributes. For the majority of the attributes, only Emma K differed from the rest of the cultivars by being characterized with lower scores for black walnut ID, overall nutty, nutty-grain-like, nutty-buttery, floral/fruity, oily, and overall sweet. That sample also was higher in acrid, burnt, fruity-dark, musty/earthy, rancid, and bitter attributes. The remaining 6 cultivars showed few differences in individual attribute ratings, but did show some differences when mapped using multivariate techniques. Future studies should include descriptive analysis of other black walnut varieties, both wild and commercial, that could be grown and harvested for production. PMID- 23627834 TI - Dual stimuli-responsive poly(N-isopropylacrylamide)-b-poly(L-histidine) chimeric materials for the controlled delivery of doxorubicin into liver carcinoma. AB - A series of dual stimuli responsive synthetic polymer bioconjugate chimeric materials, poly(N-isopropylacrylamide)55-block-poly(L-histidine)n [p(NIPAM)55-b p(His)n] (n=50, 75, 100, 125), have been synthesized by employing reversible addition-fragmentation chain transfer polymerization of NIPAM, followed by ring opening polymerization of alpha-amino acid N-carboxyanhydrides. The dual stimuli responsive properties of the resulting biocompatiable and membrenolytic p(NIPAM)55-b-p(His)n polymers are investigated for their use as a stimuli responsive drug carrier for tumor targeting. Highly uniform self-assembled micelles (~55 nm) fabricated by p(NIPAM)55-b-p(His)n polymers display sharp thermal and pH responses in aqueous media. An anticancer drug, doxorubicin (Dox), is effectively encapsulated in the micelles and the controlled Dox release is investigated in different temperature and pH conditions. Antitumor effect of the released Dox is also assessed using the HepG2 human hepatocellular carcinoma cell lines. Dox molecules released from the [p(NIPAM)55-b-p(His)n] micelles remain biologically active and have stimuli responsive capability to kill cancer cells. The self-assembling ability of these hybrid materials into uniform micelles and their efficiency to encapsulate Dox makes them a promising drug carrier to cancer cells. The new chimeric materials thus display tunable properties that can make them useful for a molecular switching device and controlled drug delivery applications needing responses to temperature and pH for the improvement of cancer chemotherapy. PMID- 23627835 TI - Stress management can facilitate weight loss in Greek overweight and obese women: a pilot study. AB - BACKGROUND: Stress and negative emotions have been shown to be critical factors in inducing overeating as a form of maladaptive coping in obese people. METHODS: The present study aimed to evaluate the efficacy of an 8-week stress management programme that includes progressive muscle relaxation (PMR) and diaphragmatic breathing on weight loss and eating behaviour in a sample of overweight and obese women who started a weight-loss programme. A total of 34 women with a mean (SD) body mass index of 38.17 (7.19) kg m(-) 2 and mean (SD) age 47.35 (11.64) years were recruited from the outpatients Obesity Clinic of a public hospital in Athens. Participants were randomly assigned into a Stress Management (SM) and a control group. Anthropometric measurements were taken before and after the intervention, and the participants completed the following questionnaires: Dutch Eating Behaviour Questionnaire (DEBQ), Eating Attitudes Test (Eat-26), Health Locus of Control (HLC) and Perceived Stress Scale (PSS) before and after the intervention. RESULTS: The findings indicated a significant improvement in weight loss in the SM group [4.44 (0.83) kg] after intervention compared to the control group [1.38 (0.78) kg] (P < 0.05). A higher restrained eating behaviour was observed in the SM group after intervention compared to the control group, although there was no significant difference in perceived stress levels. CONCLUSIONS: The intervention group showed greater weight reduction, possibly because of the stress management programme, and a greater dietary restraint was demonstrated by them compared to the control group. It is likely that stress management could facilitate weight loss in obese women; however, more studies are needed to confirm this hypothesis. PMID- 23627836 TI - Emotional bias in change deafness in multisource auditory environments. AB - Theories of auditory attention suggest that humans decompose complex auditory input into individual auditory objects, which then compete for attention to dominate auditory perception. Since emotional significance of external stimuli has been argued to provide cues for sensory prioritization and allocation of attention, emotionally salient auditory objects can receive attention to dominate auditory perception. On the basis of the function of audition as an alarm system that informs the organism about its immediate surroundings, and on empirical evidence that emotion can modulate auditory perception, we argue that auditory stimuli with greater emotional saliency would dominate perception in multisource environments. To test our hypothesis, we employed a change detection task in which participants were asked to indicate whether multisource auditory scenes were identical or different. Participants were better at detecting changes at the presence of an emotionally negative environment compared to neutral environment. Further, we found that participants were better at detecting changes of emotionally negative targets compared to neutral targets. Our results demonstrate that detecting changes in auditory scenes is influenced by emotion. The findings are discussed in the light of the theories of auditory attention, emotional modulation of attention, and the adaptive function of emotion for perception. PMID- 23627837 TI - The evolution of nutrition research. AB - "The doctor of the future will no longer treat the human frame with drugs, but will rather cure and prevent disease with nutrition". Thomas Edison's contemplation may come to fruition if the nutritional revolution continues in its current course. Two realizations have propelled the world into a new age of personalized nutrition: (i) food can provide benefits beyond its intrinsic nutrient content, and (ii) we are not all created equal in our ability to realize to these benefits. Nutrigenomics is concerned with delineating genomic propensities to respond to various nutritional stimuli and the resulting impact on individual health. This review will examine the current technologies utilized by nutrigeneticists, the available literature regarding nutrient-gene interactions, and the translation of this new awareness into public health. PMID- 23627838 TI - Involvement of mixed lineage kinase 3 in cancer. AB - Mitogen-activated protein kinase (MAPK) signaling pathways are composed of a phosphorelay signaling module where an activated MAP kinase kinase kinase (MAP3K) phosphorylates and activates a MAPK kinase (MAP2K) that in turn phosphorylates and activates a MAPK. The biological outcome of MAPK signaling is the regulation of cellular responses such as proliferation, differentiation, migration, and apoptosis. The MAP3K mixed lineage kinase 3 (MLK3) phosphorylates MAP2Ks to activate multiple MAPK signaling pathways, and MLK3 also has functions in cell signaling that are independent of its kinase activity. The recent elucidation of essential functions for MLK3 in tumour cell proliferation, migration, and invasion has drawn attention to the MLKs as potential therapeutic targets for cancer treatments. The mounting evidence that suggests a role for MLK3 in tumourigenesis and establishment of the malignant phenotype is the focus of this review. PMID- 23627839 TI - Inflammatory cytokine TNF-alpha inhibits Na(+)-glutamine cotransport in intestinal epithelial cells. AB - Glutamine (Gln), a preferred fuel source for enterocytes, is critical for intestinal epithelial cell integrity and barrier function. Chronic enteritis inhibits apical Na(+)-Gln cotransport. It is not known whether inflammatory cytokines that are secreted during inflammation inhibit Na(+)-Gln cotransport. Thus, this study aimed to examine whether TNF-alpha would affect apical Na(+)-Gln cotransport in intestinal epithelial cells. In this study, the presence of Na(+) Gln cotransport was established by measuring Gln uptake in 10 days postconfluent IEC-6 cells grown on transwell plates. Cation, amino acid specificity, and siRNA transfection studies established that Na(+)-Gln cotransport is mediated via B(0)AT1. Immunoblotting and immunofluorescence studies established the apical membrane localization of B(0)AT1 in IEC-6 cells. Tumour necrosis factor alpha (TNF-alpha) inhibited Na(+)-Gln cotransport in a concentration- and time dependent manner with an inhibitory concentration of 1.53 nmol.L(-1). Quantitative real-time PCR and Western blot analyses indicated that TNF-alpha did not alter B(0)AT1-specific transcripts or protein expression level. Kinetic studies revealed that TNF-alpha inhibited Na(+)-Gln cotransport by reducing the affinity of the cotransporters for Gln, and this effect was antagonized by genistein. Thus, we conclude that the TNF-alpha inhibition of Na(+)-Gln cotransport occurs at the post-translational level, and that the IEC-6 cell line is an excellent system to study the role of cytokines in Na(+)-Gln cotransport. PMID- 23627840 TI - Mepivacaine-induced contraction involves phosphorylation of extracellular signal regulated kinase through activation of the lipoxygenase pathway in isolated rat aortic smooth muscle. AB - Mepivacaine is an aminoamide local anesthetic with an intermediate duration that intrinsically produces vasoconstriction both in vivo and in vitro. This study investigated the arachidonic acid metabolic pathways involved in mepivacaine induced contraction, and elucidated the associated cellular mechanism with a particular focus on extracellular signal-regulated kinase (ERK) in endothelium denuded rat aorta. Isolated rat thoracic aortic rings were suspended for isometric tension recording. Cumulative mepivacaine concentration-response curves were generated in the presence or absence of the following inhibitors: quinacrine dihydrochloride, nordihydroguaiaretic acid, phenidone, AA-861, indomethacin, NS 398, SC-560, fluconazole, PD 98059, and verapamil. Mepivacaine-induced ERK phosphorylation, 5-lipoxygenase (5-LOX) expression, and cyclooxygenase (COX)-2 expression in rat aortic smooth muscle cells were detected by Western blot analysis in the presence or absence of inhibitors. Mepivacaine produced tonic contraction in isolated endothelium-denuded rat aorta. Quinacrine dihydrochloride, nordihydroguaiaretic acid, phenidone, AA-861, NS-398, PD 98059, and verapamil attenuated mepivacaine-induced contraction in a concentration dependent manner. However, fluconazole had no effect on mepivacaine-induced contraction. PD 98059, quinacrine dihydrochloride, nordihydroguaiaretic acid, AA 861, phenidone, and indomethacin attenuated mepivacaine-induced ERK phosphorylation. Mepivacaine upregulated 5-LOX and COX-2 expression. These results suggest that mepivacaine-induced contraction involves ERK activation, which is primarily mediated by the 5-LOX pathway and in part by the COX-2 pathway. PMID- 23627841 TI - Effects of chronic in-vivo treatments with protease-activated receptor 2 agonist on endothelium function and blood pressures in mice. AB - Short-term treatments with protease-activated receptor 2-activating peptides (PAR2-AP) induce endothelium-dependent vasodilation and decrease blood pressure. In this study, we tested the effect of chronic in-vivo treatment with PAR2-AP on the blood pressure and endothelium function of mice. Male PAR2 wild-type (WT) and par2-deficient (KO) mice received subcutaneous infusions of either saline, low (PAR2-LD), or high (PAR2-HD) doses of 2-furoyl-LIGRLO-amide for 1 or 2 weeks. In each treatment group, endothelium function was assessed in isolated arteries. Blood pressure, heart rate, and locomotor activity were recorded by radiotelemetry, and levels of tumour nercrosis factor alpha (TNF-alpha) and interkeukin 1beta (IL-1beta) were measured in plasma samples by ELISA. The relaxation of WT aortas and mesenteric arteries induced by PAR2-AP was decreased by PAR2-LD and PAR2-HD. In mesenteric arteries, PAR2-LD and PAR2-HD decreased the relaxation induced by acetylcholine, but not by nitroprusside; in aortas, PAR2-LD and PAR2-HD caused differential decreases in the relaxations induced by acetylcholine and nitroprusside. Only PAR2-HD lowered systolic arterial pressures in WT, when compared with all of the other groups. TNF-alpha and IL-1beta plasma concentrations were not different among the groups. We conclude that the systolic blood pressure of unrestrained mice can be lowered by chronic in-vivo activation of PAR2; however, this effect is countered by receptor desensitization and the concomitant development of endothelium and vascular dysfunction. PMID- 23627842 TI - Quinidine elicits proarrhythmic changes in ventricular repolarization and refractoriness in guinea-pig. AB - Quinidine is a class Ia Na(+) channel blocker that prolongs cardiac repolarization owing to the inhibition of I(Kr), the rapid component of the delayed rectifier current. Although quinidine may induce proarrhythmia, the contributing mechanisms remain incompletely understood. This study examined whether quinidine may set proarrhythmic substrate by inducing spatiotemporal abnormalities in repolarization and refractoriness. The monophasic action potential duration (APD), effective refractory periods (ERPs), and volume conducted electrocardiograms (ECGs) were assessed in perfused guinea-pig hearts. Quinidine was found to produce the reverse rate-dependent prolongation of ventricular repolarization, which contributed to increased steepness of APD restitution. Throughout the epicardium, quinidine elicited a greater APD increase in the left ventricular chamber compared with the right ventricle, thereby enhancing spatial repolarization heterogeneities. Quinidine prolonged APD to a greater extent than ERP, thus extending the vulnerable window for ventricular re excitation. This change was attributed to increased triangulation of epicardial action potential because of greater APD lengthening at 90% repolarization than at 30% repolarization. Over the transmural plane, quinidine evoked a greater ERP prolongation at endocardium than epicardium and increased dispersion of refractoriness. Premature ectopic beats and monomorphic ventricular tachycardia were observed in 50% of quinidine-treated heart preparations. In summary, abnormal changes in repolarization and refractoriness contribute greatly to proarrhythmic substrate upon quinidine infusion. PMID- 23627843 TI - Triton X-100 inhibits L-type voltage-operated calcium channels. AB - Triton X-100 (TX-100) is a nonionic detergent frequently used at millimolar concentrations to disrupt cell membranes and solubilize proteins. At low micromolar concentrations, TX-100 has been reported to inhibit the function of potassium channels. Here, we have used electrophysiological and functional techniques to examine the effects of TX-100 on another class of ion channels, L type voltage-operated calcium channels (VOCCs). TX-100 (30 nmol.L(-1) to 3 MUmol.L(-1)) caused reversible concentration-dependent inhibition of recombinant L-type VOCC (CaV 1.2) currents and of native L-type VOCC currents recorded from rat vascular smooth muscle cells and cardiac myocytes, and murine and human pancreatic beta-cells. In functional studies, TX-100 (165 nmol.L(-1) to 3.4 MUmol.L(-1)) caused concentration-dependent relaxation of rat isolated mesenteric resistance arteries prestimulated with phenylephrine or KCl. This effect was independent of the endothelium. TX-100 (1.6 MUmol.L(-1)) inhibited depolarization induced exocytosis in both murine and human isolated pancreatic beta-cells. These data indicate that at concentrations within the nanomolar to low micromolar range, TX-100 significantly inhibits L-type VOCC activity in a number of cell types, an effect paralleled by inhibition of cell functions dependent upon activation of these channels. This inhibition occurs at concentrations below those used to solubilize proteins and may compromise the use of solutions containing TX-100 in bioassays. PMID- 23627844 TI - Patient safety in dental care: A challenging quality issue? An exploratory cohort study. AB - OBJECTIVE: Little is known about patient safety in primary oral healthcare. The aim of this study was to describe and analyze patient safety incidents in primary oral health care. MATERIALS AND METHODS: A random sample of 1000 patient records from 20 dental practices was reviewed retrospectively over 60 months. All adverse events (AEs) were noted: unintended events happening during treatment that resulted or could have resulted in harm to the patient. RESULTS: A total of 46 (95% CI = 33-59) AEs was identified, of which 18 (95% CI = 10-26) were considered preventable. From these, 15 related to treatment, 10 to diagnostics and one to communication. CONCLUSIONS: The low incidence of AEs and absence of major harm to patients suggests that primary oral care is safe for patients. However, the low quality of record keeping may imply underestimation. PMID- 23627845 TI - Early root surface colonization by human periodontal ligament fibroblasts following treatment with different biomaterials. AB - OBJECTIVES: The present in-vitro study examined the effects of different biomaterials on early root surface colonization by human periodontal ligament (PDL) fibroblasts using confocal-laser-scanning-microscopy (CLSM). MATERIALS AND METHODS: Fifteen periodontally-diseased teeth were extracted, treated with scaling/root planing and longitudinally cut to obtain 30 root fragments. Fragments were treated either with 24% EDTA following application of enamel matrix derivative (EMD), 24% EDTA or EMD only, nanocrystalline hydroxyapatite (NHA) paste or oily calcium hydroxide suspension (OCHS) for 1 h each. The analogue untreated root specimens served as controls. Root fragments were incubated with human PDL fibroblasts and cellular proliferation and morphology were evaluated after 1, 3, 5 and 8 days using CLSM-visualization and image recognition software. RESULTS: The rate of cellular proliferation was different among treatment modalities examined (p = 0.019). Except treatment with NHA paste all treatment modalities improved cellular proliferation on root surfaces at all different points of time compared with the control specimens. A significant difference between treatment modalities was observed between EMD and NHA paste (p = 0.008). No synergistic effect could be demonstrated comparing root surface conditioning with 24% EDTA and EMD application compared to 24% EDTA or EMD application only. CONCLUSION: The present results suggest that initial root surface colonization by PDL fibroblasts may be enhanced by root surface conditioning with 24% EDTA and application of EMD, application of 24% EDTA or EMD alone and OCHS. The addition of 24% EDTA for root surface conditioning prior to EMD application provided no synergistic effects in terms of early root surface colonization by PDL fibroblasts. PMID- 23627846 TI - Influence of abutment material and luting cements color on the final color of all ceramics. AB - PURPOSE: The purpose of this study is to evaluate the effects of different abutment materials and luting cements color on the final color of implant supported all-ceramic restorations. MATERIALS AND METHODS: Ten A2 shade IPS e.max Press disc shape all-ceramic specimens were prepared (11 * 1.5 mm). Three different shades (translucent, universal and white opaque) of disc shape luting cement specimens were prepared (11 * 0.2 mm). Three different (zirconium, gold palladium and titanium) implant abutments and one composite resin disc shape background specimen were prepared at 11 mm diameter and appropriate thicknesses. All ceramic specimens colors were measured with each background and luting cement samples on a teflon mold. A digital spectrophotometer used for measurements and data recorded as CIE L*a*b* color co-ordinates. An optical fluid applied on to the samples to provide a good optical connection and measurements on the composite resin background was saved as the control group. DeltaE values were calculated from the DeltaL, Deltaa and Deltab values between control and test groups and data were analyzed with one-way variance analysis (ANOVA) and mean values were compared by the Tukey HSD test (alpha = 0.05). RESULTS: One-way ANOVA of DeltaL, Deltaa, Deltab and DeltaE values of control and test groups revealed significant differences for backgrounds and seldom for cement color groups (p the 0.05). Only zirconium implant abutment groups and gold palladium abutment with universal shade cement group were found to be clinically acceptable (DeltaE <= 3.0). CONCLUSION: Using titanium or gold-palladium abutments for implant supported all ceramics will be esthetically questionable and white opaque cement will be helpful to mask the dark color of titanium abutment. PMID- 23627847 TI - Fast-tracking development of homozygous transgenic cereal lines using a simple and highly flexible real-time PCR assay. AB - BACKGROUND: A crucial step in the evaluation of newly produced transgenic plants is the selection of homozygous plants. Here we describe an efficient and highly flexible real-time PCR-based method for the development of homozygous lines in plant models with complex (multiple) genomes and/or relatively long generation times (>3 months) using direct copy number determinations. RESULTS: An existing DNA extraction method was converted into a high-throughput plant leaf DNA extraction procedure yielding DNA suitable for real-time PCR analyses. Highly specific and efficient primer pairs were developed for a bread wheat reference gene (Epsilon Cyclase) and for standard sequence elements in the gene cassette routinely used for cereal transformations (an intron bridge and the Nopaline Synthase terminator). The real-time PCR assay reliably distinguished wheat plants with a single copy of the transgene from individuals with multiple copies or those lacking the transgene. To obtain homozygous lines carrying a unique insertion event as efficiently as possible, T0 plants (plants raised from transformed callus) with a single copy of the transgene were selected and their progeny screened for homozygous plants. Finally, the assay was adapted to work on rice. CONCLUSIONS: The ability to quickly, easily and accurately quantify the construct copy numbers, as provided by the real-time PCR assay, greatly improved the efficiency and reliability of the selection of homozygous transgenic plants in our case study. We were able to select homozygous plants in early generations, avoiding time-consuming methods such as large scale analysis of segregation patterns of descendants and/or Southern blotting. Additionally, the ability to specifically develop homozygous lines carrying a unique insertion event could be important in avoiding gene silencing due to co-suppression, and if needed assist in the selection of lines suitable for future deregulation. The same primer pairs can be used to quantify many different wheat transgenic events because the construct-specific primer pairs are targeted to standard sequence elements of the cereal gene cassettes, making the method widely applicable in wheat GM research. Moreover, because all procedures described here are standardized, the method may easily be adapted to vectors lacking the target regions used here and/or to other plant models. PMID- 23627848 TI - Invasive nontyphoidal Salmonella disease in Africa: current status. PMID- 23627849 TI - Fecal microbiota transplantation: a new standard treatment option for Clostridium difficile infection. PMID- 23627850 TI - Using geographical mapping of key vulnerable populations to control the spread of HIV epidemics. PMID- 23627853 TI - A novel mechanism of immune evasion mediated by Ebola virus soluble glycoprotein. AB - Ebola viruses encode two glycoproteins (GPs): a membrane-associated GP that is present in the viral membrane and mediates viral attachment and entry into host cells; and a secreted, nonstructural glycoprotein (sGP) that is identical to GP over approximately 90% of its length. A recent study by Mohan and colleagues attributes a novel immune evasion mechanism dubbed 'antigenic subversion' to sGP. Using DNA immunization in mice, the authors demonstrate that sGP elicits antibodies that crossreact with GP, but these antibodies are non-neutralizing. Coimmunization with sGP plus GP or sequential immunizations with GP and sGP direct the host antibody response toward non-neutralizing epitopes. Therefore, the production of sGP may prevent effective neutralization of the virus during Ebola virus infection, and may reduce the effectiveness of vaccines that rely upon neutralizing antibody responses. PMID- 23627852 TI - PegIFN-alpha2a for the treatment of chronic hepatitis B and C: a 10-year history. AB - Chronic HBV and HCV are progressive diseases leading to cirrhosis and liver transplantation. Persistent viral eradication or suppression can positively affect the natural course of the infection, by preventing disease progression. Since its introduction more than 30 years ago, IFN-alpha has represented the foundation of HBV and, lately, anti-HCV treatment. Pegylation of the IFN-alpha molecule (PegIFN-alpha2a) has provided improvements in both efficacy and administration schedule, thus becoming part of the standard-of-care regimen for HCV and HBV therapy in the last 10 years. Currently, treatment of finite duration with PegIFN-alpha2a may achieve a sustained virological response off-treatment and HBsAg seroconversion. PegIFN-alpha2a will most likely remain the backbone of HCV treatment for the next few years, despite the availability of direct-acting antivirals that are expected to improve cure rates. However, many efforts are concentrated on developing new compounds, with the goal of administrating all oral regimens and eliminating PegIFN from anti-HCV treatment. PMID- 23627854 TI - West Nile virus and kidney disease. AB - West Nile virus (WNV), the causative agent of West Nile fever and West Nile neuroinvasive disease in humans, has become endemic in many countries in all continents. Concerns on long-term mobility from WNV have arisen from recent studies that reported chronic kidney disease in patients who recovered from WNV infection, supported by data from animal models that showed prolonged excretion of the virus with urine. The purpose of this review is to summarize and discuss the results of studies in the literature that investigated WNV infection of the kidney in humans and in animal models and WNV excretion with urine, the potential damage to the kidney caused by WNV infection, the risk of WNV disease in kidney transplant recipients, the significance of detecting WNV in urine and its use in the diagnosis of WNV infection, and kidney involvement by other mosquito-borne flaviviruses. PMID- 23627855 TI - Treatment of delta hepatitis. AB - Hepatitis delta virus (HDV) is a defective RNA virus that depends on hepatitis B virus (HBV) for its lifecycle. Treatment of chronic HDV infection is difficult as it does not have an enzymatic function as a target, such as polymerases and proteases of HBV and hepatitis C virus. Recently, it has been suggested that farnesyl transferase could be an enzymatic target. Currently, interferon is the only agent against HDV infection. Virological response has risen to 20-47% with pegylated interferon. Monotherapy of nucleos(t)ide analogs are ineffective against the HDV infection, but adefovir and pegylated interferon combination therapy have had some advantages for reduction of HBV surface antigen (HBsAg) levels. Recent studies suggest that measuring HBsAg levels during treatment could be more meaningful than HDV RNA negativity to predict virological response. Prenylation inhibitors that can affect the interactions between the large HDV antigen and HBsAg in the HDV virion are expected treatments for HDV infection. More studies are needed to understand the molecular mechanisms of HDV to manage the disease. PMID- 23627856 TI - MRSA infection in the neonatal intensive care unit. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is well known as one of the most frequent etiological agents of healthcare-associated infections. The epidemiology of MRSA is evolving with emergence of community-associated MRSA, the clonal spread of some successful clones, their spillover into healthcare settings and acquisition of antibacterial drug resistances. Neonatal intensive care unit (NICU) patients are at an especially high risk of acquiring colonization and infection by MRSA. Epidemiology of MRSA in NICU can be very complex because outbreaks can overlap endemic circulation and make it difficult to trace transmission routes. Moreover, increasing prevalence of community-associated MRSA can jeopardize epidemiological investigation, screening and effectiveness of control policies. Surveillance, prevention and control strategies and clinical management have been widely studied and are still the subject of scientific debate. More data are needed to determine the most cost-effective approach to MRSA control in NICU in light of the local epidemiology. PMID- 23627857 TI - Delivering antibiotics to the lungs of patients with ventilator-associated pneumonia: an update. AB - Ventilator-associated pneumonia is a serious hospital-acquired infection, with 20 70% crude mortality and 10-40% estimated attributable mortality. Insufficient antibiotic concentrations at the infection site when these drugs are given intravenously may lead to poor outcomes, particularly when difficult-to-treat pathogens are responsible; for example, Pseudomonas aeruginosa, extended spectrum beta lactamase-producing Gram-negative bacilli, Acinetobacter spp. and/or methicillin-resistant Staphylococcus aureus. Direct drug delivery to the infection site via aerosolization combined with intravenous administration achieves concentrations exceeding MICs of the pathogens, even those with impaired susceptibility. Experimental and recent clinical results demonstrated our markedly improved ability to deliver aerosolized antibiotics to the lung with new generation devices, for example, vibrating-mesh nebulizers. Convincing clinical data from a large randomized trial are still lacking to support the routine administration of aerosolized antibiotics to treat ventilator-associated pneumonia, even though some small-randomized trials' observations are encouraging. PMID- 23627858 TI - Combination antifungal therapy for invasive fungal infections in children and adults. AB - Although therapeutic first-line approaches have been established in severely immunosuppressed patients with a high risk of invasive fungal infections, treatment modalities for cases with unsatisfactory outcome have not been well defined, especially for the pediatric age gap. Therapy with coadministration of two or three antifungals has been applied by clinicians in difficult-to-treat infections, which still have no support from randomized, controlled clinical trials. The most prevailing reason for a combination regimen is to broaden the antimycotic spectrum, which may even result in antagonistic interaction. The experience and recommendations of combinational antifungal therapy for cryptococcal infections, systemic candidiasis, invasive aspergillosis and other rare mold infections have been presented in this review, giving some information on mechanism of action and principles in combined use of mycotic anti-infectives. Most experience of combination therapy approaches are in adult patients; but in fact, there is no conclusive data documenting definite benefits of this approach, either in adults or children. PMID- 23627860 TI - Clinical application of regulatory T cells in type 1 diabetes. AB - Regulatory T cells (Tregs) are responsible for the maintenance of peripheral tolerance. Animal studies have shown that administration of Tregs can prevent type 1 diabetes (DM1). Several clinical trials attempted to induce Tregs with various agents, and thus provide long-term tolerance of beta cells in DM1. Nevertheless, most of these studies have focused on clinical parameters (e.g. C peptide) and not Treg numbers nor their function after treatment. Therefore, it is not possible to conclude if the majority of these therapies failed because the drugs did not induce Tregs, or if they failed despite Treg expansion. The current knowledge regarding Tregs, along with our experience in Treg therapy of patients with graft versus host disease, prompted us to use ex vivo expanded Tregs in 10 children with recent-onset DM1. No adverse effects in the treated individuals were observed. There was a significant increase in Treg number in peripheral blood immediately after the treatment administration, while the first clinical differences between treated and control patients were observed 4 months after Treg injection. Treated individuals had higher C-peptide levels and lower insulin requirements than non-treated children. Eleven months after diagnosis of DM1, there are still 2 individuals who are independent of exogenous insulin. These results indicate that autologous Tregs are a safe and well-tolerated therapy in children with DM1, which can inhibit or delay the destruction of pancreatic beta cells. Additionally, Tregs can be a useful tool for local protection of transplanted pancreatic islets. Isolation and expansion of antigen-specific Tregs is one of the directions for future studies on cellular therapy of DM1. PMID- 23627861 TI - Echocardiography-guided pacemaker programming can improve cardiac hemodynamics in patients undergoing transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) is an effective treatment option for patients with severe aortic stenosis who are at high surgical risk because of multiple comorbidities. Many of these patients have been treated with pacemakers for concomitant conduction disease. The combination of severe aortic stenosis, cardiomyopathy, and conduction abnormalities results in a state of low cardiac output. Here, we report 2 complex TAVR cases where Doppler echocardiography was used to guide adjustment of device settings, leading to improved cardiac hemodynamic profiles. PMID- 23627862 TI - Reductive dechlorination of TCE by chemical model systems in comparison to dehalogenating bacteria: insights from dual element isotope analysis (13C/12C, 37Cl/35Cl). AB - Chloroethenes like trichloroethene (TCE) are prevalent environmental contaminants, which may be degraded through reductive dechlorination. Chemical models such as cobalamine (vitamin B12) and its simplified analogue cobaloxime have served to mimic microbial reductive dechlorination. To test whether in vitro and in vivo mechanisms agree, we combined carbon and chlorine isotope measurements of TCE. Degradation-associated enrichment factors epsilon(carbon) and epsilon(chlorine) (i.e., molecular-average isotope effects) were -12.20/00 +/ 0.50/00 and -3.60/00 +/- 0.10/00 with Geobacter lovleyi strain SZ; -9.10/00 +/- 0.60/00 and -2.70/00 +/- 0.60/00 with Desulfitobacterium hafniense Y51; -16.10/00 +/- 0.90/00 and -4.00/00 +/- 0.20/00 with the enzymatic cofactor cobalamin; 21.30/00 +/- 0.50/00 and -3.50/00 +/- 0.10/00 with cobaloxime. Dual element isotope slopes m = Deltadelta(13)C/ Deltadelta(37)Cl ~ epsilon(carbon)/epsilon(chlorine) of TCE showed strong agreement between biotransformations (3.4 to 3.8) and cobalamin (3.9), but differed markedly for cobaloxime (6.1). These results (i) suggest a similar biodegradation mechanism despite different microbial strains, (ii) indicate that transformation with isolated cobalamin resembles in vivo transformation and (iii) suggest a different mechanism with cobaloxime. This model reactant should therefore be used with caution. Our results demonstrate the power of two-dimensional isotope analyses to characterize and distinguish between reaction mechanisms in whole cell experiments and in vitro model systems. PMID- 23627863 TI - Defects and domain boundaries in self-assembled terephthalic acid (TPA) monolayers on CVD-grown graphene on Pt(111). AB - Self-assembly of terephthalic acid (TPA), vacuum deposited on Pt(111) supported graphene, has been investigated by scanning tunneling microscopy (STM). TPA organizes in an ordered 3 * 4 superstructure with respect to the graphene lattice. This structure is a consequence of hydrogen-bonded TPA chains that arrange in a commensurate overlayer on graphene. Due to the polycrystalline nature of graphene on Pt(111), the TPA layer exhibits various grain boundaries and dislocations. Molecular resolved STM imaging has been used to characterize these defect structures in the TPA monolayer. PMID- 23627864 TI - Sultam synthesis via Cu-catalyzed intermolecular carboamination of alkenes with N fluorobenzenesulfonimide. AB - Cu-catalyzed intermolecular carboamination of alkenes is described. The reaction of terminal alkenes and an internal alkene with N-fluorobenzenesulfonimide was promoted by 2.5 mol % of a Cu(I)-salt at 60 degrees C, and six-membered ring sultams were obtained in 91-44% yields. PMID- 23627866 TI - Anti-TNF antibodies in inflammatory bowel disease: do we finally know how it works? AB - Tumor necrosis factor (TNF) is a central pro-inflammatory cytokine that regulates the expression of numerous signaling pathways implicated in the progression of the immunological reaction. Unraveling the importance of TNF on the pathogenesis of inflammatory bowel disease (IBD) promoted anti-TNF antibodies as novel therapeutic agents. Initially, the main hypothesis behind the clinical application of anti-TNF antagonists in the clinic was that they exert their effects solely through neutralization of TNF. Anti-TNF antibodies induce and maintain clinical remission in patients with minimal side-effects. However, the cellular and molecular mechanisms of actions of the anti-TNF antibodies remain unknown. Various mechanisms of action have been proposed such as activation of transmembrane TNF mediated reverse signaling, induction of apoptosis, pro inflammatory cytokine down-regulation, complement dependent cytotoxicity, antibodydependent cell-mediated cytotoxicity, and finally activation of regulatory immune cells via interactions with the Fc receptors. The observed discrepancies in the clinical efficacies as well as the differences in the structure of the various TNF antagonists nourish the investigation for additional modes of function. PMID- 23627867 TI - In vitro cholesterol-lowering properties of Lactobacillus plantarum AN6 isolated from aji-narezushi. AB - Aji-narezushi is a traditional lactic acid-fermented fish. In this study, we screened for lactose-utilizing, acidophilic, bile-resistant and cholesterol lowering lactic acid bacteria (LAB) from aji-narezushi for use as starter strains for fermented foods, as well as for use as probiotics. Of the 301 LAB isolates, 277 fermented lactose, and among these, 171 grew in de Man, Rogosa and Sharpe broth adjusted to pH 3.5. Thirty-four of the isolates were grown in a broth containing 3% (w/v) bile. All of the isolates were lactobacilli. Seven isolates that demonstrated cholesterol-lowering activity in ethanolic solution were selected. All of the isolates were identified as Lactobacillus plantarum. Lactobacillus plantarum AN6 showed the highest cholesterol-lowering activity. AN6 was more resistant to acid, salt and bile than the type strain NBRC15891(T). One half of the cholesterol-lowering effect remained after boiling AN6 for 10 min. The Fourier transform infrared (FT-IR) analysis indicated that the content of cell wall polysaccharides in AN6 is higher than ones in the type strain. These results indicate that Lact. plantarum AN6 can be used as a profitable starter organism and probiotic. PMID- 23627868 TI - Alcohol use disorders and mortality: a systematic review and meta-analysis. AB - AIMS: To conduct a systematic review and meta-analysis on all-cause mortality in people with alcohol use disorders. METHODS: Using the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines, studies were identified through MEDLINE, EMBASE, and Web of Science up to August, 2012. Prospective and historical cohort studies including a comparison of alcohol use disorder with a control group investigating all-cause mortality risk were included. RESULTS: This meta-analysis included 81 observational studies with 221 683 observed deaths among 853 722 people with alcohol use disorder. In men, the relative risk (RR) among clinical samples was 3.38 (95% confidence interval [CI]: 2.98-3.84); in women it was 4.57 (95% CI: 3.86-5.42). Alcohol use disorders identified in general population surveys showed a twofold higher risk compared with no alcohol use disorder in men; no data were available for women. RRs were markedly higher for those <=40 years old (ninefold in men, 13-fold in women) while still being at least twofold among those aged 60 years or older. CONCLUSIONS: Mortality in people with alcohol use disorders is markedly higher than thought previously. Women have generally higher mortality risks than men. Among all people with alcohol use disorders, people in younger age groups and people in treatment show substantially higher mortality risk than others in that group. PMID- 23627870 TI - Asymmetric dermal-subdermal suture in trichophytic closure for wide hair transplantation donor wound. PMID- 23627869 TI - Enhanced tissue production through redox control in stem cell-laden hydrogels. AB - Cellular bioenergetics and redox (reduction-oxidation) play an important role in cell proliferation and differentiation, key aspects of building new tissues. In the present study, we examined the metabolic characteristics of human adipose derived stem cells (hASCs) during proliferation and differentiation in both monolayer and three-dimensional biomaterial scaffolds. In monolayer, hASCs exhibited higher glycolysis and lower ox-phos as compared to both adipogenic and osteogenic differentiated cells, and hASCs demonstrated the Warburg effect (aerobic glycolysis). However, reactive oxygen species (ROS) levels increased during adipogenic differentiation, but decreased during osteogenic differentiation. Similarly, a decrease in ROS levels along with a higher mitochondrial membrane potential and viability was observed in hASCs encapsulated in poly(ethylene glycol) (PEG) hydrogels containing an adhesion peptide (RGD), compared to PEG hydrogels with a scrambled control peptide (GRD), demonstrating that adhesion-dependent signaling can also regulate ROS production and bioenergetics. As a result, we hypothesized that we could modulate osteogenesis in PEG hydrogels containing the adhesion peptide (RGD) by further reducing ROS levels using a small therapeutic molecule, L-carnitine, a metabolite with purported antioxidant effects. We observed reduced ROS levels, no effect on mitochondrial membrane potential, and increased osteogenic differentiation and tissue production in cells in the presence of L-carnitine. These results suggest the potential to manipulate tissue production by modulating cellular metabolism. PMID- 23627871 TI - Supervised surgical training and its effect on the short-term outcome in laparoscopic colorectal surgery. AB - AIM: Laparoscopic colorectal surgery requires supervised training. In this paper we examine the short-term outcome following a component-based training in laparoscopic colorectal surgery. METHOD: Surgical outcome following laparoscopic colorectal resection was recorded on a prospective database. Patients were divided into three groups, including those performed by the fellows, those completed by the consultant and those completed by a combination of both. Analysis of data was carried out for all colorectal resections and the subgroup with colorectal cancer. RESULTS: 511 operations were examined between June 2006 and January 2011. There was no statistically significant difference in operating time between fellows and consultants but it was significantly longer for procedures where consultants and fellows performed components. Conversion rate, postoperative morbidity, recovery and length of stay were similar for all three groups for the whole patient cohort and also the subgroup of cancer patients. In the cancer subgroup, there was no difference in the pathological stage in the three groups. CONCLUSION: Closely supervised training in laparoscopic colorectal surgery is not associated with any adverse effect on the short-term outcome. PMID- 23627872 TI - Cigarette smoke extract induces differential expression levels of beta-defensin peptides in human alveolar epithelial cells. AB - BACKGROUND: The damaging effects of cigarette smoke on the lungs are well known in terms of cancer risks. Additional molecular changes within the lung tissue can also occur as a result of exposure to cigarette smoke. The human beta-defensin (hBD) class of antimicrobial peptides is the focus of our research. In addition to antimicrobial activity, beta-defensins also have immunomodulatory functions. Over 30 previously unrecognized beta-defensin genes have recently been identified in the human genome, many with yet to be determined functions. We postulated that altered beta-defensin production may play a role in the pathogenesis observed in the lungs of smokers. Our hypothesis is that cigarette smoke exposure will affect the expression of beta-defensins in human lung alveolar epithelial cells (A549). METHODS: We exposed A549 cells to cigarette smoke extract (CSE) and measured the changes in mRNA levels of several antimicrobial peptides by quantitative real time PCR, and directly observed peptide expression in cells by immunofluorescence (IF) microscopy. RESULTS: We found that hBD3, hBD5, and hBD9 gene expression was upregulated in A549 cells exposed to CSE. HBD1, hBD8, hBD18 and LL-37 gene expression did not significantly change upon exposure to CSE. Expression of hBD3 and hBD4 peptides was visualized by IF. CONCLUSIONS: This differential expression suggests that hBD3, hBD5, and hBD9 may play a role in the changes to the lung tissue observed in smokers. Establishing differential beta-defensin expression following CSE treatment will add to our understanding of the molecular response of the lung alveolar epithelium to cigarette smoke exposure. PMID- 23627873 TI - Acceptance of tinnitus: validation of the tinnitus acceptance questionnaire. AB - The concept of acceptance has recently received growing attention within tinnitus research due to the fact that tinnitus acceptance is one of the major targets of psychotherapeutic treatments. Accordingly, acceptance-based treatments will most likely be increasingly offered to tinnitus patients and assessments of acceptance related behaviours will thus be needed. The current study investigated the factorial structure of the Tinnitus Acceptance Questionnaire (TAQ) and the role of tinnitus acceptance as mediating link between sound perception (i.e. subjective loudness of tinnitus) and tinnitus distress. In total, 424 patients with chronic tinnitus completed the TAQ and validated measures of tinnitus distress, anxiety, and depression online. Confirmatory factor analysis provided support to a good fit of the data to the hypothesised bifactor model (root-mean square-error of approximation = .065; Comparative Fit Index = .974; Tucker-Lewis Index = .958; standardised root mean square residual = .032). In addition, mediation analysis, using a non-parametric joint coefficient approach, revealed that tinnitus-specific acceptance partially mediated the relation between subjective tinnitus loudness and tinnitus distress (path ab = 5.96; 95% CI: 4.49, 7.69). In a multiple mediator model, tinnitus acceptance had a significantly stronger indirect effect than anxiety. The results confirm the factorial structure of the TAQ and suggest the importance of a general acceptance factor that contributes important unique variance beyond that of the first-order factors activity engagement and tinnitus suppression. Tinnitus acceptance as measured with the TAQ is proposed to be a key construct in tinnitus research and should be further implemented into treatment concepts to reduce tinnitus distress. PMID- 23627874 TI - Lower polyamine levels in breast milk of obese mothers compared to mothers with normal body weight. AB - BACKGROUND: Obesity is associated with risks for mother and infant, and the mothers' dietary habits influence breast milk composition. Polyamines are secreted in breast milk and are essential for the regulation of intestinal and immune function in newborns and infants. The present study aimed to investigate the level of polyamines in human milk obtained from obese and normal weight mothers at different times of lactation. METHODS: Breast milk from 50 mothers was obtained at day 3, and at 1 and 2 months after delivery. The mothers had normal body weight [body mass index (BMI) < 25 kg m(-2) ] or were obese (BMI > 30 kg/m(2) ). A subgroup of obese mothers participated in a weight reduction programme during pregnancy. Polyamines were analysed using high-performance liquid chromatography. RESULTS: The total polyamine content was significantly lower at all times in breast milk from obese mothers compared to milk from controls. Spermine levels did not differ between groups at any time in contrast to the levels of putrescine and spermidine. Putrescine concentrations were highest on day 3 and spermidine and spermine were highest at 1 month of lactation. The obese mothers, who received dietary advice during pregnancy based on the Nordic Nutrition Recommendations, had higher concentrations of putrescine and spermidine in their milk than the obese mothers without any intervention. CONCLUSIONS: Polyamine concentrations were lower in breast milk from obese mothers compared to mothers with a normal weight. General dietary intervention in obese mothers increased the polyamine levels, suggesting that the low levels in obesity were at least partly associated with food habits. However, the consistency of spermine suggests a special metabolic function of this polyamine. PMID- 23627875 TI - Evolutionary medicine--the quest for a better understanding of health, disease and prevention. AB - Clinical medicine has neglected the fact that the make-up of organs and body functions, as well as the human-specific repertoire of behaviors and defenses against pathogens or other potential dangers are the product of adaptation by natural and sexual selection. Even more, for many clinicians it does not seem straightforward to accept a role of evolution in the understanding of disease, let alone, treatment and prevention.Accordingly, this Editorial seeks to set the stage for an article collection that aims at dealing precisely with the question of why evolutionary aspects of health and disease are not only interesting, but necessary to improve clinical medicine. PMID- 23627876 TI - Identification of antimutagenic properties of anthocyanins and other polyphenols from rose (Rosa centifolia) petals and tea. AB - Petals from different rose (Rosa centifolia) cultivars ("passion," "pink noblesse," and "sphinx") were assessed for antimutagenicity using Escherichia coli RNA polymerase B (rpoB)-based Rif (S) ->Rif (R) (rifampicin sensitive to resistant) forward mutation assay against ethyl methanesulfonate (EMS)-induced mutagenesis. The aqueous extracts of rose petals from different cultivars exhibited a wide variation in their antimutagenicity. Among these, cv. "passion" was found to display maximum antimutagenicity. Upon further fractionation, the anthocyanin extract of cv. "passion" displayed significantly higher antimutagenicity than its phenolic extract. During thin-layer chromatography (TLC) analysis, the anthocyanin extract got resolved into 3 spots: yellow (Rf : 0.14), blue (Rf : 0.30), and pink (Rf : 0.49). Among these spots, the blue one displayed significantly higher antimutagenicity than the other 2. Upon high performance liquid chromatography analysis, this blue spot further got resolved into 2 peaks (Rt : 2.7 and 3.8 min). The 2nd peak (Rt : 3.8 min) displaying high antimutagenicity was identified by ESI-IT-MS/MS analysis as peonidin 3-glucoside, whereas less antimutagenic peak 1 (Rt : 2.7) was identified as cyanidin 3, 5 diglucoside. The other TLC bands were also characterized by ESI-IT-MS/MS analysis. The least antimutagenic pink band (Rf : 0.49) was identified as malvidin 3-acetylglucoside-4-vinylcatechol, whereas non-antimutagenic yellow band (Rf : 0.14) was identified as luteolinidin anthocyanin derivative. Interestingly, the anthocyanin extracted from rose tea of cv. "passion" exhibited a similar antimutagenicity as that of the raw rose petal indicating the thermal stability of the contributing bioactive(s). The findings thus indicated the health protective property of differently colored rose cultivars and the nature of their active bioingredients. PMID- 23627877 TI - Probing active cocaine vaccination performance through catalytic and noncatalytic hapten design. AB - Presently, there are no FDA-approved medications to treat cocaine addiction. Active vaccination has emerged as one approach to intervene through the rapid sequestering of the circulating drug, thus terminating both psychoactive effects and drug toxicity. Herein, we report our efforts examining two complementary, but mechanistically distinct active vaccines, i.e., noncatalytic and catalytic, for cocaine treatment. A cocaine-like hapten GNE and a cocaine transition-state analogue GNT were used to generate the active vaccines, respectively. GNE-KLH (keyhole limpet hemocyannin) was found to elicit persistent high-titer, cocaine specific antibodies and blunt cocaine-induced locomotor behaviors. Catalytic antibodies induced by GNT-KLH were also shown to produce potent titers and suppress locomotor response in mice; however, upon repeated cocaine challenges, the vaccine's protecting effects waned. In depth kinetic analysis suggested that loss of catalytic activity was due to antibody modification by cocaine. The work provides new insights for the development of active vaccines for the treatment of cocaine abuse. PMID- 23627878 TI - The promise and peril of mobile health applications for diabetes and endocrinology. AB - We are in the midst of what some have called a "mobile health revolution". Medical applications ("apps") for mobile phones are proliferating in the marketplace and clinicians are likely encountering patients with questions about the medical value of these apps. We conducted a review of medical apps focused on endocrine disease. We found a higher percentage of relevant apps in our searches of the iPhone app store compared with the Android marketplace. For our diabetes search in the iPhone store, the majority of apps (33%) focused on health tracking (blood sugars, insulin doses, carbohydrates), requiring manual entry of health data. Only two apps directly inputted blood sugars from glucometers attached to the mobile phone. The remainder of diabetes apps were teaching/training apps (22%), food reference databases (8%), social blogs/forums (5%), and physician directed apps (8%). We found a number of insulin dose calculator apps which technically meet criteria for being a medically regulated mobile application, but did not find evidence for FDA-approval despite their availability to consumers. Far fewer apps were focused on other endocrine disease and included medical reference for the field of endocrinology, access to endocrine journals, height predictors, medication trackers, and fertility apps. Although mobile health apps have great potential for improving chronic disease care, they face a number of challenges including lack of evidence of clinical effectiveness, lack of integration with the health care delivery system, the need for formal evaluation and review and organized searching for health apps, and potential threats to safety and privacy. PMID- 23627879 TI - The effects of cannabis use expectancies on self-initiated cannabis cessation. AB - AIMS: To prospectively investigate the relation between cannabis use expectancies and cannabis use prior to and during a self-initiated cannabis cessation attempt. DESIGN: Cohort design that followed participants for 4 weeks following a self initiated cessation attempt. SETTING: United States Department of Veterans Affairs medical center. PARTICIPANTS: One hundred cannabis dependent military veterans. MEASUREMENTS: The Marijuana Effects Expectancy Questionnaire at baseline; the timeline follow-back procedure at baseline and during the cessation attempt. FINDINGS: Cannabis use at baseline was associated with positive (P = 0.01), but not negative (P = 0.25), expectancies. Cannabis lapse was associated with positive (P = 0.03) and negative expectancies (P = 0.01), and relapse was associated with positive (P = 0.04), but not negative (P = 0.21), expectancies. The trajectory of average cannabis use during the cessation period was associated with positive (P = 0.03), but not negative (P = 0.96), expectancies. Results were similar in effect and statistical significance when adjusting for demographic factors, motivation to quit cannabis, mental disorder diagnoses, and alcohol and tobacco use, and when analyzing complete data sets obtained through multiple imputation. CONCLUSIONS: In the USA, cannabis use expectancies, especially those regarding the positive effects of cannabis use, appear to be strongly and consistently linked to cannabis use and quit failure. PMID- 23627880 TI - Paediatric visceral leishmaniasis in Italy: a 'One Health' approach is needed. AB - Here we describe a case of paediatric visceral leishmaniasis recorded in an infant initially suspected for acute lymphoblastic leukaemia due to the clinical and haematological presentation. Eventually the patient was found positive for Leishmania infantum infection and successfully treated. This case emphasises how pivotal a 'One Health' approach is for diagnosing this zoonotic disease; highlighting the importance of including Visceral Leishmaniasis in the differential diagnosis of leukaemia-like syndromes in infants travelling to, and living in, the Mediterranean region. PMID- 23627881 TI - Findings from the oral health study of the Danish Health Examination Survey 2007 2008. AB - OBJECTIVE: The aims of the oral part of the Danish Health Examination Survey (DANHES 2007-2008) were (1) to establish an oral health database for adult Danes and (2) to explore the influence of general diseases and lifestyle on oral health. This paper presents the study population, examination methods, questionnaire and baseline results. MATERIALS AND METHODS: The study population comprised 4402 subjects, aged 18-96, consecutively enrolled from 18 065 DANHES participants from 13 municipalities in Denmark. The oral part consisted of a validated questionnaire and a clinical examination, carried out in mobile units by three trained and calibrated dental hygienists. The data were processed with descriptive statistics and mono- and bivariate analyses. RESULTS: The mean age was 54.1 years and 60% were women. The mean number of natural teeth was 26.6; the mean DMFT/DMFS values were 18.9 and 61.0, and varied with age (DMFT 8.7-24.3). A higher proportion of females suffered from dental erosion in the younger age groups. Forty per cent of all subjects had a mean clinical attachment loss >= 3 mm, varying from 4% among those aged 18-34 to 80% in those over 75. A sub-optimal saliva secretion rate was more common among females than males (17.7% vs 10.4%) and this was reflected by the reported frequency of dry mouth. CONCLUSION: This extensive cross-sectional study provides a platform for obtaining future knowledge of the impact of health- and lifestyle-related factors on oral diseases. The validated questionnaire and the clinical characteristics enable robust analyses, although the conclusions may be hampered by limited external validity. PMID- 23627882 TI - 13C/12C and 15N/14N isotope analysis to characterize degradation of atrazine: evidence from parent and daughter compound values. AB - Atrazine (Atz) and its metabolite desethylatrazine (DEA) frequently occur in the environment. Conclusive interpretation of their transformation is often difficult. This study explored evidence from (13)C/(12)C and (15)N/(14)N isotope trends in parent and daughter compounds when Atz was dealkylated by (i) permanganate and (ii) the bacterium Rhodococcus sp. NI86/21. In both transformations, (13)C/(12)C ratios of atrazine increased strongly (epsilon(carbon/permanganate) = -4.6 +/- 0.60/00 and epsilon(carbon/Rhodoccoccus) = -3.8 +/- 0.20/00), whereas nitrogen isotope fractionation was small. (13)C/(12)C ratios of DEA showed the following trends. (i) When DEA was formed as the only product (Atz + permanganate), (13)C/(12)C remained constant, close to the initial value of Atz, because the carbon atoms involved in the reaction step are not present in DEA. (ii) When DEA was formed together with desisopropylatrazine (biodegradation of Atz), (13)C/(12)C increased but only within 20/00. (iii) When DEA was further biodegraded, (13)C/(12)C increased by up to 90/00 giving strong testimony of the metabolite's breakdown. Two lines of evidence emerge. (a) Enrichment of (13)C/(12)C in DEA, compared to initial Atz, may contain evidence of further DEA degradation. (b) Dual element ((15)N/(14)N versus (13)C/(12)C) isotope plots for dealkylation of atrazine agree with indirect photodegradation but differ from direct photolysis and biotic hydrolysis. Trends in multielement isotope data of atrazine may, therefore, decipher different degradation pathways. PMID- 23627887 TI - Photophysics of delocalized excitons in carbazole dendrimers. AB - The photophysical properties in solution of three generations of carbazole-based dendrons and dendrimers with fluorenyl surface groups were studied using steady state, time-resolved femtosecond transient absorption and anisotropy, and coherent two-dimensional ultraviolet spectroscopy. It was found that increasing the generation caused a switch in the nature of the emissive state between the first-generation compounds and the second- and third-generation dendrimers. Time resolved anisotropy measurements revealed low initial anisotropies that decreased with increasing dendrimer generation consistent with increasing intradendrimer interchromophore coupling. Two-dimensional UV spectroscopy showed that the signal from the second- and third-generation dendrimers is the product of multiple chromophores interacting. The maximum number of interacting chromophores is reached by the second generation. PMID- 23627886 TI - Factors associated with postoperative morbidity, reoperation and readmission rates after laparoscopic total abdominal colectomy for ulcerative colitis. AB - AIM: The aim of this study was to evaluate factors affecting postoperative outcomes after laparoscopic total abdominal colectomy (TAC) with end ileostomy (EI) for ulcerative colitis (UC). METHOD: Patients undergoing laparoscopic TAC/EI for severe UC/indeterminate colitis in our institution between 1998 and 2010 were retrospectively identified from a prospectively established database. Demographics, disease characteristics and perioperative outcomes were recorded. Associations between the 30-day postoperative outcome and patient-, disease- and treatment-related variables were assessed using univariate and multivariate logistic regression models. RESULTS: Two hundred and four patients (105 men, median age 35.5 years) were identified. The conversion rate was 4.4%. Median blood loss and operation time were 100 ml and 185 min. Length of hospital stay was 5.8 +/- 4.4 days. Overall postoperative morbidity, reoperation and readmission rates were 40, 7 and 17%, respectively Preoperative treatment with high steroid doses was significantly associated with postoperative morbidity on multivariate analysis (P = 0.011). Univariate analysis showed that lower preoperative body mass index (BMI), haemoglobin, serum albumin level and pancolitis were associated with reoperation, of which a lower BMI (P = 0.043) was also independently significant on multivariate analysis. No specific factor was significantly associated with readmission. CONCLUSION: Preoperative clinical deterioration is associated with an adverse outcome after laparoscopic TAC for UC. PMID- 23627888 TI - Preparation and double Michael addition reactions of a synthetic equivalent of the Nazarov reagent. AB - A synthetic equivalent of the Nazarov reagent, the silyl derivative 2, able to undergo base-catalyzed double Michael addition reactions with alpha,beta unsaturated carbonyl compounds has been developed. The new reagent satisfactorily reacts with unsaturated indolo[2,3-a]quinolizidine lactams to give pentacyclic yohimbinone-type derivatives. PMID- 23627889 TI - A comparison of Cohen's Kappa and Gwet's AC1 when calculating inter-rater reliability coefficients: a study conducted with personality disorder samples. AB - BACKGROUND: Rater agreement is important in clinical research, and Cohen's Kappa is a widely used method for assessing inter-rater reliability; however, there are well documented statistical problems associated with the measure. In order to assess its utility, we evaluated it against Gwet's AC1 and compared the results. METHODS: This study was carried out across 67 patients (56% males) aged 18 to 67, with a mean SD of 44.13 +/- 12.68 years. Nine raters (7 psychiatrists, a psychiatry resident and a social worker) participated as interviewers, either for the first or the second interviews, which were held 4 to 6 weeks apart. The interviews were held in order to establish a personality disorder (PD) diagnosis using DSM-IV criteria. Cohen's Kappa and Gwet's AC1 were used and the level of agreement between raters was assessed in terms of a simple categorical diagnosis (i.e., the presence or absence of a disorder). Data were also compared with a previous analysis in order to evaluate the effects of trait prevalence. RESULTS: Gwet's AC1 was shown to have higher inter-rater reliability coefficients for all the PD criteria, ranging from .752 to 1.000, whereas Cohen's Kappa ranged from 0 to 1.00. Cohen's Kappa values were high and close to the percentage of agreement when the prevalence was high, whereas Gwet's AC1 values appeared not to change much with a change in prevalence, but remained close to the percentage of agreement. For example a Schizoid sample revealed a mean Cohen's Kappa of .726 and a Gwet's AC1of .853 , which fell within the different level of agreement according to criteria developed by Landis and Koch, and Altman and Fleiss. CONCLUSIONS: Based on the different formulae used to calculate the level of chance-corrected agreement, Gwet's AC1 was shown to provide a more stable inter rater reliability coefficient than Cohen's Kappa. It was also found to be less affected by prevalence and marginal probability than that of Cohen's Kappa, and therefore should be considered for use with inter-rater reliability analysis. PMID- 23627890 TI - Targeting PPAR isoforms following CNS injury. AB - A major focus has developed for the discovery of proregenerative and neuroprotective therapeutic agents to help the millions of Americans who receive a CNS injury annually. Tribulations have been encountered along the way due to the complicated set of pathways that are initiated post-injury. To target this complicated multifaceted signaling cascade, the most promising therapeutics target multiple pathways involved in the secondary injury cascade, such as neuroinflammation, the generation of ROS and mitochondrial dysfunction. Compelling experimental data demonstrates that mitochondrial dysfunction is a pivotal link in the neuropathological sequelae of brain injury. A group of PPAR agonists, specifically rosiglitazone and pioglitazone, have shown an extreme amount of promise in the realm of drug discovery for CNS injury due to their ability to increase functional recovery and decrease lesion volumes following injury. The therapeutic effects of these PPAR agonists are thought to be a direct result of PPAR activity however new data is arising that shows some of the effects may be independent of PPAR activity, targeting a novel mitochondrial protein called mitoNEET. In this review, a thorough evaluation of the role of PPAR and mitoNEET in rosiglitazone and pioglitazone mediated neuroprotection will be completed in order to shed light on the mechanism of a new possible therapeutic intervention for CNS injury. PMID- 23627891 TI - Evo-devo of human adolescence: beyond disease models of early puberty. AB - Despite substantial heritability in pubertal development, much variation remains to be explained, leaving room for the influence of environmental factors to adjust its phenotypic trajectory in the service of fitness goals. Utilizing evolutionary development biology (evo-devo), we examine adolescence as an evolutionary life-history stage in its developmental context. We show that the transition from the preceding stage of juvenility entails adaptive plasticity in response to energy resources, other environmental cues, social needs of adolescence and maturation toward youth and adulthood. Using the evolutionary theory of socialization, we show that familial psychosocial stress fosters a fast life history and reproductive strategy rather than early maturation being just a risk factor for aggression and delinquency. Here we explore implications of an evolutionary-developmental-endocrinological-anthropological framework for theory building, while illuminating new directions for research. PMID- 23627892 TI - Salicylic acid peel incorporating triethyl citrate and ethyl linoleate in the treatment of moderate acne: a new therapeutic approach. AB - BACKGROUND: Acne affects many adolescents. Conventional therapy often results in side effects and poor adherence, and the treatment does not consider the psychological effect of acne on patients, which is comparable with that of disabling diseases. OBJECTIVES: To evaluate the efficacy and tolerability of a peel (30% salicylic acid, triethyl citrate and ethyl linoleate) combined with a home therapy with three topical agents (triethyl citrate, ethyl linoleate and salicylic acid 0.5% cream, lotion) in moderate acne of the face. DESIGN: Prospective, observational, multicenter, open-label, postmarketing, phase IV study. METHODS: Patients were assessed by comparing Global Acne Grading System (GAGS) score and total lesion count from 15 days before the first peel (T-15 ), after four salicylic peels (every 10 +/- 2 days (T0 , T10 , T20 , T30 ), and 20 days after of the end of the study (T50 ). This treatment was associated to a home therapy. RESULTS: Fifty-three patients completed the study. The average GAGS score fell 49% between T-15 and T50 (p < .001). No patient withdrew for adverse events. CONCLUSIONS: This therapy was effective and well-tolerated in all cases. Chemo-exfoliation sessions ensured the continuous monitoring of clinical results and improved patient quality of life. PMID- 23627893 TI - Antiglaucoma carbonic anhydrase inhibitors: a patent review. AB - INTRODUCTION: Glaucoma is one of the major causes of blindness, affecting together with age-related macular degeneration > 70 million people worldwide. One of the therapeutic options for its management is based on the inhibition of the metalloenyme carbonic anhydrase (CA, EC 4.2.1.1). CA inhibitors (CAIs) diminish intraocular pressure (IOP) by reducing the rate of bicarbonate formation and thus secretion of the aqueous humor. AREAS COVERED: The main classes of clinically used antiglaucoma CAIs are the sulfonamides with systemic (acetazolamide, methazolamide, ethoxzolamide and dichlorophenamide) and topical (dorzolamide and brinzolamide) action. A patent literature review covering the period 2007 - 2013 is presented. EXPERT OPINION: This review presents an overview of the patent literature in the CAI antiglaucoma drug design field during the past 6 years. Most of the patents deal with sulfonamide/sulfamide/sulfamate CAIs, sulfonamides incorporating NO-donating moieties, as well as hybrids incorporating sulfonamide and prostaglandin (PG) analogs, were also reported. There is an urgent need for new antiglaucoma CAIs/approaches to treat and diagnose this disease in the very near future, as the last drug which has been discovered in the field (latanoprost) dates back > 10 years ago. PMID- 23627896 TI - Efficacy of a dual fluorescence method in detecting the viability of overwintering cyanobacteria. AB - Chill in the light is the major environmental stress that cyanobacteria encounter in winter. Cyanobacterial cells may acquire chill-light tolerance upon exposure to low temperature in autumn and early winter. We sought to establish the efficacy of the dual fluorescence method in detecting the viability of overwintering cyanobacteria and to provide further evidence for the chill-light tolerance of preconditioned cyanobacteria. Synechocystis sp. PCC 6803 and Microcystis aeruginosa PCC 7806 were exposed to chill (5 degrees C)-light stress with or without pretreatment at 15 degrees C and stained with SYTO 9 and propidium iodide. Live and dead cells were observed under a fluorescence microscope, and the percentage of viable cells was quantified on a microplate reader. The dual fluorescence method showed consistent results with tests of the ability to reinitiate growth. Cell viability was quantitatively correlated with ratio of SYTO 9/propidium iodide fluorescence. Previously, Microcystis colonies in Lake Taihu had been found to accumulate RNA-binding protein 1 in autumn and winter. Use of this method directly showed the viability of such Microcystis colonies throughout the winter. PMID- 23627894 TI - Reprogramming adult human dermal fibroblasts to islet-like cells by epigenetic modification coupled to transcription factor modulation. AB - In this article, we describe novel conditions for culture, expansion, and transdifferentiation of primary human dermal fibroblasts (hDFs) to induce expression of transcription factors (TFs) and hormones characteristic of the islets of Langerhans. We show that histones associated with the insulin gene are hyperacetylated and that insulin gene DNA is less methylated in islet cells compared to cells that do not express insulin. Using two compounds that alter the epigenetic signature of cells, romidepsin (Romi), a histone deacetylase inhibitor, and 5-Azacytidine (5-AzC), a chemical analogue of cytidine that cannot be methylated, we show that hDFs exhibit a distinctive regulation of expression of TFs involved in islet development as well as of induction of glucagon and insulin. Overexpression of Pdx1, a TF important for islet differentiation, and silencing of musculoaponeurotic fibrosarcoma oncogene homolog B, a TF that is expressed in mature glucagon-producing cells, result in induction of insulin to a higher level compared to Romi and 5-AzC alone. The cells obtained from this protocol exhibit glucose-stimulated insulin secretion and lower blood glucose levels of diabetic mice. These data show that fully differentiated nonislet derived cells could be made to transdifferentiate to islet-like cells and that combining epigenetic modulation with TF modulation leads to enhanced insulin expression. PMID- 23627895 TI - Lessons from the Hvidoere International Study Group on childhood diabetes: be dogmatic about outcome and flexible in approach. PMID- 23627897 TI - Survival of primary molar restorations in four birth cohorts-A retrospective, practice-based study. AB - OBJECTIVE: Paediatric restorative dentistry continues being a challenge in everyday clinical practice. Practise-based survival analysis covering entire age cohorts offer an epidemiological approach to this issue in studying survival of restorations in primary teeth. The aim of this study was to compare survival of restorations in primary molars in 1985, 1990, 1995 and 2000 age cohorts associated with some population-related factors. MATERIAL AND METHODS: Data from dental records of the entire cohorts were obtained from the Health Centre of Kemi, Finland covering the period 1989-2009. The longevity of the restorations was illustrated using the Kaplan-Meier survival curves and tested with log-rank test and Cox proportional hazards regression analysis. The retrospective caries risk definition for individuals was based on the early restorations in the first permanent molars. RESULTS: Total number of the placed restorations was 2755. Survival of the restorations was the shortest in the 1995 cohort and the longest in the 1985 cohort (p < 0.001). The greatest deterioration was between the cohorts in 1990 and 1995. Survival was also shorter for the children at high risk for caries compared with the low risk children (p < 0.001). CONCLUSIONS: Survival of the restorations shortened distinctly towards the younger cohorts and was also shorter for the high risk compared with the low risk children. Due to the variety of materials in paediatric dentistry, handling them carefully according to manufacturers' instructions must be emphasized to avoid failures of restorations due to technical reasons. Also, non-invasive treatment must always be given together with invasive treatment. PMID- 23627898 TI - Prevalence and polarization of dental caries among young, healthy adults: Cross sectional epidemiological study. AB - OBJECTIVE: Oral health of young people has improved in the industrialized countries during past decades. However, stagnation of this progress has been reported recently. The main aim of this epidemiological study was to investigate the level of cariological treatment history and need (DMFT, DT) and polarization of dental caries among a healthy young male population born in the early 1990s. MATERIALS AND METHODS: Oral health of 13,564 men and 255 women born in 1990, 1991 or 1992 was screened based on the WHO criteria for epidemiological studies by 15 calibrated dentists in 20 garrisons (of a total 24) of the Finnish Defence Forces in January and July 2011. Mean DMFT and DT (SD) values and their distribution were calculated excluding wisdom teeth. Polarization was investigated using the Lorentz analysis. RESULTS: Mean DMFT, DT and FT values were DMFT = 4.1 (SD = 4.2), DT = 1.4 (SD = 2.5) and FT = 2.7 (SD = 2.9). Almost half of the men (45.1%) and one third of the women (37.3%) had at least one tooth needing restorative treatment. About 30% of the conscripts had 90% of all caries lesions and ~ 10% of the conscripts had half of all lesions. CONCLUSIONS: Oral health of young males has not improved since the previous study among conscripts 15 years ago. Polarization of dental caries still exists. About half of the young male population still has manifested dental caries. Oral health promotion must not be neglected, even in countries with low caries prevalence. PMID- 23627899 TI - Children, sport and the Olympics: Observations from the Games of the XXX Olympiad in London. PMID- 23627900 TI - Ionic liquid assisted dissolution of dissolved organic matter and PAHs from soil below the critical micelle concentration. AB - Increased use and production of ionic liquids (ILs) may result in emissions into the environment. Particularly vulnerable are industrial areas and landfills where ILs are utilized and ultimately disposed of. This study investigates how IL contamination can affect soil properties and the sorption of pre-existing contaminants. The commonly used IL 1-methyl-3-octyl imidazolium chloride ([OMIM][Cl]) was added at various quantities to a landfill soil contaminated with polycyclic aromatic hydrocarbons (PAHs). Subsequently, the release of PAHs and dissolved organic matter (DOM) from this soil was thoroughly investigated. Two fractions of PAH release into the porewater were measured, the freely dissolved fraction (measured using a passive sampler) and the total PAH concentration (which includes the freely dissolved molecules as well as those associated with colloids, micelles and DOM). As expected the highest levels of total PAH porewater concentration occurred when the critical micelle concentration (CMC) of the IL was exceeded. However, as we report here for the first time, enhanced amounts of freely dissolved PAHs were released by sub-CMC concentrations of IL. Additionally, enhanced levels of DOM, due to dissolution of soil organic matter by IL, were also observed upon addition of sub-CMC IL concentrations. Based on this, enhanced release of pre-existing contaminants and DOM is suggested as a potential risk from IL emissions at trace concentrations well below the CMC. Potential mechanisms of this sub-CMC release are discussed. PMID- 23627901 TI - Molecular analysis of Baylisascaris columnaris revealed mitochondrial and nuclear polymorphisms. AB - BACKGROUND: Baylisascaris species are intestinal nematodes of skunks, raccoons, badgers, and bears belonging to the genus Ascarididae. Oral uptake of embryonated Baylisascaris sp. eggs by a wide variety of mammals and birds can lead to visceral, ocular and neurological larva migrans. B. procyonis, the raccoon roundworm, is known to cause severe illness in intermediate hosts and in humans, whereas the skunk roundworm B. columnaris is probably less pathogenic. Skunks and raccoons are kept as pets in Europe, sometimes together with cats and dogs, living in close contact with humans. B. procyonis and B. columnaris are difficult to differentiate based on morphological criteria and molecular and phylogenetic information concerning B. columnaris is missing. This is the first study on the genetic characterisation of B. columnaris, based on mitochondrial and nuclear molecular markers. METHODS: B. columnaris worms were isolated from pet skunks, and used for molecular analysis. PCR primers targeted at mitochondrial cytochrome c oxidase 1 and 2 (CO1 and CO2), ribosomal ITS1-5.8S-ITS2 and ribosomal 28S genes were used. DNA sequences from B. columnaris, B. procyonis and B. transfuga from bears were analysed by cluster analysis. RESULTS: Four different multi-locus genotypes were found in B. columnaris, based on 14 single nucleotide polymorphisms (SNPs) and two insertions / deletions in CO1, CO2, ITS1-5.8S-ITS2 and 28S. CONCLUSIONS: The genetic characteristics of B. columnaris show close resemblance to those of B. procyonis, but in contrast to B. procyonis, show several polymorphisms in both mitochondrial and nuclear markers. These polymorphisms could be used as a tool to differentiate B. columnaris from B. procyonis in molecular diagnostic assays, and to identify B. columnaris by PCR, in addition to or replacing morphometric analysis. This might lead to more insight into the zoonotic relevance of B. columnaris in humans. PMID- 23627902 TI - Structural characterization and molecular order of rodlike mesogens with three- and four-ring core by XRD and 13C NMR spectroscopy. AB - Structural characterizations using XRD and (13)C NMR spectroscopy of two rodlike mesogens consisting of (i) three phenyl ring core with a polar cyano terminal and (ii) four phenyl ring core with flexible dodecyl terminal chain are presented. The three-ring-core mesogen with cyano terminal exhibits enantiotropic smectic A phase while the four-ring mesogen reveals polymesomorphism and shows enantiotropic nematic, smectic C, and tilted hexatic phases. The molecular organization in the three-ring mesogen is found to be partial bilayer smectic Ad type, and the interdigitation of the molecules in the neighboring layers is attributed to the presence of the polar terminal group. For the four-ring mesogen, the XRD results confirm the existence of the smectic C and the tilted hexatic mesophases. A thermal variation of the layer spacing across the smectic C phase followed by a discrete jump at the transition to the tilted hexatic phase is also observed. The tilt angles have been estimated to be about 45 degrees in the smectic C phase and about 40 degrees in tilted hexatic phase. (13)C NMR results indicate that in the mesophase the molecules are aligned parallel to the magnetic field. From the (13)C-(1)H dipolar couplings determined from the 2D experiments, the overall order parameter for the three-ring mesogen in its smectic A phase has been estimated to be 0.72 while values ranging from 0.88 to 0.44 have been obtained for the four-ring mesogen as it passes from the tilted hexatic to the nematic phase. The orientations of the different rings of the core unit with respect to each other and also with respect to the long axis of the molecule have also been obtained. PMID- 23627903 TI - How selective are the new guidelines for treatment of subclinical hypothyroidism for patients with thyrotropin levels at or below 10 mIU/L? AB - BACKGROUND: By consensus, a thyrotropin (TSH) level persistently >10 mIU/L is an indication for the treatment of subclinical hypothyroidism (SCH). Controversy exists regarding patients whose TSH level is elevated but <10 mIU/L. Recently, the American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists (AACE) published their position about factors that should be considered in the decision on treating SCH. This study evaluated the frequency of these factors among adult (non-pregnant) women with SCH whose TSH levels are <=10 mIU/L. METHODS: The presence of the conditions that should be considered for the treatment of SCH according to ATA and AACE was evaluated in 252 women who were diagnosed with SCH and had TSH levels <=10 mIU/L. Pregnant women were excluded. RESULTS: Antithyroperoxidase antibodies (TPOAbs) were detected in 137 (54.3%) women. A high cardiovascular risk was observed in 43 (17%) women. Eighty (31.7%) women who were not at high cardiovascular risk presented at least one classical risk factor (arterial hypertension, elevated level of low-density lipoprotein cholesterol or low level of high-density lipoprotein-cholesterol, smoking, or first-degree family history of premature coronary artery disease). At least one symptom or sign of hypothyroidism that could not be explained by another condition was observed in 180 (71.4%) women. Two hundred thirty-two (92%) women had positive TPOAbs, or at least one classical cardiovascular risk factor, or at least one symptom or sign of hypothyroidism. CONCLUSIONS: According to the new ATA and AACE guidelines, L-T4 therapy would be considered for 92% of women with SCH and TSH <=10 mIU/L. PMID- 23627905 TI - Positive association between plasma levels of oxidized low-density lipoprotein and myeloperoxidase after hemodialysis in patients with diabetic end-stage renal disease. AB - End-stage renal disease (ESRD) patients undergoing hemodialysis (HD) have a high prevalence of cardiovascular events. Low-density lipoprotein (LDL) in dialysis patients has been shown to be susceptible to in vitro peroxidation; therefore, oxidized-LDL (ox-LDL) could be generated in these patients. Moreover, myeloperoxidase (MPO) released from activated neutrophils may play a role in the induction of LDL oxidation. The purpose of this study was to investigate the relationship between plasma ox-LDL levels, plasma MPO levels, and serum high sensitivity C-reactive protein (hs-CRP) levels during initial HD in patients with diabetic ESRD. Patients (n=28) had serial venous blood samples drawn before and after HD at the initial, second, and third sessions. Plasma ox-LDL levels were measured using a specific monoclonal antibody (DLH3), and plasma MPO levels were measured using an enzyme-linked immunosorbent assay kit. Plasma ox-LDL levels and MPO levels after a single HD session increased significantly (ox-LDL, P<0.005; MPO, P<0.0001) compared with levels before that HD session. However, the increase was transient since the levels returned to pre-HD session levels. Additionally, plasma MPO levels showed a positive correlation with plasma ox-LDL levels during HD (R=0.62, P=0.0029). No significant change was observed in serum hs-CRP levels before and after each HD session. This study demonstrates that plasma MPO levels are directly associated with plasma ox-LDL levels in diabetic ESRD patients during initial HD. These findings suggest a pivotal role for MPO and ox-LDL in the progression and acceleration of atherosclerosis in patients undergoing HD. PMID- 23627906 TI - Dietary fat intake, circulating and membrane fatty acid composition of healthy Norwegian men and women. AB - BACKGROUND: The present study aimed to assess the dietary fat intake and blood fatty acid status of healthy Norwegian men and women living in Bergen whose habitual diet is known to be high in long-chain omega-3 fat. METHODS: Healthy men (n = 41) and women (n = 40) aged 20-50 years who were regular blood donors completed 7-day food diaries and their nutrient intake was analysed by Norwegian food database software, kbs, version 4.9 (kostberegningssystem; University of Oslo, Oslo, Norway). Blood samples were obtained before blood donation and assessed for the fatty acid composition of plasma triglycerides and cholesterol esters, phosphatidylcholine, and red cell phosphatidylcholine and phosphatidylethanolamine. RESULTS: There was no difference in dietary fat intake between men and women. Total and saturated fat intakes exceeded the upper limits of the recommendations of the National Nutrition Council of Norway. Although polyunsaturated fat intake was close to the lower limit of the recommended level, the intake varied greatly among individuals, partly as a result of the use of supplementary fish oil. Moreover, the proportional fatty acid composition of plasma and red cell lipids was similar between men and women. Enrichment of docosahexaenoic acid in red cell phosphatidylethanolamine was found in fish oil users. CONCLUSIONS: The results of the present study provide a snapshot of the current nutritional status of healthy Norwegian adults. Moreover, the detailed blood fatty acid composition of men and women whose habitual diet constitutes high long-chain polyunsaturated omega-3 fat as well as saturated fat could be used as reference value for population studies. PMID- 23627907 TI - Eyes on new product development. PMID- 23627908 TI - Cranberries and wild blueberries treated with gastrointestinal enzymes positively modify glutathione mechanisms in Caco-2 cells in vitro. AB - Beneficial health effects of cranberries (CBs) and wild blueberries (BBs), such as reduced levels of oxidative stress, have been demonstrated in feeding studies. These Vaccinium berries contain high levels of flavonoids; however, the bioavailability of flavonoids is generally low. We investigated the in vitro effects of these berries on intestinal cells, focusing on mitigating oxidative stress and associated reactive oxygen species (ROS). First, we simulated the passage of CB and BB through the gastrointestinal (GI) tract by treating berry homogenates to a battery of digestive enzymes. Then, Caco-2 cells, a model of small intestine epithelial uptake, were exposed to these homogenates for 60 min. Using a cell-free assay, we found that the antioxidant activity in CB homogenates was not affected by these enzymes, but that BB homogenates treated with gut enzymes had 43% lower free-radical quenching activity (P < 0.05). However, both of the enzyme-treated homogenates were still able to counteract the ROS generating ability of H2O2 added exogenously to Caco-2 cells. Berry homogenates also increased mitochondrial metabolic rates at 60 min posttreatment, as measured by MTT assays. Enzyme-treated CB (but not BB) homogenates increased the levels of reduced glutathione (GSH) relative to oxidized glutathione (GSSG), a critical indicator of the cellular redox state (P < 0.05). Our data suggest that CBs do not lose their antioxidant ability when passing through the GI tract, and specifically, digested CB may serve to enhance cytoprotective effects in intestinal cells by reducing potential damage caused by free radicals and ROS derived from other food sources. PMID- 23627909 TI - Different actions of endothelin-1 on chemokine production in rat cultured astrocytes: reduction of CX3CL1/fractalkine and an increase in CCL2/MCP-1 and CXCL1/CINC-1. AB - BACKGROUND: Chemokines are involved in many pathological responses of the brain. Astrocytes produce various chemokines in brain disorders, but little is known about the factors that regulate astrocytic chemokine production. Endothelins (ETs) have been shown to regulate astrocytic functions through ETB receptors. In this study, the effects of ETs on chemokine production were examined in rat cerebral cultured astrocytes. METHODS: Astrocytes were prepared from the cerebra of one- to two-day-old Wistar rats and cultured in serum-containing medium. After serum-starvation for 48 hours, astrocytes were treated with ETs. Total RNA was extracted using an acid-phenol method and expression of chemokine mRNAs was determined by quantitative RT-PCR. The release of chemokines was measured by ELISA. RESULTS: Treatment of cultured astrocytes with ET-1 and Ala(1,3,11,15)-ET 1, an ET(B) agonist, increased mRNA levels of CCL2/MCP1 and CXCL1/CINC-1. In contrast, CX3CL1/fractalkine mRNA expression decreased in the presence of ET-1 and Ala(1,3,11,15)-ET-1. The effect of ET-1 on chemokine mRNA expression was inhibited by BQ788, an ET(B) antagonist. ET-1 increased CCL2 and CXCL1 release from cultured astrocytes, but decreased that of CX3CL1. The increase in CCL2 and CXCL1 expression by ET-1 was inhibited by actinomycin D, pyrrolidine dithiocarbamate, SN50, mithramycin, SB203580 and SP600125. The decrease in CX3CL1 expression by ET-1 was inhibited by cycloheximide, Ca(2+) chelation and staurosporine. CONCLUSION: These findings suggest that ETs are one of the factors regulating astrocytic chemokine production. Astrocyte-derived chemokines are involved in pathophysiological responses of neurons and microglia. Therefore, the ET-induced alterations of astrocytic chemokine production are of pathophysiological significance in damaged brains. PMID- 23627910 TI - Metabonomic analysis of liver tissue from BALB/c mice with D galactosamine/lipopolysaccharide-induced acute hepatic failure. AB - BACKGROUND: Compared with biofluids, target tissues and organs more directly reflect the pathophysiological state of a disease process. In this study, a D galactosamine (GalN) / lipopolysaccharide (LPS)-induced mouse model was constructed to investigate metabonomics of liver tissue and directly characterize metabolic changes in acute liver failure (ALF). METHODS: After pretreatment of liver tissue, gas chromatography coupled to time-of-flight mass spectrometry (GC/TOFMS) was used to separate and identify the liver metabolites. Partial least squares--discriminant analysis models were constructed to separate the ALF and control groups and to find those compounds whose liver levels differed significantly between the two groups. RESULTS: Distinct clustering was observed between the ALF and control mice. Fifty-eight endogenous metabolites were identified. Compared with the control mice, many metabolites, including sugars, amino acids, fatty acids, and organic acids, underwent significant changes in the ALF group, some of which differed from changes observed in plasma. Significant reduction of some important intermediate metabolites indicates that production of ketone bodies, the tricarboxylic acid and urea cycles, gluconeogenesis, glycolysis and pentose phosphate pathways are inhibited after GalN/LPS administration. CONCLUSIONS: GC/TOFMS can be a powerful technique to perform metabonomic studies of liver tissue. GalN/LPS treatment can severely disturb substance metabolism in the liver, with different effects on metabolites compared with those observed in the plasma. PMID- 23627911 TI - Effects of breastfeeding on body composition and maturational tempo in the rat. AB - BACKGROUND: Features of life history are subject to environmental regulation in the service of reproductive fitness goals. We have previously shown that the infant-to-childhood transition reflects the adaptive adjustment of an individual's size to the prevailing and anticipated environment. METHODS: To evaluate effects of weaning age on life-history traits in rats, we repeatedly measured length and body mass index (BMI), as well as physiological development and sexual maturation in pups weaned early (d16), normally (d21) or late (d26). Males were bred to females of the same weaning age group for four generations. RESULTS: Here, we show that the age at weaning from lactation regulates a rat's life history, growth, body composition and maturational tempo. We show that early weaned rats developed faster than normal- or late-weaned rats; they are leaner and longer than late-weaned ones who are heavier and shorter. Early-weaned progeny develop more rapidly (that is, fur budding, pinnae detachment, eye opening); females show earlier vaginal opening and estrous and males show earlier onset of testicular growth. In generations 3 and 4, early-weaned rats bear larger litter sizes and heavier newborn pups. The entire traits complex is transmitted to subsequent generations from the paternal side. CONCLUSIONS: The findings presented here lend support to the proposition that the duration of infancy, as indexed by weaning age, predicts and perhaps programs growth, body composition, and the tempo of physiological development and maturation, as well as litter size and parity and, thereby, reproductive strategy. PMID- 23627912 TI - Autonomic neuropathy in young people with type 1 diabetes: a systematic review. AB - Autonomic neuropathy is an under-recognized complication of diabetes, although it affects multiple organ systems and has widespread clinical manifestations including orthostatic hypotension, exercise intolerance, gastroparesis, diarrhea, constipation, and urinary incontinence. The most severe consequences include hypoglycemia unawareness and cardiovascular dysfunction. Autonomic neuropathy is also implicated in sudden unexplained deaths in otherwise healthy young people- the 'dead in bed syndrome'. In adults, cardiovascular autonomic neuropathy is an independent predictor of mortality, predominantly due to cardiovascular disease, nephropathy, and hypoglycemia. While overt autonomic neuropathy is rare in childhood and adolescence, subclinical signs of autonomic dysfunction are common, and can be found soon after diabetes diagnosis. Risk factors for autonomic neuropathy in young people include diabetes duration, poor glycemic control, and presence of aldose reductase gene (AKR1B1) polymorphisms, specifically the Z-2/Z 2 genotype. Autonomic dysfunction is accelerated by puberty. PMID- 23627913 TI - A case of granular cell tumor masquerading as a keratoacanthoma. PMID- 23627914 TI - Glycogen phosphorylase inhibitors: a patent review (2008 - 2012). AB - INTRODUCTION: Glycogen phosphorylase (GP) is the enzyme responsible for the synthesis of glucose-1-phosphate, the source of energy for muscles and the rest of the body. The binding of different ligands in catalytic or allosteric sites assures activation and deactivation of the enzyme. A description of the regulation mechanism and the implications in glycogen metabolism are given. AREAS COVERED: Deregulation of GP has been observed in diseases such as diabetes mellitus or cancers. Therefore, it appears as an attractive therapeutic target for the treatment of such pathologies. Numbers of inhibitors have been published in academic literature or patented in the last two decades. This review presents the main patent claims published between 2008 and 2012. EXPERT OPINION: Good inhibitors with interesting IC50 and in vivo results are presented. However, such therapeutic strategy raises questions and some answers are proposed to bring new insights in the field. PMID- 23627915 TI - Janus kinase inhibition with tofacitinib: changing the face of inflammatory bowel disease treatment. AB - The advent of anti-Tumor Necrosis Factor (TNF) therapy has changed the way of treating inflammatory bowel disease (IBD). However, primary and secondary failure are relatively frequent with all anti-TNF agents, which are available only as parenteral agents. Tofacitinib is an oral janus kinase (JAK) inhibitor that inhibits JAK family kinase members, in particular JAK1 and JAK3, achieving a broad limitation of inflammation by interfering with several cytokine receptors. It first proved its efficacy as an immunosuppressive regimen after renal transplantation, and was recently approved by the FDA for rheumatoid arthritis. First data in IBD are promising, especially in ulcerative colitis. Ongoing clinical trials in both UC and Crohn's disease (CD) are needed to further explore its efficacy in CD and to better assess its safety profile. PMID- 23627916 TI - Perioperative handling of antiplatelet drugs. A critical appraisal. AB - Because of more and more accurate cardiovascular prevention programs and the increasing mean age of the general population, the use of antiplatelet treatments is progressively increasing in the last years. Moreover, the wide-spread use of bare-metal stents (BMS) and drug-eluting stents (DES) significantly increased the number of subjects with the need of a combined antiplatelet treatment: Aspirin (ASA) and Clopidogrel (CLO. Within the first year after coronary stenting, approximately 5% of patients needs to undergo non-cardiac surgery interventions. In such patients, current guidelines suggest to stop antiplatelet agents 7-10 days before surgery to avoid the risk of increasing blood loss. On the other hand, it has been shown that the risk of surgical bleeding, if antiplatelet drugs are continued, is lower than that of coronary thrombosis if they are withdrawn. Thus, an accurate stratification of the population according to the thrombotic risk is needed and the bleeding and the thrombotic risk should be considered in parallel. Although a growing amount of recommendations have been released by several Societies, the perioperative handling of antiplatelet drugs still represents a major concern in clinical practice. In this review we report the major literature data about the perioperative handling of antiplatelet drugs. Moreover, in order to describe future treatment perspectives and to identify valuable alternatives to current antiplatelet agents in the perioperative period, pharmacokinetic and pharmacodynamic characteristics of newer antiplatelet drugs are reported and analyzed. PMID- 23627917 TI - Inhomogeneous dose escalation increases expected local control for NSCLC patients with lymph node involvement without increased mean lung dose. AB - BACKGROUND: Higher doses to NSCLC tumours are required to increase the low control rates obtained with conventional dose prescriptions. This study presents the concept of inhomogeneous dose distributions as a general way to increase local control probability, not only for isolated lung tumours but also for patients with involved lymph nodes. MATERIAL AND METHODS: Highly modulated IMRT plans with homogeneous dose distributions with a prescribed dose of 66Gy/33F were created for 20 NSCLC patients, staged T1b-T4 N0-N3, using standard PTV dose coverage of 95-107%. For each patient, an inhomogeneous dose distribution was created with dose constraints of: PTV-coverage >= 95%, same mean lung dose as obtained in the homogeneous dose plan, maximum doses of 45 and 66 Gy to spinal canal and oesophagus, respectively, and V74Gy < 1 cm(3) for each of: aorta, trachea + bronchi, the connective tissue in mediastinum, and the thorax wall. The dose was escalated using a TCP model implemented into the planning system. The difference in TCP values between the homogeneous and inhomogeneous plans were evaluated using two different TCP models. RESULTS: Dose escalation was possible for all patients. TCP values based on assumed homogeneous distribution of clonogenic cells either in the GTV, CTV or PTV showed absolute TCP increases of approximately 15, 10 and 5 percentage points, respectively. This increase in local control was obtained without increasing the mean lung dose. However, small increases in maximum doses to the mediastinum were observed: 2.5 Gy for aorta, 4.4 Gy for the connective tissue, 1.6 Gy for the heart, and 2.6 Gy for trachea + bronchi. CONCLUSION: Increased target doses and TCP values using inhomogeneous dose distributions could be achieved for all patients, regardless of lymph node involvement, tumour stage, location, and size. These new treatment plans have the potential to increase the local tumour control by 10-15 percentage points without compromising the clinically acceptable lung toxicity level. PMID- 23627918 TI - Heptacoordinated molybdenum(VI) complexes of phenylenediamine bis(phenolate): a stable molybdenum amidophenoxide radical. AB - The syntheses, crystallographic structures, magnetic properties, and theoretical studies of two heptacoordinated molybdenum complexes with N,N'-bis(3,5-di-tert butyl-2-hydroxyphenyl)-1,2-phenylenediamine (H4N2O2) are reported. A formally molybdenum(VI) complex [Mo(N2O2)Cl2(dmf)] (1) was synthesized by the reaction between [MoO2Cl2(dmf)2] and H4N2O2, whereas the other molybdenum(VI) complex [Mo(N2O2)(HN2O2)] (2) was formed when [MoO2(acac)2] was used as a molybdenum source. Both complexes represent a rare case of the Mo(VI) ion without any multiply bonded terminal ligands. In addition, molecular structures, magnetic measurements, ESR spectroscopy, and density functional theory calculations indicate that complex 2 is the first stable molybdenum(VI) amidophenoxide radical. PMID- 23627919 TI - A tree house. PMID- 23627921 TI - A high blood level in the venous chamber and a wet-stored dialyzer help to reduce exposure for microemboli during hemodialysis. AB - During hemodialysis (HD), microemboli develop in the blood circuit of the apparatus. These microemboli can pass through the venous chamber and enter into the patient's circulation. The aim of this study was to investigate whether it is possible to reduce the risk for exposure of microemboli by altering of the treatment mode. Twenty patients on chronic HD were randomized to a prospective cross-over study of three modes of HD: (a) a dry-stored dialyzer (F8HPS, Fresenius, steam sterilized) with a low blood level in the venous chamber (DL), (b) the same dialyzer as above, but with a high level in the venous chamber (DH), and (c) a wet-stored dialyzer (Rexeed, Asahi Kasei Medical, gamma sterilized) with a high blood level (WH). Microemboli measurements were obtained in a continuous fashion during 180 minutes of HD for all settings. A greater number of microemboli were detected during dialysis with the setting DL vs. WH (odds ratio [OR] 4.07, 95% confidence interval [CI] 4.03-4.11, P<0.0001) and DH vs. WH (OR 1.18, 95% CI 1.17-1.19, P<0.0001) and less for DH vs. DL (OR 0.290, 95% CI 0.288 0.293, P<0.0001). These data indicate that emboli exposure was least when using WH, greater with DH, and most with DL. This study shows that using a high blood level in the venous chamber and wet-stored dialyzers may reduce the number of microemboli. PMID- 23627920 TI - Azacitidine in patients with WHO-defined AML - results of 155 patients from the Austrian Azacitidine Registry of the AGMT-Study Group. AB - OBJECTIVE: The Austrian Azacitidine Registry is a multi-center database (ClinicalTrials.gov: NCT01595295). The nature and intent of the registry was to gain a comprehensive view of the use, safety and efficacy of the drug in a broad range of AML-patients treated in real-life scenarios. PATIENTS AND METHODS: The sole inclusion criteria were the diagnosis of WHO-AML and treatment with at least one dose of azacitidine. No formal exclusion criteria existed. A total of 155 AML patients who were mostly unfit/ineligible for intensive chemotherapy, or had progressed despite conventional treatment, were included. True ITT-analyses and exploratory analyses regarding the potential prognostic value of baseline variables/performance-/comorbidity-/risk-scores on overall survival (OS), were performed. RESULTS: In this cohort of 155 pretreated (60%), and/or comorbid (87%), elderly (45% >=75 years) AML-patients, azacitidine was well tolerated and efficacious, with an overall response rate (CR, mCR, PR, HI) of 45% in the total cohort (ITT) and 65% in patients evaluable according to IWG-criteria, respectively. Pre-treatment with conventional chemotherapy (P = .113), age <=/>80 years (P = .853), number of comorbidities (P = .476), and bone marrow (BM) blast count (P = .663) did not influence OS. In multivariate analysis hematologic improvement alone (without the requirement of concomitant bone marrow blast reduction), although currently not regarded as a standard form of response assessment in AML, was sufficient to confer OS benefit (18.9 vs. 6.0 months; P = .0015). Further deepening of response after first response was associated with improved OS (24.7 vs. 13.7 months; P < .001). CONCLUSIONS: In this large cohort of AML-patients treated with azacitidine, age >80 years, number of comorbidities and/or BM-blasts >30% did not adversely impact OS. PMID- 23627922 TI - Robotic-assisted intracorporeal anastomosis versus extracorporeal anastomosis in laparoscopic right hemicolectomy for cancer: a case control study. AB - INTRODUCTION: Extracorporeal ileocolic anastomosis in laparoscopic right hemicolectomy for cancer has a significant risk of complications. The aim of this study is to evaluate the operative and postoperative results of hybrid right hemicolectomy with intracorporeal robotic-assisted anastomosis for adenocarcinoma of the ascending colon compared with the standard extracorporeal anastomosis in a case control study. PATIENTS AND METHODS: Forty-eight right hemicolectomies for cancer (2009-2012) with laparoscopic medial to lateral dissection, vascular ligation, bowel transection, and robotic-assisted intracorporeal anastomosis with specimen extraction through a Pfannestiel incision (robotic group [RG]) were compared with 48 laparoscopic hemicolectomies (2009-2011) with extracorporeal anastomosis (laparoscopic group [LG]). RESULTS: The two groups were comparable with respect to age, gender, stage of cancer, and body mass index. Surgery time was significantly longer in RG patients (RG, 266+/-41 minutes; LG, 223+/-51 minutes; P<.05). Operative results were similar in the two groups. Recovery of bowel function (day of first bowel movement: RG, 3.0+/-1.0 days; LG, 4.0+/-1.2 days; P<.05) and hospital stay (RG, 7.5+/-2.0 days; LG, 9.0+/-3.2 days; P<.05) were quicker and shorter, respectively, in RG. There were four anastomotic complications and four incisional hernias in LG and none in RG (P<.05). CONCLUSIONS: There are fewer anastomotic and wound complications in RG patients. Intracorporeal robotic-assisted ileocolic anastomosis allows a faster recovery compared with extracorporeal anastomosis. PMID- 23627923 TI - Voluminous "cobra-head" stone in a duplex system ureterocele: combined cysto ureteroscopic and percutaneous cystolithotomy approach. AB - We report a case of a 7-year-old boy with a voluminous 8.5-cm "cobra-head" calculus in a duplex system ureterocele causing flank pain, hematuria, and infection. Combined cysto-ureteroscopy and percutaneous cystolithotomy enables dependent ureterocele incision along its inferolateral border and efficient stone clearance in a single minimally invasive procedure. Protracted and repeated urethral instrumentation is avoided. PMID- 23627924 TI - A high-fibre bean-rich diet versus a low-carbohydrate diet for obesity. AB - BACKGROUND: High-fibre and low-carbohydrate diets may enhance satiety and promote weight loss. We compared a diet rich in beans aiming to increase dietary fibre and promote weight loss with a low-carbohydrate diet in a randomised controlled trial to assess effect and tolerability of the high-fibre bean-rich diet. METHODS AND RESULTS: One hundred and seventy-three women and men, with a mean body mass index of approximately 36 kg m(-2) (one-fifth with diabetes type 2) were randomised to a high-fibre bean-rich diet that achieved mean (SD) fibre intakes of 35.5 (18.6) g day(-1) for women and 42.5 (30.3) g day(-1) for men, or a low carbohydrate diet. Both diets were induced gradually over 4 weeks and included a 3-day feeding phase. Among 123 (71.1%) completers at 16 weeks, mean (SD) weight loss was 4.1 (4.0) kg in the high-fibre versus 5.2 (4.5) kg in the low carbohydrate group [difference, 1.1 kg, 95% confidence interval (CI) = -2.6 to 0.5; P = 0.2], with results similar to the intent-to-treat population. Low density lipoprotein (LDL)-cholesterol levels decreased with the high-fibre diet (difference in LDL-cholesterol versus low-carbohydrate diet, 0.2 mmol L(-1) , 95% CI = 0.01-0.44 mmol L(-1) ; P = 0.045), as did total cholesterol (P = 0.038), whereas changes in other lipids and glucose did not differ. After 52 weeks, the low-carbohydrate (n = 24) group tended to retain weight loss better than the high fibre group (P = 0.06), although total cholesterol remained lower with the bean rich diet (P = 0.049). CONCLUSIONS: A high-fibre bean-rich diet was as effective as a low-carbohydrate diet for weight loss, although only the bean-rich diet lowered atherogenic lipids. PMID- 23627925 TI - Change in quality of life: a follow up study among patients with HIV infection with and without TB in Ethiopia. AB - BACKGROUND: There is a dearth of literature on the impact of TB/HIV co-infection on quality of life (QoL). We conducted a study to assess the change in QoL over a 6-months period and its predictors among HIV-infected patients with and without TB in Ethiopia. METHODS: 465 HIV-infected patients without TB and 124 TB/HIV co infected patients were enrolled in a prospective study in February, 2009. 455 (98%) HIV-infected and 97 (78%) TB/HIV co-infected patients were followed for 6 months. Data on QoL at baseline and 6th month were collected by trained nurses through face to face interviews using the short Amharic version of the World Health Organization Quality of Life Instrument for HIV clients (WHOQOL HIV Brief). Common Mental Disorder (CMD) was assessed using a validated version of the Kessler-10 scale. Multivariate analysis was conducted using generalized estimating equations (GEE) using STATA to assess change in QoL and its predictors. RESULTS: There was a statistically significant improvement of the physical, psychological, social, environmental and spiritual QoL at the 6th months follow up compared to the baseline for both groups of patients (P < 0.0001). The change in QoL in all dimension were more marked for TB/HIV co infected patients compared to HIV-infected patients without TB.A severe form of CMD was strongly associated with poorer physical QoL among TB/HIV co-infected individuals (beta = -2.84; P = 0.000) and HIV clients without TB (beta = -2.34; P = 0.000). CONCLUSION: This study reveals that ART and anti-TB treatment significantly improve the QoL particularly among TB/HIV co-infected patients. We recommend that the ministry of health in collaboration with partners shall integrate mental health services into the TB/HIV programs and train health care providers to timely identify and treat CMD to improve QoL. PMID- 23627927 TI - Pre-processing, registration and selection of adaptive optics corrected retinal images. AB - PURPOSE: In this paper, the aim is to demonstrate enhanced processing of sequences of fundus images obtained using a commercial AO flood illumination system. The purpose of the work is to (1) correct for uneven illumination at the retina (2) automatically select the best quality images and (3) precisely register the best images. METHODS: Adaptive optics corrected retinal images are pre-processed to correct uneven illumination using different methods; subtracting or dividing by the average filtered image, homomorphic filtering and a wavelet based approach. These images are evaluated to measure the image quality using various parameters, including sharpness, variance, power spectrum kurtosis and contrast. We have carried out the registration in two stages; a coarse stage using cross-correlation followed by fine registration using two approaches; parabolic interpolation on the peak of the cross-correlation and maximum likelihood estimation. The angle of rotation of the images is measured using a combination of peak tracking and Procrustes transformation. RESULTS: We have found that a wavelet approach (Daubechies 4 wavelet at 6th level decomposition) provides good illumination correction with clear improvement in image sharpness and contrast. The assessment of image quality using a 'Designer metric' works well when compared to visual evaluation, although it is highly correlated with other metrics. In image registration, sub-pixel translation measured using parabolic interpolation on the peak of the cross-correlation function and maximum likelihood estimation are found to give very similar results (RMS difference 0.047 pixels). We have confirmed that correcting rotation of the images provides a significant improvement, especially at the edges of the image. We observed that selecting the better quality frames (e.g. best 75% images) for image registration gives improved resolution, at the expense of poorer signal-to-noise. The sharpness map of the registered and de-rotated images shows increased sharpness over most of the field of view. CONCLUSION: Adaptive optics assisted images of the cone photoreceptors can be better pre-processed using a wavelet approach. These images can be assessed for image quality using a 'Designer Metric'. Two stage image registration including correcting for rotation significantly improves the final image contrast and sharpness. PMID- 23627926 TI - Multicenter comparison of PEG-IFN alpha2a or alpha2b plus ribavirin for treatment naive HCV patient in Korean population. AB - BACKGROUND: Two recent Italian studies suggested that Pegylated-interferon (PEG IFN) alfa-2a achieves a higher sustained virological response (SVR) rate than PEG IFN alfa-2b. We intended to compare the efficacy and safety of PEG-IFN alfa-2a with those of PEG-IFN alfa-2b in Korean patients with chronic hepatitis C virus (HCV). METHODS: This retrospective, multi-center trial was conducted on 661 treatment-naive chronic HCV patients. Patients received PEG-IFN alfa-2a (180 MUg/week; n=402) or PEG-IFN alfa-2b (1.5 MUg/kg/week; n=259) with ribavirin (800 1200 mg/day) for 24 or 48 weeks according to HCV genotypes. RESULTS: Early virologic response and sustained virologic response (SVR) rates were not significantly different between two PEG-IFN groups both in patients with HCV genotype 1 (all P-values>0.05) and 2/3 (all P-values>0.05). SVR rates were not different between two groups in each categorized baseline characteristics: age (years) (<= 50 and >50), HCV viral load (IU/mL) (<= 7 * 10(5) and >7 * 10(5)), and hepatic fibrosis (F0-2 and F3-4) (all P-values >0.05). In additional analysis for 480 patients who sufficiently complied with treatment doses and duration (80/80/80 rule) and propensity-score matched analysis, SVR rates were not different between two groups both in patients with HCV genotype 1 and 2/3 (all P values >0.05). Adverse event rates were similar between two groups. CONCLUSIONS: Unlike the Western data, efficacy and safety of PEG-IFN alfa-2a were similar to those of PEG-IFN alfa-2b in chronically HCV-infected Korean patients regardless of age, HCV viral load, and hepatic fibrosis. PMID- 23627928 TI - Seroepidemiology of predominant norovirus strains circulating in Korea by using recombinant virus-like particle antigens. AB - An epidemiological survey on human norovirus (NoV)-associated gastroenteritis was conducted to clarify the prevalence of NoV infections in children and adults in Korea. Recombinant capsid proteins from three major NoV genotypes (GI-4, GII-3, and GII-4) were expressed using a baculovirus expression system, and the morphology and antigenicity of self-assembled virus-like particles were then confirmed by electron microscopy and Western blotting with a NoV-specific antibody. To determine seroprevalence, an enzyme-linked immunosorbent assay was performed to detect antibodies against virus-like particles antigen in 346 serum specimens collected from persons who visited five public heath care centers for regular physical examination in Jeollanam-do, Korea, between 2005 and 2006. The seroprevalence of immunoglobulin G antibodies against the GI-4, GII-3, and GII-4 NoV genotypes was 84.1%, 76.3%, and 94.5%, respectively. A rapid decrease in seroprevalence occurred after birth, with the lowest levels observed in the <23 month age group, and a steep increase in seroprevalence occurred in early childhood, reaching 60.5% for GI-4, 65.1% for GII-3, and 90.7% for GII-4 at age 2 5 years, and over 80% for all three genotypes in subjects aged 20 years or older. The seroprevalence of different NoV genotypes statistically differed across the age groups (p<0.01). PMID- 23627929 TI - Growth of a pYV-bearing Yersinia pestis KIM5 in retail raw ground pork. AB - Yersinia pestis can cause oropharyngeal plague as a result of consumption or handling of meat from infected animals. Thus, food naturally or intentionally contaminated can have a role in the dissemination of oropharyngeal plague. The growth of a conditionally virulent pYV-bearing rifampicin-resistant Y. pestis KIM5 (rif-Y. pestis KIM5) in retail raw ground pork (RGP) was studied at temperatures ranging from 4 to 30 degrees C. At 4 degrees C, rif-Y. pestis KIM5 did not grow but survived. In RGP, rif-Y. pestis KIM5 grew at refrigerated temperatures of 10 and 15 degrees C with growth rates of 0.05 and 0.16 log(10) colony-forming units (CFU)/h. The growth rates at abusive temperatures of 20, 25, and 30 degrees C were 0.26, 0.30, and 0.77 log(10) CFU/h. The growth rate was increased 15.4-fold with the increase of storage temperatures from 10 degrees C to 30 degrees C. The maximum population density ranged from 6.76 to 8.66 log(10) CFU/g. Furthermore, there was no detectable loss of pYV in surviving rif-Y. pestis KIM5 at any of the temperatures tested in retail RGP. This suggests that under these conditions, Y. pestis could cause oropharyngeal plague if the meat was not properly cooked. The individual infected by Y. pestis in food is a potential reservoir who can infect others, leading to outbreaks of plague. PMID- 23627930 TI - Protein oxidation at different salt concentrations affects the cross-linking and gelation of pork myofibrillar protein catalyzed by microbial transglutaminase. AB - In a fabricated then restructured meat product, protein gelation plays an essential role in producing desirable binding and fat-immobilization properties. In the present study, myofibrillar protein (MFP) suspended in 0.15, 0.45, and 0.6 M NaCl was subjected to hydroxyl radical stress for 2 or 24 h and then treated with microbial transglutaminase (MTGase) in 0.6 M NaCl (E : S = 1 : 20) at 4 and 15 degrees C for 2 h. Protein cross-linking and dynamic rheological tests were performed to assess the efficacy of MTGase for mediating the gelation of oxidized MFP. MTGase treatments affected more remarkable polymerization of myosin in oxidized MFP than in nonoxidized, especially for samples oxidized at 0.6 M NaCl. Notably, the extent of MTGase-induced myosin cross-linking at 15 degrees C in oxidized MFP improved up to 46.8%, compared to 31.6% in nonoxidized MFP. MTGase treatment at 4 degrees C for MFP oxidized in 0.6 M NaCl, but not MFP oxidized in 0.15 M NaCl, produced stronger gels than nonoxidized MFP (P < 0.05). The final (75 degrees C) storage modulus (G') of oxidized MFP gels was significantly greater than that of nonoxidized, although the G' of the transient peak (~44.5 degrees C) showed the opposite trend. Overall, oxidation at high salt concentrations significantly improved MTGase-mediated myosin cross-linking and MFP gelation. This might be because under this condition, MTGase had an increased accessibility to glutamine and lysine residues to effectively initiate protein protein interactions and gel network formation. PMID- 23627931 TI - Laser earlobe revision. AB - BACKGROUND: Earlobe tears and disfigurement often result from prolonged pierced earring use and trauma. They are a common cosmetic complaint for which surgical reconstruction has often been advocated. MATERIALS AND METHODS: A series of 10 patients with earlobe tears or disfigurement treated using straight-line closure, carbon dioxide (CO2 ) laser ablation, or both are described. A succinct literature review of torn earlobe repair is provided. RESULTS: Successful repair with excellent cosmesis of torn and disfigured earlobes was obtained after straight-line surgical closure, CO2 laser ablation, or both. CONCLUSION: A minimally invasive earlobe repair technique that involves concomitant surgical closure and CO2 laser skin vaporization produces excellent cosmetic results for torn or disfigured earlobes. PMID- 23627932 TI - Glaucomatous cupping and raised IOP: sine qua non for glaucoma? AB - PURPOSE: To present selected cases that highlight the confusions in daily glaucoma practice. METHODS: Four cases with raised or normal intraocular pressure (IOP) and definite glaucomatous cupping were investigated. RESULTS: While raised IOP was found in non-glaucomatous etiologies, IOP was normal in established glaucoma in a young patient. CONCLUSION: Raised IOP and glaucomatous cupping may not be pathognomonic of glaucoma and alternative etiology should be ruled out for appropriate management. PMID- 23627933 TI - Immunosenescence and gender: a study in healthy Cubans. AB - BACKGROUND: The progressive decline in the immune function during ageing is termed immunosenescence. Previous studies have reported differences between males and females in the distribution and cell responses of lymphocyte subsets. Most studies of immunosenescence have been done in populations of industrialized countries living in a rather cold environment, and facing lower antigenic challenges such as Cytomegalovirus (CMV). The aim of this study was to determine the effect of ageing on lymphocytes in a population with a high prevalence of CMV infection in all ages, and to compare gender differences related to the immunosenescence markers. RESULTS: Different populations of peripheral blood leukocytes from healthy young and old IgG-CMV seropositive individuals were examined using flow cytometry. With age, the number and frequency of B cells and T cells significantly decreased, while highly differentiated T cells increased. Such changes were different in males and females. The age-associated decline of less differentiated lymphocyte subsets (CD19, CD4 and CD8 cells) and the increase of highly differentiated T cells were more prominent in females. In males, there were no significant changes in CD19, CD4 and CD8 subsets but there was a significant increase in the proportion of highly differentiated T cells. CONCLUSION: Shifts in lymphocyte subsets distribution were influenced by age and gender in an IgG-CMV seropositive population. These results suggest different patterns of immunosenescence in respect to gender differences. These patterns could have implications in the design of immunotherapy in the elderly. PMID- 23627935 TI - Flavonoids in atherosclerosis: an overview of their mechanisms of action. AB - Polyphenols are composed of a wide variety of molecules that are classified into several categories, according to their chemical type such as phenolic acids, flavonoids, stilbenes, and lignans. Many studies have proven the beneficial effects of flavonoids in atherosclerosis progression and cardiovascular disease. Dietary flavonoids reduce oxidative stress and exert anti-inflammatory actions. Moreover, flavonoids have the ability to avoid the thrombus formation, improve endothelial function, modify lipid levels and regulate glucose metabolism. In the context of this evidence in this review article we summarize the so far acquired knowledge of the most important mechanisms of action of flavonoids in atherosclerosis progression. PMID- 23627934 TI - Functionalized mesoporous silica nanoparticles: a possible strategy to target cancer cells reducing peripheral nervous system uptake. AB - Mesoporous silica materials (MSM) have been proposed as promising tools for cell specific drug delivery or fluorescent cell tracking. In cancer therapy there is an urgent need to develop a cancer cell specific drug carrier able to limit the non-specific uptake of the drug by normal cells thereby reducing serious side effects. Chemotherapy induced peripheral neurotoxicity (CIPN) is one of the most clinically relevant side effects linked to the use of several antineoplastic drugs. In this study we showed that the uptake of MSM (synthesized using a PEG surfactant-based interfacial synthesis procedure), functionalised with folic acid (MSM-FOL) after 1, 6 and 24 hours is very limited in neuronal-like cellular systems such as differentiated SH-SY5Y human neuroblastoma cells and rat embryonic dorsal root ganglia sensory neurons. By contrast, the nanoparticles are highly internalized in A549 and IGROV-1 cancer cells. The 6 hour-treatment of A549 and IGROV-1 cells with nanoparticles loaded with the antineoplastic drug cisplatin (CP) induced significant cytotoxicity with respect to CP alone. These results were observed treating IGROV-1 cells with 25 and 50 MUg/ml nanoparticles doses (corresponding respectively to CP 6.25 and 12.5 MUM) and treating A549 with 50 MUg/ml.Our results demonstrated a selective uptake of functionalized MSM suggesting them as promising tools for targeted antineoplastic therapy. Further studies will be necessary in order to confirm if this approach may be useful in reducing neurotocity of anticancer drugs. PMID- 23627936 TI - Nanoparticles loaded with Nutlin-3 display cytotoxicity towards p53(wild-type) JVM-2 but not towards p53(mutated) BJAB leukemic cells. AB - The small molecule Nutlin-3 is a potent antagonist of the murine double minute 2 (MDM2)/p53 interaction exhibiting promising therapeutic anti-cancer activity. Nutlin-3 has been proposed as an anti-neoplastic agent for the treatment of onco hematological diseases characterized by a lower incidence of p53 mutation with respect to solid tumors. Indeed, based on its selective non-genotoxic p53 activation, Nutlin-3 might represent an alternative to the current cytotoxic chemotherapy. To overcome the poor bioavailability of Nutlin-3, we have assessed the potential efficacy of Nutlin-3 loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NP) against hematological malignancies. To test the specificity of the anti-leukemic activity, we have used leukemic cell lines characterized by different p53 status (JVM-2 and BJAB). NP loaded with Nutlin-3 (NP-Nutlin) were rapidly taken up by the leukemic cells and were as effective as native Nutlin-3 in promoting both induction of apoptosis and cell cycle arrest in p53(wild-type) JVM-2 cells, but not in p53(mutated) BJAB cells. Moreover, injection of NP Nutlin, but not of free Nutlin-3, in a JVM-2-derived xenograft mouse model, reduced the subcutaneous tumor volume and promoted induction of apoptosis in the tumor mass. Overall, the chemical and structural characteristics of the NP-Nutlin 3, as well as their biological activity in vitro and in vivo, made them promising for further preclinical evaluations as potentially useful anti-leukemic carriers. PMID- 23627937 TI - Capsaicin and its analogues: structure-activity relationship study. AB - Capsaicin, the main ingredient responsible for the hot pungent taste of chilli peppers, is an alkaloid found in the Capsicum family. Capsaicin was traditionally used for muscular pain, headaches, to improve circulation and for its gastrointestinal protective effects. It was also commonly added to herbal formulations because it acts as a catalyst for other herbs and aids in their absorption. In addition, capsaicin and other capsaicinoid compounds showed strong evidence of having promising potential in the fight against many types of cancer. The mechanism of action of capsaicin has been extensively studied over the past decade. It has been established that capsaicin binds to the transient receptor potential vanilloid 1 receptor which was expressed predominantly by sensory neurons. And many analogues of capsaicin have been synthesized and evaluated for diverse bioactivities. In this review, we will attempt to summarize the biology and structure-activity relationship of capsaicinoids. PMID- 23627938 TI - The fate of nanocarriers as nanomedicines in vivo: important considerations and biological barriers to overcome. AB - Many pharmaceuticals on the market suffer from two significant limitations to their activity: lack of specificity toward the pathological site and poor aqueous solubility. Both factors therefore require the application of a large total dose of a drug to achieve high local concentration, causing numerous off-target toxic effects. Consequently, the grand aim of targeted drug delivery - the often referred "magic bullet" - promises to improve drug concentration at the target site and maximize therapeutic response. Nanomaterial drug delivery systems have been explored extensively in the recent years for just this purpose. In the field of medicine, nanocarriers (NCs) have the potential to improve the biodistribution and pharmacokinetic characteristics of drugs, thereby reducing side effects while improving the therapeutic effect of drugs. Many nanomaterials are exquisitely designed and possess potent properties, yet it is extremely important to note that a general understanding of the interaction of nanomaterials with biological systems is essential for any such model properties to be effective in vivo, since the body presents a host of biological 'barriers' that will be encountered drug NCs. This review offers a general overview of the different biological obstacles that a NC must negotiate before it can carry out its desired role as a medicinal agent. From this standpoint we suggest aspects that should be considered for the rational design of novel nanomaterials possessing physicochemical properties that are appropriate for therapeutic or theragnostic applications. PMID- 23627939 TI - Hypoxia inducible factor stabilization as a novel strategy to treat anemia. AB - Anemia, one of the most common blood disorders, globally affecting ~1.62 billion people, occurs when the level of healthy red blood cells (RBCs) or/and hemoglobin in the body becomes too low. It can cause a variety of complications to human body, some of which are potentially very serious and carry significant risk factors, thus representing a big burden for social and economic development. Current therapeutic methods are efficient in controlling this disease but associated with many problematic issues. One way to circumvent these issues is by targeting HIF-PH (Hypoxia inducible factor prolyl hydroxylases) pathway. HIF is an oxygen-sensitive transcription factor that enables aerobic organisms to adapt to hypoxia through the transcriptional activation of up to 200 genes, many of which are critical to cell survival. Experimental and clinical studies have demonstrated that stabilization of HIF can up-regulate erythropoietin (EPO) expression and in turn increase count of RBCs potentially without causing drug resistance and cardiovascular diseases commonly seen with other therapies, rendering HIF stabilization a promising way to treat anemia. In this review, we highlight the biology of HIF-PH pathway, as well as the recent advances of HIF stabilizers of a natural or synthetic origin and concerns regarding drug development in this field. PMID- 23627940 TI - Pharmacological inhibition of protein tyrosine phosphatase 1B: a promising strategy for the treatment of obesity and type 2 diabetes mellitus. AB - Obesity and metabolic syndrome represent major public health problems, and are the biggest preventable causes of death worldwide. Obesity is the leading risk factor for type 2 diabetes mellitus (T2DM), cardiovascular diseases and non alcoholic fatty liver disease. Obesity-associated insulin resistance, which is characterized by reduced uptake and utilization of glucose in muscle, adipose and liver tissues, is a key predictor of metabolic syndrome and T2DM. With increasing prevalence of obesity in adults and children, the need to identify and characterize potential targets for treating metabolic syndrome is imminent. Emerging evidence from animal models, clinical studies and cell lines studies suggest that protein tyrosine phosphatase 1B (PTP1B), an enzyme that negatively regulates insulin signaling, is likely to be involved in the pathways leading to insulin resistance. PTP1B is tethered to the cytosolic surface of endoplasmic reticulum (ER), an organelle that is responsible for folding, modification, and trafficking of proteins. Recent evidence links the disruption of ER homeostasis, referred to as ER stress, to the pathogenesis of obesity and T2DM. PTP1B has been recognized as an important player linking ER stress and insulin resistance in obese subjects. This review highlights recent advances in the research related to the role of PTP1B in signal transduction processes implicated in pathophysiology of obesity and type 2 diabetes, and focuses on the potential therapeutic exploitation of PTP1B inhibitors for the management of these conditions. PMID- 23627941 TI - An overview on natural polysaccharides with antioxidant properties. AB - Pharmacotherapy using natural substances can be currently regarded as a very promising future alternative to conventional therapy. With the rapid development of biotechnologies and analytical techniques, a great number of methods have been developed for the identification and quantification of the material, extracts, and products of natural ingredients. The advances available today. The need for safer drugs without side effects has led to the use of natural ingredients with proven safety. In recent years, some bioactive polysaccharides isolated from natural sources have attracted much attention in the field of biochemistry and pharmacology. As an example, polysaccharides or their glycoconjugates were shown to exhibit multiple biological activities including anticarcinogenic, anticoagulant, immunostimulating, antioxidant, etc. During the last several years, we have witnessed a steady expansion in the number of publications that focus in antioxidant polysaccharides. This review presents current findings on the latest advancements and trends in antioxidant polysaccharides isolated from the following: plants, fungi, bacteria, animal sources, and algae. Some interesting studies focus on investigation of the relationship between their structure and antioxidant activity, elucidation of their antioxidant mechanism at the molecular level, and improvement of their various biological activities by chemical modifications. Although the mechanism of their antioxidant action is still not completely clear, these polysaccharides are suggested to enhance cell mediated immune responses in vivo and in vitro and act as biological response modifiers. PMID- 23627942 TI - Perovskite-structured PbTiO3 thin films grown from a single-source precursor. AB - Perovskite-structured lead titanate thin films have been grown on FTO-coated glass substrates from a single-source heterometallic molecular complex, [PbTi(MU2 O2CCF3)4(THF)3(MU3-O)]2 (1), which was isolated in quantitative yield from the reaction of tetraacetatolead(IV), tetrabutoxytitanium(IV), and trifluoroacetic acid from a tetrahydrofuran solution. Complex 1 has been characterized by physicochemical methods such as melting point, microanalysis, FTIR, (1)H and (19)F NMR, thermal analysis, and single-crystal X-ray diffraction (XRD) analysis. Thin films of lead titanate having spherical particles of various sizes have been grown from 1 by aerosol-assisted chemical vapor deposition at 550 degrees C. The thin films have been characterized by powder XRD, scanning electron microscopy, and energy-dispersive X-ray analysis. An optical band gap of 3.69 eV has been estimated by UV-visible spectrophotometry. PMID- 23627943 TI - New perspectives on evolutionary medicine: the relevance of microevolution for human health and disease. AB - Evolutionary medicine (EM) is a growing field focusing on the evolutionary basis of human diseases and their changes through time. To date, the majority of EM studies have used pure theories of hominin macroevolution to explain the present day state of human health. Here, we propose a different approach by addressing more empirical and health-oriented research concerning past, current and future microevolutionary changes of human structure, functions and pathologies. Studying generation-to-generation changes of human morphology that occurred in historical times, and still occur in present-day populations under the forces of evolution, helps to explain medical conditions and warns clinicians that their current practices may influence future humans. Also, analyzing historic tissue specimens such as mummies is crucial in order to address the molecular evolution of pathogens, of the human genome, and their coadaptations. PMID- 23627944 TI - Can friends protect genetically vulnerable children from depression? AB - The study examined whether reciprocal friendship quantity or quality can mitigate genetic vulnerability for depression symptoms in children. The sample comprised 168 monozygotic twin pairs and 126 same-sex dizygotic twin pairs assessed in Grade 4 (mean age = 10.04 years). Friendship participation was measured via reciprocal nominations of close friendships within the classroom. Friendship quality was measured through self-reports. Depression symptoms were measured through teacher and peer reports. Genetic vulnerability for depression symptoms was unrelated to friendship participation or the number of reciprocal friends, but it was negatively related to positive friendship quality. In line with gene environment interaction, genetic risk effects on depression symptoms were mitigated in girls who had at least one close reciprocal friend. In boys, only moderate main effects of genetic vulnerability and friendship participation were found but no interaction between them. However, among boys with at least one reciprocal friend, a greater number of friends was related to fewer depression symptoms whereas no cumulative effect of friendship was found for girls. Finally, positive friendship quality was related to fewer depression symptoms in girls and boys even when controlling for genetic risk. The findings emphasize the importance of teaching social interactional skills that promote high-quality friendship relations to help prevent the development of depression symptoms in children. PMID- 23627945 TI - Gene-environment interaction between dopamine receptor D4 7-repeat polymorphism and early maternal sensitivity predicts inattention trajectories across middle childhood. AB - Evidence suggests that the 7-repeat variant of a 48 base pair variable number tandem repeat polymorphism in the dopamine receptor D4 (DRD4) gene may be associated with the development of attention problems. A parallel literature suggests that genes linked to dopaminergic functioning may be associated with differential sensitivity to context, such that the direction of the genetic effect is hypothesized to vary across environmental experience. Guided by these literatures, we used data from the NICHD Study of Early Child Care and Youth Development to consider (a) whether individual differences in children's inattention problems across middle childhood are predicted by gene-environment interactions between the DRD4 gene 7-repeat polymorphism and children's experiences of maternal sensitivity across infancy and early childhood and (b) the degree to which such interactions are consistent with the differential sensitivity model. Largely consistent with the hypothesized model, gene environment interactions indicated that, in the context of insensitive early maternal care, the DRD4 7-repeat polymorphism was associated with higher levels of inattention. Although somewhat less consistently, there was also evidence that, in the context of highly sensitive care, the 7-repeat polymorphism was associated with lower levels of inattention. Overall, the magnitude of the absolute genetic effect increased over time, as children's inattention trajectories diverged. PMID- 23627946 TI - Hyporesponsiveness to social and nonsocial sensory stimuli in children with autism, children with developmental delays, and typically developing children. AB - This cross-sectional study seeks to (a) describe developmental correlates of sensory hyporesponsiveness to social and nonsocial stimuli, (b) determine whether hyporesponsiveness is generalized across contexts in children with autism relative to controls, and (c) test the associations between hyporesponsiveness and social communication outcomes. Three groups of children ages 11-105 months (N = 178; autism = 63, developmental delay = 47, typical development = 68) are given developmental and sensory measures including a behavioral orienting task (the Sensory Processing Assessment). Lab measures are significantly correlated with parental reports of sensory hyporesponsiveness. Censored regression models show that hyporesponsiveness decreased across groups with increasing mental age (MA). Group differences are significant but depend upon two-way interactions with MA and context (social and nonsocial). At a very young MA (e.g., 6 months), the autism group demonstrates more hyporesponsiveness to social and nonsocial stimuli (with larger effects for social) than developmental delay and typically developing groups, but at an older MA (e.g., 60 months) there are no significant differences. Hyporesponsiveness to social and nonsocial stimuli predicts lower levels of joint attention and language in children with autism. Generalized processes in attention disengagement and behavioral orienting may have relevance for identifying early risk factors of autism and for facilitating learning across contexts to support the development of joint attention and language. PMID- 23627947 TI - Autobiographical memory specificity in child sexual abuse victims. AB - The present study examined the specificity of autobiographical memory in adolescents and adults with versus without child sexual abuse (CSA) histories. Eighty-five participants, approximately half of whom per age group had experienced CSA, were tested on the autobiographical memory interview. Individual difference measures, including those for trauma-related psychopathology, were also administered. Findings revealed developmental differences in the relation between autobiographical memory specificity and CSA. Even with depression statistically controlled, reduced memory specificity in CSA victims relative to controls was observed among adolescents but not among adults. A higher number of posttraumatic stress disorder criteria met predicted more specific childhood memories in participants who reported CSA as their most traumatic life event. These findings contribute to the scientific understanding of childhood trauma and autobiographical memory functioning and underscore the importance of considering the role of age and degree of traumatization within the study of autobiographical memory. PMID- 23627948 TI - Chronic bullying victimization across school transitions: the role of genetic and environmental influences. AB - We investigated the antecedents and consequences of chronic victimization by bullies across a school transition using a genetically sensitive longitudinal design. Data were from the Environmental Risk Longitudinal Twin Study (E-Risk), an epidemiological cohort of 2,232 children. We used mothers' and children's reports of bullying victimization during primary school and early secondary school. Children who experienced frequent victimization at both time points were classed as "chronic victims" and were found to have an increased risk for mental health problems and academic difficulties compared to children who were bullied only in primary school, children bullied for the first time in secondary school, and never-bullied children. Biometric analyses revealed that stability in victimization over this period was influenced primarily by genetic and shared environmental factors. Regression analyses showed that children's early characteristics such as preexistent adjustment difficulties and IQ predicted chronic versus transitory victimization. Family risk factors for chronic victimization included socioeconomic disadvantage, low maternal warmth, and maltreatment. Our results suggest that bullying intervention programs should consider the role of the victims' behaviors and family background in increasing vulnerability to chronic victimization. Our study highlights the importance of widening antibullying interventions to include families to reduce the likelihood of children entering a pathway toward chronic victimization. PMID- 23627950 TI - Mapping developmental trajectories of attention and working memory in fragile X syndrome: developmental freeze or developmental change? AB - Fragile X syndrome (FXS) has a characteristic cognitive "signature" that by late childhood includes core weaknesses in attention and working memory (WM), but their earlier developmental trajectories remain uncharted. Using a combined cross sectional and prospective longitudinal design, we tested whether early profiles of attention and WM impairment in FXS indicate developmental freeze or developmental change. In Study 1, 26 young boys with FXS and 55 typically developing (TD) boys completed two experimental paradigms designed to assess cognitive aspects of attention and WM, in addition to behavioral indices of inattention and hyperactivity. Study 2 mapped longitudinal changes in 21 children with FXS and 21 TD children. In Study 1, significant weaknesses emerged for boys with FXS, with no substantial improvement over chronological age. Mapping performance against mental age level revealed delay, but it also yielded a similar attention and WM profile to TD boys. In Study 2, longitudinal improvements for boys with FXS paralleled those in TD children. In conclusion, cognitive attention and WM, although delayed in FXS, reveal developmental change, rather than "arrest." Our findings underscore the need for going beyond cross sectional group comparisons and gross behavioral indices to map cognitive changes longitudinally in developmental disorders. PMID- 23627949 TI - Dimensions of callousness in early childhood: links to problem behavior and family intervention effectiveness. AB - This study examined dimensions of callous behaviors in early childhood and the role of these behaviors in the development of conduct problems, as well as responsiveness to a family-centered preventative intervention. Caregiver reports of callous behaviors were examined using exploratory and confirmatory factor analysis. Problem behavior was examined using within- and cross-informant reports of these behaviors. Parenting was measured using observational methods within the context of a randomized control trial of the Family Check-Up with a sample of 731 ethnically diverse boys and girls (followed from ages 2 to 4) at high risk for later conduct problems. Results demonstrated that a measure of deceitful-callous (DC) behaviors had acceptable factor loadings and internal consistency at ages 3 and 4. DC behaviors at age 3 predicted problem behavior concurrently and longitudinally within and across informant. However, DC behaviors did not reduce the effectiveness of the family preventative intervention. These findings have implications for our understanding of behaviors that may precede later callous unemotional traits and for our understanding of the development and prevention of early starting conduct problems. PMID- 23627951 TI - The role of pubertal timing and temperamental vulnerability in adolescents' internalizing symptoms. AB - This longitudinal study examined the joint role of pubertal timing and temperament variables (emotional reactivity and self-regulation) in predicting adolescents' internalizing symptoms. The multiethnic sample included 1,025 adolescent girls and boys followed from age 11 to age 15 (M age = 11.03 years at Time 1). In structural equation models, age 11 measures of pubertal timing, emotional reactivity, and self-regulation and their interactions were used to predict adolescents' internalizing behavior concurrently and at age 15. Results indicated that, among girls, early pubertal timing, higher emotional reactivity, and lower self-regulation predicted increased internalizing behavior. In addition, self-regulation moderated the effect of pubertal timing such that effects of earlier timing on subsequent internalizing were seen primarily among girls with relatively poor self-regulation. Among boys, higher levels of emotional reactivity and lower self-regulation predicted increased internalizing, but there were no effects of pubertal timing. After controlling for Time 1 internalizing symptoms, only self-regulation predicted change in internalizing symptoms. Discussion focuses on the possible interplay of temperament and pubertal development in predicting internalizing problems during adolescence. PMID- 23627952 TI - The longitudinal development of emotion regulation capacities in children at risk for externalizing disorders. AB - The development of emotional regulation capacities in children at high versus low risk for externalizing disorder was examined in a longitudinal study investigating: (a) whether disturbances in emotion regulation precede and predict the emergence of externalizing symptoms and (b) whether sensitive maternal behavior is a significant influence on the development of child emotion regulation. Families experiencing high (n = 58) and low (n = 63) levels of psychosocial adversity were recruited to the study during pregnancy. Direct observational assessments of child emotion regulation capacities and maternal sensitivity were completed in early infancy, at 12 and 18 months, and at 5 years. Key findings were as follows. First, high-risk children showed poorer emotion regulation capacities than their low-risk counterparts at every stage of assessment. Second, from 12 months onward, emotion regulation capacities showed a degree of stability and were associated with behavioral problems, both concurrently and prospectively. Third, maternal sensitivity was related to child emotion regulation capacities throughout development, with poorer emotion regulation in the high-risk group being associated with lower maternal sensitivity. The results are consistent with a causal role for problems in the regulation of negative emotions in the etiology of externalizing psychopathology and highlight insensitive parenting as a potentially key developmental influence. PMID- 23627953 TI - Interactive contributions of self-regulation deficits and social motivation to psychopathology: unraveling divergent pathways to aggressive behavior and depressive symptoms. AB - Poor self-regulation has been implicated as a significant risk factor for the development of multiple forms of psychopathology. This research examined the proposition that self-regulation deficits differentially predict aggressive behavior and depressive symptoms, depending on children's social approach versus avoidance motivation. A prospective, multiple-informant approach was used to test this hypothesis in 419 children (M age = 8.92, SD = 0.36). Parents rated children's inhibitory control. Children completed measures of social approach avoidance motivation and depressive symptoms. Teachers rated children's aggressive behavior. As anticipated, poor inhibitory control predicted aggressive behavior in boys with high but not low approach motivation and low but not high avoidance motivation, whereas poor inhibitory control predicted depressive symptoms in girls with high but not low avoidance motivation. This research supports several complementary theoretical models of psychopathology and provides insight into the differential contributions of poor self-regulation to maladaptive developmental outcomes. The findings suggest the need for targeted intervention programs that consider heterogeneity among children with self regulatory deficits. PMID- 23627955 TI - Effects of early maternal distress and parenting on the development of children's self-regulation and externalizing behavior. AB - Emotional distress experienced by mothers increases young children's risk of externalizing problems through suboptimal parenting and child self-regulation. An integrative structural equation model tested hypotheses that mothers' parenting (i.e., low levels of inductive discipline and maternal warmth) would mediate adverse effects of early maternal distress on child effortful control, which in turn would mediate effects of maternal parenting on child externalizing behavior. This longitudinal study spanning ages 3, 6, and 10 included 241 children, mothers, and a subset of teachers. The hypothesized model was partially supported. Elevated maternal distress was associated with less inductive discipline and maternal warmth, which in turn were associated with less effortful control at age 3 but not at age 6. Inductive discipline and maternal warmth mediated adverse effects of maternal distress on children's effortful control. Less effortful control at ages 3 and 6 predicted smaller relative decreases in externalizing behavior at 6 and 10, respectively. Effortful control mediated effects of inductive discipline, but not maternal warmth, on externalizing behavior. Findings suggest elevated maternal distress increases children's risk of externalizing problems by compromising early parenting and child self regulation. PMID- 23627954 TI - Codevelopment of externalizing and internalizing symptoms in middle to late childhood: sex, baseline respiratory sinus arrhythmia, and respiratory sinus arrhythmia reactivity as predictors. AB - We investigated the roles of sex and respiratory sinus arrhythmia (RSA), an index of autonomic parasympathetic nervous system activity, as predictors of codeveloping externalizing and internalizing symptoms in middle childhood. We expected that sex, baseline RSA (RSA-B), and RSA reactivity (RSA-R) to two types of tasks would interact to differentiate co-occurring trajectories of symptoms. We tested these hypotheses by combining longitudinal data from two independent samples (n = 390; 210 girls, 180 boys) with repeated measures at ages 8, 9, 10, and 11. RSA-R was measured in response to a socially stressful and frustrating stressor. Indicators of growth in externalizing and internalizing symptoms were derived from multiple domain growth models and used in person-centered growth mixture analyses. Three groups of externalizing and internalizing trajectories were found. Profile membership was predicted by several two-way interactions among sex, RSA-B, or RSA-R but was not predicted by three-way interactions. Children with low RSA-B and strong RSA withdrawal, girls with low RSA-B, and girls with strong RSA withdrawal were more likely to be on a developmental trajectory of low externalizing symptoms and moderately elevated internalizing symptoms. Membership in the high externalizing and high internalizing trajectory was predicted by weak RSA withdrawal for boys and strong RSA withdrawal for girls. The type of stressor task also played a role in predicting probability of profile membership. Results are discussed in the context of developmental psychobiology and implications for the codevelopment of psychopathology symptoms in childhood. PMID- 23627956 TI - Pubertal timing and depressive symptoms in late adolescence: the moderating role of individual, peer, and parental factors. AB - This longitudinal study examined personal-accentuation and contextual amplification models of pubertal timing. In these models, individual and contextual risk factors during childhood and adolescence can magnify the effects of early or late puberty on depression symptoms that occur years later. The moderating role of prepubertal individual factors (emotional problems in late childhood) and interpersonal factors (deviant peer affiliation, early dating, perceived peer popularity, and perceived parental rejection during adolescence) were tested. A representative sample of 1,431 Canadian adolescents between 10-11 and 16-17 years of age was followed biannually. In line with the personal accentuation model, early puberty has been shown to be a predictor for depression in both girls and boys who presented emotional problems in childhood. This effect was also noted for late maturing boys. Consistent with the contextual amplification model, early puberty predicted later depression in youth who perceived greater parental rejection. Interpersonal experiences such as early dating in girls and deviant peer affiliation in boys predicted depression in early maturers as well. For girls, early dating was also found to be amplified by childhood emotional problems. In line with biopsychosocial models, results indicate that the effect of pubertal timing on depressive symptoms must be conceptualized through complex interactions between characteristics of adolescents' interpersonal relationships and prepubertal vulnerabilities. PMID- 23627957 TI - Emotional reactivity and the association between psychopathy-linked narcissism and aggression in detained adolescent boys. AB - Different patterns of emotional reactivity characterize proactive and reactive functions of aggressive behavior, and theory also suggests a link of both types with narcissism. How people with narcissistic traits respond emotionally to competitive scenarios could influence their aggressiveness. Participants were 85 adolescent boys from a detention center. Several indices of emotional functioning were assessed, including attentional bias to negative emotional stimuli and psychophysiological responding. In addition, we included self-report and laboratory measures of aggression and measures of psychopathy-linked narcissism, callous-unemotional traits, and impulsivity. Psychopathy-linked narcissism was uniquely related to unprovoked aggression (i.e., proactive aggression) and to heightened attention to pictures depicting others' distress. Compared with those scoring low on narcissism, those high on narcissism, who were the least physiologically reactive group, evinced greater proactive aggression, whereas those showing a pattern of coactivation (i.e., sympathetic and parasympathetic autonomic reactivity) evinced greater reactive aggression. Results are consistent with descriptions of narcissistic individuals as being hypervigilant to negative cues and exhibiting poor emotion regulation. These characteristics may lead to aggressive and violent behavior aimed at maintaining dominance over others. PMID- 23627958 TI - Genetic origin of the relationship between parental negativity and behavior problems from early childhood to adolescence: a longitudinal genetically sensitive study. AB - Little is known about how genetic and environmental factors contribute to the association between parental negativity and behavior problems from early childhood to adolescence. The current study fitted a cross-lagged model in a sample consisting of 4,075 twin pairs to explore (a) the role of genetic and environmental factors in the relationship between parental negativity and behavior problems from age 4 to age 12, (b) whether parent-driven and child driven processes independently explain the association, and (c) whether there are sex differences in this relationship. Both phenotypes showed substantial genetic influence at both ages. The concurrent overlap between them was mainly accounted for by genetic factors. Causal pathways representing stability of the phenotypes and parent-driven and child-driven effects significantly and independently account for the association. Significant but slight differences were found between males and females for parent-driven effects. These results were highly similar when general cognitive ability was added as a covariate. In summary, the longitudinal association between parental negativity and behavior problems seems to be bidirectional and mainly accounted for by genetic factors. Furthermore, child-driven effects were mainly genetically mediated, and parent-driven effects were a function of both genetic and shared-environmental factors. PMID- 23627959 TI - School mobility and developmental outcomes in young adulthood. AB - School mobility has been shown to increase the risk of poor achievement, behavior problems, grade retention, and high school dropout. Using data over 25 years from the Chicago Longitudinal Study, we investigated the unique risk of school moves on a variety of young adult outcomes including educational attainment, occupational prestige, depression symptoms, and criminal arrests. We also investigated how the timing of school mobility, whether earlier or later in the academic career, may differentially predict these outcomes over and above associated risks. Results indicate that students who experience more school changes between kindergarten and 12th grade are less likely to complete high school on time, complete fewer years of school, attain lower levels of occupational prestige, experience more symptoms of depression, and are more likely to be arrested as adults. Furthermore, the number of school moves predicted outcomes above and beyond associated risks such as residential mobility and family poverty. When timing of school mobility was examined, results indicated more negative outcomes associated with moves later in the grade school career, particularly between 4th and 8th grades. PMID- 23627960 TI - Emotion recognition following early psychosocial deprivation. AB - An important function of the brain is to scan incoming sensory information for the presence of relevant signals and act on this information. For humans, the most salient signals are often social in nature, such as the identity and the emotional expression of the faces we encounter in our everyday lives. It can be argued that our survival as a species depends in large measure on these skills. PMID- 23627962 TI - Multiple-object tracking among individuals with Down syndrome and typically developing children. AB - We investigated differences in multiple-object tracking among individuals with Down syndrome (DS) as compared to typically developing children matched on a visual-spatial mental age of approximately 5.5 years. In order to ensure that these effects did not originate in differences in encoding or reporting the positions of targets in distracters after a delay, immediate and delayed report were measured for static items. Although their immediate and delayed report for multiple static items was comparable to that of the typically developing children, the participants with DS performed as if they were only capable of tracking a single item at a time regardless of the number of targets that needed to be tracked. This finding is surprising because the operations used in multiple object tracking are thought to be necessary for visuospatial tasks, which are an area of relative strength among persons with DS. These results call into question the idea that abilities or deficits in multiple-object tracking predict visuospatial performance, and highlight ways that atypical development can inform our understanding of typical development. PMID- 23627961 TI - Historical variation in drug use trajectories across the transition to adulthood: the trend toward lower intercepts and steeper, ascending slopes. AB - This study examines historical variation in individual trajectories of heavy drinking and marijuana use from age 18 to 22. Unlike most studies that have examined cohort differences in drug use, it focuses on differences in both level of use and rates of change (growth). Nearly 39,000 youths from the high school classes of 1976-2004 were surveyed at biennial intervals between the ages of 18 and 22 as part of the national Monitoring the Future study. Between 1976 and 2004, adolescent heavy drinking decreased substantially. However, because the age 18-22 heavy drinking growth rate increased threefold for males and sixfold for females during this period, heavy drinking among 21- to 22-year-olds remained largely stable. The growth rate for marijuana use was more stable across cohorts, and historical declines in use were sizable across the entire 18-22 age band. Generally, historical variation in use was unrelated to college status and living arrangements as well as to historical changes in the distribution of young adult social roles. Findings suggest that historical fluctuations in use were less the result of proximal young adult factors and more the result of historical variation in distal adolescent factors, the effect of which diminished with age, especially for heavy drinking. PMID- 23627963 TI - Gene * environment effects of serotonin transporter, dopamine receptor D4, and monoamine oxidase A genes with contextual and parenting risk factors on symptoms of oppositional defiant disorder, anxiety, and depression in a community sample of 4-year-old children. AB - Genetic factors can play a key role in the multiple level of analyses approach to understanding the development of child psychopathology. The present study examined gene-environment correlations and gene * environment interactions for polymorphisms of three target genes, the serotonin transporter gene, the D4 dopamine receptor gene, and the monoamine oxidase A gene in relation to symptoms of anxiety, depression, and oppositional behavior. Saliva samples were collected from 175 non-Hispanic White, 4-year-old children. Psychosocial risk factors included socioeconomic status, life stress, caretaker depression, parental support, hostility, and scaffolding skills. In comparison with the short forms (s/s, s/l) of the serotonin transporter linked polymorphic repeat, the long form (l/l) was associated with greater increases in symptoms of oppositional defiant disorder in interaction with family stress and with greater increases in symptoms of child depression and anxiety in interaction with caretaker depression, family conflict, and socioeconomic status. In boys, low-activity monoamine oxidase A gene was associated with increases in child anxiety and depression in interaction with caretaker depression, hostility, family conflict, and family stress. The results highlight the important of gene-environment interplay in the development of symptoms of child psychopathology in young children. PMID- 23627964 TI - A dynamic flow-chamber-based adhesion assay to assess canine platelet-matrix interactions in vitro. AB - BACKGROUND: Dynamic adhesion assays allow the examination of platelet dysfunction and drug effects on platelet function. OBJECTIVE: The purpose of the study was to optimize several parameters such as type and concentration of collagen, wall shear stress, and the concentration of the platelet-activating agonist in a new biochip perfusion chamber for the study of canine platelets. METHODS: After fluorescent staining of platelets, citrated blood of 10 healthy dogs was perfused through the flow chamber coated with different concentrations of canine or bovine skin collagen. Wall shear stress ranged from 14 to 60 dynes/cm(2). Protease activating receptor 4 (PAR 4) agonist was used for platelet activation. After perfusion, platelet attachment to the collagen matrix was quantified based on fluorescent imaging. Total platelet covered area and average size of platelet covered areas were measured by planimetry. RESULTS: Canine platelet adhesion was supported by >= 200 MUg/mL canine collagen, but not bovine skin collagen. Consistent results were obtained with a wall shear stress of 14 dynes/cm(2), whereas higher wall shear stress resulted in increased variability. Platelet activation with PAR 4 agonist increased the total platelet covered area and the average size of platelet covered areas. CONCLUSIONS: This study indicates the need to carefully select collagen type and concentration to assess canine thrombus formation in a dynamic flow chamber. The established method should be a useful tool to determine changes in platelet-matrix interactions as an indicator of platelet activation or platelet dysfunction in dogs. PMID- 23627965 TI - Meta-analyses of fertility desires of people living with HIV. AB - BACKGROUND: Literature review has shown that some years back the fertility desires of people living with HIV was low but in the recent years, it was reported as increasing. However, little is known about the strength of association of fertility desire of HIV positive people with antiretroviral therapy (ART) experience, age, sex, education level, and number of children. METHODS: In these meta-analyses, twenty studies from different parts of the world were included. The odds ratios of fertility desires were determined using the random-effects model. Heterogeneity among the studies was assessed by computing values for Tau(2), Chi-square (Q), I(2) and P-value. Sensitivity analysis and funnel plot were done to assess the stability of pooled values to outliers and publication bias, respectively. RESULTS: The pooled analysis demonstrated that fertility desires of study participants had no association with ART. Similarly, the overall odds ratio did not show statistically significant association of fertility desires with sex and educational attainment of study participants although forest plots of some studies fall on increased and some others on decreased sides of fertility desires. The two variables that demonstrated a strong association with fertility desires were age less than 30 years and being childless. The lowest heterogeneity was found in a meta-analysis comparing ART experienced and ART naive HIV positive people. In all meta-analyses, the sensitivity analyses showed the stability of the pooled odds ratios; and the funnel plots did not show publication or disclosure bias. CONCLUSION: Although the fertility desires among childless and younger age group was very strong, we realized that quite a significant segment of HIV-infected people have desire for fertility. Therefore, including fertility issue as integral part of HIV patient care may help several of them in their reproductive decision making (letting them know the risks and methods of prevention while anticipating pregnancy). PMID- 23627966 TI - Scrub typhus islands in the Taiwan area and the association between scrub typhus disease and forest land use and farmer population density: geographically weighted regression. AB - BACKGROUND: The Taiwan area comprises the main island of Taiwan and several small islands located off the coast of the Southern China. The eastern two-thirds of Taiwan are characterized by rugged mountains covered with tropical and subtropical vegetation. The western region of Taiwan is characterized by flat or gently rolling plains. Geographically, the Taiwan area is diverse in ecology and environment, although scrub typhus threatens local human populations. In this study, we investigate the effects of seasonal and meteorological factors on the incidence of scrub typhus infection among 10 local climate regions. The correlation between the spatial distribution of scrub typhus and cultivated forests in Taiwan, as well as the relationship between scrub typhus incidence and the population density of farm workers is examined. METHODS: We applied Pearson's product moment correlation to calculate the correlation between the incidence of scrub typhus and meteorological factors among 10 local climate regions. We used the geographically weighted regression (GWR) method, a type of spatial regression that generates parameters disaggregated by the spatial units of analysis, to detail and map each regression point for the response variables of the standardized incidence ratio (SIR)-district scrub typhus. We also applied the GWR to examine the explanatory variables of types of forest-land use and farm worker density in Taiwan in 2005. RESULTS: In the Taiwan Area, scrub typhus endemic areas are located in the southeastern regions and mountainous townships of Taiwan, as well as the Pescadore, Kinmen, and Matou Islands. Among these islands and low-incidence areas in the central western and southwestern regions of Taiwan, we observed a significant correlation between scrub typhus incidence and surface temperature. No similar significant correlation was found in the endemic areas (e.g., the southeastern region and the mountainous area of Taiwan). Precipitation correlates positively with scrub typhus incidence in 3 local climate regions (i.e., Taiwan's central western and southwestern regions, and the Kinmen Islands). Relative humidity correlates positively with incidence in Southwestern Taiwan and the Kinmen Islands. The number of wet days correlates positively with incidence in Southwestern Taiwan. The duration of sunshine correlates positively with incidence in Central Western Taiwan, as well as the Kinmen and Matou Islands. In addition, the 10 local climatic regions can be classified into the following 3 groups, based on the warm-cold seasonal fluctuations in scrub typhus incidence: (a) Type 1, evident in 5 local climate regions (Taiwan's northern, northwestern, northeastern, and southeastern regions, as well as the mountainous area); (b) Type 2 (Taiwan's central western and southwestern regions, and the Pescadore Islands); and (c) Type 3 (the Kinmen and Matou Islands). In the GWR models, the response variable of the SIR-district scrub typhus has a statistically significantly positive association with 2 explanatory variables (farm worker population density and timber management). In addition, other explanatory variables (recreational forests, natural reserves, and "other purpose" areas) show positive or negative signs for parameter estimates in various locations in Taiwan. Negative signs of parameter estimates occurred only for the explanatory variables of national protectorates, plantations, and clear-cut areas. CONCLUSION: The results of this study show that scrub typhus in Taiwan can be classified into 3 types. Type 1 exhibits no climatic effect, whereas the incidence of Type 2 correlates positively with higher temperatures during the warm season, and the incidence of Type 3 correlates positively with higher surface temperatures and longer hours of sunshine. The results also show that in the mountainous township areas of Taiwan's central and southern regions, as well as in Southeastern Taiwan, higher SIR values for scrub typhus are associated with the following variables: farm worker population density, timber management, and area type (i.e., recreational forest, natural reserve, or other purpose). PMID- 23627967 TI - Uptake and distribution of haematoporphyrin derivative in the unicellular eukaryote Paramecium. AB - Haematoporphyrin derivative (HpD) uptake, intracellular distribution and turnover were examined in a free-living protozoan cell, Paramecium aurelia, which had been demonstrated to internalize lipoproteins. A 10 min incubation in HpD completed with low-density lipoprotein (LDL) resulted in the appearance of distinct red fluorescing vesicles, together with a diffuse fluorescence of the cytoplasm. Fluorescein labelling of LDL demonstrated the intracellular localization of HpD and LDL within the same vesicles. Pretreatment of Paramecium with the beta adrenergic antagonist l-propranolol, which blocked its phagocytotic activity, resulted in an absence of red-fluorescing vesicles; thus these were proved to be endosomes. Fluorescence emission recorded in the endosomes was characterized by a band at about 660-670 nm which was attributed to the partially unfolded oligomers; this emission was present during maintenance of the cells in drug-free culture medium for up to 120 min. Propranolol-pretreated cells exhibited only a diffuse cytoplasmic fluorescence characterized by an emission band at 630 nm, which was attributed to the monomers; this disappeared rapidly on washing. These results suggest the following: (i) HpD monomers enter Paramecium via transmembrane influx and/or fluid phase uptake; (ii) HpD oligomers are mainly internalized via receptor-mediated endocytosis; (iii) the extent of the endocytotic process is increased when HpD is completed with LDL; (iv) after internalization, aggregate species undergo a disaggregating process which accounts for the persistence of the intracellular fluorescence. PMID- 23627968 TI - Incidence and risk factors for catheter-associated bloodstream infections in neonatal intensive care. AB - AIM: To determine the incidence and potential novel risk factors for catheter associated bloodstream infections (CABSI) in neonates. METHODS: A retrospective study was conducted for infants admitted to the VU University Medical Center neonatal intensive care unit in 2007. RESULTS: One hundred and ninety six infants with a total of 369 central catheters were included. The CABSI rate was 18.1 infections/1000 catheter-days (95% CI 13.7-23.8) according to adjusted criteria used by the Centers for Disease Control and Prevention prior to 2008. Umbilical catheters had a higher infection rate than nonumbilical central catheters: rate ratio (rate ratio 2.4, 95% CI 1.2-4.9). Longer umbilical catheter dwell-time also increased infection rate (p < 0.05). Gestational age, birth weight, duration of parenteral nutrition and the administration of all-in-one feeding mixture versus parenteral nutrition administered in separate components were not related to infection rate in multivariate analysis. CONCLUSION: Of all catheter types, umbilical catheters carried the highest infection rate. Longer umbilical catheter dwell-time also increased infection rate. The present data suggest that the impact of gestational age and birth weight on infection rate is mainly due to a prolonged hospital stay. The composition, way of preparation and duration of parenteral nutrition did not seem to influence infection rate. PMID- 23627969 TI - Bone morphogenetic proteins and the polycystic ovary syndrome. AB - BACKGROUND: Polycystic Ovary Syndrome (PCOS) is defined by two out of the following three criteria being met: oligo- or anovulation, hyperandrogenism, and polycystic ovaries. Affected women are often obese and insulin resistant. Although the etiology is still unknown, members of the Transforming Growth Factor beta (TGFbeta) family, including Bone Morphogenetic Proteins (BMPs) and anti Mullerian hormone (AMH), have been implicated to play a role. In this pilot study we aimed to measure serum BMP levels in PCOS patients. METHODS: Twenty patients, fulfilling the definition of PCOS according to the Rotterdam Criteria, were randomly selected. Serum BMP2, -4, -6 and -7 levels were measured using commercially available BMP2, BMP4, BMP6 and BMP7 immunoassays. RESULTS: Serum BMP2, serum BMP4 and serum BMP6 levels were undetectable. Three patients had detectable serum BMP7 levels, albeit at the lower limit of the standard curve. CONCLUSIONS: BMP levels were undetectable in almost all patients. This suggests that with the current sensitivity of the BMP assays, measurement of serum BMP levels is not suitable as a diagnostic tool for PCOS. PMID- 23627970 TI - Share with women. Preventing pertussis (whooping cough). PMID- 23627971 TI - Relative validity of a food frequency questionnaire to assess nutrient intake in pregnant women. AB - BACKGROUND: To date, there are no food frequency questionnaires that have been validated to assess nutrient intakes in pregnant women in Ireland. The present study aimed to assess the relative validity of a self-administered food frequency questionnaire during pregnancy. METHODS: The food frequency questionnaire was administered once during pregnancy between 12 and 34 weeks. Participants also completed a 3-day food diary during each trimester of pregnancy (reference method) and intakes from both the food frequency questionnaire and the mean of the 3-day food diaries were compared in a sample of 130 participants from the control arm of an intervention study. RESULTS: Energy-adjusted Pearson's correlation coefficients ranged from 0.24 (riboflavin) to 0.59 (magnesium) and were all statistically significant (P < 0.05). The food frequency questionnaire tended to report higher energy and nutrient intakes compared to the food diaries. On average, 74% of participants were classified into the same +/- 1 quartile and 7% into opposing quartiles by the two methods. CONCLUSIONS: Overall, our food frequency questionnaire showed good relative validity. We conclude that a single administration of a food frequency questionnaire is a valid tool for ranking women in accordance with their nutrient intakes during pregnancy. PMID- 23627972 TI - Meta-analysis of the short-term effects of lamivudine treatment for severe chronic hepatitis B. AB - PURPOSE: To evaluate the short-term effect of lamivudine (LMV) treatment for severe chronic hepatitis B. METHOD: Patient data related to the safety and efficacy of using lamivudine (LMV) to treat hepatitis B virus (HBV)-induced liver failure or severe hepatitis were acquired from previous literature. These studies were retrieved from PubMed, Ovid, SpringerLink, Biosis Previews, Academic Search Premier, ProQuest Medical Library, Cochrane Library, China National Knowledge Infrastructure Full-text Database, VIP Chinese Scientific Journal Database, and Chinese Biomedicine. Relative risk and weighted mean difference were used to measure the effects. The major predictors observed included total bilirubin (TBIL), prothrombin activity (PTA), survival rate, and HBV-DNA negative change rate. Groups were further divided according to the clinical course and disease staging. RESULTS: A total of 242 studies were retrieved from the databases. At weeks 4, 8, and 12 of the treatment course, the survival rates and PTA of the test group were distinctively higher than those of the control group. However, TBIL concentrations in the test group were lower than the control group. The HBV DNA negative change rate was distinctively higher throughout the 12 weeks of LMV treatment. For patients who started LMV treatment in the middle stage, the mortality rate of the test group was lower. For patients who started LMV treatment during the advanced stage, no significant difference was observed between the test and control groups. CONCLUSION: LMV decreased HBV-DNA levels in the serum, improved liver function in patients, and enhanced survival rate during the early and medium stages of severe chronic hepatitis B. PMID- 23627973 TI - Preoperative analysis of the stability of fit of a patient-specific surgical guide. AB - Although the use of patient-specific surgical guides has gained popularity over the past decade, little research has been done to examine in an objective and qualitative way the fit of such instruments. In this study, we have developed a model to predict the stability of a guide designed to fit on a supporting bone surface, thereby providing feedback on the translational and rotational stability of the device. The method was validated by comparing different guide designs with respect to their stability on the contact surface and comparing these results to those measured with a set of experiments. This validation experiment indicates that our stability model can be used to predict the stability of the fit of a surgical guide during the preoperative design process. PMID- 23627974 TI - Editorial: the changing face of metabolic syndrome and its components in the light of current knowledge. PMID- 23627975 TI - Insulin resistance, small LDL particles, and risk for atherosclerotic disease. AB - There is a global epidemic of obesity, metabolic syndrome, and diabetes mellitus. Insulin resistance (IR) is etiologic for both metabolic syndrome and diabetes mellitus. IR induces a broad range of toxic systemic effects, including dyslipidemia, hypertension, hyperglycemia, increased production of advanced glycosylation end products, increased inflammatory tone, as well as a prothrombotic and pro-oxidative state. Patients with IR are highly vulnerable to the development of accelerated atherosclerosis as well its clinical sequelae, including coronary artery disease and myocardial infarction, carotid artery disease and ischemic stroke, peripheral arterial disease and claudication/lower extremity amputation, and coronary mortality. Among the most important risk factors patients afflicted with IR develop is the so-called atherogenic lipid triad: large numbers of small, dense low-density lipoprotein (sdLDL) particles, hypertriglyceridemia, and low serum concentrations of high-density lipoprotein cholesterol. Though controversial, much recent evidence suggests that the formation of sdLDL particles in the setting of IR is an important metabolic transition. Some studies suggest that these smaller particles are more atherogenic than their larger, more buoyant counterparts. At least part of the explanation for the apparent augmented atherogenicity of small LDL particles is their reduced systemic clearance by the LDL receptor, increased vulnerability to oxidation rendering them more apt for scavenging by macrophages, and possible increased flux into the subendothelial space of arterial walls. Numerous small studies suggest that sdLDL is highly correlated with cardiovascular events. Cardiovascular medicine is in need of a large prospective, randomized study that would more definitively investigate the impact of small, dense LDL (sdLDL) on risk for cardiovascular disease and whether therapeutic interventions designed to specifically reduce the burden of sdLDL are associated with reductions in cardiovascular events over and above that seen with LDL-C reduction per se. PMID- 23627976 TI - Is there U-turn from insulin back to pills in diabetes? AB - Type 2 diabetes is characterized by insulin resistance together with progressive loss of beta-cell function. After recognition of gluco- and lipo-toxicity, attention was focused on the preservation and/or restoration of beta cell function, especially at the early stages of the diabetes, with better beta-cell reserve and in the absence of complications. Early treatment of glucotoxicity with insulin was searched by early insulin treatment studies, and these studies have some promising results, pointing the possibility of "remission" of diabetes in some patients. According to the results of these studies, patients with early diagnosis of diabetes, the ones with better beta cell reserve, patients with low tendency for "insulin-abuse" could make "U"-turn from insulin to pills or even drug-free life. Criteria to turn back to pills could be listed as disappearance of diabetic symptoms, daily insulin need < 0.25 unit/kg, euglycemia in both fasting and postprandial state, and better beta cell function. The main problems in early insulin treatment are the ''insulin resistance'' of both patients and doctors, hypoglycemia, weight gain and increased appetite. Meanwhile, hyperinsulinemia desensitizes receptors and causes worsening of situation in a vicious cycle of insulin resistance and hyperglycemia. Therefore, patients should be selected properly and U-turn could be performed in relevant conditions explained in the text. It could be possible to see early insulin treatment and U turn strategies in future guidelines for type 2 diabetes. PMID- 23627977 TI - Controversies on HDL: should it be a target biomarker in patients with lipid disorders? AB - Low-density lipoprotein (LDL) cholesterol lowering with statins have had a profound impact on cardiovascular (CV) event rates and accordingly have become an integral component of strategies designed to reduce CV risk. The finding of a residual clinical risk, despite LDL cholesterol lowering, supports the need to develop additional therapeutic strategies for CV prevention. Numerous lines of evidence suggest that targeting the protective properties of high-density lipoproteins (HDL) may be beneficial. Disappointing results from recent reports of HDL genetics and raising agents and clinical events has fueled considerable debate as to whether attempts to target HDL will be of clinical benefit or futility. This review will reflect on challenges faced in developing new effective HDL targeted therapies. PMID- 23627978 TI - Pre-CKD- do we need another hero? AB - Screening is the systematic use of a test for a health problem or risk factor when no recognized signs or symptoms would indicate the presence of that problem or risk factor. Abnormal glucose metabolism can be documented years before the onset of overt diabetes. Nowadays, prediabetes can be subdivided into impaired fasting glucose or impaired glucose tolerance. Substantial number of subjects with either will progress to overt diabetes within years. Prediabetes bears also the increased risk of cardiovascular complications. Prehypertension is much newer term introduced by the seventh report of the Joint National Committee (JNC 7) published in 2003 as systolic blood pressure from 120 to 139 mmHg or diastolic blood pressure from 80 to 89 mmHg in adults (not receiving blood pressure lowering treatment). Similarly prehypertension also increased the risk of cardiovascular complications and progression to hypertension. Chronic kidney disease is also highly prevalent mainly in the elderly. It is associated with important adverse outcomes such as cardiovascular mortality and morbidity. Factors associated with higher risk of chronic kidney disease include mainly hypertension, diabetes, obesity and older age. Early detection and diagnosis of chronic kidney disease may prevent the full blown disease and its end-stage requiring renal replacement therapy. The review focus on the problem of high risk population for development of diabetes, hypertension and whether time has come to focus also on the conditions predisposing to the development of chronic kidney disease. PMID- 23627979 TI - Uric acid metabolism in pre-hypertension and the metabolic syndrome. AB - In humans uric acid (UA) is the end product of degradation of purines. The handling of UA by the renal system is a complex process which is not fully understood. To date, several urate transporters in the renal proximal tubule have been identified. Among them, urate transporter 1 (URAT1) and a glucose transporter 9 (GLUT9) are considered of greater importance, as potential targets for treatment of hyperuricemia and the potential associated cardio-metabolic risk. Therefore, the recognition of the metabolic pathway of UA and elucidation of occurrence of hyperuricemia may provide important insights about the relationship between UA, pre-hypertension (preHT) and the metabolic syndrome (MetS). We also review the available clinical studies in this field, including experimental studies dealing with the mechanisms of UA transport via different transporters, as well as current treatment options for hyperuricemia in patients with MetS, preHT or cardiovascular risk factors. PMID- 23627980 TI - Recommendations for severe hypertriglyceridemia treatment, are there new strategies? AB - This review considers drug combinations and newer treatment strategies for patients with severe hypertriglyceridemia. Hypertriglyceridemia is associated with an atherogenic metabolic profile and in most studies with increased cardiovascular disease risk. Patients with severe hypertriglyceridemia also have increased incidence of pancreatitis. All types of severe hypertriglyceridemia are associated with a reduction in lipoprotein lipase activity. Patients with severe hypertriglyceridemia and abdominal pain or pancreatitis should be hospitalized and treated with hypolipidemic drugs and, if needed, with insulin/dextrose infusion or therapeutic apheresis. Fibrates are the first-line treatment in patients with severe hypertriglyceridemia. Omega-3 fatty acids and niacin are very useful drugs for patients with hypertriglyceridemia. Statins in high doses exhibit a significant hypotriglyceridemic activity. Drugs that interfere with chylomicron production such as orlistat are also useful for hypertriglyceridemic patients. In most patients with severe hypertriglyceridemia drug combinations are needed to maintain an acceptable triglyceride concentration. Gene therapy is under development for patients with known genetic abnormalities of triglyceride metabolism. Clinicians should be vigilant for the recognition and prompt treatment of patients with severe hypertriglyceridemia aimed to avoid the serious complication of pancreatitis and to reduce their cardiovascular risk. PMID- 23627981 TI - Insulin resistance in brain and possible therapeutic approaches. AB - Although the brain has long been considered an insulin-independent organ, recent research has shown that insulin has significant effects on the brain, where it plays a role in maintaining glucose and energy homeostasis. To avoid peripheral insulin resistance, the brain may act via hypoinsulinemic responses, maintaining glucose metabolism and insulin sensitivity within its own confines; however, brain insulin resistance may develop due to environmental factors. Insulin has two important functions in the brain: controlling food intake and regulating cognitive functions, particularly memory. Notably, defects in insulin signaling in the brain may contribute to neurodegenerative disorders. Insulin resistance may damage the cognitive system and lead to dementia states. Furthermore, inflammatory processes in the hypothalamus, where insulin receptors are expressed at high density, impair local signaling systems and cause glucose and energy metabolism disorders. Excessive caloric intake and high-fat diets initiate insulin and leptin resistance by inducing mitochondrial dysfunction and endoplasmic reticulum stress in the hypothalamus. This may lead to obesity and diabetes mellitus (DM). Exercise can enhance brain and hypothalamic insulin sensitivity, but it is the option least preferred and/or continuously practiced by the general population. Pharmacological treatments that increase brain and hypothalamic insulin sensitivity may provide new insights into the prevention of dementia disorders, obesity, and type 2 DM in the future. PMID- 23627982 TI - Characteristics other than the diagnostic criteria associated with metabolic syndrome: an overview. AB - Metabolic syndrome (MetS), a cluster of dyslipidaemia, central obesity, hypertension and/or insulin resistance, is associated with increased cardiovascular disease (CVD) type 2 diabetes risk. Different diagnostic criteria for MetS have been proposed but in 2009 a joint statement by several scientific societies was released. Apart from the diagnostic criteria, MetS has also been associated with other risk factors including waist to hip ratio, high density lipoprotein dysfunction, small dense low density lipoprotein, postprandial hypertriglyceridaemia, lipoprotein (a), uric acid, liver function tests, prothrombotic factors, cytokines, adipokines, vitamin D, arterial stiffness, renal dysfunction, nephrolithiasis, polycystic ovary syndrome, obstructive sleep apnea. We discuss the extensive list of MetS-associated factors that may influence vascular risk. Furthermore, we discuss the impact of frequently prescribed drugs (e.g. hypolipidaemic agents) on these variables. These effects may need to be taken into consideration when treating MetS patients. PMID- 23627983 TI - Nutraceuticals for metabolic syndrome management: from laboratory to benchside. AB - Metabolic syndrome (MetS) is a world-wide epidemic disease associated with increased morbidity and mortality. Treatment strategies include pharmacologic and non-pharmacologic methods, with varying degrees of success rate all over the world. Pharmaceutical interest in this field is growing, together with patients' requests for supplementary (or "alternative") treatments. The knowledge of nutraceuticals beneficial effects in subjects with the MetS could help us to better define the appropriate treatment for these subjects, in particular those with contraindications for commonly used drugs, or to achieve guidelines suggested targets. On the other side, it could be not convenient to use a nutraceutical to treat each metabolic syndrome component (i.e. from 3 to 5) in each affected subjects. Thus, this review tries to focus on widely marketed nutraceuticals with clinically demonstrated effects on more than one component of the MetS, namely omega-3 fatty acids, berberine, psyllium and other soluble fibers, cinnamon, chromium picolinate, banaba, and bitter gourd. PMID- 23627984 TI - Patients with prehypertension - do we have enough evidence to treat them? AB - In 2003, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure established a definition of a new category of BP levels called 'prehypertension' (preHT) that included individuals with a systolic BP of 120-139 mm Hg or a diastolic BP of 80 89 mm Hg. Patients with preHT were considered to be at increased risk for progression to hypertension and in individuals with BP in the range 130/80 to 139/89 mmHg the risk of developing hypertension was twice as high as in subjects with lower values. Still then there has been a large debate whether the introduction of preHT was based on evidence and as a consequence, it was fully justified. It has been suggested that the term prehypertension may in many subjects create anxiety and a need for unnecessary medical visits and examinations. This group of patients is also very heterogeneous and it has been pointed out that subdividing preHT group into individuals with normal BP and high normal BP would much better correspond to the continuum of BP risk for CV disease. Finally, despite some data suggesting the potential benefits of antihypertensive therapy in patients with preHT (high normal BP), there are still no hard evidences on the outcome reduction by giving antihypertensive drugs in these individuals. PMID- 23627985 TI - Semiconducting [(Bi4Te4Br2)(Al2Cl(6-x)Br(x))]Cl2 and [Bi2Se2Br](AlCl4): cationic chalcogenide frameworks from Lewis acidic ionic liquids. AB - Lewis acidic organic ionic liquids provide a novel synthetic medium to prepare new semiconducting chalcogenides, [(Bi4Te4Br2)(Al2Cl5.46Br0.54)]Cl2 (1) and [Bi2Se2Br](AlCl4) (2). Compound 1 features a cationic [(Bi4Te4Br2)(Al2Cl5.46Br0.54)](2+) three-dimensional framework, while compound 2 consists of cationic layers of [Bi2Se2Br](2+). Spectroscopically measured band gaps of 1 and 2 are ~0.6 and ~1.2 eV, respectively. Thermoelectric power measurements of single crystals of 1 indicate an n-type semiconductor. PMID- 23627986 TI - Screening for overt thyroid disease in early pregnancy may be preferable to searching for small aberrations in thyroid function tests. AB - Thyroid hormones are important regulators of foetal development, and in recent years, there has been much focus on the screening and treatment of pregnant women for even small aberrations in thyroid function tests. We searched PubMed for publications on thyroid function and pregnancy outcomes including child cognition, and included references from the retrieved articles. Both small aberrations in thyroid function tests in early pregnancy and an increase in risk of pregnancy complications may be caused by a functional change in the uteroplacental unit. Thus, the association found in several studies between small thyroid test abnormalities and pregnancy complications may be due to confounding, and thyroid hormone therapy will have no effect. On the other hand, screening of thyroid function in early pregnancy may identify 200-300 women with undiagnosed overt hypothyroidism per 100,000 pregnancies, which is at least five times more than the number of hypothyroid newborns identified by screening. A number of studies indicate that untreated overt thyroid disease in pregnancy may lead to complications. The potential benefit of screening and early therapy is supported by evidence, indicating that even severe maternal hypothyroidism does not lead to neurocognitive deficiencies in the child, if the condition is detected and treated during the first half of pregnancy. Screening and therapy for overt thyroid dysfunction in early pregnancy may be indicated, rather than focusing on identifying and treating small aberrations in thyroid function tests. PMID- 23627987 TI - Measuring IPDE-SQ personality disorder prevalence in pre-sentence and early-stage prison populations, with sub-type estimates. AB - Understanding the prevalence and type of personality disorder within prison systems allows for the effective targeting of resources to implement strategies to alleviate symptoms, manage behaviour and attempt to reduce re-offending. This study aimed to determine the prevalence of personality disorder (PD) traits within a local urban high-turnover adult male prison with a remand/recently sentenced population in London, UK. The International Personality Disorder Examination - Screening Questionnaire (IPDE-SQ) self-administered questionnaire (ICD-10 version) was completed by 283 prisoners (42% completion rate). 77% of respondents reached the threshold for one or more PDs. The most common PD types were Paranoid PD (44.5%), Anankastic PD (40.3%), Schizoid PD (35%) and Dissocial PD (25.8%). These results confirm and extend existing knowledge regarding the prevalence of PD in prison populations into a high-turnover, urban, remand population. The stark comparison with community samples indicates that a more equitable standard of service delivery within the criminal justice system, focussing on preventive and early intervention services, is now required. PMID- 23627988 TI - Surgical experience of intratemporal facial nerve neurofibromas. AB - CONCLUSIONS: The first presentation of intratemporal facial neurofibromas was variable, with facial palsy most common. The tumors often involve two or more segments of facial nerve. Outcomes of the tumors were closely related to nerve integrity, preoperative facial nerve function level, and follow-up period. OBJECTIVE: The aim of this study was to present surgical experience of 11 cases with intratemporal facial neurofibroma. METHODS: Clinical data of the 11 cases with the tumors was retrospectively collected and analyzed. They were followed up for 37.9 +/- 1.7 months, range 13-59 months, except for one case that was only followed up for 5 months and was excluded from the analysis of outcomes. RESULTS: Facial palsy was the first presentation in 10 cases, with repetitive facial palsy and vertigo in 1 case; 6 cases (54.5%) were insidious and 5 (45.5%) were sudden in terms of onset. Ear pain around the onset of facial palsy was found in four cases (36.4%). The tumor involved more than one segment in six cases. Among the non-grafted cases one patient with grade V facial nerve function recovered to grade III and another patient with grade VI facial nerve function recovered to grade IV, whereas only one case with grade VI recovered to grade IV among the grafted cases. PMID- 23627989 TI - Round window vibroplasty in chronic ear surgery: comparison with conventional hearing rehabilitation. AB - CONCLUSION: Functional hearing results with round window vibroplasty in chronically disabled middle ears were comparable and, at high frequencies, superior to the results achieved with previously used conventional hearing aids even after extended surgery. Soft tissue transfer appears to be more important than floating mass transducer (FMT) alignment with the round window membrane (RWM) for efficient coupling or sonoinversion. OBJECTIVES: To evaluate the functional hearing results of an active middle ear implant (AMEI) to the round window niche (RWN). The results were compared with previously used conventional hearing aids. The position of the FMT was determined by cone-beam computed tomography (CBCT). METHODS: This was a prospective cohort study carried out in a tertiary referral center. Seven patients with severe middle ear disease were implanted with an AMEI with round window application. The postoperative hearing outcome was compared with preoperative hearing using unaided and conventionally aided conditions. The results were correlated with the physical/geometric relation of the FMT to the RWM as determined with CBCT. RESULTS: Dislocation of the FMT was not observed. One patient was re-implanted due to accidental damage to the electrode. In all patients, the pertinent functional hearing results were achieved and were comparable to previous rehabilitation results. PMID- 23627990 TI - A tandem regression-outlier analysis of a ligand cellular system for key structural modifications around ligand binding. AB - BACKGROUND: A tandem technique of hard equipment is often used for the chemical analysis of a single cell to first isolate and then detect the wanted identities. The first part is the separation of wanted chemicals from the bulk of a cell; the second part is the actual detection of the important identities. To identify the key structural modifications around ligand binding, the present study aims to develop a counterpart of tandem technique for cheminformatics. A statistical regression and its outliers act as a computational technique for separation. RESULTS: A PPARgamma (peroxisome proliferator-activated receptor gamma) agonist cellular system was subjected to such an investigation. Results show that this tandem regression-outlier analysis, or the prioritization of the context equations tagged with features of the outliers, is an effective regression technique of cheminformatics to detect key structural modifications, as well as their tendency of impact to ligand binding. CONCLUSIONS: The key structural modifications around ligand binding are effectively extracted or characterized out of cellular reactions. This is because molecular binding is the paramount factor in such ligand cellular system and key structural modifications around ligand binding are expected to create outliers. Therefore, such outliers can be captured by this tandem regression-outlier analysis. PMID- 23627991 TI - Verbal abuse from nurse colleagues and work environment of early career registered nurses. AB - PURPOSE: This study examined relationships between verbal abuse from nurse colleagues and demographic characteristics, work attributes, and work attitudes of early career registered nurses (RNs). DESIGN AND METHODS: Data are from the fourth wave of a national panel survey of early career RNs begun in 2006. The final analytic sample included 1,407 RNs. Descriptive statistics were used to describe the sample, analysis of variance to compare means, and chi square to compare categorical variables. FINDINGS: RNs reporting higher levels of verbal abuse from nurse colleagues were more likely to be unmarried, work in a hospital setting, or work in a non-magnet hospital. They also had lower job satisfaction, and less organizational commitment, autonomy, and intent to stay. Lastly, they perceived their work environments unfavorably. CONCLUSIONS: Data support the hypothesis that early career RNs are vulnerable to the effects of verbal abuse from nurse colleagues. Although more verbal abuse is seen in environments with unfavorable working conditions, and RNs working in such environments tend to have less favorable work attitudes, one cannot assume causality. It is unclear if poor working conditions create an environment where verbal abuse is tolerated or if verbal abuse creates an unfavorable work environment. CLINICAL RELEVANCE: There is a need to develop and test evidence-based interventions to deal with the problems inherent with verbal abuse from nurse colleagues. PMID- 23627992 TI - HPA system activity in alexithymia: a cortisol awakening response study. AB - OBJECTIVES: Alexithymia is a personality trait characterized by difficulties in identifying, describing and communicating one's own emotions. It is also associated with several stress-related psychiatric disorders. The aim of the study was to examine the cortisol awakening response (CAR) as a measure of HPA system function in a community based sample of psychologically and physically healthy adults with alexithymia. METHODS: Fourty-one high alexithymic individuals and thirty-seven low alexithymic subjects, well-controlled regarding gender, age and sociodemographic status, provided three saliva cortisol samples each day for three consecutive days for the calculation of mean CAR. Participants filled out questionnaires on alexithymia (TAS-20, BVAQ) and interpersonal reactivity (IRI) prior to cortisol assessment. RESULTS: The mean CAR of three sampling days was significantly lower in the alexithymic group in comparison to control participants. Additionally there was a negative correlation between CAR and perceived stress, which points to lower CAR in alexithymia accompanied by higher perceived stress in socio-emotional situations. CAR was negatively correlated with age in the alexithymic group, indicating to alterations in HPA system over longer time to stress exposure. CONCLUSION: Alexithymic individuals have a lower CAR. Hence the results of the present study indicate that certain aspects of personality modulate HPA-system functioning. PMID- 23627993 TI - Relationship between participation in leisure activities and constraints on Taiwanese breastfeeding mothers during leisure activities. AB - BACKGROUND: Participation in leisure activities strongly associates with health and well-being. Little research has explored the relationship between participation in leisure activities and constraints on breastfeeding mothers during leisure activities. The purposes of this study are: 1) to investigate constraints on breastfeeding mothers during leisure activities and participation in leisure activities; 2) to investigate the differences between preferences for leisure activities and actual participation by breastfeeding mothers; 3) to segment breastfeeding mothers with similar patterns, using a cluster analysis based on the delineated participation in leisure activities and leisure preferences; 4) to explore any differences between clusters of breastfeeding mothers with respect to socio-demographic characteristics, breastfeeding behaviours and leisure constraints. METHODS: This study has a cross-sectional design using an online survey conducted among mothers having breastfeeding experiences of more than four months. The questionnaire includes demographic variables, breastfeeding behaviours, preferences for leisure activities participation, and constraints on leisure activities. Collection of data occurred between March and July 2011, producing 415 valid responses for analysis. RESULTS: For breastfeeding mothers, this study identifies constraints on breastfeeding related to leisure activities in addition to the three traditional factors for constraints in the model. This study demonstrates that reports of constraints related to children, family, and nursing environments are the most frequent. Breastfeeding mothers in Taiwan participate regularly in family activities or activities related to their children. Cluster analysis classified breastfeeding mothers into Action and Contemplation groups, and found that mothers within the latter group participate less in leisure activities and experienced more constraints related to breastfeeding. CONCLUSIONS: Implications provide a developmental design for public health policies for nursing-friendly environments to increase opportunities for breastfeeding mothers to engage in leisure activities and suggest various types of activities to increase participation of that population. PMID- 23627994 TI - Novel application of a tissue-engineered collagen-based three-dimensional bio implant in a large tendon defect model: a broad-based study with high value in translational medicine. AB - This study was designed to investigate the effectiveness of a novel tissue engineered three-dimensional collagen implant on healing of a large tendon-defect model, in vivo. Forty rabbits were divided into two equal groups: treated and control. A 2cm full-thickness gap was created in the left Achilles tendons of all the rabbits. To maintain the gap at the desired length (2cm), a Kessler suture was anchored within the proximal and distal ends of the remaining tendon. In the treated group a collagen implant was inserted in the gap while in the control group the gap was left unfilled. At weekly intervals the animals were examined clinically and their Achilles tendons tested bioelectrically. The hematological parameters and the serum Platelet-Derived Growth Factor of the animals were analyzed at 60 days post injury (DPI) immediately prior to euthanasia. Their injured (left) and normal contralateral Achilles tendons were harvested and examined at gross morphologic level before being subjected to biomechanical testing, and biophysical and biochemical analysis. The treated animals showed superior weight-bearing and greater physical activity than their controls. New dense tendinous tissue with a transverse diameter comparable to that of intact tendons filled the defect area of the treated tendons and had entirely replaced the collagen implant, at 60 DPI. In control lesions the defect was filled with loose areolar connective tissue similar to subcutaneous fascia. Treatment significantly improved the electrical resistance, dry matter, hydroxyproline content, water uptake and water delivery characteristics, of the healing tissue, as well as maximum load, yield load, maximum stress, yield stress and modulus of elasticity of the injured treated tendons compared to those of the control tendons (P<0.05). Use of this three-dimensional collagen implant improved the healing of large tendon defects in rabbits. PMID- 23627995 TI - [Peripheral facial nerve palsy]. AB - Facial palsy can be defined as a decrease in function of the facial nerve, the primary motor nerve of the facial muscles. When the facial palsy is peripheral, it affects both the superior and inferior areas of the face as opposed to central palsies, which affect only the inferior portion. The main cause of peripheral facial palsies is Bell's palsy, which remains a diagnosis of exclusion. The prognosis is good in most cases. In cases with significant cosmetic sequelae, a variety of surgical procedures are available (such as hypoglossal-facial anastomosis, temporalis myoplasty and Tenzel external canthopexy) to rehabilitate facial aesthetics and function. PMID- 23627996 TI - Unexpectedly resolved multiple mobile thrombi in a normal thoracic aorta associated with colorectal cancer and protein C deficiency. PMID- 23627997 TI - Monitoring incomplete heparin reversal and heparin rebound after cardiac surgery. AB - OBJECTIVES: To assess the incidence of incomplete heparin reversal and heparin rebound after cardiac surgery with cardiopulmonary bypass (CPB) and the ability of the activated coagulation time (ACT) and thromboelastography (TEG) to detect these phenomena. DESIGN: Prospective single-center study. SETTING: University hospital. PARTICIPANTS: Forty-one patients undergoing elective cardiac surgery with CPB and with normal preoperative TEG parameters. INTERVENTIONS: ACT, TEG, and plasma heparin levels were measured in all patients at 5 different times between 20 minutes and 3 hours after protamine administration. The variability of TEG reaction time (R) with and without heparinase (delta-R [DR]) was used to detect the presence of residual heparin. MEASUREMENTS AND MAIN RESULTS: Plasma heparin expressed as anti-FXa activity was detected in 180 (88%) samples. At univariate analysis, ACT, R-kaolin (R-k), and DR significantly correlated with plasma heparin concentration (respectively, p = 0.007, p = 0.006, and p = 0.002). At multivariate analysis, R-k and DR remained associated with plasma heparin concentration (respectively, p = 0.014 and p = 0.004). Greater quartiles of heparin were associated with higher values of R-k and DR. Combined procedures had significantly lower DR than isolated procedures (p = 0.017), and CPB time and heparinization time positively correlated with R-k (respectively, p = 0.044 and p = 0.022). No association was observed between heparin concentration, ACT, and TEG parameters with postoperative bleeding and need for blood and blood components transfusions. CONCLUSIONS: Heparin rebound and incomplete heparin reversal are very common phenomena after cardiac surgery with CPB; ACT is not able to detect residual heparin activity, whereas TEG analysis with and without heparinase allows the diagnosis of heparin rebound. PMID- 23627998 TI - Determinants of clinical right ventricular failure after congenital heart surgery in adults. AB - OBJECTIVES: Right ventricular (RV) failure after cardiac surgery is a clinical entity with high morbidity and mortality. Patients with congenital heart disease (CHD) often undergo right-sided cardiac surgery. The authors aimed to identify determinants of RV failure after cardiac surgery to differentiate patients with increased risk. DESIGN: A retrospective chart review. SETTING: University hospital. PARTICIPANTS: Adults with CHD operated on between January 2001 and January 2011. INTERVENTIONS: Clinical characteristics, laboratory tests, surgical data, and intensive care unit outcome were obtained from medical records. MEASUREMENTS AND MAIN RESULTS: The diagnosis of clinical RV failure was made by careful review of the medical records by 2 independent physicians. Patients only were identified as having RV failure if (1) they had elevated jugular venous pressure, (2) they had impaired postoperative RV function on transthoracic echocardiography, and (3) a diagnosis of RV failure was documented clearly in the medical charts by the treating physician. Data of 412 consecutive patients (median age 36 [range 18-74] years, 56% male) were studied. Eighteen patients had clinical RV failure (4.4%) postoperatively, of whom 6 patients died. Patients undergoing left- and both-sided surgery had an equal risk of developing clinical RV failure as compared with patients undergoing right-sided surgery. In multivariate logistic regression analysis, preoperative impaired RV function, supraventricular tachycardia, and cardiopulmonary bypass time >150 minutes were the strongest determinants of clinical RV failure (p<0.05, for all). CONCLUSIONS: RV failure after cardiac surgery is a serious complication, and occurs regardless of the side of surgery. A tailored approach in patients with CHD at highest risk of RV failure should be considered. PMID- 23627999 TI - Combining extreme learning machines using support vector machines for breast tissue classification. AB - In this paper, we present a new approach for breast tissue classification using the features derived from electrical impedance spectroscopy. This method is composed of a feature extraction method, feature selection phase and a classification step. The feature extraction phase derives the features from the electrical impedance spectra. The extracted features consist of the impedivity at zero frequency (I0), the phase angle at 500 KHz, the high-frequency slope of phase angle, the impedance distance between spectral ends, the area under spectrum, the normalised area, the maximum of the spectrum, the distance between impedivity at I0 and the real part of the maximum frequency point and the length of the spectral curve. The system uses the information theoretic criterion as a strategy for feature selection and the combining extreme learning machines (ELMs) for the classification phase. The results of several ELMs are combined using the support vector machines classifier, and the result of classification is reported as a measure of the performance of the system. The results indicate that the proposed system achieves high accuracy in classification of breast tissues using the electrical impedance spectroscopy. PMID- 23628001 TI - Baclofen affects the semicircular canals but not the otoliths in humans. AB - CONCLUSION: This study showed that GABAB agonist baclofen (10 mg) affects the semicircular canals (SCCs), both centrally and peripherally, but does not influence the otolithic function. OBJECTIVES: The aim of the study was to identify the effects of baclofen on the complete vestibular system, i.e. semicircular canals, saccules and utricles. METHODS: The study had a double blind, placebo-controlled, repeated measures design and was conducted on healthy male volunteers. With electronystagmography (ENG), the SCC function was evaluated, whereas utricular function was determined by means of unilateral centrifugation (UC). Cervical vestibular evoked myogenic potentials (cVEMPs) tested saccular integrity. RESULTS: Baclofen caused a significant increase of the vestibulo-ocular reflex (VOR) phase and a significant decrease of the total caloric response (TCR), both measured during ENG. The drug also decreased the maximal contribution of the SCCs to ocular counter-rolling (OCR) evaluated during UC. No effects on saccules and utricules were observed. PMID- 23628000 TI - Inhalable particulate matter and mitochondrial DNA copy number in highly exposed individuals in Beijing, China: a repeated-measure study. AB - BACKGROUND: Mitochondria are both a sensitive target and a primary source of oxidative stress, a key pathway of air particulate matter (PM)-associated diseases. Mitochondrial DNA copy number (MtDNAcn) is a marker of mitochondrial damage and malfunctioning. We evaluated whether ambient PM exposure affects MtDNAcn in a highly-exposed population in Beijing, China. METHODS: The Beijing Truck Driver Air Pollution Study was conducted shortly before the 2008 Beijing Olympic Games (June 15-July 27, 2008) and included 60 truck drivers and 60 office workers. Personal PM2.5 and elemental carbon (EC, a tracer of traffic particles) were measured during work hours using portable monitors. Post-work blood samples were obtained on two different days. Ambient PM10 was averaged from 27 monitoring stations in Beijing. Blood MtDNAcn was determined by real-time PCR and examined in association with particle levels using mixed-effect models. RESULTS: In all participants combined, MtDNAcn was negatively associated with personal EC level measured during work hours (beta=-0.059, 95% CI: -0.011; -0.0006, p=0.03); and 5 day (beta=-0.017, 95% CI: -0.029;-0.005, p=0.01) and 8-day average ambient PM10 (beta=-0.008, 95% CI: -0.043; -0.008, p=0.004) after adjusting for possible confounding factors, including study groups. MtDNAcn was also negatively associated among office workers with EC (beta=-0.012, 95% CI: -0.022;-0.002, p=0.02) and 8-day average ambient PM10 (beta=-0.030, 95% CI: -0.051;-0.008, p=0.007). CONCLUSIONS: We observed decreased blood MtDNAcn in association with increased exposure to EC during work hours and recent ambient PM10 exposure. Our results suggest that MtDNAcn may be influenced by particle exposures. Further studies are required to determine the roles of MtDNAcn in the etiology of particle-related diseases. PMID- 23628002 TI - Phytochemical genomics--a new trend. AB - Phytochemical genomics is a recently emerging field, which investigates the genomic basis of the synthesis and function of phytochemicals (plant metabolites), particularly based on advanced metabolomics. The chemical diversity of the model plant Arabidopsis thaliana is larger than previously expected, and the gene-to-metabolite correlations have been elucidated mostly by an integrated analysis of transcriptomes and metabolomes. For example, most genes involved in the biosynthesis of flavonoids in Arabidopsis have been characterized by this method. A similar approach has been applied to the functional genomics for production of phytochemicals in crops and medicinal plants. Great promise is seen in metabolic quantitative loci analysis in major crops such as rice and tomato, and identification of novel genes involved in the biosynthesis of bioactive specialized metabolites in medicinal plants. PMID- 23628004 TI - Outcomes at least 10 years after cemented PF(r) (Zimmer) total hip arthroplasty: 83 cases. AB - INTRODUCTION: Cementless total hip arthroplasty (TKA) is gaining ground over cemented TKA. The objective of this study was to assess survival rates of a cemented THA implant (PF((r)), Zimmer), after at least 10 years and to assess changes in acetabular bone structure. MATERIAL AND METHODS: Eighty-three ceramic on-polyethylene THA prostheses were implanted between 1998 and 2001. Clinical outcomes were assessed using the Harris hip score and Postel Merle d'Aubigne score. For each hip, radiographs were examined for acetabular radiolucent lines, geodes, and granulomas; in addition, changes in bone structure and trabeculae were assessed comparatively to the other hip and classified from no change to severe osteolysis. Changes in trabeculae served to assess the loads applied to the bone. Polyethylene wear was assessed using the Livermore method. RESULTS: A single patient was lost to follow-up. At last follow-up, 16 patients had died and six were contacted and had not required revision surgery; the remaining 52 patients (59 THAs) were re-evaluated and none had evidence of loosening. The Harris hip score at last evaluation was 91.6 compared to 60.5 preoperatively. No hips had evidence of acetabular osteolysis. For two hips, the radiographs showed complete acetabular radiolucent lines less than 2mm in width, with no mobilisation. Trabecular distribution was homogeneous with no stress shielding. Mean annual rate of wear was 0.08mm. No instances of femoral component loosening were recorded; granulomas involving no more than five Gruen zones were seen in three cases. DISCUSSION: This study confirms the reliability of cemented THA, with a 12-year survival rate of 98.3%, in keeping with earlier data. Thus, our results establish that cemented ceramic-on-polyethylene prostheses remain valid options for THA. LEVEL OF EVIDENCE: IV. PMID- 23628005 TI - The prostaglandin agonist beraprost aggravates doxorubicin-mediated apoptosis by increasing iNOS expression in cardiomyocytes. AB - Doxorubicin (DOX) is widely used as an anti-cancer agent although it causes irreversible cardiomyopathy by increasing oxidative stress and deregulating nitric oxide production. Beraprost (BPS), a stable prostacyclin (PGI2) analog, is a potent vasodilator that has beneficial effects on myocardial ischemia. The objectives of the present study were to delineate the uncertain effects of prostcyclin therapy on DOX induced cardiomyopathy and to explore the mechanisms underlying PGI2 and DOX interaction. For this reason, we stimulated endogenous PGI2 production using bicistronic COX-1/PGIS gene transfer and BPS supplementation, and investigated the effects on DOX-induced cardiomyopathy. Caspase-dependent protein content, lactate dehydrogenase (LDH), DNA fragmentation, and TUNEL positive cells were elevated in DOX-treated cardiomyocytes. These indicators were further elevated by adenovirus-COX- 1/PGIS transfection or BPS supplementation. In addition, PGI2 overexpression further increased iNOS expression and superoxide accumulation in cardiomyocytes compared with DOX alone, which may be the reason for aggravated cytotoxicity. Moreover, BPS can induce cAMP response elements (CRE) binding to the iNOS promoter and phospho- cAMP response element binding protein (CREB) expression in a cyclic AMP dependent manner. Our in vivo studies show that MnTBAP and aminoguanidine treatment of DOX and BPS co-administered in mice can attenuate caspase-3 and PARP 1 protein expression, and improve mouse survival, as observed in the iNOS gene deleted mice. In conclusion, we demonstrated that BPS or adv-COX-1/PGIS increases PGI2 levels through iNOS expression and peroxynitrite production, via CREB protein phosphorylation; thereby aggravating DOX-mediated cardiotoxicity. PMID- 23628003 TI - The impact of sex on brain responses to smoking cues: a perfusion fMRI study. AB - BACKGROUND: Anecdotal and clinical theories purport that females are more responsive to smoking cues, yet few objective, neurophysiological examinations of these theories have been conducted. The current study examines the impact of sex on brain responses to smoking cues. METHODS: Fifty-one (31 males) cigarette dependent sated smokers underwent pseudo-continuous arterial spin-labeled perfusion functional magnetic resonance imaging during exposure to visual smoking cues and non-smoking cues. Brain responses to smoking cues relative to non smoking cues were examined within males and females separately and then compared between males and females. Cigarettes smoked per day was included in analyses as a covariate. RESULTS: Both males and females showed increased responses to smoking cues compared to non-smoking cues with males exhibiting increased medial orbitofrontal cortex and ventral striatum/ventral pallidum responses, and females showing increased medial orbitofrontal cortex responses. Direct comparisons between male and female brain responses revealed that males showed greater bilateral hippocampal/amygdala activation to smoking cues relative to non-smoking cues. CONCLUSIONS: Males and females exhibit similar responses to smoking cues relative to non-smoking cues in a priori reward-related regions; however, direct comparisons between sexes indicate that smoking cues evoke greater bilateral hippocampal/amygdalar activation among males. Given the current literature on sex differences in smoking cue neural activity is sparse and incomplete, these results contribute to our knowledge of the neurobiological underpinnings of drug cue reactivity. PMID- 23628006 TI - Non invasive imaging of myocardial infarction with computed tomography and magnetic resonance. AB - Myocardial infarction is a major cause of death and disability worldwide. Myocardial infarction may represent a major catastrophic event leading to severe hemodynamic failure or sudden death or it may occur repeatedly in patients with established heart disease. In this context, the role of imaging techniques may become useful for the understanding of the determinants in a preclinical setting before acute coronary events, and for an accurate and correct diagnosis of myocardial infarction. Three-dimensional noninvasive imaging techniques, such as Cardiac CT (CCT) and Cardiac MR imaging (CMR) were widely developed in the last two decades. These imaging techniques may provide new insights into understanding, assessment and follow-up of myocardial infarction. CCT is mainly oriented to morphological assessment including applications such as the detection of coronary artery stenoses even in acute settings, the evaluation of coronary atherosclerotic burden, and the follow-up of patients with known coronary artery disease who underwent myocardial revascularization. On the other hand, CMR is the reference standard for the functional assessment of the heart with evaluation of volumes, mass, and contractility of the ventricles. CMR myocardial viability imaging with delayed contrast enhancement has become broadly accepted for the detection and characterization of the extent of acute and chronic myocardial infarction. PMID- 23628007 TI - Cardiac oxidative stress and inflammatory cytokines response after myocardial infarction. AB - Oxidative stress in heart failure or during ischemia/reperfusion occurs as a result of the excessive generation or accumulation of free radicals or their oxidation products. Free radicals formed during oxidative stress can initiate lipid peroxidation, oxidize proteins to inactive states and cause DNA strand breaks. Oxidative stress is a condition in which oxidant metabolites exert toxic effects because of their increased production or an altered cellular mechanism of protection. In the early phase of acute heart ischemia cytokines have the feature to be functional pleiotropy and redundancy, moreover, several cytokines exert similar and overlapping actions on the same cell type and one cytokine shows a wide range of biological effects on various cell types. Activation of cytokine cascades in the infarcted myocardium was established in numerous studies. In experimental models of myocardial infarction, induction and release of the pro inflammatory cytokines like TNF-alpha (Tumor Necrosis Factor alpha), IL-1beta (Interleukin- 1beta) and IL-6 (Interleukin-6) and chemokines are steadily described. The current review examines the role of oxidative stress and pro inflammatory cytokines response following acute myocardial infarction and explores the inflammatory mechanisms of cardiac injury. PMID- 23628008 TI - Confocal laser scanning microscope, Raman microscopy and Western blotting to evaluate inflammatory response after myocardial infarction. AB - Cardiac muscle necrosis is associated with inflammatory cascade that clears the infarct from dead cells and matrix debris, and then replaces the damaged tissue with scar, through three overlapping phases: the inflammatory phase, the proliferative phase and the maturation phase. Western blotting, laser confocal microscopy, Raman microscopy are valuable tools for studying the inflammatory response following myocardial infarction both humoral and cellular phase, allowing the identification and semiquantitative analysis of proteins produced during the inflammatory cascade activation and the topographical distribution and expression of proteins and cells involved in myocardial inflammation. Confocal laser scanning microscopy (CLSM) is a relatively new technique for microscopic imaging, that allows greater resolution, optical sectioning of the sample and three-dimensional reconstruction of the same sample. Western blotting used to detect the presence of a specific protein with antibody-antigen interaction in the midst of a complex protein mixture extracted from cells, produced semi quantitative data quite easy to interpret. Confocal Raman microscopy combines the three-dimensional optical resolution of confocal microscopy and the sensitivity to molecular vibrations, which characterizes Raman spectroscopy. The combined use of western blotting and confocal microscope allows detecting the presence of proteins in the sample and trying to observe the exact location within the tissue, or the topographical distribution of the same. Once demonstrated the presence of proteins (cytokines, chemokines, etc.) is important to know the topographical distribution, obtaining in this way additional information regarding the extension of the inflammatory process in function of the time stayed from the time of myocardial infarction. These methods may be useful to study and define the expression of a wide range of inflammatory mediators at several different timepoints providing a more detailed analysis of the time course of the infarct. PMID- 23628009 TI - Effect of a new class of compounds of the group of substituted 5R1, 6H2-1,3,4 thiadiazine-2-amines on the inflammatory and cytokine response in experimental myocardial infarction. AB - This study investigated the effects of the L-17 compound of the group of substituted 5R1, 6H2- 1,3,4-thiadiazine-2-amines on the immune response and the plasma level of circulating cytokines in acute myocardial infarction (MI) in rats. The study was based upon experimental work which demonstrated the role of local and systemic inflammatory reactions in MI. Acute MI in rats was induced by left coronary artery coagulation. Histological study of the myocardium sections has been carried out at the 1(th) and 7(th) days of the experimental myocardial infarction. Serum activity of creatine phosphokinase (CPK), aspartate aminotransferase (AST), isoenzymes 1 and 2 and lactate dehydroge nase (LDH1-2) were investigated at days 1(st)and 7(th). ELISA analysis for plasma cytokine levels was performed using commercially available test kits following the manufacturer's instructions. Biochemical analysis in animals with the administration of the L-17 compound after MI showed that the AST and CPK levels at days 5 and 7 of experiments did not differ significantly from the values of intact animals. In animals of the group with MI without the administration of the L-17 compound, the IL-1 level 8 times and the TNF level 7.8 times exceeded the normal indicators, while the use of L-17 compound in the therapy resulted in only 1.8 times increase of IL-1 level and 4.7 times increase of TNF level in comparison with the norm. Thus, the introduction of L-17 compound in case of experimental MI delays exudative/alternative phase of inflammation, accelerates granulocytic and decreased the inflammation and anti-inflammation interleukins level. PMID- 23628010 TI - Angiotensin 1-7 promotes cardiac angiogenesis following infarction. AB - Angiogenesis is central to cardiac repair following myocardial infarction (MI). Cardiac angiotensin converting enzyme (ACE)2 significantly increased postMI, which is coincident with activated angiogenesis. The function of ACE2 is to generate angiotensin (Ang)1-7, an active peptide with cellular actions mediated by Mas receptors. The current study is to determine whether Ang(1-7) is involved in cardiac angiogenesis and facilitates cardiac repair. In the first portion of the study, the temporal expressions of cardiac ACE2 and Mas receptors were detected in rats with MI. In the second portion, MI rats were treated with or without a Mas receptor antagonist, A779 (1mg/kg/day given by minipump) for 7 days. Vascular density and expression of angiogenic mediators in the infarcted myocardium and cardiac function were examined. Compared to controls, ACE2 and Mas receptor levels were significantly increased in the infarcted myocardium for 4 weeks of the observation period. Newly formed vessels were evident in the infarcted myocardium at day 7. Mas receptor blockade significantly reduced vascular density in the infarcted myocardium and impaired ventricular function. In addition, A779 treatment significantly suppressed the cardiac expressions of vascular endothelial growth factor (VEGF)-D and matrix metalloproteinase (MMP)-9 but not expression of other angiogenic mediators, including monocyte Chemoattractant protein (MCP-1), VEGF-C, transforming growth factor (TGF)-beta1 and integrin beta3. These observations indicate that Ang(1-7) promotes angiogenesis via stimulating the expression of cardiac VEGF-D and MMP-9, thus facilitating cardiac repair and ventricular function. PMID- 23628011 TI - Role of Innate Immune System in Inflammation and Cardiac Remodeling After Myocardial Infarction. AB - The innate immune system is well recognized as the first line defense of foreign pathogens; however, it can also recognize endogenous signals released from injured tissues and induce sterile inflammation. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) have been identified as its receptors, and they have been shown to play a key role in the disease processes of sterile inflammation, including myocardial infarction (MI). In particular, NLRs are the key components of the caspase-1 activating platform known as the "inflammasome" which produces the potent proinflammatory cytokine interleukin-1beta. The current article reviews the role of the innate immune system, especially TLRs and inflammasomes, in the pathophysiology of MI. PMID- 23628012 TI - The meaning of different forms of structural myocardial injury, immune response and timing of infarct necrosis and cardiac repair. AB - Although a decline in the all-cause and cardiac mortality rates following myocardial infarction (MI) during the past 3 decades has been reported, MI is a major cause of death and disability worldwide. From a pathological point of view MI consists in a particular myocardial cell death due to prolonged ischemia. After the onset of myocardial ischemia, cell death is not immediate, but takes a finite period of time to develop. Once complete myocytes' necrosis has occurred, a process leading to a healed infarction takes place. In fact, MI is a dynamic process that begins with the transition from reversible to irreversible ischemic injury and culminates in the replacement of dead myocardium by a fibrous scar. The pathobiological mechanisms underlying this process are very complex, involving an inflammatory response by several pathways, and pose a major challenge to ability to improve our knowledge. An improved understanding of the pathobiology of cardiac repair after MI and further studies of its underlying mechanisms provide avenues for the development of future strategies directed toward the identification of novel therapies. The chronologic dating of MI is of great importance both to clinical and forensic investigation, that is, the ability to create a theoretical timeline upon which either clinicians or forensic pathologists may increase their ability to estimate the time of MI. Aging of MI has very important practical implications in clinical practice since, based on the chronological dating of MI, attractive alternatives to solve therapeutic strategies in the various phases of MI are developing. PMID- 23628013 TI - [Concept of mesenchymal stem cells: bring more insights into functional research of MSC]. AB - Mesenchymal stem cells have generated great interest among researchers and physicians due to their unique biological characteristics and potential clinical applications. Here, I propose for the first time the concept of a hierarchical system which is composed of all mesenchymal stem cells from post-embryonic subtotipotent stem cells to MSC progenitors. Post-embryonic subtotipotent stem cells are left-over cells during embryonic development and are on the top of the hierarchy. MSC system is a combination of cells that are derived from different stages of embryonic development, possess different differentiation potential and ultimately give rise to cells that share a similar set of phenotypic markers. The concept of MSC system has important implications: (1) it entirely explains the three important biological characteristics of MSC: stem cell properties of MSC, MSC as components of tissue microenvironment and immunomodulatory functions of MSC. (2) It balances immune responses and tissue metabolism. (3) It could provide tissue-specific stem cells for clinical application with high efficiency and safety. In a word, this concept constitutes an important part of the biological properties of MSC and will help researchers gain better insight into MSC. PMID- 23628014 TI - [Effects of Rheb overexpression in HL-60 and K562 leukemia cell lines]. AB - mTOR (mammalian target of rapamycin) is the center for cellular activities. It controls many cell activities via inhibiting apoptosis and promoting cell growth. Rheb can activate mTOR signaling pathway and participate in genesis and development of multiple cancers. This study was purposed to explore the underlying role of Rheb in human myeloid leukemia by using the myeloid leukemia cell lines. Two myeloid leukemia cell lines HL-60 and K562 overexpressing Rheb were established with retrovirus containing Rheb. The mRNA and protein expressions of Rheb were determined by Real-Time PCR and Western blot respectively. Cell proliferation rate was examined by CCK-8 assay and apoptosis rate was analyzed using Annexin V and 7-AAD double-staining. The results showed that Rheb was overexpressed in both HL-60 and K562 cell lines. The Rheb overexpression cell lines were successfully established. It is found that overexpression of Rheb could promote cell growth. Furthermore, the overexpression of Rheb could accelerate cells entering into G2/M phase (P < 0.01), while did not affect the apoptosis. It is concluded that Rheb overexpression promotes myeloid leukemia cell proliferation through accelerating cell cycle progression. PMID- 23628015 TI - [Methylation of CpG island in promoter region of RUNX2 gene and its expression in HOX11(+) acute T lymphoblastic leukemia]. AB - This study was purposed to detect the methylation status in promoter region of RUNX2 gene and its expression in cell lines and patients with HOX11(+) T-cell acute lymphoblastic leukemia (T-ALL) and to explore the relationship between the expression level of RUNX2 gene and methylation of CpG island in its promoter region. The methylation pattem in promoter region of RUNX2 gene was detected with bisulfite sequencing PCR, DNA methylation immunoprecipitation technique and promoter oligonucleotide microarray analysis and the expression levels of RUNX2 mRNA was detected with RT-PCR in 3 T-ALL cell lines (sil-ALL, DND41 and RPMI), as well as in 75 clinic bone marrow samples including 38 de novo T-ALL patients, 29 complete remission T-ALL patients and 8 normal samples. The results showed that there were hypermethylation of CpG island in promoter region of RUNX2 gene in patients with highly expressing HOX11(+) T-ALL. The methylation rate of the promoter CpG islands of RUNX2 gene in HOX11(+) T-ALL (78.9%) was significantly higher than that in HOX11(-) T-ALL (36.8%) (P < 0.01). The expression of RUNX2 in HOX11(+) cell lines was significantly lower than that in HOX11(-) cell lines, and the expression level of RUNX2 in the HOX11(+) T-ALL patients (0.581 +/- 0.257) was significantly lower than that in HOX11(-) T-ALL patients (0.835 +/- 0.317). The relationship between RUNX2 and HOX11 mRNA expression level showed a negative correlation (rs = -0.378, P < 0.01). The expression levels of RUNX2 gene negatively correlated with the methylation of CpG island in its promoter region (rs = -0.419, P < 0.01). It is concluded that HOX11 is a negative regulator of RUNX2 gene and the expression of RUNX2 is down regulated or even lost by promoter methylation in T-ALL, which demonstrate a better event-free survival and a marked trend for longer overall survival for HOX11-high T-ALLs. The expression and methylation level of RUNX2 gene may have some significance in evaluating the curative effect of T-ALL. The abnormal expression of RUNX2 may be a prognostic marker in T-ALL patients. PMID- 23628016 TI - [Effects of eEF1A1 re-expression on proliferation and apoptosis of Jurkat cells with knocked down eEF1A1 gene and its mechanisms]. AB - This study was aimed to explore the effects of expressing eukaryotic elongation factor 1A1 (eEF1A1) on proliferation and apoptosis in human acute T lymphocytic leukemia (T-ALL) cell line Jurkat with knocked down eEF1A1 gene and its mechanisms. eEF1A1-expressing lentivirus (LV) was constructed and used to transfect the Jurkat cells with knocked down eEF1A1 gene. Then, the expressions of eEF1A1 mRNA and protein were detected by real time PCR(RT-PCR) and Western blot respectively.Cell proliferation, apoptosis and cycle were detected by MTT method, Annexin V-APC labeling and DNA ploidy analysis respectively. The related protein expressions of phosphatidylinositol-3-kinase (PI3K)/serine/threonine kinase (Akt) signaling pathway were detected by Western blot. The results indicated that eEF1A1 mRNA and protein expressions of Jurkat cells with knocked down eEF1A1 gene were re-established by constructing eEF1A1-expression LV. Compared with negative control group (transfected with negative control LV and eEF1A1-shRNA LV), cell proliferation in eEF1A1 expression group was significantly enhanced, cell apoptosis was remarkably inhibited, percentage of cells in G0/G1 phase was significantly reduced alone with increased percentage of cells in S and G2/M phase, and the expression levels of p-Akt (Ser 473), nuclear factor kappa B (NF-kappaB), p-NF-kappaB (Ser 468), mammalian target of rapamycin (mTOR) and p mTOR (Ser 2448) protein significantly increased. It is concluded that eEF1A1 may have a carcinogenic effect in T-ALL cells. eEF1A1 expression has noticeable effects on the proliferation enhancement and apoptosis inhibition of Jurkat cells, which may be mediated by the up-regulation of PI3K/Akt/NF-kappaB and PI3K/Akt/ mTOR signaling pathway. PMID- 23628017 TI - [Correlation of HLA-A, B, DRB1 genes with leukemia]. AB - This study was aimed to investigate the correlation between HLA gene distribution and allele frequency of the patients with leukemia. PCR-SSP technique was used to detect the HLA genotype of 2994 umbilical cord blood units from healthy newborns (as control), the detecting result of which was compared with HLA genotypes of 1246 patients with leukemia searched in our cord blood bank. The differences between two groups were compared and analyzed. The results indicated that as compared with the control group, the allele frequencies of HLA-B*56 (0.56%), B*70 (0.24%) obviously increased (RR = 2.2546, 6.2598, chi(2) = 5, 5.98, P < 0.05), while the allele frequencies of HLA-A*03 (3.45%), A*30 (4.86%), B*13 (8.75%), B44* (3.25%), B61* (5.70%), DRB1*07 (8.23%), DRB1*15 (14.21%) obviously decreased in patients with leukemia (RR = 0.5889, 0.7187, 0.7359, 0.5713, 0.7127, 0.6242, 0.7976, chi(2) = 19.23, 9.82, 14.33, 20.48, 11.99, 33.21, 11.56, P < 0.01). It is concluded that HLA-B*56, B*70 alleles seem to be characterized by the genetic susceptibility to leukemia and may be served as risk markers for leukemia occurrence, while the HLA-A*03, A*30, B*13, B*44, B*61, DRB1*07, DRB1*15 can be considered as genetic indicators for resistance of leukemia. PMID- 23628018 TI - [Characteristics of 4 specific target antigens in adult acute lymphoblastic leukemia]. AB - This study was aimed to investigate clinical and prognostic significances of 4 target antigens (CD19, CD20, CD22 and CD33) for antibody-based immunotherapy and to evaluate the applications of these antibody-based target therapy to adult acute lymphoblastic leukemia (ALL). The immunophenotype of 220 adult patients with ALL were analyzed by four-color flow Cytometry, and cytogenetic and molecular parameters were detected by conventional cytogenetics, fluorescence in situ hybridization, real-time quantitative PCR, nested PCR and DNA sequencing. The results showed that CD19 positive (CD19(+)) cases were more in female (46.4% vs. 23.4%, P = 0.006), elderly patients aged > 60 years (14.4% vs. 2.1%, P = 0.022), CD33(+) co-expression cases (47.8% vs. 12.0%, P = 0.001) and genetic high risk group (55.8% vs. 20.8%, P = 0.002) compared with CD19 negative (CD19(-)) cases; CD20(+) cases had lower co-expression of CD13 than CD20(-) cases (31.6% vs.67.1%, P = 0.000) and no significant prognostic indications for CD20(+) was observed; CD22(+) cases had higher relapse rate at 12-month than CD22(-) cases (93.9% vs.57.1%, P = 0.041) in B-ALL patients; CD33(+) cases had higher incidence of Ph(+) than CD33(-) cases (43.5% vs.19.4%, P = 0.007) and significantly correlated with Ph(+) (r = 0.261, P = 0.006). It is concluded that elucidation of the characteristics of the target antigens (CD19, CD20, CD22, CD33) used for antibody-based immunotherapy will help hematologists making the correct decision whether and when to use these antibody-based target therapies. PMID- 23628019 TI - [Overexpression of eIF4E gene in acute myeloid leukemia and its relation with disease progression]. AB - The aim of this study was to detect the expression level of eIF4E gene in patients with non-treated, remission and non-remission/relapse acute myeloid leukemia (AML), and other non-malignant haematologic diseases so as to analyze and reveal the relationship of eIF4E gene expression with AML progression. SYBR Green I RT-PCR was used to assay the expression level of eIF4E mRNA extracted from bone marrow mononuclear cells in 30 patients with AML (6 in M2, 5 in M3, 8 in M4, 10 in M5, 1 in M6) and 20 patients with non-malignant hematologic diseases. The beta2-microglubin(beta2M) was used as internal reference and the formula 2(-DeltaCt)*100% was applied to calculate the expression level of eIF4E gene. The results showed that the eIF4E expression level (7.098 +/- 5.544)% in patients with non-treated and non-remitted/relapsed AML was significantly higher than that in patients with remission (0.964 +/- 0.312)% (P < 0.01) and non malignant hematologic diseases (0.248 +/- 0.163)% (P < 0.01). There was no difference between latter two group patients, even though the expression level of eIF4E gene in patients with M4 and M5 was higher. As compared with non-malignant hematologic diseases, the expression level of eIF4E gene of patients with remission patients showed no significant difference. It is concluded that the over-expression of eIF4E gene has been found in patients with AML, and its level obviously decreases along with remission of disease, thus the eIF4E gene may be a surveillance parameter for disease progression. PMID- 23628020 TI - [Abnormality of blood coagulation indexes in patients with de novo acute leukemia and its clinical significance]. AB - To explore hemorrhage risk and the clinical significance of abnormal change of prothrombin time (PT), activated partial thromboplastin time (APTT), plasma fibrinogen (FIB), plasma thrombin time (TT) and d-dimer (D-D) in de novo acute leukemia (except for APL), the different bleeding manifestations of 114 cases of de novo acute leukemia with different coagulation indexes were analyzed retrospectively. The correlation between these blood coagulation indexes and the possible correlative clinical characteristics were analysed, including age, sex, type of acute leukemia, initial white blood cell(WBC) and platelet(Plt) count, the proportion of blast cells in bone marrow and cytogenetic abnormality of patients at diagnosis. The results indicated that the incidence of abnormal blood coagulation was as high as 78.1% for de novo AL patients. These patients with 5 normal blood coagulation indexes may have mild bleeding manifestation, but the more abnormal indexes, the more severe bleeding. Both PT and D-D were sensitive indexes for diagnosis of level II bleeding. Incidence of abnormal blood coagulation significantly correlates with the proportion of blast cells in bone marrow (chi(2) = 4.184, OR = 1.021, P < 0.05) and more with D-D (P < 0.01), while age, sex, type of AL, WBC count, Plt count and abnormality of cytogenetics did not correlate with abnormal blood coagulation. It is concluded that the coagulation and fibrinolysis are abnormal in most patients with de novo acute leukemia. More abnormal indexes indicate more severe bleeding, and both PT and D D are sensitive indexes for diagnosis of level II bleeding. Higher proportion of blast cells in bone marrow predicts higher incidence of abnormal blood clotting. Acute leukemia with elderly age, high white blood cell count and adverse cytogenetics do not predict severer abnormal blood clotting. Detection of PT, APTT, TT, FIB, and D-D may help to judge whether the patients are in a state of hypercoagulability or disseminated intravenous coagulation, which will provide experiment evidences for early intervention and medication. PMID- 23628021 TI - [Clinical analysis of acute myeloid leukemia with CBFB-MYH11-positive]. AB - The study was aimed to investigate the clinical characteristics of acute myeloid leukemia (AML) with CBFB-MYH11 gene. The clinical data of 12 cases were analyzed retrospectively, including age, clinical characteristics, immunophenotype, treatment protocols and efficacy as well as the prognosis. The results indicated that 12 patients with CBFB-MYH11 were detected in 293 AML patients. The median age of the 12 patients was 32.5 (21 - 57) years old. According to French-American British (FAB) classification, 66.7% (8/12) patients was diagnosed as M4Eo and 33.3% patients was diagnosed as M4. At new diagnosis, the median WBC count was 19.8*10(9)/L (2.46 - 164.30*10(9)/L). The WBC count > 100*10(9) was found in 16.7% patients (2/12). The complete remission (CR) rate after 1 and 2 cycles of induction chemotherapy were 83.3% and 16.7% respectively, so the total CR rate was 100%. Estimated 5-year relapse-free survival (RFS) and overall survival (OS) were 80% and 83%, respectively. It is concluded that patients with CBFB-MYH11 are usually M4Eo and M4. Patients with this fusion gene are often associated with high frequency of CD33, CD34, CD117, HLA-DR, CD15, CD64 and CD14 expression. Patients with CBFB-MYH11 have a tendency of higher CR rate, longer RFS and OS. PMID- 23628022 TI - [Pathological characteristics of leukemia patients with secondary myelofibrosis and their relationship with the prognosis of disease]. AB - The objective of this study was to investigate the pathological characteristics of leukemia patients with secondary myelofibrosis and their relationship with prognosis. The pathological characteristics of 29 leukemia patients with secondary myelofibrosis were observed, the degree of hyperplasia between bone marrow smear and biopsy, as well as the changes of myelofibrosis after treatment were compared, and their relationship with the prognosis was analysed. The results indicated that the myelofibrosis may cause the decrease of pseudoepitheliomatous in bone marrow smear, and the increase of reticulin could be observed except the primary pathological characteristics in the biopsy with Gomori staining ++ - +++, and the secondary myelofibrosis could be alleviated after treatment. The overall prognosis of these patients was poor. It is concluded that the bone marrow biopsy has the important diagnostic value for the leukemia patients with secondary myelofibrosis, and the myelofibrosis can be alleviated after treatment, but the overall prognosis of leukemia patients with secondary myelofibrosis is poor. PMID- 23628023 TI - [Expression of SALL4 gene in patients with acute and chronic myeloid leukemia]. AB - The aim of this study was to investigate the expression level of the SALL4 gene and its clinical significance in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Real-time quantitative PCR (RQ-PCR) was performed to detect the expression level of SALL4 mRNA in bone marrow mononuclear cells (BMMNC) from 35 AML, 12 CML patients and 24 iron deficiency anemia patients as controls. The results indicated that the expression level of SALL4 in AML (0% 14%, median 1.43%) was obviously higher than that in controls (0% - 1%, median 0%) (P < 0.001). SALL4 expression was positive in 65.7% (23/35) AML patients. The frequency of SALL4 expression was in M2 (86.7%, 13/15) > M3 (75.0%, 6/8) > M1 (60.0%, 3/5) > M4 (14.3%, 1/7), and the difference among 4 groups was statistically significant (P = 0.008); there was no correlation of the frequency of SALL4 expression with the age, sex, white blood cell WBC count, hemoglobin concentration, platelet count and chromosomal abnormalities of AML patients (P > 0.05). All the 13 CML cases showed positive expression of SALL4 gene (1% - 128%, median 19.39%), which was higher than that in controls (P < 0.001). The analysis of receiver operating characteristic (ROC) curve showed the area under ROC curve (AUC) of AML and CML were 0.983 (95% confidence interval: 0.95 - 1.017) and 0.997 (95% confidence interval: 0.986 - 1.007) respectively. It is concluded that SALL4 expression is a common molecular event and can be considered as a molecular marker for assisting diagnosis of AML and CML. PMID- 23628024 TI - [Expression of IGF-IR and IR in children with acute lymphoblastic leukemia]. AB - This study was aimed to investigate the mRNA expression levels of insulin-like growth factor-I receptor (IGF-IR) and insulin receptor (IR) in peripheral blood lymphocytes of childhood ALL and their relationship with clinical features. The expression levels of IR and IGF-IR in peripheral blood lymphocytes of ALL children and healthy children were analysed. Peripheral blood samples were obtained from 43 ALL patients and 14 healthy children. The mRNA expression of IGF IR and IR was measured by RT-PCR. The results showed that IGF-IR was widely expressed on peripheral blood lymphocytes of ALL children and healthy controls, mRNA level of IGF-IR significantly increased in ALL children of newly diagnosed, relapsed and hyperglycemia groups (P = 0.000, P = 0.002 and P = 0.05)as compared with the normal control group. mRNA level of IGF-IR in CR group was significantly lower than that in newly diagnosed and relapsed groups (P = 0.000 and P = 0.018); mRNA level of IR in newly diagnosed and relapsed groups were significantly lower than that in the normal control group (P = 0.001 and P = 0.018). mRNA level of IR in CR group was significantly higher than that in newly diagnosed and relapsed groups (P = 0.000 and P = 0.001); mRNA levels of IGF-IR and IR correlated with the clinical stages of the disease, while they had no association with the sex, age and white blood cell counts at new diagnosis. It is concluded that IGF-IR positively correlates with the stages of the disease, indicating that IGF-IR plays a leading role in the proliferation of tumor cells, and its increased expression levels may reflect the malignant proliferation of ALL cells. PMID- 23628025 TI - [Expression of osteopontin in central nervous system leukemia and its clinical significance]. AB - This study was aimed to investigate the expression of osteopontin (OPN) in central nervous system leukemia (CNSL) and to understand its clinical significance. The expression level of OPN in serum of 62 pediatric patients (22 cases of CNSL, 20 cases of acute leukemia without extramedullary infiltration and 20 cases of nontumor patients) and 19 cases of CNSL with complete remission (CR)were assayed by ELISA; the expression changes of OPN mRNA in bone marrow of the CNSL patients were detected by RT-PCR. The results indicated that the serum OPN level was significantly higher in CNSL group (25.21 +/- 6.87 ng/ml) than that in acute leukemia group (13.24 +/- 2.73 ng/ml) (P < 0.001) and nontumorous group (3.14 +/- 1.60 ng/ml) (P < 0.001); the serum OPN level (4.35 +/- 1.50 ng/ml) in CNSL group with CR decreased obviously (P < 0.001) after therapy; RT-PCR analysis showed that the expression of OPN mRNA was higher in CNSL group as compared with other two groups (P < 0.01). It is concluded that the OPN expression may play a role in central nervous system infiltration of leukemia, the mechanism of which remains to need further clinical exploration. PMID- 23628026 TI - [Ratio balance of Th17 and Treg cells in peripheral blood of patients with chronic lymphocytic leukemia]. AB - This study was purposed to investigate the ratio of Th17 cells and CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells in peripheral blood of patients with chronic lymphocytic leukemia (CLL) and to explore their roles in the pathogenesis and clinical diagnosis. Based on the number of peripheral lymphocytes and treatment condition, the CLL patients were divided into 2 groups: untreated group (n = 30) and remission group (n = 15), the healthy control group (n = 20) was set up as well. The frequencies of Th17 and Treg cells of all cases were detected by flow cytometry (FCM). The results showed that frequencies of CD3(+)CD4(+)T cells and Th17 cells were significantly higher in untreated group than that in healthy control group (P < 0.05), the frequencies of CD3(+)CD8(+)T cells and Treg cells were significantly lower in untreated group than that in healthy control group (P < 0.05), the ratio of Th17/Treg was significantly higher in untreated group than that in healthy control group (P < 0.05). The frequencies of Th17 were not statistically different between remission and healthy control groups, the frequencies of Treg cells were significantly lower in remission group than that in healthy control group (P < 0.05), the ratio of Th17/Treg was significantly higher in remission group than that in healthy control group (P < 0.05), frequencies of Th17 cells were markedly lower in remission group than that in untreated group (P < 0.05). It is concluded that Th17/Treg imbalance exists in patients with CLL, which may play a key role in pathogenesis and development of CLL. PMID- 23628027 TI - [NVP-BEZ235 inhibits proliferation and colony-forming capability of CD34(+)CD38( ) human acute myeloid leukemia stem cells]. AB - This study was aimed to explore the effect of NVP-BEZ235, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on proliferation, cell cycle and colony forming capability of CD34(+)CD38(-) human acute myeloid leukemia (AML) KG1a cells. Flow cytometry was used to detect expression of CD34 and CD38 on the surface of human AML KG1a cells; Trypan blue assay was used to analyze the effect of NVP-BEZ235 at various concentrations on proliferation of KG1a cells; flow cytometry was performed to examine the cell cycle of KG1a cells after NVP-BEZ235 treatment; Soft agar colony-forming experiment was used to detect the colony forming ability of KG1a cells treated with NVP-BEZ235 at various concentrations. The results indicated that the percentage of CD34(+)CD38(-) AML KG1a cells was (98.02 +/- 0.72)%. NVP-BEZ235 (0.125 - 1 umol/L) inhibited the proliferation of KG1a cells in a time-and dose dependent manner (P < 0.05) and the 50% inhibition concentrations (IC50) at 24 h and 48 h were 0.597 umol/L and 0.102 umol/L, respectively. KG1a cells were arrested at G0/G1 phase after treating with 0.5 umol/L NVP-BEZ235 for 24 h, it was significantly higher than that of control group (83.2 +/- 3.80)% vs (43.47 +/ 9.60)% (P < 0.05). KG1a cells treated with NVP-BEZ235 (0 - 1 umol/L) for 14 d and 21 d, the number of colony decreased respectively from (375.67 +/- 21.46) per 2500 KG1a cells and (706.33 +/- 87.31) per 2500 KG1a cells to 0, with statistical significance (P < 0.05). It is concluded that NVP-BEZ235 can inhibit proliferation and colony-forming capability of CD34(+)CD38(-) human AML KG1a cells. PMID- 23628028 TI - [Dynamically monitoring minimal residual disease in acute leukemia after complete remission by multiparameter flow cytometry and its relation with prognosis]. AB - This study was purposed to investigate the dynamically monitoring minimal residual disease (MRD) by flow cytometry (FCM) in patients with acute leukemia (AL) after complete remission and its relation with prognosis. From October 2010 to May 2012, 58 cases of AL (including 45 cases of AML and 13 cases of ALL) were regularly monitored for MRD in bone marrow by FCM and their bone marrow morphology was observed by light microscopy at the same time which continued to relapse or to follow-up deadline in the Department of Hematology, the First Affiliated Hospital of Zhengzhou University. Through average follow-up for 9 months (3 - 21 months), the average MRD level of patients with CR was got. And the prognostic value of MRD level at different time points in AL patients after CR was analysed and summarized. MRD >= 1% was defined as positive, otherwise, as negative. The results showed that the maximum and minimum MRD levels of 45 AML patients were 9.57% and 0.01% respectively, the average was 0.67%; the maximum and minimum MRD levels of 13 cases of ALL patients were 7.9% and 0.0016% respectively, the average was 0.99%. Among 44 cases after induction therapy, the relapse rate of MRD(+) group was 53.3% (8/15), the relapse rate of MRD(-) group was 10.3% (3/29), and the relapse rate of MRD(+) group was higher than that of MRD(-) group (chi(2) = 7.58, P = 0.006). Among 58 cases after the first consolidatory therapy, the relapse rate of MRD(+) group was 62.5% (5/8), the relapse rate of MRD(-) group was 16.0% (8/50), and the relapse rate of MRD(+) group was higher than that of MRD(-) group (chi(2) = 6.11, P = 0.013). It is concluded that MRD detected by FCM has a large range (10(-6) - 10(-2)), which can not be used as a single indicator of complete remission. When MRD >= 1% after induction therapy and the first consolidatory therapy, the relapse rate significantly increases, MRD can be used as a sensitive indicator for prognosis. PMID- 23628029 TI - [Effect of valproic acid sodium on proliferation and apoptosis of acute T lymphoblastic leukemia Jurkat cells]. AB - This study was aimed to investigate the effects of valproic acid sodium (VPA) on the proliferation and apoptosis of acute T-lymphoblastic leukemia Jurkat cells. Jurkat cells were treated with different concentration of VPA. Proliferation inhibition curve was assayed and plotted by CCK-8 method and the cell apoptosis was detected by flow cytometry with Annexin V/PI double staining. The expression level of anti-apoptotic gene BCL-2 and pro-apoptosis gene Bak1 were detected by semi-quantitative RT-PCR. The results showed that the VPA inhibited the proliferation of Jurkat cells in concentration-dependent manner. As compared with the control group, the apoptosis of cells increased along with adding concentration of VPA; VPA could decrease the expression of BCL-2 gene, but did not show obvious effect on the expression of Bak1. It is concluded that the VPA can inhibit proliferation of Jurkat cells which possibly associates with the decrease of BCL-2 expression. PMID- 23628030 TI - [Mechanism for clofarabine inducing autophagic death of acute myelocytic leukemia cell U937]. AB - To explore the mechanism of autophagic death of acute myelocytic leukemia cell U937 induced by clofarabine, the MTT bioassay was used to analyze the growth inhibitory effect and half inhibition concentration on U937 incubated in vitro with different concentrations of clofarabine for 24 and 48 hours, and the flow cytometry was used to detect the autophagy rate of U937. The expression of Beclin 1 in U937 treated by clofarabine for 48h was measured by Western blot. The results indicated that when U937 cells were treated with 0.01 umol/L and 0.15 umol/L clofarabine for 48 hours, the proliferation inhibition rate was 46.92% +/- 4.24% and 86.10% +/- 1.16%, and the half inhibition concentration of clofarabine was 0.022 umol/L. With 0.01 umol/L and 0.1 umol/L clofarabine on U937 for 48 hours, the autophagy rate was 11.0033% +/- 1.4387% and 59.4133% +/- 3.5409%, and increased in dose-dependent manner (r = 0.99). Meanwhile the Beclin 1 was upregulated along with increase of clofarabine concentration, as compared with control group, the difference was statistically significant (P < 0.05). It is concluded that the different concentrations of clofarabine can significantly inhibit the proliferation of U937 in dose-dependent manner, and the mechanism of autophagic cell death in U937 may be associated with the upregulation of Beclin 1 expression. PMID- 23628031 TI - [2-DG enhances TRAIL-induced apoptosis of leukemia HL-60 cells]. AB - This study was purposed to investigate the effects of 2-deoxy-D-glucose (2-DG) on sensitizing HL-60 cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis and its possible mechanism. The proliferative inhibition of HL-60 cells treated with different concentrations of 2-DG and TRAIL was measured by MTT assay. The cells were treated with 2-DG, TRAIL, and 2-DG combined with TRAIL at the concentration < IC50 value, i.e. 10 mmol/L for 2-DG and 100 ng/ml for TRAIL. Apoptosis was analyzed by flow cytometry with PI staining; the expression of RIP1, GRP78, and PARP was analyzed by Western blot; the activity of caspase-3 was detected by special detection kit. The results showed that the combined treatment of HL-60 cells for 48 h induced an apoptotic rate of (45.1 +/- 4.3)%, which was significantly higher than that of treated with 2-DG or TRAIL alone; at the same time, the combined treatment potentiated the expression of GRP78 and caspase-3 activity, and down-regulated the expression of RIP1. It is concluded that 2-DG can sensitize HL-60 cells to TRAIL-induced apoptosis, which may be correlated with excessive endoplasmic reticulum stress response, down-regulation of RIP1, and increase of caspase-3 activity. PMID- 23628032 TI - [Effects of decitabine on proliferation and apoptosis of NB4 and K562 cells]. AB - This study was aimed to investigate the effects of decitabine (DAC) on proliferation and apoptosis of leukemia NB4 and K562 cells. The proliferation inhibition of DAC on NB4 and K562 cells was detected by Trypan blue staining. After treatment of DAC at different concentrations, the changes of cell cycle and CD11b expression was determined by flow cytometry. The cell morphological changes were observed by Wright's staining. The DNA ladder was used to detect cell apoptosis. The results indicated that DAC significantly inhibited the proliferation of NB4 and K562 cells in dose-and time-dependent manner. The median inhibitory concentration (IC50) of DAC-treated NB4 and K562 cells for 72 h was 0.113 umol/L and 0.138 umol/L, respectively. After treating these two cell lines with DAC at different concentration for 72 h, the cell ratio in G0/G1 phase significantly increased, while the cell ratio in S phase obviously decreased in 0.15 umol/L DAC group (P < 0.05). The expression levels of myeloid differentiation antigen CD11b of both cell lines significantly increased in contrast to the control group (P < 0.05). The cell morphology detected by Wright's staining displayed partial differentiation and apoptosis after treating NB4 and K562 cells with DAC for 48 h. Typical apoptotic DNA ladder was observed in 0.15 umol/L DAC group at 48 h. It is concluded that DAC can inhibit NB4 and K562 cell proliferation, induce cell differentiation and apoptosis, but more obviously for NB4 cells. PMID- 23628033 TI - [Effect of phenylhexyl isothiocyanate on Wnt/beta-catenin signaling pathway in Jurkat cell line]. AB - This study was purposed to investigate the effect of phenylhexyl isothiocyanate (PHI) on Wnt/beta-catenin signaling pathway, histone acetylation, histone methylation and cell apoptosis in Jurkat cell line. The viability of Jurkat cells after treatment with PHI was tested by MTT. Apoptotic rate of Jurkat cells was measured by flow cytometry. The levels of Wnt/beta-catenin related proteins including beta-catenin, TCF, c-myc, and cyclinD1, histone acetylated H3 and H4, histone methylated H3K9 and H3K4 were detected by Western blot. The results showed that PHI inhibited the cell growth and induced apoptosis in Jurkat cells in time-and dose-dependent manners. Its IC50 at 48 h was about 20 umol/L. Expression of histone acetylated H3, H4 and histone methylated H3k4 increased after exposure to PHI for 3 h, while histone methylated H3K9 decreased. Expression of beta-catenin was not changed after exposure to PHI for 3 h, but expression of beta-catenin, and its cell cycle-related genes such as TCF, c-myc and cyclinD1 decreased after exposure to PHI for 7 h. It is concluded that PHI regulates acetylation and methylation of histone, inhibits Wnt/beta-catenin signal pathway, and is able to induce apoptosis and inhibits growth of Jurkat cells. PMID- 23628034 TI - [Expression of PD-L1 in lymphoma and its effect on lymphoma proliferation and chemotherapy resistance]. AB - In order to investigate the effect of PD-L1 on lymphoma cell proliferation and chemotherapy resistance, and explore a new and promising approach for therapy of lymphomas. The level of PD-L1 expression in tissues of patients with lymphoma and cell lines were detected by immunohistochemistry and flow cytometry. Both the stable high-PDL1-A20 cell strain and low-PDL1-A20 cell strain were sorted by flow cytometry, then inoculated into BALB/c mice as to establish a lymphoma bearing mouse model for observing tumor genesis. Finally, the effect of PD-L1 on routinely chemotherapy drug-cisplatin were observed. The results showed that the PD-L1 highly and widely expressed in lymphoma tissue and cell strains, the stable high-PD-L1 cell strain sorted by flow cytometry have higher lymphoma genesis than that of low-PD-L1 cell strain. It is concluded that PD-L1 can promote lymphoma genesis, meanwhile the PD-L1 may resist effect of cisplatin on lymphoma cells through anti-apoptosis. PMID- 23628035 TI - [Immunophenotype analysis of leukemic mantle cell lymphoma]. AB - Mantle cell lymphoma (MCL) is a kind of mature B-cell neoplasms with significantly poor prognosis and is usually misdiagnosed. With the development of flow cytometry and cytogenetic technique, most patients were at leukemic phase when diagnosed. This study was purposed to investigate the immunophenotypes of MCL, the immunophenotype information of 22 leukemic MCL patients was analyzed retrospectively. All the patients were conformed t(11;14) translocation by fluorescence in situ hybridization. Immunophenotypes were detected by a four color flow cytometry including CD3, CD4, CD5, CD8, CD10, CD19, CD20, CD22, CD23, CD25, CD38, CD103, CD148, CD200, FMC7, ZAP-70, kappa, lambda. The results showed that CD19, CD5, CD20 and monoclonal sIg expressed in all 22 patients with CD20 high expression; CD22 expressed weakly in 17 patients; CD23 expressed in 6 patients including 2 cases highly expressed; FMC7 expressed in 12 patients. 5 patients were 4-point score and 17 patients had a score less than 4 according to CLL scoring system. CD148 and CD200 were detected in 18 patients, in which CD200 expressed negatively in 11 patients, CD200 expressed weakly in 7 patients with median fluorescence intensity (MFI) 25.8 (6.6 - 254.26); CD148 expressed positively in all 18 patients with median MFI: 337 (73.4 - 1341.9). It is concluded that the atypical immunophenotype is common in leukemia MCL, thereby the diagnosis of MCL needs comprehensively analyze with morphocytology, immunophenotype and cytogenetic, CD200 and CD148 as new bio-markers can differentiate MCL from chronic B cell lymphoproliferative disease. PMID- 23628036 TI - Analysis of clinical characteristics and prognostic factors of primary mediastinal T-cell lymphoblastic lymphoma. AB - Lymphoblastic lymphoma (LBL) comprises 2% to 4% of non-Hodgkin lymphomas cases in adults, of which 85% to 90% of LBL in adults is of T-cell phenotype. This study was aimed to evaluate the clinical characteristics and prognostic factors of patients with mediastinal T-LBL. Based on the retrospective analysis of the clinical data of 35 patients with mediastinal T-LBL during the period from January 1998 to January 2011, the clinical characteristics and prognostic factors of mediastinal T-LBL were summarized. The results showed that the total of 35 patients were identified (male 24 and female 11), with a median age of 19 (5 - 52) years. The majority of patients were in stage III/IV, 16 cases (45.7%) presented bulky mediastinal mass. Intrathoracic effusions (pleural, pericardial) were not uncommon (62.9%). Overall survival rate (OS) and progression-free survival rate (PFS) at 3 years for the entire cohort were 36% and 24%, respectively. OS and PFS at 5 years were 25% and 16.7%, respectively. Anemia at diagnosis were an important, independent predictor of OS (P = 0.048). Bulky mass (P = 0.048), superior vena cava syndrome (P = 0.021), and abnormal PLT count at diagnosis was the independent prognostic factors for PFS (P = 0.021). It is concluded that the patients with primary mediastinal T-LBL are characterized by a low incidence, bad prognosis, and short survival. For patients accompanying with anemia, bulky mass and superior vena cava syndrome, their prognosis is worse. PMID- 23628037 TI - [Expressions of VEGF and CXCR4 in diffuse large B cell lymphoma and their clinical significances]. AB - This study was aimed to investigate the expression levels of CXCR4 and VEGF in serum of patients with DLBCL and their clinical significances. The peripheral blood of 44 patients with newly diagnosed DLBCL and 20 healthy adults as a control group were chosen for study. And the expression levels of CXCR4 and VEGF in serum were detected by ELISA. The results showed that the expressions of VEGF and CXCR4 in DLBCL patients were higher than those in the control group (P < 0.05). The expression of VEGF was positively correlated with the expression of CXCR4 in DLBCL patients, and the correlation coefficient was 0.743 (P < 0.05). The VEGF expression in DLBCL patients was correlated with LDH, immunotyping, the number of extranodal involvements, Ann Arbor staging and ECOG performance score; while the expression of CXCR4 was correlated with LDH, immunotyping, the number of extranodal involvements and Ann Arbor staging. Univariate analysis showed that LDH, extranodal involvements, immunotyping, Ann Arbor staging, CXCR4 and VEGF were associated with OS. Multivariate analysis showed that the immunotyping and CXCR4 expression independently associated with OS. It is concluded that both expression levels of VEGF and CXCR4 are significant higher than those in the control group. CXCR4 expression positively correlates with VEGF expression and displays a prognostic significance for OS. This study suggests that combined targeting VEGF and CXCR4 may become a novel therapeutic strategy for diffuse large B cell lymphoma. PMID- 23628038 TI - [Clinical and prognostic analysis of 101 cases of primary gastrointestinal non Hodgkin's lymphoma]. AB - This study was purposed to analyze the clinical characteristics and prognostic factors in patients with primary gastrointestinal non-Hodgkin's lymphoma (PGI NHL). The pathological data of 101 PGI-NHL patients admitted in our hospital in the past 15 years were analyzed retrospectively. The results showed that 101 patients with PGI-NHL accounted for 14.49% of NHL in the same period, there were 64 males, 37 females, the range of ages was from 18 to 87 years old, median age was 61 years old; in disease distribution, the stomach PGI-NHL accounted for 58.42%, intestine PGI-NHL accounted for 39.60%, multiple GI involvements (MGI) accounted for 1.98%; in pathological type, diffuse large B cell lymphoma (DLBCL) accounted for 66.34%, mucosa-associated lymphoid tissue (MALT) lymphoma accounted for 17.82%, mantle cell lymphoma (MCL) accounted for 3.96%, enteropathy associated T cell lymphoma (EATL) accounted for 7.92%, extra-nodal nasal type NK/T cell lymphoma accounted for 1.98%, follicular lymphoma (FL) accounted for 0.99%, small lymphocyte lymphoma (SLL) accounted for 0.99%. Eighty-nine out of 101 patients were followed up (49 cases live, 40 cases dead), data of the 12 patients were lost; the median survival time was 29 months (1 - 173). The three year OS and five-year OS were 58.4% and 52.6% respectively. Univariate analysis revealed that the factors affecting OS included sex (P = 0.004), lesion site (P = 0.002), tumor size (P = 0.011), clinical Lugano staging for gastrointestinal non Hodgkin's lymphoma (P = 0.003), IPI score (P = 0.000), pathological cell phenotype (P = 0.001), and pathological type (P = 0.006), their differences were statistically significant (P < 0.05). Multivariate Cox regression analysis indicated that clinical Lugano staging for gastrointestinal non-Hodgkin's lymphoma, IPI score, pathological type were independent prognostic risk factors affecting OS. It is concluded that clinical Lugano staging for gastrointestinal non-Hodgkin's lymphoma, IPI score and pathological type are independent risk factors affecting OS. PMID- 23628039 TI - [The role of cytokines in lymphoma with anemia]. AB - This study was purposed to investigate the role of cytokines in pathogenesis of lymphoma-associated anemia. The levels of IFN-gamma, IL-1beta, IL-6, TNF-alpha and EPO in serum from 45 lymphoma patients and 12 normal controls were detected by using ELISA, the EPOR level on bone marrow cells were detected by flow cytometry, the CFU-E of bone marrow cultured in vitro was counted under inverted microscope. The results showed that 25 (55.6%) out of 45 newly diagnosed lymphoma patients had anemia before diagnosis, 13 (28.9%) had anemia during therapy, 7 (15.5%)never had anemia. The IFN-gamma and TNF-alpha levels in serum of patients with moderate and severe anemia were significantly higher than those in patients with mild anemia and without anemia as well as normal controls. The EPO, IL-6 and IFN-gamma levels correlated negatively with Hb concentration in patients, the EPOR level in patients without anemia significantly higher than that in patients with anemia and normal controls. The bone marrow CFU-E amount in patients showed positive correlation with Hb and EPOR levels. It is concluded that the increased IFN-gamma, TNF-alpha and IL-6 may contribute to the anemia in lymphoma, and yet the EPO and EPOR levels are elevated to balance negative regulatory effects on hematopoiesis and maintain normal hematopoiesis. PMID- 23628040 TI - [Expression and significance of p53-inducible gene 3 (PIG-3) in diffuse large B cell lymphoma]. AB - This study was aimed to investigate the expression of p53-inducible gene 3 (PIG 3) in diffuse large B cell lymphoma (DLBCL) and the relationship between PIG-3 and the pathogenesis of lymphoma. The expression of PIG-3 in 20 patients with DLBCL and 20 healthy adults (as a control group) was detected by Western blot and RT-PCR. The results showed that the expression of PIG-3 protein in patients with DLBCL was significantly lower than that in controls, but the expression of PIG-3 was higher after chemotherapy for 6 months than that before chemotherapy. RT-PCR detection demonstrated that the size of PIG-3 amplified product is 1285 bp, which is coincident with theoretic value. It is concluded that the down-regulation of PIG-3 expression may be closely related to pathogenesis of DLBCL, so the PIG-3 gene can considered as a important marker for judging therapeutic efficacy and prognosis of patients with DLBCL. PMID- 23628042 TI - [Peripheral blood monocyte hepcidin in patients with multiple myeloma is associated with anemia of chronic disease]. AB - Disorders of iron utilization caused by abnormal elevation of hepcidin levels are the main mechanism of anemia of chronic disease. Hepcidin is mainly produced by the liver. Recently it has been found that monocytes are another source of hepcidin. The increased hepcidin in serum and urine of multiple myeloma patients may be one cause of anemia of chronic disease (ACD). However it is unclear whether the peripheral blood monocyte hepcidin is involved in the pathogenesis of anemia of chronic disease. This study was purposed to investigate the role of monocyte hepcidin in multiple myeloma patients with anemia of chronic disease. The clinical data and peripheral venous blood of multiple myeloma patients were collected.Serum concentration of IL-6 and TNF-alpha was detected by ELISA. Peripheral blood monocytes were isolated by CD14(+) magnetic beads. Hepcidin, IL 6 and TNF-alpha mRNA of monocytes were detected by real time quantitative PCR. The results showed that the expression level of monocyte hepcidin mRNA in myeloma patients was higher than that in normal controls. In untreated patients, the expression level of monocyte hepcidin mRNA was negatively correlated with hemoglobin, and positively correlated with serum ferritin and IL-6 levels, but unrelated with TNF-alpha levels.It is concluded that the increased monocyte hepcidin levels in multiple myeloma patients may play an etiologic role in ACD. PMID- 23628041 TI - [Clinical analysis of 10 patients with de novo CD5 positive diffuse large B cell lymphoma]. AB - To explore the clinical characteristics, diagnosis, treatment outcome and prognosis of de novo CD5 positive diffuse large B cell lymphoma (CD5(+)DLBCL), clinical data of 10 patients with pathologically confirmed CD5(+)DLBCL were retrospectively analyzed. The results indicated that 9 out of 10 patients were older than 60 years. All cases were in III/IV stages according to Ann-Arbor Staging System. Bone marrow biopsy with immunohistochemistry showed lymphoma involvement in 5 cases. Nine patients received chemotherapy with anti-CD20 monoclonal antibody (Rituximab) except one. Five cases achieved CR, two cases achieved PR, two cases achieved SD, one case achieved PD. Eight cases died within 2 years because of relapse or disease progression, in which 3 cases developed central nervous system lymphoma. The median survival time was 16 (1-23) months, 2 year survival rate was 20.40%. It is concluded that de novo CD5(+) DLBCL is rare in clinic, but it is a kind of highly aggressive lymphoma with poor prognosis. So, new treatment strategy should be explored. PMID- 23628043 TI - [Significance of low molecular weight urinary protein for assessment of early renal damage in patients with multiple myeloma]. AB - This study was purposed to evaluate the clinical significance of low molecular weight urinary proteins for diagnosis of early renal damage in patients with multiple myeloma (MM). Medical records of 278 patients with MM in Nanjing School of Clinical Medicine from January 2004 to May 2012 were analyzed retrospectively. These patients were divided into 3 groups: glomerular damage group (n = 143), tubular damage group (n = 114) and normal group (n = 21). The clinical and laboratorial data were compared among them. The correlations of urinary retinol binding protein (RBP) or urinary N-acetyl-beta-D-amino-glucosaminidase (NAG) with blood urea nitrogen (BUN), Scr, blood cystatin-C (Cys-C), clearance of creatinine (Ccr), 24 h protein uria and 24 h urine light chains were further analyzed, and the correlation of renal tubulointerstitial lesion scores with low molecular weight urinary proteins in 61 patients were also analyzed. The area under curve (ROC curve) was used to evaluate and compare the discrimination of urinary RBP and urinary NAG. The results showed that glomerular damage group had higher urinary RBP than tubular damage group. However, glomerular damage group had lower urinary NAG than tubular damage group. The two groups had higher urinary RBP and urinary NAG than that in normal group. Urinary RBP related positively to the level of Scr, BUN, Cys-C, 24 h proteinurias and related negatively to the level of Ccr. Urinary NAG related positively to the level of 24 h proteinurias, Ccr and related negatively to the level of Cys-C. Renal tubulointerstitial lesions were significantly correlated with urinary RBP, but weakly correlated with urinary NAG. It is concluded that urinary RBP significantly correlates with renal tubular damage. Compared with urinary NAG, urinary RBP can better assess the extent of renal damage, and has higher specificity. PMID- 23628044 TI - [Correlation of chromosome karyotype with dyshaematopoiesis and reticulin in myelodysplastic syndrome]. AB - This study was purposed to explore the correlation of chromosome karyotype with dyshaematopoiesis and reticulin in myelodysplastic syndrome (MDS). The data of 202 MDS patients diagnosed and treated in the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed in term of chromosome karyotype, dyshaematopoiesis and reticulin detection results. The chromosome karyotypes were categorized according to the International Prognostic Scoring System (IPSS). The results showed that there was a positive correlation between chromosome karyotype grading and number of lineages with dyshaematopoiesis (r = 0.443, P < 0.05). The detected rates of multilineage dyshaematopoiesis in patients with good, intermediate and poor chromosome karyotypes were 44.4%, 71.4% and 96.3% respectively. There was a positive correlation between chromosome karyotype grading and reticulin grading (r = 0.451, P < 0.05). The positive rates of reticulin in patients with good grading, intermediate and poor chromosome karyotypes were 36.8%, 64.3% and 92.6% respectively. The detected rate of multilineage dyshaematopoiesis, number of lineages with dyshaematopoiesis, the positive rate of reticulin and reticulin grade in patients with poor karyotypes were higher than those in patients with intermediate or good chromosome karyotypes (separately P < 0.01). The above data in patients with intermediate chromosome karyotypes were higher than those in patients with good chromosome karyotypes (separately P < 0.01). It is concluded that the chromosome karyotype grading positively correlates with the number of lineages with dyshaematopoiesis and reticulin grading. When the chromosome karyotype changed from good to poor, the detected rate of multilineage dyshaematopoiesis, number of lineages with dyshaematopoiesis, positive rate of reticulin and reticulin grading became higher and higher. PMID- 23628046 TI - [Construction and significance of recombinant hF9 minigene and its stable nonsense mutant cell lines]. AB - This study was purposed to construct the recombinant hF9 minigene and its stable nonsense mutant cell lines, and to investigate its significance. Minigene hF9 was cloned into the mammalian expression vector pCMV-Tag3B; a nonsense mutant containing a premature termination codon (PTC) in the 121(st) amino acid residue was obtained by PCR site-directed mutagenesis; minigene hF9 and nonsense mutant were respectively transfected into HepG2 cells with G418 treatment to get stable HepG2-WT and HepG2-N cell lines. The results confirmed that the minigene hF9 and nonsense mutant were constructed successfully. The gene of interest was amplified by RT-PCR from the stable cell lines, and the minigene hF9 was expressed in the stable cell lines. It is concluded that the recombinant hF9 minigene and its stable nonsense mutant cell lines are constructed successfully. The cell lines can be used to screen the drugs treating the nonsense mutation-caused hemophilia according to PTC read-through approaches. PMID- 23628045 TI - [Clinical significance of Helicobacter pylori in children with idiopathic thrombocytopenic purpura]. AB - This study was aimed to investigate the clinic significance of helicobacter pylori (HP) in children with idiopathic thrombocytopenic purpura (ITP). The infection of HP in 92 ITP children was determined by (13) C-Urea Breath Test, the same test was also performed on 66 healthy children. The 68 children infected with HP were randomly divided into 2 groups: single drug group treated only with corticosteroid and; combined drug group treated with corticosteroid and anti helicobacter pylori treatment. The results showed that 68 patients infected with HP were found in 92 ITP children (74.7%), 26 patients infected with HP were observed in 66 healthy children (39.4%), which was lower than that in ITP children (74.7%, P < 0.05). After anti-helicobacter pylori therapy, the total effective rate and cure rate of ITP patients increased respectively from 73.5% to 94.1%, and the total recurrence rate (17.0%) was much lower than single drug group (47.1%, P < 0.05). Otherwise, after therapy the platelet count in both two groups increased continuously, and at the same time point, the platelet count in anti-helicobacter pylori group was higher than that in the single drug group (P < 0.05). It is concluded that the ITP children have a higher infection rate of HP, which may be involved in the pathogenesis of ITP. Anti-helicobacter pylori therapy would help to improve the therapeutic efficacy and reduce the recurrence of ITP children. PMID- 23628047 TI - [Therapeutic efficacy evaluation of rabbit anti-thymocyte globulin combined with cyclosporine A in children with aplastic anemia]. AB - This study was aimed to investigate the therapeutic efficacy of rabbit anti thymocyte globulin (r-ATG) combined with cyclosporine A (CsA) and to analyse the efficacy-related factors in children with aplastic anemia (AA). Twenty five AA children treated with r-ATG [3.5 mg/(kg.d)*5 days] combined with CsA were analyzed retrospectively. The lymphocyte subgroups, CD4(+)/CD8 ratio and expression of CD55, CD59 on surface of neutrophils and erythrocytes in peripheral blood were detected by direct immunofluorescence method and flow cytometry; the responsive time, effective rate, adverse effects and infections after immunosuppressive therapy (IST) were analyzed; the distribution of T-lymphocyte subgroups in IST-effective and IST-uneffective groups was compared, and therapeutic efficacy-related factors were evaluated. The results showed that the response to treatments was found in 21 out of 25 cases, the total responsive rate was 84.0%; the response time was 3 - 6 months, average of 4 months; the effective rates in month 3, 6, 9, 12 after treatment were 56.0%, 72.0%, 80.0% and 84.0% respectively. The AA children with age >= 5 years old, course of disease < 6 months and absolute neutrophil value >= 1.5 *10(9)/L on 30 days after IST had good curative effect; the effective rate in AA children with age >= 5 years old, course of disease < 6 months, high or reverse ratio of CD4(+)/CD8(+) and absolute neutrophil value >= 1.5*10(9)/L after IST was higher than that in AA children with age < 5 years old, course of disease >= 6 months, normal ratio of CD4(+)/CD8(+) and absolute neutrophil value after IST < 1.5*10(9)/L (94.4% vs 57.1%, 90.4% vs 50.0%, 94.1% vs 62.5%, 94.1% vs 62.5%) (P < 0.05). The high effective rate was observed in AA children with decrease of CD55 and CD59 expression, but there was no significant difference (P > 0.05) as compared with normal expression of CD55, CD59. It is concluded that the treatment using r-ATG (3.5 mg/kg.d * 5 d) combined with CsA is a safe and effective for children with AA. Age, course of disease and absolute neutrophil value on 30 days after IST are the main factors affecting curative affect. PMID- 23628048 TI - [Changes of Th1/Th2/Th17 in patients received non-myeloablative haploidentical hematopoietic stem cell transplantation detected by flow cytometric bead array]. AB - This study was purposed to investigate the changes of Th1/Th2/Th17 in patients received non-myeloblastic haploidentical hematopoietic stem cell transplantation (NAHSCT). The levels of IL-2, IL-4, IL-6, IL-10, TNF-alpha and IFN-gamma, as well as IL-17 level were determined by flow cytometric bead array (CBA) in samples from 18 patients underwent allo-peripheral NAHSCT at different time points before and after transplantation. The results showed that all cytokines changed obviously after transplantation, and their serum levels were higher than that before transplantation. The expression levels of IL-2, IL-4 and IL-17 changed early, and their obviously up-regulation was found after transplantation. The expression levels of IL-6, IL-10 and TNF-alpha changed significantly, and were high as compared with that before transplantation. The change of INF-gamma serum level was observed late, its rising occurred at week 4 after transplantation. The expression of all cytokines kept increasing during 4 weeks after transplantation and peaked at week 4. It is concluded that the serum levels of all cytokines from the patients after NAHSCT increased significantly, in which the levels of IL-2, IL-4 and IL-17 increased early, but the level of INF-gamma changed late. The detection of cytokines is helpful for deep understanding the pathophysiologic mechanism of transplant-related complications. PMID- 23628049 TI - [Quantitative monitoring of multi-donor chimerism after multi-donor allogeneic hematopoietic stem cell transplantation]. AB - This study was aimed to establish a model for detecting the donor chimerism rate following the multi-donor hematopoietic stem cell transplantations, and simplify its calculation method. Patients with hematologic disease receiving allogeneic hematopoietic stem cell transplantation including single-donor and multi-donor were selected in this study and the donor cell chimerism rates were detected, using STR-PCR combined with capillary electrophoresis. The results indicated that the peaks of the sister alleles coming from the same individual were confirmed to have the approximate areas and can be replaced each other in the situation of mixed chimerism. In the calculation model, the value between reference chimerism and approximate chimerism have no significant difference using the hypothetical peak areas, and the result was confirmed to be accepted basing on typical measurement error between sister alleles (5% - 20%). It is concluded that the areas of share peaks can be replaced by non-share peaks and this conclusion can be used to calculate the double-donor CHM (DD-CHM)(%). Compared to the D alleles, R alleles show more strategic importance because it can lead to more accurate result and allowed simplifying the arithmetic calculations for DD-CHM(%). PMID- 23628050 TI - [Clinical research of reduced-intensity allogeneic hematopoietic stem cell transplantation for multiple myeloma]. AB - This study was purposed to explore the efficacy and feasibility of reduced intensity allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of multiple myeloma (MM). Three patients with MM from January 2011 to January 2012 in General Hospital of Beijing Military Area were treated by reduced intensity allo-HSCT. All donors are compatriots and affinity HLA identical. Donors were mobilized with granulocyte colony-stimulating factor (G-CSF), the MM patients were given combined transplantation of bone marrow and peripheral blood stem cells. Preconditioning regimen consisted of fludarabine combined with melphalan and anti-human thymocyte globulin, and the classic cyclosporin A (CsA) combined with methotrexate (MTX) was used to prevent graft-versus-host disease (GVHD). The preventive donor peripheral blood stem cell infusion in dose 0.2*10(8)/kg mononuclear cells (MNC) was applied after 3 months of transplantation, then the toxicity, GVHD and disease-free survival (DFS) in patients were observed after transplantation. The results showed that 3 patients got hematopoietic reconstitution, the average time of neutrophils >= 0.5*10(9)/L and platelets >= 20*10(9)/L was 14.3 d and 15.3 d respectively, the detection of implanting efficacy displayed 100% complete donor hematopoiesis. Follow-up to January 2013, the median follow-up time was 13 months (12 to 15 months), As a result, none of the patients got GVHD, infection and other serious complications, all patients are still in complete remission (CR), the longest DFS time has reached to 15 months. It is concluded that the reduced-intensity allogeneic hematopoietic stem cell transplantation is the effective method for MM, this method has the high safety and efficacy, as well as high complete remission rate in early transplantation, the MM patients may get a long-term survival. This method can be used as a key technology in clinic for treating MM. PMID- 23628051 TI - [Hematopoietic potential of Flk-1(+) populations in mouse embryonic AGM region]. AB - This study aimed to investigate the expression of Flk-1 on distinct hematopoietic precursor cells in E10.5 mouse AGM region. By flow cytometry, we found that < 10% of Flk-1(+) cells of E10.5 AGM region co-expressed CD41 and CD45/Ter119. Then, E10.5 AGM cells were fractionated into two subsets, the CD31(+)CD45(-)Ter119( )Flk-1(+)CD41(+) cells (R1, putative immature hematopoietic cells) and the CD31(+)CD45(-)Ter119(-)Flk-1(+)CD41(-) cells (R2, putative endothelial cells), followed by methylcellulose-based CFU-C assay and OP9-based stromal co-culture to examine their myeloid or/and lymphoid potential in vitro. The results showed that only R1 cells could give rise to typical hematopoietic colonies in CFU-C assay. In contrast, after co-cultured with OP9 for 7-9 days, both subsets could generate abundant hematopoietic progenitor cells (CD45(+)c-Kit(+)), myeloid cells (Gr 1(+)/Mac-1(+)), erythroid cells (Ter119(+)), and B lymphocytes (CD19(+)). It is concluded that both maturing CD41(+)CD45(-) hematopoietic percursor cells and homogenic endothelial cells express Flk-1 in E10.5 AGM region. It requires further functional assay in vivo to clarify whether the hematopoietic stem cells (HSCs) and their precursors retain Flk-1 expression at this developmental stage. PMID- 23628052 TI - [Efficient isolation of mesenchymal stem cells from human bone marrow by direct plating method combined with modified primary explant culture]. AB - Human bone marrow is the major source of mesenchymal stem cells (MSC). It was reported that the standard density gradient centrifugation method was not efficient in isolating MSC and it may be caused by the existing of bone marrow particles. In previous study, a lot of MSC were obtained by culturing bone marrow particles alone combined with standard method. However, it is time- and labor consuming to obtain bone marrow particles by filtering and to isolate MNC by density gradient centrifugation. This study was purposed to explore the more simple and efficient method to isolate MSC from bone marrow. Seven normal bone marrow aspirates were collected and centrifugated. The bone marrow particles floated on surface layers were cultured by modified primary explant culture, whereas the bone marrow aspirates deposited were cultured by direct plating method, then the immun phenotype and differentiation capability of isolated cells were analyzed. The results showed that in 3 of 7 aspirates, bone marrow particles were floated on surface layers, whereas the other bone marrow cells and some particles were deposited after centrifugation. The MSC were reliably isolated from the floating layers or deposited aspirates by modified primary explant culture and direct plating method separately. After 3 passages the isolated MSC did not express CD45 and CD34, but expressed CD105, CD73, CD44, CD90, CD49e and they could differentiate into chondrocytes and adipocytes. It is concluded that normal human bone marrow MSC can be isolated simply and efficiently by direct plating method in combination with modified primary explant culture. PMID- 23628053 TI - [Inhibitory effect of human umbilical cord-derived mesenchymal stem cells on interleukin-17 production in peripheral blood T cells from spondyloarthritis patients]. AB - In this study, the inhibitory effect of human umbilical cord-derived mesenchymal stem cells (hUCMSC) on interleukin-17 (IL-17) production in peripheral blood T cells from patients with spondyloarthritis (SpA) were investigated, in order to explore the therapeutic potential of hUCMSC in the SpA. Peripheral blood mononuclear cells (PBMNC) were isolated from patients with SpA (n = 12) and healthy subjects (n = 6). PBMNC were cultured in vitro with hUCMSC or alone. The expression of IL-17 in CD4(+) T cells or gamma/delta T cells were determined in each subject group by flow cytometry. IL-17 concentrations in PBMNC culture supernatants were measured by ELISA. The results indicated that the proportion of IL-17-producing CD4(+) T cells and IL-17-producing gamma/delta T cells of SpA patients were 4.5 folds and 5 folds of healthy controls [CD3(+)CD4(+)IL-17(+) cells (3.42 +/- 0.82)% vs (0.75 +/- 0.25)%, P < 0.01; CD3(+)gammadeltaTCR(+)IL 17(+) cells (0.30 +/- 0.10)% vs (0.06 +/- 0.02)%, P < 0.01]. After co-culture of PBMNC in patients with hUCMSC, the increased proportions of CD3(+)CD4(+)IL-17(+) cells and CD3(+)gammadeltaTCR(+)IL-17(+) cells in SpA patients were inhibited significantly by hUCMSC [CD3(+)CD4(+)IL-17(+) cells (3.42 +/- 0.82)% vs (1.81 +/- 0.59)% (P < 0.01); CD3(+)gammadeltaTCR(+)IL-17(+) cells (0.30 +/- 0.10)% vs (0.16 +/- 0.06)% (P < 0.01]. In response to phytohemagglutinin (PHA, 1 ug/ml), PBMNC from SpA patients secreted more IL-17 than that from healthy control [(573.95 +/- 171.68) pg/ml vs (115.53 +/- 40.41) pg/ml (P < 0.01)]. In the presence of hUCMSC, PBMNC of SpA patients produced less amount of IL-17 [(573.95 +/- 171.68) pg/ml vs (443.20 +/- 147.94) pg/ml, (P < 0.01)]. It is concluded that the IL-17 production in peripheral blood T cells from SpA patients can be inhibited by hUCMSC, which have therapeutic potential for SpA. PMID- 23628054 TI - [Clinical analysis of Epstein-Barr virus-associated hemophagocytic syndrome in children]. AB - The primary infection of Epstein-Barr virus (EBV) may results in hemophagocytic syndrome, known as EBV-associated hemophagocytic syndrome (EBV-AHS), but the clinical risk factors complicating this fatal disease in children with infectious mononucleosis (IM) are unknown. The aim of this study was to identify clinical features of EBV-AHS and to evaluate the curative effect of HLH-2004 protocol. The clinical and laboratory data of 644 IM children including 27 children developed into EBV-AHS and 43 HPS children associated with other diseases were retrospectively analyzed and logistic regression was used to identify the clinical risk factors complicating EBV-AHS. The results showed as follows: (1) the prevalence of EBV-AHS in IM children was 4.2% (27/644), and the prevalence in group aged younger than 3 years was higher than in other age groups. The incidence age of EBV-AHS was significantly younger than that of other HPS patients; (2) Liver function damage of group aged older than 7 years was much more severe in HPS patients. (3) Compared with other HPS patients, male patients were more common and liver function damage was severe in EBV-AHS patients, especially in the patients aged at 2 years or younger. (4) The fatality rate in the EBV-AHS patients was 37.0% (10/27). (5)After treatment with HLH-2004 protocol, the fatality rate in patients with EBV-AHS decreased from 50.0% to 18.2%, the overall survival (OS) of 3 years significantly increased (P = 0.032). It is concluded that IM is a benign self-limited disease, of which only about 4.2% patients will develop into EBV-AHS. Clinical risk factors identified in this study may be helpful for early diagnosis of IM children with complicated EBV-ASH, the HLH-2004 protocol can obviously improve prognosis of EBV-HPS. PMID- 23628055 TI - [Detection of serum neopterin in patients with hemophagocytic lymphohistiocytosis and its significance]. AB - This study was aimed to detect the peripheral blood serum neopterin (Npt) level in the patients with hemophagocytic lymphohistiocytosis (HLH) and to explore its significance in HLH. The enzyme-linked immunosorbent assay (ELISA) was applied to detect the serum Npt level and sCD25 level in 20 HLH patients before and after treatment and 15 healthy controls. The results indicated that the serum Npt and sCD25 levels in HLH patients were significantly higher than those in healthy controls (P < 0.0001). The serum Npt and sCD25 levels in the HLH group decreased significantly after treatment, respectively (P < 0.0001). The correlation analysis of Npt with sCD25 before and after treatment showed that they had significant correlation (r = 0.81, P < 0.05 before treatment; r = 0.65, P < 0.05 after treatment). Meanwhile, the level of serum Npt and ferritin had a significant correlation in newly diagnosed HLH patients (r = 0.55, P < 0.05). It is concluded that the serum Npt may play an important role in the HLH pathogenesis, the enhancement of Npt levels has an important significance for diagnosis and evaluation for HLH. PMID- 23628056 TI - [Changes of FoxP3, CD4(+)CD25(+) regulatory T cells, TLR2 and TLR9 in children with infectious mononucleosis]. AB - The aim of this study was to investigate the effects of TLR2, TLR9, CD4(+)CD25(+) regulatory T cells (Treg) and transcription factor FoxP3 in the pathogenesis of children with infectious mononucleosis (IM). Thirty-five acute IM patients admitted in our hospital from April 2010 to January 2011 were enrolled in this study. Thirty-five healthy subjects were taken as control. The thirty-five patients before treatment were considered as patients in acute stage, after treatment and without clinical symptom they were thought as patients in recovery stage. The expression levels of TLR2, TLR9 and FoxP3 mRNA were detected by real time PCR using SYBR Green I. The expression of T lymphocyte subset CD4(+)CD25(+) in peripheral blood mononuclear cells was detected by flow cytometry. The results showed that the relative levels of TLR2 mRNA (4.03 +/- 0.56), TLR9 mRNA (8.88 +/- 1.56) in peripheral blood mononuclear cells of IM patients in acute stage were significantly higher than those of the controls [TLR2 mRNA (2.22 +/- 0.57), TLR9 mRNA (3.63 +/- 1.30)] and IM patients in recovery stage [TLR2 mRNA (2.76 +/- 0.83), TLR9 mRNA (5.34 +/- 1.60)] (P < 0.01). The result of CD4(+)CD25(+) (2.38 +/- 1.32%) and relative level of FoxP3 mRNA(2.82 +/- 0.90) in peripheral blood mononuclear cells of IM patients in acute stage were lower than those of the control [CD4(+)CD25(+) (7.85 +/- 1.97%), FoxP3 mRNA (4.65 +/- 1.23) ] (P < 0.01). There was no significant difference in CD4(+)CD25(+) (6.81 +/- 1.84%), FoxP3 mRNA(4.11 +/- 1.37) levels between IM patients in recovery stage and the controls (P > 0.05). It is concluded that the expression of CD4(+)CD25(+)regulatory T cells is reduced, and its special transcription factor FoxP3 mRNA is down regulated, but expression levels of TLR2 mRNA, TLR9 mRNA are up-regulated in IM patients of acute stage. PMID- 23628057 TI - [Detection of weak D antigen by flow cytometry]. AB - Flow cytometry was previously applied for analysis of Rh(D) antigen density, therefore it was suggested that the flow cytometry may be used for routine detection of weak D positive phenotypes. This study was purposed to evaluate its practicability. Six weak D positive and 7 DEL individuals were detected by using saline, IAT and absorption/elution test from 2010 to 2011 years. By RHD genotyping, zygosity analysis and sequencing, 3 cases of weak D type 15, 3 cases of partial D type DVI-III and 7 cases of DEL carrying RHD1227A alleles were identified. Taking 2 normal Rh(D)-positive and 2 D-negative samples as controls, all the samples were tested by using flow cytometry, and the median fluorescence intensities were observed as well. The results indicated that all weak D type 15 and partial D type DVI samples were detected to be positive by flow cytometry, as compared with 2 Rh(D)-negative samples (P < 0.05). Seven 7 DEL samples were tested to be negative (P > 0.05), although one of 7 DEL was tested as "+/-" in IAT and strong positive in absorption/elution. The RHD zygosity analysis showed this DEL individual as RHD(+)/RHD(+) homozygote. It is concluded that the sensitivity of detecting D antigen by flow cytometry is similar to that of IAT, but lower than absorption/elution test. As for detecting weak D or partial D antigens, IAT is easier than flow cytometry; as for identifying DEL, the flow cytometry is not sensitive enough. PMID- 23628058 TI - [Serologic and molecular biological detection of rare B(A) blood group]. AB - This study was aimed to investigate one case with rare type B(A) in ABO blood group by using serological and molecular biological methods, and analyze the cause of inconsistency resulting from multiple detections. The serological method was used to identify the serum type of ABO blood group, at the same time the PCR sequencing method was used to detect the genotypes. The results indicated that the group typing and reverse typing for the blood donor were inconsistent, the group typing was AB, the reverse typing was B. The ABO genotype was B(A) 04 /001. This genotype was involved in nt640A > G point mutation which caused valine replacing methionine at 214. It is concluded that the sample inconsistent between the group typing and reverse typing could be typed by molecular biological method, and the molecular basis of weak expression of ABO blood group is elucidated too. PMID- 23628059 TI - [Expression of endothelial nitric oxide synthase mRNA in human RBCs during storage]. AB - This study was purposed to identify endothelial nitric oxide synthase (eNOS) mRNA in human RBCs during storage and to investigate the relationship of its changing profile and preservation time at 4 degrees C. RT-PCR and gene sequencing were applied to identify eNOS-mRNA in banked RBC. Real time PCR was used to study the relationship of eNOS-mRNA expression and preservation time. The results showed that eNOS mRNA was detected in RBC. Compared with fresh RBC, the content of eNOS mRNA in RBC was 0.868 +/- 0.119 stored for 1 week, which was 0.379 +/- 0.289, 0.108 +/- 0.134, 0.141 +/- 0.141, 0.125 +/- 0.12 stored for 2, 3, 4 and 5 weeks respectively. It is concluded that eNOS mRNA exists in human RBC and its content is decreasing gradually along with the prolongation of storage time in banked RBC. Stored for 3 weeks, the content of eNOS-mRNA remains to be at lower level of concentration in human RBC. PMID- 23628060 TI - [Current understanding of iron overload hazard in patients with myelodysplastic syndrome]. AB - Patients with myelodysplastic syndromes (MDS) become dependent on blood transfusions and develop into transfusional iron overload, which is exacerbated by increased absorption of dietary iron in response to ineffective erythropoiesis. However, it is uncertain whether there is an association among iron accumulation, clinical complications, and decreased likelihood of survival in MDS patients. Thereby our current understanding of the effects of transfusion dependency and iron overload in MDS are discussed. Particular emphasis should be placed on further characterizing the role of redox-active forms of labile iron and oxidative stress in iron overload, decreased life expectancy and increased risk of leukemic transformation in MDS patients with iron overload. PMID- 23628061 TI - [Ex vivo expansion of human hematopoietic stem/progenitor cells by TAT-HOXB4 homeoprotein and the prospect of its clinical use]. AB - As one member of the HOX gene family, HOXB4 gene is a specific transcription factor, playing an important role in regulating balance between self-renewal and differentiation of hematopoietic stem/ progenitor cells (HSPC). Recombinant human TAT-HOXB4 protein carrying the protein transduction domain of the HIV transactivating protein (TAT) is comparable to that induced by the human HOXB4 retrovirus. TAT-HOXB4-expanded HSPC populations keep the potential of differentiation and long-term repopulation in vivo. In this article, whether TAT HOXB4 protein can induce leukemia or can be applied to clinical treatment are reviewed, summarizing the structures of HOX gene and HOXB4 gene, role of HOXB4 in HSPC proliferation and different ion, HOX gene and leukemia, TAT-HOXB4 protein, Clinical application prospect of TAT-HOXB4 protein and so on. PMID- 23628062 TI - [Correlation of Eps8 with proliferation, metastasis and prognosis of malignant tumors]. AB - Epidermal growth factor receptor pathway substrate 8 (Eps8) is one of crucial kinase substrates for the epidermal growth factor receptors. Eps8 is related to mitosis and differentiation of normal cells. In recent years, it has been demonstrated that Eps8 involves in proliferation, metastasis and prognosis of many malignant tumors. Experiments have shown that Eps8 involves in Ras-Rac pathway of EGFR signaling by forming Eps8-Abi1-Sos1 tri-complex or participates in endocytosis mediated by rab5. Furthermore, Eps8 has also been found to regulate cell cycle. In conclusion, it may become a monitor and a new target for the treatment of malignant tumors. This review briefly introduces molecular structure and physiological function of Eps8, focusing on its function and molecular mechanism in proliferation, metastasis and prognosis of malignant tumors. PMID- 23628063 TI - [EB virus-associated lymphoproliferative disorders and cytokine storm]. AB - Epstein-barr virus (EBV)-associated lymphoproliferative disorders (EBV-LPD) include a series of diseases from chronic to aggressive EBV-positive T-cells, NK cells, T/NK cells or B-cell LPD. The occurrence and development of EBV-LPD are closely associated with the cytokine storm, the clinical manifestations are very complex. Studies found that the different types of EBV-LPD express different cytokine secretion patterns, which help to further understand the progression of diseases, thus the EBV-LPD can be diagnosed early and treated early. In this article, different cytokine secretion patterns and their roles in EBV-LPD progression are reviewed. The main problems discussed above are the classification of EBV-LPD, T/NK-LPD and cytokine, B-LPD and cytokine, HLH and cytokine, and so on. PMID- 23628064 TI - [Research progress of N-Myc roles in hematopoiesis and hematologic malignancies]. AB - N-Myc oncogene plays an important role in the process of hematopoietic cell proliferation and differentiation in embryos. Once the body suffers from hematologic malignancies, the expression of N-Myc would increase and significantly associate with disease progression. In this article the structure of N-Myc, the regulatory mechanism in the different hematopoietic lineages, the interaction in each signal pathways, the transgenic animal model of overexpression, and intervention by drugs are reviewed. PMID- 23628065 TI - [Research advances of anti-CD40 monoclonal antibody]. AB - CD40 and its receptor CD40L are a very important pair of co-stimulating molecule in immune response, which have extensive biological effects. After stimulating CD40 signal, it can exert corresponding function through MAPK (JNK, ERK, p38) pathway, PI3K cascade, as well as NF-kappaB and STAT. The CD40 signal is closely related to tumor immunity, this moleculer has already become targeted-molecule for cancer treatment. Recently, there have been many anti-CD40 monoclonal antibodies displaying good anti-cancer effect, among which CHIR-12.12, SGN-40 and CP-870, 893 developed rapidly and successively have entered clinical research stage. This review focuses the status of anti-CD40 monoclonal antibody, including distribution of CD40, physiological function of CD40, CD40 and tumor immunity, anti-CD40 monoclonal antibodies and so on. PMID- 23628066 TI - [Progress in biochemical characteristics of hemopexin and its clinical application]. AB - Hemopexin (HPX) is a plasma protein with the strongest binding capacity to heme and widely involved in modulation of a variety of physiological and pathological processes. The main physiological function of HPX is to bind and transport free toxic heme. Recent studies indicate that HPX also plays roles of anti-oxidant, anti-apoptosis, immune regulation and organic protection. In addition, HPX participates in regulation of cell differentiation and extracellular matrix reconstruction. In recent years, a great deal of progress has been made in studies of the mechanisms of HPX protective effects and on possible clinical application. In the past few years, especially, a number of proteomic studies have demonstrated that HPX could be served as positive molecular biomarkers for cancers of lung, liver, kidney, colon, and uterine myoma as well as osteoarthritis. In this review, recent progress in the biochemical characteristics and function of HPX and its possible clinical applications are summarized. PMID- 23628067 TI - [Role of signal transducer and activator of transcription 3 in the development of tumors]. AB - Signal transducer and activator of transcription 3 (STAT3) take part in cell proliferation, differentiation, survival, apoptosis, transformation, cellular immunity and some other important physiological and pathological processes. Among STAT3 signaling pathways, the JAK-STAT signaling pathway has been comprehensively studied. Abnormal activation of STAT3 is frequently detected in various tumors, and the abnormal activation is closely related with the tumorigenesis. Recent studies have found that mutations and several specific genotypes of single nucleotide polymorphisms in STAT3 gene may be involved in tumor formation, also suggesting the important role of STAT3 in tumor biology. In this review, the role of STAT3 in the development of tumors is briefly summarized. PMID- 23628068 TI - [Advances in immunotherapy of hematological malignancies by using chimeric antigen receptor-modified lymphocytes]. AB - Chimeric antigen receptors (CAR) are fusion proteins between single-chain variable fragments (scFv) from monoclonal antibodies and signaling domains of T cells, which allow T-cells recognize specific cell-surface targets in an MHC unrestricted fashion. The structure of CAR has changed over time, from first generation CAR (scFv + signaling moiety) to 2 and 3 generation CAR (combined with one or multiple costimulatory endodomains, such as CD28, 4-1BB and OX40), which enhance persistence, expansion and cytotoxicity of CAR. Many clinical trials treating hematological malignancies using the CAR-modified T-cells targeting CD19 and CD20 are under evaluation or even finished. These clinical trials indicated that CAR-based immunotherapy prolonged the survival of patients with relapsed/refractory B-cell malignancies. Furthermore, CAR have being studied to translate to other fields like adoptive therapy after hematopoietic stem cell transplantation. As to the treatment toxicity, CAR modified T-cell infusion is tolerant and safe in most patients. However, insertional mutagenesis, off-target effect and inflammatory response are safety issues surrounding CAR-modified T cell therapy. In this review, the use of CAR technique in treatment of hematologic malignancies and evaluation of CAR safety are summarized. PMID- 23628069 TI - [Research progress of novel porous hemostatic agents]. AB - The treatment of bleeding wound of solid visceral and the rescue of uncontrollable bleeding are still confronted with difficulties in surgery and first-aid field. Many researchers devote to study in the field of hemostasis, and the novel porous hemostatic agent is one of the hot spot of research about hemostasis. The review focuses on the hemostatic effect, properties, hemostatic mechanism, shortcoming and future trends of three novel porous hemostatic agents such as polysaccharides, zeolite and wollastonite. PMID- 23628070 TI - [Advances of studies on pathogenesis and management of paroxysmal nocturnal hemoglobinuria]. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder of hematopoiesis due to the inactivation of PIG-A gene. However, the presence of mutant PIG-A gene in a group of hematopoietic cells is not enough for the development of PNH, immunologic injury and apoptotic effects are considered to play an important role in clonal expansion. Knowledge of the molecular mechanisms leading to PNH has substantially increased in the past decades, which remarkably advances the diagnostic modalities and treatment approaches of patients with PNH. Though great progress has been made because of targeted therapy method, the challenges are still ahead. In this review the advances of studies on mechanism, laboratorial diagnosis and therapeutic protocols of PNH are summarized. PMID- 23628071 TI - [Effect of methylation inhibitor in the treatment of leukemia]. AB - More and more studies have found that the occurrence of tumors are directly related to the abnormal expression of oncogene and antioncogene. If the antioncogene is mutated or absent, the function of cells will be weakened and inactivated, the cells will be duplicated repeatedly out of control, then will induce occurrence and metastasis of tumor. For example, SHP-1 tyrosine phosphatase, as an antioncogene, is a key negative regulator in signaling transduction of haematopoietic cells. The decrease and silence of SHP-1 play an important role in tumorigenesis. If the oncogene in leukemia patients lost the effect of negative regulation of antioncogene, the oncogene would be expressed abnormally high, such as the oncogene c-kit (an important member of the class III in the tyrosine kinase receptor family) in many kinds of leukemia cells expresses actively. Studies have shown that the high methylation of promoter region would induce the inactivation of tumor suppressor and active expression of oncogene, therefore, the restoring normal methylation of promoter region will contribute to restoration of normal gene expression, thus achieving the purpose of gene therapy for leukemia. In this article, the methylation, methylation abnormality and leukemia, methylation suppressors and therapy of leukemia are briefly reviewed. PMID- 23628072 TI - High-sensitive Troponin T increase after exercise in patients with pulmonary arterial hypertension. AB - BACKGROUND: The current study aimed to investigate the release of myocardial high sensitive Troponin T (hsTnT) in patients with pulmonary arterial hypertension (PAH) in response to maximal physical exercise. METHODS: In 24 patients with PAH, symptom-limited cardiopulmonary exercise testing was performed. hsTnT was measured by the novel hsTnT assay with a lower limit of detection of 2 ng/L and a total imprecision of less than 10% at the 99th percentile value. hsTnT was related to NT-proBNP, WHO functional class and right ventricular (RV) function. Serial measurement was performed before and 30 min, 180 min, and 300 min after exercise. Healthy volunteers served as a control group. RESULTS: In 21 PAH patients, hsTnT levels were detectable before exercise with a close correlation between hsTnT and NT-proBNP. hsTnT was detectable in all PAH patients after exercise and significantly increased from 7.5 ng/L at baseline to 14.62 ng/L after 300 min, whereas levels of NT-proBNP remained constant with time. CONCLUSIONS: Using the novel hsTnT assay, the current study provides first evidence that hsTnT levels increase in PAH patients after maximal physical exercise, while levels of other biomarkers remain constant after exercise testing. This might provide new insights into pathophysiology and individual risk assessment in patients with PAH. PMID- 23628073 TI - Sodium-calcium exchangers in rat trigeminal ganglion neurons. AB - BACKGROUND: Noxious stimulation and nerve injury induce an increase in intracellular Ca(2+) concentration ([Ca(2+)]i) via various receptors or ionic channels. While an increase in [Ca(2+)]i excites neurons, [Ca(2+)]i overload elicits cytotoxicity, resulting in cell death. Intracellular Ca(2+) is essential for many signal transduction mechanisms, and its level is precisely regulated by the Ca(2+) extrusion system in the plasma membrane, which includes the Na(+) Ca(2+) exchanger (NCX). It has been demonstrated that Ca(2+)-ATPase is the primary mechanism for removing [Ca(2+)]i following excitatory activity in trigeminal ganglion (TG) neurons; however, the role of NCXs in this process has yet to be clarified. The goal of this study was to examine the expression/localization of NCXs in TG neurons and to evaluate their functional properties. RESULTS: NCX isoforms (NCX1, NCX2, and NCX3) were expressed in primary cultured rat TG neurons. All the NCX isoforms were also expressed in A-, peptidergic C-, and non-peptidergic C-neurons, and located not only in the somata, dendrites, axons and perinuclear region, but also in axons innervating the dental pulp. Reverse NCX activity was clearly observed in TG neurons. The inactivation kinetics of voltage-dependent Na(+) channels were prolonged by NCX inhibitors when [Ca(2+)]i in TG neurons was elevated beyond physiological levels. CONCLUSIONS: Our results suggest that NCXs in TG neurons play an important role in regulating Ca(2+)-homeostasis and somatosensory information processing by functionally coupling with voltage-dependent Na+ channels. PMID- 23628075 TI - Quantitative proteomics comparison of arachnoid cyst fluid and cerebrospinal fluid collected perioperatively from arachnoid cyst patients. AB - BACKGROUND: There is little knowledge concerning the content and the mechanisms of filling of arachnoid cysts. The aim of this study was to compare the protein content of arachnoid cysts and cerebrospinal fluid by quantitative proteomics to increase the understanding of arachnoid cysts. METHODS: Arachnoid cyst fluid and cerebrospinal fluid from five patients were analyzed by quantitative proteomics in two separate experiments.In a label-free experiment arachnoid cyst fluid and cerebrospinal fluid samples from individual patients were trypsin digested and analyzed by Orbitrap mass spectrometry in a label-free manner followed by data analysis using the Progenesis software.In the second proteomics experiment, a patient sample pooling strategy was followed by MARS-14 immunodepletion of high abundant proteins, trypsin digestion, iTRAQ labelling, and peptide separation by mix-phase chromatography followed by Orbitrap mass spectrometry analysis. The results from these analyzes were compared to previously published mRNA microarray data obtained from arachnoid membranes. RESULTS: We quantified 348 proteins by the label-free individual patient approach and 1425 proteins in the iTRAQ experiment using a pool from five patients of arachnoid cyst fluid and cerebrospinal fluid. This is by far the largest number of arachnoid cyst fluid proteins ever identified, and the first large-scale quantitative comparison between the protein content of arachnoid cyst fluid and cerebrospinal fluid from the same patients at the same time. Consistently in both experiment, we found 22 proteins with significantly increased abundance in arachnoid cysts compared to cerebrospinal fluid and 24 proteins with significantly decreased abundance. We did not observe any molecular weight gradient over the arachnoid cyst membrane. Of the 46 proteins we identified as differentially abundant in our study, 45 were also detected from the mRNA expression level study. None of them were previously reported as differentially expressed. We did not quantify any of the proteins corresponding to gene products from the ten genes previously reported as differentially abundant between arachnoid cysts and control arachnoid membranes. CONCLUSIONS: From our experiments, the protein content of arachnoid cyst fluid and cerebrospinal fluid appears to be similar. There were, however, proteins that were significantly differentially abundant between arachnoid cyst fluid and cerebrospinal fluid. This could reflect the possibility that these proteins are affected by the filling mechanism of arachnoid cysts or are shed from the membranes into arachnoid cyst fluid. Our results do not support the proposed filling mechanisms of oncotic pressure or valves. PMID- 23628074 TI - The dual effect of mesenchymal stem cells on tumour growth and tumour angiogenesis. AB - INTRODUCTION: Understanding the multiple biological functions played by human mesenchymal stem cells (hMSCs) as well as their development as therapeutics in regenerative medicine or in cancer treatment are major fields of research. Indeed, it has been established that hMSCs play a central role in the pathogenesis and progression of tumours, but their impact on tumour growth remains controversial. METHODS: In this study, we investigated the influence of hMSCs on the growth of pre-established tumours. We engrafted nude mice with luciferase-positive mouse adenocarcinoma cells (TSA-Luc+) to obtain subcutaneous or lung tumours. When tumour presence was confirmed by non-invasive bioluminescence imaging, hMSCs were injected into the periphery of the SC tumours or delivered by systemic intravenous injection in mice bearing either SC tumours or lung metastasis. RESULTS: Regardless of the tumour model and mode of hMSC injection, hMSC administration was always associated with decreased tumour growth due to an inhibition of tumour cell proliferation, likely resulting from deep modifications of the tumour angiogenesis. Indeed, we established that although hMSCs can induce the formation of new blood vessels in a non-tumoural cellulose sponge model in mice, they do not modify the overall amount of haemoglobin delivered into the SC tumours or lung metastasis. We observed that these tumour vessels were reduced in number but were longer. CONCLUSIONS: Our results suggest that hMSCs injection decreased solid tumour growth in mice and modified tumour vasculature, which confirms hMSCs could be interesting to use for the treatment of pre-established tumours. PMID- 23628076 TI - Localization of aquaporins in the mouse vestibular end organs. AB - CONCLUSION: We found that aquaporins (AQPs) in the fluid transporting cells, such as vestibular dark cells and endolymphatic sac epithelial cells, seem to be of importance in fluid transport in the inner ear, while those in the sensory and ganglion cells may play a functional role in sensory cell transduction. OBJECTIVE: Expression of AQPs (0-12) was analyzed in normal mouse vestibular end organs. METHODS: CBA/J mice were used in this study. Localization of AQPs 0-12 in the vestibular end organs and endolymphatic sac was investigated by immunohistochemistry. RESULTS: The AQPs were found abundantly distributed in many structures in the vestibular end organs, i.e. vestibular sensory and supporting cells, vestibular dark cells, vestibular ganglion cells, and the endolymphatic sac. PMID- 23628078 TI - Inhibitory activity against epidermal growth factor receptor (EGFR) based on single point mutations of active site residues. AB - Epidermal growth factor receptors belong to the ErbB family of receptor tyrosine kinases (TKs) involved in the proliferation of normal and malignant cells. EGFR has attracted considerable attention as a target for cancer therapy. The findings reported herein are believed to provide some novel insights into the design of effective drugs for the therapeutic treatment of EGFR-related cancers. In particular, it is shown using sophisticated computational tools in a systematic way that the affinity of a wide spectrum of thiazolo[4,5-d]pyrimidine analogs can be carefully tuned up by seeking the desired goal in the structural modifications of EGFR, such as single point mutations of the critical EGFR residues in the active site. It is also demonstrated that a large number of the small ligand molecules can be efficiently divided into subgroups of the structurally similar ligands and that every such a subgroup has its unique inhibitory activity signature. The protein engineering approach, as quite reproducible, is proposed to be a viable partner to experiment in addressing a variety of issues, including investigation of clinically important mutations, development of drug resistance, identification of the most promising anti-cancer drug candidates, etc. PMID- 23628077 TI - Nontuberculous mycobacterial infection after fractionated CO(2) laser resurfacing. AB - Nontuberculous mycobacteria are increasingly associated with cutaneous infections after cosmetic procedures. Fractionated CO2 resurfacing, a widely used technique for photorejuvenation, has been associated with a more favorable side effect profile than alternative procedures. We describe 2 cases of nontuberculous mycobacterial infection after treatment with a fractionated CO2 laser at a private clinic. Densely distributed erythematous papules and pustules developed within the treated area within 2 weeks of the laser procedure. Diagnosis was confirmed by histologic analysis and culture. Both infections responded to a 4 month course of a multidrug regimen. An environmental investigation of the clinic was performed, but no source of infection was found. The case isolates differed from each other and from isolates obtained from the clinic, suggesting that the infection was acquired by postprocedure exposure. Papules and pustules after fractionated CO2 resurfacing should raise the suspicion of nontuberculous mycobacterial infection. PMID- 23628079 TI - Structural elucidation of unique inhibitory activities of two thiazolo[ 4,5 d]pyrimidines against epidermal growth factor receptor (EGFR): implications for successful drug design. AB - In our previous study, a protein engineering approach, accounting for the effects of single point mutations of the binding site residues on the stability of 22 thiazolo[4,5-d]pyrimidines in complex with the intracellular kinase domain of EGFR (PDB ID: 1XKK), was established in a systematic manner to be an efficient strategy for the identification of anti-EGFR-related-cancer drug candidates. The inhibitory activities of two lignad molecules, 4-(7-(3-chloro-4 morpholinophenylamino)thiazolo[4,5-d]pyrimidin-2-ylamino)benzenesulfonamide and 4 (7-(4-morpholinophenylamino) thiazolo[4,5-d]pyrimidin-2 ylamino)benzenesulfonamide, exhibited some sort of uniqueness. Regardless of a slight mutual structural difference between these two ligands in only a peripheral Cl atom, their inhibitory activities against EGFR appeared to be associated with two quite opposite structural bases respectively. Herein, the fundamental rationalization of the remarkable standpoint is elaborated using both molecular docking and molecular dynamics simulations. Consequently, a number of implications of vital importance for the successful structure-based design of prospective drugs against EGFR-related cancers are discussed. PMID- 23628080 TI - Synthesis and biological evaluation of some novel thieno[2,3-d] pyrimidine derivatives as potential anti-inflammatory and analgesic agents. AB - A novel series of thienopyrimidine derivatives bearing various substituents or linked to various heterocyclic moieties through atoms spacers were prepared starting from 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6- carboxamide potassium salt 3. Twelve out of the prepared compounds were selected and evaluated for their antiinflammatory activity using the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays using diclofenac sodium as a reference standard. The ulcerogenic effects and acute toxicity (ALD50) values of these compounds were also determined. In addition, the analgesic activity of the same compounds was evaluated using the rat tail withdrawal technique. The results revealed that compounds 5a, 13, 14b, 15a, 16a and 16b had high anti-inflammatory effect comparable to diclofenac sodium, whereas compounds 5a, 14a, 15a and 16a revealed pronounced analgesic activity that is equal or higher than that of the reference. All of the tested compounds revealed high GI safety profile and were well tolerated by the experimental animals with high safety margin (ALD50 > 3.0g/Kg). PMID- 23628082 TI - Tea and non-tea flavonol intakes in relation to atherosclerotic vascular disease mortality in older women. AB - Epidemiological studies have indicated that dietary flavonoids generally, and flavonols specifically, may contribute to cardiovascular health. Tea consumption, which is often the main dietary source of flavonoids and flavonols, is associated with a reduced risk of cardiovascular outcomes. The primary objective of the present study was to explore the association of the habitual intake of flavonols from tea and non-tea sources with the risk of atherosclerotic vascular disease mortality in a population of elderly women. A total of 1063 women, aged over 75 years, were randomly selected from ambulant Caucasian women living in Perth, Western Australia. Flavonoid consumption was assessed using the US Department of Agriculture Flavonoid, Flavone and Proanthocyanidin databases. Atherosclerotic vascular disease mortality was assessed over 5 years of follow-up through the Western Australian Data Linkage System. During the follow-up, sixty-four women died from atherosclerotic vascular disease. Women in the highest compared with the lowest tertile of flavonol intake had a lower risk of atherosclerotic vascular disease death (OR 0.27, 95 % CI 0.13, 0.59; P<= 0.01 for trend in multivariate-adjusted models). Similar relationships were observed for flavonol intake derived from both tea (OR 0.38, 95 % CI 0.18, 0.79; P< 0.01) and non-tea (OR 0.41, 95 % CI 0.20, 0.85; P= 0.05) sources. Tea was the main contributor to flavonol intake (65 %), and the intakes of flavonols from tea and non-tea sources were not significantly correlated. In conclusion, increased consumption of flavonols was independently associated with a lower risk of atherosclerotic vascular disease mortality. Both tea and non-tea sources of flavonols were independently associated with this benefit. PMID- 23628083 TI - Long-term CPAP treatment partially improves the link between cardiac vagal influence and delta sleep. AB - BACKGROUND: Continuous positive airway pressure (CPAP) treatment improves the risk of cardiovascular events in patients suffering from severe sleep apnea hypopnea syndrome (SAHS) but its effect on the link between delta power band that is related to deep sleep and the relative cardiac vagal component of heart rate variability, HF(nu) of HRV, is unknown. Therefore, we tested the hypothesis that CPAP restores the link between cardiac autonomic activity and delta sleep across the night. METHODS: Eight patients suffering from severe SAHS before and after 4 +/- 3 years of nasal CPAP treatment were matched with fourteen healthy controls. Sleep EEG and ECG were analysed to obtain spectral sleep and HRV components. Coherence analysis was applied between HF(nu) and delta power bands across the first three sleep cycles. RESULTS: Sleep characteristics and spectral HRV components were similar between untreated patients, treated patients and controls, with the exception of decreased Rapid Eye Movement duration in untreated patients. Coherence and gain values between HF(nu) and delta EEG variability were decreased in untreated patients while gain values normalized in treated patients. In patients before and during long-term CPAP treatment, phase shift and delay between modifications in HF(nu) and delta EEG variability did not differ from controls but were not different from zero. In healthy men, changes in cardiac vagal activity appeared 9 +/- 7 minutes before modifications in delta sleep. CONCLUSIONS: Long-term nasal CPAP restored, in severe SAHS, the information between cardiovascular and sleep brainstem structures by increasing gain, but did not improve its tightness or time shift. PMID- 23628085 TI - Life-cycle stages of a Posthodiplostomum species (Digenea: Diplostomidae) from Patagonia, Argentina. AB - In Patagonia, populations of the galaxiid fish Galaxias maculatus are parasitized by metacercariae of a species of Posthodiplostomum (Digenea: Diplostomidae). The aim of this work was to describe larval and adult stages of this species in experimental and natural hosts from an Andean Patagonian lake. Specimens of G. maculatus and the pulmonate snail, Anisancylus obliquus, were collected in Patagua Lake. The snails were isolated in individual containers to observe emergence of cercariae, dissected, and examined under a stereoscopic microscope to record sporocysts and cercariae. Fish were examined to obtain metacercariae, and uninfected fish from Gutierrez Lake were exposed to cercariae from A. obliquus to obtain experimental metacercariae. Chicks and mice were infected with metacercariae from naturally infected G. maculatus to obtain experimental adults. Specimens recovered belong to Posthodiplostomum sp. on the basis of morphological features. This is the first description of sporocysts, cercariae, metacercariae, and adults stages of a Posthodiplostomum species in Patagonia, including data about its natural intermediate hosts. PMID- 23628084 TI - Hydrogen sulfide as a vasculoprotective factor. AB - Hydrogen sulfide is a novel mediator with the unique properties of a gasotransmitter and many and varied physiological effects. Included in these effects are a number of cardiovascular effects that are proving beneficial to vascular health. Specifically, H2S can elicit vasorelaxation, prevention of inflammation and leukocyte adhesion, anti-proliferative effects and anti thrombotic effects. Additionally, H2S is a chemical reductant and nucleophile that is capable of inhibiting the production of reactive oxygen species, scavenging and neutralising reactive oxygen species and boosting the efficacy of endogenous anti-oxidant molecules. These result in resistance to oxidative stress, protection of vascular endothelial function and maintenance of blood flow and organ perfusion. H2S has been shown to be protective in hypertension, atherosclerosis and under conditions of vascular oxidative stress, and deficiency of endogenous H2S production is linked to cardiovascular disease states. Taken together, these effects suggest that H2S has a physiological role as a vasculoprotective factor and that exogenous H2S donors may be useful therapeutic agents. This review article will discuss the vascular effects and anti-oxidant properties of H2S as well as examine the protective role of H2S in some important vascular disease states. PMID- 23628086 TI - Structural analysis for colchicine binding site-targeted ATCAA derivatives as melanoma antagonists. AB - Melanoma is the fatal form of skin cancer. Herein, a three-dimensional quantitative structure-activity relationship study on a series of 105 colchicine binding site-targeted 2-arylthiazolidine-4-carboxylic acid amides (ATCAA) derivatives as melanoma antagonists was conducted. The optimal CoMSIA model yields a Q(2) of 0.556, R(2)(ncv) of 0.833 and R(2)(pred) of 0.757, while the CoMFA yields a Q(2) of 0.569, R(2)(ncv) of 0.812 and R(2)(pred) of 0.589. In addition, molecular docking was also carried out. The study results demonstrated that: (1) Bulky substituents in Rings C and D significantly increase the biological activity of compounds while decrease the activity at Rings A and B; (2) Electropositive groups at Rings A and B as well as electronegative groups at Ring C help to increase the activity; (3) HB donor favors Rings A and D while HB acceptor favors Rings B and C. Besides, a statistical analysis of the key amino acids as well as the ones forming HB with various antagonists of the colchicine binding site was conducted based on 34 essays and found HB to be the key interaction that MTAs have with the colchicine binding site and that Ala 250, Asn 258, Thr 179, Lys 254 and Lys 352 are vital in the composition of the site and the formation of HB. The results of this study provide useful information on designing antagonists with improved activity and insight on the composition of the colchicine binding site. PMID- 23628087 TI - Alkyl caffeates as anti-Helicobacter pylori and scavenger of oxidants produced by neutrophils. AB - Helicobacter pylori pathogenic action involves the colonization of the gastrointestinal tract and a large production of reactive oxygen species (ROS) by the neutrophils attracted to the site of infection. The aim of this study was to evaluate caffeic acid and its alkyl esters as inhibitors of the release of ROS by Helicobacter pylori activated neutrophils and their bactericidal effect. The increased hydrophobicity caused by esterification had direct consequence in their efficiency as bactericidal agents against H. pylori and inhibitors of the production of ROS by neutrophils. The minimum inhibitory concentration (MIC) decreased from higher than 1000 MUg/mL (caffeic acid) to 250 MUg/mL to butyl and heptyl caffeate. The release of total ROS, superoxide anion and hypochlorous acid by activated neutrophils was also significantly decreased and the esters were more efficient than the acid precursor. In conclusion, the alkyl esters of caffeic acid have two properties that are complementary for the treatment of H. pylori infections: bactericidal activity and inhibitory effect upon generation of ROS by neutrophils. Hence, we propose that these easily synthesized and non expensive substances should be applied to in vivo experimental models of H. pylori induced gastric infections. PMID- 23628088 TI - Pharmacological properties of novel cyclic pentapeptides with u-opioid receptor agonist activity. AB - In our previous paper we have reported the synthesis and biological activity of a cyclic analog, Tyr-c(D-Lys- Phe-Phe-Asp)-NH2, based on endomorphin-2 (EM-2) structure. This analog displayed high affinity for the u-opioid receptor, was much more stable than EM-2 in rat brain homogenate and showed remarkable antinociceptive activity after intracerebroventricular (i.c.v.) injection. Even more importantly, the cyclic analog elicited weak analgesia also after peripheral administration, giving evidence that it was able to cross, at least to some extent, the blood-brain barrier (BBB). Here we describe further modifications of this analog aimed at enhancing brain delivery by increasing lipophilicity. Two new cyclic pentapeptides, Tyr-c(D-Lys-D-1-Nal-Phe-Asp)-NH2 and Tyr-c(D-Lys-D-2 Nal-Phe-Asp)-NH2 (where 1-Nal=1- naphthyl-3-alanine, 2-Nal=2-naphthyl-3-alanine) were synthesized and evaluated in biological assays. Both analogs showed high u opioid receptor affinity and agonist activity and were stable in the rat brain homogenates. Unfortunately, the increase of lipophilicity was achieved at the expense of water solubility. The analog with D-2-Nal residue showed strong analgesic effect when given i.c.v. but could not be tested after intravenous (i.v.) administration where higher concentrations of the compound are required. However, this analog showed inhibitory effect on gastrointestinal (GI) motility in vivo, providing an interesting approach to the development of peripherally restricted agents that could be useful for studying gastrointestinal disorders in animal models. PMID- 23628089 TI - Foodborne disease prevention and broiler chickens with reduced Campylobacter infection. AB - Studies have suggested that flies play a linking role in the epidemiology of Campylobacter spp. in broiler chickens and that fly screens can reduce the prevalence of Campylobacter spp. We examined the year-round and long-term effects of fly screens in 10 broiler chicken houses (99 flocks) in Denmark. Prevalence of Campylobacter spp.-positive flocks was significantly reduced, from 41.4% during 2003-2005 (before fly screens) to 10.3% in 2006-2009 (with fly screens). In fly screen houses, Campylobacter spp. prevalence did not peak during the summer. Nationally, prevalence of Campylobacter spp.-positive flocks in Denmark could have been reduced by an estimated 77% during summer had fly screens been part of biosecurity practices. These results imply that fly screens might help reduce prevalence of campylobacteriosis among humans, which is closely linked to Campylobacter spp. prevalence among broiler chicken flocks. PMID- 23628090 TI - Distribution and retention of rose bengal and disulphonated aluminium phthalocyanine: a comparative study in unicellular eukaryote. AB - Enhanced video-fluorescence microscopy and microspectrofluorometry were used to characterize the internalization, distribution and retention of two photosensitizers, rose bengal--a xanthene dye--and disulphonated aluminium phthalocyanine in eukaryote Paramecium aurelia. Rose bengal, because of its anionic nature, cannot diffuse across the cell membrane and accumulates there preferentially. In a drug-free medium the membrane fluorescence disappears after a few minutes. Complexation of rose bengal with low density lipoproteins gives rise to a different fluorescence pattern, where, in addition to membrane localization and diffuse cytoplasmic fluorescence, highly fluorescent endosomes are observed, which persisted for at least 1 h after drug treatment. Disulphonated aluminium phthalocyanine, on the contrary, seems to be directly internalized through an endocytotic process leading to the appearance of fluorescent endosomes, exhibiting a long persistence, together with cytoplasmic diffuse fluorescence. The presence of low density lipoproteins does not modify the internalization of the drug significantly, because of the very low yield of the complexation reaction. The potential of rose bengal as a photosensitizer for photodynamic therapy is discussed. PMID- 23628091 TI - IgG2 Fc structure and the dynamic features of the IgG CH2-CH3 interface. AB - The analyses of two human IgG2 Fc structures, determined in different crystal forms, and the comparison with IgG1 Fc structures reveals molecular features that are involved in accommodating and stabilizing structural conformations. In the IgG2 Fc structures relative positions of the CH2 domains with respect to the CH3 domains vary significantly from those observed for IgG1 Fc structures in similar unit cells. The analysis reveals that the movement of the CH2 domain in all of the Fc structures results from a pivoting around a highly conserved ball-and socket-like joint in which the CH2 L251 side chain (the ball) interacts with a pocket (the socket) formed by CH3 M428, H429, E430, and H435. Despite the change in positioning of the CH2 and CH3 domains, conserved hydrogen bonds and electrostatic interactions are retained, stabilizing the Fc domain interface. In the high resolution IgG2 and IgG1 Fc structures the position and number of water molecules, and water networks bridging the two domains differ significantly because of the difference in positions of CH2 relative to CH3. At the domain interface, only CH2 T339 in IgG2 differs from alanine found in IgG1 and IgG4. This residue's side chain influences the water structure at the interface by interacting either directly or through a bridging water molecule with D376 in the CH3 BC loop. Thus, the analyses of the IgG2 Fc structures and their comparisons with IgG1 Fc structures reveals similar, but distinctly different dynamic CH2-CH3 interfaces that can accommodate a wide range of CH2-CH3 conformations, that in conjunction with the amino acid residues in the hinge region, may influence FcgammaR effector function profiles. PMID- 23628093 TI - [Innovative therapeutic strategies for intravesical drug administration]. AB - INTRODUCTION: Perspectives for innovative pharmaceutical molecules and intravesical administration of pharmacological agents are presented in the present review carried out from a recent literature. MATERIALS AND METHODS: This review of the literature was built by using the PubMed and ScienceDirect databases running 20keywords revealing 34publications between 1983 and 2012. The number of referenced articles on ScienceDirect has increased in recent years, highlighting the interest of scientists for intravesical drug administration and the relevance of innovating drug delivery systems. RESULTS: Different modalities of intravesical administration using physical (e.g., iontophoresis, electroporation) or chemical techniques (e.g., enzyme, solvent, nanoparticles, liposomes, hydrogels) based on novel formulation methods are reported. Finally, the development of biopharmaceuticals (e.g., bacillus Calmette-Guerin, interferon alpha) and gene therapies is also presented and analyzed in this review. CONCLUSION: The present review exhibits new development in the pipeline for emerging intravesical drug administration strategies. Knowledge of all these therapies allows practitioners to propose a specific and tailored treatment to each patient with limiting systemic side effects. PMID- 23628094 TI - [Prostate brachytherapy: indications and outcomes]. AB - INTRODUCTION: To summarize the indications and outcomes of low dose-rate prostate brachytherapy with permanent implants. METHODS: Bibliographic database PubMed was searched with prostate cancer and brachytherapy as keywords from 1995 to 2012. RESULTS: The main indication of prostate brachytherapy is the favorable group, but it could be proposed to patients with an intermediate prognostic group if the PSA is <= 15 ng/mL or if the Gleason score is 7 (3+4), under cover of a prostate MRI without any extra-capsular extension. Oncologic results are similar to those of surgery or external beam irradiation (EBRT), with a 10-yr biochemical control rate approaching 90%. Urinary toxicity is common during the year following the implant, mainly irritative symptoms; 5 to 15% of patients experienced acute urinary retention. A prostate volume higher than 50 cc or an initial high international prostatic symptom score (IPSS) are predictive of toxicity and are recognized as relative contraindications of the technique. Sexual activity is maintained in 60% of patients. CONCLUSION: Brachytherapy must be proposed as a validated option beside active surveillance, surgery and EBRT. PMID- 23628095 TI - [Treatment of bladder outlet obstruction in locally advanced prostate cancer]. AB - Bladder outlet obstruction (BOO) is one of the major complication of the locally advanced prostate cancer. Its impact on prostate cancer prognosis is low and remains controversial but its impact on patient quality of life is real. We performed a systematic search to find relevant publications from Medline and wrote a mini-review on the different therapeutic approaches to relieve obstructive symptoms. PMID- 23628096 TI - [A mini-invasive approach to renal autotransplantation in the management of loin pain hematuria syndrome]. AB - OBJECTIVE: To review retrospectively our experience with laparoscopic approach to renal autotransplantation in four patients using a single iliac incision in the management of loin pain hematuria (LPH) syndrome. METHODS: Four patients with LPH (all women, mean age 29.5 years, range 23-36 years) underwent four technically successful laparoscopic nephrectomies with renal autotransplantation, using a single iliac incision to both harvest and transplant the kidney. Hand assistance was used in two patients immediately before clamping the renal pedicle. All patients required narcotic analgesics preoperatively. RESULTS: Mean total surgical time was 4.1 hours. For laparoscopic donor nephrectomy phase, mean operative time was 1.9 hours. The warm ischemia time was 5 minutes. The cold ischemia time was 58 minutes. The hospital stay was 6 days. None of the patients had abnormal renal function postoperatively. Three of four patients had episodes of iliac fossa pain with effort at the level of the transplantation incision. Two of four patients became Morphine-free. The other two required a significantly reduced dose of oral narcotics. None of these patients required nephrectomy. (Median follow-up 9 months). CONCLUSION: Laparoscopic approach to renal autotransplantaion using a single extended iliac incision in the management of LPH syndrome can be considered as a less invasive treatment compared to open renal autotransplantation in selected patients. This technique may be extended to patients having other conditions requiring autotransplantation. PMID- 23628097 TI - [The laparoscopic nephrectomy for polycystic kidney is feasible and reproducible]. AB - PURPOSE: The aim of our study was to report our experience of laparoscopic nephrectomy in patients with polycystic kidney disease. MATERIAL: Between December 2007 and February 2012, we performed 39 consecutive laparoscopic nephrectomies in patients with polycystic kidneys. All patients were operated by a transperitoneal approach. RESULTS: Patients had a mean age of 55 with an average BMI of 25 kg/m(2). Eighty-seven percent were ASA III and 77% were on dialysis. In most of the cases, the indication concerned patients who were candidates to a renal transplantation to make space for graft implantation. Operative time was 167 minutes with a mean blood loss of 200 mL. Two open conversions were necessary (splenic injury and difficulty of dissection of the renal pedicle). Fifteen percent of patients were transfused. There were 11 complications (28%) among which five were major (Clavien >= 3). Mean length of stay was 5.2 days. CONCLUSION: Our study showed that laparoscopic nephrectomy for polycystic kidney is feasible and reproducible. We systematically offer it when indicated. PMID- 23628098 TI - [Pronostic value of ureteral location of upper tract urinary carcinoma]. AB - OBJECTIVES: The aim of this study was to evaluate the prognostic significance of the ureteral location of the upper tract urinary carcinoma (UTUC). PATIENTS AND METHODS: Between January 1998 and December 2007, 161 patients with UTUC were operated in our center. Tumors were located on renal pelvis in 51% of cases, on the ureter in 34% of cases and in both locations in 15% of cases. Nephroureterectomy was performed in 79.5% of cases (128/161) whereas a conservative treatment was performed in 20.5% of cases (33/161). RESULTS: In our series, 29.8% of patients had primary bladder cancer and 14.3% had synchronous bladder tumor. At a median follow-up of 42.5 months, 38.6% of patients developed bladder recurrence and 4.8% developed controlateral upper tract tumor. In multivariate analysis, ureteral location and existence of synchronous bladder tumor were independent prognostic factors of bladder recurrence (P=0.009 and P=0.025, respectively). Multivariate analysis retained T-stage and ureteral location as independent prognostic factors in both overall and disease-free survival (P=0.002 and P=0.0008 respectively for ureteral location). CONCLUSION: Ureteral location was an independent prognostic factor of bladder recurrence and was associated with a poorer prognosis. PMID- 23628099 TI - [Prognostic impact of tumors localized at the prostatic apex]. AB - OBJECTIVE: The apex is a particular region of the prostate in its surgical dissection and pathological analysis. We sought to evaluate the prognostic value of the apical localization of prostate tumors. METHOD: From 1988 to 2010, data pre- (age, clinical stage, preoperative PSA, biopsy Gleason score) and postoperative (prostate weight, pathologic stage TNM 2010, Gleason score, margin status) of 2765 total prostatectomies were collected prospectively. These data were compared according to existence or absence of tumor at the apex. The prognostic impact of tumor at the apex on biochemical recurrence-free survival (PSA>0.2 ng/mL) has been studied in univariate and multivariate models. RESULTS: One thousand eight hundred seventeen tumors had a location at the apex (65.7%). In univariate analysis, there was a significant difference in the clinical stage, the biopsy and pathological Gleason score, the result of curage, the pathological stage and the margin status between apical tumors and others. With a mean decline of 34.6 months, 502 patients had a biochemical recurrence (18.1%). Disease-free survival at 10 years was 60.7% for tumor at the apex versus 65.9% in other cases. The location at the apex was significantly associated with biochemical recurrence on univariate analysis (P=0.01). After adjustment for clinical and pathological stage, PSA level, Gleason score and surgical margins, the apex was not anymore a pejorative independent predictor (P=0.0087). CONCLUSION: The existence of tumor in the prostatic apex was associated with more aggressive tumoral criteria and was an independent and pejorative predictor of biochemical recurrence-free survival at 10 years in univariate analysis. The apical localization could be an additional argument in the decision of adjuvant therapy after prostatectomy. PMID- 23628100 TI - [Pediatric anterior urethral injuries: time to take stock]. AB - INTRODUCTION: Anterior urethral injuries are a rare entity in the pediatric age group. Data of the literature are limited to the injuries of the posterior urethra. The aim of this study was to take stock of the initial management of this disease, from our experience and data of the literature. PATIENTS AND METHODS: A literature review and a retrospective study were conducted. We used our department database to find all the patients treated for anterior urethral injuries at the Children's Hospital of Toulouse between 2000 and 2011. Data on patients with trauma of the anterior urethra were analysed. RESULTS: Among the 13 patients treated for urethral injuries, seven patients had trauma to the anterior urethra. The initial symptom was an acute retention of urine in three cases (43%) and urethral bleeding in six cases (85%). All patients with acute retention of urine had emergency management consisting in endoscopic realignment and urinary diversion by suprapubic catheter. Patients with hematuria were treated with paracetamol and non-steroidal anti-inflammatory. After a mean follow-up of 507 days (332-893), none had dysuria and no posttraumatic stenosis has been demonstrated in uroflowmetry. CONCLUSION: In our experience, the trauma of the anterior urethra of the child had a satisfactory development through appropriate management. Clinical and uroflometry follow-up is necessary. PMID- 23628101 TI - [Treatment of women urinary incontinence by artificial urinary sphincter: efficacy, complications and survival]. AB - OBJECTIVE: To analyze long-term results and mechanical survival of the artificial urinary sphincter (AUS) AMS 800TM (American Medical Systems, Minnetonka, MN, USA) in women with stress urinary incontinence (SUI) due to intrinsic sphincter deficiency (ISD). PATIENTS AND METHODS: Data were collected prospectively from women treated for SUI at one university hospital between 1987 and 2007. Inclusion criteria was SUI with severe ISD defined by low urodynamic closure pressure and negative continence tests. Endpoints were survival, complications and continence. RESULTS: A total of 376 AUS were implanted in 344 patients with a median age of 57 years (18-93 years). The median follow-up was 9 years (3-20 years). The 3, 5, and 10 years global device survival were 92, 88.6, and 69.2% respectively. The mean mechanical survival was 176 months (14.7 years). The two main risk factors for decreased AUS survival were the number of previous incontinence surgeries and the presence of neurogenic bladder. The continence rates assessed as full (no leakage) in 85.64% patients, social (some drops but no pad) in 8.78% and incontinence (1 pad or more) in 5.58%. CONCLUSIONS: The study has shown that in patients with ISD, the AUS represents an effective process, durable with an acceptable rate of complication. PMID- 23628102 TI - [Primary leiomyosarcoma of adrenal gland, in black African woman: diagnosis and therapeutically aspects]. AB - We report a bulky adrenal gland in black woman of 52 years old. This patient was submitted to surgery for resection of the mass. The histopathologic exam found primary leiomyosarcoma of adrenal gland. Beyond twelve month after adrenalectomy, the patient was alive without metastasis. PMID- 23628103 TI - [Comment to the laparoscopic nephrectomy for polycystic kidney is feasible and reproducible]. PMID- 23628104 TI - Callers' attitudes and experiences of UK breastfeeding helpline support. AB - BACKGROUND: Breastfeeding peer support, is considered to be a key intervention for increasing breastfeeding duration rates. Whilst a number of national organisations provide telephone based breastfeeding peer support, to date there have been no published evaluations into callers' experiences and attitudes of this support. In this study we report on the descriptive and qualitative insights provided by 908 callers as part of an evaluation of UK-based breastfeeding helpline(s). METHODS: A structured telephone interview, incorporating Likert scale responses and open-ended questions was undertaken with 908 callers over May to August, 2011 to explore callers' experiences of the help and support received via the breastfeeding helpline(s). RESULTS: Overall satisfaction with the helpline was high, with the vast majority of callers' recalling positive experiences of the help and support received. Thematic analysis was undertaken on all qualitative and descriptive data recorded during the evaluation, contextualised within the main areas addressed within the interview schedule in terms of 'contact with the helplines'; 'experiences of the helpline service', 'perceived effectiveness of support provision' and 'impact on caller wellbeing'. CONCLUSION: Callers valued the opportunity for accessible, targeted, non judgmental and convenient support. Whilst the telephone support did not necessarily influence women's breastfeeding decisions, the support they received left them feeling reassured, confident and more determined to continue breastfeeding. We recommend extending the helpline service to ensure support can be accessed when needed, and ongoing training and support for volunteers. Further advertising and promotion of the service within wider demographic groups is warranted. PMID- 23628105 TI - Pregnancy outcome after elective cervical cerclage in relation to type of suture material used. AB - Cervical weakness is an important cause of late miscarriage and extreme preterm labour. Women have been traditionally offered a cervical cerclage procedure, though studies failed to demonstrate a therapeutic effect. None of these studies has addressed the effect of non-braided to braided suture material on cerclage outcome. Type of suture material is an important determinant of surgical outcomes. This issue is of particular relevance to cerclage because the traditionally braided suture has been associated with increased risk of infection in other surgical procedures. Indeed, infection is an important underlying cause for cerclage failure. It is for this reason that some surgeons use non-braided suture material. Therefore, we hypothesise that the unrealised benefit of cervical cerclage is at least in part due to the type of suture material used. In this article, we present the rationale behind our hypothesis and a proposed way of testing it. PMID- 23628106 TI - The impact of culture conditions on early follicle recruitment and growth from human ovarian cortex biopsies in vitro. AB - OBJECTIVE: To investigate the effects of a dynamic fluidic culture system on early in vitro folliculogenesis in standardized ovarian cortex biopsies. DESIGN: Cortical small strips were cultured for 6 days in a conventional static or in a dynamic fluidic culture system. SETTING: University-affiliated laboratory with an associated cryobank facility. PATIENT(S): Ovarian cortex from postpuberal female cancer patients (26.1 +/- 1.3 y) who opted for cryopreservation of their tissue for fertility protection before gonadotoxic cancer therapy. With informed consent of the Institutional Ethics Committee, part of the tissue was available for patient-related research studies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The viability and proliferative capacity of the cortex biopsies were evaluated by chemiluminescent microparticle immunoassay for detection of in vitro produced E2 and P in the supernate, by viable follicle counting via calcein staining, by histologic analyses, and by total RNA preparation and reverse transcription for real-time polymerase chain reaction of selected early folliculogenesis genes. RESULT(S): The data support the notion that early follicle development can be better achieved in vitro in a dynamic fluidic culture system. The findings are based on the presence of more viable follicles, higher expression levels of early folliculogenesis genes KIT-L, INHB, and GDF9, and the absence of premature luteinization of follicles. CONCLUSION(S): This study provides evidence that dynamic fluidic culture is a promising approach for investigating early follicular recruitment and growth in cortical biopsies. It may serve as a first step in a multistep culture system to design a complex in vitro system for complete folliculogenesis. PMID- 23628107 TI - Conceiving of change: a brief intervention increases young adults' knowledge of fertility and the effectiveness of in vitro fertilization. AB - OBJECTIVE: To examine the effectiveness of an educational intervention in increasing knowledge of fertility and the effectiveness of IVF among university students in Australia. DESIGN: Two-group, pretest-posttest design. SETTING: A large metropolitan university in Queensland, Australia. PATIENT(S): One hundred thirty-seven male and female undergraduate students. INTERVENTION(S): Online information brochure on fertility (intervention group), or an online information brochure on home ownership (control group). MAIN OUTCOME MEASURE(S): Knowledge of fertility, knowledge of IVF effectiveness, and desired age at commencement and completion of childbearing, assessed immediately before and after exposure to the brochure. RESULT(S): Exposure to the brochure resulted in significant increases in knowledge of fertility and knowledge of IVF effectiveness in the intervention group and significant decreases in desired age at commencement and completion of childbearing. No changes were observed in the control group. CONCLUSION(S): Educational intervention is a worthwhile endeavor that can increase knowledge of fertility and IVF effectiveness in the short-term. Further research is needed to evaluate whether increased knowledge persists and affects intentions in the longer-term. Because the determinants of timing of childbearing are highly multifactorial, fertility education should be paired with policies and practices that support men and women to make informed decisions about the timing of childbearing. PMID- 23628108 TI - But isn't antimullerian hormone still better than follicle-stimulating hormone? PMID- 23628109 TI - Reduced oxygen tension improves embryo quality but not clinical pregnancy rates: a randomized clinical study into ovum donation cycles. AB - OBJECTIVE: To investigate the effect of low O2 tension during in vitro culture in terms of ongoing pregnancy rates in ovum donation cycles. DESIGN: Randomized trial. SETTING: Private university-affiliated IVF center, university-based hospital. PATIENT(S): A total of 1,125 cycles of ovum donation. INTERVENTION(S): Embryo culture in an atmosphere of 5.5% CO2, 6% O2, and 88.5% N2 versus a dual gas system of 5.5% CO2 in air. MAIN OUTCOME MEASURE(S): Ongoing clinical pregnancy rates per intention-to-treat (ITT) patients. RESULT(S): The use of low O2 tension achieved a 41.3% ongoing pregnancy rate per ITT compared with a 40.8% rate obtained for 5% CO2 in air. The mean number of blastomeres and the percentage of top-quality embryos were significantly higher after lower O2 concentration during in vitro culture (7.1 +/- 3.6 and 28.6% vs. 7.3 +/- 8.4 and 32.1%, respectively). CONCLUSION(S): In the ovum donation cycles undergoing day-3 embryo transfers, the use of low O2 tension did not improve ongoing pregnancy rates per cycle and per transfer. However, it benefited embryo quality, demonstrating the potential negative impact of high O2 tension on the in vitro embryo development. PMID- 23628110 TI - Proteomic analysis of seminal plasma from infertile patients with oligoasthenoteratozoospermia due to oxidative stress and comparison with fertile volunteers. AB - OBJECTIVE: To compare the expression protein profile of seminal plasma from infertile men with oligoasthenoteratozoospermia (OAT) due to oxidative stress with that of healthy, fertile men to determine the proteins indicative of infertility. DESIGN: Experimental study. SETTING: University hospital and research institute. PATIENT(S): Semen samples from 11 healthy, fertile (according to the 1999 World Health Organization criteria) male volunteers and 11 infertile idiopathic oligoasthenoteratozoospermia (iOAT) patients. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Proteomic analysis performed by liquid chromatography mass spectrometry on a hybrid linear trap quadrupole Orbitrap Velos mass spectrometer, carbonylation assay to determine degree of oxidative stress, semiquantitative proteomic analysis, gene ontology, and pathway analysis. RESULT(S): A total of 2,489 proteins were identified from seminal plasma, which represents the highest number of unique proteins identified to date. Twenty-four proteins were determined as >= 1.5-fold up-regulated in the infertile iOAT males as compared with the fertile controls; and 27 proteins from iOAT patients only were identified as common across all analyses. Only five of the proteins were shared between these two groups. CONCLUSION(S): A panel of 46 proteins were identified in patients with iOAT that are potential candidates in understanding the etiology of OAT due to oxidative stress. PMID- 23628111 TI - Is it time for a cardiac allocation score? First results from the Eurotransplant pilot study on a survival benefit-based heart allocation. AB - BACKGROUND: Patients awaiting heart transplantation in Eurotransplant are prioritized by waiting time and medical urgency. To reduce mortality, the introduction of post-transplant survival in an allocation model based on the concept of survival benefit might be more appropriate. The aim of this study was to assess the prognostic accuracy of the heart failure survival score (HFSS), the Seattle heart failure model (SHFM), the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) model, and the index for mortality prediction after cardiac transplantation (IMPACT) score for predicting mortality. METHODS: The HFSS, SHFM, the adapted SHFM, and the INTERMACS model were evaluated for predicting waiting list mortality among heart transplant candidates, and the IMPACT score was tested for predicting post-transplant mortality in separate Cox regression models. Included were the 448 adult heart transplant candidates listed for an urgent status between October 2010 and June 2011 in Eurotransplant. A cardiac allocation score (CAS) was calculated based on the estimated survival times as predicted by the scores. All analyses were performed for the total cohort and separately for ventricular assist device (VAD) and non-VAD patients. RESULTS: Mortality on the waiting list could significantly be predicted in the non-VAD cohort by HFSS (p = 0.005) and SHFM (p < 0.0001) and after transplant by IMPACT (p < 0.0001). None of the tested scores could predict mortality among VAD supported patients. CONCLUSIONS: In non-VAD patients, the HFSS, SHFM, and IMPACT provide accurate risk stratification. Further studies will reveal whether these models should be considered as the basis for a new heart allocation policy in Eurotransplant. PMID- 23628113 TI - Unravelling the basis of variability in cobalamin levels in the general population. AB - Cobalamin (Cbl) is an essential B vitamin involved in the normal functioning of the nervous system, the formation of key components of blood, DNA synthesis and methylation, and energy production. Physiological levels of Cbl vary greatly within populations, although the basis for this variability remains largely unknown. We conducted a twin study to characterise the basis of variation in plasma Cbl levels and to test whether common genetic polymorphisms in genes known to cause defects in inborn errors of Cbl metabolism and transport are also associated with mean plasma Cbl levels in the general population. The present results showed that plasma levels of Cbl were heritable, with genetic and phenotypic variance increasing with age, and levels significantly correlated with age, BMI, exercise, alcohol consumption, smoking status, social class and folate levels, which collectively accounted for up to 15 % of Cbl variation. Of eight genes responsible for the defects of the Cbl metabolic pathway (cblA-G and mut), MMAA, MMACHC, MTRR and MUT harboured polymorphisms that showed evidence of association with Cbl levels. Characterisation of the heritable component of variation in Cbl levels can facilitate the early diagnosis and prognosis of Cbl insufficiency/deficiency in individuals at a higher risk of associated diseases. PMID- 23628114 TI - Varying the agglomeration position of particles in a micro-channel using Acoustic Radiation Force beyond the resonance condition. AB - It is well-known that particles can be focused at mid-height of a micro-channel using Acoustic Radiation Force (ARF) tuned at the resonance frequency (h=lambda/2). The resonance condition is a strong limitation to the use of acoustophoresis (particles manipulation using acoustic force) in many applications. In this study we show that it is possible to focus the particles anywhere along the height of a micro-channel just by varying the acoustic frequency, in contradiction with the resonance condition. This result has been thoroughly checked experimentally. The different physical properties as well as wall materials have been changed. The wall materials is finally the only critical parameters. One of the specificity of the micro-channel is the thickness of the carrier and reflector layer. A preliminary analysis of the experimental results suggests that the acoustic focusing beyond the classic resonance condition can be explained in the framework of the multilayered resonator proposed by Hill [1]. Nevertheless, further numerical studies are needed in order to confirm and fully understand how the acoustic pressure node can be moved over the entire height of the micro channel by varying the acoustic frequency. Despite some uncertainties about the origin of the phenomenon, it is robust and can be used for improved acoustic sorting or manipulation of particles or biological cells in confined set ups. PMID- 23628115 TI - Vesicular mechanisms of traffic of fungal molecules to the extracellular space. AB - Fungal cells are efficient in releasing to the extracellular space molecules that lack typical secretion signals, including cytoplasmic components. Studies developed during the last five years indicate that extracellular vesicle formation is involved in the traffic of these intracellular components to the extracellular space. The cellular origin of these vesicles, however, is still unknown. Here we review the potential mechanisms involved in formation of fungal extracellular vesicles and consequent release of fungal molecules to the outer cellular space. We also propose that these compartments can originate from cytoplasmic subtractions whose formation is dependent on plasma membrane reshaping. PMID- 23628116 TI - [What's new about infantile hemangiomas?]. AB - Infantile hemangioma is the most common vascular tumor of childhood. This benign tumor appears during the first weeks of life, grows during the first months (endothelial proliferation) and then involutes slowly and spontaneously until resolution (possibly with sequelae) which is observed after several years. Although they are always benign tumors, infantile hemangiomas can cause complications. Regarding their location or size, infantile hemangiomas can be life or function-threatening. They are also painful when ulcerated and can cause permanent disfigurement or long-term adverse psychological consequences. Since 2008 and the serendipitous discovery of the efficacy of propranolol in the treatment of infantile hemangiomas, systemic propranolol therapy has been widely used, with a very interesting benefits/risks balance. It has progressively superseded general corticosteroid therapy. A Compassionate Use Program (CUP) for systemic propranolol therapy has been developed in France and represents nowadays the first-line use for the vast majority of French prescribers. PMID- 23628112 TI - Functional aspects of primary cilia in signaling, cell cycle and tumorigenesis. AB - Dysfunctional cilia underlie a broad range of cellular and tissue phenotypes and can eventually result in the development of ciliopathies: pathologically diverse diseases that range from clinically mild to highly complex and severe multi-organ failure syndromes incompatible with neonatal life. Given that virtually all cells of the human body have the capacity to generate cilia, it is likely that clinical manifestations attributed to ciliary dysfunction will increase in the years to come. Disputed but nevertheless enigmatic is the notion that at least a subset of tumor phenotypes fit within the ciliopathy disease spectrum and that cilia loss may be required for tumor progression. Contending for the centrosome renders ciliation and cell division mutually exclusive; a regulated tipping of balance promotes either process. The mechanisms involved, however, are complex. If the hypothesis that tumorigenesis results from dysfunctional cilia is true, then why do the classic ciliopathies only show limited hyperplasia at best? Although disassembly of the cilium is a prerequisite for cell proliferation, it does not intrinsically drive tumorigenesis per se. Alternatively, we will explore the emerging evidence suggesting that some tumors depend on ciliary signaling. After reviewing the structure, genesis and signaling of cilia, the various ciliopathy syndromes and their genetics, we discuss the current debate of tumorigenesis as a ciliopathy spectrum defect, and describe recent advances in this fascinating field. PMID- 23628117 TI - [Is non-IgE-mediated cow's milk protein hypersensitivity responsible for stuttering in children?]. PMID- 23628118 TI - [Acute transverse myelitis and Lyme borreliosis: a case report]. AB - Lyme disease is an infectious disease caused by a spirochete of the Borrelia sensu lato group. Its incidence has greatly increased in recent years. The main vector is a tick of the Ixodes family. Clinical manifestations are multiple and show the multi-organ character of the disease. In terms of frequency, joint and neurological presentations, respectively more frequent in North America and Europe, are the main manifestations after cutaneous symptoms, of which erythema migrans is the most common, followed by cardiac and ocular signs. Other signs exist but are anecdotal. Neuroborreliosis manifests itself most often with peripheral facial palsy, but there are other clinical forms, which include acute myelitis (4-5% of neuroborreliosis). We present here the case of a 16-year-old teenager with acute myelitis and meningeal involvement due to Lyme disease, who presented with atypical symptoms (massive and rapid weight loss, vomiting). MRI showed localized marrow edema as well as leptomeningeal and root enhancement. Lumbar puncture showed lymphocytic pleocytosis. Lyme serology was positive both in blood and cerebrospinal fluid. Even if acute myelitis remains exceptional among neuroborreliosis manifestations, this diagnosis has to be thought of when a child presents with unexplained neurological symptoms. PMID- 23628119 TI - [Acetaminophen (paracetamol) causing renal failure: report on 3 pediatric cases]. AB - Renal failure secondary to acetaminophen poisoning is rare and occurs in approximately 1-2 % of patients with acetaminophen overdose. The pathophysiology is still being debated, and renal acetaminophen toxicity consists of acute tubular necrosis, without complication if treated promptly. Renal involvement can sometimes occur without prior liver disease, and early renal manifestations usually occur between the 2nd and 7th day after the acute acetaminophen poisoning. While therapy is exclusively symptomatic, sometimes serious metabolic complications can be observed. The monitoring of renal function should therefore be considered as an integral part of the management of children with acute, severe acetaminophen intoxication. We report 3 cases of adolescents who presented with acute renal failure as a result of voluntary drug intoxication with acetaminophen. One of these 3 girls developed severe renal injury without elevated hepatic transaminases. None of the 3 girls' renal function required hemodialysis, but one of the 3 patients had metabolic complications after her acetaminophen poisoning. PMID- 23628120 TI - [Contraception and adolescence]. AB - The mean age of first sexual intercourse is still around 17 in France, but a lot of teenagers are concerned by contraception before, with approximately 25% of sexually active 15-year-old girls. The contraceptive method must take into consideration some typical features of this population, as sporadic and non planned sexual activity, with several sexual partners in a short period of time. In 2004, the "Haute Autorite de sante" has recommended, as first-line method, combined oral contraceptive (COC) pills, in association with male condoms. Copper containing intrauterine contraceptive devices (IUCD) and etonogestrel-containing subcutaneous implant have been suggested but not recommended. However, oral contraceptive pill, as a user-based method, carries an important typical-use failure rate, because remembering taking a daily pill, and dealing with stop periods, may be challenging. Some easier-to-use method should be kept in mind, as 28-day COC packs, transdermal contraceptive patches, and vaginal contraceptive rings. Moreover, American studies have shown that long-acting reversible contraceptives (LARC), i.e. IUCD and implant, have many advantages for teenagers: very effective, safe, invisible. They seem well-fitted for this population, with high satisfaction and continuation rates, as long as side effects are well explained. Thus, LARC methods should be proposed more widely to teenagers. Anyway, before prescribing a contraceptive method, it is important to determine the specific situation of every teenager, to let them choose the method that they consider as appropriate in their own case, and to think about the availability of the chosen method. It is necessary to explain how to handle mistakes or misses with user-based contraceptive methods, and emergency contraception can be anticipated and prescribed in advanced provision. The use of male condoms should be encouraged for adolescents, with another effective contraceptive method, in order to reduce the high risk of sexually transmitted infections (STI) in this population. PMID- 23628121 TI - [Value of polymerase chain reaction in serum for the diagnosis of enteroviral meningitis]. AB - Enteroviruses (EV) are a common cause of aseptic meningitis in children. Virological diagnosis of EV meningitis is currently based on the detection of the viral genome in the cerebrospinal fluid (CSF). This study attempted to determine the correlation and the temporality of the polymerase chain reaction (PCR) assay in serum and CSF and to evaluate the possibility of diagnosing EV infection only on the serum PCR. The EV genome was sought by RT real-time PCR (Smart Cycler EV Primer and Probe Set((r)), Cepheid) in CSF and serum, collected at the same time, for all children who underwent a lumbar puncture for suspected meningitis, between 1 June and 31 July 2010 at the Versailles Hospital. Forty-four patients were included in the study. EV infection was documented for 22 of them. In 10 patients, the EV genome was detected in CSF only; in 3 patients in serum only, and in 9 patients in both. Among patients with acute EV neurological infection, viremic children were significantly younger (1.6 months versus 5.8 years; P<0.001). Viremia was detected when the serum was sampled within 30 h after the beginning of symptoms. These results confirm previous reports of early and transient viremia in young children. This preliminary study shows the limits and added value of EV PCR in serum. It suggests that in some children and under certain conditions (age >3 months, clinical and biological compatibility with a viral infection, no previous antibiotic therapy, time from symptom onset to blood sampling <30 h, PCR in serum analyzed within 3h), PCR in serum, when positive, is a possible alternative. Therefore, it may be possible to diagnose EV infection without performing a lumbar puncture in a limited number of young children (11.4% of our suspected cases). This study needs to be reinforced by a multicenter study with a broader panel of patients. PMID- 23628122 TI - [Suicide attempts by young adolescents: epidemiological characteristics of 517 15 year-old or younger adolescents admitted in French emergency departments]. AB - Adolescents who attempt suicide are a major concern. A growing body of literature seeks to explain this phenomenon and to identify its predictive factors, but relatively little information is available and children and adolescents under 15 years of age who present to general hospitals because of a suicide attempt. This study aimed to describe the demographic, social, medical, and psychological characteristics of a large sample of 517 French adolescents aged not more than 15 years 3 months. A second purpose was to measure observance of psychological care in a 1-year follow-up. Third, we aimed to document the reattempt rate during the follow-up in this population of young adolescents. Following the French official recommendations, a systematic 72-h hospitalization as well as a somatic, social, and psychological assessment was proposed to every suicide attempter after his or her admission to the emergency department. The adolescent was followed for 1 year after the suicide attempt, called the index episode. This follow-up was organized by two physicians, one of whom was not associated with the care of any of the patients. It consisted in seeking regular information as well as organization and/or optimization of the patient's psychological care, which was delivered in dedicated structures for adolescents, in outpatient care by a psychiatrist, or in an adolescent psychiatric inpatient care unit. In case of a repeated suicide attempt or persistence of alarming symptoms, this follow-up was prolonged for 1 more year. Patient data were compiled by experienced clinicians during initial assessment and alongside the 1-year follow-up through patient self-reports, but also through interviews with informants (family members, social professionals) and clinical sources (general practitioner, psychiatrist, etc.). The areas covered were the characteristics of the index episode, those of the population at the time of the index episode, as well as those of the 1-year follow-up including observance to the care and potential repetition of the suicide attempt. The mean age was 14 years with a minimum of 7 years 9 months. The vast majority of the population was female (86.1%), less than one-third lived with both parents, and 27% had academic problems. The most frequent means of suicide attempt was medication (83.9%), 92.6% of adolescents were hospitalized following the index episode, only 7.5% of them were admitted to adolescent psychiatric unit inpatient care following the initial care. Psychiatric evaluation was documented for 93.3% of the adolescents. Half (n=222) had at least one symptom of a psychiatric disorder. One-year follow-up data were available for 394 adolescents: 40 had not yet completed the year and 83 were lost to follow-up. Among the analyzable population of 391 adolescents, 35.3% were optimally observant of the care proposed and 21.4% did not observe treatment. Fifty-nine youths (15%) were referred to the hospital because of a repeated suicide attempt. Two of the patients who repeated the suicide attempt within the year had died. The findings from this study are informative with regard to prevention and intervention efforts with suicidal young and very young adolescents. First, repetition of the suicide attempt in young adolescents is not rare since nearly 15% of the cohort were repeaters within the year following the index episode. Nevertheless, intensive care and follow-up resulting in good attendance appeared to have a positive impact on the repetition of the suicide attempt. PMID- 23628123 TI - [Unexplained hyperthermia following a spinal cord injury in an 11-month-old boy]. PMID- 23628124 TI - [An uncommon cause of dyspnea in children. Plexiform neurofibroma of the larynx]. AB - Plexiform neurofibroma is a rare benign tumor developed from cells of the sheath of Schwann peripheral nervous system often associated with neurofibromatosis type 1 or Von Recklinghausen disease. Laryngeal involvement in neurofibromatosis is rare and usually presents with obstructive respiratory symptoms. Imaging including CT and MRI provides the diagnosis as well as the staging of this lesion, whose treatment is primarily surgical. We report the case of a plexiform neurofibroma of the larynx found in a 4-year-old child revealing a mass completely obstructing the laryngeal vestibule. PMID- 23628125 TI - [Osteomyelitis in cat scratch disease: a case report and literature review]. AB - Cat scratch disease is the most common zoonosis in humans and its typical expression is a persistent benign regional adenopathy. In some rare cases, mono- or multifocal osteomyelitis is described. In this paper, we report the case of bone lesions in a 13-year-old girl infected with cat scratch disease. We have also undertaken a literature review and analyzed 60 other such cases. The manifestation of a bone lesion associated with cat scratch disease was characterized by a mono- or multifocal infectious osteomyelitis, fever, and a general alteration of the patient's health. The most frequent location of osteomyelitis was in the spine. Magnetic resonance imaging appeared the most sensitive test to highlight the bone lesions. Serological findings help reinforce the diagnosis of cat scratch disease caused by Bartonella henselae infection. Osteomyelitis in cat scratch disease is rare but not exceptional. Therefore, it is essential to think about this hypothesis in case of osteomyelitis associated with a general alteration of the patient's health, especially if the lesions are multifocal and if there is a known history of cat contact. PMID- 23628126 TI - Comparison of postprandial blood pressure reduction in the elderly by different body position. AB - The purpose of this study was to determine whether different body positions- Fowler's, supine, and left lateral--as compared with a sitting position can prevent postprandial drops in blood pressure in older adults. Participants included 32 persons 65 or over who had experienced postprandial drops in systolic blood pressure of more than 15 mm Hg in a pilot study. This study employed a within-subject repeated measures design using random order allocation of different body positions. To protect against a carryover effect, blood pressures in the different positions were taken at intervals of 1 week. Blood pressure and heart rate were both measured before lunch and at 15-min intervals for 120 min after lunch. Descriptive statistics, repeated measures ANOVA, and paired t-tests with a Bonferroni adjustment were used to analyze the data. No significant differences were observed in the magnitude of blood pressure drops regardless of the position taken after a meal. Therefore, different body positions alone do not adequately prevent PPH or attenuate drops in blood pressure for older adults with PPH. Nurses should carefully monitor falls in blood pressure even in persons on bed rest to prevent the complications of postprandial hypotension. PMID- 23628127 TI - Spatio-temporal trends in gastric cancer mortality in Spain: 1975-2008. AB - AIM OF THE STUDY: There has been a downward trend in gastric cancer mortality worldwide. In Spain, a marked spatial aggregation of areas with excess mortality due to this cause has long been reported. This paper sought to analyse the evolution of gastric cancer mortality risk in Spanish provinces and explore the possible attenuation of the geographical pattern. METHODS: We studied a series of gastric cancer mortality data by province, year of death, sex and age group using a conditional autoregressive (CAR) model that incorporated space, time and spatio temporal interactions. RESULTS: Gastric cancer mortality risk decreased in all Spanish provinces in both males and females. Overall, decreasing trends were more pronounced during the first years of the study period, largely due to a sharper fall in gastric cancer mortality risk among the older population. Recent decades have witnessed a slowing in the rate of decrease, especially among the younger age groups. In most areas, risk declined at a similar rate, thus serving to maintain interprovincial differences and the persistence of the geographical pattern, though with some differences. The north and northwest provinces were the areas with higher mortality risks in both sexes and age groups over the entire study period. CONCLUDING STATEMENT: Despite the decline in gastric cancer mortality risk observed for the 50 Spanish provinces studied, geographical differences still persist in Spain, and the cluster of excess mortality in the north-west of the country remains in evidence. PMID- 23628128 TI - Inter-laboratory variability in the presence of human papillomavirus in normal and abnormal cervical cytology samples. AB - INTRODUCTION: Treatment of cervical carcinoma is affected by the stage of the disease, being most likely curable with early detection. High-risk human papillomavirus (HPV) infection and persistency are necessary to the development of precancerous and cancerous lesions leaving the possibility to detect in time cells progressing in at risk behaviour. METHODS: This study documents the proportion of HPV DNA positivity in 906 samples with cytological result negative for intraepithelial lesion and malignancy (NILM), 220 atypical squamous cells of undetermined significance (ASC-US) samples and 211 low grade intraepithelial lesions (LSIL) samples collected from various pathological laboratories in Brussels, Belgium. RESULTS: The proportion of samples harbouring one or more HPV types was 10.8% (95% confidence interval, 95% CI: 8.8-12.8) in NILM, 34.5% (95% CI: 27.6-40.3) in ASC-US, 54.3% (95% CI: 47.5-61.1) in LSIL, with significant variability of HPV proportion in ASC-US and LSIL between laboratories. CONCLUSION: This study provides an on-site picture, confirming an added value of HPV DNA detection. PMID- 23628129 TI - Description of an approach based on maximum likelihood to adjust an excess hazard model with a random effect. AB - OBJECTIVE: To adjust an excess hazard regression model with a random effect associated with a geographical level, the Departement in France, and compare its parameter estimates with those obtained using a "fixed-effect" excess hazard regression model. METHODS: An excess hazard regression model with a piecewise constant baseline hazard was used and a normal distribution was assumed for the random effect. Likelihood maximization was performed using a numerical integration technique, the Quadrature of Gauss-Hermite. Results were obtained with colon-rectum and thyroid cancer data from the French network of cancer registries. RESULT: The results were in agreement with what was theoretically expected. We showed a greater heterogeneity of the excess hazard in thyroid cancers than in colon-rectum cancers. The hazard ratios for the covariates as estimated with the mixed-effect model were close to those obtained with the fixed effect model. However, unlike the fixed-effect model, the mixed-effect model allowed the analysis of data with a large number of clusters. The shrinkage estimator associated with Departement is an optimal measure of Departement specific excess risk of death and the variance of the random effect gave information on the within-cluster correlation. CONCLUSION: An excess hazard regression model with random effect can be used for estimating variation in the risk of death due to cancer between many clusters of small sizes. PMID- 23628131 TI - The special issue on the 26th Conference of European Comparative Endocrinologists (CECE 2012). PMID- 23628130 TI - Muscle morphometric effect of anterior cruciate ligament injury measured by computed tomography: aspects on using non-injured leg as control. AB - BACKGROUND: Anterior cruciate ligament (ACL) tears are common, functionally disabling, and predispose to subsequent injuries and early onset of osteoarthritis in the knee. Injuries result in muscular atrophy and impaired muscular activation. To optimize surgical methods and rehabilitation strategies, knowledge of the effects of ACL injuries on muscles size and function is needed. Asymmetry due to limb dominance implies that the effect of ACL-injury might be different in right-sided and left-sided injuries which, should be taken in account when evaluating the effect of an injury. Evaluation of the effects of injuries is usually made with the contralateral leg as control. The aim of this study is to describe the effect of ACL-injuries on thigh muscle size and also to analyze feasibility of using contralateral limb as control. METHODS: Sixty-two patients scheduled to undergo ACL reconstruction were examined with computed tomography (CT). Muscle cross sectional area (CSA) was recorded for quadriceps, hamstrings, gracilis and sartorius 15 cm above the knee joint. Comparisons were made between the injured and non-injured side and between individuals separated by gender and side of injury. Comparisons were also made for patients with or without concomitant meniscal tear, for patients differing in time between injury and examinations and for patients with different level of physical activity after the injury. RESULTS: Quadriceps CSA was 5% smaller on the injured side. There was an indication that the muscles of the right thigh were generally bigger than those of the left thigh. The difference between the injured and the non-injured side was larger for right-sided injuries than for left-sided. There was also a greater difference in semimembranosus for women than for men. There were no differences related to meniscal injury, time since injury or physical activity. CONCLUSION: The use of contralateral leg for evaluating the effect of ACL-injury is often the only available alternative but our study indicates that the difference in CSA between injured and non-injured side does not necessarily reflect the true degree of atrophy, as there are side differences both in muscle size in general and in the effect of an ACL-injury on muscle size. PMID- 23628132 TI - Effect of vitamin D administration in vitamin D-deficient pregnant women on maternal and neonatal serum calcium and vitamin D concentrations: a randomised clinical trial. AB - There are several studies in which a correlation between maternal vitamin D deficiency and serum mineral disorders in the mother and the newborn has been reported. The present randomised clinical trial was designed to investigate the effect of vitamin D administration on maternal and fetal Ca and vitamin D status. The trial was carried out on 160 pregnant women. Vitamin D-deficient (25 hydroxyvitamin D (25(OH)D) < 30 ng/ml) pregnant women were recruited at 26-28 weeks of pregnancy. In the control group, a multivitamin supplement containing 400 IU vitamin D3/d was given. Patients in the treatment group were treated with 50 000 IU vitamin D3 weekly for a total duration of 8 weeks. At delivery, maternal and fetal Ca and 25(OH)D levels in both groups were compared. In total, 81 % of pregnant women were vitamin D deficient. At the time of delivery, Ca and vitamin D levels were higher in the treatment group compared with the control group (92 (SD 3) v. 85 (SD 4) mg/l, respectively, P= 0.001 for serum Ca; 47.8 (SD 11.1) v. 15.9 (SD 6.6) ng/ml, respectively, P< 0.001 for vitamin D). At the time of delivery, 32.7 % of women in the control group had hypocalcaemia, while no hypocalcaemic case was detected in the vitamin D-treated group. Mean neonatal serum 25(OH)D was higher in the treatment group compared with the control group (27.7 (SD 5.2) v.10.9 (SD 4.4) ng/ml, respectively, P< 0.01). The neonatal Ca level in the treatment group was significantly higher than that of the control group (99 (SD 3) v. 91 (SD 3) mg/l, respectively, P< 0.001). The administration of vitamin D to pregnant women with vitamin D deficiency improves both maternal and neonatal Ca levels. PMID- 23628133 TI - Statistical analysis of dose-volume profiles and its implication for radiation therapy planning in prostate carcinoma. AB - PURPOSE: The study aimed to analyze the dose-volume profiles of 3-dimensional radiation therapy (3D-CRT) and intensity modulated RT (IMRT) in the treatment of prostate carcinoma and to specify the profiles responsible for the development of gastrointestinal (GI) toxicity. METHODS AND MATERIALS: In the period 1997 to 2007, 483 patients with prostate carcinoma in stage T1-3 N0 (pN0) M0 were treated with definitive RT. Two groups of patients were defined for the analysis: the 3D CRT group (n=305 patients) and the IMRT group (n=178 patients). In the entire cohort of 483 patients, the median follow-up time reached 4.4 years (range, 2.0 11.7 years). The cumulative absolute and relative volumes of irradiated rectum exposed to a given dose (area under the dose-volume curve, AUC) were estimated. The receiver operating characteristic analysis was then used to search for the optimal dose and volume cutoff points with the potential to distinguish patients with enhanced or escalated toxicity. RESULTS: Despite the application of high doses (78-82 Gy) in the IMRT group, GI toxicity was lower in that group than in the group treated by 3D-CRT with prescribed doses of 70 to 74 Gy. Both RT methods showed specific rectal dose-volume distribution curves. The total AUC values for IMRT were significantly lower than those for 3D-CRT. Furthermore, IMRT significantly decreased the rectal volume receiving low to intermediate radiation doses in comparison with 3D-CRT; specific cutoff limits predictable for the level of GI toxicity are presented and defined in our work. CONCLUSIONS: Total area under the dose-volume profiles and specific cutoff points in low and intermediate dose levels have significant predictive potential toward the RT GI toxicity. In treatment planning, it seems that it is valuable to take into consideration the entire dose-volume primary distribution. PMID- 23628134 TI - Dermatofibrosarcoma protuberans: long-term outcomes of 53 patients treated with conservative surgery and radiation therapy. AB - PURPOSE: To evaluate outcomes of conservative surgery and radiation therapy (RT) treatment in patients with dermatofibrosarcoma protuberans. METHODS AND MATERIALS: We retrospectively reviewed the medical records of 53 consecutive dermatofibrosarcoma protuberans patients treated with surgery and preoperative or postoperative radiation therapy between 1972 and 2010. Median tumor size was 4 cm (range, 1-25 cm). Seven patients (13%) were treated with preoperative RT (50-50.4 Gy) and 46 patients (87%) with postoperative RT (60-66 Gy). Of the 46 patients receiving postoperative radiation, 3 (7%) had gross disease, 14 (30%) positive margins, 26 (57%) negative margins, and 3 (7%) uncertain margin status. Radiation dose ranged from 50 to 66 Gy (median dose, 60 Gy). RESULTS: At a median follow-up time of 6.5 years (range, 0.5 months-23.5 years), 2 patients (4%) had disease recurrence, and 3 patients (6%) had died. Actuarial overall survival was 98% at both 5 and 10 years. Local control was 98% and 93% at 5 and 10 years, respectively. Disease-free survival was 98% and 93% at 5 and 10 years, respectively. The presence of fibrosarcomatous change was not associated with increased risk of local or distant relapse (P=.43). One of the patients with a local recurrence had gross residual disease at the time of RT and despite RT to 65 Gy developed both an in-field recurrence and a nodal and distant recurrence 3 months after RT. The other patient with local recurrence was found to have in field recurrence 10 years after initial treatment. Thirteen percent of patients had an RT complication at 5 and 10 years, and 9% had a moderate or severe complication at 5 and 10 years. CONCLUSIONS: Dermatofibrosarcoma protuberans is a radioresponsive disease with excellent local control after conservative surgery and radiation therapy. Adjuvant RT should be considered for patients with large or recurrent tumors or when attempts at wide surgical margins would result in significant morbidity. PMID- 23628135 TI - Radiation dose to the esophagus from breast cancer radiation therapy, 1943-1996: an international population-based study of 414 patients. AB - PURPOSE: To provide dosimetric data for an epidemiologic study on the risk of second primary esophageal cancer among breast cancer survivors, by reconstructing the radiation dose incidentally delivered to the esophagus of 414 women treated with radiation therapy for breast cancer during 1943-1996 in North America and Europe. METHODS AND MATERIALS: We abstracted the radiation therapy treatment parameters from each patient's radiation therapy record. Treatment fields included direct chest wall (37% of patients), medial and lateral tangentials (45%), supraclavicular (SCV, 64%), internal mammary (IM, 44%), SCV and IM together (16%), axillary (52%), and breast/chest wall boosts (7%). The beam types used were (60)Co (45% of fields), orthovoltage (33%), megavoltage photons (11%), and electrons (10%). The population median prescribed dose to the target volume ranged from 21 Gy to 40 Gy. We reconstructed the doses over the length of the esophagus using abstracted patient data, water phantom measurements, and a computational model of the human body. RESULTS: Fields that treated the SCV and/or IM lymph nodes were used for 85% of the patients and delivered the highest doses within 3 regions of the esophagus: cervical (population median 38 Gy), upper thoracic (32 Gy), and middle thoracic (25 Gy). Other fields (direct chest wall, tangential, and axillary) contributed substantially lower doses (approximately 2 Gy). The cervical to middle thoracic esophagus received the highest dose because of its close proximity to the SCV and IM fields and less overlying tissue in that part of the chest. The location of the SCV field border relative to the midline was one of the most important determinants of the dose to the esophagus. CONCLUSIONS: Breast cancer patients in this study received relatively high incidental radiation therapy doses to the esophagus when the SCV and/or IM lymph nodes were treated, whereas direct chest wall, tangentials, and axillary fields contributed lower doses. PMID- 23628136 TI - Do sexual risk behaviors differ between heterosexual youth infected with HIV perinatally versus sexually? AB - PURPOSE: To determine if sexually active heterosexual HIV-infected 15- to 24-year old youth have different sexual or other risk behaviors depending on whether they were infected perinatally or heterosexually. METHODS: We compared youth aged 15 to 24 years who acquired HIV perinatally or sexually and were interviewed in person or by phone for partner services by the New York City Department of Health and Mental Hygiene. We included heterosexually active youth with at least one sexual partner of the opposite sex in the past 12 months, and excluded men who have sex with men and injection drug users. We used chi(2) tests and t tests to compare demographics, sexual risk behaviors, partner services outcomes, and viral loads. RESULTS: Both groups reported few partners (median 1, mean 2), and only 12% of partners of perinatally infected youth were previously diagnosed (18% of sexually infected youths' partners). A minority reported always using condoms. Both groups had similar rates of sexually transmitted infections and median HIV plasma RNA (perinatally infected: 5,140 copies/mL; sexually infected: 6,835 copies/mL). Despite these similarities, among tested partners not previously HIV diagnosed, none of 17 named by perinatally infected youth was newly HIV diagnosed, whereas 21% (8/39, p = .09) of those named by sexually infected youth were newly diagnosed. CONCLUSIONS: Though perinatally infected youth did not transmit HIV infection to previously undiagnosed partners, they had similar HIV related risk behaviors to youth infected sexually who reported on risks that led to their infection. HIV prevention among HIV-infected youth remains a critical challenge. PMID- 23628138 TI - Unexpected increase of alveolar echincoccosis, Austria, 2011. AB - In Central Europe, classical alveolar echinococcosis (AE) is endemic. Annual incidences in Austria were 2.4 and 2.8 cases/100,000 population during 1991-2000 and 2001-2010, respectively. Hence, the registration of 13 new AE patients in 2011 was unexpected. Increasing fox populations and past AE underreporting might have caused this increase. PMID- 23628137 TI - Negatively charged residues in the endodomain are critical for specific assembly of spike protein into murine coronavirus. AB - Coronavirus spike (S) protein assembles into virions via its carboxy-terminus, which is composed of a transmembrane domain and an endodomain. Here, the carboxy terminal charge-rich motif in the endodomain was verified to be critical for the specificity of S assembly into mouse hepatitis virus (MHV). Recombinant MHVs exhibited a range of abilities to accommodate the homologous S endodomains from the betacoronaviruses bovine coronavirus and human SARS-associated coronavirus, the alphacoronavirus porcine transmissible gastroenteritis virus (TGEV), and the gammacoronavirus avian infectious bronchitis virus respectively. Interestingly, in TGEV endodomain chimeras the reverting mutations resulted in stronger S incorporation into virions, and a net gain of negatively charged residues in the charge-rich motif accounted for the improvement. Additionally, MHV S assembly could also be rescued by the acidic carboxy-terminal domain of the nucleocapsid protein. These results indicate an important role for negatively charged endodomain residues in the incorporation of MHV S protein into assembled virions. PMID- 23628139 TI - A test-retest fMRI dataset for motor, language and spatial attention functions. AB - BACKGROUND: Since its inception over twenty years ago, functional magnetic resonance imaging (fMRI) has been used in numerous studies probing neural underpinnings of human cognition. However, the between session variance of many tasks used in fMRI remains understudied. Such information is especially important in context of clinical applications. A test-retest dataset was acquired to validate fMRI tasks used in pre-surgical planning. In particular, five task related fMRI time series (finger, foot and lip movement, overt verb generation, covert verb generation, overt word repetition, and landmark tasks) were used to investigate which protocols gave reliable single-subject results. Ten healthy participants in their fifties were scanned twice using an identical protocol 2-3 days apart. In addition to the fMRI sessions, high-angular resolution diffusion tensor MRI (DTI), and high-resolution 3D T1-weighted volume scans were acquired. FINDINGS: Reliability analyses of fMRI data showed that the motor and language tasks were reliable at the subject level while the landmark task was not, despite all paradigms showing expected activations at the group level. In addition, differences in reliability were found to be mostly related to the tasks themselves while task-by-motion interaction was the major confounding factor. CONCLUSIONS: Together, this dataset provides a unique opportunity to investigate the reliability of different fMRI tasks, as well as methods and algorithms used to analyze, de-noise and combine fMRI, DTI and structural T1-weighted volume data. PMID- 23628140 TI - Defining syndromes using cattle meat inspection data for syndromic surveillance purposes: a statistical approach with the 2005-2010 data from ten French slaughterhouses. AB - BACKGROUND: The slaughterhouse is a central processing point for food animals and thus a source of both demographic data (age, breed, sex) and health-related data (reason for condemnation and condemned portions) that are not available through other sources. Using these data for syndromic surveillance is therefore tempting. However many possible reasons for condemnation and condemned portions exist, making the definition of relevant syndromes challenging.The objective of this study was to determine a typology of cattle with at least one portion of the carcass condemned in order to define syndromes. Multiple factor analysis (MFA) in combination with clustering methods was performed using both health-related data and demographic data. RESULTS: Analyses were performed on 381,186 cattle with at least one portion of the carcass condemned among the 1,937,917 cattle slaughtered in ten French abattoirs. Results of the MFA and clustering methods led to 12 clusters considered as stable according to year of slaughter and slaughterhouse. One cluster was specific to a disease of public health importance (cysticercosis). Two clusters were linked to the slaughtering process (fecal contamination of heart or lungs and deterioration lesions). Two clusters respectively characterized by chronic liver lesions and chronic peritonitis could be linked to diseases of economic importance to farmers. Three clusters could be linked respectively to reticulo-pericarditis, fatty liver syndrome and farmer's lung syndrome, which are related to both diseases of economic importance to farmers and herd management issues. Three clusters respectively characterized by arthritis, myopathy and Dark Firm Dry (DFD) meat could notably be linked to animal welfare issues. Finally, one cluster, characterized by bronchopneumonia, could be linked to both animal health and herd management issues. CONCLUSION: The statistical approach of combining multiple factor analysis with cluster analysis showed its relevance for the detection of syndromes using available large and complex slaughterhouse data. The advantages of this statistical approach are to i) define groups of reasons for condemnation based on meat inspection data, ii) help grouping reasons for condemnation among a list of various possible reasons for condemnation for which a consensus among experts could be difficult to reach, iii) assign each animal to a single syndrome which allows the detection of changes in trends of syndromes to detect unusual patterns in known diseases and emergence of new diseases. PMID- 23628141 TI - Dynamics of the microfauna community in a full-scale municipal wastewater treatment plant experiencing sludge bulking. AB - We investigated the dynamics of the microfauna community in activated sludge, with special reference to sludge bulking, in two parallel municipal wastewater treatment systems in Beijing, China over a period of 14 months. Annual cyclic changes in microfauna community structures occurred in both systems. RELATE analysis based on Spearman's Rank correlation indicated that microfauna community structures were highly correlated with the sludge volume index (SVI) (p<0.001), which indicates sludge settleability. Nutrient conditions of raw sewage (p<0.01) and hydraulic retention time (HRT) (p<0.05) were also related to microfauna community structures. Abundances of the species Epistylis plicatilis and Vorticella striata increased significantly with an increase in SVI (p<0.001) and decrease in water temperature (p<0.001), suggesting that sludge bulking may have created favorable conditions for the two species, even under unfavorable temperature conditions. Sludge de-flocculation primarily due to the excessive growth of Microthrix parvicella-like filaments could be an important driving force for the microfauna community changes. The release of flocculated non filamentous bacteria may represent a suitable food source for these species. The two species may be considered as potential bioindicators for sludge bulking. PMID- 23628142 TI - Comparing fungal band formulations for Asian longhorned beetle biological control. AB - Experiments were conducted with the fungal entomopathogen Metarhizium brunneum to determine the feasibility of using agar-based fungal bands versus two new types of oil-formulated fungal bands for Asian longhorned beetle management. We investigated conidial retention and survival on three types of bands attached to trees in New York and Pennsylvania: standard polyester fiber agar-based bands containing fungal cultures, and two types of bands made by soaking either polyester fiber or jute burlap with oil-conidia suspensions. Fungal band formulation did not affect the number or viability of conidia on bands over the 2 month test period, although percentage conidial viability decreased significantly with time for all band types. In a laboratory experiment testing the effect of the three band formulations on conidial acquisition and beetle survival, traditional agar-based fungal bands delivered the most conidia to adult beetles and killed higher percentages of beetles significantly faster (median survival time of 27d) than the two oil-formulated materials (36-37d). We also tested the effect of band formulation on conidial acquisition by adult beetles kept individually in cages with a single band for 24h, and significantly more conidia (3-7times) were acquired by beetles from agar-based bands compared to the two oil formulations. PMID- 23628143 TI - Characterization of baculoviruses from the Martignoni collection. AB - 47 samples from the Martignoni baculovirus collection were characterized by PCR amplification of the lef-8 gene. This led to the identification of sequences from viruses that either were not present in the database, or had been identified, but not further characterized. These included an NPV and a GV from Pseudoletia (Mythimna) unipuncta, and NPVs from Coloradia pandora, the oak and hemlock looper (probably Lambdina sp.), Peridroma sp., the pine butterfly (probably Neophasia sp.), Hemileuca sp., Orgyia vetusta, and several Choristoneura sp. A phylogenetic tree was constructed relating these viruses to their closest relatives in the database. PMID- 23628144 TI - Prevalence of claims-based recurrent low back pain in a Canadian population: a secondary analysis of an administrative database. AB - BACKGROUND: There is a vast literature reporting that the point prevalence of low back pain (LBP) is high and increasing. It is also known that a large proportion of acute LBP episodes are recurrent within 12 months. However, few studies report the annual trends in the prevalence of recurrent LBP or describe these trends according to age and sex categories. METHODS: We conducted a retrospective cohort study involving 401 264 adults selected from the administrative database of physician claims for the province of Quebec, Canada. These adults, aged 18 years and over, met the criteria of having consulted a physician three times within a 365-day period between 2000 and 2007 for a LBP condition corresponding to ICD-9 codes 721, 722, 724 or 739. All data were analyzed by sex and clustered according to specific age categories. RESULTS: We observed a decrease from 1.64% to 1.33% in the annual prevalence between 2000 and 2007 for men. This decrease in prevalence was mostly observed between 35 and 59 years of age. Older (>= 65 years) women were 1.35 times more at risk to consult a physician for LBP in a recurrent manner than older men. The most frequently reported diagnosis was non specific LBP between 2000 to 2007. During the same period, sequelae of previous back surgery and spinal stenosis were the categories with the largest increases. CONCLUSION: The annual prevalence of claims-based recurrent LBP progressively decreased between 2000 and 2007 for younger adults (<65 years) while older adults (>= 65 years) showed an increase. Given the aging Canadian population, recurrent low back pain could have an increasing impact on the quality of life of the elderly as well as on the healthcare system. PMID- 23628145 TI - Age-related changes of blood-oxygen-level-dependent signal dynamics during optokinetic stimulation. AB - The present study aimed to reveal the effects of age on the temporal profile of the positive blood-oxygen-level-dependent response (PBR) during low-velocity optokinetic nystagmus (OKN) in healthy subjects. We were specifically interested in comparing these effects with the effects of age on the PBR elicited by pure visual and motor tasks. Therefore, we conducted 2 additional control experiments: a checkerboard experiment (visual stimulation) and a finger-tapping (motor task) experiment. Whereas the oculomotor performance of the subjects remained unaltered, the temporal profile of the PBR changed significantly with increasing age in visual and oculomotor areas. None of the control experiments revealed significant age-related PBR changes. Thus, this study demonstrates that the PBR changes during OKN occur before any changes in the oculomotor performance can be detected. These effects of age are specific for the OKN task and probably reflect both changes in the neurovascular coupling and changes in the neural processing during OKN. PMID- 23628146 TI - How to improve change of shift handovers and collaborative grounding and what role does the electronic patient record system play? Results of a systematic literature review. AB - INTRODUCTION: Establishing continuity of care in handovers at changes of shift is a challenging endeavor that is jeopardized by time pressure and errors typically occurring during synchronous communication. Only if the outgoing and incoming persons manage to collaboratively build a common ground for the next steps of care is it possible to ensure a proper continuation. Electronic systems, in particular electronic patient record systems, are powerful providers of information but their actual use might threaten achieving a common understanding of the patient if they force clinicians to work asynchronously. In order to gain a deeper understanding of communication failures and how to overcome them, we performed a systematic review of the literature, aiming to answer the following four research questions: (1a) What are typical errors and (1b) their consequences in handovers? (2) How can they be overcome by conventional strategies and instruments? (3) electronic systems? (4) Are there any instruments to support collaborative grounding? METHODS: We searched the databases MEDLINE, CINAHL, and COCHRANE for articles on handovers in general and in combination with the terms electronic record systems and grounding that covered the time period of January 2000 to May 2012. RESULTS: The search led to 519 articles of which 60 were then finally included into the review. We found a sharp increase in the number of relevant studies starting with 2008. As could be documented by 20 studies that addressed communication errors, omission of detailed patient information including anticipatory guidance during handovers was the greatest problem. This deficiency could be partly overcome by structuring and systematizing the information, e.g. according to Situation, Background, Assessment and Recommendation schema (SBAR), and by employing electronic tools integrated in electronic records systems as 23 studies on conventional and 22 articles on electronic systems showed. Despite the increase in quantity and quality of the information achieved, it also became clear that there was still the unsolved problem of anticipatory guidance and presenting "the full story" of the patient. Only a small number of studies actually addressed how to establish common ground with the help of electronic tools. DISCUSSION: The increase in studies manifests the rise of great interest in the handover scenario. Electronic patient record systems proved to be excellent information feeders to handover tools, but their role in collaborative grounding is unclear. Concepts of how to move to joint information processing and IT-enabled social interaction have to be implemented and tested. PMID- 23628147 TI - [Primary biliary cirrhosis and pregnancy]. AB - Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease, asymptomatic during a protracted time, characterized by changes in the small sized bile ducts near portal spaces. The etiology of PBC is undefined, but immunologic and environmental disturbances may contribute to the disease. Infertility is often associated with PBC and cirrhosis, but pregnancy may well occur in women with PBC and without cirrhosis or in some others with compensated cirrhosis. A pluridisciplinary approach including gastroenterologists and obstetricians is recommended. The patient must be closely monitored throughout her pregnancy with maternal and routine antenatal care. Medical treatment requires ursodeoxycholic acid (UDCA). In non-cirrhotic UDCA-treated women with PBC, pregnancy often follows a normal course with vaginal delivery. In cirrhotic patients, UDCA must be continued during pregnancy, esophageal and gastric varices must be evaluated before pregnancy, and endoscopic ligature is recommended for treating large varices. Additionally, beta-blocker therapy may be associated, especially when variceal rupture occurred previously. Elective cesarean section is recommended in patients with large esophageal or gastric varices because of the potentially increased risk of variceal bleeding during maternal expulsive efforts in case of vaginal delivery. PMID- 23628148 TI - Influence of environment and climate on occurrence of the cixiid planthopper Hyalesthes obsoletus, the vector of the grapevine disease 'bois noir'. AB - Species distribution models (SDMs), which are well established in many fields of biological research, are still uncommon in the agricultural risk analysis of pest insects. To exemplify the use of SDMs, we investigated the influence of environmental factors on the occurrence of Hyalesthes obsoletus Signoret (Hemiptera: Cixiidae). The planthopper is the only known vector of the grapevine yellows disease 'bois noir'. The study was conducted in 145 locations in the Baden region of southwest Germany. The planthopper was surveyed on host plant patches, consisting of stinging nettle and/or bindweeds. We used a stratified modelling framework where (1) species presence-absence data were related to an extensive environmental dataset using logistic regressions; and (2) different types of average models were developed based on an information theoretic method. The results show that the incidence of H. obsoletus is associated to above- as well as below-ground environmental factors, particularly to the amount of fine soil and average annual precipitation. This result was consistent across all average models. The relative importance of other environmental variables was dependent upon the average model under consideration and thus may vary according to their intended use, either the explanation of habitat requirements or the prediction and mapping of occurrence risks. The study showed that SDMs offer a quantification of species' habitat requirements and thus, could represent a valuable tool for pest management purposes. By providing examples of current issues of grapevine pests in viticulture, we discuss the use of SDMs in agricultural risk analysis and highlight their advantages and caveats. PMID- 23628149 TI - Effects of continuous renal replacement therapy on renal inflammatory cytokines during extracorporeal membrane oxygenation in a porcine model. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been recommended for the treatment of patients with acute, potentially reversible, life-threatening respiratory failure which unresponsive to conventional therapy. But it is unclear about how ECMO affects renal tissue. METHODS: Twenty-four piglets weighing 25 to 32 kg were used in this experiment. The piglets were randomly allocated to 4 groups of 6 animals each: sham group (S group), control group (C group), VV-ECMO group (E group), VV-ECMO combined with CRRT group (EC group). The piglets were sacrificed and the kidney tissue were harvest to determine the levels of IL 1beta, IL-6, TNF-alpha and NF-KB by using the ELISA and RT-PCR method, respectively. RESULTS: Compared with C group and S group, E group renal tissue IL 1beta, IL-6, TNF-alpha and NF-KB expression increased significantly, respectively (p < 0.01). Compared with E group, EC group showed renal tissue IL-1beta, IL-6, TNF-alpha and NF-KB expression decreased significantly, respectively (p < 0.05). CONCLUSION: ECMO enables to inflammatory cytokines including IL-1beta, IL-6, TNFalpha, NF-KB released significantly, renal function impaired and immune homeostasis were to imbalance; ECMO combined with CRRT treatment can alleviate levels of inflammatory cytokines, maintain immune homeostasis balance and thus ameliorate the ECMO-related acute kidney injury(AKI). PMID- 23628152 TI - Stimulation of fecal bacteria in ambient waters by experimental inputs of organic and inorganic phosphorus. AB - Fecal microbial pollution of recreational and shellfishing waters is a major human health and economic issue. Microbial pollution sourced from stormwater runoff is especially widespread, and strongly associated with urbanization. However, non-point source nutrient pollution is also problematic, and may come from sources different from fecal-derived pollution (i.e. fertilization of farm fields, lawns and gardens, and ornamental urban areas). Fecal bacteria require nutrients; thus the impact of such nutrient loading on survival and abundance of fecal coliform bacteria in ambient waters was experimentally investigated in a constructed wetland in coastal North Carolina, USA. A series of nutrient-addition bioassays testing impacts of inorganic and organic nitrogen and phosphorus demonstrated that additions of neither organic nor inorganic nitrogen stimulated fecal coliform bacteria. However, phosphorus additions provided significant stimulation of fecal coliform growth at times; on other occasions such additions did not. Dilution bioassays combined with nutrient additions were subsequently devised to assess potential impacts of microzooplankton grazing on the target fecal bacteria populations. Results demonstrated grazing to be a significant bacterial reduction factor in 63% of tests, potentially obscuring nutrient effects. Thus, combining dilution experiments with nutrient addition bioassays yielded simultaneous information on microzooplankton grazing rates on fecal bacteria, fecal bacterial growth rates, and nutrient limitation. Overall, when tested against a non-amended control, additions of either organic or inorganic phosphorus significantly stimulated fecal coliform bacterial growth on 50% of occasions tested, with organic phosphorus generally providing greater stimulation. The finding of significant phosphorus stimulation of fecal bacteria indicates that extraneous nutrient loading can, at times, augment the impacts of fecal microbial pollution of shellfishing and human contact waters. PMID- 23628151 TI - Mechanical properties of human amniotic fluid stem cells using nanoindentation. AB - The aim of this study was to obtain nanomechanical properties of living cells focusing on human amniotic fluid stem (hAFS) cell using nanoindentation techniques. We modified the conventional method of atomic force microscopy (AFM) in aqueous environment for cell imaging and indentation to avoid inherent difficulties. Moreover, we determined the elastic modulus of murine osteoblast (OB6) cells and hAFS cells at the nucleus and cytoskeleton using force displacement curves and Hertz theory. Since OB6 cell line has been widely used, it was selected to validate and compare the obtained results with the previous research studies. As a result, we were able to capture high resolution images through utilization of the tapping mode without adding protein or using fixation methods. The maximum depth of indentation was kept below 15% of the cell thickness to minimize the effect of substrate hardness. Nanostructural details on the surface of cells were visualized by AFM and fluorescence microscopy. The cytoskeletal fibers presented remarkable increase in elastic modulus as compared with the nucleus. Furthermore, our results showed that the elastic modulus of hAFS cell edge (31.6 kPa) was lower than that of OB6 cell edge (42.2 kPa). In addition, the elastic modulus of nucleus was 13.9 kPa for hAFS cell and 26.9 kPa for OB6 cells. Differences in cell elastic modulus possibly resulted from the type and number of actin cytoskeleton organization in these two cell types. PMID- 23628153 TI - Aortic intimal sarcoma: report of two cases with immunohistochemical analysis for pathogenesis. AB - Primary vascular neoplasms are rare entities. They were first described as arising spontaneously in the aorta and other vessels. However, in the past several decades, a number of systemic artery-derived vascular neoplasms, mostly sarcomas, have been reported as arising in intimate association with synthetic grafts. We describe two additional cases of intimal sarcoma seen at our institution. The first is an invasive intimal sarcoma detected in a thoracoabdominal aortic aneurysm at the time of surgical intervention. The second is a superficial spreading intimal sarcoma associated with a Dacron-coated graft, in place for 9 years, detected when the graft was replaced. When the patient died 3 months later, a metastatic subcutaneous sarcomatous lesion was detected at autopsy. In these cases, we studied selective molecular pathways that may be involved in the transformation of benign endothelium to malignant endothelium, with implications for possible therapeutic targets. These cases are presented in order to contribute additional data to the literature involving these vascular neoplasms and to potentially provide a spectrum of disease seen in the vasculature tissues that may arise spontaneously or after placement of a synthetic graft. PMID- 23628155 TI - Regulation of biological function by allosteric interactions. PMID- 23628154 TI - Novel pharmacokinetic studies of the Chinese formula Huang-Lian-Jie-Du-Tang in MCAO rats. AB - Our previous studies showed that after oral administration of an Huang-Lian-Jie Du-Tang (HLJDT) decoction, there is a higher concentration of the pure components, berberine, baicalin and gardenoside in the plasma of Middle cerebral artery occlusion (MCAO) rats than in sham-operated rats, The aim of the present study was to determine whether these components could be reliably measured in MCAO rat tissues. First, the plasma concentration-time profiles of berberine, palmatine, baicalin, baicalein and gardenoside were characterised in MCAO rats after oral administration of the aqueous extract of HLJDT. Subsequently, liver, lung and kidney tissues were obtained from sudden death MCAO rats in the absorption phase (0.25 h), the distribution phase (1.0 h) and the elimination phase (8.0 h) after administration of the HLJDT aqueous extract. An HPLC method was developed and validated for the determination of the distribution characteristics of berberine, palmatine, baicalin, baicalein and gardenoside simultaneously from the above-mentioned rat tissues. The results indicated that berberine, palmatine, baicalin and baicalein distributed rapidly and accumulated at high levels in the lung, while gardenoside distributed widely in the lung and the kidney. To the best of our knowledge, this is the first report to describe the distribution of the active ingredients derived from HLJDT in MCAO rat tissues. The tissue distribution results provide a biopharmaceutical basis for the design of the clinic application of HLJDT in cerebrovascular disease. PMID- 23628156 TI - Structures of yeast Apa2 reveal catalytic insights into a canonical AP4A phosphorylase of the histidine triad superfamily. AB - The homeostasis of intracellular diadenosine 5',5"'-P(1),P(4)-tetraphosphate (Ap4A) in the yeast Saccharomyces cerevisiae is maintained by two 60% sequence identical paralogs of Ap4A phosphorylases (Apa1 and Apa2). Enzymatic assays show that, compared to Apa1, Apa2 has a relatively higher phosphorylase activity towards Ap3A (5',5"'-P(1),P(3)-tetraphosphate), Ap4A, and Ap5A (5',5"'-P(1),P(5) tetraphosphate), and Ap4A is the favorable substrate for both enzymes. To decipher the catalytic insights, we determined the crystal structures of Apa2 in the apo-, AMP-, and Ap4A-complexed forms at 2.30, 2.80, and 2.70A resolution, respectively. Apa2 is an alpha/beta protein with a core domain of a twisted eight stranded antiparallel beta-sheet flanked by several alpha-helices, similar to the galactose-1-phosphate uridylyltransferase (GalT) members of the histidine triad (HIT) superfamily. However, a unique auxiliary domain enables an individual Apa2 monomer to possess an intact substrate-binding cleft, which is distinct from previously reported dimeric GalT proteins. This cleft is perfectly complementary to the favorable substrate Ap4A, the AMP and ATP moieties of which are perpendicular to each other, leaving the alpha-phosphate group exposed at the sharp turn against the catalytic residue His161. Structural comparisons combined with site-directed mutagenesis and activity assays enable us to define the key residues for catalysis. Furthermore, multiple-sequence alignment reveals that Apa2 and homologs represent canonical Ap4A phosphorylases, which could be grouped as a unique branch in the GalT family. PMID- 23628157 TI - A novel device for the calibration of sonic and ultrasonic recording transducers. AB - Recently, there has been an increase in the analysis of animal vocalizations in behavioral neuroscience as a social cue or indicator of neurological integrity. Despite the multitude of researchers examining vocalizations in a variety of species, no inexpensive, tunable devices currently exist to calibrate the amplification applied to such vocalizations before data are collected. Many commercially available recording systems have analog adjustments for gain, but such methods are notoriously unreliable and highly variable. Without a consistent level of gain, the amplitudes of recorded acoustic signals cannot be reliably compared. Here, we describe an apparatus designed to fulfill this need, which we have labeled the Calibration Unit for Recording Transducers (CURT). To maximize application to various fields, its emitted frequency and amplitude are tunable to output frequencies in both human-sonic (20 Hz-20 kHz) and human-ultrasonic ranges (20 Hz-100 kHz). Additionally, it is a portable (weighing approximately 180 g), customizable, stand-alone unit, and fits a variety of microphone connector types. The CURT is also relatively low cost to build (under 250.00 USD), thereby making such a device available to as many researchers as possible in animal behavior and neuroscience. PMID- 23628158 TI - The effect of calcium modulating agents on peripheral nerve recovery after crush. AB - After a nerve injury, calcium concentration in the intra-nerve fiber drastically increases. The purpose of our study was to test an implantable micro-osmotic pump to deliver medications to accelerate calcium absorption, thereby greatly improving nerve regeneration. Twenty-four SD rats were divided into four groups of six each: (1) Sham control: crush injury to sciatic nerve only; (2) Crush injury with a Nifedipine pump; (3) Crush injury with a Calcitonin pump; (4) Crush injury with a Saline pump. Each rat's right sciatic nerve was crushed. The micro osmotic pump was implanted in the neck, and the dripping tube was routed to the injured nerve. After four weeks of survival time, compound muscle action potential (CMAP), tetanic muscle force (TMF), myelinated nerve fiber area (NFA), nerve calcium concentration (NCC), and calcified spots (CS) were evaluated. The calcium absorption rate (CAR) was also determined. The order from highest to lowest recovery rate was Nifedipine>Calcitonin>Sham control>Saline. Differences among the groups were statistically significant (P<0.001, ANOVA test), and the difference between Nifedipine/Calcitonin and Saline/Sham control were all statistically significant (P<0.001, t-test). The correlation rate of NCC with CMAP/TMF and with NFA/CS and CAR were calculated to be 0.99 (all P<0.001, Pearson's Correlation). We conclude from this study that nerve regeneration strongly correlated with calcium absorption; our new data has shown greatly improved nerve functional recovery, and this can potentially be translated into clinical applications. PMID- 23628159 TI - Cortical mapping by magnetic resonance imaging (MRI) and quantitative cytological analysis in the human brain: a feasibility study in the fusiform gyrus. AB - The cerebral cortex is a layered cellular structure that is tangentially organized into a mosaic of anatomically and functionally distinct fields. In spite of centuries of investigation, the precise localization and classification of many areas in the cerebral cortex remain problematic because the relationship between functional specificity and intra-cortical structure has not been firmly established. Furthermore, it is not yet clear how surface landmarks, visible through gross examination and, more recently, using non-invasive magnetic resonance imaging (MRI), relate to underlying microstructural borders and to the topography of functional activation. We have designed a multi-modal neuroimaging protocol that combines MRI and quantitative microscopic analysis in the same individual to clarify the topography of cytoarchitecture underlying gross anatomical landmarks in the cerebral cortex. We tested our approach in the region of the fusiform gyrus (FG) because, in spite of its seemingly smooth appearance on the ventral aspect of both hemispheres, this structure houses many functionally defined areas whose histological borders remain unclear. In practice, we used MRI-based automated segmentation to define the region of interest from which we could then collect quantitative histological data (specifically, neuronal size and density). A modified stereological approach was used to sample the cortex within the FG without a priori assumptions on the location of architectonic boundaries. The results of these analyses illustrate architectonic variations along the FG and demonstrate that it is possible to correlate quantitative histological data to measures that are obtained in the context of large-scale, non-invasive MRI-based population studies. PMID- 23628161 TI - Straight aortic endograft in abdominal aortic disease. AB - BACKGROUND: We describe our 8-year experience with the use of endovascular techniques (ET) for the treatment of abdominal aortic aneurysms (AAA) through a straight endograft. METHODS: We retrospectively reviewed data of all patients who were treated for AAA using ET in two centres from 1998 to 2012 and who received a single straight endograft (group A) or a double straight tube (group B). Outcomes were analyzed to assess survival, absence of endoleak and absence of reintervention for both groups. Log-rank and Chi-Square were used as appropriate to make comparison between the two groups. P values < .05 were considered statistically significant. RESULTS: Fifty-three patients from 1998 to May 2012 were treated for AAA using a straight endograft. In 28 cases (52.8%) a single aortic straight tube was used (Group A), while in the remaining cases a "double trombone technique" was used (Group B). CONCLUSIONS: In our experience the endovascular repair of AAA using straight aortic endografts was a safe and effective technique. Reintervention and endoleaks were slightly more frequent in patients who had received a single endograft compared to patients who were treated using the "trombone technique". PMID- 23628162 TI - Furthering the reliable and valid measurement of mental health screening, diagnoses, treatment and outcomes through health information technology. AB - INTRODUCTION: Measurement of mental health is challenging; however, many solutions may be found through the use of health information technology. METHOD: This article reviews current approaches to measuring mental health, focusing on screening, diagnosis, treatment, and outcomes. It then identifies several key areas in which health information technology may advance the field and provide reliable and valid measurements that are readily available to and manageable for providers, as well as acceptable, feasible, and sustainable for selected populations. RESULT AND CONCLUSIONS: Although new technologies must overcome many challenges, including privacy, efficiency, cost, and scalability, it is an exciting and fast-growing field with many potential applications and clinical benefit. PMID- 23628164 TI - Improving the reliability and reporting of genetic association studies. AB - Genetic association studies, in particular candidate gene studies, have a long history of initially promising findings which subsequently produce a confusing mixture of replications, partial replications and non-replications. Drug and Alcohol Dependence is receiving an increasing number of submissions of genetic association studies. Here we discuss the journal's approach to considering such papers, in order to encourage credible and balanced reports which will contribute positively to the field. Recently, the STrengthening the REporting of Genetic Association studies (STREGA) initiative has provided guidelines which serve to enhance transparency. We strongly encourage authors considering submitting a genetic association study to the journal to follow these guidelines. PMID- 23628163 TI - The influence of cage farming on infection of the corvine fish Plagioscion squamosissimus (Perciformes: Sciaenidae) with metacercariae of Austrodiplostomum compactum (Digenea: Diplostomidae) from the Chavantes reservoir, Sao Paulo State, Brazil. AB - The development of cage fish farms has been associated with an increase in parasitic diseases. Organic matter resulting from feed waste and faeces attracts animals such as birds and invertebrates that can act as hosts for parasites. The aim of this study was to evaluate the influence of cage farming on Austrodiplostomum compactum metacercariae infections of Plagioscion squamosissimus collected close to a cage farm in the Chavantes reservoir (Paranapanema River). Thirty-seven fish were collected in an area close to cages (CF), and 28 in an area not influenced by cages (CT). All specimens were weighed, measured and the eyes removed for morphological analyses of metacercariae. The prevalence, mean intensity of infection, mean abundance and condition factor were calculated. The prevalence (CF = 86.4%, CT = 57.1%), mean infection intensity (CF = 20.31 +/- 1.13, CT = 4.29 +/- 7.14) and mean abundance (CF = 17.70 +/- 6.27, CT = 2.35 +/- 0.77) were higher in the CF (P< 0.05) group. There were no significant correlations (P> 0.05) between the mean abundance and standard length or the total weight and condition factor in either group (P> 0.05). Fish farms may interfere with the life cycle of A. compactum, leading to more infections with P. squamosissimus. This could be due to an increase in the number of host animals that are attracted by the availability of food resources derived from fish farms. PMID- 23628165 TI - Using protein granularity to extract the protein sequence features. AB - The feature extraction of protein sequences is a challenging problem. It might need a lot of theoretical and practical knowledge from many fields. The difficulty would increase when investigators extract the features solely from protein sequences. In this paper, we present a method of protein granularity. The concepts of protein granularity, granularity order, granularity bound, granularity limit, and granularity increment are given respectively. The protein granularity can dig out the useful information solely from protein sequences. We provide an approach to construct the feature vectors. The feature vectors include the amino acid composition information, the sequence-order information, the same amino acid 'neighbor' information, and the sequence length information. Hence, the feature vectors can better represent protein sequences. Our feature extraction method does obviously consider the protein sequence length effects. An experiment of the protein structure class prediction was carried out. The prediction achieved 96.6% overall accuracy, and the success rate for each subset is all-alpha 92.3%, all-beta 100%, alpha/beta 100%, alpha+beta 93.5%, respectively. The last three success rates for subsets are equal to the best success rates in the published literatures. The overall accuracy of PG-SVM prediction is the second best result only having one protein prediction error difference with the first best result. The theoretical and experimental results demonstrate the application of protein granularity succeeds in the feature extraction of protein sequences. PMID- 23628167 TI - Impact of a family history of epilepsy on the diagnosis of epilepsy in Southern Saudi Arabia. AB - PURPOSE: Epilepsy can develop at any age for reasons that remain poorly understood. The aim of this study was to determine the impact of a family history of epilepsy (FHE) on the incidence and recurrence of seizures. METHODS: This retrospective study was conducted in Aseer central hospital, Abha, Saudi Arabia between January and June 2012. The medical records of 420 patients were analyzed to test the impact of FHE on the risk factors, etiology and diagnosis of epilepsy determined by magnetic resonance imaging (MRI) and electroencephalography (EEG). RESULTS: 420 patients were studied. Idiopathic epilepsy was seen in 140 patients (33%), symptomatic in 152 (36%), and cryptogenic in 128 patients (30%). FHE was seen in 113 patients (27%), which was associated with younger at the disease onset (15 years vs 20 years, p<0.05). Idiopathic epilepsy was seen more in patients with FHE (43% vs 30%, p value <0.05), and generalized seizures (primary or secondary) were also seen more in patients with FHE (51% vs 36%, p value <0.05). Abnormal EEG was also seen more in patients with FHE (79% vs 66%, p<0.05). Multivariate regression analysis showed that temporal epileptic discharges were the best predictor for the presence of FHE (p<0.05, OR=3.1, 95% CI 1.7-5.8), more than idiopathic epilepsy or younger age at epilepsy onset. CONCLUSIONS: FHE has a significant impact on epilepsy, its classifications, and the EEG findings, and may underlie the presence of a genetic etiology, which could be related to a high incidence of consanguinity seen in our population. Temporal epileptic discharges were the best predictor for FHE, which may suggest the presence of familial TLE. PMID- 23628166 TI - Human immune responses and potential for vaccine assessment in humanized mice. AB - The new humanized mouse models with a transplanted human immune system have a capacity for de novo multilineage human hematopoiesis and generate T cells, B cells, macrophages, dendritic cells and NK cells. Of the two current leading humanized mouse models, the hu-HSC model is created by human hematopoietic stem cell (HSC) engraftment whereas the BLT mouse model is prepared by co transplantation of human fetal liver, thymus and HSC. Humoral and cellular immune responses are seen in both models after immunization with antigens or infection with hematotropic pathogens such as EBV, HIV-1 and dengue viruses. While consistent antigen specific IgM production is seen, IgG responses were found to be generally feeble which is attributed to inefficient immunoglobulin class switching. BLT mice permit human HLA restricted T cell responses due to the autologous human thymus contributing to T cell maturation. Use of HLA Class I and II transgenic hu-HSC mice recently demonstrated that the HLA restriction deficiency could be overcome in this model. However, the overall vigor of the immune responses needs further improvement in both the models to approach that of the human. Towards this goal, supplementation with human cytokines and growth factors by transgenesis to improve human cell reconstitution and their homeostatic maintenance are beginning to yield improved mouse strains to create more robust human immune competent mice for immunoprophylaxis studies. PMID- 23628168 TI - Computerized neuropsychological testing in epilepsy: overview of available tools. AB - PURPOSE: Neuropsychology has become an essential diagnostic tool for epilepsy related cognitive comorbidities and treatment evaluation. However, a lack of resources may prevent routine neuropsychological assessments outside specialized epilepsy centers. Computerized testing appears to offer a time- and cost effective approach to assess cognitive functions in patients with epilepsy. Moreover, the technical advances of computerized tests provide interesting tools to address specific diagnostic questions around epilepsy. This review is intended: (1) to outline the advantages and disadvantages of computerized testing, (2) to delineate its indications and fields of application, and (3) to give an overview of available tools that have been applied in epilepsy or antiepileptic drug research. METHOD: Iterative review of computer-based neuropsychological assessment batteries previously applied in clinical epileptological settings or antiepileptic drug trials. RESULTS: Among nine reviewed computer tests merely three were explicitly devised for epilepsy and showed sensitivity to clinical parameters like focus lateralization or localization or the presence/absence of epileptiform activity. Concurrent validity with established measures was demonstrated for two of these three tests. Some sensitivity to antiepileptic pharmacotherapy was reported for seven of all nine reviewed test batteries. CONCLUSION: Additional studies are needed to demonstrate the sensitivity and specificity of computerized neuropsychological tests to epilepsy and treatment related variables. In most clinical scenarios exclusive computerized testing cannot substitute a thorough neuropsychological examination in patients with epilepsy at present. PMID- 23628169 TI - [Acute liver failure due to diffuse large B-cell lymphoma]. PMID- 23628170 TI - [Diabetes in liver cirrhosis]. AB - The prevalence of overt diabetes mellitus (DM) in liver cirrhosis is about 30%. However, DM or impaired glucose tolerance can be observed in 90% after an oral glucose tolerance test in patients with normal fasting plasma glucose. Type 2 DM may produce cirrhosis, whereas DM may be a complication of cirrhosis. The latter is known as "hepatogenous diabetes". Overt and subclinical DM is associated with liver complications and death in cirrhotic patients. Treating diabetes is difficult in cirrhotic patients because of the metabolic impairments due to liver disease and because the most appropriate pharmacologic treatment has not been defined. It is also unknown if glycemic control with hypoglycemic agents has any impact on the course of the liver disease. PMID- 23628171 TI - Isotherm and thermodynamic studies of Zn (II) adsorption on lignite and coconut shell-based activated carbon fiber. AB - The Zn (II) adsorption capacity of lignite and coconut shell-based activated carbon fiber (ACF) was evaluated as a function of initial Zn (II) concentration, temperature and contact time in batch adsorption process in this study. Adsorption uptake increased with initial Zn (II) concentration and temperature. Optimal contact time for the adsorption of Zn (II) ions onto lignite and coconut shell-based ACF was found to be 50 min. Removal percentage decreased from 88.0% to 78.54% with the increment in initial Zn (II) concentration from 5 to 50 mg L( 1). Equilibrium data fit well with Langmuir-I isotherm indicating homogeneous monolayer coverage of Zn (II) ions on the adsorbent surface. Maximum monolayer adsorption capacity of Zn (II) ions on ACF was found to be 9.43 mg g(-1). Surface morphology and functionality of ACF prior to and after adsorption were characterized by electron microscopy and infrared spectroscopy. Various thermodynamic parameters such as standard Gibbs free energy (DeltaG degrees ), standard enthalpy (DeltaH degrees ), and standard entropy (DeltaS degrees ) were evaluated. PMID- 23628172 TI - The distribution and partitioning of common antibiotics in water and sediment of the Pearl River Estuary, South China. AB - Antibiotics released into the aquatic environment play an important role in the spread of antibiotic resistance. In the Pearl River Estuary (PRE) and the coastal zone, the concentrations of antibiotics decreased from the Pearl River to the estuary, suggesting that antibiotics primarily originated from river tributaries and terrigenous sources. Within the PRE area, the concentrations of antibiotics in water were higher in the west coast than the east side, reflecting the high density of anthropogenic activities and hydraulic conditions along the west riverbank. Seasonal variations were also observed for most of detected antibiotics in water. The pseudo-partitioning coefficient of norfloxacin had a good correlation with the TOC content of sediments, as did erythromycin-H2O with the pH of water. The results suggest that environmental conditions can significantly affect the distribution of antibiotics between water and sediment. PMID- 23628173 TI - Stable isotope coded derivatizing reagents as internal standards in metabolite profiling. AB - Gas chromatography (GC) and liquid chromatography (LC) coupled to mass spectrometric (MS) detection have become the two main techniques for the analysis of metabolite pools (i.e. Metabolomics). These technologies are especially suited for Metabolite Profiling analysis of various metabolite groups due to high separation capabilities of the chromatographs and high sensitivity of the mass analysers. The trend in quantitative Metabolite Profiling is to add more metabolites and metabolite groups in a single method. This should not be done by compromising the analytical precision. Mass spectrometric detection comes with certain limitations, especially in the quantitative aspects as standards are needed for conversion of ion abundance to concentration and ionization efficiencies are directly dependent on eluent conditions. This calls for novel strategies to counteract all variables that can influence the quantitative precision. Usually, internal standards are used to correct any technical variation. For quantitation of single or just a few analytes this can be executed with spiking isotopically labeled standards. However, for more comprehensive analytical tasks, e.g. profiling tens or hundreds of analytes simultaneously, this strategy becomes expensive and in many cases isotopically labeled standards are not available. An alternative is to introduce a derivatizing step where the sample is derivatized with naturally labeled reagent, while a standard solution is separately derivatized with isotopically labeled reagent and spiked into the sample solution prior to analysis. This strategy, named isotope coded derivatization - ICD, is attractive in the emerging field of quantitative Metabolite Profiling where current protocols can easily comprise over hundred metabolites. This review provides an overview of isotopically labeled derivatizing reagents that have been developed for important metabolite groups with the aim to improve analytical performance and precision. PMID- 23628174 TI - A novel derivatization-based liquid chromatography tandem mass spectrometry method for quantitative characterization of naphthenic acid isomer profiles in environmental waters. AB - A method for quantitative characterization of naphthenic acid (NA) isomer groups by carbon number and extent of cyclization was developed and validated with water samples from northern Alberta. Following solid phase extraction, NAs undergo derivatization with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) allowing detection by positive electrospray ionization tandem mass spectrometry (+ESI) MS/MS. NA-EDC derivatives produce a common product ion by MS/MS, regardless of structure of the starting NA. Thus, approximately constant relative response factors (RRFs) were assumed for the various isomer groups that elute at a given point in the elution gradient (supported by calculated RRFs for individual model NAs), facilitating quantification using a single standard (1-pyrenebutyric acid). To reduce the impact of major background fatty acids on NA data, the method employed an optimized liquid chromatography method that separated straight chain (Z=0) analytes from other NAs. Method validation was performed at two spiking levels (7.72MUg and 38.6MUg total refined Merichem per 500mL of reagent water) and good accuracy (mean recoveries of 82.4+/-2.5% and 93.0+/-2.6%, respectively; range ~50-130%) and precision (<17% RSD) were achieved at both spiking levels for all 60 NA isomer groups. The method also performed well in an independent method comparison study in which method accuracy values of 107%, 120%, and 121% were obtained for 2 spiked reagent waters (1mg/L and 50mg/L NAs) and spiked Athabasca River water (0.035mg/L NAs), respectively. Application of the method to samples from northern Alberta revealed that NA concentrations decreased in the order: process water (52.8mg/L)>tailings pond water (30.6mg/L)>well water (0.086mg/L)>surface water (0.007mg/L), and that samples were distinguishable by NA isomer profile using Principal components analysis. PMID- 23628175 TI - HUS surveillance notes--Sarah's story. PMID- 23628176 TI - An interview with Per Renstrom on his personal perspective of the changes and developments in the sports medicine field over the last 40 years. PMID- 23628177 TI - Gestational age-related changes in the peripheral blood cell composition of sub Saharan African women. AB - Gestational age-related changes in the cellular composition of peripheral blood have not been described in sub-Saharan African settings. We conducted longitudinal cohort studies in Beninese and Tanzanian mothers with quantification of peripheral blood mononuclear cell-types ex vivo using flow cytometry. Between the second trimester and delivery the frequency of CD4(+) T cells declined significantly, contrasting with a non-significant increase in CD8(+) T cells, but no changes in T-regulatory, NK or NKT cell frequencies. Antigen-presenting cell profiles were also unaltered, although non-significant trends were evident. These changes resemble in some respects those reported during pregnancies in developed countries, but differ in others. PMID- 23628178 TI - What can the 2009 influenza outbreak teach us about the risk of a severe pandemic? The Madagascar experience: a reply. PMID- 23628179 TI - Thrombosis during off pump LVAD placement in a patient with heparin induced thrombocytopenia using bivalirudin. AB - Here we present our attempt at off pump HeartMate II left ventricular assist device (LVAD) implantation using the anticoagulant bivalirudin in a patient with heparin induced thrombocytopenia, which resulted in thrombosis within the LVAD device. This required that our procedure be converted to on pump, and a new HeartMate II LVAD device to be implanted. In our view, this thrombotic event may have been caused by a number of factors that include bivalirudin's (1) short half life of about 20 minutes, (2) decreased activity with blood stasis, (3) inability to prevent clot propagation, and (4) uncertainty with real-time monitoring of therapeutic levels. To prevent future thrombotic events, it may be beneficial to immediately deair the LVAD device prior to the coring of the left ventricle during off pump LVAD placement. In addition, a solution other than blood may be used for priming. If blood is used for priming of the LVAD device, the duration of blood stasis should not exceed 20 minutes when bivalirudin is being used for anticoagulation. Furthermore, this case emphasizes the importance of having a backup LVAD device available and ready to use during surgical procedures. PMID- 23628180 TI - PON1 gene polymorphisms and plasma PON1 activities in Takayasu's arteritis disease. AB - BACKGROUND: Takayasu's arteritis (TA) is a chronic inflammation that affects the large vessels; however, its etiology is still unknown. Human serum paraoxonase hydrolyzes oxidized lipids into low-density lipoproteins and could therefore be associated with the prevalence of inflammation processes. Therefore, the purpose of study was to elucidate the influence of PON1 gene polymorphisms and plasma PON1 activities in Takayasu's arteritis disease. METHODS: Fifty-four patients with TA and 173 clinically healthy Mexicans were studied. The PON1 polymorphism was determined by the TaqMan PCR method. PON1 activity was assessed spectrophotometrically by paraoxon (p-nitrophenylphosphate) hydrolysis. RESULTS: In TA patients, the frequency of PON1(192R) allele (51% vs. 39%, P=0.043, OR=1.60, 95% CI=1.03-2.47), PON1(55M) allele (21% vs. 6.6%, P=0.0001, OR=3.80, 95% CI=2.03-7.10), and PON1(-108T) (60.1% vs. 46%, P=0.011, OR 1.79 (95% CI=1.15 2.79) were significantly higher than in healthy controls. PON1 activity was significantly lower for PON in TA vs. controls (136.14 vs. 322.79 MUmol min(-1) ml(-1), P=0.001, showing a decreasing activity in all genotypes in TA patients with respect to the control subjects. CONCLUSIONS: These results show significantly lower PON1 activity associated with HDL-C in TA patients, this activity could be depending on PON1 genotypes; showing that QR/LM/CT has the lowest hydrolytic activity toward paraoxon meanwhile, PON1(192,55,-108) genetic variations are related with reduced PON1 activities, these could be factors contributing to the development of TA disease. PMID- 23628181 TI - Cancer control in Latin America and the Caribbean: a bold ambition? PMID- 23628182 TI - Back to the roots: traditional medicine for cancer control in Latin America and the Caribbean. PMID- 23628183 TI - Initiatives in cancer control from Brazil's Ministry of Health. PMID- 23628184 TI - Planning cancer control--a Mexican perspective. PMID- 23628185 TI - Argentinean perspectives on cancer control in Latin America. PMID- 23628186 TI - Planning cancer control--the view of an NGO. PMID- 23628187 TI - PAHO: priorities and challenges in cancer care. PMID- 23628189 TI - Intoxicating stories: the characteristics, contexts and implications of drinking stories among Danish youth. AB - AIMS: To study the characteristics, contexts and implications of drinking stories among young drinkers. METHODS: Ethnographic fieldwork was conducted among Danish youth at a beach resort in Bulgaria. The fieldwork included three months of participant observation and 45 semi-structured interviews with a total of 104 tourists and 11 guides. The participants in the study were aged between 16 and 26 years. RESULTS: The participants often shared drinking stories with each other. The stories they told involved alcohol consumption followed by one or several acts of transgression such as stripping, fighting or vomiting. They generally told the stories with amusement or pride. However, some stories were told in a critical tone and focused on negative experiences. The data suggest that for many participants, part of their reason for engaging in heavy drinking and drunken transgressions was that they wanted to build a repertoire of personal drinking stories. Their drinking behaviour was subtly motivated, inspired and guided by the drinking stories that they heard from others, as well as by the drinking stories that they themselves wanted to create. CONCLUSION: There is an intimate interactional relationship between drinking behaviour and drinking stories. Drinking behaviours can generate stories, but the stories, in turn, influence behaviours and attitudes related to alcohol. Drinking stories are therefore key to understanding drinking among youth. PMID- 23628188 TI - Planning cancer control in Latin America and the Caribbean. AB - Non-communicable diseases, including cancer, are overtaking infectious disease as the leading health-care threat in middle-income and low-income countries. Latin American and Caribbean countries are struggling to respond to increasing morbidity and death from advanced disease. Health ministries and health-care systems in these countries face many challenges caring for patients with advanced cancer: inadequate funding; inequitable distribution of resources and services; inadequate numbers, training, and distribution of health-care personnel and equipment; lack of adequate care for many populations based on socioeconomic, geographic, ethnic, and other factors; and current systems geared toward the needs of wealthy, urban minorities at a cost to the entire population. This burgeoning cancer problem threatens to cause widespread suffering and economic peril to the countries of Latin America. Prompt and deliberate actions must be taken to avoid this scenario. Increasing efforts towards prevention of cancer and avoidance of advanced, stage IV disease will reduce suffering and mortality and will make overall cancer care more affordable. We hope the findings of our Commission and our recommendations will inspire Latin American stakeholders to redouble their efforts to address this increasing cancer burden and to prevent it from worsening and threatening their societies. PMID- 23628190 TI - Perioperative celecoxib decreases opioid use in patients undergoing testicular surgery: a randomized, double-blind, placebo controlled trial. AB - PURPOSE: We evaluated the effect of daily perioperative celecoxib on patient reported pain control and opioid use after testicular surgery. MATERIALS AND METHODS: Men scheduled to undergo elective outpatient microsurgical testicular sperm extraction were prospectively randomized to receive 200 mg celecoxib or placebo twice daily, which was initiated the night before surgery and continued for 6 days thereafter. Using an 11-point visual analog scale, participants self reported the postoperative pain level and acetaminophen/hydrocodone use for supplemental pain control. We compared differences in pain scores and opioid use between the 2 patient groups using the Student t test with p<0.05 considered significant. RESULTS: At 1-year interim analysis 35 of 78 eligible participants (45%) had returned the study questionnaire, of whom 34 were included in the final analysis. Of the 34 patients the 16 who received celecoxib had significantly lower postoperative opioid use than those on placebo (6 vs 16 pills, p=0.02). We noted a statistically significant difference in postoperative day 1 and 2 patient reported pain scores (4 vs 6, p<0.05 and 3 vs 5, p=0.03) and opioid use (1 vs 5 pills, p<0.01 and 2 vs 4, p=0.02) seen between the celecoxib and placebo groups, respectively. No study complications were identified. The trial was terminated early based on the results of interim analysis. CONCLUSIONS: Twice daily celecoxib use started preoperatively significantly decreased patient reported postoperative pain and opioid use, especially in the early postoperative period. A short course of celecoxib is well tolerated and may be effective as part of multimodal postoperative analgesia in patients who undergo testicular surgery for sperm retrieval. PMID- 23628191 TI - A case for collaborative networks for clinical nurse educators. AB - Clinical Nurse Educators (CNEs) are a unique subspecialty of nurse educators whose primary purpose is to support the ongoing educational needs of clinical nurses. The role has been described as both isolating and overwhelming. In this paper, we first review the current context for CNEs, specifically, the lack of role clarity and explore some reasons for job dissatisfaction. We then propose collaborative networks as a strategy to address these concerns. The potential benefits of these networks include opportunities for: role clarity, decreased isolation, shared finite resources, reduced duplication of work, ongoing professional development, and mentorship. Additionally, we propose enhanced, intersectoral collaborations with Academic Nurse Educators, those nurses employed at academic institutions to educate nursing students. These networks could improve research capacity and knowledge translation to the frontlines of care delivery, professional growth, and responsible use of resources in both sectors. PMID- 23628192 TI - Sports injury to a bipartite medial cuneiform in a child. AB - We report the case of an 11-year-old boy who had sustained a soccer injury to his mid-foot. Plain radiography did not reveal any fracture to account for the severity of his symptoms or his inability to bear weight. Magnetic resonance imaging was undertaken and demonstrated the medial cuneiform to be a bipartite bone consisting of 2 ossicles connected by a synchondrosis. No acute fracture or diastasis of the bipartite bone was demonstrated; however, significant bone marrow edema was noted, corresponding to the site of the injury and his clinical point bony tenderness. This anatomic variant should be considered as a rare differential diagnosis in the skeletally immature foot. The injury was treated nonoperatively with a non-weightbearing cast and pneumatic walker immobilization, with successful resolution of his symptoms and a return to sports activity by 4 months after injury. PMID- 23628193 TI - Case report and review of primary bone diffuse large B-cell lymphoma involving the calcaneus. AB - Primary bone lymphoma from diffuse large B-cell lymphoma is a very rare condition, especially in the foot. In the present case report, a 23-year-old female patient presented with long-term pain along the lateral aspect of her right calcaneus. Ancillary magnetic resonance imaging revealed a radiolucent bone tumor in the calcaneus. Computed tomography-guided biopsy of the bone was completed and revealed chronic inflammation with hematopoietic elements. The patient continued to have pain and limitation in her daily activities after the biopsy. The patient underwent surgical excision and curettage by the senior author. Pathologic examination revealed that the lesion was consistent with diffuse, large, B-cell lymphoma, stage IAE. The lesion appeared to have been completely excised at surgery, and the patient underwent 3 cycles of chemotherapy and 15 radiotherapy sessions to the calcaneus. At the last follow-up visit, the patient had been disease free for 5 years. To our knowledge, this is the first case report of primary bone, diffuse, large B-cell lymphoma of the calcaneus to be treated with a combination of surgical excision, chemotherapy, and radiotherapy. PMID- 23628194 TI - Aftercare following syndesmotic screw placement: a systematic review. AB - For ankle fractures, in general, several studies have been published on immobilization (e.g., cast or boot) versus early motion after surgical treatment. However, no studies have been performed to determine the best aftercare strategy for surgically treated patients with ankle fractures with concomitant acute distal tibiofibular syndesmotic injuries. The aim of the present review was to compare the functional outcomes of ankle fractures with syndesmotic injury treated with a cast or boot versus early motion. We performed a systematic review using the electronic databases from January 1, 2000 to September 1, 2012 of the Cochrane Library, PubMed MEDLINE((r)), EMbase, and Google Scholar. The included studies were those in which ankle fractures with acute distal tibiofibular syndesmotic injuries had been treated with 1 or more syndesmotic screws, with a mean follow-up period of at least 12 months and at least 25 patients included. The functional outcomes, measured using the American Orthopaedic Foot Ankle Society Hindfoot scale, Olerud-Molander Ankle Scale, and Short Musculoskeletal Function Assessment, were compared. A total of 9 studies were identified with a total of 531 patients. The number of included patients ranged from 28 to 93. The mean follow-up period was 12 to 101 months. Of the 9 studies, 3 used an early motion protocol (195 patients) and 6 (336 patients) a protocol of immobilization for at least 6 weeks. For the American Orthopaedic Foot Ankle Society Hindfoot scale, the mean scores for immobilization were 86 to 91 points and for early motion, 84 to 89. For the Olerud-Molander Ankle Scale, the scores for immobilization were 47 to 90 and for early motion, 46 to 82 points. The Short Musculoskeletal Function Assessment score for immobilization was 11 and for early motion ranged from 12 to 27 points. No apparent differences could be detected in the published data considering the functional outcomes between immobilization versus an early motion protocol in ankle fractures with acute distal tibiofibular syndesmotic injuries treated with a syndesmotic screw. However, level 1 and 2 studies on this subject are lacking. PMID- 23628195 TI - Pseudoaneurysm of the posterior tibial artery after manipulation under anesthesia of a total ankle replacement. AB - Although pseudoaneurysm of the posterior tibial artery has been reported, no investigators have discussed the development of a pseudoaneurysm after manipulation under anesthesia of a total ankle replacement. We present the case of a 59-year-old female with end-stage post-traumatic tibiotalar joint disease who underwent an uneventful INBONE(r) Total Ankle Replacement. She experienced continued postoperative pain and impingement after physical therapy. Consequently, she underwent manipulation under anesthesia. The manipulation provided complete and immediate pain relief. However, she developed a pseudoaneurysm of the posterior tibial artery that required vascular repair. She recovered uneventfully and was ambulating free of pain with improved functionality. Although manipulation under anesthesia of a total ankle replacement is a valuable, noninvasive tool that can provide near-immediate pain relief, it is important to realize that this distal arterial injury, although uncommon, is a possibility. PMID- 23628196 TI - Coastal adaptations and the Middle Stone Age lithic assemblages from Hoedjiespunt 1 in the Western Cape, South Africa. AB - New excavations at the Middle Stone Age (MSA) open-air site of Hoedjiespunt 1 (HDP1) on the west coast of South Africa advance our understanding of the evolution of coastal adaptations in Homo sapiens. The archaeological site of HDP1 dates to the last interglacial and consists of three phases of occupation, each containing abundant lithic artifacts, shellfish, terrestrial fauna, ostrich eggshell and pieces of ground ocher. The site provides an excellent case study to analyze human behavioral adaptations linked to early exploitation of marine resources. Here we reconstruct human activities through a detailed study of the lithic assemblages, combining analyses of the reduction sequences, artifact attributes and quartz fracturing. These methods provide insights into raw material procurement, lithic reduction sequences, site use and mobility patterns, and foster comparison with other MSA coastal sites. The main characteristics of the lithic assemblages remain constant throughout the use of the site. Quartz dominates silcrete and other raw materials by almost four to one. Knappers at HDP1 produced different forms of flakes using multiple core reduction methods. Denticulates represent the most frequent tool type. The assemblages document complete, bipolar and hard hammer reduction sequences for the locally available quartz, but highly truncated reduction sequences with many isolated end products for silcrete, a material with a minimum transport distance of 10-30km. This observation suggests that well provisioned individuals executed planned movements to the shoreline to exploit shellfish. Our excavations at HDP1 furthermore demonstrate the simultaneous occurrence of flexible raw material use, anticipated long-distance transport, systematic gathering of shellfish and use of ground ocher. The HDP1 lithic assemblages document a robust pattern of land-use that we interpret as a stable adaptation of modern humans to coastal landscapes as early as MIS 5e. PMID- 23628197 TI - Discrepancies in data reporting for rabies, Africa. AB - Human rabies is an ancient disease but in modern times has primarily been associated with dog rabies-endemic countries of Asia and Africa. From an African perspective, the inevitable and tragic consequences of rabies require serious reflection of the factors that continue to drive its neglect. Established as a major disease only after multiple introductions during the colonial era, rabies continues to spread into new reservoirs and territories in Africa. However, analysis of reported data identified major discrepancies that are indicators of poor surveillance, reporting, and cooperation among national, international, and global authorities. Ultimately, the absence of reliable and sustained data compromises the priority given to the control of rabies. Appropriate actions and changes, in accordance to the One Health philosophy and including aspects such as synchronized, shared, and unified global rabies data reporting, will not only be necessary, but also should be feasible. PMID- 23628198 TI - Synthesis of Bi2O2CO3/Bi2S3 hierarchical microspheres with heterojunctions and their enhanced visible light-driven photocatalytic degradation of dye pollutants. AB - Bismuth subcarbonate (Bi2O2CO3) microspheres were synthesized by a simple hydrothermal method using bismuth citrate and sodium hydrogen carbonate as precursors. Furthermore, through a facile ion exchange method between the Bi2O2CO3 microspheres and thioacetamide (TAA), bismuth subcarbonate/bismuth sulfide (Bi2O2CO3/Bi2S3) heterojunctions were fabricated. The structures and morphologies of the Bi2O2CO3 and Bi2O2CO3/Bi2S3 products were characterized by X ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The photocatalytic activities of the products were evaluated by decomposing rhodamine B (RhB) under visible light irradiation. In contrast with Bi2O2CO3, the Bi2O2CO3/Bi2S3 heterojunctions showed enhanced visible light photocatalytic properties. In addition, the effect of ion exchange reaction time on the photodegradation quality was studied, and the mechanism of the enhanced photocatalytic properties was proposed. PMID- 23628199 TI - The generation of desired functional groups on poly(4-vinyl pyridine) particles by post-modification technique for antimicrobial and environmental applications. AB - Poly(4-vinyl pyridine) (p(4-VP)) particles were synthesized by a simple micro emulsion polymerization technique using sodium dodecyl sulfate (SDS) as surfactant. The prepared p(4-VP) particles were then treated various modifying agents with different functional groups. The modifying agents used in the modification of p(4-VP) particles are N-alkyl quaternizing agents such as 2-bromo ethanol (-OH), 4-bromo butyronitrile (-CN), and 2-bromoethylamine hydrobromide ( NH2). The functional groups on the modified p(4-VP) particles were confirmed by FT-IR spectrometry and zeta potential measurements. The size of p(4-VP) and modified p(4-VP) particles is between 300 and 700 nm, and the zeta potentials of modified p(4-VP) particles were varied between 2 and 45 mV. Moreover, a second post-modification was carried out on 4-bromo butyronitrile modified p(4-VP) particles by amidoximation. The modified p(4-VP) particles were also tested for their antimicrobial effects against various bacteria such as Staphylococcus aureus, Bacillus subtilis, and Escherichia coli. It was found that p(4-VP) do not posses antimicrobial properties, whereas the modified forms especially p(4-VP)(+) and p(4-VP)(+)-NH3(+) showed highly bactericidal characteristics. Due to the positive charge by means of new functional groups generated on p(4-VP)-based particles by modification, the absorption of oppositely charged reagents such as fluorescein sodium salt (FSS) was increased drastically. For example, the absorption capacity of unmodified p(4-VP) was increased to 93.3, 93.5, and 93.6 form 37.6 mg for p(4-VP)(+), p(4-VP)(+)-NH2, p(4-VP)(+)-NH3(+), respectively. Moreover, upon modification, except Cu(II), Co(II) and Ni(II) absorption capacities were increased from about 15.9, and 22.1 mg to 21.1 and 39,1 mg per gram particles. PMID- 23628200 TI - Synthesis of antibacterial surfaces by plasma grafting of zinc oxide based nanocomposites onto polypropylene. AB - Antibacterial polymer surfaces were designed using ZnO nanoparticles as a bactericide. Mineral encapsulated nanoparticles were grafted onto activated polymer surfaces through their shells. Polypropylene (PP) surfaces were treated using an innovative process coupling core-shell technology and plasma grafting, well-known techniques commonly used to obtain active surfaces for biomedical applications. First, ZnO nanoparticles were encapsulated by (co)polymers: poly(acrylic acid) (PAA) or a poly(methyl methacrylate-co-methacrylic acid) copolymer [P(MMA-MA)]. Second, PP substrates were activated using plasma treatment. Finally, plasma-treated surfaces were immersed in solutions containing the encapsulated nanoparticles dispersed in an organic solvent and allowed to graft onto it. The presence of nanoparticles on the substrates was demonstrated using Fourier-Transform Infrared Spectroscopy (FTIR) analysis, Scanning Electron Microspcopy (SEM)/Energy-Dispersive X-ray (EDX), and Atomic Force Microscopy (AFM) studies. Indeed, the ZnO-functionalized substrates exhibited an antibacterial response in Escherichia coli adhesion tests. Moreover, this study revealed that, surprisingly, native ZnO nanoparticles without any previous functionalization could be directly grafted onto polymeric surfaces through plasma activation. The antibacterial activity of the resulting sample was shown to be comparable to that of the other samples. PMID- 23628201 TI - Correlation between the hydrophilic character and affinity towards carbon dioxide of montmorillonite-supported polyalcohols. AB - Polyalcohol incorporation was found to enhance the hydrophilic character of montmorillonite and its affinity towards carbon dioxide. CO2 adsorption occurred in both dry and humid conditions, but higher amounts were retained in the presence of moisture. This suggests two adsorption pathways: 1. direct OH-CO2 interaction and 2. more predominantly via indirect ternary OH-H2O-CO2 interactions. The retained amounts of water and CO2 increased almost proportionally with the number of OH groups incorporated, thus providing clear evidence that these groups act as adsorption sites. The improvement of the CO2 retention capacity (CRC) appears to be also due to the enhancement of the hydrophilic character of the adsorbent. The CRC value was found to strongly depend on the operating conditions. The major part of the retained CO2 was desorbed at 60-70 degrees C from hydrated matrices, but at 20-50 degrees C from dry adsorbents. CO2 can be easily released even at room temperature through forced convection under a gas stream, or under static conditions in dry and CO2 free media, e.g. in the presence of KOH pellets. It results that the CO2 retention also involves physical interactions. These results open new prospects for the reversible capture of other gases on low-cost hybrid adsorbents without thermal regeneration. PMID- 23628202 TI - Competitive adsorption-desorption of IgM monomers-dimers on silica and modified silica surfaces. AB - Understanding competitive adsorption-desorption of proteins onto surfaces is an important area of research in food processing and biomedical engineering. Here, we demonstrate, how electrospray-differential mobility analysis that has been traditionally used for characterizing bionanoparticles, can be used for quantifying complex competitive adsorption-desorption of oligomeric proteins or multiprotein systems using monomers and dimers of IgM as a model example onto silica and modified silica surfaces. Using ES-DMA, we show that IgM dimers show a preference to stay adsorbed to different surfaces although monomers adsorb more easily and desorption rates of monomers and dimers of IgM are surface-type dependent and are not significantly affected by shear. We anticipate that this demonstration will make ES-DMA a popular "label-free" method for studying multicomponent multi-oligomeric protein adsorption to different surfaces in the future. PMID- 23628203 TI - Multi-walled carbon nanotube modified carbon paste electrode as a sensor for the amperometric detection of L-tryptophan in biological samples. AB - An electrochemical sensor for the amperometric determination of L-tryptophan (Trp) was fabricated by modifying the carbon paste electrode (CPE) with multi walled carbon nanotubes (MWCNTs) using drop cast method. 4.0 MUL of the dispersion containing 2.0 mg of MWCNTs in 1.0 mL of ethanol was drop cast onto the electrode surface and dried in hot air oven to form a stable layer of MWCNTs. The electro-catalytic activity of the modified electrode towards the oxidation of Trp was thoroughly investigated. The modification with MWCNTs has greatly improved the current sensitivity of CPE for the oxidation of Trp. A very minimal amount of the modifier was required to achieve such a high sensitivity. The field emission scanning electron microscopy (FESEM) images revealed a uniform coverage of the surface of CPE by MWCNTs. Nyquist plots revealed the least charge transfer resistance for the modified electrode. The analytical performance of the modified electrode was examined using amperometry under hydro-dynamic conditions. The two linear dynamic ranges observed for Trp were 0.6-9.0 MUM and 10.0-100.0 MUM. The amperometric determination of Trp did not suffer any interference from other biomolecules. The detection limit of Trp at modified electrode was (3.30+/ 0.37)*10(-8)M (S/N=3). The analytical applications of the modified electrode were demonstrated by estimating Trp in the spiked milk and biological fluid such as blood serum. The modified electrode showed good reproducibility, long-term stability and anti-fouling effects. PMID- 23628204 TI - Shape-anisotropic particles at curved fluid interfaces and role of Laplace pressure: a computational study. AB - The self-assembly behavior of shape-anisotropic particles at curved fluid interfaces is computationally investigated by diffuse interface field approach (DIFA). A Gibbs-Duhem-type thermodynamic formalism is introduced to treat heterogeneous pressure within the phenomenological model, in agreement with Young Laplace equation. Computer simulations are performed to study the effects of capillary forces (interfacial tension and Laplace pressure) on particle self assembly at fluid interfaces in various two-dimensional cases. For isolated particles, it is found that the equilibrium liquid interface remains circular and particles of different shapes do not disturb the homogeneous curvature of liquid interface, while the equilibrium position, orientation and stability of a particle at the liquid interface depend on its shape and initial location with respect to the liquid interface. For interacting particles, the curvature of local liquid interfaces is different from the apparent curvature of the particle shell; nevertheless, irrespective of the particle shapes, a particle-coated droplet always tends to deform into a circular morphology under positive Laplace pressure, loses mechanical stability and collapses under negative Laplace pressure, while adapts to any morphology and stays in neutral equilibrium under zero Laplace pressure. Finally, the collective behaviors of particles and Laplace pressure evolution in bicontinuous interfacially jammed emulsion gels (bijels) are investigated. PMID- 23628205 TI - Dynamic surface tension studies of mixtures of hydroxypropylmethylcellulose with the double chain cationic surfactants didodecyldimethylammonium bromide and ditetradecyldimethylammonium bromide. AB - Dynamic and equilibrium surface tension experiments were carried out to study the adsorption kinetics of mixtures of the nonionic polymer hydroxypropylmethylcellulose (HPMC) with two double chain cationic surfactants, didodecyldimethylammonium bromide (di-DDAB) and ditetradecyldimethylammonium bromide (di-TDAB). Results are obtained concerning the capacity of the surfactants to lower surface tension, the rate of lowering, the extent of adsorption at the interface, the possibility of changing conformation during and after adsorption, and the interactions between the adsorbed molecules. A time dependent synergy is observed in most of the mixtures, while in a few cases hindrance effects are observed. The interaction of HPMC with the double chain cationic surfactants resulted in complexes with higher surface activity than the two components alone. Two induction times were observed, the second ones being more significant in the presence of di-TDAB. At concentrations well below the critical micelle concentration (cmc), the critical aggregation concentrations (cac), evidence for clusters is observed. PMID- 23628206 TI - Impact of educational intervention on willingness-to-pay for health insurance: A study of informal sector workers in urban Bangladesh. AB - BACKGROUND: The reliance on out-of-pocket payments for health services leads to a catastrophic burden for many households in Bangladesh. The World Health Organization suggests that risk-pooling mechanisms should be used for financing healthcare. Like many low-income countries (LIC), a large share of employment in Bangladesh is in the informal sector (88%). Inclusion of these workers in health insurance is a big challenge. Among other barriers, the "literacy gap" for health insurance" is a reason for the low insurance uptake in Bangladesh. The aim of this study is, therefore, to assess the impact of an educational intervention on willingness-to-pay (WTP) for health insurance among informal sector workers in urban Bangladesh. METHOD: An educational intervention on occupational solidarity and health insurance is offered to groups of informal workers. Educational sessions take place once a week (3-4 hours) during three subsequent weeks for each occupational group. For assessing the impact of the educational intervention, WTP for joining health insurance using occupational solidarity between workers in "pre- and post-treatment" periods as well as between "control and treatment" groups were compared. Multiple-regression analysis is applied for predicting WTP by educational intervention, while controlling for demographic and socioeconomic characteristics. RESULTS: The coefficient of variation (CoV) of the WTP is estimated in control and treatment groups and expected to be lower in the latter. The WTP for health insurance is higher (33.8%) among workers who joined the educational intervention in comparison with those who did not (control group). CoV of WTP is found to be generally lower in post-treatment period and in treatment group compared to pre-treatment period and control group respectively. CONCLUSION: Educational interventions can be used for increasing demand for health insurance scheme using occupational solidarity among informal sector workers. PMID- 23628207 TI - The CXCL16-CXCR6 chemokine axis in glial tumors. AB - Since chemokines and their receptors play a pivotal role in tumors, we investigated the CXCL16-CXCR6-axis in human astroglial tumors. The transmembrane chemokine CXCL16 is heavily expressed by tumor, microglial and endothelial cells in situ and in vitro. In contrast, the receptor CXCR6 is restricted in glioblastomas to a small subset of proliferating cells positive for the stem-cell markers Musashi, Nanog, Sox2 and Oct4. In particular, the vast majority (about 90%) of Musashi-positive cells stained also for CXCR6. Thus, CXCL16 is highly expressed by glial tumor and stroma cells whereas CXCR6 defines a subset of cells with stem cell character. PMID- 23628208 TI - GABA-B-receptor antibodies in paraneoplastic brainstem encephalitis. AB - BACKGROUND: Gamma-aminobutyric-acid B (GABA-B)-receptor encephalitis represents a novel entity among autoimmune CNS disorders. Most cases are characterised by limbic encephalitis. CASE REPORT: A 63-year-old patient presented with acute vertigo, nausea and vomiting, facial palsy and dysarthria. He developed dysphagia, gait ataxia and, finally, respiratory failure. Antibodies to GABA-B receptors were positive and declined under treatment with intravenous methylprednisolone and plasma exchange, followed by clinical improvement and stabilisation. Broad tumour screening revealed oesophageal carcinoma. CONCLUSION: The spectrum of neurological manifestations and tumours associated with the paraneoplastic variant of anti-GABA-B-receptor encephalitis may be broader than previously reported. PMID- 23628210 TI - Development and initial testing of the Person-Centred Health Care for Older Adults Survey. AB - BACKGROUND: Health services are encouraged to adopt a strong person-centered approach to the provision of care and services for older people. The aim of this project was to establish a user-friendly, psychometrically valid, and reliable measure of healthcare staff's practice, attitudes, and beliefs regarding person centered healthcare. METHODS: Item reduction (factor analysis) of a previously developed "benchmarking person-centred care" survey, followed by psychometric evaluations of the internal consistency reliability and construct validity, was conducted. The initial survey was completed by 1,428 healthcare staff from 17 health services across Victoria, Australia. RESULTS: After removing 17 items from the previously developed "benchmarking person-centred care" survey, the revised 31-item survey (Person-Centred Health Care for Older Adults Survey) attained eight factors that explain 62.7% of the total variance with a Cronbach's alpha coefficient of 0.91, indicating excellent internal consistency. Expert consultation confirmed that the revised survey had content validity. CONCLUSIONS: The results indicated that the Person-Centred Health Care for Older Adults Survey is a user-friendly, psychometrically valid, and reliable measure of staff perceptions of person-centered healthcare for use in hospital settings. PMID- 23628209 TI - Segmentectomy as a safe and equally effective surgical option under complete video-assisted thoracic surgery for patients of stage I non-small cell lung cancer. AB - BACKGROUND: While video-assisted thoracic surgery lobectomy has been widely accepted for the treatment of non-small cell lung cancer, the debate over video assisted thoracic surgery segmentectomy still remains. This study compared the clinical outcomes using the two procedures for stage I non-small cell lung cancer patients. METHODS: Retrospective review was conducted on patients who underwent video-assisted thoracic surgery segmentectomy or lobectomy for clinical stage I non-small cell lung cancer at Shanghai Chest Hospital between November 2009 and May 2012. Video-assisted thoracic surgery segmentectomy was performed on 36 patients and video-assisted thoracic surgery lobectomy on 138 patients. Comparisons between the 2 groups were performed in patient demographic and clinical characteristics, intraoperative parameters and oncology outcomes. RESULTS: Mean volume of chest tube drainage after operation was smaller for segmentectomy than for lobectomy (1021 ml vs. 1328 ml, P=0.036). Other parameters analysis including blood loss, operation time, chest tube duration and length of hospital stay favors the segmentectomy group numerically without significance. There was no significant difference in distributions in both intra and post operative complications. There was one peri-operative mortality from segmentectomy group and all other patients are alive with a median follow up of 327 days. There were 1 (2.8%) locoregional recurrence after segmentectomy and 6 recurrences (4.4%) after lobectomy (P=1.00). Multivariate survival analysis revealed no significant difference in recurrence-free survivals between the two groups. Two patients successfully underwent bilateral segmentectomies and are free of disease. CONCLUSIONS: For patients with stage I non-small cell lung cancer, video-assisted thoracic surgery segmentectomy offers a safe and equally effective option and can be applied to complicated operation such as bilateral segmentectomy. PMID- 23628211 TI - Changes of hippocampal beta-alanine and citrulline levels are paralleling early and late phase of retrieval in the Morris Water Maze. AB - Although a series of amino acids (AA) have been associated with spatial memory formation, there is limited information on concentrations of beta-alanine and citrulline in rodent brains. Given the importance of AA metabolism in cognitive functions it was the aim of the study to determine hippocampal levels of beta alanine and citrulline in rats during two different phases of memory retrieval in a spatial memory paradigm. Ten rats were used per group and the first group was trained and sacrificed five min, the second six hours following retrieval in the Morris Water Maze (MWM) and the third and fourth group were untrained, yoked controls. Hippocampi were taken and free AA were determined using a well established HPLC protocol. Beta-alanine and citrulline levels were higher in trained rat hippocampi, during both, early and late phase of memory retrieval. Taurine, methionine, cysteine, lysine and ornithine levels were higher in yoked rats at the late phase while tyrosine was higher in yoked rats during the early phase. There were no significant correlations between time spent in the target quadrant and any of the AA levels. Herein, an AA pattern, different between yoked and trained animals at early and late phase of memory retrieval is shown, indicating probable involvement of different AA pathways in animals trained and untrained in the MWM. The results may be useful for the interpretation of previous studies and the design of future experiments to identify amino acids as possible targets for modulating spatial memory. PMID- 23628212 TI - Optogenetic insights into striatal function and behavior. AB - Recent breakthroughs in optogenetic technologies to alter neuronal firing and function with light, combined with cell type-specific transgenic animal lines, has led to important insights into the function of distinct neuronal cell subtypes and afferent connections in the heterogeneously complex striatum. A vital part of the basal ganglia, the striatum is heavily implicated in both motor control and motivation-based behavior; as well as in neurological disorders and psychiatric diseases including Parkinson's Disease, Huntington's Disease, drug addiction, depression, and schizophrenia. Researchers are able to manipulate firing and cell signaling with temporal precision using optogenetics in the two striatal medium spiny neuron (MSN) subpopulations, the striatal interneurons, and striatal afferents. These studies confirmed the classical hypothesis of movement control and reward seeking behavior through direct versus indirect pathway MSNs; illuminated a selective role for TANs in cocaine reward; dissected the roles of glutamatergic and dopaminergic inputs to striatum in reward; and highlighted a role for striatal signaling molecules including an adrenergic G-protein coupled receptor in reward and the rho-GTPase Rac1 in cocaine reward and cocaine induced structural plasticity. This review focuses on how the evolving optogenetic toolbox provides insight into the distinct behavioral roles of striatal cell subpopulations and striatal afferents, which has clinically relevant implications into neurological disorders and psychiatric disease. PMID- 23628213 TI - Reorganisation of primary motor cortex in a transtibial amputee during rehabilitation: a case report. PMID- 23628214 TI - Group B Streptococcus agalactiae interspecies exchange. PMID- 23628215 TI - Study on the mechanical and environmental properties of concrete containing cathode ray tube glass aggregate. AB - Cathode ray tube (CRT) glass is considered a hazardous material due to its lead toxicity. In addition, current disposal practices are being phased out due to their adverse environmental impacts. In this project, CRT glass was used as a fine aggregate replacement in concrete. Life-cycle material characterization was conducted by evaluating the durability and strength of the CRT-Concrete. Leaching tests were also conducted to investigate whether the material meets drinking water limits for Pb. Test results show that the plastic state of the CRT-Concrete was affected by the angularity of the glass particles. Moreover, the compressive strength of CRT-Concrete met and exceeded that of the control specimen. However, CRT-Concrete was susceptible to expansive alkali-silica reactions when more than 10% CRT replacement was used. Environmental leaching results show that lead concentrations from CRT-Concrete are below the drinking water limits depending on the CRT volume replacement and if biopolymers are used. PMID- 23628216 TI - BMP tests of source selected OFMSW to evaluate anaerobic codigestion with sewage sludge. AB - The aim of this study is to characterize different types of source selected organic fraction of municipal solid waste (SS-OFMSW) in order to optimize the upgrade of a sewage sludge anaerobic digestion unit by codigestion. Various SS OFMSW samples were collected from canteens, supermarkets, restaurants, households, fruit-vegetable markets and bakery shops. The substrates characterization was carried out getting traditional chemical-physical parameters, performing elemental analysis and measuring fundamental anaerobic digestion macromolecular compounds such as carbohydrates, proteins, lipids and volatile fatty acids. Biochemical methane potential (BMP) tests were conducted at mesophilic temperature both on single substrates and in codigestion regime with different substrates mixing ratios. The maximum methane yield was observed for restaurant (675 NmlCH4/gVS) and canteens organic wastes (571 and 645 NmlCH4/gVS). The best codigestion BMP test has highlighted an increase of 47% in methane production respect sewage sludge digestion. PMID- 23628217 TI - The relationship between older people's awareness of the term elder abuse and actual experiences of elder abuse. AB - BACKGROUND: Awareness and experiences of elder abuse have been researched as separate entities; this study examined the relationship between awareness of elder abuse, disclosure of abuse, and reporting of abuse among people aged 65 years or older. METHODS: A national cross-sectional survey of a random sample of 2,012 community-dwelling older people was carried out in Ireland. People described their understanding of the term elder abuse followed by their experiences of mistreatment. Descriptive statistics and logistic regression were used with frequency, percentage, odds ratios (OR), and 95% confidence intervals (CI) presented. RESULTS: The prevalence of elder abuse, including stranger abuse, since 65 years of age was 5.9% (95% CI 4.6-7.3). Overall, 80% of the population demonstrated some understanding of the term elder abuse. Older people who experienced physical abuse (OR 5.39; 95% CI 2.31-12.5) and psychological abuse (OR 2.51; 95% CI 1.58-3.97) were significantly more likely than older people who had not experienced mistreatment to relate the term elder abuse to their personal experiences. There was no association between experiences of financial abuse or neglect and awareness of the term elder abuse. CONCLUSIONS: There was a relatively high level of awareness of the term elder abuse; however, a substantial proportion of people could not readily associate abusive behaviors within their personal lives with elder abuse. Public information campaigns need to move beyond simple awareness rising to enable people to bridge the gap between a theoretical understanding of elder abuse and recognizing inappropriate behavior in their own circumstances. PMID- 23628218 TI - Biodiesel production from Vietnam heterotrophic marine microalga Schizochytrium mangrovei PQ6. AB - This work is to explore the potential of producing biodiesel and valuable co products from the biomass of Schizochytrium mangrovei PQ6 which was isolated from Phu Quoc Island, Kien Giang province, Vietnam. This microalga contains high lipid content (up to 70% of dry cell weight) and high level of total fatty acids, which is ideal for making biodiesel. The production of fatty acid methyl esters (FAME) from this marine microalga resulted in a yield of 88% based on algal oil and 44% based on algal biomass. The process of separating the obtained FAME into a first fraction enriched with saturated FAME (SFAME) and a second fraction enriched with unsaturated FAME (UFAME) was then investigated to exploit the valuable co products. The obtained results shown that the mass fraction of SFAME and UFAME were 70% and 30%, respectively. The UFAME fraction contains a high content of DHA (accounting for 69.000% of TFAs). The test results of the SFAME fraction indicated that specific gravity at 15 degrees C, flash point, water and sediment, kinematic viscosity at 40 degrees C, sulfated ash, sulfur, copper strip corrosion at 50 degrees C, cetane number, carbon residue, iodine number, workmanship meet Vietnam Biodiesel B100 Standard. Moreover, the utilization of waste glycerol from biodiesel process as carbon source for the cultivation of the microalgae S. mangrovei PQ6 and Spirulina platensis was also investigated. PMID- 23628219 TI - Impact of pseudo-continuous fermentation on the ethanol tolerance of Scheffersomyces stipitis. AB - In this work we conducted the pseudo-continuous fermentation, i.e., continuous fermentation with cell retention, using Scheffersomyces stipitis, and studied its effect on ethanol tolerance of the strain. During the fermentation experiments, S. stipitis was adapted to a mild concentration of ethanol (20-26 g/L) for two weeks. Two substrates (glucose and xylose) were used in different fermentation experiments. After fermentation, various experiments were performed to evaluate the ethanol tolerance of adapted cells and unadapted cells. Compared to the unadapted cells, the viability of adapted cells increased by 8 folds with glucose as the carbon source and 6 folds with xylose as the carbon source following exposure to 60 g/L ethanol for 2 h. Improved ethanol tolerance of the adapted cells was also revealed in the effects of ethanol on plasma membrane permeability, extracellular alkalization and acidification. The mathematical modeling of cell leakage, extracellular alkalization and acidification revealed that cells cultured on glucose show better ethanol tolerance than cells cultured on xylose but the differences become smaller for adapted cells. The results show that pseudo-continuous fermentation can effectively improve cell's ethanol tolerance due to the environmental pressure during the fermentation process. PMID- 23628220 TI - Production of ethanol from mannitol by the yeast strain Saccharomyces paradoxus NBRC 0259. AB - Mannitol is a promising marine macroalgal carbon source. However, organisms that produce ethanol from mannitol are limited; to date, only the yeast Pichia angophorae and the bacterium Escherichia coli KO11 have been reported to possess this capacity. In this study, we searched a yeast strain with a high capacity to produce ethanol from mannitol and selected Saccharomyces paradoxus NBRC 0259 for its ability to produce ethanol from mannitol. This ability was enhanced after a 3 day cultivation of this strain in medium containing mannitol; the enhanced strain was renamed S. paradoxus NBRC 0259-3. We compared the ability of strain NBRC 0259 3 to produce ethanol from mannitol and glucose, under several conditions, with those of P. angophorae and E. coli KO11. As a result, we concluded that S. paradoxus NBRC 0259-3 strain is the most suitable yeast strain for the production of ethanol from mannitol. PMID- 23628221 TI - Protective effects of edaravone against cisplatin-induced hair cell damage in zebrafish. AB - OBJECTIVE: Edaravone is known to have a potent free radical scavenging effect. The objective of the present study was to evaluate the effects of edaravone on cisplatin-induced ototoxicity in transgenic zebrafish (Brn3C: EGFP). METHODS: Five day post-fertilization zebrafish larvae were exposed to 1000 MUM cisplatin and 50 MUM, 100 MUM, 250 MUM, 500 MUM, 750 MUM, and 1000 MUM concentrations of edaravone for 4h. Hair cells within neuromasts of the supraorbital (SO1 and SO2), otic (O1), and occipital (OC1) lateral lines were analyzed by fluorescence microscopy and confocal microscopy (n=10). Hair cell survival was calculated as a percentage of the hair cells in the control group that were not exposed to cisplatin. Ultrastructural changes were evaluated using scanning electron microscopy and transmission electron microscopy. RESULTS: Edaravone protected cisplatin-induced hair cell loss of neuromasts (edaravone 750 MUM: 8.7 +/- 1.5 cells, cisplatin 1000 MUM only: 3.7 +/- 0.9 cells; n=10, p<0.0001) and decreased the Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) reaction. Structures of mitochondria and hair cell within neuromasts in ultrastructural analysis were preserved in zebrafish exposed to 1000 MUM cisplatin and 750 MUM edaravone for 4h. CONCLUSIONS: Edaravone attenuated cisplatin-induced hair cell damage in zebrafish. The results of the current study suggest that cisplatin induces apoptosis, and the apoptotic cell death can be prevented by treatment with edaravone in zebrafish. PMID- 23628222 TI - Relationship between speech motor control and speech intelligibility in children with speech sound disorders. AB - The current study was undertaken to investigate the impact of speech motor issues on the speech intelligibility of children with moderate to severe speech sound disorders (SSD) within the context of the PROMPT intervention approach. The word level Children's Speech Intelligibility Measure (CSIM), the sentence-level Beginner's Intelligibility Test (BIT) and tests of speech motor control and articulation proficiency were administered to 12 children (3:11 to 6:7 years) before and after PROMPT therapy. PROMPT treatment was provided for 45 min twice a week for 8 weeks. Twenty-four naive adult listeners aged 22-46 years judged the intelligibility of the words and sentences. For CSIM, each time a recorded word was played to the listeners they were asked to look at a list of 12 words (multiple-choice format) and circle the word while for BIT sentences, the listeners were asked to write down everything they heard. Words correctly circled (CSIM) or transcribed (BIT) were averaged across three naive judges to calculate percentage speech intelligibility. Speech intelligibility at both the word and sentence level was significantly correlated with speech motor control, but not articulatory proficiency. Further, the severity of speech motor planning and sequencing issues may potentially be a limiting factor in connected speech intelligibility and highlights the need to target these issues early and directly in treatment. LEARNING OUTCOMES: The reader will be able to: (1) outline the advantages and disadvantages of using word- and sentence-level speech intelligibility tests; (2) describe the impact of speech motor control and articulatory proficiency on speech intelligibility; and (3) describe how speech motor control and speech intelligibility data may provide critical information to aid treatment planning. PMID- 23628223 TI - Circovirus in tissues of dogs with vasculitis and hemorrhage. AB - We characterized the complete genome of a novel dog circovirus (DogCV) from the liver of a dog with severe hemorrhagic gastroenteritis, vasculitis, and granulomatous lymphadenitis. DogCV was detected by PCR in fecal samples from 19/168 (11.3%) dogs with diarrhea and 14/204 (6.9%) healthy dogs and in blood from 19/409 (3.3%) of dogs with thrombocytopenia and neutropenia, fever of unknown origin, or past tick bite. Co-infection with other canine pathogens was detected for 13/19 (68%) DogCV-positive dogs with diarrhea. DogCV capsid proteins from different dogs varied by up to 8%. In situ hybridization and transmission electron microscopy detected DogCV in the lymph nodes and spleens of 4 dogs with vascular compromise and histiocytic inflammation. The detection of a circovirus in tissues of dogs expands the known tropism of these viruses to a second mammalian host. Our results indicate that circovirus, alone or in co-infection with other pathogens, might contribute to illness and death in dogs. PMID- 23628224 TI - Development and validation of a necrotizing soft-tissue infection mortality risk calculator using NSQIP. AB - BACKGROUND: Necrotizing soft-tissue infections (NSTI) are a group of uncommon, rapidly progressive infections requiring prompt surgical debridement and systemic support. A previous attempt to define risk factors for mortality from NSTI had multiple limitations. The objective of this study was to develop and validate a 30-day postoperative mortality risk calculator for patients with NSTI using NSQIP. STUDY DESIGN: The NSQIP Participant Use Files (2005-2010) were used as the primary data source. Patients diagnosed with NSTI were identified by ICD-9 codes. Multiple logistic regression analysis identified key preoperative variables predicting mortality. Bootstrap analysis was used to validate the model. RESULTS: In 1,392 identified NSTI cases, demographics were as follows: 42% were female, median age was 55 years (interquartile range 46 to 63 years), and median body mass index was 32 kg/m(2) (interquartile range 26 to 40 kg/m(2)). Thirty-day mortality was 13%. Seven independent variables were identified that correlated with mortality: age older than 60 years (odds ratio [OR] = 2.5; 95% CI 1.7-3.6), functional status (partially dependent: OR = 1.6; 95% CI 1.0-2.7; totally dependent: OR = 2.3; 95% CI 1.4-3.8), requiring dialysis (OR = 1.9; 95% CI 1.2 3.1), American Society of Anesthesiologists class 4 or higher (OR = 3.6; 95% CI 2.3-5.6), emergent surgery (OR = 1.6; 95% CI 1.0-2.3), septic shock (OR = 2.4; 95% CI 1.6-3.6), and low platelet count (<50K/MUL: OR = 3.5; 95% CI 1.6-7.4; <150K/MUL but >50K/MUL: OR = 1.9; 95% CI 1.2-2.9). The receiver operating characteristic area was 0.85 (95% CI 0.82-0.87), which indicated a strong predictive model. Using bootstrap validation, the optimism-corrected receiver operating characteristic area was 0.83 (95% CI 0.81-0.86), which represents the model performance in future patients. The model was used to develop an interactive risk calculator. CONCLUSIONS: This risk calculator has excellent predictive ability for mortality in patients with NSTI. This simple interactive tool can aid physicians and patients in the decision-making process. PMID- 23628225 TI - Aspiration, localized pulmonary inflammation, and predictors of early-onset bronchiolitis obliterans syndrome after lung transplantation. AB - BACKGROUND: We hypothesized that immune mediator concentrations in the bronchoalveolar fluid (BALF) are predictive of bronchiolitis obliterans syndrome (BOS) and demonstrate specific patterns of dysregulation, depending on the presence of acute cellular rejection, BOS, aspiration, and timing of lung transplantation. STUDY DESIGN: We prospectively collected 257 BALF samples from 105 lung transplant recipients. The BALF samples were assessed for absolute and differential white blood cell counts and 34 proteins implicated in pulmonary immunity, inflammation, fibrosis, and aspiration. RESULTS: There were elevated BALF concentrations of interleukin (IL)-15, IL-17, basic fibroblast growth factor, tumor necrosis factor-alpha, and myeloperoxidase, and reduced concentrations of alpha1-antitrypsin, which were predictive of early-onset BOS. Patients with BOS had an increased percentage of BALF lymphocytes and neutrophils, with a reduced percentage of macrophages (p < 0.05). The BALF concentrations of IL-1beta; IL-8; interferon-gamma-induced protein 10; regulated upon activation, normal T-cell expressed and secreted; neutrophil elastase; and pepsin were higher in patients with BOS (p < 0.05). Among those with BOS, BALF concentrations of IL-1RA; IL-8; eotaxin; interferon-gamma-induced protein 10; regulated upon activation, normal T-cell expressed and secreted; myeloperoxidase; and neutrophil elastase were positively correlated with time since transplantation (p < 0.01). Those with worse grades of acute cellular rejection had an increased percentage of lymphocytes in their BALF (p < 0.0001) and reduced BALF concentrations of IL-1beta, IL-7, IL-9, IL-12, granulocyte colony stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon gamma, and vascular endothelial growth factor (p <= 0.001). Patients with aspiration based on detectable pepsin had increased percentage of neutrophils (p < 0.001) and reduced BALF concentrations of IL-12 (p < 0.001). CONCLUSIONS: The BALF levels of IL-15, IL-17, basic fibroblast growth factor, tumor necrosis factor-alpha, myeloperoxidase, and alpha1-antitrypsin at 6 to 12 months after lung transplantation are predictive of early-onset BOS, and those with BOS and aspiration have an augmented chemotactic and inflammatory balance of pulmonary leukocytes and immune mediators. These data justify the surgical prevention of aspiration and argue for the refinement of antirejection regimens. PMID- 23628226 TI - Preoperative axillary ultrasound in breast cancer: safely avoiding frozen section of sentinel lymph nodes in breast-conserving surgery. AB - BACKGROUND: The American College of Surgeons Oncology Group Z0011 trial results provided convincing evidence that completion axillary lymph node dissection (CALND) was unnecessary in selected patients with 1 to 2 positive sentinel lymph nodes (SLNs). We hypothesized that preoperative axillary ultrasound (AUS) with fine-needle aspiration is sufficiently sensitive to detect worrisome macrometastasis to preclude the need for frozen-section pathology of SLNs. STUDY DESIGN: We conducted a retrospective single-institution study at a tertiary academic referral center. A total of 1,140 T1 to 2 breast cancer patients who underwent SLN biopsy with or without CALND from January 1, 2007 to December 31, 2010 were reviewed. All patients had negative preoperative AUS with or without fine-needle aspiration. RESULTS: One hundred forty-four (13%) patients were node positive at surgery. Mean age, tumor size, histology, and estrogen receptor and progesterone receptor status were similar comparing 996 SLN-negative with 144 (13%) SLN-positive patients. Of the SLN-positive patients, 25% were premenopausal, 9% were estrogen receptor-negative, and 19% had additional lymph nodes at CALND. Only 19 (2%) patients had SLN metastasis >=6 mm, 10 (1%) had metastasis >7 mm, and only 1 patient had >=3 positive SLNs. CONCLUSIONS: The addition of preoperative AUS with or without fine-needle aspiration to management of patients who meet American College of Surgeons Oncology Group Z0011 trial eligibility criteria reduced the risk of macrometastasis measuring >=6 mm to only 2%; very few of these patients would be premenopausal, have estrogen receptor negative tumors, or >=3 positive SLNs. With the addition of AUS with or without fine-needle aspiration, we endorse the conclusions of the American College of Surgeons Oncology Group Z0011 trial to avoid CALND, and see marginal gain in frozen-section analysis of SLNs. PMID- 23628227 TI - Optimizing ACS NSQIP modeling for evaluation of surgical quality and risk: patient risk adjustment, procedure mix adjustment, shrinkage adjustment, and surgical focus. AB - The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) collects detailed clinical data from participating hospitals using standardized data definitions, analyzes these data, and provides participating hospitals with reports that permit risk-adjusted comparisons with a surgical quality standard. Since its inception, the ACS NSQIP has worked to refine surgical outcomes measurements and enhance statistical methods to improve the reliability and validity of this hospital profiling. From an original focus on controlling for between-hospital differences in patient risk factors with logistic regression, ACS NSQIP has added a variable to better adjust for the complexity and risk profile of surgical procedures (procedure mix adjustment) and stabilized estimates derived from small samples by using a hierarchical model with shrinkage adjustment. New models have been developed focusing on specific surgical procedures (eg, "Procedure Targeted" models), which provide opportunities to incorporate indication and other procedure-specific variables and outcomes to improve risk adjustment. In addition, comparative benchmark reports given to participating hospitals have been expanded considerably to allow more detailed evaluations of performance. Finally, procedures have been developed to estimate surgical risk for individual patients. This article describes the development of, and justification for, these new statistical methods and reporting strategies in ACS NSQIP. PMID- 23628228 TI - Improving clinical productivity in an academic surgical practice through transparency. AB - BACKGROUND: Patient care revenue is becoming an increasingly important source of funding to support the academic surgery department missions of research and education. Transparency regarding productivity metrics will improve clinical productivity among members of an academic surgical practice. STUDY DESIGN: Clinical productivity-related data were collected and compared between 2 time periods. Data were stratified by pretransparency and post-transparency time periods. Comparisons were made using the Wilcoxon-Mann-Whitney test, and p values <=0.05 were considered significant. RESULTS: The faculty compensation plan remained the same across both time periods; faculty members were paid a base salary plus practice plan income based on individual collections minus practice overhead and academic program support taxes. Before 2006, clinical productivity data were not made public among faculty members. In 2006, the departmental leadership developed a physician scorecard that led to transparency with regard to productivity. After publication of the scorecard, clinical productivity increased, as did the number of partners producing a threshold number of work relative value units (RVU) (6,415 wRVU = 1.0 full time equivalent [FTE]). This occurred during a time of reduced collections per RVU. There was no change in the work assignments (percent effort for clinical service, research, and teaching) for the physicians between the 2 time periods, or the overall effort assigned to the Veterans Affairs hospital. CONCLUSIONS: Clinical productivity can be improved by making productivity metrics transparent among faculty members. Additional measures must be taken to ensure that research and teaching activities are appropriately incentivized. PMID- 23628229 TI - Renal epithelioid angiomyolipoma with a negative premelanosome marker immunoprofile: a case report and review of the literature. AB - INTRODUCTION: The rare variant of renal epithelioid/pleomorphic angiomyolipoma has been reported in approximately 120 cases. One of the most important characteristics to differentiate these tumors from other renal cell neoplasms is their typical reactivity to premelanosome antigens. If such a tumor does not stain for HMB-45 or Melan-A, a specific diagnosis of epithelioid pleomorphic angiomyolipoma cannot be made with certainty. CASE PRESENTATION: We present here what is, to the best of our knowledge, the first case of epithelioid/pleomorphic angiomyolipoma of the kidney in a 50-year-old Caucasian man with no history of tuberous sclerosis, and with a tumor marker profile negative for several premelanosome antigens. The tumor was composed of sheets of pleomorphic, round to polygonal epithelioid cells with prominent eosinophilic cytoplasm, large nuclei, many multinucleated, and very prominent nucleoli. There were prominent vessels and rare interspersed smooth muscle fibers, but adipocytes were not identified. A tumor marker profile showed tumor cell reactivity for CD68, calponin and focally for CD10. Intervening smooth muscle was reactive with smooth muscle actin. The tumor lacked reactivity for melanin-associated antigens HMB-45 and Melan-A, and for CD31, pan-cytokeratin (AE1/3) and desmin. Electron microscopic examination of tumor cells confirmed the presence of premelanosome-like granules. CONCLUSIONS: Based on the characteristic microscopic appearance of this tumor, and its overall tumor marker profile, we concluded this was a renal epithelioid/pleomorphic angiomyolipoma with a negative premelanosome antigen phenotype. PMID- 23628230 TI - Low endogenous thrombin potential in trained subjects. AB - INTRODUCTION: A paradox seems to exist: exercising leads to clotting activation in conventional clotting tests, but exercising persons have a low risk of thrombosis. In this study we tried to evaluate the effect of exercise performance status on in vitro plasma thrombin generation, which represents an overall function test of hemostasis. MATERIALS AND METHODS: We compared 56 trained subjects to 98 healthy age matched sedentary volunteers. Blood samples were analyzed for thrombin generation using calibrated automated thrombography. Microparticles were quantified using ELISA. Additionally prothrombin fragments 1 + 2, thrombin-antithrombin complex, tissue factor pathway inhibitor, antithrombin and prothrombin were measured. The group of the trained subjects performed an incremental cycle-ergometer exercise test after taking the blood sample. RESULTS: A significantly lower endogenous thrombin potential was observed in the group of the trained subjects compared to the sedentary individuals (p = 0.007). Microparticles (ELISA) were significantly lower in the trained subjects compared to the sedentary subjects (p = 0.001). Prothrombin fragments 1 + 2 (p < 0.001) and thrombin-antithrombin complex (p = 0.01) were significant higher in the trained subjects and antithrombin (p = 0.02) as well as prothrombin (p < 0.0001) were significantly lower in this group, whereas tissue factor pathway inhibitor values did not show significant differences. Both maximal and submaximal power output was significantly negatively related to endogenous thrombin potential (r = -0.43, r = -0.45) and thrombin peak (r = -0.44, r = -0.42). CONCLUSIONS: Trained subjects have a lower endogenous thrombin potential than sedentary subjects possibly explaining the lower incidence of thrombosis in this group despite a higher acute clotting activation during strenuous exercise. PMID- 23628231 TI - Cerebral tissue oxygenation index, cardiac output and superior vena cava flow in infants with birth weight less than 1250 grams in the first 48 hours of life. AB - BACKGROUND: Near-infrared spectroscopy is a non-invasive method of assessing cerebral oxygenation. Functional echocardiography is increasingly used by neonatologists in the assessment of cardiovascular function. AIMS: To correlate cerebral tissue oxygenation index (cTOI) and cardiac output in infants less than 1250 g at 6, 12, 24 and 48 hours of age. STUDY DESIGN: A prospective observational study. SUBJECTS: Newborns with birth weight<1250 g. OUTCOME MEASURES: Serial assessments of superior vena cava (SVC) flow, right and left ventricular outputs, ductus arteriosus and cTOI were performed at 6, 12, 24 and 48 hours of age. Clinical parameters, including mean blood pressure, mean airway pressure, blood gas parameters and oxygen saturations were recorded. RESULTS: 22 neonates were enrolled following parental consent. The mean birth weight was 851 g (SD+/-201), mean gestational age was 25.9 weeks (SD+/-1.7). Mean SVC flow at 6 hours of age was 56.8 ml/kg/min and increased to 68.6 ml/kg/min at 48 hours of age. 9 infants (41%) had at least one measurement of low SVC flow (<41 ml/kg/min) in the first 48 hours. Mean cTOI was 65.2% at 6 hours of age, 63.9% at 12 hours of age, 68.8% at 24 hours of age and 67.2% at 48 hours of age. Cerebral fractional tissue oxygen extraction values were highest at 12 hours (0.31+/ 0.09). There was no correlation between SVC flow and cTOI values. CONCLUSION: SVC flow, left and right ventricular output increased during first 48 hours of life. cTOI decreased at 12 hours of age with a concomitant increase in fractionated oxygen extraction. These changes reflect transitional changes in both cardiac and cerebral hemodynamics in extremely low gestational age newborns during the first 48 hours. PMID- 23628232 TI - Negative reinforcement in drug addiction: the darkness within. AB - Drug seeking is associated with the activation of reward neural circuitry, but I argue that drug addiction also involves another major source of reinforcement, specifically negative reinforcement driven by the 'dark side' (i.e., a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of the brain stress systems). This combination forms the antireward system or 'darkness within.' Understanding the neuroplasticity of the neurocircuitry that comprises the negative reinforcement associated with addiction is the key to understanding the vulnerability to the transition to addiction, misery of addiction, and persistence of addiction. PMID- 23628233 TI - Respiratory syncytial virus prophylaxis in children with cardiac disease: a retrospective single-centre study. AB - OBJECTIVES: To examine the characteristics of congenital heart disease patients hospitalised with respiratory syncytial virus infection after prophylaxis and determine the associated comorbidities and the incidence of breakthrough respiratory syncytial virus infections. STUDY DESIGN: This is a retrospective, single-centre study that was conducted over a period of 7 years. Respiratory syncytial virus infection was identified by classification codes and confirmed by virological tests. Data on baseline demographics, cardiac anomalies, other underlying disease, criteria for hospitalisation, type of respiratory illness and management, complications, and palivizumab prophylaxis were analysed by standard descriptive methods and comparative statistics. RESULTS: A total of 30 patients were enrolled. The majority were <= 2 years (n = 24). The mean admission age was 15.1 months (standard deviation = 18.3). In all, 90% were acyanotic, 40% had haemodynamically significant disease, and 60% had >= 1 underlying medical illness. Patients were admitted with: respiratory distress (86.7%), hypoxaemia (66.7%), fever (60%), inability to maintain oral intake (36.7%), and apnoea (16.7%). More than 50% required mechanical ventilation and intensive care with a median stay of 11 days (range: 1-43); the length of hospital stay for all children was 10 days (range: 1-65). Complications included: concurrent bacterial sepsis (20%), electrolyte abnormalities (16.7%), and worsening pulmonary hypertension (13.3%). Of 10 infants <= 2 years with haemodynamically significant heart disease, four had received prophylaxis. There was one death, which was attributed to respiratory syncytial virus infection. CONCLUSIONS: Overall, 185 infants <= 2 years with haemodynamically significant cardiac disease received prophylaxis. In all, six qualifying infants missed immunisation and were hospitalised. Breakthrough respiratory syncytial virus infections occurred in 2.2%, demonstrating good efficacy of palivizumab in this population compared with the original, multi-centre, randomised trial. PMID- 23628234 TI - Sample preparation for the metabolomics investigation of poly-gamma-glutamate producing Bacillus licheniformis by GC-MS. AB - Metabolomics aims to analyze global intracellular metabolites of organisms. To study the intracellular metabolites of poly-gamma-glutamate-producing Bacillus licheniformis, the quenching and extraction conditions were assessed and optimized. It indicated that perchloric acid was an appropriate quenching solution for B. licheniformis by measuring livability of cells, leakage of ATP, energy charge and intracellular metabolites. 0.85% NaCl was an appropriate washing solvent for a sample because it did not lead to serious leakage and would not affect operation of GC-MS. Among the four different extraction methods (cold pure methanol, PM; hot ethanol/water (75:25 v/v), HE; cold methanol/water (50:50 v/v), MW; and cold chloroform/methanol/water (50:25:25 v/v/v), CMW), HE was superior to others on the basis of the energy charge and intracellular metabolites, which could effectively inhibit enzymatic activities and extract more intracellular metabolites. The method could obtain some metabolites which were involved in the most important synthesis pathways of poly-gamma-glutamate, including glycolysis, citric acid cycle and glutamate metabolism. It is the first evaluation of a sample preparation of poly-gamma-glutamate-producing bacteria, which might be used as one model for the preparation of polymer-producing samples for metabolomics analysis. PMID- 23628235 TI - Curtailing the voices and the need for predictors. PMID- 23628236 TI - Cognitive training in schizophrenia: golden age or wild west? PMID- 23628238 TI - Could language deficits really differentiate Mild Cognitive Impairment (MCI) from mild Alzheimer's disease? AB - Naming abilities seem to be affected in Alzheimer's disease (AD) patients, though MCI individuals tend to exhibit greater impairments in category fluency. In this study we: (1) detect language deficits of amnestic MCIs (aMCIs) and mild AD (mAD) participants and present their language performance (the Boston Diagnostic Aphasia Examination - BDAE scores) according to educational level, (2) study the diagnostic value of language deficits according to the cognitive state of the participants. One hundred nineteen participants, 38 normal controls (NC), 28 aMCIs and 53 mADs, were recruited randomly as outpatients of 2 clinical departments and administered clinical, neuropsychological and neuroimaging assessment. Language abilities were assessed by the adapted Greek edition of the BDAE (2nd edition). Our results indicate that verbal fluency, auditory, reading comprehension and narrative ability are the main language abilities to be affected in mADs, although they are almost intact in NCs and less vulnerable in aMCIs. Narrative ability seems to be significantly impaired in mADs but not so in aMCIs. Six language subtests of the BDAE assess safely the above deficits. This brief version of the BDAE discriminated mADs from the other 2 groups 92.5% of the time, NCs 86.8% and aMCI 67.9% of the time in order to save time and to be accurate in clinical practice. PMID- 23628237 TI - Modeling the response of a biofilm to silver-based antimicrobial. AB - Biofilms are found within the lungs of patients with chronic pulmonary infections, in particular patients with cystic fibrosis, and are the major cause of morbidity and mortality for these patients. The work presented here is part of a large interdisciplinary effort to develop an effective drug delivery system and treatment strategy to kill biofilms growing in the lung. The treatment strategy exploits silver-based antimicrobials, in particular, silver carbene complexes (SCC). This manuscript presents a mathematical model describing the growth of a biofilm and predicts the response of a biofilm to several basic treatment strategies. The continuum model is composed of a set of reaction-diffusion equations for the transport of soluble components (nutrient and antimicrobial), coupled to a set of reaction-advection equations for the particulate components (living, inert, and persister bacteria, extracellular polymeric substance, and void). We explore the efficacy of delivering SCC both in an aqueous solution and in biodegradable polymer nanoparticles. Minimum bactericidal concentration (MBC) levels of antimicrobial in both free and nanoparticle-encapsulated forms are estimated. Antimicrobial treatment demonstrates a biphasic killing phenomenon, where the active bacterial population is killed quickly followed by a slower killing rate, which indicates the presence of a persister population. Finally, our results suggest that a biofilm with a ready supply of nutrient throughout its depth has fewer persister bacteria and hence may be easier to treat than one with less nutrient. PMID- 23628239 TI - Dioxin and phthalate uptake and assimilation by the green mussel Perna viridis. AB - In this study, the aqueous uptake and dietary assimilation (trophic transfer) of two endocrine disrupting compounds (dioxin and phathalic acid) in the green mussel Perna viridis were quantified. During short-term exposure period, dioxin rapidly sorbed onto phytoplankton and its accumulation was much higher than that of phthalate. The uptake of these two compounds by the mussels increased with increasing temperature and salinity (for dioxin only). The dietary assimilation of the two contaminants was rather modest (10-64% for dioxin and 20-47% for phthalate), and was greatly dependent on the food species and concentration. Interestingly, dietary assimilation increased with increasing diatom food concentration. Gut passage time was partially responsible for the variable dietary assimilation. Given the high dissolved uptake rate and the modest dietary assimilation, aqueous exposure was predicted to be the dominant bioaccumulation source for both dioxin and phthalate in the green mussels under most conditions. PMID- 23628240 TI - Continuous positive airway pressure and nasal inflammation patterns in obstructive sleep apnea: anti-inflammatory or proinflammatory? PMID- 23628241 TI - Prognostic impact of sleep duration and sleep efficiency on mortality in patients with chronic heart failure. AB - BACKGROUND: Both short and long self-reported sleep duration (SDSR) has been linked to increased mortality. Our analysis tested the hypothesis that long SDSR is paralleled by impaired objective sleep efficiency (SEPSG) measured by polysomnography (PSG) and that impaired SEPSG is a risk factor for death in patients with chronic heart failure (CHF). METHODS: SDSR and SEPSG were assessed by standardized questionnaire and PSG in 188 consecutive CHF patients (age range, 63+/-10 year; left ventricular ejection fraction, 34+/-10%) admitted to the Sleep Center of the University Hospital Regensburg between 1/2002 and 12/2009. The mean follow-up period was 44+/-26 months. RESULTS: SEPSG in CHF patients from the highest quintile of SDSR (>=9h) was significantly lower compared with the middle quintile (7.25-8h; 71+/-15% vs 77%+/-11%; p=0.032) and similar to the lowest quintile (<=5.75h; 71+/-15% vs 71+/-16%, p=0.950). SEPSG is an independent predictor for death in the multivariable model after accounting for the significant confounders age, left ventricular ejection fraction, cause of CHF, and NYHA class (hazard ratio [HR] per 5% increase, 0.85; 95% confidence interval [CI], 0.77-0.93; p<0.001). CONCLUSIONS: Data indicate that subjective long sleepers with CHF have poor sleep efficiency. Objectively measured SEPSG strongly predicts mortality in CHF patients, underscoring the importance of objective assessment of sleep. PMID- 23628242 TI - Role of MHC class Ib molecule, H2-M3 in host immunity against tuberculosis. AB - The MHC class I family comprises both classical (class Ia) and non-classical (class Ib) members. While the prime function of classical MHC class I molecules (MHC class Ia) is to present peptide antigens to pathogen-specific cytotoxic T cells, non-classical MHC-I (MHC class Ib) antigens perform diverse array of functions in both innate and adaptive immunity. Vaccines against intracellular pathogens such as Mycobacterium tuberculosis need to induce strong cellular immune responses. Recent studies have shown that MHC class I molecules play an important role in the protective immune response to M. tuberculosis infection. Both MHC Ia-restricted and MHC class Ib-restricted M. tuberculosis -reactive CD8(+) T cells have been identified in humans and mice, but their relative contributions to immunity is still uncertain. Unlike MHC class Ia-restricted CD8(+) T cells, MHC class Ib-restricted CD8(+) T cells are constitutively activated in naive animals and respond rapidly to infection challenge, hence filling the temporal gap between innate and adaptive immunity. The present review article summarizes the general host immunity against M. tuberculosis infection highlighting the possible role of MHC class Ib molecule, H2-M3 and their ligands (N-formylated peptides) in protection against tuberculosis. PMID- 23628243 TI - Response to O'Brien et al. PMID- 23628244 TI - Randomized noninferiority clinical trial evaluating 3 commercial dry cow mastitis preparations: I. Quarter-level outcomes. AB - The study objective was to compare the efficacy of 3 commercial dry cow mastitis formulations regarding quarter-level prevalence of intramammary infections (IMI) postcalving, cure of preexisting infections over the dry period, prevention of new infections during the dry period, and risk for a clinical mastitis case between calving and 100d in milk (DIM). A total of 1,091 cows (4,364 quarters) from 6 commercial dairy herds in 4 different states (California, Iowa, Minnesota, and Wisconsin) were enrolled and randomized to 1 of the 3 treatments at dry-off: Quartermaster (QT; 1,000,000 IU of procaine penicillin G and 1 g of dihydrostreptomycin; Pfizer Animal Health, New York, NY), Spectramast DC (SP; 500 mg of ceftiofur hydrochloride; Pfizer Animal Health), or ToMorrow Dry Cow (TM; 300mg of cephapirin benzathine; Boehringer Ingelheim Vetmedica Inc., St. Joseph, MO). Quarter milk samples were collected for routine bacteriological culture before dry cow therapy treatment at dry-off, 0 to 6 DIM, and 7 to 13 DIM and an on-farm record-keeping system was used to retrieve data on clinical mastitis cases. Noninferiority analysis was used to evaluate the effect of treatment on the primary outcome, risk for a bacteriological cure during the dry period. Multivariable logistic regression techniques were used to describe the effect of treatment on risk for presence of IMI postcalving and risk of a new IMI during the dry period. Cox proportional hazards regression was used to describe the effect of treatment on the risk and time for quarters to experience an episode of clinical mastitis between calving and 100 DIM. The overall crude quarter-level prevalence of infection at dry-off was 19.2%. The most common pathogen isolated from milk samples at dry-off was coagulase-negative Staphylococcus, followed by Aerococcus spp. and other Streptococcus spp. Noninferiority analysis showed no effect of treatment on risk for a cure between dry-off and calving [least squares means (LSM): QT=93.3%, SP=92.6%, and TM=94.0%] and secondary analysis showed no effect of treatment on risk for presence of an IMI at 0 to 6 DIM (LSM: QT=16.5%, SP=14.1%, and TM=16.0%), risk for development of a new IMI between dry-off and 0 to 6 DIM (LSM: QT=14.8%, SP=12.3%, and TM=14.2%), or risk of experiencing a clinical mastitis event between calving and 100 DIM (LSM: QT=5.3%, SP=3.8%, and TM=4.1%). In conclusion, no difference was observed in efficacy among the 3 products evaluated when assessing the aforementioned quarter-level outcomes. PMID- 23628245 TI - Optimizing bulk milk dioxin monitoring based on costs and effectiveness. AB - Dioxins are environmental pollutants, potentially present in milk products, which have negative consequences for human health and for the firms and farms involved in the dairy chain. Dioxin monitoring in feed and food has been implemented to detect their presence and estimate their levels in food chains. However, the costs and effectiveness of such programs have not been evaluated. In this study, the costs and effectiveness of bulk milk dioxin monitoring in milk trucks were estimated to optimize the sampling and pooling monitoring strategies aimed at detecting at least 1 contaminated dairy farm out of 20,000 at a target dioxin concentration level. Incidents of different proportions, in terms of the number of contaminated farms, and concentrations were simulated. A combined testing strategy, consisting of screening and confirmatory methods, was assumed as well as testing of pooled samples. Two optimization models were built using linear programming. The first model aimed to minimize monitoring costs subject to a minimum required effectiveness of finding an incident, whereas the second model aimed to maximize the effectiveness for a given monitoring budget. Our results show that a high level of effectiveness is possible, but at high costs. Given specific assumptions, monitoring with 95% effectiveness to detect an incident of 1 contaminated farm at a dioxin concentration of 2 pg of toxic equivalents/g of fat [European Commission's (EC) action level] costs ?2.6 million per month. At the same level of effectiveness, a 73% cost reduction is possible when aiming to detect an incident where 2 farms are contaminated at a dioxin concentration of 3 pg of toxic equivalents/g of fat (EC maximum level). With a fixed budget of ?40,000 per month, the probability of detecting an incident with a single contaminated farm at a dioxin concentration equal to the EC action level is 4.4%. This probability almost doubled (8.0%) when aiming to detect the same incident but with a dioxin concentration equal to the EC maximum level. This study shows that the effectiveness of finding an incident depends not only on the ratio at which, for testing, collected truck samples are mixed into a pooled sample (aiming at detecting certain concentration), but also the number of collected truck samples. In conclusion, the optimal cost-effective monitoring depends on the number of contaminated farms and the concentration aimed at detection. The models and study results offer quantitative support to risk managers of food industries and food safety authorities. PMID- 23628246 TI - Short communication: measurements of methane emissions from feed samples in filter bags or dispersed in the medium in an in vitro gas production system. AB - The objective of this study was to compare methane (CH4) emissions from different feeds when incubated within filter bags for in vitro analysis or directly dispersed in the medium in an automated gas in vitro system. Four different concentrates and 4 forages were used in this study. Two lactating Swedish Red cows were used for the collection of rumen fluid. Feed samples were milled to pass a 1.0-mm screen. Aliquots (0.5 g) of samples were weighed directly in the bottles or within the F 0285 filter bags that were placed in the bottles. Gas samples were taken during 24 and 48 h of incubation, and CH4 concentration was determined. The data were analyzed using a general linear model. Feeds differed significantly in CH4 emission both at 24 and at 48 h of incubation. The interaction between feed and method on methane emission in vitro was significant, indicating that the ranking of feeds was not consistent between the methods. Generally, greater amounts of CH4 were emitted from samples directly dispersed in the medium compared with those incubated within the filter bags, which could be a result of lower microbial activity within the filter bags. The ratio of CH4 to total gas was greater when the feeds were incubated within bags compared with samples directly dispersed in the medium. Incubating samples in filter bags during 48 h of incubation cannot be recommended for determination of CH4 emission of feeds in vitro. PMID- 23628247 TI - Antihypertensive and hypolipidemic effect of milk fermented by specific Lactococcus lactis strains. AB - The antihypertensive and hypolipidemic effects of milk fermented by specific Lactococcus lactis strains in spontaneously hypertensive rats (SHR) were investigated. The SHR were fed ad libitum milk fermented by Lc. lactis NRRL B 50571, Lc. lactis NRRL B-50572, Captopril (40mg/kg of body weight, Sigma-Aldrich Co., St. Louis, MO) or purified water for 4 wk. Results suggested that Lc. lactis fermented milks presented a significant blood pressure-lowering effect. No significant difference was noted among milk fermented by Lc. lactis NRRL B-50571 and Captopril by the second and third week of treatment. Additionally, milk fermented by Lc. lactis strains modified SHR lipid profiles. Milk fermented by Lc. lactis NRRL B-50571 and B-50572 were able to reduce plasma low-density lipoprotein cholesterol and triglyceride contents. Thus, milk fermented by Lc. lactis strains may be a coadjuvant in the reduction of hypertension and hyperlipidemia and may be used as a functional food for better cardiovascular health. PMID- 23628248 TI - Characterization of Kentucky dairy producer decision-making behavior. AB - To address dairy clientele needs, industry professionals need to understand how dairy producers make decisions. A survey was distributed to all licensed Kentucky milk producers (n=1,074) to better understand factors that influence dairy producer decisions. A total of 236 surveys were returned; 7 were omitted because they were incomplete, leaving 229 for subsequent analyses (21% response rate). The survey consisted of questions about dairy operational success criteria, decision evaluation criteria, information sources, and technology adoption. The mean response to each survey question was calculated after assigning the following numeric values to producer response categories: 1 = not important, 3 = important, 5 = very important. The most important source of influence or information in decision making was advice from consultants, nutritionists, and veterinarians (3.70+/-1.23), followed by consultation with business partners and family members (3.68+/-1.29), and intuition and gut feeling (3.10+/-1.45). Producers with large herds (>=200 cows) relied more heavily on information from consultants, nutritionists, and veterinarians and on employee input than did producers with small herds (1 to 49 cows). Producers with small herds did not use effect on employee morale as a criterion to evaluate decisions as much as those with larger herds did. In regard to adoption of automated monitoring technologies, producers indicated that modest adoption rates were a result of (1) not being familiar with technologies that are available (55%), (2) undesirable cost to benefit ratios (42%), and (3) too much information provided without knowing what to do with it (36%). As herd size increased, the percentage of producers selecting poor technical support and training and compatibility issues as reasons for slow adoption of automated technologies increased. This insight into dairy producer decision making should help industry professionals address dairy producer issues and concerns. PMID- 23628249 TI - Transfer of terpenes from essential oils into cow milk. AB - The objective of this study was to investigate the transfer of volatile terpenes from caraway seed and oregano plant essential oils into cow's milk through respiratory and gastrointestinal exposure. Essential oils have potential applications as feed additives because of their antimicrobial properties, but very little work exists on the transfer of their volatile compounds into milk. Lactating Danish Holstein cows with duodenum cannula were used. Gastrointestinal exposure was facilitated by infusing the essential oils, mixed with deodorized sesame oil, into the duodenum cannula. Two levels were tested for each essential oil. Respiratory exposure was facilitated by placing the animal in a chamber together with a sponge soaked in the essential oils. All exposures were spread over 9h. Milk samples were collected immediately before and after exposure, as well as the next morning. Twelve monoterpenes and 2 sesquiterpenes were analyzed in essential oils and in milk samples using dynamic headspace sampling and gas chromatography-mass spectrometry. In the essential oils, almost all of the terpenes were detected in both essential oils at various levels. For caraway, the monoterpenes limonene, carvone, and carvacrol were most abundant; in oregano, the monoterpenes carvacrol and rho-cymene were most abundant. For almost all treatments, an immediate effect was detected in milk, whereas little or no effect was detected in milk the following day. This suggests that the transfer into milk of these volatile terpenes is fast, and that the milk will not be influenced when treatment is discontinued. Principal component analysis was used to elucidate the effect of the treatments on the terpene profile of the milk. Terpene content for treatment milk samples was characterized by the same terpenes found in the treatment essential oil used for that animal, regardless of pathway of exposure. The terpenes appear to be transferred unaltered into the milk, regardless of the pathway of exposure. Volatile terpenes in essential oils, which could influence milk flavor, are transferred into milk via both gastrointestinal and respiratory exposure. PMID- 23628250 TI - Grain-based versus alfalfa-based subacute ruminal acidosis induction experiments: Similarities and differences between changes in milk fatty acids. AB - Subacute ruminal acidosis (SARA) is one of the most important metabolic disorders, traditionally characterized by low rumen pH, which might be induced by an increase in the dietary proportion of grains as well as by a reduction of structural fiber. Both approaches were used in earlier published experiments in which SARA was induced by replacing part of the ration by a grain mixture or alfalfa hay by alfalfa pellets. The main differences between both experiments were the presence of blood lipopolysaccharide and Escherichia coli and associated effects on the rumen microbial population in the rumen of grain-based induced SARA animals as well as a great amount of quickly fermentable carbohydrates in the grain-based SARA induction experiment. Both induction approaches changed rumen pH although the pH decrease was more substantial in the alfalfa-based SARA induction protocol. The goal of the current analysis was to assess whether both acidosis induction approaches provoked similar shifts in the milk fatty acid (FA) profile. Similar changes of the odd- and branched-chain FA and the C18 biohydrogenation intermediates were observed in the alfalfa-based SARA induction experiment and the grain-based SARA induction experiment, although they were more pronounced in the former. The proportion of trans-10 C18:1 in the last week of the alfalfa-based induction experiment was 6 times higher than the proportion measured during the control week. The main difference between both induction experiments under similar rumen pH changes was the decreasing sum of iso FA during the grain-based SARA induction experiment whereas the sum of iso FA remained stable during the alfalfa-based SARA induction experiment. The cellulolytic bacterial community seemed to be negatively affected by either the presence of E. coli and the associated lipopolysaccharide accumulation in the rumen or by the amount of starch and quickly fermentable carbohydrates in the diet. In general, changes in the milk FA profile were related to changes in rumen pH. Nevertheless, feed characteristics (low in structural fiber vs. high in starch) also affected the milk FA profile and, as such, both effects should be taken into account when subacute acidosis occurs. PMID- 23628251 TI - Short communication: ultrasonographic assessment of the thorax as a fast technique to assess pulmonary lesions in dairy calves with bovine respiratory disease. AB - The aim of this study was to assess inter- and intraoperator agreement when assessing lung consolidation secondary to bovine respiratory disease (BRD) by thoracic ultrasonography. Ten calves were blindly assessed by 3 operators with varying expertise in thoracic ultrasound to look for lung consolidation and the presence of comet-tail artifacts (COMT). Systematic ultrasonography of the thorax was performed using an 18-site per side assessment with a linear 8.5-MHz probe. The status of the calves [healthy (n=4) vs. treated for BRD (n=6)] was not known by the operators. The interoperator kappa agreement for detecting consolidation was moderate to almost perfect (from 0.6 to 1.0) depending on the operator's experience (diagnosis of consolidation if depth >=1cm). The intraclass correlation coefficient for consistency was 0.71 for a single measurement and 0.88 for average measurement. The intraclass correlation coefficient for agreement was 0.73 for single measurements and 0.89 for average measurements. These values were considered good for single measurements and excellent for average measurements. Systematic ultrasonography of the thorax can be used routinely to assess lung consolidation in dairy calves and can therefore be of importance, especially for assessment of subclinical BRD. PMID- 23628253 TI - Cholesterol reduction from milk using beta-cyclodextrin immobilized on glass. AB - beta-Cyclodextrin (beta-CD) was converted into beta-CD-undecenyl ether by chemical modification and subsequently covalently attached to a glass surface. The functionalized glass surface was characterized by static water contact angle and x-ray photoelectron spectroscopy. Both techniques confirmed that an excellent monolayer of beta-CD was formed on the glass surface. The beta-CD solid surface was used to reduce cholesterol levels in milk. In 4h, 73.6% of the cholesterol was extracted at 25 degrees C with shaking at 170rpm. This is the highest value ever reported for milk using beta-CD immobilized on a solid surface. The same surface was repeatedly used for 10 cycles and maintained its efficiency with 72+/ 2% cholesterol reduction observed in all the cycles. X-ray photoelectron spectroscopy analysis completed after 5 and 10 cycles of cholesterol reduction showed that the beta-CD on the glass surface was not degraded. The high efficiency and long-term stability of the functional monolayer was attributed to the specific structure of beta-CD, which is composed of a relatively low number of functional groups and long spacer chain lengths that provide great flexibility. PMID- 23628252 TI - Microbiological and chemical characteristics of Brazilian kefir during fermentation and storage processes. AB - The microbial community composition and chemical characteristics of a Brazilian milk kefir sample produced during its manufacturing and refrigerated storage were investigated by culture-dependent and -independent methods and HPLC. Lactococcus lactis ssp. cremoris and ssp. lactis, Leuconostoc mesenteroides, Acetobacter lovaniensis, and Saccharomyces cerevisiae were isolated, whereas the detected bands on denaturing gel gradient electrophoresis corresponded to Lactobacillus kefiranofaciens, Lactobacillus kefiri, Lactobacillus parakefiri, and S. cerevisiae. After fermentation, lactic acid bacteria were present at levels of 10 log units, whereas acetic acid bacteria and yeast were present at levels of 7.8 and 6 log units, respectively. The lactic acid bacteria and yeast counts remained constant, whereas acetic acid bacteria counts decreased to 7.2 log units during storage. From fermentation to final storage, the pH, lactose content and citric acid of the kefir beverage decreased, followed by an increase in the concentrations of glucose, galactose, ethanol, and lactic, acetic, butyric, and propionic acids. These microbiological and chemical characteristics contribute to the unique taste and aroma of kefir. This research may serve as a basis for the future industrial production of this beverage in Brazil. PMID- 23628254 TI - Prediction of coagulating and noncoagulating milk samples using mid-infrared spectroscopy. AB - Recently, a general deterioration of milk coagulation properties (MCP) has been observed in Italy; thus, the prediction of noncoagulating (NC) milk, defined as milk not forming a curd within 30min from rennet addition, is of immediate interest in the Italian cheese industry. The present study investigated the ability of mid-infrared (MIR) spectroscopy to predict NC milk using individual and bulk samples from Holstein cows. Samples were selected according to MIR analysis to cover the range of coagulation time between 5 and 60min. Milks were then analyzed for MCP through the reference instrument (Formagraph) over an extended testing period of 60min to identify coagulating and NC samples. Measured traits were rennet coagulation time, curd-firming time, and curd firmness 30 and 60min after rennet addition. Results showed no specific spectral information distinguishing NC from coagulating samples. The most accurate prediction model was developed for rennet coagulation time followed by curd-firming time and curd firmness 30min after rennet addition, whereas curd firmness 60min after enzyme addition could not be accurately predicted. Based on these findings, MIR spectroscopy might be proposed in payment systems to reward or penalize milk according to MCP. Moreover, the ability of MIR spectroscopy to predict the MCP of samples that form a curd beyond 30min from enzyme addition may be of interest for genetic improvement of coagulation traits in dairy breeds, because until now most studies have excluded NC information from genetic analysis, leading to possible biases in the estimation of genetic parameters and in the prediction of sire's merit for MCP. PMID- 23628255 TI - Short communication: evaluation of the accuracy of an electronic on-farm test to quantify blood beta-hydroxybutyrate concentration in dairy goats. AB - The objective of this cross-sectional study was to validate the accuracy of a hand-held electronic on-farm test (Precision Xtra) for quantifying the blood beta hydroxybutyrate (BHBA) concentration in dairy goats. A total of 114 dairy goats from 3 commercial herds were sampled once for blood in the jugular vein between 1mo before and 2mo after parturition. Blood samples were centrifuged to harvest serum and sera were sent to the Animal Health Laboratory of the Universite de Montreal for quantification of BHBA concentration (gold standard). Laboratory BHBA values were between 0.1 and 3.7mmol/L. Precision Xtra values were compared with gold standard values; Pearson correlation coefficient was 0.98 and coefficient of determination was 0.95. Overall, these results suggested that Precision Xtra provides excellent accuracy for measuring blood BHBA concentration in dairy goats compared with the gold standard test. PMID- 23628256 TI - Energy partitioning and substrate oxidation by Murciano-Granadina goats during mid lactation fed soy hulls and corn gluten feed blend as a replacement for corn grain. AB - The aim of this experiment was to study the effect of substituting corn grain by soy hulls and corn gluten feed blend on energy partitioning, substrate oxidation, and milk performance in dairy goats during mid lactation. Ten multiparous Murciano-Granadina goats in mid lactation were fed 2 isoenergetic and isoproteic diets [19.08MJ/kg of dry matter (DM) and 18.7% of CP, DM basis] in a crossover design. One group of 5 goats was fed a mixed ration with 373g of corn grain/kg of DM (CRN diet) and the other diet replaced corn grain with 373g/kg DM of fibrous by-products [soy hulls and gluten feed (SHGF) diet]: 227g of soy hulls/kg of DM and 146g of gluten feed blend/kg DM. Fat was added to the SHGF diet to make it isoenergetic. After 10d of adaptation, the feed intake, refusal, total fecal and urine output, and milk yield were recorded daily over a 5-d period. Then, gas exchange measurements were recorded by a mobile open-circuit respirometry system using a head box for 10d. Dry matter intake was similar for both diets (2.07kg/d, on average). Greater and significant values were found in the SHGF diet for ammonia N, energy in urine, and oxidation of protein. Values were significantly lower for heat production of fermentation, indicating a decrease in rumen fermentation with this diet, probably due to an excess of crude protein in the diet and lack of synchronization of the nonfiber carbohydrates with rumen degraded protein. The metabolizable energy intake was no different between CRN and SHGF treatments, with an average value of 1,444kJ/kg of BW(0.75). Due to the positive energy balance during mid lactation in this trial, most of the heat production from oxidation of nutrients derived from carbohydrate oxidation (55%, on average), followed by oxidation of fat (29%, on average). No significant differences were observed for milk production, although milk fat was significantly greater for the SHGF diet than the CRN diet (7.0 vs. 5.4%, respectively). Despite the different starch levels and fibrous content used in these mixed diets, no significant differences for the efficiency of use of metabolizable energy for late lactation were observed (0.63, on average). An average nutritive value of 7.52MJ of net energy of lactation/kg of DM was obtained. This fibrous by-product was utilized by lactating goats without detrimental effect on energy metabolism and resulted in similar performance to grain bases diet. The economic advantages and sustainability of this choice should be evaluated. PMID- 23628257 TI - It is premature to test older drivers with the SIMARD-MD. AB - BACKGROUND: A new tool, the SIMARD-MD, has been proposed to help physicians identify cognitively impaired drivers who may be unfit to drive, but little empirical evidence is available to justify its use. We analyzed data from a cohort of older Canadian drivers who had undergone cognitive testing to: (1) correlate the SIMARD-MD with other tools that measure cognition (e.g., trail making test), (2) identify how many drivers, using published cut-offs on the SIMARD-MD, would be recommended to lose their license, or be considered fit to drive, or be required to undergo further driving assessment, and (3) determine if the SIMARD-MD is biased by level of education as many cognitive tools are. METHODS: Cross-sectional data from 841 drivers aged 70 and over from seven Canadian sites who are enrolled in a 5-year cohort study were used for the analyses. Scores on the SIMARD-MD were correlated with scores on the other cognitive measures. The recommendations that would be made based on the SIMARD-MD scores were based on published cut-off values suggested by the authors of the tool. The impact of education status was examined using linear regression controlling for age. RESULTS: Correlations between the SIMARD-MD and other cognitive measures ranged from .15 to .86. Using published cut-off scores, 21 participants (2.5%) would have been recommended to relinquish their licenses, 428 (50.9%) would have been deemed fit to drive, and 392 (46.6%) would have been required to undergo further testing. We found a difference of 8.19 points (95% CI=4.99, 11.40, p<.001) in favor of drivers with post-secondary education versus those without, representing over 11% of the mean score. DISCUSSION: The SIMARD-MD is unlikely to be valuable to clinicians because it lacks sufficient precision to provide clear recommendations about fitness-to-drive. Recommendations based solely on the SIMARD-MD may place many seniors at risk of losing their transportation mobility or incurring unnecessary stress and costs to prove they are safe to drive. Furthermore, the education bias may create an unwanted structural inequity. Hence, adoption of the SIMARD-MD as a tool to determine fitness-to-drive appears premature. PMID- 23628258 TI - Unfavorable course in pregnancy-associated thrombotic thrombocytopenic purpura necessitating a perimortem Cesarean section: a case report. AB - INTRODUCTION: Thrombotic thrombocytopenic purpura is a type of occlusive thrombotic microangiopathy that is not specific to pregnancy but occurs with an increased frequency during it. Prognosis of thrombotic thrombocytopenic purpura greatly depends on early diagnosis and treatment. As delivery does not generally cause resolution of thrombotic thrombocytopenic purpura, pregnancy termination is not initially considered, especially under 34 weeks, although it may be required under some conditions such as preeclampsia. Plasma therapy, including plasmapheresis, and steroids are used for treatment. In the event of an unfavorable course leading to cardiopulmonary arrest, effectiveness of cardiopulmonary resuscitation measures greatly depends on an early start of such measures. In pregnant patients, not only rapid implementation of these measures is required, but a decision should also be taken about the convenience of fetal delivery through a perimortem Cesarean section. CASE PRESENTATION: We report the case of thrombotic thrombocytopenic purpura in a 30-year-old primigravida white woman in week 28 of pregnancy that had a rapidly deteriorating course leading to cardiopulmonary arrest and an emergency perimortem Cesarean section resulting in fetal survival but maternal death. The patient was asymptomatic at admission and such an unfavorable evolution was initially unexpected. Analytical findings were treated with fresh frozen plasma and methylprednisolone but they did not improve. Plasmapheresis was considered but cardiac arrest rapidly ensued. CONCLUSIONS: Despite the low prevalence of thrombotic thrombocytopenic purpura, the finding in a pregnant woman of the triad consisting of anemia, thrombocytopenia, and neurological changes should guide clinical diagnosis, and should prompt measurement of the metalloprotease ADAMTS-13 in order to rule out or confirm diagnosis of thrombotic thrombocytopenic purpura and evaluate the best therapeutic option. If cardiopulmonary arrest occurs in a woman with a gestational age of more than 24 weeks, a perimortem Cesarean section is advised if the patient has not recovered her pulse after the first four minutes. PMID- 23628259 TI - Nonparametric multivariate inference on shift parameters. AB - RATIONALE AND OBJECTIVES: Consider a study evaluating the prognostic value of prostate-specific antigen (PSA), in the presence of Gleason score, in differentiating between early and advanced prostate cancer. This data set features subjects divided into two groups (early versus advanced cancer), with one manifest variable (PSA), one covariate (Gleason score), and one stratification variable (hospital, taking three values). We present a nonparametric method for estimating a shift in median PSA score between the two groups, after adjusting for differences in Gleason score and stratifying on hospital. This method can also be extended to cases involving multivariate manifest variable. MATERIALS AND METHODS: Our method uses estimating equations derived from an existing rank-based estimator of the area under the receiver operating characteristic curve (AUC). This existing AUC estimator is adjusted for stratification and for covariates. We use the adjusted AUC estimator to construct a family of tests by shifting manifest variables in one of the treatment groups by an arbitrary constant. The null hypothesis for these tests is that the AUC is half. We report the set of shift values for which the null hypothesis is not rejected as the resulting confidence region. RESULTS: Simulated data show performance consistent with the distributional approximations used by the proposed methodology. This methodology is applied to two examples. In the first example, the mean difference in PSA levels between advanced and nonadvanced prostate cancer patients is estimated, controlling for Gleason score. In the second example, to assess the degree to which age and baseline tumor size are prognostic factors for breast cancer recurrence, differences in age and tumor size between subjects with recurrent and nonrecurrent breast cancer, stratified on Tamoxifen treatment and adjusting for tumor grade, are estimated. CONCLUSIONS: The proposed methodology provides a nonparametric method for a statistic measuring adjusted AUC to be used to estimate shift between two manifest variables. PMID- 23628260 TI - CDC should reverse its recommendation against semen washing-intrauterine insemination for HIV-serodifferent couples. PMID- 23628261 TI - Reply: To PMID 23433324. PMID- 23628262 TI - Metaanalysis of the prevalence of intrauterine fetal death in gastroschisis. AB - OBJECTIVE: The objective of this study was to review the medical literature that has reported the risk for intrauterine fetal death (IUFD) in pregnancies with gastroschisis. STUDY DESIGN: We systematically searched the literature to identify all published studies of IUFD and gastroschisis through June 2011 that were archived in MEDLINE, PubMed, or referenced in published manuscripts. The MESH terms gastroschisis or abdominal wall defect were used. RESULTS: Fifty-four articles were included in the metaanalysis. There were 3276 pregnancies in the study and a pooled prevalence of IUFD of 4.48 per 100. Those articles that included gestational age of IUFD had a pooled prevalence of IUFD of 1.28 per 100 births at >=36 weeks' gestation. The prevalence did not appear to increase at >35 weeks' gestation. CONCLUSION: The overall incidence of IUFD in gastroschisis is much lower than previously reported. The largest risk of IUFD occurs before routine and elective early delivery would be acceptable. Risk for IUFD should not be the primary indication for routine elective preterm delivery in pregnancies that are affected by gastroschisis. PMID- 23628263 TI - Intrapartum management of category II fetal heart rate tracings: towards standardization of care. AB - There is currently no standard national approach to the management of category II fetal heart rate (FHR) patterns, yet such patterns occur in the majority of fetuses in labor. Under such circumstances, it would be difficult to demonstrate the clinical efficacy of FHR monitoring even if this technique had immense intrinsic value, since there has never been a standard hypothesis to test dealing with interpretation and management of these abnormal patterns. We present an algorithm for the management of category II FHR patterns that reflects a synthesis of available evidence and current scientific thought. Use of this algorithm represents one way for the clinician to comply with the standard of care, and may enhance our overall ability to define the benefits of intrapartum FHR monitoring. PMID- 23628264 TI - Swimming pool use and birth defect risk. AB - OBJECTIVE: Swimming during pregnancy is recommended. However, the use of swimming pools is also associated with infection by water-borne pathogens and exposure to water disinfection byproducts, which are 2 mechanisms that are suspected to increase risk for birth defects. Thus, we evaluated the relationship between maternal swimming pool use during early pregnancy and risk for select birth defects in offspring. STUDY DESIGN: Data were evaluated for nonsyndromic cases with 1 of 16 types of birth defects (n = 191-1829) and controls (n = 6826) from the National Birth Defects Prevention Study delivered during 2000-2006. Logistic regression analyses were conducted separately for each birth defect type. Separate analyses were conducted to assess any pool use (yes vs no) and frequent use (5 or more occasions in 1 month) during the month before pregnancy through the third month of pregnancy. RESULTS: There was no significant positive association between any or frequent pool use and any of the types of birth defects, even after adjustment for several potential confounders (maternal race/ethnicity, age at delivery, education, body mass index, folic acid use, nulliparity, smoking, annual household income, surveillance center, and season of conception). Frequent pool use was significantly negatively associated with spina bifida (adjusted odds ratio, 0.68; 95% confidence interval, 0.47-0.99). Among offspring of women 20 years old or older, pool use was associated with gastroschisis (adjusted odds ratio, 1.3; 95% confidence interval, 1.0-1.8), although not significantly so. CONCLUSION: We observed little evidence suggesting teratogenic effects of swimming pool use. Because swimming is a common and suggested form of exercise during pregnancy, these results are reassuring. PMID- 23628265 TI - Mortality related to 17-OHPC exposure is an important safety outcome. PMID- 23628266 TI - Histological analysis of cells and matrix mineralization of new bone tissue induced in rabbit femur bones by Mg-Zr based biodegradable implants. AB - The biological efficacy of bone inducing implant materials in situ can be assessed effectively by performing histological analysis. We studied the peri implant bone regeneration around two types of biodegradable magnesium-zirconium alloys, Mg-5Zr and Mg-Zr-2Sr, using histological, histochemical and immunohistochemical methods in the femur of New Zealand White strain rabbits. Our study includes three animal groups: (a) Mg-5Zr, (b) Mg-Zr-2Sr and (c) control. In each group three animals were used and in groups 'a' and 'b' the respective alloys were implanted in cavities made at the distal ends of the femur; control animals were left without implants to observe natural bone healing. Qualitative assessment of the cellularity and matrix mineralization events of the newly formed bone tissue was done at three months after implantation by histological methods in methyl methacrylate embedded tissue without decalcifying the bone. Quantitative mineral content and density of the new bone (NB) were evaluated by the statistical analysis of dual energy X-ray absorptiometry (DXA) data obtained from three animals in each experimental group. Based on our analysis we conclude that Mg-Zr-2Sr alloy showed better osseointegration of the newly formed bone with the implant surface. Our methodology of studying peri-implant osteoinduction of degradable implants using low temperature methyl methacrylate embedding resin can be useful as a general method for determining the bio-efficacy of implant materials. PMID- 23628267 TI - Immunohistochemical study of jejunal graft mucosa cell populations during the initial adaptation phase in the host body in rats. AB - The character of the changes in cell populations within the jejunal graft mucosa during the initial adaptation phase in the host body was investigated. 24 adult male Wistar rats underwent intestinal heterotopic allotransplantation. Aorto aortal and porto-caval anastomoses were performed using the end-to-side microsurgery technique. Graft tissues were compared to the intestinal tissues of the recipients. This study demonstrates that: (1) Distinct injury to the graft mucosa 1h after transplantation was accompanied by significant reduction in numbers of epithelial secretory cell populations. The injury was more intense in the mesenteric portion. Six hours after transplantation the graft mucosa was covered by a continuous epithelium, but the number of goblet and Paneth cells was found to be less than 30% of that in the recipient epithelium. (2) In comparison with recipients, myeloperoxidase-positive cell numbers increased significantly in the graft mucosa 1 h after transplantation. In the epithelial layer, denudation and destruction of villi was associated with a significant reduction in intraepithelial lymphocyte numbers. A significant decrease in mucosal mast cell numbers was detected 6 h after transplantation. They attained only 10% of the number found in the recipients. (3) Time-dependent changes in the graft mucosa revealed that CD163-positive cells increased significantly in the graft mucosa during 6 h after transplantation and reached the level found in the recipients. In contrast, the myeloperoxidase-positive cell population significantly decreased in the graft mucosa within the initial 6 h. PMID- 23628268 TI - Reply: To PMID 22982183. PMID- 23628269 TI - It is premature to conclude pancreatic sphincterotomy is not beneficial in idiopathic pancreatitis. PMID- 23628270 TI - The underestimated role of opiates in sphincter of Oddi dysfunction. PMID- 23628271 TI - Presentation of the Julius M. Friedenwald medal to Chung Owyang, MD. PMID- 23628272 TI - Reply: To PMID 23063972. PMID- 23628273 TI - Reply: To PMID 23063971. PMID- 23628276 TI - What is the role of noninvasive treatment for infected pancreatic necrosis: still an unanswered question. PMID- 23628277 TI - Statins and cancer in gastroenterology: new insight? PMID- 23628278 TI - Serrated polyps misclassified: the value of looking back and the impact of looking forward. PMID- 23628279 TI - Relationship between postmenopausal osteoporosis and the components of clinical sarcopenia. AB - PURPOSE: The aim of the study was to determine the relationship between the components of clinical sarcopenia and osteoporosis in postmenopausal women. METHODS: A population-based cohort of 590 Finnish postmenopausal women (mean age 67.9; range 65-72) was selected from the Osteoporosis Fracture Prevention (OSTPRE FPS) study in 2002. Bone mineral density (BMD) and lean tissue mass were assessed by dual X-ray absorptiometry (DXA). The study sample was divided into three categories according to the WHO BMD classification: normal, osteopenia and osteoporosis. The study sample was divided into non-sarcopenic, presarcopenic, sarcopenic and non-classified groups according to quartiles of RSMI i.e. relative skeletal muscle index (appendicular muscle mass (kg)/square of height (m)), hand grip strength (kPa) and walking speed. RESULTS: In logistic regression analysis sarcopenic women had 12.9 times higher odds of having osteoporosis (p <= 0.001, OR=12.9; 95% CI=3.1-53.5) in comparison to non-sarcopenic women. In comparison to women in the highest grip strength quartile, women within the lowest quartile had 11.7 times higher odds of having osteoporosis (p=0.001, OR=11.7; 2.6-53.4). Sarcopenic women had 2.7 times higher odds of having fractures than their non sarcopenic counterparts (p=0.005, OR=2.732; 1.4-5.5). Sarcopenic women had also 2.1 times higher risk of falls during the preceding 12 months compared to non sarcopenic women (p=0.021, OR=2.1; 1.1-3.9). Adjustment for age, body mass index (BMI), physical activity and hormone therapy (HT) did not significantly alter these results. CONCLUSIONS: The components of clinical sarcopenia are strongly associated with osteoporosis. Grip strength is the most significant measurement to reveal the association between sarcopenia and osteoporosis, falls and fractures. PMID- 23628280 TI - Diabetes and bone health. AB - The increasing prevalence of diabetes especially type 2 diabetes worldwide is indisputable. Diabetics suffer increased morbidity and mortality, compared to their non-diabetic counterparts, not only because of vascular complications, but also because of an increased fracture incidence. Both types 1 and 2 diabetes and some medications used to treat it are associated with osteoporotic fractures. The responsible mechanisms remain incompletely elucidated. In this review, we evaluate the role of glycemic control in bone health, and the effect of anti diabetic medications such as thiazolidinediones, sulfonylureas, DPP-4 inhibitors, and GLP-1 agonists. In addition, we examine the possible role of insulin and metformin as anabolic agents for bone. Lastly, we identify the current and future screening tools that help evaluate bone health in diabetics and their limitations. In this way we can offer individualized treatment, to the at-risk diabetic population. PMID- 23628281 TI - Disease-specific knowledge and information preferences of young patients with congenital heart disease. AB - AIMS: Persons suffering from congenital heart defects require lifelong specialist medical care. Failure to attend cardiological follow-up examinations and risky health behaviour in the transition phase may cause severe medical complications. A good level of disease-specific knowledge enhances compliance. Therefore, the study's aim was to investigate: (a) the level of disease-specific knowledge, (b) information preferences, and (c) sources of information for children, adolescents, and young adults regarding their illness. METHODS AND RESULTS: In all, 596 patients, aged 10-30 years, participated in this cross-sectional survey study (response rate: 53%). All patients were already enrolled in the German National Register for Congenital Heart Defects. The main outcome measures included disease-specific knowledge, information preferences, and information sources regarding patients' individual cardiac condition. The patients demonstrated a major knowledge gap concerning their illness and how to live with it. For all three age groups, patients' information needs were unmet on nearly half of the topics of interest. Children's information needs were comparable to those of adolescents and adults concerning several important topics, for example, work/career, sports. Information preferences varied according to age and gender, rather than disease severity. The most important sources of information were physicians (71.0%), family and friends (58.2%), and the Internet (37.5%). CONCLUSION: The study revealed substantial knowledge gaps, indicating a need for structured multidisciplinary patient education interventions. These interventions should start as early as in childhood and help patients manage their condition and assume responsibility for their own health, so that the transition phase runs smoothly. PMID- 23628282 TI - Cost-effectiveness of novel system of mosquito surveillance and control, Brazil. AB - Of all countries in the Western Hemisphere, Brazil has the highest economic losses caused by dengue fever. We evaluated the cost-effectiveness of a novel system of vector surveillance and control, Monitoramento Inteligente da Dengue (Intelligent Dengue Monitoring System [MID]), which was implemented in 21 cities in Minas Gerais, Brazil. Traps for adult female mosquitoes were spaced at 300-m intervals throughout each city. In cities that used MID, vector control was conducted specifically at high-risk sites (indicated through daily updates by MID). In control cities, vector control proceeded according to guidelines of the Brazilian government. We estimated that MID prevented 27,191 cases of dengue fever and saved an average of $227 (median $58) per case prevented, which saved approximately $364,517 in direct costs (health care and vector control) and $7,138,940 in lost wages (societal effect) annually. MID was more effective in cities with stronger economies and more cost-effective in cities with higher levels of mosquito infestation. PMID- 23628284 TI - Unanticipated parallels in architecture and mechanism between ATP-gated P2X receptors and acid sensing ion channels. AB - ATP-gated P2X receptors and acid-sensing ion channels are cation-selective, trimeric ligand-gated ion channels unrelated in amino acid sequence. Nevertheless, initial crystal structures of the P2X4 receptor and acid-sensing ion channel 1a in resting/closed and in non conductive/desensitized conformations, respectively, revealed common elements of architecture. Recent structures of both channels have revealed the ion channels in open conformations. Here we focus on common elements of architecture, conformational change and ion permeation, emphasizing general principles of structure and mechanism in P2X receptors and in acid-sensing ion channels and showing how these two sequence disparate families of ligand-gated ion channel harbor unexpected similarities when viewed through a structural lens. PMID- 23628285 TI - The present and future of solution NMR in investigating the structure and dynamics of channels and transporters. AB - Membrane channels, transporters and receptors constitute essential means for cells to maintain homeostasis and communicate with the surroundings. Investigation of their molecular architecture and the dynamic process of transporting substrate or transmitting signals across the membrane barrier has been one of the frontiers in biomedical research. The past decade has seen numerous successes in the use of X-ray or electron crystallography in determining atomic-resolution structures of membrane proteins, and in some cases, even snapshots of different physiological states of the same protein have been obtained. But there are also many cases in which long-standing efforts to crystallize proteins have yet to succeed. Therefore we have practical needs for developing complementary biophysical tools such as NMR spectroscopy and electron microscopy for tackling these systems. This paper provides a number of key examples where the utility of solution NMR was pivotal in providing structural and functional information on ion channels and transporters. PMID- 23628286 TI - Cell-free expression--making a mark. AB - Cell-free protein production opens new perspectives for the direct manipulation of expression compartments in combination with reduced complexity of physiological requirements. The technology is therefore in particular suitable for the general synthesis of difficult proteins including toxins and membrane proteins as well as for the analysis of their functional folding in artificial environments. A further key application of cell-free expression is the fast and economic labeling of proteins for structural and functional applications. Two extract sources, wheat embryos and Escherichia coli cells, are currently employed for the preparative scale cell-free production of proteins. Recent achievements in structural characterization include cell-free synthesized membrane proteins and even larger protein assemblies may become feasible. PMID- 23628287 TI - Baculovirus expression: tackling the complexity challenge. AB - Most essential functions in eukaryotic cells are catalyzed by complex molecular machines built of many subunits. To fully understand their biological function in health and disease, it is imperative to study these machines in their entirety. The provision of many essential multiprotein complexes of higher eukaryotes including humans, can be a considerable challenge, as low abundance and heterogeneity often rule out their extraction from native source material. The baculovirus expression vector system (BEVS), specifically tailored for multiprotein complex production, has proven itself to be uniquely suited for overcoming this impeding bottleneck. Here we highlight recent major achievements in multiprotein complex structure research that were catalyzed by this versatile recombinant complex expression tool. PMID- 23628288 TI - Molecular mechanism of the Escherichia coli maltose transporter. AB - ATP-binding cassette (ABC) transporters are ubiquitous membrane proteins that import and export a large variety of materials across the lipid bilayer. A key question that drives ABC transporter research is how ATP hydrolysis is coupled to substrate translocation. This review uses the maltose transporter of Escherichia coli as a model system to understand the molecular mechanism of ABC importers. X ray crystallography was used to capture the structures of the maltose transporter in multiple conformations. These structures, interpreted in the light of functional data, are discussed to address the following questions: first, what is the nature of conformational changes in a transport cycle? Second, how does substrate activate ATPase activity? Third, how does ATP hydrolysis enable substrate transport? PMID- 23628289 TI - Chronic effects of cannabis on sensory gating. AB - Chronic cannabis use has been associated with neurocognitive deficits, alterations in brain structure and function, and with psychosis. This study investigated the effects of chronic cannabis use on P50 sensory-gating in regular users, and explored the association between sensory gating, cannabis use history and the development of psychotic-like symptoms. Twenty controls and 21 regular cannabis users completed a P50 paired-click (S1 and S2) paradigm with an inter pair interval of 9s. The groups were compared on P50 amplitude to S1 and S2, P50 ratio (S2/S1) and P50 difference score (S1-S2). While cannabis users overall did not differ from controls on P50 measures, prolonged duration of regular use was associated with greater impairment in sensory gating as indexed by both P50 ratio and difference scores (including after controlling for tobacco use). Long-term cannabis users were found to have worse sensory gating ratios and difference scores compared to short-term users and controls. P50 metrics did not correlate significantly with any measure of psychotic-like symptoms in cannabis users. These results suggest that prolonged exposure to cannabis results in impaired P50 sensory-gating in long-term cannabis users. While it is possible that these deficits may have pre-dated cannabis use and reflect a vulnerability to cannabis use, their association with increasing years of cannabis use suggests that this is not the case. Impaired P50 sensory-gating ratios have also been reported in patients with schizophrenia and may indicate a similar underlying pathology. PMID- 23628290 TI - It's not only in the eyes: nonlinear relationship between face orientation and N170 amplitude irrespective of eye presence. AB - We have investigated the interplay between face orientation, eye presence, and N170 amplitude by recording Event Related Potentials. To clarify previous reports of nonlinearity in N170 amplitude changes along rotation angle changes, we adopted Itier et al.'s model (Itier et al., 2007) which links N170 face inversion effects with the presence of eyes. Comparison of N170 amplitude and latency for five stimulus categories (Faces-with-eyes, Faces-without-eyes, Eyes, Cars-with lights, Cars-without-lights) in five different rotations (0, 45, 90, 135, 180) resulted in mixed conclusions. The main findings of this study are as follows: (1) a strong nonlinear relationship between N170 and angle of rotation that is specific to faces, distinguishing face from car category even when no significant differences were observed between these categories for upright and inverted orientations; and (2) the nonlinear relationship between N170 and angle of rotation does not depend on eye presence. We also propose an alternative model according to which N170 amplitude consists of two related aspects of face processing: (A) incompatibility (relative distance of the stimulus pattern from experience-based hypothetical prototype) and (B) integration (degree to which stimulus is integrated into holistic representation), with the former affecting the latter. Moreover, we suggest two possible neural events underlying these two aspects of face processing: neural population size activated by the stimulus, and synchronization within this population. PMID- 23628291 TI - Autonomic arousal explains social cognitive abilities in high-functioning adults with autism spectrum disorder. AB - Empirical research into behavioural profiles and autonomic responsivity in individuals with autism spectrum disorders (ASDs) is highly variable and inconsistent. Two preliminary studies of children with ASDs suggest that there may be subgroups of ASDs depending on their resting arousal levels, and that these subgroups show different profiles of autonomic responsivity. The aim of the present study was to determine whether (i) adults with high-functioning ASDs may be separated into subgroups according to variation in resting arousal; and (ii) these ASD arousal subgroups differ in their behavioural profiles for basic emotion recognition, judgements of trustworthiness, and cognitive and affective empathy. Thirty high-functioning adults with ASDs and 34 non-clinical controls participated. Resting arousal was determined as the average skin conductance (SCL) across a 2 min resting period. There was a subgroup of ASD adults with significantly lower resting SCL. These individuals demonstrated poorer emotion recognition, tended to judge faces more negatively, and had atypical relationships between SCL and affective empathy. In contrast, low cognitive empathy was a feature of all ASD adults. These findings have important implications for clinical interventions and future studies investigating autonomic functioning in ASDs. PMID- 23628293 TI - Effect of skin temperature on skin endothelial function assessment. AB - PURPOSE: Microcirculatory dysfunction plays a key role in the development of sepsis during which core temperature is often disturbed. Skin microvascular assessment using laser techniques has been suggested to evaluate microvascular dysfunction during sepsis, but skin microcirculation is also a major effector of human thermoregulation. Therefore we aimed to study the effect of skin temperature on endothelial- and non-endothelial microvascular responses. METHODS: Fifteen healthy participants were studied at different randomized ambient temperatures leading to low (28.0+/-2.0 degrees C), intermediate (31.6+/-2.1 degrees C), and high (34.1+/-1.3 degrees C) skin temperatures. We measured skin blood flow using laser speckle contrast imaging on the forearm in response to vasodilator microvascular tests: acetylcholine (ACh) iontophoresis, sodium nitroprussiate (SNP) iontophoresis, and post-occlusive reactive hyperemia (PORH). The results are expressed as absolute (laser speckle perfusion units, LSPU) or normalized values (cutaneous vascular conductance, CVC in LSPU/mmHg and multiple of baseline). RESULTS: Maximal vasodilation induced by these tests is modified by skin temperature. A low skin temperature induced a significant lower vasodilation for all microvascular tests when results are expressed either in absolute values or in CVC. For example, ACh peak was 57.6+/-19.6 LSPU, 66.8+/-22.2 LSPU and 88.5+/-13.0 LSPU for low, intermediate and high skin temperature respectively (p<0.05). When results are expressed in multiple of baseline, statistical difference disappeared. CONCLUSIONS: These results suggest that skin temperature has to be well controlled when performing microvascular assessments in order to avoid any bias. The effect of skin temperature can be corrected by expressing the results in multiple of baseline. PMID- 23628294 TI - Letter to editor: Late gadolinium enhancement on cardiac magnetic resonance images predicts reverse remodeling in patients with nonischemic cardiomyopathy treated with carvedilol. PMID- 23628292 TI - Reduced angiotensin II levels cause generalized vascular dysfunction via oxidant stress in hamster cheek pouch arterioles. AB - OBJECTIVES: We investigated the effect of suppressing plasma angiotensin II (ANG II) levels on arteriolar relaxation in the hamster cheek pouch. METHODS: Arteriolar diameters were measured via television microscopy during short-term (3 6days) high salt (HS; 4% NaCl) diet and angiotensin converting enzyme (ACE) inhibition with captopril (100mg/kg/day). RESULTS: ACE inhibition and/or HS diet eliminated endothelium-dependent arteriolar dilation to acetylcholine, endothelium-independent dilation to the NO donor sodium nitroprusside, the prostacyclin analogs carbacyclin and iloprost, and the KATP channel opener cromakalim; and eliminated arteriolar constriction during KATP channel blockade with glibenclamide. Scavenging of superoxide radicals and low dose ANG II infusion (25ng/kg/min, subcutaneous) reduced oxidant stress and restored arteriolar dilation in arterioles of HS-fed hamsters. Vasoconstriction to topically-applied ANG II was unaffected by HS diet while arteriolar responses to elevation of superfusion solution PO2 were unaffected (5% O2, 10% O2) or reduced (21% O2) by HS diet. CONCLUSIONS: These findings indicate that sustained exposure to low levels of circulating ANG II leads to widespread dysfunction in endothelium-dependent and independent vascular relaxation mechanisms in cheek pouch arterioles by increasing vascular oxidant stress, but does not potentiate O2- or ANG II-induced constriction of arterioles in the distal microcirculation of normotensive hamsters. PMID- 23628295 TI - Emergency ambulance triggered "false activation" callout for primary percutaneous coronary intervention is not a benign phenomenon. PMID- 23628296 TI - Hyper-acute precipitating mechanism of Tako-Tsubo cardiomyopathy: in the beginning was basal hyperkinesis? PMID- 23628297 TI - Mitochondrial encoded NADH dehydrogenase 5 (MT-ND5) gene point mutation presents as late onset cardiomyopathy. PMID- 23628299 TI - Long term effects of intramyocardial bone marrow cell injection on anginal symptoms and quality of life in patients with chronic myocardial ischemia. PMID- 23628298 TI - Mid-term prognostic value of coronary artery disease in patients undergoing transcatheter aortic valve implantation: a meta-analysis of adjusted observational results. AB - AIMS: Coronary artery disease (CAD) negatively affects prognosis in patients undergoing surgical aortic valve replacement, being currently evaluated in the most common used risk score. Our meta-analysis aims to clarify the prognostic role of CAD on mid-term survival in patients undergoing TAVI. METHODS AND RESULTS: Studies reporting multivariate predictors of adverse outcomes in patients undergoing TAVI were systematically searched for and pooled, when appropriate, using a random-effect method. 960 citations were first screened and finally 7 studies (2472 patients) were included. Diagnosis of CAD was reported in 52%(42-65) of patients and 1169 Edwards SAPIEN and 1303 CoreValve prostheses were implanted. After a median follow up of 452 days (357-585) 24% of patients (19-33) died, and 23 (14-32) for cardiovascular death. At pooled analysis of multivariate approach, diagnosis of coronary artery disease did not increase risk of death (OR 1.0, 95% CI, confidence interval, 0.67-1.50 I(2) 0%). CONCLUSION: CAD does not affect mid-term TAVI outcome: this finding should be weighted to accurately evaluate risk and strategies for patients with severe aortic stenosis. PMID- 23628300 TI - Do exenatide truly improve the myocardial infarction size? PMID- 23628301 TI - Exercise-induced changes in left ventricular filling pressure after myocardial infarction assessed with simultaneous right heart catheterization and Doppler echocardiography. AB - BACKGROUND: To assess whether changes in E/e' (the ratio between peak early mitral inflow velocity (E) and peak early mitral annulus velocity (e')) during exercise reflect changes in filling pressure in patients with a recent myocardial infarction (MI) and mild to moderate diastolic dysfunction at rest. A low E/e' ratio is associated with low filling pressures while a high E/e' ratio is associated with high filling pressures. In the intermediate range of E/e' guidelines suggest additional measurements during exercise in order to determine filling pressures. METHODS AND RESULTS: Sixty-one patients with a recent MI and left ventricular ejection fraction (LVEF) >= 45%, left atrium (LA)>34 ml/m(2) and E/e' between 8 and 15, underwent simultaneous right heart catheterization and Doppler echocardiography during a symptom limited semi supine cycle exercise test. E velocity increased from 75 +/- 16 to 139 +/- 27 cm/s and e' increased from 7.1 +/- 1.4 to 16.1 +/- 3.6 cm/s with exercise. Thus, E/e' decreased from 10.5 +/- 1.7 to 9.3 +/- 2.3 while pulmonary capillary wedge pressure (PCWP) increased from 13 +/- 4 to 33 +/- 8 mmHg. There was no correlation between LV filling pressure and E/e' at rest, at 4 METS, at peak exercise or 5 min after termination of exercise. Neither was there any correlation between changes in PCWP and changes in E/e'. CONCLUSION: For post-MI patients with resting E/e' in the intermediate range changes in E/e' with physical exercise does not reflect changes in LV filling pressures. PMID- 23628302 TI - Who reviews the reviewers? PMID- 23628303 TI - Saphenous vein graft 'arterialization' assessed by optical coherence tomography. PMID- 23628304 TI - Combined intraoperative use of Diltiazem and N-acetylcystein increases myocardial damage and oxidative stress during off-pump cardiac surgery. PMID- 23628305 TI - Children living near chipboard and wood industries are at an increased risk of hospitalization for respiratory diseases: a prospective study. AB - Pollutants emitted from wood processing factories may be harmful to the health of the population. The aim of this prospective cohort study was to evaluate whether proximity to wood factories was associated with the risk of hospital admissions in children living in the Viadana district (Italy), where two big chipboard industries and other smaller wood factories (sawmills, multi-strata layer manufacturing) are located. In 2006, children (3-14 years) living in the Viadana district were surveyed through a parental questionnaire (n=3854), their home/school addresses were geocoded and the distances to the wood industries were calculated. Hospital discharge records for the years 2007-2009 were obtained. Cox proportional hazard regression models were used to estimate the association between hospitalization rates and distance to the factories, adjusting for sex, age, nationality, parents' education, exposure to passive smoking and reported traffic near home. During the 3-year follow-up, the risk of hospitalization for all diagnoses (Hospitalization Hazard Ratio, HHR=1.55; 95% CI: 1.24-1.95) and for respiratory diseases (HHR=1.80; 95% CI: 1.14-2.86) was greater in the children living close (<2 km) to the chipboard industries, with respect to the children who lived at >=2 km from any wood factory. The children living close to the smaller wood factories were also at increased risk of hospitalization for respiratory diseases (HHR=1.74; 95% CI: 1.06-2.85). This study highlights a health problem for the children living close to chipboard and wood factories in the Viadana district. Further research should develop accurate exposure models based on objective measurements of air pollution in order to confirm these findings. PMID- 23628306 TI - Comparative analysis of cardiovascular disease risk factors influencing nonfatal acute coronary syndrome and ischemic stroke. AB - The aim of the present work was to compare the influence of classic cardiovascular disease (CVD) risk factors on the development of acute coronary syndrome (ACS) and ischemic stroke. During 2009-2010, 1,000 participants were enrolled: 250 were consecutive patients with a first ACS, 250 were consecutive patients with a first ischemic stroke, and 500 were population-based, control subjects, 1-for-1 matched to the patients by age and gender. The following CVD risk factors were evaluated: smoking/passive smoking, family history of CVD, physical inactivity, hypertension, hypercholesterolemia, diabetes mellitus, presence of overweight and obesity, trait anxiety (assessed with the Spielberger State-Trait Anxiety Inventory form Y-2), and adherence to the Mediterranean diet (assessed by the MedDietScore). Furthermore, participants graded the perceived significance of the aforementioned factors, using a scale from 1 (not important) to 9 (very important). The risk factors with the highest effect size for ACS, as determined by the Wald criterion, were smoking and hypercholesterolemia; regarding stroke, they were anxiety and family history of CVD (all p <0.01). When the odds ratios of each factor for ACS and stroke were compared, insignificant differences were observed, except for smoking. On the basis of the participants' health beliefs, smoking and stress emerged as the most important risk factors, whereas all subjects graded passive smoking as a least important factor. In conclusion, similarities of the risk factors regarding ACS and ischemic stroke facilitate simultaneous primary prevention measures. PMID- 23628307 TI - Cardiac hemodynamics in men versus women during acute ST-segment elevation myocardial infarction. AB - Several biologic and clinical factors contribute to the increased 30-day mortality and re-infarction rate in women with ST-segment elevation myocardial infarction (STEMI). Sex differences in cardiac hemodynamic parameters such as pulmonary capillary wedge pressure (PCWP) have not been examined and might play an important role. The objectives of the present study were to examine whether female sex is an independent determinant of PCWP during acute STEMI and whether an elevated PCWP contributes to all-cause 30-day mortality and re-infarction in women. The clinical, angiographic, and hemodynamic features of 470 consecutive patients with STEMI (n = 135 women) undergoing emergency coronary angiography with right-side heart catheterization were evaluated with respect to sex. Women had an elevated PCWP (20 +/- 8 vs 16 +/- 7 mm Hg, p <0.001) and reduced mixed venous oxygen saturation (67 +/- 11% vs 71 +/- 9%, p = 0.004). On multivariate analysis, female sex (beta = 4.04, 95% confidence interval [CI] 2.04 to 6.04, p <0.001), hypertension (beta = 2.07, 95% CI 0.31 to 3.83, p = 0.021), and creatine kinase-estimated infarct size (beta = 0.001, 95% CI 0.001 to 0.002, p <=0.001) were independent predictors of an elevated PCWP. Female sex exerted a minor independent effect on 30-day mortality and re-infarction (odds ratio 2.36, 95% CI 1.25 to 4.46, p = 0.008). However, once PCWP was entered into the mediation model, sex was no longer significant, suggesting that the effect of sex on the post-STEMI outcomes is potentially mediated through PCWP (odds ratio 1.07, 95% CI 1.02 to 1.12, p = 0.011). In conclusion, during acute STEMI, women have greater left ventricular filling pressures compared with men, independent of age, hypertension, and infarct size. The biologic explanation for this difference requires additional investigation, although it does not appear to contribute to the increased 30-day mortality and re-infarction rate observed in women. PMID- 23628308 TI - Evaluation of anatomic and morphologic nomogram to predict malignant and high grade disease in a cohort of patients with small renal masses. AB - OBJECTIVE: To evaluate a nomogram using the RENAL Nephrometry Score (RENAL-NS) that was developed to characterize masses as benign vs. malignant and high vs. low grade in our patients with small renal masses treated with partial nephrectomy (PN). The nomogram was previously developed and validated in patients with widely variable tumor sizes. MATERIALS AND METHODS: Retrospective review of PN performed between 1/2003 and 7/2011. Imaging was reviewed by a urologic surgeon for RENAL-NS. Final pathology was used to classify tumors as benign or malignant and low (I/II) or high (III/IV) Fuhrman grade. Patient age, gender, and RENAL score were entered into the nomogram described by Kutikov et al. to determine probabilities of cancer and high-grade disease. Area under the curve was determined to assess agreement between observed and expected outcomes for prediction of benign vs. malignant disease and for prediction of high- vs. low grade or benign disease. RESULTS: A total of 250 patients with 252 masses underwent PN during the study period; 179/250 (71.6%) had preoperative imaging available. RENAL-NS was assigned to 181 masses. Twenty-two percent of tumors were benign. Eighteen percent of tumors were high grade. Area under the curve was 0.648 for predicting benign vs. malignant disease and 0.955 for predicting low grade or benign vs. high-grade disease. CONCLUSIONS: The RENAL-NS score nomogram by Kutikov does not discriminate well between benign and malignant disease for small renal masses. The nomogram may potentially be useful in identifying high grade tumors. Further validation is required where the nomogram probability and final pathologic specimen are available. PMID- 23628309 TI - Interferon alfa in the treatment paradigm for non-muscle-invasive bladder cancer. AB - OBJECTIVES: In this article, we review the various options for and the potential role of interferon alfa (IFN-alpha) in the treatment of non-muscle-invasive bladder cancer (NMIBC). METHODS: PubMed was searched for journal articles on IFN alpha use in treating bladder cancer. The references listed in the National Comprehensive Cancer Network guidelines were used as a guide to identify relevant publications on treatments for NMIBC. RESULTS: Transurethral resection with adjuvant intravesical chemotherapy or immunotherapy is the standard treatment option for NMIBC. Adjuvant IFN-alpha therapy has limited efficacy in preventing recurrences in intermediate-risk and high-risk patients; bacillus Calmette-Guerin (BCG) monotherapy is the recommended first-line treatment in these patients. Unfortunately, cancer progression or recurrence is a common outcome; radical cystectomy, which is often the lifesaving approach in such a scenario, is associated with significant morbidity, mortality, and decreased quality of life. Current alternatives to cystectomy include repeat intravesical immunotherapy, conventional instillation chemotherapy, and device-assisted intravesical chemotherapy. The efficacy of any chemotherapy after BCG failure, either conventional or device assisted, has not been established. BCG and IFN-alpha combination intravesical therapy has not been investigated thoroughly; based on available data, combination therapy appears to be most effective in patients with carcinoma in situ and may be preferentially considered as an alternative to radical cystectomy for patients with intermediate-risk or high-risk NMIBC who do not tolerate the standard BCG dose or experience BCG failure after 1 year of therapy. However, this approach requires close follow-up and should only be chosen after careful consideration of all risk factors. CONCLUSIONS: There is a lack of efficacious treatment options for patients with NMIBC recurrence or progression after initial BCG treatment. There is a need for well-designed clinical trials investigating the safety and efficacy of available therapies, including BCG and IFN-alpha2b combination therapy. PMID- 23628310 TI - Effect of the timing of orchiectomy on survival in patients with metastatic germ cell tumors of testis. AB - OBJECTIVES: Classically, orchiectomy (OE) is the first step of treatment in patients with metastatic germ cell tumors (mGCTs) of testis. However, some patients have severe symptoms of disease, which require immediate beginning of chemotherapy (CT) followed by OE. This retrospective analysis was performed to find the effect of time constraints of delayed OE on survival in patients with mGCT. METHODS AND MATERIALS: We analyzed the data of 1,483 CT-naive patients with advanced mGCT of the testis treated in our Department from 1986 to 2009. Delayed OE was performed on 71 (4.8%) patients: seminoma in 8 patients (11.2%), nonseminomatous tumor in 50 patients (70.4%), and unknown tumor histology in 13 patients (18.4%). Twenty percent, 40%, and 40% of patients belonged to good, intermediate, and poor International Germ Cell Cancer Consensus Group prognostic groups, respectively. Median time from the beginning of the CT to OE was 18 (range, 1-250) days. OE was performed on 39 (55%), 21 (29.5%), and 11 (15.5%) patients during cycle 1, cycle 2 to completion of CT, and after the finishing of induction CT, respectively. Median follow-up time was 156 (range, 3-241) months. Etoposide and cisplatin-based CTs were received by 66 patients (93%). RESULTS: Three-year overall survival (OS) of all 1,483 patients was 75%. An excellent primary tumor response to CT was observed among the patients, who had delayed OE after completion of CT (n = 11): only mature teratoma (n = 4) and tumor necrosis (n = 7) were found. The 3-year OS in patients with delayed OE was 63%. OE performed after completion of CT was associated with better prognosis. The 3-year OS in patients with delayed OE performed during the cycle 1 (group 1) was 67%, cycle 2 to completion of CT (group 2) was 39%, and after finishing of CT (group 3) was 88% (groups 1 vs. 3: hazard ratio 3.7, 95% confidence interval 0.69-10.1, P = 0.15; groups 2 vs. 3: P = 0.01, hazard ratio 8.1, 95% confidence interval 1.32-18.,72). It seems that if OE had been performed during CT, the beginning of the successive cycle was delayed and dose intensity of CT was decreased. CONCLUSIONS: In case of severe symptoms of disease, which require an immediate start of CT, performing OE simultaneously with other surgeries after completion of induction CT was associated with better OS, when compared with performing OE during induction CT. PMID- 23628311 TI - Inhibition of presenilins attenuates proliferation and invasion in bladder cancer cells through multiple pathways. AB - OBJECTIVE: Presenilin (PS)/gamma-secretase is a key protease that initiates various biological processes. We investigated the effect of PS/gamma-secretase on the expression and inhibition of urothelial cell carcinoma of bladder (UCB) as a potential alternative therapeutic target for UCB. MATERIALS AND METHODS: PS-1 and PS-2 were identified in normal and malignant human bladder transitional cells by immunohistochemistry. We blocked PSs using a PS/gamma-secretase inhibitor N-(N [3,5-difluorophenacetyl]-L-alanyl)-S-phenylglycine-t-butylester (DAPT), and the proliferative and invasive potential of UCB cells SW780, BIU-87, 5637, and T24, and human normal urothelial cell line SV-HUC-1 were analyzed using Western blot, cell viability test, flow cytometry, and transwell assay. All experiments were repeated at least 3 times. RESULTS: Human bladder samples of UCB, SW780, BIU-87, 5637, and T24 cells expressed higher PS-1 compared with normal ones. Cell vitality test demonstrated that DAPT attenuated UCB cell proliferation more than SV-HUC-1. Flow cytometry and transwell assay showed that T24 cells were arrested at G1/S checkpoint and its invasive ability was impaired. Western blot assay markedly showed that protein levels of CD44-intracellular domain, insulinlike growth factor-1Rbeta, extracellular regulated protein kinase 1/2, cyclin D1, proliferating cell nuclear antigen, and matrix metalloproteinase-9 were downregulated by DAPT, whereas vascular endothelial growth factor receptor-2 and vascular endothelial growth factor-165 were upregulated. CONCLUSIONS: Our study revealed that PS-1 might be implicated in the proliferation and invasion of UCB, and that it may serve as a potential therapeutic target for UCB, but further studies are warranted to verify the effects of inhibition of PS/gamma-secretase on angiogenesis. PMID- 23628312 TI - Independent prognostic factors for initial intravesical recurrence after laparoscopic nephroureterectomy for upper urinary tract urothelial carcinoma. AB - OBJECTIVE: To elucidate clinicopathologic independent prognostic factors for intravesical recurrence after laparoscopic nephroureterectomy for primary upper urinary tract urothelial carcinoma (UUT-UC). METHODS AND MATERIALS: This study included 212 consecutive patients clinically diagnosed as localized UUT-UC and treated by retroperitoneal laparoscopic nephroureterectomy between January 2002 and October 2010, after exclusion of those with a previous or concurrent history of bladder cancer. The clinicopathologic features, risk factors, and intravesical recurrence-free survival were analyzed using the Kaplan-Meier method. Univariate and multivariate analyses by Cox proportional hazards regression model was used to identify independent risk factors for intravesical tumor recurrence. RESULTS: Of the patients, 64/212 (30.2%) developed subsequent intravesical recurrence during a median follow-up period of 39 months (range 7-78 months). Among them, 56/64 (87.5%) developed recurrent bladder cancer within 2 years after the surgery for UUT-UC, and the median interval between surgery and intravesical recurrence was 14 months (range 7-51 months). Multifocal tumors, renal insufficiency, and immunosuppression were determined as risk factors for intravesical recurrence by univariate analysis. However, by multivariate analyses, multifocality (hazard ratio = 2.060, P = 0.006) and immunosuppression (hazard ratio = 1.915, P = 0.037) were identified as independent predictors for the development of recurrent bladder cancer. CONCLUSIONS: The incidence of intravesical recurrence after laparoscopic nephroureterectomy for UUT-UC is high, and most subsequent bladder cancers recur within 2 years after surgery. Tumor multifocality and immunosuppression are significant independent risk factors in developing initial intravesical recurrence after laparoscopic surgery for primary UUT-UC. PMID- 23628313 TI - Treating octogenarians with muscle-invasive bladder cancer: preoperative opportunities for increasing the benefits of surgical intervention. AB - The question posed to the authors is whether surgery is the best treatment option for octogenarians with invasive bladder cancer. Herein, we detail the rationale in favor of radical cystectomy and opportunities for improvement in the processes of care for those who may be surgical candidates. PMID- 23628314 TI - A replication study examining association of rs6983267, rs10090154, and rs1447295 common single nucleotide polymorphisms in 8q24 region with prostate cancer in Siberians. AB - INTRODUCTION: Multiple genetic studies have confirmed association of 8q24 variants with susceptibility to prostate cancer (CaP). However, the risk conferred in men living in Russia is unknown. MATERIALS AND METHODS: In this work we studied the association of rs6983267, rs10090154, and rs1447295 single nucleotide polymorphisms (SNPs) with a risk of CaP development in men of Caucasoid descent living in the Siberian region of Russia. Three 8q24 SNPs were genotyped by real-time polymerase chain reaction in histologically confirmed CaP "cases" (n = 392) and clinically evaluated "controls" (n = 344). To evaluate the SNP effects on CaP susceptibility, odds ratio (OR) and confidence interval (CI) 95% were calculated. Allele and genotype frequencies in the groups were compared using logistic regression; differences were considered statistically significant if P<0.05. RESULTS: We showed statistically significant association of the A allele of rs1447295 (OR [CI 95%] = 1.96 [1.37-2.81], P<0.0001) and the T allele of rs10090154 (OR [CI 95%] = 2.14 [1.41-3.26], P<0.0001) with CaP. The T-A rs10090154 to rs1447295 haplotype was also associated with CaP (OR [CI 95%] = 2.47 [1.59-3.85], P<0.0001). There was no significant association with the T allele of rs6983267: OR [CI 95%] = 0.9 [0.73-1.11], P> 0.05. CONCLUSION: Thus, our investigation confirms the role of chromosomal region 8q24 in the development of CaP in the Russian population. PMID- 23628315 TI - Unexplained cyanosis revealing hepatopulmonary syndrome in a child with asymptomatic congenital hepatic fibrosis: a case report. AB - INTRODUCTION: Hepatopulmonary syndrome is a rare disease that affects patients of any age with acute or chronic liver disease. Liver transplantation is the only therapeutic option of proved benefit, and can result in substantial improvement or total improvement in postoperative gas exchange abnormalities. CASE PRESENTATION: We report the case of a cyanotic 13-year-old Pakistani boy whose chest computed tomography scan showed normal lung fields and mediastinum with incidental findings of a prominent liver surface with a collateral vein connecting a portal cavernoma to the dilated terminal inferior vena cava. Sonography of his abdomen along with a portal venous Doppler study showed multiple collateral veins replacing the portal vein. A liver biopsy revealed congenital hepatic fibrosis. Contrast-enhanced echocardiography with agitated saline and a 99m Technetium-macroaggregated albumin perfusion lung scan confirmed intrapulmonary shunting. The patient underwent a successful liver transplantation that resulted in improved gas exchange. CONCLUSIONS: Hepatopulmonary syndrome should be included in the differential diagnosis of unexplained hypoxemia with an evaluation of possible portal hypertension or liver disease even in the absence of other clinical symptoms. PMID- 23628316 TI - Detection of concurrent atrial ischemia with continuous monitoring of dynamic PR segment changes in patients with acute myocardial infarction. AB - Despite its potential prognostic value concurrent atrial ischemia is often overlooked in patients with acute myocardial infarction (AMI). There is no study concerning the relationship between atrial coronary circulation and dynamic PR segment changes in patients with AMI. We evaluated dynamic PR-segment changes in 37 patients with AMI. The flow in the principal atrial coronary branches was diminished in 14 (38%) patients. Dynamic changes in the PR-segment level [median 47 (inter quartile range 19-55) MUV vs. 23 (18-30) MUV, P=0.005] and PR-segment area [3.15 (1.75-3.69) nVs vs. 1.62 (1.18-2.04) nVs, P=0.005] were significantly greater in patients with compromised than in those with normal flow in the atrial coronary branches. Our findings support the concept that atrial ischemia produces similar changes in the PR-segment as ventricular ischemia in the ST-segment. Given the possible deleterious consequences of atrial ischemia these data may have important clinical implications in evaluation of patient with AMI. PMID- 23628317 TI - Noninvasive finding of local repolarization changes in the heart using dipole models and simplified torso geometry. AB - Two inverse methods using dipole models for noninvasive assessment of local repolarization changes were investigated and compared in the simulation study. Lesions with changed repolarization were modeled by shortening of the action potential durations in ventricular regions typically influenced by occlusion of coronary arteries. Corresponding body surface potentials were computed using a multiple dipole model of the cardiac generator and an inhomogeneous torso model. Position of each lesion was then estimated by an inverse solution to a single dipole and to a group of five neighbouring dipoles. For both methods the lesion localization error was evaluated and its dependence on the lesion size and the noise in input data was studied. When no noise was present in the input data, the use of the inverse method to a group of dipoles instead of a single dipole resulted in an unsubstantial reduction of the mean localization error of small lesions from 0.6 to 0.5cm. For medium and especially for large lesions the mean localization errors decreased significantly from 1.1 to 0.6cm and from 2.3 to 1.0cm, respectively. The inverse solution to a group of five dipoles was more sensitive to noise. However, for large lesions it still gave better results than the solution to a single dipole if the signal to noise ratio was higher than 30dB. PMID- 23628318 TI - Linking TFT-LCD wastewater treatment performance to microbial population abundance of Hyphomicrobium and Thiobacillus spp. AB - This study investigated the linkage between performance of two full-scale membrane bioreactor (MBR) systems treating thin-film transistor liquid crystal display (TFT-LCD) wastewater and the population dynamics of dimethylsulfoxide (DMSO)/dimethylsulfide (DMS) degrading bacteria. High DMSO degradation efficiencies were achieved in both MBRs, while the levels of nitrification inhibition due to DMS production from DMSO degradation were different in the two MBRs. The results of real-time PCR targeting on DMSO/DMS degrading populations, including Hyphomicrobium and Thiobacillus spp., indicated that a higher DMSO oxidation efficiency occurred at a higher Hyphomicrobium spp. abundance in the systems, suggesting that Hyphomicrobium spp. may be more important for complete DMSO oxidation to sulfate compared with Thiobacillus spp. Furthermore, Thiobacillus spp. was more abundant during poor nitrification, while Hyphomicrobium spp. was more abundant during good nitrification. It is suggested that microbial population of DMSO/DMS degrading bacteria is closely linking to both DMSO/DMS degradation efficiency and nitrification performance. PMID- 23628319 TI - Analysis of chemical changes and microstructure characterization during deformation in ferritic stainless steel. AB - Uni- and biaxial tension deformation tests, with different degrees of deformation, have been done on AISI 430 (EN 1.4016) ferritic stainless steel samples, which had both different chemical compositions and had undergone different annealing treatments. The initial and deformed materials were characterized by using electron backscatter diffraction and backscatter electron imaging in a scanning electron microscope together with electron probe microanalysis. The correlation observed among the chemical compositions, annealing treatment, and strain level obtained after deformation is discussed. PMID- 23628320 TI - Serotype IV and invasive group B Streptococcus disease in neonates, Minnesota, USA, 2000-2010. AB - Group B Streptococcus (GBS) is a major cause of invasive disease in neonates in the United States. Surveillance of invasive GBS disease in Minnesota, USA, during 2000-2010 yielded 449 isolates from 449 infants; 257 had early-onset (EO) disease (by age 6 days) and 192 late-onset (LO) disease (180 at age 7-89 days, 12 at age 90-180 days). Isolates were characterized by capsular polysaccharide serotype and surface-protein profile; types III and Ia predominated. However, because previously uncommon serotype IV constitutes 5/31 EO isolates in 2010, twelve type IV isolates collected during 2000-2010 were studied further. By pulsed-field gel electrophoresis, they were classified into 3 profiles; by multilocus sequence typing, representative isolates included new sequence type 468. Resistance to clindamycin or erythromycin was detected in 4/5 serotype IV isolates. Emergence of serotype IV GBS in Minnesota highlights the need for serotype prevalence monitoring to detect trends that could affect prevention strategies. PMID- 23628321 TI - Multiparameter analyses of three-dimensionally cultured tumor spheroids based on respiratory activity and comprehensive gene expression profiles. AB - Multicellular spheroids of human breast cancer cells (MCF-7) formed with two different three-dimensional (3D) culture methods were evaluated in detail on the basis of respiratory activity and high-throughput gene expression analysis. The spheroids formed with poly(dimethylsiloxane) (PDMS) microwell arrays indicated significant restriction of the spheroid size, whereas their respiratory activity was 2-fold greater than that formed with the hanging drop culture method. Fluidigm BioMark dynamic array was used for comprehensive and quantitative real time polymerase chain reaction (qRT-PCR) analysis on the samples whose respiratory activity had been measured. Genes involved in cellular senescence and glucose metabolism indicated significantly higher values for the PDMS microwell culture method than for the hanging drop culture method (P<0.05). Interestingly, samples formed with the PDMS microwell culture method showed stronger responses for glycolysis than those formed with the hanging drop method. These results illustrate the power of multiparameter analysis to characterize multicellular spheroids cultured in different microenvironments even if they have the same morphology. PMID- 23628322 TI - The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study. AB - BACKGROUND & AIMS: The role of liver transplantation (LT) for the relief of fatigue in patients with primary biliary cirrhosis (PBC) is unclear, and while many centers exclude fatigue as an indication for transplantation, there have been no studies to prospectively evaluate the impact of LT on fatigue. We aimed at assessing the severity of fatigue in LT candidates with PBC and the impact of LT on fatigue. METHODS: In a prospective, longitudinal study, we used the PBC-40 questionnaire in 49 adult patients with PBC at listing and at 6, 12, and 24 months after LT and in two sex- and age-matched cohorts of community controls and non-transplanted PBC patients. Correlation analysis was used to assess the relationship between liver function and fatigue. ANOVA was used to compare the variation of fatigue score before and after LT. RESULTS: There was no correlation between MELD and fatigue before LT (r(2)=0.01). Overall, the fatigue score after LT was substantially lower than before LT, falling from 40.7 +/- 11.4 pre transplant to 27.7 +/- 9.5, 28.7 +/- 10.1, 26.2 +/- 10.1 (p<0.0001) at 6, 12, and 24 months after LT, respectively. The same improvement of fatigue was observed in both low-MELD (<17) and high-MELD (>= 17) patients. Improvement in fatigue was also evident in the comparison with a "non-transplant PBC" control group (31.1 +/ 11.6, p=0.03). However, 44% of the total cohort, and 47% of those with low-MELD, for whom the probability of dying of LT may be higher than that of dying without LT, had moderate to severe fatigue (defined as a fatigue score >= 29) at two years after LT. Moreover, fatigue scores at two years were higher in the transplant PBC cohort compared to a cohort of community controls (17.8 +/- 5.9, p<0.0001). CONCLUSIONS: Liver transplantation is associated with improvement in fatigue in patients with PBC. However, a substantial proportion of patients continue to suffer from significant fatigue after two years. Whether the improvement is enough to justify organ allocation in patients with fatigue alone, without liver failure, is still an open issue. Certainly, in the era of organ shortage, with many patients dying waiting for a graft, this may not represent the optimal use of donated deceased organs. PMID- 23628323 TI - Transcriptomic analysis provides insights on hexavalent chromium induced DNA double strand breaks and their possible repair in midgut cells of Drosophila melanogaster larvae. AB - Hexavalent chromium [Cr(VI)] is a well known mutagen and carcinogen. Since genomic instability due to generation of double strand breaks (DSBs) is causally linked to carcinogenesis, we tested a hypothesis that Cr(VI) causes in vivo generation of DSBs and elicits DNA damage response. We fed repair proficient Drosophila melanogaster (Oregon R(+)) larvae Cr(VI) (20.0MUg/ml) mixed food for 24 and 48h and observed a significant (p<0.05) induction of DSBs in their midgut cells after 48h using neutral Comet assay. Global gene expression profiling in Cr(VI)-exposed Oregon R(+) larvae unveiled mis-regulation of DSBs responsive repair genes both after 24 and 48h. In vivo generation of DSBs in exposed Drosophila was confirmed by an increased pH2Av immunostaining along with the activation of cell cycle regulation genes. Analysis of mis-regulated genes grouped under DSB response by GOEAST indicated the participation of non homologous end joining (NHEJ) DSB repair pathway. We selected two strains, one mutant (ligIV) and another ku80-RNAi (knockdown of ku80), whose functions are essentially linked to NHEJ-DSB repair pathway. As a proof of principle, we compared the DSBs generation in larvae of these two strains with that of repair proficient Oregon R(+). Along with this, DSBs generation in spn-A and okr [essential genes in homologous recombination repair (HR) pathway] mutants was also tested for the possible involvement of HR-DSB repair. A significantly increased DSBs generation in the exposed ku80-RNAi and ligIV (mutant) larvae because of impaired repair, concomitant with an insignificant DSBs generation in okr and spn-A mutant larvae indicates an active participation of NHEJ repair pathway. The study, first of its kind to our knowledge, while providing evidences for in vivo generation of DSBs in Cr(VI) exposed Drosophila larvae, assumes significance for its relevance to higher organisms due to causal link between DSB generation and Cr(VI)-induced carcinogenesis. PMID- 23628324 TI - Genetic polymorphisms of CYP2E1, GST, and NAT2 enzymes are not associated with risk of breast cancer in a sample of Lebanese women. AB - Changes in the activity of drug metabolizing enzymes (DMEs) are potentially associated with cancer risk. This relationship is attributed to their involvement in the bioactivation of multiple procarcinogens or the metabolism of multiple substrates including an array of xenobiotics and environmental carcinogens. 326 Lebanese women of whom 99 were cancer free (controls) and 227 were diagnosed with breast cancer (cases) were included. Blood for DNA was collected and medical charts were reviewed. Three genotyping methods were employed including: (1) restriction fragment length polymorphism (RFLP) for CYP2E1*5B, CYP2E1*6, NAT2*5 and NAT2*6; (2) gel electrophoresis for GSTM1 and GSTT1; and (3) real-time PCR for GSTP1 Ile/Val polymorphism. We analyzed the relationship between genetic susceptibilities in selected xenobiotic metabolizing genes and breast cancer risk. Allele frequencies were fairly similar to previously reported values from neighboring populations with relevant migration routes. There were no statistically significant differences in the distribution of variant carcinogen metabolizing genes between cases and controls even after adjusting for age at diagnosis, menopausal status, smoking, and alcohol intake. Despite its limitations, this is the first study that assesses the role of genetic polymorphisms in DMEs with breast cancer in a sample of Lebanese women. Further studies are needed to determine the genetic predisposition and gene-environment interactions of breast cancer in this population. PMID- 23628325 TI - EVAR deployment in anatomically challenging necks outside the IFU. AB - OBJECTIVE: Treatment of abdominal aortic aneurysms with high-risk anatomy (neck length <10-15 mm, neck angle >60 degrees ) using commercially available devices has become increasingly common with expanding institutional experience. We examined whether placement of approved devices in short angled necks provides acceptable durability at early and intermediate time points. METHODS: A total of 218 patients (197 men, 21 women) at a single academic center underwent endovascular aneurysm repair (EVAR) with a commercially available device between January 2004 and December 2007. Available medical records, pre- and postoperative imaging, and clinical follow-up were retrospectively reviewed. Patients were divided into those with suitable anatomy (instructions for use, IFU) for EVAR and those with high-risk anatomic aneurysm characteristics (non-IFU). RESULTS: IFU (n = 143) patients underwent repair with Excluder (40%), AneuRx (34%), and Zenith (26%) devices, whereas non-IFU (n = 75) were preferentially treated with Zenith (57%) over Excluder (25%) and AneuRx (17%). Demographics and medical comorbidities between the groups were similar. Operative mortality was 1.4% (2.1% IFU, 0% non-IFU) with mean follow-up of 35 months (range 12-72). Non-IFU patients tended to have larger sac diameters (46.7% >=60 mm) with shorter (30.7% <=10 mm), conical (49.3%), and more angled (68% >60 degrees ) necks (all p < .05 compared with IFU patients). Operative characteristics revealed that the non-IFU patients were more likely to be treated utilizing suprarenal fixation devices, to require placement of proximal cuffs (13.3% vs. 2.1%, p = .003), and needed increased fluoroscopy time (31 vs. 25 minutes, p = .02). Contrast dose was similar between groups (IFU = 118 mL, non-IFU = 119 mL, p = .95). There were no early or late surgical conversions. Rates of migration, endoleak, need for reintervention, sac regression, and freedom from aneurysm-related death were similar between the groups (p > .05). CONCLUSIONS: EVAR may be performed safely in high-risk patients with unfavorable neck anatomy using particular commercially available endografts. In our experience, the preferential use of active suprarenal fixation and aggressive use of proximal cuffs is associated with optimal results in these settings. Mid-term outcomes are comparable with those achieved in patients with suitable anatomy using a similar range of EVAR devices. Careful and mandatory long-term follow-up will be necessary to confirm the benefit of treating these high-risk anatomic patients. PMID- 23628326 TI - Commentary on 'EVAR deployment in anatomically challenging necks outside the IFU'. PMID- 23628327 TI - Re. 'Great saphenous vein diameter at the saphenofemoral junction and proximal thigh as parameters of venous disease class'. PMID- 23628328 TI - Short and long term mortality rates after a lower limb amputation. AB - OBJECTIVE: To determine mortality rates after a first lower limb amputation and explore the rates for different subpopulations. METHODS: Retrospective cohort study of all people who underwent a first amputation at or proximal to transtibial level, in an area of 1.7 million people. Analysis with Kaplan-Meier curves and Log Rank tests for univariate associations of psycho-social and health variables. Logistic regression for odds of death at 30-days, 1-year and 5-years. RESULTS: 299 people were included. Median time to death was 20.3 months (95%CI: 13.1; 27.5). 30-day mortality = 22%; odds of death 2.3 times higher in people with history of cerebrovascular disease (95%CI: 1.2; 4.7, P = 0.016). 1 year mortality = 44%; odds of death 3.5 times higher for people with renal disease (95%CI: 1.8; 7.0, P < 0.001). 5-years mortality = 77%; odds of death 5.4 times higher for people with renal disease (95%CI: 1.8; 16.0,P = 0.003). Variation in mortality rates was most apparent in different age groups; people 75-84 years having better short term outcomes than those younger and older. CONCLUSIONS: Mortality rates demonstrated the frailty of this population, with almost one quarter of people dying within 30-days, and almost half at 1 year. People with cerebrovascular had higher odds of death at 30 days, and those with renal disease and 1 and 5 years, respectively. PMID- 23628329 TI - Is coronary artery disease complexity valuable in the prediction of contrast induced nephropathy besides Mehran risk score, in patients with ST elevation myocardial infarction treated with primary percutaneous coronary intervention? AB - BACKGROUND: The association of coronary artery disease complexity with contrast induced nephropathy (CIN) in patients with acute ST segment elevation myocardial infarction (STEMI) is inadequately evaluated and to our knowledge the association between SYNTAX score (SS) and Mehran score (MS) have not been studied. The aim of the present study is to clarify the incidence of CIN and to identify demographic, clinical and procedural variables associated with CIN in patients who underwent primary percutaneous coronary intervention (PPCI) due to acute STEMI, besides the association between MS and SS with CIN. METHODS: We analysed the clinical data of 402 patients (309 male, 93 female, mean age 63.8 +/- 12.65 year) with 179 (44.5%) anterior MI, 104 (25.9%) inferior MI, 119 (29.6%) inferior MI with right ventricular involvement who underwent PPCI. RESULTS: We found that CIN was observed in 32.6% of patients. The SS (OR=1.037, %95CI=1.012-1.062, p=0.003), MS (OR=1.072, %95CI=1.025-1.121, p=0.003), HDL (OR=0.974, %95CI=0.949-0.999, p=0.044) were the independent predictors of CIN. The cut off value to show CIN for SS was 31.5 (sensitivity=79.4%, specificity=88.6%) and MS was 12.5 (sensitivity=73.3%, specificity=88.9%) in ROC curve analysis. CONCLUSION: In conclusion, besides MS, SS may be a valuable marker to identify patients at high risk for CIN in patients undergoing primary percutaneous intervention. PMID- 23628330 TI - Unexpected sequel of chronic Q-fever endocarditis. AB - We report a patient with chronic Q-fever endocarditis who was treated with Bentall procedure on two occasions due to persistent endocarditis. A chronic pseudoaneurysm of the aortic root was discovered incidentally by cardiac magnetic resonance and computed tomography eight years post-operatively. Due to chronicity of the pseudoaneurysm and great risk of re-intervention, conservative management was recommended. PMID- 23628331 TI - Evaluation of gender differences in Door-to-Balloon time in ST-elevation myocardial infarction. AB - BACKGROUND: A delayed Door-to-Balloon (DTB) time in women with ST-elevation myocardial infarction (STEMI) has been associated with an increased mortality. The objectives of this study were to (a) quantify the components of the delayed DTB time in women and (b) assess the independent effect of gender on DTB time in patients undergoing percutaneous coronary intervention (PCI) for STEMI. METHODS: Clinical parameters were prospectively collected for 735 STEMI patients undergoing primary PCI from 2006 to 2010, with particular attention to the components of DTB time, including the onset of chest pain and the 'code' notification of the STEMI team by the Emergency Department. RESULTS: Women were significantly older with more co-morbidity. Upon hospital arrival they also experienced delays in Door-to-Code (23 vs. 17 min, P=.012), Code-to-Balloon (63 vs. 57 min, P=.001) and thus DTB time (88 vs. 72 min, P=.001). After multivariate adjustment, independent determinants of DTB time included female gender (ratio of geometric means [RGM]=1.13; 95% CI 1.02-1.26; P=.022), hypertension (RGM=1.12, 95% CI 1.02-1.23, P=.014), maximum ST-elevation (RGM=0.97, 95% CI 0.94-0.98, P<.001), office hours (RGM=0.84, 95% CI 0.78-0.92, P<.001) and triage category (RGM=1.23, 95% CI 1.09-1.40, P=.001). CONCLUSIONS: Women experience delays in identification of the STEMI diagnosis and also in the PCI process. Thus a multifaceted approach addressing both the diagnosis and management of STEMI in women is required. PMID- 23628332 TI - Anti-adipogenic activity of compounds isolated from Idesia polycarpa on 3T3-L1 cells. AB - Recently, obesity is a complex multifactorial chronic disease increasing the risk for type 2 diabetes, coronary heart disease and hypertension, and has become a major worldwide health problem. In the course of screening natural products employing 3T3-L1 cells as an in vitro system, the methanol extract of Idesia polycarpa Maxim. Fruits (Flacourtiaceae) significantly inhibited adipocyte differentiation by measuring lipid contents using oil red O staining. One new compound, 6-(oxymethyl)-2-hydroxyphenyl-O-beta-D-glucopyranosyl-(1->6)-beta-D glucopyranoside (8), was isolated along with nine known compounds (1-7 and 9-10) from CHCl3 and n-BuOH fractions of the methanol extract of I. polycarpa fruits. Among them, idescarpin (1) with 1-hydroxy-6-oxo-2-cyclohexenecarboxylate moiety showed the most potent inhibitory activity on adipocyte differentiation with IC50 values of 23.2 MUM. Idescarpin (1) dramatically suppressed the induction of C/EBPalpha expression, whereas it significantly increased the induction of PPARgamma expression, supported by quantitative real time PCR and Western blot analysis. The down-regulation in mRNA levels of SREBP1c, SCD-1, and FAS by idescarpin (1) during adipocyte differentiation revealed that the inhibition of adipocyte differentiation was mediated by the regulation of lipogenesis. Taken together, we suggest that idescarpin (1) shows a great potential against obesity and diabetes though the anti-adipogenic activity and the up-regulation of PPARgamma. PMID- 23628333 TI - Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase. AB - A novel 2-thio-6-oxo-1,6-dihydropyrimidine-containing inhibitor of human lactate dehydrogenase (LDH) was identified by high-throughput screening (IC50=8.1 MUM). Biochemical, surface plasmon resonance, and saturation transfer difference NMR experiments indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of the screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.48 MUM). A crystal structure of an optimized compound bound to human LDHA was obtained and explained many of the observed structure-activity relationships. PMID- 23628334 TI - Evaluation of EGFR-targeted radioimmuno-gold-nanoparticles as a theranostic agent in a tumor animal model. AB - This study evaluated the tumor targeting and therapeutic efficacy of a novel theranostic agent (131)I-labeled immuno-gold-nanoparticle ((131)I-C225-AuNPs-PEG) for high epidermal growth factor receptor (EGFR)-expressed A549 human lung cancer. Confocal microscopy demonstrated the specific uptake of C225-AuNPs-PEG in A549 cells. (131)I-C225-AuNPs-PEG induced a significant reduction in cell viability, which was not observed when incubated with AuNPs-PEG and C225-AuNPs PEG. MicroSPECT/CT imaging of tumor-bearing mice after intravenous injection of (123)I-C225-AuNPs-PEG revealed significant radioactivity retention in tumor suggested that (131)I-labeled C225-conjugated radioimmuno-gold-nanoparticles may provide a new approach of targeted imaging and therapy towards high EGFR expressed cancers. PMID- 23628335 TI - Synthesis and in vitro cytotoxicity of andrographolide-19-oic acid analogues as anti-cancer agents. AB - The synthesis of a series of andrographolide-19-oic acid derivatives was described and their in vitro anti-tumor activity against two human cell lines was evaluated. Most compounds were found to exhibit significant cytotoxicity, better than andrographolide, and compounds 9d and 9b were identified as the most potent with IC50 values of 1.18 and 6.28 MUm against HCT-116 and MCF-7 cell lines, respectively. The preliminary results indicated that the oxidation of C-19 hydroxyl group of andrographolide to corresponding carboxyl group and the subsequent esterification of the formed carboxylic acid led to considerable improvement in cytotoxicity against the cancer cells. PMID- 23628336 TI - Conformational restriction in a series of GPR119 agonists: differences in pharmacology between mouse and human. AB - A series of conformationally restricted GPR119 agonists were prepared based around a 3,8-diazabicyclo[3.2.1]octane scaffold. Examples were found to have markedly different pharmacology in mouse and human despite similar levels of binding to the receptor. This highlights the large effects on GPCR phamacology that can result from small structural changes in the ligand, together with inter species differences between receptors. PMID- 23628337 TI - Gross margin losses due to Salmonella Dublin infection in Danish dairy cattle herds estimated by simulation modelling. AB - Salmonella Dublin affects production and animal health in cattle herds. The objective of this study was to quantify the gross margin (GM) losses following introduction and spread of S. Dublin within dairy herds. The GM losses were estimated using an age-structured stochastic, mechanistic and dynamic simulation model. The model incorporated six age groups (neonatal, pre-weaned calves, weaned calves, growing heifers, breeding heifers and cows) and five infection stages (susceptible, acutely infected, carrier, super shedder and resistant). The effects of introducing one S. Dublin infectious heifer were estimated through 1000 simulation iterations for 12 scenarios. These 12 scenarios were combinations of three herd sizes (85, 200 and 400 cows) and four management levels (very good, good, poor and very poor). Input parameters for effects of S. Dublin on production and animal health were based on literature and calibrations to mimic real life observations. Mean annual GMs per cow stall were compared between herds experiencing within-herd spread of S. Dublin and non-infected reference herds over a 10-year period. The estimated GM losses were largest in the first year after infection, and increased with poorer management and herd size, e.g. average annual GM losses were estimated to 49 euros per stall for the first year after infection, and to 8 euros per stall annually averaged over the 10 years after herd infection for a 200 cow stall herd with very good management. In contrast, a 200 cow stall herd with very poor management lost on average 326 euros per stall during the first year, and 188 euros per stall annually averaged over the 10-year period following introduction of infection. The GM losses arose from both direct losses such as reduced milk yield, dead animals, treatment costs and abortions as well as indirect losses such as reduced income from sold heifers and calves, and lower milk yield of replacement animals. Through sensitivity analyses it was found that the assumptions about milk yield losses for cows in the resistant or carrier stages had the greatest influence on the estimated GM losses. This was more influential in the poorer management scenarios due to increased number of infected cows. The results can be used to inform dairy farmers of the benefits of preventing introduction and controlling spread of S. Dublin. Furthermore, they can be used in cost-benefit analyses of control actions for S. Dublin both at herd and sector level. PMID- 23628338 TI - Understanding sources of sea lice for salmon farms in Chile. AB - The decline of fisheries over recent decades and a growing human population has coincided with an increase in aquaculture production. As farmed fish densities increase, so have their rates of infectious diseases, as predicted by the theory of density-dependent disease transmission. One of the pathogen that has increased with the growth of salmon farming is sea lice. Effective management of this pathogen requires an understanding of the spatial scale of transmission. We used a two-part multi-scale model to account for the zero-inflated data observed in weekly sea lice abundance levels on rainbow trout and Atlantic salmon farms in Chile, and to assess internal (farm) and external (regional) sources of sea lice infection. We observed that the level of juvenile sea lice was higher on farms that were closer to processing plants with fish holding facilities. Further, evidence for sea lice exposure from the surrounding area was supported by a strong positive correlation between the level of juvenile sea lice on a farm and the number of gravid females on neighboring farms within 30 km two weeks prior. The relationship between external sources of sea lice from neighboring farms and juvenile sea lice on a farm was one of the strongest detected in our multivariable model. Our findings suggest that the management of sea lice should be coordinated between farms and should include all farms and processing plants with holding facilities within a relatively large geographic area. Understanding the contribution of pathogens on a farm from different sources is an important step in developing effective control strategies. PMID- 23628339 TI - Differential expression of microRNAs in exhaled breath condensates of patients with asthma, patients with chronic obstructive pulmonary disease, and healthy adults. PMID- 23628340 TI - The chitinase-like protein YKL-40: a possible biomarker of inflammation and airway remodeling in severe pediatric asthma. AB - BACKGROUND: Problematic severe childhood asthma includes a subgroup of patients who are resistant to therapy. The specific mechanisms involved are unknown, and novel biomarkers are required to facilitate treatment and diagnosis of therapy resistant asthma. The chitinase-like protein YKL-40 has been related to asthma and airway remodeling. OBJECTIVES: To compare serum YKL-40 levels in children with severe, therapy-resistant asthma (n = 34), children with controlled persistent asthma (n = 39), and healthy controls (n = 27), and to investigate correlations with biomarkers of inflammation and airway remodeling. METHODS: The study protocol included questionnaires, measurement of exhaled nitric oxide in exhaled air, blood sampling for inflammatory biomarkers, and high-resolution computed tomography of the lungs to identify bronchial wall thickening (therapy resistant only). Serum YKL-40 levels were measured by ELISA, and all asthmatic children were genotyped for a CHI3L1 promoter single nucleotide polymorphism (rs4950928). RESULTS: Serum YKL-40 levels were significantly higher in children with therapy-resistant asthma than in healthy children (19.2 ng/mL vs 13.8 ng/mL, P = .03). Among children with severe, therapy-resistant asthma, YKL-40 levels correlated with fraction of exhaled nitric oxide in exhaled air (r = 0.48, P = .004), blood neutrophils (r = 0.63, P < .001), and bronchial wall thickening on high-resolution computed tomography (r = 0.45, P = .01). Following adjustment for CHI3L1 genotype, significantly greater levels of YKL-40 were found in children with therapy-resistant asthma than in children with controlled asthma. CONCLUSIONS: YKL-40 levels are increased in children with severe, therapy resistant asthma compared to healthy children, and also compared to children with controlled asthma following correction for genotype. PMID- 23628341 TI - Do rapid infant growth and childhood asthma have common developmental origins? PMID- 23628342 TI - Consortia-mediated bioprocessing of cellulose to ethanol with a symbiotic Clostridium phytofermentans/yeast co-culture. AB - BACKGROUND: Lignocellulosic ethanol is a viable alternative to petroleum-based fuels with the added benefit of potentially lower greenhouse gas emissions. Consolidated bioprocessing (simultaneous enzyme production, hydrolysis and fermentation; CBP) is thought to be a low-cost processing scheme for lignocellulosic ethanol production. However, no single organism has been developed which is capable of high productivity, yield and titer ethanol production directly from lignocellulose. Consortia of cellulolytic and ethanologenic organisms could be an attractive alternate to the typical single organism approaches but implementation of consortia has a number of challenges (e.g., control, stability, productivity). RESULTS: Ethanol is produced from alpha cellulose using a consortium of C. phytofermentans and yeast that is maintained by controlled oxygen transport. Both Saccharomyces cerevisiae cdt-1 and Candida molischiana "protect" C. phytofermentans from introduced oxygen in return for soluble sugars released by C. phytofermentans hydrolysis. Only co-cultures were able to degrade filter paper when mono- and co-cultures were incubated at 30 degrees C under semi-aerobic conditions. Using controlled oxygen delivery by diffusion through neoprene tubing at a calculated rate of approximately 8 MUmol/L hour, we demonstrate establishment of the symbiotic relationship between C. phytofermentans and S. cerevisiae cdt-1 and maintenance of populations of 105 to 106 CFU/mL for 50 days. Comparable symbiotic population dynamics were observed in scaled up 500 mL bioreactors as those in 50 mL shake cultures. The conversion of alpha-cellulose to ethanol was shown to improve with additional cellulase indicating a limitation in hydrolysis rate. A co-culture of C. phytofermentans and S. cerevisiae cdt-1 with added endoglucanase produced approximately 22 g/L ethanol from 100 g/L alpha-cellulose compared to C. phytofermentans and S. cerevisiae cdt-1 mono-cultures which produced approximately 6 and 9 g/L, respectively. CONCLUSION: This work represents a significant step toward developing consortia-based bioprocessing systems for lignocellulosic biofuels production which utilize scalable, environmentally-mediated symbiosis mechanisms to provide consortium stability. PMID- 23628343 TI - Clinical and biochemical aspects of primary and secondary hyperammonemic disorders. AB - An increased concentration of ammonia is a non-specific laboratory sign indicating the presence of potentially toxic free ammonia that is not normally removed. This does occur in many different conditions for which hyperammonemia is a surrogate marker. Hyperammonemia can occur due to increased production or impaired detoxification of ammonia and should, if associated with clinical symptoms, be regarded as an emergency. The conditions can be classified into primary or secondary hyperammonemias depending on the underlying pathophysiology. If the urea cycle is directly affected by a defect of any of the involved enzymes or transporters, this results in primary hyperammonemia. If however the function of the urea cycle is inhibited by toxic metabolites or by substrate deficiencies, the situation is described as secondary hyperammonemia. For removal of ammonia, mammals require the action of glutamine synthetase in addition to the urea cycle, in order to ensure lowering of plasma ammonia concentrations to the normal range. Independent of its etiology, hyperammonemia may result in irreversible brain damage if not treated early and thoroughly. Thus, early recognition of a hyperammonemic state and immediate initiation of the specific management are of utmost importance. The main prognostic factors are, irrespective of the underlying cause, the duration of the hyperammonemic coma and the extent of ammonia accumulation. This paper will discuss the biochemical background of primary and secondary hyperammonemia and will give an overview of the various underlying conditions including a brief clinical outline and information on the genetic backgrounds. PMID- 23628344 TI - In situ thickness assessment during ion milling of a free-standing membrane using transmission helium ion microscopy. AB - We describe a novel method for in situ measurement of the local thickness of a freely suspended solid-state membrane after thinning with a focused helium ion beam. The technique utilizes a custom stage for the helium ion microscope that allows the secondary electron detector used for normal imaging to collect information from ions transmitted through the sample. We find that relative brightness in the transmission image scales directly with the membrane thickness as determined by atomic force microscopy measurements. PMID- 23628345 TI - NMDA receptors and memory encoding. AB - It is humbling to think that 30 years have passed since the paper by Collingridge, Kehl and McLennan showing that one of Jeff Watkins most interesting compounds, R-2-amino-5-phosphonopentanoate (d-AP5), blocked the induction of long term potentiation in vitro at synapses from area CA3 of the hippocampus to CA1 without apparent effect on baseline synaptic transmission (Collingridge et al., 1983). This dissociation was one of the key triggers for an explosion of interest in glutamate receptors, and much has been discovered since that collectively contributes to our contemporary understanding of glutamatergic synapses - their biophysics and subunit composition, of the agonists and antagonists acting on them, and their diverse functions in different networks of the brain and spinal cord. It can be fairly said that Collingridge et al.'s (1983) observation was the stimulus that has led, on the one hand, to structural biological work at the atomic scale describing the key features of NMDA receptors that enables their coincidence function to happen; and, on the other, to work with whole animals investigating the contributions that calcium signalling via this receptor can have on rhythmical activities controlled by spinal circuits, memory encoding in the hippocampus (the topic of this article), visual cortical plasticity, sensitization in pain, and other functions. In this article, I lay out how my then interest in long-term potentiation (LTP) as a model of memory enabled me to recognise the importance of Collingridge et al.'s discovery - and how I and my colleagues endeavoured to take things forward in the area of learning and memory. This is in some respects a personal story, and I tell it as such. The idea that NMDA receptor activation is essential for memory encoding, though not for storage, took time to develop and to be accepted. Along the way, there have been confusions, challenges, and surprises surrounding the idea that activation of NMDA receptors can trigger memory. Some of these are described and how they have been addressed and resolved. Last, I touch on some new directions of interest with respect to the functional role of the NMDA receptor in cognition. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. PMID- 23628347 TI - Impact of limited cognitive capacity and feelings of guilt and excuse on the endowment effects for hedonic and utilitarian types of foods. AB - Consumer food choices may partly be explained by the endowment effect. Here, we focus on the influence of limited cognitive capacity on loss aversion related to food choices. We also investigate the effects of anticipated feelings on food choices. Experiments with 1614 pupils of secondary schools show that both cognitive constraint and anticipated feelings increases the overall endowment effect and that the impact of limited cognition is stronger for hedonic than for utilitarian food products. PMID- 23628346 TI - Transmission of hepatitis E virus from rabbits to cynomolgus macaques. AB - The recent discovery of hepatitis E virus (HEV) strains in rabbits in the People's Republic of China and the United States revealed that rabbits are another noteworthy reservoir of HEV. However, whether HEV from rabbits can infect humans is unclear. To study the zoonotic potential for and pathogenesis of rabbit HEV, we infected 2 cynomolgus macaques and 2 rabbits with an HEV strain from rabbits in China. Typical hepatitis developed in both monkeys; they exhibited elevated liver enzymes, viremia, virus shedding in fecal specimens, and seroconversion. Comparison of the complete genome sequence of HEV passed in the macaques with that of the inoculum showed 99.8% nucleotide identity. Rabbit HEV RNA (positive- and negative-stranded) was detectable in various tissues from the experimentally infected rabbits, indicating that extrahepatic replication may be common. Thus, HEV is transmissible from rabbits to cynomolgus macaques, which suggests that rabbits may be a new source of human HEV infection. PMID- 23628348 TI - Long-term treatment with deferiprone enhances left ventricular ejection function when compared to deferoxamine in patients with thalassemia major. AB - Transfusion and iron chelation treatment have significantly reduced morbidity and improved survival of patients with thalassemia major. However, cardiac disease continues to be the most common cause of death. We report the left-ventricular ejection fraction, determined by echocardiography, in one hundred sixty-eight patients with thalassemia major followed for at least 5years who received continuous monotherapy with deferoxamine (N=108) or deferiprone (N=60). The statistical analysis, using the generalized estimating equations model, indicated that the group treated with deferiprone had a significantly better left ventricular ejection fraction than did those treated with deferoxamine (coefficient 0.97; 95% CI 0.37; 1.6, p=0.002). The heart may be particularly sensitive to iron-induced mitochondrial damage because of the large number of mitochondria and its low level of antioxidants. Deferiprone, because of its lower molecular weight, might cross into heart mitochondria more efficiently, improving their activity and, thereby, myocardial cell function. Our findings indicate that the long-term administration of deferiprone significantly enhances left ventricular function over time in comparison with deferoxamine treatment. However, because of limitations related to the design of this study, these findings should be confirmed in a prospective, randomized clinical trial. PMID- 23628349 TI - Cataract extraction outcomes and the prevalence of zonular insufficiency in retinitis pigmentosa. AB - PURPOSE: To examine surgical outcomes in patients with retinitis pigmentosa (RP) undergoing phacoemulsification cataract extraction. DESIGN: Retrospective observational case series. PATIENTS AND METHODS: In this single-institution study of consecutive RP patients who underwent phacoemulsification cataract extraction and intraocular lens implantation by a single surgeon between 2002 and 2012, preoperative, intraoperative, and postoperative records were analyzed with attention to best-corrected visual acuity (BCVA), lens and zonular status, capsular tension ring use, incidence of posterior capsular opacification and neodymium-doped yttrium-aluminum-garnet (YAG) laser capsulotomy, and surgical complications. RESULTS: Eighty eyes of 47 RP patients (21 male) underwent cataract surgery during the study period at an average age of 48.9 years (range, 31-78 years). Mean follow-up time was 23.3 months (range, 1 day - 95 months). Posterior subcapsular cataracts were present in 97.5% of patients. Mean BCVA improved from 20/340 (logarithm of the minimal angle of resolution [logMAR] 1.23) to 20/129 (0.81) within 3 months of surgery, P < .0001. Eyes with a preoperative vision of 20/40 to 20/200 (47 eyes) improved from a mean of 20/81 (logMAR 0.61) preoperatively to 20/43 (0.33), P < .0001, postoperatively. Posterior capsule opacification occurred in 66 eyes (82.5%), and 42 eyes (52.5%) underwent a YAG laser capsulotomy at a mean of 10.8 months after surgery. Fifteen eyes (18.8%) of 10 patients (21.3%) had signs of phacodonesis (3 eyes noted preoperatively, 8 intraoperatively, and 4 postoperatively). One patient had bilateral dislocated in the-bag intraocular lenses at 5.5 years and 6 years after surgery. CONCLUSION: Cataract surgery yields significantly improved Snellen visual acuity in a majority of RP patients with a preoperative vision of 20/200 or better. Conversely, patients with a preoperative visual acuity of 20/400 or worse generally have more limited objective improvements, likely because of macular involvement, but usually report noticeable subjective improvement. A high prevalence of zonular instability is seen in RP patients undergoing cataract extraction. It is therefore important to conduct a careful preoperative assessment of lens stability with preparation for adjunctive methods that augment intraoperative and postoperative lens stabilization. PMID- 23628350 TI - Ocular biometric parameters associated with intraocular pressure reduction after cataract surgery in normal eyes. AB - PURPOSE: To evaluate the ocular biometric parameters associated with intraocular pressure (IOP) reduction after phacoemulsification. DESIGN: Prospective, observational case series. METHODS: The study included 999 patients who had undergone uncomplicated phacoemulsification. IOP and ocular biometric parameters were checked preoperatively and 3 months postoperatively using anterior segment optical coherence tomography, optical biometry, and ultrasonic biomicroscopy. The relationship between IOP change and the parameters, including preoperative IOP, anterior chamber depth, axial length, angle opening distance at 500 MUm, anterior chamber area, corneal thickness, lens thickness, and iris thickness at 750 MUm, was evaluated. RESULTS: The mean patient age was 67.1 +/- 4.3 years. The average change in IOP was -1.6 mm Hg (-11.8%). In univariate analysis, axial length, corneal thickness, and iris thickness were not significantly associated with IOP reduction. However, preoperative IOP, anterior chamber depth, angle opening distance, anterior chamber area, and lens thickness were significantly associated with IOP change (P < .05). Furthermore, changes in anterior chamber depth (standardized coefficient beta [B] = -0.082), angle opening distance (B = 0.095), and anterior chamber area (B = -0.380) were more strongly correlated with IOP change than were preoperative factors (B = -0.078, B = -0.071, and B = 0.067, respectively). In multivariate analysis, preoperative IOP, lens thickness, angle opening distance change, and anterior chamber area change were significantly associated with IOP change (P < .005). CONCLUSION: In addition to preoperative IOP and lens thickness, parameters such as changes in anterior chamber area and angle opening distance were significantly associated positively with reduced IOP after phacoemulsification. PMID- 23628351 TI - The short- and long-term effects on the visual system of children following exposure to maternal substance misuse in pregnancy. AB - PURPOSE: To document the prevalence of ophthalmic morbidities in babies born to mothers who misused substances in pregnancy and to assess whether it changes over 5 years. DESIGN: Retrospective comparative case series. METHODS: The series included: (1) a retrospective review of 301 children born between 2000 and 2004 to mothers misusing substances during pregnancy; (2) assessment at 5-year follow up of this cohort; and (3) comparison with 7887 age-matched controls drawn from the preschool screening cohort in the north of Scotland in the same time period. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. Following data collection in both patient and control groups, the following were calculated: (1) rate of referral to the ophthalmology department; (2) prevalence of nystagmus and strabismus at presentation in the study group and at 5 years of age in both patient and control group; (3) prevalence of reduced visual acuity and lack of stereopsis. RESULTS: Ophthalmology referrals, strabismus, and nystagmus were found to be statistically significantly higher in the study group compared with the control group. In the study group, at baseline referral, 46 of 301 (15.3%) had strabismus (2.8% in control group) and 11 of 301 (3.7%) nystagmus (0.004% in control group). At 5-year follow-up, the prevalence of strabismus was 14.0% (OR 5.70, 95% CI: 4.01-8.12) and that of nystagmus was 3.3% (OR 90.34, 95% CI 24.73-330.02). A total of 42.4% of these children at age 5 had no demonstrable binocular vision and 28.2% had visual acuity of 0.3 (logMAR) or worse in 1 or both eyes. Clinic attendance at last follow-up was poor (61.9%). CONCLUSIONS: Exposure to maternal drug misuse in utero is associated with a statistically significantly higher prevalence of strabismus and nystagmus. These abnormalities tend to persist at 5 years of age and are associated with long-term visual morbidity, such as lack of binocularity and poor visual acuity. Our study highlights the need for ophthalmologic surveillance of this population and supports attendance, as nonattendance may be linked to more problems with substance misuse in parents and greater pathology in the child. PMID- 23628352 TI - Sentinel lymph node biopsy in malignant eyelid tumor: hybrid single photon emission computed tomography/computed tomography and dual dye technique. AB - PURPOSE: To study the utility of hybrid single photon emission computed tomography / computed tomography (SPECT/CT) scan and dual-dye technique in identification of the sentinel lymph node (SLN) in patients with an advanced malignant eyelid tumor. DESIGN: Nonrandomized prospective interventional study. METHODS: setting: A tertiary eye care center. study population: Patients with an advanced malignant eyelid tumor without clinically involved regional lymph nodes. intervention: SLN biopsy was performed using dual-dye technique (a combination of radiotracer and vital blue dye) following localization by SPECT/CT. main outcome measures: Localization of SLN in the regional node basin by hybrid SPECT/CT scan; SLN identification rate using dual-dye technique; SLN positivity rate; false negative rate; and complications, if any, of SLN biopsy. RESULTS: Sixteen patients of biopsy-proven eyelid malignancy (7 squamous cell carcinomas [43.75%], 5 sebaceous cell carcinomas [31.25%], and 4 malignant melanomas [25%]) were included in the study. Preoperative localization of SLN was performed using SPECT/CT in 12 patients. SLN biopsy using dual-dye technique was performed in 16 patients. SPECT/CT accurately localized SLN in 11 out of 12 patients. The preauricular region was the most common site of SLN. SLN identification rates for dual-dye, radiotracer, and blue dye techniques were 100% (16/16 patients), 100% (16/16 patients), and 87.5% (14/16 patients), respectively. SLN showed metastasis in 2 patients (12.5%). On follow-up, 1 patient developed cervical lymph node metastasis, thus giving a false-negative rate of 7.14%. There were no complications associated with SLN biopsy. CONCLUSION: Accurate preoperative localization of SLN in relation to adjacent anatomic structures using SPECT/CT aids in intraoperative identification of SLN. SLN biopsy should be considered in patients with eyelid tumors at significant risk for metastasis who have clinically negative nodal basins. Dual-dye technique is safe and feasible in advanced eyelid tumors. Blue dye technique can be used for SLN biopsy in settings where nuclear medicine facilities are not available, albeit with a lower SLN identification rate. Detection of metastasis in SLNs in ~12% of cases emphasizes the utility of SLN biopsy in accurate staging and treatment of eyelid malignancies. PMID- 23628353 TI - Incidence and progression of epiretinal membranes in eyes after cataract surgery. AB - PURPOSE: To assess eye-specific epiretinal membrane (ERM) incidence 3 years after phacoemulsification surgery, and ERM detection bias attributable to cataract. DESIGN: Cohort study. METHODS: We recruited 1932 cataract surgical patients aged >=64 years at Westmead Hospital (2004-2007). The surgical eye of each patient was assessed for presence of cellophane reflex or preretinal fibrosis at preoperative and 1-month-postoperative visits, and annually thereafter, using retinal image grading. Agreement on ERM detection between preoperative and 1-month postoperative visits was assessed using kappa statistics. Cumulative incidence of ERM from 1 month to 3 years postoperatively was estimated using Kaplan-Meier methods and compared to the 5-year incidence of idiopathic ERM in right eyes of age-matched Blue Mountains Eye Study (BMES) participants. RESULTS: ERM prevalence was 13.9% among 1394 participants with retinal photographs taken 1 month postoperatively. Of 1040 participants with retinal photographs from both preoperative and 1-month-postoperative visits, ERM was detected in 3.1% and 14.8%, respectively, with low diagnostic agreement (kappa = 0.17). Of 1119 subjects without ERM 1 month post surgery, the 3-year cumulative incidence of ERM was 11.2% (95% confidence interval [CI], 9.4%-13.4%; cellophane reflex 6.6%; preretinal fibrosis 4.2%). The age-standardized 3-year incidence of ERM in the surgical cohort (12.1%, 95% CI 8.6%-16.9%) was higher than the 5-year incidence of the BMES subsample (4.4%, 95% CI 3.0%-6.0%). CONCLUSIONS: A substantial under detection of ERM in eyes before cataract surgery could incorrectly contribute to ERM incidence after surgery. Over 3 years, ERM developed in >10%, including preretinal fibrosis in 4%, of surgical eyes free of ERM 1 month post surgery. PMID- 23628354 TI - Comparisons of outcomes with different intervals between adjunctive ranibizumab and photodynamic therapy for polypoidal choroidal vasculopathy. AB - PURPOSE: To determine the optimal time for administration of intravitreal ranibizumab injections before photodynamic therapy (PDT) as combined therapy to treat polypoidal choroidal vasculopathy (PCV). DESIGN: Retrospective, comparative, interventional case series. METHODS: The study included 99 eyes (98 patients) with treatment-naive subfoveal PCV treated with an intravitreal ranibizumab injection followed by PDT. The combination therapy included 1 ranibizumab injection administered 7 days before PDT (7-day group) or 2 days before PDT (2-day group). All eyes were followed for over 12 months. RESULTS: Intravitreal ranibizumab was administered 7 days before PDT in 59 eyes and 2 days before PDT in 40 eyes. In the 7-day group, the best-corrected visual acuity (BCVA) did not improve significantly at 3 months (P = .086) or 12 months (P = .259) compared with baseline. In the 2-day group, BCVA improved significantly at 3 months (P < .001) and 12 months (P < .001). The polypoidal lesions regressed completely in 46 eyes (78.0%) in the 7-day group and in 34 eyes (85.0%) in the 2 day group; 38 eyes (64.4%) and 35 eyes (87.5%), respectively, did not require additional treatment, which differed significantly (P = .008) between the 2 groups. Subretinal hemorrhages did not develop in either group within 1 month after the combined therapy. CONCLUSIONS: Administration of an intravitreal ranibizumab injection 2 days before PDT achieves significantly better visual outcomes and requires fewer additional treatments compared with administration of the injection 7 days before PDT. PMID- 23628355 TI - Refractory idiopathic thrombocytopenic purpura treated with immunoadsorption using tryptophan column. AB - The treatment of refractory idiopathic thrombocytopenia in adult is a challenge. Here we report successful treatment of an adult ITP patient with immunoadsorption using tryptophan column who were refractory to steroids, splenectomy, eltrombopag and various immunosuppressive medications. PMID- 23628356 TI - Bone marrow processing for transplantation using Cobe Spectra cell separator. AB - Concentration of bone marrow aspirates is an important prerequisite prior to infusion of ABO incompatible allogeneic marrow and prior to cryopreservation and storage of autologous marrow. In this paper we present our experience in processing 15 harvested bone marrow for ABO incompatible allogeneic and autologous bone marrow (BM) transplantation using Cobe Spectra(r) cell separator. BM processing resulted in the median recovery of 91.5% CD34+ cells, erythrocyte depletion of 91% and volume reduction of 81%. BM processing using cell separator is safe and effective technique providing high rate of erythrocyte depletion and volume reduction, and acceptable recovery of the CD34+ cells. PMID- 23628357 TI - Predicting the successful peripheral blood stem cell harvesting. AB - Several previously defined factors affecting the mobilization success include age, prior chemotherapy lines, exposure to myelotoxic agents, extended field radiotherapy and bone marrow infiltration with the primary disease. The purpose of this study was to retrospectively analyze the influence of the predictive factors for a successful peripheral stem cell mobilization. We enrolled a total of 145 patients into the study (non-Hodgkin lymphoma (n: 40), Hodgkin lymphoma (n: 36), myeloma (n: 64), solid tumors (n:5)) who received autologous stem cell transplantation between 2009 and 2012. In multivariate analysis only platelet count was found to be related with mobilization outcome (p<0.05). Knowing predictive factors for successful mobilization may be useful to define the best timing for mobilization and the most appropriate mobilizing agents for proper patient population. PMID- 23628358 TI - Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis. AB - Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness. We sequenced RYR1 in 39 unrelated families with rhabdomyolysis and/or exertional myalgia, frequent presentations in the neuromuscular clinic that often remain unexplained despite extensive investigations. We identified 9 heterozygous RYR1 mutations/variants in 14 families, 5 of them (p.Lys1393Arg; p.Gly2434Arg; p.Thr4288_Ala4290dup; p.Ala4295Val; and p.Arg4737Gln) previously associated with MH. Index cases presented from 3 to 45 years with rhabdomyolysis, with or without exertional myalgia (n=12), or isolated exertional myalgia (n=2). Rhabdomyolysis was commonly triggered by exercise and heat and, less frequently, viral infections, alcohol and drugs. Most cases were normally strong and had no personal MH history. Inconsistent additional features included heat intolerance, and cold-induced muscle stiffness. Muscle biopsies showed mainly subtle changes. Familial RYR1 mutations were confirmed in relatives with similar or no symptoms. These findings suggest that RYR1 mutations may account for a substantial proportion of patients presenting with unexplained rhabdomyolysis and/or exertional myalgia. Associated clinico-pathological features may be subtle and require a high degree of suspicion. Additional family studies are paramount in order to identify potentially MH susceptible relatives. PMID- 23628359 TI - Object use affects motor planning in infant prehension. AB - The purpose of this study was to investigate the factors underlying the ability to plan object-oriented grasping movements in the first two years of life. In particular, we were interested in evaluating the relationship between manual motor planning, object use and infant-parent interaction. In order to achieve this aim, grasping behaviors of nineteen healthy infants, aged nine to 25 months, were examined during naturalistic play sessions with a standard set of toys. Our main finding was that, regardless of age, infants perform a better manual planning when they use an object in a functional rather than non-functional way, suggesting that the planning of an action also depends on knowing the functional properties of an object. In addition, we found that the ability to use objects in a functional way was strongly affected by infant-parent interaction. Thus, level of object use and environmental role must be taken into account in order to understand the development of manual motor planning. PMID- 23628360 TI - Postural sway in volleyball players. AB - The aim of this work was to analyze the postural sway of volleyball players in bipedal quiet stance. The center of pressure (CoP) was measured in 46 athletes and 42 non-athlete controls. Each subject was tested in 10 different conditions, 5 with their eyes open and 5 with their eyes closed. Volleyball players showed greater CoP ellipses, suggesting a different model of sensory integration in their postural stability. A multivariate approach to data analysis demonstrated that the postural sway of the two groups was different when the subjects kept their eyes open, but it was not with visual deprivation. This could partially be explained by the better 'dynamic' visual acuity of athletes, since possible ('static') refractive errors were corrected for both groups. Furthermore, we expected that national players, engaged in more intensive training programs, were more different from controls than regional ones, and that defensive players, whose role requires the quickest reaction times, were more different from controls than hitters. Our results confirmed these hypothesis. The protocol presented might be useful to assess the efficacy of intensive sport training programs and/or to select elite players with an aptitude for a specific playing position. PMID- 23628361 TI - Unilateral and bilateral fatiguing contractions similarly alter postural stability but differently modify postural position on bipedal stance. AB - The aim of the present study was to compare the effects of unilateral and bilateral muscle fatigue on bipedal postural control and neuromuscular activities. Nineteen subjects completed bilateral fatiguing contractions (BI group), and seventeen subjects completed unilateral fatiguing contractions (UNI group) of the quadriceps femoris. Postural control, maximal voluntary contraction (MVC) and central activation ratio (CAR) were measured before and after the completion of fatiguing tasks for both groups. Postural control was evaluated by using a force platform, which recorded the center of foot pressure (COP). MVC was quantified with an ergometer and CAR was determined with the superimposed electrical stimulation technique. Spatio-temporal COP parameters were used to evaluate postural stability (displacements of COP) and postural position (coordinates of COP) and a frequency analysis of COP excursions (wavelet transform) was performed to estimate the contribution of different neuronal loops. Postural stability, MVC and CAR were similarly affected after unilateral and bilateral fatiguing contractions. Moreover, the impairment of postural position was higher after unilateral fatiguing contractions than after bilateral fatiguing contractions. The study's results indicated that unilateral and bilateral fatigue equally disturbs postural control as well as central drive. However, unilateral muscle fatigue creates postural asymmetries while bilateral muscle fatigue does not engender any. PMID- 23628363 TI - Reply: comments on "The effects of vaccination on serum hormone concentrations and conception rates in synchronized naive beef heifers". PMID- 23628362 TI - Phosphoproteomics data classify hematological cancer cell lines according to tumor type and sensitivity to kinase inhibitors. AB - BACKGROUND: Tumor classification based on their predicted responses to kinase inhibitors is a major goal for advancing targeted personalized therapies. Here, we used a phosphoproteomic approach to investigate biological heterogeneity across hematological cancer cell lines including acute myeloid leukemia, lymphoma, and multiple myeloma. RESULTS: Mass spectrometry was used to quantify 2,000 phosphorylation sites across three acute myeloid leukemia, three lymphoma, and three multiple myeloma cell lines in six biological replicates. The intensities of the phosphorylation sites grouped these cancer cell lines according to their tumor type. In addition, a phosphoproteomic analysis of seven acute myeloid leukemia cell lines revealed a battery of phosphorylation sites whose combined intensities correlated with the growth-inhibitory responses to three kinase inhibitors with remarkable correlation coefficients and fold changes (> 100 between the most resistant and sensitive cells). Modeling based on regression analysis indicated that a subset of phosphorylation sites could be used to predict response to the tested drugs. Quantitative analysis of phosphorylation motifs indicated that resistant and sensitive cells differed in their patterns of kinase activities, but, interestingly, phosphorylations correlating with responses were not on members of the pathway being targeted; instead, these mainly were on parallel kinase pathways. CONCLUSION: This study reveals that the information on kinase activation encoded in phosphoproteomics data correlates remarkably well with the phenotypic responses of cancer cells to compounds that target kinase signaling and could be useful for the identification of novel markers of resistance or sensitivity to drugs that target the signaling network. PMID- 23628364 TI - Plasma concentrations of PGFM and uterine and ovarian responses in early lactation dairy cows fed omega-3 and omega-6 fatty acids. AB - A total of 120 dairy cows were assigned randomly to three diets to determine the effects of omega-6 or omega-3 fatty acid (FA) supplementation on uterine diseases, ovarian responses, and blood concentrations of estradiol, progesterone, and PGFM in lactating Holstein dairy cows. Diets contained either protected palm oil (C), extruded linseed (L), or roasted whole soybeans (S), and they were fed from calving to Day 70 postpartum. Estrous cycles were synchronized and ovarian follicular development was monitored daily for an entire cycle. There were no differences among diets in the incidence of lameness, mastitis, or metritis, but the incidence of clinical endometritis was lower (P < 0.05) in cows fed S (0%) compared with cows fed C (28.2%) and L (20.5%). Uterine involution in cows fed S occurred 3.77 and 2.78 days earlier, respectively, than in those fed C and L. The PGFM response 60 minutes after an oxytocin challenge was highest for cows fed S and lowest for cows fed L. Mean plasma progesterone concentration on Day 15 of the synchronized cycle was higher in cows fed S (14.5 ng/mL) and L (15.0 ng/mL) than in those fed C (12.0 ng/mL). The ovulatory follicle on Day 21 of the estrous cycle (estrous = Day 0) was larger in cows fed S (16.1 +/- 0.9 mm) and L (15.7 +/ 0.7 mm) compared with cows fed C (13.2 +/- 0.87 mm; P = 0.02) but there were no significant differences between cows fed diets S and L. The mean number of small and medium follicles and diameter of subordinate follicle were similar among diets. In conclusion, feeding a source of omega-6 FA can be a strategy to improve uterine health after calving, although a source of omega-3 FA such as L should be fed after uterine involution to decrease PGF2alpha secretion. PMID- 23628365 TI - Who is this person? A comparison study of current three-dimensional facial approximation methods. AB - Facial approximation is a common tool utilised in forensic human identification. Three-dimensional (3D) imaging technologies allow researchers to go beyond traditional clay models to now create virtual computed models of anatomical structures. The goal of this study was to compare the accuracy of available methods of facial approximation ranging from clay modelling to advanced computer facial approximation techniques. Two computerised reconstructions (FaceIT and FBI's ReFace) and two manual reconstructions (completed by FBI's Neville and Faraut) were completed using a skull from a known individual. A living individual's computed tomography (CT) scan was used to create a virtual 3D model of the skull and soft tissue of the face. The virtual skull models were provided to the computer-based approximation specialists. A rapid prototype of the skull was printed and provided to the practitioners who needed physical specimens. The results from all of the methods (clay and virtual) were compared visually to each other and collectively to the actual features of the living individual to compare the results of each. A quantitative study was also conducted to establish the accuracy of each method and the regions of the face that need the most improvement for all of the specialists. This project demonstrates the wide range of variation between commonly used facial identification methods. The benefit of this study was having a living individual to test the strengths and weaknesses of each method while also providing future areas of focus for soft tissue depth data studies. PMID- 23628366 TI - Iliofemoral deep vein thrombosis after tibial plateau fracture fixation related to undiagnosed May-Thurner syndrome: a case report. AB - BACKGROUND: May-Thurner Syndrome (MTS) represents an anatomic variation of the iliac vessels, in which the left common iliac vein is compressed by an overriding iliac artery. Patients with this abnormality are predisposed to the formation of a left-sided iliofemoral deep venous thrombosis (DVT). While DVT is a familiar complication in the setting of lower extremity trauma, there are no previous reports of MTS complicating the care of patients requiring orthopaedic surgery. CASE PRESENTATION: We present the case of an extensive limb-threatening DVT in a patient with previously undiagnosed MTS, resulting after internal fixation of a left tibial plateau fracture. Four days after surgery, despite standard prophylactic anticoagulation, the patient developed an extensive occlusive DVT, extending from the common iliac vein to the popliteal vein. Successful diagnosis required a CT venogram in addition to standard lower extremity ultrasound exam. Severe lower extremity edema continued to worsen despite formal anticoagulation. Urgent mechanical thrombolysis was undertaken, followed by staged catheter directed thrombolysis with recombinant tissue plasminogen activator (rTPA) and intraluminal stenting. Following this treatment, the patient was noted to have gradual but dramatic resolution of his lower extremity edema and swelling. CONCLUSION: The present case demonstrates the potential danger that may accompany MTS in the setting of lower extremity trauma. When an extensive left lower extremity DVT complicates the care of a patient with extremity trauma, clinicians should have a low threshold to pursue the diagnosis of MTS with advanced imaging studies. Venography remains the gold standard in diagnosis, but CT and MRI venography are less invasive and should allow for accurate diagnosis. In this case, formal anticoagulation proved to be ineffective, and endovascular intervention was required. PMID- 23628367 TI - Joint principles of motor and cognitive dysfunction in Parkinson's disease. AB - Traditionally, the lateral premotor cortex (PM) is assigned a role in stimulus driven rather than memory-driven motor control, whereas the opposite holds for the mesial premotor cortex (supplementary motor area, SMA). Consistently, patients with Parkinson's Disease (PD), in which a specific functional degradation of the mesial loop (i.e., SMA-Striatum) occurs, show impaired memory driven but relatively preserved stimulus-driven motor control. However, both parts of the premotor cortex are involved in perceptual prediction tasks as well. Here we tested whether the functional bias described on the motor level (i.e., memory-driven/mesial versus stimulus-driven/lateral) can also be detected in perceptual prediction tasks thereby suggesting that PD patients exhibit the same pattern of impaired memory-driven and preserved stimulus-driven control in the cognitive domain. To this end, we investigated 20 male PD-patients "on" and "off" dopaminergic medication while performing a serial prediction task (SPT). A specific modification was implemented to the classical SPT (SPT0) that caused shifts from stimulus- to memory-based prediction (SPT+). As a result, PD patients showed a significantly impaired performance "off" compared to "on" medication for SPT+, whereas no significant "on"/"off"-effects were found for SPT0. Descriptively, the "off"-performance decreased gradually with increasing demands on memory-based prediction. Furthermore, the severity of motor deficits according to the UPDRS III correlated significantly with impaired performance in SPT0 "on" medication. Importantly, an even stronger dependency was found for UPDRS III and SPT+. These findings point to a role of the SMA-striatal loop in memory-driven serial prediction beyond the motor domain. PMID- 23628368 TI - Characterizing the morphosyntactic processing deficit and its relationship to phonology in developmental dyslexia. AB - This study explores the morphosyntactic processing deficit in developmental dyslexia, addressing the on-going debate on the linguistic nature of the disorder, and directly testing the hypothesis that the deficit is based on underlying processing difficulties, such as acoustic and/or phonological impairments. Short German sentences consisting of a pronoun and a verb, either correct or containing a morphosyntactic violation, were auditorily presented to 17 German-speaking adults with dyslexia, and 17 matched control participants, while an EEG was recorded. In order to investigate the interaction between low level phonological processing and morphosyntactic processing, the verbal inflections were manipulated to consist of different levels of acoustic salience. The event-related potential (ERP) results confirm altered morphosyntactic processing in participants with dyslexia, especially when morphosyntactic violations are expressed by both lexical and inflectional changes. Moreover, ERP data on phoneme discrimination and behavioural data on phonemic awareness and verbal short-term memory reveal phonological deficits in dyslexic participants. However, a causal relationship between phonological and morphosyntactic processing was not conclusive, because anomalous morphosyntactic processing in dyslexia is not directly mediated by acoustic salience, rather it correlates with high-level phonological skills and is mediated by lexical cues. PMID- 23628369 TI - The lateralization of gustatory function and the flow of information from tongue to cortex. AB - Controversy surrounds whether crossed and/or uncrossed fibers carry taste information from tongue to cortex and whether there is hemispheric specialization for gustatory processing. The current study examined these issues in 14 patients with unilateral insula lesions, seven with right-sided and seven with left-sided damage, and in 42 healthy controls. Two tasks were carried out, with tastants applied unilaterally to the tongue tip: (1) taste discrimination; and (2) stimulus sampling followed by judgments of quality, intensity, hedonics and name recognition, for sweet, salty, bitter and sour tastants. Controls were better at discriminating tastants applied to their right tongue tip relative to their left, and better at taste quality judgments when tastants were applied to their left tongue tip relative to their right. Insula lesions to the left or right side resulted in bilateral impairments in discrimination, quality judgments and naming, when compared to controls. However, the Left insula group was poorer on tasks involving salt, and for ipsilateral hedonic judgments, relative to controls and the Right insula group. These findings are consistent with gustatory information ascending from tongue to cortex both ipsilaterally and contralaterally, and provide preliminary support for hemispheric gustatory specialization. PMID- 23628370 TI - A framework for collecting inclusive design data for the UK population. AB - Successful inclusive product design requires knowledge about the capabilities, needs and aspirations of potential users and should cater for the different scenarios in which people will use products, systems and services. This should include: the individual at home; in the workplace; for businesses, and for products in these contexts. It needs to reflect the development of theory, tools and techniques as research moves on. And it must also to draw in wider psychological, social, and economic considerations in order to gain a more accurate understanding of users' interactions with products and technology. However, recent research suggests that although a number of national disability surveys have been carried out, no such knowledge currently exists as information to support the design of products, systems and services for heterogeneous users. This paper outlines the strategy behind specific inclusive design research that is aimed at creating the foundations for measuring inclusion in product designs. A key outcome of this future research will be specifying and operationalising capability, and psychological, social and economic context measures for inclusive design. This paper proposes a framework for capturing such information, describes an early pilot study, and makes recommendations for better practice. PMID- 23628371 TI - Trefoil factor 2 expression and its significance as a predictor of severity of sepsis in children. AB - Intestinal injury significantly contributes to critical illness, sepsis and multiorgan failure. TFF2 (Trefoil Factor 2) is expressed and secreted preferentially by gastric mucous neck cells. TFF2 gene expression is promptly increased after gut injury, and its expression profile broadens to include the regenerative epithelia of virtually the entire gastrointestinal tract. The first objective of our study was an analysis of TFF2 levels dynamics in patients with Systemic Inflammatory Response Syndrome (SIRS) or septic condition during a 5-day period after admission. The second objective was to determine optimal cut-off value and quantify diagnostic characteristics of TFF2 between controls and patients with various septic states. The study included 57 children aged 0-19 years, with expected or proven SIRS and septic condition. The degree of severity was evaluated according to PELOD Score (Pediatric Logistic Organ Dysfunction). Blood samples to determine levels of TFF2 factor were taken during the time patient met the criteria of SIRS or sepsis. Control group samples to determine the serum levels of TFF2 were taken from patients undergoing elective surgery. Analysis of TFF2 levels dynamics revealed that TFF2 levels kept steady state during the 5-day period. Significantly higher levels of TFF2 were in patients with Multiple Organ Dysfunction Syndrome (MODS). The difference was noticed also in ROC analysis. PMID- 23628372 TI - Role of oxytocin in energy metabolism. AB - The basic mechanisms that lead obesity are not fully understood; however, several peptides undoubtedly play a role in regulating body weight. Obesity, a highly complex metabolic disorder, involves central mechanisms that control food intake and energy expenditure. Previous studies have shown that central or peripheral oxytocin administration induces anorexia. Recently, in an apparent discrepancy, rodents that were deficient in oxytocin or the oxytocin receptor were shown to develop late-onset obesity without changing their total food intake, which indicates the physiological importance of oxytocin to body metabolism. Oxytocin is synthesized not only within magnocellular and parvocellular neurons but also in several organs, including the ovary, uterus, placenta, testis, thymus, kidney, heart, blood vessels, and skin. The presence of oxytocin receptors in neurons, the myometrium and myoepithelial cells is well recognized; however, this receptor has also been identified in other tissues, including the pancreas and adipose tissue. The oxytocin receptor is a typical class I G protein-coupled receptor that is primarily linked to phospholipase C-beta via Gq proteins but can also be coupled to other G proteins, leading to different functional effects. In this review, we summarize the present knowledge of the effects of oxytocin on controlling energy metabolism, focusing primarily on the role of oxytocin on appetite regulation, thermoregulation, and metabolic homeostasis. PMID- 23628373 TI - Abrupt intracardiac growth of a Wilms tumor. PMID- 23628374 TI - Symptom severity predicts prolonged recovery after sport-related concussion, but age and amnesia do not. AB - OBJECTIVE: To identify predictors of prolonged symptoms in athletes who sustain concussions. STUDY DESIGN: This was a multicenter prospective cohort study of patients in 2 sport concussion clinics. Possible predictors of prolonged symptoms from concussion were compared in 2 groups, those whose symptoms resolved within 28 days and those whose symptoms persisted beyond 28 days. Candidate predictor variables were entered into a logistic regression model that was used to generate aORs. RESULTS: A total of 182 patients met the inclusion criteria during the study period. The mean patient age was 15.2 +/- 3.04 years. More than one-third of the patients (n = 65) underwent computerized neurocognitive testing on their initial visit. On univariate analyses, Post-Concussion Symptom Scale (PCSS) score and all composite scores on computerized neurocognitive testing were apparently associated with prolonged symptom duration. Sex, age, loss of consciousness at time of injury, and amnesia at time of injury were not associated with prolonged symptom duration. After adjusting for potential confounding, only total PCSS score was associated with the odds of suffering prolonged symptoms. CONCLUSION: Further efforts to develop clinical tools for predicting which athletes will suffer prolonged recoveries after concussion should focus on initial symptom score. PMID- 23628376 TI - Description and nomenclature of Neisseria meningitidis capsule locus. AB - Pathogenic Neisseria meningitidis isolates contain a polysaccharide capsule that is the main virulence determinant for this bacterium. Thirteen capsular polysaccharides have been described, and nuclear magnetic resonance spectroscopy has enabled determination of the structure of capsular polysaccharides responsible for serogroup specificity. Molecular mechanisms involved in N. meningitidis capsule biosynthesis have also been identified, and genes involved in this process and in cell surface translocation are clustered at a single chromosomal locus termed cps. The use of multiple names for some of the genes involved in capsule synthesis, combined with the need for rapid diagnosis of serogroups commonly associated with invasive meningococcal disease, prompted a requirement for a consistent approach to the nomenclature of capsule genes. In this report, a comprehensive description of all N. meningitidis serogroups is provided, along with a proposed nomenclature, which was presented at the 2012 XVIIIth International Pathogenic Neisseria Conference. PMID- 23628375 TI - The impact of short stature on health-related quality of life in children with chronic kidney disease. AB - OBJECTIVES: To compare the health-related quality of life (HRQoL) of children with chronic kidney disease (CKD) and short stature (SS) with that of children with CKD and normal height (NH), to evaluate the impact of catch-up growth and growth hormone (GH) use on HRQoL, and to describe the concordance of perceptions of HRQoL between children with SS and NH and their parents. STUDY DESIGN: Four hundred eighty-three children and/or parents enrolled in the multicenter Chronic Kidney Disease in Children study who had completed the Pediatric Quality of Life Inventory (Version 4.0) on at least 2 Chronic Kidney Disease in Children study visits composed this substudy population. Participants were dichotomized into NH or SS groups. The demographic characteristics that varied at baseline (sex, glomerular filtration rate, and parent education) were controlled for in the main analysis evaluating the impact of catch-up growth and use of GH on HRQoL. RESULTS: Multivariate modeling (controlling for confounding variables) revealed a significant association between both catch-up growth and GH use on parent-proxy reports of child physical functioning (P < .05) and social functioning (P < .05). Older children with CKD (15-17 years old) had significantly higher ratings than their parents on the Pediatric Quality of Life Inventory Physical, Emotional, Social, and School Functioning scales compared with younger children (8-14 years old). CONCLUSION: The finding that height gains and GH use are associated with increases in physical and social functioning by parent report provides additional support for interventions to improve height in children with CKD. The importance of evaluating both the parent and child perceptions of HRQoL is supported by our results. PMID- 23628378 TI - Comparison of intra-articular hyaluronic acid injections with transcutaneous electric nerve stimulation for the management of knee osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: To compare the effects of intra-articular hyaluronic acid (HA; ARTZ) and transcutaneous electric nerve stimulation (TENS) in the treatment of patients with knee osteoarthritis. DESIGN: A prospective, randomized controlled trial. SETTING: Rehabilitation clinic of a teaching hospital. PARTICIPANTS: Patients with knee osteoarthritis (N=50; aged 51-80y) were randomly assigned to the HA group (n=27) or the TENS group (n=23). INTERVENTIONS: The HA group received intra articular HA injection into the affected knee once a week for 5 consecutive weeks, and the TENS group received a 20- minute session of TENS 3 times a week for 4 consecutive weeks. MAIN OUTCOME MEASURES: The primary outcome measures used were the visual analog scale (VAS) for pain and the Lequesne index. The secondary outcome measures were range of motion of the knee, walking time, pain threshold, patient global assessment, and disability in activities of daily living. All subjects were assessed at baseline, and at 2 weeks, 2 months, and 3 months after the treatments were completed. RESULTS: The TENS group exhibited a significantly greater improvement in VAS than the HA group at 2 weeks' follow-up (4.17 +/- 1.98 vs 5.31 +/- 1.78, respectively; P=.03). In addition, the TENS group also exhibited a significantly greater improvement in the Lequesne index than the HA group at 2 weeks' follow-up (7.78 +/- 2.08 vs 9.85 +/- 3.54, respectively; P=.01) and at 3 months' follow-up (7.07 +/- 2.85 vs 9.24 +/- 4.04, respectively; P=.03). CONCLUSIONS: TENS with silver spike point electrodes was observed to be more effective than intra-articular HA injection for patients with knee osteoarthritis in improving the VAS for pain at 2 weeks' follow-up as well as the Lequesne index at 2 weeks' and 3 months' follow-up. PMID- 23628377 TI - Effects of intramuscular trunk stimulation on manual wheelchair propulsion mechanics in 6 subjects with spinal cord injury. AB - OBJECTIVE: To quantify the effects of stabilizing the paralyzed trunk and pelvis with electrical stimulation on manual wheelchair propulsion. DESIGN: Single subject design case series with subjects acting as their own concurrent controls. SETTING: Hospital-based clinical biomechanics laboratory. PARTICIPANTS: Individuals (N=6; 4 men, 2 women; mean age +/- SD, 46 +/- 10.8y) who were long time users (6.1 +/- 3.9y) of implanted neuroprostheses for lower extremity function and had chronic (8.6 +/- 2.8y) midcervical- or thoracic-level injuries (C6-T10). INTERVENTIONS: Continuous low-level stimulation to the hip (gluteus maximus, posterior adductor, or hamstrings) and trunk extensor (lumbar erector spinae and/or quadratus lumborum) muscles with implanted intramuscular electrodes. MAIN OUTCOME MEASURES: Pushrim kinetics (peak resultant force, fraction effective force), kinematics (cadence, stroke length, maximum forward lean), and peak shoulder moment at preferred speed over 10-m level surface; speed, pushrim kinetics, and subjective ratings of effort for level 100-m sprints and up a 30.5-m ramp of approximately 5% grade. RESULTS: Three of 5 subjects demonstrated reduced peak resultant pushrim forces (P<=.014) and improved efficiency (P<=.048) with stimulation during self-paced level propulsion. Peak sagittal shoulder moment remained unchanged in 3 subjects and increased in 2 others (P<.001). Maximal forward trunk lean also increased by 19% to 26% (P<.001) with stimulation in these 3 subjects. Stroke lengths were unchanged by stimulation in all subjects, and 2 showed extremely small (5%) but statistically significant increases in cadence (P<=.021). Performance measures for sprints and inclines were generally unchanged with stimulation; however, subjects consistently rated propulsion with stimulation to be easier for both surfaces. CONCLUSIONS: Stabilizing the pelvis and trunk with low levels of continuous electrical stimulation to the lumbar trunk and hip extensors can positively impact the mechanics of manual wheelchair propulsion and reduce both perceived and physical measures of effort. PMID- 23628379 TI - Effects of ghrelin on the structural complexity of exocrine pancreas tissue architecture. AB - Recent studies have shown that ghrelin increases pancreatic exocrine secretion. However, the potential effects of ghrelin on the morphology of exocrine pancreas (EP) remain unknown. In this work, using fractal analysis, we demonstrate that centrally administered ghrelin increases structural complexity and tissue disorder in rat EP. The study was carried out on a total of 40 male Wistar rats divided into four groups (n = 10): ghrelin-treated animals (average age, 1.5 months), ghrelin-treated animals (8.5 months), and controls (1.5 and 8.5 months). The pancreas tissue sections were stained with hematoxylin/eosin and visualized by light microscopy. For each animal, the average values of tissue fractal dimension, lacunarity, as well as parameters of co-occurrence matrix texture, were determined using tissue digital micrographs. The results indicate that ghrelin administration increases EP fractal dimension and textural entropy, and decreases lacunarity, regardless of the age. To our knowledge, this is the first study to investigate the effects of ghrelin on the morphological properties of pancreatic tissue, and also the first to apply fractal and textural analysis methods in quantification of EP tissue architecture. PMID- 23628380 TI - EMu: probabilistic inference of mutational processes and their localization in the cancer genome. AB - The spectrum of mutations discovered in cancer genomes can be explained by the activity of a few elementary mutational processes. We present a novel probabilistic method, EMu, to infer the mutational signatures of these processes from a collection of sequenced tumors. EMu naturally incorporates the tumor specific opportunity for different mutation types according to sequence composition. Applying EMu to breast cancer data, we derive detailed maps of the activity of each process, both genome-wide and within specific local regions of the genome. Our work provides new opportunities to study the mutational processes underlying cancer development. EMu is available at http://www.sanger.ac.uk/resources/software/emu/. PMID- 23628381 TI - Surgical pathologic features of cerebral cortical lesions taken from 600 patients with intractable epilepsy. AB - OBJECTIVES: To determine the scope of histopathological variation in lesions responsible for epileptogenesis, I retrospectively reviewed the features of surgical specimens taken consecutively from 600 patients with intractable epilepsy. METHODS: The patients were divided into three groups on the basis of age at seizure onset: 94 patients with infantile onset (before 1year of age), 307 patients with juvenile onset (between 1 and 12years of age), and 199 patients with adolescent/adult onset (at 13years of age or beyond). Histological and immunohistochemical evaluations of the surgical specimens were performed. RESULTS: In the infant group, seizure duration was significantly shorter than in the other groups, and malformations caused by abnormalities of cortical development, including focal cortical dysplasia (FCD) type IIa/b, tuberous sclerosis, hemimegalencephaly, and polymicrogyria were predominant, whereas in the juvenile and adolescent/adult groups, other lesions such as hippocampal sclerosis (HS), tumors, FCD type I, and vascular lesions were frequently observed. For patients with HS, seizure duration in the juvenile group was significantly longer than in the adolescent/adult group. FCD type IIIa was noted in nearly half of patient with HS in both juvenile and adolescent/adult groups. The causative tumors included dysembryoplastic neuroepithelial tumors, gangliogliomas, astrocytomas, and other glioneuronal and glial tumors. CONCLUSION: Various histopathological entities and types, showing clear predominance depending on the age at seizure onset, were observed in patients with epilepsy. These features appear to provide information on the pathomechanisms of the lesions and their clinical relevance in affected patients. PMID- 23628382 TI - A comprehensive analysis of adiponectin QTLs using SNP association, SNP cis effects on peripheral blood gene expression and gene expression correlation identified novel metabolic syndrome (MetS) genes with potential role in carcinogenesis and systemic inflammation. AB - BACKGROUND: Metabolic syndrome (MetS) is an aberration associated with increased risk for cancer and inflammation. Adiponectin, an adipocyte-produced abundant protein hormone, has countering effect on the diabetogenic and atherogenic components of MetS. Plasma levels of adiponectin are negatively correlated with onset of cancer and cancer patient mortality. We previously performed microsatellite linkage analyses using adiponectin as a surrogate marker and revealed two QTLs on chr5 (5p14) and chr14 (14q13). METHODS: Using individuals from 85 extended families that contributed to the linkage and who were measured for 42 clinical and biologic MetS phenotypes, we tested QTL-based SNP associations, peripheral white blood cell (PWBC) gene expression, and the effects of cis-acting SNPs on gene expression to discover genomic elements that could affect the pathophysiology and complications of MetS. RESULTS: Adiponectin levels were found to be highly intercorrelated phenotypically with the majority of MetS traits. QTL-specific haplotype-tagging SNPs associated with MetS phenotypes were annotated to 14 genes whose function could influence MetS biology as well as oncogenesis or inflammation. These were mechanistically categorized into four groups: cell-cell adhesion and mobility, signal transduction, transcription and protein sorting. Four genes were highly prioritized: cadherin 18 (CDH18), myosin X (MYO10), anchor protein 6 of AMPK (AKAP6), and neuronal PAS domain protein 3 (NPAS3). PWBC expression was detectable only for the following genes with multi organ or with multi-function properties: NPAS3, MARCH6, MYO10 and FBXL7. Strong evidence of cis-effects on the expression of MYO10 in PWBC was found with SNPs clustered near the gene's transcription start site. MYO10 expression in PWBC was marginally correlated with body composition (p = 0.065) and adipokine levels in the periphery (p = 0.064). Variants of genes AKAP6, NPAS3, MARCH6 and FBXL7 have been previously reported to be associated with insulin resistance, inflammatory markers or adiposity studies using genome-wide approaches whereas associations of CDH18 and MYO10 with MetS traits have not been reported before. CONCLUSIONS: Adiponectin QTLs-based SNP association and mRNA expression identified genes that could mediate the association between MetS and cancer or inflammation. PMID- 23628383 TI - A test of maternal programming of offspring stress response to predation risk in threespine sticklebacks. AB - Non-genetic maternal effects are widespread across taxa and challenge our traditional understanding of inheritance. Maternal experience with predators, for example, can have lifelong consequences for offspring traits, including fitness. Previous work in threespine sticklebacks showed that females exposed to simulated predation risk produced eggs with higher cortisol content and offspring with altered anti-predator behavior. However, it is unknown whether this maternal effect is mediated via the offspring glucocorticoid stress response and if it is retained over the entire lifetime of offspring. Therefore, we tested the hypothesis that maternal exposure to simulated predation risk has long-lasting effects on the cortisol response to simulated predation risk in stickleback offspring. We measured circulating concentrations of cortisol before (baseline), 15 min after, and 60 min after exposure to a simulated predation risk. We compared adult offspring of predator-exposed mothers and control mothers in two different social environments (alone or in a group). Relative to baseline, offspring plasma cortisol was highest 15 min after exposure to simulated predation risk and decreased after 60 min. Offspring of predator-exposed mothers differed in the cortisol response to simulated predation risk compared to offspring of control mothers. In general, females had higher cortisol than males, and fish in a group had lower cortisol than fish that were by themselves. The buffering effect of the social environment did not differ between maternal treatments or between males and females. Altogether the results show that while a mother's experience with simulated predation risk might affect the physiological response of her adult offspring to a predator, sex and social isolation have much larger effects on the stress response to predation risk in sticklebacks. PMID- 23628385 TI - Risk factors for falling in psychiatric inpatients: a prospective, matched case control study. AB - Falling is one the most common types of inpatient adverse events. Most fall related research was conducted retrospectively and focused on elderly population in general hospital settings. This study aimed to timely identify all potential risk factors associated with falls and fall-related injury in a psychiatric inpatient setting. We recruited 145 fall events and 145 sex- and room-matched psychiatric control inpatients without fall in a 1002-bed psychiatric teaching hospital in northern Taiwan. In addition to medical records, the study variables included patient characteristics, circumstances and medications, which were collected from the patients and/or their families within 24 h of receiving reports right after obtaining written informed consent. A psychiatrist and three head nurses conducted a comprehensive assessment of risk factors immediately after falls occurred. A conditional logistic regression model revealed four variables significantly associated with an increased risk of falling: the clinical global impression-severity (adjusted odds ratio (aOR) = 2.19; 95% confidence interval, CI = 1.13-4.24), the parkinsonism scores of the extrapyramidal syndrome rating scale (aOR = 1.14; 95% CI = 1.08-1.21), equivalent dosage of benzodiazepines use (aOR = 1.15; 95% CI = 1.03-1.30), and medication changes within 24 h (aOR = 10.3; 95% CI = 1.37-76.8). Acute settings (aORs = 2.06, 95% CI = 1.01-4.18), a fall history in the past six months and a lack of history of medical problems (aORs = 3.04; 95% CI = 1.46-6.33) were associated with fall-related injury (aOR = 2.70; 95% CI = 1.29-5.69). Our study identified the severity of psychotic symptoms, extrapyramidal symptoms, medications usage and other several specific measures for prevention of falls in psychiatric inpatient settings. PMID- 23628386 TI - Associations between morningness/eveningness and psychopathology: an epidemiological survey in three in-patient psychiatric clinics. AB - OBJECTIVE: This study aims to examine the association between the chronotype (morningness/eveningness) and specific mental disorders. METHODS: Cross-sectional epidemiological study conducted in three in-patient clinical settings. A total of 1468 consecutive in-patients who gave their written consent were enrolled. On the admission day, patients filled sleep questionnaires and a nurse filled a Clinical Global Impressions scale. Hospitalization reports and ICD-10 diagnoses were collected. RESULTS: Sleep/wake schedule was similar between the psychiatric diagnoses. On the other hand, morning type patients had an earlier bedtime, earlier wakeup time and shorter sleep duration than the other chronotype regardless of the diagnosis. In multivariate models, patients with a depressive disorder or a psychosis were more likely to be morning type. Patients with an anxiety disorder, addiction disorder or personality disorder were more likely to be evening type. CONCLUSIONS: Age and sleep/wake schedule are contributing factors for the chronotype but mental disorders too appeared to modulate chronotype preferences. PMID- 23628384 TI - Developmental differences in diffusion tensor imaging parameters in borderline personality disorder. AB - BACKGROUND: Borderline personality disorder (BPD) often presents during adolescence. Early detection and intervention decreases its subsequent severity. However, little is known about early predictors and biological underpinnings of BPD. The observed abnormal functional connectivity among brain regions in BPD led to studies of white matter, as the neural substrate of connectivity. However, diffusion tensor imaging (DTI) studies in adult BPD have been inconclusive, and, as yet, there are no published DTI studies in borderline adolescents. METHODS: We conducted DTI tractography in 38 BPD patients (14-adolescents, 24-adults) and 32 healthy controls (13-adolescents, 19-adults). RESULTS: We found bilateral tract specific decreased fractional anisotropy (FA) in inferior longitudinal fasciculus (ILF) in BPD adolescents compared to adolescent controls. ILF FA was significantly higher in adolescent controls compared to BPD adolescents, BPD adults and adult controls (Wilks F(3,57) = 3.55, p < 0.02). Follow-up voxelwise TBSS analysis demonstrated lower FA in BPD adolescents compared to adolescent controls also in uncinate and occipitofrontal fasciculi. DISCUSSION: FA generally develops along an inverted U-shape curve, increasing through adolescence, and slowly decreasing in adulthood. Our findings suggest that, in adolescent BPD, this normal developmental "peak" in FA, which is seen in healthy controls, is not achieved. This suggests a possible neural substrate for the previously reported OFC-amygdala disconnect in adults with BPD. It raises the possibility that a white matter tract abnormality in BPD present in adolescence may not be appreciable in adulthood, but a functional abnormality in the coordination among brain regions persists. Our finding represents a possible biological marker to identify those at risk for developing BPD. PMID- 23628387 TI - Systematic meta-analysis of childhood social withdrawal in schizophrenia, and comparison with data from at-risk children aged 9-14 years. AB - Social withdrawal is a robust childhood risk factor for later schizophrenia. The aims of this paper were to assess the evidence for childhood social withdrawal among adults with schizophrenia and, comparatively, in children aged 9-14 years who are putatively at-risk of developing schizophrenia. We conducted a meta analysis, including cohort and case-control studies reporting social withdrawal measured by the Child Behavior Checklist (CBCL) in adults with schizophrenia vs. controls. Further, an experimental study compared CBCL withdrawal scores from typically-developing children with scores from two groups of putatively at-risk children: (i) children displaying a triad of replicated antecedents for schizophrenia, and (ii) children with at least one first- or second-degree relative with schizophrenia or schizoaffective disorder. Six studies met inclusion criteria for the meta-analysis (N = 3828), which demonstrated a large effect of increased childhood social withdrawal in adults with schizophrenia (standardized mean difference [SMD] score = 1.035, 95% CI = 0.304-1.766, p = 0.006), with no indication of publication bias, but considerable heterogeneity (I(2) = 91%). Results from the experimental study also indicated a large effect of increased social withdrawal in children displaying the antecedent triad (SMD = 0.743, p = 0.001), and a weaker effect in children with a family history of schizophrenia (SMD = 0.442, p = 0.051). Childhood social withdrawal may constitute a vulnerability marker for schizophrenia in the presence of other antecedents and/or genetic risk factors for schizophrenia. PMID- 23628388 TI - Decreased functional response to Toll like receptor ligands in patients with oral cancer. AB - Patients with oral cancer (OC) show dysregulation of variety of anti tumor immune responses. To assess the role of Toll like receptor (TLR) signaling in peripheral blood lymphocytes (PBL) from OC patients, we analyzed the expression of TLR2, TLR3, TLR4 and TLR9 on various lymphocyte subsets. Results revealed an increased expression of TLRs on unconventional T cells (like gammadelta T cells, NKT cells and CD4(+)CD8(+) T cells) as compared to conventional alphabeta T cells. Functional studies using TLR ligands (CpG, Poly I:C, LPS and Pam3CSK4) showed defects in the TLR mediated signaling in PBLs of OC patients. Proliferation of OC PBLs in response to stimulation with TLR ligands was significantly decreased. TLR ligand induced IFN-gamma production by PBLs from OC patients were low as compared to HI. Stimulation with TLR ligands upregulated the levels of activation markers (CD25 and CD69) on PBLs from HI but not from OC patients. TLR ligands CpG, Poly I:C, LPS and Pam3CSK4 significantly augmented the tumor directed cytotoxic response of PBLs from HI but not from OC patients. Our data suggests that impairment of TLR function on PBLs may be another strategy adopted by tumor cells to dampen tumor directed immune responses. PMID- 23628389 TI - Genetic evidence for involvement of adaptive immunity in the development of IgA nephropathy: MHC class II alleles are protective in a Caucasian population. AB - There is evidence suggesting that IgA nephropathy (IgAN) is an immunological disease. The role of HLA class II DR beta 1 (DRB1) has previously not been well studied. The aim of our study was to investigate the association of HLA-DRB1 variants with IgAN in a Swedish Caucasian cohort. Our study consisted of 213 patients with biopsy proven IgAN, all of self-reported Caucasian ancestry. As a control cohort, 1569 healthy subjects from the same population in Sweden were included. HLA-DRB1 low-resolution genotyping was performed and odds ratios were calculated to assess the risk. In an allelic model the HLA-DRB1(*)03 and (*)10, demonstrated association for IgAN after correction for multiple comparison, with subsequent OR=0.54 (95% CI 0.37-0.78) and 3.44 (95% CI 1.67-7.07). When the influence of risk allelic groups was adjusted for protective allelic groups and vice versa, only a protective effect of HLA-DRB1(*)03 remained significant. In conclusion, the variants of HLA-DRB1 were associated with IgAN of which the HLA DRB1(*)03 revealed a strong protective effect for IgAN. Our data replicates finding from other Caucasian populations and suggest that involvement of adaptive immunity may be of importance in the development of the disease. PMID- 23628390 TI - No association of the HLA-DQ alleles with myasthenia gravis in Cuban patients. AB - Myasthenia gravis (MG) is a neuromuscular disorder characterized by fatigability and weakness of striated muscles. Its association with HLA molecules is well known and varies depending on age, sex and the ethnicity of the patients. A case control study was performed in 61 Cuban patients and 81 controls using polymerase chain reaction and sequence-specific primers of the HLA-DQA1/B1 alleles. The distribution of the HLA-DQ alleles individually and in a simple haplotype between patients and controls shows no statistically significance differences. This result could be due to the heterogeneity and ethnic admixture existing in Cuban population. These findings indicate that the association between a disease and a particular genetic region cannot be explained merely by similarities in the genetic background but involve environmental and immunological factors. PMID- 23628391 TI - Incidence and risk factors of anti-HLA immunization after pregnancy. AB - Pregnancy is the only natural source of anti-HLA immunization. The exact frequency of this immunization remains undetermined as prior studies either used methods with a low sensitivity or were performed late after delivery. We present here the first study on women at delivery evaluating anti-HLA immunization by Luminex. We also attempted to isolate factors influencing immunization, such as soluble HLA-G (sHLA-G) levels and genetic polymorphisms. With Luminex, anti-HLA immunization was observed in 54.4% of the women. As expected, immunization frequency increased with the number of children, reaching 74% in women with >2 deliveries. Among immunized women, strong cytotoxic Ab (as detected by Complement Dependent Cytotoxicity) were associated with a lower level of sHLA-G. None of the studied polymorphisms influenced immunization rate in the whole cohort. Among 94 first pregnant women with no history of miscarriage, the -174 IL-6 gene promoter mutation (G/C) appeared more frequently in non immunized women (69% vs. 45% in immunized ones, p=0.02). Lastly, the occurrence of a miscarriage before the first live delivery significantly decreased immunization. These results may help to understand mechanisms of pregnancy induced immunization. They also have an impact in the management of previous pregnant women requiring organ or hematopoietic stem cell transplantation. PMID- 23628392 TI - Association between polymorphisms in the promoter region of miR-143/145 and risk of colorectal cancer. AB - Emerging evidence suggests that down-regulated miRNAs play an important role in the carcinogenesis of colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in the promoter region of miRNAs may disturb miRNAs processing, alter their expression, and ultimately affect an individual's susceptibility to CRC. We conducted a case-control study and analyzed twelve SNPs in the promoter region of miR-143/145 of 525 subjects including 242 cases with CRC and 283 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The mutant genotypes or alleles of rs41291957, rs353292, rs353293, and rs4705341 were significantly associated with an increased risk of CRC compared with the wild genotypes or alleles, while rs4705343, rs17796757, rs3733845, and rs3733846 were significantly associated with a decreased risk of CRC. When stratification analysis was done by different variables, such as tumor size, tumor site, differentiated status, clinical stage, and metastasis status, we found that patients with the mutant allele of rs41291957 had an increased risk to develop a tumor size larger than 5 cm. These findings suggest that SNPs in the promoter region of miR-143/145 may be related to the etiology of CRC. However, further larger studies with different ethnic origins are needed to confirm our results due to limited sample sizes in the study. PMID- 23628393 TI - Characterization and specification of microsatellite markers in the HLA-DRB1 gene region: a revision to major histocompatibility complex database. AB - Association between HLA-DRB1 and a large number of diseases such as multiple sclerosis, type I diabetes and rheumatoid arthritis has been demonstrated. In the present study, we attempted to identify and characterize potential microsatellites in the HLA-DRB1 gene region to find specific markers for genotyping and linkage analysis of this gene. The microsatellites including M2_3_22, M2_2_36, D6S2878, D6S2805, D6S2879 and D6S2880 were selected from microsatellite resource in the Major Histocompatibility Complex database (dbMHC). In silico analysis showed that only M2_3_22 was specific for HLA-DRB1. Moreover, our findings revealed some more accurate characteristics of the other investigated microsatellites. M2_3_22 existed as a single copy in all the MHC haplotype sequences and was located next to HLA-DRB1. Therefore, a new set of primers compatible with all the last published MHC haplotype sequences were designed and used to amplify M2_3_22 in 164 DNA samples obtained from unrelated Iranian individuals. M2_3_22 was successfully amplified in all DNA samples and three different alleles were identified. This locus was found in the Hardy Weinberg equilibrium (P>0.05) in the studied population. Together, the findings suggested that M2_3_22 could be introduced as a specific locus in the HLA-DRB1 gene region for linkage analysis and disease association studies. PMID- 23628394 TI - Neem leaf glycoprotein overcomes indoleamine 2,3 dioxygenase mediated tolerance in dendritic cells by attenuating hyperactive regulatory T cells in cervical cancer stage IIIB patients. AB - Tolerogenic dendritic cells (DCs) are a subset of DCs characterized by abundant indoleamine 2,3 dioxygenase (IDO) expressions. IDO may be co-operatively induced in DCs by regulatory T (Tregs) cells and various DC maturation agents. Tregs are markedly amplified in the physiological system of cancer patients, inducing over tolerance in DCs that leads to the hyper accumulation of immunosuppressive IDO in tumor microenvironment, thereby, hampering anti-tumor immunity. Consequently, a major focus of current immunotherapeutic strategies in cancer is to minimize IDO, which is possible by reducing Tregs and using various IDO inhibitors. Neem leaf glycoprotein (NLGP), a natural and nontoxic immunomodulator, demonstrated several unique immunoregulatory activities. Noteworthy activities of NLGP are to mature DCs and to inhibit Tregs. As Tregs are inducer of IDO in DCs and hyperactive Tregs is a hallmark of cancer, we anticipated that NLGP might abrogate IDO induction in DCs by inhibiting Tregs. Evidences are presented here that in a co culture of DCs and Tregs isolated from cervical cancer stage IIIB (CaCx-IIIB) patients, NLGP does inhibit IDO induction in DCs by curtailing the over expression of Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) on Tregs and concomitantly induces optimal DC maturation. In contrast, in the presence of LPS as maturation agent the DCs displays a tolerogenic profile. This finding suggests the reduction of tolerogenecity of DCs in CaCx-IIIB patients by reducing the IDO pool using NLGP. Accordingly, this study sheds more light on the diverse immunomodulatory repertoire of NLGP. PMID- 23628395 TI - FYB gene polymorphisms are associated with susceptibility for systemic lupus erythemathosus (SLE). AB - Systemic Lupus Erythematosus (SLE) is a multifactorial autoimmune disease affecting different organs or systems. Several genes have been associated with SLE susceptibility so far. A previous study has reported, in SLE patients, a differential expression of Fyn Binding Protein gene (FYB), encoding for a protein participating in the T cells signaling cascade and in the interleukin-2A expression modulation. This study investigates the association of 10 FYB SNPs with differential susceptibility to SLE in 143 SLE patients and 184 controls from Southern Brazil. Significant differences were observed when comparing allele and genotype frequencies distribution in patients and controls: the T allele for rs6863066 C>T SNP and C for rs358501 T>C SNP were significantly more frequent in SLE patients than in controls (p=0.0002 and p=0.008) and associated with an increased risk for SLE (OR=1.93 and OR=1.69). The frequencies of rs6863066 C/T and T/T and rs358501 C/C genotypes were significantly higher in patients than in controls (p=0.001, p=0.006 and p=0.008). A significant association was also found for the rs6863066-rs358501 T-T and T-C haplotypes (OR=2.06, p=0.002 and OR=2.93, p=0.001). When considering clinical and laboratorial manifestations, an association was found between rs2161612 G allele and G/G genotype and hematological alterations (p=0.008) and rs379707 A/C genotype and anti-dsDNA (p=0.01). In conclusion, our findings indicate an association between polymorphisms located in FYB gene and SLE, suggesting their possible involvement in disease susceptibility and clinical manifestations. PMID- 23628396 TI - Anti-HLA-A, -B, -DR, -DQB1 and -DQA1 antibodies reactive epitope determination with HLAMatchmaker in multipare awaiting list for heart transplant. AB - Human leukocyte antigen (HLA) antibodies represent a significant risk factor for transplant failure. It is very important to characterize anti-HLA antibodies as epitopes rather than antigens so that this knowledge can be applied clinically. The aim of the study was to investigate the extra reactivity patterns in sensitized multipare. Here, we have used the HLAMatchmaker program, a theoretical algorithm, to explain these unexpected antibody reactivity patterns in multipare awaiting for heart transplant. The patient was sensitized during pregnancy by alleles HLA-A(*)24:02, HLA-DRB1(*)07:01, HLA-DRB4(*)01:01, DQB1(*)02:02 and DQA1(*)02:01 mismatches with development of respective antibodies. However, the patient' sera were shown an unexpected reactivity not directed toward HLA mismatches of daughters: A(*)23:01, A(*)24:03 and B(*)15:12 for class I and DRB4(*)01:03, DRB1(*)09:02, DRB1(*)09:01, DQB1(*)03:01, DQB1(*)03:03, DQB1(*)03:02, DQB1(*)04:02, DQB1(*)04:01 and DQB1(*)02:01 for class II. By HLAMatchmaker analysis we found that these antibodies reacted with eplet shared by antigens in single allele Luminex panels. These eplets were: 62EE, 66GKH, 70KAH, 71HS, 127K, 113YH, 144KR, 150AAH, 151AHV, 163TG and 167DG for class I and 4Q, 74RRAE, 71RRA, 98KN, 120N, and 135G, 25FT, 34HE, 41ER, 47EK2, 48LF for class II. Thus, HLAMatchmaker software together with to solid phase techniques could open new horizons for a more precise characterization of the HLA-antibodies. PMID- 23628397 TI - Lack of association between CTLA-4 and PDCD1 polymorphisms and acute rejection in German liver transplant recipients. AB - Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell-death 1 (PDCD1) are two genes encoding coinhibitory immunoreceptors that are involved in regulation transplant rejection and tolerance induction. Thus, CTLA-4 and PDCD1 may be good candidate genes to evaluate in liver transplant rejection. In this retrospective study, we investigated whether four functional single nucleotide polymorphisms (SNP) of the CTLA-4 gene and PDCD1 gene were associated with susceptibility to liver transplant rejection. The SNPs -1772T>C (rs733618), 1661A>G (rs4553808) of the CTLA-4 gene, and the SNPs 7146G>A (rs11568821), 7209C>T (rs41386349) of the PDCD1 gene were genotyped by polymerase chain reaction allele specific restriction enzyme analysis (PCR-ASRA) in 100 liver recipients with acute rejection, 104 liver transplant recipients without acute rejection and 100 healthy control individuals. For the selected SNPs we did not detect any significant difference in genotypic and allelic frequencies between liver transplant recipients with and without acute rejection. In conclusion, our results suggest that the tested SNPs may not be associated with susceptibility to acute liver transplant rejection in a Caucasian population. PMID- 23628398 TI - Effect of human leukocyte antigen class I and II alleles on hepatitis C viral load among chronic hepatitis C patients in Southern Taiwan. AB - The viral load of hepatitis C virus (HCV) in chronic hepatitis C patients affects clinical outcomes and response to interferon treatment. Various factors may be involved in determining the viral load, including host genetic factors. The aim of this study was to investigate the relationship between HCV viral load and human leukocyte antigen (HLA) class I and class II alleles. One hundred and six HCV RNA positive subjects were enrolled, and viral load was measured. HLA-A, -B, C, -DR, and -DQ loci were determined by sequence-based genotyping. Univariate analysis indicated that HLA-B(*)40 and HLA-C(*)07 alleles had significantly higher HCV RNA levels (P<0.05). Patients with the HLA-C(*)15 allele exhibited a trend toward a lower HCV viral load (P=0.06). After controlling for confounding factors, multivariate analysis revealed that only HLA-C(*)15 allele was identified as a significant determinant for HCV-RNA level (slope=-0.91, 95% CI: 1.58, -0.24; Holm's P<0.01). Patients expressing the HLA-C(*)15 allele had significantly lower HCV RNA levels. HCV genotype 1 was significantly associated with high HCV RNA levels (P<0.05 by Mann-Whitney U test). In conclusion, HLA C(*)15 is an important host immunogenetic factor with an inverse association to HCV viral load in CHC patients in Taiwan. HCV genotype 1 is the viral factor that associated with high viral load. PMID- 23628399 TI - Associations of HLA-DRB1 and -DQB1 alleles with severe recurrent respiratory papillomatosis in Korean patients. AB - Recurrent respiratory papillomatosis (RRP) is characterized by frequent recurrences of papilloma of the larynx with significant morbidity. It is caused by human papillomavirus (HPV) types 6 and 11. Some associations of HLA genes with RRP have been reported, mainly in Caucasians. We performed HLA class II (DRB1 and DQB1) genotyping using Dynal RELITM HLA-DRB1 SSO kit and PCR-single strand conformation polymorphism on 22 Korean patients with severe RRP and 207 healthy controls. The gene frequencies of HLA-DRB1*11:01 (18.2% vs 3.6%, p=0.0006, pc=0.02, odds ratio [OR]=5.9) and DQB1*03:01 (36.4% vs 14.5%, p=0.0009, pc=0.01, OR=3.4) and the haplotype frequency of DRB1*11:01-DQB1*03:01 (15.9% vs 3.6%, p=0.003, OR=5.0) was higher in RRP patients than controls. DRB1*11:01 and DRB1*11:01-DQB1*03:01 haplotype were strongly associated with disease susceptibility to severe RRP in Koreans. PMID- 23628400 TI - Meta-analysis reveals an association of STAT4 polymorphisms with systemic autoimmune disorders and anti-dsDNA antibody. AB - Signal transducer and activator of transcription 4 (STAT4) has been recently identified as a susceptibility gene for multiple autoimmune diseases. Here we performed a comprehensive analysis of the association between STAT4 and several different autoimmune disorders to identify potential common inflammatory principles behind this association. Our meta-analysis revealed that the STAT4 rs7574865 polymorphism is associated with four autoimmune diseases with systemic pathology, including systemic lupus erythematosus (OR = 1.52; 95% CI = 1.48 - 1.56, P<1.0 * 10(-16)), rheumatoid arthritis (OR = 1.27; 95% CI = 1.21 - 1.33, P < 1.00 * 10(-16)), systemic sclerosis (OR = 1.38; 95% CI = 1.27 - 1.50, P < 1.44 * 10(-14)), and primary Sjogren's syndrome (OR = 1.32; 95% CI = 1.01 - 1.73, P = 4.40 * 10(-2)), while no association was found with type I diabetes, juvenile idiopathic arthritis, ulcerative colitis and Crohn's disease. Furthermore, the stratified meta-analysis also demonstrate that the STAT4 rs7574865 polymorphism is associated with the presence of autoantibodies with systemic reactivity (anti ds-DNA antibodies) in SLE patients (OR = 1.37; 95% CI = 1.21 - 1.56, P = 1.12 * 10(-6)). However, no such specific association was seen in RA with regard to the presence of non-systemically reacting antibodies, including rheumatoid factor and anti-cyclic citrullinated peptide antibodies. Taken together, these results suggest that STAT4 polymorphisms are associated with autoimmune diseases which are characterized by a systemic pathology and anti-dsDNA antibody. PMID- 23628401 TI - Complex product composition generates risks for generic substitution also with dosage forms for intravenous administration. AB - Teicoplanin is an antibiotic made by fermentation in which a glycopeptide core is substituted by different fatty acids. The chemical structure and proportion of the various components are strictly dependent on the production process (Actinoplanes sp. strain, cell culture conditions and downstream process). Thus, a relevant variability can be introduced from different manufacturers. Interchangeability or substitution among the originator and the generic products of teicoplanin for injection is under debate with respect to pharmaceutical similarity. In fact, depending on the manufacturer, the six major components of teicoplanin show different quantitative distributions compared to that of the originator. The European Pharmacopoeia fixed an undifferentiated upper limit for the component content. A statistical approach is required for comparing complex products. In this paper the use of principal component analysis (PCA) as a tool for identifying the pharmaceutical equivalence among teicoplanin products from different sources was explored. The results obtained show that PCA can distinguish the differing origin of this biological drug. PMID- 23628402 TI - Development of liposomal Ginsenoside Rg3: formulation optimization and evaluation of its anticancer effects. AB - The Ginsenoside Rg3 has been shown to possess antiangiogenic and anticancer properties. Because of its limited water solubility, we decided to design and synthesize liposomal Rg3 (L-Rg3), to optimize preparation conditions, and to investigate further whether liposome could enhance the anticancer activity of Rg3. L-Rg3 was prepared using a film-dispersion method and the preparation conditions were optimized with response surface methodology (RSM). The mean encapsulation efficiency (EE) of 82.47% was close to the predicted value of 89.69%. Therefore, the optimized preparation condition was predicted correctly. We evaluated the cytotoxicity, pharmacokinetics, biodistribution and antitumor activities of L-Rg3. HepG2 and A549 cells were treated with Rg3 or L-Rg3 at different concentrations in vitro. Pharmacokinetics and biodistribution studies were carried out in Wistar rats. Tumor model was established by inoculating a suspension of A549 cells into BALB/c nude mice. The mice were divided into Saline, Rg3 solution, and L-Rg3 groups with the drug given by i.p. injection. Survival of the mice and tumor volume were monitored. In addition, CD34 immunohistochemical analysis was used for measuring microvessel density (MVD) of the tumor tissues. The cytotoxicity and ratio of tumor inhibition of L-Rg3 group were significantly higher than the Rg3 solution group. MVD values in the Rg3 solution and L-Rg3 groups decreased, especially in the L-Rg3 group. Compared to Rg3 solution, the L-Rg3 showed increased Cmax and AUC of Rg3 by 1.19- and 1.52 fold, respectively. This liposomal formulation could potentially produce a viable clinical agent for improving the anticancer activity of Rg3. PMID- 23628403 TI - In vitro-in vivo evaluation of nanosuspension release from subcutaneously implantable osmotic pumps. AB - Utilizing poorly soluble drug candidates in pharmacokinetic studies remains challenging in preclinical drug development. We investigated a nanosuspension based delivery system to achieve constant drug plasma levels by applying the nanoparticles via subcutaneously implanted micro-osmotic pumps. Various nanosuspension formulations were characterized in vitro prior to Alzet(r) pump release by means of dynamic light scattering (DLS), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and rheological measurements. In vitro formulation release was checked by HPLC/UV. The in vivo experiments compared plasma-concentration time profiles of subcutaneously injected nanosuspensions with those of formulations delivered by pumps. Two Poloxamer 338 containing nanosuspensions with different viscosities were found to be stable over observation time, physically resistant against biorelevant media and showed only a low amorphous part after preparation. The more viscous nanosuspension with 31.65 mPas revealed in vitro the expected zero-order release, while the low viscous formulation with 2.18 mPas showed first order release. In in vivo experiments, the higher viscous nanosuspension released from osmotic pumps exhibited elevated plasma levels compared to the lower viscous formulation. Compared to bolus injected nanosuspensions constant plasma levels could be maintained by adapting the viscosity of the nanosuspension. Subcutaneously implanted osmotic pumps prove to be a valuable delivery system for nanosuspensions in pharmacokinetic studies by consideration of the key parameter viscosity in release kinetics. PMID- 23628404 TI - UPEC biomimickry at the urothelial barrier: lectin-functionalized PLGA microparticles for improved intravesical chemotherapy. AB - The urgent demand for more potent treatment schedules in bladder cancer (BCa) therapy calls for a refinement of the intravesical administration modalities. However, progress on drug delivery systems tailored to the penetration-hostile urothelial barrier lags behind the advancements in comparable fields. This study reports on a multimodal, carrier-based delivery concept that combines biorecognitive targeting with modified release strategies for improved intravesical chemotherapy. The plant lectin wheat germ agglutinin (WGA) was immobilized on poly(lactide-co-glycolide) (PLGA) microparticles (MP) to induce stable cytoadhesion via cellular carbohydrate chains, similar to the specific attachment mechanism utilized by uropathogenic bacteria. A panel of DNA-selective chemotherapeutics with established track record in uro-oncology was screened for physicochemical compatibility with the polymeric carrier formulation. Critical limitations in encapsulation efficiency were found for mitomycin C (MMC), doxorubicin (DOX), and gemcitabine hydrochloride (GEM), despite multiparametric optimization of the preparation conditions. In contrast, the amphiphilic 4-(N) stearoyl prodrug of gemcitabine (GEM-C18) exhibited excellent processability with PLGA. In vitro bioassays on 5637 human BCa cells showed that the enhanced cytoadhesion of WGA-GEM-C18-PGLA-MP traces back to the specific lectin/carbohydrate interaction, and is not easily disrupted by adverse environmental factors. Owing to several synergistic effects, the combined prodrug/targeting approach resulted in strong cytostatic response even when adjusting the exposure scheme to the confined temporal conditions of instillative treatment. Our results highlight the importance of fine-tuning both pharmacokinetic and pharmacologic parameters to gain adequate impact on urothelial cancer cells, and assign promising potential to glycan-targeted delivery concepts for the intravesical route. PMID- 23628405 TI - In vitro trans-scleral iontophoresis of methylprednisolone hemisuccinate with short application time and high drug concentration. AB - Trans-scleral iontophoresis, i.e. the application of small electric current to enhance drug transport across sclera is an option for non-invasive delivery of corticosteroids to the posterior segment of the eye. In this paper, in vitro trans-scleral iontophoresis of methylprednisolone hemisuccinate was investigated using concentrated drug solutions and short application times to mimic the iontophoretic conditions of in vivo studies. The drug at the donor concentration of 45 mg/ml was delivered through isolated porcine sclera under passive and iontophoretic conditions (cathodal, 2.4 mA) for 2-15 min. In a second set of experiments, the drug was delivered for 5 min at current intensities of 0.9-7.2 mA. After donor removal, drug release was followed up to 24 h. The exposure of concentrated solutions to sclera for 2-15 min under passive conditions caused a notable accumulation of drug up to 0.8 mg/cm2, the release of which was successively followed for 24 h. In cathodal iontophoresis, the amount of accumulated drug increased proportionally to the charge between 0.3 and 1.44 Coulomb. When the charge was increased to 2.16 Coulomb by increasing the application time or current intensity, no further enhancement was recorded. This behaviour can be ascribed to substantial drug adsorption on the scleral tissue, as demonstrated through streaming potential studies, with the consequent increase of the electroosmotic flow that opposes drug transport. The set up suggested here could help in defining the optimal conditions for in vivo studies with animal models and reducing the number of in vivo experiments. PMID- 23628406 TI - Solubility enhancement of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) using polypolypropylene oxide core PAMAM dendrimers. AB - The aim of the present study was to evaluate the aqueous solubility enhancement properties of polypropylene oxide cored PAMAM (PPO@PAMAM) dendrimers. The solubility of NSAIDs (Ketoprofen, Ibuprofen and Diflunisal) was investigated in the presence of PPO@PAMAM dendrimers at room temperature in buffer solution. The effects of dendrimer concentration, generation and core size on the solubility of NSAIDs have been investigated. The experimental results showed that the solubility of the NSAIDs was approximately proportional to dendrimer concentration and generation. In addition, the effect of core size on the solubility of NSAIDs in constant generation and concentration of PPO@PAMAM dendrimer was Ketoprofen>Diflunisal>Ibuprofen. Under optimized conditions, PPO@PAMAM dendrimers are highly effective solubility enhancer for NSAIDs due to its new polypropylene oxide core. PMID- 23628407 TI - Do patients in Dutch nursing homes have more pressure ulcers than patients in German nursing homes? A prospective multicenter cohort study. AB - OBJECTIVES: To investigate whether the incidence of pressure ulcers in nursing homes in the Netherlands and Germany differs and, if so, to identify resident related risk factors, nursing-related interventions, and structural factors associated with pressure ulcer development in nursing home residents. DESIGN: A prospective multicenter cohort study. SETTING: Ten nursing homes in the Netherlands and 11 nursing homes in Germany (around Berlin and Brandenburg). PARTICIPANTS: A total of 547 newly admitted nursing home residents, of which 240 were Dutch and 307 were German. Residents had an expected length of stay of 12 weeks or longer. MEASUREMENTS: Data were collected for each resident over a 12 week period and included resident characteristics (eg, demographics, medical history, Braden scale scores, nutritional factors), pressure ulcer prevention and treatment characteristics, staffing ratios and other structural nursing home characteristics, and outcome (pressure ulcer development during the study). Data were obtained by trained research assistants. RESULTS: A significantly higher pressure ulcer incidence rate was found for the Dutch nursing homes (33.3%) compared with the German nursing homes (14.3%). Six factors that explain the difference in pressure ulcer incidence rates were identified: dementia, analgesics use, the use of transfer aids, repositioning the residents, the availability of a tissue viability nurse on the ward, and regular internal quality controls in the nursing home. CONCLUSION: The pressure ulcer incidence was significantly higher in Dutch nursing homes than in German nursing homes. Factors related to residents, nursing care and structure explain this difference in incidence rates. Continuous attention to pressure ulcer care is important for all health care settings and countries, but Dutch nursing homes especially should pay more attention to repositioning residents, the necessity and correct use of transfer aids, the necessity of analgesics use, the tasks of the tissue viability nurse, and the performance of regular internal quality controls. PMID- 23628408 TI - Mechanical energy profiles of the combined ankle-foot system in normal gait: insights for prosthetic designs. AB - Over the last half-century, the field of prosthetic engineering has continuously evolved with much attention being dedicated to restoring the mechanical energy properties of ankle joint musculatures during gait. However, the contributions of 'distal foot structures' (e.g., foot muscles, plantar soft tissue) have been overlooked. Therefore, the purpose of this study was to quantify the total mechanical energy profiles (e.g., power, work, and work-ratio) of the natural ankle-foot system (NAFS) by combining the contributions of the ankle joint and all distal foot structures during stance in level-ground steady state walking across various speeds (0.4, 0.6, 0.8 and 1.0 statures/s). The results from eleven healthy subjects walking barefoot indicated ankle joint and distal foot structures generally performed opposing roles: the ankle joint performed net positive work that systematically increased its energy generation with faster walking speeds, while the distal foot performed net negative work that systematically increased its energy absorption with faster walking speeds. Accounting for these simultaneous effects, the combined ankle-foot system exhibited increased work-ratios with faster walking. Most notably, the work-ratio was not significantly greater than 1.0 during the normal walking speed of 0.8 statures/s. Therefore, a prosthetic design that strategically exploits passive dynamic properties (e.g., elastic energy storage and return) has the potential to replicate the mechanical energy profiles of the NAFS during level-ground steady state walking. PMID- 23628409 TI - Detection of spliced mRNA from human bocavirus 1 in clinical samples from children with respiratory tract infections. AB - Human bocavirus 1 (HBoV1) is a parvovirus associated with respiratory tract infections (RTIs) in children, but a causal relation has not yet been confirmed. To develop a qualitative reverse transcription PCR to detect spliced mRNA from HBoV1 and to determine whether HBoV1 mRNA correlated better with RTIs than did HBoV1 DNA, we used samples from HBoV1 DNA-positive children, with and without RTIs, to evaluate the test. A real-time reverse transcription PCR, targeting 2 alternatively spliced mRNAs, was developed. HBoV1 mRNA was detected in nasopharyngeal aspirates from 33 (25%) of 133 children with RTIs but in none of 28 controls (p<0.001). The analytical sensitivity and specificity of the test were good. Our data support the hypothesis that HBoV1 may cause RTIs, and we propose that HBoV1 mRNA could be used with benefit, instead of HBoV1 DNA, as a diagnostic target. PMID- 23628410 TI - Genomic signature and protein sequence analysis of a novel influenza A (H7N9) virus that causes an outbreak in humans in China. AB - Very recently, a new avian flu outbreak in humans, which is caused by a novel H7N9 influenza A virus (AIV), was reported in China. As of April 13, 2013, 49 confirmed cases (mainly middle-aged to elderly males), including 11 deaths, were reported in China. Here we analyzed the genomic signatures and protein sequences of the human H7N9 AIVs. We found that the genomic signatures of A(H7N9) had high and low identity to avian and human IAVs, respectively, suggesting its avian origin. The signature amino acids of A(H7N9) had high identity to 1997 H5N1 and 2009 H1N1, but low identity to those influenza strains that caused pandemics before 1980. One of the key signature amino acids at 627 in PB2 mutated to lysine, which is associated with mammalian adaptation and increased virulence of the highly pathogenic avian influenza A(H5N1) virus. Besides, several other human like signatures, including PB2-44S, PA-100A, PA-356R, and PA-409N are also found in this avian-origin A(H7N9) virus. The HA protein has the Q226L mutation, which is associated with increased binding to mammalian-like receptors bearing alpha 2,6 receptor in the human upper airway. The M2 protein contains the N31S mutation, suggesting its resistance to the M2 channel blockers amantadine and rimantadine. These findings suggest that this avian-origin AIV gains its bird-to human, i.e., zoonotic, transmissibility and increased virulence, as well as drug resistance, by mutating key signature amino acid residues and those in the functional domains of the viral proteins. Therefore, it is prudent to monitor the evolution of A(H7N9), as well as develop strategies to combat any potential epidemic or pandemic. PMID- 23628411 TI - Proteomic analysis reveals differentially expressed proteins in macrophages infected with Leishmania amazonensis or Leishmania major. AB - CBA macrophages effectively control Leishmania major infection, yet are permissive to Leishmania amazonensis. Employing a transcriptomic approach, we previously showed the up-regulation of the genes involved in the classical pathway of macrophage activation in resistant mice. However, microarray analyses do not evaluate changes in gene expression that occur after translation. To circumvent this analytical limitation, we employed a proteomics approach to increase our understanding of the modulations that occur during infection and identify novel targets for the control of Leishmania infection. To identify proteins whose expression changes in CBA macrophages infected with L. major or L. amazonensis, protein extracts were obtained and digested and the peptides were characterized using multi-dimensional liquid chromatography coupled with tandem mass spectrometry analyses. A total of 162 proteins were selected as potentially modulated. Using biological network analyses, these proteins were classified as primarily involved in cellular metabolism and grouped into cellular development biological networks. This study is the first to use a proteomics approach to describe the protein modulations involved in cellular metabolism during the initial events of Leishmania-macrophage interaction. Based on these findings, we hypothesize that these differentially expressed proteins likely play a pivotal role in determining the course of infection. PMID- 23628412 TI - Replication of Brucella melitensis inside primary human monocytes depends on mitogen activated protein kinase signaling. AB - The clinical course of infections caused by Brucella is linked to its capacity to modulate the initial immune response of macrophages in order to ensure its intracellular replication. Signal transduction pathways implicated in the survival of Brucella in human cells are not completely elucidated. We herein investigated the involvement of the TLR-MAPK-dependent signaling pathways in the survival of Brucella in primary human monocytes using live clinical strains of Brucella melitensis. B. melitensis caused a delayed, TLR2 dependent MAPK activation. Specific MAPK inhibitors for p38 (SB203580), ERK1/2 (PD98059) and JNK (SP600125) or the anti-TLR2 blocking Ab inhibited both inflammatory and anti inflammatory responses characterized by TNF-alpha, IL-6 and IL-10 production. Intracellular replication of B. melitensis was mainly dependent on p38 and JNK activation and not affected by IL-10 levels. These are the first evidence to support that survival of B. melitensis inside human monocytes depends on interplay among the different MAPK family members, activated through TLR2, in spite of an initial pro-inflammatory response. PMID- 23628413 TI - Identification, expression and subcellular localization of ESRG. AB - ESRG (embryonic stem cell related gene, also known as HESRG), is a novel human gene first cloned and identified by our group with microarray analysis. Interestingly, it is expressed specifically in undifferentiated human embryonic stem cells (hESCs), while its expression pattern and its role in hESCs remain unclear. Here, full-length 3151nt ESRG cDNA was further identified by RNA ligase mediated rapid amplification of cDNA ends (RLM-RACE) technique. Meanwhile, an alternatively splicing ESRG transcript (ESRG-B) of 2837nt in length was also found. Surprisingly, bioinformatics analyses showed that the open reading frames (ORFs) of ESRG and ESRG-B were identical. Both of them consist of 669nt and encode a 222aa protein with a predicted molecular size of 24 kDa. The ESRG protein was located in the nuclei of hESCs as demonstrated by immunocytochemical staining and Western blotting using ESRG specific antibody generated by us. In contrast, ESRG located in the cytoplasm of COS7 cells when it was forced to be expressed in these cells by gene transfection strategy, suggesting there may be some special proteins present only in hESCs which can help ESRG protein transport into the nuclei of hESCs. By spatial expression analysis, we further discovered that ESRG only expressed in the ovary tissue and hESCs instead of other tissues or cell lines. Our current data provide us with an important basis for conducting further studies on the functions and regulatory mechanisms underlying the role of ESRG in hESCs. PMID- 23628414 TI - Genes involved in the transition from normal epithelium to intraepithelial neoplasia are associated with colorectal cancer patient survival. AB - Whether the heterogeneity in tumor cell morphology and behavior is the consequence of a progressive accumulation of genetic alterations or an intrinsic property of cancer-initiating cells established at initiation remains controversial. The hypothesis of biological predetermination in human cancer was proposed many years ago and states that the biological potency of cancer cells is predestinated in the precancerous stage. The present study aimed to investigate whether the aberrant molecular events occurring in initial cancer stages could eventually influence colorectal cancer (CRC) progression. We analyzed the mRNA and miRNA expression profiles of colorectal normal mucosa, low-grade intraepithelial neoplasia (LIN), high-grade intraepithelial neoplasia (HIN), and adenocarcinoma tissues. Compared with the transitions from LIN to HIN to invasive carcinoma, the transition from normal epithelium to LIN appeared to be associated with greater changes in the number and expression levels of mRNAs and miRNAs, with a differential expression of 2322 mRNAs and 71 miRNAs detected. Utilizing these early molecular changes, a miRNA-hub network analysis showed that 166 genes were identified as targets regulated by 30 miRNAs. Among these genes, a 55-gene signature regulated by 5 miRNAs was shown to be associated with overall survival or disease-free survival in three independent sample sets. Thus, the molecular changes in the transcriptome associated with the transition from normal to intraepithelial neoplasm may influence CRC progression. PMID- 23628415 TI - Both core and F proteins of hepatitis C virus could enhance cell proliferation in transgenic mice. AB - The role of the protein encoded by the alternative open reading frame (ARF/F/core+1) of the Hepatitis C virus (HCV) genome in viral pathogenesis remains unknown. The different forms of ARF/F/core+1 protein were labile in cultured cells, a myc-tag fused at the N-terminus of the F protein made it more stable. To determine the role of core and F proteins in HCV pathogenesis, transgenic mice with either protein expression under the control of Albumin promoter were generated. Expression of core protein and F protein with myc tag (myc-F) could be detected by Western blotting analysis in the livers of these mice. The ratio of liver to body weight is increased for both core and myc-F transgenic mice compared to that of wild type mice. Indeed, the proliferating cell nuclear antigen protein, a proliferation marker, was up-regulated in the transgenic mice with core or myc-F protein. Further analyses by microarray and Western blotting suggested that beta-catenin signaling pathway was activated by either core or myc-F protein in the transgenic mice. These transgenic mice were further treated with either Diethynitrosamine (a tumor initiator) or Phenobarbital (a tumor promoter). Phenobarbital but not Diethynitrosamine treatment could increase the liver/body weight ratio of these mice. However, no tumor formation was observed in these mice. In conclusion, HCV core and myc-F proteins could induce hepatocyte proliferation in the transgenic mice possibly through beta-catenin signaling pathway. PMID- 23628416 TI - A novel function of HPV16-E6/E7 in epithelial-mesenchymal transition. AB - Human papillomavirus (HPV) 16 is among the most important etiological factors in many human cancers, including head and neck squamous cell carcinomas (HNSCCs) not associated with alcohol or tobacco use. HPV16-E6 and E7 oncoproteins target intracellular signaling networks, altering key molecular and cellular events during tumor progression. The present study investigates the role of HPV16-E6 and E7 oncogenes on the epithelial-mesenchymal transition (EMT), a cellular process thought to be critical for tumor cell invasion and metastasis. Using the epithelial MDCK cell line as an in vitro model, we show that the stable expression of HPV16-E6 or E7 induces morphological conversion from cobblestone shaped epithelium to spindle-shaped mesenchyme-like phenotype. Consistent with these morphological changes, both E6 and E7 induce expression of the EMT activating transcriptional factors Slug, Twist, ZEB1 and ZEB2, especially ZEBs, accompanied with switch from epithelial to mesenchymal markers. Importantly, E6 and E7 expression results in induction of the migratory and invasive potential, a functional hallmark of EMT. When we examined the association between HPV16 and the EMT signature in HNSCC cell lines derived from head and neck cancer patients, we found a correlation between HPV16 positivity and the expression of EMT transcription factor ZEB1. Taken together, our findings suggest HPV16 induces EMT like processes via induction of the EMT transcription factors which may contribute to tumor progression and metastasis. PMID- 23628417 TI - Tumor suppressor BLU promotes paclitaxel antitumor activity by inducing apoptosis through the down-regulation of Bcl-2 expression in tumorigenesis. AB - In this current work, we investigated whether BLU could enhance pro-apoptotic activity of chemotherapeutic drugs in ovarian carcinoma cells. A combination with a chemotherapeutic drug showed an additive effect, and this additive effect was supplemented by the enhancement of caspase-3 and -9 activities. BLU and paclitaxel induced cell cycle arrest in the G2/M phase through the reduction of cyclin dependent kinase 1, cyclin B1, while promoting both p16 and p27 expression. In addition, both BLU and paclitaxel enhanced the expression of the pro-apoptotic protein Bax together with the suppression of anti-apoptotic protein Bcl-2, a protein which is well-known for its function as a regulator in protecting cells from apoptosis. As expected, the Bax and p21 activities were enhanced by BLU or paclitaxel, while a combination of BLU and paclitaxel were additively promoted, whereas Bcl-xL and NF-kappaB including Bcl-2 activity were inactivated. This study has yielded promising results, which evidence for the first time that BLU could suppress the growth of carcinoma cells. Furthermore, both BLU and paclitaxel inhibited the phosphorylation of signaling components downstream of phosphoinositide 3-kinase, such as 3-phosphoinositide-dependent protein kinase 1, and Akt. Also, BLU plus paclitaxel decreased phosphorylation of p70 ribosomal S6 kinase, as well as decreasing the phosphorylation of glycogen synthase kinase-3beta, which is one of the representative targets of the mammalian target of rapamycin signaling cascade. These results provide evidence that BLU enhances G2/M cell cycle arrest and apoptotic cell death through the up regulation of Bax, p21 and p53 expression. PMID- 23628418 TI - Effects of single hyperinflation using a sustained high pressure manoeuvre during inhalation anaesthesia in horses. AB - The effect of a single hyperinflation using a sustained high-pressure manoeuvre (SHPM) during inhalation anaesthesia was evaluated in horses. Twenty-eight client owned male horses were recruited; 14 were operated on in dorsal recumbency and 14 in lateral recumbency. For each category, horses were randomly allocated to either the 'breathing spontaneously' or 'mechanically ventilated' group. After 30 min of anaesthesia, baseline cardiorespiratory parameters were collected and a SHPM of 50 cmH2O during 50s was undertaken. In the group of horses breathing spontaneously and positioned in dorsal recumbency, venous admixture developed significantly more than in other groups and a single SHPM only partially and transiently improved arterial oxygenation. No benefit of the respiratory manoeuvre was observed in the other groups. PMID- 23628419 TI - Broiler ascites syndrome: collateral damage from efficient feed to meat conversion. AB - Chickens have been raised as food for human consumption for over 4000 years. Over this time they have been continuously selected for specific desirable characteristics by active selection of parents to produce birds which fit perceived needs. Despite this long history of selective breeding and improvements in rearing techniques, the efficiency with which broiler meat is produced has shown a remarkable leap in recent decades. Persistent selection for rapid growth, high feed utilisation efficiency and large cut yield has resulted in modern meat type poultry lines with superior genetic potential with regard to productivity. However, mortality and the incidence of metabolic diseases has increased in parallel with growth rate. One such disease is broiler ascites syndrome, which has been shown to be closely associated with the fast growth and high meat yield resulting from intense selection and with modern rearing techniques. The review is focused on the historical background, pathogenesis, epidemiology and prevention of broiler ascites syndrome in modern broiler production. PMID- 23628420 TI - Predicting the incidence of antipsychotic-induced movement disorders in long-stay patients: A prospective study. PMID- 23628421 TI - 2013 update on the worldwide standardization of the hemoglobin A1c measurement. PMID- 23628422 TI - Depression and pain interference among patients with chronic pain after ED encounters. AB - INTRODUCTION: Patients with chronic pain who frequent emergency departments present a challenge to health care providers. Mental health, substance abuse, and pain issues are difficult to distinguish in fast-paced clinical settings, and significant symptoms may remain unaddressed. This pilot study sought to determine whether electronically delivered screening tools measuring pain and mood could identify areas to target for improving emergency care. METHODS: A prospective, descriptive pilot study used repeated measures of validated instruments to investigate the status of patients after their ED encounter. Persons with chronic pain not related to cancer and documented opioid use were recruited by nursing personnel after an ED encounter. Consenting participants (n = 52) were invited to perform an online survey that included self-reported measurements of pain intensity, pain interference, depression, subjective health, and health distress. The survey was repeated after 8 weeks. RESULTS: The baseline survey was completed by 42.3% of 52 patients who provided consent (n = 22, 68.2% female). The mean pain severity score was 5.96 (SD 1.57) and the mean pain interference score was 7.52 (SD 1.81) using 0 to 10 scales of the Brief Pain Inventory. Personal Health Questionnaire Depression Scale ratings indicated that a major depressive disorder should be considered for 54% of the participants. DISCUSSION: Online surveys delivered to patients with chronic pain detected unmet needs for depression and persisting high levels of pain interference after ED encounters. Adding mood specific screening tools to pain assessments may be necessary in clinical settings to identify depression and refer for appropriate treatment. PMID- 23628423 TI - Update on the human immunodeficiency virus. AB - At the end of 2011, UNAIDS estimated that 34 million (31.4 to 35.9) individuals were infected by HIV worldwide and that 2.5 million were newly infected during the year. Since 2001, we have observed an increased number of HIV-infected patients in the world, due to an expanded access to antiretroviral drugs. More than 23,5 million (22.1 to 24.8) HIV-infected patients live in Sub-Saharan Africa. The number of HIV-infected patients in France is estimated at 152,000. Two types of HIV cause AIDS: HIV-1 and HIV-2 that are subdivided in groups (M, N, O, P for HIV-1; A to H for HIV-2), subtypes (A-D, F-H, J-K for HIV-1 group M), sub-subtype (A1-A4 for subtype A, F1 and F2 for subtype F in HIV-1 group M), circulating recombinant forms (CRF), and unique recombinant forms in a small number of patients. Virological diagnostic and monitoring techniques have been constantly upgraded since HIV-1 was isolated in 1983 and the first serological tests became available in 1985. This is especially true for HIV-1, the most prevalent worldwide. PMID- 23628425 TI - Clinical course and visual outcome in patients with diabetes mellitus and uveitis. AB - PURPOSE: We report the clinical course and visual outcome of patients with diabetes mellitus (DM) who subsequently developed uveitis from any cause. METHODS: Longitudinal, retrospective case note review. RESULTS: A total of 36 patients (M/F: 18/18, 58 eyes) were included, Of the 36 patients, 35 had Type 2 DM and one had Type 1 DM. Mean age of onset of DM was 49 years and uveitis 55 years. The uveitis was bilateral in 22 (61%) patients. There were 19 patients with anterior uveitis, 12 with panuveitis and 5 with intermediate uveitis. Mean follow up was 4.4 years (range 1-18). Mean number of uveitis recurrences was 3 (range 1-7). Causes of vision of 6/18 or worse appeared related to the uveitis in 9 eyes and diabetes in 4 eyes. Cataract occurred in 22 eyes, glaucoma in 17 eyes, and cystoid macular oedema in 10 eyes. Diabetic retinopathy was detected in 38 (65.5%) eyes (29 non-proliferative including 6 with clinically significant macular oedema, and 9 proliferative). Progression of diabetic retinopathy to proliferative stage occurred in 7 eyes of 4 patients over a mean duration of 4.4 years. In 10 patients with active uveitis the mean HbA1c was 80 mmol/mol [9.5%], (range 49-137 [6.6-14.7]), and 67 mmol/mol [8.3%] (range 46-105 [6.4-11.8]) when the uveitis was quiescent, p = 0.01. Better glycaemic control was required in 10 patients during episodes of uveitis. CONCLUSIONS: Patients with DM who develop uveitis may have a high complication rate, reduced vision and poor glycaemic control. Checking blood glucose during episodes of uveitis is important. PMID- 23628426 TI - Adhesion awareness: a nationwide survey of gynaecologists. AB - OBJECTIVE: Adhesions and related complications lead to substantially increased morbidity and mortality which increase medical costs. We investigated the awareness of adhesions among Dutch gynaecologists and gynaecology residents. STUDY DESIGN: A survey, assessing knowledge and opinion about adhesions, was sent to a randomly selected group of 381 gynaecologists and 256 residents. In addition, the informed consent process and application of anti-adhesive agents were questioned. RESULTS: The response rate was 56.9%. Complications due to adhesions were highly underestimated, leading to low knowledge scores (mean score 35.1%). Of all respondents 73.8% agreed that adhesions exert a clinically relevant and negative effect, but only 51.2% expressed a positive opinion on adhesion prevention. This correlated with a stronger belief in the clinically relevant and negative effects of adhesions and the opinion that adhesion prevention belongs to standard care (rho=0.212, p<0.001; rho=0.495, p<0.001). Of all respondents 31.4% expressed a positive attitude towards anti-adhesive agents and 19.8% expressed a negative one. A negative attitude correlated with a negative view in terms of cost-benefits (rho=0.245, p<0.001). Although 43.5% had used anti-adhesive agents in the past year, 20.9% had used them before but stopped using agents in the past year. Only 5.2% routinely included adhesions or related morbidity in the informed consent. CONCLUSIONS: Awareness of adhesions is limited and informed consent is provided inadequately. Implementing adhesion prevention is related with awareness of adhesions. These findings underline the need to embed adhesions, related morbidity and prevention in educational programmes. PMID- 23628424 TI - CRISPR-Cas systems target a diverse collection of invasive mobile genetic elements in human microbiomes. AB - BACKGROUND: Bacteria and archaea develop immunity against invading genomes by incorporating pieces of the invaders' sequences, called spacers, into a clustered regularly interspaced short palindromic repeats (CRISPR) locus between repeats, forming arrays of repeat-spacer units. When spacers are expressed, they direct CRISPR-associated (Cas) proteins to silence complementary invading DNA. In order to characterize the invaders of human microbiomes, we use spacers from CRISPR arrays that we had previously assembled from shotgun metagenomic datasets, and identify contigs that contain these spacers' targets. RESULTS: We discover 95,000 contigs that are putative invasive mobile genetic elements, some targeted by hundreds of CRISPR spacers. We find that oral sites in healthy human populations have a much greater variety of mobile genetic elements than stool samples. Mobile genetic elements carry genes encoding diverse functions: only 7% of the mobile genetic elements are similar to known phages or plasmids, although a much greater proportion contain phage- or plasmid-related genes. A small number of contigs share similarity with known integrative and conjugative elements, providing the first examples of CRISPR defenses against this class of element. We provide detailed analyses of a few large mobile genetic elements of various types, and a relative abundance analysis of mobile genetic elements and putative hosts, exploring the dynamic activities of mobile genetic elements in human microbiomes. A joint analysis of mobile genetic elements and CRISPRs shows that protospacer adjacent motifs drive their interaction network; however, some CRISPR-Cas systems target mobile genetic elements lacking motifs. CONCLUSIONS: We identify a large collection of invasive mobile genetic elements in human microbiomes, an important resource for further study of the interaction between the CRISPR-Cas immune system and invaders. PMID- 23628427 TI - Genotoxicity of 2-bromo-3'-chloropropiophenone. AB - Impurities are present in any drug substance or drug product. They can be process related impurities that are not completely removed during purification or are formed due to the degradation of the drug substance over the product shelf-life. Unlike the drug substance, impurities generally do not have beneficial effects and may present a risk without associated benefit. Therefore, their amount should be minimized. 2-Bromo-3'-chloropropiophenone (BCP) is an impurity of bupropion, a second-generation antidepressant and a smoking cessation aid. The United States Pharmacopeia recommends an acceptable level for BCP that is not more than 0.1% of the bupropion. Because exposure to genotoxic impurities even at low levels is of significant concern, it is important to determine whether or not BCP is genotoxic. Therefore, in this study the Ames test and the in vitro micronucleus assay were conducted to evaluate the genotoxicity of BCP. BCP was mutagenic with S9 metabolic activation, increasing the mutant frequencies in a concentration dependent manner, up to 22- and 145-fold induction over the controls in Salmonella strains TA100 and TA1535, respectively. BCP was also positive in the in vitro micronucleus assay, resulting in up to 3.3- and 5.1-fold increase of micronucleus frequency for treatments in the absence and presence of S9, respectively; and 9.9- and 7.4-fold increase of aneuploidies without and with S9, respectively. The addition of N-acetyl-l-cysteine, an antioxidant, reduced the genotoxicity of BCP in both assays. Further studies showed that BCP treatment resulted in induction of reactive oxygen species (ROS) in the TK6 cells. The results suggest that BCP is mutagenic, clastogenic, and aneugenic, and that these activities are mediated via generation of reactive metabolites. PMID- 23628428 TI - Cytochrome P450 2A5 and bilirubin: mechanisms of gene regulation and cytoprotection. AB - Bilirubin (BR) has recently been identified as the first endogenous substrate for cytochrome P450 2A5 (CYP2A5) and it has been suggested that CYP2A5 plays a major role in BR clearance as an alternative mechanism to BR conjugation by uridine diphosphate glucuronyltransferase 1A1. This study investigated the mechanisms of Cyp2a5 gene regulation by BR and the cytoprotective role of CYP2A5 in BR hepatotoxicity. BR induced CYP2A5 expression at the mRNA and protein levels in a dose-dependent manner in primary mouse hepatocytes. BR treatment also caused nuclear translocation of Nuclear factor-E2 p45-related factor 2 (Nrf2) in hepatocytes. In reporter assays, BR treatment of primary hepatocytes transfected with a Cyp2a5 promoter-luciferase reporter construct resulted in a 2-fold induction of Cyp2a5 reporter activity. Furthermore, cotransfection of the hepatocytes with a Nrf2 expression vector without BR treatment resulted in an increase in Cyp2a5 reporter activity of approximately 2-fold and BR treatment of Nrf2 cotransfectants further increased reporter activity by 4-fold. In addition, site-directed mutation of the ARE in the reporter construct completely abolished both the BR- and Nrf2-mediated increases in reporter activity. The cytoprotective role of CYP2A5 against BR-mediated apoptosis was also examined in Hepa 1-6 cells that lack endogenous CYP2A5. Transient overexpression of CYP2A5 partially blocked BR-induced caspase-3 cleavage in Hepa 1-6 cells. Furthermore, in vitro degradation of BR was increased by microsomes from Hepa 1-6 cells overexpressing CYP2A5 compared to control cells transfected with an empty vector. Collectively, these results suggest that Nrf2-mediated CYP2A5 transactivation in response to BR may provide an additional mechanism for adaptive cytoprotection against BR hepatotoxicity. PMID- 23628429 TI - Canada: Health system review. AB - Canada is a high-income country with a population of 33 million people. Its economic performance has been solid despite the recession that began in 2008. Life expectancy in Canada continues to rise and is high compared with most OECD countries; however, infant and maternal mortality rates tend to be worse than in countries such as Australia, France and Sweden. About 70% of total health expenditure comes from the general tax revenues of the federal, provincial and territorial governments. Most public revenues for health are used to provide universal medicare (medically necessary hospital and physician services that are free at the point of service for residents) and to subsidise the costs of outpatient prescription drugs and long-term care. Health care costs continue to grow at a faster rate than the economy and government revenue, largely driven by spending on prescription drugs. In the last five years, however, growth rates in pharmaceutical spending have been matched by hospital spending and overtaken by physician spending, mainly due to increased provider remuneration. The governance, organization and delivery of health services is highly decentralized, with the provinces and territories responsible for administering medicare and planning health services. In the last ten years there have been no major pan Canadian health reform initiatives but individual provinces and territories have focused on reorganizing or fine tuning their regional health systems and improving the quality, timeliness and patient experience of primary, acute and chronic care. The medicare system has been effective in providing Canadians with financial protection against hospital and physician costs. However, the narrow scope of services covered under medicare has produced important gaps in coverage and equitable access may be a challenge in these areas. PMID- 23628430 TI - The association between probable personality disorders and smoking cessation and maintenance. AB - INTRODUCTION: Although it has been suggested that persons with psychopathological disorders experience greater difficulty in quitting smoking, the few studies that have analyzed personality disorders in smokers have failed to produce conclusive results. The aim of this study was to examine whether the presence of probable personality disorders was associated with the achievement of abstinence at the end of a smoking cessation treatment, as well as the maintenance of abstinence at 6 and 12 months of follow-up. METHODS: The sample comprised 290 smokers (41% men and 59% women) who participated in a psychological smoking cessation treatment and who were followed for a year. Abstinence was tested by measuring carbon monoxide in exhaled air. RESULTS: Participants with a probable borderline, antisocial or avoidant personality disorder were less likely to quit smoking at the end of the treatment, whereas probable schizoid personality disorder predicted better maintenance of abstinence at 6 and 12 months. In addition, smoking 25 or more cigarettes before starting the treatment decreased the likelihood of maintaining abstinence at 6 and 12 months of follow-up. CONCLUSIONS: This study revealed differential (and opposing) relationships between specific personality disorders and smoking cessation outcomes, illustrating the need to consider Axis II disorders separately when predicting treatment outcomes. PMID- 23628431 TI - The impact of pregaming on subsequent blood alcohol concentrations: an event level analysis. AB - Pregaming has been highlighted as an especially deleterious college drinking ritual. The present study assessed (a) event-level associations between pregaming and biologic samples of blood alcohol concentration (BrAC) and (b) the impact of one's alcohol-related behaviors (measured by AUDIT-C scores) on the likelihood that respondents would report pregaming prior to a night out drinking. The sample included adult (n=1029; collegiate and non-college-affiliated) bar patrons in a southeastern college community. Multiple and linear regressions were conducted to determine the association between pregaming and BrAC levels, and pregaming and the presence of an alcohol use disorder, respectively. After controlling for the influence of time of data collection, gender, age, college student status, and ethnicity, the linear regression model explained 15.5% (R2=.155) of the variance in BrAC levels (F (10, 915)=16.838, p<0.001), of which 10.8% was accounted for by self-reported pregaming alone. Furthermore, pregamers exhibited significantly higher BrACs compared to non-pregamers (beta=.332, p<.001). Logistic regression analyses indicated that AUDIT-C scores were the only significant predictor of pregaming status (OR=1.305, Wald=64.843), such that respondents with higher AUDIT C scores (B=0.266) were more likely to pregame. This event-level study highlights the practice of pregaming as an insidious behavior associated with enhanced levels of drinking behavior and overall intoxication. PMID- 23628432 TI - Decreased gray matter volume of the medial orbitofrontal cortex in panic disorder with agoraphobia: a preliminary study. AB - BACKGROUND: Patients with panic disorder with agoraphobia (PDA) have clinical symptoms such as the fear of being outside or of open spaces from which escape would be difficult. Although recent neurobiological studies have suggested that fear conditioning and extinction are associated with PDA, no study has examined the possible structural abnormalities in patients with PDA. METHODS: This preliminary study compares the gray matter volume among patients with PDA, those with panic disorder without agoraphobia (PDW), and healthy controls (HC) using high-resolution 3.0 T magnetic resonance imaging (MRI) with voxel-based morphometry (VBM). RESULTS: Compared with HC, patients with PDA showed decreased gray matter volume in their left medial orbitofrontal gyrus. However, differences were not found in the gray matter volumes of patients with PDW and whole panic disorder compared with HC. CONCLUSIONS: These findings suggest that the phobic avoidance found in patients with PDA arise from abnormalities in the medial orbitofrontal cortex, which plays an important role in fear extinction. Future studies should investigate the neuroanatomical substrates of PDA and distinguish them from those of PDW. PMID- 23628434 TI - Species conserved DNA damage response at the inactive human X chromosome. AB - Chromatin modifications are long known as an essential part of the orchestrated response resulting in the repair of radiation-induced DNA double-strand breaks (DSBs). Only recently, however, the influence of the chromatin architecture itself on the DNA damage response has been recognised. Thus for heterochromatic DSBs the sensing and early recruitment of repair factors to the lesion occurs within the heterochromatic compartments, but the damage sites are subsequently relocated from the inside to the outside of the heterochromatin. While previous studies were accomplished at the constitutive heterochromatin of centromeric regions in mouse and flies, here we examine the DSB repair at the facultative heterochromatin of the inactive X chromosome (Xi) in humans. Using heavy ion irradiation we show that at later times after irradiation the DSB damage streaks bend around the Xi verifying that the relocation process is conserved between species and not specialised to repetitive sequences only. In addition, to measure chromatin relaxation at rare positions within the genome, we established live cell microscopy at the GSI microbeam thus allowing the aimed irradiation of small nuclear structures like the Xi. Chromatin decondensation at DSBs within the Xi is clearly visible within minutes as a continuous decrease of the DNA staining over time, comparable to the DNA relaxation revealed at DSBs in mouse chromocenters. Furthermore, despite being conserved between species, slight differences in the underlying regulation of these processes in heterochromatic DSBs are apparent. PMID- 23628433 TI - Genetic association and gene-gene interaction analyses suggest likely involvement of ITGB3 and TPH2 with autism spectrum disorder (ASD) in the Indian population. AB - BACKGROUND: Serotoninergic dysfunction leads to neurodevelopmental abnormalities and behavioral impairments. Platelet hyperserotoninemia is reported as the best identified endophenotype for autism spectrum disorders. Therefore, in the present study we investigate the association of TPH2, the rate limiting enzyme in 5-HT biosynthesis and ITGB3, a serotonin quantitative trait locus with ASD in the Indian population. METHODS: Population and family-based genetic association and gene-gene interaction analyses were performed to evaluate the role of ITGB3 and TPH2 markers in ASD etiology. RESULTS: Association tests using ITGB3 markers revealed significant paternal overtransmission of T allele of rs5918 to male probands. Interestingly for TPH2, we observed significant overrepresentation of A A (rs11179000-rs4290270), G-A (rs4570625-rs4290270), G-G-A (rs4570625-rs11179001 rs4290270) and A-G-A (rs11179000-rs11179001-rs4290270) haplotypes in the controls and maternal preferential transmission of A-A (rs11179001-rs7305115), T-A-A (rs4570625-rs11179001-rs7305115) and T-A-A (rs11179000-rs11179001-rs7305115) and nontransmission of G-G-A (rs4570625-rs11179001-rs7305115) haplotypes to the affected offspring. Moreover, interaction of ITGB3 marker, rs15908 with TPH2 markers was found to be significant and influenced by the sex of the probands. Predicted individual risk, which varied from very mild to moderate, supports combined effect of these markers in ASD. CONCLUSION: Overall results of the present study indicate likely involvement of ITGB3 and TPH2 in the pathophysiology of ASD in the Indian population. PMID- 23628435 TI - Genotoxicity and oxidative stress in gasoline station attendants. AB - We evaluated genotoxic effects of exposure to low levels of benzene, a class I human carcinogen, among gasoline station attendants (GSA). Oxidative stress and the protective effects of antioxidants on DNA damage were also analyzed. Although exposures were below ACGIH (American Conference of Governmental Industrial Hygienists) limits, the GSA group presented higher DNA damage indices and micronucleus frequencies, increased oxidative protein damage, and decreased antioxidant capacity relative to the control group. Duration of benzene exposure was correlated with DNA and protein damage. The biomarkers evaluated in this work may provide early signals of damage in subjects occupationally exposed to benzene. PMID- 23628436 TI - Predicting hotspots for influenza virus reassortment. AB - The 1957 and 1968 influenza pandemics, each of which killed ~1 million persons, arose through reassortment events. Influenza virus in humans and domestic animals could reassort and cause another pandemic. To identify geographic areas where agricultural production systems are conducive to reassortment, we fitted multivariate regression models to surveillance data on influenza A virus subtype H5N1 among poultry in China and Egypt and subtype H3N2 among humans. We then applied the models across Asia and Egypt to predict where subtype H3N2 from humans and subtype H5N1 from birds overlap; this overlap serves as a proxy for co infection and in vivo reassortment. For Asia, we refined the prioritization by identifying areas that also have high swine density. Potential geographic foci of reassortment include the northern plains of India, coastal and central provinces of China, the western Korean Peninsula and southwestern Japan in Asia, and the Nile Delta in Egypt. PMID- 23628437 TI - Magnesium sulfate provides neuroprotection in lipopolysaccharide-activated primary microglia by inhibiting NF-kappaB pathway. AB - BACKGROUND: Magnesium sulfate has been used as an anticonvulsant in severe preeclamptic or eclamptic women prior to surgical trauma, but its effects on neuroinflammation is not well defined. In the present study, we investigated the neuroprotective effects of magnesium sulfate in lipopolysaccharide (LPS)-induced microglia and explored the underlying mechanism. MATERIALS AND METHODS: Microglia was incubated with LPS in the presence or absence of various concentrations of magnesium sulfate, or L-type calcium channel activator BAY-K8644. The levels of inflammatory mediators, such as nitric oxide, prostaglandin E2, interleukin 1beta, and tumor necrosis factor alpha, were measured using enzyme-linked immunosorbent assay. The expression of inducible nitric oxide synthase mRNA was detected by reverse-transcription polymerase chain reaction. Nuclear factor kappaB (NF-kappaB) activity in the nuclear extract of microglia was detected by NF-kappaB p50/p65 transcription factor assay kit. RESULTS: Magnesium sulfate at 5 and 10 mmol/L significantly inhibited the release of nitric oxide, prostaglandin E2, interleukin 1beta, and tumor necrosis factor alpha, and the expression of inducible nitric oxide synthase mRNA in LPS-activated microglia. Furthermore, magnesium sulfate inhibited the translocation of NF-kappaB from the cytoplasm to the nucleus in a dose-dependent manner. Notably, these effects were significantly reversed by L-type calcium channel activator BAY-K8644. CONCLUSIONS: Magnesium sulfate protects microglia against LPS-induced release of inflammatory mediators, and these effects may be mediated by inhibiting L-type calcium channels and NF kappaB signaling. PMID- 23628438 TI - Enhanced spectral analysis of blood flow during post-occlusive reactive hyperaemia test in different tissue depths. AB - The objective of this study was to investigate the impairment of microcirculation in schizophrenic patients by means of spectral analysis of blood flow signals and to determine if microcirculation is unequally altered in different tissue depths. Furthermore, the impact of gender and age on the spectral parameters of the Laser Doppler Flowmetry (LDF) signal in healthy and diseased microcirculation are to be analysed. The segmented spectral analysis (SSA) algorithm was applied to LDF signals of a provoked post-ischemic stage and compared to the traditional total spectral analysis, hypothesizing that SSA reveals more detailed information on the dynamic behaviour of the blood flow. 15 healthy subjects (CON, mean age 32.4 years) and 15 patients (PAT, mean age 33.0 years) were enrolled. Spectral analysis was performed on two LDF signals at a depth of 2mm and 6-8mm. Features in five frequency subintervals were determined. Our results indicate that microcirculation is strongly impaired in patients. SSA of blood flow revealed differences between CON and PAT in all three frequency intervals referring to local vasomotion (endothelial p=0.03; sympathetic p=0.02, myogenic p=0.03) as well as the respiratory (p=0.02) and cardiac (p=0.006) bands in the deeper tissue. In contrast, in the near-surface tissue only the endothelial (p=0.006) and cardiac (p=0.006) components were altered. Furthermore, SSA determined a gender- and age dependency regarding blood flow. In conclusion, we could demonstrate that microcirculation in schizophrenic patients is significantly impaired, depending on its location in the near-surface skin or in the superficial muscle tissue. These alterations of microcirculation are more pronounced in the deeper tissue depth of about 6-8mm and are influenced by gender and age. PMID- 23628439 TI - Diffusion weighted imaging with trace diffusion weighted imaging, the apparent diffusion coefficient and exponential images in the diagnosis of spinal cord infarction. AB - A 73-year-old man, with a history of hypertension and left supraclavicular fossa arteriovenous malformation with multiple previous uncomplicated vessel embolisation procedures, presented with acute spastic quadriparesis and urinary retention following upper limb angiography and embolisation. There was no evidence of preceding infection or neurological disease prior to the event. Cerebrospinal fluid analysis was unremarkable. MRI of the cervical spine with a 1.5 Tesla magnet performed 13 hours from symptom onset revealed bilateral paramedian intramedullary T2-weighted signal change without gadolinium enhancement limited to the grey matter with corresponding diffusion restriction extending from C5-6 down to the mid-T1. The diagnosis of cervical spinal cord infarction (SCI) was made and the patient was given regular aspirin and atorvastatin. On follow-up at 3 months, there was modest improvement with respect to his quadriparesis and was walking unaided. An extensive literature review on the role of MRI in SCI is discussed. PMID- 23628440 TI - Effect of single nucleotide polymorphisms of the prostacyclin receptor gene on platelet activation in Japanese healthy subjects and patients with cerebral infarction. AB - Cerebral infarction (CI) is a complex multifactorial disorder that is thought to result from the interaction of various environmental factors and an individual's genetic make-up, including genes associated with platelet activation. In order to clarify whether single nucleotide polymorphisms (SNPs) of the prostacyclin receptor (IP) gene affects platelet activation in ischemic stroke, we investigated the relationship between platelet function and genetic polymorphism of the coding sequence of the IP gene in 64 Japanese patients with CI and 54 healthy subjects. We determined the entire nucleotide sequence of the IP gene in healthy Japanese subjects, and found that an adenine (A) to cytosine (C) substitution at base 984 (A984C) in exon 3 is the most frequent SNP. Using flow cytometry, the power-transformed mean percentage of PAC-1-positive platelets, [PAC-1](1/3), was significantly higher in healthy subjects with the C/C genotype than in healthy subjects with the A/A genotype (p <= 0.05), although there was no significant difference in patients with CI between these two genotypes. Furthermore, we genotyped 158 control patients and 106 patients with CI. The homozygous C/C genotype was more frequently found in the CI group (46.2%) than in the healthy control group (17.1%; p < 0.001). The present report is the first to show an association between the A984C polymorphism of the IP gene and platelet activation in Japanese subjects. This polymorphism may be clinically significant in disorders in which prostacyclin plays a key role, such as CI. PMID- 23628441 TI - Apraxia of speech in healthy 36-year-old man. AB - A 36-year-old healthy man presented with sudden onset speech difficulty. Thorough clinical examination revealed interesting deficits suggestive of apraxia of speech. He was found to have an infarct in his frontal region explaining the deficits. We have undertaken clinical evaluation and differential diagnoses of this condition. PMID- 23628442 TI - Avian influenza A H7N9 in Zhejiang, China. PMID- 23628443 TI - Mumps outbreak in private schools: public health lessons for the post-Wakefield era. PMID- 23628444 TI - [Evolution of patients treated with methadone in general practice]. PMID- 23628445 TI - The discovery of the Guillain-Barre syndrome and related disorders. PMID- 23628446 TI - [Depressive symptoms and widespread pains in a prisoner: think on vitamin D deficiency]. AB - The confinement can lead to an important limitation of sun exposure of the prisoners. This limitation can lead to a deficit in vitamin D, source of diverse disorders. Diffuse pains of members and of joints are the most classics troubles. The association of vitamin D deficiency and psychiatric disorders is frequent but badly known. Even if there is still no evidence indicating a cause and effect relationship between vitamin D deficiency and depressive episodes, the contribution of vitamin D deficiency in the arisen of a depression has to be considered. The treatment of vitamin D deficiency cannot, in itself, constitute a treatment of the depressive disorder but contributes to the improvement of the whole status The psychiatric follow-up remains indispensable, in particular because of the suicidal risk, particularly present in prison. PMID- 23628447 TI - Diagnosis, treatment and prognosis of Guillain-Barre syndrome (GBS). AB - Guillain-Barre syndrome (GBS) is an acute polyneuropathy with a variable degree of weakness that reaches its maximal severity within 4 weeks. The disease is mostly preceded by an infection and generally runs a monophasic course. Both intravenous immunoglobulin (IVIg) and plasma exchange (PE) are effective in GBS. Rather surprisingly, steroids alone are ineffective. Mainly for practical reasons, IVIg usually is the preferred treatment. GBS can be subdivided in the acute inflammatory demyelinating polyneuropathy (AIDP), the most frequent form in the western world; acute motor axonal neuropathy (AMAN), most frequent in Asia and Japan; and in Miller-Fisher syndrome (MFS). Additionally, overlap syndromes exist (GBS-MFS overlap). About 10% of GBS patients have a secondary deterioration within the first 8 weeks after start of IVIg. Such a treatment-related fluctuation (TRF) requires repeated IVIg treatment. About 5% of patients initially diagnosed with GBS turn out to have chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with acute onset (A-CIDP). It is yet unknown whether GBS patients who remain able to walk ('mildly affected GBS patients'), or patients with MFS, also benefit from IVIg. Despite current treatment, GBS remains a severe disease, as about 25% of patients require artificial ventilation during a period of days to months, about 20% of patients are still unable to walk after 6 months and 3-10% of patients die. Additionally, many patients have pain, fatigue or other residual complaints that may persist for months or years. Pain can also be very confusing in making the diagnosis, especially when it precedes the onset of weakness. Advances in prognostic modelling resulted in the development of a simple prognostic scale that predicts the chance for artificial ventilation, already at admission; and in an outcome scale that can be used to determine the chance to be able to walk unaided after 1, 3 or 6 months. GBS patients with a poor prognosis potentially might benefit from a more intensified treatment. A larger increase in serum IgG levels after standard IVIg treatment (0.4 g/kg/day for 5 consecutive days) seems to be related with an improved outcome after GBS. This was one of the reasons to start the second course IVIg trial (SID-GBS trial) in GBS patients with a poor prognosis. This study is currently going on. The international GBS outcome study (IGOS) is a new worldwide prognostic study that aims to get further insight in the (immune)pathophysiology and outcome of GBS, both in children and adults. Hopefully these and other studies will further help to improve the understanding and especially the outcome in patients with GBS. PMID- 23628448 TI - [Cutaneous nodules revealing systemic alternariosis]. PMID- 23628449 TI - Importance of the nicotinic acetylcholine receptor system in the prefrontal cortex. AB - The prefrontal cortex (PFC) is responsible for integrating cortical and subcortical inputs to execute essential cognitive functions such as attention, working memory planning and decision-making. The importance of this brain region in regulating complex cognitive processes is underscored by a decline in PFC mediated ability observed in aging and disease. The cholinergic system plays a vital role in cognitive function and treatments (e.g., cholinesterase inhibitors) to improve cholinergic neurotransmission provide the standard-of-care for diseases such as Alzheimer's. Nicotinic receptors (nAChRs) are a primary site of action for acetylcholine (ACh), and the resulting pro-cognitive effects observed by stimulating nAChRs with nicotine has long been appreciated by tobacco users, prompting investigation of therapeutic development for diseases (e.g., schizophrenia, Alzheimer or attention-deficit-hyperactivity disorder) by targeting the neuronal nAChR system. Noteworthy, improvements in attention, working memory and executive processes mediated by the PFC have been reported following nicotinic agonist exposure. Relevance of these ligand gated channels in higher brain function is further supported by the association of cognitive deficits reported in humans with mutations in CHRNB2 or CHRNA7 the genes encoding for the nicotinic receptor beta2 and alpha7 subunits, respectively. In this work we review, in light of the latest findings, how nicotinic agonists may be acting in the PFC to influence cognitive function. PMID- 23628450 TI - Linking abuse and recovery through advocacy: an observational study. AB - Aims. High numbers of psychiatric service users experience domestic violence, yet limited interventions exist for these victims. We piloted a domestic violence intervention for community mental health services to explore the feasibility of a future cluster randomized controlled trial. Methods. Quasi-experimental controlled design within five Community Mental Health Teams (three intervention and two control teams). The intervention comprised domestic violence training for clinicians' and referral to domestic violence advocacy for service users. Clinicians' (n = 29) domestic violence knowledge, attitudes and behaviours were assessed before and 6 months post-training. Service users' (n = 34) safety behaviours, unmet needs, quality of life and frequency/severity of abuse were examined at baseline and 3 months follow-up. Process evaluation data were also collected. Results. Clinicians receiving the intervention reported significant improvements in domestic violence knowledge, attitudes and behaviours at follow up (p < 0.05). Service users receiving the intervention reported significant reductions in violence (p < 0.001) and unmet needs at follow-up (p < 0.05). Conclusions. Interventions comprising domestic violence training for clinicians and referral to domestic violence advocacy may improve responses of psychiatric services. Low rates of identification among teams not receiving training suggest that future trials using service user outcomes are unlikely to be feasible. Therefore, other methods of evaluation are needed. PMID- 23628451 TI - The effects of spatial offset, temporal offset and image speed on sensitivity to global motion in human amblyopia. AB - The presence of a general global motion processing deficit in amblyopia is now well established, although its severity may depend on image speed and amblyopia type, but its underlying cause(s) is still largely indeterminate. To address this issue and to characterize further the nature of the global motion perception deficit in human amblyopia, the effects of varying spatial offset (jump size Deltas) and temporal offset (delay between positional updates-Deltat) in discriminating global motion for a range of speeds (1.5, 3 and 9 degrees /s) in both amblyopic and normal vision were evaluated. For normal adult observers (NE) and the non-amblyopic eye (FE) motion coherence thresholds measured when Deltat was varied were significantly higher than those when Deltas was varied. Furthermore when Deltat was varied, thresholds rose significantly as the speed of image motion decreased for both NEs and FEs. AE thresholds were higher overall than the other eyes and appeared independent of both the method used to create movement and speed. These results suggest that the spatial and temporal limits underlying the perception of global motion are different. In addition degrading the smoothness of motion has comparatively little effect on the motion mechanisms driven by the AE, suggesting that the internal noise associated with encoding motion direction is relatively high. PMID- 23628452 TI - Association and expression analysis of porcine HNF1A gene related to meat and carcass quality traits. AB - The aim of this study was to investigate the association and expression of HNF1A gene as a candidate gene for meat and carcass quality traits in pigs. Statistical analysis revealed that the g.8260 A>G polymorphism significantly associated with pH 24(H), meat percentage and muscle area in the F2 Duroc * Pietrain (DuPi, n=313) and with pH 24(L), fat area and backfat thickness in the Pietrain (Pi, n=110) population. HNF1A mRNA and protein expressions were higher (p<0.05) in animals with the low post-mortem muscle pH 24(L). The promoter methylation profiling suggested that methylation was not involved on HNF1A expression regulation (p>0.05) in animal with divergent muscle pH. In conclusion, polymorphism in porcine HNF1A gene could be used as a candidate marker to improve the meat and carcass quality traits, with the consideration of breed-specific effect. PMID- 23628454 TI - Scientific evidence for traditional claim of anti-obesity activity of Tecomella undulata bark. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Tecomella undulata is traditionally claimed in the treatment of various disease ailments including obesity and cancer. Till now there are no studies about anti-obesity activity of Tecomella undulata bark. AIM OF THE STUDY: The present study was aimed to establish a scientific evidence for anti-obesity efficiency of ethyl acetate extract of Tecomella undulata bark (EATUB). Further to standardize the active fractions of EATUB using different biomarkers. MATERIALS AND METHODS: We investigated activity of EATUB fractions (F1-F7) using 3T3-L1 fibroblasts. Further, F1-mediated effects were characterized by determining mRNA and protein levels of SIRT1, one of the key targets for the treatment of obesity, using semi-quantitative RT-PCR (sqRT PCR) and western blot analysis. The consequences of modulation of SIRT1 on mRNA and protein levels of various adipogenesis mediators like PPARgamma, C/EBPalpha, E2F1, leptin, adiponectin and LPL were also studied. In vivo studies were performed using High Fat Diet (HFD) obese mice. RESULTS: Our data showed that compared to controls, preadipocytes and adipocytes incubated with F1 exhibited a significant decrease in adipogenesis and lipogenesis. In addition, sqRT-PCR and western blot analysis showed significant increase in SIRT1 and adiponectin levels and decrease in PPARgamma, C/EBPalpha, E2F1, leptin and LPL levels in preadipocytes and adipocytes. In vivo studies of F1 in HFD induced obese mice showed significant improvement in lipid profile and glucose levels. The bioactive fraction (F1) was determined to possess 4.95% of ferulic acid. CONCLUSION: Thus, our findings signified the beneficial effects of Tecomella undulata bark in pharmacologic interventions related to obesity and metabolic disorders. Ferulic acid and rutin are being reported and quantified for the first time from the bark of Tecomella undulata. PMID- 23628455 TI - High salt intake does not produce additional impairment in the coronary artery relaxation of spontaneously hypertensive aged rats. AB - The effect of a salt-based diet on the coronary responsiveness in aged hypertensive rats (SHR) still is unclear. We investigated the effects of high salt intake on the relaxation properties of coronary arteries of aged SHRs. Male SHR (32 week-old) received drinking water (SHR) or 1% NaCl solution (SHR-Salt) for 8 weeks. Isolated coronary segments were subjected to concentration-response curves to acetylcholine (ACh) in the presence or absence of L-NAME (100 MUM), enalaprilate (10 MUM), losartan (10 MUM), and spironolactone (100 MUM). Salt intake did not increase blood pressure in old SHRs, but caused ventricular hypertrophy. The endothelium-dependent relaxation in SHRs was lower than in Wistar rats. However, salt intake did not add further impairment. Both enalaprilate and losartan reduced the vasodilator response in coronary arteries from Wistar, but did not affect SHR-salt rats. Conversely, losartan attenuated the impaired ACh relaxation observed in SHR. Spironolactone reduced the relaxation induced by ACh in coronary arteries from Wistar rats but not in SHR. The renin-angiotensin-aldosterone system participates in the impaired coronary relaxation in aged SHR, but does not partake in this deleterious effect under increased salt intake, indicating that age could differentiate the effects of high sodium intake in coronary arteries of SHR. PMID- 23628457 TI - Primary Stenting of Totally Occluded Native Coronary Arteries III (PRISON III): a randomised comparison of sirolimus-eluting stent implantation with zotarolimus eluting stent implantation for the treatment of total coronary occlusions. AB - AIMS: We investigated whether sirolimus-eluting stents (SES) are superior to next generation zotarolimus-eluting stents (ZES) in treating patients with total coronary occlusions (TCO). METHODS AND RESULTS: In a prospective, randomised trial we compared the SES with the zotarolimus-eluting stent (ZES; Endeavor or Resolute) after successful recanalisation of TCO. During the first phase of the trial, 51 patients were assigned to receive the SES and 46 patients to receive the Endeavor ZES. In the second phase we randomised 103 patients to the SES group and 104 patients to the Resolute ZES group. The primary endpoint was in-segment late lumen loss at eight-month follow-up. At eight months, patients in the SES group had less in-segment and in-stent late loss as compared to the Endeavor group: -0.13+/-0.3 mm vs. 0.27+/-0.6 mm (p=0.0002) and -0.13+/-0.5 mm vs. 0.54+/ 0.5 mm (p<0.0001), respectively. In contrast, the SES and the Resolute ZES showed comparable amounts of in-segment (-0.03+/-0.7 mm vs. -0.10+/-0.7 mm, p=0.6) and in-stent (0.03+/-0.8 mm vs. 0.05+/-0.8 mm, p=0.9) late loss. CONCLUSIONS: In the treatment of TCOs, the SES was associated with superior angiographic outcomes compared to the Endeavor ZES. On the other hand, the SES and the Resolute ZES showed comparable angiographic outcomes. PMID- 23628456 TI - Fas receptor-deficient lpr mice are protected against acetaminophen hepatotoxicity due to higher glutathione synthesis and enhanced detoxification of oxidant stress. AB - Acetaminophen (APAP) overdose is a classical model of hepatocellular necrosis; however, the involvement of the Fas receptor in the pathophysiology remains controversial. Fas receptor-deficient (lpr) and C57BL/6 mice were treated with APAP to compare the mechanisms of hepatotoxicity. Lpr mice were partially protected against APAP hepatotoxicity as indicated by reduced plasma ALT and GDH levels and liver necrosis. Hepatic Cyp2e1 protein, adduct formation and hepatic glutathione (GSH) depletion were similar, demonstrating equivalent reactive metabolite generation. There was no difference in cytokine formation or hepatic neutrophil recruitment. Interestingly, hepatic GSH recovered faster in lpr mice than in wild type animals resulting in enhanced detoxification of reactive oxygen species. Driving the increased GSH levels, mRNA induction and protein expression of glutamate-cysteine ligase (gclc) were higher in lpr mice. Inducible nitric oxide synthase (iNOS) mRNA and protein levels at 6h were significantly lower in lpr mice, which correlated with reduced nitrotyrosine staining. Heat shock protein 70 (Hsp70) mRNA levels were substantially higher in lpr mice after APAP. CONCLUSION: Our data suggest that the faster recovery of hepatic GSH levels during oxidant stress and peroxynitrite formation, reduced iNOS expression and enhanced induction of Hsp70 attenuated the susceptibility to APAP-induced cell death in lpr mice. PMID- 23628458 TI - Increased muscle coenzyme Q10 in riboflavin responsive MADD with ETFDH gene mutations due to secondary mitochondrial proliferation. AB - Multiple acyl-coenzyme A dehydrogenation deficiency (MADD) has a wide range of phenotypic variation ranging from a neonatal lethal form to a mild late-onset form. Our previous data showed that in a group of Chinese patients, a mild type of MADD characterized by myopathy with clinically no other systemic involvement was caused by mutations in electron transfer flavoprotein dehydrogenase (ETFDH) gene, which encodes electron transfer flavoprotein: ubiquinone oxidoreductase (ETF:QO). Coenzyme Q10 (CoQ10), a downstream electron receptor of ETF:QO was first reported deficient in muscle of MADD patients with ETFDH gene mutations. Nevertheless, this result was not confirmed in a recently published study. Therefore to elucidate muscle CoQ10 level in a large group of MADD patients may provide further insight into the pathomechanism and therapeutic strategies. In this study, we found that 34 riboflavin responsive patients with ETFDH gene mutations had an elevated CoQ10 pool in muscle by high performance liquid chromatography (HPLC). However, when CoQ10 levels were normalized to citrate synthase, a marker of mitochondrial mass, there was no significant difference between patients and normal controls. Meanwhile, the increased mitochondrial DNA copy number in muscle also supported that the elevated CoQ10 pool was mainly due to mitochondrial mass proliferation. The expression of CoQ10 biosynthesis genes showed no significant changes whereas genes involved in lipid metabolism, such as PPARalpha, were marked up regulated. Our results suggested that CoQ10 seems not to be a primary factor in riboflavin responsive MADD and the apparent increase in CoQ10 may be secondary to mitochondrial proliferation. PMID- 23628459 TI - Glucosylceramide modulates endolysosomal pH in Gaucher disease. AB - GlcCer accumulation causes Gaucher disease where GlcCer breakdown is inhibited due to a hereditary deficiency in glucocerebrosidase. Glycolipids are endocytosed and targeted to the Golgi apparatus in normal cells but in Gaucher disease they are mistargeted to lysosomes. To better understand the role of GlcCer in endocytic sorting RAW macrophages were treated with Conduritol B-epoxide to inhibit GlcCer breakdown. Lipid analysis found increases in GlcCer led to accumulation of both triacylglycerol and cholesterol consistent with increased lysosomal pH. Ratio imaging of macrophages using both acridine orange and lysosensor yellow/blue to measure endolysosomal pH revealed increases in Conduritol B-epoxide treated RAW macrophages and Gaucher patient lymphoblasts. Increased endolysosomal pH was restricted to Gaucher lymphoblasts as no significant increases in pH were seen in Fabry, Krabbe, Tay-Sachs and GM1 gangliosidosis lymphoblasts. Substrate reduction therapy utilises inhibitors of GlcCer synthase to reduce storage in Gaucher disease. The addition of inhibitors of GlcCer synthesis to RAW macrophages also led to increases in cholesterol and triacylglycerol and an endolysosomal pH increase of up to 1 pH unit. GlcCer modulation appears specific since glucosylsphingosine but not galactosylsphingosine reversed the effects of GlcCer depletion. Although no acute effects on glycolipid trafficking were observed using bafilomycin A the results are consistent with a multistep model whereby increases in pH lead to altered trafficking via cholesterol accumulation. GlcCer modulates endolysosomal pH in lymphocytes suggesting an important role in normal lysosomes which may be disrupted in Gaucher disease. PMID- 23628460 TI - Aripiprazole and trazodone cause elevations of 7-dehydrocholesterol in the absence of Smith-Lemli-Opitz Syndrome. AB - Screening for Smith-Lemli-Opitz Syndrome (SLOS) using elevated 7 dehydrocholesterol (7DHC) as a marker is sensitive, but not always specific. Elevations of 7DHC can be seen in patients who do not have a defect in 7 dehydrocholesterol reductase. These results have often been attributed to medication artifacts, but specific causes have not been well reported. We examined the medical records of patients with elevated 7DHC to determine if they had been diagnosed with SLOS; and if they had not, to identify any common medications that may have caused the elevations. We found three individuals who were affected with SLOS, and 22 with elevated 7DHC in the absence of SLOS. Seven of these individuals underwent molecular testing which showed no mutations, while the other 15 were excluded based on clinical findings and other testing. The medication history of these individuals revealed aripiprazole and trazodone as common medications to all the false positive results. PMID- 23628462 TI - Effect of 10-valent pneumococcal vaccine on pneumonia among children, Brazil. AB - Pneumonia is most problematic for children in developing countries. In 2010, Brazil introduced a 10-valent pneumococcal conjugate vaccine (PCV10) to its National Immunization Program. To assess the vaccine's effectiveness for preventing pneumonia, we analyzed rates of hospitalization among children 2-24 months of age who had pneumonia from all causes from January 2005 through August 2011. We used data from the National Hospitalization Information System to conduct an interrupted time-series analysis for 5 cities in Brazil that had good data quality and high PCV10 vaccination coverage. Of the 197,975 hospitalizations analyzed, 30% were for pneumonia. Significant declines in hospitalizations for pneumonia were noted in Belo Horizonte (28.7%), Curitiba (23.3%), and Recife (27.4%) but not in Sao Paulo and Porto Alegre. However, in the latter 2 cities, vaccination coverage was less than that in the former 3. Overall, 1 year after introduction of PCV10, hospitalizations of children for pneumonia were reduced. PMID- 23628461 TI - The effect of neonatal gene therapy on skeletal manifestations in mucopolysaccharidosis VII dogs after a decade. AB - Mucopolysaccharidosis (MPS) VII is a lysosomal storage disease due to deficient activity of beta-glucuronidase (GUSB), and results in glycosaminoglycan accumulation. Skeletal manifestations include bone dysplasia, degenerative joint disease, and growth retardation. One gene therapy approach for MPS VII involves neonatal intravenous injection of a gamma retroviral vector expressing GUSB, which results in stable expression in liver and secretion of enzyme into blood at levels predicted to be similar or higher to enzyme replacement therapy. The goal of this study was to evaluate the long-term effect of neonatal gene therapy on skeletal manifestations in MPS VII dogs. Treated MPS VII dogs could walk throughout their lives, while untreated MPS VII dogs could not stand beyond 6 months and were dead by 2 years. Luxation of the coxofemoral joint and the patella, dysplasia of the acetabulum and supracondylar ridge, deep erosions of the distal femur, and synovial hyperplasia were reduced, and the quality of articular bone was improved in treated dogs at 6 to 11 years of age compared with untreated MPS VII dogs at 2 years or less. However, treated dogs continued to have osteophyte formation, cartilage abnormalities, and an abnormal gait. Enzyme activity was found near synovial blood vessels, and there was 2% as much GUSB activity in synovial fluid as in serum. We conclude that neonatal gene therapy reduces skeletal abnormalities in MPS VII dogs, but clinically-relevant abnormalities remain. Enzyme replacement therapy will probably have similar limitations long-term. PMID- 23628463 TI - Smoking as a risk factor for development of Secondary Progressive Multiple Sclerosis: A study in IRAN, Guilan. AB - BACKGROUND: Cigarette smoking seems to contribute to susceptibility and progression of multiple sclerosis (MS).Although the incidence of MS in Iranian population has increased during recent years, the effects of smoking on progression of MS have not been studied. The aim of this study was to investigate the association between cigarette smoking and development of secondary progressive MS (SPMS) in Iranian patients with MS. METHODS: This study was carried out on patients registered in the MS Society (Guilan, Iran) database. Using a structured questionnaire, information on smoking status of 400 of patients could be obtained. The association between cigarettes smoking and SPMS was analyzed by Cox regression model. RESULTS: The relationship between smoking and development of SPMS was still evident after adjusting for age at disease onset, gender and number of relapses per year (P =0.004). Smoking more than 10 cigarettes per day increased risk of development of SPMS (HR: 2.43; 95% CI: 1.28 to 4.6; P =0.007). CONCLUSIONS: Our results indicated that smokers have an increased risk for progression of relapsing-remitting MS (RRMS) to SPMS compared with non-smokers. We also showed that the disease progression may be influenced by increase of cigarette smoking. PMID- 23628464 TI - Reservations against new oral anticoagulants after stroke and cerebral bleeding. AB - Dabigatran, rivaroxaban, and apixaban are the new oral anticoagulants (NOAC) which have been investigated in patients with atrial fibrillation (AF) for primary and secondary prevention of stroke and thromboembolism. In these trials NOAC had a similar efficacy and safety profile compared to traditional vitamin-K antagonists such as warfarin. We advise caution in the use of NOAC in patients with stroke or cerebral hemorrhage because of the following reasons: 1) Patients with cerebral bleeding were excluded from the trials. 2) Stroke within 14 days and severe stroke within 6 months before screening were exclusion criteria in the trials investigating dabigatran and rivaroxaban. 3) There is no antidote for reversal and no reliable laboratory monitoring of the anticoagulant effect for emergency situations. 4) NOAC are either substrates of the P-glycoprotein (P-gp) or are metabolized by the cytochrome P450 (CYP) system, or both. Drug-drug interactions between NOAC and P-gp and CYP-affecting drugs are largely unknown. 5) Long-term effects of thrombin generation inhibition on the occurrence of infections, malignancies, dementia, and other diseases are unknown. Based on these considerations it is our opinion that studies of NOAC in patients with stroke compared with other prevention strategies, as well as more post marketing surveillance data, are required. PMID- 23628465 TI - Mitochondria, motor neurons and aging. AB - While the role of mitochondria in aging has been well characterized, their involvement in motor neuron aging remains poorly understood. Thus, we performed an exhaustive ultrastructural study of mitochondria in motor neurons from aged rats that revealed dramatic alterations in the mitochondria of axon terminals at neuromuscular junctions, characterized by swelling, mitochondrial fusion and the presence of megamitochondria. These alterations were not observed in ventral horn motor neurons in the spinal cord of aged rats, which were only altered by the appearance of electron-dense bodies in the dilated matrix cristae. Using X-ray microanalytical techniques we demonstrated the presence of calcium in these bodies, suggesting Ca(2+) overload. Moreover, in motor neurons from aged rats, cytochrome c and activated caspase 3 were detected in the cytoplasm of axon terminals at neuromuscular junctions, factors implicated in the apoptosis. Active caspase 3 was also found in the nucleus, soma and axons of aged alpha motor neuron neurons, where it mainly associated with microtubules. The colocalization of dynein and cleaved caspase 3 in neuromuscular junctions is strongly suggestive of the retrograde transport of apoptotic factors to the soma. These results are consistent with the early stages of degeneration in neuromuscular junctions during aging, which is followed by dying back. Given that aging is a key risk factor for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), the identification of age-related motor neuron degeneration initiated at the distal end of the axon may provide a new therapeutic target for early intervention. PMID- 23628466 TI - Verbal fluency deficits in clinically isolated syndrome suggestive of multiple sclerosis. AB - BACKGROUND: Little is known about relationships between Cognitive Impairment (CI) and verbal fluency measures in patients with a Clinically Isolated Syndrome (CIS) suggestive of Multiple Sclerosis. The aim of this study was to assess the extent of verbal fluency deficits and their predictive value for the presence of a CI in a population of CIS patients. METHODS: CI was detected by the Rao's Brief Repeatable Battery (BRB) and the Stroop Test (ST) in 100 CIS patients. The BRB includes the Word List Generation (WLG) test for semantic verbal fluency. The FAS test was used to investigate phonemic verbal fluency. CI was defined as the failure in at least 3 tests on BRB (without WLG to exclude criterion contamination bias) and ST. RESULTS: Eleven patients failed in at least 3 of the BRB tests and were classified as cognitively impaired. The comparison of Receiver Operating Characteristic curves showed that the Area Under the Curve (AUC) of the WLG was not significantly different from the AUC of the FAS (0.787 vs 0.755; p=N.S.). A cut-off <17 words for the WLG achieved 64% of sensitivity and a 79% of specificity, and a cut-off <28 words achieved 82% of sensitivity and a 66% of specificity in discriminating patients with CI. CONCLUSIONS: Verbal fluency deficits occur early in the disease course and may predict the presence of CI in CIS patients. PMID- 23628467 TI - Zoster paresis: asymptomatic MRI lesions far beyond the site of rash and focal weakness. AB - We describe a patient with zoster paresis and an MRI that revealed extensive spinal cord lesions from the upper cervical to the lower thoracic spinal cord. Importantly, the patient reported considerable spontaneous improvement in strength 2-3 weeks after zoster. This report reveals a previously undescribed remarkable preponderance of MRI lesions far beyond the site of zoster rash and focal lower motor neuron weakness. PMID- 23628468 TI - Perry syndrome: a disorder to consider in the differential diagnosis of Parkinsonism. AB - A patient with a mood disorder and a Parkinsonian syndrome with frontal cognitive impairment thought to resemble progressive supranuclear palsy defied precise diagnosis until the development of respiratory compromise, prompting consideration of the diagnosis of Perry syndrome. A mutation in the dynactin 1 gene confirmed the diagnosis. Few examples of this disorder, characterised by depression, Parkinsonism, and respiratory insufficiency, have been reported but it may be more commonly recognised with the availability of genetic testing. Perry syndrome needs to be considered in the differential diagnosis of Parkinsonism, particularly in autosomal dominant pedigrees. Diagnosis early in the disease course may facilitate monitoring and prompt intervention to avoid potentially fatal respiratory failure. PMID- 23628470 TI - Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4 dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors. AB - A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4 dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure-activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC50 value of 0.59 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. PMID- 23628469 TI - Intracranial pressure variability predicts short-term outcome after intracerebral hemorrhage: a retrospective study. AB - INTRODUCTION: Elevated intracranial pressure (ICP) is generally observed in brain injury and intracerebral hemorrhage (ICH) patients and is consistently associated with poor neurological outcome. Intracranial pressure variability (IPV) is a better predictor of long-term neurological outcome than mean ICP in traumatic brain injury patients. However, whether IPV regulates functional outcome in ICH patients has not been investigated. In the present study, we investigated the relationship between IPV and functional outcome in ICH patients and determined whether IPV is a valid predictor of neurological outcome in ICH patients. METHODS: A consecutive series of 56 patients with ICH were enrolled in this study. These patients underwent surgical treatments and were planted with an ICP monitor. The ICP was continuously recorded for 7 days at one-hour intervals. The mean arterial blood pressure (MAP) and cerebral perfusion pressure (CPP) were also calculated. We used successive variation (SV) to represent IPV, which was calculated by averaging the difference in ICP between successive parameters. The short-term outcome was dichotomized into improved and deteriorated groups based on the changes in their Glasgow Coma Scale (GCS) score between admission and 30 days after admission. The long-term outcome was evaluated by Glasgow Outcome Scale (GOS) at 12 months after discharge from the hospital, and the patients were dichotomized into independent and dependent groups. RESULTS: The results showed that IPV was lower in the improved patient group and higher in patients with poorer outcome at 30 days after ICH. There was a significant positive correlation between SV and short-term neurological outcome. We also found the in-patient mortality was significantly increased in the high IPV patient group (P=0.02), which was divided by the cutoff point using receiver operating characteristic (ROC) curve analysis. The univariate correlation analysis demonstrated that the IPV levels were positively correlated with mean ICP (R(2)=0.652, P=0.000), while were negatively correlated with CPP (R(2)=0.426, P=0.000). Increases in SV of ICP were a predictor of 30-day poor short-term outcome, but not for 12-month long term outcome after adjusting for the potential confounders in a multivariable logistic regression model. CONCLUSIONS: The results suggest that high IPV is correlated with poorer outcome in ICH patients. Managing the ICP at an appropriate level during the early phase after ICH may improve functional outcome in ICH patients. PMID- 23628471 TI - Fluorescent properties of oligonucleotides doubly modified with an indole-fused cytosine analog and 2-aminopurine. AB - Single- and double-stranded oligodeoxynucleotides (ODNs) incorporating both 2 aminopurine (2AP) and an indole-fused cytosine analog (PPI) were prepared and studied for their fluorescence properties. PPI and 2AP can be excited simultaneously by irradiation at 300 nm, with emission observed at 500 nm for PPI and 370 nm for 2AP. We demonstrated the utility of these properties in the dual fluorescence labeling of ODNs giving well-separated emission peaks. In addition, both of the fluorescence signals of a doubly modified ODN changed independently, reflecting the local duplex formation at the regions containing 2AP or PPI. Potential applications of this strategy for the dual fluorescence labeling of oligonucleotides with 2AP and PPI include monitoring local structure alterations of functional nucleic acids and the multiplex detection of biologically important nucleic acids. PMID- 23628472 TI - Sugar-attached upconversion lanthanide nanoparticles: a novel tool for high throughput lectin assay. AB - To create a novel high-throughput lectin assay (HTPLA) method based on the emission of a luminophore by highly penetrable near-infrared excitation, sugar attached upconversion lanthanide nanoparticles (LNPs) were synthesized as a tool to highlight the aggregates caused by the sugar-mediated specific bridging between LNP and lectin. The emissions from a mannose-coated LNP in the aggregates with a mannose-binding lectin were much stronger than those from the non aggregated samples, being sensitive enough for HTPLA. A galactose-coated LNP was also applicable to a macrophage aggregation assay for the sugar specificity of its surface lectin. PMID- 23628473 TI - The PPARalpha agonist fenofibrate suppresses B-cell lymphoma in mice by modulating lipid metabolism. AB - Obesity is associated with an increased risk for malignant lymphoma development. We used Bcr/Abl transformed B cells to determine the impact of aggressive lymphoma formation on systemic lipid mobilization and turnover. In wild-type mice, tumor size significantly correlated with depletion of white adipose tissues (WAT), resulting in increased serum free fatty acid (FFA) concentrations which promote B-cell proliferation in vitro. Moreover, B-cell tumor development induced hepatic lipid accumulation due to enhanced hepatic fatty acid (FA) uptake and impaired FA oxidation. Serum triglyceride, FFA, phospholipid and cholesterol levels were significantly elevated. Consistently, serum VLDL/LDL-cholesterol and apolipoprotein B levels were drastically increased. These findings suggest that B cell tumors trigger systemic lipid mobilization from WAT to the liver and increase VLDL/LDL release from the liver to promote tumor growth. Further support for this concept stems from experiments where we used the peroxisome proliferator activated receptor alpha (PPARalpha) agonist and lipid-lowering drug fenofibrate that significantly suppressed tumor growth independent of angiogenesis and inflammation. In addition to WAT depletion, fenofibrate further stimulated FFA uptake by the liver and restored hepatic FA oxidation capacity, thereby accelerating the clearance of lipids released from WAT. Furthermore, fenofibrate blocked hepatic lipid release induced by the tumors. In contrast, lipid utilization in the tumor tissue itself was not increased by fenofibrate which correlates with extremely low expression levels of PPARalpha in B-cells. Our data show that fenofibrate associated effects on hepatic lipid metabolism and deprivation of serum lipids are capable to suppress B-cell lymphoma growth which may direct novel treatment strategies. This article is part of a Special Issue entitled Lipid Metabolism in Cancer. PMID- 23628474 TI - Separation of rare oligodendrocyte progenitor cells from brain using a high throughput multilayer thermoplastic-based microfluidic device. AB - Despite the advances made in the field of regenerative medicine, the progress in cutting-edge technologies for separating target therapeutic cells are still at early stage of development. These cells are often rare, such as stem cells or progenitor cells that their overall properties should be maintained during the separation process for their subsequent application in regenerative medicine. This work, presents separation of oligodendrocyte progenitor cells (OPCs) from rat brain primary cultures using an integrated thermoplastic elastomeric (TPE)- based multilayer microfluidic device fabricated using hot-embossing technology. OPCs are frequently used in recovery, repair and regeneration of central nervous system after injuries. Indeed, their ability to differentiate in vitro into myelinating oligodendrocytes, are extremely important for myelin repair. OPCs form 5-10% of the glial cells population. The traditional macroscale techniques for OPCs separation require pre-processing of cells and/or multiple time consuming steps with low efficiency leading very often to alteration of their properties. The proposed methodology implies to separate OPCs based on their smaller size compared to other cells from the brain tissue mixture. Using aforementioned microfluidic chip embedded with a 5 MUm membrane pore size and micropumping system, a separation efficiency more than 99% was achieved. This microchip was able to operate at flow rates up to 100 MUl/min, capable of separating OPCs from a confluent 75 cm(2) cell culture flask in less than 10 min, which provides us with a high-throughput and highly efficient separation expected from any cell sorting techniques. PMID- 23628475 TI - Glioma targeting and blood-brain barrier penetration by dual-targeting doxorubincin liposomes. AB - Effective chemotherapy for glioblastoma requires a carrier that can penetrate the blood-brain barrier (BBB) and subsequently target the glioma cells. Dual targeting doxorubincin (Dox) liposomes were produced by conjugating liposomes with both folate (F) and transferrin (Tf), which were proven effective in penetrating the BBB and targeting tumors, respectively. The liposome was characterized by particle size, Dox entrapment efficiency, and in vitro release profile. Drug accumulation in cells, P-glycoprotein (P-gp) expression, and drug transport across the BBB in the dual-targeting liposome group were examined by using bEnd3 BBB models. In vivo studies demonstrated that the dual-targeting Dox liposomes could transport across the BBB and mainly distribute in the brain glioma. The anti-tumor effect of the dual-targeting liposome was also demonstrated by the increased survival time, decreased tumor volume, and results of both hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling analysis. The dual-targeting Dox liposome could improve the therapeutic efficacy of brain glioma and were less toxic than the Dox solution, showing a dual-targeting effect. These results indicate that this dual-targeting liposome can be used as a potential carrier for glioma chemotherapy. PMID- 23628477 TI - Consecutive repetition effects for affective-distractor pictures in a visual oddball task: electrophysiological evidence from an ERP study. AB - Although repeated affective stimuli can promote habituation, most studies of event-related potentials (ERPs) have focused on habituation to targets that are repeated non-consecutively. However, the neural mechanisms underlying the consecutive repetition effects of affective-distractor stimuli are unclear. Using a three-stimulus oddball task (standard vs. target vs. distractor ratio: 60%:20%:20%) and measures of ERPs, we assessed the repetition effects of affective-distractor pictures that were repeated consecutively. Participants (N=16) were asked to distinguish the size of a geometric surface; they were asked to selectively respond to the target stimuli (larger geometric surfaces) and to ignore the standard stimuli (smaller geometric surfaces) and affective-distractor pictures. Forty pictures portraying a neutral affect and 40 pictures portraying a negative affect were taken from the Chinese Affective Picture System. Each picture was pseudo-randomly selected and consecutively repeated three times, and ERPs were recorded for the repeated affective-distractor pictures. Stimulus repetition was associated with amplitude increases for P3 and amplitude decreases for N1 and N2 as the presentations proceeded. Peak latency remained stable. The P2, N2, and P3 amplitudes were greater during negative vs. neutral pictures. The affective effects did not interact with stimulus repetition at any latency range. The results suggest that consecutive repetition and affective stimuli modulate ERP outcomes independently. PMID- 23628476 TI - Estradiol modulates neurotransmitter concentrations in the developing zebra finch song system. AB - The neural song system in zebra finches is highly sexually dimorphic; only males sing and the brain regions controlling song are far larger in males than females. Estradiol (E2) administered during development can partially masculinize both structure and function. However, additional mechanisms, including those through which E2 may act, remain unclear. Male and female zebra finches were treated with E2 or control vehicle from post-hatching days 3 through 25, at which time norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were measured in individual nuclei of the song system. Main effects of sex were not detected. However, E2 increased NE in the robust nucleus of the arcopallium (RA). In HVC (proper name), the hormone decreased 5-HT across the two sexes and increased DA in females only. These effects suggest that, while baseline levels of these neurotransmitters may not contribute to sexually dimorphic development of the song system, they could play specific roles in functions common to both sexes and/or in modification of the song system by exogenous E2. PMID- 23628478 TI - Retrograde study of CART- or NPY-neuronal projection from the hypothalamic arcuate nucleus to the dorsal raphe and/or the locus coeruleus in the rat. AB - The present study was designed to reveal cocaine- and amphetamine-regulated transcript (CART)- or neuropeptide Y (NPY)-immunoreactive neuronal projections from the hypothalamic arcuate nucleus (Arc) to the dorsal raphe (DR) and/or the locus coeruleus (LC) in the rat. Our results demonstrated that CART or NPY axon terminals formed close appositions to the neuronal profiles in the DR and the LC. Thus, arcuate sections were immunostained for the CART or NPY after the injections of green RetroBeads(TM) into the DR and red tracer into the LC (or vice versa). First, retrogradely-labeled CART cells were mainly observed in the lateral Arc without colchicine. Of the total population of arcuate CART neurons, DR- and LC-projecting cells were 5.7% +/- 0.9% and 6.6% +/- 0.7%, respectively. In addition, a subset (3.3% +/- 0.7%) of CART neurons provided divergent axon collaterals to the DR and the LC. Second, retrogradely-labeled NPY cells were observed in lateral or ventral borders of the medial Arc only after colchicine injection. Of the entire NPY cell population, DR- and LC-projecting neurons were 1.5% +/- 0.3% and 1.3% +/- 0.3%, respectively. Only a scanty proportion (0.1% +/- 0.0%) sent axon collaterals to the DR and the LC. These observations suggested that arcuate CART or NPY system might have a potential influence on the brainstem monoaminergic nuclei, modulating their roles in feeding, nociception, emotional behaviors, arousal, and stress responses. Furthermore, a portion of arcuate CART neurons (along with only a few NPY cells) sending divergent axon collaterals to the DR/LC might have a simultaneous (and possibly more efficient) way to exert their specific influences on the monoaminergic nuclei. PMID- 23628479 TI - Wild plant folk nomenclature of the Mongol herdsmen in the Arhorchin National Nature Reserve, Inner Mongolia, PR China. AB - BACKGROUND: Folk names of plants are the root of traditional plant biodiversity knowledge. In pace with social change and economic development, Mongolian knowledge concerning plant diversity is gradually vanishing. Collection and analysis of Mongolian folk names of plants is extremely important. During 2008 to 2012, the authors have been to the Arhorchin National Nature Reserve area 5 times. Fieldwork was done in 13 villages, with 56 local Mongol herdsmen being interviewed. This report documents plant folk names, analyzes the relationship between folk names and scientific names, looks at the structure and special characteristics of folk names, plant use information, and comparative analysis were also improved. METHODS: Ethnobotanical interviewing methods of free-listing and open-ended questionnaires were used. Ethnobotanical interview and voucher specimen collection were carried out in two ways as local plant specimens were collected beforehand and then used in interviews, and local Mongol herdsmen were invited to the field and interviewed while collecting voucher specimens. Mongolian oral language was used as the working language and findings were originally recorded in Mongolian written language. Scientific names of plants are defined through collection and identification of voucher specimens by the methods of plant taxonomy. RESULTS: A total of 146 folk names of local plants are recorded. Plant folk names corresponded with 111 species, 1 subspecies, 7 varieties, 1 form, which belong to 42 families and 88 genera. The correspondence between plant folk names and scientific names may be classified as one to one correspondence, two or three to one correspondence, and one to multitude correspondence. The structure of folk names were classified as primary names, secondary names and borrowed names. There were 12 folk names that contain animal names and they have correspondence with 15 species. There are nine folk names that contain usage information and they have correspondence with 10 species in which five species and one variety of plant are still used by the local people. The results of comparative analysis on the Mongol herdsmen in the Arhorchin National Nature Reserve and the Mongolians in the Ejina desert area shows that there are some similarities, as well as many differences whether in language or in the structure. CONCLUSION: In the corresponding rate between plant folk names and scientific names yielded a computational correspondence of 82.19%, which can be considered as a high level of consistency between scientific knowledge and traditional knowledge in botanical nomenclature. Primary names have most cultural significance in the plant folk names. Special characteristic of plant folk names were focused on the physical characteristics of animals which were closely related to their traditional animal husbandry and environment. Plant folk names are not only a code to distinguish between different plant species, but also a kind of culture rich in a deep knowledge concerning nature. The results of comparative analysis shows that Mongolian culture in terms of plant nomenclature have characteristics of diversity between the different regions and different tribes. PMID- 23628480 TI - Late myocardial perforation by pacemaker lead in an asymptomatic patient. PMID- 23628481 TI - A proteome-wide visual screen identifies fission yeast proteins localizing to DNA double-strand breaks. AB - DNA double-strand breaks (DSBs) are a major threat to genome integrity. Proteins involved in DNA damage checkpoint signaling and DSB repair often relocalize and concentrate at DSBs. Here, we used an ORFeome library of the fission yeast Schizosaccharomyces pombe to systematically identify proteins targeted to DSBs. We found 51 proteins that, when expressed from a strong exogenous promoter on the ORFeome plasmids, were able to form a distinct nuclear focus at an HO endonuclease-induced DSB. The majority of these proteins have known connections to DNA damage response, but few have been visualized at a specific DSB before. Among the screen hits, 37 can be detected at DSBs when expressed from native promoters. We classified them according to the focus emergence timing of the endogenously tagged proteins. Eight of these 37 proteins are yet unnamed. We named these eight proteins DNA-break-localizing proteins (Dbls) and performed preliminary functional analysis on two of them, Dbl1 (SPCC2H8.05c) and Dbl2 (SPCC553.01c). We found that Dbl1 and Dbl2 contribute to the normal DSB targeting of checkpoint protein Rad26 (homolog of human ATRIP) and DNA repair helicase Fml1 (homolog of human FANCM), respectively. As the first proteome-wide inventory of DSB-localizing proteins, our screen result will be a useful resource for understanding the mechanisms of eukaryotic DSB response. PMID- 23628482 TI - Assessing quality in cross-country comparisons of health systems and policies: towards a set of generic quality criteria. AB - There is a growing body of cross-country comparisons in health systems and policy research. However, there is little consensus as to how to assess its quality. This is partly due to the fact that cross-country comparison constitutes a diverse inter-disciplinary field of study, with much variation in the motives for research, foci and levels of analyses, and methodological approaches. Inspired by the views of subject area experts and using the distinction between variable based and case-based research, we briefly review the main different types of cross-country comparisons in health systems and policy research to identify pertinent quality issues. From this, we identify the following generic quality criteria for cross-country comparisons: (1) appropriate use of theory, (2) explicit selection of comparator countries, (3) rigour of the comparative design, (4) attention to the complexity of cross-national comparison, (5) rigour of the research methods, and (6) contribution to knowledge. This list may not be exclusive though publication and discussion of the list of criteria should help raise awareness in this field of what constitutes high quality research. In turn, this should be helpful for those planning, undertaking, or commissioning cross country comparative research. PMID- 23628483 TI - Do reassessments reduce the uncertainty of decision making? Reviewing reimbursement reports and economic evaluations of three expensive drugs over time. AB - OBJECTIVE: To investigate the desirability and feasibility of a cyclic reimbursement process to address uncertainty accompanying initial decision making. METHODS: We performed desk research for three expensive outpatient drugs: imatinib, pegfilgrastim, and adalimumab. We analysed the evidence base at the time of decision making (T=0) and May 2011 (T=1). For T=0, public reports of the Dutch reimbursement agency were investigated regarding available clinical and economic evidence, and a systematic review was performed to retrieve additional economic evidence. For T=1, the systematic review was extended till May 2011. RESULTS: The evidence base at T=0 lacked information on clinically relevant outcomes such as mortality, morbidity, and quality of life (5/8 reports), (long term) adverse events (2/8 reports) and experience in use (1/8 reports). One budget impact analysis and one economic evaluation were available but no pharmacoeconomic dossiers. The systematic review identified 39 cost-utility studies (of 52 economic evaluations) for T=1, characterised by methodological heterogeneity. CONCLUSIONS: Given the considerable uncertainty accompanying initial decision-making, a more cyclic reimbursement process seems feasible to reduce uncertainty regarding the therapeutical and economical value of expensive drugs. A mandatory evidence development requirement seems desirable to sufficiently meet decision makers' needs. PMID- 23628484 TI - Factors associated with prolonged length of hospital stay of elderly patients in acute care hospitals in Japan: a multilevel analysis of patients with femoral neck fracture. AB - OBJECTIVE: To analyze possible factors associated with prolonged length of stay (LOS) in hip fracture patients in Japan, such as the availability of beds in medical and nursing care facilities at the community level, as well as patient factors, clinical factors and hospital structural characteristics. METHODS: The sample for analysis consisted of 8318 hip fracture cases from 199 hospitals throughout Japan. We conducted multilevel analyses to investigate whether LOS and the discharge destinations of patients are associated with the availability and utilization of medical and nursing care resources in the communities where each hospital is located. RESULTS: After adjusting for patient factors, clinical factors and hospital structural characteristics, a higher number of long-term care beds at the community level was observed to be significantly correlated with both shorter LOS and increased rate of discharge to other facilities. DISCUSSION AND CONCLUSION: Although the Japanese government is attempting to reduce acute care hospital LOS and the number of long-term care beds in order to reduce health care costs, the results of this study suggest that a reduction in the number of long-term care beds would not necessarily reduce the LOS of acute care hospitals, and may instead exacerbate the problem. PMID- 23628487 TI - Export of dissolved organic carbon and nitrate from grassland in winter using high temporal resolution, in situ UV sensing. AB - Co-deployment of two reagentless UV sensors for high temporal resolution (15 min) real time determination of wintertime DOC and nitrate-N export from a grassland lysimeter plot (North Wyke, Devon, UK) is reported. They showed rapid, transient but high impact perturbations of DOC (5.3-23 mg CL(-1)) and nitrate-N export after storm/snow melt which discontinuous sampling would not have observed. During a winter freeze/thaw cycle, DOC export (1.25 kg Cha(-1)d(-1)) was significantly higher than typical UK catchment values (maximum 0.25 kg Chad(-1)) and historical North Wyke data (0.7 kg Cha(-1)d(-1)). DOC concentrations were inversely correlated with the key DOC physico-chemical drivers of pH (January r= 0.65), and conductivity (January r=-0.64). Nitrate-N export (0.8-1.5 mg NL(-1)) was strongly correlated with DOC export (r >= 0.8). The DOC:NO3-N molar ratios showed that soil microbial N assimilation was not C limited and therefore high N accrual was not promoted in the River Taw, which is classified as a nitrate vulnerable zone (NVZ). The sensor was shown to be an effective sentinel device for identifying critical periods when rapid ecosystem N accumulation could be triggered by a shift in resource stoichiometry. It is therefore a useful tool to help evaluate land management strategies and impacts from climate change and intensive agriculture. PMID- 23628488 TI - Peripheral kappa and delta opioid receptors are involved in the antinociceptive effect of crotalphine in a rat model of cancer pain. AB - Cancer pain is an important clinical problem and may not respond satisfactorily to the current analgesic therapy. We have characterized a novel and potent analgesic peptide, crotalphine, from the venom of the South American rattlesnake Crotalus durissus terrificus. In the present work, the antinociceptive effect of crotalphine was evaluated in a rat model of cancer pain induced by intraplantar injection of Walker 256 carcinoma cells. Intraplantar injection of tumor cells caused the development of hyperalgesia and allodynia, detected on day 5 after tumor cell inoculation. Crotalphine (6 MUg/kg), administered p.o., blocked both phenomena. The antinociceptive effect was detected 1 h after treatment and lasted for up to 48 h. Intraplantar injection of nor-binaltorphimine (50 g/paw), a selective antagonist of kappa-opioid receptors, antagonized the antinociceptive effect of the peptide, whereas N,N-diallyl-Tyr-Aib-Phe-Leu (ICI 174,864, 10 MUg/paw), a selective antagonist of delta-opioid receptors, partially reversed this effect. On the other hand, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP, 20 g/paw), an antagonist of MU-opioid receptors, did not modify crotalphine induced antinociception. These data indicate that crotalphine induces a potent and long lasting opioid-mediated antinociception in cancer pain. PMID- 23628489 TI - Lack of effect of ceftriaxone, a GLT-1 transporter activator, on spatial memory in mice. AB - In the central nervous system, glutamate appears to be the principal excitatory amino acid neurotransmitter. Recent findings show that beta-lactam antibiotics, by stimulating glutamate transporter (GLT-1) expression, offer neuroprotection. The purpose of our study is to observe the effect of ceftriaxone, a beta-lactam antibiotic, on spatial memory in mice. Male Balb-c mice, weighing 20-25 g, were trained in Morris water maze (n=12 for each group) task. Animals were given 4 trials per day for 7 consecutive days to locate a hidden platform (acquisition phase). On the eighth day, the platform is removed and the animals were swum for one session of 60 s (retention phase). Learning and memory functions of the animals were evaluated based on their performances in these tests. Ceftriaxone was given for 9 days at different doses (50, 100, and 200 mg/kg, i.p.); additionally, its acute effect was evaluated in one group (200 mg/kg, i.p.). Our immunohistochemistry findings indicate that ceftriaxone increases GLT-1 expression in CA1, CA3 and DG regions of hippocampus, especially with the dose of 200 mg/kg. Evaluation of the acquisition parameters, such as time to reach platform, distance moved, and mean distance to platform indicates that chronic ceftriaxone has no effect on learning curves of the animals. When retention phase parameters (e.g. time to reach target quadrant, swim duration in target quadrant, and mean distance to platform area) are evaluated, it was found that both chronic and acute ceftriaxone did not affect memory at any dose used. In contrast to the contribution of GLT-1 expression to various central nervous system diseases, such as chronic pain, amyotrophic lateral sclerosis, Parkinson's disease and seizures, our findings suggest that ceftriaxone has no effect on spatial memory function in mice. PMID- 23628491 TI - GW9508 inhibits insulin secretion by activating ATP-sensitive potassium channels in rat pancreatic beta-cells. AB - GW9508 is an agonist of G protein-coupled receptor 40 (GPR40) that is expressed in pancreatic beta-cells and is reported to regulate insulin secretion. However, the effects of GW9508 on pancreatic beta-cells in primary culture have not been well investigated. This study measured the acute effects of GW9508 on insulin secretion from rat pancreatic islets in primary culture, and the insulin secretion-related events such as the changes in membrane potential, ATP-sensitive potassium currents (KATP currents), and intracellular Ca(2+) concentrations ([Ca(2+)]i) of rat islet beta-cells were also recorded. GW9508 (10-40 MUM) did not influence basal insulin levels at 2 mM glucose, but it (above 20 MUM) significantly inhibited 5 and 15 mM glucose-stimulated insulin secretion (GSIS). GW9508 did not inhibit insulin secretion stimulated by tolbutamide, the closer of KATP channels. GW9508 activated KATP channels and blocked the membrane depolarization and the increase in [Ca(2+)]i that were stimulated by glucose. GW9508 itself stimulated a transient increase in [Ca(2+)]i, which was fully blocked by depletion of intracellular Ca(2+) stores with thapsigargin or by inhibition of phospholipase C (PLC) activity with U73122. GW9508-induced activation of KATP channels was only partly inhibited by U73122 treatment. In conclusion, although it stimulates a transient release of Ca(2+) from intracellular Ca(2+) stores via activation of PLC, GW9508 inhibits GSIS by activating KATP channels probably in a distal step to GPR40 activation in rat beta-cells. PMID- 23628492 TI - Intermittent androgen-deprivation therapy in prostate cancer: a critical review focused on phase 3 trials. AB - CONTEXT: Intermittent androgen deprivation (IAD) in prostate cancer (PCa) patients has been proposed to delay development of castration resistance and to reduce the side effects and costs of androgen deprivation therapy (ADT). OBJECTIVE: This review analyzes (1) the oncologic and quality of life (QoL) results from randomized phase 3 trials comparing IAD and continuous ADT and (2) the prognostic parameters for IAD. EVIDENCE ACQUISITION: We searched the Medline and Cochrane Library databases (primary fields: prostate neoplasm and intermittent androgen deprivation; secondary fields: randomized trials, survival, quality of life, predictors) without language restriction. EVIDENCE SYNTHESIS: We found seven extensively described phase 3 trials randomizing 4675 patients to IAD versus continuous ADT. Other randomized trials investigating IAD have been performed, but available data are limited and have been published only in preliminary fashion. In all seven trials, patients spent most of their time on, rather than off, ADT. The induction periods ranged from 3 mo to 8 mo; in all but one trial, the PSA level designated for ADT discontinuation was <4 ng/ml. Mean follow-up ranged from 40-108 mo. Collectively, these trials support the concept that, mainly in metastatic cases, IAD can produce oncologic results similar to continuous ADT. In terms of overall survival, the hazard ratios for IAD and continuous ADT were very similar (range: 0.98-1.08). The QoL benefit of IAD appears to be modest at best. With IAD, QoL is likely influenced by the duration of the off-treatment periods and by the rate of testosterone recovery. CONCLUSIONS: The evidence indicates that IAD is not inferior to continuous ADT. Data are insufficient to determine whether IAD is able to prevent the long-term complications of ADT. More comparative analysis focused on QoL is warranted. PMID- 23628493 TI - The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and meta-analysis. AB - CONTEXT: The role of positron emission tomography (PET) and PET/computed tomography (PET/CT) in prostate cancer (PCa) imaging is still debated, although guidelines for their use have emerged over the last few years. OBJECTIVE: To systematically review and conduct a meta-analysis of the available evidence of PET and PET/CT using 11C-choline and 18F-fluorocholine as tracers in imaging PCa patients in staging and restaging settings. EVIDENCE ACQUISITION: PubMed, Embase, and Web of Science (by citation of reference) were searched. Reference lists of review articles and included articles were checked to complement electronic searches. EVIDENCE SYNTHESIS: In staging patients with proven but untreated PCa, the results of the meta-analysis on a per-patient basis (10 studies, n = 637) showed pooled sensitivity, specificity, and diagnostic odds ratio (DOR) of 84% (95% confidence interval [CI], 68-93%), 79% (95% CI, 53-93%), and 20.4 (95% CI, 9.9-42.0), respectively. The positive and negative likelihood ratios were 4.02 (95% CI, 1.73-9.31) and 0.20 (95% CI, 0.11-0.37), respectively. On a per-lesion basis (11 studies, n = 5117), these values were 66% (95% CI, 56-75%), 92% (95% CI, 78-97%), and 22.7 (95% CI, 8.9-58.0), respectively, for pooled sensitivity, specificity, and DOR; and 8.29 (95% CI, 3.05-22.54) and 0.36 (95% CI, 0.29-0.46), respectively, for positive and negative likelihood ratios. In restaging patients with biochemical failure after local treatment with curative intent, the meta analysis results on a per-patient basis (12 studies, n = 1055) showed pooled sensitivity, specificity, and DOR of 85% (95% CI, 79-89%), 88% (95% CI, 73-95%), and 41.4 (95% CI, 19.7-86.8), respectively; the positive and negative likelihood ratios were 7.06 (95% CI, 3.06-16.27) and 0.17 (95% CI, 0.13-0.22), respectively. CONCLUSIONS: PET and PET/CT imaging with 11C-choline and 18F-fluorocholine in restaging of patients with biochemical failure after local treatment for PCa might help guide further treatment decisions. In staging of patients with proven but untreated, high-risk PCa, there is limited but promising evidence warranting further studies. However, the current evidence shows crucial limitations in terms of its applicability in common clinical scenarios. PMID- 23628494 TI - Reply to Chen Cai, Huamao Ye, and Bing Liu's letter to the editor re: Francesco Greco, Riccardo Autorino, Koon H. Rha, et al. Laparoendoscopic single-site partial nephrectomy: a multi-institutional outcome analysis. Eur Urol 2013;64:314 22. PMID- 23628495 TI - Clinical utility of CHADS2 and CHA2DS2-VASc scoring systems for predicting postoperative atrial fibrillation after cardiac surgery. AB - OBJECTIVES: The presence of postoperative atrial fibrillation predicts a higher short- and long-term mortality rates; however, no scoring system has been used to discriminate patients at high risk for this complication. The aim of this study was to investigate whether the CHADS2 and CHA2DS2-VASc scores are useful risk assessment tools for new-onset atrial fibrillation after cardiac surgery. METHODS: A total of 277 consecutive patients who underwent cardiac surgery were prospectively included in this risk stratification study. We calculated the CHADS2 and CHA2DS2-VASc scores from the data collected. The primary end point was the development of postoperative atrial fibrillation within 30 days after cardiac surgery. RESULTS: Eighty-four (30%) of the patients had postoperative atrial fibrillation at a median of 2 days (range, 0-27 days) after cardiac surgery. The CHADS2 and CHA2DS2-VASc scores were significant predictors of postoperative atrial fibrillation in separate multivariate regression analyses. The Kaplan Meier analysis obtained a higher postoperative atrial fibrillation rate when based on the CHADS2 and CHA2DS2-VASc scores of at least 2 than when based on scores less than 2 (both log rank, P < .001). In addition, the CHA2DS2-VASc scores could be used to further stratify the patients with CHADS2 scores of 0 or 1 into 2 groups with different postoperative atrial fibrillation rates at a cutoff value of 2 (12% vs 32%; P = .01). CONCLUSIONS: CHADS2 and CHA2DS2-VASc scores were predictive of postoperative atrial fibrillation after cardiac surgery and may be helpful for identifying high-risk patients. PMID- 23628496 TI - Midterm experience with modified Cabrol procedure: safe and durable for complex aortic root replacement. AB - OBJECTIVE: To evaluate the early and late outcomes of the modified Cabrol technique as a method of coronary reimplantation during complex composite graft replacement of the ascending aorta. METHODS: Between 1995 and 2012, 348 patients (mean age, 56 +/- 14 years; 283 males and 65 females) underwent composite graft replacement of the ascending aorta, 40 of whom (mean age, 60 +/- 12 years; 35 males and 5 females) had one or both coronary ostia reimplanted using a modified Cabrol technique with an 8- to 10-mm Dacron interposition graft. The mean clinical and radiologic (computed tomographic scan) postoperative follow-up was 39 months (range, 1-171 months), via our aortic database, patient interviews, and Social Security Death Index. RESULTS: Cabrol reimplantation was necessitated by reoperations with anatomically fixed coronary ostia (n = 16, 40%), severely displaced coronary arteries (n = 15, 37.5%), button calcification (n = 4, 10%), coronary anomalies (n = 3, 7.5%), and coronary aneurysm (n = 2, 5%). Of the operations, 20% (8 patients) were urgent interventions. Early mortality was 3 (7.5%) of 40, none related to the Dacron interposition graft. Total late mortality was 16.2%, also not related to the coronary graft. Actuarial survivals were 0.88 +/- 0.05, 0.79 +/- 0.07, and 0.73 +/- 0.08 at 1, 3, and 6 years, respectively. Radiologic follow-up was available for 31 (83.8%) of the surviving patients and revealed that the interposition graft was widely patent in all. CONCLUSIONS: The modified Cabrol technique using a Dacron interposition graft showed good survival rates and excellent durability over time, confirmed radiographically. These data confirm that it is appropriate to use the Cabrol technique when technical complexity prevents bringing coronary buttons to the main aortic graft. PMID- 23628497 TI - An improved Wiener deconvolution filter for high-resolution electron microscopy images. AB - We propose an improved Wiener deconvolution filter for high-resolution transmission electron microscopy (HRTEM) images and apply it to an experimental graphite image. The improved filter can simultaneously eliminate the modulation transfer function effects of CCD cameras and reduce noise, thereby confirming its superiority over the general Wiener deconvolution and Wiener denoising filters. In the resulting image, graphene lattices appear. In particular, because of our on-estimation of the noise power spectrum, the vacuum remains naturally smooth and very clear graphene-vacuum boundaries generates. Quantitatively, the signal to-noise ratio of the filtered image improves by a factor of 3. The proposed method is applicable to very noisy HRTEM images of weak scattering objects, such as few-layer graphene or boron nitride. PMID- 23628498 TI - Synthesis, radioprotective activity and pharmacokinetics characteristic of a new stable nitronyl nitroxyl radical-NIT2011. AB - A new stable nitronyl nitroxyl radical NIT2011 was synthesized and characterized. The radioprotective effect and pharmacokinetics profiles of NIT2011 were investigated. The results showed that when irradiation exposure dose was 6.5 Gy gama radiation, the survival rate in the irradiation-only group was 20% on 30th day. The survival rate was 70%, 80%, and 90% on 30th day when mice were pretreated with 0.25, 0.5 and 1.0 mmol/kg NIT2011, respectively. The pretreatment of NIT2011 increased number of spleen colonies, the numbers of bone marrow cells and protein level in bone marrow cells. Pretreatment with NIT2011 prior to radiation exposure increased the plasma SOD (superoxide dismutase) activity. 24 h after irradiation exposure, level of plasma MDA (malondialdehyde) in irradiation only mice was 14.8 +/- 2.8 nmol/mL, level of plasma MDA in NIT2011 (1 mmol/kg) pretreated mice was 9.8 +/- 2.0 nmol/mL. Three days after irradiation exposure, the micronucleus ratio in irradiation-only mice is 40.2 +/- 3.6, the micronucleus ratio in NIT2011 (1 mmol/kg) pretreated mice was 11.7 +/- 1.2. NIT2011 was easily absorbed in mice after it was oral administrated. Compared with the intraperitoneal injection, the relative oral bioavailability of the NIT2011 was 27.5% in mice. The LD50 of NIT2011 was 1510 mg/kg in mice by oral administration. Thus, NIT2011 has potential in being developed as an oral dosage form, safe and effective radioprotective agent. PMID- 23628499 TI - The edge vascular response following implantation of the Absorb everolimus eluting bioresorbable vascular scaffold and the XIENCE V metallic everolimus eluting stent. First serial follow-up assessment at six months and two years: insights from the first-in-man ABSORB Cohort B and SPIRIT II trials. AB - AIMS: To assess serially the edge vascular response (EVR) of a bioresorbable vascular scaffold (BVS) compared to a metallic everolimus-eluting stent (EES). METHODS AND RESULTS: Non-serial evaluations of the Absorb BVS at one year have previously demonstrated proximal edge constrictive remodelling and distal edge changes in plaque composition with increase of the percent fibro-fatty (FF) tissue component. The 5 mm proximal and distal segments adjacent to the implanted devices were investigated serially with intravascular ultrasound (IVUS), post procedure, at six months and at two years, from the ABSORB Cohort B1 (n=45) and the SPIRIT II (n=113) trials. Twenty-two proximal and twenty-four distal edge segments were available for analysis in the ABSORB Cohort B1 trial. In the SPIRIT II trial, thirty-three proximal and forty-six distal edge segments were analysed. At the 5-mm proximal edge, the vessels treated with an Absorb BVS from post procedure to two years demonstrated a lumen loss (LL) of 6.68% (-17.33; 2.08) (p=0.027) with a trend toward plaque area increase of 7.55% (-4.68; 27.11) (p=0.06). At the 5-mm distal edge no major changes were evident at either time point. At the 5-mm proximal edge the vessels treated with a XIENCE V EES from post procedure to two years did not show any signs of LL, only plaque area decrease of 6.90% (-17.86; 4.23) (p=0.035). At the distal edge no major changes were evident with regard to either lumen area or vessel remodelling at the same time point. CONCLUSIONS: The IVUS-based serial evaluation of the EVR up to two years following implantation of a bioresorbable everolimus-eluting scaffold shows a statistically significant proximal edge LL; however, this finding did not seem to have any clinical implications in the serial assessment. The upcoming imaging follow-up of the Absorb BVS at three years is anticipated to provide further information regarding the vessel wall behaviour at the edges. PMID- 23628500 TI - Synergistic effect of exercise and statins on femoral strength in rats. AB - It is now widely recognized that in order to optimize bone health in the later years, bone healthy behaviors should begin at a young age and continue throughout life. Prescribed orally to lower lipid levels in adults of all ages, statins have also been shown to stimulate bone formation in vitro by promoting bone morphogenic protein-2 (BMP-2) activity and to stimulate bone formation in vivo. Weight bearing exercise is well known to stimulate bone formation through a mechanism whereby mechanical loading is 'sensed' by the mechano-sensors leading to a cascade of events involving the activation of osteoblasts. For individuals with high cholesterol levels, both of these interventions are recommended throughout adult life. Since statins and exercise stimulate bone formation via different mechanisms, we hypothesized that exercise in combination with oral simvastatin synergistically increases bone mineral density and strength. Mature adult female, Sprague Dawley rats were divided into 4 groups: control (n=9), statin only (n=8), exercise only (n=11), and statin plus exercise (n=11). Simvastatin was given to the two groups at a dose of 10 mg/kg/day in standard rat chow for the entire 5 week period. All rats ate the same mass of food. The two exercise groups ran on a treadmill with progressively greater speeds and time, ending on week 5 at 30 m/min for 60 min. After 5 weeks, rats were euthanized, and excised femurs were scanned for areal bone mineral density (BMD) and tested by three point bending to obtain the following performance measures: maximum force (strength), stiffness, and work-to-fracture. Only the group treated with statins and exercise showed a positive effect on the biomechanical performance of the femurs. Compared to controls, this group had increased maximum force, stiffness, moment of inertia, and BMD. Linear regression analysis revealed that the increased performance was related to increased BMD. We conclude that the combination of oral statins and appropriate exercise increases bone strength better than either individual treatment and may provide optimal protection against osteoporosis. PMID- 23628501 TI - Aging is not a barrier to muscle and redox adaptations: applying the repeated eccentric exercise model. AB - Despite the progress of analytic techniques and the refinement of study designs, striking disagreement exists among studies regarding the influence of exercise on muscle function and redox homeostasis in the elderly. The repeated eccentric exercise model was applied to produce long-lasting and extensive changes in redox biomarkers and to reveal more effectively the potential effects of aging on redox homeostasis. Ten young (20.6+/-0.5 years) and ten elderly men (64.6+/-1.1 years) underwent an isokinetic eccentric exercise session, which was repeated after three weeks. Muscle function/damage indices (torque, range of movement, muscle soreness and creatine kinase) and redox biomarkers (F2-isoprostanes, protein carbonyls, glutathione, catalase, superoxide dismutase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, uric acid, bilirubin and albumin) were assessed in plasma, erythrocytes or urine pre-exercise, immediately post-exercise and at 2 and 4 days post-exercise. As expected, the elderly group exhibited oxidative stress in baseline compared to the young group. Extensive muscle damage and extensive alterations in redox homeostasis appeared after the first bout of eccentric exercise. Noteworthy, the redox responses were similar between the age groups despite their differences in baseline values. Likewise, both age groups demonstrated blunted alterations in muscle damage and redox homeostasis after the second bout of eccentric exercise indicating adaptations from the first bout of exercise. Elderly individuals seem to be well fitted to participate in demanding physical activities without suffering detrimental effects on skeletal muscle and/or disturbances on redox homeostasis. The repeated eccentric exercise model may be a useful and practical physiological tool to study redox biology in humans. PMID- 23628502 TI - A randomized 9-month study of blood pressure and body fat responses to aerobic training versus combined aerobic and resistance training in older men. AB - This randomized study evaluated the impact of different exercise training modalities on blood pressure and body fat responses in apparently healthy older men. Forty-eight elderly men (aged 65-75 years) were randomly assigned to an aerobic training group (ATG, n=15), a combined aerobic and resistance training group (CTG, n=16), or a control group (n=17). Both exercise training programs were moderate-to-vigorous intensity, three days/week for 9-months. Strength, aerobic endurance, body fat and blood pressure were measured on five different occasions. The data were analyzed using a mixed-model ANOVA, and the independence between systolic blood pressure (SBP), diastolic blood pressure (DBP) and group was tested. A significant main effect of group (p<0.001) was observed in strength and aerobic endurance, with higher performance observed in the CTG. A significant main effect of group (p<0.001) and time (p=0.029) was observed in body fat percentage, with a 2.3% decrease in CTG. A significant main effect of time was observed in SBP (p=0.005) and in DBP (p=0.011) for both ATG and CTG. Mean decreases in SBP and DBP, respectively, were 15 and 6 mmHg for ATG and 24 and 12 mmHg for CTG. There was a significant association for SBP (p=0.008) and DBP (p=0.005) in the CTG, with significant individual BP profile modifications. Both exercise-training programs reduce resting blood pressure. However, only the combined exercise training was effective at reducing body fat percentage; consequently, there were larger changes in blood pressure, which result in a significant reduction in hypertensive subjects. PMID- 23628503 TI - [Is the morbid obesity surgery profitable in times of crisis? A cost-benefit analysis of bariatric surgery]. AB - Morbid obesity is a serious health problem whose prevalence is increasing. Expensive co-morbidities are associated to these patients, as well as a reduction in the survival. Bariatric surgery resolves the co-morbidities (type 2 diabetes mellitus, 86.6%; cardiovascular risk, 79.0%; obstructive sleep apnea syndrome, 83.6%; hypertension, 61.7%), reduces the mortality rate (among 31-40%), and increases the morbid obese patients survival over a 10-years period. It provides significant savings for the National Health System. The obese patients consume a 20% plus of health resources and 68% plus of drugs than general population. Bariatric surgery requires an initial investment (diagnosis-related group cost: 7,468 ?), but it is recovered in a cost-effectiveness ratio of 2.5 years. Significant savings are obtained from the third year. To the direct economic benefits associated with reduced health expenditures it should be added an increase in tax collection (sick leave and unemployment reduction is estimated in 18%, with a productivity increase of 57% for self-employed people). Bariatric surgery is one of the most cost-effective procedures in the healthcare system. PMID- 23628504 TI - Obese humans with nonalcoholic fatty liver disease display alterations in fecal microbiota and volatile organic compounds. PMID- 23628505 TI - Emerging role of SUMOylation in placental pathology. AB - INTRODUCTION: Small ubiquitin-like modifiers (SUMO) conjugate to target proteins in a dynamic, reversible manner to function as post-translational modifiers. SUMOylation of target proteins can impinge on their localization, in addition to their activity or stability. Differential expression of deSUMOylating enzymes (SENP 1 and 2) contributes to altered mammalian placental development and function in mice. Severe preeclampsia (sPE) is associated with abnormal placental development and chronic ischemic injury. Extra- and intracellular stimuli/stressors that include hypoxic-activated pathways are known modulators of SUMOylation. In this current study we hypothesized that placentas from sPE patients will display up regulation in the SUMO regulatory pathway. METHODS: Utilizing qRT-PCR, immuno-blotting and Western techniques, we determined the expression levels of SUMO pathway genes in healthy and diseased placentas. We also exposed placental explants to hypoxia to study the effect on the SUMOylation pathway. RESULTS: We observed steady-state expression of SUMO1-3, SUMO-conjugated enzyme-UBC9 and deSUMOylating enzymes - SENPs, throughout normal gestation. An elevated level of free SUMO1-3 and SUMO-protein conjugates was observed in sPE placentas. Furthermore, placental UBC9 levels were strikingly increased in the same sPE patients. Hypoxia-induced SUMOylation in first trimester placental explants. DISCUSSION: Our data demonstrate an elevated steady-state of SUMOylation in sPE placentas compared with gestational aged-matched controls. The observed hyper-SUMOylation in sPE placentas correlates with elevated expression of UBC9 rather than with reduced expression of SENPs Hypoxia may contribute to alterations in placental SUMOylation pathway. CONCLUSION: Increased placental SUMOylation may contribute to the pathogenesis of serious placental pathology that causes extreme preterm birth. PMID- 23628506 TI - A triploid partial mole placenta from paternal isodisomy with a diploid fetus derived from one sperm and one oocyte may have caused angiogenic imbalance leading to preeclampsia-like symptoms at 19 weeks of gestation. AB - Partial hydatidiform mole with a normal fetus is extremely rare. A 30-year-old woman presented at 19 weeks gestation with clinical manifestations of severe preeclampsia. The fetus revealed a normal 46,XX karyotype and the placenta revealed triploid 69,XXX from paternal isodisomy. Microsatellite analysis revealed that the fetus and the triploid partial mole were derived from one sperm and one oocyte, followed by duplication of paternal chromosomes in only a trophectodermal cell. The maternal serum levels of angiogenic factors were extremely high compared with those reported in preeclampsia, suggesting an angiogenic imbalance may have caused preeclampsia-like symptoms before 20 weeks of gestation. PMID- 23628507 TI - Software for symptom association analysis in pediatric gastroesophageal reflux disease. AB - Gastroesophageal reflux (GER) disease is a serious complication of the upper gastrointestinal tract. Cardiorespiratory symptoms such as apnea, oxygen desaturation and bradycardia may be related to GER. Thus, the recommended diagnostic methodology in pediatric patients requires 24-h synchronized esophageal and cardiorespiratory monitoring. However, there is no computer tool available for this purpose and therefore, researchers and physicians are forced to seek for customized solutions. This paper presents an open source computer program for the analysis of symptom association. It allows a convenient visualization of the biological signals and implements the three main metrics for symptom association, that is, the symptom index, the symptom sensitivity index and the symptom association probability. This software represents a flexible solution and will facilitate caregivers an easy assessment of the existence of temporal association between GER and cardiorespiratory episodes. This would ideally reduce inappropriate medical and surgical treatments and would provide an early diagnosis of the medical condition. PMID- 23628508 TI - Aspidin BB, a phloroglucinol derivative, induces cell cycle arrest and apoptosis in human ovarian HO-8910 cells. AB - Aspidin BB, an effective phloroglucinol derivative from Dryopteris fragrans (L.) Schott, has been previously reported to exert high biological activities. In this study, we analyzed the underlying mechanisms of aspidin BB on human ovarian cancer cell line, HO-8910. Aspidin BB significantly inhibited HO-8910 cell proliferation in a dose- and time-dependent manner. The IC50 values were 15.02, 25.79 and 68.81MUM after 72, 48 and 24h treatment, respectively. Meanwhile, aspidin BB markedly induced apoptosis evidenced by characteristic apoptotic morphological changes, nuclear DNA fragmentation, annexin V-FITC/propidium iodide (PI) double staining and S peak. Western blot analysis showed that aspidin BB suppressed Bcl-2 expression and enhanced Bax expression to desintegrate the outer mitochondrial membrane, then caused cytochrome c release which led to the activation of effector caspase-3, and further cleaved the poly ADP-ribose polymerase (PARP) in the nucleus, finally induced cell apoptosis. Furthermore, aspidin BB provoked S phase arrest in HO-8910 cells with up-regulation of pRb, E2F1, CDK2, cyclin E and cyclin A proteins. Taken together, these findings support the conclusion that aspidin BB exhibits cytotoxicity towards human ovarian cancer HO-8910 cells through induction of apoptosis via mitochondrial pathway and arresting cell cycle progression in S phase. PMID- 23628509 TI - Cyclopenta[c]phenanthrenes--chemistry and biological activity. AB - Despite cyclopenta-fused polycyclic aromatic hydrocarbons (CP-PAHs) having been detected in the environment, the ability of these compounds to induce cellular and tissue responses remains poorly characterized. In this review, we look at the chemistry and biological activity of the cyclopenta[c]phenanthrenes (CP[c]Phs) as potential chemicals of concern in the process of risk assessment. The first part of the review deals with the environmental occurrence and chemistry of CP-PAHs, focusing on available methods of CP[c]Ph chemical synthesis. The most interesting structural feature of the CP[c]Ph is the presence of a pseudo fjord-region constructed by the cyclopentane ring. This compound can be treated either as a structurally similar one to B[c]Ph, or as a phenanthrene skeleton with an electrodonating alkyl substituent in the bay-region of the molecule. The second thread, providing available data on the adverse effects of CP[c]Ph compounds on cells and tissues of living organisms, mainly fish, improves our understanding of these possible environmental hazards. The data show that CP[c]Ph is less potent at inducing CYP1A gene expression in rainbow trout than benzo[a]pyrene (B[a]P), a well-known Ah-receptor agonist. Interestingly, the CP[c]Ph dependent up regulation of CYP1A mRNA is positively correlated with the incidences of clastogenic changes in rainbow trout erythrocytes. CP[c]Ph has, comparably to B[a]P, a potential to repress expression of tumor suppressor p53, in the head kidney of rainbow trout. Furthermore, estrogen responsive genes in fish liver, ERalpha and VTG, are not induced by CP[c]Ph, suggesting that the compound has no endocrine disrupting potential. However, some CP[c]Phs show mutagenic activity when investigated in the Ames test, and exhibit genotoxic properties in in vitro micronucleus assay. The above characteristics suggest that CP-PAHs are chemicals of concern for which potential pathways of exposure should be further identified. PMID- 23628510 TI - The predictive potential of the sweat chloride test in cystic fibrosis patients with the G551D mutation. AB - BACKGROUND: Ivacaftor, a cystic fibrosis transmembrane regulator (CFTR) potentiator, decreased sweat chloride concentrations and improved clinical measures in cystic fibrosis (CF) patients with the G551D mutation. RESULTS: Sweat chloride measurements at day 15 had an overall positive predictive value (PPV) of 86.3%, a negative predictive value (NPV) of 65.5%, sensitivity of 73.9%, and specificity of 80.9% for an FEV1 improvement of >=5% from baseline at week 16. For ivacaftor patients the median FEV1 improvement was 16.7%; for placebo patients 0.4%. For patients aged 6-11 years who received ivacaftor and who had a sweat chloride decrease of >=40 mmol/L from baseline at day 15, a median weight gain of 11.2% at week 16, compared to 6% for those with a smaller decrease was observed. CONCLUSIONS: Changes in sweat chloride concentration at day 15 following treatment with ivacaftor may have sufficient predictive potential to identify individuals that show improvement in pulmonary function and weight gain after 16 weeks of treatment. PMID- 23628511 TI - Pain in CF: review of the literature. AB - BACKGROUND: This review evaluated pain research in cystic fibrosis (CF). METHODS: OVID MEDLINE, CINAHL, AMED, Web of Science, Pubmed, PsychINFO and PsychARTICLES were searched from January 1995-December 2012 to locate papers assessing pain in CF. A proforma was used to record the rationale for the study, characteristics of the sample, pain assessment tools, pain location, frequency and severity, treatment/self-management, coping and the impact on daily activities and quality of life. RESULTS: All studies (n=13) were retrospective. Chest and abdominal pains were most commonly reported. Pain was negatively associated with pulmonary exacerbations, quality of life and treatment adherence. Approximately 50% of patients do not consult their GP or CF team about pain, with many patients reporting self-management. CONCLUSION: A high incidence of pain is reported in CF although there is little standardization of CF pain measurement. The way forward is to develop guidelines on how to assess pain and provide adequate treatment for pain in CF. PMID- 23628512 TI - ARFI and transient elastography for characterization of cystic fibrosis related liver disease: first longitudinal follow-up data in adult patients. PMID- 23628513 TI - Screening for depression in a single CF centre. AB - INTRODUCTION: The International Depression and Anxiety Epidemiological Study (TIDES) in CF attempts to provide prevalence data for mental distress in CF patients. The current study reports the results from the UK pilot in a single major CF centre in which the performances of different instruments were compared, and risk of self harm measured. METHODS: Two mental health assessment screening instruments, the Hospital Anxiety and Depression Scale (HADS) and the Patient Health Questionnaire for depression (PHQ-9) were given to all adults with CF attending the Regional Adult CF Unit in Leeds, UK. RESULTS: 232 patients took part. 13 (5.6%) scored in the clinical range for depression on the HADS and 78 (33.4%) on the PHQ9. The suicide risk item on the PHQ9 was endorsed by 24 patients (10.4%). DISCUSSION: Major discrepancies were found in rates of depression detected by two popular screening tools. A significant minority of respondents indicated suicidal ideation. Work is needed to identify the most appropriate screening tool for depression in this population, and it is important that this includes an assessment of self harm. PMID- 23628514 TI - Optimization of low-background alpha spectrometers for analysis of thick samples. AB - Results of alpha spectrometric measurements performed deep underground and above ground with and without active veto show that the underground measurement of thick samples is the most sensitive method due to significant reduction of the muon-induced background. In addition, the polonium diffusion requires for some samples an appropriate selection of an energy region in the registered spectrum. On the basis of computer simulations the best counting conditions are selected for a thick lead sample in order to optimize the detection limit. PMID- 23628515 TI - The selection and use of outcome measures in palliative and end-of-life care research: the MORECare International Consensus Workshop. AB - CONTEXT: A major barrier to widening and sustaining palliative care service provision is the requirement for better selection and use of outcome measures. Service commissioning is increasingly based on patient, carer, and service outcomes as opposed to service activity. OBJECTIVES: To generate recommendations and consensus for research in palliative and end-of-life care on the properties of the best outcome measures, enhancing the validity of proxy-reported data and optimal data collection time points. METHODS: An international expert "workshop" was convened and an online consensus survey was undertaken using the MORECare Transparent Expert Consultation to generate recommendations and level of agreement. We focused on three areas: 1) measurement properties, 2) use of proxies, and 3) measurement timing. Data analysis comprised descriptive analysis of aggregate scores and collation of narrative comments. RESULTS: There were 31 workshop attendees; 29 recommendations were included in the online survey, completed by 28 experts. The top three recommendations by area were the following: 1) the properties of the best outcome measures are responsive to change over time and capture clinically important data, 2) to enhance the validity of proxy data requires clear and specific guidelines to aid lay individuals' and/or professionals' completion of proxy measures, and 3) data collection time points need clear identification to establish a baseline. CONCLUSION: Outcome measurement in palliative and end-of-life care requires the use of psychometrically robust measures that are clinically responsive, with defined data collection time points to establish a baseline and clear administration guidelines to complete proxy measures. To further the field requires clinical imperatives to more closely inform recommendations on outcome measurement. PMID- 23628516 TI - Validation of the Edmonton Symptom Assessment System in Korean patients with cancer. AB - CONTEXT: The Edmonton Symptom Assessment System (ESAS) is a brief, widely adopted, multidimensional questionnaire to evaluate patient-reported symptoms. OBJECTIVES: To develop a Korean version of the ESAS (K-ESAS) and to perform a psychometric analysis in Korean patients with advanced cancer. METHODS: We tested the K-ESAS in two pilot studies with 15 patients each. We assessed internal consistency, test-retest reliability, and concurrent validity in 163 Korean patients, who completed the K-ESAS along with the Korean versions of the M. D. Anderson Symptom Inventory (K-MDASI) and the Hospital Anxiety and Depression Scale (K-HADS) twice. A total of 38 patients completed the questionnaires again seven days later to assess responsiveness. RESULTS: The K-ESAS scores had good internal consistency, with a Cronbach's alpha coefficient of 0.88, indicating that no questions had undue influence on the score. Pearson correlation coefficients for K-ESAS symptom scores between baseline and after two to four hours ranged from 0.72 (95% CI 0.64-0.79) to 0.87 (95% CI 0.82-0.90), indicating strong test-retest reliability. For concurrent validity, Pearson correlation coefficients between K-ESAS symptom scores and corresponding K-MDASI symptom scores ranged from 0.70 (95% CI 0.62-0.77) to 0.83 (95% CI 0.77-0.87), indicating good concurrent validity. For the K-HADS, concurrent validity was good for anxiety (r=0.73, 95% CI 0.65-0.79) but moderate for depression (r=0.4, 95% CI 0.26-0.52). For responsiveness, changes in K-ESAS scores after seven days were moderately correlated with changes in K-MDASI scores but weakly correlated with changes in K-HADS scores. CONCLUSION: The K-ESAS is a valid and reliable tool for measuring multidimensional symptoms in Korean patients with cancer. PMID- 23628517 TI - Primary care provider practices and beliefs related to cervical cancer screening with the HPV test in Federally Qualified Health Centers. AB - OBJECTIVE: Cervical cancer screening using the human papillomavirus (HPV) test and Pap test together (co-testing) is an option for average-risk women >= 30 years of age. With normal co-test results, screening intervals can be extended. The study objective is to assess primary care provider practices, beliefs, facilitators and barriers to using the co-test and extending screening intervals among low-income women. METHOD: Data were collected from 98 providers in 15 Federally Qualified Health Center (FQHC) clinics in Illinois between August 2009 and March 2010 using a cross-sectional survey. RESULTS: 39% of providers reported using the co-test, and 25% would recommend a three-year screening interval for women with normal co-test results. Providers perceived greater encouragement for co-testing than for extending screening intervals with a normal co-test result. Barriers to extending screening intervals included concerns about patients not returning annually for other screening tests (77%), patient concerns about missing cancer (62%), and liability (52%). CONCLUSION: Among FQHC providers in Illinois, few administered the co-test for screening and recommended appropriate intervals, possibly due to concerns over loss to follow-up and liability. Education regarding harms of too-frequent screening and false positives may be necessary to balance barriers to extending screening intervals. PMID- 23628518 TI - Influenza H3N2 variant viruses with pandemic potential: preventing catastrophe in remote and isolated Canadian communities. AB - OBJECTIVE: To evaluate the impact of age-specific cross-reactive antibody protection levels on the outcomes of a pandemic outbreak of new variants of H3N2 influenza A viruses (H3N2v). METHODS: We calibrated a previously validated agent based model of human-to-human transmission of influenza viruses to project the outcomes of various protection levels in a remote and isolated Canadian community, when demographics are drawn from the Statistics Canada census data. We then compared the outcomes with a scenario in which demographic variables were shifted to resemble an urban structure. This comparative evaluation was conducted using in-silico computer simulations, where the epidemiological data were drawn from relevant estimates in published literature. RESULTS: Simulations, using estimates of transmissibility for the 2009 H1N1 pandemic strain in the study population, show that the epidemic size is primarily affected by the cross reactive protection levels of young children. A lower number of secondary infections at the early stages of an outbreak does not necessarily correspond to a lower epidemic size. CONCLUSIONS: Demographic variables could play a significant role in determining the outcomes of an outbreak. The findings strongly suggest that, when an H3N2v-specific vaccine becomes available, children below the age of 17 should be prioritized for vaccination. This prioritization is essential in population settings with a low average age, including aboriginal communities in northern latitudes. PMID- 23628519 TI - Association of serum lactate and survival outcomes after cardiac arrest. PMID- 23628520 TI - The coronary artery bypass graft SYNTAX Score: final five-year outcomes from the SYNTAX-LE MANS left main angiographic substudy. PMID- 23628522 TI - Baseline ECG and VT ablation: Is there more to it than just skimming the surface? PMID- 23628521 TI - Terminating ventricular tachyarrhythmias using far-field low-voltage stimuli: mechanisms and delivery protocols. AB - BACKGROUND: Low-voltage termination of ventricular tachycardia (VT) and atrial fibrillation has shown promising results; however, the mechanisms and full range of applications remain unexplored. OBJECTIVES: To elucidate the mechanisms for low-voltage cardioversion and defibrillation and to develop an optimal low voltage defibrillation protocol. METHODS: We developed a detailed magnetic resonance imaging-based computational model of the rabbit right ventricular wall. We applied multiple low-voltage far-field stimuli of various strengths (<=1 V/cm) and stimulation rates in VT and ventricular fibrillation (VF). RESULTS: Of the 5 stimulation rates tested, stimuli applied at 16% or 88% of the VT cycle length (CL) were most effective in cardioverting VT, the mechanism being consecutive excitable gap decreases. Stimuli given at 88% of the VF CL defibrillated successfully, whereas a faster stimulation rate (16%) often failed because the fast stimuli did not capture enough tissue. In this model, defibrillation threshold energy for multiple low-voltage stimuli at 88% of VF CL was 0.58% of the defibrillation threshold energy for a single strong biphasic shock. Based on the simulation results, a novel 2-stage defibrillation protocol was proposed. The first stage converted VF into VT by applying low-voltage stimuli at times of maximal excitable gap, capturing large tissue volume and synchronizing depolarization; the second stage terminated VT. The energy required for successful defibrillation using this protocol was 57.42% of the energy for low voltage defibrillation when stimulating at 88% of VF CL. CONCLUSIONS: A novel 2 stage low-voltage defibrillation protocol using the excitable gap extent to time multiple stimuli defibrillated VF with the least energy by first converting VF into VT and then terminating VT. PMID- 23628523 TI - Determination of dextromethorphan and levomethorphan in seized heroin samples by enantioselective HPLC and electronic CD. AB - A new enantioselective HPLC method was developed for the resolution and determination of the enantiomers of methorphan, dextromethorphan (DXM) and levomethorphan (LVM), on a Chiralcel OJ column (250 mm * 4.6mm I.D.). The resolution of DXM and LVM was obtained using a mobile phase consisting of (n hexane)-(2-propanol)-diethylamine (70:30:0.1, v/v/v) at a flow rate of 0.5 mL min(-1). The enantioselective method was found to be selective (alpha=1.92) and sensitive (LOD=2.8 MUg mL(-1) for both DXM and LVM). The method was coupled with electronic circular dichroism (CD), allowing the determination of the elution order on the basis of the sign of CD signals of the single enantiomers at 285 nm (positive for DXM, negative for LVM). Under the optimized conditions, the validated method was applied to the identification and quantitation of the enantiomers of methorphan in samples of different sources of illicit drugs of abuse (heroin). DXM was found in eight seized samples of street heroin; two of these samples, for which the DXM content was found to be over 5% (w/w) and exceeding a 10% (w/w) ratio with respect to diacetylmorphine, were the cause of two deaths for overdose due to acute narcotism. PMID- 23628524 TI - Evaluation of the residual solvent content of counterfeit tablets and capsules. AB - A group of counterfeit samples of Viagra and Cialis were screened for their residual solvent content and compared to the content of the genuine products. It was observed that all counterfeit samples had higher residual solvent contents compared to the genuine products. A more diverse range of residual solvents was found as well as higher concentrations. In general these concentrations did not exceed the international imposed maximum limits. Only in a few samples the limits were exceeded. A Projection Pursuit analysis revealed clusters of samples with similar residual solvent content, possibly enabling some future perspectives in forensic research. PMID- 23628525 TI - Evaluation of four different equations for calculating LDL-C with eight different direct HDL-C assays. AB - BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is often calculated (cLDL C) by the Friedewald equation, which requires high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Because there have been considerable changes in the measurement of HDL-C with the introduction of direct assays, several alternative equations have recently been proposed. METHODS: We compared 4 equations (Friedewald, Vujovic, Chen, and Anandaraja) for cLDL-C, using 8 different direct HDL-C (dHDL-C) methods. LDL-C values were calculated by the 4 equations and determined by the beta quantification reference method procedure in 164 subjects. RESULTS: For normotriglyceridemic samples (TG<200mg/dl), between 6.2% and 24.8% of all results exceeded the total error goal of 12% for LDL-C, depending on the dHDL-C assay and cLDL-C equation used. Friedewald equation was found to be the optimum equation for most but not all dHDL-C assays, typically leading to less than 10% misclassification of cardiovascular risk based on LDL-C. Hypertriglyceridemic samples (>200mg/dl) showed a large cardiovascular risk misclassification rate (30%-50%) for all combinations of dHDL-C assays and cLDL-C equations. CONCLUSION: The Friedewald equation showed the best performance for estimating LDL-C, but its accuracy varied considerably depending on the specific dHDL-C assay used. None of the cLDL-C equations performed adequately for hypertriglyceridemic samples. PMID- 23628527 TI - [International Test Commission Guidelines for test translation and adaptation: second edition]. AB - BACKGROUND: Adapting tests across cultures is a common practice that has increased in all evaluation areas in recent years. We live in an increasingly multicultural and multilingual world in which the tests are used to support decision-making in the educational, clinical, organizational and other areas, so the adaptation of tests becomes a necessity. The main goal of this paper is to present the second edition of the guidelines of the International Test Commission (ITC) for adapting tests across cultures. METHOD: A task force of six international experts reviewed the original guidelines proposed by the International Test Commission, taking into account the advances and developments of the field. RESULTS: As a result of the revision this new edition consists of twenty guidelines grouped into six sections: Precondition, test development, confirmation, administration, score scales and interpretation, and document. The different sections are reviewed, and the possible sources of error influencing the tests translation and adaptation analyzed. CONCLUSIONS: Twenty guidelines are proposed for translating and adapting tests across cultures. Finally we discuss the future perspectives of the guidelines in relation to the new developments in the field of psychological and educational assessment. PMID- 23628526 TI - Nuclear EGFR protein expression predicts poor survival in early stage non-small cell lung cancer. AB - INTRODUCTION: Nuclear EGFR (nEGFR) has been identified in various human tumor tissues, including cancers of the breast, ovary, oropharynx, and esophagus, and has predicted poor patient outcomes. We sought to determine if protein expression of nEGFR is prognostic in early stage non-small cell lung cancer (NSCLC). METHODS: Resected stages I and II NSCLC specimens were evaluated for nEGFR protein expression using immunohistochemistry (IHC). Cases with at least one replicate core containing >=5% of tumor cells demonstrating strong dot-like nucleolar EGFR expression were scored as nEGFR positive. RESULTS: Twenty-three (26.1% of the population) of 88 resected specimens stained positively for nEGFR. Nuclear EGFR protein expression was associated with higher disease stage (45.5% of stage II vs. 14.5% of stage I; p = 0.023), histology (41.7% in squamous cell carcinoma vs. 17.1% in adenocarcinoma; p = 0.028), shorter progression-free survival (PFS) (median PFS 8.7 months [95% CI 5.1-10.7 mo] for nEGFR positive vs. 14.5 months [95% CI 9.5-17.4 mo] for nEGFR negative; hazard ratio (HR) of 1.89 [95% CI 1.15-3.10]; p = 0.011), and shorter overall survival (OS) (median OS 14.1 months [95% CI 10.3-22.7 mo] for nEGFR positive vs. 23.4 months [95% CI 20.1-29.4 mo] for nEGFR negative; HR of 1.83 [95% CI 1.12-2.99]; p = 0.014). CONCLUSIONS: Expression of nEGFR protein was associated with higher stage and squamous cell histology, and predicted shorter PFS and OS, in this patient cohort. Nuclear EGFR serves as a useful independent prognostic variable and as a potential therapeutic target in NSCLC. PMID- 23628528 TI - Dialectical behavioural therapy for oppositional defiant disorder in adolescents: a case series. AB - BACKGROUND: Oppositional defiant disorder (ODD) is characterised as a recurrent pattern of defiant behaviour towards authority figures, irritability and difficulties in regulating emotions. ODD in adolescents presents similar symptomatology to borderline personality disorder (BPD). A treatment programme that has been shown to be effective for treating problems related to emotion dysregulation such as BPD is dialectical behavioural therapy (DBT). The aim of this article is to outline a case series in which we applied DBT to two adolescents diagnosed with ODD, in addition to psychiatric comorbidity and parasuicidal behaviours. METHOD: We applied a training programme of 24 sessions in DBT skills, along with individual therapy. RESULTS: The results showed a decrease in impulsive behaviours, maladaptive behaviours to regulate affect, self mutilation behaviour, number of hospitalisations, anger and depressive symptoms. The data also showed an increase in positive emotions. CONCLUSION: These results suggest that DBT can be an alternative for the treatment of ODD in adolescents with psychiatric comorbidity and parasuicidal behaviours. PMID- 23628529 TI - Controlling social desirability may attenuate faking effects: a study with aggression measures. AB - BACKGROUND: Several studies have been conducted to better understand what happens with personality scores when faking occurs, but very few use socially undesirable trait measures such as aggression. The aim of the present research is twofold: (a) we aim to apply a General Factorial-Analytic procedure to aggression scales and determine whether it can correct for faking effects; (b) we aim to test the impact that individual differences can have on change scores due to faking. METHOD: Participants were 371 undergraduate students. Of these, 215 answered the questionnaires twice, under neutral conditions and under faking-motivating conditions. 156 were the control group who answered the questionnaires twice, both times under neutral conditions. RESULTS: The mean comparison tests as well as the repeated measures ANOVA showed significant results. Individual differences played an important role in all the scales except in physical aggression. CONCLUSIONS: The results showed that the procedure does correct for faking effects and that individual differences have an important impact on the change scores due to faking, except in the most undesirable Physical aggression measure, which was hardly affected. PMID- 23628530 TI - Cluster A maladaptive personality patterns in a non-clinical adolescent population. AB - BACKGROUND: The prevalence and expression of Cluster A personality disorders in adolescence is poorly analyzed and understood. The main goal was to analyze the rate of Cluster A traits and maladaptive personality patterns in adolescents. In addition, the underlying dimensional structure and the possible influence of sex and age in its phenotypic expression were examined. METHOD: The final sample was comprised of a total of 1,443 participants (M = 15.9 years, SD = 1.2). The instrument used was the Personality Diagnostic Questionnaire-4+ (PDQ-4+). RESULTS: Cluster A maladaptive personality traits are common among adolescents. According to the PDQ-4+, 13.1% (n = 189) of the sample reported a Cluster A maladaptive personality pattern. Analysis of the internal structure yielded two interrelated factors, namely Paranoid and Schizotypal-Schizoid. Males, compared with females, obtained higher scores on the schizotypal subscale when the score was dimensional and on the schizotypal and schizoid subscales when items were dichotomized. CONCLUSIONS: These data yield new clues that improve the understanding of Cluster A traits in this sector of the population, and advance in early detection of adolescents at risk of personality disorders. PMID- 23628531 TI - Beliefs about the effects of social sharing of emotion in alexithymia. AB - BACKGROUND: Emotional events are followed by recurrent talking about the event (Social Sharing of Emotion, SSE). Several factors that can account for variations in beliefs about SSE were examined: alexithymia, age and sex among two sample groups, Spanish (n = 388) and Uruguayan (n = 537). METHOD: Both samples completed the 20-item Toronto Alexithymia Scale (TAS-20) and the Beliefs about Social Sharing of Emotion Questionnaire (BSEQ). RESULTS: Results indicated that alexithymia was negatively related to beliefs about SSE. Low alexithymia was associated with higher agreement with positive intrapersonal effects of SSE and disagreement with benefits of non-expression or inhibition, and beliefs in positive interpersonal effect of social sharing were unrelated to alexithymia. Cultural and gender differences were found regarding beliefs about SSE. Regression analyses suggest that alexithymia significantly predicted beliefs about SSE. CONCLUSIONS: The pattern of results suggests that more collectivist and traditional cultures, such as the Uruguayan, attach less value to SSE. Results and implications are discussed. PMID- 23628532 TI - Effects of exposure to food images on physiological reactivity and emotional responses in women with bulimia nervosa. AB - BACKGROUND: The aim of this study is to compare the effectiveness of two exposure procedures on habituation of emotional responses to food stimuli: (a) exposure to external cues (food images) without eating forbidden food (CE) and (b) exposure to external cues eating forbidden food (with purge prevention). The influence of craving-trait and mood state on the habituation process is also studied. METHOD: Emotional modulation of the defense startle reflex was assessed in 26 women at risk of bulimia nervosa. After four exposure trials, changes in the following variables were measured: (a) food craving-state; (b) physiological measures: hearth rate (HR) and skin conductance response (SCR); (c) motivational patterns towards food (defense startle response); and (d) valence, arousal and dominance of the emotional response to food images. RESULTS: After treatment, subjects tended to show non-significant lower SCR and heart orientation responses (vs. defense responses); defense startle response was also significantly lower. CONCLUSIONS: The exposure procedure, the induced emotional state and the number of exposure trials are analyzed. PMID- 23628533 TI - Sources of perceived sociocultural pressure on physical self-concept. AB - BACKGROUND: The aim of this study is to analyze the four-factor structure (advertising, information, family environment and friendship setting) of the Cuestionario de Influjos Socioculturales sobre el Autoconcepto Fisico (CIAF) [Sociocultural Influences on Physical Self-concept Questionnaire] and its invariance in relation to sex, age and physical activity. METHOD: Participants were 579 students (339 men and 240 women) aged between 12 and 23, divided into three groups (137 under 14 years, 338 aged between 15 and 18 and 104 over 18 years). All completed the CIAF. RESULTS: Both the confirmatory factor analyses and the factor invariance tests support the four-factor structure of the CIAF and, therefore, the identification of four different types of sociocultural perceived influence. CONCLUSIONS: These results allow us to apply the abundant data found by previous studies on sociocultural pressure on body image to our understanding of physical self-concept. PMID- 23628534 TI - A predictive study of reading comprehension in third-grade Spanish students. AB - BACKGROUND: The study of the contribution of language and cognitive skills to reading comprehension is an important goal of current reading research. However, reading comprehension is not easily assessed by a single instrument, as different comprehension tests vary in the type of tasks used and in the cognitive demands required. METHOD: This study examines the contribution of basic language and cognitive skills (decoding, word recognition, reading speed, verbal and nonverbal intelligence and working memory) to reading comprehension, assessed by two tests utilizing various tasks that require different skill sets in third-grade Spanish speaking students. RESULTS: Linguistic and cognitive abilities predicted reading comprehension. A measure of reading speed (the reading time of pseudo-words) was the best predictor of reading comprehension when assessed by the PROLEC-R test. However, measures of word recognition (the orthographic choice task) and verbal working memory were the best predictors of reading comprehension when assessed by means of the DARC test. CONCLUSION: These results show, on the one hand, that reading speed and word recognition are better predictors of Spanish language comprehension than reading accuracy. On the other, the reading comprehension test applied here serves as a critical variable when analyzing and interpreting results regarding this topic. PMID- 23628535 TI - Peer bullying and disruption-coercion escalations in student-teacher relationship. AB - BACKGROUND: Although there have been many studies of bullying, few have linked it with the escalation of disruption-coercion that sometimes occur in the classroom. Understanding this relationship is the aim of this research. METHOD: The study included 22114 Spanish adolescents, aged 12 to 18 years (mean age = 14.22, SD = 1.41). 49.6% were boys (mean age = 14.26, SD = 1.41) and 50.4% were girls (mean age = 14.20, SD = 1.40). The design was a sample survey with stratified cluster sampling. Data were analyzed by latent class analysis. RESULTS: Based on direct involvement in bullying, five groups were detected: non-participants, bullies, followers, victim-bullies and victims. Involvement in bullying is associated with lower appraisal of school norms and a more negative perception of interaction with teachers, which seems to cause disruption and coercion escalations. We found differences in this respect among groups involved in bullying and non participants. CONCLUSIONS: The results reflect the need to try to prevent these two problems conjointly, teaching students to reject all forms of violence and, through more effective treatment of disruption, to prevent or stop escalation at early stages. PMID- 23628536 TI - Organizational injustice: third parties' reactions to mistreatment of employee. AB - BACKGROUND: Research on organizational injustice has mainly focused on the victim's perspective. This study attempts to contribute to our understanding of third parties' perspective by empirically testing a model that describes third party reactions to mistreatment of employees. METHOD: Data were obtained from a sample (N = 334) of Spanish employees from various organizations, nested into 66 work-groups, via a survey regarding their perceptions of organizational mistreatment. Structural equation modeling was used to analyze the data. RESULTS: The proposed model had a limited fit to the data and it was re-specified. Organizational mistreatment, employee performance, and employee organizational commitment explained internal attributions blaming the organization. Moreover, coworkers' organizational identification showed a positive impact on external attributions of responsibility. Lastly, supportive organizational climate and internal attributions accounted for a large percentage of variance in coworkers' perceptions of organizational unfairness. CONCLUSIONS: The final model explains the perceptions of injustice on the basis of internal attributions of responsibility in the face of organizational mistreatment of employees. PMID- 23628537 TI - On the relationships between disgust and morality: a critical review. AB - BACKGROUND: Disgust is, at its core, an emotion that responds to cues of parasites and infection, likely to be evolved to protect human organism from the risk of disease. Interestingly, a growing body of research implicates disgust as an emotion central to human morality. The fact that disgust is associated with appraisals of moral transgressions and that this emotion influences moral judgments implies a remarkable puzzle: Why does an emotion that originally functions in the domain of infectious entities become such a good candidate to play the role of a moral arbiter? The aim of the present review is to clarify the nature of the relationship between disgust and morality. METHOD: First, we examine the relevant features of disgust in order to explore whether the phenomenology of disgust favors its implementation as a defensive mechanism against offensive social entities. Second, we critically review the most striking findings about the effects of disgust on moral judgments. RESULTS: The revisited analysis of the literature strongly suggests a bidirectional causal link between disgust and moral cognition. CONCLUSIONS: We propose that the particular phenomenology of disgust (which involves a sense of offensiveness and rejection) favored the co-adaptation of this emotion to the moral domain. PMID- 23628538 TI - Why include phenomenological analysis in a Research Methods course? AB - BACKGROUND: Guidelines for Spanish university curricula include the descriptor Quantitative and Qualitative Methods, but the latter are still poorly represented. METHOD: To inform the argument for phenomenological methods, the last 20-year interval of ISI databases has been content-analyzed with the following codes: discourse analysis, grounded theory, narrative analysis, phenomenological analysis and confirmatory factor analysis, that is, four qualitative methods and a prototypical quantitative one. RESULTS: In absolute terms, the most frequent qualitative method is grounded theory, followed by discourse analysis, phenomenological analysis and narrative analysis. However, taking into account content categories, only phenomenological analysis shows a clear psychological profile, similar to confirmatory factor analysis. CONCLUSIONS: We recommend starting qualitative training with a method that does not require either big groups, or big funding, and that has a procedural core that is simple, relatively well-delimited and "secularizable," a variety of thematic analysis. Historical reasons and the clear psychological profile evidenced by our results enhance our argument to foster the inclusion of phenomenological analysis in research method courses in psychology. PMID- 23628540 TI - A new IRT-based standard setting method: application to eCat-listening. AB - BACKGROUND: Criterion-referenced interpretations of tests are highly necessary, which usually involves the difficult task of establishing cut scores. Contrasting with other Item Response Theory (IRT)-based standard setting methods, a non judgmental approach is proposed in this study, in which Item Characteristic Curve (ICC) transformations lead to the final cut scores. METHOD: eCat-Listening, a computerized adaptive test for the evaluation of English Listening, was administered to 1,576 participants, and the proposed standard setting method was applied to classify them into the performance standards of the Common European Framework of Reference for Languages (CEFR). RESULTS: The results showed a classification closely related to relevant external measures of the English language domain, according to the CEFR. CONCLUSIONS: It is concluded that the proposed method is a practical and valid standard setting alternative for IRT based tests interpretations. PMID- 23628539 TI - The factor structure of the Spanish version of the Work-Family Culture Scale in a sample of workers from the advertising sector. AB - BACKGROUND: The Work-Family Culture Scale (WFCS) was designed to assess employee perceptions of the extent to which their organizations facilitates a work-family balance. The WFCS comprises three dimensions: Oorganizational time demands, Managerial support and Negative career consequences. METHOD: The primary purpose of the present study was to analyze the factor structure and reliability of the Spanish version of the Work-Family Culture Scale in a sample of 795 employees (447 females and 348 males) working for twenty-three firms in the Spanish advertising sector. RESULTS: Both EFA and CFA using split-half data sets yielded an 11-item three-factor model (Managerial support, Career consequences and Organizational time demands) that fits the data very well. The findings for structural equation modeling were as follows: chi(2) (41) = 63.85; CFI = .99; GFI = .97; and RMSEA = .038. CONCLUSIONS: Internal consistency for the WFCS factors proved adequate. The results of the analysis indicate that this three-factor model confirms previous exploratory analyses of the original scale. PMID- 23628541 TI - Psychometric properties of Connor-Davidson Resilience Scale in a Spanish sample of entrepreneurs. AB - BACKGROUND: The literature regarding entrepreneurship suggests that the resilience of entrepreneurs may help to explain entrepreneurial success, but there is no resilience measure widely accepted by researchers. This study analyzes the psychometric properties of the Connor and Davidson Resilience Scale (CD-RISC) in a sample of Spanish entrepreneurs. METHOD: A telephone survey research method was used. The participants were entrepreneurs operating in the business services sector. Interviewers telephoned a total of 900 entrepreneurs of whom 783 produced usable questionnaires. The CD-RISC was used as data collection instrument. We used principal component analysis factor and confirmatory factor analysis to determine the factor structure of the CD-RISC. RESULTS: Confirmatory factor analysis failed to verify the original five-factor structure of the CD RISC, whereas principal component analysis factor yielded a 3-factor structure of resilience (hardiness, resourcefulness and optimism). In this research, 47.48% of the total variance was accounted for by three factors, and the obtained factor structure was verified through confirmatory factor analysis. CONCLUSIONS: The CD RISC has been shown to be a reliable and valid tool for measuring entrepreneurs' resilience. PMID- 23628542 TI - The MOOD Questionnaire: adaptation and validation of the Spanish version. AB - BACKGROUND: The aim of this study was to analyze the psychometric properties of the Spanish version of the MOOD Questionnaire in child population. This instrument was developed to cover the existing gap in the evaluation of mood in children. METHOD: The MOOD was administered to 1489 children (mean age = 9.11 years old). RESULTS: The psychometric properties of the Mood questionnaire are adequate. Moreover, the questionnaire was associated with somatic complaints and emotional awareness. CONCLUSIONS: According to the results of the study, the use of this diagnostic tool with Spanish children seems justified. PMID- 23628543 TI - Spanish version of Bus Drivers' Job Demands Scale (BDJD-24). AB - BACKGROUND: Karasek and Theorell's Job Demands-Control Model argues that adverse health-related outcomes, both psychological and physiological, arise from a combination of high job demand and a low level of job control. The objective was to adapt Meijman and Kompier's Bus Drivers' Job Demands Scale (BDJD-24), which enables us to assess the job demands of bus drivers, to Spanish. METHOD: The final version of the Spanish adaptation was applied to a sample made up of 287 bus drivers living in Spain (80.1% men and 19.9% women), whose average age was 40.44 (SD= 11.78). RESULTS: The results yielded a three-factor structure for the scale used: Time Pressure, Safety, and Passengers. These findings confirm that the Spanish version replicates the factor structure of the original English scale. The reliability of the three subscales was acceptable, ranging from .75 to .84. Furthermore, the subscales were also related to different external correlates and to other scales and showed good convergent and criterion validity. CONCLUSIONS: The present instrument can be used to evaluate job demands of bus drivers, as its psychometrics are substantially sound. PMID- 23628544 TI - Development and validation of the Family Motivational Climate Questionnaire (FMC Q). AB - BACKGROUND: The goal of this study was to develop and validate the Family Motivational Climate Questionnaire (FMCQ). Parental involvement (PI) affects children's academic orientations. However, PI questionnaires had not considered parenting behaviours from the perspective of motivational theories. It was therefore decided to develop the FMCQ. METHOD: 570 Secondary-School students formed the sample. To validate the FMCQ, confirmatory factor analyses, reliability analysis and correlation and regression analyses were conducted. Children's attribution to parents of perceived change in motivational variables affecting achievement, were used as external criteria. RESULTS: Results support most of the hypotheses either related to the FMCQ structure or to its moderating role as predictor of school achievement and of attribution to parents of changes in different motivational variables --interest, effort, perceived ability, success expectancies, resilience, and satisfaction. CONCLUSIONS: The results underline the importance of acting on FMC-components in order to improve Children's motivation and achievement. PMID- 23628545 TI - Validation of the Scale of Preferences and Expectations in Close Interpersonal Relationships (EPERIC). AB - BACKGROUND: The most commonly used instruments for assessing adult attachment have shown differing combinations of items and divergences in the resulting sub scales. METHOD: This study presents the Scale of Preferences and Expectations in Close Interpersonal Relationships ( Escala de Preferencias y Expectativas en las Relaciones Interpersonales Cercanas, EPERIC), made up of 22 items, and based upon the Relationship Scales Questionnaire (RSQ) of Griffin and Bartholomew. Exploratory and confirmatory factorial analyses (EFA and CFA) were undertaken using data from a sample of 594 people. RESULTS: Factor analysis distinguishes three sub-scales: Fear of rejection or abandonment , Desire for closeness and Preference for independence , which explains 42.78% of the total variance. The alpha coefficients reveal a high internal consistency of the instrument and its sub-scales. Regarding validity, CFA showed an adequate fit for the trifactorial solution, and the expected correlations with other instruments for assessing attachment style in adults were found. EPERIC is also suitable for predicting affective states and psychological well-being. CONCLUSIONS: The EPERIC is a potentially useful and valid instrument for research and clinical purposes. The discussion focuses on the fact that our results support a model of three factors rather than two, as is usual in studies on adult attachment. PMID- 23628546 TI - A legal and ecological perspective of 'site integrity' to inform policy development and management of Special Areas of Conservation in Europe. AB - The European Union Habitats Directive (92/43/EEC) provides for the designation and management of Special Areas of Conservation (SACs) and requires that impacting activities are subject to 'an appropriate assessment' of their implications for the 'integrity' of the site. We define the term 'site integrity' from a legal and an ecological perspective. We demonstrate that 'site integrity' is the maintenance of ecological processes and functions that support the wider delivery of ecosystem services. 'Site integrity' can be influenced by SAC management. Management that seeks to support 'site integrity' may include the use of buffer zones or connecting areas that extend beyond the SAC site's designated features. We conclude that 'site integrity' and 'favourable conservation status' are powerful legal terms that if fully transposed into the law and policy of Member States can enable the achievement of broader European and International goals for marine conservation. PMID- 23628547 TI - Temporal and spatial distribution of red tide outbreaks in the Yangtze River Estuary and adjacent waters, China. AB - Between 1972 and 2009, evidence of red tide outbreaks in the Yangtze River Estuary and adjacent waters was collected. A geographic information system (GIS) was used to analyze the temporal and spatial distribution of these red tides, and it was subsequently used to map the distribution of these events. The results show that the following findings. (1) There were three red tide-prone areas: outside the Yangtze River Estuary and the eastern coast of Sheshan, the Huaniaoshan-Shengshan-Gouqi waters, and the Zhoushan areas and eastern coast of Zhujiajian. In these areas, red tides occurred 174 total times, 25 of which were larger than 1000 km(2) in areal extent. After 2000, the frequency of red tide outbreaks increased significantly. (2) During the months of May and June, the red tide occurrence in these areas was 51% and 20%, respectively. (3) Outbreaks of the dominant red tide plankton species Prorocentrum dong-haiense, Skeletonema costatum, Prorocentrum dantatum, and Noctiluca scientillan occurred 38, 35, 15, and 10 times, respectively, during the study interval. PMID- 23628548 TI - Testing different ecological scenarios in a temperate estuary: a contribution towards the implementation of the Ecological Potential assessment. AB - The concept of Ecological Potential was explored using the macrobenthic communities of the Mondego estuary (Portugal). Different scenarios (loss of a primary producer and intertidal habitat, and habitat modification due to hydromorphological changes and continued press perturbation) were tested to predict changes in the biology if hydromorphological pressures could be reversed, assuming that differences with and without the pressure could indicate the potential. Results showed noticeable changes in the system biology in each scenario. The approach followed, indicates that when data sets exist, differences in the measurement of ecological status with and without the hydromorphological change could be a way forward to determine the potential. In the particular case of the Mondego estuary, the South arm (physically unaltered water body) proved to be richer than the North (HMWB). For the Ecological Potential determination, the South arm could thus be used to derive and adjust future reference conditions for the North. PMID- 23628549 TI - Small-scale modelling of the physiochemical impacts of CO2 leaked from sub-seabed reservoirs or pipelines within the North Sea and surrounding waters. AB - A two-fluid, small scale numerical ocean model was developed to simulate plume dynamics and increases in water acidity due to leakages of CO2 from potential sub seabed reservoirs erupting, or pipeline breaching into the North Sea. The location of a leak of such magnitude is unpredictable; therefore, multiple scenarios are modelled with the physiochemical impact measured in terms of the movement and dissolution of the leaked CO2. A correlation for the drag coefficient of bubbles/droplets free rising in seawater is presented and a sub model to predict the initial bubble/droplet size forming on the seafloor is proposed. With the case studies investigated, the leaked bubbles/droplets fully dissolve before reaching the water surface, where the solution will be dispersed into the larger scale ocean waters. The tools developed can be extended to various locations to model the sudden eruption, which is vital in determining the fate of the CO2 within the local waters. PMID- 23628550 TI - High prevalence of undiagnosed diabetes and high risk for diabetes using HbA1c criteria in middle-aged patients undergoing cataract surgery. AB - AIM: This study assessed the prevalence of undiagnosed diabetes and a high risk for diabetes using glycated haemoglobin (HbA(1c)) values in middle-aged patients undergoing cataract surgery. METHODS: The study comprised 137 consecutive patients, aged 40 to 65 years, with no known diabetes undergoing cataract surgery at a French national eye centre. Fasting glucose, obesity parameters, and vascular and ocular cataract risk factors were recorded. HbA1c was measured on the day of cataract surgery. Prevalence of undiagnosed diabetes (HbA(1c) >= 6.5%) and a high risk of diabetes (>= 6.0% but < 6.5%) in the study population was compared with recently published estimates from general French, Dutch and US populations. RESULTS: In the study population, undiagnosed diabetes was found in 12 patients (9%; 95% CI: 4-14%) and a high risk for diabetes in 47 (34%; 95% CI: 26-42%). These prevalences were four to 11 times higher than the corresponding population-based estimates, whereas obesity parameters recorded in the general populations and in our study population were similar according to HbA1c subcategories. Of the 125 patients with HbA1c less than 6.5%, values were higher in patients without ocular cataract risk factors (n = 73; 58%) than in those with cataract risk factors (n = 52; 42%) at 5.92 +/- 0.30% and 5.57 +/- 0.29%, respectively (P < 0.001), thereby suggesting a significant role for blood glucose levels in cataractogenesis. CONCLUSION: Middle-aged patients undergoing cataract surgery showed a high prevalence of diabetes and a high risk for diabetes not recognized before surgery, suggesting that this patient population should be targeted for diabetes screening and prevention. PMID- 23628551 TI - Highly effective mobilization of CD34 positive cells as a poor prognostic factor in acute myeloid leukemia. Possible causes and consequences. PMID- 23628552 TI - Azacitidine results in comparable outcome in newly diagnosed AML patients with more or less than 30% bone marrow blasts. AB - The efficacy of azacitidine has been demonstrated in acute myeloid leukemia (AML) patients with 20-30% bone marrow (BM) blasts, but limited data is available on patients with >=30% blasts. We analyzed 55 newly diagnosed AML patients, treated with azacitidine. The overall response rate was 42%. Median overall survival (OS) was 12.3 months. We confirmed poor-risk cytogenetics, therapy-related AML, performance score >=2, and white blood cell count >=15*10(9)/L as independent adverse predictors for OS. The BM blast percentage, however, had no impact on OS (P=0.55). In conclusion, administration of azacitidine is effective in AML patients with 20-30% and >30% BM blasts. PMID- 23628553 TI - The role of comorbidities in chronic myeloid leukemia. PMID- 23628554 TI - Down-regulation of signal transducer and activator of transcription 3 improves human acute myeloid leukemia-derived dendritic cell function. AB - Signal transducer and activator of transcription (STAT) 3 inhibits dendritic cell (DC) differentiation and is constitutively activated in blasts of approximately half of AML patients. We investigated the correlation between STAT3 activity, DC maturation and the ability to stimulate T-cells in primary acute myeloid leukemia (AML)-derived DCs. STAT3 knock-down by shRNAmir increased the ability of AML-DCs to stimulate T-cells. Treatment of AML-DC with arsenic trioxide, but not AG490, JSI-124 or NSC-74859, led to a more mature phenotype and enhanced T-cell stimulation, while having minimal effect on normal DC. We conclude that AML-DCs have improved immunogenicity after reducing STAT3. PMID- 23628555 TI - Preconditioning with sevoflurane ameliorates spatial learning and memory deficit after focal cerebral ischemia-reperfusion in rats. AB - Previous studies have demonstrated that sevoflurane could attenuate cerebral neuron necrosis and apoptosis in ischemia-reperfusion models in rats. The aim of our study was to investigate the effect of preconditioning with sevoflurane on spatial learning and memory ability after focal cerebral ischemia-reperfusion injury in rats and its potential mechanisms. Focal cerebral ischemia was performed via 1h of middle cerebral artery occlusion (MCAO) followed by reperfusion. Before ischemia, rats were subjected to preconditioning with inhalation of 2.4% sevoflurane for 1h. The spatial learning and memory ability of rats was measured by the Morris water maze. The activity of choline acetyltransferase (ChAT) in hippocampus CA1 region was observed by immunohistochemistry method. We found MCAO elicited a significant decrease of the ability of spatial learning and memory in contrast to the sham surgery controls. However, preconditioning with sevoflurane resulted in significantly ameliorates spatial learning and memory deficit induced by MCAO. Furthermore, the number of ChAT positive cells in hippocampus CA1 region in sevoflurane preconditioning group was striking more than that of ischemia-reperfusion group. All results suggested that preconditioning with 2.4% sevoflurane could ameliorate the ability of spatial learning and memory after focal cerebral ischemia-reperfusion in rats via protecting the cholinergic neurons in hippocampal CA1 region. PMID- 23628556 TI - Revisiting: "Comparison of intravascular ultrasound versus angiography-guided drug-eluting stent implantation: a meta-analysis of one randomised trial and ten observational studies involving 19,619 patients". PMID- 23628557 TI - A descriptive study on wrist and hand sensori-motor impairment and function following distal radius fracture intervention. AB - STUDY DESIGN: Descriptive cross-sectional design. INTRODUCTION: Wrist and hand sensori-motor impairment have been observed after distal radius fracture (DRF) treatment. This impairment and its relationship to function lack research. PURPOSE OF THE STUDY: The primary aim of this exploratory study was to determine the magnitude of wrist and hand sensori-motor impairment following surgical and non-surgical treatment among older patients following DRF. Secondary aims were to determine the relationship between wrist and hand sensori-motor impairment with function and pain as well as the relationships among wrist and hand sensori-motor impairment and function and age following DRF. METHODS: Ten Test (TT), active joint position sense (JPS), electromyography (EMG), computerized hand-grip dynamometer (CHD), and the Patient-Rated Wrist Evaluation (PRWE) were used to assess twenty-four female participants 8 weeks following DRF treatment and their 24 matched-control healthy counterparts on wrist and hand sensibility, proprioception, muscle recruitment, grip force, muscle fatigue, and functional status. RESULTS: Participants following DRF demonstrated significantly (p < .05) greater sensory (i.e., JPS, TT), and motor (i.e., EMG, CHD) deficits than their control counterparts. A significantly higher functional deficit (i.e., PRWE) also existed among participants following DRF than the control group. Participants following surgical and non-surgical DRF treatment were found to be statistically different only on total grip force. Group differences on JPS and total grip force revealed the strongest effect size with the highest correlations to PRWE. EMG and muscle fatigue ratio group differences revealed a weaker effect size with a fair degree of correlation to PRWE. Pain significantly correlated with sensori-motor function. Age did not correlate with any measured variable. CONCLUSIONS: Significant wrist and hand sensori-motor impairment and functional deficits among older females 8 weeks following DRF surgical and non-surgical interventions were revealed. JPS and total grip force were the most clinically meaningful tests for assessing the sensori-motor status as well as explaining functional disability and pain levels for these patients. LEVEL OF EVIDENCE: 2c. PMID- 23628558 TI - PIP joint volar rotatory dislocation: An anatomical study to explore extensor system lesions and the Stener effect. AB - Volar rotatory dislocation of the proximal interphalangeal joint results from volar rotation of the condyle around an intact opposite collateral ligament. A cadaveric study was preformed to better understand the mechanisms of this injury. Thirty-two long fingers (II to V) were studied. After partial section of the triangular ligament, the radial collateral ligament was cut (partly or completely, at proximal or distal insertion) and volar rotatory dislocation was induced. We studied the incidence of a fixed dislocation, the distal extension of the triangular ligament lesion, and the Stener lesion of the radial collateral ligament. A buttonhole lesion was produced by a dislocated lateral band in all cases with complete section of the collateral ligament. When the lesion of the triangular ligament extended distally, dislocation became irreducible. A Stener effect (interposition of the lateral band between the condyle and the collateral ligament) was observed after reduction in 21% of cases with proximal lesions of the radial collateral ligament. PMID- 23628559 TI - [Flexor and extensor tendon injuries in children (primary and secondary repair)]. AB - Primary or secondary flexor tendon repair after laceration in children do not have any technical specificity in comparison with adults. However, tendon ruptures may occur more frequently in case of light postoperative immobilization, especially in young children as little cooperation can be expected in the postoperative period. A closed above elbow cast should therefore be applied for onemonth. Early mobilization program has no significant effect on the final result in young children. However, these observations must be relativized in teenagers who should be rehabilitated such as adults. For extensor tendon injuries, dynamic splintage was found to be unnecessary in children. In cases with total transection in zones I, II or III, it is necessary, especially in children younger than 5 years, to transfix the IP joint in extension with a smooth Kirschner wire during postoperative immobilization period. PMID- 23628561 TI - Brachial artery injuries in children. AB - Treatment of brachial artery injuries in children, particularly those resulting from supracondylar humeral fractures, is controversial when distal pulses are absent yet the hand remains warm and pink. This article presents a retrospective study of eight children, ages 3 to 13, who underwent brachial arterial exploration because of absent distal pulses following arm trauma. Absent pulses indicate diminished blood flow, and in all eight cases brachial artery obstruction or severance was confirmed at surgery. In four of the children, who presented with cold, devascularized hands as a result of posterior elbow dislocations, supracondylar humeral fracture, or dog bites, there is no debate regarding revascularization. The other four children, with type III supracondylar humerus fractures, had pulseless, pink hands as a result of brachial artery thrombosis or arterial tethering. Brachial artery flow was reestablished in all cases with return of distal pulses, and no vascular complications. The authors believe that artery exploration is indicated when distal pulses are not present. PMID- 23628562 TI - Newer lumbar interbody fusion techniques. AB - The purpose of this review is to update the reader on more recent, less invasive lumbar interbody fusion procedures. The article contains a brief history on the development of lumbar interbody fusion methods, as well as the indications and descriptions of the various open and minimally invasive procedures, their complications, and outcomes. In contrast to the more traditional open methods of performing anterior and posterior interbody fusions, surgeons doing the less invasive techniques of transforaminal lumbar interbody fusion, extreme lateral and direct lateral interbody fusion, and the presacral axial approach are reporting less morbidity, shorter hospital stays, high rates of fusion, and improved patient outcomes. Although each technique has a different anatomical plane of approach, the goal is to achieve a solid interbody fusion of the pain generating segment(s) without complications. PMID- 23628560 TI - Methodology of clinical research in rare diseases: development of a research program in juvenile neuronal ceroid lipofuscinosis (JNCL) via creation of a patient registry and collaboration with patient advocates. AB - INTRODUCTION: Juvenile neuronal ceroid lipofuscinosis (JNCL; Batten disease) is a rare, inherited, fatal lysosomal storage childhood disorder. True for many rare diseases, there are no treatments that impact the course of JNCL. The University of Rochester Batten Center's (URBC) mission is to find treatments to slow, halt, or prevent JNCL. OBJECTIVES: Our initial objective was to develop clinical research infrastructure preparatory to clinical trials, establish a JNCL research cohort, construct a disease-specific clinical outcome measure, and validate a non invasive diagnostic sampling method. The long-term objective is to design and implement JNCL clinical trials. METHODS: The Unified Batten Disease Rating Scale (UBDRS) was developed. The Batten Disease Support and Research Association (BDSRA) referred participants; annual BDSRA meetings provided a mobile research setting for registry enrollment and UBDRS piloting. Neuropsychological examinations were performed, enabling external validation of the UBDRS. Buccal epithelial cell collection for genotyping was introduced. Telemedicine for remote UBDRS assessment was piloted. RESULTS: The registry enrolled 198 families representing 237 children with NCL. The UBDRS was piloted, was validated and has been used to collect natural history data from 120 subjects. Funding and regulatory approval were obtained for a recently launched phase II clinical trial. Several additional lines of inquiry were reported. CONCLUSION: The registry and BDSRA collaboration have enabled development of a clinical rating scale, natural history and neuropsychological studies, and genetic studies for disease confirmation. This work highlights an approach for preparatory natural history research and infrastructure development needed to facilitate efficient implementation of clinical trials in rare diseases. PMID- 23628563 TI - Effect of surgeon experience on femoral component size selection during total knee arthroplasty. AB - Femoral component size selection during total knee arthroplasty should not vary from surgeon to surgeon for patients with the same bone size. This study explored if systematic variations in femoral component size selection exist. Thirteen surgeons' choices of femoral component size (Duracon, n = 1388; Triathlon, n = 740) were analyzed using a generalized linear model with femoral component size as the dependent variable and surgeon identification, years in practice, and adult reconstruction fellowship training as the independent variables. The model adjusted for differences in bone size. It was found that more experienced surgeons implant larger femoral components. New instruments and training protocols may be necessary to adjust for surgeon experience. PMID- 23628564 TI - Orthopaedic injuries from deer stands and their functional outcomes. AB - Hunters who fall from deer stands can sustain a variety of injuries. A retrospective review was conducted at a single institution to gauge the experience in treating patients injured in falls from deer stands from 2002 to 2008. Medical records were analyzed for patient demographics, tree stand characteristics, and injury details. Patients were contacted to complete a SF-12 health survey to assess their functional outcome following their injuries. Of the 30 patients who sustained a fracture, an average of 2.08 fractures were sustained per patient. Sixteen patients sustained a spinal column fracture, and four of these sustained a spinal cord injury. Twenty-one patients underwent at least one surgical procedure by the trauma surgery (two), neurosurgery (four), or orthopaedic surgery (15) teams. The importance of understanding deer stand instructions should be emphasized during hunting education classes, and all hunters should follow safe hunting recommendations pertaining to firearms and tree stands. PMID- 23628565 TI - Septic arthritis following anterior cruciate ligament reconstruction: a comprehensive review of the literature. AB - Septic arthritis following anterior cruciate ligament (ACL) reconstruction is an uncommon but potentially serious complication. The incidence of infection is approximately 0.44%. Staphylococcus and streptococcus strains are the most common infectious pathogens. Infection is typically via direct inoculation. Articular cartilage damage is primarily the result of the unregulated host inflammatory response. The timing of presentation is typically <2 months following surgery. Presenting symptoms commonly mirror normal postoperative findings, making diagnosis difficult. Although laboratory inflammatory markers are often elevated, knee arthrocentesis is the gold standard for diagnosis. Treatment involves serial arthroscopic or open irrigation and debridement procedures and antibiotic management. Graft retention is often possible, although fixation implants may require removal or exchange. Successful results have been reported following infection eradication in both graft retention and early revision ACL reconstruction scenarios. PMID- 23628566 TI - Rotator cuff injuries in professional and recreational athletes. AB - Professional and recreational athletes involved in contact sports and sports with repetitive overhead motion are at increased risk for rotator cuff tears. Shoulder anatomy, pathology, and biomechanics place unique stress on the rotator cuff tendons during sports activity. Athletes demand effective treatment to quickly return to elite competition. A PubMed search assessed treatment options providing expedited recovery time and return to competition. Twelve of 231 articles fit the objective criteria; 90.5% of professional contact athletes, 40% of professional overhead athletes, and 83.3% of recreational athletes fully recovered following rotator cuff tear surgical repair. Prompt surgical treatment for full-thickness rotator cuff tears may be appropriate for contact athletes and recreational overhead athletes. Although professional overhead athletes have low recovery rates, surgical repair of full-thickness rotator cuff tears may still be indicated. The authors propose a treatment algorithm based on the limited literature (mainly level 4 and 5 evidence). PMID- 23628567 TI - Arthroscopic bursectomy for recalcitrant trochanteric bursitis after hip arthroplasty. AB - This study evaluated the use of arthroscopic bursectomy for pain relief in patients with trochanteric bursitis after hip arthroplasty. In this retrospective case series of 12 patients undergoing arthroscopic treatment of recalcitrant trochanteric bursitis after hip arthroplasty, outcomes were assessed via phone interview with a numeric pain rating scale from 1 to 10 and were compared with preoperative pain ratings. Patients were asked the percentage of time they had painless hip function and whether they would have the surgery again. At an average 36-month follow-up (range, 4-85 months), the average numeric pain scale rating improved from 9.3 to 3.3. At an average of 62% of the time, patients had painless use of the hip. Ten of 12 patients in the study felt the pain relief gained was substantial enough to warrant having procedure again. In these patients, arthroscopic bursectomy was a viable option for patients with recalcitrant bursitis after hip arthroplasty. PMID- 23628568 TI - Accuracy and reliability of digital templating in primary total hip arthroplasty. AB - Digital templating has been used as a method of reducing hospital costs by eliminating the need for acetate films. Digital templating techniques have been used for preoperative planning for total hip arthroplasty (THA). Fifty-four patients who underwent THA were selected for the study. Templating was performed using acetate templating overlays and digital templating software. Acetabular component sizes were accurate in 96% of patients using the acetate method and in 93% using the digital method. Femoral component sizes were accurate in 80% in the acetate method and 74% in the digital method. Digital templating is safe and effective for preoperative planning for THA. PMID- 23628569 TI - Liner exchange in total knee arthroplasty. AB - Exchange of the tibial liner in revision knee arthroplasty for wear and other indications is controversial. The purpose of the study was to determine the clinical success and reoperation rate for liner exchange performed for four groups of patients. Thirty-nine revisions were identified in which modular liner exchange was performed: polyethylene wear (12 knees), acute infection (11 knees), instability (4 knees), and a variety of other diagnoses (12 knees). The knees were evaluated using the systems of the Knee Society. The mean follow-up time was 4.3 years. Liner exchange for wear was successful in all 12 patients: for acute infection, in 9 of 11 patients; for instability, in 3 of 4 patients; for other diagnoses, in 10 of 12 patients. There were significant improvements in the pain score in all four groups and significant improvement in the function score in the infection and other diagnoses groups. With the use of six criteria, these observations suggest that liner exchange for wear is successful. PMID- 23628570 TI - Knee manipulation after total knee arthroplasty: comparison of two implant designs. AB - Substantial postoperative stiffness requiring manipulation is a well-recognized complication of total knee replacement. This study sought to determine whether the Medial-Pivot (MP) knee (Wright Medical, Memphis, TN) or the Double-High (DH) knee (Wright Medical) is more often associated with manipulation under anesthesia (MUA) for post-total knee arthroplasty (TKA) knee stiffness. It was hypothesized that manipulation rates would be similar. Retrospective review of 755 TKA patients showed that 4.1% required MUA, which is comparable to the literature. Manipulation by MUA for DH and MP knees was generally successful, with an average overall improvement in knee flexion of nearly 30 degrees . MP and DH knees appear to have a lower than average prevalence of post-TKA knee stiffness requiring manipulation when compared with the literature. The number of MP and DH knees requiring MUA did not appear to differ substantially. PMID- 23628571 TI - Predictors of length of hospital stay in elderly hip fracture patients. AB - The purpose of this study was to assess the relationship between prefracture characteristics and length of stay (LOS) at the authors' institution. Three hundred eighty-nine consecutive elderly hip fracture patients' preoperative characteristics, comorbidities, fracture type, and surgical and hospital course were retrospectively reviewed. Multiple regression was used to determine which subset of potential independent variables would be good predictors of LOS. Predictors of increased LOS included cerebral vascular disease (+1.28 days, p <.0352), chronic renal insufficiency (+1.17 days, p < .0363), and American Society of Anesthesiologists (ASA) score (+1.27 days per ASA class, p < .0005). For each increase in age by 1 year, LOS decreased by a mean of 0.085 days (p < .0041). Fracture type, prefracture mobility, or other examined comorbidities were found not to be significant predictors of LOS. Identifying high-risk patients in the preoperative period and minimizing certain perioperative events will be important to optimize care of patients who fracture their hip and to minimize future costs. PMID- 23628572 TI - Adolescent fracture of the talus associated with talus partitus. AB - A case report of an adolescent with a fracture of the talus with an associated talus partitus is presented. Unlike the more common os trigonum, which arises from a secondary ossification center, the talus partitus is substantially larger and may include articulation with the ankle and subtalar joint, making its preservation via osteosynthesis with the talus desirable. PMID- 23628573 TI - Acute lumbosacral plexopathy from gluteal compartment syndrome after drug abuse: a case report. AB - Acute lumbosacral plexus injury from gluteal compartment syndrome is extremely rare. Physicians should be aware of this diagnosis when examining patients with altered mental status, prolonged immobilization, and gluteal muscle compression. This case report presents a patient with acute complete left lumbosacral plexus paralysis and acute renal failure after gluteal compartment syndrome secondary to prolonged immobilization from drug abuse. Clinical examination, imaging of the pelvis, renal function, creatine phosphokinase, and urine myoglobin were indicative of gluteal compartment syndrome and rhabdomyolysis. Electrodiagnostic studies showed complete limb paralysis. Medical treatment and rehabilitation was administered. Renal function recovered within the 1st week; function at the proximal muscles of the left lower limb improved within 6 months, with mild discomfort on sitting at the buttock, foot drop, and sensory deficits at the leg and dorsum of foot. PMID- 23628574 TI - Displaced dorsal metaphyseal cortex associated with delayed extensor pollicis longus tendon entrapment in a pediatric Smith's fracture. AB - Extensor pollicis longus (EPL) tendon entrapment has been rarely reported as a complication of closed treatment of a pediatric Smith's type distal radius fractures. This article presents the unique case of an initially functional EPL tendon that became entrapped in fracture callus in a 9-year-old boy, the youngest reported in the literature. PMID- 23628575 TI - First perforator vein cement occlusion following total hip arthroplasty. AB - Cement intravasation of the venous system is a rare complication of total hip arthroplasty. This is a case report of a 54-year-old female who sustained cement occlusion of the first perforator vein of the femur after hybrid total hip arthroplasty. However, she was asymptomatic and attained excellent clinical outcome. Differential diagnoses for the radiographic appearance are discussed as well as possible reasons for this occurrence. PMID- 23628576 TI - Candida glabrata olecranon bursitis treated with bursectomy and intravenous caspofungin. AB - Orthopedic surgeons are becoming more involved in the care of patients with septic arthritis and bursitis caused by yeast species. This case report involves a middle-aged immunocompromised female who developed a Candida glabrata septic olecranon bursitis that developed after she received a corticosteroid injection in the olecranon bursa for presumed aseptic bursitis. Candida (Torulopsis) glabrata is the second most frequently isolated Candida species from the bloodstream in the United States. Increased use of fluconazole and other azole antifungal agents as a prophylactic treatment for recurrent Candida albicans infections in immunocompromised individuals is one reason why there appears to be increased resistance of C. glabrata and other nonalbicans Candida (NAC) species to fluconazole. In this patient, this infection was treated with surgery (bursectomy) and intravenous caspofungin, an echinocandin. This rare infectious etiology coupled with this intravenous antifungal treatment makes this case novel among cases of olecranon bursitis caused by yeasts. PMID- 23628577 TI - Middle-third clavicle fracture with associated type IV acromioclavicular separation: case report and literature review. AB - Review of available English literature suggests that combined injuries involving a clavicle shaft fracture and an acromioclavicular (AC) separation are rare. The force dissipation after the occurrence of either a midshaft clavicle fracture or an AC separation typically renders the injuries mutually exclusive. This article presents a review of literature on this combined injury pattern. A variety of treatment approaches have been put forth, including nonoperative, operative, and hybrid management of the two distinct injuries. The most appropriate treatment rendered depends on the degree of AC joint instability. This case report involves a midshaft clavicle fracture associated with a type IV AC separation in a patient ejected during a high-speed motor vehicle collision. Internal fixation of each injury was chosen and the patient had a successful final result. Other reported treatment options and recommendations are reviewed. PMID- 23628579 TI - Physician responsibility and accountability: importance of the diagnosis and plan. PMID- 23628580 TI - Early application of deep brain stimulation: clinical and ethical aspects. AB - Deep brain stimulation (DBS) has proven to be a successful therapeutic approach in several patients with movement disorders such as Parkinson's disease and dystonia. Hitherto its application was mainly restricted to advanced disease patients resistant to medication or with severe treatment side effects. However, there is now growing interest in earlier application of DBS, aimed at improving clinical outcomes, quality of life, and avoiding psychosocial consequences of chronic disease-related impairments. We address the clinical and ethical aspects of two "early" uses of DBS, (1) DBS early in the course of the disease, and (2) DBS early in life (i.e. in children). Possible benefits, risks and burdens are discussed and thoroughly considered. Further research is needed to obtain a careful balance between exposing vulnerable patients to potential severe surgical risks and excluding them from a potentially good outcome. PMID- 23628581 TI - Cytochrome c conjugated to ZnO-MAA nanoparticles: the study of interaction and influence on protein structure. AB - Nanoparticle-protein conjugates have potential for numerous applications due to the combination of the properties of both components. In this paper we studied the conjugation of horse heart cytochrome c with ZnO nanoparticles modified by mercaptoacetic acid (MAA) which may be a material with great potential in anticancer therapy as a consequence of synergic effect of both components. Cyt c adsorption to the ZnO-MAA NPs surface was studied by UV-vis spectroscopy and by a dynamic light scattering in various pH. The results indicate that the optimal pH for the association of protein with modified nanoparticles is in range 5.8-8.5 where 90-96% of cytochrome c was assembled on ZnO-MAA nanoparticles. The interaction of proteins with nanoparticles often results in denaturation or loss of protein function. Our observations from UV-vis spectroscopy and circular dichroism performed preserved protein structure after the interaction with modified nanoparticles. PMID- 23628582 TI - Purification, characterization and antiviral activity of two heteropolysaccharides from Duchesneae Indicae. AB - This study was designed to uncover the antiviral compounds contained in Duchesneae Indicae. Two non-sulfated acidic heteropolysaccharides (DIP30 and DIP60) with anti-varicella-zoster virus (anti-VZV) activity were purified and investigated with a combination of DEAE C-52 ion-exchange chromatography, Sphacryl S-300 gel chromatography, high performance size exclusion chromatography, pre-column derivation with 1-phenyl-3-methyl-5-pyrazolone (PMP) method, infrared (IR) spectroscopy, (1)H and (13)C nuclear magnetic resonance (NMR). Results indicated that molecular weight (MW) of DIP30 and DIP60 are 1.98*10(3) kDa and 34 kDa, respectively. Both DIP30 and DIP60 have a backbone of beta-conformation and consist of more than four kinds of monosaccharides. The anti-VZV 50% effective concentrations (EC50) of DIP30 and DIP60 are 265.2+/-35.4 MUg/ml and 325.6+/-42 MUg/ml, respectively, suggesting that DIP30 and DIP60 could be explored as novel antiviral agents. PMID- 23628583 TI - Ultrasound extraction optimization of Acanthopanax senticosus polysaccharides and its antioxidant activity. AB - In this study, effects of several experimental parameters, including ultrasonic time, ratio of water to material, extraction temperature and ultrasonic power on the extraction yield of polysaccharides from Acanthopanax senticosus stem (ASS) were investigated by single factor experiment and an orthogonal test design (L9(3)(4)) was used to optimize the ultrasound extraction conditions. The polysaccharides from Acanthopanax senticosus stem (ASSP) and fruit (ASFP) were further fractionated by stepwise ethanol precipitation and the anti-oxidation activities of those fractions were evaluated by hydroxyl, superoxide anion and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay. Under the optimal conditions (ultrasonic time 75min, ratio of water to material 50ml/g, extraction temperature 80 degrees C and ultrasonic power 100W), the yield was 10.9mg/g. All fractions of ASP possessed considerable antioxidant activity. The results indicated that the ultrasound extraction was a very useful method for the extraction of ASP and the polysaccharides could be explored as a potential antioxidant agent for use in medicine or functional food. PMID- 23628584 TI - Chitosan coated alginate/poly(N-isopropylacrylamide) beads for dual responsive drug delivery. AB - Temperature-/pH-responsive chitosan coated alginate/poly(N-isopropylacrylamide) beads (CAPB) were prepared as a drug delivery system. The obtained beads were characterized by Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), polarized light microscope (PLM) and scanning electron microscopy (SEM). Oscillation experiments were used to analyze the mechanical stability of the samples. Effect of chitosan concentration and sodium polyphosphate (SPPP) content on the characteristics of CAPB was discussed. Swelling and drug release behaviors of the beads were investigated in simulated intestinal fluid (pH 7.4) and gastric fluid (pH 2.1) at 25 degrees C and 37 degrees C, respectively. Results illustrated that both the equilibrium swelling degree (SDeq) and drug release of the beads were greatly affected by the chitosan shell and were responsive to pH and temperature. The SDeq value of the beads decreased with the increase in chitosan concentration; and the drug release from CAPB was obviously slower than that of alginate/poly(N isopropylacrylamide) beads without chitosan coating within 720min. These developed materials could potentially be used as sustained dual-responsive drug delivery device in vivo. PMID- 23628585 TI - Preparation and evaluation of lysozyme-loaded nanoparticles coated with poly gamma-glutamic acid and chitosan. AB - To improve the application of lysozymes, methods for coating lysozymes with poly gamma-glutamic acid and chitosan were studied. Several lysozyme-loaded chitosan/poly-gamma-glutamic acid composite nanosystems for loading and controlling the release of lysozymes were established. The lysozyme loading content and efficiency of the different systems were examined. The antibacterial activity of the composite nanoparticles was also investigated. Results showed that when the lysozymes were coated with poly-gamma-glutamic acid and further rewrapped with chitosan, smooth spherical composite nanoparticles were obtained; the loading efficiency and loading content reached 76% and 40%, respectively. The lysozyme release in vitro was slow and presented a two-stage programmed release. Antibacterial testing in vitro indicated that lysozyme-loaded nanoparticles coated with poly-gamma-glutamic acid/chitosan had outstanding antibacterial activity. An obvious assembly of bacterial cells and composite nanoparticles was observed during co-incubation. Therefore, the poly-gamma-glutamic acid/chitosan composite coating broadened the antibacterial spectrum of the composite lysozyme nanoreagent, and presented satisfactory antibacterial effect. The lysozyme-loaded chitosan/poly-gamma-glutamic acid nanocoating system established in this research could provide reference for coating and controlled releasing of alkaline proteins. PMID- 23628586 TI - Formulation optimization and evaluation of jackfruit seed starch-alginate mucoadhesive beads of metformin HCl. AB - The present study deals with the formulation optimization of jackfruit (Artocarpus heterophyllus Lam., family: Moraceae) seed starch (JFSS)-alginate mucoadhesive beads containing metformin HCl through ionotropic gelation using 3(2) factorial design. The effect of sodium alginate to JFSS ratio and CaCl2 concentration on the drug encapsulation efficiency (DEE, %), and cumulative drug release at 10h (R10h, %) was optimized. The optimized beads containing metformin HCl showed DEE of 97.48+/-3.92%, R10h of 65.70+/-2.22%, and mean diameter of 1.16+/-0.11mm. The in vitro drug release from these beads was followed controlled release (zero-order) pattern with super case-II transport mechanism. The beads were also characterized by SEM and FTIR. The swelling and degradation of these beads were influenced by pH of the test medium. The optimized beads also exhibited good mucoadhesivity and significant hypoglycemic effect in alloxan induced diabetic rats over prolonged period after oral administration. PMID- 23628588 TI - Bacterial meningitis in adults after splenectomy and hyposplenic states. AB - OBJECTIVE: To examine the occurrence, disease course, prognosis, and vaccination status of patients with community-acquired bacterial meningitis with a history of splenectomy or functional hyposplenia. PATIENTS AND METHODS: Patients with bacterial meningitis proven by cerebrospinal fluid culture were prospectively included in a nationwide cohort study between March 1, 2006, and September 1, 2011. Splenectomy or diseases associated with functional hyposplenia were scored for all patients. Vaccination status, clinical features, and outcome of patients with a history of splenectomy or functional hyposplenia were analyzed and compared with patients with normal spleen function. RESULTS: Twenty-four of 965 patients (2.5%) had an abnormal splenic function: 16 had a history of splenectomy and 8 had functional hyposplenia. All patients had pneumococcal meningitis. Pre illness vaccination status could be retrieved for 19 of 21 patients (90%), and only 6 patients (32%) were adequately vaccinated against pneumococci. Pneumococcal serotype was known in 21 patients; 52% of pneumococcal isolates had a serotype included in the 23-valent vaccine. Vaccine failure occurred in 3 patients. Splenectomized patients more often presented with signs of septic shock compared with patients with a normal spleen (63% vs 24%; P=.02). Outcome was unfavorable in 14 patients (58%), and 6 patients died (25%). CONCLUSION: Splenectomy or functional hyposplenia is an uncommon risk factor for bacterial meningitis but results in a high rate of mortality and unfavorable outcome. Most patients were not adequately vaccinated against Streptococcus pneumoniae. PMID- 23628587 TI - The therapeutic potential of IGF-I in skeletal muscle repair. AB - Skeletal muscle loss due to aging, motor-neuron degeneration, cancer, heart failure, and ischemia is a serious condition for which currently there is no effective treatment. Insulin-like growth factor 1 (IGF-I) plays an important role in muscle maintenance and repair. Preclinical studies have shown that IGF-I is involved in increasing muscle mass and strength, reducing degeneration, inhibiting the prolonged and excessive inflammatory process due to toxin injury, and increasing the proliferation potential of satellite cells. However, clinical trials have not been successful due to ineffective delivery methods. Choosing the appropriate isoforms or peptides and developing targeted delivery techniques can resolve this issue. Here we discuss the latest development in the field with special emphasis on novel therapeutic approaches. PMID- 23628589 TI - Polybrominated diphenyl ethers in residential dust: sources of variability. AB - We characterized the sources of variability for polybrominated diphenyl ethers (PBDEs) in residential dust and provided guidance for investigators who plan to use residential dust to assess exposure to PBDEs. We collected repeat dust samples from 292 households in the Northern California Childhood Leukemia Study during two sampling rounds (from 2001 to 2007 and during 2010) using household vacuum cleaners and measured 22 PBDEs using high resolution gas chromatography high resolution mass spectrometry. Median concentrations for individual PBDEs ranged from <0.1-2500ng per g of dust. For each of eight representative PBDEs, we used a random-effects model to apportion total variance into regional variability (0-11%), intra-regional between-household variability (17-50%), within-household variability over time (38-74%), and within-sample variability (0-23%) and we used a mixed-effects model to identify determinants of PBDE levels. Regional differences in PBDE dust levels were associated with residential characteristics that differed by region, including the presence of furniture with exposed or crumbling foam and the recent installation of carpets in the residence. Intra regional differences between households were associated with neighborhood urban density, racial and ethnic characteristics, and to a lesser extent, income. For some PBDEs, a decreasing time trend explained a modest fraction of the within household variability; however, most of the within-household variability was unaccounted for by our mixed-effects models. Our findings indicate that it may be feasible to use residential dust for retrospective assessment of PBDE exposures in studies of children's health (e.g., the Northern California Childhood Leukemia Study). PMID- 23628590 TI - Dual effects of peroxisome proliferator-activated receptor gamma on embryonic stem cell self-renewal in presence and absence of leukemia inhibitory factor. AB - The aim of this study was to evaluate the influence of peroxisome proliferator activated receptor gamma (PPARgamma) on self-renewal of mouse embryonic stem cells (mESCs) in the presence and absence of leukemia inhibitory factor (LIF). We demonstrated that in the presence of LIF, the activation of PPARgamma by Rosiglitazone led to an increased proliferation of mESCs whereas PPARgamma antagonist (GW9662) reversed this effect. Additionally, upon PPARgamma activation, LIF increased PPARgamma expression and resulted in the degradation of suppressor of cytokine signaling 3 (SOCS3), an important negative regulator of LIF/signal transducers and activators of transcription 3 (STAT3)-pathway. In the absence of LIF, Rosiglitazone decreased proliferation of mESCs. In this state, our results showed that extracellular signal-regulated kinase (ERK) proteins were activated and resulted in the suppression of Nanog expression, an important pluripotency determinant, whereas it did not affect Oct4 expression. These results suggest that the pivotal role of PPARgamma on mESC self-renewal depends on the presence and absence of LIF. PMID- 23628591 TI - Using peer crowds to segment Black youth for smoking intervention. AB - Studies of peer crowds show promise for enhancing public health promotion and practice through targeting. Distinct images, role models, and social norms likely influence health behaviors of different peer crowds within health disparity groups. We describe peer crowds identified by Black young people and determine whether identification with them is associated with smoking. Data from Black young people aged 13 to 20 years in Richmond, Virginia, were collected via interview and online survey (N = 583). We identified the number and type of peer crowds using principal components analysis; associations with smoking were analyzed using Pearson chi-square tests and logistic regression. Three peer crowds were identified--"preppy," "mainstream," and "hip hop." Youth who identify with the hip hop peer crowd were more likely to smoke and have friends who smoke and less likely to hold antitobacco attitudes than those identifying with preppy or mainstream crowds. Identifying with the hip hop crowd significantly increased the odds of smoking, controlling for demographic factors (odds ratio = 1.97; 95% confidence interval = 1.03-3.76). Tobacco prevention efforts for Black youth and young adults should prioritize the hip hop crowd. Crowd identity measures can aid in targeting public health campaigns to effectively engage those at highest risk. PMID- 23628592 TI - Cytotoxic effects of amphetamine mixtures in primary hepatocytes are severely aggravated under hyperthermic conditions. AB - Amphetamine consumers are often, deliberately or not, polydrug abusers. Predicting combination effects based on concentration-response analysis of individual components is a valid strategy for accurate toxicological assessment of mixtures. We previously reported that joint effects of 3,4 methylenedioxymethamphetamine (MDMA, ecstasy) and three other often co-ingested amphetamines (methamphetamine, 4-methylthyoamphetamine and D-amphetamine) could be predicted by the concentration addition (CA) model in HepG2 cells. We sought to further evaluate the relevance of these findings by extending these studies to a cell model that more closely mimics the in vivo situation. Detailed cytotoxic information of the four individual amphetamines on primary rat hepatocytes was recorded by the MTT assay, at 37 degrees C and 40.5 degrees C, simulating the rise in body temperature that could be induced following amphetamine intake. Mixture expectations were calculated using CA and independent action (IA) models. At 37 degrees C, concentration-dependent cytotoxicity occurred for the drugs individually and combined. Mixture effects were accurately predicted by the CA model, while the IA model underestimated cytotoxicity. At 40.5 degrees C these cytotoxic effects were aggravated. Our findings provide evidence of the increased risks associated with the abuse of amphetamine mixtures, especially during hyperthermia, emphasising the need to increase awareness of misinformed users who believe these drugs are safe. PMID- 23628593 TI - Reliable laboratory urinalysis results using a new standardised urine collection device. AB - OBJECTIVES: While urine sampling is necessary in the diagnosis of urinary tract infection and electrolyte disturbances, the collection of urine in neonates and non-toilet-trained children is often difficult. A universal urine collection method providing representative urinalyses results is needed. The objective of this study is to evaluate the applicability of the currently used urine collection pads (gauze compresses) and a new urine collection device (Peespot). DESIGN AND METHODS: We tested the reliability of routine (semi-)quantitative urinalysis results with these two different kinds of urine collection methods in a laboratory model. Although important in clinical diagnosis, we did not evaluate the effects on cellular and other components such as casts in the urinary sediment. RESULTS: Most semi-quantitative variables determined by urine stick (pH, blood, protein, leukocytes, nitrite, glucose, ketones, bilirubin and urobilinogen) gave concordant results for both methods compared with native urine. Using the Peespot urine collection device, reliable quantitative results were obtained for calcium, chloride, glucose, magnesium, phosphate, potassium, sodium, osmolality, urea nitrogen and urate compared with native urine. Data were concordant only for chloride, phosphate, glucose, sodium and urea nitrogen by use of gauze compresses. CONCLUSIONS: Urine collection pads are non-invasive methods useful in the collection of urine in non-toilet-trained children. Because of better practical standardisation and more reliable (semi-) quantitative urinalysis results, the Peespot urine collection device is preferred for the collection of urine. PMID- 23628594 TI - Foetal serum but not urinary beta2-microglobulin correlates with histological injury to the kidney. AB - In a context of foetal obstructive uropathies, biochemical markers can be helpful to assess the renal function, but most studies to date have focused on their correlation with ultrasound findings and neonatal outcome. Our aim was to evaluate foetal beta2-microglobulin as an index of histological injury to the kidney. beta2-microglobulin was measured in serum and/or urine from 27 foetuses with bilateral obstructive uropathy, and compared to the findings of kidney examination following the termination of pregnancy. In serum, increased beta2 microglobulin levels correlated to a decreased number of glomeruli, a reduction in the blastema and the presence of primitive ducts reflecting renal hypoplasia and dysplasia. However, elevated beta2-microglobulin levels in the urine correlated only to a decreased number of glomeruli. PMID- 23628595 TI - Improved sensitivity of point of care troponin I values using reporting to below the 99 th percentile of normals. AB - INTRODUCTION: Troponin point of care tests have been found to have inferior sensitivity to laboratory based tests, when either the 10% CV or the 99 th percentile of a healthy population is used as the cut-off. In a prospective study we evaluated a decreased cut-off in the detection of cardiac injury. METHODS: We compared 2 point of care assays (i-stat, Abbott Diagnostics and AQT 90, Radiometer) for troponin I with a laboratory assay for troponin I (ARCHITECT STAT troponin-I assay, Abbott Diagnostics), previously evaluated for diagnosis of acute coronary syndrome (ACS). We used the published 99 th percentile and a value that was 50% of that. We investigated these tests in a convenience sample of 195 patients presenting to a suburban hospital. We used chi-square tests for the comparison and a P<0.05 as significant. Clinical outcomes were obtained for patients with elevated levels of the laboratory assay. RESULTS: At the 99 th percentile both assays did only detect cardiac injury in a percentage of true positives compared to the laboratory test (34 and 51%) with a significant rate of false negative values (19.6 and 14.9%). Using a decreased cut-off (50% of 99 th percentile) increased detection of true positives (to 80.9 and 76.5%) with an acceptable rate of false positive results (7.3 and 7.1%) significantly (P<0.01). Clinical review showed POC tests missed 6 of 13 patients with confirmed AMI (a sensitivity of 46%) and that a lower cut-off allowed them to detect all (for the i-stat) or most (4 of 6 for the AQT) of them. DISCUSSION: We believe that we have described in this study a way to improve the sensitivity of point of care assays for troponin that allows us to identify additional patients without losing the specificity required to identify appropriate patients for discharge from the emergency department. PMID- 23628596 TI - Thyroid-stimulating hormone and free thyroxine on the ADVIA Centaur immunoassay system: a multicenter assessment of analytical performance. AB - OBJECTIVES: We assessed the analytical performance of the TSH and FT4 assays on ADVIA Centaur in a multicenter national evaluation. DESIGN AND METHODS: A precision study and a method comparison were performed. Reference values stated by the manufacturer were checked from 379 normal subjects. RESULTS: For TSH and FT4, the intra-assay CVs were below 2.3 and 5.2%, respectively, and the inter assay CVs below 4.4% and 7.2%, respectively. Therefore, the precision and reproducibility were acceptable. Bland-Altman bias plots revealed good correlation and agreement with Cobas assays. TSH and FT4 data yielded reference ranges of 0.64-3.24 mIU/L and 10.5-18.9 pmol/L, respectively. CONCLUSION: These assays demonstrate reliable characteristics. The reference ranges obtained can be used for interpretation of thyroid function. PMID- 23628598 TI - RE: Meta-analysis of the relationship between dose and benefit in phase I targeted agent trials. PMID- 23628601 TI - Differential correlations between plasma oxytocin and social cognitive capacity and bias in schizophrenia. AB - Social cognitive impairment is related to poor social functioning in schizophrenia. This impairment includes both deficits in emotion perception and theory of mind (ToM), and cognitive biases including attributional bias and jumping to conclusions. Oxytocin (OXT) is a hormone that has been implicated in human social behavior, and that has also been associated with regulation of inflammation. In a cross-sectional study involving 60 patients with schizophrenia and 20 healthy controls, we examined associations between OXT and social cognitive capacity and bias. Secondary analyses examined associations between OXT and inflammation. We found significant correlations between OXT and social cognitive bias in the control group and in patients with delusions, but not in patients without delusions. Social cognitive capacity only correlated significantly with OXT in patients with delusions. A correlation between OXT and inflammation was observed only in patients without delusions. Findings suggest that OXT may be implicated in social cognition both in controls and in patients with delusions, but that this association may be blunted in patients without delusions. Inflammation appears to be related to OXT rather independently of social cognition. Future longitudinal and intervention studies with OXT are needed to clarify causality in the identified associations. PMID- 23628600 TI - Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain. AB - Tanezumab is a humanized monoclonal antibody that specifically inhibits nerve growth factor as a treatment for chronic pain. This phase IIB study investigated the efficacy and safety of tanezumab for chronic low back pain vs placebo and naproxen. Patients (N=1347) received intravenous tanezumab (5, 10, or 20mg every 8weeks), naproxen (500mg twice daily), or placebo. The primary efficacy end point was mean change in daily average low back pain intensity (LBPI) from baseline to week 16. Secondary end points included mean change from baseline to week 16 in the Roland Morris Disability Questionnaire and Patient's Global Assessment (PGA) of low back pain. Tanezumab 10 and 20mg had similar efficacy profiles and significantly improved LBPI, Roland Morris Disability Questionnaire, and PGA scores vs both placebo and naproxen (P?.05). Tanezumab 5mg provided improvement of PGA scores vs placebo (P?.05), and naproxen resulted in significant improvement of LBPI vs placebo (P?.05). Adverse event incidence was comparable across tanezumab doses but higher than with placebo or naproxen. Arthralgia, pain in extremity, headache, and paresthesia were the most commonly reported adverse events by tanezumab-treated patients. The most frequently reported adverse events resulting in discontinuation of tanezumab treatment were arthralgia and paresthesia; the highest frequency was observed with tanezumab 20mg (both 1.4%). Serious adverse event incidence was similar across treatments. In conclusion, tanezumab provided significantly greater improvement in pain, function, and global scores vs placebo and naproxen in patients with chronic low back pain. PMID- 23628597 TI - Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. AB - BACKGROUND: Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. METHODS: Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. RESULTS: The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02). CONCLUSIONS: Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers. PMID- 23628602 TI - Impairment in verbal memory observed in first episode psychosis patients with persistent negative symptoms. AB - Negative symptoms are present early on during the first episode of psychosis (FEP). The severity of these symptoms has been linked to cognitive deficits, including memory; however, its relationship with persistent negative symptoms (PNS) remains unclear. Thus, the goals of the current paper were to explore memory profiles in FEP patients identified as having PNS and to delineate this relationship in PNS over a 1-year period. Patients diagnosed as having a first episode of psychosis were segregated into groups of patients who met the criteria for PNS (N = 39) and patients who did not, or non-PNS (N = 97). At an initial assessment, all subjects were administered neurocognitive tests for three memory domains including verbal, visual and working memory. In addition, in FEP patients, clinical symptoms including negative, positive and depressive symptoms were also measured at the initial assessment as well as months 1, 2, 3, 6, 9, and 12. A significant interaction of memory * group was observed (F = 4.997, d.f. = 1,181, P = 0.002), with post hoc comparisons indicating that the PNS group performed more poorly than non-PNS only in the verbal memory domain. All three memory domains remained stable over time. Hence, in comparison to non-PNS patients, FEP patients with PNS appear to have greater (selective) verbal memory impairments throughout the first year of treatment. PMID- 23628603 TI - Evidence for impaired visual prediction error in schizophrenia. AB - BACKGROUND: Mismatch negativity (MMN) is regarded a prediction error signal that is deficient in schizophrenia in the auditory modality. If, however, MMN reflects a general computational signal of the cortex, then MMN should be also deficient in the visual modality in schizophrenia patients. METHODS: Twenty-two schizophrenia patients and 24 matched healthy controls finished a visual oddball task while high-density electroencephalogram was recorded. Visual mismatch negativity was computed as a surrogate marker of prediction error. RESULTS: Visual MMN, as measured over posterior extra-striate cortical areas, was significantly reduced in schizophrenia at about 300 ms post stimulus. Standardized mean difference was -.98, corresponding to a large effect size. CONCLUSIONS: A posterior visual MMN deficit in schizophrenia is demonstrated for the first time. Our results tentatively suggest a supra-modal MMN deficit in schizophrenia and thus argue in favor of reduced prediction error estimation in schizophrenia. PMID- 23628604 TI - SET/PP2A system regulates androgen production in ovarian follicles in vitro. AB - SET has multiple cell functions including nucleosome assembly, histone binding, transcription control, and cell apoptosis. In ovaries SET is predominantly expressed in theca cells and oocytes. In our study, SET overexpression in theca cells stimulated testosterone production whereas SET knockdown decreased testosterone production. Moreover, SET negatively regulated PP2A activity. Treatment with PP2A inhibitor okadaic acid (OA) led to increased testosterone synthesis, while treatment with PP2A activators resulted in the decreased testosterone synthesis. Furthermore, PP2A knockdown confirmed the key role of PP2A in the testosterone synthesis, and OA was able to block the AdH1-SiRNA/SET mediated inhibition of testosterone production. The central role of PP2A in SET mediated regulation of testosterone production was confirmed by the finding that SET promoted the lyase activity of P450c17 and that PP2A inhibited its lyase activity. Taken together, these results reveal a specific, SET-initiated, PP2A mediated, pathway that leads to the increased lyase activity of P450c17 and testosterone biosynthesis. PMID- 23628605 TI - Steroid hormone synthesis in mitochondria. AB - Mitochondria are essential sites for steroid hormone biosynthesis. Mitochondria in the steroidogenic cells of the adrenal, gonad, placenta and brain contain the cholesterol side-chain cleavage enzyme, P450scc, and its two electron-transfer partners, ferredoxin reductase and ferredoxin. This enzyme system converts cholesterol to pregnenolone and determines net steroidogenic capacity, so that it serves as the chronic regulator of steroidogenesis. Several other steroidogenic enzymes, including 3beta-hydroxysteroid dehydrogenase, 11beta-hydroxylase and aldosterone synthase also reside in mitochondria. Similarly, the mitochondria of renal tubular cells contain two key enzymes participating in the activation and degradation of vitamin D. The access of cholesterol to the mitochondria is regulated by the steroidogenic acute regulatory protein, StAR, serving as the acute regulator of steroidogenesis. StAR action requires a complex multi component molecular machine on the outer mitochondrial membrane (OMM). Components of this machine include the 18 kDa translocator protein (TSPO), the voltage dependent anion chanel (VDAC-1), TSPO-associated protein 7 (PAP7, ACBD3), and protein kinase A regulatory subunit 1alpha (PKAR1A). The precise fashion in which these proteins interact and move cholesterol from the OMM to P450scc, and the means by which cholesterol is loaded into the OMM, remain unclear. Human deficiency diseases have been described for StAR and for all the mitochondrial steroidogenic enzymes, but not for the electron transfer proteins or for the components of the cholesterol import machine. PMID- 23628606 TI - Selenium and mercury in widely consumed seafood from South Atlantic Ocean. AB - The growing ingestion of predatory fish by humans has increased their exposure to toxic chemicals. Mercury (Hg) is an exogenous and harmful trace-element that accumulates in all marine organisms. Selenium (Se) is nutritionally important as a micronutrient, but is potentially harmful at intakes above 1mg per day. Se:Hg molar ratios in excess of 1:1 are thought to counteract the adverse effects of Hg, protecting against Hg toxicity. Evaluation of the health risk posed by Hg exposure from seafood consumption requires concurrent consideration of Se content in the same individuals. This study evaluated the Se and Hg concentrations in the edible tissues of 652 individual samples of commonly consumed varieties of carnivorous and planktivorous fish, squid, mussel, shrimp and crab collected from south-eastern Brazil. The Se:Hg molar ratios showed significant variation among and within tropical seafood. All organisms presented Se concentration in muscle of less than 2.0ugg(-1), the maximum allowed selenium concentrations. Only seven individuals of a carnivorous fish species presented Hg in muscle above the maximum permissible limit of 0.5ugg(-1) established by WHO and Brazilian legislation for human consumption of most aquatic species. These same individuals also showed Se:Hg molar ratio of less than 1:1. Se:Hg molar ratios were found to decline with increasing fish length, potentially reducing Se-dependent protection. As a result of their rich Se, low Hg contents and Se:Hg molar ratios exceeding 1:1, nearly all species included in this study provide benefits for human consumption. Two popular seafoods in the region, the carnivorous fish Centropomus undecimalis (common snook) and Micropogonias furnieri (Atlantic croaker), had the most favorable Se:Hg molar ratio values of 33 and 21, respectively. Among the invertebrates, Xiphopenaeus kroyeri (seabob shrimp) and Loligo sanpaulensis (squid) had the most favorable Se:Hg molar ratio values, higher than 20. A selenium health benefit value based on the absolute amounts and relative proportions of Se and Hg in seafood was proposed as a more comprehensive seafood safety criterion. PMID- 23628607 TI - Inactivation of food-borne viruses using natural biochemical substances. AB - Food-borne viruses such as human Noroviruses (NoVs), hepatitis A virus (HAV), Rotaviruses (RoVs) are a public health concern worldwide. Biochemical substances, which occur naturally in plants, animals or microorganisms, might possess considerable antimicrobial properties. In this study, the reported effects of biochemical substances on food-borne viruses are reviewed. The biochemical substances are grouped into several categories including (i) polyphenols and proanthocyanins, (ii) saponin, (iii) polysaccharides, (iv) organic acids, (v) proteins and polypeptides, (vi) essential oils. Although not fully understood, the mechanism of action for the antiviral activity of the natural compounds is presented. Generally, it is thought to be the prevention of the viral attachment to host cells, either by causing damage on the viral capsids or change of the receptors on the cell membranes. It is recommended that further studies are undertaken not only on the wide-range screening for novel antiviral substances, but also on the mechanism in-depth as well as the exploration for their potential application in controlling virus contamination in foods or food processing. PMID- 23628608 TI - Microdroplet-based multiplex PCR on chip to detect foodborne bacteria producing biogenic amines. AB - The development of fast, reliable and culture-independent molecular tools to detect bacteria producing biogenic amines deserves the attention of research and ultimately of the food industry in order to protect consumers' health. Here we present the application of a simple, low-cost, fast and sensitive method to perform microdroplet-based multiplex PCR, directly on a food matrix, for the simultaneous detection of bacterial genes involved in biogenic amine biosynthesis. After inoculating wine with Lactobacillus brevis IOEB 9809, cell lysis and DNA amplification are performed in one single step, without preliminary nucleic acid extraction or purification treatments. The assay is performed in about 30 min, requiring 150 nL of starting sample and it enables the detection of down to 15 bacterial cells. With respect to traditional culture techniques, the speed, the simplicity and the cheapness of this procedure allow an effective monitoring of microbial cells during food-making and processing. PMID- 23628609 TI - Inhibition of polymerase chain reaction for the detection of Escherichia coli O157:H7 and Salmonella enterica on walnut kernels. AB - The aim of this study was to determine whether Escherichia coli O157:H7 can be reliably detected and isolated from walnut kernels using standard methods of analysis. The limit of detection approached 1 cell per analytical unit (25 g) for E. coli O157:H7 on walnut kernels enriched in modified tryptic soy broth with 20 MUg/ml novobiocin and plating onto selective agar media. The presence of PCR inhibitors in walnut kernels was indicated by the failure to detect E. coli O157:H7 from culture positive enrichment broths analysed by PCR, with two separate polymerase and reagent compositions (Dupont BAX E. coli O157:H7 MP system, Promega GoTaq Green for stx) and three methods of template preparation (DuPont BAX, Qiagen DNeasy, Bio-Rad InstaGene). PCR inhibition was overcome by 1:100 dilution in TE buffer of the DNeasy or InstaGene template. PCR inhibition was not relieved by dilution of the BAX template. Similar results were observed for walnut kernels inoculated with Salmonella enterica and analysed for invA, indicating that PCR inhibition is not specific to the organism or primer/template. These results indicate that analysis of walnut kernels for pathogens should be with culture based methods or use protocols for DNA template preparation modified to remove or dilute inhibitors and the need for internal amplification controls in PCR methods. PMID- 23628610 TI - Survival of foodborne pathogens at different relative humidities and temperatures and the effect of sanitizers on apples with different surface conditions. AB - We investigated the effects of factors such as relative humidity (RH) and temperature on pathogen survival on apples with different surface conditions. Apples with different surface conditions (unblemished, bruised, or cut) were inoculated with three pathogens (Escherichia coli O157:H7, Salmonella Typhimurium, and Staphylococcus aureus) and stored at different RH levels (RH 100, 85, or 68%) at 4 degrees C or 15 degrees C for 2 days. S. aureus survived most readily on apple surfaces; it had no significant reduction on any of the apple surfaces for any of the three RH levels after 2 days of storage. The reduction levels of E. coli O157:H7 and S. Typhimurium on unblemished and bruised apple surfaces were higher at RH of 85% and 68% than at RH of 100% at 15 degrees C; and reduction levels were approximately 3 log(10) CFU/apple at 4 degrees C in RH of 68%. No significant reduction in any of the three pathogens on cut apple surfaces was observed for any RH level. The effectiveness of chemical sanitizers (chlorine sanitizer and 2% lactic acid) in reducing pathogens (E. coli O157:H7, S. Typhimurium, and S. aureus) on apple surfaces (unblemished, bruised, or cut) was also evaluated. Treatment with chlorine sanitizer and 2% lactic acid for 5 min significantly reduced pathogen levels on unblemished and bruised apple surfaces but not on cut apple surfaces. In conclusion, the surface conditions of the apple significantly affected pathogen survival and the effectiveness of sanitizing methods. PMID- 23628611 TI - Diversity of Streptococcus thermophilus in bacteriocin production; inhibitory spectrum and occurrence of thermophilin genes. AB - The bacteriocin-producing Streptococcus thermophilus strains that can dominate in natural dairy ecosystems, may also enhance safety in products obtained from natural cultures. In this study, we sought to identify bacteriocin production and bacteriocin genes in 75 strains of dairy and plant origin. The strains were tested for antimicrobial activity against pathogens or pathogen models, spoiling bacteria, and lactic acid bacteria associated with dairy products. All strains moderately inhibited Staphylococcus aureus P310, none inhibited Listeria innocua LMG 11387(T) or Clostridium tyrobutyricum LMG 1285(T). In addition, 14 were active against one or more indicators in addition to S. aureus P310. Inhibition of other starter bacteria was more common than the inhibition of unwanted microorganisms. The involvement of a proteinaceous compound was ascertained in all cases. Results suggested that the selection of bacteriocinogenic S. thermophilus strains for use in biopreservation must take into account the effects exerted on other lactic acid bacteria. PCR detection of thermophilin genes proved unreliable in predicting antimicrobial activity. For S. thermophilus PRI36 and PRI45, with relevant inhibitory features, the identity of the bacteriocin genes present in the thermophilin 9 cluster was defined, thus revealing novel variants for this genome region. PMID- 23628612 TI - Inactivation of Serratia liquefaciens on dry-cured ham by high pressure processing. AB - To quantify the inactivation of Serratia liquefaciens exerted by high pressure processing (HPP), slices of dry-cured ham were inoculated and processed combining different levels of technological parameters: pressure (347-852 MPa), time (2.3 15.8 min) and temperature (7.6-24.4 degrees C) according to a central composite design. Bacterial inactivation, as logarithmic reduction, indicated that S. liquefaciens was relatively sensitive to HPP. Six log reductions were achieved in a total of 10 trials combining pressures of 600 MPa or above with different holding times and temperatures. The inactivation of S. liquefaciens was analysed through the multiple regression analysis to generate a second order polynomial equation. Pressure and time were the two factors which significantly determined the inactivation of S. liquefaciens on dry-cured ham. Temperature did not significantly affect the lethality of the process. The response surface methodology was used to determine optimum process conditions to maximize the inactivation of S. liquefaciens in the experimental range tested. The maximum inactivation of S. liquefaciens in dry-cured ham was achieved by combining a pressure of 650 MPa with a holding time of 8 min. Combinations above these values (i.e. 750 MPa for 13 min) would not significantly improve the lethality of the process. PMID- 23628613 TI - Persistent Listeria monocytogenes subtypes isolated from a smoked fish processing facility included both phage susceptible and resistant isolates. AB - Contamination of Ready-To-Eat foods with Listeria monocytogenes can typically be traced back to post-processing contamination from environmental sources; contamination is often linked to subtypes that persist in food associated environments. Although phage-based biocontrol strategies have been proposed for controlling this pathogen, information on the efficacy of phage treatment against diverse L. monocytogenes subtypes from food associated environments is still limited. We identified subtypes that were repeatedly found ("persistent") in a smoked fish processing facility by using EcoRI ribotyping data for isolates obtained in 1998-2009. PFGE analysis of 141 isolates (9 ribotypes) supported persistence for up to 11 years. Characterization of selected isolates, representing persistent subtypes, against a panel of 28 listeriaphages showed a wide range of likelihood of phage susceptibility, ranging from 4.6% (for 7 ribotype DUP-1043A isolates) to 95.4% (for 7 ribotype DUP-1044A isolates). In challenge studies with 10(5) and 10(6) CFU/ml L. monocytogenes, using phage cocktails and a commercial phage product at different phage-host ratios, one isolate (ribotype DUP-1043A) was not affected by any treatment. A reduction in L. monocytogenes counts of up to 4 log units was observed, after 8 h of treatment, in isolates of two ribotypes, but subsequent re-growth occurred. Survivor isolates obtained after 24 h of treatment showed decreased susceptibility to individual phages included in the phage cocktail, suggesting rapid emergence of resistant subtypes. PMID- 23628614 TI - Use of propidium monoazide for the enumeration of viable Oenococcus oeni in must and wine by quantitative PCR. AB - Malolactic fermentation is an important step in winemaking, but it has to be avoided in some cases. It's carried out by lactic acid bacteria belonging mainly to the genus Oenococcus, which is known to be a slow growing bacterium. Classical microbiological methods to enumerate viable cells of Oenococcus oeni in must and wine take 7-9 days to give results. Moreover, RT-qPCR technique gives accurate quantitative results, but it requires time consuming steps of RNA extraction and reverse transcription. In the present work we developed a fast and reliable quantitative PCR (qPCR) method to enumerate cells of Oenococcus oeni, directly, in must and wine. For the first time we used a propidium monoazide treatment of samples to enumerate only Oenococcus oeni viable cells. The detection limit of the developed method is 0.33 log CFU/mL (2.14 CFU/mL) in must, and 0.69 log CFU/mL (4.90 CFU/mL) in wine, lower than that of the previously developed qPCR protocols. PMID- 23628615 TI - Molecular subtyping and virulence gene analysis of Listeria monocytogenes isolates from food. AB - A total of 67 Listeria monocytogenes isolates from 698 raw meat samples were characterized for molecular serogroup identification and antimicrobial susceptibility. Approximately one third (32.8%) of the isolates belonged to molecular serogroup 1/2a, 3a, followed by 1/2c, 3c (26.9%), 1/2b, 3b, 7 (22.4%), 4b, 4d, 4e (16.4%) and 4a, 4c (1.5%). Most of the L. monocytogenes isolates were susceptible to 14 antimicrobials tested but several were resistant to tetracycline, ciprofloxacin and nitrofurantoin. An additional 30 L. monocytogenes isolates from chicken and produce in our collection were also included to determine the presence of significant virulence markers. All 97 isolates carried inlC and inlJ except for a lineage III isolate 110-1. Most Listeriolysin S (LLS) carrying isolates (11/12) belonged to lineage I, whereas the remaining one isolate belonged to lineage III. Five 4b, 4d, 4e isolates including two from turkey and three from produce belonged to Epidemic Clone I (ECI). Four molecular serogroup associated mutation types that lead to premature stop codons (PMSCs) in inlA were identified. PFGE and inlA sequence analysis results were concordant, and different virulence potential within 1/2a, 3a and 4b, 4d, 4e isolates were observed. The study revealed that a subset of isolates from meat and produce belonged to ECI, harbored inlC, inlJ and LLS, and produced full length InlA, suggesting that they be capable of causing human illness. PMID- 23628616 TI - The effects of stainless steel finish on Salmonella Typhimurium attachment, biofilm formation and sensitivity to chlorine. AB - Bacterial colonization and biofilm formation on stainless steel (SS) surfaces can be sources for cross contamination in food processing facilities, possessing a great threat to public health and food quality. Here the aim was to demonstrate the influence of surface finish of AISI 316 SS on colonization, biofilm formation and susceptibility of Salmonella Typhimurium to disinfection. Initial attachment of S. Typhimurium on surfaces of SS was four times lower, when surface was polished by Bright-Alum (BA) or Electropolishing (EP), as compared to Mechanical Sanded (MS) or the untreated surface (NT). The correlation between roughness and initial bacterial attachment couldn't account on its own to explain differences seen. Biofilms with similar thickness (15-18 MUm) were developed on all surfaces 1-day post inoculation, whereas EP was the least covered surface (23%). Following 5-days, biofilm thickness was lowest on EP and MS (30 MUm) and highest on NT (62 MUm) surfaces. An analysis of surface composition suggested a link between surface chemistry and biofilm development, where the higher concentrations of metal ions in EP and MS surfaces correlated with limited biofilm formation. Interestingly, disinfection of biofilms with chlorine was up to 130 times more effective on the EP surface (0.005% surviving) than on the other surfaces. Overall these results suggest that surface finish should be considered carefully in a food processing plant. PMID- 23628617 TI - Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: a 24-week, randomized, placebo-controlled comparison (GetGoal-L). AB - OBJECTIVE: To examine the efficacy and safety of adding the once-daily glucagon like peptide-1 receptor agonist (GLP-1RA) lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated glycated hemoglobin (HbA1c). RESEARCH DESIGN AND METHODS: We conducted a double-blind, parallel-group, placebo-controlled trial. Patients (n = 495) with established basal insulin therapy but inadequate glycemic control were randomized to add lixisenatide 20 MUg or placebo for 24 weeks. Basal insulin dosage was unchanged except to limit hypoglycemia. HbA1c reduction from baseline was the primary end point. RESULTS: Mean duration of diabetes was 12.5 years, duration of insulin use was 3.1 years, insulin dosage was 55 units/day, and baseline HbA1c was 8.4%. With lixisenatide, the placebo-corrected change of HbA1c from baseline was -0.4% (95% CI -0.6 to -0.2; P = 0.0002), and mean HbA1c at end point was 7.8%. HbA1c <7.0% (53 mmol/mol) was attained by more lixisenatide (28%) than placebo (12%; P < 0.0001) participants. Lixisenatide reduced plasma glucose levels after a standardized breakfast (placebo-corrected reduction, -3.8 mmol/L; P < 0.0001); seven-point glucose profiles showed a reduction persisting through the day. Reductions in body weight (placebo corrected, -1.3 kg; P < 0.0001) and insulin dosage (-3.7 units/day; P = 0.012) were greater with lixisenatide. Main adverse events (AEs) with lixisenatide were gastrointestinal. Symptomatic hypoglycemia was 28% for lixisenatide and 22% for placebo; 4 of 328 subjects (1.2%) had severe hypoglycemia with lixisenatide vs. 0 of 167 with placebo. CONCLUSIONS: By improving HbA1c and postprandial hyperglycemia without weight gain in type 2 diabetes with inadequate glycemic control despite stable basal insulin, lixisenatide may provide an alternative to rapid-acting insulin or other treatment options. PMID- 23628618 TI - Glycemic control associated with secure patient-provider messaging within a shared electronic medical record: a longitudinal analysis. AB - OBJECTIVE: To study differences in glycemic control and HbA1c testing associated with use of secure electronic patient-provider messaging. We hypothesized that messaging use would be associated with better glycemic control and a higher rate of adherence to HbA1c testing recommendations. RESEARCH DESIGN AND METHODS: Retrospective observational study of secure messaging at Group Health, a large nonprofit health care system. Our analysis included adults with diabetes who had registered for access to a shared electronic medical record (SMR) between 2003 and 2006. We fit log-linear regression models, using generalized estimating equations, to estimate the adjusted rate ratio of meeting three indicators of glycemic control (HbA1c <7%, HbA1c <8%, and HbA1c >9%) and HbA1c testing adherence by level of previous messaging use. Multiple imputation and inverse probability weights were used to account for missing data. RESULTS: During the study period, 6,301 adults with diabetes registered for access to the SMR. Of these individuals, 74% used messaging at least once during that time. Frequent use of messaging during the previous calendar quarter was associated with a higher rate of good glycemic control (HbA1c <7%: rate ratio, 1.26 [95% CI, 1.15 1.37]) and a higher rate testing adherence (1.20 [1.15-1.25]). CONCLUSIONS: Among SMR users, recent and frequent messaging use was associated with better glycemic control and a higher rate of HbA1c testing adherence. These results suggest that secure messaging may facilitate important processes of care and help some patients to achieve or maintain adequate glycemic control. PMID- 23628619 TI - Serum fibroblast growth factor 19 levels are decreased in Chinese subjects with impaired fasting glucose and inversely associated with fasting plasma glucose levels. AB - OBJECTIVE: Fibroblast growth factor 19 (FGF19), a hormone secreted from the small intestine, has recently been shown to stimulate glycogen synthesis and inhibit gluconeogenesis through insulin-independent pathways. This study investigated the change of FGF19 in prediabetes and newly diagnosed type 2 diabetes mellitus (T2DM) and explored the association of serum FGF19 levels with parameters of glucose metabolism in Chinese subjects. RESEARCH DESIGN AND METHODS: Fasting serum FGF19 levels were determined by ELISA in 81 normal glucose tolerance (NGT), 91 impaired fasting glucose (IFG), 93 impaired glucose tolerance (IGT), and 104 newly diagnosed T2DM subjects, and their association with parameters of glucose metabolism was studied. An ordinal logistic regression analysis was performed in subjects with NGT, IFG, and T2DM. Serum FGF19 levels at 2 h after a 75-g oral glucose tolerance test in the different glucose tolerance categories were studied in a subgroup. RESULTS: Fasting serum FGF19 levels in subjects with IFG (210 pg/mL [142-327]) (median [interquartile range]) and T2DM (196 pg/mL [137-280]) were significantly lower than those in NGT subjects (289 pg/mL [224-393]) (both P < 0.001). However, no significant difference in fasting FGF19 levels was observed between IGT (246 pg/mL [138-379]) and NGT subjects. Fasting serum FGF19 levels were negatively associated with fasting plasma glucose and independently associated with the deterioration of glucometabolic status from NGT to IFG and T2DM. CONCLUSIONS: Fasting serum FGF19 levels were decreased in Chinese subjects with IFG and inversely associated with fasting glucose levels. PMID- 23628620 TI - Receiver operating characteristic analysis of HLA, CTLA4, and insulin genotypes for type 1 diabetes. AB - OBJECTIVE: This study assessed the ability to distinguish between type 1 diabetes affected individuals and their unaffected relatives using HLA and single nucleotide polymorphism (SNP) genotypes. RESEARCH DESIGN AND METHODS: Eight models, ranging from only the high-risk DR3/DR4 genotype to all significantly associated HLA genotypes and two SNPs mapping to the cytotoxic T-cell-associated antigen-4 gene (CTLA4) and insulin (INS) genes, were fitted to high-resolution class I and class II HLA genotyping data for patients from the Type 1 Diabetes Genetics Consortium collection. Pairs of affected individuals and their unaffected siblings were divided into a "discovery" (n = 1,015 pairs) and a "validation" set (n = 318 pairs). The discriminating performance of various combinations of genetic information was estimated using receiver operating characteristic (ROC) curve analysis. RESULTS: The use of only the presence or absence of the high-risk DR3/DR4 genotype achieved very modest discriminating ability, yielding an area under the curve (AUC) of 0.62 in the discovery set and 0.59 in the validation set. The full model-which included HLA information from the class II loci DPB1, DRB1, and DQB1; selected alleles from HLA class I loci A and B; and SNPs from the CTLA4 and INS genes-increased the AUC to 0.74 in the discovery set and to 0.71 in the validation set. A cost-effective alternative is proposed, using genotype information equivalent to typing four SNPs (DR3, DR4 DQB1*03:02, CTLA-4, and INS), which achieved an AUC of 0.72 in the discovery set and 0.69 in the validation set. CONCLUSIONS: Genotyping data sufficient to tag DR3, DR4-DQB1*03:02, CTLA4, and INS were shown to distinguish between subjects with type 1 diabetes and their unaffected siblings adequately to achieve clinically utility to identify children in multiplex families to be considered for early intervention. PMID- 23628621 TI - Quality of care of people with type 2 diabetes in eight European countries: findings from the Guideline Adherence to Enhance Care (GUIDANCE) study. AB - OBJECTIVE: We sought to determine levels of adherence in eight European countries to recommendations for the management of type 2 diabetes and to investigate factors associated with key intermediate outcomes. RESEARCH DESIGN AND METHODS: GUIDANCE was a cross-sectional study including retrospective data extraction from the medical records of people with type 2 diabetes recruited, using a shared protocol, from primary and specialist care sites in the following eight European countries: Belgium, France, Germany, Italy, Ireland, Sweden, the Netherlands, and the United Kingdom. The dataset for analysis comprised 7,597 cases. Proportions meeting process and outcome criteria were determined, including between-country variations. Logistic regression was used to investigate potential predictors of meeting targets for HbA1c, blood pressure, and LDL cholesterol. RESULTS: In the total sample, adherence to process recommendations was high for some measures, for example, HbA1c recorded in past 12 months in 97.6% of cases. Target achievement for intermediate outcome measures was lower, with only 53.6% having HbA1c <7%. Considerable between-country variation was identified for both processes and outcomes. The following characteristics were associated with an increased likelihood of meeting targets for all three measures considered (HbA1c, blood pressure, LDL cholesterol): shorter diagnosis of diabetes; having one or more macrovascular complications; lower BMI; being prescribed lipid-lowering medication; and no current antihypertensive prescribing. CONCLUSIONS: Compared with earlier reports, we have suggested some encouraging positive trends in Europe in relation to meeting targets for the management of people with type 2 diabetes, but there is still scope for further improvement and greater between country consistency. PMID- 23628623 TI - Preferred step frequency during downhill running may be determined by muscle activity. AB - It is well established that metabolic cost is minimized at an individual's running preferred step frequency (PSF). It has been proposed that the metabolic minimum at PSF is due to a tradeoff between mechanical factors, however, this ignores muscle activity, the primary consumer of energy. Thus, we hypothesized that during downhill running, total muscle activity would be greater with deviations from PSF. Specifically, we predicted that slow step frequencies would have greater stance activity while fast step frequencies would have greater swing activity. We collected metabolic cost and leg muscle activity data while 10 healthy young adults ran at 3.0m/s for 5 min at level and downhill at PSF and +/ 15% PSF. In support of our hypothesis, there was a significant main effect for step frequency for both metabolic cost and total muscle activity. In addition, there was greater muscle activity in the stance phase during the slower step frequency while muscle activity was greater in the swing phase during the fast step frequency. This suggests that PSF is partially determined by the tradeoff between the greater cost of muscle activity in the swing phase and lower cost in the stance phase with faster step frequency. PMID- 23628622 TI - Chimeric gammac cytokine receptors confer cytokine independent engraftment of human T lymphocytes. AB - Therapeutic responses following adoptive transfer of T cells correlate to levels of long-term T cell persistence. Lymphodepletion and exogenous gammac cytokine administration can improve T cell persistence following adoptive transfer, but their effects are not uniform and toxicities are significant. To overcome these limitations, we designed a chimeric gammac cytokine receptor (CgammaCR) composed of Interleukin-7 (IL-7) tethered to IL-7Ralpha/CD127 that confers exogenous cytokine independent, cell intrinsic, STAT5 cytokine signals. We additionally show that this design is modular in that the IL-2Rbeta/CD122 cytoplasmic chain can be exchanged for that of IL-7Ralpha/CD127, enhancing Shc activity. When expressed in central memory-derived primary human CD8(+) CTL (T(E/CM)), these CgammaCRs signal according to their corresponding wild-type counterparts to support exogenous cytokine independent viability and homeostatic proliferation, while retaining full effector function. In vivo studies demonstrate that both CgammaCR-CD127(+) and CgammaCR-CD122(+) CD8(+) T((E/CM)) engraft in mice and persist in an absence of exogenous cytokine administration. Engrafted CgammaCR CD127(+) CD8(+) T(E/CM) preferentially retain central memory marker expression in vivo demonstrating a dichotomy between CD127 versus CD122 signaling. Together, these results suggest that expression of CgammaCR in therapeutic T cells may aid in the in vivo persistence of these cells, particularly under conditions of limiting homeostatic cytokines. PMID- 23628624 TI - Expression of xyloglucan endotransglucosylase/hydrolase (XTH) genes and XET activity in ethylene treated apple and tomato fruits. AB - Xyloglucan endotransglucosylase/hydrolase (XTHs: EC 2.4.1.207 and/or EC 3.2.1.151), a xyloglucan modifying enzyme, has been proposed to have a role during tomato and apple fruit ripening by loosening the cell wall. Since the ripening of climacteric fruits is controlled by endogenous ethylene biosynthesis, we wanted to study whether XET activity was ethylene-regulated, and if so, which specific genes encoding ripening-regulated XTH genes were indeed ethylene regulated. XET specific activity in tomato and apple fruits was significantly increased by the ethylene treatment, as compared with the control fruits, suggesting an increase in the XTH gene expression induced by ethylene. The 25 SlXTH protein sequences of tomato and the 11 sequences MdXTH of apple were phylogenetically analyzed and grouped into three major clades. The SlXTHs genes with highest expression during ripening were SlXTH5 and SlXTH8 from Group III-B, and in apple MdXTH2, from Group II, and MdXTH10, and MdXTH11 from Group III-B. Ethylene was involved in the regulation of the expression of different SlXTH and MdXTH genes during ripening. In tomato fruit fifteen different SlXTH genes showed an increase in expression after ethylene treatment, and the SlXTHs that were ripening associated were also ethylene dependent, and belong to Group III-B (SlXTH5 and SlXTH8). In apple fruit, three MdXTH showed an increase in expression after the ethylene treatment and the only MdXTH that was ripening associated and ethylene dependent was MdXTH10 from Group III-B. The results indicate that XTH may play an important role in fruit ripening and a possible relationship between XTHs from Group III-B and fruit ripening, and ethylene regulation is suggested. PMID- 23628625 TI - Plant bioassay to assess the effects of allelochemicals on the metabolome of the target species Aegilops geniculata by an NMR-based approach. AB - A metabolomic-based approach for the study of allelopathic interactions in the Mediterranean area is proposed using Aegilops geniculata Roth (Poaceae), a Mediterranean herbaceous plant, as test species. Its metabolome has been elucidated by 1D and 2D NMR experiments. Hydroponic plant cultures of A. geniculata were treated with specific compounds of known allelopathic potential: catechol, coumarin, p-coumaric acid, p-hydroxybenzoic acid, ferulic acid and juglone. The metabolic variations due to the presence of allelochemicals have been analyzed and measured. All of the compounds showed the strongest effects at the highest concentration, with coumarin and juglone as the most active compounds, causing an increase of several metabolites. The metabolome changes in test plants confirmed the allelochemicals' reported modes of action. The results demonstrated that the proposed method is a promising tool. It can be applied to plant extracts, making it possible to evidence the metabolites responsible for the activity, as well as their mechanisms of action. PMID- 23628626 TI - Daphnane diterpenoids from the stems of Trigonostemon lii and their anti-HIV-1 activity. AB - Thirteen highly oxygenated daphnane diterpenoids, including six known compounds, were isolated from the stems of Trigonostemon lii. The structures were elucidated by extensive spectroscopic analyses including 2D NMR spectroscopy (HSQC, (1)H (1)H COSY, HMBC, and ROESY) and mass spectrometry. The absolute stereochemistries of compounds were established on the basis of CD spectra. Four of the compounds showed modest anti-HIV-1 activity (EC50=2.04, 9.17, 11.42, and 9.05 MUg/ml, TI=26.49, >21.81, 9.32, and 9.56, respectively) in vitro. PMID- 23628627 TI - Improving strength and power in trained athletes with 3 weeks of occlusion training. AB - PURPOSE: To examine the effects of moderate-load exercise with and without blood flow restriction (BFR) on strength, power, and repeated-sprint ability, along with acute and chronic salivary hormonal parameters. METHODS: Twenty male semiprofessional rugby union athletes were randomized to a lower-body BFR intervention (an occlusion cuff inflated to 180 mmHg worn intermittently on the proximal thighs) or a control intervention that trained without occlusion in a crossover design. Experimental sessions were performed 3 times a week for 3 wk with 5 sets of 5 repetitions of bench press, leg squat, and pull-ups performed at 70% of 1-repetition maximum. RESULTS: Greater improvements were observed (occlusion training vs control) in bench press (5.4 +/- 2.6 vs 3.3 +/- 1.4 kg), squat (7.8 +/- 2.1 vs 4.3 +/- 1.4 kg), maximum sprint time (-0.03 +/- 0.03 vs 0.01 +/- 0.02 s), and leg power (168 +/- 105 vs 68 +/- 50 W). Greater exercise induced salivary testosterone (ES 0.84-0.61) and cortisol responses (ES 0.65 0.20) were observed after the occlusion intervention sessions compared with the nonoccluded controls; however, the acute cortisol increases were attenuated across the training block. CONCLUSIONS: Occlusion training can potentially improve the rate of strength-training gains and fatigue resistance in trained athletes, possibly allowing greater gains from lower loading that could be of benefit during high training loads, in competitive seasons, or in a rehabilitative setting. The clear improvement in bench-press strength resulting from lower-body occlusion suggests a systemic effect of BFR training. PMID- 23628628 TI - From individualism to co-operation. PMID- 23628629 TI - Kuopio treatment strategy after deep sternal wound infection. AB - BACKGROUNDS AND AIMS: Infection of sternotomy wound is a rare potentially fatal complication because of the risk for deep sternal infection. Current treatment comprises antibiotics, debridement, negative pressure wound therapy and sometimes transposition of muscle or omental flaps to fill the anterior mediastinal dead space. MATERIAL AND METHODS: The management of 60 consecutive deep sternotomy wound infections is reviewed. The one stage treatment was mostly chosen. In 5 patients after debridement, negative pressure wound therapy was used before flap reconstruction. Fifty-seven patients were rewired and 3 patients had sternectomy. The choice of the flap was based mainly on anatomic location of a sternal wound defect and also on which grafts been used in cardiac operation. RESULTS: The unilateral turnover split pectoralis major flap was the choice for 50 patients. In 8 patients latissimus dorsi flap was used. Rectus abdominis was used as a standalone flap in 4 patients and in combination with pectoralis major in one. All patients survived after deep sternal wound infection. In only 33 patients the recovery was totally uneventful. In the remaining 27 patients there were one or more complications. Not a single flap was lost completely, but due to partial flap necrosis, a redo reconstruction was needed in 3 patients. Negative pressure wound therapy was used after flap reconstruction in eight patients with incomplete post-flap healing to prepare for wound revision and split thickness skin graft. CONCLUSIONS: A structured approach including both cardiac and plastic surgery in case of deep sternal wound infection is recommended. A single stage surgery with the help of muscle flap reconstruction is our standard treatment. With our protocol, we have been able to keep the mortality low. PMID- 23628630 TI - Chest wall reconstruction after oncological resections. AB - Most chest wall defects requiring reconstruction result from tumor resection. Bone and soft tissue sarcomas and recurrent mammary cancer are the most common tumors. Careful preoperative evaluation, meticulous surgical technique and active postoperative treatment are important. The selection of reconstruction is based on the nature, size and location of the defect as well as on the general health and prognosis of the patient. The goals of the reconstruction are adequate stability, water- and airtight closure of the chest cavity, and acceptable cosmetic appearance. The pedicled muscular or musculocutaneous flaps are usually the first choice for tis-sue coverage. These include flaps such as latissimus dorsi, vertical or transverse rectus abdominis and pectoralis. In certain cases also the breast flap or omental flap can be used. In selected cases, a free flap reconstruction is indicated if the local options for reconstruction have been used, or if they are unreliable due to earlier scars or radiotherapy. The free flaps to be used for chest wall can be harvested from the thigh (tensor fascia latae flap, anterolateral thigh flap), from the abdomen (transverse rectus abdominis flaps, deep epigastric perforator flaps) or from the chest wall (latissimus dorsi flap and other flaps based on the subscapular artery). Sometimes a fillet forearm can be used as a flap to cover a defect after extended forequarter amputation. Artificial meshes are commonly used to give stability in the defect and to give a platform for the flap. Methylmethacrylate embedded between the two layers of a mesh, or one or two rib grafts fixed to the mesh, can be used to give additional stability in extensive defects to prevent paradoxical movement. PMID- 23628631 TI - Reconstruction of complex abdominal wall defects. AB - Complex abdominal wall defects refer to situations where simple ventral hernia repair is not feasible because the defect is very large, there is a concomitant infection or failed previous re-pair attempt, or if there is not enough original skin to cover the repair. Usually a complex abdominal wall repair is preceded by a period of temporary abdominal closure where the short-term aims include closure of the catabolic drain, protection of the viscera and preventing fistula formation, preventing bowel adherence to the abdominal wall, and enabling future fascial and skin closure. Currently the best way to achieve these goals is the vacuum- and mesh-mediated fascial traction method achieving close to 90% fascial closure rates. The long-term aims of an abdominal closure following a planned hernia strategy include intact skin cover, fascial closure at midline (if possible), good functional outcome with innervated abdominal musculature, no pain and good cosmetic result. The main methods of abdominal wall reconstruction include the use of prosthetic (mesh) or autologous material (tissue flaps). In patients with original skin cover over the fascial defect (simple ventral hernia), the most commonly used method is hernia repair with an artificial mesh. For more complex defects, our first choice of reconstruction is the component separation technique, sometimes combined with a mesh. In contaminated fields where component separation alone is not feasible, a combination with a biological mesh can be used. In large defects with grafted skin, a free TFL flap is the best option, sometimes reinforced with a mesh and enhanced with components separation. PMID- 23628632 TI - Primary closure of the abdominal wall after "open abdomen" situation. AB - "Open abdomen" is a strategy used to avoid or treat abdominal compartment syndrome. It has reduced mortality both in trauma and non-trauma abdominal catastrophes but also has created a challenging clinical problem. Traditionally, open abdomen is closed in two phases; primarily with a free skin graft and later with a flap reconstruction. A modern trend is to close the abdomen within the initial hospitalization. This requires multi-professional co-operation. Temporary abdominal closure methods, e.g. negative pressure wound therapy alone or combined with mesh-mediated traction, have been developed to facilitate direct fascial closure. Components separation technique, mesh reinforcement or bridging of the fascial defect with mesh and perforator saving skin undermining can be utilized in the final closure if needed. These techniques can be combined. Choice of the treatment depends on the condition of the patient and size of the fascia and skin defect, and the state of the abdominal contents. In this paper we review the literature on the closure of an open abdomen and present the policy used in our institution in the open abdomen situations. PMID- 23628633 TI - Pelvic, perineal and genital reconstructions. AB - Perineogenital and pelvic surgery is challenging due to the complex anatomy and physiology, multi-organ involvement and microbial environment of this region. In reconstructive surgery local and pedicled flaps are usually applicable. Microvascular flaps are rarely needed. Positioning of the scars, tension in the wound edges and pressure conditions must be taken into account, because failed correction may create more functional and aesthetic problems as the defect itself. This brief review focuses on the reconstructive methods of perineum, genitals and pelvic floor, site by site, with special emphasis on functional details. PMID- 23628634 TI - Reconstruction of the vulva with sensate gluteal fold flaps. AB - BACKGROUND AND AIMS: Soft-tissue reconstruction of the vulva following resection of malignancies is challenging. The function of perineal organs should be preserved and the reconstructed area should maintain an acceptable cosmetic appearance. Reconstruction with local flaps is usually sufficient in the primary phase after a radical vulvectomy. Numerous flaps have been designed for vulvar reconstruction usually based on circulation from the internal pudendal artery branches. In this paper we introduce our modification of the gluteal fold V-Y advancement flap as a primary reconstruction after a radical vulvectomy. PATIENTS AND METHODS: Twenty-two patients were operated with a radical vulvectomy because of vulvar malignancies. The operation was primary in eight and secondary in 14 patients. The reconstruction of the vulva was performed in the same operation for each patient. RESULTS: All flaps survived completely. Wound complications were registered in three patients. Late problems with urinary stream were corrected in two patients. A local recurrence of the malignancy was observed in six patients during the follow-up period. CONCLUSIONS: Gluteal fold flap is easy to perform, has a low rate of complications and gives good functional results. Even a large defect can be reconstructed reliably with this method. A gluteal fold V-Y advancement flap is sensate and our modification allows the flap to be transposed with lesser dissection as presented before. PMID- 23628635 TI - Orthopaedic reconstruction of complex pelvic bone defects. Evaluation of various treatment methods. AB - Despite major developments in the field of revision surgery in recent decades, the management of severe acetabular deficiency at revision arthroplasty, complex primary total hip replacement or after pelvic tumour resection remains a complex problem. The options available for the management of severe bone loss include the use of uncemented press-fit cups with or without metal augments, impaction allografts, allograft-prosthesis composites, custom-made triflange cups, hip transposition, reconstruction prostheses or various combinations of these. This paper describes defect classification, various treatment options, clinical outcomes, survival of reconstruction, and typical complications in relation to treatment. PMID- 23628636 TI - Spinal reconstruction with free vascularised bone grafts; approaches and selection of acceptor vessels. AB - The use of free vascularised bone grafts is an infrequently performed surgical technique for the reconstruction of spinal defects. This field of surgery brings many challenges concerning the choice of free vascularised bone graft, planning of the operative procedure and selection of recipient vessels. This study aims to report our experience with free vascularised bone grafts, with special emphasis on the surgical approach and the selection of recipient vessels. Over a period of 17 years (1994-2011), we used these grafts for anterior spinal reconstruction in 30 patients. In 28 patients, a free vascularised fibular graft was used, and in two cases a free vascularised iliac crest graft was used. The spinal segments reconstructed involved the cervical or cervicothoracic spine (6 cases), the thoracic spine (11 cases) and the thoracolumbar and lumbosacral spine (13 cases). Revascularisation of the free vascularised bone graft proved to be technically feasible in 30 patients, but failed in one fibular graft due to difficulties with recipient vessels in the lumbar region. Technical challenges were met with respect to the choice of the recipient vessel at various anatomical sites. Availability of acceptor vessels was highly de-pendant of the type of surgery (resection or stabilisation) and the selected surgical approach. Based on these findings, a preferred approach is given for each region. The use of free vascularised bone grafts is a valuable technique for the reconstruction of complex spinal disorders. Successful execution requires microvascular expertise with respect to graft harvesting and appropriate choice of recipient vessels. Adequate preoperative planning in a multidisciplinary setting and adherence to the basic principles for spinal reconstruction are required. PMID- 23628637 TI - Sonochemiluminescence observation and acoustic detection of cavitation induced by pulsed HIFU at a tissue-fluid interface. AB - The aim of this study is to investigate the mechanism of the erosion process induced by 1.2 MHz pulsed high-intensity focused ultrasound (pulsed HIFU). By using Sonochemiluminescence (SCL) photograph, the initiation and maintenance of active cavitation were observed. In order to understand the role of both inertial cavitation and stable cavitation, a passive cavitation detection (PCD) transducer was used. Since the exposure variables of HIFU are important in the controlled ultrasound tissue erosion, the influence of pulse length (PL) and duty cycle (DC, Ton:Toff) has been examined. The results of tissue hole, SCL observation and acoustic detection revealed that the erosion was highly efficient for shorter PL. For higher DCs, the area of SCL increased with increasing PL. For lower DCs, the area of SCL increased with increasing PL from 10 to 20 MUs and then kept constant. For all PLs, the intensity of SCL decreased with lower DC. For all DCs, the intensity of SCL per unit area (the ratio of SCL intensity to SCL area) also decreased with increasing PL from 10 to 80 MUs, which suggested that the higher the intensity of SCL is, the higher the efficiency of tissue erosion is. At DC of 1:10, the position of the maximum pixel in SCL pictures was distant from the tissue-fluid interface with the increasing PL because of shielding effect. By the comparison of inertial cavitation dose (ICD) and the stable cavitation dose (SCD), the mechanisms associated with inertial cavitation are very likely to be the key factor of the erosion process. PMID- 23628638 TI - Population genetics and the evolution of virulence in Staphylococcus aureus. AB - Staphylococcus aureus is one of the most important human pathogens, causing life threatening infection in the community and hospital setting. The population genetics of S. aureus and the evolution of virulence is the focus of this review. We describe the various techniques in determining S. aureus population structure and discuss the insights gained from whole genome sequencing of various S. aureus strains. The emergence of community-acquired, methicillin-resistant S. aureus provides a framework for the discussion on evolution of virulence, and the role of horizontal gene transfer in the development of virulence and antibiotic resistance is explored. The knowledge generated from population genetics has the potential to inform strategies to assist in the prevention or treatment of this highly successful human pathogen. PMID- 23628640 TI - A novel gammaherpesvirus in a large flying fox (Pteropus vampyrus) with blepharitis. AB - A novel gammaherpesvirus was identified in a large flying fox (Pteropus vampyrus) with conjunctivitis, blepharitis, and meibomianitis by nested polymerase chain reaction and sequencing. Polymerase chain reaction amplification and sequencing of 472 base pairs of the DNA-dependent DNA polymerase gene were used to identify a novel herpesvirus. Bayesian and maximum likelihood phylogenetic analyses indicated that the virus is a member of the genus Percavirus in the subfamily Gammaherpesvirinae. Additional research is needed regarding the association of this virus with conjunctivitis and other ocular pathology. This virus may be useful as a biomarker of stress and may be a useful model of virus recrudescence in Pteropus spp. PMID- 23628639 TI - Successful establishment and global dispersal of genotype VI avian paramyxovirus serotype 1 after cross species transmission. AB - The evolutionary history of avian paramyxovirus serotype 1 (PMV1), which includes the agents of Newcastle disease (ND), is characterized by a series of strain emergence events since viruses in this family were first recognized in the 1920s. Despite the importance of ND to the poultry industry, little is known about PMV1 strain emergence events and the subsequent dispersal and evolution of new strains. The genotype VI-PMV1 was first identified in the 1980s and has been named pigeon paramyxovirus-1 (PPMV1) because of unusual host specificity with Columbiformes (Collins et al., 1996); it has been responsible for panzootics in both chickens and pigeons during that time. Here, we used evolutionary analyses to characterize the emergence of this contemporary PMV1 lineage. We demonstrate that GVI-PMV1 arose through cross-species transmission events from Galliformes (i.e. chicken) to Columbiformes, and quickly established in pigeon populations. Our studies revealed a close association between the time of viral emergence and panzootic events of this virus. The virus appeared first in Southeastern Europe and quickly spread across the European continent, which became the epicenter for global virus dissemination. With new viral gene sequences, we show that GVI-PMV1 viruses currently circulating in North America resulted from multiple invasion events from Europe, one associated with an exotic European Columbiformes species, and that extant lineages have diversified locally. This study extends our understanding of successful viral emergence subsequent to cross-species transmission and dispersal patterns of newly emerged avian viruses, which may improve surveillance awareness and disease control of this and other important avian pathogens. PMID- 23628641 TI - Enzyme-linked immunosorbent assay using a crude antigen extract to measure Cuterebra-specific immunoglobulin G in sera of cats with systemic infections. AB - In cats, larvae of the dipteran fly, Cuterebra, sometimes cause severe disease by their migration through the tissues of the larynx, pharynx, nasal sinuses, brain, and spinal cord; such infected cats may die without the maggots ever reaching the subcutaneous tissues where they would typically mature. The current study examines the ability of an indirect enzyme-linked immunosorbent assay (ELISA) using crude Cuterebra antigen from maggots to detect parasite-specific immunoglobulin (Ig)G in cats with known (n = 42), suspected (n = 25), or no known exposure to the infection (n = 68). The probability of a given optical density (OD) predicting the infection status of a given animal was determined using logistic regression, and both 1:20 and 1:80 serum dilutions were highly predictive of the potential of a cat being infected with a larval Cuterebra. In 5 cases where 2 samples were collected 1-2 weeks apart, there was a mean OD increase in the second sample for both the 1:20 and 1:80 dilutions, but it was significant (P = 0.044) only at the 1:20 dilution. Sex of the sampled cat was not a significant contributor to the ability of the OD to predict the presence of a larva, but the age of the cat added significantly to the predictive value of the generated curves, with the only exception being with the 1:20 serum dilution with the curve being generated only using the cats known to be positive for larval presence. This ELISA should aid in ruling cuterebriasis in or out in suspect systemic and, specifically, neurologic cases and provide information on kinetics of antibody presence postexposure. PMID- 23628642 TI - Post-cryopreservation viability of the benthic freshwater diatom Planothidium frequentissimum depends on light levels. AB - Over recent years, several planktonic and benthic freshwater diatom taxa have been established as laboratory model strains. In common with most freshwater diatoms the pennate diatom Planothidium frequentissimum suffers irreversible cell shrinkage on prolonged maintenance by serial transfers, without induction of the sexual cycle. Therefore, alternative strategies are required for the long-term maintenance of this strain. Conventional colligative cryopreservation approaches have previously proven unsuccessful with no regrowth. However, in this study using 5% dimethyl sulfoxide (Me2SO), controlled cooling at 1 degrees C min(-1), automated ice seeding and cooling to -40 degrees C with a final plunge into liquid nitrogen, viability levels were enhanced from 0.3 +/- 0.4% to 80 +/- 3%, by incorporating a 48 h dark-recovery phase after rewarming. Omission, or reduction, of this recovery step resulted in obvious cell damage with photo bleaching of pigments, indicative of oxidative-stress induced cell damage, with subsequent deterioration of cellular architecture. PMID- 23628644 TI - Increased cortical surface area of the left planum temporale in musicians facilitates the categorization of phonetic and temporal speech sounds. AB - We measured musicians and non-musicians by using structural magnetic resonance imaging to investigate relationships between cortical features of the left planum temporale (PT) and the categorization of consonant-vowel (CV) syllables and their reduced-spectrum analogues. The present work is based on previous functional studies consistently showing that the left PT is particularly responsive to transient acoustic features in CV syllables and their reduced-spectrum analogues, and on striking evidence pointing to structural alterations of the left PT as a function of musicianship. By combining these two observations, we hypothesized to find that differences in cortical surface area (SA) and cortical thickness (CT) of the left PT in musicians may facilitate the categorization of fast-changing phonetic cues. Behavioural results indicated that musicians and non-musicians achieved a comparable performance in the categorization of CV syllables, whereas the musicians performed significantly better than the controls in the more demanding reduced-spectrum condition. This better behavioural performance corresponds to an increased cortical SA of the left PT in musicians compared to non-musicians. No differences in CT of the left PT were found between groups. In line with our predictions, we revealed a positive correlation between cortical SA of the left PT in musicians and the behavioural performance during the acoustically more demanding reduced-spectrum condition. Hence, we provide first evidence for a relationship between musical expertise, cortical SA of the left PT, and the processing of fast-changing phonetic cues. PMID- 23628643 TI - Unique features of chicken Toll-like receptors. AB - Toll-like receptors (TLRs) are a major class of innate immune pattern recognition receptors that have a key role in immune homeostasis and the defense against infections. The research explosion that followed the discovery of TLRs more than a decade ago has boosted fundamental knowledge on the function of the immune system and the resistance against disease, providing a rational for clinical modulation of the immune response. In addition, the conserved nature of the ancient TLR system throughout the animal kingdom has enabled a comparative biology approach to understand the evolution, structural architecture, and function of TLRs. In the present review we focus on TLR biology in the avian species, and, especially, on the unique functional properties of the chicken TLR repertoire. PMID- 23628645 TI - A novel insight into Gene Ontology semantic similarity. AB - Existing methods for computing the semantic similarity between Gene Ontology (GO) terms are often based on external datasets and, therefore are not intrinsic to GO. Furthermore, they not only fail to handle identical annotations but also show a strong bias toward well-annotated proteins when being used for measuring similarity of proteins. Inspired by the concept of cellular differentiation and dedifferentiation in developmental biology, we propose a shortest semantic differentiation distance (SSDD) based on the concept of semantic totipotency to measure the semantic similarity of GO terms and further compare the functional similarity of proteins. Using human ratings and a benchmark dataset, SSDD was found to improve upon existing methods for computing the semantic similarity of GO terms. An in-depth analysis shows that SSDD is able to distinguish identical annotations and does not depend on annotation richness, thus producing more unbiased and reliable results. Online services can be accessed at the Gene Functional Similarity Analysis Tools website (GFSAT: http://nclab.hit.edu.cn/GFSAT). PMID- 23628646 TI - Putative drug and vaccine target protein identification using comparative genomic analysis of KEGG annotated metabolic pathways of Mycoplasma hyopneumoniae. AB - In the present study, a computational comparative and subtractive genomic/proteomic analysis aimed at the identification of putative therapeutic target and vaccine candidate proteins from Kyoto Encyclopedia of Genes and Genomes (KEGG) annotated metabolic pathways of Mycoplasma hyopneumoniae was performed for drug design and vaccine production pipelines against M.hyopneumoniae. The employed comparative genomic and metabolic pathway analysis with a predefined computational systemic workflow extracted a total of 41 annotated metabolic pathways from KEGG among which five were unique to M. hyopneumoniae. A total of 234 proteins were identified to be involved in these metabolic pathways. Although 125 non homologous and predicted essential proteins were found from the total that could serve as potential drug targets and vaccine candidates, additional prioritizing parameters characterize 21 proteins as vaccine candidate while druggability of each of the identified proteins evaluated by the DrugBank database prioritized 42 proteins suitable for drug targets. PMID- 23628647 TI - Does the preparation and utilization of 99mTc-sulfur colloid affect the outcomes of breast lymphoscintigraphy? AB - The purpose of this study was to determine whether certain factors in the preparation and use of (99m)Tc-sulfur colloid affected the number of sentinel lymph nodes (SLNs) detected during SLN mapping and during intraoperative SLN identification. The factors that were investigated included the use of a dry heat block versus a hot water bath to heat the (99m)Tc-sulfur colloid bulk vial, amount of (99m)TcOH4(-) added to form the sulfur colloid particles, time between the unit dose calibration and the injection of the dose, and breast quadrant in which the injection occurred. METHODS: Data were collected retrospectively and quantitatively analyzed from images and reports of 488 patients with breast cancer who had undergone SLN mapping and intraoperative SLN identification from January 1, 2008, to June 30, 2011, inclusive. The dependent variables assessed were the number of SLNs visualized during lymphoscintigraphy, number of radioactive SLNs removed during surgery, and total number of lymph nodes removed intraoperatively. RESULTS: There was no significant difference in outcomes when comparing the amount of (99m)TcOH4(-) added during the preparation process to form the sulfur colloid particles, time between the unit dose calibration time and the time that the unit doses were injected, or location in the breast tissue in which the unit dose was administered. Initially, there were observed significant differences in outcomes when the heating methods used to prepare the (99m)Tc-sulfur colloid were compared. When the increased number of patients who were administered a calibrated unit dose activity of 74 MBq in the group using a dry heat block preparation method was taken into account, however, the findings were not significant. CONCLUSION: The use of a dry heat block versus a hot water bath to heat the (99m)Tc-sulfur colloid bulk vial, amount of (99m)TcOH4(-) added to form sulfur colloid particles, time between the unit dose calibration and the injection of the dose, and breast quadrant in which the injection occurred do not affect the number of SLNs detected during SLN mapping and during intraoperative SLN identification. PMID- 23628648 TI - Spin polarized low energy electron microscopy of quantum well resonances in Fe films on the Cu-covered W(110) surface. AB - Spin polarized low energy electron microscopy has been used to investigate the quantum size effect (QSE) in electron reflectivity from Fe films grown on a pseudomorphic Cu layer on a W(110) surface. Intensity oscillations caused by the QSE as functions of Fe film thickness and incident electron energy identify quantum well resonance conditions in the film. Evaluation of these intensity oscillations using the phase accumulation model provides information on the unoccupied spin polarized band structure in the Fe film above the vacuum level. We also find evidence that the presence of the non-magnetic Cu layer shifts spin polarized quantum well resonances in the Fe layer uniformly downward in energy by 1.1eV compared to Fe/W(110) films without an interface Cu layer, suggesting that the Cu layer gives a small degree of control over the quantum well resonances. PMID- 23628649 TI - A modified technique for implantation of the HeartWareTM left ventricular assist device when using bivalirudin anticoagulation in patients with acute heparin induced thrombocytopenia. AB - In patients with acute heparin-induced thrombocytopenia (HIT) needing urgent cardiac surgery, bivalirudin is recommended as a first-line strategy for intraoperative anticoagulation. However, due to the unique elimination process of bivalirudin, careful adjustment of the perfusion and surgical strategy is mandatory as blood stasis in the circuit or prolonged interruption of areas or compartments containing blood from the systemic circulation may result in thrombus formation. We report here a modified surgical strategy for the implantation of the HeartWareTM left ventricular assist device, which avoids prolonged disconnection of the blood-filled device from the systemic blood flow, so that bivalirudin can be safely used as anticoagulant. PMID- 23628650 TI - Pure bronchoplastic resections of the bronchus without pulmonary resection for endobronchial carcinoid tumours. AB - OBJECTIVES: Bronchopulmonary carcinoid tumours are relatively uncommon primary lung neoplasms. A small proportion of these lesions are predominantly endobronchial and do not extend beyond the bronchial wall. Endoscopic resection can be performed, but carries around a one in three risk of local recurrence and, therefore, mandates long-term surveillance. An alternative is complete surgical resection via bronchoplastic resection. We present our experience of surgical resection in patients with endobronchial carcinoids. METHODS: From 2000 to 2010, 13 patients (age 45+/-16 years, 10 males) underwent pure bronchoplastic resection, including systematic nodal dissection, for endobronchial carcinoid tumours, without the resection of lung parenchyma. RESULTS: There was no significant operative morbidity or mortality. This is a retrospective review of a consecutive case series. The last follow-up for all patients was obtained in 2011. The mean maximum tumour size was 18+/-8 mm. No lymph node invasion was observed. The median follow-up was 6.3+/-3.3 years, with no regional recurrence. In 1 case, a tumourlet was identified at 5 years in the contralateral airway and viewed as a metachronous new lesion. CONCLUSIONS: Bronchial sleeve resection is a safe procedure for suitably located endobronchial carcinoid tumours. Endoscopic resection should be reserved for patients who decline, or are unfit, for surgery. PMID- 23628651 TI - Cardiac surgery in nonagenarians: not only feasible, but also reasonable? AB - OBJECTIVES: Changes in the age profile of the population in the western world and improvement in surgical techniques and postoperative care have contributed to a growing number of cardiosurgical patients aged over 90. In periods when transapical and transfemoral aortic valve replacement were done, we aimed at evaluating the outcome of nonagenarians after conventional aortic valve replacement and cardiac surgery in general, and determining perioperative parameters to predict a complicated postoperative course. METHODS: Between 1995 and 2011, 49 nonagenarians (aged 91.2+/-3.1 years) underwent cardiac surgery. A subgroup of 30 patients received aortic valve replacement alone (63%; n=19), in combination with coronary artery bypass grafting (27%; n=8) or other surgical procedures (10%; n=3). Most of the patients suffered from combined aortic valve disease with a mean valve orifice area of 0.6+/-0.3 cm2 and a mean antegrade pressure gradient of 86+/-22 mmHg. RESULTS: Cardiac surgery in nonagenarians resulted in remarkable postoperative morbidity and an overall in-hospital mortality of 10% (n=5). In the AVR subgroup, biological valve prostheses were implanted in 29 patients. In this subgroup, the length of stay was 2.9+/-0.9 days in the intensive care unit and 17.0+/-5.5 days in the hospital. The in-hospital mortality amounted to 13% (n=4). Although several general preoperative risk factors of postoperative complications such as renal failure, low cardiac output syndrome and New York Heart Association Class IV were remarkably more frequent among the patients who died after the operation, the small cohort of non surviving nonagenarians did not allow for significant differences. CONCLUSIONS: Cardiac surgery in the very elderly, particularly with regard to aortic valve replacement, carries a high risk of early morbidity and mortality. However, in selected nonagenarians, surgery can be performed with an acceptable outcome. The risk may even be reduced by an individual approach to the procedure. With regard to potential risk factors, the selection of these patients should be carried out very carefully. PMID- 23628652 TI - A multicentre Spanish study for multivariate prediction of perioperative in hospital cerebrovascular accident after coronary bypass surgery: the PACK2 score. AB - OBJECTIVES: To develop a multivariate predictive risk score of perioperative in hospital stroke after coronary artery bypass grafting (CABG) surgery. METHOD: A total of 26 347 patients were enrolled from 21 Spanish hospital databases. Logistic regression analysis was used to predict the risk of perioperative stroke (ictus or transient ischaemic attack). The predictive scale was developed from a training set of data and validated by an independent test set, both selected randomly. The assessment of the accuracy of prediction was related to the area under the ROC curve. The variables considered were: preoperative (age, gender, diabetes mellitus, arterial hypertension, previous stroke, cardiac failure and/or left ventricular ejection fraction<40%, non-elective priority of surgery, extracardiac arteriopathy, chronic kidney failure and/or creatininemia>=2 mg/dl and atrial fibrillation) and intraoperative (on/off-pump). RESULTS: Global perioperative stroke incidence was 1.38%. Non-elective priority of surgery (priority; OR=2.32), vascular disease (arteriopathy; OR=1.37), cardiac failure (cardiac; OR=3.64) and chronic kidney failure (kidney; OR=6.78) were found to be independent risk factors for perioperative stroke in uni- and multivariate models in the training set of data; P<0.0001; AUC=0.77, 95% CI 0.73-0.82. The PACK2 stroke CABG score was established with 1 point for each item, except for chronic kidney failure with 2 points (range 0-5 points); AUC=0.76, 95% CI 0.72-0.80. In patients with PACK2 score>=2 points, off-pump reduced perioperative stoke incidence by 2.3% when compared with on-pump CABG. CONCLUSIONS: PACK2 risk scale shows good predictive accuracy in the data analysed and could be useful in clinical practice for decision making and patient selection. PMID- 23628653 TI - Dissection of the pulmonary ligament during upper lobectomy: is it necessary? AB - A best evidence topic was written according to a structured protocol. The question addressed was whether dissection of the pulmonary ligament during an upper lobectomy would result in improved outcomes. A total of 85 articles were found using the reported search, of which eight represented the best evidence to answer the clinical question. The authors, date, journal, study type, population, main outcome measures and results are tabulated. Reported measures were complications associated with dissection (atelectasis, bronchial stenosis, bronchial obstruction and bronchial deformation) and preservation (insufficient lung expansion, pooling of effusion and atelectasis) of the pulmonary ligament, ratio (%) of dead space in longitudinal axis (movement of nonoperated lobes), change in the angle (degrees) of main bronchus on the operated side, overall morbidity and mortality, overall survival and conversion rates. In a randomized control trial, the dissection of the pulmonary ligament revealed no significant difference in the dead space ratio or change in the angle of the main bronchus when compared with preservation. Dissection of the ligament, in theory, reduces the free space in the upper thorax by increasing the mobility of the residual lobes. Dissection of the ligament may lead to bronchial deformation, stenosis, obstruction or lobar torsion. Preservation of the ligament may prevent this complication by suppressing the upward movement of residual lobes. However, this may result in pleural effusion in the free thoracic space that may potentially become infected resulting in an empyema or bronchial fistula. Five large case series were analysed; three routinely dissected the pulmonary ligament and two did not. There was no observed difference in clinical outcomes between the two groups. There is no convincing evidence that dissection of the pulmonary ligament in an upper lobectomy significantly improves outcomes and reduces complications. PMID- 23628654 TI - Preoperative statin therapy is associated with lower requirement of renal replacement therapy in patients undergoing cardiac surgery: a meta-analysis of observational studies. AB - OBJECTIVES: Acute kidney injury (AKI) following cardiac surgery is a common complication associated with serious morbidity and mortality. Activation of inflammatory cascade and vascular endothelial dysfunction plays a vital role during the perioperative period leading to AKI. Statins are known to suppress inflammation and improve endothelial dysfunction over and above the cholesterol lowering efficacy. METHODS: Observational studies with a defined population in terms of preoperative statin therapy and no preoperative statin therapy undergoing cardiac surgery (CABG, isolated valve surgery or both) and with reported data on the incidence of acute renal failure/injury and/or mortality were identified and analysed for inclusion in the analysis. Outcomes evaluated were occurrence of postoperative acute kidney injury/failure, requirement of any postoperative renal replacement therapy and short-term all-cause mortality rate. A meta-analysis was conducted and a pooled estimate of odds ratio (OR) was calculated using the inverse variance method. RESULTS: A total of 17 studies with a total population of 24 998 statin users and 22 082 non-statin users were included in the final analysis. PST resulted in a significantly lower incidence of renal replacement therapy in patients undergoing CABG (OR: 0.56 [0.41-0.76]) but not in isolated valve surgery (OR: 1.80 [0.73-4.44]). Also preoperative statin therapy resulted in a significantly lower postoperative mortality (0.72 [0.61-0.84]) irrespective of the type of surgery. There was no effect of preoperative statin therapy on the incidence of AKI in any of the sub-group of the patients. CONCLUSIONS: Patients undergoing CABG might derive benefit from preoperative statin therapy in terms of reducing the need for postoperative renal replacement therapy and mortality. However, the uncertainty concerning the reno protective efficacy of preoperative statin therapy in patients undergoing isolated valve surgery needs further investigation. PMID- 23628655 TI - Tricuspid atresia with aortopulmonary window: challenges in achieving a balanced circulation. AB - Tricuspid atresia and aortopulmonary window are rare congenital cardiac anomalies. The occurrence of both these anomalies in the same patient is extremely rare, with only 1 case reported in the literature. We report the surgical management of one such patient and discuss the management issues with respect to Stage 1 single ventricle palliation. PMID- 23628656 TI - Time-dependent changes of calbindin D-28K and parvalbumin immunoreactivity in the hippocampus of rats with streptozotocin-induced type 1 diabetes. AB - The hippocampus is affected by various stimuli that include hyperglycemia, depression, and ischemia. Calcium-binding proteins (CaBPs) have protective roles in the response to such stimuli. However, little is known about the expression of CaBPs under diabetic conditions. This study was conducted to examine alterations in the physiological parameters with type 1 diabetes induced with streptozotocin (STZ) as well as time-dependent changes in the expression of two CaBPs changes of were being evaluated. Rats treated with STZ (70 mg/kg) had high blood glucose levels (> 21.4 mmol/L) along with increased food intake and water consumption volumes compared to the sham controls. In contrast, body weight of the animals treated with STZ was significantly reduced compared to the sham group. CB specific immunoreactivity was generally increased in the hippocampal CA1 region and granule cell layer of the dentate gyrus (DG) 2 weeks after STZ treatment, but decreased thereafter in these regions. In contrast, the number of PV immunoreactive neurons and fibers was unchanged in the hippocampus and DG 2 weeks after STZ treatment. However, this number subsequently decreased over time. These results suggest that CB and PV expression is lowest 3 weeks after STZ administration, and these deficits lead to disturbances in calcium homeostasis. PMID- 23628657 TI - Evaluation of a canine small intestinal submucosal xenograft and polypropylene mesh as bioscaffolds in an abdominal full-thickness resection model of growing rats. AB - We evaluated the biological scaffold properties of canine small intestinal submucosa (SIS) compared to a those of polypropylene mesh in growing rats with full-thickness abdominal defects. SIS is used to repair musculoskeletal tissue while promoting cell migration and supporting tissue regeneration. Polypropylene mesh is a non-resorbable synthetic material that can endure mechanical tension. Canine SIS was obtained from donor German shepherds, and its porous collagen fiber structure was identified using scanning electron microscopy (SEM). A 2.50 cm(2) section of canine SIS (SIS group) or mesh (mesh group) was implanted in Sprague-Dawley rats. At 1, 2, 4, 12, and 24 weeks after surgery, the implants were histopathologically examined and tensile load was tested. One month after surgery, CD68+ macrophage numbers in the SIS group were increased, but the number of CD8+ T cells in this group declined more rapidly than that in rats treated with the mesh. In the SIS group, few adhesions and well-developed autologous abdominal muscle infiltration into the SIS collagen fibers were observed. No significant differences in the tensile load test results were found between the SIS and mesh groups at 24 weeks. Canine SIS may therefore be a suitable replacement for artificial biological scaffolds in small animals. PMID- 23628658 TI - Genetic diversity of porcine reproductive and respiratory syndrome virus in Korea. AB - The high genetic diversity of porcine reproductive and respiratory syndrome virus (PRRSV) has been an obstacle to developing an effective vaccine for porcine reproductive and respiratory syndrome (PRRS). This study was performed to assess the degree of genetic diversity among PRRSVs from Korean pig farms where wasting and respiratory syndrome was observed from 2005 to 2009. Samples from 786 farms were tested for the presence of PRRSV using reverse transcription PCR protocol. A total of 117 farms were positive for type 1 PRRSV while 198 farms were positive for type 2. Nucleotide sequences encoding the open reading frame (ORF) 5 were analyzed and compared to those of various published PRRSV isolates obtained worldwide. Sequence identity of the ORF 5 in the isolates was 81.6~100% for type 1 viruses and 81.4~100% for type 2 viruses. Phylogenetic analysis of the ORF 5 sequences showed that types 1 and 2 PRRSVs from Korea were mainly classified into three and four clusters, respectively. The analyzed isolates were distributed throughout the clusters independent of the isolation year or geographical origin. In conclusion, our results indicated that the genetic diversity of PRRSVs from Korean pig farms is high and has been increasing over time. PMID- 23628659 TI - In vitro effects of meloxicam on the number, Foxp3 expression, production of selected cytokines, and apoptosis of bovine CD25+CD4+ and CD25-CD4+ cells. AB - The purpose of this study was to evaluate the effect of meloxicam (MEL) on selected immune parameters of bovine CD25(high)CD4+, CD25(low)CD4+, and CD25-CD4+ cells. Peripheral blood mononuclear cells (PBMCs) collected from 12-month-old heifers were treated with MEL at a concentration corresponding to the serum level of this medication following administration at the recommended dose (MEL 5 * 10( 6) M) and at a concentration 10 times lower (MEL 5 * 10(-7) M). After 12 and 24 h of incubation with the drug, the percentage of CD25(high)CD4+ cells decreased; however, this disturbance was quickly reversed. Furthermore, the absolute number of CD25(high)CD4+ cells in the PBMC populations treated with MEL 5 * 10(-6) M for 48 and 168 h was increased. Prolonged (168 h) exposure to the drug increased the percentage of Foxp3+ cells in the CD25(high)CD4+ cell subpopulation. The higher dose of MEL was found to significantly increase the percentage of IFN-gamma+ cells among the CD25-CD4+ cells. These results indicated that MEL does not exert an immunosuppressive effect by depleting CD4+ cells and suppression of IFN-gamma+ production by these cells. Furthermore, IL-10 and TGF-beta production was not changed following exposure to MEL. PMID- 23628660 TI - Comparison between two progesterone sources and two oestradiol formulations in a Heatsynch protocol for postpartum cycling dairy cows in pasture. AB - To compare an injectable progesterone (MAD-4) with an intravaginal device (IPD), and natural O17 with synthetic oestradiol (OB) in a synchronisation protocol, 51 cows were divided into four groups. Each group was treated with one of the two sources of progesterone and one of the two oestradiol formulations. Oestrus behaviour, follicle diameter, and pregnancy rates were evaluated. Oestrus behaviour (p = 0.902), numbers of cows in oestrus (p = 0.917), follicle diameter (p = 0.416), and pregnancy rates (p = 0.873) were similar among the four groups. More cows in the group treated with the IPD and OB scored > 200 oestrus behaviour points compared to the other groups (p = 0.038). A longer interval between the end of treatment and oestrus was observed among cows treated with MAD-4 than cows given the IPD (p = 0.030), but no differences were found between animals receiving the two oestradiol formulations (OB and O17). While the use of MAD-4 requires further testing, similar responses to natural oestradiol observed in the present study could allow the use of this formulation in reproductive protocols because it is not associated with the potential human health risks of OB. PMID- 23628661 TI - The abilities of selenium dioxide and selenite ion to coordinate DNA-bound metal ions and decrease oxidative DNA damage. AB - Several transition metals react with H2O2 and produce reactive oxygen species (ROS) responsible for oxidative damage linked to many diseases and disorders, and species that form coordination complexes with these metal ions show promise as antioxidants. The present study demonstrates that metal-mediated radical and non radical oxidative DNA damage decreases when selenium dioxide (SeO2) and sodium selenite (Na2SeO3) are present. Radical-induced damage is associated with production of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), which arises from ROS generated at or near the guanine base, and the selenium compounds reduce Fe(II)-, Cr(III)- and Cu(II)-mediated radical damage to differing degrees based on the identity of the metal ion and the order in which the metals, selenium compounds and DNA are combined. Radical damage arising from Fe(II) and Cr(III) decreases substantially when they are pre-incubated with the selenium compounds prior to adding DNA. Non-radical damage is associated with oxidation of the adenine base in the presence of high H2O2 concentrations through an ionic mechanism, and this type of damage also decreases significantly when the selenium compounds are allowed to interact with the metal ions before adding DNA. Fluorescence studies using dihydrodichlorofluorescein diacetate (DCF-DA) to probe ROS formation indicate that the majority of the SeO2- and SeO3(2-)-metal systems in combination with H2O2 (no DNA present) produce ROS to the same degree as the metal/H2O2 systems in the absence of the selenium compounds, suggesting that selenium-metal complexes react with H2O2 in a sacrificial manner that protects DNA from oxidative damage. PMID- 23628662 TI - Measuring orthopaedic outcome: shoulder outcome measures. PMID- 23628663 TI - Validating a global rating scale to monitor individual resident learning curves during arthroscopic knee meniscal repair. AB - PURPOSE: To determine whether a global rating scale (GRS) with construct validity can also be used to assess the learning curve of individual orthopaedic trainees during simulated arthroscopic knee meniscal repair. METHODS: An established arthroscopic GRS was used to evaluate the technical skill of 19 orthopaedic residents performing a standardized arthroscopic meniscal repair in a bioskills laboratory. The residents had diagnostic knee arthroscopy experience but no experience with arthroscopic meniscal repair. Residents were videotaped performing an arthroscopic meniscal repair on 12 separate occasions. Their performance was assessed by use of the GRS and motion analysis objectively measuring the time taken to complete tasks, path length of the subject's hands, and number of hand movements. One author assessed all 228 videos, whereas 2 other authors rated 34 randomly selected videos, testing the interobserver reliability of the GRS. The validity of the GRS was tested against the motion analysis. RESULTS: Objective assessment with motion analysis defined the surgeon's learning curve, showing significant improvement by each subject over 12 episodes (P < .0001). The GRS also showed a similar learning curve with significant improvements in performance (P < .0001). The median GRS score improved from 15 of 34 (interquartile range, 14 to 17) at baseline to 22 of 34 (interquartile range, 19 to 23) in the final period. There was a moderate correlation (P < .0001, Spearman test) between the GRS and motion analysis parameters (r = -0.58 for time, r = -0.58 for path length, and r = -0.51 for hand movements). The inter rater reliability among 3 trained assessors using the GRS was excellent (Cronbach alpha = 0.88). CONCLUSIONS: When compared with motion analysis, an established arthroscopic GRS, with construct validity, also offers a moderately feasible method to monitor the learning curve of individual residents during simulated knee meniscal repair. CLINICAL RELEVANCE: An arthroscopic GRS can be used for monitoring skill improvement during knee meniscal repair and has the potential for use as a training and assessment tool in the real operating room. PMID- 23628664 TI - The agenda development process of the United States' National Action Alliance for Suicide Prevention Research Prioritization Task Force. PMID- 23628665 TI - The WHO START study: suicidal behaviors across different areas of the world. AB - BACKGROUND: The World Health Organization (WHO) study entitled Suicide Trends in At-Risk Territories (START) is an international multisite initiative that aims to stimulate suicide research and prevention across different areas of the globe. A central component of the study is the development of registration systems for fatal and nonfatal suicidal behaviors. AIMS: This paper provides an overview of the data collected on suicidal behaviors from the participating locations in the START study. METHOD: Descriptive statistics on the data are presented in terms of age, sex, and method. RESULTS: A greater proportion of suicide deaths occurred among males. In all areas except the Philippines more females than males engaged in nonfatal suicidal behaviors. Compared to Australia, Italy, New Zealand, the Philippines, and Hong Kong SAR, in the Pacific Islands suicide most often occurs in younger age groups. Results indicate notable variations between countries in choice of method. A greater proportion of suicides occurred by hanging in Pacific Islands, while inhalation of carbon monoxide, use of firearms, ingestion of chemicals and poisons, and drug overdose were the most frequent methods of choice in other areas. CONCLUSION: The information drawn from this study demonstrates the enormous variation in suicidal behavior across the areas involved in the START Study. Further research is needed to assess the reliability of the established data-recording systems for suicidal behaviors. The baseline data established in START may allow the development of suicide prevention initiatives sensitive to variation in the profile of suicide across different locations. PMID- 23628668 TI - Auditory stimuli from a sensor glove model modulate cortical audiotactile integration. AB - The purpose of this study was to shed light on cortical audiotactile integration and sensory substitution mechanisms, thought to serve as a basis for the use of a sensor glove in the preservation of the cortical map of the hand after peripheral nerve injuries. Fourteen subjects were selected and randomly assigned either to a training group, trained to replace touch for hearing with the use of a sensor glove, or to a control group, untrained. Training group volunteers had to identify textures just by the sound. In an fMRI experiment, all subjects received three types of stimuli: tactile only, combined audiotactile stimulation, and auditory only. Results indicate that, for trained subjects, a coupling between auditory and somatosensory cortical areas is established through associative areas. Differences in signal correlation between groups point to a pairing mechanism, which, at first, connects functionally the primary auditory and sensory areas (trained subjects). Later, this connection seems to be mediated by associative areas. The training with the sensor glove influences cortical audiotactile integration mechanisms, determining BOLD signal changes in the somatosensory area during auditory stimulation. PMID- 23628669 TI - Decreased coherence between the two olfactory bulbs in Alzheimer's disease model mice. AB - Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by cell and synapse losses and the ensued network disconnections. Olfactory impairment is common and occurs early in AD patients, suggesting its potential role in the early diagnosis of AD. However, the functional connectivity of the olfactory system in AD has received little attention. Using local field potentials symmetrically recorded from the two olfactory bulbs in awake mice, we found that in AD model mice with robust amyloid-beta burden, the coherence between the two bulbs for spontaneous activities was significantly lower in all of the four frequency bands (theta, beta, low and high gamma: 2-12, 15-35, 35-65 and 65-100 Hz, respectively). Moreover, the coherence for odor-evoked activities was also lower, particularly in the beta band, when compared to their wild-type littermates. These results demonstrate that the inter-bulbar functional connectivity is impaired in AD mice, indicating a failure of brain activation in beta-related functions, which might be of importance in the diagnosis of AD. PMID- 23628670 TI - Lateralization of activity in the parietal cortex predicts the effectiveness of bilateral transcranial direct current stimulation on performance of a mental calculation task. AB - Transcranial direct current stimulation (tDCS) is a non-invasive technique that moderates cognitive and motor function. The effects of tDCS on cognitive and motor tasks vary among individuals. However, the source of the inter-individual variability remains unknown. The purpose of the present study was to examine whether the effect of bilateral tDCS on the performance of mental calculations differs among individuals according to the functional lateralization of parietal activity observed during a mental calculation task. Sixteen healthy subjects (11 males and five females, aged 20-23 years) participated. Laterality of parietal activity during a mental calculation task was evaluated using functional magnetic resonance imaging. Subjects also performed the mental calculation task pre-, during-, 30 min post-, and 60 min post-tDCS. Bilateral tDCS with the anode over the left parietal cortex and the cathode over the right parietal cortex shortened response times of the mental calculation task in subjects with left-hemispheric parietal lateralization, but not in subjects with bilateral parietal activation. This indicates that inter-individual variability in laterality of brain activity might be an important factor underlying the effect of bilateral tDCS. In conclusion, bilateral tDCS over the parietal cortex enhanced the performance of mental calculations in subjects with left-hemispheric parietal lateralization. PMID- 23628673 TI - The role of heavy-light-hole mixing on the optical initialization of hole spin in InAs quantum dots. AB - The initialization of a resident hole spin by the absorption of a circularly polarized light at resonance involves the formation of an excited state called a trion state. For a pure heavy hole, this optical initialization is mediated by the hyperfine electron-nuclear coupling in the trion state. We show here that for a mixed-hole spin an additional mechanism for the optical initialization appears, associated to 'crossed transitions'; it becomes dominant and keeps a high level of hole spin polarization when the magnetic field screens the electron-nuclear interaction. Finally, using a simple model, we obtain a good theoretical agreement with pulsed pump-probe experiments. PMID- 23628671 TI - Enhanced excitability of guinea pig ileum myenteric AH neurons during and following recovery from chemical colitis. AB - Inflammation of the colon changes motor function of more proximal regions of the gastrointestinal tract. Colitis alters the neurophysiology of enteric neurons within the region of inflammation, which may contribute to altered colonic motor and secretory function. This study seeks to test the hypothesis that colitis alters the neurophysiology of myenteric neurons in the non-inflamed ileum, and that altered neurophysiology coincides with altered small bowel motor function. Trinitrobenzene sulfonic acid (TNBS)-induced colitis was associated with hyperexcitability of AH neurons in the ileum myenteric plexus, demonstrated by depolarized neurons and increased numbers of action potentials, but without changes in the action potential duration or afterhyperpolarization typical of plasticity in these cells. There were no changes in synaptic transmission of either AH neurons or S neurons observed in the current study. The onset of AH neuron hyperexcitability occurred 24 h following administration of TNBS, and persisted to eight weeks, a time point following the resolution of colitis. Small bowel transit was reduced as early as 12 h after TNBS and resolved by 48 h after TNBS. While AH neurons play a central role in coordinating motor function of the ileum, changes in excitability of these neurons did not coincide with changes in small bowel transit. PMID- 23628672 TI - A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. AB - Mdivi-1 is a selective inhibitor of a mitochondrial fission protein Drp1. Recent studies demonstrated that inhibition of Drp1 provides neuroprotection in vitro and in vivo. In this study, we examined the role of mdivi-1 in hippocampal neuron death after seizures induced by pilocarpine. Our data showed that pretreatment with mdivi-1 (1.25 mg/kg) significantly attenuated the neuronal death in hippocampus induced by seizures. This neuroprotective effect was dose-dependent. In addition, the seizures resulted in up-regulation of Drp1 expression and mdivi 1 treatment had no effect on the expression. Moreover, we also found that mdivi-1 (1.25 mg/kg) treatment reversed the release of cytochrome c (CytC), translocation of apoptosis-inducing factor (AIF) induced by seizures while inhibiting the activated caspase-3. Altogether, our data suggested that mdivi-1 exerts neuroprotective effects against cell death of hippocampal neurons induced by seizures, and the underlying mechanism may be through inhibiting CytC release, AIF translocation and suppression of the mitochondrial apoptosis pathway. PMID- 23628674 TI - Effects of traditional chinese medicine Wuzhi capsule on pharmacokinetics of tacrolimus in rats. AB - Wuzhi capsule (WZC) is a preparation of an ethanol herbal extract of Schisandra sphenanthera (Nan-Wuweizi), with its main active ingredients that include schisandrin, schizandrol B, schisantherin A, schisanhenol, and deoxyschizandrin. WZC and tacrolimus are often coadministered for the treatment of drug-induced hepatitis in organ transplant recipients in China. Recently, it was reported that WZC could significantly increase the blood concentration of tacrolimus. The purpose of this study was to investigate whether and how WZC affects the pharmacokinetics of tacrolimus in rats. Liquid chromatography-tandem mass spectrometry method was used to determine the plasma concentration of tacrolimus. The results showed that WZC increased the mean plasma concentration of tacrolimus. Compared with administration of tacrolimus alone [maximum plasma concentration (C(max)), 18.87 +/- 10.29 ng/ml; area under the plasma concentration-time curve from time zero to last sampling time (AUC(0->t)), 40.98 +/- 37.07 ng h/ml], a single intragastric administered dose of WZC increased the pharmacokinetic parameters of tacrolimus (C(max), 59.42 +/- 30.32 ng/ml; AUC(0 >t), 239.71 +/- 28.86 ng h/ml) by 5-fold in rat plasma. After pretreatment with WZC for 12 days, there were still significant increases in AUC(0->t) (from 40.98 +/- 37.07 to 89.21 +/- 26.39 ng h/ml; P < 0.05) and C(max) (from 18.87 +/- 10.29 to 43.16 +/- 10.61 ng/ml; P < 0.05) of tacrolimus, compared with oral of tacrolimus alone, suggesting that WZC increased the exposure of tacrolimus by one or more mechanisms. The increase in tacrolimus C(max) by WZC was dose-dependent. The effect of WZC on tacrolimus AUC(0->t) also increased with dose, with a maximal effect observed at 450 mg/kg (825.34 ng h/ml). No further increases in tacrolimus AUC(0->t) were observed at WZC dose above 450 mg/kg. It is suggested that, because of the effect of WZC on the pharmacokinetics of tacrolimus, the herb-drug interaction between WZC and tacrolimus should be taken into consideration in clinical practice. PMID- 23628676 TI - [Fall risk and fracture. The incidence and mechanisms of fractures from falls]. AB - About 10 - 20% of the elderly is falling every year, and 10 percent of them is suffered from fracture. Whether or not the fractures occur from the fall is determined by the bone strength and the load on the bone. The proximal femurs of the elderly fracture due to the load of 2,100 - 4,000N, although the load on the greater trochanter from falls is 5,600 - 8,600N. Thus, the external force from falls is never negligible. Fracture risk varies greatly depending on the conditions such as the muscle tension and the load direction. PMID- 23628675 TI - A common polymorphism of the MCT1 gene and athletic performance. AB - PURPOSE: In red skeletal muscle, monocarboxylate transporter 1 (MCT1) is required for lactate to enter the myocytes for oxidation. The A1470T polymorphism (rs1049434) in the MCT1 gene was shown to be associated with lactate transport rates in human skeletal muscles. The aim of the study was to compare genotype and allele frequencies of the MCT1 gene polymorphism in 323 Russian athletes and 467 nonathletic controls and to investigate the association of the MCT1 gene A1470T polymorphism with maximal oxygen consumption and maximal lactate concentration in rowers (n = 79). METHODS: Genotyping for the A1470T MCT1 polymorphism was performed by PCR-RFLP method. Physiological measurements of 79 Russian rowers of national competitive standard were determined during an incremental test to exhaustion on a rowing ergometer. RESULTS: Frequencies of the A allele (71.8% vs 62.5%, P < .0001) and AA genotype (59.8% vs 39.4%, P < .0001) were significantly higher in endurance-oriented athletes (n = 142) than in the control group. Mean blood lactate concentration was higher in male rowers with the T allele (AT+TT 10.26 +/- 1.89 mmol/L, AA 8.75 +/- 1.69 mmol/L, P = .005). CONCLUSIONS: MCT1 gene A1470T polymorphism is associated with endurance athlete status and blood lactate level after intensive exercise. PMID- 23628677 TI - [Fall risk and fracture. Aging and fall/fracture]. AB - Fall deteriorates QOL and ADL of elderly people, especially when they suffer from hip and vertebral fractures. It is not easy to identify the cause of falling, because falling usually result from multiple factors. Among various potential causes, osteoporosis, osteoarthritis, medication of hypnotic drugs, and environmental factors are important, because they are frequent and can be modifiable. When evaluating fall risks, grasping power, one-leg standing time, timed up&go test, are useful. On the other hand, fall risk index, 22-item self assessment test, is easy and even better in predicting future falls. In the Cochrane systematic review article 2009, exercise such as Tai-Chi, withdrawal of hypnotic drugs, and vitamin D supplementation are shown to prevent falls in community-dwelling elderly. PMID- 23628679 TI - [Fall risk and fracture. Locomotive syndrome and fall]. AB - Locomotive syndrome means a condition at a risk for requiring nursing care due to deteriorated musculoskeletal organs in the middle-aged and older people. Considering that this concept aims to care prevention and that fracture for fall consists of one-tenth of causes for requiring using care, fall prevention should be an important goal of preventing or improving locomotive syndrome. As a matter of fact, locomotion check - a short form for predicting locomotive syndrome- contains items evaluating fall risk, and locomotion training - recommended exercises designated for strengthening muscles of lower extremities and balance - likely to decrease future incidence of falls. Thus, locomotive syndrome seems to be deeply related to prevention of falls as well as care prevention. PMID- 23628678 TI - [Fall risk and fracture. Fall risk assessment]. AB - For the prevention of fall and its associated injuries including various fractures among the elderly, some simple and clinical screening tools for prediction of falls for the community-dwelling elderly have been developed. In Japan, Toba et al. (2005) explored a portable Fall Risk Index (FRI) consisting of 22items for the elderly living in the community. Among these 22 items, selected seven items which were revealed as independent risk factors for previous falls, are also now considered as good predictor for future falls with the sensitivity and specificity of 0.65 and 0.72, respectively. Thus, FRI is considered as useful screening tools to identify high risk elderly people of falls in the community in Japan. PMID- 23628680 TI - [Fall risk and fracture. Falls and fractures in patients with neurological disorders]. AB - Neurological disorders are frequently associated with risk factors for falls, such as gait and balance disorders, deficits of lower extremity strength, sensation and coordination, in addition to cognitive impairments. Patients with various kinds of neurological disorders, including Parkinson's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, peripheral neuropathy, stroke, etc, easily suffer from falls. To prevent falls among such patients, treatments of the underlying neurological diseases and assessments risk factors for falls are most important to cope effectively with these patients. In general, maintenance of the appropriate environment, consideration of the injury prevention, rehabilitation for increasing muscular strength, etc, are useful for the prevention of falls in patients with neurological disorders. PMID- 23628681 TI - [Fall risk and fracture. Drugs that affect the fall or fracture]. AB - The relationship between the fall and types of hypnotics was studied. The incidence of falls on hypnotics was lower in subjects on ultra-short-acting type, such as Myslee tablet (1.6%) than in those on short-acting type (5.0 to 6.8%) drugs. For Myslee tablet, the incidences were similar in the daytime and the nighttime, but for short-acting hypnotics, the incidence was higher in the daytime than in the nighttime, suggesting a persistent diurnal effect. In order to prevent falls, we recommend to physicians prescribe Myslee tablet whenever possible. Afterwards, the number of patients who experienced falls decreased by 40%. The hypnotics was effected the severity of the injury after falling down. The odds ratios of different types of hypnotics to Myslee tablet on severe injury after falling as follows : Depas tablet having the highest odds ratioat 48, Rohypnol tablet coming in second at 38, respectively. PMID- 23628682 TI - [Fall risk and fracture. Vitamin D and falls/fractures]. AB - Vitamin D affects both bone and muscle. Recent meta-analyses of high-quality trials showed that both native vitamin D and active forms of vitamin D3 significantly reduced the risk of vertebral and non-vertebral fractures. These anti-fracture efficacies of vitamin D are considered to be mainly exerted through direct effects on mineral metabolism. In addition, recent evidence suggests that vitamin D significantly prevents falls, to indirectly reduce fall-related fractures. The preventive effect on falls by vitamin D is considered to be exerted through effects on muscle, at least in part. Eldecalcitol, a new active vitamin D3 analogue, increases bone mineral density and shows greater evident anti-fracture efficacy than alfacalcidol. However, its effects in preventing falls remain unclear and warrant clarification. PMID- 23628683 TI - [Fall risk and fracture. Associated factors for falls in patients with inflammatory polyarthritis]. AB - Patients with rheumatoid arthritis (RA) have an increased risk of falls compared to healthy controls. Previous studies reported that the incidence of fractures in RA patients was mainly caused by falls. Some factors including tender and/or swollen joint counts, low levels of physical activity and history of falls are reported to be associated with falls in the patients with RA. Control of disease activity in the patients is essential to reduce the risk of falls and the burden of fracture. Moreover, potential interventions to prevent falls such as osteoporosis therapy and balance training are necessary for the patients. PMID- 23628684 TI - [Fall risk and fracture. Diagnosing sarcopenia and sarcopenic leg to prevent fall and fracture: its difficulty and pit falls]. AB - Diagnosis of sarcopenia is based on the combination of physical-performance assessment and muscle-mass measurement. Physical performance was estimated by gait speed and grip strength. Common measuring procedures for skeletal muscle mass were dual energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA) . Skeletal muscle mass index (SMI) was calculated from following formula ; [SMI (kg/m(2)) = (arm lean mass + leg lean mass) /height(2)] . Sarcopenia and sarcopenic leg are associated with poor body balance, falls, and subsequent fracture. Treatment of sarcopenia may result in successful prevention of fall and fracture for frail elderly. PMID- 23628685 TI - [Fall risk and fracture. The association of physical performance with falls in the elderly]. AB - A longitudinal analysis using a population-based cohort study known as Research on Osteoarthritis/osteoporosis Against Disability (ROAD) clarified the associations of physical performance and bone and joint diseases with falls. A total of 452 men and 896 women were analyzed in the present study (mean age, 63.9 years) . A questionnaire was used to assess the number of falls during the 3-year follow-up. Grip strength, 6-m walking time, and chair stand time were measured at baseline. Knee osteoarthritis (OA) and lumbar spondylosis were defined as Kellgren Lawrence = 3 or 4. Vertebral fracture (VFx) was assessed with the Japanese Society of Bone and Mineral Research criteria. Knee and lower back pain were estimated by an interview. During a 3-year follow-up, 17.4% men and 24.1% women reported at least one fall. Multinomial logistic regression analysis after adjustment for age and BMI showed that a longer 6-m walking time was a risk factor for multiple falls in men and women. Knee pan was also a risk factor for multiple falls in women. Walking time and knee pain may be a simple and quick option for measuring the risk of falling. PMID- 23628686 TI - [Fall risk and fracture. Exercise for fall prevention in the elderly]. AB - On the basis of evidence obtained in previous studies, this paper outlines effective music therapy programs for group instructions and the basic contents of exercise and training that the elderly are able to do at home by themselves in their daily lives to reduce the risk of falls. The contents of effective exercise and training are to take a series of steps as quickly as possible, back and forth and to the right and left, in a standing position in combination with vertical movement in large amplitude for center of gravity. Furthermore, simple movements such as obeying an order of "right face", as well as dynamic movements that mostly involve higher brain functions such as instant thinking and judgment, are more effective. It should be noted that it is not sufficient for instructors to merely demand that the elderly do effective exercise. To prevent falls by the participants and to also obtain comprehensive effects such as satisfaction, amusement, and quality of life (QOL) , it is important to pay appropriate attention to parts other than the narrowly-defined evidence elements, such as modifications to maintain compliance and consideration of people with locomotive syndrome. PMID- 23628687 TI - [Fall risk and fracture. Falls in patients with dementia]. AB - The fall risk has 3.6 fold in Dementia with Lewy Bodies (DLB) and 16 fold post faller syndrome among diseases to cause dementia, and it was reported that have a significant parkinsonism and a fall more. DLB has multiple symptoms such as that physical symptom, rather than worsening a symptom by characteristics of high sensibility medical intervention for medication, and has severe problem falls. It was indicated that make a decrease a fall risk for restored cognitive function with executive function in the elderly peoples. Thus, improve the quality of care and the establishment of non - pharmacological therapies, for it is important to further therapeutic exercise as prevention is required cooperation and sharing information across professions. PMID- 23628688 TI - [Fall risk and fracture. Secondary prevention of falls after sustaining a fall related fracture]. AB - It has been known that the risk of subsequent fracture after low-trauma fracture is high. Thus the secondary prevention of falls and fractures is crucial. After sustaining fractures, the secondary fall prevention as well as the treatment for osteoporosis is required. The main approach is to modify the fall risks identified by the comprehensive and detailed assessments. When the modification of the intrinsic risk factors is limited, it is important to modify the behaviors in activities of daily living and the home environment to prevent falls. PMID- 23628689 TI - FUNGALOXPHOS: an integrated database for oxidative phosphorylation in fungi. AB - The oxidative phosphorylation (OXPHOS) system is the main energy-producing pathway in aerobic organisms. Here we present FUNGALOXPHOS, a web based platform that stores OXPHOS proteins encoded in fungal nuclear genomes and that incorporates tools for the extraction, classification and bioinformatic screening of all the putative nuclear encoded fungal OXPHOS proteins. FUNGALOXPHOS includes local, parsing and remote tools that allow exploring the properties of OXPHOS proteins in fungal genomes. FUNGALOXPHOS is freely available on the web at http://bioinformatics.unavarra.es:1000/FUNGALOXPHOS_CSS/main.html. PMID- 23628690 TI - Mitochondrial genome variations in advanced stage breast cancer: a case-control study. AB - Entire mitochondrial DNA (mtDNA) sequencing was carried out in 101 primary breast cancer patients and 90 controls of south Indian origin. We identified 69 novel mutations in breast cancer patients and 637 reported polymorphisms in patients and/or controls. PolyPhen-2 analysis predicted 5 out of 14 novel missense mutations as 'probably damaging variants'. Haplogrouping analysis identified a significant association between haplogroup M5 and breast cancer risk. Microsatellite instability and tumor specific large scale mtDNA deletions were not observed in tumor tissues from the patients. In conclusion, mtDNA mutations and haplogroups may constitute an inheritable risk factor for pathogenesis of breast cancer. PMID- 23628691 TI - A multipotent transit-amplifying neuroblast lineage in the central brain gives rise to optic lobe glial cells in Drosophila. AB - The neurons and glial cells of the Drosophila brain are generated by neural stem cell-like progenitors during two developmental phases, one short embryonic phase and one more prolonged postembryonic phase. Like the bulk of the adult-specific neurons, most of glial cells found in the adult central brain are generated postembryonically. Five of the neural stem cell-like progenitors that give rise to glial cells during postembryonic brain development have been identified as type II neuroglioblasts that generate neural and glial progeny through transient amplifying INPs. Here we identify DL1 as a novel multipotent neuroglial progenitor in the central brain and show that this type II neuroblast not only gives rise to neurons that innervate the central complex but also to glial cells that contribute exclusively to the optic lobe. Immediately following their generation in the central brain during the second half of larval development, these DL1 lineage-derived glia migrate into the developing optic lobe, where they differentiate into three identified types of optic lobe glial cells, inner chiasm glia, outer chiasm glia and cortex glia. Taken together, these findings reveal an unexpected central brain origin of optic lobe glial cells and central complex interneurons from one and the same type II neuroglioblast. PMID- 23628692 TI - Statistical coronary motion models for 2D+t/3D registration of X-ray coronary angiography and CTA. AB - Accurate alignment of intra-operative X-ray coronary angiography (XA) and pre operative cardiac CT angiography (CTA) may improve procedural success rates of minimally invasive coronary interventions for patients with chronic total occlusions. It was previously shown that incorporating patient specific coronary motion extracted from 4D CTA increases the robustness of the alignment. However, pre-operative CTA is often acquired with gating at end-diastole, in which case patient specific motion is not available. For such cases, we investigate the possibility of using population based coronary motion models to provide constraints for the 2D+t/3D registration. We propose a methodology for building statistical motion models of the coronary arteries from a training population of 4D CTA datasets. We compare the 2D+t/3D registration performance of the proposed statistical models with other motion estimates, including the patient specific motion extracted from 4D CTA, the mean motion of a population, the predicted motion based on the cardiac shape. The coronary motion models, constructed on a training set of 150 patients, had a generalization accuracy of 1mm root mean square point-to-point distance. Their 2D+t/3D registration accuracy on one cardiac cycle of 12 monoplane XA sequences was similar to, if not better than, the 4D CTA based motion, irrespective of which respiratory model and which feature based 2D/3D distance metric was used. The resulting model based coronary motion estimate showed good applicability for registration of a subsequent cardiac cycle. PMID- 23628693 TI - Animal models for Francisella tularensis and Burkholderia species: scientific and regulatory gaps toward approval of antibiotics under the FDA Animal Rule. AB - The development and regulatory approval of medical countermeasures (MCMs) for the treatment and prevention of bacterial threat agent infections will require the evaluation of products in animal models. To obtain regulatory approval, these models must accurately recapitulate aspects of human disease, including, but not necessarily limited to, route of exposure, time to disease onset, pathology, immune response, and mortality. This article focuses on the state of animal model development for 3 agents for which models are largely immature: Francisella tularensis, Burkholderia mallei, and Burkholderia pseudomallei. An overview of available models and a description of scientific and regulatory gaps are provided. PMID- 23628694 TI - An immunohistochemical study of the expression of the hypoxia markers Glut-1 and Ca-IX in canine sarcomas. AB - Tumor hypoxia has been associated with increased malignancy, likelihood of metastasis, and increased resistance to radiotherapy and chemotherapy in human medicine. Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor that is induced by tumor hypoxia and regulates the pathways involved in cellular response and adaptation to the hostile tumor microenvironment. HIF-1 induces transcription of different proteins, including Ca-IX and Glut-1, which are considered endogenous markers of chronic hypoxia in solid tumors in humans. In this study, sections from 40 canine sarcomas (20 histiocytic sarcomas and 20 low grade soft-tissue sarcomas) were immunostained for these markers. Expression of Glut-1 was scored based on percentage of positive staining cells (0 = <1%; 1 = 1% 50%; 2 = >50%) and intensity of cellular staining (1 = weak; 2 = strong); Ca-IX was scored based on percentage of positive cells (0 = <1%; 1 = 1%-30%; 2 = >30%). Intratumoral microvessel density was measured using CD31 to assess intratumoral neoangiogenesis. Histiocytic sarcomas showed statistically significant higher Glut-1 immunoreactivity and angiogenesis than did low-grade soft-tissue sarcomas. Intratumoral microvessel density in histiocytic sarcomas was positively associated with Glut-1 immunoreactivity score. These findings suggest a potential role of hypoxia in the biology of these tumors and may provide a base for investigation of the potential prognostic use of these markers in naturally occurring canine tumors. PMID- 23628695 TI - Out of sight, out of mind: cognitive states alter the focus of attention. AB - People in an impulsive state are influenced mainly by the immediate incentive value of appetitive stimuli, whereas people in a reflective state usually also consider the (sometimes negative) long-term consequences of such stimuli. In order to consider all information, we hypothesize that, people in reflective states distribute their attention over all available information, whereas people in impulsive states focus their attention on the most salient information. We measured cognitive states using eye-blink rate (Experiment 1) or induced them with a procedural priming manipulation (Experiments 2 and 3). In eye-tracking Experiments 1 and 2, we established that people in an impulsive state indeed focus their attention on the salient information, whereas people in a reflective state distribute their attention. Moreover, we show that this attentional difference extends to evaluative judgments (Experiment 3), which could potentially contribute to people's increased propensity to risk in impulsive states. PMID- 23628696 TI - Inhibitory control contributes to "motor"--but not "cognitive"--impulsivity. AB - Literature on impulsivity regularly claims inhibitory control deficits underlie impulsive behavior. The current study investigated whether taxing inhibitory control will increase reflection (decision making under conditions of uncertainty), temporal (delay of gratification), and motor impulsivity (behavioral disinhibition). Inhibitory control was challenged, via a random letter generation task presented during responding to three impulsivity measures: the Information Sampling Task (IST), Single Key Impulsivity Paradigm, and the Stop Signal Task (SST). Participants (n = 33) were assigned to the inhibitory control challenging (experimental) condition, or to a control condition in which inhibitory control was not challenged. The SST was affected by the inhibitory control challenge: participants in the experimental condition displayed increased motor impulsivity, evidenced in longer stop signal reaction times (SSRTs) compared to the control group. The manipulation did not affect reflection- or temporal- impulsivity measures. These data support the suggestion that the mechanisms underlying the motor subtype of impulsivity are dissociable from the temporal and reflection subtypes, and that engagement of inhibitory control is not necessary to prevent impulsive decision making. PMID- 23628697 TI - Sensory effects of action observation: evidence for perceptual enhancement driven by sensory rather than motor simulation. AB - Recent neurophysiological and behavioral studies suggest that the brain simulates the sensorimotor processing of observed actions. The relative contributions of sensory and motor simulation in this process remain unclear. Here, we use the well-established phenomenon of sensorimotor gating as a hallmark of motor representation. Perceived intensities of external stimuli are routinely suppressed during motor preparation and execution. Therefore, motor simulation should result in reduced perceptual intensity of sensory stimuli delivered during action observation. We obtained magnitude estimates for vibrotactile stimulation of the upper lip during observation of silent speech (lip-reading). Perceptual enhancement was consistently found across three experiments. The effect appeared to be specific to the observed action, somatotopically organized, and distinct from general attentional and response biases. We conclude that action observation produces perceptual enhancement. The experience of observing others' actions may be driven more by sensory simulation than by motor simulation. PMID- 23628698 TI - The effect of a preceding cue on the conflict solving mechanism. AB - In everyday life cues and signs are used in order to improve our performance and to modify and control our behavior. This study examines whether cues can improve the performance of the mental mechanism in charge of solving conflicts when the nature of the irrelevant task remains constant. In two experiments participants performed the Stroop task in which they were asked to name the color of a stimulus while ignoring its meaning. Half the trials were preceded by a conflict cue containing information about an upcoming conflict. In addition, conflict trial proportions were manipulated. We found that only when the probability of conflict is low can cues alter the conflict solving mechanism. These findings are discussed in the context of the nature of the control mechanism and its tendency to minimize the cost of mental resources. PMID- 23628699 TI - Behavioral distraction by auditory deviance is mediated by the sound's informational value. Evidence from an auditory discrimination task. AB - Sounds deviating from an otherwise repetitive background in some task-irrelevant respect (deviant sounds among standard sounds) capture attention in an obligatory fashion and result in behavioral distraction in an ongoing task. Traditionally, such distraction has been considered as the ineluctable consequence of the deviant sound's low probability of occurrence relative to that of the standard. Recent evidence from a cross-modal oddball task challenged this idea by showing that deviant sounds only yield distraction in a visual task when auditory distractors (standards and deviants) announce with certainty the imminent presentation of a target stimulus (event information), regardless of whether they predict the target's temporal onset (temporal information). The present study sought to test for the first time whether this finding may be generalized to a purely auditory oddball task in which distractor and target information form part of the same perceptual stimulus. Participants were asked to judge whether a sound starting from a central location moved left or right while ignoring rare and unpredictable changes in the sound's identity. By manipulating the temporal and probabilistic relationship between sound onset and movement onset, we disentangled the roles of event and temporal information and found that, as in the auditory-visual oddball task, deviance distraction is mediated by the extent to which distractor information harbingers the presentation of the target information (event information). This finding suggests that the provision of event information by auditory distractors is a fundamental prerequisite of behavioral deviance distraction. PMID- 23628700 TI - Evaluation of the Genisys4, a bench-top preclinical PET scanner. AB - The Genisys4 is a small bench-top preclinical PET scanner designed to enable imaging in biology, biochemistry, and pharmacology laboratories and imaging centers. Here, we compare its performance with that of a well-established preclinical PET scanner. METHODS: Subcutaneous and lung tumor xenografts were used to compare lesion detectability and treatment responses to chemotherapy (gemcitabine) using (18)F-FDG PET. The size of subcutaneous xenografts (L1210 and L1210-10K leukemia cells) and lung metastases (B-16 melanoma cells) was measured on small-animal CT images. Tumor (18)F-FDG uptake was expressed as percentage injected dose per gram. Using list-mode data, serial images of the left ventricular blood pool were used to generate time-activity curves. RESULTS: Subcutaneous xenografts (range, 4-12 mm; mean +/- SD, 6.1 +/- 1.7 mm) and lung metastases (range, 1-5 mm; mean, 2.1 +/- 1.2 mm) were detected equally well with both scanners. Tumor (18)F-FDG uptake measured with both scanners was highly correlated for subcutaneous xenografts (r(2) = 0.93) and lung metastases (r(2) = 0.83). The new Genisys4 scanner and the established scanner provided comparable treatment response information (r(2) = 0.93). Dynamic imaging sequences permitted the generation of left ventricular blood-pool time-activity curves with both scanners. CONCLUSION: Using subcutaneous and lung xenografts, a novel and an established preclinical PET scanner provided equivalent information with regard to lesion detection, tumor (18)F-FDG uptake, tumor response to treatment, and generation of time-activity curves. Thus, the Genisys4 provides a small, efficient bench-top preclinical PET alternative for quantitatively studying murine tumor models in biology, biochemistry, and pharmacology laboratories and preclinical imaging centers. PMID- 23628701 TI - AGGF1 is a novel anti-inflammatory factor associated with TNF-alpha-induced endothelial activation. AB - Endothelial activation contributes to the development of vascular inflammation and subsequent vascular diseases, particularly atherosclerosis. AGGF1, a new member of angiogenic factors with a FHA and a G-patch domain, has been shown critical for the regulation of vascular differentiation and angiogenesis. In this study, we found that various inflammatory cytokines strongly induced the expression of AGGF1 in endothelial cells (ECs) and identified AGGF1 as a novel anti-inflammatory factor both in vivo and in vitro. Overexpression of AGGF1 significantly repressed the expression of pro-inflammatory molecules such as E Selectin, ICAM-1, and IL-8 and the adhesion of monocytes onto ECs activated by TNF-alpha. Conversely, the knockdown of AGGF1 resulted in the increased expressions of these pro-inflammatory molecules and the enhanced monocyte-EC interaction. We further demonstrated that AGGF1 potently attenuated TNF-alpha triggered NF-kappaB pathway, as indicated by the decreased promoter activity, nuclear distribution and phosphorylation of NF-kappaB p65 subunit as well as the increased protein level of IkappaBalpha. This inhibitory effect of AGGF1 was further proved through blocking the phosphorylation of ERK induced by TNF-alpha. Finally, we showed that the FHA domain of AGGF1 was required for its anti inflammatory effect. Thus, our findings for the first time demonstrate that AGGF1 suppresses endothelial activation responses to TNF-alpha by antagonizing the ERK/NF-kappaB pathway, which makes AGGF1 a promising therapeutic candidate for the prevention and treatment of inflammatory diseases. PMID- 23628702 TI - Histone acetyltransferase hMOF promotes S phase entry and tumorigenesis in lung cancer. AB - hMOF is the major acetyltransferase of histone H4 lysine 16 (H4K16) in humans, but its biological function is not well understood. In this study, hMOF was found to be more frequently highly expressed in non-small cell lung cancer (NSCLC) than corresponding normal tissues (P < 0.001). In addition, up-regulation of H4K16 acetylation was also more frequent in NSCLC than normal tissues (P = 0.002). Furthermore, hMOF promotes the cell proliferation, migration and adhesion of NSCLC cell lines. Microarray analysis and chromatin immunoprecipitation (ChIP) assays suggest that hMOF modulates proliferation and metastasis by regulating histone H4K16 acetylation at the promoter regions of downstream target genes. Moreover, hMOF promotes S phase entry via Skp2. These findings suggest that hMOF contributes to NSCLC tumorigenesis. PMID- 23628703 TI - Albumin heterogeneity in low-abundance fluids. The case of urine and cerebro spinal fluid. AB - BACKGROUND: Serum albumin is a micro-heterogeneous protein composed of at least 40 isoforms. Its heterogeneity is even more pronounced in biological fluids other than serum, the major being urine and cerebrospinal fluid. Modification 'in situ' and/or selectivity of biological barriers, such as in the kidney, determines the final composition of albumin and may help in definition of inflammatory states. SCOPE OF REVIEW: This review focuses on various aspects of albumin heterogeneity in low 'abundance fluids' and highlights the potential source of information in diseases. MAJOR CONCLUSIONS: The electrical charge of the protein in urine and CSF is modified but with an opposite change and depending on clinical conditions. In normal urine, the bulk of albumin is more anionic than in serum for the presence of ten times more fatty acids that introduce equivalent anionic charges and modify hydrophobicity of the protein. At the same time, urinary albumin is more glycosylated compared to the serum homolog. Finally, albumin fragments can be detected in urine in patients with proteinuria. For albumin in CSF, we lack information relative to normal conditions since ethical problems do not allow normal CSF to be studied. In multiple sclerosis, the albumin charge in CSF is more cationic than in serum, this change possibly involving structural anomalies or small molecules bindings. GENERAL SIGNIFICANCE: Massively fatty albumin could be toxic for tubular cells and be eliminated on this basis. Renal handling of glycosylated albumin can alter the normal equilibrium of filtration/reabsorption and trigger mechanisms leading to glomerulosclerosis and tubulo-interstitial fibrosis. This article is part of a Special Issue entitled Serum Albumin. PMID- 23628704 TI - Formaldehyde induces hyperphosphorylation and polymerization of Tau protein both in vitro and in vivo. AB - BACKGROUND: Chronic formaldehyde exposure leads to memory impairment and abnormal elevation of endogenous formaldehyde has been found in the brains of Alzheimer's disease (AD) patients. Hyperphosphorylated Tau protein with subsequent aggregates as neurofibrillary tangles (NFTs) is one of the typical pathological characteristics in AD brains. The mechanism underlying abnormally elevated concentrations of endogenous formaldehyde that induce Tau hyperphosphorylation is unknown. METHODS: N2a cells and mice were treated with formaldehyde for different time points, then Western blotting and immunocytochemistry were utilized to determine the phosphorylation and polymerization of Tau protein. HPLC was used to detect the concentration of formaldehyde in cell media. RESULTS: Under formaldehyde stress, Tau became hyperphosphorylated, not only in the cytoplasm, but also in the nucleus of neuroblastoma (N2a) cells, and mouse brains. Polymers of cellular phospho-Tau were also detected. Significant accumulation of glycogen synthase kinase-3beta (GSK-3beta) in the nucleus of N2a and mouse brain cells, and elevation of its phosphorylation at Y216, was observed under formaldehyde stress. Formaldehyde-induced Tau hyperphosphorylation was blocked in the presence of LiCl and CT99021, inhibitors of GSK-3beta, and by RNAi interference. CONCLUSIONS: Formaldehyde, which may cause age-related memory loss, can act as a factor triggering Tau hyperphosphorylation via GSK-3beta catalysis and induces polymerization of Tau. GENERAL SIGNIFICANCE: Investigation of formaldehyde induced Tau hyperphosphorylation may provide novel insights into mechanisms underlying tauopathies. PMID- 23628705 TI - Configurational assignments of conformationally restricted bis-monoterpene hydroquinones: utility in exploration of endangered plants. AB - BACKGROUND: Endangered plant species are an important resource for new chemistry. Lindera melissifolia is native to the Southeastern U.S. and scarcely populates the edges of lakes and ponds. Quantum mechanics (QM) used in combination with NMR/ECD is a powerful tool for the assignment of absolute configuration in lieu of X-ray crystallography. METHODS: The EtOAc extract of L. melissifolia was subject to chromatographic analysis by VLC and HPLC. Spin-spin coupling constant (SSCC) were calculated using DFT at the MPW1PW91/6-31G(d,p) level for all staggered rotamers. ECD calculations employed Amber* force fields followed by PM6 semi-empirical optimizations. Hetero- and homo-nuclear coupling constants were extracted from 1D (1)H, E.COSY and HETLOC experiments. RESULTS: Two meroterpenoids, melissifolianes A (1) and B (2) were purified and their 2-D structures elucidated using NMR and HRESIMS. The relative configuration of 1 was established using the combination of NOE-based distance restraints and the comparisons of experimental and calculated SSCCs. The comparison of calculated and experimental ECD assigned the absolute configuration of 1. The relative configuration of a racemic mixture, melissifoliane B (2) was established utilizing J-based analysis combined with QM and NMR techniques.Conclusion Our study of the Lindera melissifolia metabolome exemplifies how new chemistry remains undiscovered among the numerous endangered plant species and demonstrates how analysis by ECD and NMR combined with various QM calculations is a sensible approach to support the stereochemical assignment of molecules with conformationally restricted conformations. GENERAL SIGNIFICANCE: QM-NMR/ECD combined approaches are of utility for unambiguous assignment of 3-D structures, especially with limited plant material and when a molecule is conformationally restricted. Conservation of an endangered plant species can be supported through identification of its new chemistry and utilization of that chemistry for commercial purposes. PMID- 23628706 TI - A novel inhibitor, 16-hydroxy-cleroda-3,13-dien-16,15-olide, blocks the autophosphorylation site of focal adhesion kinase (Y397) by molecular docking. AB - BACKGROUND: Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine plays an important role in a number of cell signaling pathways, including cell migration, proliferation, and cell survival. This study was aimed to identify novel and specific inhibitors from natural compounds via molecular docking of FAK (Y397). METHODS: The 3D structure of FAK (PDB ID: 2AL6) was used for docking 109 natural compounds. Based on high affinity and energy interaction, four of ten candidate compounds, 16-hydroxy-cleroda-3,13-dien-16,15-olide (HCD), curcumin, quercetin, and catechin hydrate, were hit, and the inhibitory activity against FAK was validated in these compounds in C6 glioma and N18 neuroblastoma cell lines. RESULTS: HCD showed a potential effect on cell viability by MTT assay and cell arrest in the G0-G1 phase, and a TUNEL assay confirmed further apoptosis. Treatment with HCD decreased anti-apoptotic proteins and increased pro-apoptotic proteins. Atomic force microscopy data depicted that the formation of filopodia on the intracellular surface decreased in treated cells compared with the control. Zymography showed that HCD inhibited the activity of MMP-2 and MMP-9. The protein levels of FAK, pFAK, Rac1 and Cdc42, which are the key regulators for the formation of filopodia, were decreased. Additionally, HCD regulated the expression of epithelial mesenchymal transition proteins. CONCLUSIONS: HCD effectively interacted at the autophosphorylation site of FAK and interaction analysis indicated an H-bond with the Arg 86 and Arg 125 residues. GENERAL SIGNIFICANCE: This study suggests that HCD could be a potential inhibitor of FAK and could be used for anti-tumorigenesis and anti-metastasis treatments. PMID- 23628707 TI - Chest wall volumes during inspiratory loaded breathing in COPD patients. AB - Chest wall volumes and breathing patterns of 13 male COPD patients were evaluated at rest and during inspiratory loaded breathing (ILB). The sternocleidomastoid (SMM) and abdominal muscle activity was also evaluated. The main compartment responsible for the tidal volume at rest and during ILB was the abdomen. During ILB patients exhibited, in addition to increases in the ratio of inspiratory time to total time of the respiratory cycle and minute ventilation, increases (p<0.05) in the chest wall tidal volume by an increase in abdomen tidal volume as a result of improvement of end chest wall inspiratory volume without changing on end chest wall expiratory volume. The SMM and abdominal muscle activity increased 63.84% and 1.94% during ILB. Overall, to overcome the load imposed by ILB, COPD patients improve the tidal volume by changing the inspiratory chest wall volume without modifying the predominant mobility of the abdomen at rest and without affecting the end chest wall expiratory volume. PMID- 23628708 TI - Phylogeny and organization of recombinase in trio (RIT) elements. AB - Recombinase in trio (RIT) elements are composed of three adjacent tyrosine based site-specific recombinases that commonly occur in bacterial genomes. In this study, we examine RIT elements found in the genomes of strains from 63 different genera across 7 phyla of Eubacteria and examine the specific organization of these elements, their phylogenetic and environmental distribution, and their potential for mobility. We have found that each recombinase in this RIT arrangement is associated with a distinct sub-family of the tyrosine recombinases, and that the order and orientation of these sub-families is consistently maintained. We have determined that the distribution of these elements suggests that they are an ancient feature of bacterial genomes, but identical copies found within individual strains indicates that they are capable of intragenomic mobility. The occurrence of identical elements on both the main chromosome and one or more plasmids within individual strains, coupled with the finding that in some cases related genera are carrying highly similar RIT elements indicates that horizontal transfer has in some cases proceeded through a plasmid intermediate. PMID- 23628709 TI - Supercurrent modulated by magnetization in a composite topological superconductor junction. AB - We report a theoretical study of the supercurrent flowing in a composite topological superconductor (TS) junction, where a magnetized quantum dot is considered in between the two TS leads. Based on the tight-binding model and the Keldysh Green's function method, we found that the magnetization (m) in the dot can significantly modify the current-phase relationship, and a nonzero supercurrent flows at zero superconducting phase gradient when m has a component perpendicular to both the external magnetic field h and the pseudomagnetic field Bsoc from the spin-orbit coupling. The induced zero-phase supercurrent can be modulated substantially by both the magnitude and the direction of m, and takes its maximum value at the critical magnetic field of the topological phase transition. Our findings might provide an experimentally simple and accessible scheme for the detection of Majorana fermions. PMID- 23628712 TI - One world health: socioeconomic burden and parasitic disease control priorities. AB - Parasitic diseases present a considerable socio-economic impact to society. Zoonotic parasites can result in a considerable burden of disease in people and substantive economic losses to livestock populations. Ameliorating the effects of these diseases may consist of attempts at eradicating specific diseases at a global level, eliminating them at a national or local level or controlling them to minimise incidence. Alternatively with some parasitic zoonoses it may only be possible to treat human and animal cases as they arise. The choice of approach will be determined by the potential effectiveness of a disease control programme, its cost and the cost effectiveness or cost benefit of undertaking the intervention. Furthermore human disease burden is being increasingly measured by egalitarian non-financial measures which are difficult to apply to livestock. This adds additional challenges to the assessment of socio-economic burdens of zoonotic diseases. Using examples from the group of neglected zoonotic diseases, information regarding the socio-economic effects is reviewed together with how this information is used in decision making with regard to disease control and treatment. PMID- 23628711 TI - Repeated-sprint ability and team selection in Australian football league players. AB - PURPOSE: To investigate the relationship between selected physical capacities and repeated-sprint performance of Australian Football League (AFL) players and to determine which physical capacities contributed to being selected for the first competition game. METHODS: Sum of skinfolds, 40-m sprint (with 10-, 20-, 30-, and 40-m splits), repeated-sprint ability (6 * 30-m sprints), and 3-km-run time were measured during the preseason in 20 AFL players. The physical qualities of players selected to play the first match of the season and those not selected were compared. Pearson correlation coefficients were used to determine the relationship among variables, and a regression analysis identified variables significantly related to repeated-sprint performance. RESULTS: In the regression analysis, maximum velocity was the best predictor of repeated-sprint time, with 3 km-run time also contributing significantly to the predictive model. Sum of skinfolds was significantly correlated with 10-m (r = .61, P < .01) and 30-m (r = .53, P < .05) sprint times. A 2.6% +/- 2.1% difference in repeated-sprint time (P < .05, ES = 0.88 +/- 0.72) was observed between those selected (25.26 +/- 0.55 s) and not selected (25.82 +/- 0.80 s) for the first game of the season. CONCLUSIONS: The findings indicate that maximum-velocity training using intervals of 30-40 m may contribute more to improving repeated-sprint performance in AFL players than short 10- to 20-m intervals from standing starts. Further research is warranted to establish the relative importance of endurance training for improving repeated-sprint performance in AFL football. PMID- 23628713 TI - Sad facial cues inhibit temporal attention: evidence from an event-related potential study. AB - We examined the influence of different emotional cues (happy or sad) on temporal attention (short or long interval) using behavioral as well as event-related potential recordings during a Stroop task. Emotional stimuli cued short and long time intervals, inducing 'sad-short', 'sad-long', 'happy-short', and 'happy-long' conditions. Following the intervals, participants performed a numeric Stroop task. Behavioral results showed the temporal attention effects in the sad-long, happy-long, and happy-short conditions, in which valid cues quickened the reaction times, but not in the sad-short condition. N2 event-related potential components showed sad cues to have decreased activity for short intervals compared with long intervals, whereas happy cues did not. Taken together, these findings provide evidence for different modulation of sad and happy facial cues on temporal attention. Furthermore, sad cues inhibit temporal attention, resulting in longer reaction time and decreased neural activity in the short interval by diverting more attentional resources. PMID- 23628714 TI - Isolation and characterization of microsatellite loci for acorn weevil Curculio bimaculatus Faust (Coleoptera: Curculionidae). PMID- 23628715 TI - Molecular sex identification of painted storks (Mycteria leucocephala): using FTA cards, horizontal PAGE and quick silver staining. PMID- 23628716 TI - Development and characterization of twenty-nine novel polymorphic microsatellite loci in the mandarin fish Siniperca chuatsi. PMID- 23628717 TI - Novel genic microsatellite markers from Cajanus scarabaeoides and their comparative efficiency in revealing genetic diversity in pigeonpea. PMID- 23628718 TI - Identification and characterization of novel UniGene-derived microsatellite markers in Podophyllum hexandrum (Berberidaceae). PMID- 23628719 TI - Haplotypes of bovine FoxO1 gene sequence variants and association with growth traits in Qinchuan cattle. PMID- 23628720 TI - Major cereal grain fibers and psyllium in relation to cardiovascular health. AB - Numerous studies reveal the cardiovascular benefits of consuming dietary fiber and, especially, cereal fiber. Cereal fiber is associated with cardiovascular risk reduction through multiple mechanisms and consuming a variety of cereal fiber sources offers health benefits specific to the source. Certain cereal fibers have been studied more extensively than others and provide greater support for their incorporation into a healthful diet. beta-glucan from oats or barley, or a combination of whole oats and barley, and soluble fiber from psyllium reduces the risk of coronary heart disease; inulin-type fructans added to foods and beverages may modestly decrease serum triacylglycerols; arabinoxylan and resistant starch may improve glycemic control. Individuals with low cereal fiber intake should increase their intake of whole grains in order to receive the benefits of whole grains in addition to fiber. For those adjusting to the texture and palatability of whole grains, turning to added-fiber products rich in beta glucan and psyllium may allow them to reach their fiber goals without increasing caloric intake. PMID- 23628721 TI - Interaction between host cells and microbes in chemotherapy-induced mucositis. AB - Cancer patients receiving chemotherapy often develop mucositis as a direct result of their treatment. Recently, the intestinal microbiota has attracted significant attention in the investigation of the pathobiology of mucositis, with a number of studies investigating the effects of chemotherapeutic agents on the microbiota. With significant effects on the intestinal microbiota occurring following the administration of chemotherapy, there is now interest surrounding the downstream pathological effects that may be associated with the altered intestinal ecology. This review seeks to identify links between signalling pathways previously demonstrated to have a role in the development of mucositis, and the altered intestinal microbiota. PMID- 23628722 TI - Role of superoxide production in post-ischemic cardiac dysfunction and norepinephrine overflow in rat hearts. AB - Reactive oxygen species and norepinephrine are known as physiological active substances which cause cell damage and cardiac dysfunction in myocardial ischemia/reperfusion injury. We investigated the role of reactive oxygen species, especially superoxide (O2(-)), in ischemia-induced norepinephrine overflow and cardiac dysfunction using superoxide scavengers tempol and tiron. According to the Langendorff technique, isolated rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Tempol (10 and 100 uM) and tiron (100 and 500 uM) were perfused 15 min before ischemia and during reperfusion. Cardiac levels of oxidative stress markers such as O2(-) and malondialdehyde were notably increased during ischemia and following reperfusion, which were suppressed by the administration of tempol or tiron. These agents significantly improved ischemia/reperfusion-induced cardiac dysfunction such as decreased left ventricular developed pressure and the maximum and minimum value of the first derivative of left ventricular pressure and increased left ventricular end diastolic pressure. Furthermore, norepinephrine overflow in the coronary effluent after ischemia/reperfusion was significantly suppressed by the administration of each agent. These results suggest that endogenously increased O2(-) is involved in norepinephrine overflow and cardiac dysfunction after myocardial ischemia/reperfusion. PMID- 23628723 TI - Advanced biofuel production by the yeast Saccharomyces cerevisiae. AB - Replacement of conventional transportation fuels with biofuels will require production of compounds that can cover the complete fuel spectrum, ranging from gasoline to kerosene. Advanced biofuels are expected to play an important role in replacing fossil fuels because they have improved properties compared with ethanol and some of these may have the energy density required for use in heavy duty vehicles, ships, and aviation. Moreover, advanced biofuels can be used as drop-in fuels in existing internal combustion engines. The yeast cell factory Saccharomyces cerevisiae can be turned into a producer of higher alcohols (1 butanol and isobutanol), sesquiterpenes (farnesene and bisabolene), and fatty acid ethyl esters (biodiesel), and here we discusses progress in metabolic engineering of S. cerevisiae for production of these advanced biofuels. PMID- 23628724 TI - Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein. AB - Cytoplasmic dynein 1 is fundamentally important for transporting a variety of essential cargoes along microtubules within eukaryotic cells. However, in mammals, few mutants are available for studying the effects of defects in dynein controlled processes in the context of the whole organism. Here, we deleted mouse Dlic1 gene encoding DLIC1, a subunit of the dynein complex. Dlic1(-/-) mice are viable, but display severe photoreceptor degeneration. Ablation of Dlic1 results in ectopic accumulation of outer segment (OS) proteins, and impairs OS growth and ciliogenesis of photoreceptors by interfering with Rab11-vesicle trafficking and blocking efficient OS protein transport from Golgi to the basal body. Our studies show that Dlic1 deficiency partially blocks vesicle export from endoplasmic reticulum (ER), but seems not to affect vesicle transport from the ER to Golgi. Further mechanistic study reveals that lack of Dlic1 destabilizes dynein subunits and alters the normal subcellular distribution of dynein in photoreceptors, probably due to the impaired transport function of dynein. Our results demonstrate that Dlic1 plays important roles in ciliogenesis and protein transport to the OS, and is required for photoreceptor development and survival. The Dlic1(-/-) mice also provide a new mouse model to study human retinal degeneration. PMID- 23628725 TI - Long-term deregulated human hematopoiesis in goats transplanted in utero with BCR ABL-transduced lin(-)CD34(+) cord blood cells. PMID- 23628726 TI - The HER2 amplicon in breast cancer: Topoisomerase IIA and beyond. AB - HER2 gene amplification is observed in about 15% of breast cancers. The subgroup of HER2-positive breast cancers appears to be heterogeneous and presents complex patterns of gene amplification at the locus on chromosome 17q12-21. The molecular variations within the chromosome 17q amplicon and their clinical implications remain largely unknown. Besides the well-known TOP2A gene encoding Topoisomerase IIA, other genes might also be amplified and could play functional roles in breast cancer development and progression. This review will focus on the current knowledge concerning the HER2 amplicon heterogeneity, its clinical and biological impact and the pitfalls associated with the evaluation of gene amplifications at this locus, with particular attention to TOP2A and the link between TOP2A and anthracycline benefit. In addition it will discuss the clinical and biological implications of the amplification of ten other genes at this locus (MED1, STARD3, GRB7, THRA, RARA, IGFPB4, CCR7, KRT20, KRT19 and GAST) in breast cancer. PMID- 23628728 TI - [Maternal phenylketonuria]. AB - Elevated maternal phenylalanine levels during pregnancy are teratogenic, and may result in embryo-foetopathy, which could lead to stillbirth, significant psychomotor handicaps and birth defects. This foetal damage is known as maternal phenylketonuria. Women of childbearing age with all forms of phenylketonuria, including mild variants such as hyperphenylalaninaemia, should receive detailed counselling regarding their risks for adverse foetal effects, optimally before contemplating pregnancy. The most assured way to prevent maternal phenylketonuria is to maintain the maternal phenylalanine levels within the optimal range already before conception and throughout the whole pregnancy. Authors review the comprehensive programme for prevention of maternal phenylketonuria at the Metabolic Center of Budapest, they survey the practical approach of the continuous maternal metabolic control and delineate the outcome of pregnancies of mothers with phenylketonuria from the introduction of newborn screening until most recently. PMID- 23628729 TI - [Results of randomized studies on cardiac resynchronization therapy and the reevaluation of cardiac ventricular activation in left bundle branch block]. AB - If New York Heart Association Class II-IV heart failure is present, and ejection fraction <=35%, electrocardiographic QRS width >= 120 ms in the presence of left bundle branch block, cardiac resynchronization therapy is indicated. Reevaluation of the data of cardiac resynchronization trials and electrophysiologic findings in left bundle branch block provided evidence that "true" left bundle branch block requires a QRS width of >=130 ms (in woman) and >=140 ms (in man). In "true" left bundle branch block, after the 40th ms of the QRS notched/slurred R waves are characteristic in minimum two of I, aVL, V1, V2, V5 and V6 leads, in addition to a >=40 ms increase of the QRS complex, as compared to the original QRS complex. In contrast, slowly and continuously widened "left bundle branch block like" QRS patterns are mostly occur in left ventricular hypertrophy or in a metabolic/infiltrative disease. PMID- 23628727 TI - Eph/ephrin recognition and the role of Eph/ephrin clusters in signaling initiation. AB - The Eph receptors and their ephrin ligands play crucial roles in a large number of cell-cell interaction events, including those associated with axon pathfinding, neuronal cell migration and vasculogenesis. They are also involved in the patterning of most tissues and overall cell positioning in the development of the vertebrate body plan. The Eph/ephrin signaling system manifests several unique features that differentiate it from other receptor tyrosine kinases, including initiation of bi-directional signaling cascades and the existence of ligand and receptor subclasses displaying promiscuous intra-subclass interactions, but very rare inter-subclass interactions. In this review we briefly discuss these features and focus on recent studies of the unique and expansive high-affinity Eph/ephrin assemblies that form at the sites of cell-cell contact and are required for Eph signaling initiation. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases. PMID- 23628730 TI - [Cognitive functions in type 1 and type 2 diabetes. Meta-analysis]. AB - INTRODUCTION: Diabetes has been repeatedly associated with a wide variety of cognitive impairments. AIM: To clarify the differences in cognitive dysfunctions between the two types of diabetes. METHOD: Metaanalysis was performed using databases of Medline, PubMed and ScienceDirect (3 studies with type 1 and 6 with type 2 diabetes). RESULTS: Adults with type 1 diabetes showed lower performance than control subjects in all fields. The effect size had the highest value in psychomotor activity (D = -0.69). The effect size was small for delayed verbal memory (D = -0.48), attention (D = -0.47), language (D = -0.44), visual processing (D = -0.35), immediate verbal memory (D = -0.30), working memory (D = 0.27) and executive functions (D = -0.26). Adults with type 2 diabetes showed lower performance than control subjects in all cognitive domains, except for working memory (D = +0.03). The effect size had the highest value in immediate verbal memory (D = -1.12), psychomotor activity (D = -0.82) and delayed verbal memory (D = -0.81). The effect size was moderate for general intellectual abilities (D = -0.68) and small for general memory (D = -0.37), attention (D = 0.35), language (D = -0.35), visual processing (D = -0.33) and executive functions (D = -0.33). CONCLUSION: Both types of diabetes are associated with reduced performance in numerous cognitive domains. PMID- 23628731 TI - [Connection between cancer- and alcohol-related mortality in a rural practice of a South-Hungarian village]. AB - INTRODUCTION: The author, who is a sole general practitioner in a Hungarian village, has continuously followed mortality in his practice for a long period of time. He found connections between cancer- and alcohol-related mortality in the first observational period between 1987 and 1999. Among men, cancer mortality related to alcoholism reached 50% in men and 7.9% in women. AIM: The aim of the author was to obtain new data on the relation between cancer- and alcohol-related mortality during a 12-year period between 2000 and 2011, and compare them with findings in his earlier work. METHOD: Data recorded in detailed death reports were analysed. For the main cause of death, long-term data from the medical history of patients were analysed thoroughly. RESULTS: Between 2000 and 2011 there were 326 cases of death (167 men and 159 women). Despite several changes in the structure of the cause of mortality (the frequency of alcohol-related deaths considerably decreased while the frequency of cancer-related deaths somewhat increased), the proportion of alcohol-related cancer mortality has increased to 60% in men and 9.1% in women. CONCLUSION: These data confirm earlier observation of the author showing that alcoholism is frequent in this Hungarian village and that it contributes to the high cancer mortality of the inhabitants, especially in men. Therefore, decreased alcohol consumption and alcohol-related harms would be an important step in cancer prevention. PMID- 23628732 TI - [Physicians in the Alps]. PMID- 23628734 TI - Calcium-sensing receptor antagonist (calcilytic) NPS 2143 specifically blocks the increased secretion of endogenous Abeta42 prompted by exogenous fibrillary or soluble Abeta25-35 in human cortical astrocytes and neurons-therapeutic relevance to Alzheimer's disease. AB - The "amyloid-beta (Abeta) hypothesis" posits that accumulating Abeta peptides (Abetas) produced by neurons cause Alzheimer's disease (AD). However, the Abetas contribution by the more numerous astrocytes remains undetermined. Previously we showed that fibrillar (f)Abeta25-35, an Abeta42 proxy, evokes a surplus endogenous Abeta42 production/accumulation in cortical adult human astrocytes. Here, by using immunocytochemistry, immunoblotting, enzymatic assays, and highly sensitive sandwich ELISA kits, we investigated the effects of fAbeta25-35 and soluble (s)Abeta25-35 on Abeta42 and Abeta40 accumulation/secretion by human cortical astrocytes and HCN-1A neurons and, since the calcium-sensing receptor (CaSR) binds Abetas, their modulation by NPS 2143, a CaSR allosteric antagonist (calcilytic). The fAbeta25-35-exposed astrocytes and surviving neurons produced, accumulated, and secreted increased amounts of Abeta42, while Abeta40 also accrued but its secretion was unchanged. Accordingly, secreted Abeta42/Abeta40 ratio values rose for astrocytes and neurons. While slightly enhancing Abeta40 secretion by fAbeta25-35-treated astrocytes, NPS 2143 specifically suppressed the fAbeta25-35-elicited surges of endogenous Abeta42 secretion by astrocytes and neurons. Therefore, NPS 2143 addition always kept Abeta42/Abeta40 values to baseline or lower levels. Mechanistically, NPS 2143 decreased total CaSR protein complement, transiently raised proteasomal chymotrypsin activity, and blocked excess NO production without affecting the ongoing increases in BACE1/beta secretase and gamma-secretase activity in fAbeta25-35-treated astrocytes. Compared to fAbeta25-35, sAbeta25-35 also stimulated Abeta42 secretion by astrocytes and neurons and NPS 2143 specifically and wholly suppressed this effect. Therefore, since NPS 2143 thwarts any Abeta/CaSR-induced surplus secretion of endogenous Abeta42 and hence further vicious cycles of Abeta self induction/secretion/spreading, calcilytics might effectively prevent/stop the progression to full-blown AD. PMID- 23628735 TI - Alzheimer disease: Alzheimer disease biomarkers in healthy individuals can predict cognitive decline several years later. PMID- 23628736 TI - Neurodegenerative disease: Frontotemporal dementia--time to target inflammation? PMID- 23628738 TI - Opinion: A role for placebo therapy in psychogenic movement disorders. AB - Psychogenic movement disorders (PMDs) mimic known movement disorders but are not attributed to an underlying neurological pathology and are generally thought to have a psychological origin. Owing to the lack of a clear pathology, patients often experience multiple referrals, frequent office visits, and numerous--often fruitless--technically sophisticated tests and interventions. No standard of care exists for PMDs, and affected patients can experience debilitating symptoms for a lifetime. Some physicians advocate the use of placebo treatment for patients with PMDs, and placebo therapy can have beneficial neurophysiological effects. Innovative research will be necessary to develop effective therapeutics for psychogenic disorders and to make recommendations for future clinician training and health care policy. This Perspectives article aims to trigger international dialogue focusing on the diagnosis and treatment of patients with PMDs, and to reframe and deepen discussion of placebo prescribing for PMDs and beyond. PMID- 23628739 TI - Periodic dynamics of fermionic superfluids in the BCS regime. AB - We study the zero temperature non-equilibrium dynamics of a fermionic superfluid in the BCS limit and in the presence of a drive leading to a time-dependent chemical potential MU(t). We choose a periodic driving protocol characterized by a frequency omega and compute the fermion density, the wavefunction overlap, and the residual energy of the system at the end of N periods of the drive. We demonstrate that the BCS self-consistency condition is crucial in shaping the long time behaviour of the fermions subjected to the drive and provide an analytical understanding of the behaviour of the fermion density nkF (where kF is the Fermi momentum vector) after a drive period and for large omega. We also show that the momentum distribution of the excitations generated due to such a drive bears the signature of the pairing symmetry and can be used, for example, to distinguish between s- and d-wave superfluids. We propose experiments to test our theory. PMID- 23628737 TI - Characteristics of Susac syndrome: a review of all reported cases. AB - In Susac syndrome, occlusions of microvessels--presumed to be mediated by an autoimmune response to an as yet unknown antigen--lead to a characteristic clinical triad of CNS dysfunction, branch retinal artery occlusions, and sensorineural hearing impairment. Susac syndrome is considered a rare but important differential diagnosis in numerous neurological, psychiatric, ophthalmological, and ear, nose and throat disorders. Improved understanding of this disorder is crucial, therefore, to ensure that patients receive appropriate treatment and care. Current knowledge on Susac syndrome is largely based on reports of single patients, small case series, and nonsystematic reviews. The aim of this Review is to extend these previous, primarily anecdotal findings by compiling data from all 304 cases of Susac syndrome that have been published worldwide, which were identified following a literature search with predefined search, inclusion and exclusion criteria. From this data, we present an overview of demographic, clinical and diagnostic data on Susac syndrome, providing a reliable basis for our current understanding of this rare disease. Where possible, we make recommendations for clinical diagnosis, differential diagnosis, and management of patients with suspected Susac syndrome. PMID- 23628741 TI - Genes and environments in schizophrenia: The different pieces of a manifold puzzle. AB - Genetic research targeting schizophrenia has undergone tremendous development during recent years. Supported by recently developed high-throughput genotyping technologies, both rare and common genetic variants have been identified that show consistent association with schizophrenia. These results have been replicated by independent studies and refined in meta-analyses. The genetic variation uncovered consists of common alleles, i.e. single nucleotide polymorphisms (SNPs) conveying small effects (odds ratios below 1.1) on disease risk. The source of rare variants is copy number variations (CNVs), only detectable in a small proportion of patients (3-5% for all known CNVs) with schizophrenia, furthermore extremely rare de novo mutations captured by next generation sequencing, the most recent technological advancement in the field. Despite these findings, the search for the genetic architecture underlying schizophrenia continues since these variants explain only a small proportion of the overall phenotypic variance. Gene-environment interactions provide a compelling model for resolving this paradox and interpreting the risk factors of schizophrenia. Epidemiologically proven risk factors, such as prenatal infection, obstetric complications, urbanicity, cannabis, and trauma have been demonstrated to interact with genetic risk, giving rise to higher prevalence rates or more severe symptomatology in individuals with direct or indirect genetic predisposition for schizophrenia. Further research will have to explain how the different forms of genetic variation interact and how environmental factors modulate their effects. Moreover, the challenging question lying ahead of us is how genetic and environmental factors translate to molecular disease pathways. New approaches, including animal studies and in vitro disease modeling, as well as innovative real-world environment assessment methods, will help to understand the complex etiology of schizophrenia. PMID- 23628740 TI - Recovering from cocaine: insights from clinical and preclinical investigations. AB - Cocaine remains one of the most addictive substances of abuse and one of the most difficult to treat. Although increasingly sophisticated experimental and technologic advancements in the last several decades have yielded a large body of clinical and preclinical knowledge on the direct effects of cocaine on the brain, we still have a relatively incomplete understanding of the neurobiological processes that occur when drug use is discontinued. The goal of this manuscript is to review both clinical and preclinical data related to abstinence from cocaine and discuss the complementary conclusions that emerge from these different levels of inquiry. This commentary will address observed alterations in neural function, neural structure, and neurotransmitter system regulation that are present in both animal models of cocaine abstinence and data from recovering clinical populations. Although these different levels of inquiry are often challenging to integrate, emerging data discussed in this commentary suggest that from a structural and functional perspective, the preservation of cortical function that is perhaps the most important biomarker associated with extended abstinence from cocaine. PMID- 23628743 TI - Images in vascular medicine. Giant abdominal aortic aneurysm. PMID- 23628742 TI - Advances in functional neuroanatomy: a review of combined DTI and fMRI studies in healthy younger and older adults. AB - Structural connections between brain regions are thought to influence neural processing within those regions. It follows that alterations to the quality of structural connections should influence the magnitude of neural activity. The quality of structural connections may also be expected to differentially influence activity in directly versus indirectly connected brain regions. To test these predictions, we reviewed studies that combined diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) in younger and older adults. By surveying studies that examined relationships between DTI measures of white matter integrity and fMRI measures of neural activity, we identified variables that accounted for variability in these relationships. Results revealed that relationships between white matter integrity and neural activity varied with (1) aging (i.e., positive and negative DTI-fMRI relationships in younger and older adults, respectively) and (2) spatial proximity of the neural measures (i.e., positive and negative DTI-fMRI relationships when neural measures were extracted from adjacent and non-adjacent brain regions, respectively). Together, the studies reviewed here provided support for both of our predictions. PMID- 23628744 TI - Prevalence of palatine tonsilloliths: a retrospective study on 150 consecutive CT examinations. AB - OBJECTIVES: To evaluate the prevalence of palatine tonsilloliths. METHODS: 150 consecutive CT examinations (75 males and 75 females) were read. RESULTS: Tonsilloliths were found in 37 patients (24.6%; confidence interval 17.7-31.6%), of which 18 (48%) had a bilateral location. No influence of sex or age was observed (p = 0.37 and p = 0.57, respectively). 26 patients (70%) had more than 1 concretion. The largest tonsillolith was 7 mm. None of the tonsilloliths found were involved in the reason for prescribing the CT. The radiographic density of the tonsilloliths was between 216 and 2959 HU. CONCLUSIONS: Palatine tonsilloliths could affect approximately one-quarter of the population. This prevalence is likely to be underestimated in daily clinical practice because small concretions do not result in any functional impairment and are not visible on orthopantomographs. PMID- 23628745 TI - Dissociation and hierarchical assembly of chiral esters on metallic surfaces. AB - The interaction of a de novo synthesised ester with single crystal metal surfaces has been investigated as a model system for the heterogeneous hydrogenolysis of esters. Scanning tunnelling microscopy measurements show dissociative adsorption at room temperature on Cu(110) but no significant reaction on Au(111). The dissociative pathway has been identified by comparing with possible fragment species, demonstrating that the ester cleavage occurs along the RCH(CH3)-OC(O)R bond. PMID- 23628746 TI - Estradiol increases dendritic length and spine density in CA1 neurons of the hippocampus of spontaneously hypertensive rats: a Golgi impregnation study. AB - Increased neuronal vulnerability has been described in the brain of spontaneously hypertensive rats (SHR), models of primary hypertension. Previous data indicate that estradiol treatment corrects several dysfunctions of the hippocampus and hypothalamus of SHR. Considering this evidence we analyzed the dendritic arborization and spine density of the CA1 subfield in SHR and Wistar-Kyoto (WKY) normotensive rats with and without estradiol treatment. Five month old male SHR and WKY rats received single estradiol or cholesterol pellets (sham treatment) for 2 weeks. A substantial rise of circulating estradiol (>25 fold) and testicular atrophy was present in all estradiol-receiving rats. In both SHR and WKY rats, estradiol decreased blood pressure by ~20 mm Hg; however, a moderate hypertension persisted in SHR (164 mm Hg). Using a modified Golgi impregnation technique, apical and basal dendrites of the CA1 subfield were subjected to Sholl analysis. Spine density was also statistically analyzed. Apical dendritic length was significantly lower in SHR compared to WKY rats (p<0.01), whereas estradiol treatment increased dendritic length in the SHR group only (SHR vs SHR+estradiol; p<0.01). Apical dendritic length plotted against the shell distances 20-100, 120 200 and 220-300 MUm, revealed that changes were more pronounced in the range 120 200 MUm between SHR vs. WKY rats (p<0.05) and SHR vs. SHR+estradiol (p<0.05). Instead, basal dendrites were not significantly modified by hypertension or steroid treatment. Spine density of apical dendrites was lower in SHR than WKY (p<0.05) and was up-regulated in the SHR+estradiol group compared to the SHR group (p<0.001). Similar changes were obtained for basal dendritic spines. These data suggest that changes of neuronal processes in SHR are plastic events restorable by estradiol treatment. In conjunction with previous results, the present data reveal new targets of estradiol neuroprotection in the brain of hypertensive rats. PMID- 23628749 TI - A pontified cause for a headache. PMID- 23628750 TI - Can India stop drug companies giving gifts to doctors? PMID- 23628751 TI - Large US study of HIV vaccine is halted because of lack of efficacy. PMID- 23628752 TI - A third of Americans had problems paying medical bills in 2012. PMID- 23628753 TI - Whistleblowing helpline takes more than 350 calls in first four months. PMID- 23628754 TI - Neuromuscular and metabolic responses to high-intensity intermittent cycling protocols with different work-to-rest ratios. AB - PURPOSE: To investigate the effects of work-to-rest-ratio manipulation on neuromuscular and metabolic responses during 2 high-intensity intermittent training (HIT) protocols to exhaustion. Since different exercise durations were expected, the authors hypothesized that the protocol registering a longer duration would have a more pronounced effect on neuromuscular responses, while the other would challenge the cardiopulmonary system more. METHODS: Thirteen competitive cyclists (age 19 +/- 2 y) performed a preliminary incremental test to identify their maximal power output and 2 intermittent protocols to exhaustion (40:20s and 30:30s) at a fixed work rate of 135%Pmax interspersed by passive recovery. Surface electromyographic (sEMG) parameters (including muscle-fiber conduction velocity), cardiopulmonary parameters, and blood lactate concentration [La-] were recorded. RESULTS: Time to exhaustion and total work were significantly higher for the 30:30s (38 +/- 13 min, 495 +/- 161 kJ) than for the 40:20s (10 +/- 3 min, 180 +/- 51 kJ). No differences were found in sEMG parameters for the 2 protocols. Mean and peak values of VO2, heart rate, ventilatory parameters (except for the peak value of respiratory frequency), and [La-] were significantly higher in the 40:20s than in the 30:30s. CONCLUSIONS: These results do not support the hypothesis that a longer time spent at high intensity has a more pronounced effect on neuromuscular responses, as no differences in EMG parameters were found in the 2 HIT protocols. Regarding metabolic responses, while the 40:20s led to maximal values of VO2, [La-], and ventilatory parameters within a few minutes, the 30:30s allowed maintenance of moderately high values for a considerably longer period, especially for [La-] and ventilatory parameters. PMID- 23628755 TI - Manual physical therapy and exercise versus supervised home exercise in the management of patients with inversion ankle sprain: a multicenter randomized clinical trial. AB - STUDY DESIGN: Randomized clinical trial. OBJECTIVE: To compare the effectiveness of manual therapy and exercise (MTEX) to a home exercise program (HEP) in the management of individuals with an inversion ankle sprain. BACKGROUND: An in clinic exercise program has been found to yield similar outcomes as an HEP for individuals with an inversion ankle sprain. However, no studies have compared an MTEX approach to an HEP. METHODS: Patients with an inversion ankle sprain completed the Foot and Ankle Ability Measure (FAAM) activities of daily living subscale, the FAAM sports subscale, the Lower Extremity Functional Scale, and the numeric pain rating scale. Patients were randomly assigned to either an MTEX or an HEP treatment group. Outcomes were collected at baseline, 4 weeks, and 6 months. The primary aim (effects of treatment on pain and disability) was examined with a mixed-model analysis of variance. The hypothesis of interest was the 2-way interaction (group by time). RESULTS: Seventy-four patients (mean +/- SD age, 35.1 +/- 11.0 years; 48.6% female) were randomized into the MTEX group (n = 37) or the HEP group (n = 37). The overall group-by-time interaction for the mixed-model analysis of variance was statistically significant for the FAAM activities of daily living subscale (P<.001), FAAM sports subscale (P<.001), Lower Extremity Functional Scale (P<.001), and pain (P <=.001). Improvements in all functional outcome measures and pain were significantly greater at both the 4 week and 6-month follow-up periods in favor of the MTEX group. CONCLUSION: The results suggest that an MTEX approach is superior to an HEP in the treatment of inversion ankle sprains. Registered at clinicaltrials.gov (NCT00797368). LEVEL OF EVIDENCE: Therapy, level 1b-. PMID- 23628756 TI - Identifying potential themes for the Child Amblyopia Treatment Questionnaire. AB - PURPOSE: Patient-reported outcome (PRO) instruments are increasingly common in both clinical practice and research. The data obtained from these instruments can be used to help inform decision making and policy-making decisions. The methodological approaches undertaken in developing PROs is not frequently reported. Literature on the development of the descriptive systems for PROs is sparse in comparison with that on the assessment of the psychometric properties of such instruments. The purpose of this study is to describe the results of qualitative interviews conducted to identify potential themes for the Child Amblyopia Treatment Questionnaire (CAT-QoL), a pediatric disease-specific health related quality of life instrument for amblyopia designed for children aged 4 to 7 years. METHODS: Semistructured interviews were undertaken with 59 children (aged 3 years 9 months to 9 years 11 months; average, 6 years 3 months) with amblyopia. The interviews were transcribed verbatim and imported into QSR NVivo 8. Interview transcripts were analyzed to identify potential items to be included in the descriptive system. Thematic content analysis was undertaken using Framework. RESULTS: Eleven potential themes were identified for inclusion in the CAT-QoL instrument, namely, physical sensation of the treatment, pain, being able to play with other children, how other children have treated them, ability to undertake schoolwork, ability to undertake other tasks, sad or unhappy, cross, worried, frustrated, and feelings toward family members. CONCLUSIONS: Children are able to identify their thoughts and opinions of their own health and to describe what impact their amblyopia treatment has had on their daily lives. Themes for the draft descriptive system for a pediatric self-reported amblyopia QoL instrument have been identified. A draft version of the CAT-QoL instrument has been developed. Further research is required to refine and assess the psychometric properties of the instrument. PMID- 23628757 TI - Utility values in the visually impaired: comparing time-trade off and VisQoL. AB - PURPOSE: Visual impairment (VI) negatively affects quality of life (QoL). Utilities represent a way of measuring the QoL impact associated with a particular health state, like VI, and are also useful in economic evaluations of health care interventions. Utilities can be determined either directly or indirectly. Here we determine whether the Vision and Quality of Life Index, VisQoL (indirect approach), is acceptable to use in patients with VI in an urban setting in South India; whether the VisQoL utility values, derived from an Australian sample of both visually impaired and normally sighted participants, demonstrate agreement (if any) with direct utilities, determined by time trade off (TTO), from visually impaired South Indian patients; and determine the relationship between utilities and self-reported visual disability. METHODS: Three hundred forty-nine adults with VI were administered the two-item TTO item, six-item VisQoL, and the 16-item Andhra Pradesh Eye Disease-Visual Function Questionnaire (APEDS-VFQ) in a face-to-face interview. The VisQoL utilities were derived from the utility scoring algorithm. Rasch-scaled scores of the APEDS-VFQ were obtained using the conversion scores sheets. Agreement between TTO and utilities VisQoL was assessed using the Bland-Altman method. RESULTS: All participants (response rate, 100%) completed the VisQoL as compared with 72% for the TTO. There was no statistically significant difference in the mean utilities from the two methods (0.65 +/- 0.31 by TTO vs. 0.66 +/- 0.27 by VisQoL, p = 0.67). However, the 95% limits of agreement on the Bland-Altman plot were wide ( 0.65, 0.67), implying a lack of agreement between the methods. The VisQoL relates relatively strongly with APEDS-VFQ as compared with TTO (TTO vs. APEDS-VFQ, r = 0.23, VisQoL vs. APEDS-VFQ, r = -0.66, z = -6.70; p < 0.001 for both). Older participants, female, and those with less than 12 years of education had lower utilities. CONCLUSIONS: The direct (TTO) and indirect (VisQoL) methods of utility evaluation tend to disagree in our patients with VI. Given the high completion rates of the VisQoL as compared with the TTO, the VisQoL may be a suitable alternative for utility assessment in an Indian population. PMID- 23628758 TI - Optical changes of the human cornea as a function of age. AB - PURPOSE: To assess the changes of the surfaces and optical properties of the cornea as a function of age. METHODS: The corneal shape of 407 normal eyes of 211 subjects with ages ranging from 4 to 79 years old was determined by means of Scheimpflug imaging. These data were analyzed by fitting their elevation topographies to a general surface model, which consists of a biconic plus a Zernike polynomial expansion. The analysis includes the computation of the position and orientation of the model in the three-dimensional space to determine the orientation of the optical axis and the apex coordinates. RESULTS: Both average corneal surfaces show negative conic constant plus higher order aspheric terms Z(0)(4) and Z(0)(6) are significant). These surfaces are misaligned between them and with the line of sight. Such misalignment increases with age as the cornea seems to rotate as a solid body. The apex curvature and the magnitude of the conic constant along the most curved meridian increase as well, but the largest change with age correspond to the aspheric terms Z(0)(4) and Z(0)(6). As a result, the spherical aberration (SA) of the average cornea increases with age at a rate similar to the total SA of the eye. CONCLUSIONS: The average corneal surfaces are misaligned general aspheres. Corneal SA is higher than total SA, but both SAs increase with age at a similar rate. This confirms that the lens is partially compensating SA and that such compensation is preserved with aging. Misalignment and solid body rotation seem to reduce astigmatism and coma for young and middle-aged corneas. PMID- 23628760 TI - Garment counting in a textile warehouse by means of a laser imaging system. AB - Textile logistic warehouses are highly automated mechanized places where control points are needed to count and validate the number of garments in each batch. This paper proposes and describes a low cost and small size automated system designed to count the number of garments by processing an image of the corresponding hanger hooks generated using an array of phototransistors sensors and a linear laser beam. The generated image is processed using computer vision techniques to infer the number of garment units. The system has been tested on two logistic warehouses with a mean error in the estimated number of hangers of 0.13%. PMID- 23628759 TI - Inertial sensor-based two feet motion tracking for gait analysis. AB - Two feet motion is estimated for gait analysis. An inertial sensor is attached on each shoe and an inertial navigation algorithm is used to estimate the movement of both feet. To correct inter-shoe position error, a camera is installed on the right shoe and infrared LEDs are installed on the left shoe. The proposed system gives key gait analysis parameters such as step length, stride length, foot angle and walking speed. Also it gives three dimensional trajectories of two feet for gait analysis. PMID- 23628761 TI - Fast nearly ML estimation of Doppler frequency in GNSS signal acquisition process. AB - It is known that signal acquisition in Global Navigation Satellite System (GNSS) field provides a rough maximum-likelihood (ML) estimate based on a peak search in a two-dimensional grid. In this paper, the theoretical mathematical expression of the cross-ambiguity function (CAF) is exploited to analyze the grid and improve the accuracy of the frequency estimate. Based on the simple equation derived from this mathematical expression of the CAF, a family of novel algorithms is proposed to refine the Doppler frequency estimate with respect to that provided by a conventional acquisition method. In an ideal scenario where there is no noise and other nuisances, the frequency estimation error can be theoretically reduced to zero. On the other hand, in the presence of noise, the new algorithm almost reaches the Cramer-Rao Lower Bound (CRLB) which is derived as benchmark. For comparison, a least-square (LS) method is proposed. It is shown that the proposed solution achieves the same performance of LS, but requires a dramatically reduced computational burden. An averaging method is proposed to mitigate the influence of noise, especially when signal-to-noise ratio (SNR) is low. Finally, the influence of the grid resolution in the search space is analyzed in both time and frequency domains. PMID- 23628764 TI - Facile preparation of ordered mesoporous silica-carbon composite nanoparticles for glycan enrichment. AB - Silica-carbon composite nanoparticles (NP-MCM-C) with uniform shapes and highly ordered mesoporous structures are directly prepared by using template polymers as the carbon source. And, taking advantage of the size exclusion effect of the mesopores to proteins and the specific interaction between carbon and oligosaccharides, the prepared nanoparticles are utilized to enrich N-linked glycans from complex biological samples with high selectivity and efficiency. PMID- 23628762 TI - Charcot-Marie-Tooth disease-associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission. AB - Mitochondria and peroxisomes can be fragmented by the process of fission. The fission machineries of both organelles share a set of proteins. GDAP1 is a tail anchored protein of mitochondria and induces mitochondrial fragmentation. Mutations in GDAP1 lead to Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy, and affect mitochondrial dynamics. Here, we show that GDAP1 is also targeted to peroxisomes mediated by the import receptor Pex19. Knockdown of GDAP1 leads to peroxisomal elongation that can be rescued by re expressing GDAP1 and by missense mutated forms found in CMT patients. GDAP1 induced peroxisomal fission is dependent on the integrity of its hydrophobic domain 1, and on Drp1 and Mff, as is mitochondrial fission. Thus, GDAP1 regulates mitochondrial and peroxisomal fission by a similar mechanism. However, our results reveal also a more critical role of the amino-terminal GDAP1 domains, carrying most CMT-causing mutations, in the regulation of mitochondrial compared to peroxisomal fission. PMID- 23628763 TI - Cuf2 boosts the transcription of APC/C activator Fzr1 to terminate the meiotic division cycle. AB - The number of nuclear divisions in meiosis is strictly limited to two. Although the precise mechanism remains unknown, this seems to be achieved by adjusting the anaphase-promoting complex/cyclosome (APC/C) activity to degrade cyclin. Here, we describe a fission yeast cuf2 mutant that enters into a third nuclear division cycle, represented by ectopic spindle assembly and abnormal chromosome segregation. Cuf2 is a meiotic transcription factor, and its critical target is fzr1(+)/mfr1(+), which encodes a meiotic APC/C activator. fzr1Delta also enters a third nuclear division. Thus, Cuf2 ensures termination of the M-phase cycle by boosting Fzr1 expression to generate functional gametes. PMID- 23628766 TI - Connective tissue diseases: disease severity directly affected by diet in a mouse model of SLE. PMID- 23628768 TI - Osteoarthritis: chondroprotection by histone deacetylase inhibition. PMID- 23628772 TI - In silico optimization of phase-change materials for digital memories: a survey of first-row transition-metal dopants for Ge2Sb2Te5. AB - Phase-change materials are the alloys at the heart of an emerging class of next generation, non-volatile digital memory technologies. However, the widely studied Ge-Sb-Te system possesses several undesirable properties, and enhancing its properties, e.g. by doping, is an area of active research. Various first-row transition-metal dopants have been shown to impart useful property enhancements, but a systematic study of the entire period has yet to be undertaken, and little has been done to investigate their interaction with the host material at the atomic level. We have carried out first-principles computer simulations of the complete phase-change cycle in Ge2Sb2Te5 doped with each of the ten first-row transition metals. In this article, we present a comprehensive survey of the electronic, magnetic and optical properties of these doped materials. We discuss in detail their atomic-level structure, and relate the microscopic behaviours of the dopant atoms to their influence on the Ge2Sb2Te5 host. By considering an entire family of similar materials, we identify trends and patterns which might be used to predict suitable dopants for optimizing materials for specific phase change applications. The computational method employed here is general, and this materials-discovery approach could be applied in the future to study other families of potential dopants for such materials. PMID- 23628771 TI - Examining the differences in format and characteristics of zoonotic virus surveillance data on state agency websites. AB - BACKGROUND: Zoonotic viruses are infectious organisms transmittable between animals and humans. Agencies of public health, agriculture, and wildlife conduct surveillance of zoonotic viruses and often report data on their websites. However, the format and characteristics of these data are not known. OBJECTIVE: To describe and compare the format and characteristics of statistics of zoonotic viruses on state public health, agriculture, and wildlife agency websites. METHODS: For each state, we considered the websites of that state's public health, agriculture, and wildlife agency. For each website, we noted the presence of any statistics for zoonotic viruses from 2000-2012. We analyzed the data using numerous categories including type of statistic, temporal and geographic level of detail, and format. We prioritized our analysis within each category based on assumptions of individuals' preferences for extracting and analyzing data from websites. Thus, if two types of data (such as city and state-level) were present for a given virus in a given year, we counted the one with higher priority (city). External links from agency sites to other websites were not considered. RESULTS: From 2000-2012, state health departments had the most extensive virus data, followed by agriculture, and then wildlife. We focused on the seven viruses that were common across the three agencies. These included rabies, West Nile virus, eastern equine encephalitis, St. Louis encephalitis, western equine encephalitis, influenza, and dengue fever. Simple numerical totals were most often used to report the data (89% for public health, 81% for agriculture, and 82% for wildlife), and proportions were not different (chi-square P=.15). Public health data were most often presented yearly (66%), while agriculture and wildlife agencies often described cases as they occurred (Fisher's Exact test P<.001). Regarding format, public health agencies had more downloadable PDF files (68%), while agriculture (61%) and wildlife agencies (46%) presented data directly in the text of the HTML webpage (Fisher's Exact test P<.001). Demographics and other information including age, gender, and host were limited. Finally, a Fisher's Exact test showed no association between geography data and agency type (P=.08). However, it was noted that agriculture department data was often at the county level (63%), while public health was mixed between county (38%) and state (35%). CONCLUSIONS: This study focused on the format and characteristics of statistics of zoonotic viruses on websites of state public health, wildlife, and agriculture agencies in the context of population health surveillance. Data on zoonotic viruses varied across agencies presenting challenges for researchers needing to integrate animal and human data from different websites. PMID- 23628773 TI - Autologous vs. allogenic mesenchymal progenitor cells for the reconstruction of critical sized segmental tibial bone defects in aged sheep. AB - Mesenchymal progenitor cells (MPCs) represent an attractive cell population for bone tissue engineering. Their special immunological characteristics suggest that MPCs may be used in allogenic applications. The objective of this study was to compare the regenerative potential of autologous vs. allogenic MPCs in an ovine critical size segmental defect model. Ovine MPCs were isolated from bone marrow aspirates, expanded and cultured with osteogenic medium for 2weeks before implantation. Autologous and allogenic transplantation was performed using the cell-seeded scaffolds and unloaded scaffolds, while the application of autologous bone grafts served as a control group (n=6). Bone healing was assessed 12weeks after surgery by radiology, microcomputed tomography, biomechanical testing and histology. Radiology, biomechanical testing and histology revealed no significant differences in bone formation between the autologous and allogenic groups. Both cell groups showed more bone formation than the scaffold alone, whereas the biomechanical data showed no significant differences between the cell groups and the unloaded scaffolds. The results of the study suggest that scaffold-based bone tissue engineering using allogenic cells offers the potential for an off-the shelf product. Thus the results of this study serve as an important baseline for translation of the assessed concepts into clinical applications. PMID- 23628774 TI - Controllable transition of silk fibroin nanostructures: an insight into in vitro silk self-assembly process. AB - Silk fiber is one of the strongest and toughest biological materials with hierarchical structures, where nanofibril with size <20nm is a critical factor in determining its excellent mechanical properties. Although silk nanofibrils have been found in natural and regenerated silk solutions, there is no way to actively control nanofibril formation in aqueous solution. This study shows a simple but effective method of preparing silk nanofibrils by regulating the silk self assembly process. Through a repeated drying-dissolving process, a silk fibroin solution composed of metastable nanoparticles was first prepared and then used to reassemble nanofibrils with different sizes and secondary conformations under various temperatures and concentrations. These nanofibrils have a similar size to that of natural fibers, providing a suitable unit to further assemble the hierarchical structure in vitro. Several important issues, such as the relationships between silk nanofibrils, secondary conformations and viscosity, are also investigated, giving a new insight into the self-assembly process. In summary, besides rebuilding silk nanofibrils in aqueous solution, this study provides an important model for furthering the understanding of silk structures, properties and forming mechanisms, making it possible to regenerate silk materials with exceptional properties in the future. PMID- 23628775 TI - Enhanced differentiation of human neural crest stem cells towards the Schwann cell lineage by aligned electrospun fiber matrix. AB - Human pluripotent stem cell-derived neural crest stem cells (NCSCs) provide a promising cell source for generating Schwann cells in the treatment of neurodegenerative diseases and traumatic injuries in the peripheral nervous system. Influencing cell behavior through a synthetic matrix topography has been shown to be an effective approach to directing stem cell proliferation and differentiation. Here we have investigated the effect of nanofiber topography on the differentiation of human embryonic stem cell-derived NCSCs towards the Schwann cell lineage. Using electrospun fibers of different diameters and alignments we demonstrated that aligned fiber matrices effectively induced cell alignment, and that fiber matrices with average diameters of 600nm and 1.6MUm most effectively promoted NCSC differentiation towards the Schwann cell lineage compared with random fibers and two-dimensional tissue culture plates. More importantly, human NCSCs that were predifferentiated in Schwann cell medium for 2weeks exhibited higher sensitivity to the aligned fiber topography than undifferentiated NCSCs. This study provides an efficient protocol for Schwann cell derivation by combining an aligned nanofiber matrix and an optimized differentiation medium, and highlights the importance of matching extrinsic matrix signaling with cell intrinsic programming in a temporally specific manner. PMID- 23628777 TI - Temporal accuracy and variability in the left and right posterior parietal cortex. AB - Several brain-imaging and lesion studies have suggested a role for the posterior parietal cortex (PPC) in computing interval-timing tasks. PPC also seems to have a key role in modulating visuospatial mechanisms, which are known to affect temporal performance. By applying transcranial direct current stimulation (tDCS) over the left and right PPC, we aimed to modulate timing ability performance in healthy humans performing a cognitively controlled timing task. In two separate experiments we compared time-processing abilities of two groups of healthy adults submitted to anodal, cathodal or sham tDCS over right or left PPC, by employing a supra-second time reproduction task. Cathodal stimulation over the right PPC affected temporal accuracy by leading participants to overestimate time intervals. Moreover, when applied to the left PPC, it reduced variability in reproducing temporal intervals. No effect was reported for anodal stimulation. These results expand current knowledge on the role of the parietal cortex on temporal processing. We provide evidence that the parietal cortex of both hemispheres is involved in temporal processing by acting on distinct components of timing performance such as accuracy and variability. PMID- 23628776 TI - Adolescent drinking targets corticotropin-releasing factor peptide-labeled cells in the central amygdala of male and female rats. AB - Adolescence is a developmental period when many teenagers first drink alcohol and often engage in binge drinking. Early onset of alcohol is linked to increased risk of stress-related disorders in adulthood in humans, suggesting that alcohol may interfere with development of the stress regulatory system. We investigated the effect of voluntary alcohol exposure on corticotropin-releasing factor (CRF) peptide-producing cells in the central nucleus of the amygdala (CeA) in adolescent male and female rats. These cells are important for the autonomic and behavioral responses to stress, have been implicated in addiction, and change over adolescent development. Animals self-administered sweetened alcohol during early adolescence (postnatal days (PDs) 28-42) and brains were obtained on PD 43 for CRF peptide immunolabeling. Females had fewer CRF immunoreactive (-ir) cells in the CeA compared to males. In both males and females, alcohol self administration reduced the number of CRF-ir cells in the CeA compared to control conditions in which rats self-administered equivalent levels of sweetened water that did not contain alcohol. Reduced peptide labeling was not observed in the bed nucleus of the stria terminalis, indicating regional specificity of these changes. Alterations within the CRF cell population of the amygdala may have important implications for susceptibility to alcohol and stress disorders during adolescence and later on in life. PMID- 23628778 TI - Isolation and molecular characterization of Salmonella enterica serovar Javiana from food, environmental and clinical samples. AB - A total of 50 Salmonella enterica serovar Javiana isolates, isolated from food, environmental and clinical samples, were analyzed for antibiotic resistance, presence of virulence genes, plasmids and plasmid replicon types. To assess the genetic diversity, pulsed-field gel electrophoresis (PFGE) fingerprinting and plasmid profiles were performed. All of the isolates were sensitive to chloramphenicol, nalidixic acid, and sulfisoxazole, and four isolates showed intermediate resistance to gentamicin or kanamycin. Eleven isolates, including representatives from each of the source types, were resistant to ampicillin. Four isolates from either clinical or environmental sources were resistant to tetracycline, while an additional 20 isolates showed intermediate resistance to this drug. Fourteen isolates, primarily from food sources, showed intermediate resistance to streptomycin. The S. Javiana isolates were screened by PCR for 17 virulence genes (spvB, spiA, pagC, msgA, invA, sipB, prgH, spaN, orgA, tolC, iroN, sitC, IpfC, sifA, sopB, cdtB, and pefA). All isolates were positive for nine to fourteen of these genes, but none were positive for pefA, spvB and lpfC, which are typically present on the Salmonella virulence plasmid. Seven of the virulence genes including cdtB were found in all 50 isolates, suggesting that S. Javiana from food and environmental sources had virulence similar to clinical isolates. Four clinical isolates and two food isolates carried one or more plasmids of approximately 30, 38, and 58 kb, with the 58 kb plasmids belonging to incompatibility group IncFIIA. Two clinical isolates carried IncI1 type mega plasmid (80 kb), and one clinical isolate carried plasmids of 4.5 and 7 kb. The PFGE profiles resulted 34 patterns in five clusters at a 90% similarity threshold. Our results indicate that S. Javiana isolates have a diverse clonal population among the clinical, food and environmental samples and this serotype possesses several virulent genes and plasmids that can contribute to the development of salmonellosis in human. This study provides data that support the potential transmission of S. Javiana virulence factors from food and environmental sources to cause infections in humans. PMID- 23628779 TI - Intracellular trafficking of solid lipid nanoparticles and their distribution between cells through tunneling nanotubes. AB - The intracellular fate of nanosized drug delivery systems is still not well understood. Various internalization pathways have been discovered, but knowledge of their intracellular trafficking is still incomplete. The aim of this study was to examine the internalization, pathways, and positioning taken by solid lipid nanoparticles (SLNs) in cells. SLNs were fluorescence labeled with a newly synthesized fluorescent probe, 14-DACA. The probe was strongly incorporated into the nanoparticle core under the influence of its long lipophilic chain, enabling superior visualization of SLNs under complex and dynamic intracellular conditions. The intracellular distribution of SLNs was studied qualitatively using a co-localization technique and quantitatively using fluorescence intensity profiles. SLNs were seen inside the cells as distinct bright blue dots that underwent dynamic movement and were finally positioned in the proximity of the nucleus. A few SLNs were shown to be present in mitochondria and between actin filaments, but none in the cell nucleus or lysosomes. SLNs are here reported to be present in tunneling nanotubes (TNTs), which could be a new route of SLN transfer between cells. More TNTs were observed in cells treated with SLNs. The presence of TNTs was additionally confirmed by atomic force microscopy analysis, which indicated that treated cells were more rough than control cells. Detailed investigation of the subcellular localization of SLNs and the evidence for their transfer and distribution via TNTs to the cells, which are not in direct contact with the source of SLNs, are important for understanding the mechanism of targeted drug delivery. Understanding the possible intercellular distribution of SLNs via TNTs can significantly influence approaches to treating organelle specific diseases. PMID- 23628780 TI - In memory of Professor Leonor Michaelis in Nagoya: great contributions to biochemistry in Japan in the first half of the 20th century. AB - Leonor Michaelis spent the years of 1922-1926 as Professor of Biochemistry of the Aichi Medical College (now Graduate School of Medicine, Nagoya University) in Nagoya, Japan. Michaelis succeeded in gathering many bright young biochemists from all over Japan into his laboratory, and made tremendous contributions to the promotion of biochemistry in Japan. Michaelis was invited to many places in Japan to present lectures over those years. Kunio Yagi, who was Professor of Biochemistry at Nagoya University in the second half of the 20th century, succeeded in crystallizing the "Michaelis" enzyme-substrate complex. Historically, Michelis has had an enormous impact on biochemistry in Japan. PMID- 23628781 TI - Ablation of sarcolipin decreases the energy requirements for Ca2+ transport by sarco(endo)plasmic reticulum Ca2+-ATPases in resting skeletal muscle. AB - The purpose of this study was to examine the effects of sarcolipin (SLN) on sarco(endo) plasmic reticulum Ca(2+)-ATPase (SERCA pump) energetics in vivo and resting skeletal muscle metabolic rate. Using SLN knockout (Sln(-/-)) mice we show that SLN ablation increases the transport stoichiometry of SERCA pumps (Ca(2+) uptake/Ca(2+)-ATPase activity) and decreases the relative contribution of SERCA pumps to resting oxygen consumption (VO2) in soleus without affecting soleus or whole body VO2. These data suggest that the lower energy requirements for Ca(2+) cycling in resting skeletal muscle of Sln(-/-) mice do not impact significantly either skeletal muscle or whole body metabolic rate. PMID- 23628782 TI - The physiology and biomechanics of upper-body repeated sprints in ice sledge hockey. AB - PURPOSE: To investigate performance and the associated physiological and biomechanical responses during upper-body repeated-sprint work. METHODS: Twelve male ice sledge hockey players from the Norwegian national team performed eight 30-m sprints with start every 30 s and an active recovery between sprints. Time was captured every 10 m by photocells, cycle length and rate were determined by video analyses, and heart rate and blood lactate concentration were measured by conventional methods. RESULTS: The percentage sprint decrement was 7% over the 8 trials, with significant reductions in performance from the previous trial already on the second trial (all P < .05). Furthermore, cycle rate was reduced by 9% over the 8 trials (P < .05). Similar changes in performance and kinematic patterns were evident for all 10-m phases of the sprints. Heart rate gradually increased to 94% of maximal (178 +/- 10 beats/min) over the 8 trials, and the mean reduction in heart rate was 7 +/- 2 beats/min during the 22-24 s of active recovery for all trials (all P < .05). The blood lactate concentration increased to the athletes' maximal levels over the 8 sprints (P < .05). CONCLUSIONS: This is the first study to investigate performance, physiological, and biomechanical aspects of self-propelled upper-body repeated-sprint work. The observed sprint decrement over the 8 trials was associated with reductions in cycle rates and high physiological demands. However, no kinematic and physiological characteristics were significantly correlated to repeated-sprint ability or the sprint decrement. PMID- 23628783 TI - Is there a role for adrenaline during cardiopulmonary resuscitation? AB - PURPOSE OF REVIEW: To critically evaluate the recent data on the influence adrenaline has on outcome from cardiopulmonary resuscitation. RECENT FINDINGS: Two prospective controlled trials in out-of-hospital cardiac arrest (OHCA) have indicated that adrenaline increases the rate of return of spontaneous circulation (ROSC), but neither was sufficiently powered to determine the long-term outcomes. Several observational studies document higher ROSC rates in patients receiving adrenaline after OHCA, but these also document an association between receiving adrenaline and worse long-term outcomes. SUMMARY: Appropriately powered prospective, placebo-controlled trials of adrenaline in cardiac arrest are essential if the role of this drug is to be defined reliably. PMID- 23628784 TI - An ultrasensitive electrochemiluminescent immunoassay for aflatoxin M1 in milk, based on extraction by magnetic graphene and detection by antibody-labeled CdTe quantumn dots-carbon nanotubes nanocomposite. AB - An ultrasensitive electrochemiluminescent immunoassay (ECLIA) for aflatoxins M1 (ATM1) in milk using magnetic Fe3O4-graphene oxides (Fe-GO) as the absorbent and antibody-labeled cadmium telluride quantum dots (CdTe QDs) as the signal tag is presented. Firstly, Fe3O4 nanoparticles were immobilized on GO to fabricate the magnetic nanocomposites, which were used as absorbent to ATM1. Secondly, aflatoxin M1 antibody (primary antibody, ATM1 Ab1), was attached to the surface of the CdTe QDs-carbon nanotubes nanocomposite to form the signal tag (ATM1 Ab1/CdTe-CNT). The above materials were characterized. The optimal experimental conditions were obtained. Thirdly, Fe-GO was employed for extraction of ATM1 in milk. Results indicated that it can adsorb ATM1 efficiently and selectively within a large extent of pH from 3.0 to 8.0. Adsorption processes reached 95% of the equilibrium within 10 min. Lastly, the ATM1 with a serial of concentrations absorbed on Fe-GO was conjugated with ATM1 Ab1/CdTe-CNT signal tag based on sandwich immunoassay. The immunocomplex can emit a strong ECL signal whose intensity depended linearly on the logarithm of ATM1 concentration from 1.0 to 1.0 * 10(5) pg/mL, with the detection limit (LOD) of 0.3 pg/mL (S/N = 3). The method was more sensitive for ATM1 detection compared to the ELISA method. Finally, ten samples of milk were tested based on the immunoassay. The method is fast and requires very little sample preparation, which was suitable for high throughput screening of mycotoxins in food. PMID- 23628785 TI - Assessment of aflatoxin contamination of maize, peanut meal and poultry feed mixtures from different agroecological zones in Cameroon. AB - Mycotoxins affect poultry production by being present in the feed and directly causing a negative impact on bird performance. Carry-over rates of mycotoxins in animal products are, in general, small (except for aflatoxins in milk and eggs) therefore representing a small source of mycotoxins for humans. Mycotoxins present directly in human food represent a much higher risk. The contamination of poultry feed by aflatoxins was determined as a first assessment of this risk in Cameroon. A total of 201 samples of maize, peanut meal, broiler and layer feeds were collected directly at poultry farms, poultry production sites and poultry feed dealers in three agroecological zones (AEZs) of Cameroon and analyzed for moisture content and aflatoxin levels. The results indicate that the mean of the moisture content of maize (14.1%) was significantly (P < 0.05) higher than all other commodities (10.0%-12.7%). Approximately 9% of maize samples were positive for aflatoxin, with concentrations overall ranging from <=2 to 42 ug/kg. Most of the samples of peanut meal (100%), broiler (93.3%) and layer feeds (83.0%) were positive with concentrations of positive samples ranging from 39 to 950 ug/kg for peanut meal, 2 to 52 ug/kg for broiler feed and 2 to 23 ug/kg for layer feed. The aflatoxin content of layer feed did not vary by AEZ, while the highest (16.8 ug/kg) and the lowest (8.2 ug/kg) aflatoxin content of broiler feed were respectively recorded in Western High Plateau and in Rainforest agroecological zones. These results suggest that peanut meal is likely to be a high risk feed, and further investigation is needed to guide promotion of safe feeds for poultry in Cameroon. PMID- 23628786 TI - Structure, function, and biology of the Enterococcus faecalis cytolysin. AB - Enterococcus faecalis is a Gram-positive commensal member of the gut microbiota of a wide range of organisms. With the advent of antibiotic therapy, it has emerged as a multidrug resistant, hospital-acquired pathogen. Highly virulent strains of E. faecalis express a pore-forming exotoxin, called cytolysin, which lyses both bacterial and eukaryotic cells in response to quorum signals. Originally described in the 1930s, the cytolysin is a member of a large class of lanthionine-containing bacteriocins produced by Gram-positive bacteria. While the cytolysin shares some core features with other lantibiotics, it possesses unique characteristics as well. The current understanding of cytolysin biosynthesis, structure/function relationships, and contribution to the biology of E. faecalis are reviewed, and opportunities for using emerging technologies to advance this understanding are discussed. PMID- 23628788 TI - Risk factors for meniscal tears: a systematic review including meta-analysis. AB - STUDY DESIGN: Systematic review with meta-analysis. OBJECTIVES: To review and critically appraise the literature for factors that increase the risk for meniscal tears. BACKGROUND: Meniscal tears are an important cause of disability and time lost from work, and are associated with a 4-fold increase in the long term risk of knee osteoarthritis. Knowledge of the risk factors that lead to meniscal tears can help to correctly diagnose knee injuries and is important to the development of prevention strategies for knee osteoarthritis. METHODS: A search of the Cochrane Database of Systematic Reviews, MEDLINE, and Embase, from 1950 to January 2012, and a hand search of reference lists of all initially selected studies, without restriction on language or date of publication, were conducted. Prospective, retrospective, and case-control studies that included individuals over 16 years of age, who had no previous meniscal injuries or surgeries, were selected. A meta-analysis for 17 risk factors was performed. Where considerable heterogeneity among studies was present or the data did not provide sufficient information to perform a meta-analysis, a qualitative synthesis was conducted. RESULTS: Eleven studies, with a total of 7358 participants, were selected for systematic review. Data were available for meta analysis for 10 of the 11 studies. Qualitative analysis was conducted using data from 3 of the 11 studies. Results showed strong evidence that age (older than 60 years), gender (male), work-related kneeling and squatting, and climbing stairs (greater than 30 flights) were risk factors for degenerative meniscal tears. We also found strong evidence that playing soccer and playing rugby were strong risk factors for acute meniscal tears. Waiting longer than 12 months between the anterior cruciate ligament injury and reconstructive surgery was a strong risk factor for a medial meniscal tear but not for a lateral meniscal tear. CONCLUSION: The literature indicates a number of risk factors leading to either degenerative or acute meniscal tears, with some of these factors being potentially modifiable. LEVEL OF EVIDENCE: Prognosis, level 2a. PMID- 23628787 TI - The toxicological impacts of the Fusarium mycotoxin, deoxynivalenol, in poultry flocks with special reference to immunotoxicity. AB - Deoxynivalenol (DON) is a common Fusarium toxin in poultry feed. Chickens are more resistant to the adverse impacts of deoxynivalenol (DON) compared to other species. In general, the acute form of DON mycotoxicosis rarely occurs in poultry flocks under normal conditions. However, if diets contain low levels of DON (less than 5 mg DON/kg diet), lower productivity, impaired immunity and higher susceptibility to infectious diseases can occur. The molecular mechanism of action of DON has not been completely understood. A significant influence of DON in chickens is the impairment of immunological functions. It was known that low doses of DON elevated the serum IgA levels and affected both cell-mediated and humoral immunity in animals. DON is shown to suppress the antibody response to infectious bronchitis vaccine (IBV) and to Newcastle disease virus (NDV) in broilers (10 mg DON/kg feed) and laying hens (3.5 to 14 mg of DON/kg feed), respectively. Moreover, DON (10 mg DON/kg feed) decreased tumor necrosis factor alpha (TNF-alpha) in the plasma of broilers. DON can severely affect the immune system and, due to its negative impact on performance and productivity, can eventually result in high economic losses to poultry producers. The present review highlights the impacts of DON intoxication on cell mediated immunity, humoral immunity, gut immunity, immune organs and pro-inflammatory cytokines in chickens. PMID- 23628789 TI - Review of hair cell synapse defects in sensorineural hearing impairment. AB - OBJECTIVE: To review new insights into the pathophysiology of sensorineural hearing impairment. Specifically, we address defects of the ribbon synapses between inner hair cells and spiral ganglion neurons that cause auditory synaptopathy. DATA SOURCES AND STUDY SELECTION: Here, we review original publications on the genetics, animal models, and molecular mechanisms of hair cell ribbon synapses and their dysfunction. CONCLUSION: Hair cell ribbon synapses are highly specialized to enable indefatigable sound encoding with utmost temporal precision. Their dysfunctions, which we term auditory synaptopathies, impair audibility of sounds to varying degrees but commonly affect neural encoding of acoustic temporal cues essential for speech comprehension. Clinical features of auditory synaptopathies are similar to those accompanying auditory neuropathy, a group of genetic and acquired disorders of spiral ganglion neurons. Genetic auditory synaptopathies include alterations of glutamate loading of synaptic vesicles, synaptic Ca influx or synaptic vesicle turnover. Acquired synaptopathies include noise-induced hearing loss because of excitotoxic synaptic damage and subsequent gradual neural degeneration. Alterations of ribbon synapses likely also contribute to age-related hearing loss. PMID- 23628790 TI - A review of the effectiveness of otoacoustic emissions for evaluating hearing status after newborn screening. AB - OBJECTIVES: The purpose of this study was to give a brief review of the effectiveness of otoacoustic emissions for getting frequency-specific information about a hearing-loss problem in newborns after hearing screening. Especially, the advantages of distortion-product otoacoustic emissions (DPOAE) over transiently evoked otoacoustic emissions (TEOAEs) are described. DATA SOURCES: Approximately 186 ears of 104 children aged between 76 days and 15 years and 436 ears of adults with normal hearing and sensory hearing loss. METHODS: Extrapolated DPOAE I/O functions at frequencies between 1.5 and 6 kHz were obtained in the children for assessing the hearing loss and for differentiating between a transitory sound conductive hearing loss and a persisting cochlear hearing loss. For getting information on the test time needed, measurements were performed in the adult patients. RESULTS: DPOAE thresholds derived from extrapolated DPOAE I/O-functions (DPOAE audiograms) are closely related to behavior audiometric thresholds and can be used for determining characteristic quantities of the cochlear-impaired ear. A DPOAE audiogram can be obtained in a couple of minutes. DPOAE audiograms are able to reveal a transitory sound-conductive hearing loss because of Eustachian tube dysfunction and/or amniotic fluid in the tympanic cavity or to confirm a persisting cochlear hearing loss because of outer hair cell impairment in babies with a reference result in newborn hearing screening. CONCLUSION: DPOAE audiograms provide a tool for a fast automated frequency-specific and quantitative evaluation of a mild or moderate hearing in follow-up diagnosis. PMID- 23628791 TI - Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity. AB - The extra-pyramidal symptoms associated with manganism often overlap with that seen in Parkinsonism suggesting a common link between the two disorders. Since wide deviations are observed in susceptibility and characteristics of the symptoms observed in manganism, these differences may be due to underlying genetic variability. Genes linked to early onset of Parkinsonism which includes ATP13A2 and parkin have already been suggested to promote development of Mn toxicity. Of the other Parkinson-linked genes, mutations in LRRK2, an autosomal dominant gene, represent another likely candidate involved in the development of manganism. In this paper the effect of shRNA LRRK2 knock-down on Mn toxicity was examined in control and DAT transfected HEK293 cells. Results demonstrate that LRRK2 down-regulation potentiates Mn toxicity in both control and DAT-transfected cell as well as potentiates DA toxicity. Combined treatment of Mn and DA further augments cell toxicity, ROS production and JNK phosphorylation in LRRK2 deficient cells compared to controls. Consistent with studies demonstrating that LRRK2 plays a role in the phosphorylation of p38, our results similarly demonstrate a decrease in p38 activation in LRRK2 knock-down cells. Our findings suggest that null mutations in LRRK2 which cause Parkinsonism potentiate Mn toxicity and increase susceptibility to develop manganism. PMID- 23628793 TI - Label-free microRNA detection based on exchange-induced remnant magnetization. AB - We report a technique that is based on exchange-induced remnant magnetization for microRNA (miRNA) detection. In sequence-specific exchange reactions between label free miRNA and magnetically labelled RNA with one mismatched base, the decrease in magnetization quantitatively represents the target miRNA. The detection limit reaches the zeptomole regime, with no amplification or washing procedures. Therefore, our technique will be suitable for precise miRNA profiling to aid in early diagnosis of cancers. PMID- 23628792 TI - Differential response to acrylonitrile toxicity in rat primary astrocytes and microglia. AB - Acrylonitrile (ACN) is a widely used chemical in the production of plastics, resins, nitriles, acrylic fibers, synthetic rubber and acrylamide. While acute high level exposures to ACN are known to be lethal, chronic low dose exposures causes glial cell tumors in rats. Recently, these glial tumors have been characterized as microglial in origin. While effects of ACN on astrocytes, the more numerous glial cell, have been investigated, the effects on microglia are unknown. This study was conducted to compare the responses of astrocytes and microglia to ACN treatment in vitro to address differential sensitivities and adaptive responses to this toxic chemical. Cell viability, ACN uptake, lipid peroxidation byproducts (F2-isoprostanes), glutathione (GSH) levels and expression of NF-E2-related factor 2 (Nrf2) were evaluated in primary rat microglia and astrocytes following ACN treatment. Results indicate that microglia are more sensitive to ACN than astrocytes, accumulating less ACN while demonstrating higher F2-isoprostane levels. GSH levels were up-regulated in both cell types, as a protective mechanism against ACN-induced oxidative stress, while Nrf2 levels were only induced in microglia. Our data suggest that microglia and astrocytes exhibit different sensitivities and responses to ACN, which are linked to the intracellular thiol status inherent to each of these cell types. PMID- 23628794 TI - Exploiting the mechanism of cellular glucose uptake to develop an image-based high-throughput screening system in living cells. AB - Biophysical understanding of cellular glucose uptake led us to the development of an image-based high-throughput screening system by using a fluorescent glucose bioprobe, GB2. The accuracy, robustness, and practicality of our image-based HTS system were demonstrated through the pilot screening and the subsequent in vitro confirmation. PMID- 23628795 TI - The association between glycogen synthase kinase 3 beta polymorphisms and Parkinson's disease susceptibility: a meta-analysis. AB - Previous studies on the association between glycogen synthase kinase 3 beta (GSK3 beta) polymorphisms (rs334558 and rs6438552) and Parkinson's disease (PD) susceptibility remained inconsistent. Thus, the goal of this study was to re examine their exact association by a meta-analysis. All eligible studies were identified by a systematic literature search of multiple databases. Six studies (3105 cases and 4387 controls) on rs334558 and six studies (2579 cases and 4091 controls) on rs6438552 were included. The quality of these studies was generally good according to the Newcastle-Ottawa Scale (NOS). The meta-analysis showed null association between the two variants and PD susceptibility in all genetic models from the overall or Caucasian population. However, the analysis of rs334558 revealed that the risk of PD decreased in heterozygote, dominant or additive models (OR=0.60, 95% CI: 0.48, 0.74; OR=0.63, 95% CI: 0.51, 0.78; OR=0.82, 95% CI: 0.71, 0.94, respectively) from the Eastern Asian population. Moreover, the analysis on the homozygote, heterozygote, dominant or additive models suggested that rs6438552 also reduced the PD risk (OR=0.45, 95% CI: 0.24, 0.84; OR=0.62, 95% CI: 0.39, 0.97; OR=0.57, 95% CI: 0.37, 0.87; OR=0.66, 95% CI: 0.49, 0.88, respectively) in the Eastern Asian population. Together, the findings suggest that the two variants both reduced the risk of PD in the Eastern Asian subgroup but not in the overall and Caucasian populations, which should be cautiously interpreted because of limited number of included studies. PMID- 23628796 TI - Hemocyanin gene family evolution in spiders (Araneae), with implications for phylogenetic relationships and divergence times in the infraorder Mygalomorphae. AB - Hemocyanins are multimeric copper-containing hemolymph proteins involved in oxygen binding and transport in all major arthropod lineages. Most arachnids have seven primary subunits (encoded by paralogous genes a-g), which combine to form a 24-mer (4*6) quaternary structure. Within some spider lineages, however, hemocyanin evolution has been a dynamic process with extensive paralog duplication and loss. We have obtained hemocyanin gene sequences from numerous representatives of the spider infraorders Mygalomorphae and Araneomorphae in order to infer the evolution of the hemocyanin gene family and estimate spider relationships using these conserved loci. Our hemocyanin gene tree is largely consistent with the previous hypotheses of paralog relationships based on immunological studies, but reveals some discrepancies in which paralog types have been lost or duplicated in specific spider lineages. Analyses of concatenated hemocyanin sequences resolved deep nodes in the spider phylogeny and recovered a number of clades that are supported by other molecular studies, particularly for mygalomorph taxa. The concatenated data set is also used to estimate dates of higher-level spider divergences and suggests that the diversification of extant mygalomorphs preceded that of extant araneomorphs. Spiders are diverse in behavior and respiratory morphology, and our results are beneficial for comparative analyses of spider respiration. Lastly, the conserved hemocyanin sequences allow for the inference of spider relationships and ancient divergence dates. PMID- 23628797 TI - Significant association of urokinase plasminogen activator Pro141Leu with serum lipid profiles in a Japanese population. AB - Urokinase plasminogen activator (uPA) plays important physiological and pathological roles in fibrinolysis, cancer metastasis, and atherosclerosis. One study suggested that uPA also has a major role in cholesterol biosynthesis in humans via its receptor uPAR. Thus, we investigated the associations of functional uPA polymorphism (plasminogen activator, urokinase; PLAU Pro141Leu, rs2227564) with serum lipid profiles in a Japanese cohort. The study included 5152 participants (1465 male, 3687 female; age range, 35-69 years) of the Daiko Study, a part of the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). Subjects were enrolled at the Daiko Medical Center from June 2008 to May 2010. Low-density lipoprotein cholesterol (LDL-C) and non-HDL-C (subtraction of high-density lipoprotein cholesterol from total cholesterol) in fasting blood of participants were each classified into two groups, < or >= 140 mg/dL, and < or >= 170 mg/dL, respectively. Genotype frequencies of PLAU Pro141Leu (rs2227564) were 59.1% for ProPro, 35.6% for ProLeu, and 5.3% for LeuLeu, and were in Hardy Weinberg equilibrium (p=0.789). The allele frequencies were 0.769 for Pro and 0.231 for Leu. The multivariate-adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for high LDL-C and non-HDL-C were 1.11 (95%CI; 1.00-1.23) and 1.16 (95%CI; 1.03-1.30) for those with Leu allele relative to ProPro. This study suggested that PLAU Pro141Leu (rs2227564) is significantly associated with serum lipid levels in a Japanese population. PMID- 23628798 TI - Differential effects of insulin-like growth factor-1 CA repeat polymorphism on breast cancer risk along with race: a meta-analysis. AB - BACKGROUND: Insulin-like growth factor (IGF)-I has been implicated in processes leading to breast cancer initiation and progression. A CA repeat polymorphism in the promoter region of IGF-I may suppress transcriptional activity and be associated with risk of breast cancer. A variety of case-control studies have been published evaluating the association between IGF1 CA repeat polymorphism and breast cancer. However, those published studies yielded contradictory conclusions. RESULTS: This meta-analysis enrolled eleven studies to estimate the overall breast cancer risk of IGF1 CA repeat polymorphism. There was no significantly breast cancer risk found for pooled ORs among all the models. In the sub-stratified analysis by ethnicity, significantly decreased risks were found among Caucasian (19/19 versus non19/non19: OR=0.81, 95% CI: 0.70-0.94, P=0.922; 19/non19 versus non19/non19: OR=0.86, 95% CI: 0.74-0.99, P=0.005; dominant model: OR=0.84, 95% CI: 0.73-0.96, P=0.871). However, no significantly breast cancer risk was found among Asian and other ethnicities for all the genetic models. Furthermore, in the menopausal status stratified analysis, a significant decreased risk for postmenopausal woman was observed in the comparison of genotype 19/19 versus 19/non19+non19/non19: OR=0.89, 95% CI: 0.81 0.99, P=0.603. In addition, in the stratified analysis by case size, significantly decreased risk was observed in studies whose case size was more than 500 (19/19 versus 19/non19+non19/non19: OR=0.92, 95% CI: 0.86-1.00, P=0.457). CONCLUSIONS: This study suggested that genotype 19/19 of IGF1 CA repeat polymorphism is a decreased risk for developing breast cancer in Caucasian but not in Asian, indicating that the association might be adjusted by race. PMID- 23628799 TI - Hepatic nuclear factor 4alpha positively regulates complement C3 expression and does not interfere with TNFalpha-mediated stimulation of C3 expression in HepG2 cells. AB - Complement C3 is involved in various protective and regulatory mechanisms of immune system. Recently it was established that C3 expression is regulated by nuclear receptors. Hepatic nuclear factor 4alpha (HNF4alpha) is a nuclear receptor critical for hepatic development and metabolism. We have shown that HNF4alpha is a positive regulator of C3 gene expression, realizing its effects through binding to two HNF4-response elements within the C3 promoter in HepG2 cells. TNFalpha is a well established positive regulator of C3 expression in hepatocytes during acute phase of inflammation. TNFalpha decreases the amount of HNF4alpha protein in HepG2 cells through NF-kappaB and MEK1/2 pathways thereby leading to a decrease in HNF4alpha bound to the C3 promoter. TNFalpha and HNF4alpha act in a synergetic way resulting in the potent activation of C3 transcription. These results suggest a novel mechanism of C3 regulation during acute phase response in HepG2 cells and display the mechanism of interaction of TNFalpha-induced pathways and HNF4alpha in transcriptional regulation of C3 gene. PMID- 23628800 TI - Role of CYP1A2 1F polymorphism in cancer risk: evidence from a meta-analysis of 46 case-control studies. AB - BACKGROUND: Emerging evidence showed that the common polymorphism (CYP1A2 1F, rs762551 C->A) in the promoter region of the CYP1A2 gene might be associated with susceptibility to cancer in humans. But individually published results were inconclusive. The aim of this meta-analysis is to investigate the association between CYP1A2 1F polymorphism and cancer risk. METHODS: The Pubmed, Embase, Web of Science and Chinese BioMedical databases were searched for all articles published up to September 1st, 2012. Statistical analyses were performed using the STATA 12.0 software. RESULTS: Forty-six case-control studies were included with a total of 22,993 cancer cases and 28,420 healthy controls. Meta-analysis results showed that the A allele of CYP1A2 1F polymorphism was associated with a decreased cancer risk (odds ratio [OR]=0.92, 95% confidence interval [CI]: 0.87 0.98, P=0.013). In the subgroup analysis by cancer types, the A allele of CYP1A2 1F polymorphism may increase the risk of breast cancer (OR=1.05, 95% CI: 1.01 1.10, P=0.024), and is also associated with a decreased risk of ovarian cancer (OR=0.70, 95% CI: 0.54-0.89, P=0.004). However, similar results were not found in lung, colorectal, bladder, endometrial, pancreatic and gastric cancers. Further subgroup analysis by ethnicity also showed a significant association between the A allele of CYP1A2 1F polymorphism and a decreased cancer risk among Caucasian populations (OR=0.91, 95% CI: 0.84-0.98, P=0.014); but no significant associations were observed among Asian populations. CONCLUSIONS: Results from the current meta-analysis indicate that the A allele of CYP1A2 1F polymorphism may be associated with breast and ovarian cancer risk, especially among Caucasian populations. PMID- 23628801 TI - Association of the CAG repeat polymorphisms in androgen receptor gene with polycystic ovary syndrome: a systemic review and meta-analysis. AB - BACKGROUND: Many studies have reported the associations of polymorphic CAG repeats in androgen receptor (AR) gene with PCOS risk, but with inconsistent results. So, the aim of present meta-analysis was to clarify such inconsistence, so as to provide more conclusive results. METHODS: PubMed was searched for the eligible reports published until February 2012 without language limitation. The studies reporting the relationship between CAG repeat length and PCOS were selected for the meta-analysis according to the inclusion criteria. Two reviewers independently extracted the data and evaluated the study quality. PRINCIPAL FINDINGS: As for the relationship between CAG repeat length and PCOS risk, the pooled results showed that the biallelic mean was not significantly different between PCOS and controls (SMD -0.03, 95% CI -0.16-0.10, P=0.603), and that the ORs of PCOS were not demonstrated for the individuals with the biallelic mean less than median (OR 0.96, 95% CI 0.68-1.35, P=0.794), with the short CAG allele (OR 0.94, 95% CI 0.80-1.10, P=0.424), or with the X-weighted biallelic mean (OR 0.81, 95% CI 0.46-1.41, P=0.447). Further, as for the relationship between CAG repeat length and T levels in PCOS patients, the biallelic mean was not significantly different between PCOS patients with high T and those with low T (SMD 0.79, 95% CI -0.12-1.70, P=0.088), while the summary correlation r indicated that the CAG biallelic mean appeared to be positively associated with T levels in PCOS (r 0.20, 95% CI 0.11-0.30, p=0.000). CONCLUSIONS: This meta-analysis demonstrates no evident association between the CAG length variations in AR gene and PCOS risk, while the CAG length appears to be positively associated with T levels in PCOS patients. PMID- 23628802 TI - Regulation of TNF-alpha with a focus on rheumatoid arthritis. AB - Cytokines and chemokines represent two important groups of proteins that control the human immune system. Dysregulation of the network in which these immunomodulators function can result in uncontrolled inflammation, leading to various diseases including rheumatoid arthritis (RA), characterized by chronic inflammation and bone erosion. Potential triggers of RA include autoantibodies, cytokines and chemokines. The tight regulation of cytokine and chemokine production, and biological activity is important. Tumor necrosis factor-alpha (TNF-alpha) is abundantly present in RA patients' serum and the arthritic synovium. This review, therefore, discusses first the role and regulation of the major proinflammatory cytokine TNF-alpha, in particular the regulation of TNF alpha production, post-translational processing and signaling of TNF-alpha and its receptors. Owing to the important role of TNF-alpha in RA, the TNF-alpha producing cells and the dynamics of its expression, the direct and indirect action of this cytokine and possible biological therapy for RA are described. PMID- 23628803 TI - RNA decay tolerizes: MCPIP1 (Zc3h12a) keeps inflammation in check by cleaving 3' UTRs. PMID- 23628804 TI - In vivo regulation of chemokine activity by post-translational modification. AB - Cytokines and chemokines represent two important groups of proteins that control the immune system. Dysregulation of the network in which these immunomodulators function can result in uncontrolled inflammation leading to various diseases, including rheumatoid arthritis, characterized by chronic inflammation and bone erosion. Chemokine activity is regulated at multiple levels, such as post translational modification (PTM) of chemokines and their receptors by specific enzymes including proteases and peptidylarginine deiminases. Many in vitro experiments underscore the importance of post-translational processing of human chemokines. PTMs may enhance or reduce chemokine activity or may alter the receptor specificity of chemokine ligands. However, identification of chemokine isoforms in physiological in vivo settings forms the ultimate proof that PTM of chemokines is relevant in regulating the biological activity of these molecules. This review summarizes current knowledge on the in vivo role for PTMs in the regulation of chemokine activity. PMID- 23628805 TI - NKG2D CAR T-cell therapy inhibits the growth of NKG2D ligand heterogeneous tumors. AB - Tumor heterogeneity presents a substantial barrier to increasing clinical responses mediated by targeted therapies. Broadening the immune response elicited by treatments that target a single antigen is necessary for the elimination of tumor variants that fail to express the targeted antigen. In this study, it is shown that adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) inhibited the growth of target-expressing and -deficient tumor cells within ovarian and lymphoma tumors. Mice bearing the ID8 ovarian or RMA lymphoma tumors were treated with T cells transduced with a NKG2D-based CAR (chNKG2D). NKG2D CAR T-cell therapy protected mice from heterogeneous RMA tumors. Moreover, adoptive transfer of chNKG2D T cells mediated tumor protection against highly heterogeneous ovarian tumors in which 50, 20 or only 7% of tumor cells expressed significant amounts of NKG2D ligands. CAR T cells did not mediate an in vivo response against tumor cells that did not express sufficient amounts of NKG2D ligands, and the number of ligand-expressing tumor cells correlated with therapeutic efficacy. In addition, tumor-free surviving mice were protected against a tumor re-challenge with NKG2D ligand-negative ovarian tumor cells. These data indicate that NKG2D CAR T-cell treatment can be an effective therapy against heterogeneous tumors and induce tumor-specific immunity against ligand deficient tumor cells. PMID- 23628806 TI - Inside out: decoding the transcriptome of effector and memory T cells. PMID- 23628808 TI - Prostate cancer: prostatic swelling and shift upon HIFU. PMID- 23628807 TI - DNA methylation-based biomarkers in bladder cancer. AB - Urinary bladder cancer is the fifth most common cancer in the Western world. Increasing evidence has shown that DNA methylation in bladder cancer is expansive and is implicated in pathogenesis. Furthermore, distinct methylation patterns have been identified between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), as well as between FGFR3-mutant and wild type tumours. Given these distinctions in expression, methylated genes have been proposed as diagnostic and prognostic biomarkers for patients with bladder cancer. Indeed, several studies have revealed that methylated genes--including CDH1, FHIT, LAMC2, RASSF1A, TIMP3, SFRP1, SOX9, PMF1 and RUNX3--are associated with poor survival in patients with MIBC. Further validation of these markers for prognostication as well as surveillance (of patients with NMIBC) is required. Validated markers for progression, diagnosis, survival and BCG response will contribute to clinical decision-making and individualized treatment. PMID- 23628809 TI - Regenerative medicine: Transplantable functional kidney built on a biocompatible scaffold. PMID- 23628810 TI - Small renal masses: time to standardize follow-up of low-stage renal cancer. PMID- 23628811 TI - Engineering transglycosidase activity into a GH51 alpha-l-arabinofuranosidase. AB - Directed evolution was applied to the alpha-l-arabinofuranosidase from Thermobacillus xylanilyticus to confer better transglycosylation ability, particularly for the synthesis of benzyl alpha-l-arabinofuranosyl-(1,2)-alpha-d xylopyranoside, starting from p-nitrophenyl alpha-l-arabinofuranoside (donor) and benzyl alpha-d-xylopyranoside (acceptor). The aim was to obtain mutants displaying both lower hydrolytic and greater transglycosylation activities to favour the stable production of the target disaccharide. The implementation of a simple chromogenic screen ultimately provided three mutant enzymes whose properties correspond to those sought after. These all displayed lowered hydrolytic activity and conserved or slightly improved transfer activity, while one of them also displayed lowered secondary hydrolysis of the transglycosylation product. DNA sequence analysis of the mutants revealed between three and seven point mutations and biochemical analysis combined with STD-NMR experiments indicated that distinct molecular mechanisms were active among the three mutants. PMID- 23628812 TI - Global value of GM rice: a review of expected agronomic and consumer benefits. AB - Unlike the other major crops, no genetically modified (GM) varieties of rice have been commercialized at a large scale. Within the next 2-3 years new transgenic rice varieties could be ready for regulatory approval and subsequent commercialization, though. Given the importance of rice as staple crop for many of the world's poorest people, this will have implications for the alleviation of poverty, hunger and malnutrition. Thus, policy-makers need to be aware of the potential benefits of GM rice. We provide an overview of the literature and discuss the evidence on expected agronomic and consumer benefits of genetically engineered rice. We find that while GM rice with improved agronomic traits could deliver benefits similar to already commercialized biotechnology crops, expected benefits of consumer traits could be higher by an order of magnitude. By aggregating the expected annual benefits, we estimate the global value of GM rice to be US$64 billion per year. This is only an indicative value, as more GM varieties will become available in future. Nevertheless, such a figure can help guide policy-makers when deciding on the approval or funding of biotechnology crops and it may also raise awareness among consumers about what is at stake for their societies. PMID- 23628815 TI - Testing psychometric properties of the 30-item general health questionnaire. AB - This study aimed to evaluate the psychometric properties of the General Health Questionnaire (GHQ-30) given conflicting findings in the literature. A cross sectional, nonexperimental research was used with a convenience sample of 271 American female health care professionals. Data were collected by using self reported questionnaires. A series of exploratory factor analyses (EFAs), confirmatory factor analyses (CFAs), and structural equation modeling (SEM) were performed to examine underlying dimensions of the GHQ-30. Results from EFAs and CFAs revealed the three-factor composition (positive affect, anxiety, and depressed mood). All factor loadings were statistically significant, and one pair of error variance was allowed to be correlated. All factors contained questionnaire items with acceptable face validity and demonstrated good internal consistency reliability. Results from SEM further confirmed underlying constructs of the scale. To our knowledge, this is the first study that extensively tested the psychometric properties of the GHQ-30, taking both statistical and substantive issues into consideration. PMID- 23628816 TI - Analytical validation of a practical molecular assay prognostic of survival in nonsquamous non-small cell lung cancer. AB - A molecular assay prognostic of survival in resected nonsquamous non-small cell lung cancer designed to meet the need for improved risk stratification in early stage disease has recently been described. This assay measures the expression levels of 14 genes using RNA extracted from formalin-fixed, paraffin-embedded (FFPE) tissues. The assay underwent blinded clinical validation in 2 large international cohorts involving approximately 1500 patients; the analytical precision and reproducibility of this assay, however, have not yet been reported. For each of the 14 TaqMan quantitative polymerase chain reaction (PCR) primer and probe sets used in the molecular prognostic assay, the linear range, PCR efficiency, limits of blank, limits of quantitation, and quantitative bias were determined using serial dilutions of pooled RNA extracted from FFPE samples. The reproducibility of the entire molecular assay was determined by performing repeat testing of FFPE samples over multiple days. The linear range of individual quantitative TaqMan PCR primer and probe sets was between 2(10)- and 2(15)-fold input RNA. The median C(T) of the quantitative PCR primer and probe sets at 10 ng of input RNA was 24.3; the median efficiency was 91.2%. The median quantitative bias across all quantitative PCR primer and probe sets was 0.75% (range, 0.32% to 1.32%). In repeat testing, the mean SD of the risk score (scaled from 1 to 100) was 2.18, with a mean coefficient of variation of 0.08. The molecular prognostic assay presented in this study demonstrates high precision and reproducibility, validating its clinical utility as a reliable prognostic tool that can contribute to the management of patients with early-stage disease. PMID- 23628817 TI - Evaluation of 2-year experience with EGFR mutation analysis of small diagnostic samples. AB - Mutation analysis of the epidermal growth factor receptor (EGFR) gene is an essential part of the diagnostic algorithm in patients with metastatic or recurrent non-small cell lung cancer (NSCLC). Small biopsies or cytology specimens represent >80% of the available diagnostic material. EGFR mutation analyses were realized on 835 samples (675 cytology specimens, 151 formalin-fixed paraffin-embedded blocks, 5 tumors, and 4 pleural effusions). EGFR mutation analysis was performed by high-resolution melting analysis in combination with mutant-enriched polymerase chain reaction and sequencing analysis. Because of increased risk of inaccuracy in histology diagnosis of small specimens, all subtypes of NSCLC were analyzed. EGFR mutations were detected in 83 cases (10%). EGFR mutation testing failed in 5% (42/835) and was associated with poor cellularity, low percentage of tumor cells, and bad quality of DNA. Although 281 samples were evaluated as insufficient material (poor cellularity and/or unrepresentative tumor content), mutation rates were 7%. Although only adenocarcinomas or NSCLC-not otherwise specified are recommended for EGFR mutation testing, EGFR mutations in 11% of the large cell carcinomas and 4% of the squamous cell carcinomas were observed. Our results indicate that defined algorithm for EGFR testing of small diagnostic samples is sensitive, fast, and suitable even for samples with poor cellularity. The results of this testing should be evaluated depending on tumor content and DNA quality for each sample individually. At the conclusion of our results, we recommend to realize EGFR mutation analysis of small diagnostic samples regardless of the histologic subtypes of NSCLC. PMID- 23628818 TI - High-resolution genome-wide copy-number analyses identify localized copy-number alterations in Ewing sarcoma. AB - Ewing sarcoma family tumors are aggressive sarcomas of childhood and adolescence with continuing poor outcomes. Decades of research on the characteristics of the often solitary-known oncogenic-genomic aberration in Ewing sarcoma family tumors, namely a TET-ETS fusion, have provided little advancement in the understanding of the molecular pathogenesis of Ewing sarcoma or treatment thereof. In this study, the high-resolution single-nucleotide polymorphism technology was used to identify additional/secondary copy-number alterations (CNAs) in Ewing sarcoma that might elucidate the aggressive biology of this sarcoma. We compared paired constitutional and tumor DNA samples. Commonly known genomic alterations including gain of 1q and chromosome 8 were the most frequently detected changes in this study. In addition, deletions and loss of heterozygosity were identified in 10q, 11p, and 17p. Furthermore, tumor-specific CNAs were identified not only in genes previously known to be of interest, including CDKN2A, but also in genes not previously associated with Ewing sarcoma, including SOX6 and PTEN. Selected array-based findings were confirmed by fluorescence in situ hybridization, immunohistochemical studies, or sequencing. The results highlight an unexpected level of cytogenetic complexity associated with several of the samples, 2 of which contained TP53 mutations. In summary, our high-resolution genome-wide copy number data identify several novel CNAs associated with Ewing sarcoma, which are promising targets for novel therapeutic strategies in this aggressive sarcoma. PMID- 23628819 TI - Effect of HPV assay choice on perceived prevalence in a population-based sample. AB - Human papillomavirus (HPV) immunization programs clearly have considerable potential to reduce HPV-associated disease; they are also resource-intense; so, it is essential that their effectiveness is determined accurately and in a timely way. Measuring circulating HPV types in a population can provide an early measure of vaccine impact. We assessed the impact of HPV assay on the observed population prevalence of HPV in women who provided samples as part of a National HPV Immunisation Surveillance Exercise. A total of 1145 liquid-based cytology samples, 326 self-taken swabs, and 371 urine samples were tested with a line-blot assay (the Digene reverse hybridization HPV genotyping assay) and a luminex-based assay (the Mulitmetrix HPV genotyping assay). Assay agreement was determined for the different sample types. Positivity (according to assay) was compared at different levels ranging from positive for HPV 16 and/or 18 to positive for any one of the 18 HPV types common to both assays. The luminex assay consistently detected a higher prevalence of HPV--up to 10% for HPV types common to both assays. In addition, disagreement for HPV 16 and/or 18 was observed in around 9% of the overall sample, with an associated kappa score of 0.74. These data indicate that assay choice has a significant impact on observed prevalence of HPV, including vaccine types. The impact of any change of assay during longitudinal surveillance programs should thus be taken into account to avoid confounding the assessment of any vaccine-induced changes. PMID- 23628821 TI - EGFR promoter methylation detection in cervical cancer by a hybridization fluorescence polarization assay. AB - The methylation status of the epidermal growth factor receptor (EGFR) promoter is of potential predictive value for benefitting from EGFR inhibition therapy. Stratified therapy assignment for cervical cancer patients based on the EGFR promoter methylation status requires a simple detection method in the daily practice of diagnosis. A novel assay detecting the EGFR promoter methylation status in cervical cancer tissue samples using a hybridization-fluorescence polarization (FP) technique was developed. A pair of primers was used to amplify a 156 bp fragment in the promoter region of EGFR. Two probes specific for either methylated or unmethylated EGFR promoter DNA labeled with different fluorophores hybridized, respectively, with their target amplicons. The EGFR promoter methylation status was determined by the FP values. A total of 273 cervical cancer tissue samples were simultaneously analyzed using the new assay technique and combined bisulfite restriction analysis. The new assay was more sensitive compared with the combined bisulfite restriction analysis, and it allowed the discrimination of the EGFR promoter methylation status directly in solution without the restriction enzyme digestion. Sensitivity, specificity, and stability of the hybridization-FP assay had been recorded. The minimum detection level established with the new assay was 50 copies/MUL, and it was able to detect the minor population of the EGFR promoter methylation status even when its contents were as low as 10%. No cross-reaction was observed in the assay when the amount of plasmids used accounted for no more than 10(9) copies/MUL. The coefficient of variation of the reproducibility for the assay was <10%. PMID- 23628820 TI - Atypical Epstein-Barr viral genomic structure in lymphoma tissue and lymphoid cell lines. AB - Epstein-Barr virus (EBV) DNA is found within the malignant cells of some subtypes of lymphoma, and viral presence is being exploited for improved diagnosis, monitoring, and management of affected patients. Recent work suggests that viral genomic polymorphism, such as partial deletion of the viral genome, could interfere with virus detection in tumor tissues. To test for atypical forms of the EBV genome, 98 lymphomas and 6 infected cell lines were studied using a battery of 6 quantitative polymerase chain reaction assays targeting disparate sections of EBV DNA. Fifty of the lymphomas (51%) had no amplifiable EBV DNA, and 38 lymphomas (39%) had low-level EBV infection that was deemed incidental based on EBV-encoded RNA (EBER) in situ hybridization results. The remaining 10 lymphomas (10%) had high EBV loads and EBER localization to malignant cells by EBER in situ hybridization. All 10 represented lymphoma subtypes were previously associated with EBV (Burkitt, diffuse large B-cell, or T-cell type), whereas no remnants of EBV were detected in other lymphoma subtypes (follicular, small lymphocytic, mantle cell, or marginal zone type). Interestingly, 4 of the 10 infected lymphomas had evidence of atypical viral genomes, including 3 of 4 infected T-cell lymphomas with aberrant loss of LMP2 amplicons, and a single diffuse large B-cell lymphoma lacking the central part of the viral genome spanning BamH1W, BZLF1, and EBNA1 gene segments. A reasonable screening strategy for infected malignancy involves applying EBER1 and LMP1 quantitative polymerase chain reaction assays and confirming that values exceeding 2000 copies of EBV per 100,000 cells have EBER localization to malignant cells. PMID- 23628822 TI - Xp11.2 translocation renal cell carcinoma with PSF-TFE3 rearrangement. AB - Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) is a subtype of RCC characterized by translocations involving a breakpoint at the TFE3 gene (Xp11.2). Moderate to strong nuclear TFE3 immunoreactivity has been recognized as a specific diagnostic marker for this type of tumor. However, exclusive cytoplasmic localization of a TFE3 fusion protein was reported in UOK 145 cells, a cell line derived from an Xp11.2 RCC harboring the PSF-TFE3 translocation. If reproducible using immunohistochemistry (IHC), this finding would have important implications for pathologists in the diagnosis of Xp11.2 RCC, calling into question the specificity of nuclear immunoreactivity for TFE3 in these tumors. The purpose of this study was to determine whether the above-noted cytoplasmic localization of the TFE3 fusion protein could be reproduced using IHC. UOK 145 cells and fresh frozen tissue from 2 clinical cases of Xp11.2 RCC found to harbor the PSF-TFE3 gene rearrangement (by cytogenetic testing) were collected. All samples were subjected to histopathologic evaluation by board-certified pathologists, TFE3 IHC, reverse transcription polymerase chain reaction, and Sanger sequencing analysis. A strong nuclear TFE3 immunoreactivity was demonstrated in all samples including the UOK 145 cell line. No cytoplasmic immunoreactivity was seen. Reverse transcription polymerase chain reaction and Sanger sequencing confirmed the previously reported PSF-TFE3 gene fusion between exon 9 of PSF and exon 6 of TFE3 in the UOK 145 cell line and in one of 2 clinical cases of Xp11.2 RCC. A novel PSF-TFE3 gene fusion between exon 9 of PSF and exon 5 of TFE3 was detected in the second clinical case of Xp11.2 RCC. PMID- 23628823 TI - High incidence of MYCN amplification in a Moroccan series of neuroblastic tumors: comparison to current biological data. AB - MYCN protooncogene status was assessed for the first time in Morocco in peripheral neuroblastic tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Correlations with age at diagnosis, stage, mitosis karyorrhexis index, differentiation, and Shimada histology were evaluated. Thirty six formalin-fixed, paraffin-embedded peripheral neuroblastic tumor tissue specimens collected between 2007 and 2010 from the Pathology Department were assessed for MYCN amplification using fluorescence in situ hybridization. MYCN amplification was found in 27.8% of cases. An association of MYCN amplification with unfavorable Shimada grading, higher mitosis-karyorrhexis index, and undifferentiated morphologic phenotype was found. We found no correlation with older age, advanced stage, or the presence of metastasis. Our results suggested that the presence of MYCN amplification is a strong biological indicator of a poor outcome and aggressive disease in neuroblastoma and nodular ganglioneuroblastoma. PMID- 23628824 TI - Gallbladder carcinoma: high rate of mitochondrial D-loop mutations. AB - The molecular mechanisms leading to gallbladder carcinoma (GBC) are poorly understood. Different molecular disorders, including nuclear and mitochondrial genomic alteration, are associated with different cancers. The frequency of mitochondrial genome mutation has remained completely unexplored. In GBC, this is the first report of a mutation analysis in the mitochondrial genome, especially in the D-loop region. For a comprehensive D-loop view in GBC in humans, we sequenced the mitochondrial genome of 35 GBC patients and matched germ-line DNA. A wide range of point mutations and polymorphisms was observed. These variations in the D-loop sequence of human GBC represent good evidence of the mitochondrial role in GB carcinogenesis and may be used as a marker for GBC. PMID- 23628825 TI - Genetic diagnosis in recently transfused patients. AB - Analysis of recently transfused patients is usually postponed to avoid spurious results because of contamination with donor's cells. However, little is known about the extent of this influence in routine molecular diagnostic tests. To elucidate this question, we tested a mix of blood samples from 2 alpha-1 antitrypsin-deficient patients diagnosed as Pi*Z homozygous with 1 normal donor at 1:1, 1:10, 1:20, and 1:30 proportions. Human identification panel and Pi*Z allele detection were used to establish the detection limit of a blood mixture. Mixtures of 1:1 and 1:10 were easily detected with both techniques, whereas for 1:30, it was necessary to change the equipment settings to identify the mixture. Moreover, the heterozygous pattern observed for the mixtures on Pi*Z genotyping was weaker at this level of mixture. We further evaluated the degree of mixture detectable in 20 transfused patients who received 1 blood unit (concentrate of irradiated or nonirradiated red blood cells) using the human identification panel. Two days after the transfusion, the presence of the donor's markers was not detected, suggesting that after this time point the levels of admixture are below 1:30. The methods applied in the present study showed adequate sensitivity to identify alleles of the so-called "smaller population" of cells up to 3%, approximately. The same result was obtained in a "diagnostic situation," in which the blood mixture was submitted to a PCR-RFLP protocol to detect a mutation. PMID- 23628826 TI - A supramolecular switch between ground high- and low-spin states using 2,2':6',2''-terpyridine-6,6''-diyl bis(tert-butyl nitroxide). AB - Biradical 2,2':6',2''-terpyridine-6,6''-diyl bis(tert-butyl nitroxide) (tpybNO) showed intramolecular ferromagnetic coupling with 2J/kB = +2.14(10) K and its complex [Zn(tpybNO)(MeOH)2](BF4)2 exhibited intramolecular antiferromagnetic coupling with 2J/kB = -7.5(4) K, suggesting exchange coupling switchable by means of supramolecular chemistry. PMID- 23628827 TI - The role of the CoREST/REST repressor complex in herpes simplex virus 1 productive infection and in latency. AB - REST is a key component of the HDAC1 or 2, CoREST, LSD1, REST (HCLR) repressor complex. The primary function of the HCLR complex is to silence neuronal genes in non-neuronal cells. HCLR plays a role in regulating the expression of viral genes in productive infections as a donor of LDS1 for expression of alpha genes and as a repressor of genes expressed later in infection. In sensory neurons the HCLR complex is involved in the silencing of viral genome in the course of establishment of latency. The thesis of this article is that (a) sensory neurons evolved a mechanism to respond to the presence and suppress the transmission of infectious agents from the periphery to the CNS and (b) HSV evolved subservience to the HCLR with at least two objectives: to maintain a level of replication consistent with maximal person-to-person spread and to enable it to take advantage of neuronal innate immune responses to survive and be available for reactivation shielded from adaptive immune responses of the host. PMID- 23628828 TI - Antiviral activity of Bacillus sp. isolated from the marine sponge Petromica citrina against bovine viral diarrhea virus, a surrogate model of the hepatitis C virus. AB - The Hepatitis C virus causes chronic infections in humans, which can develop to liver cirrhosis and hepatocellular carcinoma. The Bovine viral diarrhea virus is used as a surrogate model for antiviral assays for the HCV. From marine invertebrates and microorganisms isolated from them, extracts were prepared for assessment of their possible antiviral activity. Of the 128 tested, 2 were considered active and 1 was considered promising. The best result was obtained from the extracts produced from the Bacillus sp. isolated from the sponge Petromica citrina. The extracts 555 (500 ug/mL, SI>18) and 584 (150 ug/mL, SI 27) showed a percentage of protection of 98% against BVDV, and the extract 616, 90% of protection. All of them showed activity during the viral adsorption. Thus, various substances are active on these studied organisms and may lead to the development of drugs which ensure an alternative therapy for the treatment of hepatitis C. PMID- 23628829 TI - Improved group contribution parameter set for the application of solubility parameters to melt extrusion. AB - Hot-melt extrusion is gaining importance for the production of amorphous solid solutions; in parallel, predictive tools for estimating drug solubility in polymers are increasingly demanded. The Hansen solubility parameter (SP) approach is well acknowledged for its predictive power of the miscibility of liquids as well as the solubility of some amorphous solids in liquid solvents. By solely using the molecular structure, group contribution (GC) methods allow the calculation of Hansen SPs. The GC parameter sets available were derived from liquids and polymers which conflicts with the object of prediction, the solubility of solid drugs. The present study takes a step from the liquid based SPs toward their application to solid solutes. On the basis of published experimental Hansen SPs of solid drugs and excipients only, a new GC parameter set was developed. In comparison with established parameter sets by van Krevelen/Hoftyzer, Beerbower/Hansen, Breitkreutz and Stefanis/Panayiotou, the new GC parameter set provides the highest overall predictive power for solubility experiments (correlation coefficient r = -0.87 to -0.91) as well as for literature data on melt extrudates and casted films (r = -0.78 to -0.96). PMID- 23628831 TI - The ideal time interval for critical care severity-of-illness assessment. AB - OBJECTIVE: Determine if the shortest sampling interval for laboratory variables used to estimate baseline severity of illness in pediatric critical care is equivalently sensitive across multiple sites without site-specific bias, while accounting for the vast majority of dysfunction compared with the standard 0- to 12-hour Pediatric Risk of Mortality III score. DESIGN: Prospective random patient selection. SETTING: General/medical and cardiac/cardiovascular PICUs in eight hospitals. PATIENTS: Patients younger than 18 years admitted to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 376 patients were included. Measurements for Pediatric Risk of Mortality III laboratory variables (pH, PCO2, total CO2, PaO2, glucose, potassium, blood urea nitrogen, creatinine, total WBC count, platelet count, and prothrombin time/partial thromboplastin time) were recorded from 2 hours prior to PICU admission through 12 hours of PICU care except for data in the operating room. Decreasing the observation period from 0 to 12 hours post-PICU admission resulted in progressive decreases in the Pediatric Risk of Mortality III laboratory variables measured. However, allowing the observation period to start 2 hours prior to PICU admission to 4 hours reduced this loss to only 3.4%. Similar trends existed for each of the individual laboratory Pediatric Risk of Mortality III variables. There was a nearly identical distribution of laboratory Pediatric Risk of Mortality III points within the -2- to 4-hour period compared with the standard period. We did not detect any institutional bias using the -2- to 4-hour time period compared with the baseline. CONCLUSIONS: Prognostically important laboratory physiologic data collected within the interval from 2 hours prior to PICU to admission through 4 hours after admission account for the vast majority of dysfunction that these variables would contribute to Pediatric Risk of Mortality III scores. There was no institutional bias associated with this sampling period. PMID- 23628832 TI - A survey of stated physician practices and beliefs on the use of steroids in pediatric fluid and/or vasoactive infusion-dependent shock. AB - OBJECTIVE: Limited evidence exists on the use of corticosteroids in pediatric shock. We sought to determine physicians' practices and beliefs with regard to the management of pediatric shock. DESIGN: Cross-sectional, Internet-based survey. SETTING: Canada. SUBJECTS: Physicians identified as practicing pediatric intensive care in any of 15 academic centers. MEASUREMENTS AND MAIN RESULTS: Seventy of 97 physicians (72.2%) responded. Physicians stated that they were more likely to prescribe steroids for septic shock than for shock following cardiac surgery (odds ratio, 1.9 [95% CI, 0.9-4.3]) or trauma (odds ratio, 11.46 [95% CI, 2.5-51.2]), and 91.4% (64/70) would administer steroids to patients who had received 60 cc/kg of fluid and two or more vasoactive medications. Thirty-five percent of respondents (25/70) reported that they rarely or never conducted adrenal axis testing before giving steroids to patients in shock. Eighty-seven percent of respondents (61/70) stated that the role of steroids in the treatment of fluid and/or vasoactive drug-dependent shock needed to be clarified and that 84.3% would be willing to randomize patients into a trial of steroid efficacy who were fluid resuscitated and on one high-dose vasoactive medication. However, 74.3% stated that they would start open-label steroids in patients who required two high-dose vasoactive medications. CONCLUSIONS: This survey provides information on the stated beliefs and practices of pediatric critical care physicians with regard to the use of steroids in fluid and/or vasoactive drug dependent shock. Clinicians feel that the role of steroids in shock still requires clarification and that they would be willing to randomize patients into a trial. This survey may be useful as an initial framework for the development of a future trial on the use of steroids in pediatric shock. PMID- 23628833 TI - Corticosteroid therapy in critically ill pediatric asthmatic patients. AB - OBJECTIVES: IV corticosteroids are routinely prescribed to treat critically ill children with asthma. However, no specific dosing recommendations have been made for children admitted to the PICU. We aim to determine current asthma corticosteroid dosing preferences in PICUs within North America. DESIGN: Cross sectional, self-administered survey. SETTING: North American PICUs. SUBJECTS: Pediatric intensivists working in the United States and Canada. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 104 intensivists completed the survey. Of these, 70% worked in the United States, 67% attended in PICUs with at most 20 beds, and 79% had more than 10 years of PICU experience. The majority of asthmatics were admitted to PICUs based on clinical asthma examination/score or because the patient was receiving continuous albuterol. IV methylprednisolone is prescribed by a large majority of intensivists (96%). Of those who prescribe methylprednisolone, 66% use a starting dose of 4 mg/kg/d, whereas 31% use a starting dose of 2 mg/kg/d, and only 3% use 1 mg/kg/d. The large majority of respondents (85%) use "clinical experience" as their rationale for their preferred dosage. In multivariate logistic regression analysis, only knowledge of the National Heart, Lung, and Blood Institute guidelines was an independent predictor of prescribing an initial corticosteroid dose of 4 mg/kg/d (odds ratio, 3.69 [95% CI, 1.26-10.80]; p = 0.017). Country of practice, years of experience, and PICU size were not associated with corticosteroid dosing preference. CONCLUSIONS: Most intensivists administer methylprednisolone to critically ill asthmatics at doses 2 to 4 times higher than recommended by the National Heart, Lung, and Blood Institute guidelines for hospitalized asthmatic children. The rationale for these decisions is likely multifactorial, but in the absence of evidence-based data, most of them cite clinical experience as their deciding factor. Future research is needed to determine the most appropriate corticosteroid dosage in this critically ill patient population. PMID- 23628834 TI - Influences of cannula size and flow rate on aerosol drug delivery through the Vapotherm humidified high-flow nasal cannula system. AB - OBJECTIVE: We investigated the in vitro inspired dose and particle size distribution of albuterol delivered by a vibrating mesh nebulizer through the Vapotherm (Stevensville, MD) humidified high-flow nasal cannula system. DESIGN: Albuterol (2.5 mg/3 mL) was delivered by an Aeroneb Solo (Aerogen, Galway, Ireland) nebulizer that was connected via adaptor proximal to the nasal cannula and downstream from the Vapotherm 2000i. Albuterol was collected onto an inspiratory filter mounted to a breath simulator programmed with age-appropriate breathing patterns. Particle sizing was completed by cascade impaction. Albuterol was quantified using ultraviolet spectrometry. Measurements were made using varying flow rates through infant, pediatric, and adult nasal cannulae. SETTING: Aerosol research laboratory. MEASUREMENTS AND MAIN RESULTS: The inspired dose (percent of nominal dose) for each cannula size and flow rate was 2.5%, 0.8%, 0.4%, and 0.2% for the adult cannula at 5, 10, 20, and 40 L/min, respectively; 1.2%, 0.6%, 0.1%, and 0.0% for the pediatric cannula at 3, 5, 10, and 20 L/min, respectively; and 0.6%, 0.6%, and 0.5% for the infant cannula at 3, 5, and 8 L/min, respectively. Most (62-80%) of the loaded albuterol dose accumulated within the adaptor. For each cannula size, there was a significant decrease in the inspired dose with increasing flow rates, p = 0.026 (infant), p = 0.001 (pediatric), and p < 0.001(adult). The inspired dose increased with increasing cannula size for 5, 10, and 20 L/min (p = 0.007, p < 0.001, and p = 0.005, respectively). The mass median aerodynamic diameter for all trials was less than 5 um. CONCLUSION: The amount of albuterol delivered with the Vapotherm system using this model was lower than the amount expected for a clinical response for the majority of flow rates and cannula size combinations. Further studies are needed before routine use of aerosolized albuterol through a Vapotherm high-flow system can be recommended. PMID- 23628835 TI - Ultrasound-guided radial artery catheterization in infants and small children. AB - OBJECTIVE: To determine whether ultrasound guidance increases the success rates, decreases the complication rates, and shortens the time to successful radial artery catheterization in infants and small children. DESIGN: Randomized study. SETTING: Single university-affiliated hospital. PATIENTS: Infants and children weighing 3-20 kg, undergoing cardiac surgery for congenital heart disease. INTERVENTION: We randomly assigned the right and left radial arteries of patients undergoing arterial catheterization to ultrasound-guided technique versus the usual palpation technique. MEASUREMENTS: The primary study endpoints were the rates of successful cannulation at first and within three attempts. The secondary endpoints were time to radial artery identification, number of attempts for successful cannulation, and rate of complications. MAIN RESULTS: Compared with palpation, ultrasound-guided radial artery catheterization was successful in 76.3% versus 35.6% of first attempts and in 94.9% versus 50.8% of arteries after three attempts (both comparisons, p < 0.01). The median time [interquartile range] to identification of the arteries (18.5 seconds [11.25-27.25] vs 30 seconds [17.75-39.5]) was significantly shorter (p < 0.01), the number of attempts [interquartile range] at successful cannulation (1 [1-1] vs 2 [1-2]) was significantly fewer (p < 0.01), and the proportion of hematomas (5.1% vs 25.4%) was significantly lower (p < 0.01) in the ultrasound group than those in the palpation group. CONCLUSIONS: In infants and small children, ultrasound-guided radial artery catheterization was more successful and expeditious than the usual palpation technique. PMID- 23628836 TI - Using administrative data for mortality risk adjustment in pediatric congenital cardiac surgery. AB - OBJECTIVE: To evaluate the performance of risk-adjustment models from the University HealthSystem Consortium and the Agency for Healthcare Research Quality on an administrative dataset for children undergoing congenital cardiac surgery. DESIGN: Retrospective cross-sectional cohort analysis. SETTING: Multi institutional database of administrative data provided by the University HealthSystem Consortium. PATIENTS: Children whose discharge diagnosis had an associated cardiac surgical procedure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The performance of two risk-adjustment modeling schemata was measured in terms of discrimination and calibration, and receiver operating characteristic curves were compared. Model calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. A total of 19,436 patients were included in the analysis with 816 deaths and an unadjusted overall mortality rate of 4.2%. The University HealthSystem Consortium models applied to the entire population resulted in an area under the curve = 0.73, and by comparison, the Agency for Healthcare Research Quality risk-adjustment model revealed area under the curve = 0.86. The risk-adjustment model of the University HealthSystem Consortium subgroup of Circulatory System Major Diagnostic Category 5 showed better performance with area under the curve = 0.81. Calibration using the Hosmer-Lemeshow test failed to show good agreement between the predicted and actual outcomes across the University HealthSystem Consortium mortality risk groups with an overall standardized mortality ratio of 1.2 (95% CI, 1.1-1.3; p < 0.0001) and poor predictive ability for the highest risk group, with a nearly 1.5-fold overprediction of death. The Agency for Healthcare Research Quality model shared similar calibration results with an overall standardized mortality ratio of 1.6 (95% CI, 1.5-1.7; p < 0.0001) and a nearly two-fold underprediction of death in the highest risk group. CONCLUSIONS: Administrative data can be used to create risk-adjustment models in the congenital cardiac surgery population. Risk adjustment models generated from administrative data may represent an attractive addition to clinically derived models in pediatric congenital cardiac surgery patients and should be considered for use either alone or in combination with clinical data in future analyses where mortality is a measure of performance and quality. PMID- 23628837 TI - A dose-response study of dexmedetomidine administered as the primary sedative in infants following open heart surgery. AB - OBJECTIVE: To evaluate the dose-response relationship of dexmedetomidine in infants with congenital heart disease postoperative from open heart surgery. DESIGN: Prospective open-label dose-escalation pharmacokinetic-pharmacodynamic study. SETTING: Tertiary pediatric cardiac ICU. PATIENTS: Thirty-six evaluable infants, 1-24 months old, postoperative from open heart surgery requiring mechanical ventilation. INTERVENTIONS: Cohorts of 12 infants were enrolled sequentially to one of the three IV loading doses of dexmedetomidine (0.35, 0.7, and 1 mcg/kg) over 10 minutes followed by respective continuous infusions (0.25, 0.5, and 0.75 mcg/kg/hr) for up to 24 hours. MEASUREMENTS AND MAIN RESULTS: Dexmedetomidine plasma concentrations were obtained at timed intervals during and following discontinuation of infusion. Pharmacodynamic variables evaluated included sedation scores, supplemental sedation and analgesia medication administration, time to tracheal extubation, respiratory function, and hemodynamic parameters. Infants achieved a deeper sedation measured by the University of Michigan Sedation Scale score (2.6 vs 1) despite requiring minimal supplemental sedation (0 unit doses/hr) and fewer analgesic medications (0.07 vs 0.15 unit doses/hr) while receiving dexmedetomidine compared with the 12-hour follow-up period. Thirty-one patients were successfully extubated while receiving the dexmedetomidine infusion. Only one patient remained intubated due to oversedation during the infusion. While receiving dexmedetomidine, there was a decrease in heart rate compared with baseline, 132 versus 161 bpm, but there was an increase in heart rate compared with postinfusion values, 132 versus 128 bpm. There was no statistically or clinically significant change in mean arterial blood pressure. CONCLUSIONS: Dexmedetomidine administration in infants following open heart surgery can provide improved sedation with reduction in supplemental medication requirements, leading to successful extubation while receiving a continuous infusion. The postoperative hemodynamic changes that occur in infants postoperative from open heart surgery are multifactorial. Although dexmedetomidine may play a role in decreasing heart rate immediately postoperative, the changes were not clinically significant and did not fall below postinfusion heart rates. PMID- 23628838 TI - Multidisciplinary quality improvement initiative to reduce ventilator-associated tracheobronchitis in the PICU. AB - OBJECTIVE: To test the hypothesis that successful implementation of a care bundle designed to prevent nosocomial airway infection will be associated with decreased incidence of ventilator-associated tracheobronchitis. DESIGN: Prospective pre- and post interventional. SETTING: PICU at an academic medical center PATIENTS: : All patients admitted to the PICU who received invasive mechanical ventilation for greater than or equal to 48 hours between March 1, 2009, and December 31, 2011. INTERVENTION: Multidisciplinary, unit wide implementation of an evidence based care bundle to prevent ventilator-associated airway infection. MEASUREMENTS AND MAIN RESULTS: There were 725 patients included in the analysis (338 patients preintervention and 387 patients postintervention). Baseline ventilator associated tracheobronchitis rate in the preintervention period was 3.9 cases per 1,000 ventilator days compared with 1.8 cases per 1,000 ventilator days postintervention (p = 0.04, Fisher exact test). Compared with patients without ventilator-associated tracheobronchitis or ventilator-associated pneumonia, patients with ventilator-associated tracheobronchitis had fewer ventilator-free days in 28 days (4.9 vs 22; p < 0.0001, Mann-Whitney U test) and fewer ICU-free days in 28 days (0.5 vs 19; p < 0.0001, Mann-Whitney U test). These relationships remained significant after adjusting for covariates by multivariable linear regression. CONCLUSIONS: Successful implementation of a care bundle to prevent ventilator-associated infection was associated with decreased incidence of ventilator-associated tracheobronchitis. Development of ventilator-associated tracheobronchitis was independently associated with adverse outcomes in our cohort of pediatric ICU patients. PMID- 23628839 TI - Response of cardiac endocrine function to surgery stress is age dependent in neonates and children with congenital heart defects: consequences in diagnostic and prognostic accuracy of brain natriuretic peptide measurement. AB - OBJECTIVE: The aim of this study was to evaluate the diagnostic and prognostic accuracy of brain natriuretic peptide assay in neonates and children undergoing surgery for congenital heart disease. DESIGN: Prospective, observational study. SETTING: Single center. PATIENTS: We enrolled 336 consecutive children (median age, 6 mo [range, 0-37 mo]) undergoing cardiac surgery (87 neonates; age, 7 d [5 12]; median, 25th-75th percentile; 24 infants and children; age, 11 mo [4-60]) and 436 healthy controls. INTERVENTIONS: Brain natriuretic peptide was measured preoperatively, on every postoperative day in the ICU, and at discharge. Intubation time was the primary outcome. MEASUREMENTS AND MAIN RESULTS: Preoperative brain natriuretic peptide values in patients with congenital heart disease were higher than those in controls (p < 0.01). Brain natriuretic peptide had a good diagnostic accuracy in discriminating between patients with congenital heart disease and healthy controls with an area under the curve = 0.918 for neonates and area under the curve = 0.894 for older children. The best cutoff values, calculated by receiver operating characteristic analysis, were different for the two age subgroups with cutoff values of 363.5 ng/L for neonates and 23.5 ng/L for older children. At 24 hours after surgery, although brain natriuretic peptide decreased in neonates (baseline 2723 vs 1290 ng/L, p < 0.001), it increased in children (60 vs 365 ng/L at 24 hours, p < 0.001). Multivariable analysis identified the preoperative level of brain natriuretic peptide in infant/children and the difference in brain natriuretic peptide value (baseline 24 hours) in neonates, as independent predictors of intubation time. Furthermore, body surface area, Aristotle score, and cardiopulmonary bypass time had an independent significant effect on the endpoint in either group. CONCLUSIONS: Baseline cardiac endocrine function and its response to surgical stress are dependent on age in neonates and children, undergoing cardiac surgery for congenital heart disease. Brain natriuretic peptide shows a good diagnostic and prognostic accuracy in this setting, with different features in either neonates or infants/children subsets. PMID- 23628840 TI - The long-term effectiveness of need-supportive physical activity counseling compared with a standard referral in sedentary older adults. AB - This study compared the long-term effectiveness of three physical activity counseling strategies among sedentary older adults: a 1-contact referral (REFER), a 1-contact individualized walking program (WALK), and multiple-contact, individually tailored, and need-supportive coaching based on the self determination theory (COACH). Participants (n = 442) completed measurements before (pretest), immediately after (posttest), and 1 yr after (follow-up test) a 10-wk intervention. Linear mixed models demonstrated significant time-by condition interaction effects from pre- to posttest. More specifically, WALK and COACH yielded larger increases in daily steps and self-reported physical activity than REFER. Similarly, self-reported physical activity increased more from pre- to follow-up test in WALK and COACH compared with REFER. Autonomous motivation mediated the effect of perceived need-support on physical activity, irrespective of counseling strategy. These results demonstrate the long-term effectiveness of both a 1-contact individualized walking program and a more time-consuming, need supportive coaching, especially in comparison with a standard referral to local opportunities. PMID- 23628841 TI - Dendritic architectures based on bis-MPA: functional polymeric scaffolds for application-driven research. AB - Dendritic polymers are highly branched, globular architectures with multiple representations of functional groups. These nanoscale organic frameworks continue to fascinate researchers worldwide and are today under intensive investigation in application-driven research. A large number of potential application areas have been suggested for dendritic polymers, including theranostics, biosensors, optics, adhesives and coatings. The transition from potential to real applications is strongly dictated by their commercial accessibility, scaffolding ability as well as biocompatibility. A dendritic family that fulfills these requirements is based on the 2,2-bismethylolpropionic acid (bis-MPA) monomer. This critical review is the first of its kind to cover most of the research activities generated on aliphatic polyester dendritic architectures based on bis MPA. It is apparent that these scaffolds will continue to be in the forefront of cutting-edge research as their structural variations are endless including dendrons, dendrimers, hyperbranched polymers, dendritic-linear hybrids and their hybridization with inorganic surfaces. PMID- 23628842 TI - Identification of LiNbO3, LiNb3O8 and Li3NbO4 phases in thin films synthesized with different deposition techniques by means of XRD and Raman spectroscopy. AB - Phase composition of epitaxial/textured LiNbO3 films on sapphire substrates, grown by pulsed laser deposition, atmospheric pressure metal organic chemical vapor deposition and pulsed injection metal organic chemical vapor deposition was studied by conventional x-ray diffraction techniques. Raman spectroscopy, being highly sensitive to the symmetry of materials, was used as a countercheck in the compositional analysis. The wavenumbers of Raman modes of LiNb3O8 and Li3NbO4 phases were identified from Raman spectra of synthesized powders. Asymmetry of profiles of x-ray diffraction reflections of LiNbO3 films was studied. This asymmetry may have different origins which consequently may result in misleading conclusions about phase composition of textured LiNbO3 films. PMID- 23628843 TI - An amperometric glutamate biosensor based on immobilization of glutamate oxidase onto carboxylated multiwalled carbon nanotubes/gold nanoparticles/chitosan composite film modified Au electrode. AB - A method is described for the construction of a novel amperometric glutamate biosensor based on covalent immobilization of glutamate oxidase (GluOx) onto, carboxylated multi walled carbon nanotubes (cMWCNT), gold nanoparticles (AuNPs) and chitosan (CHIT) composite film electrodeposited on the surface of a Au electrode. The GluOx/cMWCNT/AuNP/CHIT modified Au electrode was characterized by scanning electron microscopy (SEM), fourier transform infra-red (FTIR) spectroscopy, electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). The biosensor measured current due to electrons generated at 0.135V against Ag/AgCl from H2O2, which is produced from glutamate by immobilized GluOx. The biosensor showed optimum response within 2s at pH 7.5 and 35 degrees C. A linear relationship was obtained between a wide glutamate concentration range (5-500MUM) and current (MUA) under optimum conditions. The biosensor showed high sensitivity (155nA/MUM/cm(2)), low detection limit (1.6MUM) and good storage stability. The biosensor was unaffected by a number of serum substances at their physiological concentrations. The biosensor was evaluated and employed for determination of glutamate in sera from apparently healthy subjects and persons suffering from epilepsy. PMID- 23628844 TI - A novel glucose colorimetric sensor based on intrinsic peroxidase-like activity of C60-carboxyfullerenes. AB - C60-carboxyfullerene, C60[C(COOH)2]2, has been proven to function as peroxidase mimetics that can catalyze the reaction of peroxidase substrate 3,3',5,5' tetramethylbenzidine (TMB) in the presence of H2O2 to produce a blue color reaction. Kinetic studies further indicate that C60[C(COOH)2]2 has an even higher affinity to TMB than that of the natural enzyme, horseradish peroxidase (HRP). C60[C(COOH)2]2/glucose oxidase (GOx)/TMB system provides a novel colorimetric sensor for glucose and shows good response toward glucose detection over a range of 1.0-40MUM with a limit of detection 0.5MUM (3sigma/slope). Moreover, this sensitive and selective sensor can be successfully applied for the quantitative determination of glucose in human serum. The results indicate that it is a simple, cheap, convenient, highly selective, sensitive, and easy handling colorimetric assay. PMID- 23628845 TI - Simultaneous capture and in situ analysis of circulating tumor cells using multiple hybrid nanoparticles. AB - Using hybrid nanoparticles (HNPs), we demonstrate simultaneous capture, in situ protein expression analysis, and cellular phenotype identification of circulating tumor cells (CTCs). Each HNP consists of three parts: (i) antibodies that bind specifically to a known biomarker for CTCs, (ii) a quantum dot that emits fluorescence signals, and (iii) biotinylated DNA that allows capture and release of CTC-HNP complex to an in-house developed capture & recovery chip (CRC). To evaluate our approach, cells representative of different breast cancer subtypes (MCF-7: luminal; SK-BR-3: HER2; and MDA-MB-231: basal-like) were captured onto CRC and expressions of EpCAM, HER2, and EGFR were detected concurrently. The average capture efficiency of CTCs was 87.5% with identification accuracy of 92.4%. Subsequently, by cleaving the DNA portion with restriction enzymes, captured cells were released at efficiencies of 86.1%. Further studies showed that these recovered cells are viable and can proliferate in vitro. Using HNPs, it is possible to count, analyze in situ protein expression, and culture CTCs, all from the same set of cells, enabling a wide range of molecular- and cellular based studies using CTCs. PMID- 23628846 TI - The N-end rule proteolytic system in autophagy. AB - The N-end rule pathway is a cellular proteolytic system that utilizes specific N terminal residues as degradation determinants, called N-degrons. N-degrons are recognized and bound by specific recognition components (N-recognins) that mediate polyubiquitination of low-abundance regulators and selective proteolysis through the proteasome. Our earlier work identified UBR4/p600 as one of the N recognins that promotes N-degron-dependent proteasomal degradation. In this study, we show that UBR4 is associated with cellular cargoes destined to autophagic vacuoles and is degraded by the lysosome. UBR4 loss causes multiple misregulations in autophagic pathways, including an increased formation of LC3 puncta. UBR4-deficient mice die during embryogenesis primarily due to defective vascular development in the yolk sac (YS), wherein UBR4 is associated with a bulk lysosomal degradation system that absorbs maternal proteins from the YS cavity and digests them into amino acids. Our results suggest that UBR4 plays a role not only in selective proteolysis of short-lived regulators through the proteasome, but also bulk degradation through the lysosome. Here, we discuss a possible mechanism of UBR4 as a regulatory component in the delivery of cargoes destined to interact with the autophagic core machinery. PMID- 23628847 TI - Pt, Pd and Au nanoparticles supported on a DNA-MMT hybrid: efficient catalysts for highly selective oxidation of primary alcohols to aldehydes, acids and esters. AB - Novel DNA-MMT hybrid supported metal nanoparticle catalysts, such as Pt/DNA-MMT, Pd/DNA-MMT, Au/DNA-MMT, were prepared for application in highly selective aerobic oxidation of primary alcohols to aldehydes, acids and esters, respectively. Taking advantage of the water-soluble reversibility of these catalysts, all the transformations could be performed smoothly in water and reuse of the catalysts has also been accomplished by a very simple phase separation process. PMID- 23628849 TI - Drugs allergic disorders. PMID- 23628848 TI - Prostate cancer susceptibility genes on 8p21-23 in a Dutch population. AB - BACKGROUND: Prostate cancer is the most commonly diagnosed cancer in men in Europe and the United States. Numerous studies have indicated genetics to have a major role in the aetiology of this disease; as much as 42% of the risk may be explained by heritable factors. Genome-wide association studies have detected an association between prostate cancer and chromosome 8p21-23. In this study, we analysed eight microsatellite (MS) markers in that region in order to confirm previous results and narrow down the location of candidate prostate cancer genes. METHODS: 292 cases and 278 controls were selected from the Netherlands Cohort Study (NLCS). The following MSs were used in the analyses: D8S136, D8S1734, D8S1742, D8S261, D8S262, D8S351, D8S511 and D8S520. Associations were evaluated using a chi(2) test and logistic regression. We checked for any effects on the association by tumour stage. RESULTS: Associations that were found confirmed previous research that pointed to the 8p21-23 region. Two MSs: D8S136 (odds ratio (OR), 0.69; P=4.00 * 10(-28)), and D8S520 (OR, 0.80; P=3.37 * 10(-11)), were consistently and strongly related with prostate cancer. Genotype analysis showed an additive effect for D8S136 (P-trend=6.22 * 10(-03)) and D8S520 (P-trend=2.62 * 10(-22)), suggesting an increased risk for people with a short number of repeats on both alleles at those markers. CONCLUSIONS: This study provides strong evidence that the 8p21-23 region is likely to harbour prostate cancer genes. PMID- 23628850 TI - Effects of downregulating oct-4 transcript by RNA interference on early development of porcine embryos. AB - The objective of this study was to investigate the role of the POU family transcription factor, Oct-4, in the early development of porcine embryos. We attempted Oct-4 downregulation of porcine early embryos by RNA interference, and evaluated Oct-4 suppression of developmental competencies and gene transcripts in porcine embryos. Injection of specific siRNA resulted in a distinct decrease in Oct-4 mRNA and protein expression in porcine embryos until at least the morula stage. Although the porcine embryos injected with Oct-4 siRNA were able to develop to the morula stage, these embryos failed to form blastocysts. Gene transcripts of caudal-like transcription factor (Cdx2) and fibroblast growth factor 4 (Fgf4), which were involved in segregation of the trophectderm and functionalization of the inner cell mass, were unchanged by Oct-4 siRNA injection. Our results indicated that Oct-4 is an important factor for porcine embryos and, in particular, for the regulation of porcine blastocyst formation. PMID- 23628851 TI - The first evidence for unilamellar vesicle formation of ionic liquids in aqueous solutions. AB - It was found for the first time that single tail ionic liquid (IL) surfactants, 1 alkyl-3-methylimidazolium bromides [C(n)mim]Br (n = 10, 12, 14), form unilamellar vesicles in aqueous solutions without any additives. With the increase in IL concentrations, the self-assembly of these ILs can transfer from spherical micelles to rodlike micelles and then to vesicles. PMID- 23628852 TI - Can a weight loss of one pound a week be achieved with a 3500-kcal deficit? Commentary on a commonly accepted rule. AB - Despite theoretical evidence that the model commonly referred to as the 3500-kcal rule grossly overestimates actual weight loss, widespread application of the 3500 kcal formula continues to appear in textbooks, on respected government- and health-related websites, and scientific research publications. Here we demonstrate the risk of applying the 3500-kcal rule even as a convenient estimate by comparing predicted against actual weight loss in seven weight loss experiments conducted in confinement under total supervision or objectively measured energy intake. We offer three newly developed, downloadable applications housed in Microsoft Excel and Java, which simulates a rigorously validated, dynamic model of weight change. The first two tools available at http://www.pbrc.edu/sswcp, provide a convenient alternative method for providing patients with projected weight loss/gain estimates in response to changes in dietary intake. The second tool, which can be downloaded from the URL http://www.pbrc.edu/mswcp, projects estimated weight loss simultaneously for multiple subjects. This tool was developed to inform weight change experimental design and analysis. While complex dynamic models may not be directly tractable, the newly developed tools offer the opportunity to deliver dynamic model predictions as a convenient and significantly more accurate alternative to the 3500-kcal rule. PMID- 23628853 TI - Time-course microarrays reveal modulation of developmental, lipid metabolism and immune gene networks in intrascapular brown adipose tissue during the development of diet-induced obesity. AB - OBJECTIVE: The aim of this study was to establish the time-course of molecular events in intrascapular brown adipose tissue (iBAT) during the development of diet-induced obesity using microarrays and molecular network analysis. DESIGN: C57BL/6J male inbred mice were fed a high-fat diet (HFD) or normal diet (ND) and killed at multiple time-points over 24 weeks. METHODS: Global transcriptional changes in iBAT were determined by time-course microarrays of pooled RNA (n=6, pools per time-point) at 2, 4, 8, 20 and 24 weeks using Illumina MouseWG-6 v2.0 Beadchips. Molecular networks were constructed using the Ingenuity knowledgebase based on differentially expressed genes at each time-point. RESULTS: Body weight and subcutaneous adipose were progressively increased over 24 weeks, whereas iBAT was significantly increased between 6 and 12 weeks in HFD-fed C57BL/6J mice compared with controls. Blood glucose and insulin levels were increased between 16 and 24 weeks. Time-course microarrays, revealed 155 differentially expressed genes at one or more time-points over 24 weeks in the iBAT of HFD-fed mice compared with controls. Time-course network analysis revealed a network of skeletal muscle development genes that was activated between 2 and 4 weeks, subsequently a network of immune trafficking genes was activated at 8 weeks. After 20 and 24 weeks, multiple lipid metabolism and immune response networks were activated. Several target genes identified by time-course microarrays were independently validated using RT-qPCR. Tnnc1 was upregulated early between 2 and 4 weeks, later Cd68 and Col1a1 were upregulated between 20 and 24 weeks, whereas 11beta-hydroxysteroid dehydrogenase (Hsd11b1) was consistently downregulated during the development of diet-induced obesity. CONCLUSION: Molecular networks in iBAT are modulated in a time-dependent manner in response to a HFD. A broad range of gene targets exists to alter molecular changes within iBAT during the development of diet-induced obesity. PMID- 23628856 TI - FISH identification of Helicoverpa armigera and Mamestra brassicae chromosomes by BAC and fosmid probes. AB - Since the Bombyx mori genome sequence was published, conserved synteny between B. mori and some other lepidopteran species has been revealed by either FISH (fluorescence in situ hybridization) with BAC (bacterial artificial chromosome) probes or linkage analysis. However, no species belonging to the Noctuidae, the largest lepidopteran family which includes serious polyphagous pests, has been analyzed so far with respect to genome-wide conserved synteny and gene order. For that purpose, we selected the noctuid species Helicoverpa armigera and Mamestra brassicae, both with n = 31 chromosomes. Gene-defined fosmid clones from M. brassicae and BAC clones from a closely related species of H. armigera, Heliothis virescens, were used for a FISH analysis on pachytene chromosomes. We recognized all H. armigera chromosomes from specific cross-hybridization signals of 146 BAC probes. With 100 fosmid clones we identified and characterized all 31 bivalents of M. brassicae. Synteny and gene order were well conserved between the two noctuid species. The comparison with the model species B. mori (n = 28) showed the same phenomenon for 25 of the 28 chromosomes. Three chromosomes (#11, #23 and #24) had two counterparts each in H. armigera and M. brassicae. Since n = 31 is the modal chromosome number in Lepidoptera, the noctuid chromosomes probably represent an ancestral genome organization of Lepidoptera. This is the first identification of a full karyotype in Lepidoptera by means of BAC cross hybridization between species. The technique shows the potential to expand the range of analyzed species efficiently. PMID- 23628855 TI - iTRAQ protein profile analysis of Citrus sinensis roots in response to long-term boron-deficiency. AB - Seedlings of Citrus sinensis were fertilized with boron (B)-deficient (0MUM H3BO3) or -sufficient (10MUM H3BO3) nutrient solution for 15weeks. Thereafter, iTRAQ analysis was employed to compare the abundances of proteins from B deficient and -sufficient roots. In B-deficient roots, 164 up-regulated and 225 down-regulated proteins were identified. These proteins were grouped into the following functional categories: protein metabolism, nucleic acid metabolism, stress responses, carbohydrate and energy metabolism, cell transport, cell wall and cytoskeleton metabolism, biological regulation and signal transduction, and lipid metabolism. The adaptive responses of roots to B-deficiency might include following several aspects: (a) decreasing root respiration; (b) improving the total ability to scavenge reactive oxygen species (ROS); and (c) enhancing cell transport. The differentially expressed proteins identified by iTRAQ are much larger than those detected using 2D gel electrophoresis, and many novel B deficiency-responsive proteins involved in cell transport, biological regulation and signal transduction, stress responses and other metabolic processes were identified in this work. Our results indicate remarkable metabolic flexibility of citrus roots, which may contribute to the survival of B-deficient plants. This represents the most comprehensive analysis of protein profiles in response to B deficiency. BIOLOGICAL SIGNIFICANCE: In this study, we identified many new proteins involved in cell transport, biological regulation and signal transduction, stress responses and other metabolic processes that were not previously known to be associated with root B-deficiency responses. Therefore, our manuscript represents the most comprehensive analysis of protein profiles in response to B-deficiency and provides new information about the plant response to B-deficiency. This article is part of a Special Issue entitled: Translational Plant Proteomics. PMID- 23628854 TI - FTO predicts weight regain in the Look AHEAD clinical trial. AB - BACKGROUND: Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity. We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss. METHODS: Established obesity risk alleles available on the Illumina CARe iSelect (IBC) chip were characterized in 3899 overweight or obese participants with type 2 diabetes from the Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive lifestyle intervention (ILI) and diabetes support and education (DSE) on cardiovascular morbidity and mortality. Primary analyses examined the interaction between 13 obesity risk polymorphisms in eight genes and randomized treatment arm in predicting weight change at year 1, and weight regain at year 4 among individuals who lost 3% or more of their baseline weight by year 1. RESULTS: No single-nucleotide polymorphisms (SNPs) were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1. However, fat mass and obesity associated gene (FTO) rs3751812 predicted weight regain within DSE (1.56 kg per risk allele, P=0.005), but not ILI (P=0.761), resulting in SNP * treatment arm interaction (P=0.009). In a partial replication of prior research, the obesity risk (G) allele at BDNF rs6265 was associated with greater weight regain across treatment arms (0.773 kg per risk allele), although results were of borderline statistical significance (P=0.051). CONCLUSIONS: Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss. PMID- 23628857 TI - Characterization of a spruce budworm chitin deacetylase gene: stage- and tissue specific expression, and inhibition using RNA interference. AB - Chitin deacetylase (CDA) catalyzes the conversion of chitin into chitosan, thereby modifying the physical properties of insect cuticles and peritrophic matrices. A lepidopteran chitin deacetylase gene (CfCDA2) was cloned from the spruce budworm, Choristoneura fumiferana, and found to generate two alternatively spliced transcripts, CfCDA2a and CfCDA2b. Transcriptional analysis using isoform specific RT-PCR primers indicated that both isoforms were upregulated during the molt. Interestingly, CfCDA2b transcripts were most abundant in the head during the molting stage while those of CfCDA2a were predominant in the epidermis during the feeding period. Injection of CfCDA2-specific dsRNA into C. fumiferana larvae or pre-pupae induced both abnormal phenotypes and high mortality, which resulted from an inability to shed the old cuticle. These results suggest that CfCDA2 plays an important role in the molting process, and that the two alternatively spliced transcripts have different functions during insect development. This is the first detailed characterization of lepidopteran chitin deacetylase gene. PMID- 23628858 TI - Direct AFM force mapping of surface nanoscale organization and protein adsorption on an aluminum substrate. AB - We investigate the nanoscale organization of a superficially hydroxylated Al substrate and its effect on subsequent protein adsorption using atomic force microscopy (AFM). For this purpose we used a mode which allows a direct mapping of a variety of surface properties (adhesion, elasticity, dissipation, etc.) to be probed simultaneously with topographical images. The hydroxylation treatment leads to a drastic modification of the surface morphology, owing to the formation of AlOOH compounds. In air, AFM images revealed the formation of regular nanorod like structures randomly distributed, inducing the appearance of nanoporous domains on the surface. In buffer solution, prior to the adsorption of proteins, the surface nanoscale organization is preserved, mainly due to the chemical stability of AlOOH compounds under these conditions. The adsorption of proteins on the obtained nanostructured surface was performed using either a globular (beta-lactoglobulin) or a fibrillar (collagen) protein and by modulating the adsorbed amount through the incubation time or the concentration of proteins in solution. At low amounts, collagen adsorbs on the whole surface without preferential localization. The surface topography remains similar to the bare surface, while significant changes were evidenced on adhesion and elasticity maps. This is due to the fact that the surface became adhesive and less stiff, owing to the presence of a soft and hydrated protein layer. By contrast, beta lactoglobulin tends to diffuse into the nanoporous domains, leading to their filling up, and the surface is blurred with a thick and dense protein layer upon increasing the amount of adsorbed molecules. Our findings demonstrate the interest in using AFM for surface mapping to investigate the mechanism of protein adsorption at the nanoscale on materials with high surface roughness. PMID- 23628863 TI - Relationship between gluteal muscle strength, corticospinal excitability, and jump-landing biomechanics in healthy women. AB - CONTEXT: Components of gluteal neuromuscular function, such as strength and corticospinal excitability, could potentially influence alterations in lower extremity biomechanics during jump landing. OBJECTIVE: To determine the relationship between gluteal muscle strength, gluteal corticospinal excitability, and jump-landing biomechanics in healthy women. SETTING: University laboratory. DESIGN: Descriptive laboratory study. PARTICIPANTS: 37 healthy women (21.08 +/- 2.15 y, 164.8 +/- 5.9 cm, 65.4 +/- 12.0 kg). INTERVENTIONS: Bilateral gluteal strength was assessed through maximal voluntary isometric contractions (MVIC) using an isokinetic dynamometer. Strength was tested in the open chain in prone and side-lying positions for the gluteus maximus and gluteus medius muscles, respectively. Transcranial magnetic stimulation was used to elicit measures of corticospinal excitability. Participants then performed 3 trials of jump landing from a 30-cm box to a distance of 50% of their height, with an immediate rebound to a maximal vertical jump. Each jump-landing trial was video recorded (2-D) and later scored for errors. MAIN OUTCOME MEASURES: MVICs normalized to body mass were used to assess strength in the gluteal muscles of the dominant and nondominant limbs. Corticospinal excitability was assessed by means of active motor threshold (AMT) and motor-evoked potentials (MEP) elicited at 120% of AMT. The Landing Error Scoring System (LESS) was used to evaluate jump-landing biomechanics. RESULTS: A moderate, positive correlation was found between dominant gluteus maximus MEP and LESS scores (r = .562, P = .029). No other significant correlations were observed for MVIC, AMT, or MEP for the gluteus maximus and gluteus medius, regardless of limb. CONCLUSIONS: The findings suggest a moderate relationship between dominant gluteus maximus corticospinal excitability and a clinical measure of jump-landing biomechanics. Further research is required to substantiate the findings and expand our understanding of the central nervous system's role in athletic movement. PMID- 23628864 TI - Excystment-dependent alteration of protein expression in terrestrial ciliate Colpoda cucullus. AB - Protein expression during the excystment of Colpoda cucullus was studied by SDS PAGE. The expression levels of 60-, 50- and 49-kDa proteins were markedly changed from the early to later stage of excystment. The 60-kDa protein (p60) was temporarily expressed first, and its expression was inhibited by actinomycin D. LC-MS/MS analysis showed that the amino acid sequences of p60 partially coincided with those of the Paramecium tetraurelia unnamed protein homologous to DEAD-box RNA helicase. These results suggest that p60 expression is enhanced by transcriptional regulation and may be involved in initiating the molecular events leading to cellular morphogenesis. PMID- 23628865 TI - First-principles study of the structural stability of cubic, tetragonal and hexagonal phases in Mn3Z (Z=Ga, Sn and Ge) Heusler compounds. AB - We investigate the structural stability and magnetic properties of the cubic, tetragonal and hexagonal phases of Mn3Z (Z=Ga, Sn and Ge) Heusler compounds using first-principles density-functional theory. We propose that the cubic phase plays an important role as an intermediate state in the phase transition from the hexagonal to the tetragonal phases. Consequently, Mn3Ga and Mn3Ge behave differently from Mn3Sn, because the relative energies of the cubic and hexagonal phases are different. This result agrees with experimental observations for these three compounds. The weak ferromagnetism of the hexagonal phase and the perpendicular magnetocrystalline anisotropy of the tetragonal phase obtained in our calculations are also consistent with experiment. PMID- 23628866 TI - Heteroarenes as high performance organic semiconductors. AB - The design, synthesis, and characterization of new organic semiconductors (OSCs) are important aspects for the development of next-generation optoelectronic devices. Structurally, organic semiconductors based on pi-conjugated molecules can be easily modified via rational synthesis to tune multi-level self-assembled structures and discover novel chemical, optical, and electronic properties. Heteroarenes, which contain chalcogens and nitrogens in fused aromatic rings, are being developed as promising semiconducting materials for applications in a variety of electronic devices due to their outstanding optoelectronic properties. We highlight recent approaches toward realizing high performance p-channel field effect transistors based on linear heteroacenes and heteroatom annulated polycyclic aromatics (PAHs) as key functional components. These comprehensive, but carefully orchestrated approaches simultaneously address (i) practical synthesis, (ii) tunable self-assembled packing arrangement as well as (iii) high electronic performance. PMID- 23628867 TI - Mixed donor-acceptor charge-transfer stacks formed via hierarchical self-assembly of a non-covalent amphiphilic foldamer. AB - A non-covalent, amphiphilic foldamer design leads to an efficient charge-transfer complex between dipyrene (donor) and naphthalene diimide (acceptor) derivatives, which further self-assembles into one-dimensional nanofibers with an alternate (mixed) donor-acceptor arrangement. PMID- 23628868 TI - Biomaterials and bioengineering tomorrow's healthcare. AB - Biomaterials are being used for the healthcare applications from ancient times. But subsequent evolution has made them more versatile and has increased their utility. Biomaterials have revolutionized the areas like bioengineering and tissue engineering for the development of novel strategies to combat life threatening diseases. Together with biomaterials, stem cell technology is also being used to improve the existing healthcare facilities. These concepts and technologies are being used for the treatment of different diseases like cardiac failure, fractures, deep skin injuries, etc. Introduction of nanomaterials on the other hand is becoming a big hope for a better and an affordable healthcare. Technological advancements are underway for the development of continuous monitoring and regulating glucose levels by the implantation of sensor chips. Lab on-a-chip technology is expected to modernize the diagnostics and make it more easy and regulated. Other area which can improve the tomorrow's healthcare is drug delivery. Micro-needles have the potential to overcome the limitations of conventional needles and are being studied for the delivery of drugs at different location in human body. There is a huge advancement in the area of scaffold fabrication which has improved the potentiality of tissue engineering. Most emerging scaffolds for tissue engineering are hydrogels and cryogels. Dynamic hydrogels have huge application in tissue engineering and drug delivery. Furthermore, cryogels being supermacroporous allow the attachment and proliferation of most of the mammalian cell types and have shown application in tissue engineering and bioseparation. With further developments we expect these technologies to hit the market in near future which can immensely improve the healthcare facilities. PMID- 23628869 TI - Understanding the viscoelastic behavior of collagen matrices through relaxation time distribution spectrum. AB - This study aims to provide understanding of the macroscopic viscoelastic behavior of collagen matrices through studying the relaxation time distribution spectrum obtained from stress relaxation tests. Hydrated collagen gel and dehydrated collagen thin film was exploited as two different hydration levels of collagen matrices. Genipin solution was used to induce crosslinking in collagen matrices. Biaxial stress relaxation tests were performed to characterize the viscoelastic behavior of collagen matrices. The rate of stress relaxation of both hydrated and dehydrated collagen matrices shows a linear initial stress level dependency. Increased crosslinking reduces viscosity in collagen gel, but the effect is negligible for thin film. Relaxation time distribution spectrum was obtained from the stress relaxation data by inverse Laplace transform. For most of the collagen matrices, three peaks at the short (0.3s ~1 s), medium (3s ~90 s), and long relaxation time (> 200 s) were observed in the continuous spectrum, which likely corresponds to relaxation mechanisms involve fiber, inter-fibril, and fibril sliding. Splitting of the middle peak was observed at higher initial stress levels suggesting increased structural heterogeneity at the fibril level with mechanical loading. The intensity of the long-term peaks increases with higher initial stress levels indicating the engagement of collagen fibrils at higher levels of tissue strain. PMID- 23628870 TI - A novel device to stretch multiple tissue samples with variable patterns: application for mRNA regulation in tissue-engineered constructs. AB - A broad range of cells are subjected to irregular time varying mechanical stimuli within the body, particularly in the respiratory and circulatory systems. Mechanical stretch is an important factor in determining cell function; however, the effects of variable stretch remain unexplored. In order to investigate the effects of variable stretch, we designed, built and tested a uniaxial stretching device that can stretch three-dimensional tissue constructs while varying the strain amplitude from cycle to cycle. The device is the first to apply variable stretching signals to cells in tissues or three dimensional tissue constructs. Following device validation, we applied 20% uniaxial strain to Gelfoam samples seeded with neonatal rat lung fibroblasts with different levels of variability (0%, 25%, 50% and 75%). RT-PCR was then performed to measure the effects of variable stretch on key molecules involved in cell-matrix interactions including: collagen 1alpha, lysyl oxidase, alpha-actin, beta1 integrin, beta3 integrin, syndecan-4, and vascular endothelial growth factor-A. Adding variability to the stretching signal upregulated, downregulated or had no effect on mRNA production depending on the molecule and the amount of variability. In particular, syndecan 4 showed a statistically significant peak at 25% variability, suggesting that an optimal variability of strain may exist for production of this molecule. We conclude that cycle-by-cycle variability in strain influences the expression of molecules related to cell-matrix interactions and hence may be used to selectively tune the composition of tissue constructs. PMID- 23628871 TI - Progressive alterations in microstructural organization and biomechanical response in the ApoE mouse model of aneurysm. AB - AAA is a complex disease that leads to a localized dilation of the infrarenal aorta that develops over years. Longitudinal information in humans has been difficult to obtain for this disease, therefore mouse models have become increasingly used to study the development of AAAs. The objective of this study was to determine any changes that occur in the biomechanical response and fiber microstructure in the ApoE(-/-) AngII mouse model of aneurysm during disease progression. Adult ApoE(-/-) AngII infused mice along with wild-type controls were taken at 14 and 28 d. Aortas were excised and tested simultaneously for biaxial mechanical response and ECM organization. Data sets were fit to a Fung type constitutive model to give peak strains and stiffness values. Images from two photon microscopy were quantified in order to assess the preferred fiber alignment and degree of fiber orientation. Biomechanical results found significant differences that were present at 14 d had returned to normal by 28 d along with significant changes in fiber orientation and dispersion indicating remodeling occurring within the aneurysmal wall. This return of some of the normal biomechanical function, in addition the continuing changes that occur in the microstructure suggest a restorative response that occurs in the ApoE(-/-) AngII infused model after the initial aneurysm formation. PMID- 23628874 TI - HIV in Africa demands complex cultural responses. PMID- 23628875 TI - Making the digital future a reality. PMID- 23628872 TI - Adipose and mammary epithelial tissue engineering. AB - Breast reconstruction is a type of surgery for women who have had a mastectomy, and involves using autologous tissue or prosthetic material to construct a natural-looking breast. Adipose tissue is the major contributor to the volume of the breast, whereas epithelial cells comprise the functional unit of the mammary gland. Adipose-derived stem cells (ASCs) can differentiate into both adipocytes and epithelial cells and can be acquired from autologous sources. ASCs are therefore an attractive candidate for clinical applications to repair or regenerate the breast. Here we review the current state of adipose tissue engineering methods, including the biomaterials used for adipose tissue engineering and the application of these techniques for mammary epithelial tissue engineering. Adipose tissue engineering combined with microfabrication approaches to engineer the epithelium represents a promising avenue to replicate the native structure of the breast. PMID- 23628876 TI - Recognising and responding to victims of human trafficking. PMID- 23628877 TI - Bad medicine: the way we manage diabetes. PMID- 23628878 TI - Checklists can reduce errors in intraoperative emergencies by 75%, says expert. PMID- 23628879 TI - The expansive realm of skull base neuroendoscopy. PMID- 23628880 TI - Negative effects on postural control after anterior cruciate ligament reconstruction as measured by the balance error scoring system. AB - CONTEXT: Anterior cruciate ligament (ACL) reconstruction is the standard of care for individuals with ACL rupture. Balance deficits have been observed in patients with ACL reconstruction (ACLR) using advanced posturography, which is the current gold standard. It is unclear if postural-control deficits exist when assessed by the Balance Error Scoring System (BESS), which is a clinical assessment of balance. OBJECTIVE: The purpose of this study is to determine if postural-control deficits are present in individuals with ACLR as measured by the BESS. PARTICIPANTS: Thirty participants were included in this study. Fifteen had a history of unilateral ACLR and were compared with 15 matched controls. INTERVENTIONS: The BESS consists of 3 stances (double-limb, single-limb, and tandem) on 2 surfaces (firm and foam). Participants begin in each stance with hands on their hips and eyes closed while trying to stand as still as possible for 20 s. MAIN OUTCOME MEASURES: Each participant performed 3 trials of each stance (18 total), and errors were assessed during each trial and summed to create a total score. RESULTS: We observed a significant group x stance interaction (P = .004) and a significant main effect for stance (P < .001). Post hoc analysis revealed that the ACLR group had worse balance on the single-leg foam stance than did controls. Finally, the reconstructed group had more errors when total BESS score was examined (P = .02). CONCLUSIONS: Balance deficits exist in individuals with ACLR as measured by the BESS. Total BESS score was different between groups. The only condition that differed between groups was the single leg stance on the unstable foam surface. PMID- 23628881 TI - Different muscarinic receptor subtypes modulate proliferation of primary human detrusor smooth muscle cells via Akt/PI3K and map kinases. AB - While acetylcholine (ACh) and muscarinic receptors in the bladder are mainly known for their role in the regulation of smooth muscle contractility, in other tissues they are involved in tissue remodelling and promote cell growth and proliferation. In the present study we have used primary cultures of human detrusor smooth muscle cells (HDSMCs), in order to investigate the role of muscarinic receptors in HDSMC proliferation. Samples were obtained as discarded tissue from men >65 years undergoing radical cystectomy for bladder cancer and cut in pieces that were either immediately frozen or placed in culture medium for the cell culture establishment. HDSMCs were isolated from samples, propagated and maintained in culture. [(3)H]-QNB radioligand binding on biopsies revealed the presence of muscarinic receptors, with a Kd of 0.10+/-0.02nM and a Bmax of 72.8+/ 0.1fmol/mg protein. The relative expression of muscarinic receptor subtypes, based on Q-RT-PCR, was similar in biopsies and HDSMC with a rank order of M2>=M3>M1>M4>M5. The cholinergic agonist carbachol (CCh, 1-100MUM) concentration dependently increased [(3)H]-thymidine incorporation (up to 46+/-4%). This was concentration-dependently inhibited by the general muscarinic receptor antagonist atropine and by subtype-preferring antagonists with an order of potency of darifenacin >4-DAMP>AF-DX 116. The CCh-induced cell proliferation was blocked by selective PI-3 kinase and ERK activation inhibitors, strongly suggesting that these intracellular pathways mediate, at least in part, the muscarinic receptor mediated cell proliferation. This work shows that M2 and M3 receptors can mediate not only HDSM contraction but also proliferation; they may also contribute bladder remodelling including detrusor hypertrophy. PMID- 23628883 TI - Remote magnetic navigation for accurate, real-time catheter positioning and ablation in cardiac electrophysiology procedures. AB - New remote navigation systems have been developed to improve current limitations of conventional manually guided catheter ablation in complex cardiac substrates such as left atrial flutter. This protocol describes all the clinical and invasive interventional steps performed during a human electrophysiological study and ablation to assess the accuracy, safety and real-time navigation of the Catheter Guidance, Control and Imaging (CGCI) system. Patients who underwent ablation of a right or left atrium flutter substrate were included. Specifically, data from three left atrial flutter and two counterclockwise right atrial flutter procedures are shown in this report. One representative left atrial flutter procedure is shown in the movie. This system is based on eight coil-core electromagnets, which generate a dynamic magnetic field focused on the heart. Remote navigation by rapid changes (msec) in the magnetic field magnitude and a very flexible magnetized catheter allow real-time closed-loop integration and accurate, stable positioning and ablation of the arrhythmogenic substrate. PMID- 23628884 TI - Color tuning of black for electrochromic polymers using precursor blends. AB - We demonstrate a facile controlling of the optical and colorimetric properties of a donor-acceptor conjugated polymer simply by varying the mix ratio of two precursors in a precursor blend. The conversion of a precursor blend results in an entirely new donor-acceptor polymer, distinct from the conjugated polymer of each precursor. Careful optimization of the mix ratio of two precursors results in a black electrochromic polymer. PMID- 23628882 TI - L-carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow. AB - BACKGROUND: In our model of a congenital heart defect (CHD) with increased pulmonary blood flow (PBF; shunt), we have recently shown a disruption in carnitine homeostasis, associated with mitochondrial dysfunction and decreased endothelial nitric oxide synthase (eNOS)/heat shock protein (Hsp)90 interactions that contribute to eNOS uncoupling, increased superoxide levels, and decreased bioavailable nitric oxide (NO). Therefore, we undertook this study to test the hypothesis that L-carnitine therapy would maintain mitochondrial function and NO signaling. METHODS: Thirteen fetal lambs underwent in utero placement of an aortopulmonary graft. Immediately after delivery, lambs received daily treatment with oral L-carnitine or its vehicle. RESULTS: L-Carnitine-treated lambs had decreased levels of acylcarnitine and a reduced acylcarnitine:free carnitine ratio as compared with vehicle-treated shunt lambs. These changes correlated with increased carnitine acetyl transferase (CrAT) protein and enzyme activity and decreased levels of nitrated CrAT. The lactate:pyruvate ratio was also decreased in L-carnitine-treated lambs. Hsp70 protein levels were significantly decreased, and this correlated with increases in eNOS/Hsp90 interactions, NOS activity, and NOx levels, and a significant decrease in eNOS-derived superoxide. Furthermore, acetylcholine significantly decreased left pulmonary vascular resistance only in L-carnitine-treated lambs. CONCLUSION: L-Carnitine therapy may improve the endothelial dysfunction noted in children with CHDs and has important clinical implications that warrant further investigation. PMID- 23628885 TI - Adaptive microbial population shifts in response to a continuous ethanol blend release increases biodegradation potential. AB - The fate of fuel releases largely depends on the poorly-understood response in microbial community structure and function. Here, we evaluate the impacts to the microbial community resulting from a pilot-scale continuous release (10 months) of a 10% v:v ethanol solution mixed with benzene and toluene (50 mg/L each). Microbial population shifts were characterized by pyrosequencing-based 16S rRNA analysis and by quantitative PCR targeting Bacteria, Archaea, and functional genes for methanogenesis (mcrA), acetogenesis (fhs) and aerobic degradation of aromatic hydrocarbons (PHE), which could occur in hypoxic micro-environments. The release stimulated microbial growth, increased species richness and diversity, and selected for genotypes involved in fermentative degradation (the relative abundance of mcrA and fhs increased 18- and 6-fold, respectively). The growth of putative hydrocarbon degraders and commensal anaerobes, and increases in microbial diversity and in degradation rates suggest an adaptive response that increases the potential for natural attenuation of ethanol blend releases. PMID- 23628886 TI - Assessing the combined risks of PAHs and metals in urban soils by urbanization indicators. AB - We quantitatively describe the impacts of urbanization on the accumulation of polycyclic aromatic hydrocarbons (PAHs) and heavy metals (HMs) in urban soils as well as their health risks to residents. Residential building age, population density, road density, and distance from urban center were used as urbanization level indicators. Significant correlations were found between those urbanization indicators and the amounts of PAHs, Cu, Cd, Pb, Zn and As in residential soils. The exposure time of soils to urban air was the primary factor affecting soil pollution, followed by local road density and population density. Factor analysis suggested that 59.0% of the elevated pollutant concentrations were caused by citywide uniform deposition, and 15.3% were resulted from short-range deposition and/or non-combustion processes. The combined health risks posed by soil PAHs and HMs were aggravated with time and can be expressed as functions of residence age, road density, and other urbanization indicators. PMID- 23628887 TI - Spatial and temporal variations in pentachlorophenol dissipation at the aerobic- anaerobic interfaces of flooded paddy soils. AB - Pentachlorophenol (PCP) dissipation occurs naturally in flooded soils and although dissipation half-lives vary between soil profiles at the millimeter scale the reason is poorly understood. Vertical variations of PCP dissipation were investigated in three typical Chinese paddy soils; Soil 1 (Umbraqualf), Soil 2 (Plinthudult) and Soil 3 (Tropudult). The soil depth was divided into a surface and a deep layer based upon different PCP dissipations in the surface layer of 40 93, 42-88 and 16-100% for Soils 1-3 respectively. In the deep layer, PCP was greatly dissipated in Soil 2, but much less in Soil 1 and Soil 3. Correlation analysis indicated that SO4(2-) and Fe(III) were negatively related to PCP dissipation. SO4(2-) and Cl(-) were highly mobile in the flooded soil profiles. Fe(III) reduction increased with increasing soil depth, and was inhibited by high SO4(2-) concentrations. PMID- 23628888 TI - Validating the use of embryonic fish otoliths as recorders of sublethal exposure to copper in estuarine sediments. AB - In this study we explore the use of fish otoliths ('earbones') as a tool for detecting exposure to heavy metals in sediments. Because otoliths are metabolically inert and incorporate chemical impurities during growth, they can potentially provide a more permanent record of pollutant exposure history in aquatic environments than soft tissues. To validate this technique we cultured embryos of a native Australian fish, the common Galaxias (Galaxias maculatus), in the laboratory on sediments spiked with copper in a concentration gradient. Our aims were to test whether exposure to copper contaminated sediments is recorded in the otoliths of embryos and determine over what range in concentrations we can detect differences in exposure. We found elevated copper levels in otoliths of embryos exposed to high copper concentrations in sediments, suggesting that otoliths can be used as a tool to track a history of exposure to elevated copper levels in the environment. PMID- 23628890 TI - On the role of electron-nucleus contact and microwave saturation in thermal mixing DNP. AB - We have explored the manifold physical scenarios emerging from a model of Dynamic Nuclear Polarization (DNP) via thermal mixing under the hypothesis of highly effective electron-electron interaction. When the electron and nuclear reservoirs are also assumed to be in strong thermal contact and the microwave irradiation saturates the target electron transition, the enhancement of the nuclear polarization is expected to be considerably high even if the irradiation frequency is set far away from the centre of the ESR line (as already predicted by Borghini) and the typical polarization time is reduced on moving towards the boundaries of the said line. More reasonable behaviours are obtained by reducing the level of microwave saturation or the contact between electrons and nuclei in the presence of nuclear leakage. In both cases the function describing the dependency of the steady state nuclear polarization on the frequency of irradiation becomes sharper at the edges and the build up rate decreases on moving off-resonance. Although qualitatively similar in terms of the effects produced on nuclear polarization, the degree of microwave saturation and of electron-nucleus contact has a totally different impact on electron polarization, which is of course strongly correlated to the effectiveness of saturation and almost insensitive, at the steady state, to the magnitude of the interactions between the two spin reservoirs. The likelihood of different scenarios is discussed in the light of the experimental data currently available in the literature, to point out which aspects are suitably accounted for and which are not by the declination of thermal mixing DNP considered here. PMID- 23628889 TI - Evidence for the widespread distribution of CRISPR-Cas system in the Phylum Cyanobacteria. AB - Members of the phylum Cyanobacteria inhabit ecologically diverse environments. However, the CRISPR-Cas (clustered regularly interspaced short palindromic repeats, CRISPR associated genes), an extremely adaptable defense system, has not been surveyed in this phylum. We analyzed 126 cyanobacterial genomes and, surprisingly, found CRISPR-Cas in the majority except the marine subclade (Synechococcus and Prochlorococcus), in which cyanophages are a known force shaping their evolution. Multiple observations of CRISPR loci in the absence of cas1/cas2 genes may represent an early stage of losing a CRISPR-Cas locus. Our findings reveal the widespread distribution of their role in the phylum Cyanobacteria and provide a first step to systematically understanding CRISPR-Cas systems in cyanobacteria. PMID- 23628891 TI - Assessment of subacromial space and its relationship with scapular upward rotation in college baseball players. AB - CONTEXT: Subacromial impingement is a common injury in baseball players and has been linked to a reduction in the subacromial space. In addition, it has been suggested that decreases in scapular upward rotation will lead to decreases in the subacromial space and ultimately impingement syndrome. OBJECTIVE: The objective of this study was to evaluate the relationship between acromiohumeral distance and scapular upward rotation in healthy college baseball players. DESIGN: Posttest-only study design. SETTING: Controlled laboratory setting. PARTICIPANTS: 24 healthy college baseball players. INTERVENTION: Participants were measured for all dependent variables at preseason. MAIN OUTCOME MEASURES: Acromiohumeral distance at rest and 90 degrees of abduction was measured with a diagnostic ultrasound unit. Scapular upward rotation at rest and 90 degrees of abduction was measured with a digital inclinometer. RESULTS: Dominant-arm acromiohumeral distance at rest and 90 degrees of abduction (P = .694, P = .840) was not significantly different than in the nondominant arm. In addition, there was not a significant correlation between acromiohumeral distance and scapular upward rotation at rest and 90 degrees of abduction for either the dominant or the nondominant arm. CONCLUSIONS: These results indicate that the acromiohumeral distance is not adapting in the dominant arm in healthy throwing athletes. In addition, a relationship was not identified between acromiohumeral distance and scapular upward rotation, which was previously suggested. These results may suggest that changes that are typically seen in an injured population may be occurring due to the injury and are not preexisting. In addition, scapular upward rotation may not be the only contributing factor to acromiohumeral distance. PMID- 23628893 TI - Intravesical electrostimulation versus sacral neuromodulation for incomplete spinal cord patients suffering from neurogenic non-obstructive urinary retention. AB - OBJECTIVES: To compare the efficacy of intravesical electrostimulation (IVES) versus sacral neuromodulation (SNM) in patients with incomplete spinal cord lesions (SCL) and neurogenic non-obstructive urinary retention (N-NOR). METHODS: In this retrospective study, 77 N-NOR patients underwent IVES (minimum 28 sessions), then after returning to voiding baseline symptoms, percutaneous first stage of SNM (lasting for minimum 4 weeks). After the two neuromodulation treatments, responders were categorized as patients experiencing both a 50% reduction of volume per catheterization per ml and a 50% reduction in number of catheterizations per day when comparing the 7-day voiding diaries at the end of both procedures to baselines. New urodynamics were performed subsequently. Responders to first stage of SNM underwent permanent SNM. RESULTS: Forty-eight patients responded to neither of the treatments, whereas 29 responded to both IVES and first-stage SNM. No significant statistical differences (P>0.05) were detected in the voiding diaries. Following the two procedures, the first sensation of bladder filling was either maintained or recovered by all responders, whereas the same 11 patients reached a bladder contractility index of >100. The 29 IVES responders lost their clinical benefits in a mean follow-up of 9.6 months. Only 10 out of the 29 patients became nonresponsive to permanent SNM, in a mean follow-up of 54 months. CONCLUSION: A strict correlation in terms of clinical and urodynamic patterns was demonstrated in patients with incomplete SCL and N-NOR, following IVES and first stage of SNM. However, voiding improvement through IVES was short-term when compared with the effects of permanent SNM. PMID- 23628892 TI - RNA binding properties of novel gene silencing pyrrole-imidazole polyamides. AB - Pyrrole-imidazole (PI) polyamides are a novel group of gene-silencing compounds, which bind to a minor groove of double stranded (ds)DNA in a sequence-specific manner. To explore the RNA binding properties of PI polyamides targeting rat transforming growth factor-beta1 (TGF-beta1 Polyamide) and influenza A virus (PA polyamide), we designed dsRNAs with an identical sequence to the target DNA and analyzed RNA binding properties of the polyamide. Biacore assay showed fast binding of TGF-beta1 Polyamide to the dsRNA, whereas mismatch polyamide did not bind to the dsRNA. Dissociation equilibrium constant (KD) value was 6.7*10(-7) of the target dsRNA. These results indicate that PI polyamide could bind to RNA with a 2 log lower binding affinity than its DNA-binding affinity. We designed a PI polyamide targeting the panhandle stem region of influenza A virus. KD value of the PI polyamide to dsRNA targeting influenza A virus was 4.6*10(-7). Gel-shift assay showed that TGF-beta1 and PA polyamides bound to the appropriate dsDNA, whereas these PI polyamides did not show obvious gel-shift with the appropriate dsRNA. Structural modeling suggests that PI polyamide binds to the appropriate B form dsDNA in the minor groove, whereas it does not fit in the minor groove to dsRNA. Thus PI polyamides have a lower binding affinity with target dsRNA than they do with dsDNA. The distinct binding properties of PI polyamides to dsRNA and dsDNA may be associated with differences of secondary structure and chemical binding properties between target RNA and DNA. PMID- 23628894 TI - Ru(II)-catalyzed intermolecular ortho-C-H amidation of aromatic ketones with sulfonyl azides. AB - Ru(II)-catalyzed intermolecular ortho-C-H amidation of weakly coordinating aromatic ketones with sulfonyl azides is reported. The developed reaction protocol can be extended to various substituted aromatic ketones to afford a wide range of desired C-N bond formation products in good yields. PMID- 23628895 TI - Transfer matrix method for optics in graphene layers. AB - A transfer matrix method is developed for optical calculations of non-interacting graphene layers. Within the framework of this method, optical properties such as reflection, transmission and absorption for single-, double- and multi-layer graphene are studied. We also apply the method to structures consisting of periodically arranged graphene layers, revealing well-defined photonic band structures and even photonic bandgaps. Finally, we discuss graphene plasmons and introduce a simple way to tune the plasmon dispersion. PMID- 23628896 TI - Ubiquitous trisulfur radical anion: fundamentals and applications in materials science, electrochemistry, analytical chemistry and geochemistry. AB - The trisulfur radical anion [S3](-) is well-known from inorganic chemistry textbooks as the blue chromophore in ultramarine blues in which this highly reactive species is trapped in a zeolitic framework. Recent findings have revealed that [S3](-) has a multi-faceted role in a variety of media, including alkali metal-sulfur batteries, aqueous solutions at high temperatures and pressures, and ionic liquids; it has also been used to detect trace amounts of water in organic solvents. This tutorial review illustrates how various physical techniques are used to identify a reactive species in solution and shows how elucidation of electronic structures can be used to explain spectroscopic and structural properties. Examples of the function of [S3](-) in materials science, electrochemistry, analytical chemistry and geochemistry are used to illustrate the widespread influence of this fundamentally important triatomic sulfur species. PMID- 23628898 TI - Immune complexes activate human endothelium involving the cell-signaling HMGB1 RAGE axis in the pathogenesis of lupus vasculitis. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of immune complexes (ICs), which contain a complex mixture of autoantigens nucleic acids, nucleic acids-associated proteins and corresponding autoantibodies. In SLE, ICs are deposited in multiple organs. Vasculopathy and vasculitis in SLE are typical complications and are associated with deposition of ICs on endothelium, endothelial activation and inflammatory cell infiltration. However, the effects of ICs on endothelial cells and the mechanisms involved remain unclear. In this study, we have demonstrated for the first time that ICs upregulated cell surface expression of the receptor for advanced glycation end products (RAGE), the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), increased the secretion of the chemokines interleukin 8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), the proinflammatoy cytokines interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF alpha) and promoted the activation of the transcription factor NF-kappaB p65 in human endothelial cells (P<0.05). ICs also increased transendothelial migration of monocytes (P<0.05). One of the mechanisms underlying these activating effects of ICs on human endothelial cells involves cell signaling by high-mobility group box 1 protein (HMGB1)-RAGE axis, as these effects can be partially blocked by HMGB1 A-box, soluble RAGE (sRAGE), SB203580, PD98059, Bay 117082 (P<0.05) and co treatment with these agents (P<0.05). In conclusion, ICs elicit proinflammatory responses in human endothelial cells and alter their function involving cellular signaling via the HMGB1-RAGE axis in the pathogenesis of SLE vasculitis. PMID- 23628899 TI - TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury. AB - Acute lung injury (ALI) frequently occurs after liver transplantation and major liver surgery. Proinflammatory mediators released by damaged liver after liver ischemia/reperfusion (I/R) injury might contribute to this form of ALI, but the underlying mechanisms have not been well characterized. High-mobility group box protein 1 (HMGB1), a recently identified proinflammatory cytokine, was found to be significantly higher in the serum after liver I/R injury. This study investigated whether HMGB1 was involved as a stimulating factor, and whether its downstream Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (p38MAPK), and activator protein-1 (AP-1) signaling pathways act as mediators in the development of liver I/R injury-induced ALI. Extensive ALI and lung inflammation was induced in a rat model of liver I/R injury. Serum HMGB1 was significantly higher after liver I/R injury, and more importantly, expression of HMGB1 mRNA and protein in the lung tissue was also significantly increased. We further found that liver I/R injury enhanced the expression of TLR4 mRNA and protein, and the activity of p38MAPK and AP-1 in the lung tissue. Inhibition of TLR4 expression in the lung tissue by infection with pGCSIL-GFP-lentivirus expressing small hairpin RNAs targeting the TLR4 gene (TLR4-shRNA lentivirus) significantly attenuated ALI, lung inflammation, and activity of p38MAPK and AP-1 in the lung tissue. These findings indicate that HMGB1 might contribute to the underlying mechanism for liver I/R injury-induced ALI and that its downstream TLR4, p38MAPK, and AP-1 signaling pathways are potentially important mediators in the development of ALI. PMID- 23628900 TI - MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1alpha/Fhl-1 pathway. AB - Hypoxia-induced pulmonary hypertension (PH), which is characterized by vasoconstriction and subsequent structural remodeling of blood vessels, is an important event in chronic obstructive pulmonary disease patients and in people living at high altitudes. Hypoxia-inducible factor-1alpha (HIF-1alpha) and its regulator four-and-a-half LIM (Lin-11, Isl-1 and Mec-3) domain 1 (Fhl-1) have important roles in hypoxia-induced PH. MicroRNA-206 (miR-206) is critical for myogenesis and related diseases; however, the role of miR-206 in hypoxia-induced PH is unknown. miR-206 expression was evaluated in a hypoxic rat model and in cultured hypoxic pulmonary artery smooth muscle cells (PASMCs) using real-time quantitative PCR (RT-qPCR). HIF-1alpha and Fhl-1 expression were evaluated using RT-qPCR, western blotting, immunohistochemistry and immunofluorescence. The function of miR-206 was assessed by transfecting miR-206 mimics and inhibitors. Dual-luciferase reporter gene assays and western blotting were performed to validate the target genes of miR-206. siRNA targeted against Fhl-1 was used to investigate the effect of Fhl-1 on miR-206. Flow cytometry was used to detect the cell cycle phase distribution in each group of PASMCs. Significant downregulation of miR-206 in hypoxic lung tissue and PASMCs was identified, whereas HIF-1alpha and Fhl-1 were upregulated in these samples. The expression of miR-206 in the serum was different from that in the lung tissue. Transfection of pre-miR miR-206 in hypoxic conditions led to increased expression of HIF-1alpha and Fhl-1 rather than abolishing hypoxia-induced HIF-1alpha and Fhl-1, as was expected, and promoted the entry of cells into the S phase and enhanced PASMC proliferation. Fhl-1-targeted siRNA in PASMC prevented cell proliferation and led to an increased proportion of cells in the G1 phase without altering miR-206 expression. Bioinformatic analysis and dual-luciferase reporter gene assays revealed direct evidence for miR-206 targeting of HIF-1alpha. In conclusion, hypoxia-induced downregulation of miR-206 promotes PH by targeting the HIF 1alpha/Fhl-1 pathway in PASMCs. miR-206 could be a triggering factor of early stage of hypoxia-induced PH. PMID- 23628901 TI - Interleukin-10 deficiency aggravates kidney inflammation and fibrosis in the unilateral ureteral obstruction mouse model. AB - Interleukin-10 functions as a general immunosuppressive cytokine, which also negatively regulates inflammatory responses through complex mechanisms. Recent studies suggested that IL-10 may also inhibit fibrosis in various diseased models. However, the role of IL-10 in renal fibrosis has not been demonstrated. Here, we investigated the effects of IL-10 in the development of renal tubulointerstitial fibrosis by creating the unilateral ureteral obstruction (UUO) model in IL-10 knockout (-/-) mice. We performed sham or unilateral ureteral obstruction surgery in 8-week-old IL-10-/- male mice and age and sex-matched wild type littermates. Mice were killed at 7 days or 14 days post surgery and renal tissues were obtained for RNA, protein, and immunohistochemical analysis. Our results found IL-10 deficiency resulted in enhanced renal fibrosis demonstrated by more severe tubular injury and collagen deposition and higher expression of pro-fibrotic genes (including alpha-SMA, MMP-2, fibronectin, FSP-1 and vimentin). Our results also found IL-10-/- UUO mice developed more severe renal inflammation with a significant increase in inflammatory cells infiltration, and upregulation of inflammatory chemokines (MCP-1 and RANTES), and cytokines (TNF-alpha, IL-6, IL 8, and M-CSF). Further study revealed that enhanced renal inflammation and fibrosis was associated with significantly increased activation of both TGF beta/Smad3 and NF-kappaB signaling pathways. In summary, our study provides the direct evidence that IL-10 is an endogenous cytokine that has a key role in protecting against development of renal inflammation and fibrosis. Enhancement of IL-10 expression could be a potential anti-fibrosis therapy for patients with chronic kidney diseases. PMID- 23628902 TI - Evaluation of leachate treatment by trickling filter and sequencing batch reactor processes in Ibadan, Nigeria. AB - Strong and highly polluting leachate is continuously discharged into Omi stream and its tributaries in Ibadan, southwest Nigeria, from a municipal solid waste landfill. Previous studies have targeted physical and chemical treatment methods, which could not be implemented on site as stand-alone treatment systems. This study explored the bench-scale, trickling filter (TF) and sequencing batch reactor (SBR) treatment processes and assessed the quality of effluents produced. Leachate treatment using TF produced effluents with significant reductions (%) in suspended solids (SS) (73.17%), turbidity (71.96%), biochemical oxygen demand (BOD5) (76.69%) and ammonia (NH3) (59.50%), while SBR produced effluents with reductions in SS (62.28%), BOD5 (84.06%) and NH3 (64.83%). The dissolved oxygen of the reactors was 4.7 and 6.1mg/l, respectively, in TF and SBR. Also, NH3 values reduced marginally; however, nitrification took place significantly, but within permissible limits. The effluents produced by biological treatment processes were better in quality though the mean residual concentrations for colour, SS and dissolved solids; BOD5 and iron were above the national regulatory standards for discharge into surface water bodies. SBR gave a better effluent quality and should be combined with other treatment methods in sequence to produce quality effluents. PMID- 23628903 TI - Development of reactive artificial liner using recycled materials. 2. Chemical transport properties. AB - Volatile organic compounds (VOCs) have so far been found to permeate through geomembranes within days and potentially pollute the surrounding groundwater if no sufficient depth of underlain soil barrier existed In order to cope with the fast breakthrough of VOCs through high-density polyethylene (HDPE) geomembrane in the composite liner system, a composite material made of recycled materials was proposed and its mechanical properties were analyzed in a previous study. This artificial liner was composed of crumb rubber, organo-clay, silica fume and epoxy binder together with an environmentally-friendly solvent recycled from paper pulping, and dimethyl sulfoxide as a plasticizer. In this study, the new artificial liner and a typical HDPE geomembrane were tested to compare their abilities to mitigate the movement of VOCs, specifically partition coefficient, diffusion coefficient and mass fluxes. It was found that this new artificial liner had 2-3 orders of magnitude less VOC mass flux than the HDPE geomembrane. The new artificial liner is thought to have a great potential for containing VOCs, even with a thickness of 2.5 cm, and as a substitute for the clay liner. The cost of installing the artificial liner was estimated to be $13.78/m(2). This is lower than the current geomembrane-related price of $19.70-26.91/m(2). The new liner might give a new perspective in future liner design and alleviate the concerning issue of groundwater pollution caused by landfill leachate, which might contain highly mobile VOCs. PMID- 23628904 TI - Simulating waste temperatures in an operating landfill in Quebec, Canada. AB - A bioreactor landfill operated in Sainte-Sophie, Quebec, Canada was instrumented to better understand the waste stabilization process in northern climates. Instrument bundles were placed within the waste to monitor temperature, oxygen, moisture content, settlement, total load, mounding of leachate and electrical conductivity. A finite element model was developed to simulate the heat fluxes to and from the waste, as well as heat generation within the waste from both anaerobic and aerobic processes. The results of the analysis suggest the majority of the aerobic activity occurs in the top portion of the waste lift exposed to ambient air. In addition, the model indicates that frozen waste lifts require a significant amount of heat to thaw the liquid fraction. The model also demonstrates that when a lift of cold waste is placed at the bottom of the landfill, the subsurface acts as a significant source of heat. PMID- 23628905 TI - Predicting protein-protein interactions in the post synaptic density. AB - The post synaptic density (PSD) is a specialization of the cytoskeleton at the synaptic junction, composed of hundreds of different proteins. Characterizing the protein components of the PSD and their interactions can help elucidate the mechanism of long-term changes in synaptic plasticity, which underlie learning and memory. Unfortunately, our knowledge of the proteome and interactome of the PSD is still partial and noisy. In this study we describe a computational framework to improve the reconstruction of the PSD network. The approach is based on learning the characteristics of PSD protein interactions from a set of trusted interactions, expanding this set with data collected from large scale repositories, and then predicting novel interaction with proteins that are suspected to reside in the PSD. Using this method we obtained thirty predicted interactions, with more than half of which having supporting evidence in the literature. We discuss in details two of these new interactions, Lrrtm1 with PSD 95 and Src with Capg. The first may take part in a mechanism underlying glutamatergic dysfunction in schizophrenia. The second suggests an alternative mechanism to regulate dendritic spines maturation. PMID- 23628906 TI - New York City considers raising legal age for buying tobacco to 21. PMID- 23628907 TI - Efficacy of hypnosis in adults undergoing surgery or medical procedures: a meta analysis of randomized controlled trials. AB - This meta-analysis investigates the efficacy of hypnosis in adults undergoing surgical or medical procedures compared to standard care alone or an attention control. Through a comprehensive literature search N=34 eligible randomized controlled trials (RCTs) were included, comprising a total of 2597 patients. Random effects meta-analyses revealed positive treatment effects on emotional distress (g=0.53, CI 95% [0.37; 0.69]), pain (g=0.44, CI 95% [0.26; 0.61]), medication consumption (g=0.38, CI 95% [0.20; 0.56]), physiological parameters (g=0.10, CI 95% [0.02; 0.18]), recovery (g=0.25, CI 95% [0.04; 0.46]), and surgical procedure time (g=0.25, CI 95% [0.12; 0.38]). In conclusion, benefits of hypnosis on various surgically relevant outcomes were demonstrated. However, the internal validity of RCTs seems limited and further high methodological quality RCTs are needed to strengthen the promising evidence of hypnosis for adults undergoing surgery or medical procedures. PMID- 23628908 TI - Assessing early signs of relapse in psychosis: review and future directions. AB - Relapse of psychosis is common and has profound adverse consequences. Early signs interventions assume that timely prediction of relapse allows preventative action to reduce the chance of full relapse. The utility of early signs in this context is critically reviewed. Cohort studies suggest that early signs (e.g. anxiety, insomnia) appear in the few weeks before relapse and have modest predictive validity (sensitivity 10%-80%, median 61%; specificity 38%-100%, median 81%), indicating that accuracy of relapse prediction needs improvement. Trials using early signs to target interventions show that targeted antipsychotic medication is less effective than adequately dosed maintenance medication but relapse rates are lower than when intervention is delayed until relapse. The relative value of more complex interventions including psycho-education and relapse prevention strategies is not yet clearly established because there are few trials, some with important design limitations. Basic symptoms are subtle, subjective, qualitative changes in experience claimed to precede psychosis. One retrospective cohort study and studies of "at risk mental states'" transition to psychosis indicate some predictive validity. We suggest that basic symptoms are potentially valuable additions to the range of early signs and deserve further investigation in the effort to enhance the predictive validity of the early signs syndrome. PMID- 23628909 TI - What should we expect from psychotherapy? AB - In addressing the very general question of what we should expect from psychotherapy, this article begins by discussing what constitutes relevant evidence on which to base the efficacy and effectiveness of psychotherapy. In this context, an important distinction is made between empirically supported treatments and evidence-based practice. Although there is evidence that psychotherapy does indeed work, there are also findings that there are times when our patients are harmed by our interventions. It is noted that the therapeutic alliance plays an extremely important role in the change process, and that ruptures in the alliance can contribute to our therapeutic failures. In pointing to directions for the future, modifications of how we investigate the outcome of treatment, as well as how to close the gap between research and practice, are offered. PMID- 23628910 TI - Nona-copper(II)-containing 18-tungsto-8-arsenate(III) exhibits antitumor activity. AB - The nona-Cu(II)-containing tungstoarsenate(III) [H4{Cu(II)9As(III)6O15(H2O)6}(alpha-As(III)W9O33)2](8-) (1a) has been synthesized and characterized. Polyanion 1a comprises a unique, cylindrical {Cu(II)9As(III)6O15(H2O)6}(6+) cluster, which forms a large central cavity and is capped on either end by an [alpha-As(III)W9O33](9-) capping group. It exhibits remarkable activity against K562 leukaemia cells, as well as induces HepG2 cell apoptosis and autophagy. PMID- 23628912 TI - Interesting thermal variations owing to cationic ring structural features in protic ionic liquids. AB - The present communication divulges interesting thermal behavior of different protic ionic liquids arising due to the hydrophobicity modifications in their parent cationic ring structures. This work assists us in differentiating between protic ionic liquids, their aprotic counterparts and common electrolytes in water. The thermal signatures produced by protic ionic liquids, aprotic ionic liquids and electrolytes emerge as individual fingerprints for them. PMID- 23628911 TI - Mass spectrometric analysis of glycosphingolipid antigens. AB - Glycosphingolipids (GSL's) belong to the glycoconjugate class of biomacromolecules, which bear structural information for significant biological processes such as embryonic development, signal transduction, and immune receptor recognition(1-2). They contain complex sugar moieties in the form of isomers, and lipid moieties with variations including fatty acyl chain length, unsaturation, and hydroxylation. Both carbohydrate and ceramide portions may be basis of biological significance. For example, tri-hexosylceramides include globotriaosylceramide (Galalpha4Galbeta4Glcbeta1Cer) and isoglobotriaosylceramide (Galalpha3Galbeta4Glcbeta1Cer), which have identical molecular masses but distinct sugar linkages of carbohydrate moiety, responsible for completely different biological functions(3-4). In another example, it has been demonstrated that modification of the ceramide part of alpha-galactosylceramide, a potent agonist ligand for invariant NKT cells, changes their cytokine secretion profiles and function in animal models of cancer and auto-immune diseases(5). The difficulty in performing a structural analysis of isomers in immune organs and cells serve as a barrier for determining many biological functions(6). Here, we present a visualized version of a method for relatively simple, rapid, and sensitive analysis of glycosphingolipid profiles in immune cells(7-9). This method is based on extraction and chemical modification (permethylation, see below Figure 5A, all OH groups of hexose were replaced by MeO after permethylation reaction) of glycosphingolipids(10-15), followed by subsequent analysis using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) and ion trap mass spectrometry. This method requires 50 million immune cells for a complete analysis. The experiments can be completed within a week. The relative abundance of the various glycosphingolipids can be delineated by comparison to synthetic standards. This method has a sensitivity of measuring 1% iGb3 among Gb3 isomers, when 2 fmol of total iGb3/Gb3 mixture is present(9). Ion trap mass spectrometry can be used to analyze isomers. For example, to analyze the presence of globotriaosylceramide and isoglobtriaosylceramide in the same sample, one can use the fragmentation of glycosphingolipid molecules to structurally discriminate between the two (see below Figure 5). Furthermore, chemical modification of the sugar moieties (through a permethylation reaction) improves the ionization and fragmentation efficiencies for higher sensitivity and specificity, and increases the stability of sialic acid residues. The extraction and chemical modification of glycosphingolipids can be performed in a classic certified chemical hood, and the mass spectrometry can be performed by core facilities with ion trap MS instruments. PMID- 23628913 TI - Conduction electron spin resonance in AlB2. AB - This work reports on electron spin resonance experiments in oriented single crystals of the hexagonal AlB2 diboride compound (P6/mmm, D16h structure) which display conduction electron spin resonance. The X-band electron spin resonance spectra showed a metallic Dysonian resonance with g-value and intensity independent of temperature. The thermal broadening of the anisotropic electron spin resonance linewidth DeltaH tracks the T-dependence of the electrical resistivity below T is approximately equal to 100 K. These results confirm the observation of a conduction electron spin resonance in AlB2 and are discussed in comparison with other boride compounds. Based on our main findings for AlB2 and the calculated electronic structure of similar layered honeycomb-like structures, we conclude that any array of covalent B-B layers potentially results in a conduction electron spin resonance signal. This observation may shed new light on the nature of the non-trivial conduction electron spin resonance-like signals of complex f-electron systems such as beta-YbAlB4. PMID- 23628915 TI - Polyunsaturated fatty acids in heart failure. PMID- 23628916 TI - Polyunsaturated fatty acids in heart failure: reply. PMID- 23628914 TI - The actin cytoskeleton in presynaptic assembly. AB - Dramatic morphogenetic processes underpin nearly every step of nervous system development, from initial neuronal migration and axon guidance to synaptogenesis. Underlying this morphogenesis are dynamic rearrangements of cytoskeletal architecture. Here we discuss the roles of the actin cytoskeleton in the development of presynaptic terminals, from the elaboration of terminal arbors to the recruitment of presynaptic vesicles and active zone components. The studies discussed here underscore the importance of actin regulation at every step in neuronal circuit assembly. PMID- 23628917 TI - Assessment of left atrial-left ventricular-arterial coupling using 2-dimensional speckle tracking echocardiography. PMID- 23628918 TI - Comparison of clinical outcome after bypass surgery vs. endovascular therapy for infrainguinal artery disease in patients with critical limb ischemia. AB - BACKGROUND: The efficacy of stent-assisted endovascular therapy (EVT) in patients with critical limb ischemia (CLI) compared to bypass surgery (BSX) remains unclear. METHODS AND RESULTS: This study was performed as a multicenter retrospective registry. Between January 2004 and December 2009, 460 CLI patients (460 first treated limbs) who underwent BSX (237 patients) or EVT (223 patients) for de novo infrainguinal lesions were identified retrospectively and analyzed. The main endpoints of this study were amputation-free survival (AFS), overall survival, limb salvage rate and freedom from major adverse limb events (MALE; includes any repeat revascularization and major amputation). Three-year AFS, limb salvage rate and overall survival were not different between the BSX and EVT groups (60.3% vs. 58.0%, P=0.43; 85.1% vs. 84.2%, P=0.91; 67.2% vs. 69.8%, P=0.96, respectively), but freedom from MALE was significantly lower in the EVT group during follow-up (69.1% vs. 51.1%, P=0.002). After adjusting endpoints with covariates, there was also no significant difference in AFS, limb salvage, and overall survival between EVT and BSX. Freedom from MALE, however, was still significantly lower in the EVT group (hazard ratio, 0.66; 95% confidence interval: 0.47-0.92, adjusted P=0.01). CONCLUSIONS: Serious adverse events with the exception of MALE after EVT seem to be acceptable compared to that after BSX in patients with CLI due to infrainguinal disease. PMID- 23628919 TI - Do hyperechoic thyroid nodules on B-ultrasound represent calcification? AB - OBJECTIVE: To explore the correlation between hyperechoic thyroid nodules observed on B-ultrasound and histological calcification seen in paraffin-wax sections. METHODS: Records of patients who underwent surgical removal of thyroid nodules diagnosed on preoperative B-ultrasound were analysed retrospectively. Calcification present on B-ultrasound was compared with calcification seen in postoperative pathology specimens. RESULTS: Of the 1,655 patients included in the study, 518 had malignant and 1,137 had benign thyroid nodules. Calcification on B ultrasound was seen in 366 patients with malignant, and 414 with benign nodules. Calcification was confirmed on histology in 209 and 127 of these patients, respectively, giving a sensitivity and specificity for B-ultrasound in diagnosing calcification (compared with histology) of 95.87% and 47.67%, respectively, in thyroid cancer and 90.71%, and 71.21% respectively in benign thyroid nodules. Microcalcification was seen in 483 patients on B-ultrasound and in 186 on histology, of whom 294 (60.87%) and 152 (81.72%), respectively, had thyroid cancer. CONCLUSIONS: B-ultrasound is a useful and accurate test for detecting calcification in thyroid nodules, with a high sensitivity. There is a close association between calcification (especially microcalcification) and thyroid cancer on both B-ultrasound and pathological examination. PMID- 23628920 TI - Pharmacological and physical prevention and treatment of no-reflow after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction. AB - After successful primary percutaneous coronary intervention in ST-segment elevation myocardial infarction, adequate myocardial reperfusion is not achieved in up to 50% of patients. This phenomenon of no-reflow is associated with a poor in-hospital and long-term prognosis. Four main factors are thought to contribute to the occurrence of no-reflow: ischaemic injury; reperfusion injury; distal embolization; susceptibility of the microcirculation to injury. This review evaluates the literature, and in particular the clinical trials, concerned with pharmacological and physical methods for prevention and treatment of no-reflow. A number of drugs may improve no-reflow experimentally and clinically, but some have not yet been associated with conclusive improvements in clinical outcome. The complex interacting factors in no-reflow make it unlikely that any single agent will be effective for all patients. Confirmed methods known to be beneficial in the prevention of no-reflow (such as aspirin therapy, chronic statin therapy, blood glucose control, thrombus aspiration in patients with a high thrombus burden and ischaemic preconditioning) should be offered to patients as often as possible, to prevent and treat no-reflow. PMID- 23628921 TI - Opinions of Slovenian family physicians on medically unexplained symptoms: a qualitative study. AB - OBJECTIVES: To determine the views of Slovenian family physicians on medically unexplained symptoms (MUS) and learn more about potential types of treatment for such patients. METHODS: Five focus groups, comprising 24 family medicine physicians (FMPs) from two Slovenian University centres, were convened. Conversations were led towards the research objectives by professionally trained researchers and followed a preliminarily established protocol. Qualitative content analysis of audio and transcripts of the discussions was performed using ATLAS.ti software to establish categories ('codes') relevant to issues regarding MUS. RESULTS: Slovenian FMPs emphasized the importance of good communication and trust between physicians and patients with MUS. Systemic barriers to effective management of MUS arising from the Slovenian health system were highlighted. FMPs stressed the need for more education in the recognition and treatment of MUS in primary care. From the discussions, 64 codes comprising broader research fields of MUS were developed, then grouped into a further eight categories: communication; doctor-patient relationship; causes of MUS; patient characteristics; physician characteristics; courses of action so far; positive relationship with patients; proposals for treatment. CONCLUSIONS: The results are valuable in terms of investigating the treatment of patients with MUS in Slovenia, thereby opening new avenues of research on the subject of MUS. PMID- 23628922 TI - Zoster-associated segmental paresis in a patient with cervical spinal stenosis. AB - Segmental zoster paresis is a rare complication of herpes zoster, characterized by focal motor weakness that does not always present simultaneously with skin lesions. Zoster paresis can be easily confused with other neuromuscular or spinal diseases. This case report describes the case of a 72-year-old woman with herpes zoster and cervical spinal stenosis at the same spinal level, where it was difficult to distinguish segmental zoster paresis from cervical radiculopathy combined with motor neuropathy. Although segmental zoster paresis in the upper extremity is rare, it should be included in the differential diagnosis of segmental pain and weakness in the extremities, especially in older or immunocompromised patients. Correct diagnosis is required, to avoid unnecessary surgery and allow timely antiviral treatment. PMID- 23628923 TI - Single electron transfer-induced cross-coupling reaction of alkenyl halides with aryl Grignard reagents. AB - Alkenyl halides were found to undergo coupling with aryl Grignard reagents to give the corresponding styrene derivatives in a stereo-retained manner. The cross coupling reaction is considered to proceed through a single electron transfer mechanism. PMID- 23628924 TI - Molecular cloning, characterization, and stress-responsive expression of genes encoding glycine-rich RNA-binding proteins in Camelina sativa L. AB - Camelina sativa L. is an oil-seed crop that has potential for biofuel applications. Although the importance of C. sativa as a biofuel crop has increased in recent years, reports demonstrating the stress responsiveness of C. sativa and characterizing the genes involved in stress response of C. sativa have never been published. Here, we isolated and characterized three genes encoding glycine-rich RNA-binding proteins (GRPs) from camelina: CsGRP2a, CsGRP2b, and CsGRP2c. The three CsGRP2 proteins were very similar in amino acid sequence and contained a well-conserved RNA-recognition motif at the N-terminal region and glycine-rich domain at the C-terminal region. To understand the functional roles of CsGRP2s under stress conditions, we investigated the expression patterns of CsGRP2s under various environmental stress conditions. The expressions of the three CsGRP2s were highly up-regulated under cold stress. The expression of CsGRP2a was up-regulated under salt or dehydration stress, whereas the transcript levels of CsGRP2b and CsGRP2c were decreased under salt or dehydration stress conditions. The three CsGRP2s had the ability to complement cold-sensitive Escherichia coli mutants at low temperatures and harbored transcription anti termination and nucleic acid-melting activities, indicating that the CsGRP2s possess RNA chaperone activity. The CsGRP2a protein was localized to both the nucleus and the cytoplasm. Expression of CsGRP2a in cold-sensitive Arabidopsis grp7 mutant plants resulted in decreased electrolyte leakage at freezing temperatures. Collectively, these results suggest that the stress-responsive CsGRP2s play a role as an RNA chaperone during the stress adaptation process in camelina. PMID- 23628925 TI - Isolation of a polyphenol oxidase (PPO) cDNA from artichoke and expression analysis in wounded artichoke heads. AB - The polyphenol oxidase (PPO) enzyme, which can catalyze the oxidation of phenolics to quinones, has been reported to be involved in undesirable browning in many plant foods. This phenomenon is particularly severe in artichoke heads wounded during the manufacturing process. A full-length cDNA encoding for a putative polyphenol oxidase (designated as CsPPO) along with a 1432 bp sequence upstream of the starting ATG codon was characterized for the first time from [Cynara cardunculus var. scolymus (L.) Fiori]. The 1764 bp CsPPO sequence encodes a putative protein of 587 amino acids with a calculated molecular mass of 65,327 Da and an isoelectric point of 5.50. Analysis of the promoter region revealed the presence of cis-acting elements, some of which are putatively involved in the response to light and wounds. Expression analysis of the gene in wounded capitula indicated that CsPPO was significantly induced after 48 h, even though the browning process had started earlier. This suggests that the early browning event observed in artichoke heads was not directly related to de novo mRNA synthesis. Finally, we provide the complete gene sequence encoding for polyphenol oxidase and the upstream regulative region in artichoke. PMID- 23628926 TI - Change in desiccation tolerance of maize embryos during development and germination at different water potential PEG-6000 in relation to oxidative process. AB - Desiccation tolerance is one of the most important traits determining seed survival during storage and under stress conditions. However, the mechanism of seed desiccation tolerance is still unclear in detail. In the present study, we used a combined model system, desiccation-tolerant and -sensitive maize embryos with identical genetic background, to investigate the changes in desiccation tolerance, malonyldialdehyde (MDA) level, hydrogen peroxide (H2O2) content and antioxidant enzyme activity during seed development and germination in 0, -0.6 and -1.2 MPa polyethylene glycol (PEG)-6000 solutions. Our results indicated that maize embryos gradually acquired and lost desiccation tolerance during development and germination, respectively. The acquirement and loss of desiccation tolerance of embryos during development and germination were related to the ability of antioxidant enzymes including superoxide dismutase (SOD, EC 1.15.1.1), ascorbate peroxidase (APX, EC 1.11.1.11), catalase (CAT, EC 1.11.1.6), glutathione reductase (GR, EC 1.6.4.2) and dehydroascorbate reductase (DHAR, EC 1.8.5.1) to scavenge reactive oxygen species (ROS) and to control MDA content. Compared with treatment in water, PEG-6000 treatment could markedly delay the loss of desiccation tolerance of germinating embryos by delaying water uptake and time course of germination, increasing GR activity and decreasing MDA content. Our data showed the combination of antioxidant enzyme activity and MDA content is a good parameter for assessing the desiccation tolerance of maize embryos. In addition, H2O2 accumulated in mature embryos and PEG-treated embryos after drying, which was at least partially related to a longer embryo/seedling length in rehydration and the physiological mechanisms of priming. PMID- 23628927 TI - The role of aromatic L-amino acid decarboxylase in bacillamide C biosynthesis by Bacillus atrophaeus C89. AB - For biosynthesis of bacillamide C by Bacillus atrophaeus C89 associated with South China sea sponge Dysidea avara, it is hypothesized that decarboxylation from L-tryptophan to tryptamine could be performed before amidation by the downstream aromatic L-amino acid decarboxylase (AADC) to the non-ribosomal peptide synthetases (NRPS) gene cluster for biosynthesizing bacillamide C. The structural analysis of decarboxylases' known substrates in KEGG database and alignment analysis of amino acid sequence of AADC have suggested that L tryptophan and L-phenylalanine are the potential substrates of AADC. The enzymatic kinetic experiment of the recombinant AADC proved that L-tryptophan is a more reactive substrate of AADC than L-phenylalanine. Meanwhile, the AADC catalyzed conversion of L-tryptophan into tryptamine was confirmed by means of HPLC and LC/MS. Thus during bacillamide C biosynthesis, the decarboxylation of L tryptophan to tryptamine is likely conducted first under AADC catalysis, followed by the amidation of tryptamine with the carboxylic product of NRPS gene cluster. PMID- 23628928 TI - Comparison of the trauma and injury severity score and modified early warning score with rapid lactate level (the ViEWS-L score) in blunt trauma patients. AB - OBJECTIVE: The aim of this study was to compare the predictive value of the VitalPAC Early Warning Score-lactate (ViEWS-L) score with that of the trauma and injury severity score (TRISS), which is a pre-existing risk scoring system used in trauma patients. METHODS: The patients were blunt trauma victims admitted consecutively to the study hospital between 1 April 2010 and 31 March 2011, who were 15 years or older and had an injury severity score of 9 or higher. The lactate level, the ViEWS and revised trauma score upon arrival at the emergency department, and the injury severity score and TRISS were evaluated. The ViEWS-L score was calculated according to the formula: ViEWS-L=ViEWS+lactate (mmol/l). The ability to predict mortality was assessed by area under the receiver operating characteristic curve (AUC) analysis and calibration analysis. RESULTS: A total of 299 patients were available for analysis, of whom 33 died (11.0%). The median ViEWS-L score was 3.7 (interquartile range:1.8-6.4) and the median TRISS was 96.8 (interquartile range: 93.4-98.6). The ViEWS-L score was better than TRISS at predicting hospital mortality (AUC, 0.838; 95% confidence interval, 0.771-0.906 vs. AUC, 0.734; 95% confidence interval, 0.635-0.833, P=0.031). Calibration of the ViEWS-L score (chi=11.13, P=0.194) was good but that of TRISS was not (chi=16.97, P=0.018). CONCLUSION: The prognostic value of the ViEWS-L score in terms of discrimination was better than that of TRISS in the blunt trauma patients admitted to the emergency department with an injury severity score of 9 or higher, and the ViEWS-L score showed good calibration. PMID- 23628930 TI - Treating melancholia at home: theoretical wisdom and grim reality in the career of E.C. Seguin. AB - E.C. Seguin was one of the early, influential 19th-century neurologists who participated in the development of neurology as a specialty in the United States. Born in France, but raised from early childhood in the United States, Seguin published widely, developed a high-profile New York City practice, and was named Clinical Professor of Diseases of the Mind and Nervous System at the College of Physicians and Surgeons (New York) in 1874. Typical of the era, he studied neurologic disorders, but also several conditions that today would be considered in the realm of psychiatry. One of his seminal papers was titled "The treatment of mild cases of melancholia at home" (1876). Contrary to the widespread practice of isolating patients in either rest homes or asylums, Seguin introduced and formalized treatment of depression within the household. Against this academic backdrop, Seguin returned home on October 31, 1882, to discover that his own wife, afflicted with long-standing depression and treated at home, had committed suicide after murdering their 3 children. The grim dichotomy between the confidently written paper and the reality of the treatment failure is a neurologic lesson in humility regarding diseases and their unpredictable outcomes. PMID- 23628929 TI - Adherence to a Mediterranean diet and risk of incident cognitive impairment. AB - OBJECTIVE: We sought to determine the relationship of greater adherence to Mediterranean diet (MeD) and likelihood of incident cognitive impairment (ICI) and evaluate the interaction of race and vascular risk factors. METHODS: A prospective, population-based, cohort of individuals enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 2003-2007, excluding participants with history of stroke, impaired cognitive status at baseline, and missing data on Food Frequency Questionnaires (FFQ), was evaluated. Adherence to a MeD (scored as 0-9) was computed from FFQ. Cognitive status was evaluated at baseline and annually during a mean follow-up period of 4.0 +/- 1.5 years using Six-item-Screener. RESULTS: ICI was identified in 1,248 (7%) out of 17,478 individuals fulfilling the inclusion criteria. Higher adherence to MeD was associated with lower likelihood of ICI before (odds ratio [lsqb]OR[rsqb] 0.89; 95% confidence interval [lsqb]CI[rsqb] 0.79-1.00) and after adjustment for potential confounders (OR 0.87; 95% CI 0.76-1.00) including demographic characteristics, environmental factors, vascular risk factors, depressive symptoms, and self-reported health status. There was no interaction between race (p = 0.2928) and association of adherence to MeD with cognitive status. However, we identified a strong interaction of diabetes mellitus (p = 0.0134) on the relationship of adherence to MeD with ICI; high adherence to MeD was associated with a lower likelihood of ICI in nondiabetic participants (OR 0.81; 95% CI 0.70 0.94; p = 0.0066) but not in diabetic individuals (OR 1.27; 95% CI 0.95-1.71; p = 0.1063). CONCLUSIONS: Higher adherence to MeD was associated with a lower likelihood of ICI independent of potential confounders. This association was moderated by presence of diabetes mellitus. PMID- 23628931 TI - Holohemispheric developmental venous anomaly. PMID- 23628932 TI - Mouse brain kaleidoscope. PMID- 23628933 TI - Spontaneous intracerebral hemorrhage in Urbach-Wiethe disease. PMID- 23628934 TI - Teaching NeuroImages: treatment-resistant rapidly progressive amyloid beta related angiitis. PMID- 23628935 TI - Teaching NeuroImages: longitudinally extensive transverse myelitis in neuro Behcet disease. PMID- 23628936 TI - Teaching NeuroImages: 5-FU-induced acute leukoencephalopathy. PMID- 23628937 TI - Temporal lobe epilepsy surgery: what is the best approach? PMID- 23628938 TI - Multivalent alteration of quorum sensing in Staphylococcus aureus. AB - Virulence in Staphylococcus aureus is strongly and positively correlated with local cell density. Here we present an effective approach to modulate this group behaviour using multivalent peptide-polymer conjugates. Our results show that by attaching multiple AIP-4' units to macromolecular scaffolds, the agr QS response in S. aureus was affected strongly, while displaying a clear multivalency effect. PMID- 23628939 TI - Understanding crash mechanism on urban expressways using high-resolution traffic data. AB - Urban expressways play a vital role in the modern mega cities by serving peak hour traffic alongside reducing travel time for moderate to long distance intra city trips. Thus, ensuring safety on these roads holds high priority. Little knowledge has been acquired till date regarding crash mechanism on these roads. This study uses high-resolution traffic data collected from the detectors to identify factors influencing crash. It also identifies traffic patterns associated with different types of crashes and explains crash phenomena thereby. Unlike most of the previous studies on conventional expressways, the research separately investigates the basic freeway segments (BFS) and the ramp areas. The study employs random multinomial logit, a random forest of logit models, to rank the variables; expectation maximization clustering algorithm to identify crash prone traffic patterns and classification and regression trees to explain crash phenomena. As accentuated by the study outcome, crash mechanism is not generic throughout the expressway and it varies from the BFS to the ramp vicinities. The level of congestion and speed difference between upstream and downstream traffic best explains crashes and their types for the BFS, whereas, the ramp flow has the highest influence in determining the types of crashes within the ramp vicinities. The paper also discusses about the applicability of different countermeasures, such as, variable speed limits, temporary restriction on lane changing, posting warnings, etc., to attenuate different patterns of hazardous traffic conditions. The study outcome can be utilized in designing location and traffic condition specific proactive road safety management systems for urban expressways. PMID- 23628940 TI - Predicting crash likelihood and severity on freeways with real-time loop detector data. AB - Real-time crash risk prediction using traffic data collected from loop detector stations is useful in dynamic safety management systems aimed at improving traffic safety through application of proactive safety countermeasures. The major drawback of most of the existing studies is that they focus on the crash risk without consideration of crash severity. This paper presents an effort to develop a model that predicts the crash likelihood at different levels of severity with a particular focus on severe crashes. The crash data and traffic data used in this study were collected on the I-880 freeway in California, United States. This study considers three levels of crash severity: fatal/incapacitating injury crashes (KA), non-incapacitating/possible injury crashes (BC), and property damage-only crashes (PDO). The sequential logit model was used to link the likelihood of crash occurrences at different severity levels to various traffic flow characteristics derived from detector data. The elasticity analysis was conducted to evaluate the effect of the traffic flow variables on the likelihood of crash and its severity.The results show that the traffic flow characteristics contributing to crash likelihood were quite different at different levels of severity. The PDO crashes were more likely to occur under congested traffic flow conditions with highly variable speed and frequent lane changes, while the KA and BC crashes were more likely to occur under less congested traffic flow conditions. High speed, coupled with a large speed difference between adjacent lanes under uncongested traffic conditions, was found to increase the likelihood of severe crashes (KA). This study applied the 20-fold cross-validation method to estimate the prediction performance of the developed models. The validation results show that the model's crash prediction performance at each severity level was satisfactory. The findings of this study can be used to predict the probabilities of crash at different severity levels, which is valuable knowledge in the pursuit of reducing the risk of severe crashes through the use of dynamic safety management systems on freeways. PMID- 23628941 TI - Analyzing the severity of accidents on the German Autobahn. AB - We study the severity of accidents on the German Autobahn in the state of North Rhine-Westphalia using data for the years 2009 until 2011. We use a multinomial logit model to identify statistically relevant factors explaining the severity of the most severe injury, which is classified into the four classes fatal, severe injury, light injury and property damage. Furthermore, to account for unobserved heterogeneity we use a random parameter model. We study the effect of a number of factors including traffic information, road conditions, type of accidents, speed limits, presence of intelligent traffic control systems, age and gender of the driver and location of the accident. Our findings are in line with studies in different settings and indicate that accidents during daylight and at interchanges or construction sites are less severe in general. Accidents caused by the collision with roadside objects, involving pedestrians and motorcycles, or caused by bad sight conditions tend to be more severe. We discuss the measures of the 2011 German traffic safety programm in the light of our results. PMID- 23628942 TI - Investigating the influence of curbs on single-vehicle crash injury severity utilizing zero-inflated ordered probit models. AB - The severity of traffic-related injuries has been studied by many researchers in recent decades. However, previous research has seldom accounted for the effects of curbed outside shoulders on traffic-related injury severity. This study applies the zero-inflated ordered probit (ZIOP) model to evaluate the influences of curbed outside shoulders, speed limit change, as well as other traditional factors on the injury severity of single-vehicle crashes. Crash data from 2003 to 2007 in the Illinois Highway Safety Database were employed in this study. The ZIOP model assumes that injury severity comes from two distinct sources: injury propensity and injury severity when this crash falls into the injury prone category. The modeling results show that on one hand, single-vehicle crashes that occurring on roadways with curbed outside shoulders are more likely to be injury prone. On the other hand, the existence of a curb decreases the likelihood of severe injury if the crash was in the injury prone category. As a result, the marginal effect analysis implies that the presence of curbs is associated with a higher likelihood of no injury and minor injury involved crashes, but a lower likelihood of incapacitating injury and fatality involved crashes. In addition, in the presence of curbed outside shoulders, the change of speed limit adds no significant impact to the injury severity of single-vehicle crashes. Moreover, the modeling results also highlight some interesting effects caused by vehicle type, light and weather conditions, and drivers' characteristics, as well as crash type and location. Through a comprehensive evaluation of the modeling results, the authors find that the ZIOP model performs well relative to the traditional ordered probit (OP) model, and can serve as an alternative in future studies of crash injury severity. PMID- 23628943 TI - New Li2FeSiO4-carbon monoliths with controlled macropores: effects of pore properties on electrode performance. AB - Monolithic Li2FeSiO4-carbon composites with well-defined macropores have been prepared from the silica-based gels containing Li, Fe, and carbon sources. The macroporous precursor gels can be fabricated by the sol-gel method accompanied by phase separation. A fine control of the macropore size in the resultant composites has been achieved by controlling the macropore size of the precursor gels simply by adjusting the starting compositions. The effects of pore properties on Li insertion-extraction capabilities have been investigated by utilizing the resultant Li2FeSiO4-carbon composites as the cathode of lithium ion batteries. The electrodes prepared from the Li2FeSiO4-carbon composites with different macropore sizes exhibit significant differences in the charge-discharge properties. The results strongly suggest that the smaller macropore size (equal to the thinner macropore skeletons) and the presence of micro- and mesopores in the macropore skeletons (hierarchically porous structure) are desirable for a better electrode in the case of Li2FeSiO4, which has extremely low ionic and electrical conductivities. PMID- 23628944 TI - Multi-analyte biochip (MAB) based on all-solid-state ion-selective electrodes (ASSISE) for physiological research. AB - Lab-on-a-chip (LOC) applications in environmental, biomedical, agricultural, biological, and spaceflight research require an ion-selective electrode (ISE) that can withstand prolonged storage in complex biological media (1-4). An all solid-state ion-selective-electrode (ASSISE) is especially attractive for the aforementioned applications. The electrode should have the following favorable characteristics: easy construction, low maintenance, and (potential for) miniaturization, allowing for batch processing. A microfabricated ASSISE intended for quantifying H(+), Ca(2+), and CO3(2-) ions was constructed. It consists of a noble-metal electrode layer (i.e. Pt), a transduction layer, and an ion-selective membrane (ISM) layer. The transduction layer functions to transduce the concentration-dependent chemical potential of the ion-selective membrane into a measurable electrical signal. The lifetime of an ASSISE is found to depend on maintaining the potential at the conductive layer/membrane interface (5-7). To extend the ASSISE working lifetime and thereby maintain stable potentials at the interfacial layers, we utilized the conductive polymer (CP) poly(3,4 ethylenedioxythiophene) (PEDOT) (7-9) in place of silver/silver chloride (Ag/AgCl) as the transducer layer. We constructed the ASSISE in a lab-on-a-chip format, which we called the multi-analyte biochip (MAB) (Figure 1). Calibrations in test solutions demonstrated that the MAB can monitor pH (operational range pH 4-9), CO3(2-) (measured range 0.01 mM - 1 mM), and Ca(2+) (log-linear range 0.01 mM to 1 mM). The MAB for pH provides a near-Nernstian slope response after almost one month storage in algal medium. The carbonate biochips show a potentiometric profile similar to that of a conventional ion-selective electrode. Physiological measurements were employed to monitor biological activity of the model system, the microalga Chlorella vulgaris. The MAB conveys an advantage in size, versatility, and multiplexed analyte sensing capability, making it applicable to many confined monitoring situations, on Earth or in space. Biochip Design and Experimental Methods The biochip is 10 x 11 mm in dimension and has 9 ASSISEs designated as working electrodes (WEs) and 5 Ag/AgCl reference electrodes (REs). Each working electrode (WE) is 240 MUm in diameter and is equally spaced at 1.4 mm from the REs, which are 480 MUm in diameter. These electrodes are connected to electrical contact pads with a dimension of 0.5 mm x 0.5 mm. The schematic is shown in Figure 2. Cyclic voltammetry (CV) and galvanostatic deposition methods are used to electropolymerize the PEDOT films using a Bioanalytical Systems Inc. (BASI) C3 cell stand (Figure 3). The counter-ion for the PEDOT film is tailored to suit the analyte ion of interest. A PEDOT with poly(styrenesulfonate) counter ion (PEDOT/PSS) is utilized for H(+) and CO3(2-), while one with sulphate (added to the solution as CaSO4) is utilized for Ca(2+). The electrochemical properties of the PEDOT-coated WE is analyzed using CVs in redox-active solution (i.e. 2 mM potassium ferricyanide (K3Fe(CN)6)). Based on the CV profile, Randles-Sevcik analysis was used to determine the effective surface area (10). Spin-coating at 1,500 rpm is used to cast ~2 MUm thick ion-selective membranes (ISMs) on the MAB working electrodes (WEs). The MAB is contained in a microfluidic flow-cell chamber filled with a 150 MUl volume of algal medium; the contact pads are electrically connected to the BASI system (Figure 4). The photosynthetic activity of Chlorella vulgaris is monitored in ambient light and dark conditions. PMID- 23628945 TI - Recent progress in G-quadruplex DNA in deep eutectic solvent. AB - Guanine-rich nucleic acids are known to form four-stranded G-quadruplex structures which are attracting increasing attention in diverse areas such as biology, medicinal chemistry, supramolecular chemistry and nanotechnology. To date, the handling media for DNA has largely been limited to an aqueous phase. Since many chemical reactions and devices are required to be performed under strictly anhydrous conditions, even at high temperature, it is meaningful but challenging to conduct G-quadruplex DNA in water-free medium. Recently, deep eutectic solvent (DES), a related material to ionic liquids (ILs) was considered as a new class of anhydrous media for DNA. This review highlights the stability, structure, folding dynamics and thermodynamics of G-quadruplex in DES. Spectroscopic methodologies, like circular dichroism, UV and fluorescence, are mainly employed in these studies. PMID- 23628946 TI - Methods for detection and characterization of protein S-nitrosylation. AB - Reversible protein S-nitrosylation, defined as the covalent addition of a nitroso moiety to the reactive thiol group on a cysteine residue, has received increasing recognition as a critical post-translational modification that exerts ubiquitous influence in a wide range of cellular pathways and physiological processes. Due to the lability of the S-NO bond, which is a dynamic modification, and the low abundance of endogenously S-nitrosylated proteins in vivo, unambiguous identification of S-nitrosylated proteins and S-nitrosylation sites remains methodologically challenging. In this review, we summarize recent advancements and the use of state-of-art approaches for the enrichment, systematic identification and quantitation of S-nitrosylation protein targets and their modification sites at the S-nitrosoproteome scale. These advancements have facilitated the global identification of >3000 S-nitrosylated proteins that are associated with wide range of human diseases. These strategies hold promise to site-specifically unravel potential molecular targets and to change S nitrosylation-based pathophysiology, which may further the understanding of the potential role of S-nitrosylation in diseases. PMID- 23628947 TI - Potential role of biventricular pacing beyond advanced systolic heart failure. AB - Cardiac resynchronization therapy (CRT) is an effective therapy for advanced heart failure (HF) patients. The indications are well defined in recent guidelines and broadly indicate that CRT is suitable for chronic HF patients with left ventricular ejection fraction (EF) <=35% and in NYHA class III or IV (Class I), and those with prolonged QRS duration >=120 ms with left bundle branch block (LBBB) QRS morphology, or QRS duration >=150 ms irrespective of QRS morphology (Class IIa). For patients with NYHA class II symptoms, CRT is recommended for patients with EF <=30% and QRS duration >=130 ms with LBBB QRS morphology (Class I, level of evidence: A), or QRS duration >=150 ms irrespective of QRS morphology (Class IIa, level of evidence: A). However, CRT may benefit additional patients outside these criteria. In this review, we summarize the role of CRT in some subgroups, including patients with mild and moderate HF, upgrading to CRT from right ventricular (RV) pacing, bradycardia patients with routine pacing indications, congenital heart disease and specific cardiomyopathies. It is possible that CRT can give symptomatic and mortality benefits in some of these subgroups in the future and further clinical trials are warranted. PMID- 23628949 TI - Ethanolic extract of the Goldenseal, Hydrastis canadensis, has demonstrable chemopreventive effects on HeLa cells in vitro: Drug-DNA interaction with calf thymus DNA as target. AB - This study tested chemotherapeutic potential of Hydrastis canadensis (HC) extract in HeLa cells in vitro, with emphasis on its drug-DNA interaction and apoptosis induction ability. Nuclear uptake of HC by DAPI, Ao/Eb staining and internucleosomal DNA damage by comet assay was studied through fluorescence microscopy. Possible changes in MMP and apoptotic signalling events were critically analyzed. Cell cycle progression studied through FACS and fragmented DNA through "TUNEL" assay were critically analyzed. RT-PCR studies were conducted for analyzing Cyt-C and Bax translocation in mitochondrial and cytosolic extracts, and Caspase 3 in whole cell lysate. Role of p53-mediated regulation of NF-kappabeta and TNF-alpha was elucidated by Western blot analysis. Data of CD and Tm profile of CT-DNA were analyzed. Overall results indicated anti-cancer potential of HC through its ability to induce apoptosis, and interaction with CT DNA that changed structural conformation of DNA, proving HC to be a promising candidate for chemoprevention. PMID- 23628948 TI - IL-6 activated integrated BATF/IRF4 functions in lymphocytes are T-bet independent and reversed by subcutaneous immunotherapy. AB - IL-6 plays a central role in supporting pathological T(H2) and T(H17) cell development and inhibiting the protective T regulatory cells in allergic asthma. T(H17) cells have been demonstrated to regulate allergic asthma in general and T bet-deficiency-induced asthma in particular. Here we found an inverse correlation between T-bet and Il-6 mRNA expression in asthmatic children. Moreover, experimental subcutaneous immunotherapy (SIT) in T-bet((-/-)) mice inhibited IL 6, IL-21R and lung T(H17) cells in a setting of asthma. Finally, local delivery of an anti-IL-6R antibody in T-bet((-/-)) mice resulted in the resolution of this allergic trait. Noteworthy, BATF, crucial for the immunoglobulin-class-switch and T(H2),T(H17) development, was found down-regulated in the lungs of T-bet((-/-)) mice after SIT and after treatment with anti-IL-6R antibody, indicating a critical role of IL-6 in controlling BATF/IRF4 integrated functions in T(H2), T(H17) cells and B cells also in a T-bet independent fashion in allergic asthma. PMID- 23628950 TI - Modern temperature management in aortic arch surgery: the dilemma of moderate hypothermia. AB - Arch surgery is undoubtedly among the most technically and strategically challenging endeavours in aortic surgery, requiring thorough understanding not only of cardiovascular physiology, but also in particular, of neurophysiology (cerebral and spinal cord), and is still associated with significant mortality and morbidity. In the late 1980s, when deep hypothermic circulatory arrest (HCA) had gained widespread acceptance as the standard approach for arch surgery, antegrade selective cerebral perfusion (SCP), as an adjunct to deep HCA, began its triumphal march, offering excellent neuroprotection and improved overall outcome. This encouraged the use of antegrade SCP in combination with steadily increasing body core temperatures--a trend culminating in the progressive advocation of moderate-to-mild temperatures up to 35 degrees C, and even normothermia. The impetus for progressive temperature elevation was the limitation of adverse effects of profound hypothermia and the most welcome side effect of significantly shorter cooling and rewarming periods on cardiopulmonary bypass (CPB), and thereby, potentially, the alleviation of the systemic inflammatory response and, in particular, the risk of severe postoperative bleeding (and other organ dysfunctions). The safe limits of prolonged distal circulatory arrest, particularly with regard to the ischaemic tolerance of the viscera and the spinal cord, have not yet been clearly defined. Adverse outcomes due to inappropriate temperature management (core temperatures too high for the required duration of distal arrest) are probably highly underreported. Complications historically associated with hypothermia, namely excessive bleeding, are possibly overestimated. Trading effective neuroprotection and excellent outcomes for the risk of prolonged 'warm' distal ischaemia might constitute a significant step back, jeopardizing visceral and, in particular, spinal cord integrity, with unpredictable consequences for long-term outcome and quality of life, particularly affecting those in need of more complex surgery or with previous neurological deficits. PMID- 23628951 TI - Coronary artery bypass grafting vs percutaneous coronary intervention in a 'real world' setting: a comparative effectiveness study based on propensity score matched cohorts. AB - OBJECTIVES: Most studies comparing coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI) showed that fewer patients who had undergone CABG required repeat revascularizations , but no difference in survival, with the exception of some subgroups of patients. However, long-term real-world evidence on patients in whom both procedures are technically feasible is yet not available. The aim of this study was to compare 5-year rates of death, myocardial infarction (MI), target vessel revascularization (TVR) and stroke in a large cohort of patients with left main coronary artery (LMCA) or multivessel disease, treated with CABG or PCI (with or without DES) or PCI with DES only. METHODS: Two propensity score (PS)-matched cohorts of patients undergoing revascularization procedures at the regional public and private centres of Emilia Romagna over the period July 2002-December 2008 were used to compare long-term outcomes of PCI (6246 patients) and CABG (5504 patients). RESULTS: PCI was associated with higher risk of death (HR = 1.6; 95% CI 1.4-1.8, P < 0.0001), MI (HR = 3.3; 95% CI 2.7-4.0, P < 0.0001) and TVR (HR = 4.5; 95% CI 3.8-5.2, P < 0.0001) at 5 years. No significant difference was shown for stroke (HR = 1.1; 95% CI 0.9-1.4, P = 0.43). CABG benefit was more evident in the risk of death in patients with two-vessel disease plus LMCA and in those with three-vessel disease, LVEF <35%, congestive heart failure and diabetes. Adjusted comparison with PS between PCI with DES only and CABG confirmed significant differences in favour of CABG for mortality, MI and TVR rates. Competing risk analysis showed that the difference in the mortality rate was due to higher rate of MI in PCI. CONCLUSIONS: In the 'real-world' setting of this study, CABG was associated with significantly lower rates of death, MI and TVR in patients with LMCA or multivessel disease, so it remains the standard of care, particularly for patients with more extensive coronary disease and diabetes. PMID- 23628952 TI - A universal biosensor for multiplex DNA detection based on hairpin probe assisted cascade signal amplification. AB - A hairpin DNA probe mediated cascade signal amplification method was developed for visual and rapid DNA analysis with a detection limit of 100 aM. The implementation of tag/anti-tag DNA and gold nanoparticle reporters permits a universal platform for multiplex genotyping without instrumentation. PMID- 23628953 TI - Evening primrose oil and borage oil do not help eczema symptoms, finds Cochrane review. PMID- 23628954 TI - Children in England to get flu vaccine at age 2 years from September. PMID- 23628955 TI - Shear flow assisted decoration of carbon nano-onions with platinum nanoparticles. AB - Aqueous based controlled decoration of platinum nanoparticles on plasma treated carbon nano-onions (CNOs) occurs within the shear flow generated by a vortex fluidic device (VFD), using ascorbic acid as the reducing agent, with the electrocatalytic potential of the resulting Pt-NPs@CNOs nano-composites demonstrated. PMID- 23628956 TI - Influence of the Bi3+ electron lone pair in the evolution of the crystal and magnetic structure of La(1-x)Bi(x)Mn2O5 oxides. AB - La(1-x)Bi(x)Mn2O5 (x = 0, 0.2, 0.4, 0.6, 0.8 and 1) oxides are members of the RMn2O5 family. The entire series has been prepared in polycrystalline form by a citrate technique. The evolution of their magnetic and crystallographic structures has been investigated by neutron powder diffraction (NPD) and magnetization measurements. All the samples crystallize in an orthorhombic structure with space group Pbam containing infinite chains of Mn(4+)O6 octahedra sharing edges, linked together by Mn(3+)O5 pyramids and (La/Bi)O8 units. These units become strongly distorted as the amount of Bi increases, due to the electron lone pair of Bi(3+). All the members of the series are magnetically ordered below TN = 25-40 K and they present different magnetic structures. For the samples with low Bi content (x = 0.2 and 0.4) the magnetic structure is characterized by the propagation vector k = (0,0,1/2). The magnetic moments of the Mn(4+) ions placed at octahedral sites are ordered according to the basis vectors (Gx, Ay, 0) whereas the Mn(3+) moments, located at pyramidal sites, are ordered according to the basis vectors (0, 0, Cz). When the content of Bi increases, two different propagation vectors are needed to explain the magnetic structure: k1 = (0,0,1/2) and k2 = (1/2,0,1/2). For x = 0.6 and 0.8, k2 is predominant over k1 and for this propagation vector (k2) the magnetic arrangement is defined by the basis vectors (Gx, Ay,0) and (Fx, Cy, 0) for Mn(4+) and Mn(3+) ions, respectively. PMID- 23628959 TI - SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations. AB - Chronic myeloid malignancies are categorized to the three main categories myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDSs) and MDS/MPN overlap. So far, no specific genetic alteration profiles have been identified in the MDS/MPN overlap category. Recent studies identified mutations in SET-binding protein 1 (SETBP1) as novel marker in myeloid malignancies, especially in atypical chronic myeloid leukemia (aCML) and related diseases. We analyzed SETBP1 in 1 130 patients with MPN and MDS/MPN overlap and found mutation frequencies of 3.8% and 9.4%, respectively. In particular, there was a high frequency of SETBP1 mutation in aCML (19/60; 31.7%) and MDS/MPN unclassifiable (MDS/MPN, U; 20/240; 9.3%). SETBP1 mutated (SETBP1mut) patients showed significantly higher white blood cell counts and lower platelet counts and hemoglobin levels than SETBP1 wild-type patients. Cytomorphologic evaluation revealed a more dysplastic phenotype in SETBP1mut cases as compared with wild-type cases. We confirm a significant association of SETBP1mut with -7 and isochromosome i(17)(q10). Moreover, SETBP1mut were strongly associated with ASXL1 and CBL mutations (P<0.001 for both) and were mutually exclusive of JAK2 and TET2 mutations. In conclusion, SETBP1mut add an important new diagnostic marker for MDS/MPN and in particular for aCML. PMID- 23628960 TI - Bayesian tests of topology hypotheses with an example from diving beetles. AB - We review Bayesian approaches to model testing in general and to the assessment of topological hypotheses in particular. We show that the standard way of setting up Bayes factor tests of the monophyly of a group, or the placement of a sample sequence in a known reference tree, can be misleading. The reason for this is related to the well-known dependency of Bayes factors on model-specific priors. Specifically, when testing tree hypotheses it is important that each hypothesis is associated with an appropriate tree space in the prior. This can be achieved by using appropriately constrained searches or by filtering trees in the posterior sample, but in a more elaborate way than typically implemented. If it is difficult to find the appropriate tree sets to be contrasted, then the posterior model odds may be more informative than the Bayes factor. We illustrate the recommended techniques using an empirical test case addressing the issue of whether two genera of diving beetles (Coleoptera: Dytiscidae), Suphrodytes and Hydroporus, should be synonymized. Our refined Bayes factor tests, in contrast to standard analyses, show that there is strong support for Suphrodytes nesting inside Hydroporus, and the genera are therefore synonymized. PMID- 23628958 TI - The MLL recombinome of acute leukemias in 2013. AB - Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (~ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements. PMID- 23628961 TI - Dating phylogenies with sequentially sampled tips. AB - We develop a Bayesian Markov chain Monte Carlo (MCMC) algorithm for estimating divergence times using sequentially sampled molecular sequences. This type of data is commonly collected during viral epidemics and is sometimes available from different species in ancient DNA studies. We derive the distribution of ages of nodes in the tree under a birth-death-sequential-sampling (BDSS) model and use it as the prior for divergence times in the dating analysis. We implement the prior in the MCMCtree program in the PAML package for divergence dating. The BDSS prior is very flexible and, with different parameters, can generate trees of very different shapes, suitable for examining the sensitivity of posterior time estimates. We apply the method to a data set of SIV/HIV-2 genes in comparison with a likelihood-based dating method, and to a data set of influenza H1 genes from different hosts in comparison with the Bayesian program BEAST. We examined the impact of tree topology on time estimates and suggest that multifurcating consensus trees should be avoided in dating analysis. We found posterior time estimates for old nodes to be sensitive to the priors on times and rates and suggest that previous Bayesian dating studies may have produced overconfident estimates. PMID- 23628963 TI - Multidisciplinary strategies to improve treatment outcomes in hepatocellular carcinoma: a European perspective. AB - Hepatocellular carcinoma (HCC) is a complex disease with a poor prognosis. Incidence and mortality rates are increasing in many geographical regions, indicating a need for better management strategies. Among several risk factors for HCC, the most common are cirrhosis because of chronic hepatitis B virus or hepatitis C virus infection and alcohol consumption, obesity, and diabetes. In some patients, combined risk factors present additional challenges to the prevention and treatment of HCC. Screening and surveillance of high-risk populations varies widely by geographic regions, and access to optimal surveillance is critical for early diagnosis. The treatment choice for HCC depends on the cancer stage, patient performance status, and liver function and requires a multidisciplinary approach and close cooperation among specialists for the best patient outcomes. Despite advances in surgical treatments and locoregional therapies, recurrence and liver failure remain significant challenges. The pathogenesis of HCC is a multistep and complex process, wherein angiogenesis plays an important role. The multikinase inhibitor sorafenib is the only approved targeted agent for advanced HCC, although promising results have been obtained with other targeted agents and combinations, and the results of ongoing trials are eagerly awaited. Clinical trials with rigorous study designs, including molecular classification and validation of new molecular biomarkers, are required to improve the personalized treatment of HCC. This article provides an overview of HCC and was developed through a review of relevant literature, clinical trial data, and updated clinical guidelines. PMID- 23628962 TI - Predicting how cells spread and migrate: focal adhesion size does matter. AB - Efficient cell migration is central to the normal development of tissues and organs and is involved in a wide range of human diseases, including cancer metastasis, immune responses, and cardiovascular disorders. Mesenchymal migration is modulated by focal-adhesion proteins, which organize into large integrin-rich protein complexes at the basal surface of adherent cells. Whether the extent of clustering of focal-adhesion proteins is actually required for effective migration is unclear. We recently demonstrated that the depletion of major focal adhesion proteins, as well as modulation of matrix compliance, actin assembly, mitochondrial activity, and DNA recombination, all converged into highly predictable, inter-related, biphasic changes in focal adhesion size and cell migration. Herein, we further discuss the role of focal adhesions in controlling cell spreading and test their potential role in cell migration. PMID- 23628964 TI - Recurrent severe alcoholic hepatitis: clinical characteristics and outcomes. AB - BACKGROUND AND AIMS: Despite high recidivism rates in those treated for alcoholism, recurrent episodes of severe alcoholic hepatitis (SAH) have not been described. Our aim was to assess the clinical characteristics and outcomes in recurrent SAH. PATIENTS AND METHODS: A retrospective review of patient records was carried out. Recurrent SAH was defined as two or more discrete episodes of SAH (discriminant function>=32) coinciding with recidivism in the same patient, with documented improvement/resolution of jaundice during intervening periods of abstinence. RESULTS: Of 56 patients with recidivism following index presentation with SAH, 10 (17.9%) developed recurrent SAH. We report on 17 episodes in seven patients with complete data. The mean age and duration of alcohol use were 47.9+/ 7.4 and 16.1+/-5.2 years, respectively. Compared with those without recurrence, the cohort with recurrent SAH were more likely to be women (57.1 vs. 34.8%, P=0.405), had higher alcohol consumption during relapse (16.0+/-15.3 vs. 11.3+/ 8.1 U/day, P=0.591) and a recidivism pattern of alcohol relapse after initial abstinence rather than continuous alcohol use. Recurrent episodes were more severe compared with the index one (discriminant function 70.4+/-27.9 vs. 50.5+/ 10.9; MELD score 26.2+/-3.7 vs. 22.1+/-1.5, P<0.05), the overall mortality being 57.1%. Treatment responses to corticosteroids were consistent in 66.7% of patients. CONCLUSION: Approximately 18% of patients, especially women, develop recurrent SAH because of recidivism, with increasing disease severity and mortality approaching 60%. Our data underscore the urgent need to develop strategies to prevent recidivism following index presentation with SAH. PMID- 23628965 TI - Influence of adsorption thermodynamics on guest diffusivities in nanoporous crystalline materials. AB - Published experimental data, underpinned by molecular simulations, are used to highlight the strong influence of adsorption thermodynamics on diffusivities of guest molecules inside ordered nanoporous crystalline materials such as zeolites, metal-organic frameworks (MOFs), and zeolitic imidazolate frameworks (ZIFs). For cage-type structures (e.g. LTA, CHA, DDR, and ZIF-8), the variation of the free energy barrier for inter-cage hopping across the narrow windows, -deltaFi, provides a rationalization of the observed strong influence of pore concentrations, ci, on diffusivities. In open structures with large pore volumes (e.g. FAU, IRMOF-1, CuBTC) and within channels (MFI, BEA, MgMOF-74, MIL-47, MIL 53), the pore concentration (ci) dependence of the self- (Di,self), Maxwell Stefan (Di), and Fick (Di) diffusivities are often strongly dictated by the inverse thermodynamic correction factor, 1/Gammai=?ln ci/?ln pi; the magnitudes of the diffusivities are dictated by the binding energies for adsorption. For many guest-host combinations Di-ci dependence is directly related to the 1/Gammaivs. ci variation. When molecular clustering occurs, we get 1/Gammai > 1, causing unusual Divs. ci dependencies. The match, or mis-match, between the periodicity of the pore landscape and the conformations of adsorbed chain molecules often leads to non-monotonic variation of diffusivities with chain lengths. PMID- 23628966 TI - Quantifying glomerular permeability of fluorescent macromolecules using 2-photon microscopy in Munich Wistar rats. AB - Kidney diseases involving urinary loss of large essential macromolecules, such as serum albumin, have long been thought to be caused by alterations in the permeability barrier comprised of podocytes, vascular endothelial cells, and a basement membrane working in unison. Data from our laboratory using intravital 2 photon microscopy revealed a more permeable glomerular filtration barrier (GFB) than previously thought under physiologic conditions, with retrieval of filtered albumin occurring in an early subset of cells called proximal tubule cells (PTC)(1,2,3). Previous techniques used to study renal filtration and establishing the characteristic of the filtration barrier involved micropuncture of the lumen of these early tubular segments with sampling of the fluid content and analysis(4). These studies determined albumin concentration in the luminal fluid to be virtually non-existent; corresponding closely to what is normally detected in the urine. However, characterization of dextran polymers with defined sizes by this technique revealed those of a size similar to serum albumin had higher levels in the tubular lumen and urine; suggesting increased permeability(5). Herein is a detailed outline of the technique used to directly visualize and quantify glomerular fluorescent albumin permeability in vivo. This method allows for detection of filtered albumin across the filtration barrier into Bowman's space (the initial chamber of urinary filtration); and also allows quantification of albumin reabsorption by proximal tubules and visualization of subsequent albumin transcytosis(6). The absence of fluorescent albumin along later tubular segments en route to the bladder highlights the efficiency of the retrieval pathway in the earlier proximal tubule segments. Moreover, when this technique was applied to determine permeability of dextrans having a similar size to albumin virtually identical permeability values were reported(2). These observations directly support the need to expand the focus of many proteinuric renal diseases to included alterations in proximal tubule cell reclamation. PMID- 23628967 TI - Introduction: EEG brain waves: a wave of the future or past? PMID- 23628968 TI - ADHD and Hyperkinetic Disorder Symptoms in Australian Adults: Descriptive Scores, Incidence Rates, Factor Structure, and Gender Invariance. AB - OBJECTIVE: ADHD and Hyperkinetic Disorder (HKD) have the same 18 symptoms, covering inattention (IA), hyperactivity (HYP), and impulsivity (IMP). This study was aimed at providing descriptive scores for the different symptom groups in these disorders and how these scores varied by age and gender, the percentages of individuals meeting the symptom thresholds for the different ADHD types and HKD, the factor structure, and gender invariance of these symptoms in adults. METHOD: To accomplish this, 852 adults provided self-ratings for a scale comprising the 18 ADHD/HKD symptoms. RESULTS: The findings showed that age and gender had minimal effects on the ADHD symptoms. Also, in terms of symptom counts, 2% had HKD and 6.3% had ADHD (inattentive = 1.6%, hyperactive-impulsive = 2.7%, and combined type = 2.0%). Confirmatory factor analysis (CFA) provided most support for the three-factor HKD model, involving separate factors for the IA, HYP, and IMP symptoms. This model showed full measurement invariance across gender. CONCLUSION: The theoretical and clinical implications of the findings are discussed. PMID- 23628969 TI - Local electronic structure of aqueous zinc acetate: oxygen K-edge X-ray absorption and emission spectroscopy on micro-jets. AB - Oxygen K-edge X-ray absorption, emission, and resonant inelastic X-ray scattering spectra were measured to site selectively gain insights into the electronic structure of aqueous zinc acetate solution. The character of the acetate ion and the influence of zinc and water on its local electronic structure are discussed. PMID- 23628970 TI - Substrate dependence of Pt4 electronic properties. AB - We show through first-principles calculations that the electronic properties of Pt4 clusters can be tuned by adsorption on substrates with different electronic valence characters. Pt clusters exhibit a metallic character on gamma-Al2O3(111) and insulator properties on CaZrO3(001). The noted difference indicates the role of the electronic valence states of the substrate atoms that directly bond with Pt. PMID- 23628971 TI - Utility of serum thymidine kinase activity measurements for cases of bovine leukosis with difficult clinical diagnoses. AB - This study evaluated the clinical usefulness of serum thymidine kinase (TK) activity for diagnosing bovine leukosis cases for which clinical diagnosis was difficult ('BL with difficult diagnosis'). Median TK activity values in 24 'BL with difficult diagnosis' and 36 cattle for which BL was clinically confirmed by cytology findings of enlarged superficial lymph nodes ('clinically confirmed BL') were 36.8 and 39.4 U/l, respectively (no significant difference). The percentage with positive TK activity (> 5.4 U/l) was also similar in both groups (83.3% for 'BL with difficult diagnosis' and 97.2% for 'clinically confirmed BL'). TK activity was significantly higher in cows with 'BL with difficult diagnosis' compared to those with other tumors (N = 13) and those with inflammatory diseases (N = 14). Maximum TK activity in cows with other tumors and inflammatory diseases was not high (< 10 U/l). Median TK activities in cows with other tumors and those with inflammatory diseases were 1.8 and 1.4 IU/l, respectively. Positive TK activity was found in a significantly higher percentage of cows with 'BL with difficult diagnosis' (83.3%) relative to the percentages of cows with other tumors (15.3%) and inflammatory diseases (21.4%). Thus, TK activity is an appropriate marker for detecting BL onset in cows with 'BL with difficult diagnosis' as well as 'clinically confirmed BL' group. While the specificity of TK activity required for BL diagnosis is not clear, simultaneous evaluation of serum lactate dehydrogenase activity may assist in the differential diagnoses of other tumors and inflammatory diseases from BL. PMID- 23628972 TI - Shortened blood coagulation times in genetically obese rats and diet-induced obese mice. AB - The aim of this study was to investigate blood coagulation times in genetically obese rats and diet-induced obese (DIO) mice in order to clarify the relationship between visceral obesity and blood coagulation. WBN/Kob-Lepr(fa) (fa/fa) rats, a genetically obese model, exhibited a significantly shorter activated partial thromboplastin time (aPTT) and prothrombin time (PT) than age-matched Wistar rats. C57BL/6J mice fed a high-fat diet (60%), a DIO model, exhibited significantly shorter aPTT, PT and thrombin time than lean mice fed a standard diet. Higher body weight, visceral fat weight and insulin resistance were also shared by fa/fa rats and DIO mice. These results suggest that visceral obesity is related to accelerated blood coagulation in addition to disrupted metabolism of glucose and lipids. PMID- 23628973 TI - Origin of three Red-crowned Cranes Grus japonensis found in northeast Honshu and west Hokkaido, Japan, from 2008 to 2012. AB - The Red-crowned Crane Grus japonensis is an endangered species that has two separate breeding populations, one in the Amur River basin and the other in north and east Hokkaido, Japan. So far, only two (Gj1 and Gj2) and seven (Gj3-Gj9) haplotypes in D-loop of mtDNA were identified in Japan and in the continent, respectively. We obtained feathers from three cranes found in northeast Honshu. The crane in Akita in 2008, which also arrived at west Hokkaido, had a novel haplotype (Gj10). Another crane in Akita in 2009 showed a heteroplasmy (Gj7 and a novel type, Gj12). The third crane in Miyagi in 2010 also showed another type, Gj11. These results suggest that three Red-crowned Cranes appeared in Honshu and west Hokkaido were from the continent. PMID- 23628974 TI - Late autoimmune hepatitis after hepatitis C therapy. AB - BACKGROUND: De-novo or reactivated autoimmune hepatitis (AIH) has been reported during or a short time after administration of interferon (IFN) in patients treated for hepatitis C (HCV). Reports on AIH during long-term follow-up after IFN treatment are scarce. PATIENTS AND METHODS: Patients diagnosed with both HCV and AIH were identified in clinical databases of four gastroenterology departments. The medical records of patients diagnosed with AIH after IFN therapy were retrospectively assessed. RESULTS: Five patients (four female, one male) with a mean age of 50 years (range: 34-59) were identified. AIH developed at a mean duration of 4.8 years (range: 1-10) after HCV therapy. Three of five patients had a sustained viral response to antiviral therapy, whereas two were nonresponders. All patients were treated with immunosuppressive therapy after being diagnosed with AIH. Biochemical remission was achieved in four patients; however, one patient had an aggressive course and died despite immunosuppressive therapy. We could not identify any risk factors associated with the development of AIH. CONCLUSION: AIH may develop in patients treated with IFN, not only during or after a short time from therapy but also after a long time from discontinuation of therapy. PMID- 23628975 TI - Research on digestive and liver diseases: a priority for Europe - the societal importance of gastrointestinal diseases and research. AB - On 18 September 2012, in the European Parliament in Brussels, a public meeting was held between Science and Technology Options Assessments of the Parliament and the United European Gastroenterology to review the position of gastrointestinal and liver research in the context of the European Union. The meeting reflected the past situation, the ongoing close collaboration as well as facts and options on the upcoming European Union research programme Horizon 2020 that is in planning and will cover the years from 2014 to 2020. PMID- 23628977 TI - Is Y2(B12H12)3 the main intermediate in the decomposition process of Y(BH4)3? AB - Dodecaborates, i.e. the [B12H12](2-) containing species, are often observed as main intermediates in the hydrogen sorption cycle of metal borohydrides, hindering rehydrogenation. In the decomposition process of Y(BH4)3, yttrium octahydrotriborate, i.e. Y(B3H8)3, rather than the stable Y2(B12H12)3, is formed as the main intermediate. PMID- 23628978 TI - Doped overoxidized polypyrrole microelectrodes as sensors for the detection of dopamine released from cell populations. AB - A surface modification of interdigitated gold microelectrodes (IDEs) with a doped polypyrrole (PPy) film for detection of dopamine released from populations of differentiated PC12 cells is presented. A thin PPy layer was potentiostatically electropolymerized from an aqueous pyrrole solution onto electrode surfaces. The conducting polymer film was doped during electropolymerization by introducing counter-ions in the monomer solution. Several counter-ions were tested and the resulting electrode modifications were characterized electrochemically to find the optimal dopant that increases sensitivity in dopamine detection. Overoxidation of the PPy films was shown to contribute to a significant enhancement in sensitivity to dopamine. The changes caused by overoxidation in the electrochemical behavior and electrode morphology were investigated using cyclic voltammetry and SEM as well as AFM, respectively. The optimal dopant for dopamine detection was found to be polystyrene sulfonate anion (PSS(-)). Rat pheochromocytoma (PC12) cells, a suitable model to study exocytotic dopamine release, were differentiated on IDEs functionalized with an overoxidized PSS(-) doped PPy film. The modified electrodes were used to amperometrically detect dopamine released by populations of cells upon triggering cellular exocytosis with an elevated K(+) concentration. A comparison between the generated current on bare gold electrodes and gold electrodes modified with overoxidized doped PPy illustrates the clear advantage of the modification, yielding 2.6-fold signal amplification. The results also illustrate how to use cell population based dopamine exocytosis measurements to obtain biologically significant information that can be relevant in, for instance, the study of neural stem cell differentiation into dopaminergic neurons. PMID- 23628980 TI - Efficacy and safety of busulfan-based conditioning regimens for multiple myeloma. AB - Multiple myeloma is a malignancy of B cells characterized by accumulation of abnormal plasma cells in the bone marrow. In the past 20 years, the use of high dose therapies and novel agents has resulted in significant and meaningful improvements in survival. Autologous stem cell transplantation (auto-SCT) following a high-dose melphalan-conditioning regimen represents the standard of care for younger patients as well as older patients with a good performance status. A number of strategies have been proposed to improve the outcome of auto SCTs, including the incorporation of new agents such as thalidomide, lenalidomide, and bortezomib into the induction regimen administered before auto SCT; the administration of maintenance therapy after auto-SCT; the incorporation of novel agents into chemotherapeutic regimens after transplantation as consolidation therapy; and the use of reduced-intensity allogeneic transplantation after an initial autograft. Although these approaches have demonstrated some success in improving responses after auto-SCT, none of these strategies are curative. An additional strategy to improve outcomes after auto SCT is to enhance the immediate pretransplant conditioning regimens by either increasing the dose of melphalan or by incorporating novel agents, such as busulfan. This literature review focuses on the efficacy and safety of busulfan based conditioning regimens for auto-SCT in patients with multiple myeloma. PMID- 23628981 TI - High-level expression and efficient one-step chromatographic purification of a soluble human leukemia inhibitory factor (LIF) in Escherichia coli. AB - Leukemia inhibitor factor (LIF) is a three disulfide bridge-containing cytokine with numerous regulatory effects. In this report, we present the high level expression of a soluble recombinant human LIF (rhLIF) in Escherichia coli. A codon-optimized Profinity eXactTM-tagged hLIF cDNA was cloned into pET3b vector, and transformed into E. coli OrigamiB(DE3) harboring the bacterial thioredoxin coexpression vector. By using an enzyme-based glucose release system (EnBase(r)) and high-aeration shake flask (Ultra Yield FlaskTM), the yield of soluble proteins was significantly improved in comparison to commonly-used 2 * YT media. The recombinant protein was purified via a single chromatographic step using an affinity tag-based protein purification system that processed by cleavage with sodium fluoride, resulting in the complete proteolytic removal the N-terminal tag. Soluble rhLIF yield was estimated to be approximately 1mg/g of wet weight cells, with above 98% purity. The rhLIF protein specifically inhibited the proliferation of the murine myeloblastic leukemia M1 cell in a dose-dependent manner, and induced Stat3 phosphorylation in mouse ES cells. This novel expression and purification protocol for the production of recombinant hLIF is a simple, suitable, and effective method. PMID- 23628982 TI - The adhesion-GPCR BAI3, a gene linked to psychiatric disorders, regulates dendrite morphogenesis in neurons. AB - Adhesion-G protein-coupled receptors (GPCRs) are a poorly studied subgroup of the GPCRs, which have diverse biological roles and are major targets for therapeutic intervention. Among them, the Brain Angiogenesis Inhibitor (BAI) family has been linked to several psychiatric disorders, but despite their very high neuronal expression, the function of these receptors in the central nervous system has barely been analyzed. Our results, obtained using expression knockdown and overexpression experiments, reveal that the BAI3 receptor controls dendritic arborization growth and branching in cultured neurons. This role is confirmed in Purkinje cells in vivo using specific expression of a deficient BAI3 protein in transgenic mice, as well as lentivirus driven knockdown of BAI3 expression. Regulation of dendrite morphogenesis by BAI3 involves activation of the RhoGTPase Rac1 and the binding to a functional ELMO1, a critical Rac1 regulator. Thus, activation of the BAI3 signaling pathway could lead to direct reorganization of the actin cytoskeleton through RhoGTPase signaling in neurons. Given the direct link between RhoGTPase/actin signaling pathways, neuronal morphogenesis and psychiatric disorders, our mechanistic data show the importance of further studying the role of the BAI adhesion-GPCRs to understand the pathophysiology of such brain diseases. PMID- 23628984 TI - Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans. AB - Long-lasting neuroadaptations in the glutamatergic corticostriatal circuitry have been suggested to be responsible for the persisting nature of drug addiction. In particular, animal models have linked the metabotropic glutamate receptor 5 (mGluR5) to drug-seeking behavior and extinction learning. Accordingly, blocking mGluR5s attenuated self-administration of cocaine and other addictive drugs in rats. How these animal findings extend to humans remains unclear. Therefore, we investigated if human cocaine users (CU) exhibit altered mGluR5 availability compared with drug-naive control subjects. Seventeen male controls (11 smokers) and 18 male cocaine users (13 smokers) underwent positron emission tomography with (11)C-ABP688 to quantify mGluR5 availability in 12 volumes of interest in addiction-related brain areas. Drug use was assessed by self-report and quantitative hair toxicology. CU and controls did not significantly differ in regional mGluR5 availability. In contrast, smokers (n=24) showed significantly lower mGluR5 density throughout the brain (mean 20%) compared with non-smokers (n=11). In terms of effect sizes, lower mGluR5 availability was most pronounced in the caudate nucleus (d=1.50, 21%), insula (d=1.47, 20%), and putamen (d=1.46, 18%). Duration of smoking abstinence was positively associated with mGluR5 density in all brain regions of interest, indicating that lower mGluR5 availability was particularly pronounced in individuals who had smoked very recently. Specifically tobacco smoking was associated with lower mGluR5 availability in both CU and controls, while cocaine use was not linked to detectable mGluR5 alterations. These findings have important implications regarding the development of novel pharmacotherapies aimed at facilitating smoking cessation. PMID- 23628983 TI - White-matter microstructure and gray-matter volumes in adolescents with subthreshold bipolar symptoms. AB - Abnormalities in white-matter (WM) microstructure, as lower fractional anisotropy (FA), have been reported in adolescent-onset bipolar disorder and in youth at familial risk for bipolarity. We sought to determine whether healthy adolescents with subthreshold bipolar symptoms (SBP) would have early WM microstructural alterations and whether those alterations would be associated with differences in gray-matter (GM) volumes. Forty-two adolescents with three core manic symptoms and no psychiatric diagnosis, and 126 adolescents matched by age and sex, with no psychiatric diagnosis or symptoms, were identified after screening the IMAGEN database of 2223 young adolescents recruited from the general population. After image quality control, voxel-wise statistics were performed on the diffusion parameters using tract-based spatial statistics in 25 SBP adolescents and 77 controls, and on GM and WM images using voxel-based morphometry in 30 SBP adolescents and 106 controls. As compared with healthy controls, adolescents with SBP displayed lower FA values in a number of WM tracts, particularly in the corpus callosum, cingulum, bilateral superior and inferior longitudinal fasciculi, uncinate fasciculi and corticospinal tracts. Radial diffusivity was mainly higher in posterior parts of bilateral superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi and right cingulum. As compared with controls, SBP adolescents had lower GM volume in the left anterior cingulate region. This is the first study to investigate WM microstructure and GM morphometric variations in adolescents with SBP. The widespread FA alterations in association and projection tracts, associated with GM changes in regions involved in mood disorders, suggest altered structural connectivity in those adolescents. PMID- 23628987 TI - Kv3.1-containing K(+) channels are reduced in untreated schizophrenia and normalized with antipsychotic drugs. AB - Neuronal firing is a fundamental element of cerebral function; and, voltage-gated potassium (K(+)) channels regulate that firing through the repolarization of action potentials. Kv3-type channels (Kv3.1-Kv3.4) represent a family of voltage gated K(+) channels that have fast-spiking properties. Kv3.1 channel subunits are predominantly localized to cortical parvalbumin (PV)-positive, inhibitory interneurons. The firing properties of these interneurons participate in establishing the normal gamma oscillations and synchrony of cortical neuronal populations, thought to be the signature of higher information processing in human brain. Schizophrenia (SZ) is associated with abnormalities in cortical gamma synchrony and in information processing, particularly with dysfunction in working memory and executive function. Here, we report the distribution of Kv3.1b and Kv3.2 protein in normal human brain, showing that Kv3.1b is limited to neocortical areas, whereas Kv3.2 is abundantly represented in neo- and subcortical regions. In SZ cases, levels of Kv3.1b protein are decreased in the neocortex, but only in cases without antipsychotic drug (APD) treatment; Kv3.1 levels are normal in antipsychotic-treated cases. Kv3.2 is not different in distribution or in level between normal and SZ cases, nor influenced by APD, in any region tested. The apparent increase in Kv3.1b protein levels by APDs in SZ neocortex was confirmed in laboratory rodents treated with chronic APDs. These findings show a decrease in Kv3.1b channel protein in SZ neocortex, a deficit that is restored by APDs. This alteration could be fundamentally involved in the cortical manifestations of SZ and in the therapeutic response to APDs. PMID- 23628988 TI - What psychiatric genetics has taught us about the nature of psychiatric illness and what is left to learn. AB - Psychiatric genetics has taught us a great deal about the nature of psychiatric disorders. Traditional family, twin and adoption studies have demonstrated the substantial role of genetic factors in their etiology, clarified the role of genetic factors in comorbidity, elucidated development pathways, and documented the importance of gene-environment correlation and interaction. We have also received some hard lessons when we were unable to detect replicable genes of large effect size and found that our much-valued candidate genes did not live up to their expected promise. With more mature molecular and statistical methods, we are entering now a different era. Statistical analyses of aggregate molecular signals are validating earlier heritability estimates. Replicated findings from genome-wide association studies are beginning to emerge, as are discoveries of large-effect size rare genomic variants. The number of such findings is likely to soon grow dramatically. The most pressing question facing the field is what biological picture these results will reveal. I articulate four possible scenarios that reflect (i) no, (ii) minimal, (iii) moderate and (iv) high biological coherence in the replicated molecular variant findings, which are soon likely to emerge. I discuss the factors that will likely influence these patterns, including the problems of etiological heterogeneity and multiple realizability. These findings could provide critical insights into the underlying biology of our psychiatric syndromes and potentially permit us to perceive, 'through a glass darkly,' the levels of the mind-brain system that are disordered. PMID- 23628985 TI - A blood-based predictor for neocortical Abeta burden in Alzheimer's disease: results from the AIBL study. AB - Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Abeta (extracellular beta-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Abeta accumulation, therefore, providing a platform for developing a population-based screen. PMID- 23628990 TI - An orthotopic mouse model of anaplastic thyroid carcinoma. AB - Several types of animal models of human thyroid carcinomas have been established, including subcutaneous xenograft and orthotopic implantation of cancer cells into immunodeficient mice. Subcutaneous xenograft models have been valuable for preclinical screening and evaluation of new therapeutic treatments. There are a number of advantages to using a subcutaneous model; 1) rapid, 2) reproducible, and 3) tumor establishment, growth, and response to therapeutic agents may be monitored by visual inspection. However, substantial evidence has shed light on the short-comings of subcutaneous xenograft models(1-3). For instance, medicinal treatments demonstrating curative properties in subcutaneous xenograft models often have no notable impact on the human disease. The microenvironment of the site of xenographic transplantation or injection lies at the heart of this dissimilarity. Orthotopic tumor xenograft models provide a more biologically relevant context in which to study the disease. The advantages of implanting diseased cells or tissue into their anatomical origin equivalent within a host animal includes a suitable site for tumor-host interactions, development of disease-related metastases and the ability to examine site-specific influence on investigational therapeutic remedies. Therefore, orthotopic xenograft models harbor far more clinical value because they closely reproduce human disease. For these reasons, a number of groups have taken advantage of an orthotopic thyroid cancer model as a research tool(4-7). Here, we describe an approach that establishes an orthotopic model for the study of anaplastic thyroid carcinoma (ATC), which is highly invasive, resists treatment, and is virtually fatal in all diagnosed patients. Cultured ATC cells are prepared as a dissociated cellular suspension in a solution containing a basement membrane matrix. A small volume is slowly injected into the right thyroid gland. Overall appearance and health of the mice are monitored to ensure minimal post-operative complications and to gauge pathological penetrance of the cancer. Mice are sacrificed at 4 weeks, and tissue is collected for histological analysis. Animals may be taken at later time points to examine more advance progression of the disease. Production of this orthotopic mouse model establishes a platform that accomplishes two objectives: 1) further our understanding of ATC pathology, and 2) screen current and future therapeutic agents for efficacy in combating ATC. PMID- 23628991 TI - Self-templating amphiphilic polysiloxanes to design nanostructured silica-based architectures. AB - The self-assembly and sol-gel polymerisation of novel alkoxysilane-functionalized polymethylsiloxanes provide versatile access to nano-assembled containers, silica based micro- and nano-architectures and dispersed mixed metal oxide hybrid materials. PMID- 23628989 TI - The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. AB - Schizophrenia (SZ) is a complex disease characterized by impaired neuronal functioning. Although defective alternative splicing has been linked to SZ, the molecular mechanisms responsible are unknown. Additionally, there is limited understanding of the early transcriptomic responses to neuronal activation. Here, we profile these transcriptomic responses and show that long non-coding RNAs (lncRNAs) are dynamically regulated by neuronal activation, including acute downregulation of the lncRNA Gomafu, previously implicated in brain and retinal development. Moreover, we demonstrate that Gomafu binds directly to the splicing factors QKI and SRSF1 (serine/arginine-rich splicing factor 1) and dysregulation of Gomafu leads to alternative splicing patterns that resemble those observed in SZ for the archetypal SZ-associated genes DISC1 and ERBB4. Finally, we show that Gomafu is downregulated in post-mortem cortical gray matter from the superior temporal gyrus in SZ. These results functionally link activity-regulated lncRNAs and alternative splicing in neuronal function and suggest that their dysregulation may contribute to neurological disorders. PMID- 23628995 TI - Accurate determination of the ultrafast proton transfer rate in porphycene using nuclear spin relaxation. AB - The longitudinal (15)N relaxation rate and (15)N{(1)H} NOE enhancement were determined for porphycene in a CD2Cl2 solution. By invoking the rotational diffusion tensor of porphycene as previously determined, these data could be used to evaluate the tautomerization rate of protons in the NHN bridges. The proton transfer rate compares well to the results obtained by other authors by means of optical spectroscopy. PMID- 23628994 TI - Obesity in young men, and individual and combined risks of type 2 diabetes, cardiovascular morbidity and death before 55 years of age: a Danish 33-year follow-up study. AB - OBJECTIVES: To examine the association between body mass index (BMI) in young adulthood and cardiovascular risks, including venous thromboembolism, before 55 years of age. DESIGN: Cohort study using population-based medical databases. SETTING: Outcomes registered from all hospitals in Denmark from 1977 onwards. PARTICIPANTS: 6502 men born in 1955 and eligible for conscription in Northern Denmark. MAIN OUTCOME MEASURES: Follow-up began at participants' 22nd birthday and continued until death, emigration or 55 years of age, whichever came first. Using regression analyses, we calculated the risks and HRs, adjusting for cognitive test score and years of education. RESULTS: 48% of all obese young men (BMI >=30 kg/m(2)) were either diagnosed with type 2 diabetes, hypertension, myocardial infarction, stroke or venous thromboembolism or died before reaching 55 years of age. Comparing obese men with normal weight men (BMI 18.5 to <25.0 kg/m(2)), the risk difference for any outcome was 28% (95% CI 19% to 38%) and the HR was 3.0 (95% CI 2.3 to 4.0). Compared with normal weight, obesity was associated with an event rate that was increased more than eightfold for type 2 diabetes, fourfold for venous thromboembolism and twofold for hypertension, myocardial infarction and death. CONCLUSIONS: In this cohort of young men, obesity was strongly associated with adverse cardiometabolic events before 55 years of age, including venous thromboembolism. Compared with those of normal weight, young obese men had an absolute risk increase for type 2 diabetes, cardiovascular morbidity or premature death of almost 30%. PMID- 23628996 TI - alpha-tubulin is rapidly phosphorylated in response to hyperosmotic stress in rice and Arabidopsis. AB - By using high-resolution two-dimensional PAGE followed by phosphoprotein-specific staining and peptide mass fingerprint analysis along with other assays, we found that alpha-tubulin is phosphorylated in response to hyperosmotic stress in rice and Arabidopsis. The onset of the phosphorylation response was as early as 2 min after hyperosmotic stress treatment, and a major proportion of alpha-tubulin was phosphorylated after 60 min in root tissues. However, the phosphorylated form of alpha-tubulin was readily dephosphorylated upon stress removal. The phosphorylation site was identified as Thr349 by comprehensive mutagenesis of serine/threonine residues in a rice alpha-tubulin isoform followed by evaluation in cultured cell protoplasts. This residue is located at the surface for the interaction with beta-tubulin in polymerized alpha-beta tubulin dimers and has been proposed to be directly involved in this interaction. Thus, alpha-tubulin phosphorylation was considered to occur on free tubulin dimers in response to hyperosmotic stress. The incorporation of green fluorescent protein (GFP)-alpha tubulin into cortical microtubules was completely inhibited in transgenic Arabidopsis when Thr349 was substituted with glutamate or aspartate. Using transgenic Arabidopsis plants expressing GFP-alpha-tubulin, we found that hyperosmotic stress causes extensive cortical microtubule depolymerization. Microtubule-destabilizing treatments such as propyzamide or oryzalin and temperature stresses resulted in alpha-tubulin phosphorylation, whereas hyperosmotic stress-induced alpha-tubulin phosphorylation was partially inhibited by taxol, which stabilizes microtubules. These results and the three-dimensional location of the phosphorylation site suggested that microtubules are depolymerized in response to hyperosmotic stress via alpha-tubulin phosphorylation. Together, the results of the present study reveal a novel mechanism that globally regulates the microtubule polymerization. PMID- 23628997 TI - Magnesium deficiency phenotypes upon multiple knockout of Arabidopsis thaliana MRS2 clade B genes can be ameliorated by concomitantly reduced calcium supply. AB - Plant MRS2 membrane protein family members have been shown to play important roles in magnesium uptake and homeostasis. Single and double knockouts for two Arabidopsis thaliana genes, AtMRS2-1 and AtMRS2-5, have previously not shown significant phenotypes even under limiting Mg(2+) supply although both are strongly expressed already in early seedlings. Together with AtMRS2-10, these genes form clade B of the AtMRS2 gene family. We now succeeded in obtaining homozygous AtMRS2-1/10 double and AtMRS2-1/5/10 triple knockout lines after selection under increased magnesium supply. Although wilting early, both new mutant lines develop fully and are also fertile under standard magnesium supply, but show severe developmental retardation under limiting Mg(2+) concentrations. To investigate nutrient dependency of germination and seedling development under various conditions, including variable supplies of Mg(2+), Ca(2+), Zn(2+), Mn(2+), Co(2+), Cd(2+) and Cu(2+), in a reproducible and economical way, we employed a small-scale liquid culturing system in 24-well plate set-ups. This allowed the growth and monitoring of individual plantlets of different mutant lines under several nutritional conditions in parallel, and the scoring and statistical evaluation of developmental stages and biomass accumulation. Detrimental effects of higher concentrations of these elements were similar in mutants and the wild type. However, growth retardation phenotypes seen upon hydroponic cultivation under low Mg(2+) could be ameliorated when Ca(2+) concentrations were concomitantly lowered, supporting indications for an important interplay of these two most abundant divalent cations in the nutrient homeostasis of plants. PMID- 23629000 TI - Electrochemical determination of microRNA-21 based on bio bar code and hemin/G quadruplet DNAenzyme. AB - A simple and novel microRNA (miRNA) biosensor was developed using DNA-Au bio bar code (DNA-Au) and G-quadruplex-based DNAenzyme. DNA-Au increased the amount of miRNA-21 participating in hybridization. Hemin/G-quadruplex DNAenzyme significantly improved the catalysis of H(2)O(2) by oxidation of hydroquinone, resulting in an obvious reduction current of benzoquinone for miRNA-21 indirect detection. Under optimum conditions, the linear relationship between miRNA-21 concentration and reduction response was obtained with the detection limit of 0.006 pM, which showed a good sensitivity. Besides, selectivity of the biosensor was investigated by detecting the base mismatched miRNAs. This proposed method was further applied to detect miRNA-21 extracted from human hepatocarcinoma BEL 7402 cells and human mastocarcinoma MCF-7 cells. The influence of bisphenol A (BPA) on the expression of miRNA-21 in cells was also investigated. The biosensor performs well in practical applications, which suggests it may provide a new platform for gene diagnosis. PMID- 23629001 TI - Durable knockdown and protection from HIV transmission in humanized mice treated with gel-formulated CD4 aptamer-siRNA chimeras. AB - The continued spread of HIV underscores the need to interrupt transmission. One attractive strategy, in the absence of an effective vaccine, is a topical microbicide, but the need for application around the time of sexual intercourse leads to poor patient compliance. Intravaginal (IVAG) application of CD4 aptamer siRNA chimeras (CD4-AsiCs) targeting the HIV coreceptor CCR5, gag, and vif protected humanized mice from sexual transmission. In non-dividing cells and tissue, RNAi-mediated gene knockdown lasts for several weeks, providing an opportunity for infrequent dosing not temporally linked to sexual intercourse, when compliance is challenging. Here, we investigate the durability of gene knockdown and viral inhibition, protection afforded by CCR5 or HIV gene knockdown on their own, and effectiveness of CD4-AsiCs formulated in a gel in polarized human cervicovaginal explants and in humanized mice. CD4-AsiC-mediated gene knockdown persisted for several weeks. Cell-specific gene knockdown and protection were comparable in a hydroxyethylcellulose gel formulation. CD4-AsiCs against CCR5 or gag/vif performed as well as a cocktail in humanized mice. Transmission was completely blocked by CCR5 CD4-AsiCs applied 2 days before challenge. Significant, but incomplete, protection also occurred when exposure was delayed for 4 or 6 days. CD4-AsiCs targeting gag/vif provided some protection when administered only after exposure. These data suggest that CD4-AsiCs are a promising approach for developing an HIV microbicide. PMID- 23629002 TI - Chemically modified synthetic microRNA-205 inhibits the growth of melanoma cells in vitro and in vivo. AB - microRNA (miR)-205 is downregulated and acts as a tumor suppressor in human melanoma cells. Previously, for clinical application, we added aromatic benzene pyridine (BP-type) analogs to the 3'-overhang region of the RNA-strand and changed the sequences of the passenger strand in the miR-143 duplex. Here, we demonstrated the antitumor effect in vitro and in vivo of miR-205 that was also chemically modified by BP and had altered passenger sequence. In in vitro experiments, transfection with the synthetic miR-205 (miR-205BP/S3) significantly inhibited the growth of human melanoma cells. Exogenous miR-205BP/S3 suppressed the protein expression levels of E2F1 and VEGF, which are validated targets of miR-205-5p, and BCL2, a transcribed molecule of E2F1, as did Pre-miR-205, used as a miR-205 mimic having the wild-type sequence. On the basis of the results of a luciferase activity assay, miR-205BP/S3 directly targeted E2F1, as did Pre-miR 205. However, miR-205BP/S3 was much more resistant to RNase than Pre-miR-205 in fetal bovine serum and to RNase in mice xenografted with human melanoma tissues. In addition, the intratumoral injection of miR-205BP/S3 exhibited a significant antitumor effect compared with the case of control miRNA or Pre-miR-205 in human melanoma cell-xenografted mice. These findings indicate that miR-205BP/S3 is a possible promising therapeutic modality for melanoma. PMID- 23629005 TI - Determinants of the frequency of contact lens wear. AB - OBJECTIVES: To characterize and discover the determinants of the frequency of wear (FOW) of contact lenses. METHODS: Survey forms were sent to contact lens fitters in up to 40 countries between January and March every year for 5 consecutive years (2007-2011). Practitioners were asked to record data relating to the first 10 contact lens fits or refits performed after receiving the survey form. Only data for daily wear lens fits were analyzed. RESULTS: Data were collected in relation to 74,510 and 9,014 soft and rigid lens fits, respectively. Overall, FOW was 5.9+/-1.7 days per week (DPW). When considering the proportion of lenses worn between one to seven DPW, the distribution for rigid lenses is skewed toward full-time wear (7 DPW), whereas the distribution for soft daily disposable lenses is perhaps bimodal, with large and small peaks at seven and two DPW, respectively. There is a significant variation in FOW among nations (P<0.0001), ranging from 6.8+/-1.0 DPW in Greece to 5.1+/-2.5 DPW in Kuwait. For soft lenses, FOW increases with decreasing age. Females (6.0+/-1.6 DPW) wear lenses more frequently than males (5.8+/-1.7 DPW) (P=0.0002). FOW is greater among those wearing presbyopic corrections (6.1+/-1.4 DPW) compared with spherical (5.9+/-1.7 DPW) and toric (5.9+/-1.6 DPW) designs (P<0.0001). FOW with hydrogel peroxide systems (6.4+/-1.1 DPW) was greater than that with multipurpose systems (6.2+/-1.3 DPW) (P<0.0001). CONCLUSIONS: Numerous demographic and contact lens-related factors impact FOW. There may be a future trend toward a lower FOW associated with the increasing popularity of daily disposable lenses. PMID- 23629006 TI - Objective quantification of fluorescence intensity on the corneal surface using a modified slit-lamp technique. AB - OBJECTIVES: To improve the digital quantification of fluorescence intensity of sodium fluorescein instilled on corneal surface by modifying a slit lamp hardware and performing computerized processing of captured digital images. METHODS: The optics of a slit lamp were modified to remove corneal Purkinje reflection and to expand the illuminated area on the cornea, followed by postexperiment image processing to minimize the influence of uneven illumination. To demonstrate the feasibility and reliability of this new technique, we applied it to objective grading of corneal staining with sodium fluorescein. The results of computerized grading were compared with the results obtained using standard subjective grading of corneal staining. Objective digital grades, staining area, and staining pixel with manually and automatically defined threshold (SP-M and SP-A) were calculated for both original and processed images. Standard subjective grades of the original images were performed by 13 trained observers using National Eye Institute (NEI), Efron, and CCLRU grading scales. A series of linear regression analyses were performed to investigate the correlation between objective and subjective grades. RESULTS: Digital grades of the captured images were correlated significantly with subjective grades. After minimization of the artifact caused by the nonuniform illumination, correlations between digital and subjective grading were mostly strengthened. In some cases, digital grading of corneal staining was more sensitive than subjective grading methods when differentiating subtle differences of corneal staining. CONCLUSIONS: Modifications performed on commercial slit-lamp hardware and the proposed digital image-processing technique have improved the quality of captured images for semiautomated quantification of fluorescein intensity on the cornea. PMID- 23629003 TI - HLA engineering of human pluripotent stem cells. AB - The clinical use of human pluripotent stem cells and their derivatives is limited by the rejection of transplanted cells due to differences in their human leukocyte antigen (HLA) genes. This has led to the proposed use of histocompatible, patient-specific stem cells; however, the preparation of many different stem cell lines for clinical use is a daunting task. Here, we develop two distinct genetic engineering approaches that address this problem. First, we use a combination of gene targeting and mitotic recombination to derive HLA homozygous embryonic stem cell (ESC) subclones from an HLA-heterozygous parental line. A small bank of HLA-homozygous stem cells with common haplotypes would match a significant proportion of the population. Second, we derive HLA class I negative cells by targeted disruption of both alleles of the Beta-2 Microglobulin (B2M) gene in ESCs. Mixed leukocyte reactions and peptide-specific HLA-restricted CD8(+) T cell responses were reduced in class I-negative cells that had undergone differentiation in embryoid bodies. These B2M(-/-) ESCs could act as universal donor cells in applications where the transplanted cells do not express HLA class II genes. Both approaches used adeno-associated virus (AAV) vectors for efficient gene targeting in the absence of potentially genotoxic nucleases, and produced pluripotent, transgene-free cell lines. PMID- 23629007 TI - Artificial micro-cinderella based on self-propelled micromagnets for the active separation of paramagnetic particles. AB - In this work, we will show that ferromagnetic microjets can pick-up paramagnetic beads while not showing any interaction with diamagnetic silica microparticles for the active separation of microparticles in solution. PMID- 23629008 TI - Retrophylogenomics place tarsiers on the evolutionary branch of anthropoids. AB - One of the most disputed issues in primate evolution and thus of our own primate roots, is the phylogenetic position of the Southeast Asian tarsier. While much molecular data indicate a basal place in the primate tree shared with strepsirrhines (prosimian monophyly hypothesis), data also exist supporting either an earlier divergence in primates (tarsier-first hypothesis) or a close relationship with anthropoid primates (Haplorrhini hypothesis). The use of retroposon insertions embedded in the Tarsius genome afforded us the unique opportunity to directly test all three hypotheses via three pairwise genome alignments. From millions of retroposons, we found 104 perfect orthologous insertions in both tarsiers and anthropoids to the exclusion of strepsirrhines, providing conflict-free evidence for the Haplorrhini hypothesis, and none supporting either of the other two positions. Thus, tarsiers are clearly the sister group to anthropoids in the clade Haplorrhini. PMID- 23629009 TI - Structure-property relationship of extended pi-conjugation of ancillary ligands with and without an electron donor of heteroleptic Ru(II) bipyridyl complexes for high efficiency dye-sensitized solar cells. AB - Two new heteroleptic Ru(II) bipyridyl complexes MH06 and MH11 were designed, synthesized and characterized for DSSCs. While the ancillary ligand of MH06 was molecularly engineered with a strong electron donating group coupled with an extended pi-conjugated system, the ancillary ligand of MH11 contained a longer pi conjugated system only. Molecular modeling, photophysical, and photovoltaic properties were compared under the same experimental conditions against the benchmark N719. In an effort to understand the structure-property relationship, their photovoltaic and photoelectrochemical properties including Jsc, Voc, ground and excited state oxidation potentials, UV-Vis absorption, and molar extinction coefficients were studied. The UV-Vis results showed intense MLCT absorption peaks of MH06 and MH11 in the visible region with a red shift of 12 and 18 nm, respectively, with significantly higher molar extinction coefficients compared to N719. Tetrabutylammonium (TBA) substituted MH11-TBA demonstrated the most efficient IPCE of over 90% in the plateau region covering the entire visible spectrum and extending into the near IR region (ca. 890 nm), which showed a solar to-power conversion efficiency (eta) of 10.06%, significantly higher than that of the benchmark N719 dye (9.32%). The superior performance in terms of the IPCE and Jsc of MH11 can be attributed to the bulky and highly hydrophobic nature of the pyrene-based ancillary ligand, which behaves as a shielding barrier for hole transport recombination between TiO2 and the electrolyte. In addition, the IMPS results showed that the contribution of dyes to the conduction band shift of the TiO2 level is almost similar, regardless of different substitutions on the bipy moiety. This implies that the open-circuit photovoltage (Voc) increases with reduced charge recombination in the presence of a thick layer of tetrabutyl ammonium ions (TBA) of the dye anchored on the surface of TiO2. PMID- 23629010 TI - A ratiometric fluorescent probe based on a BODIPY-DCDHF conjugate for the detection of hypochlorous acid in living cells. AB - A colorimetric and ratiometric fluorescent probe consisting of a boron dipyrromethene (BODIPY) dye conjugated with a 2-dicyanomethylene-3-cyano-2,5 dihydrofuran (DCDHF) group has been designed for the selective and sensitive detection of HOCl/OCl(-)via oxidative cleavage of an alkene linker between BODIPY and DCDHF. PMID- 23629012 TI - Feasibility of operating a solid-liquid bioreactor with used automobile tires as the sequestering phase for the biodegradation of inhibitory compounds. AB - Finding new uses for waste or discarded material is an important environmental goal; being able to use a waste material to treat another waste is an even more attractive objective, and this was the purpose of the present work. We previously showed that used automobile tires have an affinity for a toxic contaminant, dichlorophenol (DCP), absorbing and releasing it based on concentration driving forces. Here we have exploited this phenomenon by using used tires as the sequestering phase in a Two-Phase Partitioning Bioreactor (TPPB) to treat otherwise-toxic levels of DCP, far out-performing single phase operation in a sequencing batch bioreactor. A comprehensive examination of substrate loading, reactor exchange ratio, and tire fraction used, demonstrated that the tire-TPPB system could handle a 40% higher influent substrate loading and an increase of the exchange ratio value from 0.5 (prohibitive for single phase operation) to 0.7. Such improvement was obtained with a tire fraction <=9%, comparable to that for commercial polymers previously employed in TPPBs. This study has opened the door to the identification of other waste plastics suitable for use in TPPBs for the treatment of recalcitrant organic contaminants. PMID- 23629011 TI - Climate change air toxic co-reduction in the context of macroeconomic modelling. AB - This paper examines the health implications of global PM reduction accompanying greenhouse gas emissions reductions in the 180 national economies of the global macroeconomy. A human health effects module based on empirical data on GHG emissions, PM emissions, background PM concentrations, source apportionment and human health risk coefficients is used to estimate reductions in morbidity and mortality from PM exposures globally as co-reduction of GHG reductions. These results are compared against the "fuzzy bright line" that often underlies regulatory decisions for environmental toxics, and demonstrate that the risk reduction through PM reduction would usually be considered justified in traditional risk-based decisions for environmental toxics. It is shown that this risk reduction can be on the order of more than 4 * 10(-3) excess lifetime mortality risk, with global annual cost savings of slightly more than $10B, when uniform GHG reduction measures across all sectors of the economy form the basis for climate policy ($2.2B if only Annex I nations reduce). Consideration of co reduction of PM-10 within a climate policy framework harmonized with other environmental policies can therefore be an effective driver of climate policy. An error analysis comparing results of the current model against those of significantly more spatially resolved models at city and national scales indicates errors caused by the low spatial resolution of the global model used here may be on the order of a factor of 2. PMID- 23629013 TI - Valuation of pollinator forage services provided by Eucalyptus cladocalyx. AB - We assess the monetary value of forage provisioning services for honeybees as provided by an alien tree species in the Western Cape province of South Africa. Although Eucalyptus cladocalyx is not an officially declared invader, it is cleared on a regular basis along with other invasive Eucalyptus species such as Eucalyptus camaldulensis, and Eucalyptus conferruminata (which have been prioritised for eradication in South Africa). We present some of the trade-offs associated with the clearing of E. cladocalyx by means of a practical example that illustrates a situation where the benefits of the species to certain stakeholders could support the containment of the species in demarcated areas, while allowing clearing outside such areas. Given the absence of market prices for such forage provisioning services, the replacement cost is used to present the value of the loss in forage as provided by E. cladocalyx if the alien tree species is cleared along with invasive alien tree species. Two replacement scenarios formed the basis for our calculations. The first scenario was an artificial diet as replacement for the forage provisioning service, which yielded a direct cost estimate of US$7.5 m per year. The second was based on a Fynbos cultivation/restoration initiative aimed at substituting the forage provisioning service of E. cladocalyx, which yielded a direct cost of US$20.2 m per year. These figures provide estimates of the potential additional cost burden on the beekeeping industry if E. cladocalyx is completely eradicated from the Western Cape. The cost estimates should be balanced against the negative impacts of E. cladocalyx on ecosystem services in order to make an informed decision with regard to appropriate management strategies for this species. The findings therefore serve as useful inputs to balance trade-offs for alien species that are considered as beneficial to some, but harmful to other. PMID- 23629014 TI - Diversity of beta-lactam resistance mechanisms in cystic fibrosis isolates of Pseudomonas aeruginosa: a French multicentre study. AB - OBJECTIVES: To investigate the resistance mechanisms of beta-lactam-resistant Pseudomonas aeruginosa isolated from cystic fibrosis (CF) patients in France. METHODS: Two-hundred-and-four P. aeruginosa CF isolates were collected in 10 French university hospitals in 2007. Their susceptibility to 14 antibiotics and their resistance mechanisms to beta-lactams were investigated. Their beta lactamase contents were characterized by isoelectric focusing, PCR and enzymatic assays. Expression levels of efflux pumps and the intrinsic beta-lactamase AmpC were quantified by reverse transcription real-time quantitative PCR. Genotyping was performed using multiple-locus variable number of tandem repeats analysis (MLVA). The oprD genes were sequenced and compared with those of reference P. aeruginosa strains. To assess deficient OprD production, western blotting experiments were carried out on outer membrane preparations. RESULTS: MLVA typing discriminated 131 genotypes and 47 clusters. One-hundred-and-twenty-four isolates (60.8%) displayed a susceptible phenotype to beta-lactams according to EUCAST breakpoints. In the 80 remaining isolates, resistance to beta-lactams resulted from derepression of intrinsic cephalosporinase AmpC (61.3%) and/or acquisition of secondary beta-lactamases (13.8%). Efflux pumps were up-regulated in 88.8% of isolates and porin OprD was lost in 53.8% of isolates due to frameshifting or nonsense mutations in the oprD gene. CONCLUSIONS: beta-Lactam resistance rates are quite high in CF strains of P. aeruginosa isolated in France and not really different from those reported for nosocomial strains. Development of beta-lactam resistance is correlated with patient age. It results from intrinsic mechanisms sequentially accumulated by bacteria isolated from patients who have undergone repeated courses of chemotherapy. PMID- 23629015 TI - Resistance to the most recent protease and non-nucleoside reverse transcriptase inhibitors across HIV-1 non-B subtypes. AB - OBJECTIVES: Limited data are available on resistance to etravirine, rilpivirine, darunavir and tipranavir in patients infected with HIV-1 non-B subtypes, in which natural polymorphisms at certain positions could influence the barrier and/or pathways to drug resistance. METHODS: FASTA format sequences from the reverse transcriptase and protease genes recorded within the Spanish Drug Resistance database (ResRIS) were examined. RESULTS: From 8272 genotypes derived from 5930 different HIV-1 patients included in ResRIS, 5276 genotypes had complete treatment information. Overall, 85% were from antiretroviral-experienced subjects and 7.5% belonged to HIV-1 non-B subtypes: CRF02_AG, C, F and G being the most prevalent variants. For etravirine, only G190A was more prevalent in B than non-B subtypes, whereas V90I and V179E were more frequent in non-B than B subtypes. For rilpivirine, V108I and Y188I were more frequent in B than non-B subtypes, whereas V90I was more prevalent in non-B subtypes. Despite these differences, the overall prevalence of resistance did not differ significantly when comparing etravirine or rilpivirine in B versus non-B subtypes (11.3% versus 7.4%, P = 0.13, and 10.5% versus 7.4%, P = 0.23, respectively). Despite more frequent natural polymorphisms in non-B than B subtypes at tipranavir resistance positions, the prevalence of tipranavir resistance was greater in B than non-B subtypes (11% versus 4.3%, P = 0.004), reflecting a greater antiretroviral exposure in the former. Darunavir resistance did not differ significantly when comparing B and non-B subtypes (5.8% versus 5.5%, P = 0.998). CONCLUSIONS: The rate of resistance to the most recently approved protease and non-nucleoside reverse transcriptase inhibitors is low in antiretroviral-experienced patients, regardless of the HIV-1 subtype. PMID- 23629017 TI - Changes in prostaglandin E2 levels in seminal plasma during ejaculation and the effect of exogenous prostaglandin E2 on semen volume in the dog. AB - In healthy male dogs, peripheral plasma testosterone (T), prostaglandin E2 (PGE2) and seminal plasma PGE2 levels were measured before, during and after ejaculation, and semen quality was examined after oral administration of PGE2. Plasma T and PGE2 levels did not change during these periods, but the seminal plasma PGE2 level of combined the first and second fractions was significantly higher than those at 0-5 and 5-10 min after the start of ejaculation of the third fraction. Semen volume but not quality increased after PGE2 administration. In conclusion, large amounts of PGE2 are released from the prostate gland during the early part of ejaculation, and PGE2 plays an essential role in secretion of seminal plasma. PMID- 23629016 TI - Role of the pcm-tolCsm operon in the multidrug resistance of Stenotrophomonas maltophilia. AB - OBJECTIVES: To elucidate the role of the pcm-tolCsm operon in the multidrug resistance of Stenotrophomonas maltophilia. METHODS: The presence of the pcm tolCsm operon was verified by RT-PCR. The phylogenetic relationship between the outer membrane proteins known to be involved in functional tripartite efflux in Escherichia coli, Pseudomonas aeruginosa and S. maltophilia was analysed. The contribution of TolCsm to resistance to a variety of compounds was investigated by susceptibility testing of the DeltatolCsm mutant. The role of pcm in the expression and function of tolCsm was assessed by quantitative real-time PCR and complementation assay. RESULTS: The pcm and tolCsm genes formed an operon. TolCsm of S. maltophilia, OpmH of P. aeruginosa and TolC of E. coli formed a distinguishing phylogenetic TolC-like clade. TolCsm deletion increased the susceptibility of S. maltophilia KJ2 to several antimicrobial agents (aminoglycoside, macrolide, beta-lactam, chloramphenicol, nalidixic acid, doxycycline and trimethoprim/sulfamethoxazole) and chemical compounds (acriflavine, carbonyl cyanide 3-chlorophenylhydrazone, crystal violet, fusaric acid, menadione, Paraquat, plumbagin, SDS and tetrachlorosalicylanilide). The in frame deletion of pcm caused a polar effect on the expression of tolCsm, which compromised the resistance to amikacin and gentamicin. Nevertheless, the presence of the PCM protein made an insignificant contribution to the function of TolCsm in the resistance to amikacin and gentamicin. CONCLUSIONS: The pcm-tolCsm operon makes a significant contribution to the multidrug resistance of S. maltophilia. PMID- 23629018 TI - Jejunal intussusception associated with lymphoma in a horse. AB - A 2-year-old Thoroughbred horse presented with acute onset of colitis, and the intussuscepted jejunum was surgically resected. A transmural mass protruding into the lumen was found at the leading edge of the intussusceptum. Based on histological and immunohistochemical examinations, the mass was diagnosed as diffuse large B-cell lymphoma with metastasis to the mesenteric lymph nodes. Anatomical localization of the mass in the intussusception and absence of other obvious underlying diseases indicated that the intussusception had occurred in association with the mass. To our knowledge, this case is the first report of equine intussusception associated with focal intestinal lymphoma. PMID- 23629019 TI - Fluctuation in plasma bone metabolic markers in multiparous and primiparous Holstein cows during early to peak lactation. AB - Because the role of bone turnover during early to peak lactation in dairy cows is unclear, plasma levels of osteoclast- or collagen-specific bone resorption and osteoblast-specific bone formation markers from postpartum week 3 (W+3) to W+7 were compared with prepartum W-3 levels in multiparous (n = 15) and primiparous (n = 13) Holstein cows. The multiparous group showed a consistently low level of osteoclast-specific bone resorption markers, while collagen-specific resorption and osteoblast-specific formation markers decreased at postpartum W+7 and from W+5, respectively. In the primiparous group, the plasma levels of all three markers decreased from postpartum W+3. These results suggest that the calcium demand during the transition from early to peak lactation in dairy cows is less affected by bone turnover. PMID- 23629020 TI - Characterization of anoikis-resistant cells in mouse colonic epithelium. AB - Anoikis is a form of apoptosis triggered by inadequate or inappropriate cell matrix contacts. Anoikis resistance has been utilized to isolate adult stem or progenitor cell populations from various tissues. The aim of this study was to characterize the stem or progenitor cell markers expressed in anoikis-resistant cells isolated from mouse colonic epithelium. Mouse colonic epithelial cells were isolated by Ca(2+)-depletion, and anoikis-resistant cells were obtained by culturing the cells in ultra-low attachment dishes. Flow cytometry analysis showed that anoikis-resistant cells are positive for the epithelial cell marker CD326, but negative for the hematopoietic cell marker CD45, eliminating the possibility of hematopoietic cell contamination. The majority of anoikis resistant cells were also positive for the stem or progenitor cell markers CD133 and DCLK1 by immunofluorescent analysis. Reverse transcriptase-polymerase chain reaction analysis revealed that anoikis-resistant cells express +4 position cell marker Hopx, but did not express the other reported stem or progenitor cell markers, Lgr5, Musashi1, Bmi1, mTert and Olfm4. CD133 and DCLK1 double positive cells were observed both apical and basal crypts in mouse proximal colonic tissues. Together, anoikis-resistant cells in mouse colon epithelium were shown to be positive for CD133, DCLK1, Hopx and CD326, but negative for CD45, Lgr5, Musashi1, Bmi1, mTert and Olfm4. This study has shown a possible approach to isolating stem cells from the intestinal epithelium. PMID- 23629021 TI - Light preference assay to study innate and circadian regulated photobehavior in Drosophila larvae. AB - Light acts as environmental signal to control animal behavior at various levels. The Drosophila larval nervous system is used as a unique model to answer basic questions on how light information is processed and shared between rapid and circadian behaviors. Drosophila larvae display a stereotypical avoidance behavior when exposed to light. To investigate light dependent behaviors comparably simple light-dark preference tests can be applied. In vertebrates and arthropods the neural pathways involved in sensing and processing visual inputs partially overlap with those processing photic circadian information. The fascinating question of how the light sensing system and the circadian system interact to keep behavioral outputs coordinated remains largely unexplored. Drosophila is an impacting biological model to approach these questions, due to a small number of neurons in the brain and the availability of genetic tools for neuronal manipulation. The presented light-dark preference assay allows the investigation of a range of visual behaviors including circadian control of phototaxis. PMID- 23629023 TI - Optimization of continuous infusion of piperacillin-tazobactam in children with fever and neutropenia. AB - The study through Monte Carlo simulation of beta-lactam pharmacokinetic/pharmacodynamic target attainment and determination of subsequent serum concentrations of piperacillin-tazobactam administered through continuous infusion to children treated for fever and neutropenia shows that 400 mg/kg/day has the highest probability of target attainment against Pseudomonas aeurginosa in our oncology ward compared with the standard regimen of 300 mg/kg/day. PMID- 23629024 TI - Prospective surveillance study of invasive pneumococcal disease among urban children in the Philippines. AB - BACKGROUND: Worldwide, invasive pneumococcal disease (IPD) causes considerable morbidity and mortality among children, but incidence data in Asia are lacking. This 2-year hospital-based, prospective, surveillance study was conducted at 3 study sites in urban areas of the Philippines to estimate IPD and pneumonia incidence in children and describe the serotype distribution of invasive Streptococcus pneumoniae isolates. METHODS: Children aged 28 days to <60 months residing within the 3 surveillance areas presenting with possible IPD were enrolled. Initial diagnosis, history of pneumococcal vaccine receipt and previous antimicrobial treatment were recorded. Blood specimens were collected for S. pneumoniae identification and serotyping. Final diagnosis was determined for hospitalized subjects, subjects whose culture yielded S. pneumoniae and subjects with clinically suspected meningitis. RESULTS: A total of 5940 subjects were enrolled, 47 IPD cases identified. IPD site rates were 33.49 per 100,000, 25.38 per 100,000 and 25.85 per 100,000. Chest radiograph-confirmed pneumonia incidence ranged from 633.74 to 1683.59 per 100,000. Highest chest radiograph-confirmed pneumonia incidence occurred in those 28 days to <6 months of age at 2 sites (2166.16 and 3891.94 per 100,000) and those 6-12 months of age at the third site (3847.52 per 100,000). Thirty-five S. pneumoniae isolates were serotyped; most commonly identified were serotypes 1, 2, 5, 6B, 14 and 18F. One serotype 14 isolate was erythromycin resistant. Previous antibiotic therapy was documented in 17-53% of subjects; 2 subjects had received pneumococcal vaccine. At 2 sites, one third of IPD subjects died. CONCLUSIONS: IPD is an important cause of morbidity and mortality among urban children in the Philippines. Our data support the expectation that widespread immunization would decrease IPD disease burden. PMID- 23629025 TI - The fractal spatial distribution of pancreatic islets in three dimensions: a self avoiding growth model. AB - The islets of Langerhans, responsible for controlling blood glucose levels, are dispersed within the pancreas. A universal power law governing the fractal spatial distribution of islets in two-dimensional pancreatic sections has been reported. However, the fractal geometry in the actual three-dimensional pancreas volume, and the developmental process that gives rise to such a self-similar structure, has not been investigated. Here, we examined the three-dimensional spatial distribution of islets in intact mouse pancreata using optical projection tomography and found a power law with a fractal dimension of 2.1. Furthermore, based on two-dimensional pancreatic sections of human autopsies, we found that the distribution of human islets also follows a universal power law with a fractal dimension of 1.5 in adult pancreata, which agrees with the value previously reported in smaller mammalian pancreas sections. Finally, we developed a self-avoiding growth model for the development of the islet distribution and found that the fractal nature of the spatial islet distribution may be associated with the self-avoidance in the branching process of vascularization in the pancreas. PMID- 23629026 TI - Molecular characterisation and expression analysis of the cathepsin H gene from rock bream (Oplegnathus fasciatus). AB - Cathepsins are lysosomal cysteine proteases belonging to the papain family, whose members play important roles in normal metabolism for the maintenance of cellular homeostasis. Rock bream (Oplegnathus fasciatus) cathepsin H (RbCTSH) cDNAs were identified by expressed sequence tag analysis of a lipopolysaccharide-stimulated rock bream liver cDNA library. The full-length RbCTSH cDNA (1326 bp) contained an open reading frame of 978 bp encoding 325 amino acids. The presence of an ERFNIN like motif was predicted in the propeptide region of RbCTSH. Furthermore, multiple alignments showed that the EPQNCSAT region was well conserved among other cathepsin H sequences. Phylogenetic analysis revealed that RbCTSH is most closely related to Nile tilapia cathepsin H. RbCTSH was expressed significantly in the intestine, spleen, head kidney and stomach. RbCTSH mRNA expression was also examined in several tissues under conditions of bacterial and viral challenge. All examined tissues of fish infected with Edwardsiella tarda, Streptococcus iniae and red sea bream iridovirus (RSIV) showed significant increases in RbCTSH expression compared to the control. In the kidney and spleen, RbCTSH mRNA expression was upregulated markedly following infection with bacterial pathogens. These findings indicate that RbCTSH plays an important role in the innate immune response of rock bream. Furthermore, these results provide important information for the identification of other cathepsin H genes in various fish species. PMID- 23629027 TI - A Selective Inhibitor of Human C-reactive Protein Translation Is Efficacious In Vitro and in C-reactive Protein Transgenic Mice and Humans. AB - Observational studies of patients with established rheumatoid arthritis (RA) document a positive correlation between C-reactive protein (CRP) blood concentration and worsening of RA symptoms, but whether this association is causal or not is not known. Using CRP transgenic mice (CRPTg) with collagen induced arthritis (CIA; a rodent model of RA), we explored causality by testing if CRP lowering via treatment with antisense oligonucleotides (ASOs) targeting human CRP mRNA was efficacious and of clinical benefit. We found that in CRPtg with established CIA, ASO-mediated lowering of blood human CRP levels improved the clinical signs of arthritis. In addition, in healthy human volunteers the ASO was well tolerated and efficacious i.e., treatment achieved significant CRP lowering. ASOs targeting CRP should provide a specific and effective way to lower human CRP levels, which might be an effective therapy in patients with established RA.Molecular Therapy - Nucleic Acids (2012) 1, e52; doi:10.1038/mtna.2012.44; published online 13 November 2012. PMID- 23629028 TI - Gene Silencing Mediated by siRNA-binding Fusion Proteins Is Attenuated by Double stranded RNA-binding Domain Structure. AB - Delivery of small interfering RNA (siRNA) targeted to specific cell types is a significant challenge for the development of RNA interference-based therapeutics. Recently, PTD-DRBD, a double-stranded RNA binding domain (DRBD) fused to the TAT protein transduction domain (PTD), was shown to be effective at delivering siRNA in a non-cell type-specific manner. Here, we evaluated the potential of DRBD as a general protein platform for targeted small interfering RNA (siRNA) delivery. We found that a single DRBD was insufficient to stably complex siRNA when fused to targeting peptides other than PTD, which facilitated nonspecific nucleic acid binding. In contrast to PTD-DRBD, fusion proteins containing two DRBDs (2* DRBD) yielded specific and stable siRNA binding. These proteins could mediate the cellular uptake of siRNA in vitro, though compared with PTD-DRBD gene silencing was attenuated by endosomal entrapment. Our findings suggest that unlike a single DRBD, 2* DRBD inhibits siRNA escape into the cytoplasm and/or induces an internalization pathway distinct from that of PTD-DRBD. Collectively, these data indicate that while 2* DRBD retains siRNA-binding activity when fused to different cell surface-interacting peptides, the utility of 2* DRBD for cell specific RNA interference is limited without further protein engineering to enhance the bioavailability of the delivered siRNAs.Molecular Therapy - Nucleic Acids (2012) 1, e53; doi:10.1038/mtna.2012.43; published online 13 November 2012. PMID- 23629029 TI - Random Insertion of mCherry Into VP3 Domain of Adeno-associated Virus Yields Fluorescent Capsids With no Loss of Infectivity. AB - Adeno-associated virus (AAV)-derived vectors are promising gene delivery systems, and a number of design strategies have been pursued to improve their performance. For example, genetic insertion of proteins into the capsid may be used to achieve vector retargeting, reduced immunogenicity, or to track vector transport. Unfortunately, rational approaches to genetic insertion have experienced limited success due to the unpredictable context-dependent nature of protein folding and the complexity of the capsid's macroassembly. We report the construction and use of a frame-enriched DNase-based random insertion library based on AAV2 cap, called pAAV2_RaPID (Random Peptide Insertion by DNase). The fluorescent mCherry protein was inserted randomly throughout the AAV2 capsid and the library was selected for fluorescent and infectious variants. A capsid site was identified in VP3 that can tolerate the large protein insertion. In contrast to previous efforts to incorporate fluorescent proteins into the AAV2 capsid, the isolated mCherry mutant maintains native infectivity while displaying robust fluorescence. Collectively, these results demonstrate that the pAAV2_RaPID platform library can be used to create fully infectious AAV vectors carrying large functional protein domains on the capsid.Molecular Therapy - Nucleic Acids (2012) 1, e54; doi:10.1038/mtna.2012.46; published online 13 November 2012. PMID- 23629030 TI - Moving Successful Virus-specific T-cell Therapy for Hematopoietic Stem Cell Recipients to Late Phase Clinical Trials. PMID- 23629031 TI - From the editor: the no-decision option. PMID- 23629032 TI - Health reform's impact on federally qualified community health centers: the unintended consequence of increased Medicaid enrollment on the primary care medical home. AB - The impact of recently passed health reform legislation may cause substantial changes in community health center (CHC) operations. The new legislation provides federal funding for center expansion, increased Medicaid enrollment, enhanced Medicare payments, training to increase primary care providers, and incentives to develop CHCs as accountable care organizations. Health reform could place CHCs in a vulnerable financial situation. Newly insured patients may seek care at private providers, whereas CHCs are left caring only for the uninsured. Thus, CHCs are unable to benefit from enhanced insurance payments needed to offset care given to the uninsured. Conversely, if CHCs participate in developing comprehensive care networks for low-income populations by strengthening referral networks, developing primary medical care homes and accountable care organizations, and investing in infrastructure, then health center medical care will be a desired option for the newly insured, and a robust safety-net system may result. PMID- 23629033 TI - The effects of supervisors' supportive role, job stress, and work-family conflicts on the nurses' attitudes. AB - This study developed and tested a research model that examined the effects of supervisor support (SUPPORT), work-family conflict (W-FCON), family-work conflict (F-WCON), and job stress (JSTRESS) on a number of selected consequences using data collected from nurses and nurse axillaries in Shiraz University of Medical Sciences hospitals in Fars province (south of Iran). The results demonstrated that W-FCON and F-WCON exerted a significant positive influence on JSTRESS. Contrary to the study hypothesis, the results did not provide any empirical support for the significant negative relationship between W-FCON, F-WCON, and JSTRESS with family satisfaction (FSAT). The findings further revealed that higher JSTRESS led to lower life satisfaction (LSAT). As expected, high levels of FSAT resulted in increased LSAT. However, this study failed to find significant negative relationships between conflicts in the work-family interface and LSAT. The results also revealed that JSTRESS was not significantly associated with LSAT. Consonant with the study hypotheses, W-FCON, F-WCON, and JSTRESS were found to be significant for turnover intentions, whereas LSAT did not. Implications for managers and future research directions are presented. PMID- 23629034 TI - The relationship between nursing staff levels, skill mix, and deficiencies in Maryland nursing homes. AB - The objective of this data analysis was to explore whether nurse staffing levels and skill mix influenced the number and severity of nursing home deficiencies in Maryland nursing homes. Nursing staff levels and skill mix in relation to quality outcomes in nursing homes have been explored with inconsistent results. Two multiple regression analyses were done to explore factors influencing deficiencies and the severity of the deficiencies found during the annual survey process. The factors influencing the number of deficiencies were the number of nursing home beds (beta = .29), nursing assistant hours per patient-day (beta = .206), and the location of the nursing home (beta = -.138). The only factor influencing the severity of the deficiencies was RN hours per patient-day (beta = -.199). In conclusion, it was determined that RN staffing, although not associated with the number of deficiencies, is associated with deficiency severity. PMID- 23629035 TI - Improvement of hospital performance through innovation: toward the value of hospital care. AB - The perspective of innovation as the strategic lever of organizational performance has been widespread in the hospital sector. While public value of innovation can be significant, it is not evident that innovation always ends up in higher levels of performance. Within this context, the purpose of the article was to critically analyze the relationship between innovation and performance, taking into account the specificities of the hospital sector. This article pulls together primary data on organizational flexibility, innovation, and performance from 95 hospitals in Portugal, collected through a survey, data from interviews to hospital administration boards, and a panel of 15 experts. The diversity of data sources allowed for triangulation. The article uses mixed methods to explore the relationship between innovation and performance in the hospital sector in Portugal. The relationship between innovation and performance is analyzed through cluster analysis, supplemented with content analysis of interviews and the technical nominal group. The main findings reveal that the cluster of efficient innovators has twice the level of performance than other clusters. Organizational flexibility and external cooperation are the 2 major factors explaining these differences. The article identifies various organizational strategies to use innovation in order to enhance hospital performance. Overall, it proposes the alignment of perspectives of different stakeholders on the value proposition of hospital services, the embeddedness of information loops, and continuous adjustments toward high-value services. PMID- 23629036 TI - Evidence of psychosocial and behavioral effects related to the intention to quit alcohol in South Korea. AB - This study examined psychosocial and behavioral characteristics and factors that influenced certain subjects within a population-based sample of Korean drinkers to quit alcohol consumption (N = 8910). Explored were various factors of psychosocial behaviors such as socioeconomic reasons, health behavior, cues to action, and self-control related to the intentions of alcohol abstinence. Using path analysis, it was found that, for men, self-control (B = 0.51), health behavior (B = 0.78), and health literacy (B = 0.58) were positively associated with cues to action which in turn positively induced them to quit drinking. This pattern of results appeared to apply only to men and not to women. In conclusion, this study reveals that men who do not smoke, regularly exercise, have high self control, and look for health information are likely to be active in acquiring cues for behavioral changes and making themselves motivated. However, conventions of alcohol consumption in the female population are more dependent on social factors in comparison to those of men. PMID- 23629038 TI - Can we associate the hours of clinical services at the rehabilitation outcomes? The case of the visual impairment rehabilitation program. AB - The purpose of this study was to determine the effects on the elderly of clinical interventions by professionals from a visual impairment rehabilitation program, more specifically, the effects on their daily life and the extent to which such interventions encourage social participation. In accordance with the conceptual framework of the Disability Creation Process, the clinical results of a population study group of 100 persons with various types of visual impairment enrolled in a rehabilitation program were analyzed as per the intensity of the clinical interventions (eg, hours of clinical services provided and dispensed by professionals). The results of the study tend to show that the hours of services accorded to a patient positively contribute to the progression of his or her Functional Global Profile as per the rehabilitation outcomes progression measures. In contrast, age and the spreading of services negatively contribute. The contributions of the study are innovative for assessing clinical effectiveness. For instance, the understanding of the relationship between the measurement of a patient's clinical results and the services that he or she has received should help us improve the practices and methods used in visual impairment rehabilitation. PMID- 23629039 TI - Progression in understanding and implementing the cultural and linguistic appropriate services standards: five-year follow-up at an academic center. AB - In 2001, 14 national standards on Culturally and Linguistically Appropriate Services (CLAS) in health care were issued by the US Department of Health and Human Services Office of Minority Health to guide outcomes specific to disparities affecting patients with limited English proficiency. Additionally, demographic changes are rapidly occurring throughout the United States leading to more culturally and racially diverse communities, which have increased language barriers in the health care environment. This nonrandomized, cross-sectional study assessed changes and attitudes and applications of CLAS in an academic health care setting over a 5-year period (2006 to 2011). Results indicated that, in 2006, 72.6% participants reported they were "not at all familiar with CLAS" in comparison with 28.8% in 2011. In 2006, 16.5% participants strongly agreed to the question, "I know how to work with medical interpreters" compared with 24.9% in 2011. The same trend is seen with the question, "I use medical interpreters when I have a Spanish-speaking patient," in 2006, 25.5% strongly agreed in comparison with 35.4% in 2011. This study suggests that significant improvements occurred in the use of medical interpreters and understanding of CLAS as a result of educational activities implemented from 2006 to 2011. PMID- 23629040 TI - Results of an initiative to charge for previously uncompensated care in an academic primary care practice. AB - Increasing clinical workload with dwindling compensation has challenged primary care medical practices over the past decade. This has led to more physicians leaving and fewer medical trainees entering primary care. In an effort to make primary care practices viable, many groups routinely charge for providing care that was uncompensated in the past. We initiated a program in our practice that charged for certain after-hour and electronic communications, completion of forms outside of office visits, and failure to show for appointments. We assessed the effect on workload, patient adherence to appointments, and financial outcomes. This initiative decreased our physicians' workload, increased physicians' satisfaction, and produced a modest increase in revenues. PMID- 23629041 TI - A profile of hospitals with leadership development programs. AB - Community hospitals face increasing organizational and environmental complexities that challenge effective leadership. Hospitals are embracing leadership development programs in efforts to ensure leadership talent. While prior literature has described the intent and availability of these programs, the characteristics and performance of hospitals having such programs and their associated market characteristics have not been fully addressed. This article identifies significant differences in organizational, operational, performance, and market factors that are associated with hospitals offering a leadership development program, compared with those hospitals lacking such a program. The authors used American Hospital Association Survey data for 2008, the Area Resource File, and Centers for Medicare & Medicaid data to identify hospitals with and without leadership development programs and analyzed the differences for a number of organizational, operational, performance, and market variables. Findings indicate that hospitals having leadership development programs were large-bed-size facilities, had not-for-profit ownership, were system affiliated, were located in metropolitan statistical areas, and were teaching affiliated facilities. These hospitals also generated higher patient discharges, had higher occupancy, and had a longer average length of stay, compared with hospitals without such programs. In addition, these hospitals had higher net patient revenue per adjusted discharge and higher total profit margins relative to the comparison group. PMID- 23629042 TI - Practical implications of pre-employment nurse assessments. AB - Hiring nurses is a difficult task that can have serious repercussions for medical facilities. If nurses without proper skills are hired, patients can suffer from insufficient quality of care and potentially life-threatening conditions. Nurse applicants' technical knowledge is extremely important to avoid negative outcomes; however, there are soft skills that factor into their success, such as bedside manner, personality, communication, and decision making. In order for medical facilities to select and maintain high-performing nurse staff, hiring managers must incorporate evaluations for these types of skills in their hiring process. The current study focused on using content/criterion-related validation design to create assessments by which nurse applicants can be evaluated for both technical knowledge/skills and soft skills. The study included participation of more than 876 nursing staff members. To rank applicants on divergent skills, 3 assessment types were investigated, resulting in the creation of an assessment with 3 components. The clinical, situational, and behavioral components that were created measure applicants' job knowledge, interpersonal competency in medical facility-related situations, and aspects of personality and behavior, respectively. Results indicate that using the assessment can predict 45% of a nurse applicant's future job performance. Practical implications include hiring and maintaining a higher quality of nurses and decreased hiring costs. PMID- 23629043 TI - How to create a health care organization that can succeed in an unpredictable future. AB - For those who manage organizations, it has been said that success does not come from predicting the future but instead comes from creating an organization that can succeed in an unpredictable future. Managers are responsible for creating such an organization. To do that, managers can apply management-related principles and methods. This article explains selected principles of organization structure, human resources, culture, decision making, and change management and how to apply them to health care organizations. If done well, that will help such organizations succeed in an unpredictable future. PMID- 23629044 TI - Microporous organic polymers with ketal linkages: synthesis, characterization, and gas sorption properties. AB - A series of microporous organic polymers with ketal linkages were synthesized based on the condensation of aromatic acetyl monomers with pentaerythritol. Fourier transform infrared and solid-state cross-polarization/magic-angle spinning (13)C NMR spectroscopy were utilized to confirm the ketal linkages of the resulting polymers. The morphology can be observed from scanning electron microscopy and transmission electron microscopy images. The materials possess Brunauer-Emmet-Teller specific surface area values ranging from 520 to 950 m(2) g(-1), and the highest hydrogen sorption capacity is up to 1.96 wt % (77 K and 1.0 bar), which is superior to that of most of microporous organic polymers. The facile and cost-effective preparation process and excellent gas sorption properties make these kinds of materials promising candidates for practical applications. PMID- 23629045 TI - Multinuclear complex formation in aqueous solutions of Ca(II) and heptagluconate ions. AB - The equilibria and structure of complexes formed between the Ca(2+) ion and the heptagluconate (Hglu(-)) ion in both neutral and alkaline solutions have been studied. In alkaline solutions an uncharged, multinuclear complex is formed with the composition of Ca3Hglu2(OH)4 (or [Ca3Hglu2H(-4)](0)) with an unexpectedly high stability constant (lg beta(32-4) = 14.09). The formation of the trinuclear complex was deduced from potentiometry and confirmed by freezing-point depression measurements and conductometry as well. The binding sites of Hglu(-) were determined from NMR measurements. Besides the carboxylate group, the O atoms on the second and third carbon atoms proved to be the most probable sites for Ca(2+) binding. PMID- 23629046 TI - Wired silk architectures provide a biomimetic ACL tissue engineering scaffold. AB - Silk has been increasingly investigated as a scaffold for tissue-engineered anterior cruciate ligament (ACL) grafts, primarily due to a uniquely advantageous combination of biocompatibility and robust biomechanical strength in the short and middle terms. While previous studies have explored the biomechanical and biological effects of graft geometry, these studies have largely ignored the effects of repeated loading on long term biomechanical performance-an important consideration considering the relatively slow rate with which the silk scaffold is remodeled. In the present study, we utilized a tensile bioreactor to carry out cyclic loading tests on various silk ACL scaffold designs. Silk scaffolds were fabricated with three different architectures (wired, braided, and straight fibered). These were tested in static loading, low cyclic loading to 250 cycles, and high cyclic loading to 100,000 cycles. Different scaffold conditions including dry, wet, with cells, without seeded cells were tested and compared. The ultimate tensile strength (UTS), linear stiffness and construct elongation rate were used to compare the structural behavior of each graft architecture. Based upon this analysis, silk scaffolds with a wired structure exhibited biomechanical behavior most similar to the native human ACL. We thus conclude that the wired silk scaffold design we present provides a biofidelic mechanical basis for tissue engineering strategies for ACL reconstruction. PMID- 23629048 TI - Visible-light-induced WO3/g-C3N4 composites with enhanced photocatalytic activity. AB - Novel WO3/g-C3N4 composite photocatalysts were prepared by a calcination process with different mass contents of WO3. The photocatalysts were characterized by thermogravimetric analysis (TG), powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy dispersive X-ray spectrometry (EDS), high resolution transmission electron microscopy (HRTEM), UV-vis diffuse reflection spectroscopy (DRS), X-ray photoelectron spectroscopy (XPS), photoluminescence (PL) and electrochemical impedance spectroscopy (EIS). The photocatalytic activity of the photocatalysts was evaluated by degradation of methylene blue (MB) dye and 4-chlorophenol (4-CP) under visible light. The results indicated that the WO3/g-C3N4 composite photocatalysts showed higher photocatalytic activity than both the pure WO3 and pure g-C3N4. The optimum photocatalytic activity of WO3/g-C3N4 at a WO3 mass content of 9.7% under visible light irradiation was up to 4.2 times and 2.9 times as high as that of the pure WO3 and pure g-C3N4, respectively. The remarkably increased performance of WO3/g-C3N4 was mainly attributed to the synergistic effect between the interface of WO3 and g C3N4, including enhanced optical absorption in the visible region, enlarged specific surface areas and the suitable band positions of WO3/g-C3N4 composites. PMID- 23629050 TI - Bottom up modeling of the connectome: linking structure and function in the resting brain and their changes in aging. AB - With the increasing availability of advanced imaging technologies, we are entering a new era of neuroscience. Detailed descriptions of the complex brain network enable us to map out a structural connectome, characterize it with graph theoretical methods, and compare it to the functional networks with increasing detail. To link these two aspects and understand how dynamics and structure interact to form functional brain networks in task and in the resting state, we use theoretical models. The advantage of using theoretical models is that by recreating functional connectivity and time series explicitly from structure and pre-defined dynamics, we can extract critical mechanisms by linking structure and function in ways not directly accessible in the real brain. Recently, resting state models with varying local dynamics have reproduced empirical functional connectivity patterns, and given support to the view that the brain works at a critical point at the edge of a bifurcation of the system. Here, we present an overview of a modeling approach of the resting brain network and give an application of a neural mass model in the study of complexity changes in aging. PMID- 23629052 TI - Anatomical reconstructions of the human cardiac venous system using contrast computed tomography of perfusion-fixed specimens. AB - A detailed understanding of the complexity and relative variability within the human cardiac venous system is crucial for the development of cardiac devices that require access to these vessels. For example, cardiac venous anatomy is known to be one of the key limitations for the proper delivery of cardiac resynchronization therapy (CRT)(1) Therefore, the development of a database of anatomical parameters for human cardiac venous systems can aid in the design of CRT delivery devices to overcome such a limitation. In this research project, the anatomical parameters were obtained from 3D reconstructions of the venous system using contrast-computed tomography (CT) imaging and modeling software (Materialise, Leuven, Belgium). The following parameters were assessed for each vein: arc length, tortuousity, branching angle, distance to the coronary sinus ostium, and vessel diameter. CRT is a potential treatment for patients with electromechanical dyssynchrony. Approximately 10-20% of heart failure patients may benefit from CRT(2). Electromechanical dyssynchrony implies that parts of the myocardium activate and contract earlier or later than the normal conduction pathway of the heart. In CRT, dyssynchronous areas of the myocardium are treated with electrical stimulation. CRT pacing typically involves pacing leads that stimulate the right atrium (RA), right ventricle (RV), and left ventricle (LV) to produce more resynchronized rhythms. The LV lead is typically implanted within a cardiac vein, with the aim to overlay it within the site of latest myocardial activation. We believe that the models obtained and the analyses thereof will promote the anatomical education for patients, students, clinicians, and medical device designers. The methodologies employed here can also be utilized to study other anatomical features of our human heart specimens, such as the coronary arteries. To further encourage the educational value of this research, we have shared the venous models on our free access website: www.vhlab.umn.edu/atlas. PMID- 23629053 TI - Diversification of plant species in arid Northwest China: species-level phylogeographical history of Lagochilus Bunge ex Bentham (Lamiaceae). AB - Lagochilus occurs in the arid zones across temperate steppe and desert regions of Northwest China. Cooling with strong dessication in the Pleistocene, along with rapid uplift of mountain ranges peripheral to the Qinghai-Tibet Plateau, appear to have had major impacts on the genetic structure of the flora. To understand the evolutionary history of Lagochilus and the divergence related to these past shifts of habitats among these regions, we sequenced the plastid intergenic spacers, psbA-trnH and trnS-trnG from populations throughout the known distributions of ten species of the genus. We investigated species-level phylogeographical patterns within Lagochilus. Phylogenetic trees were constructed using Neighbor-joining and Bayesian inference. The divergence times of major lineages were estimated with BEAST and IMa. Genetic structure and demographic history were inferred by AMOVA, neutrality tests, mismatch distribution, and Bayesian skyline plot analyses. The results showed that most chloroplast haplotypes were species-specific, and that the phylogeny of Lagochilus is geographically structured. The estimated Bayesian chronology and IMa suggested that the main divergence events for species between major eastern and western portions of the Chinese desert occurred at the Plio-/Pleistocene boundary (ca. 2.1-2.8 Ma ago), and likely coinciding with the formation of these deserts in Northwest China. The regional demographic expansions, in the western region at ca. 0.39 Ma, and in the eastern at ca. 0.06 Ma, or across all regions at ca. 0.26 Ma, showed the response to aridification accompanied by cooling of the Pleistocene sharply increased aridity in the Chinese deserts, which reflects a major influence of geologic and climatic events on the evolution of species of Lagochilus. We suggest that diversification is most likely the result of the past fragmentation due to aridification; the expansion of the range of species along with the deserts was an adaptation to dry and cold environments during the Quaternary. PMID- 23629049 TI - Multi-site genetic analysis of diffusion images and voxelwise heritability analysis: a pilot project of the ENIGMA-DTI working group. AB - The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA-DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18-85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/). PMID- 23629054 TI - Diversification of Fijian halictine bees: insights into a recent island radiation. AB - Although bees form a key pollinator suite for flowering plants, very few studies have examined the evolutionary radiation of non-domesticated bees over human time scales. This is surprising given the importance of bees for crop pollination and the effect of humans in transforming ecosystems via agriculture. In the Pacific, where the bee fauna appears depauperate, their importance as pollinators is not clear, particularly in Fiji where species diversity is even lower than neighbouring archipelagos. Here we explore the radiation of halictine bees in Fiji using phylogenetic analyses of mtDNA COI sequence data. Our analyses indicate the existence of several 'deep' clades whose divergences are close to the crown node, along with a highly derived 'broom' clade showing very high haplotype diversity, and mostly limited to low-lying agricultural regions. This derived clade is very abundant, whereas the more basal clades were relatively rare. Although nearly all haplotype diversity in Fijian Homalictus comprises synonymous substitutions, a small number of amino acid changes are associated with the major clades, including the hyper-diverse clade. Analyses of haplotype lineage accumulation show a steep increase in selectively neutral COI haplotypes corresponding to the emergence of this 'broom' clade. We explore three possible scenarios for this dramatic increase: (i) a key change in adaptedness to the environment, (ii) a large-scale extinction event, or (iii) a dramatic increase in suitable habitats leading to rapid population expansion. Using estimated mutation rates of mitochondrial DNA in other invertebrates, we argue that Homalictus first colonised the Fijian archipelago in the middle-late Pleistocene, and the rapid accumulation of haplotypes in the hyper-diverse clade occurred in the Holocene, but prior to recorded human presence in the Fijian region. Our results indicate that bees have not been important pollinators of Fijian ecosystems until very recent times. Post-Pleistocene climate change and anthropogenic effects on Fijian ecosystems are likely to have greatly transformed pollinator suites from the conditions when those ecosystems were first being assembled. PMID- 23629055 TI - Porphyrin sensitizers with pi-extended pull units for dye-sensitized solar cells. AB - New pi-extended porphyrin dyes YD26-YD29 with long alkoxyl chains at the ortho positions of the meso-phenyls, and meta di-tert-butylphenyl-substituted porphyrins YD12-CN, and YD13-CN were synthesized for dye-sensitized solar cells, and their optical, electrochemical and photovoltaic properties were investigated and compared with those of YD12 and YD13. The absorption spectra of YD26-YD29 showed a slight red shift of Soret bands and blue shift of Q bands as compared to the meta-substituted porphyrins due to the electron-donating effects of dioctyloxy substituents at the ortho-positions of the meso-phenyl rings. Replacement of the carboxyl with a cyanoacrylic acid as the anchoring group results in significant broadening and red shifts of the absorptions, which is due to the strong electronic coupling between the pull unit and the porphyrin ring facilitated by the C=C triple bond. The electrochemical studies and quantum chemical calculations (DFT) indicated that the ortho alkoxy-substituted sensitizers exhibit lower oxidation potential, i.e. a higher HOMO energy level, and their HOMO-LUMO gaps are comparable to the meta-substituted analogues. The photovoltaic measurements confirmed that the ortho-octyloxy groups in the two meso-phenyls of YD26 and YD27 play a significant role in preventing dye aggregation thereby enhancing the corresponding short-circuit current density and open-circuit voltage. The power conversion efficiency (eta) of YD26 is 8.04%, which is 11% higher than that of YD12, whereas the efficiency of YD27 is 6.03%, which is 135% higher than that of YD13. On the other hand, the poor performance of YD28 and YD29 is due to the floppy structural nature and limited molecular rigidity of the cyanoacrylic acid anchor. PMID- 23629057 TI - Theoretical investigation of the Diels-Alder reactions of unsaturated boronates. AB - The Diels-Alder reactions of simple unsaturated boronates have been investigated using computational methods and the results were compared with those for the analogue dihalo- and dialkylboranes. Our results indicate that the activating effect of the boronate moiety is small. All the studied reactions are concerted normal electron-demand Diels-Alder reactions with asynchronous transition structures and weak [4 + 3] C-B secondary orbital interactions, which explains the low experimental reactivity. Both electronic and steric effects contribute to give the observed low stereo- and regioselectivities. PMID- 23629059 TI - Overview of the National Ignition Facility. AB - The National Ignition Facility (NIF) at Lawrence Livermore National Laboratory is the world's largest and most energetic laser system for inertial confinement fusion (ICF) and experiments studying high energy density (HED) science. The NIF is a 192-beam, Nd-glass laser facility that is capable of producing 1.8 MJ, 500 TW of ultraviolet light, and over 50 times more energetic than other existing ICF facilities. The NIF construction began in 1997, and the facility, which was completed in 2009, is now fully operational. The facility is capable of firing up to 192 laser beams onto a target placed at the center of a 10-m-diameter spherical target chamber. Experiments involving the use of tritium have been underway for some time. These experiments present radiological issues: prompt neutron/gamma radiation, neutron activation, fission product generation, and decay radiation. This paper provides an introduction to the NIF facility and its operation, describes plans for the experimental program, and discusses radiological issues associated with the NIF's operations. PMID- 23629060 TI - Radiological design aspects of the National Ignition Facility. AB - The National Ignition Facility (NIF) has been designed to accommodate some challenging radiological conditions. The high prompt neutron source (up to 1.6 * 10(19) neutrons per shot) results in the need for significant fixed shielding. Concrete shielding approximately 2 m thick is used for the primary (target bay) shield. Penetrations in this shield, including those required for 192 laser beams, utilities, diagnostics, and 19 shielded personnel access doors, make the design challenging. An additional 28 shield doors are part of the secondary shield. In addition, the prompt neutron pulse results in activated air within the target bay, requiring special ventilation considerations. Finally, targets can use a number of hazardous and radioactive materials including tritium, beryllium, and depleted uranium (the latter of which results in the generation of small quantities of fission products). Frequent access is required to the associated potentially contaminated volumes for experimental setup, facilitating the need for local exhaust ventilation to manage these hazards. This paper reviews some of these challenges, design considerations, and the engineering solutions to these design requirements. PMID- 23629061 TI - Safety systems and access control in the National Ignition Facility. AB - The National Ignition Facility (NIF) is the world's largest and most energetic laser system. The facility has the potential to generate ionizing radiation due to the interaction between the laser beams and target material, with neutrons and gamma rays being produced during deuterium-tritium fusion reactions. To perform these experiments, several types of hazards must be mitigated and controlled to ensure personnel safety. NIF uses a real-time safety system to monitor and mitigate the hazards presented by the facility. The NIF facility Safety Interlock System (SIS) monitors for oxygen deficiency and controls access to the facility preventing exposure to laser light and radiation from the Radiation Generating Devices. It also interfaces to radiation monitoring and other radiological monitoring and alarm systems. The SIS controls permissives to the hazard generating equipment and annunciates hazard levels in the facility. To do this reliably and safely, the SIS has been designed as a fail-safe system with a proven performance record now spanning over 10 y. This paper discusses the SIS, its design, implementation, operator interfaces, validation/verification, and the hazard mitigation approaches employed in the NIF. A brief discussion of the Failure Modes and Effect Analysis supporting the SIS will also be presented. The paper ends with a general discussion of SIS do's and don'ts and common design flaws that should be avoided in SIS design. PMID- 23629062 TI - Tritium and ignition target management at the National Ignition Facility. AB - Isotopic mixtures of hydrogen constitute the basic fuel for fusion targets of the National Ignition Facility (NIF). A typical NIF fusion target shot requires approximately 0.5 mmoles of hydrogen gas and as much as 750 GBq (20 Ci) of 3H. Isotopic mix ratios are specified according to the experimental shot/test plan and the associated test objectives. The hydrogen isotopic concentrations, absolute amounts, gas purity, configuration of the target, and the physical configuration of the NIF facility are all parameters and conditions that must be managed to ensure the quality and safety of operations. An essential and key step in the preparation of an ignition target is the formation of a ~60 MUm thick hydrogen "ice" layer on the inner surface of the target capsule. The Cryogenic Target Positioning System (Cryo-Tarpos) provides gas handling, cyro-cooling, x ray imaging systems, and related instrumentation to control the volumes and temperatures of the multiphase (solid, liquid, and gas) hydrogen as the gas is condensed to liquid, admitted to the capsule, and frozen as a single spherical crystal of hydrogen in the capsule. The hydrogen fuel gas is prepared in discrete 1.7 cc aliquots in the LLNL Tritium Facility for each ignition shot. Post-shot hydrogen gas is recovered in the NIF Tritium Processing System (TPS). Gas handling systems, instrumentation and analytic equipment, material accounting information systems, and the shot planning systems must work together to ensure that operational and safety requirements are met. PMID- 23629063 TI - Analysis of decay dose rates and dose management in the National Ignition Facility. AB - A detailed model of the Target Bay (TB) at the National Ignition Facility (NIF) has been developed to estimate the post-shot radiation environment inside the facility. The model includes the large number of structures and diagnostic instruments present inside the TB. These structures and instruments are activated by neutrons generated during a shot, and the resultant gamma dose rates are estimated at various decay times following the shot. A set of computational tools was developed to help in estimating potential radiation exposure to TB workers. The results presented in this paper describe the expected radiation environment inside the TB following a low-yield DT shot of 10(16) neutrons. General environment dose rates drop below 30 MUSv h(-1) within 3 h following a shot, with higher dose rates observed in the vicinity (~30 cm) of few components. The dose rates drop by more than a factor of two at 1 d following the shot. Dose rate maps of the different TB levels were generated to aid in estimating worker stay-out times following a shot before entry is permitted into the TB. Primary components, including the Target Chamber and diagnostic and beam line components, are constructed of aluminum. Near-term TB accessibility is driven by the decay of the aluminum activation product, 24Na. Worker dose is managed using electronic dosimeters (EDs) self-issued at kiosks using commercial dose management software. The software programs the ED dose and dose rate alarms based on the Radiological Work Permit (RWP) and tracks dose by individual, task, and work group. PMID- 23629064 TI - Managing NIF safety equipment in a high neutron and gamma radiation environment. AB - The National Ignition Facility (NIF) is a 192 laser beam facility that supports the Inertial Confinement Fusion program. During the ignition experimental campaign, the NIF is expected to perform shots with varying fusion yield producing 14 MeV neutrons up to 20 MJ or 7.1 * 10(18) neutrons per shot and a maximum annual yield of 1,200 MJ. Several infrastructure support systems will be exposed to varying high yield shots over the facility's 30-y life span. In response to this potential exposure, analysis and testing of several facility safety systems have been conducted. A detailed MCNP (Monte Carlo N-Particle Transport Code) model has been developed for the NIF facility, and it includes most of the major structures inside the Target Bay. The model has been used in the simulation of expected neutron and gamma fluences throughout the Target Bay. Radiation susceptible components were identified and tested to fluences greater than 10(13) (n cm(-2)) for 14 MeV neutrons and gamma-ray equivalent. The testing includes component irradiation using a 60Co gamma source and accelerator-based irradiation using 4- and 14- MeV neutron sources. The subsystem implementation in the facility is based on the fluence estimates after shielding and survivability guidelines derived from the dose maps and component tests results. This paper reports on the evaluation and implementation of mitigations for several infrastructure safety support systems, including video, oxygen monitoring, pressure monitors, water sensing systems, and access control interfaces found at the NIF. PMID- 23629065 TI - Assuring operational readiness of the National Ignition Facility. AB - National Ignition Facility experiments involve the use of a variety of materials that generate a number of radiological issues. Along with the use of tritium and depleted uranium, shots generating neutrons create prompt radiation fields as well as fission and activation products. In order to assure readiness for these hazards, a series of readiness reviews was conducted as the hazards were introduced. Each step was built upon the previous steps, as well as the basic infrastructure and operating capability of the laser facility. A detailed preparation plan for the introduction of these hazards was developed. This included ensuring required equipment was in place and ready, all plans and procedures were developed, and personnel were trained and qualified to perform work in the environment. The approach for preparing the facility for operations under the new set of conditions, the preparations for the readiness reviews, the review process, as well as the approach to initial operations are discussed. PMID- 23629066 TI - Standing up the National Ignition Facility radiation protection program. AB - Operation of the NIF requires a large and varied number of routine and infrequent activities involving contaminated and radioactive systems, both in servicing online equipment and offline refurbishment of components. Routine radiological operations include up to several dozen entries into contaminated systems per day, multiple laboratories refurbishing radiologically impacted parts, handling of tens of curies of tritium, and (eventually) tens of workers spending most of their day working in radiation areas and handling moderately activated parts. Prior to the introduction of radioactive materials and neutron producing experiments (capable of causing activation), very few of the operating staff had any radiological qualifications or experience. To support the full NIF operating program, over 600 radiological workers needed to be trained, and a functional and large-scale radiological protection program needed to be put in place. It quickly became evident that there was a need to supplement the LLNL site radiological protection staff with additional radiological controls technicians and a radiological protection staff within NIF operations to manage day-to-day activities. This paper discusses the approach taken to stand up the radiological protection program and some lessons learned. PMID- 23629067 TI - Experiences managing radioactive material at the National Ignition Facility. AB - The National Ignition Facility at Lawrence Livermore National Laboratory is the world's largest and most energetic laser system for inertial confinement fusion and experiments studying high energy density science. Many experiments performed at the National Ignition Facility involve radioactive materials; these may take the form of tritium and small quantities of depleted uranium used in targets, activation products created by neutron-producing fusion experiments, and fission products produced by the fast fissioning of the depleted uranium. While planning for the introduction of radioactive material, it was recognized that some of the standard institutional processes would need to be customized to accommodate aspects of NIF operations, such as surface contamination limits, radiological postings, airborne tritium monitoring protocols, and personnel protective equipment. These customizations were overlaid onto existing work practices to accommodate the new hazard of radioactive materials. This paper will discuss preparations that were made prior to the introduction of radioactive material, the types of radiological work activities performed, and the hazards and controls encountered. Updates to processes based on actual monitoring results are also discussed. PMID- 23629068 TI - Implementing an operational program for determining the radiological status of material and equipment. AB - The National Ignition Facility at the Lawrence Livermore National Laboratory has implemented a protocol for evaluating and releasing material and equipment that is potentially "volumetrically contaminated" as a result of neutron activation and shown not to be "distinguishable from background." This protocol is an important element of the National Ignition Facility's operational program as the U.S. Department of Energy's (DOE) Order 458.1, Radiation Protection of the Public and the Environment, requires DOE approval of the process used to release volumetrically contaminated personal property and establishes a dose constraint of 10 uSv y(-1) (1 mrem y(-1)) for clearance of such items. The protocol uses process and historical knowledge to determine when material and equipment may be potentially impacted and field measurements to verify it has been impacted (i.e., is distinguishable from background). Material and equipment that do not meet the distinguishable-from-background criterion are considered to be non-impacted and outside the scope of the Order and may be released from radiological control. This paper provides the technical basis and methodology for determining whether or not there is radioactivity distinguishable from background in the evaluated material and equipment and documents that the measurement sensitivity exceeds the unrestricted release criteria specified in the American National Standards Institute report N13.12-1999, Surface and Volume Radioactivity Standards for Clearance. Pending DOE approval, this protocol could be used as the basis for releasing materials and equipment that exceed the distinguishable-from-background criterion and are below the specified threshold for unrestricted release. PMID- 23629069 TI - Application of the National Ignition Facility distinguishable-from-background program to accelerator facilities at Lawrence Livermore National Laboratory. AB - Lawrence Livermore National Laboratory must control potentially activated materials and equipment in accordance with U.S. Department of Energy (DOE) Order 458.1, Radiation Protection of the Public and the Environment, which requires DOE approval of the process used to release volumetrically contaminated personal property and establishes a dose constraint of 10 uSv y(-1) (1 mrem y(-1)) for clearance of such property. The National Ignition Facility at Lawrence Livermore National Laboratory developed a technical basis document and protocol for determining the radiological status of property that is potentially activated from exposure to neutron radiation produced via fusion of tritium and deuterium. The technical basis included assessment of the neutron energy, the type of materials potentially exposed and the likely activation products, and the sensitivity of radiation detectors used to survey the property. This paper evaluates the National Ignition Facility technical basis document for applicability to the release of property from Lawrence Livermore National Laboratory's various accelerator facilities considering the different types of particles accelerated, radiations produced, and resultant activation products. Extensive process knowledge regarding the accelerators' operations, accompanied by years of routine surveys, provides an excellent characterization of these facilities. Activation studies conducted at the Stanford Linear Accelerator and the High Energy Accelerator Research Organization in Japan corroborate that the long-lived radionuclides produced at accelerator facilities are of the same variety produced at the National Ignition Facility. Consequently, Lawrence Livermore National Laboratory concludes that the release protocol developed for the National Ignition Facility can be used appropriately at all its accelerator facilities. PMID- 23629070 TI - LIFE: a sustainable solution for developing safe, clean fusion power. AB - The National Ignition Facility (NIF) at the Lawrence Livermore National Laboratory (LLNL) in California is currently in operation with the goal to demonstrate fusion energy gain for the first time in the laboratory-also referred to as "ignition." Based on these demonstration experiments, the Laser Inertial Fusion Energy (LIFE) power plant is being designed at LLNL in partnership with other institutions with the goal to deliver baseload electricity from safe, secure, sustainable fusion power in a time scale that is consistent with the energy market needs. For this purpose, the LIFE design takes advantage of recent advances in diode-pumped, solid-state laser technology and adopts the paradigm of Line Replaceable Units used on the NIF to provide high levels of availability and maintainability and mitigate the need for advanced materials development. The LIFE market entry plant will demonstrate the feasibility of a closed fusion fuel cycle, including tritium breeding, extraction, processing, refueling, accountability, and safety, in a steady-state power-producing device. While many fusion plant designs require large quantities of tritium for startup and operations, a range of design choices made for the LIFE fuel cycle act to reduce the in-process tritium inventory. This paper presents an overview of the delivery plan and the preconceptual design of the LIFE facility with emphasis on the key safety design principles being adopted. In order to illustrate the favorable safety characteristics of the LIFE design, some initial accident analysis results are presented that indicate potential for a more attractive licensing regime than that of current fission reactors. PMID- 23629074 TI - Breast reconstruction modality outcome study: a comparison of expander/implants and free flaps in select patients. AB - BACKGROUND: Choosing a breast reconstructive modality after mastectomy is a critical step involving complex decisions. The authors provide outcomes data comparing two common reconstructive modalities to assist patients and surgeons in preoperative counseling and discussions. METHODS: A prospectively maintained database was queried identifying select patients undergoing expander/implant and abdominally based free flaps for breast reconstruction between 2005 and 2008. Variables evaluated included comorbidities, operations, time to reconstruction, complications, overall outcome, clinic visits, revisions, and costs. RESULTS: One hundred forty-two patients received free flaps and 60 received expander/implants. Expander/implant patients required more procedures (p < 0.001) but had shorter overall hospital lengths of stay (p < 0.001). The two cohorts experienced a similar rate of revision (p = 0.17). Free flap patients elected to undergo nipple areola reconstruction more frequently (p = 0.01) and were able to sooner (p < 0.0001). Patients undergoing expander/implant reconstruction had a higher rate of failure (7.3 versus 1.3 percent, p = 0.008). Free flap patients achieved a stable reconstruction significantly faster (p = 0.0005), with fewer visits (p = 0.02). Cost analysis demonstrated total cost trended toward significantly lower in the free flap cohort (p = 0.15). Reconstructive modality was the only independent factor associated with time to stable reconstruction and reconstructive failure (p < 0.001 and p = 0.05, respectively). CONCLUSIONS: The authors' analysis revealed that free flap reconstructions required fewer procedures, had lower rates of complications and failures, had fewer clinic visits, and achieved a final, complete reconstruction faster than expander/implant reconstructions. Although autologous reconstruction is still not ideal for every patient, these findings can be used to enhance preoperative discussions when choosing a reconstructive modality. CLINICAL QUESTION/LEVEL OF EVIDENCE: : Therapeutic, III. PMID- 23629075 TI - Discussion: breast reconstruction modality outcome study: a comparison of expander/implants and free flaps in select patients. PMID- 23629076 TI - 440 Consecutive immediate, implant-based, single-surgeon breast reconstructions in 281 patients: a comparison of early outcomes and costs between SurgiMend fetal bovine and AlloDerm human cadaveric acellular dermal matrices. AB - BACKGROUND: A 2010 nationwide survey of plastic and reconstructive surgeons indicated that approximately 83 percent performed predominantly implant-based breast reconstruction, with acellular dermal matrix used by approximately half of those practitioners. Although the medical literature documents well over 2000 cases of breast reconstruction with matrices, relatively few cases using other than human cadaveric acellular dermal matrices have been reported. The author compared complications and costs using SurgiMend fetal bovine and AlloDerm human cadaveric acellular dermal matrices. METHODS: A retrospective review of a single surgeon's 5-year experience was performed for consecutive, nonrandomized immediate breast reconstructions with acellular dermal matrix from 2005 to 2010. RESULTS: Two hundred eighty-one patients had 440 implant-based reconstructions using SurgiMend [222 patients (79.0 percent)] or AlloDerm [59 patients (21.0 percent)]. No significant differences in complication rates were observed between SurgiMend and AlloDerm for hematoma, infection, major skin necrosis, or breast implant removal. Seroma was the most prevalent complication; the seroma rate for AlloDerm (15.7 percent) was significantly greater than that for SurgiMend (8.3 percent). Using recent product costs for equivalently sized AlloDerm and SurgiMend units, the cost of SurgiMend was $1024 less per breast than AlloDerm. CONCLUSIONS: SurgiMend fetal bovine and AlloDerm human cadaveric acellular dermal matrices demonstrate similar rates of major early complications in breast reconstruction in this study. This similarity in complication rates between SurgiMend and AlloDerm and the cost savings seen with the use of SurgiMend are factors for the surgeon to consider in choosing a matrix for breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: : Therapeutic, III. PMID- 23629077 TI - A comparison of acellular dermal matrix to autologous dermal flaps in single stage, implant-based immediate breast reconstruction: a cost-effectiveness analysis. AB - BACKGROUND: The use of acellular dermal matrix has allowed for single-stage immediate breast reconstruction after mastectomy at a significantly decreased cost compared with two-stage expander/implant reconstruction. The use of a pedicled autologous dermal flap in the same fashion as acellular dermal matrix in women with larger, ptotic breasts has also allowed for single-stage immediate breast reconstruction with similarly low complication rates and without the added procedural cost of using acellular dermal matrix. There have been no prior studies evaluating whether the added procedural cost for acellular dermal matrix is cost-effective relative to using an autologous dermal flap in single-stage immediate breast reconstruction following mastectomy. METHODS: A comprehensive literature review was conducted to identify published complication rates for single-stage, implant-based immediate breast reconstruction using either acellular dermal matrix or an autologous dermal flap. The probabilities of the most common complications were combined with Medicare Current Procedural Terminology reimbursement codes and expert utility estimates to fit into a decision model to evaluate the cost-effectiveness of acellular dermal matrix. RESULTS: : The decision model revealed a baseline cost difference of $261.72 and a 0.001 increase in the quality-adjusted life years when using acellular dermal matrix, yielding an incremental cost-utility ratio of $261,720 per quality adjusted life year. Sensitivity analysis showed that acellular dermal matrix was not cost-effective when the complication rate for autologous dermal flaps was below 20 percent. CONCLUSIONS: The authors' study demonstrates that acellular dermal matrix is not a cost-effective technology in patients who can have an autologous dermal flap in single-stage immediate breast reconstruction. PMID- 23629078 TI - Nipple-sparing mastectomy in patients with a history of reduction mammaplasty or mastopexy: how safe is it? AB - BACKGROUND: Nipple-sparing mastectomy has gained popularity, but the question remains of whether it can be offered safely to women with a history of reduction mammaplasty or mastopexy. The authors present their experience with nipple sparing mastectomy in this patient population. METHODS: Patients at the authors' institution who had reduction mammaplasty or mastopexy before nipple-sparing mastectomy were identified. Outcomes measured include nipple-areola complex viability, mastectomy flap necrosis, infection, presence of cancer in the nipple areola complex, and breast cancer recurrence. RESULTS: The records of the nipple sparing mastectomy patients at the authors' institution from 2006 through 2012 were reviewed. The authors identified 13 breasts in eight patients that had nipple-sparing mastectomy following reduction mammaplasty or mastopexy. Within this subset of patients, the mean age was 46.6 years and the mean body mass index was 25.1. Nine of 13 breasts had therapeutic resections, whereas the remaining four were for prophylactic indications. Average time elapsed between reduction mammaplasty or mastopexy and nipple-sparing mastectomy was 51.8 months (range, 33 days to 11 years). In all cases, prior reduction mammaplasty/mastopexy incisions were used for nipple-sparing mastectomy. Ten breasts underwent reconstruction immediately with tissue expanders, one with a latissimus dorsi flap with immediate implant and two with immediate abdominally based free flaps. Complications included one hematoma requiring evacuation and one displaced implant requiring revision. There were no positive subareolar biopsy results, and the nipple viability was 100 percent. Mean follow-up time was 10.5 months. CONCLUSIONS: The authors' experience demonstrates that nipple-sparing mastectomy can be offered to patients with a history of reduction mammaplasty or mastopexy with reconstructive outcomes comparable to those of nipple-sparing mastectomy alone. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23629079 TI - The role of nipple-sparing mastectomy in breast cancer: a comprehensive review of the literature. AB - BACKGROUND: The role of nipple-sparing mastectomy for breast cancer is controversial, as there is concern regarding its oncologic safety and complication rate. The authors reviewed the literature to quantify the incidence of occult nipple malignancy in breast cancer, identify the factors influencing occult nipple malignancy, quantify locoregional recurrence rates, and quantify nipple-sparing mastectomy complication rates. METHODS: A search of the literature was performed using PubMed. Key words used were "mastectomy," "nipple involvement," "nipple-sparing mastectomy," "skin-sparing mastectomy," "occult nipple malignancy," "occult nipple disease," and "breast cancer recurrence." Articles were analyzed regarding incidence of occult nipple malignancy, potential factors influencing the incidence of occult malignancy, and recurrence/complications following nipple-sparing mastectomy. The incidence of occult nipple disease was compared between groups using chi-square or Fisher's exact tests for categorical variables and t tests for continuous variables. Values of p < 0.05 were considered significant. RESULTS: The overall rate of occult nipple malignancy was 11.5 percent. Primary tumor characteristics influencing occult nipple malignancy were tumor-nipple distance less than 2 cm, grade, lymph node metastasis, lymphovascular invasion, human epidermal growth factor receptor-2-positive, estrogen receptor/progesterone receptor-negative, tumor size greater than 5 cm, retroareolar/central location, and multicentric tumors. The overall nipple recurrence rate considered significant was 0.9 percent, and the skin flap recurrence rate was 4.2 percent. Full- and partial thickness nipple necrosis rates were 2.9 and 6.3 percent, respectively. CONCLUSIONS: Nipple-sparing mastectomy for primary breast cancer is appropriate in carefully selected patients. All patients should have retroareolar sampling. There is strong evidence to suggest that suitable cases are well circumscribed single or multifocal lesions that have a tumor-to-nipple distance greater than 2 cm. Tumors should be grade 1 to 2 and not have lymphovascular invasion, axillary node metastasis, or human epidermal growth factor receptor-2 positivity. PMID- 23629080 TI - Autoderm: an alternative bioprosthetic for breast reconstruction. AB - The widespread use of bioprosthetic mesh in breast reconstruction has revealed an increased risk of seroma and infection, and a high financial cost. This study introduces a technique that mitigates these shortcomings using an autologous dermal graft (Autoderm). Indications, operative technique, and 1-year outcomes are reviewed. Thirty-six breasts in 21 patients underwent six unilateral and 15 bilateral, implant-based breast reconstructions with Autoderm. Mean follow-up was 365 days (range, 273 to 575 days). The overall complication rate was 13.9 percent. No patients developed breast cellulitis, hyperemia, periprosthetic infection, or seroma. There was one implant exposure following expansion. Autoderm provides the advantages of lower pole support and breast shaping, without the disadvantages of increased infection, seroma, and the high cost associated with allograft and xenograft meshes. PMID- 23629081 TI - Discussion: patterns of target tissue reinnervation and trophic factor expression after nerve grafting. PMID- 23629082 TI - The role of different methods of nerve ablation in prevention of neuroma. AB - BACKGROUND: The aim of this study was to compare the incidence of neuroma formation and neuropathic pain following different techniques of nerve ablation in a rat sural nerve model. METHODS: Rat sural nerve was subjected to four different techniques of ablation with standardized creation of a 1-cm gap (n = 15 in each group). These included nerve avulsion, transection and burying in muscle, transection and folding of nerve, and transection alone. Animals were killed after 3 months. Explanted nerves were sectioned and stained with Masson trichrome and S-100 stain against neural tissue. The maximal neural cross-sectional area and neural-to-connective tissue ratio was quantified. Quantitative reverse transcriptase polymerase chain reaction (n = 5) was used to analyze relative mRNA expression of ciliary neurotrophic factor and calcitonin gene-related peptide. RESULTS: Neural cross-sectional area was statistically increased (p < 0.05) compared with controls in folded, muscle buried, and transected specimens but decreased in avulsed specimens. The neural-to-connective tissue ratio was statistically decreased in the avulsed group. Relative mRNA expression of ciliary neurotrophic factor was lowest in muscle buried (4 percent of control) (p < 0.05) and avulsed specimens (15 percent of control) (p < 0.05) and higher in folded (52 percent of control) and transected specimens (75 percent of control). Relative mRNA expression of calcitonin gene-related peptide was highest in folded specimens (302 percent of control) (p < 0.05). CONCLUSIONS: Folding and transection lead to increased histologic evidence of neuroma formation, whereas folding leads to neuropathic pain, assayed by calcitonin gene-related peptide expression. Avulsion and muscle burying are preferable techniques for nerve ablation and inhibit nerve regeneration, evidenced by decreased ciliary neurotrophic factor expression. Avulsion offers an alternative to muscle burying when there is no muscle in the vicinity to bury the transected nerve. PMID- 23629083 TI - Quantitative comparison of volume maintenance between inlay and onlay bone grafts in the craniofacial skeleton. AB - BACKGROUND: Nonvascularized autologous bone grafts are the criterion standard in craniofacial reconstruction for bony defects involving the craniofacial skeleton. The authors have previously demonstrated that graft microarchitecture is the major determinant of volume maintenance for both inlay and onlay bone grafts following transplantation. This study performs a head-to-head quantitative analysis of volume maintenance between inlay and onlay bone grafts in the craniofacial skeleton using a rabbit model to comparatively determine their resorptive kinetics over time. METHODS: Fifty rabbits were divided randomly into six experimental groups: 3-week inlay, 3-week onlay, 8-week inlay, 8-week onlay, 16-week inlay, and 16-week onlay. Cortical bone from the lateral mandible and both cortical and cancellous bone from the ilium were harvested from each animal and placed either in or on the cranium. All bone grafts underwent micro-computed tomographic analysis at 3, 8, and 16 weeks. RESULTS: All bone graft types in the inlay position increased their volume over time, with the greatest increase in endochondral cancellous bone. All bone graft types in the onlay position decreased their volume over time, with the greatest decrease in endochondral cancellous bone. Inlay bone grafts demonstrated increased volume compared with onlay bone grafts of identical embryologic origin and microarchitecture at all time points (p < 0.05). CONCLUSIONS: Inlay bone grafts, irrespective of their embryologic origin, consistently display less resorption over time compared with onlay bone grafts in the craniofacial skeleton. Both inlay and onlay bone grafts are driven by the local mechanical environment to recapitulate the recipient bed. PMID- 23629084 TI - The effect of microneedling with a roller device on the viability of random skin flaps in rats. AB - BACKGROUND: In a random pattern skin flap, distal flap necrosis occurs as a result of inadequate blood flow. Microneedling with a handheld roller device is a new treatment modality, especially for facial rejuvenation. In this study, the authors used microneedling to increase flap viability. METHODS: Forty adult male Sprague-Dawley rats were divided into two groups of 20. The study group was exposed to McFarlane flap elevation and repositioning. The microneedling procedure was performed four times: 3 days before, on the day of, and on the third and sixth days after surgery. The control group was only exposed to surgery. The skin flap necrosis area was measured on the seventh postoperative day topographically by digital imaging and scintigraphy. After determination of necrosis area, the amount of neovascularization and number of vascular structures within the papillary dermal layer were counted histopathologically. RESULTS: The mean percentages of necrosis in the flap area as determined by the Digimizer analysis program were 37.51 +/- 5.08 in the control group and 29.42 +/- 7.37 in the study group. The mean percentages of flap necrosis of the control group and the study group as determined by radionuclide scintigraphy were 31.4 +/- 4.1 and 22.8 +/- 5.0, respectively. The comparison of flap necrosis percentages showed that the study group had significantly lower values (p < 0.001). Vessel counts in the study group also showed significant increase (p < 0.05). CONCLUSIONS: The authors' study showed that the microneedling method applied directly on the flap could be a faster, safer, and more effective therapy modality to increase flap viability. PMID- 23629086 TI - Discussion: reconstruction of the nasal soft triangle subunit. PMID- 23629085 TI - Through gap junction communications, co-cultured mast cells and fibroblasts generate fibroblast activities allied with hypertrophic scarring. AB - BACKGROUND: The prominent inflammatory cell identified in excessive scarring is the mast cell. Hypertrophic scar exhibits myofibroblasts derived from the transformation of fibroblasts, increased collagen synthesis, and stationary nonmigratory resident cells. The co-culture of fibroblasts with an established rat mast cell line (RMC-1) was used to explore the hypothesis of whether mast cells through gap junctional intercellular communications guide fibroblasts in promoting excessive scarring. METHODS: Human dermal fibroblasts were cultured alone or co-cultured with RMC-1 cells as is or with either blocked gap junctional intercellular communications or devoid of cytoplasmic granules. Collagen synthesis was analyzed by dot blot analysis; immunohistology identified myofibroblasts, and a cell migration assay measured fibroblast locomotion. RESULTS: Fibroblasts co-cultured with RMC-1 cells transformed into myofibroblasts, had increased collagen synthesis, and showed retarded cell migration. In contrast, RMC-1 cells unable to form gap junctional intercellular communications were similar to fibroblasts alone, failing to promote these activities. Degranulated RMC-1 cells were as effective as intact RMC-1 cells. CONCLUSIONS: Mast cells induce fibroblast activities associated with hypertrophic scarring through gap junctional intercellular communications. Eliminating the mast cell or its gap junctional intercellular communications with fibroblasts may be a possible approach in preventing hypertrophic scarring or reducing fibrotic conditions. PMID- 23629087 TI - Obturator nerve anatomy and relevance to one-stage facial reanimation: limitations of a retroperitoneal approach. AB - BACKGROUND: Single-stage facial reanimation with a partial gracilis muscle coapted to the contralateral facial nerve seems an optimal surgical solution yet has not supplanted the two-stage approach. Insufficient obturator nerve length may limit reach to sizable contralateral facial nerve branches (possibly necessitating interposition nerve grafting), compromise optimal muscle positioning, or risk nerve coaptation under tension. This study evaluates whether retroperitoneal obturator nerve dissection would effectively lengthen the nerve, thus obviating the aforementioned limitations. METHODS: Ten hemifaces and obturator nerves of five cadavers were dissected. Facial measurements included modiolus to contralateral facial nerve branches of sufficient size at the vertical line of the lateral orbital rim. Obturator nerve measurements included gracilis neurovascular hilum to (1) obturator canal entry point (ab), (2) intraobturator canal point where additional adductor branches are inseparable by internal neurolysis (ac), and (3) retroperitoneal point of separation between anterior and posterior obturator branches (ad). Obturator nerve reach for cross facial nerve coaptation was assessed. RESULTS: Successful coaptation was achieved with obturator nerve dissection to point b approximately 20 percent of the time, to point c 60 to 70 percent of the time, and to retroperitoneal point d 90 to 100 percent of the time CONCLUSIONS: Successful coaptation to large contralateral facial nerve branches is feasible in 90 to 100 percent of cases if the entire anterior obturator branch is harvested. However, the increased risk of retroperitoneal dissection and sacrifice of additional adductor branches decreases the viability of this approach. Obturator canal dissection (point c) provides reach in 60 to 70 percent of cases, but short interposition nerve grafting may prove necessary. PMID- 23629088 TI - Dissection of the masseter branch of the trigeminal nerve for facial reanimation. PMID- 23629090 TI - Sequential chimeric anterolateral thigh flap for reconstruction of through-and through oropharyngeal defects with no suitable neck recipient vessels. AB - The anterolateral thigh flap is currently the frontline choice for head and neck reconstruction. The authors used a chimeric anterolateral thigh flap for reconstruction of a through-and-through oropharyngeal defect. Because of the absence of suitable recipient vessels in the proximity of the defect, the authors recruited the internal mammary vessels. To gain extra pedicle length, the authors converted the chimeric anterolateral thigh flap into a sequential iatrogenic chimeric anterolateral thigh flap. This new flap concept consists essentially of the division of the skin paddle of the anterolateral thigh that is based on two perforators, and the creation of a sequential chimeric flap by reconnecting the pedicles in the opposite order. A functionally good and aesthetically pleasing result was obtained. PMID- 23629089 TI - Current principles of facial allotransplantation: the Brigham and Women's Hospital Experience. AB - BACKGROUND: Facial allotransplantation is a revolutionary operation that has at last introduced the possibility of nearly normal facial restoration to patients afflicted by the most severe cases of facial disfigurement. METHODS: The facial transplantation team at Brigham and Women's Hospital evaluated more than 20 patients as potential face transplant recipients; of these, six became face transplant candidates and underwent full screening procedures. The team performed facial allotransplantations in four of these patients between April of 2009 and May of 2011. This is the largest clinical volume of facial transplant recipients in the United States to date. RESULTS: The authors have learned important lessons from each of these four unique cases and from the more than 20 patients that they have evaluated as potential face transplant recipients. The authors have translated lessons learned through direct experience into a set of fundamental surgical principles of the operation. CONCLUSIONS: The authors' surgical principles emphasize safety, technical feasibility, preservation of functional facial units, and return of motor and sensory function. This article describes each of these principles along with their rationale and, in some instances, illustrates their application. PMID- 23629091 TI - Bupivacaine digital blocks: how long is the pain relief and temperature elevation? AB - BACKGROUND: The goals of this study are threefold: (1) to determine what effect epinephrine has on the duration of bupivacaine finger block anesthesia; (2) to see whether the duration of action of bupivacaine on digital pain relief is the same duration as numbness to touch/pressure; and (3) to assess the fingertip temperature changes that result from bupivacaine digital blocks. METHODS: The ring fingers of both hands of 44 volunteers were randomized to injection of bupivacaine with or without 1:200,000 epinephrine. The durations of time for digits to return to normal pain, touch, pressure sensation, and fingertip temperature were measured and recorded. RESULTS: There were three main findings: (1) the pain block of bupivacaine lasts only half as long (15 hours) as the return to normal sensation (30 hours); (2) the effect of adding epinephrine to bupivacaine prolongs the duration of pain relief in a finger block for only an additional 1.5 hours; (3) in addition to pain relief, bupivacaine finger blocks cause fingertip hyperemia with consistent significant fingertip temperature elevation that lasts 15 hours. CONCLUSIONS: The duration of bupivacaine pain relief is the clinically important factor that needs to be reported in bupivacaine trials. Patients should be informed that the return of pain will occur much sooner than the return of normal sensation. Adding epinephrine to bupivacaine does not add a clinically significant length of time to pain relief. Bupivacaine finger blocks provide prolonged hyperemia and pain block to fingertips, which may be useful in the treatment of acute frostbite. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I. PMID- 23629092 TI - Incidence of concomitant airway anomalies when using the university of California, Los Angeles, protocol for neonatal mandibular distraction. AB - BACKGROUND: In newborns with micrognathia and severe upper airway obstruction, understanding potential airway lesions is important for determining appropriate treatment: observation, mandibular distraction, or tracheostomy. When concomitant airway anomalies are present, mandibular distraction is often unsuccessful at alleviating causes of obstruction, mandating the need for tracheostomy. The first part of this study evaluates 10-year results using the University of California, Los Angeles, algorithm for surgical candidacy to identify patients who will benefit from neonatal mandibular distraction. The second part describes the concomitant airway abnormalities found at the time of diagnostic laryngoscopy/bronchoscopy and how these anomalies affect neonatal distraction candidacy of these patients. METHODS: Newborns admitted to the neonatal intensive care unit with micrognathia and upper airway obstruction (n = 133) were subjected to a decision tree model protocol formulated by a multidisciplinary team at the University of California, Los Angeles, to decide on appropriate treatment. Concomitant airway abnormalities were recorded and outcomes were documented for the first 5 years of life. RESULTS: Fifty-five percent of patients underwent internal mandibular distraction with 97 percent success. Home observation with a nasopharyngeal tube was chosen in 11 percent of patients, and 34 percent had tracheostomies. On endoscopic examination, 51.7 percent of the nondistracted patients had concomitant airway anomalies: laryngomalacia (53.3 percent), tracheal web (20.0 percent), vocal cord paralysis (13.3 percent), epiglottal collapse (6.7 percent), and infraglottal narrowing (6.7 percent). CONCLUSIONS: For the management of neonatal upper airway obstruction with micrognathia, a decision tree algorithm is useful to determine candidates for mandibular distraction. Diagnostic laryngoscopy/bronchoscopy is an important component of this algorithm because a multitude of airway anomalies may be present. CLINICAL QUESTION/LEVEL OF EVIDENCE: : Therapeutic, IV. PMID- 23629093 TI - Discussion: the effect of pressure and shear on autologous fat grafting. PMID- 23629094 TI - Porcine acellular dermal matrix (strattice) in primary and revision cosmetic breast surgery. AB - BACKGROUND: Although acellular dermal matrix materials have been in use for over a decade in primary and secondary breast reconstruction and in some cosmetic breast surgery, little has been published on the outcomes of these materials for cosmetic applications. METHODS: A retrospective institutional review board approved review was conducted of all patients who had a specific acellular dermal matrix, Strattice, used for cosmetic breast surgery performed by the senior author (S.L.S.). Patient demographics, indications, surgical findings, and postoperative course were collected and data analyzed using descriptive statistical tools. RESULTS: Between 2008 and 2012, Strattice was used in 43 cosmetic breast operations (75 breasts) performed by the senior author (S.L.S.). Sixty-nine of the 75 breasts (92 percent) were revision operations. Indications included inferior pole support [39 breasts (52 percent)], fold malpositions [28 breasts (37 percent)], capsular contracture [25 breasts (33 percent)], and rippling/palpability [six breasts (8 percent)]. Three patients (six breasts) had Strattice placed during primary augmentation/mastopexy. Seventy-four of the 75 breasts (98.7 percent) had successfully achieved the indication for which the Strattice was placed; one breast (1.2 percent) had some degree of relapse. The global complication rate for all patients in this study is 5.3 percent-two breasts (2.7 percent) had postoperative malposition, one breast (1.2 percent) had bottoming out, and one breast (1.2 percent) developed an infection that resulted in temporary device explantation. CONCLUSIONS: The use of Strattice is safe and may be helpful in the management of certain situations in cosmetic breast surgery, including needed lower pole support, capsular contracture, rippling, and implant malposition. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23629095 TI - Transaxillary totally subfascial breast augmentation with anatomical breast implants: review of 27 cases. AB - BACKGROUND: The transaxillary route is a popular method of breast augmentation because it is associated with inconspicuous scars. The subfascial plane carries the advantages and decreases the disadvantages of subglandular and submuscular planes. In the technique described, the authors placed the implant totally subfascially to strengthen the advantages of the traditional subfascial plane. METHODS: Twenty-seven patients (50 breasts) were included in the study from 2009 to 2012. The mean patient age was 27.3 years (range, 19 to 32 years). An axillary incision was performed and the pectoralis major fascia was opened initially. With endoscopic assistance, the dissection continued craniocaudally underneath the fasciae of the pectoralis, serratus, and rectus abdominis muscles. Patients were followed up in terms of rippling, implant visibility, capsular contracture, and asymmetry. RESULTS: Patients were followed up for an average of 21 months (range, 7 to 28 months). Anatomical, textured, and cohesive gel implants were used, with a mean implant size of 235 cc (range, 180 to 300 cc). In terms of the Baker classification, only 16 percent of the patients had grade II capsular contractures. There were no cases of malpositions, wrinkling, or rippling. Overall satisfaction was quite high (96 percent), and none of the patients required an implant removal or change. CONCLUSIONS: A modification of the subfascial plane was demonstrated where the implants have been placed totally subfascially, in contrast to the traditional subfacial techniques. Satisfactory results have been obtained in terms of breast shape, nipple sensitivity, capsular contracture, and implant visibility. However, more long-term results are needed to evaluate the exact effect of total fascial coverage. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23629096 TI - Prospective outcome study of 225 cases of breast augmentation. AB - BACKGROUND: Despite the popularity of breast augmentation, limited information is available evaluating this procedure from the patient's perspective. No existing studies assess patient-reported data prospectively in a large number of consecutive patients with a high inclusion rate, as required by evidence-based medicine. This prospective outcome study was undertaken to obtain this information. METHODS: Over a 5-year period, 281 consecutive women underwent breast augmentation performed by the author. In-person interviews were conducted at least 1 month after surgery among 225 women (response rate, 80.1 percent). All implants, predominantly saline-filled, were placed submuscularly using primarily inframammary incisions. Questions were asked in six categories: patient data, indications, recovery, results, complications, and psychological effects. A follow-up study evaluated subjective nipple numbness. RESULTS: The mean implant volume was approximately 390 cc. The mean pain rating was 5.9 on a scale of 1 to 10. The mean time off work was 6.6 days. The mean result rating was 9.3 on a scale of 1 to 10. Expectations were met or exceeded in 98.1 percent of patients. Satisfactory size was achieved in 85.5 percent of patients and satisfactory firmness was achieved in 75.7 percent. The reported complication rate was 10.2 percent. Breast self-consciousness decreased from 86.2 percent to 12.6 percent (p < 0.001). The result rating correlated with a low rate of complications (p < 0.001). CONCLUSIONS: Breast augmentation improves self-esteem (91.1 percent) and quality of life (64.3 percent). Nipple numbness is common (39.1 percent), but persistent numbness is unusual (2.3 percent). Almost all patients (98.7 percent) would repeat the surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23629097 TI - Discussion: prospective prospective outcome study of 225 cases of breast augmentation. PMID- 23629098 TI - Breast implant procedures under conscious sedation: a 6-year experience in 461 consecutive patients. AB - BACKGROUND: Breast implant procedures are commonly performed using general anesthesia; however, patient apprehension, the potential for improved safety, lower costs, and faster recovery times have increased interest in the use of conscious sedation in plastic surgery. The authors examined the safety and efficacy of breast implant procedures performed under conscious sedation over a 6 year period using their standardized institutional protocol. METHODS: Between 2002 and 2008, 461 consecutive patients underwent breast implant procedures under conscious sedation using a protocol of preoperative intravenous diazepam along with intraoperative midazolam, fentanyl, and local anesthetic. All operative and follow-up data were recorded. Augmentation mammaplasty patients were further analyzed for conscious sedation medication dosing. RESULTS: The study population was divided into two groups (years 1 to 3 and years 4 to 6 of the study period) to analyze changes to the authors' regimen over time. In years 4 to 6, higher preoperative doses of diazepam (p = 0.01) allowed more effective local anesthesia administration, thereby reducing intraoperative fentanyl requirements (p < 0.0001). Midazolam doses and operating times did not differ significantly between groups. No patient required conversion to a deeper method of anesthesia. The overall complication rate was 4.34 percent. CONCLUSIONS: The authors' study demonstrates the safety and efficacy of conscious sedation in breast implant procedures. Higher preoperative doses of diazepam have significantly reduced fentanyl requirements, resulting in shorter recovery times, decreased postoperative nausea/vomiting, and elimination of unintended admissions. These benefits are obtained without increasing operative times or complications. The authors conclude that conscious sedation is the preferred method of anesthesia for most patients undergoing breast implant procedures. PMID- 23629099 TI - Social media use and impact on plastic surgery practice. AB - BACKGROUND: Social media platforms have revolutionized the way human beings communicate, yet there is little evidence describing how the plastic surgery community has adopted social media. In this article, the authors evaluate current trends in social media use by practicing plastic surgeons. METHODS: An anonymous survey on the use of social media was distributed to members of the American Society of Plastic Surgeons. Prevalent patterns of social media implementation were elucidated. RESULTS: One-half of respondents were regular social media users. Reasons for using social media included the beliefs that incorporation of social media into medical practice is inevitable (56.7 percent), that they are an effective marketing tool (52.1 percent), and that they provide a forum for patient education (49 percent). Surgeons with a primarily aesthetic surgery practice were more likely to use social media. Most respondents (64.6 percent) stated that social media had no effect on their practice, whereas 33.8 percent reported a positive impact and 1.5 percent reported a negative impact. CONCLUSIONS: This study depicts current patterns of social media use by plastic surgeons, including motivations driving its implementation and impressions on its impact. Many feel that social media are an effective marketing tool that generates increased exposure and referrals. A small number of surgeons have experienced negative repercussions from social media involvement. Our study reveals the presence of a void. There is a definite interest among those surveyed in developing best practice standards and oversight to ensure ethical use of social media platforms throughout the plastic surgery community. Continuing discussion regarding these matters should be ongoing as our experience with social media in plastic surgery evolves. PMID- 23629101 TI - So, how do you do high-performance teamwork? PMID- 23629100 TI - Application of the "see one, do one, teach one" concept in surgical training. AB - BACKGROUND: The traditional method of teaching in surgery is known as "see one, do one, teach one." However, many have argued that this method is no longer applicable, mainly because of concerns for patient safety. The purpose of this article is to show that the basis of the traditional teaching method is still valid in surgical training if it is combined with various adult learning principles. METHODS: The authors reviewed literature regarding the history of the formation of the surgical residency program, adult learning principles, mentoring, and medical simulation. The authors provide examples for how these learning techniques can be incorporated into a surgical resident training program. RESULTS: The surgical residency program created by Dr. William Halsted remained virtually unchanged until recently with reductions in resident work hours and changes to a competency-based training system. Such changes have reduced the teaching time between attending physicians and residents. Learning principles such as experience, observation, thinking, and action and deliberate practice can be used to train residents. Mentoring is also an important aspect in teaching surgical technique. The authors review the different types of simulators standardized patients, virtual reality applications, and high-fidelity mannequin simulators-and the advantages and disadvantages of using them. CONCLUSIONS: The traditional teaching method of "see one, do one, teach one" in surgical residency programs is simple but still applicable. It needs to evolve with current changes in the medical system to adequately train surgical residents and also provide patients with safe, evidence-based care. PMID- 23629102 TI - Are the new changes in our operating rooms really making us safer and better surgeons? PMID- 23629106 TI - Immediate breast reconstruction with a Latissimus dorsi flap has no detrimental effects on shoulder motion or postsurgical complications up to 1 year after surgery. AB - BACKGROUND: Mastectomy negatively affects scapulothoracic and glenohumeral kinematics. Breast reconstructive methods such as the latissimus dorsi flap can result in anatomical modifications that may in theory further affect the shoulder apparatus. The purpose of this study was to examine the effects of latissimus dorsi flap reconstruction on the recovery of shoulder motion and other postsurgical problems during the first year after mastectomy. METHODS: This was a prospective cohort study of 104 consecutive mastectomies (47 with immediate latissimus dorsi flaps). Shoulder range of motion was assessed before and at 1, 3, 6, and 12 months after surgery. Pain, tissue adhesion, scar enlargement, and web syndrome were assessed during follow-up. RESULTS: There was a 30 percent decrease of shoulder range of motion 1 month after surgery, with gradual recovery over time. However, mean abduction and flexion capacities did not reach baseline levels and were on average 5 to 10 percent lower than baseline, even after 1 year. Over time, the latissimus dorsi flap was not associated with restriction of flexion or abduction. Scar enlargement (at the first month, p = 0.009) and tissue adhesion (at month 12, p = 0.032) were significantly less common in the latissimus dorsi flap group. CONCLUSIONS: The authors' study clearly suggests that the additional anatomical manipulation required for the latissimus dorsi flap procedure does not further affect shoulder kinematics and is associated with a lower incidence of tissue adhesion. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 23629107 TI - Free tissue transfer in the obese patient: an outcome and cost analysis in 1258 consecutive abdominally based reconstructions. AB - BACKGROUND: The authors' institution has seen an increase in obese and morbidly obese patients seeking autologous breast reconstruction. The authors provide a comprehensive outcome analysis of patients undergoing abdominally based autologous breast reconstruction. METHODS: The authors identified obese patients receiving free tissue transfer for breast reconstruction. World Health Organization body mass index criteria were used: nonobese (body mass index, 20 to 29.9 kg/m), class I (30 to 34.9 kg/m), class II (35 to 39.9 kg/m), and class III (>40 kg/m). Patient comorbidities, body mass index, complications (medical and surgical), and hospital resource use were examined. RESULTS: Eight-hundred twelve patients undergoing 1258 free tissue transfers for breast reconstruction were included. Overall, 66.5 percent (n = 540) were considered nonobese, 22.9 percent (n = 186) had class I obesity, 5.0 percent (n = 41) had class II, and 5.7 percent (n = 45) had class III. Obesity was associated with a significant increase in minor (p = 0.001) and major (p = 0.013) complications. Morbidly obese patients had significantly higher rates of total flap loss (p = 0.006) and longer operative times (p = 0.0002). Complications translated into greater cost and resource consumption (p < 0.001). Muscle-sparing transverse rectus abdominis myocutaneous flap experienced a significantly higher rate of hernia compared with other flaps (p = 0.02), without a difference in flap loss rate (p = 0.61). CONCLUSIONS: Increasing obesity is associated with increased perioperative risk in free abdominally based autologous breast reconstruction, which translated into greater perioperative morbidity, higher hospital cost, and increased health care resource consumption. Higher body mass index is directly related to intraoperative technical difficulty, flap loss, donor-site morbidity, and cost use. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 23629108 TI - A comparison of free autologous breast reconstruction with and without the use of laser-assisted indocyanine green angiography: a cost-effectiveness analysis. AB - BACKGROUND: Laser-assisted indocyanine green angiography is a U.S. Food and Drug Administration-approved technology used to assess tissue viability and perfusion. Its use in plastic and reconstructive surgery to assess flap perfusion in autologous breast reconstruction is relatively new. There have been no previous studies evaluating the cost-effectiveness of this new technology compared with the current practice of clinical judgment in evaluating tissue perfusion and viability in free autologous breast reconstruction in patients who have undergone mastectomy. METHODS: A comprehensive literature review was performed to identify the complication rate of the most common complications with and without laser assisted indocyanine green angiography in free autologous breast reconstruction after mastectomy. These probabilities were combined with Medicare Current Procedural Terminology provider reimbursement codes (cost) and utility estimates for common complications from a survey of 10 plastic surgeons to fit into a decision model to evaluate the cost-effectiveness of laser-assisted indocyanine green angiography. RESULTS: The decision model revealed a baseline cost difference of $773.66 and a 0.22 difference in the quality-adjusted life-years, yielding an incremental cost-utility ratio of $3516.64 per quality-adjusted life year favoring laser-assisted indocyanine green angiography. Sensitivity analysis showed that using laser-assisted indocyanine green angiography was more cost effective when the complication rate without using laser-assisted indocyanine green angiography (clinical judgment alone) was 4 percent or higher. CONCLUSIONS: The authors' study demonstrates that laser-assisted indocyanine green angiography is a cost-effective technology under the most stringent acceptable thresholds when used in immediate free autologous breast reconstruction. PMID- 23629109 TI - A monitoring tool for performance improvement in plastic surgery at the individual level. AB - BACKGROUND: The assessment of performance in surgery is expanding significantly. Application of relevant frameworks to plastic surgery, however, has been limited. In this article, the authors present two robust graphic tools commonly used in other industries that may serve to monitor individual surgeon operative time while factoring in patient- and surgeon-specific elements. METHODS: The authors reviewed performance data from all bilateral reduction mammaplasties performed at their institution by eight surgeons between 1995 and 2010. Operative time was used as a proxy for performance. Cumulative sum charts and exponentially weighted moving average charts were generated using a train-test analytic approach, and used to monitor surgical performance. Charts mapped crude, patient case-mix adjusted, and case-mix and surgical-experience-adjusted performance. RESULTS: Operative time was found to decline from 182 minutes to 118 minutes with surgical experience (p < 0.001). Cumulative sum and exponentially weighted moving average charts were generated using 1995 to 2007 data (1053 procedures) and tested on 2008 to 2010 data (246 procedures). The sensitivity and accuracy of these charts were significantly improved by adjustment for case mix and surgeon experience. CONCLUSIONS: The consideration of patient- and surgeon-specific factors is essential for correct interpretation of performance in plastic surgery at the individual surgeon level. Cumulative sum and exponentially weighted moving average charts represent accurate methods of monitoring operative time to control and potentially improve surgeon performance over the course of a career. PMID- 23629110 TI - Deferoxamine restores callus size, mineralization, and mechanical strength in fracture healing after radiotherapy. AB - BACKGROUND: Therapeutic augmentation of fracture-site angiogenesis with deferoxamine has proven to increase vascularity, callus size, and mineralization in long-bone fracture models. The authors posit that the addition of deferoxamine would enhance pathologic fracture healing in the setting of radiotherapy in a model where nonunions are the most common outcome. METHODS: Thirty-five Sprague Dawley rats were divided into three groups. Fracture, irradiated fracture, and irradiated fracture plus deferoxamine. The irradiated fracture and irradiated fracture plus deferoxamine groups received a human equivalent dose of radiotherapy [7 Gy/day for 5 days, (35 Gy)] 2 weeks before mandibular osteotomy and external fixation. The irradiated fracture plus deferoxamine group received injections of deferoxamine into the fracture callus after surgery. After a 40-day healing period, mandibles were dissected, clinically assessed for bony union, imaged with micro-computed tomography, and tension tested to failure. RESULTS: Compared with irradiated fractures, metrics of callus size, mineralization, and strength in deferoxamine-treated mandibles were significantly increased. These metrics were restored to a level demonstrating no statistical difference from control fractures. In addition, the authors observed an increased rate of achieving bony unions in the irradiated fracture plus deferoxamine-treated group when compared with irradiated fracture (67 percent and 20 percent, respectively). CONCLUSIONS: The authors' data demonstrate nearly total restoration of callus size, mineralization, and biomechanical strength, and a threefold increase in the rate of union with the use of deferoxamine. The authors' results suggest that the administration of deferoxamine may have the potential for clinical translation as a new treatment paradigm for radiation-induced pathologic fractures. PMID- 23629111 TI - Functional outcomes following multiple acute rejections in experimental vascularized composite allotransplantation. AB - BACKGROUND: Vascularized composite allotransplantation has become a clinical reality. Patients undergoing vascularized composite allotransplantation have modest functional return. Most patients have had multiple acute rejections. The effect of multiple acute rejections influencing functional outcomes is unknown. This study systematically analyzes the effects of multiple acute rejections on functional outcome. METHODS: Rat functional orthotopic hind-limb transplants were performed from Brown-Norway to Lewis rats. Group 1 consisted of isografts. In group 2, daily cyclosporine was administered to prevent acute rejection. In group 3, recipients did not receive regular immunosuppression but received only pulsed cyclosporine and dexamethasone to rescue acute rejection. The study endpoint was 90 days. Muscle and sciatic nerve biopsy specimens were taken for histologic analyses. Hind-limb function was assessed using sciatic nerve axon density, nerve conduction velocity, and muscle force generated by the gastrocnemius muscle. Novel video kinematics was used to analyze gait. RESULTS: By the endpoint, group 3 animals had 17 +/- 5.1 acute rejections. Muscle biopsy showed significant atrophy and fibrosis in group 3 compared with groups 1 and 2. Withdrawal to pin prick was evident by days 31 +/- 1.2, 30 +/- 2.3, and 31 +/- 3.7 in groups 1, 2, and 3, respectively. At the endpoint, there was no significant difference in the axon density or nerve conduction velocity among the three groups, but muscle force generated was significantly less in group 3. Gait was abnormal in group 3 animals compared with other groups. CONCLUSIONS: In this study, multiple acute rejections induced muscle atrophy and fibrosis and consequent decreased function. This emphasizes the importance of preventing acute rejection to achieve optimum function following vascularized composite allotransplantation. PMID- 23629112 TI - Collagen/Polypropylene composite mesh biocompatibility in abdominal wall reconstruction. AB - BACKGROUND: Intraperitoneal placement of polypropylene mesh leads to extensive visceral adhesions and is contraindicated. Different coatings are used to improve polypropylene mesh properties. Collagen is a protein with unique biocompatibility and cell ingrowth enhancement potential. A novel acetic acid extracted collagen coating was developed to allow placement of polypropylene mesh in direct contact with viscera. The authors' aim was to evaluate the long-term influence of acetic acid extracted collagen coating on surgical aspects and biomechanical properties of polypropylene mesh implanted in direct contact with viscera, including complications, adhesions with viscera, strength of incorporation, and microscopic inflammatory reaction. METHODS: Forty adult Wistar rats were divided into two groups: experimental (polypropylene mesh/acetic acid extracted collagen coating) and control (polypropylene mesh only). Astandardized procedure of mesh implantation was performed. Animals were killed 3 months after surgery and analyzed for complications, mesh area covered by adhesions, type of adhesions, strength of incorporation, and intensity of inflammatory response. RESULTS: The mean adhesion area was lower for polypropylene mesh/acetic acid extracted collagen coating (14.5 percent versus 69.9 percent, p < 0.001). Adhesion severity was decreased in the experimental group: grades 0 and 1 were more frequent (p < 0.04 and p < 0.002, respectively) and grade 3 was less frequent (p < 0.0001). An association between adhesion area and severity was found (p < 0.0001). Complications, strength of incorporation, and intensity of inflammatory response to the mesh were similar. CONCLUSIONS: Visceral adhesions to polypropylene mesh are significantly reduced because of acetic acid extracted collagen coating. The collagen coating does not increase complications or induce alterations of polypropylene mesh incorporation. PMID- 23629113 TI - Analysis of acellular dermal matrix integration and revascularization following tissue expander breast reconstruction in a clinically relevant large-animal model. AB - BACKGROUND: Postmastectomy breast reconstruction remains one of the most frequently performed plastic surgery procedures in the United States. Acellular dermal matrix has been used extensively in expander-implant breast reconstruction and therefore is an appropriate material to be used to develop a clinically relevant animal model of breast reconstruction. METHODS: The study population consisted of 18 female Yorkshire pigs, which were assigned randomly to bilateral expander breast reconstruction with either AlloMax Surgical Graft or AlloDerm Regenerative Tissue Matrix (n = 9 per group). Each group was further randomized to 4-, 8-, or 12-week time points (n = 3), to evaluate integration and neovascularization by means of microcirculatory and histologic techniques. RESULTS: Microcirculatory analysis revealed early acellular dermal matrix angiogenesis at 4 weeks on the skin flap surfaces only, and well-formed vasculature on both acellular dermal matrix surfaces at 8 weeks. Both surfaces were vascularized and exhibited detectable flow at 12 weeks after implantation. Progressive acellular dermal matrix angiogenesis was also histologically observed over time by means of hematoxylin and eosin-stained slides, as indicated by direct vascular identification/scoring at 4, 8, and 12 weeks. CONCLUSIONS: The authors have developed a clinically relevant large-animal model of breast reconstruction using acellular dermal matrix. The acellular dermal matrix inflammatory, neovascularization, and tissue integration response should be evaluated in an in vivo setting that accurately simulates the anatomy, biomaterials, surgical techniques, and timeframes encountered in human postmastectomy breast reconstruction to appropriately predict clinical performance. Neovascularization of the acellular dermal matrix with detectable blood flow took place after postimplantation week 8, a much slower process than previously reported in models not clinically relevant to acellular dermal matrix assisted tissue expander breast reconstruction. PMID- 23629114 TI - A novel design of the multilobed latissimus dorsi myocutaneous flap to achieve primary donor-site closure in the reconstruction of large defects. AB - BACKGROUND: The main drawback of the latissimus dorsi myocutaneous flap for large defect repairs is the relatively small skin paddle size that can be raised to allow primary closure of the donor site. In this article, the authors describe a novel design of the flap using multiple separate skin paddles, with each paddle nourished by independent perforators, to repair very large defects while maintaining primary donor-site closure. METHODS: After the size of the defect was calculated, its total area was split into two or three skin paddles and marked on the back skin so that the largest width of each paddle did not exceed 8 cm. A multilobed skin paddle was designed with a total area that was much larger than traditional latissimus dorsi flaps. After harvesting the flap, several smaller skin paddles were transferred and rejoined at the recipient site. RESULTS: From June of 2009 to March of 2012, this method was used to restore posttraumatic and postoncologic defects of the head in seven cases and lower limb defects in two cases. Seven flaps were raised as bilobed flaps, and two flaps were raised as trilobed flaps. The donor site was closed primarily in all cases. One case was complicated by partial necrosis of one paddle and required further local flap coverage. Donor-site breakdown was not observed in any of the cases. CONCLUSIONS: The multilobed myocutaneous latissimus dorsi flap enables a customized reconstruction of large defects for all types of patients and direct closure of the donor site. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23629115 TI - Thoracoacromial artery perforator flap: anatomical basis and clinical applications. AB - BACKGROUND: Concerns and criticism have been reported on the feasibility and vascular reliability of the thoracoacromial artery perforator flap because of the inconsistent size of the pectoral branch of the thoracoacromial artery and its cutaneous perforators. The authors have investigated its vascular basis through a cadaver dissection and described their clinical experience in the surgical strategy, range of application, and indications for the thoracoacromial artery perforator flap. METHODS: Twelve fresh human cadavers were dissected to define the anatomy of the branches of the thoracoacromial artery and their perforators and the anatomical landmarks for clinical application. Single pectoral branch perforators were injected to measure the extension of the thoracoacromial artery perforator vascular territory. RESULTS: A constant thoracoacromial artery perforator was present in the septum between the clavicular and sternocostal heads of the pectoralis major muscle in 21 of 24 hemichests. The mean caliber of the perforator was 0.7 mm and the mean length of the vascular pedicle was 7.1 cm. The territory of the thoracoacromial artery perforator flap extended up to the fourth intercostal space inferiorly. Between 2006 and 2011, the thoracoacromial artery perforator flap was used to reconstruct head and neck defects in seven patients. All patients healed uneventfully. CONCLUSIONS: The authors' studies provide evidence of the vascular supply and the clinical application of the thoracoacromial artery perforator flap. The recruitment of the chest skin through a thoracoacromial artery perforator flap resulted in an adequate color match, texture, and pliability for local adjacent defect restoration and for head and neck reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23629116 TI - Merkel cell carcinoma: diagnosis, management, and outcomes. AB - Merkel cell carcinoma is a rare, aggressive cutaneous malignancy with high rates of recurrence, metastases, and mortality. Its nonspecific clinical presentation often delays the diagnosis, and its treatment is still controversial because of the infrequent nature of the tumor. The authors provide an overview of the current literature on epidemiology, cause, pathogenesis, staging, management, and outcomes of this disease. Effective diagnostic and treatment modalities such as wide local excision of the primary tumor, importance of sentinel node biopsy for staging, evidence for the use of adjuvant radiation therapy, and emphasis on a multidisciplinary treatment approach of Merkel cell carcinoma as it pertains to surgical practice are reviewed. PMID- 23629118 TI - The simple transverse intraosseous phalangeal suture for zone 1 flexor digitorum profundus injuries: case series and review of the literature. AB - BACKGROUND: Zone 1 flexor digitorum profundus injury often precludes the use of a simple core suture as a result of a distal remnant that is too short. The aim of this study was to assess the senior author's (S.I.) simple technique for reinsertion of the flexor digitorum profundus tendon. METHODS: The case series consisted of 12 patients who required a primary flexor digitorum profundus repair in zone 1, with all repairs performed by the senior author. A Bruner incision was extended to the pulp to expose the base of the distal phalanx. A two-strand repair was anchored to the distal phalanx using the author's technique, which involved passing a 3-0 polypropylene suture on a straight needle through a hypodermic needle that had been drilled through the base of the distal phalanx. This provided a stable, intraosseous, internal repair, allowing a standard early active mobilization regimen. RESULTS: Two patients had excellent results and 10 had good results in terms of distal interphalangeal joint range of movement (mean, 57 degrees; range, 51 to 80 degrees) and Quick Disabilities of the Arm, Shoulder and Hand questionnaire scores (mean, 12; range, 0 to 31.8). There were no reported tendon ruptures at the time of writing this article (range, 6 to 37 months after surgery). CONCLUSIONS: The authors present a technique for the repair of zone 1 flexor digitorum profundus injuries that is simple, can be performed quickly, is easily learned, and has results that compare favorably with other techniques in the literature. Furthermore, there is limited morbidity to surrounding fingertip structures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23629117 TI - The Michigan hand outcomes questionnaire after 15 years of field trial. AB - BACKGROUND: The Michigan Hand Outcomes Questionnaire has been used to assess a variety of hand and upper extremity injuries and conditions for nearly 15 years. It has been included in several overviews of upper extremity outcomes measures, but it has not been systematically examined regarding its clinometric properties during field trials. METHODS: The authors conducted a review of the Michigan Hand Outcomes Questionnaire in the English language literature from 1998 through March of 2012. Data from clinical studies were abstracted and compiled. RESULTS: The Michigan Hand Outcomes Questionnaire has been used in 58 clinical studies, and its clinometric properties have been analyzed in an additional 18 publications. The Michigan Hand Outcomes Questionnaire compares favorably with other hand outcomes instruments in the areas of test-retest reliability, validity, and responsiveness. High internal consistency may indicate redundancy within the items in the Michigan Hand Outcomes Questionnaire. The strength of the Michigan Hand Outcomes Questionnaire is its multidimensional construct in measuring patient-rated outcomes in symptom, function, aesthetics, and satisfaction. CONCLUSIONS: The Michigan Hand Outcomes Questionnaire has been applied across a variety of conditions affecting the hand and upper limb. Its psychometric properties have been tested through field trials in various clinical settings around the world. PMID- 23629119 TI - The contribution of endogenous and exogenous factors to male alopecia: a study of identical twins. AB - BACKGROUND: The purpose of this study was to investigate the potential contribution of environmental factors and testosterone on male alopecia. METHODS: Ninety-two identical male twins were recruited from 2009 to 2011. A comprehensive questionnaire was completed followed by the acquisition of sputum samples for testosterone analysis and standardized digital photography. Frontal, temporal, and vertex hair loss was assessed from these photographs. Hair loss was then correlated with survey responses and testosterone levels between twin pairs. Two independent, blinded observers also rated the photographs for hair thinning. RESULTS: Increased smoking duration (p < 0.001) and the presence of dandruff (p = 0.028) were significantly associated with increased frontal hair loss. Increased exercise duration (p = 0.002), consumption of more than four alcoholic drinks per week (p = 0.042), and increased money spent on hair loss products (p = 0.050) were all associated with increased temporal hair loss. Daily hat use (p = 0.050), higher body mass index (p = 0.012), and higher testosterone levels (p = 0.040) were associated with decreased temporal hair loss. Factors that were significantly associated with increased vertex hair loss included abstinence from alcohol consumption (p = 0.030), consumption of more than four alcoholic drinks per week (p = 0.004), increased smoking duration (p = 0.047), increased exercise duration (p = 0.050), and increased stress duration (p = 0.010). Lower body mass index, more children, increased caffeine consumption, history of skin disease, and abstinence from alcohol were significantly associated with increased hair thinning scores (p < 0.05). CONCLUSION: This study offers substantial evidence that exogenous factors may have a clinically significant impact on hair loss. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 23629120 TI - Prospective photographic measurement study of 196 cases of breast augmentation, mastopexy, augmentation/mastopexy, and breast reduction. AB - BACKGROUND: Our understanding of breast shape and size changes after surgery is limited by a lack of measurement studies that evaluate and compare changes in breast dimensions after cosmetic breast procedures. This study was undertaken to remedy this deficiency. METHODS: Women undergoing primary vertical mastopexy, augmentation/mastopexy, and reduction were evaluated prospectively from 2002 to 2012. Breast augmentation patients were also measured prospectively over a 6 month period during the study. A total of 196 consecutive patients meeting the inclusion criteria-at least 3 months' follow-up and no subsequent breast surgery were evaluated (inclusion rate, 88.3 percent). RESULTS: Both nipples were located at or above the level of maximum preoperative breast projection in 60 percent of women presenting with ptosis. The maximum preoperative nipple displacement was 6.5 cm. All four procedures increased breast projection and upper pole projection, with a significantly greater boost when implants were combined with mastopexy (p < 0.01). Breast augmentation lowered the lower pole level (p < 0.001) and minimally elevated the breast mound, with no change in nipple level. Vertical mastopexy and reduction elevated the lower pole and breast mound, reduced areola size, and increased the breast parenchymal ratio (p < 0.001). CONCLUSIONS: Vertical mammaplasty corrects glandular sagging and provides a modest increase in breast projection and upper pole projection. Augmentation/mastopexy most effectively treats upper pole deflation and ptosis. In ptosis, the nipple descends primarily with the breast, not on it. Nipple repositioning (<6.5 cm) is preferred over transposition to avoid overelevation and improve safety. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 23629121 TI - Local anesthetics in liposuction: considerations for new practice advisory guidelines to improve patient safety. AB - The Practice Advisory on Liposuction published by the American Society of Plastic Surgeons provides a thorough review of anesthetic techniques and guidelines for surgeons who perform liposuction. However, there is evidence to support several changes to the anesthetic infiltrate guidelines that will improve patient safety. These proposed recommendations will have the most impact on patients undergoing office-based procedures, where dedicated anesthesia providers may not be present, but they should also guide practice in both ambulatory care centers and hospitals. The primary foci of the proposed changes include restrictions on bupivacaine use and creation of lidocaine concentration guidelines. PMID- 23629122 TI - Current methods of burn reconstruction. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Explain the present challenges in reconstructive burn surgery. 2. Describe the most appropriate treatment methods and techniques for specific burn injury types, including skin grafts, dermal substitutes, and a variety of flap options. 3. Identify the appropriate use, advantages, and disadvantages of specific flaps in the treatment of burn injuries, including local, regional, superthin, prefabricated, prelaminated, and free flaps. SUMMARY: Victims of thermal burns often form heavy scars and develop contractures around joints, inhibiting movement. As burns can occur in all cutaneous areas of the body, a wide range of reconstructive options have been utilized. Each method has advantages and disadvantages that must be considered by both patients and surgeons. The authors reviewed the literature for burn reconstruction and focused their discussion on areas that have been recently developed. They reviewed the mechanism of burn injury and discussed how this relates to the pathophysiology of the burn injury. Surgeons now have a wide array of plastic surgical techniques that can be used to treat burn victims. These range from skin grafts and local flaps to free flaps, prefabricated flaps, superthin flaps, and dermal scaffolds. Recent advances in burn reconstruction provide methods to decrease scar tissue and joint contractures. In the future, the authors hope that further developments in burn treatment will foster the development of new technologies that will allow site specific reconstruction with minimal donor-site morbidity. PMID- 23629123 TI - Mentorship: concepts and application to plastic surgery training programs. AB - BACKGROUND: Countless articles have demonstrated and emphasized the importance of mentoring in academic medicine. However, the upcoming role of mentors in the evolving medical field is poorly defined. As translational medicine, collaboration, and health care priorities change, so too must the goals and use of mentoring. The aims of this article are to demonstrate key aspects of effective mentoring in academic plastic surgery, show institutions how to cultivate mentoring relationships among their faculty and trainees, and provide direction for how to optimize the future use of mentoring to best prepare the next generation of plastic surgeons. METHODS: The authors reviewed the current literature regarding mentorship and the evolution of academic plastic surgery. RESULTS: Mentors not only facilitate their proteges' entrance into the field and future success, but can also attract medical students and residents to careers in research and reduce the racial and gender discrepancies in plastic surgery and academia. Ideally, faculty should undergo some form of training before they enter mentoring relationships. This will ensure that they are aware of their specific duties as mentors, are able to communicate with mentees, and can avoid potential pitfalls. CONCLUSIONS: Mentorship is a tool. If used correctly, it can help recruit and retain talented physician-scientists to plastic surgery to satisfy the growing demand. This will require institutions to actively support mentorship, provide opportunities and resources for training mentors, and enable faculty to allocate time to this vital pursuit. PMID- 23629124 TI - Anatomy of the supratrochlear nerve: implications for the surgical treatment of migraine headaches. PMID- 23629125 TI - Extended applications of vascularized preauricular and helical rim flaps in reconstruction of nasal defects. PMID- 23629126 TI - Reply: extended applications of vascularized preauricular and helical rim flaps in reconstruction of nasal defects. PMID- 23629127 TI - Protective lipofilling allows immediate expander-implant breast [corrected] reconstruction in the setting of postoperative radiotherapy. PMID- 23629128 TI - Reply: protective lipofilling allows immediate expander-implant reconstruction in the setting of postoperative radiotherapy. PMID- 23629129 TI - Contradicting an established Mantra: microsurgeon experience determines free flap outcome. PMID- 23629130 TI - Reply: contradicting an established Mantra: microsurgeon experience determines free flap outcome. PMID- 23629131 TI - Evaluation of the long-term stability of sheath plication. PMID- 23629132 TI - Reply: evaluation of the long-term stability of sheath plication. PMID- 23629133 TI - Auricular wedge excision revisited: technical refinements to avoid postoperative ear deformities. PMID- 23629134 TI - Osteocutaneous femur perforator flap for salvage reconstruction of the nasal septum and columella. PMID- 23629135 TI - Alar width: refining norms to the aesthetic ideal. PMID- 23629136 TI - Refinements in anchoring the gracilis muscle for facial reanimation. PMID- 23629137 TI - Improved blunt dissectors for greater safety in face lift surgery. PMID- 23629138 TI - Mastering the approach of internal mammary vessels: a new training model in pigs. PMID- 23629139 TI - Postaugmentation galactocele. PMID- 23629140 TI - Gynecomastia: tips and tricks-classification and surgical approach. PMID- 23629141 TI - Tweeting all surgeons: update your facebook status, enhance your reputation, and "pin" your practice on the wild, wild web. PMID- 23629142 TI - A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages. AB - Oct4 is considered a master transcription factor for pluripotent cell self renewal, but its biology remains poorly understood. Here, we investigated the role of Oct4 using the process of induced pluripotency. We found that a defined embryonic stem cell (ESC) level of Oct4 is required for pluripotency entry. However, once pluripotency is established, the Oct4 level can be decreased up to sevenfold without loss of self-renewal. Unexpectedly, cells constitutively expressing Oct4 at an ESC level robustly differentiated into all embryonic lineages and germline. In contrast, cells with low Oct4 levels were deficient in differentiation, exhibiting expression of naive pluripotency genes in the absence of pluripotency culture requisites. The restoration of Oct4 expression to an ESC level rescued the ability of these to restrict naive pluripotent gene expression and to differentiate. In conclusion, a defined Oct4 level controls the establishment of naive pluripotency as well as commitment to all embryonic lineages. PMID- 23629143 TI - High-throughput quality control of DMSO acoustic dispensing using photometric dye methods. AB - One high-throughput technology gaining widespread adoption in industry and academia is acoustic liquid dispensing, in which focused sound waves eject nanoliter-sized droplets from a solution into a recipient microplate. This technology allows for direct dispensing of small-molecule compounds or reagents dissolved in DMSO, while keeping a low final concentration of organic solvent in an assay. However, acoustic dispensing presents unique quality control (QC) challenges when measuring the accuracy and precision of small dispense volumes ranging from 2.5 to 100 nL. As part of an effort to develop a rapid and cost effective QC method for acoustic dispensing of 100% DMSO, we implemented the first high-throughput photometric dual-dye-based QC protocol in the nanoliter volume range. This technical note validates the new photometric 100% DMSO QC method and highlights its cost-effectiveness when compared with conventional low throughput fluorimetric QC methods. In addition, a potential software solution is described for the analysis, storage, and display of accumulated high-throughput QC data, called LabGauge. As the need for high-throughput QC grows, conventional low-throughput methods can no longer meet demand. Validated high-throughput techniques, such as the dual-dye photometric method, will need to be implemented. PMID- 23629144 TI - Effect of photogenerated charge transfer on the photocatalysis in high performance hybrid Pt-Co:ZnO nanostructure photocatalyst. AB - Hybrid Pt-Co:ZnO nanostructure photocatalysts were prepared via a facile two-step synthetic strategy. SPS and TPV investigations demonstrate the existence of the synergetic effect between Pt and Co dopants. Such synergetic effect could make use of visible photons as well as facilitates the separation of photogenerated charges to prevent recombination, effectively prolongating the charges lifetime to participate photocatalytic reaction. The synergetic effect exist in Pt-Co:ZnO inducing as high as 7.7-fold in photovoltaic response and 10-fold in the photo activity for hybrids compared to Co:ZnO. PMID- 23629145 TI - The association between weight loss in caregivers and adolescents in a treatment trial of adolescents with obesity. AB - OBJECTIVE: The relationship between weight change in caregivers and their adolescents was evaluated following a randomized trial of lifestyle modification for adolescents, which included either a conventional diet or meal replacements. METHODS: Adolescents (N = 113) had an M +/- SD age of 15.0 +/- 1.3 years (62% African American; 26% Caucasian, 12% other; 81% female) and body mass index of 37.1 +/- 5.1 kg/m(2). RESULTS: Mixed effects models yielded a significant association between percentage change in body mass index of caregivers and adolescents from baseline to months 4 and 12 (p = .01). When caregivers lost above the median (-1.67%) at month 4, their adolescents achieved a significantly greater loss at month 12 (-9.1 +/- 1.3%) compared with adolescents whose caregivers lost less than the median (-4.3 +/- 1.3%) (p = .003). CONCLUSION: Engaging caregivers in their own weight loss efforts during adolescent weight loss treatment may improve adolescent weight loss. PMID- 23629148 TI - Infrared-light-induced photocatalysis on BiErWO6. AB - A novel BiErWO6 photocatalyst with infrared responsive property was designed and synthesized by a simple hydrothermal method. The BiErWO6 photocatalyst exhibited high photocatalytic activity under an infrared lamp (lambda > 700 nm). PMID- 23629147 TI - Only kids who are fools would do that! Peer social norms influence children's risk-taking decisions. AB - OBJECTIVES: The current research examined the impact of peer social norms on the physical risk-taking decisions of elementary-school children. METHOD: Children 6 12 years of age completed a novel video-viewing decision task in which they observed risk and non-risk child behaviors on a playground and, after each behavior, indicated their willingness to model each of the behaviors in their own video, both before and after exposure to peer-communicated social norms (encouragement, discouragement). RESULTS: Exposure to peer social norms resulted in significant changes in risk taking, with changes predicted from ratings of perceived social norms and appraisals of injury vulnerability and severity. CONCLUSION: Exposure to peer social norms can provide another means by which injury prevention programs can aim to reduce injury-risk behaviors among school age children. PMID- 23629150 TI - Thrombus aspiration therapy and coronary thrombus components in patients with acute ST-elevation myocardial infarction. AB - Inflammation and oxidative stress play key roles in atherosclerotic plaque instability, and plaque rupture/erosion and subsequent thrombus formation constitute the principal mechanisms of total vessel occlusion and acute ST elevation myocardial infarction (STEMI). Plaque disruption triggers the formation of initial platelet aggregates that grow in association with an increase in fibrin formation, leading to persistent coronary flow obstruction and blood coagulation. The fibrin network may trap large numbers of erythrocytes and inflammatory cells to form an erythrocyte-rich thrombus. In fact, previous clinical studies have shown that not only platelet-rich white thrombi, but also erythrocyte-rich red thrombi can be visualized using angioscopy in patients with acute coronary syndrome. Recently, the development of thrombus aspiration and distal protection devices has significantly improved the clinical outcomes of percutaneous intervention in STEMI patients and has enabled the evaluation of antemortem coronary artery thrombi. This is important because previous autopsy studies were unable to differentiate coronary thrombi responsible for myocardial ischemia from postmortem clots. Using frozen samples of aspirated thrombi and specific monoclonal antibodies, we investigated the cellular components of thrombi (platelets, erythrocytes, fibrin and inflammatory cells, such as myeloperoxidase-positive cells) and pathologically evaluated the relationships between erythrocyte-rich thrombi and inflammation, oxidative stress and clinical outcomes in STEMI patients. Therefore, this review article focuses on the efficacy of thrombus aspiration therapy and the components of aspirated intracoronary thrombi in STEMI patients and presents the results of recent studies regarding the relationship between the composition of aspirated intracoronary thrombi and clinical outcomes. PMID- 23629149 TI - Feasibility of interstitial diffuse optical tomography using cylindrical diffusing fibers for prostate PDT. AB - Interstitial diffuse optical tomography (DOT) has been used to characterize spatial distribution of optical properties for prostate photodynamic therapy (PDT) dosimetry. We have developed an interstitial DOT method using cylindrical diffuse fibers (CDFs) as light sources, so that the same light sources can be used for both DOT measurement and PDT treatment. In this novel interstitial CDF DOT method, absolute light fluence per source strength (in unit of 1 cm(-2)) is used to separate absorption and scattering coefficients. A mathematical phantom and a solid prostate phantom including anomalies with known optical properties were used, respectively, to test the feasibility of reconstructing optical properties using interstitial CDF-DOT. Three dimension spatial distributions of the optical properties were reconstructed for both scenarios. Our studies show that absorption coefficient can be reliably extrapolated while there are some cross talks between absorption and scattering properties. Even with the suboptimal reduced scattering coefficients, the reconstructed light fluence rate agreed with the measured values to within +/-10%, thus the proposed CDF-DOT allows greatly improved light dosimetry calculation for interstitial PDT. PMID- 23629151 TI - Measurement of vacuolar and cytosolic pH in vivo in yeast cell suspensions. AB - Vacuolar and cytosolic pH are highly regulated in yeast cells and occupy a central role in overall pH homeostasis. We describe protocols for ratiometric measurement of pH in vivo using pH-sensitive fluorophores localized to the vacuole or cytosol. Vacuolar pH is measured using BCECF, which localizes to the vacuole in yeast when introduced into cells in its acetoxymethyl ester form. Cytosolic pH is measured with a pH-sensitive GFP expressed under control of a yeast promoter, yeast pHluorin. Methods for measurement of fluorescence ratios in yeast cell suspensions in a fluorimeter are described. Through these protocols, single time point measurements of pH under different conditions or in different yeast mutants have been compared and changes in pH over time have been monitored. These methods have also been adapted to a fluorescence plate reader format for high-throughput experiments. Advantages of ratiometric pH measurements over other approaches currently in use, potential experimental problems and solutions, and prospects for future use of these techniques are also described. PMID- 23629146 TI - Social ecological predictors of longitudinal HIV treatment adherence in youth with perinatally acquired HIV. AB - OBJECTIVE: To apply a social ecological model to explore the psychosocial factors prospectively associated with longitudinal adherence to antiretroviral treatment in youth perinatally infected with HIV. METHODS: Randomly selected youth, age 8 to <19 years old, completed cognitive testing and psychosocial questionnaires at baseline as part of a multisite protocol (N = 138). A validated caregiver-report measure of adherence was completed at baseline and 24 and 48 weeks after baseline. RESULTS: In multivariate analysis, youth awareness of HIV status, caregiver not fully responsible for medications, low caregiver well-being, adolescent perceptions of poor caregiver-youth relations, caregiver perceptions of low social support, and African American ethnicity were associated with nonadherence over 48 weeks. CONCLUSIONS: Interventions focusing on caregivers and their interactions with the individual youth and extrafamilial system should be prioritized for prevention and treatment efforts to address nonadherence during the transition into adolescents. PMID- 23629152 TI - Sulfur dioxide preconditioning increases antioxidative capacity in rat with myocardial ischemia reperfusion (I/R) injury. AB - BACKGROUND: The study was designed to explore if sulfur dioxide (SO2) preconditioning increased antioxidative capacity in rat with myocardial ischemia reperfusion (I/R) injury. METHODS: The myocardial I/R model was made by left coronary artery ligation for 30min and reperfusion for 120min in rats. Myocardial infarct size and plasma lactate dehydrogenase (LDH) and creatine kinase (CK) activities, plasma superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and glutathione (GSH) changes were detected for the rats. The contents of myocardial hydrogen sulfide (H2S) and nitric oxide (NO) were measured. Myocardial protein expressions of SOD1, SOD2, cystathionine gamma-lyase (CSE) and iNOS were tested using Western blot. RESULTS: Myocardial infarction developed and plasma CK and LDH activities were significantly increased in I/R group compared with those in control group, but SO2 preconditioning significantly reduced myocardial infarct size, and plasma CK and LDH activities. SO2 preconditioning successfully increased plasma SOD, GSH and GSH-Px levels and myocardial SOD1 protein expression, but decreased MDA level in rats of I/R group. Compared with controls, the myocardial H2S level and CSE expression were decreased after I/R, but myocardial NO level and iNOS expression were increased. With the treatment of SO2, myocardial H2S level and CSE expression were increased, but myocardial NO level and iNOS expression were decreased compared with those in I/R group. CONCLUSIONS: SO2 preconditioning could significantly reduce I/R-induced myocardial injury in vivo in association with increased myocardial antioxidative capacity, upregulated myocardial H2S/CSE pathway but downregulated NO/iNOS pathway. PMID- 23629153 TI - Endothelium dysfunction classification: keeping the discussion opened. PMID- 23629154 TI - The 'Jedward' versus the 'Mohawk': a prospective study on a paediatric distraction technique. AB - OBJECTIVE: To examine the use of a standard hospital glove, inflated as a balloon with a face drawn on it, as a distraction technique in children with an acute injury. METHODS: We designed a study to assess the 'best' way to orientate the glove when drawing a face on it. A prospective study was performed in the authors' institution, where all children between the ages of 2 and 8 years presenting during the study period were given the option of playing with one of two glove balloons with a face drawn on it in two different ways. RESULTS: 149 paediatric patients were assessed, of whom 136 picked a glove, 75 picked the 'Jedward' version and 61 the 'Mohawk' version. CONCLUSIONS: A standard hospital glove, inflated as a balloon with a face drawn on it, is a useful distraction for children with an acute injury. The face drawn should be drawn 'Jedward' style. PMID- 23629155 TI - An all-cotton-derived, arbitrarily foldable, high-rate, electrochemical supercapacitor. AB - The pure natural cotton provides a low-cost material platform for the facile assembly of all-cotton-derived electrochemical supercapacitors (allC-ECs) with a remarkable character of arbitrary foldability and high response rate, which can be bent, rolled-up, and fully folded without loss of high-rate (<50 ms) capacitive performance. PMID- 23629157 TI - Manipulating non-innocent pi-spacers: the challenges of using 2,6-disubstituted BODIPY cores within donor-acceptor light-harvesting motifs. AB - The syntheses and physicochemical properties for a series of 2,6-disubstituted 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes are reported. The use of chromophores or redox active species as pi-spacers, such as BODIPY, requires the inclusion of a sufficiently conjugated donor in order to achieve appropriate charge separation upon photoexcitation. The information derived from this study offers guiding principles for incorporating strongly absorbing, non-innocent pi spacers in organic dye design. PMID- 23629158 TI - Exploring the sampling universe of RNA-seq. AB - How deep is deep enough? While RNA-sequencing represents a well-established technology, the required sequencing depth for detecting all expressed genes is not known. If we leave the entire biological overhead and meta-information behind we are dealing with a classical sampling process. Such sampling processes are well known from population genetics and thoroughly investigated. Here we use the Pitman Sampling Formula to model the sampling process of RNA-sequencing. By doing so we characterize the sampling by means of two parameters which grasp the conglomerate of different sequencing technologies, protocols and their associated biases. We differ between two levels of sampling: number of reads per gene and respectively, number of reads starting at each position of a specific gene. The latter approach allows us to evaluate the theoretical expectation of uniform coverage and the performance of sequencing protocols in that respect. Most importantly, given a pilot sequencing experiment we provide an estimate for the size of the underlying sampling universe and, based on these findings, evaluate an estimator for the number of newly detected genes when sequencing an additional sample of arbitrary size. PMID- 23629385 TI - Scab-inspired cytophilic membrane of anisotropic nanofibers for rapid wound healing. AB - This work investigates the influence of cytophilic and anisotropic nanomaterials on accelerated cell attachment and directional migration toward rapid wound healing. Inspired by the anisotropic protein nanofibers in scab, a polyurethane (PU) nanofibrous membrane with an aligned structure was fabricated. The membrane showed good affinity for wound-healing-related cells and could guide cell migration in the direction of PU nanofibers. Also, the morphology and distribution of F-actin and paxillin of attached cells were influenced by the underlying nanofibers. The randomly distributed PU nanofibers and planar PU membrane did not show a distinct impact on cell migration. This scab-inspired cytophilic membrane is promising in applications as functional interfacial biomaterials for rapid wound healing, bone repair, and construction of neural networks. PMID- 23629159 TI - Efavirenz-mediated induction of omeprazole metabolism is CYP2C19 genotype dependent. AB - Efavirenz increases CYP2C19- and CYP3A-mediated omeprazole metabolism. We hypothesized that CYP2C19 and CYP2B6 genetic polymorphisms influence the extent of induction of omeprazole metabolism by efavirenz. Healthy subjects (n=57) were administered a single 20 mg oral dose of omeprazole on two occasions: with a single 600 mg efavirenz dose; and after a 17-day treatment with efavirenz (600 mg per day). DNA was genotyped for CYP2C19*2, *3 and *17 alleles and CYP2B6*6, *4 and *9 alleles using Taqman assays. Omeprazole, its enantiomers and metabolites were measured by liquid chromatography/tandem mass spectrometry. Our results showed that efavirenz increased omeprazole clearances in all CYP2C19 genotypes in non-stereoselective manner, but the magnitude of induction was genotype dependent. Metabolic ratios of 5-hydroxylation of omeprazole were reduced in extensive and intermediate metabolizers of CYP2C19 (P<0.05). No significant associations were observed between CYP2B6 genotypes and induction by efavirenz on omeprazole metabolism. Our data indicate how interplays between drug interactions and CYP2C19 genetic variations may influence systemic exposure of CYP2C19 substrates. PMID- 23629386 TI - Confessed abusive blunt head trauma. AB - It is generally accepted that terms referring to specific craniocerebral injury mechanisms must be replaced by the more general term abusive head trauma (AHT). Although blunt impact trauma remains an essential part of AHT, it has received far less attention in the literature than shaken-impact injuries. The current article presents 19 confessed cases of a series of 47 highly suspected AHT cases. Of these, 13 were confessed shaken-impact cases, and the other 6 confessed blunt trauma cases. There were no significant differences in the appearance of subdural hematoma, which was present in each case. Retinal hemorrhage, which was present in 10 of the 13 shaken-impact cases in which an ophthalmologic examination was conducted, occurred in 2 of the 6 blunt trauma cases. In 1 case, retinal hemorrhage probably had of metabolic origin. Skull fractures with an overlying subgaleal hematoma and a subdural hematoma below the fracture side were found in 5 of the blunt trauma cases but was also seen in the 2 shaken-impact cases with a skull fracture. The most important finding was a lucid interval (LI) in 3 blunt AHT cases. An LI does not seem to occur in shaking injuries because of the immediate and persistent effect of brain damage that such injuries involve. Therefore, LI makes it important to conduct a detailed investigation of the clinical course in time in suspected AHT cases. PMID- 23629387 TI - The importance of an anthropological scene of crime investigation in the case of burnt remains in vehicles: 3 case studies. AB - Inspection of a crime scene is a crucial step in forensic medicine, and even the methods taught by forensic anthropology are essential. Whereas a thorough inspection can provide crucial information, an approximate inspection can be useless or even harmful. This study reports 3 cases of burnt bodies found inside vehicles between 2006 and 2009 in the outskirts of Milan (Italy). In all 3 cases, the victim was killed by gunshot, and the body was burnt in the vehicle to destroy signs of skeletal injury and prevent identification. In every case, the assistance of forensic anthropologists was requested, but only after the inspection of the body at autopsy showed that the remains were incomplete, thus making it more difficult to determine the identity, cause, and manner of death. A second scene of crime inspection was therefore performed with strict anthropological and adapted archeological methods by forensic anthropologists to perform a more complete recovery, proving how much material had been left behind. These cases clearly show the importance of a proper recovery and of the application of forensic anthropology methods on badly charred bodies and the importance of recovering every fragment of bone: even the smallest fragment can provide essential information. Thus, a precise coordination, a correct and thorough recovery of bone fragments, and an anthropological approach are crucial for many issues: analysis of the scene of crime, reconstruction of the corpse, and reconstruction of the perimortem events. PMID- 23629388 TI - Could postmortem hemorrhage occur in the brain?: a preliminary study on the establishment and investigation of postmortem hypostatic hemorrhage using rabbit models. AB - OBJECTIVE: The aim of this study was to explore whether postmortem hemorrhage can occur in brain tissue using rabbit models. METHODS: The rabbits killed by air embolism were randomly divided into the horizontal-position group and the upside down group. Autopsy was performed after 48 hours, and the brains were investigated with macroscopic assessment and histologic examination. RESULTS: Macroscopically, congestion of vessels on the surface of the brain was identified in all the subjects in both groups. Microscopically, the presence of multifocal extravascular red blood cell aggregation was observed in brain parenchyma and subarachnoid space in the upside-down group. In contrast, no leakage of extravascular red blood cells was observed in the brain parenchyma and the subarachnoid space in the horizontal-position group. CONCLUSIONS: Hypostatic and leakage bleeding can occur in sites of subarachnoid space and brain parenchyma of rabbits after death by nonforce with a certain period and certain position of the placement. This type of hemorrhage is challenging to differentiate from traumatic hemorrhage in pathologic practice. To avoid misdiagnosis, the clinical pathologists should keep in mind that the possibility of postmortem hypostatic hemorrhage needs to be ruled out when the diagnosis of subarachnoid hemorrhage or cerebral hemorrhage is established. PMID- 23629389 TI - Death due to eosinophilic necrotizing myocarditis despite steroid treatment. AB - We report a case of a 16-year-old boy who was treated for a suspected dental infection with a tooth extraction and amoxicillin therapy. The decedent developed a rash and presented to the emergency department with what was thought to be a possible allergic reaction to amoxicillin despite completion of the antibiotic course. The patient was given a course of prednisone. Several weeks later, while still completing the course of prednisone, the patient experienced shortness of breath and collapsed. Resuscitation efforts were unsuccessful. Postmortem examination revealed a necrotizing eosinophilic myocarditis. This case reveals that despite steroid therapy, a patient may still die of eosinophilic myocarditis. PMID- 23629390 TI - Intracranial segmental arterial mediolysis: report of 2 cases and review of the literature. AB - Extensive nontraumatic subarachnoid hemorrhage is an important cause of unexpected death in young adults. Segmental arterial mediolysis (SAM) represents an uncommon pathologic finding in the intracranial blood vessels associated with this type of hemorrhage. Segmental arterial mediolysis is a pathologic entity with putative vasospastic etiology, which recently has been reported to be associated with Ehlers-Danlos syndrome type 4. We describe 2 additional cases of ruptured intracranial vertebral artery with features of SAM that resulted in fatal subarachnoid hemorrhage. We also review the literature on vessels with features of SAM that are either intracranial or affecting the internal carotid artery with major direct effects (ie, stroke or transient ischemic attack) on the central nervous system. PMID- 23629391 TI - Spontaneous acute aortic dissection in pregnancy: report of a case devoid of known risk factors. AB - Acute aortic dissection in pregnancy is a rare condition with a potentially catastrophic outcome. The low rate of incidence together with variable presenting features in such circumstances makes diagnosis elusive. A high degree of clinical suspicion and diagnostic acumen is especially required in pregnant women without any history of connective tissue disorder, congenital aortic valvular malformation, or chronic hypertension. In this report, we present a case of aortic dissection with multiple aortic intimal tears in a medicolegal autopsy of a young pregnant woman who developed circulatory collapse and died during labor. PMID- 23629392 TI - Demonstration control agents: evaluation of 64 cases after massive use in Istanbul. AB - An uncontrolled use of "demonstration control agents" commonly known as "teargas agents" has recently been a common practice in Turkey. One of the first massive uses of these agents had been during a meeting of the North Atlantic Council and NATO in 2004, in Istanbul. After the demonstrations, 64 patients were evaluated and treated by the Human Rights Foundation of Turkey. Their files have been reviewed retrospectively and were classified regarding age, sex, physical findings related of chemical agents, and other injuries.The patients were received 1 to 9 days after the chemical gas exposure. The maximum referral was 35 patients on the day of the gas exposure. The last application was 9 days after the exposure. Complaints and physical findings/symptoms were highest during the first 3 days.This study has been carried out to reveal the short- and long-term aftereffects of "demonstration control agents." The safety and effects of these agents are discussed in this article, based on our findings and existing references. PMID- 23629393 TI - Should postmortem subclavian blood be considered a peripheral or central sample? AB - The phenomenon of postmortem redistribution has long been described, but the processes driving it have not, as yet, been fully elucidated. Peripheral blood samples are currently used, when available, in an effort to minimize the effects of postmortem redistribution on drug concentrations, but what sources of blood are peripheral sources? A study was undertaken to determine if postmortem subclavian (SC) blood should be considered a peripheral or central blood sample. Twenty-eight cases were identified in which drugs were quantified in at least 2 of the following blood sources: femoral (F), SC, and heart (H); the concentrations found in each source were compared. Twenty different drugs were analyzed including 6 antidepressants, 6 opioid medications and metabolites, 3 benzodiazepines, 2 antihistamines, 2 sedative hypnotics, and 1 muscle relaxant. Analysis found that SC blood concentrations reflect neither F nor H blood concentrations, with the exception of the benzodiazepines where SC blood concentrations closely mirrored H blood concentrations. Overall, SC blood drug concentrations tended to be 1.3 times greater than F blood and 0.77 times less than H blood. Therefore, it is recommended that the exact source of the blood, rather than simply "peripheral" or "central," be notated on toxicology results to ensure appropriate interpretation. PMID- 23629394 TI - Suicide due to four speargun shots: a case report. AB - In the literature, only a few cases of deaths related to the use of atypical firearms are present and even more rare are cases of suicide due to multiple lesions.In the present case, the authors report a rare occurrence of suicide due to 4 speargun shots, 3 to the chest and 1 to the head.A complete forensic approach led to attribute the death to acute cardiac failure due to hemopericardium after the injury of the left coronary artery.Scene investigation and autoptic findings allowed authors to hypothesize that injury to the head was a last attempt of suicide, elapsed during the progression of cardiac tamponade.With this report, the authors would like to share knowledge with the forensic community about speargun-related lesions distinguishing them from the very similar ones produced by cold steels.It also shows how it is possible to survive for some time after being shot by such a weapon. PMID- 23629395 TI - Vallecular rupture with cervical spine fracture after a failed hanging suicide attempt. AB - Hanging is a common method of suicide. We present a case of vallecular rupture and cervical spine fracture without an external wound after a failed hanging suicide attempt. Surgical treatment involved posterior fusion of C2 to 3, followed by repair of the vallecular rupture via an external approach. The patient recovered with no residual physical or mental sequelae. PMID- 23629396 TI - Gunshot deaths in Geneva, Switzerland: 2001 to 2010. AB - We have conducted a retrospective study of all gunshot deaths that occurred in Geneva, Switzerland, over a 10-year period (2001-2010). The 133 cases reviewed were classified according to the manner of death, that is, suicide (106 cases), homicide (25 cases), and accident (2 cases). Various data from police authorities and the medicolegal examinations of the bodies were studied, including the age and sex of the victims, location of the event, type of firearm used, concomitant use or nonuse of alcohol and/or other drugs, seasonality, and entry site. These various elements were compared with data found in the literature. PMID- 23629397 TI - Virtual autopsy in hanging. AB - The aim of the study was to compare postmortem computed tomographic (CT) imaging findings from a case of hanging with the autopsy findings. The CT showed a good match with autopsy findings especially for bone, soft tissue, and spinal injuries. The CT images of the injuries of the neck obtained by CT scan clearly showed the ligature mark, the hemorrhagic suffusion in the soft tissue (thickening of derma) and in the muscles (sternocleidomastoid) of the neck. Furthermore, CT 3-dimensional reconstruction showed brain edema, fracture of the left posterior horn of the hyoid bone, and a grade 1 retrolisthesis of C5 on C6. This last finding was not detected by autopsy because of the anterior approach that is frequently used in necropsy technique. Nevertheless, the CT virtual autopsy did not show vascular findings (like Amussat mark) because a barium mixture was not injected in the body. PMID- 23629398 TI - Giant cell interstitial pneumonia: an unusual finding in a case of preoperative death. AB - Giant cell interstitial pneumonia (GIP) is an exceedingly rare, debatable, perplexing, occupational lung disease, which most commonly affects individuals exposed to hard metal dust. We report a case of GIP in a 60-year-old man, scheduled for coronary artery bypass graft surgery and died during induction of general anesthesia despite all efforts to resuscitate him. Patient's relatives lodged complaint with the police alleging the negligence by the attending physicians. Despite inaccessible data pertaining to the occupation, clinical history, and radiographic findings, the diagnosis was GIP due to the presence of intra-alveolar, bizarre, "cannibalistic" multinucleated giant cells-the histologic sine qua non of GIP. To the best of our knowledge, this is the first case report of GIP in the world literature that was diagnosed on histopathologic examination of lung tissue obtained at medicolegal autopsy. PMID- 23629399 TI - Fatal barium chloride poisoning: four cases report and literature review. AB - Barium is an alkaline earth metal which has a variety of uses including in the manufacturing industry and in medicine. However, adverse health effects and fatalities occur due to absorption of soluble barium compounds, notably the chloride, nitrate, and hydroxide, which are toxic to humans. Although rare, accidental and suicidal modes of poisoning are sporadically reported in the literature.We describe 4 cases of poisoning due to barium chloride in China. In witnessed cases, severe gastrointestinal symptoms, hypokalemia leading to muscle weakness, cardiac arrhythmias, and respiratory failure were noted. Autopsy showed some nonspecific but common findings, such as subendocardial hemorrhage in the ventricles, visceral petechiae, and fatty changes in the liver. Interestingly, microscopic examination showed degenerative changes and amorphous, flocculent foamy materials in the renal tubules. Toxicology was relevant for barium in blood and tissues. Three of the cases were accidental and 1 homicidal in nature. A round-up of relevant literature on fatal barium compounds poisoning is also provided. Forensic pathologists should be aware of the clinical presentations of barium compound poisoning and especially look for any evidence of hypokalemia. Still, postmortem toxicological and histological studies are essential for an accurate identification of the cause of death. PMID- 23629400 TI - Fatality in a wine vat. AB - Intoxication with carbon dioxide (CO2), a nonexplosive, colorless, and odorless gas does not cause any clinical symptoms or signs, with the occasional exception of sudation. Carbon dioxide is principally used in the food industry (70% of CO2 production), in particular to preserve foods and to carbonate beverages. Most fatalities resulting from CO2 intoxication are accidental and occur either in closed spaces or when dry ice is used in the food industry. In this case report, a 42-year-old male winemaker engineer was found dead, his head inside a wine vat that had been filled with grapes on the previous day and supplemented with dry ice to improve the taste of wine. PMID- 23629401 TI - Retinal hemorrhage after cardiopulmonary resuscitation with chest compressions. AB - Retinal hemorrhages in children in the absence of risk factors are regarded to be pathognomonic of shaken baby syndrome or other nonaccidental injuries. The physician must decide whether the retinal hemorrhages in children without risk factors are due to abuse or cardiopulmonary resuscitation with chest compression (CPR-CC). The objective of this study was to determine if CPR-CC can lead to retinal hemorrhages in children. Twenty-two patients who received in-hospital CPR CC between February 15, 1990, and June 15, 1990, were enrolled. Pediatric ophthalmology fellows carried a code beeper and responded to calls for cardiopulmonary arrest situations. At the scene of CPR-CC, an indirect funduscopic examination was conducted for presence of retinal hemorrhages in the posterior pole. Follow-up examinations were performed at 24 and 72 hours. Of the 22 patients, 6 (27%) had retinal hemorrhages at the time of CPR-CC. Of these 6 patients, 5 had risk factors for retinal hemorrhages. The sixth patient had no risk factors and may have represented the only true case of retinal hemorrhages due to CPR-CC. Retinal hemorrhages are uncommon findings after CPR-CC. Retinal hemorrhages that are found after CPR-CC usually occur in the presence of other risk factors for hemorrhage with a mild hemorrhagic retinopathy in the posterior pole. PMID- 23629402 TI - Identification of forensically important Sarcophagidae (Diptera) based on partial mitochondrial cytochrome oxidase I and II genes. AB - Entomological evidence is of great importance in forensic cases for postmortem interval calculation. The use of Sarcophagidae (Diptera) for postmortem interval estimation is limited because morphological determination is often hampered because of similar characteristics in the larval, pupal, and even adult stage. To make the species identification more accurate and reliable, DNA-based identification is considered. In this study, we assessed the use of partial mitochondrial cytochrome oxidase I and II genes for discrimination of forensically important Sarcophagidae from Egypt and China [Sarcophaga argyrostoma (Robineau-Desvoidy), Sarcophaga dux (Thomson), Sarcophaga albiceps (Meigen), and Wohlfahrtia nuba (Wiedemann)]. This region was amplified using polymerase chain reaction followed by direct sequencing of the amplification products and using restriction enzymes HinfI and MfeI. Nucleotide sequence divergences were calculated using the Kimura 2-parameter distance model, and a neighbor-joining phylogenetic tree was generated. All examined specimens were assigned to the correct species. Combinations of the restriction enzymes HinfI and MfeI provide different restriction fragment length polymorphism profiles even among 3 sympatric species that belong to the Sarcophaga genus. Therefore, this study demonstrates that the studied partial mitochondrial cytochrome oxidase I and II genes were found to be instrumental for the molecular identification of these forensically important flesh fly species. PMID- 23629403 TI - Florid bronchial cartilage ossification: a case report with literature revisited. AB - Pulmonary ossification is a rare phenomenon which has been observed in the lungs of patients with chronic obstructive pulmonary disease, pulmonary fibrosis, and tuberculosis. It has also been observed as a part of aging process. Approximately 130 cases of pulmonary ossification have been reported in literature so far. We report here an unusual autopsy case of bone and bone marrow metaplasia in the bronchial wall and discuss theories related to the development of metaplastic ossification. PMID- 23629404 TI - Mortality in black esophagus. PMID- 23629405 TI - Deaths due to sharp force injuries in Bexar County, Texas, with respect to manner of death. AB - In the United States, there is a paucity of studies examining sharp force injuries (SFIs), defined as an injury inflicted by cutting or stabbing with a sharp instrument. Few studies exist that discriminate between the injury patterns of suicidal or homicidal deaths incurred by SFI. In this retrospective study, all deaths secondary to SFI were evaluated at the Bexar County Medical Examiner's Office from January 1988 through May 2010. Exclusion criteria were deaths occurring more than 24 hours after injury and wounds obscured by healing or extensive medical intervention. The following data were analyzed: age of decedent, sex, wound location, number of wounds, type of SFI (stab vs incised), visceral organ or vascular injury, concomitant injuries, and manner of death. Defensive injuries in homicides and hesitation marks in suicides were also recorded. A total of 418 deaths met inclusion criteria: 349 homicides, 54 suicides, 12 accidents, and 2 where the manner of death could not be determined.The average age of homicide victims was 35 years, whereas that of suicide victims was 47 years. Gender was not significantly different between the homicide and suicide groups. Homicide victims incurred a greater number of wounds per case compared with suicides, 5.3 versus 4.1, respectively, and had a greater number of stab wounds, 3.3 per case compared with 0.7 per case, respectively. Incisional wounds were statistically greater in suicides, with an average number of 3.3 per case compared with 2.1 in homicides.Injuries to the head, chest, and back were more common in homicides when compared with suicides, whereas injuries to the abdomen and extremities were more frequent in suicides. Comparison of major visceral and vascular damage between homicides and suicides revealed statistically greater injury to the heart, lungs, and thoracic vessels in homicides, but there was a greater frequency of injury to the vasculature of the extremities in suicides. The presence of additional (non-SFI) injuries was more common in homicides than in suicides. Hesitation marks/tentative wounds occurred in 35% of suicides, whereas defensive injuries occurred in 31% of homicides. This epidemiological study can assist the forensic pathologist in determining the most probable manner of death from SFI but does not substitute for a thorough examination of the circumstances of death and a meticulous autopsy. PMID- 23629406 TI - Undiagnosed primary cardiac liposarcoma in an adult: a case report and review of the literature. AB - Well-differentiated liposarcomas are locally aggressive malignant mesenchymal neoplasms, which rarely metastasize to the heart and pericardium. Primary cardiac liposarcomas are extremely rare as well, and in both instances, symptoms are difficult to recognize. Therefore, accurate antemortem diagnosis seldom happens. A rare case of an undiagnosed, primary, well-differentiated cardiac liposarcoma is presented, in a 67-year-old man who suffered a sudden cardiac death. The tumor seemed to arise from the epicardium of the left ventricle and expand into the myocardium of the left ventricle and intraventricular septum. Macroscopic and histopathological findings are presented, as well as a short review of current literature. PMID- 23629407 TI - "Dead in hot bathtub" phenomenon: accidental drowning or natural disease? AB - Sudden death in a hot bathtub occurs frequently in Japan, particularly among elderly people. This retrospective report describes the epidemiologic circumstances and physical findings at autopsy. In total, 268 victims were found unconscious or dead during tub bathing. After postmortem examination, the manner of death was judged as natural cause in 191 (71.2%) and accidental drowning in 63 (23.5%) cases. Mean age (SD) was 72.1 (15.2) years with no significant difference between males and females. A seasonal difference was evident: the winter displayed the highest frequency. Drowning water inhalation, which was confirmed in 72% of victims, was absent in the others. The most common observations on postmortem examination were cardiac ischemic changes and cardiomegaly. Water inhalation signs were evident in a significantly fewer victims exhibiting these factors. In contrast, inhalational findings were observed more frequently in victims with other backgrounds such as alcohol intake, mobility disturbance, and history of epilepsy. Annual mortality in Japan from accidental drowning in persons aged older than 75 years is 33 deaths per 100,000 population. However, this number may be considerably underestimated as pathologists tend to regard lack of water inhalation as indicating a natural cause of death. Confusion in diagnosis remains consequent to the accidental and natural aspects of "dead in hot bathtub" phenomenon. PMID- 23629408 TI - Correlations between CCN1 immunoexpression and myocardial histologic lesions in sudden cardiac death. AB - CCN1 (CYR61) is a member of the CCN family of secreted matricellular proteins; it can regulate the expression of genes involved in angiogenesis and matrix remodeling. The latter mechanisms seem to be of vital importance in the pathophysiology of sudden cardiac death. We performed an immunohistochemical analysis on 62 cardiac tissue specimens derived from individuals of young and middle age who had died of sudden cardiac death. CCN1 immunopositivity was detected in 80.6% of all specimens. Semiquantitative statistical analysis of the staining results revealed that CCN1 immunoreactivity was significantly associated with ischemic morphology and hypertrophy of myocardial fibers, interstitial edema, and atheromatosis of coronary arteries in more than 10% of the myocardial fibers. Taking the previously mentioned correlations into account, ischemia seems to induce myocardial expression of CCN1; therefore, CCN1 immunostaining could be evaluated as a complementary tool in the assessment of ischemic areas when no tissue evidence of necrosis is available. PMID- 23629409 TI - Acute necrotizing large vessel arteritis in a newborn: a case report and review of the literature. AB - Acute arteritis of the aorta and the main pulmonary arteries is unusual in a newborn. This type of vasculitis should be described as a separate entity. There are many differences between this entity and polyarteritis nodosa or Takayasu disease. Moreover, neither Takayasu disease nor polyarteritis nodosa and other forms of classic primary large vessels vasculitis have been reported in a neonate until now. The presence of chronic inflammation, fibrosis, and calcification would suggest that this process had been present before birth.We report a 27-day old newborn with acute necrotizing aortitis. The feature of this entity is not those of any of the classic entities described in infants or children. PMID- 23629410 TI - Reanalysis of Richter et al. (2010) on reproducibility. PMID- 23629411 TI - Does systematic variation improve the reproducibility of animal experiments? PMID- 23629412 TI - Reply to: "Reanalysis of Richter et al. (2010) on reproducibility". PMID- 23629413 TI - Exploring long-range genome interactions using the WashU Epigenome Browser. PMID- 23629414 TI - PCR: living life amplified and standardized. PMID- 23629415 TI - Scaling up the systematic hunt for mammalian genetic interactions. PMID- 23629416 TI - Inner-outer beauty: DNA-binding surface tags as cellular barcodes. PMID- 23629417 TI - Pathological gambling in X-linked dystonia Parkinsonism. PMID- 23629418 TI - Visible light-harvesting trans bis(alkylphosphine) platinum(II)-alkynyl complexes showing long-lived triplet excited states as triplet photosensitizers for triplet triplet annihilation upconversion. AB - Symmetric and asymmetric linear trans-bis(tributylphosphine) Pt(II) bis(acetylide) complexes with functionalized aryl alkynyl ligands (coumarin, naphthalimide and phenyl acetylides) were prepared, which show enhanced absorption in the visible region (molar absorption coefficients up to 76,800 M( 1) cm(-1) at 459 nm) and long-lived triplet excited states (up to 139.9 MUs). At room temperature, the naphthalimide acetylide-phenyl acetylide complex (Pt-4) shows dual emission (fluorescence-phosphorescence), whereas other complexes show only fluorescence emission. The triplet excited states of the complexes were studied with nanosecond time-resolved transient difference absorption spectroscopy and DFT calculations on the spin density surface. The complexes were used as triplet photosensitizers for ratiometric O2 sensing, as well as triplet triplet annihilation (TTA) upconversion (upconversion quantum yield up to 27.2%). The TTA upconversion of the complexes requires triplet acceptors with different T1 state energy levels and was studied with nanosecond time-resolved emission spectroscopy. Our results are useful for designing new Pt(II) complexes that show strong absorption of visible light and long-lived triplet excited states, as well as for the application of these complexes as triplet photosensitizers for O2 sensing, photocatalysis and TTA upconversion. PMID- 23629419 TI - Polar biophenolics in sweet potato greens extract synergize to inhibit prostate cancer cell proliferation and in vivo tumor growth. AB - Polyphenolic phytochemicals present in fruits and vegetables indisputably confer anticancer benefits upon regular consumption. Recently, we demonstrated the growth-inhibitory and apoptosis-inducing properties of polyphenol-rich sweet potato greens extract (SPGE) in cell culture and in vivo prostate cancer xenograft models. However, the bioactive constituents remain elusive. Here, we report a bioactivity-guided fractionation of SPGE based upon differential solvent polarity using chromatographic techniques that led to the identification of a remarkably active polyphenol-enriched fraction, F5, which was ~100-fold more potent than the parent extract as shown by IC50 measurements in human prostate cancer cells. High-performance liquid chromatography-ultraviolet and mass spectrometric analyses of the seven SPGE fractions suggested varying abundance of the major phenols, quinic acid (QA), caffeic acid, its ester chlorogenic acid, and isochlorogenic acids, 4,5-di-CQA, 3,5-di-CQA and 3,4-di-CQA, with a distinct composition of the most active fraction, F5. Subfractionation of F5 resulted in loss of bioactivity, suggesting synergistic interactions among the constituent phytochemicals. Quantitative analyses revealed a ~2.6- and ~3.6-fold enrichment of QA and chlorogenic acid, respectively, in F5 and a definitive ratiometric relationship between the isochlorogenic acids. Daily oral administration of 400mg/kg body wt of F5 inhibited growth and progression of prostate tumor xenografts by ~75% in nude mice, as evidenced by tumor volume measurements and non-invasive real-time bioluminescence imaging. These data generate compelling grounds to further examine the chemopreventive efficacy of the most active fraction of SPGE and suggest its potential usefulness as a dietary supplement for prostate cancer management. PMID- 23629420 TI - Community intervention to prevent child maltreatment in England: evaluating the contribution of the Family Nurse Partnership. AB - BACKGROUND: The Government in England has recognized the importance of early intervention to promote positive child development and prevent maltreatment. In doing so, efforts have been made to increase the implementation of the Family Nurse Partnership (FNP) to target a greater number of families who require intensive secondary intervention. METHODS: This paper presents an argument that the FNP can be targeted more effectively to yield a greater return on investment. This is based on the re-analysis of data collected by the largest cohort study carried out into risk factors for child maltreatment in England. RESULTS: Currently, around 315 health visitors are estimated to be implementing this programme, projected to increase to around 585 health visitors in 2015. However, targeting the programme towards first-time, young vulnerable mothers with low socio-economic status means that around 1350 health visitors would be needed. Critically, targeting only this population is estimated to prevent only 10% of cases of child abuse and neglect. CONCLUSIONS: By targeting risk factors which are less common in the general population but which are more prevalent amongst abusive families, fewer specialist health visitors would be needed to prevent a higher percentage of child maltreatment. PMID- 23629421 TI - Functional analysis of duplicated genes and N-terminal splice variant of phospholipase C-delta1 in Paralichthys olivaceus. AB - Phosphoinositide-specific phospholipase C delta (PLC delta) plays an important role in many cellular responses and is involved in the production of second messenger. Here, we describe the presence of novel N-terminal extended alternative splice form of PLC-delta1B in Paralichthys olivaceus, which differs from the reported mammalian PLC-delta1 isoform. The two variants PoPLC-delta1B-Lf and PoPLC-delta1B-Sf share exon 3 (including the PH domain) to exon 16, but differ at the exon 1 (Short form: Sf) and novel exon 2 (Long form: Lf) of the transcript. For the characterization of the novel duplicated gene variant of PLC delta1B in P. olivaceus, tissue-specific expression with RT-PCR and real-time PCR, and purification and enzymatic characterization of native and recombinant proteins of all the three-types of PLC-delta1 isoforms (PoPLC-delta1A, PoPLC delta1B-Lf and PoPLC-delta1B-Sf) of P. olivaceus were studied. The PoPLC-delta1A was ubiquitously distributed in gill, kidney and spleen. The PoPLC-delta1B-Lf gene was widely detected in various tissues, especially in the digestive system, while PoPLC-delta1B-Sf was highly expressed in the stomach. The recombinant PoPLC delta1A, PoPLC-delta1B-Lf and PoPLC-delta1B-Sf proteins were expressed as a histidine-tagged fusion protein in Escherichia coli. The PLC activity of the PoPLC-delta1 isoform proteins showed a concentration-dependent activity to phosphatidylinositol (PI) and phosphatidylinositol 4,5-bisphosphate (PIP(2)). In addition, U73122, the PLC inhibitor, effectively inhibited PLC activities of PoPLC-delta1A, PoPLC-delta1B-Lf and PoPLC-delta1B-Sf proteins. However, PoPLC delta1A and PoPLC-delta1B-Lf were sensitive at pH 7.5, while PoPLC-delta1B-Sf was relatively sensitive at pH 7. These results might be useful for the study of phospholipase C-mediated signal transduction in fish. PMID- 23629422 TI - Prekallikrein deficiency. AB - Nurses often encounter abnormal laboratory assays that require them to investigate further to ensure that appropriate patient care is provided. A prolonged activated partial thromboplastin time (PTT) with a normal prothrombin time (PT) assay demand further examination, to rule out laboratory error or bleeding disorders. Prekallikrein deficiency is a rare coagulation deficiency that presents itself with a prolonged PTT and a normal PT. It was first identified in 4 of the 11 Fletcher family children in 1965, coincidentally when one of the Fletcher children was undergoing a workup for an adenoidectomy. Both the Fletcher parents had normal coagulation laboratory assays with no history of bleeding tendencies. The term Fletcher factor deficiency was used until Fletcher factor was later identified as plasma prekallikrein. A prekallikrein deficiency is inherited as an autosomal recessive trait. The purpose of this article is to provide a basic review for nurses on hemostasis, identify the 6 causes of a prolonged PTT with a normal or slightly prolonged PT, and to present 2 recently diagnosed adult cases, not previously reported in the medical literature. PMID- 23629423 TI - Fluence correction factors for graphite calorimetry in a low-energy clinical proton beam: I. Analytical and Monte Carlo simulations. AB - The conversion of absorbed dose-to-graphite in a graphite phantom to absorbed dose-to-water in a water phantom is performed by water to graphite stopping power ratios. If, however, the charged particle fluence is not equal at equivalent depths in graphite and water, a fluence correction factor, kfl, is required as well. This is particularly relevant to the derivation of absorbed dose-to-water, the quantity of interest in radiotherapy, from a measurement of absorbed dose-to graphite obtained with a graphite calorimeter. In this work, fluence correction factors for the conversion from dose-to-graphite in a graphite phantom to dose-to water in a water phantom for 60 MeV mono-energetic protons were calculated using an analytical model and five different Monte Carlo codes (Geant4, FLUKA, MCNPX, SHIELD-HIT and McPTRAN.MEDIA). In general the fluence correction factors are found to be close to unity and the analytical and Monte Carlo codes give consistent values when considering the differences in secondary particle transport. When considering only protons the fluence correction factors are unity at the surface and increase with depth by 0.5% to 1.5% depending on the code. When the fluence of all charged particles is considered, the fluence correction factor is about 0.5% lower than unity at shallow depths predominantly due to the contributions from alpha particles and increases to values above unity near the Bragg peak. Fluence correction factors directly derived from the fluence distributions differential in energy at equivalent depths in water and graphite can be described by kfl = 0.9964 + 0.0024.zw-eq with a relative standard uncertainty of 0.2%. Fluence correction factors derived from a ratio of calculated doses at equivalent depths in water and graphite can be described by kfl = 0.9947 + 0.0024.zw-eq with a relative standard uncertainty of 0.3%. These results are of direct relevance to graphite calorimetry in low-energy protons but given that the fluence correction factor is almost solely influenced by non elastic nuclear interactions the results are also relevant for plastic phantoms that consist of carbon, oxygen and hydrogen atoms as well as for soft tissues. PMID- 23629425 TI - [The significance of antiphospholipid antibodies tests]. AB - Antiphospholipid syndrome (APS) is an autoimmune disease defined by the presence of antiphospholipid antibodies (APL) in plasma of patients with thrombosis and/or pregnancy morbidity. In the classification criteria of APS, the presence of lupus anticoagulant (LA), anticardiolipin antibodies (aCL) or anti-beta2-glycoprotein I antibodies (abeta2GPI) is necessary to diagnose APS. Recently, we defined "antiphospholipid score (aPL-S)" and evaluate the predictive value for thrombosis. In the study, aPL-S may be a predictive marker for developing thrombosis in patients with autoimmune diseases. In this article, we explain various APL assays for diagnosing APS in a clinical practice, introduce the study of "aPL-S", and discuss the significance of APL tests not only for a diagnosis of APS but also for a predictive marker of thrombosis in patients with autoimmune diseases. PMID- 23629426 TI - [Anti-MDA5 (melanoma differentiation-associated gene 5) antibody and dermatomyositis with rapidly progressive interstitial pneumonia]. AB - Anti-MDA5 antibody is one of the dermatomyositis-specific autoantibodies and anti MDA5-potsitive patients show characteristic clinical features, such as hypomyositis, high prevalence of acute/subacute interstitial pneumonia (A/SIP) with poor prognosis, hyperferritinemia and elevated hepatobiliary enzyme. We found that serum IL-6, IL-18, M-CSF and IL-10 were significantly higher and serum IL-12 and IL-22 were significantly lower in anti-MDA5-positive patients than in anti-MDA5-negative patients before treatment. Taking together these serological findings, we hypothesized that monocyte and macrophage activation may underlie in the pathophysiology of anti-MDA5-positive patients. They rarely survive after they become to need oxygenation, and so need to be treated as soon as possible once the diagnosis has been made. Intensive regimen of combined immunosuppressive therapy (high-dose corticosteroids, oral cyclosporin and intravenous cyclophosphamide (IVCY, 900-1000 mg/m(2) in every other week)) improved the survival rate of anti-MDA5-positive patients. Especially, the serum ferritin levels tended to go down about 14 days after IVCY, suggesting that IVCY might be a key drug in the treatment of anti-MDA5-positive A/SIP patients. PMID- 23629427 TI - [Anti-M3 muscarinic acetylcholine receptor antibodies and Sjogren's syndrome]. AB - Sjogren's syndrome (SS) is an autoimmune disease that affects exocrine glands including salivary and lacrimal glands. It is characterized by lymphocytic infiltration into exocrine glands, leading to dry mouth and eyes. A number of auto-antibodies are detected in patients with SS. However, no SS-specific pathologic auto-antibodies have yet been found in this condition. M3 muscarinic acetylcholine receptor (M3R) plays a crucial role in the secretion of saliva. It is reported that some patients with SS carried inhibitory auto-antibodies against M3R. To clarify the epitopes and function of anti-M3R antibodies in SS, we examined antibodies to the extracellular domains (N terminal region, the first, second, and third extracellular loop) of M3R by ELISA using synthesized peptide antigens encoding these domains in 42 SS and 42 healthy controls (HC). Titers and positivity of anti-M3R antibodies to every extracellular domain of M3R were significantly higher in SS than in HC. Our results indicated the presence of several B cell epitopes on M3R in SS. Moreover, we analyzed the functions of anti M3R antibodies by Ca(2+)-influx assays using a human salivary gland (HSG) cell line. The functional analysis indicated that the influence of such anti-M3R antibodies on Ca(2+)-influx in HSG cells might differ based on the epitopes to which they bind. Interestingly, both IgG from anti-M3R antibodies to the second extracellular loop positive SS and anti-M3R monoclonal antibodies against the second extracellular loop of M3R, which we generated, suppressed Ca(2+)-influx in the HSG cells induced by cevimeline stimulation. These observations suggested that auto-antibodies against the second extracellular loop of M3R could be involved in salivary dysfunction in patients with SS. These results indicated the presence of several B cell epitopes on M3R in SS and the influence of anti-M3R antibodies on salivary secretion might differ based on these epitopes. Thus, anti M3R antibodies could be not only potential pathologic auto-antibodies, but also new diagnostic makers and therapeutic targets for SS. PMID- 23629428 TI - [Recent concept of limbic encephalitis: progress in anti-NMDA receptor encephalitis]. AB - Patients with limbic encephalitis usually present with rapidly progressive short term memory deficits, psychiatric symptoms, and seizures. The recent concept of limbic encephalitis has been expanded. Especially, various types of autoimmune limbic encephalitis are associated with autoantibodies of intracellular or cell membrane antigens. Sine autoimmune limbic encephalitis is also associated with some types of tumors, it has also an aspect of paraneoplastic syndrome. Anti-N methyl-D-aspartate (NMDA) receptor encephalitis is a new category of treatment responsive limbic encephalitis associated with anti-NMDAR antibodies, which is the most frequent autoantibody to cell membrane antigen. The autoantibodies are detected in the CSF and serum of young women with ovarian teratoma, who typically develop schizophrenia-like psychiatric symptoms. There is a highly characteristics syndrome evolving in 5 stages; the prodromal, psychotic, unresponsive, hyperkinetic, and gradual recovery phases. The hyperkinetic phase is the most prolonged and crucial. This disorder is usually severe and can be fatal, but it is potentially reversible. Although the pathogenesis remains unclear, this disorder is considered to be the autoantibody-mediated encephalitis. This review focuses in the recent concept of limbic encephalitis and clinical characteristics of anti-NMDA receptor encephalitis. PMID- 23629429 TI - [anti-ADAMTS13 autoantibodies in patients with thrombotic thrombocytopenic purpura]. AB - Thrombotic thrombocytopenic purpura (TTP) is a disorder caused by excessive platelet aggregation in multiple organs. Unless the patients are treated with plasma exchange, this disorder leads to early death. Recent studies show that TTP is caused by deficiency of a plasma metalloprotease ADAMTS13, which specifically cleaves von Willebrand factor (VWF). In the absence of ADAMTS13, unusually large VWF multimers (UL-VWFMs) released from endothelial cells are not cleaved appropriately, and cause platelet-rich microvascular thrombosis under high shear stress. Deficiency of ADAMTS13 is caused by autoantibodies against ADAMTS13 in patients with acquired TTP and mutations of the ADAMTS13 gene in congenital TTP. ADAMTS13 antibodies may inhibit enzymatic function or clear ADAMTS13 from circulation. Anti-ADAMTS13 antibodies are comprised predominantly of immunoglobulin class G (IgG). Epitope mapping studies showed that antibodies direct towards the spacer domain of ADAMTS13 are present in most patients with acquired TTP. The Spacer domain contributes to the binding of ADAMTS13 to unfolded VWF. Plasma exchange therapy for acquired TTP is effective because of removing ADAMTS13 autoantibodies and UL-VWFMs, and supply of ADAMTS13. In addition to plasma exchange, corticostroids are usually used for reducing the production of anti-ADAMTS13 antibodies. Recent studies have shown benefit in using rituximab as a first line therapy of acute acquired TTP. PMID- 23629430 TI - [Comparison of nine second- and third-generation anti-cyclic citrullinated peptide antibody assays for the diagnosis of rheumatoid arthritis]. AB - The aim of this study was to compare the diagnostic and analytical performances of nine anti-cyclic citrullinated peptide (CCP) antibody assays. Anti-CCP antibody titers were measured in sera from 89 patients with rheumatoid arthritis (RA), 121 with rheumatic diseases other than RA (non-RA), 47 with osteoarthritis (OA), 142 with chronic inflammatory diseases (CID) and 168 healthy subjects. Reproducibility, sensitivity, specificity, correlation and concordance rate of the nine assays were compared. Coefficients of variations of within-run and between-run reproducibility at two different concentrations for each assay ranged from 0.7 to 8.5% and from 0.6 to 8.3%, respectively. With our proposed optimal cut-off value for the third-generation assay, concordance rates were 96.8~99.6%. The range of sensitivity was 75.3~78.7% and the ranges of specificity for non-RA, OA, CID, and healthy subjects were 93.4~97.5%, 97.9%, 96.5~98.6% and 98.8~100%, respectively. However, several discrepant samples were detected and their titer levels were about 3 times higher than the normal upper limit in the 2010 RA classification criteria. Good positive correlations were observed for parts of the second-generation assay. Our study showed that each of the nine assays has good reproducibility and high diagnostic accuracy, and is thus equally useful for the diagnosis of RA. PMID- 23629431 TI - [A case of abortive type of Heerfordt syndrome associated with paralysis of trigeminal nerve]. AB - We report a 39-year-old female admitted for fever. She showed physical findings of bilateral granulomatous uveitis, swelling of the bilateral parotid glands, and paralysis of the left second branch of the trigeminal nerve. Her chest X-ray showed evidence of bilateral hilar lymphadenopathy. We performed biopsy of her parotid gland, and leading to a diagnosis of noncaseating epithelioid granuloma characterized by lymphocyte and multinucleated giant cell invasion. Therefore, she was diagnosed with the abortive type of Heerfordt syndrome which is a subtype of sarcoidosis. This is the only case associated with paralysis of the trigeminal nerve without paralysis of facial nerves to be reported in Japan. PMID- 23629432 TI - Successful combination therapy with corticosteroids, biweekly intravenous pulse cyclophosphamide and cyclosporin A for acute interstitial pneumonia in patients with dermatomyositis : report of three cases. AB - We report three patients with dermatomyositis (DM) complicated with acute interstitial pneumonia (AIP). All of them complained of fever and acutely worsening dyspnea and were treated immediately by combination therapies with pulse therapy with methylprednisone (mPSL) followed by corticosteroids, biweekly intravenous pulse cyclophosphamide (IVCY) and cyclosporine A (CSA). They recovered rapidly soon after an initiation of this combination regimen. Early intervention with aggressive combination therapy is life-saving for the treatment of AIP in patients with DM. PMID- 23629434 TI - Generation of high quality chromatin immunoprecipitation DNA template for high throughput sequencing (ChIP-seq). AB - ChIP-sequencing (ChIP-seq) methods directly offer whole-genome coverage, where combining chromatin immunoprecipitation (ChIP) and massively parallel sequencing can be utilized to identify the repertoire of mammalian DNA sequences bound by transcription factors in vivo. "Next-generation" genome sequencing technologies provide 1-2 orders of magnitude increase in the amount of sequence that can be cost-effectively generated over older technologies thus allowing for ChIP-seq methods to directly provide whole-genome coverage for effective profiling of mammalian protein-DNA interactions. For successful ChIP-seq approaches, one must generate high quality ChIP DNA template to obtain the best sequencing outcomes. The description is based around experience with the protein product of the gene most strongly implicated in the pathogenesis of type 2 diabetes, namely the transcription factor transcription factor 7-like 2 (TCF7L2). This factor has also been implicated in various cancers. Outlined is how to generate high quality ChIP DNA template derived from the colorectal carcinoma cell line, HCT116, in order to build a high-resolution map through sequencing to determine the genes bound by TCF7L2, giving further insight in to its key role in the pathogenesis of complex traits. PMID- 23629435 TI - Device therapy: variation in the use of inferior vena cava filters for VTE. PMID- 23629437 TI - New directions in immunosuppression after heart transplantation. AB - Heart transplantation has evolved into the treatment of choice for eligible patients with end-stage heart failure. Effective immunosuppression is critical to the success of this treatment, with the modern era beginning with the advent of cyclosporin A in the 1980s. In this Perspectives article, the major prospective, randomized trials of immunosuppression after heart transplantation are briefly reviewed. These trials provided the setting for the 2011 TICTAC trial, in which combined immunosuppression was compared with monotherapy. The results of the study are discussed, as are the implications of these data for future research, including the importance of frameworks, the risks and benefits of changes in immunosuppression regimen, the future of funding for such research, and the selection of appropriate end points in trials of heart transplantation. The presupposed need for multidrug immunosuppression is challenged, and the potential efficacy and benefits of monotherapy are explored. PMID- 23629438 TI - Vascular disease: vorapaxar prevents progression of peripheral artery disease. PMID- 23629439 TI - Age-independent telomere shortening and ion-channel defects in SCD. PMID- 23629441 TI - Surgical pathology of atrial appendages removed during the cox-maze procedure: a review of 86 cases (2004 to 2005) with implications for prognosis. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Some patients are managed surgically (Cox-maze procedure) with removal of 1 or both atrial appendages. A retrospective review was performed on surgically excised atrial appendages from 86 consecutive patients with AF (2004 to 2005), at Mayo Clinic in Rochester, MN. These were compared with atrial appendages removed from 2 autopsy control groups without a history of AF (26 without heart disease, and 20 with heart disease). Compared with the 2 control groups, appendages from patients with AF contained more myocyte vacuolization, fatty infiltration, and myocardial inflammation. Among the AF patients, left atrial appendages (LAA) were larger and more likely to show fatty infiltration, endocardial fibroelastosis, and mural thrombus than were right atrial appendages (RAA); in contrast, RAA were more likely to show myocyte hypertrophy and interstitial fibrosis than were LAA. In the LAA, myocyte hypertrophy and interstitial fibrosis were more often seen in patients with long-term AF recurrence than were those who remained in normal sinus rhythm postoperatively (P=0.045 and 0.036, respectively). Given the potential clinical relevance of these findings, it is recommended that the presence or absence of hypertrophy and fibrosis, and their extent, be incorporated into the surgical pathology report of all patients undergoing resection of an atrial appendage. PMID- 23629440 TI - Localized pleuropulmonary crystal-storing histiocytosis: 5 cases of a rare histiocytic disorder with variable clinicoradiologic features. AB - Crystal-storing histiocytosis (CSH) localized to the thoracic region is a rare occurrence, often secondary to lymphoproliferative or plasma cell diseases. About 10 case reports have been previously published, and 3 of these have no relationship with clonal hematologic disorders. We collected here the first series of 5 consecutive cases of CSH involving lungs (4 cases) and pleura (1 case). There were 3 women and 2 men with a mean age at diagnosis of 65 years. All cases had an underlying hematologic disorder (2 B-cell marginal-zone lymphomas, 2 monoclonal gammopathy of undetermined significance and 1 pulmonary plasmacytoma). Despite a common morphology characterized by a dense and irregular growth of large eosinophilic histiocytes with intracytoplasmic refractile crystals, 2 cases presented with cystic changes at gross and imaging examinations, calcified amyloid was found in 2 cases, and 1 case showed an interstitial lung disease with nonspecific interstitial pneumonia pattern. Histiocytes were immunoreactive for CD68 (clones PGM-1 and KP-1) but were not for CD1a and S100; the associated lymphoplasmacellular disorder had a clonal profile on molecular analysis with kappa light-chain restriction. Two cases were originally misdiagnosed as cystic fibrohistiocytic tumor and carcinoid tumor, thus confirming that CSH localized to this site may result in a diagnostic challenge with a broad spectrum of differential diagnoses. The presence of intracytoplasmic crystals and a plasma cell infiltrate around a histiocytic proliferation should alert the pathologist to consider CSH and to carefully investigate the presence of clonal hematologic disease. PMID- 23629442 TI - High-grade lung adenocarcinoma with fetal lung-like morphology: clinicopathologic, immunohistochemical, and molecular analyses of 17 cases. AB - Low-grade lung adenocarcinoma of fetal lung type, which is well characterized by its unique clinicopathologic and molecular features, is recognized as a distinct variant of lung cancer. In contrast, high-grade lung adenocarcinoma with fetal lung-like morphology (HG-LAFM) has not been studied widely. To characterize this subset better, we analyzed 17 high-grade adenocarcinomas with at least focal component resembling a developing epithelium in the pseudoglandular phase of the fetal lung. These rare (ca. 0.4%) carcinomas occurred predominantly in elderly men with a heavy smoking history, who showed elevated serum alpha-fetoprotein in 4 of 5 cases tested. Histologic examination revealed a fetal lung-like component as a focal finding accounting for 5% to 60% of the total tumor volume. It was invariably admixed with tissues having a morphology not resembling that of a fetal lung. A coexisting non-fetal lung-like element was quite heterogenous in appearance, showing various growth patterns. However, clear-cell (88%), hepatoid (29%), and large cell neuroendocrine carcinoma (24%) histology seemed overrepresented. HG-LAFM was characterized immunohistochemically by frequent expression of alpha-fetoprotein (41%), glypican-3 (88%), SALL-4 (59%), neuroendocrine markers (82%), CDX-2 (35%), and p53 (65%). HG-LAFM was molecularly heterogenous in that EGFR or KRAS mutation was observed in 22% of cases tested for both. Our data indicate that HG-LAFMs might form a coherent subgroup of lung adenocarcinomas. However, the uniformly focal nature of the fetal lung-like element, widely diverse coexisting non-fetal lung-like histology, and inhomogenous molecular profiles lead us to believe that HG-LAFM is best regarded as a morphologic pattern showing characteristic association with several clinicopathologic parameters rather than a specific tumor entity. PMID- 23629444 TI - Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma. AB - Patients with high-grade subtypes of endometrial carcinoma (grade 3 endometrioid, serous, clear cell, or carcinosarcoma) have a relatively poor prognosis. The specific subtype may be used to guide patient management, but there is little information on the reproducibility of subtype diagnosis in cases of high-grade endometrial carcinoma. Fifty-six cases diagnosed as a high-grade subtype of endometrial carcinoma were identified from the pathology archives of Vancouver General Hospital. All slides for each case were reviewed independently by 3 pathologists, who diagnosed the specific tumor subtype(s) and assigned the percentage of each subtype for mixed tumors. Agreement between observers was categorized as follows: major disagreement: (A) no consensus for low-grade endometrioid versus high-grade carcinoma (any subtype), or (B) no consensus with respect to the predominant high-grade subtype present; minor disagreement: consensus was reached about the cell type of the predominant component of a mixed tumor, but there was disagreement about the subtype of the minor component. A tissue microarray was constructed from these cases and immunostained for p16, ER, PR, PTEN, and p53. In 35 of 56 (62.5%) cases, there was agreement between all 3 reviewers regarding the subtype diagnosis of the exclusive (in pure tumors) or predominant (in mixed tumors) high-grade component. Of these cases, there was a minor disagreement (ie, disagreement about the minor high-grade component subtype in a mixed tumor) in 4 cases (4/56, 7.1%). In 20 of 56 (35.8%) cases there was a major disagreement; in 17 (30.4%) of these cases there was no consensus about the major subtype diagnosis, whereas in 3 (5.4%) cases there was disagreement about whether a component of high-grade endometrial carcinoma was present. In the final case, all 3 reviewers diagnosed the case as low-grade endometrioid carcinoma, disagreeing with the original diagnosis of high-grade carcinoma. The most frequent areas of disagreement were serous versus clear cell (7 cases) and serous versus grade 3 endometrioid (6 cases). Immunostaining results using the 5-marker immunopanel were then used to adjudicate in the 6 cases in which there was disagreement between reviewers with respect to serous versus endometrioid carcinoma, and these supported a diagnosis of serous carcinoma in 4 of 6 cases and endometrioid carcinoma in 2 of 6 cases. Pairwise comparison between the reviewers for the 20 cases classified as showing major disagreement was as follows: reviewer 1 and reviewer 2 agreed in 5/20 cases, reviewer 1 and reviewer 3 agreed in 7/20 cases, and reviewer 2 and reviewer 3 agreed in 8/20 cases, indicating that disagreements were not because of a single reviewer holding outlier opinions. Diagnostic consensus among 3 reviewers about the exclusive or major subtype of high-grade endometrial carcinoma was reached in only 35/56 (62.5%) cases, and in 4 of these cases there was disagreement about the minor component present. This poor reproducibility did not reflect systematic bias on the part of any 1 reviewer. There is a need for molecular tools to aid in the accurate and reproducible diagnosis of high-grade endometrial carcinoma subtype. PMID- 23629443 TI - Mitotic rate in melanoma: prognostic value of immunostaining and computer assisted image analysis. AB - The prognostic value of mitotic rate in melanoma is increasingly recognized, particularly in thin melanoma in which the presence or absence of a single mitosis/mm can change staging from T1a to T1b. Still, accurate mitotic rate calculation (mitoses/mm) on hematoxylin and eosin (H&E)-stained sections can be challenging. Antimonoclonal mitotic protein-2 (MPM-2) and antiphosphohistone-H3 (PHH3) are 2 antibodies reported to be more mitosis-specific than other markers of proliferation such as Ki-67. We used light microscopy and computer-assisted image analysis software to quantify MPM-2 and PHH3 staining in melanoma. We then compared mitotic rates by each method with conventional H&E-based mitotic rate for correlation with clinical outcomes. Our study included primary tissues from 190 nonconsecutive cutaneous melanoma patients who were prospectively enrolled at New York University Langone Medical Center with information on age, gender, and primary tumor characteristics. The mitotic rate was quantified manually by light microscopy of corresponding H&E-stained, MPM-2-stained, and PHH3-stained sections. Computer-assisted image analysis was then used to quantify immunolabeled mitoses on the previously examined PHH3 and MPM-2 slides. We then analyzed the association between mitotic rate and both progression-free and melanoma-specific survival. Univariate analysis of PHH3 found significant correlation between increased PHH3 mitotic rate and decreased progression-free survival (P=0.04). Computer-assisted image analysis enhanced the correlation of PHH3 mitotic rate with progression-free survival (P=0.02). Regardless of the detection method, neither MPM-2 nor PHH3 offered significant advantage over conventional H&E determination of mitotic rate. PMID- 23629445 TI - The new AJCC guidelines in practice: utility of the MITF immunohistochemical stain in the evaluation of single-cell metastasis in melanoma sentinel lymph nodes. AB - The American Joint Commission on Cancer 2010 guideline changes recommend all patients with single-cell melanoma metastasis identified by immunhistochemical staining of sentinel lymph nodes to be classified as N1 stage. In this study we evaluated the utility of adding microphthalmia transcription factor (MITF) to our current sentinel node evaluation protocol. Twenty benign lymph nodes from nonmelanoma patients were stained with MITF, MART-1/Melan-A, and HMB-45. Hematoxylin and eosin-stained and immunohistochemically stained slides were assessed for the frequency of positive staining, pattern and location of staining, and for the presence of pigment within the node. Fifteen of 20 (75%) lymph nodes evaluated showed >1 cell staining with MITF in variable locations and patterns throughout the lymph node. MART-1/Melan-A-positive cells were identified in 4 of 20 cases (20.0%), mostly in the sinusoidal location (3/4). Fifty percent (10/20) of the lymph nodes contained cells that stained positive for HMB-45. Nine of 10 of the HMB-45-positive cells were in a sinusoidal location corresponding to easily discernible pigmented histiocytes. We conclude that MITF stains nonmelanocytic cells in benign lymph nodes 75% of the time. MITF has a much higher rate of positive staining in benign lymph nodes compared with MART-1/Melan A, which had positive staining only 20% of the time. MITF showed 2 different staining patterns, type A and type B. Both patterns could be difficult to distinguish from true metastasis, and thus adding MITF to sentinel node evaluation panels is not helpful and may be histologically vexing. PMID- 23629446 TI - JAZF1 rearrangement in a mesenchymal tumor of nonendometrial stromal origin: report of an unusual ossifying sarcoma of the heart demonstrating JAZF1/PHF1 fusion. AB - Rearrangements of JAZF1 are a frequent genetic aberration in endometrial stromal tumors. We report a distinct primary cardiac ossifying sarcoma that harbored a JAZF1/PHF1 fusion. The patient was a 70-year-old man with a history of a 6.8 cm calcific intramural left ventricular mass. Six years after his initial evaluation, the patient developed multiple lung metastases and ultimately died of disease-related complications. Histologically, the cardiac tumor and lung metastases demonstrated an infiltrative, malignant spindle cell neoplasm that grew in short fascicles with areas of bone formation, nuclear palisading, and necrosis. The neoplastic cells were relatively monomorphic in a background of an amorphous collagenous matrix. Immunohistochemical analysis was positive for vimentin and negative for wide-spectrum cytokeratins, S100 protein, desmin, smooth muscle actin, and CD34. Fluorescence in situ hybridization using a dual color, single-fusion probe set identified the JAZF1/PHF1 fusion. The unique morphology and the presence of a JAZF1/PHF1 rearrangement suggest that this distinctive ossifying sarcoma is not part of a currently established diagnostic entity, representing instead a novel primary cardiac sarcoma. This case also represents the first description of a JAZF1 fusion in a tumor outside the spectrum of endometrial stromal neoplasms. PMID- 23629447 TI - Primary squamous cell carcinoma of the breast: predictors of locoregional recurrence and overall survival. AB - Studies evaluating the biological behavior of primary squamous cell carcinoma (SCC) of the breast have yielded inconsistent results, perhaps in part because most studies have not taken into consideration specific histologic subtypes. We identified 21 cases of primary SCC of the breast diagnosed between the years 1985 and 2010 and analyzed the association between particular histologic features and disease outcome. Most tumors (17/21) were moderately or poorly differentiated, and most had a high nuclear grade (15/21). Five-year locoregional recurrence-free survival (LRRFS) for all patients was 54%+/-12%, and 5-year overall survival (OS) was 51%+/-13%. The only statistically significant feature associated with LRRFS was the presence of a spindle cell component in the tumor. Patients with >10% spindle cell component had decreased LRRFS (log rank; P=0.006). The only statistically significant features associated with OS were patient age and tumor keratinization. Patients more than 60 years of age had decreased OS (log rank; P=0.035), and patients with tumors having at least focal keratinization had improved OS (log rank; P=0.027). Lymph node status, mitotic rate, tumor necrosis, cystic degeneration, clear cell change, and the presence of a pleomorphic component or associated ductal carcinoma in situ were not associated with either LRRFS or OS. In summary, primary SCC of the breast tends to be aggressive, particularly in patients more than 60 years of age and those with tumors having >10% spindle cell component. The presence of at least focal keratinization, however, is associated with significantly improved OS. PMID- 23629448 TI - Colorectal carcinoma grading quantified by counting poorly differentiated clusters: is it feasible on endoscopic biopsies? PMID- 23629450 TI - A route to rapid carbon nanotube growth. AB - CNTs were synthesized in 15-20 seconds by a single carbon fiber initiating the pyrolysis of ferrocene under microwave field without any other chemicals. The growth of CNTs can also be triggered by other carbonaceous materials and influenced by their configurations. PMID- 23629449 TI - Design and synthesis of tryptophan containing dipeptide derivatives as formyl peptide receptor 1 antagonist. AB - Our previous studies identified an Fmoc-(S,R)-tryptophan-containing dipeptide derivative, 1, which selectively inhibited neutrophil elastase release induced by formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) in human neutrophils. In an attempt to improve pharmacological activity, a series of tryptophan-containing dipeptides were synthesized and their pharmacological activities were investigated in human neutrophils. Of these, five compounds 3, 6, 19a, 24a, and 24b exhibited potent and dual inhibitory effects on FMLP-induced superoxide anion (O2(-)) generation and neutrophil elastase release in neutrophils with IC50 values of 0.23/0.60, 1.88/2.47, 1.87/3.60, 0.12/0.37, and 1.32/1.03 MUM, respectively. Further studies indicated that inhibition of superoxide production in human neutrophils by these dipeptides was associated with the selective inhibition of formyl peptide receptor 1 (FPR1). Furthermore, the results of structure-activity relationship studies concluded that the fragment N-benzoyl-Trp Phe-OMe (3) was most suitable as a core structure for interaction with FPR1, and may be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases. As some of the synthesized compounds exhibited separable conformational isomers, and showed diverse bioactivities, the conformation analysis of these compounds is also discussed herein. PMID- 23629451 TI - Fabrication of reduced graphene oxide and sliver nanoparticle hybrids for Raman detection of absorbed folic acid: a potential cancer diagnostic probe. AB - Reduced graphene oxide (RGO) and silver nanoparticle (AgNP) hybrids (RGO-AgNP) were prepared by a facile one-pot method using Poly (N-vinyl-2-pyrrolidone) as reductant and stabilizer. Folic acid (FA) molecules were attached to the RGO-AgNP by physisorption for targeting specific cancer cells with folate receptors (FRs) and using as Raman reporter molecules. The internalization of the FA loaded RGO AgNP (RGO-AgNP-FA) inside the FRs-positive cancer cell was confirmed by confocal laser scanning and transmission electron microscopy. The Raman signals of the FA in live cancer cells were detected by confocal Raman spectroscope at 514 nm excitation, indicating that the RGO-AgNP-FA material has great potential as a Raman probe for cancer diagnosis in vitro. PMID- 23629452 TI - Atom probe tomography studies on the Cu(In,ga)Se2 grain boundaries. AB - Compared with the existent techniques, atom probe tomography is a unique technique able to chemically characterize the internal interfaces at the nanoscale and in three dimensions. Indeed, APT possesses high sensitivity (in the order of ppm) and high spatial resolution (sub nm). Considerable efforts were done here to prepare an APT tip which contains the desired grain boundary with a known structure. Indeed, site-specific sample preparation using combined focused ion-beam, electron backscatter diffraction, and transmission electron microscopy is presented in this work. This method allows selected grain boundaries with a known structure and location in Cu(In,Ga)Se2 thin-films to be studied by atom probe tomography. Finally, we discuss the advantages and drawbacks of using the atom probe tomography technique to study the grain boundaries in Cu(In,Ga)Se2 thin-film solar cells. PMID- 23629453 TI - Dual-purpose PEG scaffolds for the preparation of soft and biofunctional hydrogels: the convergence between CuAAC and thiol-ene reactions. AB - Orthogonally functionalized PEGs displaying alkenes and azides have been prepared and their dual-purpose scaffolding potential was exploited via click chemistry for controlled insertion of biorelevant moieties as well as facile fabrication of soft, non-toxic and degradable hydrogels. PMID- 23629454 TI - Do authors report surgical expertise in open spine surgery related randomized controlled trials? A systematic review on quality of reporting. AB - STUDY DESIGN: A systematic review of published trials in orthopedic spine literature. OBJECTIVE: To determine the quality of reporting in open spine surgery randomized controlled trials (RCTs) between 2005 and 2010 with special focus on the reporting of surgical skill or expertise. SUMMARY OF BACKGROUND DATA: In technically demanding procedures such as spine surgery, a surgeon's skill and expertise is expected to play an important role in the outcome of the procedure. To appraise the reported treatment effect of spine surgery related RCTs adequately, any potential skill or experience bias must be reported. METHODS: MEDLINE, the Cochrane Library, and EMBASE were systematically searched for open spine surgery RCTs published between January 1, 2005, and December 31, 2010. Percutaneous techniques were excluded. The quality of reporting of all eligible studies was determined using the checklist to evaluate a report of a nonpharmacological trial. The reporting of surgeons' skill and experience was scored additionally. Subsequently, all authors were surveyed to determine if any information on methodological safeguards was omitted from their reports. All data were analyzed in 2-year time frames. RESULTS: Ninety-nine RCTs were included. Ten studies (10%) described surgical skill or experience, mostly as a description of the learning curve. The majority of publications were unclear about "concealment of treatment allocation" (77%), "blinding of participants" (68%), "blinding of outcome assessors" (77%), and "adhering to the intention-to-treat principle" (67%). Of the 99 surveys, we received 22 (22%) completed questionnaires. In these questionnaires, information about essential methodological safeguards was often available, although not reported in the primary publication. CONCLUSION: This study shows that in open spine surgery RCTs information on skill and experience is scarcely reported. Authors often fail to report essential methodological safeguards. These studies may therefore be prone to expertise bias. PMID- 23629457 TI - Genetic model selection in genome-wide association studies: robust methods and the use of meta-analysis. AB - In genetic association studies (GAS) as well as in genome-wide association studies (GWAS), the mode of inheritance (dominant, additive and recessive) is usually not known a priori. Assuming an incorrect mode of inheritance may lead to substantial loss of power, whereas on the other hand, testing all possible models may result in an increased type I error rate. The situation is even more complicated in the meta-analysis of GAS or GWAS, in which individual studies are synthesized to derive an overall estimate. Meta-analysis increases the power to detect weak genotype effects, but heterogeneity and incompatibility between the included studies complicate things further. In this review, we present a comprehensive summary of the statistical methods used for robust analysis and genetic model selection in GAS and GWAS. We then discuss the application of such methods in the context of meta-analysis. We describe the theoretical properties of the various methods and the foundations on which they are based. We also present the available software implementations of the described methods. Finally, since only few of the available robust methods have been applied in the meta analysis setting, we present some simple extensions that allow robust meta analysis of GAS and GWAS. Possible extensions and proposals for future work are also discussed. PMID- 23629458 TI - Statistical issues associated with modeling of synonymous mutation data. AB - The explosion of data in evolutionary bioinformatics has led to sometimes ad hoc, incomplete and even inaccurate data analyses. Taking dS data, namely, data on synonymous substitutions per synonymous sites, we go through a statistical analysis for modeling the time since duplications of genes. We explore the shortcomings of previous analyses, especially with a view towards their effect on inference for the gene duplication process. We present a statistical analysis which respects the assumptions of the models and the integrity of the data, and emphasize that exploratory data analysis, formulation of a data model, its estimation and finally, assessment of the model are important steps in a complete data analysis. Furthermore, for dS data, we develop Bayesian discrete-continuous mixture models and present analyses using two genomes. PMID- 23629460 TI - Sensitivity to prior specification in Bayesian genome-based prediction models. AB - Different statistical models have been proposed for maximizing prediction accuracy in genome-based prediction of breeding values in plant and animal breeding. However, little is known about the sensitivity of these models with respect to prior and hyperparameter specification, because comparisons of prediction performance are mainly based on a single set of hyperparameters. In this study, we focused on Bayesian prediction methods using a standard linear regression model with marker covariates coding additive effects at a large number of marker loci. By comparing different hyperparameter settings, we investigated the sensitivity of four methods frequently used in genome-based prediction (Bayesian Ridge, Bayesian Lasso, BayesA and BayesB) to specification of the prior distribution of marker effects. We used datasets simulated according to a typical maize breeding program differing in the number of markers and the number of simulated quantitative trait loci affecting the trait. Furthermore, we used an experimental maize dataset, comprising 698 doubled haploid lines, each genotyped with 56110 single nucleotide polymorphism markers and phenotyped as testcrosses for the two quantitative traits grain dry matter yield and grain dry matter content. The predictive ability of the different models was assessed by five-fold cross-validation. The extent of Bayesian learning was quantified by calculation of the Hellinger distance between the prior and posterior densities of marker effects. Our results indicate that similar predictive abilities can be achieved with all methods, but with BayesA and BayesB hyperparameter settings had a stronger effect on prediction performance than with the other two methods. Prediction performance of BayesA and BayesB suffered substantially from a non optimal choice of hyperparameters. PMID- 23629459 TI - Hierarchical Bayesian mixture modelling for antigen-specific T-cell subtyping in combinatorially encoded flow cytometry studies. AB - Novel uses of automated flow cytometry technology for measuring levels of protein markers on thousands to millions of cells are promoting increasing need for relevant, customized Bayesian mixture modelling approaches in many areas of biomedical research and application. In studies of immune profiling in many biological areas, traditional flow cytometry measures relative levels of abundance of marker proteins using fluorescently labeled tags that identify specific markers by a single-color. One specific and important recent development in this area is the use of combinatorial marker assays in which each marker is targeted with a probe that is labeled with two or more fluorescent tags. The use of several colors enables the identification of, in principle, combinatorially increasingly numbers of subtypes of cells, each identified by a subset of colors. This represents a major advance in the ability to characterize variation in immune responses involving larger numbers of functionally differentiated cell subtypes. We describe novel classes of Markov chain Monte Carlo methods for model fitting that exploit distributed GPU (graphics processing unit) implementation. We discuss issues of cellular subtype identification in this novel, general model framework, and provide a detailed example using simulated data. We then describe application to a data set from an experimental study of antigen-specific T-cell subtyping using combinatorially encoded assays in human blood samples. Summary comments discuss broader questions in applications in immunology, and aspects of statistical computation. PMID- 23629461 TI - Psychometric properties of the lasater clinical judgment rubric. AB - Simulation is integrated into nursing curricula as a means of developing and evaluating clinical judgment, but there are few valid and reliable tools available and evaluation is not consistently theory based. When the Lasater Clinical Judgment Rubric (LCJR) was introduced in 2007, it provided a common evaluative language for assessment of clinical judgment but had limited support of its validity and reliability. Based on Tanner's Model, the LCJR organized nursing actions into eleven dimensions and four behavioral categories and defined specific actions in each which are typical of developmental phases (Lasater, 2007). The LCJR has been adopted by many nursing programs with limited support of its validity and reliability. This article attempts to organize current knowledge available on the LCJR in an effort to assess its use as a valid and reliable measurement tool, and to identify specific needs for continued testing of the instrument. PMID- 23629462 TI - Critical service learning in community health nursing: enhancing access to cardiac health screening. AB - Critical service learning (CSL) offers promise for preparing community health nursing students to be advocates for social justice and social change. The purpose of this article is to describe a community based CSL project designed to provide cardiac health screening to an underserviced population, wherein nursing's role in social justice is integrated into nursing practice. First, the relationship between social justice and CSL is explored. Then, the CSL approach is examined and differentiated from the traditional service learning models frequently observed in the nursing curriculum. The CSL project is described and the learning requisites, objectives, requirements, and project outcomes are outlined. While not a panacea for system reform, CSL offers nursing students avenues for learning about social justice and understanding the social conditions that underlie health inequalities. Nurse educators may benefit from the new strategies for incorporating social justice into nursing curriculum; this paper suggests that CSL offers one possibility. PMID- 23629463 TI - Writing history: case study of the university of Victoria School of Nursing. AB - A historical examination of a nursing curriculum is a bridge between past and present from which insights to guide curriculum development can be gleaned. In this paper, we use the case study method to examine how the University of Victoria School of Nursing (UVic SON), which was heavily influenced by the ideology of second wave feminism, contributed to a change in the direction of nursing education from task-orientation to a content and process orientation. This case study, informed by a feminist lens, enabled us to critically examine the introduction of a "revolutionary" caring curriculum at the UVic SON. Our research demonstrates the fault lines and current debates within which a feminist informed curriculum continues to struggle for legitimacy and cohesion. More work is needed to illuminate the historical basis of these debates and to understand more fully the complex landscape that has constructed the social and historical position of women and nursing in Canadian society today. PMID- 23629464 TI - Education reforms in Nigeria: how responsive is the nursing profession? AB - Abstractworldwide because of the link between education and development. What appears not to have been fully explored in the Nigerian context is the responsiveness of various professions, especially nursing, to the consistently changing educational system. Yet innovative advances in health care system in the twenty-first century demands that Nursing as a profession should prepare practitioners who are well equipped to meet the challenges of care within the context of a complex milieu. This paper, therefore, examines the Nigeria educational system, its reforms and current status of nursing education in Nigeria. Some of the challenges in the emergence of professional nursing in Nigeria and the progress made so far to advance professional as well as university education for nurses are articulated with propositions of possibilities and the gains for the Nigeria nation. PMID- 23629465 TI - Fear and loathing: undergraduate nursing students' experiences of a mandatory course in applied statistics. AB - This article describes the results of a qualitative research study evaluating nursing students' experiences of a mandatory course in applied statistics, and the perceived effectiveness of teaching methods implemented during the course. Fifteen nursing students in the third year of a four-year baccalaureate program in nursing participated in focus groups before and after taking the mandatory course in statistics. The interviews were transcribed and analyzed using content analysis to reveal four major themes: (i) "one of those courses you throw out?," (ii) "numbers and terrifying equations," (iii) "first aid for statistics casualties," and (iv) "re-thinking curriculum." Overall, the data revealed that although nursing students initially enter statistics courses with considerable skepticism, fear, and anxiety, there are a number of concrete actions statistics instructors can take to reduce student fear and increase the perceived relevance of courses in statistics. PMID- 23629466 TI - Arts-based learning: analysis of the concept for nursing education. AB - Teaching and learning strategies are needed to support learner-centered curricula, and prepare nurses who are capable of working in today's challenging health care environments. Although the traditional lecture is still widely used in nursing education, innovative approaches are needed to encourage discussion, debate, and critical reflection, activities that support lifelong learning. Arts based learning [ABL] is a creative strategy with the potential to engage learners, foster understanding of multiple perspectives, and simultaneously connect cognitive and affective domains of learning. Walker and Avant's method of concept analysis is applied to examine the uses of ABL in the literature, define the attributes, distinguish the antecedents and consequences, identify model and other cases, and determine empirical referents of this concept. This analysis is presented to facilitate the conceptual understanding of ABL for use in research and nursing education. PMID- 23629467 TI - How does the nurse educator measure caring? AB - The purpose of this article is to advance worldwide scholarship of nursing education by introducing a novel approach to evaluate nursing students' level of human caring. We propose an innovative tool that can be used by nurse educators to measure the construct of caring. Caring encompasses three dimensions: intentionality, relationality, and responsivity. The dimensions are drawn from theoretical, practice, and education literatures. The innovative tool, named the Caring Interaction Inventory, exposes nursing students to audio-video recordings of complex real-life healthcare encounters. Nursing students are required to choose from several options, caring behaviors that would best address holistic patient needs. Caring behaviors chosen for a given healthcare encounter and the rationale provided by the student, enable the nurse educator to evaluate the student's caring in terms of intentionality, relationality, and responsivity. The sum total of the student's performance within each dimension constitutes the student's overall caring grade. PMID- 23629468 TI - Cultural competence and cultural safety in Canadian schools of nursing: a mixed methods study. AB - Cultural competence and cultural safety are essential knowledge in contemporary nursing care. Using a three-phase, mixed methods sequential triangulation design, this study examines the extent to which Anglophone Schools of Nursing in Canada have integrated cultural competence and/or cultural safety into the undergraduate nursing curricula. Factors that influence successful integration are identified through the lens of Donabedian's structure, process, and outcome model. Results suggest that several facilitating factors are present, such as leadership, partnerships and linkages, and educational supports for students. Of particular concern is the lack of policies to recruit and retain Aboriginal faculty, financial resources, and outcome evaluation indicators. A conceptual model of integration is offered to explain how Schools of Nursing function to support the implementation of these concepts into their curriculum. This study provides theoretical and practical implications for initiation and improvement of cultural competence and/or cultural safety integration strategies in Schools of Nursing. PMID- 23629470 TI - Current modalities of accelerated partial breast irradiation. AB - The benefits of adjuvant whole-breast irradiation (WBI) after breast-conserving surgery are well established and WBI is a standard of care. In selected patients with early stage breast cancer, accelerated partial breast irradiation (APBI) has emerged as an alternative treatment option to WBI. Early trials of APBI have demonstrated an excellent local control rate and an associated good-to-excellent cosmetic outcome. APBI can reduce both the treatment volume and overall treatment time of adjuvant radiation therapy, which potentially overcomes logistical barriers associated with WBI that have previously prevented eligible women from pursuing breast-conserving therapy. Likewise, the addition of new modalities for APBI delivery has increased the number of patients who might be eligible for this adjuvant treatment-in the setting of breast-conserving surgery-despite the limited availability of long-term data on APBI outcomes compared to historical WBI outcomes. Ongoing phase III trials aim to compare APBI with WBI and also point the practitioner to the appropriate APBI patient selection criteria. Here, we review available modalities, patient selection criteria and consensus guideline recommendations, and current controversies in APBI. PMID- 23629469 TI - Scapula fractures: interobserver reliability of classification and treatment. AB - OBJECTIVES: There is substantial variation in the classification and management of scapula fractures. The first purpose of this study was to analyze the interobserver reliability of the OTA/AO classification and the New International Classification for Scapula Fractures. The second purpose was to assess the proportion of agreement among orthopaedic surgeons on operative or nonoperative treatment. DESIGN: Web-based reliability study. SETTING: Independent orthopaedic surgeons from several countries were invited to classify scapular fractures in an online survey. PARTICIPANTS: One hundred three orthopaedic surgeons evaluated 35 movies of three-dimensional computerized tomography reconstruction of selected scapular fractures, representing a full spectrum of fracture patterns. MAIN OUTCOME MEASUREMENTS: Fleiss kappa (kappa) was used to assess the reliability of agreement between the surgeons. RESULTS: The overall agreement on the OTA/AO classification was moderate for the types (A, B, and C, kappa = 0.54) with a 71% proportion of rater agreement (PA) and for the 9 groups (A1 to C3, kappa = 0.47) with a 57% PA. For the New International Classification, the agreement about the intraarticular extension of the fracture (Fossa (F), kappa = 0.79) was substantial and the agreement about a fractured body (Body (B), kappa = 0.57) or process was moderate (Process (P), kappa = 0.53); however, PAs were more than 81%. The agreement on the treatment recommendation was moderate (kappa = 0.57) with a 73% PA. CONCLUSIONS: The New International Classification was more reliable. Body and process fractures generated more disagreement than intraarticular fractures and need further clear definitions. PMID- 23629471 TI - Urological cancer: second-line option for metastatic RCC. PMID- 23629473 TI - Targeted therapies: HER2-positive breast cancer-sifting through many good options. PMID- 23629474 TI - Aerosol-assisted delivery of precursors for chemical vapour deposition: expanding the scope of CVD for materials fabrication. AB - The production of thin films of materials has become the attention of a great deal of research throughout academia and industry worldwide owing to the array of applications which utilise them, including electronic devices, gas sensors, solar cells, window coatings and catalytic systems. Whilst a number of deposition techniques are in common use, chemical vapour deposition (CVD) is an attractive process for the production of a wide range of materials due to the control it offers over film composition, coverage and uniformity, even on large scales. Conventional CVD processes can be limited, however, by the need for suitably volatile precursors. Aerosol-assisted (AA)CVD is a solution-based process which relies on the solubility of the precursor, rather than its volatility and thus vastly extends the range of potentially applicable precursors. In addition, AACVD offers extra means to control film morphology and concurrently the properties of the deposited materials. In this perspective we discuss the AACVD process, the influence of deposition conditions on film characteristics and a number of materials and applications to which AACVD has been found beneficial. PMID- 23629472 TI - Advanced-stage pancreatic cancer: therapy options. AB - Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, and surgical resection is a requirement for a potential cure. However, the majority of patients are diagnosed with advanced-stage disease, either metastatic (50%) or locally advanced cancer (30%). Although palliative chemotherapy is the standard of care for patients with metastatic disease, management of locally advanced adenocarcinoma is controversial. Several treatment options, including extended surgical resections, neoadjuvant therapy with subsequent resections, as well as palliative radiotherapy and/or chemotherapy, should be considered. However, there is little evidence available to support treatment options for locally advanced disease. As valid predictive biomarkers for stratification of therapy are not available today, future trials need to define the role of the different treatment options. This Review summarizes the current evidence and discusses available treatment options for both locally advanced and metastatic pancreatic adenocarcinoma. PMID- 23629475 TI - A convenient method for selective detection of 5-hydroxymethylcytosine and 5 formylcytosine sites in DNA sequences. AB - Treatment of DNA containing 5-formylcytosine with hot piperidine produced a cleaved band at the position of 5-formylcytosine in DNA sequences. After oxidation with KRuO4, 5-hydroxymethylcytosine could also be detected using the same method. Using our strategy, we could detect 5-hydroxymethylcytosine and 5 formylcytosine respectively. PMID- 23629476 TI - Endometrial surveillance in tamoxifen users: role, timing and accuracy of hysteroscopic investigation: observational longitudinal cohort study. AB - To determine the role, timing and indications for endometrial hysteroscopic investigation in relation to the clinical, ultrasound and histological features of the endometrium during tamoxifen (TAM) use. We performed an observational longitudinal cohort study (years 2007-2012) that investigated the endometria of 151 TAM users with hysteroscopy and histology. For all patients, gynaecological history, years of adjuvant treatment, ultrasound endometrial thickness measurement and indications for hysteroscopy were recorded. Hysteroscopic findings showed that 100% of patients referred for simple follow-up had no evidence of endometrial disease. We found a strong correlation between previous history of abnormal uterine bleeding (with or without endometrial thickening) and hysteroscopic suspicion of endometrial atypia that was confirmed by histology. Hysteroscopy had 83.3% sensitivity, 99% specificity, 83.3% positive predictive value (PPV) and 99% negative predictive value (NPV) in detecting endometrial atypia. No significant correlation was found between endometrial thickening to >5 mm without bleeding and histological atypia. Similarly, the duration of treatment was not related to endometrial thickening and histological atypia. Endometrial stromal hyperplasia was detected by histology in 70.5% of patients with endometrial thickness measurements ranging from 5 to 10 mm. In contrast, no atypia was detected when endometrial thickness was <5 mm. Ultrasound performed using a 5-mm cut-off threshold for endometrial thickness resulted in 100% sensitivity, 15% specificity, 4% PPV and 100% NPV in detecting endometrial atypia, while a 10-mm cut-off threshold resulted in 84% sensitivity, 69% specificity, 10% PPV and 99% NPV. Low-risk TAM users do not require different endometrial surveillance than the general population. Hysteroscopy could play a fundamental role in determining the endometrial status of patients before the initiation of TAM treatment and in assessing the endometrial status of patients when bleeding occurs. PMID- 23629478 TI - Ocimum sanctum Linn. (Tulsi): an ethnomedicinal plant for the prevention and treatment of cancer. AB - Ocimum sanctum Linn., commonly known as 'Tulsi' or 'Holy Basil', is considered to be the most sacred herb of India. Several anatomical parts of O. sanctum are known to have an impressive number of therapeutic properties and accordingly find use in several traditional systems of medicine, such as Ayurveda, Unani, and Siddha. Scientific investigations have shown that O. sanctum has a plethora of biological and pharmacological activities. The presence of an impressive number of phytoconstituents in O. sanctum could explain its exceptional beneficial effects. Although several recent articles provide an overview of the various pharmacological properties of O. sanctum, the use of this herb for either prevention or therapy of oncologic diseases has not been exclusively and critically discussed in the literature. The present review critically and comprehensively examines the current knowledge on the chemopreventive and therapeutic potential of O. sanctum. The review also examines, in detail, the biochemical and molecular mechanisms involved in the antineoplastic effects of O. sanctum. Finally, we discuss the role of synergy, current limitations, and future directions of research toward the effective use of this ethnomedicinal plant for the prevention and treatment of human cancer. PMID- 23629477 TI - Evaluations of auto-focusing methods under a microscopic imaging modality for metaphase chromosome image analysis. AB - BACKGROUND: Auto-focusing is an important operation in high throughput imaging scanning. Although many auto-focusing methods have been developed and tested for a variety of imaging modalities, few investigations have been performed on the selection of an optimal auto-focusing method that is suitable for the pathological metaphase chromosome analysis under a high resolution scanning microscopic system. OBJECTIVE: The purpose of this study is to investigate and identify an optimal auto-focusing method for the pathological metaphase chromosome analysis. METHODS: In this study, five auto-focusing methods were applied and tested using metaphase chromosome images acquired from bone marrow and blood specimens. These methods were assessed by measuring a number of indices including execution time, accuracy, number of false maxima, and full width at half maximum (FWHM). RESULTS: For the specific condition investigated in this study, the results showed that the Brenner gradient and threshold pixel counting methods were the optimal methods for acquiring high quality metaphase chromosome images from the bone marrow and blood specimens, respectively. CONCLUSIONS: Selecting an optimal auto-focusing method depends on the specific clinical tasks. This study also provides useful information for the design and implementation of the high throughput microscopic image scanning systems in the future digital pathology. PMID- 23629479 TI - Cost analysis of S1 and XELOX as adjuvant therapy for gastric cancer. AB - Both S1 and XELOX (capecitabine+oxaliplatin) have been recommended as an adjuvant treatment for gastric cancer according to the guidelines of the National Comprehensive Cancer Network (NCCN). This study compared the two regimens in terms of monetary costs, assuming equal efficacy of both regimens. Chemotherapy cost data of 188 patients were collected from the medical records, 91 for the S1 group and 97 for XELOX. Costs were classified as direct costs (chemotherapy, hospitalization, venous access, and tests), adverse event-related treatments costs, and societal (travel and time) costs. The total direct costs of S1 and XELOX per cycle per patient were $1938+/-236 and $2317+/-315, respectively. S1 cost $27 and $9 less than XELOX on total adverse event-related costs and societal costs, respectively. The total costs of S1 and XELOX were $1994+/-322 versus $2410+/-391 per cycle per patient, respectively. The total cost of S1 was 17.3% less than that of XELOX for the average patient. All the differences were statistically significant. S1, compared with XELOX, could be a more affordable option as an adjuvant treatment for gastric cancer when all healthcare resources are taken into account in China. PMID- 23629480 TI - Deubiquitinases as potential anti-cancer targets for gold(III) complexes. AB - A panel of [Au(III)(C^N)(R2NCS2)](+) (HC^N = 2-phenylpyridine) complexes displayed significant deubiquitinases (DUBs) inhibitory activity; one of these complexes showed selective in vitro cytotoxicity towards breast cancer cells correlated to high cellular uptake of gold, and induced cell-cycle arrest, apoptosis, and anti-angiogenic property that could be related to DUB inhibitory activity. PMID- 23629481 TI - Palladium-catalyzed ortho-acylation of 2-aryl pyridine derivatives using arylmethyl amines as new acyl sources. AB - A facile and efficient protocol for palladium-catalyzed ortho-acylation of 2-aryl pyridines was developed. Note that this acylation utilized arylmethyl amines as new, cheap and readily available acylation reagents and exhibited high regioselectivity for 2-aryl pyridines bearing a meta-substituent in the aryl ring moiety. PMID- 23629483 TI - Evidence-based recommendations for spine surgery. PMID- 23629482 TI - Dry oxidation and vacuum annealing treatments for tuning the wetting properties of carbon nanotube arrays. AB - In this article, we describe a simple method to reversibly tune the wetting properties of vertically aligned carbon nanotube (CNT) arrays. Here, CNT arrays are defined as densely packed multi-walled carbon nanotubes oriented perpendicular to the growth substrate as a result of a growth process by the standard thermal chemical vapor deposition (CVD) technique.(1,2) These CNT arrays are then exposed to vacuum annealing treatment to make them more hydrophobic or to dry oxidation treatment to render them more hydrophilic. The hydrophobic CNT arrays can be turned hydrophilic by exposing them to dry oxidation treatment, while the hydrophilic CNT arrays can be turned hydrophobic by exposing them to vacuum annealing treatment. Using a combination of both treatments, CNT arrays can be repeatedly switched between hydrophilic and hydrophobic.(2) Therefore, such combination show a very high potential in many industrial and consumer applications, including drug delivery system and high power density supercapacitors.(3-5) The key to vary the wettability of CNT arrays is to control the surface concentration of oxygen adsorbates. Basically oxygen adsorbates can be introduced by exposing the CNT arrays to any oxidation treatment. Here we use dry oxidation treatments, such as oxygen plasma and UV/ozone, to functionalize the surface of CNT with oxygenated functional groups. These oxygenated functional groups allow hydrogen bond between the surface of CNT and water molecules to form, rendering the CNT hydrophilic. To turn them hydrophobic, adsorbed oxygen must be removed from the surface of CNT. Here we employ vacuum annealing treatment to induce oxygen desorption process. CNT arrays with extremely low surface concentration of oxygen adsorbates exhibit a superhydrophobic behavior. PMID- 23629484 TI - Complications associated with the use of the recombinant human bone morphogenetic proteins for posterior interbody fusions of the lumbar spine. AB - STUDY DESIGN: Systematic review. OBJECTIVE: The objectives of this review are to examine the spectrum of complications that have been reported in the literature after posterior interbody fusions of the lumbar spine augmented with bone morphogenetic proteins (BMPs) and discuss potential methods for their prevention. SUMMARY OF BACKGROUND DATA: The use of BMPs for spinal arthrodesis procedures has increased dramatically during the past decade. These products are commonly used in "off-label" fashion in posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF) constructs. Recently, a number of adverse events have been attributed to the use of BMP for PLIF and TLIF surgical procedure, including heterotopic ossification within the epidural space or neuroforamina, postoperative radiculitis, and endplate osteolysis with interbody device subsidence. METHODS: A computer aided literature search was performed on the electronic databases PubMed, MEDLINE, EMBASE, CINAHL, and Cochrane Database of Systematic Reviews. Key words of interest included BMPs, PLIF, TLIF, complications, heterotopic ossification, radiculitis, and osteolysis. All articles, in the English language, between 1990 and 2011 were considered relating to the use of BMPs in PLIF and TLIF constructs. RESULTS: Seventeen articles discussing the use and potential complications of BMPs in PLIF and TLIF constructs were identified and reviewed. The studies were in the range of a level I prospective randomized trial to case reports of complications. There is a wide variation of published complications associated with BMP-augmented PLIF and TLIF constructs. CONCLUSION: Despite high fusion rates there is a growing body of evidence that the use of BMP in PLIF and TLIF constructs does not come without potential complication. There are appreciable rates of BMP-specific complications, which include heterotopic ossification within the epidural space or neuroforamina, postoperative radiculitis, and endplate osteolysis with interbody device subsidence. PMID- 23629485 TI - Bone marrow-derived mesenchymal stem cell transplantation for chronic spinal cord injury in rats: comparative study between intralesional and intravenous transplantation. AB - STUDY DESIGN: Animal experimental study. OBJECTIVE: To present experimental evidence for mesenchymal cell therapy for spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: Prior to clinical application of stem cell therapy for SCI, many critical issues have to be addressed including efficiency, safety, method of transplantation, and differentiation of the transplanted cells. METHODS: Chronic contusive SCI was induced in 36 Sprague-Dawley rats and randomly assigned to the intralesional (IL), intravenous (IV), or control groups. At 6 weeks post injury, allogenic mesenchymal stem cells (MSCs, 1 * 10 cells) were transplanted either intralesionally or intravenously for the intervention groups. Engraftment of the transplanted MSCs was evaluated with PKH 26 staining. Differentiation was evaluated using double stain with neuronal and glial cell markers. Brain-derived neurotrophic factor and nerve growth factor (NGF) were used for neurotrophic factor expression. Basso, Beattie, and Bresnahan locomotor rating scale was used for evaluation of functional recovery. RESULTS: The estimated engraftment percentage of the transplanted cells in the IL group and IV group were 36.5%, and 15.5%, respectively. The engraftment of the transplanted MSCs was higher in the IL group than in the IV group. Most of the transplanted MSCs were colocalized with GFAP in both transplantation groups. Brain-derived neurotrophic factor and NGF expression (Western blot and real-time polymerase chain reaction) in the injured spinal cord was higher in both transplanted groups compared with those in the control group. At 6 weeks post transplantation, the mean Basso, Beattie, and Bresnahan locomotor scales in the IL, IV, and control groups were 5.63 +/- 0.89, 5.63 +/- 1.03, and 2.88 +/- 0.44, respectively. The functional recovery seen in the rats that underwent transplantation was significantly better than that in the control group (P < 0.05). CONCLUSION: Although the number of engrafted cells and expression of neurotrophic factors were lower in the IV group than those in the IL group, both IL and IV transplantation of MSC in the chronic SCI gave a significant clinical improvement. However, there were no differences in differentiation of the transplanted cells between the IL group and IV group. Astrocytic differentiation of the transplanted cells was predominant. LEVEL OF EVIDENCE: N/A. PMID- 23629486 TI - Facile water-assisted synthesis of cupric oxide nanourchins and their application as nonenzymatic glucose biosensor. AB - We have demonstrated an interesting approach for the one-pot synthesis of cupric oxide (CuO) nanourchins with sub-100 nm through a sequential dissolution precipitation process in a water/ethanol system. The first stage produces a precursory crystal [Cu7Cl4(OH)10H2O] that is transformed into monoclinic CuO nanourchins during the following stage. Water is a required reactant for the morphology-controlled growth of different CuO nanostructures. When evaluated for their nonenzymatic glucose-sensing properties, these CuO nanourchins manifest higher sensitivity. Significantly, this water-dependent precursor transformation method may be widely used to effectively control the growth of other metal oxide nanostructures. PMID- 23629487 TI - Social networks to biological networks: systems biology of Mycobacterium tuberculosis. AB - Contextualizing relevant information to construct a network that represents a given biological process presents a fundamental challenge in the network science of biology. The quality of network for the organism of interest is critically dependent on the extent of functional annotation of its genome. Mostly the automated annotation pipelines do not account for unstructured information present in volumes of literature and hence large fraction of genome remains poorly annotated. However, if used, this information could substantially enhance the functional annotation of a genome, aiding the development of a more comprehensive network. Mining unstructured information buried in volumes of literature often requires manual intervention to a great extent and thus becomes a bottleneck for most of the automated pipelines. In this review, we discuss the potential of scientific social networking as a solution for systematic manual mining of data. Focusing on Mycobacterium tuberculosis, as a case study, we discuss our open innovative approach for the functional annotation of its genome. Furthermore, we highlight the strength of such collated structured data in the context of drug target prediction based on systems level analysis of pathogen. PMID- 23629488 TI - The effect of social contingencies on nursing students' reactions during a rural clinical placement. AB - Students' feedback of their practicum experiences are typically documented only in terms of established nursing competencies and learning objectives. How nursing students cope with social contingencies (e.g., personal health) while away on clinical placement is not commonly reported in the literature. A sample of Australian student nurses was surveyed as a way of contributing new knowledge about what and how social contingencies could impact on a practicum experience. An analysis of the survey data provided by 244 students revealed that of the 14 contingencies used, financial pressure, accommodation, and geographic location, were rated as having the most influence. All of these social contingencies were examined by a principal components analysis. Three factors were identified and interpreted as professional organization, home organization, and personal organization. Three subscales were then derived using these factors and other measures were also calculated. Bivariate and multivariate relationships were subsequently determined. One key finding was that the first year students, compared to their more senior counterparts, expressed less stress during their practicum. The first year students, as opposed to their more experienced peers, also attached less importance to the professional organizational contingencies. The implications of the study for university administrators, nursing education faculty, and managers of clinical facilities conclude the paper. PMID- 23629489 TI - An olecranon chondral flap and osteochondral coronoid fracture in a spontaneously reduced elbow dislocation in a child. AB - Elbow injuries in children are very common and radiographs are often difficult to interpret because of the radiolucency of the cartilaginous anlage and the progressive appearance of multiple secondary ossification centres. Elbow dislocations are rare injuries in children. Coronoid fractures can occur during dislocation or relocation of the elbow and can be the only hallmark of a severe injury. The understanding of the mechanics of these injuries has undergone considerable evolution over the past decade. Intra-articular chondral flap fractures are a traumatic elevation of the hyaline cartilage from the subchondral bone. They are also rare injuries in children but should be included in the differential when examining an injured joint. The infrequency of these injuries provides little opportunity to become accustomed to the radiographic signs. We present a case report of a 4-year-old boy with both an olecranon chondral flap and coronoid cartilaginous fracture after a joint dislocation. We present his plain radiography and MRI with illustrated photographic records of the operative findings. This injury has been little described in the literature and never with such imaging to aid understanding of both the pathology and the injury mechanism. PMID- 23629490 TI - Translational medicine: mitigating risks for investigators. PMID- 23629491 TI - Maturing antibody-drug conjugate pipeline hits 30. PMID- 23629495 TI - Trial watch: Sepsis study failure highlights need for trial design rethink. PMID- 23629496 TI - Trial watch: PDE4 inhibitor leads wave of target-specific oral psoriasis drugs. PMID- 23629497 TI - Commercial prospects for genomic sequencing technologies. PMID- 23629498 TI - Tumour vaccination: Devil in the details of adjuvant choice. PMID- 23629499 TI - Blood disorders: Boosting the stem cell harvest. PMID- 23629504 TI - Implementing personalized cancer genomics in clinical trials. AB - The recent surge in high-throughput sequencing of cancer genomes has supported an expanding molecular classification of cancer. These studies have identified putative predictive biomarkers signifying aberrant oncogene pathway activation and may provide a rationale for matching patients with molecularly targeted therapies in clinical trials. Here, we discuss some of the challenges of adapting these data for rare cancers or molecular subsets of certain cancers, which will require aligning the availability of investigational agents, rapid turnaround of clinical grade sequencing, molecular eligibility and reconsidering clinical trial design and end points. PMID- 23629507 TI - Thermodynamic control of oxidative addition and reductive elimination processes in cis-bis(dimethoxyboryl)-bis(tricyclohexylphosphine)platinum(II). AB - cis-[(Cy3P)2Pt{B(OMe)2}2] (1) was obtained in quantitative yield and fully characterised. The thermal stability of 1 was investigated in solution using multinuclear NMR spectroscopy revealing a hitherto unknown temperature-dependent equilibrium between 1 and the corresponding starting materials [Pt(PCy3)2] and free B2(OMe)4. PMID- 23629505 TI - Platforms for antibiotic discovery. AB - The spread of resistant bacteria, leading to untreatable infections, is a major public health threat but the pace of antibiotic discovery to combat these pathogens has slowed down. Most antibiotics were originally isolated by screening soil-derived actinomycetes during the golden era of antibiotic discovery in the 1940s to 1960s. However, diminishing returns from this discovery platform led to its collapse, and efforts to create a new platform based on target-focused screening of large libraries of synthetic compounds failed, in part owing to the lack of penetration of such compounds through the bacterial envelope. This article considers strategies to re-establish viable platforms for antibiotic discovery. These include investigating untapped natural product sources such as uncultured bacteria, establishing rules of compound penetration to enable the development of synthetic antibiotics, developing species-specific antibiotics and identifying prodrugs that have the potential to eradicate dormant persisters, which are often responsible for hard-to-treat infections. PMID- 23629506 TI - Advances in the development of new tuberculosis drugs and treatment regimens. AB - Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide. For the first time since the 1960s, new and novel drugs and regimens for all forms of TB are emerging. Such regimens are likely to utilize both repurposed drugs and new chemical entities, and several of these regimens are now progressing through clinical trials. This article covers current concepts and recent advances in TB drug discovery and development, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies. PMID- 23629508 TI - Neurometric amplitude-modulation detection threshold in the guinea-pig ventral cochlear nucleus. AB - Amplitude modulation (AM) is a pervasive feature of natural sounds. Neural detection and processing of modulation cues is behaviourally important across species. Although most ecologically relevant sounds are not fully modulated, physiological studies have usually concentrated on fully modulated (100% modulation depth) signals. Psychoacoustic experiments mainly operate at low modulation depths, around detection threshold (~5% AM). We presented sinusoidal amplitude-modulated tones, systematically varying modulation depth between zero and 100%, at a range of modulation frequencies, to anaesthetised guinea-pigs while recording spikes from neurons in the ventral cochlear nucleus (VCN). The cochlear nucleus is the site of the first synapse in the central auditory system. At this locus significant signal processing occurs with respect to representation of AM signals. Spike trains were analysed in terms of the vector strength of spike synchrony to the amplitude envelope. Neurons showed either low-pass or band pass temporal modulation transfer functions, with the proportion of band-pass responses increasing with increasing sound level. The proportion of units showing a band-pass response varies with unit type: sustained chopper (CS) > transient chopper (CT) > primary-like (PL). Spike synchrony increased with increasing modulation depth. At the lowest modulation depth (6%), significant spike synchrony was only observed near to the unit's best modulation frequency for all unit types tested. Modulation tuning therefore became sharper with decreasing modulation depth. AM detection threshold was calculated for each individual unit as a function of modulation frequency. Chopper units have significantly better AM detection thresholds than do primary-like units. AM detection threshold is significantly worse at 40 dB vs. 10 dB above pure-tone spike rate threshold. Mean modulation detection thresholds for sounds 10 dB above pure-tone spike rate threshold at best modulation frequency are (95% CI) 11.6% (10.0-13.1) for PL units, 9.8% (8.2-11.5) for CT units, and 10.8% (8.4-13.2) for CS units. The most sensitive guinea-pig VCN single unit AM detection thresholds are similar to human psychophysical performance (~3% AM), while the mean neurometric thresholds approach whole animal behavioural performance (~10% AM). PMID- 23629509 TI - Apelin acts in the subfornical organ to influence neuronal excitability and cardiovascular function. AB - Apelin is an adipocyte-derived hormone involved in the regulation of water balance, food intake and the cardiovascular system partially through actions in the CNS. The subfornical organ (SFO) is a circumventricular organ with identified roles in body fluid homeostasis, cardiovascular control and energy balance. The SFO lacks a normal blood-brain barrier, and is thus able to detect circulating signalling molecules such as angiotensin II and leptin. In this study, we investigated actions of apelin-13, the predominant apelin isoform in brain and circulatory system, on the excitability of dissociated SFO neurons using electrophysiological approaches, and determined the cardiovascular consequences of direct administration into the SFO of anaesthetized rats. Whole cell current clamp recording revealed that bath-applied 100 nm apelin-13 directly influences the excitability of the majority of SFO neurons by eliciting either depolarizing (31.8%, mean 7.0 +/- 0.8 mV) or hyperpolarizing (28.6%, mean -10.4 +/- 1.8 mV) responses. Using voltage-clamp techniques, we also identified modulatory actions of apelin-13 on specific ion channels, demonstrating that apelin-13 activates a non-selective cationic conductance to depolarize SFO neurons while activation of the delayed rectifier potassium conductance underlies hyperpolarizing effects. In anaesthetized rats, microinjection of apelin into SFO decreased both blood pressure (BP) (mean area under the curve -1492.3 +/- 357.1 mmHg.s, n = 5) and heart rate (HR) (-32.4 +/- 10.39 beats, n = 5). Our data suggest that circulating apelin can directly affect BP and HR as a consequence of the ability of this peptide to modulate the excitability of SFO neurons. PMID- 23629511 TI - Carbon monoxide release catalysed by electron transfer: electrochemical and spectroscopic investigations of [Re(bpy-R)(CO)4](OTf) complexes relevant to CO2 reduction. AB - [Re(bpy-tBu)(CO)4](OTf) (bpy-tBu = 4,4'-di-tert-butyl-2,2'-bipyridine, OTf = trifluoromethanesulfonate) (1) and [Re(bpy)(CO)4](OTf) (bpy = 2,2'-bipyridine) (2) were synthesized and studied as proposed intermediates in the electrocatalytic reduction of carbon dioxide (CO2) by Re(bpy-R)(CO)3X. Both compounds demonstrated increased current responses in cyclic voltammograms under CO2. Complex 1 was also characterized by X-ray crystallography. Infrared spectroelectrochemistry (IR-SEC) of 1 and 2 indicated that upon exposure of the cationic tetracarbonyl compounds to a reducing potential, a CO ligand is labilised and [Re(bpy-R)(CO)3(CH3CN)](+) species are formed. This is proposed to occur via an electron-transfer-catalysed process wherein a catalytic amount of reduced species propagates a ligand exchange reaction. Addition of a catalytic amount of potassium intercalated graphite (KC8), a chemical reductant, to a solution of 1 or 2 also yielded quantitative formation of [Re(bpy R)(CO)3(CH3CN)](+), which indicates that the CO loss is catalysed by electron transfer, and not the electrode itself. PMID- 23629510 TI - Contractility and kinetics of human fetal and human adult skeletal muscle. AB - Little is known about the contraction and relaxation properties of fetal skeletal muscle, and measurements thus far have been made with non-human mammalian muscle. Data on human fetal skeletal muscle contraction are lacking, and there are no published reports on the kinetics of either fetal or adult human skeletal muscle myofibrils. Understanding the contractile properties of human fetal muscle would be valuable in understanding muscle development and a variety of muscle diseases that are associated with mutations in fetal muscle sarcomere proteins. Therefore, we characterised the contractile properties of developing human fetal skeletal muscle and compared them to adult human skeletal muscle and rabbit psoas muscle. Electron micrographs showed human fetal muscle sarcomeres are not fully formed but myofibril formation is visible. Isolated myofibril mechanical measurements revealed much lower specific force, and slower rates of isometric force development, slow phase relaxation, and fast phase relaxation in human fetal when compared to human adult skeletal muscle. The duration of slow phase relaxation was also significantly longer compared to both adult groups, but was similarly affected by elevated ADP. F-actin sliding on human fetal skeletal myosin coated surfaces in in vitro motility (IVM) assays was much slower compared with adult rabbit skeletal myosin, though the Km(app) (apparent (fitted) Michaelis-Menten constant) of F-actin speed with ATP titration suggests a greater affinity of human fetal myosin for nucleotide binding. Replacing ATP with 2 deoxy-ATP (dATP) increased F-actin speed for both groups by a similar amount. Titrations of ADP into IVM assays produced a similar inhibitory affect for both groups, suggesting ADP binding may be similar, at least under low load. Together, our results suggest slower but similar mechanisms of myosin chemomechanical transduction for human fetal muscle that may also be limited by immature myofilament structure. PMID- 23629512 TI - Rearrangements and addition reactions of biarylazacyclooctynones and the implications to copper-free click chemistry. AB - Highly strained biarylazacyclooctynone (BARAC) and analogous bioconjugation reagents were shown to undergo novel rearrangement and addition reactions leading to tetracyclic products. This may limit their practical applicability as bioorthogonal reporters for imaging biomolecules within living systems. PMID- 23629513 TI - Free radicals in chemical biology: from chemical behavior to biomarker development. AB - The involvement of free radicals in life sciences has constantly increased with time and has been connected to several physiological and pathological processes. This subject embraces diverse scientific areas, spanning from physical, biological and bioorganic chemistry to biology and medicine, with applications to the amelioration of quality of life, health and aging. Multidisciplinary skills are required for the full investigation of the many facets of radical processes in the biological environment and chemical knowledge plays a crucial role in unveiling basic processes and mechanisms. We developed a chemical biology approach able to connect free radical chemical reactivity with biological processes, providing information on the mechanistic pathways and products. The core of this approach is the design of biomimetic models to study biomolecule behavior (lipids, nucleic acids and proteins) in aqueous systems, obtaining insights of the reaction pathways as well as building up molecular libraries of the free radical reaction products. This context can be successfully used for biomarker discovery and examples are provided with two classes of compounds: mono trans isomers of cholesteryl esters, which are synthesized and used as references for detection in human plasma, and purine 5',8-cyclo-2'-deoxyribonucleosides, prepared and used as reference in the protocol for detection of such lesions in DNA samples, after ionizing radiations or obtained from different health conditions. PMID- 23629514 TI - Electrocatalytic oxidation of water observed on a nano-gold/palladium electrode. AB - New and unknown electrocatalytic oxidation of water was found to occur on a nano gold attached palladium electrode. Since the oxidation potential was negative enough to that of well-known normal oxidation of water to form O2, the direct use of water as a fuel, instead of alcohols, might be possible using the nano gold/palladium electrode. PMID- 23629516 TI - In Ovo effects of two organophosphate flame retardants--TCPP and TDCPP--on pipping success, development, mRNA expression, and thyroid hormone levels in chicken embryos. AB - Tris(1-chloro-2-propyl) phosphate (TCPP) and tris(1,3-dichloro-2-propyl) phosphate (TDCPP) are organic flame retardants detected in the environment and biota for which avian toxicological data are limited. In this study, domestic chicken eggs were injected with TCPP or TDCPP (maximum dose = 51,600 and 45,000ng/g egg, respectively) to determine dose-dependent effects on pipping success, development, hepatic messenger RNA (mRNA) expression levels of genes associated with xenobiotic metabolism and the thyroid hormone (TH) pathway, and TH levels following 20-22 days of incubation. Neither compound reduced pipping success; however, TCPP significantly delayed pipping at 9240 and 51,600ng/g and reduced tarsus length at 51,600ng/g. TDCPP exposure resulted in significant decreases in head plus bill length, embryo mass, and gallbladder size at 45,000ng/g and reduced plasma free T4 levels at 7640ng/g. Type I deiodinase, liver fatty acid-binding protein, and cytochrome P450 (CYP) 3A37 mRNA levels were significantly induced by TCPP, whereas TDCPP induced CYP3A37 and CYP2H1. Chemical analysis of egg contents at incubation days 0, 5, 11, 18, and 19 revealed that > 92% of the injected TCPP or TDCPP concentration was detectable up to day 5; however, < 1% was detected by day 19. The observed phenotypic responses to TCPP and TDCPP exposure may be associated with disruption of the TH axis, which is critical for normal growth and development in birds. The effects of TDCPP on the gallbladder indicate that the disturbance of lipid metabolism is a likely mechanism of toxicity. PMID- 23629518 TI - Chromosomal instability, DNA index, dysplasia, and subsite in oral premalignancy as intermediate endpoints of risk of cancer. AB - BACKGROUND: Chromosomal instability and aneuploidy may represent biomarkers of oral exposure to damaging agents and early signs of clinical disease according to the theory of "oral field cancerization." METHODS: The hypothesis was tested that the DNA index (DI) values, obtained by high-resolution DNA flow cytometry (DNA FCM), may potentially contribute to oral cancer risk prediction. For this purpose, the DI of oral fields of normal-appearing mucosa and oral potentially malignant disorders (OPMDs) in 165 consecutive patients was tested for association with dysplasia and/or the oral subsites of tongue and floor of the mouth taken as high-risk intermediate endpoints surrogate of cancer clinical endpoints. The association was evaluated by logistic regression using patient gender, age, tobacco, cigarette smoking habit, and alcohol abuse as confounding variables. RESULTS: Different DI models provided evidence of statistical significant associations. Subdividing the DI values in diploid, near-diploid aneuploid, and high or multiple aneuploid from both OPMDs and oral normal appearing mucosa, ORs, respectively, of 1, 4.3 (P = 0.001), and 18.4 (P < 0.0005) were obtained. CONCLUSION: Routine DI analysis by high-resolution DNA-FCM seems potentially useful to complement dysplasia and subsite analysis for assessment of oral cancer risk prediction and for a better management of the patients with OPMDs. Work is in progress to validate the present findings in a prospective study with clinical endpoints. IMPACT: Identifying DNA abnormalities in oral premalignancy may lead to biomarkers of oral exposure and cancer risk and potentially to more effective prevention measures. PMID- 23629517 TI - Complete artificial saliva alters expression of proinflammatory cytokines in human dermal fibroblasts. AB - Complete artificial saliva (CAS) is a saliva substitute often used as a vehicle for test articles, including smokeless tobacco products. In the course of a study employing normal adult human dermal fibroblasts (HDFa) as a model in vitro, we discovered that CAS as a vehicle introduced a significant change in the expression of proinflammatory cytokines. To determine the effects of CAS on gene expression, real-time quantitative reverse-transcriptase PCR gene array analysis was used. Results indicate that robust changes in the expression of the proinflammatory cytokine interleukin 8 (IL8) and the vascular cell adhesion molecule 1 (VCAM1) occur within 5h of exposure to CAS. To determine whether CAS also alters cytokine release into the culture media, cytometric bead array assays for human inflammatory cytokines were performed. Analysis shows that CAS induced the release of IL8 and IL6. This study focused on determining which components in CAS were responsible for the proinflammatory response in HDFa. The following components were investigated: alpha-amylase, lysozyme, acid phosphatase, and urea. Results demonstrated that enzymatically active alpha-amylase induced gene expression for proinflammatory cytokines IL8, IL6, tumor necrosis factor-alpha, and IL1alpha and for VCAM1. Therefore, it is important to carefully evaluate the "vehicle effects" of CAS and its components in in vitro toxicology research. PMID- 23629519 TI - Gender differences in correlates of colorectal cancer screening among Black Medicare beneficiaries in Baltimore. AB - BACKGROUND: Previous research has shown colorectal cancer (CRC) screening disparities by gender. Little research has focused primarily on gender differences among older Black individuals, and reasons for existing gender differences remain poorly understood. METHODS: We used baseline data from the Cancer Prevention and Treatment Demonstration Screening Trial. Participants were recruited from November 2006 to March 2010. In-person interviews were used to assess self-reported CRC screening behavior. Up-to-date CRC screening was defined as self-reported colonoscopy or sigmoidoscopy in the past 10 years or fecal occult blood testing in the past year. We used multivariable logistic regression to examine the association between gender and self-reported screening, adjusting for covariates. The final model was stratified by gender to examine factors differentially associated with screening outcomes for males and females. RESULTS: The final sample consisted of 1,552 female and 586 male Black Medicare beneficiaries in Baltimore, Maryland. Males were significantly less likely than females to report being up-to-date with screening (77.5% vs. 81.6%, P = 0.030), and this difference was significant in the fully adjusted model (OR: 0.72; 95% confidence interval, 0.52-0.99). The association between having a usual source of care and receipt of cancer screening was stronger among males compared with females. CONCLUSIONS: Although observed differences in CRC screening were small, several factors suggest that gender-specific approaches may be used to promote screening adherence among Black Medicare beneficiaries. IMPACT: Given disproportionate CRC mortality between White and Black Medicare beneficiaries, gender-specific interventions aimed at increasing CRC screening may be warranted among older Black patients. PMID- 23629515 TI - Mitochondria as a target of environmental toxicants. AB - Enormous strides have recently been made in our understanding of the biology and pathobiology of mitochondria. Many diseases have been identified as caused by mitochondrial dysfunction, and many pharmaceuticals have been identified as previously unrecognized mitochondrial toxicants. A much smaller but growing literature indicates that mitochondria are also targeted by environmental pollutants. We briefly review the importance of mitochondrial function and maintenance for health based on the genetics of mitochondrial diseases and the toxicities resulting from pharmaceutical exposure. We then discuss how the principles of mitochondrial vulnerability illustrated by those fields might apply to environmental contaminants, with particular attention to factors that may modulate vulnerability including genetic differences, epigenetic interactions, tissue characteristics, and developmental stage. Finally, we review the literature related to environmental mitochondrial toxicants, with a particular focus on those toxicants that target mitochondrial DNA. We conclude that the fields of environmental toxicology and environmental health should focus more strongly on mitochondria. PMID- 23629520 TI - Batch effects and pathway analysis: two potential perils in cancer studies involving DNA methylation array analysis. AB - BACKGROUND: DNA methylation microarrays have become an increasingly popular means of studying the role of epigenetics in cancer, although the methods used to analyze these arrays are still being developed and existing methods are not always widely disseminated among microarray users. METHODS: We investigated two problems likely to confront DNA methylation microarray users: (i) batch effects and (ii) the use of widely available pathway analysis software to analyze results. First, DNA taken from individuals exposed to low and high levels of drinking water arsenic were plated twice on Illumina's Infinium 450 K HumanMethylation Array, once in order of exposure and again following randomization. Second, we conducted simulations in which random CpG sites were drawn from the 450 K array and subjected to pathway analysis using Ingenuity's IPA software. RESULTS: The majority of differentially methylated CpG sites identified in Run One were due to batch effects; few sites were also identified in Run Two. In addition, the pathway analysis software reported many significant associations between our data, randomly drawn from the 450 K array, and various diseases and biological functions. CONCLUSIONS: These analyses illustrate the pitfalls of not properly controlling for chip-specific batch effects as well as using pathway analysis software created for gene expression arrays to analyze DNA methylation array data. IMPACT: We present evidence that (i) chip-specific effects can simulate plausible differential methylation results and (ii) popular pathway analysis software developed for expression arrays can yield spurious results when used in tandem with methylation microarrays. PMID- 23629522 TI - Polyionic and cysteine-containing fusion peptides as versatile protein tags. AB - In response to advances in proteomics research and the use of proteins in medical and biotechnological applications, recombinant protein production and the design of specific protein characteristics and functions has become a widely used technology. In this context, protein fusion tags have been developed as indispensable tools for protein expression, purification, and the design of functionalized surfaces or artificially bifunctional proteins. Here we summarize how positively or negatively charged polyionic fusion peptides with or without an additional cysteine can be used as protein tags for protein expression and purification, for matrix-assisted refolding of aggregated protein, and for coupling of proteins either to technologically relevant matrices or to other proteins. In this context we used cysteine-containing polyionic fusion peptides for the design of immunotoxins. In general, polyionic fusion tags can be considered as a multifunctional module in protein technology. PMID- 23629521 TI - Physical activity, tumor PTGS2 expression, and survival in patients with colorectal cancer. AB - BACKGROUND: Higher levels of physical activity are associated with lower colorectal carcinoma incidence and mortality, perhaps through influencing energy balance, cellular prosta7 systemic inflammation. Although evidence suggests interactive effects of energetics, sedentary lifestyle, and tumor CTNNB1 (beta catenin) or CDKN1B (p27) status on colon cancer prognosis, interactive effects of physical activity and tumor PTGS2 (the official symbol for COX-2) status on clinical outcome remain unknown. METHODS: Using molecular pathological epidemiology database of 605 stage I-III colon and rectal cancers in two prospective cohort studies (the Nurse's Health Study and the Health Professionals Follow-up Study), we examined patient survival according to postdiagnosis physical activity and tumor PTGS2 status (with 382 PTGS2-positive and 223 PTGS2 negative tumors by immunohistochemistry). Cox proportional hazards models were used to calculate colorectal cancer-specific mortality HR, adjusting for clinical and other tumor variables including microsatellite instability status. RESULTS: Among PTGS2-positive cases, compared with the least active first quartile, the multivariate HRs (95% confidence interval) were 0.30 (0.14-0.62) for the second, 0.38 (0.20-0.71) for the third, and 0.18 (0.08-0.41) for the fourth quartile of physical activity level (Ptrend = 0.0002). In contrast, among PTGS2-negative cases, physical activity level was not significantly associated with survival (Ptrend = 0.84; Pinteraction = 0.024, between physical activity and tumor PTGS2 status). CONCLUSIONS: Postdiagnosis physical activity is associated with better survival among patients with PTGS2-positive tumors but not among patients with PTGS2-negative tumors. IMPACT: Immunohistochemical PTGS2 expression in colorectal carcinoma may serve as a predictive biomarker in pathology practice, which may predict stronger benefit from exercise. PMID- 23629523 TI - Cathepsin K: a unique collagenolytic cysteine peptidase. AB - Cathepsin K has emerged as a promising target for the treatment of osteoporosis in recent years. Initially identified as a papain-like cysteine peptidase expressed in high levels in osteoclasts, the important role of this enzyme in bone metabolism was highlighted by the finding that mutations in the CTSK gene cause the rare recessive disorder pycnodysostosis, which is characterized by severe bone anomalies. At the molecular level, the physiological role of cathepsin K is reflected by its unique cleavage pattern of type I collagen molecules, which is fundamentally different from that of other endogenous collagenases. Several cathepsin K inhibitors have been developed to reduce the excessive bone matrix degradation associated with osteoporosis, with the frontrunner odanacatib about to successfully conclude Phase 3 clinical trials. Apart from osteoclasts, cathepsin K is expressed in different cell types throughout the body and is involved in processes of adipogenesis, thyroxine liberation and peptide hormone regulation. Elevated activity of cathepsin K has been associated with arthritis, atherosclerosis, obesity, schizophrenia, and tumor metastasis. Accordingly, its activity is tightly regulated via multiple mechanisms, including competitive inhibition by endogenous macromolecular inhibitors and allosteric regulation by glycosaminoglycans. This review provides a state-of-the-art description of the activity of cathepsin K at the molecular level, its biological functions and the mechanisms involved in its regulation. PMID- 23629524 TI - Short-term outcomes for open and laparoscopic midline incisional hernia repair: a randomized multicenter controlled trial: the ProLOVE (prospective randomized trial on open versus laparoscopic operation of ventral eventrations) trial. AB - OBJECTIVE: : The aim of the trial was to compare laparoscopic technique with open technique regarding short-term pain, quality of life (QoL), recovery, and complications. BACKGROUND: : Laparoscopic and open techniques for incisional hernia repair are recognized treatment options with pros and cons. METHODS: : Patients from 7 centers with a midline incisional hernia of a maximum width of 10 cm were randomized to either laparoscopic (LR) or open sublay (OR) mesh repair. Primary end point was pain at 3 weeks, measured as the bodily pain subscale of Short Form-36 (SF-36). Secondary end points were complications registered by type and severity (the Clavien-Dindo classification), movement restrictions, fatigue, time to full recovery, and QoL up to 8 weeks. RESULTS: : Patients were recruited between October 2005 and November 2009. Of 157 randomized patients, 133 received intervention: 64 LR and 69 OR. Measurements of pain did not differ, nor did movement restriction and postoperative fatigue. SF-36 subscales favored the LR group: physical function (P < 0.001), role physical (P < 0.012), mental health (P < 0.022), and physical composite score (P < 0.009). Surgical site infections were 17 in the OR group compared with 1 in the LR group (P < 0.001). The severity of complications did not differ between the groups (P < 0.213). CONCLUSIONS: : Postoperative pain or recovery at 3 weeks after repair of midline incisional hernias does not differ between LR and OR, but the LR results in better physical function and less surgical site infections than the OR does. (ClinicalTrials.gov Identifier: NCT00472537). PMID- 23629525 TI - Peridural analgesia may affect long-term survival in patients with colorectal cancer after surgery (PACO-RAS-Study): an analysis of a cancer registry. AB - OBJECTIVE: To determine the effect of peridural analgesia on long-term survival in patients who underwent surgical treatment of colorectal carcinoma. BACKGROUND: Clinical and animal studies suggest a potential benefit of peridural analgesia on morbidity and mortality after cancer surgery. The effect of peridural analgesia on long-term outcome after surgery for colorectal cancer remains undefined. METHODS: From 2003 to 2009, there were 749 patients who underwent surgery for colorectal carcinoma under general anesthesia with or without peridural analgesia. Clinical data were reviewed retrospectively and analyzed with multivariate analysis and Kaplan-Meier plots. RESULTS: There were 442 patients who received peridural analgesia and 307 patients who did not receive peridural analgesia. A substantial survival benefit was observed in patients who received peridural analgesia (5-year survival rate: peridural analgesia, 62%; no peridural analgesia, 54%; P < 0.02). The hazard rate for death was decreased by 27% in patients who received peridural analgesia. When peridural analgesia was included simultaneously in a Cox model with the confounding factors age, American Society of Anesthesiologists classification, and stage, there was a significant survival benefit in patients who received peridural analgesia. In patients with America Society of Anesthesiologists classification 3 to 4, there was significantly greater survival with peridural analgesia than without peridural analgesia (P < 0.009). CONCLUSIONS: Peridural analgesia may improve survival in patients underwent surgery for colorectal carcinoma. The survival benefit with peridural analgesia was greater in patients who had greater medical morbidity. PMID- 23629526 TI - Biologic mesh for ventral hernia repair: a cautionary tale. PMID- 23629527 TI - For patients with early esophageal cancer endoscopic mucosa resection is not the end of the story! PMID- 23629528 TI - Reply to letter: "Does duration of perioperative antibiotic prophylaxis matter in cardiac surgery?". PMID- 23629529 TI - The ALPPS procedure for extended indications in liver surgery: an old finding applied in surgical oncology. PMID- 23629530 TI - Effect of platelet-rich plasma on bone engineering with an alloplastic substitute containing BMP2. AB - A robust method for inducing bone-formation without an autograft has not been established. Currently, both platelet-rich plasma (PRP) and bone morphogenetic protein (BMP) have been widely investigated for their clinical use in such cases. However, their synergistic effect is still controversial and previously shown diversity of this effect depends on various factors such as the bone substitutes involved. In this study, we investigated the synergistic effect of PRP and BMP2 on an alloplastic substitute as potentiators to induce in vivo bone-formation. A 10 mm diameter bony defect in rabbit calvarium was reconstructed using biphasic calcium phosphate (BCP) ceramics with or without PRP, recombinant human (rh) BMP2, and their combination. At 6 and 12 weeks after implantation, rabbits were euthanized and the radiographic and histomorphometric features of bone reconstruction were analyzed. The results showed that defects filled by rhBMP2/BCP with or without PRP had high bone density at 6 and 12 weeks in radiological evaluation. However, in histomorphometric analysis, the defects filled by rhBMP2/BCP with PRP showed significant new bone formation compared with that by rhBMP2/BCP without PRP, especially at 6 weeks. We propose that the synergistic effect of PRP and rhBMP2 gives highly osteoinductive properties to alloplastic substitutes in vivo. PMID- 23629531 TI - Biomechanical study of healing of patellar tendon after resection of the central one-third in an adult-mature rabbit model. AB - The present study was performed to investigate effects of ageing on biomechanical properties of healing tissues of the patellar tendon (PT) after the removal of its central portion. An entire one-third defect was made in the PT of 0.5 year- (0.5 yr) and 2 year-old rabbits (2 yr). After 6 or 12 weeks, the tissue regenerated in the defect and the remaining, residual tissue was examined biomechanically and histologically. Age-related difference in the PT length was only observed in operated tendons at 6 weeks, and in the cross-sectional area such difference was observed only in unoperated, normal tendons. At 12 weeks, tensile strength and tangent modulus of regenerated tissues in 0.5 yr were significantly higher than those in 2 yr. By contrast, these properties of residual tissues in 2 yr were significantly higher than those of 0.5 yr at 6 weeks. The histology of each of regenerated and residual tissues was essentially similar between the two age groups. Accordingly, ageing exhibited adverse effects on the mechanical properties of tissues regenerated in the central third defect of the PT. This may be due to high tangent modulus of normal and residual PT tissues in aged animals, which reduces the amount of mechanical stimulation applied to regenerated tissues during healing. PMID- 23629532 TI - Influence of porosity on corrosion behaviour of Ti-39Nb alloy for dental applications. AB - Porous materials allow for easier osseointegration of implants and their firmer connection with the bone. The presence of pores in a material may become a source of both mechanical and corrosion problems. The presented study explored a Ti-39Nb alloy with a porosity of 0-33%. Specimens were exposed in the physiological solution of two pH values. In view of this material's possible use in dental applications, the effect of fluoride ions on its corrosion behaviour was studied. The open circuit potential and polarization resistance were measured. Data concerning susceptibility to crevice corrosion were obtained from potentiostatic measurements based on the ASTM F746 standard. In terms of corrosion behaviour, specimens with a lower porosity were not much different from the non-porous material. Porosity produced its effect at the level of 24 and 33%. It is obvious that porosity affects corrosion behaviour of this type of material. This conclusion was confirmed by measurements of susceptibility to crevice corrosion which grew with the specimens' increasing porosity. Corrosion resistance of the Ti-39Nb alloy was comparable with that of the compact material, but the presence of pores initiated a local attack of the material. PMID- 23629533 TI - Preparation and properties of alpha-calcium sulphate hemihydrate and beta tricalcium phosphate bone substitute. AB - Autogenous bone graft carries the risk of complications. In contrast, artificial bone graft provides initial strength and allows new bone ingrowth. In this study, we examined methods of preparation of alpha-calcium sulphate hemihydrate (alpha CSH) and beta-tricalcium phosphate (beta-TCP), and a composite of the two materials. Characterization of the materials was determined with X-ray diffraction, differential thermal analysis (DTA), scanning electron microscopy (SEM), and porosity analysis. beta-TCP exhibited the spatial structure and porosity of normal bone with a macropore size of 50-400 MUm and some 1 MUm micropores. alpha-CSH exhibited a regular crystal structure. A combined material was prepared in a 1:1 weight ratio, and in a rabbit model, the rate of new bone mineralization was similar to that of autogenous bone graft. The combined material of beta-TCP and alpha-CSH in this study may provide similar efficacy as autogenous bone graft. PMID- 23629534 TI - Synthesis and characterization of glutaraldehyde-based crosslinked gelatin as a local hemostat sponge in surgery: an in vitro study. AB - In this study, preparation and characterization of soft crosslinked gelatin sponge for blood hemostasis application was considered. The effects of gelatin and crosslinker concentrations and altering freeze-drying temperature on sponges' density and structure, water absorption ability and biodegradation, cytotoxicity, mechanical properties and hemostatic effect were investigated. The density measurement indicated that the density of freeze-dried sponges increased when the freezing temperature was lowered. Scanning electron microscope and optical microscope images showed that gelatin sponges had uniform small pores (60 MUm) after freezing at liquid nitrogen (-196 degrees C). Biodegradation study demonstrated that the crosslinked sponges containing 1% and 2% gelatin lost respectively nearly 40 to 70% of their weight during 24 h. Prepared sponges showed desired water absorption ability (30-40 times of own dry weight) improved by lowering glutaraldehyde concentration. Cell toxicity was not detected in any of the samples. Compression modulus of sponges decreased four times (160 to 40 kPa) as the gelatin content varied from 2 to 1% w/v. Hemostasis study confirmed that the hemolytic ability of sponges increased through raising gelatin content and porosity of sponge. We suggest using gelatin sponges containing 1% w/v gelatin, 0.5% w/v glutaraldehyde frozen in liquid nitrogen, as a potential substitution for local hemostat absorbable sponge. PMID- 23629535 TI - Bioreactor and scaffold design for the mechanical stimulation of anterior cruciate ligament grafts. AB - Various studies have shown that physical stimuli modulate cell function and this has motivated the development of a bioreactor to engineer tissues in vitro by exposing them to mechanical loads. Here, we present a bioreactor for the physical stimulation of anterior cruciate ligament (ACL) grafts, whereby complex multi dimensional strain can be applied to the matrices. Influences from environmental conditions to the behavior of different cells on our custom-made silk scaffold can be investigated since the design of the bioreactor allows controlling these parameters precisely. With the braided design of the presented silk scaffold we achieve maximum loads and stiffness values matching those of the human ACL. Thus, the existent degummed and wet silk scaffolds absorb maximum loads of 2030+/-109 N with stiffness values of 336+/-40 N/mm. PMID- 23629536 TI - The adsorptive behavior of albumin and lysozyme proteins on rod-shaped and plate shaped hydroxyapatite. AB - The adsorption behavior of albumin (BSA) and lysozyme (LSZ) on rod-shaped and plate-shaped hydroxyapatite (HA) was investigated to evaluate the influence of crystal orientation and morphology on the selective protein adsorption of HA. The rod-shaped HA was prepared by hydrothermal treatment from beta-tricalcium phosphate (beta-TCP) in H3PO4 solution (pH 2.0 and 4.0 for HA-pH 2.0 and HA-pH 4.0). The plate-shaped HA was synthesized by hydrolysis of CaHPO4-2H2O (DCPD) in NaOH solution at 40 degrees C and 80 degrees C (HA-40 degrees C and HA-80 degrees C). The synthesized HA was characterized using scanning electron microscopy (SEM) and X-ray diffractometry (XRD). HA-pH 2.0 and HA-pH 4.0 produced rod-shaped crystals that were highly oriented to the a-face plane, whereas HA-40 degrees C and HA-80 degrees C showed a plate-like shape and a c-face preferred orientation. The peak intensity ratio I(300)/I(002) (a/c intensity ratio) from the XRD patterns increased in the following order: HA-80 degrees C, HA-40 degrees C, HA pH 2.0 and HA-pH 4.0. It also increased as the Ca/P ratio decreased. The amount of adsorbed BSA increased in the following order: HA-pH 4.0, HA-pH 2.0, HA-40 degrees C and HA-80 degrees C. The amount of adsorbed LSZ on HA increased in the following order--HA-pH 2.0, HA-pH 4.0, HA-40 degrees C and HA-80 degrees C--with a corresponding decrease in the a/c intensity ratio. The BSA/LSA adsorption ratio increased with the a/c intensity ratio in the range of 3.3-8.9, and the BSA and LSZ were selectively adsorbed on HA, depending on the crystal shape. PMID- 23629537 TI - Identification of calcium binding sites on calsequestrin 1 and their implications for polymerization. AB - Biophysical studies have shown that each molecule of calsequestrin 1 (CASQ1) can bind about 70-80 Ca(2+) ions. However, the nature of Ca(2+)-binding sites has not yet been fully characterized. In this study, we employed in silico approaches to identify the Ca(2+) binding sites and to understand the molecular basis of CASQ1 Ca(2+) recognition. We built the protein model by extracting the atomic coordinates for the back-to-back dimeric unit from the recently solved hexameric CASQ1 structure (PDB id: ) and adding the missing C-terminal residues (aa350 364). Using this model we performed extensive 30 ns molecular dynamics simulations over a wide range of Ca(2+) concentrations ([Ca(2+)]). Our results show that the Ca(2+)-binding sites on CASQ1 differ both in affinity and geometry. The high affinity Ca(2+)-binding sites share a similar geometry and interestingly, the majority of them were found to be induced by increased [Ca(2+)]. We also found that the system shows maximal Ca(2+)-binding to the CAS (consecutive aspartate stretch at the C-terminus) before the rest of the CASQ1 surface becomes saturated. Simulated data show that the CASQ1 back-to-back stacking is progressively stabilized by the emergence of an increasing number of hydrophobic interactions with increasing [Ca(2+)]. Further, this study shows that the CAS domain assumes a compact structure with an increase in Ca(2+) binding, which suggests that the CAS domain might function as a Ca(2+)-sensor that may be a novel structural motif to sense metal. We propose the term "Dn-motif" for the CAS domain. PMID- 23629538 TI - Growth hormone and cognitive function. AB - Emerging data indicate that growth hormone (GH) therapy could have a role in improving cognitive function. GH replacement therapy in experimental animals and human patients counteracts the dysfunction of many behaviours related to the central nervous system (CNS). Various behaviours, such as cognitive behaviours related to learning and memory, are known to be induced by GH; the hormone might interact with specific receptors located in areas of the CNS that are associated with the functional anatomy of these behaviours. GH is believed to affect excitatory circuits involved in synaptic plasticity, which alters cognitive capacity. GH also has a protective effect on the CNS, as indicated by its beneficial effects in patients with spinal cord injury. Data collected from animal models indicates that GH might also stimulate neurogenesis. This Review discusses the mechanisms underlying the interactions between GH and the CNS, and the data emerging from animal and human studies on the relationship between GH and cognitive function. In this article, particular emphasis is given to the role of GH as a treatment for patients with cognitive impairment resulting from deficiency of the hormone. PMID- 23629539 TI - Diagnosis and treatment of growth hormone deficiency in adults. AB - The availability of synthetic recombinant human growth hormone (GH) in potentially unlimited quantities since the 1980s has improved understanding of the many nonstatural effects of GH on metabolism, body composition, physical and psychological function, as well as the consequences of GH deficiency in adult life. Adult GH deficiency is now recognized as a distinct if nonspecific syndrome with considerable adverse health consequences. GH replacement therapy in lower doses than those used in children can reverse many of these abnormalities and restore functional capacities toward or even to normal; if dosed appropriately, GH therapy has few adverse effects. Although some doubts remain about possible long-term risks of childhood GH therapy, most registries of adult GH replacement therapy, albeit limited in study size and duration, have not shown an increased incidence of cancers or of cardiovascular morbidity or mortality. PMID- 23629541 TI - Structural trends in ten-vertex endohedral clusters, M@E(10) and the synthesis of a new member of the family, [Fe@Sn10]3-. AB - The synthesis of a new endohedral ten-vertex Zintl ion cluster, [Fe@Sn10](3-), isoelectronic with [Fe@Ge10](3-), is reported. In an attempt to place this new cluster within the context of the known structural chemistry of the M@E10 family (M = transition metal, E = main group element), we have carried out a detailed electronic structure analysis of the different structural types: viz bicapped square antiprismatic ([Ni@Pb10](2-), [Zn@In10](8-)), tetra-capped trigonal prismatic ([Ni@In10](10-)) and the remarkable pentagonal prismatic [Fe@Ge10](3-) and [Co@Ge10](3-). We establish that the structural trends can be interpreted in terms of a continuum of effective electron counts at the E10 cage, ranging from electron deficient (<4n + 2) in [Ni@In10](10-) to highly electron rich (>4n + 2) in [Fe@Ge10](3-). The effective electron count differs from the total valence electron count in that it factors in the increasingly active role of the metal d electrons towards the left of the transition series. The preference for a pentagonal prismatic geometry in [Fe@Ge10](3-) emerges as a natural consequence of backbonding to the cage from four orthogonal 3d orbitals of the low-valent metal ion. Our calculations suggest that the new [Fe@Sn10](3-) cluster should also exhibit structural consequences of backbonding from the metal to the cage, albeit to a less extreme degree than in its Ge analogue. The global minimum lies on a very flat surface connecting D4d, C2v and C3v-symmetric minima, suggesting a very plastic structure that may be easily deformed by the surrounding crystal environment. If so, then this provides a new and quite distinct structural type for the M@E10 family. PMID- 23629540 TI - Circulating microRNAs as novel biomarkers for diabetes mellitus. AB - Diabetes mellitus is characterized by insulin secretion from pancreatic beta cells that is insufficient to maintain blood glucose homeostasis. Autoimmune destruction of beta cells results in type 1 diabetes mellitus, whereas conditions that reduce insulin sensitivity and negatively affect beta-cell activities result in type 2 diabetes mellitus. Without proper management, patients with diabetes mellitus develop serious complications that reduce their quality of life and life expectancy. Biomarkers for early detection of the disease and identification of individuals at risk of developing complications would greatly improve the care of these patients. Small non-coding RNAs called microRNAs (miRNAs) control gene expression and participate in many physiopathological processes. Hundreds of miRNAs are actively or passively released in the circulation and can be used to evaluate health status and disease progression. Both type 1 diabetes mellitus and type 2 diabetes mellitus are associated with distinct modifications in the profile of miRNAs in the blood, which are sometimes detectable several years before the disease manifests. Moreover, circulating levels of certain miRNAs seem to be predictive of long-term complications. Technical and scientific obstacles still exist that need to be overcome, but circulating miRNAs might soon become part of the diagnostic arsenal to identify individuals at risk of developing diabetes mellitus and its devastating complications. PMID- 23629542 TI - Isolation of precursor B-cell subsets from umbilical cord blood. AB - Umbilical cord blood is highly enriched for hematopoietic progenitor cells at different lineage commitment stages. We have developed a protocol for isolating precursor B-cells at four different stages of differentiation. Because genes are expressed and epigenetic modifications occur in a tissue specific manner, it is vital to discriminate between tissues and cell types in order to be able to identify alterations in the genome and the epigenome that may lead to the development of disease. This method can be adapted to any type of cell present in umbilical cord blood at any stage of differentiation. This method comprises 4 main steps. First, mononuclear cells are separated by density centrifugation. Second, B-cells are enriched using biotin conjugated antibodies that recognize and remove non B-cells from the mononuclear cells. Third the B-cells are fluorescently labeled with cell surface protein antibodies specific to individual stages of B-cell development. Finally, the fluorescently labeled cells are sorted and individual populations are recovered. The recovered cells are of sufficient quantity and quality to be utilized in downstream nucleic acid assays. PMID- 23629543 TI - The Problem With Estimating Public Health Spending. AB - Accurate information on how much the United States spends on public health is critical. These estimates affect planning efforts; reflect the value society places on the public health enterprise; and allows for the demonstration of cost effectiveness of programs, policies, and services aimed at increasing population health. Yet, at present, there are a limited number of sources of systematic public health finance data. Each of these sources is collected in different ways, for different reasons, and so yields strikingly different results. This article aims to compare and contrast all 4 current national public health finance data sets, including data compiled by Trust for America's Health, the Association of State and Territorial Health Officials (ASTHO), the National Association of County and City Health Officials (NACCHO), and the Census, which underlie the oft cited National Health Expenditure Account estimates of public health activity. In FY2008, ASTHO estimates that state health agencies spent $24 billion ($94 per capita on average, median $79), while the Census estimated all state governmental agencies including state health agencies spent $60 billion on public health ($200 per capita on average, median $166). Census public health data suggest that local governments spent an average of $87 per capita (median $57), whereas NACCHO estimates that reporting LHDs spent $64 per capita on average (median $36) in FY2008. We conclude that these estimates differ because the various organizations collect data using different means, data definitions, and inclusion/exclusion criteria--most notably around whether to include spending by all agencies versus a state/local health department, and whether behavioral health, disability, and some clinical care spending are included in estimates. Alongside deeper analysis of presently underutilized Census administrative data, we see harmonization efforts and the creation of a standardized expenditure reporting system as a way to meaningfully systematize reporting of public health spending and revenue. PMID- 23629544 TI - Reliability, validity, sensitivity and specificity of Guajarati version of the Roland-Morris Disability Questionnaire. AB - BACKGROUND: The most common instruments developed to assess the functional status of patients with Non specific low back pain is the Roland-Morris Disability Questionnaire (RMDQ). Clinical and epidemiological research related to low back pain in the Gujarati population would be facilitated by the availability of well established outcome measures. AIM: To find the reliability, validity, sensitivity and specificity of the Gujarati version of the RMDQ for use in Non Specific Chronic low back pain. STUDY DESIGN: A reliability, validity, sensitivity and specificity study of Gujarati version of the Roland-Morris Disability Questionnaire (RMDQ). METHODOLOGY: Thirty out patients with Non Specific Chronic low back pain were assessed by the RMDQ. Reliability is assessed by using internal consistency and the intra-class correlation coefficient (ICC). Internal construct validity is assessed by RASCH Analysis and external construct validity is assessed by association with pain and spinal movement. Clinical calculator was used to determine the sensitivity and specificity. RESULTS: Internal consistency of the RMDQ is found to be adequate (> 0.65) at both times, with high ICC's also at both time points. Internal construct validity of the scale is good, indicating a single underlying construct. Expected associations with pain and spinal movement confirm external construct validity. The Sensitivity and Specificity at cut off point of 0.5 was 80% and 84% with respectively positive predictive value (PPV) of 83.33% and negative predictive value (NPV) of 80.76%. The Questionnaire is at the ordinal level. CONCLUSION: The RMDQ is a one-dimensional, ordinal measure, which works well in the Gujarati population. PMID- 23629545 TI - Hypertrophic ancenous epitrochlearis muscle as a cause of ulnar neuropathy at elbow. AB - We report herein a 35-year-old man who suffered from pain at his left elbow and numbness in his left hand. Electromyographic studies demonstrated a localized nerve conduction block in the left elbow region. Ultrasonographic evaluation revealed enlargement of the ulnar nerve at the level of the medial epicondyle as well as bilateral anconeus epitrochlearis muscles, one of which was hypertrophic, causing the ulnar neuropathy at the symptomatic site. We emphasize with this case report the complementary role of ultrasound in peripheral nerve pathologies, as it confirmed the entrapment and determined the underlying cause. PMID- 23629546 TI - Application of proteomics technology in adipocyte biology. AB - Obesity and its associated complications have reached epidemic proportions in Western-type societies. Concomitantly, the obesity incidence in developing countries is increasing. One hallmark of obesity is the differentiation of pre adipocytes into mature triglyceride-loaded adipocytes present in subcutaneous and visceral adipose tissue depots. This may ultimately lead to dysfunctional adipose tissue together with detrimental changes in the profiles of (pre-)adipocyte secreted proteins, known as adipokines. Obesity-induced alterations in adipokine profiles contribute to the development of obesity-associated disorders. Consequently, the interest in the molecular events responsible for adipose tissue modifications during weight gain and weight loss as well as in the aetiology of obesity-associated disorders is growing. Molecular mechanisms involved in pre adipocyte differentiation and alterations in adipokine profiles have been examined at the gene and protein level by high-throughput technologies. Independent proteomics studies have contributed significantly to further insight into adipocyte biology, particularly with respect to adipokine profiling. In this review novel findings obtained with adipo-proteomics studies are highlighted and the relevance of proteomics technologies to further understand molecular aspects of adipocyte biology is discussed. PMID- 23629547 TI - 350-MUm side-view optical probe for imaging the murine brain in vivo from the cortex to the hypothalamus. AB - Miniature endoscopic probes offer a solution for deep brain imaging by overcoming the limited depth of intravital microscopy. We describe a small-diameter (350 MUm) graded-index optical probe with a side-view design for in vivo cellular imaging of the mammalian brain. The side-view probe provides a unique view of the vertical network of neurons and penetrating blood vessels. At a given insertion site, the translational and rotational scanning of the probe provides access to a large tissue area (>1 mm(2)) across the cortex, hippocampus, thalamus, and hypothalamus. PMID- 23629548 TI - NHC-Cu(I) catalysed asymmetric conjugate silyl transfer to unsaturated lactones: application in kinetic resolution. AB - The scope of the asymmetric silyl transfer to unsaturated lactones utilising a C2 symmetric NHC-Cu(I) catalyst has been established and kinetic resolutions mediated by silyl transfer have been used to prepare enantiomerically enriched anti-4,5-disubstituted 5-membered lactones. The method has been exploited in an expedient synthesis of (+)-blastmycinone. PMID- 23629549 TI - Genomics: New zebrafish genome resources. PMID- 23629550 TI - Population genomics: Noah's Ark arrives. PMID- 23629551 TI - The Chronic Care Model: Will it Work in Malaysia for Hypertension? PMID- 23629552 TI - Preventing Mother-to-child Transmission of Hepatitis B Virus - A Success Story Which Can Be Enhanced. PMID- 23629553 TI - Prevalence of depression in stroke patients with vascular dementia in universiti kebangsaan malaysia medical center. AB - OBJECTIVE: Depression among patients with vascular dementia is frequently overlooked and potentially causes significant morbidity. There is limited data in Malaysia on the subject and this study was conducted to determine the prevalence of depression in vascular dementia (VaD) in UKMMC. METHODS: This was a cross sectional study involving diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) criteria and who had a mini mental state examination (MMSE) score of less than 26. All patients were interviewed, examined clinically and their previous brain computer tomography (CT) were reviewed. The prevalence of depression was determined using the Cornell scale of depression. RESULTS: A total of 76 patients were recruited with a mean age of 70.5 +/- 9.5 years. The median duration of illness was 2.0 (1.0-4.8) years. The prevalence of depression in the study population was 31.6%. The patients with depression had a significant older mean age (74.5+/-8.7 years old) compared to those without depression (68.6+/-9.4 years old). Patients with large artery stroke of less than 3 years had significant higher frequency of depression (53.6%) compared to patients with small artery stroke (23.8%) and patients with right sided large artery stroke had significantly higher frequency of depression compared to left (70% vs. 44.4%). Median MMSE score (17.0) for depressed patients was significantly lower compared with median MMSE score (22.5) for non depressed patients. Median Barthel Index (30.0) for depressed patients was significantly lower compared with median Barthel score for non depressed patients. CONCLUSIONS: Depression was prevalent among post stroke patients with VaD in UKMMC particularly for patients with older age, large artery stroke, right sided large artery stroke, low MMSE score and low Barthel Index. Early recognition of high risk patients is important in the holistic management of patients to prevent significant morbidity arising from depression. PMID- 23629554 TI - Evaluation of Community and Family Case Studies (CFCS): A Community based training of medical students. AB - The International Medical University has a Community and Family Case Study (CFCS) programme as part of the training for medical students. The aim of the programme is to emphasize the family and community perspective of patient care in the home environment. A cross-sectional descriptive study was done among 66 final year medical students using a questionnaire. The students were in the 10th Semester and had completed their Community and Family Case Studies (CFCS) programme. Majority (54.5%) of the students who were interviewed were Malays, 34.8% Chinese and 9.1% Indians. Majority of the students (87.9%) liked the programme because it was a good opportunity to understand the patient in their home environment; it improved their commination skills and made them understand the patient better in the community setting. The perceived problem in this programme by the students were mainly choosing an index patient initially (32.8%), patient cooperation (19.0%) and transportation to the patients' house (13.8%). They said that this programme was useful because they learnt more about the disease (45%) and understood the patient management better (15%). The programme also provided the students a wider exposure to medicine (37.9%) and the opportunity to practice clinical skills. Overall the CFCS programme in IMU was well liked by the students as it gave them an opportunity to practice some of the clinical skills in the patients' home environment and it provided an opportunity to manage the patient better. The major problem the students faced was in selecting the index patient. PMID- 23629555 TI - The Activity Leading to ACL Injury and the ability to Resume Duty following Reconstructive Surgery in Malaysian Military Patients. AB - INTRODUCTION: Anterior cruciate ligament (ACL) injuries are common among Malaysian military patients but has not been studied closely. The purpose of this study was to assess the type of activities leading to the ACL injury and the outcome of reconstructive ACL surgery at one year follow up. METHODS: From the registry record, military patients who had undergone ACL reconstruction in two Malaysian military hospitals were identified. Their medical records were reviewed. The activities that they performed when the ACL injury occurred were identified. After ACL reconstruction, the patients' ability to resume previous duty at one year follow up was evaluated. RESULTS: From 111 patients, 82% of the ACL injuries were due to sporting activities whereas military activities and road traffic accident accounted for 14% and 4% respectively. Out of 69 patients with isolated ACL injury who were followed up at one year, all except two were able to resume their previous duty. CONCLUSIONS: Among the military patients who underwent ACL reconstruction, ACL injury was mainly due to sporting activity. ACL reconstruction showed good outcome at one year follow up. PMID- 23629556 TI - Prevalence of macrolide resistance and in vitro activities of six antimicrobial agents against clinical isolates of Streptococcus pneumoniae from a multi-center surveillance in Malaysia. AB - The in vitro activities of 6 antimicrobial agents against clinical isolates of Streptococcus pneumoniae (pneumococci) were investigated and the erythromycin minimum inhibitory concentrations (MICs) were correlated with the two major macrolide resistance determinants, mef(A) and erm(B). MICs of commonly used antibiotics as well as the presence of macrolide resistance determinant genes in all isolates were tested. Seventy one pneumococcal isolates collected at Institute for Medical Research (IMR) were included in this study. Phenotypic characterization, MIC determination using E-test strips and polymerase chain reactions for antibiotic resistance determination were included. Among the isolates, 25 (35.2%) isolates were erythromycin susceptible, 3 (4.2%) were intermediate and 42 (60.6%) were resistant. Fifty three isolates (74.7%) were found with mef(A) alone, 15 (21.1%) isolates with erm(B) + mef(A) combination and 3 (4.2%) isolates with none of the two genes. The in vitro activity of penicillin, amoxicillin clavulanic acid, ceftriaxone and cefotaxime is superior to trimethoprim-sulfamethoxazole and erythromycin. In conclusion, pneumococcal isolates in this study were highly susceptible to penicillin with very low MICs. However, a very high prevalence rate of erythromycin resistance was observed. Erythromycin resistant S. pneumoniae isolates with both mef(A) and erm(B) showed very high MICs >=256 MUg/mL. PMID- 23629557 TI - Pacifier Use and its Association with Breastfeeding and Acute Respiratory Infection (ARI) in Children Below 2 Years Old. AB - Extensive literature reviews showed that pacifier usage is associated with early cessation of breast feeding, as well as respiratory infection. This cross sectional study was a part of the bigger study of The Third National Health Morbidity Survey conducted throughout Malaysia in 2006. Survival and pearson cox regression was done to find association between pacifier user and breast feeding duration. Logistic Regression was done to find association between variables of interest. The prevalence of pacifier use was 32.9%. Chinese children reported significantly higher usage of pacifier (95% CI; 47.5, 58.7) as well as those resided in urban area (95% CI;32.5,37.7). One third of pacifier user had stopped breastfeeding at 6 months of age. Those with pacifier users were significantly shorter in breast feeding duration and significantly associated with non exclusivity in breastfeeding. Those without pacifier user were significantly associated with ever breast fed.(p value=0.001). There was no significant association between pacifier use with acute respiratory infection. Factors such as ethnicity and residential are non modifiable whereas modifiable factor such as pacifier use is certainly needed to be addressed at maternal and child health care level. PMID- 23629558 TI - Community-based cardiovascular Risk Factors Intervention Strategies (CORFIS) in managing hypertension: A pragmatic non-randomised controlled trial. AB - BACKGROUND: Hypertension is the number one cardiovascular risk factor in Malaysia. This study aimed to evaluate the effectiveness of a Community-Based Cardiovascular Risk Factors Intervention Strategies (CORFIS) in the management of hypertension in primary care. METHODS: This is a pragmatic, non-randomized controlled trial. Seventy general practitioners (GPs) were selected to provide either CORFIS (44 GPs) or conventional care (26 GPs) for 6 months. A total of 486 hypertensive patients were recruited; 309 were in the intervention and 177 in the control groups. Primary outcome was the proportion of hypertensive patients who achieved target blood pressure (BP) of <140/90mmHg (for those without diabetes mellitus) and <130/80mmHg (with diabetes mellitus). Secondary outcomes include change in the mean/median BP at 6-month as compared to baseline. RESULTS: The proportion of hypertensive patients who achieved target BP at 6-month was significantly higher in the CORFIS arm (69.6%) as compared to the control arm (57.6%), P=0.008. Amongst those who had uncontrolled BP at baseline, the proportion who achieved target BP at 6-month was also significantly higher in the CORFIS arm (56.6%) as compared to the control arm (34.1%), p<0.001. There was no difference in the patients who had already achieved BP control at baseline. There were significant reductions in SBP in the CORFIS arm (median -9.0mmHg; -60 to 50) versus control (median -2mmHg; -50 to 48), p=0.003; as well as in DBP (CORFIS arm: median -6.0mmHg; ranged from -53 to 30 versus control arm: median 0.0mmHg; ranged from -42 to 30), p<0.001. CONCLUSIONS: Patients who received CORFIS care demonstrated significant improvements in achieving target BP. PMID- 23629559 TI - Antibiotic prescribing for upper respiratory tract infections in sarawak district hospitals. AB - Upper respiratory tract infection (URTI) is mostly viral in aetiology, but patients presenting with such complaints are frequently prescribed antibiotics. This may result in increased development of antimicrobial resistance. The objectives of this study are to determine the choice and proportion of oral antibiotics prescribed in patients with URTI, in a Sarawak district hospital setting. All outpatient prescriptions received in July 2011 in 10 hospitals with relevant diagnoses were analysed. A total of 6747 URTI prescriptions met the inclusion criteria, and 64.8% (95% CI 63.7%, 65.9%) had antibiotic prescribed. Medical Assistants (MAs) were significantly more likely to prescribe antibiotics compared to Medical Officers (MOs) (p < 0.001). Prescribers were significantly influenced by the patient's age and specific diagnosis when prescribing antibiotics for URTI (p < 0.001). Antibiotic choices differed between MOs and MAs, where some of the antibiotic choices were inappropriate. There is a need for multi-faceted interventions to improve antibiotic prescribing rate and choice. PMID- 23629560 TI - Prevalence of asymptomatic atrial fibrillation in malaysian patients with hypertension. AB - Atrial fibrillation (AF) is usually asymptomatic and often associated with established cardiovascular risk factors such as hypertension. The prevalence atrial fibrillation in patients admitted to Malaysian hospitals has been determined, but asymptomatic atrial fibrillation (AAF) in hypertensive patients in the primary care setting is not established. This study reports the prevalence of AAF in hypertensive patients in Malaysia, in a primary care setting. The overall prevalence of AAF was 0.75% with no differences between the gender. The prevalence of AAF increases with age - in the age groups of 30-39, >40-49, >50 59, >60-69, 70-79 and >80 years old were 0%, 0.17%, 0.35%, 2.32%, 2.59%, and 0% respectively. Hypertensive patients with age of >= 61 year old were associated with a probability of 10.6 times higher for AAF. We suggest the age threshold to screen for AAF to be age of 60. It is estimated that there are 49,029 Malaysians with AAF in 2010. A large population is at risk of AAF-related complications. There is justification for an even greater emphasis on diagnostic, primary and secondary prevention strategies. PMID- 23629561 TI - Hepatitis B seroprevalence among University of Malaya Students in the Post universal Infant Vaccination Era. AB - AIM: A nationwide HBV vaccination for neonates in the Expanded Programme on Immunization (EPI) was implemented in Malaysia in 1989. The objective of this study was to investigate the prevalence of HBsAg, anti-HBs and anti-HBc among the new student intakes in the Faculties of Medicine and Dentistry, University of Malaya from 2005 to 2011. MATERIALS AND METHODS: All new students enrolled for undergraduate and postgraduate courses were screened for HBV infection. Serum samples collected were tested for the presence of HBsAg, anti-HBs and anti-HBc with the use of fully automated analysers. Statistical analyses were done using Open Epi version 2.3.1 RESULTS: The overall HBsAg prevalence among the 2923 new intakes was 0.62%. The HBsAg prevalence rate was 1.08% (15/1390) for those born before 1989 and only 0.20% (3/1533) among those born in or after 1989. By year of testing, HBsAg prevalence declined steadily from 1.27% (5/394) in 2005 to 1.20% (5/418) in 2006, 0.95% (4/421) in 2007, 0.49% (2/410) in 2008, 0.49% (2/407) in 2009 and finally 0% in both 2010 (0/445) and 2011 (0/428). Although 66.14% of those vaccinated during infancy had no demonstrable immunity at the time of screening, only 6 (0.39%) students were found to have anti-HBc, including the 3 who were HBsAg positive. CONCLUSION: These findings suggested effective prevention of HBV transmission with the universal and voluntary vaccination programs in Malaysia. PMID- 23629562 TI - The pattern of death related to trauma cases presented to the emergency department of a tertiary university hospital. AB - Trauma is an ever increasing problem and it is the leading cause of morbidity and mortality in the under 40s age group. The main purpose of this study is to determine the pattern of death related to trauma cases presenting to the emergency department (ED) of a university hospital. This was a retrospective analysis of 75 consecutive trauma case records at a university hospital for a one year period. The most common cause of deaths is motor vehicle crashes. The mean score for the injury severity score (ISS) and revised trauma score (RTS) on arrival to the ED among the succumbed patients were 27.8 (s.d 8.6) and 5.7 (s.d 1.1) respectively. 58.7% of deaths occurred within 48 hours after the admission. Less than 50% of studied patients were still alive beyond 45 hours post admission and less than 10% still alive beyond 11 days. Our analysis also showed that 28% (n=21) and 56% (n=41) of the studied sample had a probability of survival between 50% to 75% and more than 75% respectively upon arrival based on the initial vital signs in the ED and the trauma and injury severity score (TRISS) methodology. Overall, we observed similar injury mechanisms, demographics and causes of death compare to other studies. The figures from this study, mandate further exploration of preventive issues and management improvements that should be applied not only to the current trauma system, but also to the health care system in general. PMID- 23629563 TI - Association of creatinine clearance with neutropenia in breast cancer patients undergoing chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC). AB - AIMS: Fluorouracil, doxorubicin, cyclophosphamide protocol (FAC) is a commonly used regimen for breast cancer due to its proven efficacy, acceptable toxicity, high affordability. While hepatic insufficiency dosing for doxorubicin and fluorouracil have been set, there is paucity of data in the literature on how to reduce doses in renal insufficiency. We sought to determine whether there is an association with pre-chemotherapy creatinine clearance, and the occurrence of clinically significant grade 3 to 5 neutropenia during the course of FAC chemotherapy. METHODS: A retrospective study involving chart review from 2009 to June 2012, of breast cancer patients given FAC was conducted. Demographic profile, pre-chemotherapy complete blood count and creatinine clearance (CrCl) were recorded. Occurrence of Grade 3 to 5 neutropenia was the endpoint of the study. Descriptive statistics, one tailed t test, logistic regression analysis were done between the outcome and variables. RESULTS: A total of 53 patients were included in the study. The mean age of the patients was 49.77 +/- 10.82 years. Patients had an ECOG performance status range of 1 to 3. Patients received mean 5.64 +/- 0.92 cycles of FAC protocol chemotherapy. Pre-treatment chemotherapy WBC was 7.41 +/- 2.68x109/L, Hemoglobin was 12.60 +/- 1.16 g/dL, ANC 4656.89 +/- 2379.32. Pre treatment CrCl was 90.79 +/- 31.49 ml/min. Thirteen subjects, or 24.53% developed at least grade 3 neutropenia. Patients who developed neutropenia were significantly different from those who did not in terms of baseline WBC p=0.046 and Weight p=0.0119, CrCl p=0.032. Using logistic regression analysis, only creatinine clearance was a significant predictor of neutropenia. There was an inverse association between creatinine clearance and neutropenia, OR 0.887, 95% confidence interval (CI): 0.808- 0.973, p=0.011. CONCLUSION: The study revealed that breast cancer patients treated with FAC, there was an inverse association between creatinine clearance and occurrence of neutropenia. PMID- 23629564 TI - Herbal Ingestion During Pregnancy and Post-Partum Period is A Cause For Concern. AB - The potential harms of herbs to the pregnant mothers and their foetuses as well as the effect of herbs taken by nursing mothers on their babies remain largely unknown. Common perception is that herbal medicines ingestion during pregnancy and confinement period is a common practice among multi-racial Malaysian mothers. The purpose of this study was to explore the usage of herbal medicines during pregnancy and post-partum period among mothers who gave birth at a tertiary hospital in a metropolitan city of Malaysia. This cross sectional study was conducted between October and December 2010. The subjects were interviewed twice after giving birth: before hospital discharge and 6 to 8 weeks later. A total of 323 mothers were recruited for this study. The prevalence of herbs ingestion during pregnancy was 13.9%, with half of the users consuming it during the first trimester. A total of 163 (52.9%) mothers ingested herbs during the post-partum period. Significantly more Chinese (p=0.01) and Malay (p=0.04) mothers ingested herbs during pregnancy and post-partum period, respectively. Infants of mothers who ingested herbs had a higher rate of neonatal jaundice compared to infants of mothers who did not ingest herbs during the post-partum period (P=0.001). PMID- 23629565 TI - Blastic plasmacytoid dendritic cell neoplasm in an elderly woman. AB - Blastic plasmacytoid dendritic cell neoplasm (a.k.a. NK cell lymphoma, CD4+CD56+ haematodermic neoplasm) is a rare aggressive tumour that arises from plasmacytoid dendritic cell precursors. We report the first case from Malaysia of a 79-year old Chinese woman who presented with purpuric plaques and nodules produced by pleomorphic CD4+, CD56+, CD68+, CD123+ and CD303+, but CD2APmononuclear cell infiltrates. Leukemic dissemination occurred and she succumbed to disease without treatment 4 weeks after diagnosis and 9 months after onset of cutaneous disease. PMID- 23629566 TI - Papillary thyroid carcinoma presenting with intraluminal tracheal mass symptoms. AB - Papillary thyroid carcinoma is a common thyroid malignancy reported world wide. It affects females more commonly in the 4th to 6th decades of life. The patients usually present with a painless anterior neck mass and occasionally with lymph node involvement. We report a case of an elderly male who presented with hoarseness and hemoptysis, which warranted bronchoscopy. Biopsy of the intraluminal tracheal mass revealed the diagnosis of papillary thyroid carcinoma. Computed tomography scan of the neck confirmed the presence of the primary lesion in the right thyroid lobe with invasion into the adjacent trachea and esophagus. PMID- 23629567 TI - Intramuscular sternohyoid hemangioma: an unusual neck mass. AB - A neck mass with soft consistency suggests the diagnosis of a cyst which is usually congenital in origin. Needle aspiration yielding blood should alert the physician the possibility of hemangioma although it is very rare. Ultrasonography and computed tomography will delineate the extent and nature of the lesion and provide the roadmap for surgical excision. We report a case of a girl who presented with a painless neck mass which was later found to be a hemangioma originating from the sternohyoid muscle. The morphology and immunohistochemical stain were consistent with hemangioma. PMID- 23629568 TI - Cutaneous lesions as a presenting sign of metastases in male breast cancer: a rare clinical entity. AB - Male breast cancer accounts for only 1% of cancers in men and 1% of breast cancers. Cutaneous metastases occur less than 10% of all patients with visceral malignancies and are considered a rare and late event in progression of metastatic disease. A 45-year-old man presented with a lump in the left breast which was confirmed to be infiltrating ductal carcinoma. He underwent a left mastectomy and axillary clearance followed by chemotherapy and radiotherapy to the left chest wall. However, he was non-compliant to adjuvant tamoxifen due to hot flushes. One year later, he presented with biopsy proven cutaneous metastases. Initially he had complete excision of the lesions, however, two months later more skin lesions appeared predominantly over the chest wall and back. Hormonal therapy failed to control the metastases as such he was treated with systemic chemotherapy. He is currently on third line chemotherapy. PMID- 23629569 TI - Coronary artery bypass surgery in a patient with asymptomatic brugada syndrome. PMID- 23629570 TI - Iatrogenic corneal perforation in Terrien Marginal Degeneration. AB - This case report is about a rare disease with unusual presentation. Failure to recognise atypical presentation may lead to error in managing the patient and cause disastrous complications. Here we highlight a case of Terrien Marginal Degeneration in both eyes with atypical presentation; namely pseudopterygium. A 22 year old man was referred to our centre for iatrogenic right eye corneal perforation after having an atypical pterygium removed at another hospital. On arrival, his vision was 1/60 in both eyes with bilateral cornea Terrien Marginal Degeneration. His right eye anterior chamber was deep with a conjunctival flap covering the perforation site which was located from the 2.30 - 3.30 clock position nasally with no aqueous leak. However after a day his right eye anterior chamber became flat and there was fast aqueous leak from the perforation site. An emergency C shaped peripheral corneal lamellar keratoplasty was performed to seal the perforation. Post operatively his right eye improved to 6/24. PMID- 23629571 TI - Post-operative immunohistochemical diagnosis of two synchronous primary non-small cell lung cancers in a single lobe. AB - Synchronous primary non-small cell lung cancers (NSCLC) are rare and may be discovered unexpectedly following lung resection. Discrimination from intrapulmonary metastases is important to guide treatment and prognosis but is difficult solely on clinical or radiological findings. Histopathological evaluation with immunohistochemistry (IHC) markers can prove decisive and should feature in the diagnostic algorithm of such patients. We report a rare case of two synchronous primary NSCLCs diagnosed post operatively following pathological examination of the resected lobe, highlighting the value of IHC and discuss the management of such patients. PMID- 23629572 TI - Left Bundle Branch Block Under General Anaesthesia in an Athlete's Heart. AB - Left bundle branch block (LBBB) during anaesthesia is uncommon. During general anaesthesia, LBBB may be related to hypertension or tachycardia and its acute onset makes the diagnosis of acute myocardial ischemia or infarction difficult. We would like to present a case report of a healthy patient who developed LBBB intra operatively. Acute LBBB should lead to suspicion of acute coronary syndrome until proven otherwise. Inability to exclude an acute cardiac event resulted in postponement of surgery twice after general anaesthesia was administered. Cardiological investigation of our patient showed physiological left ventricular hypertrophy (LVH), "athlete's heart" which was the most likely cause of the LBBB under anaesthesia. PMID- 23629573 TI - Melioidosis and peritoneal dialysis related peritonitis. AB - We report a case of melioidosis presenting as peritonitis in a patient on continuous ambulatory peritoneal dialysis (CAPD). A 47-year-old man, a lorry driver, with end-stage renal disease due to diabetes mellitus on CAPD presented in PD-related peritonitis. He was started on intraperitoneal cloxacillin and ceftazidime, and changed to intraperitoneal vancomycin and meropenam after day 5 due to nonresponse. Burkholderia pseudomallei was identified from the dialysate culture. He was treated with intraperitoneal meropenam for two weeks, and IV ceftazidime for 4 weeks. He responded, and the Tenckhoff catheter was not removed. He was discharged well and continued on oral sulfamethoxazole/trimethoprim for six months. This patient had done his PD exchanges in a lorry. PMID- 23629574 TI - Gradual Recovery from Bilateral Severe Sensorineural Hearing Loss post Motor Vehicle Accident. AB - Sensorineural hearing loss following trauma is a common finding in daily clinical practice and usually associated with a poor prognosis. Our case illustrates a patient who was involved in motor vehicle accident sustaining bilateral severe to profound sensorineural hearing loss but subsequently recovered fully after two years. Unless there is clear trauma to the cochlea or auditory nerve, a substantial duration of follow up is needed in the treatment of such cases. PMID- 23629575 TI - Ultrasonic scissors-assisted 'open-book' thyroidectomy in massive goiter compressing airway and causing unilateral vocal cord paralysis. AB - A massive goiter may constrict the trachea resulting in shortness of breath. Recurrent laryngeal nerve compression may cause vocal cord paralysis. We highlight a case of a 62- year-old female with a 30 year history of an anterior neck swelling gradually increasing in size. She presented with acute symptoms of upper airway obstruction and voice changes. Emergency thyroidectomy was performed by dividing the middle part of the gland using ultrasonic scissors. The recovery was uneventful and the patient regained normal vocal cord function post operatively. PMID- 23629576 TI - The late sequalae of coronary artery in a grown up kawasaki disease patient. PMID- 23629577 TI - Stroke care in Pusat Perubatan UKM; the actual picture. PMID- 23629578 TI - Cardiovascular effects of common analgesics. AB - The clycoxygenase (COX) enzyme forms locally active prostaglandins responsible for producing inflammation and pain. Classical non-steroidal anti-inflammatory drugs (NSAID) inhibit the COX-2 enzyme that produces inflammatory prostaglandins as well as the COX-1 enzyme that produces gastric mucosa protecting prostaglandins. By specifically inhibiting only the COX-2 enzyme, coxibs thus reduce pain but do not damage the gastric mucosa. However, COX-2 at the vascular endothelium produces antithrombotic prostaglandins, and so by inhibiting COX-2 enzyme, the coxibs promote thrombosis. Rofecoxib and valdecoxib have been withdrawn because of the adverse cardiovascular events they induce. Amongst presently available coxibs cardiovascular risk is highest with enterocoxib and lowest with celecoxib. NSAIDS also increase cardiovascular events, the risk is highest with diclofenac and lowest with naproxen. Paracetamol and corticosteroids induce hypertension, while steroids also adversely affect the heart from metabolic change as well as fluid retention. Aspirin is an anti-thrombotic agent because of its ability to inhibit the COX-1 enzyme that produces the pro aggregatory thromboxane. However, it increases gastrointestinal bleeding, can promote fluid retention and is nephrotoxic, all of which may lead to adverse cardiovascular outcomes. Patients at especially high risk of cardiovascular events from analgesic use include the elderly, and those with heart failure, hypertension, rheumatoid arthritis, chronic renal disease, chronic obstructive airway disease and previous myocardial infarction, cerebrovascular disease or peripheral vascular disease. Adverse cardiovascular events can occur within a week of initiation of analgesic treatment. PMID- 23629579 TI - Assembly and spontaneous resolution of the chiral inorganic polyoxometalates based frameworks via helical chains association. AB - Two pairs of enantiomerically pure three-dimensional (3D) chiral polyoxometalate (POM) framework materials l,d-[K(H2O)]6.[H2GeW12O40]3.35H2O (1a and 1b) and l,d [K(H2O)]6.[H2SiW12O40]3.29H2O (2a and 2b) based on inorganic achiral building blocks, have been synthesized and characterized by X-ray crystallography, elemental analysis, powder X-ray diffraction (PXRD), UV-Vis spectroscopy, circular dichroism (CD) spectra. Single-crystal X-ray diffraction analyses revealed that 1a and 1b, 2a and 2b are enantiomers, respectively. In 1a and 1b, 2a and 2b, {K(H2O)}n link terminal oxygen and MU2-bridging oxygen of Keggin-type polyanion moieties to generate 1D 31 helical infinite chiral chains, which are further connected by the achiral Keggin-type polyoxoanions to form 3D 4,8 connected chiral self-assembly frameworks with {4(12).6(10).8(6)}{4(6)}2 topology. 1 and 2 are isostructural. They are obtained by spontaneous resolution upon crystallization in the absence of any chiral source. They represent new examples of chiral self-penetrating pure inorganic frameworks known for POM systems. Compounds 1 and 2 display adsorption activity toward volatile organic compounds (VOCs). PMID- 23629580 TI - Construction of a high resolution microscope with conventional and holographic optical trapping capabilities. AB - High resolution microscope systems with optical traps allow for precise manipulation of various refractive objects, such as dielectric beads (1) or cellular organelles (2,3), as well as for high spatial and temporal resolution readout of their position relative to the center of the trap. The system described herein has one such "traditional" trap operating at 980 nm. It additionally provides a second optical trapping system that uses a commercially available holographic package to simultaneously create and manipulate complex trapping patterns in the field of view of the microscope (4,5) at a wavelength of 1,064 nm. The combination of the two systems allows for the manipulation of multiple refractive objects at the same time while simultaneously conducting high speed and high resolution measurements of motion and force production at nanometer and piconewton scale. PMID- 23629581 TI - Relations between water balance, wood traits and phenological behavior of tree species from a tropical dry forest in Costa Rica--a multifactorial study. AB - Drought tolerance is a key factor for the establishment and survival of tree species in tropical ecosystems. Specific mechanisms of drought resistance can be grouped into four functional ecotypes based on differences in leaf fall behavior: deciduous, brevi-deciduous, stem succulent and evergreen. To identify the key factors influencing phenology and cambial activity and thus drought tolerance, we tested the stomatal conductance, leaf water potential and stable carbon isotopes in the leaves and wood of 12 species from a tropical dry forest in Costa Rica. With wood anatomical techniques, we further studied seasonal cambial activity and a suite of wood traits related to water transport for each of the functional ecotypes. Using a principal component analysis, we identified two groups of variables that can be related to (i) hydraulic conductivity and (ii) control of transpiration and water loss. Hydraulic conductivity is controlled by vessel size as the limiting variable, water potential as the driving force and wood density as the stabilizing factor of the anatomical structure of an effective water transport system. Stomatal control plays a major role in terms of water loss or saving and is the dominant factor for differences in phenological behavior. Stem succulent species in particular developed a rarely identified but highly effective strategy against drought stress, which makes it a successful pioneer species in tropical dry forests. PMID- 23629582 TI - Serotonin regulates performance nonmonotonically in a spatial working memory network. AB - The prefrontal cortex (PFC) contains a dense network of serotonergic [serotonin, 5-hydroxytryptamine (5-HT)] axons, and endogenous 5-HT markedly modulates PFC neuronal function via several postsynaptic receptors. The therapeutic action of atypical antipsychotic drugs, acting mainly via 5-HT receptors, also suggests a role for serotonergic neurotransmission in cognitive functions. However, psychopharmacological studies have failed to find a consistent relationship between serotonergic transmission and cognitive functions of the PFC, including spatial working memory (SWM). Here, we built a computational network model to investigate 5-HT modulation of SWM in the PFC. We found that 5-HT modulates network's SWM performance nonmonotonically via 5-HT1A and 5-HT2A receptors, following an inverted U-shape. This relationship may contribute to blur the effects of serotonergic agents in previous SWM group-based behavioral studies. Our simulations also showed that errors occurring at low and high 5-HT concentrations are due to different network dynamics instabilities, suggesting that these 2 conditions can be distinguished experimentally based on their distinct dependency on experimental variables. We inferred specific predictions regarding the expected behavioral effects of serotonergic agents in 2 classic working-memory tasks. Our results underscore the relevance of identifying different error types in SWM tasks in order to reveal the association between neuromodulatory systems and SWM. PMID- 23629583 TI - Impact of range of motion during ecologically valid resistance training protocols on muscle size, subcutaneous fat, and strength. AB - The impact of using different resistance training (RT) kinematics, which therefore alters RT mechanics, and their subsequent effect on adaptations remain largely unreported. The aim of this study was to identify the differences to training at a longer (LR) compared with a shorter (SR) range of motion (ROM) and the time course of any changes during detraining. Recreationally active participants in LR (aged 19 +/- 2.6 years; n = 8) and SR (aged 19 +/- 3.4 years; n = 8) groups undertook 8 weeks of RT and 4 weeks of detraining. Muscle size, architecture, subcutaneous fat, and strength were measured at weeks 0, 8, 10, and 12 (repeated measures). A control group (aged 23 +/- 2.4 years; n = 10) was also monitored during this period. Significant (p > 0.05) posttraining differences existed in strength (on average 4 +/- 2 vs. 18 +/- 2%), distal anatomical cross sectional area (59 +/- 15 vs. 16 +/- 10%), fascicle length (23 +/- 5 vs. 10 +/- 2%), and subcutaneous fat (22 +/- 8 vs. 5 +/- 2%), with LR exhibiting greater adaptations than SR. Detraining resulted in significant (p > 0.05) deteriorations in all muscle parameters measured in both groups, with the SR group experiencing a more rapid relative loss of postexercise increases in strength than that experienced by the LR group (p > 0.05). Greater morphological and architectural RT adaptations in the LR (owing to higher mechanical stress) result in a more significant increase in strength compared with that of the SR. The practical implications for this body of work follow that LR should be observed in RT where increased muscle strength and size are the objective, because we demonstrate here that ROM should not be compromised for greater external loading. PMID- 23629584 TI - Reversible chemoselective tagging and functionalization of methionine containing peptides. AB - Reagents were developed to allow chemoselective tagging of methionine residues in peptides and polypeptides, subsequent bioorthogonal functionalization of the tags, and cleavage of the tags when desired. This methodology can be used for triggered release of therapeutic peptides, or release of tagged protein digests from affinity columns. PMID- 23629585 TI - Increase in cerebrospinal fluid F2-isoprostanes is related to cognitive decline in APOE epsilon4 carriers. AB - In this longitudinal study we investigated the effect of apolipoprotein E (APOE) genotype on the relation between cognitive decline and cerebrospinal fluid (CSF) F2-isoprostanes, the reference marker for oxidative stress. Twenty non-demented subjects, 58 mild cognitive impairment (MCI) patients, and 63 Alzheimer's disease (AD) patients with measurements of CSF F2-isoprostanes at two time points (with a mean interval of 2.0 +/- 1.1 years) and known APOE genotype were included. Mean clinical follow-up time was 3.9 +/- 2.4 years. For change in F2-isoprostanes over time and associations with Mini-Mental State Examination scores, age- and gender adjusted linear mixed models were used. Analyses were done for APOE epsilon4 carriers and non-carriers separately. In APOE epsilon4 carriers, annual change in F2-isoprostane levels appeared larger than in APOE epsilon4 non-carriers (beta[SE] 2.5[0.5], p < 0.001 versus 1.8[0.5], p < 0.01). In addition, increase in F2-isoprostanes was associated with further cognitive decline in APOE epsilon4 carriers (p < 0.05), but not in non-carriers (p = 0.28). Our results reiterate the importance of oxidative stress in neurodegeneration, especially in APOE epsilon4 carrying patients. Future studies should focus on the possibility of increased vulnerability to oxidative damage in APOE epsilon4 carriers. PMID- 23629586 TI - Improved design of prodromal Alzheimer's disease trials through cohort enrichment and surrogate endpoints. AB - Alzheimer's disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: 1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and 2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n = 358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n = 6,243). To identify a "mid risk" subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases. PMID- 23629587 TI - Endothelin-converting enzyme-1 activity, endothelin-1 production, and free radical-dependent vasoconstriction in Alzheimer's disease. AB - Alzheimer's disease (AD) patients have reduced cerebral blood flow. This precedes dementia and may contribute to its progression. In mice that overexpress amyloid beta protein precursor, cerebral blood flow declines before the development of plaques or cognitive abnormalities. In the brain, endothelin-1 (ET-1) is a locally acting vasoconstrictor, produced in neurons by endothelin-converting enzyme (ECE)-2 and in endothelial cells by ECE-1. Both ECEs are also capable of cleaving amyloid-beta (Abeta). We previously showed ECE-2 and ET-1 to be elevated in postmortem temporal cortex from AD patients, and ECE-2 expression and ET-1 release to be upregulated by Abeta42 in vitro. We have now studied isolated leptomeningeal blood vessels from postmortem brains and found that although ECE-1 level is reduced, ECE-1 activity and ET-1 level are significantly elevated in AD vessels. This is specific to AD as there is no specific change in vascular dementia vessels. In primary cultures of human brain endothelial cells, both Abeta40 and Abeta42 caused a significant increase in ET-1 release, the increase being particularly pronounced with Abeta40. In view of previous studies implicating free radicals in the endothelial dysfunction caused by Abeta40, we examined whether Abeta-mediated ET-1 release could be prevented by the antioxidant superoxide dismutase. Addition of superoxide dismutase to cells exposed to Abeta40 prevented the increase in the concentration of ET-1. Our findings indicate that cerebral vasoconstriction induced by Abeta results in part from a free radical-mediated increase in ECE-1 activity and ET-1 production. PMID- 23629588 TI - The GERAS Study: a prospective observational study of costs and resource use in community dwellers with Alzheimer's disease in three European countries--study design and baseline findings. AB - To address socioeconomic challenges associated with its increasing prevalence, data are needed on country-level resource use and costs associated with Alzheimer's disease (AD). GERAS is an 18-month observational study being conducted in France, Germany, and the U.K. (with an 18-month extension in France and Germany), aimed at determining resource use and total costs associated with AD, stratified by AD severity at baseline. Resource use information and time spent on informal care by non-professional caregivers was obtained using the Resource Utilization in Dementia instrument. Total baseline societal costs were based on four cost components: patient health care costs, patient social care costs, caregiver health care costs, and caregiver informal care costs. Overall, 1,497 community-dwelling patients with AD were analyzed at baseline. Estimated mean monthly total societal costs per patient at baseline differed significantly between groups with mild, moderate, and moderately severe/severe AD (p < 0.001 in each country): euro $1,418, euro 1,737, and euro 2,453 in France; euro 1,312, euro $2,412, and euro 3,722 in Germany; and euro 1,621, euro 1,836, andeuro 2,784 in the U.K., respectively. All cost components except caregiver health care costs increased with AD severity. Informal caregiver costs were the largest cost component accounting for about half to just over 60% of total societal costs, depending on country and AD severity group. In conclusion, GERAS study baseline results showed that country-specific costs increase with AD severity. Informal care costs formed the greatest proportion of total societal costs, increasing with AD severity independent of costing method. Longitudinal data will provide information on cost trends with disease progression. PMID- 23629589 TI - Exploring higher-order EGFR oligomerisation and phosphorylation--a combined experimental and theoretical approach. AB - The epidermal growth factor receptor (EGFR) kinase is generally considered to be activated by either ligand-induced dimerisation or a ligand-induced conformational change within pre-formed dimers. Ligand-induced higher-order EGFR oligomerisation or clustering has been reported but it is not clear how EGFR oligomers, as distinct from EGFR dimers, influence signaling outputs. To address this question, we combined measures of receptor clustering (microscopy; image correlation spectroscopy) and phosphorylation (Western blots) with modelling of mass-action chemical kinetics. A stable BaF/3 cell-line that contains a high proportion (>90%) of inactive dimers of EGFR-eGFP but no secreted ligand and no other detectable ErbB receptors was used as the model cell system. EGF at concentrations of greater than 1 nM was found to cluster EGFR-eGFP dimers into higher-order complexes and cause parallel increases in EGFR phosphorylation. The kinetics of EGFR clustering and phosphorylation were both rapid, plateauing within 2 minutes after stimulation with 30 nM EGF. A rule-based model was formulated to interpret the data. This model took into account ligand binding, ligand-induced conformational changes in the cytosolic tail, monomer-dimer-trimer tetramer transitions via ectodomain- and kinase-mediated interactions, and phosphorylation. The model predicts that cyclic EGFR tetramers are the predominant phosphorylated species, in which activated receptor dimers adopt a cyclic side-by-side orientation, and that receptor kinase activation is stabilised by the intramolecular interactions responsible for cyclic tetramerization. PMID- 23629590 TI - Identification of physician impairment. PMID- 23629591 TI - Need for improved risk communication of fish consumption advisories to protect maternal and child health: influence of primary informants. AB - Fish consumption has established benefits, including the promotion of cardiovascular health and pre- and neonatal brain and eye development, but local freshwater fish may be a source of contaminants that are especially harmful to fetuses and young children, such as the neurotoxic and developmentally toxic methylmercury and polychlorinated biphenyls. Fish consumption advisories may be issued by state health departments to limit human exposure to these and other toxicants. This study examined the efficacy of a sign designed by the North Carolina Division of Public Health that was posted along a reservoir (Badin Lake) in central North Carolina, USA, for increasing anglers' awareness of a fish consumption advisory, with a special focus on anglers who share their catch with women and children. In this study, 109 anglers were interviewed about their awareness of fish consumption advisories in general and their knowledge of the Badin Lake fish advisory in particular. Shore anglers were significantly less likely to be aware of the term "fish consumption advisory" and of the specific advisory for Badin Lake than boat anglers. Although a significant increase in knowledge of the specific fish consumption advisory was found for the entire sample of study participants after the sign intervention, a commensurate increase in knowledge was not found for a subsample of anglers who reported sharing their catch with women and children. Study findings underscore differences in fish consumption advisory awareness among subpopulations. Specifically, the study revealed the importance of characterizing the communication needs of shore anglers and anglers who share their catch with sensitive subpopulations (e.g., women and children) for the creation of more targeted communications of fish consumption advisories. PMID- 23629592 TI - Social service utilization, sense of community, family functioning and the mental health of new immigrant women in Hong Kong. AB - Drawing upon a sample of 296 new immigrant women in Hong Kong, this study investigated how social service utilization, family functioning, and sense of community influenced the depressive symptoms of new immigrant women. Results of the structural equation modeling suggested that family functioning and sense of community were both significantly and negatively associated with the depression of new immigrant women. Utilization of community services also influenced the depression of immigrant women indirectly through the mediating effect of sense of community. Implications of the research findings for mental health intervention were discussed. PMID- 23629593 TI - Two high-connected metal-organic frameworks based on d10-metal clusters: syntheses, structural topologies and luminescent properties. AB - The d(10)-metal-oxo clusters connected by the asymmetric tricarboxylate and linear neutral ligands give rise to two novel high-connected MOFs. They feature the highest (3,16)- and (3,8)-connected three-dimensional frameworks based on cube-like octanuclear [Zn8(MU2-OH)4(CO2)12] clusters and butterfly-like tetranuclear [Cd4(MU3-OH)2(CO2)6] clusters as the secondary building units, respectively. PMID- 23629595 TI - Response to: Cheng et al. Comparative outcomes of cooled versus traditional radiofrequency ablation of the lateral branches for sacroiliac joint pain. Clin J Pain 2013;29:132-137. PMID- 23629594 TI - Characteristics of sensitization associated with chronic pain conditions. AB - OBJECTIVES: To describe and understand varieties and characteristics of sensitization contributing to hyperalgesia in participants with chronic pain conditions. METHODS: Thermal stimulation was delivered to the face, forearm, and calf of pain-free participants and individuals with irritable bowel syndrome, temporomandibular pain disorder (TMD), and fibromyalgia syndrome (FM). Three second contacts by a preheated thermode occurred at 30-second intervals in ascending and then in descending series (0.7 degrees C steps). RESULTS: Thermal pain ratings during ascending series were greater at each site in individuals diagnosed with chronic pain. Intense pain at the time of testing further enhanced the ratings at all sites, but mild or moderate clinical pain did not have this effect. Thermal pain in all participants was greater during descending series compared with the ascending series of arm and leg stimulation. The hypersensitivity during the descending series was comparable in pain-free, FM and TMD participants but was increased in duration for arm or leg stimulation of FM participants. DISCUSSION: The widespread sensitization for irritable bowel syndrome and TMD participants does not rely on mechanisms of spatial and temporal summation often invoked to explain widespread hyperalgesia associated with chronic pain. Increased sensitivity during descending series of stimulation of an arm or leg but not the face indicates a propensity for sensitization of nociceptive input to the spinal cord. Abnormally prolonged sensitization for FM participants reveals a unique influence of widespread chronic pain referred to deep somatic tissues. PMID- 23629596 TI - Thermal pain and sensory processing in children with sickle cell disease. AB - OBJECTIVES: Early tissue injury and recurrent pain in sickle cell disease (SCD) may alter pain and sensory processing. In this study, we evaluate thermal pain and sensory processing for 27 children aged 10.3 to 18.3 years with SCD and 28 African-American control patients. MATERIALS AND METHODS: Outcome measures included heat and cold detection thresholds, heat and cold pain thresholds, and thermal perceptual sensitization at the volar surface of the dominant forearm and thenar eminence of the nondominant hand. RESULTS: Children with SCD were less sensitive to heat detection (P=0.006) and cold detection (P=0.015) stimuli at the thenar eminence compared with controls. At the forearm, no difference was found between groups for cold (P=0.58) or heat (P=0.07) detection thresholds. Children with SCD had increased sensitivity to cold pain at the forearm (P=0.03) compared with controls, but not when measured at the thenar eminence (P=0.084). There was no evidence that children with SCD had altered heat pain thresholds compared with controls. There was no difference between groups for perceptual sensitization at the thenar eminence (41% vs. 39%) (chi=0.15, P>0.1) or at the forearm (30% vs. 36%) (chi=0.23, P>0.5). DISCUSSION: Three of ten quantitative sensory tests were found to differ between groups. These results suggest that SCD may influence pain and sensory processing in children, but our interpretation is necessarily cautious. Due to the small differences in measures found between groups, further investigation is required to confirm our findings. If confirmed, the development of population-specific reference standards for quantitative sensory testing may emerge as a useful clinical tool for pain physicians in identifying and quantifying pain and sensory processing in children with SCD. PMID- 23629597 TI - Paraspinal stimulation combined with trigger point needling and needle rotation for the treatment of myofascial pain: a randomized sham-controlled clinical trial. AB - BACKGROUND: There are different types and parameters of dry needling (DN) that can affect its efficacy in the treatment of pain that have not been assessed properly. OBJECTIVE: To test the hypothesis that either multiple deep intramuscular stimulation therapy multiple deep intramuscular stimulation therapy (MDIMST) or TrP lidocaine injection (LTrP-I) is more effective than a placebo sham for the treatment of myofascial pain syndrome (MPS) and that MDIMST is more effective than LTrP-I for improving pain relief, sleep quality, and the physical and mental state of the patient. METHODS: Seventy-eight females aged 20 to 40 who were limited in their ability to perform active and routine activities due to MPS in the previous 3 months were recruited. The participants were randomized into 1 of the 3 groups as follows: placebo-sham, LTrP-I, or MDIMST. The treatments were provided twice weekly over 4 weeks using standardized MDIMST and LTrP-I protocols. RESULTS: There was a significant interaction (time vs. group) for the main outcomes. Compared with the sham-treated group, MDIMST and LTrP-I administration improved pain scores based on a visual analog scale, the pain pressure threshold (P<0.001 for all analyses), and analgesic use (P<0.01 for all analyses). In addition, when comparing the active groups for these outcomes, MDIMST resulted in better improvement than LTrP-I (P<0.01 for all analyses). In addition, both active treatments had a clinical effect, as assessed by a sleep diary and by the SF-12 physical and mental health scores. CONCLUSIONS: This study highlighted the greater efficacy of MDIMST over the placebo-sham and LTrP-I and indicated that both active treatments are more effective than placebo-sham for MPS associated with limitations in active and routine activities. PMID- 23629598 TI - Identification of hepatic microvascular adhesion-related genes of human colon cancer cells using random homozygous gene perturbation. AB - Random homozygous gene perturbation (RHGP), in combination with liver sinusoidal endothelial cell (LSEC) adhesion screening of clonal colon cancer cells with perturbed genes, was used to identify genes contributing to the hepatic microvascular adhesion of colon cancer cells. Plasmid vector encoding transactivator and gene search vector were transfected into HT-29 human colorectal cancer cells to create a HT-29 RHGP cell library; the adhesion of these library cells to primary cultured mouse LSEC significantly decreased in the presence of RSL1 ligand (inducer), indicating that most of the genes contributing to HT-29 adhesion to LSEC were altered. Next, HT-29 RHGP cell library fractions with upregulated or silenced LSEC adhesion-related genes were isolated. Around 160 clones having altered expression in LSEC adhesion-related genes were obtained, and nine relevant protein-coding genes were identified. Some were proadhesive genes detected because of their overexpression in adherent HT-29 cells (DGCR8 and EFEMP1 genes) and their silenced status in nonadherent HT-29 cells (DGKE, DPY19L1, KIAA0753, PVR and USP11 genes). Others were antiadhesive genes detected because of their overexpression in nonadherent HT-29 cells (ITPKC gene) and their silenced status in adherent HT-29 cells (PPP6R2 gene). Silencing of PVR, DGCR8 and EFEMP1 genes decreased adhesion to LSEC and hepatic microvascular retention of HT-29 cells. The results conclude that RHGP was a valuable strategy for the discovery of mechanisms regulating microvascular adhesion of circulating colon cancer cells before hepatic metastasis formation. Identified genes may contribute to understand the metastatic process of colon cancer and to discovering molecular targets for hepatic metastasis therapeutics. PMID- 23629599 TI - The acid pocket: a target for treatment in reflux disease? AB - The nadir esophageal pH of reflux observed during pH monitoring in the postprandial period is often more acidic than the concomitant intragastric pH. This paradox prompted the discovery of the "acid pocket", an area of unbuffered gastric acid that accumulates in the proximal stomach after meals and serves as the reservoir for acid reflux in healthy individuals and gastroesophageal reflux disease (GERD) patients. However, there are differentiating features between these populations in the size and position of the acid pocket, with GERD patients predisposed to upward migration of the proximal margin onto the esophageal mucosa, particularly when supine. This upward migration of acid, sometimes referred to as an "acid film", likely contributes to mucosal pathology in the region of the squamocolumnar junction. Furthermore, movement of the acid pocket itself to a supradiaphragmatic location with hiatus hernia increases the propensity for acid reflux by all conventional mechanisms. Consequently, the acid pocket is an attractive target for GERD therapy. It may be targeted in a global way with proton pump inhibitors that attenuate acid pocket development, or with alginate/antacid combinations that colocalize with the acid pocket and displace it distally, thereby demonstrating the potential for selective targeting of the acid pocket in GERD. PMID- 23629600 TI - Spleen stiffness in patients with cirrhosis in predicting esophageal varices. AB - OBJECTIVES: Screening for esophageal varices (EV) is recommended in patients with cirrhosis. Noninvasive tests had shown varying sensitivity (Se) and specificity (Sp) for predicting EV. Splenomegaly is a common finding in liver cirrhosis because of portal and splenic congestion. These changes can be quantified by transient elastography; hence, the aim of this study was to investigate the utility of spleen stiffness (SS) in evaluating EV in comparison with other noninvasive tests. METHODS: We measured SS and liver stiffness (LS) by using FibroScan in 200 consecutive cirrhotic patients who met the inclusion criteria. Patients were also assessed by hepatic venous pressure gradient (HVPG), upper gastrointestinal endoscopy, LS-spleen diameter to platelet ratio score (LSPS), and platelet count to spleen diameter ratio (PSR). RESULTS: Of 200 patients enrolled, 174 patients had valid LS and SS measurement, and 124 (71%) patients had EV (small, n=46 and large n=78). There was a significant difference in median LS (51.4 vs. 23.9 kPa, P=0.001), SS (54 vs. 32 kPa, P=0.001), LSPS (6.1 vs. 2.5, P=0.001), and PSR (812 vs. 1,165, P=0.001) between patients with EV and those without EV. LS >=27.3 kPa had an Se of 91%, Sp of 72%, positive predictive value (PPV) of 89%, negative predictive value (NPV) of 76%, and a diagnostic accuracy of 86% in predicting EV. LSPS >=3.09 had Se and Sp of 89% and 76%, respectively, and a PSR cutoff value of 909 or less had Se of 64%, Sp of 76%, and diagnostic accuracy of 68% in predicting EV. SS >=40.8 kPa had Se (94%), Sp (76%), PPV (91%), NPV (84%), and diagnostic accuracy of 86% for predicting EV. SS was significantly higher in patients who had large varices (56 vs. 49 kPa, P=0.001) and variceal bleed (58 vs. 50.2 kPa, P=0.001). Combining LS+SS (27.3+40.8 kPa) had Se of 90%, Sp 90%, PPV 96%, NPV 79%, and a diagnostic accuracy of 90%. HVPG (n=52) showed significant correlation with SS (r=0.433, P=0.001), LSPS (r=0.335, P=0.01), and PSR (r=-0.270, P=0.05), but not with LS (r=0.178, P=0.20). CONCLUSIONS: Measurement of SS can be used for noninvasive assessment of EV and can differentiate large vs. small varices and nonbleeder vs. bleeder. PMID- 23629601 TI - Oral nucleoside/nucleotide analogs without hepatitis B immune globulin after liver transplantation for hepatitis B. AB - OBJECTIVES: The long-term outcomes of oral antiviral therapy without hepatitis B immune globulin (HBIG) in prevention of reinfection with hepatitis B after liver transplantation are not known. We aimed to determine the long-term outcomes from a large population of chronic hepatitis B (CHB) liver transplant recipients using oral antiviral therapy alone. METHODS: A total of 362 consecutive CHB patients transplanted from January 2003 to May 2011 were included. None of the patients received HBIG. Viral serology, viral load, and liver biochemistry were performed at regular intervals during follow-up. RESULTS: Of the 362 patients, 176 (49%), 142 (39%), and 44 (12%) were on lamivudine (LAM), entecavir (ETV), and combination therapy (predominantly LAM+adefovir), respectively, at the time of transplant. The median follow-up length was 53 months. The rate of hepatitis B surface antigen seronegativity and hepatitis B virus (HBV) DNA suppression to undetectable levels at 8 years was 88 and 98%, respectively. The virological relapse rates (>1 log increase IU/ml) at 1, 3, 5, and 8 years was 5, 10, 13 and 16%, respectively. The virological relapse rate at 3 years for LAM, ETV, and combination group was 17, 0, and 7%, respectively (P<0.001). Forty-two patients had virological relapse, of which 36 had YMDD mutation (31 in the LAM group and 5 in the combination group). The overall 8-year survival was 83%, with no difference between the three treatment groups (P=0.94). No mortality from HBV recurrence occurred in the 362 patients. CONCLUSIONS: Oral nucleoside/nucleotide analogs without HBIG are effective in preventing graft loss secondary to hepatitis B recurrence after liver transplantation. However, new agents with a high barrier to resistance should be used to minimize drug resistance and to prevent virological rebound. PMID- 23629602 TI - CT with hepatic arterioportography as a pretreatment examination for hepatocellular carcinoma patients: a randomized controlled trial. AB - OBJECTIVES: The combination of computed tomography with hepatic arteriography and arterial portography (CTHA/CTAP) can detect additional hepatocellular carcinoma (HCC) nodules undetected by conventional dynamic CT. METHODS: In this single center, randomized, open-label, controlled trial, we randomly assigned 280 patients who were diagnosed as having HCC by conventional dynamic CT, and eligible for radiofrequency ablation (RFA), to undergo CTHA/CTAP before treatment, or to the control group. Newly detected HCC nodules by CTHA/CTAP were intended to be ablated completely. The primary end point was recurrence-free survival and the key secondary end point was overall survival. The analysis was conducted on an intention-to-treat basis. Those with nonablated nodules were treated as for recurrence. RESULTS: A total of 75 nodules were newly diagnosed as HCC by CTHA/CTAP in 45 patients. Three patients (one in the CTHA/CTAP group and two in the control group) who refused treatment were excluded from all analyses. The cumulative recurrence-free survival rates at 1, 2, and 3 years were 60.1, 29.0, and 18.9% in the CTHA/CTAP group and 52.2, 29.7, and 23.1% in the control group, respectively (P=0.66 by log-rank test; hazard ratio, 0.94 for CTHA/CTAP vs. control; 95% confidence interval (CI), 0.73-1.22). The cumulative overall survival rates at 3 and 5 years were 79.7 and 56.4% in the CTHA/CTAP group and 86.8 and 60.1% in the control group, respectively (P=0.50; hazard ratio, 1.15, 95% CI, 0.77-1.71). CONCLUSIONS: CTHA/CTAP may detect recurrent lesions earlier. However, CTHA/CTAP before RFA did not improve cumulative recurrence-free survival or overall survival. PMID- 23629603 TI - Risk of gastrointestinal bleeding in patients undergoing total hip or knee replacement compared with matched controls: a nationwide cohort study. AB - OBJECTIVES: Gastrointestinal (GI) bleeding may impose a serious threat in patients undergoing total hip or knee replacement (THR/TKR). The objectives of this study are to evaluate the timing of GI bleeding following THR/TKR and to determine the effect modification by proton pump inhibitor (PPI) use. METHODS: In a nationwide Danish cohort study, we selected all patients with a primary THR/TKR between 1998 and 2007 (n=95,115). Three control subjects without THR/TKR were matched by age, sex, and region. We calculated disease and medication adjusted (adj.) Hazard ratios (HRs) for GI bleeding with THR/TKR vs. controls. PPI use was assessed in the previous 3 months (in a time-dependent manner). RESULTS: We identified a 6-fold increased risk of GI bleeding during the first 2 weeks following THR (adj. HR, 6.02; 95% confidence interval (CI), 4.06-8.92) and a 2.3 fold increased risk for TKR patients (adj. HR, 2.30; 95% CI, 1.17-4.54), both vs. matched controls. The elevated risk lasted longer in THR patients (12 weeks) as compared with TKR patients (6 weeks). PPI use lowered the HR for GI bleeding by 74% during the first 6 weeks following THR, but not TKR. CONCLUSIONS: This study demonstrated an increased risk of GI bleeding during the first 2 weeks following THR (6-fold) and TKR (2.3-fold), and remained increased for up to 6 (TKR) to 12 weeks (THR) after surgery. PPI use substantially lowered this elevated risk in THR patients, but not in TKR patients. PMID- 23629604 TI - Barrett oesophagus: Is RFA the overall answer to all Barrett oesophagus issues? PMID- 23629605 TI - Liver: Abstinence to improve survival from alcoholic cirrhosis--a waiting game. PMID- 23629606 TI - Transplantation: Assessment of liver allograft steatosis. PMID- 23629607 TI - Endoscopy: Diminutive colorectal polyps--is narrow-band imaging ready for prime time? PMID- 23629610 TI - New questions on the road to safer health care. PMID- 23629608 TI - Medication errors in the home: a multisite study of children with cancer. AB - OBJECTIVE: As home medication use increases, medications previously managed by nurses are now managed by patients and their families. Our objective was to describe the types of errors occurring in the home medication management of children with cancer. METHODS: In a prospective observational study at 3 pediatric oncology clinics in the northeastern and southeastern United States, patients undergoing chemotherapy and their parents were recruited from November 2007 through April 2011. We reviewed medical records and checked prescription doses. A trained nurse visited the home, reviewed medication bottles, and observed administration. Two physicians independently made judgments regarding whether an error occurred and its severity. Overall rates of errors were weighted to account for clustering within sites. RESULTS: We reviewed 963 medications and observed 242 medication administrations in the homes of 92 patients. We found 72 medication errors. Four errors led to significant patient injury. An additional 40 errors had potential for injury: 2 were life-threatening, 13 were serious, and 25 were significant. Error rates varied between study sites (40-121 errors per 100 patients); the weighted overall rate was 70.2 errors per 100 patients (95% confidence interval [CI]: 58.9-81.6). The weighted rate of errors with injury was 3.6 (95% CI: 1.7-5.5) per 100 patients and with potential to injure the patient was 36.3 (95% CI: 29.3-43.3) per 100 patients. Nonchemotherapy medications were more often involved in an error than chemotherapy. CONCLUSIONS: Medication errors were common in this multisite study of outpatient pediatric cancer care. Rates of preventable medication-related injuries in this outpatient population were comparable or higher than those found in studies of hospitalized patients. PMID- 23629611 TI - Treatment of severe pulmonary hypertension in the setting of the large patent ductus arteriosus. AB - Treatment of the large patent ductus arteriosus (PDA) in the setting of pulmonary hypertension (PH) is challenging. Left patent, the large PDA can result in irreversible pulmonary vascular disease. Occlusion, however, may lead to right ventricular failure for certain patients with severe PH. Our center has adopted a staged management strategy using medical management, noninvasive imaging, and invasive cardiac catheterization to treat PH in the presence of a large PDA. This approach determines the safety of ductal closure but also leverages medical therapy to create an opportunity for safe PDA occlusion. We reviewed our experience with this approach. Patients with both severe PH and PDAs were studied. PH treatment history and hemodynamic data obtained during catheterizations were reviewed. Repeat catheterizations, echocardiograms, and clinical status at latest follow-up were also reviewed. Seven patients had both PH and large, unrestrictive PDAs. At baseline, all patients had near-systemic right ventricular pressures. Nine catheterizations were performed. Two patients underwent 2 catheterizations each due to poor initial response to balloon test occlusion. Six of 7 patients exhibited subsystemic pulmonary pressures during test occlusion and underwent successful PDA occlusion. One patient did not undergo PDA occlusion. In follow-up, 2 additional catheterizations were performed after successful PDA occlusion for subsequent hemodynamic assessment. At the latest follow-up, the 6 patients who underwent PDA occlusion are well, with continued improvement in PH. Five patients remain on PH treatment. A staged approach to PDA closure for patients with severe PH is an effective treatment paradigm. Aggressive treatment of PH creates a window of opportunity for PDA occlusion, echocardiography assists in identifying the timing for closure, and balloon test occlusion during cardiac catheterization is critical in determining safety of closure. By safely eliminating the large PDA, this treatment algorithm can halt the perilous combination of the large shunting from the PDA and PH in a population at high risk of morbidity and mortality. PMID- 23629612 TI - Ethical controversies in organ donation after circulatory death. AB - The persistent mismatch between the supply of and need for transplantable organs has led to efforts to increase the supply, including controlled donation after circulatory death (DCD). Controlled DCD involves organ recovery after the planned withdrawal of life-sustaining treatment and the declaration of death according to the cardiorespiratory criteria. Two central ethical issues in DCD are when organ recovery can begin and how to manage conflicts of interests. The "dead donor rule" should be maintained, and donors in cases of DCD should only be declared dead after the permanent cessation of circulatory function. Permanence is generally established by a 2- to 5-minute waiting period. Given ongoing controversy over whether the cessation must also be irreversible, physicians should not be required to participate in DCD. Because the preparation for organ recovery in DCD begins before the declaration of death, there are potential conflicts between the donor's and recipient's interests. These conflicts can be managed in a variety of ways, including informed consent and separating the various participants' roles. For example, informed consent should be sought for premortem interventions to improve organ viability, and organ procurement organization personnel and members of the transplant team should not be involved in the discontinuation of life-sustaining treatment or the declaration of death. It is also important to emphasize that potential donors in cases of DCD should receive integrated interdisciplinary palliative care, including sedation and analgesia. PMID- 23629613 TI - Effects of reduced juice allowances in food packages for the women, infants, and children program. AB - OBJECTIVES: In 2009, the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) implemented revisions to the composition and quantities of WIC food packages. Juice allowances were reduced by approximately half. This report describes changes in purchases of 100% juice and other beverages among WIC participants after the WIC revisions. METHODS: Scanner data from a New England supermarket chain were used to assess juice and other beverage purchases among 2137 WIC-participating households during a 2-year period (N = 36 051 household-months). Purchased beverage amounts were compared before (January September 2009) and after (January-September 2010) implementation of the revised WIC packages. Generalized estimating equation models were used. RESULTS: Before the revisions, WIC juice accounted for two-thirds of purchased juice volume among WIC households. After implementation of the revisions, WIC juice purchases were reduced on par with allowance changes (43.5% of juice volume, 95% confidence interval [CI] 41.9%-45.1%). This reduction was only partly compensated for by an increase of 13.6% (8.4%-19.0%) in juice purchases using personal and other non WIC funds. In total, juice purchases declined by 23.5% (21.4%-25.4%) from an adjusted monthly total of 238 oz to 182 oz per household. WIC households increased purchases of fruit drinks by 20.9% (14.9%-27.3%) and other noncarbonated beverages by 21.3% (12.1%-31.2%) but purchased 12.1% (8.1%-15.0%) less soft drinks. CONCLUSIONS: After the WIC revisions, total purchases of 100% juice among WIC households declined by about a quarter, with little compensation occurring from non-WIC funds for juice and other beverages. The public health impact of the shift in beverage purchase patterns could be significant. PMID- 23629614 TI - Supraventricular tachycardia in the pediatric trauma patient: a case report. AB - Any injured patient who is cool and tachycardic is considered to be in shock until proven otherwise.(1) We describe the diagnostic challenge when evaluating persistent tachycardia in the setting of multiple system trauma with hemorrhagic shock. This is a unique case of a 17-year-old patient with the secondary condition of cardiogenic shock due to supraventricular tachycardia (SVT) complicating ongoing hemorrhagic shock from a facial laceration. She had sustained tachycardia despite aggressive resuscitation and required medical cardioversion 30 minutes after arrival to the emergency department. After successful conversion, she maintained normal sinus rhythm for the rest of her hospitalization. During her follow-up cardiac catheterization, she was found to have a left-sided accessory pathway, consistent with atrioventricular reciprocating tachycardia. This is a unique and rare case of SVT in the traumatic patient. We review causes of tachycardia in the setting of pediatric multisystem trauma, as well as discuss acute SVT evaluation and management in the pediatric emergency department. PMID- 23629615 TI - Association of procalcitonin with acute pyelonephritis and renal scars in pediatric UTI. AB - BACKGROUND AND OBJECTIVE: Urinary tract infections (UTIs) are common childhood bacterial infections that may involve renal parenchymal infection (acute pyelonephritis [APN]) followed by late scarring. Prompt, high-quality diagnosis of APN and later identification of children with scarring are important for preventing future complications. Examination via dimercaptosuccinic acid scanning is the current clinical gold standard but is not routinely performed. A more accessible assay could therefore prove useful. Our goal was to study procalcitonin as a predictor for both APN and scarring in children with UTI. METHODS: A systematic review and meta-analysis of individual patient data were performed; all data were gathered from children with UTIs who had undergone both procalcitonin measurement and dimercaptosuccinic acid scanning. RESULTS: A total of 1011 patients (APN in 60.6%, late scarring in 25.7%) were included from 18 studies. Procalcitonin as a continuous, class, and binary variable was associated with APN and scarring (P < .001) and demonstrated a significantly higher (P < .05) area under the receiver operating characteristic curve than either C reactive protein or white blood cell count for both pathologies. Procalcitonin >=0.5 ng/mL yielded an adjusted odds ratio of 7.9 (95% confidence interval [CI]: 5.8-10.9) with 71% sensitivity (95% CI: 67-74) and 72% specificity (95% CI: 67 76) for APN. Procalcitonin >=0.5 ng/mL was significantly associated with late scarring (adjusted odds ratio: 3.4 [95% CI: 2.1-5.7]) with 79% sensitivity (95% CI: 71-85) and 50% specificity (95% CI: 45-54). CONCLUSIONS: Procalcitonin was a more robust predictor compared with C-reactive protein or white blood cell count for selectively identifying children who had APN during the early stages of UTI, as well as those with late scarring. PMID- 23629617 TI - Can a patient designate his doctor as his proxy decision maker? AB - Most lawyers and bioethicists recommend that patients enact a durable power of attorney for health care designating somebody as their proxy decision maker should they become unable to make decisions. Most people choose family members as their agent. But what if a patient wants his or her doctor to be his or her proxy decision maker? Can the doctor be both physician and surrogate decision maker? Or should those roles necessarily be kept separate? We present a case in which those issues arose, and sought comments from Sabrina Derrington, a pediatric palliative care physician; Arthur Derse, an emergency department physician and lawyer; and Phil Black, a pulmonologist. PMID- 23629618 TI - Gastroesophageal reflux: management guidance for the pediatrician. AB - Recent comprehensive guidelines developed by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition define the common entities of gastroesophageal reflux (GER) as the physiologic passage of gastric contents into the esophagus and gastroesophageal reflux disease (GERD) as reflux associated with troublesome symptoms or complications. The ability to distinguish between GER and GERD is increasingly important to implement best practices in the management of acid reflux in patients across all pediatric age groups, as children with GERD may benefit from further evaluation and treatment, whereas conservative recommendations are the only indicated therapy in those with uncomplicated physiologic reflux. This clinical report endorses the rigorously developed, well-referenced North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines and likewise emphasizes important concepts for the general pediatrician. A key issue is distinguishing between clinical manifestations of GER and GERD in term infants, children, and adolescents to identify patients who can be managed with conservative treatment by the pediatrician and to refer patients who require consultation with the gastroenterologist. Accordingly, the evidence basis presented by the guidelines for diagnostic approaches as well as treatments is discussed. Lifestyle changes are emphasized as first-line therapy in both GER and GERD, whereas medications are explicitly indicated only for patients with GERD. Surgical therapies are reserved for children with intractable symptoms or who are at risk for life threatening complications of GERD. Recent black box warnings from the US Food and Drug Administration are discussed, and caution is underlined when using promoters of gastric emptying and motility. Finally, attention is paid to increasing evidence of inappropriate prescriptions for proton pump inhibitors in the pediatric population. PMID- 23629619 TI - Validity of the ages and stages questionnaires in term and preterm infants. AB - BACKGROUND: This study assessed the concurrent validity of the parent-completed developmental screening measure Ages and Stages Questionnaires, Third Edition (ASQ-3) compared with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) in children born term, late preterm, or extremely preterm at 8, 18, or 30 months of corrected gestational ages (CGA). METHODS: Data were collected from 306 term and preterm children ages 8, 18, and 30 months' CGA recruited from an ambulatory well-child clinic in Santiago, Chile. Parents completed the ASQ-3 in their homes, and afterward a trained professional administered the Bayley-III in a clinic setting. On the ASQ-3, the presence of any domain screened <2 SDs below the mean area score was considered a positive screen (indicating failure or delay). A Bayley-III score less than <=1 SD indicated mild or severe delay. RESULTS: ASQ-3 showed adequate psychometric properties (75% sensitivity and 81% specificity) and modest agreement with the Bayley-III (r = 0.56). Sensitivity, specificity, and correlations between measures improved with testing age and in children who were born extremely preterm. CONCLUSIONS: Considering its psychometric properties, the ASQ-3 can be recommended for routine use in screening low-risk children at 8, 18, and 30 months' CGA and is advisable to be included in follow-up programs for children with biological risk factors such as those born preterm. PMID- 23629620 TI - Calcium and vitamin d requirements of enterally fed preterm infants. AB - Bone health is a critical concern in managing preterm infants. Key nutrients of importance are calcium, vitamin D, and phosphorus. Although human milk is critical for the health of preterm infants, it is low in these nutrients relative to the needs of the infants during growth. Strategies should be in place to fortify human milk for preterm infants with birth weight <1800 to 2000 g and to ensure adequate mineral intake during hospitalization and after hospital discharge. Biochemical monitoring of very low birth weight infants should be performed during their hospitalization. Vitamin D should be provided at 200 to 400 IU/day both during hospitalization and after discharge from the hospital. Infants with radiologic evidence of rickets should have efforts made to maximize calcium and phosphorus intake by using available commercial products and, if needed, direct supplementation with these minerals. PMID- 23629622 TI - Total synthesis of (-)-kaitocephalin. AB - (-)-Kaitocephalin has been synthesized. With the C9 stereocenter from Garner's aldehyde, the C4 quaternary carbon was installed by the desymmetrization of the Cbz-protected serinol. The remaining stereogenic centers were generated through mercuriocyclization, epoxidation and regioselective epoxide opening, in which the quaternary carbon most likely played crucial roles in the stereoinduction. PMID- 23629621 TI - Biopolymer-based hydrogels as injectable materials for tissue repair scaffolds. AB - The progress in tissue regeneration is strongly dependent on the development of biocompatible materials with properties resembling those of a native tissue. Also, the application of noninvasive methods of delivering the scaffold into the tissue defect is of great importance. In this study we present a group of biopolymer-based materials as potential injectable scaffolds. In contrast to other studies involving collagen neutralization or additional incubation of gel in genipin solution, we propose collagen and collagen-chitosan gels crosslinked in situ with genipin. Since some parameters of the cells should be considered in the microscale, the steady-state fluorescence anisotropy was applied to study the microenvironment of the gels. To our knowledge we are the first to report on microrheological properties, such as gel time and microviscosity, for this group of hydrogels. Rapid gelation at physiological temperatures found makes these materials of special interest in applications requiring gel injectability. Physico-chemical investigation showed the influence of the crosslinking agent concentration and chitosan addition on the crosslinking degree, swelling ratio, gel microviscosity, and the degradation rate. Strong correlation was revealed between the surface wettability and the viability of cultured mesenchymal stem cells. Cytotoxicity studies indicated that the collagen-chitosan hydrogels showed the best biocompatibility. PMID- 23629623 TI - The pheromone frontalin and its dual function in the invasive bark beetle Dendroctonus valens. AB - The red turpentine beetle, Dendroctonus valens LeConte, is one of the most destructive invasive forest pests in China, having killed more than 6 million pines since its first outbreak in 1999. Little is known about D. valens pheromone biology and no aggregation pheromone has yet been identified. Analysis by gas chromatograph/mass spectrometer of volatiles collected from live beetles in China showed that female beetles produce frontalin and males do not. Olfactory assays in the laboratory showed that males were attracted to frontalin at a wide range of concentrations, whereas females were attracted to it at a narrow range of concentrations. In field trials, 3-carene, a monoterpene kairomone from a pine tree selected to host the beetles attracted both sexes, and when frontalin was added, the total number of beetles captured increased by almost 200%. However, increasing concentrations of frontalin significantly decreased the percentage of female beetles trapped. These results suggest a new role of frontalin as an aggregation pheromone in addition to a female-produced sex pheromone, which was previously shown in a North American population. The dual functions of the pheromone frontalin produced by D. valens females, as well as its ecological significance for overcoming host resistance, are discussed. PMID- 23629624 TI - Seasonality of cutaneous melanoma diagnoses: a comprehensive comparison of results in Bavaria and Northern Ireland. AB - Ultraviolet radiation is an established skin carcinogen. By analysing the seasonality of melanoma diagnoses, the effect of this risk factor can be examined indirectly. However, previous studies yielded conflicting results, because of vastly differing analytical methods and diverse study designs. Therefore, to validate the findings by Chaillol and colleagues based on 3868 melanoma diagnoses from Northern Ireland, we used an identical methodology to examine the seasonal effects on monthly incidences of 11,901 cutaneous malignant melanoma cases registered from 2003 until 2008 in Bavaria, Germany. Multivariable regression models for count data were used to estimate the effect of seasons while taking into account sex, age, year of diagnosis, Breslow thickness and anatomical site. Point and interval estimates of the adjusted relative risks associated with seasons were compared with the findings of the Irish study. Both analyses demonstrated a promoting effect of intermittent ultraviolet radiation on cutaneous melanoma of a thickness of 2 mm or less evolving on the extremities, whereas no seasonality for melanomas on the trunk was evident. Differences were identified with regard to thick melanomas. In the present analysis, only melanomas with a Breslow thickness of more than 2 mm were also found to be associated with season, in particular, the melanomas on the limbs. Hence, in contrast to the data of, and to the interpretation by, Chaillol and colleagues, an effect of ultraviolet radiation on melanoma progression from thin to thick cannot be excluded. PMID- 23629625 TI - SAD-A potentiates glucose-stimulated insulin secretion as a mediator of glucagon like peptide 1 response in pancreatic beta cells. AB - Type 2 diabetes is characterized by defective glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells, which can be restored by glucagon like peptide 1 (GLP-1), an incretin hormone commonly used for the treatment of type 2 diabetes. However, molecular mechanisms by which GLP-1 affects glucose responsiveness in islet beta cells remain poorly understood. Here we investigated a role of SAD-A, an AMP-activated protein kinase (AMPK)-related kinase, in regulating GSIS in mice with conditional SAD-A deletion. We show that selective deletion of SAD-A in pancreas impaired incretin's effect on GSIS, leading to glucose intolerance. Conversely, overexpression of SAD-A significantly enhanced GSIS and further potentiated GLP-1's effect on GSIS from isolated mouse islets. In support of SAD-A as a mediator of incretin response, SAD-A is expressed exclusively in pancreas and brain, the primary targeting tissues of GLP-1 action. Additionally, SAD-A kinase is activated in response to stimulation by GLP-1 through cyclic AMP (cAMP)/Ca(2+)-dependent signaling pathways in islet beta cells. Furthermore, we identified Thr443 as a key autoinhibitory phosphorylation site which mediates SAD-A's effect on incretin response in islet beta cells. Consequently, ablation of Thr443 significantly enhanced GLP-1's effect on GSIS from isolated mouse islets. Together, these findings identified SAD-A kinase as a pancreas-specific mediator of incretin response in islet beta cells. PMID- 23629626 TI - Wnt7a regulates multiple steps of neurogenesis. AB - Although Wnt7a has been implicated in axon guidance and synapse formation, investigations of its role in the early steps of neurogenesis have just begun. We show here that Wnt7a is essential for neural stem cell self-renewal and neural progenitor cell cycle progression in adult mouse brains. Loss of Wnt7a expression dramatically reduced the neural stem cell population and increased the rate of cell cycle exit in neural progenitors in the hippocampal dentate gyrus of adult mice. Furthermore, Wnt7a is important for neuronal differentiation and maturation. Loss of Wnt7a expression led to a substantial decrease in the number of newborn neurons in the hippocampal dentate gyrus. Wnt7a(-/-) dentate granule neurons exhibited dramatically impaired dendritic development. Moreover, Wnt7a activated beta-catenin and its downstream target genes to regulate neural stem cell proliferation and differentiation. Wnt7a stimulated neural stem cell proliferation by activating the beta-catenin-cyclin D1 pathway and promoted neuronal differentiation and maturation by inducing the beta-catenin-neurogenin 2 pathway. Thus, Wnt7a exercised critical control over multiple steps of neurogenesis by regulating genes involved in both cell cycle control and neuronal differentiation. PMID- 23629628 TI - Efficient initiation of DNA replication in eukaryotes requires Dpb11/TopBP1-GINS interaction. AB - Dpb11/Cut5/TopBP1 is evolutionarily conserved and is essential for the initiation of DNA replication in eukaryotes. The Dpb11 of the budding yeast Saccharomyces cerevisiae has four BRCT domains (BRCT1 to -4). The N-terminal pair (BRCT1 and 2) and the C-terminal pair (BRCT3 and -4) bind to cyclin-dependent kinase (CDK) phosphorylated Sld3 and Sld2, respectively. These phosphorylation-dependent interactions trigger the initiation of DNA replication. BRCT1 and -2 and BRCT3 and -4 of Dpb11 are separated by a short stretch of ~100 amino acids. It is unknown whether this inter-BRCT region functions in DNA replication. Here, we showed that the inter-BRCT region is a GINS interaction domain that is essential for cell growth and that mutations in this domain cause replication defects in budding yeast. We found the corresponding region in the vertebrate ortholog, TopBP1, and showed that the corresponding region also interacts with GINS and is required for efficient DNA replication. We propose that the inter-BRCT region of Dpb11 is a functionally conserved GINS interaction domain that is important for the initiation of DNA replication in eukaryotes. PMID- 23629630 TI - Digital and analogical reality in proteomics investigation. AB - Are protein functions continuous or discretized? Proteomics investigations are starting to address this non-trivial awesome question focusing upon determining the nature of biological molecular relationships. In the following editorial we present a number of experimental studies published in this themed Proteomics Issue demonstrating the development of a new analogical vision for the interpretation of genotype-phenotype relationships. New metrics and languages are evolving, which may complement the insufficiency based on a binary digital interpretation of biological phenomena, providing new tools for the interpretation of large scale-experimental studies. PMID- 23629631 TI - [Schizophrenia--a mild encephalitis?]. AB - The mild encephalitis (ME) hypothesis describes a subgroup of severe psychiatric disorders, with a focus on a subgroup of schizophrenias, in which low-level neuroinflammation (LLNI) represents the core in pathogenesis. LLNI is increasingly recognised in experimental neuroimmunology and is in principle able to explain various types of psychopathology. Epidemiology and course of schizophrenia are well compatible with the ME hypothesis, indirectly indicating that the ME subgroup may be rather large. With the ME model connected is a set of three contributing factors: genes, environment (especially infectious agents) and the immune system. The type of psychopathology observed in the individual case may heavily depend upon other conditions, e. g. pre-existing vulnerabilities. The first large-scale epidemiological study in psychiatry identified two factors during lifetime, severe infectious diseases and autoimmune diseases, as risk factors. This and clinical findings more and more support the ME hypothesis, e. g., activated monocytes or proteome changes in blood and slight CSF pathologies in more than 60 % of therapy-resistant schizophrenia, or activated microglia and dysconnectivity in neuroimaging. PMID- 23629632 TI - Photo-cleavage of the cobalt-carbon bond: visible light-induced living radical polymerization mediated by organo-cobalt porphyrins. AB - This article describes the photo-induced living radical polymerization of acrylamides mediated by organo-cobalt porphyrins through photo-cleavage of the Co C bond to give organic radicals, which propagate polymerization, and cobalt(II), which is a persistent metal-centered radical. Photo stimulus controls the initiation steps and regulates chain growth by activating the Co-C bond. PMID- 23629627 TI - alphaCP Poly(C) binding proteins act as global regulators of alternative polyadenylation. AB - We have previously demonstrated that the KH-domain protein alphaCP binds to a 3' untranslated region (3'UTR) C-rich motif of the nascent human alpha-globin (halpha-globin) transcript and enhances the efficiency of 3' processing. Here we assess the genome-wide impact of alphaCP RNA-protein (RNP) complexes on 3' processing with a specific focus on its role in alternative polyadenylation (APA) site utilization. The major isoforms of alphaCP were acutely depleted from a human hematopoietic cell line, and the impact on mRNA representation and poly(A) site utilization was determined by direct RNA sequencing (DRS). Bioinformatic analysis revealed 357 significant alterations in poly(A) site utilization that could be specifically linked to the alphaCP depletion. These APA events correlated strongly with the presence of C-rich sequences in close proximity to the impacted poly(A) addition sites. The most significant linkage was the presence of a C-rich motif within a window 30 to 40 bases 5' to poly(A) signals (AAUAAA) that were repressed upon alphaCP depletion. This linkage is consistent with a general role for alphaCPs as enhancers of 3' processing. These findings predict a role for alphaCPs in posttranscriptional control pathways that can alter the coding potential and/or levels of expression of subsets of mRNAs in the mammalian transcriptome. PMID- 23629633 TI - Cardiac toxicity in breast cancer patients treated with dual HER2 blockade. AB - Although dual HER2 blockade shows promising results in patients with HER2 positive breast cancer it is unclear whether this treatment strategy increases the risk for cardiac adverse events. We conducted a meta-analysis of randomized trials to investigate the risk of cardiac adverse events when a combination of anti-HER2 therapies compared to anti-HER2 monotherapy. We searched Medline, the Cochrane library, as well as the electronic abstract databases of the major international congresses' proceedings to identify randomized trials that evaluated the administration of anti-HER2 monotherapy (lapatinib or trastuzumab or pertuzumab) versus anti-HER2 combination (pertuzumab plus trastuzumab or trastuzumab plus lapatinib) therapy in breast cancer. The trials were considered eligible if the only systematic difference between the study arms was the type of anti-HER2 therapy used. Study outcomes were the congestive heart failure (CHF) grade >=3 and left ventricular ejection fraction (LVEF) decline <50% or more than 10% from baseline. Six trials were considered eligible. Overall incidence results for CHF in the combined anti-HER2 therapy and the anti-HER2 monotherapy were 0.88% (95% CI: 0.47-1.64%) and 1.49% (95% CI: 0.98-2.23%). The incidence of LVEF decline was 3.1% (95% CI: 2.2-4.4%) and 2.9% (95% CI: 2.1-4.1%), respectively. The OR of CHF between anti-HER2 combination and monotherapy was 0.58 (95% CI: 0.26-1.27, p-value= 0.17) while the OR of LVEF decline was 0.88 (95% CI: 0.53 1.48, p-value= 0.64). This meta-analysis provides evidence supporting comparable cardiac toxicity between anti-HER2 combination therapy and anti-HER2 monotherapy. PMID- 23629634 TI - Cooperative effect of "flexible" interaction and "flexible" framework in reversible intake and removal of aromatic guest molecules. AB - The metal-organic frameworks of amide based "flexible" ligands has been explored. The reaction of bis-(3-pyridyl)ethanediamide with Cu(PF6)2 resulted in a 1D looped chain, where the PF6(-) anions interact with the amide groups of the chains. This resulted in unavailability of space for guest inclusion in the loops. The exchange of PF6(-) ion with ClO4(-) ion resulted in the intake of aromatic guest molecules, which were monitored by IR and UV-Vis spectroscopy. The capability of the flexible ethyl spacer of bis-(3-pyridyl)ethanediamide to adjust the conformation according to the requirements of the other components of the networks is observed in the present study. This resulted in reversible inclusion and removal of guest molecules triggered by the exchange of anions. PMID- 23629635 TI - Analysing conjoint data with OLS and PLS regression: a case study with wine. AB - BACKGROUND: This paper presents a case study with wine where two statistical methods for the analysis of rating-based conjoint analysis data were applied. Traditionally, ordinary least squares (OLS) regression is used to estimate the relative importance of the experimental factors and the part-worth utilities of factor levels. Partial least squares (PLS) regression, which is a popular tool in sensory and consumer science, can also be used for the analysis of interval-level conjoint data. RESULTS: Using conjoint analysis, purchase intentions for Californian red and white wine were obtained from a convenience sample of young US adults (n ~ 250). OLS and PLS regression uncovered the same systematic patterns in the data: negative utility associated with more expensive wine, and positive utility associated with famous wine regions. While OLS regression provided more accessible top-line results, an advantage of PLS regression was the graphical format of results. This provided easy insight to individual differences in the importance attached to the factors driving purchase intention. CONCLUSION: OLS and PLS regression can complement each other in the analysis of interval level conjoint data. Dual analysis can help to ensure that the right insights are drawn from the study and communicated to internal/external clients. It may also facilitate communication within project teams. PMID- 23629636 TI - Diabetic nephropathy: FRMD3 in diabetic nephropathy--guilt by association. PMID- 23629638 TI - Renin-angiotensin system: Meta-analyses can misdirect decisions on treatment. PMID- 23629639 TI - Chronic kidney disease: Renal adenosine in hypertensive CKD. PMID- 23629640 TI - Risk factors: Body fat distribution and renal risk. PMID- 23629641 TI - End-stage renal disease: A bioengineered kidney with excretory function. PMID- 23629644 TI - Chronic kidney disease: How effective and safe are antiplatelet agents in CKD? PMID- 23629646 TI - Epidemiology of esophageal cancer in Japan and China. AB - In preparation for a collaborative multidisciplinary study of the pathogenesis of esophageal cancer, the authors reviewed the published literature to identify similarities and differences between Japan and China in esophageal cancer epidemiology. Esophageal squamous cell carcinoma (ESCC) is the predominant histologic type, while the incidence of esophageal adenocarcinoma remains extremely low in both countries. Numerous epidemiologic studies in both countries show that alcohol consumption and cigarette smoking are contributing risk factors for ESCC. There are differences, however, in many aspects of esophageal cancer between Japan and China, including cancer burden, patterns of incidence and mortality, sex ratio of mortality, risk factor profiles, and genetic variants. Overall incidence and mortality rates are higher in China than in Japan, and variation in mortality and incidence patterns is greater in China than in Japan. During the study period (1987-2000), the decline in age-adjusted mortality rates was more apparent in China than in Japan. Risk factor profiles differed between high- and low-incidence areas within China, but not in Japan. The association of smoking and drinking with ESCC risk appears to be weaker in China than in Japan. Genome-wide association studies in China showed that variants in several chromosome regions conferred increased risk, but only genetic variants in alcohol metabolizing genes were significantly associated with ESCC risk in Japan. A well designed multidisciplinary epidemiologic study is needed to examine the role of diet and eating habits in ESCC risk. PMID- 23629647 TI - Seroepidemiology of hepatitis a in South Korea: a nationwide study by the Eone Reference Laboratory. AB - BACKGROUND: We evaluated the recent prevalence of serologic markers of hepatitis A virus (HAV) in South Korea. METHODS: The study data were the results of 60 126 anti-HAV (total) tests and 30 786 anti-HAV IgM tests that were performed during April 2009 through March 2010 by the Eone Reference Laboratory at the request of 1935 institutions throughout Korea. RESULTS: The overall positivity rate was 51.06% on the anti-HAV (total) test and 11.20% on the anti-HAV IgM test. As compared with the other age groups the rate of anti-HAV (total) positivity was significantly lower (P < 0.001), and the rate of anti-HAV IgM positivity was significantly higher (P < 0.001), among Koreans aged 11 to 40 years. The seroprevalence of anti-HAV IgM significantly differed according to region but not by referral date. CONCLUSIONS: This was the largest nationwide study in South Korea by 1 laboratory, and it provides useful recent baseline data on hepatitis A in Asia. The findings suggest that active immunization of younger Koreans should be made a priority. PMID- 23629648 TI - Detection of G protein-selective G protein-coupled receptor (GPCR) conformations in live cells. AB - Although several recent studies have reported that GPCRs adopt multiple conformations, it remains unclear how subtle conformational changes are translated into divergent downstream responses. In this study, we report on a novel class of FRET-based sensors that can detect the ligand/mutagenic stabilization of GPCR conformations that promote interactions with G proteins in live cells. These sensors rely on the well characterized interaction between a GPCR and the C terminus of a Galpha subunit. We use these sensors to elucidate the influence of the highly conserved (E/D)RY motif on GPCR conformation. Specifically, Glu/Asp but not Arg mutants of the (E/D)RY motif are known to enhance basal GPCR signaling. Hence, it is unclear whether ionic interactions formed by the (E/D)RY motif (ionic lock) are necessary to stabilize basal GPCR states. We find that mutagenesis of the beta2-AR (E/D)RY ionic lock enhances interaction with Gs. However, only Glu/Asp but not Arg mutants increase G protein activation. In contrast, mutagenesis of the opsin (E/D)RY ionic lock does not alter its interaction with transducin. Instead, opsin-specific ionic interactions centered on residue Lys-296 are both necessary and sufficient to promote interactions with transducin. Effective suppression of beta2-AR basal activity by inverse agonist ICI 118,551 requires ionic interactions formed by the (E/D)RY motif. In contrast, the inverse agonist metoprolol suppresses interactions with Gs and promotes Gi binding, with concomitant pertussis toxin-sensitive inhibition of adenylyl cyclase activity. Taken together, these studies validate the use of the new FRET sensors while revealing distinct structural mechanisms for ligand dependent GPCR function. PMID- 23629649 TI - Stabilization, characterization, and selective removal of cystatin C amyloid oligomers. AB - The pathophysiological process in amyloid disorders usually involves the transformation of a functional monomeric protein via potentially toxic oligomers into amyloid fibrils. The structure and properties of the intermediary oligomers have been difficult to study due to their instability and dynamic equilibrium with smaller and larger species. In hereditary cystatin C amyloid angiopathy, a cystatin C variant is deposited in arterial walls and cause brain hemorrhage in young adults. In the present investigation, we use redox experiments of monomeric cystatin C, stabilized against domain swapping by an intramolecular disulfide bond, to generate stable oligomers (dimers, trimers, tetramers, decamers, and high molecular weight oligomers). These oligomers were characterized concerning size by gel filtration, polyacrylamide gel electrophoresis, and mass spectrometry, shape by electron and atomic force microscopy, and, function by assays of their capacity to inhibit proteases. The results showed the oligomers to be highly ordered, domain-swapped assemblies of cystatin C and that the oligomers could not build larger oligomers, or fibrils, without domain swapping. The stabilized oligomers were used to induce antibody formation in rabbits. After immunosorption, using immobilized monomeric cystatin C, and elution from columns with immobilized cystatin C oligomers, oligomer-specific antibodies were obtained. These could be used to selectively remove cystatin C dimers from biological fluids containing both dimers and monomers. PMID- 23629650 TI - Tubulin polymerization-promoting protein (TPPP/p25alpha) promotes unconventional secretion of alpha-synuclein through exophagy by impairing autophagosome-lysosome fusion. AB - Aggregation of alpha-synuclein can be promoted by the tubulin polymerization promoting protein/p25alpha, which we have used here as a tool to study the role of autophagy in the clearance of alpha-synuclein. In NGF-differentiated PC12 catecholaminergic nerve cells, we show that de novo expressed p25alpha co localizes with alpha-synuclein and causes its aggregation and distribution into autophagosomes. However, p25alpha also lowered the mobility of autophagosomes and hindered the final maturation of autophagosomes by preventing their fusion with lysosomes for the final degradation of alpha-synuclein. Instead, p25alpha caused a 4-fold increase in the basal level of alpha-synuclein secreted into the medium. Secretion was strictly dependent on autophagy and could be up-regulated (trehalose and Rab1A) or down-regulated (3-methyladenine and ATG5 shRNA) by enhancers or inhibitors of autophagy or by modulating minus-end-directed (HDAC6 shRNA) or plus-end-directed (Rab8) trafficking of autophagosomes along microtubules. Finally, we show in the absence of tubulin polymerization-promoting protein/p25alpha that alpha-synuclein release was modulated by dominant mutants of Rab27A, known to regulate exocytosis of late endosomal (and amphisomal) elements, and that both lysosomal fusion block and secretion of alpha-synuclein could be replicated by knockdown of the p25alpha target, HDAC6, the predominant cytosolic deacetylase in neurons. Our data indicate that unconventional secretion of alpha-synuclein can be mediated through exophagy and that factors, which increase the pool of autophagosomes/amphisomes (e.g. lysosomal disturbance) or alter the polarity of vesicular transport of autophagosomes on microtubules, can result in an increased release of alpha-synuclein monomer and aggregates to the surroundings. PMID- 23629651 TI - Cystatin C properties crucial for uptake and inhibition of intracellular target enzymes. AB - To elucidate the molecular requirements for cancer cell internalization of the extracellular cysteine protease inhibitor cystatin C, 12 variants of the protein were produced and used for uptake experiments in MCF-7 cells. Variants with alterations in the cysteine cathepsin binding region ((Delta1-10)-, K5A-, R8G-, (R8G,L9G,V10G)-, (R8G,L9G,V10G,W106G)-, and W106G-cystatin C) were internalized to a very low extent compared with the wild-type inhibitor. Substitutions of N39 in the legumain binding region (N39K- and N39A-cystatin C) decreased the internalization and (R24A,R25A)-cystatin C, with substitutions of charged residues not involved in enzyme inhibition, was not taken up at all. Two variants, W106F- and K75A-cystatin C, showed that the internalization can be positively affected by engineering of the cystatin molecule. Microscopy revealed vesicular co-localization of internalized cystatin C with the lysosomal marker proteins cathepsin D and legumain. Activities of both cysteine cathepsins and legumain, possible target enzymes associated with cancer cell invasion and metastasis, were down-regulated in cell homogenates following cystatin C uptake. A positive effect on regulation of intracellular enzyme activity by a cystatin variant selected from uptake properties was illustrated by incubating cells with W106F-cystatin C. This resulted in more efficient down-regulation of intracellular legumain activity than when cells were incubated with wild-type cystatin C. Uptake experiments in prostate cancer cells corroborated that the cystatin C internalization is generally relevant and confirmed an increased uptake of W106F-cystatin C, in PC3 cells. Thus, intracellular cysteine proteases involved in cancer-promoting processes might be controled by cystatin uptake. PMID- 23629652 TI - Kallikrein-related peptidase 5 functions in proteolytic processing of profilaggrin in cultured human keratinocytes. AB - Filaggrin protein is synthesized in the stratum granulosum of the skin and contributes to the formation of the human skin barrier. Profilaggrin is cleaved by proteolytic enzymes and converted to functional filaggrin, but its processing mechanism remains not fully elucidated. Kallikrein-related peptidase 5 (KLK5) is a major serine protease found in the skin, which is secreted from lamellar granules following its expression in the stratum granulosum and activated in the extracellular space of the stratum corneum. Here, we searched for profilaggrin processing protease(s) by partial purification of epidermal extracts and found KLK5 as a possible candidate. We used high performance liquid chromatography coupled with electrospray tandem mass spectrometry to show that KLK5 cleaves profilaggrin. Furthermore, based on a proximity ligation assay, immunohistochemistry, and immunoelectron microscopy analysis, we reveal that KLK5 and profilaggrin co-localize in the stratum granulosum in human epidermis. KLK5 knockdown in normal cultured human epidermal keratinocytes resulted in higher levels of profilaggrin, indicating that KLK5 potentially functions in profilaggrin cleavage. PMID- 23629653 TI - The immunologically active oligosaccharides isolated from wheatgrass modulate monocytes via Toll-like receptor-2 signaling. AB - Wheatgrass is one of the most widely used health foods, but its functional components and mechanisms remain unexplored. Herein, wheatgrass-derived oligosaccharides (WG-PS3) were isolated and found to induce CD69 and Th1 cytokine expression in human peripheral blood mononuclear cells. In particular, WG-PS3 directly activated the purified monocytes by inducing the expression of CD69, CD80, CD86, IL-12, and TNF-alpha but affected NK and T cells only in the presence of monocytes. After further purification and structural analysis, maltoheptaose was identified from WG-PS3 as an immunomodulator. Maltoheptaose activated monocytes via Toll-like receptor 2 (TLR-2) signaling, as discovered by pretreatment of blocking antibodies against Toll-like receptors (TLRs) and also determined by click chemistry. This study is the first to reveal the immunostimulatory component of wheatgrass with well defined molecular structures and mechanisms. PMID- 23629654 TI - Molecular mechanism of 17-allylamino-17-demethoxygeldanamycin (17-AAG)-induced AXL receptor tyrosine kinase degradation. AB - The receptor tyrosine kinase AXL is overexpressed in many cancer types including thyroid carcinomas and has well established roles in tumor formation and progression. Proper folding, maturation, and activity of several oncogenic receptor tyrosine kinases require HSP90 chaperoning. HSP90 inhibition by the antibiotic geldanamycin or its derivative 17-allylamino-17-demethoxygeldanamycin (17-AAG) causes destabilization of its client proteins. Here we show that AXL is a novel client protein of HSP90. 17-AAG induced a time- and dose-dependent down regulation of endogenous or ectopically expressed AXL protein, thereby inhibiting AXL-mediated signaling and biological activity. 17-AAG-induced AXL down regulation specifically affected fully glycosylated mature receptor present on cell membrane. By using biotin and [(35)S]methionine labeling, we showed that 17 AAG caused depletion of membrane-localized AXL by mediating its degradation in the intracellular compartment, thus restricting its exposure on the cell surface. 17-AAG induced AXL polyubiquitination and subsequent proteasomal degradation; under basal conditions, AXL co-immunoprecipitated with HSP90. Upon 17-AAG treatment, AXL associated with the co-chaperone HSP70 and the ubiquitin E3 ligase carboxyl terminus of HSC70-interacting protein (CHIP). Overexpression of CHIP, but not of the inactive mutant CHIP K30A, induced accumulation of AXL polyubiquitinated species upon 17-AAG treatment. The sensitivity of AXL to 17-AAG required its intracellular domain because an AXL intracellular domain-deleted mutant was insensitive to the compound. Active AXL and kinase-dead AXL were similarly sensitive to 17-AAG, implying that 17-AAG sensitivity does not require receptor phosphorylation. Overall our data elucidate the molecular basis of AXL down-regulation by HSP90 inhibitors and suggest that HSP90 inhibition in anticancer therapy can exert its effect through inhibition of multiple kinases including AXL. PMID- 23629655 TI - Mixed lineage leukemia 5 (MLL5) protein regulates cell cycle progression and E2F1 responsive gene expression via association with host cell factor-1 (HCF-1). AB - Trithorax group proteins methylate lysine 4 of histone 3 (H3K4) at active gene promoters. MLL5 protein, a member of the Trithorax protein family, has been implicated in the control of the cell cycle progression; however, the underlying molecular mechanism(s) have not been fully determined. In this study, we found that the MLL5 protein can associate with the cell cycle regulator "host cell factor" (HCF-1). The interaction between MLL5 and HCF-1 is mediated by the "HCF-1 binding motif" (HBM) of the MLL5 protein and the Kelch domain of the HCF-1 protein. Confocal microscopy showed that the MLL5 protein largely colocalized with HCF-1 in the nucleus. Knockdown of MLL5 resulted in reduced cell proliferation and cell cycle arrest in the G1 phase. Moreover, down-regulation of E2F1 target gene expression and decreased H3K4me3 levels at E2F1-responsive promoters were observed in MLL5 knockdown cells. Additionally, the core subunits, including ASH2L, RBBP5, and WDR5, that are necessary for effective H3K4 methyltransferase activities of the Trithorax protein complexes, were absent in the MLL5 complex, suggesting that a distinct mechanism may be used by MLL5 for exerting its H3K4 methyltransferase activity. Together, our findings demonstrate that MLL5 could associate with HCF-1 and then be recruited to E2F1-responsive promoters to stimulate H3K4 trimethylation and transcriptional activation, thereby facilitating the cell cycle G1 to S phase transition. PMID- 23629656 TI - Nuclear corepressors mediate the repression of phospholipase A2 group IIa gene transcription by thyroid hormone. AB - Secretory phospholipase A2 group IIa (PLA2g2a) is associated with inflammation, hyperlipidemia, and atherogenesis. Transcription of the PLA2g2a gene is induced by multiple cytokines. Here, we report the surprising observation that thyroid hormone (T3) inhibited PLA2g2a gene expression in human and rat hepatocytes as well as in rat liver. Moreover, T3 reduced the cytokine-mediated induction of PLA2g2a, suggesting that the thyroid status may modulate aspects of the inflammatory response. In an effort to dissect the mechanism of repression by T3, we cloned the PLA2g2a gene and identified a negative T3 response element in the promoter. This T3 receptor (TRbeta)-binding site differed considerably from consensus T3 stimulatory elements. Using in vitro and in vivo binding assays, we found that TRbeta bound directly to the PLA2g2a promoter as a heterodimer with the retinoid X receptor. Knockdown of nuclear corepressor or silencing mediator for retinoid and thyroid receptors by siRNA blocked the T3 inhibition of PLA2g2a. Using chromatin immunoprecipitation assays, we showed that nuclear corepressor and silencing mediator for retinoid and thyroid receptors were associated with the PLA2g2a gene in the presence of T3. In contrast with the established role of T3 to promote coactivator association with TRbeta, our experiments demonstrate a novel inverse recruitment mechanism in which liganded TRbeta recruits corepressors to inhibit PLA2g2a expression. PMID- 23629657 TI - Campylobacter jejuni lipooligosaccharide sialylation, phosphorylation, and amide/ester linkage modifications fine-tune human Toll-like receptor 4 activation. AB - Campylobacter jejuni is a leading cause of acute gastroenteritis. C. jejuni lipooligosaccharide (LOS) is a potent activator of Toll-like receptor (TLR) 4 mediated innate immunity. Structural variations of the LOS have been previously reported in the oligosaccharide (OS) moiety, the disaccharide lipid A (LA) backbone, and the phosphorylation of the LA. Here, we studied LOS structural variation between C. jejuni strains associated with different ecological sources and analyzed their ability to activate TLR4 function. MALDI-TOF MS was performed to characterize structural variation in both the OS and LA among 15 different C. jejuni isolates. Cytokine induction in THP-1 cells and primary monocytes was correlated with LOS structural variation in each strain. Additionally, structural variation was correlated with the source of each strain. OS sialylation, increasing abundance of LA d-glucosamine versus 2,3-diamino-2,3-dideoxy-d glucose, and phosphorylation status all correlated with TLR4 activation as measured in THP-1 cells and monocytes. Importantly, LOS-induced inflammatory responses were similar to those elicited by live bacteria, highlighting the prominent contribution of the LOS component in driving host immunity. OS sialylation status but not LA structure showed significant association with strains clustering with livestock sources. Our study highlights how variations in three structural components of C. jejuni LOS alter TLR4 activation and consequent monocyte activation. PMID- 23629658 TI - Insights into the photoprotective switch of the major light-harvesting complex II (LHCII): a preserved core of arginine-glutamate interlocked helices complemented by adjustable loops. AB - Light-harvesting antennae of the LHC family form transmembrane three-helix bundles of which two helices are interlocked by conserved arginine-glutamate (Arg Glu) ion pairs that form ligation sites for chlorophylls. The antenna proteins of photosystem II have an intriguing dual function. In excess light, they can switch their conformation from a light-harvesting into a photoprotective state, in which the excess and harmful excitation energies are safely dissipated as heat. Here we applied magic angle spinning NMR and selective Arg isotope enrichment as a noninvasive method to analyze the Arg structures of the major light-harvesting complex II (LHCII). The conformations of the Arg residues that interlock helix A and B appear to be preserved in the light-harvesting and photoprotective state. Several Arg residues have very downfield-shifted proton NMR responses, indicating that they stabilize the complex by strong hydrogen bonds. For the Arg Calpha chemical shifts, differences are observed between LHCII in the active, light harvesting and in the photoprotective, quenched state. These differences are attributed to a conformational change of the Arg residue in the stromal loop region. We conclude that the interlocked helices of LHCII form a rigid core. Consequently, the LHCII conformational switch does not involve changes in A/B helix tilting but likely involves rearrangements of the loops and helical segments close to the stromal and lumenal ends. PMID- 23629659 TI - Phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1) on tyrosine 164 inhibits its activity and promotes cell survival. AB - In BCR-ABL-expressing cells, sphingolipid metabolism is altered. Because the first step of sphingolipid biosynthesis occurs in the endoplasmic reticulum (ER), our objective was to identify ABL targets in the ER. A phosphoproteomic analysis of canine pancreatic ER microsomes identified 49 high scoring phosphotyrosine containing peptides. These were then categorized in silico and validated in vitro. We demonstrated that the ER-resident human protein serine palmitoyltransferase long chain-1 (SPTLC1), which is the first enzyme of sphingolipid biosynthesis, is phosphorylated at Tyr(164) by the tyrosine kinase ABL. Inhibition of BCR-ABL using either imatinib or shRNA-mediated silencing led to the activation of SPTLC1 and to increased apoptosis in both K562 and LAMA-84 cells. Finally, we demonstrated that mutation of Tyr(164) to Phe in SPTLC1 increased serine palmitoyltransferase activity. The Y164F mutation also promoted the remodeling of cellular sphingolipid content, thereby sensitizing K562 cells to apoptosis. Our observations provide a mechanistic explanation for imatinib mediated cell death and a novel avenue for therapeutic strategies. PMID- 23629660 TI - Selective metabolism of hypothiocyanous acid by mammalian thioredoxin reductase promotes lung innate immunity and antioxidant defense. AB - The endogenously produced oxidant hypothiocyanous acid (HOSCN) inhibits and kills pathogens but paradoxically is well tolerated by mammalian host tissue. Mammalian high molecular weight thioredoxin reductase (H-TrxR) is evolutionarily divergent from bacterial low molecular weight thioredoxin reductase (L-TrxR). Notably, mammalian H-TrxR contains a selenocysteine (Sec) and has wider substrate reactivity than L-TrxR. Recombinant rat cytosolic H-TrxR1, mouse mitochondrial H TrxR2, and a purified mixture of both from rat selectively turned over HOSCN (kcat = 357 +/- 16 min(-1); Km = 31.9 +/- 10.3 MUM) but were inactive against the related oxidant hypochlorous acid. Replacing Sec with Cys or deleting the final eight C-terminal peptides decreased affinity and turnover of HOSCN by H-TrxR. Similarly, glutathione reductase (an H-TrxR homologue lacking Sec) was less effective at HOSCN turnover. In contrast to H-TrxR and glutathione reductase, recombinant Escherichia coli L-TrxR was potently inhibited by HOSCN (IC50 = 2.75 MUM). Similarly, human bronchial epithelial cell (16HBE) lysates metabolized HOSCN, but E. coli and Pseudomonas aeruginosa lysates had little or no activity. HOSCN selectively produced toxicity in bacteria, whereas hypochlorous acid was nonselectively toxic to both bacteria and 16HBE. Treatment with the H-TrxR inhibitor auranofin inhibited HOSCN metabolism in 16HBE lysates and significantly increased HOSCN-mediated cytotoxicity. These findings demonstrate both the metabolism of HOSCN by mammalian H-TrxR resulting in resistance to HOSCN in mammalian cells and the potent inhibition of bacterial L-TrxR resulting in cytotoxicity in bacteria. These data support a novel selective mechanism of host defense in mammals wherein HOSCN formation simultaneously inhibits pathogens while sparing host tissue. PMID- 23629661 TI - Myocilin stimulates osteogenic differentiation of mesenchymal stem cells through mitogen-activated protein kinase signaling. AB - Myocilin is a secreted glycoprotein that is expressed in ocular and non-ocular tissues. Mutations in the MYOCILIN gene may lead to juvenile- and adult-onset primary open-angle glaucoma. Here we report that myocilin is expressed in bone marrow-derived mesenchymal stem cells (MSCs) and plays a role in their differentiation into osteoblasts in vitro and in osteogenesis in vivo. Expression of myocilin was detected in MSCs derived from mouse, rat, and human bone marrow, with human MSCs exhibiting the highest level of myocilin expression. Expression of myocilin rose during the course of human MSC differentiation into osteoblasts but not into adipocytes, and treatment with exogenous myocilin further enhanced osteogenesis. MSCs derived from Myoc-null mice had a reduced ability to differentiate into the osteoblastic lineage, which was partially rescued by exogenous extracellular myocilin treatment. Myocilin also stimulated osteogenic differentiation of wild-type MSCs, which was associated with activation of the p38, Erk1/2, and JNK MAP kinase signaling pathways as well as up-regulated expression of the osteogenic transcription factors Runx2 and Dlx5. Finally, cortical bone thickness and trabecular volume, as well as the expression level of osteopontin, a known factor of bone remodeling and osteoblast differentiation, were reduced dramatically in the femurs of Myoc-null mice compared with wild-type mice. These data suggest that myocilin should be considered as a target for improving the bone regenerative potential of MSCs and may identify a new role for myocilin in bone formation and/or maintenance in vivo. PMID- 23629663 TI - Biodegradable polycaprolactone-titania nanocomposites: preparation, characterization and antimicrobial properties. AB - Nanocomposites obtained from the incorporation of synthesized TiO2 nanoparticles (~10 nm average primary particle size) in different amounts, ranging from 0.5 to 5 wt.%, into a biodegradable polycaprolactone matrix are achieved via a straightforward and commercial melting processing. The resulting nanocomposites have been structurally and thermally characterized by transmission electron microscopy (TEM), wide/small angle X-ray diffraction (WAXS/SAXS, respectively) and differential scanning calorimetry (DSC). TEM evaluation provides evidence of an excellent nanometric dispersion of the oxide component in the polymeric matrix, with aggregates having an average size well below 100 nm. Presence of these TiO2 nanoparticles induces a nucleant effect during polymer crystallization. Moreover, the antimicrobial activity of nanocomposites has been tested using both UV and visible light against Gram-negative Escherichia coli bacteria and Gram-positive Staphylococcus aureus. The bactericidal behavior has been explained through the analysis of the material optical properties, with a key role played by the creation of new electronic states within the polymer-based nanocomposites. PMID- 23629662 TI - Lipids as tumoricidal components of human alpha-lactalbumin made lethal to tumor cells (HAMLET): unique and shared effects on signaling and death. AB - Long-chain fatty acids are internalized by receptor-mediated mechanisms or receptor-independent diffusion across cytoplasmic membranes and are utilized as nutrients, building blocks, and signaling intermediates. Here we describe how the association of long-chain fatty acids to a partially unfolded, extracellular protein can alter the presentation to target cells and cellular effects. HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a tumoricidal complex of partially unfolded alpha-lactalbumin and oleic acid (OA). As OA lacks independent tumoricidal activity at concentrations equimolar to HAMLET, the contribution of the lipid has been debated. We show by natural abundance (13)C NMR that the lipid in HAMLET is deprotonated and by chromatography that oleate rather than oleic acid is the relevant HAMLET constituent. Compared with HAMLET, oleate (175 MUm) showed weak effects on ion fluxes and gene expression. Unlike HAMLET, which causes metabolic paralysis, fatty acid metabolites were less strongly altered. The functional overlap increased with higher oleate concentrations (500 MUm). Cellular responses to OA were weak or absent, suggesting that deprotonation favors cellular interactions of fatty acids. Fatty acids may thus exert some of their essential effects on host cells when in the deprotonated state and when presented in the context of a partially unfolded protein. PMID- 23629664 TI - Differential activity of plasma and vacuolar membrane transporters contributes to genotypic differences in salinity tolerance in a Halophyte Species, Chenopodium quinoa. AB - Halophytes species can be used as a highly convenient model system to reveal key ionic and molecular mechanisms that confer salinity tolerance in plants. Earlier, we reported that quinoa (Chenopodium quinoa Willd.), a facultative C3 halophyte species, can efficiently control the activity of slow (SV) and fast (FV) tonoplast channels to match specific growth conditions by ensuring that most of accumulated Na+ is safely locked in the vacuole (Bonales-Alatorre et al. (2013) Plant Physiology). This work extends these finding by comparing the properties of tonoplast FV and SV channels in two quinoa genotypes contrasting in their salinity tolerance. The work is complemented by studies of the kinetics of net ion fluxes across the plasma membrane of quinoa leaf mesophyll tissue. Our results suggest that multiple mechanisms contribute towards genotypic differences in salinity tolerance in quinoa. These include: (i) a higher rate of Na+ exclusion from leaf mesophyll; (ii) maintenance of low cytosolic Na+ levels; (iii) better K+ retention in the leaf mesophyll; (iv) a high rate of H+ pumping, which increases the ability of mesophyll cells to restore their membrane potential; and (v) the ability to reduce the activity of SV and FV channels under saline conditions. These mechanisms appear to be highly orchestrated, thus enabling the remarkable overall salinity tolerance of quinoa species. PMID- 23629665 TI - The role of strigolactones in nutrient-stress responses in plants. AB - Strigolactones (SLs) are a new group of plant hormones, which have been intensively investigated during the last few years. The wide spectrum of SLs actions, including the regulation of shoot/root architecture, and the stimulation of the interactions between roots and fungi or bacteria, as well as the stimulation of germination of parasitic plants, indicates that this group of hormones may play an important role in the mechanisms that control soil exploration, and the root-mediated uptake of nutrients. Current studies have shown that SLs might be factors that have an influence on the plant response to a deficiency of macronutrients. Experimental data from the last four years have confirmed that the biosynthesis and exudation of SLs are increased under phosphorus and nitrogen deficiency. All these data suggest that SLs may regulate the complex response to nutrient stress, which include not only the modification of the plant developmental process, but also the cooperation with other organisms in order to minimize the effects of threats. In this paper the results of studies that indicate that SLs play an important role in the response to nutrient stress are reviewed and the consequences of the higher biosynthesis and exudation of SLs in response to phosphorus and nitrogen deficiency are discussed. PMID- 23629666 TI - Off-target effect of endogenous siRNA derived from RMRP in human cells. AB - Endogenous siRNAs (endo-siRNAs) are key regulators of RNA silencing in plants and worms; however, the biogenesis and function of endogenous siRNAs in mammals remain largely unknown. We previously demonstrated that human telomerase reverse transcriptase produces a self-targeting endogenous siRNA from non-coding RMRP RNA via RNA-dependent RNA polymerase (RdRP) activity. Here, we investigated whether the endo-siRNA derived from RMRP targets other genes in addition to RMRP. Four algorithms for microRNA target prediction were used to identify possible targets of the endo-siRNA, and the phytanoyl-CoA hydroxylase-interacting protein-like gene (PHYHIPL) was identified as the most promising candidate. The 3' UTR of PHYHIPL was found to contain three possible target sites with perfect seed pairing; deletion of each of these sites resulted in recovery of upstream luciferase expression. In addition, sequence-specific inhibition of the RMRP derived endo-siRNA increased expression of PHYHIPL mRNA. The results described here suggest that the endo-siRNA uses silencing mechanisms that are similar to those used by microRNAs for gene silencing. To our knowledge, this study is the first confirmation of the off-target effect of human endogenous siRNA produced by RdRP activity. PMID- 23629667 TI - Effects of nanotoxicity on female reproductivity and fetal development in animal models. AB - The extensive application of nanomaterials in industry, medicine and consumer products has raised concerns about their potential toxicity. The female population is particularly vulnerable and deserves special attention because toxicity in this group may impact both female reproductivity and fetal development. Mouse and zebrafish models each have their own unique features and studies using these models to examine the potential toxicity of various nanoparticles are compared and summarized in this review. Several nanoparticles exhibit detrimental effects on female reproductivity as well as fetal development, and these adverse effects are related to nanoparticle composition, surface modification, dose, exposure route and animal species. Limited studies on the mechanisms of nanotoxicity are also documented and reviewed herein. PMID- 23629669 TI - Simple and rapid synthesis of magnetite/hydroxyapatite composites for hyperthermia treatments via a mechanochemical route. AB - This paper presents a simple method for the rapid synthesis of magnetite/hydroxyapatite composite particles. In this method, superparamagnetic magnetite nanoparticles are first synthesized by coprecipitation using ferrous chloride and ferric chloride. Immediately following the synthesis, carbonate substituted (B-type) hydroxyapatite particles are mechanochemically synthesized by wet milling dicalcium phosphate dihydrate and calcium carbonate in a dispersed suspension of magnetite nanoparticles, during which the magnetite nanoparticles are incorporated into the hydroxyapatite matrix. We observed that the resultant magnetite/hydroxyapatite composites possessed a homogeneous dispersion of magnetite nanoparticles, characterized by an absence of large aggregates. When this material was subjected to an alternating magnetic field, the heat generated increased with increasing magnetite concentration. For a magnetite concentration of 30 mass%, a temperature increase greater than 20 K was achieved in less than 50 s. These results suggest that our composites exhibit good hyperthermia properties and are promising candidates for hyperthermia treatments. PMID- 23629668 TI - Biomarkers for anti-angiogenic therapy in cancer. AB - Angiogenesis, the development of new vessels from existing vasculature, plays a central role in tumor growth, survival, and progression. On the molecular level it is controlled by a number of pro- and anti-angiogenic cytokines, among which the vascular endothelial growth factors (VEGFs), together with their related VEGF receptors, have an exceptional position. Therefore, the blockade of VEGF signaling in order to inhibit angiogenesis was deemed an attractive approach for cancer therapy and drugs interfering with the VEGF-ligands, the VEGF receptors, and the intracellular VEGF-mediated signal transduction were developed. Although promising in pre-clinical trials, VEGF-inhibition proved to be problematic in the clinical context. One major drawback was the generally high variability in patient response to anti-angiogenic drugs and the rapid development of therapy resistance, so that, in total, only moderate effects on progression-free and overall survival were observed. Biomarkers predicting the response to VEGF inhibition might attenuate this problem and help to further individualize drug and dosage determination. Although up to now no definitive biomarker has been identified for this purpose, several candidates are currently under investigation. This review aims to give an overview of the recent developments in this field, focusing on the most prevalent tumor species. PMID- 23629671 TI - Recent advances in understanding the control of secretory proteins by the unfolded protein response in plants. AB - The membrane transport system is built on the proper functioning of the endoplasmic reticulum (ER). The accumulation of unfolded proteins in the ER lumen (ER stress) disrupts ER homeostasis and disturbs the transport system. In response to ER stress, eukaryotic cells activate intracellular signaling (named the unfolded protein response, UPR), which contributes to the quality control of secretory proteins. On the other hand, the deleterious effects of UPR on plant health and growth characteristics have frequently been overlooked, due to limited information on this mechanism. However, recent studies have shed light on the molecular mechanism of plant UPR, and a number of its unique characteristics have been elucidated. This study briefly reviews the progress of understanding what is happening in plants under ER stress conditions. PMID- 23629670 TI - Neuroprotective effect of melatonin: a novel therapy against perinatal hypoxia ischemia. AB - One of the most common causes of mortality and morbidity in children is perinatal hypoxia-ischemia (HI). In spite of the advances in neonatology, its incidence is not diminishing, generating a pediatric population that will require an extended amount of chronic care throughout their lifetime. For this reason, new and more effective neuroprotective strategies are urgently required, in order to minimize as much as possible the neurological consequences of this encephalopathy. In this sense, interest has grown in the neuroprotective possibilities of melatonin, as this hormone may help to maintain cell survival through the modulation of a wide range of physiological functions. Although some of the mechanisms by which melatonin is neuroprotective after neonatal asphyxia remain a subject of investigation, this review tries to summarize some of the most recent advances related with its use as a therapeutic drug against perinatal hypoxic-ischemic brain injury, supporting the high interest in this indoleamine as a future feasible strategy for cerebral asphyctic events. PMID- 23629672 TI - Senescence marker protein-30 (SMP30) deficiency impairs myocardium-induced dilation of coronary arterioles associated with reactive oxygen species. AB - Senescence marker protein-30 (SMP30) decreases with aging. Mice with SMP30 deficiency, a model of aging, have a short lifespan with increased oxidant stress. To elucidate SMP30's effect on coronary circulation derived from myocytes, we measured the changes in the diameter of isolated coronary arterioles in wild-type (WT) mice exposed to supernatant collected from isolated paced cardiac myocytes from SMP30 KO or WT mice. Pacing increased hydrogen peroxide in myocytes, and hydrogen peroxide was greater in SMP30 KO myocytes compared to WT myocytes. Antimycin enhanced and FCCP (oxidative phosphorylation uncoupler in mitochondria) decreased superoxide production in both groups. Addition of supernatant from stimulated myocytes, either SMP30 KO or WT, caused vasodilation. The degree of the vasodilation response to supernatant was smaller in SMP30 KO mice compared to WT mice. Administration of catalase to arterioles eliminated vasodilation in myocyte supernatant of WT mice and converted vasodilation to vasoconstriction in myocyte supernatant of SMP30 KO mice. This vasoconstriction was eliminated by olmesartan, an angiotensin II receptor antagonist. Thus, SMP30 deficiency combined with oxidant stress increases angiotensin and hydrogen peroxide release from cardiac myocytes. SMP30 plays an important role in the regulation of coronary vascular tone by myocardium. PMID- 23629673 TI - Synthesis, cytotoxicity, DNA binding and apoptosis of rhein-phosphonate derivatives as antitumor agents. AB - Several rhein-phosphonate derivatives (5a-c) were synthesized and evaluated for in vitro cytotoxicity against HepG-2, CNE, Spca-2, Hela and Hct-116 cell lines. Some compounds showed relatively high cytotoxicity. Especially compounds 5b exhibited the strongest cytotoxicity against HepG-2 and Spca-2 cells (IC50 was 8.82 and 9.01 uM), respectively. All the synthesized compounds exhibited low cytotoxicity against HUVEC cells. Further experiments proved that 5b could disturb the cell cycle in HepG-2 cells and induce apoptosis. In addition, the binding properties of a model conjugate 5b to DNA were investigated by methods (UV-Vis, fluorescence, CD spectroscopy). Results indicated that 5b showed moderate ability to interact ct-DNA. PMID- 23629674 TI - Characterization of Rice NADPH oxidase genes and their expression under various environmental conditions. AB - Plasma membrane NADPH oxidases (Noxs) are key producers of reactive oxygen species under both normal and stress conditions in plants. We demonstrate that at least eleven genes in the genome of rice (Oryza sativa L.) were predicted to encode Nox proteins, including nine genes (OsNox1-9) that encode typical Noxs and two that encode ancient Nox forms (ferric reduction oxidase 1 and 7, OsFRO1 and OsFRO7). Phylogenetic analysis divided the Noxs from nine plant species into six subfamilies, with rice Nox genes distributed among subfamilies I to V. Gene expression analysis using semi-quantitative RT-PCR and real-time qRT-PCR indicated that the expression of rice Nox genes depends on organs and environmental conditions. Exogenous calcium strongly stimulated the expression of OsNox3, OsNox5, OsNox7, and OsNox8, but depressed the expression of OsFRO1. Drought stress substantially upregulated the expression of OsNox1-3, OsNox5, OsNox9, and OsFRO1, but downregulated OsNox6. High temperature upregulated OsNox5 9, but significantly downregulated OsNox1-3 and OsFRO1. NaCl treatment increased the expression of OsNox2, OsNox8, OsFRO1, and OsFRO7, but decreased that of OsNox1, OsNox3, OsNox5, and OsNox6. These results suggest that the expression profiles of rice Nox genes have unique stress-response characteristics, reflecting their related but distinct functions in response to different environmental stresses. PMID- 23629675 TI - Improved nutritive quality and salt resistance in transgenic maize by simultaneously overexpression of a natural lysine-rich protein gene, SBgLR, and an ERF transcription factor gene, TSRF1. AB - Maize (Zea mays L.), as one of the most important crops in the world, is deficient in lysine and tryptophan. Environmental conditions greatly impact plant growth, development and productivity. In this study, we used particle bombardment mediated co-transformation to obtain marker-free transgenic maize inbred X178 lines harboring a lysine-rich protein gene SBgLR from potato and an ethylene responsive factor (ERF) transcription factor gene, TSRF1, from tomato. Both of the target genes were successfully expressed and showed various expression levels in different transgenic lines. Analysis showed that the protein and lysine content in T1 transgenic maize seeds increased significantly. Compared to non transformed maize, the protein and lysine content increased by 7.7% to 24.38% and 8.70% to 30.43%, respectively. Moreover, transgenic maize exhibited more tolerance to salt stress. When treated with 200 mM NaCl for 48 h, both non transformed and transgenic plant leaves displayed wilting and losing green symptoms and dramatic increase of the free proline contents. However, the degree of control seedlings was much more serious than that of transgenic lines and much more increases of the free proline contents in the transgenic lines than that in the control seedlings were observed. Meanwhile, lower extent decreases of the chlorophyll contents were detected in the transgenic seedlings. Quantitative RT PCR was performed to analyze the expression of ten stress-related genes, including stress responsive transcription factor genes, ZmMYB59 and ZmMYC1, proline synthesis related genes, ZmP5CS1 and ZmP5CS2, photosynthesis-related genes, ZmELIP, ZmPSI-N, ZmOEE, Zmrbcs and ZmPLAS, and one ABA biosynthesis related gene, ZmSDR. The results showed that with the exception of ZmP5CS1 and ZmP5CS2 in line 9-10 and 19-11, ZmMYC1 in line 19-11 and ZmSDR in line 19-11, the expression of other stress-related genes were inhibited in transgenic lines under normal conditions. After salt treatment, the expressions of the ten stress related genes were significantly induced in both wild-type (WT) and transgenic lines. However, compared to WT, the increases of ZmP5CS1 in all these three transgenic lines and ZmP5CS2 in line 9-10 were less than WT plants. This study provides an effective approach of maize genetic engineering for improved nutritive quality and salt tolerance. PMID- 23629676 TI - Oxidative stress mediates the disruption of airway epithelial tight junctions through a TRPM2-PLCgamma1-PKCalpha signaling pathway. AB - Oxidative stress has been implicated as an important contributing factor in the pathogenesis of several pulmonary inflammatory diseases. Previous studies have indicated a relationship between oxidative stress and the attenuation of epithelial tight junctions (TJs). In Human Bronchial Epithelial-16 cells (16HBE), we demonstrated the degradation of zonula occludens-1 (ZO-1), and claudin-2 exhibited a great dependence on the activation of the transient receptor potential melastatin (TRPM) 2 channel, phospholipase Cgamma1 (PLCgamma1) and the protein kinase Calpha (PKCalpha) signaling cascade. PMID- 23629677 TI - The role of microRNA in gastric malignancy. AB - Helicobacter pylori (H. pylori) infection is the main cause of gastritis, gastro duodenal ulcer, and gastric cancer. MicroRNAs (miRNAs) are small noncoding RNAs that function as endogenous silencers of numerous target genes. Many miRNA genes are expressed in a tissue-specific manner and play important roles in cell proliferation, apoptosis, and differentiation. Recent discoveries have shed new light on the involvement of miRNAs in gastric malignancy. However, at the same time, several miRNAs have been associated with opposing events, leading to reduced inflammation, inhibition of malignancy, and increased apoptosis of transformed cells. The regulation of miRNA expression could be a novel strategy in the chemoprevention of human gastric malignancy. In this article, the biological importance of miRNAs in gastric malignancy is summarized. PMID- 23629678 TI - Clinical practice guidelines for the prevention, diagnosis, evaluation and treatment of mineral and bone disorders in chronic kidney disease (CKD-MBD) in adults. AB - The clinical practice guidelines for the prevention, diagnosis, evaluation and treatment of chronic kidney disease mineral and bone disorders (CKD-BMD) in adults, of the Latin American Society of Nephrology and Hypertension (SLANH) comprise a set of recommendations developed to support the doctor in the management of these abnormalities in adult patients with stages 3-5 kidney disease. This excludes changes associated with renal transplantation. The topics covered in the guidelines are divided into four chapters: 1) Evaluation of biochemical changes, 2) Evaluation of bone changes, 3) Evaluation of vascular calcifications, and 4) Treatment of CKD-MBD. The guidelines are based on the recommendations proposed and published by the Kidney Disease: Improving Global Outcomes (KDIGO) for the prevention, diagnosis, evaluation and treatment of CKD MBD (KDIGO Clinical practice guidelines for the diagnosis, evaluation, prevention and treatment of Chronic Kidney Disease Mineral and Bone Disorder [CKD-MBD]), adapted to the conditions of patients, institutions and resources available in Latin America, with the support of KDIGO. In some cases, the guidelines correspond to management recommendations directly defined by the working group for their implementation in our region, based on the evidence available in the literature. Each chapter contains guidelines and their rationale, supported by numerous updated references. Unfortunately, there are few controlled studies with statistically sufficient weight in Latin America to support specific recommendations for the region, and as such, most of the references used correspond to studies carried out in other regions. This highlights the need to plan research studies designed to establish the current status of mineral and bone metabolism disorders in Latin America as well as defining the best treatment options for our population. PMID- 23629680 TI - An overview of the magnetoresistance phenomenon in molecular systems. AB - In this review, the classification of magnetoresistance effects, the electrical conduction mechanisms without and with magnetic field, and the spintronics are briefly summarized. The magnetoresistance effect in the molecular systems including small organic molecules, carbon nanotubes, graphene, conductive polymers and their nanocomposites is critically reviewed. The four normally used models are elaborated to disclose the mechanisms of organic magnetoresistance (OMAR) in the organic systems. The most current applications of these molecular systems are also summarized. These molecular systems are envisioned to create next-generation spintronic and electronic devices for flexible applications. PMID- 23629679 TI - Effects of angiotensin II blockade on cardiomyocyte regeneration after myocardial infarction in rats. AB - INTRODUCTION: We studied the effects of angiotensin type 1 receptor blockade (ARB) on formation of new cardiomyocytes, neovascularization and ventricular remodelling after myocardial infarction (MI). METHODS: Male Wistar rats with MI or sham-operated controls were treated with either losartan or vehicle. Bromodeoxyuridine (BrdU) was given to identify newly formed cardiac cells. Immunohistochemical analysis was used to quantify proliferative and apoptotic cardiomyocytes, vascular structures and c-Kit+ stem/progenitor cells, western blotting to evaluate gene expression, and planimetry and echocardiography to assess cardiac structure and function. RESULTS: The number of BrdU+ cardiomyocytes increased similarly in the vehicle and losartan treated MI groups. The number of apoptotic or proliferating cardiomyocytes did not differ between losartan and vehicle treated rats. Losartan induced an increase in capillary and BrdU+ vascular densities in the infarct border zone. Losartan treatment completely prevented post-MI cardiac hypertrophy. In the non-infarcted myocardium the amount of all BrdU+ cells (including non-cardiomyocyte cells) was highest in the vehicle treated MI rats at week 4. CONCLUSIONS: The number of newly formed cardiomyocytes increased after MI. Angiotensin II blockade neither stimulated nor prevented cardiomyocyte regeneration. ARB treatment increased vascular densities in the infarct border zone and modulated remodelling of the non-infarcted myocardium preventing effectively post-MI cardiac hypertrophy. PMID- 23629682 TI - [Surgical treatment of gynecomastia: an algorithm]. AB - INTRODUCTIONS: Gynecomastia is a persistent benign uni- or bilateral enlargement of the male breast ranging from small to excessive findings with marked skin redundancy. In this paper we introduce an algorithm to facilitate the selection of the appropriate surgical technique according to the presented morphological aspects. PATIENTS AND METHODS: The records of 118 patients (217 breasts) with gynecomastia from 01/2009 to 08/2012 were retrospectively reviewed. The authors conducted three different surgical techniques depending on four severity grades. The outcome parameters complication rate, patient satisfaction with the aesthetic result, nipple sensitivity and the need to re-operate were observed and related to the employed technique. RESULTS: In 167 (77%) breasts with moderate breast enlargement without skin redundancy (Grade I-IIa by Simon's classification) a subcutaneous semicircular periareolar mastectomy was performed in combination with water-jet assisted liposuction. In 40 (18%) breasts with skin redundancy (Grade IIb) a circumferential mastopexy was performed additionally. An inferior pedicled mammaplasty was used in 10 (5%) severe cases (Grade III). Complication rate was 4.1%. Surgical corrections were necessary in 17 breasts (7.8%). The patient survey revealed a high satisfaction level: 88% of the patients rated the aesthetic results as "very good" or "good", nipple sensitivity was rated as "very good" or "good" by 83%. CONCLUSION: Surgical treatment of gynecomastia should ensure minimal scarring while respecting the aesthetic unit. The selection of the appropriate surgical method depends on the severity grade, the presence of skin redundancy and the volume of the male breast glandular tissue. The presented algorithm rarely leads to complications, is simple to perform and shows a high satisfaction rate and a preservation of the nipple sensitivity. PMID- 23629683 TI - [Breast augmentation with autologous fat - experience of 96 procedures with the BEAULI-technique]. AB - Over the past 30 years, interest in the use of autologous fat for aesthetic body contouring, especially for breast augmentation has been continuously on the rise. The benefits of an autologous fat transplant include the absence of any inflammatory reaction to a foreign body, its harmonious appearance and a natural feeling. In earlier years, complications such as necrosis, infections or the formation of cysts, poor resorption rates as well as the difficulty of harvesting large amounts of fat within a reasonable amount of time provided grounds for criticism of the methodology of autologous fat transplantation. With the advent of the so-called BEAULI method, since 2007 a procedure is available for the efficient harvesting and processing of larger quantities of transplantable fat. The aim of the study is to describe the technique in detail and reproducibly and to present a detailed overview of autologous fat transfer due to the basis of our own clinical experience. Between 1 September 2010 and 30 June 2012 the author performed 96 fat transfer procedures on 84 patients. Patients aged 18-60 with a desire for a moderate augmentation of volume and shape of the breasts were selected for the procedure. The fat was harvested using water jet-assisted liposuction (Bodyjet) to flush out the fat cells and subsequent separation of the fat components with the Lipo-Collector. There were no occurrences of post operative complications in any of the cases. The results were evaluated in the context of a check-up, a photographic comparison and with the completion of a questionnaire. With regard to the increase in size and/or shape enhancement of the breasts, 31% of the patients were very happy with the results, 45% indicated they were satisfied, 23% would have liked more volume, while 1% were dissatisfied. This study indicates that the autologous fat transplant into the female breast using the BEAULI method represents an excellent, safe method for the achievement of a moderate and harmonious breast size augmentation as well as sustainable and natural-looking contour improvements in selected patients. Additional studies with a larger number of cases and longer observation periods over several years as well as guidelines from the professional associations could contribute to the further perfection of the autologous fat transplant method in terms of resorption rate, efficiency and safety. PMID- 23629684 TI - [Autologous fat grafts and supportive enrichment with adipose tissue stromal cells]. AB - Liposuction is a most common surgical procedure in aesthetic surgery that aims at the local fat reduction. The obtained adipose tissue is currently used as a biocompatible filler. Autologous fat transplantation, also known as lipofilling, has become an attractive treatment method in the field of aesthetic facial surgery and scar tissue reconstruction. Lipofilling may also offer an alternative method to prosthetic breast surgery. Nevertheless, postoperative fat tissue resorption is still a limitiation to lipofilling in breast reconstruction leading to multiple revisions in order to reach the requested clinical outcome. The therapeutic effect of autologous fat grafts does not solely lie in its role as a filler material, but also in its wound healing and angiogenetic properties. The latter is not attributed to the mature adipocytes, but rather to the undifferentiated adipose derived stromal cells (ASC). Thus enrichment of the fat graft with autologous ASC, known as cell-assisted lipotransfer (CAL) may lead to further optimisation of lipofilling concerning fat graft survival. Still aiming to establish the application of autologous fat grafts and ASC in breast reconstruction, there is a necessity for systematic analyses in order to resolve questions regarding the operational technique and qualitative aspects of the ASC manufacturing in accordance with pharmaceutical guidelines and regulations in Germany. Besides, some open questions need to be addressed regarding the ASC differentiation potential in vivo. PMID- 23629685 TI - [Erythropoietin in plastic surgery]. AB - EPO is an autologous hormone, which is known to regulate erythropoiesis. For 30 years it has been used for the therapy of diverse forms of anaemia, such as renal anaemia, tumour-related anaemias, etc. Meanwhile, a multitude of scientific publications were able to demonstrate its pro-regenerative effects after trauma. These include short-term effects such as the inhibition of the "primary injury response" or apoptosis, and mid- and long-term effects for example the stimulation of stem cell recruitment, growth factor production, angiogenesis and re-epithelialisation. Known adverse reactions are increases of thromboembolic events and blood pressure, as well as a higher mortality in patients with tumour anaemias treated with EPO. Scientific investigations of EPO in the field of plastic surgery included: free and local flaps, nerve regeneration, wound healing enhancement after dermal thermal injuries and in chronic wounds.Acute evidence for the clinical use of EPO in the field of plastic surgery is still not satisfactory, due to the insufficient number of Good Clinical Practice (GCP) conform clinical trials. Thus, the initiation of more scientifically sound trials is indicated. PMID- 23629686 TI - Synthetic sickness or lethality points at candidate combination therapy targets in glioblastoma. AB - Synthetic lethal interactions in cancer hold the potential for successful combined therapies, which would avoid the difficulties of single molecule targeted treatment. Identification of interactions that are specific for human tumors is an open problem in cancer research. This work aims at deciphering synthetic sick or lethal interactions directly from somatic alteration, expression and survival data of cancer patients. To this end, we look for pairs of genes and their alterations or expression levels that are "avoided" by tumors and "beneficial" for patients. Thus, candidates for synthetic sickness or lethality (SSL) interaction are identified as such gene pairs whose combination of states is under-represented in the data. Our main methodological contribution is a quantitative score that allows ranking of the candidate SSL interactions according to evidence found in patient survival. Applying this analysis to glioblastoma data, we collect 1,956 synthetic sick or lethal partners for 85 abundantly altered genes, most of which show extensive copy number variation across the patient cohort. We rediscover and interpret known interaction between TP53 and PLK1, as well as provide insight into the mechanism behind EGFR interacting with AKT2, but not AKT1 nor AKT3. Cox model analysis determines 274 of identified interactions as having significant impact on overall survival in glioblastoma, which is more informative than a standard survival predictor based on patient's age. PMID- 23629687 TI - Three novel 1D lanthanide-carboxylate polymeric complexes: syntheses, crystal structures and magnetic analyses. AB - Three novel one-dimensional (1D) lanthanide coordination complexes involving the 4-methyl-3-nitrobenzoic acid (HL) ligand, with the general formulae [Gd(L)3(H2O)(CH3OH)] (1), [Gd(L)3(H2O)2].(4,4'-bpy).CH3OH (2), [Dy(L)3(H2O)(CH3OH)] (3), have been synthesized by solvothermal reactions. These complexes have been structurally characterized by single-crystal X-ray diffraction, IR, PXRD, TGA, and elemental analysis. Complexes 1 and 3 are isostructural except for the distinction of the metal ion. Magnetic measurements indicate that complexes 1-3 show antiferromagnetic behaviors. Complex 3 behaves with slow relaxation of the magnetization, where the frequency-dependent out-of phase signals are noticed. However, the characteristic maxima were not reached above 2 K under zero direct current (DC) fields. When a DC field of 5000 Oe was employed, the frequency dependent peaks of alternating current (AC) signals were obtained. PMID- 23629689 TI - Altered semantic integration in autism beyond language: a cross-modal event related potentials study. AB - Autism spectrum disorders (ASDs) are characterized by impaired communication, particularly pragmatic and semantic language, resulting in verbal comprehension deficits. Semantic processing in these conditions has been studied extensively, but mostly limited only to linguistic material. Emerging evidence, however, suggests that semantic integration deficits may extend beyond the verbal domain. Here, we explored cross-modal semantic integration using visual targets preceded by musical and linguistic cues. Particularly, we have recorded the event-related potentials to evaluate whether the N400 and late positive potential (LPP) components, two widely studied electrophysiological markers of semantic processing, are differently sensitive to congruence with respect to typically developing children. Seven ASD patients and seven neurotypical participants matched by age, education and intelligence quotient provided usable data. Neuroelectric activity was recorded in response to visual targets that were related or unrelated to a preceding spoken sentence or musical excerpt. The N400 was sensitive to semantic congruence in the controls but not the patients, whereas the LPP showed a complementary pattern. These results suggest that semantic processing in ASD children is also altered in the context of musical and visual stimuli, and point to a functional decoupling between the generators of the N400 and LPP, which may indicate delayed semantic processing. These novel findings underline the importance of exploring semantic integration across multiple modalities in ASDs and provide motivation for further investigation in large clinical samples. PMID- 23629688 TI - 5-Hydroxytryptamine 1A receptors inhibit glutamate release in rat medullary dorsal horn neurons. AB - We examined 5-hydroxytryptamine 1A (5-HT1A) receptor-mediated modulation of glutamatergic transmission in rat medullary dorsal horn neurons using a conventional whole-cell patch clamp technique. 5-HT reversibly and concentration dependently decreased the amplitude of glutamatergic excitatory postsynaptic currents and increased the paired-pulse ratio, indicating that 5-HT acts presynaptically to reduce glutamate release from primary afferents. The 5-HT induced inhibition of excitatory postsynaptic currents was partially occluded by NAN-190, a 5-HT1A receptor antagonist, and mimicked by 8-OH-DPAT, a 5-HT1A receptor agonist. Our results suggest that presynaptic 5-HT1A receptors inhibit glutamate release from trigeminal primary afferents onto medullary dorsal horn neurons, and thus in addition to other 5-HT1 receptor subtypes, 5-HT1A receptors could be a potential target for treatment of pain from orofacial tissues. PMID- 23629690 TI - Depleted uranium induces disruption of energy homeostasis and oxidative stress in isolated rat brain mitochondria. AB - Depleted uranium (DU) is emerging as an environmental pollutant primarily due to its military applications. Gulf War veterans with embedded DU showed cognitive disorders that suggest that the central nervous system is a target of DU. Recent evidence has suggested that DU could induce oxidative stress and mitochondrial dysfunction in brain tissue. However, the underlying mechanisms of DU toxicity in brain mitochondria are not yet well understood. Brain mitochondria were obtained using differential centrifugation and were incubated with different concentrations (50, 100 and 200 MUM) of uranyl acetate (UA) as a soluble salt of U(238) for 1 h. In this research, mitochondrial ROS production, collapse of mitochondrial membrane potential and mitochondrial swelling were examined by flow cytometry following the addition of UA. Meanwhile, mitochondrial sources of ROS formation were determined using specific substrates and inhibitors. Complex II and IV activity and also the extent of lipid peroxidation and glutathione (GSH) oxidation were detected via spectroscopy. Furthermore, we investigated the concentration of ATP and ATP/ADP ratio using luciferase enzyme and cytochrome c release from mitochondria which was detected by ELISA kit. UA caused concentration-dependent elevation of succinate-linked mitochondrial ROS production, lipid peroxidation, GSH oxidation and inhibition of mitochondrial complex II. UA also induced mitochondrial permeability transition, ATP production decrease and increase in cytochrome c release. Pre-treatment with antioxidants significantly inhibited all the above mentioned toxic effects of UA. This study suggests that mitochondrial oxidative stress and impairment of oxidative phosphorylation in brain mitochondria may play a key role in DU neurotoxicity as reported in Gulf War Syndrome. PMID- 23629691 TI - Men and women as perpetrators and victims of sexual aggression in heterosexual and same-sex encounters: a study of first-year college students in Germany. AB - This study examined the prevalence of sexual aggression and victimization in a large convenience sample of N = 2,149 first-year college students from different universities in Germany. Participants were asked about both victimization by, and perpetration of, sexual aggression since the age of 14. Both same-sex and heterosexual victim-perpetrator constellations were examined. Prevalence rates were established for different victim-perpetrator relationships (partners, acquaintances, strangers) and for incidents involving alcohol consumption by one or both partners. The overall perpetration rate was 13.2%, for men and 7.6% for women. The overall victimization rate was 35.9% for women and 19.4% for men. A disparity between victimization and perpetration reports was found for both men and women. Perpetration and victimization rates were highest among participants who had sexual contacts with both opposite-sex and same-sex partners. Sexual aggression and victimization rates were higher between current or former partners and acquaintances than between strangers. Alcohol consumption by one or both partners was involved in almost 75% of all victimization and almost 70% of all perpetration incidents. The findings portray a comprehensive picture of the scale of sexual aggression and victimization in college students with different sexual lifestyles. PMID- 23629692 TI - Genomic analysis of a child with Down syndrome-related congenital cataract. PMID- 23629693 TI - Clinical classification of targeted agents used for anticancer treatment. AB - The introduction of targeted agents has resulted in a breakthrough in advanced cancer treatment. We propose a new classification for these agents to evaluate them in appropriate clinical trials according to agent class. Class I agents that inhibit driver oncogene activities result in massive and rapid tumor shrinkage, with response rates as high as 70% when administered to patients with appropriate targets. These agents can be evaluated in single-arm phase II trials with response rate as the primary endpoint. Class II agents inhibit one oncogene that is partially responsible for accelerating tumor cell proliferation. Their clinical features include synergism with cytotoxic agents and moderate single agent activity, as shown by response rates of between 10% and 30%. Randomized phase II trials in patients with over-expressed targets are appropriate for the evaluation of these agents. Class III agents inhibit proliferation regulators that are not always oncogenic. Their clinical activity is unique, as they confer a survival benefit on patients with a minimum tumor shrinkage effect. Class IV agents target environmental molecules that act on normal cells surrounding tumor cells, such as the endothelial cells that form vessels. Placebo-controlled randomized phase II trials are required to identify the clinical activities of both class III and IV agents. Class V agents act by enhancing anti-tumor immunity. Immune-related response criteria should aid the evaluation of these agents. We believe that this classification for targeted agents should facilitate their further clinical development. PMID- 23629694 TI - Elevated plasma hyaluronan levels in pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is a progressive disease, with a poor prognosis. The pathophysiologic mechanism of PAH is unknown, but may involve both tissue remodeling and inflammatory processes. Hyaluronan (HA) is a large glycosaminoglycan polymer and a major component of the extracellular matrix. In the present study, we measured plasma HA levels in PAH associated with systolic congestive heart failure (CHF, n = 16) or chronic obstructive pulmonary disease (COPD, n = 18). The control group was consisted of 14 healthy individuals without pulmonary or cardiovascular disease. Plasma HA levels (ng/mL) were determined in all patients by an enzyme linked HA binding assay. Pulmonary arterial pressure (PAP) was calculated in echocardiography (mmHg). Pulmonary arterial pressures were significantly higher in CHF and COPD (CHF: 55.0 +/- 11 mmHg and COPD: 62.5 +/- 21 mmHg, p < 0.001 for each), compared to the control group (25.4 +/- 5.9 mmHg). Plasma HA levels were significantly higher in CHF (73.0 +/- 37.5 ng/ml, p = 0.007) and COPD (87.3 +/- 53.2 ng/ml, p = 0.001) compared to control patients (26.2 +/- 8.4 ng/ml). There was no significant difference in plasma HA levels between the CFH and COPD groups (p = 0.690). In COPD, plasma HA levels were significantly correlated with PAP, left atrium diameter. There was no significant correlation between plasma HA levels and age or with echocardiography parameters in CHF. Both CHF and COPD are associated with increased plasma HA levels. Elevated plasma HA may contribute to the development of PAH. PMID- 23629695 TI - Discovery and mass spectrometric analysis of novel splice-junction peptides using RNA-Seq. AB - Human proteomic databases required for MS peptide identification are frequently updated and carefully curated, yet are still incomplete because it has been challenging to acquire every protein sequence from the diverse assemblage of proteoforms expressed in every tissue and cell type. In particular, alternative splicing has been shown to be a major source of this cell-specific proteomic variation. Many new alternative splice forms have been detected at the transcript level using next generation sequencing methods, especially RNA-Seq, but it is not known how many of these transcripts are being translated. Leveraging the unprecedented capabilities of next generation sequencing methods, we collected RNA-Seq and proteomics data from the same cell population (Jurkat cells) and created a bioinformatics pipeline that builds customized databases for the discovery of novel splice-junction peptides. Eighty million paired-end Illumina reads and ~500,000 tandem mass spectra were used to identify 12,873 transcripts (19,320 including isoforms) and 6810 proteins. We developed a bioinformatics workflow to retrieve high-confidence, novel splice junction sequences from the RNA data, translate these sequences into the analogous polypeptide sequence, and create a customized splice junction database for MS searching. Based on the RefSeq gene models, we detected 136,123 annotated and 144,818 unannotated transcript junctions. Of those, 24,834 unannotated junctions passed various quality filters (e.g. minimum read depth) and these entries were translated into 33,589 polypeptide sequences and used for database searching. We discovered 57 splice junction peptides not present in the Uniprot-Trembl proteomic database comprising an array of different splicing events, including skipped exons, alternative donors and acceptors, and noncanonical transcriptional start sites. To our knowledge this is the first example of using sample-specific RNA-Seq data to create a splice-junction database and discover new peptides resulting from alternative splicing. PMID- 23629696 TI - Ischemic culture of dental pulp-derived cells is a useful model in which to investigate mechanisms of post-ischemic tissue recovery. AB - Dental pulp is a soft tissue characterized by unique regenerative properties. It is located in the center of each tooth, and is surrounded by hard tissue (dentin). Vascular access is limited to a small foramen at the root apex. Because of this anatomical limitation, dental pulp can easily lose its blood supply, causing the tissue to become ischemic. This occurs, for example, when a tooth is dislocated by traumatic injury or is subjected to inflammation. Since ischemia is caused by a critical shortage of oxygen and nutrients, ischemic damage is usually irreversible, even when the ischemic event is transient. However, unlike ischemia sensitive organs such as the brain and heart, dental pulp is relatively ischemia resistant, and recovers from ischemic injury by regenerating damaged tissue. The mechanisms by which this regeneration occurs are poorly understood, but are being investigated in cell culture models that mimic in vivo ischemic conditions using a combination of hypoxia and nutrient deprivation. Here, we review the use of ischemic cell culture to investigate the mechanisms of post-ischemic dental pulp tissue recovery. PMID- 23629697 TI - Fluorescent graphene quantum dots with a boronic acid appended bipyridinium salt to sense monosaccharides in aqueous solution. AB - Using graphene quantum dots (GQDs) with a boronic acid-substituted bipyridinium salt (BBV), a label-free fluorescence assay for glucose detection is presented. PMID- 23629698 TI - Male and female Plasmodium falciparum mature gametocytes show different responses to antimalarial drugs. AB - It is the mature gametocytes of Plasmodium that are solely responsible for parasite transmission from the mammalian host to the mosquito. They are therefore a logical target for transmission-blocking antimalarial interventions, which aim to break the cycle of reinfection and reduce the prevalence of malaria cases. Gametocytes, however, are not a homogeneous cell population. They are sexually dimorphic, and both males and females are required for parasite transmission. Using two bioassays, we explored the effects of 20 antimalarials on the functional viability of both male and female mature gametocytes of Plasmodium falciparum. We show that mature male gametocytes (as reported by their ability to produce male gametes, i.e., to exflagellate) are sensitive to antifolates, some endoperoxides, methylene blue, and thiostrepton, with submicromolar 50% inhibitory concentrations (IC50s), whereas female gametocytes (as reported by their ability to activate and form gametes expressing the marker Pfs25) are much less sensitive to antimalarial intervention, with only methylene blue and thiostrepton showing any significant activity. These findings show firstly that the antimalarial responses of male and female gametocytes differ and secondly that the mature male gametocyte should be considered a more vulnerable target than the female gametocyte for transmission-blocking drugs. Given the female biased sex ratio of Plasmodium falciparum (~3 to 5 females:1 male), current gametocyte assays without a sex-specific readout are unlikely to identify male targeted compounds and prioritize them for further development. Both assays reported here are being scaled up to at least medium throughput and will permit identification of key transmission-blocking molecules that have been overlooked by other screening campaigns. PMID- 23629699 TI - Identification of PTC725, an orally bioavailable small molecule that selectively targets the hepatitis C Virus NS4B protein. AB - While new direct-acting antiviral agents for the treatment of chronic hepatitis C virus (HCV) infection have been approved, there is a continued need for novel antiviral agents that act on new targets and can be used in combination with current therapies to enhance efficacy and to restrict the emergence of drug resistant viral variants. To this end, we have identified a novel class of small molecules, exemplified by PTC725, that target the nonstructural protein 4B (NS4B). PTC725 inhibited HCV 1b (Con1) replicons with a 50% effective concentration (EC50) of 1.7 nM and an EC90 of 9.6 nM and demonstrated a >1,000 fold selectivity window with respect to cytotoxicity. The compounds were fully active against HCV replicon mutants that are resistant to inhibitors of NS3 protease and NS5B polymerase. Replicons selected for resistance to PTC725 harbored amino acid substitutions F98L/C and V105M in NS4B. Anti-replicon activity of PTC725 was additive to synergistic in combination with alpha interferon or with inhibitors of HCV protease and polymerase. Immunofluorescence microscopy demonstrated that neither the HCV inhibitors nor the F98C substitution altered the subcellular localization of NS4B or NS5A in replicon cells. Oral dosing of PTC725 showed a favorable pharmacokinetic profile with high liver and plasma exposure in mice and rats. Modeling of dosing regimens in humans indicates that a once-per-day or twice-per-day oral dosing regimen is feasible. Overall, the preclinical data support the development of PTC725 for use in the treatment of chronic HCV infection. PMID- 23629700 TI - The Staphylococcus aureus thiol/oxidative stress global regulator Spx controls trfA, a gene implicated in cell wall antibiotic resistance. AB - S. aureus combats cell wall antibiotic stress by altered gene expression mediated by various environmental signal sensors. In this study, we examined the transcriptional regulation of trfA, a gene related to mecA of Bacillus subtilis encoding an adaptor protein implicated in multiple roles, notably, proteolysis and genetic competence. Despite strong sequence similarity to B. subtilis mecA, the function of S. aureus trfA remains largely unexplored; however, its deletion leads to almost complete loss of resistance to oxacillin and glycopeptide antibiotics in glycopeptide-intermediate S. aureus (GISA) derivatives of methicillin-susceptible or methicillin-resistant S. aureus (MRSA) clinical or laboratory isolates. Northern blot analysis and 5' rapid amplification of cDNA ends (RACE) mapping revealed that trfA was expressed monocistronically by three promoters. Cell wall-active antibiotic exposure led to both increased trfA transcription and enhanced steady-state TrfA levels. trfA promoter regulation was not dependent upon the cell wall stress sentinel VraSR and other sensory stress systems, such as GraRS, WalkRK, Stk1/Stp1, and SigB. Notably, we discovered that the global oxidative-stress regulator Spx controlled trfA transcription. This finding was also confirmed using a strain with enhanced Spx levels resulting from a defect in yjbH, encoding a Spx-interacting protein governing Spx proteolytic degradation. A cohort of clinical GISA strains revealed significant steady-state upregulation of trfA compared to corresponding susceptible parental strains, further supporting a role for trfA in antibiotic resistance. These data provide strong evidence for a link between cell wall antibiotic stress and evoked responses mediated by an oxidative-stress sensor. PMID- 23629701 TI - Novel erm(T)-carrying multiresistance plasmids from porcine and human isolates of methicillin-resistant Staphylococcus aureus ST398 that also harbor cadmium and copper resistance determinants. AB - This study describes three novel erm(T)-carrying multiresistance plasmids that also harbor cadmium and copper resistance determinants. The plasmids, designated pUR1902, pUR2940, and pUR2941, were obtained from porcine and human methicillin resistant Staphylococcus aureus (MRSA) of the clonal lineage ST398. In addition to the macrolide-lincosamide-streptogramin B (MLSB) resistance gene erm(T), all three plasmids also carry the tetracycline resistance gene tet(L). Furthermore, plasmid pUR2940 harbors the trimethoprim resistance gene dfrK and the MLSB resistance gene erm(C), while plasmids pUR1902 and pUR2941 possess the kanamycin/neomycin resistance gene aadD. Sequence analysis of approximately 18.1 kb of the erm(T)-flanking region from pUR1902, 20.0 kb from pUR2940, and 20.8 kb from pUR2941 revealed the presence of several copies of the recently described insertion sequence ISSau10, which is probably involved in the evolution of the respective plasmids. All plasmids carried a functional cadmium resistance operon with the genes cadD and cadX, in addition to the multicopper oxidase gene mco and the ATPase copper transport gene copA, which are involved in copper resistance. The comparative analysis of S. aureus RN4220 and the three S. aureus RN4220 transformants carrying plasmid pUR1902, pUR2940, or pUR2941 revealed an 8-fold increase in CdSO4 and a 2-fold increase in CuSO4 MICs. The emergence of multidrug resistance plasmids that also carry heavy metal resistance genes is alarming and requires further surveillance. The colocalization of antimicrobial resistance genes and genes that confer resistance to heavy metals may facilitate their persistence, coselection, and dissemination. PMID- 23629702 TI - Gentamicin-loaded borate bioactive glass eradicates osteomyelitis due to Escherichia coli in a rabbit model. AB - The treatment of osteomyelitis induced by Gram-negative bacilli is rarely reported in the literature. This study established a rabbit tibia model of osteomyelitis induced by the Gram-negative bacillus Escherichia coli. Using this model, pellets composed of a chitosan-bonded mixture of borate bioactive glass and gentamicin were evaluated in vitro and in vivo for the treatment of osteomyelitis induced by Escherichia coli. Our results showed that the pellets in phosphate-buffered saline released gentamicin continuously over 26 days. Without the simultaneous use of a systemic antibiotic, the implantation of the gentamicin loaded pellets into the osteomyelitis region of the tibia resulted in the eradication of 81.82% of infections, as determined by microbiological, histological and radiographic evaluation, and supported the ingrowth of new bone into the tibia defects after 6 weeks of implantation. The results indicate that the gentamicin-loaded borate bioactive glass implant, combining sustained drug release with the ability to support new bone formation, could provide a method for treating osteomyelitis induced by Gram-negative bacilli. PMID- 23629703 TI - Emergence of colistin resistance in Enterobacteriaceae after the introduction of selective digestive tract decontamination in an intensive care unit. AB - Selective decontamination of the digestive tract (SDD) selectively eradicates aerobic Gram-negative bacteria (AGNB) by the enteral administration of oral nonabsorbable antimicrobial agents, i.e., colistin and tobramycin. We retrospectively investigated the impact of SDD, applied for 5 years as part of an infection control program for the control of an outbreak with extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae in an intensive care unit (ICU), on resistance among AGNB. Colistin MICs were determined on stored ESBL producing K. pneumoniae isolates using the Etest. The occurrence of both tobramycin resistance among pathogens intrinsically resistant to colistin (CIR) and bacteremia caused by ESBL-producing K. pneumoniae and CIR were investigated. Of the 134 retested ESBL-producing K. pneumoniae isolates, 28 were isolated before SDD was started, and all had MICs of <1.5 mg/liter. For the remaining 106 isolated after starting SDD, MICs ranged between 0.5 and 24 mg/liter. Tobramycin resistant CIR isolates were found sporadically before the introduction of SDD, but their prevalence increased immediately afterward. Segmented regression analysis showed a highly significant relationship between SDD and resistance to tobramycin. Five patients were identified with bacteremia caused by ESBL producing K. pneumoniae before SDD and 9 patients thereafter. No bacteremia caused by CIR was found before SDD, but its occurrence increased to 26 after the introduction of SDD. In conclusion, colistin resistance among ESBL-producing K. pneumoniae isolates emerged rapidly after SDD. In addition, both the occurrence and the proportion of tobramycin resistance among CIR increased under the use of SDD. SDD should not be applied in outbreak settings when resistant bacteria are prevalent. PMID- 23629704 TI - How does colistin-induced nephropathy develop and can it be treated? AB - Colistin is an old antibiotic used in the treatment of Gram-negative infections. It was once suspended because of its nephrotoxic effect but has since been reintroduced due to multidrug-resistant bacterial infections. The pathogenesis of colistin-associated nephropathy has not been clarified, and there is currently no effective therapeutic or prophylactic agent available. The aim of this study was to investigate the roles of caspase-associated apoptosis and caspase 1, calpain 1, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) expression in the pathogenesis of colistin-associated nephrotoxicity and the effect of grape seed proanthocyanidin extract (GSPE) in preventing it. Twenty four rats were divided into three groups: control, colistin, and colistin plus GSPE (colistin+GSPE). Colistin-associated nephropathy was induced by the administration of 300,000 IU/kg of body weight/day colistin intraperitoneally for 7 days. The experiment was discontinued on the seventh day. Blood was collected for measurements of blood urea nitrogen (BUN) and creatinine levels. Histopathological examination of kidney tissue and caspase 1 and 3, iNOS, eNOS, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL), and calpain 1 staining was also performed. Significant increases in BUN levels; creatinine levels; renal histopathological scores; and TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining were observed for the colistin group compared to the control group. Significant decreases in BUN levels; creatinine levels; renal histopathological scores; and TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining were observed in the colistin+GSPE group compared to the colistin group. Our study shows, for the first time in the literature, that caspase-mediated apoptosis, iNOS, caspase 1, and calpain 1 are involved in the pathogenesis of colistin-associated nephropathy. GSPE had a renoprotective effect, as shown by the lowered levels of these mediators. PMID- 23629705 TI - Pharmacokinetics-pharmacodynamics of tazobactam in combination with ceftolozane in an in vitro infection model. AB - Despite beta-lactamase inhibitors being available for clinical use for nearly 30 years, a paucity of data exists describing the pharmacokinetic-pharmacodynamic (PK-PD) determinants of efficacy for these agents. Herein, we describe dose fractionation studies designed to determine the exposure measure most predictive of tazobactam efficacy in combination with ceftolozane and the magnitude of this measure necessary for efficacy in a PK-PD in vitro infection model. The challenge organism panel was comprised of an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of bla(CTX-M 15). These recombinant strains exhibited ceftolozane MIC values of 4, 16, and 64 MUg/ml representing low, moderate, and high levels of CTX-M-15, respectively. Different bla(CTX-M-15) transcription levels were confirmed by relative quantitative real-time PCR (qRT-PCR) and beta-lactamase hydrolytic assays. The exposure measure associated with efficacy was the percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold), regardless of enzyme expression (r(2) = 0.938). The threshold concentrations identified were 0.05 MUg/ml for low and moderate and 0.25 MUg/ml for the high-beta-lactamase expression strain constructs. The magnitudes of %Time>threshold for tazobactam associated with net bacterial stasis and a 1- and 2-log10 CFU reduction in bacteria at 24 h were approximately 35, 50, and 70%, respectively. These data provide an initial target tazobactam concentration-time profile and a paradigm to optimize tazobactam dosing when combined with ceftolozane. PMID- 23629706 TI - Is azole resistance in Aspergillus fumigatus a problem in Spain? AB - Aspergillus fumigatus complex comprises A. fumigatus and other morphologically indistinguishable cryptic species. We retrospectively studied 362 A. fumigatus complex isolates (353 samples) from 150 patients with proven or probable invasive aspergillosis or aspergilloma (2, 121, and 6 samples, respectively) admitted to the hospital from 1999 to 2011. Isolates were identified using the beta-tubulin gene, and only 1 isolate per species found in each sample was selected. Antifungal susceptibility to azoles was determined using the CLSI M38-A2 procedure. Isolates were considered resistant if they showed an MIC above the breakpoints for itraconazole, voriconazole, or posaconazole (>2, >2, or >0.5 MUg/ml). Most of the samples yielded only 1 species (A. fumigatus [n = 335], A. novofumigatus [n = 4], A. lentulus [n = 3], A. viridinutans [n = 1], and Neosartorya udagawae [n = 1]). The remaining samples yielded a combination of 2 species. Most of the patients were infected by a single species (A. fumigatus [n = 143] or A. lentulus [n = 2]). The remaining 5 patients were coinfected with multiple A. fumigatus complex species, although A. fumigatus was always involved; 4 of the 5 patients were diagnosed in 2009 or later. Cryptic species were less susceptible than A. fumigatus. The frequency of resistance among A. fumigatus complex and A. fumigatus to itraconazole, voriconazole, and posaconazole was 2.5 and 0.3%, 3.1 and 0.3%, and 4.2 and 1.8%, respectively, in the per-isolate analysis and 1.3 and 0.7%, 2.6 and 0.7%, and 6 and 4% in the per-patient analysis. Only 1 of the 6 A. fumigatus isolates in which the cyp51A gene was sequenced had a mutation at position G448. The proportion of patients infected by azole-resistant A. fumigatus isolates was low. PMID- 23629707 TI - Multiplex liquid chromatography-tandem mass spectrometry assay for simultaneous therapeutic drug monitoring of ribavirin, boceprevir, and telaprevir. AB - New directly acting antivirals (DAAs) that inhibit hepatitis C virus (HCV) replication are increasingly used for the treatment of chronic hepatitis C. A marked pharmacokinetic variability and a high potential for drug-drug interactions between DAAs and numerous drug classes have been identified. In addition, ribavirin (RBV), commonly associated with hemolytic anemia, often requires dose adjustment, advocating for therapeutic drug monitoring (TDM) in patients under combined antiviral therapy. However, an assay for the simultaneous analysis of RBV and DAAs constitutes an analytical challenge because of the large differences in polarity among these drugs, ranging from hydrophilic (RBV) to highly lipophilic (telaprevir [TVR]). Moreover, TVR is characterized by erratic behavior on standard octadecyl-based reversed-phase column chromatography and must be separated from VRT-127394, its inactive C-21 epimer metabolite. We have developed a convenient assay employing simple plasma protein precipitation, followed by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for the simultaneous determination of levels of RBV, boceprevir, and TVR, as well as its metabolite VRT-127394, in plasma. This new, simple, rapid, and robust HPLC-MS/MS assay offers an efficient method of real time TDM aimed at maximizing efficacy while minimizing the toxicity of antiviral therapy. PMID- 23629708 TI - Candida glabrata drug:H+ antiporter CgQdr2 confers imidazole drug resistance, being activated by transcription factor CgPdr1. AB - The widespread emergence of antifungal drug resistance poses a severe clinical problem. Though predicted to play a role in this phenomenon, the drug:H(+) antiporters (DHA) of the major facilitator superfamily have largely escaped characterization in pathogenic yeasts. This work describes the first DHA from the pathogenic yeast Candida glabrata reported to be involved in antifungal drug resistance, the C. glabrata QDR2 (CgQDR2) gene (ORF CAGL0G08624g). The expression of CgQDR2 in C. glabrata was found to confer resistance to the antifungal drugs miconazole, tioconazole, clotrimazole, and ketoconazole. By use of a green fluorescent protein (GFP) fusion, the CgQdr2 protein was found to be targeted to the plasma membrane in C. glabrata. In agreement with these observations, CgQDR2 expression was found to decrease the intracellular accumulation of radiolabeled clotrimazole in C. glabrata and to play a role in the extrusion of this antifungal from preloaded cells. Interestingly, the functional heterologous expression of CgQDR2 in the model yeast Saccharomyces cerevisiae further confirmed the role of this gene as a multidrug resistance determinant: its expression was able to complement the susceptibility phenotype exhibited by its S. cerevisiae homologue, QDR2, in the presence of imidazoles and of the antimalarial and antiarrhythmic drug quinidine. In contrast to the findings reported for Qdr2, CgQdr2 expression does not contribute to the ability of yeast to grow under K(+)-limiting conditions. Interestingly, CgQDR2 transcript levels were seen to be upregulated in C. glabrata cells challenged with clotrimazole or quinidine. This upregulation was found to depend directly on the transcription factor CgPdr1, the major regulator of multidrug resistance in this pathogenic yeast, which has also been found to be a determinant of quinidine and clotrimazole resistance in C. glabrata. PMID- 23629709 TI - ACH-806, an NS4A antagonist, inhibits hepatitis C virus replication by altering the composition of viral replication complexes. AB - Treatment of hepatitis C patients with direct-acting antiviral drugs involves the combination of multiple small-molecule inhibitors of distinctive mechanisms of action. ACH-806 (or GS-9132) is a novel, small-molecule inhibitor specific for hepatitis C virus (HCV). It inhibits viral RNA replication in HCV replicon cells and was active in genotype 1 HCV-infected patients in a proof-of-concept clinical trial (1). Here, we describe a potential mechanism of action (MoA) wherein ACH 806 alters viral replication complex (RC) composition and function. We found that ACH-806 did not affect HCV polyprotein translation and processing, the early events of the formation of HCV RC. Instead, ACH-806 triggered the formation of a homodimeric form of NS4A with a size of 14 kDa (p14) both in replicon cells and in Huh-7 cells where NS4A was expressed alone. p14 production was negatively regulated by NS3, and its appearance in turn was associated with reductions in NS3 and, especially, NS4A content in RCs due to their accelerated degradation. A previously described resistance substitution near the N terminus of NS3, where NS3 interacts with NS4A, attenuated the reduction of NS3 and NS4A conferred by ACH-806 treatment. Taken together, we show that the compositional changes in viral RCs are associated with the antiviral activity of ACH-806. Small molecules, including ACH-806, with this novel MoA hold promise for further development and provide unique tools for clarifying the functions of NS4A in HCV replication. PMID- 23629711 TI - Antimicrobial susceptibility of Propionibacterium acnes isolates from shoulder surgery. AB - Orthopedic surgeons at our institution have noticed an increase in the number of infections due to Propionibacterium acnes, especially following operations on the shoulder. We collected P. acnes isolates from our hospital microbiology laboratory for 1 year and performed antimicrobial susceptibility testing on 28 strains from the shoulder. Antibiotics with the lowest MIC values against P. acnes (MIC50 and MIC90) included penicillin G (0.006, 0.125), cephalothin (0.047 and 0.094), and ceftriaxone (0.016, 0.045), while others also showed activity. Strains resistant to clindamycin were noted. PMID- 23629710 TI - Structural analysis of the role of Pseudomonas aeruginosa penicillin-binding protein 5 in beta-lactam resistance. AB - Penicillin-binding protein 5 (PBP5) is one of the most abundant PBPs in Pseudomonas aeruginosa. Although its main function is that of a cell wall dd carboxypeptidase, it possesses sufficient beta-lactamase activity to contribute to the ability of P. aeruginosa to resist the antibiotic activity of the beta lactams. The study of these dual activities is important for understanding the mechanisms of antibiotic resistance by P. aeruginosa, an important human pathogen, and to the understanding of the evolution of beta-lactamase activity from the PBP enzymes. We purified a soluble version of P. aeruginosa PBP5 (designated Pa sPBP5) by deletion of its C-terminal membrane anchor. Under in vitro conditions, Pa sPBP5 demonstrates both dd-carboxypeptidase and expanded spectrum beta-lactamase activities. Its crystal structure at a 2.05-A resolution shows features closely resembling those of the class A beta-lactamases, including a shortened loop spanning residues 74 to 78 near the active site and with respect to the conformations adopted by two active-site residues, Ser101 and Lys203. These features are absent in the related PBP5 of Escherichia coli. A comparison of the two Pa sPBP5 monomers in the asymmetric unit, together with molecular dynamics simulations, revealed an active-site flexibility that may explain its carbapenemase activity, a function that is absent in the E. coli PBP5 enzyme. Our functional and structural characterizations underscore the versatility of this PBP5 in contributing to the beta-lactam resistance of P. aeruginosa while highlighting how broader beta-lactamase activity may be encoded in the structural folds shared by the PBP and serine beta-lactamase classes. PMID- 23629712 TI - Antimicrobial activity of ceftaroline tested against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin from U.S. hospitals, 2008 to 2011. AB - Vancomycin, linezolid, and daptomycin are very active against staphylococci, but isolates with decreased susceptibility to these antimicrobial agents are isolated sporadically. A total of 19,350 Staphylococcus aureus isolates (51% methicillin resistant [MRSA]) and 3,270 coagulase-negative staphylococci (CoNS) were collected consecutively from 82 U.S. medical centers from January 2008 to December 2011 and tested for susceptibility against ceftaroline and comparator agents by the reference broth microdilution method. Among S. aureus strains, 14 isolates (0.07%) exhibited decreased susceptibility to linezolid (MIC, >= 8 MUg/ml), 18 (0.09%) to daptomycin (MIC, >= 2 MUg/ml), and 369 (1.9%) to vancomycin (MIC, >= 2 MUg/ml; 368 isolates at 2 MUg/ml and 1 at 4 MUg/ml). Fifty one (1.6%) CoNS were linezolid resistant (MIC, >= 8 MUg/ml), and four (0.12%) were daptomycin nonsusceptible (MIC, >= 2 MUg/ml). Ceftaroline was very active against S. aureus overall (MIC50/90, 0.5/1 MUg/ml; 98.5% susceptible), including MRSA (MIC50/90, 0.5/1 MUg/ml; 97.2% susceptible). All daptomycin-nonsusceptible and 85.7% of linezolid-resistant S. aureus isolates were susceptible to ceftaroline. Against S. aureus isolates with a vancomycin MIC of >= 2 MUg/ml, 91.9, 96.2, and 98.9% were susceptible to ceftaroline, daptomycin, and linezolid, respectively. CoNS strains were susceptible to ceftaroline (MIC50/90, 0.25/0.5 MUg/ml; 99.1% inhibited at <= 1 MUg/ml), including methicillin-resistant (MIC50/90, 0.25/0.5 MUg/ml), linezolid-resistant (MIC50/90, 0.5/0.5 MUg/ml), and daptomycin-nonsusceptible (4 isolates; MIC range, 0.03 to 0.12 MUg/ml) strains. In conclusion, ceftaroline demonstrated potent in vitro activity against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin, and it may represent a valuable treatment option for infections caused by these multidrug-resistant staphylococci. PMID- 23629713 TI - Human monoclonal antibodies against Clostridium difficile toxins A and B inhibit inflammatory and histologic responses to the toxins in human colon and peripheral blood monocytes. AB - Clostridium difficile infection (CDI) is a common and debilitating nosocomial infection with high morbidity and mortality. C. difficile mediates diarrhea and colitis by releasing two toxins, toxin A and toxin B. Since both toxins stimulate proinflammatory signaling pathways in human colonocytes and both are involved in the pathophysiology of CDI, neutralization of toxin A and B activities may represent an important therapeutic approach against CDI. Recent studies indicated that human monoclonal antibodies (MAbs) against toxins A and B reduce their cytotoxic and secretory activities and prevent CDI in hamsters. Moreover, anti toxin A and anti-toxin B MAbs together with antibiotics also effectively reduced recurrent CDI in humans. However, whether these MAbs neutralize toxin A- and toxin B-associated immune responses in human colonic mucosa or human peripheral blood monocyte cells (PBMCs) has never been examined. We used fresh human colonic biopsy specimens and peripheral blood monocytes to evaluate the effects of these antibodies against toxin A- and B-associated cytokine release, proinflammatory signaling, and histologic damage. Incubation of anti-toxin A (MK3415) or anti toxin B (MK6072) MAbs with human PBMCs significantly inhibited toxin A- and toxin B-mediated tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL 1beta) expression. MK3415 and MK6072 also diminished toxin A- and toxin B mediated NF-kappaB p65 phosphorylation in human monocytes, respectively, and significantly reduced toxin A- and B-induced TNF-alpha and IL-1beta expression as well as histologic damage in human colonic explants. Our results underline the effectiveness of MK3415 and MK6072 in blocking C. difficile toxin A- and toxin B mediated inflammatory responses and histologic damage. PMID- 23629714 TI - Development of a population pharmacokinetic model to describe azithromycin whole blood and plasma concentrations over time in healthy subjects. AB - Azithromycin (AZI), a broad-spectrum antibiotic, accumulates in polymorphonuclear cells and peripheral blood mononuclear cells. The distribution of AZI in proinflammatory cells may be important to the anti-inflammatory properties. Previous studies have described plasma AZI pharmacokinetics. The objective of this study was to describe the pharmacokinetics of AZI in whole blood (concentration in whole blood [Cb]) and plasma (concentration in plasma [Cp]) of healthy subjects. In this study, 12 subjects received AZI (500 mg once a day for 3 days). AZI Cb and Cp were quantified in serial samples collected up to 3 weeks after the last dose and analyzed using noncompartmental and compartmental methods. After the last dose, Cb was greater than Cp. Importantly, Cb, but not Cp, was quantifiable in all but one subject at 3 weeks. The blood area under the curve during a 24-h dosing interval (AUC24) was ~2-fold greater than the plasma AUC24, but simulations suggested that Cb was not at steady state by day 3. Upon exploration of numerous models, an empirical 3-compartment model adequately described Cp and Cb, but Cp was somewhat underestimated. Intercompartmental clearance (CL; likely representing cells) was lower than apparent oral CL (18 versus 118 liters/h). Plasma, peripheral, and cell compartmental volumes were 439 liters, 2,980 liters, and 3,084 liters, respectively. Interindividual variability in CL was low (26.2%), while the volume of distribution variability was high (107%). This is the first report to describe AZI Cb in healthy subjects, the distribution parameters between Cp and Cb, and AZI retention in blood for up to 3 weeks following 3 daily doses. The model can be used to predict Cb from Cp for AZI under various dosing regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01026064.). PMID- 23629715 TI - Pharmacokinetics of first-line tuberculosis drugs in Tanzanian patients. AB - East Africa has a high tuberculosis (TB) incidence and mortality, yet there are very limited data on exposure to TB drugs in patients from this region. We therefore determined the pharmacokinetic characteristics of first-line TB drugs in Tanzanian patients using intensive pharmacokinetic sampling. In 20 adult TB patients, plasma concentrations were determined just before and at 1, 2, 3, 4, 6, 8, 10, and 24 h after observed drug intake with food to estimate the areas under the curve from 0 to 24 h (AUC0-24) and peak plasma concentrations (Cmax) of isoniazid, rifampin, pyrazinamide, and ethambutol. Acetylator status for isoniazid was assessed phenotypically using the isoniazid elimination half-life and the acetylisoniazid/isoniazid metabolic ratio at 3 h postdose. The geometric mean AUC0-24s were as follows: isoniazid, 11.0 h . mg/liter; rifampin, 39.9 h . mg/liter; pyrazinamide, 344 h . mg/liter; and ethambutol, 20.2 h . mg/liter. The Cmax was below the reference range for isoniazid in 10/19 patients and for rifampin in 7/20 patients. In none of the patients were the Cmaxs for pyrazinamide and ethambutol below the reference range. Elimination half-life and metabolic ratio of isoniazid gave discordant phenotyping results in only 2/19 patients. A substantial proportion of patients had an isoniazid and/or rifampin Cmax below the reference range. Intake of TB drugs with food may partly explain these low drug levels, but such a drug intake reflects common practice. The finding of low TB drug concentrations is concerning because low concentrations have been associated with worse treatment outcome in several other studies. PMID- 23629716 TI - Ergothioneine is a secreted antioxidant in Mycobacterium smegmatis. AB - Ergothioneine (ERG) and mycothiol (MSH) are two low-molecular-weight thiols synthesized by mycobacteria. The role of MSH has been extensively investigated in mycobacteria; however, little is known about the role of ERG in mycobacterial physiology. In this study, quantification of ERG at various points in the growth cycle of Mycobacterium smegmatis revealed that a significant portion of ERG is found in the culture media, suggesting that it is actively secreted. A mutant of M. smegmatis lacking egtD (MSMEG_6247) was unable to synthesize ERG, confirming its role in ERG biosynthesis. Deletion of egtD from wild-type M. smegmatis and an MSH-deficient mutant did not affect their susceptibility to antibiotics tested in this study. The ERG- and MSH-deficient double mutant was significantly more sensitive to peroxide than either of the single mutants lacking either ERG or MSH, suggesting that both thiols play a role in protecting M. smegmatis against oxidative stress and that ERG is able to partly compensate for the loss of MSH. PMID- 23629717 TI - Steady-state pharmacokinetics of oral voriconazole and its primary metabolite, N oxide voriconazole, pre- and post-autologous peripheral stem cell transplantation. AB - Voriconazole (VCZ) is frequently utilized for prevention and treatment of invasive fungal infections in peripheral stem cell transplant (PSCT) patients. We performed an open-label pharmacokinetic study to compare VCZ and N-oxide voriconazole (N-oxide VCZ) pharmacokinetics in patients pre- and post-PSCT. Ten patients completed both sampling periods. The pharmacokinetics of VCZ were unchanged; however, those of N-oxide VCZ were significantly different pre- and post-PSCT. PMID- 23629718 TI - Molecular mechanisms of drug resistance in clinical Candida species isolated from Tunisian hospitals. AB - Antifungal resistance of Candida species is a clinical problem in the management of diseases caused by these pathogens. In this study we identified from a collection of 423 clinical samples taken from Tunisian hospitals two clinical Candida species (Candida albicans JEY355 and Candida tropicalis JEY162) with decreased susceptibility to azoles and polyenes. For JEY355, the fluconazole (FLC) MIC was 8 MUg/ml. Azole resistance in C. albicans JEY355 was mainly caused by overexpression of a multidrug efflux pump of the major facilitator superfamily, Mdr1. The regulator of Mdr1, MRR1, contained a yet-unknown gain-of function mutation (V877F) causing MDR1 overexpression. The C. tropicalis JEY162 isolate demonstrated cross-resistance between FLC (MIC > 128 MUg/ml), voriconazole (MIC > 16 MUg/ml), and amphotericin B (MIC > 32 MUg/ml). Sterol analysis using gas chromatography-mass spectrometry revealed that ergosterol was undetectable in JEY162 and that it accumulated 14alpha-methyl fecosterol, thus indicating a perturbation in the function of at least two main ergosterol biosynthesis proteins (Erg11 and Erg3). Sequence analyses of C. tropicalis ERG11 (CtERG11) and CtERG3 from JEY162 revealed a deletion of 132 nucleotides and a single amino acid substitution (S258F), respectively. These two alleles were demonstrated to be nonfunctional and thus are consistent with previous studies showing that ERG11 mutants can only survive in combination with other ERG3 mutations. CtERG3 and CtERG11 wild-type alleles were replaced by the defective genes in a wild-type C. tropicalis strain, resulting in a drug resistance phenotype identical to that of JEY162. This genetic evidence demonstrated that CtERG3 and CtERG11 mutations participated in drug resistance. During reconstitution of the drug resistance in C. tropicalis, a strain was obtained harboring only defective Cterg11 allele and containing as a major sterol the toxic metabolite 14alpha-methyl-ergosta-8,24(28)-dien-3alpha,6beta-diol, suggesting that ERG3 was still functional. This strain therefore challenged the current belief that ERG11 mutations cannot be viable unless accompanied by compensatory mutations. In conclusion, this study, in addition to identifying a novel MRR1 mutation in C. albicans, constitutes the first report on a clinical C. tropicalis with defective activity of sterol 14alpha-demethylase and sterol Delta(5,6)-desaturase leading to azole-polyene cross-resistance. PMID- 23629719 TI - In vitro and in vivo antimalarial efficacies of optimized tetracyclines. AB - With increasing resistance to existing antimalarials, there is an urgent need to discover new drugs at affordable prices for countries in which malaria is endemic. One approach to the development of new antimalarial drugs is to improve upon existing antimalarial agents, such as the tetracyclines. Tetracyclines exhibit potent, albeit relatively slow, action against malaria parasites, and doxycycline is used for both treatment (with other agents) and prevention of malaria. We synthesized 18 novel 7-position modified tetracycline derivatives and screened them for activity against cultured malaria parasites. Compounds with potent in vitro activity and other favorable drug properties were further tested in a rodent malaria model. Ten compounds inhibited the development of cultured Plasmodium falciparum with a 50% inhibitory concentration (IC50) after 96 h of incubation of <30 nM, demonstrating activity markedly superior to that of doxycycline (IC50 at 96 h of 320 nM). Most compounds showed little mammalian cell cytotoxicity and no evidence of in vitro phototoxicity. In a murine Plasmodium berghei model, 13 compounds demonstrated improved activity relative to that of doxycycline. In summary, 7-position modified tetracyclines offer improved activity against malaria parasites compared to doxycycline. Optimized compounds may allow lower doses for treatment and chemoprophylaxis. If safety margins are adequate, dosing in children, the group at greatest risk for malaria in countries in which it is endemic, may be feasible. PMID- 23629720 TI - Dormancy is not necessary or sufficient for bacterial persistence. AB - The antibiotic tolerances of bacterial persisters have been attributed to transient dormancy. While persisters have been observed to be growth inhibited prior to antibiotic exposure, we sought to determine whether such a trait was essential to the phenotype. Furthermore, we sought to provide direct experimental evidence of the persister metabolic state so as to determine whether the common assumption of metabolic inactivity was valid. Using fluorescence-activated cell sorting (FACS), a fluorescent indicator of cell division, a fluorescent measure of metabolic activity, and persistence assays, we found that bacteria that are rapidly growing prior to antibiotic exposure can give rise to persisters and that a lack of replication or low metabolic activity prior to antibiotic treatment simply increases the likelihood that a cell is a persister. Interestingly, a lack of significant growth or metabolic activity does not guarantee persistence, as the majority of even "dormant" subpopulations (>99%) were not persisters. These data suggest that persistence is far more complex than dormancy and point to additional characteristics needed to define the persister phenotype. PMID- 23629722 TI - Emergence of extended-spectrum-beta-lactamase CTX-M-2-producing Salmonella enterica serovars Schwarzengrund and Agona in poultry farms. PMID- 23629721 TI - Characterization of pKP1433, a novel KPC-2-encoding plasmid from Klebsiella pneumoniae sequence type 340. AB - The nucleotide sequence of pKP1433 (55,417 bp), a blaKPC-2-carrying plasmid from Klebsiella pneumoniae sequence type 340, was determined. pKP1433 displayed extensive sequence and structural similarities with the IncN plasmids possessing the KPC-2-encoding Tn4401b isoform. However, the replication, partitioning, and stability of pKP1433 were determined by sequences related to diverse non-IncN plasmids. PMID- 23629723 TI - Decreased vancomycin susceptibility in Staphylococcus aureus caused by IS256 tempering of WalKR expression. AB - Vancomycin-intermediate Staphylococcus aureus (VISA) strains often arise by mutations in the essential two-component regulator walKR; however their impact on walKR function has not been definitively established. Here, we investigated 10 MRSA strains recovered serially after exposure of vancomycin-susceptible S. aureus (VSSA) JKD6009 to simulated human vancomycin dosing regimens (500 mg to 4,000 mg every 12 h) using a 10-day hollow fiber infection model. After continued exposure to the vancomycin regimens, two isolates displayed reduced susceptibility to both vancomycin and daptomycin, developing independent IS256 insertions in the walKR 5' untranslated region (5' UTR). Quantitative reverse transcription-PCR (RT-PCR) revealed a 50% reduction in walKR gene expression in the IS256 mutants compared to the VSSA parent. Green fluorescent protein (GFP) reporter analysis, promoter mapping, and site-directed mutagenesis confirmed these findings and showed that the IS256 insertions had replaced two SigA-like walKR promoters with weaker, hybrid promoters. Removal of IS256 reverted the phenotype to VSSA, showing that reduced expression of WalKR did induce the VISA phenotype. Analysis of selected WalKR-regulated autolysins revealed upregulation of ssaA but no change in expression of sak and sceD in both IS256 mutants. Whole genome sequencing of the two mutants revealed an additional IS256 insertion within agrC for one mutant, and we confirmed that this mutation abolished agr function. These data provide the first substantial analysis of walKR promoter function and show that prolonged vancomycin exposure can result in VISA through an IS256-mediated reduction in walKR expression; however, the mechanisms by which this occurs remain to be determined. PMID- 23629725 TI - The double-breasted dermal flap in nipple reconstruction. PMID- 23629724 TI - Potential factors for inadequate voriconazole plasma concentrations in intensive care unit patients and patients with hematological malignancies. AB - Voriconazole plasma concentrations (VPCs) vary widely, and concentrations outside the therapeutic range are associated with either worse outcome in invasive aspergillosis (IA) or increased toxicity. The primary goal of this cohort study conducted in a real-life setting was to identify potential factors associated with inadequate VPCs in ICU patients and patients with hematological malignancies. Within a period of 12 months, trough VPCs were obtained and analyzed with high-performance liquid chromatography, and the adequate range was defined as 1.5 to 5.5 mg/liter. VPCs of <1.5 mg/liter were defined as low, whereas VPCs of >5.5 mg/liter were defined as potentially toxic. A total of 221 trough VPCs were obtained in 61 patients receiving voriconazole, and 124/221 VPCs (56%) were found to be low. Multivariate analysis revealed that low VPCs were significantly associated with clinical failure of voriconazole, prophylactic use, younger age, underlying hematological malignancy, concomitant proton pump inhibitor (PPI) (pantoprazole was used in 88% of the patients), and absence of side effects. Low VPCs remained an independent predictor of clinical failure of voriconazole. The defined adequate range was reached in 79/221 (36%) VPCs. In 18 samples (8%), potentially toxic levels were measured. Multivariate analysis revealed higher body mass index (BMI), absence of hematological malignancy, therapeutic application, and diarrhea as factors associated with potentially toxic VPCs. Neurotoxic adverse events occurred in six patients and were mostly associated with VPCs in the upper quartile of our defined adequate range. In conclusion, potential factors like younger age, prophylaxis, underlying hematological malignancy, BMI, and concomitant PPI should be considered within the algorithm of voriconazole treatment. PMID- 23629726 TI - Total synthesis and biological activity of marine alkaloid Eudistomins Y1-Y7 and their analogues. AB - Eudistomin Y class compounds are a series of beta-carbolines which was originally isolated from a marine turnicate or ascidian near the South Korea Sea. These compounds contain bromo-substituted groups, which is one of the typical characters of marine natural products. We report herein the chemical synthesis and biological evaluation of seven new beta-carboline-based metabolites, Eudistomins Y1-Y7, and their hydroxyl-methylated phenyl derivatives. Using bromo substituted tryptamines and bromo-substituted phenylglyoxals as the key intermediates, Eudistomins Y1-Y7 and their derivatives were synthesized via the acid-catalyzed Pictet-Spengler reaction and fully characterized by 1H- and 13C NMR and mass spectroscopy. Biological studies revealed that all of the compounds showed moderate growth inhibitory activity against breast carcinoma cell line MDA 231 with IC50 of 15-63 MUM and the inhibitory activities of hydroxyl-methylated phenyl products were higher than that of the corresponding natural products Eudistomins Y1-Y7. PMID- 23629727 TI - Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib resistant human lung and colorectal cancer cells. AB - The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR pathways are key regulators of proliferation and survival in human cancer cells. Selective inhibitors of different transducer molecules in these pathways have been developed as molecular targeted anti-cancer therapies. The in vitro and in vivo anti-tumor activity of pimasertib, a selective MEK 1/2 inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR inhibitor (everolimus), or with multi-targeted kinase inhibitors (sorafenib and regorafenib), that block also BRAF and CRAF, were tested in a panel of eight human lung and colon cancer cell lines. Following pimasertib treatment, cancer cell lines were classified as pimasertib-sensitive (IC50 for cell growth inhibition of 0.001 uM) or pimasertib-resistant. Evaluation of basal gene expression profiles by microarrays identified several genes that were up-regulated in pimasertib-resistant cancer cells and that were involved in both RAS/RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or regorafenib were conducted, demonstrating a synergistic effect in cell growth inhibition and induction of apoptosis with sustained blockade in MAPK- and AKT dependent signaling pathways in pimasertib-resistant human colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the combined treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor) or with sorafenib caused significant tumor growth delays and increase in mice survival as compared to single agent treatment. These results suggest that dual blockade of MAPK and PI3K pathways could overcome intrinsic resistance to MEK inhibition. PMID- 23629728 TI - Tremor of the eyes, or of the head, in Parkinson's disease? PMID- 23629729 TI - Predicting reading ability for bilingual Latino children using dynamic assessment. AB - This study investigated the predictive validity of a dynamic assessment designed to evaluate later risk for reading difficulty in bilingual Latino children at risk for language impairment. During kindergarten, 63 bilingual Latino children completed a dynamic assessment nonsense-word recoding task that yielded pretest to posttest gain scores, residuum gain scores, and modifiability scores. At the end of first grade, the same participants completed criterion reading measures of word identification, decoding, and reading fluency. The dynamic assessment yielded high classification accuracy, with sensitivity and specificity at or above 80% for all three criterion reading measures, including 100% sensitivity for two out of the three first-grade measures. The dynamic assessment used in this study has promise as a means for predicting first-grade word-level reading ability in Latino, bilingual children. PMID- 23629731 TI - Ratiometric temperature imaging using environment-insensitive luminescence of Mn doped core-shell nanocrystals. AB - We report a ratiometric temperature imaging method based on Mn luminescence from Mn-doped CdS-ZnS nanocrystals (NCs) with controlled doping location, which is designed to exhibit strong temperature dependence of the spectral lineshape while being insensitive to the surrounding chemical environment. Ratiometric thermometry on the Mn luminescence spectrum was performed by using Mn-doped CdS ZnS core-shell NCs that have a large local lattice strain on the Mn site, which results in the enhanced temperature dependence of the bandwidth and peak position. The Mn luminescence spectral lineshape is highly robust with respect to the change in the polarity, phase and pH of the surrounding medium and aggregation of the NCs, showing great potential in temperature imaging under chemically heterogeneous environment. The temperature sensitivity (DeltaIR/IR = 0.5%/K at 293 K, IR = intensity ratio at two different wavelengths) is highly linear in a wide range of temperatures from cryogenic to above-ambient temperatures. We demonstrate the surface temperature imaging of a cryo-cooling device showing a temperature variation of >200 K by imaging the luminescence of the NC film formed by simple spin coating, taking advantage of the environment insensitive luminescence. PMID- 23629734 TI - Electrophysiological features differentiating the atypical atrioventricular node dependent long RP supraventricular tachycardias. AB - BACKGROUND: Diagnosing atypical atrioventricular node-dependent long RP supraventricular tachycardias (SVTs) can be challenging. METHODS AND RESULTS: Nineteen patients with 20 SVTs (atypical atrioventricular nodal reentrant tachycardia without [n=11]/with [n=3] a bystander nodofascicular [NF] accessory pathway, orthodromic reciprocating tachycardia [ORT] using a decremental atrioventricular [permanent form of junctional reciprocating tachycardia; n=4] or NF [NF reentrant tachycardia; n=2]) accessory pathway underwent electrophysiological study. Postpacing interval (PPI)-tachycardia cycle length (TCL), corrected PPI, VA (ventriculoatrial), HA (His-atrial), AH (atrio-His) values, and responses to His-refractory ventricular premature depolarizations were studied. Compared with atrioventricular nodal reentrant tachycardia, ORT patients were younger (42+/-13 years versus 54+/-19 years; P=0.036) and were women (5/6 [83%] versus 3/14 [21%]; P=0.036); TCLs were similar (435 ms versus 429 ms; 95% confidence interval, -47.5 to 35.5). PPI-TCL was shorter for ORT (118 ms versus 176 ms; 95% confidence interval, 26.3-89.7) but only 50% had PPI-TCL <115 ms, whereas 5 of 6 (83%) had PPI-TCL <125 ms (sensitivity, 83%; specificity, 100%). Corrected PPI <110 ms, VA <85 ms, and HA <0 ms had equivalent sensitivity (67%) and 100% specificity for ORT. Compared with permanent form of junctional reciprocating tachycardia, NF reentrant tachycardia/atrioventricular nodal reentrant tachycardia had longer AH (29 ms versus 10 ms; 95% confidence interval, 3.03-35.0) or AH(SVT) A might affect breast cancer risk through the interruption of miRNA binding. PMID- 23629746 TI - [Screening for attention deficit hyperactivity disorder in adult patients in primary care]. AB - AIMS. To estimate the proportion of adult patients in primary care with a positive screening test for attention deficit hyper-activity disorder (ADHD) and to analyse their characteristics. PATIENTS AND METHODS. A cross-sectional descriptive study was performed in nine primary care clinics in the province of Tarragona. The sample consisted of 432 consecutive patients in primary care who visited for any reason, with ages ranging from 18 to 55 years. Screening for ADHD was carried out by means of the Adult ADHD Self-Report Scale (ASRS). Data about functional impact (Sheehan Disability Inventory) were obtained and a review of the patient records provided data concerning psychiatric comorbidity and the consumption of psychopharmaceuticals. RESULTS. The percentage of positive results in the screening tests was 19.9% (95% CI = 16.4-23.9%). Taking into account the sensitivity and specificity of the ASRS, the 'real' prevalence was estimated to be 12.5% (95% CI = 8.2-16.8%). None of these patients were diagnosed or treated for ADHD. Positive screening tests are associated with occupational, social and familial dysfunction, and greater perceived stress. There is also a higher level of comorbidity with affective disorders and substance abuse, as well as greater use of psychopharmaceuticals. CONCLUSIONS. Screening for ADHD in adult patients in primary care gives rise to a notably high proportion of positive screening test results, which suggests that there could be a significant prevalence of patients with ADHD. These data contrast with the absence of this diagnosis in the patient records. Further research is needed to determine the usefulness of the diagnosis of ADHD and the possible role that must be played by primary care. PMID- 23629747 TI - [In vitro effect of the S3Pvac vaccine against cysticercosis in human mononucleate cells]. AB - INTRODUCTION: Neurocysticercosis (NCC) is a parasitic infection caused by the establishment of Taenia solium cysticerci in the central nervous system. The larval stage of the parasite also affects the pig, which is the essential intermediate host for transmission. For this reason, many researchers have focused on identifying protective antigens to prevent swine cysticercosis and interrupt the transmission. These include S3Pvac vaccine antigens. Vaccine is constituted by three protective synthetic peptides: KETc1, KETc12 and GK1. AIM. To evaluate the effect of the vaccine peptides KETc1, KETc12 and GK1 in mononuclear cells of patients with neuro-cysticercosis and healthy individuals. SUBJECTS AND METHODS: Comparative, prospective, transverse study. We studied the proliferation and cytokine profile induced by the three peptides in mononuclear cells from three patients with active NCC, 16 patients by calcified NCC and 16 healthy subjects. RESULTS: KETc1 induces low levels of proliferation in cells from patients with active and controlled NCC, both in lymphocytes and in monocytes. KETc12 and GK-1 induce positive proliferation levels of monocytes in healthy subjects. CONCLUSIONS: KETc1 peptide could be used as an adjuvant in the treatment of patients with active NCC, as induced a Th2 response also GK1 peptide as stimulator of monocyte/macrophage in immunizations with other proteins. PMID- 23629748 TI - [Detection of vascular risk factors and unknown atrial fibrillation in patients hospitalised in the stroke unit]. AB - INTRODUCTION: Certain modifiable cerebrovascular risk factors, such as arterial hypertension, diabetes mellitus, dyslipidaemia and atrial fibrillation, must be recognised and controlled if a decrease in the appearance of cerebrovascular diseases is to be achieved. On some occasions the presenting symptom of these risk factors may be a stroke. PATIENTS AND METHODS: A prospective observation based study was conducted with a sample of patients who were admitted to the stroke unit of our hospital due to an acute cerebrovascular disease, namely transient ischaemic attack and ischaemic stroke, in order to determine the percentage of patients with previously undiagnosed arterial hypertension, diabetes mellitus, dyslipidaemia and atrial fibrillation. RESULTS: A total of 186 patients were selected for the study. Of the total number of patients, 24 presented unknown arterial hypertension (12.9%); 11 had unknown diabetes mellitus (5.9%); 49 had unknown hypercholesterolemia (26.3%); 15 had unknown hypertriglyceridemia (8.1%); and 22 had unknown atrial fibrillation (11.8%). Altogether 96 of them (51.6%) had at least one of these cerebrovascular risk factors. The existence of a previously undiagnosed risk factor was higher in the rural setting, in subjects who had not died at six months and in transient ischaemic attacks than in cases of ischaemic strokes. CONCLUSIONS: Over half the subjects who suffer a cerebrovascular event have a risk factor that has not previously been diagnosed. Campaigns should be carried out to implement detection of these factors, and increased efforts must be made to lower the appearance and recurrence of vascular pathologies. PMID- 23629749 TI - [Pharmacogenetics and antiepileptic drug metabolism: implication of genetic variants in cytochromes P450]. AB - INTRODUCTION: Antiepileptic drugs (AEDs) are used for the seizures control in patients with epilepsy, however 20-30% of epileptic patients are drug resistant. Several factors contributing to the variability of the AEDs response, and this variability can be partially attributed to the presence of sequence variations (polymorphisms) in genes encoding enzymes involved in the AEDs metabolism. AIM: To describe the polymorphisms in genes that encoding for proteins involved in the metabolism of some of the major AEDs, focusing on enzymes cytochrome P450 (CYP450). DEVELOPMENT: There are some polymorphisms in genes encoding proteins involved in drug metabolism, particularly enzymes of superfamily CYP450, that are already considered of clinical utility in the therapeutic management. These genetic variants contribute to the variability of the activity of metabolizing enzymes, which in turn influencing the poor or inadequate therapeutic response, as well as in the occurrence of adverse effects. CONCLUSIONS: The identification of interindividual variability in the response to AEDs may allow the personalized treatment with the aim of maximize the efficiency and minimize risk, regardless of the clinical variability and adverse effects could be manifest in a minority of the patients. PMID- 23629751 TI - [Intracranial aneurysms and epilepsy]. PMID- 23629752 TI - [Spinal muscular atrophy-type I with respiratory distress]. PMID- 23629753 TI - [Opercular syndrome caused by infarct in a single brain operculum in a patient with a history of cerebral infarction]. PMID- 23629754 TI - Role of the P2Y13 receptor in the differentiation of bone marrow stromal cells into osteoblasts and adipocytes. AB - Accumulating evidence indicates that extracellular nucleotides, signaling through purinergic receptors, play a significant role in bone remodeling. Mesenchymal stem cells (MSCs) express functional P2Y receptors whose expression level is regulated during osteoblast or adipocyte differentiation. P2Y13 -deficient mice were previously shown to exhibit a decreased bone turnover associated with a reduction in the number of both osteoblasts and osteoclasts on the bone surfaces. We therefore examined whether P2Y13 R activation was involved in the osteogenic differentiation of MSC. Our study demonstrated that ADP stimulation of P2Y13 R(+/+) (but not P2Y13 R(-/-) ) adherent bone marrow stromal cells (BMSCs) increased significantly the formation of alkaline phosphatase-colony-forming units (CFU-ALP) as well as the expression of osteoblastic markers (osterix, alkaline phosphatase, and collagen I) involved in the maturation of preosteoblasts into osteoblasts. The number of CFU-ALP obtained from P2Y13 R(-/-) BMSC and the level of osteoblastic gene expression after osteogenic stimulation were strongly reduced compared to those obtained in wild-type cell cultures. In contrast, when P2Y13 R(-/-) BMSCs were incubated in an adipogenic medium, the number of adipocytes generated and the level of adipogenic gene expression (PPARgamma2 and Adipsin) were higher than those obtained in P2Y13 R(+/+) MSC. Interestingly, we observed a significant increase of the number of bone marrow adipocytes in tibia of P2Y13 R(-/-) mice. In conclusion, our findings indicate that the P2Y13 R plays an important role in the balance of osteoblast and adipocyte terminal differentiation of bone marrow progenitors. Therefore, the P2Y13 receptor can be considered as a new pharmacological target for the treatment of bone diseases like osteoporosis. STEM Cells 2013;31:2747-2758. PMID- 23629755 TI - Spectroscopic studies of amino acid ionic liquid-supported Schiff bases. AB - Amino acid ionic liquid-supported Schiff bases, derivatives of salicylaldehyde and various amino acids (L-threonine, L-valine, L-leucine, L-isoleucine and L histidine) have been investigated by means of various spectroscopic techniques (NMR, UV-Vis, IR, MS) and deuterium isotope effects on 13C-NMR chemical shifts. The results have shown that in all studied amino acid ionic liquid-supported Schiff bases (except the L-histidine derivative) a proton transfer equilibrium exists and the presence of the COO- group stabilizes the proton transferred NH form. PMID- 23629756 TI - Folate-based radiotracers for PET imaging--update and perspectives. AB - The folate receptor (FR) is expressed in many tumor types, among those ovarian and lung cancer. Due to the high FR affinity of folic acid, it has been used for targeting of FR-positive tumors, allowing specific delivery of attached probes to the malignant tissue. Therefore, nuclear imaging of FR-positive cancer is of clinical interest for selecting patients who could benefit from innovative therapy concepts based on FR-targeting. Positron emission computed tomography (PET) has become an established technique in clinical routine because it provides an increased spatial resolution and higher sensitivity compared to single photon emission computed tomography (SPECT). Therefore, it is of critical importance to develop folate radiotracers suitable for PET imaging. This review article updates on the design, preparation and pre-clinical investigation of folate derivatives for radiolabeling with radioisotopes for PET. Among those the most relevant radionuclides so far are fluorine-18 (t(1/2): 110 min, E(av) beta+: 250 keV) and gallium-68 (t(1/2): 68 min, E(av) beta+: 830 keV). Recent results obtained with new PET isotopes such as terbium-152 (t(1/2): 17.5 h, Ebeta+: 470 keV) or scandium-44 (t(1/2): 3.97 h, (Eav) beta+: 632 keV) are also presented and discussed. Current endeavors for clinical implementation of PET agents open new perspectives for identification of FR-positive malignancies in patients. PMID- 23629757 TI - Identification of electronic and structural descriptors of adenosine analogues related to inhibition of leishmanial glyceraldehyde-3-phosphate dehydrogenase. AB - Quantitative structure-activity relationship (QSAR) studies were performed in order to identify molecular features responsible for the antileishmanial activity of 61 adenosine analogues acting as inhibitors of the enzyme glyceraldehyde 3 phosphate dehydrogenase of Leishmania mexicana (LmGAPDH). Density functional theory (DFT) was employed to calculate quantum-chemical descriptors, while several structural descriptors were generated with Dragon 5.4. Variable selection was undertaken with the ordered predictor selection (OPS) algorithm, which provided a set with the most relevant descriptors to perform PLS, PCR and MLR regressions. Reliable and predictive models were obtained, as attested by their high correlation coefficients, as well as the agreement between predicted and experimental values for an external test set. Additional validation procedures were carried out, demonstrating that robust models were developed, providing helpful tools for the optimization of the antileishmanial activity of adenosine compounds. PMID- 23629758 TI - Sesquiterpenoids from the herb of Leonurus japonicus. AB - Two new sesquiterpenoids, (-)-(1S*,2S*,3R*)-3-ethoxycupar-5-ene-1,2-diol (1) and (-)-(1S*,4S*,9S*)-1,9-epoxybisabola-2,10-diene-4-ol (2), along with six known compounds 3-8, were isolated from the EtOH extract of the herb of Leonurus japonicus. Their structures were elucidated by physical and spectroscopic analysis. In the in vitro assays, compounds 7 and 8 showed obvious antibacterial activity against several bacteria strains, while compound 3 significantly inhibited abnormal increase of platelet aggregation induced by ADP. PMID- 23629759 TI - Novel substituted heteroaromatic piperazine and piperidine derivatives as inhibitors of human enterovirus 71 and coxsackievirus a16. AB - A series of substituted heteroaromatic piperazine and piperidine derivatives were found through virtual screening based on the structure of human enterovirus 71 capsid protein VP1. The preliminary biological evaluation revealed that compounds 8e and 9e have potent activity against EV71 and Coxsackievirus A16 with low cytotoxicity. PMID- 23629761 TI - How do multivalent glycodendrimers benefit from sulfur chemistry? AB - Sulfur-containing glycodendrimers have steadily emerged over a few decades and this review describes the first survey of this field. Although the contribution of sulfur chemistry to glycodendrimers could be seen at the moment as a development of various linking strategies, there is more than synthesis because the presence of sulfur itself modulates unique photophysical and electrochemical properties. This fact has long been recognized in materials science, for instance. Emphasis on the numerous advantages of sulfur in glycosylated dendrimers is thus put forward in this review. The synergy between sulfur, dendrimers, and carbohydrate chemistry conveys novel synthetic avenues, properties, and applications toward innovative perspectives in chemistry, glycobiology, materials science and nanoscience, with a particular significance for biosensors. PMID- 23629762 TI - Cu doped V2O5 flowers as cathode material for high-performance lithium ion batteries. AB - Hierarchical Cu doped vanadium pentoxide (V2O5) flowers were prepared via a simple hydrothermal approach followed by an annealing process. The flower precursors are self-assembled with 1D nanobelts surrounding a central core. The morphological evolution is investigated and a plausible mechanism is proposed. As the cathode material for lithium ion batteries, the Cu doped V2O5 samples exhibit improved electrochemical performance compared to the un-doped ones. Among them Cu0.02V1.98O5 delivered higher reversible specific capacities, better cycling stabilities and excellent rate capabilities, e.g. 97 mA h g(-1) at 20.0 C. PMID- 23629763 TI - Critical comments on "One molecule, two atoms, three views, four bonds?". PMID- 23629764 TI - A novel approach to treat residual peridevice leakage after left-atrial appendage closure. AB - Left atrial appendage (LAA) device closure has emerged as an alternative treatment to conventional anticoagaluation therapy for the prevention of thromboembolic events in patients with atrial fibrillation. In 8-10% of patients with interventional LAA obliteration, relevant residual flow into the LAA persists due to incomplete seal. We present two cases in whom for the first time two different devices were placed to complete occlusion after residual leak with a first device. PMID- 23629765 TI - [Highlights from yesterday in the Clinical Monthly of Ophthalmology]. PMID- 23629766 TI - [Highlights from today's monthly on clinical ophthalmology ]. PMID- 23629767 TI - Editorial: IgG4-related inflammatory disease--a new entity. PMID- 23629768 TI - [Lens exchange for subluxation of posterior chamber lenses implanted in the capsular bag or in the ciliary sulcus]. AB - PURPOSE: There are an increasing number of patients with decreased vision due to dislocated posterior chamber lenses, with pseudoexfoliation being the main risk factor. Various techniques for refixation of the subluxated posterior chamber IOL have been described. Experience with our technique of IOL-explantation, anterior vitrectomy and implantation of an Artisan anterior chamber lens are presented. PATIENTS AND METHODS: In a retrospective study design all lens exchanges with implantation of an Artisan anterior chamber lens performed between 2003 and 2012 are analyzed. The study included 65 eyes of 61 patients (age 79.6 +/- 9.2 years: 43-98). The majority of eyes (46/65; 70.8%) had Sundown Syndrome (late in-the-bag intraocular lens dislocation), in 19 eyes the posterior chamber lens was implanted primary or secondary into the ciliary sulcus. In the 46 eyes with Sundown Syndrome cataract surgery with implantation of a posterior chamber lens in the capsular bag was performed 7.4 +/- 3.7 (1-22) years before subluxation within the bag. Pseudoexfoliation was the main risk factor in 42/46 (91.2%) of these eyes. A capsular tension ring (CTR) was implanted during cataract surgery in 34/46 (73.9%) eyes. The 34 IOLs with a CTR luxated significantly earlier (p < 0.02 Mann-Whitney U) than the 12 IOLs without a CTR (6.6 +/- 3.6 years; median 5.8 vs. 9.4 +/- 3.1 years; median 9.2). RESULTS: The average visual gain was 0.2 logMAR in the group of luxated capsular bag lenses and 0.12 logMAR in the group of luxated sulcus lenses. Postoperative IOP decompensation was seen in 17/65 (26.2%) eyes (requiring IOP-lowering surgery in 8 eyes), 7 eyes developed corneal decompensation, 5 eyes had central retinal vein occlusion and one eye developed postoperative endophthalmitis. CONCLUSIONS: Lens exchange with implantation of an Artisan anterior chamber lens has become a routine procedure to improve vision in patients with subluxated IOLs. Postoperative IOP decompensation and vascular problems are the major complications. PMID- 23629769 TI - Complications after prosthetic iris implantation in a case of traumatic aniridia. PMID- 23629770 TI - Impact of preoperative and intraoperative factors in cataract surgery. AB - BACKGROUND: Cataract surgery is the most common procedure in ophthalmology. However the surgical outcome depends on various factors. The impact of preoperative and intraoperative factors on the surgical procedure were investigated. PATIENTS AND METHODS: Prospective consecutive study of eyes that underwent cataract surgery. The studied parameters included: age, body mass index (BMI), medical history, type of anaesthesia, preoperative patient's anxiety level (scale from 0 to 10), spherical equivalent (SE), keratometry, axial length (AL), time and percentage of ultrasounds (US), intraoperative complications, duration of surgery. The eyes were separated into two groups: the "no complication group" and the "complication group". RESULTS: 529 eyes were included. Age averaged 75.5 years old (44; 100), mean BMI (kg/m2) was 26.3 (13.7; 45.2), patients had cardiovascular history in 61.05% of cases, the type of anaesthesia used was topical in 93.4%, subtenon in 4.7% and general in 1.9% of cases. Mean preoperative anxiety was 4.04 (0; 10), mean preoperative SE was -0.12 (-10; 7.5), mean keratometry (diopters) was 43.88 (39.5; 49), mean AL (mm) was 23.29 (20.91; 29.78), mean time of US (minutes) was 1.89 (0.08; 9.2), mean percentage of US was 10.5 (2; 30) and mean surgical duration (minutes) was 17.15 (5; 50). There was a statistically significant difference (p < 0.0001 in all cases) between both groups in the preoperative anxiety, the time of US and the duration of surgery. The "complication group" had higher scores in all cases as well as more proportion of patients with cardiovascular history. There was no statistically significant difference between both groups for the BMI, SE, AL, keratometry and percentage of US. CONCLUSIONS: The preoperative anxiety level and a cardiovascular medical history together with a prolonged time of US and a longer surgical duration seem to provide more complications during the surgery. The BMI, SE, AL and keratometry did not influence the surgical procedure. PMID- 23629771 TI - [The calculation of the intraocular lens power based on raytracing methods: a systematic review]. AB - A problem in cataract surgery consists in the preoperative identification of the appropriate intraocular lens (IOL) power. Different calculation approaches have been developed for this purpose; raytracing methods represent one of the most exact but also mathematically more challenging methods. This article gives a systematic overview of the different raytracing calculations available and described in the literature and compares their results. It has been shown that raytracing includes physical measurements and IOL manufacturing data but no approximations. The prediction error is close to zero and an essential advantage is the applicability to different conditions without the need of modifications. Compared to the classical formulae the raytracing methods are more precise overall, but due to the various data and property situations they are hardly comparable yet. The raytracing calculations represent a good alternative to the 3rd generation formulae. They minimize refractive errors, are wider applicable and provide better results overall, particularly in eyes with preconditions. PMID- 23629772 TI - Central corneal regularization--optimization of uncorrected visual acuity in keratoconus patients. AB - BACKGROUND: Combined excimer laser correction and corneal cross-linking is a promising concept in treating keratoconus patients. Central corneal regularization represents advanced topography-guided custom ablation for ectatic corneas, aiming at correcting irregular astigmatism and at increasing the optical regularity of the corneal surface. PATIENTS AND METHODS: In a prospective single centre study, 10 keratoconus patients underwent combined treatment with corneal cross-linking and central corneal regularization by an iRES-Laser. Uncorrected visual acuity at 1 and 3 months postoperatively represented the primary endpoint. RESULTS: Mean preoperative uncorrected decimal visual acuity was 0.15 (+/- 0.28 standard deviation). Mean postoperative visual acuity was 0.28 (+/- 0.47) at one month and 0.24 (+/- 0.25) at three months, respectively. CONCLUSIONS: Combined corneal cross-linking and central corneal regularization treatment has the potential to achieve a clinically significant improvement of uncorrected visual acuity. PMID- 23629773 TI - Moving from a mechanical microkeratome to a femtosecond laser for LASIK to correct astigmatic patients: clinical outcomes of a retrospective, consecutive, comparative study. AB - BACKGROUND: To evaluate outcomes after optimized laser in situ keratomileusis (LASIK) for astigmatism correction with flap created by a mechanical microkeratome or a femtosecond laser. PATIENTS AND METHODS: In this retrospective study, a total of 102 eyes of 71 consecutive patients were enrolled undergoing optimized LASIK treatments using the Allegretto laser system (WaveLight Laser Technologie AG, Erlangen, Germany). A mechanical microkeratome for flap creation was used (One Use, Moria(r)) in 46 eyes (31 patients, spherical equivalent [SE] 4.44 D +/- 2.4) and a femtosecond laser was used (LDV, Ziemer(r)) in 56 eyes (40 patients, spherical equivalent [SE] -3.07 D +/- 3.3). The two groups were matched for inclusion criteria and were operated under similar conditions by the same surgeon. RESULTS: Overall, the preoperative spherical equivalent was -9.5 diopters (D) to +3.37 D; the preoperative manifest astigmatism was between -1.5 D and -3.5 D. At 6 months postoperatively, the mean postoperative uncorrected distance visual acuity (UDVA) was 0.93 +/- 0.17 (range 0.4 to 1.2) in the Moria group and 1.0 +/- 0.21 (range 0.6 to 1.6) in the Femto group, which was statistically significant (p = 0.003). Comparing the cylinder power there was a statistical difference between the two groups (p = 0.0015). CONCLUSIONS: This study shows that the method of flap creation has a significant impact on postoperative astigmatism with a significantly better postoperative UDVA in the Femto group. These findings suggest that the femtosecond laser provides a better platform for LASIK treatment of astigmatism than the commonly used microkeratome. PMID- 23629774 TI - [Cataract development following posterior chamber phakic intraocular lens implantation in eyes with high myopia]. PMID- 23629775 TI - [Methotrexate treatment in severe chronic ocular graft versus host disease (GvHD)]. PMID- 23629776 TI - Ligneous conjunctivitis in a young patient with homozygous K19E plasminogen gene mutation: a diagnostic and therapeutic challenge. PMID- 23629777 TI - A field report on self-screening visual acuity using a computerized vision screener. AB - BACKGROUND: Large-scale examinations are costly and time consuming. Costs could be reduced by asking patients to carry out tests by themselves. This study aimed to gain practical experience on how patients handle self-administered acuity tests. MATERIAL AND METHODS: We developed two computerized self-test acuity screening devices consisting out of a commercially available vision screener, an answering box and a PC. The answering box served to record the responses of the participants and to present verbal instructions to the participants. Participants took acuity tests for far (5 m, OS, OD, OU) and an acuity test for near (40 cm, OU) using the self-test screener. For the reason of privacy personal data like age, gender and habitual correction was entered on a separate PC. The devices were installed in two different locations and run without supervision. RESULTS: Personal data records of 2528 participants (4% women) were collected in both locations. The age in 45% of the participants ranged between 41 and 50 years. 31% of the participants declared to wear spectacles and 3% contact lenses. 66% of participants declared not to need a correction. A total of 1078 participants completed four acuity tests (OD far, OS far, OU far, OD near) using the self-test screening device. Depending on the acuity test and location, the average duration required to complete one acuity test ranged between 29.7 s to 39.1 s. The total duration for completing the four acuity tests was on average 133 +/- 46 s. CONCLUSIONS: The duration for completing the acuity tests is considered as being short. Made experience speaks in favor of feasibility of self-tests in acuity screening. PMID- 23629778 TI - [Transscleral cyclophotocoagulation as primary surgical intervention in glaucoma]. AB - BACKGROUND: The gold standard of surgical interventions in medically uncontrolled glaucoma is trabeculectomy. Cyclophotocoagulation is often performed only as a secondary/tertiary surgery. Since trabeculectomy demands a high degree of postsurgical compliance to achieve satisfying results, some patients do not qualify for trabeculectomy. PATIENTS AND METHODS: During cyclophotocoagulation, the ciliary processes were coagulated using a transscleral diode laser. 49 eyes of 47 patients (25 women and 22 men) were included in our study. Patients were regularly followed up for 24 months. During follow-up, IOP, best corrected visual acuity and number of antiglaucoma drugs were recorded. RESULTS: The mean age was 69.27 +/- 14.45 years. The diagnosis was open-angle glaucoma in 15 eyes, pseudoexfoliative glaucoma in 12 eyes, secondary rubeotic glaucoma in 7 eyes and secondary glaucoma without further specification in 15 eyes. On average, cyclophotocoagulation reduced intraocular pressure by 14.45 +/- 11.77 mmHg ( 42.7%, p < 0.001). Medication could be reduced by 1.31 +/- 1.27 (-52%, p < 0.001). On average, visual acuity deteriorated by 0.383 LogMAR (+/- 0.848, p = 0.004). CONCLUSION: For selected glaucoma patients, cyclophotocoagulation could be an option as primary surgical intervention to lower intraocular pressure. PMID- 23629779 TI - [Analysis of retinal vein motion in glaucoma patients]. AB - BACKGROUND: Analysis of retinal vein amplitude in eyes of glaucoma patients. PATIENTS AND METHODS: Motion of retinal veins was captured by Retinal Vessel Analyzer in duration of 30 seconds. Inferotemporal vein segments of 500 micrometers length in the immediate vicinity of, as well as away from the optic disc were chosen. Time behavior of the average segment diameter was analyzed by the self made software: dominating frequency (heart rate) was determined by Fourier analysis, and based on this an average pulse form was produced. Difference between the highest and lowest diameter point was the subject of analysis in 25 eyes of 25 glaucoma patients and 25 age-sex-matched healthy controls. RESULTS: Pulse amplitude of retinal veins in healthy eyes was higher than in glaucoma patients: in the optic disc vicinity the pulse amplitude relative to baseline was 2.6 +/- 2.1% in control eyes and 1.4 +/- 0.8% in glaucoma eyes (t-test, p = 0.009). Away from the disc, it was 1.7 +/- 1.0% and 1.1 +/- 0.5% respectively (p = 0.01). CONCLUSIONS: Retinal veins in glaucoma eyes demonstrate lower pulse amplitudes than healthy eyes, indicating disturbance in venous outflow and increased intraluminal venous pressure. PMID- 23629780 TI - Reattachment of Descemet's membrane using C3F8 gas in an eye with a Baerveldt aqueous shunt. AB - Descemet's membrane detachment (DMD) is a rare complication following cataract and glaucoma surgery as well as lamellar graft procedures. DMD can lead to blurry vision, halos and severe visual loss. Clinically, when there is a large central detachment, a double anterior chamber is seen to form. In this scenario, surgical repair may be needed. Repair of localised DMD may be achieved by injection of gases such as perfluoropropane (C3F8) and sulfurhexafluoride (SF6) or sterile air. The effect of a functioning Baerveldt tube in situ during these injections has not been reported. We report a case of DMD repair in an eye with a Baerveldt aqueous shunt. PMID- 23629781 TI - Isolated Horner syndrome and orbital hemangioma. PMID- 23629782 TI - Bisphosphonate-associated orbital inflammatory disease and uveitis anterior--a case report and review. AB - BACKGROUND: Drug-induced cases of orbital inflammation and uveitis are rare.We present a bisphosphonate-induced case of unilateral orbital inflammation and bilateral anterior uveitis. PATIENTS AND METHODS: A 75-year-old female presents because of pain and swelling around her left eye with an onset 2 days after an intravenous zoledronic acid therapy for osteoporosis. Examination reveals reduced visual acuity of 0.2, proptosis of 4 mm, marked conjunctival chemosis and hyperemia, ophthalmoplegia and choroidal folds in the left eye and a bilateral anterior uveitis. CT and MRI scans show signs of diffuse pre- and postseptal inflammation in the left orbit. RESULTS: Initiation of intravenous methylprednisolon leads to a complete regression of the inflammatory process within days. This causality between the therapy with bisphosphonates and an orbital inflammation as well as an anterior uveitis corresponds to the literature. Drug-induced cases of orbital inflammation and uveitis have also been reported following use of antiinfectious drugs, biologica and vaccines. CONCLUSIONS: Iatrogenic causes should be considered in the differential diagnosis of orbital inflammations, scleritis and uveitis. Findings are mostly reversible after discontinuation of the drug and therapy of inflammation. PMID- 23629783 TI - [IgG4-related orbital inflammation]. AB - INTRODUCTION: Serum immunoglobulin G4 (IgG4)-related systemic disease is a newly found entity and should be considered as a further differential diagnosis to the big pool of unspecific orbital inflammation. We describe clinical appearance and treatment options. PATIENTS AND METHODS: We retrospectively analyzed all patients with the diagnosis IgG4-related orbital inflammation who were examined in our outpatient clinic. We compared symptoms, clinical and histological findings and therapy. RESULTS: In the last 17 months five patients were diagnosed with IgG4 related orbital disease. Biopsies were performed of most affected areas as seen in the computerised tomography scan. Histology revealed marked infiltration with IgG4-positive plasma cells. Serum IgG4-levels were partly significantly elevated. Based on these findings diagnosis of an IgG4-related disease was agreed and treatment with oral prednisone installed. In one patient a therapy with Rituximab was successfully started. CONCLUSION: Extended unspecific orbital inflammation, especially when bilateral and associated with systemic disease should be considered to be IgG4-related. Histological proof of IgG4-positive plasma cells and elevated IgG4 serum levels do confirm this diagnosis. Strict follow-up and interdisciplinary work-up is recommended. PMID- 23629784 TI - Giant cell arteritis causing retinal and posterior carotid circulation strokes. PMID- 23629785 TI - [Hypoglobus--illusive or real? Etiologies of vertical globe displacement in a tertiary referral centre]. AB - BACKGROUND: While exophthalmus is quantifiable with readily available measurement tools, there is no such tool for hypoglobus/hyperglobus. Despite its possible life-threatening causes only few articles address the etiologies of vertical globe displacement in the current literature. The aim of our study was to describe etiologies of hypoglobus and to analyze the ratio of malignant diseases. PATIENTS AND METHODS: 3000 portrait photographs taken in our ophthalmology department between 2005 and 2009 were retrospectively screened for patients with vertical globe displacement. Pictures were assessed by three independent ophthalmology-trained observers and matched to the diagnosis based on patient records. RESULTS: 95 patients with supposed vertical globe displacement were identified. Vertical globe displacement was due to an intracranial or orbital disease in 45 patients including 6 patients with a malignant disease. Additional 10 patients had thyroid associated orbitopathy. 11 patients turned out to have mere facial asymmetry, 26 patients had strabism and four patients had an ocular prosthesis. CONCLUSIONS: The etiologies of hypoglobus ranges from orbital fractures to life-threatening malignant tumors. Distinction between apparent and true hypoglobus can be challenging. PMID- 23629786 TI - [Early surgical rehabilitation due to modified exenteration technique]. AB - BACKGROUND: Orbital exenteration is a life intruding surgical procedure with severe functional, aesthetic and psychological consequences. Apart from the correct tumor treatment, early aesthetic and psychosocial rehabilitation is crucial for the well-being of the patient. We discuss reasons leading to exenteration and present new surgical techniques. Local flaps in the anterior socket improve wound healing allowing early placement of the prosthesis and therefore faster social rehabilitation of the patient. PATIENTS AND METHODS: Between 2007 and 2011 seven patients with malignant orbital tumors (1 * plasmocytoma, 1 * melanoma, 1 * sarcoma, 1 * squamous cell carcinoma and 3 * basal cell carcinoma) received a radical orbital exenteration at the Department of Ophthalmology of the Zurich University Hospital. The medical histories were evaluated according to reasons for exenteration, surgical techniques and postoperative follow-up. Reconstruction of the anterior socket border succeeded using local flaps (Mustarde, Glabella and combined with further modified pedicled local full thickness skin flaps). The central defects were covered with split skin graft from the thigh. RESULTS: Three weeks after surgery the anterior border of the socket was completely healed without problems by local flaps with good blood supply. This allowed the early prosthetic fitting and wearing as well as quick social rehabilitation of the patient. CONCLUSIONS: The use of local flaps improves wound healing even in anticoagulated patients. This reduces the time of hospitalization and rehabilitation, and allows an early, satisfactory, social reintegration of the patient. PMID- 23629787 TI - Treatment of epiphora in connection with endolacrimal surgery using trephines: new and overview data. AB - BACKGROUND: To provide new and to summarize published data on endolacrimal surgery with Piffaretti's trephines, in particular in patients having patent lacrimal drainage system (syringing) and epiphora resistant to medical treatments. PATIENTS AND METHODS: From two tertiary referral centers (Basel/Switzerland; Belo Horizonte/Brazil), 126 patients undergoing endolacrimal surgery with Piffaretti's trephines, combined, when clinically indicated, with other procedures known to improve epiphora (canthoplasty/pexie and/or conjunctivochalasisplasty). RESULTS: I) A study (Basel) in 17 patients showed one year after surgery marked epiphora symptoms' improvement in 88% (15/17) of patients, 65% (11/17) being symptom-free. II) Unpublished data (Belo Horizonte) in 42 patients found 81% (34/42) symptom-free six-months after surgery. Dacryoscintigraphy illustrated postoperative tears' clearance improvement. III) Unpublished data (Belo Horizonte) in 45 patients solely undergoing endolacrimal surgery for complete ductal obstruction found symptom-free, six-months after surgery, 27% (8/30) of patients with preoperatively enlarged lacrimal sac and 80% (12/15) with none-enlarged sac (p < 0.01, Fisher's test). IV) A study (Basel) in 22 epiphora patients reported no correlation (p = 0.62, rho -0.11, Spearman) between preoperative basal Schirmer's test II (oxybuprocain-HCL 0.4%) values and one-year surgical outcome. Patients with preoperative Schirmer's test's values <= or > 6 mm had similar mean postoperative symptoms' improvement (82 +/- 30%, n = 11 vs. 76 +/- 34%, n = 11, p = 0.97, Mann-Whitney). CONCLUSIONS: Endolacrimal surgery with Piffaretti's trephines, sometimes combined, when clinically indicated, with other procedures also known to ameliorate epiphora, can in particular improve (different conditions, surgeons, centers) epiphora's symptoms resistant to medical treatments in patients with patent lacrimal drainage system, and this apparently, even when pre-operative basal Schirmer-test values are low. By enlarged lacrimal sac, outcome is poor. PMID- 23629788 TI - Unusually long foreign body of the conjunctival fornix in a child overlooked by 3 ophthalmologists. PMID- 23629789 TI - Intravitreal anti-VEGF therapy for retinal macroaneurysm. AB - BACKGROUND: We evaluated the effect of intravitreal anti-vascular endothelial growth factor therapy using bevacizumab or ranibizumab for retinal macroaneurysms with macular exudation. METHODS: In a retrospective interventional case series patients with retinal macroaneurysms were treated with either 1.25 mg intravitreal bevacizumab or 0.5 mg ranibizumab as first-line therapy. Patients were imaged by fluorescein angiography and optical coherence tomography. Retreatment was performed in case of persistent intraretinal or subretinal fluid in optical coherence tomography. RESULTS: Ten patients (10 eyes) with macroaneurysm involving the macula were treated with an average of 3.0 intravitreal anti-vascular endothelial growth factor injections. Mean best corrected visual acuity of all patients improved by 17 letters from baseline to the last follow-up visit. In 7 out of 10 patients, the fovea was affected by a secondary edema. In cases with foveal involvement, central retinal thickness decreased from 366 um at baseline to 266 um at the last follow-up visit. In the course of treatment 8 out of 10 patients showed evidence of marked regression of macular exsudation. CONCLUSION: Intravitreal anti-vascular endothelial growth factor therapy appears to be a promising treatment alternative to laser treatment in cases of retinal macroaneurysms with macular exudation. PMID- 23629790 TI - [Dexamethason implant in the treatment of macular edema in retinal vein occlusion and intraocular inflammatory disease]. AB - BACKGROUND: The efficacy of a single dose of Ozurdex(r) was evaluated over a 6 month period in eyes with macular edema due to retinal vein occlusion and intraocular inflammatory disease. HISTORY AND SIGNS: 20 eyes of 20 consecutive patients with macular edema received a single injection of Ozurdex(r) (intravitreal dexamethasone implant 0.7 mg). Patients with branch retinal vein occlusion (n = 11), central retinal vein occlusion (n = 6), non-infectious posterior uveitis (n = 1) and Irvine-Gass Syndrome (n = 2) were included. In 10 patients Ozurdex(r) was used as the first treatment, 10 patients had undergone previous treatments for macular edema. The mean duration from the symptoms to the initiation of the treatment was 14.2 (1-60) months. The follow-up measurements were performed 1, 3 and 6 months after treatment. The main interest of the study was the visual and structural development over the duration of 6 months after a single dose of Ozurdex(r) with outcome measures including changes in best corrected visual acuity and central retinal thickness. THERAPY AND OUTCOME: At baseline, the mean best-corrected visual acuity of all patients was 50 (+/- 16) ETDRS letters and the mean central retinal thickness was 632 (+/- 168.3) microns. Mean follow-up time was 3.4 (+/- 1.5) months and 7 patients dropped out during the follow-up period (4 patients after 3 months, additional 3 patients after 6 months). One month after treatment, 14 out of 20 patients (70%) showed a complete regression of macular edema, and in 6 cases (30%) it was partially recurrent. The mean best-corrected visual acuity improved to 56 (+/- 20.8) ETDRS. Central retinal thickness showed a mean decrease to 278 (+/- 84.9) microns. 6 months after treatment, recurrence was observed in 9 cases out of the remaining 13 patients (69.2%). In 3 cases, macular edema persisted (23.1%) and in one case (7.7%) the macula remained dry. The mean best-corrected visual acuity was 55 (+/- 13.9) ETDRS letters. The mean central retinal thickness decreased to 603 (+/- 174.6) microns. CONCLUSIONS: Ozurdex(r) showed a good effect in the treatment of macular edema one month after its application, namely a temporary decrease in central retinal thickness and a corresponding increase in best-corrected visual acuity. 6 months after treatment, the recurrence rate was high, and only one person with a branch retinal vein occlusion remained relapse-free over the entire follow-up. Based on our data, the patients should be checked at the latest after 3 months and then monthly in order to detect relapse in time and to initiate another treatment if needed. PMID- 23629791 TI - Three years follow-up results of ranibizumab treatment for choroidal neovascularization secondary to pathologic myopia. AB - BACKGROUND: Choroidal neovascularization (CNV) secondary to pathological myopia (PM) is one of the main causes of severe visual impairment in patients younger than 50 years. In this analysis we want to demonstrate the long-term results of Ranibizumab treating CNV secondary to PM. PATIENTS AND METHODS: We retrospectively analysed 15 treatment naive eyes of 13 patients (10 women, 3 men, mean age: 61.5, SD 11.6, range: 41-80) with visual impairment due to CNV secondary to PM, which were treated with ranibizumab. Criteria for re-treatment were reduction of visual acuity and/or activity in OCT or fluorescence angiography. RESULTS: We applied a mean of 3 injections (standard deviation [SD] 2.5, range: 1-8) ranibizumab during a mean period of 39.6 months (SD 5.3, range: 31-52). The spherical equivalent was -12.4 diopters +/- 4.1 (range -7.5 to -20.5 diopters). Before the first injection mean visual acuity (logMAR) was 0.69 +/- 0.26. After one month visual acuity improved to 0.39 +/- 0.23 (p = 0.002), after 3 months to 0.30 +/- 0.22 (p = 0.002) and after 6 months up to 0.30 +/- 0.22 (p = 0.002). After 12 months visual acuity was 0.30 +/- 0.22 (p = 0.001) and after 24 months 0.30 +/- SD 0.24 (p = 0.001). 11 patients reached a follow-up of at least 36 months and visual acuity was 0.30 +/- 0.13 (p = 0.001). CONCLUSIONS: Treating CNV secondary to PM with ranibizumab during a follow-up of 36 months, we found considerable improvement of visual acuity. Compared to treatment of CNV secondary to exudative age-related macular degeneration, CNVs secondary to PM seem to respond faster to ranibizumab treatment and less injections are neccessary to reach stabilization. PMID- 23629792 TI - [Bevacizumab and Ranibizumab for macular edema due to retinal vein occlusions]. AB - BACKGROUND: The effect of Bevacizumab (BE) (Avastin(r)) or Ranibizumab (RA) (Lucentis(r)) on the visual acuity (VA) and on the central foveal thickness (CFT) was evaluated in macular edema due to retinal vein occlusion. PATIENTS AND METHODS: Eyes with a macular edema due to a central retinal vein occlusion or to a branch retinal vein occlusion were considered if at least 3 intravitreal injections of Bevacizumab (1.25 mg) or Ranibizumab (0.5 mg) had been performed. The visual acuity with ETDRS and the central foveal thickness with spectral optical coherence tomography (OCT) were measured. The 3-months follow-up and, if further injections were necessary, the 6-months follow-up were evaluated. RESULTS: After 3 months a significant improvement of the visual acuity was measured in both groups (p < 0.001) while during the same period the mean central foveal thickness diminished significantly (p < 0.001). At the 3-months follow-up there were no significant differences between the two groups for the mean visual acuity and for the mean central foveal thickness. The treatment was continued in 36 eyes and the visual acuity and the central foveal thickness were compared between the 3-months and the 6-months follow-up. No further improvements of the visual acuity or of the central foveal thickness were measured in both groups. A relapse of the macular edema was diagnosed in 30 eyes without a significant difference in the Bevacizumab group compared to the Ranibizumab group. CONCLUSION: Intravitreal injections of Bevacizumab and Ranibizumab improved the visual acuity and the central foveal thickness in macular edema due to retinal vein occlusion at 3 months. A further improvement was not measured if the treatment was prolonged to 6 months. There were no significant differences measured between Bevacizumab and Ranibizumab. The ratio of relapses is important to note. PMID- 23629793 TI - Anatomical and functional results of primary pars plana vitrectomy in rhegmatogenous retinal detachment. AB - BACKGROUND: It was the aim of this retrospective study to analyse the anatomical success rate and functional outcome of patients with rhegmatogenous retinal detachments treated primarily by pars plana vitrectomy (PPV). MATERIAL, PATIENTS AND METHODS: 157 of 200 eyes (79%, 89 phakic (57%), 67 pseudophakic (43%), 1 aphakic) with rhegmatogenous retinal detachment were treated by primary pars plana vitrectomy. 132 cases (84%) completed 6 months, 131 (83%) 12 months, and 108 cases (69%) 24 months of follow-up. Selection of surgical methods was guided by recommendations from the SPR study. Different from these recommendations, phakic eyes were treated by primary PPV if the chance of successful scleral buckling was estimated to be < 90%. RESULTS: Initial retinal attachment was achieved in all eyes. In 4 eyes peripheral tractional detachment presented during silicon removal. A second surgical intervention for the treatment of re detachment became necessary in 8 eyes during follow-up. The rate of permanent single-intervention (except silicon removal) attachment was 92.4%. Finally the retina was completely attached in all eyes. Visual acuity improved from a preoperative level of logMAR 1.01 to 0.48 at month 6, 0.40 at month 12 and 0.33 at month 24. Mean final visual acuity at month 24 was 0.32 in phakic eyes and 0.35 in pseudophakic eye (difference not significant). Significant differences in visual acuity were found in relation to the preoperative status of the fovea. CONCLUSIONS: The results of this case series, together with the previous published outcome of a cohort treated in the identical study period by scleral buckling, indicate that the outcome of retinal detachment surgery in an average cohort of patients can be expected to be much better than suggested by results of the SPR study. PMID- 23629794 TI - Long-term follow-up of multilayer amniotic membrane transplantation (MLAMT) for non-traumatic corneal perforations or deep ulcers with descemetocele. AB - BACKGROUND: To evaluate the long-term efficacy of multilayer amniotic membrane transplantation for reconstruction of epithelium and stroma in non-traumatic corneal perforations (less than 2 mm) or deep ulcers with descemetocele. DESIGN: Retrospective, non-comparative, interventional case series. PATIENTS AND METHODS: Eleven consecutive patients with non-traumatic corneal perforations or deep corneal ulcers with descemetocele refractory to conventional treatments: herpetic or zoster keratitis (n = 4), Sjogren's syndrome (n = 2), rosacea (n = 1), hydrops (n = 1), mucous membrane pemphigoid (n = 1), bacterial keratitis (n = 1) and perforation after protontherapy for melanoma (n = 1). Intervention was: multilayer amniotic membrane transplantation with cryopreserved amniotic membrane. Complication rate and clinical outcome were evaluated in this long-term follow-up. RESULTS: Mean follow-up was 32 months (12 to 60). Integration of the multilayer amniotic membrane was obtained in 10 cases after one year. Corneal epithelium healed above the membrane in 10 cases within 3 weeks and remained stable after 32 months in 9 cases. Thickness of the stroma was increased and remained stable during the follow-up in 9 cases. In one case herpetic keratitis recurred with a corneal perforation. The clearing of the amniotic membrane was gradually obtained over a period of 11 months. Complications occurred in 15% of the eyes during the long-term follow-up. CONCLUSION: Multilayer amniotic membrane transplantation is a safe and efficient technique for a long restoration of the corneal integrity after non-traumatic corneal perforations or deep corneal ulcers with descemetocele. Long-term prognosis of these eyes depends of the gravity of the initial disease. PMID- 23629795 TI - [Terson's syndrome--a neglected problem?]. AB - BACKGROUND: The aim of our study was to analyze the incidence and prognostic value of intraocular hemorrhages caused by subarachnoid hemorrhages. PATIENTS AND METHODS: Retrospective data analysis of all patients with subarachnoid hemorrhage admitted to the University Hospital Zurich between 2005 and 2010. All patients have been classified according to Glasgow Coma, Hunt and Hess, WFNS and Fisher Scales. RESULTS: Out of 391 patients only 26 have been examined by an ophthalmologist. 11/26 (42%) showed Terson's syndrome, compared to 11/391 (2.8%) in the overall cohort. In patients with intraocular hemorrhages there was a trend for a lower GCS and higher Hunt and Hess, WFNS and Fisher scales. CONCLUSION: Intraocular hemorrhages are a relatively frequent, seemingly neglected complication of subarachnoid hemorrhages, and correlate with a higher mortality and morbidity in prospective studies. Routine fundoscopy of heavily impaired patients should be considered. PMID- 23629796 TI - Intravitreal dexamethasone implant for the treatment of macular edema after retinal vein occlusion in a clinical setting. AB - BACKGROUND: To study the efficacy and safety of a new intravitreal implant (sustained release of dexamethasone, Ozurdex(r)) recently approved in Switzerland for the treatment of macular edema secondary to retinal vein occlusion in a clinical setting. PATIENTS AND METHODS: Prospective non-consecutive study of patients with macular edema secondary to central retinal vein occlusion or branch retinal vein occlusion treated with implant of dexamethasone 0.7 mg. Follow-up visits were performed at day 1, week 1 and monthly thereafter. ETDRS best corrected visual acuity, Goldmann tonometry and macular thickness on SD-OCT were registered. Retreatment was carried out on a pro re nata basis starting from month 3. RESULTS: Fifteen eyes of 15 patients were included (8 branch retinal vein occlusions, 7 central retinal vein occlusions). 33% of the patients achieved 3 lines or more of vision gain. The central retinal vein occlusion subgroup showed a mean decline in visual acuity at month 3. A reduction of 36% of macular edema was already observed at day 1. All maculae were dry at month 1. The mean time of recurrence of macular edema for both groups was 4.6 months. A similar reduction of macular edema was obtained after a second implantation. An intraocular pressure increase of >= 20% was observed after the first implantation in 53% of patients. CONCLUSION: Our study showed efficacy and safety of intravitreal dexamethasone implant in the treatment of macular edema due to retinal vein occlusion. Anatomical efficacy was observed at day 1 but seems to have shorter effect than previously published data. No serious side effects were observed. PMID- 23629797 TI - [Spectral-domain optical coherence tomography (SD-OCT) in Valsalva retinopathy with premacular hemorrhage treated by Nd:YAG laser membranotomy]. PMID- 23629798 TI - Bilateral non-arteritic anterior ischaemic optic neuropathy (NAION) associated with essential thrombocytosis. PMID- 23629799 TI - [Treatment of serous macular detachment where optic disc pit is present--two cases]. PMID- 23629800 TI - Systematic treatment of central retinal vein occlusion. PMID- 23629801 TI - Peripheral serous pigment epithelial detachment and retinal detachment presumably associated with hydrochlorothiazide use. PMID- 23629802 TI - Hyaloidotomy for subhyaloidal hemorrhage: OCT findings of two different treatment modalities. PMID- 23629803 TI - Conjunctival extrascleral extension of a myeloid sarcoma: a clinicopathological case report. PMID- 23629804 TI - [Conjunctival degenerative lesions and tumours]. PMID- 23629806 TI - Commentary for "Delayed onset of progressive chorea after acute basal ganglia injury". PMID- 23629805 TI - Novel mechanism for disrupted circadian blood pressure rhythm in a rat model of metabolic syndrome--the critical role of angiotensin II. AB - BACKGROUND: This study was performed to determine the characteristics and mechanism of hypertension in SHR/NDmcr-cp(+/+) rats (SHRcp), a new model of metabolic syndrome, with a focus on the autonomic nervous system, aldosterone, and angiotensin II. METHODS AND RESULTS: We measured arterial blood pressure (BP) in SHRcp by radiotelemetry combined with spectral analysis using a fast Fourier transformation algorithm and examined the effect of azilsartan, an AT1 receptor blocker. Compared with control Wistar-Kyoto rats (WKY) and SHR, SHRcp exhibited a nondipper-type hypertension and displayed increased urinary norepinephrine excretion and increased urinary and plasma aldosterone levels. Compared with WKY and SHR, SHRcp were characterized by an increase in the low-frequency power (LF) of systolic BP and a decrease in spontaneous baroreflex gain (sBRG), indicating autonomic dysfunction. Thus, SHRcp are regarded as a useful model of human hypertension with metabolic syndrome. Oral administration of azilsartan once daily persistently lowered BP during the light period (inactive phase) and the dark period (active phase) in SHRcp more than in WKY and SHR. Thus, angiotensin II seems to be involved in the mechanism of disrupted diurnal BP rhythm in SHRcp. Azilsartan significantly reduced urinary norepinephrine and aldosterone excretion and significantly increased urinary sodium excretion in SHRcp. Furthermore, azilsartan significantly reduced LF of systolic BP and significantly increased sBRG in SHRcp. CONCLUSIONS: These results strongly suggest that impairment of autonomic function and increased aldosterone in SHRcp mediate the effect of angiotensin II on circadian blood pressure rhythms. PMID- 23629807 TI - Somatic instability of CTG repeats in the cerebellum of myotonic dystrophy type 1. AB - INTRODUCTION: We statistically analyzed somatic instability of the CTG expansion in the central nervous system and visceral organs in 7 patients with myotonic dystrophy type 1 and also report intracerebellar instability in 2 patients. METHODS: CTG repeat expansion was estimated in the samples from autopsied brains and visceral organs by Southern blot analysis. Pathological study was performed. Samples were taken from several sites in the cerebellum to examine intracerebellar instability. RESULTS: The CTG repeat expansion was shortest in the cerebellar cortex among all tissues examined. With regard to the intracerebellar difference, the shortest expansion was seen in the cortices of the hemisphere and vermis, whereas it was moderate in the dentate nucleus and longest in the white matter of the hemisphere and middle cerebellar peduncle. CONCLUSIONS: The shortest expansion might be attributable to packed granule cells in the cerebellar cortex. Further analysis of cell-specific methylation states might elucidate the enigma of somatic instability. PMID- 23629809 TI - Cathepsin S from both tumor and tumor-associated cells promote cancer growth and neovascularization. AB - Recent murine studies have demonstrated that tumor-associated macrophages in the tumor microenvironment are a key source of the pro-tumorigenic cysteine protease, cathepsin S. We now show in a syngeneic colorectal carcinoma murine model that both tumor and tumor-associated cells contribute cathepsin S to promote neovascularization and tumor growth. Cathepsin S depleted and control colorectal MC38 tumor cell lines were propagated in both wild type C57Bl/6 and cathepsin S null mice to provide stratified depletion of the protease from either the tumor, tumor-associated host cells, or both. Parallel analysis of these conditions showed that deletion of cathepsin S inhibited tumor growth and development, and revealed a clear contribution of both tumor and tumor-associated cell derived cathepsin S. The most significant impact on tumor development was obtained when the protease was depleted from both sources. Further characterization revealed that the loss of cathepsin S led to impaired tumor vascularization, which was complemented by a reduction in proliferation and increased apoptosis, consistent with reduced tumor growth. Analysis of cell types showed that in addition to the tumor cells, tumor-associated macrophages and endothelial cells can produce cathepsin S within the microenvironment. Taken together, these findings clearly highlight a manner by which tumor-associated cells can positively contribute to developing tumors and highlight cathepsin S as a therapeutic target in cancer. PMID- 23629810 TI - Effect of chondroitinase ABC on adhesion and behavior of synovial membrane derived mesenchymal stem cells in rabbit partial-thickness chondral defects. AB - Transplanted cells may have difficulty attaching to the surface of partial thickness chondral lesions because of the anti-adhesive properties of the proteoglycan rich matrix. Therefore, the current study attempts to evaluate the effect of chondroitinase ABC (chABC) on the adhesion and behavior of transplanted synovial membrane-derived mesenchymal stem cells (SDSCs) in rabbit partial thickness chondral defects. In ex vivo adhesion experiments, chABC treatment (0.1 U/ml) was increased in SDSC attachment to the cartilage explants, and significantly diminished by pretreatment with neutralizing antibody against fibronectin. In the in vivo experiments, 1 day and 4 weeks after the chABC treatment (0.1 and 1 U/ml), the immunoreactivity (IR) against CS-56 (intact chondroitin sulfate antibody) was markedly decreased; however, the IR of 2B6 (stub of the chondroitin 4-sulfate chain), 3B3 (stub of the chondroitin 6-sulfate chain), and fibronectin was increased. At 12 weeks, this IR returned to normal except in the high-dose chABC-treated group (1 U/ml). Furthermore, the attachment of SDSCs to the chondral defects after chABC treatment was increased at 7 days compared with that in the chondral defects pretreated with saline. However, the tissue repaired by SDSCs was negatively stained for type II collagen at 12 weeks. In conclusion, these results showed that the exposure to fibronectin by chABC treatment enhances the attachment of SDSCs to partial-thickness chondral defects. However, the tissue regenerated by SDSCs showed lack of hyaline cartilage regeneration. Thus, to understand the fate of transplanted MSCs in cartilage defect is very important for successful cell therapies. PMID- 23629811 TI - Changes in pericytic expression of NG2 and PDGFRB and vascular permeability in the sensory circumventricular organs of adult mouse by osmotic stimulation. AB - The blood-brain barrier (BBB) is a barrier that prevents free access of blood derived substances to the brain through the tight junctions and maintains a specialized brain environment. Circumventricular organs (CVOs) lack the typical BBB. The fenestrated vasculature of the sensory CVOs, including the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO) and area postrema (AP), allows parenchyma cells to sense a variety of blood-derived information, including osmotic ones. In the present study, we utilized immunohistochemistry to examine changes in the expression of NG2 and platelet derived growth factor receptor beta (PDGFRB) in the OVLT, SFO and AP of adult mice during chronic osmotic stimulation. The expression of NG2 and PDGFRB was remarkably prominent in pericytes, although these angiogenesis-associated proteins are highly expressed at pericytes of developing immature vasculature. The chronic salt loading prominently increased the expression of NG2 in the OVLT and SFO and that of PDGFRB in the OVLT, SFO and AP. The vascular permeability of low-molecular-mass tracer fluorescein isothiocyanate was increased significantly by chronic salt loading in the OVLT and SFO but not AP. In conclusion, the present study demonstrates changes in pericyte expression of NG2 and PDGFRB and vascular permeability in the sensory CVOs by chronic osmotic stimulation, indicating active participation of the vascular system in osmotic homeostasis. PMID- 23629812 TI - Ex vivo expansion of human outgrowth endothelial cells leads to IL-8-mediated replicative senescence and impaired vasoreparative function. AB - Harnessing outgrowth endothelial cells (OECs) for vasoreparative therapy and tissue engineering requires efficient ex vivo expansion. How such expansion impacts on OEC function is largely unknown. In this study, we show that OECs become permanently cell-cycle arrested after ex vivo expansion, which is associated with enlarged cell size, beta-galactosidase activity, DNA damage, tumor suppressor pathway activation, and significant transcriptome changes. These senescence hallmarks were coupled with low telomerase activity and telomere shortening, indicating replicative senescence. OEC senescence limited their regenerative potential by impairing vasoreparative properties in vitro and in vivo. Integrated transcriptome-proteome analysis identified inflammatory signaling pathways as major mechanistic components of the OEC senescence program. In particular, IL8 was an important facilitator of this senescence; depletion of IL8 in OECs significantly extended ex vivo lifespan, delayed replicative senescence, and enhanced function. While the ability to expand OEC numbers prior to autologous or allogeneic therapy remains a useful property, their replicative senescence and associated impairment of vasorepair needs to be considered. This study also suggests that modulation of the senescence-associated secretory phenotype could be used to optimize OEC therapy. PMID- 23629813 TI - Measles outbreak in a pediatric oncology unit and the role of ribavirin in prevention of complications and containment of the outbreak. AB - The role of oral ribavirin in treatment and containment of a measles outbreak in 15 children in an oncology unit is presented. Measles was diagnosed on clinical features and history of contact. Measles specific IgM ELISA and RNA were positive in 7 of 15 and 2 of 7 tested children, respectively. Duration of illness was longer in unimmunized as compared to immunized children (P = 0.02). Complications were higher in hematological malignancies (P = 0.025). Delay in starting ribavirin was associated with fatal complications (2 of 2 vs. 0 of 13, P = 0.009). Ribavirin prevented measles in all (21 of 21) patients exposed to the cases. PMID- 23629814 TI - The expanding universe of thiolated gold nanoclusters and beyond. AB - Thiolated gold nanoclusters form a universe of their own. Researchers in this field are constantly pushing the boundary of this universe by identifying new compositions and in a few "lucky" cases, solving their structures. Such solved structures, even if there are only few, provide important hints for predicting the many identified compositions that are yet to be crystallized or structure determined. Structure prediction is the most pressing issue for a computational chemist in this field. The success of the density functional theory method in gauging the energetic ordering of isomers for thiolated gold clusters has been truly remarkable, but to predict the most stable structure for a given composition remains a great challenge. In this feature article from a computational chemist's point of view, the author shows how one understands and predicts structures for thiolated gold nanoclusters based on his old and new results. To further entertain the reader, the author also offers several "imaginative" structures, claims, and challenges for this field. PMID- 23629815 TI - Relationship between observable emotional expression and wandering behavior of people with dementia. AB - OBJECTIVE: This study explored the relationship between observable emotional expression and wandering behaviors of people with dementia (PWD). METHODS: A secondary data analysis was conducted of a multi-site study that used a cross sectional design with repeated measures nested within subjects. Participants included 142 PWD residing in 17 nursing homes and six assisted-living facilities in Michigan and Pennsylvania who were randomly assigned to six 20-min videotaped observation periods, conducted on two non-consecutive days. Poisson hierarchical linear modeling was used to examine associations between emotional expression and wandering. RESULTS: Participants exhibited an average of 13.5 (standard deviation [SD] +/- 12.4) episodes of positive emotional expression per observation; only 1.5 (SD +/- 2.3) episodes of negative emotional expression per observation were noted. The mean wandering rate was 2.9 episodes (SD +/- 6.9) per hour. Positive emotional expression was positively related to wandering rates, whereas negative emotional expression and higher cognitive status were negatively related to wandering rates after controlling for other predictors (age, education, gender, facility type, mobility, and time of day). CONCLUSIONS: Both positive and negative emotional expressions, along with cognitive status, should be considered when developing interventions to improve wandering behaviors of PWD. PMID- 23629816 TI - Cemented total hip arthroplasty in rheumatoid arthritis. A systematic review of the literature. AB - BACKGROUND: Cemented total hip arthroplasty (THA) in rheumatoid arthritis (RA) is allegedly associated with increased rates of infection, dislocation and aseptic loosening of cup and stem. METHOD: Systematic review of the literature on clinical and radiological results of cemented THA in RA. RESULTS: Twenty-one case series and eight reports on four implant registries were included. The quality of most studies was judged to be poor. The reported rates of infection and dislocation in the case series were conflicting with a risk of bias due to under registration. The registries proved unsuitable for providing reliable data on the incidence of these two complications. Increased rates of aseptic loosening were reported in 10 out of 20 case series on the cup and in six out of 19 on the stem. Nearly all of these were based on series implanted before 1980. None of the registries reported a significantly increased risk of aseptic loosening of cup or stem. CONCLUSIONS: Considering the relatively frequent reports of increased infection rates in combination with the potential under-registration of complications, RA patients have to be considered to have a mild increased risk of postoperative infection. Case series and registries cannot answer the question of whether RA is a risk factor for dislocation as multivariate analysis is required. Increased rates of cup and stem failure due to aseptic loosening in RA patients are found in older but not in more recent studies. PMID- 23629817 TI - Sensorimotor polyneuropathy in patients with SMA type-1: electroneuromyographic findings. AB - INTRODUCTION: Generally, spinal muscular atrophy (SMA) is believed to be a pure motor neuron disease. We retrospectively evaluated our electrodiagnostic findings in SMA type 1 patients to demonstrate co-existence of sensorimotor neuropathies. METHODS: Electroneuromyographic (ENMG) studies in 15 patients (11 boys, 4 girls) were reviewed independently by 2 neurophysiologists. Upper extremity findings were compared with normal right arm controls. RESULTS: Patient ages ranged from 1.5 to 26 months. Four SMA patients (26.7%) had decreased sensory nerve action potentials (SNAPs) or sensory nerve conduction velocities. Of them, median SNAPs could not be elicited in 3, and sural SNAPs could not be elicited in 2. Compound muscle action potential amplitudes were severely decreased in 14 (93.3%) and normal in 1. CONCLUSIONS: Survival motor neuron 1 (SMN1) gene analysis should be considered if clinical features are consistent with SMA, even if pathological or electrophysiological findings demonstrate peripheral sensorimotor polyneuropathies. PMID- 23629818 TI - Construction of enantiomerically enriched diazo compounds using diazo esters as nucleophiles: chiral Lewis base catalysis. PMID- 23629819 TI - Development and validation of a hydrophilic interaction ultra-high-performance liquid chromatography with triple quadrupole MS/MS for the absolute and relative quantification of amino acids in Sophora alopecuroides L. AB - Amino acids are naturally occurring compounds in many edible or medicinal plants, which possess a variety of pharmacological effects on humans. The aim of this study is to develop and validate a hydrophilic interaction LC coupled with MS/MS method for the absolute and relative quantification of amino acids without derivatization. The application of this method has been proven through 20 naturally occurring amino acids in 21 samples from different parts and phenological growth stage of Sophora alopecuroides. The method was performed on an ultra-high performance LC separation system coupled with ESI-MS on a triple quadrupole mass spectrometer. The proposed absolute quantitative method was fully validated in terms of linearity, sensitivity, precision, repeatability as well as recovery. The analysis results showed that S. alopecuroides is rich in free amino acids. In addition, relative quantitative determination of amino acids with several amino acids selected for the best accuracy was investigated. The accuracies of relative quantitative method for amino acids determinations suggest that it is feasible to quantify amino acids by the proposed relative quantitative determination method, which contributes to breaking through the choke point of lack of standards. PMID- 23629820 TI - Risk of venous thromboembolism in patients with inflammatory bowel disease. AB - There is ample evidence of an increased risk of venous thromboembolism (VTE) in inflammatory bowel disease (IBD). Recent large studies have quantified this risk showing that IBD patients run a 1.5 to 3.6 higher risk of developing VTE than healthy controls. The development of VTE in IBD seems to be multifactorial, resulting from multiple interactions between acquired and inherited risk factors. The most important independent acquired risk factors include disease activity, hospitalization, colonic localization, and recent surgery. The main genetic defects that have been established as risk factors for VTE in the general population are rather uncommon in IBD, but when present, they increase the risk of VTE. IBD has been demonstrated to represent an independent risk factor for the recurrence of VTE. An increased risk of VTE-related mortality when compared with non-IBD patients has been reported. The guidelines for diagnosis and treatment of IBD patients with VTE are similar to that of thrombotic non-IBD patients. There is a consensus on the use of thromboprophylaxis mainly in hospitalized IBD patients with acute flares, but the prevention strategies need further evaluation in future studies. PMID- 23629821 TI - Cancer and venous thrombosis: current comprehensions and future perspectives. AB - Venous thromboembolism (VTE) is a common complication in all types of cancer and adversely impacts cancer prognosis. Randomized controlled trials with primary thromboprophylaxis in cancer patients generally show effective VTE relative risk reductions of up to 60%. However, absolute risks of VTE were fairly low. Thromboprophylaxis should therefore only be recommended to cancer patients at highest risk of VTE, who may benefit most from prophylaxis. Predictive risk models to identify patients at a high risk of VTE are promising, however additional validation is required. An increasing proportion of cancer-associated VTE is formed by incidental VTE, with similar risk factors and clinical consequences. Randomized trials are not yet available, but it seems reasonable to treat incidental VTE similarly to symptomatic VTE. In a substantial proportion of patients with unprovoked VTE without known cancer at the time of VTE diagnosis, concomitant or occult cancer is identified. Studies have investigated the value of extensive screening over routine examinations alone for occult cancer. Although extensive screening may be able to identify more occult cancers, its clinical benefit over routine screening has not been demonstrated. PMID- 23629822 TI - Venous thrombosis associated with HMG-CoA reductase inhibitors. AB - Among the various hypolipidemic drugs, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (also known as "statins") belong to a heterogeneous class of compounds, sharing an identical hypocholesterolemic effect that develops through direct inhibition of a rate-limiting step in endogenous cholesterol synthesis. Their mechanism of action entails competitive inhibition of HMG-CoA reductase. Several lines of evidence suggest that the pleiotropic effects of statins may also play a role in prevention of venous thrombosis, wherein hypercholesterolemic patients are characterized by enhanced thrombin generation, increased susceptibility to endothelial dysfunction and platelet hyperreactivity, so that limiting or counteracting the burden of one or more of these mechanisms would provide an effective means of prophylaxis. Plausible biological links can also be found between statin therapy and reduction of thrombotic risk, mainly targeting immune system, blood coagulation, endothelium, lipid metabolism, and inflammation. The earlier JUPITER (Justification for the Use of Statins in Primary Prevention) trial provided appealing evidence that the risk of venous thrombosis may be lowered by statins. The results of the following studies and those of recent meta-analyses have, however, questioned this assumption. Currently, it seems thereby cautious to conclude that the use of statins as part of the approach used for preventing venous thromboembolism appears unwarranted. This is due to the existence of controversial clinical evidence, to the large number of patients who would need to be treated to prevent one case of venous thrombosis, as well as to the tangible risk of side effects. More randomized and the larger studies are needed before definitive conclusions can be drawn. PMID- 23629823 TI - Prothrombotic changes in diabetes mellitus. AB - Although our understanding of vascular pathology has greatly improved in recent years, the cellular and molecular mechanisms underlying the enhanced thrombotic propensity in type 2 diabetes mellitus (T2DM) remain incompletely characterized. Detrimental interactions between activated vascular cells (i.e., platelets, leukocytes, endothelial cells) and the vulnerable atheromatous plaque are a major determinant of the increased atherothrombotic burden in T2DM patients. Endothelial damage and accelerated senescence, impairment of the endothelial progenitor cell repair system, plaque neovascularization and inflammation, decreased clearance of detrimental molecules within the plaque, and increased expression of matrix metalloproteinases may collectively contribute to intraplaque hemorrhage and subsequent rupture. Notably, recent data demonstrates the central importance of the tissue factor-microparticle-mediated pathway in diabetic thrombophilia and cardiovascular complications. Acting as detrimental amplifiers of various biological responses (including thrombogenicity and plaque remodeling), microparticles have also emerged as a key marker of global vascular damage in T2DM patients. Available evidence suggests that targeting the tissue factor-microparticle pathway may be a promising approach for reducing the burden of the atherosclerotic complications of diabetes. PMID- 23629824 TI - Venous thromboembolism after traumatic brain injury. AB - No standard exists for venous thromboembolism (VTE) prophylaxis after traumatic brain injury (TBI). Caregivers agree that there is an early time point after injury in which the chances of spontaneous injury progression are high and the risks of prophylactic anticoagulation are excessive, and that these injuries eventually stabilize to the point that anticoagulation may be safely started. Translating this consensus into an application that can inform bedside decision making has not occurred. National groups have promulgated guidelines in the United States suggesting that anticoagulants be used when the risk of renewed intracranial hemorrhage has ceased with no guidance beyond this vague recommendation. This is largely due to the relative paucity of literature about pharmacologic prophylaxis, which has in turn been due to fears of propagation of intracranial hemorrhage. Although interest in this field has increased of late, many studies are limited by the simple dichotomization of TBI patients as having the presence or absence of intracranial blood. Although methodologically easier, this approach does not account for the heterogeneity of TBI and, consequently, the spectrum of time to stabilization. To address this, our group has created an algorithm which stratifies patients by risk for spontaneous progression and tailors a unique VTE prophylaxis regimen to each arm. PMID- 23629826 TI - Pediatric lupus nephritis: more options, more chances? AB - Lupus nephritis (LN) is more common and severe in childhood-onset systemic lupus erythematosus (SLE) than in adults. It is one of the major causes of acute kidney injury (AKI) and chronic kidney disease (CKD) in children. Steroid therapy has been used as the first-line treatment for SLE since 1970, and has improved the survival of SLE patients from ~ 50% to >80%. Over the years many immunosuppressive drugs, including pulse methylprednisolone, oral cyclophosphamide, pulse intravenous cyclophosphamide, mycophenolate mofitil, rituximab, and tacrolimus, have been combined with prednisolone, further improving survival rates to 90%-95%. However, the effectiveness of these drugs is still uncertain, as most seem very good in the beginning, but in studies examining longer-term follow-up the remission of disease does not remain. Fatal infection is still a major complication of aggressive chemotherapy, and the potential benefits as well as adverse events from each drug need to be considered. Induction of remission is the major aim of therapy, with safe and effective maintenance therapy for long-term remission. The survival rates of many published studies vary widely because of differences in patients and treatment modalities, severity of disease, renal histopathology, racial factors, and duration of follow-up. Finding the optimal treatment for SLE and related co morbidities is highly challenging, and will likely involve a complex combination of different drugs for different patients in the search for giving them an opportunity to be free from this debilitating disease. PMID- 23629827 TI - Urinary CXCL-10/IP-10 and MCP-1 as markers to assess activity of lupus nephritis. AB - OBJECTIVE: IP-10 and MCP-1 are pro-inflammatory chemokines which are involved in the immunopathogenesis of lupus nephritis and may thus be useful biomarkers. METHODS: SLE patients fulfilling ACR 1997 criteria were included. SLEDAI was calculated and blood and urine samples collected. Active lupus was defined as SLEDAI >=4. Active patients were divided into active renal (proteinuria >= 500 mg/day or active sediment in urine) and active non-renal lupus. Patients with active renal lupus were followed until the nephritis became inactive, when a second sample was collected. Serum and urinary levels of MCP-1 and IP-10 (pg/ml) were measured by ELISA. Urinary values were normalized for urinary spot creatinine (in mg/dL. Thus the values were expressed as pg/mg creatinine * 100 creatinine). RESULTS: A total of 136 patients with SLE including 78 active (46 active renal and 32 active non-renal) were included. Median age was 25 (10-55) years and SLE duration was 23 (six to 48) months. Both serum (data not shown) and urinary levels of MCP-1 (35.2 (12.7-71.7), 9.4 (4.4-17), p < 0.001) and IP-10 (9.5 (4.4-17.9), 3.9 (1.9-9.3), p < 0.001) were higher in active compared to inactive SLE. However, in active renal compared to active non-renal SLE, there was no difference in serum levels; only urinary levels of MCP-1 (46.2 (19.9-125), 12.7 (5.8-43.9), p < 0.001) and IP-10 (12.5 (5.6-22.7), 5.2 (2.3-12.2), p < 0.05) were higher. On longitudinal follow-up of active renal patients (n = 24), there was a decrease in urinary levels of MCP-1 and IP-10 (p = 0.005). On ROC analysis, urinary MCP-1 outperformed C4 and urinary IP-10, but was similar to dsDNA and C3 in differentiating active renal from non-renal SLE. CONCLUSIONS: Urinary and serum IP-10 and MCP-1 are potentially useful markers of lupus activity; however, only the urinary levels are indicative of renal activity. However, on ROC analysis, they are not better than conventional markers. PMID- 23629828 TI - Relationship between cell proliferation and eruption rate in the rat incisor. AB - The aim of this study was to further define the relationship between cell proliferation and the rate of tooth eruption in the rat incisor. Vinblastine is a drug that blocks cellular mitosis and was used to inhibit cell proliferation in the odontogenic region of rat incisors that were submitted to a shortening treatment or to higher masticatory forces. Male Wistar rats were divided into five groups: normofunctional (control group for incisor eruption), hypofunctional (incisor submitted to eruption acceleration), hyperfunctional (incisors under higher masticatory forces), hypofunctional with vinblastine and hyperfunctional with vinblastine. In incisors submitted to shortening procedures, a significant decrease in the eruption rate and cell proliferation was observed two days after vinblastine injection, suggesting that incisor eruption is dependent on cell proliferation. PMID- 23629829 TI - Sectioning the medial patellofemoral ligament alters patellofemoral joint kinematics and contact mechanics. AB - Medial patellofemoral ligament (MPFL) disruption may alter patellofemoral joint (PFJ) kinematics and contact mechanics, potentially causing pain and joint degeneration. In this controlled laboratory study, we investigated the hypothesis that MPFL transection would change patellar tracking and PFJ contact pressures and increase the distance between the attachment points of the MPFL. Eight fresh frozen dissected cadaveric knees were mounted in a rig with the quadriceps and ITB loaded to 205 N. An optical tracking system measured joint kinematics, and pressure sensitive film between the patella and trochlea measured PFJ contact pressures. Length patterns of the distance between the femoral and patellar attachments of the MPFL were measured using a suture led to a linear displacement transducer. Measurements were repeated with the MPFL intact and following MPFL transection. A significant increase in the distance between the patellar and femoral MPFL attachment points was noted following transection (p < 0.05). MPFL transection resulted in significantly increased lateral translation and lateral tilt of the patella in early flexion (p < 0.05). Peak and mean medial PFJ contact pressures were significantly reduced and peak lateral contact pressures significantly elevated in early knee flexion following MPFL transection (p < 0.05). MPFL transection resulted in significant alterations to PFJ tracking and contact pressures, which may affect articular cartilage health. PMID- 23629830 TI - Cell proliferation is promoted by compressive stress during early stage of chondrogenic differentiation of rat BMSCs. AB - The presence of an appropriate number of viable cells is prerequisite for successive differentiation during chondrogenesis. Chondrogenic differentiation has been reported to be influenced by mechanical stimuli. This research aimed to study the effects of cyclic compressive stress on cell viability of rat bone marrow-derived MSCs (BMSCs) during chondrogenesis as well as its underlying mechanisms. The results showed that dynamic compression increased cell quantity and viability remarkably in the early stage of chondrogenesis, during which the expression of Ihh, Cyclin D1, CDK4, and Col2alpha1 were enhanced significantly. Possible signal pathways implicated in the process were explored in our study. MEK/ERK and p38 MAPK were not found to function in this process while BMP signaling seemed to play an important role in the mechanotransduction during chondrogenic proliferation. In conclusion, dynamic compressive stress could enhance cell viability during chondrogenesis, which might be achieved by activating BMP signaling. PMID- 23629831 TI - Purging disorder: a comparison to established eating disorders with purging behaviour. AB - This study is part of the larger Christina Barz Study, and it compared consecutively admitted patients with purging disorder (PurD; N = 225) with consecutively admitted patients with anorexia nervosa binge eating/purging subtype (AN-bp; N = 503) and bulimia nervosa purging subtype (BN-p; N = 756). Participants answered self-rating questionnaires on admission, at the end of inpatient treatment, and in a 5-year follow-up. Patients with PurD reported lower severity of general psychopathology than patients with AN-bp and lower severity of eating disorder symptoms than patients with AN-bp and BN-p on admission. Eating disorder symptoms of patients with PurD improved less during the course than of the comparison groups. Diagnostic perseverance was stronger in the PurD group than for patients with AN-bp; mortality was higher than for patients with BN-p. Predictors for better outcome differed for the groups. Our results provide new data about the long-term course of patients with PurD and indicate clinical relevance of the disorder. PMID- 23629832 TI - MULTI-FLORET SPIKELET1, which encodes an AP2/ERF protein, determines spikelet meristem fate and sterile lemma identity in rice. AB - The spikelet is a unique inflorescence structure of grass. The molecular mechanism that controls the development of the spikelet remains unclear. In this study, we identified a rice (Oryza sativa) spikelet mutant, multi-floret spikelet1 (mfs1), that showed delayed transformation of spikelet meristems to floral meristems, which resulted in an extra hull-like organ and an elongated rachilla. In addition, the sterile lemma was homeotically converted to the rudimentary glume and the body of the palea was degenerated in mfs1. These results suggest that the MULTI-FLORET SPIKELET1 (MFS1) gene plays an important role in the regulation of spikelet meristem determinacy and floral organ identity. MFS1 belongs to an unknown function clade in the APETALA2/ethylene responsive factor (AP2/ERF) family. The MFS1-green fluorescent protein fusion protein is localized in the nucleus. MFS1 messenger RNA is expressed in various tissues, especially in the spikelet and floral meristems. Furthermore, our findings suggest that MFS1 positively regulates the expression of LONG STERILE LEMMA and the INDETERMINATE SPIKELET1 (IDS1)-like genes SUPERNUMERARY BRACT and OsIDS1. PMID- 23629833 TI - A regulatory cascade involving class II ETHYLENE RESPONSE FACTOR transcriptional repressors operates in the progression of leaf senescence. AB - Leaf senescence is the final process of leaf development that involves the mobilization of nutrients from old leaves to newly growing tissues. Despite the identification of several transcription factors involved in the regulation of this process, the mechanisms underlying the progression of leaf senescence are largely unknown. Herein, we describe the proteasome-mediated regulation of class II ETHYLENE RESPONSE FACTOR (ERF) transcriptional repressors and involvement of these factors in the progression of leaf senescence in Arabidopsis (Arabidopsis thaliana). Based on previous results showing that the tobacco (Nicotiana tabacum) ERF3 (NtERF3) specifically interacts with a ubiquitin-conjugating enzyme, we examined the stability of NtERF3 in vitro and confirmed its rapid degradation by plant protein extracts. Furthermore, NtERF3 accumulated in plants treated with a proteasome inhibitor. The Arabidopsis class II ERFs AtERF4 and AtERF8 were also regulated by the proteasome and increased with plant aging. Transgenic Arabidopsis plants with enhanced expression of NtERF3, AtERF4, or AtERF8 showed precocious leaf senescence. Our gene expression and chromatin immunoprecipitation analyses suggest that AtERF4 and AtERF8 targeted the EPITHIOSPECIFIER PROTEIN/EPITHIOSPECIFYING SENESCENCE REGULATOR gene and regulated the expression of many genes involved in the progression of leaf senescence. By contrast, an aterf4 aterf8 double mutant exhibited delayed leaf senescence. Our results provide insight into the important role of class II ERFs in the progression of leaf senescence. PMID- 23629834 TI - Divergent DNA-binding specificities of a group of ETHYLENE RESPONSE FACTOR transcription factors involved in plant defense. AB - Transcription factors (TFs) recognize target DNA sequences with distinct DNA binding domains (DBDs). The DBD of Arabidopsis (Arabidopsis thaliana) ETHYLENE RESPONSE FACTOR1 (AtERF1) uses three consecutive beta-strands to recognize a GCC containing sequence, but tobacco (Nicotiana tabacum) ERF189 and periwinkle (Catharanthus roseus) Octadecanoid-derivative Responsive Catharanthus AP2-domain protein3 (ORCA3) of the same TF subgroup appear to target similar but divergent DNA sequences. Here, we examined how DNA-binding specificities of these TFs have diverged in each plant lineage to regulate distinct defense metabolisms. Extensive mutational analyses of these DBDs suggest that two modes of protein-DNA interactions independently contribute to binding specificity and affinity. Substitution of a conserved arginine to lysine in the first beta-strand of ERF189 relaxes its interaction with the second GC pair of the GCC DNA sequence. By contrast, an increased number of basic amino acids in the first two beta-strands of ORCA3 allows this TF to recognize more than one GCC-related target, presumably via increased electrostatic interactions with the negatively charged phosphate backbone of DNA. Divergent DNA-binding specificities of the ERFs may have arisen through mutational changes of these amino acid residues. PMID- 23629835 TI - The methylation of the PcMYB10 promoter is associated with green-skinned sport in Max Red Bartlett pear. AB - Varieties of the European pear (Pyrus communis) can produce trees with both red- and green-skinned fruits, such as the Max Red Bartlett (MRB) variety, although little is known about the mechanism behind this differential pigmentation. In this study, we investigated the pigmentation of MRB and its green-skinned sport (MRB-G). The results suggest that a reduction in anthocyanin concentration causes the MRB-G sport. Transcript levels of PcUFGT (for UDP-glucose:flavonoid 3-O glucosyltransferase), the key structural gene in anthocyanin biosynthesis, paralleled the change of anthocyanin concentration in both MRB and MRB-G fruit. We cloned the PcMYB10 gene, a transcription factor associated with the promoter of PcUFGT. An investigation of the 2-kb region upstream of the ATG translation start site of PcMYB10 showed the regions -604 to -911 bp and -1,218 to -1,649 bp to be highly methylated. A comparison of the PcMYB10 promoter methylation level between the MRB and MRB-G forms indicated a correlation between hypermethylation and the green-skin phenotype. An Agrobacterium tumefaciens infiltration assay was conducted on young MRB fruits by using a plasmid constructed to silence endogenous PcMYB10 via DNA methylation. The infiltrated fruits showed blocked anthocyanin biosynthesis, higher methylation of the PcMYB10 promoter, and lower expression of PcMYB10 and PcUFGT. We suggest that the methylation level of PcMYB10 is associated with the formation of the green-skinned sport in the MRB pear. The potential mechanism behind the regulation of anthocyanin biosynthesis is discussed. PMID- 23629837 TI - Epileptic Seizure Detection Using Lacunarity and Bayesian Linear Discriminant Analysis in Intracranial EEG. AB - Automatic seizure detection plays an important role in long-term epilepsy monitoring, and seizure detection algorithms have been intensively investigated over the years. This paper proposes an algorithm for seizure detection using lacunarity and Bayesian linear discriminant analysis (BLDA) in long-term intracranial EEG. Lacunarity is a measure of heterogeneity for a fractal. The proposed method first conducts wavelet decomposition on EEGs with five scales, and selects the wavelet coefficients at scale 3, 4, and 5 for subsequent processing. Effective features including lacunarity and fluctuation index are extracted from the selected three scales, and then sent into the BLDA for training and classification. Finally, postprocessing which includes smoothing, threshold judgment, multichannels integration, and collar technique is applied to obtain high sensitivity and low false detection rate. The proposed algorithm is evaluated on 289.14 h intracranial EEG data from 21-patient Freiburg dataset and yields a sensitivity of 96.25% and a false detection rate of 0.13/h with a mean delay time of 13.8 s. PMID- 23629838 TI - Physically based nonrigid registration using smoothed particle hydrodynamics: application to hepatic metastasis volume-preserving registration. AB - Recent advances in computing hardware have enabled the application of physically based simulation techniques to various research fields for improved accuracy. In this paper, we present a novel physically based nonrigid registration method using smoothed particle hydrodynamics for hepatic metastasis volume-preserving registration between follow-up liver CT images. Our method models the liver and hepatic metastasis as a set of particles carrying their own physical properties. Based on the fact that the hepatic metastasis is stiffer than other normal cells in the liver parenchyma, the candidate regions of hepatic metastasis are modeled with particles of higher stiffness compared to the liver parenchyma. Particles placed in the liver and candidate regions of hepatic metastasis in the source image are transformed along a gradient vector flow-based force field calculated in the target image. In this transformation, the particles are physically interacted and deformed by a novel deformable particle method which is proposed to preserve the hepatic metastasis to the best. In experimental results using ten clinical datasets, our method matches the liver effectively between follow-up CT images as well as preserves the volume of hepatic metastasis almost completely, enabling the accurate assessment of the volume change of the hepatic metastasis. These results demonstrated a potential of the proposed method that it can deliver a substantial aid in measuring the size change of index lesion (i.e., hepatic metastasis) after the chemotheraphy of metastasis patients in radiation oncology. PMID- 23629839 TI - Quantification of the variability in response to propofol administration in children. AB - Closed-loop control of anesthesia is expected to decrease drug dosage and wake up time while increasing patient safety and decreasing the work load of the anesthesiologist. The potential of closed-loop control in anesthesia has been demonstrated in several clinical studies. One of the challenges in the development of a closed-loop system that can be widely accepted by clinicians and regulatory authorities is the effect of interpatient variability in drug sensitivity. This system uncertainty may lead to unacceptable performance, or even instability of the closed-loop system for some individuals. The development of reliable models of the effect of anesthetic drugs and characterization of the uncertainty is, therefore, an important step in the development of a closed-loop system. Model identification from clinical data is challenging due to limited excitation and the lack of validation data. In this paper, approximate models are validated for controller design by evaluating the predictive accuracy of the closed-loop behavior. A set of 47 validated models that describe the interpatient variability in the response to propofol in children is presented. This model set can be used for robust linear controller design provided that the experimental conditions are similar to the conditions during data collection. PMID- 23629836 TI - Collapsed abnormal pollen1 gene encoding the Arabinokinase-like protein is involved in pollen development in rice. AB - We isolated a pollen-defective mutant, collapsed abnormal pollen1 (cap1), from Tos17 insertional mutant lines of rice (Oryza sativa). The cap1 heterozygous plant produced equal numbers of normal and collapsed abnormal grains. The abnormal pollen grains lacked almost all cytoplasmic materials, nuclei, and intine cell walls and did not germinate. Genetic analysis of crosses revealed that the cap1 mutation did not affect female reproduction or vegetative growth. CAP1 encodes a protein consisting of 996 amino acids that showed high similarity to Arabidopsis (Arabidopsis thaliana) l-arabinokinase, which catalyzes the conversion of l-arabinose to l-arabinose 1-phosphate. A wild-type genomic DNA segment containing CAP1 restored mutants to normal pollen grains. During rice pollen development, CAP1 was preferentially expressed in anthers at the bicellular pollen stage, and the effects of the cap1 mutation were mainly detected at this stage. Based on the metabolic pathway of l-arabinose, cap1 pollen phenotype may have been caused by toxic accumulation of l-arabinose or by inhibition of cell wall metabolism due to the lack of UDP-l-arabinose derived from l-arabinose 1-phosphate. The expression pattern of CAP1 was very similar to that of another Arabidopsis homolog that showed 71% amino acid identity with CAP1. Our results suggested that CAP1 and related genes are critical for pollen development in both monocotyledonous and dicotyledonous plants. PMID- 23629840 TI - Time Series Modeling of Nano-Gold Immunochromatographic Assay via Expectation Maximization Algorithm. AB - In this paper, the expectation maximization (EM) algorithm is applied to the modeling of the nano-gold immunochromatographic assay (nano-GICA) via available time series of the measured signal intensities of the test and control lines. The model for the nano-GICA is developed as the stochastic dynamic model that consists of a first-order autoregressive stochastic dynamic process and a noisy measurement. By using the EM algorithm, the model parameters, the actual signal intensities of the test and control lines, as well as the noise intensity can be identified simultaneously. Three different time series data sets concerning the target concentrations are employed to demonstrate the effectiveness of the introduced algorithm. Several indices are also proposed to evaluate the inferred models. It is shown that the model fits the data very well. PMID- 23629841 TI - Rider trunk and bicycle pose estimation with fusion of force/inertial sensors. AB - Estimation of human pose in physical human-machine interactions such as bicycling is challenging because of highly-dimensional human motion and lack of inexpensive, effective motion sensors. In this paper, we present a computational scheme to estimate both the rider trunk pose and the bicycle roll angle using only inertial and force sensors. The estimation scheme is built on a rider bicycle dynamic model and the fusion of the wearable inertial sensors and the bicycle force sensors. We take advantages of the attractive properties of the robust force measurements and the motion-sensitive inertial measurements. The rider-bicycle dynamic model provides the underlying relationship between the force and the inertial measurements. The extended Kalman filter-based sensor fusion design fully incorporates the dynamic effects of the force measurements. The performance of the estimation scheme is demonstrated through extensive indoor and outdoor riding experiments. PMID- 23629843 TI - Isolation of volatiles from Nigella sativa seeds using microwave-assisted extraction: effect of whole extracts on canine and murine CYP1A. AB - The volatile components of Nigella sativa seeds were isolated using microwave assisted extraction (MAE) and identified using gas chromatography. Further investigations were carried out to demonstrate the effects of whole extracts on canine (dog) and murine (rat) cytochrome P450 1A (CYP1A). The optimal extraction conditions of MAE were as follows: 25 mL of water, medium level of microwave oven power and 10 min of extraction time. A total of 32 compounds were identified under the conditions using GC-FID and GC-MS. Thymoquinone (38.23%), p-cymene (28.61%), 4-isopropyl-9-methoxy-1-methyl-1-cyclohexene (5.74%), longifolene (5.33%), alpha-thujene (3.88) and carvacol (2.31%) were the main compounds emitted from N. sativa seeds. Various extracts including pure compounds, essential oil, nonpolar partition, relatively high-polar/nonpolar partition, and polar partition extracts effectively inhibited the reaction of ethoxyresorufin O de-ethylation, which is specified for CYP1A activity both in dog and rat. This in vitro data should be heeded as a signal of possible in vivo interactions. The use of human liver preparations would considerably strengthen the practical impact of the data generated from this study. PMID- 23629842 TI - The crystal structure of an octapeptide repeat of the prion protein in complex with a Fab fragment of the POM2 antibody. AB - Prion diseases are progressive, infectious neurodegenerative disorders caused primarily by the misfolding of the cellular prion protein (PrP(c)) into an insoluble, protease-resistant, aggregated isoform termed PrP(sc). In native conditions, PrP(c) has a structured C-terminal domain and a highly flexible N terminal domain. A part of this N-terminal domain consists of 4-5 repeats of an unusual glycine-rich, eight amino acids long peptide known as the octapeptide repeat (OR) domain. In this article, we successfully report the first crystal structure of an OR of PrP(c) bound to the Fab fragment of the POM2 antibody. The structure was solved at a resolution of 2.3 A by molecular replacement. Although several studies have previously predicted a beta-turn-like structure of the unbound ORs, our structure shows an extended conformation of the OR when bound to a molecule of the POM2 Fab indicating that the bound Fab disrupts any putative native beta turn conformation of the ORs. Encouraging results from several recent studies have shown that administering small molecule ligands or antibodies targeting the OR domain of PrP result in arresting the progress of peripheral prion infections both in ex vivo and in in vivo models. This makes the structural study of the interactions of POM2 Fab with the OR domain very important as it would help us to design smaller and tighter binding OR ligands. PMID- 23629845 TI - Phylogenetic relationships and character evolution analysis of Saxifragales using a supermatrix approach. AB - PREMISE OF THE STUDY: We sought novel evolutionary insights for the highly diverse Saxifragales by constructing a large phylogenetic tree encompassing 36.8% of the species-level biodiversity. * METHODS: We built a phylogenetic tree for 909 species of Saxifragales and used this hypothesis to examine character evolution for annual or perennial habit, woody or herbaceous habit, ovary position, petal number, carpel number, and stamen to petal ratio. We employed likelihood approaches to investigate the effect of habit and life history on speciation and extinction within this clade. * KEY RESULTS: Two major shifts occurred from a woody ancestor to the herbaceous habit, with multiple secondary changes from herbaceous to woody. Transitions among superior, subinferior, and inferior ovaries appear equiprobable. A major increase in petal number is correlated with a large increase in carpel number; these increases have co occurred multiple times in Crassulaceae. Perennial or woody lineages have higher rates of speciation than annual or herbaceous ones, but higher probabilities of extinction offset these differences. Hence, net diversification rates are highest for annual, herbaceous lineages and lowest for woody perennials. The shift from annuality to perenniality in herbaceous taxa is frequent. Conversely, woody perennial lineages to woody annual transitions are infrequent; if they occur, the woody annual state is left immediately. * CONCLUSIONS: The large tree provides new insights into character evolution that are not obvious with smaller trees. Our results indicate that in some cases the evolution of angiosperms might be conditioned by constraints that have been so far overlooked. PMID- 23629844 TI - Cytotype coexistence leads to triploid hybrid production in a diploid-tetraploid contact zone of Chamerion angustifolium (Onagraceae). AB - PREMISE OF THE STUDY: Polyploids are often geographically segregated from their diploid progenitors, but the extent of sympatry and the consequences for reproductive isolation and coexistence are rarely quantified. * METHODS: In this study, we document the distribution and co-occurrence of diploid and tetraploid Chamerion angustifolium among 57 populations within the diploid-tetraploid contact zone in the Canadian Rocky Mountains. Rates of hybrid mating in mixed ploidy populations were inferred from the frequency of triploid offspring in open pollinated seed families. * KEY RESULTS: Twenty-three of 57 populations sampled contained a single cytotype; 20 (87%) were tetraploid and three (13%) were diploid. Thirty-four populations (60%) contained multiple ploidies. Diploid and tetraploid plants occurred in all mixed-ploidy populations; triploids occurred in 13 populations and averaged 1.4% of plants per population. The proportion of tetraploids in a population was negatively related to elevation (partial regression: F = 27.2, P <0.0001) and latitude (partial regression: F = 17.4, P < 0.0001). Triploids were detected in seed from all eight mixed-ploidy populations sampled ( = 3.7% of seed per population), comprising 7% of that expected with random mating (G = 2589.2, df = 1, P <0.0001, n = 2628), and were more often produced by diploid maternal parents than tetraploid parents. * CONCLUSIONS: Our results indicate that tetraploids regularly coexist with diploids in the contact zone and that this coexistence is likely promoted by both strong reproductive isolation and asymmetric intercytotype mating between diploid and tetraploid C. angustifolium. PMID- 23629847 TI - Photoresponsive two-component organogelators based on trisphenylisoxazolylbenzene. AB - Photochromic tris(phenylisoxazolyl)benzene 1 and bispyridine derivatives 2a-e were mixed in a certain ratio to generate stable gels in benzyl alcohol, 4 methoxybenzyl alcohol, and aniline. Supramolecular assembly of 1 in solution was confirmed by 1H NMR study. The Tgel value was saturated in a 2 : 3 ratio of 1 and 2c. The intermolecular hydrogen bonds OH...N and salt bridge O(-)...H(-)N(+) between 1 and 2c coexisted evidently, and these hydrogen bonds contributed to the stabilization of the gel networks. The lengths of alkyl chains of 2a-e governed the stabilities of the gels. The gel formations were driven by the morphological transition of 1 before and after the addition of 2a-e. Mixtures of 1 and 2a-e led to the well developed fibrillar networks, generating a lot of voids that are responsible for immobilizing solvent molecules. When the benzyl alcohol gel was irradiated at 360 nm, the gel turned to the sol. The sol was reversed to the gel by warming. This gel-to-sol phase transition was completely reversible. PMID- 23629848 TI - Spine segmentation in medical images using manifold embeddings and higher-order MRFs. AB - We introduce a novel approach for segmenting articulated spine shape models from medical images. A nonlinear low-dimensional manifold is created from a training set of mesh models to establish the patterns of global shape variations. Local appearance is captured from neighborhoods in the manifold once the overall representation converges. Inference with respect to the manifold and shape parameters is performed using a higher-order Markov random field (HOMRF). Singleton and pairwise potentials measure the support from the global data and shape coherence in manifold space respectively, while higher-order cliques encode geometrical modes of variation to segment each localized vertebra models. Generic feature functions learned from ground-truth data assigns costs to the higher order terms. Optimization of the model parameters is achieved using efficient linear programming and duality. The resulting model is geometrically intuitive, captures the statistical distribution of the underlying manifold and respects image support. Clinical experiments demonstrated promising results in terms of spine segmentation. Quantitative comparison to expert identification yields an accuracy of 1.6 +/- 0.6 mm for CT imaging and of 2.0 +/- 0.8 mm for MR imaging, based on the localization of anatomical landmarks. PMID- 23629849 TI - Modelling and estimation of multicomponent T(2) distributions. AB - Estimation of multiple T2 components within single imaging voxels typically proceeds in one of two ways; a nonparametric grid approximation to a continuous distribution is made and a regularized nonnegative least squares algorithm is employed to perform the parameter estimation, or a parametric multicomponent model is assumed with a maximum likelihood estimator for the component estimation. In this work, we present a Bayesian algorithm based on the principle of progressive correction for the latter choice of a discrete multicomponent model. We demonstrate in application to simulated data and two experimental datasets that our Bayesian approach provides robust and accurate estimates of both the T2 model parameters and nonideal flip angles. The second contribution of the paper is to present a Cramer-Rao analysis of T2 component width estimators. To this end, we introduce a parsimonious parametric and continuous model based on a mixture of inverse-gamma distributions. This analysis supports the notion that T2 spread is difficult, if not infeasible, to estimate from relaxometry data acquired with a typical clinical paradigm. These results justify the use of the discrete distribution model. PMID- 23629850 TI - Versatile access to chiral indolines by catalytic asymmetric Fischer indolization. PMID- 23629851 TI - Thiol-acrylate nanocomposite foams for critical size bone defect repair: A novel biomaterial. AB - Bone tissue engineering approaches using polymer/ceramic composites show promise as effective biocompatible, absorbable, and osteoinductive materials. A novel class of in situ polymerizing thiol-acrylate based copolymers synthesized via an amine-catalyzed Michael addition was studied for its potential to be used in bone defect repair. Both pentaerythritol triacrylate-co-trimethylolpropane tris(3 mercaptopropionate) (PETA-co-TMPTMP) and PETA-co-TMPTMP with hydroxyapatite (HA) composites were fabricated in solid cast and foamed forms. These materials were characterized chemically and mechanically followed by an in vitro evaluation of the biocompatibility and chemical stability in conjunction with human adipose derived mesenchymal pluripotent stem cells (hASC). The solid PETA-co-TMPTMP with and without HA exhibited compressive strength in the range of 7-20 MPa, while the cytotoxicity and biocompatibility results demonstrate higher metabolic activity of hASC on PETA-co-TMPTMP than on a polycaprolactone control. Scanning electron microscope imaging of hASC show expected spindle shaped morphology when adhered to copolymer. Micro-CT analysis indicates open cell interconnected pores. Foamed PETA-co-TMPTMP HA composite shows promise as an alternative to FDA-approved biopolymers for bone tissue engineering applications. PMID- 23629853 TI - One-dimensional CdS nanostructures: a promising candidate for optoelectronics. AB - As a promising candidate for optoelectronics, one-dimensional CdS nanostructures have drawn great scientific and technical interest due to their interesting fundamental properties and possibilities of utilization in novel promising optoelectronical devices with augmented performance and functionalities. This progress report highlights a selection of important topics pertinent to optoelectronical applications of one-dimensional CdS nanostructures over the last five years. This article begins with the description of rational design and controlled synthesis of CdS nanostructure arrays, alloyed nanostructucures and kinked nanowire superstructures, and then focuses on the optoelectronical properties, and applications including cathodoluminescence, lasers, light emitting diodes, waveguides, field emitters, logic circuits, memory devices, photodetectors, gas sensors, photovoltaics and photoelectrochemistry. Finally, the general challenges and the potential future directions of this exciting area of research are highlighted. PMID- 23629852 TI - Metal ions activate vascular endothelial cells and increase lymphocyte chemotaxis and binding. AB - Metal on metal articulations in hip arthroplasty offer advantages, including lower volumetric wear compared to conventional metalonpolyethylene bearings, and increased resistance to dislocation. Reports described early failures, with histologic features similar to a Type IV immune response. Mechanisms by which metal wear products cause this reaction are not completely understood. We hypothesized a mechanism through direct activation of endothelial cells (ECs) by metal ions, resulting in both vasculitis and accumulation of lymphocytes without prior immune sensitization. Effects of metal ions were evaluated using human ECs in culture. Alterations in chemotactic proteins IL8 and MCP1 were assessed, as was upregulation of the adhesion molecule ICAM-1 and lymphocyte binding to ECs. Cobalt increased secretion of IL8 and MCP1 significantly, and upregulated the expression of ICAM-1 in ECs compared to stimulation by chromium and controls. Binding of lymphocytes to ECs and transEC migration were both significantly increased by cobalt but not chromium. These findings suggest that cobalt contributes more to the activation of ECs and lymphocyte binding than chromium without an allergic response. Some of the adverse tissue reactions to implants with components made of cobalt-chromium-molybdenium alloys may be due in part to activation of the endothelium by metal ions. PMID- 23629854 TI - Determination of polycyclic aromatic hydrocarbon metabolites in milk by a quick, easy, cheap, effective, rugged and safe extraction and capillary electrophoresis. AB - We describe the first application of a quick, easy, cheap, effective, rugged and safe extraction technique to the CZE analysis of monohydroxylated metabolites of polycyclic aromatic hydrocarbons in milk. Complete resolution of 2 hydroxyfluorenene, 1-hydroxynaphthalene, 2-hydroxynaphthalene, 3 hydroxyphenanthrene, and 9-hydroxyphenanthrene was accomplished in 4 min of electrophoretic run. Limits of detection at the parts-per-billion were obtained with a single solvent (acetonitrile) for metabolite extraction and sample stacking. The small sample volume (1.2 mL) and the conservative usage of chemicals provided a simple and rapid procedure for the simultaneous extraction of numerous samples. Adding 4 min of electrophoretic run per sample, it should be possible to screen ten samples in approximately 1 h of analysis time. The nanoliter extract volume required for sample injection allows for further chromatographic usage and confirmation of positive samples. The unique electrophoretic pattern of the studied metabolites demonstrates the potential for the unambiguous determination of positional isomers with very similar chromatographic behaviors and undistinguishable mass fragmentation patterns. PMID- 23629855 TI - Dimensionality reduction for registration of high-dimensional data sets. AB - Registration of two high-dimensional data sets often involves dimensionality reduction to yield a single-band image from each data set followed by pairwise image registration. We develop a new application-specific algorithm for dimensionality reduction of high-dimensional data sets such that the weighted harmonic mean of Cramer-Rao lower bounds for the estimation of the transformation parameters for registration is minimized. The performance of the proposed dimensionality reduction algorithm is evaluated using three remotes sensing data sets. The experimental results using mutual information-based pairwise registration technique demonstrate that our proposed dimensionality reduction algorithm combines the original data sets to obtain the image pair with more texture, resulting in improved image registration. PMID- 23629856 TI - Towards online iris and periocular recognition under relaxed imaging constraints. AB - Online iris recognition using distantly acquired images in a less imaging constrained environment requires the development of a efficient iris segmentation approach and recognition strategy that can exploit multiple features available for the potential identification. This paper presents an effective solution toward addressing such a problem. The developed iris segmentation approach exploits a random walker algorithm to efficiently estimate coarsely segmented iris images. These coarsely segmented iris images are postprocessed using a sequence of operations that can effectively improve the segmentation accuracy. The robustness of the proposed iris segmentation approach is ascertained by providing comparison with other state-of-the-art algorithms using publicly available UBIRIS.v2, FRGC, and CASIA.v4-distance databases. Our experimental results achieve improvement of 9.5%, 4.3%, and 25.7% in the average segmentation accuracy, respectively, for the UBIRIS.v2, FRGC, and CASIA.v4-distance databases, as compared with most competing approaches. We also exploit the simultaneously extracted periocular features to achieve significant performance improvement. The joint segmentation and combination strategy suggest promising results and achieve average improvement of 132.3%, 7.45%, and 17.5% in the recognition performance, respectively, from the UBIRIS.v2, FRGC, and CASIA.v4-distance databases, as compared with the related competing approaches. PMID- 23629857 TI - Cluster-based co-saliency detection. AB - Co-saliency is used to discover the common saliency on the multiple images, which is a relatively underexplored area. In this paper, we introduce a new cluster based algorithm for co-saliency detection. Global correspondence between the multiple images is implicitly learned during the clustering process. Three visual attention cues: contrast, spatial, and corresponding, are devised to effectively measure the cluster saliency. The final co-saliency maps are generated by fusing the single image saliency and multiimage saliency. The advantage of our method is mostly bottom-up without heavy learning, and has the property of being simple, general, efficient, and effective. Quantitative and qualitative experiments result in a variety of benchmark datasets demonstrating the advantages of the proposed method over the competing co-saliency methods. Our method on single image also outperforms most the state-of-the-art saliency detection methods. Furthermore, we apply the co-saliency method on four vision applications: co segmentation, robust image distance, weakly supervised learning, and video foreground detection, which demonstrate the potential usages of the co-saliency map. PMID- 23629858 TI - Artistic image analysis using graph-based learning approaches. AB - We introduce a new methodology for the problem of artistic image analysis, which among other tasks, involves the automatic identification of visual classes present in an art work. In this paper, we advocate the idea that artistic image analysis must explore a graph that captures the network of artistic influences by computing the similarities in terms of appearance and manual annotation. One of the novelties of our methodology is the proposed formulation that is a principled way of combining these two similarities in a single graph. Using this graph, we show that an efficient random walk algorithm based on an inverted label propagation formulation produces more accurate annotation and retrieval results compared with the following baseline algorithms: bag of visual words, label propagation, matrix completion, and structural learning. We also show that the proposed approach leads to a more efficient inference and training procedures. This experiment is run on a database containing 988 artistic images (with 49 visual classification problems divided into a multiclass problem with 27 classes and 48 binary problems), where we show the inference and training running times, and quantitative comparisons with respect to several retrieval and annotation performance measures. PMID- 23629859 TI - Self-supervised online metric learning with low rank constraint for scene categorization. AB - Conventional visual recognition systems usually train an image classifier in a bath mode with all training data provided in advance. However, in many practical applications, only a small amount of training samples are available in the beginning and many more would come sequentially during online recognition. Because the image data characteristics could change over time, it is important for the classifier to adapt to the new data incrementally. In this paper, we present an online metric learning method to address the online scene recognition problem via adaptive similarity measurement. Given a number of labeled data followed by a sequential input of unseen testing samples, the similarity metric is learned to maximize the margin of the distance among different classes of samples. By considering the low rank constraint, our online metric learning model not only can provide competitive performance compared with the state-of-the-art methods, but also guarantees convergence. A bi-linear graph is also defined to model the pair-wise similarity, and an unseen sample is labeled depending on the graph-based label propagation, while the model can also self-update using the more confident new samples. With the ability of online learning, our methodology can well handle the large-scale streaming video data with the ability of incremental self-updating. We evaluate our model to online scene categorization and experiments on various benchmark datasets and comparisons with state-of-the art methods demonstrate the effectiveness and efficiency of our algorithm. PMID- 23629861 TI - Basic evidence for epidermal H2O2/ONOO(-)-mediated oxidation/nitration in segmental vitiligo is supported by repigmentation of skin and eyelashes after reduction of epidermal H2O2 with topical NB-UVB-activated pseudocatalase PC-KUS. AB - Nonsegmental vitiligo (NSV) is characterized by loss of inherited skin color. The cause of the disease is still unknown despite accumulating in vivo and in vitro evidence of massive epidermal oxidative stress via H2O2 and peroxynitrite (ONOO( )) in affected individuals. The most favored hypothesis is based on autoimmune mechanisms. Strictly segmental vitiligo (SSV) with dermatomal distribution is a rare entity, often associated with stable outcome. Recently, it was documented that this form can be associated with NSV (mixed vitiligo). We here asked the question whether ROS and possibly ONOO(-) could be players in the pathogenesis of SSV. Our in situ results demonstrate for the first time epidermal biopterin accumulation together with significantly decreased epidermal catalase, thioredoxin/thioreoxin reductase, and MSRA/MSRB expression. Moreover, we show epidermal ONOO(-) accumulation. In vivo FT-Raman spectroscopy reveals the presence of H2O2, methionine sulfoxide, and tryptophan metabolites; i.e., N formylkynurenine and kynurenine, implying Fenton chemistry in the cascade (n=10). Validation of the basic data stems from successful repigmentation of skin and eyelashes in affected individuals, regardless of SSV or segmental vitiligo in association with NSV after reduction of epidermal H2O2 (n=5). Taken together, our contribution strongly supports H2O2/ONOO-mediated stress in the pathogenesis of SSV. Our findings offer new treatment intervention for lost skin and hair color. PMID- 23629862 TI - Leukotriene B4 type-1 receptor signaling promotes liver repair after hepatic ischemia/reperfusion injury through the enhancement of macrophage recruitment. AB - Recruited macrophages play a critical role in liver repair after acute liver injury. Leukotriene B4 (LTB4) is a potent chemoattractant for macrophages. In this study, we investigated the role of LTB4 receptor type 1 (BLT1) in liver repair during hepatic ischemia/reperfusion (I/R) injury. BLT1-knockout mice (BLT1(-/-)) or their wild-type counterparts (WT) were subjected to partial hepatic I/R. Compared with WT, BLT1(-/-) exhibited delayed liver repair and hepatocyte proliferation accompanied by a 70% reduction in the recruitment of macrophages and a 70-80% attenuation in hepatic expression of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1). Disruption of BLT1 signaling also reduced the expression of EGF by 67% on recruited macrophages expressing VEGFR1 in the injured liver. Treatment of WT mice with an EGF-neutralizing antibody delayed liver repair and reduced macrophage recruitment, compared with control immunoglobulin G (IgG). BLT1 signaling enhanced the expression of VEGF, VEGFR1, and EGF in isolated peritoneal macrophages in vitro. These results indicate that BLT1 signaling plays a role in liver repair after hepatic I/R through enhanced expression of EGF in recruited macrophages and that the development of a specific agonist for BLT1 could be useful for liver recovery from acute liver injury. PMID- 23629860 TI - Epidermal growth factor-induced cellular invasion requires sphingosine-1 phosphate/sphingosine-1-phosphate 2 receptor-mediated ezrin activation. AB - Ezrin, radixin, and moesin (ERM) proteins link cortical actin to the plasma membrane and coordinate cellular events that require cytoskeletal rearrangement, including cell division, migration, and invasion. While ERM proteins are involved in many important cellular events, the mechanisms regulating their function are not completely understood. Our laboratory previously identified reciprocal roles for the sphingolipids ceramide and sphingosine-1-phosphate (S1P) in the regulation of ERM proteins. We recently showed that ceramide-induced activation of PP1alpha leads to dephosphorylation and inactivation of ERM proteins, while S1P results in phosphorylation and activation of ERM proteins. Following these findings, we aimed to examine known inducers of the SK/S1P pathway and evaluate their ability to regulate ERM proteins. We examined EGF, a known inducer of the SK/S1P pathway, for its ability to regulate the ERM family of proteins. We found that EGF induces ERM c-terminal threonine phosphorylation via activation of the SK/S1P pathway, as this was prevented by siRNA knockdown or pharmacological inhibition of SK. Using pharmacological, as well as genetic, knockdown approaches, we determined that EGF induces ERM phosphorylation via activation of S1PR2. In addition, EGF led to cell polarization in the form of lamellipodia, and this occurred through a mechanism involving S1PR2-mediated phosphorylation of ezrin T567. EGF-induced cellular invasion was also found to be dependent on S1PR2 induced T567 ezrin phosphorylation, such that S1PR2 antagonist, JTE-013, and expression of a dominant-negative ezrin mutant prevented cellular invasion toward EGF. In this work, a novel mechanism of EGF-stimulated invasion is unveiled, whereby S1P-mediated activation of S1PR2 and phosphorylation of ezrin T567 is required. PMID- 23629863 TI - Resolvin E1 regulates osteoclast fusion via DC-STAMP and NFATc1. AB - Interactions between the immune and skeletal systems in inflammatory bone diseases are well appreciated, but the underlying molecular mechanisms that coordinate the resolution phase of inflammation and bone turnover have not been unveiled. Here we investigated the direct actions of the proresolution mediator resolvin E1 (RvE1) on bone-marrow-cell-derived osteoclasts in an in vitro murine model of osteoclast maturation and inflammatory bone resorption. Investigation of the actions of RvE1 treatment on the specific stages of osteoclast maturation revealed that RvE1 targeted late stages of osteoclast maturation to decrease osteoclast formation by 32.8%. Time-lapse vital microscopy and migration assays confirmed that membrane fusion of osteoclast precursors was inhibited. The osteoclast fusion protein DC-STAMP was specifically targeted by RvE1 receptor binding and was down-regulated by 65.4%. RvE1 did not affect the induction of the essential osteoclast transcription factor nuclear factor of activated T cells c1 (NFATc1) or its nuclear translocation; however, NFATc1 binding to the DC-STAMP promoter was significantly inhibited by 60.9% with RvE1 treatment as shown in electrophoresis mobility shift assay. Our findings suggest that proresolution mediators act directly on osteoclasts, in addition to down-regulation of inflammation, providing a novel mechanism for modulating osteoclast signaling in osteolytic inflammatory disease. PMID- 23629864 TI - Expansion of an osteopontin-expressing T follicular helper cell subset correlates with autoimmunity in B6.Sle1b mice and is suppressed by the H1-isoform of the Slamf6 receptor. AB - The costimulatory receptor Slamf6 partially controls lupus-related autoimmunity in congenic Sle1b mice; for instance, the presence of the protein isoform Slamf6 H1 in Sle1b.Slamf6-H1 mice mitigates disease. Here, we report that young Sle1b mice, but not Sle1b.Slamf6-H1 or B6 mice, contain a memory T-helper cell subset identified by ]mt]2-fold increase in expression of 17 genes, chief among which is Spp1, encoding the cytokine osteopontin (OPN). These T follicular helper (TFH) cells, including OPN(+) TFH cells, expand concomitantly with severity of the disease. By contrast, Sle1b.Slamf6-H1 or Sle1b.SAP(-)/(-) mice do not develop autoantibodies and the number of T(FH) cells is 5 times lower than in age-matched Sle1b mice. By comparing Sle1b and Sle1b.OPN(-)/(-) mice, we find that the lack of OPN expression impedes early autoantibody production. Furthermore, on the adoptive transfer of Sle1b.OPN(-)/(-) CD4(+) T cells into bm12 recipients autoantibody production and germinal center formation is reduced compared to recipients of Sle1b.OPN(+/+) CD4(+) T cells. We propose a model in which OPN provides a survival signal for a precursor T(FH) cell subset, which is a key factor in autoimmunity. PMID- 23629865 TI - US valuation of the SF-6D. AB - BACKGROUND: The original SF-6D valuation study collected 3503 standard gambled responses from 611 UK respondents to predict quality-adjusted life year (QALY) values. METHODS: Using 19,980 paired comparison responses from 666 US respondents and a stacked probit model, the 25 coefficients of the original SF-6D multiattribute utility (MAU) regression were estimated, such that each coefficient represents a QALY decrement. The US QALY predictions were compared with UK predictions using 8428 SF-6D states in the US Medicare Health Outcomes Survey (MHOS), 1998 to 2003. RESULTS: Twenty-two of the 25 decrements in the SF 6D MAU regression are statistically significant. The remaining decrements are insignificant based on US and UK results. The US and UK QALY predictions for the MHOS SF-6D states are remarkably similar given differences in experimental design, format, and sampling (Lin's coefficient of agreement, 0.941; absolute mean difference, 0.043). Limitations. The underlying theoretical framework for the STUDY DESIGN: and econometric analysis builds from the episodic random utility model and the concept of QALYs and inherits their limitations. CONCLUSIONS: This study enhances the potential for US comparative effectiveness research by translating SF-6D states into US QALYs as well as improves upon discrete choice experiment design and econometric methods for health valuation. PMID- 23629866 TI - Inflammation markers: new actors in the cancer biomarker tale. PMID- 23629867 TI - H-coil repetitive transcranial magnetic stimulation for pain relief in patients with diabetic neuropathy. AB - BACKGROUND: Painful neuropathy is associated with plasticity changes in the nervous system. Standard repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique used to study changes in cortical excitability and to inhibit pain perception. Deep rTMS is a newer development that allows direct activation of deeper neuronal populations, by a unique coil design termed the H coil. This study was designed to assess whether deep rTMS applied over the motor cortical lower-limb representation relieves pain in patients with diabetic neuropathy. METHODS: Patients were randomly assigned to receive daily real or sham H-coil rTMS for 5 consecutive days. After a 5-week washout period, they crossed over to the alternative treatment for additional 5 days (according to a crossover study design). Outcome measures were changes in the visual analogue scale (VAS) for pain and in area and threshold of RIII nociceptive flexion reflex (RIII reflex). RESULTS: Of the 25 patients randomized, 23 completed the study. After real rTMS, the VAS scores decreased significantly (p=0.01), and so did RIII reflex area (p<0.01), while no significant effects in these variables were induced by the sham rTMS treatment. The rTMS-induced changes in the outcome measures disappeared about 3 weeks after stimulation. All patients tolerated stimulation well. CONCLUSIONS: Deep H-coil rTMS provides pain relief in patients with diabetic neuropathy. This innovative technique can induce a therapeutic effect on brain areas that otherwise remain difficult to target. rTMS may produce its analgesic effects, inducing motor cortex plasticity and activating descending inhibitory pain control systems. PMID- 23629869 TI - Neuromuscular ultrasound in polyneuropathies and motor neuron disease. AB - Current standards for diagnosing polyneuropathies (PN) and motor neuron disease (MND) sometimes lack early sensitivity and result in delayed diagnosis and treatment. Neuromuscular ultrasound (NMUS), already established in the diagnosis of entrapment neuropathies, may offer another means of diagnosis and monitoring response to therapy. This review of current evidence discusses diffuse nerve hypertrophy in hereditary demyelinating neuropathies, multifocal nerve enlargement in acquired demyelinating PN and the lack of readily apparent structural change in axonal neuropathies. NMUS detection of fasciculations and muscular change in MND is also reviewed, along with the need for further research to better define the role of nerve imaging in patients with PN. PMID- 23629868 TI - A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile. AB - The Clostridium difficile toxins A and B are primarily responsible for symptoms of C. difficile associated disease and are prime targets for vaccine development. We describe a plasmid-based system for the production of genetically modified toxins in a non-sporulating strain of C. difficile that lacks the toxin genes tcdA and tcdB. TcdA and TcdB mutations targeting established glucosyltransferase cytotoxicity determinants were introduced into recombinant plasmids and episomally expressed toxin mutants purified from C. difficile transformants. TcdA and TcdB mutants lacking glucosyltransferase and autoproteolytic processing activities were ~10 000-fold less toxic to cultured human IMR-90 cells than corresponding recombinant or native toxins. However, both mutants retained residual cytotoxicity that could be prevented by preincubating the antigens with specific antibodies or by formalin treatment. Such non-toxic formalin-treated mutant antigens were immunogenic and protective in a hamster model of infection. The remaining toxicity of untreated TcdA and TcdB mutant antigens was associated with cellular swelling, a phenotype consistent with pore-induced membrane leakage. TcdB substitution mutations previously shown to block vesicular pore formation and toxin translocation substantially reduced residual toxicity. We discuss the implications of these results for the development of a C. difficile toxoid vaccine. PMID- 23629870 TI - [Acute effects of postactivation potentiation on strength and speed performance in athletes]. AB - BACKGROUND: The contractile history of a muscle or a muscle group can result in an acute enhancement of subsequent muscle force output. This phenomenon is referred to as postactivation potentiation (PAP) and it was frequently substantiated in original research manuscripts, systematic literature reviews, and meta-analyses. However, there is a lack in the literature regarding precise dose-response relations. This literature review describes the main determinants of PAP effects and additionally presents the state of the art regarding the acute effects of PAP protocols on measures of strength, power, and speed in subelite and elite athletes of different sport disciplines. Furthermore, an attempt is made to demonstrate evidence-based information concerning the design of effective PAP protocols. METHODS: Our literature search included the electronic databases Pubmed, SportDiscus, and Google Scholar (1995-March 2013). In total, 23 studies met the inclusionary criteria for review. RESULTS: Findings from our literature review indicate that various conditioning activities produce acute PAP effects in subelite and particularly elite athletes. More specifically, conditioning activities that are characterised by multiple sets, moderate to high intensities (60-84 % of the one repetition maximum), and rest intervals of 7-10 min. following the conditioning activity have the potential to induce short-term improvements in muscle force output and sports performance. CONCLUSION: It is recommended that subelite and particularly elite athletes from strength, power, and speed disciplines apply specifically tailored conditioning activities during the acute preparation process for competition to induce performance enhancing PAP effects. PMID- 23629871 TI - Functional and morphological impact of ER stress on mitochondria. AB - Over the past years, knowledge and evidence about the existence of crosstalks between cellular organelles and their potential effects on survival or cell death have been constantly growing. More recently, evidence accumulated showing an intimate relationship between endoplasmic reticulum (ER) and mitochondria. These close contacts not only establish extensive physical links allowing exchange of lipids and calcium but they can also coordinate pathways involved in cell life and death. It is now obvious that ER dysfunction/stress and unfolded protein response (UPR) as well as mitochondria play major roles in apoptosis. However, while the effects of major ER stress on cell death have been largely studied and reviewed, it becomes more and more evident that cells might regularly deal with sublethal ER stress, a condition that does not necessarily lead to cell death but might affect the function/activity of other organelles such as mitochondria. In this review, we will particularly focus on these new, interesting and intriguing metabolic and morphological events that occur during the early adaptative phase of the ER stress, before the onset of cell death, and that remain largely unknown. Relevance and implication of these mitochondrial changes in response to ER stress conditions for human diseases such as type II diabetes and Alzheimer's disease will also be considered. PMID- 23629872 TI - Ruthenium-catalyzed carbonylative C-C coupling in water by directed C-H bond activation. PMID- 23629873 TI - UPLC-ESI/MS determination of 17 active constituents in two categorized formulas of traditional Chinese medicine, Sanhuang Xiexin Tang and Fuzi Xiexin Tang: application in comparing the differences in decoctions and macerations. AB - A rapid and sensitive UPLC-ESI/MS method was established and validated to determine 17 active constituents (aconitine, hypaconitine, mesaconitine, benzoylaconine, benzoylhypaconine, benzoylmesaconine, berberine, palmatine, jatrorrhizine, coptisine, baicalein, wogonin, baicalin, wogonoside, emodin, aloe emodin and rhein) in Sanhuang Xiexin Tang (SXT) and Fuzi Xiexin Tang (FXT), which are two classic compound recipes from Xiexin Tang categorized formulas in traditional Chinese medicien. The separation was performed on a UPLC BEH C18 column gradient eluted using acetonitrile and 0.1% formic acid as mobile phase. ESI/MS was operated in positive ([M + H](+)) in selected ion recording mode for analysis of alkaloids and flavones, while in negative ([M - H](-)) selected ion recording mode for anthraquinones. All of the 17 constituents exhibited good linearity in a relatively wide concentration ranges with the lowest limits of detection of 0.38 ng/mL. All of the relative standard deviation values of intra- and inter-precisions and stabilities of 17 constituents were within 5%. The method was successfully applied to determine 17 active constituents in decoctions and macerations of SXT and FXT. The results indicated that different preparative methods resulted in significant diversity in concentrations of the 17 analytes. Herb-herb interaction appeared between aconitum alkaloids in Aconiti Lateralis Radix Preparata and another three herbs. PMID- 23629874 TI - The serial intervals of seasonal and pandemic influenza viruses in households in Bangkok, Thailand. AB - The serial interval (SI) of human influenza virus infections is often described by a single distribution. Understanding sources of variation in the SI could provide valuable information for understanding influenza transmission dynamics. Using data from a randomized household study of nonpharmaceutical interventions to prevent influenza transmission in Bangkok, Thailand, over 34 months between 2008 and 2011, we estimated the influence of influenza virus type/subtype and other characteristics of 251 pediatric index cases and their 315 infected household contacts on estimates of household SI. The mean SI for all households was 3.3 days. Relative to influenza A(H1N1)pdm09 (3.1 days), the SI for influenza B (3.7 days) was 22% longer (95% confidence interval: 4, 43), or about half a day. The SIs for influenza viruses A(H1N1) and A(H3N2) were similar to that for A(H1N1)pdm09. SIs were shortest for older index cases (age 11-14 years) and for younger infected household contacts (age <=15 years). Greater time spent in proximity to the index child was associated with shorter SIs. Differences in the SI might reflect differences in incubation period, viral shedding, contact, or susceptibility. These findings could improve parameterization of mathematical models to better predict the impact of epidemic or pandemic influenza mitigation strategies. PMID- 23629875 TI - A rapid and convenient method for preparative separation of three indissolvable polyphenols from Euphorbia pekinensis by the flexible application of solvent extraction combined with counter-current chromatography. AB - A rapid and convenient method was established to preparatively isolate the three ellagic acid types of compounds, which were the main polyphenols in Euphorbia pekinensis, by flexibly applying solvent extraction combined with counter-current chromatography (CCC). The total extract (extracted using 95% ethanol) of E. pekinensis was pretreated by two simple steps before CCC isolation, following the procedure: the total extract was extracted by classical solvent extraction using petroleum ether and ethyl acetate, respectively, and then the ethyl acetate extract was suspended using 95% ethanol, after being allowed to stand overnight, the sediment was obtained. Partial sediment (100 mg) was then directly separated by CCC with a two-phase solvent system composed of chloroform-95% ethanol-water 85% formic acid (50:50:50:5, v/v/v/v). About 22 mg of 3,3'-dimethoxy ellagic acid (1), 12 mg of 3,3'-di-O-methyl-4-O-(beta-D-xylopyranosyl)ellagic acid (2), and 35 mg of ellagic acid (3) with purities of 96.0, 95.2, and 95.4% were obtained respectively in one step within 4 h. After being purified by washing with methanol, the purities of the three compounds obtained were all above 98%. The purities were determined by HPLC and their chemical structures were further identified by (1)H and (13)C NMR spectroscopy. The recoveries were calculated as 84.6, 85.7, and 89.5%, respectively. The result demonstrated that the present isolation method was rapid, economical and efficient for the preparative separation of polyphenols from E. pekinensis. PMID- 23629876 TI - Reinforcing bioceramic scaffolds with in situ synthesized epsilon polycaprolactone coatings. AB - In situ ring-opening polymerization of epsilon-caprolactone (epsilon-CL) was performed to coat beta-tricalcium phosphate (beta-TCP) scaffolds fabricated by robocasting in order to enhance their mechanical performance while preserving the predesigned macropore architecture. Concentrated colloidal inks prepared from beta-TCP commercial powders were used to fabricate porous structures consisting of a three-dimensional mesh of interpenetrating rods. Then, epsilon-CL was in situ polymerized within the ceramic structure using a lipase as catalyst and toluene as solvent, to obtain a highly homogeneous coating and full impregnation of in-rod microporosity. The strength and toughness of scaffolds coated by epsilon-polycaprolactone (epsilon-PCL) were significantly increased (twofold and fivefold increase, respectively) over those of the bare structures. Enhancement of both properties is associated to the healing of preexisting microdefects in the bioceramic rods. These enhancements are compared to results from previous work on fully impregnated structures. The implications of the results for the optimization of the mechanical and biological performance of scaffolds for bone tissue engineering applications are discussed. PMID- 23629877 TI - Novel and recurrent mutations in the EXT1 and EXT2 genes in Chinese kindreds with multiple osteochondromas. AB - Multiple osteochondromas (MO) is an autosomal dominant hereditary disorder caused by heterozygous germline mutations in the exostonsin-1 (EXT1) or exostosin-2 (EXT2) genes. In this study, we screened mutations in the EXT1/EXT2 genes in four Chinese MO kindreds by direct sequencing. Three point mutations were detected, including a nonsense mutation in the EXT2 gene (c.544C > T) and two splice site mutations in the EXT1 and EXT2 genes, respectively (EXT1: c.1883 + 1G > A and EXT2: c.1173 + 1G > T). Although splice site mutations constitute at least 10% of all mutations that cause MO, there has been limited research on their pathogenic effect on RNA processing due to poor availability of patient RNA samples. In this study, ex vivo and in vivo splicing assays were used to investigate the effect of EXT1 and EXT2 mutations on aberrant splicing at the mRNA level. Our results indicate that identified splice site mutations can cause either cryptic splice site usage or exon skipping. PMID- 23629880 TI - Bioelectric fields of marine organisms: voltage and frequency contributions to detectability by electroreceptive predators. AB - Behavioral responses of elasmobranch fishes to weak electric fields have been well studied. These studies typically employ a stimulator that produces a dipole electric field intended to simulate the natural electric field of prey items. However, the characteristics of bioelectric fields have not been well described. The magnitude and frequency of the electric field produced by 11 families of marine organisms were quantified in this study. Invertebrate electric potentials ranged from 14 to 28 MUV and did not differ from those of elasmobranchs, which ranged from 18 to 30 MUV. Invertebrates and elasmobranchs produced electric potentials smaller than those of teleost fishes, which ranged from 39 to 319 MUV. All species produced electric fields within the frequency range that is detectable by elasmobranch predators (<16 Hz), with the highest frequencies produced by the penaeids (10.3 Hz) and the gerreids (4.6 Hz). Although voltage differed by family, there was no relationship between voltage and mass or length of prey. Differences in prey voltage may be related to osmoregulatory strategies; invertebrates and elasmobranchs are osmoconformers and have less ion exchange with the surrounding seawater than teleosts species, which are hyposmotic. As predicted, voltage production was greatest at the mucous membrane-lined mouth and gills, which are sites of direct ion exchange with the environment. PMID- 23629879 TI - Comparative visual function in predatory fishes from the Indian River Lagoon. AB - Visual temporal resolution and spectral sensitivity of three coastal teleost species (common snook [Centropomus undecimalis], gray snapper [Lutjanus griseus], and pinfish [Lagodon rhomboides]) were investigated by electroretinogram. Temporal resolution was quantified under photopic and scotopic conditions using response waveform dynamics and maximum critical flicker fusion frequency (CFFmax). Photopic CFFmax was significantly higher than scotopic CFFmax in all species. The snapper had the shortest photoreceptor response latency time (26.7 ms) and the highest CFFmax (47 Hz), suggesting that its eyes are adapted for a brighter photic environment. In contrast, the snook had the longest response latency time (36.8 ms) and lowest CFFmax (40 Hz), indicating that its eyes are adapted for a dimmer environment or nocturnal lifestyle. Species spectral responses ranged from 360 to 620 nm and revealed the presence of rods sensitive to dim and twilight conditions, as well as multiple cone visual pigments providing the basis for color and contrast discrimination. Collectively, our results demonstrate differences in visual function among species inhabiting the Indian River Lagoon system, representative of their unique ecology and life histories. PMID- 23629878 TI - The multiplicity of human formins: Expression patterns in cells and tissues. AB - Formins are actin-binding proteins conserved across species from plants to humans. The formin family is defined by their common formin homology (FH2) domains. The 15 distinct human formins are involved in a broad range of cellular functions, including cell adhesion, cytokinesis, cell polarity, and cell morphogenesis. Their commonality is actin polymerization activity inherent to FH2 domains. Although still requiring much study, biochemical activity of formins has been carefully described. In contrast, much less is known of their activities in complex living systems. With the diversity of the formin family and the actin structures that they affect, an extensive future of study beckons. In this study, we report the expression level of all 15 formins in 22 different human cell and tissue types using quantitative real-time PCR. Identification of major themes in formin expression and documentation of expression profiles should facilitate the cellular study of formins. PMID- 23629881 TI - Dietary carotenoids increase yellow nonpigment coloration of female convict cichlids (Amantitlania nigrofasciata). AB - The carotenoid trade-off hypothesis states that diet-derived carotenoids are traded off among competing physiological demands, but this statement is rarely tested in ornamented females. In this study, reverse sexually dimorphic convict cichlids (Amantitlania nigrofasciata) were fed diets containing carotenoid supplementation at three biologically relevant levels for 12 wk. This treatment was followed by spectral, microscopic, and chemical analysis to determine how females allocated the pigments to tissues and how those decisions affected their ventral patch coloration. Yellow coloration of the integument increased with carotenoids in the diet, as did carotenoids deposited in ovaries, but diet did not change carotenoid allocation to skin. The results of this study suggest that females have the ability to modulate their expression of yellow coloration via an alternative coloration strategy. Gonadosomatic index and tank environment were also related to ventral patch color, supporting previous behavioral work highlighting the importance of social selection in reinforcing signal honesty. PMID- 23629882 TI - Effect of prenatal and natal administration of testosterone on production of structurally based plumage coloration. AB - Testosterone has been implicated as a developmental mechanism involved in the organization and expression of sexually dimorphic traits, such as plumage coloration, in birds. Although research findings relating testosterone levels to plumage expression is equivocal, few studies have investigated how testosterone may influence the expression of structurally based plumage coloration. Here, we use experimental and correlational evidence to test the hypothesis that testosterone influences the development and maintenance of structurally based plumage coloration in a wild-breeding population of eastern bluebirds (Sialia sialis). First, we experimentally manipulated yolk testosterone and measured the effect on the development of plumage coloration of nestlings. Second, we implanted juvenile bluebirds with testosterone and measured the effect on nestling growth, body condition, and plumage coloration of nestlings. Third, we measured covariation between circulating testosterone and plumage coloration of breeding males. Yolk testosterone injections had no significant effect on nestling plumage coloration. Testosterone implantation, however, caused a reduction in plumage brightness, elevated corticosterone, and slower growth in nestlings. Finally, in breeding adult males we found no significant relationship between structural coloration and testosterone; however, males with higher testosterone levels exhibited duller chestnut (melanin-based) plumage. Our observations lead us to reject the hypothesis that testosterone increases structural plumage coloration in male eastern bluebirds. PMID- 23629883 TI - Effects of prenatal testosterone exposure on antioxidant status and bill color in adult zebra finches. AB - Permanent offspring modification through maternal hormone transfer is thought to be a tool for mothers to influence life-history trajectories of individual offspring. In birds, yolk hormones influence numerous aspects of the offspring's physiology, including antioxidant status, an important physiological measure that is linked to growth, reproductive effort, and survival. While it is evident that yolk hormones can affect antioxidant status of nestlings, it is not known whether their effect extends beyond the nestling stage. In this study, we use the zebra finch (Taeniopygia guttata) to test experimentally whether exposure to elevated yolk testosterone (T) levels can result in long-term effects on antioxidant status and traits likely to be associated with this measure. Our data show a significant but sex-specific effect with respect to a period from fledging to the age of 7 mo; T males had higher antioxidant status than control males, whereas antioxidant levels did not differ among females and were intermediate compared with the two male groups. Bill color, a trait associated with carotenoids (a specific group of antioxidants) and known to be under the control of circulating levels of T, was not affected by our yolk T manipulation. Bill color (alone or in covariation with egg treatment or sex) did not predict immune responsiveness or antioxidant status. Moreover, there was only weak evidence that antioxidant status predicted the strength of different immune responses. Antioxidant status (in covariation with egg treatment and sex) predicted levels of circulating total antibody levels but did not predict the strength of cell-mediated and humoral immune responses. Our results suggest that yolk T affects antioxidant status independently of these other traits. PMID- 23629884 TI - Baseline corticosterone in wintering marine birds: methodological considerations and ecological patterns. AB - Previous studies have related levels of plasma corticosterone (CORT) of seabirds to variation in foraging conditions during the breeding period, but it is unclear whether similar relationships between foraging conditions and baseline CORT exist during other life stages. We validated methods for identifying baseline CORT of lethally sampled birds and assessed variation in baseline CORT relative to winter habitat conditions. We collected free-living white-winged scoters (Melanitta fusca) at four wintering sites during December and February. We found increasing CORT values beyond 3 min after time since flush (the duration between initial flush and death), presumably reflecting acute stress responses. Our results demonstrate that it is possible to obtain baseline CORT from lethally sampled birds if the time from initial flush until death is measured. Our study sites varied appreciably in exposure to wind and waves, predation danger, diving depths, and the fraction of preferred foods in scoter diets. Despite these habitat differences, baseline CORT did not vary across sites or winter periods. We interpret this lack of variation as evidence that birds select wintering areas where they can successfully manage site-specific costs and maintain physiological homeostasis. PMID- 23629885 TI - Time course and metabolic costs of a humoral immune response in the little ringed plover Charadrius dubius. AB - Despite host defense against parasites and pathogens being considered a costly life-history trait, relatively few studies have assessed the energetic cost of immune responsiveness. Knowledge of such energetic costs may help to understand the mechanisms by which trade-offs with other demanding activities occur. The time course and associated metabolic costs of mounting a primary and secondary humoral immune response was examined in little ringed plovers Charadrius dubius challenged with sheep red blood cells. As was expected, the injection with this antigen increased the production of specific antibodies significantly, with peaks 6 d postinjection in both primary and secondary responses. At the peak of secondary antibody response, the antibody production was 29% higher than that observed during the primary response, but the difference was nonsignificant. Mounting the primary response did not significantly increase the resting metabolic rate (RMR) of birds, whereas the secondary response did by 21%, suggesting that the latter was more costly in terms of RMR. In spite of the fact that the primary response did not involve an increase in RMR, birds significantly decreased their body mass. This could imply an internal energy reallocation strategy to cope with the induced immune challenge. Last, we found that RMR and antibody production peaks were not coupled, which could help to conciliate the variable results of previous studies. Collectively, the results of this study support the hypothesis that humoral immunity, especially the secondary response, entails energetic costs that may trade-off with other physiological activities. PMID- 23629886 TI - Balancing the energy budget in free-ranging male Myotis daubentonii bats. AB - Mammals use five main, mutually nonexclusive mechanisms to balance energy budgets: torpor, metabolic compensation, change in activity patterns, change in ingested energy, and/or variability in digestive efficiency. Bats, as small and actively flying mammals, have a high mass-specific energy demand; therefore, balancing mechanisms should be pronounced in this group. We found that male Myotis daubentonii exhibited marked variation in the relative importance of these different mechanisms during their period of seasonal activity in response to extrinsic (ambient temperature, insect abundance) and intrinsic (reproduction, body condition) factors. Cold ambient temperatures in spring facilitated long and frequent daily torpor bouts, whereas in early summer, increased energy intake was the dominant factor in energy balancing. Intake was further increased in late summer, when insect abundance was highest, and daily torpor bouts were shorter and less frequent than in early summer. In autumn, males used metabolic compensation to reduce their resting metabolic rate in addition to daily torpor. Metabolic compensation might be one of the mechanisms that allow males to maintain high body temperature during the day while decreasing the need for foraging time at night, thus maximizing their opportunities to mate. PMID- 23629887 TI - Reduced heart rate and cardiac output differentially affect angiogenesis, growth, and development in early chicken embryos (Gallus domesticus). AB - An increase in both vascular circumferential tension and shear stress in the developing vasculature of the chicken embryo has been hypothesized to stimulate angiogenesis in the developing peripheral circulation chorioallantoic membrane (CAM). To test this hypothesis, angiogenesis in the CAM, development, and growth were measured in the early chicken embryo, following acute and chronic topical application of the purely bradycardic drug ZD7288. At hour 56, ZD7288 reduced heart rate (f(H)) by ~30% but had no significant effect on stroke volume (~0.19 +/- 0.2 MUL), collectively resulting in a significant fall in cardiac output (CO) from ~27 +/- 3 to 18 +/- 2 MUL min(-1). Mean f(H) at 72 h of development was similarly significantly lowered by acute ZD7288 treatment (250 MUM) to 128 +/- 0.3 beats min(-1), compared with 174.5 +/- 0.3 and 174.7 +/- 0.8 beats min(-1) in control and Pannett-Compton (P-C) saline-treated embryos, respectively. Chronic dosing with ZD7288-and the attendant decreases in f(H) and CO-did not change eye diameter or cervical flexion (key indicators of development rate) at 120 h but significantly reduced overall growth (wet and dry body mass decreased by 20%). CAM vessel density index (reflecting angiogenesis) measured 200-400 MUm from the umbilical stalk was not altered, but ZD7288 reduced vessel numbers-and therefore vessel density-by 13%-16% more distally (500-600 MUm from umbilical stalk) in the CAM. In the ZD7288-treated embryos, a decrease in vessel length was found within the second branch order (~300-400 MUm from the umbilical stock), while a decrease in vessel diameter was found closer to the umbilical stock, beginning in the first branch order (~200-300 MUm). Paradoxically, chronic application of P-C saline also reduced peripheral CAM vessel density index at 500 and 600 MUm by 13% and 7%, respectively, likely from washout of local angiogenic factors. In summary, decreased f(H) with reduced CO did not slow development rate but reduced embryonic growth rate and angiogenesis in the CAM periphery. This study demonstrates for the first time that different processes in the ontogeny of the early vertebrate embryo (i.e., hypertrophic growth vs. development) have differential sensitivities to altered convective blood flow. PMID- 23629889 TI - Ternary K2Zn5As4-type pnictides Rb2Cd5As4 and Rb2Zn5Sb4, and the solid solution Rb2Cd5(As,Sb)4. AB - Dirubidium pentacadmium tetraarsenide, Rb2Cd5As4, dirubidium pentazinc tetraantimonide, Rb2Zn5Sb4, and the solid-solution phase dirubidium pentacadmium tetra(arsenide/antimonide), Rb2Cd5(As,Sb)4 [or Rb2Cd5As3.00(1)Sb1.00(1)], have been prepared by direct reaction of the component elements at high temperature. These compounds are charge-balanced Zintl phases and adopt the orthorhombic K2Zn5As4-type structure (Pearson symbol oC44), featuring a three-dimensional [M5Pn4](2-) framework [M = Zn or Cd; Pn is a pnicogen or Group 15 (Group V) element] built of linked MPn4 tetrahedra, and large channels extending along the b axis which host Rb(+) cations. The As and Sb atoms in Rb2Cd5(As,Sb)4 are randomly disordered over the two available pnicogen sites. Band-structure calculations predict that Rb2Cd5As4 is a small-band-gap semiconductor and Rb2Zn5Sb4 is a semimetal. PMID- 23629890 TI - A new oxyfluorotellurate(IV), InTe2O5F. AB - A new oxyfluorotellurate(IV), indium fluoridopentaoxidotellurate(IV), InTe2O5F, has been synthesized by solid-state reaction and structurally characterized. The crystal structure consists of a three-dimensional framework formed by InO4F2 octahedra and Te2O5 units. The InO4F2 octahedra are linked through the F atoms, which lie on twofold axes, giving rise to helical chains. These helical chains are connected via the Te2O5 units. The helical chains of indium octahedra surround cavities, into which the lone pairs of electrons of the Te atoms point. PMID- 23629891 TI - A square-pyramidal copper(II) complex with strong intramolecular hydrogen bonds: diaqua(N,N'-dimethylformamide-kappaO)bis[2-(diphenylphosphoryl)benzoato kappaO]copper(II). AB - In the title Cu(II) complex, [Cu(C19H14O3P)2(C3H7NO)(H2O)2], the molecule is bisected by a twofold axis relating the two 2-(diphenylphosphoryl)benzoate (ODPPB) ligands. The asymmetric unit consists of a Cu(II) metal centre on the symmetry axis, an ODPPB ligand, one water ligand and one dimethylformamide (DMF) ligand (disordered around the twofold axis). The Cu(II) ion has fivefold coordination provided by two carboxylate O atoms from two ODPPB ligands, two O atoms from two coordinated water molecules and another O atom from a (disordered) DMF molecule, giving a CuO5 square-pyramidal coordination geometry. The ODPPB ligand adopts a terminal monocoordinated mode with two free O atoms forming two strong intramolecular hydrogen bonds with the coordinated water molecules, which may play a key role in the stability of the molecular structure, as shown by the higher release temperature for the coordinated water molecules than for the coordinated DMF molecule. The optical absorption properties of powder samples of the title compound have also been studied. PMID- 23629892 TI - A new three-dimensional silver(I) coordination framework with a diamondoid topology constructed from 2-(pyridin-4-yl)-1H-imidazole-4,5-dicarboxylic acid. AB - The title compound, poly[[MU4-5-carboxy-4-carboxylato-2-(pyridin-4-yl)-1H imidazol-1-ido]disilver(I)], [Ag2(C10H5N3O4)]n, was synthesized by reacting silver nitrate with 2-(pyridin-4-yl)-1H-imidazole-4,5-dicarboxylic acid (H3PyIDC) under hydrothermal conditions. The asymmetric unit contains two crystallographically independent Ag(I) cations and one unique HPyIDC(2-) anion. Both Ag(I) cations are three-coordinated in distorted T-shaped coordination geometries. One Ag(I) cation is coordinated by one N and two O atoms from two HPyIDC(2-) anions, while the other is bonded to one O and two N atoms from two HPyIDC(2-) anions. It is interesting to note that the HPyIDC(2-) group acts as a MU4-bridging ligand to link the Ag(I) cations into a three-dimensional framework, which can be simplified as a diamondoid topology. The thermal stability and photoluminescent properties of the title compound have also been studied. PMID- 23629894 TI - Two one-dimensional coordination polymers generated from a new benzimidazole bridging ligand and CdX2 (X = Br and I). AB - The novel asymmetric bridging ligand 1-[(pyridin-3-yl)methyl]-2-[4-(pyridin-3 yl)phenyl]-1H-benzimidazole (L) has been used to construct the coordination polymers catena-poly[[[dibromidocadmium(II)]-MU3-1-[(pyridin-3-yl)methyl]-2-[4 (pyridin-3-yl)phenyl]-1H-benzimidazole] monohydrate], {[CdBr2(C24H18N4)].H2O}n, (I), and catena-poly[[diiodidocadmium(II)]-MU3-1-[(pyridin-3-yl)methyl]-2-[4 (pyridin-3-yl)phenyl]-1H-benzimidazole], [CdI2(C24H18N4)]n, (II). Compounds (I) and (II) are closely related one-dimensional polymers based on 16- and 20 membered macrocycles along the chains, but they are not isomorphous. The chains are crosslinked into a two-dimensional network via hydrogen bonds and pi-pi interactions in (I), and into a three-dimensional framework through pi-pi interactions in (II). One well-ordered solvent water molecule per asymmetric unit is included in (I) and forms O...Br hydrogen bonds. PMID- 23629893 TI - Binuclear and chain-structure zinc(II) complexes constructed from 3,4-dimethoxy trans-cinnamic acid and N-donor coligands 4-(1H-pyrazol-3-yl)pyridine and 4,4' bipyridine. AB - 3,4-Dimethoxy-trans-cinnamic acid (Dmca) reacts with zinc sulfate in the presence of 4-(1H-pyrazol-3-yl)pyridine (L1) or 4,4'-bipyridine (L2) under hydrothermal conditions to afford two mixed-ligand coordination complexes, namely tetrakis(MU 3,4-dimethoxy-trans-cinnamato-kappa(2)O:O')bis[[4-(1H-pyrazol-3 yl)pyridine]zinc(II)] heptahydrate, [Zn2(C11H11O4)4(C8H7N3)2].7H2O or [Zn2(Dmca)4(L1)2].7H2O, (I), and catena-poly[[bis(3,4-dimethoxy-trans-cinnamato kappaO)zinc(II)]-MU-4,4'-bipyridine-kappa(2)N:N'], [Zn(C11H11O4)2(C10H8N2)]n or [Zn(Dmca)2(L2)]n, (II). The Zn(II) centres in the two compounds display different coordination polyhedra. In complex (I), the Zn(II) cation is five-coordinated with a pseudo-square-pyramidal geometry, while in complex (II) the Zn(II) cation sits on a twofold axis and adopts a distorted tetrahedral coordination environment. Complex (I) features a centrosymmetric binuclear paddle-wheel-like structure, while complex (II) shows a chain structure. This study emphasizes the significant effect of the coordination mode of both carboxylate-group and N-donor coligands on the formation of complex structures. PMID- 23629895 TI - The correct assignment of stereochemistry in di-MU-dichlorido-bis{bis[2-(5 benzylsulfonyl)-3-fluoro-2-(pyridin-2-yl)phenyl-kappa2N,C1]iridium(III)} toluene monosolvate. AB - The title complex, [Ir2(C18H13FNO2S)4Cl2].C7H8, was crystallized from dichloromethane solution under a toluene atmosphere. It is a dimeric complex in which each of the two Ir(III) centres is octahedrally coordinated by two bridging chloride ligands and by two chelating cyclometalated 2-(4-benzylsulfonyl-2 fluorophenyl)pyridine ligands. The crystal structure analysis unequivocally establishes the trans disposition of the two cyclometalated ligands bound to each Ir(III) centre, contrary to our previous hypothesis of a cis disposition. The latter was based on the (1)H NMR spectra of a series of dimeric benzylsulfonyl functionalized dichloride-bridged iridium complexes, including the compound described in the present work [Ragni et al. (2009). Chem. Eur. J. 15, 136-148]. The toluene solvent molecules, embedded in cavities in the crystal structure, are highly disordered and could not be modelled successfully; their contribution was removed from the refinement using the SQUEEZE routine in the program PLATON [Spek (2009). Acta Cryst. D65, 148-155]. PMID- 23629896 TI - A three-dimensional manganese(II) metal-organic framework based on 5 methoxybenzene-1,3-dicarboxylic acid and exhibiting a pts net. AB - The solvothermal reaction of MnCl2.H2O and 5-methoxybenzene-1,3-dicarboxylic acid (MeO-m-H2BDC) led to a three-dimensional Mn(II) metal-organic framework, namely poly[(dimethylformamide-kappaO)(MU4-5-methoxybenzene-1,3-dicarboxylato kappa(4)O(1):O(1'):O(3),O(3'):O(3))manganese(II)], [Mn(C9H6O5)(C3H7NO)]n or [Mn(MeO-m-BDC)(DMF)]n (DMF is dimethylformamide). The Mn(II) atom is six coordinated and exhibits a distorted octahedral geometry formed by five carboxylate O atoms from four different MeO-m-BDC(2-) anionic ligands and by one DMF O atom. The three-dimensional framework of (I) formed by the bridging MeO-m BDC(2-) ligands and the Mn(II) atoms exhibits a pts topological network when MeO m-BDC(2-) and Mn(II) are viewed as four-connected nodes. PMID- 23629897 TI - A one-dimensional zinc(II) coordination polymer incorporating [1,1'-biphenyl] 4,4'-dicarboxylate and N,N'-bis(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4,4' dicarboxamide ligands. AB - In the title compound, catena-poly[[[N,N'-bis(pyridin-3-ylmethyl)-[1,1'-biphenyl] 4,4'-dicarboxamide]chloridozinc(II)]-MU-[1,1'-biphenyl]-4,4'-dicarboxylato-[[N,N' bis(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4,4'-dicarboxamide]chloridozinc(II)]-MU [N,N'-bis(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4,4'-dicarboxamide]], [Zn2(C14H8O4)Cl2(C26H22N4O2)3]n, the Zn(II) centre is four-coordinate and approximately tetrahedral, bonding to one carboxylate O atom from a bidentate bridging dianionic [1,1'-biphenyl]-4,4'-dicarboxylate ligand, to two pyridine N atoms from two N,N'-bis(pyridin-3-ylmethyl)-[1,1'-biphenyl]-4,4'-dicarboxamide ligands and to one chloride ligand. The pyridyl ligands exhibit bidentate bridging and monodentate terminal coordination modes. The bidentate bridging pyridyl ligand and the bridging [1,1'-biphenyl]-4,4'-dicarboxylate ligand both lie on special positions, with inversion centres at the mid-points of their central C-C bonds. These bridging groups link the Zn(II) centres into a one dimensional tape structure that propagates along the crystallographic b direction. The tapes are interlinked into a two-dimensional layer in the ab plane through N-H...O hydrogen bonds between the monodentate ligands. In addition, the thermal stability and solid-state photoluminescence properties of the title compound are reported. PMID- 23629898 TI - A one-dimensional ABX3-type coordination polymer: catena poly[benzyltrimethylammonium [tri-MU-chlorido-cadmium(II)]]. AB - The crystal structure of the title novel one-dimensional ABX3-type organic inorganic hybrid complex {(C10H16N)[CdCl3]}n, (I), consists of benzyltrimethylammonium (Me3BzN(+)) cations and one-dimensional anionic {[Cd(MU Cl)3](-)}infinity chains. Each Cd(II) centre is hexacoordinated by bridging chloride ligands, giving a slightly distorted octahedral Cd(MU-Cl)6 arrangement. The octahedra are linked by two opposite shared faces, giving rise to an almost perfectly linear anionic {[Cd(MU-Cl)3](-)}infinity chain in the a-axis direction. Me3BzN(+) cations located in the inter-chain spaces balance the charge. Noncovalent static attracting forces (Coulombic and van der Waals forces) and nonclassical C-H...Cl hydrogen-bond interactions stabilize the crystal structure. PMID- 23629899 TI - Poly[bis(MU-5-iodoisophthalato)(methanol)dilead(II)] exhibiting a novel centrosymmetric rhombus-shaped I4 unit. AB - The asymmetric unit of the title compound, [Pb2(C8H3IO4)2(CH4O)]n, contains two Pb(II) atoms, two 5-iodoisophthalate (5-IIP(2-)) ligands and one coordinated methanol molecule. One Pb atom is eight-coordinated, surrounded by seven carboxylate O atoms from five 5-IIP(2-) ligands and one O atom from the terminal methanol ligand. The other Pb atom is seven-coordinated in a hemidirected geometry, surrounded by seven carboxylate O atoms from five 5-IIP(2-) ligands. Both Pb atoms are connected by carboxylate groups to form a one-dimensional infinite rod along the a axis; neighbouring rods are further linked by the aromatic rings of 5-IIP(2-) to generate the final three-dimensional structure with channels in the a direction. An O-H...O hydrogen bond between the methanol ligand and one of the carboxylate groups of a 5-IIP(2-) ligand stablizes the three-dimensional framework. Interestingly, a centrosymmetric rhombus-shaped I4 unit is formed by four 5-IIP(2-) ligands, with I...I distances of 3.8841 (8) and 3.9204 (8) A. PMID- 23629900 TI - X-ray and synchrotron diffraction studies of 2-(pyridin-2-yl)-1,10-phenanthroline in the role of ligand for two copper polymorphs or hydrogen bonded with 2,2,6,6 tetramethyl-4-oxopiperidinium hexafluorophosphate. AB - Different extended packing motifs of dichlorido[2-(pyridin-2-yl)-1,10 phenanthroline]copper(II), [CuCl2(C17H11N3)], are obtained, depending on the crystallization conditions. A triclinic form, (I), is obtained from dimethylformamide-diethyl ether or methanol, whereas crystallization from dimethylformamide-water yields a monoclinic form, (II). In each case, the Cu(II) centre is in a five-coordinate distorted square-pyramidal geometry. The extended packing for both forms can be described as a highly offset pi-stacking arrangement, with interlayer distances of 3.674 (3) and 3.679 (3) A for forms (I) and (II), respectively. The reaction of diprotonated Pt(tmpip2NCN)Cl [tmpip2NCN = 2,6-bis(2,2,6,6-tetramethylpiperidylmethyl)benzyl] with AgPF6 under acidic conditions, followed by the addition of 2-(pyridin-2-yl)-1,10-phenanthroline, results in a hydrogen-bonded cocrystal, 2,2,6,6-tetramethyl-4-oxopiperidinium hexafluorophosphate-2-(pyridin-2-yl)-1,10-phenanthroline (1/1), C9H18NO(+).PF6( ).C17H11N3, (III). The extended packing maximizes pi-pi interactions in a parallel face-to-face arrangement, with an interlayer stacking distance of 3.4960 (14) A. PMID- 23629901 TI - A clothes-peg-shaped binuclear trans-bis(2-aminotroponato)palladium(II) complex bearing pentamethylene spacers. AB - rac-Bis{MU-trans-2,2'-[pentane-1,5 diylbis(azanediyl)]ditroponato}dipalladium(II), [Pd2(C19H20N2O2)2], has been synthesized and fully characterized using single-crystal X-ray diffraction, (1)H NMR, FT-IR and mass spectroscopy. The trans coordination, vaulted structure and anti conformation have been unequivocally established from the X-ray diffraction studies. This is the first example of a bis(aminotroponato)palladium complex. In the crystalline state, the molecule has twofold symmetry and each molecular unit undergoes intermolecular offset pi-stacking of the tropone rings to afford heterochiral interpenetrating dimers that are aligned in a lamellar manner with a herringbone packing motif. PMID- 23629902 TI - catena-Poly[tris(MU3-acetylacetonato)nickelate(II)sodium(I)]. AB - The title complex, [NaNi(C5H7O2)3]n, contains an anionic tris(acetylacetonato)nickelate(II) unit, [Ni(acac)3](-) (acac is acetylacetonate), with a highly regular octahedral coordination geometry. The Ni(II) cation lies on a Wyckoff a site, resulting in D3 symmetry of the anion. Charge balance is provided by sodium cations, which occupy Wyckoff type b sites. Each sodium cation is surrounded by two [Ni(acac)3](-) anions, each of which is connected to the alkali metal through three O atoms, in a fac configuration. This arrangement leads to the formation of linear [Na{Ni(acac)3}]n chains along the c axis. The Ni...Na distance is 2.9211 (10) A. The title complex is one of the few examples of heterometallic systems based on alkali and transition metal cations bridged by acetylacetonate ligands. PMID- 23629903 TI - A cocrystal of two Mo(VI) complexes bearing different diastereomers of the 2,4-di tert-butyl-6-{[(1-oxido-1-phenylpropan-2-yl)(methyl)amino]methyl}phenolate ligand derived from (+)-ephedrine. AB - The title cocrystal contains two chiral conformational diastereomers, viz. (1S,2R,RN)- and (1S,2R,SN)-, of [2,4-di-tert-butyl-6-{[(1-oxido-1-phenylpropan-2 yl)(methyl)amino]methyl}phenolato](methanol)-cis-dioxidomolybdenum(VI), [Mo(C25H35NO2)O2(CH3OH)], representing the first example of a structurally characterized molybdenum complex with enantiomerically pure ephedrine derivative ligands. The Mo(VI) cations exhibit differently distorted octahedral coordination environments, with two oxide ligands positioned cis to each other. The remainder of the coordination comprises phenoxide, alkoxide and methanol O atoms, with an amine N atom completing the octahedron. The distinct complexes are linked by strong intermolecular O-H...O hydrogen bonds, resulting in one-dimensional molecular chains. Furthermore, the phenyl rings are involved in weak T shaped/edge-to-face pi-pi interactions with each other. PMID- 23629904 TI - A simple and safe method for the preparation of bis[2-(2H-tetrazol-5 yl)pyridinium] tetrachloridozincate(II). AB - In the title complex salt, (C6H6N5)2[ZnCl4], the Zn(II) cation is coordinated by four chloride ligands in a distorted tetrahedral geometry. The organic cations and complex anions are connected by N-H...Cl hydrogen bonds, leading to the formation of a three-dimensional network. The title complex salt was synthesized by the reaction of sodium azide, pyridine-2-carbonitrile and ZnCl2 in aqueous solution. The salt was characterized by elemental analysis and IR and UV-Vis spectroscopy. PMID- 23629905 TI - Semi-maleate salts of L- and DL-serinium: the first example of chiral and racemic serinium salts with the same composition and stoichiometry. AB - L-serinium semi-maleate, (I), and DL-serinium semi-maleate, (II), both C3H8NO3(+).C4H3O4(-), provide the first example of chiral and racemic anhydrous serine salts with the same organic anion. A comparison of their crystal structures with each other, with the structures of the pure components (L-serine polymorphs, DL-serine and maleic acid) and with other amino acid maleates is important for understanding the formation of the crystal structures, their response to variations in temperature and pressure, and structure-property relationships. As in other known crystal structures of amino acid maleates, there are no direct links between the semi-maleate anions in the two new structures. The serinium cations have different conformations in (I) and (II). In (I), they are linked into infinite chains via hydrogen bonds between carboxylic acid and hydroxy groups. In (II), there are no such chains formed by the serinium cations. In both (I) and (II), there are C2(2)(12) chains consisting of alternating semi maleate anions and serinium cations. Two types of such chains are present in (I) and (II), termed C2(2)(12) and C2(2)(12)'. In (I), these chains, lying in the same plane, are further linked to each other via hydrogen bonds, whereas in (II) they are not. PMID- 23629906 TI - Isomeric 3- and 4-chloro-N-[1-(1H-pyrrol-2-yl)ethylidene]aniline. AB - The title isomers, namely 3-chloro-N-[1-(1H-pyrrol-2-yl)ethylidene]aniline, (I), and 4-chloro-N-[1-(1H-pyrrol-2-yl)ethylidene]aniline, (II), both C12H11ClN2, differ in the position of the chlorine substitution. Both compounds have the basic iminopyrrole structure, which shows a planar backbone with similar features. The dihedral angle formed by the planes of the pyrrole and benzene rings is 75.65 (7) degrees for (I) and 86.56 (8) degrees for (II). The H atom bound to the pyrrole N atom is positionally disordered and partial protonation occurs at the imino N atom in (I), while this phenomenon is absent from the structure of (II). Packing interactions for both compounds include intermolecular N-H...N hydrogen bonds and C-H...pi interactions, forming centrosymmetric dimers for both (I) and (II). PMID- 23629907 TI - Pentane-1,5-diaminium dibromide. AB - The crystal structure of the title salt, C5H16N2(2+).2Br(-), with Z = 12 and more unusually Z' = 3, forms part of a small group of crystal structures in the Cambridge Structural Database that are ammonium bromide salts. One of the diaminium cation chains in the asymmetric unit exhibits positional disorder, which was modelled using a suitable disorder model. This compound also exhibits organic-inorganic layering in its packing arrangement that is typical of this class of compound. An extensive complex three-dimensional hydrogen-bonding network is also identified. The hydrogen bonds evident in this crystal structure were identified as being most likely strong charge-assisted hydrogen bonds. PMID- 23629908 TI - Biphenyl- and phenylnaphthalenyl-substituted 1H-imidazole-4,5-dicarbonitrile catalysts for the coupling reaction of nucleoside methyl phosphonamidites. AB - Crystal structures are reported for three substituted 1H-imidazole-4,5 dicarbonitrile compounds used as catalysts for the coupling reaction of nucleoside methyl phosphonamidites, namely 2-(3',5'-dimethylbiphenyl-2-yl)-1H imidazole-4,5-dicarbonitrile, C19H14N4, (I), 2-(2',4',6'-trimethylbiphenyl-2-yl) 1H-imidazole-4,5-dicarbonitrile, C20H16N4, (II), and 2-[8-(3,5 dimethylphenyl)naphthalen-1-yl]-1H-imidazole-4,5-dicarbonitrile, C23H16N4, (III). The asymmetric unit of (I) contains two independent molecules with similar conformations. There is steric repulsion between the imidazole group and the terminal phenyl group in all three compounds, resulting in the nonplanarity of the molecules. The naphthalene group of (III) shows significant deviation from planarity. The C-N bond lengths in the imidazole rings range from 1.325 (2) to 1.377 (2) A. The molecules are connected into zigzag chains by intermolecular N H...N(imidazole) [for (I)] or N-H....N(cyano) [for (II) and (III)] hydrogen bonds. PMID- 23629909 TI - Hydrogen bonding in two ammonium salts of 5-sulfosalicylic acid: ammonium 3 carboxy-4-hydroxybenzenesulfonate monohydrate and triammonium 3-carboxy-4 hydroxybenzenesulfonate 3-carboxylato-4-hydroxybenzenesulfonate. AB - The structures of two ammonium salts of 3-carboxy-4-hydroxybenzenesulfonic acid (5-sulfosalicylic acid, 5-SSA) have been determined at 200 K. In the 1:1 hydrated salt, ammonium 3-carboxy-4-hydroxybenzenesulfonate monohydrate, NH4(+).C7H5O6S( ).H2O, (I), the 5-SSA(-) monoanions give two types of head-to-tail laterally linked cyclic hydrogen-bonding associations, both with graph-set R4(4)(20). The first involves both carboxylic acid O-H...O(water) and water O-H...O(sulfonate) hydrogen bonds at one end, and ammonium N-H...O(sulfonate) and N-H...O(carboxy) hydrogen bonds at the other. The second association is centrosymmetric, with end linkages through water O-H...O(sulfonate) hydrogen bonds. These conjoined units form stacks down c and are extended into a three-dimensional framework structure through N-H...O and water O-H...O hydrogen bonds to sulfonate O-atom acceptors. Anhydrous triammonium 3-carboxy-4-hydroxybenzenesulfonate 3-carboxylato-4 hydroxybenzenesulfonate, 3NH4(+).C7H4O6S(2-).C7H5O6S(-), (II), is unusual, having both dianionic 5-SSA(2-) and monoanionic 5-SSA(-) species. These are linked by a carboxylic acid O-H...O hydrogen bond and, together with the three ammonium cations (two on general sites and the third comprising two independent half cations lying on crystallographic twofold rotation axes), give a pseudo centrosymmetric asymmetric unit. Cation-anion hydrogen bonding within this layered unit involves a cyclic R3(3)(8) association which, together with extensive peripheral N-H...O hydrogen bonding involving both sulfonate and carboxy/carboxylate acceptors, gives a three-dimensional framework structure. This work further demonstrates the utility of the 5-SSA(-) monoanion for the generation of stable hydrogen-bonded crystalline materials, and provides the structure of a dianionic 5-SSA(2-) species of which there are only a few examples in the crystallographic literature. PMID- 23629910 TI - Proton-transfer compounds with 4-amino-N-(4,6-dimethylpyrimidin-2 yl)benzenesulfonamide (sulfamethazine): the structures and hydrogen bonding in the salts with 5-nitrosalicylic acid and picric acid. AB - The structures of the anhydrous proton-transfer compounds of the sulfa drug sulfamethazine with 5-nitrosalicylic acid and picric acid, namely 2-(4 aminobenzenesulfonamido)-4,6-dimethylpyrimidinium 2-hydroxy-5-nitrobenzoate, C12H15N4O2S(+).C7H4NO4(-), (I), and 2-(4-aminobenzenesulfonamido)-4,6 dimethylpyrimidinium 2,4,6-trinitrophenolate, C12H15N4O2S(+).C6H2N3O7(-), (II), respectively, have been determined. In the asymmetric unit of (I), there are two independent but conformationally similar cation-anion heterodimer pairs which are formed through duplex intermolecular N(+)-H...O(carboxylate) and N H...O(carboxylate) hydrogen-bond pairs, giving a cyclic motif [graph set R2(2)(8)]. These heterodimers form separate and different non-associated substructures through aniline N-H...O hydrogen bonds, one one-dimensional, involving carboxylate O-atom acceptors, the other two-dimensional, involving both carboxylate and hydroxy O-atom acceptors. The overall two-dimensional structure is stabilized by pi-pi interactions between the pyrimidinium ring and the 5 nitrosalicylate ring in both heterodimers [minimum ring-centroid separation = 3.4580 (8) A]. For picrate (II), the cation-anion interaction involves a slightly asymmetric chelating N-H...O R2(1)(6) hydrogen-bonding association with the phenolate O atom, together with peripheral conjoint R1(2)(6) interactions between the same N-H groups and O atoms of the ortho-related nitro groups. An inter-unit amine N-H...O(sulfone) hydrogen bond gives one-dimensional chains which extend along a and inter-associate through pi-pi interactions between the pyrimidinium rings [centroid-centroid separation = 3.4752 (9) A]. The two structures reported here now bring to a total of four the crystallographically characterized examples of proton-transfer salts of sulfamethazine with strong organic acids. PMID- 23629911 TI - A chain of pi-stacked molecules in 4-(2-chlorophenyl)pyrrolo[1,2-a]quinoxaline and a hydrogen-bonded sheet in (4RS)-4-(1,3-1,3-benzodioxol-6-yl)-4,5 dihydropyrrolo[1,2-a]quinoxaline. AB - In the molecule of 4-(2-chlorophenyl)pyrrolo[1,2-a]quinoxaline, C17H11ClN2, (I), the bond lengths are consistent with electron delocalization in the two outer rings of the fused tricyclic system, with a localized double bond in the central ring. The molecules of (I) are linked into chains by a pi-pi stacking interaction. In (4RS)-4-(1,3-benzodioxol-6-yl)-4,5-dihydropyrrolo[1,2 a]quinoxaline, C18H14N2O2, (II), the central ring of the fused tricyclic system adopts a conformation intermediate between screw-boat and half-chair forms. A combination of N-H...O and C-H...pi(arene) hydrogen bonds links the molecules of (II) into a sheet. Comparisons are made with related compounds. PMID- 23629912 TI - Five N'-benzylidene-N-methylpyrazine-2-carbohydrazides. AB - The compounds N'-benzylidene-N-methylpyrazine-2-carbohydrazide, C13H12N4O, (IIa), N'-(2-methoxybenzylidene)-N-methylpyrazine-2-carbohydrazide, C14H14N4O2, (IIb), N'-(4-cyanobenzylidene)-N-methylpyrazine-2-carbohydrazide dihydrate, C14H11N5O.2H2O, (IIc), N-methyl-N'-(2-nitrobenzylidene)pyrazine-2-carbohydrazide, C13H11N5O3, (IId), and N-methyl-N'-(4-nitrobenzylidene)pyrazine-2-carbohydrazide, C13H11N5O3, (IIe), have dihedral angles between the pyrazine rings and the benzene rings in the range 55-78 degrees . These methylated pyrazine-2 carbohydrazides have supramolecular structures which are formed by weak C-H...O/N hydrogen bonds, with the exception of (IIc) which is hydrated. There are pi-pi stacking interactions in all five compounds. Three of these structures are compared with their nonmethylated counterparts, which have dihedral angles between the pyrazine rings and the benzene rings in the range 0-6 degrees . PMID- 23629913 TI - A water wire in L-prolyl-L-serine monohydrate. AB - Despite the extra functional group in the serine side chain, the crystal packing arrangement of the title compound {systematic name: (S)-3-hydroxy-2-[(S) pyrrolidine-2-carboxamido]propanoic acid monohydrate}, C8H14N2O4.H2O, is essentially the same as observed for a series of L-Pro-L-Nop peptide hydrates, where Nop is a strictly nonpolar residue. This is rendered possible by a monoclinic P2(1) packing arrangement with Z' = 2 that deviates from orthorhombic P2(1)2(1)2(1) symmetry only for the seryl hydroxy groups, which form infinite O H...O-H hydrogen-bonded chains along the 5.3 A a axis. At the same time, cocrystallized water molecules form parallel water wires. PMID- 23629914 TI - Tribenzylphosphane and its hydrochloride salt, tribenzylphosphonium hydrogen dichloride-tribenzylphosphane (1/1). AB - Tribenzylphosphane, PBz3 (C21H21P), crystallizes in a notably different unit cell to its Group 15 analogues NBz3 and SbBz3. The packing is dominated by face-edge pi-interactions which result in infinite columns of molecules parallel to the b axis; these columns are linked by further face-edge pi-interactions into sheets of columns parallel to the [101] direction. Its hydrochloride salt, tribenzylphosphonium hydrogen dichloride-tribenzylphosphane (1/1), lies on a threefold axis within a trigonal crystal system. It exists in the solid state as a hydrogen-bridged dimer with the composition [H(PBz3)2](+)[HCl2](-) (C42H43P2(+).HCl2(-)). The cation is the first structurally authenticated example of a phosphane acting as a hydrogen-bond acceptor to a phosphonium group and the cations are linked into a three-dimensional network through intermolecular face edge pi-interactions. PMID- 23629917 TI - Highly conductive [3*n] gold-ion clusters enclosed within self-assembled cages. PMID- 23629918 TI - Motor unit loss and weakness in association with diabetic neuropathy in humans. AB - INTRODUCTION: Diabetes mellitus can be associated with peripheral neuropathy which may affect numbers of functioning motor units (MUs) of limb muscles. Direct quantitative assessment of MU numbers and muscle strength have not been performed in humans. We compared the estimated number of MUs of individuals with diabetic polyneuropathy (DPN) versus controls. METHODS: Patients with signs/symptoms of DPN were studied using decomposition-enhanced quantitative electromyography of the tibialis anterior (TA). Motor unit number estimates were derived from this analysis. RESULTS: Dorsiflexion strength was ~60% less in DPN than controls (P < 0.05). Additionally, the estimated number of functioning TA MUs was ~60% fewer in patients with DM (~46) versus controls (~111) (P < 0.05). CONCLUSIONS: These data directly measure MU loss associated with DPN in a proximal muscle in humans. It remains to be determined whether quantifying MU loss has clinical utility in monitoring the progression or management of DPN. PMID- 23629920 TI - Localization of folds and cracks in thin metal films coated on flexible elastomer foams. AB - Thin metal films coated on soft elastomeric foam substrates exhibit enhanced electromechanical performance. The open-cell foam structure conveys highly anisotropic mechanical properties within the top, thin capping elastomer at the surface of the foam. Upon stretching, large strain fields inducing cracks and folds localize above the foam cells, while the surrounding cell ligaments remain almost strain-free, enabling stable electrical conduction in the metallic coating. PMID- 23629919 TI - Helicobacter pylori-induced alteration of epithelial cell signaling and polarity: a possible mechanism of gastric carcinoma etiology and disparity. AB - Gastric cancer, a disease of disparity associated with Helicobacter pylori (H. pylori) infection, is the world's second leading cause of cancer deaths. The pathogen H. pylori target the epithelial adhesion receptors, E-cadherin, and beta1-integrin, to modulate the host cytoskeleton via disruption of the epithelial cell polarity necessary for maintaining the infection, but how this leads to the development of the carcinoma is widely unclear. While Rho family GTPases' signaling to the cytoskeleton and these receptors is required for initiating and maintaining the infection, the responsible effectors, and how they might influence the etiology of the carcinomas are currently unknown. Here we discuss the potential role of the Cdc42-IQGAP1 axis, a negative regulator of the tumor suppressors E-cadherin and beta1-integrin, as a potential driver of H. pylori-induced gastric carcinoma and propose avenues for addressing its disparity. Chronic dysfunction of the IQGAP1-signaling pathway, resulting from H. pylori-induced disruption of cell polarity, can explain the pathogenesis of the carcinoma, at least, in subsets of infected population, and thus could provide a potential means for personalized medicine. PMID- 23629921 TI - Andrographolide protects against cigarette smoke-induced lung inflammation through activation of heme oxygenase-1. AB - This study was conducted to check whether andrographolide, a bioactive molecule isolated from Andrographis paniculata, could protect against cigarette smoke (CS) induced lung injury through activation of heme oxygenase-1 (HO-1). Pretreatment with andrographolide (1 mg/kg body weight) markedly attenuated lung inflammation in CS-exposed mice, coupled with reduced numbers of total cells, neutrophils, and macrophages in bronchial alveolar lavage fluid (BALF) and decreased production of cytokine/chemokine into BALF. Furthermore, andrographolide pretreatment increased the expression and activation of HO-1 in the lung of CS-exposed animals. Notably, these histological and biochemical changes induced by andrographolide were blocked by prior administration of zinc protoporphyrin IX (ZnPP; 20 mg/kg body weight), a potent heme oxygenase inhibitor. Moreover, andrographolide-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) was attenuated by ZnPP treatment in CS-exposed animals. Our data collectively demonstrate that andrographolide confers protection against CS-induced lung inflammation, partially through activation of HO-1 and STAT3. PMID- 23629922 TI - Single walled carbon nanotube composites for bone tissue engineering. AB - The purpose of this study was to develop single walled carbon nanotubes (SWCNT) and poly lactic-co-glycolic acid (PLAGA) composites for orthopedic applications and to evaluate the interaction of human stem cells (hBMSCs) and osteoblasts (MC3T3-E1 cells) via cell growth, proliferation, gene expression, extracellular matrix production and mineralization. PLAGA and SWCNT/PLAGA composites were fabricated with various amounts of SWCNT (5, 10, 20, 40, and 100 mg), characterized and degradation studies were performed. Cells were seeded and cell adhesion/morphology, growth/survival, proliferation and gene expression analysis were performed to evaluate biocompatibility. Imaging studies demonstrated uniform incorporation of SWCNT into the PLAGA matrix and addition of SWCNT did not affect the degradation rate. Imaging studies revealed that MC3T3-E1 and hBMSCs cells exhibited normal, non-stressed morphology on the composites and all were biocompatible. Composites with 10 mg SWCNT resulted in highest rate of cell proliferation (p < 0.05) among all composites. Gene expression of alkaline phosphatase, collagen I, osteocalcin, osteopontin, Runx-2, and Bone Sialoprotein was observed on all composites. In conclusion, SWCNT/PLAGA composites imparted beneficial cellular growth capabilities and gene expression, and mineralization abilities were well established. These results demonstrate the potential of SWCNT/PLAGA composites for musculoskeletal regeneration and bone tissue engineering (BTE) and are promising for orthopedic applications. PMID- 23629923 TI - Caveolae-mediated endocytosis of conjugated polymer nanoparticles. AB - Understanding the cellular entry pathways of synthetic biomaterials is highly important to improve overall labeling and delivery efficiency. Herein, cellular entry mechanisms of conjugated polymer nanoparticles (CPNs) are presented. CPNs are intrinsic fluorescent materials used for various biological applications. While CPNs cause no toxicity, decreased CPN uptake is observed from cancer cells pretreated with genistein, which is an inhibitor of caveolae-mediated endocytosis (CvME). CvME is further confirmed by high co-localization with caveolin-1 proteins found in the caveolae and caveosomes. Excellent photophysical properties, non-toxicity, and non-destructive delivery pathways support that CPNs are promising multifunctional carriers minimizing degradation of contents during delivery. PMID- 23629924 TI - Akt inhibition promotes hexokinase 2 redistribution and glucose uptake in cancer cells. AB - Hexokinase II (HK2), the enzyme that catalyzes the first committed step of glycolysis, is overexpressed in many cancers, as is the central signaling kinase Akt. Akt activity promotes HK2 association with the mitochondria, as well as glucose uptake by cancer cells. In HeLa cervical cancer cells, Akt inhibitor IV (Ai4) increased nuclear HK2 localization, while in MDA-MB-231 breast cancer cells, Ai4 merely induced cytoplasmic redistribution without increased nuclear accumulation. Small interfering RNA (siRNA) directed against Akt confirmed the effect in HeLa cells. Next, we treated the cells with clotrimazole (CTZ), which detaches HK2 from the mitochondria, or leptomycin B (LMB), which promotes HK2 nuclear accumulation, and determined the effect on HK2 subcellular distribution. In both cell lines, CTZ detached HK2 from the mitochondria, without substantially increasing nuclear HK2, while LMB increased nuclear HK2, without redistributing cytoplasmic HK2. Contrary to expectations, Akt inhibition promoted glucose uptake in both cell lines, suggesting that Akt inhibition may increase glucose uptake by detaching HK2 from the mitochondria. In both cell lines, CTZ and LMB increased glucose uptake. However, the results in the HeLa cells showed greater effects: CTZ increased glucose uptake to a similar degree to Ai4, while LMB was far more effective than either. These data suggest that both detachment of HK2 from the mitochondria and increased nuclear HK2 are important for Ai4-induced increased glucose uptake. PMID- 23629925 TI - Determination of isoniazid concentration in rabbit vertebrae by isotope tracing technique in conjunction with HPLC. AB - Medications compounded with isoniazid (INH) are usually applied to surgical sites at the completion of surgery to locally kill postoperative residual tubercle bacilli. However, the distribution and elimination of INH in the vertebrae in vivo are not known. In this study, isotope tracing was used in conjunction with high-pressure liquid chromatography (HPLC) to address this. INH and technetium-99 m-labeled INH were applied to the vertebrae of rabbits. After 2 and 6 h, osseous tissues containing INH, as determined by radionuclide imaging, were collected for detection with HPLC. The results showed that INH mainly stayed around the vertebrae 6 h after its application and did not permeate widely into the blood or other organs, except for the kidneys. The standard deviations of INH concentrations in the technetium-99 m-INH group were approximately four-fold smaller than those in the INH group. This method of coupling isotope tracing and HPLC can effectively limit experimental error during sample collection, allowing accurate and reliable identification of the concentration levels of INH in osseous tissues in vivo. PMID- 23629926 TI - Health Care Utilization and Attitudes Survey: understanding diarrheal disease in rural Gambia. AB - Diarrheal disease causes ~1.34 million deaths per year among children under 5 years of age globally. We conducted a Health Care Utilization and Attitudes Survey of 1,012 primary caregivers of children aged 0-11, 12-23, and 24-59 months randomly selected from a Demographic Surveillance population in rural Gambia. Point prevalence of diarrhea was 7.7% (95% confidence interval [CI] = 6.1-9.8); 23.3% had diarrhea within the previous 2 weeks. Caregivers of 81.5% of children with diarrhea sought healthcare outside their home, but only 48.4% of them visited a health center. Only 17.0% (95% CI = 12.1-23.2) of children with diarrhea received oral rehydration solution (ORS) at home. Abbreviated surveys conducted on six occasions over the subsequent 2 years showed no change in prevalence or treatment-seeking behavior. Diarrhea remains a significant problem in rural young Gambian children. Encouraging care-seeking behavior at health centers and promoting ORS use can reduce mortality and morbidity in this population. PMID- 23629927 TI - Health care utilization and attitudes survey in cases of moderate-to-severe diarrhea among children ages 0-59 months in the District of Manhica, southern Mozambique. AB - In the predominantly rural Manhica district, in southern Mozambique, diarrhea is one of the leading causes of death among children under 5 years. Caretakers randomly selected from the Demographic Surveillance Database were invited to participate in a community-based survey on use of healthcare services for gastroenteritis. Of those caretakers reporting an episode of diarrhea during the recall period, 65.2% in the first survey and 43.8% in the second survey reported seeking care at a health facility. Independent risk factors for seeking care in health facilities in the first survey included the presence of diarrhea with fever and not knowing any sign of dehydration; having a television at home was related with an independent decreased use of the health facilities. In the second survey, the use of health services was significantly associated with diarrhea with fever and vomiting. Establishment of continuous prospective monitoring allows accounting for changes in healthcare use that may occur because of seasonality or secular events. PMID- 23629928 TI - Health care use patterns for diarrhea in children in low-income periurban communities of Karachi, Pakistan. AB - Diarrhea causes 16% of all child deaths in Pakistan. We assessed patterns of healthcare use among caretakers of a randomly selected sample of 959 children ages 0-59 months in low-income periurban settlements of Karachi through a cross sectional survey. A diarrheal episode was reported to have occurred in the previous 2 weeks among 298 (31.1%) children. Overall, 280 (80.3%) children sought care. Oral rehydration solution and zinc were used by 40.8% and 2%, respectively; 11% were admitted or received intravenous rehydration, and 29% sought care at health centers identified as sentinel centers for recruiting cases of diarrhea for a planned multicenter diarrheal etiology case-control study. Odds ratios for independent predictors of care-seeking behavior were lethargy, 4.14 (95% confidence interval = 1.45-11.77); fever, 2.67 (1.27-5.59); and stool frequency more than six per day, 2.29 (1.03-5.09). Perception of high cost of care and use of home antibiotics were associated with reduced care seeking: odds ratio = 0.28 (0.1-0.78) and 0.29 (0.11-0.82), respectively. There is a need for standardized, affordable, and accessible treatment of diarrhea as well as community education regarding appropriate care in areas with high diarrheal burden. PMID- 23629929 TI - Health care-seeking behavior during childhood diarrheal illness: results of health care utilization and attitudes surveys of caretakers in western Kenya, 2007-2010. AB - We interviewed caretakers of 1,043 children < 5 years old in a baseline cross sectional survey (April to May 2007) and > 20,000 children on five separate subsequent occasions (May of 2009 to December 31, 2010) to assess healthcare seeking patterns for diarrhea. Diarrhea prevalence during the preceding 2 weeks ranged from 26% at baseline to 4-11% during 2009-2010. Caretakers were less likely to seek healthcare outside the home for infants (versus older children) with diarrhea (adjusted odds ratio [aOR] = 0.33, confidence interval [CI] = 0.12 0.87). Caretakers of children with reduced food intake (aOR = 3.42, CI = 1.37 8.53) and sunken eyes during their diarrheal episode were more likely to seek care outside home (aOR = 4.76, CI = 1.13-8.89). Caretakers with formal education were more likely to provide oral rehydration solution (aOR = 3.01, CI = 1.41 6.42) and visit a healthcare facility (aOR = 3.32, CI = 1.56-7.07). Studies calculating diarrheal incidence and healthcare seeking should account for seasonal trends. Improving caretakers' knowledge of home management could prevent severe diarrhea. PMID- 23629930 TI - Rare case of disseminated cysticercosis and taeniasis in a Japanese traveler after returning from India. AB - We report disseminated cysticercosis concurrent with taeniasis in a 31-year-old male Japanese, who had visited India three times and stayed for 1 month each time during the previous 1 year. The patient presented increasing numbers of subcutaneous nodules and expelled proglottids, although numerous cysts were also found in the brain in imaging findings, though no neurological symptoms were observed. Histopathological and serological findings strongly indicated cysticercosis. We found taeniid eggs in his stool by microscopic examination and revealed them as the Indian haplotype of Taenia solium by mitochondrial DNA analysis. We concluded that disseminated cysticercosis was caused by the secondary autoinfection with eggs released from the tapeworm carrier himself. After confirming the absence of adult worms in the intestine by copro-polymerase chain reaction, the patient was successfully treated with albendazole at a dose of 15 mg/kg/day for 28 days. Subcutaneous and intracranial lesions had completely disappeared by the end of the treatment period. PMID- 23629931 TI - Household environmental conditions are associated with enteropathy and impaired growth in rural Bangladesh. AB - We assessed the relationship of fecal environmental contamination and environmental enteropathy. We compared markers of environmental enteropathy, parasite burden, and growth in 119 Bangladeshi children (<= 48 months of age) across rural Bangladesh living in different levels of household environmental cleanliness defined by objective indicators of water quality and sanitary and hand-washing infrastructure. Adjusted for potential confounding characteristics, children from clean households had 0.54 SDs (95% confidence interval [CI] = 0.06, 1.01) higher height-for-age z scores (HAZs), 0.32 SDs (95% CI = -0.72, 0.08) lower lactulose:mannitol (L:M) ratios in urine, and 0.24 SDs (95% CI = -0.63, 0.16) lower immunoglobulin G endotoxin core antibody (IgG EndoCAb) titers than children from contaminated households. After adjusting for age and sex, a 1-unit increase in the ln L:M was associated with a 0.33 SDs decrease in HAZ (95% CI = 0.62, -0.05). These results are consistent with the hypothesis that environmental contamination causes growth faltering mediated through environmental enteropathy. PMID- 23629932 TI - Ultrasensitive real-time PCR for the clinical management of visceral leishmaniasis in HIV-Infected patients. AB - Molecular methods have been proposed as an alternative tool for the diagnosis of visceral leishmaniasis (VL), but no data are available regarding use for monitoring clinical outcome. A prospective cohort study of human immunodeficiency virus-(HIV) and VL-coinfected patients was conducted in a university-affiliated hospital in Barcelona, Spain. Leishmania parasite load was monitored using a real time polymerase chain reaction (PCR) at baseline and every 3 months. Cutoff values for PCR were determined using receiver operating characteristic (ROC) curves. Overall, 37 episodes were analyzed, and 25 of these episodes were considered as relapsing episodes. A significant decrease of parasite load measured 3 months after treatment could predict the clinical evolution of VL. A parasite load over 0.9 parasites/mL measured 12 months after treatment could predicts relapse with a sensitivity of 100% and a specificity of 90.9%. Monitoring parasite load by an ultrasensitive quantitative Leishmania PCR is useful to predict the risk of relapse after a VL episode in HIV-infected patients. PMID- 23629933 TI - Diarrheal disease constitutes one of the top two causes of mortality among young children in developing countries. Preface. PMID- 23629934 TI - Genetic and shared environmental influences on interferon-gamma production in response to Mycobacterium tuberculosis antigens in a Ugandan population. AB - Interferon-gamma (IFN-gamma) is a key cytokine in the immune response to Mycobacterium tuberculosis (Mtb). Many studies established IFN-gamma responses are influenced by host genetics, however differed widely by the study design and heritability estimation method. We estimated heritability of IFN-gamma responses to Mtb culture filtrate (CF), ESAT-6, and Antigen 85B (Ag85B) in 1,104 Ugandans from a household contact study. Our method separately evaluates shared environmental and genetic variance, therefore heritability estimates were not upwardly biased, ranging from 11.6% for Ag85B to 22.9% for CF. Subset analyses of individuals with latent Mtb infection or without human immunodeficiency virus infection yielded higher heritability estimates, suggesting 10-30% of variation in IFN-gamma is caused by a shared environment. Immunosuppression does not negate the role of genetics on IFN-gamma response. These estimates are remarkably close to those reported for components of the innate immune response. These findings have implications for the interpretation of IFN-gamma response assays and vaccine studies. PMID- 23629935 TI - Seeking care for pediatric diarrheal illness from traditional healers in Bamako, Mali. AB - Diarrhea is a leading cause of child mortality worldwide. Early recognition of symptoms and referral to medical treatment are essential. In 2007, we conducted a Healthcare Utilization and Attitudes Survey (HUAS) of 1,000 children randomly selected from a population census to define care-seeking patterns for diarrheal disease in Bamako, Mali, in preparation for the Global Enteric Multicenter Study (GEMS). We found that 57% of caretakers sought care for their child's diarrheal illness from traditional healers, and 27% of caretakers sought care from the government health center (GHC). Weighted logistic regression showed that seeking care from a traditional healer was associated with more severe reported diarrheal disease, like decreased urination (odds ratio [OR] = 3.35, 95% confidence interval [95% CI] = 1.19-9.41) and mucus or pus in stool (OR = 4.42, 95% CI = 1.35-14.51), along with other indicators of perceived susceptibility. A locally designed traditional healer referral system was, therefore, created that emphasized more severe disease. This system may serve as a model for health systems in West Africa. PMID- 23629936 TI - Determinants of health care seeking for diarrheal illness in young children in urban slums of Kolkata, India. AB - Maternal practices regarding children's health care have been recognized as an important factor associated with mortality rates among children < 5 years of age. We focused on health care-seeking practices of primary caretakers of children < 5 years of age with diarrheal disease in Kolkata. We interviewed caretakers of 1,058 children in a baseline survey and 6,077 children on six subsequent surveys. The prevalence of diarrhea during the preceding 2 weeks was 7.9% in the baseline survey and 5.7% (lowest 3.5% to highest 7.8%) in subsequent surveys. Multivariate logistic regression showed that formal education of primary caretakers was associated with seeking care outside the home (odds ratio [OR] = 15.5; 95% confidence interval [CI] [2.5-85.7]; P = 0.002). Multinomial logistic regression showed that formal education of the primary caretaker (OR = 21.4; 95% CI [3.2 139.0]; P = 0.002) and presence of dry mouth during diarrhea (OR = 17.3; 95% CI [2.7-110.9]; P = 0.003) were associated with seeking care from licensed providers compared with the children for whom care was not sought outside of the home. This health care utilization and attitudes survey (HUAS) can serve as a tool to identify the factors that influence a better health care-seeking pattern in urban slums of Kolkata. PMID- 23629937 TI - Health care-seeking behavior for childhood diarrhea in Mirzapur, rural Bangladesh. AB - We evaluated patterns of health care use for diarrhea among children 0-59 months of age residing in Mirzapur, Bangladesh, using a baseline survey conducted during May-June 2007 to inform the design of a planned diarrheal etiology case/control study. Caretakers of 7.4% of 1,128 children reported a diarrheal illness in the preceding 14 days; among 95 children with diarrhea, 24.2% had blood in the stool, 12.2% received oral rehydration solution, 27.6% received homemade fluids, and none received zinc at home. Caretakers of 87.9% sought care outside the home; 49.9% from a pharmacy, and 22.1% from a hospital or health center. The primary reasons for not seeking care were maternal perception that the illness was not serious enough (74.0%) and the high cost of treatment (21.9%). To improve management of childhood diarrhea in Mirzapur, Bangladesh, it will be important to address knowledge gaps in caretakers' assessment of illness severity, appropriate home management, and when to seek care in the formal sector. In addition, consideration should be given to inclusion of the diverse care-giving settings in clinical training activities for diarrheal disease management. PMID- 23629938 TI - Unusual Enterocytozoon bieneusi genotypes and Cryptosporidium hominis subtypes in HIV-infected patients on highly active antiretroviral therapy. AB - Human immunodeficiency virus (HIV)-infected persons are commonly infected with Cryptosporidium species and Enterocytozoon bieneusi in both developed and developing countries, particularly patients with CD4+ cell counts below 200 cells/MUL; 285 HIV-infected patients on highly active antiretroviral therapy (HAART) were enrolled in this study, and both stool and blood specimens were collected from participants. The stool specimens were analyzed and typed for E. bieneusi and Cryptosporidium spp. by polymerase chain reaction (PCR) and DNA sequencing. CD4 count was analyzed using flow cytometry. E. bieneusi and Cryptosporidium were detected in 18 (6.3%) and 4 (1.4%) patients, respectively. The E. bieneusi detected mostly belonged to a new genotype group that, thus far, has only been found in a few humans: genotype Nig4 in 2 patients and two new genotypes related to Nig4 in 12 patients. The Cryptosporidium detected included C. hominis (two patients), C. parvum (one patient), and C. felis (one patient), with the two C. hominis infections belonging to an unusual subtype family. Additional studies are required to determine whether some E. bieneusi genotypes and C. hominis subtypes are more prevalent in HIV patients on HAART. PMID- 23629939 TI - Health care seeking for childhood diarrhea in developing countries: evidence from seven sites in Africa and Asia. AB - We performed serial Health Care Utilization and Attitudes Surveys (HUASs) among caretakers of children ages 0-59 months randomly selected from demographically defined populations participating in the Global Enteric Multicenter Study (GEMS), a case-control study of moderate-to-severe diarrhea (MSD) in seven developing countries. The surveys aimed to estimate the proportion of children with MSD who would present to sentinel health centers (SHCs) where GEMS case recruitment would occur and provide a basis for adjusting disease incidence rates to include cases not seen at the SHCs. The proportion of children at each site reported to have had an incident episode of MSD during the 7 days preceding the survey ranged from 0.7% to 4.4% for infants (0-11 months of age), from 0.4% to 4.7% for toddlers (12 23 months of age), and from 0.3% to 2.4% for preschoolers (24-59 months of age). The proportion of MSD episodes at each site taken to an SHC within 7 days of diarrhea onset was 15-56%, 17-64%, and 7-33% in the three age strata, respectively. High cost of care and insufficient knowledge about danger signs were associated with lack of any care-seeking outside the home. Most children were not offered recommended fluids and continuing feeds at home. We have shown the utility of serial HUASs as a tool for optimizing operational and methodological issues related to the performance of a large case-control study and deriving population-based incidence rates of MSD. Moreover, the surveys suggest key targets for educational interventions that might improve the outcome of diarrheal diseases in low-resource settings. PMID- 23629940 TI - Characterization of chondrocyte scaffold carriers for cell-based gene therapy in articular cartilage repair. AB - Articular cartilage lesions in the knee are common injuries. Chondrocyte transplant represents a promising therapeutic modality for articular cartilage injuries. Here, we characterize the viability and transgene expression of articular chondrocytes cultured in three-dimensional scaffolds provided by four types of carriers. Articular chondrocytes are isolated from rabbit knees and cultured in four types of scaffolds: type I collagen sponge, fibrin glue, hyaluronan, and open-cell polylactic acid (OPLA). The cultured cells are transduced with adenovirus expressing green fluorescence protein (AdGFP) and luciferase (AdGL3-Luc). The viability and gene expression in the chondrocytes are determined with fluorescence microscopy and luciferase assay. Cartilage matrix production is assessed by Alcian blue staining. Rabbit articular chondrocytes are effectively infected by AdGFP and exhibited sustained GFP expression. All tested scaffolds support the survival and gene expression of the infected chondrocytes. However, the highest transgene expression is observed in the OPLA carrier. At 4 weeks, Alcian blue-positive matrix materials are readily detected in OPLA cultures. Thus, our results indicate that, while all tested carriers can support the survival of chondrocytes, OPLA supports the highest transgene expression and is the most conductive scaffold for matrix production, suggesting that OPLA may be a suitable scaffold for cell-based gene therapy of articular cartilage repairs. PMID- 23629942 TI - Clinical outcomes for reconstruction of the posterolateral corner and posterior cruciate ligament in injuries with mild grade 2 or less posterior translation: comparison with isolated posterolateral corner reconstruction. AB - BACKGROUND: There have been no previous studies showing clinical outcomes according to treatment options of posterior cruciate ligament (PCL) injury with mild grade 2 or less posterior translation (<7 mm) combined with posterolateral rotatory instability. PURPOSE: To compare the clinical outcomes of posterolateral corner (PLC) reconstruction with or without simultaneous PCL reconstruction in PCL injuries with mild posterior translation. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 46 patients with a PCL injury with mild posterior translation combined with posterolateral rotatory instability were retrospectively reviewed. Twenty-two patients had undergone isolated PLC reconstruction (group A), and 24 patients had undergone simultaneous reconstruction of the PCL and PLC (group B). Each patient was assessed for knee instability with the dial test at 30 degrees and 90 degrees as well as with varus and posterior stress radiography and were evaluated with the Lysholm knee score and International Knee Documentation Committee (IKDC) subjective and objective grading. RESULTS: In all cases, the minimum follow-up period was 24 months. At the final follow-up evaluation, no significant side-to-side difference was found on varus stress radiography (group A, 1.55 +/- 0.78 mm vs group B, 1.35 +/- 1.00 mm; P = .458) or the dial test (at 30 degrees : group A, 4.00 degrees +/- 1.83 degrees vs group B, 4.04 degrees +/- 1.30 degrees ; P = .929; at 90 degrees : group A, 3.64 degrees +/- 1.18 degrees vs group B, 3.67 degrees +/- 1.37 degrees ; P = .937). However, group B showed a significant improvement compared with group A on posterior stress radiography (group A, 0.16 +/- 0.44 mm vs group B, -1.44 +/- 0.74 mm; P < .001), Lysholm knee score (group A, 18.36 +/- 8.73 vs group B, 23.42 +/- 7.44; P = .040), IKDC subjective score (group A, 25.51 +/- 7.11 vs group B, 33.08 +/- 5.89; P < .001), and IKDC objective score (group A preoperatively: grade C = 19 patients, grade D = 3; group B preoperatively: grade C = 20, grade D = 4; group A postoperatively: grade B = 11, grade C = 11; group B postoperatively: grade A = 12, grade B = 9, grade C = 3) (P < .001). CONCLUSION: Simultaneous reconstruction of the PCL and PLC is recommended when addressing PCL injuries with mild grade 2 or less posterior translation combined with posterolateral rotary instability. PMID- 23629941 TI - Telomere length, telomere-related genes, and breast cancer risk: the breast cancer health disparities study. AB - Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere-related genes with cancer. We evaluated associations between telomere-related genes, TL, and breast cancer risk in an admixed population of US non-Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL-related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL-related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (ORadj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER-/PR+) tumors and TERT rs2735940 (ORadj 0.73, 95% CI 0.59, 0.91) with ER-/PR- tumors. These data provide support for an association between TL and TL-related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry. PMID- 23629943 TI - Increased thyroid autoimmunity among women with multiple sclerosis in the postpartum setting. AB - BACKGROUND: Multiple sclerosis (MS) patients are predisposed to thyroid abnormalities, but the risk for pregnancy-related thyroid pathology among MS patients has not been evaluated. OBJECTIVES: The objectives of this research are to prospectively evaluate the prevalence of thyroid autoimmunity among MS patients in relation to pregnancy, and to investigate its impact on pregnancy outcome, postpartum depression and fatigue. METHODS: Forty-six pregnant MS patients underwent repeat testing for serum thyroid antibodies (Abs), clinical evaluation and thyroid hormone measurement. Results were compared to 35 age matched healthy mothers. RESULTS: At six months postpartum 35.3% of MS patients presented elevated levels of thyroid Abs compared to 5.7% of controls, p = 0.01. Mean thyroid Ab concentrations among MS patients were significantly reduced during pregnancy and returned to maximal levels at six months postpartum. The proportion of individuals with postpartum thyroid dysfunction did not differ significantly between MS patients and healthy controls (3.4% vs 2.9%, p = 1.00). Elevated thyroid Ab levels did not increase the risk for adverse pregnancy outcome, fatigue or postpartum depression. CONCLUSIONS: Considering the tendency of MS mothers to develop thyroid autoimmunity postpartum and in association to treatments, we recommend screening MS patients for thyroid dysfunction (TSH) during early pregnancy and after delivery. PMID- 23629944 TI - Androgen receptors in muscle fibers induce rapid loss of force but not mass: implications for spinal bulbar muscular atrophy. AB - INTRODUCTION: Testosterone (T) induces motor dysfunction in transgenic (Tg) mice that overexpress wild-type androgen receptor (AR) in skeletal muscles. Because many genes implicated in motor neuron disease are expressed in skeletal muscle, mutant proteins may act in muscle to cause dysfunction in motor neuron disease. METHODS: We examined contractile properties of the extensor digitorum longus (EDL) and soleus (SOL) muscles in vitro after 5 and 3 days of T treatment in motor-impaired Tg female mice. RESULTS: Both muscles showed deficits in tetanic force after 5 days of T treatment, without losses in muscle mass, protein content, or fiber number. After 3 days of T treatment, only SOL showed a deficit in tetanic force comparable to that of 5 days of treatment. In both treatments, EDL showed slowed twitch kinetics, whereas SOL showed deficits in the twitch/tetanus ratio. CONCLUSIONS: These results suggest calcium-handling mechanisms in muscle fibers are defective in motor-impaired mice. PMID- 23629945 TI - 3D interconnected porous biomimetic scaffolds: In vitro cell response. AB - Bone cell response to 3D bioinspired scaffolds was tested on osteoblast culture supernatants and by means of quantitative polymerase chain reaction (qPCR). Foaming and freeze-drying method was optimized in order to obtain three dimensional interconnected porous scaffolds of gelatin at different contents of nanocrystalline hydroxyapatite (HA). Addition of a non toxic crosslinking agent during foaming stabilized the scaffolds, as confirmed by the slow and relatively low gelatin release in phosphate buffer up to 28 days. Micro-computed tomography reconstructed images showed porous interconnected structures, with interconnected pores displaying average diameter ranging from about 158 to about 71 MUm as the inorganic phase content increases from 0 to 50 wt %. The high values of connectivity (>99%), porosity (> 60%), and percentage of pores with a size in the range 100-300 MUm (>50%) were maintained up to 30 wt % HA, whereas higher content provoked a reduction of these parameters, as well as of the average pore size, and a significant increase of the compressive modulus and collapse strength up to 8 +/- 1 and 0.9 +/- 0.2 MPa, respectively. Osteoblast cultured on the scaffolds showed good adhesion, proliferation and differentiation. The presence of HA promoted ALP activity, TGF-beta1, and osteocalcin production, in agreement with the observed upregulation of ALP, OC, Runx2, and TGF-beta1 gene in qPCR analysis, indicating that the composite scaffolds enhanced osteoblast activation and extra cellular matrix mineralization processes. PMID- 23629946 TI - Exercise and negative energy balance in males who perform mental work. AB - BACKGROUND: Although energy expenditure during mental work is not higher than energy expenditure at rest, a stressful mental task is related to an increase in energy intake. It is suggested that mental work produces physiological changes, thereby influencing food intake. OBJECTIVE: Because physical activity can influence hunger, the aim of the study was to determine if the introduction of an active pause could counteract the negative effects of mental work on energy intake and energy balance. METHOD: Twelve male students, of normal weight, between 15 and 20 years old were evaluated. All subjects participated in three different sessions realized in a randomized order: (i) without pause = relaxation/mental work/meal; (ii) relaxation pause = mental work/relaxation/meal; and (iii) exercise pause = mental work/exercise/meal. Energy expenditure was measured with indirect calorimetry, energy intake was measured with a cold buffet type meal of 40 items, and appetite-related sensations were measured with visual analogue scales. The effect of introducing an active pause in energy intake and energy balance was studied. RESULTS: The introduction of an active pause did not influence energy intake; although, higher appetite-related sensations were observed (16-26 mm on a 150-mm scale; P < 0.05). After accounting for the energy expenditure related to physical activity, a lower energy balance was measured for the exercise pause visit compared with the visit without a pause (-1137 kJ; P < 0.05). CONCLUSION: This study indicates that being active between mental work and a meal could represent a strategy to create a negative energy balance following mental work via an increased energy expenditure and a maintenance of energy intake. Globally, these results could help individuals attain and/or maintain a healthy body weight in a context where mental work is omnipresent. PMID- 23629949 TI - A base-stabilized lead(I) dimer and an aromatic plumbylidenide anion. PMID- 23629948 TI - Short-Form CDYLb but not long-form CDYLa functions cooperatively with histone methyltransferase G9a in hepatocellular carcinomas. AB - In hepatocellular carcinomas (HCCs), the levels of histone H3 dimethylation at lysine 9 (H3K9me2) and its corresponding histone methyltransferase G9a are significantly elevated. Recently, G9a was reported to form a complex with the H3K9 methylation effector protein CDYL, but little is known about the expression of CDYL in HCC patients. The human CDYL gene produces two transcripts, a long form (CDYLa) and a short form (CDYLb), but it is unclear whether the protein products have different functions. The aim of this study was to investigate the distinctions between CDYLa and CDYLb and their expression levels in HCC tissues. We first examined binding abilities of the different CDYL forms with methylated H3 peptides by a pull-down assay. Human CDYLb (h-CDYLb) specifically recognized H3Kc9me2 and H3Kc9me3 modifications, whereas human CDYLa (h-CDYLa) did not interact with any methylated H3 peptides. Similarly, mouse CDYLb (m-CDYLb) specifically bound with di- and tri-methylated H3Kc9 peptides, while mouse CDYLa (m-CDYLa) lacked that ability. Affinity purification also was used to identify the distinct composition of the h-CDYLa or h-CDYLb protein complex. h-CDYLb was found in a multiprotein complex with G9a and GLP, while the h-CDYLa complex did not contain these two enzymes. Consistent with the protein complex composition, h CDYLb and G9a were both upregulated in HCC tissues, compared with adjacent non cancerous liver tissues. Furthermore, the positive correlation between expression levels of h-CDYLb and G9a was statistically significant. In contrast, h-CDYLa showed no enrichment in HCC tissues. These findings suggest that h-CDYLb and G9a are cooperatively involved in HCC. PMID- 23629947 TI - Genetic susceptibility to Candida infections. AB - Candida spp. are medically important fungi causing severe mucosal and life threatening invasive infections, especially in immunocompromised hosts. However, not all individuals at risk develop Candida infections, and it is believed that genetic variation plays an important role in host susceptibility. On the one hand, severe fungal infections are associated with monogenic primary immunodeficiencies such as defects in STAT1, STAT3 or CARD9, recently discovered as novel clinical entities. On the other hand, more common polymorphisms in genes of the immune system have also been associated with fungal infections such as recurrent vulvovaginal candidiasis and candidemia. The discovery of the genetic susceptibility to Candida infections can lead to a better understanding of the pathogenesis of the disease, as well as to the design of novel immunotherapeutic strategies. This review is part of the review series on host-pathogen interactions. See more reviews from this series. PMID- 23629950 TI - Cobalt-substituted magnetite nanoparticles and their assembly into ferrimagnetic nanoparticle arrays. AB - A simple process to prepare monodisperse ferrimagnetic cobalt-substituted magnetite Co(x)Fe(3-x)O4 nanoparticles is reported. These ferrimagnetic nanoparticles are readily dispersed in hexane, forming a stable ferrimagnetic nanoparticle dispersion, and allowing easy nanoparticle self-assembly. When assembled under an external magnetic field (5.5 kOe), these nanoparticles show preferred magnetic alignment with their H(c) reaching 2.49 kOe. PMID- 23629951 TI - Purification, characterization, and chemical modification of neurotoxic peptide from Daboia russelii snake venom of India. AB - Comprehensive knowledge of venom composition is very important for effective management of snake envenomation and antivenom preparation. Daboia russelii venom from the eastern region of India is the most neurotoxic among the four venom samples investigated. From the eastern D. russelii venom sample, neurotoxic peptide has been purified by combined method of ion exchange gel permeation chromatography and reversed phase high performance liquid chromatography. Molecular weight of Daboia neurotoxin III (DNTx-III) found to be 6,849 Da (as measured on matrix-assisted laser desorption/ionisation-time of flight mass spectrometer), and N-terminal amino acid sequences is I K C F I T P D U T S Q A. Approximate LD50 dosage was 0.24 mg/kg body weight. It produced concentration- and time-dependent inhibition of indirectly stimulated twitches of Rana hexadactyla sciatic nerve gastrocnemius muscle preparations. Chemical modification of DNTx-III tryptophan residue(s) reduced the twitch height inhibition property of toxin, signifying the importance of tryptophan residues for the neurotoxic function. This type of neurotoxic peptide is unique to east Indian regional D. russelii venom. PMID- 23629952 TI - Coping strategies predictive of adverse outcomes among community adults. AB - OBJECTIVES: To examine associations between coping strategies at baseline and adverse outcomes 13 years later, and whether gender and age moderated these associations. METHOD: Participants (N = 651) completed a survey on demographic characteristics, coping strategies, and psychosocial outcomes (negative life events, alcohol consumption, drinking problems, and suicidal ideation). RESULTS: At the follow-up (N = 521), more use of avoidance coping was associated with more drinking problems and suicidal ideation at follow-up. Men high in avoidance coping reported more alcohol consumption and suicidal ideation at follow-up than did men low on avoidance coping. Younger adults high in avoidance coping reported more negative life events at follow-up than did younger adults low on avoidance coping. CONCLUSIONS: Reliance on avoidance coping may be especially problematic among men and younger adults. PMID- 23629953 TI - The biotransformation of oleuropein in rats. AB - A highly sensitive and specific LC-MS/MS method was developed to investigate the in vivo bio-transformation of oleuropein in rat. Rat feces and urine samples collected after oral administration were determined by liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the negative ion mode. The assay procedure involves a simple liquid-liquid extraction of parent oleuropein and the metabolite from rat feces and urine with ethyl acetate. Chromatographic separation was operated with 0.1% formic acid aqueous and methanol in gradient program at a flow rate of 0.50 mL/min on an RP-C18 column with a total run time of 31 min. This method was successfully applied to simultaneous determination of oleuropein and its metabolites in rat feces and urine. De-glucosylation, hydrolysis, oxygenation and methylation were found to comprise the major metabolic pathway of oleuropein in rat gastrointestinal tract and three metabolites were absorbed into the blood circulatory system within 24 h after oral administration. PMID- 23629954 TI - Variable flip angle balanced steady-state free precession for lower SAR or higher contrast cardiac cine imaging. AB - PURPOSE: Cardiac cine balanced steady-state free precession (bSSFP) imaging uses a high flip angle (FA) to obtain high blood-myocardium signal-to-noise and contrast-to-noise ratios (CNR). Use of high FAs, however, results in substantially increased SAR. Our objective was to develop a variable FA bSSFP cardiac cine imaging technique with: (1) low SAR and blood-myocardium CNR similar to conventional constant FA bSSFP (CFA-bSSFP) or (2) increased blood-myocardium CNR compared to CFA-bSSFP with similar SAR. METHODS: Variable FA bSSFP cardiac cine imaging was achieved using an asynchronous k-space acquisition, which is asynchronous to the cardiac cycle (aVFA-bSSFP). Bloch simulations and phantom experiments were performed to compare the signal, resolution, and frequency response of the variable FA bSSFP and CFA-bSSFP schemes. Ten volunteers were imaged with different aVFA-bSSFP and asynchronous CFA-bSSFP schemes and compared to conventional segmented CFA-bSSFP. RESULTS: The SAR of aVFA-bSSFP is significantly decreased by 36% compared to asynchronous CFA-bSSFP (1.9 +/- 0.2 vs. 3.0 +/- 0.2 W/kg, P < 10(-10)) for similar blood-myocardium CNR (34 +/- 6 vs. 35 +/- 9, P = 0.5). Alternately, the CNR of the aVFA-bSSFP is improved by 28% compared to asynchronous CFA-bSSFP (49 +/- 9 vs. 38 +/- 8, P < 10(-4)) with similar SAR (3.2 +/- 0.5 vs. 3.3 +/- 0.5 W/kg, P = 0.6). CONCLUSION: aVFA-bSSFP can be used for lower SAR or higher contrast cardiac cine imaging compared to the conventional segmented CFA-bSSFP imaging. PMID- 23629955 TI - Multiple pilomatricomas with somatic CTNNB1 mutations in children with constitutive mismatch repair deficiency. AB - Constitutional mismatch repair deficiency (CMMR-D) due to biallelic germline mutations in one of four mismatch repair genes causes a childhood cancer syndrome characterized by a broad tumor spectrum including hematological malignancies, and brain and Lynch syndrome-associated tumors. Herein, we report three children who had in addition to CMMR-D-associated malignancies multiple pilomatricomas. These are benign skin tumors of hair matrical differentiation frequently associated with somatic activating mutations in the beta-catenin gene CTNNB1. In two of the children, the diagnosis of CMMR-D was confirmed by the identification of biallelic germline PMS2 mutations. In the third individual, we only found a heterozygous germline PMS2 mutation. In all nine pilomatricomas with basophilic cells, we detected CTNNB1 mutations. Our findings indicate that CTNNB1 is a target for mutations when mismatch repair is impaired due to biallelic PMS2 mutations. An elevated number of activating CTNNB1 alterations in hair matrix cells may explain the development of multiple pilomatricomas in CMMR-D patients. Of note, two of the children presented with multiple pilomatricomas and other nonmalignant features of CMMR-D before they developed malignancies. To offer surveillance programs to CMMR-D patients, it may be justified to suspect CMMR-D syndrome in individuals fulfilling multiple nonmalignant features of CMMR-D (including multiple pilomatricomas) and offer molecular testing in combination with interdisciplinary counseling. PMID- 23629956 TI - Genetic risk profiles for a childhood with severe overweight. AB - OBJECTIVE: The objective of this study was the description of a valid genetic risk score (GRS) to predict individuals with high susceptibility to childhood overweight by their genetic profiles. DESIGN AND METHODS: Case-control study including a group of children with high-risk familial predisposition to morbid obesity. Birth cohort from general population constituted the validation sample. For the discovery sample, 218 children with non-syndromic obesity and 190 control individuals were included. The validation sample was 653 children from two birth cohorts belonging to the INMA (Infancia y Medio Ambiente [Environment and Childhood] )project. 109 SNPs located in the genes FTO, SEC16B, BDNF, ETV5, SH2B1, GNPDA2, LYPLAL1, MSRA, TFAP2, KCTD15, MTCH2 and NEGR1, previously reported in association to body mass index (BMI) were analysed. For the validation sample, association between genome-wide data and BMI measurements between 3.5 and 5 years of age, were evaluated. RESULTS: The GRS includes six SNPs in the genes FTO, TFAP2B, SEC16B, ETV5 and SH2B1. The score distribution differs among cases and controls (P = 9.2 * 10(-14) ) showing a significant linear association with obesity (odds ratio [OR] per allele = 1.69; confidence interval [CI] 95% = 1.46 1.97; P = 4.3 * 10(-1) and area under the receiver operating characteristic curve [AUC] = 0.727; CI 95% = 0.676-0.778). The results were validated by the INMA cohort (OR per allele = 1.23 CI 95% = 1.03-1.48 and AUC = 0.601 CI 95% = 0.522 0.680). CONCLUSIONS: The use of our proposed genetic score provides useful information to determine those children who are susceptible to obesity. To improve the efficiency of clinical prevention and treatment of obesity, it is essential to design individualized based protocols in advance knowledge of the molecular basis of inherited susceptibility. PMID- 23629958 TI - Wound healing process and mediators: Implications for modulations for hernia repair and mesh integration. AB - In recent years, major advances have been accomplished in abdominal wall reconstruction. Introduction of newer prostheses have improved outcomes, but elimination of mesh-related morbidity is still an elusive issue. It is believed that host foreign body reaction to prosthesis plays an important role in the biology of these complications, so understanding of the molecular mechanisms behind mesh-tissue interactions may be a key for upcoming therapies. It appears that increasing biocompatibility of both synthetic prosthesis and biologic scaffolds might be the main avenues to achieve better outcomes. This manuscript provides an overview of major effectors of wound healing with particular emphasis on how their modulation might improve outcomes in tissue remodeling and mesh integration. PMID- 23629957 TI - Inhibition of endotrophin, a cleavage product of collagen VI, confers cisplatin sensitivity to tumours. AB - Endotrophin is a cleavage product of collagenVIalpha3 (COL6A3). Here, we explore the relationship between thiazolidinediones (TZDs), endotrophin and cisplatin resistance in the context of a mammary tumour model. COL6A3 levels are increased in response to cisplatin exposure in tumours. Endotrophin, in turn, causes cisplatin resistance. The effects of endotrophin can be bypassed, either through use of COL6 null (COL6(-/-)) mice or by administering TZDs in wild-type mice (leading to a downregulation of endotrophin). Both approaches sensitize tumours to cisplatin through the suppression of endotrophin-induced epithelial mesenchymal transition. The beneficial effects of TZDs on cisplatin sensitivity are diminished in COL6(-/-) mice, whereas endotrophin(+) tumours are sensitive to the TZD/cisplatin combination. Therefore, the chemosensitization obtained with TZDs is achieved through a downregulation of endotrophin. Treatment with an endotrophin neutralizing antibody in combination with cisplatin completely inhibits tumour growth of tumour allografts. Combined, our data suggest that endotrophin levels are a strong prognostic marker for the effectiveness of the combination therapy of TZDs with cisplatin, and neutralization of endotrophin activity dramatically improves the therapeutic response to combination therapy. PMID- 23629959 TI - Efficacy of a cognitive-behavioral treatment for insomnia and nightmares in Afghanistan and Iraq veterans with PTSD. AB - OBJECTIVE: Sleep disturbances are a core and salient feature of posttraumatic stress disorder (PTSD). Pilot studies have indicated that combined cognitive behavioral therapy for insomnia (CBT-I) and imagery rehearsal therapy (IRT) for nightmares improves sleep as well as PTSD symptoms. METHOD: The present study randomized 40 combat veterans (mean age 37.7 years; 90% male and 60% African American) who served in Afghanistan and/or Iraq (Operation Enduring Freedom [OEF]/Operation Iraqi Freedom [OIF]) to 4 sessions of CBT-I with adjunctive IRT or a waitlist control group. Two thirds of participants had nightmares at least once per week and received the optional IRT module. RESULTS: At posttreatment, veterans who participated in CBT-I/IRT reported improved subjectively and objectively measured sleep, a reduction in PTSD symptom severity and PTSD-related nighttime symptoms, and a reduction in depression and distressed mood compared to the waitlist control group. CONCLUSION: The findings from this first controlled study with OEF/OIF veterans suggest that CBT-I combined with adjunctive IRT may hold promise for reducing both insomnia and PTSD symptoms. Given the fact that only half of the patients with nightmares fully implemented the brief IRT protocol, future studies should determine if this supplement adds differential efficacy to CBT-I alone. PMID- 23629960 TI - Nitrogen deposition and warming - effects on phytoplankton nutrient limitation in subarctic lakes. AB - The aim of this study was to predict the combined effects of enhanced nitrogen (N) deposition and warming on phytoplankton development in high latitude and mountain lakes. Consequently, we assessed, in a series of enclosure experiments, how lake water nutrient stoichiometry and phytoplankton nutrient limitation varied over the growing season in 11 lakes situated along an altitudinal/climate gradient with low N-deposition (<1 kg N ha(-1) yr(-1) ) in northern subarctic Sweden. Short-term bioassay experiments with N- and P-additions revealed that phytoplankton in high-alpine lakes were more prone to P-limitation, and with decreasing altitude became increasingly N- and NP-colimited. Nutrient limitation was additionally most obvious in midsummer. There was also a strong positive correlation between phytoplankton growth and water temperature in the bioassays. Although excess nutrients were available in spring and autumn, on these occasions growth was likely constrained by low water temperatures. These results imply that enhanced N-deposition over the Swedish mountain areas will, with the exception of high-alpine lakes, enhance biomass and drive phytoplankton from N- to P limitation. However, if not accompanied by warming, N-input from deposition will stimulate limited phytoplankton growth due to low water temperatures during large parts of the growing season. Direct effects of warming, allowing increased metabolic rates and an extension of the growing season, seem equally crucial to synergistically enhance phytoplankton development in these lakes. PMID- 23629961 TI - Molecular subtypes of glioma identified by genome-wide methylation profiling. AB - Recent studies have indicated a prognostic role for genome-wide methylation in gliomas: Tumors that show an overall increase in DNA methylation at CpG sites (CIMP+; CpG island methylator phenotype) have a more favorable prognosis than CIMP- gliomas. Here, we have determined whether methylation profiling can identify more and clinically relevant molecular subtypes of glioma by performing genome-wide methylation profiling on 138 glial brain tumors of all histological diagnosis. Hopach (Hierarchical ordered partitioning and collapsing hybrid) clustering using the 1,000 most variable CpGs identified three distinct glioma subtypes (C+(1p19q), C+(wt), and C-) and one adult brain subtype. All "C+(1p19q) " and "C+(wt)" tumors were CIMP+ whereas most (50/54) "C-" tumors were CIMP-. The C- subtype gliomas contained many glioblastomas and all pilocytic astrocytomas. 1p19q LOH was frequent in the C+(1p19q) subtype. Other genetic changes (IDH1 mutation and EGFR amplification) and gene-expression based molecular subtypes also segregated in distinct methylation subtypes, demonstrating that these subtypes are also genetically distinct. Each subtype was associated with its own prognosis: median survival for C-, C+(1p19q), and C+(wt) tumors was 1.18, 5.00, and 2.62 years, respectively. The prognostic value of these methylation subtypes was validated on an external dataset from the TCGA. Analysis of recurrences of 14 primary tumors samples indicates that shifts between some C+(wt) and C+(1p/19q) tumors can occur between the primary and recurrent tumor, but CIMP status remained stable. Our data demonstrate that methylation profiling identifies at least three prognostically relevant subtypes of glioma that can aid diagnosis and potentially guide treatment for patients. PMID- 23629962 TI - Carla Koehler: Small TIMs are a big deal. Interviewed by Caitlin Sedwick. PMID- 23629963 TI - Stress granules as crucibles of ALS pathogenesis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis. PMID- 23629964 TI - The level of origin firing inversely affects the rate of replication fork progression. AB - DNA damage slows DNA synthesis at replication forks; however, the mechanisms remain unclear. Cdc7 kinase is required for replication origin activation, is a target of the intra-S checkpoint, and is implicated in the response to replication fork stress. Remarkably, we found that replication forks proceed more rapidly in cells lacking Cdc7 function than in wild-type cells. We traced this effect to reduced origin firing, which results in fewer replication forks and a consequent decrease in Rad53 checkpoint signaling. Depletion of Orc1, which acts in origin firing differently than Cdc7, had similar effects as Cdc7 depletion, consistent with decreased origin firing being the source of these defects. In contrast, mec1-100 cells, which initiate excess origins and also are deficient in checkpoint activation, showed slower fork progression, suggesting the number of active forks influences their rate, perhaps as a result of competition for limiting factors. PMID- 23629965 TI - Heterochromatin protein 1 promotes self-renewal and triggers regenerative proliferation in adult stem cells. AB - Adult stem cells (ASCs) capable of self-renewal and differentiation confer the potential of tissues to regenerate damaged parts. Epigenetic regulation is essential for driving cell fate decisions by rapidly and reversibly modulating gene expression programs. However, it remains unclear how epigenetic factors elicit ASC-driven regeneration. In this paper, we report that an RNA interference screen against 205 chromatin regulators identified 12 proteins essential for ASC function and regeneration in planarians. Surprisingly, the HP1-like protein SMED HP1-1 (HP1-1) specifically marked self-renewing, pluripotent ASCs, and HP1-1 depletion abrogated self-renewal and promoted differentiation. Upon injury, HP1-1 expression increased and elicited increased ASC expression of Mcm5 through functional association with the FACT (facilitates chromatin transcription) complex, which consequently triggered proliferation of ASCs and initiated blastema formation. Our observations uncover an epigenetic network underlying ASC regulation in planarians and reveal that an HP1 protein is a key chromatin factor controlling stem cell function. These results provide important insights into how epigenetic mechanisms orchestrate stem cell responses during tissue regeneration. PMID- 23629966 TI - Deacetylation of p53 induces autophagy by suppressing Bmf expression. AB - Interferon gamma (IFN-gamma)-induced cell death is mediated by the BH3-only domain protein, Bik, in a p53-independent manner. However, the effect of IFN gamma on p53 and how this affects autophagy have not been reported. The present study demonstrates that IFN-gamma down-regulated expression of the BH3 domain only protein, Bmf, in human and mouse airway epithelial cells in a p53-dependent manner. p53 also suppressed Bmf expression in response to other cell death stimulating agents, including ultraviolet radiation and histone deacetylase inhibitors. IFN-gamma did not affect Bmf messenger RNA half-life but increased nuclear p53 levels and the interaction of p53 with the Bmf promoter. IFN-gamma induced interaction of HDAC1 and p53 resulted in the deacetylation of p53 and suppression of Bmf expression independent of p53's proline-rich domain. Suppression of Bmf facilitated IFN-gamma-induced autophagy by reducing the interaction of Beclin-1 and Bcl-2. Furthermore, autophagy was prominent in cultured bmf(-/-) but not in bmf(+/+) cells. Collectively, these observations show that deacetylation of p53 suppresses Bmf expression and facilitates autophagy. PMID- 23629967 TI - Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds. AB - Basic mechanisms by which cellular barriers sense and respond to integrity disruptions remain poorly understood. Despite its tenuous structure and constitutive exposure to disruptive strains, the vascular endothelium exhibits robust barrier function. We show that in response to micrometer-scale disruptions induced by transmigrating leukocytes, endothelial cells generate unique ventral lamellipodia that propagate via integrins toward and across these "micro-wounds" to close them. This novel actin remodeling activity progressively healed multiple micro-wounds in succession and changed direction during this process. Mechanical probe-induced micro-wounding of both endothelia and epithelia suggests that ventral lamellipodia formed as a response to force imbalance and specifically loss of isometric tension. Ventral lamellipodia were enriched in the Rac1 effectors cortactin, IQGAP, and p47Phox and exhibited localized production of hydrogen peroxide. Together with Apr2/3, these were functionally required for effective micro-wound healing. We propose that barrier disruptions are detected as local release of isometric tension/force unloading, which is directly coupled to reactive oxygen species-dependent self-restorative actin remodeling dynamics. PMID- 23629969 TI - Video-assisted harvesting of anterolateral thigh free flap: technique validation and initial results. AB - OBJECTIVE: To provide a description of a minimally invasive, video-assisted technique (VAT) to identify the cutaneous perforators of the anterolateral thigh (ALT). The objective of the study was to compare this technique with standard open exploration of the thigh and to describe the learning curve for the procedure. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary institution. SUBJECTS AND METHODS: Twenty-six cases operated between December 2009 and June 2012. In all of these cases, an open thigh exploration, considered the gold standard, was performed immediately after the VAT. Data retrieved included surgical findings, demographics, and outcomes. RESULTS: There were 17 men and 9 women with a mean age of 60 years. The average flap size was 91 cm(2) (range, 39-264 cm(2)), and a chimeric double skin paddle flap was harvested in 6 cases. Forty-nine of 53 total perforators were successfully identified endoscopically. Findings on endoscopic and open exploration were highly correlated (r = 0.92, P = .000). The overall sensitivity for the technique was 92.4% (confidence interval, 80.9-97.5) but reached 100% for perforators located at the midpoint of the anterior-superior iliac spine-patella line. All flaps survived, and there were no technique-related complications. The learning curve plateaued after 15 cases, with a mean endoscopic operative time of 18.2 minutes for the last 10 procedures. CONCLUSION: This VAT is a safe and reliable method to identify cutaneous perforators of the lateral thigh. The procedure is straightforward and has a moderate learning curve. This approach has a role in minimizing donor site morbidity and assisting in flap design. PMID- 23629970 TI - Preliminary results of diode laser surgery for early glottic cancer. AB - OBJECTIVE: To analyze the complications and preliminary oncologic results of microscopic diode laser surgery. STUDY DESIGN: Prospective research. SETTING: Ankara Oncology Education and Research Hospital. SUBJECTS AND METHODS: This prospective study was conducted on a series of 64 patients with glottic carcinoma (Tis, T1, T2) treated with microscopic endolaryngeal diode laser surgery. RESULTS: Four patients had local recurrence (6.2%). Local control and larynx preservation rates were 93.8% and 100%, respectively, for all groups of patients. Two-year disease-free survival after primary surgery was 100% for the Tis group, 96.4% for the T1 group, and 89.7% for the T2 group. When considering anterior commissure involvement, 2-year disease-free survival after primary surgery was 100% for the AC0 group, 85.7% for the AC1 group, and 85.7% for the AC2 group. CONCLUSION: Our study of microscopic diode laser resection of Tis, T1, and T2 glottic tumors showed similar oncologic results to previous reports about CO2 laser surgery. In anterior commissure tumors, both techniques had high complication and recurrence rates. PMID- 23629971 TI - Interlocked porphyrin switches. AB - We describe the synthesis of a series of interlocked structures from porphyrin glycoluril cage compounds and bis(olefin)-terminated viologens by an olefin metathesis protocol. The length of the chain connecting the olefin substituents with the viologen has a marked effect on the products of the ring-closure reaction. Long chains give [2]- and [3]catenane structures, whereas short chains give a mixture of [3]-, [4]-, and [5]catenanes. For comparison several [2]rotaxane compounds were prepared. The interlocked catenane and rotaxane structures display switching behavior, which can be controlled by the addition of acid and base. The kinetic and thermodynamic parameters of the switching processes have been determined by NMR spectroscopy. PMID- 23629968 TI - EphA2 cleavage by MT1-MMP triggers single cancer cell invasion via homotypic cell repulsion. AB - Changes in EphA2 signaling can affect cancer cell-cell communication and motility through effects on actomyosin contractility. However, the underlying cell-surface interactions and molecular mechanisms of how EphA2 mediates these effects have remained unclear. We demonstrate here that EphA2 and membrane-anchored membrane type-1 matrix metalloproteinase (MT1-MMP) were selectively up-regulated and coexpressed in invasive breast carcinoma cells, where, upon physical interaction in same cell-surface complexes, MT1-MMP cleaved EphA2 at its Fibronectin type-III domain 1. This cleavage, coupled with EphA2-dependent Src activation, triggered intracellular EphA2 translocation, as well as an increase in RhoA activity and cell junction disassembly, which suggests an overall repulsive effect between cells. Consistent with this, cleavage-prone EphA2-D359I mutant shifted breast carcinoma cell invasion from collective to rounded single-cell invasion within collagen and in vivo. Up-regulated MT1-MMP also codistributed with intracellular EphA2 in invasive cells within human breast carcinomas. These results reveal a new proteolytic regulatory mechanism of cell-cell signaling in cancer invasion. PMID- 23629972 TI - Expressed protein ligation at methionine: N-terminal attachment of homocysteine, ligation, and masking. PMID- 23629973 TI - Screening and determination of drugs in human saliva utilizing microextraction by packed sorbent and liquid chromatography-tandem mass spectrometry. AB - This study presents a new method for collecting and handling saliva samples using an automated analytical microsyringe and microextraction by packed syringe (MEPS). The screening and determination of lidocaine in human saliva samples utilizing MEPS and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were carried out. An exact volume of saliva could be collected. The MEPS C8 -cartridge could be used for 50 extractions before it was discarded. The extraction recovery was about 60%. The pharmacokinetic curve of lidocaine in saliva using MEPS-LC MS/MS is reported. PMID- 23629975 TI - Editorial: Thoracolumbar spinal injuries. PMID- 23629974 TI - Integrated parallel reception, excitation, and shimming (iPRES). AB - PURPOSE: To develop a new concept for a hardware platform that enables integrated parallel reception, excitation, and shimming. THEORY: This concept uses a single coil array rather than separate arrays for parallel excitation/reception and B0 shimming. It relies on a novel design that allows a radiofrequency current (for excitation/reception) and a direct current (for B0 shimming) to coexist independently in the same coil. METHODS: Proof-of-concept B0 shimming experiments were performed with a two-coil array in a phantom, whereas B0 shimming simulations were performed with a 48-coil array in the human brain. RESULTS: Our experiments show that individually optimized direct currents applied in each coil can reduce the B0 root-mean-square error by 62-81% and minimize distortions in echo-planar images. The simulations show that dynamic shimming with the 48-coil integrated parallel reception, excitation, and shimming array can reduce the B0 root-mean-square error in the prefrontal and temporal regions by 66-79% as compared with static second-order spherical harmonic shimming and by 12-23% as compared with dynamic shimming with a 48-coil conventional shim array. CONCLUSION: Our results demonstrate the feasibility of the integrated parallel reception, excitation, and shimming concept to perform parallel excitation/reception and B0 shimming with a unified coil system as well as its promise for in vivo applications. PMID- 23629976 TI - Commentary: Accuracy of core needle biopsy for musculoskeletal tumours. PMID- 23629977 TI - Commentary: Position of the patella in adults in central India: evaluation of the Insall-Salvati ratio. PMID- 23629978 TI - Medium-term outcome of mosaicplasty for grade III-IV cartilage defects of the knee. AB - PURPOSE: To evaluate the medium-term outcome of mosaicplasty for full-thickness cartilage defects of the knee joint in 17 patients. METHODS: Records of 12 men and 5 women aged 16 to 57 (mean, 35) years who underwent mosaicplasty for grade III/IV osteochondral defects in the lateral (n=14) or medial (n=3) femoral condyle were reviewed. 12 of the patients had undergone knee surgeries. The mean size of the defects was 3.4 (range, 1-4) cm(2). Three patients had defects of >2 cm(2). All operations were performed by a single surgeon using mini-arthrotomy. The lateral edge of the trochlea was the donor site. Graft integration and the presence of any abnormality at the articular surface were assessed using magnetic resonance imaging (MRI). In addition, patients were evaluated using the International Knee Documentation Committee (IKDC) rating scale, the SF-36 health questionnaire, visual analogue scale (VAS) score for pain. RESULTS: Two of the 17 patients developed necrosis and cystic degeneration of the grafts and underwent conversion to unicompartmental knee arthroplasty within 2 years. They were older than 45 years and had defects of >2 cm(2). Respectively in years 4 and 7, one and 4 patients were lost to follow-up, the mean IKDC score was 75% and 88%, the SF-36 score was 83% and 90%, and the VAS score was <=3 in 13 of 14 patients at year 4 and in all 11 patients at year 7. At the 7-year follow-up, patient satisfaction with mosaicplasty was excellent in 8 patients, good in 3, and poor in 2 (who underwent unicompartmental knee arthroplasty). At year 4, MRI showed integration of the cartilage repair tissue and incorporation of the osseous portion of the graft into the bone in 13 of the 14 patients. The remaining patient had osteoarthritis at the graft donor site. At year 7, MRI showed good integration of the implant in all 11 available patients, but fissures were seen on the cartilage surface in 3 patients. CONCLUSION: The medium-term outcome of autologous mosaicplasty for symptomatic osteochondral defects in the femoral condyle is good. Longer follow-up is needed to determine the structural and functional integrity of the graft over time. PMID- 23629980 TI - Predictors of posterior cruciate ligament degeneration in osteoarthritic knees. AB - PURPOSE: To evaluate the tibial articular cartilage and histology of the posterior cruciate ligament (PCL) in osteoarthritic knees so as to determine predictors of PCL degeneration. METHODS: 23 advanced osteoarthritic knees (mean patient age, 61 years) treated with total knee arthroplasty (TKA) were prospectively studied. The Knee Society Score was assessed. Osteoarthritic changes on radiographs were graded as mild, moderate, or severe. Tibial articular cartilage erosion was assessed. The appearance of both cruciate ligaments was classified as normal, abnormal (thinner and sclerotic), or ruptured. Both ligaments were examined histologically for degenerative changes. Each degenerative change of the PCL was graded by 2 histopathologists twice separately. Higher scores indicated more severe degeneration. RESULTS: Of the 23 knees, the gross appearance of the anterior cruciate ligaments (ACLs) was normal in 6, abnormal in 11, and ruptured in 6. Histologically, the PCLs were normal in 4, minimally degenerated in 2, mildly in 8, moderately in 5, and severely in 4. The predominant degenerative change was the presence of loose fibrous tissue. ACL appearance correlated positively with PCL degeneration (r=0.883, p=0.001). The mean Knee Society Score was 24 (range, 0-43), and the mean function score was 30 (range, 5-55). PCL degeneration correlated positively with the Knee Society Score (r=0.565, p=0.02) but not with the function score (r=0.061, p=0.447). Anteroposterior instability correlated positively with PCL degeneration (r=0.691, p=0.01). Erosion in the lateral tibiofemoral compartment and ACL insufficiency were indicators of PCL degeneration (despite a normal appearance). Inter-observer reliability and intra-observer reproducibility were 0.82 and 0.87, respectively. CONCLUSION: The Knee Society Score, anteroposterior instability, ACL appearance, and erosion in the lateral tibiofemoral compartment are predictors of PCL degeneration and can help decide on the optimal type of TKA implant (PCL retaining vs. PCL-sacrificing design). PMID- 23629979 TI - Magnetic resonance imaging evaluation of patellar tendon graft remodelling after anterior cruciate ligament reconstruction with or without platelet-rich plasma. AB - PURPOSE: To evaluate the stages of patellar tendon graft remodelling using magnetic resonance imaging (MRI) after anterior cruciate ligament (ACL) reconstruction with or without platelet-rich plasma (PRP) injection. METHODS: 98 patients aged 18 to 65 years with complete rupture of the ACL were randomised to undergo reconstruction with the autologous patellar tendon grafts with or without PRP injection. For the PRP group, 8 ml of PRP was obtained in the surgery room and was percutaneously injected into the suprapatellar joint after portal suture. MRI was obtained at months 4, 6, and 12. Remodelling stages of the grafts were classified as hypointense, mildly hyperintense, moderately hyperintense, severely hyperintense, and diffusely hyperintense by a radiologist blinded to treatment allocation. RESULTS: More patients in the PRP group than controls attained higher stages of remodelling at month 4 (p=0.003), month 6 (p=0.0001), and month 12 (p=0.354). CONCLUSION: PRP enabled faster remodelling of patellar tendon grafts. PMID- 23629981 TI - Simultaneous bilateral total knee replacement: a prospective study of 150 patients. AB - PURPOSE: To evaluate the safety of simultaneous bilateral total knee replacement (TKR). METHODS: 124 women and 26 men (mean age, 66 years) underwent simultaneous bilateral TKR for tricompartmental osteoarthritis using a posteriorstabilised, high-flexion implant. All patients underwent dobutamine stress echocardiography for detection of any silent cardiac comorbidity by a cardiologist. None had any adverse effect after testing. Five patients had positive outcome and underwent coronary angiography to detect any significant coronary blockage. Functional outcome was evaluated using the Knee Society Score (KSS) and Western Ontario and McMaster Universities Arthritis Index (WOMAC). Tranexamic acid was given intravenously to reduce peri-operative blood loss. Femoral blocks and patient controlled analgesia were used to facilitate early recovery. Aggressive physiotherapy was allowed. Patients were followed up at months 3, 6, and 12, and yearly thereafter. RESULTS: At the 2-year follow-up, the mean range of motion improved from 95o to 129o (p=0.032), the mean KSS from 120 to 158 (p<0.001), and the WOMAC from 51 to 88 (p=0.002). One patient developed patellar crepitus at week 6, which resolved with conservative treatment. Another patient developed infection in both knees at month 6. Despite salvage procedures, infection recurred after 3 months and the patient underwent bilateral arthrodesis. No patient developed deep vein thrombosis or pulmonary embolism, myocardial infarction, atrial fibrillation, or other cardiac event. CONCLUSION: Simultaneous bilateral TKR is safe for properly selected patients. PMID- 23629982 TI - Position of the patella in adults in central India: evaluation of the Insall Salvati ratio. AB - PURPOSE: To assess the Insall-Salvati ratio in normal Indian adults to determine its applicability and the incidence of patella alta and baja in Indian populations. METHODS: 800 knees in 200 men and 200 women aged 18 to 50 (mean, 30) years were evaluated using lateral radiographs. The knee was set in semi-flexion (30o) to enable good visualisation of the patellar tendon and its insertion into the tibia on radiographs. The length of the patellar tendon (LT) over the length of the patella (LP)-the Insall-Salvati ratio-was measured, using a vernier caliper. RESULTS: The mean LT/LP ratio was 1.14 (standard deviation, 0.18). Based on the 95% confidence interval, the ratio was considered normal if within +/-40%. The LT/LP ratio was significantly higher in females than males (1.17 vs. 1.12, p<0.01). The cut-off point of patella alta was significantly greater in our Indian subjects than in western subjects (>1.5 vs. >1.2, p<0.0001). In the present cohort, the frequencies of patella alta (ratio, >1.5) and patella baja (ratio, <0.7) were 2.8% and 1%, respectively. CONCLUSION: The use of the Insall Salvati ratio to determine the patellar position is less applicable to Indian populations in which squatting, sitting cross-legged, and kneeling are customs. We propose that the normal range of the ratio for squatters among Indian populations be 0.7 to 1.5. PMID- 23629983 TI - Reliability of two-dimensional computed tomography for measuring hip anatomy. AB - PURPOSE: To evaluate the reliability (inter- and intra-observer variability) of 4 hip anatomies using 2-dimensional pelvic computed tomography (CT). METHODS: Two dimensional pelvic CT of 10 men and 10 women aged 33 to 89 (mean, 69) years presenting with non-orthopaedic conditions within one month were evaluated by 3 observers. The centre-edge angle of Wiberg, the Sharp angle, the acetabular depth ratio of Murray, and the acetabular anteversion angle of every hip were measured by each observer. After 6 weeks, these measurements were repeated. Reliability was evaluated using intraclass correlation coefficient (ICC), which represents the variation between patients as a percentage of the variation from all 3 sources (patients, inter-observers, and intra-observers). The ICC was classified as poor (<0.20), fair (0.21-0.40), moderate (0.41-0.60), substantial (0.61-0.80), and excellent (0.81-1.00). RESULTS: Reliability was substantial for the Sharp angle (ICC=0.74), the acetabular anteversion angle (ICC=0.69), and the acetabular depth ratio of Murray (ICC=0.62), and was fair for the centre-edge angle of Wiberg (ICC=0.40). CONCLUSION: The Sharp angle, the acetabular anteversion angle, and the acetabular depth ratio of Murray could be reliably measured using 2 dimensional CT. These measurements are appropriate for population-based studies of hip anatomy. PMID- 23629984 TI - Flatfoot in Indian population. AB - PURPOSE: To compare outcomes of different conservative treatments for flatfoot using the foot print index and valgus index. METHODS: 150 symptomatic flatfoot patients and 50 controls (without any flatfoot or lower limb deformity) aged older than 8 years were evaluated. The diagnosis was based on pain during walking a distance, the great toe extension test, the valgus index, the foot print index (FPI), as well as eversion/ inversion and dorsiflexion at the ankle. The patients were unequally randomised into 4 treatment groups: (1) foot exercises (n=60), (2) use of the Thomas crooked and elongated heel with or without arch support (n=45), (3) use of the Rose Schwartz insoles (n=18), and (4) foot exercises combined with both footwear modifications (n=27). RESULTS: Of the 150 symptomatic flatfoot patients, 96 had severe flatfoot (FPI, >75) and 54 had incipient flatfoot (FPI, 45-74). The great toe extension test was positive in all 50 controls and 144 patients, and negative in 6 patients (p=0.1734, one-tailed test), which yielded a sensitivity of 96% and a positive predictive value of 74%. Symptoms correlated with the FPI (Chi squared=9.7, p=0.0213). Combining foot exercises and foot wear modifications achieved best outcome in terms of pain relief, gait improvement, and decrease in the FPI and valgus index. CONCLUSION: The great toe extension test was the best screening tool. The FPI was a good tool for diagnosing and grading of flatfoot and evaluating treatment progress. Combining foot exercises and foot wear modifications achieved the best outcome. PMID- 23629985 TI - Medial arch orthosis for paediatric flatfoot. AB - PURPOSE: To evaluate any correlation between various foot angles and their respective American Orthopaedic Foot and Ankle Society (AOFAS) scores for pain, and the effectiveness of a medial arch orthosis. METHODS: 81 children with bilateral symptomatic flatfoot were randomised into orthosis (n=55) and control (n=26) groups. The orthosis group consisted of 33 male and 22 female patients aged 36 to 204 (mean, 99) months and they were given a medial arch support. The control group consisted of 15 male and 11 female patients aged 36 to 192 (mean, 100) months and they were managed with analgesics. Foot angles including anteroposterior (AP) and lateral talocalcaneal (TC) angles, AP and lateral talo- first metatarsal (TFM) angles, calcaneal pitch angle (in lateral plane), and talonavicular (TN) angle were measured, as were AOFAS scores for pain for the forefoot, midfoot, and hindfoot. RESULTS: After orthosis treatment, all AOFAS scores and all foot angles (except for the AP-TN angle) improved significantly. In the controls, all AOFAS scores (except for the midfoot score) and only the AP TFM angle improved significantly. In the orthosis group, the AOFAS hindfoot score correlated positively with the lateral TC angle of the left foot (r=0.345, p=0.010) and negatively with the calcaneal pitch angle of the right foot (r= 0.33, p=0.015). In the control group, the lateral TFM angle of the left foot correlated negatively with the AOFAS forefoot (r=-0.566, p=0.003) and midfoot scores (r=-0.497, p=0.001), whereas the calcaneal pitch angle of the left foot correlated positively with the AOFAS forefoot score (r=0.497, p=0.010). CONCLUSION: Medial arch support orthosis significantly improved AOFAS scores and foot angles. Calcaneal pitch angle and lateral TC angle correlated well with AOFAS hindfoot scores. PMID- 23629986 TI - Conservative treatment for acute Achilles tendon rupture: survey of current practice. AB - PURPOSE: To survey the practice of orthopaedic consultants in the Greater London area for treating Achilles tendon ruptures. METHODS: 221 orthopaedic consultants working in 28 hospitals within the Greater London area were identified. A questionnaire regarding conservative treatment for acute Achilles tendon ruptures was sent. The choice of immobilisation, the period of immobilisation, the time to weight bearing, the use of heel raises, and the use of diagnostic ultrasonography were enquired about. RESULTS: 62 of 86 respondents treated Achilles tendon ruptures conservatively by below-knee casts (n=51), above-knee casts (n=5), or functional braces (n=6). The most common immobilisation regimen (n=7) was to keep the foot in a sequence of an equinus position, a semi-equinus position, and a neutral position (3 weeks in each position). After cast removal, 45 of respondents preferred to use a heel raise for a median duration of 4 (range, 2 36) weeks. Respectively for foot and ankle specialists (n=24) and other orthopaedic specialists (n=38), the median immobilisation period prescribed was 8 (range, 3-13) and 9 (range, 6-36) weeks, respectively (p=0.625), whereas the median time to weight bearing prescribed was 6 (range, 0-9) and 6 (range, 0-12) weeks, respectively (p=0.402). CONCLUSION: Functional bracing was not as widely used as below-knee cast immobilisation. There was no consensus on the optimal immobilisation regimen. PMID- 23629987 TI - The Endolog system for moderate-to-severe hallux valgus. AB - PURPOSE: To report the midterm outcome of the Endolog system for correction of moderate-to-severe hallux valgus. METHODS: 23 women and 2 men (33 feet) aged 35 to 80 (mean, 52) years underwent minimally invasive surgery for moderate (n=25) and severe (n=8) hallux valgus using the Endolog system. The hallux valgus angle (HVA), the intermetatarsal angle (IMA), and the proximal articular set angle (PASA) were measured on radiographs. The feet were also assessed based on the American Orthopaedic Foot and Ankle Society (AOFAS) scale. RESULTS: The mean follow-up duration was 18.2 (range, 12-36) months. The mean HVA, IMA, PASA, and the mean AOFAS score improved significantly after surgery (all p<0.0001). Periosteal reaction was noted by week 4, and callus formation after 3 months. There were no delayed or non-union or other complications. CONCLUSION: The Endolog system achieved good outcome for moderate-to-severe hallux valgus. PMID- 23629988 TI - Tibiotalocalcaneal arthrodesis in a Singaporean hospital. AB - PURPOSE: To report 18 patients who underwent tibiotalocalcaneal arthrodesis using a retrograde intramedullary nail or cannulated screws. METHODS: 10 men and 8 women (19 ankles) aged 36 to 70 (mean, 52) years underwent tibiotalocalcaneal arthrodesis using a retrograde intramedullary nail (n=13) or cannulated screws (n=6). Indications for arthrodesis were severe cavovarus deformity secondary to polio or charcot-marie-tooth disease (n=7), severe osteoarthritis in the ankle and subtalar joints (n=6), Charcot joint deformity (n=3), failed fusion procedures (n=2), and foot drop secondary to T12 tumour surgery (n=1). The visual analogue score (VAS) for pain was assessed, as were the American Orthopaedic Foot and Ankle Society (AOFAS) scores (for subjective and objective pain, function, and stability of the ankle), short form 36 (SF-36), and patient expectation and satisfaction scores. RESULTS: The mean follow-up period was 35.6 (range, 11-144) months. 13 of 18 patients returned for assessment of scores. 18 of the 19 ankles achieved fusion after a mean period of 5.9 (range, 3-11) months. The mean VAS scores for pain, AOFAS scores, and SF-36 scores all improved. 11 patients had good-to-excellent satisfaction and expectation scores. Two patients had severe wound infections and underwent implant removal (after bone union), debridement, and intravenous antibiotic therapy. Two other patients had superficial wound infections. One patient with retrograde intramedullary nailing had a pseudoarthrosis and underwent implant removal, redebridement, re-autografting, and cannulated screw fixation. Fusion was achieved subsequently. CONCLUSION: Tibiotalocalcaneal arthrodesis improved the pain score and quality of life, despite a high risk of complications. PMID- 23629989 TI - Triplane fractures of the distal tibia in children. AB - PURPOSE: To review 28 cases of paediatric triplane fractures of the distal tibia over a 7-year period in a tertiary paediatric hospital. METHODS: Records of 21 boys and 7 girls aged 11 to 15 (mean, 13) years presented with triplane fractures of the left (n=14) and right (n=14) ankles were retrospectively reviewed. RESULTS: Injury mechanism included low-energy trauma (n=10) and moderate-energy trauma (n=18). Fractures were 2-part in 20 patients, 3-part in 6, and 4-part in 2. 11 patients had concomitant fibular fractures. Articular displacement was <2 mm in 17 patients and >=2 mm in 11 patients. 17 patients were treated conservatively (cast immobilisation); 11 were treated surgically by closed reduction and percutaneous pinning (n=1), open reduction and percutaneous pinning (n=5), closed reduction and internal fixation (n=3), or open reduction and internal fixation (n=2). Transepiphyseal partially threaded cannulated screws were used for fixation. The mean period of casting was 5.8 weeks, and the mean non- weight bearing period was 6.1 weeks. The mean follow-up period was 14.2 (range, 9-20) weeks. All patients had excellent outcome. No patient had any infections, delayed or non-union. Six patients had decreased range of motion and 4 had pain 4 weeks after cast removal. CONCLUSION: Treatment outcome of triplane fractures of the distal tibia in children is good when guidelines are closely adhered to. PMID- 23629990 TI - Percutaneous autologous bone marrow injections for delayed or non-union of bones. AB - PURPOSE: To evaluate 12 patients with delayed or nonunion of bones treated with bone marrow injections. METHODS: 6 men and 6 women aged 15 to 70 (mean, 45) years underwent bone marrow injections for delayed union (n=2) or atrophic non-union (n=10) of the ulna (n=6), femur (n=3), humerus (n=2), or metacarpal (n=1). Bone marrow was aspirated from the anterior iliac crest and injected to the delayed and non-union sites. Two injections were given for children and adolescents, and 3 for adults. The interval between the injections was 6 to 8 weeks. The amount of bone marrow injected was 30 to 40 ml for long bones and 20 ml for metacarpals. RESULTS: Ten of the 12 delayed or non-union of bones healed after bone marrow injections. The mean time for callus formation was 5.8 (range, 3-10) weeks, for clinical union was 7 (range, 4-12) weeks, and for radiological union was 16 (range, 10-24) weeks. CONCLUSION: Multiple injections of low-volume bone marrow can be used for treatment of delayed or non-union of bones. PMID- 23629991 TI - Prevention of knot slippage with the use of cyanoacrylate glue: a mechanical study. AB - PURPOSE: To assess the effect of cyanoacrylate glue on knot slippage and strength in vitro. METHODS: Ethibond 3/0 was tested using a tensile tester. A single drop of cyanoacrylate glue was applied to the knots. Seven knot configurations (10 samples each) were tested: (1) a surgeon's knot (S) plus 4 square throws (+4) without glue (control group), (2) S plus one square throw (+1) without glue, (3) S+1 with glue, (4) S with glue, (5) S+1 wet posttie without glue, (6) S+1 wet pre tie without glue, and (7) S+1 wet pre-tie with glue. Wet sutures were immersed in normal saline for 24 hours prior to knot tying. Wet pre- and post-tie sutures were immersed for one minute prior to knot tying and tensile testing, respectively. Outcome measures were the mode of failure (knot slippage or suture snapping) and the ultimate tensile strength. RESULTS: All knots without glue failed owing to knot slippage, except for the controls, whereas all knots with glue failed owing to suture snapping. The ultimate tensile strength was significantly higher in knots with glue and controls than in knots without glue. The ultimate tensile strength did not differ significantly between S+4 without glue and S with glue (p=0.48), indicating that glue could reinforce knots and reduce the number of throws needed. Wet suture is protective against failure (p<0.01). CONCLUSION: Cyanocrylate glue may have clinical applications for flexor tendon repairs for which a reduced knot size is advantageous. PMID- 23629992 TI - Prevalence of insomnia in patients with chronic back pain. AB - PURPOSE: To estimate the prevalence of insomnia in patients with chronic back pain, and to correlate insomnia with severity of back pain and disability. METHODS: 63 women and 57 men aged 24 to 83 (mean, 55) years who presented with chronic back pain for >6 months were asked to complete a self-administered questionnaire to evaluate the Insomnia Severity Index (ISI), Oswestry Disability Index (ODI), and Numerical Rating Scale (NRS) for back pain. RESULTS: Of the 120 patients, 25 had no insomnia, 39 had sub-threshold insomnia, and 56 had clinically significant insomnia. According to the ODI, disability was minimal in 12 patients, moderate in 38, severe in 43, bed-binding in 26, and crippling in one. Of the 120 patients, 91 rated their NRS for back pain as 5 to 10 and 29 rated it as 1 to 4. Correlation was stronger between ISI and ODI than between ISI and NRS for back pain (r=0.59 vs. r=0.38). CONCLUSION: 47% of patients with chronic back pain had insomnia. The ODI was more reliable than the NRS for back pain to detect insomnia. Back pain should be treated early to avoid serious health problems associated with insomnia. PMID- 23629994 TI - Safe zone for retractor placement to the lumbar spine via the transpsoas approach. AB - PURPOSE: To measure anatomic variations of the lumbar plexus within the psoas in relation to the L2/3, L3/4, and L4/5 disc spaces and to delineate a safe zone to avoid nerve injury during retractor placement via the transpsoas approach. METHODS: Six male and 6 female cadavers (24 psoas/ lumbar plexuses) aged 35 to 74 years were dissected. The lumbar plexus was isolated bilaterally. The L2, L3, and L4 nerve roots were identified and isolated without disturbing their natural anatomic course. The anteroposterior (AP) diameter of each intervertebral disc at L2/3, L3/4, and L4/5 was used as a reference. Four measurements were made using a caliper: the AP and mediolateral (ML) diameters of the psoas and AP and ML excursions of each nerve root. Percentages were calculated for the 4 measurements using the reference of the AP diameter of the intervertebral disc at each level. Comparison between left and right sides, between males and females, and between excursions of nerve roots were made. RESULTS: The AP diameter of the psoas increased from L2 to L4, with a mean vertebral body coverage of 80%, 86%, and 85% at L2/3, L3/4, and L4/5, respectively. Both the L2 and L3 nerve roots demonstrated substantial anterior trajectories as they coursed distally in the lumbar spine. No nerve root encroached anteriorly beyond 33% of the intervertebral disc space at L2 to L5. CONCLUSION: The lumbar plexus area corresponding to the anterior half of the intervertebral disc was the safe zone. Procedures to the lumbar spine via the transpsoas approach should be performed within the safe zone to avoid nerve injury. PMID- 23629993 TI - Single screw-rod anterior instrumentation for thoracolumbar burst fractures with incomplete neurological deficit. AB - PURPOSE: To evaluate the outcome of single screwrod anterior instrumentation for thoracolumbar burst fractures with incomplete neurological deficit. METHODS: 16 men and 5 women aged 22 to 55 (mean, 34) years underwent single screw-rod anterior instrumentation for thoracolumbar burst fractures with incomplete neurological deficit. The vertebrae involved were T10 (n=2), T11 (n=2), T12 (n=7), L1 (n=8), and L2 (n=2). No patient had disruption of the posterior ligament complex. Postoperatively, a thoracolumbar sacral orthosis was used until solid fusion. Outcome measures included neurological recovery, degree of kyphosis, complications, and pain and functional status of the patients. RESULTS: The mean follow-up duration was 36 (range, 13-50) months. All patients recovered neurologically by at least one grade. Of the 21 patients, 6 improved from grade B to grade C (n=4) or grade D (n=2), 13 from grade C to grade D, and 2 from grade D to grade E. The mean degree of kyphosis improved from 23o +/- 5o to 7o +/- 3o. Seven patients had complications including ipsilateral basal atelectasis (n=3), urinary tract infection (n=1), haematuria (n=1), postoperative ileus (n=1), and superficial wound infection (n=1). None had iatrogenic visceral or vascular injury, pseudoarthrosis or hardware-related complications. Only one patient had severe back pain persistently. CONCLUSION: Single screw-rod anterior instrumentation supplemented with an orthosis can be an alternative for double screw-rod anterior instrumentation for thoracolumbar burst fractures in patients with smaller vertebral bodies. PMID- 23629995 TI - Coronal shear fracture of the humeral trochlea. AB - PURPOSE: To review records of 5 patients with anterior coronal trochlear fractures. METHODS: Four men and one woman aged 25 to 46 (mean, 34) years underwent cancellous screw (n=3) or Kirschner wire (n=2) fixation for anterior coronal fractures of the humeral trochlea after falling on a flexed elbow. Patients were operated on through a medial approach. Three patients who had a large osteochondral fragment underwent fixation using 4-mm AO partially threaded cancellous screws. Two patients who had a small un-amenable osteochondral fragment (with articular cartilage damage) underwent fixation using Kirschner wires. Patients were evaluated using the Mayo Elbow Performance Index (MEPI) based on pain, arc of motion, stability, and functional disability. RESULTS: The mean time from injury to surgery was 7 (range, 5-10) days. The mean follow-up period was 2.7 years. No patient had any wound-related problems, postoperative neurovascular compromise, or avascular necrosis. Radiographic union was noted after a mean of 14 weeks. Outcome was excellent in 4 patients and good in one. The mean arc of flexion-extension was 101o and the mean arc of supination pronation was 130o. The mean MEPI was 92. The MEPI was relatively low in the 2 patients with a small osteochondral fragment who underwent Kirschner wire fixation. One patient with articular cartilage damage developed mild degenerative changes and had to change his occupation. The remaining 4 patients were pain-free and had returned to their occupations within 4 months. CONCLUSION: Open reduction and screw fixation restores articular congruency and enables early mobilisation. Small coronal shear fractures of the trochlea not amenable to screw fixation should be fixed with Kirschner wires. PMID- 23629996 TI - Mortality and re-operation rate after proximal femoral fracture surgery by trainees. AB - PURPOSE: To review records of 761 patients who underwent surgery for proximal femoral fractures to determine whether surgeon's experience and volume was associated with 6-month mortality and reoperation rates. METHODS: Records of 761 patients who underwent surgery for proximal femoral fractures were reviewed. Patients operated on by a consultant or trainees with supervision of a scrubbed consultant were classified as the consultant group (n=214). Patients operated on by trainees alone (n=516) or trainees with supervision of an unscrubbed consultant (n=31) were classified as the trainee group (n=547). A total of 21 trainees were identified. They had different levels of experience, which was quantified according to the total number of operations performed for proximal femoral fractures from the start of their training to the start of the study. RESULTS: Patients in the trainee group were older (80 +/- 12 vs. 77 +/- 14 years, p<0.001), and the fractures were more complex in the consultant group. The 6 month mortality rate was 24.2% (n=184). The odds of dying within 6 months after operation was 80% higher in patients operated on by trainees without supervision of a scrubbed consultant (odds ratio, 1.8; 95% confidence interval, 1.1-2.7). Variables associated with the 6-month mortality rate were age (p<0.001), American Society of Anesthesiologists grade (p<0.001), pre-injury activity level (p<0.001), and the surgeon's grade (p<0.05). The 6-month reoperation rate was 3.8% (n=29) and did not differ significantly in the 2 groups. The experience level of the trainees was not associated with the 6-month reoperation rate. CONCLUSION: The odds of dying within 6 months after a surgery for proximal femoral fractures was 80% higher in patients operated on by trainees without supervision of a scrubbed consultant. PMID- 23629997 TI - Accuracy of core needle biopsy for musculoskeletal tumours. AB - PURPOSE: To evaluate the sensitivity and specificity of core needle biopsy in determining musculoskeletal tumours in our hospital. METHODS: Records of 134 patients who underwent core needle biopsy followed by definitive surgery were retrospectively reviewed. Results of the core needle biopsy were compared with those of the final histology. Histology was classified into benign versus malignant, and bony versus soft-tissue lesions. The sensitivity and specificity of core needle biopsy were calculated. RESULTS: Based on final histology, there were 33 bone tumours (3 benign and 30 malignant), 74 soft-tissue tumours (6 benign and 68 malignant), 11 schwannomas (7 benign and 4 malignant), and 16 inflammatory/necrotic (benign) lesions. For 118 (88%) tumours, the biopsy results matched the final histological results. For 7 tumours, biopsy results were non diagnostic, as the amount of tissue obtained was insufficient. For 9 tumours, biopsy results did not match the final histological results; 5 considered benign but turned out to be malignant, one considered malignant but turned out to be benign, and 3 were correctly identified as malignant but incorrectly subtyped. The sensitivity and specificity of core needle biopsy were 95% (97/102) and 97% (31/32), respectively, assuming that the 7 non-diagnostic tumours were correctly diagnosed. CONCLUSION: Core needle biopsy is an accurate and reliable diagnostic tool for musculoskeletal tumours if performed by skilled persons and adequate tissue is obtained. PMID- 23629998 TI - Telangiectatic osteosarcoma. AB - PURPOSE: To review records of 8 patients with telangiectatic osteosarcoma (TOS) and determine whether pathologic fractures correlate with recurrence and survival. METHODS: Records of 4 men and 4 women aged 17 to 44 (mean, 28) years treated for TOS were reviewed. RESULTS; Of the 8 patients, 4 developed a pathologic fracture and 4 did not. In each group, 2 patients underwent limb salvage surgery and 2 underwent amputation. All patients received neoadjuvant and adjuvant chemotherapy with a combination of at least 2 of the following drugs: doxorubicin, methotrexate, cisplatin, and vincristin. After a mean follow-up of 5.6 (range, 2-16) years, all 4 patients with a pathologic fracture and 2 of the 4 patients without a pathologic fracture were still alive and disease-free. For the remaining patients, one died after 31 months from progression of a lung metastasis, and the other was alive with the disease and had had 2 recurrences, a lung metastasis, and an infection with Klebsiella oxytoca that eventually led to an amputation. CONCLUSION: The presence of a pathologic fracture in patients with TOS was not associated with worse outcome in terms of recurrence and survival. PMID- 23629999 TI - Proximal disinsertion of the common extensor tendon for lateral elbow tendinopathy. AB - PURPOSE: To evaluate surgical outcomes of disinsertion of the common extensor tendon for lateral elbow tendinopathy. METHODS: Records of 277 men and 128 women who underwent surgery for lateral elbow tendinopathy were reviewed. The indication for surgery was insufficient improvement of pain and inability to return to work after 3 weeks of physiotherapy (stretching, ultrasound) and local corticosteroid injections. According to the Tavernier technique, the origin of the tendons of the extensor carpi radialis brevis and extensor digitorum communis was located, and proximal disinsertion of the common extensor tendon was performed. RESULTS: Outcome was excellent in 344 (85%) of the patients, good in 46 (11.5%), regular in 9 (2%), and poor in 2 (0.5%). The mean time to return to work was 29 (range, 5-93) days. Immediate complications included infection (n=1), seroma (n=1), cicatricial fibrosis (n=10), radial neuritis (sensory) [n=4], and reactive dermatitis (n=2). Late complications included Frohse's arcade syndrome (n=1) and carpal tunnel syndrome (n=2). CONCLUSION: Disinsertion of the proximal common tendon is a good option for treating lateral elbow tendinopathy. PMID- 23630000 TI - Insufficiency fracture of the proximal fibula and then tibia: a case report. AB - Elderly people with osteoarthritis of the knee and postpartum women are at risk of insufficiency fractures of the proximal fibular or tibia. We report on an 82 year-old woman with valgus osteoarthritis of the knee who developed insufficiency fractures of the right proximal fibula and then the right proximal tibia. She underwent total knee arthroplasty using a long tibial stem and a tibial locking plate with the Less Invasive Stabilization System. PMID- 23630001 TI - Simultaneous dislocation of proximal and distal radio-ulnar joints: a case report. AB - Simultaneous dislocation of the radial head and distal radio-ulnar joint is rare. We report a 71-year-old man with volar dislocation of the radial head and dorsal dislocation of the distal radio-ulnar joint, and discuss the injury mechanism and its management with closed reduction. PMID- 23630002 TI - Posterior intrafocal pinning for reduction of oblique, extension supracondylar humeral fractures in children: a technical note. AB - A closed reduction technique using a posteriorly inserted intrafocal Kirschner wire for unstable Gartland type-III supracondylar humeral fractures in children is described. This surgical technique has been used in 7 patients. None had neurovascular complications, and all achieved bone union and had good or excellent functional and cosmetic results. PMID- 23630004 TI - Synovial osteochondromatosis of the hip with femoroacetabular impingement and osteoarthritis: a case report. AB - Synovial osteochondromatosis is a rare, benign condition characterised by synovial metaplasia and the formation of cartilaginous and osteocartilaginous bodies in the capsule. We report one such case in a 30-year-old woman with synovial osteochondromatosis of the hip and progressive osteoarthritis caused by femoroacetabular impingement with joint-space narrowing. She underwent surgical removal of 32 loose bodies and osteochondroplasty. A coronal osteophyte at the junction of the femoral head and neck was also excised. At 2-year follow-up, her Harris Hip Score had improved from 62 to 90. PMID- 23630003 TI - Notching of the femoral stem neck in metal-on-metal total hip replacement: a case report. AB - We report a case of impingement in a metal-on-metal total hip replacement causing both notching of the femoral stem neck and aseptic loosening of the acetabular component. The acetabular component was inserted in excessive anteversion. The femoral stem and acetabular components were retrieved. A larger femoral head was used, and an acetabular component was placed in a less anteverted position. Intra operative testing through different ranges of movement is recommended to identify potential impingement. PMID- 23630005 TI - Salvage of the lower limb after a full thickness burn with loss of the knee extensor mechanism: a case report. AB - We report on a 79-year-old woman who underwent salvage of the knee and lower leg using a Whichita Fusion Nail for knee arthrodesis, combined with a medial gastrocnemius muscle flap for a 3% contact burn that resulted in loss of the extensor mechanism. This provided an alternative to above-knee amputation when extensor mechanism reconstruction was not feasible. PMID- 23630006 TI - Congenital insensitivity to pain and anhydrosis: a report of two cases. AB - We report on 2 patients with congenital insensitivity to pain and anhydrosis. The first one was a 7-month-old boy who presented with non-traumatic, haematogenous septic dislocation of the right elbow with physeal separation of the distal humerus. The second one was a 3-year-old girl suspected to have Job syndrome with an altered immunological profile. PMID- 23630007 TI - Recurrent solitary osteochondroma of the metacarpal: a case report. AB - Osteochondromas are the most common benign bone tumours and account for 20 to 50% of benign bone tumours and 10 to 15% of all bone tumours. They usually occur in long bones; 40% occur around the knee joint, but in the hand they are uncommon and usually affect the proximal phalanx. The metacarpal is rarely involved. We report a 32-year-old man with a recurrent solitary osteochondroma of the metacarpal. PMID- 23630008 TI - Dynamic hip screw blade fixation for intertrochanteric hip fractures. PMID- 23630009 TI - Intramedullary nailing supplemented with Poller screws for proximal tibial fractures. PMID- 23630010 TI - Online counseling: a narrative and critical review of the literature. AB - OBJECTIVE: This article aimed to critically review the literature on online counseling. METHOD: Database and hand-searches were made using search terms and eligibility criteria, yielding a total of 123 studies. RESULTS: The review begins with what characterizes online counseling. Outcome and process research in online counseling is reviewed. Features and cyberbehaviors of online counseling such as anonymity and disinhibition, convenience, time-delay, the loss of social signaling, and writing behavior in cyberspace are discussed. Ethical behavior, professional training, client suitability, and clients' and therapists' attitudes and experiences of online counseling are reviewed. CONCLUSION: A growing body of knowledge to date is positive in showing that online counseling can have a similar impact and is capable of replicating the facilitative conditions as face to-face encounters. A need remains for stronger empirical evidence to establish efficacy and effectiveness and to understand better the unique mediating and facilitative variables. PMID- 23630011 TI - Frequent PLAG1 gene rearrangements in skin and soft tissue myoepithelioma with ductal differentiation. AB - A subset of cutaneous and superficial soft tissue myoepithelial (ME) tumors displays a distinct ductal component and closely resembles mixed tumors/pleomorphic adenomas of salivary gland. As PLAG1 and HMGA2 rearrangements are the most common genetic events in pleomorphic adenomas, we sought to investigate if these abnormalities are also present in the skin/soft tissue ME lesions. In contrast, half of the deep-seated soft tissue ME tumors lacking ductal differentiation are known to be genetically unrelated, showing EWSR1 rearrangements. FISH analysis to detect PLAG1 and HMGA2 abnormalities was performed in 35 ME tumors, nine skin and 26 soft tissue, lacking EWSR1 and FUS rearrangements. For the PLAG1-rearranged tumors, FISH and RACE were performed to identify potential fusion partners, including CTNNB1 (beta-catenin) on 3p21 and LIFR (leukemia inhibitory factor receptor) on 5p13. Recurrent PLAG1 rearrangement by FISH was detected in 13 (37%) lesions, including three (33%) in the skin and 10 (38%) in the soft tissue. All were classified as benign and all except one showed abundant tubulo-ductal differentiation (comprising 12/24 [50%] of all tumors with ductal structures). A LIFR-PLAG1 fusion was detected by RACE and then confirmed by FISH in one soft tissue ME tumor with tubular formation. No CTNNB1 or LIFR abnormalities were detected in any of the remaining PLAG1-rearranged tumors. No structural HMGA2 abnormalities were detected in any of the 22 ME lesions tested. A subset of cutaneous and soft tissue ME tumors appears genetically linked to their salivary gland counterparts, displaying frequent PLAG1 gene rearrangements and occasionally LIFR-PLAG1 fusion. PMID- 23630014 TI - Effects of nutrient content claims, sports celebrity endorsements and premium offers on pre-adolescent children's food preferences: experimental research. AB - OBJECTIVES: To assess pre-adolescent children's responses to common child oriented front-of-pack food promotions. METHODS: Between-subjects, web-based experiment with four front-of-pack promotion conditions on energy-dense and nutrient-poor (EDNP) foods: no promotion [control]; nutrient content claims; sports celebrity endorsements (male athletes) and premium offers. Participants were 1302 grade 5 and 6 children (mean age 11 years) from Melbourne, Australia. Participants chose their preferred product from a randomly assigned EDNP food pack and comparable healthier food pack then completed detailed product ratings. Child-oriented pack designs with colourful, cartooned graphics, fonts and promotions were used. RESULTS: Compared to the control condition, children were more likely to choose EDNP products featuring nutrient content claims (both genders) and sports celebrity endorsements (boys only). Perceptions of nutritional content were enhanced by nutrient content claims. Effects of promotions on some product ratings (but not choice) were negated when children referred to the nutrition information panel. Premium offers did not enhance children's product ratings or choice. CONCLUSIONS: Nutrient content claims and sports celebrity endorsements influence pre-adolescent children's preferences towards EDNP food products displaying them. Policy interventions to reduce the impact of unhealthy food marketing to children should limit the use of these promotions. PMID- 23630013 TI - Conformation change of bovine serum albumin induced by bioactive titanium metals and its effects on cell behaviors. AB - The conformation change of bovine serum albumin (BSA) induced by bioactive titanium surfaces, including acid-alkali-treated titanium (AA-Ti) and alkali-heat treated titanium (AH-Ti), was studied, and its effects on the activity of MC3T3 E1 cell were evaluated. Pure titanium metal (P-Ti) was used as control. The AA-Ti could adsorb more BSA on its surface than AH-Ti and P-Ti. The alpha-helix part of the protein adsorbed on P-Ti has weakly decreased compared with native BSA, and it dramatically decreased on AA-Ti and AH-Ti. The beta-sheet segment of proteins adsorbed on P-Ti and AH-Ti had obviously increased. Much more tryptophan residues were exposed after the protein conformation changed when it interacted with AH Ti, and some tryptophan residues were enveloped after it interacted with AA-Ti and P-Ti. AA-Ti has more tryptophan residues enveloped than P-Ti. All titanium surfaces induced tyrosine residues exposed, especially for the P-Ti. The higher ratio of COO(-)/NH3(+) for the proteins on P-Ti and AA-Ti indicated an orientation of proteins on P-Ti and AA-Ti, which makes more COO(-) exposed. The lower ratio of COO(-)/NH3(+) on AH-Ti indicates that more NH3(+) is exposed on its surface. The cell proliferation ability on different treated titanium surfaces coated with BSA followed by the order: P-Ti > AA-Ti > AH-Ti, which indicated that the protein conformation change on different bioactive titanium surfaces has great effect on the cell activity. Our results showed that the different biological response of bioactive titanium metals might depend on the protein conformation change induced by the surface structure. PMID- 23630015 TI - Winter climate change effects on soil C and N cycles in urban grasslands. AB - Despite growing recognition of the role that cities have in global biogeochemical cycles, urban systems are among the least understood of all ecosystems. Urban grasslands are expanding rapidly along with urbanization, which is expected to increase at unprecedented rates in upcoming decades. The large and increasing area of urban grasslands and their impact on water and air quality justify the need for a better understanding of their biogeochemical cycles. There is also great uncertainty about the effect that climate change, especially changes in winter snow cover, will have on nutrient cycles in urban grasslands. We aimed to evaluate how reduced snow accumulation directly affects winter soil frost dynamics, and indirectly greenhouse gas fluxes and the processing of carbon (C) and nitrogen (N) during the subsequent growing season in northern urban grasslands. Both artificial and natural snow reduction increased winter soil frost, affecting winter microbial C and N processing, accelerating C and N cycles and increasing soil : atmosphere greenhouse gas exchange during the subsequent growing season. With lower snow accumulations that are predicted with climate change, we found decreases in N retention in these ecosystems, and increases in N2 O and CO2 flux to the atmosphere, significantly increasing the global warming potential of urban grasslands. Our results suggest that the environmental impacts of these rapidly expanding ecosystems are likely to increase as climate change brings milder winters and more extensive soil frost. PMID- 23630012 TI - Defects of Vps15 in skeletal muscles lead to autophagic vacuolar myopathy and lysosomal disease. AB - The complex of Vacuolar Protein Sorting 34 and 15 (Vps34 and Vps15) has Class III phosphatidylinositol 3-kinase activity and putative roles in nutrient sensing, mammalian Target Of Rapamycin (mTOR) activation by amino acids, cell growth, vesicular trafficking and autophagy. Contrary to expectations, here we show that Vps15-deficient mouse tissues are competent for LC3-positive autophagosome formation and maintain mTOR activation. However, an impaired lysosomal function in mutant cells is traced by accumulation of adaptor protein p62, LC3 and Lamp2 positive vesicles, which can be reverted to normal levels after ectopic overexpression of Vps15. Mice lacking Vps15 in skeletal muscles, develop a severe myopathy. Distinct from the autophagy deficient Atg7(-/-) mutants, pathognomonic morphological hallmarks of autophagic vacuolar myopathy (AVM) are observed in Vps15(-/-) mutants, including elevated creatine kinase plasma levels, accumulation of autophagosomes, glycogen and sarcolemmal features within the fibres. Importantly, Vps34/Vps15 overexpression in myoblasts of Danon AVM disease patients alleviates the glycogen accumulation. Thus, the activity of the Vps34/Vps15 complex is critical in disease conditions such as AVMs, and possibly a variety of other lysosomal storage diseases. PMID- 23630016 TI - Platelet inhibitory effect of clopidogrel in patients treated with omeprazole, pantoprazole, and famotidine: a prospective, randomized, crossover study. AB - BACKGROUND: Concerns about an inhibitory effect of proton pump inhibitors (PPIs) on clopidogrel metabolism have been raised. Because the pharmacological effect of clopidogrel is dependent on genetically determined activity of the hepatic cytochrome P450 isoenzymes system, it is important to examine the interaction between different PPIs and high on-treatment platelet reactivity (HPR) after controlling for genetic variability. The aim of the study was to assess the effect of 2 PPIs and a histamine-2 (H2) receptor-blocker on platelet reactivity in a crossover trial where each patient was alternately treated with each drug. HYPOTHESIS: Omeprazole reduces HPR more than other PPI or H2 blockers. METHODS: Patients treated with aspirin and clopidogrel for at least 1 month were assigned to 3 consecutive 1-month treatment periods during which they were treated with each of the 3 study medications twice daily: omeprazole 20 mg, famotidine 40 mg, and pantoprazole 20 mg. At the end of each treatment phase, platelet function was evaluated with the Verify Now system using 2 cutoff values (>208 P2Y12 reaction units [PRUs] and >230 PRUs) for the definition of HPR. RESULTS: Patients with HPR were older than those without HPR (62 +/- 10 vs 55 +/- 8 years, respectively, P = 0.03). HPR was more prevalent during omeprazole therapy compared to famotidine or pantoprazole (48%, 33%, and 31%, respectively, for the 208 PRU cutoff, P= 0.04; and 37%, 17%, and 23%, respectively, for the 230 PRU cutoff, P= 0.003). CONCLUSIONS: After eliminating the effects of interindividual variability in clopidogrel metabolism, omeprazole therapy was associated with substantially more HPR than famotidine or pantoprazole. PMID- 23630017 TI - Hydrolysis of tetravalent cerium for a simple route to nanocrystalline cerium dioxide: an in situ spectroscopic study of nanocrystal evolution. AB - Despite the rapid developments in recent nanocrystal research and their expanding applications, the evolution mechanism of nanocrystals remains veiled for the most part due to the lack of appropriate analytical techniques. Here we demonstrate one promising multi-spectroscopic approach for the in situ investigation of nanocrystal evolution. That is, the formation of nanocrystalline cerium dioxide (NC-CeO2) has been probed by dynamic light scattering (DLS), X-ray absorption spectroscopy (XAS) and high-energy X-ray scattering (HEXS). The obtained results indicate that the fine colloidal particles of NC-CeO2 are formed in an acidic aqueous solution simply through the hydrolysis of the initial precursor of small oligomer Ce(IV) species. This information on how NC-CeO2 evolves is fundamental to simplifying and alleviating the synthetic strategy for NC-CeO2 production. PMID- 23630018 TI - Lactobacillus GG and tributyrin supplementation reduce antibiotic-induced intestinal injury. AB - BACKGROUND: Antibiotic therapy negatively alters the gut microbiota. Lactobacillus GG (LGG) decreases antibiotic-associated diarrhea (AAD) symptoms, but the mechanisms are unknown. Butyrate has beneficial effects on gut health. Altered intestinal gene expression occurs in the absence of gut microbiota. We hypothesized that antibiotic-induced changes in gut microbiota reduce butyrate production, varying genes involved with gut barrier integrity and water and electrolyte absorption, lending to AAD, and that simultaneous supplementation with LGG and/or tributyrin would prevent these changes. METHODS: C57BL/6 mice aged 6-8 weeks received a chow diet while divided into 8 treatment groups (+/- saline, +/- LGG, +/- tributyrin, or both). Mice received treatments orally for 7 days with +/- broad-spectrum antibiotics. Water intake was recorded daily and body weight was measured. Intestine tissue samples were obtained and analyzed for expression of genes and proteins involved with water and electrolyte absorption, butyrate transport, and gut integrity via polymerase chain reaction and immunohistochemistry. RESULTS: Antibiotics decreased messenger RNA (mRNA) expression (butyrate transporter and receptor, Na(+)/H(+) exchanger, Cl(-)/HCO3 ( ), and a water channel) and protein expression (butyrate transporter, Na(+)/H(+) exchanger, and tight junction proteins) in the intestinal tract. LGG and/or tributyrin supplementation maintained intestinal mRNA expression to that of the control animals, and tributyrin maintained intestinal protein intensity expression to that of control animals. CONCLUSION: Broad-spectrum antibiotics decrease expression of anion exchangers, butyrate transporter and receptor, and tight junction proteins in mouse intestine. Simultaneous oral supplementation with LGG and/or tributyrin minimizes these losses. Optimizing intestinal health with LGG and/or tributyrin may offer a preventative therapy for AAD. PMID- 23630019 TI - NUP98-NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia. AB - The cryptic t(5;11)(q35;p15.5) creates a fusion gene between the NUP98 and NSD1 genes. To ascertain the significance of this gene fusion, we explored its frequency, clinical impact, and gene expression pattern using DNA microarray in pediatric acute myeloid leukemia (AML) patients. NUP98-NSD1 fusion transcripts were detected in 6 (4.8%) of 124 pediatric AML patients. Supervised hierarchical clustering analyses using probe sets that were differentially expressed in these patients detected a characteristic gene expression pattern, including 18 NUP98 NSD1-negative patients (NUP98-NSD1-like patients). In total, a NUP98-NSD1-related gene expression signature (NUP98-NSD1 signature) was found in 19% (24/124) and in 58% (15/26) of cytogenetically normal cases. Their 4-year overall survival (OS) and event-free survival (EFS) were poor (33.3% in NUP98-NSD1-positive and 38.9% in NUP98-NSD1-like patients) compared with 100 NUP98-NSD1 signature-negative patients (4-year OS: 86.0%, 4-year EFS: 72.0%). Interestingly, t(7;11)(p15;p15)/NUP98-HOXA13, t(6;11)(q27;q23)/MLL-MLLT4 and t(6;9)(p22;q34)/DEK NUP214, which are known as poor prognostic markers, were found in NUP98-NSD1-like patients. Furthermore, another type of NUP98-NSD1 fusion transcript was identified by additional RT-PCR analyses using other primers in a NUP98-NSD1-like patient, revealing the significance of this signature to detect NUP98-NSD1 gene fusions and to identify a new poor prognostic subgroup in AML. PMID- 23630020 TI - Exercise does not counteract the effects of a "westernized" diet on prostate cancer xenografts. AB - BACKGROUND: The relationships between diet, exercise, and prostate cancer (PCa) remain unclear. We have previously reported that a "Western" diet promotes PCa tumor growth in vivo. Presently, we report the effects of sustained aerobic exercise on PCa progression in animals fed a high-fat diet versus a standard diet. METHODS: Athymic mice (n = 43) were inoculated subcutaneously with human PCa (LNCaP) cells, fed ad libitum with either a high-fat or a standard diet, and randomized into forced exercising and non-exercising groups. Body weight, tumor volume, and food consumption were recorded tri-weekly. Terminal serum samples and tumor biopsies were obtained for analysis. RESULTS: Body weight differences were not observed between the groups over time. The high-fat diet with exercise (HF Ex) group showed significantly increased tumor growth rate compared to all other groups (P < 0.0007). Tumor growth rate of the standard diet with exercise (Std Ex) group was reduced significantly compared to the high-fat diet without exercise (HF-No Ex) group (P = 0.0008). Significant differences (P <= 0.012) were observed in energy consumption (kcal) between the groups over time. Exercising mice consumed significantly more kcal than non-exercising mice, and the HF-Ex group consumed significantly more than each of the other three groups (P < 0.0007). The expression levels of p27 and p21 were increased in exercising animals, while AR expression was elevated in the HF-Ex group versus the Std-Ex and HF-No Ex groups. CONCLUSIONS: Sustained aerobic exercise did not counteract the tumor-promotional effect of increased consumption of a high-fat diet, suggesting that diet is more influential in PCa progression than exercise. Combining exercise with a healthy diet reduced the rate of PCa progression in this model. This study may have implications for PCa risk reduction in humans. PMID- 23630021 TI - An estimate of the global sink for nitrous oxide in soils. AB - A literature survey of studies reporting nitrous oxide uptake in the soils of natural ecosystems is used to suggest that the median uptake potential is 4 MUg m(-2) h(-1). The highest values are nearly all associated with soils of wetland and peatland ecosystems. Globally, the consumption of nitrous oxide in soils is not likely to exceed 0.3 TgN yr(-1), indicating that the projected sink is not more than 2% of current estimated sources of N(2)O in the atmosphere. PMID- 23630023 TI - Unusual radial artery calcification. PMID- 23630024 TI - Total synthesis, proof of absolute configuration, and biosynthetic origin of stylopsal, the first isolated sex pheromone of strepsiptera. AB - The asymmetric total synthesis of the diastereomers of stylopsal establishes the absolute configuration of the first reported sex pheromone of the twisted-wing parasite Stylops muelleri as (3R,5R,9R)-trimethyldodecanal. The key steps for the diastereo- and enantiodivergent introduction of the methyl groups are two different types of asymmetric conjugate addition reactions of organocopper reagents to alpha,beta-unsaturated esters, whereas the dodecanal skeleton is assembled by Wittig reactions. The structure of the natural product was confirmed by chiral gas chromatography (GC) techniques, GC/MS and GC/electroantennography (EAD) as well as field tests. An investigation into the biosynthesis of the pheromone revealed that it is likely to be produced by decarboxylation of a 4,6,10-trimethyltridecanoic acid derivative, which was found in substantial amounts in the fat body of the female, but not in the host bee Andrena vaga. This triple-branched fatty acid precursor thus seems to be biosynthesized de novo through a polyketide pathway with two consecutive propionate-propionate-acetate assemblies to form the complete skeleton. The simplified, motionless and fully host-dependent female exploits a remarkable strategy to maximize its reproductive success by employing a relatively complex and potent sex pheromone. PMID- 23630025 TI - Indeno[2,1-b]fluorene: a 20-pi-electron hydrocarbon with very low-energy light absorption. AB - Smaller can be better: The first example of meta-quinodimethane embedded in an indenofluorene framework has been synthesized. 10,12-Dimesitylindeno[2,1 b]fluorene exhibits extremely low-energy light absorption, despite the small conjugation space of the molecule, which consists of only 20 pi electrons. PMID- 23630026 TI - Glycine-immunoreactive neurons in the brain of a shark (Scyliorhinus canicula L.). AB - The glycinergic cell populations in the brain of the lesser spotted dogfish were studied by a glycine immunofluorescence method. Numerous glycine-immunoreactive (Gly-ir) neurons were observed in different brain nuclei. In the telencephalon, Gly-ir cells were observed in the olfactory bulb, telencephalic hemispheres, and preoptic region. In the hypothalamus, cerebrospinal fluid-contacting Gly-ir neurons were observed in the lateral and posterior recess nuclei. Coronet cells of the saccus vasculosus were Gly-ir. In the diencephalon, Gly-ir neurons were observed in the prethalamus and pretectum. In the midbrain, both the optic tectum and lateral mesencephalic nucleus contained numerous Gly-ir neurons. In the cerebellum, many Golgi cells were Gly-ir. In the rhombencephalon, Gly-ir cells were observed in the medial and ventral octavolateral nuclei, vagal lobe, visceromotor nuclei, and reticular formation, including the inferior raphe nucleus. In the spinal cord, some neurons of the marginal nucleus and some cells of the dorsal and ventral horns were Gly-ir. Comparison of dogfish Gly-ir cell populations with those reported for the sea lamprey, Siberian sturgeon, and zebrafish revealed some shared features but also notable differences. For example, Gly-ir cells were observed in the dogfish cerebellum, unlike the case in the Siberian sturgeon and zebrafish, whereas the absence of Gly-ir neurons in the isthmus is shared by all these species, except for lampreys. Gly-ir populations in the dogfish hypothalamus and telencephalon are notable in comparison with those of the other jawed vertebrates investigated to date. Together, these results reveal a complex and divergent evolution of glycinergic systems in the major groups of fishes. PMID- 23630027 TI - Case study: Nutrition and hydration status during 4,254 km of running over 78 consecutive days. AB - The aims of this study were to assess the dietary intake and monitor self reported recovery quality and clinical symptomology of a male ultra-endurance runner who completed a multiday ultra-endurance running challenge covering 4,254 km from North Scotland to the Moroccan Sahara desert over 78 consecutive days. Food and fluid intakes were recorded and analyzed through dietary analysis software. Body mass (BM) was determined before and after running each day, and before sleep. Clinical symptomology and perceived recovery quality were recorded each day. Whole blood hemoglobin and serum ferritin were determined before and after the challenge. Total daily energy (mean +/- SD: 23.2 +/- 3.2 MJ . day(-1)) and macronutrient intake (182 +/- 31 g . day(-1) protein, 842 +/- 115 g . day(-1) carbohydrate, 159 +/- 55 g . day(-1) fat) met consensus nutritional guidelines for endurance performance. Total daily water intake through foods and fluids was 4.8 +/- 2.0 L . day(-1). Water and carbohydrate intake rates during running were 239 +/- 143 ml . h(-1) and 56 +/- 19 g . h(-1), respectively. Immediately after running, carbohydrate and protein intakes were 1.3 +/- 1.0 g . kg BM(-1) and 0.4 +/- 0.2 g . kg BM(-1), respectively. Daily micronutrient intakes ranged from 109 to 662% of UK RNIs. Prerunning BM was generally maintained throughout. Overall exercise-induced BM loss averaged 0.8 +/- 1.0%; although BM losses of >= 2% occurred in the latter stages, a reflection of the warmer climate. Varying degrees of self-reported perceived recovery quality and clinical symptomology occurred throughout the challenge. This case study highlights oscillations in dietary habits along 78 consecutive days of ultra-endurance running, dependent on changes in ambient conditions and course topography. Nevertheless, nutrition and hydration status were maintained throughout the challenge. Despite dietary iron intake above RNI and iron supplementation, this alone did not prevent deficiency symptoms. PMID- 23630028 TI - Cytokinesis-blocked micronucleus cytome assay and spectral karyotyping as methods for identifying chromosome damage in a lung cancer case-control population. AB - Lung cancer is the leading cause of all cancer-related deaths in the US. The need to develop more accurate cancer risk assessment tools is imperative to improve the ability to identify individuals at greatest risk of developing disease. The Cytokinesis-Blocked Micronucleus Cytome Assay (CBMNcyt) presents a sensitive and specific method of assessing DNA damage. We have previously reported that this assay is sensitive to genetic damage caused by the tobacco-specific nitrosamine 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and that binucleated cells with micronuclei, nucleoplasmic bridges and nuclear buds are strong predictors of lung cancer risk. The current study confirmed our previous findings and sought to identify the specific chromosomes involved in lung carcinogenesis. Spectral karyotyping was conducted on a subset of lung cancer cases [n = 116] and cancer free controls [n = 126] with the highest CBMNcyt endpoints, on baseline and NNK treated blood lymphocytes. After adjusting for age, gender, race/ethnicity, smoking status, and pack and smoke years, consistent significant associations between chromosome: 9, 19, 22, X, at baseline; chromosome: 3, 4, and 16 after NNK induction; and chromosome: 1, 13, and 17 at both baseline and NNK-induction; and lung cancer risk (all P <= 0.05) were observed. Several of these chromosomes harbor critical genes involved in lung carcinogenesis, such as the FHIT gene, CDKN2A, PADPRP, and TP53. Our results indicate that the CBMNcyt assay when used in conjunction with other cytogenetic methodologies can increase our ability to identify specific chromosomal regions associated with DNA damage, thereby improving our understanding of the underlying mechanisms involved in individual cancer predisposition. PMID- 23630029 TI - Dynamic and inherent B0 correction for DTI using stimulated echo spiral imaging. AB - PURPOSE: To present a novel technique for high-resolution stimulated echo diffusion tensor imaging with self-navigated interleaved spirals readout trajectories that can inherently and dynamically correct for image artifacts due to spatial and temporal variations in the static magnetic field (B0) resulting from eddy currents, tissue susceptibilities, subject/physiological motion, and hardware instabilities. METHODS: The Hahn spin echo formed by the first two 90 degrees radiofrequency pulses is balanced to consecutively acquire two additional images with different echo times and generate an inherent field map, while the diffusion-prepared stimulated echo signal remains unaffected. For every diffusion-encoding direction, an intrinsically registered field map is estimated dynamically and used to effectively and inherently correct for off-resonance artifacts in the reconstruction of the corresponding diffusion-weighted image. RESULTS: After correction with the dynamically acquired field maps, local blurring artifacts are specifically removed from individual stimulated echo diffusion-weighted images and the estimated diffusion tensors have significantly improved spatial accuracy and larger fractional anisotropy. CONCLUSION: Combined with the self-navigated interleaved spirals acquisition scheme, our new method provides an integrated high-resolution short-echo time diffusion tensor imaging solution with inherent and dynamic correction for both motion-induced phase errors and off-resonance effects. PMID- 23630030 TI - Association between sweet drink intake and adiposity in Danish children participating in a long-term intervention study. AB - BACKGROUND: In some previous studies direct associations between intake of soft drinks, sugar-sweetened beverages and adiposity have been reported. The majority of these studies were, however, conducted in the USA and it is uncertain if the results are applicable to non-US countries. OBJECTIVE: To assess the association between sweet drink intake at age 6 and 9 years and the subsequent 3- to 7-year changes in body mass index (BMI) and sum of four skin-folds (Sigma4SF). METHODS: Information on sweet drink intake (7 days food record) and physical activity (accelerometer) was obtained at age 6 years (n = 366) [Correction made here after initial online publication.] and 9 years (n = 269). Weight, height and Sigma4SF were measured at age 6, 9 and 13 years. Additional information on socio-economic status, maternal BMI and pubertal status was obtained. RESULTS: No associations were observed between sweet drink intake at age 6 years and change in BMI or logSigma4SF from age 6 to 9 years or 6 to 13 years. Also, no associations were observed between change in sweet drink intake from age 6 to 9 years and subsequent change in BMI or logSigma4SF from age 9 to 13 years. A weak direct association was observed between sweet drink intake at age 9 years and change in logSigma4SF from age 9 to 13 years (per 100 g ~ 3.38 fl oz) (beta: 0.014, 95% confidence interval [CI]: -0.001 to 0.029, P = 0.06), while no association was seen for BMI. In supplementary analyses a similar association was observed for soft drinks (beta: 0.087, 95% CI: 0.048 to 0.126, P = 0.001) but only in the intervention group. CONCLUSION: We observed associations between intake of sweet drinks and soft drinks and change in skin-fold thickness in a group of Danish children. However, as the associations did not remain significant when multiple testing was considered or was only significant among children from the intervention group, the results do not confirm or refute the direct association reported in previous studies. PMID- 23630031 TI - Total synthesis, stereochemical assignment, and biological activity of chamuvarinin and structural analogues. AB - A highly stereocontrolled synthesis of (+)-chamuvarinin has been completed in 1.5% overall yield over 20 steps. The key fragment coupling reactions were the addition of alkyne 8 to aldehyde 7 (under Felkin-Anh control), followed by the two step activation/cyclization to close the C20-C23 2,5-cis-substituted tetrahydrofuran ring and a Julia-Kocienski olefination at C8-C9 to introduce the terminal butenolide. The inherent flexibility of our coupling strategy led to a streamlined synthesis with 17 steps in the longest sequence (2.2% overall yield), in which the key bond couplings are reversed. In addition, a series of structural analogues of chamuvarinin have been prepared and screened for activity against HeLa cancer cell lines and both the bloodstream and insect forms of Trypanosoma brucei, the parasitic agent responsible for African sleeping sickness. PMID- 23630032 TI - Biotin-conjugated anti-CD44 antibody-avidin binding system for the improvement of chondrocyte adhesion to scaffolds. AB - The clinical need for improved treatment options for patients with cartilage injuries has motivated tissue-engineering studies aimed at the in vitro generation of cell-based implants with functional properties. The success of tissue-engineered repair of cartilage may depend on the rapid and efficient adhesion of transplanted cells to the scaffold. In the present study, chondrocyte scaffold constructs were engineered by planting porcine chondrocytes into nonporous chitosan membranes and 3D porous chitosan scaffolds that were treated with or without biotin-conjugated anti-CD44 antibody-avidin binding system and avidin-biotin binding system. The spreading area, cell exfoliation rates, cell proliferation rates, histological analysis, DNA and glycosaminoglycan (GAG) content, and mRNA expression were investigated to evaluate the efficiency of biotin-conjugated anti-CD44 antibody-avidin binding system for the improvement of cell adhesion to scaffolds in the cartilage tissue. The results showed that the biotin-conjugated anti-CD44 antibody-avidin binding system improved cell adhesion to scaffolds effectively. These studies suggest that this binding system has the potential to provide improved tissue-engineered cartilage for clinical applications. PMID- 23630033 TI - Study design and rationale of a dose-ranging trial of LX4211, a dual inhibitor of SGLT1 and SGLT2, in type 2 diabetes inadequately controlled on metformin monotherapy. AB - Sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) are the major cellular transporters responsible for gastrointestinal (GI) glucose absorption and renal glucose reabsorption, respectively. LX4211, a dual inhibitor of SGLT1 and SGLT2, reduces glucose absorption from the GI tract and enhances urinary glucose excretion. Although several SGLT2-selective inhibitors have been tested in large phase 2 studies, dual inhibition of SGLT1 and SGLT2 is novel at this stage of drug development, and it has implications for clinical-trial design. In this article, we describe the design and rationale of a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of LX4211 in subjects with type 2 diabetes mellitus who have inadequate glycemic control on metformin monotherapy. The primary endpoint is the change in glycated hemoglobin A1c from baseline to week 12. Secondary endpoints include the proportion of subjects achieving a glycated hemoglobin A1c value of <7%, change from baseline in fasting plasma glucose and postprandial glucose (as part of an oral glucose tolerance test), body weight, and blood pressure. Safety is evaluated with particular focus on hypoglycemia, GI symptoms, and incidence of genitourinary tract infections. PMID- 23630035 TI - Rebuttal: Response to letter about unusual radial artery calcification. PMID- 23630037 TI - A pyridyl-monoannulated naphthalene diimide motif self-assembles into tuneable nanostructures by means of solvophobic control. AB - The supramolecular self-assembly of the core-substituted naphthalene diimide bearing pyridyl motifs leads to the formation of a variety of nanostructures with pH and solvent control. The detection of HCl can be monitored by UV/Vis and fluorescence spectroscopy, as well as the naked eye, with a change in colour (blue to red, see figure). The cycle is fully reversed by the addition of triethylamine (TEA). PMID- 23630036 TI - Temperature variation makes ectotherms more sensitive to climate change. AB - Ectotherms are considered to be particularly vulnerable to climate warming. Descriptions of habitat temperatures and predicted changes in climate usually consider mean monthly, seasonal or annual conditions. Ectotherms, however, do not simply experience mean conditions, but are exposed to daily fluctuations in habitat temperatures. Here, we highlight how temperature fluctuation can generate 'realized' thermal reaction (fitness) norms that differ from the 'fundamental' norms derived under standard constant temperatures. Using a mosquito as a model organism, we find that temperature fluctuation reduces rate processes such as development under warm conditions, increases processes under cool conditions, and reduces both the optimum and the critical maximum temperature. Generalizing these effects for a range of terrestrial insects reveals that prevailing daily fluctuations in temperature should alter the sensitivity of species to climate warming by reducing 'thermal safety margins'. Such effects of daily temperature dynamics have generally been ignored in the climate change literature. PMID- 23630039 TI - Effect of beta-alanine supplementation on 800-m running performance. AB - Beta-alanine supplementation has been shown to improve exercise performance in short-term, high-intensity efforts. PURPOSE: The aim of this study was to assess if beta-alanine supplementation could improve 800 m track running performance in male recreational club runners (n = 18). METHODS: Participants completed duplicate trials (2 presupplementation, 2 postsupplementation) of an 800 m race, separated by 28 days of either beta-alanine (n = 9; 80 mg.kg-1BM.day-1) or placebo (n = 9) supplementation. RESULTS: Using ANCOVA (presupplementation times as covariate), postsupplementation race times were significantly faster following beta-alanine (p = .02), with post- versus presupplementation race times being faster after beta-alanine (-3.64 +/- 2.70 s, -2.46 +/- 1.80%) but not placebo ( 0.59 +/- 2.54 s, -0.37 +/- 1.62%). These improvements were supported by a moderate effect size (d = 0.70) and a very likely (99%) benefit in the beta alanine group after supplementation. Split times (ANCOVA) at 400 m were significantly faster (p = .02) postsupplementation in the beta-alanine group, compared with placebo. This was supported by large effect sizes (d = 1.05-1.19) and a very likely (99%) benefit at the 400 and 800 m splits when comparing pre- to postsupplementation with beta-alanine. In addition, the first and second halves of the race were faster post- compared with presupplementation following beta-alanine (1st half -1.22 +/- 1.81 s, likely 78% chance of benefit; 2nd half 2.38 +/- 2.31 s, d = 0.83, very likely 98% chance of benefit). No significant differences between groups or pre- and postsupplementation were observed for postrace blood lactate and pH. CONCLUSION: Overall, 28 days of beta-alanine supplementation (80 mg.kg-1BM.day-1) improved 800 m track performance in recreational club runners. PMID- 23630038 TI - Muller cells express the cannabinoid CB2 receptor in the vervet monkey retina. AB - The presence of the cannabinoid receptor type 1 (CB1R) has been largely documented in the rodent and primate retinae in recent years. There is, however, some controversy concerning the presence of the CB2 receptor (CB2R) within the central nervous system. Only recently, CB2R has been found in the rodent retina, but its presence in the primate retina has not yet been demonstrated. The aim of this study was twofold: 1) to characterize the distribution patterns of CB2R in the monkey retina and compare this distribution with that previously reported for CB1R and 2) to resolve the controversy on the presence of CB2R in the neural component of the retina. We therefore thoroughly examined the cellular localization of CB2R in the vervet monkey (Chlorocebus sabeus) retina, using confocal microscopy. Our results demonstrate that CB2R, like CB1R, is present throughout the retinal layers, but with striking dissimilarities. Double labeling of CB2R and glutamine synthetase shows that CB2R is restricted to Muller cell processes, extending from the internal limiting membrane, with very low staining, to the external limiting membrane, with heavy labeling. We conclude that CB2R is indeed present in the retina but exclusively in the retinal glia, whereas CB1R is expressed only in the neuroretina. These results extend our knowledge on the expression and distribution of cannabinoid receptors in the monkey retina, although further experiments are still needed to clarify their role in retinal functions. PMID- 23630040 TI - Identification of the transcription factor HOXB4 as a novel target of miR-23a. AB - The transcription factor HOXB4 not only plays a role during nephrogenesis, but displays also oncogenic characteristics in different malignant neoplasms. An in silico analysis revealed HOXB4 as a new target of microRNA-23a (miR-23a). Nephroblastomas are malignant embryonal renal neoplasms of childhood resembling developing kidney morphologically and genetically. In our study we verified HOXB4 as a target of miR-23a and furthermore examined the expression of HOXB4 and miR 23a in nephroblastomas. We investigated binding of miR-23a to the 3'UTR of HOXB4 by a luciferase assay. Effects on protein levels of HOXB4 were analysed in Western blot experiments. Expression of HOXB4 in nephroblastomas was assessed by quantitative REALtime PCR (qRT PCR) and immunohistochemistry. The luciferase reporter assay showed a statistically significant downregulation of activity by 72,5% demonstrating direct binding of miR-23a to the 3'UTR of HOXB4. In addition, miR-23a reduced the protein expression of HOXB4 statistically significantly by 65.1%. All 21 nephroblastomas investigated had statistically significantly decreased expression levels of miR-23a. A high level of HOXB4 mRNA was found in five out of 33 nephroblastomas including mixed, blastema-type and stroma-type tumors. Protein expression of HOXB4 was stronger in 15 out of 27 nephroblastomas of all subtypes in a semiquantitative comparison to normal kidney parenchyma. Our study demonstrates for the first time the regulation of HOXB4 by miR-23a. In comparison to mature kidney, nephroblastomas had low levels of miR-23a, and in a majority of them a stronger protein expression in comparison to mature kidney was found. PMID- 23630042 TI - Intellectual freedom in academic scientific research under threat. PMID- 23630041 TI - The energy cost of playing active video games in children with obesity and children of a healthy weight. AB - BACKGROUND: Increasing physical activity and reducing sedentary behaviour form a large part of the treatment of paediatric obesity. However, many children today spend prolonged periods of time playing sedentary video games. Active video games (AVGs) represent a novel and child friendly form of physical activity. OBJECTIVES: To measure the energy cost of playing two AVGs in children with obesity and healthy age- and gender-matched children. METHODS: The energy cost of gaming and heart rates achieved during gaming conditions were compared between groups. RESULTS: AVG play can result in light-to-moderate intensity physical activity (2.7-5.4 metabolic equivalents). When corrected for fat-free mass those with obesity expended significantly less energy than healthy weight peers playing Nintendo Wii Fit Free Jogging (P = 0.017). No significant difference was seen between groups in the energy cost of playing Boxing. CONCLUSION: Certain AVGs, particularly those that require lower limb movement, could be used to increase total energy expenditure, replace more sedentary activities, or achieve moderate intensity physical activity among children with obesity. There seems to be some differences in how children with obesity and children of a healthy weight play AVGs. This could result in those with obesity expending less energy than their lean peers during AVG play. PMID- 23630043 TI - Synthesis and characterization of 5-(1,2,4-triazol-3-yl)tetrazoles with various energetic functionalities. AB - In this contribution the synthesis and full structural as well as spectroscopic characterization of three 5-(1,2,4-triazol-3-yl)tetrazoles along with selected energetic moieties like nitro, nitrimino, and azido groups are presented. The main goal is a comparative study on the influence of those variable energetic moieties on structural and energetic properties. A complete characterization including IR and Raman as well as multinuclear NMR spectroscopy of all compounds is presented. Additionally, X-ray crystallographic measurements were performed and reveal insights into structural characteristics as well as inter- and intramolecular interactions. The standard enthalpies of formation were calculated for all compounds at the CBS-4M level of theory and reveal high positive heats of formation for all compounds. The calculated detonation parameters (using the EXPLO5.05 program) are in the range of 8000 m s(-1) (8097 m s(-1) (5), 8020 m s( 1) (6), 7874 m s(-1) (7)). As expected, the measured impact and friction sensitivities as well as decomposition temperatures strongly depend on the energetic moiety at the triazole ring. The C-C connection of a triazole ring with its opportunity to introduce a large variety of energetic moieties and a tetrazole ring, implying a large energy content, leads to the selective synthesis of primary and secondary explosives. PMID- 23630044 TI - Fallback foods, preferred foods, adaptive zones, and primate origins. AB - Appreciation has grown for the impact of tropical forest seasonality and fallback foods on primate diets, behaviors, and morphology. As critically important resources in times of shortage, seasonal fallback foods may have an outsized role in selecting for form and function while the diversity of preferred plant foods has played an equally prominent role in shaping primate evolution. Here, hypotheses of primate origins are examined in the context of food choice models developed by Marshall and Wrangham [2007] and related to the broader concepts of adaptive zones and radiations. The integrated evolution of primate diet and positional behavior is consistent with a growing reliance on angiosperm products- not prey--as preferred and seasonal fallback foods, temporally and phylogenetically coordinated with evolutionary phases of the angiosperm adaptive radiation. Selection for an incisor oriented but non-specialized heterodont dentition, in contrast with most other orders, attests to the universal role of a highly varied vegetation diet as the primates' primary food resource, with diverse physical properties, phenology and high seasonality. A preference by plesiadapiforms for eating small protein- and lipid-rich seeds may have predisposed the primates and advanced angiosperms to diversify their evolving ecological interdependence, which established the primate adaptive zone and became realized more fully with the rise of the modern euprimate and angiosperm phenotypes. The "narrow niche" hypothesis, a recent challenge to the angiosperm co-evolution hypothesis, is evaluated further. Finally, I note support for visual predation as a core adaptive breakthrough for primates or euprimates remains elusive and problematic, especially considering the theoretical framework provided by the Marshall-Wrangham model, updated evidence of primate feeding habits and the counterpoint lessons of the most successful primate predators, the tarsiiforms. PMID- 23630045 TI - Study of subcellular dynamics on cell-substrate interactions by live cell imaging. AB - Cellular adhesiveness to biomaterial is one of the important properties for the success of tissue engineering. The cell-biomaterial interactions involve close cooperation of adhesion proteins, plasma membrane, and cytoskeletons to form focal adhesions during the process of anchoring. Dynamic development of the plasma membrane in the process reflects the cellular biocompatibility and motility. The process of cell attachment beginning from seeding, contact, attachment, and spreading has not been investigated. In this study, we monitored the whole process of cells attaching to the substrate surface by time-lapse confocal microscopy. We observed that the surface configuration of the substratum effects plasma membrane expansion and genomic materials distribution. In contrast to the cells grown on the plate, the cells attached on pillars are with rounded nuclei and with prominent lamellipodia spreading out. Membrane expansion is involved in dynamic development of the plasma membrane and lamellipodia formation for attachment, migration, or proliferation and reflects the cellular physiology status of the cells. This study provides a platform for investigation of cell behavior and dynamic development of subcellular structures regarding cell biomaterial interactions. PMID- 23630046 TI - Influence of Er,Cr:YSGG laser on CaF2 -like products formation because of professional acidulated fluoride or to domestic dentifrice application. AB - This study evaluated the synergy of professional acidulated fluoride gel (APF) or fluoridated dentifrice application combined with Er,Cr:YSGG laser irradiation on the formation of CaF2 -like products (CaF2 ), in vitro. Thus, 272 bovine enamel slabs were randomly distributed among eight groups: G1: untreated enamel; G2: treated with fluoridated dentifrice (NaF, 1,100 MUgF/g); G3: treated with acidulated phosphate fluoride gel (APF, 1.23% F(-) ); G4: irradiated with Er,Cr:YSGG laser at 8.5 J/cm(2) ; G5 and G6: combination of pre-irradiation with Er,Cr:YSGG followed by dentifrice or APF application, respectively; G7: combination of dentifrice application followed by Er,Cr:YSGG irradiation; G8: combination of APF application followed by Er,Cr:YSGG irradiation. After treatments, samples were evaluated by scanning electron microscopy, and the content of CaF2 was determined by an ion specific electrode. Both APF and dentifrice application promoted the formation of CaF2 on enamel, whereas Er,Cr:YSGG irradiation promoted an increase of roughness of the enamel, increasing the surface area. Laser irradiation before fluoridated products increased the content of CaF2 formed when compared to groups that APF or dentifrice were applied isolated. However, the content of CaF2 formed when irradiation was performed after APF or dentifrice was not statically significant when compared to the control groups. In conclusion, Er,Cr:YSGG laser increases the formation of CaF2 on enamel when the irradiation is performed before the application of APF or dentifrice. The association of laser with APF is most promissory for caries prevention because of the higher concentration of CaF2 formation and also the chemical changes promoted by laser irradiation demonstrated in literature. PMID- 23630047 TI - Angiographic characteristics of femoropopliteal in-stent restenosis: association with long-term outcomes after endovascular intervention. AB - OBJECTIVES: The purpose of this study was to identify the relationship between angiographic patterns of restenosis and outcomes after endovascular treatment of femoro-popliteal in-stent restenosis (FP-ISR). BACKGROUND: ISR is a frequent clinical problem after femoro-popliteal stenting. METHODS: This was a single center study of all endovascular interventions for FP-ISR from 2006 to 2012. Class I ISR was defined as focal lesions <=50 mm; Class II ISR as lesions > 50 mm; and Class III ISR as stent chronic total occlusion. Recurrent ISR was defined as peak systolic velocity ratio > 2.4 by duplex ultrasound. RESULTS: Among 75 cases of FP-ISR, 28 (37%) were Class I, 22 (29%) were Class II, and 25 (33%) were Class III. The mean lesion length was 26 mm for Class I, 135 mm for Class II, and 178 mm for Class III ISR. Patients with Class III ISR more frequently had ISR extending into both the superficial femoral and popliteal artery (48% vs. 18%, P = 0.005). Balloon angioplasty was used most frequently to treat Class I ISR, while adjunctive atherectomy and/or stenting was used for almost all cases of Class III ISR. During 2-year follow-up, rates of repeat restenosis were 39% for Class I, 67% for Class II, and 72% for Class III ISR (P = 0.04). Rates of stent occlusion were 8% for Class I, 11% for Class II, and 52% for Class III ISR (P = 0.009). Class III ISR was associated with significantly increased risk of recurrent ISR (HR 2.4, 95% CI 1.1-5.6) and recurrent occlusion (HR 5.8, 95% CI 1.8-19.0) compared to other types of ISR. CONCLUSION: Angiographic patterns of FP ISR are important determinants of subsequent outcomes. Repeat restenosis and occlusion remain common despite currently available technologies. PMID- 23630048 TI - Ultrashort echo time bi-component analysis of cortical bone--a field dependence study. AB - PURPOSE: The purpose of this study is to investigate the effect of differing field strength on the T2* of cortical bone at 1.5 T and 3 T. METHODS: Ultrashort echo time pulse sequences were used to study six bovine and nine human bone samples at 1.5 T and 3 T using single- and bi-component T2* analysis. RESULTS: On average, the bound water T2* of bovine bone decreased by 16% (from 0.32 ms at 1.5 T to 0.27 ms at 3 T, P < 0.01) and the bound water T2* of human bone decreased by 21% (from 0.42 ms at 1.5 T to 0.33 ms at 3 T, P < 0.01) at the higher field strength. The free water T2* of bovine bone decreased by 50% (from 4.23 ms at 1.5 T to 2.12 ms at 3 T, P < 0.001) and the free water T2* of human bone decreased by 68% (from 7.65 ms at 1.5 T to 2.46 ms at 3 T, P < 0.001) at the higher field strength. Bound and free water fractions showed only minor change with field strength in bovine (< 2%, P > 0.05) and human bone (< 4%, P > 0.05). CONCLUSION: Ultrashort echo time bi-component analysis provides consistent bound and free water fractions at 1.5 T and 3 T, thereby allowing field-independent comparisons. PMID- 23630050 TI - Systematic review of upper-limb function measurement methods in botulinum toxin intervention for focal spasticity. AB - BACKGROUND AND PURPOSE: This paper aimed to select studies evaluating botulinum toxin (BoNT) intervention applied for upper-limb spasticity and from these identify outcome measures that are a) applicable in the hemiparetic upper limb and b) include evaluation of functional outcome in the context of everyday real life activities. METHODS: A systematic search was used to identify peer-reviewed papers evaluating BoNT intervention for focal spasticity management in the upper limb. From these papers, outcome evaluation methods were identified, which attempted to capture 'active function' improvement (functional use of the hand and/or arm) or passive function improvement (care for the affected limb, for example to maintain hygiene and dress or support the arm). RESULTS: The search yielded 411 studies. Seventy papers were identified following a final review of the abstracts as potentially including evaluation of functional outcome (active and/or passive function). Following the review of the papers, a total of 22 studies contained specific methods for evaluating functional outcome in the upper limb. DISCUSSION: Three different patient-focused methods to evaluate functional outcome following focal spasticity intervention using BoNT have been identified: 1) use of patient report of upper-limb items (including the Leeds Adult Spasticity Impact Scale and the Disability Assessment Scale), 2) use of a composite measure of function incorporating functional items and 3) Goal Attainment Scaling. None of these methods fully address evaluation of functional outcome in this context but may go some way to recording these improvements. An alternative or complementary measure, recently published, is the Arm Activity Measure for evaluation of active and passive function in this context. The Arm Activity Measure addresses active and passive function changes from the perspective of patients and carers and has been developed for application in this context. PMID- 23630051 TI - Window blind cords and accidental strangulation. PMID- 23630052 TI - The effect of beta-alanine supplementation on isokinetic force and cycling performance in highly trained cyclists. AB - Beta-alanine may benefit short-duration, high-intensity exercise performance. The aim of this randomized double-blind placebo-controlled study was to examine the effects of beta-alanine supplementation on aspects of muscular performance in highly trained cyclists. Sixteen highly trained cyclists (mean +/- SD; age = 24 +/- 7 yr; mass = 70 +/- 7 kg; VO2max = 67 +/- 4 ml . kg(-1) . min(-1)) supplemented with either beta-alanine (n = 8, 65 mg . kg - 1BM) or a placebo (n = 8; dextrose monohydrate) over 4 weeks. Pre- and postsupplementation cyclists performed a 4-minute maximal cycling test to measure average power and 30 reciprocal maximal isokinetic knee contractions at a fixed angular velocity of 180 degrees . sec(-1) to measure average power/repetition, total work done (TWD), and fatigue index (%). Blood pH, lactate (La-) and bicarbonate (HCO3-) concentrations were measured pre- and postisokinetic testing at baseline and following the supplementation period. Beta-alanine supplementation was 44% likely to increase average power output during the 4-minute cycling time trial when compared with the placebo, although this was not statistically significant (p = .25). Isokinetic average power/repetition was significantly increased post beta alanine supplementation compared with placebo (beta-alanine: 6.8 +/- 9.9 W, placebo: -4.3 +/- 9.5 W, p = .04, 85% likely benefit), while fatigue index was significantly reduced (p = .03, 95% likely benefit). TWD was 89% likely to be improved following beta-alanine supplementation; however, this was not statistically significant (p = .09). There were no significant differences in blood pH, lactate, and HCO3- between groups (p > .05). Four weeks of beta-alanine supplementation resulted in worthwhile changes in time-trial performance and short-duration muscular force production in highly trained cyclists. PMID- 23630049 TI - Stimulation of the midbrain periaqueductal gray modulates preinspiratory neurons in the ventrolateral medulla in the rat in vivo. AB - The midbrain periaqueductal gray (PAG) is involved in many basic survival behaviors that affect respiration. We hypothesized that the PAG promotes these behaviors by changing the firing of preinspiratory (pre-I) neurons in the pre Botzinger complex, a cell group thought to be important in generating respiratory rhythm. We tested this hypothesis by recording single unit activity of pre Botzinger pre-I neurons during stimulation in different parts of the PAG. Stimulation in the dorsal PAG increased the firing of pre-I neurons, resulting in tachypnea. Stimulation in the medial part of the lateral PAG converted the pre-I neurons into inspiratory phase-spanning cells, resulting in inspiratory apneusis. Stimulation in the lateral part of the lateral PAG generated an early onset of the pre-I neuronal discharge, which continued throughout the inspiratory phase, while at the same time attenuating diaphragm contraction. Stimulation in the ventral part of the lateral PAG induced tachypnea but inhibited pre-I cell firing, whereas stimulation in the ventrolateral PAG inhibited not only pre-I cells but also the diaphragm, leading to apnea. These findings show that PAG stimulation changes the activity of the pre-Botzinger pre-I neurons. These changes are in line with the different behaviors generated by the PAG, such as the dorsal PAG generating avoidance behavior, the lateral PAG generating fight and flight, and the ventrolateral PAG generating freezing and immobility. PMID- 23630053 TI - The toxicity of graphene oxides: dependence on the oxidative methods used. AB - Graphene, a class of two-dimensional carbon nanomaterial, has attracted extensive interest in recent years, with a significant amount of research focusing on graphene oxides (GOs). They have been primed as potential candidates for biomedical applications such as cell labeling and drug delivery, thus the toxicity and behavior of graphene oxides in biological systems are fundamental issues that need urgent attention. The production of GO is generally achieved through a top-down route, which includes the usage of concentrated H2SO4 along with: 1) concentrated nitric acid and KClO3 oxidant (Hoffmann); 2) fuming nitric acid and KClO3 oxidant (Staudenmaier); 3) concentrated phosphoric acid with KMnO4 (Tour); or 4) sodium nitrate for in-situ production of nitric acid in the presence of KMnO4 (Hummers). It has been widely assumed that the properties of these four GOs produced by using the above different methods are roughly similar, so the methods have been used interchangeably. However, several studies have reported that the toxicity of graphene-related nanomaterials in biological systems may be influenced by their physiochemical properties, such as surface functional groups and structural defects. In addition, considering how GOs are increasingly used in the field of biomedicine, we are interested to see how the oxygen content/functional groups of GOs can impact their toxicological profiles. Since in-vitro testing is a common first step in assessing the health risks related with engineered nanomaterials, the cytotoxicity of the GOs prepared by the four different oxidative treatments was investigated by measuring the mitochondrial activity in adherent lung epithelial cells (A549) by using commercially available viability assays. The dose-response data was generated by using two assays, the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and the water-soluble tetrazolium salt (WST-8). From the viability data, it is evident that there is a strong dose-dependent cytotoxic response resulting from the four GO nanomaterials tested after a 24 h exposure, and it is suggested that there is a correlation between the amounts of oxygen content/functional groups of GOs with their toxicological behavior towards the A549 cells. PMID- 23630054 TI - Impact of a palliative care initiative on end-of-life care in the general wards: a before-and-after study. AB - BACKGROUND: Data on deaths in the general wards of our hospital in 2007 revealed infrequent discussions on end-of-life care and excessive burdensome interventions. AIM: A physician order form to withhold inappropriate life sustaining interventions was initiated in 2009. The use of the form was facilitated by staff educational sessions and a palliative care consult service. This study aims to evaluate the impact of these interventions in 2010. DESIGN: Retrospective medical chart review with comparisons was made for the following: baseline patient characteristics, orders concerning life-sustaining therapies, treatment provided in last 24 h of life, and discussion of specific life sustaining therapies with patients and families. SETTINGS/PARTICIPANTS: This study included all adult patients who died in our hospital's general wards in 2007 (N = 683) versus 2010 (N = 714). RESULTS: There was an increase in orders to withhold life-sustaining therapies, such as cardiopulmonary resuscitation (66.2% 80.0%). There was a decrease in burdensome interventions such as antibiotics (44.9%-24.9%) and a small increase in palliative treatments such as analgesia (29.1%-36.7%). There were more discussions on the role of cardiopulmonary resuscitation with conversant patients (4.6%-10.2%) and families (56.5%-79.8%) (p value all < 0.05). On multivariate analysis, the physician order form independently predicted orders to withhold cardiopulmonary resuscitation. CONCLUSIONS: A multifaceted intervention of a physician order form, educational sessions, and palliative care consult service led to an improvement in documentation of end-of-life discussions and was associated with an increase in such discussions and less burdensome treatments. There were small improvements in the proportion of palliative treatments administered. PMID- 23630055 TI - A question prompt list for patients with advanced cancer in the final year of life: development and cross-cultural evaluation. AB - BACKGROUND: Clinicians and patients find prognosis and end-of-life care discussions challenging. Misunderstanding one's prognosis can contribute to poor decision-making and end-of-life quality of life. A question prompt list (booklet of questions patients can ask clinicians) targeting these issues may help overcome communication barriers. None exists for end-of-life discussions outside the palliative care setting. AIM: To develop/pilot a question prompt list facilitating discussion/planning of end-of-life care for oncology patients with advanced cancer from Australia and the United States and to explore acceptability, perceived benefits/challenges of using the question prompt list, suggestions for improvements and the necessity of country-specific adaptations. DESIGN: An expert panel developed a question prompt list targeting prognosis and end-of-life issues. Australian/US semi-structured interviews and one focus group elicited feedback about the question prompt list. Transcribed data were analysed using qualitative methods. SETTING/PARTICIPANTS: Thirty-four patients with advanced cancer (15 Australian/19 US) and 13 health professionals treating such patients (7 Australian/6 US) from two Australian and one US cancer centre participated. RESULTS: Most endorsed the entire question prompt list, though a minority queried the utility/appropriateness of some questions. Analysis identified four global themes: (1) reinforcement of known benefits of question prompt lists, (2) appraisal of content and suggestions for further developments, (3) perceived benefits and challenges in using the question prompt list and (4) contrasts in Australian/US feedback. These contrasts necessitated distinct Australian/US final versions of the question prompt list. CONCLUSIONS: Participants endorsed the question prompt list as acceptable and useful. Feedback resulted in two distinct versions of the question prompt list, accommodating differences between Australian and US approaches to end-of-life discussions, highlighting the appropriateness of tailoring communication aides to individual populations. PMID- 23630057 TI - Colorless to purple-red switching electrochromic anthraquinone imides with broad visible/near-IR absorptions in the radical anion state: simulation-aided molecular design. AB - The large redshift of near-infrared (NIR) absorptions of nitro-substituted anthraquinone imide (Nitro-AQI) radical anions, relative to other AQI derivatives, is rationalized based on quantum chemical calculations. Calculations reveal that the delocalization effects of electronegative substitution in the radical anion states is dramatically enhanced, thus leading to a significant decrease in the HOMO-LUMO band gap in the radical anion states. Based on this understanding, an AQI derivative with an even stronger electron-withdrawing dicyanovinyl (di-CN) substituent was designed and prepared. The resulting molecule, di-CN-AQI, displays no absorption in the Vis/NIR region in the neutral state, but absorbs intensively in the range of lambda=700-1000 (lambdamax ~860 nm) and lambda=1100-1800 nm (lambdamax ~1400 nm) upon one-electron reduction; this is accompanied by a transition from a highly transmissive colorless solution to one that is purple-red. The relationship between calculated radical anionic HOMO-LUMO gaps and the electron-withdrawing capacity of the substituents is also determined by employing Hammett parameter, which could serve as a theoretical tool for further molecular design. PMID- 23630058 TI - Integration of microfluidic chip with biomimetic hydrogel for 3D controlling and monitoring of cell alignment and migration. AB - A biomimetic hydrogel was integrated into microfluidic chips to monitor glioma cell alignment and migration. The extracellular matrix-based biomimetic hydrogel was remodeled by matrix metalloprotease (MMP) secreted by glioma cells and the hydrogel could thus be used to assess cellular behavior. Both static and dynamic cell growth conditions (flow rate of 0.1 mL/h) were used. Cell culture medium with and without vascular endothelial growth factor (VEGF), insensitive VEGF and tissue inhibitor of metalloproteinases (TIMP) were employed to monitor cell behavior. A concentration gradient formed in the hydrogel resulted in differences in cell behavior. Glioma cell viability in the microchannel was 75-85%. Cells in the VEGF-loaded microchannels spread extensively, degrading the MMP-sensitive hydrogel, and achieved cell sizes almost fivefold larger than seen in the control medium. Our integrated system can be used as a model for the study of cellular behavior in a controlled microenvironment generated by fluidic conditions in a biomimetic matrix. PMID- 23630056 TI - Three-dimensional nuclear telomere architecture changes during endometrial carcinoma development. AB - Endometrioid or type-I endometrial carcinoma (EC) develops from hyperproliferative glandular pathologies. Inactivation of the tumor suppressor gene PTEN is frequently associated with type-I EC. Using a previously characterized Pten heterozygous (Pten+/-) mouse model, this study investigates the three-dimensional (3D) telomere profiles during progression from hyperplastic lesions to EC to test the hypothesis that altered 3D telomere profiles can be detected prior to Pten loss in early hyperproliferative lesions. We used immunohistochemistry and 3D-telomere fluorescent in-situ hybridization to investigate Pten expression, telomere length and signal distribution, average number and spatial distribution of telomeres and formation of telomere aggregates in uterine glandular epithelial cells from wildtype and Pten+/- mice. Pten showed nuclear and cytoplasmic localization in WT, predominantly cytoplasmic staining in simple hyperplasia (SH) and was markedly reduced in atypical hyperplasia (AH). Telomere length in glandular epithelial cells does not shorten with age. The average number of telomeres per nucleus was not different in WT and Pten+/- mice indicating the lack of substantial numeric chromosome aberrations during EC development. We observed telomere aggregates in lesions of AH and EC. SH lesions in Pten+/- mice differed from normal glandular epithelium by an increased relative number of shorter telomeres and by a telomere signal distribution indicative of a heterogeneous cell population. Our study revealed that alterations in the nuclear 3D telomere architecture are present in early proliferative lesions of mouse uterine tissues indicative of EC development. The changes in telomere length distribution and nuclear signal distribution precede the loss of Pten. PMID- 23630059 TI - Crystallographic texture and elemental composition mapped in bovine root dentin at the 200 nm level. AB - The relationship between the mineralization of peritubular dentin (PTD) and intertubular dentin (ITD) is not well understood. Tubules are quite small, diameter ~2 um, and this makes the near-tubule region of dentin difficult to study. Here, advanced characterization techniques are applied in a novel way to examine what organic or nanostructural signatures may indicate the end of ITD or the beginning of PTD mineralization. X-ray fluorescence intensity (Ca, P, and Zn) and X-ray diffraction patterns from carbonated apatite (cAp) were mapped around dentintubules at resolutions ten times smaller than the feature size (200 nm pixels), representing a 36% increase in resolution over earlier work. In the near tubule volumes of near-pulp, root dentin, Zn intensity was higher than in ITD remote from the tubules. This increase in Zn(2+), as determined by X-ray absorption near edge structure analysis, may indicate the presence of metalloenzymes or transcription factors important to ITD or PTD mineralization. The profiles of the cAp 00.2 X-ray diffraction rings were fitted with a pseudo Voigt function, and the spatial and azimuthal distribution of these rings' integrated intensities indicated that the cAp platelets were arranged with their c-axes aligned tangential to the edge of the tubule lumen. This texture was continuous throughout the dentin indicating a lack of structural difference between in the Zn rich near-tubular region and the remote ITD. PMID- 23630061 TI - Visible-light-responsive beta-rhombohedral boron photocatalysts. PMID- 23630060 TI - Does consumption of high-fructose corn syrup beverages cause obesity in children? AB - The consumption of high-fructose corn syrup (HFCS) beverages has increased since the 1970s. At the same time, childhood obesity is on the rise, causing children to be at risk of heart disease, diabetes and other diseases. Healthcare providers have attributed childhood obesity to the consumption of HFCS in the form of beverages. This article will look at the available research and determine if there is scientific evidence underlying the idea that sweetened soft drinks, especially those containing HFCS, could cause or contribute to childhood obesity. A thorough literature search was performed using the ISI Web of Sciences, PubMed and Scopus databases within the years 2006-2012. The search generated 19 results. The articles were screened, and six were deemed eligible: four systematic reviews and two meta-analyses. Two systematic reviews found that there is no relationship between consumption of HFCS beverages and obesity in children. The other two systematic reviews found possible links between HFCS and childhood obesity. The meta-analysis articles found that consumption of HFCS beverages can contribute to childhood obesity, and limitation of sweetened beverages may help decrease obesity in children. Available research studies demonstrate inconclusive scientific evidence definitively linking HFCS to obesity in children. PMID- 23630062 TI - Carotid artery stenting: patient, lesion, and procedural characteristics that increase procedural complications. AB - From the earliest experiences with carotid artery stenting (CAS) presumptive high risk features have included thrombus-containing lesions, heavily calcified lesions, very tortuous vessels, and near occlusions. In addition patients have been routinely excluded from CAS trials if they have contra-indications to dual antiplatelet therapy (aspirin and thienopyridines), a history of bleeding complications and severe peripheral arterial disease (PAD) making femoral artery vascular access difficult. Variables that increase the risk of CAS complications can be attributed to patient characteristics, anatomic or lesion features, and procedural factors. Clinical features such as older age (>=80 years), decreased cerebral reserve (dementia, multiple prior strokes, or intracranial microangiopathy) and angiographic characteristics such as excessive tortuosity (more than two 90 degrees bends within 5 cm of the target lesion) and heavy calcification (concentric calcification >= 3 mm in width) have been associated with increased CAS complications. Other high risk CAS features include those that prolong catheter or guide wire manipulation in the aortic arch, make crossing a carotid stenosis more difficult, decrease the likelihood of successful deployment or retrieval of an embolic protection device (EPD), or make stent delivery or placement more difficult. Procedure volume for the operator and the catheterization laboratory team are critical elements in reducing the risk of the procedure. In this article, we help CAS operators better understand procedure risk to allow more intelligent case selection, further improving the outcomes of this emerging procedure. PMID- 23630063 TI - Complete NMR assignment of retinal and its related compounds. AB - Complete and unambiguous (1)H and (13)C NMR chemical shift assignments for all trans-retinal, 13-cis-retinal, 11-cis-retinal and 9-cis-retinal (1-4) have been established by means of two-dimensional COSY, HSQC, HMBC and NOESY spectroscopic experiments. PMID- 23630064 TI - Designs for randomized phase II clinical trials with two treatment arms. AB - The most common primary statistical end point of a phase II clinical trial is the categorization of a patient as either a 'responder' or 'nonresponder'. The primary objective of typical randomized phase II anticancer clinical trials is to evaluate experimental treatments that potentially will increase response rate over a historical baseline and select one to consider for further study. We propose single-stage and two-stage designs for randomized phase II clinical trials, precisely defining various type I error rates and powers to achieve this objective. We develop a program to compute these error rates and powers exactly, and we provide many design examples to satisfy pre-fixed requirements on error rates and powers. Finally, we apply our method to a randomized phase II trial in patients with relapsed non-Hodgkin's disease. PMID- 23630067 TI - Thermodynamics of electrochemical lithium storage. AB - The thermodynamics of electrochemical lithium storage are examined by taking into account that it is the point defects that enable storage. While the Li defects are mobile, most of the other point defects have to be considered as frozen owing to the performance temperature being low compared to the melting point of the electrode materials. The defect chemistry needs to be considered to fully understand equilibrium charge/discharge curves. On this basis, single phase and multiphase storage mechanisms can be discussed in terms of theoretical storage capacity and theoretical voltage. Of paramount interest in the field of Li batteries are metastable materials, in particular nanocrystalline and amorphous materials. The thermodynamics of storage and voltage, also at interfaces, thus deserve a special treatment. The relationship between reversible cell voltage and lithium content is derived for the novel job-sharing mechanism. With respect to the classic storage modes, thermodynamic differences for cathodes and anodes are elaborated with a special attention being paid to the search for new materials. As this contribution concentrates on the equilibrium state, current-related phenomena (irreversible thermodynamics) are only briefly touched upon. PMID- 23630068 TI - Morphological variations of Mn-doped ZnO dilute magnetic semiconductors thin films grown by succesive ionic layer by adsorption reaction method. AB - Transparent conducting Mn-doped ZnO thin films have been prepared by successive ionic layer by adsorption reaction (SILAR) method. The deposition conditions have been optimized based on their structure and on the formation of smoothness, adherence, and stoichiometry. The results of the studies by X-ray diffraction, scanning electron microscope (SEM), reveal the varieties of structural and morphological modifications feasible with SILAR method. The X-ray diffraction patterns confirm that the ZnO:Mn has wurtzite structure. The interesting morphological variations with dopant concentration are observed and discussed. The films' quality is comparable with those grown with physical methods and is suitable for spintronic applications. PMID- 23630069 TI - Na11B21O36X2 (X = Cl, Br): halogen sodium borates with a new graphene-like borate double layer. AB - Borate not graphene: The [B6O12]infinity(6-) single borate layer is a graphene like layer (see figure). The weak Na(+)-Br(Cl)(-) ionic connection between the layers leads to the layer cleavage, and difficulty of the block crystal growth. PMID- 23630070 TI - RNA sequencing identifies fusion of the EWSR1 and YY1 genes in mesothelioma with t(14;22)(q32;q12). AB - Mesothelioma is a rare but very aggressive tumor derived from mesothelial cells. A number of often complex but nonrandom cytogenetic abnormalities have been found in these tumors, resulting in loss of chromosome bands 14q32 and 22q12 in more than 35% of the cases. In this study, we used RNA sequencing to search for fusion transcripts in a mesothelioma carrying a t(14;22)(q32;q12) as the sole chromosomal aberration and found an EWSR1-YY1 and its reciprocal YY1-EWSR1 fusion transcript. Screening 15 additional cases of mesothelioma from which we had RNA but no cytogenetic information, we identified one more tumor carrying an EWSR1 YY1 fusion gene but not the reciprocal YY1-EWSR1 transcript. RT-polymerase chain reaction and sequencing showed that in both cases exon 8 of EWSR1 (nucleotide 1,139, accession number NM_013986 version 3, former exon 7 in sequence with accession number X66899) was fused to exon 2 of YY1 (nucleotide 1,160, accession number NM_003403 version 3). The EWSR1 breakpoint in exon 8 in the EWSR1-YY1 chimeric transcript is similar to what is found in other fusions involving EWSR1 such as EWSR1-FLI1, EWSR1-DDIT3, and EWSR1-ATF1. The EWSR1-YY1-encoded protein is an abnormal transcription factor with the transactivation domain of EWSR1 and the DNA-binding domain of YY1. This is the first study to detect a specific fusion gene in mesothelioma (the reason how frequent the EWSR1-YY1 fusion is remains uncertain) and also the first time that direct involvement of YY1 in oncogenesis has been demonstrated. PMID- 23630071 TI - Rat-derived processed nerve allografts support more axon regeneration in rat than human-derived processed nerve xenografts. AB - Processed nerve allografts are increasingly used as "off the shelf" nerve replacements for surgically bridging nerve gaps. Benchmarking the regenerative capacity of a commercially available human-derived nerve or xenograft in a rat nerve injury model would provide a convenient platform for future studies seeking to modify the processed nerve graft. Human and rat processed nerve grafts were used to bridge a 14 mm defect in a Sprague-Dawley rat sciatic nerve. Reversed autografts served as a positive control group. Twelve weeks following surgery, the distal nerve stumps were retrograde labeled and harvested for histology and histomorphometry. The cross-sectional areas of the human- and rat-derived processed nerve grafts were similar. Neuron counts and myelinated axon counts following use of the human-derived processed xenografts were decreased compared with those obtained from both the rat-derived processed nerve allografts and the autografts; the rat-derived processed nerve allografts were statistically equivalent to autografts. Measures of nerve fiber diameter and myelination revealed inferior axon regeneration maturity in both processed nerve grafts compared with autografts. Processed xenografts showed significantly reduced regeneration compared with autografts or processed allografts indicating that cross-species immunological reactions are important considerations in this rat model. PMID- 23630072 TI - Morphology of fungal stains on paper characterized with multi-scale and multi sensory surface metrology. AB - Pigmentation of paper induced by fungi is one of the most complex phenomenons because it involves living organisms growing on a heterogeneous paper substrate. A novel approach to the study of interfaces of fungi and paper in black stains produced by pigmented Dematiaceous fungi with meristematic growth was undertaken applying surface metrology techniques: confocal laser scanning microscope (CLSM) white-light, confocal chromatic aberration profilometer (LCA) and scanning electron microscope in variable pressure (SEM-VP); fungal morphology was examined with transmitted light microscopy (TLM). The role of paper topography and surface morphology in fungi-induced biodeterioration was investigated elucidating some of the dynamic interactions of fungi with paper, spatial distribution of biological deposits, inclusions in paper matrix, and patterns of fungal growth on paper thus contributing to a better understanding of biodeterioration of paper-based cultural heritage. So far, to the authors' knowledge, there are no published reports on the investigation of interfaces of bio-stains and paper utilizing surface metrology techniques. PMID- 23630073 TI - Emerging roles of the corepressors NCoR1 and SMRT in homeostasis. AB - Epigenetic regulation of gene expression is strongly influenced by the accessibility of nucleosomal DNA or the state of chromatin compaction. In this context, coregulators, including both coactivators and corepressors, are pivotal intermediates that bridge chromatin-modifying enzymes and transcription factors. NCoR1 (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) are among the best-characterized corepressors from a molecular point of view. These coregulators have conserved orthologs in lower organisms, which underscores their functional importance. Here we summarize the results from recent in vivo studies that reveal the wide-ranging roles of NCoR1 and SMRT in developmental as well as homeostatic processes, including metabolism, inflammation, and circadian rhythms. We also discuss the potential implications of NCoR1 and SMRT regulation of pathways ranging from genomic stability and carcinogenesis to metabolic diseases such as type 2 diabetes. PMID- 23630075 TI - Conservation and de novo acquisition of dosage compensation on newly evolved sex chromosomes in Drosophila. AB - Dosage compensation has arisen in response to the evolution of distinct male (XY) and female (XX) karyotypes. In Drosophila melanogaster, the MSL complex increases male X transcription approximately twofold. X-specific targeting is thought to occur through sequence-dependent binding to chromatin entry sites (CESs), followed by spreading in cis to active genes. We tested this model by asking how newly evolving sex chromosome arms in Drosophila miranda acquired dosage compensation. We found evidence for the creation of new CESs, with the analogous sequence and spacing as in D. melanogaster, providing strong support for the spreading model in the establishment of dosage compensation. PMID- 23630076 TI - Survival factor NFIL3 restricts FOXO-induced gene expression in cancer. AB - Depending on the circumstance, FOXO (Forkhead O) (FOXO1, FOXO3, and FOXO4) transcription factors activate the expression of markedly different sets of genes to produce different phenotypic effects. For example, distinct FOXO-regulated transcriptional programs stimulate cell death or enhance organism life span. To gain insight into how FOXOs select specific genes for regulation, we performed a screen for genes that modify FOXO activation of TRAIL, a death receptor ligand capable of inducing extrinsic apoptosis. We discovered that the bZIP transcriptional repressor NFIL3 (nuclear factor interleukin 3-regulated) hindered FOXO transcription factor access to chromatin at the TRAIL promoter by binding to nearby DNA and recruiting histone deacetylase-2 (HDAC2) to reduce histone acetylation. In the same manner, NFIL3 repressed expression of certain FOXO targets--e.g., FAS, GADD45alpha (growth arrest and DNA damage-inducible, alpha), and GADD45beta--but not others. NFIL3, which we found to be overexpressed in different cancers, supported tumor cell survival largely through repression of TRAIL and antagonized hydrogen peroxide-induced cell death. Moreover, its expression in cancer was associated with lower patient survival. Therefore, NFIL3 alters cancer cell behavior and FOXO function by acting on chromatin to restrict the menu of FOXO target genes. Targeting of NFIL3 could be of therapeutic benefit for cancer patients. PMID- 23630074 TI - What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. AB - Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similar metabolite (R)-2 hydroxyglutarate [(R)-2HG]. Here we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies. PMID- 23630077 TI - Structure-function studies of STAR family Quaking proteins bound to their in vivo RNA target sites. AB - Mammalian Quaking (QKI) and its Caenorhabditis elegans homolog, GLD-1 (defective in germ line development), are evolutionarily conserved RNA-binding proteins, which post-transcriptionally regulate target genes essential for developmental processes and myelination. We present X-ray structures of the STAR (signal transduction and activation of RNA) domain, composed of Qua1, K homology (KH), and Qua2 motifs of QKI and GLD-1 bound to high-affinity in vivo RNA targets containing YUAAY RNA recognition elements (RREs). The KH and Qua2 motifs of the STAR domain synergize to specifically interact with bases and sugar-phosphate backbones of the bound RRE. Qua1-mediated homodimerization generates a scaffold that enables concurrent recognition of two RREs, thereby plausibly targeting tandem RREs present in many QKI-targeted transcripts. Structure-guided mutations reduced QKI RNA-binding affinity in vitro and in vivo, and expression of QKI mutants in human embryonic kidney cells (HEK293) significantly decreased the abundance of QKI target mRNAs. Overall, our studies define principles underlying RNA target selection by STAR homodimers and provide insights into the post transcriptional regulatory function of mammalian QKI proteins. PMID- 23630079 TI - Resistant starch from high amylose maize (HAM-RS2) and dietary butyrate reduce abdominal fat by a different apparent mechanism. AB - OBJECTIVE: Obesity is a health concern. Resistant starch (RS) type 2 from high amylose maize (HAM-RS2) and dietary sodium butyrate (SB) reduce abdominal fat in rodents. RS treatment is associated with increased gut hormones peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), but it is not known if SB increases these hormones. DESIGN AND METHODS: This was investigated in a 2 * 2 rat study with HAM RS2 (0 or 28% weight) and dietary sodium butyrate (0 and 3.2%) resulting in isocaloric treatments: energy control (EC), sodium butyrate (SB), HAM-RS2 (RS), and the combination (SBRS). RESULTS: RS and SB reduced abdominal fat and the combination reduced abdominal fat compared to SB and RS. RS was associated with increased fermentation in the cecum. Serum PYY and GLP-1 total were increased with RS treatment. RS treatment was associated with increased cecal butyrate produced from fermentation of RS, but there was no cecal increase for dietary SB. CONCLUSIONS: SB after its absorption into the blood appears to not affect production of PYY and GLP-1, while butyrate from fermentation in the cecum promotes increased PYY and GLP-1. Future studies with lower doses of RS and SB are warranted and the combination may be beneficial for human health. PMID- 23630078 TI - Let-7 represses Nr6a1 and a mid-gestation developmental program in adult fibroblasts. AB - MicroRNAs (miRNAs) are critical to proliferation, differentiation, and development. Here, we characterize gene expression in murine Dicer-null adult mesenchymal stem cell lines, a fibroblast cell type. Loss of Dicer leads to derepression of let-7 targets at levels that exceed 10-fold to 100-fold with increases in transcription. Direct and indirect targets of this miRNA belong to a mid-gestation embryonic program that encompasses known oncofetal genes as well as oncogenes not previously associated with an embryonic state. Surprisingly, this mid-gestation program represents a distinct period that occurs between the pluripotent state of the inner cell mass at embryonic day 3.5 (E3.5) and the induction of let-7 upon differentiation at E10.5. Within this mid-gestation program, we characterize the let-7 target Nr6a1, an embryonic transcriptional repressor that regulates gene expression in adult fibroblasts following miRNA loss. In total, let-7 is required for the continual suppression of embryonic gene expression in adult cells, a mechanism that may underlie its tumor-suppressive function. PMID- 23630080 TI - Macroscale plasmonic substrates for highly sensitive surface-enhanced Raman scattering. PMID- 23630081 TI - Multivariate meta-analysis of mixed outcomes: a Bayesian approach. AB - Multivariate random effects meta-analysis (MRMA) is an appropriate way for synthesizing data from studies reporting multiple correlated outcomes. In a Bayesian framework, it has great potential for integrating evidence from a variety of sources. In this paper, we propose a Bayesian model for MRMA of mixed outcomes, which extends previously developed bivariate models to the trivariate case and also allows for combination of multiple outcomes that are both continuous and binary. We have constructed informative prior distributions for the correlations by using external evidence. Prior distributions for the within study correlations were constructed by employing external individual patent data and using a double bootstrap method to obtain the correlations between mixed outcomes. The between-study model of MRMA was parameterized in the form of a product of a series of univariate conditional normal distributions. This allowed us to place explicit prior distributions on the between-study correlations, which were constructed using external summary data. Traditionally, independent 'vague' prior distributions are placed on all parameters of the model. In contrast to this approach, we constructed prior distributions for the between-study model parameters in a way that takes into account the inter-relationship between them. This is a flexible method that can be extended to incorporate mixed outcomes other than continuous and binary and beyond the trivariate case. We have applied this model to a motivating example in rheumatoid arthritis with the aim of incorporating all available evidence in the synthesis and potentially reducing uncertainty around the estimate of interest. PMID- 23630082 TI - Is there a specific role for sucrose in sports and exercise performance? AB - The consumption of carbohydrate before, during, and after exercise is a central feature of the athlete's diet, particularly those competing in endurance sports. Sucrose is a carbohydrate present within the diets of athletes. Whether sucrose, by virtue of its component monosaccharides glucose and fructose, exerts a meaningful advantage for athletes over other carbohydrate types or blends is unclear. This narrative reviews the literature on the influence of sucrose, relative to other carbohydrate types, on exercise performance or the metabolic factors that may underpin exercise performance. Inference from the research to date suggests that sucrose appears to be as effective as other highly metabolizable carbohydrates (e.g., glucose, glucose polymers) in providing an exogenous fuel source during endurance exercise, stimulating the synthesis of liver and muscle glycogen during exercise recovery and improving endurance exercise performance. Nonetheless, gaps exist in our understanding of the metabolic and performance consequences of sucrose ingestion before, during, and after exercise relative to other carbohydrate types or blends, particularly when more aggressive carbohydrate intake strategies are adopted. While further research is recommended and discussed in this review, based on the currently available scientific literature it would seem that sucrose should continue to be regarded as one of a variety of options available to help athletes achieve their specific carbohydrate-intake goals. PMID- 23630083 TI - Thermal quenching of luminescence of LiSr4 (BO3)3:Eu2+ orange-emitting phosphor. AB - An orange-emitting phosphor, Eu(2+)-activated LiSr4(BO3)3, was synthesized using the conventional solid-state reaction. The photoluminescence excitation and emission spectra, and temperature dependence of the luminescence intensity of the phosphor were investigated. The results showed that LiSr4(BO3)3:Eu(2+) could be efficiently excited by incident light of 250-450 nm, and emits a strong orange light. With increasing temperature, the emission bands of LiSr4(BO3)3:Eu(2+) show an abnormal blue-shift with broadening bandwidth and decreasing emission intensity. PMID- 23630084 TI - Nanoceria-triggered synergetic drug release based on CeO(2) -capped mesoporous silica host-guest interactions and switchable enzymatic activity and cellular effects of CeO(2). AB - Herein, a pH stimuli-responsive vehicle for intracellular drug delivery using CeO2 capped mesoporous silica nanoparticles (MSN) is reported. beta-Cyclodextrin modified CeO2 nanoparticles could cap onto ferrocene-functionalized mesoporous silica through host-guest interactions. After internalization into A549 cells by a lysosomal pathway, the ferrocenyl moieties are oxidized to ferrocenium ions by CeO2 lids, which could trigger the uncapping of the CeO2 and cause the drugs release. Because of the pH-dependent toxicity, the CeO2 here behaves as a multi purpose entity that not only acts as a lid but also exhibits a synergistic antitumor effect on cancer cells. Meanwhile, the cell protective effect of CeO2 nanoparticles alone is demonstrated, which ensures that the dissolved CeO2 nanoparticles can be non-toxic to normal cells. PMID- 23630085 TI - Coronary angiography: is it time to reassess? PMID- 23630086 TI - Digital social networks and health. PMID- 23630087 TI - Bochdalek hernia causing pulmonary hypertension. PMID- 23630088 TI - Peripheral artery disease as a manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and practical implications. PMID- 23630089 TI - Cardiology patient page. Heart-healthy exercise. PMID- 23630091 TI - Letter by Marin et al regarding article, "Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study". PMID- 23630092 TI - Prevalence of unwanted pregnancy in Iran: a systematic review and meta-analysis. AB - INTRODUCTION: Different studies show that a considerable number of pregnancies are unwanted and can have side effects on mothers'' children's and finally society's health. Accordingly, this meta-analysis study has been carried out to estimate a relatively accurate level of unwanted pregnancies in Iran. METHODS: Present studies and published documents were retrieved from Persian and English electronic databases. To increase sensitivity and to select more studies, the reference list of the published studies was checked. After studying the titles and texts of documents, repeated and irrelevant ones were excluded. Data was analyzed using STATA V.11. RESULTS: Forty-nine qualified papers were selected with a 43,061 sample size. The meta-analysis of unwanted pregnancy prevalence in Iran equals 30.6% (CI = 28.1-33.1). Also' according to the present meta-analysis' the most common contraceptive methods used by couples prior to unwanted pregnancies are as follows: pills 27.1%' withdrawal 38.6%' IUD 11.4%' injection contraceptives 2.8%' vasectomy 0.28% and no method 24.5%. DISCUSSION AND CONCLUSION: The results of meta-analysis showed that about one-third of pregnancies in Iran are unwanted and a high percent of them are among women who had used contraceptives. Therefore' it is necessary to adopt more appropriate policies on the following: education, proper pregnancy age, using contraceptive methods, men's role in family planning programs and quality promotion in family planning services. PMID- 23630093 TI - Ultrafast hopping from band to band: assigning infrared spectra based on vibrational energy transfer. PMID- 23630094 TI - Chromothripsis in Hodgkin lymphoma. AB - Chromosomal rearrangements are common features of most cancers, where they contribute to deregulated gene expression. Chromothripsis is a recently described oncogenic mechanism whereby small genomic pieces originating from one chromosomal region undergo massive rearrangements in a single step. Here, we document chromothripsis in Hodgkin lymphoma (HL) cell lines by genomic profiling, showing alternating amplicons of defined chromosomal regions. In L-1236 cells, fluorescent in situ hybridization analyses identified aberrations affecting amplified chromosomal segments that derived from the long arm regions of chromosomes 3 and 9 and that colocalized to a derivative chromosome 6, indicating the cataclysmic origin of this mutation. The ABL1 gene at 9q34 was targeted by these rearrangements leading to its overexpression in L-1236 cells, correlating with pharmacological resistance to treatment with the kinase inhibitor dasatinib. Collectively, we identified and characterized chromothriptic rearrangements in HL cell lines to serve as models for analyzing this novel oncogenomic mechanism. PMID- 23630095 TI - HIV: an underrecognized secondary cause of osteoporosis? PMID- 23630097 TI - Distinguishing alternative reaction pathways by single-molecule fluorescence spectroscopy. PMID- 23630096 TI - A single mutation in a regulatory protein produces evolvable allosterically regulated catalyst of nonnatural reaction. PMID- 23630098 TI - Evaluation of lophine derivatives as L-012 (luminol analog)-dependent chemiluminescence enhancers for measuring horseradish peroxidase and H2O2. AB - 8-Amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4(2H,3H)dione (L-012) was recently synthesized as a new chemiluminescence (CL) probe; the light intensity and the sensitivity of L-012 are higher than those of other CL probes such as luminol. Previously, our group developed four lophine-based CL enhancers of the horseradish peroxidase (HRP)-catalyzed CL oxidation of luminol, namely 2-(4 hydroxyphenyl)-4,5-diphenylimidazole (HDI), 2-(4-hydroxyphenyl)-4,5-di(2 pyridyl)imidazole (HPI), 4-(4,5-diphenyl-1H-imidazol-2-yl)phenylboronic acid (DPA), and 4-[4,5-di(2-pyridyl)-1H-imidazol-2-yl]phenylboronic acid (DPPA), and showed that DPPA was suitable for the photographic detection of HRP. In this study, we replaced luminol with L-012 and evaluated these as L-012-dependent CL enhancers. In addition, to detect HRP and/or H2O2 with higher sensitivity, each detection condition for the L-012-HRP-H2O2 enhanced CL was optimized. All the derivatives enhanced the L-012-dependent CL as well as luminol CL; HPI generated the highest enhanced luminescence. Under optimized conditions for HRP detection, the detection limit of HRP was 0.08 fmol. By contrast, the detection limit of HRP with the enhanced L-012-dependent CL using 4-iodophenol, which is a common enhancer of luminol CL, was 1.1 fmol. With regard to H2O2 detection, the detection limits for enhanced CL with HPI and 4-iodophenol were 0.29 and 1.5 pmol, respectively. Therefore, it is demonstrated that HPI is the most superior L 012-dependent CL enhancer. PMID- 23630099 TI - Effect of substrate stiffness on the functions of rat bone marrow and adipose tissue derived mesenchymal stem cells in vitro. AB - Regenerative medicine treatments that combine the use of cells and materials may open new options for tissue/organ repair and regeneration. The microenvironment of mesenchymal stem cells (MSCs) strictly regulates their self-renewal and functions. In this study, when rat bone marrow derived MSCs (rBMSCs) and rat adipose tissue derived MSCs (rAMSCs) in passages 2-4 were cultured on different substrates, they presented the cellular functions to be dependent of substrate stiffness. The cells attached better on the softer substrate than on the stiffer one. The substrate stiffness had no significant influence on the proliferation of those cells. However, the substrate stiffness significantly promoted the osteogenic differentiation of the two kinds of stem cells. Furthermore, rBMSCs cultured on the same stiffness expressed more osteoblast-related markers than rAMSCs. In addition, combined biomaterials and biochemical reagents treatment yielded a stronger effect on osteogenic differentiation of MSCs than either treatment alone. These results have significant implications for further extending our capabilities in engineering functional tissue substitutes. PMID- 23630100 TI - The geographic concentration of US adult obesity prevalence and associated social, economic, and environmental factors. AB - OBJECTIVE: This study used spatial statistical methods to test the hypotheses that county-level adult obesity prevalence in the United States is (1) regionally concentrated at significant levels, and (2) linked to local-level factors, after controlling for state-level effects. METHODS: Data were obtained from the Centers for Disease Control and Prevention and other secondary sources. The units of analysis were counties. The dependent variable was the age-adjusted percentage of adults who were obese in 2009 (body mass index >30 kg/m2). RESULTS: The prevalence of county-level obesity varied from 13.5% to 47.9% with a mean of 30.3%. Obesity prevalence across counties was not spatially random: 15.8% belonged to high-obesity regions and 13.5% belonged to low-obesity regions. Obesity was positively associated with unemployment, outpatient healthcare visits, physical inactivity, female-headed families, black populations, and less education. Obesity was negatively correlated with physician numbers, natural amenities, percent >=65 years, Hispanic populations, and larger population size. A number of variables were notable for not reaching significance after controlling for other factors, including poverty and food environment measures. CONCLUSIONS: The findings demonstrate the importance of local-level factors in explaining geographic variation in obesity prevalence, and thus hold implications for geographically targeted interventions to combat the obesity epidemic. PMID- 23630101 TI - Upconversion nanoparticles conjugated with Gd(3+) -DOTA and RGD for targeted dual modality imaging of brain tumor xenografts. AB - Glioblastoma multiforme (GBM) is the most common and malignant form of primary brain tumors in human. Small molecular magnetic resonance imaging (MRI) contrast agents are used for GBM diagnosis. However, conventional contrast agents have several limitations, such as low T1 relaxivity, short circulation half lives and absence of tumor targeting. Herein, we develop an upconversion nanoprobe labeled with Gd(3+) -DOTA and RGD (UCNP-Gd-RGD) for dual-modality imaging of glioblastoma. The preparation of UCNP-Gd-RGD starts with amine-functional upconversion nanoparticle core, followed by PEGylation, Gd(3+) DOTA conjugation and RGD labeling. The obtained UCNP-Gd-RGD has improved colloidal stability and reduced cytotoxicity compared with the UCNP core counterpart. Meanwhile, UCNP-Gd RGD shows strong upconversion luminescence in deep-red region and three times enhancement of T1 relaxivity over Gd(3+) DOTA. Due to the recognition between UCNP-Gd-RGD and integrin alphav beta3 receptors, the nanoprobe specifically binds to U87MG cells, as evidenced by confocal microscopy and quantified by ICP-MS. Furthermore, UCNP-Gd-RGD demonstrates a preferential retention in subcutaneous U87MG tumor xenograft as shown in both in vivo upconversion fluorescence/MR imaging studies and ex vivo analysis. UCNP-Gd-RGD, conjugated with numerous RGD peptide and T1 contrast enhancing molecules, is promising for MR imaging of glioblastoma and delineating the tumor boundary before surgery. In addition, NIR to-red upconversion characteristic of UCNP-Gd-RGD facilitates its potential intra operative use for fluorescence-guided tumor resection. PMID- 23630102 TI - Maternal age and adverse pregnancy outcome: a cohort study. AB - OBJECTIVE: To examine the association between maternal age and a wide range of adverse pregnancy outcomes after adjustment for confounding factors in obstetric history and maternal characteristics. METHODS: This was a retrospective study in women with singleton pregnancies attending the first routine hospital visit at 11 + 0 to 13 + 6 weeks' gestation. Data on maternal characteristics, and medical and obstetric history were collected and pregnancy outcomes ascertained. Maternal age was studied, both as a continuous and as a categorical variable. Regression analysis was performed to examine the association between maternal age and adverse pregnancy outcome including pre-eclampsia, gestational hypertension, gestational diabetes mellitus (GDM), preterm delivery, small-for-gestational age (SGA) neonate, large-for-gestational age (LGA) neonate, miscarriage, stillbirth and elective and emergency Cesarean section. RESULTS: The study population included 76 158 singleton pregnancies with a live fetus at 11 + 0 to 13 + 6 weeks. After adjusting for potential maternal and pregnancy confounding variables, advanced maternal age (defined as >= 40 years) was associated with increased risk of miscarriage (odds ratio (OR), 2.32 (95% CI, 1.83-2.93); P < 0.001), pre-eclampsia (OR, 1.49 (95% CI, 1.22-1.82); P < 0.001), GDM (OR, 1.88 (95% CI, 1.55-2.29); P < 0.001), SGA (OR, 1.46 (95% CI, 1.27-1.69); P < 0.001) and Cesarean section (OR, 1.95 (95% CI, 1.77-2.14); P < 0.001), but not with stillbirth, gestational hypertension, spontaneous preterm delivery or LGA. CONCLUSIONS: Maternal age should be combined with other maternal characteristics and obstetric history when calculating an individualized adjusted risk for adverse pregnancy complications. Advanced maternal age is a risk factor for miscarriage, pre-eclampsia, SGA, GDM and Cesarean section, but not for stillbirth, gestational hypertension, spontaneous preterm delivery or LGA. PMID- 23630103 TI - Escalation with overdose control for phase I drug-combination trials. AB - Dose finding for combined drugs has grown rapidly in oncology drug development. The escalation with overdose control (EWOC) method is a popular model-based dose finding approach to single-agent phase I clinical trials. When two drugs are combined as a treatment, we propose a two-dimensional EWOC design for dose finding on the basis of a four-parameter logistic regression model. During trial conduct, we continuously update the posterior distribution of the maximum tolerated dose (MTD) combination to find the most appropriate dose combination for each cohort of patients. The probability that the next assigned dose combination exceeds the MTD combination can be controlled by a feasibility bound, which is based on a prespecified quantile level of the MTD distribution such as to reduce the possibility of overdosing. We determine dose escalation, de escalation, or staying at the same doses by searching the MTD combination along the rows and columns in a two-drug combination matrix, respectively. We conduct simulation studies to examine the performance of the two-dimensional EWOC design under various practical scenarios, and illustrate it with a trial example. PMID- 23630104 TI - Defects of leukocyte migration in primary immunodeficiencies. AB - This Viewpoint gives an overview of the inherited disorders that are characterized by defects of leukocyte trafficking. Three paradigmatic diseases have been selected: warts, hypogammaglobulinemia, infections, and myelokathexis; Wiskott-Aldrich; and leukocyte adhesion deficiency syndromes. These conditions encompass defects in the steps that are required for leukocyte motility: from the response to chemokines, which is altered in warts, hypogammaglobulinemia, infections, and myelokathexis syndrome, to the impairment of leukocyte adhesion and migration found in leukocyte adhesion deficiency syndrome, and finally to abnormal actin filament formation, which is affected in leukocytes of Wiskott Aldrich syndrome patients. PMID- 23630105 TI - Clinical efficiency and reusability of the reciprocating nickel-titanium instruments according to the root canal anatomy. AB - The application of the single-file technique using the reciprocating motion is gaining concern in root canal preparation. The purpose of this research is to compare the efficiency of the reciprocating motion-employing files (RECIPROC and WaveOne) by measuring the working time for complete canal shaping, and to evaluate their reusability under scanning examinations. One hundred curved root canals of the extracted molars were used. The working length was determined and the glide path was confirmed using a #15 K-file. Canals shaping was completed to the length either with RECIPROC R25 file (n = 50), or with WaveOne Primary file (n = 50). The time taken for the file to reach the working length was also measured. Each file was repeatedly used in a maximum of 10 canals for comparing the change of the efficiency (shaping time) according to the working length, canal curvature, and number of file re-use. The deformations or surface defects of the files after the in vitro use were observed using a scanning electron microscope (SEM). There was no difference under the SEM between the 2 file groups with no initiation of micro-cracks until they were re-used up to 5 canals. WaveOne Primary file showed significantly shorter working time than RECIPROC R25 (p < 0.05). There was a statistically significant correlation between the working time and three variables. As the working length and the curvature of the canal increased, the shaping time was increased in both file systems. Reusability of these reciprocating instruments might be maximum 5 canals with minimal surface deformations. PMID- 23630106 TI - Perceived exertion in coaches and young swimmers with different training experience. AB - Session rating of perceived exertion (SRPE) is a practical method to assess internal training load to provide appropriate stimuli. However, coaches and athletes might rate training sessions differently, which can impair performance development. In addition, SRPE might be influenced by athletes' training experience. The authors studied 160 swimmers of different age groups and different competitive swimming experience and 9 coaches. SRPE was indicated by the swimmers 30 min after the end of a training session and before the training session by the coaches. Training-session intensities were classified into easy (SRPE <3), moderate (SRPE 3-5), and difficult (SRPE >5), based on coaches' perception. We observed that the correlation between coaches' and athletes' SRPE increased with increased age and competitive swimming experience, r = .31 for the 11- to 12-y-old group (P < .001), r = .51 for the 13- to 14-y-old group (P < .001), and r = .74 for the 15- to 16-y-old group (P < .001). In addition, younger swimmers (11-12 y, P < .01; 13-14 y, P < .01) rated training intensity differently from coaches in all 3 categories (easy, moderate, and difficult), while the older group rated differently in only 1 category (difficult, P < .01). These findings suggest that the more experienced swimmers are, the more accurate their SRPE is. PMID- 23630107 TI - Precise comparison of protein localization among OCT, OAT, and MATE in human kidney. AB - Organic anion transporters (OATs) and organic cation transporters (OCT) play pivotal roles in the uptake of drugs into epithelial cells at the basolateral membranes, and multidrug and toxin extrusion (MATE) mediates drug secretion into urine at the brush-border membranes. In this study, the expression and distribution of apical MATE1 and MATE2-K, and basolateral OAT1, OAT3, and OCT2 were compared using serial sections of human kidney cortex. First, mRNA expression in the proximal tubules was evaluated using laser microdissection. Levels of OAT, OCT2, and MATE mRNA in the proximal tubules were greatly higher compared with glomerulus. The results quantitatively indicated that these transporters were localized to proximal tubules in the renal cortex. Second, MATE1 and MATE2-K protein were detected in proximal epithelial cells in which OCT2 protein was expressed at the basolateral membranes. In addition, MATE1 was expressed at the brush-border membranes of tubular epithelial cells in which OAT1 and OAT3 were expressed. The results confirmed that OAT1, OAT3, OCT2, MATE1, and MATE2-K were coexpressed in tubular epithelial cells. The cooperation among OAT, OCT, and MATE in renal drug secretion was consistent with their distribution. PMID- 23630109 TI - Towards first principles calculation of electron impact mass spectra of molecules. PMID- 23630108 TI - Parity and body mass index in US women: a prospective 25-year study. AB - OBJECTIVE: To investigate long-term body mass index (BMI) changes associated with childbearing. DESIGN AND METHODS: Adjusted mean BMI changes were estimated by race-ethnicity, baseline BMI, and parity using longitudinal regression models for 3,943 young females over 10 and 25 year follow-up from the ongoing 1979 National Longitudinal Survey of Youth cohort. RESULTS: Estimated BMI increases varied by group, ranging from a low of 2.1 BMI units for white, non-overweight nulliparas over the first 10 years to a high of 10.1 BMI units for black, overweight multiparas over the full 25-year follow-up. Impacts of parity were strongest among overweight multiparas and primaparas at 10 years, ranges 1.4-1.7 and 0.8 1.3 BMI units, respectively. Among non-overweight women, parity-related gain at 10 years varied by number of births among black and white but not Hispanic women. After 25 years, childbearing significantly increased BMI only among overweight multiparous black women. CONCLUSION: Childbearing is associated with permanent weight gain in some women, but the relationship differs by maternal BMI in young adulthood, number of births, race-ethnicity, and length of follow-up. Given that overweight black women may be at special risk for accumulation of permanent, long term weight after childbearing, effective interventions for this group are particularly needed. PMID- 23630110 TI - Potential teratogenicity of methimazole: exposure of zebrafish embryos to methimazole causes similar developmental anomalies to human methimazole embryopathy. AB - While methimazole (MMI) is widely used in the therapy for hyperthyroidism, several groups have reported that maternal exposure to MMI results in a variety of congenital anomalies, including choanal and esophageal atresia, iridic and retinal coloboma, and delayed neurodevelopment. Thus, adverse effects of maternal exposure to MMI on fetal development have long been suggested; however, direct evidence for the teratogenicity of MMI has not been presented. Therefore, we studied the effects of MMI on early development by using zebrafish as a model organism. The fertilized eggs of zebrafish were collected immediately after spawning and grown in egg culture water containing MMI at various concentrations. External observation of the embryos revealed that exposure to high concentrations of MMI resulted in loss of pigmentation, hypoplastic hindbrain, turbid tissue in the forebrain, swelling of the notochord, and curly trunk. Furthermore, these effects occurred in a dose-dependent manner. Precise observation of the serial cross-sections of MMI-exposed embryos elucidated delayed development and hypoplasia of the whole brain and spinal cord, narrowing of the pharynx and esophagus, severe disruption of the retina, and aberrant structure of the notochord. These neuronal, pharyngeal, esophageal, and retinal anomalous morphologies have a direct analogy to the congenital anomalies observed in children exposed to MMI in utero. Here, we show the teratogenic effects of MMI on the development of zebrafish and provide the first experimental evidence for the connection between exposure to MMI and human MMI embryopathy. PMID- 23630112 TI - Morphometric evaluation and nonclassical criteria for the diagnosis of HPV infection and cytological atypia in cervical samples. AB - Herein, we evaluated cervical samples from normal tissue or HPV-infected tissue, to determine if the relative nuclear/cytoplasmic ratio (NA/CA) and the presence of nonclassical cytological criteria are a novel cytological criterion for the diagnosis of HPV. Significantly, larger NA/CA ratios were found for the HPV ATYPIA+ and HPV+ATYPIA+ groups compared with HPV-ATYPIA- group, regardless of collection method. For the samples collected with a spatula, only three samples from the HPV-ATIPIA- group showed four or more nonclassical parameters (i.e., were positive), while a larger number of the samples in the HPV-ATYPIA+, HPV+ATYPIA-, and HPV+ATYPIA+ groups were positive (13, 4, and 13 samples, respectively). Among those collected with a brush, no sample showed four or more nonclassical criteria in the HPV-ATYPIA- group, while a number of samples were positive in the HPV-ATYPIA+, HPV+ATYPIA-, and HPV+ATYPIA+ groups (4, 3, and 4 samples, respectively). HPV infection was associated with significant morphometrical changes; no increase in the NA/CA ratio was found in the HPV+ATYPIA- samples, compared with the HPV-ATIPIA- samples collected with either a spatula or a brush. In conclusion, by including nonclassical cytological criteria into the patient diagnosis, we were able to reduce the number of false negative and false positive HPV diagnoses made using conventional cytology alone. PMID- 23630113 TI - A response to the critical comments on "One molecule, two atoms, three views, four bonds?". PMID- 23630111 TI - Bone and skeletal muscle: neighbors with close ties. AB - The musculoskeletal system evolved in mammals to perform diverse functions that include locomotion, facilitating breathing, protecting internal organs, and coordinating global energy expenditure. Bone and skeletal muscles involved with locomotion are both derived from somitic mesoderm and accumulate peak tissue mass synchronously, according to genetic information and environmental stimuli. Aging results in the progressive and parallel loss of bone (osteopenia) and skeletal muscle (sarcopenia) with profound consequences for quality of life. Age associated sarcopenia results in reduced endurance, poor balance, and reduced mobility that predispose elderly individuals to falls, which more frequently result in fracture because of concomitant osteoporosis. Thus, a better understanding of the mechanisms underlying the parallel development and involution of these tissues is critical to developing new and more effective means to combat osteoporosis and sarcopenia in our increasingly aged population. This perspective highlights recent advances in our understanding of mechanisms coupling bone and skeletal muscle mass, and identify critical areas where further work is needed. PMID- 23630114 TI - Fabrication of highly stretchable conductors via morphological control of carbon nanotube network. AB - Stretchable conductors, which can keep their excellent electrical conductivity while highly stretched, have been investigated extensively due to their wide range of applications in flexible and stretchable electronics, wearable displays, etc.; however, their preparation is often complicated and expensive. Herein, an efficient method to prepare high performance stretchable conductors through morphological control of conductive networks formed with carbon nanotubes (CNTs) in an elastomer matrix is reported. It is observed that an interface-mediated method could be used to align randomly oriented filler during stretching and to induce buckling of CNTs during relaxation. Further morphological studies indicate the possible formation of a wavy CNT structure induced by cyclic pre-straining. Subsequent thermal annealing is observed to collapse the oriented network and improve the local contacts between conductive networks. Through such a simple procedure, a conductivity of nearly 1000 S m(-1) and a stretchability of 200% can be achieved for composites containing 20 wt% CNTs. CNTs are observed to buckle over a large area in polymer bulk, and the combination of pre-straining and thermal annealing modifies the conductive network in the elastomer matrix. As a general method, this could be used for easy fabrication of high-performance stretchable conductors for arbitrary-shaped objects on a large scale. PMID- 23630115 TI - Looking back into the future: 30 years of metabolomics at TNO. AB - Metabolites have played an essential role in our understanding of life, health, and disease for thousands of years. This domain became much more important after the concept of metabolism was discovered. In the 1950s, mass spectrometry was coupled to chromatography and made the technique more application-oriented and allowed the development of new profiling technologies. Since 1980, TNO has performed system-based metabolic profiling of body fluids, and combined with pattern recognition has led to many discoveries and contributed to the field known as metabolomics and systems biology. This review describes the development of related concepts and applications at TNO in the biomedical, pharmaceutical, nutritional, and microbiological fields, and provides an outlook for the future. PMID- 23630116 TI - Impact of chorionicity on first-trimester nuchal translucency screening in ART twin pregnancies. AB - OBJECTIVE: Nuchal translucency (NT) measurement in assisted reproduction treatment (ART) twins is less extensively investigated. Therefore, the present study compared NT measurements of spontaneously conceived twins with ART twins in dichorionic (DC) and monochorionic (MC) pregnancies. METHODS: Retrospective analysis of 706 unaffected twins between 11 + 0 and 13 + 6 weeks conceived either spontaneously (n = 362) or with ART (n = 344). The group with spontaneous conception included 234 DC (64.6%) and 128 MC (35.4%) pregnancies. In the ART group, 326 were DC (94.7%) and 18 were MC (5.3%). NT values were transformed into multiples of median (MoM). RESULTS: In the DC group, no significant differences between ART and spontaneously conceived twins (NT MoM 1.06 +/- 0.28 vs 1.03 +/- 0.29; p > 0.05) were observed. NT MoM of MC ART twins was higher compared with spontaneous MC twins (1.23 +/- 0.82 vs 0.99 +/- 0.27; p = 0.011). Although the incidence of twin-to-twin transfusion syndrome (TTTS) was higher among ART twins (11.1% vs 4.7%), inter-twin NT difference was similar between pregnancies with TTTS (0.42 +/- 0.21) or without (0.40 +/- 0.71). CONCLUSIONS: Measurement of NT thickness in DC ART twins achieves comparable results with twins conceived spontaneously. Conclusions in MC twins are limited; however, higher NT MoM was not related to TTTS or selective intrauterine growth restriction. PMID- 23630117 TI - Acidic pH-responsive siRNA conjugate for reversible carrier stability and accelerated endosomal escape with reduced IFNalpha-associated immune response. PMID- 23630118 TI - Species differences in developmental toxicity of epoxiconazole and its relevance to humans. AB - Epoxiconazole, a triazole-based fungicide, was tested in toxicokinetic, prenatal and pre-postnatal toxicity studies in guinea pigs, following oral (gavage) administration at several dose levels (high dose: 90 mg/kg body weight per day). Maternal toxicity was evidenced by slightly increased abortion rates and by histopathological changes in adrenal glands, suggesting maternal stress. No compound-related increase in the incidence of malformations or variations was observed in the prenatal study. In the pre-postnatal study, epoxiconazole did not adversely affect gestation length, parturition, or postnatal growth and development. Administration of epoxiconazole did not alter circulating estradiol levels. Histopathological examination of the placentas did not reveal compound related effects. The results in guinea pigs are strikingly different to those observed in pregnant rats, in which maternal estrogen depletion, pathological alteration of placentas, increased gestation length, late fetal death, and dystocia were observed after administration of epoxiconazole. In the studies reported here, analysis of maternal plasma concentrations and metabolism after administration of radiolabeled epoxiconazole demonstrated that the different results in rats and guinea pigs were not due to different exposures of the animals. A comprehensive comparison of hormonal regulation of pregnancy and birth in murid rodents and primates indicates that the effects on pregnancy and parturition observed in rats are not applicable to humans. In contrast, the pregnant guinea pig shares many similarities to pregnant humans regarding hormonal regulation and is therefore considered to be a suitable species for extrapolation of related effects to humans. PMID- 23630119 TI - Factors predictive of the development of Levodopa-induced dyskinesia and wearing off in Parkinson's disease. AB - The Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease (STRIDE-PD) study compared the initiation of levodopa (l-dopa) therapy with l-dopa/carbidopa (LC) versus l-dopa/carbidopa/entacapone (LCE) in patients with Parkinson's disease. In the current study, the STRIDE-PD study population was investigated to determine the effect of l-dopa dose and other risk factors on the development of dyskinesia and wearing-off. Patients were randomized to receive LCE (n=373) or LC (n=372). Blinded assessments for dyskinesia and wearing-off were performed at 3 month intervals for the 134- to 208-week duration of the study. The patients were divided into 4 dose groups based on nominal l-dopa dose at the time of onset of dyskinesia (or at study conclusion if there was no dyskinesia): group 1, <400 mg/day (n=157); group 2, 400 mg/day (n=310); group 3, 401 to 600 mg/day (n=201); and group 4, >600 mg/day (n=77). Similar analyses were performed with respect to wearing-off and any motor complication. The times to onset and frequency of dyskinesia, wearing-off, or any motor complication were compared using the log rank test (overall trend test) and a Cox proportional hazards model (pairwise comparisons). A stepwise Cox proportional hazards model was used to screen predictive factors in a multivariate analysis. The risk of developing dyskinesia and wearing-off increased in an l-dopa dose-dependent manner (P<0.001 for both). Analyses using l-dopa equivalent doses produced comparable results. Factors that were predictive of dyskinesia, in rank order, were: young age at onset, higher l dopa dose, low body weight, North American geographic region, LCE treatment group, female gender, and more severe Unified Parkinson's Disease Rating Scale (UPDRS) Part II. Multivariate analyses identified similar predictors for wearing off but included baseline UPDRS Part III and excluded weight and treatment allocation. The risk of developing dyskinesia or wearing-off was closely linked to l-dopa dose. The current results suggest that physicians should use the lowest dose of l-dopa that provides satisfactory clinical control to minimize the risk of both dyskinesia and wearing-off. PMID- 23630121 TI - Functional movement scores and longitudinal performance outcomes in elite track and field athletes. AB - Subjects with scores on the Functional Movement Screen (FMS) assessment of <=14 or with at least 1 bilateral asymmetry have been shown to have greater future injury incidence than subjects with FMS scores >14 or no movement asymmetries. PURPOSE: To determine if FMS injury risk factors extend to longitudinal competitive performance outcomes in elite track and field athletes. METHODS: Elite track and field athletes were examined (N = 121), each completing an FMS before the 2011 competitive season. Best competition marks for the year were obtained from athletes' actual performances for 2010 and 2011. Performance change between 2010 and 2011 was examined in cohorts of FMS scores <=14 (LoFMS) vs >14 (HiFMS), athletes with bilateral asymmetry in at least 1 of the 5 FMS movements vs athletes with no asymmetry, and athletes who scored 1 on the deep-squat movement vs athletes who scored 2 or 3. RESULTS: HiFMS had a significantly different change in performance from 2010 to 2011 (0.41% +/- 2.50%, n = 80) compared with LoFMS (-0.51% +/- 2.30%, P = .03, n = 41). Athletes with no asymmetries had a longitudinal improvement in performance (+0.60% +/- 2.86%, n = 50) compared with athletes with at least 1 asymmetry (-0.26% +/- 2.10%, P = .03, n = 71). Athletes who scored 1 on the deep-squat movement had a significantly different change in performance (-1.07 +/- 2.08%, n = 22) vs athletes who scored 2 (0.13% +/- 2.28%, P = .03, n = 87) or 3 (1.98% +/- 3.31%, P = .001, n = 12). CONCLUSION: Functional movement ability, known to be associated with the likelihood of future injury, is also related to the ability to improve longitudinal competitive performance outcomes. PMID- 23630123 TI - Nanoparticles for gene delivery. AB - Nanocarriers are a new type of nonviral gene carriers, many of which have demonstrated a broad range of pharmacological and biological properties, such as being biodegradable in the body, stimulus-responsive towards the surrounding environment, and an ability to specifically targeting certain disease sites. By summarizing some main types of nanocarriers, this Concept considers the current status and possible future directions of the potential clinical applications of multifunctional nanocarriers, with primary attention on the combination of such properties as biodegradability, targetability, transfection ability, and stimuli sensitivity. PMID- 23630120 TI - Traumatic brain injury induces macrophage subsets in the brain. AB - Traumatic brain injury (TBI) elicits innate inflammatory responses that can lead to secondary brain injury. To better understand the mechanisms involved in TBI induced inflammation, we examined the nature of macrophages responding to TBI in mice. In this model, brain macrophages were increased >20-fold the day after injury and >77-fold 4 days after injury in the ipsilateral hemisphere compared with sham controls. TBI macrophage subsets were identified by using a reporter mouse strain (YARG) that expresses eYFP from an internal ribosome entry site (IRES) inserted at the 3' end of the gene for arginase-1 (Arg1), a hallmark of alternatively activated (M2) macrophages. One day after TBI, 21 +/- 1.5% of ipsilateral brain macrophages expressed relatively high levels of Arg1 as detected by yellow fluorescent protein, and this subpopulation declined thereafter. Arg1(+) cells localized with macrophages near the TBI lesion. Gene expression analysis of sorted Arg1(+) and Arg1(-) brain macrophages revealed that both populations had profiles that included features of conventional M2 macrophages and classically activated (M1) macrophages. The Arg1(+) cells differed from Arg1(-) cells in multiple aspects, most notably in their chemokine repertoires. Thus, the macrophage response to TBI initially involves heterogeneous polarization toward at least two major subsets. PMID- 23630122 TI - B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and classical hodgkin lymphoma: diagnosis by fine-needle aspiration cytology. AB - A 58-year-old lady presented with mediastinal lymphadenopathy. A thoracoscopic ultrasound-guided fine-needle aspiration showed large atypical epithelioid cells arranged in cohesive sheets and dispersed as single cells with intact cytoplasm amid a background of lymphocytes and histiocytes. A cytological diagnosis of "a malignant neoplasm" was made, raising a broad list of differential diagnoses. A broad panel of immunocytochemical stains performed on the cell block was indicative of a lymphoproliferative disorder, but the immunophenotype was intermediate between diffuse large B cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). Diffuse and strong reactivity to CD20, CD79a, and PAX-5, and weak reactivity to CD30, was in favor of a DLBCL, or more precisely mediastinal (thymic) large B cell lymphoma (MLBL). However, there were negative staining for LCA, OCT-2, and BOB-1 as well as positive staining for EBV-encoded RNA, which were against a diagnosis of MLBL and raised the possibility of cHL. The absence of RS cells and the typical mileu, the negativity for CD15 and the strong positivity of CD20 and PAX-5 were against a diagnosis of cHL. On this basis, the diagnosis of "B-cell lymphoproliferative disorder with features intermediate between DLBCL and cHL" was rendered. The diagnosis was subsequently confirmed on excisional biopsy. This case report demonstrates broad differential diagnoses raised by this diagnostic entity and the importance of an adequate cell block for accurate designation. PMID- 23630124 TI - Synthesis of pyrroles by click reaction: silver-catalyzed cycloaddition of terminal alkynes with isocyanides. PMID- 23630125 TI - Effects of asymmetry on the strength of the chelonian shell: a comparison of three species. AB - A major focus of the field of organismal biology is to understand how morphology impacts performance. Although the functional implications of certain aspects of shape have been widely examined, the functional implications of a related parameter, symmetry, remain mostly unknown. We used finite-element models to examine the effects of turtle shell asymmetry on shell strength across three morphologically distinct emydid species. The goals of this study were to: 1) test the hypothesis that increased asymmetry (independent of differences in shape) is associated with increased stress levels for a given load, and thus with weaker shells, 2) ascertain how asymmetry and the position of load application interact to influence shell strength, and 3) determine how interspecific differences in shape influence the effect of asymmetry. We found that increased asymmetry does produce higher stresses for both midline and non-midline loads. Non-midline loads produce slightly larger and more variable stresses. Species-specific shell shape can mitigate the effects of asymmetry; stronger shapes are potentially more resistant to the negative effects of asymmetry. Our findings indicate that changes in asymmetry associated with relatively small changes in shape can have as much of an effect on stress incurred by the shell as the changes in shape themselves. PMID- 23630126 TI - A method comparison study to validate a novel parameter of obesity, the body adiposity index, in Chinese subjects. AB - OBJECTIVE: A recently developed parameter, the body adiposity index (BAI)-a composite index based on hip circumference and height-estimates the percentage (%) body adiposity indirectly. The BAI was compared with dual energy X-ray absorptiometer (DEXA)-derived % adiposity to validate the BAI in the local Chinese population. DESIGN AND METHODS: 105 Chinese were recruited and % adiposity estimated by BAI was compared with that derived from DEXA using the Bland Altman plot. A correlation study comparing the BAI with body mass index (BMI) was also done. RESULTS: BAI underestimated DEXA-derived % adiposity by a mean of 5.77% with 95% limits of agreement of +/-8.4%. When stratified by gender, BMI correlated with DEXA-derived % adiposity better than BAI (r = 0.81 vs. 0.74 for males, P = 0.088, and r = 0.87 vs. 0.82 for females, P = 0.087). Hip circumference and waist circumference also correlated better with the BMI than BAI (r = 0.94 vs. 0.71 for hip circumference, P < 0.001, and r = 0.93 vs. 0.50 for waist circumference, P < 0.001, respectively). CONCLUSIONS: The BAI underestimates DEXA-derived % adiposity in a Chinese population in Singapore and is unlikely to be a better overall index of adiposity than the established BMI. PMID- 23630127 TI - The significance of the second trimester sonographic soft markers in pregnancies after normal first trimester screening. PMID- 23630128 TI - Promotion of physical activity for children and adults with congenital heart disease: a scientific statement from the American Heart Association. PMID- 23630130 TI - Prolyl hydroxylase domain protein 2 plays a critical role in diet-induced obesity and glucose intolerance. AB - BACKGROUND: Recent studies suggest that the oxygen-sensing pathway consisting of transcription factor hypoxia-inducible factor and prolyl hydroxylase domain proteins (PHDs) plays a critical role in glucose metabolism. However, the role of adipocyte PHD in the development of obesity has not been clarified. We examined whether deletion of PHD2, the main oxygen sensor, in adipocytes affects diet induced obesity and associated metabolic abnormalities. METHODS AND RESULTS: To delete PHD2 in adipocyte, PHD2-floxed mice were crossed with aP2-Cre transgenic mice (Phd2(f/f)/aP2-Cre). Phd2(f/f)/aP2-Cre mice were resistant to high-fat diet induced obesity (36.7+/-1.7 versus 44.3+/-2.0 g in control; P<0.01) and showed better glucose tolerance and homeostasis model assessment-insulin resistance index than control mice (3.6+/-1.0 versus 11.1+/-2.1; P<0.01). The weight of white adipose tissue was lighter (epididymal fat, 758+/-35 versus 1208+/-507 mg in control; P<0.01) with a reduction in adipocyte size. Macrophage infiltration into white adipose tissue was also alleviated in Phd2(f/f)/aP2-Cre mice. Target genes of hypoxia-inducible factor, including glycolytic enzymes and adiponectin, were upregulated in adipocytes of Phd2(f/f)/aP2-Cre mice. Lipid content was decreased and uncoupling protein-1 expression was increased in brown adipose tissue of Phd2(f/f)/aP2-Cre mice. Knockdown of PHD2 in 3T3L1 adipocytes induced a decrease in the glucose level and an increase in the lactate level in the supernatant with upregulation of glycolytic enzymes and reduced lipid accumulation. CONCLUSIONS: PHD2 in adipose tissue plays a critical role in the development of diet-induced obesity and glucose intolerance. PHD2 might be a novel target molecule for the treatment of obesity and associated metabolic abnormalities. PMID- 23630129 TI - 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. PMID- 23630131 TI - 'Translational formative evaluation': critical in up-scaling public health programmes. AB - The process of generating evidence-based public health interventions is understood to include steps that define the issue, generate and test solutions in controlled settings, replicate and then disseminate more widely. However, to date models have not considered the types and scale of formative evaluation tasks that are needed to up-scale interventions, from efficacy to population-wide dissemination in the real world. In this paper, we propose that an additional stage of 'translational formative evaluation' is necessary for the translation of effectiveness evidence into wide-scale public health practice. We illustrate the utility of translational formative evaluation, through a case study of the Get Healthy Information and Coaching Service((r)) (GHS), a population-based telephone service designed to assist adults change lifestyle-related behaviours. The additional translational formative evaluation steps comprised synthesis of efficacy studies, qualitative research with the wider target audience, environmental analysis and stakeholder consultation. They produced precise recommendations to refine GHS design and implementation. Translational formative evaluation is a necessary intermediate step, following efficacy studies and a precursor to population-wide implementation of public health programmes. PMID- 23630132 TI - A risky occupation? (Un)healthy lifestyle behaviors among Danish seafarers. AB - Sedentary working conditions, smoking, unhealthy eating habits and lack of exercise are some of the lifestyle risk factors that form a potentially growing problem for seafarers within certain parts of the maritime sector creating a heightened risk for chronic diseases such as diabetes and cardiovascular disease. Health promotion initiatives to combat this negative development requires as a first step identifying the magnitude of the different risk factors. A survey was conducted in 2007-08 with two Danish shipping companies on seafarers' health, wellbeing, diet, smoking and physical activity. In addition, a health profile was offered to the respondents, consisting of physiological measurements, such as fitness rating, body mass index (BMI), cholesterol measurement and blood pressure. The response rate in the questionnaire study was 57% (n = 360) of which 76% (n = 272) of the respondents received a health profile. Results (males) showed 44% daily smokers compared with 32% in the general Danish adult male population. Twenty-five percent of the seafarers were obese with a BMI > 30 compared with 12% of the Danish adult male population. Fifty-one percent of the respondents were defined as having metabolic syndrome, compared with 20% of the Danish adult male population. Seafaring is a risky occupation when looking at the seafarers' health and wellbeing. The results of this survey confirm the need for health promotion interventions such as smoking cessation courses, healthy cooking courses and physical exercise programs, etc. that can enable healthier lifestyle. The challenge will be to take into account the special seafaring conditions when implementing the interventions. PMID- 23630133 TI - Working better together: new approaches for understanding the value and challenges of organizational partnerships. AB - Inter-agency partnerships are critical for addressing the interrelated circumstances associated with the social and health determinants of health inequalities. However, there are many challenges in evaluating partnership processes and outcomes. We discuss a mixed methods study that explored partnership processes in an innovative program that aims to promote social and economic inclusion for young newly arrived refugees. A theoretically informed evaluation was designed and data collected in three ways: an organizational ethnographic approach; a partnership self-assessment tool and semi-structured interviews. Partnership assessments and interviews were collected at two points in time providing progressive process data. Analyses explore divergent levels of staff satisfaction with the partnership's operations, particularly between staff working in program development (strategic management) and program delivery (service provision) roles. Follow-up data collection indicated satisfaction with partnership processes had improved. The partnership did achieve its aim of increasing the level of cooperation between service providers to support young people from refugee backgrounds. This paper presents insights into how to evaluate inter-agency partnerships and reports both methodological and empirical findings. It provides an approach for a better understanding of the levels at which individuals operate within such partnerships, indicates areas where support and attention is needed. PMID- 23630134 TI - Improving memory in Parkinson's disease: a healthy brain ageing cognitive training program. AB - This study aimed to evaluate the efficacy of a multifactorial 'healthy brain ageing cognitive training program' for Parkinson's disease. Using a single blinded waitlist control design, 50 participants with Parkinson's disease were recruited from the Brain & Mind Research Institute, Sydney, Australia. The intervention encompassed both psychoeducation and cognitive training; each component lasted 1-hour. The 2-hour sessions were delivered in a group format, twice-weekly over a 7-week period. Multifactorial psychoeducation was delivered by a range of health professionals. In addition to delivering cognitive strategies, it targeted depression, anxiety, sleep, vascular risk factors, diet, and exercise. Cognitive training was computer-based and was conducted by clinical neuropsychologists. The primary outcome was memory. Secondary outcomes included other aspects of cognition and knowledge pertaining to the psychoeducation material. Results demonstrated that cognitive training was associated with significant improvements in learning and memory corresponding to medium to large effect sizes. Treatment was also associated with medium effect size improvements in knowledge. Although the study was limited by the lack of randomized allocation to treatment and control groups, these findings suggest that a healthy brain ageing cognitive training program may be a viable tool to improve memory and/or slow cognitive decline in people with Parkinson's disease. It also appeared successful for increasing awareness of adaptive and/or compensatory cognitive strategies, as well as modifiable risk factors to optimize brain functioning. PMID- 23630136 TI - Tandem synthesis of photoactive benzodifuran moieties in the formation of microporous organic networks. PMID- 23630135 TI - Schimke Immunoosseous Dysplasia associated with undifferentiated carcinoma and a novel SMARCAL1 mutation in a child. AB - Schimke Immunoosseous Dysplasia (SIOD) is a rare, autosomal recessive disorder of childhood with classical features of spondyloepiphyseal dysplasia, renal failure, and T cell immunodeficiency. SIOD has been associated with several malignancies, including non-Hodgkin lymphoma and osteosarcoma. About half of SIOD patients have biallelic mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin dependent regulator of chromatin, subfamily a-like 1). This gene encodes an annealing helicase and replication stress response protein that localizes to damage-stalled DNA replication forks. We report a child with SIOD and a novel S859P missense mutation in SMARCAL1 who developed undifferentiated carcinoma of the sinus. PMID- 23630137 TI - Identification of an inhibitory mechanism of luteolin on the insulin-like growth factor-1 ligand-receptor interaction. AB - Using single-molecule force measurement and fluorescence imaging, we have demonstrated that luteolin has an inhibitory effect on IGF-1 ligand-receptor binding, the initial step in IGF-1 signaling. This inhibition mechanism, which was confirmed by flow cytometry and molecular docking, could play a role in cancer therapy. PMID- 23630138 TI - Achieving millennium development goals 4 and 5: do every mother and child really count? PMID- 23630139 TI - Risk factors for severe acute lower respiratory infections in children: a systematic review and meta-analysis. AB - AIM: To identify the risk factors in children under five years of age for severe acute lower respiratory infections (ALRI), which are the leading cause of child mortality. METHODS: We performed a systematic review of published literature available in the public domain. We conducted a quality assessment of all eligible studies according to GRADE criteria and performed a meta-analysis to report the odds ratios for all risk factors identified in these studies. RESULTS: We identified 36 studies that investigated 19 risk factors for severe ALRI. Of these, 7 risk factors were significantly associated with severe ALRI in a consistent manner across studies, with the following meta-analysis estimates of odds ratios (with 95% confidence intervals): low birth weight 3.18 (1.02-9.90), lack of exclusive breastfeeding 2.34 (1.42-3.88), crowding - more than 7 persons per household 1.96 (1.53-2.52), exposure to indoor air pollution 1.57 (1.06 2.31), incomplete immunization 1.83 (1.32-2.52), undernutrition - weight-for-age less than 2 standard deviations 4.47 (2.10-9.49), and HIV infection 4.15 (2.57 9.74). CONCLUSION: This study highlights the role of the above seven risk factors in the development of severe pneumonia in under-five children. In addition, it emphasizes the need for further studies investigating other potential risk factors. Since these risk factors are potentially preventable, health policies targeted at reducing their prevalence provide a basis for decreasing the burden of childhood pneumonia. PMID- 23630140 TI - Viral etiology of hospitalized acute lower respiratory infections in children under 5 years of age -- a systematic review and meta-analysis. AB - AIM: To estimate the proportional contribution of influenza viruses (IV), parainfluenza viruses (PIV), adenoviruses (AV), and coronaviruses (CV) to the burden of severe acute lower respiratory infections (ALRI). METHODS: The review of the literature followed PRISMA guidelines. We included studies of hospitalized children aged 0-4 years with confirmed ALRI published between 1995 and 2011. A total of 51 studies were included in the final review, comprising 56091 hospitalized ALRI episodes. RESULTS: IV was detected in 3.0% (2.2%-4.0%) of all hospitalized ALRI cases, PIV in 2.7% (1.9%-3.7%), and AV in 5.8% (3.4%-9.1%). CV are technically difficult to culture, and they were detected in 4.8% of all hospitalized ALRI patients in one study. When respiratory syncytial virus (RSV) and less common viruses were included, at least one virus was detected in 50.4% (40.0%-60.7%) of all hospitalized severe ALRI episodes. Moreover, 21.9% (17.7% 26.4%) of these viral ALRI were mixed, including more than one viral pathogen. Among all severe ALRI with confirmed viral etiology, IV accounted for 7.0% (5.5% 8.7%), PIV for 5.8% (4.1%-7.7%), and AV for 8.8% (5.3%-13.0%). CV was found in 10.6% of virus-positive pneumonia patients in one study. CONCLUSIONS: This article provides the most comprehensive analysis of the contribution of four viral causes to severe ALRI to date. Our results can be used in further cost effectiveness analyses of vaccine development and implementation for a number of respiratory viruses. PMID- 23630141 TI - Effectiveness of seasonal influenza vaccines in children -- a systematic review and meta-analysis. AB - AIM: To assess the efficacy and effectiveness of seasonal influenza vaccines in healthy children up to the age of 18 years. METHODS: MedLine, EMBASE, CENTRAL, CINAHL, WHOLIS, LILACS, and Global Health were searched for randomized controlled trials and cohort and case-control studies investigating the efficacy or effectiveness of influenza vaccines in healthy children up to the age of 18 years. The studies were assessed for their quality and data on the outcomes of influenza-like illness, laboratory-confirmed influenza, and hospitalizations were extracted. Seven meta-analyses were performed for different vaccines and different study outcomes. RESULTS: Vaccine efficacy for live vaccines, using random effects model, was as follows: (i) for similar antigen, using per-protocol analysis: 83.4% (78.3%-88.8%); (ii) for similar antigen, using intention to treat analysis: 82.5 (76.7%-88.6%); (iii) for any antigen, using per protocol analysis: 76.4% (68.7%-85.0%); (iv) for any antigen, using intention to treat analysis: 76.7% (68.8%-85.6%). Vaccine efficacy for inactivated vaccines, for similar antigen, using random effects model, was 67.3% (58.2%-77.9%). Vaccine effectiveness against influenza-like illness for live vaccines, using random effects model, was 31.4% (24.8%-39.6%) and using fixed-effect model 44.3% (42.6% 45.9%). Vaccine effectiveness against influenza-like illness for inactivated vaccines, using random effects model, was 32.5% (20.0%-52.9%) and using fixed effect model 42.6% (38.3%-47.5%). CONCLUSIONS: Influenza vaccines showed high efficacy in children, particularly live vaccines. Effectiveness was lower and the data on hospitalizations were very limited. PMID- 23630142 TI - A comparison between antenatal care quality in public and private sector in rural Hebei, China. AB - AIM: To evaluate the quality of antenatal care (ANC) in Hebei Province and compare it between the public and private sector and within the public sector. METHODS: We conducted a Maternal, Newborn and Child Health Household Survey in 2010 using a two-stage sampling procedure and included 1079 mothers. The quality of ANC was assessed on the basis of the number of ANC visits, the time of the first ANC visit, 16 different ANC procedures, owning a maternal health care booklet, and the type of service provider. RESULTS: Almost all women (98%) received ANC services at least once, 80% at least four times, and 54% at least five times. About half of the women (46%) visited ANC facility within their first trimester. Neither public nor private sector provided all 16 standardized services, but significantly more women in public sector received ANC procedures. Most women received ANC in county or higher-level hospitals (75%) and very few in township hospitals (8%). Significantly fewer women were weighed and tested for HIV/AIDS in township than in county or higher-level hospitals. CONCLUSION: The quality of ANC in Hebei was poorer than required by China's national and World Health Organization norms. Although the public sector performed better than the private sector, the utilization and quality of care of ANC services in this sector varied and women generally visited county or higher-level health facilities. PMID- 23630143 TI - Improving the intake of nutritious food in children aged 6-23 months in Wuyi County, China -- a multi-method approach. AB - AIM: To develop affordable, appropriate, and nutritious recipes based on local food resources and dietary practices that have the potential to improve infant feeding practices. METHODS: We carried out a mixed methods study following the World Health Organization's evaluation guidelines on the promotion of child feeding. We recruited caregivers with children aged 6-23 months in Wuyi County, Hebei Province, China. The study included a 24-hour dietary recall survey, local food market survey, and development of a key local food list, food combinations, and recipes. Mothers tested selected recipes at their homes for two weeks. We interviewed mothers to obtain their perceptions on the recipes. RESULTS: The 24 hour dietary recall survey included 110 mothers. Dietary diversity was poor; approximately 10% of children consumed meat and only 2% consumed vitamin A-rich vegetables. The main reason for not giving meat was the mothers' belief that their children could not chew and digest meat. With the help of mothers, we developed six improved nutritious recipes with locally available and affordable foods. Overall, mothers liked the recipes and were willing to continue using them. CONCLUSIONS: This is the first study using a systematic evidence-based method to develop infant complementary recipes that can address complementary feeding problems in China. We developed recipes based on local foods and preparation practices and identified the barriers that mothers faced toward feeding their children with nutritious food. To improve nutrition practices, it is important to both give mothers correct feeding knowledge and assist them in cooking nutritious foods for their children based on locally available products. Further research is needed to assess long-term effects of those recipes on the nutritional status of children. PMID- 23630145 TI - Arterial blood architecture of the maxillary sinus in dentate specimens. AB - AIM: To describe vascular anatomy of the maxillary sinus in dentate specimens dissected from human cadavers. METHODS: Twenty dentate maxillary specimens were dissected, anatomically prepared, and injected with liquid latex for a better visualization of the maxillary sinus artery. RESULTS: We found an intraosseous anastomosis in 100% and an extraosseous anastomosis in 90% of the cases. The anterior lateral wall of the maxillary sinus was transversed by two anastomoses between the posterior superior alveolar artery (PSAA) and the infraorbital artery (IOA). The PSAA was divided into a gingival and dental branch. The gingival branch anastomosed with the terminal extraosseous branch of the extraosseous anastomosis (EOA) and the dental branch with the intraosseous branch of the intraosseous anastomosis (IOA). The mean distances from the alveolar ridge to the extraosseus anastomosis were 16 mm for the second maxillary molar, 12.3 mm for the first maxillary molar, and 13.1 mm for the second maxillary premolar. The mean distances from the intraosseous anastomosis to the alveolar ridge were 17.7 mm for the second maxillary molar, 14.5 mm for the first maxillary molar, and 14.66 mm for the second maxillary premolar. CONCLUSION: These findings provide relevant data for clinical dentistry in order to avoid bleeding complications and minimize the risk of injury to the arterial network of the maxillary sinus during surgical procedures in the dentate maxilla region. PMID- 23630144 TI - Taurine attenuates oxidative stress and alleviates cardiac failure in type I diabetic rats. AB - AIM: To investigate cardioprotective effect of taurine in diabetic rats. METHODS: Male Sprague-Dawley rats were assigned randomly into four groups of 15 rats: control group, control+taurine group, streptozotocin (STZ) group, and STZ + taurine group. Rats in STZ and STZ+ taurine groups were treated by a single injection of STZ (70 mg kg-1, intraperitoneally) dissolved in 0.01 M citrate buffer (pH 4.5) for induction of diabetes, and rats in control and control+taurine groups were treated with the same volume citrate buffer. Taurine was orally administered to rats in control+taurine and STZ + taurine groups daily for 8 weeks. Rats were examined for diabetic cardiomyopathy by left ventricular (LV) hemodynamic analysis. Myocardial oxidative stress was assessed by measuring the activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA). Myocardial protein kinase B (Akt/PKB) phosphorylation and heme oxygenase-1 (HO-1) protein levels were measured by Western blot in all rats at the end of the study. RESULTS: In untreated diabetic rats, LV systolic pressure, rate of pressure rise, and rate of pressure fall were decreased, while LV end-diastolic pressure was increased, indicating reduced LV contractility and slowing of LV relaxation. The levels of Akt/PKB phosphorylation and SOD activity were decreased and HO-1 protein expression and MDA content increased. Taurine treatment significantly improved LV systolic and diastolic function, and there were persistent increases in activities of Akt/PKB and SOD, and the level of HO-1 protein. CONCLUSION: Taurine treatment ameliorates myocardial function and heart oxidant status, while increasing myocardial Akt/PKB phosphorylation, and HO-1 levels have beneficial effects on diabetic cardiomyopathy. PMID- 23630146 TI - Are physician-patient communication practices slowly changing in Croatia? -- a cross-sectional questionnaire study. AB - AIM: To explore physician-patient communication practices during the process of obtaining informed consent in a hospital setting in Croatia. METHODS: Two hundred and fifty patients (response rate 78%) from five tertiary level hospitals in Zagreb, Croatia, anonymously filled in the questionnaire on informed consent and communication practices by Nemcekova et al in the period from April to December 2011. RESULTS: Eighty five percent of patients received complete, understandable information, presented in a considerate manner. Patients in surgical departments received a higher level of information than those in internal medicine departments. Patients were informed about health risks of the proposed treatments (in 74% of cases) and procedures (76%), health consequences of refusing a medical intervention (69%), and other methods of treatment (46%). However, patients pointed out a number of problems in physician-patient communication. CONCLUSION: Communication practices during informed consent-obtaining process in hospitals in Zagreb are based on a model of shared decision-making, but paternalistic physician-patient relationship is still present. Our results indicate that Croatia is undergoing a transition in the physician-patient relationship and communication. PMID- 23630147 TI - Impact of extended course duration and stricter study organization on attrition and academic performance of medical students. AB - AIM: To assess whether extended medical school duration, block/modular structure of subjects, not allowing students to transfer exams into the higher course year, and curriculum implementation in line with the Bologna Accord are associated with lower attrition and better academic outcomes of medical students. METHODS: We retrospectively investigated curricula at the University of Split School of Medicine and academic outcomes of 2301 medical students during a 33-year period (1979-2011). The following data were obtained: grade point average (GPA) at the end of the studies, duration of studies, graduation on time, and whether the student graduated or not. RESULTS: After extension of medical curriculum from 5 to 6 years, students had significantly better grades (3.35 vs 3.68; P<0.001), shorter study duration (7.0 vs 6.0 years; P<0.001), and more students graduated on time (6.5% vs 57%; P<0.001). Changes in the 6-year curriculum, such as stricter study regulations and adoption of Bologna Accord, were associated with better indicators of students' academic success. The lowest attrition and the highest grades during the studied period were observed after the implementation of the Bologna Accord in 2005. CONCLUSION: Introduction of a longer medical curriculum, block/modular subject structure, stricter regulations of exam transfer, and curriculum in line with the Bologna Accord may contribute to better academic outcomes and lower attrition of medical students. PMID- 23630148 TI - Breech presentation and the cornual-fundal location of the placenta. AB - AIM: To investigate the association of cornual-fundal location of the placenta and breech presentation at term delivery. METHODS: This study was conducted at the Department of Obstetrics and Gynecology, Novi Sad, in 2011. The inclusion criteria were delivery at >=37 weeks of gestation, singleton gestation, and cornual-fundal location of the placenta determined by ultrasonography at >=37 weeks of gestation when 3/4 or more of the placenta was in the cornual-fundal region. RESULTS: Out of 2750 ultrasound examinations performed, 143 showed cornual-fundal location of the placenta (frequency 5.2%). Eighty six cases had cephalic presentation (60.14%) and 57 (39.86%) had breech presentation. Of the remaining cases with non- cornual-fundal location, 2585 had cephalic presentation and 22 (0.84%) had breech presentation. The difference in the frequency of breech presentation between the cornual-fundal and non-cornual-fundal groups was significant (chi(2)=77.78, P<0.001). CONCLUSION: Cornual-fundal location of the placenta may be an important clue in resolving the etiology of a number of cases of breech presentation at term delivery. PMID- 23630149 TI - Vaginal delivery through annular placenta -- case report. AB - Annular placenta is an extremely rare morphological type of human placenta. It is commonly related to placental vessel abnormalities frequently causing antenatal and postnatal hemorrhage and operative delivery. Gravida 4 para 1 had an uneventful course of pregnancy and normal vaginal delivery followed by moderate postpartum hemorrhage. Hemorrhage was found to be local in origin but the placenta was annular in shape and the newborn was delivered through one of the openings. Annular placenta was not recognized before delivery. Its implantation site was in the lower uterine segment but high enough to allow the passage of the fetus through its annular defect and vaginal birth. To our knowledge, this is a first report of annular placenta ending in normal vaginal delivery. PMID- 23630150 TI - Bio-objects' political capacity: a research agenda. AB - This article explores the merits of foregrounding the dichotomy of politicization vs de-politicization for our understanding of bio-objects in order to study their production, circulation, and governance in European societies. By asking how bio objects are configured in science, policy, public, and media discourses and practices, we focus on the role of socio-technical configurations in generating political relations. The bio-object thereby serves as an entry point to approach and conceptualize "the political" in an innovative way. PMID- 23630151 TI - Palliative care education in Zagreb -- an assessment of the effectiveness of an undergraduate course. PMID- 23630152 TI - Nanohinge-induced plasticity of helical carbon nanotubes. AB - Helical carbon nanotubes with intentionally incorporated non-hexagonal defects have unexpectedly high toughness and plasticity, in addition to the well recognized extreme elasticity. The obtained toughness approaches 5000 J g(-1) with decreasing spring radius. The high toughness originates from the plastic nanohinge formation as a result of distributed partial fractures. A strong spring size effect, contradictory to the continuum solution, is precisely described by an atomistic bond-breaking model. PMID- 23630153 TI - Curcumin acts as a pro-oxidant inducing apoptosis via JNKs in the isolated perfused Rana ridibunda heart. AB - Amphibians are known to better tolerate and endure adverse environmental conditions such as redox imbalances conferred by reactive oxygen species (ROS), compared to mammals. Interestingly, the exact adaptation strategies and signaling mechanisms mediating these effects have not been fully elucidated. Therefore, in the present study, we probed into the molecular response of the isolated perfused Rana ridibunda heart to curcumin, in the context of mitogen-activated protein kinases (MAPKs) phosphorylation patterns and apoptotic markers occurrence. In particular, this polyphenol was found to exert a pro-oxidant effect in our model and to significantly upregulate p38-MAPK and JNKs phosphorylation (thus activation). The early apoptosis observed, substantiated by poly(ADP-ribose) polymerase (PARP) cleavage, was established to be JNKs- and ROS-mediated, while no involvement of p38-MAPK was detected. Subsequently, the pro-oxidative activity of curcumin was confirmed to mimic H(2) O(2). Furthermore, NADPH oxidase as well as Na(+) /K(+) -ATPase were found to mediate JNKs phosphorylation as well as PARP proteolytic cleavage. Curcumin exerts pleiotropic actions, both beneficial and detrimental and is currently the subject of intense scientific research. Being a low-molecular-weight antioxidant, it is intriguing to investigate curcumin's role in redox homeostasis in the amphibian heart, under conditions that apparently favor its pro-oxidative properties. Comparative studies of its multifaceted role in different species may contribute to the clarification of the signaling mechanisms it triggers and the terminal physiological response it confers. Collectively, this is to our knowledge, the first time that the signal transduction pathways stimulated by curcumin have been assessed in a non mammalian species. PMID- 23630154 TI - Ultrastructure of the spermatozoon of the digenean Plagiorchis elegans (Rudolphi, 1802) (Plagiorchioidea, Plagiorchiidae). AB - The ultrastructure of the mature spermatozoon of the type genus of the Plagiorchiidae Plagiorchis elegans (Rudolphi, 1802), a parasite of the Golden hamster, Mesocricetus auratus is described. This study is the first ultrastructural study of the spermatozoon of a Plagiorchis, the second of a plagiorchiid species and only the third in the Plagiorchioidea. Previously data on spermatozoon ultrastructure existed only for the plagiorchiid Enodiotrema reductum and the omphalometrid Rubenstrema exasperatum. The mature spermatozoon of P. elegans exhibited the general pattern described in most digenean species, namely two axonemes of the 9 + "1" Trepaxonemata pattern, nucleus, mitochondria, external ornamentation of the plasma membrane, spine-like bodies, and glycogen granules. However, the rather typical expansion of the plasma membrane is not found in P. elegans. Another peculiarity of the spermatozoon of P. elegans is the presence of a structure called thin cytoplasm termination. Spermatozoon ultrastructure of P. elegans is compared with that of E. reductum and R. exasperatum. Spermatozoon of P. elegans conforms to the general pattern described in E. reductum. Thus, this study further expands our knowledge on the spermatozoon ultrastructure among the members of the Plagiorchioidea, one of the most phylogenetically derived groups of the digenea. PMID- 23630155 TI - Psychosocial predictors of four health-promoting behaviors for cancer prevention using the stage of change of Transtheoretical Model. AB - OBJECTIVES: The present study aimed to examine whether demographic as well as psychosocial variables related to the five stages of change of the Transtheoretical Model can predict non-clinical adults' cancer preventive and health-promoting behaviors. This study specifically focused on cancer, one of the major chronic diseases, which is a serious threat of national health. METHODS: A total of 1530 adults participated in the study and completed questionnaires. Collected data were analyzed by using multinominal logistic regression. RESULTS: The significant predictors of later stages varied among the types of health promoting behaviors. Certain cancer preventive health-promoting behaviors such as well-balanced diet and exercise were significantly associated with psychosocial variables including cancer prevention-related self-efficacy, personality traits, psychosocial stress, and social support. On the other hand, smoking cessation and moderate or abstinence from drinking were more likely to be predicted by demographic variables including sex and age. CONCLUSIONS: The present study found that in addition to self-efficacy-a relatively well-studied psychological variable-other personality traits and psychological factors including introversion, neuroticism, psychosocial stress, and social support also significantly predicted later stages of change with respect to cancer preventive health-promoting behaviors. The implications of this study are also discussed. PMID- 23630156 TI - In vivo probing of the temperature responses of intracellular biomolecules in yeast cells by label-free Raman microspectroscopy. AB - Environmental temperature is an essential physical quantity that substantially influences cell physiology by changing the equilibria and kinetics of biochemical reactions occurring in cells. Although it has been extensively used as a readily controllable parameter in genetic and biochemical research, much remains to be explored about the temperature responses of intracellular biomolecules in vivo and at the molecular level. Here we report in vivo probing, achieved with label free Raman microspectroscopy, of the temperature responses of major intracellular components such as lipids and proteins in living fission yeast cells. The characteristic Raman band at 1602 cm(-1), which has been attributed mainly to ergosterol, showed a significant decrease (~47 %) in intensity at elevated temperatures above 35 degrees C. In contrast to this high temperature sensitivity of the ergosterol Raman band, the phospholipid and protein Raman bands did not vary much with increasing culture temperature in the 26-38 degrees C range. This finding agrees with a previous biochemical study that showed that the initial stages of ergosterol biosynthesis in yeast are hindered by temperature elevation. Moreover, our result demonstrates that Raman microspectroscopy holds promise for elucidation of temperature-dependent cellular activities in living cells, with a high molecular specificity that the commonly used fluorescence microscopy cannot offer. PMID- 23630157 TI - Cross-linked g-C3 N4 /rGO nanocomposites with tunable band structure and enhanced visible light photocatalytic activity. AB - Cross-linked rather than non-covalently bonded graphitic carbon nitride (g-C3 N4 )/reduced graphene oxide (rGO) nanocomposites with tunable band structures have been successfully fabricated by thermal treatment of a mixture of cyanamide and graphene oxide with different weight ratios. The experimental results indicate that compared to pure g-C3 N4 , the fabricated CN/rGO nanocomposites show narrowed bandgaps with an increased in the rGO ratio. Furthermore, the band structure of the CN/rGO nanocomposites can be readily tuned by simply controlling the weight ratio of the rGO. It is found that an appropriate rGO ratio in nanocomposite leads to a noticeable positively shifted valence band edge potential, meaning an increased oxidation power. The tunable band structure of the CN/rGO nanocomposites can be ascribed to the formation of C-O-C covalent bonding between the rGO and g-C3 N4 layers, which is experimentally confirmed by Fourier transform infrared (FT-IR) and X-ray photoelectron (XPS) data. The resulting nanocomposites are evaluated as photocatalysts by photocatalytic degradation of rhodamine B (RhB) and 4-nitrophenol under visible light irradiation (lambda > 400 nm). The results demonstrate that the photocatalytic activities of the CN/rGO nanocomposites are strongly influenced by rGO ratio. With a rGO ratio of 2.5%, the CN/rGO-2.5% nanocomposite exhibits the highest photocatalytic efficiency, which is almost 3.0 and 2.7 times that of pure g-C3 N4 toward photocatalytic degradation of RhB and 4-nitrophenol, respectively. This improved photocatalytic activity could be attributed to the improved visible light utilization, oxidation power, and electron transport property, due to the significantly narrowed bandgap, positively shifted valence band-edge potential, and enhanced electronic conductivity. PMID- 23630158 TI - gamma-Ray-responsive supramolecular hydrogel based on a diselenide-containing polymer and a peptide. PMID- 23630159 TI - Pilot study of vincristine, oral irinotecan, and temozolomide (VOIT regimen) combined with bevacizumab in pediatric patients with recurrent solid tumors or brain tumors. AB - BACKGROUND: The combination of vincristine, oral irinotecan, and temozolomide (VOIT regimen) has shown antitumor activity in a pediatric Phase I trial. To further potentiate synergy, we assessed the safety and feasibility of adding bevacizumab to VOIT for children and young adults with recurrent tumors. METHODS: Patients received vincristine (1.5 mg/m(2) on day 1), oral irinotecan (90 mg/m(2) on days 1-5), temozolomide (100-150 mg/m(2) on days 1-5), and bevacizumab (15 mg/kg on day 1) in 3-week cycles, which were repeated for up to six cycles. Cefixime prophylaxis was used to reduce irinotecan-associated diarrhea. RESULTS: Thirteen patients received 36 total cycles. Six of the first 10 patients required dose reductions due to toxicity during the first cycle (n = 3) or subsequent cycles (n = 3), and these grade 3 side effects included prolonged nausea, dehydration, anorexia, neuropathy, diarrhea, and abdominal pain, as well as prolonged grade 4 neutropenia. After reducing daily temozolomide to 100 mg/m(2) , three additional patients tolerated therapy well without the need for dose reductions. Toxicities attributed to bevacizumab were limited to grade 1 epistaxis (1) and grade 2 proteinuria (1). Tumor responses were seen in both patients with Ewing sarcoma. CONCLUSIONS: Reducing temozolomide from 150 to 100 mg/m(2) /day improved tolerability, and treatment with this lower temozolomide dose was feasible and convenient as outpatient therapy. Although responses were seen in Ewing sarcoma, the benefit of adding bevacizumab remains unclear. PMID- 23630160 TI - Zac1 regulates astroglial differentiation of neural stem cells through Socs3. AB - Cell-fate decisions and differentiation of embryonic and adult neural stem cells (NSC) are tightly controlled by lineage-restricted and temporal factors that interact with cell-intrinsic programs and extracellular signals through multiple regulatory loops. Imprinted genes are important players in neurodevelopment and mental health although their molecular and cellular functions remain poorly understood. Here, we show that the paternally expressed transcriptional regulator Zac1 (zinc finger protein regulating apoptosis and cell cycle arrest) is transiently induced during astroglial and neuronal differentiation of embryonic and adult NSC lines. Thereby, Zac1 transactivates Socs3 (suppressor of cytokine signaling 3), a potent inhibitor of prodifferentiative Jak/Stat3 signaling, in a lineage-specific manner to prevent precocious astroglial differentiation. In vivo, Zac1 and Socs3 colocalize in the neocortical ventricular zone during incipient astrogliogenesis. Zac1 overexpression in primary NSCs delays astroglial differentiation whereas knockdown of Zac1 or Socs3 facilitates formation of astroglial cells. This negative feedback loop is unrelated to Zac1's cell cycle arrest function and specific to the Jak/Stat3 pathway. Hence, reinstating Jak/Stat3 signaling in the presence of increased Zac1 expression allows for timely astroglial differentiation. Overall, we suggest that the imprinted gene Zac1 curtails astroglial differentiation of NSCs in the developing and adult brain. PMID- 23630161 TI - Primary homologies of the circumorbital bones of snakes. AB - Some snakes have two circumorbital ossifications that in the current literature are usually referred to as the postorbital and supraorbital. We review the arguments that have been proposed to justify this interpretation and provide counter-arguments that reject those conjectures of primary homology based on the observation of 32 species of lizards and 81 species of snakes (both extant and fossil). We present similarity arguments, both topological and structural, for reinterpretation of the primary homologies of the dorsal and posterior orbital ossifications of snakes. Applying the test of similarity, we conclude that the posterior orbital ossification of snakes is topologically consistent as the homolog of the lacertilian jugal, and that the dorsal orbital ossification present in some snakes (e.g., pythons, Loxocemus, and Calabaria) is the homolog of the lacertilian postfrontal. We therefore propose that the terms postorbital and supraorbital should be abandoned as reference language for the circumorbital bones of snakes, and be replaced with the terms jugal and postfrontal, respectively. The primary homology claim for the snake "postorbital" fails the test of similarity, while the term "supraorbital" is an unnecessary and inaccurate application of the concept of a neomorphic ossification, for an element that passes the test of similarity as a postfrontal. This reinterpretation of the circumorbital bones of snakes is bound to have important repercussions for future phylogenetic analyses and consequently for our understanding of the origin and evolution of snakes. PMID- 23630163 TI - The mechanistic action of carbon dioxide on a neural circuit and NMJ communication. AB - Previous studies examining behavioral responses to CO(2) revealed that high [CO(2)] acts as a natural repellent in a concentration dependent manner for crayfish. Physiologically, CO(2) can rapidly block the autonomic responses in heart rate, as well as, inhibit an escape tail flip reflex in crayfish. Here, we demonstrate that the behavioral observations can be mechanistically explained by CO(2) blocking glutamate receptors at the neuromuscular junction and through inhibition of recruiting motor neurons within the CNS. The effects are not mimicked with a lower pH in the bathing solution. Since spontaneous and sensory evoked activities in the sensory root and motor neurons are reduced by CO(2), this is an anesthetic effect. We propose this is due to blockage of electrical synapses, as well as, some of the central glutamatergic-drive. We used agonists and antagonists (glutamate, nicotine, domoic acid, cadmium, heptanol) to various synaptic inputs, which are possibly present in the ventral nerve cord (VNC). Results from these chemicals supported the idea that there is electrical as well as chemical drive within the circuit that can modulate intrinsic as well as sensory evoked activity in the motor neurons. We have documented that CO(2) has actions in the periphery as well as in the CNS, to account for the behavioral responses previously shown. Furthermore, we document that gap junctions as well as glutamatergic synapses are potential targets. This study also aids in the dissection of a neural circuitry within the VNC that drives spontaneous and sensory evoked activity of the superficial flexor motor neurons. PMID- 23630164 TI - Adsorption of water on an MgSO4 (100) surface: a first-principles investigation. AB - The adsorption properties of water molecules on an MgSO4 (100) surface were investigated by using density functional theory (DFT) and supercell models. Optimized stable geometries of one and more than one water molecules adsorbed on an ideal MgSO4 (100) surface were obtained. The configurations with water molecules adsorbed on atoms of the second and third atomic layers of the MgSO4 (100) surface are quite stable. After adsorption, the separations between both the adjacent Mg atoms (R(Mg-Mg)) and the adjacent O atoms of the surface (R(O-O)) increase, which indicates that the MgSO4 (100) surface starts to deliquesce. In addition, water molecules are more likely to adsorb onto a defective surface rather than an ideal surface. Mulliken population analysis suggests that fewer charges transfer to the water molecule from the Mg atom of a defective substrate. Finally, Raman spectra were calculated for 0.5, 1, and 2 ML (ML=monolayer) water adsorbed on an MgSO4 (100) surface, which is helpful for further related experiments. PMID- 23630165 TI - Couples facing advanced cancer: examination of an interdependent relational system. AB - BACKGROUND: The relational impact of advanced cancer on both patients and spouse caregivers has rarely been examined simultaneously. This study describes a framework for understanding distress in each partner as a consequence of psychosocial characteristics, burden of disease or of caregiving, and the distress of the other person. A model focusing on the protective value of social relatedness was tested to illustrate the interdependence of patients and spouses in their mutual adaptation to disease. METHODS: A total of 278 advanced cancer patients and their spouse caregivers completed measures of psychological distress (e.g., depression), physical burden from cancer (e.g., symptom count), caregiving burden (i.e., time and task demand), and social relatedness (i.e., social support and attachment security). Structural equation modeling was used to extract latent factors associated with these constructs and to examine their interrelationships. RESULTS: The model fit was adequate. Patient distress was related to disease burden (standardized path coefficient = 0.52) and patient social relatedness ( 0.32). Caregiver distress was related to caregiving burden (0.21) and caregiver social relatedness (-0.51). Caregiving burden was related to patient disease burden (0.43) and caregiver social relatedness (-0.37). Reciprocal pathways between patient and caregiver distress indicated that caregiver distress was influenced by patient distress (0.30) but not vice versa (0.12). CONCLUSIONS: These findings support the view that patients and caregivers constitute an interdependent relational system and interventions in this setting should take into account both interactions between patients and caregivers and the nature of their social relatedness. PMID- 23630162 TI - Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette's disorder. AB - To evaluate the hypothesis that functionally over-expressing alleles of the serotonin transporter (SERT) gene (solute carrier family 6, member 4, SLC6A4) are present in Tourette's disorder (TD), just as we previously observed in obsessive compulsive disorder (OCD), we evaluated TD probands (N = 151) and controls (N = 858). We genotyped the refined SERT-linked polymorphic region 5-HTTLPR/rs25531 and the associated rs25532 variant in the SLC6A4 promoter plus the rare coding variant SERT isoleucine-to-valine at position 425 (I425V). The higher expressing 5-HTTLPR/rs25531 LA allele was more prevalent in TD probands than in controls (chi(2) = 5.75; P = 0.017; odds ratio [OR], 1.35); and, in a secondary analysis, surprisingly, it was significantly more frequent in probands who had TD alone than in those who had TD plus OCD (Fisher's exact test; P = 0.0006; OR, 2.29). Likewise, the higher expressing LAC haplotype (5-HTTLPR/rs25531/rs25532) was more frequent in TD probands than in controls (P = 0.024; OR, 1.33) and also in the TD alone group versus the TD plus OCD group (P = 0.0013; OR, 2.14). Furthermore, the rare gain-of-function SERT I425V variant was observed in 3 male siblings with TD and/or OCD and in their father. Thus, the cumulative count of SERT I425V becomes 1.57% in OCD/TD spectrum conditions versus 0.15% in controls, with a recalculated, family-adjusted significance of chi(2) = 15.03 (P < 0.0001; OR, 9.0; total worldwide genotyped, 2914). This report provides a unique combination of common and rare variants in one gene in TD, all of which are associated with SERT gain of function. Thus, altered SERT activity represents a potential contributor to serotonergic abnormalities in TD. The present results call for replication in a similarly intensively evaluated sample. (c) 2013 Movement Disorder Society. PMID- 23630166 TI - Prolonged inhibition of glioblastoma xenograft initiation and clonogenic growth following in vivo Notch blockade. AB - PURPOSE: To examine the effects of clinically relevant pharmacologic Notch inhibition on glioblastoma xenografts. EXPERIMENTAL DESIGN: Murine orthotopic xenografts generated from temozolomide-sensitive and -resistant glioblastoma neurosphere lines were treated with the gamma-secretase inhibitor MRK003. Tumor growth was tracked by weekly imaging, and the effects on animal survival and tumor proliferation were assessed, along with the expression of Notch targets, stem cell, and differentiation markers, and the biology of neurospheres isolated from previously treated xenografts and controls. RESULTS: Weekly MRK003 therapy resulted in significant reductions in growth as measured by imaging, as well as prolongation of survival. Microscopic examination confirmed a statistically significant reduction in cross-sectional tumor area and mitotic index in a MRK003 treated cohort as compared with controls. Expression of multiple Notch targets was reduced in the xenografts, along with neural stem/progenitor cell markers, whereas glial differentiation was induced. Neurospheres derived from MRK003 treated xenografts exhibited reduced clonogenicity and formed less aggressive secondary xenografts. Neurospheres isolated from treated xenografts remained sensitive to MRK003, suggesting that therapeutic resistance does not rapidly arise during in vivo Notch blockade. CONCLUSIONS: Weekly oral delivery of MRK003 results in significant in vivo inhibition of Notch pathway activity, tumor growth, stem cell marker expression, and clonogenicity, providing preclinical support for the use of such compounds in patients with malignant brain tumors. Some of these effects can persist for some time after in vivo therapy is complete. PMID- 23630168 TI - Visualization of oxygen consumption of single living cells by scanning electrochemical microscopy: the influence of the faradaic tip reaction. PMID- 23630167 TI - Frequent inactivation of cysteine dioxygenase type 1 contributes to survival of breast cancer cells and resistance to anthracyclines. AB - PURPOSE: Genome-wide DNA methylation analyses have identified hundreds of candidate DNA-hypermethylated genes in cancer. Comprehensive functional analyses provide an understanding of the biologic significance of this vast amount of DNA methylation data that may allow the determination of key epigenetic events associated with tumorigenesis. EXPERIMENTAL DESIGN: To study mechanisms of cysteine dioxygenase type 1 (CDO1) inactivation and its functional significance in breast cancer in a comprehensive manner, we screened for DNA methylation and gene mutations in primary breast cancers and analyzed growth, survival, and reactive oxygen species (ROS) production in breast cancer cells with restored CDO1 function in the context of anthracycline treatment. RESULTS: DNA methylation associated silencing of CDO1 in breast cancer is frequent (60%), cancer specific, and correlates with disease progression and outcome. CDO1 function can alternatively be silenced by repressive chromatin, and we describe protein damaging missense mutations in 7% of tumors without DNA methylation. Restoration of CDO1 function in breast cancer cells increases levels of ROS and leads to reduced viability and growth, as well as sensitization to anthracycline treatment. Priming with 5-azacytidine of breast cancer cells with epigenetically silenced CDO1 resulted in restored expression and increased sensitivity to anthracyclines. CONCLUSION: We report that silencing of CDO1 is a critical epigenetic event that contributes to the survival of oxidative-stressed breast cancer cells through increased detoxification of ROS and thus leads to the resistance to ROS-generating chemotherapeutics including anthracyclines. Our study shows the importance of CDO1 inactivation in breast cancer and its clinical potential as a biomarker and therapeutic target to overcome resistance to anthracyclines. PMID- 23630169 TI - A detailed experimental and theoretical study into the properties of C60 dumbbell junctions. AB - A combined experimental and theoretical investigation is carried out into the electrical transport across a fullerene dumbbell one-molecule junction. The newly designed molecule comprises two C60 s connected to a fluorene backbone via cyclopropyl groups. It is wired between gold electrodes under ambient conditions by pressing the tip of a scanning tunnelling microscope (STM) onto one of the C60 groups. The STM allows us to identify a single molecule before the junction is formed through imaging, which means unambiguously that only one molecule is wired. Once lifted, the same molecule could be wired many times as it was strongly fixed to the tip, and a high conductance state close to 10(-2) G0 is found. The results also suggest that the relative conductance fluctuations are low as a result of the low mobility of the molecule. Theoretical analysis indicates that the molecule is connected directly to one electrode through the central fluorene, and that to bind it to the gold fully it has to be pushed through a layer of adsorbates naturally present in the experiment. PMID- 23630170 TI - Clinical prediction models for anthracycline-associated cardiotoxicity among pediatric cancer survivors--ready for prime time? PMID- 23630171 TI - Electron-dense lamellated inclusions in 2 siblings with Kufor-Rakeb syndrome. PMID- 23630172 TI - Functional nasal morphology of chimaerid fishes. AB - Holocephalans (chimaeras) are a group of marine fishes comprising three families: the Callorhinchidae (callorhinchid fishes), the Rhinochimaeridae (rhinochimaerid fishes) and the Chimaeridae (chimaerid fishes). We have used X-ray microcomputed tomography and magnetic resonance imaging to characterise in detail the nasal anatomy of three species of chimaerid fishes: Chimaera monstrosa, C. phantasma and Hydrolagus colliei. We have shown that the nasal chamber of these three species is linked to the external environment by an incurrent channel and to the oral cavity by an excurrent channel via an oral groove. A protrusion of variable morphology is present on the medial wall of the incurrent channel in all three species, but is absent in members of the two other holocephalan families that we inspected. A third nasal channel, the lateral channel, functionally connects the incurrent nostril to the oral cavity, by-passing the nasal chamber. From anatomical reconstructions, we have proposed a model for the circulation of water, and therefore the transport of odorant, in the chimaerid nasal region. In this model, water could flow through the nasal region via the nasal chamber or the lateral channel. In either case, the direction of flow could be reversed. Circulation through the entire nasal region is likely to be driven primarily by the respiratory pump. We have identified several anatomical features that may segregate, distribute, facilitate and regulate flow in the nasal region and have considered the consequences of flow reversal. The non-sensory cilia lining the olfactory sensory channels appear to be mucus-propelling, suggesting that these cilia have a common protective role in cartilaginous fishes (sharks, rays and chimaeras). The nasal region of chimaerid fishes shows at least two adaptations to a benthic lifestyle, and suggests good olfactory sensitivity, with secondary folding enhancing the hypothetical flat sensory surface area by up to 70%. PMID- 23630173 TI - Target innervation is necessary for neuronal polyploidization in the terrestrial slug Limax. AB - The brain of gastropod mollusks contains many giant neurons with polyploid genomic DNAs. Such DNAs are generated through repeated DNA endoreplication during body growth. However, it is not known what triggers DNA endoreplication in neurons. There are two possibilities: (1) DNAs are replicated in response to some unknown molecules in the hemolymph that reflect the nutritive status of the animal; or (2) DNAs are replicated in response to some unknown factors that are retrogradely transported through axons from the innervated target organs. We first tested whether hemolymph with rich nutrition could induce DNA endoreplication. We tested whether the transplanted brain exhibits enhanced DNA endoreplication like an endogenous brain does when transplanted into the homocoel of the body of a slug whose body growth is promoted by an increased food supply. However, no enhancement was observed in the frequency of DNA endoreplication when we compared the transplanted brains in the growth-promoted and growth-suppressed host slugs, suggesting that the humoral environment is irrelevant to triggering the body growth-dependent DNA endoreplication. Next, we tested the requirement of target innervation by surgically dissecting a unilateral posterior pedal nerve of an endogenous brain. Substantially lower number of neurons exhibited DNA endoreplication in the pedal ganglion ipsilateral to the dissected nerve. These results support the view that enhanced DNA endoreplication is mediated by target innervation and is not brought about through the direct effect of humoral factors in the hemolymph during body growth. PMID- 23630174 TI - Brief report: impaired cell reprogramming in nonhomologous end joining deficient cells. AB - Although there is an increasing interest in defining the role of DNA damage response mechanisms in cell reprogramming, the relevance of proteins participating in nonhomologous end joining (NHEJ), a major mechanism of DNA double-strand breaks repair, in this process remains to be investigated. Herein, we present data related to the reprogramming of primary mouse embryonic fibroblasts (MEF) from severe combined immunodeficient (Scid) mice defective in DNA-PKcs, a key protein for NHEJ. Reduced numbers of induced pluripotent stem cell (iPSC) colonies were generated from Scid cells using reprogramming lentiviral vectors (LV), being the reprogramming efficiency fourfold to sevenfold lower than that observed in wt cells. Moreover, these Scid iPSC-like clones were prematurely lost or differentiated spontaneously. While the Scid mutation neither reduce the proliferation rate nor the transduction efficacy of fibroblasts transduced with reprogramming LV, both the expression of SA-beta-Gal and of P16/INK(4a) senescence markers were highly increased in Scid versus wt MEFs during the reprogramming process, accounting for the reduced reprogramming efficacy of Scid MEFs. The use of improved Sleeping Beauty transposon/transposase systems allowed us, however, to isolate DNA-PKcs-deficient iPSCs which preserved their parental genotype and hypersensitivity to ionizing radiation. This new disease-specific iPSC model would be useful to understand the physiological consequences of the DNA-PKcs mutation during development and would help to improve current cell and gene therapy strategies for the disease. PMID- 23630175 TI - RUbioSeq: a suite of parallelized pipelines to automate exome variation and bisulfite-seq analyses. AB - MOTIVATION: RUbioSeq has been developed to facilitate the primary and secondary analysis of re-sequencing projects by providing an integrated software suite of parallelized pipelines to detect exome variants (single-nucleotide variants and copy number variations) and to perform bisulfite-seq analyses automatically. RUbioSeq's variant analysis results have been already validated and published. AVAILABILITY: http://rubioseq.sourceforge.net/. PMID- 23630176 TI - BioBlend: automating pipeline analyses within Galaxy and CloudMan. AB - We present BioBlend, a unified API in a high-level language (python) that wraps the functionality of Galaxy and CloudMan APIs. BioBlend makes it easy for bioinformaticians to automate end-to-end large data analysis, from scratch, in a way that is highly accessible to collaborators, by allowing them to both provide the required infrastructure and automate complex analyses over large datasets within the familiar Galaxy environment. AVAILABILITY AND IMPLEMENTATION: http://bioblend.readthedocs.org/. Automated installation of BioBlend is available via PyPI (e.g. pip install bioblend). Alternatively, the source code is available from the GitHub repository (https://github.com/afgane/bioblend) under the MIT open source license. The library has been tested and is working on Linux, Macintosh and Windows-based systems. PMID- 23630177 TI - Intervention in gene regulatory networks with maximal phenotype alteration. AB - MOTIVATION: A basic issue for translational genomics is to model gene interaction via gene regulatory networks (GRNs) and thereby provide an informatics environment to study the effects of intervention (say, via drugs) and to derive effective intervention strategies. Taking the view that the phenotype is characterized by the long-run behavior (steady-state distribution) of the network, we desire interventions to optimally move the probability mass from undesirable to desirable states Heretofore, two external control approaches have been taken to shift the steady-state mass of a GRN: (i) use a user-defined cost function for which desirable shift of the steady-state mass is a by-product and (ii) use heuristics to design a greedy algorithm. Neither approach provides an optimal control policy relative to long-run behavior. RESULTS: We use a linear programming approach to optimally shift the steady-state mass from undesirable to desirable states, i.e. optimization is directly based on the amount of shift and therefore must outperform previously proposed methods. Moreover, the same basic linear programming structure is used for both unconstrained and constrained optimization, where in the latter case, constraints on the optimization limit the amount of mass that may be shifted to 'ambiguous' states, these being states that are not directly undesirable relative to the pathology of interest but which bear some perceived risk. We apply the method to probabilistic Boolean networks, but the theory applies to any Markovian GRN. AVAILABILITY: Supplementary materials, including the simulation results, MATLAB source code and description of suboptimal methods are available at http://gsp.tamu.edu/Publications/supplementary/yousefi13b. CONTACT: edward@ece.tamu.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23630179 TI - Association between natriuretic peptides and mortality among patients admitted with myocardial infarction: a report from the ACTION Registry(R)-GWTGTM. AB - BACKGROUND: Patients with increased blood concentrations of natriuretic peptides (NPs) have poor cardiovascular outcomes after myocardial infarction (MI). The objectives of this analysis were to evaluate the utilization and the prognostic value of NP in a large, real-world MI cohort. METHODS: Data from 41 683 patients with non-ST-segment elevation MI (NSTEMI) and 27 860 patients with ST-segment elevation MI (STEMI) at 309 US hospitals were collected as part of the ACTION Registry(r)-GWTGTM (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get with the Guidelines) (AR-G) between July 2008 and September 2009. RESULTS: B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) was measured in 19 528 (47%) of NSTEMI and 9220 (33%) of STEMI patients. Patients in whom NPs were measured were older and had more comorbidities, including prior heart failure or MI. There was a stepwise increase in the risk of in-hospital mortality with increasing BNP quartiles for both NSTEMI (1.3% vs 3.2% vs 5.8% vs 11.1%) and STEMI (1.9% vs 3.9% vs 8.2% vs 17.9%). The addition of BNP to the AR-G clinical model improved the C statistic from 0.796 to 0.807 (P < 0.001) for NSTEMI and from 0.848 to 0.855 (P = 0.003) for STEMI. The relationship between NPs and mortality was similar in patients without a history of heart failure or cardiogenic shock on presentation and in patients with preserved left ventricular function. CONCLUSIONS: NPs are measured in almost 50% of patients in the US admitted with MI and appear to be used in patients with more comorbidities. Higher NP concentrations were strongly and independently associated with in hospital mortality in the almost 30 000 patients in whom NPs were assessed, including patients without heart failure. PMID- 23630180 TI - The influence of dispositional optimism on post-visit anxiety and risk perception accuracy among breast cancer genetic counselees. AB - OBJECTIVE: Much is unknown about the influence of dispositional optimism and affective communication on genetic counselling outcomes. This study investigated the influence of counselees' optimism on the counselees' risk perception accuracy and anxiety, while taking into account the affective communication during the first consultation for breast cancer genetic counselling. METHODS: Counselees completed questionnaires measuring optimism, anxiety and the perceived risk that hereditary breast cancer runs in the family before, and anxiety and perceived risk after the first consultation. Consultations were videotaped. The duration of eye contact was measured, and verbal communication was rated using the Roter Interaction Analysis System. RESULTS: Less-optimistic counselees were more anxious post-visit (beta = -.29; p = .00). Counsellors uttered fewer reassuring statements if counselees were more anxious (beta = -.84; p = .00) but uttered more reassurance if counselees were less optimistic (beta = -.76; p = .01). Counsellors expressed less empathy if counselees perceived their risk as high (beta = -1.51; p = .04). An increase in the expression of reassurance was related to less post-visit anxiety (beta = -.35; p = .03). More empathy was related to a greater overestimation of risk (beta = .92; p = .01). CONCLUSIONS: Identification of a lack of optimism as a risk factor for high anxiety levels enables the adaptation of affective communication to improve genetic counselling outcomes. Because reassurance was related to less anxiety, beneficial adaptation is attainable by increasing counsellors' reassurance, if possible. Because of a lack of optimally adapted communication in this study, further research is needed to clarify how to increase counsellors' ability to adapt to counselees. PMID- 23630181 TI - Extracellular electron transfer across bacterial cell membranes via a cytocompatible redox-active polymer. AB - A redox-active phospholipid polymer with a phospholipid-mimicking structure (2 methacryloyloxyethyl phosphorylcholine; MPC) was synthesized to construct a biocompatible electron mediator between bacteria and an electrode. In this study, a copolymer of MPC and vinylferrocene [VF; poly(MPC-co-VF)] (PMF) is synthesized. When PMF is added to cultures of the bacterial species Escherichia coli (Gram negative) and Lactobacillus plantarum (Gram positive), which have different cell wall structures, a catalytic current mediated by PMF is observed. In addition, growth curves and live/dead assays indicate that PMF does not decrease metabolic activity or cell viability. These results indicate that PMF mediates extracellular electron transfer across bacterial cell membranes without associated cytotoxicity. PMID- 23630182 TI - Heterostructured calcium carbonate microspheres with calcite equatorial loops and vaterite spherical cores. PMID- 23630183 TI - Adenovirus pneumonia during induction therapy for childhood acute lymphoblastic leukemia. PMID- 23630184 TI - Effective protein extraction protocol for proteomics studies of Jerusalem artichoke leaves. AB - Protein extraction is a crucial step for proteomics studies. To establish an effective protein extraction protocol suitable for two-dimensional electrophoresis (2DE) analysis in Jerusalem artichoke (Helianthus tuberosus L.), three different protein extraction methods-trichloroacetic acid/acetone, Mg/NP 40, and phenol/ammonium acetate-were evaluated using Jerusalem artichoke leaves as source materials. Of the three methods, trichloroacetic acid/acetone yielded the best protein separation pattern and highest number of protein spots in 2DE analysis. Proteins highly abundant in leaves, such as Rubisco, are typically problematic during leaf 2DE analysis, however, and this disadvantage was evident using trichloroacetic acid/acetone. To reduce the influence of abundant proteins on the detection of low-abundance proteins, we optimized the trichloroacetic acid/acetone method by incorporating a PEG fractionation approach. After optimization, 363 additional (36.2%) protein spots were detected on the 2DE gel. Our results suggest that trichloroacetic acid/acetone method is a better protein extraction technique than Mg/NP-40 and phenol/ammonium acetate in Jerusalem artichoke leaf 2DE analysis, and that trichloroacetic acid/acetone method combined with PEG fractionation procedure is the most effective approach for leaf 2DE analysis of Jerusalem artichoke. PMID- 23630185 TI - Effect of expectancy and personality on cortical excitability in Parkinson's disease. AB - Our previous studies in Parkinson's disease have shown that both levodopa and expectancy of receiving levodopa reduce cortical excitability. We designed this study to evaluate how degree of expectancy and other individual factors modulate placebo response in Parkinson's patients. Twenty-six Parkinson's patients were randomized to 1 of 3 groups: 0%, 50%, and 100% expectancy of receiving levodopa. All subjects received placebo regardless of expectancy group. Subjects completed the NEO-Five Factor Inventory, General Perceived Self-Efficacy Scale, and Perceived Stress Scale. Cortical excitability was measured by the amplitude of motor-evoked potential (MEP) evoked by transcranial magnetic stimulation. Objective physical fatigue of extensor carpi radialis before and after placebo levodopa was also measured. Responders were defined as subjects who responded to the placebo levodopa with a decrease in MEP. Degree of expectancy had a significant effect on MEP response (P < .05). Subjects in the 50% and 100% expectancy groups responded with a decrease in MEP, whereas those in the 0% expectancy group responded with an increase in MEP (P < .05). Responders tended to be more open to experience than nonresponders. There were no significant changes in objective physical fatigue between the expectancy groups or between responders and nonresponders. Expectancy is associated with changes in cortical excitability. Further studies are needed to examine the relationship between personality and placebo effect in Parkinson's patients. (c) 2013 Movement Disorder Society. PMID- 23630186 TI - CXC chemokine receptor 4 is essential for maintenance of renal cell carcinoma initiating cells and predicts metastasis. AB - In many solid tumors, cancer stem cells (CSC) represent a population with tumor initiating, self-renewal, and differentiation potential, which can be identified by surface protein markers. No generally applicable markers are yet known for renal cell carcinoma (RCC). Two RCC cell lines (RCC-26, RCC-53) were found to differ widely in their capacity to form spheres in vitro and to establish tumors in mice, potentially reflecting differences in CSC content. A subpopulation expressing the CXC chemokine receptor 4 (CXCR4) was present only in the more tumorigenic cell line RCC-53. When grown as spheres, most of the RCC-53 cells were CXCR4-positive, expressed stem cell-associated transcription factor genes at elevated levels, and were more resistant toward the tyrosine kinase inhibitors sunitinib, sorafenib, and pazopanib. Sorted CXCR4-positive cells exhibited greater capacity for sphere formation and tumor growth-inducing potential in vivo than CXCR4-negative cells. Significantly, higher CXCR4 mRNA levels in primary RCC tumors from patients with localized but not disseminated disease predicted shorter survival. Downregulation of CXCR4 expression by small interfering RNA (siRNA) or pharmacological inhibition by AMD3100 compromised tumor sphere formation, viability of CXCR4-positive cells, and increased their responsiveness toward tyrosine kinase inhibitors. In conclusion, CXCR4 identifies a subpopulation of tumor-initiating cells in RCC cell lines and plays a role in their maintenance. The relative insensitivity of such cells to tyrosine kinase inhibitors might contribute to the development of therapy resistance in RCC patients. Future therapies therefore could combine blockade of the CXCR4 signaling pathway with standard therapies for more effective treatments of metastatic RCC. PMID- 23630187 TI - Planning a personalised future with dementia: 'the misleading simplicity of advance directives'. PMID- 23630188 TI - Association between patient dignity and anxiety in geriatric palliative care. PMID- 23630189 TI - Case report of flipper anatomic anomaly of Sotalia guianensis from Sepetiba Bay, Rio de Janeiro. AB - The cetacean flipper consists of a soft tissue that encases most of the forelimb containing humerus, radius, ulna, carpals, metacarpals, and phalanges. Several studies have documented the typical cetacean's flipper anatomy, but only a few described digital anomalies and the most common are fusions and supernumerary such as polydactily and polyphalangy. The flippers of the Guiana dolphin, Sotalia guianensis have a falciform general aspect showing individual differences and marks produced by individual contact in social interactions that mainly occur on the posterior border. Here, we report for the first time a case of flippers with anatomical anomalies of loss of digits and deviation of radius of an adult S. guianensis from Baia de Sepetiba (22 degrees 54'-23 degrees 04', 43 degrees 36' 44 degrees 02'W), Rio de Janeiro, Southeastern Brazil. PMID- 23630190 TI - Evaluating the COSMO-RS method for modeling hydrogen bonding in solution. AB - The ability of the Conductor-like Screening Model for Realistic Solvation (COSMO RS) computational method to model hydrogen bond (HB) formation in solution is examined by comparing computational data with experimental data from literature. This is the first study of this kind where mixed solvents are also involved. Hydrogen bond formation is examined between neutral molecules, between acids and their anions, and between various anion receptor molecules and different anions in a number of aprotic solvents. HB formation equilibrium constants, the corresponding Gibbs' free energies and, when available from the literature, enthalpies were calculated. The supermolecule (SM) approach and the contact probability (CP) approach were used. Both in the case of the SM and CP approach, good to very good correlations between the experiment and computations are found for complexes formed from neutral species, enabling quantitative predictions. When the HB acceptor is an anion, the correlations are poor and in some cases even qualitative predictions fail. PMID- 23630191 TI - Limited renal prophylaxis in regular plasmatherapy for heritable ADAMTS13 deficiency. PMID- 23630192 TI - Dispersive liquid-phase microextraction in combination with HPLC for the enrichment and rapid determination of benzoylurea pesticides in environmental water samples. AB - Benzoylurea (BU) insecticides have contributed greatly to the output of crops. Their residue in the environment put serious threats on human health and environmental safety. In this study, we have established a new, rapid, and reliable method for the monitoring of typical BU insecticides such as diflubenzuron, flufenoxuron, triflumuron, and chlorfluazuron with dispersive liquid-liquid microextraction prior to HPLC. Chlorobenzene and ethanol were employed as the extraction solvent and disperser solvent, respectively. The possible parameters which would influence the extraction efficiency such as the kinds and volumes of extraction and disperser solvents, extraction time, sample pH, centrifuging time, and salting-out effect were optimized in detail. Under the optimal conditions, the linear range of proposed method was in the range of 1.0 70 MUg/L. The detection limits varied from 0.24 to 0.82 MUg/L and the precision of the method was <6.5% (RSD, n = 6). The proposed method was validated with real water samples and satisfactory spiked recoveries were achieved. All these results indicate that the proposed method is a low cost, easy to operate, efficient, and sensitive method for the analysis of BU insecticides in water samples. PMID- 23630193 TI - Astrocytic adenosine 5'-triphosphate release regulates the proliferation of neural stem cells in the adult hippocampus. AB - Astrocytes are key components of the niche for neural stem cells (NSCs) in the adult hippocampus and play a vital role in regulating NSC proliferation and differentiation. However, the exact molecular mechanisms by which astrocytes modulate NSC proliferation have not been identified. Here, we identified adenosine 5'-triphosphate (ATP) as a proliferative factor required for astrocyte mediated proliferation of NSCs in the adult hippocampus. Our results indicate that ATP is necessary and sufficient for astrocytes to promote NSC proliferation in vitro. The lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficient ATP release from astrocytes. This deficiency led to a dysfunction in NSC proliferation that could be rescued via the administration of exogenous ATP. Moreover, P2Y1-mediated purinergic signaling is involved in the astrocyte promotion of NSC proliferation. As adult hippocampal neurogenesis is potentially involved in major mood disorder, our results might offer mechanistic insights into this disease. PMID- 23630194 TI - Seasonal changes in the activity of the adrenal medulla of Viscacha (Lagostomus maximus maximus). AB - Animals living in nontropical climates modify their physiology and behavior to adapt to seasonal environmental changes. Part of this adaptation involves the release of catecholamine from sympathetic nerve endings and the adrenal medulla, which play a major role in regulating energy balance. The aim of this work was to investigate whether adult male viscachas in their natural habitat exhibits structural changes in the adrenal medulla during the annual seasonal cycle. In August-September, chromaffin granules revealed ultrastructural changes suggestive of piecemeal degranulation. Quantitative morphometric analysis by transmission electron microscopy showed a significantly lower percentage of resting chromaffin granules and a higher percentage of altered granules and empty containers in August-September (late winter) compared to February-March (late summer), suggesting an increased secretory process of catecholamines in August-September. The mechanism of piecemeal degranulation might amplify this process, encouraging the adaptive response to winter environmental conditions. Tissue levels of epinephrine, norepinephrine, and dopamine (analyzed by high-performance liquid chromatography) changed throughout the year, reaching maximum values in February March and minimum values in August-September. These results demonstrate morphological and biochemical seasonal variations of the adrenal medulla, suggesting that epinephrine might promote energy mobilization, which allow the Lagostomus to cope with adverse environmental conditions and thus to survive during winter season. PMID- 23630195 TI - Recent methodological advances in the analysis of protein tyrosine nitration. AB - Tyrosine nitration is a common post-translational modification affecting protein structure and function. It is based on the addition of a -NO2 group at the ortho position of the phenolic hydroxyl group of tyrosine to yield 3-nitrotyrosine (3 NTyr). Understanding how tyrosine nitration affects the structure and functionality of proteins is of considerable interest, as it is associated with pathogenesis in diseases related to oxidative stress in all living organisms. There are several methods to nitrate tyrosine residues in native proteins. Among them, nitration by the chemical agent peroxynitrite stands out for its biological relevance. Recently, a genetically evolved suppressor tRNA has been developed to provide in vivo incorporation of 3-NTyr into proteins. In this minireview, we discuss the advantages and limitations of these chemical and biological methods and propose a non-damaging method to analyze the configuration and dynamics of nitrotyrosine residues in native proteins by NMR spectroscopy. PMID- 23630196 TI - The use of extracorporeal membrane oxygenation in pediatric patients with sickle cell disease. AB - Previous reports have described the use of extracorporeal membrane oxygenation (ECMO) for acute chest syndrome of sickle cell disease (SCD). However, there have been no reports of venoarterial (VA) ECMO for cardiac dysfunction in patients with SCD. We describe a patient with SCD and life-threatening cardiogenic shock who was successfully treated with VA ECMO. Furthermore, SCD patients have unique comorbidities that warrant particular consideration when utilizing ECMO. We discuss these considerations and review the documented experience with ECMO for pediatric SCD patients from the Extracorporeal Life Support Organization (ELSO) registry. From 1990 until 2012, 52% of the 65 pediatric patients with SCD placed on ECMO survived, with 85% of those receiving venovenous (VV) ECMO surviving and 43% of those receiving VA ECMO surviving. However, significant complications, such as bleeding, neurological injury and kidney injury, also occurred with both VV and VA ECMO. Ten percent of SCD patients receiving VA ECMO experienced either a cerebral infarct or hemorrhage; our patient suffered a cerebrovascular accident while on ECMO, though she survived with good neurologic outcome. To our knowledge, this is the first report of a pediatric patient with SCD and cardiogenic shock successfully managed with VA ECMO. In conjunction with the ELSO registry review, this case report suggests that, while VA ECMO can be successfully used in patients with SCD and severe cardiovascular dysfunction, clinicians should also be aware of the potential for serious complications in this high-risk population. PMID- 23630197 TI - Are any biocompatible coatings capable of attenuating the deleterious effects of cardiopulmonary bypass? AB - BACKGROUND: Biocompatible circuits (BCC) are intended to decrease the activation of blood to the artificial cardiopulmonary bypass (CPB) surface. Typically, the coatings are made of various inert substances or molecules physiologically similar to endothelium. Thromboelastography (TEG) graphically represents clot formation, strength of clotting and fibrinolysis. TEG analysis was undertaken to determine if coagulation could be preserved by the BCC. METHODS: Five different BCC were studied in clinical applications. These five coated circuits were then compared to an identical circuit where only the oxygenator was coated. A pre- and post-bypass TEG was done for comparison. Six well-studied parameters of TEG analysis were compared: R time, angle, K, maximum amplitude (MA), LY30% and Clot Index (CI). Postoperative bleeding and transfusion requirements were compared to TEG results for comparison. RESULTS: All postoperative TEG results were significantly different from preoperative parameters except LY30%. No BCC circuit was able to prevent the significant disruption of the observed TEG coagulation parameters R, K, angle, MA and CI. Of note, the postoperative TEG parameters resulting from the Control and Trillium groups--which had the same type of oxygenator - were practically identical. The oxygenator, which represents the largest surface area in the CPB circuit, is the single most important factor influencing coagulation. CONCLUSION: While not harmful, BCC are ineffective in preserving TEG coagulation parameters post CPB. Clinical findings support laboratory TEG results in that there were no differences in bleeding or transfusion requirements between groups. PMID- 23630199 TI - Geminin restrains mesendodermal fate acquisition of embryonic stem cells and is associated with antagonism of Wnt signaling and enhanced polycomb-mediated repression. AB - Embryonic cells use both growth factor signaling and cell intrinsic transcriptional and epigenetic regulation to acquire early cell fates. Underlying mechanisms that integrate these cues are poorly understood. Here, we investigated the role of Geminin, a nucleoprotein that interacts with both transcription factors and epigenetic regulatory complexes, during fate acquisition of mouse embryonic stem cells. In order to determine Geminin's role in mesendoderm formation, a process which occurs during embryonic gastrulation, we selectively over-expressed or knocked down Geminin in an in vitro model of differentiating mouse embryonic stem cells. We found that Geminin antagonizes mesendodermal fate acquisition, while these cells instead maintain elevated expression of genes associated with pluripotency of embryonic stem cells. During mesendodermal fate acquisition, Geminin knockdown promotes Wnt signaling, while Bmp, Fgf, and Nodal signaling are not affected. Moreover, we showed that Geminin facilitates the repression of mesendodermal genes that are regulated by the Polycomb repressor complex. Geminin directly binds several of these genes, while Geminin knockdown in mesendodermal cells reduces Polycomb repressor complex occupancy at these loci and increases trimethylation of histone H3 lysine 4, which correlates with active gene expression. Together, these results indicate that Geminin is required to restrain mesendodermal fate acquisition of early embryonic cells and that this is associated with both decreased Wnt signaling and enhanced Polycomb repressor complex retention at mesendodermal genes. PMID- 23630201 TI - Self-reported conflicts of interest of authors, trial sponsorship, and the interpretation of editorials and related phase III trials in oncology. AB - PURPOSE: Growing participation by industry in cancer research has resulted in increased reporting of conflicts of interest (COI). We aimed to test any association between authors' conclusions and self-reported COI or trial sponsorship in cancer studies. METHODS: Editorials and related phase III trials published in six clinical oncology journals in the last 3.5 years were analyzed independently by two investigators who classified study conclusions according to authors' endorsement of the experimental therapy. Logistic regression multivariable models were used to assess predictors of favorable conclusions of editorialists and of phase III authors. RESULTS: From January 2008 to October 2011, 1,485 articles were retrieved: 150 phase III trials and 150 editorials were eligible. Among the phase III trials, 82 (54.7%) had positive results, and 78 (52.0%) were entirely or partially funded by industry. Any COI were disclosed in 103 phase III trials (68.7%) and in 71 editorials (47.3%). Multivariable analysis showed that phase III trial results were the only significant predictor for a positive conclusion by trial authors (odds ratio [OR], 92.2; 95% CI, 19.7 to 431.6; P < .001). Sponsorship did not predict for positive conclusion by phase III authors (OR, 0.86; 95% CI, 0.3 to 2.5; P = .788). The only factor associated with positive conclusions by editorial authors was a positive conclusion by phase III trial authors (OR, 36.3; 95% CI, 6.8 to 194.2; P < .001). CONCLUSION: The interpretation of recently published phase III cancer trials by their authors or by editorialists was not influenced by financial relationships or industry sponsorship. Increased awareness of COI policies may have led to more integrity in cancer research reporting. PMID- 23630200 TI - Cediranib for metastatic alveolar soft part sarcoma. AB - PURPOSE: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs). PATIENTS AND METHODS: We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging. RESULTS: Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis. CONCLUSION: In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib. PMID- 23630198 TI - MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome enriched extracellular particles. AB - To test, in vivo, the hypothesis that exosomes from multipotent mesenchymal stromal cells (MSCs) mediate microRNA 133b (miR-133b) transfer which promotes neurological recovery from stroke, we used knockin and knockdown technologies to upregulate or downregulate the miR-133b level in MSCs (miR-133b(+) MSCs or miR 133b(-) MSCs) and their corresponding exosomes, respectively. Rats were subjected to middle cerebral artery occlusion (MCAo) and were treated with naive MSCs, miR 133b(+) MSCs, or miR-133b(-) MSC at 1 day after MCAo. Compared with controls, rats receiving naive MSC treatment significantly improved functional recovery and exhibited increased axonal plasticity and neurite remodeling in the ischemic boundary zone (IBZ) at day 14 after MCAo. The outcomes were significantly enhanced with miR-133b(+) MSC treatment, and were significantly decreased with miR-133b(-) MSC treatment, compared to naive MSC treatment. The miR-133b level in exosomes collected from the cerebral spinal fluid was significantly increased after miR-133b(+) MSC treatment, and was significantly decreased after miR-133b( ) MSC treatment at day 14 after MCAo, compared to naive MSC treatment. Tagging exosomes with green fluorescent protein demonstrated that exosomes-enriched extracellular particles were released from MSCs and transferred to adjacent astrocytes and neurons. The expression of selective targets for miR-133b, connective tissue growth factor and ras homolog gene family member A, was significantly decreased in the IBZ after miR-133b(+) MSC treatment, while their expression remained at similar elevated levels after miR-133b(-) MSC treatment, compared to naive MSC treatment. Collectively, our data suggest that exosomes from MSCs mediate the miR-133b transfer to astrocytes and neurons, which regulate gene expression, subsequently benefit neurite remodeling and functional recovery after stroke. PMID- 23630202 TI - Epstein-Barr virus-induced secondary high-grade transformation of Sjogren's syndrome-related mucosa-associated lymphoid tissue lymphoma. PMID- 23630203 TI - The future of drug development? Seeking evidence of activity of novel drugs in small groups of patients. PMID- 23630204 TI - Strategies for relapsed peripheral T-cell lymphoma: the tail that wags the curve. AB - A 69-year-old woman was referred for further evaluation and management of relapsed angioimmunoblastic T-cell lymphoma. At diagnosis, she received six cycles of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and achieved a complete response (CR). Her first surveillance computed tomography scan 3 months later demonstrated enlarging cervical lymphadenopathy. A lymph node excision confirmed relapsed angioimmunoblastic T-cell lymphoma with atypical lymphocytes expressing CD3, CD4, CD10, PD-1, and EBER, with loss of CD5 (Fig 1). A clonal T-cell receptor beta and gamma rearrangement by polymerase chain reaction was identical to that in her initial diagnostic biopsy. At our initial consultation, options for standard as well as investigational therapies were discussed, and HLA typing was initiated. The patient was enrolled onto an investigational phase II study; however, she developed progressive disease after two cycles. She was then treated with romidepsin 14 mg/m(2) administered intravenously for 3 consecutive weeks with 1 week off. After two cycles, she achieved a partial response, and after four additional cycles, she maintained her response without further improvement. We discussed additional treatment options. PMID- 23630205 TI - Efficacy of ruxolitinib in chronic eosinophilic leukemia associated with a PCM1 JAK2 fusion gene. PMID- 23630206 TI - Financial disclosure, industry sponsorship, and integrity in cancer research reporting. PMID- 23630207 TI - Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small cell lung cancer. AB - PURPOSE: Characterization of the genomic changes that drive an individual patient's disease is critical in management of many cancers. In patients with non small-cell lung cancer (NSCLC), obtaining tumor samples of sufficient size for genomic profiling on recurrence is often challenging. We undertook this study to compare genomic alterations identified in archived primary tumors from patients with NSCLC with those identified in metachronous or synchronous metastases. PATIENTS AND METHODS: Primary and matched metastatic tumor pairs from 15 patients were analyzed by using a targeted next-generation sequencing assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. RESULTS: Among 30 tumors, 311 genomic alterations were identified of which 63 were known recurrent (32 in primary tumor, 31 in metastasis) and 248 were nonrecurrent (likely passenger). TP53 mutations were the most frequently observed recurrent alterations (12 patients). Tumors harbored two or more (maximum four) recurrent alterations in 10 patients. Comparative analysis of recurrent alterations between primary tumor and matched metastasis revealed a concordance rate of 94% compared with 63% for likely passenger alterations. CONCLUSION: This high concordance suggests that for the purposes of genomic profiling, use of archived primary tumor can identify the key recurrent somatic alterations present in matched NSCLC metastases and may provide much of the relevant genomic information required to guide treatment on recurrence. PMID- 23630208 TI - Treatment of orbital metastases from a primary midgut neuroendocrine tumor with peptide-receptor radiolabeled therapy using 177 lutetium-DOTATATE. PMID- 23630209 TI - "Invisible" primary cutaneous diffuse large B-cell lymphoma, leg type, as a cause of fever of unknown origin. PMID- 23630210 TI - High-dose cytarabine consolidation with or without additional amsacrine and mitoxantrone in acute myeloid leukemia: results of the prospective randomized AML2003 trial. AB - PURPOSE: To assess the treatment outcome benefit of multiagent consolidation in young adults with acute myeloid leukemia (AML) in a prospective, randomized, multicenter trial. PATIENTS AND METHODS: Between December 2003 and November 2009, 1,179 patients (median age, 48 years; range, 16 to 60 years) with untreated AML were randomly assigned at diagnosis to receive either standard high-dose cytarabine consolidation with three cycles of 18 g/m(2) (3* HD-AraC) or multiagent consolidation with two cycles of mitoxantrone (30 mg/m(2)) plus cytarabine (12 g/m(2)) and one cycle of amsacrine (500 mg/m(2)) plus cytarabine (10 g/m(2); MAC/MAMAC/MAC). Allogeneic and autologous hematopoietic stem-cell transplantations were performed in a risk-adapted and priority-based manner. RESULTS: After double induction therapy using a 3 + 7 regimen including standard dose cytarabine and daunorubicin, complete remission was achieved in 65% of patients. In the primary efficacy population of patients evaluable for consolidation outcomes, consolidation with either 3* HD-AraC or MAC/MAMC/MAC did not result in any significant difference in 3-year overall (69% v 64%; P = .18) or disease-free survival (46% v 48%; P = .99) according to the intention-to-treat analysis. Furthermore, MAC/MAMAC/MAC led to additional GI and hepatic toxicity and a higher rate of infection and bleeding, resulting in significantly shorter 3 year overall survival in the per-protocol analysis compared with 3* HD-AraC (63% v 72%; P = .04). CONCLUSION: In younger adults with AML, multiagent consolidation using mitoxantrone and amsacrine in combination with high-dose cytarabine does not improve treatment outcome and confers additional toxicity. PMID- 23630211 TI - Primary granulocyte colony-stimulating factor prophylaxis during the first two cycles only or throughout all chemotherapy cycles in patients with breast cancer at risk for febrile neutropenia. AB - PURPOSE: Early breast cancer is commonly treated with anthracyclines and taxanes. However, combining these drugs increases the risk of myelotoxicity and may require granulocyte colony-stimulating factor (G-CSF) support. The highest incidence of febrile neutropenia (FN) and largest benefit of G-CSF during the first cycles of chemotherapy lead to questions about the effectiveness of continued use of G-CSF throughout later cycles of chemotherapy. PATIENTS AND METHODS: In a multicenter study, patients with breast cancer who were considered fit enough to receive 3-weekly polychemotherapy, but also had > 20% risk for FN, were randomly assigned to primary G-CSF prophylaxis during the first two chemotherapy cycles only (experimental arm) or to primary G-CSF prophylaxis throughout all chemotherapy cycles (standard arm). The noninferiority hypothesis was that the incidence of FN would be maximally 7.5% higher in the experimental compared with the standard arm. RESULTS: After inclusion of 167 eligible patients, the independent data monitoring committee advised premature study closure. Of 84 patients randomly assigned to G-CSF throughout all chemotherapy cycles, eight (10%) experienced an episode of FN. In contrast, of 83 patients randomly assigned to G-CSF during the first two cycles only, 30 (36%) had an FN episode (95% CI, 0.13 to 0.54), with a peak incidence of 24% in the third cycle (ie, first cycle without G-CSF prophylaxis). CONCLUSION: In patients with early breast cancer at high risk for FN, continued use of primary G-CSF prophylaxis during all chemotherapy cycles is of clinical relevance and thus cannot be abandoned. PMID- 23630212 TI - Estimating cancer risks from a retrospective cohort of patients with MMR gene mutations. PMID- 23630213 TI - Consolidation chemotherapy for adults with AML in first remission: is there a best choice? PMID- 23630214 TI - Treatment of metastatic colon cancer: "the times they are A-changing". PMID- 23630215 TI - Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. AB - PURPOSE: We undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non-small-cell lung cancer (NSCLC). METHODS: KRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model. RESULTS: Among 1,543 patients (763 OBS, 780 ACT), 300 had KRAS mutations (codon 12, n = 275; codon 13, n = 24; codon 14, n = 1). In OBS patients, there was no prognostic difference for overall survival for codon-12 (mutation v wild type [WT] hazard ratio [HR] = 1.04; 95% CI, 0.77 to 1.40) or codon-13 (HR = 1.01; 95% CI, 0.47 to 2.17) mutations. No significant benefit from ACT was observed for WT-KRAS (ACT v OBS HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) or codon-12 mutations (HR = 0.95; 95% CI, 0.67 to 1.35; P = .77); with codon-13 mutations, ACT was deleterious (HR = 5.78; 95% CI, 2.06 to 16.2; P < .001; interaction P = .002). There was no prognostic effect for specific codon 12 amino acid substitution. The effect of ACT was variable among patients with codon-12 mutations: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02). CONCLUSION: KRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT. PMID- 23630216 TI - Treatment of prostate cancer with intermittent versus continuous androgen deprivation: a systematic review of randomized trials. AB - PURPOSE: Uncertainty exists regarding benefits of intermittent androgen deprivation (IAD) compared with continuous androgen deprivation (CAD) for treatment of prostate cancer. On the basis of a systematic review of evidence, our aim was to formulate a recommendation for either IAD or CAD to treat relapsing, locally advanced, or metastatic prostate cancer. METHODS: We searched literature published up to September 2012 from MEDLINE, EMBASE, the Cochrane Library, and major conference proceedings. We included randomized controlled trials comparing IAD and CAD if they reported overall survival (OS) or biochemical/radiologic time to disease progression. RESULTS: Nine studies with 5,508 patients met our criteria. There were no significant differences in time-to event outcomes between the groups in any studies. The pooled hazard ratio (HR) for OS was 1.02 (95% CI, 0.94 to 1.11) for IAD compared with CAD, and the HR for progression-free survival was 0.96 (95% CI, 0.76 to 1.20). More prostate cancer related deaths with IAD tended to be balanced by more deaths not related to prostate cancer with CAD. Superiority of IAD for sexual function, physical activity, and general well-being was observed in some trials. Median cost savings with IAD was estimated to be 48%. CONCLUSION: There is fair evidence to recommend use of IAD instead of CAD for the treatment of men with relapsing, locally advanced, or metastatic prostate cancer who achieve a good initial response to androgen deprivation. This recommendation is based on evidence against superiority of either strategy for time-to-event outcomes and substantial decrease with IAD in exposure to androgen deprivation, resulting in less cost, inconvenience, and potential toxicity. PMID- 23630217 TI - Insights from mixture cure modeling of molecular markers for prognosis in breast cancer. AB - With the ultimate aim of improving clinical management of breast cancer, investigators have sought to identify molecular genetic markers that stratify newly diagnosed patients into subtypes differing in short- or long-term prognosis. Conventional survival models can fail to describe adequately the relationship between subtype and disease recurrence, particularly when there is a substantial proportion of long-term disease-free survivors. The observed patterns of disease-free survival in an undifferentiated patient cohort may be explained by an underlying mixture of two subgroups: patients who will remain free of disease in the long term (ie, cured), and those who will experience disease recurrence within their lifetime (ie, susceptible.) In this article, we review the concepts and methods of the mixture cure models and apply them in the analysis of molecular genetic prognostic factors for disease-free survival and time to disease recurrence in a cohort of patients with axillary lymph node negative breast cancer. PMID- 23630218 TI - Harnessing technology to improve clinical trials: study of real-time informatics to collect data, toxicities, image response assessments, and patient-reported outcomes in a phase II clinical trial. AB - PURPOSE: In clinical trials, traditional monitoring methods, paper documentation, and outdated collection systems lead to inaccuracies of study information and inefficiencies in the process. Integrated electronic systems offer an opportunity to collect data in real time. PATIENTS AND METHODS: We created a computer software system to collect 13 patient-reported symptomatic adverse events and patient-reported Karnofsky performance status, semi-automated RECIST measurements, and laboratory data, and we made this information available to investigators in real time at the point of care during a phase II lung cancer trial. We assessed data completeness within 48 hours of each visit. Clinician satisfaction was measured. RESULTS: Forty-four patients were enrolled, for 721 total visits. At each visit, patient-reported outcomes (PROs) reflecting toxicity and disease-related symptoms were completed using a dedicated wireless laptop. All PROs were distributed in batch throughout the system within 24 hours of the visit, and abnormal laboratory data were available for review within a median of 6 hours from the time of sample collection. Manual attribution of laboratory toxicities took a median of 1 day from the time they were accessible online. Semi automated RECIST measurements were available to clinicians online within a median of 2 days from the time of imaging. All clinicians and 88% of data managers felt there was greater accuracy using this system. CONCLUSION: Existing data management systems can be harnessed to enable real-time collection and review of clinical information during trials. This approach facilitates reporting of information closer to the time of events, and improves efficiency, and the ability to make earlier clinical decisions. PMID- 23630219 TI - Visual long-term memory has the same limit on fidelity as visual working memory. AB - Visual long-term memory can store thousands of objects with surprising visual detail, but just how detailed are these representations, and how can one quantify this fidelity? Using the property of color as a case study, we estimated the precision of visual information in long-term memory, and compared this with the precision of the same information in working memory. Observers were shown real world objects in random colors and were asked to recall the colors after a delay. We quantified two parameters of performance: the variability of internal representations of color (fidelity) and the probability of forgetting an object's color altogether. Surprisingly, the fidelity of color information in long-term memory was comparable to the asymptotic precision of working memory. These results suggest that long-term memory and working memory may be constrained by a common limit, such as a bound on the fidelity required to retrieve a memory representation. PMID- 23630221 TI - Perceived hotness affects behavior of basketball players and coaches. AB - Although "hot hands" in basketball are illusory, the belief in them is so robust that it not only has sparked many debates but may also affect the behavior of players and coaches. On the basis of an entire National Basketball Association season's worth of data, the research reported here shows that even a single successful shot suffices to increase a player's likelihood of taking the next team shot, increase the average distance from which this next shot is taken, decrease the probability that this next shot is successful, and decrease the probability that the coach will replace the player. PMID- 23630220 TI - Loneliness promotes inflammation during acute stress. AB - Although evidence suggests that loneliness may increase risk for health problems, the mechanisms responsible are not well understood. Immune dysregulation is one potential pathway: Elevated proinflammatory cytokines such as interleukin-6 (IL 6) increase risk for health problems. In our first study (N = 134), lonelier healthy adults exposed to acute stress exhibited greater synthesis of tumor necrosis factor-alpha (TNF-alpha) and IL-6 by peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharide (LPS) than their less lonely counterparts. Similarly, in the second study (N = 144), lonelier posttreatment breast-cancer survivors exposed to acute stress exhibited greater synthesis of IL 6 and interleukin-1 beta (IL-1beta) by LPS-stimulated PBMCs than their counterparts who felt more socially connected. However, loneliness was unrelated to TNF-alpha in Study 2, although the result was in the expected direction. Thus, two different populations demonstrated that lonelier participants had more stimulated cytokine production in response to stress than less lonely participants, which reflects a proinflammatory phenotype. These data provide a glimpse into the pathways through which loneliness may affect health. PMID- 23630222 TI - Medial temporal lobe volume predicts elders' everyday memory. AB - Deficits in memory for everyday activities are common complaints among healthy and demented older adults. The medial temporal lobes and dorsolateral prefrontal cortex are both affected by aging and early-stage Alzheimer's disease, and are known to influence performance on laboratory memory tasks. We investigated whether the volume of these structures predicts everyday memory. Cognitively healthy older adults and older adults with mild Alzheimer's-type dementia watched movies of everyday activities and completed memory tests on the activities. Structural MRI was used to measure brain volume. Medial temporal but not prefrontal volume strongly predicted subsequent memory. Everyday memory depends on segmenting activity into discrete events during perception, and medial temporal volume partially accounted for the relationship between performance on the memory tests and performance on an event-segmentation task. The everyday memory measures used in this study involve retrieval of episodic and semantic information as well as working memory updating. Thus, the current findings suggest that during perception, the medial temporal lobes support the construction of event representations that determine subsequent memory. PMID- 23630223 TI - I know not to, but i can't help it: weight gain and changes in impulsivity related personality traits. AB - Reciprocal relations between weight and psychological factors suggest that there are deep connections between mind and body. Personality traits are linked to weight gain; weight gain may likewise be associated with personality change. Using data from two diverse longitudinal samples (N = 1,919) collected at two time points an average of 10 years apart, we showed that significant weight gain is associated with increases in both impulsiveness and deliberation: In both samples, middle-aged adults who gained 10% or more of their baseline body weight by follow-up increased in their tendency to give in to temptation, yet were more thoughtful about the consequences of their actions. The present research moves beyond life events to implicate health status in adult personality development. The findings also suggest that interventions focusing on the emotional component of impulse control may be more effective because even people who become more thoughtful about the consequences of their actions may have limited success at inhibiting their behavior. PMID- 23630225 TI - Development of Vermont assessment of sex offender risk-2 (VASOR-2) reoffense risk scale. AB - The present study aimed to revise the Vermont Assessment of Sex Offender Risk (VASOR) Reoffense Risk Scale, a commonly used sex offender risk assessment tool. The revised tool was named the VASOR-2. Among models tested to revise the scale, a logistic regression model showed the best balance between simplicity of use, goodness of fit, and internal validity (as tested with K-10 cross-validation), and maximized predictive accuracy. Predictive accuracy was tested using four meta analytically combined data sets drawn from Canada and Vermont (N = 1,581). At 5 year fixed follow-up, the predictive accuracy for sexual recidivism for VASOR-2 (AUC = .74) was similar to the VASOR (AUC = .71). The findings show the VASOR-2 is well calibrated with observed recidivism rates for all but the highest risk sex offenders. The instrument showed good interrater reliability (ICC = .88). An advantage of the VASOR-2 is that it has fewer items and simpler scoring instructions than the VASOR. Norms are presented for a contemporary, nonselected, routine sample of Vermont sex offenders (n = 887). PMID- 23630226 TI - The relationship of PTSD to key somatic complaints and cultural syndromes among Cambodian refugees attending a psychiatric clinic: the Cambodian Somatic Symptom and Syndrome Inventory (CSSI). AB - This article describes a culturally sensitive questionnaire for the assessment of the effects of trauma in the Cambodian refugee population, the Cambodian Somatic Symptom and Syndrome Inventory (CSSI), and gives the results of a survey with the instrument. The survey examined the relationship of the CSSI, the two CSSI subscales, and the CSSI items to posttraumatic stress disorder (PTSD) severity and self-perceived functioning. A total of 226 traumatized Cambodian refugees were assessed at a psychiatric clinic in Lowell, MA, USA. There was a high correlation of the CSSI, the CSSI somatic and syndrome scales, and all the CSSI items to the PTSD Checklist (PCL), a measure of PTSD severity. All the CSSI items varied greatly across three levels of PTSD severity, and patients with higher levels of PTSD had very high scores on certain CSSI-assessed somatic items such as dizziness, orthostatic dizziness (upon standing), and headache, and on certain CSSI-assessed cultural syndromes such as khyal attacks, "fear of fainting and dying upon standing up," and "thinking a lot." The CSSI was more highly correlated than the PCL to self-perceived disability assessed by the Short Form 12 Health Survey (SF-12). The study demonstrates that the somatic symptoms and cultural syndromes described by the CSSI form a central part of the Cambodian refugee trauma ontology. The survey indicates that locally salient somatic symptoms and cultural syndromes need be profiled to adequately assess the effects of trauma. PMID- 23630227 TI - Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection. AB - Nitric oxide (NO) generated by inducible NO synthase 2 (NOS2) affects cellular iron homeostasis, but the underlying molecular mechanisms and implications for NOS2-dependent pathogen control are incompletely understood. In this study, we found that NO up-regulated the expression of ferroportin-1 (Fpn1), the major cellular iron exporter, in mouse and human cells. Nos2(-/-) macrophages displayed increased iron content due to reduced Fpn1 expression and allowed for an enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium. Nos2 gene disruption or inhibition of NOS2 activity led to an accumulation of iron in the spleen and splenic macrophages. Lack of NO formation resulted in impaired nuclear factor erythroid 2-related factor-2 (Nrf2) expression, resulting in reduced Fpn1 transcription and diminished cellular iron egress. After infection of Nos2(-/-) macrophages or mice with S. typhimurium, the increased iron accumulation was paralleled by a reduced cytokine (TNF, IL-12, and IFN-gamma) expression and impaired pathogen control, all of which were restored upon administration of the iron chelator deferasirox or hyperexpression of Fpn1 or Nrf2. Thus, the accumulation of iron in Nos2(-/-) macrophages counteracts a proinflammatory host immune response, and the protective effect of NO appears to partially result from its ability to prevent iron overload in macrophages. PMID- 23630228 TI - p53 Integrates host defense and cell fate during bacterial pneumonia. AB - Cancer and infection are predominant causes of human mortality and derive, respectively, from inadequate genomic and host defenses against environmental agents. The transcription factor p53 plays a central role in human tumor suppression. Despite its expression in immune cells and broad responsiveness to stressors, it is virtually unknown whether p53 regulates host defense against infection. We report that the lungs of naive p53(-/-) mice display genome-wide induction of NF-kappaB response element-enriched proinflammatory genes, suggestive of type 1 immune priming. p53-null and p53 inhibitor-treated mice clear Gram-negative and -positive bacteria more effectively than controls after intrapulmonary infection. This is caused, at least in part, by cytokines produced by an expanded population of apoptosis-resistant, TLR-hyperresponsive alveolar macrophages that enhance airway neutrophilia. p53(-/-) neutrophils, in turn, display heightened phagocytosis, Nox-dependent oxidant generation, degranulation, and bacterial killing. p53 inhibition boosts bacterial killing by mouse neutrophils and oxidant generation by human neutrophils. Despite enhanced bacterial clearance, infected p53(-/-) mice suffer increased mortality associated with aggravated lung injury. p53 thus modulates host defense through regulating microbicidal function and fate of phagocytes, revealing a fundamental link between defense of genome and host during environmental insult. PMID- 23630229 TI - Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance. AB - The (histone) deacetylase Sirt1 is a mediator of genomic and epigenetic maintenance, both of which are critical aspects of stem cell homeostasis and tightly linked to their functional decline in aging and disease. We show that Sirt1 ablation in adult hematopoietic stem and progenitor cells (HSPCs) promotes aberrant HSPC expansion specifically under conditions of hematopoietic stress, which is associated with genomic instability as well as the accumulation of DNA damage and eventually results in a loss of long-term progenitors. We further demonstrate that progenitor cell expansion is mechanistically linked to the selective up-regulation of the HSPC maintenance factor and polycomb target gene Hoxa9. We show that Sirt1 binds to the Hoxa9 gene, counteracts acetylation of its histone target H4 lysine 16, and in turn promotes polycomb-specific repressive histone modification. Together, these findings demonstrate a dual role for Sirt1 in HSPC homeostasis, both via epigenetic regulation of a key developmental gene and by promoting genome stability in adult stem cells. PMID- 23630231 TI - Tuning the auxin transcriptional response. AB - How does auxin provoke such a diverse array of responses? This long-standing question is further complicated by a remarkably short nuclear auxin signalling pathway. To crack the auxin code, several potential sources of specificity need to be evaluated. These include: specificity of interactions among the core auxin response components, specificity resulting from higher order complex dynamics, and specificity in interactions with global factors controlling protein turnover and transcriptional repression. Here, we review recent progress towards characterizing and quantifying these interactions and highlight key gaps that remain. PMID- 23630232 TI - Extracellular vesicles: communication, coercion, and conditioning. AB - Cells communicate with neighboring cells and condition their local environment by secreting soluble factors into the extracellular space. These well-studied facets of cell biology are essential for the establishment and maintenance of physiological homeostasis. However, accumulating evidence has revealed that specific ligands, enzymes, and macromolecules are distributed into the extracellular space by virtue of their association with small vesicles, which are released by a variety of cell types. Although the biological significance of such vesicles was initially debated, purification and subsequent functional studies have shown that these extracellular vesicles are bioactive organelles carrying a wide range of protein and nucleic acid cargoes. In many cases these vesicles are laden with molecules that are involved in cell signaling, although other diverse functions are being revealed at a rapid pace. In this Perspective, we discuss recent developments in the understanding of the major pathways of extracellular vesicle biogenesis and how these vesicles contribute to the maintenance of physiological homeostasis. PMID- 23630235 TI - The dance of death. PMID- 23630234 TI - Functional human sperm capacitation requires both bicarbonate-dependent PKA activation and down-regulation of Ser/Thr phosphatases by Src family kinases. AB - In all mammalian species studied so far, sperm capacitation correlates with an increase in protein tyrosine (Tyr) phosphorylation mediated by a bicarbonate dependent cAMP/protein kinase A (PKA) pathway. Recent studies in mice revealed, however, that a Src family kinase (SFK)-induced inactivation of serine/threonine (Ser/Thr) phosphatases is also involved in the signaling pathways leading to Tyr phosphorylation. In view of these observations and with the aim of getting a better understanding of the signaling pathways involved in human sperm capacitation, in the present work we investigated the involvement of both the cAMP/PKA and SFK/phosphatase pathways in relation to the capacitation state of the cells. For this purpose, different signaling events and sperm functional parameters were analyzed as a function of capacitation time. Results revealed a very early bicarbonate-dependent activation of PKA indicated by the rapid (1 min) increase in both phospho-PKA substrates and cAMP levels (P < 0.05). However, a complete pattern of Tyr phosphorylation was detected only after 6-h incubation at which time sperm exhibited the ability to undergo the acrosome reaction (AR) and to penetrate zona-free hamster oocytes. Sperm capacitated in the presence of the SFK inhibitor SKI606 showed a decrease in both PKA substrate and Tyr phosphorylation levels, which was overcome by exposure of sperm to the Ser/Thr phosphatase inhibitor okadaic acid (OA). However, OA was unable to induce phosphorylation when sperm were incubated under PKA-inhibitory conditions (i.e. in the absence of bicarbonate or in the presence of PKA inhibitor). Moreover, the increase in PKA activity by exposure to a cAMP analog and a phosphodiesterase inhibitor did not overcome the inhibition produced by SKI606. Whereas the presence of SKI606 during capacitation produced a negative effect (P < 0.05) on sperm motility, progesterone-induced AR and fertilizing ability, none of these inhibitions were observed when sperm were exposed to SKI606 and OA. Interestingly, different concentrations of inhibitors were required to modulate human and mouse capacitation revealing the species specificity of the molecular mechanisms underlying this process. In conclusion, our results describe for the first time the involvement of both PKA activation and Ser/Thr phosphatase down regulation in functional human sperm capacitation and provide convincing evidence that early PKA-dependent phosphorylation is the convergent regulatory point between these two signaling pathways. PMID- 23630236 TI - FDA ban of generic oxycodone calls into question Health Canada's approval. PMID- 23630237 TI - Drug patents: innovation v. accessibility. PMID- 23630238 TI - Left atrial-esophageal fistula after atrial fibrillation ablation. PMID- 23630239 TI - Drug patents: the evergreening problem. PMID- 23630240 TI - Should a reversible, but lethal, incident not be treated when a patient has a do not-resuscitate order? PMID- 23630241 TI - World watching as troubling new type of avian influenza surfaces in China. PMID- 23630243 TI - Can naturopaths deliver complementary preventive medicine? PMID- 23630245 TI - More than 100 countries still not using global outbreak surveillance regulations. PMID- 23630244 TI - Naturopathic medicine for the prevention of cardiovascular disease: a randomized clinical trial. AB - BACKGROUND: Although cardiovascular disease may be partially preventable through dietary and lifestyle-based interventions, few individuals at risk receive intensive dietary and lifestyle counselling. We performed a randomized controlled trial to evaluate the effectiveness of naturopathic care in reducing the risk of cardiovascular disease. METHODS: We performed a multisite randomized controlled trial of enhanced usual care (usual care plus biometric measurement; control) compared with enhanced usual care plus naturopathic care (hereafter called naturopathic care). Postal workers aged 25-65 years in Toronto, Vancouver and Edmonton, Canada, with an increased risk of cardiovascular disease were invited to participate. Participants in both groups received care by their family physicians. Those in the naturopathic group also received individualized care (health promotion counselling, nutritional medicine or dietary supplementation) at 7 preset times in work-site clinics by licensed naturopathic doctors. The body weight, waist circumference, lipid profile, fasting glucose levels and blood pressure of participants in both groups were measured 3 times during a 1-year period. Our primary outcomes were the 10-year risk of having a cardiovascular event (based on the Framingham risk algorithm) and the prevalence of metabolic syndrome (based on the Adult Treatment Panel III diagnostic criteria). RESULTS: Of 246 participants randomly assigned to a study group, 207 completed the study. The characteristics of participants in both groups were similar at baseline. Compared with participants in the control group, at 52 weeks those in the naturopathic group had a reduced adjusted 10-year cardiovascular risk (control: 10.81%; naturopathic group: 7.74%; risk reduction -3.07% [95% confidence interval (CI) -4.35% to -1.78%], p < 0.001) and a lower adjusted frequency of metabolic syndrome (control group: 48.48%; naturopathic care: 31.58%; risk reduction 16.90% [95% CI -29.55% to -4.25%], p = 0.002). INTERPRETATION: Our findings support the hypothesis that the addition of naturopathic care to enhanced usual care may reduce the risk of cardiovascular disease among those at high risk. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT0071879. PMID- 23630246 TI - The MetaboLights repository: curation challenges in metabolomics. AB - MetaboLights is the first general-purpose open-access curated repository for metabolomic studies, their raw experimental data and associated metadata, maintained by one of the major open-access data providers in molecular biology. Increases in the number of depositions, number of samples per study and the file size of data submitted to MetaboLights present a challenge for the objective of ensuring high-quality and standardized data in the context of diverse metabolomic workflows and data representations. Here, we describe the MetaboLights curation pipeline, its challenges and its practical application in quality control of complex data depositions. Database URL: http://www.ebi.ac.uk/metabolights. PMID- 23630247 TI - The comet assay, DNA damage, DNA repair and cytotoxicity: hedgehogs are not always dead. AB - DNA damage is commonly measured at the level of individual cells using the so called comet assay (single-cell gel electrophoresis). As the frequency of DNA breaks increases, so does the fraction of the DNA extending towards the anode, forming the comet tail. Comets with almost all DNA in the tail are often referred to as 'hedgehog' comets and are widely assumed to represent apoptotic cells. We review the literature and present theoretical and empirical arguments against this interpretation. The level of DNA damage in these comets is far less than the massive fragmentation that occurs in apoptosis. 'Hedgehog' comets are formed after moderate exposure of cells to, for example, H2O2, but if the cells are incubated for a short period, 'hedgehogs' are no longer seen. We confirm that this is not because DNA has degraded further and been lost from the gel, but because the DNA is repaired. The comet assay may detect the earliest stages of apoptosis, but as it proceeds, comets disappear in a smear of unattached DNA. It is clear that 'hedgehogs' can correspond to one level on a continuum of genotoxic damage, are not diagnostic of apoptosis and should not be regarded as an indicator of cytotoxicity. PMID- 23630248 TI - Engineering recombinant reoviruses with tandem repeats and a tetravirus 2A-like element for exogenous polypeptide expression. AB - We tested a strategy for engineering recombinant mammalian reoviruses (rMRVs) to express exogenous polypeptides. One important feature is that these rMRVs are designed to propagate autonomously and can therefore be tested in animals as potential vaccine vectors. The strategy has been applied so far to three of the 10 MRV genome segments: S3, M1, and L1. To engineer the modified segments, a 5' or 3' region of the essential, long ORF in each was duplicated, and then exogenous sequences were inserted between the repeats. The inner repeat and exogenous insert were positioned in frame with the native protein-encoding sequences but were separated from them by an in-frame "2A-like" sequence element that specifies a cotranslational "stop/continue" event releasing the exogenous polypeptide from the essential MRV protein. This design preserves a terminal region of the MRV genome segment with essential activities in RNA packaging, assortment, replication, transcription, and/or translation and alters the encoded MRV protein to a limited degree. Recovery of rMRVs with longer inserts was made more efficient by wobble-mutagenizing both the inner repeat and the exogenous insert, which possibly helped via respective reductions in homologous recombination and RNA structure. Immunogenicity of a 300-aa portion of the simian immunodeficiency virus Gag protein expressed in mice by an L1-modified rMRV was confirmed by detection of Gag-specific T-cell responses. The engineering strategy was further used for mapping the minimal 5'-terminal region essential to MRV genome segment S3. PMID- 23630249 TI - Differential hERG ion channel activity of ultrasmall gold nanoparticles. AB - Understanding the mechanism of toxicity of nanomaterials remains a challenge with respect to both mechanisms involved and product regulation. Here we show toxicity of ultrasmall gold nanoparticles (AuNPs). Depending on the ligand chemistry, 1.4 nm-diameter AuNPs failed electrophysiology-based safety testing using human embryonic kidney cell line 293 cells expressing human ether-a-go-go-Related gene (hERG), a Food and Drug Administration-established drug safety test. In patch clamp experiments, phosphine-stabilized AuNPs irreversibly blocked hERG channels, whereas thiol-stabilized AuNPs of similar size had no effect in vitro, and neither particle blocked the channel in vivo. We conclude that safety regulations may need to be reevaluated and adapted to reflect the fact that the binding modality of surface functional groups becomes a relevant parameter for the design of nanoscale bioactive compounds. PMID- 23630250 TI - Metallothioneins negatively regulate IL-27-induced type 1 regulatory T-cell differentiation. AB - IL-27-induced type 1 regulatory T (Tr1) cells suppress autoimmunity by producing IL-10. Signal transducer and activator of transcription (STAT) 1 and STAT3 have been described as key transcription factors that promote IL-10 secretion from Tr1 cells induced by IL-27. However, the molecular pathways for negatively regulating Tr1 cell differentiation remain elusive. Here, we show that IL-27 induces metallothioneins (MTs) that in turn prevent Tr1 cell development. MT expression leads to the reduction of STAT1 and STAT3 phosphorylation under Tr1 differentiation condition, resulting in impaired IL-10 production. Accordingly, Tr1 cells derived from MT-deficient mice showed an increased ability to produce IL-10 and potently suppress experimental autoimmune encephalomyelitis upon adoptive transfer. Moreover, activation of STAT1 and/or STAT3 can overcome the suppression of IL-10 by MTs, indicating a dynamic balance between STATs and MTs in regulating IL-10 during Tr1 cell differentiation. PMID- 23630251 TI - Structure-kinetic relationship study of CDK8/CycC specific compounds. AB - In contrast with the very well explored concept of structure-activity relationship, similar studies are missing for the dependency between binding kinetics and compound structure of a protein ligand complex, the structure kinetic relationship. Here, we present a structure-kinetic relationship study of the cyclin-dependent kinase 8 (CDK8)/cyclin C (CycC) complex. The scaffold moiety of the compounds is anchored in the kinase deep pocket and extended with diverse functional groups toward the hinge region and the front pocket. These variations can cause the compounds to change from fast to slow binding kinetics, resulting in an improved residence time. The flip of the DFG motif ("DMG" in CDK8) to the inactive DFG-out conformation appears to have relatively little influence on the velocity of binding. Hydrogen bonding with the kinase hinge region contributes to the residence time but has less impact than hydrophobic complementarities within the kinase front pocket. PMID- 23630252 TI - Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles. AB - Whether or not mammalian females generate new oocytes during adulthood from germ line stem cells to sustain the ovarian follicle pool has recently generated controversy. We used a sensitive lineage-labeling system to determine whether stem cells are needed in female adult mice to compensate for follicular losses and to directly identify active germ-line stem cells. Primordial follicles generated during fetal life are highly stable, with a half-life during adulthood of 10 mo, and thus are sufficient to sustain adult oogenesis without a source of renewal. Moreover, in normal mice or following germ-cell depletion with Busulfan, only stable, single oocytes are lineage-labeled, rather than cell clusters indicative of new oocyte formation. Even one germ-line stem cell division per 2 wk would have been detected by our method, based on the kinetics of fetal follicle formation. Thus, adult female mice neither require nor contain active germ-line stem cells or produce new oocytes in vivo. PMID- 23630253 TI - Quantification of cellular penetrative forces using lab-on-a-chip technology and finite element modeling. AB - Tip-growing cells have the unique property of invading living tissues and abiotic growth matrices. To do so, they exert significant penetrative forces. In plant and fungal cells, these forces are generated by the hydrostatic turgor pressure. Using the TipChip, a microfluidic lab-on-a-chip device developed for tip-growing cells, we tested the ability to exert penetrative forces generated in pollen tubes, the fastest-growing plant cells. The tubes were guided to grow through microscopic gaps made of elastic polydimethylsiloxane material. Based on the deformation of the gaps, the force exerted by the elongating tubes to permit passage was determined using finite element methods. The data revealed that increasing mechanical impedance was met by the pollen tubes through modulation of the cell wall compliance and, thus, a change in the force acting on the obstacle. Tubes that successfully passed a narrow gap frequently burst, raising questions about the sperm discharge mechanism in the flowering plants. PMID- 23630254 TI - Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice. AB - Adipose tissue (AT) inflammation and infiltration by macrophages is associated with insulin resistance and type 2 diabetes in obese humans, offering a potential target for therapeutics. However, whether AT macrophages (ATMs) directly contribute to systemic glucose intolerance has not been determined. The reason is the lack of methods to ablate inflammatory genes expressed in macrophages specifically localized within AT depots, leaving macrophages in other tissues unaffected. Here we report that i.p. administration of siRNA encapsulated by glucan shells in obese mice selectively silences genes in epididymal ATMs, whereas macrophages within lung, spleen, kidney, heart, skeletal muscle, subcutaneous (SubQ) adipose, and liver are not targeted. Such administration of GeRPs to silence the inflammatory cytokines TNF-alpha or osteopontin in epididymal ATMs of obese mice caused significant improvement in glucose tolerance. These data are consistent with the hypothesis that cytokines produced by ATMs can exacerbate whole-body glucose intolerance. PMID- 23630255 TI - Honey constituents up-regulate detoxification and immunity genes in the western honey bee Apis mellifera. AB - As a managed pollinator, the honey bee Apis mellifera is critical to the American agricultural enterprise. Recent colony losses have thus raised concerns; possible explanations for bee decline include nutritional deficiencies and exposures to pesticides and pathogens. We determined that constituents found in honey, including p-coumaric acid, pinocembrin, and pinobanksin 5-methyl ether, specifically induce detoxification genes. These inducers are primarily found not in nectar but in pollen in the case of p-coumaric acid (a monomer of sporopollenin, the principal constituent of pollen cell walls) and propolis, a resinous material gathered and processed by bees to line wax cells. RNA-seq analysis (massively parallel RNA sequencing) revealed that p-coumaric acid specifically up-regulates all classes of detoxification genes as well as select antimicrobial peptide genes. This up-regulation has functional significance in that that adding p-coumaric acid to a diet of sucrose increases midgut metabolism of coumaphos, a widely used in-hive acaricide, by ~60%. As a major component of pollen grains, p-coumaric acid is ubiquitous in the natural diet of honey bees and may function as a nutraceutical regulating immune and detoxification processes. The widespread apicultural use of honey substitutes, including high fructose corn syrup, may thus compromise the ability of honey bees to cope with pesticides and pathogens and contribute to colony losses. PMID- 23630257 TI - Nanoscale analysis of pyritized microfossils reveals differential heterotrophic consumption in the ~1.9-Ga Gunflint chert. AB - The 1.88-Ga Gunflint biota is one of the most famous Precambrian microfossil lagerstatten and provides a key record of the biosphere at a time of changing oceanic redox structure and chemistry. Here, we report on pyritized replicas of the iconic autotrophic Gunflintia-Huroniospora microfossil assemblage from the Schreiber Locality, Canada, that help capture a view through multiple trophic levels in a Paleoproterozoic ecosystem. Nanoscale analysis of pyritic Gunflintia (sheaths) and Huroniospora (cysts) reveals differing relic carbon and nitrogen distributions caused by contrasting spectra of decay and pyritization between taxa, reflecting in part their primary organic compositions. In situ sulfur isotope measurements from individual microfossils (delta(34)S(V-CDT) +6.70/00 to +21.50/00) show that pyritization was mediated by sulfate-reducing microbes within sediment pore waters whose sulfate ion concentrations rapidly became depleted, owing to occlusion of pore space by coeval silicification. Three dimensional nanotomography reveals additional pyritized biomaterial, including hollow, cellular epibionts and extracellular polymeric substances, showing a preference for attachment to Gunflintia over Huroniospora and interpreted as components of a saprophytic heterotrophic, decomposing community. This work also extends the record of remarkable biological preservation in pyrite back to the Paleoproterozoic and provides criteria to assess the authenticity of even older pyritized microstructures that may represent some of the earliest evidence for life on our planet. PMID- 23630256 TI - Cofactor-dependent specificity of a DEAD-box protein. AB - DEAD-box proteins, a large class of RNA-dependent ATPases, regulate all aspects of gene expression and RNA metabolism. They can facilitate dissociation of RNA duplexes and remodeling of RNA-protein complexes, serve as ATP-dependent RNA binding proteins, or even anneal duplexes. These proteins have highly conserved sequence elements that are contained within two RecA-like domains; consequently, their structures are nearly identical. Furthermore, crystal structures of DEAD box proteins with bound RNA reveal interactions exclusively between the protein and the RNA backbone. Together, these findings suggest that DEAD-box proteins interact with their substrates in a nonspecific manner, which is confirmed in biochemical experiments. Nevertheless, this contrasts with the need to target these enzymes to specific substrates in vivo. Using the DEAD-box protein Rok1 and its cofactor Rrp5, which both function during maturation of the small ribosomal subunit, we show here that Rrp5 provides specificity to the otherwise nonspecific biochemical activities of the Rok1 DEAD-domain. This finding could reconcile the need for specific substrate binding of some DEAD-box proteins with their nonspecific binding surface and expands the potential roles of cofactors to specificity factors. Identification of helicase cofactors and their RNA substrates could therefore help define the undescribed roles of the 19 DEAD-box proteins that function in ribosome assembly. PMID- 23630258 TI - Self-assembled, aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics. AB - Nanotechnology has allowed the construction of various nanostructures for applications, including biomedicine. However, a simple target-specific, economical, and biocompatible drug delivery platform with high maximum tolerated doses is still in demand. Here, we report aptamer-tethered DNA nanotrains (aptNTrs) as carriers for targeted drug transport in cancer therapy. Long aptNTrs were self-assembled from only two short DNA upon initiation by modified aptamers, which worked like locomotives guiding nanotrains toward target cancer cells. Meanwhile, tandem "boxcars" served as carriers with high payload capacity of drugs that were transported to target cells and induced selective cytotoxicity. aptNTrs enhanced maximum tolerated dose in nontarget cells. Potent antitumor efficacy and reduced side effects of drugs delivered by biocompatible aptNTrs were demonstrated in a mouse xenograft tumor model. Moreover, fluorophores on nanotrains and drug fluorescence dequenching upon release allowed intracellular signaling of nanotrains and drugs. These results make aptNTrs a promising targeted drug transport platform for cancer theranostics. PMID- 23630259 TI - Genome-wide comparative diversity uncovers multiple targets of selection for improvement in hexaploid wheat landraces and cultivars. AB - Domesticated crops experience strong human-mediated selection aimed at developing high-yielding varieties adapted to local conditions. To detect regions of the wheat genome subject to selection during improvement, we developed a high throughput array to interrogate 9,000 gene-associated single-nucleotide polymorphisms (SNP) in a worldwide sample of 2,994 accessions of hexaploid wheat including landraces and modern cultivars. Using a SNP-based diversity map we characterized the impact of crop improvement on genomic and geographic patterns of genetic diversity. We found evidence of a small population bottleneck and extensive use of ancestral variation often traceable to founders of cultivars from diverse geographic regions. Analyzing genetic differentiation among populations and the extent of haplotype sharing, we identified allelic variants subjected to selection during improvement. Selective sweeps were found around genes involved in the regulation of flowering time and phenology. An introgression of a wild relative-derived gene conferring resistance to a fungal pathogen was detected by haplotype-based analysis. Comparing selective sweeps identified in different populations, we show that selection likely acts on distinct targets or multiple functionally equivalent alleles in different portions of the geographic range of wheat. The majority of the selected alleles were present at low frequency in local populations, suggesting either weak selection pressure or temporal variation in the targets of directional selection during breeding probably associated with changing agricultural practices or environmental conditions. The developed SNP chip and map of genetic variation provide a resource for advancing wheat breeding and supporting future population genomic and genome-wide association studies in wheat. PMID- 23630260 TI - Controlling electron transfer at the microbe-mineral interface. PMID- 23630261 TI - Structures of the phage Sf6 large terminase provide new insights into DNA translocation and cleavage. AB - Many DNA viruses use powerful molecular motors to cleave concatemeric viral DNA into genome-length units and package them into preformed procapsid powered by ATP hydrolysis. Here we report the structures of the DNA-packaging motor gp2 of bacteriophage Sf6, which reveal a unique clade of RecA-like ATPase domain and an RNase H-like nuclease domain tethered by a regulatory linker domain, exhibiting a strikingly distinct domain arrangement. The gp2 structures complexed with nucleotides reveal, at the atomic detail, the catalytic center embraced by the ATPase domain and the linker domain. The gp2 nuclease activity is modulated by the ATPase domain and is stimulated by ATP. An extended DNA-binding surface is formed by the linker domain and the nuclease domain. These results suggest a unique mechanism for translation of chemical reaction into physical motion of DNA and provide insights into coordination of DNA translocation and cleavage in a viral DNA-packaging motor, which may be achieved via linker-domain-mediated interdomain communication driven by ATP hydrolysis. PMID- 23630262 TI - Activation of heme biosynthesis by a small molecule that is toxic to fermenting Staphylococcus aureus. AB - Staphylococcus aureus is a significant infectious threat to global public health. Acquisition or synthesis of heme is required for S. aureus to capture energy through respiration, but an excess of this critical cofactor is toxic to bacteria. S. aureus employs the heme sensor system (HssRS) to overcome heme toxicity; however, the mechanism of heme sensing is not defined. Here, we describe the identification of a small molecule activator of HssRS that induces endogenous heme biosynthesis by perturbing central metabolism. This molecule is toxic to fermenting S. aureus, including clinically relevant small colony variants. The utility of targeting fermenting bacteria is exemplified by the fact that this compound prevents the emergence of antibiotic resistance, enhances phagocyte killing, and reduces S. aureus pathogenesis. Not only is this small molecule a powerful tool for studying bacterial heme biosynthesis and central metabolism; it also establishes targeting of fermentation as a viable antibacterial strategy. PMID- 23630263 TI - Consumers mediate the effects of experimental ocean acidification and warming on primary producers. AB - It is well known that ocean acidification can have profound impacts on marine organisms. However, we know little about the direct and indirect effects of ocean acidification and also how these effects interact with other features of environmental change such as warming and declining consumer pressure. In this study, we tested whether the presence of consumers (invertebrate mesograzers) influenced the interactive effects of ocean acidification and warming on benthic microalgae in a seagrass community mesocosm experiment. Net effects of acidification and warming on benthic microalgal biomass and production, as assessed by analysis of variance, were relatively weak regardless of grazer presence. However, partitioning these net effects into direct and indirect effects using structural equation modeling revealed several strong relationships. In the absence of grazers, benthic microalgae were negatively and indirectly affected by sediment-associated microalgal grazers and macroalgal shading, but directly and positively affected by acidification and warming. Combining indirect and direct effects yielded no or weak net effects. In the presence of grazers, almost all direct and indirect climate effects were nonsignificant. Our analyses highlight that (i) indirect effects of climate change may be at least as strong as direct effects, (ii) grazers are crucial in mediating these effects, and (iii) effects of ocean acidification may be apparent only through indirect effects and in combination with other variables (e.g., warming). These findings highlight the importance of experimental designs and statistical analyses that allow us to separate and quantify the direct and indirect effects of multiple climate variables on natural communities. PMID- 23630264 TI - Glycolytic strategy as a tradeoff between energy yield and protein cost. AB - Contrary to the textbook portrayal of glycolysis as a single pathway conserved across all domains of life, not all sugar-consuming organisms use the canonical Embden-Meyerhoff-Parnass (EMP) glycolytic pathway. Prokaryotic glucose metabolism is particularly diverse, including several alternative glycolytic pathways, the most common of which is the Entner-Doudoroff (ED) pathway. The prevalence of the ED pathway is puzzling as it produces only one ATP per glucose--half as much as the EMP pathway. We argue that the diversity of prokaryotic glucose metabolism may reflect a tradeoff between a pathway's energy (ATP) yield and the amount of enzymatic protein required to catalyze pathway flux. We introduce methods for analyzing pathways in terms of thermodynamics and kinetics and show that the ED pathway is expected to require several-fold less enzymatic protein to achieve the same glucose conversion rate as the EMP pathway. Through genomic analysis, we further show that prokaryotes use different glycolytic pathways depending on their energy supply. Specifically, energy-deprived anaerobes overwhelmingly rely upon the higher ATP yield of the EMP pathway, whereas the ED pathway is common among facultative anaerobes and even more common among aerobes. In addition to demonstrating how protein costs can explain the use of alternative metabolic strategies, this study illustrates a direct connection between an organism's environment and the thermodynamic and biochemical properties of the metabolic pathways it employs. PMID- 23630265 TI - Dynamics of internal pore opening in K(V) channels probed by a fluorescent unnatural amino acid. AB - Atomic-scale models on the gating mechanism of voltage-gated potassium channels (Kv) are based on linear interpolations between static structures of their initial and final state derived from crystallography and molecular dynamics simulations, and, thus, lack dynamic structural information. The lack of information on dynamics and intermediate states makes it difficult to associate the structural with the dynamic functional data obtained with electrophysiology. Although voltage-clamp fluorometry fills this gap, it is limited to sites extracellularly accessible, when the key region for gating is located at the cytosolic side of the channels. Here, we solved this problem by performing voltage-clamp fluorometry with a fluorescent unnatural amino acid. By using an orthogonal tRNA-synthetase pair, the fluorescent unnatural amino acid was incorporated in the Shaker voltage-gated potassium channel at key regions that were previously inaccessible. Thus, we defined which parts act independently and which parts act cooperatively and found pore opening to occur in two sequential transitions. PMID- 23630266 TI - Political ideology affects energy-efficiency attitudes and choices. AB - This research demonstrates how promoting the environment can negatively affect adoption of energy efficiency in the United States because of the political polarization surrounding environmental issues. Study 1 demonstrated that more politically conservative individuals were less in favor of investment in energy efficient technology than were those who were more politically liberal. This finding was driven primarily by the lessened psychological value that more conservative individuals placed on reducing carbon emissions. Study 2 showed that this difference has consequences: In a real-choice context, more conservative individuals were less likely to purchase a more expensive energy-efficient light bulb when it was labeled with an environmental message than when it was unlabeled. These results highlight the importance of taking into account psychological value-based considerations in the individual adoption of energy efficient technology in the United States and beyond. PMID- 23630267 TI - Mechanism of somatic hypermutation at the WA motif by human DNA polymerase eta. AB - Somatic hypermutation is programmed base substitutions in the variable regions of Ig genes for high-affinity antibody generation. Two motifs, RGYW and WA (R, purine; Y, pyrimidine; W, A or T), have been found to be somatic hypermutation hotspots. Overwhelming evidence suggests that DNA polymerase eta (Pol eta) is responsible for converting the WA motif to WG by misincorporating dGTP opposite the templating T. To elucidate the molecular mechanism, crystal structures and kinetics of human Pol eta substituting dGTP for dATP in four sequence contexts, TA, AA, GA, and CA, have been determined and compared. The T:dGTP wobble base pair is stabilized by Gln-38 and Arg-61, two uniquely conserved residues among Pol eta. Weak base paring of the W (T:A or A:T) at the primer end and their distinct interactions with Pol eta lead to misincorporation of G in the WA motif. Between two WA motifs, our kinetic and structural data indicate that A-to-G mutation occurs more readily in the TA context than AA. Finally, Pol eta can extend the T:G mispair efficiently to complete the mutagenesis. PMID- 23630268 TI - Synaptopodin regulates denervation-induced homeostatic synaptic plasticity. AB - Synaptopodin (SP) is a marker and essential component of the spine apparatus (SA), an enigmatic cellular organelle composed of stacked smooth endoplasmic reticulum that has been linked to synaptic plasticity. However, SP/SA-mediated synaptic plasticity remains incompletely understood. To study the role of SP/SA in homeostatic synaptic plasticity we here used denervation-induced synaptic scaling of mouse dentate granule cells as a model system. This form of plasticity is of considerable interest in the context of neurological diseases that are associated with the loss of neurons and subsequent denervation of connected brain regions. In entorhino-hippocampal slice cultures prepared from SP-deficient mice, which lack the SA, a compensatory increase in excitatory synaptic strength was not observed following partial deafferentation. In line with this finding, prolonged blockade of sodium channels with tetrodotoxin induced homeostatic synaptic scaling in wild-type, but not SP-deficient, slice cultures. By crossing SP-deficient mice with a newly generated transgenic mouse strain that expresses GFP-tagged SP under the control of the Thy1.2 promoter, the ability of dentate granule cells to form the SA and to homeostatically strengthen excitatory synapses was rescued. Interestingly, homeostatic synaptic strengthening was accompanied by a compensatory increase in SP cluster size/stability and SA stack number, suggesting that activity-dependent SP/SA remodeling could be part of a negative feedback mechanism that aims at adjusting the strength of excitatory synapses to persisting changes in network activity. Thus, our results disclose an important role for SP/SA in homeostatic synaptic plasticity. PMID- 23630269 TI - Ash from the Toba supereruption in Lake Malawi shows no volcanic winter in East Africa at 75 ka. AB - The most explosive volcanic event of the Quaternary was the eruption of Mt. Toba, Sumatra, 75,000 y ago, which produced voluminous ash deposits found across much of the Indian Ocean, Indian Peninsula, and South China Sea. A major climatic downturn observed within the Greenland ice cores has been attributed to the cooling effects of the ash and aerosols ejected during the eruption of the Youngest Toba Tuff (YTT). These events coincided roughly with a hypothesized human genetic bottleneck, when the number of our species in Africa may have been reduced to near extinction. Some have speculated that the demise of early modern humans at that time was due in part to a dramatic climate shift triggered by the supereruption. Others have argued that environmental conditions would not have been so severe to have such an impact on our ancestors, and furthermore, that modern humans may have already expanded beyond Africa by this time. We report an observation of the YTT in Africa, recovered as a cryptotephra layer in Lake Malawi sediments, >7,000 km west of the source volcano. The YTT isochron provides an accurate and precise age estimate for the Lake Malawi paleoclimate record, which revises the chronology of past climatic events in East Africa. The YTT in Lake Malawi is not accompanied by a major change in sediment composition or evidence for substantial temperature change, implying that the eruption did not significantly impact the climate of East Africa and was not the cause of a human genetic bottleneck at that time. PMID- 23630270 TI - A tribute to C. Everett Koop. PMID- 23630271 TI - Used planet: a global history. AB - Human use of land has transformed ecosystem pattern and process across most of the terrestrial biosphere, a global change often described as historically recent and potentially catastrophic for both humanity and the biosphere. Interdisciplinary paleoecological, archaeological, and historical studies challenge this view, indicating that land use has been extensive and sustained for millennia in some regions and that recent trends may represent as much a recovery as an acceleration. Here we synthesize recent scientific evidence and theory on the emergence, history, and future of land use as a process transforming the Earth System and use this to explain why relatively small human populations likely caused widespread and profound ecological changes more than 3,000 y ago, whereas the largest and wealthiest human populations in history are using less arable land per person every decade. Contrasting two spatially explicit global reconstructions of land-use history shows that reconstructions incorporating adaptive changes in land-use systems over time, including land-use intensification, offer a more spatially detailed and plausible assessment of our planet's history, with a biosphere and perhaps even climate long ago affected by humans. Although land-use processes are now shifting rapidly from historical patterns in both type and scale, integrative global land-use models that incorporate dynamic adaptations in human-environment relationships help to advance our understanding of both past and future land-use changes, including their sustainability and potential global effects. PMID- 23630272 TI - Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder. AB - Childhood maltreatment is likely to influence fundamental biological processes and engrave long-lasting epigenetic marks, leading to adverse health outcomes in adulthood. We aimed to elucidate the impact of different early environment on disease-related genome-wide gene expression and DNA methylation in peripheral blood cells in patients with posttraumatic stress disorder (PTSD). Compared with the same trauma-exposed controls (n = 108), gene-expression profiles of PTSD patients with similar clinical symptoms and matched adult trauma exposure but different childhood adverse events (n = 32 and 29) were almost completely nonoverlapping (98%). These differences on the level of individual transcripts were paralleled by the enrichment of several distinct biological networks between the groups. Moreover, these gene-expression changes were accompanied and likely mediated by changes in DNA methylation in the same loci to a much larger proportion in the childhood abuse (69%) vs. the non-child abuse-only group (34%). This study is unique in providing genome-wide evidence of distinct biological modifications in PTSD in the presence or absence of exposure to childhood abuse. The findings that nonoverlapping biological pathways seem to be affected in the two PTSD groups and that changes in DNA methylation appear to have a much greater impact in the childhood-abuse group might reflect differences in the pathophysiology of PTSD, in dependence of exposure to childhood maltreatment. These results contribute to a better understanding of the extent of influence of differences in trauma exposure on pathophysiological processes in stress-related psychiatric disorders and may have implications for personalized medicine. PMID- 23630273 TI - Single-molecule DNA repair in live bacteria. AB - Cellular DNA damage is reversed by balanced repair pathways that avoid accumulation of toxic intermediates. Despite their importance, the organization of DNA repair pathways and the function of repair enzymes in vivo have remained unclear because of the inability to directly observe individual reactions in living cells. Here, we used photoactivation, localization, and tracking in live Escherichia coli to directly visualize single fluorescent labeled DNA polymerase I (Pol) and ligase (Lig) molecules searching for DNA gaps and nicks, performing transient reactions, and releasing their products. Our general approach provides enzymatic rates and copy numbers, substrate-search times, diffusion characteristics, and the spatial distribution of reaction sites, at the single cell level, all in one measurement. Single repair events last 2.1 s (Pol) and 2.5 s (Lig), respectively. Pol and Lig activities increased fivefold over the basal level within minutes of DNA methylation damage; their rates were limited by upstream base excision repair pathway steps. Pol and Lig spent >80% of their time searching for free substrates, thereby minimizing both the number and lifetime of toxic repair intermediates. We integrated these single-molecule observations to generate a quantitative, systems-level description of a model repair pathway in vivo. PMID- 23630274 TI - Reorganization of an intersubunit bridge induced by disparate 16S ribosomal ambiguity mutations mimics an EF-Tu-bound state. AB - After four decades of research aimed at understanding tRNA selection on the ribosome, the mechanism by which ribosomal ambiguity (ram) mutations promote miscoding remains unclear. Here, we present two X-ray crystal structures of the Thermus thermophilus 70S ribosome containing 16S rRNA ram mutations, G347U and G299A. Each of these mutations causes miscoding in vivo and stimulates elongation factor thermo unstable (EF-Tu)-dependent GTP hydrolysis in vitro. Mutation G299A is located near the interface of ribosomal proteins S4 and S5 on the solvent side of the subunit, whereas G347U is located 77 A distant, at intersubunit bridge B8, close to where EF-Tu engages the ribosome. Despite these disparate locations, both mutations induce almost identical structural rearrangements that disrupt the B8 bridge--namely, the interaction of h8/h14 with L14 and L19. This conformation most closely resembles that seen upon EF-Tu-GTP-aminoacyl-tRNA binding to the 70S ribosome. These data provide evidence that disruption and/or distortion of B8 is an important aspect of GTPase activation. We propose that, by destabilizing B8, G299A and G347U reduce the energetic cost of attaining the GTPase-activated state and thereby decrease the stringency of decoding. This previously unappreciated role for B8 in controlling the decoding process may hold relevance for many other ribosomal mutations known to influence translational fidelity. PMID- 23630275 TI - Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8+ T cell skewing in allergic lung disease. AB - Allergic asthma is a heterogeneous inflammatory disorder of the airways characterized by chronic airway inflammation and airway hyperresponsiveness. Numbers of CD8(+)IL-13(+) T cells are increased in asthmatics and during the development of experimental asthma in mice. In an atopic environment rich in IL 4, these CD8(+) T cells mediate asthmatic responses, but the mechanisms regulating the conversion of CD8(+) effector T cells from IFN-gamma- to pathogenic IL-13-producing effector cells that contribute to an asthma phenotype have not been defined. Here, we show that cholesterol side-chain cleavage P450 enzyme, Cyp11a1, is a key regulator of CD8(+) T-cell conversion. Expression of the gene, protein, and enzymatic activity of Cyp11a1 were markedly increased in CD8(+) T cells differentiated in the presence of IL-2 plus IL-4 compared with cells differentiated in IL-2 alone. Inhibition of Cyp11a1 enzymatic activity with aminoglutethimide or reduction in the expression of Cyp11a1 using short hairpin RNA prevented the IL-4-induced conversion of IFN-gamma- to IL-13-producing cells without affecting expression of the lineage-specific transcription factors T-box expressed in T cells (T-bet) or GATA binding protein 3 (GATA3). Adoptive transfer of aminoglutethimide-treated CD8(+) T cells into sensitized and challenged CD8 deficient recipients failed to restore airway hyperresponsiveness and inflammation. We demonstrate that Cyp11a1 controls the phenotypic conversion of CD8(+) T cells from IFN-gamma to IL-13 production, linking steroidogenesis in CD8(+) T cells, a nonclassical steroidogenic tissue, to a proallergic differentiation pathway. PMID- 23630276 TI - Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian tumorigenesis. AB - In recent years, the role played by the stromal microenvironment has been given growing attention in order to achieve a full understanding of cancer initiation and progression. Because cancer is a tissue-based disease, the integrity of tissue architecture is a major constraint toward cancer growth. Indeed, a large contribution of the natural resistance to cancer stems from stromal microenvironment components, the dysregulation of which can facilitate cancer occurrence. For instance, recent experimental evidence has highlighted the involvement of stromal cells in ovarian carcinogenesis, as epitomized by ovarian xenografts obtained by a double KO of the murine Dicer and Pten genes. Likewise, we reported the role of an ancient extracellular RNase, called Ribonuclease T2 (RNASET2), within the ovarian stromal microenvironment. Indeed, hyperexpression of RNASET2 is able to control tumorigenesis by recruiting macrophages (mostly of the anticancer M1 subtype) at the tumor sites. We present biological data obtained by RNASET2 silencing in the poorly tumorigenetic and highly RNASET2 expressing human OVCAR3 cell line. RNASET2 knockdown was shown to stimulate in vivo tumor growth early after microinjection of OVCAR3 cells in nude mice. Moreover, we have investigated by molecular profiling the in vivo expression signature of human and mouse cell xenografts and disclosed the activation of pathways related to activation of the innate immune response and modulation of ECM components. Finally, we provide evidence for a role of RNASET2 in triggering an in vitro chemotactic response in macrophages. These results further highlight the critical role played by the microenvironment in RNASET2-mediated ovarian tumor suppression, which could eventually contribute to better clarify the pathogenesis of this disease. PMID- 23630277 TI - Self-cleaning of superhydrophobic surfaces by self-propelled jumping condensate. AB - The self-cleaning function of superhydrophobic surfaces is conventionally attributed to the removal of contaminating particles by impacting or rolling water droplets, which implies the action of external forces such as gravity. Here, we demonstrate a unique self-cleaning mechanism whereby the contaminated superhydrophobic surface is exposed to condensing water vapor, and the contaminants are autonomously removed by the self-propelled jumping motion of the resulting liquid condensate, which partially covers or fully encloses the contaminating particles. The jumping motion off the superhydrophobic surface is powered by the surface energy released upon coalescence of the condensed water phase around the contaminants. The jumping-condensate mechanism is shown to spontaneously clean superhydrophobic cicada wings, where the contaminating particles cannot be removed by gravity, wing vibration, or wind flow. Our findings offer insights for the development of self-cleaning materials. PMID- 23630278 TI - An essential role for gamma-herpesvirus latency-associated nuclear antigen homolog in an acute lymphoproliferative disease of cattle. AB - Wildebeests carry asymptomatically alcelaphine herpesvirus 1 (AlHV-1), a gamma herpesvirus inducing malignant catarrhal fever (MCF) to several ruminant species (including cattle). This acute and lethal lymphoproliferative disease occurs after a prolonged asymptomatic incubation period after transmission. Our recent findings with the rabbit model indicated that AlHV-1 infection is not productive during MCF. Here, we investigated whether latency establishment could explain this apparent absence of productive infection and sought to determine its role in MCF pathogenesis. First, whole-genome cellular and viral gene expression analyses were performed in lymph nodes of MCF-developing calves. Whereas a severe disruption in cellular genes was observed, only 10% of the entire AlHV-1 genome was expressed, contrasting with the 45% observed during productive infection in vitro. In vivo, the expressed viral genes included the latency-associated nuclear antigen homolog ORF73 but none of the regions known to be essential for productive infection. Next, genomic conformation analyses revealed that AlHV-1 was essentially episomal, further suggesting that MCF might be the consequence of a latent infection rather than abortive lytic infection. This hypothesis was further supported by the high frequencies of infected CD8(+) T cells during MCF using immunodetection of ORF73 protein and single-cell RT-PCR approaches. Finally, the role of latency-associated ORF73 was addressed. A lack of ORF73 did not impair initial virus replication in vivo, but it rendered AlHV-1 unable to induce MCF and persist in vivo and conferred protection against a lethal challenge with a WT virus. Together, these findings suggest that a latent infection is essential for MCF induction. PMID- 23630279 TI - AMPA receptor exchange underlies transient memory destabilization on retrieval. AB - A consolidated memory can be transiently destabilized by memory retrieval, after which memories are reconsolidated within a few hours; however, the molecular substrates underlying this destabilization process remain essentially unknown. Here we show that at lateral amygdala synapses, fear memory consolidation correlates with increased surface expression of calcium-impermeable AMPA receptors (CI-AMPARs), which are known to be more stable at the synapse, whereas memory retrieval induces an abrupt exchange of CI-AMPARs to calcium-permeable AMPARs (CP-AMPARs), which are known to be less stable at the synapse. We found that blockade of either CI-AMPAR endocytosis or NMDA receptor activity during memory retrieval, both of which blocked the exchange to CP-AMPARs, prevented memory destabilization, indicating that this transient exchange of AMPARs may underlie the transformation of a stable memory into an unstable memory. These newly inserted CP-AMPARs gradually exchanged back to CI-AMPARs within hours, which coincided with the course of reconsolidation. Furthermore, blocking the activity of these newly inserted CP-AMPARs after retrieval impaired reconsolidation, suggesting that they serve as synaptic "tags" that support synapse-specific reconsolidation. Taken together, our results reveal unexpected physiological roles of CI-AMPARs and CP-AMPARs in transforming a consolidated memory into an unstable memory and subsequently guiding reconsolidation. PMID- 23630280 TI - Escalation of polymerization in a thermal gradient. AB - For the emergence of early life, the formation of biopolymers such as RNA is essential. However, the addition of nucleotide monomers to existing oligonucleotides requires millimolar concentrations. Even in such optimistic settings, no polymerization of RNA longer than about 20 bases could be demonstrated. How then could self-replicating ribozymes appear, for which recent experiments suggest a minimal length of 200 nt? Here, we demonstrate a mechanism to bridge this gap: the escalated polymerization of nucleotides by a spatially confined thermal gradient. The gradient accumulates monomers by thermophoresis and convection while retaining longer polymers exponentially better. Polymerization and accumulation become mutually self-enhancing and result in a hyperexponential escalation of polymer length. We describe this escalation theoretically under the conservative assumption of reversible polymerization. Taking into account the separately measured thermophoretic properties of RNA, we extrapolate the results for primordial RNA polymerization inside a temperature gradient in pores or fissures of rocks. With a dilute, nanomolar concentration of monomers the model predicts that a pore length of 5 cm and a temperature difference of 10 K suffice to polymerize 200-mers of RNA in micromolar concentrations. The probability to generate these long RNAs is raised by a factor of >10(600) compared with polymerization in a physical equilibrium. We experimentally validate the theory with the reversible polymerization of DNA blocks in a laser-driven thermal trap. The results confirm that a thermal gradient can significantly enlarge the available sequence space for the emergence of catalytically active polymers. PMID- 23630281 TI - Aptamer to ErbB-2/HER2 enhances degradation of the target and inhibits tumorigenic growth. AB - Aptamers, oligonucleotides able to avidly bind cellular targets, are emerging as promising therapeutic agents, analogous to monoclonal antibodies. We selected from a DNA library an aptamer specifically recognizing human epidermal growth factor receptor 2 (ErbB-2/HER2), a receptor tyrosine kinase, which is overexpressed in a variety of human cancers, including breast and gastric tumors. Treatment of human gastric cancer cells with a trimeric version (42 nucleotides) of the selected aptamer (14 nucleotides) resulted in reduced cell growth in vitro, but a monomeric version was ineffective. Likewise, when treated with the trimeric aptamer, animals bearing tumor xenografts of human gastric origin reflected reduced rates of tumor growth. The antitumor effect of the aptamer was nearly twofold stronger than that of a monoclonal anti-ErbB-2/HER2 antibody. Consistent with aptamer-induced intracellular degradation of ErbB-2/HER2, incubation of gastric cancer cells with the trimeric aptamer promoted translocation of ErbB-2/HER2 from the cell surface to cytoplasmic puncta. This translocation was associated with a lysosomal hydrolase-dependent clearance of the ErbB-2/HER2 protein from cell extracts. We conclude that targeting ErbB 2/HER2 with DNA aptamers might retard the tumorigenic growth of gastric cancer by means of accelerating lysosomal degradation of the oncoprotein. This work exemplifies the potential pharmacological utility of aptamers directed at cell surface proteins, and it highlights an endocytosis-mediated mechanism of tumor inhibition. PMID- 23630282 TI - Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist. AB - Vertebrate Toll-like receptor 5 (TLR5) recognizes bacterial flagellin proteins and activates innate immune responses to motile bacteria. In addition, activation of TLR5 signaling can inhibit growth of TLR5-expressing tumors and protect normal tissues from radiation and ischemia-reperfusion injuries. To understand the mechanisms behind these phenomena at the organismal level, we assessed nuclear factor kappa B (NF-kappaB) activation (indicative of TLR5 signaling) in tissues and cells of mice treated with CBLB502, a pharmacologically optimized flagellin derivative. This identified the liver and gastrointestinal tract as primary CBLB502 target organs. In particular, liver hepatocytes were the main cell type directly and specifically responding to systemic administration of CBLB502 but not to that of the TLR4 agonist LPS. To assess CBLB502 impact on other pathways, we created multireporter mice with hepatocytes transduced in vivo with reporters for 46 inducible transcription factor families and found that along with NF kappaB, CBLB502 strongly activated STAT3-, phenobarbital-responsive enhancer module (PREM), and activator protein 1 (AP-1-) -driven pathways. Livers of CBLB502-treated mice displayed induction of numerous immunomodulatory factors and massive recruitment of various types of immune cells. This led to inhibition of growth of liver metastases of multiple tumors regardless of their TLR5 status. The changed liver microenvironment was not, however, hepatotoxic, because CBLB502 induced resistance to Fas-mediated apoptosis in normal liver cells. Temporary occlusion of liver blood circulation prevented CBLB502 from protecting hematopoietic progenitors in lethally irradiated mice, indicating involvement of a factor secreted by responding liver cells. These results define the liver as the key mediator of TLR5-dependent effects in vivo and suggest clinical applications for TLR5 agonists as hepatoprotective and antimetastatic agents. PMID- 23630283 TI - Lipid phosphatases identified by screening a mouse phosphatase shRNA library regulate T-cell differentiation and protein kinase B AKT signaling. AB - Screening a complete mouse phosphatase lentiviral shRNA library using high throughput sequencing revealed several phosphatases that regulate CD4 T-cell differentiation. We concentrated on two lipid phosphatases, the myotubularin related protein (MTMR)9 and -7. Silencing MTMR9 by shRNA or siRNA resulted in enhanced T-helper (Th)1 differentiation and increased Th1 protein kinase B (PKB)/AKT phosphorylation while silencing MTMR7 caused increased Th2 and Th17 differentiation and increased AKT phosphorylation in these cells. Irradiated mice reconstituted with MTMR9 shRNA-transduced bone marrow cells had an elevated proportion of T-box transcription factor T-bet expressors among their CD4 T cells. After adoptive transfer of naive cells from such reconstituted mice, immunization resulted in a greater proportion of T-box transcription factor T-bet expressing cells. Thus, myotubularin-related proteins have a role in controlling in vitro and in vivo Th-cell differentiation, possibly through regulation of phosphatidylinositol [3,4,5]-trisphosphate activity. PMID- 23630284 TI - Intermediate intrinsic diversity enhances neural population coding. AB - Cell-to-cell variability in molecular, genetic, and physiological features is increasingly recognized as a critical feature of complex biological systems, including the brain. Although such variability has potential advantages in robustness and reliability, how and why biological circuits assemble heterogeneous cells into functional groups is poorly understood. Here, we develop analytic approaches toward answering how neuron-level variation in intrinsic biophysical properties of olfactory bulb mitral cells influences population coding of fluctuating stimuli. We capture the intrinsic diversity of recorded populations of neurons through a statistical approach based on generalized linear models. These models are flexible enough to predict the diverse responses of individual neurons yet provide a common reference frame for comparing one neuron to the next. We then use Bayesian stimulus decoding to ask how effectively different populations of mitral cells, varying in their diversity, encode a common stimulus. We show that a key advantage provided by physiological levels of intrinsic diversity is more efficient and more robust encoding of stimuli by the population as a whole. However, we find that the populations that best encode stimulus features are not simply the most heterogeneous, but those that balance diversity with the benefits of neural similarity. PMID- 23630285 TI - Arabidopsis nanodomain-delimited ABA signaling pathway regulates the anion channel SLAH3. AB - The phytohormone abscisic acid (ABA) plays a key role in the plant response to drought stress. Hence, ABA-dependent gene transcription and ion transport is regulated by a variety of protein kinases and phosphatases. However, the nature of the membrane-delimited ABA signal transduction steps remains largely unknown. To gain insight into plasma membrane-bound ABA signaling, we identified sterol dependent proteins associated with detergent resistant membranes from Arabidopsis thaliana mesophyll cells. Among those, we detected the central ABA signaling phosphatase ABI1 (abscisic-acid insensitive 1) and the calcium-dependent protein kinase 21 (CPK21). Using fluorescence microscopy, we found these proteins to localize in membrane nanodomains, as observed by colocalization with the nanodomain marker remorin Arabidopsis thaliana remorin 1.3 (AtRem 1.3). After transient coexpression, CPK21 interacted with SLAH3 [slow anion channel 1 (SLAC1) homolog 3] and activated this anion channel. Upon CPK21 stimulation, SLAH3 exhibited the hallmark properties of S-type anion channels. Coexpression of SLAH3/CPK21 with ABI1, however, prevented proper nanodomain localization of the SLAH3/CPK21 protein complex, and as a result anion channel activation failed. FRET studies revealed enhanced interaction of SLAH3 and CPK21 within the plasma membrane in response to ABA and thus confirmed our initial observations. Interestingly, the ABA-induced SLAH3/CPK21 interaction was modulated by ABI1 and the ABA receptor RCAR1/PYL9 [regulatory components of ABA receptor 1/PYR1 (pyrabactin resistance 1)-like protein 9]. We therefore propose that ABA signaling via inhibition of ABI1 modulates the apparent association of a signaling and transport complex within membrane domains that is necessary for phosphorylation and activation of the S-type anion channel SLAH3 by CPK21. PMID- 23630286 TI - Neural predictors of individual differences in response to math tutoring in primary-grade school children. AB - Now, more than ever, the ability to acquire mathematical skills efficiently is critical for academic and professional success, yet little is known about the behavioral and neural mechanisms that drive some children to acquire these skills faster than others. Here we investigate the behavioral and neural predictors of individual differences in arithmetic skill acquisition in response to 8-wk of one to-one math tutoring. Twenty-four children in grade 3 (ages 8-9 y), a critical period for acquisition of basic mathematical skills, underwent structural and resting-state functional MRI scans pretutoring. A significant shift in arithmetic problem-solving strategies from counting to fact retrieval was observed with tutoring. Notably, the speed and accuracy of arithmetic problem solving increased with tutoring, with some children improving significantly more than others. Next, we examined whether pretutoring behavioral and brain measures could predict individual differences in arithmetic performance improvements with tutoring. No behavioral measures, including intelligence quotient, working memory, or mathematical abilities, predicted performance improvements. In contrast, pretutoring hippocampal volume predicted performance improvements. Furthermore, pretutoring intrinsic functional connectivity of the hippocampus with dorsolateral and ventrolateral prefrontal cortices and the basal ganglia also predicted performance improvements. Our findings provide evidence that individual differences in morphometry and connectivity of brain regions associated with learning and memory, and not regions typically involved in arithmetic processing, are strong predictors of responsiveness to math tutoring in children. More generally, our study suggests that quantitative measures of brain structure and intrinsic brain organization can provide a more sensitive marker of skill acquisition than behavioral measures. PMID- 23630287 TI - Evidence of a liquid-liquid phase transition in hot dense hydrogen. AB - We use pulsed-laser heating of hydrogen at static pressures in the megabar pressure region to search for the plasma phase transition to liquid atomic metallic hydrogen. We heat our samples substantially above the melting line and observe a plateau in a temperature vs. laser power curve that otherwise increases with power. This anomaly in the heating curve appears correlated with theoretical predictions for the plasma phase transition. PMID- 23630288 TI - Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons. AB - Acute or chronic alterations in energy status alter the balance between excitatory and inhibitory synaptic transmission and associated synaptic plasticity to allow for the adaptation of energy metabolism to new homeostatic requirements. The impact of such changes on endocannabinoid and cannabinoid receptor type 1 (CB1)-mediated modulation of synaptic transmission and strength is not known, despite the fact that this signaling system is an important target for the development of new drugs against obesity. We investigated whether CB1 expressing excitatory vs. inhibitory inputs to orexin-A-containing neurons in the lateral hypothalamus are altered in obesity and how this modifies endocannabinoid control of these neurons. In lean mice, these inputs are mostly excitatory. By confocal and ultrastructural microscopic analyses, we observed that in leptin knockout (ob/ob) obese mice, and in mice with diet-induced obesity, orexinergic neurons receive predominantly inhibitory CB1-expressing inputs and overexpress the biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol, which retrogradely inhibits synaptic transmission at CB1-expressing axon terminals. Patch-clamp recordings also showed increased CB1-sensitive inhibitory innervation of orexinergic neurons in ob/ob mice. These alterations are reversed by leptin administration, partly through activation of the mammalian target of rapamycin pathway in neuropeptide-Y-ergic neurons of the arcuate nucleus, and are accompanied by CB1-mediated enhancement of orexinergic innervation of target brain areas. We propose that enhanced inhibitory control of orexin-A neurons, and their CB1-mediated disinhibition, are a consequence of leptin signaling impairment in the arcuate nucleus. We also provide initial evidence of the participation of this phenomenon in hyperphagia and hormonal dysregulation in obesity. PMID- 23630289 TI - Subjective costs drive overly patient foraging strategies in rats on an intertemporal foraging task. AB - Laboratory studies of decision making often take the form of two-alternative, forced-choice paradigms. In natural settings, however, many decision problems arise as stay/go choices. We designed a foraging task to test intertemporal decision making in rats via stay/go decisions. Subjects did not follow the rate maximizing strategy of choosing only food items associated with short delays. Instead, rats were often willing to wait for surprisingly long periods, and consequently earned a lower rate of food intake than they might have by ignoring long-delay options. We tested whether foraging theory or delay discounting models predicted the behavior we observed but found that these models could not account for the strategies subjects selected. Subjects' behavior was well accounted for by a model that incorporated a cost for rejecting potential food items. Interestingly, subjects' cost sensitivity was proportional to environmental richness. These findings are at odds with traditional normative accounts of decision making but are consistent with retrospective considerations having a deleterious influence on decisions (as in the "sunk-cost" effect). More broadly, these findings highlight the utility of complementing existing assays of decision making with tasks that mimic more natural decision topologies. PMID- 23630290 TI - In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction. AB - Mutational activation of the Ras oncogene products (H-Ras, K-Ras, and N-Ras) is frequently observed in human cancers, making them promising anticancer drug targets. Nonetheless, no effective strategy has been available for the development of Ras inhibitors, partly owing to the absence of well-defined surface pockets suitable for drug binding. Only recently, such pockets have been found in the crystal structures of a unique conformation of Ras?GTP. Here we report the successful development of small-molecule Ras inhibitors by an in silico screen targeting a pocket found in the crystal structure of M-Ras?GTP carrying an H-Ras-type substitution P40D. The selected compound Kobe0065 and its analog Kobe2602 exhibit inhibitory activity toward H-Ras?GTP-c-Raf-1 binding both in vivo and in vitro. They effectively inhibit both anchorage-dependent and independent growth and induce apoptosis of H-ras(G12V)-transformed NIH 3T3 cells, which is accompanied by down-regulation of downstream molecules such as MEK/ERK, Akt, and RalA as well as an upstream molecule, Son of sevenless. Moreover, they exhibit antitumor activity on a xenograft of human colon carcinoma SW480 cells carrying the K-ras(G12V) gene by oral administration. The NMR structure of a complex of the compound with H-Ras?GTP(T35S), exclusively adopting the unique conformation, confirms its insertion into one of the surface pockets and provides a molecular basis for binding inhibition toward multiple Ras?GTP-interacting molecules. This study proves the effectiveness of our strategy for structure based drug design to target Ras?GTP, and the resulting Kobe0065-family compounds may serve as a scaffold for the development of Ras inhibitors with higher potency and specificity. PMID- 23630291 TI - Blood meal-induced changes to antennal transcriptome profiles reveal shifts in odor sensitivities in Anopheles gambiae. AB - Olfactory-driven behaviors are central to the lifecycle of the malaria vector mosquito Anopheles gambiae and are initiated by peripheral signaling in the antenna and other olfactory tissues. To continue gaining insight into the relationship between gene expression and olfaction, we have performed cohort comparisons of antennal transcript abundances at five time points after a blood meal, a key event in both reproduction and disease transmission cycles. We found that more than 5,000 transcripts displayed significant abundance differences, many of which were correlated by cluster analysis. Within the chemosensory gene families, we observed a general reduction in the level of chemosensory gene transcripts, although a subset of odorant receptors (AgOrs) was modestly enhanced in post-blood-fed samples. Integration of AgOr transcript abundance data with previously characterized AgOr excitatory odorant response profiles revealed potential changes in antennal odorant receptivity that coincided with the shift from host-seeking to oviposition behaviors in blood-fed female mosquitoes. Behavioral testing of ovipositing females to odorants highlighted by this synthetic analysis identified two unique, unitary oviposition cues for An. gambiae, 2-propylphenol and 4-methylcyclohexanol. We posit that modest, yet cumulative, alterations of AgOr transcript levels modulate peripheral odor coding resulting in biologically relevant behavioral effects. Moreover, these results demonstrate that highly quantitative, RNAseq transcript abundance data can be successfully integrated with functional data to generate testable hypotheses. PMID- 23630292 TI - Genetic deletion of Rnd3 results in aqueductal stenosis leading to hydrocephalus through up-regulation of Notch signaling. AB - Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of the small Rho GTPase family, is involved in the regulation of cell actin cytoskeleton dynamics, cell migration, and proliferation through the Rho kinase-dependent signaling pathway. We report a role of Rnd3 in the pathogenesis of hydrocephalus disorder. Mice with Rnd3 genetic deletion developed severe obstructive hydrocephalus with enlargement of the lateral and third ventricles, but not of the fourth ventricles. The cerebral aqueducts in Rnd3-null mice were partially or completely blocked by the overgrowth of ependymal epithelia. We examined the molecular mechanism contributing to this Rnd3-deficiency-mediated hydrocephalus and found that Rnd3 is a regulator of Notch signaling. Rnd3 deficiency, through either gene deletion or siRNA knockdown, resulted in a decrease in Notch intracellular domain (NICD) protein degradation. However, there was no correlated change in mRNA change, which in turn led to an increase in NICD protein levels. Immunoprecipitation analysis demonstrated that Rnd3 and NICD physically interacted, and that down-regulation of Rnd3 attenuated NICD protein ubiquitination. This eventually enhanced Notch signaling activity and promoted aberrant growth of aqueduct ependymal cells, resulting in aqueduct stenosis and the development of congenital hydrocephalus. Inhibition of Notch activity rescued the hydrocephalus disorder in the mutant animals. PMID- 23630293 TI - A model comparison approach shows stronger support for economic models of fertility decline. AB - The demographic transition is an ongoing global phenomenon in which high fertility and mortality rates are replaced by low fertility and mortality. Despite intense interest in the causes of the transition, especially with respect to decreasing fertility rates, the underlying mechanisms motivating it are still subject to much debate. The literature is crowded with competing theories, including causal models that emphasize (i) mortality and extrinsic risk, (ii) the economic costs and benefits of investing in self and children, and (iii) the cultural transmission of low-fertility social norms. Distinguishing between models, however, requires more comprehensive, better-controlled studies than have been published to date. We use detailed demographic data from recent fieldwork to determine which models produce the most robust explanation of the rapid, recent demographic transition in rural Bangladesh. To rigorously compare models, we use an evidence-based statistical approach using model selection techniques derived from likelihood theory. This approach allows us to quantify the relative evidence the data give to alternative models, even when model predictions are not mutually exclusive. Results indicate that fertility, measured as either total fertility or surviving children, is best explained by models emphasizing economic factors and related motivations for parental investment. Our results also suggest important synergies between models, implicating multiple causal pathways in the rapidity and degree of recent demographic transitions. PMID- 23630294 TI - Regulator of G protein signaling 4 [corrected] is a crucial modulator of antidepressant drug action in depression and neuropathic pain models. AB - Regulator of G protein signaling 4 (Rgs4) is a signal transduction protein that controls the function of monoamine, opiate, muscarinic, and other G protein coupled receptors via interactions with Galpha subunits. Rgs4 is expressed in several brain regions involved in mood, movement, cognition, and addiction and is regulated by psychotropic drugs, stress, and corticosteroids. In this study, we use genetic mouse models and viral-mediated gene transfer to examine the role of Rgs4 in the actions of antidepressant medications. We first analyzed human postmortem brain tissue and found robust up-regulation of RGS4 expression in the nucleus accumbens (NAc) of subjects receiving standard antidepressant medications that target monoamine systems. Behavioral studies of mice lacking Rgs4, including specific knockdowns in NAc, demonstrate that Rgs4 in this brain region acts as a positive modulator of the antidepressant-like and antiallodynic-like actions of several monoamine-directed antidepressant drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and norepinephrine reuptake inhibitors. Studies using viral-mediated increases in Rgs4 activity in NAc further support this hypothesis. Interestingly, in prefrontal cortex, Rgs4 acts as a negative modulator of the actions of nonmonoamine-directed drugs that are purported to act as antidepressants: the N-methyl-D-aspartate glutamate receptor antagonist ketamine and the delta opioid agonist (+)-4-[(alphaR)-alpha ((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N diethylbenzamide. Together, these data reveal a unique modulatory role of Rgs4 in the brain region-specific actions of a wide range of antidepressant drugs and indicate that pharmacological interventions at the level of RGS4 activity may enhance the actions of such drugs used for the treatment of depression and neuropathic pain. PMID- 23630295 TI - Provincialization of terrestrial faunas following the end-Permian mass extinction. AB - In addition to their devastating effects on global biodiversity, mass extinctions have had a long-term influence on the history of life by eliminating dominant lineages that suppressed ecological change. Here, we test whether the end-Permian mass extinction (252.3 Ma) affected the distribution of tetrapod faunas within the southern hemisphere and apply quantitative methods to analyze four components of biogeographic structure: connectedness, clustering, range size, and endemism. For all four components, we detected increased provincialism between our Permian and Triassic datasets. In southern Pangea, a more homogeneous and broadly distributed fauna in the Late Permian (Wuchiapingian, ~257 Ma) was replaced by a provincial and biogeographically fragmented fauna by Middle Triassic times (Anisian, ~242 Ma). Importantly in the Triassic, lower latitude basins in Tanzania and Zambia included dinosaur predecessors and other archosaurs unknown elsewhere. The recognition of heterogeneous tetrapod communities in the Triassic implies that the end-Permian mass extinction afforded ecologically marginalized lineages the ecospace to diversify, and that biotic controls (i.e., evolutionary incumbency) were fundamentally reset. Archosaurs, which began diversifying in the Early Triassic, were likely beneficiaries of this ecological release and remained dominant for much of the later Mesozoic. PMID- 23630296 TI - miRNA regulation of BK polyomavirus replication during early infection. AB - Viral microRNAs (miRNAs) play an important role during infection by posttranscriptionally regulating both host and viral gene expression. However, the function of many viral miRNAs remains poorly understood. In this study, we investigated the role of the BK polyomavirus (BKPyV) miRNA in regulating virus replication. The function of the polyomavirus miRNA was investigated in archetype BKPyV, which is the transmissible form of the virus and thought to establish a persistent infection in the host urinary tract. In agreement with previous studies, we show that the BKPyV miRNA targets early mRNAs. Importantly, we show that the miRNA plays a significant role in limiting archetype BKPyV replication in a natural host cell model of infection. This regulation is accomplished through the balance of regulatory elements located within the noncoding control region that control early gene expression and miRNA expression before genome replication. We therefore provide evidence for a unique function of the polyomavirus miRNA that may have important implications for the mechanism of viral persistence. PMID- 23630297 TI - Toxic RNA as a driver of disease in a common form of ALS and dementia. PMID- 23630298 TI - Systemic regulation of the age-related decline of pancreatic beta-cell replication. AB - The frequency of pancreatic beta-cell replication declines dramatically with age, potentially contributing to the increased risk of type 2 diabetes in old age. Previous studies have shown the involvement of cell-autonomous factors in this phenomenon, particularly the decline of polycomb genes and accumulation of p16/INK4A. Here, we demonstrate that a systemic factor found in the circulation of young mice is able to increase the proliferation rate of old pancreatic beta cells. Old mice parabiosed to young mice have increased beta-cell replication compared with unjoined old mice or old mice parabiosed to old mice. In addition, we demonstrate that old beta-cells transplanted into young recipients have increased replication rate compared with cells transplanted into old recipients; conversely, young beta-cells transplanted into old mice decrease their replication rate compared with young cells transplanted into young recipients. The expression of p16/INK4A mRNA did not change in heterochronic parabiosis, suggesting the involvement of other pathways. We conclude that systemic factors contribute to the replicative decline of old pancreatic beta-cells. PMID- 23630299 TI - Somatostatin receptor type 2 antagonism improves glucagon counterregulation in biobreeding diabetic rats. AB - Impaired counterregulation during hypoglycemia in type 1 diabetes (T1D) is partly attributable to inadequate glucagon secretion. Intra-islet somatostatin (SST) suppression of hypoglycemia-stimulated alpha-cell glucagon release plays an important role. We hypothesized that hypoglycemia can be prevented in autoimmune T1D by SST receptor type 2 (SSTR2) antagonism of alpha-cells, which relieve SSTR2 inhibition, thereby increasing glucagon secretion. Diabetic biobreeding diabetes prone (BBDP) rats mimic insulin-dependent human autoimmune T1D, whereas nondiabetic BBDP rats mimic prediabetes. Diabetic and nondiabetic rats underwent a 3-h infusion of vehicle compared with SSTR2 antagonist (SSTR2a) during insulin induced hypoglycemia clamped at 3 +/- 0.5 mmol/L. Diabetic rats treated with SSTR2a needed little or no glucose infusion compared with untreated rats. We attribute this effect to SSTR2a restoration of the attenuated glucagon response. Direct effects of SSTR2a on alpha-cells was assessed by resecting the pancreas, which was cut into fine slices and subjected to perifusion to monitor glucagon release. SSTR2a treatment enhanced low-glucose-stimulated glucagon and corticosterone secretion to normal levels in diabetic rats. SSTR2a had similar effects in vivo in nondiabetic rats and promoted glucagon secretion from nondiabetic rat and human pancreas slices. We conclude that SST contributes to impaired glucagon responsiveness to hypoglycemia in autoimmune T1D. SSTR2a treatment can fully restore hypoglycemia-stimulated glucagon release sufficient to attain normoglycemia in both diabetic and prediabetic stages. PMID- 23630300 TI - Improvement in beta-cell secretory capacity after human islet transplantation according to the CIT07 protocol. AB - The Clinical Islet Transplantation 07 (CIT07) protocol uses antithymocyte globulin and etanercept induction, islet culture, heparinization, and intensive insulin therapy with the same low-dose tacrolimus and sirolimus maintenance immunosuppression as in the Edmonton protocol. To determine whether CIT07 improves engrafted islet beta-cell mass, our center measured beta-cell secretory capacity from glucose-potentiated arginine tests at days 75 and 365 after transplantation and compared those results with the results previously achieved by our group using the Edmonton protocol and normal subjects. All subjects were insulin free, with CIT07 subjects receiving fewer islet equivalents from a median of one donor compared with two donors for Edmonton protocol subjects. The acute insulin response to glucose-potentiated arginine (AIRpot) was greater in the CIT07 protocol than in the Edmonton protocol and was less in both cohorts than in normal subjects, with similar findings for C-peptide. The CIT07 subjects who completed reassessment at day 365 exhibited increasing AIRpot by trend relative to that of day 75. These data indicate that engrafted islet beta-cell mass is markedly improved with the CIT07 protocol, especially given more frequent use of single islet donors. Although several peritransplant differences may have each contributed to this improvement, the lack of deterioration in beta-cell secretory capacity over time in the CIT07 protocol suggests that low-dose tacrolimus and sirolimus are not toxic to islets. PMID- 23630301 TI - Strong parent-of-origin effects in the association of KCNQ1 variants with type 2 diabetes in American Indians. AB - Parent-of-origin effects were observed in an Icelandic population for several genetic variants associated with type 2 diabetes, including those in KLF14 (rs4731702), MOB2 (rs2334499), and KCNQ1 (rs2237892, rs231362). We analyzed parent-of-origin effects for these variants, along with two others in KCNQ1 identified in previous genome-wide association studies (rs2237895, rs2299620), in 7,351 Pima Indians from 4,549 nuclear families; 34% of participants had diabetes. In a subset of 287 normoglycemic individuals, acute insulin secretion was measured by an intravenous glucose tolerance test. Statistically significant (P < 0.05) parent-of-origin effects were seen for association with type 2 diabetes for all variants. The strongest effect was seen at rs2299620 in KCNQ1; the C allele was associated with increased diabetes when maternally derived (odds ratio [OR], 1.92; P = 4.1 * 10(-12)), but not when paternally derived (OR, 0.93; P = 0.47; P = 9.9 * 10(-6) for difference in maternal and paternal effects). A maternally derived C allele also was associated with a 28% decrease in insulin secretion (P = 0.002). This study confirms parent-of-origin effects in the association with type 2 diabetes for variants in KLF14, MOB2, and KCNQ1. In Pima Indians, the effect of maternally derived KCNQ1 variants appears to be mediated through decreased insulin secretion and is particularly strong, accounting for 4% of the variance in liability to diabetes. PMID- 23630302 TI - Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis. AB - Pancreatic islets adapt to insulin resistance through a complex set of changes, including beta-cell hyperplasia and hypertrophy. To determine if islet vascularization changes in response to insulin resistance, we investigated three independent models of insulin resistance: ob/ob, GLUT4(+/-), and mice with high fat diet-induced obesity. Intravital blood vessel labeling and immunocytochemistry revealed a vascular plasticity in which islet vessel area was significantly increased, but intraislet vessel density was decreased as the result of insulin resistance. These vascular changes were independent of islet size and were only observed within the beta-cell core but not in the islet periphery. Intraislet endothelial cell fenestration, proliferation, and islet angiogenic factor/receptor expression were unchanged in insulin-resistant compared with control mice, indicating that islet capillary expansion is mediated by dilation of preexisting vessels and not by angiogenesis. We propose that the islet capillary dilation is modulated by endothelial nitric oxide synthase via complementary signals derived from beta-cells, parasympathetic nerves, and increased islet blood flow. These compensatory changes in islet vascularization may influence whether beta-cells can adequately respond to insulin resistance and prevent the development of diabetes. PMID- 23630303 TI - Development of the human pancreas from foregut to endocrine commitment. AB - Knowledge of human pancreas development underpins our interpretation and exploitation of human pluripotent stem cell (PSC) differentiation toward a beta cell fate. However, almost no information exists on the early events of human pancreatic specification in the distal foregut, bud formation, and early development. Here, we have studied the expression profiles of key lineage specific markers to understand differentiation and morphogenetic events during human pancreas development. The notochord was adjacent to the dorsal foregut endoderm during the fourth week of development before pancreatic duodenal homeobox-1 detection. In contrast to the published data from mouse embryos, during human pancreas development, we detected only a single-phase of Neurogenin 3 (NEUROG3) expression and endocrine differentiation from approximately 8 weeks, before which Nirenberg and Kim homeobox 2.2 (NKX2.2) was not observed in the pancreatic progenitor cell population. In addition to revealing a number of disparities in timing between human and mouse development, these data, directly assembled from human tissue, allow combinations of transcription factors to define sequential stages and differentiating pancreatic cell types. The data are anticipated to provide a useful reference point for stem cell researchers looking to differentiate human PSCs in vitro toward the pancreatic beta-cell so as to model human development or enable drug discovery and potential cell therapy. PMID- 23630304 TI - DNA aptamer raised against AGEs blocks the progression of experimental diabetic nephropathy. AB - Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. We screened DNA aptamer directed against AGEs (AGEs aptamer) in vitro and examined its effects on renal injury in KKAy/Ta mice, an animal model of type 2 diabetes. Eight-week-old male KKAy/Ta or C57BL/6J mice received continuous intraperitoneal infusion of AGEs- or control-aptamer for 8 weeks. AGEs-aptamer was detected and its level was increased in the kidney for at least 7 days. The elimination half-lives of AGEs-aptamer in the kidney were about 7 days. Compared with those in C57BL/6J mice, glomerular AGEs levels were significantly increased in KKAy/Ta mice, which were blocked by AGEs-aptamer. Urinary albumin and 8-hydroxy-2'-deoxy-guanosine levels were increased, and glomerular hypertrophy and enhanced extracellular matrix accumulation were observed in KKAy/Ta mice, all of which were prevented by AGEs-aptamer. Moreover, AGEs-aptamer significantly reduced gene expression of RAGE, monocyte chemoattractant protein-1, connective tissue growth factor, and type IV collagen both in the kidney of KKAy/Ta mice and in AGE-exposed human cultured mesangial cells. Our present data suggest that continuous administration of AGEs-aptamer could protect against experimental diabetic nephropathy by blocking the AGEs-RAGE axis and may be a feasible and promising therapeutic strategy for the treatment of diabetic nephropathy. PMID- 23630305 TI - Cord serum lipidome in prediction of islet autoimmunity and type 1 diabetes. AB - Previous studies show that children who later progress to type 1 diabetes (T1D) have decreased preautoimmune concentrations of multiple phospholipids as compared with nonprogressors. It is still unclear whether these changes associate with development of beta-cell autoimmunity or specifically with clinical T1D. Here, we studied umbilical cord serum lipidome in infants who later developed T1D (N = 33); infants who developed three or four (N = 31) islet autoantibodies, two (N = 31) islet autoantibodies, or one (N = 48) islet autoantibody during the follow up; and controls (N = 143) matched for sex, HLA-DQB1 genotype, city of birth, and period of birth. The analyses of serum molecular lipids were performed using the established lipidomics platform based on ultra-performance liquid chromatography coupled to mass spectrometry. We found that T1D progressors are characterized by a distinct cord blood lipidomic profile that includes reduced major choline containing phospholipids, including sphingomyelins and phosphatidylcholines. A molecular signature was developed comprising seven lipids that predicted high risk for progression to T1D with an odds ratio of 5.94 (95% CI, 1.07-17.50). Reduction in choline-containing phospholipids in cord blood therefore is specifically associated with progression to T1D but not with development of beta cell autoimmunity in general. PMID- 23630306 TI - A meta-analysis of mental health treatments and cardiac rehabilitation for improving clinical outcomes and depression among patients with coronary heart disease. AB - OBJECTIVE: To quantify the efficacy of mental health (antidepressants & psychotherapies) and cardiac rehabilitation treatments for improving secondary event risk and depression among patients with coronary heart disease (CHD). METHODS: Using meta-analytic methods, we evaluated mental health and cardiac rehabilitation therapies for a) reducing secondary events and 2) improving depression severity in patients with CHD. Key word searches of PubMed and Psychlit databases and previous reviews identified relevant trials. RESULTS: Eighteen mental health trials evaluated secondary events and 22 trials evaluated depression reduction. Cardiac rehabilitation trials for the same categories numbered 17 and 13, respectively. Mental health treatments did not reduce total mortality (absolute risk reduction [ARR] = -0.001, confidence interval [95% CI] = -0.016 to 0.015; number needed to treat [NNT] = infinity), showed moderate efficacy for reducing CHD events (ARR = 0.029, 95% CI = 0.007 to 0.051; NNT = 34), and a medium effect size for improving depression (Cohen d = 0.297). Cardiac rehabilitation showed similar efficacy for treating depression (d = 0.23) and reducing CHD events (ARR = 0.017, 95% CI = 0.007 to 0.026; NNT = 59) and reduced total mortality (ARR = 0.016, 95% CI = 0.005 to 0.027; NNT = 63). CONCLUSIONS: Among patients with CHD, mental health treatments and cardiac rehabilitation may each reduce depression and CHD events, whereas cardiac rehabilitation is superior for reducing total mortality risk. The results support a continued role for mental health treatments and a larger role for mental health professionals in cardiac rehabilitation. PMID- 23630308 TI - How many meta-analyses does it take to settle a question? AB - Psychological treatments (PTs) are used as adjuncts to cardiac care. This issue of Psychosomatic Medicine provides a meta-analysis by Rutledge et al. (3) on the effects of PT and cardiac rehabilitation on depression and cardiac outcomes, and the journal recently published a systematic review and meta-regression on a similar topic by Dickens et al. (4). This editorial compares the results from these two meta-analyses and discusses the problems associated with combining different types of PT and other treatments, dose-response effects, floor effects, collapsing across outcomes, and therapist qualifications. PTs have mixed but generally positive effects on reducing mortality and cardiac outcomes, but it remains a challenge explaining how such beneficial outcomes can be achieved by relatively small effects on well-being (typical effect sizes: d = 0.2-0.3). Randomized controlled trials are needed on timing of PT, patients with cardiac problems who will benefit most from PT, and the mechanisms by which PT improves cardiac outcomes. PMID- 23630310 TI - CT colonography: preliminary assessment of a double-read paradigm that uses computer-aided detection as the first reader. AB - PURPOSE: To compare diagnostic performance and time efficiency of double-reading first-reader computer-aided detection (CAD) (DR FR CAD) followed by radiologist interpretation with that of an unassisted read using segmentally unblinded colonoscopy as reference standard. MATERIALS AND METHODS: The local ethical committee approved this study. Written consent to use examinations was obtained from patients. Three experienced radiologists searched for polyps 6 mm or larger in 155 computed tomographic (CT) colonographic studies (57 containing 10 masses and 79 polyps >= 6 mm). Reading was randomized to either unassisted read or DR FR CAD. Data sets were reread 6 weeks later by using the opposite paradigm. DR FR CAD consists of evaluation of CAD prompts, followed by fast two-dimensional review for mass detection. CAD sensitivity was calculated. Readers' diagnoses and reviewing times with and without CAD were compared by using McNemar and Student t tests, respectively. Association between missed polyps and lesion characteristics was explored with multiple regression analysis. RESULTS: With mean rate of 19 (standard deviation, 14; median, 15; range, 4-127) false-positive results per patient, CAD sensitivity was 90% for lesions 6 mm or larger. Readers' sensitivity and specificity for lesions 6 mm or larger were 74% (95% confidence interval [CI]: 65%, 84%) and 93% (95% CI: 89%, 97%), respectively, for the unassisted read and 77% (95% CI: 67%, 85%) and 90% (95% CI: 85%, 95%), respectively, for DR FR CAD (P = .343 and P = .189, respectively). Overall unassisted and DR FR CAD reviewing times were similar (243 vs 239 seconds; P = .623); DR FR CAD was faster when the number of CAD marks per patient was 20 or fewer (187 vs 220 seconds, P <01). Odds ratio of missing a polyp with CAD decreased as polyp size increased (0.6) and for polyps visible on both prone and supine scans (0.12); it increased for flat lesions (9.1). CONCLUSION: DR FR CAD paradigm had similar performance compared with unassisted interpretation but better time efficiency when 20 or fewer CAD prompts per patient were generated. PMID- 23630307 TI - Aerobic exercise and strength training effects on cardiovascular sympathetic function in healthy adults: a randomized controlled trial. AB - OBJECTIVE: Exercise has widely documented cardioprotective effects, but the mechanisms underlying these effects are not entirely known. Previously, we demonstrated that aerobic but not strength training lowered resting heart rate and increased cardiac vagal regulation, changes that were reversed by sedentary deconditioning. Here, we focus on the sympathetic nervous system and test whether aerobic training lowers levels of cardiovascular sympathetic activity in rest and that deconditioning would reverse this effect. METHODS: We conducted a randomized controlled trial contrasting the effects of aerobic (A) versus strength (S) training on indices of cardiac (preejection period, or PEP) and vascular (low frequency blood pressure variability, or LF BPV) sympathetic regulation in 149 young, healthy, and sedentary adults. Participants were studied before and after conditioning, as well as after 4 weeks of sedentary deconditioning. RESULTS: As previously reported, aerobic capacity increased in response to conditioning and decreased after deconditioning in the aerobic, but not the strength, training group. Contrary to prediction, there was no differential effect of training on either PEP (A: mean [SD] -0.83 [7.8] milliseconds versus S: 1.47 [6.69] milliseconds) or LF BPV (A: mean [SD] -0.09 [0.93] ln mm Hg(2) versus S: 0.06 [0.79] ln mm Hg(2)) (both p values > .05). CONCLUSIONS: These findings, from a large randomized controlled trial using an intent-to-treat design, show that moderate aerobic exercise training has no effect on resting state cardiovascular indices of PEP and LF BPV. These results indicate that in healthy, young adults, the cardioprotective effects of exercise training are unlikely to be mediated by changes in resting sympathetic activity. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00358137. PMID- 23630311 TI - Use of image features in predicting visually lossless thresholds of JPEG2000 compressed body CT images: initial trial. AB - PURPOSE: To test the image features that may be useful in predicting the visually lossless thresholds (VLTs) of body computed tomographic (CT) images for Joint Photographic Experts Group 2000 (JPEG2000) compression. MATERIALS AND METHODS: The institutional review board approved this study, with a waiver of informed patient consent. One hundred body CT studies obtained in different patients by using five scanning protocols were obtained, and 100 images, each of which was selected from each of the 100 studies, were collected. Five radiologists independently determined the VLT of each image for JPEG2000 compression by using the QUEST algorithm. The 100 images were randomly divided into two data sets-the training set (50 images) and the testing set (50 images)-and the division was repeated 200 times. For each of the 200 divisions, a multiple linear regression model was constructed on a training set and tested on a testing set regarding each of five image features-standard deviation of image intensity, image entropy, relative percentage of low-frequency (LF) energy, variation in high-frequency (HF) energy, and visual complexity-as independent variables and considering the VLTs determined with the median value of the radiologists' responses as a dependent variable. The root mean square residual and intraclass correlation coefficient (ICC) for the 200 divisions between the VLTs predicted by the models and those determined by radiologists were compared between the models by using repeated-measures analysis of variance with post-hoc comparisons. RESULTS: Mean root-mean-square residuals for multiple linear regression models constructed with variation in HF energy (1.20 +/- 0.10 [standard deviation]) and visual complexity (1.09 +/- 0.07) were significantly lower than those for standard deviation of image intensity (1.65 +/- 0.13), image entropy (1.63 +/- 0.14), and relative percentage of LF energy (1.58 +/- 0.12) (P < .01). ICCs for variation in HF energy (0.64 +/- 0.05) and visual complexity (0.71 +/- 0.04) were significantly higher than those for standard deviation of image intensity (0.04 +/- 0.02), image entropy (0.05 +/- 0.02), and relative percentage of LF energy (0.20 +/- 0.04) (P < .01). CONCLUSION: Among the five tested image features, variation in HF energy and visual complexity were the most promising in predicting the VLTs of body CT images for JPEG2000 compression. PMID- 23630312 TI - Liver fibrosis: noninvasive assessment with acoustic radiation force impulse elastography--comparison with FibroScan M and XL probes and FibroTest in patients with chronic liver disease. AB - PURPOSE: To compare the diagnostic performance of acoustic radiation force impulse (ARFI) elastography with that of FibroScan M and XL probes and FibroTest in the staging of fibrosis in patients with chronic liver disease. MATERIALS AND METHODS: This study received ethics approval, and all participants provided written informed consent. A total of 321 consecutive patients with chronic liver disease who underwent liver biopsy were prospectively enrolled from April 2010 to May 2012. Liver disease was caused by viral hepatitis (n = 136), alcoholic or nonalcoholic steatohepatitis disorders (n = 113), or some other disease (n = 72). In each patient, liver stiffness was evaluated with ARFI elastography, M and XL probes, and FibroTest within 1 month before liver biopsy. Histologic staging of liver fibrosis served as the reference standard. RESULTS: Liver stiffness measurement failure rates were 11.2% with the M probe (36 of 321 patients), 2.3% with the XL probe (six of 260 patients), and 0% with ARFI elastography (0 of 321 patients). Unreliable results with ARFI elastography were more frequent in obese patients (those with a body mass index of 30 kg/m(2) or more) (42 of 86 patients [48.8%] vs 34 of 235 patients [14.5%], P < .0001). No significant difference was found between ARFI elastography and the M probe in the diagnosis of cirrhosis (area under under the receiver operating characteristic curve [Az], 0.88 vs 0.91; P = .12) or severe fibrosis (Az, 0.85 vs 0.89; P = .15); however, the M probe demonstrated better results in the diagnosis of moderate fibrosis (Az, 0.81 vs 0.88; P = .008). No significant difference was found between ARFI elastography and the XL probe in the diagnosis of moderate fibrosis, severe fibrosis, or cirrhosis. The diagnostic performance of ARFI elastography improved when it was applied in nonobese patients (Az of ARFI for cirrhosis and severe fibrosis = 0.92 and 0.91, respectively, in nonobese patients [P = .0002] and 0.63 and 0.63, respectively, in obese patients [P < .0001]). CONCLUSION: ARFI elastography is reliable in the assessment of liver fibrosis in patients with chronic liver disease, especially nonobese patients. PMID- 23630313 TI - The DEAD-box helicase DDX3 substitutes for the cap-binding protein eIF4E to promote compartmentalized translation initiation of the HIV-1 genomic RNA. AB - Here, we show a novel molecular mechanism promoted by the DEAD-box RNA helicase DDX3 for translation of the HIV-1 genomic RNA. This occurs through the adenosine triphosphate-dependent formation of a translation initiation complex that is assembled at the 5' m(7)GTP cap of the HIV-1 mRNA. This is due to the property of DDX3 to substitute for the initiation factor eIF4E in the binding of the HIV-1 m(7)GTP 5' cap structure where it nucleates the formation of a core DDX3/PABP/eIF4G trimeric complex on the HIV-1 genomic RNA. By using RNA fluorescence in situ hybridization coupled to indirect immunofluorescence, we further show that this viral ribonucleoprotein complex is addressed to compartmentalized cytoplasmic foci where the translation initiation complex is assembled. PMID- 23630314 TI - The tRNA-modifying function of MnmE is controlled by post-hydrolysis steps of its GTPase cycle. AB - MnmE is a homodimeric multi-domain GTPase involved in tRNA modification. This protein differs from Ras-like GTPases in its low affinity for guanine nucleotides and mechanism of activation, which occurs by a cis, nucleotide- and potassium dependent dimerization of its G-domains. Moreover, MnmE requires GTP hydrolysis to be functionally active. However, how GTP hydrolysis drives tRNA modification and how the MnmE GTPase cycle is regulated remains unresolved. Here, the kinetics of the MnmE GTPase cycle was studied under single-turnover conditions using stopped- and quench-flow techniques. We found that the G-domain dissociation is the rate-limiting step of the overall reaction. Mutational analysis and fast kinetics assays revealed that GTP hydrolysis, G-domain dissociation and Pi release can be uncoupled and that G-domain dissociation is directly responsible for the 'ON' state of MnmE. Thus, MnmE provides a new paradigm of how the ON/OFF cycling of GTPases may regulate a cellular process. We also demonstrate that the MnmE GTPase cycle is negatively controlled by the reaction products GDP and Pi. This feedback mechanism may prevent inefficacious GTP hydrolysis in vivo. We propose a biological model whereby a conformational change triggered by tRNA binding is required to remove product inhibition and initiate a new GTPase/tRNA modification cycle. PMID- 23630315 TI - Recombineering in Corynebacterium glutamicum combined with optical nanosensors: a general strategy for fast producer strain generation. AB - Recombineering in bacteria is a powerful technique for genome reconstruction, but until now, it was not generally applicable for development of small-molecule producers because of the inconspicuous phenotype of most compounds of biotechnological relevance. Here, we establish recombineering for Corynebacterium glutamicum using RecT of prophage Rac and combine this with our recently developed nanosensor technology, which enables the detection and isolation of productive mutants at the single-cell level via fluorescence-activated cell sorting (FACS). We call this new technology RecFACS, which we use for genomic site-directed saturation mutagenesis without relying on pre-constructed libraries to directly isolate L-lysine-producing cells. A mixture of 19 different oligonucleotides was used targeting codon 81 in murE of the wild-type, at a locus where one single mutation is known to cause L-lysine production. Using RecFACS, productive mutants were screened and isolated. Sequencing revealed 12 different amino acid exchanges in the targeted murE codon, which caused different L-lysine production titers. Apart from introducing a rapid genome construction technology for C. glutamicum, the present work demonstrates that RecFACS is suitable to simply create producers as well as genetic diversity in one single step, thus establishing a new general concept in synthetic biology. PMID- 23630316 TI - High-efficiency and heritable gene targeting in mouse by transcription activator like effector nucleases. AB - Transcription activator-like effector nucleases (TALENs) are a powerful new approach for targeted gene disruption in various animal models, but little is known about their activities in Mus musculus, the widely used mammalian model organism. Here, we report that direct injection of in vitro transcribed messenger RNA of TALEN pairs into mouse zygotes induced somatic mutations, which were stably passed to the next generation through germ-line transmission. With one TALEN pair constructed for each of 10 target genes, mutant F0 mice for each gene were obtained with the mutation rate ranged from 13 to 67% and an average of ~40% of total healthy newborns with no significant differences between C57BL/6 and FVB/N genetic background. One TALEN pair with single mismatch to their intended target sequence in each side failed to yield any mutation. Furthermore, highly efficient germ-line transmission was obtained, as all the F0 founders tested transmitted the mutations to F1 mice. In addition, we also observed that one bi allele mutant founder of Lepr gene, encoding Leptin receptor, had similar diabetic phenotype as db/db mouse. Together, our results suggest that TALENs are an effective genetic tool for rapid gene disruption with high efficiency and heritability in mouse with distinct genetic background. PMID- 23630318 TI - Small molecule induced reactivation of mutant p53 in cancer cells. AB - The p53 cancer mutant Y220C is an excellent paradigm for rescuing the function of conformationally unstable p53 mutants because it has a unique surface crevice that can be targeted by small-molecule stabilizers. Here, we have identified a compound, PK7088, which is active in vitro: PK7088 bound to the mutant with a dissociation constant of 140 MUM and raised its melting temperature, and we have determined the binding mode of a close structural analogue by X-ray crystallography. We showed that PK7088 is biologically active in cancer cells carrying the Y220C mutant by a battery of tests. PK7088 increased the amount of folded mutant protein with wild-type conformation, as monitored by immunofluorescence, and restored its transcriptional functions. It induced p53 Y220C-dependent growth inhibition, cell-cycle arrest and apoptosis. Most notably, PK7088 increased the expression levels of p21 and the proapoptotic NOXA protein. PK7088 worked synergistically with Nutlin-3 on up-regulating p21 expression, whereas Nutlin-3 on its own had no effect, consistent with its mechanism of action. PK7088 also restored non-transcriptional apoptotic functions of p53 by triggering nuclear export of BAX to the mitochondria. We suggest a set of criteria for assigning activation of p53. PMID- 23630317 TI - Influence of genome-scale RNA structure disruption on the replication of murine norovirus--similar replication kinetics in cell culture but attenuation of viral fitness in vivo. AB - Mechanisms by which certain RNA viruses, such as hepatitis C virus, establish persistent infections and cause chronic disease are of fundamental importance in viral pathogenesis. Mammalian positive-stranded RNA viruses establishing persistence typically possess genome-scale ordered RNA secondary structure (GORS) in their genomes. Murine norovirus (MNV) persists in immunocompetent mice and provides an experimental model to functionally characterize GORS. Substitution mutants were constructed with coding sequences in NS3/4- and NS6/7-coding regions replaced with sequences with identical coding and (di-)nucleotide composition but disrupted RNA secondary structure (F1, F2, F1/F2 mutants). Mutants replicated with similar kinetics to wild-type (WT) MNV3 in RAW264.7 cells and primary macrophages, exhibited similar (highly restricted) induction and susceptibility to interferon-coupled cellular responses and equal replication fitness by serial passaging of co-cultures. In vivo, both WT and F1/F2 mutant viruses persistently infected mice, although F1, F2 and F1/F2 mutant viruses were rapidly eliminated 1 7 days post-inoculation in competition experiments with WT. F1/F2 mutants recovered from tissues at 9 months showed higher synonymous substitution rates than WT and nucleotide substitutions that potentially restored of RNA secondary structure. GORS plays no role in basic replication of MNV but potentially contributes to viral fitness and persistence in vivo. PMID- 23630319 TI - A bistable hysteretic switch in an activator-repressor regulated restriction modification system. AB - Restriction-modification (RM) systems are extremely widespread among bacteria and archaea, and are often specified by mobile genetic elements. In type II RM systems, where the restriction endonuclease (REase) and protective DNA methyltransferase (MTase) are separate proteins, a major regulatory challenge is delaying expression of the REase relative to the MTase after RM genes enter a new host cell. Basic understanding of this regulation is available for few RM systems, and detailed understanding for none. The PvuII RM system is one of a large subset in which the central regulatory role is played by an activator repressor protein (called C, for controller). REase expression depends upon activation by C, whereas expression of the MTase does not. Thus delay of REase expression depends on the rate of C-protein accumulation. This is a nonlinear process, as C also activates transcription of its own gene. Mathematical modeling of the PvuII system led to the unexpected predictions of responsiveness to a factor not previously studied in RM system control--gene copy number--and of a hysteretic response. In this study, those predictions have been confirmed experimentally. The results may apply to many other C-regulated RM systems, and help explain their ability to spread so widely. PMID- 23630320 TI - Single-cell paired-end genome sequencing reveals structural variation per cell cycle. AB - The nature and pace of genome mutation is largely unknown. Because standard methods sequence DNA from populations of cells, the genetic composition of individual cells is lost, de novo mutations in cells are concealed within the bulk signal and per cell cycle mutation rates and mechanisms remain elusive. Although single-cell genome analyses could resolve these problems, such analyses are error-prone because of whole-genome amplification (WGA) artefacts and are limited in the types of DNA mutation that can be discerned. We developed methods for paired-end sequence analysis of single-cell WGA products that enable (i) detecting multiple classes of DNA mutation, (ii) distinguishing DNA copy number changes from allelic WGA-amplification artefacts by the discovery of matching aberrantly mapping read pairs among the surfeit of paired-end WGA and mapping artefacts and (iii) delineating the break points and architecture of structural variants. By applying the methods, we capture DNA copy number changes acquired over one cell cycle in breast cancer cells and in blastomeres derived from a human zygote after in vitro fertilization. Furthermore, we were able to discover and fine-map a heritable inter-chromosomal rearrangement t(1;16)(p36;p12) by sequencing a single blastomere. The methods will expedite applications in basic genome research and provide a stepping stone to novel approaches for clinical genetic diagnosis. PMID- 23630321 TI - The RNAsnp web server: predicting SNP effects on local RNA secondary structure. AB - The function of many non-coding RNA genes and cis-regulatory elements of messenger RNA largely depends on the structure, which is in turn determined by their sequence. Single nucleotide polymorphisms (SNPs) and other mutations may disrupt the RNA structure, interfere with the molecular function and hence cause a phenotypic effect. RNAsnp is an efficient method to predict the effect of SNPs on local RNA secondary structure based on the RNA folding algorithms implemented in the Vienna RNA package. The SNP effects are quantified in terms of empirical P values, which, for computational efficiency, are derived from extensive pre computed tables of distributions of substitution effects as a function of gene length and GC content. Here, we present a web service that not only provides an interface for RNAsnp but also features a graphical output representation. In addition, the web server is connected to a local mirror of the UCSC genome browser database that enables the users to select the genomic sequences for analysis and visualize the results directly in the UCSC genome browser. The RNAsnp web server is freely available at: http://rth.dk/resources/rnasnp/. PMID- 23630322 TI - Efficient Flp-Int HK022 dual RMCE in mammalian cells. AB - Recombinase-mediated cassette exchange, or RMCE, is a clean approach of gene delivery into a desired chromosomal location, as it is able to insert only the required sequences, leaving behind the unwanted ones. RMCE can be mediated by a single site-specific DNA recombinase or by two recombinases with different target specificities (dual RMCE). Recently, using the Flp-Cre recombinase pair, dual RMCE proved to be efficient, provided the relative ratio of the enzymes during the reaction is optimal. In the present report, we analyzed how the efficiency of dual RMCE mediated by the Flp-Int (HK022) pair depends on the variable input of the recombinases-the amount of the recombinase expression vectors added at transfection-and on the order of the addition of these vectors: sequential or simultaneous. We found that both in the sequential and the simultaneous modes, the efficiency of dual RMCE was critically dependent on the absolute and the relative concentrations of the Flp and Int expression vectors. Under optimal conditions, the efficiency of 'simultaneous' dual RMCE reached ~12% of the transfected cells. Our results underline the importance of fine-tuning the reaction conditions for achieving the highest levels of dual RMCE. PMID- 23630323 TI - Non-polyadenylated transcription in embryonic stem cells reveals novel non-coding RNA related to pluripotency and differentiation. AB - The transcriptional landscape in embryonic stem cells (ESCs) and during ESC differentiation has received considerable attention, albeit mostly confined to the polyadenylated fraction of RNA, whereas the non-polyadenylated (NPA) fraction remained largely unexplored. Notwithstanding, the NPA RNA super-family has every potential to participate in the regulation of pluripotency and stem cell fate. We conducted a comprehensive analysis of NPA RNA in ESCs using a combination of whole-genome tiling arrays and deep sequencing technologies. In addition to identifying previously characterized and new non-coding RNA members, we describe a group of novel conserved RNAs (snacRNAs: small NPA conserved), some of which are differentially expressed between ESC and neuronal progenitor cells, providing the first evidence of a novel group of potentially functional NPA RNA involved in the regulation of pluripotency and stem cell fate. We further show that minor spliceosomal small nuclear RNAs, which are NPA, are almost completely absent in ESCs and are upregulated in differentiation. Finally, we show differential processing of the minor intron of the polycomb group gene Eed. Our data suggest that NPA RNA, both known and novel, play important roles in ESCs. PMID- 23630324 TI - Influence of temperature on measurements of the CO2 compensation point: differences between the Laisk and O2-exchange methods. AB - The CO2 compensation point in the absence of day respiration (Gamma*) is a key parameter for modelling leaf CO2 exchange. Gamma* links the kinetics of ribulose 1,5-bisphosphate carboxylase-oxygenase (Rubisco) with the stoichiometry of CO2 released per Rubisco oxygenation from photorespiration (alpha), two essential components of biochemical models of photosynthesis. There are two main gas exchange methods for measuring Gamma*: (i) the Laisk method, which requires estimates of mesophyll conductance to CO2 (g m) and (ii) measurements of O2 isotope exchange, which assume constant values of alpha and a fixed stoichiometry between O2 uptake and Rubisco oxygenation. In this study, the temperature response of Gamma* measured using the Laisk and O2-exchange methods was compared under ambient (25 degrees C) and elevated (35 degrees C) temperatures to determine whether both methods yielded similar results. Previously published temperature responses of Gamma* estimated with the Laisk and O2-exchange methods in Nicotiana tabacum demonstrated that the Laisk-derived model of Gamma* was more sensitive to temperature compared with the O2-exchange model. Measurements in Arabidopsis thaliana indicated that the Laisk and O2-exchange methods produced similar Gamma* at 25 degrees C; however, Gamma* values from O2 exchange were lower at 35 degrees C compared with the Laisk method. Compared with a photorespiratory mutant (pmdh1pmdh2hpr) with increased alpha, wild-type (WT) plants had lower Laisk values of Gamma* at 25 degrees C but were not significantly different at 35 degrees C. These differences between Laisk and O2 exchange values of Gamma* at 35 degrees C could be explained by temperature sensitivity of alpha in WT and/or errors in the assumptions of O2 exchange. The differences between Gamma* measured using the Laisk and O2-exchange method with temperature demonstrate that assumptions used to measure Gamma*, and possibly the species-specific validity of these assumptions, need to be considered when modelling the temperature response of photosynthesis. PMID- 23630325 TI - Expression of ABA synthesis and metabolism genes under different irrigation strategies and atmospheric VPDs is associated with stomatal conductance in grapevine (Vitis vinifera L. cv Cabernet Sauvignon). AB - The influence of different levels of irrigation and of variation in atmospheric vapour pressure deficit (VPD) on the synthesis, metabolism, and transport of abscisic acid (ABA) and the effects on stomatal conductance were examined in field-grown Cabernet Sauvignon grapevines. Xylem sap, leaf tissue, and root tissue were collected at regular intervals during two seasons in conjunction with measurements of leaf water potential (Psileaf) and stomatal conductance (gs). The different irrigation levels significantly altered the Psileaf and gs of the vines across both seasons. ABA abundance in the xylem sap was correlated with gs. The expression of genes associated with ABA synthesis, NCED1 and NCED2, was higher in the roots than in the leaves throughout and highest in the roots in mid January, a time when soil moisture declined and VPD was at its highest. Their expression in roots was also inversely related to the levels of irrigation and correlated with ABA abundance in the roots, xylem sap, and leaves. Three genes encoding ABA 8'-hydroxylases were isolated and their identities confirmed by expression in yeast cells. The expression of one of these, Hyd1, was elevated in leaves when VPD was below 2.0-2.5 kPa and minimal at higher VPD levels. The results provide evidence that ABA plays an important role in linking stomatal response to soil moisture status and that changes in ABA catabolism at or near its site of action allows optimization of gas exchange to current environmental conditions. PMID- 23630326 TI - Visualization and quantification of protein interactions in the biosynthetic pathway of molybdenum cofactor in Arabidopsis thaliana. AB - The molybdenum cofactor (Moco) is the active compound at the catalytic site of molybdenum enzymes. Moco is synthesized by a conserved four-step pathway involving six proteins in Arabidopsis thaliana. Bimolecular fluorescence complementation was used to study the subcellular localization and interaction of those proteins catalysing Moco biosynthesis. In addition, the independent split luciferase approach permitted quantification of the strength of these protein protein interactions in vivo. Moco biosynthesis starts in mitochondria where two proteins undergo tight interaction. All subsequent steps were found to proceed in the cytosol. Here, the heterotetrameric enzyme molybdopterin synthase (catalysing step two of Moco biosynthesis) and the enzyme molybdenum insertase, which finalizes Moco formation, were found to undergo tight protein interaction as well. This cytosolic multimeric protein complex is dynamic as the small subunits of molybdopterin synthase are known to go on and off in order to become recharged with sulphur. These small subunits undergo a tighter protein contact within the enzyme molybdopterin synthase as compared with their interaction with the sulphurating enzyme. The forces of each of these protein contacts were quantified and provided interaction factors. To confirm the results, in vitro experiments using a technique combining cross-linking and label transfer were conducted. The data presented allowed the outline of the first draft of an interaction matrix for proteins within the pathway of Moco biosynthesis where product-substrate flow is facilitated through micro-compartmentalization in a cytosolic protein complex. The protected sequestering of fragile intermediates and formation of the final product are achieved through a series of direct protein interactions of variable strength. PMID- 23630327 TI - Heterozygous alleles restore male fertility to cytoplasmic male-sterile radish (Raphanus sativus L.): a case of overdominance. AB - The practice of hybridization has greatly contributed to the increase in crop productivity. A major component that exploits heterosis in crops is the cytoplasmic male sterility (CMS)/nucleus-controlled fertility restoration (Rf) system. Through positional cloning, it is shown that heterozygous alleles (RsRf3 1/RsRf3-2) encoding pentatricopeptide repeat (PPR) proteins are responsible for restoring fertility to cytoplasmic male-sterile radish (Raphanus sativus L.). Furthermore, it was found that heterozygous alleles (RsRf3-1/RsRf3-2) show higher expression and RNA polymerase II occupancy in the CMS cytoplasmic background compared with their homozygous alleles (RsRf3-1/RsRf3-1 or RsRf3-2/RsRf3-2). These data provide new insights into the molecular mechanism of fertility restoration to cytoplasmic male-sterile plants and illustrate a case of overdominance. PMID- 23630328 TI - Cloning and characterization of TaSnRK2.3, a novel SnRK2 gene in common wheat. AB - Environmental stresses such as drought, salinity, and cold are major adverse factors that significantly affect agricultural productivity. Protein phosphorylation/dephosphorylation is a major signalling event induced by osmotic stress in higher plants. Sucrose non-fermenting 1-related protein kinase 2 (SnRK2) family members play essential roles in the response to hyperosmotic stresses in plants. In this study, the TaSnRK2.3 gene, a novel SnRK2 member was cloned, and three copies located on chromosomes 1A, 1B, and 1D were identified in common wheat. TaSnRK2.3 was strongly expressed in leaves, and responded to polyethylene glycol, NaCl, abscisic acid, and cold stresses. To characterize its function, transgenic Arabidopsis overexpressing TaSnRK2.3-GFP controlled by the cauliflower mosaic virus 35S promoter was generated and subjected to severe abiotic stresses. Overexpression of TaSnRK2.3 resulted in an improved root system and significantly enhanced tolerance to drought, salt, and freezing stresses, simultaneously demonstrated by enhanced expression of abiotic stress-responsive genes and ameliorative physiological indices, including a decreased rate of water loss, enhanced cell membrane stability, improved photosynthetic potential, and significantly increased osmotic potential and free proline content under normal and/or stressed conditions. These results demonstrate that TaSnRK2.3 is a multifunctional regulator, with potential for utilization in transgenic breeding for improved abiotic stress tolerance in crop plants. PMID- 23630329 TI - Nutrient status: a missing factor in phenological and pollen research? AB - Phenology ranks among the best ecosystem processes for fingerprinting climate change since temperature explains a high percentage of the interannual or spatial variation in phenological onset dates. However, roles of other environmental variables, such as foliar nutrient concentrations, are far from adequately understood. This observational study examined the effects of air temperature and 11 nutrients on spring phenology of Betula pendula Roth (birch) along an urban rural gradient in Munich, Germany, during the years 2010/2011. Moreover, the influence of temperature, nutrients, and air pollutants (NO2 and O3) on the amounts of pollen and catkin biomass in 2010 was evaluated. In addition to the influence of higher temperatures advancing phenological onset dates, higher foliar concentrations of potassium, boron, zinc, and calcium were statistically significantly linked to earlier onset dates. Since flushing of leaves is a turgor driven process and all the influential nutrients are involved in cell extension, membrane function, and stability, there might be a reasonable physiological interpretation of the observed association. The amounts of pollen were negatively correlated with temperature, atmospheric NO2, and foliar iron concentration, suggesting that these variables restrict pollen production. The results of this study suggested an influence of nutritional status on both phenology and pollen production. The interaction of urbanization and climate change should be considered in the assessment of the impact of global warming on ecosystems and human health. PMID- 23630330 TI - Polymorphisms in double-strand breaks repair genes are associated with impaired fertility in Chinese population. AB - The DNA double-strand breaks (DSBs) repair pathway plays a critical role in repairing double-strand breaks, and genetic variants in DSBs repair pathway genes are potential risk factors for various diseases. To test the hypothesis that polymorphisms in DSBs genes are associated with susceptibility to male infertility, we examined 11 single nucleotide polymorphisms in eight key DSBs genes (XRCC3, XRCC2, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in 580 infertility cases and 580 controls from a Chinese population-based case-control study (NJMU Infertility Study). Genotypes were determined using the OpenArray platform, and sperm DNA fragmentation was detected using the TUNEL assay. The adjusted odds ratio (OR) and 95% CI were estimated using logistic regression. The results indicate that LIG4 rs1805388 (Ex2+54C>T, Thr9Ile) T allele could increase the susceptibility to male infertility (adjusted OR=2.78; 95% CI, 1.77-4.36 for TT genotype; and adjusted OR=1.58; 95% CI, 1.77-4.36 for TC genotype respectively). In addition, the homozygous variant genotype GG of RAG1 rs2227973 (A>G, K820R) was associated with a significantly increased risk of male infertility (adjusted OR, 1.44; 95% CI, 1.01-2.04). Moreover, linear regression analysis revealed that carriers of LIG4 rs1805388 or RAG1 rs2227973 variants had a significantly higher level of sperm DNA fragmentation and that T allele carriers of LIG4 rs1805388 also had a lower level of sperm concentration when compared with common homozygous genotype carriers. This study demonstrates, for the first time, to our knowledge, that functional variants of RAG1 rs2227973 and LIG4 rs1805388 are associated with susceptibility to male infertility. PMID- 23630331 TI - Reactive oxygen species production and redox state in parthenogenetic and sperm mediated bovine oocyte activation. AB - The knowledge concerning redox and reactive oxygen species (ROS)-mediated regulation of early embryo development is scarce and remains controversial. The aim of this work was to determine ROS production and redox state during early in vitro embryo development in sperm-mediated and parthenogenetic activation of bovine oocytes. Sperm-mediated oocyte activation was carried out in IVF-modified synthetic oviductal fluid (mSOF) with frozen-thawed semen. Parthenogenetic activation was performed in TALP plus ionomycin and then in IVF-mSOF with 6 dimethylaminopurine plus cytochalasin B. Embryos were cultured in IVF-mSOF. ROS and redox state were determined at each 2-h interval (7-24 h from activation) by 2',7'-dichlorodihydrofluorescein diacetate and RedoxSensor Red CC-1 fluorochromes respectively. ROS levels and redox state differed between activated and non activated oocytes (P<0.05 by ANOVA). In sperm-activated oocytes, an increase was observed between 15 and 19 h (P<0.05). Conversely, in parthenogenetically activated oocytes, we observed a decrease at 9 h (P<0.05). In sperm-activated oocytes, ROS fluctuated throughout the 24 h, presenting peaks around 7, 19, and 24 h (P<0.05), while in parthenogenetic activation, peaks were detected at 7, 11, and 17 h (P<0.05). In the present work, we found clear distinctive metabolic patterns between normal and parthenogenetic zygotes. Oxidative activity and ROS production are an integral part of bovine zygote behavior, and defining a temporal pattern of change may be linked with developmental competence. PMID- 23630332 TI - Season-induced variation in lipid composition is associated with semen quality in Holstein bulls. AB - Season-induced variation in fatty acid and cholesterol composition in bovine semen has been associated with semen quality. Given the specific roles of the various semen compartments (seminal fluids, sperm head, and sperm tail) in fertilization, we hypothesized that environmental-stress-induced alterations in the lipid composition of a specific compartment might impair semen quality and sperm function. Semen samples were collected from five mature Holstein-Friesian bulls during the summer (August to September) and winter (December to January). Semen was evaluated by computerized sperm-quality analyzer, calibrated for bulls' semen, and centrifuged to separate the spermatozoa from the seminal fluids. The spermatozoal fraction was sonicated to separate the sperm head and tail compartments. Cold lipid extraction was performed with chloroform:methanol (2:1, vol/vol). Lipids were identified and quantified by gas chromatography. Seasonal variation was found in both physiological and structural parameters. The proportion of spermatozoa defined as morphologically normal was higher in the winter, with higher motility, progressive motility, and velocity relative to summer samples. Lipid composition within fractions varied between seasons with prominent impairment in the tail compartment, characterized by high saturated fatty acid, low polyunsaturated fatty acid, and low cholesterol concentrations during the summer. Given the association between alterations in lipid composition and reduced sperm motility and velocity during the summer, it is suggested that lipid composition might serve to predict sperm quality. PMID- 23630333 TI - Regulation of the hyaluronan system in ovine endometrium by ovarian steroids. AB - In this study, we investigated steroid regulation of the hyaluronan (HA) system in ovine endometrium including HA synthases (HAS), hyaluronidases, and HA receptor-CD44 using 30 adult Welsh Mountain ewes. Eight ewes were kept intact and synchronized to estrous (day 0). Intact ewes were killed on day 9 (luteal phase; LUT; n=5) and day 16 (follicular phase; FOL; n=3). The remaining ewes (n=22) were ovariectomized and then treated (i.m.) with vehicle (n=6) or progesterone (n=8) for 10 days, or estrogen and progesterone for 3 days followed by 7 days of progesterone alone (n=8). Estradiol and progesterone concentrations in plasma correlated with the stage of estrous or steroid treatment. Our results showed trends (P<0.1) and statistically significant effects (P<0.05, by t-test) indicating that LUT had lower HAS1 and HAS2 and higher HAS3 and CD44 mRNA expression compared with FOL. This was reflected in immunostaining of the corresponding HAS proteins. Similarly, in ovariectomized ewes, progesterone decreased HAS1 and HAS2 and increased HAS3 and CD44, whereas estradiol tended to increase HAS2 and decrease CD44. Sometimes, HAS mRNA expression did not follow the same trend observed in the intact animals or the protein expression. HA and its associated genes and receptors were regulated by the steroids. In conclusion, these results show that the level of HA production and the molecular weight of HA in the endometrium are regulated by ovarian steroids through differential expression of different HAS both at the gene and at the protein levels. PMID- 23630334 TI - Tasting the bitter and the sweet, honeybee memories, and visualizing calcium throughout entire astrocytes. PMID- 23630335 TI - A mechanism for different receptors coupled to the same G protein to generate different responses mediated by different second messengers. PMID- 23630336 TI - Skeletal muscle fibers: Inactivated or depleted after long depolarizations? PMID- 23630337 TI - Quantitative properties and receptor reserve of the IP(3) and calcium branch of G(q)-coupled receptor signaling. AB - Gq-coupled plasma membrane receptors activate phospholipase C (PLC), which hydrolyzes membrane phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). This leads to calcium release, protein kinase C (PKC) activation, and sometimes PIP2 depletion. To understand mechanisms governing these diverging signals and to determine which of these signals is responsible for the inhibition of KCNQ2/3 (KV7.2/7.3) potassium channels, we monitored levels of PIP2, IP3, and calcium in single living cells. DAG and PKC are monitored in our companion paper (Falkenburger et al. 2013. J. Gen. Physiol. http://dx.doi.org/10.1085/jgp.201210887). The results extend our previous kinetic model of Gq-coupled receptor signaling to IP3 and calcium. We find that activation of low-abundance endogenous P2Y2 receptors by a saturating concentration of uridine 5'-triphosphate (UTP; 100 uM) leads to calcium release but not to PIP2 depletion. Activation of overexpressed M1 muscarinic receptors by 10 uM Oxo-M leads to a similar calcium release but also depletes PIP2. KCNQ2/3 channels are inhibited by Oxo-M (by 85%), but not by UTP (<1%). These differences can be attributed purely to differences in receptor abundance. Full amplitude calcium responses can be elicited even after PIP2 was partially depleted by overexpressed inducible phosphatidylinositol 5-phosphatases, suggesting that very low amounts of IP3 suffice to elicit a full calcium release. Hence, weak PLC activation can elicit robust calcium signals without net PIP2 depletion or KCNQ2/3 channel inhibition. PMID- 23630339 TI - Major contribution of sarcoplasmic reticulum Ca(2+) depletion during long-lasting activation of skeletal muscle. AB - Depolarization of skeletal muscle fibers induces sarcoplasmic reticulum (SR) Ca(2+) release and contraction that progressively decline while depolarization is maintained. Voltage-dependent inactivation of SR Ca(2+) release channels and SR Ca(2+) depletion are the two processes proposed to explain the decline of SR Ca(2+) release during long-lasting depolarizations. However, the relative contribution of these processes, especially under physiological conditions of activation, is not clearly established. Using Fura-2 and Fluo-5N to monitor cytosolic and SR Ca(2+) changes, respectively, in voltage-controlled mouse muscle fibers, we show that 2-min conditioning depolarizations reduce voltage-activated cytosolic Ca(2+) signals with a V1/2 of -53 mV but also induce SR Ca(2+) depletion that decreased the releasable pool of Ca(2+) with the same voltage sensitivity. In contrast, measurement of SR Ca(2+) changes indicated that SR Ca(2+) release channels were inactivated after SR had been depleted and in response to much higher depolarizations with a V1/2 of -13 mV. In response to trains of action potentials, cytosolic Ca(2+) signals decayed with time, whereas SR Ca(2+) changes remained stable over 1-min stimulation, demonstrating that SR Ca(2+) depletion is exclusively responsible for the decline of SR Ca(2+) release under physiological conditions of excitation. These results suggest that previous studies using steady-state inactivation protocols to investigate the voltage dependence of Ca(2+) release inactivation in fact probed the voltage dependence of SR Ca(2+) depletion, and that SR Ca(2+) depletion is the only process that leads to Ca(2+) release decline during continuous stimulation of skeletal muscle. PMID- 23630338 TI - Quantitative properties and receptor reserve of the DAG and PKC branch of G(q) coupled receptor signaling. AB - Gq protein-coupled receptors (GqPCRs) of the plasma membrane activate the phospholipase C (PLC) signaling cascade. PLC cleaves the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers diacylgycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), leading to calcium release, protein kinase C (PKC) activation, and in some cases, PIP2 depletion. We determine the kinetics of each of these downstream endpoints and also ask which is responsible for the inhibition of KCNQ2/3 (KV7.2/7.3) potassium channels in single living tsA-201 cells. We measure DAG production and PKC activity by Forster resonance energy transfer-based sensors, and PIP2 by KCNQ2/3 channels. Fully activating endogenous purinergic receptors by uridine 5'triphosphate (UTP) leads to calcium release, DAG production, and PKC activation, but no net PIP2 depletion. Fully activating high-density transfected muscarinic receptors (M1Rs) by oxotremorine-M (Oxo-M) leads to similar calcium, DAG, and PKC signals, but PIP2 is depleted. KCNQ2/3 channels are inhibited by the Oxo-M treatment (85%) and not by UTP (<1%), indicating that depletion of PIP2 is required to inhibit KCNQ2/3 in response to receptor activation. Overexpression of A kinase-anchoring protein (AKAP)79 or calmodulin (CaM) does not increase KCNQ2/3 inhibition by UTP. From these results and measurements of IP3 and calcium presented in our companion paper (Dickson et al. 2013. J. Gen. Physiol. http://dx.doi.org/10.1085/jgp.201210886), we extend our kinetic model for signaling from M1Rs to DAG/PKC and IP3/calcium signaling. We conclude that calcium/CaM and PKC-mediated phosphorylation do not underlie dynamic KCNQ2/3 channel inhibition during GqPCR activation in tsA-201 cells. Finally, our experimental data provide indirect evidence for cleavage of PI(4)P by PLC in living cells, and our modeling revisits/explains the concept of receptor reserve with measurements from all steps of GqPCR signaling. PMID- 23630340 TI - Comparison of myoplasmic calcium movements during excitation-contraction coupling in frog twitch and mouse fast-twitch muscle fibers. AB - Single twitch fibers from frog leg muscles were isolated by dissection and micro injected with furaptra, a rapidly responding fluorescent Ca(2+) indicator. Indicator resting fluorescence (FR) and the change evoked by an action potential (DeltaF) were measured at long sarcomere length (16 degrees C); DeltaF/FR was scaled to units of DeltafCaD, the change in fraction of the indicator in the Ca(2+)-bound form. DeltafCaD was simulated with a multicompartment model of the underlying myoplasmic Ca(2+) movements, and the results were compared with previous measurements and analyses in mouse fast-twitch fibers. In frog fibers, sarcoplasmic reticulum (SR) Ca(2+) release evoked by an action potential appears to be the sum of two components. The time course of the first component is similar to that of the entire Ca(2+) release waveform in mouse fibers, whereas that of the second component is severalfold slower; the fractional release amounts are ~0.8 (first component) and ~0.2 (second component). Similar results were obtained in frog simulations with a modified model that permitted competition between Mg(2+) and Ca(2+) for occupancy of the regulatory sites on troponin. An anatomical basis for two release components in frog fibers is the presence of both junctional and parajunctional SR Ca(2+) release channels (ryanodine receptors [RyRs]), whereas mouse fibers (usually) have only junctional RyRs. Also, frog fibers have two RyR isoforms, RyRalpha and RyRbeta, whereas the mouse fibers (usually) have only one, RyR1. Our simulations suggest that the second release component in frog fibers functions to supply extra Ca(2+) to activate troponin, which, in mouse fibers, is not needed because of the more favorable location of their triadic junctions (near the middle of the thin filament). We speculate that, in general, parajunctional RyRs permit increased myofilament activation in fibers whose triadic junctions are located at the z line. PMID- 23630341 TI - TMEM16F (Anoctamin 6), an anion channel of delayed Ca(2+) activation. AB - Members of the TMEM16 (Anoctamin) family of membrane proteins have been shown to be essential constituents of the Ca(2+)-activated Cl(-) channel (CaCC) in many cell types. In this study, we have investigated the electrophysiological properties of mouse TMEM16F. Heterologous expression of TMEM16F in HEK293 cells resulted in plasma membrane localization and an outwardly rectifying ICl,Ca that was activated with a delay of several minutes. Furthermore, a significant Na(+) current was activated, and the two permeabilities were correlated according to PNa = 0.3 PCl. The current showed an EC50 of 100 uM intracellular free Ca(2+) concentration and an Eisenman type 1 anion selectivity sequence of PSCN > PI > PBr > PCl > PAsp. The mTMEM16F-associated ICl,Ca was abolished in one mutant of the putative pore region (R592E) but retained in two other mutants (K616E and R636E). The mutant K616E had a lower relative permeability to iodide, and the mutant R636E had an altered anion selectivity sequence (PSCN = PI = PBr = PCl > PAsp). Our data provide evidence that TMEM16F constitutes a Ca(2+)-activated anion channel or a pore-forming subunit of an anion channel with properties distinct from TMEM16A. PMID- 23630344 TI - IL-6 cooperates with G-CSF to induce protumor function of neutrophils in bone marrow by enhancing STAT3 activation. AB - Neutrophils are known to have antitumor potential. However, in recent years the tumor-promoting effect of neutrophils has been well demonstrated. So far, it remains unclear what causes the conversion of neutrophil function from tumor suppressive to tumor promoting. In this article, we report that the conversion of murine neutrophil function occurs in bone marrow, and that IL-6 cooperation with G-CSF is required for this conversion. IL-6 cooperated with G-CSF to modulate neutrophils in bone marrow, altering the activation potential of signaling pathways in neutrophils, especially that of STAT3. Costimulation with G-CSF and IL-6 induced a higher level of phospho-STAT3 in neutrophils, which was further increased by upregulation of STAT3 expression in neutrophils owing to downregulation of IFN-beta expression in bone marrow macrophages by IL-6. Augmented STAT3 activation was crucial for upregulating the expression of Mmp9 and Bv8 genes and downregulating the expression of Trail and Rab27a genes in neutrophils. Moreover, G-CSF/IL-6-modulated neutrophils could not efficiently release azurophilic granules because of downregulation of Rab27a and inefficient activation of PI3K and p38 MAPK pathways. Because of premodulation by G-CSF and IL-6, neutrophils in response to complex stimuli in tumor released much less myeloperoxidase, neutrophil elastase, and TRAIL, but showed much higher expression of Mmp9 and Bv8 genes. Taken together, these results demonstrate that G-CSF and IL-6, despite their well-known physiological functions, could modulate the activation potential of signaling pathways in neutrophils, resulting in the production or release of the above-mentioned factors in a way that favors tumor angiogenesis and tumor growth. PMID- 23630345 TI - Multiplex B cell characterization in blood, lymph nodes, and tumors from patients with malignancies. AB - B lymphocytes contribute to immune surveillance, by tumor-specific Abs and Ag presentation to T lymphocytes, but are insufficiently studied in humans. In this article, we report a flow cytometric investigation of B lymphocyte subpopulations in blood, lymph nodes (LNs), and malignant tissues from 20 patients operated on because of advanced solid tumors. The CD19(+) compartment in peripheral blood was essentially unaltered in patients, as compared with healthy control subjects. In metastatic LNs, signs of B lymphocyte activation were observed, as evidenced by increased proportions of plasmablasts and CD86-expressing cells. In tumor infiltrating B lymphocytes (TIL-B), both switched memory cells and plasmablasts were expanded, as compared with nonmalignant epithelium. Moreover, pronounced skewing of Iglambda/Igkappa ratio was evident among TIL-Bs. By spectratype analysis on IgH, we confirmed a monoclonal expansion of the Vh7 family in TIL-B, also present in a tumor-associated LN. Sequencing the clonally expanded Vh7 revealed signs of somatic hypermutation. In conclusion, B lymphocytes in cancer patients exhibit signs of activation in tumor-associated tissues, likely induced by recognition of tumor Ags. Increased numbers of switched memory cells and plasmablasts in combination with clonal expansion and signs of somatic hypermutation suggest a CD4(+) T lymphocyte-dependent antitumoral response, which may be exploited for immunotherapy. PMID- 23630346 TI - Catecholamine-Induced beta2-adrenergic receptor activation mediates desensitization of gastric cancer cells to trastuzumab by upregulating MUC4 expression. AB - Trastuzumab is currently used for patients with Her2(+) advanced gastric cancer. However, the response rate to trastuzumab among the patients is low. The molecular mechanisms underlying trastuzumab resistance in gastric cancer are unknown. Our in vitro data show that activation of beta2-adrenergic receptor (beta2-AR) triggered by catecholamine caused "targeting failure" of trastuzumab in gastric cancer cells. The antitumor activities of trastuzumab were significantly impeded by chronic catecholamine stimulation in gastric cancer cells and in the mice bearing human gastric cancer xenografts. Mechanistically, catecholamine induced upregulation of the MUC4 expression at both transcription and protein levels via activating STAT3 and ERK. The effects of catecholamine could be effectively blocked by beta2-AR antagonist ICI-118,551, indicating that beta2-AR-mediated signaling pathway plays a key role in upregulation of MUC4, which was previously demonstrated to interfere with the recognition and physical binding of trastuzumab to Her2 molecules. Moreover, a significant elevation of the MUC4 level was observed in the xenograft tissues in nude mice chronically treated with isoproterenol. Knockdown of MUC4 restored the binding activities of trastuzumab to Her2-overexpressing gastric cancer cells. In addition, coexpression of beta2-AR and MUC4 were observed in gastric cancer tissues. Our data indicated a novel trastuzumab resistance mechanism, by which catecholamine induced beta2-AR activation mediates desensitization of gastric cancer cells to trastuzumab through upregulating the MUC4 expression. PMID- 23630347 TI - Invariant NKT cells induce plasmacytoid dendritic cell (DC) cross-talk with conventional DCs for efficient memory CD8+ T cell induction. AB - A key goal of vaccine immunotherapy is the generation of long-term memory CD8(+) T cells capable of mediating immune surveillance. We discovered a novel intercellular pathway governing the development of potent memory CD8(+) T cell responses against cell-associated Ags that is mediated through cross-presentation by XCR1(+) dendritic cells (DCs). Generation of CD8(+) memory T cells against tumor cells pulsed with an invariant NKT cell ligand depended on cross-talk between XCR1(+) and plasmacytoid DCs that was regulated by IFN-alpha/IFN-alphaR signals. IFN-alpha production by plasmacytoid DCs was stimulated by an OX40 signal from the invariant NKT cells, as well as an HMGB1 signal from the dying tumor cells. These findings reveal a previously unknown pathway of intercellular collaboration for the generation of tumor-specific CD8(+) memory T cells that can be exploited for strategic vaccination in the setting of tumor immunotherapy. PMID- 23630348 TI - Regulation of VH replacement by B cell receptor-mediated signaling in human immature B cells. AB - VH replacement provides a unique RAG-mediated recombination mechanism to edit nonfunctional IgH genes or IgH genes encoding self-reactive BCRs and contributes to the diversification of Ab repertoire in the mouse and human. Currently, it is not clear how VH replacement is regulated during early B lineage cell development. In this article, we show that cross-linking BCRs induces VH replacement in human EU12 MUHC(+) cells and in the newly emigrated immature B cells purified from peripheral blood of healthy donors or tonsillar samples. BCR signaling-induced VH replacement is dependent on the activation of Syk and Src kinases but is inhibited by CD19 costimulation, presumably through activation of the PI3K pathway. These results show that VH replacement is regulated by BCR mediated signaling in human immature B cells, which can be modulated by physiological and pharmacological treatments. PMID- 23630349 TI - Location of CD4+ T cell priming regulates the differentiation of Th1 and Th17 cells and their contribution to arthritis. AB - Th cytokines IFN-gamma and IL-17 are linked to the development of autoimmune disease. In models of rheumatoid arthritis, that is, proteoglycan (PG)-induced arthritis, IFN-gamma is required, whereas in collagen-induced arthritis, IL-17 is necessary for development of arthritis. In this study we show that the route of immunization determines the requirement for either IFN-gamma or IL-17 in arthritis. Intraperitoneal immunization with PG induces a CD4(+) T cell IFN-gamma response with little IL-17 in the spleen and peripheral lymph nodes. However, s.c. immunization induces both an IFN-gamma and an IL-17 CD4(+) T cell response in spleen and lymph nodes. The failure to induce a CD4(+) T cell IL-17 response after i.p. immunization is associated with T cell priming, as naive T cells activated in vitro were fully capable of producing IL-17. Moreover, PG-induced arthritis is converted from an IFN-gamma to an IL-17-mediated disease by altering the route of immunization from i.p. to s.c. The histological appearance of joint inflammation (cellular inflammation and bone erosion) is similar in the i.p. versus s.c. immunized mice despite the presence of CD4(+) T cells producing IL-17 in joint tissues only after s.c. immunization. These data indicate a critical role for the site of initial T cell priming and the Th cytokines required for susceptibility to arthritis. Our findings suggest that T cell activation at different anatomical sites in rheumatoid arthritis patients may skew the T cells toward production of either IFN-gamma or IL-17. PMID- 23630350 TI - SerpinB2 is critical to Th2 immunity against enteric nematode infection. AB - SerpinB2, a member of the serine protease inhibitor family, is expressed by macrophages and is significantly upregulated by inflammation. Recent studies implicated a role for SerpinB2 in the control of Th1 and Th2 immune responses, but the mechanisms of these effects are unknown. In this study, we used mice deficient in SerpinB2 (SerpinB2(-/-)) to investigate its role in the host response to the enteric nematode, Heligmosomoides bakeri. Nematode infection induced a STAT6-dependent increase in intestinal SerpinB2 expression. The H. bakeri-induced upregulation of IL-4 and IL-13 expression was attenuated in SerpinB2(-/-) mice coincident with an impaired worm clearance. In addition, lack of SerpinB2 in mice resulted in a loss of the H. bakeri-induced smooth muscle hypercontractility and a significant delay in infection-induced increase in mucosal permeability. Th2 immunity is generally linked to a CCL2-mediated increase in the infiltration of macrophages that develop into the alternatively activated phenotype (M2). In H. bakeri-infected SerpinB2(-/-) mice, there was an impaired infiltration and alternative activation of macrophages accompanied by a decrease in the intestinal CCL2 expression. Studies in macrophages isolated from SerpinB2(-/-) mice showed a reduced CCL2 expression, but normal M2 development, in response to stimulation of Th2 cytokines. These data demonstrate that the immune regulation of SerpinB2 expression plays a critical role in the development of Th2-mediated protective immunity against nematode infection by a mechanism involving CCL2 production and macrophage infiltration. PMID- 23630351 TI - Yersinia enterocolitica provides the link between thyroid-stimulating antibodies and their germline counterparts in Graves' disease. AB - Graves' disease results from thyroid-stimulating Abs (TSAbs) activating the thyrotropin receptor (TSHR). How TSAbs arise from early precursor B cells has not been established. Genetic and environmental factors may contribute to pathogenesis, including the bacterium Yersinia enterocolitica. We developed two pathogenic monoclonal TSAbs from a single experimental mouse undergoing Graves' disease, which shared the same H and L chain germline gene rearrangements and then diversified by numerous somatic hypermutations. To address the Ag specificity of the shared germline precursor of the monoclonal TSAbs, we prepared rFab germline, which showed negligible binding to TSHR, indicating importance of somatic hypermutation in acquiring TSAb activity. Using rFab chimeras, we demonstrate the dominant role of the H chain V region in TSHR recognition. The role of microbial Ags was tested with Y. enterocolitica proteins. The monoclonal TSAbs recognize 37-kDa envelope proteins, also recognized by rFab germline. MALDI TOF identified the proteins as outer membrane porin (Omp) A and OmpC. Using recombinant OmpA, OmpC, and related OmpF, we demonstrate cross-reactivity of monoclonal TSAbs with the heterogeneous porins. Importantly, rFab germline binds recombinant OmpA, OmpC, and OmpF confirming reactivity with Y. enterocolitica. A human monoclonal TSAb, M22 with similar properties to murine TSAbs, also binds recombinant porins, showing cross-reactivity of a spontaneously arising pathogenic Ab with Y. enterocolitica. The data provide a mechanistic framework for molecular mimicry in Graves' disease, where early precursor B cells are expanded by Y. enterocolitica porins to undergo somatic hypermutation to acquire a cross-reactive pathogenic response to TSHR. PMID- 23630352 TI - OX40L/Jagged1 cosignaling by GM-CSF-induced bone marrow-derived dendritic cells is required for the expansion of functional regulatory T cells. AB - Earlier, we had demonstrated that treatment with low dose of GM-CSF can prevent the development of experimental autoimmune thyroiditis (EAT), experimental autoimmune myasthenia gravis, and type 1 diabetes, and could also reverse ongoing EAT and experimental autoimmune myasthenia gravis. The protective effect was mediated through the induction of tolerogenic CD11C(+)CD8alpha(-) dendritic cells (DCs) and consequent expansion of Foxp3(+) regulatory T cells (Tregs). Subsequently, we showed that GM-CSF acted specifically on bone marrow precursors and facilitated their differentiation into tolerogenic dendritic cells (DCs; GM CSF-induced bone marrow-derived DCs [GM-BMDCs]), which directed Treg expansion in a contact-dependent manner. This novel mechanism of Treg expansion was independent of TCR-mediated signaling but required exogenous IL-2 and cosignaling from DC-bound OX40L. In this study, we observed that OX40L-mediated signaling by GM-BMDCs, although necessary, was not sufficient for Treg expansion and required signaling by Jagged1. Concurrent signaling induced by OX40L and Jagged1 via OX40 and Notch3 receptors expressed on Tregs was essential for the Treg expansion with sustained FoxP3 expression. Adoptive transfer of only OX40L(+)Jagged1(+) BMDCs led to Treg expansion, increased production of IL-4 and IL-10, and suppression of EAT in the recipient mice. These results showed a critical role for OX40L- and Jagged1-induced cosignaling in GM-BMDC-induced Treg expansion. PMID- 23630353 TI - The restricted DH gene reading frame usage in the expressed human antibody repertoire is selected based upon its amino acid content. AB - The Ab repertoire is not uniform. Some variable, diversity, and joining genes are used more frequently than others. Nonuniform usage can result from the rearrangement process, or from selection. To study how the Ab repertoire is selected, we analyzed one part of diversity generation that cannot be driven by the rearrangement mechanism: the reading frame usage of DH genes. We have used two high-throughput sequencing methodologies, multiple subjects and advanced algorithms to measure the DH reading frame usage in the human Ab repertoire. In most DH genes, a single reading frame is used predominantly, and inverted reading frames are practically never observed. The choice of a single DH reading frame is not limited to a single position of the DH gene. Rather, each DH gene participates in rearrangements of differing CDR3 lengths, restricted to multiples of three. In nonproductive rearrangements, there is practically no reading frame bias, but there is still a striking absence of inversions. Biases in DH reading frame usage are more pronounced, but also exhibit greater interindividual variation, in IgG(+) and IgA(+) than in IgM(+) B cells. These results suggest that there are two developmental checkpoints of DH reading frame selection. The first occurs during VDJ recombination, when inverted DH genes are usually avoided. The second checkpoint occurs after rearrangement, once the BCR is expressed. The second checkpoint implies that DH reading frames are subjected to differential selection. Following these checkpoints, clonal selection induces a host-specific DH reading frame usage bias. PMID- 23630354 TI - Engineered regulatory T cells coexpressing MHC class II:peptide complexes are efficient inhibitors of autoimmune T cell function and prevent the development of autoimmune arthritis. AB - Regulatory T cells (Tregs) are critical homeostatic components in preventing the development of autoimmunity, and are a major focus for their therapeutic potential for autoimmune diseases. To enhance the efficacy of Tregs in adoptive therapy, we developed a strategy for generating engineered Tregs that have the capacity to target autoimmune T cells in an Ag-specific manner. Using a retroviral expression system encoding Foxp3 and HLA-DR1 covalently linked to the immunodominant peptide of the autoantigen type II collagen (DR1-CII), naive T cells were engineered to become Tregs that express DR1-CII complexes on their surface. When these cells were tested for their ability to prevent the development of collagen induced arthritis, both the engineered DR1-CII-Foxp3 and Foxp3 only Tregs significantly reduced the severity and incidence of disease. However, the mechanism by which these two populations of Tregs inhibited disease differed significantly. Disease inhibition by the DR1-CII-Foxp3 Tregs was accompanied by significantly lower numbers of autoimmune CII-specific T cells in vivo and lower levels of autoantibodies in comparison with engineered Tregs expressing Foxp3 alone. In addition, the numbers of IFN-gamma- and IL-17 expressing T cells in mice treated with DR1-CII-Foxp3 Tregs were also significantly reduced in comparison with mice treated with Foxp3 engineered Tregs or vector control cells. These data indicate that the coexpression of class II autoantigen-peptide complexes on Tregs provides these cells with a distinct capacity to regulate autoimmune T cell responses that differs from that used by conventional Tregs. PMID- 23630355 TI - Radiation-induced equilibrium is a balance between tumor cell proliferation and T cell-mediated killing. AB - Local failures following radiation therapy are multifactorial, and the contributions of the tumor and the host are complex. Current models of tumor equilibrium suggest that a balance exists between cell birth and cell death due to insufficient angiogenesis, immune effects, or intrinsic cellular factors. We investigated whether host immune responses contribute to radiation-induced tumor equilibrium in animal models. We report an essential role for immune cells and their cytokines in suppressing tumor cell regrowth in two experimental animal model systems. Depletion of T cells or neutralization of IFN-gamma reversed radiation-induced equilibrium, leading to tumor regrowth. We also demonstrate that PD-L1 blockade augments T cell responses, leading to rejection of tumors in radiation-induced equilibrium. We identify an active interplay between tumor cells and immune cells that occurs in radiation-induced tumor equilibrium and suggest a potential role for disruption of the PD-L1/PD-1 axis in increasing local tumor control. PMID- 23630356 TI - Reversal of global CD4+ subset dysfunction is associated with spontaneous clinical resolution of pulmonary sarcoidosis. AB - Sarcoidosis pathogenesis is characterized by peripheral anergy and an exaggerated, pulmonary CD4(+) Th1 response. In this study, we demonstrate that CD4(+) anergic responses to polyclonal TCR stimulation are present peripherally and within the lungs of sarcoid patients. Consistent with prior observations, spontaneous release of IL-2 was noted in sarcoidosis bronchoalveolar lavage CD4(+) T cells. However, in contrast to spontaneous hyperactive responses reported previously, the cells displayed anergic responses to polyclonal TCR stimulation. The anergic responses correlated with diminished expression of the Src kinase Lck, protein kinase C-theta, and NF-kappaB, key mediators of IL-2 transcription. Although T regulatory (Treg) cells were increased in sarcoid patients, Treg depletion from the CD4(+) T cell population of sarcoidosis patients did not rescue IL-2 and IFN-gamma production, whereas restoration of the IL-2 signaling cascade, via protein kinase C-theta overexpression, did. Furthermore, sarcoidosis Treg cells displayed poor suppressive capacity indicating that T cell dysfunction was a global CD4(+) manifestation. Analyses of patients with spontaneous clinical resolution revealed that restoration of CD4(+) Th1 and Treg cell function was associated with resolution. Conversely, disease progression exhibited decreased Th1 cytokine secretion and proliferative capacity, and reduced Lck expression. These findings implicate normalized CD4(+) T cell function as a potential therapeutic target for sarcoidosis resolution. PMID- 23630357 TI - Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through mincle/CARD9 signaling and the inflammasome. AB - Although adjuvants are critical vaccine components, their modes of action are poorly understood. In this study, we investigated the mechanisms by which the heat-killed mycobacteria in CFA promote Th17 CD4(+) T cell responses. We found that IL-17 secretion by CD4(+) T cells following CFA immunization requires MyD88 and IL-1beta/IL-1R signaling. Through measurement of Ag-specific responses after adoptive transfer of OTII cells, we confirmed that MyD88-dependent signaling controls Th17 differentiation rather than simply production of IL-17. Additional experiments showed that CFA-induced Th17 differentiation involves IL-1beta processing by the inflammasome, as mice lacking caspase-1, ASC, or NLRP3 exhibit partially defective responses after immunization. Biochemical fractionation studies further revealed that peptidoglycan is the major component of heat-killed mycobacteria responsible for inflammasome activation. By assaying Il1b transcripts in the injection site skin of CFA-immunized mice, we found that signaling through the adaptor molecule caspase activation and recruitment domain 9 (CARD9) plays a major role in triggering pro-IL-1beta expression. Moreover, we demonstrated that recognition of the mycobacterial glycolipid trehalose dimycolate (cord factor) by the C-type lectin receptor mincle partially explains this CARD9 requirement. Importantly, purified peptidoglycan and cord factor administered in mineral oil synergized to recapitulate the Th17-promoting activity of CFA, and, as expected, this response was diminished in caspase-1- and CARD9-deficient mice. Taken together, these findings suggest a general strategy for the rational design of Th17-skewing adjuvants by combining agonists of the CARD9 pathway with inflammasome activators. PMID- 23630358 TI - Prostaglandin E2-induced changes in alveolar macrophage scavenger receptor profiles differentially alter phagocytosis of Pseudomonas aeruginosa and Staphylococcus aureus post-bone marrow transplant. AB - The effectiveness of hematopoietic stem cell transplantation as a therapy for malignant and nonmalignant conditions is complicated by pulmonary infections. Using our syngeneic bone marrow transplant (BMT) mouse model, BMT mice with a reconstituted hematopoietic system displayed increased susceptibility to Pseudomonas aeruginosa and Staphylococcus aureus. BMT alveolar macrophages (AMs) exhibited a defect in P. aeruginosa phagocytosis, whereas S. aureus uptake was surprisingly enhanced. We hypothesized that the difference in phagocytosis was due to an altered scavenger receptor (SR) profile. Interestingly, MARCO expression was decreased, whereas SR-AI/II was increased. To understand how these dysregulated SR profiles might affect macrophage function, CHO cells were transfected with SR-AI/II, and phagocytosis assays revealed that SR-AI/II was important for S. aureus uptake but not for P. aeruginosa. Conversely, AMs treated in vitro with soluble MARCO exhibited similar defects in P. aeruginosa internalization as did BMT AMs. The 3'-untranslated region of SR-AI contains a putative target region for microRNA-155 (miR-155), and miR-155 expression is decreased post-BMT. Anti-miR-155-transfected AMs exhibited an increase in SR AI/II expression and S. aureus phagocytosis. Elevated PGE2 has been implicated in driving an impaired innate immune response post-BMT. In vitro treatment of AMs with PGE2 increased SR-AI/II and decreased MARCO and miR-155. Despite a difference in phagocytic ability, BMT AMs harbor a killing defect to both P. aeruginosa and S. aureus. Thus, our data suggest that PGE2-driven alterations in SR and miR-155 expression account for the differential phagocytosis of P. aeruginosa and S. aureus, but impaired killing ultimately confers increased susceptibility to pulmonary infection. PMID- 23630359 TI - TGF-beta1 limits the onset of innate lung inflammation by promoting mast cell derived IL-6. AB - TGF-beta1 is an important suppressive mediator of inflammation, but it can also drive fibrosis and remodeling in the lung. In response to intratracheal LPS, neutrophils migrate into the lung, and TGF-beta1 was suggested to protect against the ensuing injury. However, the mechanisms for this protective role remain unknown. Using a model of acute lung injury, we demonstrate that TGF-beta1 decreases neutrophil numbers during the onset of injury. This was due to increased apoptosis rather than reduced migration. We demonstrate that TGF-beta1 does not directly regulate neutrophil apoptosis but instead functions through IL 6 to promote neutrophil clearance. rIL-6 is sufficient to promote neutrophil apoptosis and reduce neutrophilia in bronchoalveolar lavage fluid, while IL-6 increases rapidly following LPS-induced injury. Mast cells are a critical source of IL-6, because mast cell-deficient mice exhibit increased neutrophil numbers that are reduced by reconstitution with wild-type, but not IL-6(-/-), mast cells. Although IL-6 diminishes neutrophilia in mast cell-deficient mice, TGF-beta1 is ineffective, suggesting that these effects were mast cell dependent. Taken together, our findings establish a novel pathway through which TGF-beta1, likely derived from resident regulatory T cells, controls the severity and magnitude of early innate inflammation by promoting IL-6 from mast cells. PMID- 23630360 TI - IL-33 induces nuocytes and modulates liver injury in viral hepatitis. AB - Molecules containing damage-associated molecular patterns play an important role in many pathogenic processes. In this study, our aim was to investigate the role of IL-33, a damage-associated molecular pattern molecule, in adenovirus (Ad) induced liver inflammation. Ad-infected mice exhibited a steadily increased IL-33 and its receptor IL-1R-like 1 expression in the liver during the first week of infection. Treatment of exogenous IL-33 resulted in a great decrease in the serum alanine aminotransferase levels and the number of Councilman bodies in the liver. Attenuated liver injury by IL-33 correlated with an increase in T regulatory cells but with a decrease in macrophages, dendritic cells, and NK cells in the liver. IL-33 enhanced both type 1 (IL-2 and IFN-gamma) and type 2 (IL-5 and IL 13) immune responses in infected mice. However, IL-33 inhibited TNF-alpha expression in hepatic T cells and macrophages, and significantly reduced TNF alpha levels in the liver. We found that in addition to its direct effects, IL-33 strongly induced novel nuocytes in the livers and spleens of infected mice. When cocultured with nuocytes, hepatic T cells and macrophages expressed lower levels of TNF-alpha. The IL-33-treated mice also demonstrated a slight delay, but no significant impairment, in eliminating an intrahepatic infection with Ad. In conclusion, this study reveals that IL-33 acts as a potent immune stimulator and a hepatoprotective cytokine in acute viral hepatitis. Its direct immunoregulatory functions and ability to induce novel nuocytes further suggest to us that it may be a potentially promising therapeutic candidate for the management of viral hepatitis. PMID- 23630361 TI - Copresentation of intact and processed MHC alloantigen by recipient dendritic cells enables delivery of linked help to alloreactive CD8 T cells by indirect pathway CD4 T cells. AB - In transplantation, direct-pathway CD8 T cells that recognize alloantigen on donor cells require CD4 help for activation and cytolytic function. The ability of indirect-pathway CD4 T cells to provide this help remains unexplained, because a fundamental requirement for epitope linkage is seemingly broken. The simultaneous presentation, by host dendritic cells (DCs), of both intact MHC class I alloantigen and processed alloantigen would deliver linked help, but has not been demonstrated definitively. In this study, we report that following in vitro coculture with BALB/c DCs, small numbers (~1.5%) of C57BL/6 (B6) DCs presented acquired H-2(d) alloantigen both as processed allopeptide and as unprocessed Ag. This represented class I alloantigen provides a conformational epitope for direct-pathway allorecognition, because B6 DCs isolated from cocultures and transferred to naive B6 mice provoked cytotoxic CD8 T cell alloimmunity. Crucially, this response was dependent upon simultaneous presentation of class II-restricted allopeptide, because despite acquiring similar amounts of H-2(d) alloantigen upon coculture, MHC class II-deficient B6 DCs failed to elicit cytotoxic alloimmunity. The relevance of this pathway to solid-organ transplantation was then confirmed by the demonstration that CD8 T cell cytotoxicity was provoked in secondary recipients by transfer of DCs purified from wild-type, but not from MHC class II-deficient, C57BL/6 recipients of BALB/c heart transplants. These experiments demonstrate that representation of conformationally intact MHC alloantigen by recipient APC can induce cytotoxic alloimmunity, but simultaneous copresentation of processed allopeptide is essential, presumably because this facilitates linked recognition by indirect pathway CD4 Th cells. PMID- 23630362 TI - Role of IL-22- and TNF-alpha-producing Th22 cells in uveitis patients with Behcet's disease. AB - Behcet's disease is a systemic inflammatory disorder with recurrent episodes of oral ulceration, skin lesions, genital ulceration, and intraocular inflammation (uveitis). The intraocular inflammation is strictly associated with Th effector cells. IL-22 is a member of the IL-10 cytokine family that is involved in inflammatory processes. Recently, Th22 cells were identified as a Th cell population that produces IL-22 and TNF-alpha and are distinct from Th1, Th2, and Th17 cells. In this study, we established Th22-type T cell clones from ocular samples taken from Behcet's disease patients with active uveitis. These clones produced large amounts of IL-22 and TNF-alpha but not the Th1 cytokine IFN-gamma and the Th17 cytokine IL-17. CD4(+) T cells from the peripheral blood of Behcet's disease patients differentiated into Th22 cells in the presence of IL-6 and TNF alpha in vitro. The polarized Th22 cell lines produced large amounts of IL-22, and the polarized Th1 and Th17 cells also produced IL-22. In the presence of anti TNF-alpha- and anti-IL-6-blocking Abs, Behcet's disease Th22-type T cells failed to produce IL-22. In addition, infliximab-pretreated Th22 cells and Th22-type ocular T cells produced less IL-22 and TNF-alpha. Moreover, IL-22-producing T cells were isolated from mice with experimental autoimmune uveitis, an animal model of Behcet's disease, and the intraocular T cells from uveitis models produced large amounts of IL-22 in the presence of retinal Ags. Our results suggest that inflammatory cytokines IL-22 and TNF-alpha may play a key role in the ocular immune response in Behcet's disease. PMID- 23630363 TI - Targeting of antigens to B lymphocytes via CD19 as a means for tumor vaccine development. AB - Ab therapy against surface Ags on tumor cells has demonstrated significant efficacy for some cancers. However, it is costly and patients frequently develop acquired resistance over time. In cases of Ab therapy resistance, T cell responses have been shown to be essential in controlling disease progression. Thus, vaccination that generates a sustained Ab response as well as a T cell response may be more effective and economical. In this article, we have developed a vaccination strategy by targeting protein Ags to B cells via a CD19 single chain variable fragment miniAb. Using the tumor-associated Ag her-2/neu extracellular domain, we showed that the coengagement of CD19 and BCR induced full B cell activation to produce a high titer of Abs and enhanced CD4 Th2 response and CD8 T cell activation and differentiation. These Abs competitively inhibited humanized her-2/neu Ab binding and were capable of activating the complement and inhibiting human breast cancer growth in vitro. Therapeutic efficacy was demonstrated in vivo using murine mammary carcinoma models. Furthermore, four different extracellular domains of her-2/neu could be targeted to B cells to generate Abs against particular domains with different antitumor properties. This approach may offer a new avenue for vaccine development with significantly lower cost, which may be of use not only for cancer therapy but also for infectious agents. PMID- 23630364 TI - Histidine-rich protein 2 plasma levels predict progression to cerebral malaria in Malawian children with Plasmodium falciparum infection. AB - Some children with uncomplicated malaria progress to cerebral malaria despite appropriate treatment; identifying them in advance might improve their care. The objective of this study was to determine if plasma concentrations of a malaria protein, HRP2 (histidine-rich protein 2) would serve this purpose. Cases and controls were children presenting with uncomplicated malaria; the cases (n = 25) developed cerebral malaria, and the controls (n = 125) did not. Mean plasma HRP2 concentrations were significantly higher in the cases, and an HRP2 cutoff was identified that could predict disease progression (sensitivity and specificity, 88% for each). Quantitative measurements of HRP2 may be a useful screening tool. PMID- 23630367 TI - Cost-effectiveness of exercise therapy after corticosteroid injection for moderate to severe shoulder pain due to subacromial impingement syndrome: a trial based analysis. AB - OBJECTIVE: To perform a cost-effectiveness analysis of subacromial corticosteroid injection combined with exercise compared with exercise alone in patients with moderate to severe shoulder pain from subacromial impingement syndrome. METHODS: A within-trial cost-effectiveness analysis with 232 patients randomized to physiotherapy-led injection combined with exercise (n = 115) or exercise alone (n = 117). The analysis was from a health care perspective with 24-week follow-up. Resource use information was collected from all patients on interventions, medication, primary and secondary care contacts, private health care use and over the-counter purchases. The measure of outcome was quality-adjusted life years (QALYs), calculated from EQ-5D responses at baseline and three further time points. An incremental cost-effectiveness analysis was conducted. RESULTS: Mean per patient NHS costs (L255 vs L297) and overall health care costs (L261 vs L318) were lower in the injection plus exercise arm, but this difference was not statistically significant. Total QALYs gained were very similar in the two trial arms (0.3514 vs 0.3494 QALYs), although slightly higher in the injection plus exercise arm, indicating that injection plus exercise may be the dominant treatment option. At a willingness to pay of L20,000 per additional QALY gained, there was a 61% probability that injection plus exercise was the most cost effective option. CONCLUSION: Injection plus exercise delivered by therapists may be a cost-effective use of resources compared with exercise alone and lead to lower health care costs and less time off work. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register, http://www.controlled trials.com/isrctn/, ISRCT 25817033. PMID- 23630365 TI - Potent antitrypanosomal activities of heat shock protein 90 inhibitors in vitro and in vivo. AB - African sleeping sickness, caused by the protozoan parasite Trypanosoma brucei, is universally fatal if untreated, and current drugs are limited by severe toxicities and difficult administration. New antitrypanosomals are greatly needed. Heat shock protein 90 (Hsp90) is a conserved and ubiquitously expressed molecular chaperone essential for stress responses and cellular signaling. We investigated Hsp90 inhibitors for their antitrypanosomal activity. Geldanamycin and radicicol had nanomolar potency in vitro against bloodstream-form T. brucei; novobiocin had micromolar activity. In structure-activity studies of geldanamycin analogs, 17-AAG and 17-DMAG were most selective against T. brucei as compared to mammalian cells. 17-AAG treatment sensitized trypanosomes to heat shock and caused severe morphological abnormalities and cell cycle disruption. Both oral and parenteral 17-DMAG cured mice of a normally lethal infection of T. brucei. These promising results support the use of inhibitors to study Hsp90 function in trypanosomes and to expand current clinical development of Hsp90 inhibitors to include T. brucei. PMID- 23630366 TI - Efficacy and safety of axitinib versus sorafenib in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from the global randomized Phase 3 AXIS trial. AB - OBJECTIVE: Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated. METHODS: A subgroup analysis was conducted in Japanese patients enrolled in the randomized Phase III trial of axitinib versus sorafenib after failure of one prior systemic therapy for metastatic renal cell carcinoma. RESULTS: Twenty-five (of 361) and 29 (of 362) patients randomized to the axitinib and sorafenib arms, respectively, were Japanese and included in this analysis. Median progression-free survival in Japanese patients was 12.1 months (95% confidence interval 8.6 to not estimable) for axitinib and 4.9 months (95% confidence interval 2.8-6.6) for sorafenib (hazard ratio 0.390; 95% confidence interval 0.130-1.173; stratified one-sided P = 0.0401). The objective response rate was 52.0% for axitinib and 3.4% for sorafenib (P = 0.0001). The common all causality adverse events (all grades) in Japanese patients were dysphonia (68%), hypertension (64%), hand-foot syndrome (64%) and diarrhea (56%) for axitinib, and hand-foot syndrome (86%), hypertension (62%) and diarrhea (52%) for sorafenib. The safety profiles of axitinib and sorafenib in Japanese patients were generally similar to those observed in the overall population, with the exceptions of higher incidences of hypertension, dysphonia, hand-foot syndrome, hypothyroidism and stomatitis. CONCLUSIONS: Axitinib is efficacious and well tolerated in Japanese patients with previously treated metastatic renal cell carcinoma, consistent with the results in the overall population, providing a new targeted therapy for these Japanese patients. PMID- 23630369 TI - Properties of long gamma-ray bursts from massive compact binaries. AB - We consider the implications of a model for long-duration gamma-ray bursts in which the progenitor is spun up in a close binary by tidal interactions with a massive black-hole companion. We investigate a sample of such binaries produced by a binary population synthesis, and show that the model predicts several common features in the accretion on to the newly formed black hole. In all cases, the accretion rate declines as approximately t(-5/3) until a break at a time of order 10(4) s. The accretion rate declines steeply thereafter. Subsequently, there is flaring activity, with the flare peaking between 10(4) and 10(5) s, the peak time being correlated with the flare energy. We show that these times are set by the semi-major axis of the binary, and hence the process of tidal spin-up; furthermore, they are consistent with flares seen in the X-ray light curves of some long gamma-ray bursts. PMID- 23630368 TI - Recent developments in disease activity indices and outcome measures for juvenile idiopathic arthritis. AB - There has been a concerted and important international effort to develop and validate disease activity and outcome instruments specific to JIA in recent years. This review aims to describe the disease assessment indices important to routine clinical care and integral to the design of outcome studies and clinical trials in JIA. In view of the increasing number of JIA clinical studies and clinical trials, together with a number of national and international paediatric biologic registers, it is important that knowledge of these new outcome measures is widespread, such that results can be placed in a meaningful context. PMID- 23630370 TI - Amsterdam-ASTRON radio transient facility and analysis centre: towards a 24 x 7, all-sky monitor for the low-frequency array (LOFAR). AB - The Amsterdam-ASTRON Radio Transient Facility And Analysis Centre (AARTFAAC) project aims to implement an all-sky monitor (ASM), using the low-frequency array (LOFAR) telescope. It will enable real-time, 24 * 7 monitoring for low-frequency radio transients over most of the sky locally visible to the LOFAR at time scales ranging from seconds to several days, and rapid triggering of follow-up observations with the full LOFAR on detection of potential transient candidates. These requirements pose several implementation challenges: imaging of an all-sky field of view, low latencies of processing, continuous availability and autonomous operation of the ASM. The first of these has already resulted in the correlator for the ASM being the largest in the world in terms of the number of input data streams. We have carried out test observations using existing LOFAR infrastructure, in order to quantify and constrain crucial instrumental design criteria for the ASM. In this study, we present an overview of the AARTFAAC data processing pipeline and illustrate some of the aforementioned challenges by showing all-sky images obtained from one of the test observations. These results provide quantitative estimates of the capabilities of the instrument. PMID- 23630371 TI - A complete sample of long bright Swift gamma ray bursts. AB - Complete samples are the basis of any population study. To this end, we selected a complete subsample of Swift long bright gamma ray bursts (GRBs). The sample, made up of 58 bursts, was selected by considering bursts with favourable observing conditions for ground-based follow-up observations and with the 15-150 keV 1 s peak flux above a flux threshold of 2.6 photons cm(-2) s(-1). This sample has a redshift completeness level higher than 90 per cent. Using this complete sample, we investigate the properties of long GRBs and their evolution with cosmic time, focusing in particular on the GRB luminosity function, the prompt emission spectral-energy correlations and the nature of dark bursts. PMID- 23630372 TI - Merging white dwarfs and thermonuclear supernovae. AB - Thermonuclear supernovae result when interaction with a companion reignites nuclear fusion in a carbon-oxygen white dwarf, causing a thermonuclear runaway, a catastrophic gain in pressure and the disintegration of the whole white dwarf. It is usually thought that fusion is reignited in near-pycnonuclear conditions when the white dwarf approaches the Chandrasekhar mass. I briefly describe two long standing problems faced by this scenario, and the suggestion that these supernovae instead result from mergers of carbon-oxygen white dwarfs, including those that produce sub-Chandrasekhar-mass remnants. I then turn to possible observational tests, in particular, those that test the absence or presence of electron captures during the burning. PMID- 23630373 TI - Gamma-ray burst progenitors and the population of rotating Wolf-Rayet stars. AB - In our quest for gamma-ray burst (GRB) progenitors, it is relevant to consider the progenitor evolution of normal supernovae (SNe). This is largely dominated by mass loss. We discuss the mass-loss rate for very massive stars up to 300M?. These objects are in close proximity to the Eddington Gamma limit. We describe the new concept of the transitional mass-loss rate, enabling us to calibrate wind mass loss. This allows us to consider the occurrence of pair-instability SNe in the local Universe. We also discuss luminous blue variables and their link to luminous SNe. Finally, we address the polarization properties of Wolf-Rayet (WR) stars, measuring their wind asphericities. We argue to have found a group of rotating WR stars that fulfil the required criteria to make long-duration GRBs. PMID- 23630374 TI - Transient astronomy with the Gaia satellite. AB - Gaia is a cornerstone European Space Agency astrometry space mission and a successor to the Hipparcos mission. Gaia will observe the whole sky for 5 years, providing a serendipitous opportunity for the discovery of large numbers of transient and anomalous events, e.g. supernovae, novae and microlensing events, gamma-ray burst afterglows, fallback supernovae, as well as theoretical or unexpected phenomena. In this paper, we discuss our preparations to use Gaia to search for transients at optical wavelengths, and briefly describe the early detection, classification and prompt publication of anomalous sources. PMID- 23630375 TI - Pan-STARRS, ATLAS and optical transient searches. AB - The Pan-STARRS1 survey is collecting multi-epoch, multi-colour observations of the sky north of declination -30 degrees , and has designated 70 deg(2) for nightly observations that are particularly useful for transient detection. A duplicate, Pan-STARRS2, is nearing completion that offers opportunities to improve the quality of transient search and observation, as well as simply increasing the number of detections. A new system, the Asteroid Terrestrial impact Last Alert System (ATLAS), increases the search area to all-sky in return for diminished sensitivity, and highlights tension among optimization for static sky images, optimization for faint transients and optimization for an unbiased number of transients. ATLAS gives up sub-arcsecond images and full colour information to specialize in the third category, but should detect many more transients than the Pan-STARRS1 Medium Deep fields or the Palomar Transient Factory, with examples of transient classes that are considerably closer and brighter. PMID- 23630376 TI - High-energy transients. AB - We present an overview of high-energy transients in astrophysics, highlighting important advances over the past 50 years. We begin with early discoveries of gamma-ray transients, and then delve into physical details associated with a variety of phenomena. We discuss some of the unexpected transients found by Fermi and Swift, many of which are not easily classifiable or in some way challenge conventional wisdom. These objects are important insofar as they underscore the necessity of future, more detailed studies. PMID- 23630377 TI - The dynamic ejecta of compact object mergers and eccentric collisions. AB - Compact object mergers eject neutron-rich matter in a number of ways: by the dynamical ejection mediated by gravitational torques, as neutrino-driven winds, and probably also a good fraction of the resulting accretion disc finally becomes unbound by a combination of viscous and nuclear processes. If compact binary mergers indeed produce gamma-ray bursts, there should also be an interaction region where an ultra-relativistic outflow interacts with the neutrino-driven wind and produces moderately relativistic ejecta. Each type of ejecta has different physical properties, and therefore plays a different role for nucleosynthesis and for the electromagnetic (EM) transients that go along with compact object encounters. Here, we focus on the dynamic ejecta and present results for over 30 hydrodynamical simulations of both gravitational wave-driven mergers and parabolic encounters as they may occur in globular clusters. We find that mergers eject approximately 1 per cent of a Solar mass of extremely neutron rich material. The exact amount, as well as the ejection velocity, depends on the involved masses with asymmetric systems ejecting more material at higher velocities. This material undergoes a robust r-process and both ejecta amount and abundance pattern are consistent with neutron star mergers being a major source of the 'heavy' (A>130) r-process isotopes. Parabolic collisions, especially those between neutron stars and black holes, eject substantially larger amounts of mass, and therefore cannot occur frequently without overproducing gala- ctic r process matter. We also discuss the EM transients that are powered by radioactive decays within the ejecta ('macronovae'), and the radio flares that emerge when the ejecta dissipate their large kinetic energies in the ambient medium. PMID- 23630378 TI - The long, the short and the weak: the origin of gamma-ray bursts. AB - The origin of gamma-ray bursts (GRBs) is one of the most interesting puzzles in recent astronomy. During the last decade a consensus has formed that long GRBs (LGRBs) arise from the collapse of massive stars, and that short GRBs (SGRBs) have a different origin, most likely neutron star mergers. A key ingredient of the collapsar model that explains how the collapse of massive stars produces a GRB is the emergence of a relativistic jet that penetrates the stellar envelope. The condition that the emerging jet penetrates the envelope imposes strong constraints on the system. Using these constraints we show the following. (i) Low luminosity GRBs (llGRBs), a subpopulation of GRBs with very low luminosities (and other peculiar properties: single-peaked, smooth and soft), cannot be formed by collapsars. llGRBs must have a different origin (most likely a shock breakout). (ii) On the other hand, regular LGRBs must be formed by collapsars. (iii) While for BATSE the dividing line between collapsars and non-collapsars is indeed at approximately 2 s, the dividing line is different for other GRB detectors. In particular, most Swift bursts longer than 0.8 s are of a collapsar origin. This last result requires a revision of many conclusions concerning the origin of Swift SGRBs, which were based on the commonly used 2 s limit. PMID- 23630379 TI - The supernova-gamma-ray burst-jet connection. AB - The observed association between supernovae and gamma-ray bursts represents a cornerstone in our understanding of the nature of gamma-ray bursts. The collapsar model provides a theoretical framework for this connection. A key element is the launch of a bipolar jet (seen as a gamma-ray burst). The resulting hot cocoon disrupts the star, whereas the (56)Ni produced gives rise to radioactive heating of the ejecta, seen as a supernova. In this discussion paper, I summarize the observational status of the supernova-gamma-ray burst connection in the context of the 'engine' picture of jet-driven supernovae and highlight SN 2012bz/GRB 120422A--with its luminous supernova but intermediate high-energy luminosity--as a possible transition object between low-luminosity and jet gamma-ray bursts. The jet channel for supernova explosions may provide new insights into supernova explosions in general. PMID- 23630380 TI - High-energy emission from transients. AB - Cosmic explosions dissipate energy into their surroundings on a very wide range of time scales: producing shock waves and associated particle acceleration. The historical culprits for the acceleration of the bulk of Galactic cosmic rays are supernova remnants: explosions on approximately 10(4) year time scales. Increasingly, however, time-variable emission points to rapid and efficient particle acceleration in a range of different astrophysical systems. Gamma-ray bursts have the shortest time scales, with inferred bulk Lorentz factors of approximately 1000 and photons emitted beyond 100 GeV, but active galaxies, pulsar wind nebulae and colliding stellar winds are all now associated with time variable emission at approximately teraelectron volt energies. Cosmic photons and neutrinos at these energies offer a powerful probe of the underlying physical mechanisms of cosmic explosions, and a tool for exploring fundamental physics with these systems. Here, we discuss the motivations for high-energy observations of transients, the current experimental situation, and the prospects for the next decade, with particular reference to the major next-generation high-energy observatory, the Cherenkov Telescope Array. PMID- 23630381 TI - Supernovae and cosmology with future European facilities. AB - Prospects for future supernova surveys are discussed, focusing on the European Space Agency's Euclid mission and the European Extremely Large Telescope (E-ELT), both expected to be in operation around the turn of the decade. Euclid is a 1.2 m space survey telescope that will operate at visible and near-infrared wavelengths, and has the potential to find and obtain multi-band lightcurves for thousands of distant supernovae. The E-ELT is a planned, general-purpose ground based, 40-m-class optical-infrared telescope with adaptive optics built in, which will be capable of obtaining spectra of type Ia supernovae to redshifts of at least four. The contribution to supernova cosmology with these facilities will be discussed in the context of other future supernova programmes such as those proposed for DES, JWST, LSST and WFIRST. PMID- 23630382 TI - The square kilometre array and the transient universe. AB - The square kilometre array (SKA) is a next generation radio telescope that will be built in southern Africa and Australasia. It will be built in two phases and will use a range of detectors, from aperture arrays to dishes, to span the frequency range from a few tens of megahertz to a few gigahertz. The combination of great sensitivity, wide field of view and unprecedented computing power mean that the SKA will be an excellent instrument for studying the transient radio universe. Transient radio emission is generated in extremes of: gravitational and magnetic fields, velocity, temperature, pressure and density. While we know about plenty of source classes for this type of short duration radio emission, there is still a large range of transient parameter space that has not yet been sampled owing to the limitations of current generation radio telescopes. PMID- 23630383 TI - Interpreting signals from astrophysical transient experiments. AB - Time-domain astronomy has come of age with astronomers now able to monitor the sky at high cadence, both across the electromagnetic spectrum and using neutrinos and gravitational waves. The advent of new observing facilities permits new science, but the ever-increasing throughput of facilities demands efficient communication of coincident detections and better subsequent coordination among the scientific community so as to turn detections into scientific discoveries. To discuss the revolution occurring in our ability to monitor the Universe and the challenges it brings, on 25-26 April 2012, a group of scientists from observational and theoretical teams studying transients met with representatives of the major international transient observing facilities at the Kavli Royal Society International Centre, UK. This immediately followed the Royal Society Discussion Meeting 'New windows on transients across the Universe' held in London. Here, we present a summary of the Kavli meeting at which the participants discussed the science goals common to the transient astronomy community and analysed how to better meet the challenges ahead as ever more powerful observational facilities come on stream. PMID- 23630384 TI - Assessment of radiological hazards of Lawrencepur sand, Pakistan using gamma spectrometry. AB - The Lawrencepur sand had remained refrigerated during a long period of glaciations in the study area. Owing to its derivation from the granitic rocks of the Himalayas and its preservation under glacial environment, the sand grains are still fresh and may contain high level of primordial radioactivity. For that reason, radiological hazards of Lawrencepur sand were assessed using a high purity germanium gamma spectrometry technique. The average activity concentrations of (226)Ra, (232)Th and (40)K were found to be 15.97+/-3.05, 27.98+/-4.89 and 498.20+/-15.91 Bq kg(-1), respectively. These values are higher than those of the sands of many countries of the world but lower than those of some of the Pakistani, Indian and Egyptian sands. The outdoor and indoor hazard indices and annual effective doses of the Lawrencepur sand are higher than those of some of the sand deposits of European, African and American countries but lower than those of nearby Pakistani and Indian sands. However, the hazard indices and annual effective doses of the Lawrencepur sand are within the safe limits. Overall, the Lawrencepur sand does not pose any radiological health hazard as a building material. PMID- 23630385 TI - Activity levels of some radionuclides in Mariout and Brullus lakes, Egypt. AB - Mariout and Brullus are two of the highly fish-productive lakes in the northern coast of Egypt along the Mediterranean Sea. They are widely used to drain industrial wastes, sewage and agriculture drainage. The activities of (238)U, (232)Th, (40)K and (137)Cs were measured in the uppermost part of the surface sediments of the two lakes, using gamma-ray spectrophotometry. Brullus Lake recorded significantly higher (238)U and (232)Th and lower (40)K (17.22+/-2.49, 10.03+/-0.56 and 299.70+/-17.78 Bq kg(-1)) than Mariout Lake (12.65+/-1.53, 7.24+/-0.76 and 518.75+/-46.24 Bq kg(-1), respectively). Cesium-137 shows nearly equal activities in both lakes (3.33+/-0.46 and 3.68+/-0.70 Bq kg(-1), respectively). Activity distributions of (238)U and (232)Th in the sediments of Mariout Lake show a significant increase to the west, southwest and northeast, (40)K activity increased westwards, while the (137)Cs level was increased to the east and northeast, indicating agriculture drainage, industrial wastes and lands reclamation around the lake. At Brullus Lake, the activity trends of (238)U, (232)Th, (40)K and(137)Cs were increasing to the west and south towards the agriculture and industrial waste-water-feeding drains. PMID- 23630386 TI - Narrow-band imaging for the head and neck region and the upper gastrointestinal tract. AB - Endoscopy is essential for the diagnosis and treatment of cancers derived from the gastrointestinal tract. However, a conventional white-light image has technical limitations in detecting small or superficial lesions. Narrow-band imaging, especially with magnification, allows visualization of microstructure patterns and microvascular patterns on the mucosal surface. These technical breakthroughs enable endoscopists to easily detect small pre-neoplastic and neoplastic lesions and to make a differential diagnosis of these lesions. Appropriate diagnosis with narrow-band imaging contributes to minimally invasive endoscopic resection. PMID- 23630387 TI - A case of esophageal carcinoma in a patient with right aortic arch (RAA). PMID- 23630388 TI - Worldwide burden of cancer death below the age of 40 extrapolated from the WHO mortality database. PMID- 23630389 TI - The B cell helper side of neutrophils. AB - Neutrophils use opsonizing antibodies to enhance the clearance of intruding microbes. Recent studies indicate that splenic neutrophils also induce antibody production by providing helper signals to B cells lodged in the MZ of the spleen. Here, we discuss the B cell helper function of neutrophils in the context of growing evidence indicating that neutrophils function as sophisticated regulators of innate and adaptive immune responses. PMID- 23630390 TI - Homologous recombination into the eosinophil peroxidase locus generates a strain of mice expressing Cre recombinase exclusively in eosinophils. AB - Eosinophils are generally linked to innate host defense against helminths, as well as the pathologies associated with allergic diseases, such as asthma. Nonetheless, the activities of eosinophils remain poorly understood, which in turn, has prevented detailed definitions of their role(s) in health and disease. Homologous recombination in embryonic stem cells was used to insert a mammalianized Cre recombinase in the ORF encoding Epx. This knock-in strategy overcame previous inefficiencies associated with eosinophil-specific transgenic approaches and led to the development of a knock-in strain of mice (eoCRE), capable of mediating recombination of "floxed" reporter cassettes in >95% of peripheral blood eosinophils. We also showed that this Cre expression was limited exclusively to eosinophil-lineage committed cells with no evidence of Cre mediated toxicity. The efficiency and specificity of Cre expression in eoCRE mice were demonstrated further in a cross with a knock-in mouse containing a "(flox stop-flox)" DTA cassette at the ROSA26 locus, generating yet another novel, eosinophil-less strain of mice. The development of eoCRE mice represents a milestone in studies of eosinophil biology, permitting eosinophil-specific gene targeting and overexpression in the mouse as part of next-generation studies attempting to define eosinophil effector functions. PMID- 23630392 TI - Late-onset obsessive-compulsive disorder presenting as genital self-mutilation. PMID- 23630391 TI - Regulatory B cells suppress imiquimod-induced, psoriasis-like skin inflammation. AB - Psoriasis is an inflammatory cutaneous disorder characterized by marked epidermal thickening and Th1 and Th17 cell infiltration. At present, the contribution of B cells to the pathogenesis of psoriasis is unclear. In mice, topical application of imiquimod induces inflamed skin lesions and serves as an experimental animal model for human psoriasis. In this study, we showed that imiquimod-induced skin inflammation was more severe in CD19(-/-) than WT mice. These inflammatory responses were negatively regulated by a unique IL-10-producing CD1d(hi)CD5(+) regulatory B cell subset (B10 cells) that was absent in CD19(-/-) mice and represented only 1-2% of splenic B220(+) cells in WT mice. Splenic B10 cells entered the circulation and migrated to draining LNs during imiquimod-induced skin inflammation, thereby suppressing IFN-gamma and IL-17 production. Furthermore, adoptive transfer of these B10 cells from WT mice reduced inflammation in CD19(-/-) mice. The present findings provide direct evidence that B10 cells regulate imiquimod-induced skin inflammation and offer insights into regulatory B cell-based therapies for the treatment of psoriasis. PMID- 23630393 TI - The co-occurrence of common mental and physical disorders within Australian families: a national population-based study. AB - OBJECTIVE: Because comorbidity between mental and physical disorders is commonly found in patients, it would be expected that this pattern would also be reflected at the family level. During a recent population-based survey of common mental disorders, respondents were asked about the presence of selected mental and physical disorders in their relatives. The aim of this research was to describe the within-family co-occurrence of selected common physical and mental disorders in a population-based sample. METHODS: Subjects were drawn from the Australian National Survey of Mental Health and Wellbeing 2007. A modified version of the World Mental Health Survey Initiative of the Composite International Diagnostic Interview (WMH-CIDI 3.0, henceforth CIDI) was used to identify lifetime-ever common psychiatric disorders (anxiety disorders, depression, drug or alcohol disorders). The respondents were asked if any of their relatives had one of a list of psychiatric (anxiety, bipolar disorder, depression, drug or alcohol problem, schizophrenia) or general physical disorders (cancer, heart problems, intellectual disability, memory problems). We examined the relationship between the variables of interest using logistic regression, adjusting for potential confounding factors. RESULTS: Compared to otherwise-well respondents, those who had a CIDI diagnosis of major depressive disorders, anxiety disorders, or drug or alcohol abuse/dependence were significantly more likely to have first-degree relatives with (a) the same diagnosis as the respondent, (b) other mental disorders not identified in the respondent, and (c) a broad range of general physical conditions. CONCLUSIONS: Individuals with common mental disorders report greater familial co-occurrence for a range of mental and physical disorders. When eliciting family histories, clinicians should remain mindful that both mental and physical disorders can co-occur within families. PMID- 23630394 TI - Dermatitis artefacta in an intellectually disabled man with monosymptomatic hypochondriacal delusion of HIV infection. PMID- 23630395 TI - Beyond DSM: early stages of disorder pose predictable and modifiable risk for persistent disorder. PMID- 23630396 TI - Olanzapine-induced neuroleptic malignant syndrome after 10 years of treatment. PMID- 23630398 TI - After an inpatient suicide: the aim and outcome of review mechanisms. AB - OBJECTIVE: To describe the intent and process of reviews undertaken following the death by suicide of an inpatient and suggest possible improvements. METHOD: The current processes of review undertaken in Victoria following the death by suicide of an inpatient were considered in the context of a review of unnatural, unexpected or violent inpatient deaths undertaken by the Chief Psychiatrist of Victoria in late 2011. RESULTS: Review processes seeking to elucidate a cause or to find errors in the system that may have contributed to an incident are not always suitable nor sufficient in cases of inpatient suicide, where the patient's actions (as opposed to the actions or inactions of clinicians) led to patient death; therefore, the cause of death is not independent of the patient's condition and the treatment provided. CONCLUSION: While Root Cause Analysis remains a useful methodology, review of inpatient suicides should go beyond examination of systems issues only, and include consideration of the care and treatment provided: whether it met accepted clinical standards and was delivered by staff with adequate skills to consider the inherent risks of mental illness. Review of aggregate data has a useful role in identifying significant common features associated with inpatient deaths. PMID- 23630399 TI - Evaluating the correspondence of different cognitive batteries. AB - It is widely accepted that abilities are a meaningful level of abstraction for distinguishing among individuals with respect to their levels of cognitive functioning. However, relatively little is known about the extent to which different combinations of tests reflect the same cognitive abilities, or about the relation of cognitive abilities in one test battery with specific tests in another battery. Data from two cognitive batteries were analyzed to determine the correspondence of ability factors in the two batteries, and to evaluate the relative influence of cognitive abilities from one battery on the subtest scores in the other battery. Although the batteries involved different combinations of tests, correlations between the theoretically similar ability factors in the two batteries were very high (i.e., r > .84). Furthermore, with only a few exceptions, the primary influences on the subtest scores in one battery were from the theoretically relevant ability factor in the other battery. PMID- 23630400 TI - Hypothalamic dopaminergic stimulation in cluster headache. AB - BACKGROUND: Cluster headache is associated with structural abnormalities of the hypothalamus. We were interested in the association of cluster headache with endocrinological functional abnormalities. Therefore, we applied the apomorphine challenge test, which is a specific test of hypothalamic dopaminergic activation. METHODS: We enrolled 13 patients with cluster headache outside the bout and without medication. They were stimulated with 0.005 mg/kg of body weight subcutaneous apomorphine hydrochloride. After 45 and 60 minutes, growth hormone (GH), prolactin and cortisol were measured. The test was also applied to 14 sex- and age-matched healthy control subjects. RESULTS: There were significantly higher GH levels in healthy subjects as compared to cluster headache patients 45 minutes after injection (10.8 +/- 10.8 versus 4.4 +/- 7.4 ng/ml; P = 0.038). Only in cluster headache, the GH level after 60 minutes was not significantly different from the baseline. The levels of prolactin and cortisol did not show any significant differences between cluster headache patients and in healthy subjects. DISCUSSION: Our data suggest that cluster headache is associated with an impaired dopaminergic stimulation. This finding supports the body of evidence that cluster headache is associated with a functional abnormality of the hypothalamus and that this association is a primary (i.e. idiopathic) and not a secondary phenomenon during the bout. PMID- 23630397 TI - Enzymology of retinoic acid biosynthesis and degradation. AB - All-trans-retinoic acid is a biologically active derivative of vitamin A that regulates numerous physiological processes. The concentration of retinoic acid in the cells is tightly regulated, but the exact mechanisms responsible for this regulation are not completely understood, largely because the enzymes involved in the biosynthesis of retinoic acid have not been fully defined. Recent studies using in vitro and in vivo models suggest that several members of the short-chain dehydrogenase/reductase superfamily of proteins are essential for retinoic acid biosynthesis and the maintenance of retinoic acid homeostasis. However, the exact roles of some of these recently identified enzymes are yet to be characterized. The properties of the known contributors to retinoid metabolism have now been better defined and allow for more detailed understanding of their interactions with retinoid-binding proteins and other retinoid enzymes. At the same time, further studies are needed to clarify the interactions between the cytoplasmic and membrane-bound proteins involved in the processing of hydrophobic retinoid metabolites. This review summarizes current knowledge about the roles of various biosynthetic and catabolic enzymes in the regulation of retinoic acid homeostasis and outlines the remaining questions in the field. PMID- 23630402 TI - Sense of coherence as a resource for quality of life in patients with congenital heart disease: the benefits continue into adulthood. PMID- 23630401 TI - Problem-specific racial/ethnic disparities in pathways from maltreatment exposure to specialty mental health service use for youth in child welfare. AB - The authors examined racial/ethnic differences in pathways from maltreatment exposure to specialty mental health service use for youth in contact with the Child Welfare system. Participants included 1,600 non-Hispanic White, African American, and Latino youth (age 4-14) who were the subjects of investigations for alleged maltreatment and participated in the National Survey of Child and Adolescent Well-Being. Maltreatment exposure, internalizing, and externalizing problems were assessed at baseline and subsequent specialty mental health service use was assessed 1 year later. Maltreatment exposure predicted both internalizing and externalizing problems across all racial/ethnic groups, but non-Hispanic White youth were the only group for whom maltreatment exposure was linked with subsequent service use via both internalizing and externalizing problem severity. Only externalizing problems predicted subsequent service use for African American youth and this association was significantly stronger relative to non-Hispanic White youth. Neither problem type predicted service use for Latinos. Future research is needed to understand how individual-, family-, and system-level factors contribute to racial/ethnic differences in pathways linking maltreatment exposure to services via internalizing/externalizing problems. PMID- 23630403 TI - Effects of tailored telemonitoring on heart failure patients' knowledge, self care, self-efficacy and adherence: a randomized controlled trial. AB - BACKGROUND: The education of patients with heart failure (HF) is an essential part of disease management. The perspectives of an increasing number of patients and a shortage of professionals force healthcare to explore new strategies in supporting patients to be better informed and more active. METHODS: Three hundred and eighty-two patients with HF (age 71+/-SD 11.2 years) were randomly assigned to either a telemonitoring or a usual care group. Patients received four postal questionnaires to assess their levels of self-reported knowledge, self-care, self efficacy and adherence. Generalized estimating equations analysis was performed to assess the effects of telemonitoring during the 1-year follow-up. Corrections for baseline were performed if needed. RESULTS: Baseline differences between groups were found for self-care (p=0.001) and self-efficacy (p=0.024). Knowledge of patients in the telemonitoring group significantly improved with 0.9 point on a 15-points scale (p<0.001). Their self-care abilities improved with 1.5 point on a 10-item scale whereas no changes were found in patients receiving usual care (p<0.001). Self-efficacy of patients in the intervention group improved significantly after 6 months yet was not significantly different after 3 months and 1 year. For patients in the intervention group adherence improved for daily weighing (p<0.001) during the whole follow-up and for fluid intake (p=0.019) after 3 months and after 12 months (p=0.086). Adherence for activity recommendations improved (p=0.023) after 3 months and importance of medication adherence increased after 6 (p=0.012) and 12 months (p=0.037). No effects were found regarding appointments, diet, smoking and use of alcohol. CONCLUSIONS: Tailored telemonitoring was found to educate patients with HF and to improve their self-care abilities and sense of self-efficacy. PMID- 23630404 TI - Cognitive dysfunction and self-care decision making in chronic heart failure: a review of the literature. AB - BACKGROUND: Memory and executive function may be associated with poorer self-care management behaviors (indicators of self-care decision making). Dysfunction of self-care decision making processes often results in worsening of heart failure symptoms that necessitates hospitalization for acute management. AIMS: The purposes of this literature review are to (a) synthesize the published literature (2000-2012) examining the relationship between cognitive dysfunction (CD) (executive function and memory) and self-care management decisions in heart failure (HF) patients; (b) identify gaps in knowledge; and (c) provide recommendations for future research to fill this gap. METHODS: Literature from January 2000-September 2012 was reviewed to determine the relationship between cognitive dysfunction and self-care decision making in patients with HF. Studies were included that used measures to examine the relationship between cognitive dysfunction and self-care decision making in patients with HF. RESULTS: The ability to identify a significant relationship between CD and self-care decision making processes was limited by the paucity of studies, small sample sizes, use of convenience samples and the use of single center recruitment sites. CONCLUSION: Despite the importance of memory and executive function in decision making, there is a paucity of studies describing the relationship between CD and self-care decision making processes. A knowledge gap exists regarding the relationship between CD and self-care decision making processes. The influence of executive function and memory on self-care decision making abilities needs further study in diverse populations, using standardized and valid measures for CD and self-care decision making processes. PMID- 23630405 TI - Attitudes Toward Divorce, Commitment, and Divorce Proneness in First Marriages and Remarriages. AB - A random multistate sample of married individuals (N = 1,931) was used to explore whether more positive attitudes toward divorce and weaker commitment to marriage may contribute to the greater instability of remarriages than first marriages. Remarried adults, whether or not they brought children from a previous union into the remarriage, reported marital quality (happiness and conflict) equal to those in first marriages. They also reported more positive attitudes toward divorce, which were associated with higher divorce proneness (i.e., thinking about and taking actions toward divorce). Marriage type interacted with marital quality to predict divorce proneness, such that the association between low marital quality and divorce proneness was stronger for remarried individuals than for those in first marriages. This suggests that remarried adults may be more likely than adults in first marriages to take steps toward divorce when experiencing marital distress, possibly reflecting a weaker commitment to marriage. PMID- 23630406 TI - Estimating Individualized Treatment Rules Using Outcome Weighted Learning. AB - There is increasing interest in discovering individualized treatment rules for patients who have heterogeneous responses to treatment. In particular, one aims to find an optimal individualized treatment rule which is a deterministic function of patient specific characteristics maximizing expected clinical outcome. In this paper, we first show that estimating such an optimal treatment rule is equivalent to a classification problem where each subject is weighted proportional to his or her clinical outcome. We then propose an outcome weighted learning approach based on the support vector machine framework. We show that the resulting estimator of the treatment rule is consistent. We further obtain a finite sample bound for the difference between the expected outcome using the estimated individualized treatment rule and that of the optimal treatment rule. The performance of the proposed approach is demonstrated via simulation studies and an analysis of chronic depression data. PMID- 23630407 TI - Explaining the Early Development and Health of Teen Mothers' Children. AB - The transmission of social disadvantage from teenage mothers to their children is well established, but when and why do these disparities emerge in the early life course? Using nationally representative data from the Early Childhood Longitudinal Study-Birth Cohort, this study investigated the relationship between teen childbearing and children's cognition, behavior, and health from infancy through preschool. Developmental disparities between teenage mothers' children and others were largely nonexistent at 9 months but accumulated with age. Having a teenage mother predicted compromised development across several domains by age 41/2. Our conceptual model expected preexisting disadvantage, ongoing resource disadvantage, and compromised parenting quality to explain the association between teen childbearing and child outcomes. Preexisting social disadvantage accounted for much of this relationship. Financial, social, and material resources in the child's household partially or fully explained each of the remaining significant relationships between teenage childbearing and child outcomes. Parenting quality explained a smaller proportion of these relationships than did resources, and these factors' influences were largely independent. Because children of teenage mothers with a modest set of resources were not predicted to have compromised development, resources provided in early childhood may have the potential to reduce developmental disparities for teenage mothers' children. PMID- 23630408 TI - Early motherhood and the disruption in significant attachments: Autonomy and reconnection as a response to separation and loss among African American and Latina mothers. PMID- 23630409 TI - Toward a Computer Vision-based Wayfinding Aid for Blind Persons to Access Unfamiliar Indoor Environments. AB - Independent travel is a well known challenge for blind and visually impaired persons. In this paper, we propose a proof-of-concept computer vision-based wayfinding aid for blind people to independently access unfamiliar indoor environments. In order to find different rooms (e.g. an office, a lab, or a bathroom) and other building amenities (e.g. an exit or an elevator), we incorporate object detection with text recognition. First we develop a robust and efficient algorithm to detect doors, elevators, and cabinets based on their general geometric shape, by combining edges and corners. The algorithm is general enough to handle large intra-class variations of objects with different appearances among different indoor environments, as well as small inter-class differences between different objects such as doors and door-like cabinets. Next, in order to distinguish intra-class objects (e.g. an office door from a bathroom door), we extract and recognize text information associated with the detected objects. For text recognition, we first extract text regions from signs with multiple colors and possibly complex backgrounds, and then apply character localization and topological analysis to filter out background interference. The extracted text is recognized using off-the-shelf optical character recognition (OCR) software products. The object type, orientation, location, and text information are presented to the blind traveler as speech. PMID- 23630410 TI - The Legacy of the U. S. Public Health Services Study of Untreated Syphilis in African American Men at Tuskegee on the Affordable Care Act and Health Care Reform Fifteen Years After President Clinton's Apology. AB - This special issue addresses the legacy of the United States Public Health Service Syphilis Study on health reform, particularly the Affordable Care Act (ACA). The 12 manuscripts cover the history and current practices of ethical abuses affecting American Indians, Latinos, Asian Americans and African Americans in the United States and in one case, internationally. Commentaries and essays include the voice of a daughter of one of the study participants in which we learn of the stigma and maltreatment some of the families experienced and how the study has impacted generations within the families. Consideration is given in one essay to utilizing narrative storytelling with the families to help promote healing. This article provides the reader a roadmap to the themes that emerged from the collection of articles. These themes include population versus individual consent issues, need for better government oversight in research and health care, the need for overhauling our bioethics training to develop a population level, culturally driven approach to research bioethics. The articles challenge and inform us that some of our assumptions about how the consent process best works to protect racial/ethnic minorities may be merely assumptions and not proven facts. Articles challenge the belief that low participation rates seen in biomedical studies have resulted from the legacy of the USPHS Syphilis Study rather than a confluence of factors rooted in racism, bias and negative treatment. Articles in this special issue challenge the "cultural paranoia" of mistrust and provide insights into how the distrust may serve to lengthen rather than shorten the lives of racial/ethnic minorities who have been used as guinea pigs on more than one occasion. We hope that the guidance offered on the importance of developing a new framework to bioethics can be integrated into the foundation of health care reform. PMID- 23630411 TI - Large bilateral foveal cysts in the inner retina of a patient treated with tamoxifen, diagnosed with Fourier-domain optical coherence tomography. AB - PURPOSE: To report a case of a patient receiving tamoxifen with visual deterioration and describe the unusual optical coherence tomography (OCT) findings. METHOD: Observational case report. RESULTS: A 55-year-old female patient was referred to our department complaining of gradual visual deterioration in both eyes. Medical history was unremarkable apart from breast cancer for which she had received tamoxifen for 10 years (mean dosage 20 mg/day). Best corrected visual acuity was 20/400 in her right eye and 20/40 in her left eye. Fundoscopy in both eyes was without any obvious signs of maculopathy. However, Fourier-domain OCT demonstrated bilateral extensive areas of disruption in inner retinal layers without any signs of crystalline retinopathy. Six months after the cessation of tamoxifen, the situation remains unchanged. CONCLUSION: Patients receiving tamoxifen should be monitored with high-resolution OCT for fundoscopically invisible changes in the inner retinal layers, the progression of which may seriously affect the patient's vision and subsequently their quality of life. PMID- 23630412 TI - Phentermine and topiramate for the management of obesity: a review. AB - Obesity is now a major public health concern worldwide with increasing prevalence and a growing list of comorbidities and complications. The morbidity, mortality and reduced productivity associated with obesity and its complications result in a major burden to health care costs. Obesity is a complex chronic medical syndrome often with multiple different etiologic factors in individual patients. The long term successful management of obesity remains particularly challenging and invariably requires a multifaceted approach including lifestyle and behavioral modification, increased physical activity, and adjunctive pharmacotherapy. Bariatric surgery remains a last resort though at present it has the best results for achieving sustained robust weight loss. Obesity pharmacotherapy has been very limited in its role for long term obesity management because of the past history of several failed agents as well as the fact that presently available agents are few, and generally utilized as monotherapy. The recent FDA approval of the fixed drug combination of phentermine and extended release topiramate (topiramate-ER) (trade name QsymiaTM) marks the first FDA approved combination pharmacotherapeutic agent for obesity since the Phen-Fen combination of the 1990s. This review details the history and clinical trial basis for the use of both phentermine and topiramate in obesity therapeutics as well as the results of clinical trials of their combination for obesity treatment in humans. The initial clinical approval trials offer evidence that this fixed drug combination offers synergistic potential for effective, robust and sustained weight loss with mean weight loss of at least 10% of baseline achieved and sustained for up to 2 years in over 50% of subjects treated. It is anticipated that this agent will be the first in a new trend of multi-agent combination therapy for the chronic adjunctive management of obesity. PMID- 23630414 TI - Management of difficult-to-treat patients with ulcerative colitis: focus on adalimumab. AB - The treatment of ulcerative colitis has changed over the last decade, with the introduction of biological drugs. This article reviews the currently available therapies for ulcerative colitis and the specific use of these therapies in the management of patients in different settings, particularly the difficult-to-treat patients. The focus of this review is on adalimumab, which has recently obtained approval by the European Medicines Agency and the US Food and Drug Administration, for use in treating adult patients with moderate-to-severe, active ulcerative colitis, who are refractory, intolerant, or who have contraindications to conventional therapy, including corticosteroids and thiopurines. Since the results emerging from the pivotal trials have been subject to some debate, the aim of this review was to summarize all available data on the use of adalimumab in ulcerative colitis, focusing also on a retrospective series of real-life experiences. Taken together, the current evidence indicates that adalimumab is effective for the treatment of patients with different types of ulcerative colitis, including biologically naive and difficult-to-treat patients. PMID- 23630413 TI - Find novel dual-agonist drugs for treating type 2 diabetes by means of cheminformatics. AB - The high prevalence of type 2 diabetes mellitus in the world as well as the increasing reports about the adverse side effects of the existing diabetes treatment drugs have made developing new and effective drugs against the disease a very high priority. In this study, we report ten novel compounds found by targeting peroxisome proliferator-activated receptors (PPARs) using virtual screening and core hopping approaches. PPARs have drawn increasing attention for developing novel drugs to treat diabetes due to their unique functions in regulating glucose, lipid, and cholesterol metabolism. The reported compounds are featured with dual functions, and hence belong to the category of dual agonists. Compared with the single PPAR agonists, the dual PPAR agonists, formed by combining the lipid benefit of PPARalpha agonists (such as fibrates) and the glycemic advantages of the PPARgamma agonists (such as thiazolidinediones), are much more powerful in treating diabetes because they can enhance metabolic effects while minimizing the side effects. This was observed in the studies on molecular dynamics simulations, as well as on absorption, distribution, metabolism, and excretion, that these novel dual agonists not only possessed the same function as ragaglitazar (an investigational drug developed by Novo Nordisk for treating type 2 diabetes) did in activating PPARalpha and PPARgamma, but they also had more favorable conformation for binding to the two receptors. Moreover, the residues involved in forming the binding pockets of PPARalpha and PPARgamma among the top ten compounds are explicitly presented, and this will be very useful for the in-depth conduction of mutagenesis experiments. It is anticipated that the ten compounds may become potential drug candidates, or at the very least, the findings reported here may stimulate new strategies or provide useful insights for designing new and more powerful dual-agonist drugs for treating type 2 diabetes. PMID- 23630415 TI - Effects of vildagliptin (Galvus(r)) therapy in patients with type 2 diabetes mellitus after heart transplantation. AB - BACKGROUND: Type 2 Diabetes mellitus (T2DM) is a common comorbidity in patients after heart transplantation (HTx) and is associated with adverse long-term outcomes. METHODS: The retrospective study reported here analyzed the effects of vildagliptin therapy in stable patients post-HTx with T2DM and compared these with control patients for matched-pairs analysis. A total of 30 stable patients post-HTx with T2DM were included in the study. Fifteen patients (mean age 58.6 +/ 6.0 years, mean time post-HTx 4.9 +/- 5.3 years, twelve male and three female) were included in the vildagliptin group (VG) and 15 patients were included in the control group (CG) (mean age 61.2 +/- 8.3 years, mean time post-HTx 7.2 +/- 6.6 years, all male). RESULTS: Mean glycated hemoglobin (HbA1c) in the VG was 7.4% +/ 0.7% before versus 6.8% +/- 0.8% after 8 months of vildagliptin therapy (P = 0.002 vs baseline). In the CG, HbA1c was 7.0% +/- 0.7% versus 7.3% +/- 1.2% at follow-up (P = 0.21). Additionally, there was a significant reduction in mean blood glucose in the VG, from 165.0 +/- 18.8 mg/dL to 147.9 +/- 22.7 mg/dL (P = 0.002 vs baseline), whereas mean blood glucose increased slightly in the CG from 154.7 +/- 19.7 mg/dL to 162.6 +/- 35.0 mg/dL (P = 0.21). No statistically significant changes in body weight (from 83.3 +/- 10.8 kg to 82.0 +/- 10.9 kg, P = 0.20), total cholesterol (1.5%, P = 0.68), or triglyceride levels (8.0%, P = 0.65) were seen in the VG. No significant changes in immunosuppressive drug levels or dosages were observed in either group. CONCLUSION: Vildagliptin therapy significantly reduced HbA1c and mean blood glucose levels in post-HTx patients in this study with T2DM and did not have any negative effects on lipid profile or body weight. Thus, vildagliptin therapy presented an interesting therapeutic approach for this selected patient cohort. PMID- 23630416 TI - Evaluation of preference for a novel durable insulin pen with memory function among patients with diabetes and health care professionals. AB - BACKGROUND: Improving adherence to insulin treatment for better glycemic control remains a challenge in the management of diabetes. New technological aids are required to help support adherence. This study evaluated preference for the NovoPen((r)) 5 (NP5), a durable insulin pen with memory function, compared with the HumaPen Luxura((r)) (HPL) among patients with diabetes and health care professionals. METHODS: This crossover, multicenter usability study included insulin pen-experienced patients with diabetes and health care professionals treating patients with diabetes in Canada, China, and Germany. Participants evaluated NP5 and HPL in a randomized order by performing handling tasks in a usability test related to everyday use during a face-to-face interview. Tasks, pens, and preferences were assessed by completing a questionnaire comprised of rating and open-ended questions relating to confidence in everyday diabetes management. RESULTS: Overall, 300 patients with diabetes and 150 health care professionals participated in the study. Significantly more participants preferred NP5 (81%) to HPL (18%) (P < 0.001). Also, 82% of patients with diabetes had more confidence in NP5 for managing their daily injections versus 11% with HPL (P < 0.001), and 7% had no preference. Memory function was most helpful in giving patients with diabetes confidence about when they last injected (63%), how much insulin they last injected (62%) and improving diabetes management (55%). Participants gave higher ratings to NP5 than to HPL on all parameters relating to performing an injection (ease of handling, satisfaction when using the pen, convenience of using the pen day-to-day, quality of the pen, and the extent to which the pen meets their needs; P < 0.05 for all comparisons). CONCLUSION: NP5 was preferred to HPL by most participants. Significantly more patients with diabetes had more confidence for managing daily insulin injections when using NP5, the pen with a memory function. PMID- 23630418 TI - Enhanced in vivo osteogenesis by nanocarrier-fused bone morphogenetic protein-4. AB - PURPOSE: Bone defects and nonunions are major clinical skeletal problems. Growth factors are commonly used to promote bone regeneration; however, the clinical impact is limited because the factors do not last long at a given site. The introduction of tissue engineering aimed to deter the diffusion of these factors is a promising therapeutic strategy. The purpose of the present study was to evaluate the in vivo osteogenic capability of an engineered bone morphogenetic protein-4 (BMP4) fusion protein. METHODS: BMP4 was fused with a nanosized carrier, collagen-binding domain (CBD), derived from fibronectin. The stability of the CBD-BMP4 fusion protein was examined in vitro and in vivo. Osteogenic effects of CBD-BMP4 were evaluated by computer tomography after intramedullary injection without a collagen-sponge scaffold. Recombinant BMP-4, CBD, or vehicle were used as controls. Expressions of bone-related genes and growth factors were compared among the groups. Osteogenesis induced by CBD-BMP4, BMP4, and CBD was also assessed in a bone-defect model. RESULTS: In vitro, CBD-BMP4 was retained in a collagen gel for at least 7 days while BMP4 alone was released within 3 hours. In vivo, CBD-BMP4 remained at the given site for at least 2 weeks, both with or without a collagen-sponge scaffold, while BMP4 disappeared from the site within 3 days after injection. CBD-BMP4 induced better bone formation than BMP4 did alone, CBD alone, and vehicle after the intramedullary injection into the mouse femur. Bone-related genes and growth factors were expressed at higher levels in CBD-BMP4 treated mice than in all other groups, including BMP4-treated mice. Finally, CBD BMP4 potentiated more bone formation than did controls, including BMP4 alone, when applied to cranial bone defects without a collagen scaffold. CONCLUSION: Altogether, nanocarrier-CBD enhanced the retention of BMP4 in the bone, thereby promoting augmented osteogenic responses in the absence of a scaffold. These results suggest that CBD-BMP4 may be clinically useful in facilitating bone formation. PMID- 23630417 TI - Application of liposomes in drug development--focus on gastroenterological targets. AB - Over the past decade, liposomes became a focal point in developing drug delivery systems. New liposomes, with novel lipid molecules or conjugates, and new formulations opened possibilities for safely and efficiently treating many diseases including cancers. New types of liposomes can prolong circulation time or specifically deliver drugs to therapeutic targets. This article concentrates on current developments in liposome based drug delivery systems for treating diseases of the gastrointestinal tract. We will review different types and uses of liposomes in the development of therapeutics for gastrointestinal diseases including inflammatory bowel diseases and colorectal cancer. PMID- 23630419 TI - Arginine-based cationic liposomes for efficient in vitro plasmid DNA delivery with low cytotoxicity. AB - BACKGROUND: Currently available gene delivery vehicles have many limitations such as low gene delivery efficiency and high cytotoxicity. To overcome these drawbacks, we designed and synthesized two cationic lipids comprised of n tetradecyl alcohol as the hydrophobic moiety, 3-hydrocarbon chain as the spacer, and different counterions (eg, hydrogen chloride [HCl] salt or trifluoroacetic acid [TFA] salt) in the arginine head group. METHODS: Cationic lipids were hydrated in 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer to prepare cationic liposomes and characterized in terms of their size, zeta potential, phase transition temperature, and morphology. Lipoplexes were then prepared and characterized in terms of their size and zeta potential in the absence or presence of serum. The morphology of the lipoplexes was determined using transmission electron microscopy and atomic force microscopy. The gene delivery efficiency was evaluated in neuronal cells and HeLa cells and compared with that of lysine-based cationic assemblies and LipofectamineTM 2000. The cytotoxicity level of the cationic lipids was investigated and compared with that of LipofectamineTM 2000. RESULTS: We synthesized arginine-based cationic lipids having different counterions (ie, HCl-salt or TFA-salt) that formed cationic liposomes of around 100 nm in size. In the absence of serum, lipoplexes prepared from the arginine-based cationic liposomes and plasmid (p) DNA formed large aggregates and attained a positive zeta potential. However, in the presence of serum, the lipoplexes were smaller in size and negative in zeta potential. The morphology of the lipoplexes was vesicular. Arginine-based cationic liposomes with HCl-salt showed the highest transfection efficiency in PC-12 cells. However, arginine-based cationic liposomes with TFA salt showed the highest transfection efficiency in HeLa cells, regardless of the presence of serum, with very low associated cytotoxicity. CONCLUSION: The gene delivery efficiency of amino acid based cationic assemblies is influenced by the amino acids (ie, arginine or lysine) present as the hydrophilic head group and their associated counterions. PMID- 23630420 TI - Novel targeted nuclear imaging agent for gastric cancer diagnosis: glucose regulated protein 78 binding peptide-guided 111In-labeled polymeric micelles. AB - Increased expression of cellular membrane bound glucose-regulated protein 78 (GRP78) is considered to be one of the biomarkers for gastric cancers. Therefore, peptides or molecules with specific recognition to GRP78 can act as a guiding probe to direct conjugated imaging agents to localized cancers. Based on this rationale, GRP78-guided polymeric micelles were designed and manufactured for nuclear imaging detection of tumors. Thiolated GRP78 binding peptide (GRP78BP) was first labeled with maleimide-terminated poly(ethylene glycol)- poly(E caprolactone) and then mixed with diethylenetriaminepentaacetic acid (DTPA) linked poly(ethylene glycol)-poly(E-caprolactone) to form DTPA/GRP78BP-conjugated micelles. The coupling efficiency of micelles with radioisotope indium-111 ((111)In) was measured and analyzed by instant thin layer chromatography. The coupling efficiency of DTPA-conjugated micelles and DTPA/GRP78BP-conjugated micelles with (111)In was 85% and 93%, respectively. For characterization and trace imaging, the radioisotope (111)In-targeting tumors were detected and imaged in a xenograft murine model using nano single photon emission computed tomography/computed tomography. The results revealed that the radioactive intensity measured in the animals administered with GRP78BP-guided (111)In labeled micelles was statistically higher than that in animals administered with (111)In-labeled micelles, demonstrating that GRP78BP more than doubled the accumulation of micelles to the tumor tissue (P < 0.05). The results indicate that the gastric cancer biomarker GRP78 is a probing target in the application of nuclear imaging for tumor diagnosis. This novel GRP78BP-guided micelle agent may be applied in clinical practice to complement the histological diagnosis. PMID- 23630422 TI - Profile of lacosamide and its role in the long-term treatment of epilepsy: a perspective from the updated NICE guideline. AB - AIM: The goal of antiepileptic treatment is to achieve seizure freedom or seizure control. The aim of this paper is to review the evidence for the use of lacosamide for adjunctive treatment of refractory focal seizures with or without secondary generalization, within the scope of the 2012 update of the Clinical Guideline published by the National Institute for Health and Clinical Excellence (NICE). METHODS: Clinical evidence for the use of lacosamide and other antiepileptic drugs (AEDs) was systematically reviewed, evaluated, and presented to the Guideline Development Group. Only randomized clinical trials were included. Outcomes of clinical efficacy (seizure freedom, 50% reduction in seizure frequency, time to first seizure, time to 12-month remission, treatment withdrawal, and time to treatment withdrawal), experience of adverse events, and cognitive and quality of life outcomes were reviewed. A decision model was built to weigh the clinical benefits of each adjunctive AED, measured by seizure control and seizure reduction, compared with the harm from adverse events, as measured by withdrawals from treatment due to adverse events. RESULTS: Lacosamide was included as part of the recommended AEDS to be used in tertiary epilepsy centers. The evidence review showed that more participants who received lacosamide as an adjunctive treatment had at least a 50% reduction in seizure frequency compared with those taking placebo. However, more participants on lacosamide were found to experience adverse events and withdrawal from treatment compared with those on placebo. The cost-effectiveness analysis showed that compared with placebo, the benefits gained from adjunctive lacosamide were modest and uncertain, whereas the costs were significantly high. Compared with other AEDs licensed for adjunctive therapy in focal seizures, lacosamide was associated with fewer quality-adjusted life years and higher costs. Therefore, the Guideline Development Group noted that the balance of benefit and harm needs to be carefully monitored in all patients. PMID- 23630421 TI - Formulation and evaluation of drug-loaded targeted magnetic microspheres for cancer therapy. AB - Enhanced and targeted drug delivery using biodegradable microspheres is emerging as a promising approach for cancer therapy. The main objective of the present research was to formulate, characterize, and evaluate iron oxide (magnetic) containing a bovine serum albumin-based microsphere drug delivery system, capable of efficiently delivering sulforaphane, a histone deacetylase inhibitor, for an extended period of time in vivo. Magnetic microspheres were prepared by spray drying and characterized for their physicochemical properties and dissolution profile. Further, they were evaluated for therapeutic efficacy in in vitro and in vivo systems. In vitro studies in B16 melanoma cells revealed that there was about 13%-16% more inhibition of cell viability when either 30 MUM or 50 MUM of sulforaphane was used with iron oxide in the polymeric carrier. Data from in vivo studies in C57BL/6 mice revealed that the magnetic microspheres (localized to the tumor site with the help of a strong magnet) inhibited 18% more tumor growth as compared with sulforaphane in solution. In addition, there was a 40% reduction in histone deacetylation levels in mice treated with iron oxide microspheres containing sulforaphane. Thus, magnetic microspheres are shown to be an effective drug delivery system for anticancer drugs. PMID- 23630423 TI - Effects of primary caregiver participation in vestibular rehabilitation for unilateral neglect patients with right hemispheric stroke: a randomized controlled trial. AB - INTRODUCTION: The current study aims to investigate the effects of primary caregiver participation in vestibular rehabilitation (VR) on improving the measures of neglect, activities of daily living (ADL), balance, and falls of unilateral neglect (UN) patients. METHODS: This study is a single-blind randomized controlled trial. Both experimental (n = 24) and control groups (n = 24) received conventional rehabilitation. The experimental group undertook VR for a month. During the first and second weeks, a registered nurse trained the experimental group in VR. The primary caregivers in the experimental group supervised and guided their patients in VR during the third and fourth weeks. The outcome measures were neglect, ADL, balance, and falls. RESULTS: The two groups of UN patients showed a significant improvement in neglect, ADL, and balance over time. Based on the generalized estimating equations model, an interaction was observed between groups and times. Significant interactions were observed between the VR group at days 14 and 28 in the areas of neglect, ADL, and balance. No significant difference was observed between the two groups in the number of falls. CONCLUSION: Neglect, ADL, and balance among UN patients with right hemispheric stroke can be improved through the participation of primary caregivers in VR. Trained informal caregivers were recommended to provide VR guidance and supervision to patients who suffer from UN. PMID- 23630424 TI - A feasibility study of NIR fluorescent image-guided surgery in head and neck cancer based on the assessment of optimum surgical time as revealed through dynamic imaging. AB - BACKGROUND: In order to minimize surgical stress and preserve organs, endoscopic or robotic surgery is often performed when conducting head and neck surgery. However, it is impossible to physically touch tumors or to observe diffusely invaded deep organs through the procedure of endoscopic or robotic surgery. In order to visualize and safely resect tumors even in these cases, we propose using an indocyanine green (ICG) fluorescence method for navigation surgery in head and neck cancer. OBJECTIVE: To determine the optimum surgical time for tumor resection after the administration of ICG based on the investigation of dynamic ICG fluorescence imaging. METHODS: Nine patients underwent dynamic ICG fluorescence imaging for 360 minutes, assessing tumor visibility at 10, 30, 60, 120, 180, and 360 minutes. All cases were scored according to near-infrared (NIR) fluorescence imaging visibility scored from 0 to 5. RESULTS: Dynamic NIR fluorescence imaging under the HyperEye Medical System indicated that the greatest contrast in fluorescent images between tumor and normal tissue could be observed from 30 minutes to 1 hour after the administration of ICG. The optimum surgical time was determined to be between 30 minutes to 2 hours after ICG injection. These findings are particularly useful for detection and safe resection of tumors invading the parapharyngeal space. CONCLUSION: ICG fluorescence imaging is effective for the detection of head and neck cancer. Preliminary findings suggest that the optimum timing for surgery is from 30 minutes to 2 hours after the ICG injection. PMID- 23630425 TI - HER2-positive breast cancer patients receiving trastuzumab treatment obtain prognosis comparable with that of HER2-negative breast cancer patients. AB - PURPOSE: The efficacy of trastuzumab in Chinese breast cancer (BC) patients has rarely been reported. This study was designed to compare the clinical outcomes of HER2-positive BC patients receiving or not receiving trastuzumab treatment and HER2-negative BC patients. PATIENTS AND METHODS: This study involved three groups of patients. The first group was 115 human epidermal growth factor receptor 2 (HER2)-positive BC patients treated with trastuzumab who were enrolled at Sun Yat sen University Cancer Center between January 2002 and July 2010; the second group was a matched control group of 115 HER2-positive patients who did not receive trastuzumab treatment; the third group was a matched group of 115 HER2-negative patients who received conventional therapy in the adjuvant setting. The primary endpoint was 3-year and 5-year disease-free survival (3-DFS and 5-DFS, respectively). The Kaplan-Meier method, log-rank test, and multivariate Cox proportional hazard regression model were used for survival analysis. The differences in survival rates among the three groups were also analyzed according to two different periods: 2002-2006 and 2007-2010. RESULTS: The median duration of follow-up was 36 months (range, 12-111 months). The 3-DFS rates in the HER2 negative group, the HER2-positive group who received trastuzumab treatment, and the HER2-positive group who did not receive trastuzumab treatment were 82.6%, 89.6%, and 67.0%, respectively. The 3-DFS rate for the total study population was statistically significant (P < 0.001). Further analysis indicated a statistically significant difference in 3-DFS between either of the first two groups and the third group (P < 0.01), but the difference between the first two groups was not statistically significant (P = 0.157). Among the three groups, the 3-DFS rates during 2002-2006 did not have a significant difference compared with that during 2007-2010. CONCLUSION: This study has further confirmed the efficacy of trastuzumab for HER2-positive operable BC in Chinese patients. It has also demonstrated that the 3-DFS and 5-DFS rates between HER2-positive patients receiving trastuzumab treatment and HER2-negative patients are comparable. PMID- 23630426 TI - Update on the treatment of non-small-cell lung cancer: focus on the cost effectiveness of new agents. AB - BACKGROUND: The incidence of lung cancer and the cost of drug treatment have increased dramatically in the last decade. This article examines the costs of new target agents, such as tyrosine kinase inhibitors (TKIs) and anti-angiogenic drugs. METHODS: This study uses PubMed research to focus on the topics of lung cancer, economics, and new targeted therapies. RESULTS: The published papers only addressed TKIs and anti-angiogenic antibodies. For gefitinib, the results favored a clinical-based selection, despite the low number of studies. Erlotinib was studied in second line and as a maintenance treatment (with the studies reaching opposite conclusions in terms of cost-effectiveness). Economic analyses were not in favor of bevacizumab, but the studies on this topic were very heterogeneous. CONCLUSION: The economic impact of a drug depends on the health care system organization. Future clinical trials must include economic analyses, particularly with TKIs in the first line. PMID- 23630427 TI - Gender difference in response predictors after 1-year exenatide therapy twice daily in type 2 diabetic patients: a real world experience. AB - PURPOSE: To investigate whether gender affects therapeutic response by exenatide twice a day (BID) in type 2 diabetes by using a database concerning patients monitored by five outpatient clinics in Tuscany, Italy. PATIENTS AND METHODS: We considered a cohort of 315 (154 male/161 female) patients experiencing therapeutic failure while on oral therapy (metformin, or combination therapy metformin + sulphonylureas), who were given exenatide (10 MUg/BID) and who fully completed 4 months, 8 months, and 12 months of follow-ups. RESULTS: Among patients stratified by gender and well matched for age, body mass index, and hemoglobin A1c (HbA1c), it was found that the length of disease was longer in females than in males (12 +/- 8 years versus 10 +/- 7 years; P = 0.037), and the ratio of patients on metformin to those on combination therapy was higher in men (P = 0.018). Target glycemic response (1-year HbA1c <= 7%) was achieved in a significantly higher proportion of males than females (38% versus 27%; chi(2) = 4.66; P = 0.03). Target weight loss expressed as 1-year weight percent fall from baseline >= 75th percentile (8.5%) was significantly higher in females at 8 and 12 months (P < 0.05; for both). One-year glycemic target response was inversely related to baseline HbA1c levels and diabetes duration among males, while metformin therapy (compared to oral combination therapy) was a significant predictor of better glycemic targets among females. Homeostasis model assessment B, measured in 117 patients, predicted hypoglycemic response only in women (P = 0.009). Target 1-year weight loss was predicted by longer diabetes duration among males and by lower baseline HbA1c among females. Finally, no significant difference between genders was noted as to gastrointestinal side effects after exenatide therapy. CONCLUSION: According to this "real world" experience, predictors of glycemic control and body weight loss after 12 months of exenatide BID therapy are different between genders in type 2 diabetes. PMID- 23630428 TI - Clinical utility of phentermine/topiramate (QsymiaTM) combination for the treatment of obesity. AB - QsymiaTM (Vivus Inc, Mountain View, CA, USA), a combination of phentermine and delayed-release topiramate, has been available in the US since September 2012 for the treatment of obesity. Phentermine is an anorexigenic agent, which is approved for the short-term treatment of obesity, while topiramate is approved for nonweight loss indications - seizure disorders and migraine prophylaxis. The amount of weight loss achieved with combination therapy is of a greater magnitude than what could be achieved with either agent alone. Adverse events that occur with the combination therapy are in line with the known side effect profiles of the constituent drugs; teratogenicity, a slight increase in heart rate, psychiatric and cognitive adverse effects, and metabolic acidosis are concerns. PMID- 23630429 TI - An observational study of acarbose treatment in patients with type 2 diabetes from the Middle East and Morocco. AB - BACKGROUND: The prevalence of type 2 diabetes is increasing dramatically in the Middle East and North Africa region. However, there are few trials that have determined the effect of antidiabetic treatment in an observational setting in these countries. METHODS: This was a noninterventional study performed in Morocco in 2006-2007 and in the Middle East in 2005-2006 to observe the efficacy and safety of acarbose in patients with pretreated or untreated type 2 diabetes. Glycemic parameters (fasting blood glucose, one-hour postprandial blood glucose, and HbA1c) were recorded within a 3-month period. The observation period included an initial visit at the start of acarbose therapy and up to three follow-ups. RESULTS: Acarbose was effective in reducing glycemic parameters in patients from Morocco (n = 1082) and the Middle East (n = 1737). The mean one-hour postprandial blood glucose decreased by 35.5% to 165.4 +/- 47.9 mg/dL in the Middle East and by 35.5% to 179.0 +/- 49.9 mg/dL in Morocco. Mean fasting blood glucose decreased by 30.8% to 126.6 +/- 34.2 mg/dL (Middle East) and by 34.5% to 150.6 +/- 47.1 mg/dL (Morocco). The absolute reduction in HbA1c was 1.3% in the Middle East (final value 7.4%) and 1.0% in Morocco (final value 7.5%). Overall, 107 patients (Middle East) and 26 patients (Morocco) experienced minor drug-related adverse events, which were mainly gastrointestinal. The tolerability of acarbose was rated as very good/good by 80.8% in the Middle East and by 68.6% in Morocco. CONCLUSION: This study illustrates the efficacy and safety of acarbose in the treatment of type 2 diabetic patients in an observational setting. PMID- 23630430 TI - Autologous fat grafting: use of closed syringe microcannula system for enhanced autologous structural grafting. AB - OBJECTIVES: Provide background for use of acquiring autologous adipose tissue as a tissue graft and source of adult progenitor cells for use in cosmetic plastic surgery. Discuss the background and mechanisms of action of closed syringe vacuum lipoaspiration, with emphasis on accessing adipose-derived mesenchymal/stromal cells and the stromal vascular fraction (SVF) for use in aesthetic, structural reconstruction and regenerative applications. Explain a proven protocol for acquiring high-quality autologous fat grafts (AFG) with use of disposable, microcannula systems. DESIGN: Explain the components and advantage of use of the patented super luer-lock and microcannulas system for use with the closed-syringe system. A sequential explanation of equipment selection for minimally traumatic lipoaspiration in small volumes is presented, including use of blunt injection cannulas to reduce risk of embolism. RESULTS: Thousands of AFG have proven safe and efficacious for lipoaspiration techniques for large and small structural fat grafting procedures. The importance and advantages of gentle harvesting of the adipose tissue complex has become very clear in the past 5 years. The closed syringe system offers a minimally invasive, gentle system with which to mobilize subdermal fat tissues in a suspension form. Resulting total nuclear counting of undifferentiated cells of the adipose-derived -SVF suggests that the yield achieved is better than use of always-on, constant mechanical pump applied vacuum systems. CONCLUSION: Use of a closed-syringe lipoaspiration system featuring disposable microcannulas offers a safe and effective means of harvesting small volumes of nonmanipulated adipose tissues and its accompanying progenitor cells within the SVF. Closed syringes and microcannulas are available as safe, sterile, disposable, compact systems for acquiring high-quality AFG. Presented is a detailed, step-by-step, proven protocol for performing quality autologous structural adipose transplantation. PMID- 23630431 TI - Can treatment success with 5% lidocaine medicated plaster be predicted in cancer pain with neuropathic components or trigeminal neuropathic pain? AB - An expert group of 40 pain specialists from 16 countries performed a first assessment of the value of predictors for treatment success with 5% lidocaine medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain. Results were based on the retrospective analysis of 68 case reports (sent in by participants in the 4 weeks prior to the conference) and the practical experience of the experts. Lidocaine plaster treatment was mostly successful for surgery or chemotherapy-related cancer pain with neuropathic components. A dose reduction of systemic pain treatment was observed in at least 50% of all cancer pain patients using the plaster as adjunct treatment; the presence of allodynia, hyperalgesia or pain quality provided a potential but not definitively clear indication of treatment success. In trigeminal neuropathic pain, continuous pain, severe allodynia, hyperalgesia, or postherpetic neuralgia or trauma as the cause of orofacial neuropathic pain were perceived as potential predictors of treatment success with lidocaine plaster. In conclusion, these findings provide a first assessment of the likelihood of treatment benefits with 5% lidocaine-medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain and support conducting large, well-designed multicenter studies. PMID- 23630432 TI - The efficacy of the semi-blind approach of transversus abdominis plane block on postoperative analgesia in patients undergoing inguinal hernia repair: a prospective randomized double-blind study. AB - PURPOSE: In this prospective, randomized, double-blind study, our aim was to compare the analgesic efficacy of the semi-blind approach of transversus abdominis plane (TAP) block with a placebo block in patients undergoing unilateral inguinal hernia repair. METHODS: After receiving hospital ethical committee approval and informed patient consents, American Society of Anesthesiologists (ASA) I-III patients aged 18-80 were enrolled in the study. Standard anesthesia monitoring was applied to all patients. After premedication, spinal anesthesia was administered to all patients with 3.5 mL heavy bupivacaine at the L3-L4 subarachnoid space. Patients were randomly allocated into 2 groups. Group I (n = 32) received a placebo block with 20 mL saline, Group II (n = 32) received semi-blind TAP block with 0.25% bupivacaine in 20 mL with a blunt regional anesthesia needle into the neurofascial plane via the lumbar triangle of Petit near the midaxillary line before fascial closure. At the end of the operation, intravenous (IV) dexketoprofen was given to all patients. The verbal analog scale (VAS) was recorded at 2, 4, 6, 12, and 24 hours postoperatively. Paracetamol IV was given to patients if their VAS score > 3. A rescue analgesic of 0.05 mg/kg morphine IV was applied if VA S > 3. Total analgesic consumption and morphine requirement in 24 hours were recorded. RESULTS: TAP block reduced VAS scores at all postoperative time points (P < 0.001). Postoperative analgesic and morphine requirement in 24 hours was significantly lower in group II (P < 0.01). CONCLUSION: Semi-blind TAP block provided effective analgesia, reducing total 24-hour postoperative analgesic consumption and morphine requirement in patients undergoing elective unilateral inguinal hernia repair. PMID- 23630433 TI - A new, lateral, continuous, combined, femoral-sciatic nerve approach via a single skin puncture for postoperative analgesia in intramedullary tibial nail insertion. AB - BACKGROUND: The prevalence of anterior knee pain following intramedullary tibial nail insertion is high. Continuous peripheral nerve blockade is an alternative method of pain control to opiods. This case illustrates the use of femoral nerve and sciatic nerve peripheral catheters with an elastomeric infusion pump for major intramedullary nailing surgery. CASE REPORT: A 36-year-old male with fractures to the left leg bones presented for placement of an intramedullary nail under spinal anesthesia. At the end of the procedure, access to the lateral femoral and sciatic continuous nerve block was achieved by using a stimulator connected to a 110 mm 18G Tuohy needle. Postoperative analgesia was provided with a 40-hour infusion of 0.1% bupivacaine (400 mL) at a rate of 10 mL hour(-1) with an elastomeric pump. Anesthetic dispersion and contrast were investigated. The analog scale remained with scores below 3 during the 40 hours after surgery, and boluses were not necessary. CONCLUSION: The use of a femoral and sciatic nerve peripheral catheter offered an alternative to conventional pain control. Continuous femoral-sciatic peripheral blockade via a skin puncture with an infusion of 0.1% bupivacaine with elastomeric pumps is a safe and effective procedure in adults. PMID- 23630434 TI - Saphenous nerve innervation of the medial ankle. AB - BACKGROUND: The distal saphenous nerve is commonly known to provide cutaneous innervation of the medial side of the ankle and distally to the base of the great toe. We hypothesize that the saphenous nerve innervates the periosteum of the medial malleolus and joint capsule. METHODS: Five fresh limbs were dissected and the saphenous nerve was traced distally with magnification. The medial malleolus, talus, and soft tissue were fixed in formaldehyde, decalcified, and embedded in paraffin and sectioned. Histologic slides were then prepared using S100 antibody nerve stains. RESULTS: Histologic slides were examined and myelinated nerves could be observed within the medial capsule and periosteum in all the specimens. CONCLUSION: We have demonstrated that the saphenous nerve innervates the periosteum of the medial malleolus and joint capsule. PMID- 23630435 TI - Pseudolaric acid B induced cell cycle arrest, autophagy and senescence in murine fibrosarcoma l929 cell. AB - OBJECTIVE: PAB induced various cancer cell apoptosis, cell cycle arrest and senescence. But in cell line murine fibrosarcoma L929, PAB did not induce apoptosis, but autophagy, therefore it was thought by us as a good model to research the relationship of cell cycle arrest, autophagy and senescence bypass apoptosis. METHODS: Inhibitory ratio was assessed by 3-(4,5-Dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) analysis. Phase contrast microscopy visualized cell morphology. Hoechst 33258 staining for nuclear change, propidium iodode (PI) staining for cell cycle, monodansylcadaverine (MDC) staining for autophagy, and rodanmine 123 staining for mitochondrial membrane potential (MMP) were measured by fluorescence microscopy or flowcytometry. Apoptosis was determined by DNA ladder test. Protein kinase C (PKC) activity was detected by PKC assay kit. SA-beta-galactosidase assay was used to detect senescence. Protein expression was examined by western blot. RESULTS: PAB inhibited L929 cell growth in time-and dose-dependent manner. At 12 h, 80 MUmol/L PAB induced obvious mitotic arrest; at 24 h, PAB began to induce autophagy; at 36 h, cell-treated with PAB slip into G1 cell cycle; and 3 d PAB induced senescence. In time sequence PAB induced firstly cell cycle arrest, then autophagy, then slippage into G1 phase, lastly senescence. Senescent cells had high level of autophagy, inhibiting autophagy led to apoptosis, and no senescence. PAB activated PKC activity to induce cell cycle arrest, autophagy and senescence, inhibiting PKC activity suppressed cell cycle arrest, autophagy and senescence. CONCLUSION: PAB induced cell cycle arrest, autophagy and senescence in murine fibrosarcoma L929 cell through PKC. PMID- 23630436 TI - Inhibition of dengue virus entry into target cells using synthetic antiviral peptides. AB - Despite the importance of DENV as a human pathogen, there is no specific treatment or protective vaccine. Successful entry into the host cells is necessary for establishing the infection. Recently, the virus entry step has become an attractive therapeutic strategy because it represents a barrier to suppress the onset of the infection. Four putative antiviral peptides were designed to target domain III of DENV-2 E protein using BioMoDroid algorithm. Two peptides showed significant inhibition of DENV when simultaneously incubated as shown by plaque formation assay, RT-qPCR, and Western blot analysis. Both DET4 and DET2 showed significant inhibition of virus entry (84.6% and 40.6% respectively) using micromolar concentrations. Furthermore, the TEM images showed that the inhibitory peptides caused structural abnormalities and alteration of the arrangement of the viral E protein, which interferes with virus binding and entry. Inhibition of DENV entry during the initial stages of infection can potentially reduce the viremia in infected humans resulting in prevention of the progression of dengue fever to the severe life-threatening infection, reduce the infected vector numbers, and thus break the transmission cycle. Moreover these peptides though designed against the conserved region in DENV-2 would have the potential to be active against all the serotypes of dengue and might be considered as Hits to begin designing and developing of more potent analogous peptides that could constitute as promising therapeutic agents for attenuating dengue infection. PMID- 23630437 TI - Status of essential trace minerals and oxidative stress in viral hepatitis C patients with nonalcoholic fatty liver disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) may be an important factor leading to altered trace mineral homeostasis, thereby accelerating the progression of hepatitis C virus (HCV) infection. Our aim was to determine whether NAFLD influenced the status of certain essential trace minerals and oxidative stress in chronic HCV-infected patients. DESIGN AND METHODS: Blood biochemical parameters were determined in a group of 30 healthy, non-obese, non diabetic participants (CNL group), and hepatitis C patients without NAFLD (HCV group, n = 30) and with NAFLD (HCV-NAFLD group, n = 32). RESULTS: Concentrations of thiobarbituric acid reactive substances (TBARS; a measure of oxidative stress), C-reactive protein (CRP), ferritin, aminotransferases, lipid profiles, and insulin metabolism were markedly abnormal in both patient groups than in CNL subjects. Compared to patients in the HCV group, those with HCV-NAFLD group had lower high-density lipoprotein concentrations, higher low-density lipoprotein and homeostasis model assessment-insulin resistance (HOMA-IR) values, disrupted antioxidant enzyme activities, and elevated TBARS concentrations, as well as decreased plasma concentrations of trace minerals zinc (Zn) and selenium (Se) and increased copper (Cu). The alterations in mineral homeostasis were also linked to TBARS, CRP, ferritin, lipoproteins, and HOMA-IR values in the HCV-NAFLD group. CONCLUSIONS: There is a progressive deterioration in the homeostasis of minerals (Zn, Se, and Cu) in HCV-NAFLD patients, which may reflect greater oxidative stress and inflammation. These results suggest that the disturbance in mineral metabolism by NAFLD has an impact on the effectiveness of treatment for chronic HCV infection. PMID- 23630438 TI - Lef1 contributes to the differentiation of bulge stem cells by nuclear translocation and cross-talk with the Notch signaling pathway. AB - Lymphoid enhancer binding factor-1 (Lef1) is an essential regulatory protein in the Wnt signal pathway, which controls cell growth and differentiation. Investigators in the field of skin biology have confirmed that multipotent bulge stem cells (BSCs) are responsible for hair follicle development and regeneration. However, the role of Lef1 remains poorly understood. In this study, we investigated the pattern of Lef1 expression at different stages of the hair growth cycle. Lef1 was strongly expressed during anagen but attenuated in both catagen- and telogen-phase hair follicles in vivo. When stem cells were induced to differentiate toward a hair fate in a co-culture system, Lef1 was notably up regulated and accumulated in the nucleus, appearing to activate the target protein c-myc and jagged1. Simultaneously, the Wnt and Notch signaling pathways were co-activated, as confirmed by the increased expression of beta-catenin and notch1. Plasmids expressing Lef1 and DeltaNLef1, a construct in which the beta catenin-binding domain of Lef1 was deleted, were used to evaluate the effects of Lef1 on stem cell differentiation. Lef1 overexpression promoted bulge stem cell differentiation toward a hair fate, which was accompanied by the subsequent migration of beta-catenin into the nucleus, whereas no changes were observed in the control group. Taken together, our results demonstrate that Lef1 plays an important role in bulge stem cell differentiation, promoting beta-catenin translocation into the nucleus, activating downstream signaling molecules, eventually causing hair follicle bulge stem cells to adopt the hair fate. PMID- 23630439 TI - Why is saline so acidic (and does it really matter?). AB - Commercial 0.9% saline solution for infusion has a pH around 5.5. There are many reasons for this acidity, some of them still obscure. It is also true that infusion of normal saline can lead to metabolic acidaemia, yet the link between the acidity of saline solution and the acidaemia it can engender is not straightforward. This commentary draws together the known and putative sources of acidity in saline solutions: it turns out that the acidity of saline solution is essentially unrelated to the acidaemia complicating saline infusion. PMID- 23630440 TI - Is stroke volume variation a useful preload index in liver transplant recipients? A retrospective analysis. AB - BACKGROUND: The right ventricular end-diastolic volume index (RVEDVI) is a good indicator of preload in patients undergoing liver transplantation. Although dynamic indices, such as stroke volume variation (SVV), have been used as reliable indicators in predicting fluid responsiveness, the evaluation of the relationship between SVV and direct preload status is limited. We investigated the relationship between SVV and RVEDVI, and tested the cutoff value of SVV to predict RVEDVI during liver transplantation. METHODS: A total of 150 data pairs in 30 living donor liver transplant recipients were retrospectively investigated. Hemodynamic parameters, including SVV and RVEDVI were obtained from each patient at the 5 specific time points. Linear regression and receiver operating characteristic (ROC) curve analyses were performed. RESULTS: The SVV significantly correlated with the RVEDVI (r = -0.616, P < 0.001). Cutoff values for the upper and lower tertiles of RVEDVI were 157 mL/m(2) and 128 mL/m(2), respectively. Tertile analysis indicated that upper tertile of RVEDVI had a significantly lower SVV than the middle tertile (median; 5% vs 8%, P < 0.05), and middle tertile of RVEDVI had a significantly lower SVV than the lower tertile (median; 8% vs 11%, P < 0.05). A 6% cutoff value of SVV estimated the upper tertile RVEDVI (>157 mL/m(2)) with the area under the curve of ROC curve of 0.832. A 9% cutoff value of SVV estimated the lower tertile RVEDVI (<128 mL/m(2)) with the area under the curve of ROC curve of 0.792. CONCLUSION: SVV may be a valuable estimator of RVEDVI in patients undergoing liver transplantation. PMID- 23630441 TI - Correlation between peripheral white blood cell counts and hyperglycemic emergencies. AB - OBJECTIVE: To determine the correlation between differential leukocyte counts and hyperglycemic emergencies. METHODS: Fifty patients with diabetic ketoacidosis (DKA), 50 patients with diabetic ketosis (DK), 50 non-DK diabetic patients with stable glycemic control, and 50 normal controls were enrolled. Their total and differential leukocyte counts were measured and evaluated at admission and after treatment. RESULTS: The patients with DKA and DK had higher plasma glucose levels (20.84+/-6.73 mmol/L, 15.55+/-2.6 mmol/L, respectively) and more median leukocytes (13325/mm(3) and 6595/mm(3), respectively) and median neutrophils (11124 /mm(3) and 4125/mm(3), respectively) but fewer median eosinophils (28/mm(3) and 72/mm(3), respectively) compared to non-DK and control groups (all p < 0.05). Acute infection increased the elevating extent. The median leukocyte counts in DK and non-DK patients (6595/mm(3) and 6008/mm(3), respectively) were within the normal range. The counts of total leukocytes and neutrophils were significantly higher but eosinophils lower in severe DKA cases than in mild/moderate cases (p < 0.05). When the DKA and DK and infection resolved, total leukocytes and neutrophils fell, but eosinophils increased. The counts of total leukocytes, neutrophils, and monocytes were negatively correlated with arterial pH levels (r = -0.515, r = -0.510, r = -0.517, all p < 0.001, respectively) and positively correlated with plasma glucose levels (r = 0.722, r = 0.733, r = 0.632, all p < 0.05, respectively) in DKA patients. The arterial pH level was the most significant factor affecting total leukocytes in DKA (beta = 0.467, p = 0.003). The diagnosis analysis showed that higher total leukocyte and neutrophil counts and lower eosinophil counts had a significant ability to reflect the presence of hyperglycemic emergencies. CONCLUSION: More total leukocytes and neutrophils but fewer eosinophils was significantly correlated with DKA and DK. Leukocyte counts can add valuable information to reflect the presence of hyperglycemic crisis and acute infection. PMID- 23630442 TI - Identification of a novel nonsense mutation in POLH in a Chinese pedigree with xeroderma pigmentosum, variant type. AB - Xeroderma pigmentosum-variant (XPV) is one type of XP, a rare autosomal recessive disorder, and caused by defects in the post replication repair machinery while nucleotide-excision repair (NER) is not impaired. In the present study, we reported a Chinese family with XPV phenotype, which was confirmed by histopathological results. Genetic variants were detected by polymerase chain reaction and exon sequencing. Furthermore, the reported molecular defects in XPV patients from previous literatures were reviewed. A homozygous c.67C>T mutation in the exon 2 of DNA polymerase eta (POLH), a novel non-sense mutation in POLH, was discovered. PMID- 23630443 TI - Endogenous estrogen attenuates hypoxia-induced pulmonary hypertension by inhibiting pulmonary arterial vasoconstriction and pulmonary arterial smooth muscle cells proliferation. AB - Exogenous estrogen was shown to exert various beneficial effects on multiple diseases including hypoxia-induced pulmonary hypertension (HPH). However, the effect of endogenous estrogen on HPH was seldom investigated. In the present study, we explored the protective effects and mechanisms of endogenous estrogen on hypoxia-induced pulmonary hypertension. Male, female, pregnant and ovariectomized rats were housed in a hypoxic condition for 21 days, and then hemodynamic together with morphologic indexes of pulmonary circulation were measured. The right ventricular systolic pressure, mean pulmonary artery pressure, right ventricular hypertrophy index, and arterial remodeling index were significantly elevated after chronic hypoxia exposure. Experimental data showed less severity in female, especially in pregnant rats. In vitro, artery rings of different sex or estrus cycle rats were obtained, and then artery rings experiments were performed to investigate pulmonary vasoconstriction by recording the maximum phase II vasoconstriction. Data showed that the vasoconstriction was milder in proestrus female than diestrus female or male groups, which could be leveled by treating U0126 (a MAPK pathway inhibitor). Pulmonary arterial smooth muscle cells isolated from different sex or estrus cycle rats were cultured in the condition of 2% oxygen for 24 hours, and cell proliferation was evaluated by the [3H]-thymidine incorporation assay. Cells from proestrus rats exhibited lower proliferation than the other groups, which could be countered by both U0126 and raloxifene (a selective estrogen receptor modulator). Serum estradiol levels were detected, and rats with higher levels showed less severity of pulmonary hypertension. Conclusively, endogenous estrogen may alleviate hypoxia-induced pulmonary hypertension by attenuating vasoconstriction through non-genomic mechanisms and inhibiting smooth muscle cells proliferation through both genomic and non-genomic mechanisms. PMID- 23630444 TI - A novel semisynthetic molecule icaritin stimulates osteogenic differentiation and inhibits adipogenesis of mesenchymal stem cells. AB - BACKGROUND: We previously reported that the constitutional flavonoid glycosides derived from herb Epimedium (EF, composed of seven flavonoid compounds with common nuclear stem) exerted beneficial effects on the bone, including promoting bone formation and inhibiting bone marrow fat deposition. Recent in vivo study showed that Icaritin was a common metabolite of these constitutional flavonoid glycosides, indicating that Icaritin is a bioactive compound. The present study was designed to investigate whether Icaritin could promote osteogenic differentiation and suppress adipogenic differentiation of marrow mesenchymal stem cells (MSCs). METHODS: Primary MSCs were harvested from adult mice and exposed to Icaritin to evaluate whether it could promote osteogenesis and suppress adipogenesis using the following assays: determination of alkaline phosphatase (ALP) activity and mineralization; mRNA expression of osteogenic differentiation marker Runx2; osteocalcin and bone sialoprotein (BSP) by RT-PCR; quantification of adipocyte-like cells by Oil Red O staining assay and mRNA expression for adipogenic differentiation markers peroxisome proliferator activated receptor gamma (PPARgamma); adipocyte fatty acid binding protein (aP2) and lipoprotein lipase (LPL) by RT-PCR. For the underlying mechanism, glycogen synthase kinase-3beta (GSK3beta) and beta-catenin were also explored by western blotting. RESULTS: Icaritin promoted osteogenic differentiation and maturation of MSCs as indicated by increased mRNA expression for Runx2, osteocalcin and BSP, and enhanced ALP activity and mineralization; Icaritin inhibited adipogenic differentiation, as indicated by decreased mRNA expression for PPARgamma, LPL, aP2, and suppressed formation of adipocyte-like cells; Icaritin inactivated GSK3beta and suppressed PPARgamma expression when promoting osteogenesis and suppressing adipogenesis of MSCs. CONCLUSION: This was the first study demonstrating that the novel semisynthetic molecule Icaritin could stimulate osteogenic differentiation and inhibit adipogenesis of MSCs, which was associated with the suppression of GSK3beta and PPARgamma. PMID- 23630446 TI - Endosulfan-induced biomarkers in Japanese rice fish (Oryzias latipes) analyzed by SELDI-TOF-MS. AB - The objective of this study was to find and validate estrogen-related biomarkers from plasma proteins in Oryzias latipes after exposure to an estrogen disrupting compound, alpha-endosulfan. The acute toxicity of alpha-endosulfan on O. latipes after 96 h of exposure was 13.72, 16.18, and 22.18 MUg L(-1) for the LC10, LC20, and LC50 values, respectively. To confirm estrogenic disturbance by alpha endosulfan, the expression level of vitellogenin in the liver of male fishes was measured at the LC10 value, and it was found to be significantly different from the reference group, confirming the estrogenic effect of endosulfan in this concentration range. Proteinchip(r) array techniques using a weak cation exchange (CM10) and a strong anion exchange proteinchip (Q10) in conjunction with surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS) were used to determine plasma proteins of O. latipes differently expressed in response to endosulfan exposure at LC10 and LC20 concentrations. Analysis of protein profiling of the male fish exposed to alpha-endosulfan detected 48 significantly different protein peaks and the proteins at m/z 2819, 8462, 8860, and 9462 were significantly different (p<0.05). The protein peaks at m/z 2819, 8860, and 9462 were up-regulated and the peak at m/z 8462 was down-regulated. Therefore, these four differentially expressed proteins could be used as biomarkers to rapidly determine a possible risk of endosulfan on aquatic ecosystems, although these are not necessarily produced as a result of endocrine disruption. PMID- 23630445 TI - The clinical pattern of knee osteoarthritis in Jordan: a hospital based study. AB - BACKGROUND: Different clinical profiles of knee osteoarthritis (KOA) have been reported in the literature. The aim of this investigation was to describe the clinical patterns of KOA in an ethnically distinct and homogenous population that has not been widely reported. Patients with KOA were seen in outpatient rehabilitation and orthopedic clinic of Jordan University Hospital (JUH), to determine any possible association between age, BMI, radiographic severity, and pain severity. METHODS: Patients diagnosed with KOA attending an outpatient rehabilitation clinic at JUH were studied to describe their clinical characteristics. They were included based on criteria developed by the American College of Rheumatology. Detailed histories, clinical examinations and X-rays, and anthropometric data were obtained. Data analysis focused on descriptive statistics and correlations among demographic and clinical characteristics. RESULTS: The study included 214 patients with a mean age of 55.3 years (range = 30-84 years). The mean BMI was 29.5+/- 5.6. We found a significant moderate positive correlation between age and radiographic severity of KOA (0.435; p <. 001) and pain severity (0.383; p. <. 001). There was also a significant weak positive correlation between BMI, radiographic severity of KOA (0.242, p <. 05), and pain severity (0.266, p. <. 01). CONCLUSIONS: We concluded that in this hospital-based cohort study in Jordan, the clinical pattern of KOA is comparable to Western cultures. However, the combination of BMI and mechanical loading during everyday activities that include different religious and cultural habits and may help explain the high level of radiographic severity in our sample. PMID- 23630447 TI - Genomic profiling reveals the potential role of TCL1A and MDR1 deficiency in chemotherapy-induced cardiotoxicity. AB - BACKGROUND: Anthracyclines, such as doxorubicin (Adriamycin), are highly effective chemotherapeutic agents, but are well known to cause myocardial dysfunction and life-threatening congestive heart failure (CHF) in some patients. METHODS: To generate new hypotheses about its etiology, genome-wide transcript analysis was performed on whole blood RNA from women that received doxorubicin based chemotherapy and either did, or did not develop CHF, as defined by ejection fractions (EF)<=40%. Women with non-ischemic cardiomyopathy unrelated to chemotherapy were compared to breast cancer patients prior to chemo with normal EF to identify heart failure-related transcripts in women not receiving chemotherapy. Byproducts of oxidative stress in plasma were measured in a subset of patients. RESULTS: The results indicate that patients treated with doxorubicin showed sustained elevations in oxidative byproducts in plasma. At the RNA level, women who exhibited low EFs after chemotherapy had 260 transcripts that differed >2-fold (p<0.05) compared to women who received chemo but maintained normal EFs. Most of these transcripts (201) were not altered in non-chemotherapy patients with low EFs. Pathway analysis of the differentially expressed genes indicated enrichment in apoptosis-related transcripts. Notably, women with chemo-induced low EFs had a 4.8-fold decrease in T-cell leukemia/lymphoma 1A (TCL1A) transcripts. TCL1A is expressed in both cardiac and skeletal muscle, and is a known co-activator for AKT, one of the major pro-survival factors for cardiomyocytes. Further, women who developed low EFs had a 2-fold lower level of ABCB1 transcript, encoding the multidrug resistance protein 1 (MDR1), which is an efflux pump for doxorubicin, potentially leading to higher cardiac levels of drug. In vitro studies confirmed that inhibition of MDR1 by verapamil in rat H9C2 cardiomyocytes increased their susceptibility to doxorubicin-induced toxicity. CONCLUSIONS: It is proposed that chemo-induced cardiomyopathy may be due to a reduction in TCL1A levels, thereby causing increased apoptotic sensitivity, and leading to reduced cardiac MDR1 levels, causing higher cardiac levels of doxorubicin and intracellular free radicals. If so, screening for TCL1A and MDR1 SNPs or expression level in blood, might identify women at greatest risk of chemo induced heart failure. PMID- 23630448 TI - Complete mitochondrial genome sequence data provides genetic evidence that the brown dog tick Rhipicephalus sanguineus (Acari: Ixodidae) represents a species complex. AB - Ticks are blood-sucking ectoparasites of great medical and veterinary significance that can transmit bacteria, protozoa, fungi and viruses, and cause a variety of human and animal diseases worldwide. In the present study, we sequenced the complete mitochondrial (mt) genome of Rhipicephalus sanguineus from China (RSC) and compared with that of R. sanguineus from USA (RSU). Nucleotide sequence difference in the full mt genome was 11.23% between RSC and RSU. For the 13 protein-coding genes, comparison revealed sequence divergences at both the nucleotide (9.34-15.65%) and amino acid (2.54-19.23%) levels between RSC and RSU. In addition, sequence comparison of the conserved mt cox1 and cytb genes among multiple individual R. sanguineus revealed substantial nucleotide differences between RSC and RSU but limited sequence variation within RSC. Phylogenetic analysis of ticks based on the amino acid sequence data of 13 protein-coding genes revealed that R. sanguineus from China and R. sanguineus from USA represent sister taxa (likely separate species). Taken together, the findings support the recently proposal that R. sanguineus tick may represents a species complex of at least two closely related species. PMID- 23630449 TI - Silencing the HaHR3 gene by transgenic plant-mediated RNAi to disrupt Helicoverpa armigera development. AB - RNA interference (RNAi) caused by exogenous double-stranded RNA (dsRNA) has developed into a powerful technique in functional genomics, and to date it is widely used to down-regulate crucial physiology-related genes to control pest insects. A molt-regulating transcription factor gene, HaHR3, of cotton bollworm (Helicoverpa armigera) was selected as the target gene. Four different fragments covering the coding sequence (CDS) of HaHR3 were cloned into vector L4440 to express dsRNAs in Escherichia coli. The most effective silencing fragment was then cloned into a plant over-expression vector to express a hairpin RNA (hpRNA) in transgenic tobacco (Nicotiana tabacum). When H. armigera larvae were fed the E. coli or transgenic plants, the HaHR3 mRNA and protein levels dramatically decreased, resulting developmental deformity and larval lethality. The results demonstrate that both recombinant bacteria and transgenic plants could induce HaHR3 silence to disrupt H. armigera development, transgenic plant-mediated RNAi is emerging as a powerful approach for controlling insect pests. PMID- 23630450 TI - Dpysl4 is involved in tooth germ morphogenesis through growth regulation, polarization and differentiation of dental epithelial cells. AB - Dihydropyrimidinase-related protein 4 (Dpysl4) is a known regulator of hippocampal neuron development. Here, we report that Dpysl4 is involved in growth regulation, polarization and differentiation of dental epithelial cells during tooth germ morphogenesis. A reduction in Dpysl4 gene expression in the tooth germ produced a loss of ameloblasts, resulting in the decrease of synthesis and secretion of enamel. The inhibition of Dpysl4 gene expression led to promotion of cell proliferation of inner enamel epithelial cells and inhibition of the differentiation of these cells into pre-ameloblasts, which was confirmed by analyzing cell polarization, columnar cell structure formation and the expression of ameloblast marker genes. By contrast, overexpression of Dpysl4 in dental epithelial cells induces inhibition of growth and increases the expression of the inner enamel epithelial cell marker gene, Msx2. These findings suggest that Dpysl4 plays essential roles in tooth germ morphogenesis through the regulation of dental epithelial cell proliferation, cell polarization and differentiation. PMID- 23630451 TI - An introduction to social media for scientists. AB - Online social media tools can be some of the most rewarding and informative resources for scientists-IF you know how to use them. PMID- 23630452 TI - When the most potent combination of antibiotics selects for the greatest bacterial load: the smile-frown transition. AB - Conventional wisdom holds that the best way to treat infection with antibiotics is to 'hit early and hit hard'. A favoured strategy is to deploy two antibiotics that produce a stronger effect in combination than if either drug were used alone. But are such synergistic combinations necessarily optimal? We combine mathematical modelling, evolution experiments, whole genome sequencing and genetic manipulation of a resistance mechanism to demonstrate that deploying synergistic antibiotics can, in practice, be the worst strategy if bacterial clearance is not achieved after the first treatment phase. As treatment proceeds, it is only to be expected that the strength of antibiotic synergy will diminish as the frequency of drug-resistant bacteria increases. Indeed, antibiotic efficacy decays exponentially in our five-day evolution experiments. However, as the theory of competitive release predicts, drug-resistant bacteria replicate fastest when their drug-susceptible competitors are eliminated by overly aggressive treatment. Here, synergy exerts such strong selection for resistance that an antagonism consistently emerges by day 1 and the initially most aggressive treatment produces the greatest bacterial load, a fortiori greater than if just one drug were given. Whole genome sequencing reveals that such rapid evolution is the result of the amplification of a genomic region containing four drug-resistance mechanisms, including the acrAB efflux operon. When this operon is deleted in genetically manipulated mutants and the evolution experiment repeated, antagonism fails to emerge in five days and antibiotic synergy is maintained for longer. We therefore conclude that unless super-inhibitory doses are achieved and maintained until the pathogen is successfully cleared, synergistic antibiotics can have the opposite effect to that intended by helping to increase pathogen load where, and when, the drugs are found at sub-inhibitory concentrations. PMID- 23630453 TI - PICK1 and ICA69 control insulin granule trafficking and their deficiencies lead to impaired glucose tolerance. AB - Diabetes is a metabolic disorder characterized by hyperglycemia. Insulin, which is secreted by pancreatic beta cells, is recognized as the critical regulator of blood glucose, but the molecular machinery responsible for insulin trafficking remains poorly defined. In particular, the roles of cytosolic factors that govern the formation and maturation of insulin granules are unclear. Here we report that PICK1 and ICA69, two cytosolic lipid-binding proteins, formed heteromeric BAR domain complexes that associated with insulin granules at different stages of their maturation. PICK1-ICA69 heteromeric complexes associated with immature secretory granules near the trans-Golgi network (TGN). A brief treatment of Brefeldin A, which blocks vesicle budding from the Golgi, increased the amount of PICK1 and ICA69 at TGN. On the other hand, mature secretory granules were associated with PICK1 only, not ICA69. PICK1 deficiency in mice caused the complete loss of ICA69 and led to increased food and water intake but lower body weight. Glucose tolerance tests demonstrated that these mutant mice had high blood glucose, a consequence of insufficient insulin. Importantly, while the total insulin level was reduced in PICK1-deficient beta cells, proinsulin was increased. Lastly, ICA69 knockout mice also displayed similar phenotype as the mice deficient in PICK1. Together, our results indicate that PICK1 and ICA69 are key regulators of the formation and maturation of insulin granules. PMID- 23630455 TI - A pair of crescent-shaped proteins shape vesicles at the golgi. PMID- 23630454 TI - PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance. AB - Secretory vesicles in endocrine cells store hormones such as growth hormone (GH) and insulin before their release into the bloodstream. The molecular mechanisms governing budding of immature secretory vesicles from the trans-Golgi network (TGN) and their subsequent maturation remain unclear. Here, we identify the lipid binding BAR (Bin/amphiphysin/Rvs) domain protein PICK1 (protein interacting with C kinase 1) as a key component early in the biogenesis of secretory vesicles in GH-producing cells. Both PICK1-deficient Drosophila and mice displayed somatic growth retardation. Growth retardation was rescued in flies by reintroducing PICK1 in neurosecretory cells producing somatotropic peptides. PICK1-deficient mice were characterized by decreased body weight and length, increased fat accumulation, impaired GH secretion, and decreased storage of GH in the pituitary. Decreased GH storage was supported by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate with vesicles budding from the TGN and to possess membrane-sculpting properties in vitro. In mouse pituitary, PICK1 co localized with the BAR domain protein ICA69, and PICK1 deficiency abolished ICA69 protein expression. In the Drosophila brain, PICK1 and ICA69 co immunoprecipitated and showed mutually dependent expression. Finally, both in a Drosophila model of type 2 diabetes and in high-fat-diet-induced obese mice, we observed up-regulation of PICK1 mRNA expression. Our findings suggest that PICK1, together with ICA69, is critical during budding of immature secretory vesicles from the TGN and thus for vesicular storage of GH and possibly other hormones. The data link two BAR domain proteins to membrane remodeling processes in the secretory pathway of peptidergic endocrine cells and support an important role of PICK1/ICA69 in maintenance of metabolic homeostasis. PMID- 23630456 TI - Subgrouping the autism "spectrum": reflections on DSM-5. AB - DSM-5 has moved autism from the level of subgroups ("apples and oranges") to the prototypical level ("fruit"). But making progress in research, and ultimately improving clinical practice, will require identifying subgroups within the autism spectrum. PMID- 23630458 TI - Industry use of evidence to influence alcohol policy: a case study of submissions to the 2008 Scottish government consultation. AB - Jim McCambridge and colleagues analyze industry submissions to a Scottish Government consultation on whole-population approaches to alcohol policy. PMID- 23630457 TI - RanBP2/Nup358 potentiates the translation of a subset of mRNAs encoding secretory proteins. AB - In higher eukaryotes, most mRNAs that encode secreted or membrane-bound proteins contain elements that promote an alternative mRNA nuclear export (ALREX) pathway. Here we report that ALREX-promoting elements also potentiate translation in the presence of upstream nuclear factors. These RNA elements interact directly with, and likely co-evolved with, the zinc finger repeats of RanBP2/Nup358, which is present on the cytoplasmic face of the nuclear pore. Finally we show that RanBP2/Nup358 is not only required for the stimulation of translation by ALREX promoting elements, but is also required for the efficient global synthesis of proteins targeted to the endoplasmic reticulum (ER) and likely the mitochondria. Thus upon the completion of export, mRNAs containing ALREX-elements likely interact with RanBP2/Nup358, and this step is required for the efficient translation of these mRNAs in the cytoplasm. ALREX-elements thus act as nucleotide platforms to coordinate various steps of post-transcriptional regulation for the majority of mRNAs that encode secreted proteins. PMID- 23630459 TI - Risk of a second primary cancer after non-melanoma skin cancer in white men and women: a prospective cohort study. AB - BACKGROUND: Previous studies suggest a positive association between history of non-melanoma skin cancer (NMSC) and risk of subsequent cancer at other sites. The purpose of this study is to prospectively examine the risk of primary cancer according to personal history of NMSC. METHODS AND FINDINGS: In two large US cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Study (NHS), we prospectively investigated this association in self-identified white men and women. In the HPFS, we followed 46,237 men from June 1986 to June 2008 (833,496 person-years). In the NHS, we followed 107,339 women from June 1984 to June 2008 (2,116,178 person-years). We documented 29,447 incident cancer cases other than NMSC. Cox proportional hazard models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). A personal history of NMSC was significantly associated with a higher risk of other primary cancers excluding melanoma in men (RR=1.11; 95% CI 1.05-1.18), and in women (RR=1.20; 95% CI 1.15 1.25). Age-standardized absolute risk (AR) was 176 in men and 182 in women per 100,000 person-years. For individual cancer sites, after the Bonferroni correction for multiple comparisons (n=28), in men, a personal history of NMSC was significantly associated with an increased risk of melanoma (RR=1.99, AR=116 per 100,000 person-years). In women, a personal history of NMSC was significantly associated with an increased risk of breast (RR=1.19, AR=87 per 100,000 person years), lung (RR=1.32, AR=22 per 100,000 person-years), and melanoma (RR=2.58, AR=79 per 100,000 person-years). CONCLUSION: This prospective study found a modestly increased risk of subsequent malignancies among individuals with a history of NMSC, specifically breast and lung cancer in women and melanoma in both men and women. PMID- 23630461 TI - General anesthesia as a possible GABAergic modulator affects visual processing in children. AB - Gamma-Aminobutyric Acid (GABA) inhibitory interneurons play an important role in visual processing, as is revealed by studies administering drugs in human and monkey adults. Investigating this process in children requires different methodologies, due to ethical considerations. The current study aimed to investigate whether a new method, being general anesthesia using Sevoflurane, can be used to trace the effects of GABAergic modulation on visual brain functioning in children. To this aim, visual processing was investigated in children aged 4 12 years who were scheduled for minor urologic procedures under general anesthesia in day-care treatment. In a visual segmentation task, the difference in Event-Related Potential (ERP) response to homogeneous and textured stimuli was investigated. In addition, psychophysical performance on visual acuity and contrast sensitivity were measured. Results were compared between before and shortly after anesthesia. In two additional studies, effects at 1 day after anesthesia and possible effects of task-repetition were investigated. ERP results showed longer latency and lower amplitude of the Texture Negativity (TN) component shortly after compared to before anesthesia. No effects of anesthesia on psychophysical measurements were found. No effects at 1 day after anesthesia or of repetition were revealed either. These results show that GABAergic modulation through general anesthesia affects ERP reflections of visual segmentation in a similar way in children as benzodiazepine does in adults, but that effects are not permanent. This demonstrates that ERP measurement after anesthesia is a successful method to study effects of GABAergic modulation in children. PMID- 23630460 TI - D-serine as a gliotransmitter and its roles in brain development and disease. AB - The development of new techniques to study glial cells has revealed that they are active participants in the development of functional neuronal circuits. Calcium imaging studies demonstrate that glial cells actively sense and respond to neuronal activity. Glial cells can produce and release neurotransmitter-like molecules, referred to as gliotransmitters, that can in turn influence the activity of neurons and other glia. One putative gliotransmitter, D-serine is believed to be an endogenous co-agonist for synaptic N-methyl-D-aspartate receptors (NMDARs), modulating synaptic transmission and plasticity mediated by this receptor. The observation that D-serine levels in the mammalian brain increase during early development, suggests a possible role for this gliotransmitter in normal brain development and circuit refinement. In this review we will examine the data that D-serine and its associated enzyme serine racemase are developmentally regulated. We will consider the evidence that D serine is actively released by glial cells and examine the studies that have implicated D-serine as a critical player involved in regulating NMDAR-mediated synaptic transmission and neuronal migration during development. Furthermore, we will consider how dysregulation of D-serine may play an important role in the etiology of neurological and psychiatric diseases. PMID- 23630462 TI - Factors regulating microglia activation. AB - Microglia are resident macrophages of the central nervous system (CNS) that display high functional similarities to other tissue macrophages. However, it is especially important to create and maintain an intact tissue homeostasis to support the neuronal cells, which are very sensitive even to minor changes in their environment. The transition from the "resting" but surveying microglial phenotype to an activated stage is tightly regulated by several intrinsic (e.g., Runx-1, Irf8, and Pu.1) and extrinsic factors (e.g., CD200, CX3CR1, and TREM2). Under physiological conditions, minor changes of those factors are sufficient to cause fatal dysregulation of microglial cell homeostasis and result in severe CNS pathologies. In this review, we discuss recent achievements that gave new insights into mechanisms that ensure microglia quiescence. PMID- 23630463 TI - Resilience to audiogenic seizures is associated with p-ERK1/2 dephosphorylation in the subiculum of Fmr1 knockout mice. AB - Young, but not adult, fragile X mental retardation gene (Fmr1) knockout (KO) mice display audiogenic seizures (AGS) that can be prevented by inhibiting extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation. In order to identify the cerebral regions involved in these phenomena, we characterized the response to AGS in Fmr1 KO mice and wild type (WT) controls at postnatal day (P) 45 and P90. To characterize the diverse response to AGS in various cerebral regions, we evaluated the activity markers FosB/DeltaFosB and phosphorylated ERK1/2 (p-ERK1/2). Wild running (100% of tested mice) followed by clonic/tonic seizures (30%) were observed in P45 Fmr1 KO mice, but not in WT mice. In P90 Fmr1 KO mice, wild running was only present in 25% of tested animals. Basal FosB/DeltaFosB immunoreactivity was higher (P < 0.01 vs. WT) in the CA1 and subiculum of P45 Fmr1 KO mice. Following the AGS test, FosB/DeltaFosB expression consistently increased in most of the analyzed regions in both groups at P45, but not at P90. Interestingly, FosB/DeltaFosB immunoreactivity was significantly higher in P45 Fmr1 KO mice in the medial geniculate body (P < 0.05 vs. WT) and CA3 (P < 0.01). Neurons presenting with immunopositivity to p-ERK1/2 were more abundant in the subiculum of Fmr1 KO mice in control condition (P < 0.05 vs. WT, in both age groups). In this region, p-ERK1/2-immunopositive cells significantly decreased (-75%, P < 0.01) in P90 Fmr1 KO mice exposed to the AGS test, but no changes were found in P45 mice or in other brain regions. In both age groups of WT mice, p-ERK1/2-immunopositive cells increased in the subiculum after exposure to the acoustic test. Our findings illustrate that FosB/DeltaFosB markers are overexpressed in the medial geniculate body and CA3 in Fmr1 KO mice experiencing AGS, and that p-ERK1/2 is markedly decreased in the subiculum of Fmr1 KO mice resistant to AGS induction. These findings suggest that resilience to AGS is associated with dephosphorylation of p-ERK1/2 in the subiculum of mature Fmr1 KO mice. PMID- 23630465 TI - Physiological temperature during brain slicing enhances the quality of acute slice preparations. AB - We demonstrate that brain dissection and slicing using solutions warmed to near physiological temperature (~ +34 degrees C), greatly enhance slice quality without affecting intrinsic electrophysiological properties of the neurons. Improved slice quality is seen not only when using young (<1 month), but also mature (>2.5 month) mice. This allows easy in vitro patch-clamp experimentation using adult deep cerebellar nuclear slices, which until now have been considered very difficult. As proof of the concept, we compare intrinsic properties of cerebellar nuclear neurons in juvenile (<1 month) and adult (up to 7 months) mice, and confirm that no significant developmental changes occur after the fourth postnatal week. The enhanced quality of brain slices from old animals facilitates experimentation on age-related disorders as well as optogenetic studies requiring long transfection periods. PMID- 23630464 TI - Placental serotonin: implications for the developmental effects of SSRIs and maternal depression. AB - In addition to its role in the pathophysiology of numerous psychiatric disorders, increasing evidence points to serotonin (5-HT) as a crucial molecule for the modulation of neurodevelopmental processes. Recent evidence indicates that the placenta is involved in the synthesis of 5-HT from maternally derived tryptophan (TRP). This gives rise to the possibility that genetic and environmental perturbations directly affecting placental TRP metabolism may lead to abnormal brain circuit wiring in the developing embryo, and therefore contribute to the developmental origin of psychiatric disorders. In this review, we discuss how perturbations of the placental TRP metabolic pathway may lead to abnormal brain development and function throughout life. Of particular interest is prenatal exposure to maternal depression and antidepressants, both known to alter fetal development. We review existing evidence on how antidepressants can alter placental physiology in its key function of maintaining fetal homeostasis and have long-term effects on fetal forebrain development. PMID- 23630466 TI - The essential roles of protein-protein interaction in sigma-1 receptor functions. PMID- 23630467 TI - Analyzing the structure and function of neuronal circuits in zebrafish. AB - The clever choice of animal models has been instrumental for many breakthrough discoveries in life sciences. One of the outstanding challenges in neuroscience is the in-depth analysis of neuronal circuits to understand how interactions between large numbers of neurons give rise to the computational power of the brain. A promising model organism to address this challenge is the zebrafish, not only because it is cheap, transparent and accessible to sophisticated genetic manipulations but also because it offers unique advantages for quantitative analyses of circuit structure and function. One of the most important advantages of zebrafish is its small brain size, both at larval and adult stages. Small brains enable exhaustive measurements of neuronal activity patterns by optical imaging and facilitate large-scale reconstructions of wiring diagrams by electron microscopic approaches. Such information is important, and probably essential, to obtain mechanistic insights into neuronal computations underlying higher brain functions and dysfunctions. This review provides a brief overview over current methods and motivations for dense reconstructions of neuronal activity and connectivity patterns. It then discusses selective advantages of zebrafish and provides examples how these advantages are exploited to study neuronal computations in the olfactory bulb. PMID- 23630468 TI - The olivo-cerebellar system and its relationship to survival circuits. AB - How does the cerebellum, the brain's largest sensorimotor structure, contribute to complex behaviors essential to survival? While we know much about the role of limbic and closely associated brainstem structures in relation to a variety of emotional, sensory, or motivational stimuli, we know very little about how these circuits interact with the cerebellum to generate appropriate patterns of behavioral response. Here we focus on evidence suggesting that the olivo cerebellar system may link to survival networks via interactions with the midbrain periaqueductal gray, a structure with a well known role in expression of survival responses. As a result of this interaction we argue that, in addition to important roles in motor control, the inferior olive, and related olivo-cortico nuclear circuits, should be considered part of a larger network of brain structures involved in coordinating survival behavior through the selective relaying of "teaching signals" arising from higher centers associated with emotional behaviors. PMID- 23630469 TI - Integrating anatomy and function for zebrafish circuit analysis. AB - Due to its transparency, virtually every brain structure of the larval zebrafish is accessible to light-based interrogation of circuit function. Advanced stimulation techniques allow the activation of optogenetic actuators at different resolution levels, and genetically encoded calcium indicators report the activity of a large proportion of neurons in the CNS. Large datasets result and need to be analyzed to identify cells that have specific properties-e.g., activity correlation to sensory stimulation or behavior. Advances in three-dimensional (3D) functional mapping in zebrafish are promising; however, the mere coordinates of implicated neurons are not sufficient. To comprehensively understand circuit function, these functional maps need to be placed into the proper context of morphological features and projection patterns, neurotransmitter phenotypes, and key anatomical landmarks. We discuss the prospect of merging functional and anatomical data in an integrated atlas from the perspective of our work on long range dopaminergic neuromodulation and the oculomotor system. We propose that such a resource would help researchers to surpass current hurdles in circuit analysis to achieve an integrated understanding of anatomy and function. PMID- 23630470 TI - Imaging zebrafish neural circuitry from whole brain to synapse. AB - Recent advances in imaging tools are inspiring zebrafish researchers to tackle ever more ambitious questions in the neurosciences. Behaviorally fundamental conserved neural networks can now be potentially studied using zebrafish from a brain-wide scale to molecular resolution. In this perspective, we offer a roadmap by which a zebrafish researcher can navigate the course from collecting neural activities across the brain associated with a behavior, to unraveling molecular identities and testing the functional relevance of active neurons. In doing so, important insights will be gained as to how neural networks generate behaviors and assimilate changes in synaptic connectivity. PMID- 23630471 TI - Surround suppression maps in the cat primary visual cortex. AB - In the primary visual cortex and higher-order areas, it is well known that the stimulation of areas surrounding the classical receptive field of a neuron can inhibit its responses. In the primate area middle temporal (MT), this surround suppression was shown to be spatially organized into high and low suppression modules. However, such an organization has not been demonstrated yet in the primary visual cortex. Here, we used optical imaging of intrinsic signals to spatially evaluate surround suppression in the cat visual cortex. The magnitude of the response was measured in areas 17 and 18 for stimuli with different diameters, presented at different eccentricities. Delimited regions of the cortex were revealed by circumscribed stimulations of the visual field ("cortical response field"). Increasing the stimulus diameter increased the spread of cortical activation. In the cortical response field, the optimal stimulation diameter and the level of suppression were evaluated. Most pixels (>=3/4) exhibited surround suppression profiles. The optimal diameter, corresponding to a population of receptive fields, was smaller in area 17 (22 degrees ) than in area 18 (36 degrees ) in accordance with electrophysiological data. No difference in the suppression strength was observed between both areas (A17: 25%, A18: 21%). Further analysis of our data revealed the presence of surround modulation maps, organized in low and high suppression domains. We also developed a statistical method to confirm the existence of this cortical map and its neuronal origin. The organization for center/surround suppression observed here at the level of the primary visual cortex is similar to those found in higher order areas in primates (e.g., area MT) and could represent a strategy to optimize figure ground discrimination. PMID- 23630472 TI - Motor learning of mice lacking cerebellar Purkinje cells. AB - The cerebellum plays a key role in the acquisition and execution of motor tasks whose physiological foundations were postulated on Purkinje cells' long-term depression (LTD). Numerous research efforts have been focused on understanding the cerebellum as a site of learning and/or memory storage. However, the controversy on which part of the cerebellum participates in motor learning, and how the process takes place, remains unsolved. In fact, it has been suggested that cerebellar cortex, deep cerebellar nuclei, and/or their combination with some brain structures other than the cerebellum are responsible for motor learning. Different experimental approaches have been used to tackle this question (cerebellar lesions, pharmacological agonist and/or antagonist of cerebellar neurotransmitters, virus tract tracings, etc.). One of these approaches is the study of spontaneous mutations affecting the cerebellar cortex and depriving it of its main input-output organizer (i.e., the Purkinje cell). In this review, we discuss the results obtained in our laboratory in motor learning of both Lurcher (Lc/+) and tambaleante (tbl/tbl) mice as models of Purkinje-cell devoid cerebellum. PMID- 23630473 TI - Cerebral low-molecular metabolites influenced by intestinal microbiota: a pilot study. AB - Recent studies suggest that intestinal microbiota influences gut-brain communication. In this study, we aimed to clarify the influence of intestinal microbiota on cerebral metabolism. We analyzed the cerebral metabolome of germ free (GF) mice and Ex-GF mice, which were inoculated with suspension of feces obtained from specific pathogen-free mice, using capillary electrophoresis with time-of-flight mass spectrometry (CE-TOFMS). CE-TOFMS identified 196 metabolites from the cerebral metabolome in both GF and Ex-GF mice. The concentrations of 38 metabolites differed significantly (p < 0.05) between GF and Ex-GF mice. Approximately 10 of these metabolites are known to be involved in brain function, whilst the functions of the remainder are unclear. Furthermore, we observed a novel association between cerebral glycolytic metabolism and intestinal microbiota. Our work shows that cerebral metabolites are influenced by normal intestinal microbiota through the microbiota-gut-brain axis, and indicates that normal intestinal microbiota closely connected with brain health and disease, development, attenuation, learning, memory, and behavior. PMID- 23630474 TI - A role of the human thalamus in predicting the perceptual consequences of eye movements. AB - Internal monitoring of oculomotor commands may help to anticipate and keep track of changes in perceptual input imposed by our eye movements. Neurophysiological studies in non-human primates identified corollary discharge (CD) signals of oculomotor commands that are conveyed via thalamus to frontal cortices. We tested whether disruption of these monitoring pathways on the thalamic level impairs the perceptual matching of visual input before and after an eye movement in human subjects. Fourteen patients with focal thalamic stroke and 20 healthy control subjects performed a task requiring a perceptual judgment across eye movements. Subjects reported the apparent displacement of a target cue that jumped unpredictably in sync with a saccadic eye movement. In a critical condition of this task, six patients exhibited clearly asymmetric perceptual performance for rightward vs. leftward saccade direction. Furthermore, perceptual judgments in seven patients systematically depended on oculomotor targeting errors, with self generated targeting errors erroneously attributed to external stimulus jumps. Voxel-based lesion-symptom mapping identified an area in right central thalamus as critical for the perceptual matching of visual space across eye movements. Our findings suggest that trans-thalamic CD transmission decisively contributes to a correct prediction of the perceptual consequences of oculomotor actions. PMID- 23630475 TI - Neural connectivity, music, and movement: a response to Pat Amos. PMID- 23630477 TI - Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: effects on fear-potentiated startle. AB - The serotonin (5-HT) and neuropeptide S (NPS) systems are discussed as important genetic modulators of fear and sustained anxiety contributing to the etiology of anxiety disorders. Sustained anxiety is a crucial characteristic of most anxiety disorders which likely develops through contextual fear conditioning. This study investigated if and how genetic alterations of the 5-HT and the NPS systems as well as their interaction modulate contextual fear conditioning; specifically, function polymorphic variants in the genes coding for the 5-HT transporter (5HTT) and the NPS receptor (NPSR1) were studied. A large group of healthy volunteers was therefore stratified for 5HTTLPR (S+ vs. LL carriers) and NPSR1 rs324981 (T+ vs. AA carriers) polymorphisms resulting in four genotype groups (S+/T+, S+/AA, LL/T+, LL/AA) of 20 participants each. All participants underwent contextual fear conditioning and extinction using a virtual reality (VR) paradigm. During acquisition, one virtual office room (anxiety context, CXT+) was paired with an unpredictable electric stimulus (unconditioned stimulus, US), whereas another virtual office room was not paired with any US (safety context, CXT-). During extinction no US was administered. Anxiety responses were quantified by fear potentiated startle and ratings. Most importantly, we found a gene * gene interaction on fear-potentiated startle. Only carriers of both risk alleles (S+/T+) exhibited higher startle responses in CXT+ compared to CXT-. In contrast, anxiety ratings were only influenced by the NPSR1 polymorphism with AA carriers showing higher anxiety ratings in CXT+ as compared to CXT-. Our results speak in favor of a two level account of fear conditioning with diverging effects on implicit vs. explicit fear responses. Enhanced contextual fear conditioning as reflected in potentiated startle responses may be an endophenotype for anxiety disorders. PMID- 23630476 TI - Motor development and motor resonance difficulties in autism: relevance to early intervention for language and communication skills. AB - Research suggests that a sub-set of children with autism experience notable difficulties and delays in motor skills development, and that a large percentage of children with autism experience deficits in motor resonance. These motor related deficiencies, which evidence suggests are present from a very early age, are likely to negatively affect social-communicative and language development in this population. Here, we review evidence for delayed, impaired, and atypical motor development in infants and children with autism. We then carefully review and examine the current language and communication-based intervention research that is relevant to motor and motor resonance (i.e., neural "mirroring" mechanisms activated when we observe the actions of others) deficits in children with autism. Finally, we describe research needs and future directions and developments for early interventions aimed at addressing the speech/language and social-communication development difficulties in autism from a motor-related perspective. PMID- 23630478 TI - Neural response in obsessive-compulsive washers depends on individual fit of triggers. AB - BACKGROUND: Patients with obsessive-compulsive disorder (OCD) have highly idiosyncratic triggers. To fully understand which role this idiosyncrasy plays in the neurobiological mechanisms behind OCD, it is necessary to elucidate the impact of individualization regarding the applied investigation methods. This functional magnetic resonance imaging (fMRI) study explores the neural correlates of contamination/washing-related OCD with a highly individualized symptom provocation paradigm. Additionally, it is the first study to directly compare individualized and standardized symptom provocation. METHODS: Nineteen patients with washing compulsions created individual OCD hierarchies, which later served as instructions to photograph their own individualized stimulus sets. The patients and 19 case-by-case matched healthy controls participated in a symptom provocation fMRI experiment with individualized and standardized stimulus sets created for each patient. RESULTS: OCD patients compared to healthy controls displayed stronger activation in the basal ganglia (nucleus accumbens, nucleus caudatus, pallidum) for individualized symptom provocation. Using standardized symptom provocation, this group comparison led to stronger activation in the nucleus caudatus. The direct comparison of between-group effects for both symptom provocation approaches revealed stronger activation of the orbitofronto-striatal network for individualized symptom provocation. CONCLUSIONS: The present study provides insight into the differential impact of individualized and standardized symptom provocation on the orbitofronto-striatal network of OCD washers. Behavioral and neural responses imply a higher symptom-specificity of individualized symptom provocation. PMID- 23630479 TI - The role of the primary auditory cortex in the neural mechanism of auditory verbal hallucinations. AB - Auditory verbal hallucinations (AVHs) are a subjective experience of "hearing voices" in the absence of corresponding physical stimulation in the environment. The most remarkable feature of AVHs is their perceptual quality, that is, the experience is subjectively often as vivid as hearing an actual voice, as opposed to mental imagery or auditory memories. This has lead to propositions that dysregulation of the primary auditory cortex (PAC) is a crucial component of the neural mechanism of AVHs. One possible mechanism by which the PAC could give rise to the experience of hallucinations is aberrant patterns of neuronal activity whereby the PAC is overly sensitive to activation arising from internal processing, while being less responsive to external stimulation. In this paper, we review recent research relevant to the role of the PAC in the generation of AVHs. We present new data from a functional magnetic resonance imaging (fMRI) study, examining the responsivity of the left and right PAC to parametrical modulation of the intensity of auditory verbal stimulation, and corresponding attentional top-down control in non-clinical participants with AVHs, and non clinical participants with no AVHs. Non-clinical hallucinators showed reduced activation to speech sounds but intact attentional modulation in the right PAC. Additionally, we present data from a group of schizophrenia patients with AVHs, who do not show attentional modulation of left or right PAC. The context appropriate modulation of the PAC may be a protective factor in non-clinical hallucinations. PMID- 23630480 TI - Disrupting the brain to validate hypotheses on the neurobiology of language. AB - Comprehension of words is an important part of the language faculty, involving the joint activity of frontal and temporo-parietal brain regions. Transcranial Magnetic Stimulation (TMS) enables the controlled perturbation of brain activity, and thus offers a unique tool to test specific predictions about the causal relationship between brain regions and language understanding. This potential has been exploited to better define the role of regions that are classically accepted as part of the language-semantic network. For instance, TMS has contributed to establish the semantic relevance of the left anterior temporal lobe, or to solve the ambiguity between the semantic vs. phonological function assigned to the left inferior frontal gyrus (LIFG). We consider, more closely, the results from studies where the same technique, similar paradigms (lexical-semantic tasks) and materials (words) have been used to assess the relevance of regions outside the classically-defined language-semantic network-i.e., precentral motor regions-for the semantic analysis of words. This research shows that different aspects of the left precentral gyrus (primary motor and premotor sites) are sensitive to the action-non action distinction of words' meanings. However, the behavioral changes due to TMS over these sites are incongruent with what is expected after perturbation of a task-relevant brain region. Thus, the relationship between motor activity and language-semantic behavior remains far from clear. A better understanding of this issue could be guaranteed by investigating functional interactions between motor sites and semantically-relevant regions. PMID- 23630481 TI - Rapid Presentation of Emotional Expressions Reveals New Emotional Impairments in Tourette's Syndrome. AB - OBJECTIVE: Based on a variety of empirical evidence obtained within the theoretical framework of embodiment theory, we considered it likely that motor disorders in Tourette's syndrome (TS) would have emotional consequences for TS patients. However, previous research using emotional facial categorization tasks suggests that these consequences are limited to TS patients with obsessive compulsive behaviors (OCB). METHOD: These studies used long stimulus presentations which allowed the participants to categorize the different emotional facial expressions (EFEs) on the basis of a perceptual analysis that might potentially hide a lack of emotional feeling for certain emotions. In order to reduce this perceptual bias, we used a rapid visual presentation procedure. RESULTS: Using this new experimental method, we revealed different and surprising impairments on several EFEs in TS patients compared to matched healthy control participants. Moreover, a spatial frequency analysis of the visual signal processed by the patients suggests that these impairments may be located at a cortical level. CONCLUSION: The current study indicates that the rapid visual presentation paradigm makes it possible to identify various potential emotional disorders that were not revealed by the standard visual presentation procedures previously reported in the literature. Moreover, the spatial frequency analysis performed in our study suggests that emotional deficit in TS might lie at the level of temporal cortical areas dedicated to the processing of HSF visual information. PMID- 23630482 TI - The emotional attentional blink: what we know so far. AB - The emotional attentional blink (EAB), also known as emotion-induced blindness, refers to a phenomenon in which the brief appearance of a task-irrelevant, emotionally arousing image captures attention to such an extent that individuals cannot detect target stimuli for several hundred ms after the emotional stimulus. The EAB allows for mental chronometry of stimulus-driven attention and the time needed to disengage and refocus goal-directed attention. In this review, we discuss current evidence for the mechanisms through which the EAB occurs. Although the EAB shares some similarities to both surprise-induced blindness (SiB) and other paradigms for assessing emotion-attention interactions, it possesses features that are distinct from these paradigms, and thus appears to provide a unique measure of the influence of emotion on stimulus-driven attention. The neural substrates of the EAB are not completely understood, but neuroimaging and neuropsychological data suggest some possible neural mechanisms underlying the phenomenon. The importance of understanding the EAB is highlighted by recent evidence indicating that EAB tasks can detect altered sensitivity to disorder relevant stimuli in psychiatric conditions such as post-traumatic stress disorder (PTSD). PMID- 23630484 TI - Vicarious ostracism. PMID- 23630485 TI - Directing spatial attention to locations within remembered and imagined mental representations. AB - Spatial attention enables us to enhance the processing of items at target locations, at the expense of items presented at irrelevant locations. Many studies have explored the neural correlates of these spatial biases using event related potentials (ERPs). More recently some studies have shown that these ERP correlates are also present when subjects search visual short-term memory (VSTM). This suggests firstly that this type of mental representation retains a spatial organization that is based upon that of the original percept, and secondly that these attentional biases are flexible and can act to modulate remembered as well as perceptual representations. We aimed to test whether it was necessary for subjects to have actually seen the memoranda at those spatial locations, or whether simply imagining the spatial layout was sufficient to elicit the spatial attention effects. On some trials subjects performed a "visual" search of an array held in VSTM, and upon other trials subjects imagined the items at those spatial locations. We found ERP markers of spatial attention in both the memory search and the imagery-search conditions. However, there were differences between the conditions, the effect in the memory-search began earlier and included posterior electrode sites. By contrast the ERP effect in the imagery-search condition was apparent only over fronto-central electrode sites and emerged slightly later. Nonetheless, our data demonstrate that it is not necessary for subjects to have ever seen the items at spatial locations for neural markers of spatial attention to be elicited; searching an imaginary spatial layout also triggers spatially-specific attention effects in the ERP data. PMID- 23630483 TI - Testing the excitability of human motoneurons. AB - The responsiveness of the human central nervous system can change profoundly with exercise, injury, disuse, or disease. Changes occur at both cortical and spinal levels but in most cases excitability of the motoneuron pool must be assessed to localize accurately the site of adaptation. Hence, it is critical to understand, and employ correctly, the methods to test motoneuron excitability in humans. Several techniques exist and each has its advantages and disadvantages. This review examines the most common techniques that use evoked compound muscle action potentials to test the excitability of the motoneuron pool and describes the merits and limitations of each. The techniques discussed are the H-reflex, F wave, tendon jerk, V-wave, cervicomedullary motor evoked potential (CMEP), and motor evoked potential (MEP). A number of limitations with these techniques are presented. PMID- 23630486 TI - TMS-evoked changes in brain-state dynamics quantified by using EEG data. AB - To improve our understanding of the combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) method in general, it is important to study how the dynamics of the TMS-modulated brain activity differs from the dynamics of spontaneous activity. In this paper, we introduce two quantitative measures based on EEG data, called mean state shift (MSS) and state variance (SV), for evaluating the TMS-evoked changes in the brain-state dynamics. MSS quantifies the immediate TMS-elicited change in the brain state, whereas SV shows whether the rate at which the brain state changes is modulated by TMS. We report a statistically significant increase for a period of 100-200 ms after the TMS pulse in both MSS and SV at the group level. This indicates that the TMS modulated brain state differs from the spontaneous one. Moreover, the TMS modulated activity is more vigorous than the natural activity. PMID- 23630487 TI - An Investigation of RSN Frequency Spectra Using Ultra-Fast Generalized Inverse Imaging. AB - With the advancements in MRI hardware, pulse sequences and reconstruction techniques, many low TR sequences are becoming more and more popular within the functional MRI (fMRI) community. In this study, we have investigated the spectral characteristics of resting state networks (RSNs) with a newly introduced ultra fast fMRI technique, called generalized inverse imaging (GIN). The high temporal resolution of GIN (TR = 50 ms) enables to sample cardiac signals without aliasing into a separate frequency band from the BOLD fluctuations. Respiration related signal changes are, on the other hand, removed from the data without the need for external physiological recordings. We have observed that the variance over the subjects is higher than the variance over RSNs. PMID- 23630488 TI - Overlapping multivoxel patterns for two levels of visual expectation. AB - According to predictive accounts of perception, visual cortical regions encode sensory expectations about the external world, and the violation of those expectations by inputs (surprise). Here, using multi-voxel pattern analysis (MVPA) of functional magnetic resonance imaging (fMRI) data, we asked whether expectations and surprise activate the same pattern of voxels, in face-sensitive regions of the extra-striate visual cortex (the fusiform face area or FFA). Participants viewed pairs of repeating or alternating faces, with high or low probability of repetitions. As in previous studies, we found that repetition suppression (the attenuated BOLD response to repeated stimuli) in the FFA was more pronounced for probable repetitions, consistent with it reflecting reduced surprise to anticipated inputs. Secondly, we observed that repetition suppression and repetition enhancement responses were both consistent across scanner runs, suggesting that both have functional significance, with repetition enhancement possibly indicating the build up of sensory expectation. Critically, we also report that multi-voxels patterns associated with probability and repetition effects were significantly correlated within the left FFA. We argue that repetition enhancement responses and repetition probability effects can be seen as two types of expectation signals, occurring simultaneously, although at different processing levels (lower vs. higher), and different time scales (immediate vs. long term). PMID- 23630489 TI - Beta event-related desynchronization as an index of individual differences in processing human facial expression: further investigations of autistic traits in typically developing adults. AB - The human mirror neuron system (hMNS) has been associated with various forms of social cognition and affective processing including vicarious experience. It has also been proposed that a faulty hMNS may underlie some of the deficits seen in the autism spectrum disorders (ASDs). In the present study we set out to investigate whether emotional facial expressions could modulate a putative EEG index of hMNS activation (mu suppression) and if so, would this differ according to the individual level of autistic traits [high versus low Autism Spectrum Quotient (AQ) score]. Participants were presented with 3 s films of actors opening and closing their hands (classic hMNS mu-suppression protocol) while simultaneously wearing happy, angry, or neutral expressions. Mu-suppression was measured in the alpha and low beta bands. The low AQ group displayed greater low beta event-related desynchronization (ERD) to both angry and neutral expressions. The high AQ group displayed greater low beta ERD to angry than to happy expressions. There was also significantly more low beta ERD to happy faces for the low than for the high AQ group. In conclusion, an interesting interaction between AQ group and emotional expression revealed that hMNS activation can be modulated by emotional facial expressions and that this is differentiated according to individual differences in the level of autistic traits. The EEG index of hMNS activation (mu suppression) seems to be a sensitive measure of the variability in facial processing in typically developing individuals with high and low self-reported traits of autism. PMID- 23630490 TI - Stability constraints on large-scale structural brain networks. AB - Stability is an important dynamical property of complex systems and underpins a broad range of coherent self-organized behavior. Based on evidence that some neurological disorders correspond to linear instabilities, we hypothesize that stability constrains the brain's electrical activity and influences its structure and physiology. Using a physiologically-based model of brain electrical activity, we investigated the stability and dispersion solutions of networks of neuronal populations with propagation time delays and dendritic time constants. We find that stability is determined by the spectrum of the network's matrix of connection strengths and is independent of the temporal damping rate of axonal propagation with stability restricting the spectrum to a region in the complex plane. Time delays and dendritic time constants modify the shape of this region but it always contains the unit disk. Instabilities resulting from changes in connection strength initially have frequencies less than a critical frequency. For physiologically plausible parameter values based on the corticothalamic system, this critical frequency is approximately 10 Hz. For excitatory networks and networks with randomly distributed excitatory and inhibitory connections, time delays and non-zero dendritic time constants have no impact on network stability but do effect dispersion frequencies. Random networks with both excitatory and inhibitory connections can have multiple marginally stable modes at low delta frequencies. PMID- 23630491 TI - Characterizing Functional Connectivity Differences in Aging Adults using Machine Learning on Resting State fMRI Data. AB - The brain at rest consists of spatially distributed but functionally connected regions, called intrinsic connectivity networks (ICNs). Resting state functional magnetic resonance imaging (rs-fMRI) has emerged as a way to characterize brain networks without confounds associated with task fMRI such as task difficulty and performance. Here we applied a Support Vector Machine (SVM) linear classifier as well as a support vector machine regressor to rs-fMRI data in order to compare age-related differences in four of the major functional brain networks: the default, cingulo-opercular, fronto-parietal, and sensorimotor. A linear SVM classifier discriminated between young and old subjects with 84% accuracy (p value < 1 * 10(-7)). A linear SVR age predictor performed reasonably well in continuous age prediction (R (2) = 0.419, p-value < 1 * 10(-8)). These findings reveal that differences in intrinsic connectivity as measured with rs-fMRI exist between subjects, and that SVM methods are capable of detecting and utilizing these differences for classification and prediction. PMID- 23630492 TI - Cortical information flow in Parkinson's disease: a composite network/field model. AB - The basal ganglia play a crucial role in the execution of movements, as demonstrated by the severe motor deficits that accompany Parkinson's disease (PD). Since motor commands originate in the cortex, an important question is how the basal ganglia influence cortical information flow, and how this influence becomes pathological in PD. To explore this, we developed a composite neuronal network/neural field model. The network model consisted of 4950 spiking neurons, divided into 15 excitatory and inhibitory cell populations in the thalamus and cortex. The field model consisted of the cortex, thalamus, striatum, subthalamic nucleus, and globus pallidus. Both models have been separately validated in previous work. Three field models were used: one with basal ganglia parameters based on data from healthy individuals, one based on data from individuals with PD, and one purely thalamocortical model. Spikes generated by these field models were then used to drive the network model. Compared to the network driven by the healthy model, the PD-driven network had lower firing rates, a shift in spectral power toward lower frequencies, and higher probability of bursting; each of these findings is consistent with empirical data on PD. In the healthy model, we found strong Granger causality between cortical layers in the beta and low gamma frequency bands, but this causality was largely absent in the PD model. In particular, the reduction in Granger causality from the main "input" layer of the cortex (layer 4) to the main "output" layer (layer 5) was pronounced. This may account for symptoms of PD that seem to reflect deficits in information flow, such as bradykinesia. In general, these results demonstrate that the brain's large-scale oscillatory environment, represented here by the field model, strongly influences the information processing that occurs within its subnetworks. Hence, it may be preferable to drive spiking network models with physiologically realistic inputs rather than pure white noise. PMID- 23630493 TI - Synaptic and functional linkages between spinal premotor interneurons and hand muscle activity during precision grip. AB - Grasping is a highly complex movement that requires the coordination of a number of hand joints and muscles. Previous studies showed that spinal premotor interneurons (PreM-INs) in the primate cervical spinal cord have divergent synaptic effects on hand motoneurons and that they might contribute to hand muscle synergies. However, the extent to which these PreM-IN synaptic connections functionally contribute to modulating hand-muscle activity is not clear. In this paper, we explored the contribution of spinal PreM-INs to hand-muscle activation by quantifying the synaptic linkage (SL) and functional linkage (FL) of the PreM INs with hand-muscle activities. The activity of 23 PreM-INs was recorded from the cervical spinal cord (C6-T1), with EMG signals measured simultaneously from hand and arm muscles in two macaque monkeys performing a precision grip task. Spike-triggered averages (STAs) of rectified EMGs were compiled for 456 neuron muscle pairs; 63 pairs showed significant post-spike effects (PSEs; i.e., SL). Conversely, 231 of 456 pairs showed significant cross-correlations between the IN firing rate and rectified EMG (i.e., FL). Importantly, a greater proportion of the neuron-muscle pairs with SL showed FL (43/63 pairs, 68%) compared with the pairs without SL (203/393, 52%), and the presence of SL was significantly associated with that of FL. However, a significant number of pairs had SL without FL (SL?!FL, n = 20) or FL without SL (!SL?FL, n = 203), and the proportions of these incongruities exceeded the number expected by chance. These results suggested that spinal PreM-INs function to significantly modulate hand-muscle activity during precision grip, but the contribution of other neural structures is also needed to recruit an adequate combination of hand-muscle motoneurons. PMID- 23630494 TI - A model of microsaccade-related neural responses induced by short-term depression in thalamocortical synapses. AB - Microsaccades during fixation have been suggested to counteract visual fading. Recent experiments have also observed microsaccade-related neural responses from cellular record, scalp electroencephalogram (EEG), and functional magnetic resonance imaging (fMRI). The underlying mechanism, however, is not yet understood and highly debated. It has been proposed that the neural activity of primary visual cortex (V1) is a crucial component for counteracting visual adaptation. In this paper, we use computational modeling to investigate how short term depression (STD) in thalamocortical synapses might affect the neural responses of V1 in the presence of microsaccades. Our model not only gives a possible synaptic explanation for microsaccades in counteracting visual fading, but also reproduces several features in experimental findings. These modeling results suggest that STD in thalamocortical synapses plays an important role in microsaccade-related neural responses and the model may be useful for further investigation of behavioral properties and functional roles of microsaccades. PMID- 23630495 TI - Coding of odors by temporal binding within a model network of the locust antennal lobe. AB - The locust olfactory system interfaces with the external world through antennal receptor neurons (ORNs), which represent odors in a distributed, combinatorial manner. ORN axons bundle together to form the antennal nerve, which relays sensory information centrally to the antennal lobe (AL). Within the AL, an odor generates a dynamically evolving ensemble of active cells, leading to a stimulus specific temporal progression of neuronal spiking. This experimental observation has led to the hypothesis that an odor is encoded within the AL by a dynamically evolving trajectory of projection neuron (PN) activity that can be decoded piecewise to ascertain odor identity. In order to study information coding within the locust AL, we developed a scaled-down model of the locust AL using Hodgkin Huxley-type neurons and biologically realistic connectivity parameters and current components. Using our model, we examined correlations in the precise timing of spikes across multiple neurons, and our results suggest an alternative to the dynamic trajectory hypothesis. We propose that the dynamical interplay of fast and slow inhibition within the locust AL induces temporally stable correlations in the spiking activity of an odor-dependent neural subset, giving rise to a temporal binding code that allows rapid stimulus detection by downstream elements. PMID- 23630496 TI - Granger causality is designed to measure effect, not mechanism. PMID- 23630498 TI - Mesobiliverdin IXalpha Enhances Rat Pancreatic Islet Yield and Function. AB - The aims of this study were to produce mesobiliverdin IXalpha, an analog of anti inflammatory biliverdin IXalpha, and to test its ability to enhance rat pancreatic islet yield for allograft transplantation into diabetic recipients. Mesobiliverdin IXalpha was synthesized from phycocyanobilin derived from cyanobacteria, and its identity and purity were analyzed by chromatographic and spectroscopic methods. Mesobiliverdin IXalpha was a substrate for human NADPH biliverdin reductase. Excised Lewis rat pancreata infused with mesobiliverdin IXalpha and biliverdin IXalpha-HCl (1-100 MUM) yielded islet equivalents as high as 86.7 and 36.5%, respectively, above those from non-treated controls, and the islets showed a high degree of viability based on dithizone staining. When transplanted into livers of streptozotocin-induced diabetic rats, islets from pancreata infused with mesobiliverdin IXalpha lowered non-fasting blood glucose (BG) levels in 55.6% of the recipients and in 22.2% of control recipients. In intravenous glucose tolerance tests, fasting BG levels of 56 post-operative day recipients with islets from mesobiliverdin IXalpha infused pancreata were lower than those for controls and showed responses that indicate recovery of insulin dependent function. In conclusion, mesobiliverdin IXalpha infusion of pancreata enhanced yields of functional islets capable of reversing insulin dysfunction in diabetic recipients. Since its production is scalable, mesobiliverdin IXalpha has clinical potential as a protectant of pancreatic islets for allograft transplantation. PMID- 23630497 TI - Genetic influences on cystic fibrosis lung disease severity. AB - Understanding the causes of variation in clinical manifestations of disease should allow for design of new or improved therapeutic strategies to treat the disease. If variation is caused by genetic differences between individuals, identifying the genes involved should present therapeutic targets, either in the proteins encoded by those genes or the pathways in which they function. The technology to identify and genotype the millions of variants present in the human genome has evolved rapidly over the past two decades. Originally only a small number of polymorphisms in a small number of subjects could be studied realistically, but speed and scope have increased nearly as dramatically as cost has decreased, making it feasible to determine genotypes of hundreds of thousands of polymorphisms in thousands of subjects. The use of such genetic technology has been applied to cystic fibrosis (CF) to identify genetic variation that alters the outcome of this single gene disorder. Candidate gene strategies to identify these variants, referred to as "modifier genes," has yielded several genes that act in pathways known to be important in CF and for these the clinical implications are relatively clear. More recently, whole-genome surveys that probe hundreds of thousands of variants have been carried out and have identified genes and chromosomal regions for which a role in CF is not at all clear. Identification of these genes is exciting, as it provides the possibility for new areas of therapeutic development. PMID- 23630499 TI - Cytoskeleton and regulation of mitochondrial function: the role of beta-tubulin II. AB - The control of mitochondrial function is a cardinal issue in the field of cardiac bioenergetics, and the analysis of mitochondrial regulations is central to basic research and in the diagnosis of many diseases. Interaction between cytoskeletal proteins and mitochondria can actively participate in mitochondrial regulation. Potential candidates for the key roles in this regulation are the cytoskeletal proteins plectin and tubulin. Analysis of cardiac cells has revealed regular arrangement of beta-tubulin II, fully co-localized with mitochondria. beta Tubulin IV demonstrated a characteristic staining of branched network, beta tubulin III was matched with Z-lines, and beta-tubulin I was diffusely spotted and fragmentary polymerized. In contrast, HL-1 cells were characterized by the complete absence of beta-tubulin II. Comparative analysis of cardiomyocytes and HL-1 cells revealed a dramatic difference in the mechanisms of mitochondrial regulation. In the heart, colocalization of beta-tubulin isotype II with mitochondria suggests that it can participate in the coupling of ATP-ADP translocase (ANT), mitochondrial creatine kinase (MtCK), and VDAC (ANT-MtCK VDAC). This mitochondrial supercomplex is responsible for the efficient intracellular energy transfer via the phosphocreatine pathway. Existing data suggest that cytoskeletal proteins may control the VDAC, contributing to maintenance of mitochondrial and cellular physiology. PMID- 23630500 TI - Effects of perinatal oxycodone exposure on the cardiovascular response to acute stress in male rats at weaning and in young adulthood. AB - Oxycodone (OXY) is one of the most commonly abused opiates during pregnancy. Perinatal opiate exposure (POE) is associated with neurobehavioral and hormone changes. Little is known about the effects of perinatal OXY on the cardiovascular (CV) responses to stress. OBJECTIVES: to determine the effects of POE on: (1) CV responses to acute stress and ability to discriminate using a classical conditioning paradigm; (2) changes in CV response to the paradigm and retention of the ability to discriminate from postnatal day (PD) 40 to young adulthood. METHODS: Pregnant rats were given i.v. OXY or vehicle (CON) daily. OXY and CON males were fitted with BP telemetry units. Offspring were classically conditioned by following a pulsed tone (CS+) with tail shock. A steady tone (CS-) was not followed by shock. BP and HR were recorded during resting periods and conditioning. Changes in BP, HR from composite analysis were compared. The paradigm was repeated on PD 75. RESULTS: At PD 40, OXY rats had a lower baseline mean BP (OXY: 114.8 +/- 1.0 vs. CON: 118.3 +/- 1.0 mm Hg; mean +/- SEM) but larger amplitude of the conditional BP increase during the stress response (OXY: +3.9 +/- 0.4 vs. CON: +1.7 +/- 0.4 mm Hg). Both OXY and CON rats were able to discriminate between CS+ and CS-. At PD 75, the effects of OXY on the increased amplitude of the conditional BP had dissipated (CON: +3.4 +/- 2.3 vs. OXY: +4.5 +/- 1.4 mm Hg). BP responses to the stress and non-stress stimuli did not differ in the OXY group, suggesting that OXY may have decreased the ability of the offspring to discriminate (OXY: CS+: 147.1 +/- 1.6, CS-: 145.9 +/- 1.6 mm Hg vs. CON: CS+: 155.4 +/- 2.7, CS-: 147.8 +/- 2.7 mm Hg). CONCLUSION: POE is associated with subtle alterations in stress CV responses in weanling rats which dissipate when the conditioning is repeated at an early adult age. Although POE effect on the ability to discriminate at weanling age could not be detected, POE may impair retention of this ability in adulthood. PMID- 23630501 TI - Intensity and directionality of bat echolocation signals. AB - The paper reviews current knowledge of intensity and directionality of bat echolocation signals. Recent studies have revealed that echolocating bats can be much louder than previously believed. Bats previously dubbed "whispering" can emit calls with source levels up to 110 dB SPL at 10 cm and the louder open space hunting bats have been recorded at above 135 dB SPL. This implies that maximum emitted intensities are generally 30 dB or more above initial estimates. Bats' dynamic control of acoustic features also includes the intensity and directionality of their sonar calls. Aerial hawking bats will increase signal directionality in the field along with intensity thus increasing sonar range. During the last phase of prey pursuit, vespertilionid bats broaden their echolocation beam considerably, probably to counter evasive maneuvers of eared prey. We highlight how multiple call parameters (frequency, duration, intensity, and directionality of echolocation signals) in unison define the search volume probed by bats and in turn how bats perceive their surroundings. Small changes to individual parameters can, in combination, drastically change the bat's perception, facilitating successful navigation and food acquisition across a vast range of ecological niches. To better understand the function of echolocation in the natural habitat it is critical to determine multiple acoustic features of the echolocation calls. The combined (interactive) effects, not only of frequency and time parameters, but also of intensity and directionality, define the bat's view of its acoustic scene. PMID- 23630502 TI - Novel insights into obesity and diabetes through genome-scale metabolic modeling. AB - The growing prevalence of metabolic diseases, such as obesity and diabetes, are putting a high strain on global healthcare systems as well as increasing the demand for efficient treatment strategies. More than 360 million people worldwide are suffering from type 2 diabetes (T2D) and, with the current trends, the projection is that 10% of the global adult population will be affected by 2030. In light of the systemic properties of metabolic diseases as well as the interconnected nature of metabolism, it is necessary to begin taking a holistic approach to study these diseases. Human genome-scale metabolic models (GEMs) are topological and mathematical representations of cell metabolism and have proven to be valuable tools in the area of systems biology. Successful applications of GEMs include the process of gaining further biological and mechanistic understanding of diseases, finding potential biomarkers, and identifying new drug targets. This review will focus on the modeling of human metabolism in the field of obesity and diabetes, showing its vast range of applications of clinical importance as well as point out future challenges. PMID- 23630503 TI - Role of a genetic polymorphism in the corticotropin-releasing factor receptor 1 gene in alcohol drinking and seeking behaviors of marchigian sardinian alcohol preferring rats. AB - Marchigian Sardinian alcohol-preferring (msP) rats exhibit innate preference for alcohol, are highly sensitive to stress and stress-induced alcohol seeking. Genetic analysis showed that over-expression of the corticotropin-releasing factor (CRF) system of msP rats is correlated with the presence of two single nucleotide polymorphisms (SNPs) occurring in the promoter region (position -1836 and -2097) of the CRF1 receptor (CRF1-R) gene. Here we examined whether these point mutations were associated to the innate alcohol preference, stress-induced drinking, and seeking. We have recently re-derived the msP rats to obtain two distinct lines carrying the wild type (GG) and the point mutations (AA), respectively. The phenotypic characteristics of these two lines were compared with those of unselected Wistar rats. Both AA and GG rats showed similar patterns of voluntary alcohol intake and preference. Similarly, the pharmacological stressor yohimbine (0.0, 0.625, 1.25, and 2.5 mg/kg) elicited increased operant alcohol self-administration under fixed and progressive ratio reinforcement schedules in all three lines. Following extinction, yohimbine (0.0, 0.625, 1.25, and 2.5 mg/kg) significantly reinstated alcohol seeking in the three groups. However, at the highest dose this effect was no longer evident in AA rats. Treatment with the CRF1-R antagonist antalarmin (0, 5, 10, and 20 mg/kg) significantly reduced alcohol-reinforced lever pressing in the AA line (10 and 20 mg/kg) while a weaker or no effect was observed in the Wistar and the GG group, respectively. Finally, antalarmin significantly reduced yohimbine-induced increase in alcohol drinking in all three groups. In conclusion, these specific SNPs in the CRF1-R gene do not seem to play a primary role in the expression of the msP excessive drinking phenotype or stress-induced drinking but may be associated with a decreased threshold for stress-induced alcohol seeking and an increased sensitivity to the effects of pharmacological blockade of CRF1-R on alcohol drinking. PMID- 23630504 TI - Effects of exercise and physical activity on anxiety. PMID- 23630505 TI - The immediate and chronic influence of spatio-temporal metaphors on the mental representations of time in english, mandarin, and mandarin-english speakers. AB - In this paper we examine whether experience with spatial metaphors for time has an influence on people's representation of time. In particular we ask whether spatio-temporal metaphors can have both chronic and immediate effects on temporal thinking. In Study 1, we examine the prevalence of ego-moving representations for time in Mandarin speakers, English speakers, and Mandarin-English (ME) bilinguals. As predicted by observations in linguistic analyses, we find that Mandarin speakers are less likely to take an ego-moving perspective than are English speakers. Further, we find that ME bilinguals tested in English are less likely to take an ego-moving perspective than are English monolinguals (an effect of L1 on meaning-making in L2), and also that ME bilinguals tested in Mandarin are more likely to take an ego-moving perspective than are Mandarin monolinguals (an effect of L2 on meaning-making in L1). These findings demonstrate that habits of metaphor use in one language can influence temporal reasoning in another language, suggesting the metaphors can have a chronic effect on patterns in thought. In Study 2 we test Mandarin speakers using either horizontal or vertical metaphors in the immediate context of the task. We find that Mandarin speakers are more likely to construct front-back representations of time when understanding front-back metaphors, and more likely to construct up-down representations of time when understanding up-down metaphors. These findings demonstrate that spatio-temporal metaphors can also have an immediate influence on temporal reasoning. Taken together, these findings demonstrate that the metaphors we use to talk about time have both immediate and long-term consequences for how we conceptualize and reason about this fundamental domain of experience. PMID- 23630506 TI - Two sides of meaning: the scalp-recorded n400 reflects distinct contributions from the cerebral hemispheres. AB - The N400, a component of the event-related potential (ERP) associated with the processing of meaning, is sensitive to a wide array of lexico-semantic, sentence level, and discourse-level manipulations across modalities. In sentence contexts, N400 amplitude varies inversely and nearly linearly with the predictability of a word in its context. However, recent theories and empirical evidence from studies employing the visual half-field technique (to selectively bias processing to one cerebral hemisphere) suggest that the two hemispheres use sentence context information in different ways. Thus, each hemisphere may not respond to manipulations of contextual predictability in an equivalent manner. This possibility was investigated by recording ERPs while presenting [in the left and right visual fields (VFs)] sentence-final words that varied over the full range of sentence-level predictability. RVF/left hemisphere items were facilitated (as evidenced by reduced N400 amplitudes) over a broader range of predictability compared with LVF/right hemisphere items, although both strongly predictable and completely unexpected items evoked similar responses in each VF/hemisphere. Further, the pattern of N400 amplitudes over the full range of predictability significantly differed from a linear response function for both VFs/hemispheres. This suggests that the N400 response recorded with standard central field presentation comprises different contributions from both cerebral hemispheres, neither of which on its own is sensitive to contextual predictability in an evenly graded manner. These data challenge the notion of a singular or unitary mode of comprehension and instead support the view that the left and right hemispheres instantiate unique, complementary language comprehension architectures in parallel. PMID- 23630507 TI - Emotional communication in speech and music: the role of melodic and rhythmic contrasts. AB - Many acoustic features convey emotion similarly in speech and music. Researchers have established that acoustic features such as pitch height, tempo, and intensity carry important emotional information in both domains. In this investigation, we examined the emotional significance of melodic and rhythmic contrasts between successive syllables or tones in speech and music, referred to as Melodic Interval Variability (MIV) and the normalized Pairwise Variability Index (nPVI). The spoken stimuli were 96 tokens expressing the emotions of irritation, fear, happiness, sadness, tenderness, or no emotion. The music stimuli were 96 phrases, played with or without performance expression and composed with the intention of communicating the same emotions. Results showed that nPVI, but not MIV, operates similarly in music and speech. Spoken stimuli, but not musical stimuli, were characterized by changes in MIV as a function of intended emotion. The results suggest that these measures may signal emotional intentions differently in speech and music. PMID- 23630508 TI - Short-term attentional perseveration associated with real-life creative achievement. AB - There are at least two competing hypotheses of how attention interacts with creative cognition, although they are not mutually exclusive. The first hypothesis is that highly creative people are particularly flexible at switching their attention - that is, they adaptively shift focus among different attentional levels using cognitive control. The second, less common, view is that creative people exhibit attentional persistence, or an ability for sustained attention. We suggest these two views need not be competing, as they may both operate, but on different time scales or on different components of creativity. In the present study we examined the role of attention in real-world creative achievement and in divergent thinking. In Experiment 1 participants with high and low real-world creative achievements identified whether the stimulus contained letters S or H within hierarchically constructed letters (e.g., large S made of small Es - global level; large E made up of small Ss - local level), which were presented in blocks of eight trials per level. In Experiment 2 participants with high, medium, and low creative achievements identified the same stimulus letters, but in blocks of five, seven, and nine trials per level. Results from both experiments indicated that people with high creative achievements made significantly more errors on trials in which they had to switch the level of attention, even after controlling for general intelligence. In Experiment 2, divergent thinking was also assessed, but it was not related to switching cost. Results from both experiments demonstrate that real-world creative acts relate to increased levels of attentional persistence, even if it comes with the cost of perseveration in certain circumstances. PMID- 23630509 TI - Subjectively reported symptoms in patients with persistent atrial fibrillation and emotional distress. AB - BACKGROUND: Patients with atrial fibrillation (AF) are characterized by emotional distress and poor quality of life. Little is known about the relation between emotional distress and subjectively reported AF symptoms. Our aims were to compare emotional distress levels in AF patients with distress levels in the general population and to examine the cross-sectional and prospective relationship between subjective AF symptom reports and emotional distress around electrical cardioversion (ECV). METHODS: At baseline, this study included 118 patients with persistent AF planned for ECV (aged 68 +/- 10 years, 60% men) in which depression (BDI), anxiety (STAI), Type D personality (DS14), perceived stress (PSS-10), and AF symptoms (ATSSS) were assessed. The prospective substudy included 52 patients. Objective AF status was determined by ECG. RESULTS: AF patients experienced significantly higher levels of anxiety (p < 0.001) and depression (p < 0.001) than age and gender matched persons from the general population. Linear regression analyses showed that AF patients with higher depression levels reported significantly more AF symptoms (beta = 0.44; p < 0.0005) and reported symptoms to occur with a higher frequency (beta = 0.51; p < 0.0005) during the AF episode, independent of age, sex, cardiac disease, BMI, and physical activity. At 4 weeks follow-up, 56% of all patients had maintained sinus rhythm. Repeated Measures Linear mixed modeling showed that these patients reported fewer AF symptoms and a lower frequency of AF symptoms pre and post-ECV (p = 0.04). Also, the course of the number and frequency of reported symptoms was significantly associated with the change in depression over that same time period (p < 0.0005). CONCLUSION: Patients with persistent AF are characterized by emotional distress. Distressed AF patients, particularly the depressed, report more AF symptoms before and after ECV. These findings call for increased attention of clinicians to emotional distress in this patient population. PMID- 23630511 TI - Mental imagery. PMID- 23630512 TI - Accentuate the positive: semantic access in english compounds. AB - The present study supplements research on semantic effects in word processing by focusing on the role that meanings of morphemes play in recognition of complex words. We present an overview of behavioral effects of six semantic properties characterizing the emotional and sensory connotations of English compounds and their morphemes, as well as their semantic richness. Semantics of compounds affected latencies to those compounds, and semantics of morphemes affected latencies to those morphemes presented as isolated words. Yet semantics of morphemes had little bearing on recognition of compounds, with the exception of longer recognition times for compounds with emotionally negative morphemes (e.g., seasick). We interpret the data as evidence against obligatory decomposition and dual-route accounts of morphological processing and in favor of the naive discriminative learning account that posits independent, morphologically unmediated, and simultaneous access to all meanings activated by orthographic cues in the visual input. We discuss selectivity and division of attention as driving forces in complex word recognition. PMID- 23630510 TI - Numerical Transcoding Proficiency in 10-Year-Old Schoolchildren is Associated with Gray Matter Inter-Individual Differences: A Voxel-Based Morphometry Study. AB - Are individual differences in numerical performance sustained by variations in gray matter volume in schoolchildren? To our knowledge, this challenging question for neuroeducation has not yet been investigated in typical development. We used the Voxel-Based Morphometry method to search for possible structural brain differences between two groups of 10-year-old schoolchildren (N = 22) whose performance differed only in numerical transcoding between analog and symbolic systems. The results indicated that children with low numerical proficiency have less gray matter volume in the parietal (particularly in the left intraparietal sulcus and the bilateral angular gyri) and occipito-temporal areas. All the identified regions have previously been shown to be functionally involved in transcoding between analog and symbolic numerical systems. Our data contribute to a better understanding of the intertwined relationships between mathematics learning and brain structure in healthy schoolchildren. PMID- 23630513 TI - Xenomelia: a social neuroscience view of altered bodily self-consciousness. AB - Xenomelia, the "foreign limb syndrome," is characterized by the non-acceptance of one or more of one's own extremities and the resulting desire for elective limb amputation or paralysis. Formerly labeled "body integrity identity disorder" (BIID), the condition was originally considered a psychological or psychiatric disorder, but a brain-centered Zeitgeist and a rapidly growing interest in the neural underpinnings of bodily self-consciousness has shifted the focus toward dysfunctional central nervous system circuits. The present article outlays both mind-based and brain-based views highlighting their shortcomings. We propose that full insight into what should be conceived a "xenomelia spectrum disorder" will require interpretation of individual symptomatology in a social context. A proper social neuroscience of xenomelia respects the functional neuroanatomy of corporeal awareness, but also acknowledges the brain's plasticity in response to an individual's history, which is lived against a cultural background. This integrated view of xenomelia will promote the subfield of consciousness research concerned with the unity of body and self. PMID- 23630514 TI - Impaired global, and compensatory local, biological motion processing in people with high levels of autistic traits. AB - People with Autism Spectrum Disorder (ASD) are hypothesized to have poor high level processing but superior low-level processing, causing impaired social recognition, and a focus on non-social stimulus contingencies. Biological motion perception provides an ideal domain to investigate exactly how ASD modulates the interaction between low and high-level processing, because it involves multiple processing stages, and carries many important social cues. We investigated individual differences among typically developing observers in biological motion processing, and whether such individual differences associate with the number of autistic traits. In Experiment 1, we found that individuals with fewer autistic traits were automatically and involuntarily attracted to global biological motion information, whereas individuals with more autistic traits did not show this pre attentional distraction. We employed an action adaptation paradigm in the second study to show that individuals with more autistic traits were able to compensate for deficits in global processing with an increased involvement in local processing. Our findings can be interpreted within a predictive coding framework, which characterizes the functional relationship between local and global processing stages, and explains how these stages contribute to the perceptual difficulties associated with ASD. PMID- 23630515 TI - The oscillatory entrainment of virtual pitch perception. AB - Evidence suggests that synchronized brain oscillations in the low gamma range (around 33 Hz) are involved in the perceptual integration of harmonic complex tones. This process involves the binding of harmonic components into "harmonic templates" - neural structures responsible for pitch coding in the brain. We investigated the hypothesis that oscillatory harmonic binding promotes a change in pitch perception style from spectral (frequency) to virtual (relational). Using oscillatory priming we asked 24 participants to judge as rapidly as possible, the direction of an ambiguous target with ascending spectral and descending virtual contour. They made significantly more virtual responses when primed at 29, 31, and 33 Hz and when the first target tone was harmonically related to the prime, suggesting that neural synchronization in the low gamma range could facilitate a shift toward virtual pitch processing. PMID- 23630516 TI - The psychology of eating. PMID- 23630517 TI - White-matter changes correlate with cognitive functioning in Parkinson's disease. AB - Diffusion tensor imaging (DTI) findings from emerging studies of cortical white matter integrity in Parkinson's disease (PD) without dementia are inconclusive. When white-matter changes have been found, their relationship to cognitive functioning in PD has not been carefully investigated. To better characterize changes in tissue diffusivity and to understand their functional significance, the present study conducted DTI in 25 PD patients without dementia and 26 controls of similar ages. An automated tract-based DTI method was used. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were analyzed. Neuropsychological measures of executive functioning (working memory, verbal fluency, cognitive flexibility, inhibitory control) and visuospatial ability were then correlated with regions of interest that showed abnormal diffusivity in the PD group. We found widespread reductions in FA and increases in MD in the PD group relative to controls. These changes were predominantly related to an increase in RD. Increased AD in the PD group was limited to specific frontal tracks of the right hemisphere, possibly signifying more significant tissue changes. Motor symptom severity did not correlate with FA. However, different measures of executive functioning and visuospatial ability correlated with FA in different segments of tracts, which contain fiber pathways to cortical regions that are thought to support specific cognitive processes. The findings suggest that abnormal tissue diffusivity may be sensitive to subtle cognitive changes in PD, some of which may be prognostic of future cognitive decline. PMID- 23630518 TI - ROS and Sympathetically Mediated Mitochondria Activation in Brown Adipose Tissue Contribute to Methamphetamine-Induced Hyperthermia. AB - Methamphetamine (Meth) abuse has been shown to induce alterations in mitochondrial function in the brain as well as to induce hyperthermia, which contributes to neurotoxicity and Meth-associated mortality. Brown adipose tissue (BAT), a thermogenic site known to be important in neonates, has recently regained importance since being identified in significant amounts and in correlation with metabolic balance in human adults. Given the high mitochondrial content of BAT and its role in thermogenesis, we aimed to investigate whether BAT plays any role in the development of Meth-induced hyperthermia. By ablating or denervating BAT, we identified a partial contribution of this organ to Meth induced hyperthermia. BAT ablation decreased temperature by 0.5 degrees C and reduced the length of hyperthermia by 1 h, compared to sham-operated controls. BAT denervation also affected the development of hyperthermia in correlation with decreased the expression of electron transport chain molecules, and increase on PCG1a levels, but without affecting Meth-induced uncoupling protein 1 upregulation. Furthermore, in isolated BAT cells in culture, Meth, but not Norepinephrine, induced H2O2 upregulation. In addition, we found that in vivo Reactive Oxygen Species (ROS) play a role in Meth hyperthermia. Thus, sympathetically mediated mitochondrial activation in the BAT and Meth-induced ROS are key components to the development of hyperthermia in Meth abuse. PMID- 23630520 TI - Ecology and management of grapevine leafroll disease. AB - Grapevine leafroll disease (GLD) is caused by a complex of vector-borne virus species in the family Closteroviridae. GLD is present in all grape-growing regions of the world, primarily affecting wine grape varieties. The disease has emerged in the last two decades as one of the major factors affecting grape fruit quality, leading to research efforts aimed at reducing its economic impact. Most research has focused on the pathogens themselves, such as improved detection protocols, with limited work directed toward disease ecology and the development of management practices. Here we discuss the ecology and management of GLD, focusing primarily on Grapevine leafroll-associated virus 3, the most important virus species within the complex. We contextualize research done on this system within an ecological framework that forms the backbone of the discussion regarding current and potential GLD management strategies. To reach this goal, we introduce various aspects of GLD biology and ecology, followed by disease management case studies from four different countries and continents (South Africa, New Zealand, California-USA, and France). We review ongoing regional efforts that serve as models for improved strategies to control this economically important and worldwide disease, highlighting scientific gaps that must be filled for the development of knowledge-based sustainable GLD management practices. PMID- 23630519 TI - Citrus tristeza virus: Evolution of Complex and Varied Genotypic Groups. AB - Amongst the Closteroviridae, Citrus tristeza virus (CTV) is almost unique in possessing a number of distinct and characterized strains, isolates of which produce a wide range of phenotype combinations among its different hosts. There is little understanding to connect genotypes to phenotypes, and to complicate matters more, these genotypes are found throughout the world as members of mixed populations within a single host plant. There is essentially no understanding of how combinations of genotypes affect symptom expression and disease severity. We know little about the evolution of the genotypes that have been characterized to date, little about the biological role of their diversity and particularly, about the effects of recombination. Additionally, genotype grouping has not been standardized. In this study we utilized an extensive array of CTV genomic information to classify the major genotypes, and to determine the major evolutionary processes that led to their formation and subsequent retention. Our analyses suggest that three major processes act on these genotypes: (1) ancestral diversification of the major CTV lineages, followed by (2) conservation and co evolution of the major functional domains within, though not between CTV genotypes, and (3) extensive recombination between lineages that have given rise to new genotypes that have subsequently been retained within the global population. The effects of genotype diversity and host-interaction are discussed, as is a proposal for standardizing the classification of existing and novel CTV genotypes. PMID- 23630521 TI - Chlorella mirabilis as a Potential Species for Biomass Production in Low Temperature Environment. AB - Successful adaptation/acclimatization to low temperatures in micro-algae is usually connected with production of specific biotechnologically important compounds. In this study, we evaluated the growth characteristics in a micro scale mass cultivation of the Antarctic soil green alga Chlorella mirabilis under different nitrogen and carbon sources followed by analyses of fatty acid contents. The micro-scale mass cultivation was performed in stable (in-door) and variable (out-door) conditions during winter and/or early spring in the Czech Republic. In the in-door cultivation, the treatments for nitrogen and carbon sources determination included pure Z medium (control, Z), Z medium + 5% glycerol (ZG), Z medium + 5% glycerol + 50 MUM KNO3 (ZGN), Z medium + 5% glycerol + 200 MUM NH4Cl (ZGA), Z medium + 5% glycerol + 1 mM Na2CO3 (ZNC), Z medium + 5% glycerol + 1 mM Na2CO3 + 200 MUM NH4Cl (ZGCA) and Z medium + 5% glycerol + 1 mM Na2CO3 + 50 MUM KNO3 (ZGCN) and were performed at 15 degrees C with an irradiance of 75 MUmol m(-2) s(-1). During the out-door experiments, the night-day temperature ranged from -6.6 to 17.5 degrees C (daily average 3.1 +/- 5.3 degrees C) and irradiance ranged from 0 to 2,300 MUmol m(-2) s(-1) (daily average 1,500 +/- 1,090 MUmol m(-2) s(-1)). Only the Z, ZG, ZGN, and ZGC treatments were used in the out-door cultivation. In the in-door mass cultivation, all nitrogen and carbon sources additions increased the growth rate with the exception of ZGA. When individual sources were considered, only the effect of 5% glycerol addition was significant. On the other hand, the growth rate decreased in the ZG and ZGN treatments in the out-door experiment, probably due to carbon limitation. Fatty acid composition showed increased production of linoleic acid in the glycerol treatments. The studied strain of C. mirabilis is proposed to be a promising source of linoleic acid in low-temperature-mass cultivation biotechnology. This strain is a perspective model organism for biotechnology in low-temperature conditions. PMID- 23630522 TI - The environmental bioinorganic chemistry of aquatic microbial organisms. PMID- 23630523 TI - Biogeography of Persephonella in deep-sea hydrothermal vents of the Western Pacific. AB - Deep-sea hydrothermal vent fields are areas on the seafloor with high biological productivity fueled by microbial chemosynthesis. Members of the Aquificales genus Persephonella are obligately chemosynthetic bacteria, and appear to be key players in carbon, sulfur, and nitrogen cycles in high temperature habitats at deep-sea vents. Although this group of bacteria has cosmopolitan distribution in deep-sea hydrothermal ecosystem around the world, little is known about their population structure such as intraspecific genomic diversity, distribution pattern, and phenotypic diversity. We developed the multi-locus sequence analysis (MLSA) scheme for their genomic characterization. Sequence variation was determined in five housekeeping genes and one functional gene of 36 Persephonella hydrogeniphila strains originated from the Okinawa Trough and the South Mariana Trough (SNT). Although the strains share >98.7% similarities in 16S rRNA gene sequences, MLSA revealed 35 different sequence types (ST), indicating their extensive genomic diversity. A phylogenetic tree inferred from all concatenated gene sequences revealed the clustering of isolates according to the geographic origin. In addition, the phenotypic clustering pattern inferred from whole-cell matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS) analysis can be correlated to their MLSA clustering pattern. This study represents the first MLSA combined with phenotypic analysis indicative of allopatric speciation of deep-sea hydrothermal vent bacteria. PMID- 23630524 TI - Immunodeficiency with autoimmunity: beyond the paradox. PMID- 23630525 TI - Properdin and factor h: opposing players on the alternative complement pathway "see-saw". AB - Properdin and factor H are two key regulatory proteins having opposite functions in the alternative complement pathway. Properdin up-regulates the alternative pathway by stabilizing the C3bBb complex, whereas factor H downregulates the pathway by promoting proteolytic degradation of C3b. While factor H is mainly produced in the liver, there are several extrahepatic sources. In addition to the liver, factor H is also synthesized in fetal tubuli, keratinocytes, skin fibroblasts, ocular tissue, adipose tissue, brain, lungs, heart, spleen, pancreas, kidney, muscle, and placenta. Neutrophils are the major source of properdin, and it is also produced by monocytes, T cells and bone marrow progenitor cell line. Properdin is released by neutrophils from intracellular stores following stimulation by N-formyl-methionine-leucine-phenylalanine (fMLP) and tumor necrosis factor alpha (TNF-alpha). The HEP G2 cells derived from human liver has been found to produce functional properdin. Endothelial cells also produce properdin when induced by shear stress, thus is a physiological source for plasma properdin. The diverse range of extrahepatic sites for synthesis of these two complement regulators suggests the importance and need for local availability of the proteins. Here, we discuss the significance of the local synthesis of properdin and factor H. This assumes greater importance in view of recently identified unexpected and novel roles of properdin and factor H that are potentially independent of their involvement in complement regulation. PMID- 23630527 TI - Caution Should be Used in the Recognition of Adult-Onset Autoinflammatory Disorders: Facts or Fiction? PMID- 23630526 TI - Innate and Adaptive Immunity in Long-Term Non-Progression in HIV Disease. AB - Long-term non-progressors (LTNP) were identified after 10-15 years of the epidemic, and have been the subject of intense investigation ever since. In a small minority of cases, infection with nef/3'LTR deleted attenuated viral strains allowed control over viral replication. A common feature of LTNP is the readily detected proliferation of CD4 T-cells in vitro, in response to p24. In some cases, the responding CD4 T-cells have cytotoxic effector function and may target conserved p24 epitopes, similar to the CD8 T-cells described below. LTNP may also carry much lower HIV DNA burden in key CD4 subsets, presumably resulting from lower viral replication during primary infection. Some studies, but not others, suggest that LTNP have CD4 T-cells that are relatively resistant to HIV infection in vitro. One possible mechanism may involve up-regulation of the cell cycle regulator p21/waf in CD4 T-cells from LTNP. Delayed progression in Caucasian LTNP is also partly associated with heterozygosity of the Delta32 CCR5 allele, probably through decreased expression of CCR5 co-receptor on CD4 T-cells. However, in approximately half of Caucasian LTNP, two host genotypes, namely HLA B57 and HLA-B27, are associated with viral control. Immunodominant CD8 T-cells from these individuals target epitopes in p24 that are highly conserved, and escape mutations have significant fitness costs to the virus. Furthermore, recent studies have suggested that these CD8 T-cells from LTNP, but not from HLA-B27 or HLA-B57 progressors, can cross-react with intermediate escape mutations, preventing full escape via compensatory mutations. Humoral immunity appears to play little part in LTNP subjects, since broadly neutralizing antibodies are rare, even amongst slow progressors. Recent genome-wide comparisons between LTNP and progressors have confirmed the HLA-B57, HLA-B27, and delta32 CCR5 allelic associations, plus indicated a role for HLA-C/KIR interactions, but have not revealed any new genotypes so far. Nevertheless, it is hoped that studying the mechanisms of intracellular restriction factors, such as the recently identified SAMHD1, will lead to a better understanding of non-progression. PMID- 23630529 TI - Deciphering new molecular mechanisms of mast cell activation. PMID- 23630528 TI - Ca(2+) influx in T cells: how many ca(2+) channels? PMID- 23630530 TI - E-2-hexenal promotes susceptibility to Pseudomonas syringae by activating jasmonic acid pathways in Arabidopsis. AB - Green leaf volatiles (GLVs) are C6-molecules - alcohols, aldehydes, and esters - produced by plants upon herbivory or during pathogen infection. Exposure to this blend of volatiles induces defense-related responses in neighboring undamaged plants, thus assigning a role to GLVs in regulating plant defenses. Here we compared Arabidopsis thaliana ecotype Landsberg erecta (Ler) with a hydroperoxide lyase line, hpl1, unable to synthesize GLVs, for susceptibility to Pseudomonas syringae pv. tomato (DC3000). We found that the growth of DC3000 was significantly reduced in the hpl1 mutant. This phenomenon correlated with lower jasmonic acid (JA) levels and higher salicylic acid levels in the hpl1 mutant. Furthermore, upon infection, the JA-responsive genes VSP2 and LEC were only slightly or not induced, respectively, in hpl1. This suggests that the reduced growth of DC3000 in hpl1 plants is due to the constraint of JA-dependent responses. Treatment of hpl1 plants with E-2-hexenal, one of the more reactive GLVs, prior to infection with DC3000, resulted in increased growth of DC3000 in hpl1, thus complementing this mutant. Interestingly, the growth of DC3000 also increased in Ler plants treated with E-2-hexenal. This stronger growth was not dependent on the JA-signaling component MYC2, but on ORA59, an integrator of JA and ethylene signaling pathways, and on the production of coronatine by DC3000. GLVs may have multiple effects on plant-pathogen interactions, in this case reducing resistance to Pseudomonas syringae via JA and ORA59. PMID- 23630531 TI - Metabolomics of cereals under biotic stress: current knowledge and techniques. AB - Prone to attacks by pathogens and pests, plants employ intricate chemical defense mechanisms consisting of metabolic adaptations. However, many plant attackers are manipulating the host metabolism to counteract defense responses and to induce favorable nutritional conditions. Advances in analytical chemistry have allowed the generation of extensive metabolic profiles during plant-pathogen and pest interactions. Thereby, metabolic processes were found to be highly specific for given tissues, species, and plant-pathogen/pest interactions. The clusters of identified compounds not only serve as base in the quest of novel defense compounds, but also as markers for the characterization of the plants' defensive state. The latter is especially useful in agronomic applications where meaningful markers are essential for crop protection. Cereals such as maize make use of their metabolic arsenal during both local and systemic defense responses, and the chemical response is highly adapted to specific attackers. Here, we summarize highlights and recent findings of metabolic patterns of cereals under pathogen and pest attack. PMID- 23630532 TI - Plant systemic induced responses mediate interactions between root parasitic nematodes and aboveground herbivorous insects. AB - Insects and nematodes are the most diverse and abundant groups of multicellular animals feeding on plants on either side of the soil-air interface. Several herbivore-induced responses are systemic, and hence can influence the preference and performance of organisms in other plant organs. Recent studies show that plants mediate interactions between belowground plant parasitic nematodes (PPNs) and aboveground herbivorous insects. Based on the knowledge of plant responses to pathogens, we review the emerging insights on plant systemic responses against root-feeding nematodes and shoot-feeding insects. We discuss the potential mechanisms of plant-mediated indirect interactions between both groups of organisms and point to gaps in our knowledge. Root-feeding nematodes can positively or negatively affect shoot herbivorous insects, and vice versa. The outcomes of the interactions between these spatially separated herbivore communities appear to be influenced by the feeding strategy of the nematodes and the insects, as well as by host plant susceptibility to both herbivores. The potential mechanisms for these interactions include systemic induced plant defense, interference with the translocation and dynamics of locally induced secondary metabolites, and reallocation of plant nutritional reserves. During evolution, PPNs as well as herbivorous insects have acquired effectors that modify plant defense responses and resource allocation patterns to their advantage. However, it is also known that plants under herbivore attack change the allocation of their resources, e.g., for compensatory growth responses, which may affect the performance of other organisms feeding on the plant. Studying the chemical and molecular basis of these interactions will reveal the molecular mechanisms that are involved. Moreover, it will lead to a better understanding of the ecological relevance of aboveground-belowground interactions, as well as support the development of sustainable pest management technologies. PMID- 23630533 TI - The Arabidopsis NIMIN proteins affect NPR1 differentially. AB - NON-EXPRESSOR OF PATHOGENESIS-RELATED GENES1 (NPR1) is the central regulator of the pathogen defense reaction systemic acquired resistance (SAR). NPR1 acts by sensing the SAR signal molecule salicylic acid (SA) to induce expression of PATHOGENESIS-RELATED (PR) genes. Mechanistically, NPR1 is the core of a transcription complex interacting with TGA transcription factors and NIM1 INTERACTING (NIMIN) proteins. Arabidopsis NIMIN1 has been shown to suppress NPR1 activity in transgenic plants. The Arabidopsis NIMIN family comprises four structurally related, yet distinct members. Here, we show that NIMIN1, NIMIN2, and NIMIN3 are expressed differentially, and that the encoded proteins affect expression of the SAR marker PR-1 differentially. NIMIN3 is expressed constitutively at a low level, but NIMIN2 and NIMIN1 are both responsive to SA. While NIMIN2 is an immediate early SA-induced and NPR1-independent gene, NIMIN1 is activated after NIMIN2, but clearly before PR-1. Notably, NIMIN1, like PR-1, depends on NPR1. In a transient assay system, NIMIN3 suppresses SA-induced PR-1 expression, albeit to a lesser extent than NIMIN1, whereas NIMIN2 does not negatively affect PR-1 gene activation. Furthermore, although binding to the same domain in the C-terminus, NIMIN1 and NIMIN2 interact differentially with NPR1, thus providing a molecular basis for their opposing effects on NPR1. Together, our data suggest that the Arabidopsis NIMIN proteins are regulators of the SAR response. We propose that NIMINs act in a strictly consecutive and SA-regulated manner on the SA sensor protein NPR1, enabling NPR1 to monitor progressing threat by pathogens and to promote appropriate defense gene activation at distinct stages of SAR. In this scenario, the defense gene PR-1 is repressed at the onset of SAR by SA-induced, yet instable NIMIN1. PMID- 23630534 TI - The xylem as battleground for plant hosts and vascular wilt pathogens. AB - Vascular wilts are among the most destructive plant diseases that occur in annual crops as well as in woody perennials. These diseases are generally caused by soil borne bacteria, fungi, and oomycetes that infect through the roots and enter the water-conducting xylem vessels where they proliferate and obstruct the transportation of water and minerals. As a consequence, leaves wilt and die, which may lead to impairment of the whole plant and eventually to death of the plant. Cultural, chemical, and biological measures to control this group of plant pathogens are generally ineffective, and the most effective control strategy is the use of genetic resistance. Owing to the fact that vascular wilt pathogens live deep in the interior of their host plants, studies into the biology of vascular pathogens are complicated. However, to design novel strategies to combat vascular wilt diseases, understanding the (molecular) biology of vascular pathogens and the molecular mechanisms underlying plant defense against these pathogens is crucial. In this review, we discuss the current knowledge on interactions of vascular wilt pathogens with their host plants, with emphasis on host defense responses against this group of pathogens. PMID- 23630535 TI - Arabidopsis peroxisome proteomics. AB - The analytical depth of investigation of the peroxisomal proteome of the model plant Arabidopsis thaliana has not yet reached that of other major cellular organelles such as chloroplasts or mitochondria. This is primarily due to the difficulties associated with isolating and obtaining purified samples of peroxisomes from Arabidopsis. So far only a handful of research groups have been successful in obtaining such fractions. To make things worse, enriched peroxisome fractions frequently suffer from significant organellar contamination, lowering confidence in localization assignment of the identified proteins. As with other cellular compartments, identification of peroxisomal proteins forms the basis for investigations of the dynamics of the peroxisomal proteome. It is therefore not surprising that, in terms of functional analyses by proteomic means, peroxisomes are lagging considerably behind chloroplasts or mitochondria. Alternative strategies are needed to overcome the obstacle of hard-to-obtain organellar fractions. This will help to close the knowledge gap between peroxisomes and other organelles and provide a full picture of the physiological pathways shared between organelles. In this review, we briefly summarize the status quo and discuss some of the methodological alternatives to classic organelle proteomic approaches. PMID- 23630536 TI - Phloem parenchyma transfer cells in Arabidopsis - an experimental system to identify transcriptional regulators of wall ingrowth formation. AB - In species performing apoplasmic loading, phloem cells adjacent to sieve elements often develop into transfer cells (TCs) with wall ingrowths. The highly invaginated wall ingrowths serve to amplify plasma membrane surface area to achieve increased rates of apoplasmic transport, and may also serve as physical barriers to deter pathogen invasion. Wall ingrowth formation in TCs therefore plays an important role in phloem biology, however, the transcriptional switches regulating the deposition of this unique example of highly localized wall building remain unknown. Phloem parenchyma (PP) TCs in Arabidopsis veins provide an experimental system to identify such switches. The extent of ingrowth deposition responds to various abiotic and applied stresses, enabling bioinformatics to identify candidate regulatory genes. Furthermore, simple fluorescence staining of PP TCs in leaves enables phenotypic analysis of relevant mutants. Combining these approaches resulted in the identification of GIGANTEA as a regulatory component in the pathway controlling wall ingrowth development in PP TCs. Further utilization of this approach has identified two NAC (NAM, ATAF1/2 and CUC2)-domain and two MYB-related genes as putative transcriptional switches regulating wall ingrowth deposition in these cells. PMID- 23630537 TI - Spatial patterns of ectomycorrhizal assemblages in a monospecific forest in relation to host tree genotype. AB - Ectomycorrhizas (EcM) are important for soil exploration and thereby may shape belowground interactions of roots. We investigated the composition and spatial structures of EcM assemblages in relation to host genotype in an old-growth, monospecific beech (Fagus sylvatica) forest. We hypothesized that neighboring roots of different beech individuals are colonized by similar EcM assemblages if host genotype had no influence on the fungal colonization and that the similarity would decrease with increasing distance of the sampling points. The alternative was that the EcM species showed preferences for distinct beech genotypes resulting in intraspecific variation of EcM-host assemblages. EcM species identities, abundance and exploration type as well as the genotypes of the colonized roots were determined in each sampling unit of a 1 L soil core (r = 0.04 m, depth 0.2 m). The Morisita-Horn similarity indices (MHSI) based on EcM species abundance and multiple community comparisons were calculated. No pronounced variation of MHSI with increasing distances of the sampling points within a plot was found, but variations between plots. Very high similarities and no between plot variation were found for MHSI based on EcM exploration types suggesting homogenous soil foraging in this ecosystem. The EcM community on different root genotypes in the same soil core exhibited high similarity, whereas the EcM communities on the root of the same tree genotype in different soil cores were significantly dissimilar. This finding suggests that spatial structuring of EcM assemblages occurs within the root system of an individual. This may constitute a novel, yet unknown mechanism ensuring colonization by a diverse EcM community of the roots of a given host individual. PMID- 23630538 TI - Genomic heterogeneity and structural variation in soybean near isogenic lines. AB - Near isogenic lines (NILs) are a critical genetic resource for the soybean research community. The ability to identify and characterize the genes driving the phenotypic differences between NILs is limited by the degree to which differential genetic introgressions can be resolved. Furthermore, the genetic heterogeneity extant among NIL sub-lines is an unaddressed research topic that might have implications for how genomic and phenotypic data from NILs are utilized. In this study, a recently developed high-resolution comparative genomic hybridization (CGH) platform was used to investigate the structure and diversity of genetic introgressions in two classical soybean NIL populations, respectively varying in protein content and iron deficiency chlorosis (IDC) susceptibility. There were three objectives: assess the capacity for CGH to resolve genomic introgressions, identify introgressions that are heterogeneous among NIL sub lines, and associate heterogeneous introgressions with susceptibility to IDC. Using the CGH approach, introgression boundaries were refined and previously unknown introgressions were revealed. Furthermore, heterogeneous introgressions were identified within seven sub-lines of the IDC NIL "IsoClark." This included three distinct introgression haplotypes linked to the major iron susceptible locus on chromosome 03. A phenotypic assessment of the seven sub-lines did not reveal any differences in IDC susceptibility, indicating that the genetic heterogeneity among the lines does not have a significant impact on the primary NIL phenotype. PMID- 23630539 TI - Maintenance of xylem Network Transport Capacity: A Review of Embolism Repair in Vascular Plants. AB - Maintenance of long distance water transport in xylem is essential to plant health and productivity. Both biotic and abiotic environmental conditions lead to embolism formation within the xylem resulting in lost transport capacity and ultimately death. Plants exhibit a variety of strategies to either prevent or restore hydraulic capacity through cavitation resistance with specialized anatomy, replacement of compromised conduits with new growth, and a metabolically active embolism repair mechanism. In recent years, mounting evidence suggests that metabolically active cells surrounding the xylem conduits in some, but not all, species are capable of restoring hydraulic conductivity. This review summarizes our current understanding of the osmotically driven embolism repair mechanism, the known genetic and anatomical components related to embolism repair, rehydration pathways through the xylem, and the role of capacitance. Anatomical differences between functional plant groups may be one of the limiting factors that allow some plants to refill while others do not, but further investigations are necessary to fully understand this dynamic process. Finally, xylem networks should no longer be considered an assemblage of dead, empty conduits, but instead a metabolically active tissue finely tuned to respond to ever changing environmental cues. PMID- 23630540 TI - When proteomics reveals unsuspected roles: the plastoglobule example. AB - Plastoglobules are globular compartments found in plastids. Before initial proteomic studies were published, these particles were often viewed as passive lipid droplets whose unique role was to store lipids coming from the thylakoid turn-over, or to accumulate carotenoids in the chromoplasts. Yet, two proteomic studies, published concomitantly, suggested for the first time that plastoglobules are more than "junk cupboards" for lipids. Indeed, both studies demonstrated that plastoglobules do not only include structural proteins belonging to the plastoglobulin/fibrillin family, but also contain active enzymes. The specific plastoglobule localization of these enzymes has been confirmed by different approaches such as immunogold localization and GFP protein fusions, thus providing evidence that plastoglobules actively participate in diverse pathways of plastid metabolism. These proteomic studies have been the basis for numerous recent works investigating plastoglobule function. However, a lot still needs to be discovered about the molecular composition and the role of plastoglobules. In this chapter, we will describe how the proteomic approaches have launched new perspectives on plastoglobule functions. PMID- 23630541 TI - miR-221 affects multiple cancer pathways by modulating the level of hundreds messenger RNAs. AB - microRNA miR-221 is frequently over-expressed in a variety of human neoplasms. Aim of this study was to identify new miR-221 gene targets to improve our understanding on the molecular tumor-promoting mechanisms affected by miR-221. Gene expression profiling of miR-221-transfected-SNU-398 cells was analyzed by the Sylamer algorithm to verify the enrichment of miR-221 targets among down modulated genes. This analysis revealed that enforced expression of miR-221 in SNU-398 cells caused the down-regulation of 602 mRNAs carrying sequences homologous to miR-221 seed sequence within their 3'UTRs. Pathways analysis performed on these genes revealed their prominent involvement in cell proliferation and apoptosis. Activation of E2F, MYC, NFkB, and beta-catenin pathways was experimentally proven. Some of the new miR-221 target genes, including RB1, WEE1 (cell cycle inhibitors), APAF1 (pro-apoptotic), ANXA1, CTCF (transcriptional repressor), were individually validated as miR-221 targets in SNU-398, HepG2, and HEK293 cell lines. By identifying a large set of miR-221 gene targets, this study improves our knowledge about miR-221 molecular mechanisms involved in tumorigenesis. The modulation of mRNA level of 602 genes confirms the ability of miR-221 to promote cancer by affecting multiple oncogenic pathways. PMID- 23630542 TI - Uncertainty and certainty in cellular dynamics. PMID- 23630544 TI - Role of T-cell epitope-based vaccine in prophylactic and therapeutic applications. AB - Prophylactic and therapeutic vaccines against viral infections have advanced in recent years from attenuated live vaccines to subunit-based vaccines. An ideal prophylactic vaccine should mimic the natural immunity induced by an infection, in that it should generate long-lasting adaptive immunity. To complement subunit vaccines, which primarily target an antibody response, different methodologies are being investigated to develop vaccines capable of driving cellular immunity. T-cell epitope discovery is central to this concept. In this review, the significance of T-cell epitope-based vaccines for prophylactic and therapeutic applications is discussed. Additionally, methodologies for the discovery of T cell epitopes, as well as recent developments in the clinical testing of these vaccines for various viral infections, are explained. PMID- 23630546 TI - Treatment-enhanced paired action contributes substantially to change across multiple health behaviors: secondary analyses of five randomized trials. AB - The dominant paradigm of changing multiple health behaviors (MHBs) is based on treating, assessing, and studying each behavior separately. This study focused on individuals with co-occurring baseline health-risk behavior pairs and described whether they changed over time on both or only one of the behaviors within each pair. Data from five randomized trials of computer-tailored interventions (CTIs) that simultaneously treated MHBs were analyzed. The differences between treatment and control proportions that achieved paired action and singular action at 24 months follow-up, and the proportional contribution of paired action to overall change on each behavior, were assessed across 12 behavior pairs (including energy balance, addictive, and appearance-related behaviors). CTIs consistently produced more paired action across behavior pairs. Paired action contributed substantially more to the treatment-related outcomes than singular action. Studying concurrent changes on MHBs as demonstrated allows the effect of simultaneously treating MHBs to be assessed. PMID- 23630547 TI - Fast track in large intestine surgery - review of randomized clinical trials. AB - Fast track surgery is a specific perioperative procedure. Its aim is to reduce the number of complications, to improve the comfort and satisfaction of treated patients and to shorten the time of their hospital stay. In this paper we present randomized clinical trials relating to fast track surgery including patients after colorectal resection. PMID- 23630545 TI - Mechanisms of oxysterol-induced disease: insights from the biliary system. AB - Oxysterols are oxidized species of cholesterol that are derived from exogenous (e.g. dietary) and endogenous (in vivo) sources. Oxysterols play critical roles in normal physiologic functions as well as in pathophysiologic processes in a variety of organ systems. This review provides an overview of oxysterol biology from the vantage point of the biliary system. Several oxysterols have been identified in human bile in the context of biliary tract infection and inflammation. This finding has led to investigations regarding the potential pathophysiologic significance of biliary oxysterols in diseases affecting the biliary system, with an emphasis on cholangiocarcinoma. Emerging evidence implicates specific oxysterols in the development and progression of this malignancy. This review will summarize the literature on oxysterols in the biliary system and discuss how the accumulated evidence contributes to a hypothesis describing the molecular basis of cholangiocarcinogenesis. PMID- 23630548 TI - Laparoscopic surgery of the spleen through single umbilical incision. AB - INTRODUCTION: Single incision transumbilical laparoscopic procedures are the next step in development of minimally invasive surgery. Recent studies prove that the new technique can be a safe alternative to multiport laparoscopy; therefore it is becoming more and more popular. AIM: We present our preliminary experience with single incision laparoscopy of the spleen. MATERIAL AND METHODS: We analyse a group of 9 patients (7 women and 2 men) in whom we attempted single incision laparoscopic surgery of the spleen. RESULTS: Single incision laparoscopy was successful in all patients - in 7 of them we performed splenectomy and in 2 unroofing of the splenic cyst. Additionally, in 3 patients we performed concomitant cholecystectomy. The operative technique was identical to multiport procedures. One patient required reoperation due to intra-abdominal bleeding from the wound on the first postoperative day. In one patient due to superficial injury of the stomach wall continuous suture was used to prevent perforation. In our opinion these complications are not the result of the new technique. CONCLUSIONS: The described technique can become a safe alternative to multiport laparoscopy. It is a reasonable alternative in young patients to whom an excellent cosmetic effect is particularly important because until now it is the only documented advantage of this surgical technique. PMID- 23630549 TI - Metabolic changes one year after laparoscopic adjustable gastric banding operation in morbidly obese subjects. AB - INTRODUCTION: Laparoscopic adjustable gastric banding (LAGB) is effective for weight reduction in severely obese patients. However, the data about its effect on metabolic syndrome (MS) are limited. AIM: To assess weight loss and changes of metabolic parameters 1 year after LAGB in a prospective, nonrandomized single center cohort study in morbidly obese subjects. MATERIAL AND METHODS: Physical examination, body weight (BW) parameters and metabolic profile were assessed at baseline and 1 year after LAGB in morbidly obese subjects. The incidence of MS was evaluated according to National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: One year after the operation data from 90 patients out of 103 were available. Mean excess weight (EW) loss of 33.1% was associated with a significant improvement in all metabolic parameters: decrease of hypertension by 15.8%, hypertriglyceridemia by 42.6%, and hyperglycemia by 46.3%; and increase in high density lipoprotein cholesterol by 48.3%. This resulted in the resolution of MS in 44.2% of subjects. The significant change in the distribution of MS components was observed with the highest frequency of 4 components before and 2 components after surgery. Patients with MS at baseline lost 29.9% of EW compared to 44.3% in those without MS (p = 0.009). CONCLUSIONS: The LAGB resulted in effective reduction of BW parameters in morbidly obese subjects 1 year after the operation. Along with the weight loss, resolution of MS and a significant shift towards decrease in the number of MS components was observed. Patients with MS were more resistant to the weight loss. PMID- 23630550 TI - Effects of sleeve gastrectomy on parameters of lipid and glucose metabolism in obese women - 6 months after operation. AB - INTRODUCTION: Surgical intervention in obesity is today the most effective treatment method in high level obesity management with long-term clinical results and satisfaction of operated patients. Bariatric interventions not only ensure body weight reduction, but may influence lipid and saccharide metabolism as well. AIM: To monitor the dynamics of changes in selected lipid and glucose metabolism parameters after laparoscopic sleeve gastrectomy (LSG) in obese women. MATERIAL AND METHODS: During the period from September 2010 to June 2011, 35 women, operated on by sleeve gastrectomy, were monitored within a pilot open study. Parameters of lipid and glucose metabolism were measured, and body composition was evaluated, using dual X-ray absorptiometry (DXA). Laboratory parameters were assessed prior to LSG and at 3 and 6 months after the surgery. RESULTS: Data of the 35 study subjects are presented. Average age was 41.9 years (27-68 years). Six months after LSG, body weight reduction was achieved from 117.7 +/-17.1 kg to 91.2 +/-17.2 kg (p < 0.001). The body mass index (BMI) dropped from 42.7 +/-4.7 kg/m(2) to 33.0 +/-4.9 kg/m(2) (p < 0.001). The excess weight loss (EWL) was 49.01%. High density lipoprotein (HDL) cholesterol increased from 1.29 mmol/l to 1.39 mmol/l (p < 0.025). Triacylglycerols dropped from 1.97 mmol/l to 1.31 mmol/l (p < 0.001). Glycated hemoglobin dropped from 4.03% to 3.59% (p < 0.001), and C peptide decreased from 1703 pmol/l to 1209 pmol/l (p < 0.002). The observed changes of low density lipoprotein (LDL) cholesterol, total cholesterol or fasting glucose levels were not significant. Six months after LSG, both weight and BMI significantly decreased. CONCLUSIONS: Six months after the operation, glucose homeostasis was improved. Despite the rather short-term monitoring period, our study did confirm LSG to influence not only total weight loss and fat tissue reduction but to improve risk factors, mainly glucose homeostasis and dyslipidemia, as well. PMID- 23630551 TI - Minimally invasive retroperitoneal necrosectomy in management of acute necrotizing pancreatitis. AB - INTRODUCTION: One of the most important requirements in treatment of acute necrotizing pancreatitis is minimized invasion. AIM: We are presenting experience in treatment of acute necrotizing pancreatitis by an original minimally invasive retroperitoneal necrosectomy technique, comparing our results to other studies, evaluating feasibility and safety, discussing advantages and disadvantages of this method. MATERIAL AND METHODS: We performed a retrospective analysis of 13 patients who had acute necrotizing pancreatitis with large fluid collections in retroperitoneal space and underwent retroperitoneal necrosectomy. RESULTS: There were eight males and three females aged between 24 and 60 years, average age was 42.8 +/-9.2 years. The most common cause of pancreatitis was alcohol, 10 patients (76.9%). Average time between diagnosis and performance of operation was 25.7 +/ 11.3 days. One patient underwent eight repeated interventions: two retroperitoneal necrosectomies; five laparotomies; ultrasound-guided drainage. One patient underwent four reinterventions: lumbotomy; revision; two lavages. Three patients had two reinterventions: one had laparotomy and tamponation; one had two repeated retroperitoneal necrosectomies; third had one repeated retroperitoneal necrosectomy and one had ultrasound-guided drainage. Three patients needed one additional retroperitoneal necrosectomy. Five patients did not required additional interventions. 61.5% of our patients did not require more than one reintervention. Postoperative stay varied from 9 to 94 days, average 50.8 +/-32.6 days. CONCLUSIONS: Minimally invasive techniques should be considered as first-choice surgical option in treating patients with acute necrotizing pancreatitis. Pancreatic necrosis occupying less than 30% and with massive fluid collections in the left retroperitoneal space can be safely managed by minimally invasive retroperitoneal necrosectomy. PMID- 23630552 TI - Effectiveness of Lichtenstein repairs in planned treatment of giant inguinal hernia - own experience. AB - INTRODUCTION: Occurrence of giant inguinal hernias is not frequent because of growing medical awareness in the community as well as progress in surgical treatment in this field. AIM: To evaluate the effectiveness of repairs using the Lichtenstein technique in scheduled treatment of giant inguinal hernias. MATERIAL AND METHODS: Between 2006 and 2010 in the Department of Surgery with the Subdepartment of Proctology, Hospital at Solec in Warsaw, 909 repairs of inguinal hernia were performed, including 15 patients (1.65%) with the diagnosis of giant hernia. In 3 cases it was direct inguinal hernia and in 12 cases indirect inguinal hernia. All giant hernias occurred in male patients between 33 and 87 years of age (mean age 65 years old) and developed for many years, median of 14.2 years. All patients underwent scheduled repairs using the tension-free Lichtenstein technique. A non-absorbable polypropylene mesh was used for hernioplasty. Exact Fisher's test (p < 0.01) was used for statistical analysis. RESULTS: In all cases contents of the hernial sac consisted of loops of small intestine, colon and omentum. Early complications occurred in 11 patients (73%) in the group of patients with giant hernias, whereas in the remaining group of patients early complications occurred in 53 patients (5.9%). The difference was statistically significant. In the group of patients with giant hernias no recurrence was observed over the observation period ranging from 6 months to 4.5 years. In the remaining group of patients recurrences occurred in 23 patients (2.6%). CONCLUSIONS: The Lichtenstein technique of repair is effective in management of giant inguinal hernias. A statistically significantly higher percentage of complications was observed in the group of patients with giant hernias as compared to the remaining group of patients with inguinal hernias. Patients with giant hernias require proper preparation for surgery, especially in relation to their respiratory efficiency. PMID- 23630553 TI - Bipolar radiofrequency-induced thermotherapy of haemorrhoids: a new minimally invasive method for haemorrhoidal disease treatment. Early results of a pilot study. AB - INTRODUCTION: Haemorrhoidal disease is the most frequent benign anorectal disease. Conservative, minimally invasive and surgical methods are used in the treatment of haemorrhoidal disease. Radiofrequency thermoablation is a popular new technique in the treatment of varicose veins. AIM: Assessment of the use of the method in the treatment of haemorrhoidal disease using bipolar radiofrequency induced thermotherapy (RFITT or so-called Celon method). MATERIAL AND METHODS: We used the CelonLab PRECISION (Celon AG medical instruments, Teltow, Germany) with the bipolar RFITT applicator Celon ProBREATH for the treatment of haemorrhoidal disease stages III and IV. RESULTS: In the Department of Surgery at the Atlas Hospital in Zlin, Czech Republic, a total of 71 patients were treated from 9/2007 to 10/2010 with this new treatment approach. The success rate was 100%, local recurrence rate was 2.8%, and medium-term satisfaction of patients who underwent the procedure was 99.5%. Complications appeared in 4.26% of cases. CONCLUSIONS: The new RFITTH technique for treatment of advanced stages of haemorrhoidal disease is a new treatment modality with good curative response, low level of complications, minimum pain and quick return of patients to their usual activities. PMID- 23630554 TI - Managing urine leakage following laparoscopic radical prostatectomy with active suction of the prevesical space. AB - INTRODUCTION: Urine leakage following laparoscopic radical prostatectomy (LRP) is a possible complication that may herald chronic urine incontinence. Intraoperative measures aiming to prevent this is not standardised. AIM: Presentation of experience with active suction of the prevesical space in managing postoperative urine leakage. MATERIAL AND METHODS: At the Department of Urology, where laparoscopy of the upper abdomen and open RP were performed, a protocol for extraperitoneal LRP was established in 8/2008. Until 5/2011, 154 LRPs have been performed. Urine leakage from a suction drain appeared in 9 cases (5.8%). Permanent active suction (with a machine for Bullae thoracic drainage) of the prevesical space with negative pressure of 7-12 cm of H2O was started immediately. RESULTS: Urine leakage started after a mean of 0.9 (0-2) days postoperatively and stopped after a mean of 8.1 (15-42) days. Leakage stopped with only suctioning in 7 cases. In one case, open re-anastomosis was performed on the 7(th) postoperative day (POD). In another case, ineffective active suction was replaced on the 10(th) POD by needle vented suction without effect and the leakage stopped following gradual shortening of the drain up to the 15(th) POD. CONCLUSIONS: Active suction of the prevesical space seems to be an effective intervention to stop postoperative urine leakage after laparoscopic radical prostatectomy. PMID- 23630555 TI - The use of magnetic resonance mammography in women at increased risk for developing breast cancer. AB - INTRODUCTION: The use of conventional imaging techniques, namely mammography (MMG) and ultrasound (US), for breast cancer (BC) detection in women at high risk for the disease does not bring optimal results in many cases. AIM: The present study evaluated the effectiveness of magnetic resonance (MR) mammography (MRM) in cases where US and MMG failed to detect suspected breast lesions. MATERIAL AND METHODS: The study group consisted of 379 women who had had no breast pathologies detected by US and MMG. This group was then divided into 4 groups according to the relative risk of breast cancer development. All the women underwent MRM, and any breast pathology detected by MRM was then verified by open surgical biopsy (OSB). RESULTS: Based on the MRM findings, 37 women with breast pathologies were identified. All detected pathologies were then classified into one of the BIRADS (Breast Imaging Reporting and Data System) categories. Of these, 33 patients underwent open surgical biopsy. There were a total of 17 benign and 16 malignant breast pathologies that were not visualized by US and MMG. The types of malignancies found, in order of their frequency, were as follows: invasive ductal carcinoma (11 cases), ductal carcinoma in situ (2 cases), invasive lobular carcinoma (2 cases), and lobular carcinoma in situ (1 case). An analysis of MRM effectiveness in detecting BC showed 93.7% sensitivity and 64.71% specificity. CONCLUSIONS: All women with a 20% or greater lifetime risk of developing BC should undergo annual MRM as a diagnostic adjunct to US and MMG. PMID- 23630556 TI - Ultrasound-guided vacuum-assisted core biopsy in the diagnosis and treatment of focal lesions of the breast - own experience. AB - INTRODUCTION: Vacuum-assisted core biopsy (VACB) guided by ultrasound is a minimally invasive method used in diagnosis and treatment of breast focal lesions. Vacuum-assisted core biopsy is an interesting minimally invasive alternative to open surgical biopsy. AIM: To assess the value of ultrasound guided vacuum-assisted core biopsy in the diagnosis and treatment of breast focal lesions. MATERIAL AND METHODS: In the period 2009-2010, 397 ultrasound-guided vacuum-assisted core biopsies were performed. Mean age of the patients was 41.7 years (18-92 years), and size of the lesions ranged from 3 mm to 65 mm, mean size being 12 mm. All women with diagnosed atypical ductal hyperplasia or cancer were qualified for surgery. The patients with histopathologically benign lesions were under follow-up. RESULTS: Samples sufficient for histopathological examination were obtained from 394 cases (99.2%). Of all 397 lesions, 293 (73.7%) were diagnosed as benign, there were 6 (1.6%) cases of atypical ductal hyperplasia and 98 (24.7%) malignant lesions. Three hundred and sixty-nine lesions were below 15 mm in diameter, of which 339 (91.9%) were totally removed during the VACB. CONCLUSIONS: The results obtained confirm high efficiency of ultrasound-guided VACB in the differential diagnosis of breast focal lesions, including impalpable ones. It is a safe method with a low complication rate. In the case of benign lesions with a diameter not exceeding 15 mm, it allows one to excise the whole lesion and is a very good alternative to an open surgical biopsy. Vacuum-assisted core biopsy should be a standard and the method of choice in diagnosing breast lesions. PMID- 23630557 TI - Analysis of intracorporeal knotting with invaginating suture versus endoloops in appendiceal stump closure. AB - INTRODUCTION: Laparoscopic appendectomy is a well-described surgical technique and has gained wide clinical acceptance. Laparoscopic appendectomy offers fewer wound infections, faster recovery and an earlier return to work in comparison to open surgery. However, concerns still exist regarding the appendiceal stump closure. AIM: The aim of this study was to compare the overall incidence and specific intraoperative and postoperative complications after application of intracorporeal knotting with invaginating suture versus endoloops for stump closure in laparoscopic appendectomy. MATERIAL AND METHODS: ONE HUNDRED FIFTY TWO CONSECUTIVE PATIENTS ACCORDING TO THE FOLLOWING INCLUSION CRITERIA WERE INCLUDED IN THE STUDY: 1. Laparoscopic appendectomy was performed during the study period; 2. Acute phlegmonous or gangrenous appendicitis without perforation was diagnosed during operation. Exclusion criteria - patients with acute perforated appendicitis and local or diffuse peritonitis. Data was grouped according to the appendiceal stump closure technique, with either endoloops - 112 patients (73.7 percent) or intracorporeal knotting with invaginating suture - 40 patients (26.3 per cent). The primary outcome measure was the rate of intraabdominal surgical site infection, defined as post-operative intra-abdominal abscess. Secondary outcome variables were intraoperative and postoperative complications, duration of operation, hospital stay. RESULTS: There were no significant differences between the two groups in overall intraoperative and postoperative complications rate and in hospital stay. The median duration of operation was significantly shorter when the endoloop was used. The use of intracorporeal knotting with invaginating suture instead of endoloop to close the appendiceal stump decreased the total cost of laparoscopic appendectomy. CONCLUSIONS: According our study results, intracorporeal knotting with invaginating suture appendiceal stump closure technique is acceptable laparoscopic procedure, which intraoperative and postoperative results do not differ from endoloops technique. The total cost of this procedure is 80 ? cheaper then endoloops technique. PMID- 23630558 TI - Surgical pitfalls of minimally invasive direct coronary artery bypass procedure from the viewpoint of a surgeon in the learning curve. AB - INTRODUCTION: Minimally invasive direct coronary artery bypass grafting (MIDCAB) offers arterial revascularization of the left anterior descending (LAD) coronary artery especially in lesions unsuitable for percutaneous coronary interventions. By avoidance of sternotomy and cardiopulmonary bypass its invasiveness is less than that of conventional bypass surgery. AIM: We in this study discuss our surgical experience in the MIDCAB procedure. MATERIAL AND METHODS: Thirteen patients were operated on with the MIDCAB procedure. The inclusion criteria for MIDCAB were pure LAD disease totally occluded or severely stenotic. Patient demographics and preoperative and postoperative data were analyzed. RESULTS: Mean age of the patients was 60.0 +/-8.6 years. Patients' preoperative and postoperative levels of cardiac CK-MB (creatine kinase MB) were not significantly different (p = 0.993). However, cardiac troponin I (p < 0.001), hemoglobin (p < 0.001) and hematocrit (p < 0.001) were significantly different. No perioperative myocardial infarctions or cerebrovascular accidents were seen. The patients were discharged at a mean day of 4.77 with oral antiaggregant therapy. No mortality was seen in the study population. CONCLUSIONS: Minimally invasive direct coronary artery bypass is associated with few perioperative complications. Minimally invasive direct coronary artery bypass in our experience is a very good option for single vessel LAD disease. PMID- 23630559 TI - In vitro evaluation of stereoscopic liver surface reconstruction. AB - INTRODUCTION: Tracking abdominal motion of organs is an important factor in image guided navigation systems. The paper presents the evaluation methodology of a practical approach to measure liver motion, both respiratory and laparoscopic, with a tool guided in the operating room. AIM: Evaluation of the methodology of a practical approach to measure liver motion, both respiratory and laparoscopic, with a tool guided in the operating room. MATERIAL AND METHODS: The presented evaluation method is based on standard operating room equipment, i.e. laparoscopic cameras. We decided to use two rigid cameras to gain stereo in order to reconstruct characteristic points by triangulation. Our research aim was to survey the impact of three parameters on reconstruction accuracy: the number of calibration points, the imprecision of camera assembly, and the difference in resolution of images. RESULTS: Three calibration chessboard configurations were tested. The reconstructed landmark positions and residual mean square errors were presented in three phantom poses: the reference position, translated position and rotated position. CONCLUSIONS: The presented approach is a development of the previous work. Our research proved the importance of a rigid stereo camera system and the use of high definition image resolution for both stages, namely calibration and reconstruction. PMID- 23630560 TI - The use of minimally invasive videoscopic technique in large vessel and cardiac surgery. Does the potentially increased difficulty bring benefits to the patient? AB - We present the clinical case of a 63-year-old patient who underwent in the Department of Cardiac Surgery implantation of an aorto-bifemoral graft prosthesis and coronary artery bypass revascularization with application of less invasive off-pump technique. Graft selection (arterial grafts, venous grafts) is very important during qualification for coronary artery bypass revascularization. Minimally invasive saphenous vein harvesting was performed during the presented case. The endoscopic technique of vein harvesting is a relatively rarely applied technique during myocardial revascularization surgery. The concept of minimally invasive videoscopic technique is presented. There is a discussion on why the team decided to prolong duration of the case consisting of two major operations performed simultaneously. Minimally invasive videoscopic technique may have a significant positive impact on postoperative outcome in a selected group of patients. PMID- 23630561 TI - Rapid onset anterior segment complication following diode laser photocoagulation for retinopathy of prematurity: a case report. AB - Laser treatment for retinopathy of prematurity (ROP) has been proven to be beneficial. We present a case of uncommon, progressive anterior eye segment complication treated with diode laser photocoagulation for ROP which subsequently required surgical management. A 1210 g premature infant, born at 28 weeks of gestation, had bilateral stage 3 threshold ROP on his first screening, at 5 weeks of age. Confluent, laser ablation of avascular retina (Iris Medical, OcuLight S) in order to prevent the progression of ROP was applied. On the next ophthalmological examination, only in the right eye, an uncommon complication, not responding to conservative treatment, was noted. It was described as excessive conjunctiva hypertrophy, misdirected toward the center of the cornea. Indispensable surgical excision of hypertrophied conjunctiva was required, yielding a beneficial outcome. Histology revealed the presence of fibrous tissue. Hypertrophy of conjunctiva after diode laser photocoagulation requires surgical removal in order to prevent vision impairment. PMID- 23630568 TI - Comparison of models for IP3 receptor kinetics using stochastic simulations. AB - Inositol 1,4,5-trisphosphate receptor (IP3R) is a ubiquitous intracellular calcium (Ca(2+)) channel which has a major role in controlling Ca(2+) levels in neurons. A variety of computational models have been developed to describe the kinetic function of IP3R under different conditions. In the field of computational neuroscience, it is of great interest to apply the existing models of IP3R when modeling local Ca(2+) transients in dendrites or overall Ca(2+) dynamics in large neuronal models. The goal of this study was to evaluate existing IP3R models, based on electrophysiological data. This was done in order to be able to suggest suitable models for neuronal modeling. Altogether four models (Othmer and Tang, 1993; Dawson et al., 2003; Fraiman and Dawson, 2004; Doi et al., 2005) were selected for a more detailed comparison. The selection was based on the computational efficiency of the models and the type of experimental data that was used in developing the model. The kinetics of all four models were simulated by stochastic means, using the simulation software STEPS, which implements the Gillespie stochastic simulation algorithm. The results show major differences in the statistical properties of model functionality. Of the four compared models, the one by Fraiman and Dawson (2004) proved most satisfactory in producing the specific features of experimental findings reported in literature. To our knowledge, the present study is the first detailed evaluation of IP3R models using stochastic simulation methods, thus providing an important setting for constructing a new, realistic model of IP3R channel kinetics for compartmental modeling of neuronal functions. We conclude that the kinetics of IP3R with different concentrations of Ca(2+) and IP3 should be more carefully addressed when new models for IP3R are developed. PMID- 23630569 TI - Beta atomic contacts: identifying critical specific contacts in protein binding interfaces. AB - Specific binding between proteins plays a crucial role in molecular functions and biological processes. Protein binding interfaces and their atomic contacts are typically defined by simple criteria, such as distance-based definitions that only use some threshold of spatial distance in previous studies. These definitions neglect the nearby atomic organization of contact atoms, and thus detect predominant contacts which are interrupted by other atoms. It is questionable whether such kinds of interrupted contacts are as important as other contacts in protein binding. To tackle this challenge, we propose a new definition called beta (beta) atomic contacts. Our definition, founded on the beta-skeletons in computational geometry, requires that there is no other atom in the contact spheres defined by two contact atoms; this sphere is similar to the van der Waals spheres of atoms. The statistical analysis on a large dataset shows that beta contacts are only a small fraction of conventional distance-based contacts. To empirically quantify the importance of beta contacts, we design betaACV, an SVM classifier with beta contacts as input, to classify homodimers from crystal packing. We found that our betaACV is able to achieve the state-of the-art classification performance superior to SVM classifiers with distance based contacts as input. Our betaACV also outperforms several existing methods when being evaluated on several datasets in previous works. The promising empirical performance suggests that beta contacts can truly identify critical specific contacts in protein binding interfaces. beta contacts thus provide a new model for more precise description of atomic organization in protein quaternary structures than distance-based contacts. PMID- 23630567 TI - Short-term in-vitro expansion improves monitoring and allows affordable generation of virus-specific T-cells against several viruses for a broad clinical application. AB - Adenoviral infections are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. Adoptive transfer of donor-derived human adenovirus (HAdV)-specific T-cells represents a promising treatment option. However, the difficulty in identifying and selecting rare HAdV-specific T-cells, and the short time span between patients at high risk for invasive infection and viremia are major limitations. We therefore developed an IL-15-driven 6 to 12 day short-term protocol for in vitro detection of HAdV-specific T cells, as revealed by known MHC class I multimers and a newly identified adenoviral CD8 T-cell epitope derived from the E1A protein for the frequent HLA-type A*02?01 and IFN-gamma. Using this novel and improved diagnostic approach we observed a correlation between adenoviral load and reconstitution of CD8(+) and CD4(+) HAdV-specific T-cells including central memory cells in HSCT-patients. Adaption of the 12-day protocol to good manufacturing practice conditions resulted in a 2.6-log (mean) expansion of HAdV specific T-cells displaying high cytolytic activity (4-fold) compared to controls and low or absent alloreactivity. Similar protocols successfully identified and rapidly expanded CMV-, EBV-, and BKV-specific T-cells. Our approach provides a powerful clinical-grade convertible tool for rapid and cost-effective detection and enrichment of multiple virus-specific T-cells that may facilitate broad clinical application. PMID- 23630570 TI - Expression of tryptophan 2,3-dioxygenase and production of kynurenine pathway metabolites in triple transgenic mice and human Alzheimer's disease brain. AB - To assess the role of the kynurenine pathway in the pathology of Alzheimer's disease (AD), the expression and localization of key components of the kynurenine pathway including the key regulatory enzyme tryptophan 2,3 dioxygenase (TDO), and the metabolites tryptophan, kynurenine, kynurenic acid, quinolinic acid and picolinic acid were assessed in different brain regions of triple transgenic AD mice. The expression and cell distribution of TDO and quinolinic acid, and their co-localization with neurofibrillary tangles and senile beta amyloid deposition were also determined in hippocampal sections from human AD brains. The expression of TDO mRNA was significantly increased in the cerebellum of AD mouse brain. Immunohistochemistry demonstrated that the density of TDO immuno-positive cells was significantly higher in the AD mice. The production of the excitotoxin quinolinic acid strongly increased in the hippocampus in a progressive and age dependent manner in AD mice. Significantly higher TDO and indoleamine 2,3 dioxygenase 1 immunoreactivity was observed in the hippocampus of AD patients. Furthermore, TDO co-localizes with quinolinic acid, neurofibrillary tangles-tau and amyloid deposits in the hippocampus of AD. These results show that the kynurenine pathway is over-activated in AD mice. This is the first report demonstrating that TDO is highly expressed in the brains of AD mice and in AD patients, suggesting that TDO-mediated activation of the kynurenine pathway could be involved in neurofibrillary tangles formation and associated with senile plaque. Our study adds to the evidence that the kynurenine pathway may play important roles in the neurodegenerative processes of AD. PMID- 23630571 TI - Qualitative evaluation of advanced care planning in early dementia (ACP-ED). AB - BACKGROUND: End-of-life-care is often poor in individuals with dementia. Advanced care planning (ACP) has the potential to improve end-of-life care in dementia. Commonly ACP is completed in the last six months of life but in dementia there may be problems with this as decision-making capacity and ability to communicate necessarily decrease as the disease progresses. Choosing the right time to discuss ACP with people with dementia may be challenging given the duration of the illness may be up to nine years. AIMS: To explore the acceptability of discussing ACP with people with memory problems and mild dementia shortly after diagnosis. METHODS: In-depth interviews were conducted with 12 patients and eight carers who had participated in ACP discussions and six staff members from a memory clinic and a community mental health team who had either conducted or attended the discussions for training purposes. RESULTS: Patients and carers found ACP a positive intervention that helped them think about the future, enabled people with dementia to make their wishes known, and resulted in their feeling relieved and less worried about the future. The importance of sharing the ACP documentation between health service providers was highlighted. CONCLUSIONS: This qualitative evaluation of ACP in early dementia has encouragingly positive results which support the wider application of the intervention in memory services and community mental health teams. Strategies are suggested to support the implementation of ACP further in clinical practice. PMID- 23630572 TI - Deficiency of C5L2 increases macrophage infiltration and alters adipose tissue function in mice. AB - BACKGROUND: Obesity is considered as a systemic chronic low grade inflammation characterized by increased serum pro-inflammatory proteins and accumulation of macrophages within white adipose tissue (WAT) of obese patients. C5L2, a 7 transmembrane receptor, serves a dual function, binding the lipogenic hormone acylation stimulating protein (ASP), and C5a, involved in innate immunity. AIM: We evaluated the impact of C5L2 on macrophage infiltration in WAT of wildtype (Ctl) and C5L2 knock-out (C5L2(-/-)) mice over 6, 12 and 24 weeks on a chow diet and moderate diet-induced obesity (DIO) conditions. RESULTS: In Ctl mice, WAT C5L2 and C5a receptor mRNA increased (up to 10-fold) both over time and with DIO. By contrast, in C5L2(-/-), there was no change in C5aR in WAT. C5L2(-/-) mice displayed higher macrophage content in WAT, varying by time, fat depot and diet, associated with altered systemic and WAT cytokine patterns compared to Ctl mice. However, in all cases, the M1 (pro-) vs M2 (anti-inflammatory) macrophage proportion was unchanged but C5L2(-/-) adipose tissue secretome appeared to be more chemoattractant. Moreover, C5L2(-/-) mice have increased food intake, increased WAT, and altered WAT lipid gene expression, which is reflected systemically. Furthermore, C5L2(-/-) mice have altered glucose/insulin metabolism, adiponectin and insulin signalling gene expression in WAT, which could contribute to development of insulin resistance. CONCLUSION: Disruption of C5L2 increases macrophage presence in WAT, contributing to obesity-associated pathologies, and further supports a dual role of complement in WAT. Understanding this effect of the complement system pathway could contribute to targeting treatment of obesity and its comorbidities. PMID- 23630574 TI - Inferring animal densities from tracking data using Markov chains. AB - The distributions and relative densities of species are keys to ecology. Large amounts of tracking data are being collected on a wide variety of animal species using several methods, especially electronic tags that record location. These tracking data are effectively used for many purposes, but generally provide biased measures of distribution, because the starts of the tracks are not randomly distributed among the locations used by the animals. We introduce a simple Markov-chain method that produces unbiased measures of relative density from tracking data. The density estimates can be over a geographical grid, and/or relative to environmental measures. The method assumes that the tracked animals are a random subset of the population in respect to how they move through the habitat cells, and that the movements of the animals among the habitat cells form a time-homogenous Markov chain. We illustrate the method using simulated data as well as real data on the movements of sperm whales. The simulations illustrate the bias introduced when the initial tracking locations are not randomly distributed, as well as the lack of bias when the Markov method is used. We believe that this method will be important in giving unbiased estimates of density from the growing corpus of animal tracking data. PMID- 23630575 TI - Detection and organ-specific ablation of neuroendocrine cells by synaptophysin locus-based BAC cassette in transgenic mice. AB - The role of cells of the diffuse neuroendocrine system in development and maintenance of individual organs and tissues remains poorly understood. Here we identify a regulatory region sufficient for accurate in vivo expression of synaptophysin (SYP), a common marker of neuroendocrine differentiation, and report generation of Tg(Syp-EGFP(loxP)-DTA)147(Ayn) (SypELDTA) mice suitable for flexible organ-specific ablation of neuroendocrine cells. These mice express EGFP and diphtheria toxin fragment A (DTA) in SYP positive cells before and after Cre loxP mediated recombination, respectively. As a proof of principle, we have crossed SypELDTA mice with EIIA-Cre and PB-Cre4 mice. EIIA-Cre mice express Cre recombinase in a broad range of tissues, while PB-Cre4 mice specifically express Cre recombinase in the prostate epithelium. Double transgenic EIIA-Cre; SypELDTA embryos exhibited massive cell death in SYP positive cells. At the same time, PB Cre4; SypELDTA mice showed a substantial decrease in the number of neuroendocrine cells and associated prostate hypotrophy. As no increase in cell death and/or Cre loxP mediated recombination was observed in non-neuroendocrine epithelium cells, these results suggest that neuroendocrine cells play an important role in prostate development. High cell type specificity of Syp locus-based cassette and versatility of generated mouse model should assure applicability of these resources to studies of neuroendocrine cell functions in various tissues and organs. PMID- 23630573 TI - Pharmacologic inhibition of CXCL10 in combination with anti-malarial therapy eliminates mortality associated with murine model of cerebral malaria. AB - Despite appropriate anti-malarial treatment, cerebral malaria (CM)-associated mortalities remain as high as 30%. Thus, adjunctive therapies are urgently needed to prevent or reduce such mortalities. Overproduction of CXCL10 in a subset of CM patients has been shown to be tightly associated with fatal human CM. Mice with deleted CXCL10 gene are partially protected against experimental cerebral malaria (ECM) mortality indicating the importance of CXCL10 in the pathogenesis of CM. However, the direct effect of increased CXCL10 production on brain cells is unknown. We assessed apoptotic effects of CXCL10 on human brain microvascular endothelial cells (HBVECs) and neuroglia cells in vitro. We tested the hypothesis that reducing overexpression of CXCL10 with a synthetic drug during CM pathogenesis will increase survival and reduce mortality. We utilized atorvastatin, a widely used synthetic blood cholesterol-lowering drug that specifically targets and reduces plasma CXCL10 levels in humans, to determine the effects of atorvastatin and artemether combination therapy on murine ECM outcome. We assessed effects of atorvastatin treatment on immune determinants of severity, survival, and parasitemia in ECM mice receiving a combination therapy from onset of ECM (day 6 through 9 post-infection) and compared results with controls. The results indicate that CXCL10 induces apoptosis in HBVECs and neuroglia cells in a dose-dependent manner suggesting that increased levels of CXCL10 in CM patients may play a role in vasculopathy, neuropathogenesis, and brain injury during CM pathogenesis. Treatment of ECM in mice with atorvastatin significantly reduced systemic and brain inflammation by reducing the levels of the anti-angiogenic and apoptotic factor (CXCL10) and increasing angiogenic factor (VEGF) production. Treatment with a combination of atorvastatin and artemether improved survival (100%) when compared with artemether monotherapy (70%), p<0.05. Thus, adjunctively reducing CXCL10 levels and inflammation by atorvastatin treatment during anti-malarial therapy may represent a novel approach to treating CM patients. PMID- 23630576 TI - CMS: a web-based system for visualization and analysis of genome-wide methylation data of human cancers. AB - BACKGROUND: DNA methylation of promoter CpG islands is associated with gene suppression, and its unique genome-wide profiles have been linked to tumor progression. Coupled with high-throughput sequencing technologies, it can now efficiently determine genome-wide methylation profiles in cancer cells. Also, experimental and computational technologies make it possible to find the functional relationship between cancer-specific methylation patterns and their clinicopathological parameters. METHODOLOGY/PRINCIPAL FINDINGS: Cancer methylome system (CMS) is a web-based database application designed for the visualization, comparison and statistical analysis of human cancer-specific DNA methylation. Methylation intensities were obtained from MBDCap-sequencing, pre-processed and stored in the database. 191 patient samples (169 tumor and 22 normal specimen) and 41 breast cancer cell-lines are deposited in the database, comprising about 6.6 billion uniquely mapped sequence reads. This provides comprehensive and genome-wide epigenetic portraits of human breast cancer and endometrial cancer to date. Two views are proposed for users to better understand methylation structure at the genomic level or systemic methylation alteration at the gene level. In addition, a variety of annotation tracks are provided to cover genomic information. CMS includes important analytic functions for interpretation of methylation data, such as the detection of differentially methylated regions, statistical calculation of global methylation intensities, multiple gene sets of biologically significant categories, interactivity with UCSC via custom-track data. We also present examples of discoveries utilizing the framework. CONCLUSIONS/SIGNIFICANCE: CMS provides visualization and analytic functions for cancer methylome datasets. A comprehensive collection of datasets, a variety of embedded analytic functions and extensive applications with biological and translational significance make this system powerful and unique in cancer methylation research. CMS is freely accessible at: http://cbbiweb.uthscsa.edu/KMethylomes/. PMID- 23630577 TI - Effects of microparticle size and Fc density on macrophage phagocytosis. AB - Controlled induction of phagocytosis in macrophages offers the ability to therapeutically regulate the immune system as well as improve delivery of chemicals or biologicals for immune processing. Maximizing particle uptake by macrophages through Fc receptor-mediated phagocytosis could lead to new delivery mechanisms in drug or vaccine development. Fc ligand density and particle size were examined independently and in combination in order to optimize and tune the phagocytosis of opsonized microparticles. We show the internalization efficiency of small polystyrene particles (0.5 um to 2 um) is significantly affected by changes in Fc ligand density, while particles greater than 2 um show little correlation between internalization and Fc density. We found that while macrophages can efficiently phagocytose a large number of smaller particles, the total volume of phagocytosed particles is maximized through the non-specific uptake of larger microparticles. Therefore, larger microparticles may be more efficient at delivering a greater therapeutic payload to macrophages, but smaller opsonized microparticles can deliver bio-active substances to a greater percentage of the macrophage population. This study is the first to treat as independent variables the physical and biological properties of Fc density and microparticle size that initiate macrophage phagocytosis. Defining the physical and biological parameters that affect phagocytosis efficiency will lead to improved methods of microparticle delivery to macrophages. PMID- 23630578 TI - Principal networks. AB - Graph representations of brain connectivity have attracted a lot of recent interest, but existing methods for dividing such graphs into connected subnetworks have a number of limitations in the context of neuroimaging. This is an important problem because most cognitive functions would be expected to involve some but not all brain regions. In this paper we outline a simple approach for decomposing graphs, which may be based on any measure of interregional association, into coherent "principal networks". The technique is based on an eigendecomposition of the association matrix, and is closely related to principal components analysis. We demonstrate the technique using cortical thickness and diffusion tractography data, showing that the subnetworks which emerge are stable, meaningful and reproducible. Graph-theoretic measures of network cost and efficiency may be calculated separately for each principal network. Unlike some other approaches, all available connectivity information is taken into account, and vertices may appear in none or several of the subnetworks. Subject-by-subject "scores" for each principal network may also be obtained, under certain circumstances, and related to demographic or cognitive variables of interest. PMID- 23630579 TI - Hyperthermia-induced NDRG2 upregulation inhibits the invasion of human hepatocellular carcinoma via suppressing ERK1/2 signaling pathway. AB - Hyperthermia (HT) has been proven to be able to alter the invasion capacity of cancer cells. However, the detailed mechanisms responsible for the anti metastasis effects of HT have not been elucidated. N-myc downstream-regulated gene 2 (NDRG2), as a member of the NDRG family, has been suggested to be highly responsive to various stresses and is associated with tumor suppression. The present study aimed to investigate the biological role of NDRG2 in the invasion of human hepatocellular carcinoma (HCC) cells exposed to HT. We found that NDRG2 could be induced by HT at 45 degrees C. In addition, NDRG2 overexpression inhibited the expression of matrix metallo proteinases-2 (MMP-2) and MMP-9 as well as the invasion of HCC cells, whereas knockingdown NDRG2 reversed the anti invasion effect of HT in vivo. Further investigation revealed that the phosphorylation level of ERK1/2, but not that of JNK and p38MAPK, was reduced in NDRG2 overexpressing cells. Moreover, the knockdown of NDRG2 expression resulted in increased cell invasion, which was rescued by treating the HepG2 cells with the ERK1/2 inhibitor PD98059, but not with the p38MAPK inhibitor SB203580 or the JNK inhibitor SP600125. Finally, the synergistic cooperation of HT at 43 degrees C and NDRG2 expression effectively reduced cytotoxicity and promoted the anti invasion effect of HT at 45 degrees C. Taken together, these data suggest that NDRG2 can be induced by HT and that it mediates the HT-caused inhibition of invasion in HCC cells by suppressing the ERK1/2 signaling pathway. The combined application of constitutive NDRG2 expression with HT may yield an optimized therapeutic benefit. PMID- 23630580 TI - SIMPL enhancement of tumor necrosis factor-alpha dependent p65-MED1 complex formation is required for mammalian hematopoietic stem and progenitor cell function. AB - Significant insight into the signaling pathways leading to activation of the Rel transcription factor family, collectively termed NF-kappaB, has been gained. Less well understood is how subsets of NF-kappaB-dependent genes are regulated in a signal specific manner. The SIMPL protein (signaling molecule that interacts with mouse pelle-like kinase) is required for full Tumor Necrosis Factor-alpha (TNFalpha) induced NF-kappaB activity. We show that SIMPL is required for steady state hematopoiesis and the expression of a subset of TNFalpha induced genes whose products regulate hematopoietic cell activity. To gain insight into the mechanism through which SIMPL modulates gene expression we focused on the Tnf gene, an immune response regulator required for steady-state hematopoiesis. In response to TNFalpha SIMPL localizes to the Tnf gene promoter where it modulates the initiation of Tnf gene transcription. SIMPL binding partners identified by mass spectrometry include proteins involved in transcription and the interaction between SIMPL and MED1 was characterized in more detail. In response to TNFalpha, SIMPL is found in p65-MED1 complexes where SIMPL enhances p65/MED1/SIMPL complex formation. Together our results indicate that SIMPL functions as a TNFalpha dependent p65 co-activator by facilitating the recruitment of MED1 to p65 containing transcriptional complexes to control the expression of a subset of TNFalpha-induced genes. PMID- 23630581 TI - phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. AB - BACKGROUND: the analysis of microbial communities through dna sequencing brings many challenges: the integration of different types of data with methods from ecology, genetics, phylogenetics, multivariate statistics, visualization and testing. With the increased breadth of experimental designs now being pursued, project-specific statistical analyses are often needed, and these analyses are often difficult (or impossible) for peer researchers to independently reproduce. The vast majority of the requisite tools for performing these analyses reproducibly are already implemented in R and its extensions (packages), but with limited support for high throughput microbiome census data. RESULTS: Here we describe a software project, phyloseq, dedicated to the object-oriented representation and analysis of microbiome census data in R. It supports importing data from a variety of common formats, as well as many analysis techniques. These include calibration, filtering, subsetting, agglomeration, multi-table comparisons, diversity analysis, parallelized Fast UniFrac, ordination methods, and production of publication-quality graphics; all in a manner that is easy to document, share, and modify. We show how to apply functions from other R packages to phyloseq-represented data, illustrating the availability of a large number of open source analysis techniques. We discuss the use of phyloseq with tools for reproducible research, a practice common in other fields but still rare in the analysis of highly parallel microbiome census data. We have made available all of the materials necessary to completely reproduce the analysis and figures included in this article, an example of best practices for reproducible research. CONCLUSIONS: The phyloseq project for R is a new open-source software package, freely available on the web from both GitHub and Bioconductor. PMID- 23630582 TI - Quantifying dispersal of european culicoides (Diptera: Ceratopogonidae) vectors between farms using a novel mark-release-recapture technique. AB - Studying the dispersal of small flying insects such as Culicoides constitutes a great challenge due to huge population sizes and lack of a method to efficiently mark and objectively detect many specimens at a time. We here describe a novel mark-release-recapture method for Culicoides in the field using fluorescein isothiocyanate (FITC) as marking agent without anaesthesia. Using a plate scanner, this detection technique can be used to analyse thousands of individual Culicoides specimens per day at a reasonable cost. We marked and released an estimated 853 specimens of the Pulicaris group and 607 specimens of the Obsoletus group on a cattle farm in Denmark. An estimated 9,090 (8,918-9,260) Obsoletus group specimens and 14,272 (14,194-14,448) Pulicaris group specimens were captured in the surroundings and subsequently analysed. Two (0.3%) Obsoletus group specimens and 28 (4.6%) Pulicaris group specimens were recaptured. The two recaptured Obsoletus group specimens were caught at the release point on the night following release. Eight (29%) of the recaptured Pulicaris group specimens were caught at a pig farm 1,750 m upwind from the release point. Five of these were recaptured on the night following release and the three other were recaptured on the second night after release. This is the first time that movement of Culicoides vectors between farms in Europe has been directly quantified. The findings suggest an extensive and rapid exchange of disease vectors between farms. Rapid movement of vectors between neighboring farms may explain the the high rate of spatial spread of Schmallenberg and bluetongue virus (BTV) in northern Europe. PMID- 23630583 TI - Effect of adiponectin on kidney crystal formation in metabolic syndrome model mice via inhibition of inflammation and apoptosis. AB - The aims of the present study were to elucidate a possible mechanism of kidney crystal formation by using a metabolic syndrome (MetS) mouse model and to assess the effectiveness of adiponectin treatment for the prevention of kidney crystals. Further, we performed genome-wide expression analyses for investigating novel genetic environmental changes. Wild-type (+/+) mice showed no kidney crystal formation, whereas ob/ob mice showed crystal depositions in their renal tubules. However, this deposition was remarkably reduced by adiponectin. Expression analysis of genes associated with MetS-related kidney crystal formation identified 259 genes that were >2.0-fold up-regulated and 243 genes that were <0.5-fold down-regulated. Gene Ontology (GO) analyses revealed that the up regulated genes belonged to the categories of immunoreaction, inflammation, and adhesion molecules and that the down-regulated genes belonged to the categories of oxidative stress and lipid metabolism. Expression analysis of adiponectin induced genes related to crystal prevention revealed that the numbers of up- and down-regulated genes were 154 and 190, respectively. GO analyses indicated that the up-regulated genes belonged to the categories of cellular and mitochondrial repair, whereas the down-regulated genes belonged to the categories of immune and inflammatory reactions and apoptosis. The results of this study provide compelling evidence that the mechanism of kidney crystal formation in the MetS environment involves the progression of an inflammation and immunoresponse, including oxidative stress and adhesion reactions in renal tissues. This is the first report to prove the preventive effect of adiponectin treatment for kidney crystal formation by renoprotective activities and inhibition of inflammation and apoptosis. PMID- 23630585 TI - Pleiotrophin gene therapy for peripheral ischemia: evaluation of full-length and truncated gene variants. AB - Pleiotrophin (PTN) is a growth factor with both pro-angiogenic and limited pro tumorigenic activity. We evaluated the potential for PTN to be used for safe angiogenic gene therapy using the full length gene and a truncated gene variant lacking the domain implicated in tumorigenesis. Mouse myoblasts were transduced to express full length or truncated PTN (PTN or T-PTN), along with a LacZ reporter gene, and injected into mouse limb muscle and myocardium. In cultured myoblasts, PTN was expressed and secreted via the Golgi apparatus, but T-PTN was not properly secreted. Nonetheless, no evidence of uncontrolled growth was observed in cells expressing either form of PTN. PTN gene delivery to myocardium, and non-ischemic skeletal muscle, did not result in a detectable change in vascularity or function. In ischemic hindlimb at 14 days post-implantation, intramuscular injection with PTN-expressing myoblasts led to a significant increase in skin perfusion and muscle arteriole density. We conclude that (1) delivery of the full length PTN gene to muscle can be accomplished without tumorigenesis, (2) the truncated PTN gene may be difficult to use in a gene therapy context due to inefficient secretion, (3) PTN gene delivery leads to functional benefit in the mouse acute ischemic hindlimb model. PMID- 23630584 TI - Mutant p53 attenuates the anti-tumorigenic activity of fibroblasts-secreted interferon beta. AB - Mutations in the p53 tumor suppressor protein are highly frequent in tumors and often endow cells with tumorigenic capacities. We sought to examine a possible role for mutant p53 in the cross-talk between cancer cells and their surrounding stroma, which is a crucial factor affecting tumor outcome. Here we present a novel model which enables individual monitoring of the response of cancer cells and stromal cells (fibroblasts) to co-culturing. We found that fibroblasts elicit the interferon beta (IFNbeta) pathway when in contact with cancer cells, thereby inhibiting their migration. Mutant p53 in the tumor was able to alleviate this response via SOCS1 mediated inhibition of STAT1 phosphorylation. IFNbeta on the other hand, reduced mutant p53 RNA levels by restricting its RNA stabilizer, WIG1. These data underscore mutant p53 oncogenic properties in the context of the tumor microenvironment and suggest that mutant p53 positive cancer patients might benefit from IFNbeta treatment. PMID- 23630586 TI - Drug synergy of tenofovir and nanoparticle-based antiretrovirals for HIV prophylaxis. AB - BACKGROUND: The use of drug combinations has revolutionized the treatment of HIV but there is no equivalent combination product that exists for prevention, particularly for topical HIV prevention. Strategies to combine chemically incompatible agents may facilitate the discovery of unique drug-drug activities, particularly unexplored combination drug synergy. We fabricated two types of nanoparticles, each loaded with a single antiretroviral (ARV) that acts on a specific step of the viral replication cycle. Here we show unique combination drug activities mediated by our polymeric delivery systems when combined with free tenofovir (TFV). METHODOLOGY/PRINCIPAL FINDINGS: Biodegradable poly(lactide co-glycolide) nanoparticles loaded with efavirenz (NP-EFV) or saquinavir (NP-SQV) were individually prepared by emulsion or nanoprecipitation techniques. Nanoparticles had reproducible size (d ~200 nm) and zeta potential (-25 mV). The drug loading of the nanoparticles was approximately 7% (w/w). NP-EFV and NP-SQV were nontoxic to TZM-bl cells and ectocervical explants. Both NP-EFV and NP-SQV exhibited potent protection against HIV-1 BaL infection in vitro. The HIV inhibitory effect of nanoparticle formulated ARVs showed up to a 50-fold reduction in the 50% inhibitory concentration (IC50) compared to free drug. To quantify the activity arising from delivery of drug combinations, we calculated combination indices (CI) according to the median-effect principle. NP-EFV combined with free TFV demonstrated strong synergistic effects (CI50 = 0.07) at a 1?50 ratio of IC50 values and additive effects (CI50 = 1.05) at a 1?1 ratio of IC50 values. TFV combined with NP-SQV at a 1?1 ratio of IC50 values also showed strong synergy (CI50 = 0.07). CONCLUSIONS: ARVs with different physicochemical properties can be encapsulated individually into nanoparticles to potently inhibit HIV. Our findings demonstrate for the first time that combining TFV with either NP-EFV or NP-SQV results in pronounced combination drug effects, and emphasize the potential of nanoparticles for the realization of unique drug-drug activities. PMID- 23630587 TI - Selective and efficient neural coding of communication signals depends on early acoustic and social environment. AB - Previous research has shown that postnatal exposure to simple, synthetic sounds can affect the sound representation in the auditory cortex as reflected by changes in the tonotopic map or other relatively simple tuning properties, such as AM tuning. However, their functional implications for neural processing in the generation of ethologically-based perception remain unexplored. Here we examined the effects of noise-rearing and social isolation on the neural processing of communication sounds such as species-specific song, in the primary auditory cortex analog of adult zebra finches. Our electrophysiological recordings reveal that neural tuning to simple frequency-based synthetic sounds is initially established in all the laminae independent of patterned acoustic experience; however, we provide the first evidence that early exposure to patterned sound statistics, such as those found in native sounds, is required for the subsequent emergence of neural selectivity for complex vocalizations and for shaping neural spiking precision in superficial and deep cortical laminae, and for creating efficient neural representations of song and a less redundant ensemble code in all the laminae. Our study also provides the first causal evidence for 'sparse coding', such that when the statistics of the stimuli were changed during rearing, as in noise-rearing, that the sparse or optimal representation for species-specific vocalizations disappeared. Taken together, these results imply that a layer-specific differential development of the auditory cortex requires patterned acoustic input, and a specialized and robust sensory representation of complex communication sounds in the auditory cortex requires a rich acoustic and social environment. PMID- 23630588 TI - Spatiotemporal alterations in primary odorant representations in olfactory marker protein knockout mice. AB - Olfactory marker protein (OMP) is highly and selectively expressed in primary olfactory sensory neurons (OSNs) across species, but its physiological function remains unclear. Previous studies in the olfactory epithelium suggest that it accelerates the neural response to odorants and may modulate the odorant selectivity of OSNs. Here we used a line of gene-targeted mice that express the fluorescent exocytosis indicator synaptopHluorin in place of OMP to compare spatiotemporal patterns of odorant-evoked neurotransmitter release from OSNs in adult mice that were heterozygous for OMP or OMP-null. We found that these patterns, which constitute the primary neural representation of each odorant, developed more slowly during the odorant presentation in OMP knockout mice but eventually reached the same magnitude as in heterozygous mice. In the olfactory bulb, each glomerulus receives synaptic input from a subpopulation of OSNs that all express the same odor receptor and thus typically respond to a specific subset of odorants. We observed that in OMP knockout mice, OSNs innervating a given glomerulus typically responded to a broader range of odorants than in OMP heterozygous mice and thus each odorant evoked synaptic input to a larger number of glomeruli. In an olfactory habituation task, OMP knockout mice behaved differently than wild-type mice, exhibiting a delay in their onset to investigate an odor stimulus during its first presentation and less habituation to that stimulus over repeated presentations. These results suggest that the actions of OMP in olfactory transduction carry through to the primary sensory representations of olfactory stimuli in adult mice in vivo. PMID- 23630589 TI - FGF21 can be mimicked in vitro and in vivo by a novel anti-FGFR1c/beta-Klotho bispecific protein. AB - The endocrine hormone FGF21 has attracted considerable interest as a potential therapeutic for treating diabetes and obesity. As an alternative to the native cytokine, we generated bispecific Avimer polypeptides that bind with high affinity and specificity to one of the receptor and coreceptor pairs used by FGF21, FGFR1c and beta-Klotho. These Avimers exhibit FGF21-like activity in in vitro assays with potency greater than FGF21. In a study conducted in obese male cynomolgus monkeys, animals treated with an FGFR1c/beta-Klotho bispecific Avimer showed improved metabolic parameters and reduced body weight comparable to the effects seen with FGF21. These results not only demonstrate the essential roles of FGFR1c and beta-Klotho in mediating the metabolic effects of FGF21, they also describe a first bispecific activator of this unique receptor complex and provide validation for a novel therapeutic approach to target this potentially important pathway for treating diabetes and obesity. PMID- 23630590 TI - Molecular ageing of alpha- and Beta-synucleins: protein damage and repair mechanisms. AB - Abnormal alpha-synuclein aggregates are hallmarks of a number of neurodegenerative diseases. Alpha synuclein and beta-synucleins are susceptible to post-translational modification as isoaspartate protein damage, which is regulated in vivo by the action of the repair enzyme protein L-isoaspartyl O methyltransferase (PIMT). We aged in vitro native alpha-synuclein, the alpha synuclein familial mutants A30P and A53T that give rise to Parkinsonian phenotypes, and beta-synuclein, at physiological pH and temperature for a time course of up to 20 days. Resolution of native alpha-synuclein and beta-synuclein by two dimensional techniques showed the accumulation of a number of post translationally modified forms of both proteins. The levels of isoaspartate formed over the 20 day time course were quantified by exogenous methylation with PIMT using S-Adenosyl-L-[(3)H-methyl]methionine as a methyl donor, and liquid scintillation counting of liberated (3)H-methanol. All alpha-synuclein proteins accumulated isoaspartate at ~1% of molecules/day, ~20 times faster than for beta synuclein. This disparity between rates of isoaspartate was confirmed by exogenous methylation of synucleins by PIMT, protein resolution by one dimensional denaturing gel electrophoresis, and visualisation of (3)H-methyl esters by autoradiography. Protein silver staining and autoradiography also revealed that alpha-synucleins accumulated stable oligomers that were resistant to denaturing conditions, and which also contained isoaspartate. Co-incubation of approximately equimolar beta-synuclein with alpha-synuclein resulted in a significant reduction of isoaspartate formed in all alpha-synucleins after 20 days of ageing. Co-incubated alpha- and beta-synucleins, or alpha, or beta synucleins alone, were resolved by non-denaturing size exclusion chromatography and all formed oligomers of ~57.5 kDa; consistent with tetramerization. Direct association of alpha-synuclein with beta-synuclein in column fractions or from in vitro ageing co-incubations was demonstrated by their co-immunoprecipitation. These results provide an insight into the molecular differences between alpha- and beta-synucleins during ageing, and highlight the susceptibility of alpha synuclein to protein damage, and the potential protective role of beta-synuclein. PMID- 23630591 TI - Criminal defectors lead to the emergence of cooperation in an experimental, adversarial game. AB - While the evolution of cooperation has been widely studied, little attention has been devoted to adversarial settings wherein one actor can directly harm another. Recent theoretical work addresses this issue, introducing an adversarial game in which the emergence of cooperation is heavily reliant on the presence of "Informants," actors who defect at first-order by harming others, but who cooperate at second-order by punishing other defectors. We experimentally study this adversarial environment in the laboratory with human subjects to test whether Informants are indeed critical for the emergence of cooperation. We find in these experiments that, even more so than predicted by theory, Informants are crucial for the emergence and sustenance of a high cooperation state. A key lesson is that successfully reaching and maintaining a low defection society may require the cultivation of criminals who will also aid in the punishment of others. PMID- 23630592 TI - Vivo-morpholinos induced transient knockdown of physical activity related proteins. AB - Physical activity is associated with disease prevention and overall wellbeing. Additionally there has been evidence that physical activity level is a result of genetic influence. However, there has not been a reliable method to silence candidate genes in vivo to determine causal mechanisms of physical activity regulation. Vivo-morpholinos are a potential method to transiently silence specific genes. Thus, the aim of this study was to validate the use of Vivo morpholinos in a mouse model for voluntary physical activity with several sub objectives. We observed that Vivo-morpholinos achieved between 60-97% knockdown of Drd1-, Vmat2-, and Glut4-protein in skeletal muscle, the delivery moiety of Vivo-morpholinos (scramble) did not influence physical activity and that a cocktail of multiple Vivo-morpholinos can be given in a single treatment to achieve protein knockdown of two different targeted proteins in skeletal muscle simultaneously. Knocking down Drd1, Vmat2, or Glut4 protein in skeletal muscle did not affect physical activity. Vivo-morpholinos injected intravenously alone did not significantly knockdown Vmat2-protein expression in the brain (p = 0.28). However, the use of a bradykinin analog to increase blood-brain-barrier permeability in conjunction with the Vivo-morpholinos significantly (p = 0.0001) decreased Vmat2-protein in the brain with a corresponding later over-expression of Vmat2 coincident with a significant (p = 0.0016) increase in physical activity. We conclude that Vivo-morpholinos can be a valuable tool in determining causal gene-phenotype relationships in whole animal models. PMID- 23630593 TI - The video Head Impulse Test (vHIT) detects vertical semicircular canal dysfunction. AB - BACKGROUND: The video head impulse test (vHIT) is a useful clinical tool to detect semicircular canal dysfunction. However vHIT has hitherto been limited to measurement of horizontal canals, while scleral search coils have been the only accepted method to measure head impulses in vertical canals. The goal of this study was to determine whether vHIT can detect vertical semicircular canal dysfunction as identified by scleral search coil recordings. METHODS: Small unpredictable head rotations were delivered by hand diagonally in the plane of the vertical semicircular canals while gaze was directed along the same plane. The planes were oriented along the left-anterior-right-posterior (LARP) canals and right-anterior-left-posterior (RALP) canals. Eye movements were recorded simultaneously in 2D with vHIT (250 Hz) and in 3D with search coils (1000 Hz). Twelve patients with unilateral, bilateral and individual semicircular canal dysfunction were tested and compared to seven normal subjects. RESULTS: Simultaneous video and search coil recordings were closely comparable. Mean VOR gain difference measured with vHIT and search coils was 0.05 (SD = 0.14) for the LARP plane and -0.04 (SD = 0.14) for the RALP plane. The coefficient of determination R(2) was 0.98 for the LARP plane and 0.98 for the RALP plane and the results of the two methods were not significantly different. vHIT and search coil measures displayed comparable patterns of covert and overt catch-up saccades. CONCLUSIONS: vHIT detects dysfunction of individual vertical semicircular canals in vestibular patients as accurately as scleral search coils. Unlike search coils, vHIT is non-invasive, easy to use and hence practical in clinics. PMID- 23630594 TI - Modulation of light-enhancement to symbiotic algae by light-scattering in corals and evolutionary trends in bleaching. AB - Calcium carbonate skeletons of scleractinian corals amplify light availability to their algal symbionts by diffuse scattering, optimizing photosynthetic energy acquisition. However, the mechanism of scattering and its role in coral evolution and dissolution of algal symbioses during "bleaching" events are largely unknown. Here we show that differences in skeletal fractal architecture at nano/micro lengthscales within 96 coral taxa result in an 8-fold variation in light scattering and considerably alter the algal light environment. We identified a continuum of properties that fall between two extremes: (1) corals with low skeletal fractality that are efficient at transporting and redistributing light throughout the colony with low scatter but are at higher risk of bleaching and (2) corals with high skeletal fractality that are inefficient at transporting and redistributing light with high scatter and are at lower risk of bleaching. While levels of excess light derived from the coral skeleton is similar in both groups, the low-scatter corals have a higher rate of light-amplification increase when symbiont concentration is reduced during bleaching, thus creating a positive feedback-loop between symbiont concentration and light-amplification that exposes the remaining symbionts to increasingly higher light intensities. By placing our findings in an evolutionary framework, in conjunction with a novel empirical index of coral bleaching susceptibility, we find significant correlations between bleaching susceptibility and light-scattering despite rich homoplasy in both characters; suggesting that the cost of enhancing light-amplification to the algae is revealed in decreased resilience of the partnership to stress. PMID- 23630595 TI - Structure of spike count correlations reveals functional interactions between neurons in dorsolateral prefrontal cortex area 8a of behaving primates. AB - Neurons within the primate dorsolateral prefrontal cortex (dlPFC) are clustered in microcolumns according to their visuospatial tuning. One issue that remains poorly investigated is how this anatomical arrangement influences functional interactions between neurons during behavior. To investigate this question we implanted 4 mm*4 mm multielectrode arrays in two macaques' dlPFC area 8a and measured spike count correlations (rsc ) between responses of simultaneously recorded neurons when animals maintained stationary gaze. Positive and negative rsc were significantly higher than predicted by chance across a wide range of inter-neuron distances (from 0.4 to 4 mm). Positive rsc were stronger between neurons with receptive fields (RFs) separated by <=90 degrees of angular distance and progressively decreased as a function of inter-neuron physical distance. Negative rsc were stronger between neurons with RFs separated by >90 degrees and increased as a function of inter-neuron distance. Our results show that short- and long-range functional interactions between dlPFC neurons depend on the physical distance between them and the relationship between their visuospatial tuning preferences. Neurons with similar visuospatial tuning show positive rsc that decay with inter-neuron distance, suggestive of excitatory interactions within and between adjacent microcolumns. Neurons with dissimilar tuning from spatially segregated microcolumns show negative rsc that increase with inter-neuron distance, suggestive of inhibitory interactions. This pattern of results shows that functional interactions between prefrontal neurons closely follow the pattern of connectivity reported in anatomical studies. Such interactions may be important for the role of the prefrontal cortex in the allocation of attention to targets in the presence of competing distracters. PMID- 23630596 TI - Genetic structure and gene flows within horses: a genealogical study at the french population scale. AB - Since horse breeds constitute populations submitted to variable and multiple outcrossing events, we analyzed the genetic structure and gene flows considering horses raised in France. We used genealogical data, with a reference population of 547,620 horses born in France between 2002 and 2011, grouped according to 55 breed origins. On average, individuals had 6.3 equivalent generations known. Considering different population levels, fixation index decreased from an overall species FIT of 1.37%, to an average [Formula: see text] of -0.07% when considering the 55 origins, showing that most horse breeds constitute populations without genetic structure. We illustrate the complexity of gene flows existing among horse breeds, a few populations being closed to foreign influence, most, however, being submitted to various levels of introgression. In particular, Thoroughbred and Arab breeds are largely used as introgression sources, since those two populations explain together 26% of founder origins within the overall horse population. When compared with molecular data, breeds with a small level of coancestry also showed low genetic distance; the gene pool of the breeds was probably impacted by their reproducer exchanges. PMID- 23630597 TI - Better prognosis of patients with glioma expressing FGF2-dependent PDGFRA irrespective of morphological diagnosis. AB - Signaling of platelet derived growth factor receptor alpha (PDGFRA) is critically involved in the development of gliomas. However, the clinical relevance of PDGFRA expression in glioma subtypes and the mechanisms of PDGFRA expression in gliomas have been controversial. Under the supervision of morphological diagnosis, analysis of the GSE16011 and the Repository of Molecular Brain Neoplasia Data (Rembrandt) set revealed enriched PDGFRA expression in low-grade gliomas. However, gliomas with the top 25% of PDGFRA expression levels contained nearly all morphological subtypes, which was associated with frequent IDH1 mutation, 1p LOH, 19q LOH, less EGFR amplification, younger age at disease onset and better survival compared to those gliomas with lower levels of PDGFRA expression. SNP analysis in Rembrandt data set and FISH analysis in eleven low passage glioma cell lines showed infrequent amplification of PDGFRA. Using in vitro culture of these low passage glioma cells, we tested the hypothesis of gliogenic factor dependent expression of PDGFRA in glioma cells. Fibroblast growth factor 2 (FGF2) was able to maintain PDGFRA expression in glioma cells. FGF2 also induced PDGFRA expression in glioma cells with low or non-detectable PDGFRA expression. FGF2 dependent maintenance of PDGFRA expression was concordant with the maintenance of a subset of gliogenic genes and higher rates of cell proliferation. Further, concordant expression patterns of FGF2 and PDGFRA were detected in glioma samples by immunohistochemical staining. Our findings suggest a role of FGF2 in regulating PDGFRA expression in the subset of gliomas with younger age at disease onset and longer patient survival regardless of their morphological diagnosis. PMID- 23630598 TI - Size constancy in bat biosonar? Perceptual interaction of object aperture and distance. AB - Perception and encoding of object size is an important feature of sensory systems. In the visual system object size is encoded by the visual angle (visual aperture) on the retina, but the aperture depends on the distance of the object. As object distance is not unambiguously encoded in the visual system, higher computational mechanisms are needed. This phenomenon is termed "size constancy". It is assumed to reflect an automatic re-scaling of visual aperture with perceived object distance. Recently, it was found that in echolocating bats, the 'sonar aperture', i.e., the range of angles from which sound is reflected from an object back to the bat, is unambiguously perceived and neurally encoded. Moreover, it is well known that object distance is accurately perceived and explicitly encoded in bat sonar. Here, we addressed size constancy in bat biosonar, recruiting virtual-object techniques. Bats of the species Phyllostomus discolor learned to discriminate two simple virtual objects that only differed in sonar aperture. Upon successful discrimination, test trials were randomly interspersed using virtual objects that differed in both aperture and distance. It was tested whether the bats spontaneously assigned absolute width information to these objects by combining distance and aperture. The results showed that while the isolated perceptual cues encoding object width, aperture, and distance were all perceptually well resolved by the bats, the animals did not assign absolute width information to the test objects. This lack of sonar size constancy may result from the bats relying on different modalities to extract size information at different distances. Alternatively, it is conceivable that familiarity with a behaviorally relevant, conspicuous object is required for sonar size constancy, as it has been argued for visual size constancy. Based on the current data, it appears that size constancy is not necessarily an essential feature of sonar perception in bats. PMID- 23630599 TI - Rabies and canine distemper virus epidemics in the red fox population of northern Italy (2006-2010). AB - Since 2006 the red fox (Vulpes vulpes) population in north-eastern Italy has experienced an epidemic of canine distemper virus (CDV). Additionally, in 2008, after a thirteen-year absence from Italy, fox rabies was re-introduced in the Udine province at the national border with Slovenia. Disease intervention strategies are being developed and implemented to control rabies in this area and minimise risk to human health. Here we present empirical data and the epidemiological picture relating to these epidemics in the period 2006-2010. Of important significance for epidemiological studies of wild animals, basic mathematical models are developed to exploit information collected from the surveillance program on dead and/or living animals in order to assess the incidence of infection. These models are also used to estimate the rate of transmission of both diseases and the rate of vaccination, while correcting for a bias in early collection of CDV samples. We found that the rate of rabies transmission was roughly twice that of CDV, with an estimated effective contact between infected and susceptible fox leading to a new infection occurring once every 3 days for rabies, and once a week for CDV. We also inferred that during the early stage of the CDV epidemic, a bias in the monitoring protocol resulted in a positive sample being almost 10 times more likely to be collected than a negative sample. We estimated the rate of intake of oral vaccine at 0.006 per day, allowing us to estimate that roughly 68% of the foxes would be immunised. This was confirmed by field observations. Finally we discuss the implications for the eco-epidemiological dynamics of both epidemics in relation to control measures. PMID- 23630600 TI - Isolation and characterization of antimicrobial compounds in plant extracts against multidrug-resistant Acinetobacter baumannii. AB - The number of fully active antibiotic options that treat nosocomial infections due to multidrug-resistant Acinetobacter baumannii (A. baumannii) is extremely limited. Magnolia officinalis, Mahonia bealei, Rabdosia rubescens, Rosa rugosa, Rubus chingii, Scutellaria baicalensis, and Terminalia chebula plant extracts were previously shown to have growth inhibitory activity against a multidrug resistant clinical strain of A. baumannii. In this study, the compounds responsible for their antimicrobial activity were identified by fractionating each plant extract using high performance liquid chromatography, and determining the antimicrobial activity of each fraction against A. baumannii. The chemical structures of the fractions inhibiting >40% of the bacterial growth were elucidated by liquid chromatography/mass spectrometry analysis and nuclear magnetic resonance spectroscopy. The six most active compounds were identified as: ellagic acid in Rosa rugosa; norwogonin in Scutellaria baicalensis; and chebulagic acid, chebulinic acid, corilagin, and terchebulin in Terminalia chebula. The most potent compound was identified as norwogonin with a minimum inhibitory concentration of 128 ug/mL, and minimum bactericidal concentration of 256 ug/mL against clinically relevant strains of A. baumannii. Combination studies of norwogonin with ten anti-Gram negative bacterial agents demonstrated that norwogonin did not enhance the antimicrobial activity of the synthetic antibiotics chosen for this study. In conclusion, of all identified antimicrobial compounds, norwogonin was the most potent against multidrug-resistant A. baumannii strains. Further studies are warranted to ascertain the prophylactic and therapeutic potential of norwogonin for infections due to multidrug-resistant A. baumannii. PMID- 23630602 TI - Explicating the face perception network with white matter connectivity. AB - A network of multiple brain regions is recruited in face perception. Our understanding of the functional properties of this network can be facilitated by explicating the structural white matter connections that exist between its functional nodes. We accomplished this using functional MRI (fMRI) in combination with fiber tractography on high angular resolution diffusion weighted imaging data. We identified the three nodes of the core face network: the "occipital face area" (OFA), the "fusiform face area" (mid-fusiform gyrus or mFus), and the superior temporal sulcus (STS). Additionally, a region of the anterior temporal lobe (aIT), implicated as being important for face perception was identified. Our data suggest that we can further divide the OFA into multiple anatomically distinct clusters - a partitioning consistent with several recent neuroimaging results. More generally, structural white matter connectivity within this network revealed: 1) Connectivity between aIT and mFus, and between aIT and occipital regions, consistent with studies implicating this posterior to anterior pathway as critical to normal face processing; 2) Strong connectivity between mFus and each of the occipital face-selective regions, suggesting that these three areas may subserve different functional roles; 3) Almost no connectivity between STS and mFus, or between STS and the other face-selective regions. Overall, our findings suggest a re-evaluation of the "core" face network with respect to what functional areas are or are not included in this network. PMID- 23630601 TI - Efficacy of influenza vaccination and tamiflu(r) treatment--comparative studies with Eurasian Swine influenza viruses in pigs. AB - Recent epidemiological developments demonstrated that gene segments of swine influenza A viruses can account for antigenic changes as well as reduced drug susceptibility of pandemic influenza A viruses. This raises questions about the efficacy of preventive measures against swine influenza A viruses. Here, the protective effect of vaccination was compared with that of prophylactic Tamiflu(r) treatment against two Eurasian swine influenza A viruses. 11-week-old pigs were infected by aerosol nebulisation with high doses of influenza virus A/swine/Potsdam/15/1981 (H1N1/1981, heterologous challenge to H1N1 vaccine strain) and A/swine/Bakum/1832/2000 (H1N2/2000, homologous challenge to H1N2 vaccine strain) in two independent trials. In each trial (i) 10 pigs were vaccinated twice with a trivalent vaccine (RESPIPORC(r) FLU3; 28 and 7 days before infection), (ii) another 10 pigs received 150 mg/day of Tamiflu(r) for 5 days starting 12 h before infection, and (iii) 12 virus-infected pigs were left unvaccinated and untreated and served as controls. Both viruses replicated efficiently in porcine respiratory organs causing influenza with fever, dyspnoea, and pneumonia. Tamiflu(r) treatment as well as vaccination prevented clinical signs and significantly reduced virus shedding. Whereas after homologous challenge with H1N2/2000 no infectious virus in lung and hardly any lung inflammation were detected, the virus titre was not and the lung pathology was only partially reduced in H1N1/1981, heterologous challenged pigs. Tamiflu(r) application did not affect these study parameters. In conclusion, all tested preventive measures provided protection against disease. Vaccination additionally prevented virus replication and histopathological changes in the lung of homologous challenged pigs. PMID- 23630603 TI - In vitro electrochemical corrosion and cell viability studies on nickel-free stainless steel orthopedic implants. AB - The corrosion and cell viability behaviors of nanostructured, nickel-free stainless steel implants were studied and compared with AISI 316L. The electrochemical studies were conducted by potentiodynamic polarization and electrochemical impedance spectroscopic measurements in a simulated body fluid. Cytocompatibility was also evaluated by the adhesion behavior of adult human stem cells on the surface of the samples. According to the results, the electrochemical behavior is affected by a compromise among the specimen's structural characteristics, comprising composition, density, and grain size. The cell viability is interpreted by considering the results of the electrochemical impedance spectroscopic experiments. PMID- 23630604 TI - Characterization of the muscle electrical properties in low back pain patients by electrical impedance myography. AB - OBJECTIVES: This study aims to investigate the electrical properties of lumbar paraspinal muscles (LPM) of patients with acute lower back pain (LBP) and to study a new approach, namely Electrical Impedance Myography (EIM), for reliable, low-cost, non-invasive, and real-time assessment of muscle-strained acute LBP. DESIGN: Patients with muscle-strained acute LBP (n = 30) are compared to a healthy reference group (n = 30). Electrical properties of LPM are studied. BACKGROUND: EIM is a novel technique under development for the assessment of neuromuscular disease. Therefore, it is speculated that EIM can be employed for the assessment of muscle-strained acute LBP. METHODS: Surface electrodes, in 2 electrode configurations, was used to measure the electrical properties of patient's and healthy subject's LPM at six different frequencies (0.02, 25.02, 50.02, 1000.02, 3000.02, and 5000.02 kHz), with the amplitude of the applied voltage limited to 200 mV. Parameters of impedance (Z), extracellular resistance (Re), intracellular resistance (Ri), and the ratio of extracellular resistance to intracellular resistance (Re/Ri) of LBP patient's and healthy subject's LPM were assessed to see if significant difference in values obtained in muscle-strained acute LBP patients existed. RESULTS: Intraclass correlation coefficient (ICC) showed that all measurements (ICC>0.96 for all studying parameters: Z, Re, Ri, and Re/Ri) had good reliability and validity. Significant differences were found on Z between LBP patient's and healthy subject's LPM at all studying frequencies, with p<0.05 for all frequencies. It was also found that Re (p<0.05) and Re/Ri (p<0.05) of LBP patient's LPM was significant smaller than that of healthy subjects while Ri (p<0.05) of LBP patient's LPM was significant greater than that of healthy subjects. No statistical significant difference was found between the left and right LPM of LBP patients and healthy subjects on the four studying parameters. CONCLUSION: EIM is a promising technique for assessing muscle strained acute LBP. PMID- 23630605 TI - Study of double-side ultrasonic embossing for fabrication of microstructures on thermoplastic polymer substrates. AB - Double-side replication of polymer substrates is beneficial to the design and the fabrication of 3-demensional devices. The ultrasonic embossing method is a promising, high efficiency and low cost replication method for thermoplastic substrates. It is convenient to apply silicon molds in ultrasonic embossing, because microstructures can be easily fabricated on silicon wafers with etching techniques. To reduce the risk of damaging to silicon molds and to improve the replication uniformity on both sides of the polymer substrates, thermal assisted ultrasonic embossing method was proposed and tested. The processing parameters for the replication of polymethyl methacrylate (PMMA), including ultrasonic amplitude, ultrasonic force, ultrasonic time, and thermal assisted temperature were studied using orthogonal array experiments. The influences of the substrate thickness, pattern style and density were also investigated. The experiment results show that the principal parameters for the upper and lower surface replication are ultrasonic amplitude and thermal assisted temperature, respectively. As to the replication uniformity on both sides, the ultrasonic force has the maximal influence. Using the optimized parameters, the replication rate reached 97.5% on both sides of the PMMA substrate, and the cycle time was less than 50 s. PMID- 23630606 TI - Characterization of the non-polio enterovirus infections associated with acute flaccid paralysis in South-Western India. AB - Non-polio enteroviruses (NPEVs) have been reported frequently in association with acute flaccid paralysis (AFP) cases during Polio Surveillance Programs (PSPs) worldwide. However, there is limited understanding on the attributes of their infections. This study reports characteristics of NPEVs isolated from AFP cases, investigated during PSPs held in 2009-2010, in Karnataka and Kerala states of south-western India having varied climatic conditions. NPEV cell culture isolates derived from stool specimens that were collected from 422 of 2186 AFP cases (<1 14 years age) and 17 of 41 asymptomatic contacts; and details of all AFP cases/contacts were obtained from National Polio Laboratory, Bangalore. The distribution of NPEV infections among AFP cases and circulation pattern of NPEV strains were determined by statistical analysis of the data. Genotyping of all NPEV isolates was carried out by partial VP1 gene sequencing and phylogenetic analysis. NPEV positive AFP cases were significantly higher in children aged <2 years; with residual paralysis; in summer months; and in regions with relatively hot climate. Genotyping of NPEVs identified predominance of human enteroviruses (HEV)-B species [81.9%-Echoviruses (E): 57.3%; coxsackieviruses (CV) B: 15%; numbered EVs: 8.9%; CVA9: 0.7%] and low levels of HEV-A [14.5%-CVA: 6%; numbered EVs: 8.5%] and HEV-C [3.6%-CVA: 2.6%; numbered EVs: 1%] species, encompassing 63 genotypes. EV76 (6.3%) and each of E3, CVB3 and E9 (4.97%) were found frequently during 2009 while E11 (6.7%), CVB1 (6.1%), E7 (5.1%) and E20 (5.1%) were detected commonly in 2010. A marked proportion of AFP cases from children aged <2 years; presenting with fever; and from north and south interior parts of Karnataka state was detected with E/numbered EVs than that found with CVA/CVB. This study highlights the extensive genetic diversity and diverse circulation patterns of NPEV strains in AFP cases from different populations and climatic conditions. PMID- 23630607 TI - The outcome of prophylactic intravenous cefazolin and ceftriaxone in cirrhotic patients at different clinical stages of disease after endoscopic interventions for acute variceal hemorrhage. AB - Antibiotic prophylaxis with norfloxacin, intravenous ciprofloxacin, or ceftriaxone has been recommended for cirrhotic patients with gastrointestinal hemorrhage but little is known about intravenous cefazolin. This study aimed to compare the outcome of intravenous cefazolin and ceftriaxone as prophylactic antibiotics among cirrhotic patients at different clinical stages, and to identify the associated risk factors. The medical records of 713 patients with acute variceal bleeding who had received endoscopic procedures from were reviewed. Three hundred and eleven patients were entered for age-matched adjustment after strict exclusion criteria. After the adjustment, a total of 102 patients were enrolled and sorted into 2 groups according to the severity of cirrhosis: group A (Child's A patients, n = 51) and group B (Child's B and C patients, n = 51). The outcomes were prevention of infection, time of rebleeding, and death. Our subgroup analysis results failed to show a significant difference in infection prevention between patients who received prophylactic cefazolin and those who received ceftriaxone among Child's A patients (93.1% vs. 90.9%, p = 0.641); however, a trend of significance in favor of ceftriaxone prophylaxis (77.8% vs. 87.5%, p = 0.072) was seen among Child's B and C patients. More rebleeding cases were observed in patients who received cefazolin than in those who received ceftriaxone among Child's B and C patients (66.7% vs. 25.0%, p = 0.011) but not in Child's A patients (32% vs. 40.9%, p = 0.376). The risk factors associated with rebleeding were history of bleeding and use of prophylactic cefazolin among Child's B and C patients. In conclusion, this study suggests that prophylactic intravenous cefazolin may not be inferior to ceftriaxone in preventing infections and reducing rebleeding among Child's A cirrhotic patients after endoscopic interventions for acute variceal bleeding. Prophylactic intravenous ceftriaxone yields better outcome among Child's B and C patients. PMID- 23630608 TI - Suppression of mitochondrial complex I influences cell metastatic properties. AB - Despite the fact that mitochondrial dysfunction has an important role in tumorigenesis and metastasis, the underlying mechanism remains to be elucidated. Mitochondrial Complex I (NADH:ubiquinone oxidoreductase) is the first and the largest protein complex of the mitochondrial electron-transport chain (ETC),which has an essential role in maintaining mitochondrial function and integrity. In this study, we separately knocked down two subunits of mitochondrial complex I, GRIM-19 or NDUFS3, and investigated their effects on metastatic behaviors and explored the possible mechanisms. Our data showed that stable down-modulation of GRIM-19 or NDUFS3 decreased complex I activity and reactive oxygen species (ROS) production; led to enhanced cell adhesion, migration, invasion, and spheroid formation; and influenced the expressions of extracellular matrix (ECM) molecules and its related proteins. We also observed that the expressions of GRIM-19, NDUFS3, and ECM elements were correlated with invasive capabilities of breast cancer cell lines. These results suggest that inhibition of complex I affects metastatic properties of cancer cells, and mitochondrial ROS might play a crucial role in these processes by regulating ECM. PMID- 23630609 TI - Mitochondrial genomes of two Barklice, Psococerastis albimaculata and Longivalvus hyalospilus (Psocoptera: Psocomorpha): contrasting rates in mitochondrial gene rearrangement between major lineages of Psocodea. AB - The superorder Psocodea has ~10,000 described species in two orders: Psocoptera (barklice and booklice) and Phthiraptera (parasitic lice). One booklouse, Liposcelis bostrychophila and six species of parasitic lice have been sequenced for complete mitochondrial (mt) genomes; these seven species have the most rearranged mt genomes seen in insects. The mt genome of a barklouse, lepidopsocid sp., has also been sequenced and is much less rearranged than those of the booklouse and the parasitic lice. To further understand mt gene rearrangements in the Psocodea, we sequenced the mt genomes of two barklice, Psococerastis albimaculata and Longivalvus hyalospilus, the first representatives from the suborder Psocomorpha, which is the most species-rich suborder of the Psocodea. We found that these two barklice have the least rearranged mt genomes seen in the Psocodea to date: a protein-coding gene (nad3) and five tRNAs (trnN, trnS1, trnE, trnM and trnC) have translocated. Rearrangements of mt genes in these two barklice can be accounted for by two events of tandem duplication followed by random deletions. Phylogenetic analyses of the mt genome sequences support the view that Psocoptera is paraphyletic whereas Phthiraptera is monophyletic. The booklouse, L. bostrychophila (suborder Troctomorpha) is most closely related to the parasitic lice. The barklice (suborders Trogiomorpha and Psocomorpha) are closely related and form a monophyletic group. We conclude that mt gene rearrangement has been substantially faster in the lineage leading to the booklice and the parasitic lice than in the lineage leading to the barklice. Lifestyle change appears to be associated with the contrasting rates in mt gene rearrangements between the two lineages of the Psocodea. PMID- 23630610 TI - Role of circulating angiotensin converting enzyme 2 in left ventricular remodeling following myocardial infarction: a prospective controlled study. AB - Angiotensin-converting enzyme 2 (ACE2) cleaves Angiotensin-II to Angiotensin-(1 7), a cardioprotective peptide. Serum soluble ACE2 (sACE2) activity is raised in chronic heart failure, suggesting a compensatory role in left ventricular dysfunction. Our aim was to study the relationship between sACE2 activity, infarct size, left ventricular systolic function and remodeling following ST elevation myocardial infarction (STEMI). A contrast-enhanced cardiac magnetic resonance study was performed acutely in 95 patients with first STEMI and repeated at 6 months to measure LV end-diastolic volume index, ejection fraction and infarct size. Baseline sACE2 activities, measured by fluorescent enzymatic assay 24 to 48 hours and at 7 days from admission, were compared to that obtained in 22 matched controls. Patients showed higher sACE2 at baseline than controls (104.4 [87.4-134.8] vs 74.9 [62.8-87.5] RFU/ul/hr, p<0.001). At seven days, sACE2 activity significantly increased from baseline (115.5 [92.9-168.6] RFU/ul/hr, p<0.01). An inverse correlation between sACE2 activity with acute and follow-up ejection fraction was observed (r = -0.519, p<0.001; r = -0.453, p = 0.001, respectively). Additionally, sACE2 directly correlated with infarct size (r = 0.373, p<0.001). Both, infarct size (beta = -0.470 [95%CI:-0.691:-0.248], p<0.001) and sACE2 at 7 days (beta = -0.025 [95%CI:-0.048:-0.002], p = 0.030) were independent predictors of follow-up ejection fraction. Patients with sACE2 in the upper tertile had a 4.4 fold increase in the incidence of adverse left ventricular remodeling (95% confidence interval: 1.3 to 15.2, p = 0.027). In conclusion, serum sACE2 activity rises in relation to infarct size, left ventricular systolic dysfunction and is associated with the occurrence of left ventricular remodeling. PMID- 23630611 TI - Multisensory origin of the subjective first-person perspective: visual, tactile, and vestibular mechanisms. AB - In three experiments we investigated the effects of visuo-tactile and visuo vestibular conflict about the direction of gravity on three aspects of bodily self-consciousness: self-identification, self-location, and the experienced direction of the first-person perspective. Robotic visuo-tactile stimulation was administered to 78 participants in three experiments. Additionally, we presented participants with a virtual body as seen from an elevated and downward-directed perspective while they were lying supine and were therefore receiving vestibular and postural cues about an upward-directed perspective. Under these conditions, we studied the effects of different degrees of visuo-vestibular conflict, repeated measurements during illusion induction, and the relationship to a classical measure of visuo-vestibular integration. Extending earlier findings on experimentally induced changes in bodily self-consciousness, we show that self identification does not depend on the experienced direction of the first-person perspective, whereas self-location does. Changes in bodily self-consciousness depend on visual gravitational signals. Individual differences in the experienced direction of first-person perspective correlated with individual differences in visuo-vestibular integration. Our data reveal important contributions of visuo vestibular gravitational cues to bodily self-consciousness. In particular we show that the experienced direction of the first-person perspective depends on the integration of visual, vestibular, and tactile signals, as well as on individual differences in idiosyncratic visuo-vestibular strategies. PMID- 23630612 TI - Polyacetylenes from Notopterygium incisum--new selective partial agonists of peroxisome proliferator-activated receptor-gamma. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a key regulator of glucose and lipid metabolism and therefore an important pharmacological target to combat metabolic diseases. Since the currently used full PPARgamma agonists display serious side effects, identification of novel ligands, particularly partial agonists, is highly relevant. Searching for new active compounds, we investigated extracts of the underground parts of Notopterygium incisum, a medicinal plant used in traditional Chinese medicine, and observed significant PPARgamma activation using a PPARgamma-driven luciferase reporter model. Activity guided fractionation of the dichloromethane extract led to the isolation of six polyacetylenes, which displayed properties of selective partial PPARgamma agonists in the luciferase reporter model. Since PPARgamma activation by this class of compounds has so far not been reported, we have chosen the prototypical polyacetylene falcarindiol for further investigation. The effect of falcarindiol (10 uM) in the luciferase reporter model was blocked upon co-treatment with the PPARgamma antagonist T0070907 (1 uM). Falcarindiol bound to the purified human PPARgamma receptor with a Ki of 3.07 uM. In silico docking studies suggested a binding mode within the ligand binding site, where hydrogen bonds to Cys285 and Glu295 are predicted to be formed in addition to extensive hydrophobic interactions. Furthermore, falcarindiol further induced 3T3-L1 preadipocyte differentiation and enhanced the insulin-induced glucose uptake in differentiated 3T3-L1 adipocytes confirming effectiveness in cell models with endogenous PPARgamma expression. In conclusion, we identified falcarindiol-type polyacetylenes as a novel class of natural partial PPARgamma agonists, having potential to be further explored as pharmaceutical leads or dietary supplements. PMID- 23630613 TI - The risk of type 2 diabetes in men is synergistically affected by parental history of diabetes and overweight. AB - Interactions between genetic- and lifestyle factors may be of specific importance for the development of type 2 diabetes. Only a few earlier studies have evaluated interaction effects for the combination of family history of diabetes and presence of risk factors related to lifestyle. We explored whether 60-year-old men and women from Stockholm with a parental history of diabetes are more susceptible than their counterparts without a parental history of diabetes to the negative influence from physical inactivity, overweight or smoking regarding risk of developing type 2 diabetes. The study comprised 4232 participants of which 205 men and 113 women had diabetes (the vast majority type 2 diabetes considering the age of study participants) and 224 men and 115 women had prediabetes (fasting glucose 6.1-6.9 mmol/l). Prevalence odds ratios (OR) with 95% confidence intervals (95% CI) were calculated using logistic regression. Biologic interaction was analyzed using a Synergy index (S) score. The crude OR for type 2 diabetes associated with a parental history of diabetes was 2.4 (95% CI 1.7-3.5) in men and 1.4 (95% CI 0.9-2.3) in women. Adjustments for overweight, physical inactivity and current smoking had minimal effects on the association observed in men whereas in women it attenuated results. In men, but not in women, a significant interaction effect that synergistically increases the risk of developing type 2 diabetes was observed for the combination of BMI>30 and a parental history of diabetes, S 2.4 (95% CI 1.1-5.1). No signs of interactions were noted for a parental history of diabetes combined with physical inactivity and smoking, respectively. In conclusion, obesity in combination with presence of a parental history of diabetes may be particularly hazardous in men as these two factors were observed to synergistically increase the risk of developing type 2 diabetes in men. PMID- 23630615 TI - Predicting national suicide numbers with social media data. AB - Suicide is not only an individual phenomenon, but it is also influenced by social and environmental factors. With the high suicide rate and the abundance of social media data in South Korea, we have studied the potential of this new medium for predicting completed suicide at the population level. We tested two social media variables (suicide-related and dysphoria-related weblog entries) along with classical social, economic and meteorological variables as predictors of suicide over 3 years (2008 through 2010). Both social media variables were powerfully associated with suicide frequency. The suicide variable displayed high variability and was reactive to celebrity suicide events, while the dysphoria variable showed longer secular trends, with lower variability. We interpret these as reflections of social affect and social mood, respectively. In the final multivariate model, the two social media variables, especially the dysphoria variable, displaced two classical economic predictors - consumer price index and unemployment rate. The prediction model developed with the 2-year training data set (2008 through 2009) was validated in the data for 2010 and was robust in a sensitivity analysis controlling for celebrity suicide effects. These results indicate that social media data may be of value in national suicide forecasting and prevention. PMID- 23630614 TI - RNA-Seq profiling reveals novel hepatic gene expression pattern in aflatoxin B1 treated rats. AB - Deep sequencing was used to investigate the subchronic effects of 1 ppm aflatoxin B1 (AFB1), a potent hepatocarcinogen, on the male rat liver transcriptome prior to onset of histopathological lesions or tumors. We hypothesized RNA-Seq would reveal more differentially expressed genes (DEG) than microarray analysis, including low copy and novel transcripts related to AFB1's carcinogenic activity compared to feed controls (CTRL). Paired-end reads were mapped to the rat genome (Rn4) with TopHat and further analyzed by DESeq and Cufflinks-Cuffdiff pipelines to identify differentially expressed transcripts, new exons and unannotated transcripts. PCA and cluster analysis of DEGs showed clear separation between AFB1 and CTRL treatments and concordance among group replicates. qPCR of eight high and medium DEGs and three low DEGs showed good comparability among RNA-Seq and microarray transcripts. DESeq analysis identified 1,026 differentially expressed transcripts at greater than two-fold change (p<0.005) compared to 626 transcripts by microarray due to base pair resolution of transcripts by RNA-Seq, probe placement within transcripts or an absence of probes to detect novel transcripts, splice variants and exons. Pathway analysis among DEGs revealed signaling of Ahr, Nrf2, GSH, xenobiotic, cell cycle, extracellular matrix, and cell differentiation networks consistent with pathways leading to AFB1 carcinogenesis, including almost 200 upregulated transcripts controlled by E2f1 related pathways related to kinetochore structure, mitotic spindle assembly and tissue remodeling. We report 49 novel, differentially-expressed transcripts including confirmation by PCR-cloning of two unique, unannotated, hepatic AFB1 responsive transcripts (HAfT's) on chromosomes 1.q55 and 15.q11, overexpressed by 10 to 25-fold. Several potentially novel exons were found and exon refinements were made including AFB1 exon-specific induction of homologous family members, Ugt1a6 and Ugt1a7c. We find the rat transcriptome contains many previously unidentified, AFB1-responsive exons and transcripts supporting RNA-Seq's capabilities to provide new insights into AFB1-mediated gene expression leading to hepatocellular carcinoma. PMID- 23630616 TI - Ablation of ghrelin O-acyltransferase does not improve glucose intolerance or body adiposity in mice on a leptin-deficient ob/ob background. AB - Type 2 Diabetes is a global health burden and based on current estimates will become an even larger problem in the future. Developing new strategies to prevent and treat diabetes is a scientific challenge of high priority. The stomach hormone ghrelin has been associated with playing a role in the regulation of glucose homeostasis. However, its precise mechanism and impact on whole glucose metabolism remains to be elucidated. This study aims to clarify the role of the two ghrelin isoforms acyl- and desacyl ghrelin in regulating glucose homeostasis. Therefore ghrelin activating enzyme Ghrelin-O-acyltransferase (GOAT) was ablated in leptin-deficient ob/ob mice to study whether specific acyl ghrelin deficiency or desacyl ghrelin abundance modifies glucose tolerance on a massively obese background. As targeted deletion of acyl ghrelin does not improve glucose homeostasis in our GOAT-ob/ob mouse model we conclude that neither acyl ghrelin nor the increased ratio of desacyl/acyl ghrelin is crucial for controlling glucose homeostasis in the here presented model of massive obesity induced by leptin deficiency. PMID- 23630618 TI - Effects of reading health and appearance exercise magazine articles on perceptions of attractiveness and reasons for exercise. AB - OBJECTIVE: To examine the effects of reading exercise-related magazine articles (health, appearance, or control) and the moderating effects of exercise self identity on reasons for exercise and perceptions of attractiveness, among women in first year university. An additional purpose was to use a thought listing technique, the results of which were examined for evidence of internalization of the exercise-related messages. PARTICIPANTS: Female students in their first year of studies between September 2010 and April 2011 (N = 173; mean age = 19.31 years, mean body mass index = 22.01). METHODS: Participants read a health, appearance, or control article, listed thoughts, and completed questionnaires measuring reasons for exercising, physical self-perception, and exercise self identity. RESULTS: Participants in the health condition rated exercise for health significantly higher than control condition participants. Participants with high exercise self-identity rated attractiveness as a reason for exercising significantly higher than low exercise self-identity participants in both the health and appearance conditions. Participants with higher internalization scores (i.e., accepted societal norms of appearance) reported exercising for attractiveness reasons more so than participants with lower internalization scores. CONCLUSIONS: The good news is that health messages may be influential and result in wanting to exercise for health purposes. However, exercising for attractiveness was rated highly by participants with high exercise identity who read either the health or appearance articles. Health and appearance are not necessarily distinct concepts for female undergraduate students and the media may influence cited reasons for exercise. PMID- 23630617 TI - Preferential biological processes in the human limbus by differential gene profiling. AB - Corneal epithelial stem cells or limbal stem cells (LSCs) are responsible for the maintenance of the corneal epithelium in humans. The exact location of LSCs is still under debate, but the increasing need for identifying the biological processes in the limbus, where LSCs are located, is of great importance in the regulation of LSCs. In our current study we identified 146 preferentially expressed genes in the human limbus in direct comparison to that in the cornea and conjunctiva. The expression of newly identified limbal transcripts endomucin, fibromodulin, paired-like homeodomain 2 (PITX2) and axin-2 were validated using qRT-PCR. Further protein analysis on the newly identified limbal transcripts showed protein localization of PITX2 in the basal and suprabasal layer of the limbal epithelium and very low expression in the cornea and conjunctiva. Two other limbal transcripts, frizzled-7 and tenascin-C, were expressed in the basal epithelial layer of the limbus. Gene ontology and network analysis of the overexpressed limbal genes revealed cell-cell adhesion, Wnt and TGF-beta/BMP signaling components among other developmental processes in the limbus. These results could aid in a better understanding of the regulatory elements in the LSC microenvironment. PMID- 23630619 TI - Targeted deletion of the ERK5 MAP kinase impairs neuronal differentiation, migration, and survival during adult neurogenesis in the olfactory bulb. AB - Recent studies have led to the exciting idea that adult-born neurons in the olfactory bulb (OB) may be critical for complex forms of olfactory behavior in mice. However, signaling mechanisms regulating adult OB neurogenesis are not well defined. We recently reported that extracellular signal-regulated kinase (ERK) 5, a MAP kinase, is specifically expressed in neurogenic regions within the adult brain. This pattern of expression suggests a role for ERK5 in the regulation of adult OB neurogenesis. Indeed, we previously reported that conditional deletion of erk5 in adult neurogenic regions impairs several forms of olfactory behavior in mice. Thus, it is important to understand how ERK5 regulates adult neurogenesis in the OB. Here we present evidence that shRNA suppression of ERK5 in adult neural stem/progenitor cells isolated from the subventricular zone (SVZ) reduces neurogenesis in culture. By contrast, ectopic activation of endogenous ERK5 signaling via expression of constitutive active MEK5, an upstream activating kinase for ERK5, stimulates neurogenesis. Furthermore, inducible and conditional deletion of erk5 specifically in the neurogenic regions of the adult mouse brain interferes with cell cycle exit of neuroblasts, impairs chain migration along the rostral migratory stream and radial migration into the OB. It also inhibits neuronal differentiation and survival. These data suggest that ERK5 regulates multiple aspects of adult OB neurogenesis and provide new insights concerning signaling mechanisms governing adult neurogenesis in the SVZ-OB axis. PMID- 23630620 TI - Virome profiling of bats from Myanmar by metagenomic analysis of tissue samples reveals more novel Mammalian viruses. AB - Bats are reservoir animals harboring many important pathogenic viruses and with the capability of transmitting these to humans and other animals. To establish an effective surveillance to monitor transboundary spread of bat viruses between Myanmar and China, complete organs from the thorax and abdomen from 853 bats of six species from two Myanmar counties close to Yunnan province, China, were collected and tested for their virome through metagenomics by Solexa sequencing and bioinformatic analysis. In total, 3,742,314 reads of 114 bases were generated, and over 86% were assembled into 1,649,512 contigs with an average length of 114 bp, of which 26,698 (2%) contigs were recognizable viral sequences belonging to 24 viral families. Of the viral contigs 45% (12,086/26,698) were related to vertebrate viruses, 28% (7,443/26,698) to insect viruses, 27% (7,074/26,698) to phages and 95 contigs to plant viruses. The metagenomic results were confirmed by PCR of selected viruses in all bat samples followed by phylogenetic analysis, which has led to the discovery of some novel bat viruses of the genera Mamastrovirus, Bocavirus, Circovirus, Iflavirus and Orthohepadnavirus and to their prevalence rates in two bat species. In conclusion, the present study aims to present the bat virome in Myanmar, and the results obtained further expand the spectrum of viruses harbored by bats. PMID- 23630621 TI - Detection of rifampicin resistance in Mycobacterium tuberculosis by padlock probes and magnetic nanobead-based readout. AB - Control of the global epidemic tuberculosis is severely hampered by the emergence of drug-resistant Mycobacterium tuberculosis strains. Molecular methods offer a more rapid means of characterizing resistant strains than phenotypic drug susceptibility testing. We have developed a molecular method for detection of rifampicin-resistant M. tuberculosis based on padlock probes and magnetic nanobeads. Padlock probes were designed to target the most common mutations associated with rifampicin resistance in M. tuberculosis, i.e. at codons 516, 526 and 531 in the gene rpoB. For detection of the wild type sequence at all three codons simultaneously, a padlock probe and two gap-fill oligonucleotides were used in a novel assay configuration, requiring three ligation events for circularization. The assay also includes a probe for identification of the M. tuberculosis complex. Circularized probes were amplified by rolling circle amplification. Amplification products were coupled to oligonucleotide-conjugated magnetic nanobeads and detected by measuring the frequency-dependent magnetic response of the beads using a portable AC susceptometer. PMID- 23630622 TI - Characterization and generation of male courtship song in Cotesia congregata (Hymenoptera: Braconidae). AB - BACKGROUND: Male parasitic wasps attract females with a courtship song produced by rapid wing fanning. Songs have been described for several parasitic wasp species; however, beyond association with wing fanning, the mechanism of sound generation has not been examined. We characterized the male courtship song of Cotesia congregata (Hymenoptera: Braconidae) and investigated the biomechanics of sound production. METHODS AND PRINCIPAL FINDINGS: Courtship songs were recorded using high-speed videography (2,000 fps) and audio recordings. The song consists of a long duration amplitude-modulated "buzz" followed by a series of pulsatile higher amplitude "boings," each decaying into a terminal buzz followed by a short inter-boing pause while wings are stationary. Boings have higher amplitude and lower frequency than buzz components. The lower frequency of the boing sound is due to greater wing displacement. The power spectrum is a harmonic series dominated by wing repetition rate ~220 Hz, but the sound waveform indicates a higher frequency resonance ~5 kHz. Sound is not generated by the wings contacting each other, the substrate, or the abdomen. The abdomen is elevated during the first several wing cycles of the boing, but its position is unrelated to sound amplitude. Unlike most sounds generated by volume velocity, the boing is generated at the termination of the wing down stroke when displacement is maximal and wing velocity is zero. Calculation indicates a low Reynolds number of ~1000. CONCLUSIONS AND SIGNIFICANCE: Acoustic pressure is proportional to velocity for typical sound sources. Our finding that the boing sound was generated at maximal wing displacement coincident with cessation of wing motion indicates that it is caused by acceleration of the wing tips, consistent with a dipole source. The low Reynolds number requires a high wing flap rate for flight and predisposes wings of small insects for sound production. PMID- 23630623 TI - Regulation and migratory role of P-selectin ligands during intestinal inflammation. AB - Dendritic cells from mesenteric lymph nodes (MLN) can convert retinal to retinoic acid (RA), which promotes induction of the gut-specific homing receptor alpha4beta7. In contrast, priming within peripheral lymph nodes leads to upregulation of E- and P-selectin ligands (E- and P-lig). Apart from its alpha4beta7 promoting effect, RA was shown to suppress E- and P-lig induction in vitro. However, enhanced frequencies of P-lig(+) CD4(+) T cells were reported during intestinal inflammation. To understand this contradiction, we first determined whether location of intestinal inflammation, that is, ileitis or colitis, affects P-lig induction. Both conditions promoted P-lig expression on CD4(+) T cells; however, P-lig expressed on T cells facilitated Th1 cell recruitment only into the inflamed colon but not into inflamed small intestine induced by oral Toxoplasma gondii infection. A majority of P-lig(+)CD4(+) T cells found within MLN during intestinal inflammation co-expressed alpha4beta7 confirming their activation in the presence of RA. Mesenteric P-lig(+)CD4(+) cells co-expressed the 130 kDa isoform of CD43 which requires activity of core 2 (beta)1,6-N-acetyl-glycosaminyltransferase-I (C2GlcNAcT-I) suggesting that C2GlcNAcT-I contributes to P-lig expression under these conditions. To test whether inflammatory mediators can indeed overrule the inhibitory effect of RA on P-lig expression we stimulated CD4(+) T cells either polyclonal in the presence of IL-12 and IFNgamma or by LPS-activated MLN-derived dendritic cells. Both conditions promoted P-lig induction even in the presence of RA. While RA impeded the induction of fucosyltransferase-VII it did not affect IL-12-dependent C2GlcNAcT-I induction suggesting that C2GlcNAcT-I can support P-lig expression even if fucosyltransferase-VII mRNA upregulation is dampened. PMID- 23630624 TI - Circulating biomarkers for predicting cardiovascular disease risk; a systematic review and comprehensive overview of meta-analyses. AB - BACKGROUND: Cardiovascular disease is one of the major causes of death worldwide. Assessing the risk for cardiovascular disease is an important aspect in clinical decision making and setting a therapeutic strategy, and the use of serological biomarkers may improve this. Despite an overwhelming number of studies and meta analyses on biomarkers and cardiovascular disease, there are no comprehensive studies comparing the relevance of each biomarker. We performed a systematic review of meta-analyses on levels of serological biomarkers for atherothrombosis to compare the relevance of the most commonly studied biomarkers. METHODS AND FINDINGS: Medline and Embase were screened on search terms that were related to "arterial ischemic events" and "meta-analyses". The meta-analyses were sorted by patient groups without pre-existing cardiovascular disease, with cardiovascular disease and heterogeneous groups concerning general populations, groups with and without cardiovascular disease, or miscellaneous. These were subsequently sorted by end-point for cardiovascular disease or stroke and summarized in tables. We have identified 85 relevant full text articles, with 214 meta-analyses. Markers for primary cardiovascular events include, from high to low result: C-reactive protein, fibrinogen, cholesterol, apolipoprotein B, the apolipoprotein A/apolipoprotein B ratio, high density lipoprotein, and vitamin D. Markers for secondary cardiovascular events include, from high to low result: cardiac troponins I and T, C-reactive protein, serum creatinine, and cystatin C. For primary stroke, fibrinogen and serum uric acid are strong risk markers. Limitations reside in that there is no acknowledged search strategy for prognostic studies or meta-analyses. CONCLUSIONS: For primary cardiovascular events, markers with strong predictive potential are mainly associated with lipids. For secondary cardiovascular events, markers are more associated with ischemia. Fibrinogen is a strong predictor for primary stroke. PMID- 23630625 TI - In-situ effects of eutrophication and overfishing on physiology and bacterial diversity of the red sea coral Acropora hemprichii. AB - Coral reefs of the Central Red Sea display a high degree of endemism, and are increasingly threatened by anthropogenic effects due to intense local coastal development measures. Overfishing and eutrophication are among the most significant local pressures on these reefs, but there is no information available about their potential effects on the associated microbial community. Therefore, we compared holobiont physiology and 16S-based bacterial communities of tissue and mucus of the hard coral Acropora hemprichii after 1 and 16 weeks of in-situ inorganic nutrient enrichment (via fertilizer diffusion) and/or herbivore exclusion (via caging) in an offshore reef of the Central Red Sea. Simulated eutrophication and/or overfishing treatments did not affect coral physiology with respect to coral respiration rates, chlorophyll a content, zooxanthellae abundance, or delta (15)N isotopic signatures. The bacterial community of A. hemprichii was rich and uneven, and diversity increased over time in all treatments. While distinct bacterial species were identified as a consequence of eutrophication, overfishing, or both, two bacterial species that could be classified to the genus Endozoicomonas were consistently abundant and constituted two thirds of bacteria in the coral. Several nitrogen-fixing and denitrifying bacteria were found in the coral specimens that were exposed to experimentally increased nutrients. However, no particular bacterial species was consistently associated with the coral under a given treatment and the single effects of manipulated eutrophication and overfishing could not predict the combined effect. Our data underlines the importance of conducting field studies in a holobiont framework, taking both, physiological and molecular measures into account. PMID- 23630626 TI - Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is caused by loss of the Survival Motor Neuron 1 (SMN1) gene, resulting in reduced SMN protein. Humans possess the additional SMN2 gene (or genes) that does produce low level of full length SMN, but cannot adequately compensate for loss of SMN1 due to aberrant splicing. The majority of SMN2 gene transcripts lack exon 7 and the resultant SMNDelta7 mRNA is translated into an unstable and non-functional protein. Splice intervention therapies to promote exon 7 retention and increase amounts of full-length SMN2 transcript offer great potential as a treatment for SMA patients. Several splice silencing motifs in SMN2 have been identified as potential targets for antisense oligonucleotide mediated splice modification. A strong splice silencer is located downstream of exon 7 in SMN2 intron 7. Antisense oligonucleotides targeting this motif promoted SMN2 exon 7 retention in the mature SMN2 transcripts, with increased SMN expression detected in SMA fibroblasts. We report here systematic optimisation of phosphorodiamidate morpholino oligonucleotides (PMO) that promote exon 7 retention to levels that rescued the phenotype in a severe mouse model of SMA after intracerebroventricular delivery. Furthermore, the PMO gives the longest survival reported to date after a single dosing by ICV. PMID- 23630627 TI - Regional insect inventories require long time, extensive spatial sampling and good will. AB - Understanding how faunistic knowledge develops is of paramount importance to correctly evaluate completeness of insect inventories and to plan future research at regional scale, yet this is an unexplored issue. Aim of this paper was to investigate the processes that lead to a complete species inventory at a regional level for a beetle family. The tenebionid beetles of Latium region (Italy) were analysed as a case study representative of general situations. A comprehensive faunistic database including 3,561 records spanning from 1871 to 2010 was realized examining 25,349 museum specimens and published data. Accumulation curves and non-parametric estimators of species richness were applied to model increase in faunistic knowledge over time, through space and by collectors' number. Long time, large spatial extent and contribution of many collectors were needed to obtain a reliable species inventory. Massive sampling was not effective in recovering more species. Amateur naturalists (here called parafaunists) were more efficient collectors than professional entomologists. Museum materials collected by parafaunists over long periods and large spatial extent resulted to be a cost effective source of faunistic information with small number of collected individuals. It is therefore important to valuate and facilitate the work of parafaunists as already suggested for parataxonomists. By contrast, massive collections by standardized techniques for ecological research seem to be of scarce utility in improving faunistic knowledge, but their value for faunistic studies may be enhanced if they are conducted in poorly surveyed areas. PMID- 23630628 TI - Host stress response is important for the pathogenesis of the deadly amphibian disease, Chytridiomycosis, in Litoria caerulea. AB - Chytridiomycosis, a disease caused by Batrachochytrium dendrobatidis, has contributed to worldwide amphibian population declines; however, the pathogenesis of this disease is still somewhat unclear. Previous studies suggest that infection disrupts cutaneous sodium transport, which leads to hyponatremia and cardiac failure. However, infection is also correlated with unexplained effects on appetite, skin shedding, and white blood cell profiles. Glucocorticoid hormones may be the biochemical connection between these disparate effects, because they regulate ion homeostasis and can also influence appetite, skin shedding, and white blood cells. During a laboratory outbreak of B. dendrobatidis in Australian Green Tree Frogs, Litoria caerulea, we compared frogs showing clinical signs of chytridiomycosis to infected frogs showing no signs of disease and determined that diseased frogs had elevated baseline corticosterone, decreased plasma sodium and potassium, and altered WBC profiles. Diseased frogs also showed evidence of poorer body condition and elevated metabolic rates compared with frogs showing no signs of disease. Prior to displaying signs of disease, we also observed changes in appetite, body mass, and the presence of shed skin associated with infected but not yet diseased frogs. Collectively, these results suggest that elevated baseline corticosterone is associated with chytridiomycosis and correlates with some of the deleterious effects observed during disease development. PMID- 23630629 TI - Urine and serum microRNA-1 as novel biomarkers for myocardial injury in open heart surgeries with cardiopulmonary bypass. AB - MicroRNA-1 (miR-1) is a cardio-specific/enriched microRNA. Our recent studies have revealed that serum and urine miR-1 could be a novel sensitive biomarker for acute myocardial infarction. Open-heart surgeries with cardiopulmonary bypass (CPB) are often accompanied with surgery injury and CPB-associated injury on the hearts. However, the association of miR-1 and these intra-operative and post operative cardiac injures is unknown. The objective of this study was to test the hypothesis that urine and serum miR-1 might be a novel biomarker for myocardial injuries in open-heart surgeries with CPB. Serum and urine miR-1 levels in 20 patients with elective mitral valve surgery were measured at pre-surgery, pre CPB, 60 min post-CBP, and 24h post-CBP. Serum cardiac troponin-I (cTnI) was used as a positive control biomarker for cardiac injury. Compared with these in pre operative and pre-CPB groups, the levels of miR-1 in serum and urine from patients after open-heart surgeries and CPB were significant increased at all observed time points. A similar pattern of serum cTnI levels and their strong positive correlation with miR-1 levels were identified in these patients. The results suggest that serum and urine miR-1 may be a novel sensitive biomarker for myocardial injury in open-heart surgeries with CPB. PMID- 23630630 TI - Transcriptome analysis of crucian carp (Carassius auratus), an important aquaculture and hypoxia-tolerant species. AB - The crucian carp is an important aquaculture species and a potential model to study genome evolution and physiological adaptation. However, so far the genomics and transcriptomics data available for this species are still scarce. We performed de novo transcriptome sequencing of four cDNA libraries representing brain, muscle, liver and kidney tissues respectively, each with six specimens. The removal of low quality reads resulted in 2.62 million raw reads, which were assembled as 127,711 unigenes, including 84,867 isotigs and 42,844 singletons. A total of 22,273 unigenes were found with significant matches to 14,449 unique proteins. Around14,398 unigenes were assigned with at least one Gene Ontology (GO) category in 84,876 total assignments, and 6,382 unigenes were found in 237 predicted KEGG pathways. The gene expression analysis revealed more genes expressed in brain, more up-regulated genes in muscle and more down-regulated genes in liver as compared with gene expression profiles of other tissues. In addition, 23 enzymes in the glycolysis/gluconeogenesis pathway were recovered. Importantly, we identified 5,784 high-quality putative SNP and 11,295 microsatellite markers which include 5,364 microsatellites with flanking sequences >=50 bp. This study produced the most comprehensive genomic resources that have been derived from crucian carp, including thousands of genetic markers, which will not only lay a foundation for further studies on polyploidy origin and anoxic survival but will also facilitate selective breeding of this important aquaculture species. PMID- 23630632 TI - Neonatal disruption of serine racemase causes schizophrenia-like behavioral abnormalities in adulthood: clinical rescue by d-serine. AB - BACKGROUND: D-Serine, an endogenous co-agonist of the N-methyl-D-aspartate (NMDA) receptor, is synthesized from L-serine by serine racemase (SRR). Given the role of D-serine in both neurodevelopment and the pathophysiology of schizophrenia, we examined whether neonatal disruption of D-serine synthesis by SRR inhibition could induce behavioral abnormalities relevant to schizophrenia, in later life. METHODOLOGY/PRINCIPAL FINDINGS: Neonatal mice (7-9 days) were injected with vehicle or phenazine methosulfate (Met-Phen: 3 mg/kg/day), an SRR inhibitor. Behavioral evaluations, such as spontaneous locomotion, novel object recognition test (NORT), and prepulse inhibition (PPI) were performed at juvenile (5-6 weeks old) and adult (10-12 weeks old) stages. In addition, we tested the effects of D serine on PPI deficits in adult mice after neonatal Met-Phen exposure. Finally, we assessed whether D-serine could prevent the onset of schizophrenia-like behavior in these mice. Neonatal Met-Phen treatment reduced D-serine levels in the brain, 24 hours after the final dose. Additionally, this treatment caused behavioral abnormalities relevant to prodromal symptoms in juveniles and to schizophrenia in adults. A single dose of D-serine improved PPI deficits in adult mice. Interestingly, chronic administration of D-serine (900 mg/kg/day from P35 to P70) significantly prevented the onset of PPI deficits after neonatal Met-Phen exposure. CONCLUSIONS/SIGNIFICANCE: This study shows that disruption of D-serine synthesis during developmental stages leads to behavioral abnormalities relevant to prodromal symptoms and schizophrenia, in later life. Furthermore, early pharmacological intervention with D-serine may prevent the onset of psychosis in adult. PMID- 23630631 TI - Evidence that adrenergic ventrolateral medullary cells are activated whereas precerebellar lateral reticular nucleus neurons are suppressed during REM sleep. AB - Rapid eye movement sleep (REMS) is generated in the brainstem by a distributed network of neurochemically distinct neurons. In the pons, the main subtypes are cholinergic and glutamatergic REMS-on cells and aminergic REMS-off cells. Pontine REMS-on cells send axons to the ventrolateral medulla (VLM), but little is known about REMS-related activity of VLM cells. In urethane-anesthetized rats, dorsomedial pontine injections of carbachol trigger REMS-like episodes that include cortical and hippocampal activation and suppression of motoneuronal activity; the episodes last 4-8 min and can be elicited repeatedly. We used this model to determine whether VLM catecholaminergic cells are silenced during REMS, as is typical of most aminergic neurons studied to date, and to investigate other REMS-related cells in this region. In 18 anesthetized, paralyzed and artificially ventilated rats, we obtained extracellular recordings from VLM cells when REMS like episodes were elicited by pontine carbachol injections (10 mM, 10 nl). One major group were the cells that were activated during the episodes (n = 10). Their baseline firing rate of 3.7+/-2.1 (SD) Hz increased to 9.7+/-2.1 Hz. Most were found in the adrenergic C1 region and at sites located less than 50 um from dopamine beta-hydroxylase-positive (DBH(+)) neurons. Another major group were the silenced or suppressed cells (n = 35). Most were localized in the lateral reticular nucleus (LRN) and distantly from any DBH(+) cells. Their baseline firing rates were 6.8+/-4.4 Hz and 15.8+/-7.1 Hz, respectively, with the activity of the latter reduced to 7.4+/-3.8 Hz. We conclude that, in contrast to the pontine noradrenergic cells that are silenced during REMS, medullary adrenergic C1 neurons, many of which drive the sympathetic output, are activated. Our data also show that afferent input transmitted to the cerebellum through the LRN is attenuated during REMS. This may distort the spatial representation of body position during REMS. PMID- 23630633 TI - Intestinal anti-inflammatory activity of lentinan: influence on IL-8 and TNFR1 expression in intestinal epithelial cells. AB - Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. It is unknown whether beta-1,3;1,6-glucan can induce immune suppressive effects. Here, we study intestinal anti-inflammatory activity of Lentinula edodes-derived beta-1,3;1,6-glucan, which is known as lentinan. Dextran sulfate sodium (DSS)-induced colitis mice were used to elucidate effects of lentinan in vivo. In the cellular level assessment, lentinan was added into a co-culture model consisting of intestinal epithelial Caco-2 cells and LPS stimulated macrophage RAW264.7 cells. Ligated intestinal loop assay was performed for assessing effects of lentinan on intestinal epithelial cells (IECs) in vivo. Oral administration of lentinan (100 ug/mouse) significantly ameliorated DSS induced colitis in body weight loss, shortening of colon lengths, histological score, and inflammatory cytokine mRNA expression in inflamed tissues. Lentinan reduced interleukin (IL)-8 mRNA expression and nuclear factor (NF)-kappaB activation in Caco-2 cells without decreasing of tumor necrosis factor (TNF) alpha production from RAW264.7 cells. Flow cytometric analysis revealed that surface levels of TNF receptor (TNFR) 1 were decreased by lentinan treatment. A clathrin-mediated endocytosis inhibitor, monodansylcadaverine, canceled lentinan inhibition of IL-8 mRNA expression. Moreover, lentinan inhibited TNFR1 expression in Caco-2 cells in both protein and mRNA level. Lentinan also inhibited TNFR1 mRNA expression in mouse IECs. These results suggest that lentinan exhibits intestinal anti-inflammatory activity through inhibition of IL-8 mRNA expression associated with the inhibition of NF-kappaB activation which is triggered by TNFR1 endocytosis and lowering of their expression in IECs. Lentinan may be effective for the treatment of gut inflammation including IBD. PMID- 23630635 TI - Characterisation of the bacterial and fungal communities associated with different lesion sizes of dark spot syndrome occurring in the coral Stephanocoenia intersepta. AB - The number and prevalence of coral diseases/syndromes are increasing worldwide. Dark Spot Syndrome (DSS) afflicts numerous coral species and is widespread throughout the Caribbean, yet there are no known causal agents. In this study we aimed to characterise the microbial communities (bacteria and fungi) associated with DSS lesions affecting the coral Stephanocoenia intersepta using nonculture molecular techniques. Bacterial diversity of healthy tissues (H), those in advance of the lesion interface (apparently healthy AH), and three sizes of disease lesions (small, medium, and large) varied significantly (ANOSIM R = 0.052 p<0.001), apart from the medium and large lesions, which were similar in their community profile. Four bacteria fitted into the pattern expected from potential pathogens; namely absent from H, increasing in abundance within AH, and dominant in the lesions themselves. These included ribotypes related to Corynebacterium (KC190237), Acinetobacter (KC190251), Parvularculaceae (KC19027), and Oscillatoria (KC190271). Furthermore, two Vibrio species, a genus including many proposed coral pathogens, dominated the disease lesion and were absent from H and AH tissues, making them candidates as potential pathogens for DSS. In contrast, other members of bacteria from the same genus, such as V. harveyii were present throughout all sample types, supporting previous studies where potential coral pathogens exist in healthy tissues. Fungal diversity varied significantly as well, however the main difference between diseased and healthy tissues was the dominance of one ribotype, closely related to the plant pathogen, Rhytisma acerinum, a known causal agent of tar spot on tree leaves. As the corals' symbiotic algae have been shown to turn to a darker pigmented state in DSS (giving rise to the syndromes name), the two most likely pathogens are R. acerinum and the bacterium Oscillatoria, which has been identified as the causal agent of the colouration in Black Band Disease, another widespread coral disease. PMID- 23630636 TI - Clinical Predictors of Urinary Tract Infection in the Neonatal Intensive Care Unit. AB - OBJECTIVE: To identify clinical predictors associated with urinary tract infections (UTI) in patients in a referral neonatal intensive care unit (NICU). STUDY DESIGN: We performed a nested case control study of all NICU patients with urine cultures obtained as part of late-onset sepsis evaluations from January 1, 2007 through December 31, 2007 (N=266). Clinical factors and laboratory results were compared between subjects with positive urine cultures (cases, N= 27) and randomly selected subjects with negative cultures (controls, N= 54). RESULTS: Cases were significantly older than controls at the time of urine culture (75 days vs. 29 days, p=0.003). Maximal peripheral white blood cell (WBC) count and C reactive protein (CRP) did not differ between cases and controls. Only 24% of cases had a simultaneously positive blood culture. In multivariable analysis, only increased chronological age was statistically associated with a positive culture (OR 3.02, 95% CI 1.09, 8.39). CONCLUSION: Limited clinical factors exist to identify NICU patients at increased risk for UTI. Peripheral WBC count and CRP do not help discriminate between patients with and without UTI. Clinicians should evaluate chronologically older NICU patients for infection like other young infants, including a urine culture, to adequately identify potential sources of infection. PMID- 23630634 TI - Genetic control of courtship behavior in the housefly: evidence for a conserved bifurcation of the sex-determining pathway. AB - In Drosophila melanogaster, genes of the sex-determination hierarchy orchestrate the development and differentiation of sex-specific tissues, establishing sex specific physiology and neural circuitry. One of these sex-determination genes, fruitless (fru), plays a key role in the formation of neural circuits underlying Drosophila male courtship behavior. Conservation of fru gene structure and sex specific expression has been found in several insect orders, though it is still to be determined whether a male courtship role for the gene is employed in these species due to the lack of mutants and homologous experimental evidence. We have isolated the fru ortholog (Md-fru) from the common housefly, Musca domestica, and show the gene's conserved genomic structure. We demonstrate that male-specific Md fru transcripts arise by conserved mechanisms of sex-specific splicing. Here we show that Md-fru, is similarly involved in controlling male courtship behavior. A male courtship behavioral function for Md-fru was revealed by the behavioral and neuroanatomical analyses of a hypomorphic allele, Md-tra(man) , which specifically disrupted the expression of Md-fru in males, leading to severely impaired male courtship behavior. In line with a role in nervous system development, we found that expression of Md-fru was confined to neural tissues in the brain, most prominently in optic neuropil and in peripheral sensory organs. We propose that, like in Drosophila, overt sexual differentiation of the housefly depends on a sex-determining pathway that bifurcates downstream of the Md-tra gene to coordinate dimorphic development of non-neuronal tissues mediated by Md dsx with that of neuronal tissues largely mediated by Md-fru. PMID- 23630637 TI - Multiple cutaneous and uterine leiomyomatosis syndrome: a review. AB - Multiple cutaneous and uterine leiomyomatosis is an autosomal dominant disease characterized by leiomyomas of the skin and uterus. A small proportion of patients affected by multiple cutaneous and uterine leiomyomatosis will develop renal cell carcinoma and this condition is known as hereditary leiomyomatosis and renal cell carcinoma. Diagnosis usually occurs during histological analysis of a cutaneous biopsy. Management should involve a multidisciplinary team along with periodical radiological studies to closely monitor tumor size in the uterus and kidneys. Gonadotropin-releasing hormone analogues are helpful in reducing the size of uterine fibroids. PMID- 23630638 TI - Nonmedical-grade Injections of Permanent Fillers: Medical and Medicolegal Considerations. AB - Silicone injections may result in complications that bring patients to a dermatologist or plastic surgeon. These complications may be due to the use of nonmedical grade products, large volume injections, incorrect placement of the product, or a combination of the above. Frequently, complications result when injections are performed by unlicensed practitioners. Individuals who undergo large volume procedures may develop a variety of life-threatening problems ranging from infections to pulmonary emboli. Once they develop problems, these patients often present to licensed and board-certified physicians for treatment. Based on a review of the literature, this article provides a management algorithm for various complications. In addition, a medicolegal perspective is presented. Finally, the transgender experience as it relates to silicone injections is also reviewed. PMID- 23630639 TI - The effect of pulsed dye laser on the dermatology life quality index in erythematotelangiectatic rosacea patients: an assessment. AB - BACKGROUND: Erythematotelangiectatic rosacea is a common cutaneous disorder. It has a major psychosocial impact on a patient's life. OBJECTIVE: This study aims to investigate the impact of pulsed dye laser on the quality of life of affected patients as measured by the Dermatology Life Quality Index. METHODS: The authors report a prospective study of 20 patients (in a wide range of skin phototypes) attending a laser clinic. All patients completed the Dermatology Life Quality Index questionnaires before and after three sessions of laser treatment. RESULTS: The mean Dermatology Life Quality Index scores pre- and post-laser treatment were 17.3 and 4.3, respectively. All patients experienced a statistically significant improvement in their quality of life (p<0.0001, paired t test). CONCLUSION: The Dermatology Life Quality Index questionnaire (pre- and post-laser treatment) is an important tool for monitoring the efficacy of therapy and patient satisfaction. PMID- 23630640 TI - Mohs micrographic surgery in the setting of squamoid eccrine ductal carcinoma: addressing a diagnostic and therapeutic challenge. AB - OBJECTIVE: The purpose of this case report and literature review was to summarize the current knowledge surrounding this rare cutaneous tumor and promote awareness of the success of Mohs micrographic surgery as a definitive therapeutic modality in a case of squamoid eccrine ductal carcinoma. DESIGN: Case report and literature review. SETTING: Squamoid eccrine ductal carcinoma has been introduced as a rare type of eccrine carcinoma with only eight previously reported cases in the literature. Despite the tumor's introduction as a type of eccrine carcinoma, the true etiology is currently contentious; the lesion represents a diagnostic challenge, and its malignant potential remains uncertain. Thus, proper histological diagnosis and definitive management are under active discussion. PARTICIPANTS: Index case patient records review and peer-reviewed literature. RESULTS: The authors present the ninth reported case of squamoid eccrine ductal carcinoma and the third report of Mohs micrographic surgery for complete extirpation of the lesion. CONCLUSION: The anecdotal success of Mohs micrographic surgery as a therapeutic modality in the treatment of three cases of squamoid eccrine ductal carcinoma (including the case reported herein) suggests that this is an effective yet tissue-sparing surgical modality. However, given the poorly understood natural history of squamoid eccrine ductal carcinoma and the uncertainty of the lesion's etiological and malignant taxonomy, further experiences with this tumor are necessary and close follow up of patients is suggested. PMID- 23630641 TI - Atypical presentation of cutaneous lupus mucinosis. AB - OBJECTIVE: To describe the epidemiological, clinical, and serological features of cutaneous lupus mucinosis and its relationship to systemic lupus erythematosus as well as elucidate the histopathological features of cutaneous lupus mucinosis and describe how these features differ from tumid lupus erythematosus. DESIGN: Case review and assessment of the literature. SETTING: University academic setting. PARTICIPANT: One patient. RESULTS: The authors report a case of antinuclear antibody negative cutaneous lupus mucinosis in a patient without systemic involvement who responded to hydroxychloroquine and intralesional triamcinolone. A review of the literature found 30 reported cases of cutaneous lupus mucinosis, three of which were antinuclear antibody negative and the majority had systemic lupus erythematosus. The most common therapy reported is systemic corticosteroids; however, the patient described in this case had significant improvement of the lesions with only intralesional steroid injections and hydroxychloroquine. Considering the proportion of patients with cutaneous lupus mucinosis who progress to systemic lupus is uncertain, the authors suggest following these patients closely for evidence of multisystem disease. CONCLUSION: The authors report a case of antinuclear antibody-negative cutaneous lupus mucinosis in a patient without systemic lupus erythematosus who responded to hydroxychloroquine and intralesional triamcinolone. Given the rarity of this condition and reported association with systemic lupus erythematosus, it is important to follow these patients clinically for any signs or symptoms of systemic involvement. PMID- 23630642 TI - Telangiectasia macularis eruptiva persians presenting as island sparing. AB - Mastocytosis is characterized by the proliferation and accumulation of mast cells within organs and most commonly the skin; localization accounting for the frequent presentation of skin lesions in affected individuals. The authors detail a case report involving a patient with telangiectasia macularis eruptive perstans, a rare cutaneous form of mastocytosis, accompanied by an unusual clinical finding of island sparing. PMID- 23630643 TI - A young boy with itchy papules on the trunk. PMID- 23630644 TI - Oxide Formation on Biological Nanostructures via a Structure-Directing Agent: Towards an Understanding of Precise Structural Transcription. AB - Biomimetic silica formation is strongly dependent on the presence of cationic amine groups which hydrolyze organosilicate precursors and bind to silicate oligomers. Since most biological species possess anionic surfaces, the dependence on amine groups limits utilization of biotemplates for fabricating materials with specific morphologies and pore structures. Here, we report a general aminopropyltriethoxysilane (APTES) directed method for preparing hollow silica with well-defined morphologies using varying biotemplates (proteins, viruses, flagella, bacteria and fungi). Control experiments, pH evolution measurements and 29Si NMR spectroscopic studies have revealed a mechanism of the assembly of APTES on bio-surfaces with subsequent nucleation and growth of silica. The APTES assembly and nuclei formation on bio-surfaces ensured precise transcription of the morphologies of biotemplates to the resulting silica. This method could be extended to the preparation of other oxides. PMID- 23630645 TI - Minkowski revisited: glancing at the clinical core of schizophrenic vulnerability. PMID- 23630646 TI - Improving Quality of Life for Patients with Major Depressive Disorder by Increasing Hope and Positive Expectations with Future Directed Therapy (FDT). AB - OBJECTIVE: Impaired quality of life is a significant problem for people with major depressive disorder and is often not addressed through symptom remediation alone. This study examines a new therapy for the treatment for depression that focuses on reducing hopelessness and increasing positive future anticipation, which are factors posited to contribute to quality of life. The new treatment was compared to depressed patients in the same setting treated with group cognitive behavioral therapy. DESIGN: This study used a quasi-experimental design to examine the differences between future directed therapy and cognitive behavioral therapy on improving quality of life in patients with major depressive disorder. The main variables assessed at pre and post-treatment were quality of life, depressive symptoms, and hopelessness. SETTING: Outpatient Department of Psychiatry Cedars-Sinai Medical Center Participants: Twenty-two patients completed the future directed therapy intervention and 20 patients completed the cognitive behavioral therapy intervention. MEASUREMENTS: Patient-reported outcomes were collected using the Quick Inventory of Depressive Symptoms, the Beck Hopelessness Scale, and the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form. RESULTS: Though both treatments were effective at improving depression, hopelessness and positive future anticipation, those patients treated with future directed therapy demonstrated significant improvements in quality of life (p=0.002) while those treated in the cognitive behavioral therapy group did not (p=0.463). The magnitude of change for the main variables was significantly larger in the future directed therapy group and change in hopelessness and change in positive anticipation predicted change in quality of life in the future directed therapy group but not the cognitive behavioral therapy group. CONCLUSIONS: Future directed therapy is a useful treatment for patients with major depressive disorder and quality of life impairment. PMID- 23630647 TI - Predicting pharmacokinetic stability by multiple oral administration of atypical antipsychotics. AB - Lower fluctuation, i.e., lower peak-to-trough plasma-concentration variation at steady-state pharmacokinetics, has several advantages for the treatment of schizophrenia with antipsychotics. The reduction of peak concentration can decrease the risk of dose-dependent side effects, such as extrapyramidal symptom and somnolence, and by contrast the increase in trough concentration can decrease the incidence of lack of efficacy due to subtherapeutic drug concentration. Using a one-compartment simulation technique with pharmacokinetic parameters of each atypical antipsychotic collected from package inserts, the fluctuation index was calculated. Among the antipsychotics, the indices varied from 0.018 to 1.9, depending on dosing regimens, formulations and several pharmacokinetic properties. The order of simulated fluctuation index is active-moiety aripiprazole (b.i.d.) .057). Only 3.2% of the AO patients had no reports of abnormal sensitivity on any of the tests, compared with 59.6% of the healthy subjects (P < .001). CONCLUSION: Intraoral qualitative somatosensory testing can detect intraoral sensory disturbances in AO patients, and the reliability is sufficient for initial screening of orofacial somatosensory function. PMID- 23630689 TI - Lavage therapy versus nonsurgical therapy for the treatment of arthralgia of the temporomandibular joint: a systematic review of randomized controlled trials. AB - AIMS: To carry out a systematic review of randomized controlled trials (RCTs) to investigate in patients with arthralgia of the temporomandibular joint (TMJ) the effectiveness of TMJ lavage compared to nonsurgical treatment with regard to pain intensity and mandibular range of motion. METHODS: The electronic databases Cochrane Controlled Trials Register (1960-2012), PubMed/Medline (1966-2012), and Embase (1966-2012) were systematically searched for relevant RCTs. References of relevant articles were searched for additional studies, as well as citing reports. Two authors independently performed data extraction by using predefined quality indicators. Relevant outcome data included reduction in pain, as assessed by a visual analog scale (VAS) or a pain score, and maximal mouth opening (MMO) before and 6 months after treatment. Included trials were combined using fixed and random effects meta-analysis. RESULTS: Three RCTs (222 patients) were included for meta-analysis. The statistically significant overall standardized mean difference (SMD) (P < .001) with regard to pain intensity was -1.07 (95% CI = -1.38, - 0.76) in favor of TMJ lavage. The MMO did not change significantly (P > .05, SMD = .05 [95% CI = -0.33, 0.23]). CONCLUSIONS: The results suggest that lavage of the TMJ may be slightly more effective than nonsurgical treatment for pain reduction. However, this difference is not likely to be clinically relevant. PMID- 23630944 TI - A novel function of Ataxin-1 in the modulation of PP2A activity is dysregulated in the spinocerebellar ataxia type 1. AB - An expansion of glutamines within the human ataxin-1 protein underlies spinocerebellar ataxia type 1 (SCA1), a dominantly inherited neurodegenerative disorder characterized by ataxia and loss of cerebellar Purkinje neurons. Although the mechanisms linking the mutation to the disease remain unclear, evidence indicates that it involves a combination of both gain and loss of functions of ataxin-1. We previously showed that the mutant ataxin-1 interacts with Anp32a, a potent and selective PP2A inhibitor, suggesting a role of PP2A in SCA1. Herein, we found a new function of ataxin-1: the modulation of Pp2a activity and the regulation of its holoenzyme composition, with the polyglutamine mutation within Atxn1 altering this function in the SCA1 mouse cerebellum before disease onset. We show that ataxin-1 enhances Pp2a-bbeta expression and down regulates Anp32a levels without affecting post-translational modifications of Pp2a catalytic subunit (Pp2a-c) known to regulate Pp2a activity. In contrast, mutant Atxn1 induces a decrease in Y307-phosphorylation in Pp2a-c, known to enhance its activity, while reducing Pp2a-b expression and inhibiting Anp32a levels. qRT-PCR and chromatin immunoprecipitation analyses show that ataxin-1 mediated regulations of the Pp2a-bbeta subunit, specifically bbeta2, and of Anp32a occur at the transcriptional level. The Pp2a pathway alterations were confirmed by identified phosphorylation changes of the known Pp2a-substrates, Erk2 and Gsk3beta. Similarly, mutant ataxin-1-expressing SH-SY5Y cells exhibit abnormal neuritic morphology, decreased levels of both PP2A-Bbeta and ANP32A, and PP2A pathway alterations, all of which are ameliorated by overexpressing ANP32A. Our results point to dysregulation of this newly assigned function of ataxin-1 in SCA1 uncovering new potential targets for therapy. PMID- 23630945 TI - Ambulatory central blood pressure: a new opportunity for mechanistic and clinical cardiovascular research. PMID- 23630946 TI - Progression of glomerular filtration rate reduction determined in conscious Dahl salt-sensitive hypertensive rats. AB - Sequential changes in glomerular filtration rate during development of hypertension in the conscious Dahl salt-sensitive rats were determined using a new method for measurement. Using a miniaturized device, disappearance curves of fluorescein isothiocyanate-sinistrin were measured by transcutaneous excitation and real-time detection of the emitted light through the skin. Rats with implanted femoral venous catheters (dye injection and sampling) and carotid catheters (mean arterial pressure by telemetry) were studied, while maintained on a 0.4% NaCl diet and on days 2, 5, 7, 14, and 21 after switching to 4.0% (high salt [HS]) diet. A separate group of rats were maintained on 0.4% for 21 days as a time control. Mean arterial pressure rose progressively from the last day of 0.4% (130+/-2 mm Hg) reaching significance by day 5 of HS and averaged 162+/-7 mm Hg by day 21. Urine albumin excretion was significantly elevated (*3) by day 7 of HS in Dahl salt-sensitive rats. Glomerular filtration rate reduced on day 14 of HS falling from 1.53+/-0.06 mL/min per 100 g body weight to 1.27+/-0.04. By day 21, glomerular filtration rate had fallen 28% to 1.1+/-0.04 mL/min per 100 g (t(1/2) 28.4+/-1.1 minute.) No significant reductions of creatinine clearance were observed throughout the study in response to HS demonstrating the insensitivity of creatinine clearance measurements even with creatinine measured using mass spectrometry. We conclude that the observed reduction of glomerular filtration rate was a consequence and not a cause of the hypertension and that this noninvasive approach could be used in these conscious Dahl salt-sensitive rats for a longitudinal assessment of renal function. PMID- 23630947 TI - Vascular lesions in Ehlers-Danlos syndrome: is angiotensin II the culprit? PMID- 23630948 TI - Angiotensin II promotes thoracic aortic dissections and ruptures in Col3a1 haploinsufficient mice. AB - Vascular Ehlers-Danlos syndrome is a dramatic inherited disease caused by mutations of type III collagen (COL3A1) gene, associated with early-onset occurrence of arterial ruptures. Col3a1(+/-) heterozygous mice, the only vascular Ehlers-Danlos syndrome model available to date, have no spontaneous early vascular phenotype. Our objective was to determine the susceptibility of Col3a1(+/-) mice to develop arterial ruptures under high blood pressure (BP) conditions induced by a 4-week infusion of angiotensin II (AngII). AngII (1 MUg/kg per minute) significantly and comparably increased systolic BP in Col3a1(+/-) and Col3a1(+/+) mice but led to a higher premature mortality rate in Col3a1(+/-) mice compared with Col3a1(+/+) mice (73% versus 36%; P=0.03), particularly during the first-week infusion (55% versus 0%). Echocardiography and histological analysis evidenced that early deaths were caused by thoracic aortic ruptures preceded by dissections and associated with low aortic collagen fibrils content. Remarkably, lowering the dose of AngII (0.5 MUg/kg per minute) rescued the first-week premature deaths of Col3a1(+/-) mice while decreasing the rises in systolic BP (P=0.05 compared with the high-dose AngII), resulting in similar mortality rates in both groups of mice at the end of the 4-week period (30% versus 50% in Col3a1(+/-) and Col3a1(+/+) mice; P=0.30). Finally, norepinephrine infusion (3.9 MUg/kg per minute) did not induced significant mortality in both groups, whereas it significantly increased systolic BP, comparably with the high and with the low dose of AngII in Col3a1(+/-) mice (P=0.53 and P=1.00, respectively). Our findings demonstrated the extreme sensitivity of Col3a1 insufficient mice to prematurely develop thoracic aortic ruptures in response to AngII and its associated high levels in BP. PMID- 23630949 TI - Prevalence and risk factors for hypertension in hemophilia. AB - Hypertension (HTN) is a major risk factor for intracranial hemorrhage. We, therefore, investigated the prevalence, treatment, and control of HTN in adult patients with hemophilia (PWH). PWH>=18 years (n=458) from 3 geographically different cohorts in the United States were evaluated retrospectively for HTN and risk factors. Results were compared with the nationally representative sample provided by the contemporary National Health and Nutrition Examination Survey (NHANES). PWH had a significantly higher prevalence of HTN compared with NHANES. Overall, the prevalence of HTN was 49.1% in PWH compared with 31.7% in NHANES. At ages 18 to 44, 45 to 64, 65 to 74, and >=75 years, the prevalence of HTN for PWH was 31.8%, 72.6%, 89.7%, and 100.0% compared with 12.5%, 41.2%, 64.1%, and 71.7% in NHANES, respectively. Of treated hypertensive PWH, only 27.1% were controlled, compared with 47.7% in NHANES (all P<0.05). Age, body mass index, diabetes mellitus, and renal function were independently associated with HTN. Among patients with moderate or severe hemophilia there was a trend (~1.5-fold) for higher odds of having HTN compared with patients with mild hemophilia. On the basis of these results, new care models for adult PWH and further studies for the causes of HTN in hemophilia are recommended. PMID- 23630950 TI - Novel description of the 24-hour circadian rhythms of brachial versus central aortic blood pressure and the impact of blood pressure treatment in a randomized controlled clinical trial: The Ambulatory Central Aortic Pressure (AmCAP) Study. AB - Elevated brachial blood pressure (BP) is associated with increased cardiovascular risk and predicts morbidity and mortality in humans. Recently, 24-hour ambulatory BP monitoring and assessment of central aortic BP have been introduced to improve BP phenotyping. The Ambulatory Central Aortic Pressure (AmCAP) study combines these approaches and describes, for the first time, the diurnal patterns of simultaneously measured 24-hour ambulatory brachial and central pressures in a prespecified substudy embedded within a clinical trial of BP lowering in patients with hypertension. Twenty-four-hour ambulatory brachial and central pressure measurements were acquired using a tonometer mounted into the articulating strap of a wristwatch-like device (BPro) in 171 participants with hypertension recruited into the ASSERTIVE (AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients) trial. Participants were randomly assigned to BP lowering with either aliskiren 300 mg QD or telmisartan 80 mg QD for 12 weeks. Ambulatory brachial and central BP was measured in all participants both at baseline and at study end. Brachial and central BP both demonstrated typical diurnal patterns with lower pressures at night. However, night time was associated with smaller reductions in central relative to brachial pressure and decreased pulse pressure amplification (P<0.0001 for both). These effects were not modulated after BP lowering and were maintained after adjustment for day and night-time BP and heart rate (P=0.02). This study demonstrates that brachial and central pressure show different diurnal patterns, which are not modulated by BP lowering therapy, with relatively higher night-time central pressures. These novel data indicate that night-time central BP may provide prognostic importance and warrants further investigation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865020. PMID- 23630952 TI - The stimulated innate resistance event in Bordetella pertussis infection is dependent on reactive oxygen species production. AB - The exacerbated induction of innate immune responses in airways can abrogate diverse lung infections by a phenomenon known as stimulated innate resistance (StIR). We recently demonstrated that the enhancement of innate response activation can efficiently impair Bordetella pertussis colonization in a Toll like receptor 4 (TLR4)-dependent manner. The aim of this work was to further characterize the effect of lipopolysaccharide (LPS) on StIR and to identify the mechanisms that mediate this process. Our results showed that bacterial infection was completely abrogated in treated mice when the LPS of B. pertussis (1 MUg) was added before (48 h or 24 h), after (24 h), or simultaneously with the B. pertussis challenge (10(7) CFU). Moreover, we detected that LPS completely cleared bacterial infection as soon as 2 h posttreatment. This timing suggests that the observed StIR phenomenon should be mediated by fast-acting antimicrobial mechanisms. Although neutrophil recruitment was already evident at this time point, depletion assays using an anti-GR1 antibody showed that B. pertussis clearance was achieved even in the absence of neutrophils. To evaluate the possible role of free radicals in StIR, we performed animal assays using the antioxidant N-acetyl cysteine (NAC), which is known to inactivate oxidant species. NAC administration blocked the B. pertussis clearance induced by LPS. Nitrite concentrations were also increased in the LPS-treated mice; however, the inhibition of nitric oxide synthetases did not suppress the LPS-induced bacterial clearance. Taken together, our results show that reactive oxygen species (ROS) play an essential role in the TLR4-dependent innate clearance of B. pertussis. PMID- 23630951 TI - Lipopolysaccharide modifications of a cholera vaccine candidate based on outer membrane vesicles reduce endotoxicity and reveal the major protective antigen. AB - The causative agent of the life-threatening gastrointestinal infectious disease cholera is the Gram-negative, facultative human pathogen Vibrio cholerae. We recently started to investigate the potential of outer membrane vesicles (OMVs) derived from V. cholerae as an alternative approach for a vaccine candidate against cholera and successfully demonstrated the induction of a long-lasting, high-titer, protective immune response upon immunization with OMVs using the mouse model. In this study, we present immunization data using lipopolysaccharide (LPS)-modified OMVs derived from V. cholerae, which allowed us to improve and identify the major protective antigen of the vaccine candidate. Our results indicate that reduction of endotoxicity can be achieved without diminishing the immunogenic potential of the vaccine candidate by genetic modification of lipid A. Although the protective potential of anti-LPS antibodies has been suggested many times, this is the first comprehensive study that uses defined LPS mutants to characterize the LPS-directed immune response of a cholera vaccine candidate in more detail. Our results pinpoint the O antigen to be the essential immunogenic structure and provide a protective mechanism based on inhibition of motility, which prevents a successful colonization. In a detailed analysis using defined antisera, we can demonstrate that only anti-O antigen antibodies, but not antibodies directed against the major flagellar subunit FlaA or the most abundant outer membrane protein, OmpU, are capable of effectively blocking the motility by binding to the sheathed flagellum and provide protection in a passive immunization assay. PMID- 23630953 TI - Pasteurella multocida toxin as a transporter of non-cell-permeating proteins. AB - The protein toxin Pasteurella multocida toxin (PMT) is the causative agent of atrophic rhinitis in pigs, leading to atrophy of the nasal turbinate bones by affecting osteoblasts and osteoclasts. The mechanism of PMT-induced intoxication is a deamidation of alpha-subunits of heterotrimeric G proteins, including Galphaq, Galpha13, and Galphai, thereby causing persistent activation of the G proteins. Here we utilized PMT as a transporter of the non-cell-permeating A domain of diphtheria toxin (DTa). Fusion proteins of PMT and DTa ADP-ribosylated elongation factor 2, the natural target of diphtheria toxin, leading to cell toxicity. PMT-DTa effects were competed by PMT, indicating binding to the same cell surface receptor. Fluorescently labeled PMT-DTa and PMT colocalized with specific markers of early and late endosomes. Bafilomycin A, which inhibits vacuolar H(+)-ATPase, blocked PMT-DTa-induced intoxication of HEK-293 cells. By constructing various PMT-DTa chimeras, we identified a minimal region of PMT necessary for uptake of DTa. The data suggest that PMT is able to transport cargo proteins into eukaryotic cells by utilizing the PMT-specific uptake route. PMID- 23630954 TI - Regulation of Rab5 function during phagocytosis of live Pseudomonas aeruginosa in macrophages. AB - Pseudomonas aeruginosa, a Gram-negative opportunistic human pathogen, is a frequent cause of severe hospital-acquired infections. Effectors produced by the type III secretion system disrupt mammalian cell membrane trafficking and signaling and are integral to the establishment of P. aeruginosa infection. One of these effectors, ExoS, ADP-ribosylates several host cell proteins, including Ras and Rab GTPases. In this study, we demonstrated that Rab5 plays a critical role during early stages of P. aeruginosa invasion of J774-Eclone macrophages. We showed that live, but not heat-inactivated, P. aeruginosa inhibited phagocytosis and that this occurred in conjunction with downregulation of Rab5 activity. Inactivation of Rab5 was dependent on ExoS ADP-ribosyltransferase activity, and in J744-Eclone cells, ExoS ADP-ribosyltransferase activity caused a more severe inhibition of phagocytosis than ExoS Rho GTPase activity. Furthermore, we found that expression of Rin1, a Rab5 guanine exchange factor, but not Rabex5 and Rap6, partially reversed the inactivation of Rab5 during invasion of live P. aeruginosa. These studies provide evidence that live P. aeruginosa cells are able to influence their rate of phagocytosis in macrophages by directly regulating activation of Rab5. PMID- 23630955 TI - Anaplasma phagocytophilum inhibits apoptosis and promotes cytoskeleton rearrangement for infection of tick cells. AB - Anaplasma phagocytophilum causes human granulocytic anaplasmosis. Infection with this zoonotic pathogen affects gene expression in both the vertebrate host and the tick vector, Ixodes scapularis. Here, we identified new genes, including spectrin alpha chain or alpha-fodrin (CG8) and voltage-dependent anion-selective channel or mitochondrial porin (T2), that are involved in A. phagocytophilum infection/multiplication and the tick cell response to infection. The pathogen downregulated the expression of CG8 in tick salivary glands and T2 in both the gut and salivary glands to inhibit apoptosis as a mechanism to subvert host cell defenses and increase infection. In the gut, the tick response to infection through CG8 upregulation was used by the pathogen to increase infection due to the cytoskeleton rearrangement that is required for pathogen infection. These results increase our understanding of the role of tick genes during A. phagocytophilum infection and multiplication and demonstrate that the pathogen uses similar strategies to establish infection in both vertebrate and invertebrate hosts. PMID- 23630957 TI - Epsilon toxin is essential for the virulence of Clostridium perfringens type D infection in sheep, goats, and mice. AB - Clostridium perfringens type D causes disease in sheep, goats, and other ruminants. Type D isolates produce, at minimum, alpha and epsilon (ETX) toxins, but some express up to five different toxins, raising questions about which toxins are necessary for the virulence of these bacteria. We evaluated the contribution of ETX to C. perfringens type D pathogenicity in an intraduodenal challenge model in sheep, goats, and mice using a virulent C. perfringens type D wild-type strain (WT), an isogenic ETX null mutant (etx mutant), and a strain where the etx mutation has been reversed (etx complemented). All sheep and goats, and most mice, challenged with the WT isolate developed acute clinical disease followed by death in most cases. Sheep developed various gross and/or histological changes that included edema of brain, lungs, and heart as well as hydropericardium. Goats developed various effects, including necrotizing colitis, pulmonary edema, and hydropericardium. No significant gross or histological abnormalities were observed in any mice infected with the WT strain. All sheep, goats, and mice challenged with the isogenic etx mutant remained clinically healthy for >=24 h, and no gross or histological abnormalities were observed in those animals. Complementation of etx knockout restored virulence; most goats, sheep, and mice receiving this complemented mutant developed clinical and pathological changes similar to those observed in WT-infected animals. These results indicate that ETX is necessary for type D isolates to induce disease, supporting a key role for this toxin in type D disease pathogenesis. PMID- 23630956 TI - Innate recognition by neutrophil granulocytes differs between Neisseria gonorrhoeae strains causing local or disseminating infections. AB - Members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family serve as cellular receptors for Neisseria gonorrhoeae. More specifically, neisserial colony opacity (OpaCEA)) proteins bind to epithelial CEACAMs (CEACAM1, CEA, CEACAM6) to promote bacterial colonization of the mucosa. In contrast, recognition by CEACAM3, expressed by human granulocytes, results in uptake and destruction of Opa(CEA)-expressing bacteria. Therefore, CEACAM3-mediated uptake might limit the spread of gonococci. However, some strains can cause disseminating gonococcal infections (DGIs), and it is currently unknown how these strains escape detection by granulocyte CEACAM3. Therefore, the opa gene loci from N. gonorrhoeae strain VP1, which was derived from a patient with disseminated gonococcal disease, were cloned and constitutively expressed in Escherichia coli. Similar to Opa proteins of the nondisseminating strain MS11, the majority of Opa proteins from strain VP1 bound epithelial CEACAMs and promoted CEACAM-initiated responses by epithelial cells. In sharp contrast to the Opa proteins of strain MS11, the Opa proteins of strain VP1 failed to interact with the human granulocyte receptor CEACAM3. Accordingly, bacteria expressing VP1 Opa proteins were not taken up by primary human granulocytes and did not trigger a strong oxidative burst. Analysis of Opa variants from four additional clinical DGI isolates again demonstrated a lack of CEACAM3 binding. In summary, our results reveal that particular N. gonorrhoeae strains express an Opa protein repertoire allowing engagement of epithelial CEACAMs for successful mucosal colonization, while avoiding recognition and elimination via CEACAM3-mediated phagocytosis. A failure of CEACAM3-mediated innate immune detection might be linked to the ability of gonococci to cause disseminated infections. PMID- 23630958 TI - Characterization and functional analysis of AatB, a novel autotransporter adhesin and virulence factor of avian pathogenic Escherichia coli. AB - Autotransporter (AT) proteins constitute a large family of extracellular proteins that contribute to bacterial virulence. A novel AT adhesin gene, aatB, was identified in avian pathogenic Escherichia coli (APEC) DE205B via genomic analyses. The open reading frame of aatB was 1,017 bp, encoding a putative 36.3 kDa protein which contained structural motifs characteristic for AT proteins: a signal peptide, a passenger domain, and a translocator domain. The predicted three-dimensional structure of AatB consisted of two distinct domains, the C terminal beta-barrel translocator domain and an N-terminal passenger domain. The prevalence analyses of aatB in APEC indicated that aatB was detected in 26.4% (72/273) of APEC strains and was strongly associated with phylogenetic groups D and B2. Quantitative real-time reverse transcription-PCR analyses revealed that AatB expression was increased during infection in vitro and in vivo. Moreover, AatB could elicit antibodies in infected ducks, suggesting that AatB is involved in APEC pathogenicity. Thus, APEC DE205B strains with a mutated aatB gene and mutated strains complemented with the aatB gene were constructed. Inactivation of aatB resulted in a reduced capacity to adhere to DF-1 cells, defective virulence capacity in vivo, and decreased colonization capacity in lung during systemic infection compared with the capacities of the wild-type strain. Furthermore, these capacities were restored in the complementation strains. These results indicated that AatB makes a significant contribution to APEC virulence through bacterial adherence to host tissues in vivo and in vitro. In addition, biofilm formation assays with strain AAEC189 expressing AatB indicated that AatB mediates biofilm formation. PMID- 23630959 TI - Phylogeographic origin of Helicobacter pylori determines host-adaptive responses upon coculture with gastric epithelial cells. AB - While Helicobacter pylori infects over 50% of the world's population, the mechanisms involved in the development of gastric disease are not fully understood. Bacterial, host, and environmental factors play a role in disease outcome. To investigate the role of bacterial factors in H. pylori pathogenesis, global gene expression of six H. pylori isolates was analyzed during coculture with gastric epithelial cells. Clustering analysis of six Colombian clinical isolates from a region with low gastric cancer risk and a region with high gastric cancer risk segregated strains based on their phylogeographic origin. One hundred forty-six genes had increased expression in European strains, while 350 genes had increased expression in African strains. Differential expression was observed in genes associated with motility, pathogenicity, and other adaptations to the host environment. European strains had greater expression of the virulence factors cagA, vacA, and babB and were associated with increased gastric histologic lesions in patients. In AGS cells, European strains promoted significantly higher interleukin-8 (IL-8) expression than did African strains. African strains significantly induced apoptosis, whereas only one European strain significantly induced apoptosis. Our data suggest that gene expression profiles of clinical isolates can discriminate strains by phylogeographic origin and that these profiles are associated with changes in expression of the proinflammatory and protumorigenic cytokine IL-8 and levels of apoptosis in host epithelial cells. These findings support the hypothesis that bacterial factors determined by the phylogeographic origin of H. pylori strains may promote increased gastric disease. PMID- 23630960 TI - Mapping and regulation of genes within Salmonella pathogenicity island 12 that contribute to in vivo fitness of Salmonella enterica Serovar Typhimurium. AB - Salmonella pathogenicity island 12 (SPI-12) of Salmonella enterica serovar Typhimurium is a 15-kb region that encompasses genes STM2230 to STM2245 and encodes a remnant phage known to contribute to bacterial virulence. In mouse infection experiments and replication assays in macrophages, we demonstrated a role for four genes in SPI-12 for bacterial survival in the host. STM2239, a potential Q antiterminator, showed a prominent contribution to bacterial fitness. Transcriptional reporter experiments, quantitative reverse transcription-PCR (RT PCR), and immunoblotting demonstrated that the virulence regulator SsrB and STM2239 contribute to transcriptional activation of genes in SPI-12. SsrB was found to indirectly regulate this locus by transcriptional read-through from the sspH2 (STM2241) promoter. Chromatin immunoprecipitation showed that STM2239 copurified with the promoter regulating STM2237, suggesting that STM2239 may function as an antiterminator to activate adjacent genes. These results demonstrate that bacteriophage genes may be adapted by pathogenic bacteria to improve fitness in the host. PMID- 23630961 TI - A phenotype at last: essential role for the Yersinia enterocolitica Ysa type III secretion system in a Drosophila melanogaster S2 cell model. AB - The highly pathogenic Yersinia enterocolitica strains have a chromosomally encoded type III secretion system (T3SS) that is expressed and functional in vitro only when the bacteria are cultured at 26 degrees C. Mutations that render this system nonfunctional are slightly attenuated in the mouse model of infection only following an oral inoculation and only at early time points postinfection. The discrepancy between the temperature required for the Ysa gene expression and the physiological temperature required for mammalian model systems has made defining the role of this T3SS challenging. Therefore, we explored the use of Drosophila S2 cells as a model system for studying Ysa function. We show here that Y. enterocolitica is capable of infecting S2 cells and replicating intracellularly to high levels, an unusual feature of this pathogen. Importantly, we show that the Ysa T3SS is required for robust intracellular replication. A secretion-deficient mutant lacking the secretin gene, ysaC, is defective in replication within S2 cells, marking the first demonstration of a pronounced Ysa dependent virulence phenotype. Establishment of S2 cells as a model for Y. enterocolitica infection provides a versatile tool to elucidate the role of the Ysa T3SS in the life cycle of this gastrointestinal pathogen. PMID- 23630962 TI - Toll-like receptor 4-linked Janus kinase 2 signaling contributes to internalization of Brucella abortus by macrophages. AB - Brucella abortus is an intracellular pathogen that uses a crafty strategy to invade and proliferate within host cells, but the distinct signaling pathways associated with phagocytic mechanisms of B. abortus remain unclear. The present study was performed to test the hypothesis that Toll-like receptor 4 (TLR4) linked signaling interacting with Janus kinase 2 (JAK2) plays an essential role in B. abortus phagocytosis by macrophages. The effects of TLR4-JAK2 signaling on B. abortus phagocytosis in murine macrophage RAW 264.7 cells were observed through an infection assay and confocal microscopy. We determined that the uptake of B. abortus was negatively affected by the dysfunction of TLR4 and JAK2. F actin polymerization detected by flow cytometry and F-actin assay was amplified for B. abortus entry, whereas that event was attenuated by the disruption of TLR4 and JAK2. Importantly, JAK2 phosphorylation and actin skeleton reorganization were suppressed immediately after B. abortus infection in bone marrow-derived macrophages (BMDMs) from TLR4(-/-) mice, showing the cooperation of JAK2 with TLR4. Furthermore, small GTPase Cdc42 participated in the intermediate pathway of TLR4-JAK2 signaling on B. abortus phagocytosis. Consequently, TLR4-associated JAK2 activation in the early cellular signaling events plays a pivotal role in B. abortus-induced phagocytic processes in macrophages, implying the pathogenic significance of JAK2-mediated entry. Here, we elucidate that this specific phagocytic mechanism of B. abortus might provide achievable strategies for inhibiting B. abortus invasion. PMID- 23630963 TI - Borrelia burgdorferi bba66 gene inactivation results in attenuated mouse infection by tick transmission. AB - The impact of the Borrelia burgdorferi surface-localized immunogenic lipoprotein BBA66 on vector and host infection was evaluated by inactivating the encoding gene, bba66, and characterizing the mutant phenotype throughout the natural mouse tick-mouse cycle. The BBA66-deficient mutant isolate, Bb(DeltaA66), remained infectious in mice by needle inoculation of cultured organisms, but differences in spirochete burden and pathology in the tibiotarsal joint were observed relative to the parental wild-type (WT) strain. Ixodes scapularis larvae successfully acquired Bb(DeltaA66) following feeding on infected mice, and the organisms persisted in these ticks through the molt to nymphs. A series of tick transmission experiments (n = 7) demonstrated that the ability of Bb(DeltaA66) infected nymphs to infect laboratory mice was significantly impaired compared to that of mice fed upon by WT-infected ticks. trans-complementation of Bb(DeltaA66) with an intact copy of bba66 restored the WT infectious phenotype in mice via tick transmission. These results suggest a role for BBA66 in facilitating B. burgdorferi dissemination and transmission from the tick vector to the mammalian host as part of the disease process for Lyme borreliosis. PMID- 23630965 TI - Rho kinase regulates induction of T-cell immune dysfunction in abdominal sepsis. AB - T-cell dysfunction increases susceptibility to infections in patients with sepsis. In the present study, we hypothesized that Rho kinase signaling might regulate induction of T-cell dysfunction in abdominal sepsis. Male C57BL/6 mice were treated with the specific Rho kinase inhibitor Y-27632 (5 mg/kg of body weight) prior to cecal ligation and puncture (CLP). Spleen CD4 T-cell apoptosis, proliferation, and percentage of regulatory T cells (CD4(+) CD25(+) Foxp3(+)) were determined by flow cytometry. Formation of gamma interferon (IFN-gamma) and interleukin 4 (IL-4) in the spleen and plasma levels of HMBG1, IL-17, and IL-6 were quantified by use of enzyme-linked immunosorbent assay (ELISA). It was found that CLP evoked apoptosis and decreased proliferation in splenic CD4 T cells. Inhibition of Rho kinase activity decreased apoptosis and enhanced proliferation of CD4 T cells in septic animals. In addition, CLP-evoked induction of regulatory T cells in the spleen was abolished by Rho kinase inhibition. CLP reduced the levels of IFN-gamma and IL-4 in the spleen. Pretreatment with Y-27632 inhibited the sepsis-induced decrease in IFN-gamma but not IL-4 formation in the spleen. CLP increased plasma levels of high-mobility group box 1 (HMGB1) by 20-fold and IL-6 by 19-fold. Inhibition of Rho kinase decreased this CLP-evoked increase of HMGB1, IL-6, and IL-17 levels in the plasma by more than 60%, suggesting that Rho kinase regulates systemic inflammation in sepsis. Moreover, we observed that pretreatment with Y-27632 abolished CLP-induced bacteremia. Together, our novel findings indicate that Rho kinase is a powerful regulator of T-cell immune dysfunction in abdominal sepsis. Thus, targeting Rho kinase signaling might be a useful strategy to improve T-cell immunity in patients with abdominal sepsis. PMID- 23630964 TI - Attenuation of Leishmania infantum chagasi metacyclic promastigotes by sterol depletion. AB - The infectious metacyclic promastigotes of Leishmania protozoa establish infection in a mammalian host after they are deposited into the dermis by a sand fly vector. Several Leishmania virulence factors promote infection, including the glycosylphosphatidylinositol membrane-anchored major surface protease (MSP). Metacyclic Leishmania infantum chagasi promastigotes were treated with methyl beta-cyclodextrin (MbetaCD), a sterol-chelating reagent, causing a 3-fold reduction in total cellular sterols as well as enhancing MSP release without affecting parasite viability in vitro. MbetaCD-treated promastigotes were more susceptible to complement-mediated lysis than untreated controls and reduced the parasite load 3-fold when inoculated into BALB/c mice. Paradoxically, MbetaCD treated promastigotes caused a higher initial in vitro infection rate in human or murine macrophages than untreated controls, although their intracellular multiplication was hindered upon infection establishment. There was a corresponding larger amount of covalently bound C3b than iC3b on the parasite surfaces of MbetaCD-treated promastigotes exposed to healthy human serum in vitro, as well as loss of MSP, a protease that enhances C3b cleavage to iC3b. Mass spectrometry showed that MbetaCD promotes the release of proteins into the extracellular medium, including both MSP and MSP-like protein (MLP), from virulent metacyclic promastigotes. These data support the hypothesis that plasma membrane sterols are important for the virulence of Leishmania protozoa at least in part through retention of membrane virulence proteins. PMID- 23630966 TI - IgG and IgE collaboratively accelerate expulsion of Strongyloides venezuelensis in a primary infection. AB - The host deploys a subset of immune responses to expel helminths, which differs depending on the nature of the helminth. Strongyloides venezuelensis, a counterpart of the human pathogen S. stercoralis, naturally infects rodents and has been used as an experimental model. Here we show that induction of immunoglobulin G (IgG) and IgE is a prerequisite for rapid expulsion of S. venezuelensis during a primary infection. Activation-induced cytidine deaminase deficient (AID(-/-)) mice, which lack the ability to switch IgM to other isotypes, normally developed T-helper 2 (Th2) cells and intestinal mastocytosis after infection with S. venezuelensis. Although AID(-/-) mice expelled Nippostrongylus brasiliensis normally, they required a much longer period to expel S. venezuelensis than wild-type (WT) mice. Adoptive transfers of immune sera from S. venezuelensis-infected but not N. brasiliensis-infected mice restored the ability of AID(-/-) mice to promptly expel S. venezuelensis. Immune serum-derived IgG and IgE induced worm expulsion via Fc gamma receptor III (FcgammaRIII) and Fc epsilon receptor I (FcepsilonRI), respectively, and a mixture of IgG and IgE showed collaborative effects. Whereas FcgammaRIII(-/-) mice or FcepsilonRIalpha(-/-) mice normally could expel S. venezuelensis, FcgammaRIII(-/-) mice, when their IgE was neutralized by anti-IgE, or FcepsilonRIalpha(-/-) mice, when their IgG binding to FcgammaRIII was blocked by anti-FcgammaRIII, showed a markedly reduced ability to expel S. venezuelensis. These data reveal that IgG and IgE play redundant roles but act in concert to accelerate S. venezuelensis expulsion. Mast cell-deficient mice, even those equipped with immune serum-derived IgG or IgE, failed to expel S. venezuelensis promptly, suggesting that mast cells are cellular targets of IgG and IgE. PMID- 23630967 TI - Heme catabolism by heme oxygenase-1 confers host resistance to Mycobacterium infection. AB - Heme oxygenases (HO) catalyze the rate-limiting step of heme degradation. The cytoprotective action of the inducible HO-1 isoform, encoded by the Hmox1 gene, is required for host protection against systemic infections. Here we report that upregulation of HO-1 expression in macrophages (M) is strictly required for protection against mycobacterial infection in mice. HO-1-deficient (Hmox1(-/-)) mice are more susceptible to intravenous Mycobacterium avium infection, failing to mount a protective granulomatous response and developing higher pathogen loads, than infected wild-type (Hmox1(+/+)) controls. Furthermore, Hmox1(-/-) mice also develop higher pathogen loads and ultimately succumb when challenged with a low-dose aerosol infection with Mycobacterium tuberculosis. The protective effect of HO-1 acts independently of adaptive immunity, as revealed in M. avium infected Hmox1(-/-) versus Hmox1(+/+) SCID mice lacking mature B and T cells. In the absence of HO-1, heme accumulation acts as a cytotoxic pro-oxidant in infected M, an effect mimicked by exogenous heme administration to M. avium infected wild-type M in vitro or to mice in vivo. In conclusion, HO-1 prevents the cytotoxic effect of heme in M, contributing critically to host resistance to Mycobacterium infection. PMID- 23630969 TI - The link between environmental variation and evolutionary shifts in dormancy in zooplankton. AB - Sex and dormancy are intertwined in organisms that engage in asexual and sexual reproduction. The transition between asexual and sexual reproduction typically results in a dormant stage that provides a mechanism for persisting under harsh environmental conditions. For example, many zooplankton engage in sexual reproduction when environmental conditions deteriorate and produce resting eggs that remain viable for decades. It has long been assumed that observed variation in the timing and magnitude of investment into a dormant stage among populations or species reflects local environmental conditions. Yet, the importance of dormancy for the persistence of a given population can differ dramatically among habitats (i.e., permanent vs. seasonal ponds). As a result, environmental conditions may exert selection on the propensity for zooplankton to engage in sexual reproduction and enter dormancy in natural populations. Here, I highlight a growing body of research illustrating an important link between environmental conditions and divergent reproductive strategies in zooplankton. I specifically: (1) review the environmental cues that initiate a transition between asexual and sexual reproduction in zooplankton and (2) describe recent work demonstrating an evolutionary consequence of ecological selective pressures, such as predation and habitat predictability, on variation in the extent to which organisms engage in sex and enter dormancy. Such results have implications for the genetics and ecology of these organisms. PMID- 23630968 TI - Investigation of the function of Candida albicans Als3 by heterologous expression in Candida glabrata. AB - During hematogenously disseminated infection, blood-borne Candida albicans invades the endothelial cell lining of the vasculature to invade the deep tissues. Although the C. albicans Als3 invasin is critical for invasion and damage of endothelial cells in vitro, a C. albicans als3Delta/Delta mutant has normal virulence in the mouse model of disseminated infection. We hypothesized that the contribution of Als3 to virulence is obscured by the presence of additional C. albicans invasins. To elucidate the in vivo function of Als3, we heterologously expressed C. albicans ALS3 in Candida glabrata, a yeast that lacks a close ALS3 ortholog and has low virulence in mice. We found that following intravenous inoculation into mice, the ALS3-expressing strain preferentially trafficked to the brain, where it induced significantly elevated levels of myeloperoxidase, tumor necrosis factor, monocyte chemoattractant protein 1, and gamma interferon. Also, the ALS3-expressing strain had enhanced adherence to and invasion of human brain microvascular endothelial cells in vitro, demonstrating a potential mechanism for ALS3-mediated neurotropism. In addition, upon initiation of infection, the ALS3-expressing strain had increased trafficking to the cortex of the kidneys. With prolonged infection, this strain persisted in the kidneys at significantly higher levels than the control strain but did not induce an elevated inflammatory response. Finally, the ALS3-expressing strain had increased resistance to neutrophil killing in vitro. These results indicate that during disseminated infection, Als3 mediates initial trafficking to the brain and renal cortex and contributes to fungal persistence in the kidneys. PMID- 23630970 TI - Evidence for a phototransduction cascade in an early brachiopod embryo. AB - Bilaterian photoreceptor cells are characterized by the expression of opsins, signal transduction genes, and ion channels, which together facilitate behavioral responses to light. We have previously identified a ciliary opsin gene from the brachiopod Terebratalia transversa, whose expression in gastrula stage embryos coincides with a photoresponse behavior, suggesting the presence of a functional phototransduction system in these early embryos. To further evaluate the potential for light reception in these embryos, we surveyed transcriptome data to identify phototransduction genes and evaluated their expression. In addition to the previously described ciliary opsin gene, we have identified two Go-class opsins that are also expressed in gastrula stage embryos. Representative members from all classes of Galpha-protein genes were also expressed, with a Galpha12 class gene being localized in the same anterior ectodermal domain as the opsin transcripts. Both CNG-class and TRP-class ion channels were expressed in the gastrula stage embryos, as were GRK and arrestin genes, which are associated with inhibition of rhodopsin activity. Taken together, these data support the presence of a functional phototransduction system in the early brachiopod embryo. PMID- 23630971 TI - Negation, questions, and structure building in a homesign system. AB - Deaf children whose hearing losses are so severe that they cannot acquire spoken language, and whose hearing parents have not exposed them to sign language, use gestures called homesigns to communicate. Homesigns have been shown to contain many of the properties of natural languages. Here we ask whether homesign has structure building devices for negation and questions. We identify two meanings (negation, question) that correspond semantically to propositional functions, that is, to functions that apply to a sentence (whose semantic value is a proposition, phi) and yield another proposition that is more complex (!phi for negation; ?phi for question). Combining phi with ! or ? thus involves sentence modification. We propose that these negative and question functions are structure building operators, and we support this claim with data from an American homesigner. We show that: (a) each meaning is marked by a particular form in the child's gesture system (side-to-side headshake for negation, manual flip for question); (b) the two markers occupy systematic, and different, positions at the periphery of the gesture sentences (headshake at the beginning, flip at the end); and (c) the flip is extended from questions to other uses associated with the wh form (exclamatives, referential expressions of location) and thus functions like a category in natural languages. If what we see in homesign is a language creation process (Goldin-Meadow, 2003), and if negation and question formation involve sentential modification, then our analysis implies that homesign has at least this minimal sentential syntax. Our findings thus contribute to ongoing debates about properties that are fundamental to language and language learning. PMID- 23630972 TI - [Idiopathic pulmonary fibrosis: treatment with pirfenidone]. PMID- 23630973 TI - [Patient treated with pirfenidone]. PMID- 23630974 TI - [Idiopathic pulmonary fibrosis of difficult diagnosis]. PMID- 23630975 TI - [Familial pulmonary fibrosis]. PMID- 23630976 TI - A call to action: ensuring reasonable break time for nursing mothers. PMID- 23630977 TI - Reply to Townsend et al.: Decoupling contributions from canopy structure and leaf optics is critical for remote sensing leaf biochemistry. PMID- 23630978 TI - Facilitating nurse scientist career development: the CANS grant program. PMID- 23630980 TI - Retraction notice to "Designing for healthy living: supporting reflectivity on interactions in healthcare" [Int. J. Med. Inform. 80 (2011) e230-e244]. PMID- 23630979 TI - Epigenetic regulation of vascular smooth muscle cell function in atherosclerosis. AB - Epigenetics involve heritable and acquired changes in gene transcription that occur independently of the DNA sequence. Epigenetic mechanisms constitute a hierarchic upper-level of transcriptional control through complex modifications of chromosomal components and nuclear structures. These modifications include, for example, DNA methylation or post-translational modifications of core histones; they are mediated by various chromatin-modifying enzymes; and ultimately they define the accessibility of a transcriptional complex to its target DNA. Integrating epigenetic mechanisms into the pathophysiologic concept of complex and multifactorial diseases such as atherosclerosis may significantly enhance our understanding of related mechanisms and provide promising therapeutic approaches. Although still in its infancy, intriguing scientific progress has begun to elucidate the role of epigenetic mechanisms in vascular biology, particularly in the control of smooth muscle cell phenotypes. In this review, we will summarize epigenetic pathways in smooth muscle cells, focusing on mechanisms involved in the regulation of vascular remodeling. PMID- 23630981 TI - Intra-articular injection of levobupivacaine. Reply from the authors. PMID- 23630982 TI - Reply to J.E. Galgani and G. Valentino. PMID- 23630983 TI - Characterizing the state of the art in the computational assignment of gene function: lessons from the first critical assessment of functional annotation (CAFA). AB - The assignment of gene function remains a difficult but important task in computational biology. The establishment of the first Critical Assessment of Functional Annotation (CAFA) was aimed at increasing progress in the field. We present an independent analysis of the results of CAFA, aimed at identifying challenges in assessment and at understanding trends in prediction performance. We found that well-accepted methods based on sequence similarity (i.e., BLAST) have a dominant effect. Many of the most informative predictions turned out to be either recovering existing knowledge about sequence similarity or were "post dictions" already documented in the literature. These results indicate that deep challenges remain in even defining the task of function assignment, with a particular difficulty posed by the problem of defining function in a way that is not dependent on either flawed gold standards or the input data itself. In particular, we suggest that using the Gene Ontology (or other similar systematizations of function) as a gold standard is unlikely to be the way forward. PMID- 23630984 TI - Reforms urged to tackle violence against women in India. PMID- 23630985 TI - Indigenous Canadians confront prescription opioid misuse. PMID- 23630986 TI - The Doctor in early Cold War America. PMID- 23630987 TI - Zurich Heart House. PMID- 23630988 TI - Renal nerve ablation for treatment of therapy-resistant hypertension. PMID- 23630990 TI - Bibliography. Stem cell transplantation. Current world literature. PMID- 23630989 TI - Announcement on NCE2013. PMID- 23630991 TI - Bibliography. Pancreas transplantation. Current world literature. PMID- 23630994 TI - [Research progress in medicinal plant cell suspension culture]. AB - China consumes and exports traditional Chinese medicinal resources the most in the world. However, we cannot anchor our hope on field production of traditional Chinese medicinal materials and their active ingredients, due to limited land resources. Therefore, the development of biotechnology is of great importance for China to solve the problem of traditional Chinese medicinal resources. Plant cell culture is an important approach for the sustainable development of precious medicinal resources. This essary summarizes the optimization of conditions for medicinal plant cell culture, the regulation of secondary metabolic pathways and cell bioreactor culture, and realizes that the authentic commercial production of more medicinal plants requires efforts from all aspects. PMID- 23630992 TI - Author response. PMID- 23630995 TI - Preface. TRIM/RBCC proteins. PMID- 23630996 TI - Genomics and evolution of the TRIM gene family. AB - The TRIM family comprises proteins characterized by the presence of thetripartite motifthat is composed of a RING domain, one or two B-box domains and a Coiled coil region. These proteins are implicated in a plethora of cellular processes such as apoptosis, cell cycle regulation, muscular physiology and innate immune response. Consistently, their alteration results in several pathological conditions emphasizing their medical relevance. The TRIM members domain structure underscores a common biochemical function as E3 ligases within the ubiquitylation cascade, which is then translated into diverse biological processes. The TRIM proteins represent one of the largest families in mammals counting in human almost 70 members. TRIM proteins are metazoan-specific and have been now identified in several species although the great increase in their number was generated in vertebrate species. The important expansion of the number of TRIM genes underlie the success of the tripartite module in ubiquitylation process. Furthermore, their massive diversification among species was achieved through fast evolution of the TRIM genes implicated in pathogen response. PMID- 23630997 TI - The tripartite motif: structure and function. AB - The TRIM/RBCC proteins belong to a family whom members are involved in a variety of cellular processes such as apoptosis and cell cycle regulation. These proteins are defined by the presence of a tripartite motif composed of three zinc-binding domains, a RING finger, one or two B-box motifs, a coiled-coil region and a highly variable C-terminal region. Interestingly, the preserved order of the tripartite motif from the N- to the C-terminal end of the protein and the highly conserved overall architecture of this motif throughout evolution suggest that common biochemical functions may underline their assorted cellular roles. Here we present the structure and the proposed function of each TRIM domain including the highly variable C-terminal domain. PMID- 23630998 TI - TRIM proteins as RING finger E3 ubiquitin ligases. AB - The tripartite motif(TRIM) proteins harboring the RING finger, B-box and coiled coil (RBCC) domain motifs form a large protein family. The members of this family are involved in various biological processes, including growth, differentiation, apoptosis and transcription and also in diseases and oncogenesis. Recent studies have revealed that TRIM proteins play key roles in innate antiviral immunity. An accumulating body of evidence has demonstrated that some TRIM proteins function as E3 ubiquitin ligases in specific ubiquitin-mediated protein degradation pathways; however, the precise mechanisms underlying this function have not been fully elucidated. In this chapter, we focus on the TRIM family of proteins specially with regard to E3 ligase. PMID- 23630999 TI - PML nuclear bodies and other TRIM-defined subcellular compartments. AB - Tripartite motif (TRIM) proteins are defined by their possession of a RING, B-box and predicted coiled coil (RBCC) domain. The coiled-coil region facilitates the oligomerisation of TRIMs and contributes to the formation of high molecular weight complexes that show interesting subcellular compartmentalisations and structures. TRIM protein compartments include both nuclear and cytoplasmic filaments and aggregates (bodies), as well as diffuse subcellular distributions. TRIM 19, otherwise known as promyelocytic leukaemia (PML) protein forms nuclear aggregates termed PML nuclear bodies (PML NBs), at which a number of functionally diverse proteins transiently or covalently associate. PML NBs are therefore implicated in a wide variety of cellular functions such as transcriptional regulation, viral response, apoptosis and nuclear protein storage. PMID- 23631000 TI - TRIM involvement in transcriptional regulation. AB - Members of the tripartite motif (TRIM) protein family are found in all multicellular eukaryotes and function in a wide range of cellular processes such as cell cycle regulation, differentiation, development, oncogenesis and viral response. Over the past few years, several TRIM proteins have been reported to control gene expression through regulation of the transcriptional activity of numerous sequence-specific transcription factors. These proteins include the transcriptional intermediary factor 1 (TIF1) regulators, the promyelocytic leukemia tumor suppressor PML and the RET finger protein (RFP). In this chapter, we will consider the molecular interactions made by these TRIM proteins and will attempt to clarify some of the molecular mechanisms underlying their regulatory effect on transcription. PMID- 23631001 TI - TRIM proteins in cancer. AB - Some members of the tripartite motif (TRIM/RBCC) protein family are thought to be important regulators of carcinogenesis. This is not surprising as the TRIM proteins are involved in several biological processes, such as cell growth, development and cellular differentiation and alteration of these proteins can affect transcriptional regulation, cell proliferation and apoptosis. In particular, four TRIM family genes are frequently translocated to other genes, generating fusion proteins implicated in cancer initiation and progression. Among these the most famous is the promyelocytic leukaemia gene PML, which encodes the protein TRIM19. PML is involved in the t(15;17) translocation that specifically occurs in Acute Promyelocytic Leukaemia (APL), resulting in a PML-retinoic acid receptor-alpha (PML-RARalpha) fusion protein. Other members of the TRIM family are linked to cancer development without being involved in chromosomal re arrangements, possibly through ubiquitination or loss of tumour suppression functions. This chapter discusses the biological functions of TRIM proteins in cancer. PMID- 23631002 TI - TRIM proteins and the innate immune response to viruses. AB - Many TRIM proteins are up-regulated by interferons, suggesting that they might be involved in the innate immune response against viruses. Indeed, some members of the family have been shown to be either regulators of the interferon pathways or to be directly involved in the restriction of viruses. While the mechanisms of actions are varied, the modular organization of these proteins seems to be important for their activities, many of which are linked to the ubiquitination/proteasomal degradation system. The different domains enable the TRIM proteins to interact with either viral components or signaling molecules in the interferon induction pathways. PMID- 23631004 TI - MuRFs: specialized members of the TRIM/RBCC family with roles in the regulation of the trophic state of muscle and its metabolism. AB - MuRFs, brief for muscle specific RING finger proteins, correspond to a subfamily of the TRIM/RBCC protein family. Here, we review recent progress on the structural biology of MuRF1, the MuRF family member being most clearly associated with muscle diseases. The emerging understanding of the structural biology of MuRFs and their interaction with their numerous myocellular proteins, at least in part representing ubiquitination targets for MuRFs, is likely to provide future rationales to modulate their activity, thus affecting their roles in muscle disease progression. PMID- 23631003 TI - The microtubule-associated C-I subfamily of TRIM proteins and the regulation of polarized cell responses. AB - TRIM proteins are multidomain proteins that typically assemble into large molecular complexes, the composition of which likely explains the diverse functions that have been attributed to this group of proteins. Accumulating data on the roles of many TRIM proteins supports the notion that those that share identical C-terminal domain architectures participate in the regulation of similar cellular processes. At least nine different C-terminal domain compositions have been identified. This chapter will focus on one subgroup that possess a COS motif, FNIII and SPRY/B30.2 domain as their C-terminal domain arrangement. This C-terminal domain architecture plays a key role in the interaction of all six members of this subgroup with the microtubule cytoskeleton. Accumulating evidence on the functions of some of these proteins will be discussed to highlight the emerging similarities in the cellular events in which they participate. PMID- 23631005 TI - TRIM proteins in development. AB - TRIM proteins play important roles in several patho-physiological processes. Their common activity within the ubiquitylation pathway makes them amenable to a number of diverse biological roles. Many of the TRIM genes are highly and sometimes specifically expressed during embryogenesis, it is therefore not surprising that several of them might be involved in developmental processes. Here, we primarily discuss the developmental implications of two subgroups of TRIM proteins that conserved domain composition and functions from their invertebrate ancestors. The two groups are: the TRIM-NHL proteins implicated in miRNA processing regulation and the TRIM-FN3 proteins involved in ventral midline development. PMID- 23631006 TI - Ronald Haxton Girdwood (1917-2006). PMID- 23631007 TI - Sir Stuart Threipland's medicine chest. PMID- 23631008 TI - GHLIT medical insurance coverage. PMID- 23631009 TI - Veterinary college accreditation. PMID- 23631010 TI - Response from the Chair of the Council on Education. PMID- 23631011 TI - Representations of human-animal interactions in advertising. PMID- 23631012 TI - Menace response in muzzled dogs. PMID- 23631013 TI - What is our profession? PMID- 23631014 TI - [Comment on this case report]. PMID- 23631015 TI - In response. PMID- 23631016 TI - Federal Housing Administration (FHA): Section 232 Healthcare Facility Insurance Program--Strengthening Accountability and Regulatory Revisions Update Final Rule Amendment--revision of date of applicability. Final rule amendment. AB - On September 7, 2012, HUD published a final rule that revised the regulations governing the insurance of healthcare facilities under section 232 of the National Housing Act (Section 232). HUD's Section 232 program insures mortgage loans to facilitate the construction, substantial rehabilitation, purchase, and refinancing of nursing homes, intermediate care facilities, board and care homes, and assisted-living facilities. The amendments made by the September 7, 2012, final rule updated the Section 232 regulations to reflect current policy and practices, improve accountability and strengthen risk management in the program. The final rule provided an applicability date of April 9, 2013, for certain of the updated requirements. This final rule amendment changes the applicability date to July 12, 2013, for the purpose of allowing more time to transition to the new requirements. PMID- 23631017 TI - Expert testimony may be required to establish what a reasonable person might do. Spencer v. Goodill, C.A. No. 08C-06-183 (Del. April 6,2011). PMID- 23631018 TI - EMTALA may apply to preterm miscarriages. Morin v. Eastern Maine Medical Center, No. 1:09-cv-00258-JAW (D. Me. March 25, 2011). PMID- 23631019 TI - Hospitals do not have free rein to report crimes to law enforcement. Bonney v. Stephens Memorial Hospital, 2011 ME 46; 2011 ME LEXIS 46 (April 12, 2011). PMID- 23631020 TI - Claim for patient fall after delivery was a medical malpractice claim. Martins v. Williamson Medical Center, No. M2010-00258-COA-R3-CV (Tenn. Ct. App. November 22, 2010). PMID- 23631021 TI - There is no duty to third parties in child abuse cases in South Carolina. Oblachinski v. Reynolds, No. 26932 (S.C. February 22,2011). PMID- 23631022 TI - EMERGENCY MEDICINE: EMTALA requires medical screening of newborns. Preston v. Meriter Hospital, Inc. PMID- 23631023 TI - Patient may sue for damages if negligent act caused him to commit homicide. O'Brien v. Bruscato, 289 Ga. 739; 715 S.E.2d 120 (Ga. 2011). PMID- 23631024 TI - Nurses have limited responsibility to override physician. Daniels v. Durham County Hospital Corp., 615 S.E. 2d 60 (Ct. App. N.C. 2005). PMID- 23631025 TI - Extinguishment of the liability of the agent releases the principal in Ohio. Comer v. Risko, 106 Ohio St. 3d 185, 833 N.E. 2d 712 (Ohio 2005). PMID- 23631026 TI - Past practices may dictate what is an appropriate screening. Hale v. Northeastern Vermont Regional Hospital, _____ F. Supp. 2nd _____, _____, No. 1:08-cv-82-jgm (D. Vt. September 30, 2011). PMID- 23631027 TI - Single telepsychiatric session may impose a duty of care. White v. Harris, No. 2010-246 (Vt. September 29, 2011). PMID- 23631028 TI - Hospital may have duty to ensure that consent for anesthesia was obtained. Villines v. North Arkansas Regional Medical Center, No. CA 10-1196 (Ct. App. Ark. September 7, 2011). PMID- 23631029 TI - Liability may attach for injuries that cause a stillbirth. Spangler v. Bechtel, No. 49S05-1012-CV-703 (Ind December 13, 2011). PMID- 23631030 TI - Hospital may waive peer review protections by making full disclosure. Smith v. Cleveland Clinic, No. CV-744959 (8th Dist Ct App Ohio December 22, 2011). PMID- 23631031 TI - Whether factual statements are defamatory is question of fact for jury. McKee v. Laurion, No. A11-1154 (Ct App Minn January 23, 2012). PMID- 23631032 TI - Hospital may be required to divulge aggregate performance data. Medina v. Medina General Hospital, No. 96171 (Ct App Ohio August 11, 2011). PMID- 23631033 TI - [Definition and epidemiology of androgen disorder of aging male (ADAM)]. PMID- 23631034 TI - [Physiology and pathophysiology of testosterone ADAM]. PMID- 23631035 TI - [Aging male hormonal disorders unrelated to testosterone]. PMID- 23631036 TI - [Clinical and laboratory diagnosis of hypogonadism]. PMID- 23631037 TI - [Treatment of androgen disorder of aging male (ADAM)]. PMID- 23631038 TI - [Benefits of hormone replacement therapy]. PMID- 23631039 TI - [Risks, contraindications, abuse and monitoring risks of testosterone replacement therapy (TRT)]. PMID- 23631040 TI - [Prostate and hormone replacement therapy]. PMID- 23631041 TI - [Parkinson's disease and elderly subjects: is there movement? ]. PMID- 23631042 TI - [Advanced Parkinson's disease]. AB - The stage of advanced Parkinson's disease usually occurs 10 years after the diagnosis but sometimes after 30 years. It is characterized by a severe handicap with gait disorders, posture changes, speech abnormalities and deglutition perturbations. Cognitive disorders (hallucinations, delirium, delusions, dementia) did not occur in all patients. Dysautonomic disorders are usual. Treatment is difficult and may include paradoxical prescriptions such as both apomorphine pump and clozapine. PMID- 23631043 TI - [Parkinson's disease: psychological and behavioral disorders]. AB - Many patients with Parkinson's disease (PD) have clinically significant anxiety, depression, apathy, fatigue and sleep disturbances. These non motor symptoms of Parkinson's disease are still not well recognized in clinical practice, either in primary or in secondary care, and are frequently missed during routine examination, but often contribute to impair the functional abilities in PD patients. Awareness of behavioral and psychological symptoms in PD should generate new approaches to improve their diagnosis accuracy and facilitate timely therapeutic interventions. PMID- 23631044 TI - [Psychotic symptoms in Parkinson's disease]. AB - About one third of patients with Parkinson's disease (PD) experience hallucinations, mostly of a complex visual type, less often auditory or tactile. Minor hallucinatory phenomena, including sense of presence, passage hallucinations and visual illusions are frequent. Hallucinations primarily occur in a context of clear sensorium in patients with longstanding PD. They are more frequent in the evening or during the night. Insight in the hallucinatory nature of the phenomenon may be retained, partial, fluctuating, or abolished. An altered insight is common when cognitive impairment is present, and may be associated with delusions and (or) delusional misidentifications. Pharmacological factors such as dopaminergic treatment clearly trigger or increase the occurence of hallucinations in PD. However, in the recent years, emphasis has been made on disease-related factors including cognitive impairment, diurnal somnolence, visual disorders (either contrast and color discrimination impairment due to PD, or coincident ocular disorders), long duration of PD, late onset, severe axial impairment and autonomic dysfunction. The pathophysiology of hallucinations of PD is poorly understood but is likely to be multifactorial. The first steps of the treatment consist in giving information and reassurance to the patient and his/her caregiver, re-evaluating the antiparkinsonian treatment and associated medications, and evaluating the patient for mood disorder, visual impairment, and cognitive impairment. Cholinesterase inhibitors, when prescribed for associated cognitive impairment, may be beneficial on hallucinations. In the more severe forms, clozapine has been proved to be safe and effective. PMID- 23631045 TI - [Cognitive disorders in Parkinson's disease without dementia]. AB - The cognitive disorders observed in non-demented Parkinsonian patients are frequent but subtle. They mostly result from difficulties to control attentional resources. These deficits particularly disturb the strategies involved in planning as well as in encoding and retrieval processing of memory, whereas consolidation of the mnemonic traces and instrumental functions are relatively spared. These deficits can be related to the striatal dopamine depletion (in particular in the caudate nuclei) which seems sufficient to account for the cognitive disorders that appear early in the course of the disease. In particular, the caudate dopamine depletion induces a cascade of dysfunction within the basal ganglia, downstream of the striatum, which ultimately affects the prefrontal functions. It is likely that, in the course of the disease, lesions of other ascending systems of neurotransmission (cholinergic, serotoninergic and noradrenergic pathways) contribute to worsen the cognitive disorders and also to modify their clinical pattern. The impact of direct cortical lesions can also be discussed but it seems that these lesions mostly contribute to the cognitive deficits in the late stages of Parkinson's disease. PMID- 23631046 TI - [Parkinson's disease dementia and Lewy body dementia]. AB - To specify the existing relationship between Parkinson's disease dementia (PDD) and Lewy body dementia (LBD), it is necessary to retrace the natural history of an histopathological lesion, which, although being non-specific, is essential for a precise diagnosis, the Lewy body. The occurrence of Lewy bodies in Parkinson's disease, as in the other two types of dementia, unveils a potential continuum between these affections, which could be reunited under the term of alpha synucleinopathy. However, defining the modalities of various types of alpha synucleinopathy has not been historically based on the notion of a continuum. Thus, their nosological framework remains imprecise and controversial. Nevertheless, the LBD and PDD clinical, radiological and neuropathological expressions reveal many similarities. Their clinical distinction could then seem quite arbitrary. Furthermore, some studies underline the relationships between the various "proteinopathies" described in the degenerative dementias (Lewy body dementia, Parkinson's disease dementia and Alzheimer's disease). Finally, the role played by associated vascular lesions needs to be specified. It becomes essential to better define the boundaries of these cerebral neurodegenerative diseases. The perspective of common physiopathological mechanisms and certain vulnerability profiles could lead to new therapeutic pathways. PMID- 23631047 TI - [Specificities of the treatment of Parkinson's disease in the elderly]. AB - The treatment of Parkinson's disease (PD) in subjects over 70 years old is simpler than in younger subjects for correcting the consequences of dopamine deficiency, but more complex with regard to symptoms resulting from non dopaminergic lesions (axial symptoms, cognitive decline). Due to the lower risk of occurrence of motor fluctuations and severe dyskinesia, L-DOPA is the dopaminergic treatment with the best ratio of efficacy to side effects, and can be used without reservation. Treatment of non-dopaminergic symptoms is still disappointing. Apart from a partial beneficial effect of functional rehabilitation programmes, no treatment was demonstrated to be really effective for correcting dysarthria, swallowing disorders or impairment of gait and balance. Some efficacy in reducing the cognitive deficit in PD has been recently shown by cholinergic drugs, but their functional efficacy and their mid-term impact remain poor. Analysis of the different factors involved in the genesis of symptoms in PD (with the putative interest of the use of L-DOPA as a 'diagnostic tool'), and of the comorbidity usually enables cautious and pragmatic solutions to be found. PMID- 23631048 TI - [Rehabilitation in the elderly subject with Parkinson's disease]. AB - In the elderly, the aging of the locomotor, cardiorespiratory, and sensory apparatus, the cognitive and psychic changes, and the interaction of several pathologies require adaptation of the rehabilitation techniques in Parkinson's disease. Rehabilitation should be initiated early and directed toward functional objectives defined by a pluridisciplinary team. To maintain movements is a fundamental aim and must take into account the tiredness of the old subject. Gymnic, active and passive techniques are proposed to preserve the posture, balance and walk. The prevention of falls is a major goal to avoid the risks of grabatisation and trauma. Multiple respiratory disorders are related to disturbances of swallowing and affect the deficiencies of voice and speech. The objectives of care are different if the patient presents a parkinsonan syndrome different from Parkinson's disease or if dementia is associated. The treatment by neurostimulation in old subjects also raises new questions for rehabilitation. PMID- 23631049 TI - Viscosupplementation: managed care issues for osteoarthritis of the knee. AB - BACKGROUND: Osteoarthritis (OA) affects an estimated 49 million adults in North America, or nearly 1 of every 6 adults. More than 8 million North Americans have limited mobility to some extent because of OA. By 2030, an estimated 71 million North Americans will be diagnosed with OA, an increase of 45% over current figures. For one group-model health maintenance organization (HMO), the average cost of care for patients with OA was $543 per member, a total annual cost to the HMO of $4,728,425. Of this total amount, 46% was for inpatient care, 32% was for medication, and 22% was for ambulatory care. OBJECTIVE: To determine the impact of OA on managed care and discuss treatment options available to those with OA, particularly of the knee. SUMMARY: OA represents an advanced stage of an active, progressive disease process. We know from medical research that OA is the endpoint of a progression in tissue degradation that results in loss of cartilage structure and function. Relief of pain and preservation of joint tissue must evolve to encompass treatments that interfere with cartilage-degrading mechanisms that follow acute or chronic injury, restore normal cartilage and joint homeostasis, and arrest the progression of disease. Optimal future treatments will also reverse existing damage and restore normal cartilage structure and function. Viscosupplementation with an elastoviscous fluid containing polymers of hylan derivatives of the natural glycosaminoglycan hyaluronan is indicated for treating pain of OA of the knee that has not responded to or is contraindicated for conservative nonpharmacologic therapy and traditional analgesics. These analgesics include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors. Clinicians in the managed care setting may consider using viscosupplementation in patients (1) who have persistent pain despite their use of conservative nonpharmacologic and pharmacologic therapy (e.g., exercise, weight loss, physician therapy, bracing/orthotics, NSAIDs, COX-2 inhibitors, and intra-articular glucocorticoids); (2) who have compromised gastrointestinal (GI) function or who are at risk for GI bleeding due to the adverse events of NSAIDs; (3) who are taking concomitant anticoagulant therapy for any condition; (4) who have cardiovascular or renal risk factors that preclude use of COX-2 inhibitors; and (5) for whom surgery is not appropriate. Further study should be conducted with larger numbers of patients to help identify a subgroup of patients with OA in whom viscosupplementation may have even greater effects. Additional research should also concentrate on assessing the risks and benefits of extended treatments, because limited data are available concerning the effectiveness of multiple courses of therapy. CONCLUSION: OA is an important public health issue as the leading cause of disability in North America. As populations age, socioeconomic costs of OA will dramatically increase. Among available treatment options, viscosupplementation is a valuable alternative to more conservative therapy and has the benefit of circumventing the possible side effects of systemically administered pharmacologic agents. Viscosupplementation demonstrated efficacy in OA of the knee, and its use in the managed care arena may generate savings in hospitalizations and other costs. PMID- 23631050 TI - [Presentation. Low back pain]. PMID- 23631051 TI - [Epidemiology and socio-economic cost of low back pain]. PMID- 23631052 TI - [The natural history of disc herniation: from the mechanical to the inflammatory hypothesis]. PMID- 23631053 TI - [The evidence-based-medicine diagnosis of low back pain. Which specialists and which pathways for low back pain?]. PMID- 23631054 TI - [Accuracy and appropriateness in the diagnosis of symptomatic disc herniation]. PMID- 23631056 TI - [Low back pain and fibromyalgia syndrome]. PMID- 23631055 TI - Chondroprotective/structure-modifying drugs: a neverending story. PMID- 23631057 TI - [From acute low back pain to chronic: the natural history and physiopathological mechanisms]. PMID- 23631058 TI - [Progress in the pathogenesis of spondylarthrosis]. PMID- 23631059 TI - [Mechanical problems, posture, and low back pain]. PMID- 23631060 TI - [The narrow spinal canal: from diagnosis to therapeutic options]. PMID- 23631062 TI - [Corticosteroid-induced osteoporosis: epidemiology, physiopathology and clinical aspects]. PMID- 23631061 TI - [Clinical red flags vs laboratory red flags]. PMID- 23631063 TI - [What preventive measures and what therapy for vertebral collapse?]. PMID- 23631064 TI - [Inflammatory and infectious spondylodiscitis]. PMID- 23631066 TI - [Clinical features and laboratory examination: inflammatory diseases vs infectious diseases]. PMID- 23631065 TI - [The existence of a regulatory system for cortisol activation and deactivation at the osseous level in humans offers a new possibility for therapeutic intervention in corticosteroid osteoporosis]. PMID- 23631067 TI - Treatment of spondyloarthritides with anti-TNFalpha biologic agents. PMID- 23631069 TI - [Inflammatory rheumatic diseases: MRI]. PMID- 23631068 TI - [Low back pain. Inflammatory rheumatic disease: conventional radiology]. PMID- 23631070 TI - [Imaging diagnosis of low back pain]. PMID- 23631071 TI - [Analgesics, NSAIDS, and coxibs in rheumatic pain]. PMID- 23631072 TI - [The clinical course and surgical indications (the RAND Corporation method]. PMID- 23631073 TI - [Minimally invasive surgery and vertebro-kyphoplasty]. PMID- 23631074 TI - [Current surgical treatment of lumbar instability]. PMID- 23631075 TI - [Rehabilitation, physical therapy or Back School?]. PMID- 23631076 TI - [Similarities and differences in the characteristics of psychiatric care in Europe]. PMID- 23631078 TI - [European campaign against addiction to alcohol among youth]. PMID- 23631077 TI - [A confirmed link between anorexia and hyperactivity]. PMID- 23631079 TI - [Thinking of fun with therapeutic intent]. PMID- 23631080 TI - [Adapted physical activities and psychiatry]. AB - Adapted physical activities can take place within hospitals as well as outside. They hold a special place in the psychiatric landscape. The framework in which they take place is structured, well thought-out and organised. They are used, among others purposes, for prevention and rehabilitation and their influence on patients' well-being is proven. PMID- 23631081 TI - [Care outside the hospital walls]. AB - Physical activity can benefit people suffering from mental disorders, on the condition however that it is closely supervised by caregivers. It enables patients and caregivers to leave the hospital, physically, as well as figuratively speaking, by offering another space in which the nurse-patient relationship can bear fruit. PMID- 23631083 TI - [Joining in the dance, taking a step towards care]. AB - The dance workshop offers an original approach to care: reaching thought by working the body. In this group therapy which brings people together, creativity becomes possible. By becoming familiar with one's body and making oneself a place within the group, the opening of a "gateway onto care" can be envisaged. PMID- 23631082 TI - [Coming together through tennis]. AB - Providing a space to come together with the patient is part of the nursing strategy. Sport can represent an opportunity to create a relationship of understanding. Sometimes, the symptomatology persists and catches up with the present moment, but the shared physical activity always enables the people involved to push themselves and remains a rewarding experience. This article presents the personal account of a caregiver. PMID- 23631084 TI - [Developing touch through rugby]. AB - Rugby subjects the body to a tough test. Attack, defence, contact, touching are all elements which form part of this physical activity. It is very structured and safe from a psychological perspective. Taking pleasure in the game, with its rules, helps patients to develop interpersonal and relationship skills. PMID- 23631085 TI - [Climbing or the ascent towards oneself]. AB - Among the sports activities offered as part of the psychiatric care pathway, climbing, practised notably with a group of children, becomes a demonstration of the art of surpassing oneself. Thanks to the interaction within the group, between teachers, health professionals and children, it influences the psychological patterning of children presenting development disorders. PMID- 23631087 TI - [Bibliography]. PMID- 23631086 TI - [Discover the sport en institution]. AB - In order to promote physical activity to users of psychiatric services, the Maison Blanche public health facility organised a sports discovery day with a specialised partner, the French Federation of Adapted Sport (FFSA). Feedback on the day revealed a high level of satisfaction. Such initiatives favour physical activity among users and thereby help to fight the negative somatic effects of mental illness and antipsychotic drugs. PMID- 23631089 TI - [Jacques Lacan]. PMID- 23631088 TI - [Breaking the silence in Colombia to resist violence 2/2]. AB - The war in Columbia is the source of permanent and widespread violence, of which the civilian population is the main victim. Medical-psychological teams from Medecins Sans Frontieres France worked in Tolima, a region particularly affected by the conflict, between 2001 and 2008, and were able to study the complexity of the forms of violence and their consequences. While the consequences for individuals, analysed in part one, are devastating, the impact of the conflict on society and families provides a better understanding of this society and its generalised violence. PMID- 23631090 TI - "You shouldn't have to be brave to tell the truth". PMID- 23631092 TI - "Making time to listen to staff is the key to providing better care". PMID- 23631091 TI - Hike in spending on agency nurses. PMID- 23631093 TI - "Paperwork is important but some of it must be culled". PMID- 23631094 TI - The nurse's role in hospital ward rounds. AB - Ward rounds are a crucial aspect of acute care, but nurses' involvement varies. While their responsibilities on ward rounds may vary from ward to ward, nurses have a vital role to play and should make it a priority to attend. This article discusses key aspects of nurses' responsibilities and the different stages in the ward-round process. PMID- 23631095 TI - How nurses can lead from the frontline. AB - These recommendations aim to develop a health service with frontline leadership by improving the flow of information between members of the healthcare team. The recommendation of key nurses should improve patient care by making sure someone is responsible for each patient at all times. By enhancing the importance of ward rounds, everyone involved should be kept informed of the plan of care for each patient and know who is responsible for ensuring it is carried out. The recommendations encourage a multidisciplinary approach, centred on patients so they receive specialist care that is tailored to their specific needs. PMID- 23631096 TI - Policy +. The benefits and challenges of "bedside" nursing handovers. PMID- 23631097 TI - Managing hay fever during the exam period. AB - Hay-fever symptoms are common and debilitating and can have a detrimental effect on students' examination results. It is important to provide effective treatment using medication that optimises symptom control while ensuring drug side-effects are minimised. Research has confirmed that uncontrolled hay fever or medication side-effects can have a detrimental outcome on exam results. Ideally treatment should commence shortly before the start of the hay-fever season. PMID- 23631098 TI - Patient information that promotes healt literacy. AB - Health literacy is the ability to make informed health decisions in everyday life. For many patients and carers, decision-making is made more difficult by the fact that high-quality information is unavailable to them. The Pulmonary Hypertension Association has created patient materials that promote health literacy to help patients and their families make decisions that are well informed. PMID- 23631099 TI - Reforming dementia care. PMID- 23631100 TI - How to tackle poor performance. PMID- 23631101 TI - Tele-ICU: state of the art care. PMID- 23631102 TI - Not all nurses wear scrubs. Nursing informatics: what is it and what do they do? PMID- 23631103 TI - Success for nurses during the lame duck session of the General Assembly. PMID- 23631104 TI - Ohio: how are we doing with health information technology? PMID- 23631105 TI - Sing a song of HIPAA. PMID- 23631107 TI - Are you a good steward? Choose wisely my friend! PMID- 23631106 TI - From the Advancing Nursing Education Task Force: the case for expanding nursing practice competencies. PMID- 23631108 TI - Paget-Schroetter syndrome in a lacrosse player. AB - Paget Schroetter Syndrome (PSS) or "effort thrombosis" is a rare form of primary upper extremity deep vein thrombosis often seen in individuals with anatomic variants involving the thoracic outlet and exacerbated by repetitive microtrauma to the subclavian vein. Diagnosis can be made with ultrasound and confirmed with MR venography or conventional venography. We report a case of PSS in a young male athlete who was treated with pharmacologic and mechanical thrombolysis. PMID- 23631110 TI - Cuba's health system: is political repression worth the price? PMID- 23631109 TI - Breast cancer management in a case of hemihypertrophy/lymphedema. AB - Breast cancer can occur in women affected by congenital disorders because of its very high incidence. The circumstances of the underlying disease may affect the treatment plan for the cancer. In our case, breast cancer occurred in a 43-year old woman with congenital hemihypertrophy and lymphedematous features of the overgrowth. These conditions are described in the article while questions about the best practice for the cancer surgery are mentioned. PMID- 23631111 TI - How physician practices and physicians can take advantage of the ACA. PMID- 23631112 TI - Experimental tooth clenching. A model for studying mechanisms of muscle pain. AB - The overall goal of this thesis was to broaden knowledge of pain mechanisms in myofascial temporomandibular disorders (M-TMD). The specific aims were to: Develop a quality assessment tool for experimental bruxism studies (study I). Investigate proprioceptive allodynia after experimental tooth clenching exercises (study II). Evaluate the release of serotonin (5-HT), glutamate, pyruvate, and lactate in healthy subjects (study III) and in patients with M-TMD (study IV), after experimental tooth clenching exercises. In (I), tool development comprised 5 steps: (i) preliminary decisions, (ii) item generation, (iii) face-validity assessment, (iv) reliability and discriminative validity testing, and (v) instrument refinement. After preliminary decisions and a literature review, a list of 52 items to be considered for inclusion in the tool was generated. Eleven experts were invited to participate on the Delphi panel, of which 10 agreed. After four Delphi rounds, 8 items remained and were included in the Quality Assessment Tool for Experimental Bruxism Studies (Qu-ATEBS). Inter-observer reliability was acceptable (k = 0.77), and discriminative validity high (phi coefficient 0.79; P < 0.01). During refinement, 1 item was removed; the final tool comprised 7 items. In (II), 16 healthy females participated in three 60-min sessions, each with 24- and 48-h follow-ups. Participants were randomly assigned to a repetitive experimental tooth clenching task with a clenching level of 10%, 20%, or 40% of maximal voluntary clenching force (MVCF). Pain intensity, fatigue, perceived intensity of vibration (PIV), perceived discomfort (PD), and pressure pain threshold (PPT) were measured throughout. A significant increase in pain intensity and fatigue but not in PD was observed over time. A significant increase in PIV was only observed at 40 min, and PPT decreased significantly over time at 50 and 60 min compared to baseline. In (III), 30 healthy subjects (16 females, and 14 males) participated in two sessions at a minimum interval of 1 wk. Microdialysis was done to collect 5-HT, glutamate, pyruvate, and lactate and to measure masseter muscle blood flow. Two hours after the start of microdialysis, participants were randomized to a 20-min repetitive experimental tooth clenching task (50% of MVCF) or a control session (no clenching). Pain intensity was measured throughout the experiment. Substance levels and blood flow were unaltered at all time points between sessions, and between genders in each session. Pain intensity was significantly higher after clenching in the clenching session compared to the same time point in the control session. In (IV), 15 patients with M-TMD and 15 healthy controls participated in one session and the methodology described above was used. M-TMD patients had significantly higher levels of 5-HT and significantly lower blood flows than healthy controls. No significant differences for any substance at any time point were observed between groups. Time and group had significant main effects on pain intensity. Qu-ATEBS, the 7-item evidence-based quality assessment tool, is reliable, exhibits face validity, and has excellent discriminative validity. Tooth clenching was associated with pain, fatigue, and short-lasting mechanical hyperalgesia, but not with proprioceptive allodynia. It seems that tooth clenching is not directly related to delayed onset muscle soreness. In healthy subjects and in patients with M-TMD, levels of 5-HT, glutamate, pyruvate, and lactate were unaltered after tooth clenching. But 5-HT levels were significantly higher and blood flows significantly lower in M-TMD patients than in healthy controls at all time points. These two factors may facilitate the release, and enhance the effects, of other algesic substances that may cause pain. PMID- 23631113 TI - [The receptors and entry of measles virus: a review]. AB - Measles virus is an enveloped virus with a non-segmented negative-sense RNA genome. Two envelope glycoproteins on the viral surface, namely hemagglutinin (H) and membrane fusion protein (F), are responsible for the virus entry into susceptible host cells. The specific interaction between H and its cellular receptors is a key step in successful virus infection, determining the infectivity and tissue tropism of the measles virus. Thus far, three H receptors have been identified, including the complement regulatory molecule CD46, the signaling lymphocyte activation molecule (SLAM) and the cell adhesion molecule Nectin-4. Here, we reviewed our molecular understanding on the recognition mechanism of these receptors by the viral H protein, aiming to promote future studies on antiviral drug design and measles virus-based oncolytic therapy. PMID- 23631114 TI - [Application of functional quantum dots in cancer diagnosis and therapy: a review]. AB - Quantum dots (QDs) are nanometer-sized luminescent semiconductor nanocrystals. Their unique optical properties, such as high brightness, long-term stability, simultaneous detection of multiple signals and tunable emission spectra, make them appealing as potential diagnostic and therapeutic systems in oncology. Preparing the functional QDs by modifying bio-molecules such as antibody will have potential value for cancer diagnosis and treatment. This paper summarized the recent progress of promising application of QDs in cancer diagnosis and therapy, from identifying molecular targets, to drug delivery and therapy; from limitations of toxicity issues related to QDs in living organisms to multifunctional design and development. Finally, the promising applications of QDs are also discussed. PMID- 23631115 TI - [Expression and identification of truncated Nsp7 protein of North American and Europe genotype porcine reproductive and respiratory syndrome virus]. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) non-structural protein 7 (Nsp7) plays an important role in the induction of host humoral immune response and could serve as an ideal antigen for serological genotyping assay for PRRSV based on the significant difference in immunoreactivities of North American (NA) and European (EU) PRRSV Nsp7. In this study, Nsp7 of NA and EU PRRSVwas separately expressed and purified using prokaryotic expression system. The purified recombinant Nsp7 proteins reacted with serum antibodies against corresponding genotype PRRSV in Western blotting. However, nonspecific reaction of whole recombinant Nsp7 with antibodies against another genotype PRRSV was observed, indicating that whole NA PRRSV Nsp7 and EU PRRSV Nsp7 have similar antigenic epitopes and recombinant proteins could not be used for genotyping of antibodies against PRRSV. Based on the analysis of similar antigenic epitopes at the hydrophilic region of NA PRRSV Nsp7 and EU PRRSV Nsp7 by bioinformatics assessment, partial Nsp7 gene region deleted sequences encoding similar antigenic epitopes was constructed by fusion PCR. The recombinant truncated Nsp7 (NA deltaNsp7 and EU-deltaNsp7, about 43 kDa) was expressed and the molecular weight was about 43 kDa. The results of Western blotting showed that NA-deltaNSP7 and EU deltaNSP7 could be specifically recognized by positive serum to NA or EU PRRSV individually and nonspecific reaction was eliminated. This study provided a basis for further development of serological genotyping assay for North American and European genotype PRRSV infection. PMID- 23631117 TI - [Modulation of isoprenoid gene expression with multiple regulatory parts for improved beta-carotene production]. AB - Strong promoters might not be optimal to obtain maximum metabolic flux towards desired products, whereas modulating gene expression with multiple regulatory parts is an option to obtain optimal expression strength. Therefore, we assessed the difference of impact on beta-carotene production between modulating isoprenoid gene expression with multiple regulatory parts and strong promoter, to improve beta-carotene production through combined modulation of essential isoprenoid genes. Eight isoprenoid genes were modulated with six artificial regulatory parts having a wide range of strengths to assess their effects on beta carotene production. Optimal strength for each isoprenoid gene expression was identified, leading to 1.2 to 3.5-fold increase in beta-carotene production. In contrast to previous reports, our work suggests that modulating dxr, ispG and ispH genes with appropriate strengths increase beta-carotene production. Beta carotene yield reached 17.59 mg/g after combined modulation of dxs and idi genes, 8-fold higher than that of the parent strain. Modulating gene expression with multiple regulatory parts was better than strong promoter, providing a new gene modulation strategy for targeted biosynthesis. PMID- 23631116 TI - [Biocatalytic desymmetric hydrolysis of 3-(4-chlorophenyl)-glutaronitrile to the key precursor of optically pure baclofen]. AB - We produced (S)-4-cyano-3-(4-chlorophenyl)-butyrate by highly stereoselective biocatalyst in this study. A nitrilase-producing strain, named Gibberella intermedia WX12, was isolated by 3-(4-chlorophenyl)-glutaronitrile as substrate in the screening with phenol-sodium hypochlorite method. The fermentation conditions and catalytic properties of this strain were investigated. The preferred carbon and nitrogen sources for nitrilase production were lactose (30 g/L) and peptone (20 g/L). After being cultivated for 96 h, the cells were collected for use in biotransformation. The hydrolysis of 3-(4-chlorophenyl) glutaronitrile was performed at 30 degrees C in phosphate buffer (pH 8.0, 50 mmol/L) for 24 h to give (S)-4-cyano-3-(4-chlorophenyl)-butyric acid with 90% yield and > 99% of ee, which can be used for the synthesis of (R)- and (S) baclofen. The configuration of product was determined by chemically converting it to baclofen and comparison with the authentic sample by chiral HPLC analysis. PMID- 23631118 TI - [Rational design and construction of an overproducing shikimic acid Escherichia coli by metabolic engineering]. AB - Shikimic acid (SA), as a hydroaromatic intermediate in the common pathway of aromatic amino acid biosynthesis, is the starting material for the synthesis of neuraminidase inhibitors and other useful compounds. The fermentative production of SA by metabolically engineered microorganisms is an excellent alternative to the extraction from fruits of the Illicium plant. In this study, Escherichia coli was metabolically engineered by rational design and genetic manipulation for fermentative production of SA. Firstly, blocking the aromatic amino acid pathway after the production of SA was carried out by deletion of aroL and aroK genes encoding SA kinase. Secondly, the ptsG gene encoding protein EIICBglc were removed in the aroL/aroK mutant strain to make the phosphotransferase system (PTS) system default. In the resulting strain, the phosphoenolpyruvate-dependent PTS pathway, a main pathway for glucose transport, were replaced by ATP-dependent GalP (galactose permease). Thus, more PEP flux was used to produce SA as a critical precursor of SA. Furthermore, ydiB gene (encoding quinic acid/SA dehydrogenase) was deleted to prevent SA precursors of 3-dehyroquinic acid into the byproduct of quinic acid. Thus, the engineered strain with four genes deletion was constructed and 576 mg/L SA was produced in the shake flask fermentation. Results show that SA produciton was increased 90 times compared to the parent strain E. coli CICIM B0013. PMID- 23631119 TI - [Cloning and characterization of a novel carbonyl reductase for asymmetric reduction of bulky diaryl ketones]. AB - Asymmetric reduction of bulky diaryl ketones is still one of the challenging tasks in biocatalysis. By genomic data mining, a putative carbonyl reductase gene pascr was found in Pichia pastoris GS115. pascr was cloned and over-expressed in Escherichia coli Rosseta2 (DE3). The recombinant enzyme was purified to homogeneity by Ni-NTA column and its catalytic properties were studied. PasCR strictly used NADPH as cofactor, gel filtration and SDS-PAGE analysis suggested that the native form of PasCR was a dimmer. PasCR exhibited the highest activity at 35 degrees C in phosphate buffer at pH 6.5. The enzyme catalyzed the reduction of some bulky diaryl ketones, such as 4-methylbenzophenone, 2-methylbenzophenone and 4-chlorobenzophenone, especially for 4-methylbenzophenone, the product S- alcohol was obtained with 85% ee. PMID- 23631120 TI - [Construction, expression and enzymatic activity analysis of AUR1 eukaryotic expression vector of Botrytis cinerea]. AB - In order to study the expression and the activity of inositol phosphorylceramide synthase (BcAUR1 gene) in Botrytis cinerea, we amplified BcAUR1 by RT-PCR from Botrytis cinerea, using the special primers with FLAG and BamH I/Xho I restriction sites. Recombinant pYES2-BcAUR1 was constructed to transform into Saccharomyces cerevisae deltayorl by LiAC. The expression of inositol phosphorylceramide (IPC) synthase and its activity were detected by Western blotting and HPLC, respectively. The results show that pYES2-BcAUR1 could express in uracil mutant deltayorl of Saccharomyces cerevisae. IPC synthase enzyme activity of pYES2-BcAUR1 transformants significantly increased and was approximately double than no-load BcAUR1 transformants. The low concentration of Aureobasidin A could inhibit growth of no-load BcAUR1 transformants, but pYES2 BcAUR1 transformants could resist fungal growth inhibition which was induced by Aureobasidin A. PMID- 23631122 TI - [Anti-HBV effect of nucleotide analogues on mouse model of chronic HBV infection mediated by recombinant adeno-associated virus 8]. AB - We evaluated the anti-HBV effects of nucleotide analogues, Entecavir (ETV) and Lamivudine (LAM) targeting mouse model of HBV persistent infection with recombinant adeno-associated virus 8 carrying 1.3 copies of HBV genome (rAAV8 1.3HBV). Ninety percent (27 of 30 mice) of rAAVS-treated mice were chosen as mouse model. Four groups were orally administrated with different doses of ETV (1 mg/(kgd) or 0.1 mg/(kgd)) and LAM (500 mg/(kgd) or 100 mg/(kgd)) once a day for 10 days. The other two groups were set as normal saline treated and untreated control. We detected the levels of HBV DNA, HBeAg and HBsAg in sera at different time. Results indicate that HBV DNA level decreased significantly (P < 0.05) in drug-treated groups compared with normal saline group after drug administration. Fifteen days after the drug withdrawal, HBV DNA level rebounded back obviously (P < 0.05) in groups with low doses of ETV and LAM. However, there was no apparent change of HBeAg and HBsAg in the whole process among all groups. These results showed that our model could reflect the anti-viral effect of nucleotide analogues. This model can be a useful and convenient tool for anti-HBV drug discovery. PMID- 23631121 TI - [Conserved W52 led to reduced binding of glucogan-like peptide 1 receptor]. AB - Through phage display, we tried to find out whether the N-terminal fragment of glucogan-like peptide 1 receptor (nGLP-1R) still had binding activity to Exendin 4 after missing one or two gene segments. By error-prone PCR, We constructed a randomly mutated phage display peptide library with different length of the N terminal (21-145 residues) extracellular domain of glucogan-like peptide 1 receptor (GLP-1R) from rat lung. A mutant named EP16 without binding activity was found by ELISA. Through sequence alignment we found that EP16 missed the first 20 and last 10 amino acids and the 52nd tryptophan was mutated to arginine. In order to determine why Ep16 did not show its binding ability to Exendin-4, a wild type EP16 without the first 20 and last 10 amino acids and nGLP-1R(W52R) was constructed in which the 52nd tryptophan was mutated to arginine. The contrastive analysis showed that the substitution of W52R led to a markedly reduced binding ability of EP16. The mutation of the conserved W52 could change the biologic activity of the protein. The lack of the first 20 and last 10 amino acids had no effect on its biologic activity. Therefore, the mutation of a single amino acid residue of the key sequence could change the biologic activity of the nGLP-1R. PMID- 23631123 TI - [Optimization of enzymatic preparation of glucose 1-phosphate by response surface methodology]. AB - With glucose as substrate, sodium tripolyphosphate as the phosphorus acylating agent, and phosphorylase of Solanum tuberosum as the catalyst, glucose 1 phosphate was synthesized. Based on a three-level, three-variable Box-Behnken experimental design, response surface methodology was used to evaluate the effects of temperature, molar ratio of glucose to sodium tripolyphosphate and time on the production. The structure of the product was confirmed by 1H NMR spectra. The results show that the optimum conditions were as follows: temperature 35 degrees C, molar ratio of glucose to sodium tripolyphosphate 1.35:1 and time 19 h. PMID- 23631124 TI - [Temperature-switched high-efficiency D-lactate production from glycerol]. AB - Glycerol from oil hydrolysis industry is being considered as one of the abundent raw materials for fermentation industry. In present study, the aerobic and anaerobic metabolism and growth properties on glycerol by Esherichia coli CICIM B0013-070, a D-lactate over-producing strain constructed previously, at different temperatures were investigated, followed by a novel fermentation process, named temperature-switched process, was established for D-lactate production from glycerol. Under the optimal condition, lactate yield was increased from 64.0% to 82.6%. Subsequently, the yield of D-lactate from glycerol was reached up to 88.9% while a thermo-inducible promoter was used to regulate D-lactate dehydrogenase transcription. PMID- 23631125 TI - [Comparison of two types of cell cultures for preparation of sTNFRII-gAD fusion protein]. AB - In this study we used two types of cell cultures, i.e., anchorage-dependent basket and full suspension batch cultures of sTNFRII-gAD-expressing CHO cells in the CelliGen 310 bioreactor (7.5 L) to compare their yields in order to optimize the culturing conditions for efficient expression of sTNFRII-gAD fusion protein consisting of soluble tumor necrosis factor receptor II and globular domain of adiponectin. The anchorage-dependent basket culture was performed in 4L 10% serum containing medium with the final inoculating concentration of 3 x 10(5) to 4 x 10(5) cells/mL of sTNFRII-gAD-expressing CHO cells for 3 days, and then switched to 4 L serum-free LK021 medium to continue the culture for 4 days. The full suspension batch culture was carried out in the 4 L serum-free LK021 medium with the final inoculating concentration of 3 x 10(5) to 4 x 10(5) cells/mL of sTNFRII gAD-expressing CHO cells for 7 days. The culturing conditions were monitored in real-time to maintain pH and dissolved oxygen stability through the whole process. The supernatants were collected by centrifuge, and the protein was concentrated through Pellicon flow ultrafiltration system and then purified by DEAE anion exchange. The results showed that the yields of sTNFRII-gAD fusion protein were 8.0 mg/L with 95% purity and 7.5 mg/L with 98% purity in the anchorage-dependent basket and the full suspension batch cultures, respectively. The study provided the framework for the pilot production of sTNFRII-gAD fusion protein. PMID- 23631126 TI - [Improved lipid productivity of Nannochloropsis by heavy-ion irradiation mutagenesis]. AB - Nannochloropsis has been considered as a promising feedstock for biodiesel production in recent years. To improve its lipid productivity, heavy-ion irradiation mutagenesis, an effectively breeding method used in plants and microorganisms was applied in Nannochloropsis oceanica OZ-1. After large-scale screening using Imaging-PAM and microplate-reader, two mutants (HP-1 and HP-2) with higher growth rate were isolated from the wild type N. oceanica. Subsequently analysis showed that after 18 days of cultivation biomass accumulation of the HP-1 and HP-2 mutant was increased by 18% and 26% respectively compare to the wild type. Total lipid productivity of the HP-1 and HP-2 mutant was 295 mg/(L x d) and 275 mg/(L x d), respectively, whereas that of the wild type was 247 mg/(L x d). Both mutants showed significantly advantage over their wild type concerning biomass accumulation and lipid productivity. PMID- 23631127 TI - [Research of postoperative quality of life of laryngeal carcinoma patients]. AB - OBJECTIVE: To explore and compare the effect of clinical characters on quality of life (QOL) of laryngeal carcinoma postoperative patients. METHOD: We performed a retrospective cohort follow up study of 303 patients who underwent operation for laryngeal carcinoma. The Chinese version of the general and the head and neck specific quality of life questionnaires of the European Organization for the Research and Treatment of Cancer (EORTC QLQ-C30 and EORTC QLQ-H&H35) were used to measure the quality of life of those patients in the cohort, to study the relationship between QOL and clinical factors. RESULT: In the 303 cases, there were 78 cases retaining the permanent tracheostomies (59 total laryngectomy and 19 partial laryngectomy); 4 patient retain the nasal feed pipe. Female patients were worse than male patients in the domain of physical function and global QOL (P<0.05). Older patients were worse than younger patients in the domain of physical function and speech (P<0.05). Patients with glottic tumors experience better global QOL than their peers with under glottic or supraglottic tumors. The patients with supraglottic tumor have more problem with swallowings (P<0.05). Earlier stage patients have better suitation in many domains than later stage patients, but III stage have more difficulty with swallowing than IV stage. Patients who accepted minimally invasive operation and laryngofissure have better QOL than those accepted partial laryngectomy or total laryngectomy; total laryngectomee have more problems with physical, emotion function, global QOL, sense, speech, cough and morbid feeling than patients with partial laryngectomy, but less problem with fatigue, pain, dyspnea, swollowing and dry mouth; Patients with partial horizontal laryngectomy have more difficulty with swallowing. In the multivariable analysis, the operation mode was an independent factor to speech problem. Patients who accepted neck dissction have more negative outcomes than patients without neck dissection. In the univariable analysis, the permanent tracheostomy was a notable factor which affected many domains in the quality of life; multivariable analysis showed that permanent tracheostomy was an important factor which worked on global quality of life. CONCLUSION: The quality of life was affected by many clinical factors. The operation mode was an independent factor which affect speech problem. Decannulation after partial laryngectomy was very important to keep the quality of life. PMID- 23631128 TI - [Quality of life after adenotonsillectomy for obstructive sleep apnea in children]. AB - OBJECTIVE: To study changes in quality of life in children after adenotonsillectomy for obstructive sleep apnea (OSA) documented by full night polysomnography. METHOD: Children with OSA who fit the standard have been selected. They were asked to complete the OSA 18 quality of life survey before adenotonsillectomy and between 6 and 18 months after surgery. Scores from the preoperative and postoperative surveys were compared using the paired t test. RESULT: The mean total OSA 18 score was 70.59 (SD=15.015) before surgery and 39.94 (SD=14.232) after surgery. The changes in total score, in the scores for sleep disturbance, physical symptoms, emotional symptoms, daytime functioning, and caregiver concerns, and for each item of the OSA 18 survey was highly significant (P<0.01). CONCLUSION: OSA has a relevant impact on quality of life and the children show a marked improvements after adenotonsillectomy. PMID- 23631129 TI - [The expressions of EphrinB2 and VEGF in nasopharyngeal carcinoma and their clinical significance]. AB - OBJECTIVE: To investigate the expressions of EphrinB2 and VEGF in nasopharyngeal carcinoma and their relationships with clinic pathological factors. METHOD: The expressions of EphrinB2 and VEGF in 136 cases of nasopharyngeal carcinomas, and 20 cases of nasopharyngitis tissues were detected by SP method immunohistochemistry. RESULT: 1) The positive rates of EphrinB2 and VEGF were 63.2% and 67.6% respectively in 136 cases of nasopharyngeal carcinomas. Their positive rate in nasopharyneal carcinoma tissues was significantly higher than those in nasopharyngitis tissues (P<0.01). 2) Intensity of the expression of EphrinB2 and VEGF protein was related to lymphnodes metabasis, cranial nerve palsy, basalis encroachment, clinical stage respectively (P<0.01). 3) The expression of EphrinB2 in nasopharyngeal carcinoma tissues and was positively correlated with VEGF (P< 0.01). CONCLUSION: Ephrinbeta2 and VEGF may play important roles in invasiveness, metastasis and angiogenesis of nasopharyngeal carcinoma. There may be certain inter regulation mechanism between them and they are hoped to become new biologic parameters to judge the pathogenesis, development and prognosis of nasopharyngeal carcinoma and to guide the treatment. PMID- 23631130 TI - [Expressions of HMGB1, MMP-2 and MMP-9 and prognostic alue in human laryngeal carcinoma]. AB - OBJECTIVE: To investigate the expressions of high mobility group box B1 protein (HMGB1), matrix metalloproteinases-2(MMP-2) and matrix metalloproteinases-9 (MMP 9) in human laryngeal carcinoma and study their relationships with clinicopathological characteristics and prognosis. METHOD: The expressions of HMGB1, MMP-2 and MMP-9 proteins were examined with the EnVision immunohistochemical method in 61 cases of laryngeal carcinoma. The expressions of HMGB1, MMP-2 and MMP-9 mRNA were detected by real-time quantitative RT-PCR method in 30 cases of laryngeal carcinoma. RESULT: The positive expression rates of HMGB1, MMP-2 and MMP-9 proteins were significantly higher in laryngeal carcinoma than those in adjacent tissue (chi2=44.934, 49.923 and 36.054, P<0.01). The relative expression levels of HMGB1, MMP-2 and MMP-9 mRNA in laryngeal carcinoma were significantly higher than those in adjacent tissue (t=5.940, 7.005 and 7.664, P<0.01). The high level expression of HMGB1, MMP-2, MMP-9 proteins was closely associated with T stage, clinical stage and the status of lymph node metastasis (P<0.05 or P<0.01). There was a positive correlation between the expression of HMGB1 and MMP-9 protein (r=0.381, P<0.01). Univariate analysis indicated that the overall survival rate was lower in patients with a positive expression of HMGB1 and MMP-9 than those with negative expression (chi2= 4.974, 6.418, P<0.05). Multivariate analysis showed that HMGB1 was a risk predictor. A higher expression of HMGB1 was associated with a shorter survival time. CONCLUSION: HMGB1, MMP-2 and MMP-9 play a role in invasion and metastasis of laryngeal carcinoma; Also there is a synergistic effect between HMGB1 and MMP-9; Moreover HMGB1 may be a independent prognostic factor. PMID- 23631131 TI - [Manujet III manual jet ventilation used in tracheobronchial foreign bodies removal in children]. AB - OBJECTIVE: To evaluate the effect of applying Manujet III manual jet ventilation to remove tracheo-bronchial foreign bodies in children. METHOD: Before 2009, 62 patients, using the controlled positive pressure ventilation through the side holes of the rigid bronchoscopy, is signed as group P. Another group J ,from January 2009 to January 2012, 48 cases, utilizing Manujet III device manual jet ventilation. The satisfaction rate at placed in bronchoscopy, intraoperative hypoxia. removal of foreign body situation, operative time, incidence of adverse reactions were recorded and contrasted. RESULT: The difference of satisfaction rate in placing endoscopy between the two groups was not statistically significant (P>0.05). But in operative time, intraoperative hypoxia, incidence of adverse reaction rate was statistically significant (P<0.05), J group is better than the group P. CONCLUSION: In the tracheobronchial foreign bodies removal, application Manujet III device to manual jet ventilation can reduce the incidence of intraoperative hypoxia, easier to surgical operation. PMID- 23631132 TI - [Clinical analysis of 182 cases esophageal foreign bodies and treatment for special cases]. AB - OBJECTIVE: To provide clinical reference by summarizing and analyzing characteristics, therapeutic principles and methods for special cases of esophageal foreign bodies. METHOD: Statistical analysis 182 cases with esophageal foreign bodies, including 41 special cases. Surgery 165 cases, 17 cases without surgery. RESULT: One hundred and seventy-five cases were cured, 7 cases improved. Hospitalization time 0.5-50 d (average 4.5 d). CONCLUSION: It is important to learn about characteristics of esophageal foreign bodies, therapeutic principles and methods for special cases, and it's a key point to diagnosis early and remove the foreign bodies as soon as possible, and comprehensive treatment measures are really effective to process special cases. PMID- 23631133 TI - [Detection of Runx2 mRNA expression using relatively real-time RT-PCR in papillary thyroid carcinoma]. AB - OBJECTIVE: To relatively detect the Runx2 mRNA expression in papillary thyroid carcinoma (PTC) and thyroid adenoma, then to investigate the role of Runx2 in the development and progression in PTC and the relationship with the micro calcification in PTC. METHOD: The expression of Runx2 mRNA in 14 samples of PTC and 14 samples of thyroid adenoma was examined by relatively real-time RT-PCR. RESULT: The deltaCT value of the carcinoma group and adenoma group was 2.395 +/- 0.302 and 5.028 +/- 1.179 respectively (P<0.01). The 2(-deltadeltaCT) value of the carcinoma group and adenoma group was 7.826 +/- 5.004 and 1 respectively (P<0.01). The carcinoma group was divided into two groups by calcification and there was no statistical difference (P>0.05), and the adenoma group as well. The carcinoma group was divided into two groups by the size of carcinoma (<1 cm and > or = 1 cm). The deltaCT value was 2.629 +/- 0.300 and 2.212 +/- 0.124 respectively (P<0.05) and the 2(-deltadeltaCT) value was 167.33 +/- 33. 823 and 221.69 +/- 18.843 respectively (P<0.01). The TSH level in carcinoma group and adenoma group had no statistical significance (P>0.05). CONCLUSION: The expression of Runx2 mRNA was high in PTC, and was related to the size of carcinoma which was higher in bigger size carcinoma. The role of Runx2 may contribute to the formation of the micro-calcification and the development and progression in PTC and other malignant tumors, such as breast cancer, prostatic carcinoma and osteosarcoma. PMID- 23631134 TI - [Comparison of the exposure when using endoscopes of different angles for microlaryngoscopic surgery]. AB - OBJECTIVE: To observe the exposure of the vocal lesions under endoscopes of different angles and to contrast the endoscopes' influence on surgery. METHOD: Fifty patients with benign vocal lesions were selected randomly. During microlaryngoscopic surgery, the laryngoscope was placed softly and the different rigid endoscope (30 degrees, 45 degrees or 70 degrees) was connected to video system to expose the glottis and vocal folds. The operation was taken through looking at the color monitor. RESULT: The vocal fold lesions were completely examined and successfully excised in all patients, only two of them got soft palate mucosal abrasion. No one got complications. CONCLUSION: Rigid endoscopy associated with microlaryngeal surgery brings a better observation to the vocal lesions and a lower incidence rate of complicatons. It's regarded that 45 degrees rigid endoscope is better than the others, for it provides not only a good exposure to the vocal cords, anterior commissure and subglottis, but also convenience to operate. The second one is 30 degrees rigid endoscope, which can save the cost, because of the widely using in many other departments. PMID- 23631135 TI - [Effect of tanshinone II A to B7H3 expression in human nasopharyngeal carcinoma CNE1 cell lines]. AB - OBJECTIVE: To explore the proliferation of human nasopharyngeal carcinoma CNE1 cell and B7H3 expiration after treating by Tanshinone II A (Tan II A). METHOD: The CNE1 cell was cultured in vitro and treated by Tan II A with different concentrations; Cell proliferation was valuated by MTT; Apoptotic rate and cell cycle were investigated by flow cytometry; Bcl2 and B7H3 expiration were detected by direct immunofluorescence assay. RESULT: The CNE1 cell's proliferation has been significantly inhibited by Tan II A, the inhibition was in dose and time effect with Tan II A, with significant difference (P<0.01); IC50 value in 24, 48 and 72 hours was respective 12.5 micromol/L, 4.8 micromol/L and 3.0 micromol/L; Comparing with the control group, Tan II A group increased apoptosis rate (P<0.01); Cell cycle was blocked in G2/M phase; Bcl2 and B7H3 expression were more decreased in Tan II A group than in control group with significant difference (P<0.05); CONCLUSION: Tan II A caused obviously growth inhibitory effect and induced apoptosis in CNE1 cells and the mechanisms might be related to down regulation of Bcl2 and B7H3. PMID- 23631136 TI - [Is horizontal semicircular canal ocular reflex influenced by otolith organs input?]. PMID- 23631137 TI - [Clinical study and survival analysis of combined modality therapies for advanced hypopharyngeal carcinoma]. AB - OBJECTIVE: To evaluate the efficacy of combined modality therapy for advanced hypopharyngeal carcinoma in order to improve the curative effect of hypopharyngeal carcinoma. METHOD: Seventy-six male patients with the stage III - IV hypopharyngeal carcinoma were treated with postoperative combined modality. Of all the 76 cases, 44 were treated with postoperative radiotherapy, and the other 32 treated with chemoradiotherapy concurrently. RESULT: Kaplan Meier analysis indicated that the overall 5 survival rates of patients treated with postoperative radiotherapy was 25.9%, and that of patients treated with postoperative chemoradiotherapy was 27.8%. There was no significant difference between the two groups (P>0.05). Three and five years relapse-free survival rates of the patients treated with postoperative radiotherapy were 36.0%, 22.5%, and those of the patients treated with postoperative chemoradiotherapy were 68.0%, 45.3%. Significant difference was calculated between the two groups (P<0.05). According to the NCI CTC3.0 criteria, the toxicities on grade 3 or above of the two groups showed no significant difference (P>0.05). CONCLUSION: For advanced hypopharyngeal carcinoma, postoperative chemoradiotherapy yielded satisfactory relapse free survival and laryngeal function preservation rate which was superior to that of postoperative radiotherapy. Also the treatment toxicities were not increased. PMID- 23631138 TI - [Study on the height and weight in children with obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To investigate the influence of obstructive sleep apnea hypopnea syndrome (OSAHS) on children's growth. METHOD: Fifty-three children diagnosed as OSAHS were included in the treatment group and underwent tonsillectomy or adenoidectomy, and 51 normal children were employed as the control group. Main data monitored by PSG and growth hormone (GH) in children of the treatment group were recorded before and after surgery, in addition, growth hormone, height and weight of children in the treatment group and control group were respectively recorded and compared. RESULT: Height and weight of children with OSAHS before treatment were lower than that of the normal children and the difference was significant (P<0.05). Compared with the data before surgery, oxygen saturation of blood in children of treatment group recorded by PSG increased (P<0.05), while value of other data decreased (P<0.05). Growth hormone in children of the treatment group was lower than that of the control group and the difference between two group was significant (P<0.05), while the content of growth hormone in children of the treatment group elevated after 3 months postoperatively and at this time no difference was found between the two groups. CONCLUSION: Children with OSAHS present the symptom of upper airway obstruction, which badly affects sleep quality and results in decreased secretion of growth hormone and finally the height and weight of children is got involved. Timely surgery is necessary to alleviate the symptom. PMID- 23631139 TI - [The research of immune function for Coblation treatment of partial tonsillectomy in children]. PMID- 23631140 TI - [Efficacy analysis of 210 cases vocal cord polyp by microlaryngoscopy carbon dioxide laser treatment]. PMID- 23631141 TI - [Clinical analysis on 10 cases with laryngeal mycosis]. PMID- 23631142 TI - [Non Hodgkin's lymphoma misdiagnosed as mixed salivary gland tumor which located on hard palate one case]. PMID- 23631143 TI - [One patient of giant lymph node hyperplasia with laryngeal obstruction]. PMID- 23631144 TI - [A case report with esophageal foreign body of muskmelon]. AB - A male patient, 41 years old, swallowed a chunk of muskmelon because his attention was not centralized. Odynophagia and dysphagia were the two main clinical manifestations. The esophagus barium swallow examination showed a foreign body in the upper esophagus. The patient did the rigid esophagoscope examination in the operating room under general anesthesia. There was a chunk of muskmelon in the upper esophagus and could not take it out from the esophagus by using foreign body forceps because the muskmelon was very crisp. In the end the muskmelon was sent in the stomach. The patient's symptoms were alleviated after operation. PMID- 23631145 TI - [Eustachian orifice malignant melanoma: a case report]. AB - The patient, a 52 year old male was admitted to the hospital, because of right hearing loss before three months. Six months ago; the patient had the right former group sinusitis and nasal polyps, and had the right former group sinus open and polypectomy operation outside the hospital. The surgery was uneventful and the postoperative dressing was done. He has no history of tinnitus, earache, ear pus, epistaxis, headache, dizziness. Physical examination on admission shows the right external auditory canal was clean, tympanic membrane integrity, pale yellow, mild depression, and poorly eardrum movement. The electronic nasopharyngoscopy show a black mass in the edge of the anterior lip of the right eustachian tube. The mass has a smooth surface, and only seen partly. Nasopharynx magnetic resonance shows in the right pharyngeal orifice visible there was a round short T2 node, maximum diameter of 13 mm, the border was clear. The parapharyngeal space had been compressed which close to the right eustachian tube torus. After the scan enhanced, the lesions was strengthened. The pure tone audiometry shows right mild conduction deafness, and the acoustic impedance showing right type B tympanogram curve. Eardrum puncture extracted got about 0.2 ml yellow liquid. Otitis media with effusion is considered. A biopsy is taken by means of the nasal endoscopic. The pathology report is the right eustachian orifice malignant melanoma. The immunohistochemical examination (Horton-Magath Brown 45) showed a positive reaction. PMID- 23631146 TI - [The application of sentinel lymph node detection in thyroid cancer]. AB - Thyroid cancer is more common in thyroid diseases, because of its slow growth and good prognosis, different scholars have different views on lymph node dissection. During the study of definition and positioning methods of sentinel lymph node biopsy, discuss the necessity of cervical node dissection and the application of cleaning scope in thyroid cancer surgery. PMID- 23631147 TI - Plastic problem in Africa. PMID- 23631148 TI - Antibiotic residues in food: the African scenario. AB - Antibiotics are substances either produced naturally by living organisms or synthetically in the laboratory, and they are able to kill or inhibit the growth of microorganisms. Antibiotics are also used as feed additives for the purpose of livestock health maintenance. Antibiotic residues in feedstuffs are currently a problem of some magnitude in different parts of the world, particularly due to associated public health concerns that include hypersensitivity reactions, antibiotic resistance, toxicity, teratogenicity, and carcinogenicity. In Africa, as in other parts of the world, antibiotic residues in animal-derived foods have been extensively recorded in many African countries; these residues have exceeded the WHO maximum residue levels in many cases. It has been reported that tetracyclines are the most predominantly prescribed antibiotics in Africa, and of all antibiotic-associated residues they represent 41% of cases, followed by beta lactams at 18%. Great care should be taken to monitor antibiotic cessation periods before the release of animal-derived foods for human consumption. In addition, strict legislation should be implemented in order to minimize the abuse of antibiotics. PMID- 23631149 TI - Economic and toxicological aspects of copper industry in Katanga, DR Congo. AB - The Katanga province is well known for its copper and cobalt reserves. During the early 2000s a boom of mining projects in Katanga brought again hope for better future to Congolese people. The paper aims to evaluate the impact of recent production recovery on economy and environment. We collected primary and secondary sources on copper industry for economic analysis. We use results of laboratory analysis conducted at the Congolese Office of Control by provincial division of environment for toxicological analysis. The comparison of heavy metal concentration to standards shows that mining industry is the main source of environmental pollution in Katanga. Copper industry generates income for economic growth of the region. PMID- 23631150 TI - Determination of multiple mycotoxins levels in poultry feeds from Cameroon. AB - For the first time in Cameroon, this paper reports on multiple mycotoxins occurrences in poultry feeds. Twenty feed samples collected from different poultry farms were analyzed for 320 fungal metabolites by liquid chromatography electrospray ionization tandem mass spectrometry. Results showed feeds contamination by 68 metabolites including 18 mycotoxins/metabolites currently regulated in the European Union such as fumonisins B1 (FB1), B2, and B3; deoxynevalenol (DON); and beta-zearalenol recovered in all samples. FB1 reported highest FB mean level of 468 (range 16-1930) microg kg(-1). Levels of DON and ZEN were mostly concentrated in feeds from western-highlands conversely for FBs and aflatoxins concentrations in Yaounde. Aflatoxin B1 mean level of 40 microg kg(-1) exceeded the worldwide permitted limit for aflatoxins in feed and generally inversely proportional to weight gain in chicken. PMID- 23631151 TI - Lactuca spp. seeds as a bioindicator for the toxicity of Gezira Tannery Corporation wastewater. AB - This study was conducted to establish the potential of lettuce (Lactuca sativa L. var. buttercrunch) seeds as a bioindicator (BI), or a biological tool for detecting the presence of some toxic materials used in tanning industry and determining their concentrations using the germination percentage as a parameter (indicator). Samples of Gezira Tannery Corporation (GTC) wastewater (WW) were collected from both the mouth and the tail of the drainage stream. Lettuce seeds (10/Petri dish, replicated 3x and each experiment was repeated 3x) were treated by GTC WW and other important tanning agents (chromium oxide, sodium sulfide, Preventol WB) in solution using different concentrations of each and their mixture. The bioassay experiment revealed that the seeds were intoxicated (i.e. reduced the germination percentage), when exposed to the WW. On exposure to several concentrations from each input, the concentrations that can be measured by this BI (i.e. sensitivity and reliability) are: chromium oxide from 0.1 to 3.25%, sodium sulfide from 0.19 to 1.5% and Preventol WB from 18.75 to 150 ppm. Lower concentrations cannot be measured, and higher concentrations resulted in 100% inhibition. The IC50 was determined by probit analysis for the WW, mixture of the three inputs, chromium oxide alone, sodium sulfide alone and Preventol WB alone were: 35.5, 14.5, 0.44, 0.45 and 0.005%, respectively. The slopes of the log-dose probability lines (Ld-P) showed that this BI response to all treatments was homogeneous (> 2) (tabulated X2 (df = n - 2) at 5% = 0.172, 0.11, 0.064, 0.05 and 0.05). It is concluded that lettuce seeds satisfy almost all the required properties of the ideal BI. PMID- 23631152 TI - Oxytetracycline residues in bovine carcasses slaughtered at Mansoura Abattoir, Egypt. AB - Oxytetracycline residues were examined in 600 samples (200 each of muscles, livers and kidneys) collected randomly from bovine carcasses slaughtered at Mansoura abattoir in Dakahlia Province, Egypt. A microbial inhibition test using Bacillus subtilis ATCC- 6633 was employed to screen the obtained samples for antibiotic residues in meat. The results showed that 2% of samples were positive. Oxytetracycline residues exceeded the maximum residue limits (MRLs) in 1.33% of the examined samples. Thus, regulatory authorities should insure proper withdrawal period before slaughtering of the animals (28 days for oxytetracycline). Public health importance was discussed. PMID- 23631153 TI - Biological responses of xenobiotic metabolizing enzymes to lead exposure in cultured H4IIE rat cells. AB - This study was undertaken to investigate the constitutive response of xenobiotic metabolizing enzymes (XMEs) to lead (Pb2+) exposure in cultured rat liver (H4IIE) cell lines. Phase I enzymes such as CYP1A1 and CYP1A2 had mRNA expressions that were slightly induced after exposure to low concentrations of Pb2+; however, under higher concentrations of Pb2+, the mRNA expressions of CYP1A1 and CYP1A2 were significantly down-regulated. These effects were in correspondence with AhR mRNA expression. Phase II enzymes had mRNA expressions that were reduced upon exposure to Pb2+. Metallothionein mRNA expression was induced after treatment with Pb2+ in a dose-dependent trend. In conclusion, Phase I and II enzymes were significantly modulated upon lead exposure indicating some toxicological implications for lead exposure in cultured H4IIE cells. PMID- 23631154 TI - Heavy metal residues in canned fishes in Egypt. AB - A total of 75 random canned fish samples, 25 each of canned (canned tuna, sardine and mackerel) during 2009, were collected from Zagazig Markets for determination of lead, cadmium, zinc, copper and tin residues using atomic absorption spectrophotometer. The obtained results revealed that the mean values of the lead residues in the examined canned tuna, sardine and mackerel were 0.127 +/- 0.02, 0.013 +/- 0.004 and 0.023 +/- 0.01 (ppm) respectively. The mean concentrations of cadmium residues were 0.022 +/- 0.001, 0.048 +/- 0.003 and 0.027 +/- 0.003 ppm, respectively. While in case of zinc, the residual levels were 1.97 +/- 0.12, 2.369 +/- 0.32 and 1.126 +/- 0.24 ppm, respectively. Copper residual levels in the examined samples were 0.293 +/- 0.08, 0.221 +/- 0.03 and 0.08 +/- 0.02 ppm, respectively. In case of tin, the residual levels were 1.496 +/- 0.30, 1.209 +/- 0.26 and 0.379 +/- 0.11 ppm respectively. PMID- 23631155 TI - Determination of organochlorine pesticides (OCPs) in the edible offal of Egyptian buffalo. AB - Environmental contamination by OCPs has a great concern, since most of these pesticide compounds are very toxic and harmful to human and ecosystems. This study was conducted to determine the concentrations of OCPs residues in the edible offal (livers, kidneys and tongues) of Egyptian buffalo collected from three locations (Zagazig, Ismailia and Mansoura) in Egypt. Examined samples from Mansura city had the highest OCPs contamination load. Tongues had the highest concentration of these toxic residues in a comparison to livers and kidneys in the examined samples. The overall results showed that OCPs residues did not exceed the Egyptian maximum permissible limits in all of the samples analyzed from the three different locations. PMID- 23631156 TI - Forensic case of lead poisoning from a battery manufacturing company in Nakuru, Kenya. AB - Acute sickness involving dairy cattle (n = 5) with a morbidity of 100% occurred in a farm in Nakuru, Kenya. A case study was undertaken with the objective of establishing the cause of the sickness. Samples of blood, soil and industrial waste contained high levels of lead. The symptoms, results of postmortem and history of the case were used to establish the diagnosis of acute lead poisoning. This is a forensic case in court between the owner of the animals and a lead recycling company that dumped the industrial waste that was associated with the poisoning. There could be many unreported cases of lead poisoning in Kenya areas with heavy industrial activities since data on of lead poisoning in Kenya is scanty. PMID- 23631157 TI - Effects of endosulfan pesticide on toad. AB - The lethal and sublethal toxicity of Endosulfan on the African toad, Bufo regularis were evaluated to assess changes in behaviour and energy reserves. 96 hours LC50 was 0.730 mg/l while the estimated safe concentration was 0.07 mg/L indicating the high toxicity of the insecticide. Toads exposed to lethal concentrations of endosulfan showed dose-dependent behavioural abnormalities with more pronounced poisoning symptoms occurring at higher concentrations. The pesticide caused differential increase in serum glucose levels with a concomitant reduction in liver glycogen indicating disorders in carbohydrate metabolism due to pesticide induced stress and hence can serve as suitable biomarkers in pesticide toxicity studies. PMID- 23631158 TI - Distribution of metals in organs of Clarias gariepinus, Heterobranchus bidorsalis, and Chrysichthys nigrodigitatus from the Offin River at Dunkwa-on Offin, Ghana. AB - All heavy metals are potentially harmful to most organisms at some level of exposure and absorption. Concentrations of Co, Cr, Cu, Ni, Zn, Hg, Cd, As, and Pb were determined by atomic absorption spectrophotometry (AAS) in three fish species (C. gariepinus, C. nigrodigitatus, and H. bidorsalis) from the Offin River in Dunkwa township, Ghana. In the fish species, gills, livers, and muscles were analyzed. The metal that recorded the highest concentration was Zn, which was highly accumulated in the liver of C. gariepinus, but had the lowest concentration in the muscles of C. nigrodigitatus. PMID- 23631159 TI - Determination of benzo[a]pyrene levels in ambient air and the source of polycyclic aromatic hydrocarbons using a diagnostic ratio method in Ghana. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants produced from incomplete combustion of fuel or vegetation fires. Their presence in air deserves attention because they can produce carcinogenic and mutagenic effects. As an industrialized and economically significant city in Ghana, Kumasi has been subject to heavy anthropogenic influences due to rapid economic development and urbanization leading to a greater fuel combustion rate. Airborne particulate samples were collected on filters using a Sibata air sampler and analyzed by gas chromatography-mass spectrometry (GC-MS). Our results indicated that air from the city center can be classified as highly polluted with benzo[a] pyrene (B[a]P). The diagnostic ratios of the results showed that PAHs in the air samples were mainly from fuel combustion. PMID- 23631160 TI - Heavy metal pollution in Japanese seabirds. AB - It is reported that seabirds accumulate high levels of metals, prompting concerns regarding poisoning. The present study investigated the accumulation patterns of metals in tissues among four species of seabirds (Fratercula corniculata, Uria lomvia, Puffinus tenuirostris, and Fulmarus glacialis). Furthermore, we focused on Slaty-backed Gulls, which accumulated high levels of cadmium and mercury, and compared the areal differences. Geographic variation of metal levels could also contribute to differences in metal accumulation levels in these bird species. Therefore, the concentrations of metals in seabirds are considered to reflect their habitat. There are differences in the accumulation pattern among the seabird species. The high accumulation of metals could affect seabirds even if they do not show any symptoms. PMID- 23631161 TI - Metabolism of pyrene, a polycyclic aromatic hydrocarbon in freshwater turtles. AB - Reptile population decrease is an alarming trend all around the world. Yet little is known about the role of xenobiotics in this decrease. In this study, we investigated the metabolism of pyrene in three freshwater turtle species (Red EARED sliders (Trachemys scripta elegans), Chinese pond turtles (Mauremys reevesii) and Chinese softshell turtles (Pelodiscus sinensis). Compared to other vertebrates, all turtles showed an unique metabolite distribution, pyrene-1 sulfate being the main metabolite. The observed low phase II enzyme metabolic rates raises the question of the effect of long-time exposure. PMID- 23631162 TI - Metal contaminated soil from mining area caused metal accumulation and biological responses in rats. AB - In order to assess the effects of metal contamination on wildlife, we collected wild black rats (Rattus sp.) from mining areas (Kabwe and Chingola) and a control area (Lusaka) in Zambia and compared metal and metallothionein (MT) levels in their tissues. Furthermore, we exposed metal-contaminated soil from Kabwe to laboratory Wistar rats (Rattus norvegicus) for one year in order to determine the accumulation factors and effects of metals caused by soil exposure. Results of both the field and laboratory studies suggested that metal-contaminated soil caused accumulation and biological responses such as elevation of MT-2 mRNA expression levels in rats. PMID- 23631163 TI - In vitro diazepam metabolism in horses. AB - There is little information about drug metabolism and pharmacokinetics in horses. Therefore, it is necessary to characterize the profiles of drug metabolites for the safe use of drugs. In this study, we focused on cytochrome P450 enzymes (CYPs), which represent an important enzyme group to determine pharmacological effects of drugs. We chose diazepam as the drug of choice for this study. The aim of this study was to elucidate the metabolic pathway of diazepam in horses in comparison with rats, and to clarify CYP subfamilies responsible for diazepam metabolism in horses. Our results showed temazepam was the major diazepam metabolite produced from microsomal reactions in horse liver, but horses produced drastically less p-hydroxydiazepam as compared with rats. Furthermore, CYP3A was a major contributor from the CYP subfamily of temazepam production. PMID- 23631164 TI - [Progress in 3D mapping system in the diagnosis and treatment cardiac arrhythmia]. PMID- 23631165 TI - [History, changes, and perspectives of AF therapy and research]. AB - By reviewing the history of therapy and research regarding to atrial fibrillation(AF), we will be able to understand the most important viewpoint over the current and future treatment of AF, which would provide an aid for future perspective into the clinical and basic research targeting AF. Around 2000's, a major turning point of a paradigm shift occurred from the changes in the age proportion of the society that altered the prevalence and prognosis of AF patients and also the changes in the needs from the society. A future perspective should be discussed from this turning point. PMID- 23631166 TI - [Epidemiology and prognosis of atrial fibrillation in Japanese population]. AB - Atrial fibrillation (AF) is one of the common arrhythmias encountered in general practice as well as in the field of cardiology. AF could be responsible for increased mortality and various morbidities including clinical symptoms, impaired cardiac function and thromboembolism. An epidemiological study showed that prevalence of AF increased with the aging of the population and that the increase became striking after 60 years of age, affecting approximately 4 % in men and 2 % in women aged 80 years or more. Rhythm control with antiarrhythmic drugs and/or catheter ablation could not fully prevent AF reccurence. Understanding the epidemiology, risk factors, clinical course and prognosis of AF is very important to management of AF. PMID- 23631167 TI - [Pathophysiology and clinical manifestations of atrial fibrillation]. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia among elderly people. The condition is frequently associated with structural heart disease, although a substantial number of patients have no underlying disease. Stretch in the pulmonary vein is considered to play the most important role in its pathogenesis, particularly in patients with hypertension and heart failure. The autonomic nervous system is known to contribute to its initiation. Based on its duration, AF can be classified into paroxysmal, persistent, and permanent, but its progression from the former to the latter is common over years. Palpitations are most frequently complained in paroxysmal AF, whereas absence of symptoms is not unusual in permanent AF. But regardless of types or symptoms of AF, AF is notorious for potentially causing stroke and heart failure, which increase morbidity and mortality. PMID- 23631168 TI - [Mechanisms for onset and maintenance of atrial fibrillation and its risk factors]. PMID- 23631169 TI - [Mechanism and risk factors of cardiogenic thromboembolism in patients with atrial fibrillation]. AB - Atrial fibrillation (AF) is well known as one of the cardiogenic causes for thromboembolism. Here, the role of 3 important components as known Virchow's triad, blood coagulability, abnormalities in the blood flow, and the endocardial function of the atria, in thrombus formation in the fibrillating atria are discussed. In the experimental model, rapid atrial pacing acutely downregulated the gene expression of thrombomodulin(TM) and tissue factor pathway inhibitor (TFPI) in the atrial endocardium. In the clinical practice, CHADS2 score had been used for the risk stratification of thromboembolism in patients with AF. High CHADS2 score might be associated with abnormalities of left atrial blood flow or progression of fibrosis in the left atrial wall. PMID- 23631170 TI - [ECG, Holter ECG, event recorder]. AB - ECG, 24-h ambulatory ECG, and related tests have been used to clarify the pathophysiological features of atrial fibrillation as well as to detect the relationship between symptoms and episodes of tachyarrhythmia. These testes are also potent to estimate the efficacy of pharmacological and nonpharmacological treatments. Proarrhythmic events during the treatment with antiarrhythmic agents may be avoided by careful follow-up using ECG. Recently, an implantable loop recorder electrocardiogram is available to identify the culprit episode of syncope. Atrial fibrillation is a cause of syncope in only a small proportion of patients. PMID- 23631171 TI - [Echocardiogram in atrial fibrillation]. AB - The echocardiogram should be performed in the patients with atrial fibrillation to detect cardiac structurally abnormality and assess left ventricular systolic and diastolic functions. Parameters that reflect left atrium (LA) size such as LA dimension and LA volume have been proposed as predictors of success of the radiofrequency catheter ablation. The transthoracic echocardiogram can provide useful information to guide the management of atrial fibrillation, but cannot exclude thrombus in the left atrial appendage (LAA). The transesophageal echocardiography must be used to rule out intra LA thrombus especially prior to cardioversion and the radiofrequency catheter ablation. The smoke-like echo and sludge in the LA or LAA and the decreased LAA flow velocity are associated with high risk for LA thrombus. PMID- 23631172 TI - [Electrophysiological study in atrial fibrillation]. AB - Electrophysiological study should be done in patients who suppose to undergo the treatment including pulmonary vein isolation using catheter ablation for atrial fibrillation. The purpose of the electrophysiological study consist with confirmation of the induction and the origin of atrial fibrillation, and with recognition of electrical potential and arrhythmogenic substrate for maintenance of atrial fibrillation. The shortening and irregularity of the refractory periods and prolongation of conduction time are important factor in occurrence of atrial fibrillation. Moreover, the complex fractionated atrial electrograms(CFAE) and ganglionated plexus(GP) play an important role in maintenance of atrial fibrillation. As it is indispensable to record and distinguish the electrical potential of atrium and pulmonary vein for the ablation of atrial fibrillation, every physician who is concerned in the catheter ablation requires accustoming to these potentials. PMID- 23631173 TI - [General therapeutic strategy for atrial fibrillation]. AB - There are two principles in therapeutic strategy for atrial fibrillation (AF). One is the preventive strategy for thromboembolic events associated with AF. Usefulness of warfarin has been established in various large clinical trials. However, the introduction of new anticoagulant agents, such as dabigatran and rivaroxaban, has given not only much benefits but some confusion in choice of these agents in real clinical situations. Remaining one is intervention to rhythm management, such as "rhythm control" or "rate control". AFFIRM study denied the predominancy of "rhythm control" in management of patients with AF. On the other hand, the indication of catheter ablation for AF, which is the potential tactic for "rhythm control", has been extended. So, general therapeutic strategy for AF has been still obscure. PMID- 23631174 TI - [Pharmacological rhythm control strategy for atrial fibrillation]. AB - Rhythm control therapy improves the quality of life in properly selected patients with atrial fibrillation (AF). Sodium channel blockers are recommended as a first line therapy for lone paroxysmal AF. Pilsicainide, a pure sodium channel blocker is the most frequently used drug in Japan. In addition to amiodarone, several reports performed in Japan described defibrillating effect of bepridil. These two drugs are considered as first choice for rhythm control treatment to lone persistent AF. Since sodium channel blockers increase mortality in patients with reduced cardiac function, amiodarone or bepridil are recommended for rhythm control in AF accompanied with structural heart disease. However, sufficient treatment for underlying heart disease is required prior to administration of antiarrhythmic drugs. PMID- 23631175 TI - [Pharmacological rate control therapy for atrial fibrillation]. AB - Many studies have reported that there is no significant difference in survival rate between rhythm control and rate control strategies in combination of with anticoagulation in patients with atrial fibrillation. Even in patients with atrial fibrillation and with heart failure there is no significant difference in survival rate between both strategies. There is no need of strict rate control. In patients with permanent atrial fibrillation, lemient rate control(resting heart rate of below 110 beats per minute) is as effective as strict rate control (< 70 beats per minute) and easier to achieve. Digitalis, beta-blockers and Ca channel blockers are used for rate control treatments. Digitalis is the only drug that has both decreasing ventricular response by suppressing atrioventricular conduction and inotropic effects. However, digitalis can not suppress heart rates during exercise. Beta-blockers and Ca channel blockers can suppress heart rates not only at rest but also during exercise. Ca channel blockers can not be used for patients with heart failure due to reduction in contractility of heart muscle. It has been reported that cardiac function and survival rate can be improved by beta-blockers in patients with heart failure if starting low dose and increasing gradually. PMID- 23631176 TI - [Clinical characteristics and management of proarrhythmias during antiarrhythmic therapy]. AB - A number of antiarrhythmic agents have been used for both rhythm and rate control strategies in the patients with atrial fibrillation. One of the limitations in pharmacological management is the occurrence of proarrhythmias including torsades de pointes (Tdp) associated with drug-induced QT prolongation by class Ia and class III agents. The clinical characteristics, predisposing factors and the management of Tdp ventricular tachycardia (VT) are discussed in this section. Another lethal proarrhythmia is wide-QRS (sine-wave-shaped) VT which results from strong Na channel blocking effect of class Ic agents. Various bradyarrhythmias including sinus node dysfunction and AV conduction disturbance are sometimes observed during pharmacological treatment of atrial fibrillation, and may require cessation of drug use or permanent pacemaker implantation. PMID- 23631177 TI - [Upstream therapy for atrial fibrillation]. AB - Upstream therapy to prevent atrial remodeling associated with hypertension, heart failure, or inflammation may deter the development of new AF or rate of recurrence or progression to permanent AF. Treatments with ACEI, ARB, and statins are usually referred to as upstream therapies for AF. There is a sustained reduction in new-onset AF in patients with significant underlying heart disease treated with ACEI or ARB, but evidence is less robust in patients with moderate structural heart disease and recurrent AF. Evidence in support of the use of statins for prevention of AF, except for post-operative AF, is insufficient to produce any robust recommendation. There is as yet no consensus regarding the intensity and duration of treatment and type of statins. PMID- 23631178 TI - [Advancement and current indication of catheter ablation for atrial fibrillation]. AB - New era of catheter ablation (CA) therapy for atrial fibrillation (AF) was opened by the new insight that the pulmonary vein (PV) might play a role of triggering AF. For paroxysmal AF, extensive PV isolation (PVI) is highly effective with superiority to medical treatment shown. For persistent AF with its persistent mechanism unknown, challenging stepwise ablation comprised of PVI and substrate ablation has been widely performed due to its acceptable efficacy in spite of prolonged procedure time with extensive ablation and requirement of repetitive sessions. The outcome of CABANA Trial concerning the effect of CA on improvement of patient's QOL, survival and prevention of cerebral infarction and other cardiovascular events are awaited to optimize its method and indication. PMID- 23631179 TI - [The outcome and prognosis of catheter ablation for atrial fibrillation]. AB - The effect of radiofrequency catheter ablation for atrial fibrillation (AF-ABL) has been established in the last decade and has become one of the major therapeutic options. As for the outcome of AF-ABL, there exit wide varieties in the success rate among the reports published so far, mainly due to the differences in the patient characteristics, ablation methods, and the observation manner/periods. In general, approximately 90% of success can be obtained in paroxysmal AF by a single procedure without the use of antiarrhythmic drugs, while it is around 60 to 80 % in persistent AF even with both repeat sessions and the use of drugs. The success rate has been shown to be constantly reduced during the long-term followup periods irrespective of the AF-type. Although AF-ABL has been shown to be effective to maintain sinus-rhythm compared to the pharmacological method, its impact on the prognosis has not been established yet. PMID- 23631180 TI - [Clinical risk stratification schemes to predict thromboembolism in patients with atrial fibrillation]. AB - Stroke is a serious complication associated with atrial fibrillation, but the risk can vary with clinical characteristics of individual patients. CHADS2 score is the most commonly used stratification scheme because of its simplicity. However, the predictive value for ischemic stroke has been limited in patients at "low and intermediate risk". CHA2DS2-VASc score, which extends CHADS2 scheme by considering additional stroke risk factors, has been recommended to identify "truly low risk" patients who may not need any antithrombotic treatment. This new scheme could improve decision-making for thromboprophylaxis in patients with atrial fibrillation. PMID- 23631181 TI - [Direct oral thrombin inhibitor, "dabigatran"]. AB - Dabigatran is an oral, direct, and competitive inhibitor of thrombin, which is administered to patients with non-valvular atrial fibrillation for prevention of stroke at a dose of 110 mg twice daily or 150 mg twice daily. Anticoagulation by dabigatran is "hybrid anticoagulation", consisting of action of both dabigatran and physiological coagulation inhibitors because warfarin inhibits production of protein C and protein S but dabigatran does not. Management of dabigatran is easier than that of warfarin because food restriction is unnecessary, drug interaction is small, and absorption time is short and serum concentration corresponds to the anticoagulatory effect in dabigatran treatment. The RE-LY trial confirmed effectiveness and safety of both doses of dabigatran for prevention of stroke and both doses of dabigatran had much lower risks of intracranial bleeding compared with warfarin. Compliance to guidance of dabigatran treatment is essential for avoidance of severe hemorrhagic complications. PMID- 23631182 TI - [Factor Xa inhibitor (rivaroxaban and drugs under investigation)]. AB - The first factor Xa inhibitor, rivaroxaban had been released on market, and apixaban and edoxaban are preparing for clinical use in patients with atrial fibrillation. These newer antithrombotic agents are attractive for prevention of thromboembolism in patients with atrial fibrillation because of their favorable pharmacokinetic and pharmacodynamic profiles that seems to be better than that of direct thrombin inhibitor. The reports of rivaroxaban and apixaban have been showed noninferiority or superiority in their efficacy endpoints and also in safety endpoints even on fixed dose regimen without anticoagulation monitoring. There may be still present an important issue that we have to pay attention to find appropriate doses for the patients with renal impairment, aged or low body weight. PMID- 23631183 TI - [Positioning of new generation of oral anticoagulant and good old warfarin]. AB - Several new generation of oral anticoagulant has been tested their safety and efficacy over warfarin in patients with atrial fibrillation. These new generation of drugs have shown their superior safety over warfarin controlled with PT-INR 2 3. The real superiority of warfarin is the potential for individualization for the target PT-INR. Indeed, in the real world clinical setting, PT-INR is controlled relatively lower (around 2) in some countries such as Japan. In this context, superior safety profile shown in the clinical trials might not reflect in the real world clinical practice. It is important to accumulate data with the use of new generation of oral anticoagulant in the real world clinical practice. Moreover, risk factor control within daily life is much more important than anticoagulant intervention. PMID- 23631184 TI - [Atrial fibrillation in patients with heart failure: treatment and management]. AB - Atrial fibrillation (AF) is common in patients with heart failure (HF). It is recognized that AF leads to clinical deterioration and results in worsening HE AF also increases the risk of mortality and morbidity in HF patients. For the management of AF in HF patients, (1) background HF treatment should be optimized, (2) oral anticoagulant is generally indicated when AF is present, (3) ventricular rate control is required and beta-blockers are preferred over digitalis, (4) rhythm control strategy has not been shown to be superior to rate control in HF patients with AF. Amiodarone can be safely used in HF patients. Catheter ablation may be considered in selected HF patients with AF. The therapeutic goal is improvement in survival and quality of life in HF patients with AF. PMID- 23631185 TI - [Atrial fibrillation concomitant with valvular heart disease]. AB - Patients with valvular heart disease frequently have atrial fibrillation(AF) due to elevated pressure and dilatation of the left and right atria and pulmonary veins. Guidelines for valvular heart disease and AF recommend that surgical treatment for the valvular heart disease should be performed concomitantly with AF surgery. The Full-Maze procedure has evolved into the gold standard of treatment for medically refractory AF. In addition to the pulmonary vein isolation, the right and left atrial incisions of the Full-Maze procedure are designed to block potential macroreentrant pathways. According to the mechanisms of AF with valvular heart disease, the Full-Maze procedure is more effective for the patients than the pulmonary vein isolation alone. PMID- 23631186 TI - [Management of atrial fibrillation comorbid with coronary heart disease]. AB - Atrial fibrillation (AF) and coronary artery disease (CAD) can be comorbid with each other, because they can develop based on common risk factors such as aging, hypertension, diabetes mellitus and obesity. The management for stroke prevention in patients with AF and CAD needs some cautions. The vascular disease including CAD has been approved as one of the risk developing stroke in the CHA2DS2-VASc score for patients with AF. Patients with AF and CAD often should take antiplatelet and anticoagulant and sometimes take double antiplatelets and anticoagulant, which associates with increased bleeding risk. On terms of the management of AF, the medications of the rhythm control therapy for the AF would be limited if a patient has CAD. A K channel blocker would be selected for the 1st line therapy. PMID- 23631187 TI - [Atrial fibrillation in Graves' disease]. AB - Heart is easy to be affected by the abnormal thyroid function because cardiac muscle cells have many thyroid hormone receptors. In addition, thyroid hormone goes higher sensitivity to sympathetic nerve as it increases the number of myocardial beta receptor. Therefore, when the thyroid hormone is excessive value, tachycardia and atrial fibrillation may occur regardless of the cause. The atrial fibrillation in Graves' disease can expect spontaneous reversion to sinus rhythm when the hyperthyroidism is controlled. However, cardioversion is indicated for patients who have not returned to sinus rhythm for at least 3 months after the hyperthyroidism is controlled. In this paper, we report the relationship between hyperthyroidism and heart, and the treatment of atrial fibrillation in Graves' disease. PMID- 23631188 TI - [Atrial fibrillation in the elderly]. AB - Elderly people more than 70 years develop atrial fibrillation that causes stroke and heart failure. Furthermore, the elderly people who have atrial fibrillation accompany many risk factor, and develop cerebral infarction easily. Therefore, it is very important to prevent cerebral infarction using anticoagulant drugs. So far we usually use warfarin, which has many limitations, especially cerebral bleeding. Now new anticoagulant drugs(dabigatran and rivaroxaban) can become available. Therefore, we have to learn how to use those drugs. They have to carefully be used because they discharge from kidney and old aged patients have potential renal dysfunction. We mainly explain anticoagulant therapy in old aged patients. PMID- 23631189 TI - [Atrial fibrillation and genetic abnormalities]. AB - Atrial fibrillation (AF) is one of the most common arrhythmias, especially in elderly subjects. During the last decade, the contribution of genetic factors in pathogenesis of AF has been focused. Three categories of genetic patterns are considered to relate to AF: (1) familial AF as a monogenic disease, (2) familial AF presenting in the setting of another inherited cardiac diseases (hypertrophic cardiomyopathy, dilated cardiomyopathy, familial amyloidosis) or another inherited arrhythmic syndromes (congenital long QT syndrome, short QT syndrome, Brugada syndrome), and (3) non-familial AF associated with genetic backgrounds that may predispose to AF, such as a polymorphism in the ACE gene. More recently, the genome-wide association study (GWAS) has identified several genomic regions associated with AF. In this review article, genetic backgrounds underlying familial and non-familial AF will be discussed. PMID- 23631190 TI - [Onset of atrial fibrillation and hypertensive treatment]. AB - The incidence of atrial fibrillation (AF) is increased in patients with hypertension and high blood pressure is a well-known risk factor for AF. The target of hypertensive therapy is to reduce the incidence of cardiovascular events. Since AF is associated with increased risks of death, heart failure and stroke, it is desirable if hypertensive therapy is able to reduce the onset of AF. In patients with hypertension or heart failure, anti-hypertensive drug is expected to reduce the onset of AF because of regression of left ventricular hypertrophy or preventing left ventricular remodeling. However, in patients with AF, anti-hypertensive drugs including angiotensin receptor blocker could not reduce the recurrence of AF and cardiovascular events. These results indicated that tight control of blood pressure might be useful for preventing the new-onset of AF in hypertensive patients. PMID- 23631191 TI - [Hydrogen sulfide and its effect on pancreatic beta-cells]. AB - Hydrogen sulfide (H2S), a potentially toxic gas, is also an important signaling molecule in various mammalian cells and tissues. H2S is involved in the neuroprotection, neuromodulation, cardioprotection, vasodilatation and the regulation of inflammatory response. In pancreatic beta-cells, H2S can be produced by cystathionine beta-synthase (CBS) or cystathionine gamma-lyase (CSE). The produced H2S inhibits insulin release and regulates beta-cell survival. We demonstrated that glucose stimulation increase CSE expression in mouse pancreatic islets. We also indicated that H2S protects beta-cells that are chronically exposed to high glucose. Loss of beta-cell mass is important in the pathogenesis and/or progression of diabetes mellitus; therefore, molecular analyses of the mechanisms of H2S production and its protective effects on beta-cells may lead to new insights into diabetes mellitus. PMID- 23631192 TI - [A new strategy of treatment of insomnia in the field of cardiology--potential of ramelteon]. AB - Most of patients who visit cardiovascular internal medicine have insomnia. Recently, it becomes evident that insomnia is a risk of developing cardiovascular diseases; therefore, treatment of insomnia is important for treatment of cardiovascular diseases. Because benzodiazepine (BZD) hypnotics, which have been used widely for treatment of insomnia, have several issues in long-term use, this study investigated the potential of ramelteon. The results showed that it is desirable to ask actively about sleep status in routine clinical practice for patients with cardiovascular diseases and to start early treatment with ramelteon for new patients. Moreover, for patients already taken BZD hypnotics, leading them to reduce gradually and discontinue BZD hypnotics by coadministration of ramelteon is preferred. PMID- 23631193 TI - [Pathologies of metabolic diseases regulated by AIM]. PMID- 23631194 TI - [Concept and classification of obesity]. PMID- 23631195 TI - [Epidemiological aspects of overweight and obesity in Japan--international comparisons]. AB - Prevalence of obesity (BMI > or = 30) in Japanese adults (aged 20 years and over) was 3.8% in males and 3.2% in females (National Health and Nutrition Survey, 2010), being quite low compared with other countries listed in the Global Database on Body Mass Index (WHO). On the other hand, prevalence of overweight (BMI > or = 25) was 30.4% in males and 21.1% in females, of which overweight in males has increased in recent 35 years almost twice from 15% to 30%. Although the prevalence of overweight and obesity in Japanese adults is rather low in international comparisons, control for the obesity-associated risks through the promotion of appropriate body weight management has been prioritized in the national health programs. PMID- 23631196 TI - [Obesity and the central regulation of energy metabolism]. AB - Energy homeostasis is maintained by the balance between energy intake (food intake) and energy expenditure, when the former exceeds the latter, one becomes obesity. The hypothalamus is the center of controlling food intake and energy expenditure by integrating information from hormones and nutrients. FoxO1 is a downstream effector of insulin signaling and Sirt1 is an NAD(+)-dependent deacetylase, both of which work as energy sensors at the cellular level. In this review, I focused on hypothalamic FoxO1 and Sirt1 in the regulation of energy metabolism. Meanwhile, recent studies have suggested that hypothalamic inflammation and ER stress cause leptin/insulin resistance, which predisposes to diet-induced obesity. PMID- 23631197 TI - [Role of chronic inflammation in adipose tissue in the pathophysiology of obesity]. AB - Obesity may be viewed as a chronic low-grade inflammatory disease as well as a metabolic disease. Evidence has accumulated suggesting that chronic inflammation in adipose tissue leads to dramatic changes in number and cell type of stromal cells during the course of obesity, which is referred to as"adipose tissue remodeling". Among stromal cells, macrophages in obese adipose tissue are considered to be crucial for adipose tissue inflammation, which results in dysregulated adipocytokine production and ectopic fat accumulation. Understanding the molecular mechanism underlying adipose tissue inflammation would contribute to the identification of novel therapeutic strategies to prevent or treat obesity induced metabolic derangements. PMID- 23631198 TI - [New insight of genome-wide association study (GWAS)]. AB - The number of obese patients is increasing in Japan, due to the westernization of lifestyle. Obesity, especially visceral fat obesity, is important for the development of metabolic syndrome. Genetic factors are important for the development of obesity as well as environmental factors. Importance of genetic factors of fat distribution is also reported. Recent genome-wide association studies (GWASs) have revealed the obesity and fat distribution-related polymorphisms. GWAS will highlight a better understanding of the underlying molecular mechanisms in the regulation of obesity and distribution of body fat. PMID- 23631199 TI - [Nutritional environment in utero and development of obesity]. AB - Obesity and metabolic syndrome have been acutely increasing worldwide with far reaching health care and economic implications. The steep increase of these diseases' patients suggests us that environmental and life-style influences, rather than genetic causes, are fueling the epidemic. The developmental origins of health and disease (DOHaD) hypothesis has highlighted the relation between the poor nutritional state of the periconceptional, embryonic, fetal, and early infant phases and the subsequent metabolic disorders in later life. Especially newly constructed epigenetic modification has persisted for long time and induces metabolic disruption. Some experimental animal studies are disclosing developmental programming for diseases are reversible by nutritional or targeted therapeutic interventions during the time of developmental plasticity. PMID- 23631200 TI - [The roles of clock genes in obesity]. AB - Several epidemiological studies have suggested that the perturbation of circadian rhythm has adverse metabolic consequences (e.g., obesity) in humans. At the molecular level, circadian rhythms are encoded by an autoregulatory loop composed of a set of transcription activators (BMAL1/CLOCK) that induce expression of repressors (PER/CRY). The mammalian molecular clock is not only expressed within the master suprachiasmatic nucleus pacemaker neurons, but also within nearly all cells. In addition to this core loop, BMAL1/CLOCK also induce expression of the orphan nuclear hormone receptor, which modulates Bmal1 transcription. Disruption of clock genes results in metabolic dysregulation in mice. In this article, the roles of clock genes in the regulation of metabolism were summarized based on the phenotypes of the knockout mice. PMID- 23631201 TI - [Adipocytokines]. PMID- 23631202 TI - [Characteristics and significance of criteria for obesity disease in Japan 2011]. AB - The Committee of Japan Society for the Study of Obesity reported the new criteria for 'obesity disease' for Japanese in 2011. 1) Obesity: This is judged by body mass index (BMI) at initial screening and defined as a BMI > or = 25. 2) Definition of 'obesity disease': obesity disease is a clinical designation based on the presence of associated complications or their likely occurrence. A person in this situation needs to reduce their weight for medical reasons. 3) Criteria for'obesity disease': a) obesity with complications that require weight reduction for their improvement or elimination. b) high-risk obesity as specified by an excess of visceral fat confirmed by CT scan (visceral fat obesity). PMID- 23631203 TI - [Abdomen specific bioelectrical impedance analysis (BIA) methods for evaluation of abdominal fat distribution]. AB - Two novel bioelectrical impedance analysis (BIA) methods have been developed recently for evaluation of intra-abdominal fat accumulation. Both methods use electrodes that are placed on abdominal wall and allow evaluation of intra abdominal fat area (IAFA) easily without radiation exposure. Of these, "abdominal BIA" method measures impedance distribution along abdominal anterior-posterior axis, and IAFA by BIA method(BIA-IAFA) is calculated from waist circumference and the voltage occurring at the flank. Dual BIA method measures impedance of trunk and body surface at the abdominal level and calculates BIA-IAFA from transverse and antero-posterior diameters of the abdomen and the impedance of trunk and abdominal surface. BIA-IAFA by these two BIA methods correlated well with IAFA measured by abdominal CT (CT-IAFA) with correlatipn coefficient of 0.88 (n = 91, p < 0.0001) for the former, and 0.861 (n = 469, p < 0.01) for the latter. These new BIA methods are useful for evaluating abdominal adiposity in clinical study and routine clinical practice of metabolic syndrome and obesity. PMID- 23631204 TI - [Metabolic syndrome]. AB - Metabolic syndrome (Mets) is a combination of disorders including abdominal obesity, impaired glucose tolerance, dyslipidemia and hypertension, which increases risk for cardiovascular disease (CVD) and type 2 diabetes when occurring together. In Japan, diagnosis criteria of Mets consists of an increased waist circumference and 2 or more of CVD risk factors. Annual health checkups and health guidance using Mets criteria were established in 2008 for the prevention of life-style related diseases in Japan. In this issue, history and diagnostic criteria of Mets and concerns for Mets concept were described. PMID- 23631205 TI - [Type 2 diabetes and impaired glucose tolerance]. AB - Due to the changes of lifestyle in Japan, the number of subjects with type 2 diabetes due to obesity has been increasing. Obesity usually accompanies with an increase of the size of fat cells, which causes the changes of adipokines, such as the decrease of adiponectin and the increase of TNFalpha and free fatty acids, and leads to insulin resistance. As it has been suggested that the capacity of insulin secretion in pancreatic beta cells of Japanese is lower than that of Caucasian, the Japanese likely to develop diabetes with mild obesity. In the treatment of type 2 diabetes accompanied with obesity, more strict diet therapy and exercise are required. In drug therapy of such patients, the drugs to improve insulin resistance, such as biguanides, thiazolidine derivatives, DPP-4 inhibitors and GLP-1 analogues should be selected. PMID- 23631206 TI - [Dyslipidemia]. AB - Obesity-associated dyslipidemia is characterized as hyper-triglyceridemia and hypo-high-density lipoproteinemia. Visceral fat accumulation results in the dysregulation of various adipocytokines as well as the elevation of portal free fatty acid and glycerol levels. The latter cause hepatic overproduction of very low-density lipoprotein, and the adipocytokine dysregulations impair the transfer of cholesterol from extra-hepatic tissues to the liver. In addition, obesity disease associates with the elevated atherogenic remnant lipoprotein as a result of increased lipid absorption and decreased lipoprotein hydrolysis due to insulin resistance. It is important to further elucidate the regulatory mechanisms of adipocytokines on lipid metabolism for the prevention of atherosclerosis. PMID- 23631207 TI - [Hypertension]. AB - As the population of obesity increases by the change of living habits, hypertensive prevalence increases in particularly middle-aged Japanese men. Obesity affects the development of hypertension and other metabolic risk factors. And the mechanism of development hypertension has been investigated from adipocyte standpoints. Recently, physiology or pathophysiology functions of adipocyte including TNF-alpha or leptin have been elucidated. Leptin makes sympathetic nerve activity by effects of the central nerve system. TNF-alpha induces insulin resistance. These effects cause hypertension. In particular, knowledge of insulin resistance has been clear by epidemiologic studies. Hypertension with obesity is often refractory, and it is poor prognosis. We have to develop an effective prevention and therapy in hypertension with obese subjects. PMID- 23631208 TI - [Sleep-disordered breathing]. AB - Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction resulting in apneas, hypopneas, oxygen desaturation, and arousal from sleep. Obesity is one of the most significant risk factors for OSA. Although continuous positive airway pressure is considered the first choice of treatment of OSA, weight reduction is another important measure in obese OSA patients. Conversely, a couple of studies showed that OSA itself might lead to increase weight gain by the reduction in sleep and/or the daytime sleepiness. And obesity hypoventilation syndrome (OHS) is defined as chronic daytime hypercapnia in combination with obesity and OSA. OHS patients are more likely to suffer from congestive heart failure, pulmonary hypertension and have worse prognosis than obese eucapnic OSA patients. PMID- 23631209 TI - [Symptomatic obesity--classification, pathogenesis, diagnosis and therapy]. AB - Obesity is mainly classified by two types, such as simple obesity and symptomatic obesity. Symptomatic obesity is not so rare, which occupies by approximately 10 20% among whole obese patients. Especially, when we encounter high-grade obese patients with BMI more than 35 kg/m2, we have to carefully find out masked symptomatic obesity through medical examinations. Symptomatic obesity is divided into 4 groups according to its pathogenesis, that include endocrinological-, hereditary-, central- and pharmacological obesity. Therapy to the disorder is, in principle, the treatment to original diseases leading to obesity, in addition to dietary-, exercise-, behavioral therapy required to simple obesity. We want to emphasize that the adequate discovery of symptomatic obesity, by our careful medical checks and various laboratory examinations could determine QOL and life prognosis of those obese patients. PMID- 23631210 TI - [Monogenic obesity in human]. AB - Obesity is a heterogeneous pathologic condition that is driven by interactions between multiple genetic and environmental factors. The discovery of leptin has provided the useful clue to the molecular dissection of central pathways involved in the regulation of food intake and body weight. Monogenic obesity in human has been documented. Several obesity causing genes within the leptin-POMC melanocortin axis have been identified: Leptin, leptin receptor, proopiomelanocortin (POMC), prohormone convertase 1 (PC1), and melanocortin receptor-4 (MC4-R) genes. The patients who have a mutation of such genes developed early onset of obesity and distinct metabolic abnormalities. Also, several gene mutations have been identified in some syndromes presenting hereditary symptomatic obesity. PMID- 23631211 TI - [Causes and pathophysiology of pediatric obesity and its diagnostic criteria]. AB - Recently, obesity has been listed as important health problems not only in adults but also in children. Prevalence of pediatric obesity has been rising in the last half century in most of the developed countries including Japan. In addition to changes in lifestyle, which are shown to have contributed greatly to promote weight gain in recent years, patients with some syndromes or diseases may have obesity as one of the manifestations of the disorders especially in childhood. Obese individuals are commonly accompanied by derangement in various organs, such as metabolic and cardiovascular systems, in children as well as adults. Diagnostic criteria for obesity-disease and metabolic syndrome were proposed on the basis of data obtained from Japanese children. PMID- 23631212 TI - [Prevention and treatment of obesity in children]. AB - The prevalence of childhood obesity and its comorbidities is high in Japan. Increasing prevalence of obesity among children emphasizes the importance of focusing on primary prevention to avoid health complications later in life. We emphasize the prevention of obesity by recommending breast-feeding of infants for at least 6 months and advocating that schools provide for 60 min of moderate to vigorous daily exercise in all grades. Treatment interventions include behavioral therapy, reduction in sedentary behavior, and dietary and exercise education. After dietary treatment combined with exercise treatment, the areas of subcutaneous and visceral fat decreased significantly. These data suggest that dietary treatment combined with exercise treatment in obese children normalizes the distribution of abdominal fat and reduces the risk factors for chronic disease. PMID- 23631213 TI - [Dietary therapy for obesity]. AB - In the majority of obese patients adjustment of the diet will be required to reduce calorie intake. In general, diets containing 1,000 to 1,800 kcal/day should be selected for obese patients. VLCD (very low calorie diet) is below 600 kcal/day. VLCD should not be used routinely for weight loss therapy because they require special monitoring and supplementation. A diet should be integral part of any program aimed an achieving a weight loss of 5%. Protein is approximately 15 20%, carbohydrate 60%, fat is 20-25% of total calories. Low carbohydrate-high protein diets, used on a regular basis and without consideration of the nature of carbohydrates the source of proteins, are associated with the increased risk of cardiovascular disease. Consumption of high-fructose corn syrup in beverages may play a role the epidemic of obesity. PMID- 23631214 TI - [Exercise therapy for obesity]. AB - It is very difficult for an obese person to lose weight or maintain a standard body weight, even when exercise therapy is carried out. However, in studies in recent years, it has been reported that the risk of metabolic diseases may be reduced, even regarding physical activities that do not meet the guidelines (for physical activity). Physical activities that allow for sustainable everyday life, rather than goals that are difficult to accomplish, are therefore required in future exercise therapies. PMID- 23631215 TI - [Current status of medical therapy for obesity and the potential of novel anti obesity drug development]. AB - Obesity-related diseases including diabetes, dyslipidemia, and hypertension worsen quality of life of patients and waste medical expenses. To reduce the excess body weight, anti-obesity drugs that reduce appetite or lipid absorption from the intestine have been developed. Only Mazindol can be used in Japan at present, whereas Orlistat was launched and very recently Lorcaserin and Qsymia have been accepted in the US and/or European countries. In addition, a variety of drugs having various mechanisms have been investigated in clinical and basic stages. Some anti-obesity drugs were withdrawn from the market because of their severe adverse effects, however, the tremendous research to develop novel, safety anti-obesity drugs is ongoing. PMID- 23631216 TI - [Cognitive behavioral therapy for obesity]. AB - A change in the traditional Japanese diet to include foods from other countries and increased reliance on motorized transportation has resulted in higher-caloric intake and lower energy expenditure. In consequence, the number of obese patients has grown rapidly, as has the number of patients with type 2 diabetes, hyperlipidemia, hyperuricemia, hypertension and coronary vascular disease. These have come to be called lifestyle-related diseases because changes in lifestyle are deeply associated with their onset and development. In the U.S. and Europe, lifestyle modification and medication are considered important to the treatment of such diseases. Cognitive behavioral therapy plays a central role in lifestyle modification. We here focus on our cognitive behavioral therapy for obesity. PMID- 23631217 TI - [Bariatric surgery--indication and contraindication]. AB - The field of obesity surgery (bariatric surgery) expands as a consequence of the rapid increase of overweight and obesity not only in the western countries but also in Asia. Japan is still far behind the western progression but the problem of obesity is rising in our country so that necessity for bariatric surgery will also rise in Japan. A few statements of indication of bariatric surgery for Asian are published recently. According to the statements from IFSO-APC (International Federation of Surgery for Obesity and Metabolic Disorders, Asian Pacific Chapter) consensus 2011, bariatric surgery for Asian should be considered for the patient with BMI over 35 without co-morbidity and for the patient with BMI over 30 with co-morbidities. PMID- 23631218 TI - [Criteria of therapeutic effects on obesity]. AB - Therapeutic effects of obesity disease (obesity as a disease) are determined by the weight reduction, decrease of visceral fat and improvement of comorbidities. Evaluation criterion of therapeutic effect is determined a decrease of more than 3% weight reduction, because improvement of comorbidities in obesity, especially visceral obesity, is observed in the weight loss of more than 3%. In obesity more than 30 in BMI or morbid obesity, it is necessary to weight reduction more than 5%. PMID- 23631219 TI - [The current situation and challenges of the recognition systems for specialist in obesity disease and certified life-related disease educator]. AB - The recognition systems for specialist in obesity disease and certified life related disease educator were started in 2012. These systems are designed to cultivate medical specialists of obesity disease or metabolic syndrome. A hundred and several dozen doctors and about 30 co-medical staffs intend to take the certification examinations. It is important for the establishment of the systems to increase the specialized hospitals for obesity disease and to expand the identifiable medical checkup and health guidance in the future. PMID- 23631220 TI - [Diet-induced obesity and GPR120]. AB - Free fatty acids (FFAs) have been demonstrated to act as ligands of several G protein-coupled receptors (GPCRs). GPR120 is activated by unsaturated long-chain FFAs and has a crucial role in various physiological homeostasis mechanisms such as incretin hormone secretion and adipogenesis. Recent studies showed that a lipid sensor GPR120 has a key role in sensing dietary fat and in the control of energy homeostasis in both humans and rodents. Dysfunction of GPR120 is identified as a novel risk factor for diet-induced obesity. In this review, I provides recent development in the field and discusses its physiological roles and potential as drug targets. PMID- 23631221 TI - [Miyake's disease]. AB - Miyake's disease (occult macular dystrophy: OMD) was first described by Miyake et al. to be a hereditary macular dystrophy without visible fundus abnormalities. Patients with OMD are characterized by a progressive decrease of visual acuity with normal appearing fundus and normal fluorescein angiograms. The important signs of OMD are normal full-field electroretinograms (ERGs) but abnormal focal macular ERGs. In 2010, we found that dominant mutations in the RP1L1 gene were responsible for OMD by a linkage analysis of two OMD families, and recently, the same mutations were known to cause OMD in non-Japanese patients. Here, we describe how this disorder has been discovered and the causative gene was found by Miyake's group, together with the detailed characteristics of OMD. PMID- 23631222 TI - [Antithrombotic drug and gastrointestinal injuries]. AB - Gastrointestinal injuries induced by anti-coagulant agents, especially low-dose aspirin (LDA) increased. Concomitant usage of LDA and NSAIDs, LDA and anti coagulant are risk factor of upper gastrointestinal (UGI)-bleeding. Time of UGI bleeding occurred in early periods after starting of LDA and NSAIDs. H. pylori infection and LDA interact synergic and negative synergic with reference to gastric mucosal injury. PMID- 23631223 TI - [Smoking related respiratory diseases: imaging and pathology]. PMID- 23631224 TI - [Compounds in tobacco smoke and pathogenesis of the diseases]. AB - Tobacco smoke is a complex mixture of more than 5,000 compounds including about 200 hazardous chemicals. These chemicals are distributed between the particulate and vapor phases of the smoke, and initiate and progress various human diseases. Polycyclic aromatic hydrocarbons existing in tar can induce DNA damage by direct addiction and cause cancers in respiratory tract. Carbon monoxide must jam normal oxygen transport to tissue and enhance the severity of cardiovascular disease. Oxidative stress induced by hazardous compounds in smoke results in pulmonary disease. Nicotine promotes physical addiction to tobacco as well as causes pulmonary diseases, cardiovascular diseases or cancers to smokers. We should investigate compounds in smoke from new type of cigarette and must educate citizens to avoid risky compounds to our health. PMID- 23631225 TI - [Tobacco smoking and cancer risk: epidemiological evidence]. AB - The positive association between tobacco smoking and the risk of various sites of cancer has been consistently observed in a large number of epidemiological studies in which chance, bias and confounding could be ruled out with reasonable confidence. The relative risk of developing any cancer among smokers is estimated to be 1.6-2.0 in men and 1.3-1.6 in women based on a meta- and pooled-analysis of Japanese studies. More than 29% of total cancer in Japan is estimated to be attributed to tobacco smoking in men while 4% in women. Environmental tobacco smoke, namely passive smoking, is also a cause of lung cancer without any scientific controversy. The relative risk of nonsmoking women with smoking husbands to without is estimated to be approximately 1.3 based on evidence from cohort studies in Japan and a meta-analysis of world-wide epidemiological studies. Tobacco control is the most important and effective strategy for primary prevention of cancer. PMID- 23631226 TI - [Tobacco control in Japan: what it is, and what it should be]. AB - The Framework Convention on Tobacco Control has been effective as of February 2005. This is an epoch making event for the world tobacco control. However, in Japan, almost nothing has been changed due to the intrusion of the tobacco industry and Ministry of Finance. In article 8, the Government still cannot pass a law to protect Japanese people from passive smoking. In article 11, Ministry of Finance is still permitting an old package. In article 13, no restriction is possible except a self-imposed control. Japan Society for Tobacco Control has made a passive smoking prevention bill and presented a petition to the Minister of Health, Labor and Welfare with related 4 bills. Cooperation, money and champion are the three most important issues that we have to pursue. PMID- 23631227 TI - [Problems of tobacco smoke and positive effects of quit-smoking on human health]. AB - Cigarette smoking dominates among Japanese smokers. A smoker takes a small amount of nicotine into the body by one aspiration of cigarette; this amount is not large enough to cause acute symptoms. The way of consuming one cigarette by about 10 aspirations may supply a sufficient amount of nicotine to the body without producing unpleasant symptoms of acute toxicity. Cigarette is very effective goods of nicotine delivery to increase the nicotine-dependent patients. In addition, owing to the tricky image strategy by a tobacco company, the citizens in Japan have not become sufficiently aware of hazards of tobacco. For health hazards of smoking, people do not fully understand cigarette smoking may affect the whole body because of the strong impression of "cancer" particularly "lung cancer" as the disease of smoking. Therefore, we, healthcare professionals, should treat diseases with accurate knowledge of tobacco hazards and also should play a positive role to enlighten people about the truth of tobacco hazards, which do not mean cancer alone. PMID- 23631228 TI - [Smoking and respiratory diseases]. AB - Since lung is a directly affected organ by cigarette smoking, various respiratory diseases including lung cancer, chronic obstructive pulmonary disease, interstitial lung diseases, bronchial asthma, are caused and worsen by cigarette smoking not only in case of active smoking but also in case of passive smoking. A lot of carcinogen in cigarette smoke causes lung cancer through the DNA damage. Oxidants in cigarette smoke induce airway inflammation and tissue injury. Various kinds of protease including neutrophil elastase and matrix metalloproteinase cause emphysema. Meanwhile, inflammation also induces lung fibrosis. Cigarette smoking is a risk factor for the development of asthmas and is associated with decreased asthma control and increased risk of mortality and exacerbations. PMID- 23631229 TI - [Smoking and neurological disorders]. AB - Some meta-analysis on smoking and risk of stroke showed that current smoking raised risks of total stroke, subarachnoid hemorrhage, and ischemic stroke but did not raise risk of intraparenchymal hemorrhage. On the other hand, previous meta-analysis showed that smoking was inversely associated with risk of Parkinson's disease. Early research found that nicotine improved short-term cognitive function and inhibited amyloid formation. More recently, it has showed with meta-analysis that smoking raised risk of Alzheimer's disease. Cigarette smoking has a disadvantage for neurological disorders. PMID- 23631230 TI - [Smoking and aortic diseases]. AB - Smoking is a major cause of cardiovascular risk factor. It is an independent risk factor for the onset and development of atherosclerotic vascular disease. Inflammation--and/or oxidative stress-induced vascular wall damage, particularly endothelial dysfunction, can be influenced by smoking. Endothelial dysfunction is an initiating event in atherogenesis, as well as a major factor in causing acute cardiovascular events. This review focuses on the mechanisms by which smoking causes aortic wall damage and subsequently induces clinical manifestation. Smoking cessation plays an important role in the management of atherosclerotic vascular disease. PMID- 23631231 TI - [Smoking and alimentary diseases]. AB - Tobacco smoking directly or hematogenously acts on digestive organ and induces benign and malignant alimentary diseases. Nicotine, nitrosamines, and polycyclic aromatic hydrocarbons included in tobacco smoke are major causative agents of tobacco smoking-related alimentary diseases. These agents have harmful effects on digestive organ through compromised blood circulation, impaired neural regulation, and cell dysfunction. These malfunctions cause tissue destruction, such as chronic inflammation and ulcer formation. Besides forming DNA adducts, they also act on endogenous signal transduction, leading to gene mutation and abnormal cell death and growth. Interestingly, in inflammatory diseases, smoking improves symptoms of ulcerative colitis, while it worsens the condition of Crohn diseases. Smoking is also involved in lately increasing Barrette's esophagus. Future studies are needed. PMID- 23631232 TI - [Effect of smoking on diabetes mellitus and dyslipidemia (effect of smoking on glucose and lipid metabolism)]. AB - Smoking is one of the important risk factors of cardiovascular disease. Its effects on arteriosclerotic diseases act not only directly but indirectly, by worsening control of blood pressure, lipid metabolism and glucose metabolism. And in patients with diabetes, it affects both macroangiopathy and diabetic microangiopathy(especially diabetic nephronpathy) adversely. Unfortunately, all effects and mechanisms of smoking on metabolic diseases are not yet unclear. But smoking cessation improves lipid metabolism and may improve glucose metabolism and may decrease risk of impaired glucose tolerance, type 2 diabetes, and diabetic microangiopathy. All patients with metabolic diseases must quit smoking for control of diseases and prevention of arteriosclerotic disease as soon as possible. PMID- 23631233 TI - [Smoking and obstetric and gynecological disorders]. AB - Smoking causes various health problems in women in relation to their life cycle. About the effects of smoking on obstetric and gynecological disorders, it is clarified that smoking has adverse effects on menopausal disorders, miscarriage, premature birth, low birth weight infant, breast cancer, uterine cancer and ovarian cancer. The high rate of smoking among women of reproductive age is of particular concern for the next generation because smoking affects not only the women themselves, but also the fetus. It is necessary to promote smoking prevention education to prevent women from developing a smoking habit and to provide smoking cessation education and support for smokers. PMID- 23631234 TI - [Effects of tobacco smoke on fetus and children]. AB - What is caused on fetus and children by parental smoking? Parental smoking, especially maternal smoking cause oral cleft which makes baby difficult to suck milk. It causes not only respiratory illness such as asthma bronchialis but also fire accident or burn by child abuse. These things decrease quality of life of children. Low birth weight caused by parental smoking is the major risk factor of lifestyle-related diseases, according to DOHaD hypothesis. Moreover, parental smoking drive children active smokers. If children start to smoke, they will get bad lifestyle led to metabolic syndrome. So it is important not to make children start the first smoking. PMID- 23631235 TI - [Influence of tobacco on dental and oral diseases]. AB - Oral cavity is an entrance of the human body and it is directly exposed by the smoke of tobacco. Thus oral cavity is the place where many disorders appear due to tobacco; such as periodontal disease, oral cancer, tooth loss, melanin pigmentation etc. Smoking also carries a poor prognosis of dental treatment. A smoking cessation or support intervention at dental setting has benefits because it is easy to motivate the smoking patients by showing them direct influence of tobacco on their oral health, possible to follow up the patients regularly, and feasible to start quitting before a substantial harm of tobacco to general health. It is important that various fields of health professionals co-operate closely to promote smoking cessation. PMID- 23631236 TI - [Health risks induced by secondhand smoke and declines of risks after comprehensive smoke-free legislation]. AB - Secondhand smoke is the major health risk among non-smokers. It is estimated that more than 6,800 non-smokers who are exposed to secondhand smoke die every year in Japan. WHO Framework Convention on Tobacco Control requires all the governments to implement comprehensive smoking ban in order to protect non-smokers' health. Many countries and municipal offices implemented comprehensive smoking ban in workplaces and public spaces including restaurants and bars. The number of patients of acute coronary syndrome and respiratory disease rapidly decreased in those countries. These facts should be announced to the people and policy makers where comprehensive smoking ban has not implemented yet in order to protect non smokers' health. PMID- 23631237 TI - [Diagnosis and treatment strategy of diseases due to passive smoking]. AB - Passive smoking causes a wide range of diseases from membrane irritation such as sore throat or nasal symptom, to fatal diseases such as lung cancer or heart attack. Extensive epidemiological studies have revealed that passive smoking at home or at workplaces raises the all cause mortality of nonsmoking family members by 14-75%. Moreover, many people in Japan are suffered from chemical hypersensitivity due to chronic persistent passive smoking at workplaces. Most critical diagnostic clue of passive smoking caused disease is the temporal relationship of tobacco smoke exposure and disease onset. One hundred percent smoke free workplace or environment is the only effective measure for curing and preventing illnesses caused by passive smoke exposure. PMID- 23631238 TI - [Nicotine dependence and its molecular pharmacology]. AB - Mounting evidence indicates that addictive effects of nicotine occur through interaction with its receptors in the mesolimbic dopamine system, particularly ventral tegmental area neurons, where nicotinic acetylcholine receptors (nAChRs) act to promote the release of dopamine. Indeed chronic treatment with nicotine leads to an up-regulation in the number of alpha4beta2-subunit nAChRs. Moreover, N-methyl-D-aspartate receptors and gamma-aminobutyric acid receptors are also involved in the regulation of dopamine release. PMID- 23631239 TI - [Psychiatric and psychological features of nicotine dependence]. AB - Nicotine dependence involves both psychological and physiological dependence on nicotine. Evidences suggest that nicotine depends on dopamine for its reinforcing effects. A recent summary description of the clinical aspects of nicotine dependence disorders is provided in the DSM-IV-TR of the American Psychiatric Association. Nicotine withdrawal is defined by the DSM-IV-TR as a condition in which a person, after using nicotine daily for at least several weeks, exhibits at least four of the following symptoms within 24 hours after reduction or cessation of nicotine use: (1) dysphoric or depressed mood, (2) insomnia, (3) irritability, frustration or anger, (4) anxiety, (5) difficulty concentrating, (6) restlessness, (7) decreased heart rate, (8) increased appetite or weight gain. Among those symptoms, depression needs special consideration. PMID- 23631240 TI - [Nicotine replacement therapy]. AB - For the habitual smokers with nicotine dependence, it is difficult for them to quit smoking. The nicotine replacement therapy (NRT) is a helpful measure for the persons who want to quit smoking. The concept, medication and practice of the NRT are described. PMID- 23631241 TI - [On oral medications, especially varenicline]. AB - Varenicline is an orally administered alpha4beta2 nicotinic acetylcholine receptor partial agonist. It has been widely used in smoking cessation therapy. It reduces craving and withdrawal symptoms during abstinence and lowers the reinforcing effects of nicotine. A third action of the drug is to blunt responses to smoking cues. Varenicline has higher abstinence rates than nicotine transdermal patches or bupropion. As serious neuro-psychiatric symptoms had been reported post market, including drowsiness, suicidal thoughts and suicide, clinicians are recommended to review the patient's psychiatric history and should monitor them for changes in mood and behavior when prescribing this medication. Studies on flexible dosing regimens, flexible quit dates, and an increased pre quit medication period have indicated possible improvement to varenicline's effectiveness. PMID- 23631242 TI - [Motivational interviewing and cognitive behavior therapy for smoking cessation]. AB - The combination therapy of counseling and medication is very important in smoking cessation treatment. Motivational interviewing (MI) and cognitive behavior therapy (CBT) are interventions recommended in two well-recognized guidelines for smoking cessation in the United States. MI is effective for those who do not want to quit smoking; CBT for those who cannot but want to quit smoking, those who repeatedly quit and re-smoke, those who are depressed, and women who are concerned about their weight. However, neither MI nor CBT for smoking cessation is widely practiced in Japan. We describe the nature of, evidence for, and practice of MI and CBT in smoking cessation treatment, hopeful that clinicians and other healthcare staff learn and apply these techniques. PMID- 23631243 TI - [Health insurance coverage for smoking cessation treatment in Japan: current status and future issues]. AB - In Japan, nicotine dependence treatment service for outpatients at registered medical institutions has been started under health insurance coverage since 2006. The reimbursed treatment program consists of five treatment sessions over 12 week duration. Nicotine patch or varenicline can be prescribed under health insurance coverage during the treatment period. The surveys conducted in 2007 and 2009 have proved the effectiveness of the service. However, the accessibility and utilization of smoking cessation treatment are not sufficient, considering the fact that the percentage of smokers who underwent smoking cessation treatment in Japan remained low compared with other countries. Future challenges call for implementing effective measures to improve the accessibility and utilization of the service, while maintaining a satisfactory level of treatment quality. PMID- 23631244 TI - [Intervention and assistance by doctor for smoking cessation]. AB - Patients with nicotine dependence require suitable intervention and assistance for smoking cessation. We should try to provide every patient with the appropriate way to quit smoking. I'm making the patient classification (motivation-confidence typing) with a questionnaire. When the patient has poor motivation, the motivational interviewing and intervention are required. If the patient has poor self-confidence, I will encourage him and admire his efforts. So varenicline significantly reduce smoking satisfaction, that I allow patients to smoke intentionally during two weeks after starting smoking cessation program. Smoking under the influence of varenicline may be useful to quit without regret. PMID- 23631245 TI - [Nurses' support in smoking cessation therapy in Japan]. AB - Smoking cessation therapy (SCT) was introduced in 2006 in Japan. The patients who wish to stop smoking and receive SCT routinely undergo counseling and advice provided by trained nurse. This paper introduces rationale, methods and contents of the nurses counseling and advice by differentiating physicians' roles in the SCT. We show these supports performed at Nagoya Medical Center, which is one of the famous hospital for the SCT in Japan. Three key issues for the nurses' approach: encouragement of self-decision, promoting self-efficacy and yielding positive thinking are discussed in this paper. PMID- 23631246 TI - [The pharmacist's role in smoking cessation]. AB - Since they have very good opportunities to aid smokers in quitting smoking at clinics or pharmacies, pharmacists play an important role in encouraging smoking cessation. They should be aware of the significance of tobacco abstinence. Therapeutic assistance for cessation includes drug treatment of nicotine dependence and counseling based on behavioral science for psychological dependence. Particularly in drug treatment, pharmacists are able to exercise their professional knowledge by assisting smoking cessation from a pharmaceutical viewpoint. It is possible for any pharmacist to provide a brief smoking cessation intervention, such as asking a patient whether or not they smoke and advising them, if they smoke, to stop smoking. PMID- 23631247 TI - [Supporting programs for maintenance of quitting]. PMID- 23631248 TI - [Anti-smoking education for tobacco-free society]. AB - The Science Council of Japan handed a proposal entitled "For the establishment of tobacco-free society" to the Japanese government in 2008, demanding stronger policy implementation. Among the 7 demands, top priority was placed on"education for improvement of knowledge on health risks of smoking". Ample scientific evidences have proven the health hazards that smoking causes directly and indirectly, which, however, are not well acknowledged among Japanese people, leaving Japan an underdeveloped country in terms of smoke-free society. More education is indispensable in schools and by mass media such as TV. The government must allocate more budgets for the education and advertisements, and, if unsuccessful, should request NHK, which collects mandatory TV reception fees akin to broadcast tax, to assume this task. PMID- 23631249 TI - [Global trends of tobacco control and fostering a tobacco free generation]. AB - Japan ratified the WHO Framework Convention on Tobacco Control(FCTC) in 2004, with the aim to catch up with the global trends of tobacco control in order to save billions of lives worldwide which would be eventually lost without our concerted actions against tobacco epidemic. Some countries with a half century's history of tobacco control are further advancing their efforts beyond the limitations of FCTC but more countries are following the directions of FCTC to lift up their policies to the global standard levels such as smokefree legislations and pictorial health warnings. The recently adopted UN political declaration on non-communicable diseases (NCDs) is another tool to highlight tobacco as a common risk factor of NCDs in the global health agenda. PMID- 23631250 TI - [Preventive measures against minor's smoking]. AB - Adolescents are unique for tobacco control. They are easy to become tobacco addicted and more than 70 % of adult smokers start to smoke tobacco during adolescence. Therefore, they are good targets for sales campaign by tobacco industry to secure their profit by making a large reservoir of smokers. Tobacco industry's tactics are very ingenious. It conducts many kinds of hidden advertisement. It supports many activities of youth and nonprofit organizations. Therefore, our effort should also put targets on adolescents. Adolescence is a unique stage of development and it is important to know its characteristics for effective approach to prevent starting and to facilitate quitting smoking. It is important to make tobacco-free environment surrounding adolescents, such as school campuses and other public places. PMID- 23631251 TI - [Hereditary cerebral small-vessel disease]. AB - The cerebral small vessel disease (CSVD) refers to a group of pathological condition that affects the intracranial small vessels. CSVD causes lacunar infarction, white matter disease and hemorrhage, and may contribute to development of dementia and motor disability in the elderly. CSVD is a common aging phenomenon, however, little is known about its molecular pathogenesis. To understand the molecular pathogenesis for CSVD, here, we review the clinical spectrum, pathological findings and the molecular pathogenesis of CSVD caused by single gene defect: including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, COLAA1-related disorders, retinal vasculopathy with cerebral leukodystrophy, Fabry disease, and hereditary cerebral amyloid angiopathy. PMID- 23631252 TI - [Significance of combination therapy with an insulin sensitizer and a DPP 4(dipeptidyl peptidase-4) inhibitor]. AB - Type 2 diabetes mellitus is characterized by insulin resistance in peripheral tissues and relative impairment in insulin secretion from pancreatic beta cell. Insulin sensitizers such as metformin and pioglitazone reduce peripheral insulin resistance, whereas dipeptidyl peptidase-4(DPP-4) inhibitors augment postprandial insulin secretion and inhibit glucagon secretion. Combination therapy with an insulin sensitizer and a DPP-4 inhibitor provides substantial and additive glycemic improvement because of the complementary mechanisms of action of these agents. In addition, combination therapy with these agents is an attractive from the perspective of low incidence of hypoglycemia, beta cell preservation, augmentation of the incretin effect, and anti-atherogenic action. PMID- 23631253 TI - [Council designated lectures "progress in study into neuro-ophthalmology"]. PMID- 23631254 TI - [New insights into the study of optic nerve diseases]. AB - Optical coherence tomography (OCT) provides a new dimenstion in ophthalmology because it allows evaluation of the pathology in vivo, and provides information to assist the management of macular disease and glaucoma. It is necessary to differentiate the diagnosis of glaucoma from diseases of the optic nerve and of the visual pathway. This study evaluates the usefulness of OCT in detecting disorders of the optic nerve and visual pathway. In addition, the pathogenesis of glaucomatous optic neuropathy (GON), the most common optic neuropathy, was investigated by focusing on the dynamics of aquaporin. I. Evaluation of optic nerve and visual pathway disorders by optical coherence tomography. The swinging flashlight test is an easy, sensitive, objective test to detect relative afferent pupillary defects (RAPD). The number of RAPD detected by the swinging flashlight test was closely correlated with the ratio of retinal nerve fiber layer thickness (RNFLT) between the two eyes of 20 cases of unilateral optic atrophy. OCT could assess the amount of RAPD that reflected an asymmetrical functional disturbance of the optic nerves, as a structural difference. The time courses of RNFLT and ganglion cell complex (GCC) changes' were observed immediately following the time of injury in 4 cases of traumatic optic neuropathy. OCT revealed that both the RNFLT and GCC decreased rapidly from 2 weeks after the injury until 20 weeks later. The RNFLT decreased significantly in the horizontal direction in comparison to the perpendicular direction in 34 eyes from the cases of optic chiasm syndrome. This means that OCT could quantitatively detect the band atrophy of the optic disc in optic chiasm syndrome. Measuring the RNFLT showed a thinning of RNFLT in the perpendicular direction in comparison to the horizontal direction in ipsilateral eyes and thinning in the horizontal direction in comparison to the perpendicular direction in the contralateral eyes in optic tract syndrome. Measuring the GCC showed a thinning of the GCC in the temporal hemifield to the central fovea of the ipsilateral eyes, and thinning of the GCC in the nasal hemifield of the contralateral eyes. This means that OCT could detect the structural changes of hourglass atrophy in the ipsilateral eye and band atrophy in the contralateral eye at the optic disc as well as the homonymous hemianopia in the visual field. OCT was useful in evaluating the optic nerve and visual pathway disorders, but there were also some limitations. The thinning area of RNFLT measured by OPTVue and Cirrus were in entirely opposite directions in cases of optic chasm syndrome. The reason was attributed to the better performance of RTVue in measuring a thin RNFLT on the nasal side of the optic disc in comparison to Cirrus. The specific characteristics of the instruments should be considered when the results of OCT are evaluated. II. Dynamics of aquaporin in the optic nerve Aquaporin (AQP) is a membrane protein that forms a water channel to facilitate water crossing the plasma membrane. AQP-4 was originally thought to be expressed in the optic nerve, but it is expressed only in the retrobulbar medullated region of the optic nerve and the expression of AQPs in the optic disc has not been detected. This study investigated the expressions of AQPs in the optic nerve in rat, monkey and human. The results demonstrate that only AQP-9 was expressed at the unmedullated pre-lamina cribrosa and lamina cribrosa regions, and both AQP-4 and AQP-9 were expressed at the medullated retrobulbar region. Astrocytes were observed to express AQP-9, because AQP-9 immunoreactivity was identical to that of glial fibrillary acidic protein. Elevated intraocular pressure substantially reduced AQP-9 expression in the optic nerve, whereas expression of AQP-4 was not changed in rat eyes. The same phenomena were also observed in the monkey eye with ocular hypertension as well as human eye with glaucoma. AQP-9 is an aquaglyceroporin that allows solutes such as lactate rather than water to cross the cell membrane. The astrocyte-to-neuron lactate shuttle hypothesis has been proposed, in which lactate transported from astrocytes is used by neurons as an energy substrate. Reduction of AQP-9 expression in the optic nerve head under elevated intraocular pressures might be closely related to the pathogenesis of GON. PMID- 23631255 TI - [Noninvasive analysis of retinal microstructure and function: challenges and a promising future]. AB - Challenges in the evaluation of the retinal microstructure. To facilitate evaluation of the retinal microstructure we participated in the development of a scanning laser ophthalmoscope (SLO) for 32 years. The 'retro-mode' is the latest developed lateral aperture SLO made in Japan. This instrument enables us to observe the cystoid spaces and retinal microfolds underlying the epiretinal membrane. We investigated the pathogenesis and the mechanism of early development of idiopathic macular holes (MHs) and the vitreomacular interface in idiopathic full-thickness MHs using spectral-domain optical coherence tomography (SD-OCT). We studied the anatomic morphology of stage 1-A impending MHs, characterized by a foveolar yellow spot, using SD-OCT in the fellow eyes of patients diagnosed with a full-thickness MH. SD-OCT showed the reflectivity of the perifoveal posterior vitreous detachment (PVD) with vitreofoveal adhesion in the eyes with a yellow spot; the foveal microstructure had a triangular foveolar detachment of the cone outer segment tip line. The foveolar detachment of the cone outer segment tip line might be responsible for the yellow spot seen in stage 1-A MHs. Using SD OCT, we also analyzed the vitreomacular interface in idiopathic full-thickness MHs and identified four configurations of the vitreomacular interface in MHs without a complete PVD. The majority, i.e., 92%, of eyes with a MH without a complete PVD are likely due to the anteroposterior vitreofoveal traction exerted by a perifoveal PVD. About 55% of cases with an open roof in the eyes without a complete PVD might be at risk of progression to operculum formation (loss of retinal tissue). 2. Challenges in the evaluation of retinal function SLO microperimetry is used to evaluate the retinal function during observation of the retinal microstructure. We evaluated the retinal sensitivity and the focal visual acuity using our original microperimetry program and clarified the characteristics of the preferred retinal locus (PRL) in macular diseases and the importance of the PRL evaluation. Further refinement of the SLO as an all-in-one instrument with the addition of a treatment feature is planned. We evaluated the retinal blood flow (RBF) using a laser Doppler velocimetry instrument that we developed. In clinical studies, we found that the RBF decreased in patients with type 2 diabetes mellitus with no or mild retinopathy compared with healthy subjects. In in vivo animal studies performed in anesthetized cats, we elucidated the mechanism of RBF regulation in response to physiologic stimuli, i.e., systemic hypoxia, hypercapnia, hyperoxia, hyperglycemia and hypertension. We showed that the retinal vascular endothelium plays an important role in regulating the RBF. In in vitro studies, we examined the effects of laminar shear stress on gene expression in human retinal microvascular endothelial cells (HRMECs) and found that long-term exposure to physiologic shear stress in the retinal arterioles upregulated eNOS and thrombomodulin mRNA expression and down regulated ET-1 mRNA expression in the HRMECs. In ex vivo studies, we found that simvastatin, pioglitazone, resveratrol and fenofibrate dilated isolated porcine retinal arterioles, suggesting that systemic administration of these drugs may have the therapeutic potential to improve the impaired RBF in patients with type 2 diabetes mellitus. 3. Challenges to the development of a telemedicine support system We established a real-time telemedicine system that can transmit precise retinal images of patients between Asahikawa Medical University Hospital and our branch hospitals. We also developed a method of 3-dimensional high-definition transmission and stereoscopic display for ophthalmology. Moreover, we established a system to share medical information using Peer to Peer technology and network control technology that can transmit urgent information during a disaster. In response to a request from the Chinese Government, which has limited medical facilities in rural areas, we donated our system to four hospitals in Beijing, Shanghai, Sichuan and Shaanxi Provinces. As a result of the development of our unique telemedicine home medical care system, patients can be followed at home even after discharge from a hospital. 4. Conclusions. We believe that ophthalmologists can obtain important information about not only ocular but also systemic diseases by analyzing the retinal microstructure and functions simultaneously and can share this information worldwide via the telemedicine technology that we established, which can be a promising advance in patient care. PMID- 23631256 TI - [Pupil and melanopsin photoreception]. AB - The iris is the most anterior portion of the uveal tract. The pupil is round opening near the center of the iris; it is displaced slightly downward and nasally with respect to the center of the cornea. The mammalian iris sphincter is considered to be innervated by cholinergic, and the dilator muscle by adrenergic excitatory nerve fibers, and both miosis and mydriasis are the result of contraction of the iris sphincter and the dilator muscles due to activation of these excitatory nerve fibers. Pharmacological and histological investigations also reveal that the sphincter muscle is innervated in part by inhibitory adrenergic nerve fibers, and that the dilator muscle is also innervated by inhibitory cholinergic nerve fibers. In addition to the release of acetylcholine and norepinephrine by these nerves, the peripheral nerves to the mammalian iris contain various neuropeptides, although the functional role of these pepetides is not clear. It has been known for more than 100 years that two types of photosensitive cells exist in man. However, some totally blind individuals maintain a normal circadian rhythm. Such a phenomenon cannot be explained by the rod and cone functions. Recently, a new photosensitive pigment, melanopsin, was found in the dermal melanophore cells of the frog. In 2002, melanopsin-containing retinal ganglion cells (mRGCs) were discovered and revealed that mRGCs would depolarize without input from the photoreceptors, meaning that these cells are photosensitive. In the human retina, mRGCs comprise only 0.2% of all ganglion cells. Electrophysiological studies show that light slowly depolarizes mRGCs but rapidly hyperpolarizes rods and cones. The mRGCs innervate the suprachiasmatic nucleus, which is the master circadian pacemaker in mammals, and the olivary pretectal nucleus of the midbrain. In addition to their role in circadian entrainment, the mRGCs mediate the pupillary light reflex. We investigated the mechanism of photoreception by retinal photoreceptor cells, and to evaluate the relative contribution of pupil light response using the control, instigated pharmacological blockade of neurotransmission (PB) model and a transgenic model of retinal degeneration (Tg) rabbit. Although rod and cone photoreceptors disappeared in the PB and Tg models, miosis was still induced during exposure to blue light (470 nm). The greater sustained constriction of pupils to blue light in eyes with outer retinal damage reflects mRGC activation. Our study also indicated that some histologically-identified RGCs were consistent with the characteristics and structures of mRGC. Clinically, in age-related macular degeneration patients, there was no reliable recordable pupil response to red light, even at the brightest intensity but a blue light evoked a sustained pupil constriction. However, in glaucoma patients, there was no reliable recordable pupil response to the brightest intensity of blue light. These preliminary recordings in human subjects demonstrate that changes in the pupil responses to chromatic stimuli are readily detectable and easily quantifiable with standard instruments of clinical testing. We hypothesize that changes in the transient pupil response to red light and low intensity blue light may be more sensitive to cone and rod disease, whereas changes in the sustained pupil response to bright blue light may be more sensitive to optic nerve disease. Ongoing studies of the pupil are aimed at optimizing stimulus conditions that elicit pupil responses that can better localize the site of damage to rods, cones, and RGCs, to quantify the extent of disease. PMID- 23631257 TI - [Optic neuritis--immunological approach to elucidate pathogenesis and develop innovative therapy]. AB - The pathogenesis of optic neuritis developed rapidly from the end of the 19th century to the beginning of the 20th century accompanying progress in morpho anatomy and physiology. Thereafter, the pathology of the disease continues to be clarified with the advances in medicine and clinical peripheral devices. The analysis of optic neuritis is about to enter a new phase, triggered by the advent of molecular immunology and genetic engineering. This article describes the results of recent studies on the pathogenetic mechanism of optic neuritis and the potential of utilizing these new findings in the development of novel therapies. Studies revealed that optic neuritis associated with anti-aquaporin(AQP) 4 antibodies is refractory to steroid therapy and causes injuries to the optic nerve-optic chiasma-optic tract, resulting in a broad array of visual field abnormalities. Especially, the disease becomes severe in individuals who possess anti-AQP4 antibodies that target astrocytes, together with anti-myelin oligodendrocyte glycoprotein (MOG) antibodies that target myelin oligodendrocytes. Furthermore, measurement of glial fibrillary acidic protein (GFAP) levels in cerebrospinal fluid may be useful in the diagnosis of anti-AQP4 antibody positive optic neuritis. Studies using experimental autoimmune optic neuritis (EAON) models demonstrate two patterns: a pattern of myelin oligodendrocyte damage as in optic neuritis associated with multiple sclerosis, and a pattern of astrocyte damage as in anti-AQP4 antibody positive optic neuritis, which in optic neuritis associated with anti-AQP4 antibodies, incites IgG deposits in the optic nerve to damage astrocytes. In multiple sclerosis associated optic neuritis models, visual acuity decreases first, followed by deposition of complements in the optic nerve and infiltration of microglia and inflammatory cells. Thereafter, the number of axons decreases and latency of visually evoked potential (VEP) is prolonged. The implication of these findings to treatment is that appropriate treatment should be started at the stage when visual acuity has decreased but before VEP latency is prolonged; that is, at the time when cells start to infiltrate the optic nerve. Evaluations of various immunotherapies in the EAON model, considered to be a model of optic neuritis associated with multiple sclerosis, suggest that optic neuritis may be suppressed by inducing anterior chamber-associated immune deviation (ACAID). Applying this phenomenon, cell therapy using dendritic cells transfected with CGRP or dendritic cells transfected with IL-10 was attempted, and was found to be effective in suppressing optic neuritis. At the same time, as a more practical therapy, administration of the new multiple sclerosis drug FTY720 (fingolimod) suggests suppression of cell infiltration into the optic nerve. The results of these studies show that therapies that suppress cell infiltration of the optic nerve at the early stage after onset is important to maintain visual function. PMID- 23631258 TI - The beneficial effects of Brassica vegetables on human health. AB - The products of plant origin are a rich source of biologically active substances, both nutritive and referred as anti-nutritive. A large group of these compounds are substances with antioxidant activity that fights against free radicals. In the family of Brassicaceae vegetables, Brassica, is the largest and most widely consumed a group of plants in Europe and all over the world. They are characterized by different levels of nutrients. However because of their large and frequent consumption, they may become a significant source of nutrients and bioactive compounds in the daily diet. The beneficial effects of Brassica vegetables on human health have been somewhat linked to phytochemicals. They prevent oxidative stress, induce detoxification enzymes, stimulate immune system, decrease the risk of cancers, inhibit malignant transformation and carcinogenic mutations, as well as, reduce proliferation of cancer cells. Brassica vegetables contain a lot of valuable metabolites, which are effective in chemoprevention of cancer, what has been already documented by numerous studies. Due to the presence of vitamins C and E, carotenoids and antioxidant enzymes such as catalase, superoxide dismutase (SOD) and peroxidase, these vegetables are considerable source ofantioxidants, and due to the presence of polyphenols and the sulfur organic compounds exert also antimutagenic action. Moreover, these vegetables are also rich in glucosinolates, which are unstable compounds and undergo degradation into biologically active indoles and isothiocyanates under the influence of enzyme presented in plant tissues- myrosynase. These substances through the induction of enzymatic systems I and II phase of xenobiotics metabolism may affect the elimination or neutralization of carcinogenic and mutagenic factors, and consequently inhibit DNA methylation and cancer development. Despite many healthy benefits upon eating of cruciferous vegetables, it has been also seen a negative impact of their certain ingredients on the human body. PMID- 23631259 TI - [The new microbiological hazards in food]. AB - This paper describes the new microbiological hazards in food. For protecting human health, nowadays food safety authorities face with many challenges, that years ago were largely unheard. In 2011 verocytotoxigenic Escherichia coli O104:H4 has been isolated in Germany. Strain came from fenugreek sprouts originated from Egypt. It was characterized by unique features such as presence of enteroaggregative Escherichia coli genes (aatA, aggR, aap, aggA, aggC) and resistance to most antibiotics. In Poland only three cases of disease caused by O104:H4 strain have been reported. Another emergence pathogen in Poland is Yersinia enterocolitica 08, biotype 1B. It is the most pathogenic bioserotype recently isolated in the USA only. Food-borne is commonly associated with raw or undercooked pork. The source of Yersinia spp. may be also milk and water. The presence ofbotulinum neurotoxins in food is not new, but still an important issue because of their high toxicity to human. Botulinum neurotoxins are high-molecular thermolabile proteins produced by Clostridium botulinum and some strains of Clostridium butyricum and Clostridium baratii. Based on their antigenic properties, botulin neurotoxins are divided into seven types A-G, however only types A, B, E and F are toxic to humans and some animals. Increasing risk associated with food results from antimicrobial resistance eg. extended spectrum beta-lactamases (ESBLs) producing bacteria, particularly Enterobacteriaceae. Until recently strains ESBL+ were isolated in hospitals, however during last years they have been isolated from healthy humans, animals and food of animal origin. Increasingly common microbiological hazard in food is methicillin resistant Staphylococcus aureus (MRSA). Although prevalence of this pathogen in food is not high, the thread comes from difficulties of treating of infections caused by MRSA. The occurrence of food-borne in humans may also be associated with presence of viruses in food and water. The carrier of viruses may be equipment in food plant, production line, packaging and man. Most food-borne are caused by noroviruses, rotaviruses, hepatitis A virus and hepatitis E virus. An increased number of food-borne viral outbreaks are recorded in several countries. Reasons for this include the improved diagnostic methods that have enhanced detection of some virus groups, and the increased marketing of fresh and frozen foods that has led to a worldwide availability of high risk food. Viruses may contaminate food either through contamination at source, principally through sewage pollution of the environment, or in association with food PMID- 23631260 TI - Risk assessment for infants exposed to furan from ready-to-eat thermally processed food products in Poland. AB - BACKGROUND: Thermal processes and long storage of food lead to reactions between reducing sugars and amino acids, or with ascorbic acid, carbohydrates or polyunsaturated fatty acids. As a result of these reactions, new compounds are created. One of these compounds having an adverse effect on human health is furan. OBJECTIVE: The aim of this paper was to estimate the infants exposure to furan found in thermally processed jarred food products, as well as characterizing the risk by comparing the exposure to the reference dose (RfD) and calculating margins of exposure. MATERIALS AND METHODS: The material consisted of 301 samples of thermally processed food for infants taken from the Polish market in years 2008 - 2010. The samples included vegetable-meat, vegetables and fruit jarred meals for infants and young children in which the furan levels were analyzed by GC/MS technique. The exposure to furan has been assessed for the 3, 4, 6, 9,12 months old infants using different consumption scenarios. RESULTS: The levels of furan ranged from <1 microg/kg (LOQ) to 166.9 microg/kg. The average furan concentration in all samples was 40.2 microg/kg. The estimated exposures, calculated with different nutrition scenarios, were in the range from 0.03 to 3.56 microg/kg bw/day and exceeded in some cases RfD set at level of 1 microg/kg bw/day. Margins of exposure (MOE) achieved values even below 300 for scenarios assuming higher consumption of vegetable and vegetable-meat products. CONCLUSIONS: The magnitude of exposure to furan present in ready-to-eat meals among Polish infants is similar to data reported previously in other European countries but slightly higher than indicated in the recent EFSA report. As for some cases the estimated intake exceeds the RfD, and MOE) values are much lower than 10000 indicating a potential health concern, it is necessary to continue monitoring of furan in jarred food and estimate of its intake by infants. PMID- 23631261 TI - [Identification of alkylbenzenes being formed in the model reaction of ribose with lysine]. AB - BACKGROUND: While studying volatile compounds in model experiments which simulated the broiling of meat (the reactions of ribose with lysine), there were alkylbenzenes identified. They belong to food contaminants and they could be originated from the detergents and petroleum as well as geochemical samples, but they were also obtained in Maillard reactions. OBJECTIVE: The aim of the studies was the attempt of the alkylbenzenes identification being formed in the model reaction of ribose with lysine. MATERIAL AND METHODS: Aqueous solutions of ribose and lysine (at concentration of 0.1 mol/dm3 each) were mixed in equal volumes 10 cm3 + 10 cm3. The pH of the mixtures were adjusted to 5.6 using citrate phosphorous buffer. In that way conditions simulating pH of meat were obtained. The mixtures were heated inside the gastronomic roaster during 0, 5, 10, 15, 30, 45 and 60 minutes respectively, at the temperature 185 +/- 5 degrees C. After reactions, in the mixtures, the profiles of volatile compounds, including alkylbenzenes, were analyzed by GC-MS method. The compounds were being identified by: comparing each mass spectrum (MS) with spectra from the known libraries of MS; calculating the linear retention indexes (LRI); seeking similar LRI values of analogue compounds in literature. Amounts of volatiles were calculated in relation to amount of internal standard (IS) [-], dividing the area of the compound by area of IS. RESULTS: The kinds and amounts of alkylbenzenes depended on the duration of the reaction time. Maximally 16 various alkylbenzenes were developed. More of these compounds could be identified with the probability of 85 90%, using only MS, because of the lack information in literature. Moreover, the multi-dimensional GCxGC-MS or other chromatographic methods in order to make these compounds being better explored seems to be advisable. CONCLUSIONS: The identification of the compounds being formed during broiling of meat is very important, because of the fact that many of arising substances are considered to be unhealthy and undesirable food contaminants. Thus these compounds should be routinely investigated in food products. PMID- 23631262 TI - [DNA damage to somatic cells of mice exposed to nonylphenol and to a combination of ionizing radiation and nonylphenol]. AB - BACKGROUND: Nonylphenol (NP) has been found in daily used products reach in polyvinyl chloride (PVC). The main routes of human exposure are consumption of contaminated food and water. Radiation comes from natural and man-made sources, and is used in medicine, science and industry. Both agents are widely present in environment, therefore human exposure to their combined effect seems to be highly probable. OBJECTIVE: The aim of the study was the estimation of the effects of subchronic exposure of male mice to nonylphenol alone and in a combination with ionizing radiation on the induction of DNA strand breaks of multiple somatic cells. MATERIAL AND METHOD: Pzh:SFIS male mice were exposed for 8 weeks, 5 days/week to nonylphenol alone (25 mg/kg bw or 50 mg/kg bw ) or in a combination with X-rays (0.05 Gy + 25 mg/kg bw NP). Animal were killed at 24 h, 1,4 and 8 weeks after the end of exposure. The bone marrow, spleens, livers, kidneys and lungs were isolated from mice. The estimation of DNA damage was carried out by using Comet assay. RESULTS: The most sensitive to nonylphenol occurred bone marrow lymphocytes, less sensitive were cells of spleen and lungs. NP did not induce the strand breaks in cells coming from liver and kidneys. Eight-weeks combined exposure to ionizing radiation and nonylphenol (0.05 Gy + 25 mg/kg bw NP) caused significantly enhanced level of DNA strand breaks in all tested cells. The most sensitive occurred bone marrow lymphocytes and spleen cells, whereas cells from kidneys and lungs were the least sensitive. CONCLUSION: Subchronic application ofnonylphenol to mice induced damage to genetic material of bone marrow lymphocytes and cells of spleen and lungs. Combined exposure to ionizing radiation and nonylphenol caused, significantly higher than NP alone, level of DNA strand breaks of bone marrow lymphocytes, cells of liver, spleen, lungs and kidneys. Such damages might be stimulated by ionizing radiation. PMID- 23631263 TI - [The effect of dibutyl phthalate (DBP) on the methylation and expression level of p53 gene in the liver of Wistar rats]. AB - BACKGROUND: Currently, nongenotoxic carcinogens-induced changes in DNA methylation profile are considered as mechanism of their toxicity, including carcinogenic action. OBJECTIVE: The aim of the study was to determine the effect of dibutyl phthalate (DBP) on the methylation levels of the p53 promoter region, as well as mRNA and protein level of this gene. MATERIAL AND METHOD: Male Wistar rats received DBP in one, three or fourteen daily oral doses (at 24-h intervals) of 1800 mg/kg b.w. x day(-1). The methylation level of c-myc gene was determined by PCR-based methylation sensitive restriction enzyme analysis (MSRA). The expression of gene was assessed by Real-Time PCR (at mRNA level) and Western blot (at protein level) analysis. RESULTS: There was observed the hypermethylation of p53 promoter region after short (1 day) exposure of the animals to DBP. No correlation was found between mRNA expression and methylation level of p53 gene. The present study showed decreased level of p53 protein, during the whole period of study. CONCLUSIONS: No direct correlation was observed between the methylation and expression level of p53. The decreased protein level might be a consequence of the repressive effect of c-myc, which was involved in signal transduction pathways, the same as p53 protein. PMID- 23631264 TI - [The value of glycemic index and glycemic load from selected corn flakes eaten with milk]. AB - BACKGROUND: Carbohydrates consumed with the daily diet are the cause of fluctuations in the concentrations of glucose in the blood, known as the glycemic effect. Glucose content in blood after eating any meal, and usually reaches its maximum after 20-30 min after ingestion of food and then gradually decreases to 1 2 hours to return to fasting levels. Knowing the GI along with information on their composition and nutrient content is important in terms of knowing the effect of carbohydrates on health. OBJECTIVE: The glycemic indexes (GI) and the calculate values of the glycemic loads (GL) of the corn flakes eaten with milk (nesquik chocolate balls, cheerios, muesli tropical, fitness chocolate, oatmeal and instant flakes, corn flakes) were investigated. The relationship between IG and sex was calculated and examined. MATERIAL AND METHOD: 67 young, healthy volunteers: 42 women and 25 men participated in the study. The average age of the participants was between 23.1 +/- 1.0 years, mean BMI- 22.4 +/- 3.1 kg/m2. Cereal with milk were given in 50 grams of digestible carbohydrates. The reference product was a solution in water (250 ml) containing 50 g glucose. In the morning, 7 times the blood was calleced - on an empty stomach and 15, 30, 45, 60, 90 and 120 minutes after eating. RESULTS: An average value GI and GL were calculated (for women and men), which were respectively: 48,6 and 25,5 - the milk soup with nesquik chocolate balls, 67,5 and 36,1 the milk soup with cheerios, 58,8 and 31,9 - the milk soup with muesli tropical, 66,7 and 34,9 - the milk soup with fitness chocolate, 42,5 and 23,4 - the milk soup with oatmeal flakes, 54,0 and 29,5 - the milk soup with oatmeal instant flakes, 54,4 i 27,9 - the milk soup with corn flakes. CONCLUSIONS: The results allowed the meal for the meals of low and medium GI. Showed statistically significant correlation between the glycemic index and gender of respondents. PMID- 23631265 TI - [Evaluation of the dietary intake of vitamins and minerals in the daily food rations by the students of the Rzeszow University]. AB - BACKGROUND: To function properly the human body needs, from a nutritional point of view, the supply of a wide variety of nutrients. In this respect, in addition to essential nutrients, vitamins and minerals play an important role. Particular attention should be paid to the nutrition of studying youth as in their diet there are observed many irregularities arising from the specific nature of student life. OBJECTIVE: The aim of the study was to identify and assess the level of intake of selected vitamins and minerals in a group of students with consideration of gender. MATERIAL AND METHODS: The study included the group of 200 persons studying at the Faculty of Biology and Agriculture at the University of Rzeszow. The assessment of intake was made using the method of immediate recording of products and beverages consumed by students within three successive days. Using the Tables of Nutritional Value of Foods and Dishes there was calculated the average daily intake of minerals (sodium, potassium, calcium, phosphorus, magnesium, iron, zinc, copper, manganese) and vitamins (A, D, E, thiamine, riboflavin, niacin, vitamin B6, folates and vitamin B12). RESULTS: It was found that the nutrition of women had seriously deficient intake of vitamin D (49%), folates (54%), thiamine and niacin. In terms of mineral intake in women there was diagnosed insufficient contribution of iron (46%), potassium (51.4%), calcium (55.4%) and magnesium (71.6%) in the diet. In the group of men deficiencies were found in the case of vitamin D (79.4%), foliates (71.6%) and vitamin C (76.0%). The excess of manganese (210.0%), phosphorus (198.9%), sodium (170.2%) in the diet and deficiency of potassium (65.5%), calcium (67.0%) and magnesium (73.9%) were found. CONCLUSIONS: The diet of men to a greater extent fulfils the need for vitamins and minerals. The results of the study show the necessity of education in order to foster healthy nutritional habits and to increase the share of natural sources of vitamins and minerals in the diet to prevent the occurrence of adverse effects related to their insufficient consumption. PMID- 23631266 TI - [Evaluation of nutritive value of daily food rations consumed by children attending to primary schools in Warsaw]. AB - BACKGROUND: Meals served in schools are significant part of proper nutrition of children and adolescents. OBJECTIVE: The aim of the study was to compare nutritive value of daily food rations intake by children attending to primary schools in Warsaw who consumed school lunches regularly with those who don't consume school lunches. MATERIAL AND METHODS: From 2009 to 2010, 380 children in age 11-13 years attending to five randomly selected schools from Warsaw were enrolled. Dietary intake was assessed by using 24h dietary recall for 1 day before the egzamination. RESULTS: 45,5% of examined children declared the consumption school lunches regularly. There was no significant differences in energy and most of the nutrient intake between children who consumed school lunches regularly and children, who didn't eat lunches in school. The exception was sodium and iodine intake which was higher in children who regularly consumed school lunches. Sodium intake in children who consumed school lunches regularly was 3278 +/- 1251 mg and in the group of children who didn't consume lunches in school - 2919 +/- 863 mg (p<0.001). The iodine intake in the group of children who consumed school lunches regularly was 136 +/- 70.5 microg and in the group of children who didn't consume lunches in school - 102 +/- 59 microg (p<0.0001). CONCLUSIONS: Regular consumption of school lunches did not improve the nutritional habits of examined school-aged children from Warsaw. Obligatory standards based on nutritional recommendations relating to nutritional value of school lunches should help to improve the schoolchildren nutrition. PMID- 23631267 TI - [Frequency and preferences of consumption of high-fat products by students of catering school in Krakow]. AB - BACKGROUND: Dyslipidemia is one of the most important risk factors for atherosclerotic disease and may lead to coronary heart disease, obesity, type II diabetes and certain cancers. The choice of food and meals by adults is a large part determined by the dietary habits and knowledge acquired in earlier periods of life. OBJECTIVE: The aim of this study was to evaluate frequency of consumption of food products containing fats among students of the Catering School in Krakow. MATERIAL AND METHODS: The study was conducted with the participation of 140 students divided into two subgroups, depending on gender and age, in the autumn and winter season. During the studies a food frequency questionnaire containing question about frequency intake of selected groups of food products containing fats was used. This questionnaire was prepared at the Department of Human Nutrition Agricultural University of Krakow. RESULTS: A significant (P <0.05) effect of gender on preferences for the choice of milk, eating greasy food and the type of fat used for frying foods was found. Girls more often chose milk with reduced fat content compared to boys. It was observed that the fatty parts of food more often were eliminated by girls than boys. Girls more often than boys chose to fry foods oil or margarine, while boys more often used lard and bacon. Frequency of consumption offish or fish products, milk consumption preferences and eating fatty foods depended significantly (P <0.05) oon age. Older students less likely to eat the fish or fish products more often left fatty cuts compared to the younger students. Fatty milk was likely consumed by younger students, while fat free milk by older youth. CONCLUSIONS: It was found that the students of the Catering School, despite the acquired knowledge of nutrition, make many mistakes. PMID- 23631268 TI - [Assessment of dietary habits in haemodialysis patients with differentiated nutritional status]. AB - OBJECTIVE: The aim of the study was the assessment of dietary habits in haemodialysed women and men with differentiated state of nutrition. MATERIAL AND METHOD: The study was conducted into 74 haemodialysed patients who, based on BMI (kg/m2), were allocated into two research groups of women: normal-weight group n =17 (48.6%) and excessive body weight group n = 18 (51.4%) and two groups of men: normal-weight group n = 17 (43.6%) and excessive body weight group n = 22 (56.4%). Daily food rations (DFR) were quantitatively evaluated by a 24h dietary recall method covering 3 days preceding the examination. The computer program "Diet 4" designed in the Institute of Food and Nutrition in Warsaw was used for calculations. Calculations were performed using the Statistica 9.0 program. Results were compared to the nutritional standards for haemodialysed subjects. RESULTS: Energetic value and basic nutrients supply was estimated and also the average content of dietary fiber and cholesterol. The results of the conducted research indicate lack of balanced content of essential nutrients in daily food rations of the patients of both sexes, irrespective of nutritional status. The diet was characterized by low energetic value and low contents of proteins and carbohydrates in all the study groups of women. The mean intake of protein (89.4 +/- 40.6 g/day) and cholesterol (343.9 +/- 207.4 mg/day) in the daily food rations of men with normal weight were found to have a significantly higher as compared to the mean intake of protein (71.9 +/- 25.2 g/day) and cholesterol (253.4 +/- 142.5 mg/day) in the daily food rations of hemodialysed men with excessive body weight. The research showed low consumption of dietary fiber in all investigated groups of women and men. CONCLUSIONS: Since improper the energetic value of daily food rations and intake of the basic nutrients in the diets, may have an unfavourable effect on the disease course, the provision of regular dietary advice is a necessity. PMID- 23631269 TI - [Assessment of dietary intake of lower secondary school students from Bialystok with differentiated state of nutrition]. AB - BACKGROUND: The studies has indicated that mistakes related to nutritional manner and continuously decreasing level of physical activity cause that diet related diseases became an important issue of nutritional epidemiology. OBJECTIVE: The aim of the study was the estimation of dietary intake of lower secondary school students with differentiated state of nutrition. The effect of selected socio economic determinants (parents education, the number of children in the family) on the nutritional status of examined children was also considered. MATERIAL AND METHODS: The study group involved 947 students from lower secondary school in Bialystok, including 517 girls and 430 boys. Children with normal weight (total number 666, BMI 10-85c) and excessive body weight (total number 243)- with overweight (BMI 85-95c) and obesity (BMI > or = 95c) were selected based on the value of BMI indicator. The study questionnaire contained questions concerning socio-economic determinants. A 24h dietary recall was taken of the day preceding the examination in order to perform a quantitative evaluation of daily food rations. RESULTS: Daily food rations of the study children were characterized by insufficient intakes of energy, carbohydrates and dietary fiber. Excessive intake of protein were noted in the study children. Excessive intake of fats was also noted in daily food rations of boys with overweight or obesity. There were no statistically significant differences in the education of parents, depending on the nutritional status of children, however boys of normal weight had a statistically significant lower number of siblings, compared with boys with excessive body weight. CONCLUSIONS: The investigation showed the inappropriate dietary intake for children and adolescent, independently on their gender and nutritional status. Found in our study the presence of a significant proportion of children with excessive body weight with incorrect dietary intake requires the nutrition education including the ability to select products, not only because of their caloric value, but also relative proportions of intake of essential nutrients. PMID- 23631270 TI - [Dietary patterns in nursery school children from an urban environment]. AB - BACKGROUND: A correct dietary pattern optimizes development processes and is a factor in the prevention of diet-related diseases. Attitudes and dietary habits of children, shaped by their family, nursery school and school environments, affect their dietary patterns later in their life. OBJECTIVE: The aim of the study was to evaluate dietary behaviours and preferences of a group of nursery school children, based on their parents' declarations. MATERIAL AND METHOD: The research was carried out in the spring on a group of 126 parents of children (66 boys and 60 girls) aged 3-6 in Krakow, based on a survey questionnaire constructed by the author. The distribution of the data was presented for the whole sample in general, due to a lack of statistically significant differences in this respect depending on the gender (P>0.05). RESULTS: The study has demonstrated the prevalence of the 4-5 meal-a-day dietary pattern (97.6%), though with a limited regularity (52.4%), and snacking between main meals (86.5%), usually on sweets (63.5%), fruit (56.3%) and dairy products (42.9%). Daily consumption of wholegrain cereal products was the case in 38.1% of the children, of fruit in 50.8% of the children, vegetables in 41.2%, and dairy products in 82% of the children. Fish was served to the children usually once a week (50%). Parents gave their children whole fat products more frequently than reduced fat versions (54.8% vs 45.2%). The children consumed fast food products less frequently than once a month (61.7%), while 26.4% consumed them every month and 10.3 % every week. A common mistake involved a high prevalence of sweets, which were consumed daily by 57.9% of the group. Children preferably drank fruit juices (62.7%), tea (45.2%) and mineral water (39.7%), and consumed flour products (84.1%), sweets and confectionery products (42.1%) and meat products (30.2%). Products disliked by children, according to their parents' reports, included vegetables (63.5%), milk (48.4%) and grits (34.1%). CONCLUSIONS: A preference for the consumption of sweets and confectionery, fruit, fruit juices and flour products demonstrated that the children had a liking for the sweet taste. PMID- 23631271 TI - [Dietary behaviours of volleyball and basketball players]. AB - BACKGROUND: In sports, such as basketball and volleyball, players must demonstrate the speed, strength, stamina and concentration. Correct nutrition affects the strength of the muscles and the extension of capacity. It is also necessary for the proper functioning of the nervous system and determines the rate of regeneration after physical effort. OBJECTIVE: The aim of this study was to assess dietary behaviours of professional volleyball and basketball players and compare the prevalence of correct behaviours in both groups. MATERIAL AND METHODS: 209 professional volleyball and basketball players from sports clubs localized in six Silesian cities were survived with the mean of author questionnaire. The chi-square test was used to examine differences in the prevalence of the correct behaviours among players. RESULTS: Analysis of the results obtained showed that 52% of the players had 4-5 meals a day. 35% of respondents had wholemeal bread and/or groats daily. Milk and dairy products daily ate 71% of surveyed players, meat and sausages 70% respectively. 41% of respondents had cottage cheese and 28% had fish several times a week. Vegetables and fruit were eaten by 21% and respectively 23% of respondents. Sweets were eaten daily by 40% of surveyed, while fast-food were eaten several times a week by 17% of players. Nutrients for athletes were used by 32%, and vitamin supplementation by 48% of respondents. Prevalence of correct dietary behaviour in the group of professional volleyball and basketball players differed. Basketball players statistically more frequently than volleyball players had 4-5 meals a day, had wholemeal bread and/or thick groats, milk and dairy products, meat and sausages, especially poultry. They had raw vegetables and fruit several times a day. They drank more than 2.5 liters of fluids per day. They also significantly more frequently than volleyball players consumed the fast-food occasionally or never. CONCLUSIONS: Dietary behaviours of surveyed players were incorrect. Comparison of prevalence of proper behaviours showed that a group of basketball players had more favourable nutrition habits. PMID- 23631272 TI - [Studies on the determinants of energy drinks intake by students]. AB - BACKGROUND: Energy drinks are among the most popular functional products. They contain bioactive substances which may produce beneficial effects on the body, but excessive consumption of energy drinks or use them in accordance with their intended use may be dangerous to health. OBJECTIVE: The aim of the study was to assess determinants and circumstances of energy drinks consuming in selected group of students, their opinion and knowledge on energy drinks. MATERIAL AND METHOD: The study was conducted in March 2011 in Warsaw and included 92 students from Warsaw University of Life Sciences (WULS) and from University of Physical Education (UPE). The data was collected using diagnostic survey. RESULTS: Energy drinks consumed 67% of the respondents. The most common reason for drinking energy drinks was to stay awake (45.2%). They most often drank them during the examination session (21.0%) and afterwards they experienced stimulation (72.9%), but also palpitations (32.2%) and insomnia (25.8%). Students who consumed energy drinks confirmed that they are effective (88.7%) and tasty (41.9%), but dangerous for health (43.5%). Majority of all users of energy drinks (80.7%) mixed them with alcohol. Every fourth respondent did not read the composition of the consumed beverages. CONCLUSIONS: Energy drinks have been a popular food product among students. After energy drinks consumption students often felt agitated but also experienced negative symptoms. Young people have to pay attention to the composition of energy drinks, what proves their consciousness. PMID- 23631273 TI - [Optimization of Cryptosporidium and Giardia detection in water environment using automatic elution station Filta-Max xpress]. AB - BACKGROUND: The presence of parasitic protozoa in drinking water is mostly a result of improperly maintened the water treatment process. Currently, in Poland the testing of Cryptosporidium and Giardia in water as a part of routine monitoring of water is not perform. OBJECTIVE: The aim of this study was the optimization of the method of Cryptosporidium and Giardia detection in water according to the main principles of standard ISO 15553:2006 and using Filta-Max xpress automatic elution station. MATERIAL AND METHOD: Preliminary tests were performed on the samples contaminated with oocysts and cysts of reference strains of both parasitic protozoa. Further studies were carried out on environmental samples of surface water sampled directly from the intakes of water (21 samples from Vistula River and 8 samples from Zegrzynski Lake). Filtration process and samples volume reducing were performed using an automatic elution system Filta Max xpress. Next, samples were purified during immunomagnetic separation process (IMS). Isolated cysts and oocysts were stained with FITC and DAPI and than the microscopic observation using an epifluorescence microscope was carried out. RESULTS: Recovery of parasite protozoa in all contaminated water samples after 9 cycles elution process applied was mean 60.6% for Cryptosporidium oocysts and 36.1% for Giardia cysts. Studies on the environmental surface water samples showed the presence of both parasitic protozoa. Number of detected Giardia cysts ranged from 1.0/10 L up to 4.5/10 L in samples from Zegrzynski Lake and from 1.0/10 L up to 38.9/10 L in samples from Vistula River. Cryptosporidium oocysts were present in 50% of samples from the Zegrzynski Lake and in 47.6% of samples from the Vistula River, and their number in both cases was similar and ranged from 0.5 up to 2.5 oocyst/10 L. The results show that applied procedure is appropriate for detection the presence of parasitic protosoan in water, but when water contains much amount of inorganic matter and suspended solids test method have to be modified like subsamples preparation and filtration process speed reduction. CONCLUSIONS: The applied method with the modification using Filta-Max xpress system can be useful for the routine monitoring of water. Detection of Cryptosporidium and Giardia in all samples of water taken from the intakes of surface water shows the possibility oftransfering of the protozoan cysts into the water intended for the consumption, therefore the testing of Cryptosporidium and Giardia should be included into the monitoring of water. PMID- 23631274 TI - [Specific features of the anticonvulsant effect of memantine in mice intoxicated with a model organic phosphate]. AB - The effect of memantine administration has been studied on the model of mice poisoning with an anticholinesterase compound. It is established that the memantine action is due to its influence on the cholinesterase activity in the brain, blood plasma, and erythrocytes in addition to its NMDA-blocking action. Memantine promotes oxime-induced erythrocyte enzyme reactivation on the model of mice poisoning with anticholinesterase compound (0.8 LD50). PMID- 23631275 TI - [Coenzyme Q10 single intravenous infusion protects rat myocardium against subsequent ischemia/reperfusion]. AB - Cardioprotective effects of coenzyme Q10 (CoQ10) injected intravenously 30 min before coronary artery occlusion were assessed on the model of myocardial ischemia/reperfusion in Wistar rats. Rats treated with CoQ10 after 30 min of ischemia and 120 min of reperfusion exhibited smaller (by 35%, p < 0.01) size of irreversibly damaged myocardium, shorter duration and decreased number of arrhythmias during reperfusion, and increased content of myocardial CoQ10 (by 210%, p < 0.01) as compared to saline-treated rats. Increased CoQ10 levels in myocardium were accompanied by smaller size of damaged myocardium (r = -0.77, p = 0.0002). Thus, there is evidence of the cardioprotective effect of CoQ10 injected intravenously before myocardial ischemia/reperfusion. PMID- 23631276 TI - [Efficiency of trimetazidine treatment of experimental ischemic heart disease in age aspect]. AB - Introduction of trimetazidine to 10-month-aged rats with experimental ischemic heart disease leads to an increase in carbohydrate utilization with energy purposes in myocardium, which is manifested by increasing activity of glycolysis enzymes with decreasing lactate level in myocardium, increasing activity of pyruvate dehydrogenase and citrate synthase in mitochondrial cardiomyocytes, and increasing ATP content in myocardium. This is accompanied by signs of stabilization of cardiomyocyte membranes and reduction in the degree of tissue hypoxia. The efficiency of trimetazidine decreases with increasing age: in 24 month-aged rats, the direction of changes is retained, but they are less pronounced. PMID- 23631277 TI - [The antiaggregant action of 2-morpholino-5-(thienyl-2)-6-H-1,3,4-thiadiazine in in vitro and ex vivo experiments]. AB - The influence of 2-morpholino-5-(thienyl-2)-6-H-1,3,4-thiadiazine (H-29) on the platelet aggregation has been studied in experiments on donor plasma in vitro. It is established that H-29 causes a decrease in the platelet interaction induced by ADP and arachidonic acid. The influence of H-29 on platelet aggregation was also studied in ex vivo experiments with intravenous and oral administration, and some parameters of plasmatic hemostasis were evaluated. PMID- 23631278 TI - [Application of immunospecific drug in the treatment of rotavirus gastroenteritis in children]. AB - The case records of 120 children older than 4 years with rotavirus infection have been studied. In this group, 22 patients received basic therapy and 98 received complex therapy with cycloferon. Appropriate therapy resulted in rapid positive dynamics of clinical symptoms, the disease outcomes have been improved. Cytokine reaction has been studied as dependent on the treatment method. Positive dynamics of clinical symptoms and cytokine level has been revealed in a group of children having received cycloferon. It is recommended to include cycloferon in the basic therapy of rotavirus diarrhea in children. PMID- 23631279 TI - [Bacteriological substantiation of the antituberculosis effect of immunotropic drug tubosan]. AB - The antituberculosis effect of tubosan registered in the Russian Federation as an immunostimulant drug has been studied on a series of 53 clinical strains of Mycobacterium tuberculosis (MBT). It is established that tubosan produces a bactericidal effect on drug-sensitive MBT strains and a bacteriostatic effect on resistant MBT strains. Use of tubosan for the treatment of 102 patients with drug resistant destructive tuberculosis showed evident clinical-radiological involution process, with prospects of clinical recovery for 75% of patients. Results of this study show that tubosan possesses both antituberculosis and immunostimulant properties. It is recommended to use tubosan for complex treatment of patients with drug-resistant tuberculosis. PMID- 23631280 TI - [Evaluating adaptogenic properties of Rhodiola rosea extract in human mononuclear cell culture and rat tissues]. AB - The administration of various doses of Rhodiola rosea roots and rhizome spissum with known concentrations of salidroside, n-tyrosol, and rosavine leads to an increase in stress proteins 70 content in human mononuclear cell culture and in tissues of Wistar rats. A one-week peroral administration of Rh. Rosea preparation increases the content of constitutive Hsc70 in liver and the amount of hepatocytes with low succinate dehydrogenase activity. A two-week administration of Rh. Rosea extract leads to an increase in the levels of inducible Hsp70 and constitutive Hsc70 proteins in liver, hippocampus and left heart ventricle. These results are indicative of an increase in nonspecific resistance and the activation of adaptogenic processes. PMID- 23631281 TI - [Effect of antihypoxant infusion on microbial endotoxin circulation in obstructive jaundice patients]. AB - The dynamics of microbial endotoxemia in group of 149 patients with cholelithiasis complicated by obstructive jaundice has been studied as dependent on the perioperative tactics of infusion therapy. The perioperative period in obstructive jaundice patients is complicated by a significant increase in lipopolysaccharidemia caused by translocation mechanisms and disorders of the liver detoxification function. In Group 1, 47 patients received infusion therapy including Ringer's solution and 10% glucose solution at a 1:1 ratio. In group 2, 55 patients received infusion therapy with only Sterofundin G-5 solution. In Group 3, 47 patients received the infusion therapy with remaxol in a dose of 800 ml/day. It is established that the infusion of Sterofundin G-5, and to a greater extent the infusion of remaxol, reduces the early postoperative degree of decompensation and accelerates recovery of the detoxifying function of Kupffer cells with respect to microbial endotoxin. PMID- 23631282 TI - [Effects of melatonin on oxygen-dependent processes]. AB - Original and literature data on melatonin effects on various oxygen-dependent processes, in particular, blood oxygen transport and the free-radical reactions, are analyzed. Melatonin influences the oxygen binding properties of hemoglobin by changing hemoglobin oxygen affinity and optimizes the process of tissue oxygenation and prooxidant--antioxidant balance by reducing oxygen participation in free-radical processes. PMID- 23631283 TI - [Heart rate reduction due to selective specific inhibition of the If current opens new possibilities in treatment of basic cardiovascular diseases]. AB - It is shown that the heart rate (HR) is a predictor of the general and cardiovascular death rate. Ivabradine, being the If current inhibitor, induces a selective reduction in the HR and produces related positive effects on the course of basic cardiovascular diseases including ischemic heart disease, arterial hypertension, chronic heart failure, atherosclerosis, etc. Ivabradine is the powerful antiischemic and antianginal drug that acts by means of selective HR decrease. It can be used both in monotherapy and in a combination with beta adrenoblockers. Ivabradine improves the function of left ventricule at chronic heart failure, increases stroke volume, and maintains cardiac output on a higher level. It optimises the energy consumption by myocardium and reduces heart electrophysiological and structural remodeling at patients with chronic heart failure and left ventricular systolic dysfunction. The drug also produces a pronounced antiatherogenic effect. PMID- 23631284 TI - [Problems of toxicity of nanopharmacological preparations]. PMID- 23631285 TI - Predictors of irinotecan toxicity and efficacy in treatment of metastatic colorectal cancer. AB - The colorectal cancer ranks high among the malignant tumours in incidence and mortality and irinotecan is standardly used in palliative treatment of metastatic disease in every therapeutic line. Unfortunately, the treatment with irinotecan is often associated with severe toxicities, especially neutropenia and diarrhea. The majority of the toxic manifestation is caused by the insufficient deactivation (glucuronidation) of irinotecan active metabolite SN-38 by UGT1A enzyme. The elevated SN-38 plasma concentration is responsible for the hematological and gastrointestinal toxicity that can become life-threatening. The patients carrying the mutation of the gene encoding UGT1A enzyme lack the ability of bilirubin glucuronidation, and suffer from the inherited un-conjugated hyperbilirubinemia (Gilbert syndrome, Crigler-Najjar type 1 and 2 syndrome). The mutations in other enzyme systems also play role in the etiopathogenesis of the irinotecan toxicity: CYP3A (cytochrome P-450), ABC family of transmembrane transporters (adenosine-triphosphate binding cassette). The goal of the contemporary research is to determine the predictive factors that will enable the individual adjustment of the individual drug dosage while minimising the adverse effects and maintaining the treatment benefit. PMID- 23631286 TI - Polyadenylated sequencing primers enable complete readability of PCR amplicons analyzed by dideoxynucleotide sequencing. AB - Dideoxynucleotide DNA sequencing is one of the principal procedures in molecular biology. Loss of an initial part of nucleotides behind the 3' end of the sequencing primer limits the readability of sequenced amplicons. We present a method which extends the readability by using sequencing primers modified by polyadenylated tails attached to their 5' ends. Performing a polymerase chain reaction, we amplified eight amplicons of six human genes (AMELX, APOE, HFE, MBL2, SERPINA1 and TGFB1) ranging from 106 bp to 680 bp. Polyadenylation of the sequencing primers minimized the loss of bases in all amplicons. Complete sequences of shorter products (AMELX 106 bp, SERPINA1 121 bp, HFE 208 bp, APOE 244 bp, MBL2 317 bp) were obtained. In addition, in the case of TGFB1 products (366 bp, 432 bp, and 680 bp, respectively), the lengths of sequencing readings were significantly longer if adenylated primers were used. Thus, single strand dideoxynucleotide sequencing with adenylated primers enables complete or near complete readability of short PCR amplicons. PMID- 23631287 TI - Hyperleptinemia as a prognostic factor for preeclampsia: a cohort study. AB - INTRODUCTION: Leptin is an adipokine which has a direct relationship to obesity. Our aim was to measure this hormone in pregnant women at three months intervals throughout their pregnancies to determine the serum value of those who developed preeclampsia. MATERIAL AND METHODS: We followed 19 women (median age 24.8 +/- 5.7 years) with pre-gestational Body Mass Index (BMI) less than 25 kg/m2, 21 (median age 26.1 +/- 4.6 years) with BMI higher than 25 kg/m2 and 16 (median age 30.9 +/- 5.8 years) with Gestational Diabetes Mellitus (GDM) (median age 30.9 +/- 5.8 years), recruited in the 1st trimester of pregnancy. Serum levels of leptin were measured with radioimmunoassay (RIA) technique. RESULTS: In the first trimester of pregnancy leptin levels showed statistically significant differences between normal weight and overweight-obese women (p < 0.001), diabetic women (p < 0.05) and the subgroup of preeclamptic women (p < 0.001). For those women with PGBMI > or = 40 kg/m2 and leptin > or = 40 ng/ml in the second trimester, the Odds Ratio (OR) to develop preeclampsia was of 47.95% CI (4.1-527.2). Analyzing leptin values with ROC curves, the greatest area under the curve (AUC) was for leptin in the second trimester (0.773, CI: 0.634-0.911). CONCLUSION: Women with morbid obesity (BMI > or = 40 kg/m2) had significantly higher levels of serum leptin (p < 0.01) and a value of 40 ng/ml of this hormone seems to be predictive of developing preeclampsia in this group of patients. PMID- 23631288 TI - The TT genotype of the MTHFR 677C > T polymorphism increases susceptibility to premature coronary artery disease in interaction with some of the traditional risk factors. AB - BACKGROUND: The presence of several risk factors (genetic and non-genetic) has greater impact on the risk of premature coronary artery disease (CAD) than single risk factor. OBJECTIVE: The aim of the study was to establish possible relations between genotypes and alleles of 677C>T polymorphism of MTHFR gene and some traditional risk factors e.g. elevated levels of lipid parameters and smoking in development of premature CAD. METHODS: The groups comprised 152 patients with angiographically documented premature CAD (aged 42.9 +/- 5.5) and 121 age-matched blood donors (aged 42.3 +/- 6.5) were studied. The MTHFR 677C>T polymorphism was genotyped with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. RESULTS: Patients with TT genotype who simultaneously smoked had increased risk of premature CAD compared to non-smoking cases with CC genotype (OR = 24.62). We also found that individuals with TT genotype and elevated LDL-cholesterol (LDL-chol.) level had significantly higher risk of CAD (OR = 9.92) than individuals with normal LDL-chol. level and CC genotype. CONCLUSIONS: The present study shows that simultaneous presence of MTHFR TT genotype and smoking or elevated levels of LDL-chol. influences the risk of premature CAD. This findings give interesting contribution to gene-environment interaction problem that may have clinical implications in the future. PMID- 23631289 TI - Therapeutic erythrocytapheresis in the initial treatment of hereditary hemochromatosis. AB - BACKGROUND: The current treatment of hereditary hemochromatosis (HH) consists of performing periodic whole blood phlebotomies. Erythrocytapheresis (EA) can remove up to three times more red blood cells per single procedure and could thus have a clinical benefit. A prospective study of 30 consecutive cases of HH were included in a periodic EA program. METHODS AND PATIENTS: EA were performed using a discontinuous flow cell separators. The protocol consisted of a bimonthly EA until normalization of the serum ferritin was reached. The aim was to reduce the total erythrocyte volume by 25-35%, eventually, to adjust the amount so that hematocrit would not drop below 0.25. RESULTS: 530 +/- 101 ml of erythrocytes were removed (median 517, range 116-761 ml). Iron depletion (ferritin < 20 microg/l) was achieved in all patients after a mean 6.9 +/- 7.6 months, median 5 months, range 1-36 months and a mean 14 EA sessions. The procedures were well tolerated and there were no severe side-effects. CONCLUSIONS: We conclude that HH patients treated with EA achieved iron depletion quickly under good conditions of tolerance. The efficacy, speed, tolerability, and more favorable schedule of an EA program facilitate treatment of HH. PMID- 23631290 TI - Successful treatment of intracardiac and pulmonary thrombi in Behcet's disease with oral anticoagulant and immunosuppressive therapy. AB - Behcet's disease is a multisystem chronic inflammatory disease generally presenting as recurrent oral-genital ulcers and uveitis. Vascular involvement is a common presentation. However, cardiac involvement is rare in this disorder. In this case report, we present a large right ventricular thrombus detected both in computed tomography and echocardiography in a 32 year-old male patient with complaints of fever, haemoptysis and weight loss. Intracardiac thrombus showed both clinical and radiological regression with oral anticoagulant and immunosuppressive therapy. PMID- 23631291 TI - Asymmetric bilateral variations in the musculocutaneous and median nerves with high branching of brachial artery. AB - Brachial Plexus is formed by the union of the anterior rami of cervical 5, 6, 7, 8 and thoracic 1 nerves. These nerves unite and divide to form the key nerves innervating the upper limb. Variations in the course of these nerves are clinically important to anesthetists, neurologists and orthopedicians. We report bilateral variations in the arterial and neural structures in the upper limb of a 65 year old cadaver. The muscles of the arm on one side were innervated by the median nerve with absence ofmusculocutaneous. While on the other side the musculocutaneous nerve contributed to the formation of the median nerve. There was a presence of high bifurcation of brachial artery on both sides. Knowledge of such variations in the innervations of muscles and the arterial supply of the limbs are important to remember before performing any reconstructive procedures or interventions on the limb. PMID- 23631292 TI - Avascular necrosis of stapes crura in one case of operated otosclerosis. AB - Unilateral otosclerosis combined with avascular necrosis of stapes crura is a rare entity. It should be considered in a case of high grade otosclerosis. Symptoms are the same as in patients who suffer from common otosclerosis. Patients complain on progressive hearing loss and tinnitus. The diagnosis is made clinically by conventional audiologic evaluation and radiologically by x-ray mastoid Schuller's view and CT scan. HRCT scan makes visible all parts of ossicular chain and gives surgeon some information about ossicular chain damage. Surgery with stapedotomy and stapes prosthesis implantation in a case of otosclerosis with avascular necrosis of stapes crura can be success therapy to improve patient's hearing PMID- 23631294 TI - [Kidney transplantation. Introduction]. PMID- 23631293 TI - [Diagnostic criteria of atypical hemolytic uremic syndrome]. PMID- 23631295 TI - [Banff classification in kidney allograft pathology: history and update]. PMID- 23631296 TI - [Detection of HLA antibody in renal transplantation]. PMID- 23631297 TI - [The new immunosuppressive drugs for renal transplantation: inhibitors of the mammalian target of rapamycin (mTOR) and anti-thymocyte globulin (Thymoglobulin)]. PMID- 23631298 TI - [Preemptive kidney transplantation]. PMID- 23631299 TI - [Immunohistochemical markers in human renal allograft rejection]. PMID- 23631300 TI - [Viral infection in kidney transplant recipients]. PMID- 23631301 TI - [Post transplantation anemia (PTA): management and therapeutic target]. PMID- 23631302 TI - [Management of CKD-MBD in kidney transplant patients]. PMID- 23631303 TI - [Factors associated with cardiovascular death and events in patients with end stage renal disease]. AB - BACKGROUND: It is very important to evaluate atherosclerosis at an early stage since cardiovascular disease is the main cause of death in patients with end stage renal disease. The purpose of our study was to examine which of the following parameters of atherosclerosis is the best index for the prediction of cardiovascular death or events in hemodialysis patients: intima media thickness (IMT), ankle-brachial index (ABI) and cardio-ankle vascular index (CAVI), and whether visceral fat area (VFA) and subcutaneous fat area (SFA), also predict those events. METHODS: VFA, SFA, IMT, ABI and CAVI were measured using CT or a dedicated device in 270 hemodialysis patients(age: 63.3 +/- 12.3 years, male 56.3%). RESULTS: During a median follow-up period of 54 months, cardiovascular deaths or events occurred in 92 (34.1%) patients. Seventy (25.9%) patients died, 27 (38.6%) of them due to cardiovascular events. Whereas several baseline clinical covariates showed an associated risk for composite cardiovascular events in a univariate Cox proportional hazards analysis, almost all of them became insignificant when analyzed together. Only age, SFA, and a prevalence of diabetes remained significant in multivariate analysis. When both IMT and ABI were included in this model, all other covariates became insignificant, while ABI, but not IMT, was also related to the prediction of cardiovascular death on top of age and SFA. CONCLUSIONS: Both ABI and IMT were useful predictors for composite cardiovascular events, with ABI being also associated with a risk for cardiovascular deaths. In addition, SFA was a useful predictor for both cardiovascular events and cardiovascular deaths. PMID- 23631304 TI - [A case of drug-induced granulomatous interstitial nephritis during the long course of Crohn's disease]. AB - A 33-year-old man was diagnosed with Crohn's disease in 2001, and treated with mesalazine and ranitidine. Administration of infliximab was started in 2007 and led to a decrease in the activity of the Crohn's disease. He was referred to our department in the summer of 2011 following rapid progression of renal insufficiency, with serum creatinine levels increasing from 1.5 mg/dL to 4.3 mg/dL within 2 months. On admission, laboratory findings showed signs of inflammation, anemia, proteinuria, and hematuria. Renal biopsy results indicated the diagnosis of granulomatous interstitial nephritis. Neither clinical manifestations nor laboratory findings were suggestive of infectious disease, sarcoidosis, Wegener's granulomatosis or tubulointerstitial nephritis and uveitis. Mesalazine and ranitidine were discontinued in view of reports of drug induced granulomatous interstitial nephritis. Levels of C-reactive protein immediately decreased, but renal function remained unimproved. Treatment with steroid pulse therapy was then initiated, followed by oral prednisolone at 40 mg/day, and his serum creatinine recovered to 2.3 mg/dL. Mesalazine and/or ranitidine appear to have been responsible for the granulomatous interstitial nephritis. In cases of Crohn's disease showing rapid deterioration of renal function, drug-induced renal disease should be considered, even if the drugs have been taken without apparent problems for a long duration. PMID- 23631305 TI - [A case of MPO-ANCA-related nephritis caused by an anti-tuberculosis drug]. AB - We report a rare case of MPO-ANCA-related nephritis induced by an anti tuberculosis drug. The patient was a 67-year-old woman who was admitted to our hospital because of proteinuria and renal dysfunction. She had been under treatment with rifampicin (RFP) and ethambutol hydrochloride (EB) for pulmonary nontuberculous mycobacteriosis. Her serum myeloperoxidase (MPO)-ANCA titer was high. Drug-induced MPO-ANCA-related nephritis was suspected. When medication with RFP and EB was terminated, the levels of serum Cr and MPO-ANCA decreased. Renal biopsy examination revealed cell infiltration and fibrosis in the interstitium as well as crescent formations and necrotization of the capillary wall in the glomeruli. These findings were compatible with the diagnosis of ANCA-related nephritis. The standard treatment for ANCA-related glomerular nephritis (GN)is generally steroid pulse therapy, steroid therapy and immunosuppressive drugs. The lymphocyte stimulation test was positive for EB and negative for RFP, suggesting that in our patient EB was the cause of ANCA-related GN. After withdrawal of RFP and EB, the titer of MPO-ANCA decreased and the patient's renal function improved. This outcome is characteristic of drug-induced ANCA-related vasculitis. PMID- 23631306 TI - [A case of combination therapy with MMF and steroids for idiopathic membranoproliferative glomerulonephritis]. AB - A 26-year-old man diagnosed with nephrotic syndrome was administered steroid monotherapy. Urinary protein excretion was 2-3 g/day despite the therapy. Percutaneous renal biopsy revealed Type I idiopathic membranoproliferative glomerulonephritis (IMPGN). Although intravenous steroid therapy at the dose of 1,000 mg/day for 3 days was administered, proteinuria persisted at the level of 1 g/day. Renal dysfunction (cystatin C, 1.33 mg/L) was evident. Strong inflammation was suggested by occult blood (3+) and urinary (red blood cells: 30-50/high power field) sediment. We considered steroid monotherapy to be ineffective, and initiated combina-tion therapy with mycophenolate mofetil (MMF) and steroids. Consequently, urinary protein excretion moderately decreased to 0.34 g/day without adverse events or worsening of the renal function. The steroid quantity could be reduced without relapse. Subsequently, we were able to reduce the dose of MMF gradually, then terminated the medication. IMPGN is a rare disease with a poor renal prognosis. Recently, MMF therapies for IMPGN have been attempted, but there are few cases in Japan. Our case suggests that combination therapy with MMF and steroids is effective and safe for treating IMPGN. PMID- 23631307 TI - [Molecular cloning and characterisation of UVSSA, the responsible gene for UV sensitive syndrome]. PMID- 23631308 TI - [DNA damage checkpoint and cancer--pros and cons of Chk1 inhibitors]. PMID- 23631309 TI - [Regulation of p53-MDM2 pathway by nucleolar stress]. PMID- 23631310 TI - [Mitochondrial stress in diseases]. PMID- 23631311 TI - [Stress signaling and diseases via the ASK family kinases]. PMID- 23631312 TI - [Redox-dependent regulation of intracellular signaling via nucleoredoxin]. PMID- 23631313 TI - [Peroxiredoxin triggers post-ischemic inflammation]. PMID- 23631314 TI - [Hypoxic stress and HIF]. PMID- 23631315 TI - [Roles of angiopoietin-like protein ANGPTL2 in tissue microenvironmental stress response and the development of lifestyle-related diseases and cancer]. PMID- 23631316 TI - [Regulation of TOR complex 1 activity by stress]. PMID- 23631318 TI - The physical basis of explosion and blast injury processes. AB - Energetic materials are widely used in civilian and military applications, such as quarrying and mining, flares, and in munitions. Recent conflicts have involved the widespread use of improvised explosive devices to attack military, civilians and infrastructure. This article gives a basic overview of explosive technology and the underlying physical processes that produce the injuries encountered. In particular aspects relevant to primary and secondary injuries are discussed. PMID- 23631317 TI - Blast injury to the perineum. AB - Recent military operations have resulted in a small but significant number of military personnel suffering severe perineal injuries. In association with lower limb amputation and pelvic fracture, this complex is described as the 'signature injury' of the current conflict in Afghanistan. There are significant consequences of surviving severe perineal injury but the experience of managing these casualties is limited. This article gives an overview of the processes developed to meet these challenges and introduces a series of articles which examine the subject in finer detail. PMID- 23631319 TI - The surgical anatomy of the perineum. AB - The anatomy of the perineum and pelvis is complex. Those outside the specialist fields of colorectal surgery, urology and gynaecological surgery often have a less-than-complete understanding of the anatomical details of this region. The recent increase in complicated pelvic and perineal injuries caused by the detonation of Improvised Explosive Devices has brought into sharp focus, the importance of this area of surgical anatomy. The following article describes, in a systematic and detailed manner, the anatomy of the urogenital and anal regions of the perineum. The terminology in relation to the fascial layers and structures encountered in the perineum is elucidated. In addition, the surgical anatomy of the scrotum and its contents and the ligamentous support of the penis are described, with clear illustrations throughout. It is intended that this article will go some way towards clarifying the anatomy underlying the surgical management of complex perineal/pelvic injuries, and benefit both the specialist and non-specialist military surgeon. PMID- 23631320 TI - The development and introduction of ballistic protection of the external genitalia and perineum. AB - In response to an Urgent Operational Requirement, the UK Ministry of Defence (MoD) investigated, designed, developed, trialled and subsequently fielded a Tiered Pelvic Protection System to service personnel deployed on Operation HERRICK in Afghanistan. An Urgent Statement of User Requirement (USUR) was drafted in order to equip service personnel with protection for the groin, perineum, buttocks and upper thigh areas from the effects of buried Improvised Explosive Devices (IEDs). Injuries to the groin and pelvic area from buried IEDs can have severe physiological and psychological impact; therefore the aim of the pelvic protection was to reduce the number and severity of such injuries and to improve the outcome, both in terms of quality of life of the survivors and increase the chances of survival. The aim of this paper is to outline some of the research and development that contributed to the design(s) of the Tiered Pelvic Protection System; describe the components of, and report the medical success of, the Tiered Pelvic Protection System. PMID- 23631321 TI - Immediate surgical management of combat-related injury to the external genitalia. AB - Patterns of survivable injury after combat injury have changed during recent years as wounding mechanisms have altered, ballistic protection has improved and the military chain of trauma care has evolved. Combat casualties now survive injuries that would have been fatal in previous wars and service personnel can be left with injuries that have significantly detrimental effects on their quality of life. Severe, destructive injuries to the external genitalia are rarely life threatening, but can be profoundly life altering and the immediate management of these injuries deserves special scrutiny. The general principles of haemorrhage control, wound debridement, urinary diversion, and organ preservation should be observed. An up-to-date review of the management of these relative rare injuries is based on recent, albeit scanty literature and the experiences of managing casualties in the medical evacuation chain of the United Kingdom Defence Medical Services. The rationale behind the current emphasis on post-injury fertility preservation is also discussed. PMID- 23631322 TI - The role of diagnostic CT imaging in the acute assessment of battlefield external genital injuries. AB - INTRODUCTION: The external genitalia are routinely included in the 'CT Traumagram' at the Role 3 hospital in Afghanistan. Although the radiologist may have the opportunity to diagnose clinically undetected genital injury, little emphasis has been placed on the CT appearances of the external genitalia after Improvised Explosive Device related injury. METHODS: A prospective observational study was carried out on casualties admitted during 1 month in 2011. Genital findings on CT were correlated with clinical operative findings. RESULTS: One hundred and twenty-eight casualties were admitted of which 12 (9%) had genital injury. 17 testes were exposed to blast injury-5/17 (29%) were unharmed, one was dislocated, two were lost, one had a testicular haematoma and 8/17 (47%) were disrupted and underwent salvage. The CT findings-loss of the definition of the tunica albuginea and intra-testicular contrast blushing correlated with testicular disruption in all cases. The single dislocated testis and the two cases where there were no testes remaining after injury were all evident on CT. DISCUSSION: The CT appearance of the external genitalia following trauma are unfamiliar. However, despite the small numbers and clear limitations, the results suggest that CT has an important role to play in the diagnosis of significant genital trauma. Ultrasound assessment should be considered if there is persisting uncertainty. CONCLUSIONS: 'CT-Traumagram' provides rapid, whole body information in casualties exposed to blast injury and this should be exploited in its entirety by the trauma team. Abnormal genital findings on contrast CT should alert radiologists and surgeons to the possibility of significant genital trauma. PMID- 23631323 TI - Anorectal injury in pelvic blast. AB - The signature injury of the Afghanistan campaign has, amongst other things, included an increased incidence of destructive anorectal injury. There is no significant body of evidence about this type of injury on which to base management strategies. This review examines the historical military data, later civilian reports, many of which have challenged the military dogmas of Vietnam, and the spartan contemporaneous military data which does not particularly address pelviperineal blast injury. There is no evidence to support a move away from the doctrine of the four D's (diversion, distal washout, drainage and direct repair), but sound surgical judgement remains the mainstay of managing these challenging and highly morbid injuries. PMID- 23631324 TI - Pelvic fracture-related urethral and bladder injury. AB - Major pelvic ring fracture (PRF) due to blunt trauma results in lower urinary tract injury (LUTI) in up to 10% of cases. Significant comorbidity may result and this is particularly the case for unrecognised injury. The increase in military injuries due to improvised explosive devices in recent conflicts has revealed a complex injury cohort. The incidence of pelvic fracture related LUTI in these casualties is up to three times higher than that seen in civilian patients with pelvic fracture. A complete understanding of LUTI following pelvic fracture is still lacking. Complex fractures of the anterior pelvic arch are associated with LUTI and initial management is largely conservative. In battlefield injuries, the combination of the blast wave, penetrating fragment and bodily displacement results in open pelvic fracture combined with gross perineal and pelvic soft tissue destruction and traumatic femoral amputations. These are some of the most challenging injuries that any surgical team will manage and life saving measures are the priority. There are established pathways for the management of LUTI following blunt trauma related pelvic fracture. Military injuries are more complex and require a significantly different approach. This paper outlines the developments in the understanding and management of pelvic fracture-related LUTI, focussing primarily on injury mechanisms and early management. Recent military surgical experience is discussed, highlighting the significant differences to civilian practice. PMID- 23631325 TI - Developing a cumulative anatomic scoring system for military perineal and pelvic blast injuries. AB - BACKGROUND: Improvised explosive device (IED) yields in Afghanistan have increased resulting in more proximal injuries. The injury severity score (ISS) is an anatomic aggregate score of the three most severely injured anatomical areas but does not accurately predict severity in IED related pelvi-perineal trauma patients. A scoring system based on abbreviated injury score (AIS) was developed to reflect the severity of these injuries in order to better understand risk factors, develop a tool for future audit and improve performance. METHOD: Using standard AIS descriptors, injury scales were constructed for the pelvis (1, minor to 6, maximal). The perineum was divided into anterior and posterior zones as relevant to injury patterns and blast direction with each soft tissue structure being allocated a score from its own severity scale. A cumulative score, from 1 to 36 for soft tissue, or a maximum of 42 if a pelvic fracture was involved, was created for all structures injured in the anterior and posterior zones. RESULTS: Using this new scoring system, 77% of patients survived with a pelvi-perineal trauma score (PPTS) below 5. There was a significant increase in mortality, number of pelvic fractures and amputations with increase in score when comparing the first group (score 1-5) to the second group (score 6-10). For scores between 6 and 16 survival was 42% and 22% for scores between 17 and 21. In our cohort of 62 survivors, 1 patient with an IED related pelvi-perineal injury had a 'theoretically un-survivable' maximal ISS of 75 and survived, whereas there were no survivors with a PPTS greater than 22 but this group had no-one with an ISS of 75 suggesting ISS is not an accurate reflection of the true severity of pelvi perineal blast injury. CONCLUSIONS: This scoring system is the initial part of a more complex logistic regression model that will contribute towards a unique trauma scoring system to aid surgical teams in predicting fluid requirements and operative timelines. In austere environments, it may also help to prevent futile resuscitations. Better correlation between measurement of severity and outcome would aid performance improvement monitoring. In the longer term it will also allow benchmarking of current survival rates and comparisons in the future. PMID- 23631326 TI - Managing endocrine dysfunction following blast injury to the male external genitalia. AB - Blast injury to the external genitalia is associated with considerable morbidity, including the risk of primary hypogonadism due to insufficient testosterone. It is of the utmost importance that, prior to any testosterone replacement being commenced, serious consideration is given to sperm retrieval. The clinical and biochemical picture of hypogonadism allows a relatively straightforward diagnosis in most cases although it is important to be alert to the possibility of hypogonadism in the context of partial testicular tissue preservation. It is also prudent to consider the possibility of secondary hypogonadism especially in patients with chronic pain or those on opiate medication. Therapeutic options for testosterone replacement are diverse but relatively simple. This article aims to give guidance to the non-specialist in the consideration, diagnosis, and treatment of hypogonadism, with particular reference to blast injury of the external genitalia. PMID- 23631327 TI - Complex lower genitourinary reconstruction following combat-related injury. AB - There is little data in the literature on the reconstruction of combat related lower genitourinary trauma. Published reports document patterns of injury, which is useful for epidemiological analysis of military trauma, but very few describe the reconstructive management. We aim to describe a systematic multidisciplinary approach to planning the challenging reconstruction of the severely injured male perineum. PMID- 23631328 TI - The psychological challenge of genital injury. AB - INTRODUCTION: Injuries sustained from Improvised Explosive Devices (IEDs) can have a devastating impact on bodily integrity; physical injuries can be severe and include traumatic amputation of limbs, pelvic fracture, abdominal trauma, extremity fragmentation wounds and genital trauma. Soldiers suffering from genital trauma can experience overwhelming emotions and adjusting to their injuries is a process that occurs over time, that some find easier than others. This paper explores current practice and identifies guidelines for psychological interventions within this arena. METHODS: Relevant associated literature has been reviewed to identify the long-term consequences of genital trauma and to ascertain best practice in supporting this patient population. Current practices within the Royal Centre for Defence Medicine (RCDM) and the Defence Medical Rehabilitation Centre (DMRC) Headley Court have been explored. RESULTS: There is little published literature in this area. Therefore, in respect of guiding treatment of this patient population, related research on the psychological consequences of prostate and penile cancer, limb amputation, acquired infertility and acquired disability has been used as a base to inform interventions. Current practices at RCDM and DMRC have been found to support interventions within related areas. CONCLUSIONS: There is no published evidence base to guide psychological interventions for genital trauma. Professional multidisciplinary intervention will potentially be beneficial in establishing the long-term needs of this patient population, together with qualitative research exploring the experience of soldiers suffering genital trauma. PMID- 23631329 TI - The management of genitourinary war injuries: a multidisciplinary consensus. AB - Genitourinary injuries as a result of current warfare may be severe and result in significant long term morbidity. There is no high quality evidence to guide management and the logistics involved require the development of bespoke management strategies. The multidisciplinary Genitourinary Working Group (Trauma) has the remit of leading this service, primarily addressing the management of casualties in the medical evacuation chain of the Defence Medical Services of the UK. The recommendations made are based mainly upon expert opinion and are intended to provide guidance to the deploying surgeon and the teams that manage these casualties thereafter. PMID- 23631330 TI - The best place for bare-knuckled ethics. AB - In the documentary Boston Med, patients, their family members, and their careproviders agree to be filmed in real medical situations. Why would they do this? The possible answers to this question may help us to make sense of the paradoxical results of a recent study, in which patients with terminal illness ranked their careproviders highly for communication, even though the patients had failed to learn that they had a fatal illness. Based on this analysis, I offer careproviders a practical approach they can use to improve communication with patients, particularly to help patients to feel less alone. This same approach can also be applied in bioethics consultation. PMID- 23631331 TI - Surmounting elusive barriers: the case for bioethics mediation. AB - This article describes, analyzes, and advocates for management of clinical healthcare conflict by a process commonly referred to as bioethics mediation. Section I provides a brief introduction to classical mediation outside the realm of clinical healthcare. Section II highlights certain distinguishing characteristics of bioethics mediation. Section III chronicles the history of bioethics mediation and references a number of seminal writings on the subject. Finally, Section IV analyzes barriers that have, thus far, limited the widespread implementation of bioethics mediation. PMID- 23631332 TI - Commentary on Bergman: "yes... but". AB - In "Surmounting Elusive Barriers: The Case for Bioethics Mediation," Bergman argues that professionals trained in bioethics, reluctant to acquire the skills of mediation, would better be replaced by a cadre of mediators with some bioethics knowledge, to which I respond, "yes ... but." PMID- 23631333 TI - The chiaroscuro of accountability in the second edition of the Core Competencies for Healthcare Ethics Consultation. AB - "Chiaroscuro" is a art technique that makes use of light and shade to suggest depth and solidity on a flat surface. I argue that the standards regarding accountability in the second edition of the Core Competencies for Healthcare Ethics Consultation (CC2), are chiaroscuro, because, despite the offered lists of competencies, it is very difficult to imagine how consultants might be held accountable to such standards. It is not clear to which of the many suggested standards a consultant should be held accountable, and even if one stipulates that only the tabulated competencies are meant as standards, the vague wording makes it hard to know how a consultant might fail to meet the standards or perform excellently. In addition, because terms such as "ethics" and "ethical" are not defined in the document, we are left with no way to determine whether consultants have made appropriate recommendations.The document is useful as a point of discussion, but not yet ready to serve as a tool for holding practitioners accountable. PMID- 23631334 TI - Prescribing for co-workers: practices and attitudes of faculty and residents. AB - BACKGROUND: Physicians sometimes are asked by co-workers for prescriptions to deal with their medical problems. These "hallway" requests typically occur outside a formal doctor-patient relationship.There are professional guidelines on serving as physician for family members and friends, but no guidelines address writing prescriptions for co-workers. The frequency of these requests and the factors physicians consider in responding to them have not been examined. OBJECTIVES: To obtain data on the frequency of these requests and physicians' attitudes and practices in responding to them, and to explore the ethical considerations in writing prescriptions for co-workers. DESIGN: A survey was administered to all physician faculty and residents in an academic department of internal medicine. The questions included whether the respondent had ever been asked for a prescription by a co-worker and how often the respondent had received such requests and written such prescriptions in the previous three months. Respondents also were asked to rate how likely they would be to write such a prescription in 15 hypothetical scenarios. RESULTS: Of the 113 respondents who completed surveys, 68 percent reported having been asked for a prescription by a co-worker. Among those who had ever been asked, 59 percent had been asked one or more times during the previous three months and 88 percent had ever written such a prescription. Also, 88 percent of all respondents stated they were "very likely" or "likely" to write the prescription in one or more of the hypothetical scenarios. CONCLUSIONS: Most physicians in our sample had been asked for prescriptions by co-workers, and most had written such prescriptions. Many respondents indicated a willingness to write such prescriptions in a variety of scenarios, despite the absence of a formal doctor-patient relationship. Further discussion of the ethical considerations in writing prescriptions for co-workers is needed. PMID- 23631335 TI - The ethics of reality medical television. AB - Reality medical television, an increasingly popular genre, depicts private medical moments between patients and healthcare providers. Journalists aim to educate and inform the public, while the participants in their documentaries providers and patients-seek to heal and be healed. When journalists and healthcare providers work together at the bedside, moral problems precipitate. During the summer of 2010, ABC aired a documentary, Boston Med, featuring several Boston hospitals. We examine the ethical issues that arise when journalism and medicine intersect. We provide a framework for evaluating the potential benefits and harms of reality medical television, highlighting critical issues such as informed consent, confidentiality, and privacy. PMID- 23631336 TI - Not a "reality" show. AB - The authors of the preceding articles raise legitimate questions about patient and staff rights and the unintended consequences of allowing ABC News to film inside teaching hospitals. We explain why we regard their fears as baseless and not supported by what we heard from individuals portrayed in the filming, our decade-long experience making medical documentaries, and the full un-aired context of the scenes shown in the broadcast. The authors don't and can't know what conversations we had, what documents we reviewed, and what protections we put in place in each televised scene. Finally, we hope to correct several misleading examples cited by the authors as well as their offhand mischaracterization of our program as a "reality" show. PMID- 23631337 TI - First, do no harm. AB - In a television news documentary series such as Boston Med, doctors' duty to their patients may be at odds with the duty of TV journalists to their audience. If this happens, who should win out? The patients. If there is any possibility that harm is being done to patients, we must put them first, and turn off the cameras. PMID- 23631338 TI - Watching Boston Med. AB - The author reflects on the ABC news documentary series Boston Med--both what it achieved, and what it could have achieved. PMID- 23631339 TI - Legal briefing: Shared decision making and patient decision aids. AB - This "Legal Briefing" column covers recent legal developments involving patient decision aids.This topic has been the subject of recent articles in JCE. It is included in the 2010 Patient Protection and Affordable Care Act. And it has received significant attention in the biomedical literature, including a new book, a thematic issue of Health Affairs, and a recent article in the New England Journal of Medicine. Moreover, physicians and health systems across the United States are increasingly integrating decision aids into their clinical practice. Both federal and state laws play a significant role in promoting this expanded use. On the other hand, concerns about liability could stymie development and implementation. We categorize legal developments concerning patient decision aids into the following five sections: 1. Development of decision aids. 2. Effectiveness of decision aids. 3. Federal regulation of decision aids. 4. State regulation of decision aids. 5. Legal concerns regarding decision aids. PMID- 23631340 TI - Confinement effects in block copolymer modified bicontinuous microemulsions. AB - It has been established that the addition of amphiphilic diblock copolymers has a boosting effect in bicontinuous microemulsions by decreasing the minimum amount of surfactant needed to solubilize equal volumes of oil and water. The strength of the polymer effect was found to be about twice larger than the theoretical prediction. This discrepancy is explained by confinement. Previous experimental studies always considered large oil and water domains of size d compared to the typical polymer end-to-end radius, R(ee). The ratio of these two parameters R(ee)/d defines the confinement parameter. We investigated the sensitivity of the polymer influence extending the range of confinement. We combined macroscopic observations of the phase behavior with microscopic measurements of the structure by small-angle neutron scattering (SANS). Both results were compared with computer simulations on the basis of the theoretical concept of Helfrich. The simulations predict an enhanced sensitivity of the polymer at medium confinement and a reversed behavior at larger confinement. The higher sensitivity at medium confinement is only slightly visible experimentally, whereas the reversed behavior (antiboosting) is clearly present. Finally, a comparison with homopolymer addition showed a common high confinement behavior for diblock copolymers and for homopolymers. PMID- 23631341 TI - Self-healing coatings based on halloysite clay polymer composites for protection of copper alloys. AB - Halloysite clay nanotubes loaded with corrosion inhibitors benzotriazole (BTA), 2 mercaptobenzimidazole (MBI), and 2-mercaptobenzothiazole (MBT) were used as additives in self-healing composite paint coating of copper. These inhibitors form protective films on the metal surface and mitigate corrosion. Mechanisms involved in the film formation have been studied with optical and electron microscopy, UV-vis spectrometry, and adhesivity tests. Efficiency of the halloysite lumen loading ascended in the order of BTA < MBT < MBI; consequently, MBI and MBT halloysite formulations have shown the best protection. Inhibitors were kept in the tubes buried in polymeric paint layer for a long time and release was enhanced in the coating defects exposed to humid media with 20-50 h, sufficient for formation of protective layer. Anticorrosive performance of the halloysite-based composite acrylic and polyurethane coatings have been demonstrated for 110-copper alloy strips exposed to 0.5 M aqueous NaCl for 6 months. PMID- 23631342 TI - Induced dipoles incorporated into all-atom Zn protein simulations with multiscale modeling. AB - Zinc is found saturated in the deposited Amyloid-beta (Abeta) peptide plaques in Alzheimer's disease (AD) patients' brains. Binding of zinc promotes aggregation of Abeta, including the pathogenic aggregates. Up to now, only the region 1-16 of Abeta complexed with zinc (Abeta(1-16)-Zn) is defined structurally in experiment. In order to explore the induced polarization effect of zinc on the global fluctuations and the experimentally observed coordination mode of Abeta(1-16)-Zn, we consider an all-atom molecular dynamics (MD) of Abeta(1-16)-Zn solvated in implicit water. In our model, the zinc polarization affects the whole peptide. The induced dipoles are divided into three distinct scales according to their distances from zinc. Besides, the atomistic polarizability on the coordinating side chains is rescaled to describe the electron redistribution effect. We show that, associated with proper van der Waals (vdW) parameters, our model not only obtains the reasonable coordinating configuration of zinc binding site but also retains the global stabilization, especially the N-terminal region, of the Abeta(1-16)-Zn. We suggest that it is the induced polarization effect that promotes reasonable solvent exposures of hydrophobic/hydrophilic residues regarding zinc-induced Abeta aggregation. PMID- 23631343 TI - Children's report of lifestyle counseling differs by BMI status. AB - BACKGROUND: This study examined whether children's report of receiving weight, nutrition, and physical activity counseling from their clinicians differs by their BMI status and identified factors associated with higher rates of counseling. METHODS: Physical assessments and health surveys were collected from a school-based sample of 959 5(th) and 6(th) grade students. Multivariate logistic regression analysis was used to examine how lifestyle counseling differs by BMI status, adjusting for race, gender, socioeconomic status, co-morbidities, site of care provider, and age. RESULTS: Healthy weight children reported receiving the least amount of lifestyle counseling, with nearly one-quarter reporting none at all. Overweight children were no more likely than their healthy weight peers to report receiving weight and nutrition counseling. As expected, obese children were approximately two times more likely to report being counseled on their weight, nutrition, or physical activity as compared to healthy weight children (all p values at least <0.01). However, 23.9% of obese children reported receiving no counseling about their weight. After adjusting for BMI and all other confounding factors, for each lifestyle topic, Hispanics were at least 1.84 times more likely than whites to report being counseled (all p values at least <0.05). Blacks were at least 1.38 times more likely than whites to report being counseled (all p values at least <0.05). Girls were at least 1.38 times more likely than boys to report being counseled (all p values at least <0.05). CONCLUSION: Although lifestyle counseling is universally recommended, many children report not receiving counseling. Despite clinical indications for more intensive counseling, overweight children report similar counseling rates as their healthy weight peers. Furthermore, a substantial proportion of obese children report not receiving lifestyle counseling. Future research should examine how lifestyle counseling can more effectively reach all children. PMID- 23631344 TI - In their own words: learning from families attending a multidisciplinary pediatric weight management program at the YMCA. AB - BACKGROUND: A family-based multidisciplinary weight management program for obese children 7-11 years old was implemented by a pediatric weight management center and local YMCA. The purpose of this study was to explore parents' and children's perceptions of the program to gain insight about factors that may enhance engagement and retention of families in weight management treatment. METHODS: Families were invited to participate in a telephone interview after their participation in the program. The interviews assessed satisfaction with program components, acceptability of the intervention, barriers to treatment participation, and suggestions for improvement. RESULTS: A total of 34 semistructured telephone interviews were performed, including 19 parents and 15 children. The majority of children (mean age=9.2+/-1.5 years) interviewed were female (74%) and recipients of Medicaid (79%). The population was racially diverse (63% black, 26% white, 11% other). Results suggest families were generally very positive about the program and viewed the major components of the program as helpful (i.e., nutrition, exercise, behavior). Families particularly enjoyed exercise and cooking demonstrations, whereas self-monitoring activities and learning about behavior change strategies were less enjoyable. Parents noted that increasing the length of individual sessions would likely be beneficial. Families who did not complete the program cited factors such as transportation barriers (e.g., gas money, distance), scheduling conflicts, and unmet expectations as contributing to their decision to discontinue participation. CONCLUSIONS: This study may have implications for how to enhance family-based pediatric weight management programs for children ages 7-11 years. PMID- 23631346 TI - On the differing sensitivity to chemical gating of single and double layer epitaxial graphene explored using scanning Kelvin probe microscopy. AB - Using environmental scanning Kelvin probe microscopy, we show that the position of the Fermi level of single layer graphene is more sensitive to chemical gating than that of double layer graphene. We calculate that the difference in sensitivity to chemical gating is not entirely due to the difference in band structure of 1 and 2 layer graphene. The findings are important for gas sensing where the sensitivity of the electronic properties to gas adsorption is monitored and suggest that single layer graphene could make a more sensitive gas sensor than double layer graphene. We propose that the difference in surface potential between adsorbate-free single and double layer graphene, measured using scanning kelvin probe microscopy, can be used as a noninvasive method of estimating substrate-induced doping in epitaxial graphene. PMID- 23631345 TI - Differences in gut microbiota composition between obese and lean children: a cross-sectional study. AB - BACKGROUND: An altered gut microbiota composition has recently been linked to obesity. The principal aim of this study is to investigate and compare the gut microbiota composition in obese and lean children. Secondly, associations between analysed gut bacterial species, dietary compounds, energy intake and biochemical blood parameters are evaluated. METHODS: In this prospective cross-sectional study, 26 overweight/obese (mean BMI: 28.7 +/- 6.5) and 27 lean (mean BMI: 16.5 +/- 2.1) children aged 6 to 16 were included. Faecal samples were collected and subjected to selective plating and quantitative real-time PCR (qPCR) in order to determine the concentrations of bacterial species belonging to the genera: Bacteroides, Bifidobacterium, Clostridium, Staphylococcus and Lactobacillus. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was applied for an in-depth identification of species of Bacteroides fragilis group. Differences in the concentrations of gut bacterial species between obese and lean children were statistically analysed using Mann Whitney U test. Subsequently, random forest analysis and multiple linear regression analysis were performed in order to test associations between gut bacterial species, dietary compounds and blood parameters. RESULTS: Obese children showed an elevated Firmicutes-to-Bacteroidetes ratio compared with lean children. Furthermore, low relative proportions of B. vulgatus and high concentrations of Lactobacillus spp. were observed in the obese microbiota. In all children, Staphylococcus spp. were positively associated with energy intake. Additionally, in obese children, Lactobacillus spp. were positively associated with plasma hs-CRP. CONCLUSIONS: Our findings corroborate a significant difference in the gut microbiota composition of important bacterial species between obese and lean children. In future, non-invasive manipulation of gut microbiota composition in early infancy could offer a new approach to manage childhood obesity and associated disorders. PMID- 23631347 TI - Structural characterization and unusual reactivity of oxosulfido-Mo(V) compounds: implications for the structure and electronic description of the very rapid form of xanthine oxidase. AB - The first structural characterization of a mononuclear, EPR-active, oxosulfido Mo(V) compound related to the very rapid form of xanthine oxidase (VR-XnO) is reported. The compound, [CoCp2][Tp(iPr)Mo(V)OS(2-OC6H4CO2Et)] [Cp = cyclopentadienyl; Tp(iPr) = hydrotris(3-isopropylpyrazol-1-yl)borate], exhibits a distorted octahedral geometry with Mo?O and Mo=/--S distances of 1.761(5) and 2.215(2) A, respectively, and an O?Mo=/--S angle of 107.33(14) degrees . Significantly, the Mo(V)=/--S distance is much shorter than the value of 2.36 A reported for oxosulfido-Mo(V) compounds (Singh, R.; et al. Inorg. Chem. 1989, 28, 8) but close to the range established for VR-XnO by protein crystallography. The methyl and phenyl esters were also prepared but the latter is highly reactive and undergoes an intramolecular, radical-based cyclization/elimination reaction to form [CoCp2][Tp(iPr)Mo(IV)O{2-OC6H4C(O)S-kappaO,kappaS}]. This study provides the first definitive measurement of the Mo(V)=/--S bond distance in an unambiguously characterized oxosulfido-Mo(V) compound and supports the presence of a short (ca. 2.22 A) Mo=/--S bond in VR-XnO. It also demonstrates that the Mo(V)=/--S moiety participates in radical-based reactions that are facilitated by the facile redox interplay of Mo and S and by substrates susceptible to radical eliminations. PMID- 23631351 TI - Novel acetylated chalcone and biflavonoid glycosides from Trigonosciadium brachytaenium (Boiss.) Alava. AB - A new acetylated chalcone glycoside, trans-2',6'-dihydroxy-4'-O-(4"-acetyl rhamnoside)-4-methoxychalcone (1) and a new biflavonoid glycosides, 5,3',5",4"' tetrahydroxy-3"',5"'dimethoxy-biflavone (4' -> 8")-7-O-((2-rhamnoside) rhamnoside) (2) were isolated from the ethyl acetate soluble fraction of the methanol extract obtained from Trigonosciadium brachytaenium and have been purified by column chromatography and preparative TLC. Those structures were elucidated by UV, (1)H NMR and (13)C NMR, HMBC, EI-MS and IR spectra. The antioxidant activity of ethyl acetate extract was evaluated by 1,1-diphenyl-2 picrylhydrazyl method. The results indicate that ethyl acetate extract from aerial part of T. brachytaenium possesses considerable antioxidant activity. PMID- 23631352 TI - Angiotensin system-blocking medications are associated with fewer falls over 12 months in community-dwelling older people. AB - OBJECTIVES: To investigate relationships between the use of cardiovascular medications, including angiotensin system-blocking medications (ASBMs), orthostatic hypotension (OH), fall risk, and falls in community-dwelling older people. DESIGN: Prospective cohort study. SETTING: Sydney, Australia. PARTICIPANTS: Five hundred twenty community-dwelling older adults. MEASUREMENTS: Medical, medication and falls history were obtained from a standardized questionnaire in all participants. Blood pressure was measured in supine, seated, and tilted positions. Fall risk was assessed using the Physiological Profile Assessment (PPA). Falls data were collected prospectively for 12 months using monthly fall calendars. Participants were defined as nonfallers (no falls) and fallers (>= 1 falls) at the end of the 12-month follow-up. RESULTS: Participants taking medications affecting the angiotensin system had greater quadriceps strength, but after adjusting for sex, this difference became insignificant. People taking ASBMs were less likely to fall (odds ratio = 0.68, 95% confidence interval = 0.48-0.97), and the association between ASBMs and falls remained significant after adjusting for sex, body mass index, PPA score, and psychotropic medication and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor (statin) use. OH was more frequently observed in participants taking alpha adrenergic receptor blockers (alpha-blockers), but the presence of OH did not increase fall risk. CONCLUSION: The use of cardiovascular medications in older people did not increase the risk of falls, and the use of ASBMs was associated with lower fall risk. The mechanisms for this apparent protective effect are unclear and appear not to be directly related to muscle strength. More research is required to elucidate the possible protective effects of certain cardiovascular medications in relation to falls in older people. PMID- 23631354 TI - Long-term low DO enriches and shifts nitrifier community in activated sludge. AB - In the activated sludge process, reducing the operational dissolved oxygen (DO) concentration can improve oxygen transfer efficiency, thereby reducing energy use. The low DO, however, may result in incomplete nitrification. This research investigated the long-term effect of low DO on the nitrification performance of activated sludge. Results indicated that, for reactors with 10 and 40 day solids retention times (SRTs), complete nitrification was accomplished after a long-term operation with a DO of 0.37 and 0.16 mg/L, respectively. Under long-term low DO conditions, nitrite oxidizing bacteria (NOB) became a better oxygen competitor than ammonia oxidizing bacteria (AOB) and, as a result, no nitrite accumulated. Real-time PCR assays indicated that the long-term low DO enriched both AOB and NOB in activated sludge, increasing the sludge nitrification capacity and diminishing the adverse effect of low DO on the overall nitrification performance. The increase in the population size of nitrifiers was likely resulted from the reduced nitrifier endogenous decay rate by a low DO. Under long term low DO conditions, Nitrosomonas europaea/eutropha remained as the dominant AOB, whereas the number of Nitrospira-like NOB became much greater than Nitrobacter-like NOB, especially for the 40 day SRT sludge. The enrichment and shift of the nitrifier community reduced the adverse effect of low DO on nitrification; therefore, low DO operation of a complete nitrification process is feasible. PMID- 23631353 TI - Mechanistic aspects of metal valence change in SalenCo(III)OAc-catalyzed hydrolytic kinetic resolution of racemic epoxides. AB - The chiral SalenCo(III)OAc-catalyzed hydrolytic kinetic resolution (HKR) of racemic terminal epoxides to afford both enantioenriched epoxides and diols presents one of the most important achievements in asymmetric synthesis chemistry. Previous studies mainly focused on the development of highly efficient catalysts, while rare reports concerned the mechanistic understanding of metal valence change, associated with the formation of inactive Co(II)-Salen complex. Herein, we report the mechanistic aspects of catalyst deactivation regarding the transformation of Co(III) to Co(II) derivative in the HKR of racemic epoxides catalyzed by SalenCo(III)OAc complexes with an appended 1,5,7 triazabicyclo[4.4.0]dec-5-ene on the ligand framework by means of electrospray ionization mass spectrometry (ESI-MS). Continuous determination of transient cationic species in ESI-MS positive mode in conjunction with UV-vis spectroscopic studies at various time points provides evidence that a certain amount of SalenCo(III)OAc molecules were reduced to the corresponding Co(II) derivatives in the HKR of racemic propylene oxide or styrene oxide. To be accompanied by the reduction of Co(III) to Co(II), the resultant diols were oxidized to alpha hydroxy ketones. These analyses along with some control experiments gave a mechanistic understanding of catalyst deactivation of SalenCo(III)OAc-catalyzed HKR of racemic epoxides regarding an unveiled redox reaction between Co(III) Salen and diol, the hydrolyzed product. PMID- 23631355 TI - The mechanisms of space-time association: comparing motor and perceptual contributions in time reproduction. AB - The spatial-temporal association indicates that time is represented spatially along a left-to-right line. It is unclear whether the spatial-temporal association is mainly related to a perceptual or a motor component. In addition, the spatial-temporal association is not consistently found using a time reproduction task. Our rationale for this finding is that, classically, a non lateralized button for performing the task has been used. Using two lateralized response buttons, the aim of the study was to find a spatial-temporal association in a time reproduction task. To account for the perceptual component, reference and target stimuli were presented in different spaces through four experiments. In all experiments, a Spatial-Temporal Association of Response Codes (STEARC) effect was found and this effect was not modulated by the spatial position of both reference and target stimuli. The results suggested that the spatial temporal association was mainly derived from the spatial information provided by response buttons, reflecting a motor but not visuospatial influence. PMID- 23631356 TI - Anti-inflammatory effect of Prunus yedoensis through inhibition of nuclear factor kappaB in macrophages. AB - BACKGROUND: Prunus yedoensis (PY) is a traditional anti-allergy and anti inflammatory herb medicine used in South Korea. However, until date, little is known regarding its mechanism of action. METHODS: In order to elucidate the mechanism of anti-inflammatory effect of PY, the constituents of PY were analysed by high performance liquid chromatography (HPLC), and nitric oxide (NO) and prostaglandin E2 (PGE2) production were measured enzyme-linked immuno sorbent assay (ELISA). The expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor-kappaB (NF-kappaB) were also measured by western blotting in lipopolysaccharide (LPS)-induced RAW 264.7 macrophage cells treated with PY. RESULTS: The results indicate that (50, 100 MUg/mL) methanol and ethyl acetate fractionation extracts of PY not only inhibited LPS-mediated NO production and iNOS expression, but also decreased LPS induced PGE2 production and COX-2 expression. The anti-inflammatory effects of PY were also due to the attenuation of nuclear translocation of NF-kappaB, as evaluated by the use of anti-p50 on nuclear fractions. LPS-induced nuclear translocation of NF-kappaB decreased significantly by the methanol extract and ethyl acetate fraction of PY. High performance liquid chromatography (HPLC) analyses revealed that methanol extract and ethyl acetate fraction have similar patterns of retention time and peaks. CONCLUSION: Our results demonstrate that methanol extracts and the ethyl acetate fraction of PY have anti-inflammatory properties, thus emphasizing the potential of PY as a natural health product. PMID- 23631357 TI - Assessment of exposure of Korean consumers to acesulfame K and sucralose using a stepwise approach. AB - Using a stepwise assessment of the exposure of Korean consumers to acesulfame K and sucralose, theoretical maximum daily intakes of the sweeteners were calculated using the Budget screening method, which resulted in values greater than the acceptable daily intakes (ADIs). Accordingly, the daily intakes of the sweeteners based on food consumption data and concentrations determined by instrumental analysis of 605 food samples were estimated for the more refined approach. The estimated daily intakes (EDIs) of all ordinary consumers were lower than the ADI, which was considered safe. However, for infants and 95th percentile high-level consumers (especially those who choose sucralose-containing foods), the EDIs of sucralose were very close to and higher than the ADI. Therefore, the sucralose concentration in sweetened beverages should be reduced; this would benefit the health of both high-level consumers and infants. PMID- 23631358 TI - Maquet III procedure: what remains after initial complications--long-term results. AB - BACKGROUND: Maquet III procedure, unloved due to its complications (2% to 59%), has been progressively abandoned. At long-term follow-up, what happens to patients with complications that exceeded the initial ones (Acta Orthop Scand 60:20, 1989)? We retrospectively studied patients who were submitted to Maquet III procedure, by functional and radiologic long-term outcomes, in order to determine if this surgery has or has not fulfilled its initially proposed objectives. From 1970 to 1991, 116 patients benefit from the Maquet III procedure. From this, we were able to review in 2011, 23 patients (25 knees) who went through a single Maquet III procedure. Of these patients, 52% were males. Age at surgery was 39.7 +/- 11.4, with a postoperative follow-up of 27.2 +/- 3.1 years. METHODS: A questionnaire has been prepared for collecting data, and it has been supplemented by clinical records. We evaluated the preoperative complaints, postoperative complications, and range of motion during the recovery time, as well as the postoperative pain-absence period. All patients underwent an objective assessment using the visual analog scale (VAS) at rest and activity, and the Kujala patellofemoral scoring system. A radiological assessment was also made in order to evaluate the arthrosis degree. The bicondylo-patellar angle described by Delgado-Martins (Arch Orthop Traumat Surg 96:303-304, 1980) was used to measure patellar tilt, and the Caton-Deschamps index to calculate the patellar height. RESULTS: Only one knee had benefited from a total knee arthroplasty (20 years after the Maquet III procedure). Preoperative complains were mainly anterior knee pain, crepitus, and patellar instability. Nowadays, 10 patients (40%) still are pain free. Others had an average period without pain of 19.1 +/- 6.1 years. VAS at rest was 1.7 +/- 0.7 and in activity 4.4 +/- 3.0. KPS was 61.9 +/- 22.3 points. X-ray shows that 40% had a Kellgren-Lawrence grade of 1 at the patellofemoral joint. CONCLUSION: Maquet proposed this technique for knee-pain relief, maintenance of the knee range of motion, and for slowly progressive osteoarthritic development. Viewed in a dispassionately way, we could notice that the initial objectives of this procedure were completely achieved. A part of 80% of the initial population was lost during follow-up, which may compromise the conclusions, perhaps, it is time to reflect again on this solution, so unloved by so many. PMID- 23631359 TI - T-wave alternans, QRST-wave alternans and atrioventricular block: three consecutive rate-dependent phenomena in a child with congenital long-QT syndrome. PMID- 23631361 TI - Complete mitochondrial genome of the chocolate hind Cephalopholis boenak (Pisces: Perciformes). AB - The complete mitochondrial (mt) genome of the chocolate hind Cephalopholis boenak was obtained in this study, which is the first complete mitogenome in the genus Cephalopholis. The circular mtDNA molecule was 16 771 bp in size and the overall nucleotide composition of the H-strand was 29.58% A, 27.36% T, 15.84% G, and 27.22% C, with an A + T bias. The complete mitogenome encoded 13 protein-coding genes, 2 rRNAs, 22 tRNAs and 1 control region (D-loop), with the gene arrangement and translation direction basically identical to other typical vertebrate mitogenomes. The control region located between the tRNA (Pro) and tRNA (Phe) genes and the length was 1 064 bp, rich in A + T (70.11%); it was composed of 13 complete continuity tandem repeat units, 5'-TACATATCTATGTACTTAA-3', and one imperfect tandem repeat. PMID- 23631360 TI - Alterations in gene expression in Caenorhabditis elegans associated with organophosphate pesticide intoxication and recovery. AB - BACKGROUND: The principal toxicity of acute organophosphate (OP) pesticide poisoning is the disruption of neurotransmission through inhibition of acetylcholinesterase (AChE). However, other mechanisms leading to persistent effects and neurodegeneration remain controversial and difficult to detect. Because Caenorhabditis elegans is relatively resistant to OP lethality- particularly through the inhibition of AChE--studies in this nematode provide an opportunity to observe alterations in global gene expression following OP exposure that cannot be readily observed in less resistant organisms. RESULTS: We exposed cultures of worms in axenic, defined medium to dichlorvos under three exposure protocols. In the first, worms were exposed continuously throughout the experiment. In the second and third, the worms were exposed for either 2 or 8 h, the dichlorvos was washed out of the culture, and the worms were allowed to recover. We then analyzed gene expression using whole genome microarrays from RNA obtained from worms sampled at multiple time points throughout the exposure. The worms showed a time-dependent increase in the expression of genes involved in stress responses. Early in the exposure, the predominant effect was on metabolic processes, while at later times, an immune-like response and cellular repair mechanisms dominated the expression pattern. Following removal of dichlorvos, the gene expression in the worms appeared to relatively rapidly return to steady state levels. CONCLUSION: The changes in gene expression observed in the worms following exposure to dichlorvos point towards two potential mechanisms of toxicity: inhibition of AChE and mitochondrial disruption. PMID- 23631362 TI - Complete mitochondrial DNA genome of Pseudobagrus truncatus (Siluriformes: Bagridae). AB - In this study, the complete mitochondrial DNA (mtDNA) sequence of Pseudobagrus truncatus (Siluriformes: Bagridae) was determined. The complete mtDNA genome sequence of P. truncatus is 16,533 bp in size. It consists of 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and one non-coding control region. The gene order and genes were the same as that found in other previously reported catfishes. The overall-based composition was 31.6% A, 26.7% T, 14.9% G and 26.8% C, with a high A + T content (58.3%). This complete mitogenome of P. truncatus provides a basic data for studies on species identification, molecular systematics and conservation genetics. PMID- 23631363 TI - Mitochondrial genome of the black-faced bunting (Emberiza spodocephala). AB - Black-faced bunting (Emberiza spodocephala) is a common small songbird with widely geographical range. In this study, the complete mitochondrial genome of the Emberiza spodocephala was determined. The study showed that the total length of the mitogenome was 16,796 bp as a circular DNA consists of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and 1 control region (CR). Overall base composition of the complete mitochondrial DNA was 29.81% A, 23.12% T, 32.51% C, and 14.56% G. The CR is 1215 bp in length and was located between the tRNA(Gln) and tRNA(Phe) genes. The mitochondrial genes from Emberiza spodocephala were overlapped in a total of 29 bp at 6 locations, as well as interleaved with a total of 96 bp intergenic spacers at 18 locations. PMID- 23631364 TI - The phylogenetic placement of Siniperca obscura base on complete mitochondrial DNA sequence. AB - Abstract The extant freshwater sinipercids represent a group of 12 species and they are endemic to East Asia. In this study, we cloned and sequenced the complete mitochondrial DNA of Siniperca obscura from the Lijiang River. The size of the complete mitochondrial genome is 16,492 bp. The organization of the mitochondrial contained 37 genes (13 protein-coding genes, 2 ribosomal RNA and 22 transfer RNAs) and a major non-coding control region as well as those reported sinipercid fishes. Among the 13 protein-coding genes, three reading-frame overlaps were found: ATP8 and ATP6 overlap by 10 nucleotides and ND4 and ND4L overlap by 7 nucleotides and ND5 and ND6 overlap by 5 nucleotides. Phylogenetic analyses using N-J and maximum parsimony (MP) computational algorithms showed that S. chuatsi and S. kneri are sister species, next joined by S. Obscura, based on combined 12 protein-coding genes (excluding DN6). PMID- 23631365 TI - Complete mitochondrial genome of the Tioman Island rock gecko, Cnemaspis limi (Sauria, Gekkota, Gekkonidae). AB - We sequenced the complete mitochondrial genome of the Tioman Island rock gecko, Cnemaspis limi, which is known as an endemic species to Malaysia. The complete mitogenome is 16,680 bp in size, consisting of 37 genes coding for 13 proteins, 22 transfer RNAs, two ribosomal RNAs and one control region. The A + T content of the overall base composition of H-strand is 53.09% (T: 23.20%, C: 32.48%, A: 29.89% and G: 14.43%). The major non-coding region (control region) is 1254 bp in length with the A + T content of 55.09% and four replicates of a 76-bp repeat within this region. PMID- 23631366 TI - The complete mitochondrial genome of Scolopocryptops sp. (Chilopoda: Scolopendromorpha: Scolopocryptopidae). AB - The first complete mitogenome sequence of Scolopendromorpha is reported herein. The mitochondrial genome of Scolopocryptops sp. (Scolopendromorpha: Scolopocryptopidae) is a circular molecule of 15,119 bp in length. The orientation and gene order of the Scolopocryptops mitogenome are identical to that of Limulus polyphemus, except that the position of trnL1 and trnL2 is interchanged. TrnS1 (AGN) lacks the dihydrouridine arm. PMID- 23631367 TI - The complete mitochondrial genome of the big-eye thresher shark, Alopias superciliosus (Chondrichthyes, Alopiidae). AB - The complete mitochondrial genome of the big-eye thresher shark was sequenced using a polymerase chain reaction (PCR)-based method. The total length of mitochondrial DNA is 16,719 bp and includes 13 protein-coding genes, 2 ribosomal RNA, 22 transfer RNA genes, 1 replication origin region and 1 control region. The mitochondrial gene arrangement of the big-eye thresher shark is the same as the one observed in the most vertebrates. Base composition of the genome is A (31.8%), T (28.9%), C (25.8%) and G (13.5%). PMID- 23631368 TI - Complete mitochondrial genome of the longfin grouper Epinephelus quoyanus (Serranidae: Epinephelinae). AB - The complete mitochondrial genome of Epinephelus quoyanus is first presented in this article. It is a circular DNA double strand of 16,797 bp in length, consisting of 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA (tRNA) genes and a control region. The gene order and transcriptional orientation of E. quoyanus was same with most vertebrates. Several short overlaps and intergenic spacers were found at different gene junctions. Unusually, the CO1 gene started with GTG codon and the ATP6 gene started with CTG codon. The tRNA Ser2 (GCU) lost the DHU stem. Within the control region, the termination associated sequence was found near the tRNA-Pro and the conserved sequence blocks (1-3) were identified near the tRNA-Phe. PMID- 23631369 TI - Complete mitochondrial genome of Microphysogobio alticorpus (Cypriniformes, Cyprinidae). AB - In this study, we determined the complete mitochondrial (mt) genome of Microphysogobio alticorpus (Cypriniformes, Cyprinidae). This mt genome, consisting of 16,568 base pairs (bp), encoded genes for 13 protein-coding genes, 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs) and a noncoding control region (CR) as those found in other vertebrates, with the gene order identical to that of typical vertebrates. The overall base composition of the heavy strand shows T: 26.03%, C: 26.73%, A: 30.20% and G: 17.04%, apparently with a slight AT bias. The two rRNA genes of 12S rRNA (958 bp) and 16S rRNA (1693 bp) are located between tRNA(Phe) and tRNA(Leu()(UUR)) and separated by the tRNA(Val) gene. CR, of 890 bp in length, is located between tRNA(Pro) and tRNA(Phe). PMID- 23631370 TI - Development of a DNA barcoding system for the Ixodida (Acari: Ixodida). AB - To control the spread of tick-borne diseases, there is an urgent need to develop a reliable technique that can distinguish different species of ticks. DNA barcoding has been proved to be a powerful tool to identify species of arthropods, but this technique has not yet been developed for identifying ticks. Here, we screened and analyzed 1082 sequences of ticks from BOLD system and GenBank, consisting of 647 16S, 325 COI, and 110 18S. These sequences are reported in previous studies and considered to be correctly identified at the species level. Through the analyses of genetic divergences and neighbor-joining (NJ) phylogenetic relationships between the species of ticks, our results show that COI and 16S are reliable in discriminating species of ticks and the 18S could discriminate ticks at the genera level. New universal primers for 16S, 18S, and COI of ticks were designed and a DNA barcoding system for the Ixodida was developed. To assess the performance of this system, 57 specimens of ticks were collected within China. Our results show that DNA barcoding system could correctly identify the species of specimens in adult and subadult stages. This system would assist non-taxonomists to conveniently identify the species of Ixodida based on DNA sequences rather than morphological traits. However, there are still serious deficiencies in the information of 16S and COI of some species of ticks, and additional research is needed to resolve this problem. PMID- 23631371 TI - Mitochondrial genome sequence of the Japanese white croaker Pennahia argentata (Perciformes: Sciaenidae). AB - Through primer walking method, the mitochondrial genome sequence of white croaker (Pennahia argentata) from Japanese coastal water was obtained in this study. The mitogenome length of Japanese white croaker was 16,486 bp. The genome contains 13 protein-coding genes, 2 ribosomal RNA genes, and 22 transfer RNA genes, a control region (CR) and a dominating non-coding region. The termination-associated sequence, the central conserved domain, and the conserved sequence blocks were identified in the control region. The origin of L-strand replication was located in a cluster of five tRNA genes between tRNA-Asn and tRNA-Cys. PMID- 23631372 TI - Complete mitochondrial genome of the megamouth shark Megachasma pelagios (Chondrichthyes, Megachasmidae). AB - Here we describe the complete mitochondrial genome sequence of the megamouth shark, Megachasma pelagios, which is an extremely rare species of deepwater shark. The circle genome (16,694 bp) consists of 13 protein coding, 22 tRNA, 2 rRNA genes and 1 control region. It has the typical vertebrate mitochondrial gene arrangement. PMID- 23631374 TI - X-ray structure analysis of a solid solution of milbemycins A3 and A4. AB - Milbemycins A3 and A4 are pharmaceutically and agriculturally useful macrolides isolated from Streptomyces species. The molecular structures of the title compounds were unambiguously established by a single crystal X-ray analysis of the solid solution of both compounds. The crystals present trigonal system, space group P32 with Z = 3, unit cell dimensions: a = 12.2211(4), c = 17.5372(7) A; V = 2268.4(1) A(3), MU = 0.082 mm(- 1); d = 1.183 g cm(- 3). An interesting system of intramolecular hydrogen bonds and weak intermolecular CH...O type hydrogen bond was observed in the solid state. PMID- 23631373 TI - Lipoprotein subclass profiles in young adults born preterm at very low birth weight. AB - BACKGROUND: Adults born preterm at very low birth weight (VLBW <= 1500g) have increased risk factors for cardiovascular diseases including high blood pressure and impaired glucose regulation. Non-optimal lipoprotein profile is generally also likely to affect the increased cardiovascular risk, but lipoprotein subclass level data on adults born at VLBW are sparse. SUBJECTS AND METHODS: We studied 162 subjects born at VLBW and 169 term-born controls, aged 19 to 27 years. Total lipid, triglyceride and cholesterol concentrations of 14 lipoprotein subclasses were determined by proton nuclear magnetic resonance spectroscopy in the fasting state and in 2-hour serum samples from an oral glucose tolerance test. FINDINGS: In comparison to controls, VLBW subjects had significantly higher fasting concentration of triglycerides in chylomicrons and largest very-low-density lipoprotein particles [XXL-VLDL-TG, difference 0.026 (95% CI: 0.004 to 0.049), P=0.024], and of triglycerides in small high-density lipoprotein particles [S-HDL TG, 0.026 (95% CI: 0.002 to 0.051), P=0.037]. The seemingly important role of triglycerides was further supported by principal component analysis in which the first component was characterized by multiple lipoprotein triglyceride measures. CONCLUSIONS: Young adults born at VLBW and their peers born at term had triglyceride-related differences in both VLDL and HDL subclasses. These differences suggest that the increased risk factors for cardiovascular diseases among the VLBW individuals in adulthood may partly relate to impaired triglyceride metabolism. PMID- 23631375 TI - Spontaneous calcium transients in human neural progenitor cells mediated by transient receptor potential channels. AB - Calcium signals affect many developmental processes, including proliferation, migration, survival, and apoptosis, processes that are of particular importance in stem cells intended for cell replacement therapies. The mechanisms underlying Ca(2+) signals, therefore, have a role in determining how stem cells respond to their environment, and how these responses might be controlled in vitro. In this study, we examined the spontaneous Ca(2+) activity in human neural progenitor cells during proliferation and differentiation. Pharmacological characterization indicates that in proliferating cells, most activity is the result of transient receptor potential (TRP) channels that are sensitive to Gd(3+) and La(3+), with the more subtype selective antagonist Ruthenium red also reducing activity, suggesting the involvement of transient receptor potential vanilloid (TRPV) channels. In differentiating cells, Gd(3+) and La(3+)-sensitive TRP channels also appear to underlie the spontaneous activity; however, no sub-type-specific antagonists had any effect. Protein levels of TRPV2 and TRPV3 decreased in differentiated cells, which is demonstrated by western blot. Thus, it appears that TRP channels represent the main route of Ca(2+) entry in human neural progenitor cells (hNPCs), but the responsible channel types are subject to substitution under differentiating conditions. The level of spontaneous activity could be increased and decreased by lowering and raising the extracellular K(+) concentration. Proliferating cells in low K(+) slowed the cell cycle, with a disproportionate increased percentage of cells in G1 phase and a reduction in S phase. Taken together, these results suggest a link between external K(+) concentration, spontaneous Ca(2+) transients, and cell cycle distribution, which is able to influence the fate of stem and progenitor cells. PMID- 23631379 TI - Preparation and evaluation of double-walled microparticles prepared with a modified water-in-oil-in-oil-in-water (w1/o/o/w3) method. AB - In this study, a modified water-in-oil-in-oil-in-water (w1/o/o/w3) method was developed to prepare double-walled microparticles containing ovalbumin (OVA). The microparticles were characterized with respect to their morphology, particle size, encapsulation efficiency, production yield, thermal properties and in vitro drug release. Microscopy observations clearly showed that microparticles have spherical shape and smooth surface. These microparticles were characterized to have double-walled structure, with a cavity in the centre. By using w1/o/o/w3 method, a significant decrease in mean particle size and a significant increase in encapsulation efficiency were obtained. The mean particle size and the encapsulation efficiency of double-walled microparticles were also affected by the changing amount of OVA and mass ratio of polymers. Microparticles prepared with two polymers exhibited a significantly lower initial burst release followed by sustained release compared to microparticles made from poly(d,l-lactide-co glycolide) 50/50 only. It can be concluded that these microparticles can be a potential delivery system for therapeutic proteins. PMID- 23631380 TI - Microencapsulation of alpha-mangostin into PLGA microspheres and optimization using response surface methodology intended for pulmonary delivery. AB - Documented to exhibit cytotoxicity and poor oral bioavailability, alpha-mangostin was encapsulated into PLGA microspheres with optimization of formulation using response surface methodology. Mixed levels of four factors Face central composite design was employed to evaluate critical formulation variables. With 30 runs, optimized formula was 1% w/v polyvinyl alcohol, 1:10 ratio of oil to aqueous and sonicated at 2 and 5 min time for primary and secondary emulsion, respectively. Optimized responses for encapsulation efficiency, particle size and polydispersity index were found to be 39.12 +/- 0.01%, 2.06 +/- 0.017 um and 0.95 +/- 0.009, respectively, which matched values predicted by mathematical models. About 44.4% of the encapsulated alpha-mangostin was released over 4 weeks. Thermal analysis of the microspheres showed physical conversion of alpha mangostin from crystallinity to amorphous with encapsulated one had lower in vitro cytotoxicity than free alpha-mangostin. Aerodynamic diameter (784.3 +/- 7.5 nm) of this alpha-mangostin microsphere suggests suitability for peripheral pulmonary delivery. PMID- 23631381 TI - Fate of nanostructured lipid carriers (NLCs) following the oral route: design, pharmacokinetics and biodistribution. AB - The aim of this study was to develop a nanostructured lipid carriers (NLC) formulation containing spironolactone (SPN-NLCs), and to investigate its potential for the oral delivery of poorly water-soluble compounds. SPN-NLCs were orally administered to rabbits and the pharmacokinetics of spironolactone and its metabolites was evaluated. As reference formulation, we administered syrup. Spironolactone was only detected in a few plasma samples; hence, metabolite levels were employed for the pharmacokinetic analysis. The absolute bioavailability of 7alpha-TMS was significantly higher with the syrup than those obtained with the SPN-NLCs (0.7 versus 0.4, p < 0.05). However, no significant differences were observed in the bioavailability of canrenone, revealing a different canrenone/7alpha-TMS ratio depending on the administered formulation. Orally administered (99m)Tc-radiolabeled SPN-NLCs were mainly detected in the small intestine. These results suggest the retention of the nanocarriers in the underlying epithelium and further uptake by the epithelial cells. PMID- 23631382 TI - Simvastatin nanoemulsion for improved oral delivery: design, characterisation, in vitro and in vivo studies. AB - Simvastatin is poorly bioavailable as it is practically insoluble in water and shows dissolution rate-limited absorption. Therefore, the present study was aimed at preparing nanoemulsion (NE) of simvastatin for improving its solubility and/or dissolution rate for enhancing its bioavailability. The NEs were evaluated for particle size (PS), zeta potential, transmission electron microscopy (TEM), viscosity, in vitro release and stability studies. The optimised NE showed PS of 132 +/- 9 nm and zeta potential of 17.1 +/- 1.2 mV. TEM studies demonstrated spherical shape and size of the globules. In vitro release studies showed increased dissolution rate of NE compared with plain drug (PD). Pharmacokinetic studies showed relative bioavailability of simvastatin NE was 369.0% with respect to PD suspension. Pharmacodynamic studies conducted in hyperlipidemic rats showed that significant decrease in the total cholesterol and triglyceride levels for NE as compared with PD proving improvement in bioavailability. In conclusion, NE has great potential for improving bioavailability of poorly water-soluble drugs like simvastatin. PMID- 23631383 TI - Concanavalin A-conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles for intranasal drug delivery to the cervical lymph nodes. AB - Concanavalin A (ConA)-conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles (ConA-NPs) were prepared for targeted drug delivery to the cervical lymph nodes after intranasal administration. ConA, a lectin specifically binding to alpha-mannose and alpha-glucose, was covalently conjugated on NPs without loss of its carbohydrates binding bioactivity. In vitro cellular uptake experiment demonstrated that NPs could be uptaken by Calu-3 cells in a time- and concentration-dependent manner, and conjugation of ConA on NPs could significantly increase the rate and amount of cellular uptake. ConA-NP showed no obvious toxicity to Calu-3 cells in vitro or to the nasal cilia of rats in vivo. Compared with NPs without ConA, ConA-NP is more effective in targeting drugs to the deep cervical lymph nodes, as evidenced by 1.36-2.52 times increase of targeting efficiency, demonstrating that ConA-NP is a potential carrier for targeted drug delivery to the cervical lymph nodes via nasal route. PMID- 23631384 TI - Producing xylan/Eudragit(r) S100-based microparticles by chemical and physico mechanical approaches as carriers for 5-aminosalicylic acid. AB - Xylan is a biopolymer found in a variety of cell wall plants. Eudragit(r) S-100 (ES100), a pH-dependent polymer, is used as a coating material in gastroresistant delivery systems. In this study, microparticles based on both polymers were produced by interfacial cross-linking polymerisation and/or spray-drying technique in order to investigate feasibility and stability of the systems. Size and morphology of the microparticles were characterised by optical and SEM while FT-IR, thermal analysis (TG/DTA), and X-ray diffraction (XRD) evaluated the drug polymer interactions and the thermal behaviour of the systems. FT-IR confirmed the absence of chemical interaction between the polymers. TG/DTA analysis showed a higher stability for spray-dried microparticles and XRD data proved the amorphous feature of both carriers. The results reveal that xylan/ES100 microparticles can be produced by chemical or physico-mechanical ways, the latter being the best option due to the lack of toxic cross-linking agents and easy scale-up. PMID- 23631385 TI - Niosomes encapsulating paclitaxel for oral bioavailability enhancement: preparation, characterization, pharmacokinetics and biodistribution. AB - In this study, niosome formulations were prepared and evaluated for their effects on improving the oral bioavailability of paclitaxel (PCT). Niosomes were prepared from Span 40 and coated with bioadhesive carbopol polymers. The niosomes encapsulated 98.7% +/- 0.8 of the initially added PCT and their size ranged from 133 +/- 6 nm to 320 +/- 6 nm. The stability of Carbopol 974P coated niosomes in bile salts was better than uncoated niosomes. Extended release of PCT was observed. After oral administration of formulations to Wistar rats, higher drug plasma concentrations were observed for niosomes comparing to PCT suspension. The high PCT accumulation in intestine and liver obtained after Carbopol 974P coated niosomes administration indicated their potential regarding effective treatment of localized carcinomas in intestine and liver. The relative bioavailability of PCT was increased 3.8- and 1.4-fold by uncoated and Carbopol 974P coated niosomes emphasizing the ability of niosomes on improving the oral bioavailability of PCT. PMID- 23631386 TI - Microparticles-entrapped micelles: a novel delivery system to improve solubility and dissolution rate of poorly water-soluble valsartan. AB - Surfactants are routinely included in tablets during wet or dry granulations or along with directly compressible vehicles to improve wetting, disintegration and dissolution. Besides this micellar solubilization can improve permeability of poorly soluble drugs via gastrointestinal tract membranes thereby enhancing oral bioavailability. Microparticle-entrapped micelles (MEM) technology is a novel method of incorporating surfactants in tablets for improving in vitro and in vivo performance of poorly water-soluble drugs. Valsartan (VAL) was solubilized in cremophor EL micelles at cloud point temperature; lactose was dissolved in micellar dispersion and the dispersion was directly spray-dried to obtain solid product, which was subsequently converted into tablets using suitable excipients. VAL tablets produced by applying MEM technology improved dissolution performance of valsartan tablets. These tablets exhibited superior dissolution rate over controls and marketed tablets in all media employed irrespective of pH conditions and composition. PMID- 23631388 TI - Biodegradable core-shell carriers for simultaneous encapsulation of synergistic actives. AB - Simultaneous encapsulation of multiple active substances in a single carrier is essential for therapeutic applications of synergistic combinations of drugs. However, traditional carrier systems often lack efficient encapsulation and release of incorporated substances, particularly when combinations of drugs must be released in concentrations of a prescribed ratio. We present a novel biodegradable core-shell carrier system fabricated in a one-step, solvent-free process on a microfluidic chip; a hydrophilic active (doxorubicin hydrochloride) is encapsulated in the aqueous core, while a hydrophobic active (paclitaxel) is encapsulated in the solid shell. Particle size and composition can be precisely controlled, and core and shell can be individually loaded with very high efficiency. Drug-loaded particles can be dried and stored as a powder. We demonstrate the efficacy of this system through the simultaneous encapsulation and controlled release of two synergistic anticancer drugs using two cancer derived cell lines. This solvent-free platform technology is also of high potential value for encapsulation of other active ingredients and chemical reagents. PMID- 23631387 TI - Genome-wide transcriptional responses of two metal-tolerant symbiotic Mesorhizobium isolates to zinc and cadmium exposure. AB - BACKGROUND: Mesorhizobium metallidurans STM 2683T and Mesorhizobium sp. strain STM 4661 were isolated from nodules of the metallicolous legume Anthyllis vulneraria from distant mining spoils. They tolerate unusually high Zinc and Cadmium concentrations as compared to other mesorhizobia. This work aims to study the gene expression profiles associated with Zinc or Cadmium exposure and to identify genes involved in metal tolerance in these two metallicolous Mesorhizobium strains of interest for mine phytostabilization purposes. RESULTS: The draft genomes of the two Mezorhizobium strains were sequenced and used to map RNAseq data obtained after Zinc or Cadmium stresses. Comparative genomics and transcriptomics allowed the rapid discovery of metal-specific or/and strain specific genes. Respectively 1.05% (72/6,844) and 0.97% (68/6,994) predicted Coding DNA Sequences (CDS) for STM 2683 and STM 4661 were significantly differentially expressed upon metal exposure. Among these, a significant number of CDS involved in transport (13/72 and 13/68 for STM 2683 and STM 4661, respectively) and sequestration (15/72 and 16/68 for STM 2683 and STM 4661, respectively) were identified. Thirteen CDS presented homologs in both strains and were differentially regulated by Zinc and/or Cadmium. For instance, several PIB-type ATPases and genes likely to participate in metal sequestration were identified. Among the conserved CDS that showed differential regulation in the two isolates, we also found znuABC homologs encoding for a high affinity ABC-type Zinc import system probably involved in Zinc homeostasis. Additionally, global analyses suggested that both metals also repressed significantly the translational machinery. CONCLUSIONS: The comparative RNAseq-based approach revealed a relatively low number of genes significantly regulated in the two Mesorhizobium strains. Very few of them were involved in the non-specific metal response, indicating that the approach was well suited for identifying genes that specifically respond to Zinc and Cadmium. Among significantly up-regulated genes, several encode metal efflux and sequestration systems which can be considered as the most widely represented mechanisms of rhizobial metal tolerance. Downstream functional studies will increase successful phytostabilization strategies by selecting appropriate metallicolous rhizobial partners. PMID- 23631390 TI - TRPM2 channels are not required for acute airway inflammation in OVA-induced severe allergic asthma in mice. AB - BACKGROUND: Airway inflammation and asthma have been linked to oxidative stress and the melastatin-related transient receptor potential cation channel, member 2 (TRPM2), which can be activated by reactive oxygen species (ROS), has emerged as a potential therapeutic target for inflammatory diseases. OBJECTIVE: Using TRPM2 deficient (TRPM2-/-) mice, we investigated whether the TRPM2 ion channel, which mediates calcium (Ca2+) influx and lysosomal Ca2+ release, plays a role in the pathophysiology of severe allergic asthma in mouse. METHODS: Severe allergic asthma was initiated in wild type (WT) and TRPM2-/- mice by repeated sensitization with ovalbumin (OVA)/aluminum hydroxide on Days 0, 7 and 14, followed by intranasal challenge on Days 21, 22 and 23. Mice were investigated for the presence of airway responsiveness, airway inflammation, production of allergen-specific antibodies, cytokine response and lung pathology. RESULTS: The absence of TRPM2 channels has no obvious effect on major etiologic markers of severe allergic asthma in this mouse model. Neither airway resistance nor mucus production are affected in TRPM2-/- mice. TRPM2 channel ablation also does not alter airway inflammation or immunocyte infiltration and does not affect antibody response or cytokine levels. CONCLUSIONS: TRPM2 is not required for airway inflammation in OVA-induced severe allergic asthma in mice. Accordingly, TRPM2 might not be a suitable therapeutic target for airway inflammation caused by allergens in humans. PMID- 23631389 TI - Site-specific and far-red-light-activatable prodrug of combretastatin A-4 using photo-unclick chemistry. AB - Although tissue-penetrable light (red and NIR) has great potential for spatiotemporally controlled release of therapeutic agents, it has been hampered because of the lack of chemistry translating the photonic energy to the cleavage of a chemical bond. Recently, we discovered that an aminoacrylate group could be cleaved to release parent drugs after oxidation by SO and have called this "photo unclick chemistry". We demonstrate its application to far-red-light-activated prodrugs. A prodrug of combretastatin A-4 (CA4) was prepared, CMP-L-CA4, where CMP is dithiaporphyrin, a photosensitizer, and L is an aminoacrylate linker. Upon irradiation with 690 nm diode laser, the aminoacrylate linker of the prodrug was cleaved, rapidly releasing CA4 (>80% in 10 min) in CDCl3. In tissue culture, it showed about a 6-fold increase in its IC50 in MCF-7 after irradiation, most likely because of the released CA4. Most significantly, CMP-L-CA4 had better antitumor efficacy in vivo than its noncleavable (NC) analog, CMP-NCL-CA4. This is the first demonstration of the in vivo efficacy of the novel low-energy-light activatable prodrug using the photo-unclick chemistry. PMID- 23631391 TI - Modeling of steroid estrogen contamination in UK and South Australian rivers predicts modest increases in concentrations in the future. AB - The prediction of risks posed by pharmaceuticals and personal care products in the aquatic environment now and in the future is one of the top 20 research questions regarding these contaminants following growing concern for their biological effects on fish and other animals. To this end it is important that areas experiencing the greatest risk are identified, particularly in countries experiencing water stress, where dilution of pollutants entering river networks is more limited. This study is the first to use hydrological models to estimate concentrations of pharmaceutical and natural steroid estrogens in a water stressed catchment in South Australia alongside a UK catchment and to forecast their concentrations in 2050 based on demographic and climate change predictions. The results show that despite their differing climates and demographics, modeled concentrations of steroid estrogens in effluents from Australian sewage treatment works and a receiving river were predicted (simulated) to be similar to those observed in the UK and Europe, exceeding the combined estradiol equivalent's predicted no effect concentration for feminization in wild fish. Furthermore, by 2050 a moderate increase in estrogenic contamination and the potential risk to wildlife was predicted with up to a 2-fold rise in concentrations. PMID- 23631392 TI - Selenium nanoparticle-enriched Lactobacillus brevis causes more efficient immune responses in vivo and reduces the liver metastasis in metastatic form of mouse breast cancer. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: Selenium enriched Lactobacillus has been reported as an immunostimulatory agent which can be used to increase the life span of cancer bearing animals. Lactic acid bacteria can reduce selenium ions to elemental selenium nanoparticles (SeNPs) and deposit them in intracellular spaces. In this strategy two known immunostimulators, lactic acid bacteria (LAB) and SeNPs, are concomitantly administered for enhancing of immune responses in cancer bearing mice. METHODS: Forty five female inbred BALB/c mice were divided into three groups of tests and control, each containing 15 mice. Test mice were orally administered with SeNP-enriched Lactobacillus brevis or Lactobacillus brevis alone for 3 weeks before tumor induction. After that the administration was followed in three cycles of seven days on/three days off. Control group received phosphate buffer saline (PBS) at same condition. During the study the tumor growth was monitored using caliper method. At the end of study the spleen cell culture was carried out for both NK cytotoxicity assay and cytokines measurement. Delayed type hypersensitivity (DTH) responses were also assayed after 72h of tumor antigen recall. Serum lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels were measured, the livers of mice were removed and prepared for histopathological analysis. RESULTS: High level of IFN-gamma and IL 17 besides the significant raised in NK cytotoxicity and DTH responses were observed in SeNP-enriched L. brevis administered mice and the extended life span and decrease in the tumor metastasis to liver were also recorded in this group compared to the control mice or L.brevis alone administered mice. CONCLUSION: Our results suggested that the better prognosis could be achieved by oral administration of SeNP-enriched L. brevis in highly metastatic breast cancer mice model. PMID- 23631394 TI - "Breeding" diagnostic antibodies for higher assay performance: a 250-fold affinity-matured antibody mutant targeting a small biomarker. AB - Conventional immunization-based antibodies are not always applicable to monitor trace amounts of clinical biomarkers due to insufficient antigen-binding affinity. The development of in vitro affinity maturation for native antibodies has paved the way to solve this problem, but there has been minimal success in obtaining improved antibody mutants for small molecule biomarkers (haptens). We here describe a "molecular breeding" approach, in which a practical anti-hapten antibody mutant has successfully been generated from a prototype antibody with poor binding properties. Random point mutations were introduced by error-prone polymerase chain reaction in the V(H) and V(L) genes of a second-generation mutant of a single-chain Fv fragment (scFv) that binds estradiol-17beta (E2), whose parent mouse Fab fragment showed poor affinity for E2 (Ka = 5.2 * 10(7) M( 1)). The resulting scFv gene library was expressed on filamentous phage particles. Phage clones with strong E2 binding were isolated with dissociation independent methods using newly developed reagents. The binding characteristics and clinical applicability of the soluble scFvs prepared from the selected clones were examined in a competitive enzyme-linked immunosorbent assay (ELISA). We finally obtained a third-generation scFv mutant, scFv#m3-a18 (11 amino acid substitutions), which showed ~250-fold greater Ka (1.3 * 10(10) M(-1)) than the parent Fab, and yielded sensitive ELISA dose-response curves for E2 (limit of detection < 0.5 pg/assay) with practical specificity. The average human serum E2 levels, determined after acetonitrile extraction, were compatible with reported reference ranges. The present results will prompt a new era for preparing diagnostic reagents. PMID- 23631393 TI - Comparison of cost-effectiveness of vitamin D screening with that of universal supplementation in preventing falls in community-dwelling older adults. AB - OBJECTIVES: To compare the cost-effectiveness of population screening for vitamin D insufficiency with that of universal vitamin D supplementation in community dwelling older adults. DESIGN: A Markov decision model simulating follow-up over a 36-month period. Published data were used to estimate values for the model, including costs (measured in 2011 U.S. dollars), utilities (measured in quality adjusted life years (QALYs)), and probabilities. SETTING: Decision analysis simulation from a societal perspective. PARTICIPANTS: Hypothetical cohort of community-dwelling women and men aged 65 to 80. MEASUREMENTS: Net monetary benefit (NMB) was calculated by subtracting the incremental cost of the strategy from the product of incremental QALYs and willingness-to-pay threshold. A higher NMB indicates greater cost-effectiveness. RESULTS: In women aged 65 to 80, population screening was slightly more cost-effective than universal supplementation, with an incremental NMB of $224 compared with $189 (P < .001). Population screening in men was also more cost-effective than universal supplementation (incremental NMB $298 vs $260, P < .001). Results differed according to age group. In those aged 65, population screening had cost effectiveness similar to that of universal supplementation in women ($59 vs $71) and men ($114 vs $120), whereas in those aged 80, population screening was substantially more cost-effective than universal supplementation in women ($563 vs $428) and men ($703 vs $571). CONCLUSION: Population screening and universal supplementation for vitamin D insufficiency are cost-effective strategies in community-dwelling older women and men. In the oldest old, population screening may be more cost-effective than universal supplementation. PMID- 23631395 TI - "Strange kinetics" in the temperature dependence of methionine ligand rebinding dynamics in cytochrome c. AB - The temperature dependence of methionine ligand dissociation and rebinding dynamics in cytochrome c in aqueous solution has been studied using classical molecular dynamics simulation. Results are compared with previous study of rebinding dynamics at 300 K in water in order to understand how the change of protein environment and the underlying protein energy landscape influence the dynamics. Rebinding dynamics at 77, 180, and 300 K exhibits changes in both time scale and mechanism as the protein and solvent undergo a dynamic "glass transition". At each temperature, the rebinding dynamics yields a subset of trajectories that undergo fast rebinding as well as a subset of trajectories that undergo slower rebinding. At 300 K in water, both a fast (4.0 ps) and slow (14.6 ps) rebinding is observed. While fast rebinding occurs from a "downward" (heme pointing) substate of the methionine, the slow rebinding involves interconversion between an "upward" substate, from which rebinding cannot occur, and the downward substate. At lower temperatures (77 and 180 K), the upward dissociated substate was not observed due to the high barrier imposed by the "frozen" protein structure. However, a slow rebinding phase is observed at both 77 and 180 K and is associated with a process of trapping in downward but "binding forbidden" substates with subsequent slow dynamical conversion to "binding competent" substates from which rebinding is relatively rapid. Distinctive rebinding dynamics at 77 and 180 K suggest that different rebinding time scales are predetermined by the protein and solvent structural arrangement prior to photodissociation, which causes either fast rebinding (about 2 ps) or slow (>50 ps) rebinding. Suggestions for future experiments to further probe the role of dynamic heterogeneity in the kinetics of methionine ligand binding in cytochrome c protein are proposed. PMID- 23631397 TI - Ab initio molecular dynamics study of the reaction of U+ and U2+ with H2O in the gas phase: direct classical trajectory calculations. AB - The gas phase reactions of U(+) and U(2+) with H2O were investigated using an ab initio molecular dynamics method. All of the information along the minimum energy path were calculated with density functional theory (DFT) and coupled cluster methods. For U(+) with H2O, the molecular dynamics simulations yield a branching ratio of 86% for the H2 elimination channel to 14% for the H atomic elimination channel in agreement with the quadruple ion trap mass spectrometry (QIT/MS) experimental ratio of 91% to 9%. In the case of U(2+) + H2O, there is a crossing of the potential energy surfaces (PES) after the first transition state. Crossing seams between the PES and possible spin inversion processes were studied by means of the intrinsic reaction coordinate (IRC) approach. For U(2+) with H2O, all trajectories are corresponds to H atom elimination channel, this is consistent with the Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) experimental results. The chemical bonding evolution along the reaction pathways was discussed by using topological methodologies of the electron localization function (ELF). PMID- 23631396 TI - Prepackaged central line kits reduce procedural mistakes during central line insertion: a randomized controlled prospective trial. AB - BACKGROUND: Central line catheter insertion is a complex procedure with a high cognitive load for novices. Providing a prepackaged all-inclusive kit is a simple measure that may reduce the cognitive load. We assessed whether the use of prepackaged all-inclusive central line insertion kits reduces procedural mistakes during central line catheter insertion by novices. METHODS: Thirty final year medical students and recently qualified physicians were randomized into two equal groups. One group used a prepackaged all-inclusive kit and the other used a standard kit containing only the central vein catheter and all other separately packaged components provided in a materials cart. The procedure was videotaped and analyzed by two blinded raters using a checklist. Both groups performed central line catheter insertion on a manikin, assisted by nursing students. RESULTS: The prepackaged kit group outperformed the standard kit group in four of the five quality indicators: procedure duration (26:26 +/- 3:50 min vs. 31:27 +/- 5:57 min, p = .01); major technical mistakes (3.1 +/- 1.4 vs. 4.8 +/- 2.6, p = .03); minor technical mistakes (5.2 +/- 1.7 vs. 8.0 +/- 3.2, p = .01); and correct steps (83 +/- 5% vs. 75 +/- 11%, p = .02). The difference for breaches of aseptic technique (1.2 +/- 0.8 vs. 3.0 +/- 3.6, p = .06) was not statistically significant. CONCLUSIONS: Prepackaged all-inclusive kits for novices improved the procedure quality and saved staff time resources in a controlled simulation environment. Future studies are needed to address whether central line kits also improve patient safety in hospital settings. PMID- 23631398 TI - A dinoflagellate Amylax triacantha with plastids of the cryptophyte origin: phylogeny, feeding mechanism, and growth and grazing responses. AB - The gonyaulacalean dinoflagellates Amylax spp. were recently found to contain plastids of the cryptophyte origin, more specifically of Teleaulax amphioxeia. However, not only how the dinoflagellates get the plastids of the cryptophyte origin is unknown but also their ecophysiology, including growth and feeding responses as functions of both light and prey concentration, remain unknown. Here, we report the establishment of Amylax triacantha in culture, its feeding mechanism, and its growth rate using the ciliate prey Mesodinium rubrum (= Myrionecta rubra) in light and dark, and growth and grazing responses to prey concentration and light intensity. The strain established in culture in this study was assigned to A. triacantha, based on morphological characteristics (particularly, a prominent apical horn and three antapical spines) and nuclear SSU and LSU rDNA sequences. Amylax triacantha grew well in laboratory culture when supplied with the marine mixotrophic ciliate M. rubrum as prey, reaching densities of over 7.5 * 10(3) cells/ml. Amylax triacantha captured its prey using a tow filament, and then ingested the whole prey by direct engulfment through the sulcus. The dinoflagellate was able to grow heterotrophically in the dark, but the growth rate was approximately two times lower than in the light. Although mixotrophic growth rates of A. triacantha increased sharply with mean prey concentrations, with maximum growth rate being 0.68/d, phototrophic growth (i.e. growth in the absence of prey) was -0.08/d. The maximum ingestion rate was 2.54 ng C/Amylax/d (5.9 cells/Amylax/d). Growth rate also increased with increasing light intensity, but the effect was evident only when prey was supplied. Increased growth with increasing light intensity was accompanied by a corresponding increase in ingestion. In mixed cultures of two predators, A. triacantha and Dinophysis acuminata, with M. rubrum as prey, A. triacantha outgrew D. acuminata due to its approximately three times higher growth rate, suggesting that it can outcompete D. acuminata. Our results would help better understand the ecophysiology of dinoflagellates retaining foreign plastids. PMID- 23631399 TI - Flotillin-1 is an evolutionary-conserved memory-related protein up-regulated in implicit and explicit learning paradigms. AB - INTRODUCTION: Studies of synaptic plasticity using the marine mollusk Aplysia californica as model system have been successfully used to identify proteins involved in learning and memory. The importance of molecular elements regulated by the learning- related neurotransmitter serotonin in Aplysia can then be explored in rodent models and finally tested for their relevance for human physiology and pathology. MATERIALS AND METHODS: Herein, 2-DE gel-based electrophoresis has been used to investigate protein level changes after treatment with serotonin in Aplysia abdominal ganglia. RESULTS: Twenty-one proteins have been found to be regulated by serotonin, and protein level changes of actin depolymerizing factor (ADF), deleted in azoospermia associated protein (DAZAP-1), and Flotillin-1 have been verified by Western blotting. DISCUSSION: Flotillin-1, a member of the flotillin/reggie family of scaffolding proteins, has been previously found to be involved in neuritic branching and synapse formation in hippocampal neurons in vitro. However, its importance for hippocampal- dependent learning and memory in the mouse has not been examined. Here, elevated levels of Flotillin-1 in hippocampal tissue of mice trained in the Morris water maze confirmed the relevance of Flotillin-1 for memory-related processes in a mammalian system. Thus, a translational approach-from invertebrates to rodents led to the identification of Flotillin-1 as evolutionary-conserved memory-related protein. PMID- 23631400 TI - Obesity and statins are both independent predictors of enhanced coronary arteriolar dilation in patients undergoing heart surgery. AB - BACKGROUND: A paradoxical inverse relationship between body mass index, morbidity and mortality in patients with ischemic heart disease has been noted; but the underlying mechanisms remain unclear. Given that coronary resistance arteries are the primary regulators of myocardial blood flow, we examined the effects of obesity and medication on dilator function in coronary microvessels. METHODS: Bradykinin-induced coronary dilation was assessed by videomicroscopy in ex vivo coronary arterioles obtained from 64 consecutive patients undergoing heart surgery. Multi-variable linear regression and logistic regression were used to investigate the effects of obesity (BMI >= 30 kg/M2) and the influences of medications on vessel responses. RESULTS: In isolated, pressurized (80 mmHg) coronary arterioles of obese and non-obese patient the active (73+/-4 vs. 79+/-13 MUm) and passive (111 +/- 5.5 vs. 118 +/- 5.0 MUm) diameters were similar. Bradykinin elicited substantial dilation in coronary arterioles, with a similar magnitude in obese and non-obese patients (to 10-8 M: 55 +/- 5% vs. 46 +/- 5%, P = 0.20), but with significantly enhanced sensitivity in obesity (EC50: 8.2x10-9 M vs. 1.9x10-8 M, respectively, P = 0.03). When adjusted for other risk factors and medications, obesity and statins were determined to be the only positive predictors of enhanced dilation, as assessed with multiple regression analysis. Moreover, obese patients with or without statin exhibited significantly increased coronary dilation to bradykinin, when compared to non-obese patients without statin therapy. CONCLUSIONS: Obesity and statin therapy are independently associated with an enhanced dilator function of coronary arterioles in patients undergoing heart surgery, which may offer a potential mechanism for the better cardiovascular outcome described earlier as the obesity paradox. PMID- 23631401 TI - Risk stratification of opioid misuse among patients with cancer pain using the SOAPP-SF. AB - BACKGROUND: Opioids are recognized as an integral part of the armamentarium in the management of cancer pain. There has been a growing awareness of the misuse of prescription opioids among cancer patients. More research is needed to detail risk factors and incidence for opioid misuse among cancer pain patients. METHODS: We reviewed 522 patient charts that were seen in our Pain Center from January 1, 2009 to June 30, 2009 for risk stratification of opioid misuse with demographic and clinical factors utilizing the Screener and Opioid Assessment for Patients with Pain-short form (SOAPP-SF). Group differences based on High (>=4) and Low (<4) SOAPP-SF scores were evaluated at initial visit, follow-up within a month and 6-9 months. RESULTS: One hundred forty-nine of the 522 (29%) patients had a SOAPP-SF score of >=4. The mean age for patients with high SOAPP-SF score (>=4) was 50 +/- 14 vs 56 +/- 14 for patients with low SOAPP-SF score (<4) (P < 0.0001). The pain scores were higher for patients with high SOAPP-SF score compared with patients with low SOAPP-SF score at consult (P < 0.0001). Morphine equivalent daily dose (MEDD) was higher for patients with high SOAPP-SF score compared with patients with low SOAPP-SF score at consult (P = 0.0461). Fatigue, feeling of well-being, and poor appetite were higher among the high SOAPP-SF group at initial visit (P < 0.0001, <0.0001, <0.0149, respectively). The high SOAPP-SF score patients also had statistically significant (P < 0.05) higher anxiety and depression scores at all three time points. In the multivariate analysis, patients younger than 55 years have a higher odds of having a "high" SOAPP-SF score than patients 55 years and older {odds ratio (OR) (95% confidence interval [CI]) = 2.76 (1.58, 4.81), P = 0.0003} adjusting for employment status, disease status, treatment status, usual pain score, and morphine equivalency at consult. Patients with higher usual pain score at consult have higher odds of a "high" SOAPP-SF score (OR [95% CI] = 1.34 [1.19, 1.51], P < 0.0001) adjusting for age, employment status, disease status, treatment status, and morphine equivalency at consult. CONCLUSION: Patients classified by the SOAPP-SF in the current study as high risk tended to be younger, endorse more pain, have higher MEDD requirement, and endorse more symptoms of depression and anxiety. These findings are consistent with the literature on risk factors of opioid abuse in chronic pain patients which suggests that certain patient characteristics such as younger age, anxiety, and depression symptomatology are associated with greater risk for opioid misuse. However, a limitation of the current study is that other measures of opioid abuse were not available for validation and comparison with the SOAPP-SF. PMID- 23631402 TI - (De)lithiation mechanism of Li/SeS(x) (x = 0-7) batteries determined by in situ synchrotron X-ray diffraction and X-ray absorption spectroscopy. AB - Electrical energy storage for transportation has gone beyond the limit of converntional lithium ion batteries currently. New material or new battery system development is an alternative approach to achieve the goal of new high-energy storage system with energy densities 5 times or more greater. A series of SeSx carbon (x = 0-7) composite materials has been prepared and evaluated as the positive electrodes in secondary lithium cells with ether-based electrolyte. In situ synchrotron high-energy X-ray diffraction was utilized to investigate the crystalline phase transition during cell cycling. Complementary, in situ Se K edge X-ray absorption near edge structure analysis was used to track the evolution of the Se valence state for both crystalline and noncrystalline phases, including amorphous and electrolyte-dissolved phases in the (de)lithiation process. On the basis of these results, a mechanism for the (de)lithiation process is proposed, where Se is reduced to the polyselenides, Li2Sen (n >= 4), Li2Se2, and Li2Se sequentially during the lithiation and Li2Se is oxidized to Se through Li2Sen (n >= 4) during the delithiation. In addition, X-ray photoelectron spectroscopy and electrochemical impedance spectroscopy demonstrated the reversibility of the Li/Se system in ether-based electrolyte and the presence of side products in the carbonate-based electrolytes. For Li/SeS2 and Li/SeS7 cells, Li2Se and Li2S are the discharged products with the presence of Se only as the crystalline phase in the end of charge. PMID- 23631403 TI - "Made in China" doctors. PMID- 23631404 TI - Personal characteristics may affect evaluation of teaching: a prospective study in medical students. PMID- 23631405 TI - Medical education: changes and perspectives. AB - As medical education undergoes significant internationalization, it is important for the medical education community to understand how different countries structure and provide medical education. This article highlights the current landscape of medical education in China, particularly the changes that have taken place in recent years. It also examines policies and offers suggestions about future strategies for medical education in China. Although many of these changes reflect international trends, Chinese medical education has seen unique transformations that reflect its particular culture and history. PMID- 23631406 TI - Use of simulation to teach appropriate management of a crying infant. PMID- 23631407 TI - Direct to consumer advertising's effect on medical students: the case of fibromyalgia. PMID- 23631408 TI - Assessment in the post-psychometric era: learning to love the subjective and collective. AB - Since the 1970s, assessment of competence in the health professions has been dominated by a discourse of psychometrics that emphasizes the conversion of human behaviors to numbers and prioritizes high-stakes, point-in-time sampling, and standardization. There are many advantages to this approach, including increased fairness to test takers; however, some limitations of overemphasis on this paradigm are evident. Further, two shifts are underway that have significant consequences for assessment. First, as clinical practice becomes more interprofessional and team-based, the locus of competence is shifting from individuals to teams. Second, expensive, high-stakes final examinations are not well suited for longitudinal assessment in workplaces. The result is a need to consider assessment methods that are subjective and collective. PMID- 23631409 TI - Medical education in Poland. AB - Both undergraduate and postgraduate medical education in Poland are currently undergoing a significant reform, based on new national educational standards, arising from European Union recommendations. This article describes the previous system and the new approach to medical curriculum, draws a picture of the current situation and discusses the impact of this educational change on the quality of future graduates. PMID- 23631410 TI - Creation of an interprofessional clinical experience for healthcare professions trainees in a nursing home setting. AB - Successful interprofessional teams are essential when caring for older adults with multiple complex medical conditions that require ongoing management from a variety of disciplines across healthcare settings. To successfully integrate interprofessional education into the healthcare professions curriculum, the most effective learning experiences should utilize adult learning principles, reflect real-life practice, and allow for interaction among trainees representing a variety of health professions. Interprofessional clinical experiences are essential to prepare future healthcare professionals to provide quality patient care and understand the best methods for utilizing members of the healthcare team to provide that care. To meet this need, the University of Alabama at Birmingham Geriatric Education Center has developed an Interprofessional Clinical Experience (ICE) to expose future healthcare providers to an applied training experience with older adults in the nursing home setting. This paper outlines how this program was developed, methods used for program evaluation, and how the outcome data influenced program revisions. PMID- 23631411 TI - Exploiting drug-resistant enzymes as tools to identify thienopyrimidinone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H. AB - The thienopyrimidinone 5,6-dimethyl-2-(4-nitrophenyl)thieno[2,3-d]pyrimidin-4(3H) one (DNTP) occupies the interface between the p66 ribonuclease H (RNase H) domain and p51 thumb of human immunodeficiency virus reverse transcriptase (HIV RT), thereby inducing a conformational change incompatible with catalysis. Here, we combined biochemical characterization of 39 DNTP derivatives with antiviral testing of selected compounds. In addition to wild-type HIV-1 RT, derivatives were evaluated with rationally designed, p66/p51 heterodimers exhibiting high level DNTP sensitivity or resistance. This strategy identified 3',4' dihydroxyphenyl (catechol) substituted thienopyrimidinones with submicromolar in vitro activity against both wild type HIV-1 RT and drug-resistant variants. Thermal shift analysis indicates that, in contrast to active site RNase H inhibitors, these thienopyrimidinones destabilize the enzyme, in some instances reducing the Tm by 5 degrees C. Importantly, catechol-containing thienopyrimidinones also inhibit HIV-1 replication in cells. Our data strengthen the case for allosteric inhibition of HIV RNase H activity, providing a platform for designing improved antagonists for use in combination antiviral therapy. PMID- 23631412 TI - Using sequence-specific oligonucleotides to inhibit bacterial rRNA. AB - The majority of antibiotics used in the clinic target bacterial protein synthesis. However, the widespread emergence of bacterial resistance to existing drugs creates a need to discover or develop new therapeutic agents. Ribosomal RNA (rRNA) has been a target for numerous antibiotics that bind to functional rRNA regions such as the peptidyl transferase center, polypeptide exit tunnel, and tRNA binding sites. Even though the atomic resolution structures of many ribosome antibiotic complexes have been solved, improving the ribosome-acting drugs is difficult because the large rRNA has a complicated 3D architecture and is surrounded by numerous proteins. Computational approaches, such as structure based design, often fail when applied to rRNA binders because electrostatics dominate the interactions and the effect of ions and bridging waters is difficult to account for in the scoring functions. Improving the classical anti-ribosomal agents has not proven particularly successful and has not kept pace with acquired resistance. So one needs to look for other ways to combat the ribosomes, finding either new rRNA targets or totally different compounds. There have been some efforts to design translation inhibitors that act on the basis of the sequence specific hybridization properties of nucleic acid bases. Indeed oligonucleotides hybridizing with functional regions of rRNA have been shown to inhibit translation. Also, some peptides have been shown to be reasonable inhibitors. In this review we describe these nonconventional approaches to screening for ribosome inhibition and function of particular rRNA regions. We discuss inhibitors against rRNA that may be designed according to nucleotide sequence and higher order structure. PMID- 23631413 TI - A data-driven approach to preprocessing Illumina 450K methylation array data. AB - BACKGROUND: As the most stable and experimentally accessible epigenetic mark, DNA methylation is of great interest to the research community. The landscape of DNA methylation across tissues, through development and in disease pathogenesis is not yet well characterized. Thus there is a need for rapid and cost effective methods for assessing genome-wide levels of DNA methylation. The Illumina Infinium HumanMethylation450 (450K) BeadChip is a very useful addition to the available methods for DNA methylation analysis but its complex design, incorporating two different assay methods, requires careful consideration. Accordingly, several normalization schemes have been published. We have taken advantage of known DNA methylation patterns associated with genomic imprinting and X-chromosome inactivation (XCI), in addition to the performance of SNP genotyping assays present on the array, to derive three independent metrics which we use to test alternative schemes of correction and normalization. These metrics also have potential utility as quality scores for datasets. RESULTS: The standard index of DNA methylation at any specific CpG site is beta = M/(M + U + 100) where M and U are methylated and unmethylated signal intensities, respectively. Betas (betas) calculated from raw signal intensities (the default GenomeStudio behavior) perform well, but using 11 methylomic datasets we demonstrate that quantile normalization methods produce marked improvement, even in highly consistent data, by all three metrics. The commonly used procedure of normalizing betas is inferior to the separate normalization of M and U, and it is also advantageous to normalize Type I and Type II assays separately. More elaborate manipulation of quantiles proves to be counterproductive. CONCLUSIONS: Careful selection of preprocessing steps can minimize variance and thus improve statistical power, especially for the detection of the small absolute DNA methylation changes likely associated with complex disease phenotypes. For the convenience of the research community we have created a user-friendly R software package called wateRmelon, downloadable from bioConductor, compatible with the existing methylumi, minfi and IMA packages, that allows others to utilize the same normalization methods and data quality tests on 450K data. PMID- 23631414 TI - The biological stress of early weaned piglets. AB - Pigs experience biological stress such as physiological, environmental, and social challenges when weaned from the sow. The process of weaning is one of the most stressful events in the pig's life that can contribute to intestinal and immune system dysfunctions that result in reduced pig health, growth, and feed intake, particularly during the first week after weaning. Technological improvements in housing, nutrition, health, and management have been used to minimize some of the adverse effects of weaning stress, but a greater understanding of the biological impact of stress is needed to improve strategies to overcome weaning stress. The focus of this review paper is to briefly describe how the biological stress associated with weaning impacts intestinal morphology, structure, physiology, and intestinal immune responses that can impact subsequent production efficiencies such as growth, intake, morbidity, and mortality. PMID- 23631415 TI - Association between sedating medications and delirium in older inpatients. AB - OBJECTIVES: To examine the association between Beers criteria sedative medications and delirium in a large cohort of hospitalized elderly adults with common medical conditions. DESIGN: Retrospective cohort and nested case-control studies. SETTING: 374 U.S. hospitals. PARTICIPANTS: All individuals aged 65 and older admitted to the hospital between September 2003 and June 2005 with one of six principal diagnoses (acute myocardial infarction, chronic obstructive pulmonary disease, community-acquired pneumonia, congestive heart failure, ischemic stroke, urinary tract infection). MEASUREMENTS: Primary outcome was presumed hospital-acquired delirium, defined as initiation of an antipsychotic medication or restraints on hospital Day 3 or later. Logistic and proportional hazards regression were used to model the associations between sedative exposure and delirium. RESULTS: The dataset contained 225,028 participants (median age 82; 58% female). Four percent fit the definition of hospital-acquired delirium (median onset Day 5). In all, 38,883 (17%) participants received one or more sedative medications. In the cohort study, diphenhydramine (adjusted odds ratio (AOR) = 1.22, 95% confidence interval (CI) = 1.09-1.36) and short-acting benzodiazepines (AOR = 1.18, 95% CI = 1.03-1.34) were associated with greater risk of subsequent delirium. In the nested case-control study, diphenhydramine, short- and long-acting benzodiazepines and promethazine were associated with delirium. Amitriptyline and muscle relaxants were not associated with delirium in either study. Confounding by indication could not be excluded for drugs that are sometimes used improperly to treat delirium. CONCLUSION: An association was found between several Beers criteria sedative medications and delirium in hospitalized medical patients. Given the prevalence of these medications and the morbidity associated with delirium, further investigation into the appropriateness of such prescribing is warranted. PMID- 23631416 TI - Nitrogen deposition in and near an urban ecosystem. AB - Excess nitrogen (N) is a serious water-quality problem in most of the estuaries in the United States, especially those downstream of developed coastal basins. Understanding sources of N is a key first step in managing and mitigating N pollution. While the major sources of this N, atmospheric deposition, wastewater, fertilizer, and other agricultural sources are well-known, their relative importance as N sources to particular estuaries is not. Much of this uncertainty is due to difficulties associated with estimating the amount of atmospheric N deposition. Here, we show that deposition is 47% higher in urban and 22% higher in suburban areas compared to nonurban areas and that this deposition is primarily due to dry deposition. Moreover, this deposition is not being measured by the current deposition monitoring networks that were designed to measure broader regional patterns causing an underestimation of N inputs in urban areas. PMID- 23631417 TI - Risk factors for postoperative hypoxemia in patients undergoing Stanford A aortic dissection surgery. AB - BACKGROUND: The purpose of this study is to identify the risk factors for postoperative hypoxemia in patients with Stanford A aortic dissection surgery and their relation to clinical outcomes. METHODS: Clinical records of 186 patients with postoperative hypoxemia in Stanford A aortic dissection were analyzed retrospectively. The patients were divided into two groups by postoperative oxygen fraction (PaO2/FiO2):hypoxemia group (N=92) and non-hypoxemia group (N=94). RESULTS: We found that the incidence of postoperative hypoxemia was 49.5%. Statistical analysis by t-test and chi2 indicated that acute onset of the aortic dissection (p=0.000), preoperative oxygen fraction (PaO2/FiO2) <=200 mmHg(p=0.000), body mass index (p=0.008), circulatory arrest (CA) time (p=0.000) and transfusion more than 3000 ml(p=0.000) were significantly associated with postoperative hypoxemia. Multiple logistic regression analysis showed that preoperative hypoxemia, CA time and transfusion more than 3000 ml were independently associated with postoperative hypoxemia in Stanford A aortic dissection. CONCLUSION: Our results suggest that postoperative hypoxemia is a common complication in patients treated by Stanford A aortic dissection surgery. Preoperative oxygen fraction lower than 200 mmHg, longer CA time and transfusion more than 3000 ml are predictors of postoperative hypoxemia in Stanford A aortic dissection. PMID- 23631418 TI - Naked amoebae in biofilms collected from a temperate freshwater pond. AB - Biofilms collected on Plexiglass substrates, from a freshwater pond in northern New York State, were examined microscopically for naked amoebae densities, sizes, diversity, and estimated C-biomass. Five samples were obtained during summer 2006 and 2007. The densities ranged from 109 to 136/cm(2) biofilm surface and 285 to 550/mg biofilm dry weight. Sizes ranged from 13 to 200 MUm. Diversities ranged from 4.23 to 4.55. C-biomass ranged from 64 to 543 ng C/cm(2) and 125 to 1,700 MUg C/g dry weight. Thirty morphospecies were identified among the five samples, including very large amoebae in the range of 100-200 MUm. Large amoebae (>= 50 MUm) accounted for the largest proportion of the C-biomass. PMID- 23631419 TI - What pre-deployment and early post-deployment factors predict health function after combat deployment?: a prospective longitudinal study of Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) soldiers. AB - BACKGROUND: Physical and mental function are strong indicators of disability and mortality. OEF/OIF Veterans returning from deployment have been found to have poorer function than soldiers who have not deployed; however the reasons for this are unknown. METHODS: A prospective cohort of 790 soldiers was assessed both pre- and immediately after deployment to determine predictors of physical and mental function after war. RESULTS: On average, OEF/OIF Veterans showed significant declines in both physical (t=6.65, p<.0001) and mental function (t=7.11, p<.0001). After controlling for pre-deployment function, poorer physical function after deployment was associated with older age, more physical symptoms, blunted systolic blood pressure reactivity and being injured. After controlling for pre deployment function, poorer mental function after deployment was associated with younger age, lower social desirability, lower social support, greater physical symptoms and greater PTSD symptoms. CONCLUSIONS: Combat deployment was associated with an immediate decline in both mental and physical function. The relationship of combat deployment to function is complex and influenced by demographic, psychosocial, physiological and experiential factors. Social support and physical symptoms emerged as potentially modifiable factors. PMID- 23631420 TI - Synthesis of D-abrines by palladium-catalyzed reaction of ortho-iodoanilines with N-Boc-N-methylalanyl-substituted acetaldehyde and acetylene. AB - A novel strategy to N-Boc-N-methyl--tryptophans (abrine derivatives) was developed that relies on the palladium-catalyzed annulation of ortho-iodoanilines 12 with either N-Boc-N-methyl-propargylglycine 16 or aldehyde 11. Both 11 and 16 can be prepared from d-serine. An alternative route to propargylglycine 16 utilizes an enantioselective propargylation reaction of glycine imine 17. PMID- 23631421 TI - Arthroscopic proficiency: methods in evaluating competency. AB - BACKGROUND: The current paradigm of arthroscopic training lacks objective evaluation of technical ability and its adequacy is concerning given the accelerating complexity of the field. To combat insufficiencies, emphasis is shifting towards skill acquisition outside the operating room and sophisticated assessment tools. We reviewed (1) the validity of cadaver and surgical simulation in arthroscopic training, (2) the role of psychomotor analysis and arthroscopic technical ability, (3) what validated assessment tools are available to evaluate technical competency, and (4) the quantification of arthroscopic proficiency. METHODS: The Medline and Embase databases were searched for published articles in the English literature pertaining to arthroscopic competence, arthroscopic assessment and evaluation and objective measures of arthroscopic technical skill. Abstracts were independently evaluated and exclusion criteria included articles outside the scope of knee and shoulder arthroscopy as well as original articles about specific therapies, outcomes and diagnoses leaving 52 articles cited in this review. RESULTS: Simulated arthroscopic environments exhibit high levels of internal validity and consistency for simple arthroscopic tasks, however the ability to transfer complex skills to the operating room has not yet been established. Instrument and force trajectory data can discriminate between technical ability for basic arthroscopic parameters and may serve as useful adjuncts to more comprehensive techniques. There is a need for arthroscopic assessment tools for standardized evaluation and objective feedback of technical skills, yet few comprehensive instruments exist, especially for the shoulder. Opinion on the required arthroscopic experience to obtain proficiency remains guarded and few governing bodies specify absolute quantities. CONCLUSIONS: Further validation is required to demonstrate the transfer of complex arthroscopic skills from simulated environments to the operating room and provide objective parameters to base evaluation. There is a deficiency of validated assessment tools for technical competencies and little consensus of what constitutes a sufficient case volume within the arthroscopy community. PMID- 23631422 TI - Modified reactivity toward O2 in first shell variants of Fet3p: geometric and electronic structure requirements for a functioning trinuclear copper cluster. AB - Multicopper oxidases (MCOs) carry out the most energy efficient reduction of O2 to H2O known, i.e., with the lowest overpotential. This four-electron process requires an electron mediating type 1 (T1) Cu site and an oxygen reducing trinuclear Cu cluster (TNC), consisting of a binuclear type 3 (T3)- and a mononuclear type 2 (T2) Cu center. The rate-determining step in O2 reduction is the first two-electron transfer from one of the T3 Cu's (T3beta) and the T2 Cu, forming a bridged peroxide intermediate (PI). This reaction has been investigated in T3beta Cu variants of the Fet3p, where a first shell His ligand is mutated to Glu or Gln. This converts the fast two-electron reaction of the wild-type (WT) enzyme to a slow one-electron oxidation of the TNC. Both variants initially react to form a common T3beta Cu(II) intermediate that converts to the Glu or Gln bound resting state. From spectroscopic evaluation, the nonmutated His ligands coordinate linearly to the T3beta Cu in the reduced TNCs in the two variants, in contrast to the trigonal arrangement observed in the WT enzyme. This structural perturbation is found to significantly alter the electronic structure of the reduced TNC, which is no longer capable of rapidly transferring two electrons to the two perpendicular half occupied pi*-orbitals of O2, in contrast to the WT enzyme. This study provides new insight into the geometric and electronic structure requirements of a fully functional TNC for the rate determining two electron reduction of O2 in the MCOs. PMID- 23631423 TI - Incidence and management of elevated intraocular pressure with antivascular endothelial growth factor agents. AB - PURPOSE: To review recent literature regarding ocular hypertension following intravitreal antivascular endothelial growth factors (anti-VEGF). METHOD: An electronic literature search was performed using MEDLINE, OVID, and PubMed. Key search terms were elevated IOP, anti-VEGF, sustained IOP elevation in anti-VEGF, chronic intraocular pressure elevation in anti-VEGF, high IOP with anti-VEGF, acute elevation in intraocular pressure with anti-VEGF, glaucoma and anti-VEGF. RESULT: Transient elevation of intraocular pressure after intravitreal anti-VEGF injection is due to temporary increase in volume, and the acute spike generally does not affect a healthy eye. Caution should be taken in a glaucomatous eye, and pretreatment with an IOP-lowering medication is recommended. Persistent elevation of intraocular pressure is more common than previously thought and may be correlated to several factors including increased number of intravitreal injections. CONCLUSION: Persistent ocular hypertension may be associated with intravitreal anti-VEGF injections. Physicians should be aware of this condition and monitor their patients for persistent ocular hypertension, especially in eyes with preexisting glaucoma. Prompt diagnosis and treatment can prevent potential loss of vision. PMID- 23631424 TI - Clinical features of cluster headache: an outpatient clinic study from China. AB - OBJECTIVE: The aim of this study was to investigate the clinical characteristics of cluster headache (CH) in a neurology outpatient population in China. METHODS: A cross-sectional survey was conducted from June to December 2011 in a tertiary care, university-affiliated hospital. All consecutive patients citing headache as their chief complaint were asked to participate in a face-to-face interview with a qualified headache specialist and to complete a detailed self-administered questionnaire. The diagnosis of CH was made according to the International Classification of Headache Disorders, Second Edition (ICHD-II). RESULTS: Of the 1,526 headache patients screened, 26 were diagnosed with CH (6 women, 20 men). Mean age at onset was 27 +/- 8 years (range, 17-47), and 50% of patients were 20 30 years of age. Of the 26 CH patients, 61.5% reported that pain was usually centered at the right temporal region, and 69.2% characterized the pain as swelling. Attacks lasted 87 minutes on average and were associated with cranial autonomic symptoms (100%). A seasonal predilection was reported by 69.2% of CH patients. No patient reported significant changes in pain severity after physical activity. Tobacco use was common (14/26 patients), and alcohol was the most frequently cited trigger. CONCLUSIONS: This study details the clinical features of CH in a neurology outpatient population in China. Compared with Western studies, our patients were different in several aspects including the absence of chronic CH. PMID- 23631425 TI - The governing role of surface hydration in ion specific adsorption to silica: an AFM-based account of the Hofmeister universality and its reversal. AB - AFM measurements of the force acting between silica surfaces in the presence of varied alkali chloride salts and pH's elucidate the origin of the Hofmeister adsorption series and its reversal. At low pH, electrostatics is shown to be insignificant. The preferential adsorption of Cs(+) to the silica surface is traced to the weak hydration of neutral silanols and the resulting hydrophobic expulsion of weakly hydrated ions from bulk solution to the interface. The same interactions keep the strongly hydrated Na(+) and Li(+) in solution. As pH is increased, a tightly bound hydration layer forms on deprotonating silanols. Cs(+) is correspondingly expelled from the surface, and adsorption of small ions is encouraged. The deduced role of surface hydration is corroborated by hydration repulsion observed at high pH, surface overcharging at low pH, and data in other oxides. PMID- 23631426 TI - Self-referential processing in Alzheimer's disease: two different ways of processing self-knowledge? AB - Two previous studies showed that self-reference encoding had no effect on Alzheimer's disease (AD) patients' recollective experience when it was compared to other-reference encoding, whereas it did have an effect when it was compared to semantic processing, but only for emotional trait adjectives. In the present study, the performance of 22 AD patients was compared with that of 21 normal controls on a task involving recognition of emotional versus neutral adjective traits following self-reference versus other-reference encoding, using the remember/know/guess paradigm. Results showed that although AD patients had a positive explicit view of themselves, their self became salient for negative adjective traits only. We concluded that there might exist two ways of processing self-referential knowledge in human cognition: one explicit and the other more implicit. PMID- 23631427 TI - Dual targeting of adenosine A(2A) receptors and monoamine oxidase B by 4H-3,1 benzothiazin-4-ones. AB - Blockade of A2A adenosine receptors (A2AARs) and inhibition of monoamine oxidase B (MAO-B) in the brain are considered attractive strategies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD). In the present study, benzothiazinones, e.g., 2-(3-chlorophenoxy)-N-(4-oxo-4H-3,1-benzothiazin-2 yl)acetamide (13), were identified as a novel class of potent MAO-B inhibitors (IC50 human MAO-B: 1.63 nM). Benzothiazinones with large substituents in the 2 position, e.g., methoxycinnamoylamino, phenylbutyrylamino, or chlorobenzylpiperazinylbenzamido residues (14, 17, 27, and 28), showed high affinity and selectivity for A2AARs (Ki human A2AAR: 39.5-69.5 nM). By optimizing benzothiazinones for both targets, the first potent, dual-acting A2AAR/MAO-B inhibitors with a nonxanthine structure were developed. The best derivative was N (4-oxo-4H-3,1-benzothiazin-2-yl)-4-phenylbutanamide (17, Ki human A2A, 39.5 nM; IC50 human MAO-B, 34.9 nM; selective versus other AR subtypes and MAO-A), which inhibited A2AAR-induced cAMP accumulation and showed competitive, reversible MAO B inhibition. The new compounds may be useful tools for validating the A2AAR/MAO B dual target approach in PD. PMID- 23631428 TI - Structure-function paradigm in human myoglobin: how a single-residue substitution affects NO reactivity at low pO2. AB - This work is focused on the two more expressed human myoglobin isoforms. In the literature, their different overexpression in high-altitude natives was proposed to be related to alternative/complementary functions in hypoxia. Interestingly, they differ only at residue-54, lysine or glutamate, which is external and far from the main binding site. In order to ascertain whether these two almost identical myoglobins might exert different functions and to contribute to a deeper understanding about myoglobin's oxygen-level dependent functioning, they have been compared with respect to dynamics, heme electronic structure, and NO reactivity at different O2 levels. Electron paramagnetic resonance (EPR) spectroscopy was employed to investigate the electronic structure of the nitrosyl form, obtaining fundamental clues about a different bond interaction between the heme-iron and the proximal histidine and highlighting striking differences in NO reactivity, especially at a very low pO2. The experimental results well matched with the information provided by molecular dynamics simulations, which showed a significantly different dynamics for the two proteins only in the absence of O2. The single mutation differentiating the two myoglobins resulted in strongly affecting the plasticity of the CD-region (C-helix-loop-D-helix), whose fluctuations, being coupled to the solvent, were found to be correlated with the dynamics of the distal binding site. In the absence of O2, on the one hand a significantly different probability for the histidine-gate opening has been shown by MD simulations, and on the other a different yield of myoglobin-NO formation was experimentally observed through EPR. PMID- 23631429 TI - Association of GSTM1 and GSTT1 genes with the susceptibility to male infertility: result from a meta-analysis. AB - The deletion polymorphisms of the glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) genes were considered as candidates for genetic susceptibility factors of male infertility. Previous studies concerning the relationship between the null genotype of the two genes and male infertility have been reported in recent years. However, the results remain elusive. A meta analysis was performed to estimate the relationship between the deletion polymorphism of the GSTM1 or GSTT1 gene, and male infertility in this study. Sixteen studies concerning the GSTM1 gene, including 2174 cases and 1861 controls, and 13 case-control studies on the GSTT1 gene with a total number of 1992 cases and 1617 controls were processed. The results showed that the null genotype of the GSTM1 gene was associated with male infertility in the overall populations (P=0.003, OR=1.40, 95%CI=1.12-1.75), especially in Caucasian (P=0.012, OR=1.50, 95%CI=1.09-2.07) as well as Chinese (P=0.001, OR=1.55, 95%CI=1.19-2.03). The null genotype of the GSTT1 gene was strongly related to male infertility only in Chinese (P=0.000, OR=1.70, 95%CI=1.34-2.14). These results indicated that the null genotype of the GSTM1 gene might contribute to the susceptibility of male infertility, whereas the null genotype of the GSTT1 gene may be a genetic susceptibility factor of male infertility for the Chinese. PMID- 23631430 TI - Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. AB - AIM: Our aim was to examine the diagnostic yield of genetic testing in 855 consecutive unrelated cases referred for Long QT syndrome (LQTS). RESULTS: Eight hundred fifty five consecutive patients with a mean age at testing of 27.5+/-18.6 years, were referred for LQTS genetic testing and had accompanying clinical information. KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, CACNA1C, KCNJ2, CAV3, and SCN4B were analyzed using Next-Generation sequencing in all patients, and 395 patients were also tested for an additional two genes, AKAP9 and SNTA1. We retrospectively analyzed the diagnostic yield of this genetic test and factors that predicted the likelihood of a disease causing mutation using ANOVA, chi2, t test, and receiver operator curves. At least one mutation was identified in 30.3% of the patients (n=259), and 18 patients (2.1%) had two mutations. Patients with two mutations had a longer QTc interval (p<0.01) than patients with one mutation. A longer QTc duration and family history of LQTS were each associated with a higher yield of positive results on genetic testing (p<0.01 for each). Using a QTc cutoff of 476 msec or greater, the genetic testing had a sensitivity of 72% and a specificity of 49%. Mutations within the transmembrane domain of KCNQ1 were associated with a greater risk of cardiac arrest and syncope relative to mutations in other domains of the gene. Mutations in SCN5A were associated with a higher frequency of cardiac arrest (52.6%). CONCLUSION: Sequencing-based genetic testing has a sensitivity of 72% and has clinical utility. PMID- 23631431 TI - Association between the LCE3C_LCE3B deletion polymorphism and susceptibility to psoriasis: a meta-analysis of published studies. AB - OBJECTIVE: To determine whether a deletion comprising the LCE3C and LCE3B genes (LCE3C_LCE3B-del) confers susceptibility to psoriasis. METHODS: A meta-analysis was conducted to assess the association between the LCE3C_LCE3B-del polymorphism and psoriasis. RESULTS: A total of 12,196 patients with psoriasis and 13,092 controls from 19 comparative studies were included in this meta-analysis. The meta-analysis showed a significant association between psoriasis and the LCE3C_LCE3B-del allele (odds ratio [OR], 1.220; 95% confidence interval [CI], 1.152-1.292; p<1.0*10(-9)). Stratification by ethnicity indicated an association between the LCE3C_LCE3B-del allele and psoriasis in Europeans and Asians (OR, 1.213; 95% CI, 1.130-1.302; p=8.0*10(-9) and OR, 1.260; 95% CI, 1.135-1.398; p=1.4*10(-6), respectively). Analysis using a recessive model, dominant model, and homozygote contrast showed the same pattern for the LCE3C_LCE3B-del allele. The analysis performed in a single Tunisian study showed no association between the LCE3C_LCE3B-del allele and psoriasis. Meta-analysis of the LCE3C_LCE3B-del allele showed no association between psoriatic arthritis and the LCE3C_LCE3B-del polymorphism (OR, 1.087; 95% CI, 0.870-1.359; p=0.464). CONCLUSION: Our meta analysis demonstrates a significant association between psoriasis and the LCE3C_LCE3B-del polymorphism in Europeans and Asians, but no association with psoriatic arthritis. PMID- 23631433 TI - Process optimization of ultrasonic spray coating of polymer films. AB - In this work we have performed a detailed study of the influence of various parameters on spray coating of polymer films. Our aim is to produce polymer films of uniform thickness (500 nm to 1 MUm) and low roughness compared to the film thickness. The coatings are characterized with respect to thickness, roughness (profilometer), and morphology (optical microscopy). Polyvinylpyrrolidone (PVP) is used to do a full factorial design of experiments with selected process parameters such as temperature, distance between spray nozzle and substrate, and speed of the spray nozzle. A mathematical model is developed for statistical analysis which identifies the distance between nozzle and substrate as the most significant parameter. Depending on the drying of the sprayed droplets on the substrate, we define two broad regimes, "dry" and "wet". The optimum condition of spraying lies in a narrow window between these two regimes, where we obtain a film of desired quality. Both with increasing nozzle-substrate distance and temperature, the deposition moves from a wet state to a dry regime. Similar results are also achieved for solvents with low boiling points. Finally, we study film formation during spray coating with poly (D,L-lactide) (PDLLA). The results confirm the processing knowledge obtained with PVP and indicate that the observed trends are identical for spraying of other polymer films. PMID- 23631432 TI - Quantification of cellular poly(ADP-ribosyl)ation by stable isotope dilution mass spectrometry reveals tissue- and drug-dependent stress response dynamics. AB - Poly(ADP-ribosyl)ation is an essential post-translational modification with the biopolymer poly(ADP-ribose) (PAR). The reaction is catalyzed by poly(ADP-ribose) polymerases (PARPs) and plays key roles in cellular physiology and stress response. PARP inhibitors are currently being tested in clinical cancer treatment, in combination therapy, or as monotherapeutic agents by inducing synthetic lethality. We have developed an accurate and sensitive bioanalytical platform based on isotope dilution mass spectrometry in order to quantify steady state and stress-induced PAR levels in cells and tissues and to characterize pharmacological properties of PARP inhibitors. In contrast to existing PAR detection techniques, the LC-MS/MS method uses authentic isotope-labeled standards, which provide unequivocal chemical specificity to quantify cellular PAR in absolute terms with femtomol sensitivity. Using this platform we analyzed steady-state levels as well as stress-induced dynamics of poly(ADP-ribosyl)ation in a series of biological systems including cancer cell lines, mouse tissues, and primary human lymphocytes. Our results demonstrate a rapid and transient stress induced increase in PAR levels by >100-fold in a dose- and time-dependent manner with significant differences between cell types and individual human lymphocyte donors. Furthermore, ex vivo pharmacodynamic studies in human lymphocytes provide new insight into pharmacological properties of clinically relevant PARP inhibitors. Finally, we adapted the LC-MS/MS method to quantify poly(ADP ribosyl)ation in solid tissues and identified tissue-dependent associations between PARP1 expression and PAR levels in a series of different mouse organs. In conclusion, this study demonstrates that mass spectrometric quantification of cellular poly(ADP-ribosyl)ation has a wide range of applications in basic research as well as in drug development. PMID- 23631434 TI - Fabrication of highly crystalline SnNb2O6 shell with a visible-light response on a NaNbO3 nanowire core. AB - A visible-light-absorbing SnNb2O6 shell with high crystallinity was successfully fabricated on a NaNbO3 nanowire through a molten salt treatment of the NaNbO3 nanowire of the starting material with SnCl2, whereas the fabrication was not successful on the TT phase of a niobia nanowire. The difference will come from the formation processes of SnNb2O6 crystals (ion-exchange reaction vs thermally induced crystallization reaction). The core/shell nanowire obtained from NaNbO3 showed photocatalytic activity comparable to that of H2 evolution in the presence of an electron donor under visible-light irradiation (lambda > 420 nm), compared with the corresponding bulky counterpart. PMID- 23631435 TI - Non-invasive prenatal diagnosis for single gene disorders: experience of patients. AB - The aim of this study is to explore women's experiences of using newly developed non-invasive prenatal diagnosis (NIPD) for single gene disorders. Methods used in this study include qualitative one-to-one interviews with eight women with pregnancies at risk of achondroplasia, Apert syndrome, thanatophoric dysplasia or a neuromuscular condition. The results of the study show that the women were positive about an accurate, safe, and early test. Where the foetus was at increased risk of inheriting a genetic condition, the benefits of NIPD over invasive testing were that it reduced the period of uncertainty and worry by being conducted within the first trimester. For those women for whom there was a low recurrence risk, the period of uncertainty could be reduced and pregnancy 'normalized' earlier. For women who would not have risked invasive testing, NIPD enabled them to have an early diagnostic test that was more accurate than ultrasound. Where ultrasound abnormalities were detected, NIPD ended the 'diagnostic odyssey', enabling women to make practical and psychological preparations for the birth. NIPD conducted through specialist services was considered most appropriate. NIPD for these particular single gene disorders was appreciated by women and appears to be satisfactory. Further exploration of stakeholder views may be required to inform more widespread implementation of NIPD for a broader range of genetic conditions. PMID- 23631436 TI - Acetate induced enhancement of photocatalytic hydrogen peroxide production from oxalic acid and dioxygen. AB - The addition of acetate ion to an O2-saturated mixed solution of acetonitrile and water containing oxalic acid as a reductant and 2-phenyl-4-(1 naphthyl)quinolinium ion (QuPh(+)-NA) as a photocatalyst dramatically enhanced the turnover number of hydrogen peroxide (H2O2) production. In this photocatalytic H2O2 production, a base is required to facilitate deprotonation of oxalic acid forming oxalate dianion, which acts as an actual electron donor, whereas a Bronsted acid is also necessary to protonate O2(*-) for production of H2O2 by disproportionation. The addition of acetate ion to a reaction solution facilitates both the deprotonation of oxalic acid and the protonation of O2(*-) owing to a pH buffer effect. The quantum yield of the photocatalytic H2O2 production under photoirradiation (lambda = 334 nm) of an O2-saturated acetonitrile-water mixed solution containing acetate ion, oxalic acid and QuPh(+) NA was determined to be as high as 0.34, which is more than double the quantum yield obtained by using oxalate salt as an electron donor without acetate ion (0.14). In addition, the turnover number of QuPh(+)-NA reached more than 340. The reaction mechanism and the effect of solvent composition on the photocatalytic H2O2 production were scrutinized by using nanosecond laser flash photolysis. PMID- 23631438 TI - Pushing the perialar: a modified perialar crescentic advancement flap for the reconstruction of large nasal sidewall defects. PMID- 23631437 TI - Evidence for extensive heterotrophic metabolism, antioxidant action, and associated regulatory events during winter hardening in Sitka spruce. AB - BACKGROUND: Cold acclimation in woody perennials is a metabolically intensive process, but coincides with environmental conditions that are not conducive to the generation of energy through photosynthesis. While the negative effects of low temperatures on the photosynthetic apparatus during winter have been well studied, less is known about how this is reflected at the level of gene and metabolite expression, nor how the plant generates primary metabolites needed for adaptive processes during autumn. RESULTS: The MapMan tool revealed enrichment of the expression of genes related to mitochondrial function, antioxidant and associated regulatory activity, while changes in metabolite levels over the time course were consistent with the gene expression patterns observed. Genes related to thylakoid function were down-regulated as expected, with the exception of plastid targeted specific antioxidant gene products such as thylakoid-bound ascorbate peroxidase, components of the reactive oxygen species scavenging cycle, and the plastid terminal oxidase. In contrast, the conventional and alternative mitochondrial electron transport chains, the tricarboxylic acid cycle, and redox associated proteins providing reactive oxygen species scavenging generated by electron transport chains functioning at low temperatures were all active. CONCLUSIONS: A regulatory mechanism linking thylakoid-bound ascorbate peroxidase action with "chloroplast dormancy" is proposed. Most importantly, the energy and substrates required for the substantial metabolic remodeling that is a hallmark of freezing acclimation could be provided by heterotrophic metabolism. PMID- 23631439 TI - Catch and release: integrated system for multiplexed detection of bacteria. AB - An integrated system with automated immunomagnetic separation and processing of fluidic samples was demonstrated for multiplexed optical detection of bacterial targets. Mixtures of target-specific magnetic bead sets were processed in the NRL MagTrap with the aid of rotating magnet arrays that entrapped and moved the beads within the channel during reagent processing. Processing was performed in buffer and human serum matrixes with 10-fold dilutions in the range of 10(2)-10(6) cells/mL of target bacteria. Reversal of magnets' rotation post-processing released the beads back into the flow and moved them into the microflow cytometer for optical interrogation. Identification of the beads and the detection of PE fluorescence were performed simultaneously for multiplexed detection. Multiplexing was performed with specifically targeted bead sets to detect E. coli 0157.H7, Salmonella Common Structural Antigen, Listeria sp., and Shigella sp., dose-response curves were obtained, and limits of detection were calculated for each target in the buffer and clinical matrix. Additional tests demonstrated the potential for using the MagTrap to concentrate target from larger volumes of sample prior to the addition of assay reagents. PMID- 23631440 TI - Matrix metalloproteinase inhibitors based on the 3-mercaptopyrrolidine core. AB - New series of pyrrolidine mercaptosulfide, 2-mercaptocyclopentane arylsulfonamide, and 3-mercapto-4-arylsulfonamidopyrrolidine matrix metalloproteinase inhibitors (MMPIs) were designed, synthesized, and evaluated. Exhibiting unique properties over other MMPIs (e.g., hydroxamates), these newly reported compounds are capable of modulating activities of several MMPs in the low nanomolar range, including MMP-2 (~2 to 50 nM), MMP-13 (~2 to 50 nM), and MMP 14 (~4 to 60 nM). Additionally these compounds are selective to intermediate- and deep-pocket MMPs but not shallow-pocketed MMPs (e.g., MMP-1, ~850 to >50,000 nM; MMP-7, ~4000 to >25,000 nM). Our previous work with the mercaptosulfide functionality attached to both cyclopentane and pyrrolidine frameworks demonstrated that the cis-(3S,4R)-stereochemistry was optimal for all of the MMPs tested. However, in our newest compounds an interesting shift of preference to the trans form of the mercaptosulfonamides was observed with increased oxidative stability and biological compatibility. We also report several kinetic and biological characteristics showing that these compounds may be used to probe the mechanistic activities of MMPs in disease. PMID- 23631441 TI - The alphaA66-80 peptide interacts with soluble alpha-crystallin and induces its aggregation and precipitation: a contribution to age-related cataract formation. AB - Formation of protein aggregates in the aging eye lens has been shown to correlate with progressive accumulation of specific low-molecular weight (LMW) peptides derived from crystallins. Prominent among the LMW fragments is alphaA66-80, a peptide derived from alphaA-crystallin and present at higher concentrations in the water-insoluble nuclear fractions of the aging lens. The alphaA66-80 peptide has amyloid-like properties and preferentially insolubilizes alpha-crystallin from soluble lens fractions. However, the specific interactions and mechanisms by which the peptide induces alpha-crystallin aggregation have not been delineated. To gain insight into the mechanisms of peptide-induced aggregation, we investigated the interactions of the peptide with alpha-crystallin by various biochemical approaches. The peptide weakens alpha-crystallin chaperone ability and drastically promotes alpha-crystallin aggregation via the formation of insoluble peptide-protein complexes through transient intermediates. 4,4' Dianilino-1,1'-binaphthyl-5,5'-disulfonic acid studies suggest that the peptide induces changes in the hydrophobicity of alpha-crystallin that could trigger the formation and growth of aggregates. The peptide-alpha-crystallin aggregates were found to be resistant to dissociation by high ionic strengths, whereas guanidinium hydrochloride and urea were effective dissociating agents. We conclude that the alphaA66-80 peptide forms a hydrophobically driven, stable complex with alpha-crystallin and reduces its solubility. Using isotope-labeled chemical cross-linking and mass spectrometry, we show that the peptide binds to multiple sites, including the chaperone site, the C-terminal extension, and subunit interaction sites in alphaB-crystallin, which may explain the antichaperone property of the peptide and the consequential age-related accumulation of aggregated proteins. Thus, the alpha-crystallin-derived peptide could play a role in the pathogenesis of cataract formation in the aging lens. PMID- 23631442 TI - Health literacy and women's health: challenges and opportunities. AB - INTRODUCTION: This article describes the impact of health literacy on women's health and provides strategies for addressing this public health issue. METHODS: A comprehensive literature review was conducted of peer-reviewed journals. Multiple electronic databases were used, including CINAHL, MEDLINE, PubMed, and Google Scholar. Key words were used to identify articles and were combined to include health literacy, health behavior, women's health, patient education, and professional role. Additional articles were identified as a result of reviewing reference lists found during the electronic search. RESULTS: Health literacy is a complex issue that affects many women and can adversely affect women's knowledge, ability to adhere to clinical plans of care, and health outcomes for women and their children. It is estimated that 36% of adults in the United States possess limited health literacy skills. Effective strategies can be used by health care providers to address this serious problem, including clear and effective communication, development of health education materials, professional education, and development of community partnerships. DISCUSSION: Health literacy is a serious problem. Effective approaches can be employed to blunt the adverse effect on women's health. Health care providers are well positioned to demonstrate leadership within the health care system regarding health literacy. PMID- 23631443 TI - Safety, pharmacokinetics and pharmacodynamics of remogliflozin etabonate, a novel SGLT2 inhibitor, and metformin when co-administered in subjects with type 2 diabetes mellitus. AB - BACKGROUND: The sodium-dependent glucose co-transporter-2 (SGLT2) is expressed in absorptive epithelia of the renal tubules. Remogliflozin etabonate (RE) is the prodrug of remogliflozin, the active entity that inhibits SGLT2. An inhibitor of this pathway would enhance urinary glucose excretion (UGE), and potentially improve plasma glucose concentrations in diabetic patients. RE is intended for use for the treatment of type 2 diabetes mellitus (T2DM) as monotherapy and in combination with existing therapies. Metformin, a dimethylbiguanide, is an effective oral antihyperglycemic agent widely used for the treatment of T2DM. METHODS: This was a randomized, open-label, repeat-dose, two-sequence, cross-over study in 13 subjects with T2DM. Subjects were randomized to one of two treatment sequences in which they received either metformin alone, RE alone, or both over three, 3-day treatment periods separated by two non-treatment intervals of variable duration. On the evening before each treatment period, subjects were admitted and confined to the clinical site for the duration of the 3-day treatment period. Pharmacokinetic, pharmacodynamic (urine glucose and fasting plasma glucose), and safety (adverse events, vital signs, ECG, clinical laboratory parameters including lactic acid) assessments were performed at check in and throughout the treatment periods. Pharmacokinetic sampling occurred on Day 3 of each treatment period. RESULTS: This study demonstrated the lack of effect of RE on steady state metformin pharmacokinetics. Metformin did not affect the AUC of RE, remogliflozin, or its active metabolite, GSK279782, although Cmax values were slightly lower for remogliflozin and its metabolite after co administration with metformin compared with administration of RE alone. Metformin did not alter the pharmacodynamic effects (UGE) of RE. Concomitant administration of metformin and RE was well tolerated with minimal hypoglycemia, no serious adverse events, and no increase in lactic acid. CONCLUSIONS: Coadministration of metformin and RE was well tolerated in this study. The results support continued development of RE as a treatment for T2DM. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00376038. PMID- 23631444 TI - The South Asian culture and palliative care for children, young people, and families--a discussion paper. AB - A fundamental element of quality healthcare is that provision is accessible to all users and culturally sensitive to them. However, there is evidence to suggest that there is inequity of provision across all cultures. Furthermore, there is a paucity of published research in the United Kingdom concerning palliative care for minority ethnic families with a life-threatened or life-limited child or young person. The article sets out to discuss the findings of a literature review and, drawing on current work by the Centre for Children and Families Applied Research at Coventry University under the leadership of Professor Jane Coad, to explore the interface between South Asian cultures and the experience of palliative care services of children, young peoples, and families. All families require a broad range of services which are appropriately delivered and accessible throughout the trajectory of their child's illness. The literature review findings reveal that how families understand concepts such as health and disease arise from the complex interaction between personal experience and cultural lifestyle including language, family values, and faith. There is an urgent need to involve South Asian families in research in order to provide a robust evidence-base on which to develop service provision so that care is matched to the unique needs of individuals concerned. PMID- 23631446 TI - Clinicopathological study of glomerular diseases associated with sarcoidosis: a multicenter study. AB - BACKGROUND: The association between sarcoidosis and glomerular diseases has not been extensively investigated in a large series and the potential features of this uncommon association remain to be determined. METHODS: We retrospectively identified 26 patients with biopsy-proven glomerular lesions that occurred in a sarcoidosis context. Potential remission of glomerular disease and sarcoidosis under specific treatment (steroid and/or immunosuppressive agents) was recorded for all patients. Demographic, clinical and biological characteristics were assessed at the time of kidney biopsy for each patient. Therapeutic data were analyzed for all patients. RESULTS: Glomerular disease occurred after the diagnosis of sarcoidosis in 11 of 26 cases (42%) (mean delay of 9.7 years). In six patients (23%), the glomerulopathy preceded the sarcoidosis diagnosis (mean delay 8 years). In the last nine patients (35%), both conditions occurred simultaneously. The most frequent glomerular disease occurring in sarcoidosis patients was membranous nephropathy in eleven cases. Other glomerular lesions included IgA nephropathy in six cases, focal segmental glomerulosclerosis in four patients, minimal change nephrotic syndrome for three patients and proliferative lupus nephritis in two patients. Granulomatous interstitial nephritis was associated with glomerular disease in six patients and was exclusively found in patients in whom the both disease occurred simultaneously. In nine patients with simultaneous glomerular and sarcoidosis diseases, we observed a strong dissociation between glomerular disease and sarcoidosis in terms of steroid responsiveness. At the end of the follow-up (mean of 8.4 years), six patients had reached end-stage renal disease and three patients had died. CONCLUSIONS: A wide spectrum of glomerular lesions is associated with sarcoidosis. The close temporal relationship observed in some patients suggests common causative molecular mechanisms of glomerular injury but complete remission of both diseases in response to exclusive steroid therapy is infrequent. PMID- 23631447 TI - Evaluating performance of a Lead Road Safety Agency (LRSA) in a low-income country: a case study from Pakistan. AB - The World Health Organization recommends identifying a Lead Road Safety Agency (LRSA) within the government to coordinate preventive interventions. As LRSAs in developing countries have rarely been evaluated, this case study describes the performance of the LRSA of Pakistan with respect to the World Bank criteria. The designated LRSA, the National Road Safety Secretariat, was put into operation in 2006 and worked for about two years with World Bank funding. The agency had a stand-alone structure headed by an experienced road safety specialist during the first year only and faced difficulty in recruiting other required experts. The LRSA drafted the first National Road Safety Plan, including strategic review of road safety and existing legislation, articulated multisectorial collaboration nationally and provincially, and collected traffic injury data in some districts. Its progress was halted by its dissolution because of funding problems. Currently, two agencies specialising in traffic enforcement and transport research respectively are fulfilling LRSA functions on an ad-hoc basis. Results suggest that sustainability and consistency of LRSAs in developing countries like Pakistan may only be ensured if they are legally protected, inter-ministerial, have permanent funding and are provided with the required expertise through international cooperation, so they can perform their required functions effectively. PMID- 23631445 TI - Bariatric surgery for obese children and adolescents: a review of the moral challenges. AB - BACKGROUND: Bariatric surgery for children and adolescents is becoming widespread. However, the evidence is still scarce and of poor quality, and many of the patients are too young to consent. This poses a series of moral challenges, which have to be addressed both when considering bariatric surgery introduced as a health care service and when deciding for treatment for young individuals. A question based (Socratic) approach is applied to reveal underlying moral issues that can be relevant to an open and transparent decision making process. DISCUSSION: A wide range of moral issues with bariatric surgery for children and adolescents is identified in the literature. There is a moral imperative to help obese minors avoiding serious health problems, but there is little high quality evidence on safety, outcomes, and cost-effectiveness for bariatric surgery in this group. Lack of maturity and family relations poses a series of challenges with autonomy, informed consent, assent, and assessing the best interest of children and adolescents. Social aspects of obesity, such as medicalization, prejudice, and discrimination, raise problems with justice and trust in health professionals. Conceptual issues, such as definition of obesity and treatment end-points, present moral problems. Hidden interests of patients, parents, professionals, industry, and society need to be revealed. SUMMARY: Performing bariatric surgery for obese children and adolescents in order to discipline their behavior warrants reflection and caution. More evidence on outcomes is needed to be able to balance benefits and risks, to provide information for a valid consent or assent, and to advise minors and parents. PMID- 23631448 TI - Catalytic, asymmetric indolizidinone aza-quaternary stereocenter synthesis: expedient synthesis of the cylindricine alkaloid core. AB - The Rh(I)*CKphos catalyzed [2 + 2 + 2] cycloaddition of 1,1-disubstituted alkenyl isocyanates and alkyl alkynes selectively forms previously inaccessible vinylogous amide indolizidinone cycloadducts, establishing an aza-quaternery stereocenter with excellent enantioselectivities (up to 98% ee). This advance enables a seven step catalytic, asymmetric synthesis of the tricyclic core of the cylindricine alkaloids with excellent control of product selectivity as well as regio- and enantioselectivity. PMID- 23631450 TI - Analysis of competition between transformation pathways in the functioning of biotic abstract dual automata. AB - Properties of avenues of transformation and their mutualism with forms of organization in dynamic systems are essential for understanding the evolution of prebiotic order. We have analyzed competition between two avenues of transformation in an A<->B system, using the simulation approach called BiADA (Biotic Abstract Dual Automata). We discuss means of avoiding common pitfalls of abstract system modeling and benefits of BiADA-based simulations. We describe the effect of the availability of free energy, energy sink magnitude, and autocatalysis on the evolution of energy flux and order in the system. Results indicate that prebiotic competition between avenues of transformation was more stringent in energy-limited environments. We predict that in such conditions the efficiency of autocatalysis during competition between alternative system states will increase for systems with forms of organization having short half-lives and thus information that is time-sensitive to energy starvation. Our results also offer a potential solution to Manfred Eigen's error catastrophe dilemma. In the conditions discussed above, the exponential growth of quasi species is curbed through the removal of less competitive "genetic" variants via energy starvation. We propose that one of the most important achievements (and selective edges) of a dynamic network during competition in energy-limited or energy-variable environments was the capacity to correlate the internal energy flux and the need for free energy with the availability of free energy in the environment. PMID- 23631449 TI - Peptide crystal simulations reveal hidden dynamics. AB - Molecular dynamics simulations of biomolecular crystals at atomic resolution have the potential to recover information on dynamics and heterogeneity hidden in X ray diffraction data. We present here 9.6 MUs of dynamics in a small helical peptide crystal with 36 independent copies of the unit cell. The average simulation structure agrees with experiment to within 0.28 A backbone and 0.42 A all-atom RMSD; a model refined against the average simulation density agrees with the experimental structure to within 0.20 A backbone and 0.33 A all-atom RMSD. The R-factor between the experimental structure factors and those derived from this unrestrained simulation is 23% to 1.0 A resolution. The B-factors for most heavy atoms agree well with experiment (Pearson correlation of 0.90), but B factors obtained by refinement against the average simulation density underestimate the coordinate fluctuations in the underlying simulation where the simulation samples alternate conformations. A dynamic flow of water molecules through channels within the crystal lattice is observed, yet the average water density is in remarkable agreement with experiment. A minor population of unit cells is characterized by reduced water content, 310 helical propensity and a gauche(-) side-chain rotamer for one of the valine residues. Careful examination of the experimental data suggests that transitions of the helices are a simulation artifact, although there is indeed evidence for alternate valine conformers and variable water content. This study highlights the potential for crystal simulations to detect dynamics and heterogeneity in experimental diffraction data as well as to validate computational chemistry methods. PMID- 23631451 TI - Campus food and beverage purchases are associated with indicators of diet quality in college students living off campus. AB - PURPOSE: To examine the association between college students' dietary patterns and frequency of purchasing food/beverages from campus area venues, purchasing fast food, and bringing food from home. DESIGN: Cross-sectional Student Health and Wellness Study. SETTING: One community college and one public university in the Twin Cities, Minnesota. SUBJECTS: Diverse college students living off campus (n = 1059; 59% nonwhite; mean [SD] age, 22 [5] years). MEASURES: Participants self-reported sociodemographic characteristics and frequency of purchasing food/beverages around campus, purchasing fast food, and bringing food from home. Campus area purchases included a la carte facilities, vending machines, beverages, and nearby restaurants/stores. Dietary outcomes included breakfast and evening meal consumption (d/wk) and summary variables of fruit and vegetable, dairy, calcium, fiber, added sugar, and fat intake calculated from food frequency screeners. ANALYSIS: The associations between each purchasing behavior and dietary outcomes were examined using t-tests and linear regression. RESULTS: Approximately 45% of students purchased food/beverages from at least one campus area venue >=3 times per week. Frequent food/beverage purchasing around campus was associated with less frequent breakfast consumption and higher fat and added sugar intake, similar to fast-food purchasing. Bringing food from home was associated with healthier dietary patterns. CONCLUSION: Increasing the healthfulness of campus food environments and promoting healthy food and beverage purchasing around campuses may be an important target for nutrition promotion among college students. PMID- 23631453 TI - Workplace physical activity interventions: a systematic review. AB - OBJECTIVE: To assess the effectiveness of workplace interventions in improving physical activity. DATA SOURCE: EBSCO research database (and all subdatabases). STUDY INCLUSION AND EXCLUSION CRITERIA: Articles were published from 2000 to 2010 in English, had appropriate designs, and measured employees' physical activity, energy consumption, and/or body mass index (BMI) as primary outcomes. Articles that did not meet the inclusion criteria were excluded. DATA EXTRACTION: Data extracted included study design, study population, duration, intervention activities, outcomes, and results. DATA SYNTHESIS: Data were synthesized into one table. Results of each relevant outcome including p values were combined. RESULTS: Twelve (60%) of 20 selected interventions reported an improvement in physical activity level, steps, or BMI, and there was one slowed step reduction in the intervention group. Among these, 10 were less than 6 months in duration; 9 used pedometers; 6 applied Internet-based approaches; and 5 included activities targeting social and environmental levels. Seven of 8 interventions with pre posttest and quasi-experimental controlled design showed improvement on at least one outcome. However, 7 of 12 randomized controlled trials (RCTs) did not prove effective in any outcome. CONCLUSION: Interventions that had less rigorous research designs, used pedometers, applied Internet-based approaches, and included activities at social and environmental levels were more likely to report being effective than those without these characteristics. PMID- 23631452 TI - Associations between neighborhood amenity density and health indicators among rural and urban youth. AB - PURPOSE: To examine associations between the built/social environment (neighborhood amenity density, crime) and health indicators (body mass index [BMI] percentile, cardiovascular fitness, and time spent in moderate to vigorous physical activity [MVPA]) among rural and urban youth. DESIGN: Cross-sectional. SETTING: Eastern North Carolina. SUBJECTS: Youth (n = 296) were recruited from three middle schools. MEASURES: Neighborhood density was estimated using Walk Score. Crime was assessed using Regional Analysis and Information Sharing online. BMI percentiles were calculated from measured height and weight. Cardiovascular fitness was estimated using heart rate measured at the conclusion of a 3-minute step test. Time spent in MVPA was measured objectively via accelerometer. ANALYSIS: Bivariate and multivariate statistics were used to examine associations between Walk Score, crime, BMI percentile, cardiovascular fitness (as measured via heart rate), and MVPA. RESULTS: Walk Score was positively correlated with crime. There were positive, statistically significant associations between Walk Score and (1) BMI percentile (p = .0223) and (2) heart rate (p = .0044), and (3) inverse associations between Walk Score and MVPA (p = .0042), indicating that high neighborhood density was associated with greater BMI percentiles, lower fitness, and less MVPA among urban youth. CONCLUSION: These counterintuitive findings may be due to the negative effect of crime on health indicators, which may outweigh potential positive health impacts of high neighborhood amenity density. PMID- 23631454 TI - What do veterans service organizations' web sites say about tobacco control? AB - PURPOSE: Little is known about veterans service organizations (VSOs) and their perspectives on veterans smoking or military tobacco control. Veterans have high smoking rates and many started smoking in the military, where a culture promoting use exists. DESIGN: A qualitative content analysis of VSO Web sites was conducted to classify health topics and identify tobacco-related information. SETTING: Web sites were coded by trained raters from January to June of 2011. Data were entered, cleaned, and analyzed from July 2011 to January 2012. SUBJECTS: Twenty four active VSO Web sites meeting inclusion criteria were rated independently. MEASURES: A comprehensive form was used to code 15 veteran-relevant health topics across multiple content areas/domains within the Web sites. Raters achieved 94.5% interrater agreement over nearly 5000 data points. ANALYSIS: Health content was coded as present or not within multiple VSO Web site areas/domains. The frequency of coverage by each VSO Web site and the number of VSO Web sites that mentioned a health topic in different Web site areas/domains were tabulated. RESULTS: A total of 277 health topics were addressed, with the top five being insurance/Tricare/Veterans Administration issues (28.2%), posttraumatic stress disorder (PTSD; 15.5%), disability/amputation/wounds (13.4%), Agent Orange (10.5%), and traumatic brain injury (9.0%). Tobacco was mentioned four times (1.4%) across all 24 VSO Web sites, and smoking cessation was never addressed. CONCLUSION: VSO Web sites provide little information on tobacco-related topics and none offered information about smoking cessation. Given the high rates of tobacco use among veterans and active-duty service members, and the interaction between smoking and PTSD symptoms and treatment outcomes, VSOs should consider making tobacco control and smoking cessation higher-priority health issues on their Web sites. PMID- 23631455 TI - HCV Envelope protein 2 sequence comparison of Pakistani isolate and In-silico prediction of conserved epitopes for vaccine development. AB - BACKGROUND: HCV is causing hundreds of cases yearly in Pakistan and has become a threat for Pakistani population. HCV E2 protein is a transmembrane protein involved in viral attachment and thus can serve as an important target for vaccine development but because of its variability, vaccine development against it has become a challenge. Therefore, this study was designed to isolate the HCV E2 gene from Pakistani HCV infected patients of 3a genotype, to perform In-silico analysis of HCV E2 isolated in Pakistan and to analyze HCV E2 protein sequence in comparison with other E2 proteins belonging to 3a and 1a genotypes to find potential conserved B-cells and T-cell epitopes that can be important in designing novel inhibitory compounds and peptide vaccine against genotype 3a and 1a. PATIENTS AND METHODS: Patients were selected on the basis of elevated serum ALT and AST levels at least for six months, histological examination, and detection of serum HCV RNA anti-HCV antibodies (3rd generation ELISA). RNA isolation, cDNA synthesis, amplification, cloning and sequencing was performed from 4 patient's serum samples in order to get the HCV E2 sequence. HCV E2 protein of Pakistani origin was analyzed using various bioinformatics tools including sequence and structure tools. RESULTS: HCV E1 protein modeling was performed with I-TASSER online server and quality of the model was assessed with ramchandran plot and Z-score. A total of 3 B-cell and 3 T-cell epitopes were found to be highly conserved among HCV 3a and 1a genotype. CONCLUSION: The present study revealed potential conserved B-cell and T-cell epitopes of the HCV E2 protein along with 3D protein modeling. These conserved B-cell and T-cell epitopes can be helpful in developing effective vaccines against HCV and thus limiting threats of HCV infection in Pakistan. PMID- 23631456 TI - Faked headaches becoming real. AB - In the gangster movie White Heat, the main character, Cody (played by James Cagney), suffers from 2 headache attacks. Here, I analyze these attacks by using the International Headache Society criteria, but an unequivocal diagnosis is not possible. Nevertheless, the attacks play an important role in the narrative and- as representation of something between "real" (mimesis) and not real--provide a ground for reflection on how to think of headache in general. PMID- 23631457 TI - Re and Br X-ray absorption near-edge structure study of the ground and excited states of [ReBr(CO)3(bpy)] interpreted by DFT and TD-DFT calculations. AB - X-ray absorption spectra of fac-[ReBr(CO)3(bpy)] near the Re L3- and Br K-edges were measured in a steady-state mode as well as time-resolved at 630 ps after 355 nm laser pulse excitation. Relativistic spin-orbit time-dependent density functional theory (TD-DFT) calculations account well for the shape of the near edge absorption (the "white line") of the ground-state Re spectrum, assigning the lowest-lying transitions as core-to-ligand metal-to-ligand charge transfer from Re 2p(3/2) into predominantly pi*(bpy) molecular orbitals (MOs) containing small 5d contributions, followed in energy by transitions into pi* Re(CO)3 and delocalized sigma*/pi* MOs. Transitions gain their intensities from Re 5d and 6s participation in the target orbitals. The 5d character is distributed over many unoccupied MOs; the 5d contribution to any single empty MO does not exceed 29%. The Br K-edge spectrum is dominated by the ionization edge and multiple scattering features, the pre-edge electronic transitions being very weak. Time resolved spectra measured upon formation of the lowest electronic excited state show changes characteristic of simultaneous Re and Br electronic depopulation: shifts of the Re and Br edges and the Re white line to higher energies and emergence of new intense pre-edge features that are attributed by TD-DFT to transitions from Re 2p(3/2) and Br 1s orbitals into a vacancy in the HOMO-1 created by electronic excitation. Experimental spectra together with quantum chemical calculations provide a direct evidence for a ReBr(CO)3 -> bpy delocalized charge transfer character of the lowest excited state. Steady-state as well as time-resolved Re L3 spectra of [ReCl(CO)3(bpy)] and [Re(Etpy)(CO)3(bpy)](+) are very similar to those of the Br complex, in agreement with similar (TD) DFT calculated transition energies as well as delocalized excited-state spin densities and charge changes upon excitation. PMID- 23631458 TI - An alternative approach to reconstruction of the lateral nose. PMID- 23631459 TI - Effect of osmotic stress on membrane fusion on solid substrate. AB - There is currently a lack of comprehensive understanding of osmotic effect on lipid vesicle fusion on solid oxide surface. The question has both biological and biomedical implications. We studied the effect by quartz crystal microbalance with dissipation monitoring using NaCl, sucrose as osmolytes, and two different osmotic stress imposition methods, which allowed us to separate the osmotic effects from the solute impacts. Osmotic stress was found to have limited influence on the fusion kinetics, independently of the direction of the gradient. Further atomic force microscopy experiments and energy consideration implied that osmotic stress spends the majority of chemical potential energy associated in directed transport of water across membrane. Its contribution to vesicle deformation and fusion on substrate is therefore small compared to that of adhesion. PMID- 23631460 TI - Sodium nitroprusside is not associated with metabolic acidosis during intraoperative infusion in children. AB - BACKGROUND: Sodium nitroprusside (SNP) is a potent vasodilator that has been used to induce deliberate hypotension in children during surgery involving significant blood loss, including craniofacial and spinal fusion procedures. SNP metabolism liberates cyanide, which may cause interference with cellular energy metabolism, leading to metabolic acidosis and central nervous system injury. We performed a retrospective, case-control study to determine whether the short-term intra operative use of SNP for deliberate hypotension is associated with metabolic acidosis in children undergoing surgical procedures for craniofacial or spinal anomalies. Cyanide and thiocyanate concentrations were also recorded in patients who received SNP. METHODS: Data from 166 children undergoing craniofacial and spinal fusion surgery between 2005 and 2010 at Lucile Packard Children's Hospital (LPCH) at Stanford were analyzed. Records from 60 patients who received SNP (SNP group) as part of a multicenter, randomized, double-blind study were compared with records from 106 eligible patients who had blood pressure reduction using anesthetic agents and did not receive SNP (control group). Metabolic acidosis was defined as serum bicarbonate (HCO3) < 18.5 mEq/L. Whole blood CN, plasma thiocyanate and urinary thiocyanate concentrations were measured in patients in the SNP group. Differences in metabolic acidosis rates between the SNP and control groups were assessed through a test of noninferiority in the rate for the SNP group with a noninferiority threshold of 0.2. A z-test was used to test the null hypothesis. The alternative hypothesis was that the difference in these rates was less than 0.2. The same noninferiority threshold of 0.2 was also used to perform separate, secondary tests for noninferiority in the proportion of patients with HCO3 levels below 18.5 mEq/L and the proportion of patients who required HCO3 administration. RESULTS: Fewer patients in the SNP group experienced metabolic acidosis compared to the control group (31.7% vs. 36.8%, respectively; p < .001). No whole blood CN levels above the lower limit of quantification were detected in any of the 51 patients with validated CN data. Plasma and urinary thiocyanate levels were also low. CONCLUSIONS: Our findings suggest that SNP, when used for short-term deliberate hypotension, does not cause an increased incidence of metabolic acidosis compared with the use of anesthetic agents alone. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: NCT00135668. PMID- 23631461 TI - The safety of statins in children. AB - Current American Academy of Pediatrics Guidelines recommended that statins should be considered as a first-line agent in children as early as 8 years of age. The aim of our work is to assess the safety of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in children with hypercholesterolaemia. CONCLUSION: Controlled studies in children show that statin monotherapy is efficacious, well tolerated and safe in the short-time. Unfortunately, these studies have relatively short-term follow-up periods, and therefore, long-term safety remains unclear. PMID- 23631462 TI - Interconception care for women with prior gestational diabetes mellitus. AB - The diagnosis of gestational diabetes mellitus (GDM) signals greater pregnancy risk but also increased lifelong risk of developing diabetes and cardiovascular disease. In women with GDM, insulin resistance exceeds that observed in normal pregnancy and to varying degrees may persist or worsen after birth. Therefore, during postpartum and interconception periods, women with a history of GDM must be monitored for manifestations of increasing insulin resistance, hyperglycemia, dyslipidemia, hypertension, and increased adiposity. Care of women with prior GDM in the postpartum and interconception periods affords clinicians a unique opportunity for targeted screening and health promotion. The objective of this review was to synthesize evidence related to interconception care for women following a pregnancy complicated by GDM and to suggest principles of care: 1) case finding and multiple patient/clinician reminders for women with prior GDM are necessary so that screening occurs in the postpartum through interconception periods; 2) monitoring of metabolic (glucose) and cardiovascular risk (lipids, blood pressure, adiposity) should occur at regular intervals and more often in women with additional risk factors such as insulin use during pregnancy, early diagnosis of GDM, obesity, prediabetes, and dyslipidemia; 3) breastfeeding and use of long-term contraception should be encouraged; and 4) lifestyle modifications that are effective in preventing and delaying disease should be encouraged. PMID- 23631464 TI - Cardiac metastasis from yolk sac tumor: case report and review. AB - Cardiac metastasis of germ cell tumors is extremely rare, particularly in females. We report a case of a 26-year-old previously healthy woman who presented with a 5-month history of abdominal pain, weight loss, fever, generalized lymphadenopathy, and acanthosis nigricans. Biopsy of cervical lymph nodes revealed a poorly differentiated neoplasm. Immunohistochemical staining was positive for alpha-fetoprotein suggesting the diagnosis of a germ cell tumor. During the investigation, the patient developed heart failure and a mass attached to the right ventricle was detected by the echocardiogram. In a few days, she developed multiple organ failure and died. Post-mortem examination revealed a malignant mixed germ cell tumor of the right ovary with extensive hematogenic and lymphatic dissemination, a polypoid mass attached to the right ventricle, emboli in the endocardial and epicardial vessels, and infiltration surrounding the coronary arteries. To the best of our knowledge this is the third report of grossly visible heart metastases from a yolk sac tumor in a female patient. A summary of all published cases of germ cell tumors with cardiac metastasis over the last 20 years is also presented. PMID- 23631463 TI - Design, synthesis, and biological evaluation of aminoalkylindole derivatives as cannabinoid receptor ligands with potential for treatment of alcohol abuse. AB - Attenuation of increased endocannabinoid signaling with a CB1R neutral antagonist might offer a new therapeutic direction for treatment of alcohol abuse. We have recently reported that a monohydroxylated metabolite of the synthetic aminoalkylindole cannabinoid JHW-073 (3) exhibits neutral antagonist activity at CB1Rs and thus may serve as a promising lead for the development of novel alcohol abuse therapies. In the current study, we show that systematic modification of an aminoalkylindole scaffold identified two new compounds with dual CB1R antagonist/CB2R agonist activity. Similar to the CB1R antagonist/inverse agonist rimonabant, analogues 27 and 30 decrease oral alcohol self-administration without affecting total fluid intake and block the development of alcohol-conditioned place preference. Collectively, these initial findings suggest that design and systematic modification of aminoalkylindoles such as 3 may lead to development of novel cannabinoid ligands with dual CB1R antagonist/CB2R agonist activity with potential for use as treatments of alcohol abuse. PMID- 23631465 TI - John Fothergill: a biographical sketch and his contributions to neurology. AB - John Fothergill was a remarkable but largely forgotten physician, plant collector, and philanthropist, born of Quaker parents in Yorkshire. This article summarizes the legacy of his work on trigeminal neuralgia and migrainous "sick headaches," and his seminal studies on angina, scarlatina, and diptheria. He became hugely influential and fostered both education and many medical careers in Britain and America. PMID- 23631466 TI - Investigation of the inhibitory effect of nitrite on Photosystem II. AB - The role of chloride in photosystem II (PSII) is unclear. Several monovalent anions compete for the Cl(-) site(s) in PSII, and some even support activity. NO2(-) has been reported to be an activator in Cl(-)-depleted PSII membranes. In this paper, we report a detailed investigation of the chemistry of NO2(-) with PSII. NO2(-) is shown to inhibit PSII activity, and the effects on the donor side as well as the acceptor side are characterized using steady-state O2-evolution assays, electron paramagnetic resonance (EPR) spectroscopy, electron-transfer assays, and flash-induced polarographic O2 yield measurements. Enzyme kinetics analysis shows multiple sites of NO2(-) inhibition in PSII with significant inhibition of oxygen evolution at <5 mM NO2(-). By EPR spectroscopy, the yield of the S2 state remains unchanged up to 15 mM NO2(-). However, the S2-state g = 4.1 signal is favored over the g = 2 multiline signal with increasing NO2(-) concentrations. This could indicate competition of NO2(-) for the Cl(-) site at higher NO2(-) concentrations. In addition to the donor-side chemistry, there is clear evidence of an acceptor-side effect of NO2(-). The g = 1.9 Fe(II)-QA(-*) signal is replaced by a broad g = 1.6 signal in the presence of NO2(-). Additionally, a g = 1.8 Fe(II)-Q(-*) signal is present in the dark, indicating the formation of a NO2(-)-bound Fe(II)-QB(-*) species in the dark. Electron transfer assays suggest that the inhibitory effect of NO2(-) on the activity of PSII is largely due to the donor-side chemistry of NO2(-). UV-visible spectroscopy and flash-induced polarographic O2 yield measurements indicate that NO2(-) is oxidized by the oxygen-evolving complex in the higher S states, contributing to the donor-side inhibition by NO2(-). PMID- 23631467 TI - Asymmetric synthesis of anti-beta-amino-alpha-hydroxy esters via dynamic kinetic resolution of beta-amino-alpha-keto esters. AB - A method for the asymmetric synthesis of enantioenriched anti-alpha-hydroxy-beta amino acid derivatives by enantioconvergent reduction of the corresponding racemic alpha-keto esters is presented. The requisite alpha-keto esters are prepared via Mannich addition of ethyl diazoacetate to imines followed by oxidation of the diazo group with Oxone. Implementation of a recently developed dynamic kinetic resolution of beta-substituted-alpha-keto esters via Ru(II) catalyzed asymmetric transfer hydrogenation provides the title motif in routinely high diastereo- and enantioselectivity. PMID- 23631469 TI - Is it time to celebrate? PMID- 23631468 TI - Patient neglect in healthcare institutions: a systematic review and conceptual model. AB - BACKGROUND: Patient neglect is an issue of increasing public concern in Europe and North America, yet remains poorly understood. This is the first systematic review on the nature, frequency and causes of patient neglect as distinct from patient safety topics such as medical error. METHOD: The Pubmed, Science Direct, and Medline databases were searched in order to identify research studies investigating patient neglect. Ten articles and four government reports met the inclusion criteria of reporting primary data on the occurrence or causes of patient neglect. Qualitative and quantitative data extraction investigated (1) the definition of patient neglect, (2) the forms of behaviour associated with neglect, (3) the reported frequency of neglect, and (4) the causes of neglect. RESULTS: Patient neglect is found to have two aspects. First, procedure neglect, which refers to failures of healthcare staff to achieve objective standards of care. Second, caring neglect, which refers to behaviours that lead patients and observers to believe that staff have uncaring attitudes. The perceived frequency of neglectful behaviour varies by observer. Patients and their family members are more likely to report neglect than healthcare staff, and nurses are more likely to report on the neglectful behaviours of other nurses than on their own behaviour. The causes of patient neglect frequently relate to organisational factors (e.g. high workloads that constrain the behaviours of healthcare staff, burnout), and the relationship between carers and patients. CONCLUSION: A social psychology-based conceptual model is developed to explain the occurrence and nature of patient neglect. This model will facilitate investigations of i) differences between patients and healthcare staff in how they perceive neglect, ii) the association with patient neglect and health outcomes, iii) the relative importance of system and organisational factors in causing neglect, and iv) the design of interventions and health policy to reduce patient neglect. PMID- 23631470 TI - Breastfeeding in obstetrics residency: exploring maternal and colleague resident perspectives. AB - BACKGROUND: Pregnancy is becoming more common in residency, and about 80% of residents are female. This leads to questions of breastfeeding, work demands, and perception of burden by colleagues. This study was designed to assess experiences of (1) breastfeeding obstetrics residents and (2) their colleagues. MATERIALS AND METHODS: This was a cross-sectional study of obstetrics and gynecology residents. Residents were categorized into experience with or no experience with breastfeeding to determine differences. RESULTS: Responses were obtained from 404 residents in obstetrics. Breastfeeding is common, with 90% of residents knowing a breastfeeding resident and 22% of residents reporting personal experience with breastfeeding. Breastfeeding residents (n=89) felt support from their faculty and fellow residents. More than one in three breastfeeding mothers felt they placed extra demands on colleagues, despite 80% of colleagues reporting that they did not feel that breastfeeding colleagues placed extra demands. A breastfeeding policy was important to 85% of residents, but only 7% believed their program had one. Two-thirds of breastfeeding residents struggled with low milk supply and stopped breastfeeding early. CONCLUSIONS: Despite high levels of perceived support from faculty/fellow residents, breastfeeding residents struggle with low milk supply and work demands that lead to early discontinuation. PMID- 23631471 TI - Mapping condition-dependent regulation of metabolism in yeast through genome scale modeling. AB - BACKGROUND: The genome-scale metabolic model of Saccharomyces cerevisiae, first presented in 2003, was the first genome-scale network reconstruction for a eukaryotic organism. Since then continuous efforts have been made in order to improve and expand the yeast metabolic network. RESULTS: Here we present iTO977, a comprehensive genome-scale metabolic model that contains more reactions, metabolites and genes than previous models. The model was constructed based on two earlier reconstructions, namely iIN800 and the consensus network, and then improved and expanded using gap-filling methods and by introducing new reactions and pathways based on studies of the literature and databases. The model was shown to perform well both for growth simulations in different media and gene essentiality analysis for single and double knock-outs. Further, the model was used as a scaffold for integrating transcriptomics, and flux data from four different conditions in order to identify transcriptionally controlled reactions, i.e. reactions that change both in flux and transcription between the compared conditions. CONCLUSION: We present a new yeast model that represents a comprehensive up-to-date collection of knowledge on yeast metabolism. The model was used for simulating the yeast metabolism under four different growth conditions and experimental data from these four conditions was integrated to the model. The model together with experimental data is a useful tool to identify condition-dependent changes of metabolism between different environmental conditions. PMID- 23631472 TI - Cytotoxicity of quantum dots and graphene oxide to erythroid cells and macrophages. AB - Great concerns have been raised about the exposure and possible adverse influence of nanomaterials due to their wide applications in a variety of fields, such as biomedicine and daily lives. The blood circulation system and blood cells form an important barrier against invaders, including nanomaterials. However, studies of the biological effects of nanomaterials on blood cells have been limited and without clear conclusions thus far. In the current study, the biological influence of quantum dots (QDs) with various surface coating on erythroid cells and graphene oxide (GO) on macrophages was closely investigated. We found that QDs posed great damage to macrophages through intracellular accumulation of QDs coupled with reactive oxygen species generation, particularly for QDs coated with PEG-NH2. QD modified with polyethylene glycol-conjugated amine particles exerted robust inhibition on cell proliferation of J744A.1 macrophages, irrespective of apoptosis. Additionally, to the best of our knowledge, our study is the first to have demonstrated that GO could provoke apoptosis of erythroid cells through oxidative stress in E14.5 fetal liver erythroid cells and in vivo administration of GO-diminished erythroid population in spleen, associated with disordered erythropoiesis in mice. PMID- 23631473 TI - Two pathways for electrocatalytic oxidation of hydrogen by a nickel bis(diphosphine) complex with pendant amines in the second coordination sphere. AB - A nickel bis(diphosphine) complex containing pendant amines in the second coordination sphere, [Ni(P(Cy)2N(t-Bu)2)2](BF4)2 (P(Cy)2N(t-Bu)2 = 1,5-di(tert butyl)-3,7-dicyclohexyl-1,5-diaza-3,7-diphosphacyclooctane), is an electrocatalyst for hydrogen oxidation. The addition of hydrogen to the Ni(II) complex gives three isomers of the doubly protonated Ni(0) complex [Ni(P(Cy)2N(t Bu)2H)2](BF4)2. Using the pKa values and Ni(II/I) and Ni(I/0) redox potentials in a thermochemical cycle, the free energy of hydrogen addition to [Ni(P(Cy)2N(t Bu)2)2](2+) was determined to be -7.9 kcal mol(-1). The catalytic rate observed in dry acetonitrile for the oxidation of H2 depends on base size, with larger bases (NEt3, t-BuNH2) resulting in much slower catalysis than n-BuNH2. The addition of water accelerates the rate of catalysis by facilitating deprotonation of the hydrogen addition product before oxidation, especially for the larger bases NEt3 and t-BuNH2. This catalytic pathway, where deprotonation occurs prior to oxidation, leads to an overpotential that is 0.38 V lower compared to the pathway where oxidation precedes proton movement. Under the optimal conditions of 1.0 atm H2 using n-BuNH2 as a base and with added water, a turnover frequency of 58 s(-1) is observed at 23 degrees C. PMID- 23631474 TI - Evaluation of the national prevention strategy in reference to historical population health. AB - Scientists have estimated that approximately half of all deaths in the United States are attributed to largely preventable behaviors and exposures, such as tobacco use, diet and physical activity, and alcohol consumption. These findings are similar to reflections reported more than 100 years ago by public health authorities. Is it inevitable that half of the population will die prematurely, even as the average life span increases? PMID- 23631478 TI - Will classic workplace health promotion program strategies work for Medicare? PMID- 23631480 TI - Layer-by-layer assembly of azulene-based supra-amphiphiles: reversible encapsulation of organic molecules in water by charge-transfer interaction. AB - Stable multilayer films have been fabricated on the basis of alternating layer-by layer assembly of an azulene-based supra-amphiphile and a photoreactive polyanion. Moreover, one component of the supra-amphiphile, pyrene, can be removed from the multilayer films, generating functional surface-imprinted multilayer films. Uptake experiments show that the surface-imprinted films are capable of recognizing the hydrophobic template molecule in water. The reloading process increases with increasing of temperature. The loading capacity can be regulated by change of the layer pairs. In addition, the as-prepared multilayers are promising in purification of pyrene-polluted water. PMID- 23631481 TI - Primate laterality and the biology and evolution of human handedness: a review and synthesis. AB - We review evidence for and against lateralization of manual control, communication, visual processing, and auditory processing in nonhuman primates. Compared to humans and some other vertebrate species, manual specialization in nonhuman primates is relatively weak. A right-bias in chimpanzees may exist, but is so weak that many studies using simple tasks fail to reveal it. Slightly stronger biases may exist in baboons and chimpanzees for communicative signals in the manual and facial domains. Several studies have found robust visual side biases that depend on the object being viewed, in primates including chimpanzees. Evidence for lateralization of auditory processing remains inconclusive. We conclude that the robust, species-wide lateralization that exists in humans is unusual, and perhaps unique among primates, and discuss several possible evolutionary explanations for this strong asymmetry. In particular, we consider the hypothesis that preexisting hemispheric asymmetry for perception and language processing drove the evolution of human handedness. PMID- 23631483 TI - Fungal ABC transporter-associated activity of isoflavonoids from the root extract of Dalea formosa. AB - New potential treatments for disseminated fungal infections are needed, especially for infections caused by the commonly drug-resistant pathogens Candida albicans and C. glabrata. These pathogens cause systemic candidiasis, a significant cause of mortality in immune-compromised patients. ABC transporters of the pleiotropic drug resistance subfamily, such as Cdr1p of C. albicans, play an important role in antifungal resistance and are potential bioassay targets for antifungal therapies against drug-resistant pathogens. We observed strong antifungal growth inhibitory activity in the methanol extract of Dalea formosa roots. This extract afforded six new isoflavonoids, sedonans A-F (1-6), a new but 2-enolide, 4'-O-methylpuerol A (7), and the new pterocarpan ent-sandwicensin (8). The structures and absolute configurations of these compounds were assigned using spectroscopic and chiroptical techniques. The direct antifungal activity of 1 against C. glabrata (MIC = 20 MUM) was higher than that of fluconazole. Sedonans A-F and ent-sandwicensin were also active against Saccharomyces cerevisiae strains that express differing ABC transporter-associated resistance mechanisms but differed in their susceptibility to Cdr1p-mediated detoxification. A sedonan A (1)/ent-sandwicensin (8) combination exhibited synergistic growth inhibition. The results demonstrate that multiple crude extract compounds are differentially affected by efflux-mediated resistance and are collectively responsible for the observed bioactivity. PMID- 23631482 TI - Predictors of persistent symptoms and reduced quality of life in treated coeliac disease patients: a large cross-sectional study. AB - BACKGROUND: Evidence suggests that many coeliac disease patients suffer from persistent clinical symptoms and reduced health-related quality of life despite a strict gluten-free diet. We aimed to find predictors for these continuous health concerns in long-term treated adult coeliac patients. METHODS: In a nationwide study, 596 patients filled validated Gastrointestinal Symptom Rating Scale and Psychological General Well-Being questionnaires and were interviewed regarding demographic data, clinical presentation and treatment of coeliac disease, time and place of diagnosis and presence of coeliac disease-associated or other co morbidities. Dietary adherence was assessed by a combination of self-reported adherence and serological tests. Odds ratios and 95% confidence intervals were calculated by binary logistic regression. RESULTS: Diagnosis at working age, long duration and severity of symptoms before diagnosis and presence of thyroidal disease, non-coeliac food intolerance or gastrointestinal co-morbidity increased the risk of persistent symptoms. Patients with extraintestinal presentation at diagnosis had fewer current symptoms than subjects with gastrointestinal manifestations. Impaired quality of life was seen in patients with long duration of symptoms before diagnosis and in those with psychiatric, neurologic or gastrointestinal co-morbidities. Patients with persistent symptoms were more likely to have reduced quality of life. CONCLUSIONS: There were a variety of factors predisposing to increased symptoms and impaired quality of life in coeliac disease. Based on our results, early diagnosis of the condition and consideration of co-morbidities may help in resolving long-lasting health problems in coeliac disease. PMID- 23631484 TI - Apparent diffusion coefficient values predict outcomes of abusive head trauma. AB - AIM: To evaluate the apparent diffusion coefficient (ADC) values for predicting the long-term neurodevelopmental outcomes of patients with abusive head trauma (AHT). METHODS: Apparent diffusion coefficient maps were retrospectively reviewed for 14 patients who presented with AHT at a mean age of 6.7 months (range 1-18 months), and the clinical outcomes of the survivors were based on the Glasgow Outcome Score. RESULTS: One of 14 infants died, and two were severely disabled. One had mild impairment and four had moderate disability. In the 4 days after admission, the ADC values in all brain regions were strongly associated with a poor neurodevelopmental outcome (p < 0.05): basal ganglia, thalamus, brain stem, corpus callosum, frontal white matter, central white matter, parietal white matter, frontal grey matter, parietal grey matter, cerebellar vermis, cerebellar cortex and mean total brain. CONCLUSION: Apparent diffusion coefficient values during the acute phase of AHT were significantly associated with poor long-term neurodevelopmental outcomes. PMID- 23631485 TI - Phaeohyphomycosis of the hand treated using Mohs micrographic surgery. PMID- 23631486 TI - Share with women. Prenatal tests for Down syndrome. PMID- 23631487 TI - An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype. AB - BACKGROUND: A DNA methylation signature has been characterized that distinguishes rheumatoid arthritis (RA) fibroblast like synoviocytes (FLS) from osteoarthritis (OA) FLS. The presence of epigenetic changes in long-term cultured cells suggest that rheumatoid FLS imprinting might contribute to pathogenic behavior. To understand how differentially methylated genes (DMGs) might participate in the pathogenesis of RA, we evaluated the stability of the RA signature and whether DMGs are enriched in specific pathways and ontology categories. METHODS: To assess the RA methylation signatures the Illumina HumanMethylation450 chip was used to compare methylation levels in RA, OA, and normal (NL) FLS at passage 3, 5, and 7. Then methylation frequencies at CpGs within the signature were compared between passages. To assess the enrichment of DMGs in specific pathways, DMGs were identified as genes that possess significantly differential methylated loci within their promoter regions. These sets of DMGs were then compared to pathway and ontology databases to establish enrichment in specific categories. RESULTS: Initial studies compared passage 3, 5, and 7 FLS from RA, OA, and NL. The patterns of differential methylation of each individual FLS line were very similar regardless of passage number. Using the most robust analysis, 20 out of 272 KEGG pathways and 43 out of 34,400 GO pathways were significantly altered for RA compared with OA and NL FLS. Most interestingly, we found that the KEGG 'Rheumatoid Arthritis' pathway was consistently the most significantly enriched with differentially methylated loci. Additional pathways involved with innate immunity (Complement and Coagulation, Toll-like Receptors, NOD-like Receptors, and Cytosolic DNA-sensing), cell adhesion (Focal Adhesion, Cell Adhesion Molecule), and cytokines (Cytokine-cytokine Receptor). Taken together, KEGG and GO pathway analysis demonstrates non-random epigenetic imprinting of RA FLS. CONCLUSIONS: The DNA methylation patterns include anomalies in key genes implicated in the pathogenesis of RA and are stable for multiple cell passages. Persistent epigenetic alterations could contribute to the aggressive phenotype of RA synoviocytes and identify potential therapeutic targets that could modulate the pathogenic behavior. PMID- 23631488 TI - Synthesis of cyclic 1-alkenylboronates via Zr-mediated double functionalization of alkynylboronates and sequential Ru-catalyzed ring-closing olefin metathesis. AB - Synthesis of novel cyclic 1-alkenylboronates is accomplished through the zirconium-mediated regio- and stereoselective double functionalization of 1 alkynylboronates and the subsequent ruthenium-catalyzed ring-closing metathesis (RCM). The obtained substituted cyclic 1-alkenylboronates are transformed into o terphenyl and triphenylene derivatives. PMID- 23631490 TI - Green tea polyphenols improve bone microarchitecture in high-fat-diet-induced obese female rats through suppressing bone formation and erosion. AB - This study evaluates the effects of green tea polyphenols (GTPs) on bone microarchitecture in high-fat-diet (HFD)-induced obese female rats. Thirty-six 3 month-old female rats were fed either a control diet or a HFD for 4 months. Animals in the control group continued on the control diet for another 4 months. Animals in the HFD group were divided into two groups, with 0.5 g/100 mL GTP (the HFD+GTP group) or without GTP (the HFD group) in drinking water, in addition to the HFD for another 4 months. Compared to the control group, the HFD group increased bone formation and erosion rates at the tibia, decreased trabecular volume and thickness, but had no impact on bone mineral density (BMD), trabecular number (Tb.N), and separation. Compared to the control group, the HFD+GTP group demonstrates a greater Tb.N at the proximal tibia, and a greater trabecular thickness at the femur and the lumbar vertebrae, but a smaller trabecular separation (Tb.Sp) and mineralizing surface at the proximal tibia, and a reduced endocortical mineral apposition rate (MAR) at the tibia shaft. Relative to the HFD group, the HFD+GTP group demonstrates (1) a higher BMD at the femur, a greater trabecular volume, thickness, and number at the proximal tibia, a larger cortical area and thickness at the tibial shaft, and a greater trabecular volume and thickness at the femur and the lumbar vertebrae, (2) a smaller Tb.Sp, MAR, bone formation rate, and eroded surface at the tibia. We concluded that GTP supplementation in drinking water improves bone microarchitecture in the HFD induced obese female rats, possibly through suppressing bone turnover, resulting in a larger net bone volume. PMID- 23631489 TI - Porcine skin gelatin hydrolysate promotes longitudinal bone growth in adolescent rats. AB - Collagen hydrolysates (CHs) are mixtures of peptides obtained by partial hydrolysis of gelatin that are receiving scientific attention as potential oral supplements for the restoration of osteoarticular tissues. The aim of this study was to evaluate the effectiveness of CHs for promoting longitudinal bone growth in growing rats. An in vitro study was carried out in osteoblast-like MG63 cells and the most effective CH on bone formation was selected among 36 various CHs. An in vivo study confirmed the functional effects of a selected CH with molecular weight of <3 kDa on longitudinal bone growth. CHs dose-dependently promoted the longitudinal bone growth and height of the growth plate in adolescent male rats, whereas gelatin failed to affect longitudinal bone growth. Insulin-like growth factor-1 and bone morphogenetic protein-2 in the CH treated group were highly expressed in the growth plate. These results suggest that CHs isolated in this study may provide beneficial effects on bone metabolism of growing animals and humans. PMID- 23631491 TI - Chloroform extract of alfalfa (Medicago sativa) inhibits lipopolysaccharide induced inflammation by downregulating ERK/NF-kappaB signaling and cytokine production. AB - Alfalfa (Medicago sativa L.) is commonly used as a traditional medicine and functional food. This study investigated the anti-inflammatory potential of alfalfa and the mechanisms involved. The chloroform extract of alfalfa aerial parts inhibited lipopolysaccharide (LPS)-stimulated immune responses more than ether, butanol, or water soluble extracts. Treatment with 1 MUg/mL LPS increased nitrite concentrations to 44.3 MUM in RAW267.4 macrophages, but it was reduced to 10.6 MUM by adding 100 MUg/mL chloroform extract. LPS treatment also increased the concentrations of tumor necrosis factor-alpha, interleukin (IL)-6, and IL 1beta to 41.3, 11.6, and 0.78 ng/mL in culture supernatants of the cells, but these cytokine levels decreased to 12.5, 3.1, and 0.19 ng/mL, respectively, by pretreating with 100 MUg/mL of the extract. ICR mice injected with LPS (30 mg/kg body weight) alone showed a 0% survival rate after 48 h of the injection, but 48 h survival of the mice increased to 60% after oral administration of the extract. Subfractions of the chloroform extract markedly suppressed LPS-mediated activation of the extracellular signal-regulated kinase and nuclear factor kappa B. Cinnamic acid derivatives and fatty acids were found to be active constituents of the extract. This research demonstrated that alfalfa aerial parts exert anti inflammatory activity and may be useful as a functional food for the prevention of inflammatory disorders. PMID- 23631492 TI - Biochemical composition, antimicrobial activities,and anti-quorum-sensing activities of ethanol and ethyl acetate extracts from Hypericum connatum Lam. (Guttiferae). AB - We studied the polyphenol composition and antioxidant activity of the ethanolic and ethyl acetate extracts of Hypericum connatum (Guttiferae), in addition to their antimicrobial and antiquorum-sensing (AQS) properties. The extracts exhibited a similar polyphenol content and a notable antioxidant activity, which was stronger in the ethanolic extract (EC50=3.2 MUg/mL). Ultrahigh-performance liquid chromatography analyses revealed different polyphenol profiles, with rutin and apigen being the main components of the ethanolic extract and caffeic acid, ( )-epicatechin and p-coumaric acid being abundant in the ethyl acetate extract. The ethyl acetate extract exhibited a more effective antimicrobial activity than the ethanolic extract against the pathogens Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa. For the first time, AQS activity was detected in H. connatum: the ethanolic extract inhibited the production of violacein, a quorum-sensing-regulated pigment, in a Chromobacterium violaceum tester strain, without interfering with its growth. PMID- 23631495 TI - Raw drone milk of honeybees elicits uterotrophic effect in rats: evidence for estrogenic activity. AB - Numerous honeybee products are used in medicine, but the literature furnishes no information concerning the effects of the drone milk (DM), although drone brood, which is similar to DM, was reported to elicit a hormone-like strengthening effect. In certain countries, DM is traditionally used to treat infertility and to promote vitality in both men and women. The aim of this study was to determine the putative estrogen hormone-like effect of raw DM in rats and to identify the effective compounds. Uterotrophic assays revealed that DM increased the relative weight of the immature rat uterus. This effect was confirmed by reverse transcription polymerase chain-reaction and Western blot methods, in which the mRNA and protein expression of the estrogen-dependent peptide complement component C3 was determined. Column chromatography and uterotrophic assays were used to fractionate and check bioactivity, respectively. The active compound after the last fractionation was identified by the nuclear magnetic resonance and mass spectrometry techniques as E-dec-2-enedioic acid, which is very similar to the fatty acids with estrogenic activity that were previously isolated from royal jelly. These results lead us to suppose that E-dec-2-enedioic acid is responsible for the estrogen-like effect of DM. This appears to be the first report on the pharmacological effects of DM and E-dec-2-enedioic acid in mammals. PMID- 23631494 TI - Milk-derived peptides, Val-Pro-Pro and Ile-Pro-Pro, attenuate atherosclerosis development in apolipoprotein e-deficient mice: a preliminary study. AB - Milk-derived peptides, Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), have angiotensin I-converting enzyme inhibitory activities and blood pressure-lowering effects. We examined the effects of these peptides on the development of atherosclerosis in apolipoprotein E-deficient [apoE(-/-)] mice. For 31 weeks, six-week-old male apoE(-/-) mice received a diet that included one of the following: fermented milk containing both VPP and IPP; casein hydrolysate containing both of these peptides; synthesized VPP; synthesized IPP; enalapril; captopril; or control diet. At the end of feeding, blood biochemistry, aortic atherogenesis, and gene expression by DNA microarray analysis were evaluated. There were no significant changes in the plasma lipid levels and 8-isoprostane, a marker of oxidative stress. The area ratio of intima to media in the aortic arch was significantly lower in the fermented milk, casein hydrolysate, synthesized VPP, enalapril, and captopril groups than in the control group. As is common with diets containing VPP and/or IPP, we observed reductions in mRNA expression of inflammatory cytokines, such as interleukin (IL)-6 and IL-1beta, oxidized low-density lipoprotein receptor, and transcription regulators. These results suggest that a continuous intake of VPP and IPP might be beneficial for preventing atherosclerosis caused by hypercholesterolemia. PMID- 23631496 TI - A chemometric approach to distribution of selenium in medicinal plants cultivated in poland. AB - The aim of this study was to evaluate the level of selenium (Se) in common raw plant materials (herbs, leaves, flowers, fruits, and roots) obtained from medicinal plants cultivated in Poland. Furthermore, the relationship between the morphological part of a plant and its species was examined, and the concentration of Se in it was measured. Spectrofluorimetric determination of Se in 148 samples of 44 plant species revealed that the majority of the plants contained Se at a level from several to several tens of MUg/kg dry weight (d.w.). A relatively high Se concentration, in the order of 50 MUg/kg d.w., was found in Majoranae herba, Crataegi fructus, and Lini semen. An especially high Se level, >100 MUg/kg d.w., was found in only three plants-Equiseti herba, Farfarae folium, and Cichorii radix. Application of a nonparametric Kruskal-Wallis analysis of variance test indicates that the morphological variable influences the level of Se in the studied groups of raw plant materials. The mean concentration of Se in fruits differs significantly from that found in flowers and roots. However, there was no statistically significant difference between the Se content in herbs and leaves and its levels in fruits, flowers, and roots. Cluster analysis and principal component analysis calculations show that it is possible to relate the Se concentration in plant material to the plant species and botanical family of the medicinal plant in only a few cases. Analysis of average Se levels in the plant species showed that the plants belonging to the Apiaceae and Labiatae botanical families are more Se-rich than those belonging to Rosaceae. PMID- 23631493 TI - Effect of lycopene supplementation on oxidative stress: an exploratory systematic review and meta-analysis of randomized controlled trials. AB - Lycopene is a potentially useful compound for preventing and treating cardiovascular diseases and cancers. Studies on the effects of lycopene on oxidative stress offer insights into its mechanism of action and provide evidence based rationale for its supplementation. In this analysis, randomized controlled trials of the effects of oral lycopene supplementation on any valid outcomes of oxidative stress were identified and pooled through a search of international journal databases and reference lists of relevant publications. Two reviewers extracted data from each of the identified studies. Only studies of sufficient quality were included. Twelve parallel trials and one crossover trial were included in the systematic review, and six trials provided data for quantitative meta-analysis. Our results indicate that lycopene supplementation significantly decreases the DNA tail length, as determined using comet assays, with a mean difference (MD) of -6.27 [95% confidence interval (CI) -10.74, -1.90] (P=.006) between the lycopene intervention groups and the control groups. Lycopene supplementation does not significantly prolong the lag time of low-density lipoprotein (MD 3.76 [95% CI -2.48, 10.01]; P=.24). Lycopene possibly alleviates oxidative stress; however, biomarker research for oxidative stress needs be more consistent with the outcomes in lycopene intervention trials for disease prevention. PMID- 23631497 TI - Potential efficacy of broccoli sprouts as a unique supplement for management of type 2 diabetes and its complications. AB - Functional foods and their nutraceutical components are now considered as supplementary treatments in type 2 diabetes and prevention of its long-term complications. Young broccoli sprouts as a functional food contain many bioactive compounds specially sulforaphane. In hyperglycemic and oxidative conditions, sulforaphane has the potential to activate the NF-E2-related factor-2 (Nrf2) dependent antioxidant response-signaling pathway, induces phase 2 enzymes, attenuates oxidative stress, and inactivates nuclear factor kappa-B (NF-kappaB), a key modulator of inflammatory pathways. Interestingly, sulforaphane induces some peroxisome proliferator-activated receptors, which contribute to lipid metabolism and glucose homeostasis. In animal and in vitro models, sulforaphane also shows antihypertensive, anticancer, cardioprotective, and hypocholesterolemic capacity, and has bactericidal properties against Helicobacter pylori. Supplementation of type 2 diabetics with high sulforaphane content broccoli sprouts resulted in increased total antioxidant capacity of plasma and in decreased oxidative stress index, lipid peroxidation, serum triglycerides, oxidized low-density lipoprotein (LDL)/LDL-cholesterol ratio, serum insulin, insulin resistance, and serum high-sensitive C-reactive protein. Sulforaphane could prevent nephropathy, diabetes-induced fibrosis, and vascular complications. Potential efficacy of sulforaphane and probably other bioactive components of young broccoli sprouts makes it as an excellent choice for supplementary treatment in type 2 diabetes. PMID- 23631498 TI - Inhibition of foodborne pathogens by pomegranate juice. AB - Pomegranates have health-promoting benefits because of their polyphenol constituents. Previous studies have demonstrated the antimicrobial activity of aqueous and organic extracts of pomegranate components and by-products. We sought to determine the antimicrobial activity against 40 foodborne pathogens representing eight bacterial species using juice itself. In addition, we sought to determine the synergistic antimicrobial activity between pomegranate juice and other plant products displaying antimicrobial activity. The antimicrobial activity of pomegranate juice was dependent on the test organism, which varied to highly susceptible (four Gram-positive species) to unaffected (Salmonella and Escherichia coli O157:H7). Two Gram-negative species, which were inhibited were Helicobacter pylori and Vibrio parahemolyticus. No synergistic antimicrobial activity was seen between pomegranate and either barberry, oregano, or cranberry. The antimicrobial activity of pomegranate juice is dependent on the test organism and extraction method. The sensitivity of H. pylori suggests that pomegranate juice may be an alternative or supplemental treatment for gastric ulcers caused by this organism. PMID- 23631499 TI - Possible therapeutic uses of Salvia triloba and Piper nigrum in Alzheimer's disease-induced rats. AB - This study aimed to investigate the role of Salvia triloba L. and Piper nigrum extracts in ameliorating neuroinflammatory insults characteristic of Alzheimer's disease (AD) in an experimentally induced rat model. Adult male Sprague-Dawley rats were classified into Group 1 (n=10): normal healthy animals serving as the negative control group; Group 2 (n=60): the AD-induced group. After AD induction, animals in the AD-induced group were divided randomly and equally into 6 subgroups. The first subgroup served as AD control; the second one, which served as positive control, was treated orally with the conventional therapy for AD (rivastigmine) at a dose of 0.3 mg/kg body weight (b.w.) daily for 3 months. The third and fourth subgroups were, respectively, treated orally with the S. triloba extract at a dose of 750 and 375 mg/kg b.w. daily for 3 months. The fifth and sixth subgroups were, respectively, treated orally with the P. nigrum extract at a dose of 187.5 and 93.75 mg/kg b.w. daily for 3 months. Levels of brain acetylcholine (Ach), serum and brain acetylcholinesterase (AchE) activity, C reactive protein (CRP), total nuclear factor kappa-B (NF-kappaB), and monocyte chemoattractant protein-1 (MCP-1) were estimated. The results showed that administration of AlCl3 resulted in a significant elevation in the levels of AchE activity, CRP, NF-kappaB, and MCP-1 accompanied with a significant depletion in the Ach level. Treatment of AD rats with each of the selected medicinal plant extracts caused marked improvement in the measured biochemical parameters. In conclusion, S. triloba and P. nigrum methanolic extracts have potent anti inflammatory effects against neuroinflammation characterizing AD. PMID- 23631500 TI - Antibacterial, antiadherence, antiprotease, and anti-inflammatory activities of various tea extracts: potential benefits for periodontal diseases. AB - Porphyromonas gingivalis is a key etiologic agent of chronic periodontitis. This Gram-negative anaerobic bacterium produces several virulence factors and can induce a host inflammatory response that contributes to periodontal disease. In the present study, we investigated green tea, white tea, oolong tea, and black tea extracts with a high polyphenol content for their effects on (i) the growth and adherence of P. gingivalis, (ii) the activity of host and bacterial proteases, and (iii) cytokine secretion by oral epithelial cells. All the tea extracts inhibited the growth of P. gingivalis (minimal inhibitory concentrations ranging from 200 to 500 MUg/mL; minimal bactericidal concentrations=500 MUg/mL). In addition, they dose dependently reduced the adherence of P. gingivalis to oral epithelial cells. Tea extracts also inhibited the catalytic activity of matrix metalloproteinase (MMP)-9, neutrophil elastase, and P. gingivalis collagenase. Lastly, the tea extracts dose dependently inhibited the secretion of interleukin (IL)-6, IL-8, and chemokine (C-C motif) ligand 5 (CCL-5) by P. gingivalis stimulated oral epithelial cells. No marked differences in the various effects were observed among the four tea extracts. Extracts from green tea, white tea, oolong tea, and black tea show promise for controlling periodontal disease by their capacity to interfere with P. gingivalis growth and virulence properties, host destructive enzymes, and inflammatory mediator secretion. Such extracts may be incorporated to oral hygiene products or locally delivered into diseased periodontal sites. PMID- 23631501 TI - Factors associated with reported service use for mental health problems by residents of rural and remote communities: cross-sectional findings from a baseline survey. AB - BACKGROUND: The patterns of health service use by rural and remote residents are poorly understood and under-represented in national surveys. This paper examines professional and non-professional service use for mental health problems in rural and remote communities in Australia. METHODS: A stratified random sample of adults was drawn from non-metropolitan regions of New South Wales, Australia as part of a longitudinal population-based cohort. One-quarter (27.7%) of the respondents were from remote or very remote regions. The socio-demographic, health status and service utilization (professional and non-professional) characteristics of 2150 community dwelling residents are described. Hierarchical logistic regressions were used to identify cross-sectional associations between socio-demographic, health status and professional and non-professional health service utilization variables. RESULTS: The overall rate of professional contacts for mental health problems during the previous 12 months (17%) in this rural population exceeded the national rate (11.9%). Rates for psychologists and psychiatrists were similar but rates for GPs were higher (12% vs. 8.1%). Non professional contact rates were 12%. Higher levels of help seeking were associated with the absence of a partner, poorer finances, severity of mental health problems, and higher levels of adversity. Remoteness was associated with lower utilization of non-professional support. A Provisional Service Need Index was devised, and it demonstrated a broad dose-response relationship between severity of mental health problems and the likelihood of seeking any professional or non-professional help. Nevertheless, 47% of those with estimated high service need had no contact with professional services. CONCLUSIONS: An examination of self-reported patterns of professional and non-professional service use for mental health problems in a rural community cohort revealed relatively higher rates of general practitioner attendance for such problems compared with data from metropolitan centres. Using a measure of Provisional Service Need those with greater needs were more likely to access specialist services, even in remote regions, although a substantial proportion of those with the highest service need sought no professional help. Geographic and financial barriers to service use were identified and perception of service adequacy was relatively low, especially among those with the highest levels of distress and greatest adversity. PMID- 23631502 TI - Convection-enhanced delivery of targeted quantum dot-immunoliposome hybrid nanoparticles to intracranial brain tumor models. AB - AIM: The aim of this work is to evaluate combining targeting strategy and convection-enhanced delivery in brain tumor models by imaging quantum dot immunoliposome hybrid nanoparticles. MATERIALS & METHODS: An EGF receptor targeted, quantum dot-immunoliposome hybrid nanoparticle (QD-IL) was synthesized. In vitro uptake was measured by flow cytometry and intracellular localization was imaged by confocal microscopy. In the in vivo study, QD-ILs were delivered to intracranial xenografts via convection-enhanced delivery and fluorescence was monitored noninvasively in real-time. RESULTS: QD-ILs exhibited specific and efficient uptake in vitro and exhibited approximately 1.3- to 5.0-fold higher total fluorescence compared with nontargeted counterpart in intracranial brain tumor xenografts in vivo. CONCLUSION: QD-ILs serve as an effective imaging agent in vitro and in vivo, and the data suggest that ligand-directed liposomal nanoparticles in conjunction with convection-enhanced delivery may offer therapeutic benefits for glioblastoma treatment as a result of specific and efficient uptake by malignant cells. PMID- 23631503 TI - Topographically targeted osteogenesis of mesenchymal stem cells stimulated by inclusion bodies attached to polycaprolactone surfaces. AB - AIM: Bacterial inclusion bodies (IBs) are nanostructured (submicron), pseudospherical proteinaceous particles produced in recombinant bacteria resulting from ordered protein aggregation. Being mechanically stable, several physicochemical and biological properties of IBs can be tuned by appropriate selection of the producer strain and of culture conditions. It has been previously shown that IBs favor cell adhesion and surface colonization by mammalian cell lines upon decoration on materials surfaces, but how these biomaterials could influence the behavior of mesenchymal stem cells remains to be explored. MATERIALS & METHODS: Here, the authors vary topography, stiffness and wettability using the IBs to decorate polycaprolactone surfaces on which mesenchymal stem cells are cultured. RESULTS: The authors show that these topographies can be used to specifically target osteogenesis from mesenchymal stem cells, and through metabolomics, they show that the cells have increased energy demand during this bone-related differentiation. CONCLUSION: IBs as topographies can be used not only to direct cell proliferation but also to target differentiation of mesenchymal stem cells. PMID- 23631504 TI - Nanodiamonds activate blood platelets and induce thromboembolism. AB - AIM: Nanodiamonds (NDs) have been evaluated for a wide range of biomedical applications. Thus, thorough investigation of the biocompatibility of NDs has become a research priority. Platelets are highly sensitive and are one of the most abundant cell types found in blood. They have a central role in hemostasis and arterial thrombosis. In this study, we aim to investigate the direct and acute effects of carboxylated NDs on platelet function. METHODS: In this study, pro-coagulant parameters such as platelet aggregability, intracellular Ca(2+) flux, mitochondrial transmembrane potential (DeltaPsim), generation of reactive oxygen species, surface exposure of phosphatidylserine, electron microscopy, cell viability assay and in vivo thromboembolism were analyzed in great detail. RESULTS: Carboxylated NDs evoked significant activation of human platelets. When administered intravenously in mice, NDs were found to induce widespread pulmonary thromboembolism, indicating the remarkable thrombogenic potential of this nanomaterial. CONCLUSION: Our findings raise concerns regarding the putative biomedical applications of NDs pertaining to diagnostics and therapeutics, and their toxicity and prothrombotic properties should be critically evaluated. PMID- 23631505 TI - Characteristics of children with the best and poorest first- and second-year growth during rhGH therapy: data from 25 years of the Genentech national cooperative growth study (NCGS). AB - BACKGROUND: Models assessing characteristics contributing to response to recombinant human growth hormone (rhGH) response rarely address growth extremes in both years 1 and 2 or examine how children track from year to year. Using National Cooperative Growth Study (NCGS) data, we determined characteristics contributing to responsiveness to rhGH and the pattern of change from years 1 to 2. PATIENTS AND METHODS: Height velocity standard deviation score (HV SDS) for 2 years for prepubertal children with idiopathic GH deficiency (IGHD) (n = 1899) and idiopathic short stature (ISS) (n = 1186) treated with similar doses for two years were computed. Group 1 = HV SDS < -1; 2 = HV SDS -1 to +1; 3 = HV SDS > +1. RESULTS: For IGHD, mean age was 7.5 years and similar in all groups. Year 1 HV SDS was associated with greater body mass index (BMI) SDS, lower pre-treatment HV, baseline height SDS, greater target height SDS minus height SDS, and lower maximum stimulated GH (P <0.0001). Year 2, 172/271 (73%) in group 1 moved to either group 2 (n = 156) or 3 (n = 16). Year 2 HV SDS was associated with greater year 1 HV SDS (r = 0.045, P <0.0001), greater BMI SDS, taller parents and lower peak GH.For ISS, year 1 HV SDS was associated with greater BMI SDS and lower pre treatment HV (P <=0.0001). 109/169 (64%) in group 1 moved to group 2 (n = 90) or group 3 (n = 19). Greater year 2 HV SDS was related to year 1 HV SDS (r = 0.27, P <0.0001). CONCLUSION: For IGHD, multiple characteristics contributed to best first-year response but for ISS, best first-year HV SDS was associated only with BMI SDS and inversely with pre-treatment HV. For both GHD and ISS, year 1 HV SDS was not a strong enough predictor of year 2 HV SDS to use first-year HV alone to determine GH continuation. PMID- 23631506 TI - Dynamic modeling of yeast meiotic initiation. AB - BACKGROUND: Meiosis is the sexual reproduction process common to eukaryotes. The diploid yeast Saccharomyces cerevisiae undergoes meiosis in sporulation medium to form four haploid spores. Initiation of the process is tightly controlled by intricate networks of positive and negative feedback loops. Intriguingly, expression of early meiotic proteins occurs within a narrow time window. Further, sporulation efficiency is strikingly different for yeast strains with distinct mutations or genetic backgrounds. To investigate signal transduction pathways that regulate transient protein expression and sporulation efficiency, we develop a mathematical model using ordinary differential equations. The model describes early meiotic events, particularly feedback mechanisms at the system level and phosphorylation of signaling molecules for regulating protein activities. RESULTS: The mathematical model is capable of simulating the orderly and transient dynamics of meiotic proteins including Ime1, the master regulator of meiotic initiation, and Ime2, a kinase encoded by an early gene. The model is validated by quantitative sporulation phenotypes of single-gene knockouts. Thus, we can use the model to make novel predictions on the cooperation between proteins in the signaling pathway. Virtual perturbations on feedback loops suggest that both positive and negative feedback loops are required to terminate expression of early meiotic proteins. Bifurcation analyses on feedback loops indicate that multiple feedback loops are coordinated to modulate sporulation efficiency. In particular, positive auto-regulation of Ime2 produces a bistable system with a normal meiotic state and a more efficient meiotic state. CONCLUSIONS: By systematically scanning through feedback loops in the mathematical model, we demonstrate that, in yeast, the decisions to terminate protein expression and to sporulate at different efficiencies stem from feedback signals toward the master regulator Ime1 and the early meiotic protein Ime2. We argue that the architecture of meiotic initiation pathway generates a robust mechanism that assures a rapid and complete transition into meiosis. This type of systems-level regulation is a commonly used mechanism controlling developmental programs in yeast and other organisms. Our mathematical model uncovers key regulations that can be manipulated to enhance sporulation efficiency, an important first step in the development of new strategies for producing gametes with high quality and quantity. PMID- 23631507 TI - A novel native derived coronary artery tissue-flap model. AB - Although tissue-engineering approaches have led to significant progress in the quest of finding a viable substitute for dysfunctional myocardium, the vascularization of such bioartificial constructs still remains a major challenge. Hence, there is a need for model systems that allow us to study and better understand cardiac and vascular biology to overcome current limitations. Therefore, in this study, in toto decellularized rat hearts with a patent vessel system were processed into standardized coronary artery tissue flaps adherent to the ascending aorta. Protein diffusivity analysis and blood perfusion of the coronary arteries showed proper sealing of the de-endothelialized vessels. Retrograde aortic perfusion allowed for selective seeding of the coronary artery system, while surface seeding of the tissue flaps allowed for additional controlled coculture with cardiac cells. The coronary artery tissue-flap model offers a patent and perfusable coronary vascular architecture with a preserved cardiac extracellular matrix, therefore mimicking nature's input to the highest possible degree. This offers the possibility to study re-endothelialization and endothelial function of different donor cell types and their interaction with cardiac cells in a standardized biologically derived cardiac in vitro model, while establishing a platform that could be used for in vitro drug testing and stem cell differentiation studies. PMID- 23631508 TI - Psychotherapeutic treatment of survivors of traumatic brain injury: review of the literature and special considerations. AB - Abstract Primary objective: To provide an overview of useful clinical information for healthcare providers involved in traumatic brain injury (TBI) rehabilitation, including current methods used with survivors of TBI, therapeutic considerations in light of this population's cognitive, emotional and social difficulties and issues regarding the therapeutic working alliance from both survivor and provider perspectives. RESEARCH DESIGN: Non-systematic clinical review. METHOD: The literature was intended to be comprehensive to reflect both past and present contributions to the field. To that end, citations were included from seminal and current texts as well as relevant original and review articles from 1985-2012 in PubMed and PubMedCentral online research databases. MAIN OUTCOMES AND RESULTS: This article highlights the usefulness of psychotherapy for treatment of psychiatric symptoms in the TBI population, reviews available modalities and offers considerations and suggestions to facilitate and improve treatment. CONCLUSIONS: Although challenging and perhaps frustrating at times, psychotherapy with this population can be validly attempted and ultimately very rewarding for both the survivor and therapist. Future research should seek to perform controlled studies to examine therapeutic efficacy and compare gains by injury severity in the hopes of creating best practice guidelines for practitioners. PMID- 23631509 TI - Structural dynamics of N-propionyl-D-glucosamine probed by infrared spectroscopies and ab initio computations. AB - N-Acylglucosamine is an important component in many oligosaccharides in eukaryotes, where it plays a very important biological role. Located between a glucose ring and an alkyl group of such species is an amide unit (-CONH-), which exhibits an infrared absorption band, mainly due to the C?O stretching, in the region of 1600-1700 cm(-1), similar to the amide-I band found in polypeptides. In this work, vibrational properties of such an "amide-I mode" in N-propionyl-d glucosamine (GlcNPr) are examined in three typical solvents (water, methanol, and dimethylsulfoxide) by using steady-state infrared and femtosecond infrared dispersed pump-probe spectroscopies. As a result of solute-solvent interactions, multiple structured GlcNPr-solvent clusters are formed in water and methanol but are unlikely in dimethylsulfoxide. The vibrational relaxation rate of the amide-I mode is slightly frequency-dependent, supporting the presence of multiple solvated structures. Further, the amide-I lifetime is significantly shorter in GlcNPr than that in a well-known monopeptide, N-methylacetamide, which can be attributed to the presence of additional downstream vibrational modes caused by the sugar unit. Ab initio molecular dynamics simulations are used to reveal microscopic details of the first solvation shell of GlcNPr. Our results demonstrate that the amide-I mode in glucosamine exhibits both structural and solvent sensitivities that can be used to characterize the three-dimensional arrangement of sugar residues and their structural dynamics in glycopeptides. PMID- 23631510 TI - Analysis of responsive polymer films using surface acoustic waves. AB - The Surface Acoustic Wave (SAW) technique is applied for the first time to quantify the properties of a responsive polymer brush layer. Using a single SAW chip, the response of five different brush compositions to several pH changes was monitored in parallel in a single run. These results were compared with QCM-D studies on the same system. SAW exhibited two remarkable advantages against QCM D: (i) multiplexing capability, which allowed considerable reduction in experimental time and expenses (1/8 reduction of experimental time, 1/5 in the number of chips, and 1/10 in solvent consumption in our case), and (ii) higher sensitivity in both mass and viscosity change than QCM-D (4-5 times higher in our systems). Our results demonstrate the suitability and advantages of the SAW technology for application in polymer science, in particular for the study of the compositional effects in responsive thin layers. PMID- 23631511 TI - Multilocus genetic models of handedness closely resemble single-locus models in explaining family data and are compatible with genome-wide association studies. AB - Right- and left-handedness run in families, show greater concordance in monozygotic than dizygotic twins, and are well described by single-locus Mendelian models. Here we summarize a large genome-wide association study (GWAS) that finds no significant associations with handedness and is consistent with a meta-analysis of GWASs. The GWAS had 99% power to detect a single locus using the conventional criterion of P < 5 * 10(-8) for the single locus models of McManus and Annett. The strong conclusion is that handedness is not controlled by a single genetic locus. A consideration of the genetic architecture of height, primary ciliary dyskinesia, and intelligence suggests that handedness inheritance can be explained by a multilocus variant of the McManus DC model, classical effects on family and twins being barely distinguishable from the single locus model. Based on the ENGAGE meta-analysis of GWASs, we estimate at least 40 loci are involved in determining handedness. PMID- 23631512 TI - T.E.A. Study: three-day ertapenem versus three-day Ampicillin-Sulbactam. AB - BACKGROUND: Intra-abdominal infections are one of the most common infections encountered by a general surgeon. However, despite this prevalence, standardized guidelines outlining the proper use of antibiotic therapy are poorly defined due to a lack of clinical trials investigating the ideal duration of antibiotic treatment. The aim of this study is to compare the efficacy and safety of a three day treatment regimen of Ampicillin-Sulbactam to that of a three-day regimen of Ertapenem in patients with localized peritonitis ranging from mild to moderate severity. METHODS: This study is a prospective, multi-center, randomized investigation performed in the Department of General, Emergency, and Transplant Surgery of St. Orsola-Malpighi University Hospital in Bologna, Italy. Discrete data were analyzed using the Chi-squared and Fisher exact tests. Differences between the two study groups were considered statistically significant for p values less than 0.05. RESULTS: 71 patients were treated with Ertapenem and 71 patients were treated with Ampicillin-Sulbactam. The two groups were comparable in terms of age and gender as well as the site of abdominal infection. Post operative infection was identified in 12 patients: 10 with wound infections and 2 with intra-abdominal infections. In the Ertapenem group, 69 of the 71 patients (97%) were treated successfully, while the therapy failed in 2 cases (3%). Therapy failures were more frequent in the Unasyn group, amounting to 10 of 71 cases (p = 0.03). CONCLUSION: According to these preliminary findings, the authors conclude that a three-day Ertapenem treatment regimen is the most effective antibiotic therapy for patients with localized intra-abdominal infections ranging from mild to moderate severity. TRIAL REGISTRATION: Trial registration: ClinicalTrials.gov: NCT00630513. PMID- 23631513 TI - Early postoperative treatment of surgical scars using a fractional carbon dioxide laser: a split-scar, evaluator-blinded study. AB - BACKGROUND: Although focus has recently been directed toward the early treatment of surgical scars, the optimal time at which to initiate treatment with fractional laser and its effect on scar remodeling remains controversial. OBJECTIVES: To assess the safety and efficacy of treating surgical scars using an ablative carbon dioxide (CO2 ) fractional laser during the early postoperative period. MATERIALS AND METHODS: We performed a prospective, split-scar, evaluator blinded study on 16 postoperative scars of 15 patients. Patients began treatment 3 weeks after surgery and were treated in two sessions of CO2 fractional laser therapy on half of the scar at 2-week intervals. All patients were followed for 3 months after the final treatment session. RESULTS: Three months after the last treatment, a greater decrease in Vancouver Scar Scale score was noted in the treated half of the scars, especially in terms of texture and thickness. Patients also expressed a significantly greater degree of satisfaction with the treated side as assessed using a subjective 4-point scale. Only one patient experienced any adverse effect, which was the development of hypertrophy, on the treated and untreated side of the scar. CONCLUSION: CO2 fractional laser is an effective treatment modality for surgical scars in the early postoperative period. PMID- 23631514 TI - Age-related changes in melatonin release in the murine distal colon. AB - Constipation and fecal impaction are conditions of the bowel whose prevalence increases with age. Limited information is known about how these conditions manifest; however, functional deficits are likely to be due to changes in signaling within the bowel. This study investigated the effects of age on colonic mucosal melatonin (MEL) release and the consequences this had on colonic motility. Electrochemical measurements of MEL overflow demonstrated that both basal and mechanically stimulated MEL release decreased with age. The MEL/serotonin also decreased with increasing age, and the trend was similar to that of MEL overflow, suggestive that age-related changes were primarily due to a reduction in MEL levels. Levels of N-acetylserotonin and the N acetylserotonin/serotonin ratio were reduced with age, providing an explanation for the reduction in MEL release. Decreases in colonic motility were observed in animals between 3 and 24 months old. Exogenous application of MEL could reverse this deficit in aged colon. In summary, we propose that the age-related decline in MEL release may be due to either decreases or alterations in mechanosensory channels and/or a loss in levels/activity of the N-acetyltransferase enzyme responsible for the synthesis of N-acetylserotonin. Decreases in MEL release may explain the decreases in colonic motility observed in 24 month old animals and could offer a new potential therapeutic treatment for age-related constipation. PMID- 23631515 TI - Synthesis and study of three novel macrocyclic selena[n]ferrocenophanes containing a naphthalene unit. AB - Three novel macrocyclic ligands, L1-L3, in which a ferrocene unit and a fluorescent moiety are linked to polyselena rings have been designed and prepared from 1,1'-bis(3-bromopropylseleno)ferrocene. Reaction of L with [M(NCMe)4](PF6)2 (M = Pd and Pt) led to complexes [ML](PF6)2 (M = Pd and Pt). Crystal structure analysis revealed that after complexation, the macrocyclic ligand adopts the unusual c,c,c conformation due to intramolecular C-H...pi interactions from the hydrogen atoms of ferrocene moieties to the naphthalene ring. Electrochemical studies showed that in [ML](PF6)2 (M = Pd and Pt) the half-wave potential of the 1,1'-ferrocenediyl group shifts to much more positive potentials due to electron density withdrawn from Se donor atoms. Electrochemical and optical measurements were used to calculate HOMO and LUMO levels as well as HOMO-LUMO band gaps. Results were compared and correlated with the differences in molecular structures. PMID- 23631516 TI - 2-Bromopalmitate analogues as activity-based probes to explore palmitoyl acyltransferases. AB - Reversible S-palmitoylation is an important post-translational modification that regulates the trafficking, localization, and activity of proteins. Cysteine-rich Asp-His-His-Cys (DHHC) domain-containing enzymes are evolutionarily conserved protein palmitoyl acyltransferases (PATs). The human genome encodes 23 DHHC-PATs that regulate diverse cellular functions. Although chemical probes and proteomic methods to detect palmitoylated protein substrates have been reported, no probes for direct detection of the activity of PATs are available. Here we report the synthesis and characterization of 2-bromohexadec-15-ynoic acid and 2-bromooctadec 17-ynoic acid, which are analogues of 2-bromopalmitate (2-BP), as activity-based probes for PATs as well as other palmitoylating and 2-BP-binding enzymes. These probes will serve as new chemical tools for activity-based protein profiling to explore PATs, to dissect the functions of PATs in cell signaling and diseases, and to facilitate the identification of their inhibitors. PMID- 23631517 TI - Bridges, brokers and boundary spanners in collaborative networks: a systematic review. AB - BACKGROUND: Bridges, brokers and boundary spanners facilitate transactions and the flow of information between people or groups who either have no physical or cognitive access to one another, or alternatively, who have no basis on which to trust each other. The health care sector is a context that is rich in isolated clusters, such as silos and professional "tribes," in need of connectivity. It is a key challenge in health service management to understand, analyse and exploit the role of key agents who have the capacity to connect disparate groupings in larger systems. METHODS: The empirical, peer reviewed, network theory literature on brokerage roles was reviewed for the years 1994 to 2011 following PRISMA guidelines. RESULTS: The 24 articles that made up the final literature set were from a wide range of settings and contexts not just healthcare. Methods of data collection, analysis, and the ways in which brokers were identified varied greatly. We found four main themes addressed in the literature: identifying brokers and brokerage opportunities, generation and integration of innovation, knowledge brokerage, and trust. The benefits as well as the costs of brokerage roles were examined. CONCLUSIONS: Collaborative networks by definition, seek to bring disparate groups together so that they can work effectively and synergistically together. Brokers can support the controlled transfer of specialised knowledge between groups, increase cooperation by liaising with people from both sides of the gap, and improve efficiency by introducing "good ideas" from one isolated setting into another.There are significant costs to brokerage. Densely linked networks are more efficient at diffusing information to all their members when compared to sparsely linked groups. This means that while a bridge across a structural hole allows information to reach actors that were previously isolated, it is not the most efficient way to transfer information. Brokers who become the holders of, or the gatekeepers to, specialised knowledge or resources can become overwhelmed by the role and so need support in order to function optimally. PMID- 23631519 TI - A signal processing approach for the diagnosis of asthma from cough sounds. AB - Asthma is not very easy to be correctly diagnosed by physicians where asthma is considered a common chronic inflammatory disease. Distinguishing of cough sound can be used to diagnose asthma. The use of signal processing techniques of cough sound for detecting asthma will be addressed in this paper to help the diagnosis of asthma by physicians. Since cough sounds are non-stationary and are stochastic signals inherently, time-frequency transform techniques are used to deal with such signals. Time-frequency analyses are performed to show in a comprehensive approach the characteristics of the cough sound signal. Time-frequency analysis techniques, specifically Wigner distribution in addition to wavelet transform to analyse cough signals, are used in this paper. The features extracted from the time-frequency domain of the cough sound are used as inputs to the asthma and non asthma classifier. The results of the proposed algorithm are competitive to the best existing algorithms in the literature. PMID- 23631520 TI - Non-invasive, minute-to-minute estimates of systemic arterial pressure and pulse pressure variation using radial artery tonometry. AB - The Tensys T-line uses tonometry to reproduce the arterial blood pressure tracing non-invasively. The purpose of this study was to assess the agreement between estimates of the T-line and an intra-arterial catheter (for both mean arterial pressure [MAP] and pulse pressure variation [PPV]) in the setting of spine surgery. Continuous blood pressure data were collected for 7507 minutes from 25 patients. Five increasingly aggressive T-line filters were applied. The mean bias for mean, diastolic and systolic blood pressure ranged from 3.4-6.4, 3.1-7.1 and 0.1-0.8 mmHg and 6.5-11.8% for PPV. Ninety-five per cent confidence intervals for mean, diastolic and systolic blood pressure ranged from 24-28, 23.1-24.7 and 33.4 35.6 mmHg for 14-21% for PPV. The limits of agreement preclude the use of the T line for reliable estimation of MAP or PPV in spine surgery. PMID- 23631518 TI - Comparison of two functional kappa light-chain transcripts amplified from a hybridoma. AB - Three heavy-chain and three kappa (kappa)-chain transcripts were amplified from hybridoma cells secreting a monoclonal antibody (mAb) against transferrin receptor. Sequence analysis via IMGT/V-QUEST yielded the functional/aberrant prediction. Two functional kappa-chain transcripts, Vkappa2 and Vkappa3, and one functional VH1 were revealed. Comprehensive bioinformatics analyses including sequence alignment, phylogenetic tree, somatic hypermutation prediction, and three-dimensional-molecular structure modeling were used to predict the origin of the two kappa-chain transcripts. The results of bioinformatics analysis suggest that Vkappa3 is derived from the myeloma partner of the hybridoma; Vkappa2 is derived from B-cell. Functional transcripts VH1 and Vkappa2 and Vkappa3 were then used to construct two chimeric antibodies chi-C2 (Vkappa2-VH1) and chi-C3 (Vkappa3-VH1), respectively. Antigen-binding experiments showed that only chi-C2 remained the same affinity as its parental mAb. Possible explanations for the coexistence of two functional kappa-chain transcripts and the different affinity of the two chimeric antibodies are discussed. PMID- 23631521 TI - Effect of thermal cycling and disinfection on microhardness of acrylic resin denture base. AB - The purpose of this study was to investigate the effect of thermal cycling and disinfection on the microhardness of acrylic resins denture base. Four different brands of acrylic resins were evaluated: Onda Cryl, QC 20, Classico and Lucitone. Each brand of acrylic resin was divided into four groups (n = 7) according to the disinfection method (microwave, Efferdent, 4% chlorhexidine and 1% hypochlorite). Samples were disinfected during 60 days. Before and after disinfection, samples were thermal cycled between 5-55 degrees C with 30-s dwell times for 1000 cycles. The microhardness was measured using a microhardener, at baseline (B), after first thermal cycling (T1), after disinfection (D) and after second thermal cycling (T2). The microhardness values of all groups reduced over time. QC-20 acrylic resin exhibited the lowest microhardness values. At B and T1 periods, the acrylic resins exhibited statistically greater microhardness values when compared to D and T2 periods. It can be concluded that the microhardness values of the acrylic resins denture base were affected by the thermal cycling and disinfection procedures. However, all microhardness values obtained herein are within acceptable clinical limits for the acrylic resins. PMID- 23631523 TI - Evaluation of the Force Sensing Application pressure mapping system. AB - Pressure mapping techniques are used in wheelchair and seating services to assess posture and assist in the prevention and treatment of pressure ulcers. The Force Sensitive Application (FSA) pressure mapping systems in Wales have a high clinical use and frequent calibration is required. This project aimed to assess the performance of the systems and develop a calibration strategy. Testing of the systems was spilt into three stages. The pilot stage compared different calibration techniques (manual, automated and with new software) to determine the optimal calibration frequency. The second stage, longer term, was like the pilot stage with the best calibration method tested over 10 weeks. The third test was a simple before-and-after calibration test, conducted to determine the effect of calibration. It was concluded that the calibration process is essential to maintain the reliability of the mats and it was decided that the systems in Wales should be calibrated every 2 months to provide a more consistent output. PMID- 23631522 TI - The effect of probe to skin contact force on Cutometer MPA 580 measurements. AB - The purpose of this study is to test the hypothesis that increasing the force applied on the skin by the Cutometer MP580 probe will result in a decrease in the skin elasticity measures. Specifically, this study assessed the probe intrinsic weight plus the addition of a light mass (10 g and 20 g), a moderate mass (50 g and 100 g) and a high mass (200 g and 500 g) on skin elasticity measures. Primary outcome measures Uv, Ur, Uf, Ue and Ua, along with calculated measures Uv/Uf, Ua/Uf and Ur/Uf were assessed under each loading condition. A general linear model ANOVA with repeated measures was used to assess for differences in each outcome measure between each loading condition. Thirty-two patients were enrolled and all completed the testing. For all primary variables except Uv (p < 0.001), there was no statistically significant effect of adding a light mass to the probe. There was a significant effect of the addition of a moderate and heavy mass for all variables (p < 0.005) except Ue/Uf. These results suggest that the addition of a low mass results in no significant effect on outcome measures. However, if moderate-to-heavy additional force is applied to the probe, the outcome measures are significantly altered. Of all the variables, Ue/Uf appears to be influenced the least by alterations in force. Users should ensure light contact is made between the skin and probe during testing to avoid a false alteration in outcome measures of skin elasticity. PMID- 23631524 TI - Algorithm for detection of the internal components of the heart sounds and their split using a Hilbert transform. AB - Valvular heart disease is a serious heart condition that is difficult to diagnose in ambulatory settings. Heart sounds is one of the most relevant diagnosis signals in this context. The time interval between the two internal components of the two heart sounds in the medical field known as 'split' was considered by many researchers and one study is described as the key medical diagnosis by many clinicians. Compared to the energy envelope Shannon Hilbert envelope is greater awareness of the internal components of the first and second heart sound. The morphology of this envelope will allow one to apply the necessary tests for the temporal localization of the internal components of the two heart sounds. According to the results obtained, the Hilbert envelope is an approach and representation taking into account the physiological attenuation and giving a good separation. PMID- 23631527 TI - Solubility properties and spectral investigation of dilute SO2 in a triethylene glycol + water + La3+ system. AB - Isothermal gas-liquid equilibrium (GLE) data were determined for dilute SO2 in a triethylene glycol (TEG) + water (W) system (TEGW) at 298.15 K and 123.15 kPa, in which SO2 partial pressures were calculated in the range 0-130 Pa. When La(3+) was added into TEGWs, GLE data suggested that adding of La(3+) ion markedly increased the solubility of dilute SO2. By fitting of these data, Henry's law constants (HLC) were obtained. For acquiring the important absorption mechanism, UV, FTIR, (1)H NMR, and fluorescence spectra in absorption processes of SO2 were investigated. On the basis of these spectral results, the possibility of intermolecular hydrogen bond formation by hydroxyl oxygen atoms in the TEG molecule with hydrogen atoms in the H2O molecule and S...O interaction formation by hydroxyl oxygen atoms in the TEG molecule with the sulfur atom in the SO2 molecule was discussed. PMID- 23631528 TI - Designed amphiphilic beta-sheet peptides as templates for paraoxon adsorption and detection. AB - Amphiphilic peptides were designed to fold into a beta-sheet monolayer structure while presenting the catalytic triad residues of the enzyme, acetylcholinesterase (Glu, His, and Ser), to a solution containing the organophosphate, paraoxon. Three peptides, in which the catalytic triad residues were arranged in different orders along the strand, were generated to reveal potential differences in interactions with paraoxon as a function of the order of these amino acids. One additional peptide with amino acids introduced in random order was studied to highlight the contribution of the beta-sheet secondary structure to any interactions with paraoxon. Langmuir isotherms, Brewster angle microscope at interfaces, and circular dichroism measurements in bulk showed that both the beta sheet conformation and the order of the amino acids along the strand influenced the interactions of paraoxon with the peptides. Compression isotherm curves as well as Brewster angle microscopy images provided evidence for enhanced adsorption of the paraoxon to the monolayers of peptides, which present neighboring Glu and Ser residues along the hydrophilic face of the beta-strand. Circular dichroism revealed that the peptide most sensitive to interactions with paraoxon was that with the triad residues in the order Glu, Ser, and His, which appears to be appropriate for supporting a catalytic mechanism similar to that in the acetylcholinesterase enzyme. These rationally designed peptides may be further used for the development of technologies for organophosphate adsorption and detection. PMID- 23631530 TI - Enhanced recovery of alkaline protease from fish viscera by phase partitioning and its application. AB - BACKGROUND: Too many different protein and enzyme purification techniques have been reported, especially, chromatographic techniques. Apart from low recovery, these multi-step methods are complicated, time consuming, high operating cost. So, alternative beneficially methods are still required. Since, the outstanding advantages of aqueous two phase system (ATPS) such as simple, low cost, high recovery and scalable, ATPS have been used to purify various enzymes. To improve purification efficiency, parameters affected to enzyme recovery or purity was investigated. The objectives of the present study were to optimize of alkaline protease recovery from giant catfish fish viscera by using ATPS and to study of hydrolytic patterns against gelatin. RESULTS: Using 70% (w/w) crude enzyme extract (CE) in system (15% PEG2000-15% sodium citrate) provided the highest recovery, PF and KE. At unmodified pH (8.5) gave the best recovery and PF with compare to other pHs of the system. The addition of 1% (w/w) NaCl showed the recovery (64.18%), 3.33-fold and 15.09 of KE compared to the system without NaCl. After addition of 10% (w/w) sodium citrate in the second ATPS cycle, the highest protease recovery (365.53%) and PF (11.60-fold) were obtained. Thus, the top phase from the system was subjected to further studied. The protein bands with molecular weights (MWs) of 20, 24, 27, 36, 94 and 130 kDa appeared on the protein stained gel and also exhibited clear zone on casein-substrate gel electrophoresis. The beta, alpha1, alpha2 of skin gelatin extensively degraded into small molecules when treated with 10 units of the extracted alkaline protease compared to those of the level of 0.21 units of Flavourzyme. CONCLUSIONS: Repetitive ATPS is the alternative strategy to increase both recovery and purity of the alkaline protease from farmed giant catfish viscera. Extracted alkaline protease exposed very high effectiveness in gelatin hydrolysis. It is suggested that the alkaline protease from this fish viscera can further be used in protein hydrolysate production. PMID- 23631532 TI - Esthetic and functional rehabilitation via reattachment of dental fragments. AB - Anterior teeth fractures are frequently encountered in clinical practice. The reattachment of dental fragments, if possible, is a conservative and effective technique, which is utilized in this case. This case presentation concerns an 18 year-old male patient with a root-crown fracture of the left maxillary central incisor, which involves the periodontal biologic space. The treatment was the reattachment of the dental fragment with a composite resin and adhesive, in association with periodontal surgery. The reattachment technique described in this case report is simple, but it provides long-lasting esthetics and improved function via a very conservative approach. PMID- 23631531 TI - Ancient origin of somatic and visceral neurons. AB - BACKGROUND: A key to understanding the evolution of the nervous system on a large phylogenetic scale is the identification of homologous neuronal types. Here, we focus this search on the sensory and motor neurons of bilaterians, exploiting their well-defined molecular signatures in vertebrates. Sensorimotor circuits in vertebrates are of two types: somatic (that sense the environment and respond by shaping bodily motions) and visceral (that sense the interior milieu and respond by regulating vital functions). These circuits differ by a small set of largely dedicated transcriptional determinants: Brn3 is expressed in many somatic sensory neurons, first and second order (among which mechanoreceptors are uniquely marked by the Brn3+/Islet1+/Drgx+ signature), somatic motoneurons uniquely co-express Lhx3/4 and Mnx1, while the vast majority of neurons, sensory and motor, involved in respiration, blood circulation or digestion are molecularly defined by their expression and dependence on the pan-visceral determinant Phox2b. RESULTS: We explore the status of the sensorimotor transcriptional code of vertebrates in mollusks, a lophotrochozoa clade that provides a rich repertoire of physiologically identified neurons. In the gastropods Lymnaea stagnalis and Aplysia californica, we show that homologues of Brn3, Drgx, Islet1, Mnx1, Lhx3/4 and Phox2b differentially mark neurons with mechanoreceptive, locomotory and cardiorespiratory functions. Moreover, in the cephalopod Sepia officinalis, we show that Phox2 marks the stellate ganglion (in line with the respiratory--that is, visceral--ancestral role of the mantle, its target organ), while the anterior pedal ganglion, which controls the prehensile and locomotory arms, expresses Mnx. CONCLUSIONS: Despite considerable divergence in overall neural architecture, a molecular underpinning for the functional allocation of neurons to interactions with the environment or to homeostasis was inherited from the urbilaterian ancestor by contemporary protostomes and deuterostomes. PMID- 23631533 TI - Odontogenic osteomyelitis or bisphosphonate-related osteonecrosis of mandible of patient with autoimmune disease: clinical dilemma. AB - The key to appropriate treatment of odontogenic osteomyelitis or bisphosphonate related osteonecrosis of the mandible in patients with autoimmune diseases lies in making the correct diagnosis based on meticulous review of signs and symptoms. As this complex case involving a patient with multiple comorbidities illustrates, diagnosis can be difficult, because these conditions may overlap or be mistaken for other conditions. However, prompt treatment is essential to limit the progression, which can be devastating for these medically complex patients. It is, therefore, important to understand local and systemic conditions that can weaken the immune system and predispose patients to chronic bone infection, meticulously go through signs and symptoms, and have a complete medical history, including patient medications. PMID- 23631534 TI - Conservative approach for esthetic repair of fractured ceramic facing in ceramic fused-to-metal crowns: a case series. AB - The new era of dentistry works on the principle of conservation and minimal intervention for treatment of any dental pathology. Thus, there is greater emphasis on repair procedures than on replacement protocols required. The following article outlines a common conservative repair protocol for fractured ceramic facings of ceramic-fused-to-metal (CFM) crowns. It also includes brief descriptions of several patients treated using the same basic protocol along with modifications as per the case requirement. PMID- 23631535 TI - Re-reattachment of a fractured maxillary central incisor: a case study. AB - There has been a rise in incidence of dental trauma and crown fractures as reported in the literature. Children and teenagers are the most affected age groups, and the maxillary central incisors are the teeth most often affected. This article discusses reattachment techniques for the restoration of fractured teeth when the tooth fragment is recovered after a traumatic dental injury. This particular case study reports re-reattachment of a previously fractured and reattached tooth fragment. PMID- 23631536 TI - Treatment of peri-implantitis using nonsurgical debridement with bioresorbable nanospheres for controlled release of doxycycline: case report. AB - Peri-implantitis treatment is often surgical; however, in this case report, an alternative approach has been documented using a combination of nonsurgical debridement with the local controlled release of doxycycline by bioresorbable nanospheres in the peri-implant defect. After 15 months, remission on clinical inflammatory parameters of bleeding and suppuration on probing, as well as reduction of probing depths, was observed. This alternative approach may enhance clinical parameter improvements in some cases of peri-implantitis without the need for a surgical approach for implant decontamination. PMID- 23631537 TI - Self-report of latex allergy by patients visiting a dental clinic. AB - BACKGROUND: The prevalence of latex allergy among dental patients is not known, although it has been increasing in the population since 1982, when the use of gloves was expanded to prevent the transmission of infectious diseases. METHODS: A retrospective cross-sectional study was undertaken of 1,798 electronic health records (EHRs) of new clinic patients who registered at the University of Pittsburgh School of Dental Medicine (SDM) dental clinic between January and June 2010. Data extracted from the EHRs included age, gender, and a history of a previous latex reaction, asthma, or allergy to penicillin. RESULTS: A previous reaction to latex was reported by 59 patients (3.3%). Women were almost three times more likely to report this (4.7% versus 1.6%, P = 0.0005). Histories of asthma or penicillin allergy in women were significantly associated with latex allergy (P = 0.0005 and P = 0.0001, respectively). CONCLUSIONS: The reported rate of a previous reaction to latex in this patient sample was higher than that of the general population. This may, in part, be related to repeated exposures to latex-containing gloves. CLINICAL IMPLICATIONS: Practitioners are increasingly likely to encounter patients who have had a reaction to latex. Non-latex products must be available for these patients, who are more likely to be women and individuals with asthma or an allergy to penicillin. PMID- 23631538 TI - Non-destructive monitoring of creaming of oil-in-water emulsion-based formulations using magnetic resonance imaging. AB - A non-destructive method for monitoring creaming of emulsion-based formulations is in great demand because it allows us to understand fully their instability mechanisms. This study was aimed at demonstrating the usefulness of magnetic resonance (MR) techniques, including MR imaging (MRI) and MR spectroscopy (MRS), for evaluating the physicochemical stability of emulsion-based formulations. Emulsions that are applicable as the base of practical skin creams were used as test samples. Substantial creaming was developed by centrifugation, which was then monitored by MRI. The creaming oil droplet layer and aqueous phase were clearly distinguished by quantitative MRI by measuring T1 and the apparent diffusion coefficient. Components in a selected volume in the emulsions could be analyzed using MRS. Then, model emulsions having different hydrophilic-lipophilic balance (HLB) values were tested, and the optimal HLB value for a stable dispersion was determined. In addition, the MRI examination enables the detection of creaming occurring in a polyethylene tube, which is commonly used for commercial products, without losing any image quality. These findings strongly indicate that MR techniques are powerful tools to evaluate the physicochemical stability of emulsion-based formulations. This study will make a great contribution to the development and quality control of emulsion-based formulations. PMID- 23631539 TI - Evaluation of intratympanic formulations for inner ear delivery: methodology and sustained release formulation testing. AB - A convenient and efficient in vitro diffusion cell method to evaluate formulations for inner ear delivery via the intratympanic route is currently not available. The existing in vitro diffusion cell systems commonly used to evaluate drug formulations do not resemble the physical dimensions of the middle ear and round window membrane. The objectives of this study were to examine a modified in vitro diffusion cell system of a small diffusion area for studying sustained release formulations in inner ear drug delivery and to identify a formulation for sustained drug delivery to the inner ear. Four formulations and a control were examined in this study using cidofovir as the model drug. Drug release from the formulations in the modified diffusion cell system was slower than that in the conventional diffusion cell system due to the decrease in the diffusion surface area of the modified diffusion cell system. The modified diffusion cell system was able to show different drug release behaviors among the formulations and allowed formulation evaluation better than the conventional diffusion cell system. Among the formulations investigated, poly(lactic-co-glycolic acid) poly(ethylene glycol)-poly(lactic-co-glycolic acid) triblock copolymer systems provided the longest sustained drug delivery, probably due to their rigid gel structures and/or polymer-to-cidofovir interactions. PMID- 23631541 TI - Suicide: a national health challenge, an army health threat. PMID- 23631540 TI - Combined neurostimulation and neuroimaging in cognitive neuroscience: past, present, and future. AB - Modern neurostimulation approaches in humans provide controlled inputs into the operations of cortical regions, with highly specific behavioral consequences. This enables causal structure-function inferences, and in combination with neuroimaging, has provided novel insights into the basic mechanisms of action of neurostimulation on distributed networks. For example, more recent work has established the capacity of transcranial magnetic stimulation (TMS) to probe causal interregional influences, and their interaction with cognitive state changes. Combinations of neurostimulation and neuroimaging now face the challenge of integrating the known physiological effects of neurostimulation with theoretical and biological models of cognition, for example, when theoretical stalemates between opposing cognitive theories need to be resolved. This will be driven by novel developments, including biologically informed computational network analyses for predicting the impact of neurostimulation on brain networks, as well as novel neuroimaging and neurostimulation techniques. Such future developments may offer an expanded set of tools with which to investigate structure-function relationships, and to formulate and reconceptualize testable hypotheses about complex neural network interactions and their causal roles in cognition. PMID- 23631543 TI - Reflections on suicide among soldiers. AB - This commentary considers the Nock et al. review article (this issue) and provides additional perspectives pertaining to current concerns about Soldier suicides. The review article is relevant to the current Army STARRS research project, which is one of the most significant scientific undertakings in the history of suicide research. The review is an outstanding and thorough consideration of psychosocial risk and protective factors that may be related to Soldier suicide. While Army STARRS is a landmark effort, the author does note the need for innovation and alternative approaches to addressing alarming increases in Soldier suicides. Indeed, the dramatic increase seen in Soldier suicides over the past several years poses one of the more vexing challenges that the field of suicidology has faced to date. To this end, the author explores some alternative considerations that were not particularly featured in the review article. Some of these considerations include perspectives on military culture in relation to conventional suicide prevention as well as exciting developments emerging from clinical trial treatment research using suicidal military samples. It is argued that the magnitude of the current problem requires both innovative approaches and a sound scientific foundation to meaningfully impact and reduce the unprecedentedly high rates of Soldier suicide. PMID- 23631544 TI - Psychoanalytic versus psychodynamic therapy for depression: a three-year follow up study. AB - The aim of this study was to investigate the effectiveness of long-term psychoanalytic and psychodynamic psychotherapies. In a prospective, randomized outcome study, psychoanalytic (mean duration: 39 months, mean dose: 234 sessions) and psychodynamic (mean duration: 34 months, mean dose: 88 sessions) therapy were compared at post-treatment and at one-, two-, and three-year follow-up in the treatment of patients with a primary diagnosis of unipolar depression. All treatments were carried out by experienced psychotherapists. Primary outcome measures were the Beck Depression Inventory and the Scales of Psychological Capacities, and secondary outcome measures were the Global Severity Index of the Symptom Checklist 90-R, the Inventory of Interpersonal Problems, the Social Support Questionnaire, and the INTREX Introject Questionnaire. Interviewers at pre- and post-treatment and at one-year follow-up were blinded; at two- and three year follow-up, all self-report instruments were mailed to the patients. Analyses of covariance, effect sizes, and clinical significances were calculated to contrast the groups. We found significant outcome differences between treatments in terms of depressive and global psychiatric symptoms, personality functioning, and social relations at three-year follow-up, with psychoanalytic therapy being more effective. No outcome differences were found in terms of interpersonal problems. We concluded that psychoanalytic therapy associated with its higher treatment dose shows longer-lasting effects. PMID- 23631545 TI - Hospitalization-based treatment for postpartum depressed mothers and their babies: rationale, principles, and preliminary follow-up data. AB - This paper describes the rationale and treatment principles of a mother-infant unit for severely depressed mothers and their infants in Flanders (Belgium). The unit integrates systemic, psychodynamic, and cognitive behavioral treatment approaches, and aims at improvements on three levels: (1) improving mood and interpersonal relationships in depressed mothers, (2) fostering a positive mother infant relationship, and (3) establishing a supportive environment outside the treatment setting for both mother and infant. In addition, we present preliminary data of a 3.5-year naturalistic follow-up study of postpartum depressed mothers (n = 41) admitted at this mother-infant unit between April 2003 and April 2005. Results showed that at 3.5-year follow-up a considerable subgroup of mothers (61%) were functioning relatively well, as indicated by low levels of depressive symptoms, anxiety and anger, negative affect, and relatively high levels of positive affect. Yet, in line with other studies, a relatively large subgroup of mothers (39%) continued to suffer from (severe) depression during follow-up. Using a Life History Calendar method, it was found that, compared to currently nondepressed mothers, mothers who were depressed at follow-up did not have more depressive episodes but had longer depressive episodes, received more psychotherapy after hospitalization, and experienced more negative life events during the 3.5-year follow-up period. Implications of these findings for future research and intervention strategies in postpartum depression are discussed. PMID- 23631542 TI - Suicide among soldiers: a review of psychosocial risk and protective factors. AB - Suicide is difficult to predict and prevent and remains a leading cause of death worldwide. Although soldiers historically have had a suicide rate well below that of the general population, the suicide rate among members of the U.S. Army has increased markedly over the past several years and now exceeds that of the general population. This paper reviews psychosocial factors known to be associated with the increased risk of suicidal behavior in general and describes how some of these factors may be especially important in understanding suicide among soldiers. Moving forward, the prevention of suicide requires additional research aimed at: (a) better describing when, where, and among whom suicidal behavior occurs, (b) using exploratory studies to discover new risk and protective factors, (c) developing new methods of predicting suicidal behavior that synthesize information about modifiable risk and protective factors from multiple domains, and (d) understanding the mechanisms and pathways through which suicidal behavior develops. Although the scope and severity of this problem is daunting, the increasing attention and dedication to this issue by the Armed Forces, scientists, and society provide hope for our ability to better predict and prevent these tragic outcomes in the future. PMID- 23631546 TI - Peer deviance, social support, and symptoms of internalizing disorders among youth exposed to Hurricane Georges. AB - This study examined the influence of peers in meeting DSM-IV symptom criteria for an internalizing disorder in adolescents exposed to Hurricane Georges. Participants included a representative community sample of 905 youth (n = 476 boys) ages 11-17, residing in Puerto Rico. Data were gathered on hurricane exposure, symptoms of internalizing disorders, peer social support, peer violence, and peer substance use through in-person structured interviews with adolescents and caretakers from 1999 to 2000 in Puerto Rico, 12-27 months after Hurricane Georges. Hurricane exposure, peer violence, and peer substance use predicted whether adolescents met DSM-IV symptom criteria for a measured internalizing disorder. An interaction was found between hurricane exposure and peer violence, which indicated that hurricane exposure was significantly related to meeting DSM-IV symptom criteria for an internalizing disorder among adolescents who do not report associating with violent peers. However, for participants who reported high levels of peer violence, hurricane exposure did not convey additional risk for meeting DSM-IV symptom criteria for an internalizing disorder. With the increasing role peers play in adolescents' lives, understanding the influence of peers on the development of internalizing symptoms following hurricane exposure may assist in planning developmentally sensitive response plans. PMID- 23631549 TI - Share with women. Making decisions about prenatal tests for birth defects. PMID- 23631550 TI - Coping and distress in caregivers of patients with disorders of consciousness. AB - OBJECTIVES: To study depression, anxiety, maladjustment and coping in caregivers of patients in vegetative state (VS) or minimally conscious state (MCS). MATERIALS AND METHODS: Fifty-three caregivers of 43 patients with VS or MCS were assessed using Beck Anxiety Inventory, Beck Depression Inventory, maladjustment scale and Brief Coping Orientation of Problems Experienced (COPE-28). RESULTS: There were 15 clinical cases (cut-off >= 21) of anxiety (28.30%); 16 cases (cut off >= 21) of depression (30.20%); and 45 cases (cut-off >= 12) of maladjustment (84.8%). Active and problem-focused (Active coping, Instrumental support, Planning and Acceptance) were the most frequently used coping strategies. Acceptance predicted the absence of depression (p = 0.000, Cohen's d = 1.08) and anxiety (p = 0.000, Cohen's d = 1.08). Denial was associated with depression (p = 0.000, Cohen's d = 1.65) and anxiety (p = 0.000, Cohen's d = 1.23). Self-blame was associated with greater anxiety (p = 0.001, Cohen's d = 1.06) and depression (p = 0.001, Cohen's d = 1.07). Emotion-focused coping was associated with anxiety (p = 0.000, Cohen's d = 1.29) and depression (p = 0.001, Cohen's d = 1.11). CONCLUSIONS: Caregivers of patients with VS or MCS presented high levels of distress. Psychological support for caregivers of patients with VS or MCS is necessary. The most frequently used coping strategies were Active and Problem focused. Acceptance was highly protective, but Denial, Self-blame and Emotion focused strategies were very negative. PMID- 23631551 TI - Implicit and explicit second language training recruit common neural mechanisms for syntactic processing. AB - In contrast to native language acquisition, adult second-language (L2) acquisition occurs under highly variable learning conditions. Although most adults acquire their L2 at least partially through explicit instruction, as in a classroom setting, many others acquire their L2 primarily through implicit exposure, as is typical of an immersion environment. Whether these differences in acquisition environment play a role in determining the neural mechanisms that are ultimately recruited to process L2 grammar has not been well characterized. This study investigated this issue by comparing the ERP response to novel L2 syntactic rules acquired under conditions of implicit exposure and explicit instruction, using a novel laboratory language-learning paradigm. Native speakers tested on these stimuli showed a biphasic response to syntactic violations, consisting of an earlier negativity followed by a later P600 effect. After merely an hour of training, both implicitly and explicitly trained learners who were capable of detecting grammatical violations also elicited P600 effects. In contrast, learners who were unable to discriminate between grammatically correct and incorrect sentences did not show significant P600 effects. The magnitude of the P600 effect was found to correlate with learners' behavioral proficiency. Behavioral measures revealed that successful learners from both the implicit and explicit groups gained explicit, verbalizable knowledge about the L2 grammar rules. Taken together, these results indicate that late, controlled mechanisms indexed by the P600 play a crucial role in processing a late-learned L2 grammar, regardless of training condition. These findings underscore the remarkable plasticity of later, attention-dependent processes and their importance in lifelong learning. PMID- 23631553 TI - Biobased chitosan/polybenzoxazine cross-linked films: preparation in aqueous media and synergistic improvements in thermal and mechanical properties. AB - A novel class of polymer blends has been prepared from main-chain-type benzoxazine polymer (MCBP) and chitosan (CTS), a modified biomacromolecule. A water-soluble, main-chain-type benzoxazine polymer, MCBP(BA-tepa), was synthesized from the reaction of bisphenol A (BA), tetraethylenepentamine (TEPA) and formalin. The structure of the MCBP(BA-tepa) was confirmed by proton nuclear magnetic resonance spectroscopy ((1)H NMR) and Fourier transform infrared spectroscopy (FT-IR). The polymer blends were prepared by mixing MCBP(BA-tepa) and CTS in aqueous acetic acid solution (1%). The CTS/MCBP(BA-tepa) films are cross-linked by thermal treatment via the ring-opening polymerization of benzoxazine structures in the main chain to produce an AB-cross-linked network. Differential scanning calorimetry (DSC) and FT-IR were used to study the effects of CTS on the polymerization behavior of benzoxazine. Hydrogen bonding between polybenzoxazine and CTS structures was also observed. The mechanical and thermal properties of cross-linked CTS/MCBP(BA-tepa) films were evaluated, and the results showed unusual levels of synergism. In particular, the tensile strength and thermal stability were significantly enhanced in a nonlinear fashion. PMID- 23631552 TI - Murine muscle engineered from dermal precursors: an in vitro model for skeletal muscle generation, degeneration, and fatty infiltration. AB - Skeletal muscle can be engineered by converting dermal precursors into muscle progenitors and differentiated myocytes. However, the efficiency of muscle development remains relatively low and it is currently unclear if this is due to poor characterization of the myogenic precursors, the protocols used for cell differentiation, or a combination of both. In this study, we characterized myogenic precursors present in murine dermospheres, and evaluated mature myotubes grown in a novel three-dimensional culture system. After 5-7 days of differentiation, we observed isolated, twitching myotubes followed by spontaneous contractions of the entire tissue-engineered muscle construct on an extracellular matrix (ECM). In vitro engineered myofibers expressed canonical muscle markers and exhibited a skeletal (not cardiac) muscle ultrastructure, with numerous striations and the presence of aligned, enlarged mitochondria, intertwined with sarcoplasmic reticula (SR). Engineered myofibers exhibited Na(+)- and Ca(2+) dependent inward currents upon acetylcholine (ACh) stimulation and tetrodotoxin sensitive spontaneous action potentials. Moreover, ACh, nicotine, and caffeine elicited cytosolic Ca(2+) transients; fiber contractions coupled to these Ca(2+) transients suggest that Ca(2+) entry is activating calcium-induced calcium release from the SR. Blockade by d-tubocurarine of ACh-elicited inward currents and Ca(2+) transients suggests nicotinic receptor involvement. Interestingly, after 1 month, engineered muscle constructs showed progressive degradation of the myofibers concomitant with fatty infiltration, paralleling the natural course of muscular degeneration. We conclude that mature myofibers may be differentiated on the ECM from myogenic precursor cells present in murine dermospheres, in an in vitro system that mimics some characteristics found in aging and muscular degeneration. PMID- 23631554 TI - Matrix isolation studies of carbonic acid--the vapor phase above the beta polymorph. AB - Twenty years ago two different polymorphs of carbonic acid, alpha- and beta H2CO3, were isolated as thin, crystalline films. They were characterized by infrared and, of late, by Raman spectroscopy. Determination of the crystal structure of these two polymorphs, using cryopowder and thin film X-ray diffraction techniques, has failed so far. Recently, we succeeded in sublimating alpha-H2CO3 and trapping the vapor phase in a noble gas matrix, which was analyzed by infrared spectroscopy. In the same way we have now investigated the beta-polymorph. Unlike alpha-H2CO3, beta-H2CO3 was regarded to decompose upon sublimation. Still, we have succeeded in isolation of undecomposed carbonic acid in the matrix and recondensation after removal of the matrix here. This possibility of sublimation and recondensation cycles of beta-H2CO3 adds a new aspect to the chemistry of carbonic acid in astrophysical environments, especially because there is a direct way of beta-H2CO3 formation in space, but none for alpha-H2CO3. Assignments of the FTIR spectra of the isolated molecules unambiguously reveal two different carbonic acid monomer conformers (C(2v) and C(s)). In contrast to the earlier study on alpha-H2CO3, we do not find evidence for centrosymmetric (C(2h)) carbonic acid dimers here. This suggests that two monomers are entropically favored at the sublimation temperature of 250 K for beta-H2CO3, whereas they are not at the sublimation temperature of 210 K for alpha-H2CO3. PMID- 23631555 TI - Developing a questionnaire to identify perceived barriers for implementing the Dutch physical therapy COPD clinical practice guideline. AB - BACKGROUND: Clinical practice guidelines have been developed to assist healthcare practitioners in clinical decision making. Publication of clinical practice guidelines does not automatically lead to their uptake and barrier identification has been recognized as an important step in implementation planning. This study aimed at developing a questionnaire to identify perceived barriers for implementing the Dutch COPD guideline for physical therapists and its recommended measurement instruments. METHODS: An overall questionnaire, based on two existing questionnaires, was constructed to identify barriers and facilitators for implementing the COPD guideline. The construct of the questionnaire was assessed in a cross-sectional study among 246 chest physical therapists. Factor analysis was conducted to explore underlying dimensions. Psychometric properties were analyzed using Cronbach's alpha. Barriers and facilitators were assessed using descriptive statistics. RESULTS: Some 139 physical therapists (57%) responded. Factor analysis revealed 4-factor and 5-factor solutions with an explained variance of 36% and 39% respectively. Cronbach's alpha of the overall questionnaire was 0.90, and varied from 0.66 to 0.92 for the different factors. Underlying domains of the 5-factor solution were characterized as: attitude towards using measurement instruments, knowledge and skills of the physical therapist, applicability of the COPD guideline, required investment of time & money, and patient characteristics. Physical therapists showed a positive attitude toward using the COPD guideline. Main barriers for implementation were required time investment and financial constraints. CONCLUSIONS: The construct of the questionnaire revealed relevant underlying domains for the identification of barriers and facilitators for implementing the COPD guideline. The questionnaire allowed for tailoring to the target group and may be used across health care professionals as basis for in-depth analysis of barriers to specific recommendations in guidelines. The results of the questionnaire alone do not provide sufficient information to inform the development of an implementation strategy. The infrastructure for developing the guideline can be used for addressing key barriers by the guideline development group, using the questionnaire as well as in-depth analysis such as focus group interviews. Further development of methods for prospective identification of barriers and consequent tailoring of implementation interventions is required. PMID- 23631557 TI - Pathological (late) fractures of the mandibular angle after lower third molar removal: a case series. AB - INTRODUCTION: Pathological (late) fracture of the mandibular angle after third molar surgery is very rare (0.005% of third molar removals). There are 94 cases reported in the literature; cases associated with osseous pathologies such as osteomyelitis or any local and systemic diseases that may compromise mandibular bone strength have not been included. We describe three new cases of pathological (late) fracture of the mandibular angle after third molar surgery. CASE PRESENTATIONS: The first patient was a 27-year-old Caucasian man who had undergone surgical removal of a 3.8, mesioangular variety, class II-C third molar 20 days before admission to our clinic. The fracture of his left mandibular angle, complete and composed, occurred during chewing. The second patient was a 32-year-old Caucasian man. He had undergone surgical removal of a 3.8, mesioangular variety, class II-B third molar 22 days before his admission. The fracture, which occurred during mastication, was studied by computed tomography that showed reparative tissue in the fracture site. The third patient was a 36 year-old Caucasian man who had undergone surgical removal of a 3.8, vertical variety, class II-C third molar 25 days before the observation. In this case the fracture of his mandibular angle was oblique (unfavorable), complete and composed. The fracture had occurred during chewing. We studied the fracture by optical projection tomography and computed tomography.All of the surgical removals of the 3.8 third molars, performed by the patients' dentists who had more than 10 years of experience, were difficult. We treated the fractures with open surgical reduction, internal fixation by titanium miniplates and intermaxillary elastic fixation removed after 6 weeks. CONCLUSIONS: The literature indicates that the risk of pathological (late) fracture of the mandibular angle after third molar surgery for total inclusions (class II-III, type C) is twice that of partial inclusions due to the necessity of ostectomies more generous than those for partial inclusions. Other important factors are the anatomy of the teeth and the features of the teeth roots. These fractures predominantly occur in patients who are older than 25 years. The highest incidence (67.8% of cases) is found in the second and third week postsurgery. We emphasize that before the third molar surgery it is extremely important to always provide adequate instructions to the patient in order to avoid early masticatory loads and prevent this rare event. PMID- 23631558 TI - Conductance enhancement of InAs/InP heterostructure nanowires by surface functionalization with oligo(phenylene vinylene)s. AB - We have investigated the electronic transport through 3 MUm long, 45 nm diameter InAs nanowires comprising a 5 nm long InP segment as electronic barrier. After assembly of 12 nm long oligo(phenylene vinylene) derivative molecules onto these InAs/InP nanowires, we observed a pronounced, nonlinear I-V characteristic with significantly increased currents of up to 1 MUA at 1 V bias, for a back-gate voltage of 3 V. As supported by our model calculations based on a nonequilibrium Green Function approach, we attribute this effect to charge transport through those surface-bound molecules, which electrically bridge both InAs regions across the embedded InP barrier. PMID- 23631559 TI - Heterologous expression and biochemical characterization of an endo-beta-1,4 glucanase from Thermobifida fusca. AB - The endoglucanase Cel5A from Thermobifida fusca was cloned and expressed in Escherichia coli BL21(DE3). The carboxymethyl cellulase (CMCase) activity in shake flasks and 3-L fermentation scale reached 46.8 and 656.6 IU/mL, respectively. The CMCase activity in 3-L fermentation scale represented the highest yield of T. fusca Cel5A reported so far. Recombinant Cel5A was purified and characterized in detail. The optimum temperature of recombinant enzyme was 80 degrees C, and the half-life of the enzyme was 132 H at 50 degrees C and 65 H at 60 degrees C. The activity of recombinant Cel5A was retained more than 90% over the range of pH 5.0-10.0 with maximal activity at pH 5.5. Using carboxymethyl cellulose as the substrate, the Km and Vmax values were 5.1 mg/mL and 48.7 IU/mg, respectively. The enzyme showed superstability in surfactants and was retained above 90% activity after treatment with sodium dodecyl sulfate, linear alkyl benzene sulfonate, fatty alcohol polyoxyethylene (9) ether, and polyoxyethylene (10) nonyl phenyl ether at 25 degrees C for 1 H, indicating that the enzyme could be a valuable component in detergents. The potential mechanism of this stability was investigated by analysis of the electrostatic potential of the surface of the enzyme. PMID- 23631560 TI - Comparison of phenol matricectomy and nail-splinting with a flexible tube for the treatment of ingrown toenails. AB - BACKGROUND: The treatment of ingrown toenail is usually bothersome for patients and doctors. OBJECTIVES: To compare two treatment techniques of ingrown toenails phenol matricectomy (PM) and nail-splinting using a flexible tube (FT)-in terms of efficacy, postoperative pain, postoperative cosmetic satisfaction, amount of tissue damage, and recurrence. METHODS AND MATERIALS: One hundred twenty ingrown toenails were randomized and divided into PM and FT groups. All cases were evaluated 2 days and 1 and 6 months after treatment. Postoperative pain, cosmetic satisfaction, time to recovery, and recurrence rate were measured. RESULTS: Postoperative pain was less and cosmetic satisfaction was good in both groups (p <.001). Our recurrence rate was 8.4%. There were no statistical differences between groups in these measures. Tissue improvement rate was 6% in the PM group and 93% in the FT group 2 days after the procedures (p <.001). CONCLUSIONS: Although FT provides faster recovery and less postoperative morbidity than PM, the techniques are equally effective in treating ingrown toenails. PMID- 23631561 TI - Membrane fusion-competent virus-like proteoliposomes and proteinaceous supported bilayers made directly from cell plasma membranes. AB - Virus-like particles are useful materials for studying virus-host interactions in a safe manner. However, the standard production of pseudovirus based on the vesicular stomatitis virus (VSV) backbone is an intricate procedure that requires trained laboratory personnel. In this work, a new strategy for creating virus like proteoliposomes (VLPLs) and virus-like supported bilayers (VLSBs) is presented. This strategy uses a cell blebbing technique to induce the formation of nanoscale vesicles from the plasma membrane of BHK cells expressing the hemagglutinin (HA) fusion protein of influenza X-31. These vesicles and supported bilayers contain HA and are used to carry out single particle membrane fusion events, monitored using total internal reflection fluorescence microscopy. The results of these studies show that the VLPLs and VLSBs contain HA proteins that are fully competent to carry out membrane fusion, including the formation of a fusion pore and the release of fluorophores loaded into vesicles. This new strategy for creating spherical and planar geometry virus-like membranes has many potential applications. VLPLs could be used to study fusion proteins of virulent viruses in a safe manner, or they could be used as therapeutic delivery particles to transport beneficial proteins coexpressed in the cells to a target cell. VLSBs could facilitate high throughput screening of antiviral drugs or pathogen-host cell interactions. PMID- 23631562 TI - Gut microbiota composition modifies fecal metabolic profiles in mice. AB - The gut microbiome is known to be extensively involved in human health and disease. In order to reveal the metabolic relationship between host and microbiome, we monitored recovery of the gut microbiota composition and fecal profiles of mice after gentamicin and/or ceftriaxone treatments. This was performed by employing (1)H nuclear magnetic resonance (NMR)-based metabonomics and denaturing gradient gel electrophoresis (DGGE) fingerprint of gut microbiota. The common features of fecal metabolites postantibiotic treatment include decreased levels of short chain fatty acids (SCFAs), amino acids and primary bile acids and increased oligosaccharides, d-pinitol, choline and secondary bile acids (deoxycholic acid). This suggests suppressed bacterial fermentation, protein degradation and enhanced gut microbial modification of bile acids. Barnesiella, Prevotella, and Alistipes levels were shown to decrease as a result of the antibiotic treatment, whereas levels of Bacteroides, Enterococcus and Erysipelotrichaceae incertae sedis, and Mycoplasma increased after gentamicin and ceftriaxone treatment. In addition, there was a strong correlation between fecal profiles and levels of Bacteroides, Barnesiella, Alistipes and Prevotella. The integration of metabonomics and gut microbiota profiling provides important information on the changes of gut microbiota and their impact on fecal profiles during the recovery after antibiotic treatment. The correlation between gut microbiota and fecal metabolites provides important information on the function of bacteria, which in turn could be important in optimizing therapeutic strategies, and developing potential microbiota-based disease preventions and therapeutic interventions. PMID- 23631564 TI - Bonding and structure of oxofluoroniobate-based glasses. AB - Glasses based on the oxofluoroniobate anion have been characterized by vibrational and solid-state NMR spectroscopy. The mechanism of glass formation in the systems K2NbOF5-MF3 (M = Al, In) has been suggested. A glass network is built from the chains of corner-sharing octahedra through -Nb-F(O)-M- and -Nb-F-Nb- bridges. Isolated NbOF5(2-) octahedra are also present, which is consistent with the glass composition. The high ionic mobility of NbOF5(2-) due to its fast reorientations results in equalization of the Nb-O and Nb-F distances, which is reflected in the appearance of the IR band at 700-800 cm(-1) not observed in the Raman spectrum. Its assignment to bridging -Nb-O-Nb- species accepted in the literature was not proven. PMID- 23631563 TI - Risk factors for pulmonary tuberculosis in patients with chronic obstructive airway disease in Taiwan: a nationwide cohort study. AB - BACKGROUND: An association between chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) has been described, mainly due to smoking and corticosteroid use. Whether inhaled corticosteroid (ICS) therapy is associated with an increased risk of TB remains unclear. METHODS: We selected COPD cases by using six diagnostic scenarios and control subjects from a nationwide health insurance database, and applied time-dependent Cox regression analysis to identify the risk factors for TB. RESULTS: Among 1,000,000 beneficiaries, 23,594 COPD cases and 47,188 non-COPD control subjects were selected. Cox regression analysis revealed that age, male gender, diabetes mellitus, end-stage renal disease, and cirrhosis, as well as COPD (hazard ratio = 2.468 [2.205-2.762]) were independent risk factors for TB. Among the COPD cases, those who developed TB received more oral corticosteroids and oral beta-agonists. Time-dependent Cox regression analysis revealed that age, male gender, diabetes mellitus, low income, oral corticosteroid dose, and oral beta-agonist dose, but not ICS dose, were independent risk factors for TB. The identified risk factors and their hazard ratios were similar among the COPD cases selected using different scenarios. CONCLUSION: Keeping a high suspicion and regularly monitoring for the development of pulmonary TB in COPD patients are necessary, especially for those receiving higher doses of oral corticosteroids and other COPD medications. Although ICS therapy has been shown to predispose COPD patients to pneumonia in large randomized clinical trials, it does not increase the risk of TB in real world practice. PMID- 23631567 TI - Effect of combination of essential oils and bacteriocins on the efficacy of gamma radiation against Salmonella Typhimurium and Listeria monocytogenes. AB - PURPOSE: Using essential oils (EO) alone or combined EO with nisin to enhance the lethality of Salmonella Typhimurium and Listeria monocytogenes to gamma irradiation treatment. MATERIALS AND METHODS: Cell suspension or inoculated carrots (10(6) colony forming unit (CFU)/ml) of L. monocytogenes or Salmonella Typhimurium were treated with carvacrol and mountain savory EO alone or treated by the combined EO plus nisin and were irradiated at different doses. The radiation dose required to reduce bacterial population by 90% (D(10) value) and the relative sensitivity (RS) of treated bacteria to irradiation were calculated. RESULTS: The RS of L. monocytogenes cell suspension to irradiation was increased by 4.19 and 6.31 times when treated by carvacrol plus nisin and mountain savory plus nisin, respectively, as compared to the control. The RS of Salmonella Typhimurium cell suspension to irradiation was increased by 1.84-fold when treated with carvacrol plus nisin. Coated carrots by nisin plus carvacrol increased the RS of L. monocytogenes to irradiation by 2.74 times while coated carrots by nisin and nisin plus carvacrol increased the RS of Salmonella Typhimurium to irradiation by 2.46 and 2.52, respectively. CONCLUSIONS: The combined EO with nisin and irradiation could increase the RS of L. monocytogenes and Salmonella Typhimurium. PMID- 23631568 TI - Share with women. Promoting skin-to-skin contact. PMID- 23631570 TI - Somatic and visceral nervous systems - an ancient duality. AB - The vertebrate nervous system is deeply divided into 'somatic' and 'visceral' subsystems that respond to external and internal stimuli, respectively. Molecular characterization of neurons in different groups of mollusks by Nomaksteinsky and colleagues, published in this issue of BMC Biology, reveals that the viscero somatic duality is evolutionarily ancient, predating Bilateria.See research article: http://www.biomedcentral.com/1741-7007/11/53. PMID- 23631571 TI - Infection and inflammatory mechanisms. AB - This introductory article examines the potential mechanisms that may play a role in the associations between periodontitis and the systemic conditions being considered in the EFP/AAP Workshop in Segovia, Spain. Three basic mechanisms have been postulated to play a role in these interactions; metastatic infections,inflammation and inflammatory injury, and adaptive immunity. The potential role of each alone and together is considered in in vitro and animal studies and in human studies when available. This is not a systematic or critical review, but rather an overview of the field to set the stage for the critical reviews in each of the working groups. PMID- 23631572 TI - Diabetes and periodontal diseases: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. AB - BACKGROUND: Diabetes and periodontitis are complex chronic diseases with an established bidirectional relationship. There is long-established evidence that hyperglycaemia in diabetes is associated with adverse periodontal outcomes. However, given the ubiquity of periodontal diseases and the emerging global diabetes epidemic, the complications of which contribute to significant morbidity and premature mortality, it is timely to review the role of periodontitis in diabetes. AIMS: To report the epidemiological evidence from cross-sectional, prospective and intervention studies for the impact of periodontal disease on diabetes incidence, control and complications and to identify potential underpinning mechanisms. EPIDEMIOLOGY: Over the last 20 years, consistent and robust evidence has emerged that severe periodontitis adversely affects glycaemic control in diabetes and glycaemia in non-diabetes subjects. In diabetes patients, there is a direct and dose-dependent relationship between periodontitis severity and diabetes complications. Emerging evidence supports an increased risk for diabetes onset in patients with severe periodontitis. Biological mechanisms: Type 2 diabetes is preceded by systemic inflammation, leading to reduced pancreatic b cell function, apoptosis and insulin resistance.Increasing evidence supports elevated systemic inflammation (acute-phase and oxidative stress biomarkers) resulting from the entry of periodontal organisms and their virulence factors into the circulation, providing biological plausibility for the effects of periodontitis on diabetes. AGE (Advanced Glycation Endproducts)-RAGE (Receptor for AGEs) interactions and oxidative-stress-mediated pathways provide plausible mechanistic links in the diabetes to periodontitis direction. INTERVENTIONS: Randomized controlled trials (RCTs) consistently demonstrate that mechanical periodontal therapy associates with approximately a 0.4% reduction in HbA1C at 3 months, a clinical impact equivalent to adding a second drug to a pharmacological regime for diabetes. RCTs are needed with larger numbers of subjects and longer term follow-up, and if results are substantiated, adjunctive periodontal therapies subsequently need to be evaluated. There is no current evidence to support adjunctive use of antimicrobials for periodontal management of diabetes patients. GUIDELINES: Given the current evidence, it is timely to provide guidelines for periodontal care in diabetes patients for medical and dental professionals and recommendations for patients/the public. PMID- 23631573 TI - A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes. AB - AIMS: To review the evidence for the molecular and cellular processes that may potentially link periodontal disease and diabetes. The pathogenic roles of cytokines and metabolic molecules (e.g. glucose, lipids) are explored and the role of periodontal bacteria is also addressed. Paradigms for bidirectional relationships between periodontitis and diabetes are discussed and opportunities for elaborating these models are considered. METHODS: Database searches were performed using MeSH terms, keywords, and title words. Studies were evaluated and summarized in a narrative review. RESULTS: Periodontal microbiota appears unaltered by diabetes and there is little evidence that it may influence glycaemic control. Small-scale clinical studies and experiments in animal models suggest that IL-1b, TNF-a, IL-6, OPG and RANKL may mediate periodontitis in diabetes. The AGE-RAGE axis is likely an important pathway of tissue destruction and impaired repair in diabetes-associated periodontitis. A role for locally activated pro-inflammatory factors in the periodontium, which subsequently impact on diabetes, remains speculative. CONCLUSION: There is substantial information on potential mechanistic pathways which support a close association between diabetes and periodontitis, but there is a real need for longitudinal clinical studies using larger patient groups, integrated with studies of animal models and cells/tissues in vitro. PMID- 23631574 TI - Effect of periodontal disease on diabetes: systematic review of epidemiologic observational evidence. AB - BACKGROUND: Periodontal disease and diabetes mellitus are common, chronic diseases worldwide. Epidemiologic and biologic evidence suggest periodontal disease may affect diabetes. OBJECTIVE: To systematically review non experimental, epidemiologic evidence for effects of periodontal disease on diabetes control, complications and incidence. DATA SOURCES: Electronic bibliographic databases, supplemented by hand searches of recent and future issues of relevant journals. Study eligibility criteria and participants: Longitudinal and cross-sectional epidemiologic, non-interventional studies that permit determination of directionality of observed effects were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Four reviewers evaluated pair-wise each study. Review findings regarding study results and quality were summarized in tables by topic, using the PRISMA Statement for reporting and the Newcastle-Ottawa System for quality assessment, respectively. From 2246 citations identified and available abstracts screened, 114 full-text reports were assessed and 17 included in the review. RESULTS: A small body of evidence supports significant, adverse effects of periodontal disease on glycaemic control, diabetes complications, and development of type 2 (and possibly gestational) diabetes. LIMITATIONS: There were only a limited number of eligible studies, several of which included small sample sizes. Exposure and outcome parameters varied, and the generalizability of their results was limited. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Current evidence suggests that periodontal disease adversely affects diabetes outcomes, and that further longitudinal studies are warranted. PMID- 23631575 TI - Evidence that periodontal treatment improves diabetes outcomes: a systematic review and meta-analysis. AB - CONTEXT: The effect of periodontal therapy on diabetes outcomes has not been established. OBJECTIVE: This update examines the effect of periodontal treatment on diabetes outcomes. DATA SOURCES: Literature since October 2009 using MEDLINE. STUDY ELIGIBILITY CRITERIA: Published RCTs including periodontal therapy for diabetic subjects, a metabolic outcome, an untreated control group, and follow-up of 3 months. DATA EXTRACTION: Pre-defined data fields, including study quality indicators were used. DATA SYNTHESIS: A search revealed 56 publications of which 9 met inclusion criteria. Mean change of HbA1c from baseline was compared across treatment groups. Pooled analysis was based on random effects models. RESULTS: A meta-analysis indicated a mean treatment effect of _0.36% HbA1c (CI _0.54, _0.19) compared to no treatment after periodontal therapy (p < 0.0001). Heterogeneity tests revealed only minimal evidence of publication bias (I2 = 9%). LIMITATIONS: Small sample size and high risk of bias remain problematic for studies of this type. Periodontal therapy varied considerably. CONCLUSION: The modest reduction in HbA1c observed as a result of periodontal therapy in subjects with type 2 diabetes is consistent with previous systematic reviews. Despite this finding, there is limited confidence in the conclusion due to a lack of multi-centre trials of sufficient sample size are lacking. PMID- 23631576 TI - Periodontitis and adverse pregnancy outcomes: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. AB - BACKGROUND: Pregnancy sometimes has adverse outcomes including low birthweight (<2500 g), pre-term birth (<37 weeks), growth restriction, pre-eclampsia, miscarriage and/or stillbirth. Maternal periodontitis directly and/or indirectly have potential to influence the health of the foetal-maternal unit. AIMS: To assess the epidemiological evidence for the impact of periodontal disease on adverse pregnancy outcomes and to identify potential underpinning mechanisms. EPIDEMIOLOGY: Low birthweight, pre-term birth and pre-eclampsia have been associated with maternal periodontitis exposure. However, the strength of the observed associations is modest and seems to vary according to the population studied, the means of periodontal assessment and the periodontal disease classification employed. BIOLOGICAL MECHANISMS: Two major pathways have been identified, One direct, in which oral microorganisms and/or their components reach the foetal-placental unit and one indirect, in which Inflammatory mediators circulate and impact the foetal-placental unit. INTERVENTIONS: Although periodontal therapy has been shown to be safe and leads to improved periodontal conditions in pregnant women, case-related periodontal therapy, with or without systemic antibiotics does not reduce overall rates of pre-term birth and low birthweight. GUIDELINES: Given the current evidence, various treatment strategies could be evaluated that consider specific target populations, as well as timing and intensity of treatment. PMID- 23631577 TI - Adverse pregnancy outcomes (APOs) and periodontal disease: pathogenic mechanisms. AB - AIM: To evaluate the evidence on potential biological pathways underlying the possible association between periodontal disease (PD) and adverse pregnancy outcomes (APOs). MATERIAL & METHODS: Human, experimental and in vitro studies were evaluated. RESULTS: Periodontal pathogens/byproducts may reach the placenta and spread to the foetal circulation and amniotic fluid. Their presence in the foeto-placental compartment can stimulate a foetal immune/inflammatory response characterized by the production of IgM antibodies against the pathogens and the secretion of elevated levels of inflammatory mediators, which in turn may cause miscarriage or premature birth. Moreover, infection/inflammation may cause placental structural changes leading to pre-eclampsia and impaired nutrient transport causing low birthweight. Foetal exposure may also result in tissue damage, increasing the risk for perinatal mortality/morbidity. Finally, the elicited systemic inflammatory response may exacerbate local inflammatory responses at the foeto-placental unit and further increase the risk for APOs. CONCLUSIONS: Further investigation is still necessary to fully translate the findings of basic research into clinical studies and practice. Understanding the systemic virulence potential of the individual's oral microbiome and immune response may be a distinctly different issue from categorizing the nature of the challenge using clinical signs of PD. Therefore, a more personalized targeted therapy could be a more predictive answer to the current "one-size-fits-all" interventions. PMID- 23631578 TI - Epidemiology of association between maternal periodontal disease and adverse pregnancy outcomes--systematic review. AB - BACKGROUND AND OBJECTIVES: There is still debate regarding potential relationships between maternal periodontitis during pregnancy and adverse pregnancy outcomes. The aim of this systematic review was to synthesize the available epidemiological evidence on this association. DATA SOURCES: Combined electronic and hand search of MEDLINE, EMBASE, WEB OF SCIENCE and Cochrane Central Register databases. STUDY ELIGIBILITY CRITERIA: Original publications reporting data from cross-sectional, case-control or prospective cohort epidemiological studies on the association between periodontal status and preterm birth, low birthweight (LBW) or preeclampsia. The search was not limited to publications in English. All selected studies provided data based on professional assessments of periodontal status, and outcome variables, including preterm birth (<37 weeks gestation), LBW (<2500 g), gestational age, small for gestational age, birthweight, pregnancy loss or miscarriage, or pre-eclampsia. PARTICIPANTS: Pregnant women with or without periodontal disease, and with or without adverse pregnancy outcomes, assessed either during pregnancy or postpartum. No intervention studies were included. Study appraisal and synthesis methods - Publications were assessed based on predefined screening criteria including type of periodontal assessment, consistency in the timing of the periodontal assessment with respect to gestational age, examiner masking and consideration of additional exposures and confounders. RESULTS: Maternal periodontitis is modestly but significantly associated with LBW and preterm birth, but the use of a categorical or a continuous exposure definition of periodontitis appears to impact the findings: Although significant associations emerge from case-control and cross-sectional studies using periodontitis "case definitions," these were substantially attenuated in studies assessing periodontitis as a continuous variable. Data from prospective studies followed a similar pattern, but associations were generally weaker. Maternal periodontitis was significantly associated with pre-eclampsia. LIMITATIONS: There is a high degree of variability in study populations, recruitment and assessment, as well as differences in how data are recorded and handled. As a result, studies included in meta-analyses show a high degree of heterogeneity. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Maternal periodontitis is modestly but independently associated with adverse pregnancy outcomes, but the findings are impacted by periodontitis case definitions. It is suggested that future studies employ both continuous and categorical assessments of periodontal status. Further use of the composite outcome preterm LBW is not encouraged. PMID- 23631579 TI - The effects of periodontal treatment on pregnancy outcomes. AB - BACKGROUND: Preterm infants are at greater risk than term infants for physical and developmental disorders. Morbidity and mortality increases as gestational age at delivery decreases. Observational studies indicate an association between poor periodontal health and risk for preterm birth or low birthweight, making periodontitis a potentially modifiable risk factor for prematurity. AIM: To identify randomized controlled trials (RCTs) published between January 2011 and July 2012 and discuss all published RCTs testing whether periodontal therapy reduces rates of preterm birth and low birthweight. METHODS: Search of databases including PubMed, ISI Web of Science and Cochrane Library. RESULTS: The single RCT identified showed no significant effect of periodontal treatment on birth outcomes. DISCUSSION: All published trials included non-surgical periodontal therapy; only two included systemic antimicrobials as part of test therapy. The trials varied substantially in terms of sample size, obstetric histories of subjects, study preterm birth rates and the periodontal treatment response. The largest trials--also judged to be high-quality and at low risk of bias--have yielded consistent results, and indicate that treatment does not alter rates of adverse pregnancy outcomes. CONCLUSION: Non-surgical periodontal therapy, scaling and root planing, does not improve birth outcomes in pregnant women with periodontitis. PMID- 23631580 TI - Periodontitis and systemic diseases: a record of discussions of working group 4 of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. AB - BACKGROUND: There has been an explosion in research into possible associations between periodontitis and various systemic diseases and conditions. AIM: To review the evidence for associations between periodontitis and various systemic diseases and conditions, including chronic obstructive pulmonary disease (COPD), pneumonia, chronic kidney disease, rheumatoid arthritis, cognitive impairment, obesity, metabolic syndrome and cancer, and to document headline discussions of the state of each field. Periodontal associations with diabetes, cardiovascular disease and adverse pregnancy outcomes were not discussed by working group 4. RESULTS: Working group 4 recognized that the studies performed to date were largely cross-sectional or case-control with few prospective cohort studies and no randomized clinical trials. The best current evidence suggests that periodontitis is characterized by both infection and pro-inflammatory events, which variously manifest within the systemic diseases and disorders discussed. Diseases with at least minimal evidence of an association with periodontitis include COPD, pneumonia, chronic kidney disease, rheumatoid arthritis, cognitive impairment, obesity, metabolic syndrome and cancer. The working group agreed that there is insufficient evidence to date to infer causal relationships with the exception that organisms originating in the oral microbiome can cause lung infections. CONCLUSIONS: The group was unanimous in their opinion that the reported associations do not imply causality, and establishment of causality will require new studies that fulfil the Bradford Hill or equivalent criteria. Precise and community-agreed case definitions of periodontal disease states must be implemented systematically to enable consistent and clearer interpretations of studies of the relationship to systemic diseases. The members of the working group were unanimous in their opinion that to develop data that best inform clinicians, investigators and the public, studies should focus on robust disease outcomes and avoid surrogate endpoints. It was concluded that because of the relative immaturity of the body of evidence for each of the purported relationships, the field is wide open and the gaps in knowledge are large. PMID- 23631582 TI - Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. AB - BACKGROUND: This consensus report is concerned with the association between periodontitis and atherosclerotic cardiovascular disease (ACVD). Periodontitis is a chronic multifactorial inflammatory disease caused by microorganisms and characterized by progressive destruction of the tooth supporting apparatus leading to tooth loss; as such, it is a major public health issue. AIMS: This report examined biological plausibility, epidemiology and early results from intervention trials. PLAUSIBILITY: Periodontitis leads to entry of bacteria in the blood stream. The bacteria activate the host inflammatory response by multiple mechanisms. The host immune response favors atheroma formation, maturation and exacerbation. EPIDEMIOLOGY: In longitudinal studies assessing incident cardiovascular events, statistically significant excess risk for ACVD was reported in individuals with periodontitis. This was independent of established cardiovascular risk factors. The amount of the adjusted excess risk varies by type of cardiovascular outcome and across populations by age and gender. Given the high prevalence of periodontitis, even low to moderate excess risk is important from a public health perspective. INTERVENTION: There is moderate evidence that periodontal treatment: (i) reduces systemic inflammation as evidenced by reduction in C-reactive protein (CRP) and improvement of both clinical and surrogate measures of endothelial function; but (ii) there is no effect on lipid profiles--supporting specificity. Limited evidence shows improvements in coagulation, biomarkers of endothelial cell activation, arterial blood pressure and subclinical atherosclerosis after periodontal therapy. The available evidence is consistent and speaks for a contributory role of periodontitis to ACVD. There are no periodontal intervention studies on primary ACVD prevention and there is only one feasibility study on secondary ACVD prevention. CONCLUSIONS: It was concluded that: (i) there is consistent and strong epidemiologic evidence that periodontitis imparts increased risk for future cardiovascular disease; and (ii) while in vitro, animal and clinical studies do support the interaction and biological mechanism, intervention trials to date are not adequate to draw further conclusions. Well-designed intervention trials on the impact of periodontal treatment on prevention of ACVD hard clinical outcomes are needed. PMID- 23631583 TI - Periodontal bacterial invasion and infection: contribution to atherosclerotic pathology. AB - OBJECTIVE: The objective of this review was to perform a systematic evaluation of the literature reporting current scientific evidence for periodontal bacteria as contributors to atherosclerosis. METHODS: Literature from epidemiological, clinical and experimental studies concerning periodontal bacteria and atherosclerosis were reviewed. Gathered data were categorized into seven "proofs" of evidence that periodontal bacteria: 1) disseminate from the oral cavity and reach systemic vascular tissues; 2) can be found in the affected tissues; 3) live within the affected site; 4) invade affected cell types in vitro; 5) induce atherosclerosis in animal models of disease; 6) non-invasive mutants of periodontal bacteria cause significantly reduced pathology in vitro and in vivo; and 7) periodontal isolates from human atheromas can cause disease in animal models of infection. RESULTS: Substantial evidence for proofs 1 to 6 was found. However, proof 7 has not yet been fulfilled. CONCLUSIONS: Despite the lack of evidence that periodontal bacteria obtained from human atheromas can cause atherosclerosis in animal models of infection, attainment proofs 1 to 6 provides support that periodontal pathogens can contribute to atherosclerosis. PMID- 23631584 TI - Inflammatory mechanisms linking periodontal diseases to cardiovascular diseases. AB - AIMS: In this article, inflammatory mechanisms that link periodontal diseases to cardiovascular diseases are reviewed. METHODS: This article is a literature review. RESULTS: Studies in the literature implicate a number of possible mechanisms that could be responsible for increased inflammatory responses in atheromatous lesions due to periodontal infections. These include increased systemic levels of inflammatory mediators stimulated by bacteria and their products at sites distant from the oral cavity, elevated thrombotic and hemostatic markers that promote a prothrombotic state and inflammation, cross reactive systemic antibodies that promote inflammation and interact with the atheroma, promotion of dyslipidemia with consequent increases in pro-inflammatory lipid classes and subclasses, and common genetic susceptibility factors present in both disease leading to increased inflammatory responses. CONCLUSIONS: Such mechanisms may be thought to act in concert to increase systemic inflammation in periodontal disease and to promote or exacerbate atherogenesis. However, proof that the increase in systemic inflammation attributable to periodontitis impacts inflammatory responses during atheroma development, thrombotic events or myocardial infarction or stroke is lacking. PMID- 23631585 TI - The epidemiological evidence behind the association between periodontitis and incident atherosclerotic cardiovascular disease. AB - OBJECTIVES: The objective of this study was to systematically review the epidemiological evidence for an association between periodontitis (PD) and incident atherosclerotic cardiovascular disease (ACVD), including coronary heart disease (CHD), cerebrovascular disease and peripheral arterial disease. METHODS: Systematic review of cohort and case-control studies on the association of clinically or radiographically diagnosed PD and ACVD. RESULTS: Overall, 12 studies were included in this study (six studies on CHD, three studies on cerebrovascular disease, two studies on both coronary heart and cerebrovascular disease mortality and one study on peripheral arterial disease).All but one study reported positive associations between various periodontal disease measures and the incidence of ACVD, at least in specific subgroups. The association was stronger in younger adults and there was no evidence for an association between PD and incident CHD in subjects older than 65 years. Only one study evaluated the association between PD and secondary cardiovascular events. CONCLUSIONS: There is evidence for an increased risk of ACVD in patients with PD compared to patients without. However, this may not apply to all groups of the population. There is insufficient evidence for an association between PD and the incidence of secondary cardiovascular events. PMID- 23631586 TI - Periodontal systemic associations: review of the evidence. AB - AIM: To critically appraise recent research into associations between periodontal disease and systemic diseases and conditions specifically respiratory disease, chronic kidney disease, rheumatoid arthritis, cognitive impairment, obesity, metabolic syndrome and cancer. METHODS: A MEDLINE literature search of papers published between 2002 and April 2012 was conducted. Studies that included periodontitis as an exposure were identified. Cross-sectional epidemiological investigations on large samples, prospective studies and systematic reviews formed the basis of the narrative review. A threshold set for the identification of periodontitis was used to identify those studies that contributed to the conclusions of the review. RESULTS: Many of the investigations were cross sectional secondary analyses of existing data sets in particular the NHANES studies. There were a small number of systematic reviews and prospective studies. There was substantial variability in the definitions of exposure to periodontitis. A small number of studies met the threshold set for periodontitis and supported associations; however, in some of the chronic diseases there were no such studies. There was strong evidence from randomized controlled trials that interventions, which improve oral hygiene have positive effects on the prevention of nosocomial pneumonias. CONCLUSIONS: There was substantial heterogeneity in the definitions used to identify periodontitis and very few studies met a stringent threshold for periodontitis. Published evidence supports modest associations between periodontitis and some, although not all, of the diseases and conditions reviewed. There is a need to reach a consensus on what constitutes periodontitis for future studies of putative associations with systemic diseases. PMID- 23631587 TI - Evidence that periodontal treatment improves biomarkers and CVD outcomes. AB - AIM: The aim of this review was to critically appraise the evidence on the impact of periodontal treatment of cardiovascular diseases (CVDs) biomarkers and outcomes. METHODS: A systematic search was performed in Cinhal, Cochrane, Embase and Medline for relevant articles up to July 2012. Duplicate screening and reference hand searching were performed. Data were then summarized and evidence graded in tables. RESULTS: The search resulted in: (a) no evidence on the effects of periodontal therapy on subclinical atherosclerosis, serum levels of CD40 ligand, serum amyloid A and monocyte chemoattractant protein-1, (b) limited evidence on the effects of periodontal therapy on arterial blood pressure, leucocyte counts, fibrinogen, tissue necrosis factor-a, sE-selectin, von Willebrand factors, d-dimers, matrix metalloproteinases, oxidative stress and CVD events, and (c) moderate evidence suggesting a negligible effect of periodontal therapy in reducing interleukin-6 and lipids levels, whilst a positive effect in reducing serum C-reactive protein levels and improving endothelial function. CONCLUSIONS: Periodontal therapy triggers a short-term inflammatory response followed by (a) a progressive and consistent reduction of systemic inflammation and (b) an improvement in endothelial function. There is however limited evidence that these acute and chronic changes will either increase or reduce CVD burden of individuals suffering from periodontitis in the long term. PMID- 23631588 TI - A physiologically based pharmacokinetic model for the prediction of the depletion of methyl-3-quinoxaline-2-carboxylic acid, the marker residue of olaquindox, in the edible tissues of pigs. AB - To estimate the consumer exposure to olaquindox (OLA) residues in porcine edible tissues, a physiologically based pharmacokinetic (PBPK) model for methyl-3 quinoxaline-2-carboxylic acid (MQCA), the marker residue of OLA, was developed in pigs based on the assumptions of the flow-limited distribution, hepatic metabolism, and renal excretion. The model included separate compartments corresponding to blood, muscle, liver, kidney, adipose, and an extra compartment representing the remaining carcass. Physiological parameters were determined from literatures. Plasma protein binding, partition coefficients, and renal clearance for MQCA were determined in in vitro and in vivo studies. The metabolic conversion of OLA to MQCA was assumed as a simple, one-step process, and an apparent first-order rate constant (k) was employed to describe this metabolic process. The PBPK model was optimized and validated with plasma and tissue data from literatures and our study. Sensitivity analysis and Monte Carlo simulation were also implemented to estimate the influence of model parameters on the goodness of fit. When compared with the observed data, the PBPK model underestimated the MQCA level in all compartments at the early time points, whereas gave excellent predictions of MQCA concentration in porcine edible tissues at later time points. The correlation coefficients between the predicted and observed values were over 0.88. The consistency between the model predictions and the real residues of OLA in pigs proved the good applicability of our model in food safety risk assessment. PMID- 23631589 TI - Measurement adherence in the blood pressure self-measurement room. AB - BACKGROUND: Patients with hypertension or receiving blood pressure (BP)-lowering treatment are often required to self-measure their BP in a dedicated self measurement room before consultation. Current praxis does not guarantee valid measurements, possibly leading to misdiagnoses or inappropriate antihypertensive medication. The aim of this study was to investigate patients' ability to correctly self-report and follow recommendations. PATIENTS AND METHODS: We used a context-aware system to gather information on BP measurements and relevant context parameters. Patients were not informed that the system automatically collected behavior data and were instructed to self-report their measurements on a paper sheet as usual. We then compared the automatically recorded data with the self-reported data in order to detect any nonadherent reporting behavior. Also, we investigated the patients' ability to adhere to the measurement recommendations. RESULTS: We found that (1) a third of all 113 participating patients failed to self-report measured BP data correctly and (2) none of the 642 measurements obtained adhered fully to the recommendations. CONCLUSIONS: Results indicate that context-aware technology may be useful for accurately modeling aspects of nonadherent patient behavior. This may be used to inform staff of the validity of the measurement and pinpoint patients in need of additional training or to design better aids to assist the patients. The developed system is generally applicable to other self-measurement environments, including the home setting and remote outpatient clinics, as it is built using telemedicine technology and thus well suited for remote monitoring and diagnosis. PMID- 23631590 TI - Synthesis of amylose-polystyrene inclusion complexes by a facile preparation route. AB - The formation of amylose-polystyrene inclusion complexes via a novel two-step approach is described. In the first-step, styrene was inserted inside the amylose helical cavity, followed by free radical polymerization in the second step. The inclusion complexes were characterized by attenuated total reflection fourier transform infrared spectroscopy (ATR-FTIR), ultraviolet spectroscopy (UV), X-ray diffraction (XRD), atomic force microscopy (AFM), and differential scanning calorimetry (DSC). The formation of polystyrene was confirmed by gel permeation chromatography (GPC). The molecular weight of polystyrene can be varied by using amylose bearing different molar masses. The approach described here is general and could be used to synthesize other host-polymer inclusion complexes for which long chains of polymeric guests are difficult to insert into the host cavity. PMID- 23631591 TI - Structural and functional insights into human vitamin K epoxide reductase and vitamin K epoxide reductase-like1. AB - Human vitamin K epoxide reductase (hVKOR) is a small integral membrane protein involved in recycling vitamin K. hVKOR produces vitamin K hydroquinone, a crucial cofactor for gamma-glutamyl carboxylation of vitamin K dependent proteins, which are necessary for blood coagulation. Because of this, hVKOR is the target of a common anticoagulant, warfarin. Spurred by the identification of the hVKOR gene less than a decade ago, there have been a number of new insights related to this protein. Nonetheless, there are a number of key issues that have not been resolved; such as where warfarin binds hVKOR, or if human VKOR shares the topology of the structurally characterized but distantly related prokaryotic VKOR. The pharmacogenetics and single nucleotide polymorphisms of hVKOR used in personalized medicine strategies for warfarin dosing should be carefully considered to inform the debate. The biochemical and cell biological evidence suggests that hVKOR has a distinct fold from its ancestral protein, though the controversy will likely remain until structural studies of hVKOR are accomplished. Resolving these issues should impact development of new anticoagulants. The paralogous human protein, VKOR-like1 (VKORL1) was recently shown to also participate in vitamin K recycling. VKORL1 was also recently characterized and assigned a functional role as a housekeeping protein involved in redox homeostasis and oxidative stress with a potential role in cancer regulation. As the physiological interplay between these two human paralogs emerge, the impacts could be significant in a number of diverse fields from coagulation to cancer. PMID- 23631592 TI - Direct measurement of sequential folding pathway and energy landscape of human telomeric G-quadruplex structures. AB - Single-stranded guanine-rich sequences fold into compact G-quadruplexes. Although G-triplexes have been proposed and demonstrated as intermediates in the folding of G-quadruplexes, there is still a debate on their folding pathways. In this work, we employed magnetic tweezers to investigate the folding kinetics of single human telomeric G-quadruplexes in 100 mM Na(+) buffer. The results are consistent with a model in which the G-triplex is an in-pathway intermediate in the folding of the G-quadruplex. By finely tuning the force exerted on the G-quadruplex, we observed reversible transitions from the G-quadruplex to the G-triplex as well as from the G-triplex to the unfolded coil when the force was increased from 26 to 39 pN. The energy landscape derived from the probability distribution shows clearly that the G-quadruplex goes through an intermediate when it is unfolded, and vice versa. PMID- 23631594 TI - Catfish spine envenomation and bacterial abscess with Proteus and Morganella: a case report. AB - INTRODUCTION: Abscess formation and cellulitis in the setting of envenomation are rare complications of handling catfish. To the best of our knowledge, isolation of Proteus vulgaris has not been previously recorded, and recovery of Morganella morganii has been reported in only one prior case from wound cultures in patients injured by catfish stings. We report a case of catfish envenomation characterized by abscess formation and cellulitis, in which wound cultures grew these unusual organisms. CASE PRESENTATION: A 52-year-old Chinese-American man was hospitalized with erythema and swelling of his right arm of 10 days' duration after skin penetration by a catfish barb. An abscess of his right thumb had undergone incision and drainage, with purulent drainage sent for wound culture immediately prior to admission. Laboratory studies revealed elevated white blood count, sedimentation rate, and C-reactive protein. The patient was treated with intravenous ampicillin-sulbactam and vancomycin during his hospitalization, and symptoms improved. Wound cultures obtained prior to presentation grew many Proteus vulgaris and Morganella morganii. He was subsequently discharged on a 10 day course of oral ciprofloxacin and amoxicillin-clavulanate. At a 12-month telephone follow-up, the patient denied developing further symptoms and reported that the wound had healed completely without complication. CONCLUSION: Although envenomation and secondary infection are not uncommon sequelae of handling catfish, the present case is unique by virtue of the infecting organisms isolated. Given the prevalence of injury from catfish stings, a review of the literature is presented in order to provide recommendations for prevention and treatment of catfish envenomation. PMID- 23631593 TI - Independent of ErbB1 gene copy number, EGF stimulates migration but is not associated with cell proliferation in non-small cell lung cancer. AB - BACKGROUND: Lung cancer often exhibits molecular changes, such as the overexpression of the ErbB1 gene. ErbB1 encodes epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, involved mainly in cell proliferation and survival. EGFR overexpression has been associated with more aggressive disease, poor prognosis, low survival rate and low response to therapy. ErbB1 amplification and mutation are associated with tumor development and are implicated in ineffective treatment. The aim of the present study was to investigate whether the ErbB1 copy number affects EGFR expression, cell proliferation or cell migration by comparing two different cell lines. METHODS: The copies of ErbB1 gene was evaluated by FISH. Immunofluorescence and Western blotting were performed to determine location and expression of proteins mentioned in the present study. Proliferation was studied by flow cytometry and cell migration by wound healing assay and time lapse. RESULTS: We investigated the activation and function of EGFR in the A549 and HK2 lung cancer cell lines, which contain 3 and 6 copies of ErbB1, respectively. The expression of EGFR was lower in the HK2 cell line. EGFR was activated after stimulation with EGF in both cell lines, but this activation did not promote differences in cellular proliferation when compared to control cells. Inhibiting EGFR with AG1478 did not modify cellular proliferation, confirming previous data. However, we observed morphological alterations, changes in microfilament organization and increased cell migration upon EGF stimulation. However, these effects did not seem to be consequence of an epithelial-mesenchymal transition. CONCLUSION: EGFR expression did not appear to be associated to the ErbB1 gene copy number, and neither of these aspects appeared to affect cell proliferation. However, EGFR activation by EGF resulted in cell migration stimulation in both cell lines. PMID- 23631595 TI - Consumer subjectivity and U.S. health care reform. AB - Health care consumerism is an important frame in U.S. health care policy, especially in recent media and policy discourse about federal health care reform. This article reports on qualitative fieldwork with health care users to find out how people interpret and make sense of the identity of "health care consumer." It proposes that while the term consumer is normally understood as a descriptive label for users who purchase health care and insurance services, it should actually be understood as a metaphor, carrying with it a host of associations that shape U.S. health care policy debates in particular ways. Based on interviews with 36 people, patient was the dominant term people used to describe themselves, but consumer was the second most popular. Informants interpreted the health care consumer as being informed, proactive, and having choices, but there were also "semiotic traps," or difficult-to-resolve tensions for this identity. The discourse of consumerism functions in part as code for individual responsibility, and therefore as a classed moral discourse, with implications for U.S. health care policy. PMID- 23631596 TI - Is hair transplantation indicated in frontal fibrosing alopecia? The results of test grafting in three patients. PMID- 23631598 TI - Experimental determination of the charge neutrality level of poly[2-methoxy-5-(2' ethylhexyloxy)-p-phenylene vinylene] (MEH-PPV). AB - The charge neutrality level (CNL) of poly[2-methoxy-5-(2'-ethylhexyloxy)-p phenylene vinylene] (MEH-PPV) was determined. This was achieved by measuring the hole injection barrier at the MEH-PPV/Al interface with X-ray and ultraviolet photoemission spectroscopies in combination with in situ multistep electrospray based thin film deposition. This deposition technique allows the deposition of polymers into a vacuum environment from solution, preventing significant contamination of the interface. Hence, the hole injection barrier energy at the interface between MEH-PPV and Al could be determined without the presence of significant amounts of ambient contamination. The result of this measurement was combined with published barrier energies for Au and Ag measured with the same technique. This enabled the correlation between barrier heights and substrate work functions as prescribed by the "induced density of states" (IDIS) model. This yielded a CNL of MEH-PPV of 3.76 eV relative to the vacuum level. The corresponding "screening factor" was calculated to be 0.21. The results are discussed in light of the IDIS, which was initially developed for small molecular materials, as well as the integer charge transfer model (ICT). The ICT model was determined for contaminated polymer interfaces featuring only weak interaction. PMID- 23631597 TI - Identifying and quantifying secondhand smoke in source and receptor rooms: logistic regression and chemical mass balance approaches. AB - Identifying and quantifying secondhand tobacco smoke (SHS) that drifts between multiunit homes is critical to assessing exposure. Twenty-three different gaseous and particulate measurements were taken during controlled emissions from smoked cigarettes and six other common indoor source types in 60 single-room and 13 two room experiments. We used measurements from the 60 single-room experiments for (i) the fitting of logistic regression models to predict the likelihood of SHS and (ii) the creation of source profiles for chemical mass balance (CMB) analysis to estimate source apportionment. We then applied these regression models and source profiles to the independent data set of 13 two-room experiments. Several logistic regression models correctly predicted the presence of cigarette smoke more than 80% of the time in both source and receptor rooms, with one model correct in 100% of applicable cases. CMB analysis of the source room provided significant PM2.5 concentration estimates of all true sources in 9 of 13 experiments and was half-correct (i.e., included an erroneous source or missed a true source) in the remaining four. In the receptor room, CMB provided significant estimates of all true sources in 9 of 13 experiments and was half correct in another two. PMID- 23631599 TI - Synthesis and structure of a carbene-stabilized boraallene coordinated to rhodium. AB - Reaction of the (B,C-eta(2))-1-aza-2-borabutatriene rhodium complex 1 with 1,3 dimethylimidazol-2-ylidene) (IMe, 2) afforded the N-heterocyclic carbene stabilized (C,C-eta(2))-1-boraallene rhodium complex 3, which has been characterized in solution and by X-ray crystallography. Density functional theory calculations were carried out to elucidate the observed base-induced B-C to C-C coordination mode shift, which suggested that the latter is 25 kJ/mol lower in energy. PMID- 23631600 TI - Global metabolite profiling of human colorectal cancer xenografts in mice using HPLC-MS/MS. AB - Reversed-phase gradient LC-MS was used to perform untargeted metabonomic analysis on extracts of human colorectal cancer (CRC) cell lines (COLO 205, HT-29, HCT 116 and SW620) subcutaneously implanted into age-matched athymic nude male mice to study small molecule metabolic profiles and examine possible correlations with human cancer biopsies. Following high mass accuracy data analysis using MS and MS/MS, metabolites were identified by searching against major metabolite databases including METLIN, MASSBANK, The Human Metabolome Database, PubChem, Biospider, LipidMaps and KEGG. HT-29 and COLO 205 tumor xenografts showed a distribution of metabolites that differed from SW620 and HCT 116 xenografts (predominantly on the basis of relative differences in the amounts of amino acids and lipids detected). This finding is consistent with NMR-based analysis of human colorectal tissue, where the metabolite profiles of HT-29 tumors exhibit the greatest similarity to human rectal cancer tissue with respect to changes in the relative amounts of lipids and choline-containing compounds. As the metabolic signatures of cancer cells result from oncogene-directed metabolic reprogramming, the HT-29 xenografts in mice may prove to be a useful model to further study the tumor microenvironment and cancer biology. PMID- 23631601 TI - Screening for substance abuse in women's health: a public health imperative. AB - Alcohol and drug use is a significant public health problem with particular implications for the health and safety of women. Women who abuse these substances are more likely to have untreated depression and anxiety and are at higher risk for intimate partner violence, homelessness, incarceration, infectious disease, and unplanned pregnancy. Substance abuse during pregnancy places both mother and fetus at risk for adverse perinatal outcomes. Data regarding the prevalence of substance abuse in women are conflicting and difficult to interpret. On the clinical level, strong arguments exist against routine urine drug testing and in favor of the use of validated instruments to screen women for drug and alcohol use both in primary women's health care and during pregnancy. A number of sex specific screening tools are available for clinicians, some of which have also been validated for use during pregnancy. Given the risks associated with untreated substance abuse and dependence in women, the integration of drug and alcohol screening into daily clinical practice is imperative. This article reviews screening tools available to providers in both the prenatal and primary women's health care settings and addresses some of the challenges raised when women screen positive for drug and alcohol abuse. PMID- 23631602 TI - Prevalence and predictors of cervicitis in female sex workers in Peru: an observational study. AB - BACKGROUND: Cervicitis is a syndrome of cervical inflammation and a common condition in female sex workers (FSW), a subpopulation vulnerable to sexually transmitted infections. Local data is essential for guiding syndromic management of cervicitis in FSW working in Peru. We sought to describe the prevalence and etiologies of cervicitis in this population. We also aimed to identify sociodemographic, behavioral and biological factors associated with cervicitis, including bacterial vaginosis (BV), a condition with a possible role in cervicitis. METHODS: FSW 18 years of age or older presenting to a free public sexual health clinic in Callao-Lima, Peru were eligible for inclusion upon consent. 467 participants completed a face-to-face questionnaire and underwent genital examination. Vaginal, endocervical and blood samples were collected and tested for C. trachomatis (CT), N. gonorrhea (GC), T. vaginalis (TV), BV, HIV and Human T-Cell Lymphotropic Virus -1. Logistic regression was used to determine whether sociodemographic, behavioral, or other sexual health related characteristics were associated with the diagnosis of cervicitis. RESULTS: Cervicitis was detected in 99 (24.9%) of 397 FSW. The presence of cervicitis was unable to be determined in 70 participants. In women with cervicitis, CT was present in 4.6% (4/87), TV in 4.0% (4/99), GC in 0% (0/87) and no pathogen was detected on cervical microbiology in 91.9% (91/99). BV was detected on vaginal microbiology in 36.9% (31/84) of cervicitis cases. BV was more common in women with cervicitis, however this association did not reach statistical significance (aOR = 1.47 [0.87, 2.48], p = 0.15). Other STI were not associated with cervicitis. Regular clinic attendance (aOR = 0.54 [0.34, 0.87], p = 0.01) and Ecuadorian nationality (aOR = 0.31 [0.13, 0.76], p = 0.01) were associated with reduced risk of cervicitis. CONCLUSIONS: Cervicitis was common in FSW working Peru and was predominantly nongonococcal and non-chlamydial in etiology. Further study is warranted to clarify the role of BV and other emerging cervicitis pathogens in this population. The current Peruvian program of free health checks for FSW may be effective for reducing rates of cervicitis. The protective effect of Ecuadorian nationality prompts further study. PMID- 23631603 TI - Spatial and temporal in vivo analysis of circulating and sessile immune cells in mosquitoes: hemocyte mitosis following infection. AB - BACKGROUND: Mosquitoes respond to infection by mounting immune responses. The primary regulators of these immune responses are cells called hemocytes, which kill pathogens via phagocytosis and via the production of soluble antimicrobial factors. Mosquito hemocytes are circulated throughout the hemocoel (body cavity) by the swift flow of hemolymph (blood), and data show that some hemocytes also exist as sessile cells that are attached to tissues. The purpose of this study was to create a quantitative physical map of hemocyte distribution in the mosquito, Anopheles gambiae, and to describe the cellular immune response in an organismal context. RESULTS: Using correlative imaging methods we found that the number of hemocytes in a mosquito decreases with age, but that regardless of age, approximately 75% of the hemocytes occur in circulation and 25% occur as sessile cells. Infection induces an increase in the number of hemocytes, and tubulin and nuclear staining showed that this increase is primarily due to mitosis and, more specifically, autonomous cell division, by circulating granulocytes. The majority of sessile hemocytes are present on the abdominal wall, although significant numbers of hemocytes are also present in the thorax, head, and several of the appendages. Within the abdominal wall, the areas of highest hemocyte density are the periostial regions (regions surrounding the valves of the heart, or ostia), which are ideal locations for pathogen capture as these are areas of high hemolymph flow. CONCLUSIONS: These data describe the spatial and temporal distribution of mosquito hemocytes, and map the cellular response to infection throughout the hemocoel. PMID- 23631604 TI - Real-time continuous glucose monitoring or continuous subcutaneous insulin infusion, what goes first?: results of a pilot study. AB - BACKGROUND: Dual devices allow both continuous subcutaneous insulin infusion (CSII) and real-time (RT) continuous glucose monitoring (CGM). Patients usually start with CSII, adding RT-CGM later (CGM post-CSII). Lack of use of RT-CGM is the main limiting factor of dual device results. Initiating RT-CGM before CSII (CGM pre-CSII) could increase RT-CGM frequency use and further improve glycemic control. SUBJECTS AND METHODS: In this 26-week pilot study, we randomly assigned, via sealed envelopes, 16 CSII and RT-CGM to naive patients 14 years of age or older with type 1 diabetes mellitus (T1DM) to CGM post-CSII or CGM pre-CSII. The Paradigm(r) VeoTM (Medtronic Inc., Northridge, CA) was the dual device used in all patients. The primary end point was frequency of use of RT-CGM between both groups at week 26. RESULTS: We detected a significant higher RT-CGM frequency use in the CGM pre-CSII group at week 26 (78.4+/-10.9% vs. 56.0+/-40.8%; P=0.01), although we did not detect hemoglobin A1c level differences. In addition, CGM pre CSII patients presented less time in hypoglycemia (average daily area under curve <70 mg/dL per 24 h, 0.87+/-1.02 mg/dL/day vs. 3.32+/-2.19 mg/dL/day; P=0.021), and no severe hypoglycemia events were detected during 26 weeks in this group. CONCLUSIONS: CGM pre-CSII is effective in increasing RT-CGM frequency use in T1DM patients. This is accompanied by a significant reduction in time in hypoglycemia. PMID- 23631605 TI - Advanced glycation end products assessed by skin autofluorescence: a new marker of diabetic foot ulceration. AB - BACKGROUND: Accumulation of advanced glycation end products (AGEs) may contribute to diabetic foot ulceration (DFU). Our goal was to determine whether AGEs measurement by skin autofluorescence (SAF) would be an additional marker for DFU management. PATIENTS AND METHODS: We performed SAF analysis in 66 patients with a history of DFU prospectively included and compared the results with those of 84 control patients with diabetic peripheral neuropathy without DFU. We then assessed the prognostic value of SAF levels on the healing rate in the DFU group. RESULTS: Mean SAF value was significantly higher in the DFU group in comparison with the control group, even after adjustment for other diabetes complications (3.2+/-0.6 arbitrary units vs. 2.9+/-0.6 arbitrary units; P=0.001). In the DFU group, 58 (88%) patients had an active wound at inclusion. The mean DFU duration was 14+/-13 weeks. The healing rate was 47% after 2 months of appropriate foot care. A trend for a correlation between SAF levels and healing time in DFU subjects was observed but was not statistically significant (P=0.06). CONCLUSIONS: Increased SAF levels are associated with neuropathic foot complications in diabetes. Use of SAF measurement to assess foot vulnerability and to predict DFU events in high-risk patients appears to be promising. PMID- 23631606 TI - Abnormal glycemic profiles by CGMS in obese first-degree relatives of type 2 diabetes mellitus patients. AB - INTRODUCTION: The conventionally used oral glucose tolerance test (OGTT) has been the mainstay for diagnosis of diabetes and prediabetes. However, recent studies have indicated that a continuous glucose monitoring system (CGMS) could detect impaired glycemia much earlier than OGTT, especially in certain groups. We aimed to study the 24-h glucose profile of high-risk obese first-degree relatives of type 2 diabetes patients by CGMS and ascertain if it was better than OGTT for early detection of type 2 diabetes. SUBJECTS AND METHODS: CGMS data of 20 subjects each in normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and newly detected diabetes mellitus (NDDM) groups were obtained. We considered minimum, maximum, mean, and range of glucose levels as well as number, duration, and area under the curve (AUC) for excursions. RESULTS: We found three (15%) NGT, seven (35%) IFG, and eight (40%) IGT subjects showed excursions in the diabetes range, whereas 18 (90%) NGT and 17 (85%) pure IFG subjects showed excursions in the IGT range. The maximum glucose values for NGT and IFG subjects were 176.0+/-41.4 mg/dL and 186.5+/-39.3 mg/dL, respectively, which is much above the present 2-h OGTT cutoff limit of 140 mg/dL. However, the average number of excursions and AUC of excursions did not differ significantly among the NGT, IFG, and IGT groups. The differences in the duration of excursion between NGT subjects with IFG values and NGT subjects with IGT values were statistically significant for an excursion limit of 140 mg/dL. However, this did not differ significantly between the IFG and IGT groups. CONCLUSIONS: CGMS indicated the presence of significant dysglycemia in first degree relatives of diabetes patients without diabetes who were centrally obese. Hence it could be useful for early identification of individuals at greater risk of diabetes. A deranged glycemic profile may precede onset of overt diabetes by a long time, which may partly explain why some patients with new-onset type 2 diabetes or even prediabetes present with vascular complications at the outset. PMID- 23631607 TI - Nateglinide and acarbose are comparably effective reducers of postprandial glycemic excursions in chinese antihyperglycemic agent-naive subjects with type 2 diabetes. AB - BACKGROUND: Recent studies have identified postprandial glycemic excursions as risk factors for diabetes complications. This study aimed to compare the effects of nateglinide and acarbose treatments on postprandial glycemic excursions in Chinese subjects with type 2 diabetes. SUBJECTS AND METHODS: This was a multicenter, open-label, randomized, active-controlled, parallel-group study. One hundred three antihyperglycemic agent-naive subjects with type 2 diabetes (hemoglobin A1c range, 6.5-9.0%) were prospectively recruited from four hospitals in China. The intervention was nateglinide (120 mg three times a day) or acarbose (50 mg three times a day) therapy for 2 weeks. A continuous glucose monitoring system was used to calculate the incremental area under the curve of postprandial blood glucose (AUCpp), the incremental glucose peak (IGP), mean amplitude of glycemic excursions, SD of blood glucose, the mean of daily differences, and 24-h mean blood glucose (MBG). Subjects' serum glycated albumin and the plasma insulin levels were also analyzed. RESULTS: Both agents caused significant reductions on AUCpp and IGP. Similarly, both treatment groups showed significant improvements in the intra- and interday glycemic excursions, as well as the 24-h MBG and serum glycated albumin compared with baseline (P<0.001). However, neither of the agents produced a significantly better effect (P>0.05). Moreover, the nateglinide treated group had significantly increased insulin levels at 30 min and at 120 min after a standard meal compared with baseline, whereas the acarbose-treated group decreased. No serious adverse events occurred in either group. The rates of hypoglycemic episodes were comparable in the two groups, and no severe hypoglycemic episode occurred in either group. CONCLUSIONS: Nateglinide and acarbose were comparably effective in reducing postprandial glycemic excursions in antihyperglycemic agent-naive Chinese patients with type 2 diabetes, possibly through different pathophysiological mechanisms. PMID- 23631608 TI - Real-time hypoglycemia detection from continuous glucose monitoring data of subjects with type 1 diabetes. AB - BACKGROUND: Hypoglycemia is a potentially fatal condition. Continuous glucose monitoring (CGM) has the potential to detect hypoglycemia in real time and thereby reduce time in hypoglycemia and avoid any further decline in blood glucose level. However, CGM is inaccurate and shows a substantial number of cases in which the hypoglycemic event is not detected by the CGM. The aim of this study was to develop a pattern classification model to optimize real-time hypoglycemia detection. MATERIALS AND METHODS: Features such as time since last insulin injection and linear regression, kurtosis, and skewness of the CGM signal in different time intervals were extracted from data of 10 male subjects experiencing 17 insulin-induced hypoglycemic events in an experimental setting. Nondiscriminative features were eliminated with SEPCOR and forward selection. The feature combinations were used in a Support Vector Machine model and the performance assessed by sample-based sensitivity and specificity and event-based sensitivity and number of false-positives. RESULTS: The best model was composed by using seven features and was able to detect 17 of 17 hypoglycemic events with one false-positive compared with 12 of 17 hypoglycemic events with zero false positives for the CGM alone. Lead-time was 14 min and 0 min for the model and the CGM alone, respectively. CONCLUSIONS: This optimized real-time hypoglycemia detection provides a unique approach for the diabetes patient to reduce time in hypoglycemia and learn about patterns in glucose excursions. Although these results are promising, the model needs to be validated on CGM data from patients with spontaneous hypoglycemic events. PMID- 23631611 TI - Rotating to oral methadone in advanced cancer patients: a case series. AB - CONTEXT: Methadone is increasingly being used to treat patients whose pain does not respond well to other opioids. Advantages over morphine sulphate and its alternatives include low cost, lack of active metabolites and efficacy against neuropathic pain. OBJECTIVES: To describe our experience with opioid rotation to methadone and compare the morphine to methadone ratios to previously published data; To discuss two commonly used rotation methods--the Edmonton and Morley Makin methods. METHOD: We describe two cases with cancer pain successfully switched to methadone. In both cases the dose of the previous opioid was limited by development of opioid toxicity. We used the Morley-Makin conversion method and modified it by reducing the 'as required' dose by a third. The initial methadone doses for these cases were lower than predicted doses. CONCLUSION: In cases where cancer patients fail to respond or develop tolerance to opioids, conversion to methadone is a reasonable approach. Although equianalgesic tables may not always predict final methadone doses, when properly selected can be useful tools for the experienced clinician. A customised and cautious approach is thus advisable when rotating to oral methadone, especially in patients who have experienced opioid toxicity. PMID- 23631610 TI - Immunobiology of Plasmodium in liver and brain. AB - Malaria remains one of the most serious health problems globally, but our understanding of the biology of the parasite and the pathogenesis of severe disease is still limited. Multiple cellular effector mechanisms that mediate parasite elimination from the liver have been described, but how effector cells use classical granule-mediated cytotoxicity to attack infected hepatocytes and how cytokines and chemokines spread via the unique fluid pathways of the liver to reach the parasites over considerable distances remains unknown. Similarly, a wealth of information on cerebral malaria (CM), one of the most severe manifestations of the disease, was gained from post-mortem analyses of human brain and murine disease models, but the cellular processes that ultimately cause disease are not fully understood. Here, we discuss how imaging of the local dynamics of parasite infection and host response as well as consideration of anatomical and physiological features of liver and brain can provide a better understanding of the initial asymptomatic hepatic phase of the infection and the cascade of events leading to CM. Given the increasing drug resistance of both parasite and vector and the unavailability of a protective vaccine, the urgency to reduce the tremendous morbidity and mortality associated with severe malaria is obvious. PMID- 23631613 TI - An innovative self-care module for palliative care medical learners. AB - Palliative care is a uniquely demanding field in that clinicians routinely address the complex needs of patients living with incurable illness. Due to their relative inexperience, medical learners completing a palliative care educational experience are particularly vulnerable to the stresses that are often encountered. To address this educational need, a structured Self-Care Module was developed for medical learners rotating through a palliative care clinical rotation. Components of this module include completion of a process recording exercise, a structured reflection, and participation in a facilitated group discussion. An examination of the acceptability, utility, and operational feasibility of the module demonstrated that 86% (n=35) of learners found the module helpful in reflecting on their clinical encounters, 86% (n=35) gained an appreciation for the importance of self-reflection and self-awareness as a component of self-care and 97% (n=35) gained a greater appreciation for sharing clinical experiences with other learners. This novel Self-Care Module was found to be a well accepted, useful, and operationally feasible educational experience for postgraduate and undergraduate learners completing a palliative care educational experience. PMID- 23631612 TI - Informed consent in palliative care clinical trials: challenging but possible. AB - Obtaining informed consent is a key protection that should be afforded universally to people using health services and the basis around which any participation in clinical trials is built. Randomized controlled effectiveness studies are necessary to answer key questions in hospice and palliative care, in order to help systematically improve the quality of care. In order to be properly generalizable, such trials need to have broad inclusion criteria to reflect the population most likely to be affected by the condition. The inclusion of patients who are seriously ill, and therefore potentially vulnerable, requires careful exploration of ethical and legal principles that underpin informed consent. Specific challenges in obtaining informed consent for randomised clinical trials (RCTs) in clinically unstable populations such as hospice and palliative care include higher rates of people with impaired cognitive capacity as well as interventional studies in clinical situations which may present as a sudden change in condition. None of these challenges is unique to hospice and palliative care research, but the combination and frequency with which they are encountered require systematic and considered solutions. This article outlines five different ethically valid consent approaches and discusses their applicability to hospice and palliative care research trials. These include: consent by the patient (at the time of enrolment, in advance of the study, or delayed until after the study has commenced); a proxy (or legally authorised representative); or a consent waiver. Increased use of the less traditional modes of informed consent may lead to greater participation rates in hospice and palliative care trials, thereby improving the evidence base more rapidly in part by better reflecting the population served and hence improving generalizability. PMID- 23631609 TI - Preclinical evaluation of radiosensitizing activity of Pluronic block copolymers. AB - PURPOSE: Pluronic block copolymers are non-ionic surfactants with demonstrated sensitizing activity in chemotherapy and hyperthermia in various tumor cell lines. In the current study we investigated the potential activity of Pluronic as a radiosensitizing agent. MATERIALS AND METHODS: As a possible mechanism, the effect of Pluronic on Hsp70 and Hsp90 was examined. Gli36 human glioma cells were treated with radiation alone as well as with a combination treatment of Pluronic and radiation. RESULTS: Clonogenic cell survival assays show that Pluronic has an elevated effect on radiosensitization (50% high, p < 0.01), even with radiation doses as low as 2 Gy. The Hsp90 level was reduced 24 h after the combined treatment in both in vitro and in vivo. Similarly, Hsp70 levels were also decreased 24 h post treatment. When Gli36 cells were exposed to Pluronic before and during irradiation, DNA DSB: double-strand breaks repair was reduced, and elevated apoptosis was also seen in tumor xenografts. CONCLUSION: Data suggest the potential use of L10 as a radiosensitizer. While the mechanism of sensitization requires additional investigation, the presented results indicate that the effect may be due, in part, to a decrease in Hsp90 and 70 levels and increased DNA damage. PMID- 23631614 TI - Access to outreach specialist palliative care teams among cancer patients in Denmark. AB - BACKGROUND: Equal access to end-of-life care is important. However, social inequality has been found in relation to place-of-death. The question is whether social and economic factors play a role in access to specialist palliative care services. OBJECTIVE: The study analyzed the association between access to outreach specialist palliative care teams (SPCTs) and socioeconomic characteristics of Danish cancer patients who died of their cancer. METHODS: The study was a population-based, cross-sectional register study. We identified 599 adults who had died of cancer from March 1 to November 30, 2006, in Aarhus County, Denmark. Data from health registers were retrieved and linked based on the unique personal identifier number. RESULTS: Multivariate analysis with adjustment for age, gender, and general practitioner (GP) involvement showed a higher probability of contact with an SPCT among immigrants and descendants of immigrants than among people of Danish origin (prevalence ratio [PR]: 1.55; 95% confidence interval (CI): 1.04;2.31) and among married compared to unmarried patients (PR: 1.25; 95% CI: 1.01;1.54). The trends were most marked among women. CONCLUSION: We found an association between females, married patients, and female immigrants and their descendants and access to an SPCT in Denmark. However, no association with the examined economic factor was found. Need for specialized health care, which is supposed to be the main reason for access to an SPCT, may be related to economic imbalance; and despite the relative equality found, SPCT access may not be equal for all Danish residents. Further research into social and economic consequences in palliative care services is warranted. PMID- 23631620 TI - Pesticide residues in food-based proficiency test materials, spiking values versus consensus assigned values. AB - We examine the differences among the three estimates of the true value of the measurand derived from routine proficiency testing of laboratories analyzing foodstuffs for pesticide residues. The three values are (i) the spike level (Sp), (ii) the mean result found by the laboratory conducting the test for sufficient homogeneity (Ho), and (iii) the consensus of the participants' results used as the assigned value (AV) in converting results into z scores. Data amounting to 205 examples were collected from successive rounds of three series of proficiency tests from the Food Analysis Performance Assessment Scheme (FAPAS): namely, series 05 (fats, oils, and animal products), series 09 (cereals and their products), and series 19 (fruits, vegetables, and their products). Irrespective of the class of test material, we found that the means of AV and Ho were almost identical, while the value of Sp was systematically higher than AV by a factor of 1.22. The dispersion of the individual values of both ratios, Ho/AV and Sp/AV, was examined by analysis of variance. A small part of the variance was attributed to the series, but a greater part, about 40%, was attributed to individual rounds within series. We discovered no connection between the ratios and the chemistry of the analyte. PMID- 23631619 TI - Solvent effect and hydrogen bond interaction on tautomerism, vibrational frequencies, and Raman spectra of guanine: a density functional theoretical study. AB - Stable structures and Raman spectra of guanine have been investigated by density functional theory (DFT). Focusing on solvent effect and hydrogen bonding interaction, we have calculated the two keto-amino tautomers G17K and G19K as well as their guanine-water complexes and tetramers. The results show G17K is more stable than G19K in the gas phase, whereas in polar solvents G19K dominates. The vibrational fundamentals of G17K have been reassigned based on normal-mode analysis, since the previous assignment was limited to the G19K only. In the Raman spectra, the modes of the ring breathing vibration and those in the fingerprint region (from 1000 to 1600 cm(-1)) affected by the solvent effect and the hydrogen bonding interaction dramatically. The band at 1163 cm(-1) of G17K in gas has a large blue shift when water molecule forms hydrogen bonds with N7-H16 and C6?O13 sites. The blue shift can be explained by the influence of hydrogen bonding interaction along with shortening the N1-C6 bond distance. In addition, the dominant existing tautomer in polycrystalline and powder guanine is proposed to be G17K, whose calculated vibrational frequencies agree with the experimental Raman spectra reported before. PMID- 23631621 TI - Assessment of potential anti-cancer stem cell activity of marine algal compounds using an in vitro mammosphere assay. AB - BACKGROUND: The cancer stem cell (CSC) theory proposes that tumours arise from and are sustained by a subpopulation of cells with both cancer and stem cell properties. One of the key hallmarks of CSCs is the ability to grow anchorage independently under serum-free culture conditions resulting in the formation of tumourspheres. It has further been reported that these cells are resistant to traditional chemotherapeutic agents. METHODS: In this study, the tumoursphere assay was validated in MCF-7 cells and used to screen novel marine algal compounds for potential anti-cancer stem cell (CSC) activity in vitro. RESULTS: MCF-7 breast cancer cells were observed to generate tumourspheres or mammospheres after 3-5 days growth in anchorage-independent conditions and an apparent enrichment in potential CSCs was observed by an increase in the proportion of CD44high/CD24low marker-bearing cells and Oct4 expression compared to those in the bulk population grown in regular adherent conditions. Using this assay, a set of algal metabolites was screened for the ability to inhibit mammosphere development as a measure of potential anti-CSC activity. We report that the polyhalogenated monoterpene stereoisomers RU017 and RU018 isolated from the red alga Plocamium cornutum, both of which displayed no cytotoxicity against either adherent MCF-7 breast cancer or MCF-12A non-transformed breast epithelial cells, were able to prevent MCF-7 mammosphere formation in vitro. On the other hand, neither the brown algal carotenoid fucoxanthin nor the chemotherapeutic paclitaxel, both of which were toxic to adherent MCF-7 and MCF-12A cells, were able to inhibit mammosphere formation. In fact, pre-treatment with paclitaxel appeared to enhance mammosphere formation and development, a finding which is consistent with the reported resistance of CSCs to traditional chemotherapeutic agents. CONCLUSION: Due to the proposed clinical significance of CSC in terms of tumour initiation and metastasis, the identification of agents able to inhibit this subpopulation has clinical significance. PMID- 23631622 TI - Change in biased thinking in a 10-session treatment for borderline personality disorder: further evidence of the motive-oriented therapeutic relationship. AB - Borderline Personality Disorder (BPD) is characterized by both maladaptive thinking and problematic schemas. Kramer and colleagues (2011) showed that using the motive-oriented therapeutic relationship (MOTR), based on the individualized understanding of the patient according to Plan Analysis (Caspar, 2007), can improve treatment outcomes for BPD. The present process-outcome pilot study aimed to examine the effects of the motive-oriented therapeutic relationship on the cognitive biases of patients with BPD. Change in biased cognitions in N=10 patients who were subject to MOTR was compared to that of N=10 patients who received psychiatric-psychodynamic treatment (Gunderson & Links, 2008). Results show a greater decrease in over-generalizations in patients who received MOTR, compared to the patients who received the psychiatric-psychodynamic treatment. These changes were related to outcome in various ways. These findings underline the importance of an individualized case formulation method in bringing about therapeutic change. PMID- 23631624 TI - Depression is to diabetes as antidepressants are to insulin: the unraveling of an analogy? AB - The common comparison of depression to diabetes enables the construction of depression as a nonstigmatizing chronic illness that requires medication. We explore, through the use of discourse analysis, how both long-term users of antidepressants and family physicians invoked this analogy in research interviews. Specifically, we show how these participants explicitly or implicitly challenged the aptness of the depression-diabetes analogy as framed either within a generic (and presumably type 1) conception of diabetes or within the model of type 2 diabetes. These challenges include demonstrating how the elements or inferences of the analogy do not correspond, and how the analogy does not have its intended effects. We consider the implications of the unraveling of this analogy for the construction of depression as a chronic medical condition, for the supposed ease of prescribing and taking antidepressants, and for the reduction of stigma. PMID- 23631626 TI - Health literacy and the readability of written information for hormone therapies. AB - INTRODUCTION: Health education and counseling are important elements of the care provided by clinicians. Counseling efforts may involve helping women to understand their options for symptom management related to various reproductive life transitions. In light of this, the need for information during the menopausal transition is critical for assisting women with their health care decisions. Yet the Institute of Medicine estimates that approximately half the adult population in the United States has difficulty understanding and using health information. The US Food and Drug Administration (FDA) mandates the distribution of written information for estrogen-containing products; however, the readability of information for these pharmaceutical products has not been widely studied. To address this gap, this study examined the readability of written information for FDA-approved prescription menopausal hormone therapies (N = 31). METHODS: Readability of the written information about hormone therapies from 31 hormone therapy products was assessed using the Flesch Reading Ease and Flesch-Kincaid Grade Level formulas. RESULTS: The reading level ranged from 6.70 to 12.30, with an average grade level of 9.33 (ninth-grade reading level). All but one of the hormone therapy products evaluated in this study exceeded the recommended sixth-grade reading level for written health information. In addition, only 48% of the written information instructions in the study sample (n = 15) included illustrations. DISCUSSION: Assessment of written information about menopausal hormone therapies showed that the majority of the materials are written at a high reading level. These findings have implications for health literacy and counseling efforts when helping women to understand their options for menopausal symptom management. Midwives, nurses, and other health care providers may need to supplement written information with additional consumer friendly written information, utilize illustrations, and use verbal instructions more frequently to help support women in evaluating their treatment options. PMID- 23631627 TI - Mass quantification of nanoparticles by single droplet calibration using inductively coupled plasma mass spectrometry. AB - Utilization of metallic engineered nanoparticles (ENP) is progressing rapidly; therefore, characterization of their most important properties, e.g., size/mass, elemental composition, and number concentration, is inevitable and currently uses a set of different techniques. In this work, a new setup is proposed for the quantitative size and mass determination of ENPs employing a monodisperse microdroplet generator (MDG) with transport efficiencies >95% coupled to an ICPMS. Two different MDG sample introduction configurations (vertical and horizontal) were tested, and their performance characteristics were evaluated. Due to a 5-fold reduced temporal jitter resulting in a shorter measurement time, the horizontal droplet introduction approach was used for the analysis of ENPs. With this setup, the quantification of Au, Ag, and CeO2 nanoparticles of different sizes and polydispersities was achieved. Results are compared to complementary techniques such as transmission electron microscopy (TEM) and asymmetric flow field flow fractionation (AF4), and advantages as well as limitations of this newly proposed technique are discussed. PMID- 23631625 TI - Metabolic engineering of Escherichia coli for the biosynthesis of alpha-pinene. AB - BACKGROUND: alpha-Pinene is an important natural product that is widely used in flavorings, fragrances, medicines, fine chemicals and high-density renewable fuels. Currently, alpha-Pinene used in industry is mainly produced either by tapping trees (gum turpentine) or as a byproduct of paper pulping (crude sulfate turpentine, CST). However, the extraction of it from trees is tedious and inefficient and requires substantial expenditure of natural resources. Therefore, it is necessary to seek sustainable technologies for alpha-pinene production. RESULTS: To construct the microbial synthetic pathway of alpha-pinene in E. coli, we co-expressed native geranyl diphosphate synthase (IspA) from E. coli and alpha pinene synthase (Pt30) from Pinus taeda, and then to increase the geranyl diphosphate (GPP) content in the cells, a suitable geranyl diphosphate synthase (GPPS2) was selected from two different origins. Furthermore, to enhance alpha pinene production, a novel biosynthetic pathway of alpha-pinene was assembled in E. coli BL21(DE3) with the heterologous hybrid mevalonate (MVA) pathway, GPPS2 and alpha-pinene synthase (Pt30). The final genetic strain, YJM28, harboring the above novel biosynthetic pathway of alpha-pinene, accumulated alpha-pinene up to 5.44 mg/L and 0.97 g/L under flask and fed-batch fermentation conditions, respectively. The conversion efficiency of glucose to alpha-pinene (gram to gram) in the metabolically engineered strain reached 2.61%. CONCLUSIONS: In this paper, by using metabolic engineering techniques, the more efficient biosynthetic pathway of alpha-pinene was successfully assembled in E. coli BL21(DE3) with the heterologous hybrid MVA pathway, GPPS2 and alpha-pinene synthase (Pt30). In addition, this is the first report on alpha-pinene fed-batch fermentation, and our results represent improvements over previous reports. PMID- 23631629 TI - Banana: a new simulation model to teach surgical techniques for treating ingrown toenails. PMID- 23631631 TI - Intra-articular use of a platelet-rich product in normal horses: clinical signs and cytologic responses. AB - OBJECTIVES: (1) To report the clinical and synovial effects of a platelet-rich product (PRPr) in normal equine joints, (2) to assess the persistence of platelets within synovial fluid after intra-articular injection, (3) to compare responses to different preparations of that product, and (4) to evaluate a gravity filtration system for PRPr preparation in horses. STUDY DESIGN: Experimental. METHODS: A platelet-rich saline product (PRPr) was prepared from 7 normal horses using a proprietary preparation device and was divided into 3 treatments: resting, CaCl2 -activated (23 mM, final), and bovine thrombin activated (10 U/mL, final). Each horse had 3 concurrent randomly assigned intra articular PRPr treatments administered in their metacarpophalangeal/metatarsophalangeal joints; the fourth limb was injected with saline (0.9% NaCl) solution as a control. Clinical assessments, cytologic analysis of synovial fluid and hemograms were performed at 6, 24, 48, and 96 hours after injection. PRPr composition and growth factor content were analyzed. RESULTS: The gravity filtration system produced a moderately concentrated PRPr. At 6 and 24 hours, when compared to control values, all PRPr treatments caused a significant increase in synovial WBC concentration (P < .0059) and neutrophil percentage (P < .0005). Bovine thrombin-activated PRPr injection consistently caused increased effusion scores and periarticular signs. At all time points, the synovial WBC concentration after thrombin-activated PRPr was significantly greater (P < .001) than for the control, CaCl2 -activated or resting PRPr. Intact platelets could be observed in synovial fluid for up to 5 days after intra articular PRPr injection. CONCLUSIONS: Resting and CaCl2 -activated PRPr may be safely used to treat equine joints, but bovine thrombin activation is not recommended at 10 U/mL. A PRPr can be prepared using a gravity filtration system, eliminating the need for centrifugation. PMID- 23631630 TI - Improvement in process of care and outcome in patients requiring intensive care unit admission for community acquired pneumonia. AB - BACKGROUND: The present study was performed to assess the prognosis of patients admitted to the intensive care unit (ICU) for community acquired pneumonia (CAP) after implementation of new processes of care. METHODS: Two groups of patients with CAP were admitted to a 16-bed multidisciplinary ICU in an urban teaching hospital during two different periods: the years 1995-2000, corresponding to the historical group; and 2005-2010, corresponding to the intervention group. New therapeutic procedures were implemented during the period 2005-2010. These procedures included a sepsis management bundle derived from the Surviving Sepsis Campaign, use of a third-generation cephalosporin and levofloxacin as the initial empirical antimicrobial regimen, and noninvasive mechanical ventilation following extubation. RESULTS: A total of 317 patients were studied: 142 (44.8%) during the historical period and 175 (55.2%) during the intervention period. Sequential Organ Failure Assessment scores were higher in patients in the intervention group (7.2 +/- 3.7 vs 6.2 +/- 2.8; p=0.008). Mortality changed significantly between the two studied periods, decreasing from 43.6% in the historical group to 30.9% in the intervention group (p < 0.02). A restrictive transfusion strategy, use of systematic postextubation noninvasive mechanical ventilation in patients with severe chronic respiratory or cardiac failure patients, less frequent use of dobutamine and/or epinephrine in patients with sepsis or septic shock, and delivery of a third-generation cephalosporin associated with levofloxacin as empirical antimicrobial therapy were independently associated with better outcomes. CONCLUSION: Positive outcomes in ICU patients with CAP have significantly increased in our ICU in recent years. Many new interventions have contributed to this improvement. PMID- 23631633 TI - Hierarchical organization of spherical assembly with reversibly photocontrollable cross-links. AB - A ternary photocontrollable assembly was hierarchically constructed by the "orthogonal" host-guest interaction of different types of cyclodextrins toward the porphyrin and azobenzene. Spectroscopic titrations and microscopic investigations demonstrate that the inclusion complex of azobenzene modified water-soluble porphyrin (1) with phthalocyanine-grafted permethyl beta cyclodextrins (2) could be reversibly cross-linked to relatively larger nanospheres with naphthyl bridged bis(alpha-cyclodextrin)s (3). Moreover, the large-sized spheres (1.2.3) could be disassembled and switched to small-sized complex (1.2) upon the photoinduced isomerization of an azophenyl group. PMID- 23631632 TI - Expression of cyclins and cyclin-dependent kinase inhibitors in granulosa cells from bovine ovary. AB - The regulation of granulosa cell proliferation is complex, and it is essential for normal follicular development in mammals. The aim of this study was to examine the expression of cyclins and their inhibitors in the granulosa cells of follicles at different developmental stages. Follicles were classified into three groups: oestrogen-inactive dominant follicles (EIDs), oestrogen-active dominant follicles (EADs) and pre-ovulatory follicles (POs). The expression of CCND2 (cyclin D2) mRNA was significantly higher in granulosa cells from EADs and POs than in those from EIDs. The expression of CCND3 (cyclin D3) mRNA was significantly higher in granulosa cells from EADs than in those from other follicles. CCND1 (cyclin D1), CCNE1 (cyclin E1) and CCNE2 (cyclin E2) mRNA expression did not differ among the different follicular stages. The expression of CDKN1A (p21(cip1) ) and CDKN1B (p27(kip1) ) mRNA was significantly higher in granulosa cells from EIDs and POs, respectively, than in those from other follicles. Expression of CDKN2D (p19(INK4d) ) mRNA did not differ among the different follicular stages. Taken together, our study suggested that cyclins and their inhibitors are associated with granulosa cell proliferation at specific follicular developmental stages. PMID- 23631634 TI - Fungal arachidonic acid-rich oil: research, development and industrialization. AB - Fungal arachidonic acid (ARA)-rich oil is an important microbial oil that affects diverse physiological processes that impact normal health and chronic disease. In this article, the historic developments and technological achievements in fungal ARA-rich oil production in the past several years are reviewed. The biochemistry of ARA, ARA-rich oil synthesis and the accumulation mechanism are first introduced. Subsequently, the fermentation and downstream technologies are summarized. Furthermore, progress in the industrial production of ARA-rich oil is discussed. Finally, guidelines for future studies of fungal ARA-rich oil production are proposed in light of the current progress, challenges and trends in the field. PMID- 23631635 TI - Reduced alpha-synuclein levels in cerebrospinal fluid in Parkinson's disease are unrelated to clinical and imaging measures of disease severity. AB - BACKGROUND AND PURPOSE: The cerebrospinal fluid (CSF) concentration of alpha synuclein may reflect the aggregation of alpha-synuclein in brain tissue that neuropathologically characterizes Parkinson's disease (PD). Although most studies in large cohorts report reduced CSF alpha-synuclein levels in PD, the available data to date are not consistent due to variation in group sizes, pre-analytical confounding factors and assay characteristics. Furthermore, it remains unclear whether CSF alpha-synuclein concentrations correlate with measures of disease severity. Acknowledging the methodological issues that emerged from previous studies, we evaluated whether CSF alpha-synuclein levels differ between patients with PD and controls, and relate to disease duration or severity. METHODS: alpha Synuclein levels were measured in CSF samples of 53 well-characterized patients with PD and 50 healthy controls employing a recently developed time-resolved Forster's resonance energy transfer assay. In addition, we studied the relationship of CSF alpha-synuclein levels with disease duration, clinical measures of disease severity and the striatal dopaminergic deficit as measured by dopamine transporter binding and single photon emission computed tomography. RESULTS: In patients with PD, we observed a decrease in mean CSF alpha-synuclein levels that was unrelated to disease duration or measures of disease severity. Using total protein normalized alpha-synuclein, a sensitivity and specificity of 70% and 74% could be reached for distinguishing between patients with PD and controls. CONCLUSION: CSF alpha-synuclein levels are reduced in patients with PD compared with healthy controls. However, sensitivity and specificity indicate that alpha-synuclein will not suffice as a single biomarker. CSF alpha-synuclein levels do not correlate with measures of disease severity, including striatal dopaminergic deficit. PMID- 23631636 TI - Antibiotic prophylaxis: a literature review. AB - Antibiotic prophylaxis has been a matter of great interest and has been discussed by researchers and clinicians over the years. Changes and recommendations have been made in order to clarify protocol and make it safer for patients. Various organizations such as the American Heart Association, American Academy of Oral Surgeons, American Dental Association, and American Academy of Oral Medicine have played vital roles in formulating guidelines for antibiotic prophylaxis. These recommendations for prevention of infective endocarditis have been based on clinical experiences and research as well as expert opinion. This paper summarizes the most recent guidelines for general readers so that informed decisions may be made that are in the interest of patients and practitioners. PMID- 23631637 TI - Mineral trioxide aggregate: part 2 - a review of the material aspects. AB - The purpose of this two-part series is to review the composition, properties, and products of mineral trioxide aggregate (MTA) materials. PubMed and MedLine electronic databases were used to identify scientific papers from January 1991 to May 2010. Based on the selected inclusion criteria, citations were referenced from the scientific peer-reviewed dental literature. Mineral trioxide aggregate is a refined form of the parent compound, Portland cement (PC), and demonstrates a strong biocompatibility due to the high pH level and the material's ability to form hydroxyapatite. Mineral trioxide aggregate materials provide better microleakage protection than traditional endodontic materials as observed in findings from dye-leakage, fluid-filtration, protein-leakage, and bacterial penetration-leakage studies and has been recognized as a bioactive material. Various MTA commercial products are available, including gray mineral trioxide aggregate (GMTA), white mineral trioxide aggregate (WMTA), and mineral trioxide aggregate-Angelus (AMTA). Although these materials are indicated for various dental uses and applications, long-term in-vivo clinical studies are needed. Part 1 of this article highlighted and discussed the composition and characteristics of the material. Part 2 provides an overview of commercially available MTA materials. PMID- 23631638 TI - Postoperative hypersensitivity and its relationship to preparation variables in Class I resin-based composite restorations: findings from the practitioners engaged in applied research and learning (PEARL) Network. Part 1. AB - BACKGROUND: This study investigated postoperative hypersensitivity at 1, 4, and 13 weeks following resin-based composite (RBC) restorations of occlusal caries and its relationship with prepreparation (baseline) sensitivity and preparation related variables, including dentin caries activity, cavity dimension and volume, and lesion radiographic visibility. METHODS: Investigators in a practice-based research network enrolled patients with occlusal caries deemed to require operative treatment. The 45 dental practitioners then placed restorations using their preferred techniques. Complete baseline data on 665 restorations from 602 patients included patient-reported sensitivity (pre-preparation); dentists' ranking of dentin caries on opening the enamel; measurements of preparation depth, width, and length; and patient demographics. At 1, 4, and 13 weeks post treatment, patients anonymously reported any sensitivity to hot and cold stimuli, sweets, clenching, and chewing, as well as quality-of-life indicators related to the restorations. RESULTS: At baseline, 30% of teeth had reported sensitivities of >=3 on an anchored scale from 0 to 10 points and were designated as appreciable hypersensitivity (AH). Appreciable hypersensitivity at baseline was related to lesion radiographic visibility and patient age but not to dentin caries activity ranking, type of posterior tooth, gender, or race/ethnicity. Patients reported on 491 restorations at 4 weeks post-treatment--18% had AH. Of those who had AH, 39% (34 of 87) had no baseline AH. With restoration, 63% of teeth with baseline AH no longer had AH. Changes in AH were not associated with preparation depth, length, width, or volume. CONCLUSION: Patient-reported occlusal caries tooth sensitivity was high at baseline and eliminated by RBC restoration in 63% of cases; however, new sensitivity after restoration was reported in 10% of lesions that had none at pretreatment. Sensitivity was not related to preparation dimensions, volume, tooth type, or patient demographics (other than age) in these early lesions. PMID- 23631639 TI - Dens invaginatus: a case report. AB - Dens invaginatus, also known as dens in dente, is a rare anomaly affecting human dentition. The condition results in invagination of an amelodental structure within the pulp. This case report discusses the current management protocol of dens invaginatus as demonstrated in an adolescent female and describes treatment options. As with most conditions, early diagnosis and preventive measures help minimize complications in dens invaginatus cases. PMID- 23631640 TI - Update to "antibiotic prophylaxis: a literature review". PMID- 23631642 TI - Partition and turnover of glutathione reductase from Saccharomyces cerevisiae: a proteomic approach. AB - Glutathione reductase (Glr1) is a low abundance protein involved in defense mechanisms against reactive oxygen species. Expressed on cytosolic ribosomes, the same gene, GLR1, uses alternative start codons to generate two forms of Glr1. Translation from the first AUG codon generates the mitochondrial form incorporating a presequence necessary for import; translation from the second AUG codon yields the cytosolic counterpart. Proteomic strategies were used to analyze the N-terminal sequences and the turnover of Saccharomyces cerevisiae Glr1. The N terminus of cytosolic Glr1 was found normally to be N-acetylserine. When a Glr1 overproducing strain was employed, unprocessed mitochondrial Glr-1 with N terminal acetylmethionine also accumulated in the cytosol. The processed mitochondrial Glr1 was surprisingly found to have three alternative N-termini, none of them acetylated. Mitochondrial Glr1 was turned over faster than the cytosolic form by a factor of about 2, consistent with the importance of redox homeostasis in the mitochondria. These experiments also allowed us to estimate the extent of "leaky scanning" in the synthesis of Glr1. Surprisingly, the second AUG appears to be responsible for most of the cellular Glr1. This is the first report of protein turnover measurements of a low-abundance protein distributed in different compartments of a eukaryotic cell. PMID- 23631643 TI - Photoelectron spectroscopic and theoretical study of aromatic-Bi(m) anionic complexes (aromatic = C6H5, C5H4N, C4H3O, and C4H4N; m = 1-3): a comparative study. AB - The reactions between Bi clusters generated by laser ablation and different aromatic molecules (C6H6, C5H5N, C4H4O, or C4H5N) seeded in argon carrier gas were studied by a reflectron time-of-flight mass spectrometer (RTOF-MS) with a photoelectron spectrometer. The photoelectron (PE) spectra of the dominant anionic products Bi(m)C6H5(-), Bi(m)C5H4N(-) (m = 1-4) and Bi(m)C4H3O(-), Bi(m)C4H4N(-) (m = 1-3) dehydrogenated complexes were obtained by 308 and 193 nm laser, respectively. It was found that the adiabatic electron affinities (EAs) of Bi(m)C4H4N are higher than those of Bi(m)C6H5, Bi(m)C5H4N, and Bi(m)C4H3O with the same metal number m. Theoretical calculations with density functional theory (DFT) were carried out to elucidate the possible structures for Bi(m)C4H4N(-) and Bi(m)C4H4N complexes. By comparison of the theoretical and experimental EAs, the most possible structures were the isomers in which the C4H4N group binds to metal clusters with the N-Bi bond, and their simulated spectra based on Koopmans' theorem were in correct agreement with the PES results. Furthermore, the analysis of the molecular orbital composition provided evidence that the C4H4N group contributes a single electron to bind to Bi(m) clusters with the Bi-N sigma bond. PMID- 23631641 TI - Standardizing operational vector sampling techniques for measuring malaria transmission intensity: evaluation of six mosquito collection methods in western Kenya. AB - BACKGROUND: Operational vector sampling methods lack standardization, making quantitative comparisons of malaria transmission across different settings difficult. Human landing catch (HLC) is considered the research gold standard for measuring human-mosquito contact, but is unsuitable for large-scale sampling. This study assessed mosquito catch rates of CDC light trap (CDC-LT), Ifakara tent trap (ITT), window exit trap (WET), pot resting trap (PRT), and box resting trap (BRT) relative to HLC in western Kenya to 1) identify appropriate methods for operational sampling in this region, and 2) contribute to a larger, overarching project comparing standardized evaluations of vector trapping methods across multiple countries. METHODS: Mosquitoes were collected from June to July 2009 in four districts: Rarieda, Kisumu West, Nyando, and Rachuonyo. In each district, all trapping methods were rotated 10 times through three houses in a 3 * 3 Latin Square design. Anophelines were identified by morphology and females classified as fed or non-fed. Anopheles gambiae s.l. were further identified as Anopheles gambiae s.s. or Anopheles arabiensis by PCR. Relative catch rates were estimated by negative binomial regression. RESULTS: When data were pooled across all four districts, catch rates (relative to HLC indoor) for An. gambiae s.l (95.6% An. arabiensis, 4.4% An. gambiae s.s) were high for HLC outdoor (RR = 1.01), CDC-LT (RR = 1.18), and ITT (RR = 1.39); moderate for WET (RR = 0.52) and PRT outdoor (RR = 0.32); and low for all remaining types of resting traps (PRT indoor, BRT indoor, and BRT outdoor; RR < 0.08 for all). For Anopheles funestus, relative catch rates were high for ITT (RR = 1.21); moderate for HLC outdoor (RR = 0.47), CDC-LT (RR = 0.69), and WET (RR = 0.49); and low for all resting traps (RR < 0.02 for all). At finer geographic scales, however, efficacy of each trap type varied from district to district. CONCLUSIONS: ITT, CDC-LT, and WET appear to be effective methods for large-scale vector sampling in western Kenya. Ultimately, choice of collection method for operational surveillance should be driven by trap efficacy and scalability, rather than fine-scale precision with respect to HLC. When compared with recent, similar trap evaluations in Tanzania and Zambia, these data suggest that traps which actively lure host-seeking females will be most useful for surveillance in the face of declining vector densities. PMID- 23631645 TI - Manufacturing consent?: Media messages in the mobilization against HIV/AIDS in India and lessons for health communication. AB - Despite repeated calls for a more critical and "culture-centered" approach to health communication, textual analysis of televised public service advertising (PSA) campaigns has been largely neglected, even by critical communication scholars. In the case of "developing" countries in particular, there is an acute shortage of such literature. On the other hand, following the outbreak of major public health diseases such as AIDS, most countries have adopted PSA campaigns as the most preferred means of communicating messages. Drawing on insights from cultural studies (especially Antonio Gramsci and Stuart Hall), this article engages in textual analysis of the televised PSA campaigns launched by the Indian state to prevent HIV/AIDS between 2002 and 2005. Through such analysis, it argues that although few diseases in Indian history have spurred such massive and creative efforts for mass mobilization as AIDS, these efforts, in terms of their ethical implications, have been far from emancipatory. In fact, they have constructed and perpetuated the logic of domination and control along class, gender, sexuality, and knowledge systems, often contradicting and potentially harming the very goal of HIV prevention and of health promotion and empowerment. This article also holds that assessing public health campaigns through textual analysis, a highly neglected tool in health communication, can shed important light on a far more complex and changing nature of the state and public policy, especially in the developing world, thereby opening up space for alternative theorizing for health communication and social change. PMID- 23631644 TI - Assessing the stochastic intermittency of single quantum dot luminescence for robust quantification of biomolecules. AB - Single molecule detection schemes promise that one has the ability to reach the ultimate limit of detection: one molecule. In this paper, we use the stochastic luminescence of single semiconductor nanocrystals (quantum dots, QDs) to detect and localize particles as digital counts. These digital counts can be correlated to the concentration of analytes in solution. Here, we use total internal reflection fluorescence (TIRF) microscopy to probe individual QDs immobilized on a functionalized substrate. QDs have found their niche in the bioanalytical community due to their remarkable brightness and stability. Despite their numerous outstanding photophysical properties, QDs at the single particle level display a pronounced intermittent luminescence, posing a challenge for the detection of individual particles. In this paper, we demonstrate a reliable method for detecting QDs that takes advantage of these signal fluctuations by comparing the variations in the QD's fluorescence signals against variations of the background signal. The quantitative methodology developed here results in signal-to-background ratios up to 90:1, which is at least 8-times higher than the ratios obtained using methodologies relying solely on signal integration. This enhanced signal-to-background ratio facilitates a robust thresholding process and results in femtomolar limits of detection. PMID- 23631646 TI - MicroRNA-376c inhibits cell proliferation and invasion in osteosarcoma by targeting to transforming growth factor-alpha. AB - MicroRNAs are a class of small noncoding RNAs that function as critical gene regulators through targeting mRNAs for translational repression or degradation. In this study, we showed that miR-376c expression level was decreased while transforming growth factor-alpha (TGFA) mRNA expression levels were increased in osteosarcoma tissues and cell lines, and we identified TGFA as a novel direct target of miR-376c. Overexpression of miR-376c suppressed TGFA expression and the expression of its downstream signaling molecule such as epidermal growth factor receptor, and attenuated cell proliferation and invasion. Forced expression of TGFA could partly rescue the inhibitory effect of miR-376c in the cells. Taken together, these findings will shed light on the role and mechanism of miR-376c in regulating osteosarcoma cell growth via miR-376c/TGFA axis, and miR-376c may serve as a potential therapeutic target in osteosarcoma in the future. PMID- 23631647 TI - Identifying disruptors of male germ cell development by small molecule screening in ex vivo gonad cultures. AB - BACKGROUND: Germ cell development involves formation of the spermatogenic or oogenic lineages from the bipotential primordial germ cells. Signaling mechanisms in the fetal testis and ovary determine whether germ cells enter the male or female developmental pathway, respectively. These signaling processes underpin an important phase of germ cell development, disruption of which can lead to failed germ cell function resulting in infertility or the formation of germ cell tumours. FINDINGS: In this study we have developed a small molecule screening protocol combined with flow cytometry to identify signaling pathways that direct male-specific development of germ cells. Here we provide a detailed method for this screening protocol, which we have used to identify signaling pathways important for male germ cell development. CONCLUSION: This method will be of particular use in screening inhibitors of signaling pathways, endocrine disruptors or other chemicals for their ability to disrupt testis and germ cell development, thereby providing insight into testicular dysgenesis and factors underlying poor male reproductive health. PMID- 23631649 TI - Impact of dose-rate on the low-dose hyper-radiosensitivity and induced radioresistance (HRS/IRR) response. AB - PURPOSE: To ask whether dose-rate influences low-dose hyper- radiosensitivity and induced radioresistance (HRS/IRR) response in rat colon progressive (PRO) and regressive (REG) cells. METHODS: Clonogenic survival was applied to tumorigenic PRO and non-tumorigenic REG cells irradiated with (60)Co gamma-rays at 0.0025-500 mGy.min(-1). Both clonogenic survival and non-homologous end-joining (NHEJ) pathway involved in DNA double-strand breaks (DSB) repair assays were applied to PRO cells irradiated at 25 mGy.min(-1) with 75 kV X-rays only. RESULTS: Irrespective of dose-rates, marked HRS/IRR responses were observed in PRO but not in REG cells. For PRO cells, the doses at which HRS and IRR responses are maximal were dependent on dose-rate; conversely exposure times during which HRS and IRR responses are maximal (t(HRSmax) and t(IRRmax)) were independent of dose-rate. The t(HRSmax) and t(IRRmax) values were 23 +/- 5 s and 66 +/- 7 s (mean +/- standard error of the mean [SEM], n = 7), in agreement with literature data. Repair data show that t(HRSmax) may correspond to exposure time during which NHEJ is deficient while t(IRRmax) may correspond to exposure time during which NHEJ is complete. CONCLUSION: HRS response may be maximal if exposure times are shorter than t(HRSmax) irrespective of dose, dose-rate and cellular model. Potential application of HRS response in radiotherapy is discussed. PMID- 23631648 TI - Time evolution of nanoparticle-protein corona in human plasma: relevance for targeted drug delivery. AB - When nanoparticles (NPs) enter a biological fluid (e.g., human plasma (HP)), proteins and other biomolecules adsorb on the surface leading to formation of a rich protein shell, referred to as "protein corona". This corona is dynamic in nature and its composition varies over time due to continuous protein association and dissociation events. Understanding the time evolution of the protein corona on the time-scales of a particle's lifetime in blood is fundamental to predict its fate in vivo. In this study, we used lipid NPs, the cationic lipid 3beta-[N (N',N'-dimethylaminoethane)-carbamoyl] (DC-Chol) and the zwitterionic lipid dioleoylphosphatidylethanolamine (DOPE), that are among the most promising nanocarriers both in vitro and in vivo. Here, we investigated the time evolution of DC-Chol-DOPE NPs upon exposure to HP. On time scales between 1 and 60 minutes, nanoliquid tandem mass spectrometry revealed that the protein corona of DC-Chol DOPE NPs is mainly constituted of apolipoproteins (Apo A-I, Apo C-II, Apo D, and Apo E are the most enriched). Since the total apolipoprotein content is relevant, we exploited the protein corona to target PC3 prostate carcinoma cell line that expresses high levels of scavenger receptor class B type 1 receptor, which mediates the bidirectional lipid transfer between low-density lipoproteins, high density lipoproteins, and cells. Combining laser scanning confocal microscopy experiments with flow cytometry we demonstrated that DC-Chol-DOPE/HP complexes enter PC3 cells by a receptor-mediated endocytosis mechanism. PMID- 23631650 TI - Alcohol and other drug use, partner violence, and mental health problems among female sex workers in southwest China. AB - In this study we investigated the association between mental health problems and negative experiences among female sex workers (FSWs) in China. A total of 1,022 FSWs completed a self-administered survey on their demographic characteristics, mental health status, substance use behaviors, and experiences of partner violence. We found that alcohol use was independently predictive of mental health problems when both partner violence and illicit drug use were accounted for in the multivariate logistic regression models. The findings underscore the urgent need for effective alcohol reduction interventions and mental health promotion programs among FSWs in China and other developing countries. PMID- 23631651 TI - Progesterone and cerebral ischaemia: the relevance of ageing. AB - Cerebral stroke is a leading cause of long-term disability and a major cause of death in the developed world. The total incidence of stroke is projected to rise substantially over the next 20 years as a result of the rising elderly population. Although age is one of the most significant prognostic markers for poor outcome after stroke, very few experimental studies have been conducted in aged animals. Importantly, sex differences in both vulnerability to stroke and outcome after cerebral ischaemia have frequently been reported and attributed to the action of steroid hormones. Progesterone is a candidate neuroprotective factor for stroke, although the majority of pre-clinical studies have focused on using young, healthy adult animals. In terms of cerebral stroke, males and postmenopausal females represent the groups at highest risk of cerebral stroke and these categories can be modelled using either aged or ovariectomised female animals. In this review, we discuss the importance of conducting experimental studies in aged animals compared to young, healthy animals, as well as the impact this has on experimental outcomes. In addition, we focus on reviewing the studies that have been conducted to date examining the neuroprotective potential of progesterone in aged animals. Importantly, the limited studies that have been conducted in aged animals do lend further support to progesterone as a therapeutic option after ischaemic stroke that warrants further investigation. PMID- 23631652 TI - Evaluation of hypoxia in a feline model of head and neck cancer using 64Cu-ATSM positron emission tomography/computed tomography. AB - BACKGROUND: Human and feline head and neck squamous cell carcinoma (HNSCC) share histology, certain molecular features, as well as locally aggressive and highly recurrent clinical behavior. In human HNSCC, the presence of significant hypoxia within these tumors is considered an important factor in the development of a more aggressive phenotype and poor response to therapy. We hypothesized that feline head and neck tumors, particularly HNSCC, would exhibit hypoxia and that 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) positron emission tomography/computed tomography (PET/CT) would permit detection of intratumoral hypoxia. METHODS: 12 cats with measureable head and neck tumors were given 64Cu ATSM and iodinated contrast for PET/CT scan. The presence or absence of hypoxia was also assessed using an intratumoral fluorescent life-time probe to quantitate pO2 and pimonidazole immunohistochemical staining in biopsy specimens. In two cats, intratumoral O2 and 64Cu-ATSM uptake was measured before and after treatment with anti-angiogenic agents to determine the effect of these agents on hypoxia. RESULTS: Eleven of twelve feline tumors demonstrated significant 64Cu ATSM uptake, regardless of malignant or benign etiology. The presence (and absence) of hypoxia was confirmed using the fluorescent O2 detection probe in nine tumors, and using pimonidazole staining in three tumors. Squamous cell carcinomas (HNSCC) demonstrated the highest degree of hypoxia, with Tmax/M ratios ranging from 4.3 to 21.8. Additional non-neoplastic tissues exhibited 64Cu-ATSM uptake suggestive of hypoxia including reactive draining lymph nodes, non malignant thyroid pathology, a tooth root abscess, and otitis media. In two cats with HNSCC that received anti-vascular agents, the pattern of 64Cu-ATSM uptake was altered after treatment, demonstrating the potential of the feline model to study the modulation of tumor oxygenation. CONCLUSION: Feline HNSCC serves as a clinically relevant model for the investigation of intratumoral hypoxia including its measurement, modulation and targeting. PMID- 23631655 TI - Cytomegalovirus infection and end-organ disease in Asian patients with lymphoma receiving chemotherapy. AB - This study aimed to describe the epidemiology and risk factors for cytomegalovirus (CMV) infection and end-organ disease in patients with lymphoma undergoing potentially curative or salvage therapy. We retrospectively reviewed 534 patients with lymphoma treated at an Asian tertiary cancer center between January 2007 and December 2010. Overall, 48 patients (9.0%) experienced CMV infection, with 12 patients (25.0%) being further diagnosed with CMV end-organ disease. Many patients with CMV infection were male, with poor performance status, non-Hodgkin lymphoma and advanced disease, and received rituximab use. Moreover, patients receiving rituximab and HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone) regimens had a high rate of CMV end-organ disease. In Asian patients with lymphoma receiving curative or salvage therapy, CMV infection was relatively common (9.0%). Most of these were likely to be reactivation in nature. A small group, especially those on rituximab or HyperCVAD, developed CMV end-organ disease (12/534). Such patients should be monitored closely for CMV end-organ disease. Alternatively, prophylaxis should be studied. PMID- 23631654 TI - Second-line therapies of patients initially treated with fludarabine and cyclophosphamide or fludarabine, cyclophosphamide and rituximab for chronic lymphocytic leukemia within the CLL8 protocol of the German CLL Study Group. AB - Updated results of the CLL8 trial confirm that the addition of rituximab to chemotherapy with fludarabine and cyclophosphamide (FC) leads to a prolongation of progression-free (PFS) and overall survival (OS) in first-line treatment of physically fit patients. After a median observation time of 47 months, median PFS was 57.9 months for patients treated with FC and rituximab (FCR) and 32.9 months for patients treated with FC alone (hazard ratio 0.56, 95% confidence interval 0.465-0.673; p < 0.001). A total of 232 patients were treated for relapse, among them 91 of 408 (22%) initially treated with FCR and 141 of 409 (35%) initially treated with FC. The drugs most frequently used either alone or in combination were rituximab (52% of all second-line therapies), fludarabine (21%), bendamustine (21%) and alemtuzumab (12%). The regimens chosen for second-line treatment after FC or FCR were heterogeneous, which underlines a need for further trials in order to define treatment recommendations for patients with relapsed chronic lymphocytic leukemia. PMID- 23631656 TI - Body, coping and self-identity. A qualitative 5-year follow-up study of stroke. AB - OBJECTIVE: The purpose of this article is to identify, from a long-term perspective, stroke survivors' self-identity, their views of any associated disabilities and how they manage their lives after stroke. METHODS: The interviews and analyses were conducted using a phenomenological qualitative method. A total of 10 men and 5 women, aged 42-84, participated. All had suffered first-time stroke 5 years earlier. RESULTS: After 5 years, participants had greater acceptance of their situation compared with immediately after participating in the rehabilitation programme. However, they described how they still had to deal with the consequences of stroke. They had suffered further illnesses and additions to side effects of the stroke. In dealing with their disabilities and changes to self-identity and life patterns, they seemed to be in a continuous process of change that never truly stabilised. They coped with this continuous process in at least two different ways, including resignation or personal growth. CONCLUSION: Stroke survivors suffered considerable ongoing and changing difficulties in relation to disability, self-perception and to coping with a new life. This continuous process of change could be seen to drain their energy. The study shows that many survivors live a more home-centred life with fewer social relations and less active participation in their community. This can entail the risk of depression and loneliness. The study also shows, however, that adopting an optimistic approach to life can lead to continued learning about abilities and limitations, to the development of new skills and to the fashioning of a new self-identity. PMID- 23631657 TI - Are 25 SNPs from the CARDIoGRAM study associated with ischaemic stroke? AB - BACKGROUND AND PURPOSE: The Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Study (CARDIoGRAM) reported 25 single-nucleotide polymorphisms (SNPs) on 15 chromosomes to be associated with coronary artery disease (CAD) risk. Because common vascular risk factors are shared between CAD and ischaemic stroke (IS), these SNPs may also be related to IS overall or one or more of its pathogenetic subtypes. METHODS: We performed a candidate gene study comprising 3986 patients with IS and 2459 control subjects. The 25 CAD-associated SNPs reported by CARDIoGRAM were examined by allelic association analysis including logistic regression. Weighted and unweighted genetic risk scores (GRSs) were also compiled and likewise analysed against IS. We furthermore considered the IS main subtypes large-vessel disease (LVD), small-vessel disease and cardioembolic stroke [according to Trial of Org 10172 in Acute Stroke Treatment (TOAST)] separately. RESULTS: SNP rs4977574 on chromosome 9p21.3 was associated with overall IS [odds ratio (OR) = 1.12; 95% confidence interval (CI): 1.04-1.20; P = 0.002] as well as LVD (OR = 1.36; 95% CI: 1.13-1.64; P = 0.001). No other SNP was significantly associated with IS or any of its main subtypes. Analogously, the GRSs did not show any noticeable effect. CONCLUSIONS: Besides the previously reported association with SNPs on chromosome 9p21, this study did not detect any significant association between IS and CAD-susceptible genetic variants. Also, GRSs compiled from these variants did not predict IS or any pathogenetic IS subtype, despite a total sample size of 6445 participants. PMID- 23631653 TI - FLT3 tyrosine kinase inhibitors in acute myeloid leukemia: clinical implications and limitations. AB - Internal tandem duplications of the FMS-like tyrosine kinase 3 (FLT3) gene are one of the most frequent gene mutations in acute myeloid leukemia (AML) and are associated with poor clinical outcome. The remission rate is high with intensive chemotherapy, but most patients eventually relapse. During the last decade, FLT3 mutations have emerged as an attractive target for a molecularly specific treatment strategy. Targeting FLT3 receptor tyrosine kinases in AML has shown encouraging results in the treatment of FLT3 mutated AML, but in most patients responses are incomplete and not sustained. Newer, more specific compounds seem to have a higher potency and selectivity against FLT3. During therapy with FLT3 tyrosine kinase inhibitors (TKIs) the induction of acquired resistance has emerged as a clinical problem. Therefore, optimization of the targeted therapy and potential treatment options to overcome resistance is currently the focus of clinical research. In this review we discuss the use and limitations of TKIs as a therapeutic strategy for the treatment of FLT3 mutated AML, including mechanisms of resistance to TKIs as well as possible novel strategies to improve FLT3 inhibitor therapy. PMID- 23631658 TI - Temperature-dependent regioselectivity of nucleophilic aromatic photosubstitution. Evidence that activation energy controls reactivity. AB - Irradiation (lambda > 330 nm) of 2-chloro-4-nitroanisole (1) at 25 degrees C in aqueous NaOH forms three substitution photoproducts: 2-methoxy-5-nitrophenol (2), 2-chloro-4-nitrophenol (3), and 3-chloro-4-methoxyphenol (4), in chemical yields of 69.2%, 14.3%, and 16.5%. The activation energies for the elementary steps from the triplet state at 25 degrees C were determined to be 1.8, 2.4, and 2.7 kcal/mol, respectively. The chemical yields of each of the three products were determined for exhaustive irradiations at 0, 35, and 70 degrees C. The variation with temperature of the experimental yields is reproduced almost exactly by the yields calculated with the Arrhenius equation. This indicates that activation energy is the fundamental property related to regioselectivity in nucleophilic aromatic photosubstitution of the S(N)2 Ar* type. The many methods proposed for predicting regioselectivity in reactions of this type have had limited success and have not been related to activation energy. PMID- 23631659 TI - The PGAM4 gene in non-obstructive azoospermia. AB - Non-obstructive azoospermia (NOA) is considered to be a severe infertility factor due to impaired spermatogenesis with the consequent absence of spermatozoa in the ejaculate. However, the underlying etiology and mechanism(s) remain elusive. The aim of this study was to investigate the mutation and association of single nucleotide polymorphisms (SNPs) of the phosphoglycerate mutase 4 (PGAM4) gene in Chinese Han infertile men with NOA. The entire coding region of PGAM4 gene was sequenced from 214 participants including 103 infertile men with NOA and 111 controls with proven fertility. Screening was carried out using PCR and DNA sequencing to identify novel mutations and SNPs of the entire coding region of PGAM4. No mutation, including A138C or G539A, was detected in the coding region of PGAM4. One novel synonymous mutation (G111A, rs20100573) in control individuals was identified. There was no significant difference between NOA patients and controls in the G75C (rs138178131) frequencies (1.9% (2/103) and 4.5% (5/111), respectively, P = 0.292 and P = 0.374, adjusted by age). PGAM4 coding region mutations were not observed and the G75C polymorphism is not associated with NOA susceptibility among the Chinese Han population. PMID- 23631660 TI - Human marrow stromal cells reduce microglial activation to protect motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis. AB - BACKGROUND: Human marrow stromal cells (hMSCs) injected intrathecally can effectively increase the lifespan and protect motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis. However, how the transplanted cells exert a neuroprotective effect is still unclear. More recently, the anti-inflammation effect of marrow stromal cells has generated a great deal of interest. In the present study, we sought to investigate whether intrathecally injected hMSCs protect motor neurons through attenuating microglial activation and the secretion of inflammatory factors in Cu/Zn superoxide dismutase 1 (SOD1) transgenic mice. In addition, we also focused on the mode of hMSCs inhibiting microglial activation. METHODS: We transplanted hMSCs into the cisterna magna of SOD1 mice at the age of 8, 10 and 12 weeks. At sacrifice, tissues were harvested for analysis of neuron counts, microglial activation, TNFalpha secretion and inducible nitric oxide synthase (iNOS) protein expression. In vitro, microglial cells were treated with hMSC co-culture, hMSC transwell culture or hMSC conditioned medium to investigate the mode of hMSCs exerting an anti-inflammation effect. RESULTS: Intrathecally transplanted hMSCs inhibited inflammatory response in SOD1 transgenic mice, which was evidenced by the decreases in microglial activation, TNFalpha secretion and iNOS protein expression. In addition, the inhibitory effect on microglial activation of hMSCs was through secretion of diffusible molecules adjusted to environmental cues. CONCLUSION: Intrathecally injected hMSCs can attenuate microglial activation through secretion of diffusible molecules to exert a therapeutic effect in SOD1 transgenic mice. Further studies are needed to explore the exact mechanisms by which hMSCs inhibit inflammation for facilitating the therapeutic effect. PMID- 23631661 TI - Estimating net anthropogenic nitrogen inputs to U.S. watersheds: comparison of methodologies. AB - The net anthropogenic nitrogen input (NANI) approach is a simple quasi-mass balance that estimates the human-induced nitrogen inputs to a watershed. Across a wide range of watersheds, NANI has been shown to be a good predictor of riverine nitrogen export. In this paper, we review various methodologies proposed for NANI estimation since its first introduction and evaluate alternative calculations suggested by previous literature. Our work is the first study in which a consistent NANI calculation method is applied across the U.S. watersheds and tested against available riverine N flux estimates. Among the tested methodologies, yield-based estimation of agricultural N fixation (instead of crop area-based) made the largest difference, especially in some Mississippi watersheds where the tile drainage was a significant factor reducing watershed N retention. Across the U.S. watersheds, NANI was particularly sensitive to farm N fertilizer application, cattle N consumption, N fixation by soybeans and alfalfa, and N yield by corn, soybeans, and pasture, although their relative importance varied among different regions. PMID- 23631663 TI - Associations between sports participation, levels of moderate to vigorous physical activity and cardiorespiratory fitness in childrenand adolescents. AB - The purpose of this study was to analyse the associations between sports participation, levels of moderate to vigorous physical activity (MVPA) and cardiorespiratory fitness (CRF). The study comprised 310 participants (183 girls and 127 boys) aged 11-18 years. Sports participation was assessed by questionnaire and habitual physical activity (PA) was measured objectively with accelerometers. The 20-m shuttle-run test was used to estimate CRF. Logistic regression analyses were carried out with CRF as the outcome. The odds ratio (OR) for being fit was greater for those who comply with 60 min . day(-1) in MVPA (OR = 2.612; 95%confidence interval [CI] = 1.614-4.225) in comparison with those who do not. Participation in competitive sports at club levels increased the chances of being fit (OR = 13.483; 95%CI = 4.560-39.864), independently of MVPA levels. There were positive and significant trends in CRF and objectively measured PA across the levels of engagement in competitive sports (P < 0.05). Concluding, participation in competitive sports at club level is more effective than other organised or non-organised sports to reach healthier levels of CRF and recommend levels of MVPA. PMID- 23631662 TI - Limited sequence polymorphisms of four transmission-blocking vaccine candidate antigens in Plasmodium vivax Korean isolates. AB - BACKGROUND: Transmission-blocking vaccines (TBVs), which target the sexual stages of malaria parasites to interfere with and/or inhibit the parasite's development within mosquitoes, have been regarded as promising targets for disrupting the malaria transmission cycle. In this study, genetic diversity of four TBV candidate antigens, Pvs25, Pvs28, Pvs48/45, and PvWARP, among Plasmodium vivax Korean isolates was analysed. METHODS: A total of 86 P. vivax-infected blood samples collected from patients in Korea were used for analyses. Each of the full length genes encoding four TBV candidate antigens, Pvs25, Pvs28, Pvs48/45, and PvWARP, were amplified by PCR, cloned into T&A vector, and then sequenced. Polymorphic characteristics of the genes were analysed using the DNASTAR, MEGA4, and DnaSP programs. RESULTS: Polymorphism analyses of the 86 Korean P. vivax isolates revealed two distinct haplotypes in Pvs25 and Pvs48/45, and three different haplotypes in PvWARP. In contrast, Pvs28 showed only a single haplotype. Most of the nucleotide substitutions and amino acid changes identified in all four TBV candidate antigens were commonly found in P. vivax isolates from other geographic areas. The overall nucleotide diversities of the TBV candidates were much lower than those of blood stage antigens. CONCLUSIONS: Limited sequence polymorphisms of TBV candidate antigens were identified in the Korean P. vivax population. These results provide baseline information for developing an effective TBV based on these antigens, and offer great promise for applications of a TBV against P. vivax infection in regions where the parasite is most prevalent. PMID- 23631665 TI - Endoscopic submucosal dissection for gastrointestinal mesenchymal tumors adjacent to the esophagogastric junction: we need to do more. AB - OBJECTIVE: Extensive surgery is the mainstay of therapy for patients with gastrointestinal mesenchymal tumors (GIMTs) adjacent to the esophagogastric junction (EGJ). However, this modality is invasive and may interfere with anatomic consistency of the digestive tract. Therefore, we evaluated the feasibility, safety, and efficacy of endoscopic submucosal dissection (ESD) for GIMTs close to the EGJ and factors related to incomplete resection. PATIENTS AND METHODS: For 39 GIMTs adjacent to the EGJ in 39 consecutive patients, the baseline information, complications, and therapeutic outcomes were recorded. Subsequently, risk factors, focusing on age, sex, tumor size, extent, shape, perforation presence/absence, and histopathology, were analyzed. RESULTS: Complete removal of junctional GIMTs was achieved in 32 cases, giving an overall complete resection rate of 82%. The mean tumor size was 16.1+/-12.7 (median, 12; range, 4-50) mm. There were no major intra- and postoperative complications, but two small perforations were found. The final histopathologic diagnoses included 28 leiomyomas, 10 gastrointestinal stromal tumors, and 1 schwannoma. No local recurrence or distant metastasis was observed during a mean follow-up of 15.7+/ 8.4 (median, 16; range, 6-35) months. Univariate analysis showed incomplete resection was associated with tumor shape and size. Multivariate regression analysis identified tumor irregularity (odds ratio=37.50, 95% confidence interval=4.253-330.627) as the single factor associated with incomplete resection. CONCLUSIONS: ESD is feasible and safe for well-selected patients with GIMTs adjacent to the EGJ. Irregular tumor shape should be considered as a technical difficulty while performing ESD. Oncologic outcomes need to be assessed with longer follow-up. PMID- 23631664 TI - Single-platform, volumetric, CD45-assisted pan-leucogating flow cytometry for CD4 T lymphocytes monitoring of HIV infection according to the WHO recommendations for resource-constrained settings. AB - BACKGROUND: Validation of new affordable CD4 T cell measurement technologies is crucial specifically in resource-poor countries for antiretroviral treatment eligibility and immunologic CD4 monitoring of HIV-infected patients. METHODS: The absolute and percentage CD4 T cell counts of 258 HIV-1-infected blood samples (182 adults and 76 children), living in N'Djamena, Chad, were performed by single platform, volumetric, CD45-assisted pan-leucogating Auto40 flow cytometer (Apogee Flow Systems Ltd, Hemel Hempstead, UK) comparing to the FACSCalibur flow cytometer as a reference method. RESULTS: Absolute and percentage CD4 T cell counts obtained by Auto40 and FACSCalibur of 258 HIV-1-infected blood samples were highly correlated (r = 0.99 and r = 0.96, respectively). The mean absolute bias and percent bias between Apogee Auto40 and FACSCalibur absolute CD4 T cell counts, were -9.4 cells/MUl with limits of agreement from -15 to 93 cells/MUl, and +2.0% with limits of agreement from -0.9 to 4.9%, respectively. The mean of absolute bias and percent bias between Apogee Auto40 and FACSCalibur of CD4 percentage results were +0.4% (95% CI: -0.02 - 0.86) with limits of agreement from -2.4 to 0.3%, and +3.0% with limits of agreement from -6.6 to 0.6%, respectively. The Auto40 counting allowed to identify the majority of adults with CD4 T cells below 200 cells/MUl (sensitivity: 89%; specificity: 99%) or below 350 cells/MUl (sensitivity: 94%; specificity:98%); and of children below 750 cells/MUl (sensitivity: 99%; specificity: 96%) or below 25% CD4+ (sensitivity: 94%; specificity: 98%). CONCLUSION: The Auto40 analyzer is an alternative flow cytometer for CD4 T lymphocyte enumeration to be used in routine for immunological monitoring according to the current WHO recommendations in HIV infected adults as well as children living in resource-constrained settings like Chad. PMID- 23631666 TI - Transient occlusion of uterine arteries with endoscopic vascular clip preceding laparoscopic myomectomy. AB - BACKGROUND: To determine whether performing transient occlusion of uterine arteries (TOUA) immediately before laparoscopic myomectomy can reduce intraoperative complications. SUBJECTS AND METHODS: In a retrospective case control study, laparoscopic myomectomy with and without TOUA was examined. Data were analyzed from 89 laparoscopic myomectomies performed by a single surgeon (Y. S. Kwon) at Ulsan University Hospital (Ulsan, Korea) between March 2011 and December 2011. Surgical outcomes included preoperative myoma size, number of myoma, operative time, and operative blood loss. RESULTS: Forty-nine women underwent laparoscopic myomectomy with TOUA with endoscopic vascular clipping, whereas 40 control patients underwent laparoscopic myomectomy alone. The TOUA group had no case of nerve or vascular injury during the operation time. The mean time of occlusion of both the uterine arteries was 15 minutes. The TOUA group had less mean blood loss during the operation than the group with laparoscopic myomectomy alone (111.9 versus 203.4 mL; P<.001). There were no significant differences in size and number of uterine myomas and intraoperative complications between the two groups. Moreover, there was not even a single case of conversion of laparoscopy to laparotomy in either group. CONCLUSIONS: TOUA performed immediately before laparoscopic myomectomy facilitated minimally invasive surgery with lower blood loss and no differences in other intraoperative complications. PMID- 23631667 TI - Minor changes in gene expression in the mouse preoptic hypothalamic region by inflammation-induced prostaglandin E2. AB - We investigated to what extent inflammation-induced prostaglandin E2 (PGE2 ) regulates gene expression in the central nervous system. Wild-type mice and mice with deletion of the gene encoding microsomal prostaglandin E synthase-1 (mPGES 1), which cannot produce inflammation-induced PGE2 , were subjected to peripheral injection of bacterial wall lipopolysaccharide (LPS) and killed after 5 h. The median and medial preoptic nuclei, which are rich in prostaglandin E receptors, were isolated by laser capture microdissection (LCM), and subjected to whole genome microarray analysis. Although the immune stimulus induced robust transcriptional changes in the brain, as seen by a quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on selected genes, only small PGE2 -dependent gene expression changes were observed in the gene array analysis and, for only two genes, a pronounced differential expression between LPS-treated wild-type and mPGES-1 knockout mice could be verified by qRT-PCR. These were Hspa1a and Hspa1b, encoding heat shock proteins, which showed a two- to three fold higher expression in wild-type mice than in knockout mice after immune challenge. However, the induced expression of these genes was found to be secondary to increased body temperature because they were induced also by cage exchange stress, which did not elicit PGE2 synthesis, and thus were not induced per se by PGE2 -elicited transcriptional events. Our findings suggest that inflammation-induced PGE2 has little effect on gene expression in the preoptic region, and that centrally elicited disease symptoms, although PGE2 -dependent, occur as a result of regulation of neuronal excitability that is a consequence of intracellular, transcriptional-independent signalling cascades. Our findings also imply that the profound changes in gene expression in the brain that are elicited by peripheral inflammation occur independently of PGE2 via a yet unidentified mechanism. PMID- 23631668 TI - Neuropathology and behavioral impairments in Wistar rats with a 6-OHDA lesion in the substantia nigra compacta and exposure to a static magnetic field. AB - Studies have sought to assess various potential neuroprotective therapeutics in Parkinson's disease. The aim of this study was to evaluate the effects of static magnetic field stimulation 14 days after a 6-Hydroxydopamine (6-OHDA) substantia nigra compacta (SNc) lesion on motor behavior, as assessed by the rotarod (RR) test and brain tissue morphology. Forty male Wistar rats were used and were divided into five groups: control group, sham group (SG), lesion group (LG), lesion north pole group (LNPG) and lesion south pole group (LSPG). In groups with magnetic stimulation, a 3200-gauss magnet was fixed to the skull. After the experiments, the animals were anesthetized for brain perfusion. Coronal sections of the SNc were stained with Nissl. The RR test showed a decrease in the time spent on the apparatus in the LG compared with all groups. The LNPG and LSPG had significant increases in the time spent when compared to the LG. A morphometric analysis revealed a significant reduction in the number of neurons in the LG, LNPG and LSPG in relation to the SG. There were a higher number of neurons in the LNPG and LSPG than the LG, and a higher number of neurons in the LSPG than the LNPG. We observed that the LG, LNPG and LSPG showed a higher number of glial cells than the SG, and the LNPG and LSPG showed a lower number of glial cells than the LG. Our results demonstrate a potential therapeutic use of static magnetic fields for the preservation of motor behavior and brain morphology in the SNc after 14 days with 6-OHDA lesion. PMID- 23631669 TI - Optical anisotropy of flagellin layers: in situ and label-free measurement of adsorbed protein orientation using OWLS. AB - The surface adsorption of the protein flagellin was followed in situ using optical waveguide lightmode spectroscopy (OWLS). Flagellin did not show significant adsorption on a hydrophilic waveguide, but very rapidly formed a dense monolayer on a hydrophobic (silanized) surface. The homogeneous and isotropic optical layer model, which has hitherto been generally applied in OWLS data interpretation for adsorbed protein films, failed to characterize the flagellin layer, but it could be successfully modeled as an uniaxial thin film. This anisotropic modeling revealed a significant positive birefringence in the layer, suggesting oriented protein adsorption. The adsorbed flagellin orientation was further evidenced by monitoring the surface adsorption of truncated flagellin variants, in which the terminal protein regions or the central (D3) domain were removed. Without the terminal regions the protein adsorption was much slower and the resulting films were significantly less birefringent, implying that intact flagellin adsorbs on the hydrophobic surface via its terminal regions. PMID- 23631671 TI - Notes from the back room: gender, power, and (In)visibility in women's experiences of masturbation. AB - While popular culture has more frequently depicted women's masturbation in recent years, scholarly attention to women's own meaning making about masturbation remains largely absent. Existing research that emphasizes women's masturbation frequency, health correlates, masturbation as a factor in couples therapy, and masturbation as a substitute for partnered sexual behaviors have dominated the research, largely neglecting social identity correlates and women's subjectivities about masturbation. This study drew upon qualitative interviews with 20 women (mean age = 34, SD = 13.35) from diverse backgrounds to illuminate five themes in women's experiences with masturbation: (a) assumptions that most women self-penetrate during masturbation even when primarily using clitoral stimulation; (b) masturbation as sexual labor; (c) masturbation as a threat to male dominance; (d) masturbation as routine tension release; and (e) masturbation as a source of joy, fun, and pleasure. Because women revealed such a diverse set of experiences, we explored the advantages and disadvantages of the invisibility of women's masturbation. As a result of the internalization of stereotypically masculine scripts about sexuality-including an imagined penetrative focus, goal oriented drive toward orgasm, sex as labor, and masturbation as nonemotional women's masturbation experiences, regardless of sexual orientation, revealed the power imbalances often present in partnered (hetero)sexual dynamics. PMID- 23631670 TI - Migration and maternity: insights of context, health policy, and research evidence on experiences and outcomes from a three country preliminary study across Germany, Canada, and the United kingdom. AB - A group from Germany, Canada, and the United Kingdom undertook country-specific scoping reviews and stakeholder consultations before joining to holistically compare migration and maternity in all three countries. We examined four interlinking dimensions to understand how international migrant/minority maternal health might be improved upon using transnational research: (a) wider sociopolitical context, (b) health policy arena, (c) constellation, outcomes, and experiences of maternity services, and (d) existing research contexts. There was clear evidence that the constellation and delivery of services may undermine good experiences and outcomes. Interventions to improve access and quality of care remain small scale, short term, and lacking in rigorous evaluation. PMID- 23631672 TI - Spectroscopic study of the light-harvesting CP29 antenna complex of photosystem II--part I. AB - Recent structural data revealed that the CP29 protein of higher plant photosystem II (PSII) contains 13 chlorophylls (Chl's) per complex (Pan et al. Nat. Struct. Mol. Biol. 2011, 18, 309), i.e., five Chl's more than in the predicted CP29 homology-based structure model (Bassi et al. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 10056). This lack of consensus presents a constraint on the interpretation of CP29 optical spectra and their underlying electronic structure. To address this problem, we present new low-temperature (5 K) absorption, fluorescence, and hole burned (HB) spectra for CP29 proteins from spinach, which are compared with the previously reported data. We focus on excitation energy transfer (EET) and the nature of the lowest-energy state(s). We argue that CP29 proteins previously studied by HB spectroscopy lacked at least one Chl a molecule (i.e., a615 or a611), which along with Chl a612 contribute to the lowest energy state in more intact CP29, and one Chl b (most likely b607). This is why the low-energy state and fluorescence maxima reported by Pieper et al. (Photochem. Photobiol.2000, 71, 574) were blue-shifted by ~1 nm, the low-energy state appeared to be highly localized on a single Chl a molecule, and the position of the low-energy state was independent of burning fluence. In contrast, the position of the nonresonant HB spectrum shifts blue with increasing fluence in intact CP29, as this state is strongly contributed to by several pigments (i.e., a611, a612, a615, and a610). Zero-phonon hole widths obtained for the Chl b band at 638.5 nm (5 K) revealed two independent Chl b -> Chl a EET times, i.e., 4 +/- 0.5 and 0.4 +/- 0.1 ps. The latter value is a factor of 2 faster than previously observed by HB spectroscopy and very similar to the one observed by Gradinaru et al. (J. Phys. Chem. B 2000, 104, 9330) in pump-probe experiments. EET time from 650 nm Chl b -> Chl a and downward EET from Chl(s) a state(s) at 665 nm occurs in 4.9 +/- 0.7 ps. These findings provide important constraints for excitonic calculations that are discussed in the accompanying paper (part II, DOI 10.1021/jp4004278 ). PMID- 23631674 TI - Synthesis of silver octahedra with controlled sizes and optical properties via seed-mediated growth. AB - Silver octahedra with edge lengths controlled in the range of 20-72 nm were synthesized via seed-mediated growth. The key to the success of this synthesis is the use of single-crystal Ag seeds with uniform and precisely controlled sizes to direct the growth and the use of citrate as a selective capping agent for the {111} facets. Our mechanistic studies demonstrated that Ag seeds with both cubic and quasi-spherical shapes could evolve into octahedra. For the first time, we were able to precisely control the edge lengths of Ag octahedra below 100 nm, and the lower limit of size could even be pushed down to 20 nm. Using the as-obtained Ag octahedra as sacrificial templates, Au nanocages with an octahedral shape and precisely tunable optical properties were synthesized through a galvanic replacement reaction. Such hollow nanostructures are promising candidates for a broad range of applications related to optics, catalysis, and biomedicine. PMID- 23631673 TI - External birth defects in Southern Vietnam: a population-based study at the grassroots level of health care in Binh Thuan Province. AB - BACKGROUND: There currently exists no data on birth defects from population-based studies in Vietnam. Our study's aim was to assess external birth defect (EBD) prevalence among live newborns in Binh Thuan Province in Vietnam with the help of health workers at all levels of the health system. METHODS: A 2-month training session for 452 health professionals (HP) practicing delivery care in 127 Commune Health Stations (CHS) and in 12 provincial or district hospitals (DH) was setup in 2006. After a successful 6-month pilot study, a one-year registry of EBDs was established in 2008. All live newborns were screened for EBDs within 24 hours after birth in all DH obstetric departments and in all CHSs. Trained local HPs collected information by filling out a predesigned form and by photographing the affected newborn. EBDs were coded using the International Classification of Diseases system-10, Clinical Modification. The study was repeated in 2010. RESULTS: Throughout 2010, out of a total of 13,954 newborns, 84 cases with one or more EBDs were reported, representing an overall prevalence rate of 60.2 per 10,000 live births. The most common groups of EBDs were limbs (27.2/10,000), orofacial clefts (20.1/10,000) and the central nervous system (7.9/10,000). CONCLUSIONS: This first population-based study in Vietnam, which required coordination efforts at the local level, provides baseline prevalences of external birth defects. Data on EBDs from this study in southern Vietnam may be useful for setting up a regional population-based registry of birth defects in Vietnam. PMID- 23631675 TI - Cryo-immunoelectron microscopy of adherent cells improved by the use of electrospun cell culture substrates. AB - Electrospun nanofibres are an excellent cell culture substrate, enabling the fast and non-disruptive harvest and transfer of adherent cells for microscopical and biochemical analyses. Metabolic activity and cellular structures are maintained during the only half a minute-long harvest and transfer process. We show here that such samples can be optimally processed by means of cryofixation combined either with freeze-substitution, sample rehydration and cryosection immunolabelling or with freeze-fracture replica-immunolabelling. Moreover, electrospun fibre substrates are equally suitable for complementary approaches, such as biochemistry, fluorescence microscopy and cytochemistry. PMID- 23631676 TI - Fetal growth restriction alters hippocampal 17-beta estradiol and estrogen receptor alpha levels in the newborn male rat. AB - Fetal growth restriction (FGR) is associated with impaired neurodevelopmental outcomes in affected newborns. The pathogenesis of FGR-associated neurodevelopmental impairment implicates abnormal hippocampal function. The steroid hormone estrogen and its receptor, estrogen receptor alpha (ERalpha), are involved in the normal programming of hippocampal development and structure. However, the impact of FGR on hippocampal estrogen and hippocampal ERalpha is not well characterized. We hypothesized that FGR will reduce hippocampal and serum levels of 17-beta estradiol and its receptor, ERalpha, in the newborn rat hippocampus. We further hypothesize that FGR will reduce hippocampal ERalpha levels in a region-specific manner. To test our hypotheses, we used the well characterized rat model of FGR induced by uteroplacental-insufficiency in the pregnant Sprague-Dawley rat. Hippocampi and serum were obtained from FGR and control day 0 rat pups and examined for hippocampal 17-beta estradiol, serum 17 beta estradiol, and ERalpha mRNA and protein levels. Immunohistochemistry was performed to examine region-specific ERalpha staining. FGR decreased hippocampal 17-beta estradiol levels in the hippocampi of male newborn rats but not females. Serum 17-beta estradiol levels were not affected by FGR in either gender. FGR decreased hippocampal ERalpha mRNA levels in males but not females. Hippocampal ERalpha protein levels by Western blotting were not affected by FGR. However, FGR decreased apparent ERalpha staining in the cornu ammonis (CA)1, CA3, and dentate gyrus regions in the hippocampi of male newborn rats but not females. We conclude that FGR affects the programming of hippocampal estrogen and hippocampal ERalpha levels in the newborn rat in a gender-specific manner. PMID- 23631677 TI - Biopolymer interactions, water dynamics, and bread crumb firming. AB - To establish the relationship between biopolymer interactions, water dynamics, and crumb texture evolution in time, proton mobilities in starch and gluten model systems and bread were investigated with NMR relaxometry. Amylopectin recrystallization was observed as an increased amount of fast-relaxing protons, while network strengthening and changes in water levels were noted as a reduced mobility and amount, respectively, of slowly relaxing protons. Amylopectin recrystallization strengthened the starch network with concomitant inclusion of water and increased crumb firmness, especially at the beginning of storage. The inclusion of water and the thermodynamic immiscibility of starch and gluten resulted in local gluten dehydration during bread storage. Moisture migration from crumb to crust further reduced the level of plasticizing water of the biopolymer networks and contributed to crumb firmness at longer storage times. Finally, we noted a negative relationship between the mobility of slowly relaxing protons of crumb polymers and crumb firmness. PMID- 23631678 TI - Computational studies of ion pairing. 8. Ion pairing of tetraalkylammonium ions to nitrosobenzene and benzaldehyde redox species. A general binding motif for the interaction of tetraalkylammonium ions with benzenoid species. AB - Very little data is available on the detailed structures of ion pairs in solution, since few general experimental methods are available for obtaining such information. For this reason, computational methods have emerged as the method of choice for determining the structures of organic ion pairs in solution. The present study examines the ion pairs between a series of tetraalkylammonium ions and several redox forms of nitrosobenzene and a series of substituted benzaldehydes. The structures, though previously unexpected, are chemically reasonable and fit into a previous pattern of ion pairing described in previous publications in this series. To date in these studies, a total of 73 ion pairs and related species have in fact been identified having exactly the same unusual orientation of the tetraalkylammonium component with respect to the donor species. The results are pertinent to topics of general current interest, including self-assembly, molecular recognition, and supramolecular assembly. PMID- 23631679 TI - Clarification requests in everyday interaction involving children with cochlear implants. AB - The aim of the present study is to explore the form and function of clarification request sequences in interaction involving children with cochlear implants. Clarification request sequences are investigated in everyday interaction, and it is demonstrated that children with CI use both general/open and specific requests for clarification. It is also shown that there is relatively lower frequency of requests for clarification in interactions involving children with CI with high intelligibility scores. The results may be useful in clinical assessment and intervention demonstrating the importance of assessing interactional ability in everyday interaction. PMID- 23631680 TI - Chronic exposure to a 2 mT static magnetic field affects the morphology, the metabolism and the function of in vitro cultured swine granulosa cells. AB - In recent years, the exposure of organisms to static magnetic fields (SMFs) is continuously increasing. Thus, we investigated the effect of chronic exposure to a 2 mT SMF on in vitro cultured swine granulosa cells (GCs). In particular, the culture expansion (cell viability and doubling time), the cell phenotype (cell morphology and orientation, actin and alpha-tubulin cytoskeleton), the cell metabolism (intracellular Ca(2+) concentration [Ca(2+)]i and mitochondrial activity) and the cell function (endocrine activity) were assessed. It has been found that the exposure to the field did not affect the cell viability, but the doubling time was significantly reduced (p < 0.05) in exposed samples after 72 h of culture. At the same time, the cell length and thickness significantly changed (p < 0.05), while the cell orientation was unaffected. Evident modifications were induced on actin and alpha-tubulin cytoskeleton after 3 days of exposure and, simultaneously, a change in [Ca(2+)]i and mitochondrial activity started to become evident. Finally, the SMF exposure of GCs longer than 72 h determined a significant alteration of progesterone and estrogen production (p < 0.05). In conclusion, our results demonstrate that the chronic exposure of swine GCs to a 2 mT SMF exerts a negative effect on cell proliferation, morphology, biochemistry and endocrine function in an in vitro model. PMID- 23631681 TI - IL-11/IL11RA receptor mediated signaling: a web accessible knowledgebase. AB - Abstract Interleukin-11 (IL-11) is a pleiotropic cytokine that belongs to gp130 family. It plays a significant role in the synthesis and maturation of hematopoietic cells, inhibition of adipogenesis, regulation of embryo implantation, and trophoblasts invasion. Although IL-11 signaling has been described in several biological processes, a centralized resource documenting these molecular reactions induced by IL-11 is not publicly available. In the current study, we have manually annotated the molecular reactions and interactions induced by IL-11 from literature available. We have documented 40 unique molecules involved in 18 protein-protein interactions, 26 enzyme-substrate reactions, 7 translocation events, and 4 activation/ inhibition reactions. We have also annotated 23 genes reported to be differentially regulated under IL-11 stimulation. We have enabled the data availability in standard exchange formats from 'NetPath', a repository for signaling pathways. We believe that this will help in the identification of potential therapeutic targets in IL-11-associated disorders. PMID- 23631682 TI - A rapid stability-indicating, fused-core HPLC method for simultaneous determination of beta-artemether and lumefantrine in anti-malarial fixed dose combination products. AB - BACKGROUND: Artemisinin-based fixed dose combination (FDC) products are recommended by World Health Organization (WHO) as a first-line treatment. However, the current artemisinin FDC products, such as beta-artemether and lumefantrine, are inherently unstable and require controlled distribution and storage conditions, which are not always available in resource-limited settings. Moreover, quality control is hampered by lack of suitable analytical methods. Thus, there is a need for a rapid and simple, but stability-indicating method for the simultaneous assay of beta-artemether and lumefantrine FDC products. METHODS: Three reversed-phase fused-core HPLC columns (Halo RP-Amide, Halo C18 and Halo Phenyl-hexyl), all thermostated at 30 degrees C, were evaluated. beta-Artemether and lumefantrine (unstressed and stressed), and reference-related impurities were injected and chromatographic parameters were assessed. Optimal chromatographic parameters were obtained using Halo RP-Amide column and an isocratic mobile phase composed of acetonitrile and 1 mM phosphate buffer pH 3.0 (52:48; V/V) at a flow of 1.0 ml/min and 3 MUl injection volume. Quantification was performed at 210 nm and 335 nm for beta-artemether and for lumefantrine, respectively. In-silico toxicological evaluation of the related impurities was made using Derek Nexus v2.0(r). RESULTS: Both beta-artemether and lumefantrine were separated from each other as well as from the specified and unspecified related impurities including degradants. A complete chromatographic run only took four minutes. Evaluation of the method, including a Plackett-Burman robustness verification within analytical QbD-principles, and real-life samples showed the method is suitable for quantitative assay purposes of both active pharmaceutical ingredients, with a mean recovery relative standard deviation (+/- RSD) of 99.7 % (+/- 0.7%) for beta artemether and 99.7 % (+/- 0.6%) for lumefantrine. All identified beta-artemether related impurities were predicted in Derek Nexus v2.0(r) to have toxicity risks similar to beta-artemether active pharmaceutical ingredient (API) itself. CONCLUSIONS: A rapid, robust, precise and accurate stability-indicating, quantitative fused-core isocratic HPLC method was developed for simultaneous assay of beta-artemether and lumefantrine. This method can be applied in the routine regulatory quality control of FDC products. The in-silico toxicological investigation using Derek Nexus(r) indicated that the overall toxicity risk for beta-artemether-related impurities is comparable to that of beta-artemether API. PMID- 23631683 TI - Methods for the evaluation of the Jamie Oliver Ministry of Food program, Australia. AB - BACKGROUND: Community-based programs aimed at improving cooking skills, cooking confidence and individual eating behaviours have grown in number over the past two decades. Whilst some evidence exists to support their effectiveness, only small behavioural changes have been reported and limitations in study design may have impacted on results.This paper describes the first evaluation of the Jamie Oliver Ministry of Food Program (JMoF) Australia, in Ipswich, Queensland. JMoF Australia is a community-based cooking skills program open to the general public consisting of 1.5 hour classes weekly over a 10 week period, based on the program of the same name originating in the United Kingdom. METHODS/DESIGN: A mixed methods study design is proposed. Given the programmatic implementation of JMoF in Ipswich, the quantitative study is a non-randomised, pre-post design comparing participants undergoing the program with a wait-list control group. There will be two primary outcome measures: (i) change in cooking confidence (self-efficacy) and (ii) change in self-reported mean vegetable intake (serves per day). Secondary outcome measures will include change in individual cooking and eating behaviours and psycho-social measures such as social connectedness and self esteem. Repeated measures will be collected at baseline, program completion (10 weeks) and 6 months follow up from program completion. A sample of 250 participants per group will be recruited for the evaluation to detect a mean change of 0.5 serves a day of vegetables at 80% power (0.5% significance level). Data analysis will assess the magnitude of change of these variables both within and between groups and use sub group analysis to explore the relationships between socio-demographic characteristics and outcomes.The qualitative study will be a longitudinal design consisting of semi-structured interviews with approximately 10-15 participants conducted at successive time points. An inductive thematic analysis will be conducted to explore social, attitudinal and behavioural changes experienced by program participants. DISCUSSION: This evaluation will contribute to the evidence of whether cooking programs work in terms of improving health and wellbeing and the underlying mechanisms which may lead to positive behaviour change. TRIAL REGISTRATION: Australian and New Zealand Trial registration number: ACTRN12611001209987. PMID- 23631684 TI - Neuroendocrine mechanisms underlying sensory integration of social signals. AB - Individuals integrate information about their environment into adaptive behavioural responses, yet how different sensory modalities contribute to these decisions and where in the brain this integration occurs is not well understood. We presented male cichlid fish (Astatotilapia burtoni) with sensory information in three social contexts: intruder challenge, reproductive opportunity and a socially neutral situation. We then measured behavioural and hormonal responses along with induction of the immediate early gene c-Fos in candidate forebrain regions. In the intruder challenge context, males were exposed to either a visual stimulus of a dominant male, the putative male pheromone androstenedione, or both. We found that, compared to the neutral context, a visual stimulus was necessary and sufficient for an aggressive response, whereas both chemical and visual stimuli were needed for an androgen response. In the reproductive opportunity context, males were exposed to either a visual stimulus of a receptive female, a progesterone metabolite (female pheromone) only, or both. We further found that the visual stimulus is necessary and sufficient for an androgen response in the reproductive opportunity context. In the brain, we observed c-Fos induction in response to a visual challenge stimulus specifically in dopaminergic neurones of area Vc (the central region of the ventral telencephalon), a putative striatal homologue, whereas presentation of a chemical stimulus did not induce c-Fos induction in the intruder challenge context. Our results suggest that different sensory cues are processed in a social context specific manner as part of adaptive decision-making processes. PMID- 23631685 TI - Determination of multiple mycotoxins in dietary supplements containing green coffee bean extracts using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). AB - An ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS) method for the determination of 34 mycotoxins in dietary supplements containing green coffee bean (GCB) extracts was developed, evaluated, and used in the analysis of 50 commercial products. A QuEChERS-like procedure was used for isolation of target analytes from the examined matrices. Average recoveries of the analytes were in the range of 75-110%. The precision of the method expressed as relative standard deviation was below 12%. Limits of detection (LODs) and limits of quantitation (LOQs) ranged from 1.0 to 50.0 MUg/kg and from 2.5 to 100 MUg/kg, respectively. Due to matrix effects, the method of standard additions was used to ensure accurate quantitation. Ochratoxin A, ochratoxin B, fumonisin B1 and mycophenolic acid were found in 36%, 32%, 10%, and 16% of tested products, respectively. Mycotoxins occurred in the following concentration ranges: ochratoxin A, <1.0-136.9 MUg/kg; ochratoxin B, <1.0-20.2 MUg/kg; fumonisin B1, <50.0-415.0 MUg/kg; mycophenolic acid, <5.0-395.0 MUg/kg. High-resolution mass spectrometry operated in full MS and MS/MS mode was used to confirm the identities of the reported compounds. PMID- 23631686 TI - Different degrees of disorder in long disordered peptides can be discriminated by vibrational spectroscopy. AB - The isotropic Raman, anisotropic Raman, IR, and vibrational circular dichroism (VCD) amide I profiles of a 20 residue homopeptide were calculated for different conformational mixtures that one would generally characterize as random coil or disordered. We first show that (1) pure polyproline II (pPII) coils, (2) statistical coils with different fractions pPII, beta-strand, and right-handed helical residue conformations, and (3) ideal random coils (nearly equal probabilities for pPII, beta, and right-handed helical) can be discriminated based on their respective VCD signal and, to a more limited extent, by means of the peak positions and asymmetries of the corresponding IR and Raman bands. Since molecular dynamics (MD) simulations of unfolded peptides (e.g., Abeta-segments) suggest a mixture of statistical coil and temporarily folded conformations, we calculated the amide I profiles of such mixtures composed of helical, beta strand, and disordered conformers and show that they give rise to rather distinct amide I profiles. Mixtures of regular structures with statistical coil segments can be discriminated from pure statistical and random coils by the amplitude of the negative amide I couplet in the VCD spectrum. We finally demonstrate the usefulness of such simulations by applying them to monomeric state of salmon calcitonin and the amyloid beta fragment Abeta1-28, for which NMR data provide evidence for a coexistence between statistical coil and helical conformations. Altogether, our results show that the combined use of the four amide I profiles provides spectroscopists with a powerful tool to discriminate between different conformational manifolds that long unfolded and disordered peptides and proteins might adopt in solution. PMID- 23631687 TI - Stress and anxiety-depression levels following first-trimester miscarriage: a comparison between women who conceived naturally and women who conceived with assisted reproduction. AB - OBJECTIVE: To compare the psychological impact following early miscarriage between women who conceived naturally and women who conceived following assisted reproduction. DESIGN: Prospective cohort study. SETTING: Assisted reproduction clinic and general gynaecological unit in a university-affiliated, tertiary referral hospital. POPULATION: A cohort of 150 women (75 after natural conception; 75 after assisted reproduction). METHODS: Completed semi-structured interviews using two standard questionnaires [the 12-item General Health Questionnaire (GHQ-12) and the 22-item Revised Impact of Events Scale (IES-R)], at 1, 4, and 12 weeks after a diagnosis of first-trimester miscarriage. MAIN OUTCOME MEASURES: The GHQ-12 and IES-R scores for the two groups of women. RESULTS: The GHQ-12 and IES-R scores were significantly higher in the assisted reproduction group than the scores in the natural conception group, at 4 weeks and 12 weeks after miscarriage. Further breakdown of the scores revealed significantly higher hyperarousal symptoms at 4 and 12 weeks in the assisted reproduction group, indicating the traumatic effect of miscarriage to these women. CONCLUSIONS: Following first-trimester miscarriage, subfertile women who conceived after assisted reproduction had higher stress and anxiety-depression levels, and experienced more traumatic impact from the event, than those after natural conception. A timely support and psychological intervention would be beneficial in the management of this group of women. PMID- 23631688 TI - Little impact of tsunami-stricken nuclear accident on awareness of radiation dose of cardiac computed tomography: a questionnaire study. AB - BACKGROUND: With the increased use of cardiac computed tomography (CT), radiation dose remains a major issue, although physicians are trying to reduce the substantial risks associated with use of this diagnostic tool. This study was performed to investigate recognition of the level of radiation exposure from cardiac CT and the differences in the level of awareness of radiation before and after the Fukushima nuclear plant accident. METHODS: We asked 30 physicians who were undergoing training in internal medicine to determine the equivalent doses of radiation for common radiological examinations when a normal chest X-ray is accepted as one unit; questions about the absolute radiation dose of cardiac CT data were also asked. RESULTS: According to the results, 86.6% of respondents believed the exposure to be 1 mSv at most, and 93.3% thought that the exposure was less than that of 100 chest X-rays. This finding indicates that their perceptions were far lower than the actual amounts. Even after the occurrence of such a large nuclear disaster in Fukushima, there were no significant differences in the same subjects' overall awareness of radiation amounts. CONCLUSIONS: Even after such a major social issue as the Fukushima nuclear accident, the level of awareness of the accurate radiation amount used in 64-channel multidetector CT (MDCT) by clinical physicians who order this test was not satisfactory. Thus, there is a need for the development of effective continuing education programs to improve awareness of radiation from ionizing radiation devices, including cardiac CT, and emphasis on risk-benefit evaluation based on accurate knowledge during medical training. PMID- 23631689 TI - Forbidden fruit? A longitudinal study of Christianity, sex, and marriage. AB - Does religion still play a role in explorations of romance and sexuality among adolescents and young adults in a secular society such as Norway? Does it influence the type of living arrangements chosen? A population-based sample (n = 2,454) was followed longitudinally from their midteens to their late 20s using survey and register data. Christian involvement in teenage years was associated with subsequent less "precoital" exploration, less masturbation, delayed sexual intercourse, and a smaller number of sex partners. However, there were no associations with prevalence of same-sex experiences. Christians also postponed initiating romantic relationships and chose marriage over cohabitation. Associations were reduced after controlling for confounding factors but remained significant. Some associations (for example, the form of residential union chosen) were present only in the most "active" Christians. In other areas, such as "precoital explorations" and the age at which intercourse is initiated, Christian norms seem to play a role in much broader segments of the population. The findings indicate that Christianity may continue to influence young Norwegians' experiences of sexuality and cohabitation more than has been expected. PMID- 23631690 TI - Which drop jump technique is most effective at enhancing countermovement jump ability, "countermovement" drop jump or "bounce" drop jump? AB - The drop jump is a popular form of plyometric exercise often undertaken to enhance countermovement jump ability (jump height). Despite its popularity the effects of drop jump training on countermovement jump height are often inconsistent. Such inconsistencies may be as a result of differences in the drop jump technique being employed. Two recognised forms of drop jump are the "countermovement" drop jump and the "bounce" drop jump and the current study examined the effects of eight weeks of training with these drop jump techniques on countermovement jump height. METHODS: A kinetic and kinematic analysis of each participant's countermovement jump, bounce- and countermovement drop jumps was undertaken prior to training. Participants were then randomly assigned to a bounce drop jump training group (n = 34), a countermovement drop jump training group (n = 35) or a control group (n = 34). Changes in jump height were examined following training. RESULTS: The countermovement drop jump training group increased their countermovement jump height by 2.9 cm (6%), which was a significant change (P < 0.05) in comparison to that experienced by the bounce drop jump (-0.2 cm, -0.4%) and the control group (-0.1 cm, 0.2%). CONCLUSION: The countermovement drop jump may be more effective than the bounce drop jump at enhancing countermovement jump height. PMID- 23631692 TI - Sexual compulsivity scale: adaptation and validation in the spanish population. AB - Sexual compulsivity has been studied in relation to high-risk behavior for sexually transmitted infections. The aim of this study was the adaptation and validation of the Sexual Compulsivity Scale to a sample of Spanish young people. This scale was applied to 1,196 (891 female, 305 male) Spanish college students. The results of principal components factor analysis using a varimax rotation indicated a two-factor solution. The reliability of the Sexual Compulsivity Scale was found to be high. Moreover, the scale showed good temporal stability. External correlates were examined through Pearson correlations between the Sexual Compulsivity Scale and other constructs related with HIV prevention. The authors' results suggest that the Sexual Compulsivity Scale is an appropriate measure for assessing sexual compulsivity, showing adequate psychometric properties in the Spanish population. PMID- 23631693 TI - Anterior positioning of sex chromosomes on the head of human sperm sorted using visible wavelengths. AB - The human ejaculate contains subpopulations of sperm with distinct properties. Human X- and Y-bearing sperm were separated with fluorescence activated cell sorting. To avoid the use of UV light the quantitative DNA dyes DRAQ5(r) and DyecycleTM Vybrant(r) Violet were used. Sorting efficiency was similar for both dyes, but lower than what is usually obtained with the classical method involving Hoechst 33342 and UV light (60-70% enrichment, versus 80-90%). A total of 2,739 spermatozoa were evaluated, from seven distinct samples using fluorescence in situ hybridization (FISH) chromosomal probes. No differences were found in sorted and unsorted populations in terms of chromosome positioning, and numeric chromosomal anomalies were not more evident following cell sorting. Furthermore in both sorted and unsorted populations the sex chromosomes were clearly located in the anterior portion of the sperm head, while a control autosome (chromosome 18) showed no such tendency, confirming previous findings. These results suggest that other quantitative DNA dyes may be used for sex chromosome-based human sperm sorting, but with lower efficiency than the standard UV-Hoechst based assay. PMID- 23631691 TI - Comparative expression of Toll-like receptors and inflammatory cytokines in pigs infected with different virulent porcine reproductive and respiratory syndrome virus isolates. AB - BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is largely responsible for heavy economic losses in the swine industry worldwide because of its high mutation rate and subsequent emergence of virulent strains. However, the immunological and pathological responses of pigs to PRRSV strains with different virulence have not been completely elucidated. METHODS: Twenty four piglets were divided into 4 groups (n = 6 each) and inoculated with highly pathogenic PRRSV isolate BB0907 (HP), low pathogenic PRRSV NT0801 (LP), LP derivative strain NT0801-F70 (LP-der), and DMEM medium (control), respectively. The changes in TLR2, 3, 7, and 8 gene expression and TNF-alpha, IL-1beta, IL-6, IFN-gamma, and IL-10 secretion were evaluated using real-time PCR and ELISA at 6, 9, and 15 days post inoculation (d.p.i.). The cytokine levels were evaluated in the supernatants of porcine alveolar macrophages (PAMs) and peripheral blood mononuclear cells (PBMCs) following stimulation with LTA, poly(I:C), CL097, and PRRSV individually. RESULTS: HP caused more severe clinical signs and pathological lesions in swine than LP and LP-der had almost no virulence compared with LP. The serum levels of IL-1beta, IL-6, TNF-alpha, and IFN-gamma were increased in HP-infected piglets, which were greater than in those infected with LP or LP-der. The mRNA levels of TLR3, 7, and 8 were significantly up-regulated in PAMs in HP-infected pigs compared to those in groups LP and LP-der. Furthermore, TNF-alpha and IL-1beta secretion in PAMs from group LP was statistically greater than those from the control group after stimulation with either poly(I:C) or CL097. Meanwhile, TNF-alpha, IL-1beta, and IL-6 levels in CL097-stimulated PBMCs from HP-infected pigs were markedly higher than those from the LP- and LP-der-infected groups. CONCLUSIONS: We found that HP was a stronger inducer of TLR 3, 7, and 8 expression and IL-1beta, IL-6, TNF-alpha, and IFN gamma production compared to LP and LP-der. HP enhanced production of TNF-alpha, IL-1beta, and IL-6 in PBMCs following CL097-stimulation more than LP and LP-der, whereas LP enhanced the secretion of TNF-alpha and IL-1beta in poly(I:C)- and CL097-stimulated PAMs. Our data regarding cellular reactivity to different isolates should be useful in the development of more efficacious vaccines. PMID- 23631694 TI - Well-defined aminooxy terminated N-(2-hydroxypropyl) methacrylamide macromers for site specific bioconjugation of glycoproteins. AB - Syntheses and characterization of aminooxy terminated polymers of N-(2 hydroxyproyl) methacrylamide (HPMA) of controlled molecular weight and narrow molecular weight distribution are presented here. Design of a chain transfer agent (CTA) containing N-tert-butoxycarbonyl (t-Boc) protected aminooxy group enabled us to use reversible addition-fragmentation (RAFT) polymerization technique to polymerize the HPMA monomer. An amide bond was utilized to link the aminooxy group and the CTA through a triethylene glycol spacer. As a result, the aminooxy group is linked to the poly(HPMA) backbone through a hydrolytically stable amide bond. By varying the monomer to initiator ratios, polymers with targeted molecular weights were obtained. The molecular weights of the polymers were determined by gel permeation chromatography (GPC) and mass spectrometry (ESI and MALDI-TOF). The t-Boc protecting group was quantitatively removed to generate aminooxy terminated poly(HPMA) macromers. These macromers were converted to rhodamine B terminated poly(HPMA) by reacting N-hydroxysuccinimide (NHS) ester of the dye with the terminal aminooxy group to form a stable alkoxyamide bond. Utility of these dye-labeled polymers as molecular probes was evaluated by fluorescence microscopy by studying their intracellular uptake by renal epithelial cells. These aminooxy terminated poly(HPMA) were also tested as biocompatible carriers to prepare chemoselective bioconjugates of proteins using transferrin (Tf) as the protein. Oxidation of the sialic acid side chains of Tf generated aldehyde functionalized protein that was reacted with aminooxy terminated poly(HPMA), which resulted in protein-polymer bioconjugates carrying oxime linkages. These bioconjugates were characterized by gel electrophoresis and MALDI-TOF mass spectrometry. PMID- 23631695 TI - Effects of extremely low frequency electromagnetic field on the health of workers in automotive industry. AB - OBJECTIVE: To observe the effects of extremely low frequency electromagnetic fields (ELF-EMFs) in automotive industry on occupational workers. METHODS: A total of 704 workers were investigated, and 374 workers were chosen and divided into two groups (control group and exposure group) according to the inclusive criteria, namely male with age 20-40 years old and >= 2 years of exposure. The intensities of ELF-EMFs and noise were detected with EFA-300 Field Analyzer (Narda company, Pfullingen, Germany) and AWA5610D integrating sound level meter (Hangzhou Aihua Instruments Co., Ltd, Hangzhou, China), respectively. Survey data were collected by questionnaire, and the physical check-up was done in hospital. All the data were input into SPSS17.0 software (SPSS Inc, Chicago, USA), and the appropriate statistic analyses were carried out. RESULTS: The intensity of EMFs in exposure group was significantly higher than that in control group (p < 0.05), while the noise in two workplaces showed no difference (p>0.05). The survey data collected by questionnaires showed that the symptoms of loss of hair in exposure group were significantly different as compared with that in control group (p < 0.05). The check-up parameters of cardiovascular, liver and hematology system showed significant differences between the two groups (p < 0.05). CONCLUSIONS: Survey and check-up data suggest that exposure to ELF-EMFs might have effects on the nervous, cardiovascular, liver, and hematology system of workers. PMID- 23631696 TI - Evaluation of the structural determinants of polymeric precipitation inhibitors using solvent shift methods and principle component analysis. AB - The presence of polymers within solid dose forms, such as solid dispersions, or liquid or semisolid formulations, such as lipid-based formulations, can promote the maintenance of drug supersaturation after dissolution or dispersion/digestion of the vehicle in the gastrointestinal tract. Transiently stable supersaturation delays precipitation, increases thermodynamic activity, and may enhance bioavailability and reduce variability in exposure. In the current study a diverse range of 42 different classes of polymers, with a total of 78 polymers across all classes, grades, and molecular weights were examined, to varying degrees, as potential polymeric precipitation inhibitors (PPIs) using a solvent shift method to initiate supersaturation. To provide a deeper understanding of the molecular determinants of polymer utility the data were also analyzed, along with a range of physicochemical descriptors of the polymers employed, using principle component analysis (PCA). Polymers were selectively tested for their ability to stabilize supersaturation for nine poorly water-soluble model drugs, representing a range of nonelectrolytes, weak acids, and weak bases. In general, the cellulose-based polymers (and in particular hydroxypropylmethyl cellulose, HPMC, and its derivatives) provided robust precipitation inhibition across most of the drugs tested. Subsequent PCA indicate that there is consistent PPI behavior of a given polymer for a given drug type, with clear clustering of the performance of polymers with each of the nonelectrolytes, weak bases, and weak acids. However, there are some exceptions to this, with some specific drug type polymer interactions also occurring. Polymers containing primary amine functional groups should be avoided as they are prone to enhancing precipitation rates. An inverse relationship was also documented for the number of amide, carboxylic acid, and hydroxyl functional groups; therefore for general good PPI performance the number of these contained within the polymer should be minimized. Molecular weight is a poor predictor of performance, having only a minor influence, and in some cases a higher molecular weight enhances the precipitation process. The importance of ionic interactions to the ability of a PPI to stabilize the supersaturated state was demonstrated by the advantage of choosing a polymer with an opposite charge with respect to the drug. Additionally, when the polymer charge is the same as the supersaturated drug, precipitation is likely to be enhanced. A PCA model based on polymer molecular properties is presented, which has a central oval region where the polymer will general perform well across all three drug types. If the polymer is located outside of this region, then they either show compound-specific inhibition or enhance precipitation. Incomplete separation of the PPI performance based on the molecular properties on the polymers indicates that there are some further molecular properties that might improve the correlation. PMID- 23631697 TI - Phosphatidylinositol-4,5-bisphosphate is enriched in granulovacuolar degeneration bodies and neurofibrillary tangles. AB - AIMS: Among the pathological findings in Alzheimer's disease (AD), the temporal and spatial profiles of granulovacuolar degeneration (GVD) bodies are characteristic in that they seem to be related to those of neurofibrillary tangles (NFTs), suggesting a common mechanism underlying the pathogenesis of these structures. Flotillin-1, a marker of lipid rafts, accumulates in lysosomes of tangle-bearing neurones in AD patients. In addition, recent reports have shown that GVD bodies accumulate at the nexus of the autophagic and endocytic pathways. The aim of this study was to elucidate the distribution of the lipid component of lipid rafts, phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2], in AD and other neurodegenerative disorders. METHODS: We compared PtdIns(4,5)P2 immunoreactivity in the hippocampus, entorhinal cortex and neocortex of five AD cases, 17 cases of other neurodegenerative disorders and four controls. In addition, we performed double staining using markers of GVD, NFTs and lipid rafts for further characterization. RESULTS: Immunohistochemical analysis revealed that PtdIns(4,5)P2 was selectively enriched in GVD bodies and NFTs. Although immunoreactivity for PtdIns(4,5)P2 was also evident in NFTs composed of hyperphosphorylated tau, PtdIns(4,5)P2 was segregated from phosphorylated tau within NFTs by double immunofluorescence staining. In contrast, PtdIns(4,5)P2 colocalized with the lipid raft markers flotillin-1 and annexin 2, within GVD bodies and NFTs. CONCLUSIONS: These results suggest that lipid raft components including PtdIns(4,5)P2 play a role in the formation of both GVD bodies and NFTs. PMID- 23631699 TI - P-stereogenic phospholanes or phosphorinanes from o-biarylylphosphines: two bridges not too far. AB - The discovery of a concise regiodivergent asymmetric route to nonclassical P stereogenic 5- or 6-membered benzophosphacycles, under conditions-dependent radical (oxidative addition) versus anionic (S(N)Ar) benzannulation, is reported. PMID- 23631698 TI - Psychosocial predictors of treatment response to cognitive-behavior therapy for late-life depression: an exploratory study. AB - OBJECTIVE: The primary objective of this study was to examine a variety of potential predictors of response to Cognitive Behavioral Therapy (CBT) in depressed older adults. METHOD: Sixty older adults with a clinical diagnosis of major or minor depression or dysthymic disorder received 12 individual sessions of CBT over a three- to four-month-period. The BDI-II was administered pre- and post-intervention to assess change in the level of depression. A cutoff score of 13 or less at post was used to determine positive treatment response. A variety of measures (obtained at baseline) were evaluated using hierarchical regression techniques to predict improvement following treatment. RESULTS: Individuals who showed greater improvement were: (a) more open to new experiences; (b) less negatively affected by past stressors; (c) less inclined to have an external locus of control but more likely to cite others as responsible for negative stress in their lives; and (d) were more likely to seek emotional support when symptomatic. Lower education level and reported use of active coping strategies at baseline were associated with less improvement. Other variables (e.g., age, overall physical health, and cognitive status) were not associated with treatment response. Use of logistic regression to predict responders vs. nonresponders yielded a similar pattern. CONCLUSION: These findings agree with prior research confirming the effectiveness of a brief CBT intervention for older depressed persons and suggest further exploration of several psychosocial factors that may contribute to a stronger response to CBT. PMID- 23631700 TI - A video-fiberscopic study of laryngopharyngeal behaviour in the human beatbox. AB - The human beatbox is the art of reproducing all types of sounds with the mouth while 'adapting' them for better control. To understand how these 'voice virtuosos' juggle with so many different sounds--instrumental, rhythmic, and vocal--at the same time, we have performed a descriptive analysis of three beatboxers by observing their vocal tract behaviour by fiberscopic imaging using an OCM visual scale. From an anatomical-dynamic point of view, beatboxers mobilize all the structures of their laryngopharynx separately. With this first physiological study of the human beatbox, we could observe a well-developed laryngopharyngeal system with extreme articulatory configurations to perform their art. PMID- 23631701 TI - Parental knowledge of alcohol consumption: a cross sectional survey of 11-17 year old schoolchildren and their parents. AB - BACKGROUND: Developing timely and effective strategies for preventing alcohol misuse in young people is required in order to prevent related harms since, worldwide, alcohol consumption was associated with 320,000 deaths amongst 15-29 year olds in 2004. Providing guidance and advice to parents is essential if alcohol misuse is to be reduced. However, prevention of risky behaviours is hampered if parents are unaware of the risks involved. METHODS: A cross-sectional school-based survey of parent-child dyads, simultaneously questioning 935 children aged 11-17 years old and their parent(s). Univariate and multivariate associations are reported between demography, alcohol behaviours and parental knowledge of their child's alcohol consumption. RESULTS: 41.1% (n = 384) of children reported drinking alcohol. Of these, 79.9% of their parents were aware of their child's alcohol consumption. Children aged 11-14 years had over a twofold greater odds of consuming alcohol without parental knowledge compared with 15-17 year olds (AOR: 2.7, 95% CI: 1.3-5.7). Of parent-child dyads where the child reported consuming alcohol, 92.7% of parents reported that they had spoken to their child about alcohol at least once in the past three months, whereas 57.3% of their children reported that this had occurred. Children who consumed alcohol and whose parents did not know they drank alcohol were less likely to report having a parental discussion about alcohol in the last three months (AOR: 0.4, 95% CI: 0.1-1.0) or report lifetime receipt of at least one other parenting protective measure (AOR: 0.5, 95% CI: 0.2-0.9) compared with those children who drank alcohol with parental knowledge. CONCLUSIONS: Whilst only small numbers of young adolescents in our sample were drinking alcohol compared with older adolescents, those who did were more likely to do so without their parents' knowledge. These two factors combined (drinking earlier and drinking without parental knowledge) could place children at risk of immediate harm. Further research is essential to identify whether public health strategies should be developed which could support parents to employ lifestyle parenting techniques even before the parent believes the child to be at risk. PMID- 23631702 TI - Early repolarization: a rare primary arrhythmic syndrome and common modifier of arrhythmic risk. AB - Despite longstanding beliefs, early repolarization is not always a benign electrocardiographic observation. Its association with increased arrhythmic events has been observed in 2 strikingly different groups of individuals, retrospectively in young subjects with idiopathic ventricular fibrillation and in long-term cohort studies from the general population. This form of primary electrical disease is now referred to as the early repolarization syndrome and has mechanistically been demonstrated to occur secondary to a transmural gradient of early cellular repolarization, resulting in the presence of an ST-elevation pattern and J-waves merged within or offset from the terminal QRS complex. In addition to creating a milieu of increased arrhythmic risk in isolation, an increasing number of studies have highlighted that the presence of early repolarization and J-waves may provide a baseline electrical substrate that modifies the risk of malignant arrhythmias in other clinical settings, such as acute myocardial ischemia. The challenge ahead lies in discerning when early repolarization may represent an ominous ECG marker, as opposed to a benign entity. PMID- 23631703 TI - Effect of lifestyle on quality of life of couples receiving infertility treatment. AB - This study investigated the effect of lifestyle on the quality of life among couples undergoing infertility treatment. The research universe consisted of 200 couples undergoing infertility treatment in Akdeniz University's Center of Reproductive Endocrinology and Assisted Reproductive Techniques. The data collection tools the authors used were a personal information form requesting sociodemographic characteristics and history of infertility, the SF-36 Quality of Life Scale, and the Healthy Lifestyle Behaviors Scale. This study revealed that the quality of life of the women in the study was lower than that of the men. The authors also found that the couples' quality of life was reduced by variables such as advanced age, low education level, unemployment status, lower income, long duration of infertility, high body mass index, history of andrological surgery, and previous experience of assisted reproduction techniques three or more times. Last, it was determined that the couples' quality of life improved as their healthy lifestyle behaviors increased. Demonstrating positive health behavior is likely to improve the quality of life of couples undergoing infertility treatment. PMID- 23631704 TI - The socket-shield technique: first histological, clinical, and volumetrical observations after separation of the buccal tooth segment - a pilot study. AB - BACKGROUND: The "socket-shield technique" has shown its potential in preserving buccal tissues. However, front teeth often have to be extracted due to vertical fractures in buccolingual direction. It has not yet been investigated if the socket-shield technique can only be used with intact roots or also works with a modified shield design referring to vertical fracture lines. PURPOSE: The aim of this study was to assess histologically, clinically, and volumetrically the effect of separating the remaining buccal root segment in two pieces before immediate implant placement. MATERIAL AND METHODS: Three beagle dogs were selected in the study. The third and fourth premolars on both sides of the upper jaw were hemisected and the clinical crown of the distal root was removed. Then, the implant bed preparation was performed into the distal root so that a buccal segment of healthy tooth structure remained. This segment was then separated in a vertical direction into two pieces and implants placed lingual to it. After 4 months of healing, the specimens were processed for histological diagnosis. In a clinical case, the same technique was applied and impressions taken for volumetric evaluation by digital superimposition. RESULTS: The tooth segments showed healthy periodontal ligament on the buccal side. New bone was visible between implant surface and shield as well as inside the vertical drill line. No osteoclastic remodeling of the coronal part of the buccal plate was observed. The clinical volumetric analysis showed a mean loss of 0.88 mm in labial direction with a maximum of 1.67 mm and a minimum of 0.15 mm. CONCLUSION: The applied modification seems not to interfere with implant osseointegration and may still preserve the buccal plate. It may offer a feasible treatment option for vertically fractured teeth. PMID- 23631705 TI - Quantitative detection of relative expression levels of the whole genome of Southern rice black-streaked dwarf virus and its replication in different hosts. AB - BACKGROUND: In recent years, a disease caused by Southern rice black-streaked dwarf virus (SRBSDV) has resulted in significant loss in rice production in Southern China and has spread quickly throughout East and Southeast Asia. This virus is transmitted by an insect vector, white-backed planthopper (WBPH) Sogatella furcifera (Hemiptera: Delphacidae), in a persistent propagative manner. Aside from rice, SRBSDV can also infect numerous Poaceae plants. However, the molecular mechanism of interaction between SRBSDV and its plant or insect vector remains unclear. In order to address this, we investigated the whole viral genome relative mRNA expression level in distinct hosts and monitored their expression level in real-time in rice plants. METHODS: In this study, a reliable, rapid, and sensitive method for detecting viral gene expression transcripts is reported. A SYBR Green I based real-time polymerase chain reaction (PCR) method was adopted for the quantitative detection of SRBSDV gene expression in different hosts and real-time changes in gene expression in rice. RESULTS: Compared to the relative mRNA expression level of the whole genome of SRBSDV, P3, P7-1, and P9-2 were dominantly expressed in rice and WBPH. Similarly, these genes also exhibited high expression levels in corn, suggesting that they have more important functions than other viral genes in the interaction between SRBSDV and hosts, and that they could be used as molecular detection target genes of SRBSDV. In contrast, the levels of P6 and P10 were relative low. Western blotting analysis partially was also verified our qPCR results at the level of protein expression. Analysis of the real-time changes in SRBSDV-infected rice plants revealed four distinct temporal expression patterns of the thirteen genes. Moreover, expression levels of P1 and other genes were significantly down-regulated on days 14 and 20, respectively. CONCLUSION: SRBSDV genes showed similar expression patterns in distinct hosts (rice, corn, and WBPH), indicating that SRBSDV uses the same infection strategy in plant and insect hosts. P3, P7-1, and P9-2 were the dominantly expressed genes in the three tested hosts. Therefore, they are likely to be genes with the most crucial function and could be used as sensitive molecular detection targets for SRBSDV. Furthermore, real-time changes in SRBSDV genes provided a basis for understanding the mechanism of interaction between SRBSDV and its hosts. PMID- 23631706 TI - Quality control, analysis and secure sharing of Luminex(r) immunoassay data using the open source LabKey Server platform. AB - BACKGROUND: Immunoassays that employ multiplexed bead arrays produce high information content per sample. Such assays are now frequently used to evaluate humoral responses in clinical trials. Integrated software is needed for the analysis, quality control, and secure sharing of the high volume of data produced by such multiplexed assays. Software that facilitates data exchange and provides flexibility to perform customized analyses (including multiple curve fits and visualizations of assay performance over time) could increase scientists' capacity to use these immunoassays to evaluate human clinical trials. RESULTS: The HIV Vaccine Trials Network and the Statistical Center for HIV/AIDS Research and Prevention collaborated with LabKey Software to enhance the open source LabKey Server platform to facilitate workflows for multiplexed bead assays. This system now supports the management, analysis, quality control, and secure sharing of data from multiplexed immunoassays that leverage Luminex xMAP(r) technology. These assays may be custom or kit-based. Newly added features enable labs to: (i) import run data from spreadsheets output by Bio-Plex ManagerTM software; (ii) customize data processing, curve fits, and algorithms through scripts written in common languages, such as R; (iii) select script-defined calculation options through a graphical user interface; (iv) collect custom metadata for each titration, analyte, run and batch of runs; (v) calculate dose-response curves for titrations; (vi) interpolate unknown concentrations from curves for titrated standards; (vii) flag run data for exclusion from analysis; (viii) track quality control metrics across runs using Levey-Jennings plots; and (ix) automatically flag outliers based on expected values. Existing system features allow researchers to analyze, integrate, visualize, export and securely share their data, as well as to construct custom user interfaces and workflows. CONCLUSIONS: Unlike other tools tailored for Luminex immunoassays, LabKey Server allows labs to customize their Luminex analyses using scripting while still presenting users with a single, graphical interface for processing and analyzing data. The LabKey Server system also stands out among Luminex tools for enabling smooth, secure transfer of data, quality control information, and analyses between collaborators. LabKey Server and its Luminex features are freely available as open source software at http://www.labkey.com under the Apache 2.0 license. PMID- 23631708 TI - Intermediate structures for higher level arrangements: catching disk-like micelles in decane phosphonic acid aqueous solutions. AB - It has been proposed that disk-like micelles may be precursors to the formation of lamellar liquid crystals. The possibility of obtaining n-decane phosphonic acid (DPA) disk-like micelles in aqueous solution without the addition of a second ionic surfactant led us to study in detail the low-concentration range of this system by both a battery of experimental techniques and molecular dynamics (MD) simulations. The experimental results indicate that premicelles with some capacity to solubilize dyes are formed at 0.05 mM. The critical micelle concentration (cmc) was found to be 0.260 +/- 0.023 mM, much lower than that previously reported in the literature. Spherical micelles, which immediately grow, leading to disk-like micelles, are probably formed at this concentration. At 0.454 +/- 0.066 mM, disk-like micelles become unstable, giving rise to the formation of an emulsion of lamellar mesophase that dominates the system beyond 0.670 +/- 0.045 mM. These experimental results were corroborated by MD simulations which, additionally, allow describing the structure of the obtained micelles at atomic level. The analysis of the MD trajectories revealed the presence of strong intermolecular hydrogen bonds between the surfactant headgroups, producing a compact polar layer with low water content. The formation of such H-bond network could explain the ability of this surfactant to form disk like micelles at concentrations close to the cmc. PMID- 23631707 TI - Conjugation of antibodies to gold nanorods through Fc portion: synthesis and molecular specific imaging. AB - Anisotropic gold nanorods provide a convenient combination of properties, such as tunability of plasmon resonances and strong extinction cross sections in the near infrared to red spectral region. These properties have created significant interest in the development of antibody conjugation methods for synthesis of targeted nanorods for a number of biomedical applications, including molecular specific imaging and therapy. Previously published conjugation approaches have achieved molecular specificity. However, the current conjugation methods have several downsides including low stability and potential cytotoxicity of bioconjugates that are produced by electrostatic interactions, as well as lack of control over antibody orientation during covalent conjugation. Here we addressed these shortcomings by introducing directional antibody conjugation to the gold nanorod surface. The directional conjugation is achieved through the carbohydrate moiety, which is located on one of the heavy chains of the Fc portion of most antibodies. The carbohydrate is oxidized under mild conditions to a hydrazide reactive aldehyde group. Then, a heterofunctional linker with hydrazide and dithiol groups is used to attach antibodies to gold nanorods. The directional conjugation approach was characterized using electron microscopy, zeta potential, and extinction spectra. We also determined spectral changes associated with nanorod aggregation; these spectral changes can be used as a convenient quality control of nanorod bioconjugates. Molecular specificity of the synthesized antibody targeted nanorods was demonstrated using hyperspectral, optical and photoacoustic imaging of cancer cell culture models. Additionally, we observed characteristic changes in optical spectra of molecular specific nanorods after their interactions with cancer cells; the observed spectral signatures can be explored for sensitive cancer detection. PMID- 23631709 TI - Screening and identification of novel B cell epitopes of Toxoplasma gondii SAG1. AB - BACKGROUND: The identification of protein epitopes is useful for diagnostic purposes and for the development of peptide vaccines. In this study, the epitopes of Toxoplasma gondii SAG1 were identified using synthetic peptide techniques with the aid of bioinformatics. FINDINGS: Eleven peptides derived from T. gondii SAG1 were assessed by ELISA using pig sera from different time points after infection. Four (PS4, PS6, PS10 and PS11), out of the eleven peptides tested were recognized by all sera. Then, shorter peptides that were derived from PS4, PS6, PS10 and PS11 were predicted using bioinformatics and tested by experimentation. Four out of nine shorter peptides were identified successfully (amino acids 106-120, 166 180, 289-300 and 313-332). CONCLUSIONS: We have precisely located the epitopes of T. gondii SAG1 using pig sera collected at different time points after infection. The identified epitopes may be useful for the further study of epitope-based vaccines and diagnostic reagents. PMID- 23631710 TI - Development of sexual expectancies among adolescents: contributions by parents, peers and the media. AB - To expand the scant research on sexual expectancies development among non sexually active adolescents, we examined the relationship between adolescents' exposure to four socializing agents--mother/female guardian, father/male guardian, peers, and television programs with high sexual content--and their endorsement of four sexual expectancies: social benefit, pleasure, social risk, and health risk. Data are from Waves 2 and 3 of a three-wave annual longitudinal study conducted among California adolescents, the majority of whom were not sexually active (N = 914, 84%). Structural equation models were conducted to examine cross-sectional and longitudinal associations between the socializing agents and the sexual expectancies. Cross-sectional results indicate associations between peer sexual communication and social benefit, pleasure, and social risk expectancies. A positive association was found between exposure to music videos and social benefit expectancies, and a negative association was found between exposure to music videos and health risk expectancies. Longitudinal results suggest that communication with peers positively predicted pleasure expectancies and negatively predicted social risk expectancies. No other socializing agents were associated with any sexual expectancies. An invariance test found that significant correlations were similar across the different age groups. Results suggest that efforts to support positive sexual decision making among non sexually active adolescents should target peer sexual communication. PMID- 23631711 TI - An integrated framework for the optimisation of sport and athlete development: a practitioner approach. AB - This paper introduces a new sport and athlete development framework that has been generated by multidisciplinary sport practitioners. By combining current theoretical research perspectives with extensive empirical observations from one of the world's leading sport agencies, the proposed FTEM (Foundations, Talent, Elite, Mastery) framework offers broad utility to researchers and sporting stakeholders alike. FTEM is unique in comparison with alternative models and frameworks, because it: integrates general and specialised phases of development for participants within the active lifestyle, sport participation and sport excellence pathways; typically doubles the number of developmental phases (n = 10) in order to better understand athlete transition; avoids chronological and training prescriptions; more optimally establishes a continuum between participation and elite; and allows full inclusion of many developmental support drivers at the sport and system levels. The FTEM framework offers a viable and more flexible alternative for those sporting stakeholders interested in managing, optimising, and researching sport and athlete development pathways. PMID- 23631712 TI - Parental divorce in late adolescence does not seem to increase mental health problems: a population study from Norway. AB - BACKGROUND: Former studies have shown increased mental health problems in adolescents after parental divorce all over the Western world. We wanted to see if that still is the case in Norway today when divorce turns to be more and more common. METHODS: In a prospective study design, two samples were constituted, adolescents at a baseline survey in 2001/02 (n = 2422) and those at follow-up in 2003/04 (n = 1861), when the adolescents were 15/16 and 18/19 years-old, respectively. They answered self-administered questionnaires in both surveys of Young-HUBRO in Oslo. Early parental divorce was defined as that which occured before age 15/16 years, and late divorce occured between age 15/16 and 18/19. Internalized and externalized mental health problems were measured by the Hopkin's Symptom Check List (HSCL-10) and the Strengths and Difficulties Questionnaire (SDQ). RESULTS: After linear regression models were adjusted for gender, ethnicity, family economy, social support, and mental health problem symptoms measured at baseline before parental divorce occured, late parental divorce did not lead to significant increase in mental health problems among adolescents in the city of Oslo. Early parental divorce was associated with internal mental health problems among young adolescents when adjusted only for the first four possible confounders. CONCLUSIONS: It seems that parental divorce in late adolescence does not lead to mental health problems in Norway any more, as has been shown before, while such problems may prevail among young adolescents. This does not mean that parental divorce create less problems in late adolescence than before but these youths might have developed adjustment abilities against health effects as divorce have turned to be more common. PMID- 23631713 TI - Stigma towards PLWHA: the role of internalized homosexual stigma in Latino gay/bisexual male and transgender communities. AB - Stigma negatively affects the health of people living with HIV/AIDS (PLWHA). Negative attitudes and discriminatory actions towards PLWHA are thought to be based, among other factors, on stigma towards sexual minorities and beliefs about personal responsibility. Yet, there is little evidence to support these linkages and explain how they take place, especially among Latinos. This study analyzes attitudes towards PLWHA among 643 Latino gay/bisexual men and transgender (GBT) people. It examines whether discriminatory actions are predicted by beliefs about personal responsibility and internalized homosexual stigma. Results indicate that Discriminatory Actions towards PLWHA is associated with HIV/AIDS Personal Responsibility Beliefs and Internalized Homosexual Stigma. Further, HIV/AIDS Personal Responsibility Beliefs partially mediates the relationship between Internalized Homosexual Stigma and Discriminatory Actions towards PLWHA. Latino GBT persons who have internalized negative views about homosexuality may project those onto PLWHA. They may think PLWHA are responsible for their serostatus and, hence, deserving of rejection. PMID- 23631714 TI - Sisters empowered, sisters aware: three strategies to recruit African American women for HIV testing. AB - African American women account for 66% of new HIV infections among U.S. women, and many are not aware of their status. The authors compared three strategies (targeted outreach, alternate venues, and social networks) to recruit African American women for HIV testing in Houston, New York City, Baltimore, and Dayton. A quasi-experimental design (N = 4,942) was used to compare HIV-positivity rates and to identify risk factors for previously undiagnosed infection. A total of 2.1% of the women were newly diagnosed with HIV. The proportion newly identified as HIV-positive did not differ significantly among the three strategies (2.4% for social networks, 1.7% for both targeted outreach and alternate venues). However, the social networks strategy recruited women with greater risk behaviors and other characteristics associated with newly identified HIV infection and thus may be effective at reaching some high-risk women before they become infected. A combination of recruitment strategies may be warranted to reach various subgroups of African American women at risk for HIV. PMID- 23631715 TI - Project power: Adapting an evidence-based HIV/STI prevention intervention for incarcerated women. AB - Incarcerated women are a critical population for targeted HIV/STI prevention programming; however, there is a dearth of evidence-based, genderspecific behavioral interventions for this population. Systematically adapting existing evidence-based interventions (EBIs) can help fill this gap. We illustrate the adaptation of the HIV/STI prevention EBI, Project Safe, for use among incarcerated women and delivery in prisons. Project POWER, the final adapted intervention, was developed using formative research with prison staff and administration, incarcerated and previously incarcerated women, and input of community advisory boards. Intervention delivery adaptations included: shorter, more frequent intervention sessions; booster sessions prior to and just after release; facilitator experience in prisons and counseling; and new videos. Intervention content adaptations addressed issues of empowerment, substance use, gender and power inequity in relationships, interpersonal violence, mental health, reentry, and social support. This illustration of the adaption process provides information to inform additional efforts to adapt EBIs for this underserved population. PMID- 23631716 TI - Jaboya vs. jakambi: Status, negotiation, and HIV risks among female migrants in the "sex for fish" economy in Nyanza Province, Kenya. AB - In Nyanza Province, Kenya, HIV incidence is highest (26.2%) in the beach communities along Lake Victoria. Prior research documented high mobility and HIV risks among fishermen; mobility patterns and HIV risks faced by women in fishing communities are less well researched. This study aimed to characterize forms of mobility among women in the fish trade in Nyanza; describe the spatial and social features of beaches; and assess characteristics of the "sex-for-fish" economy and its implications for HIV prevention. We used qualitative methods, including participant observation in 6 beach villages and other key destinations in the Kisumu area of Nyanza that attract female migrants, and we recruited individuals for in-depth semi-structured interviews at those destinations. We interviewed 40 women, of whom 18 were fish traders, and 15 men, of whom 7 were fishermen. Data were analyzed using Atlas.ti software. We found that female fish traders are often migrants to beaches; they are also highly mobile. They are at high risk of HIV acquisition and transmission via their exchange of sex for fish with jaboya fishermen. PMID- 23631717 TI - Characteristics of a sexual network of behaviorally bisexual men in Vientiane, Lao PDR, 2010. AB - Men who have sex with both men and women (behaviorally bisexual men) may be at increased risk of HIV acquisition and transmission due to risky sexual behaviors. We recruited a sexual network comprised of behaviorally bisexual men and their sexual partners in Vientiane, Lao PDR in 2010 to inform our understanding of the potential for HIV transmission among heterosexual, homosexual, and bisexual networks. Participants completed a sexual behavior questionnaire and referred < 5 sexual partners. A total of 298 people were recruited, including 63 behaviorally bisexual men. Behaviorally bisexual men reported riskier sexual behaviors (number of sexual partners in the previous 12 months and consistent condom use) than behaviorally homosexual and heterosexual men. Using social network diagrammatic representation, heterosexual, homosexual, and bisexual networks are shown to be interlinked. This study demonstrates that behaviorally bisexual men are potential key drivers of HIV epidemics and require a targeted approach to sexual health promotion. PMID- 23631718 TI - Correlates of HIV and HCV risk and testing among Chinese, Filipino, and Vietnamese men who have sex with men and other at-risk men. AB - Asian Americans are one of the more under-researched groups in the United States. This holds true with regard to research on risk assessment, screening, and testing for human immunodeficiency virus (HIV) and hepatitis C (HCV). Here, we address that lack by exploring correlates of risk and testing for the two diseases among Chinese, Filipino, and Vietnamese men who have sex with men (MSM) and other at-risk men in the San Francisco Bay Area. We do so by analyzing findings from the study of a community-based prevention program, Project 3-3-3 (P333), designed to address the often comorbid conditions of substance abuse, HIV infection, and HCV infection among underserved and high-risk Chinese, Filipino, and Vietnamese adults, most of whom are MSM. A risk-behavior survey completed at preintervention identified risk factors related to HIV, HCV, and substance use among this population (n = 273). The study of survey data identifies and distinguishes between correlates of HIV and HCV testing. Among our findings, significant differences were found between Asian ethnic subpopulation groups with respect to number of sexual partners (p = .007), and HIV testing rates comparing MSM and heterosexual men differed significantly (p < .002). Those who spoke English at home were more likely to be tested for HIV (p < .008). With HCV testing, the number of partners was positively correlated to getting tested (p < .047), and Filipino men were significantly more likely to get tested for HCV than Chinese men (p < .022). PMID- 23631719 TI - Hydrogermylation of 5-ethynyluracil nucleosides: formation of 5-(2 germylvinyl)uracil and 5-(2-germylacetyl)uracil nucleosides. AB - A stereoselective radical-mediated hydrogermylation of the protected 5 ethynyluracil nucleosides with trialkyl-, triaryl,- or tris(trimethylsilyl)germanes gave (Z)-5-(2-germylvinyl)uridine, 2'-deoxyuridine, or ara-uridine as major products. Reaction of the beta-triphenylgermyl vinyl radical intermediate with oxygen and fragmentation of the resulting peroxyradical provided also 5-[2-(triphenylgermyl)acetyl]pyrimidine nucleosides in low to moderate yields. Thermal isomerization of the latter in MeOH occurred via a four centered activated complex, and subsequent hydrolysis of the resulting O-germyl substituted enol yielded 5-acetyluracil nucleosides in quantitative yield. PMID- 23631720 TI - Design, synthesis, and characterization of new 5-fluorocytosine salts. AB - 5-Fluorocytosine (FC), an antifungal drug and a cytosine derivative, has a complex solid-state landscape that challenges its development into a drug product. A total of eight new FC salts, both cytosinium and hemicytosinium, with four strong acids were prepared by controlling acid concentration in the crystallization medium. The pharmaceutically acceptable saccharin salt of FC exhibits superior phase stability and, hence, has the potential to address the instability problem of FC associated with hydration. PMID- 23631721 TI - Depression among family caregivers of community-dwelling older people who used services under the Long Term Care Insurance program: a large-scale population based study in Japan. AB - OBJECTIVE: To identify predictors for depression among family caregivers of community-dwelling older people under the Long Term Care Insurance (LTCI) program in Japan through a large-scale population-based survey. METHOD: All 5938 older people with disabilities, using domiciliary services under the LTCI in the city of Toyama, and their family caregivers participated in this study. Caregiver depression was defined as scores of >=16 on the Center for Epidemiological Studies Depression Scale (CES-D). Other caregiver measures included age, sex, hours spent caregiving, relationship to the care recipient, income adequacy, living arrangement, self-rated health, and work status. Care recipient measures included age, sex, level of functional disability, and severity of dementia. The data from 4128 pairs of the care recipients and their family caregivers were eligible for further analyses. A multiple logistic regression analysis was used to examine the predictors associated with being at risk of clinical depression (CES-D of >=16). RESULTS: Overall, 34.2% of caregivers scored >=16 on the CES-D. The independent predictors for depression by logistic regression analysis were six caregiver characteristics (female, income inadequacy, longer hours spent caregiving, worse subjective health, and co-residence with the care recipient) and one care-recipient characteristic (moderate dementia). CONCLUSION: This is one of the first population-based examinations of caregivers of older people who are enrolled in a national service system that provides affordable access to services. The results highlighted the importance of monitoring caregivers who manifest the identified predictors to attenuate caregiver depression at the population level under the LTCI. PMID- 23631722 TI - Follicular lymphoma in Taiwan: a low frequency of t(14;18), with grade 3A tumours more closely related to grade 3B than to low-grade tumours. AB - AIMS: To investigate t(14;18)/IGH-BCL2 in follicular lymphoma (FL) cases from Taiwan. METHODS AND RESULTS: We retrospectively studied 93 consecutive cases, using immunohistochemistry and fluorescence in-situ hybridization (FISH). Fifty nine (63%) tumours were low-grade (LG) and 34 (37%) were high-grade (HG; 24% FL3A and 13% FL3B). FISH showed IGH, BCL2 and BCL6 rearrangements in 59%, 47% and 11% of cases, respectively, and MYC rearrangement in 5% of FL3A tumours and 25% of FL3B tumours. The translocation partner of all BCL2 rearrangements was IGH, with IGH-BCL2 fusion in 63% of LG tumours and 18% of HG tumours. LG tumours were enriched with a CD10+/bcl-2+/MUM1- phenotype, and were frequently associated with BCL2 rearrangement but less commonly with BCL6 rearrangement. FL3A tumours were more closely related to FL3B tumours than to LG tumours in immunophenotype and genetic aberrations. There was no statistically significant difference between grade 1 and two tumours, between FL3A and FL3B tumours or between nodal and extranodal tumours in immunophenotypic or FISH findings. The cumulative survival rate was higher in LG FL patients with IGH-BCL2 translocation than in those without rearrangement. CONCLUSIONS: In Taiwan, FL3A tumours were more closely related to FL3B tumours than to LG tumours, and a literature review showed that the frequency of t(14;18)/IGH-BCL2 in FL in Taiwan is among the lowest in the world. PMID- 23631723 TI - Novel tretinoin formulations: a drug-in-cyclodextrin-in-liposome approach. AB - PURPOSE: The aims of this experimental work were the incorporation and full characterization of the system Tretinoin-in-dimethyl-beta-cyclodextrin-in ultradeformable vesicles (Tretinoin-CyD-UDV) and Tretinoin-in-ultradeformable vesicles (Tretinoin-UDV). METHODS: The Tretinoin-CyD complex was prepared by kneading and the UDV by adding soybean phosphatidylcholine (SPC) to Tween(r) 80 followed by an appropriate volume of sodium phosphate buffer solution to make a 10%-20% lipid suspension. The resulting suspension was brought to the final mean vesicles size, of approximately 150 nm, by sequential filtration. The physicochemical characterization was based on: the evaluation of mean particle size and polydispersity index (PI) measured by photon correlation spectroscopy (PCS) and atomic force microscopy (AFM) topographic imaging; zeta potential (zeta potential) and the SPC concentration determined by Laser-Doppler anemometry and an enzymatic-colorimetric test, respectively. The quantification of the incorporated Tretinoin and its chemical stability (during preparation and storage) was assayed by a HPLC at 342 nm. RESULTS: It was possible to obtain the system Tretinoin-CyD-UDV. The mean vesicle size was the most stable parameter during experiments time course. AFM showed that Tretinoin-CyD-UDV samples were very heterogeneous in size, having three distinct subpopulations, while Tretinoin UDV samples had only one homogeneous size population. The results of the zeta potential measurements have shown that vesicle surface charge was low, as expected, presenting negative values. The incorporation efficiency was high, and no significant differences between Tretinoin-CyD-UDV and Tretinoin-UDV were observed. However, only Tretinoin-UDV with 20% lipid concentration formulation remained chemically stable during the evaluation period. CONCLUSION: According to our results, Tretinoin-UDV with 20% lipid concentration seems to be a better approach than Tretinoin-CyD-UDV, attending to the higher chemical stability. PMID- 23631724 TI - Reactive oxygen species (ROS) production in human peripheral blood neutrophils exposed in vitro to static magnetic field. AB - The aim of this study was to determine the effect of gradient static magnetic field (SMF) on reactive oxygen species (ROS) production in human neutrophils in peripheral blood in vitro. Blood samples collected from healthy individuals were incubated in an inhomogeneous SMF (in a south or north pole of the field) for 15, 30 or 45 minutes. The maximum value of induction (B max) amounted to ~ 60 mT. To determine the strength of the ROS production, dihydrorhodamine (123DHR) as fluorophore and phorbol 12-myristate 13-acetate (PMA) as respiratory burst stimulator were used. 123DHR oxidation by ROS was measured by flow cytometry. The exposure of blood samples to SMF induced statistically significant changes in ROS production in unstimulated and PMA-stimulated neutrophils. The observed effects were highly correlated with the exposure time and depended on the orientation of the field. Although intracellular mechanisms underlying such interactions are not thoroughly understood, it could be presumed that SMF affects ROS metabolic oscillations and their formation and inactivation. This study emphasizes the importance of proper adjustment of exposure time to SMF for any potential therapeutic applications. PMID- 23631725 TI - Body weight status and cardiovascular risk factors in adults by frequency of candy consumption. AB - BACKGROUND: Limited information is available regarding the impact of candy consumption on health. The purpose of this study was to investigate associations between typical frequency of candy consumption and body weight status and select cardiovascular risk factors among adults in the United States. METHODS: Using data collected in the 2003-2006 National Health and Nutrition Examination Surveys (NHANES), adults were categorized as infrequent (<= 3 eating occasions [EO]/month), moderate (> 3 EO/month and <= 3.5 EO/week), or frequent (> 3.5 EO/week) candy consumers based on the combined frequency of chocolate and other candy consumption over the previous 12 months. Weight and adiposity status were analyzed using logistic regression models, and blood pressure, lipids, and insulin sensitivity were analyzed using linear regression models. Models were adjusted for age, sex and race/ethnicity, and also for additional covariates with potential associations with the outcomes. Appropriate statistical weights were used to yield results generalizable to the US population. RESULTS: Frequency of candy consumption was not associated with the risk of obesity, overweight/obesity, elevated waist circumference, elevated skinfold thickness, blood pressure, low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol, triglycerides, or insulin resistance. Increased frequency of candy consumption was associated with higher energy intakes and higher energy adjusted intakes of carbohydrates, total sugars and added sugars, total fat, saturated fatty acids and monounsaturated fatty acids (p < 0.05), and lower adjusted intakes of protein and cholesterol (p < 0.001). CONCLUSIONS: Increased frequency of candy consumption among adults in the United States was not associated with objective measures of adiposity or select cardiovascular risk factors, despite associated dietary differences. Given the cross-sectional study design, however, it cannot be concluded that candy consumption does not cause obesity or untoward levels of cardiovascular risk markers. The lack of an association between frequency of candy consumption and cardiovascular risk factors could be due to reduced intake of candy among the overweight due to dieting or a health professional's recommendations. Additionally, it is important to note that the analysis was based on frequency of candy consumption and not amount of candy consumed. Longitudinal studies are needed to confirm the lack of associations between frequency of candy consumption and cardiovascular risk factors. PMID- 23631726 TI - The novel H7N9 influenza A virus: its present impact and indeterminate future. PMID- 23631729 TI - Biology Direct: celebrating 7 years of open, published peer review. PMID- 23631728 TI - Peripheral blood-derived endothelial progenitor cells enhance vertical bone formation. AB - BACKGROUND: This study presents a novel cell-based approach for extra-cortical bone regeneration. OBJECTIVE: To enhance vertical bone formation by combining guided bone regeneration and transplantation of peripheral blood-derived endothelial progenitor cells (EPCs) in a rat calvaria model. MATERIALS AND METHODS: EPCs were isolated from peripheral blood of inbred rats. Gold domes (7 mm radius, 5 mm height) were filled with beta-tricalcium phosphate (betaTCP) mixed with 5 * 10(5) EPC. Domes filled with betaTCP served as control (CNT). Rats were sacrificed after 3 months. Vertical bone augmentation was analyzed using histology, histomorphometry, and microcomputed tomography (MUCT). RESULTS: In all rats, hard tissue filled the space under the dome. Histomorphometric analysis revealed that EPC transplantations doubled vertical bone height (EPC 4.04 +/- 0.22 mm vs CNT 2.29 +/- 0.22 mm, p <= .001). EPC also caused ~50% increase in bone area fraction (EPC 47.3 +/- 3.1% vs CNT 31.1 +/- 2.7%, p <= .003). MUCT results also showed that bone volume fraction (BV/TV) was higher in EPC group (p = .0169). In both groups, BV/TV declined from the bottom to the top of the samples. No differences in tissue mineral density were found between EPC and CNT groups. CONCLUSION: EPC transplantation significantly improved bone formation especially in the areas that are remote from the original bone. PMID- 23631727 TI - An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia. AB - BACKGROUND: Sinus node (SN) dysfunction is observed in some long-QT syndrome (LQTS) patients, but has not been studied as a function of LQTS genotype. LQTS6 involves mutations in the hERG beta-subunit MiRP1, which also interacts with hyperpolarization-activated, cyclic nucleotide gated (HCN) channels-the molecular correlate of SN pacemaker current (If ). An LQTS registry search identified a 55 year male with M54T MiRP1 mutation, history of sinus bradycardia (39-56 bpm), and prolonged QTc. OBJECTIVE: We tested if LQTS6 incorporates sinus bradycardia due to abnormal If . METHODS: We transiently co-transfected neonatal rat ventricular myocytes (to study currents in a myocyte background) with human HCN4 (hHCN4, primary SN isoform) or human HCN2 (hHCN2) and one of the following: empty vector, wild-type hMiRP1 (WT), M54T hMiRP1 (M54T). Current amplitude, voltage dependence, and kinetics were measured by whole cell patch clamp. RESULTS: M54T co-expression decreased HCN4 current density by 80% compared to hHCN4 alone or with WT, and also slowed HCN4 activation at physiologically relevant voltages. Neither WT nor M54T altered HCN4 voltage dependence. A computer simulation predicts that these changes in HCN4 current would decrease rate and be additive with published effects of M54T mutation on hERG kinetics on rate. CONCLUSIONS: We conclude that M54T LQTS6 mutation can cause sinus bradycardia through effects on both hERG and HCN currents. Patients with other LQTS6 mutations should be examined for SN dysfunction, and the effect on HCN current determined. PMID- 23631730 TI - Synergistic stimulation of antigen presenting cells via TLR by combining CpG ODN and poly(gamma-glutamic acid)-based nanoparticles as vaccine adjuvants. AB - CpG oligodeoxynucleotide (ODN) encapsulated poly(gamma-glutamic acid)-graft-l phenylalanine ethyl ester (gamma-PGA-Phe) nanoparticles (NPs) employing polycations were prepared to develop vaccine delivery and adjuvant systems. The CpG ODN was stably encapsulated into the NPs when protamine was used as the polycation. The CpG ODN-encapsulated gamma-PGA-Phe NPs were taken up by macrophages and CpG ODN which was encapsulated into the NPs internalized into endo/lysosomes, where the toll-like receptor (TLR) 9, which recognizes CpG ODN, is expressed. The examination of release behavior in vitro revealed that the encapsulated CpG ODN into NPs was released when these NPs were immersed into the early endosomal environment. Interestingly, CpG ODN-encapsulated gamma-PGA-Phe NPs synergistically activated macrophages. This may be due to the multiple stimulation of TLRs by gamma-PGA-Phe NPs (TLR4 ligand) and CpG ODN (TLR9 ligand). We previously reported that gamma-PGA-Phe NPs are excellent vaccine adjuvants for inducing potent innate and adaptive immune responses via TLR4. Moreover, coencapsulated CpG ODN and antigen in gamma-PGA-Phe NPs induced potent antigen specific cellular immunity at a higher level than the mixture of CpG ODN and antigen which is the conventional vaccine system. These findings suggest that the conjugation strategies of biologically derived adjuvant and polymeric NPs will aid the development of a novel approach for safe and effective vaccine delivery and adjuvant systems. PMID- 23631731 TI - Effect of hip flexion angle on hamstring optimum length after a single set of concentric contractions. AB - The eccentric contraction mode was proposed to be the primary stimulus for optimum angle (angle at which peak torque occurs) shift. However, the training range of motion (or muscle excursion range) could be a stimulus as important. The aim of this study was to assess the influence of the training range of motion stimulus on the hamstring optimum length. It was hypothesised that performing a single set of concentric contractions beyond optimal length (seated at 80 degrees of hip flexion) would lead to an immediate shift of the optimum angle to longer muscle length while performing it below (supine at 0 degrees of hip flexion) would not provide any shift. Eleven male participants were assessed on an isokinetic dynamometer. In both positions, the test consisted of 30 consecutive knee flexions at 4.19 rad . s-1. The optimum angle was significantly shifted by ~15 degrees in the direction of longer muscle length after the contractions at 80 degrees of hip flexion, while a non-significant shift of 3 degrees was found at 0 degrees . The hamstring fatigability was not influenced by the hip position. It was concluded that the training range of motion seems to be a relevant stimulus for shifting the optimum angle to longer muscle length. Moreover, fatigue appears as a mechanism partly responsible for the observed shift. PMID- 23631732 TI - Hydrodynamic effects on the relative rotational velocity of associating proteins. AB - Hydrodynamic steering effects on the barnase-barstar association were studied through the analysis of the relative rotational velocity of the proteins. We considered the two proteins approaching each other in response to their electrostatic attraction and employed a method that accounts for the long-range and many-body character of the hydrodynamic interactions, as well as the complicated shapes of the proteins. Hydrodynamic steering effects were clearly seen when attractive forces were applied to the geometric centers of the proteins (resulting in zero torques) and the attraction acted along the line that connects centers of geometry of proteins in their crystallographic complex. When we rotated barstar relative to barnase around this line by an angle in the range from -90 degrees to 60 degrees , the rotational velocity arising solely from hydrodynamic interactions restored the orientation of the proteins in the crystal structure. However, because, in reality, both electrostatic forces and torques act on the proteins and these forces and torques depend on the protein-protein distance and the relative orientation of the binding partners, we also investigated more realistic situations employing continuum electrostatics calculations based on atomistic protein models. Overall, we conclude that hydrodynamic interactions aid barnase and barstar in assuming a proper relative orientation upon complex formation. PMID- 23631733 TI - Combining MEDLINE and publisher data to create parallel corpora for the automatic translation of biomedical text. AB - BACKGROUND: Most of the institutional and research information in the biomedical domain is available in the form of English text. Even in countries where English is an official language, such as the United States, language can be a barrier for accessing biomedical information for non-native speakers. Recent progress in machine translation suggests that this technique could help make English texts accessible to speakers of other languages. However, the lack of adequate specialized corpora needed to train statistical models currently limits the quality of automatic translations in the biomedical domain. RESULTS: We show how a large-sized parallel corpus can automatically be obtained for the biomedical domain, using the MEDLINE database. The corpus generated in this work comprises article titles obtained from MEDLINE and abstract text automatically retrieved from journal websites, which substantially extends the corpora used in previous work. After assessing the quality of the corpus for two language pairs (English/French and English/Spanish) we use the Moses package to train a statistical machine translation model that outperforms previous models for automatic translation of biomedical text. CONCLUSIONS: We have built translation data sets in the biomedical domain that can easily be extended to other languages available in MEDLINE. These sets can successfully be applied to train statistical machine translation models. While further progress should be made by incorporating out-of-domain corpora and domain-specific lexicons, we believe that this work improves the automatic translation of biomedical texts. PMID- 23631735 TI - Pathogenesis of H9N2 virus in Chukar partridges. AB - Low-pathogenic avian influenza virus (H9N2) is circulating in the poultry industry of many countries in the Middle East and Asia, causing serious economic damage. In this study the clinical signs, antibody response, viral shedding and efficacy of oil emulsion vaccines in Chukar partridges were investigated until 9 days post inoculation (d.p.i.). Seventy-five Chukar partridges (Alectoris chukar) were divided randomly in three groups of challenged (Group C), vaccinated and challenged (Group VC) and control (non-vaccinated and non-challenged [Group NC]), 25 birds/group. Groups C and VC were inoculated with 0.4 ml allantoic fluid containing 10(7) median embryo infective dose/bird of A/Chicken/Iran/772/1998(H9N2) avian influenza virus. Clinical signs, antibody response, viral shedding and vaccine efficacy were evaluated and compared among these groups over 9 days. Clinical signs such as coughing and sneezing with depression and decreased feed and water consumption were observed in Group C. In Group VC only a slight decrease in food and water consumption was observed. Both Groups C and VC showed maximum antibody titre at 9 d.p.i. At 1 d.p.i. the virus was detected from all tissues in challenged group, but the virus was not detected from the spleen and caecal tonsil of Group VC. Group C showed the longest period of viral shedding in the trachea and kidney. PMID- 23631736 TI - Highly enantioselective zirconium-catalyzed cyclization of aminoalkenes. AB - Aminoalkenes are catalytically cyclized in the presence of cyclopentadienylbis(oxazolinyl)borato group 4 complexes {PhB(C5H4)(Ox(R))2}M(NMe2)2 (M = Ti, Zr, Hf; Ox(R) = 4,4-dimethyl-2-oxazoline, 4S isopropyl-5,5-dimethyl-2-oxazoline, 4S-tert-butyl-2-oxazoline) at room temperature and below, affording five-, six-, and seven-membered N-heterocyclic amines with enantiomeric excesses of >90% in many cases and up to 99%. Mechanistic investigations of this highly selective system employed synthetic tests, kinetics, and stereochemistry. Secondary aminopentene cyclizations require a primary amine (1-2 equiv vs catalyst). Aminoalkenes are unchanged in the presence of a zirconium monoamido complex {PhB(C5H4)(Ox(4S-iPr,Me2))2}Zr(NMe2)Cl or a cyclopentadienylmono(oxazolinyl)borato zirconium diamide {Ph2B(C5H4)(Ox(4S iPr,Me2))}Zr(NMe2)2. Plots of initial rate versus [substrate] show a rate dependence that evolves from first-order at low concentration to zero-order at high concentration, and this is consistent with a reversible substrate-catalyst interaction preceding an irreversible step. Primary kinetic isotope effects from substrate conversion measurements (k'obs((H))/k'obs((D)) = 3.3 +/- 0.3) and from initial rate analysis (k2((H))/k2((D)) = 2.3 +/- 0.4) indicate that a N-H bond is broken in the turnover-limiting and irreversible step of the catalytic cycle. Asymmetric hydroamination/cyclization of N-deutero-aminoalkenes provides products with higher optical purities than obtained with N-proteo-aminoalkenes. Transition state theory, applied to the rate constant k2 that characterizes the irreversible step, provides activation parameters consistent with a highly organized transition state (DeltaS(++) = -43(7) cal.mol(-1) K(-1)) and a remarkably low enthalpic barrier (DeltaH(++) = 6.7(2) kcal.mol(-1)). A six-centered, concerted transition state for C-N and C-H bond formation and N-H bond cleavage involving two amidoalkene ligands is proposed as most consistent with the current data. PMID- 23631734 TI - Abnormal interneuron development in disrupted-in-schizophrenia-1 L100P mutant mice. AB - BACKGROUND: Interneuron deficits are one of the most consistent findings in post mortem studies of schizophrenia patients and are likely important in the cognitive deficits associated with schizophrenia. Disrupted-in-Schizophrenia 1 (DISC1), a strong susceptibility gene for schizophrenia and other mental illnesses, is involved in neurodevelopment, including that of interneurons. However, the mechanism by which DISC1 regulates interneuron development remains unknown. In this study, we analyzed interneuron histology in the Disc1-L100P single point mutation mouse, that was previously shown to have behavioral abnormalities and cortical developmental defects related to schizophrenia. RESULTS: We sought to determine whether a Disc1-L100P point mutation in the mouse would alter interneuron density and location. First, we examined interneuron position in the developing mouse cortex during embryonic days 14-16 as an indicator of interneuron tangential migration, and found striking migration deficits in Disc1-L100P mutants. Further analysis of adult brains revealed that the Disc1-L100P mutants have selective alterations of calbindin- and parvalbumin expressing interneurons in the cortex and hippocampus, decreased GAD67/PV co localization and mis-positioned interneurons across the neocortex when compared to wild-type littermates. CONCLUSION: Our results are consistent with the anomalies seen in post-mortem schizophrenia studies and other Disc1 mutant mouse models. Future research is required to determine the specific mechanisms underlying these cellular deficits. Overall, these findings provide further evidence that DISC1 participates in interneuron development and add to our understanding of how DISC1 variants can affect susceptibility to psychiatric illness. PMID- 23631737 TI - Mental illness in metropolitan, urban and rural Georgia populations. AB - BACKGROUND: Mental illness represents an important public health problem. Local level data concerning mental illness in different populations (e.g., socio demographics and residence--metropolitan/urban/rural) provides the evidence-base for public health authorities to plan, implement and evaluate control programs. This paper describes prevalence and covariates of psychiatric conditions in Georgia populations in three defined geographic areas. METHODS: Data came from the Georgia population-based random-digit-dialing study investigating unwellness and chronic fatigue syndrome (CFS) in Georgia populations of three defined geographic areas (metropolitan, urban, and rural). Respondents were screened for symptoms of fatigue, sleep, cognition, and pain at household screening interviews, and a randomly selected sample completed detailed individual phone interviews. Based on the detailed phone interviews, we conducted one-day clinical evaluations of 292 detailed interview participants classified as unwell with a probable CFS (i.e. CFS-like; a functional somatic syndrome), 268 classified as other unwell, and 223 well (matched to CFS-like). Clinical evaluation included psychiatric classification by means of the Structured Clinical Interview for DSM (SCID). To derive prevalence estimates we used sample weighting to account for the complexity of the multistage sampling design. We used 2- and 3-way table analyses to examine socio-demographic and urbanicity specific associations and multiple logistic regression to calculate adjusted odds ratios. RESULTS: Anxiety and mood disorders were the most common psychiatric conditions. Nineteen percent of participants suffered a current anxiety disorder, 18% a mood disorder and 10% had two or more conditions. There was a significant linear trend in occurrence of anxiety or mood disorders from well to CFS-like. The most common anxiety disorders were post-traumatic stress disorder (PTSD) (6.6%) and generalized anxiety disorder (GAD) (5.8%). Logistic regression showed that lower education and female sex contributed significantly to risk for both PTSD and GAD. In addition, rural/urban residence and Hispanic ethnicity were associated with PTSD. We defined moderate to severe depression as Major Depressive Disorder or a Zung score>60 and logistic regression found lower education to be significantly associated but sex, age and urbanicity were not. CONCLUSIONS: Overall occurrence of anxiety and mood disorders in Georgia mirrored national findings. However, PTSD and GAD occurred at twice the published national rates (3.6 and 2.7%, respectively). State and local prevalence and associations with education, sex and urbanicity comprise important considerations for developing control programs. The increased prevalence of anxiety and mood disorders in people with a functional somatic syndrome (or CFS-like illness) is important for primary care providers, who should consider additional psychiatric screening or referral of individuals presenting with somatoform symptoms. PMID- 23631738 TI - Detection of the valvular split within the second heart sound using the reassigned smoothed pseudo Wigner-Ville distribution. AB - BACKGROUND: In this paper, we developed a novel algorithm to detect the valvular split between the aortic and pulmonary components in the second heart sound which is a valuable medical information. METHODS: The algorithm is based on the Reassigned smoothed pseudo Wigner-Ville distribution which is a modified time frequency distribution of the Wigner-Ville distribution. A preprocessing amplitude recovery procedure is carried out on the analysed heart sound to improve the readability of the time-frequency representation. The simulated S2 heart sounds were generated by an overlapping frequency modulated chirp-based model at different valvular split durations. RESULTS: Simulated and real heart sounds are processed to highlight the performance of the proposed approach. The algorithm is also validated on real heart sounds of the LGB-IRCM (Laboratoire de Genie biomedical-Institut de recherches cliniques de Montreal) cardiac valve database. The A2-P2 valvular split is accurately detected by processing the obtained RSPWVD representations for both simulated and real data. PMID- 23631739 TI - "It feels so good it almost hurts": young adults' experiences of orgasm and sexual pleasure. AB - Orgasm is a "goal" of much sexual activity, and a source of potentially intense pleasure and fulfillment, yet can be fraught with difficulty or distress. Relatively little social science research has explored people's experiences around, and their meanings related to, orgasm, and indeed other sexual pleasures, especially with young adults. This study aimed to provide a rich exploration of the meanings associated with orgasm and sexual pleasure during sex with a partner, to understand the social patterning of orgasm experience. A qualitative survey was used to collect data from 119 sexually experienced British young adults (81% women, mean age 20, 92% heterosexual). A descriptive form of thematic analysis that prioritizes participants' meanings and experiences was used to identify and explore patterns in the data. Five main themes are reported here: (a) orgasm: the purpose and end of sex; (b) "it's more about my partner's orgasm"; (c) orgasm: the ultimate pleasure?; (d) orgasm is not a simple physiological response; and (e) faking orgasm is not uncommon. These (mostly not gendered) themes demonstrate the complex and contradictory meanings around orgasm, and reveal meaning to be dependent on situation and context. However, they do resonate strongly with widespread discourses of sexuality that prioritize heterosexual coitus, orgasm, and orgasm reciprocity. PMID- 23631740 TI - Rapid measurement of intracellular unbound drug concentrations. AB - Intracellular unbound drug concentrations determine affinity to targets in the cell interior. However, due to difficulties in measuring them, they are often overlooked in pharmacology. Here we present a simple experimental technique for the determination of unbound intracellular drug concentrations in cultured cells that is based on parallel measurements of cellular drug binding and steady-state intracellular drug concentrations. Binding in HEK293 cells was highly correlated with binding in liver-derived systems, whereas binding in plasma did not compare well with cellular binding. Compound lipophilicity increased drug binding, while negative charge and aromatic functional groups decreased binding. Intracellular accumulation of unbound drug was consistent with pH-dependent subcellular sequestration, as confirmed by modeling and by inhibition of subcellular pH gradients. The approach developed here can be used to measure intracellular unbound drug concentrations in more complex systems, for example, cell lines with controlled expression of transporters and enzymes or primary cells. PMID- 23631741 TI - Dissecting the complex recognition interfaces of potent tetrazole- and pyrrole based anion binders. AB - Tetrazoles are potent anion binders. We report here a new family of tetrazole pyrrole-amide hosts that arise when a tetrazole is incorporated as a new binding element alongside the well-known amidopyrrole anion-binding scaffold. In addition to reporting three new, modular synthetic routes that can be used to access these structures, we also report that the new hosts are highly potent binders of chloride. Along the way, we carried out studies of a pyrrole ester control compound that, surprisingly, bound anions almost as strongly as did the amide analogues. This led us to investigate further the relative importance of the amide NH in halide binding. We report that, despite the regular appearance of this close amide NH---Cl contact in calculated and experimental X-ray structures, the amide NH in this family of anion hosts does not hydrogen bond strongly to chloride in solution. PMID- 23631742 TI - High hydrostatic pressure-induced inactivation of bacterial spores. AB - High hydrostatic pressure (HHP) is the most-widely adopted novel non-thermal technology for the commercial pasteurization of foods. However, HHP-induced inactivation of bacterial spores remains a challenge due to spore resistance to the treatment limits of currently available industrial HHP units (i.e. ~650 MPa and 50 degrees C). Several reports have demonstrated that high pressure can modulate the germination machinery of bacterial spores, rendering them susceptible to subsequent inactivation treatments. Unfortunately, high pressure induced germination is a unique phenomenon for spores of the genus Bacillus but not of Clostridium. Alternative strategies to inactivate bacterial spores at commercially available pressure and temperature levels include promoting the germination step by inclusion of known germinants into the food formulation to increase the lethality of HHP treatments on bacterial spores. The aim of this review is to provide an overview of the molecular basis involved in pressure triggered germination of bacterial spores and of novel strategies to inactivate bacterial spores with HHP treatments. PMID- 23631743 TI - Overcoming resistance to mTOR inhibition for enhanced strategies in clinical trials. PMID- 23631744 TI - Elucidation of the biochemical basis for a clinical drug-drug interaction between atorvastatin and 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778875), a subtype selective agonist of the peroxisome proliferator activated receptor alpha. AB - 1. 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP 778875), an agonist of the peroxisome proliferator-activated receptor alpha, has been evaluated in the clinic to treat dyslipidemia and type 2 diabetes mellitus. Herein, we investigate the effect of CP-778875 on the pharmacokinetics of atorvastatin acid and its metabolites in humans. 2. The study incorporated a fixed-sequence design conducted in two groups. Group A was designed to estimate the effects of multiple doses of CP-778875 on the single dose pharmacokinetics of atorvastatin. Subjects in group A (n = 26) received atorvastatin (40 mg) on days 1 and 9 and CP-778875 (1.0 mg QD) on days 5-12. Group B was designed to examine the effects of multiple doses of atorvastatin on the single dose pharmacokinetics of CP-778875. Subjects in group B (n = 29) received CP-778875 (0.3 mg) on days 1 and 9 and atorvastatin (40 mg QD) on days 5-12. 3. Mean maximum serum concentration (Cmax) and area under the curve of atorvastatin were increased by 45% and 20%, respectively, upon co-administration with CP-778875. Statistically significant increases in the systemic exposure of ortho- and para hydroxyatorvastatin were also observed upon concomitant dosing with CP-778875. CP 778875 pharmacokinetics, however, were not impacted upon concomitant dosing with atorvastatin. 4. Inhibition of organic anion transporting polypeptide 1B1 by CP 778875 (IC50 = 2.14 +/- 0.40 MUM) could be the dominant cause of the pharmacokinetic interaction as CP-778875 did not exhibit significant inhibition of cytochrome P450 3A4/3A5, multidrug resistant protein 1 or breast cancer resistant protein, which are also involved in the hepatobiliary disposition of atorvastatin. PMID- 23631745 TI - Are reports of life event stress among suicidal youth subject to cognitive bias? AB - Severity of depressive symptoms, hopelessness, and suicidal ideation were examined to determine whether they were significantly associated with the accuracy of suicidal adolescents' ratings of stressful life events. The sample included 130 inpatient adolescents who endorsed suicide-related behaviors. Stress interviews were administered, and the severity of stressful events was rated separately by adolescents and an independent team. A residualized cognitive bias score was created by regressing adolescents' severity ratings to the independent team's severity ratings of the same events. Depressive symptoms, but not hopelessness or suicidal ideation, were significantly associated with cognitive bias scores. A negative cognitive bias in adolescents' reports of life stress may be present at higher levels of depression relative to minimal levels of depression. Further research on the relations between stress and suicide-related behaviors is encouraged to include independent ratings of stress severity. PMID- 23631746 TI - Necessity of keratinized tissues for dental implants: a clinical, immunological, and radiographic study. AB - BACKGROUND: Necessity of keratinized tissues (KTs) for maintaining health around dental implants (DIs) remains as a controversial issue. PURPOSE: The aim of this study was to investigate the effects of KT width (KTW) on peri-implant tissues by evaluating peri-implant clinical and inflammatory parameters. MATERIALS AND METHODS: Sixty DIs were included in this 6-month longitudinal study. After classifying DI based on the presence of KTs at the buccal aspect as with adequate/inadequate KTW, DIs were randomly assigned into three study groups. In the first group, while free gingival graft (FGG) was performed, DIs in maintenance (M) group were followed up by standardized maintenance procedures at baseline, first, third, and sixth months as with DI with adequate KTW (Control). Clinical parameters, peri-implant sulcular fluid (PISF) volume, PISF Interleukin 1beta concentration, and bone loss were analyzed. RESULTS: Significant improvements in clinical and immunological parameters were noted only for FGG for the whole study period. Statistical differences detected between the treatment groups (FGG vs M) were for gingival index at all time points and for PISF volume at sixth month. For the other parameters evaluated, while lower values were observed for FGG, statistically no differences were noted between the groups. CONCLUSIONS: Based on the results of this study, it can be suggested that FGG performed around DIs lacking KT is a reliable method, leading to significant improvements in clinical and inflammatory parameters. Further long-term studies including more DIs are needed to clarify the role of KT on maintenance of DIs. PMID- 23631747 TI - Atrial fibrillation in the elderly: to ablate or not to ablate. PMID- 23631748 TI - Associations between affect, context, and sexual desire in depressed young women. AB - We investigated associations of sexual desire with time of day, physical and social context, and positive and negative affect using momentary sampling in 44 depressed young women (mean age = 18). Analyses revealed that depressed young women experienced sexual desire when with their boyfriends and later in the evening. Sexual desire was also positively associated with positive affect. Sexual desire was not associated with negative affect or physical context. This research suggests that sexual desire is experienced by depressed young women in normative developmental social contexts. Our findings may help clinicians and sexual health educators in correcting the myth that depressed women do not have sexual desire. PMID- 23631749 TI - Electronic measurements of single-molecule catalysis by cAMP-dependent protein kinase A. AB - Single-molecule studies of enzymes open a window into their dynamics and kinetics. A single molecule of the catalytic domain of cAMP-dependent protein kinase A (PKA) was attached to a single-walled carbon nanotube device for long duration monitoring. The electronic recording clearly resolves substrate binding, ATP binding, and cooperative formation of PKA's catalytically functional, ternary complex. Using recordings of a single PKA molecule extending over 10 min and tens of thousands of binding events, we determine the full transition probability matrix and conversion rates governing formation of the apo, intermediate, and closed enzyme configurations. We also observe kinetic rates varying over 2 orders of magnitude from one second to another. Anti-correlation of the on and off rates for PKA binding to the peptide substrate, but not ATP, demonstrates that regulation of enzyme activity results from altering the stability of the PKA substrate complex, not its binding to ATP. The results depict a highly dynamic enzyme offering dramatic possibilities for regulated activity, an attribute useful for an enzyme with crucial roles in cell signaling. PMID- 23631750 TI - Multicenter implementation of a severe sepsis and septic shock treatment bundle. AB - RATIONALE: Severe sepsis and septic shock are leading causes of intensive care unit (ICU) admission, morbidity, and mortality. The effect of compliance with sepsis management guidelines on outcomes is unclear. OBJECTIVES: To assess the effect on mortality of compliance with a severe sepsis and septic shock management bundle. METHODS: Observational study of a severe sepsis and septic shock bundle as part of a quality improvement project in 18 ICUs in 11 hospitals in Utah and Idaho. MEASUREMENTS AND MAIN RESULTS: Among 4,329 adult subjects with severe sepsis or septic shock admitted to study ICUs from the emergency department between January 2004 and December 2010, hospital mortality was 12.1%, declining from 21.2% in 2004 to 8.7% in 2010. All-or-none total bundle compliance increased from 4.9-73.4% simultaneously. Mortality declined from 21.7% in 2004 to 9.7% in 2010 among subjects noncompliant with one or more bundle element. Regression models adjusting for age, severity of illness, and comorbidities identified an association between mortality and compliance with each of inotropes and red cell transfusions, glucocorticoids, and lung-protective ventilation. Compliance with early resuscitation elements during the first 3 hours after emergency department admission caused ineligibility, through lower subsequent severity of illness, for these later bundle elements. CONCLUSIONS: Total severe sepsis and septic shock bundle compliances increased substantially and were associated with a marked reduction in hospital mortality after adjustment for age, severity of illness, and comorbidities in a multicenter ICU cohort. Early resuscitation bundle element compliance predicted ineligibility for subsequent bundle elements. PMID- 23631752 TI - Re: Predictors of immediate continence following robot-assisted radical prostatectomy (From: Sammon JD, Sharma P, Trinh, QD, et al. J Endourol 2013;27:442-446). PMID- 23631751 TI - Low erythrocyte catalase enzyme activity is correlated with high serum total homocysteine levels in Tunisian patients with acute myocardial infarction. AB - BACKGROUND: An imbalance between pro-oxidants and antioxidant systems has been suggested to be implicated in the physiopathology of acute myocardial infarction (AMI). We aimed to evaluate the antioxidant capacity in Tunisian patients and to assess the possible relationship between erythrocyte catalase enzyme activity and hyperhomocysteinaemia. METHODS: 108 patients with AMI and 81 healthy subjects were enrolled in this study. Catalase erythrocyte enzyme activity was determined spectrophotometrically whereas "total antioxidant status" (TAS) concentration was measured by a commercially available method. Serum total homocysteine (tHcy) level was determined by a fluorescence polarization immunoassay (FPIA). Lipid peroxidation was measured with a fluorimetric method as "thiobarbituric acid reactive substances" (TBARS). RESULTS: Compared with healthy subjects, patients with AMI had significantly lower catalase activity (P<0.001), TAS concentrations (P<0.001), and significantly higher serum tHcy (P<0.001) and TBARS levels (P<0.001). Erythrocyte catalase enzyme activity was negatively correlated with serum tHcy and TBARS while serum tHcy and TBARS were in positive correlation. Furthermore, the unbalance between pro-oxidants and antioxidants seems to be more aggravated in patients with Q wave AMI compared to patients with non-Q wave AMI. CONCLUSION: Our results suggest the involvement of hyperhomocysteinaemia in the drop of erythrocyte catalase activity related to myocardial ischemia reperfusion. Hyperhomocysteinaemia may increase the myocardial wall dysfunction under ischemia reperfusion by excessive production of reactive oxygen species which is made evident by increased lipid peroxidation. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1623509866881834. PMID- 23631753 TI - Synthesis and evaluation of polymeric gold glyco-conjugates as anti-cancer agents. AB - The antitumor activity of organo-gold compounds is a focus of research from the past two decades. A variety of gold stabilizing ligands such as vitamins and xanthanes have been prepared and explored for their 'chelating effect' as well as for their antitumor activity. Dithiocarbamates (DTC) compounds and their metallic conjugates have been well explored for their antiproliferative activities. In this study, glycopolymer based DTC-conjugates are prepared by reversible addition fragmentation chain transfer polymerization (RAFT) and subsequently modified with gold(I) phosphine. These polymer-DTC derivatives and their gold compounds are tested for their in vitro toxicity in both normal and cancer cell lines. The Au(I) phosphine conjugated cationic glycopolymers of 10 kDa and 30 kDa are evaluated for their cytotoxicity profiles using MTT assay. Au(I) compounds are well-known for their mitochondrial toxicity, hence hypoxic cell lines bearing unusually enlarged mitochondria are subjected to these anticancer compounds. It is concluded that these polymeric DTC derivatives and their gold conjugates indeed show higher accumulation as well as cytotoxicity to cancer cells under hypoxic conditions in comparison to the normoxic ones. Hypoxic MCF-7 cells showed significant sensitivity toward the low molecular weight (10 kDa) glycopolymer Au(I) complexes. PMID- 23631754 TI - Agreement between weight bearing and non-weight bearing joint position replication tasks at the knee and hip. AB - Peak joint angles assumed during the stance phase of running may indicate a runner's ability to sense limb position in space. Joint position sense can be assessed through weight bearing and non-weight bearing tasks. The purpose of this investigation was to determine if weight bearing and non-weight bearing knee and hip joint replication tasks elicited similar joint position sense test results. Absolute replication error was measured during sagittal plane knee and frontal plane hip conditions on 23 healthy runners. Three-dimensional kinematics was recorded during running. Intraclass correlation coefficients (ICCs) determined agreement between the two measures of joint position sense. Pearson's correlation coefficients measured the relationship between hip and knee absolute error and peak joint angles during running. Despite similar mean absolute error, ICCs indicated low agreement between weight bearing and non-weight bearing conditions at each joint. The results indicate the tests are not interchangeable. Absolute error for non-weight bearing hip replication was correlated with peak stance hip adduction during running. Weight bearing and non-weight bearing joint position sense tasks within the knee and hip joints measure joint position sense differently. Therefore, a task that is relevant to the activity of interest should be selected to measure joint position sense. PMID- 23631755 TI - Structural, kinetic, and pharmacodynamic mechanisms of D-amino acid oxidase inhibition by small molecules. AB - We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (Kd ~ 2-4 MUM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (Kd ~ 100-200 nM) and slow release kinetics (k < 0.01 s(-1)) in the presence of substrate, while inhibitors with pendent aromatic groups altered conformations of the active site lid, as evidenced by X-ray crystallography, and showed slower kinetics of association. Rigid bioisosteres of benzoic acid induced a closed-lid conformation, had slower release in the presence of substrate, and were more potent than benzoate. Steady-state d-serine concentrations were described in a PK/PD model, and competition for d-serine sites on NMDA receptors was demonstrated in vivo. DAAO inhibition increased the spatiotemporal influence of glial-derived d-serine, suggesting localized effects on neuronal circuits where DAAO can exert a neuromodulatory role. PMID- 23631756 TI - Atrial flutter following pulmonary vein isolation: what is the mechanism? AB - A 70-year-old man with atrial flutter (AFL) following pulmonary vein (PV) isolation (PVI) underwent electrophysiologic testing. The AFL exhibited positive P waves in the inferior leads and lead V1. Left atrial activation mapping revealed 2 remote sites with early activation that were located at the antrum of the left superior PV roof and the left inferior PV bottom. A single irrigated radiofrequency ablation targeting the earliest PV activation at the left PV carina eliminated the AFL. This case demonstrated that PV carina tachycardia with multiple conduction gaps and inter-PV conduction after PVI might mimic double focal atrial tachycardias. PMID- 23631757 TI - Substituent effects and pH profiles for stability constants of arylboronic acid diol esters. AB - Stability constants of boronic acid diol esters in aqueous solution have been determined potentiometrically for a series of meta-, para-substituted phenylboronic acids and diols of variable acidity. The constants beta(11-1) for reactions between neutral forms of reactants producing the anionic ester plus proton follow the Hammett equation with rho depending on pKa of diol and varying from 2.0 for glucose to 1.29 for 4-nitrocatechol. Observed stability constants (K(obs)) measured by UV-vis and fluorometric titrations at variable pH for esters of 4,5-dihydroxy-1,3-benzenedisulfonate (Tiron) generally agree with those expected on the basis of beta(11-1) values, but the direct fitting of K(obs) vs pH profiles gives shifted pKa values both for boronic acids and diol as a result of significant interdependence of fitting parameters. The subsituent effects on absorption and fluorescence spectra of Tiron arylboronate esters are characterized. The K(obs) for Tiron determined by (11)B NMR titrations are approximately 1 order of magnitude smaller than those determined by UV-vis titrations under identical conditions. A general equation, which makes possible an estimate of beta(11-1) for any pair of boronic acid and diol from their pKa values, is proposed on the basis of established Bronsted-type correlation of Hammett parameters for beta(11-1) with acidity of diols. The equation allows one to calculate stability constants expected only on basis of acid-base properties of the components, thus permitting more strict evaluation of contributions of additional factors such as steric or charge effects to the ester stability. PMID- 23631758 TI - Association between serum uric acid levels and cardiovascular risk among university workers from the State of Mexico: a nested case-control study. AB - BACKGROUND: Recent evidence suggests that serum uric acid (SUA) can be an inexpensive and easy-to-obtain indicator of cardiovascular risk (CR). This is especially important in developing countries with high prevalence of cardiovascular disease. We examined the association between SUA levels and 10 year global CR among university workers from the State of Mexico, Mexico. METHODS: A case-control study nested within a cohort was conducted between 2004 and 2006. Anthropometric measures, lifestyle variables, family background and CR factors were assessed. The analysis estimated odds ratios using conditional logistic regression. RESULTS: The study included 319 cases with CR and 638 controls. Subjects in the upper tertile of SUA had 48.0% higher odds of having an elevated CR than those in the lower tertile (OR = 1.48, 95% CI: 1.04-2.10) in the crude analysis, but the association was non-significant when adjusting for other covariates. Among physically inactive individuals, being in the third tertile of SUA doubled the odds of high CR, compared with those who perform physical activity three or more hours per week being in the first tertile of SUA (OR = 2.35, 95% CI: 1.24-4.45). CONCLUSION: Serum concentration of uric acid is associated with 10-year global CR among individuals with high levels of physical inactivity. PMID- 23631759 TI - Identification of Lens culinaris defense genes responsive to the anthracnose pathogen Colletotrichum truncatum. AB - BACKGROUND: Anthracnose of lentil, caused by the hemibiotrophic fungal pathogen Colletotrichum truncatum is a serious threat to lentil production in western Canada. Colletotrichum truncatum employs a bi-phasic infection strategy characterized by initial symptomless biotrophic and subsequent destructive necrotrophic colonization of its host. The transition from biotrophy to necrotrophy (known as the biotrophy-necrotrophy switch [BNS]) is critical in anthracnose development. Understanding plant responses during the BNS is the key to designing a strategy for incorporating resistance against hemibiotrophic pathogens either via introgression of resistance genes or quantitative trait loci contributing to host defense into elite cultivars, or via incorporation of resistance by biotechnological means. RESULTS: The in planta BNS of C. truncatum was determined by histochemical analysis of infected lentil leaf tissues in time course experiments. A total of 2852 lentil expressed sequence tags (ESTs) derived from C. truncatum-infected leaf tissues were analyzed to catalogue defense related genes. These ESTs could be assembled into 1682 unigenes. Of these, 101 unigenes encoded membrane and transport associated proteins, 159 encoded proteins implicated in signal transduction and 387 were predicted to be stress and defense related proteins (GenBank accessions: JG293480 to JG293479). The most abundant class of defense related proteins contained pathogenesis related proteins (encoded by 125 ESTs) followed by heat shock proteins, glutathione S-transferase, protein kinases, protein phosphatase, zinc finger proteins, peroxidase, GTP binding proteins, resistance proteins and syringolide-induced proteins. Quantitative RT-PCR was conducted to compare the expression of two resistance genes of the NBS-LRR class in susceptible and partially resistant genotypes. One (contig186) was induced 6 days post-inoculation (dpi) in a susceptible host genotype (Eston) whereas the mRNA level of another ( LT21-1990) peaked 4 dpi in a partially resistant host genotype (Robin), suggesting roles in conditioning the susceptibility and conferring tolerance to the pathogen, respectively. CONCLUSIONS: Data obtained in this study suggest that lentil cells recognize C. truncatum at the BNS and in response, mount an inducible defense as evident by a high number of transcripts (23% of the total pathogen-responsive lentil transcriptome) encoding defense related proteins. Temporal expression polymorphism of defense related genes could be used to distinguish the response of a lentil genotype as susceptible or resistant. PMID- 23631760 TI - Simultaneous determination by LC-MS/MS of 25-methoxydammarane-3beta,12beta,20 triol epimers and active metabolites in rat plasma after intravenous administration. AB - 1. The pharmacokinetics of the 25-OCH3-PPD epimers and active metabolites in rat plasma after a single intravenous (i.v.) administration were studied by a rapid, selective and sensitive UPLC-MS/MS method. 2. Chromatographic separation was performed on an Acquity UPLC with Agela C18 column, and the solvents of 5 mM ammonium acetate (pH 7.8) - acetonitrile (65: 35, v/v) were used as mobile phase for elution. The quantification was performed with the transitions of m/z 493.5 > 475.5 for 20(R,S)-25-OCH3-PPD, m/z 479.5 -> 461.5 for 20(R,S)-25-OH-PPD. The Lower Limit Of Quantitation (LLOQ) was 20.0 ng mL(-1) for 20(R,S)-25-OCH3-PPD, 2.0 ng mL(-1) for 20(R,S)-25-OH-PPD in the plasma samples assay. 3. The pharmacokinetic parameters of AUC, t1/2 and MRT had no difference between 20(R)- and (S)-25-OCH3-PPD, but S-epimer has a lower plasma clearance compared to the R isomer. The active metabolite 20(S)-25-OH-PPD showed significantly higher AUC, MRT and a longer half-life than that of 20(R)-25-OH-PPD. These assay results are necessary for the evaluation of the pharmacokinetic behavior of 25 methoxydammarane-3beta,12beta,20-triol in vivo. PMID- 23631761 TI - Electronic measurements of single-molecule processing by DNA polymerase I (Klenow fragment). AB - Bioconjugating single molecules of the Klenow fragment of DNA polymerase I into electronic nanocircuits allowed electrical recordings of enzymatic function and dynamic variability with the resolution of individual nucleotide incorporation events. Continuous recordings of DNA polymerase processing multiple homopolymeric DNA templates extended over 600 s and through >10,000 bond-forming events. An enzymatic processivity of 42 nucleotides for a template of the same length was directly observed. Statistical analysis determined key kinetic parameters for the enzyme's open and closed conformations. Consistent with these nanocircuit-based observations, the enzyme's closed complex forms a phosphodiester bond in a highly efficient process >99.8% of the time, with a mean duration of only 0.3 ms for all four dNTPs. The rate-limiting step for catalysis occurs during the enzyme's open state, but with a nearly 2-fold longer duration for dATP or dTTP incorporation than for dCTP or dGTP into complementary, homopolymeric DNA templates. Taken together, the results provide a wealth of new information complementing prior work on the mechanism and dynamics of DNA polymerase I. PMID- 23631763 TI - Charge delocalization through benzene, naphthalene, and anthracene bridges in pi conjugated oligomers: an experimental and quantum chemical study. AB - To understand the influence of orthogonal conjugation pathways fused directly to pi-conjugated polymer backbones, we synthesized and studied three series of thiophene-based model compounds containing benzene, naphthalene, and anthracene peri-substituted central cores as representative acenes. These models were functionalized with methyl groups at the reactive thiophene positions in order to generate and observe oxidized species without complications from follow-up polymerization. The neutral monomers and their oxidized charged counterparts were subjected to cyclic voltammetry, spectroelectrochemistry, and EPR spectroscopy as appropriate, and these results were further corroborated with thorough density functional theory studies. This joint experimental and theoretical analysis allowed us to determine that benzene-based conjugated linkers led to more delocalized charge carriers on account of the quinoidal character maintained within the benzene core. In contrast, anthracene-based linkers displayed very localized carriers due to torsional strain between the adjacent aryl groups and to the local evolution of formal aromatic sextets on the benzo-fused rings orthogonal to the backbone in the quinoidal state. In some cases, the electronics of the thiophene-based substituent dominated the electronic properties of the oxidized species regardless of the nature of the central acene linker. These results highlight the dramatic influence that orthogonal conjugation pathways can exert on the electronic properties of pi-conjugated materials. PMID- 23631762 TI - Genotyping analysis and 18FDG uptake in breast cancer patients: a preliminary research. AB - BACKGROUND: Diagnostic imaging plays a relevant role in the care of patients with breast cancer (BC). Positron Emission Tomography (PET) with 18F-fluoro-2-deoxy-D glucose (FDG) has been widely proven to be a clinical tool suitable for BC detection and staging in which the glucose analog supplies metabolic information about the tumor. A limited number of studies, sometimes controversial, describe possible associations between FDG uptake and single nucleotide polymorphisms (SNPs). For this reason this field has to be explored and clarified. We investigated the association of SNPs in GLUT1, HIF-1a, EPAS1, APEX1, VEGFA and MTHFR genes with the FDG uptake in BC. METHODS: In 26 caucasian individuals with primary BC, whole-body PET-CT scans were obtained and quantitative analysis was performed by calculating the maximum Standardized Uptake Value normalized to body weight (SUVmax) and the mean SUV normalized to body-weight corrected for partial volume effect (SUVpvc). Human Gene Mutation Database and dbSNP Short Genetic Variations database were used to analyze gene regions containing the selected SNPs. Patient genotypes were obtained using Sanger DNA sequencing analysis performed by Capillary Electrophoresis. RESULTS: BC patients were genotyped for the following nine SNPs: GLUT1: rs841853 and rs710218; HIF-1a: rs11549465 and rs11549467; EPAS1: rs137853037 and rs137853036; APEX1: rs1130409; VEGFA: rs3025039 and MTHFR: rs1801133. In this work correlations between the nine potentially useful polymorphisms selected and previously suggested with tracer uptake (using both SUVmax and SUVpvc) were not found. CONCLUSIONS: The possible functional influence of specific SNPs on FDG uptake needs further studies in human cancer. In summary, this is the first pilot study, to our knowledge, which investigates the association between a large panel of SNPs and FDG uptake specifically in BC patients. This work represents a multidisciplinary and translational medicine approach to study BC where, the possible correlation between SNPs and tracer uptake, may be considered to improve personalized cancer treatment and care. PMID- 23631765 TI - Melting lizards and crying mailboxes: children's preferential recall of minimally counterintuitive concepts. AB - Previous research with adults suggests that a catalog of minimally counterintuitive concepts, which underlies supernatural or religious concepts, may constitute a cognitive optimum and is therefore cognitively encoded and culturally transmitted more successfully than either entirely intuitive concepts or maximally counterintuitive concepts. This study examines whether children's concept recall similarly is sensitive to the degree of conceptual counterintuitiveness (operationalized as a concept's number of ontological domain violations) for items presented in the context of a fictional narrative. Seven- to nine-year-old children who listened to a story including both intuitive and counterintuitive concepts recalled the counterintuitive concepts containing one (Experiment 1) or two (Experiment 2), but not three (Experiment 3), violations of intuitive ontological expectations significantly more and in greater detail than the intuitive concepts, both immediately after hearing the story and 1 week later. We conclude that one or two violations of expectation may be a cognitive optimum for children: They are more inferentially rich and therefore more memorable, whereas three or more violations diminish memorability for target concepts. These results suggest that the cognitive bias for minimally counterintuitive ideas is present and active early in human development, near the start of formal religious instruction. This finding supports a growing literature suggesting that diverse, early-emerging, evolved psychological biases predispose humans to hold and perform religious beliefs and practices whose primary form and content is not derived from arbitrary custom or the social environment alone. PMID- 23631764 TI - Effect of kefir and low-dose aspirin on arterial blood pressure measurements and renal apoptosis in unhypertensive rats with 4 weeks salt diet. AB - Abstract We aim to study the effect of low-dose aspirin and kefir on arterial blood pressure measurements and renal apoptosis in unhypertensive rats with 4 weeks salt diet. Forty adult male Sprague-Dawley rats were divided into five groups: control, high-salt (HS) (8.0% NaCl), HS+aspirin (10 mg/kg), HS+kefir (10.0%w/v), HS+aspirin +kefir. We measured sistolic blood pressure (SBP), mean arterial pressure (MAP), diastolic pressure, pulse pressure in the rats. Cathepsin B, L, DNA fragmentation and caspase-3 activities were determined from rat kidney tissues and rats clearance of creatinine calculated. Although HS diet increased significantly SBP, MAP, diastolic pressure, pulse pressure parameters compared the control values. They were not as high as accepted hypertension levels. When compared to HS groups, kefir groups significantly decrease Cathepsin B and DNA fragmentation levels. Caspase levels were elevated slightly in other groups according to control group. While, we also found that creatinine clearance was higher in HS+kefir and HS+low-dose aspirin than HS group. Thus, using low dose aspirin had been approximately decreased of renal function damage. Kefir decreased renal function damage playing as Angiotensin-converting enzyme inhibitor. But, low-dose aspirin together with kefir worsened rat renal function damage. Cathepsin B might play role both apoptosis and prorenin-processing enzyme. But not caspase pathway may be involved in the present HS diet induced apoptosis. In conclusion, kefir and low-dose aspirin used independently protect renal function and renal damage induced by HS diet in rats. PMID- 23631766 TI - Phytostimulation of poplars and Arabidopsis exposed to silver nanoparticles and Ag+ at sublethal concentrations. AB - The increasing likelihood of silver nanoparticle (AgNP) releases to the environment highlights the importance of understanding AgNP interactions with plants, which are cornerstones of most ecosystems. In this study, poplars (Populus deltoides * nigra) and Arabidopsis thaliana were exposed hydroponically to nanoparticles of different sizes (PEG-coated 5 and 10 nm AgNPs, and carbon coated 25 nm AgNPs) or silver ions (Ag(+), added as AgNO3) at a wide range of concentrations (0.01 to 100 mg/L). Whereas all forms of silver were phytotoxic above a specific concentration, a stimulatory effect was observed on root elongation, fresh weight, and evapotranspiration of both plants at a narrow range of sublethal concentrations (e.g., 1 mg/L of 25 nm AgNPs for poplar). Plants were most susceptible to the toxic effects of Ag(+) (1 mg/L for poplar, 0.05 mg/L for Arabidopsis), but AgNPs also showed some toxicity at higher concentrations (e.g., 100 mg/L of 25 nm AgNPs for poplar, 1 mg/L of 5 nm AgNPs for Arabidopsis) and this susceptibility increased with decreasing AgNP size. Both poplars and Arabidopsis accumulated silver, but silver distribution in shoot organs varied between plant species. Arabidopsis accumulated silver primarily in leaves (at 10 fold higher concentrations than in the stem or flower tissues), whereas poplars accumulated silver at similar concentrations in leaves and stems. Within the particle subinhibitory concentration range, silver accumulation in poplar tissues increased with exposure concentration and with smaller AgNP size. However, compared to larger AgNPs, the faster silver uptake associated with smaller AgNPs was offset by their toxic effect on evapotranspiration, which was exerted at lower concentrations (e.g., 1 mg/L of 5 nm AgNPs for poplar). Overall, the observed phytostimulatory effects preclude generalizations about the phytotoxicity of AgNPs and encourage further mechanistic research. PMID- 23631768 TI - Assessment of toxic potential of primary and secondary particulates/aerosols from biodiesel vis-a-vis mineral diesel fuelled engine. AB - Toxicity of engine out emissions from primary and secondary aerosols has been a major cause of concern for human health and environmental impact. This study aims to evaluate comparative toxicity of nanoparticles emitted from a modern common rail direct injection engine (CRDI) fuelled with biodiesel blend (B20) vis-a-vis mineral diesel. The toxicity and potential health hazards of exhaust particles were assessed using various parameters such as nanoparticle size and number distribution, surface area distribution, elemental and organic carbon content and polycyclic aromatic hydrocarbons adsorbed onto the particle surfaces, followed by toxic equivalent factor assessment. It was found that biodiesel particulate toxicity was considerably lower in comparison to mineral diesel. PMID- 23631767 TI - Gold nanoparticles as a vaccine platform: influence of size and shape on immunological responses in vitro and in vivo. AB - This paper demonstrates how the shape and size of gold nanoparticles (AuNPs) affect immunological responses in vivo and in vitro for the production of antibodies for West Nile virus (WNV). We prepared spherical (20 and 40 nm in diameter), rod (40 * 10 nm), and cubic (40 * 40 * 40 nm) AuNPs as adjuvants and coated them with WNV envelope (E) protein. We measured anti-WNVE antibodies after inoculation of these WNVE-coated AuNPs (AuNP-Es) into mice. The 40 nm spherical AuNP-Es (Sphere40-Es) induced the highest level of WNVE-specific antibodies, while rod AuNP-Es (Rod-Es) induced only 50% of that of Sphere40-E. To examine the mechanisms of the shape-dependent WNVE antibody production, we next measured the efficiency of cellular uptake of AuNP-Es into RAW264.7 macrophage cells and bone marrow-derived dendritic cells (BMDCs) and the subsequent cytokine secretion from BMDCs. The uptake of Rod-Es into the cells proceeded more efficiently than those of Sphere-Es or cubic WNVE-coated AuNPs (Cube-Es), suggesting that antibody production was not dependent on the uptake efficiency of the different AuNP-Es. Cytokine production from BMDCs treated with the AuNP-Es revealed that only Rod-E treated cells produced significant levels of interleukin-1beta (IL-1beta) and interleukin-18 (IL-18), indicating that Rod-Es activated inflammasome-dependent cytokine secretion. Meanwhile, Sphere40-Es and Cube-Es both significantly induced inflammatory cytokine production, including tumor necrosis factor-alpha (TNF alpha), IL-6, IL-12, and granulocyte macrophage colony-stimulating factor (GM CSF). These results suggested that AuNPs are effective vaccine adjuvants and enhance the immune response via different cytokine pathways depending on their sizes and shapes. PMID- 23631769 TI - Synthetic ion channels. AB - The objective of this historical review is to recall the development of the field of synthetic ion channels over the past three decades. The most inspiring and influential breakthroughs with regard to structure and function are brought together to give the general reader an easily accessible understanding of the field. Pioneering work in the 1980s is followed by the golden age in the 1990s with structures emphasizing crown ethers, calixarenes, and peptide mimetics. Following the emergence of questions concerning specific functions such as ion selectivity, voltage gating, ligand gating and blockage, and with pi-stacks, metal-organic scaffolds, and DNA origami, a new wave of innovative structures has emerged. The perspectives outline promising directions and major challenges waiting to be addressed. PMID- 23631770 TI - The midline mandibular lingual canal: importance in implant surgery. AB - PURPOSE: The study aims to determine if midline mandibular dental implants pose a risk for the midline lingual canal (MLC). MATERIALS AND METHODS: Cone beam computed tomography was used to scan 122 mandibles (31 black males; 28 black females; 32 white males and 31 white females). Midsagittal sections in the reconstructed images were made. A measurement of 6 mm across bucco-lingually was delineated as the minimum dimensions for implant placement. In dentate cases with a bucco-lingual distance in excess of 6 mm, the measurement was across the apex of the socket to determine the bone dimension available below the socket for implant placement. From these markers a vertical line was dropped to the MLC to measure the available bone. RESULTS: The MLC was a consistent finding. A statistical significant difference in bone availability among the sexes and dentition pattern was found, indicating that midline implants in edentulous females posed a risk of injury to the vessels of the MLC. CONCLUSION: Implants in the position of lower central incisors are regarded as a safe procedure. Clinicians should however take note of the position of the midline mandibular lingual canal and approach this area with caution, especially if the alveolar ridge is to be reduced before implant placement. PMID- 23631771 TI - A spectral analysis of team dynamics and tactics in Brazilian football. AB - The purposes of this study were to characterise the total space covered and the distances between players within teams over ten Brazilian First Division Championship matches. Filmed recordings, combined with a tracking system, were used to obtain the trajectories of the players (n = 277), before and after half time. The team surface area (the area of the convex hull formed by the positions of the players) and spread (the Frobenius norm of the distance-between-player matrix) were calculated as functions of time. A Fast Fourier Transform (FFT) was applied to each time series. The median frequency was then calculated. The results of the surface area time series median frequencies for the first half (0.63 +/- 0.10 cycles . min-1) were significantly greater (P < 0.01) than the second-half values (0.47 +/- 0.14 cycles . min-1). Similarly, the spread variable median frequencies for the first half (0.60 +/- 0.14 cycles . min-1) were significantly greater (P < 0.01) than the second-half values (0.46 +/- 0.16 cycles . min-1). The median frequencies allowed the characterisation of the time series oscillations that represent the speed at which players distribute and then compact their team formation during a match. This analysis can provide insights that allow coaches to better control the team organisation on the pitch. PMID- 23631773 TI - Standards and classification: a perspective on the 'obesity epidemic'. AB - In this paper I critique the increasing standardization of obesity. Specifically, I consider two 'definitional turns': the way language has been standardized to such an extent that it obscures uncertainty and variation, and the appearance of objectivity through quantification and standardized measurement. These, I suggest, have fostered a simplified picture of obesity, promoting the classification of weight and thereby facilitating the emergence of the 'obesity epidemic'. These definitional turns fail to acknowledge the distinctions between fat and mass and intraclass variation within weight categories. A consequence of this process of simplification has been the erroneous application of population level information to individuals in a clinical context, with potentially harmful results. PMID- 23631772 TI - "Eyes that don't see, heart that doesn't feel": coping with sex work in intimate relationships and its implications for HIV/STI prevention. AB - Partner communication about HIV sexual risk behaviors represents a key area of epidemiologic and social importance in terms of infection acquisition and potential for tailored interventions. Nevertheless, disclosing sexual risk behaviors often presents myriad challenges for marginalized couples who engage in stigmatized behaviors. Using qualitative data from a social epidemiology study of risk for HIV and other sexually transmitted infections (STIs) among female sex workers and their intimate, non-commercial male partners along the Mexico-U.S. border, we examined both partners' perspectives on sex work and the ways in which couples discussed associated HIV/STI risks in their relationship. Our thematic analysis of individual and joint interviews conducted in 2010 and 2011 with 44 couples suggested that broader contexts of social and economic inequalities profoundly shaped partner perspectives of sex work. Although couples accepted sex work as an economic contribution to the relationship in light of limited alternatives and drug addiction, it exacted an emotional toll on both partners. Couples employed multiple strategies to cope with sex work, including psychologically disconnecting from their situation, telling "little lies," avoiding the topic, and to a lesser extent, superficially discussing their risks. While such strategies served to protect both partners' emotional health by upholding illusions of fidelity and avoiding potential conflict, non-disclosure of risk behaviors may exacerbate the potential for HIV/STI acquisition. Our work has direct implications for designing multi-level, couple-based health interventions. PMID- 23631774 TI - How institutional change and individual researchers helped advance clinical guidelines in American health care. AB - Clinical guidelines are important tools for managing health care quality. Research on the origins of guidelines primarily focuses on the institutional causes of their emergence and growth. Individual medical researchers, however, have played important roles. This paper develops knowledge of the role of individual medical researchers in advancing guidelines, and of how researchers' efforts were enabled or constrained by broader institutional changes. Drawing on an analytical case study focused on the role of Kerr White, John Wennberg, and Robert Brook, it shows that guidelines were a product of the interplay between institutional change in the medical field and actions by individual researchers, acting as institutional entrepreneurs. Increased government involvement in the health care field triggered the involvement of a range of new actors in health care. These new organizations created a context that allowed individual researchers to advance guidelines by creating job opportunities, providing research funding, and creating opportunities for researchers to engage with the policy process. Individual researchers availed of this context to both advance their ideas, and to draw new actors into the field. PMID- 23631775 TI - Interactive effects of social support and social conflict on medication adherence in multimorbid older adults. AB - With increasing age and multimorbidity, medication regimens become demanding, potentially resulting in suboptimal adherence. Social support has been discussed as a predictor of adherence, but previous findings are inconsistent. The study examines general social support, medication-specific social support, and social conflict as predictors of adherence at two points in time (6 months apart) to test the mobilization and social conflict hypotheses. A total of 309 community dwelling multimorbid adults (65-85 years, mean age 73.27, 41.7% women; most frequent illnesses: hypertension, osteoarthritis and hyperlipidemia) were recruited from the population-representative German Ageing Survey. Only medication-specific support correlated with adherence. Controlling for baseline adherence, demographics, physical fitness, medication regimen, and attitude, Time 1 medication-specific support negatively predicted Time 2 adherence, and vice versa. The negative relation between earlier medication-specific support and later adherence was not due to mobilization (low adherence mobilizing support from others, which over time would support adherence). Social conflict moderated the medication-specific support to adherence relationship: the relationship became more negative, the more social conflict participants reported. Presence of social conflict should be considered when received social support is studied, because well-intended help might have the opposite effect, when it coincides with social conflict. PMID- 23631776 TI - The world as the new local clinic: a critical analysis of three discourses of global medical competency. AB - The effects of globalization on health are the focus of administrators, educators, policy makers and researchers as they work to consider how best to train and regulate health professionals to practice in a globalized world. This study explores what happens to constructs such as medical competence when the context of medical practice is discursively expanded to include the whole world. An archive of texts was assembled (1970-2011) totaling 1100 items and analyzed using a governmentality approach. Texts were included that articulated rationales for pursuing global education activities, and/or that implicitly or explicitly took a position on medical competencies in relation to practicing medicine in international or culturally diverse contexts, or in dealing with health issues as global concerns. The analysis revealed three distinct visions, representative of a primarily western mentality, for preparing physicians to practice in a globalized world: the universal global physician, the culturally versed global physician and the global physician advocate. Each has its own epistemological relationship to globalization and is supported by an evidence base. All three discourses are active and productive, sometimes within the same context. However, the discourse of the universal global physician is currently the most established. The challenge to policy makers and educators in evolving regulatory frameworks and curricula that are current and relevant necessitates a better understanding of the socio-political effects of globalization on medical education, and the ethical, political, cultural and scientific issues underlying efforts to prepare students to practice competently in a globalized world. PMID- 23631777 TI - Family structure, victimization, and child mental health in a nationally representative sample. AB - Utilizing the 2008 National Survey of Children's Exposure to Violence (NatSCEV), the current study compares past year rates of 7 forms of child victimization (maltreatment, assault, peer victimization, property crime, witnessing family violence and exposure to community violence) across 3 different family structure types (two biological/adoptive parents, single parent, step/cohabiting family) among a representative sample of 4046 U.S. children ages 2-17. The study also considers whether certain social-contextual risk factors help to explain family structure variations in victimization, and the extent to which victimization exposure accounts for family structure differences in distress symptom levels. Findings showed significantly elevated rates of almost all types of victimization among children in both nontraditional family types, relative to those living with two biological/adoptive parents. Factors associated with increased victimization risk in these families include high parental conflict, drug or alcohol problems, family adversity, and community disorder. A summary measure of children's exposure to multiple forms of victimization was the strongest predictor of distress symptoms. PMID- 23631778 TI - Becoming and remaining community health workers: perspectives from Ethiopia and Mozambique. AB - Many global health practitioners are currently reaffirming the importance of recruiting and retaining effective community health workers (CHWs) in order to achieve major public health goals. This raises policy-relevant questions about why people become and remain CHWs. This paper addresses these questions, drawing on ethnographic work in Addis Ababa, the capital of Ethiopia, between 2006 and 2009, and in Chimoio, a provincial town in central Mozambique, between 2003 and 2010. Participant observation and in-depth interviews were used to understand the life histories that lead people to become CHWs, their relationships with intended beneficiaries after becoming CHWs, and their social and economic aspirations. People in Ethiopia and Mozambique have faced similar political and economic challenges in the last few decades, involving war, structural adjustment, and food price inflation. Results suggest that these challenges, as well as the socio moral values that people come to uphold through the example of parents and religious communities, influence why and how men and women become CHWs. Relationships with intended beneficiaries strongly influence why people remain CHWs, and why some may come to experience frustration and distress. There are complex reasons why CHWs come to seek greater compensation, including desires to escape poverty and to materially support families and other community members, a sense of deservingness given the emotional and social work involved in maintaining relationships with beneficiaries, and inequity vis-a-vis higher salaried elites. Ethnographic work is needed to engage CHWs in the policy process, help shape new standards for CHW programs based on rooting out social and economic inequities, and develop appropriate solutions to complex CHW policy problems. PMID- 23631779 TI - Motivational interviewing within the different stages of change: an analysis of practice nurse-patient consultations aimed at promoting a healthier lifestyle. AB - Combining the Stages of Change (SOC) model with Motivational Interviewing (MI) is seen as a helpful strategy for health care providers to guide patients in changing unhealthy lifestyle behaviour. SOC suggests that people are at different stages of motivational readiness for engaging in health behaviours and that intervention methods are most useful when tailored to a person's stage of change. However, it is unknown whether practice nurses (PNs) actually adapt their MI and more generic communication skills to a particular stage during real-life face-to face consultations with their patients. The aim of this study was to explore whether and how PNs apply MI and general communication skills to the different SOC of patients, targeting behaviour change about smoking, alcohol use, dietary habits and/or physical activity. Real-life consultations between nineteen Dutch PNs and 103 patients were recorded on video between June 2010 and March 2011. All consultations focused on a discussion of patients' lifestyle behaviour. The Behaviour Change Counselling Index (BECCI) was used to code PNs' MI skills. Generic communication skills were rated with the MAAS-global. Patients' SOC was assessed for each consultation by observing the communication between patient and PN regarding the patient's current lifestyle behaviour. Multilevel analyses revealed that PNs adapt their MI skills to a patient's SOC to some extent. On average PNs apply MI skills more to patients in the preparation stage (P < 0.05) than during the other stages of change. PNs adjusted three MI skills and one generic communication skill to patients' SOC. This explorative study suggests that, at least to some extent, PNs intuitively assess the stage of patients' readiness to change and tailor their communication accordingly. However, differences between the stages were small. By teaching PNs to explicitly identify patients' SOC they could further enhance and adapt their MI and general communication skills to the individual. PMID- 23631780 TI - Resisting the colonization of the lifeworld? Immigrant patients' experiences with co-ethnic healthcare workers. AB - This article analyzes how "ethnic concordance" (i.e., matching the ethnicity of patients and healthcare workers) shapes patients' experiences of clinical interaction. Adopting the Habermasian framework of lifeworld-medicine contention, we inductively analyze 60 in-depth interviews with low-income LEP (limited English proficiency) Vietnamese and Mexican immigrants, which were conducted in a metropolitan area in Northern California between January 2006 and April 2007. Our findings indicate that, net of linguistic concordance, ethnic concordance appeared to exacerbate rather than alleviate the problem of "the colonization of the lifeworld." Patients often felt that co-ethnic healthcare workers introduced additional power struggles from other systems, such as boundary work among co ethnic immigrants, into the institution of healthcare. Likewise, immigrant patients sometimes racialized the professional competence and virtues of healthcare providers, ranking co-ethnic doctors below white doctors. While these two general themes characterize the experiences of ethnic concordance among both Mexican and Vietnamese patients, the comparison between the two groups also highlights some differences. Existing research has documented the impacts of ethnic concordance, but little is known about patients' subjective experiences of these interactions. Our findings address this empirical gap. Drawing heavily on the Habermasian theoretical framework, our research in turn broadens this framework by showing how both lifeworld and medicine can become distorted by strategic actions in other systems, such as class and immigration, in which the American healthcare system has become deeply imbedded. PMID- 23631781 TI - Exploring tuberculosis by types of housing development. AB - Tuberculosis (TB) is known as a disease of poverty. It has also been related to poor living environment. This study examines the relationship between TB outcome and housing characteristics which is reflective of the socio-economic standing. We sought to investigate the association from two novel angles: (1) TB outcome against floor level of residence, and (2) TB outcome against types of housing development. A total of 1787 culture-positive TB cases were collected by the Centralized Mycobacterium Laboratory from 2007 to 2009. Most of the cases fell in the catchment area of the Kowloon West Cluster, a densely populated urban area in Hong Kong. The distribution of culture-positive TB cases by floor levels of residence and types of housing was examined by descriptive and non-parametric statistical analyses. The effects of vertical distance of residence from the street level on TB outcome by different types of housing development were further explored by regression methods. Our study confirmed more TB cases among tenants on the lower floors and observed a decreasing trend towards higher floors. It also revealed that significantly more TB cases were residing in public as opposed to private or other types of housing (Chi-square = 151.14, p < 0.0001). Regression analysis by different housing types showed significantly different rates of change between floor number and TB cases (p < 0.0001). Our findings offer evidence on the inverse associations between floor levels of residence and TB occurrences and showed that the patterns were dependent on housing types. We demonstrated how housing characteristics could be useful input in an ecological study of the TB disease. These results have significant design and health implications for Asian cities that are getting denser and growing taller. PMID- 23631782 TI - A new theory-based social classification in Japan and its validation using historically collected information. AB - Studies of health inequalities in Japan have increased since the millennium. However, there remains a lack of an accepted theory-based classification to measure occupation-related social position for Japan. This study attempts to derive such a classification based on the National Statistics Socio-economic Classification in the UK. Using routinely collected data from the nationally representative Comprehensive Survey of the Living Conditions of People on Health and Welfare, the Japanese Socioeconomic Classification was derived using two variables - occupational group and employment status. Validation analyses were conducted using household income, home ownership, self-rated good or poor health, and Kessler 6 psychological distress (n ~ 36,000). After adjustment for age, marital status, and area (prefecture), one step lower social class was associated with mean 16% (p < 0.001) lower income, and a risk ratio of 0.93 (p < 0.001) for home ownership. The probability of good health showed a trend in men and women (risk ratio 0.94 and 0.93, respectively, for one step lower social class, p < 0.001). The trend for poor health was significant in women (odds ratio 1.12, p < 0.001) but not in men. Kessler 6 psychological distress showed significant trends in men (risk ratio 1.03, p = 0.044) and in women (1.05, p = 0.004). We propose the Japanese Socioeconomic Classification, derived from basic occupational and employment status information, as a meaningful, theory-based and standard classification system suitable for monitoring occupation-related health inequalities in Japan. PMID- 23631783 TI - The equalisation hypothesis and changes in geographical inequalities of age based mortality in England, 2002-2004 to 2008-2010. AB - The equalisation hypothesis argues that during adolescence and early adulthood, inequality in mortality declines and begins to even out. However the evidence for this phenomenon is contested and mainly based on old data. This study proposes to examine how age-specific inequalities in mortality rates have changed over the past decade, during a time of widening health inequalities. To test this, mortality rates were calculated for deprivation quintiles in England, split by individual ages and sex for three time periods (2002-2004, 2005-2007 and 2008 2010). The results showed evidence for equalisation, with a clear decline in the ratio of mortality rates during late adolescence. However this decline was not accounted for by traditional explanations of the hypothesis. Overall, geographical inequalities were shown to be widening for the majority of ages, although there was some narrowing of patterns observed. PMID- 23631784 TI - Combining work and family: rewards or risks for children's mental health? AB - Prevailing child psychopathology paradigms focus on caregiving in isolation from market work. Yet most children's caregivers - mothers and fathers - are also employed. Although policy and academic debate has voiced concerns that employment could hamper mothers' capacity to care, less emphasis is given to the benefits generated by mothers' jobs. By contrast, theories of child mental health often view fathers' employment as beneficial, indeed necessary, for children's wellbeing, and few problematise fathers' capacity to combine work and care. This paper aims to integrate these seemingly contradictory concerns. We consider whether mothers' and fathers' rewards from combining employment with childcare may be protective for children's mental health, and whether their conflicts and dilemmas generate risks. Analyses use cross-sectional data from a representative survey of families with 4-5 year old children (Growing Up in Australia Study). We restricted our sample to employed parents (N = 2809 mothers; 3982 fathers), using data gathered in 2004. While a majority of parents reported benefits and rewards from working (work-family facilitation), more than one third also reported difficulties and conflicts (work-family conflict). When mothers or fathers experienced conflict we found elevations in young children's emotional and behavioural symptoms, with the risks compounding if both parents experienced conflict between work and family. Associations persisted after adjusting for family socioeconomic circumstances and composition, and they were not offset by work-family facilitation. We did not find evidence for heightened vulnerability to work-family conflict in families with few socioeconomic resources. However, among these disadvantaged families we observed stronger protective associations with children's mental health when parents had rewarding and supportive jobs. Our study extends current paradigms of child mental health by considering the interplay between care environments and market work. Jobs which help mothers and fathers to combine employment with caregiving could yield health benefits across generations. PMID- 23631786 TI - Can capabilities be self-reported? A think aloud study. AB - Direct assessment of capability to function may be useful in healthcare settings, but poses many challenges. This paper reports a first investigation of the feasibility of individuals self-reporting their capabilities and the meaning of the responses. The study was conducted in 2010, using think-aloud interviews with participants in the UK. The findings of the study suggest that the majority of participants were able to comprehend questions about their capabilities, felt able to judge their own capability wellbeing and provided responses in line with this judgement. In a number of cases, for example in relation to 'autonomy', participants highlighted that their capability was potentially greater than their functioning. The findings also show varying interpretations of the capability concept, with some participants finding the capability concept unintuitive in relation to specific aspects of life (in particular, 'attachment'). The findings suggest that guiding individuals in the process of identifying their capabilities may be important in generating consistent responses to capability questions. PMID- 23631785 TI - Associations among environmental supports, physical activity, and blood pressure in African-American adults in the PATH trial. AB - High blood pressure disproportionately affects African-American adults and is a leading cause of stroke and heart attack. Engaging in recommended levels of physical activity reduces blood pressure, and social and physical environmental supports for physical activity may increase engagement in physical activity. Based on social cognitive theory within a bioecological framework, the present study tested hypotheses that perceived peer social support for physical activity and neighborhood walkability would be positively associated with physical activity, and that physical activity would mediate their relation with blood pressure. Baseline data were collected with 434 African-American adults in underserved communities (low income, high crime) participating in the Positive Action for Today's Health (PATH) trial. Perceived peer social support for physical activity and neighborhood walkability were measured with validated surveys. Physical activity was assessed with 7-day accelerometry (moderate-to vigorous physical activity, min/day) and with a 4-week recall of walking. Three blood pressure assessments were taken by trained staff using standard protocols, with values from the second and third assessments averaged. The sample was predominantly female (63%), overweight (mean body mass index = 30.9, SD = 8.4), and had slightly elevated blood pressures with a mean systolic blood pressure of 132.4 (SD = 17.9) and a mean diastolic blood pressure of 81.4 (SD = 11.0). Results demonstrated that peer social support for physical activity (B = 2.43, p = .02) and neighborhood walkability (B = 2.40, p = .046) were significantly related to average daily moderate-to-vigorous physical activity. Neighborhood walkability was also significantly associated with self-reported average daily walking (B = 8.86, p = .02). Physical activity did not mediate their relation with blood pressure and no significant direct effects of these variables on blood pressure were found. The positive influence of social and physical environmental supports on physical activity in underserved African-American communities may guide intervention efforts and contribute to our understanding of physical activity and related health outcomes. PMID- 23631788 TI - Smoking initiation, continuation and prevalence in deprived urban areas compared to non-deprived urban areas in The Netherlands. AB - Previous studies have shown that smoking prevalence is higher in deprived areas than in affluent areas. We aimed to determine whether smoking initiation or continuation contributes most to inequalities in current smoking, and in which population subgroups these area differences were largest. Therefore, we assessed the relationship between area deprivation and current smoking, initiation and continuation in urban areas, in subgroups defined by gender, generation and educational level. Cross-sectional data of 20,603 Dutch adults (18 years and over) living in 963 urban areas in The Netherlands were obtained from the annual national health survey (2003-2009). Three interrelated smoking outcomes were used: current smoking (smokers/total population), initiation (ever-smokers/total population) and continuation (smokers/ever-smokers). Area deprivation was dichotomised; deprived urban areas (as defined by the Dutch government) and non deprived urban areas (reference group) were distinguished. Multilevel logistic regression models controlled for individual characteristics (including education and income) and tested for interaction with gender, generation and education. After controlling for individual characteristics, odds for smoking were not significantly higher in deprived areas (current smoking: OR = 1.04 [0.92-1.18], initiation: OR = 1.05 [0.93-1.18], continuation: OR = 1.03 [0.88-1.19]). For smoking initiation, significant differences between deprived areas and other areas remained in younger generations (OR = 1.19 [1.02-1.38]) and higher educated (OR = 1.23 [1.04-1.45]) respondents. For continuation and current smoking, after controlling for individual characteristics, no associations were found in any subgroups. In conclusion, area deprivation appears to be independently related to smoking initiation in, respectively, higher educated and younger generations. These results suggest that initiatives to reduce area-level inequalities in smoking should focus on preventing smoking initiation in deprived areas. PMID- 23631787 TI - Racial attitudes, physician-patient talk time ratio, and adherence in racially discordant medical interactions. AB - Physician racial bias and patient perceived discrimination have each been found to influence perceptions of and feelings about racially discordant medical interactions. However, to our knowledge, no studies have examined how they may simultaneously influence the dynamics of these interactions. This study examined how (a) non-Black primary care physicians' explicit and implicit racial bias and (b) Black patients' perceived past discrimination affected physician-patient talk time ratio (i.e., the ratio of physician to patient talk time) during medical interactions and the relationship between this ratio and patients' subsequent adherence. We conducted a secondary analysis of self-report and video-recorded data from a prior study of clinical interactions between 112 low-income, Black patients and their 14 non-Black physicians at a primary care clinic in the Midwestern United States between June, 2006 and February, 2008. Overall, physicians talked more than patients; however, both physician bias and patient perceived past discrimination affected physician-patient talk time ratio. Non Black physicians with higher levels of implicit, but not explicit, racial bias had larger physician-patient talk time ratios than did physicians with lower levels of implicit bias, indicating that physicians with more negative implicit racial attitudes talked more than physicians with less negative racial attitudes. Additionally, Black patients with higher levels of perceived discrimination had smaller physician-patient talk time ratios, indicating that patients with more negative racial attitudes talked more than patients with less negative racial attitudes. Finally, smaller physician-patient talk time ratios were associated with less patient subsequent adherence, indicating that patients who talked more during the racially discordant medical interactions were less likely to adhere subsequently. Theoretical and practical implications of these findings are discussed in the context of factors that affect the dynamics of racially discordant medical interactions. PMID- 23631789 TI - "Never mind the logic, give me the numbers": former Australian health ministers' perspectives on the social determinants of health. AB - The articulation of strong evidence and moral arguments about the importance of social determinants of health (SDH) and health equity has not led to commensurate action to address them. Policy windows open when, simultaneously, an issue is recognised as a problem, policy formulation and refinement happens and the political will for action is present. We report on qualitative interviews with 20 former Australian Federal, State or Territory health ministers conducted between September 2011 and January 2012 concerning their views about how and why the windows of policy opportunity on the SDH did or did not open during their tenure. Almost all ex-health ministers were aware of the existence of health inequalities and SDH but their complexity meant that this awareness rarely crystalised into a clear problem other than as a focus on high needs groups, especially Aboriginal people. Formulation of policies about SDH was assisted by cross-portfolio structures, policy entrepreneurs, and evidence from reviews and reports. It was hindered by the complexity of SDH policy, the dominance of medical power and paradigms and the weakness of the policy community advocating for SDH. The political stream was enabling when the general ideological climate was supportive of redistributive policies, the health care sector was not perceived to be in crisis, there was support for action from the head of government and cabinet colleagues, and no opposition from powerful lobby groups. There have been instances of Australian health policy which addressed the SDH over the past twenty five years but they are rare and the windows of opportunity that made them possible did not stay open for long. PMID- 23631790 TI - The impact of social context on self-management in women living with HIV. AB - HIV self-management is central to the health of people living with HIV and is comprised of the daily tasks individuals employ to manage their illness. Women living with HIV are confronted with social context vulnerabilities that impede their ability to conduct HIV self-management behaviors, including demanding social roles, poverty, homelessness, decreased social capital, and limited access to health care. We examined the relationship between these vulnerabilities and HIV self-management in a cross-sectional secondary analysis of 260 women living with HIV from two U.S. sites. All social context variables were assessed using validated self-report scales. HIV Self-Management was assessed using the HIV Self Management Scale that measures daily health practices, HIV social support, and the chronic nature of HIV. Data were analyzed using appropriate descriptive statistics and multivariable regression. Mean age was 46 years and 65% of participants were African-American. Results indicated that social context variables, particularly social capital, significantly predicted all domains of HIV self-management including daily health practices (F = 5.40, adjusted R(2) = 0.27, p < 0.01), HIV social support (F = 4.50, adjusted R(2) = 0.22, p < 0.01), and accepting the chronic nature of HIV (F = 5.57, adjusted R(2) = 0.27, p < 0.01). We found evidence to support the influence of the traditional social roles of mother and employee on the daily health practices and the chronic nature of HIV domains of HIV self-management. Our data support the idea that women's social context influences their HIV self-management behavior. While social context has been previously identified as important, our data provide new evidence on which aspects of social context might be important targets of self-management interventions for women living with HIV. Working to improve social capital and to incorporate social roles into the daily health practices of women living with HIV may improve the health of this population. PMID- 23631791 TI - "I'm afraid I have bad news for you..." Estimating the impact of different health impairments on subjective well-being. AB - Bad health decreases individuals' happiness, but few studies measure the impact of specific illnesses. We apply matching estimators to examine how changes in different (objective) conditions of bad health affect subjective well-being for a sample of 100,265 observations from the British Household Panel Survey (BHPS) database (1996-2006). The strongest effect is for alcohol and drug abuse, followed by anxiety, depression and other mental illnesses, stroke and cancer. Adaptation to health impairments varies across health impairments. There is also a puzzling asymmetry: strong adverse reactions to deteriorations in health appear alongside weak increases in well-being after health improvements. In conclusion, our analysis offers a more detailed account of how bad health influences happiness than accounts focusing on how bad self-assessed health affects individual well-being. PMID- 23631792 TI - The uses of ultrasonography in relation to foetal malformations in Rio de Janeiro, Brazil. AB - The world-wide diffusion of prenatal ultrasound has encountered local historical, cultural and political particularities. The purpose of this article is to study the varied uses of this technology in cases of detection of a foetal anomaly, in Rio de Janeiro, in a context of generalized access to ultrasound, restrictive legislation on abortion and major social inequalities. An ethnographic approach was chosen combining from 2009 to 2011, observations of prenatal consultations and interviews with specialist physicians and pregnant women, in both public and private sector institutions. Analysis of the data allowed us to identify three ideal-typical moments in the trajectory of the pregnant women when a foetal malformation was detected. The first moment occurs before the detection of the anomaly, when an initial ultrasound is carried out, essentially in private centres. The standardized actions of pregnancy monitoring are performed in the background while practitioners use the technology to support the local culture of praise to motherhood and the family. The second ideal-typical moment shows how detection of an anomaly leads to fragmentation of the foetus at the public referral centre for foetal malformations. But far from depersonalizing the consultation, the formalism of the diagnostic procedure is considered by some professionals as a political lever to empower women from poor neighbourhoods as they acquire knowledge and comprehension of the situation despite their lack of decisional autonomy. During the third ideal-typical moment, professionals put the data produced by the image into the larger perspective of the logic of care: the focus is no longer on access to knowledge and autonomy, but on the joint collaboration of women and professionals towards solving the problems of everyday life. The combination of these three moments in time illustrates a process whereby the malformed foetus is humanised, dehumanised and re-humanised with respect to the technological tool. PMID- 23631793 TI - Discussion networks, physician visits, and non-conventional medicine: probing the relational correlates of health care utilization. AB - Building from the premise that network ties influence why and how people seek health care, this study examines whether different types of close relations predict two distinct, but overlapping forms of care utilization. To that end, I examine the use of conventional care and complementary and alternative medicine (CAM). Analyses are conducted with a national sample of older American adults aged 57-85 in 2005/2006 (n = 3005). I find that partnered men who are very likely to discuss health with a partner had a greater number of physician visits in the past year, net of their health status and other relevant factors. Having children with whom health is likely to be discussed was also associated with more visits, as was the presence of non-kin ties. On the other hand, the use of complementary and alternative medicine was predicted not by spousal or other kin-based relationships, but only by having non-kin ties with whom a respondent could discuss health. Results suggest that understanding the relational undercurrents of care utilization requires attention to diverse forms of social relations and to diverse expressions of care participation. PMID- 23631794 TI - Pathways from parental AIDS to child psychological, educational and sexual risk: developing an empirically-based interactive theoretical model. AB - Increasing evidence demonstrates negative psychological, health, and developmental outcomes for children associated with parental HIV/AIDS illness and death. However, little is known about how parental AIDS leads to negative child outcomes. This study used a structural equation modelling approach to develop an empirically-based theoretical model of interactive relationships between parental or primary caregiver AIDS-illness, AIDS-orphanhood and predicted intervening factors associated with children's psychological distress, educational access and sexual health. Cross-sectional data were collected in 2009-2011, from 6002 children aged 10-17 years in three provinces of South Africa using stratified random sampling. Comparison groups included children orphaned by AIDS, orphaned by other causes and non-orphans, and children whose parents or primary caregivers were unwell with AIDS, unwell with other causes or healthy. Participants reported on psychological symptoms, educational access, and sexual health risks, as well as hypothesized sociodemographic and intervening factors. In order to build an interactive theoretical model of multiple child outcomes, multivariate regression and structural equation models were developed for each individual outcome, and then combined into an overall model. Neither AIDS-orphanhood nor parental AIDS illness were directly associated with psychological distress, educational access, or sexual health. Instead, significant indirect effects of AIDS-orphanhood and parental AIDS-illness were obtained on all measured outcomes. Child psychological, educational and sexual health risks share a common set of intervening variables including parental disability, poverty, community violence, stigma, and child abuse that together comprise chain effects. In all models, parental AIDS-illness had stronger effects and more risk pathways than AIDS orphanhood, especially via poverty and parental disability. AIDS-orphanhood and parental AIDS-illness impact child outcomes through multiple, interlinked pathways. The interactive model developed in this study suggests key areas of focus for interventions with AIDS-affected children. PMID- 23631796 TI - Inhalation treatment with glutathione in patients with cystic fibrosis. A randomized clinical trial. AB - RATIONALE: Glutathione is the major antioxidant in the extracellular lining fluid of the lungs and depleted in patients with cystic fibrosis (CF). OBJECTIVES: We aimed to assess glutathione delivered by inhalation as a potential treatment for CF lung disease. METHODS: This randomized, double-blind, placebo-controlled trial evaluated inhaled glutathione in subjects with CF 8 years of age and older and FEV1 of 40-90% of predicted. Subjects were randomized to receive 646 mg glutathione in 4 ml (n = 73) or placebo (n = 80) via an investigational eFlow nebulizer every 12 hours for 6 months. MEASUREMENTS AND MAIN RESULTS: FEV1 (absolute values), both as pre-post differences (P = 0.180) and as area under the curves (P = 0.205), were the primary efficacy endpoints, and were not different between the glutathione group and the placebo group over the 6-month treatment period. Exploratory analysis showed an increase of FEV1 from baseline over placebo of 100 ml or 2.2% predicted; this was significant at 3 months, but not later. Subjects receiving glutathione had neither fewer pulmonary exacerbations, nor better scores for quality of life. Whereas increased glutathione and metabolites in sputum demonstrated significant delivery to the lungs, there was no indication of diminished oxidative stress to proteins or lipids, and no evidence for anti-inflammatory or antiproteolytic actions of glutathione supplemented to the airways. The adverse event incidence was similar between glutathione and placebo. CONCLUSIONS: Inhaled glutathione in the dose administered did not demonstrate clinically relevant improvements in lung function, pulmonary exacerbation frequency, or patient-reported outcomes. Glutathione delivery to the airways was not associated with changes in markers of oxidation, proteolysis, or inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT00506688) and https://eudract.ema.europa.eu/index.html (EudraCT 2005-003870-88). PMID- 23631797 TI - An innovative distillation device for tritiated water analysis with high decontamination factor. AB - Institute of Nuclear Energy Research (INER) has designed an air-cooling distillation device and got a US patent. The decontamination factor (60)Co and (137)Cs is above 23,000. Tritium loss rate is one of testing items in ASTM D4107 Standard Test Method for Tritium in Drinking Water. In this study, the 3 levels (high, middle and low level) of tritium concentration of testing samples for the loss rate test were prepared similar to the concentrations reported in ASTM D4107. The loss rate of the high level is -2.37%, the middle is -2.31% and the low level is -2.47%. These results show that the air-cooling distillation device has good performance in the environmental water tritium analysis work. PMID- 23631799 TI - Continuing performance feedback and use of the ultraviolet visible marker to assess cleaning compliance in the healthcare environment. AB - BACKGROUND: Environmental surfaces have long been suspected to be a reservoir that could contribute to the presence of micro-organisms in healthcare facilities. The objective of this study was to evaluate the effect of providing weekly feedback to the housekeeping staff in improving and sustaining cleaning compliance when using ultraviolet visible marker (UVM) as an audit tool. METHODS: The housekeeping staff selected 90% as the cleaning compliance target. The UVM was applied to the toilet seat, sink, soap dispenser and door knob surfaces within the patient's washrooms on consecutive weekdays. The study included three arms: staff in arm 1 received cleaning compliance feedback throughout the 24-week study period, arm 2 and arm 3 staff received feedback for weeks 13-24 and weeks 1 12, respectively. Feedback was also provided to housekeeping staff by posting graphs on the wards and in the housekeeping office. FINDINGS: A pre-study audit showed 66.9%, 66.5% and 66.4% cleaning compliance for arms 1, 2 and 3 respectively. While receiving weekly feedback, all three arms demonstrated significantly improved cleaning compliance (86.7%, 80.4% and 73.7% for arms 1, 2 and 3, respectively). The use of casual staff may have contributed to difficulty in achieving better cleaning compliance as arms 1, 2 and 3 had 16.1%, 26% and 40.3% of shifts filled by casual staff, respectively. CONCLUSIONS: The use of UVM as an audit tool combined with weekly feedback of results to housekeeping staff resulted in significant, sustained improvement in the overall level of cleaning compliance of housekeeping staff. PMID- 23631801 TI - Investigation of the bulk modulus of silica aerogel using molecular dynamics simulations of a coarse-grained model. AB - Structural and mechanical properties of silica aerogels are studied using a flexible coarse-grained model and a variety of simulation techniques. The model, introduced in a previous study (J. Phys. Chem. C 2007, 111, 15792-15802), consists of spherical "primary" gel particles that interact through weak nonbonded forces and through microscopically motivated interparticle bonds that may break and form during the simulations. Aerogel models are prepared using a three-stage protocol consisting of separate simulations of gelation, aging, and a final relaxation during which no further bond formation is permitted. Models of varying particle size, density, and size dispersity are considered. These are characterized in terms of fractal dimensions and pore size distributions, and generally good agreement with experimental data is obtained for these metrics. The bulk moduli of these materials are studied in detail. Two different techniques for obtaining the bulk modulus are considered, fluctuation analysis and direct compression/expansion simulations. We find that the fluctuation result can be subject to systematic error due to coupling with the simulation barostat but, if performed carefully, yields results equivalent with those of compression/expansion experiments. The dependence of the bulk modulus on density follows a power law with an exponent between 3.00 and 3.15, in agreement with reported experimental results. The best correlate for the bulk modulus appears to be the volumetric bond density, on which there is also a power law dependence. Polydisperse models exhibit lower bulk moduli than comparable monodisperse models, which is due to lower bond densities in the polydisperse materials. PMID- 23631802 TI - Healthcare financing and conflict of interests in Hungary: the system of irregular payments and its challenges to the integrity of healthcare ethics. PMID- 23631803 TI - Regioselectivity in sequential nucleophilic substitution of tetrabromonaphthalene diimides. AB - Nucleophilic substitution of tetrabromosubstituted naphthalene diimides (NDIs) with aniline was studied in detail to explore the regioselectivity as three different diamino-substituted regioisomeric products can be formed. We found that the regioselectivity of the nucleophilic disubstitution of 2,3,6,7 tetrabromonaphthalene diimide with aniline is dependent on reaction solvents and additives. In dichloromethane and chloroform without an additive the 2,7-diamino 3,6-dibromo-NDI isomer was formed regioselectively, while in DMF under similar reaction conditions the 2,3-diamino-6,7-dibromo isomer was observed as the major regioisomer. The third possible regioisomer 2,6-diamino-3,7-dibromo product was formed, if at all, in an insignificant amount. Tetrabutylammonium fluoride (TBAF) additive exerts a dramatic effect on the regioselectivity of this reaction, as in dichloromethane without TBAF the 2,7-diamino isomer was formed regioselectively, while without TBAF the 2,3-diamino isomer was formed exclusively. This remarkable effect of TBAF can be rationalized in terms of a deprotonation of the monoamino tribromo-NDI generated in the first step of this sequential reaction as an intermediate by fluoride ions leading to an anionic species as indicated by UV vis and NMR experiments whose electronic properties direct the regioselective attack of the second amine molecule. Our efforts led to the exclusively regioselective synthesis of 2,7-diamino-3,6-dibromo- and 2,3-diamino-6,7-dibromo NDIs for the first time. PMID- 23631798 TI - Neurovascular coupling: in vivo optical techniques for functional brain imaging. AB - Optical imaging techniques reflect different biochemical processes in the brain, which is closely related with neural activity. Scientists and clinicians employ a variety of optical imaging technologies to visualize and study the relationship between neurons, glial cells and blood vessels. In this paper, we present an overview of the current optical approaches used for the in vivo imaging of neurovascular coupling events in small animal models. These techniques include 2 photon microscopy, laser speckle contrast imaging (LSCI), voltage-sensitive dye imaging (VSDi), functional photoacoustic microscopy (fPAM), functional near infrared spectroscopy imaging (fNIRS) and multimodal imaging techniques. The basic principles of each technique are described in detail, followed by examples of current applications from cutting-edge studies of cerebral neurovascular coupling functions and metabolic. Moreover, we provide a glimpse of the possible ways in which these techniques might be translated to human studies for clinical investigations of pathophysiology and disease. In vivo optical imaging techniques continue to expand and evolve, allowing us to discover fundamental basis of neurovascular coupling roles in cerebral physiology and pathophysiology. PMID- 23631804 TI - Study protocol: the effect of vitamin D supplements on cardiometabolic risk factors among urban premenopausal women in a tropical country -- a randomized controlled trial. AB - BACKGROUND: Besides its classical role in musculoskeletal diseases, vitamin D deficiency has recently been found to be associated with cardiometabolic risks such as hypertension, diabetes mellitus and hypercholesterolemia. Although Malaysia is a sunshine-abundant country, recent studies found that vitamin D deficiency prevalence was significantly high. However, few published studies that measured its effect on cardiometabolic risk factors were found in Malaysia. There are also limited clinical trials carried out globally that tried to establish the causality of vitamin D and cardiometabolic risks. Therefore, a double blind, parallel, randomized controlled trial on vitamin D and cardiometabolic risks is planned to be carried out.The objective of this study is to investigate whether vitamin D supplements can reduce the cardiometabolic risk and improve the quality of life in urban premenopausal women with vitamin D deficiency. METHODS/DESIGN: Three hundred and twenty premenopausal women working in a public university in Kuala Lumpur, Malaysia will be randomized to receive either vitamin D supplement (50,000 IU weekly for 8 weeks and 50,000 IU monthly for 10 months) or placebo for 12 months. At baseline, all participants are vitamin D deficient (<= 20 ng/ml or 50 nmol/l). Both participants and researchers will be blinded. The serum vitamin D levels of all participants collected at various time points will only be analysed at the end of the trial. Outcome measures such as 25(OH) D3, HOMA-IR, blood pressure, full lipid profiles will be taken at baseline, 6 months and 12 months. Health related quality of life will be measured at baseline and 12 months. The placebo group will be given delayed treatment for six months after the trial. DISCUSSION: This trial will be the first study investigating the effect of vitamin D supplements on both the cardiometabolic risk and quality of life among urban premenopausal women in Malaysia. Our findings will contribute to the growing body of knowledge in the role of vitamin D supplements in the primary prevention for cardiometabolic disease. TRIAL REGISTRATION: ACTRN12612000452897. PMID- 23631805 TI - Cyclohexa-2,5-diene-1,4-dione-based antiproliferative agents: design, synthesis, and cytotoxic evaluation. AB - BACKGROUND: Tumors are diseases characterized by uncontrolled cell growth and, in spite of the progress of medicine over the years, continue to represent a major threat to the health, requiring new therapies. Several synthetic compounds, such as those derived from natural sources, have been identified as anticancer drugs; among these compounds quinone represent the second largest class of anticancer agents in use. Several studies have shown that these act on tumor cells through several mechanisms. An important objective of this work is to develop quinoidscompounds showing antitumor activity, but with fewer side effects. The parachinone cannabinol HU-331, is a small molecule that with its core 4-hydroxy 1,4-benzoquinone, exhibits a potent and selective cytotoxic activity on different tumor cell lines. A series of derivatives 3-hydroxy-1,4-benzochinoni were thus developed through HU-331 chemical modifications. The purpose of the work is to test the ability of the compounds to induce proliferative inhibition and study the mechanisms of cell death. METHODS: The antitumor activities were evaluated in vitro by examining their cytotoxic effects against different human cancer cell lines. All cell lines tested were plated in 96-multiwell and treated with HU-100 V at different concentrations and cell viability was evaluated byMTT assay. Subsequently via flow cytometry (FACS) it was possible to assess apoptosis by the system of double labeling with PI and Annexin-V, and the effect of the compounds on ROS formation by measuring the dichlorofluorescein fluorescence. RESULTS: The substitution by n-hexyl chain considerably enhanced the bioactivity of the compounds. In details, 2-hexyl-5-hydroxycyclohexa-2,5-diene-1,4-dione (V), 2,5 Dimethoxy-3-hexyl-2,5-cyclohexadiene-1,4-dione (XII) and 2-hydroxy-5-methoxy-3 hexyl-cyclohexa-2,5-diene-1,4-dione (XIII) showed most prominent cytotoxicity against almost human tumour cell lines. Compound V was further subjected to downstream apoptotic analysis, demostrating a time-dependent pro-apoptotic activity on human melanoma M14 cell line mediated by caspases activation and poly (ADP-ribose)-polymerase (PARP) protein cleavage. CONCLUSIONS: These findings indicate that 2-hexyl-5-idrossicicloesa-2,5-diene-1,4-dione can be a promising compound for the design of a new class of antineoplastic derivatives.Carmen Petronzi, Michela Festa, Antonella Peduto and Maria Castellano: equally contributed equally to this work. PMID- 23631807 TI - Anterior segment changes produced in response to long-term overnight orthokeratology. AB - PURPOSE: To evaluate the effect of overnight orthokeratology (OK) on anterior chamber depth (ACD), posterior radius of corneal curvature (PRCC) and axial length (AL) over one year. METHODS: In this prospective longitudinal study, measurements were made in 34 right eyes of 34 subjects at baseline, 15 days, 1 and 12 months after starting OK treatment. ACD and PRCC measurements were obtained using a Pentacam system and AL was measured using an IOL-Master. ACD and PRCC were measured along the horizontal and vertical meridians at 1 mm intervals. These measurements were expressed as the distance from the center in the nasal (N), temporal (T), superior (S) and inferior (I) directions. RESULTS: A significant reduction in ACD was observed in both meridians during treatment. PRCC flattened significantly in the (T) direction after 15 d (1 mm, p < 0.05), at the corneal center after 15 d (p < 0.01), in the (T) direction after 1 month (1 mm, p < 0.05), in the (S) direction after 12 months (1 mm p < 0.05), in the (N) direction after 12 months (1 mm p < 0.05), in the (N) and (T) directions after 12 months (3 mm, p < 0.05) and in the (T) direction after 12 months (4 mm p < 0.05), at the corneal center after 12 months (p < 0.01). AL was significantly reduced during treatment (p < 0.05). CONCLUSIONS: A long period of OK reduces ACD and AL and changes PRCC. PMID- 23631806 TI - Upregulation of microRNA-224 is associated with aggressive progression and poor prognosis in human cervical cancer. AB - OBJECTIVE: Accumulating evidence for differential expression of microRNA-224 (miR 224) in various types of human cancer suggests that it may be play a crucial role in tumor biology. The previous microarray detection also shown that miR-224 was one of miRNAs with significant upregulation in cervical cancer tissues relative to adjacent normal tissues. However, little is known about the function of miR 224 in human cervical cancer. The aim of this study was to investigate the clinical significance of miR-224 expression in cervical cancer. METHODS: MiR-224 expression in 126 pairs of fresh human cervical cancer and adjacent normal tissues was measured by real-time quantitative RT-PCR assay. RESULTS: miR-224 expression was significantly upregulated in cervical cancer tissues when compared with corresponding adjacent normal tissues (P<0.001). It was also significantly higher in the cancerous tissues of patients with advanced FIGO stage cervical cancer than those with early FIGO stage (P=0.02). In addition, miR-224 was expressed at significantly higher levels in lymph node metastasis-positive patients than in lymph node metastasis-negative patients (P=0.008). Moreover, we found that lesser differentiated tumors expressed higher miR-224 (P=0.03). Finally, there were sufficient evidence to confirm its value in the status of vascular invasion (P=0.01) and human papillomavirus (HPV) infection (P=0.02) in cervical cancer. More importantly, Kaplan-Meier analysis showed that cervical cancer patients with high miR-224 expression tend to have shorter overall survival. In multivariate analysis stratified for known prognostic variables, miR 224 was identified as an independent prognostic marker. CONCLUSION: Our data indicated that miR-224 upregulation was associated with aggressive progression and poor prognosis in cervical cancer. MiR-224 was identified for the first time as an independent marker for predicting the clinical outcome of cervical cancer patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2170449349527493. PMID- 23631808 TI - Stability of genomic imprinting in human induced pluripotent stem cells. AB - BACKGROUND: hiPSCs are generated through epigenetic reprogramming of somatic tissue. Genomic imprinting is an epigenetic phenomenon through which monoallelic gene expression is regulated in a parent-of-origin-specific manner. Reprogramming relies on the successful erasure of marks of differentiation while maintaining those required for genomic imprinting. Loss of imprinting (LOI), which occurs in many types of malignant tumors, would hinder the clinical application of hiPSCs. RESULTS: We examined the imprinting status, expression levels and DNA methylation status of eight imprinted genes in five independently generated hiPSCs. We found a low frequency of LOI in some lines. Where LOI was identified in an early passage cell line, we found that this was maintained through subsequent passages of the cells. Just as normal imprints are maintained in long-term culture, this work suggests that abnormal imprints are also stable in culture. CONCLUSIONS: Analysis of genomic imprints in hiPSCs is a necessary safety step in regenerative medicine, with relevance both to the differentiation potential of these stem cells and also their potential tumorigenic properties. PMID- 23631810 TI - Disturbance in uniformly 13C-labelled DHA metabolism in elderly human subjects carrying the apoE epsilon4 allele. AB - Carrying the apoE epsilon4 allele (E4+ ) is the most important genetic risk for Alzheimer's disease. Unlike non-carriers (E4- ), E4+ seem not to be protected against Alzheimer's disease when consuming fish. We hypothesised that this may be linked to a disturbance in n-3 DHA metabolism in E4+. The aim of the present study was to evaluate [13C]DHA metabolism over 28 d in E4+ v. E4-. A total of forty participants (twenty-six women and fourteen men) received a single oral dose of 40 mg [13C]DHA, and its metabolism was monitored in blood and breath over 28 d. Of the participants, six were E4+ and thirty-four were E4-. In E4+, mean plasma [13C]DHA was 31% lower than that in E4-, and cumulative b-oxidation of [13C]DHA was higher than that in E4- 1-28 d post-dose (P <=0.05). A genotype x time interaction was detected for cumulative b-oxidation of [13C]DHA (P <= 0.01). The whole-body half-life of [13C]DHA was 77% lower in E4+ compared with E4- (P <=0.01). In E4+ and E4-, the percentage dose of [13C]DHA recovered/h as 13CO2 correlated with [13C]DHA concentration in plasma, but the slope of linear regression was 117% steeper in E4+ compared with E4- (P <= 0.05). These results indicate that DHA metabolism is disturbed in E4+, and may help explain why there is no association between DHA levels in plasma and cognition in E4+. However, whether E4+ disturbs the metabolism of 13C-labelled fatty acids other than DHA cannot be deduced from the present study. PMID- 23631809 TI - Comparison of extravillous trophoblast cells derived from human embryonic stem cells and from first trimester human placentas. AB - INTRODUCTION: Preeclampsia and other placental pathologies are characterized by a lack of spiral artery remodeling associated with insufficient invasion by extravillous trophoblast cells (EVT). Because trophoblast invasion occurs in early pregnancy when access to human placental tissue is limited, there is a need for model systems for the study of trophoblast differentiation and invasion. Human embryonic stem cells (hESC) treated with BMP4- differentiate to trophoblast, and express HLA-G, a marker of EVT. The goals of the present study were to further characterize the HLA-G(+) cells derived from BMP4-treated hESC, and determine their suitability as a model. METHODS: HESC were treated with BMP4 under 4% or 20% oxygen and tested in Matrigel invasion chambers. Both BMP4 treated hESC and primary human placental cells were separated into HLA-G(+) and HLA-G(-)/TACSTD2(+) populations with immunomagnetic beads and expression profiles analyzed by microarray. RESULTS: There was a 10-fold increase in invasion when hESC were BMP4-treated. There was also an independent, stimulatory effect of oxygen on this process. Invasive cells expressed trophoblast marker KRT7, and the majority were also HLA-G(+). Gene expression profiles revealed that HLA-G(+), BMP4-treated hESC were similar to, but distinct from, HLA-G(+) cells isolated from first trimester placentas. Whereas HLA-G(+) and HLA-G(-) cells from first trimester placentas had highly divergent gene expression profiles, HLA-G(+) and HLA-G(-) cells from BMP4-treated hESC had somewhat similar profiles, and both expressed genes characteristic of early trophoblast development. CONCLUSIONS: We conclude that hESC treated with BMP4 provide a model for studying transition to the EVT lineage. PMID- 23631811 TI - Association of the ADRB2 Gly16Arg and Glu27Gln polymorphisms with athlete status. AB - The beta-adrenergic receptors (beta-ARs) have known functional roles in cardiovascular and pulmonary responses as well as the appropriate substrate metabolism required for athletic ability. Thus, the beta-AR genes are plausible candidates for the variations observed in strength/power and endurance performance levels. The aims of the present study were to compare the frequency distribution of the ADRB2 Gly16Arg and ADRB2 Glu27Gln polymorphisms among athletes of sports with different metabolic and cardiopulmonary demands (endurance vs. strength/power) and to test the association between the Gly16Arg and Glu27Gln genotypes and athlete status. The study was performed in a group of 223 Polish athletes of the highest nationally competitive standard (123 endurance oriented athletes and 100 strength/power athletes). Control samples were prepared from 354 unrelated, sedentary volunteers. The chi2 test of independence revealed that the frequencies of the Gly16 and Glu27 alleles were significantly higher in the strength/power athletes than in the controls (69.0% vs. 59.7%; df = 1, P = 0.017 and 51% vs. 41.5%; df = 1 P = 0.017, respectively). The study showed that ADRB2 Gly16Arg and Glu27Gln markers are associated with athlete status in Polish athletes. An excess of Gly16 and Glu27 alleles and the Gly16:Glu27 haplotype observed in the strength/power athlete subgroup suggests that the Gly16 and Glu27 alleles might increase the probability of becoming a strength/power athlete rather than an endurance-oriented athlete. PMID- 23631812 TI - MondoA senses adenine nucleotides: transcriptional induction of thioredoxin interacting protein. AB - The MondoA-Mlx transcription complex plays a pivotal role in glucose homoeostasis by activating target gene expression in response to G6P (glucose 6-phosphate), the first reaction intermediate in glycolysis. TXNIP (thioredoxin-interacting protein) is a direct and glucose-responsive target of MondoA that triggers a negative-feedback loop by restricting glucose uptake when G6P levels increase. We show in the present study that TXNIP expression is also activated by AICAR (5 amino-4-imidazolecarboxamide ribofuranoside) and adenosine. Using pharmacological inhibitors and genetic knockdowns of purine metabolic enzymes, we establish that TXNIP induction by AICAR and adenosine requires their cellular uptake and metabolism to adenine nucleotides. AICAR induction of TXNIP depended on MondoA, but was independent of AMPK (AMP-activated protein kinase) activation and calcium. The findings of the present study have two important implications. First, in addition to activating AMPK, AICAR may have AMPK-independent effects on gene expression by regulating MondoA-Mlx activity following its flux into the adenine nucleotide pool. Secondly, MondoA-Mlx complexes sense elevated levels of G6P and adenine nucleotides to trigger a TXNIP-dependent feedback inhibition of glycolysis. We propose that this mechanism serves as a checkpoint to restore metabolic homoeostasis. PMID- 23631813 TI - Association of air pollution and use of glyceryl trinitrate against angina pectoris: a population-based case-crossover study. AB - BACKGROUND: Ambient air pollution has been associated with increased cardiovascular morbidity and mortality. In Reykjavik, Iceland, air pollutant concentrations exceed official health limits several times every year. The aim was to study the association of concentrations of NO2, O3, PM10, and H2S in the Reykjavik capital area with the dispensing of anti-angina pectoris medication, glyceryl trinitrate to the inhabitants. METHODS: Data on daily dispensing of glyceryl trinitrate, were retrieved from the Icelandic Medicines Registry. Data on hourly concentrations of NO2, O3, PM10, and H2S were obtained from the Environment Agency of Iceland. A case-crossover design was used, based on the dispensing of glyceryl trinitrate to 5,246 individuals (>=18 years) between 2005 and 2009. RESULTS: For every 10 MUg/m3 increase of NO2 and O3 3-day mean concentrations, the odds ratio (OR) for daily dispensing of glyceryl trinitrates was 1.136 (95% confidence intervals (CI) 1.069-1.207) and 1.094 (95% CI 1.029 1.163) at lag 0, and OR was 1.096 (95% CI 1.029-1.168) and 1.094 (95% CI 1.028 1.166) at lag 1, respectively. CONCLUSIONS: These findings suggest that NO2 and O3 ambient air concentrations may adversely affect cardiovascular health, as measured by the dispensing of glyceryl trinitrates for angina pectoris. Further, the findings suggest that data on the dispensing of medication may be a valuable health indicator when studying the effect of air pollution on cardiovascular morbidity. PMID- 23631815 TI - Interactions of antimicrobial peptide chrysophsin-3 with Bacillus anthracis in sporulated, germinated, and vegetative states. AB - Bacillus anthracis spores contain on their surface multilayered protein coats that provide barrier properties, mechanical strength, and elasticity that aid in protecting the sporulated state and preventing germination, outgrowth, and transition into the virulent vegetative bacterial state. In this work, the antimicrobial peptide (AMP) chrysophsin-3 was tested against B. anthracis in each of the three distinct metabolic states (sporulated, germinated, and vegetative) for its bacteria-killing activity and its ability to modify the surface nanomechanical properties. Our results provide the first demonstration that chrysophsin-3 killed B. anthracis even in its sporulated state while more killing was observed for germinated and vegetative states. The elasticity of vegetative B. anthracis increased from 12 +/- 6 to 84 +/- 17 MPa after exposure to 0.22 mM chrysophsin-3. An increase in cellular spring constant was also observed for chrysophsin-3-treated vegetative B. anthracis. Atomic force microscopy images suggested that the changes in mechanical properties of vegetative B. anthracis after chrysophsin-3 treatment are due to loss of water content and cellular material from the cell, possibly caused by the disruption of the cell membrane by the AMP. In contrast, sporulated and germinated B. anthracis retained their innate mechanical properties. Our data indicate that chrysophsin-3 can penetrate the spore coat of B. anthracis spores and kill them without causing any significant mechanical changes on the spore surface. These results reveal a yet unrecognized role for chrysophsin-3 in the killing of B. anthracis spores without the need for complete germination or release of spore coats. PMID- 23631814 TI - Evolution of mortality over time in patients receiving mechanical ventilation. AB - RATIONALE: Baseline characteristics and management have changed over time in patients requiring mechanical ventilation; however, the impact of these changes on patient outcomes is unclear. OBJECTIVES: To estimate whether mortality in mechanically ventilated patients has changed over time. METHODS: Prospective cohort studies conducted in 1998, 2004, and 2010, including patients receiving mechanical ventilation for more than 12 hours in a 1-month period, from 927 units in 40 countries. To examine effects over time on mortality in intensive care units, we performed generalized estimating equation models. MEASUREMENTS AND MAIN RESULTS: We included 18,302 patients. The reasons for initiating mechanical ventilation varied significantly among cohorts. Ventilatory management changed over time (P < 0.001), with increased use of noninvasive positive-pressure ventilation (5% in 1998 to 14% in 2010), a decrease in tidal volume (mean 8.8 ml/kg actual body weight [SD = 2.1] in 1998 to 6.9 ml/kg [SD = 1.9] in 2010), and an increase in applied positive end-expiratory pressure (mean 4.2 cm H2O [SD = 3.8] in 1998 to 7.0 cm of H2O [SD = 3.0] in 2010). Crude mortality in the intensive care unit decreased in 2010 compared with 1998 (28 versus 31%; odds ratio, 0.87; 95% confidence interval, 0.80-0.94), despite a similar complication rate. Hospital mortality decreased similarly. After adjusting for baseline and management variables, this difference remained significant (odds ratio, 0.78; 95% confidence interval, 0.67-0.92). CONCLUSIONS: Patient characteristics and ventilation practices have changed over time, and outcomes of mechanically ventilated patients have improved. Clinical trials registered with www.clinicaltrials.gov (NCT01093482). PMID- 23631816 TI - Philosophy for public good: the current state of bioethics in Serbia. PMID- 23631817 TI - Occult hepatitis B virus infection in chacma baboons, South Africa. AB - During previous studies of susceptibility to hepatitis B virus (HBV) infection, HBV DNA was detected in 2/6 wild-caught baboons. In the present study, HBV DNA was amplified from 15/69 wild-caught baboons. All animals were negative for HBV surface antigen and antibody against HBV core antigen. Liver tissue from 1 baboon was immunohistochemically negative for HBV surface antigen but positive for HBV core antigen. The complete HBV genome of an isolate from this liver clustered with subgenotype A2. Reverse transcription PCR of liver RNA amplified virus precore and surface protein genes, indicating replication of virus in baboon liver tissue. Four experimentally naive baboons were injected with serum from HBV DNA-positive baboons. These 4 baboons showed transient seroconversion, and HBV DNA was amplified from serum at various times after infection. The presence of HBV DNA at relatively low levels and in the absence of serologic markers in the baboon, a nonhuman primate, indicates an occult infection. PMID- 23631818 TI - The microtubule stabilizer patupilone counteracts ionizing radiation-induced matrix metalloproteinase activity and tumor cell invasion. AB - BACKGROUND: Ionizing radiation (IR) in combination with microtubule stabilizing agents (MSA) is a promising combined treatment modality. Supra-additive treatment responses might result from direct tumor cell killing and cooperative indirect, tumor cell-mediated effects on the tumor microenvironment. Here we investigated deregulation of matrix metalloproteinase (MMP) activity, as an important component of the tumor microenvironment, by the combined treatment modality of IR with the clinically relevant MSA patupilone. METHODS: Expression, secretion and activity of MMPs and related tissue inhibitors of metalloproteinases (TIMPs) were determined in cell extracts and conditioned media derived from human fibrosarcoma HT1080 and human glioblastoma U251 tumor cells in response to treatment with IR and the MSA patupilone. Treatment-dependent changes of the invasive capacities of these tumor cell lines were analysed using a Transwell invasion assay. Control experiments were performed using TIMP-directed siRNA and TIMP-directed inhibitory antibodies. RESULTS: Enzymatic activity of secreted MMPs was determined after treatment with patupilone and irradiation in the human fibrosarcoma HT1080 and the human glioblastoma U251 tumor cell line. IR enhanced the activity of secreted MMPs up to 2-fold and cellular pretreatment with low dose patupilone (0.05-0.2 nM) counteracted specifically the IR-induced MMP activity. The cell invasive capacity of HT1080 and U251 cells was increased after irradiation with 2 Gy by 30% and 50%, respectively, and patupilone treatment completely abrogated IR induced cell invasion. Patupilone did not alter the level of MMP expression, but interestingly, the protein level of secreted TIMP-1 and TIMP-2 was lower after combined treatment than after irradiation treatment alone. Furthermore, siRNA depletion of TIMP-1 or TIMP-2 prevented IR-mediated induction of MMP activity and cell invasion. CONCLUSIONS: These results indicate that patupilone counteracts an IR-induced MMP activation process by the reduction of secreted TIMP-1 and TIMP-2 proteins, which are required for activation of MMPs. Since IR-induced MMP activity could contribute to tumor progression, treatment combination of IR with patupilone might be of great clinical benefit for tumor therapy. PMID- 23631819 TI - Tau protein as a potential predictive marker in epithelial ovarian cancer patients treated with paclitaxel/platinum first-line chemotherapy. AB - BACKGROUND: The aim of the study was to evaluate predictive and prognostic significance of microtubule-associated protein Tau in epithelial ovarian cancer (EOC) patients treated with paclitaxel and platinum-based chemotherapy. METHODS: 74 patients with EOC (stage I-IV) who underwent cytoreductive surgery followed by standard paclitaxel/platinum chemotherapy were included in the retrospective analysis. Their formalin-fixed, paraffin-embedded tissue specimens were immunohistochemically stained for Tau protein, using semi-quantitative DAKO test. Tau expression was acknowledged as negative (0 and 1+) or positive (2+ and 3+). The correlation between Tau expression, progression free survival (PFS) and overall survival (OS) was evaluated. Statistical analysis included Kaplan-Meyer estimator, long rank test, Mann Whitney test and Cox proportional hazards model. RESULTS: 25.7% (19/74) and 74.3% (55/74) of the patients were classified as Tau negative and Tau-positive, respectively. Median PFS was 28.7 months for Tau negative group and 15.9 months for Tau-positive group (p = 0.0355). In the univariate analysis 3-year OS in Tau-negative and Tau-positive groups was 80.2% and 52.4%, respectively (p = 0.0198). Low expression of protein Tau was associated with better OS, whereas an advanced stage at diagnosis, suboptimal surgery, serous histological type and resistance to first line chemotherapy were each correlated with worse OS (p <0,05). In multivariate analysis only resistance to first line chemotherapy remained significant (HR 22.59; 95% CI, 8.71-58.55; p <0.0001). CONCLUSIONS: Negative tau protein seems to be both good prognostic factor and a predictor of response to paclitaxel/platinum-based chemotherapy in EOC patients. PMID- 23631820 TI - Annexin A3 is associated with a poor prognosis in breast cancer and participates in the modulation of apoptosis in vitro by affecting the Bcl-2/Bax balance. AB - OBJECTIVE: Annexins are a family of intracellular proteins that bind membrane phospholipids in a Ca(2+) concentration-dependent manner. Several annexins play important roles during tumor progression. However, little is known about the clinical implications and biological functions of Annexin A3 in breast cancer. METHODS: Using immunohistochemistry, we analyzed 60 breast cancers for the levels of annexin A3 and investigated the correlation of its expression change with patient's survival via Kaplan-Meier survival analysis. Furthermore, via knockdown of Annexin A3 expression in breast cancer cells with special siRNA, the role of Annexin A3 in the proliferation and apoptosis of breast cancer cells was examined. RESULTS: Annexin A3 was expressed at higher level in breast cancer than that in normal breast tissue. The expression of Annexin A3 in human breast carcinoma closely correlated with tumor size and axillary lymph node metastasis. Kaplan-Meier survival analysis revealed a significant inverse correlation between strong Annexin A3 expression and overall patient survival. Moreover, Annexin A3 overexpression was inversely associated with Bax staining and the apoptosis index. Annexin A3 small interfering RNA in MCF-7 and MDA-MB-435 could inhibit cell proliferation, decrease Bcl-2 mRNA and protein expression, and increase Bax mRNA and protein expression. CONCLUSION: Our findings indicated that Annexin A3 might be a novel and potential prognostic marker for patients with breast cancer and be involved in regulating apoptosis by affecting Bcl-2/Bax balance. PMID- 23631822 TI - Effects of dietary energy density and digestible protein:energy ratio on de novo lipid synthesis from dietary protein in gilthead sea bream (Sparus aurata) quantified with stable isotopes. AB - The effects of varying dietary digestible protein (DP) and digestible energy (DE) content on performance, nutrient retention efficiency and the de novo lipogenesis of DP origin were examined in triplicate groups of gilthead sea bream (Sparus aurata), fed nine extruded experimental diets. In order to trace the metabolic fate of dietary protein, 1.8% fishmeal was replaced with isotope-labelled whole protein (.98% 13C). The experiment was divided into a growth period lasting 89 d, growing fish from approximately 140 to 350 g, followed by a 3 d period feeding isotope-enriched diets. Isotope ratio MS was applied to quantify the 13C enrichment of whole-body lipid from dietary DP. Between 18.6 and 22.4% of the carbon derived from protein was recovered in the lipid fraction of the fish, and between 21.6 and 30.3% of the total lipid deposited could be attributed to dietary protein. DP retention was significantly improved by reductions in dietary DP:DE ratio, while the opposite was true for apparent digestible lipid retention. Both overall DE retention and whole-body proximate composition of whole fish were largely unaffected by dietary treatments, while feed conversion ratios were significantly improved with increasing dietary energy density. The present study suggests that gilthead sea bream efficiently utilises dietary nutrients over a wide range of DP:DE ratios and energy densities. In addition, they appear to endeavour a certain body energy status rather than maximising growth, which in the present trial was apparent from inherently high de novo lipogenesis originating from DP. PMID- 23631823 TI - Effects of insulin and IGF-I on growth hormone- induced STAT5 activation in 3T3 F442A adipocytes. AB - BACKGROUND: Growth hormone (GH) and insulin signaling pathways are known important regulators of adipose homeostasis. The cross-talk between GH and insulin signaling pathways in mature adipocytes is poorly understood. METHODS: In the present study, the impact of insulin on GH-mediated signaling in differentiated 3T3-F442A adipocytes and primary mice adipocytes was examined. RESULTS: Insulin alone did not induce STAT5 tyrosine phosphorylation, but enhanced GH-induced STAT5 activation. This effect was more pronounced when insulin was added 20 min prior to GH treatment. The above results were further confirmed by in vivo study, showing that insulin pretreatment potentiated GH- induced STAT5 tyrosine phosphorylation in visceral adipose tissues of C57/BL6 mice. In addition, our in vitro results showed that IGF-I had similar potentiating effect as insulin on GH-induced STAT5 activation. In vitro, insulin and IGF-I had an additive effect on GH- induced MAPK activation. CONCLUSION: These results indicate that both insulin and IGF-I specifically potentiated GH mediated STAT5 activation in mature adipose cells. These findings suggest that insulin and GH, usually with antagonistic functions, might act synergistically to regulate some specific functions in mature adipocytes. PMID- 23631821 TI - Substance use disorders: psychoneuroimmunological mechanisms and new targets for therapy. AB - An estimated 76.4 million people worldwide meet criteria for alcohol use disorders, and 15.3 million meet criteria for drug use disorders. Given the high rates of addiction and the associated health, economic, and social costs, it is essential to develop a thorough understanding of the impact of substance abuse on mental and physical health outcomes and to identify new treatment approaches for substance use disorders (SUDs). Psychoneuroimmunology is a rapidly expanding, multidisciplinary area of research that may be of particular importance to addiction medicine, as its focus is on the dynamic and complex interactions among behavioral factors, the central nervous system, and the endocrine and immune systems (Ader, 2001). This review, therefore, focuses on: 1) the psychoneuroimmunologic effects of SUDs by substance type and use pattern, and 2) the current and future treatment strategies, including barriers that can impede successful recovery outcomes. Evidence-based psychosocial and pharmacotherapeutic treatments are reviewed. Psychological factors and central nervous system correlates that impact treatment adherence and response are discussed. Several novel therapeutic approaches that are currently under investigation are introduced; translational data from animal and human studies is presented, highlighting immunotherapy as a promising new direction for addiction medicine. PMID- 23631825 TI - Translational utility of next-generation sequencing. AB - The development of next-generation sequencing (NGS) technology has made DNA sequencing not only rapid and cost-effective, but also highly accurate and reproducible. The translational utility of genomic sequencing is clear, from understanding of human genetic variation and its association with disease risk and individual response to treatment, to the interpretation and translation of the data for clinical decision making. It will be a critical technology for disease characterization and monitoring in molecular pathology and is expected to become a central piece of routine healthcare management which will result in accurate and reliable reporting, a prerequisite for physicians to practice genomic medicine. PMID- 23631824 TI - Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome. AB - Mitochondrial diseases are notoriously difficult to diagnose due to extreme locus and allelic heterogeneity, with both nuclear and mitochondrial genomes potentially liable. Using exome sequencing we demonstrate the ability to rapidly and cost effectively evaluate both the nuclear and mitochondrial genomes to obtain a molecular diagnosis for four patients with three distinct mitochondrial disorders. One patient was found to have Leigh syndrome due to a mutation in MT ATP6, two affected siblings were discovered to be compound heterozygous for mutations in the NDUFV1 gene, which causes mitochondrial complex I deficiency, and one patient was found to have coenzyme Q10 deficiency due to compound heterozygous mutations in COQ2. In all cases conventional diagnostic testing failed to identify a molecular diagnosis. We suggest that additional studies should be conducted to evaluate exome sequencing as a primary diagnostic test for mitochondrial diseases, including those due to mtDNA mutations. PMID- 23631826 TI - Multilevel functional and structural defects induced by two pathogenic mitochondrial tRNA mutations. AB - Point mutations in hmtRNAs (human mitochondrial tRNAs) can cause various disorders, such as CPEO (chronic progressive external ophthalmoplegia) and MM (mitochondrial myopathy). Mitochondrial tRNALeu, especially the UUR codon isoacceptor, is recognized as a hot spot for pathogenic mtDNA point mutations. Thus far, 40 mutations have been reported in hmtRNAsLeu. In the present paper, we describe the wide range of effects of two substitutions found in the TPsiC arms of two hmtRNAsLeu isoacceptors. The G52A substitution, corresponding to the pathogenic G12315A mutation in tRNALeu(CUN), and G3283A in tRNALeu(UUR) exhibited structural changes in the outer corner of the tRNA shape as shown by RNase probing. These mutations also induced reductions in aminoacylation, 3'-end processing and base modification processes. The main effects of the A57G substitution, corresponding to mutations A12320G in tRNALeu(CUN) and A3288G in tRNALeu(UUR), were observed on the aminoacylation activity and binding to hmEF-Tu (human mitochondrial elongation factor Tu). These observations suggest that the wide range of effects may amplify the deleterious impact on mitochondrial protein synthesis in vivo. The findings also emphasize that an exact understanding of tRNA dysfunction is critical for the future development of therapies for mitochondrial diseases. PMID- 23631827 TI - Profiling post-centrifugation delay of serum and plasma with antibody bead arrays. AB - Several biobanking initiatives have emerged to create extensive collections of specimen for biomedical studies and various analytical platforms. An affinity proteomic analysis with antibody suspension bead arrays was conducted to investigate the influence of the pre-analytical time and temperature conditions on blood derived samples. Serum and EDTA plasma prepared from 16 individuals was centrifuged and aliquots were kept either at 4 degrees C or in ambient temperature for 1h and up to 36h prior to first storage. Multiplexed protein profiles of post-centrifugation delay were generated in 384 biotinylated samples using 373 antibodies that targeted 343 unique proteins. Very few profiles were observed as significantly altered by the studied temperature and time intervals. Single binder and sandwich assays revealed decreasing levels of caldesmon 1 (CALD1) related to EDTA standard tubes and prolonged post-centrifugation delay of 36h. Indications from changes in CALD1 levels require further confirmation in independent material, but the current data suggests that samples should preferentially be frozen during the day of collection when to be profiled with antibody arrays selected for this study. BIOLOGICAL SIGNIFICANCE: Affinity-based profiling of serum and plasma by microarray assays can provide unique opportunities for the discovery of biomarkers. It is though often not known how differences in sample handling after collection influence the downstream analysis. By profiling three types of blood preparations for alterations in protein profiles with respect to time and temperature post centrifugation, we addressed an important component in the analysis and of such specimen. We believe that this analysis adds valuable information to be considered when biobanking blood derived samples. This article is part of a Special Issue entitled: Standardization and Quality Control in Proteomics. PMID- 23631828 TI - Identification of potential bladder cancer markers in urine by abundant-protein depletion coupled with quantitative proteomics. AB - In this study, we evaluated the reproducibility of abundant urine protein depletion by hexapeptide-based library beads and an antibody-based affinity column using the iTRAQ technique. The antibody-based affinity-depletion approach, which proved superior, was then applied in conjunction with iTRAQ to discover proteins that were differentially expressed between pooled urine samples from hernia and bladder cancer patients. Several proteins, including seven apolipoproteins, TIM, SAA4, and proEGF were further verified in 111 to 203 individual urine samples from patients with hernia, bladder cancer, or kidney cancer. Six apolipoproteins (APOA1, APOA2, APOB, APOC2, APOC3, and APOE) were able to differentiate bladder cancer from hernia. SAA4 was significantly increased in bladder cancer subgroups, whereas ProEGF was significantly decreased in bladder cancer subgroups. Additionally, the combination of SAA4 and ProEGF exhibited higher diagnostic capacity (AUC=0.80 and p<0.001) in discriminating bladder cancer from hernia than either marker alone. Using MetaCore software to interpret global changes of the urine proteome caused by bladder cancer, we found that the most notable alterations were in immune-response/alternative complement and blood-coagulation pathways. This study confirmed the clinical significance of the urine proteome in the development of non-invasive biomarkers for the detection of bladder cancer. BIOLOGICAL SIGNIFICANCE: In this study, we evaluated the reproducibility of abundant urine protein depletion by hexapeptide-based library beads and an antibody-based affinity column using the iTRAQ technique. The antibody-based affinity-depletion approach, which proved superior, was then applied in conjunction with iTRAQ to discover proteins that were differentially expressed between pooled urine samples from hernia and bladder cancer patients. Several proteins, including seven apolipoproteins, TIM, SAA4, and proEGF were further verified in 111 to 203 individual urine samples from patients with hernia, bladder cancer, or kidney cancer. SAA4 was significantly increased in bladder cancer subgroups, whereas ProEGF was significantly decreased in bladder cancer subgroups. Additionally, the combination of SAA4 and ProEGF exhibited higher diagnostic capacity in discriminating bladder cancer from hernia than either marker alone. A marker panel composed by two novel biomarker candidates, SAA4 and proEGF, was first discovered and verified successfully using Western blotting. To the best of our knowledge, the associations of urinary SAA4 and proEGF with bladder tumor and kidney cancer have not been mentioned before. In the present study, we discovered and verified SAA4 and proEGF as potential bladder cancer biomarker for the first time. PMID- 23631830 TI - Religious minorities and justice in healthcare: the current situation in Spain. PMID- 23631829 TI - Sensitive Cu2+-Cu2+ distance measurements in a protein-DNA complex by double quantum coherence ESR. AB - Double quantum coherence (DQC) ESR spectroscopy is applied to measure the Cu(2+) Cu(2+) distance in the EcoRI-DNA complex. A simple method is proposed to reduce the contribution of nuclear hyperfine and quadrupole interactions to such data. The effects of such interactions between the electron spin of Cu(2+) and neighboring nuclei on the DQC data make it difficult to measure the nanometer range interspin distance. The DQC data is in good agreement with results obtained by double electron electron resonance (DEER) spectroscopy. At the same time, the signal-to-noise ratio per shot in DQC is high. Taken together, these results provide impetus for further development of paramagnetic metal ion-based DQC techniques. PMID- 23631832 TI - Automatic segmentation of male pelvic anatomy on computed tomography images: a comparison with multiple observers in the context of a multicentre clinical trial. AB - BACKGROUND: This study investigates the variation in segmentation of several pelvic anatomical structures on computed tomography (CT) between multiple observers and a commercial automatic segmentation method, in the context of quality assurance and evaluation during a multicentre clinical trial. METHODS: CT scans of two prostate cancer patients ('benchmarking cases'), one high risk (HR) and one intermediate risk (IR), were sent to multiple radiotherapy centres for segmentation of prostate, rectum and bladder structures according to the TROG 03.04 "RADAR" trial protocol definitions. The same structures were automatically segmented using iPlan software for the same two patients, allowing structures defined by automatic segmentation to be quantitatively compared with those defined by multiple observers. A sample of twenty trial patient datasets were also used to automatically generate anatomical structures for quantitative comparison with structures defined by individual observers for the same datasets. RESULTS: There was considerable agreement amongst all observers and automatic segmentation of the benchmarking cases for bladder (mean spatial variations < 0.4 cm across the majority of image slices). Although there was some variation in interpretation of the superior-inferior (cranio-caudal) extent of rectum, human observer contours were typically within a mean 0.6 cm of automatically-defined contours. Prostate structures were more consistent for the HR case than the IR case with all human observers segmenting a prostate with considerably more volume (mean +113.3%) than that automatically segmented. Similar results were seen across the twenty sample datasets, with disagreement between iPlan and observers dominant at the prostatic apex and superior part of the rectum, which is consistent with observations made during quality assurance reviews during the trial. CONCLUSIONS: This study has demonstrated quantitative analysis for comparison of multi-observer segmentation studies. For automatic segmentation algorithms based on image-registration as in iPlan, it is apparent that agreement between observer and automatic segmentation will be a function of patient specific image characteristics, particularly for anatomy with poor contrast definition. For this reason, it is suggested that automatic registration based on transformation of a single reference dataset adds a significant systematic bias to the resulting volumes and their use in the context of a multicentre trial should be carefully considered. PMID- 23631831 TI - Risk factors for influenza among health care workers during 2009 pandemic, Toronto, Ontario, Canada. AB - This prospective cohort study, performed during the 2009 influenza A(H1N1) pandemic, was aimed to determine whether adults working in acute care hospitals were at higher risk than other working adults for influenza and to assess risk factors for influenza among health care workers (HCWs). We assessed the risk for influenza among 563 HCWs and 169 non-HCWs using PCR to test nasal swab samples collected during acute respiratory illness; results for 13 (2.2%) HCWs and 7 (4.1%) non-HCWs were positive for influenza. Influenza infection was associated with contact with family members who had acute respiratory illnesses (adjusted odds ratio [AOR]: 6.9, 95% CI 2.2-21.8); performing aerosol-generating medical procedures (AOR 2.0, 95% CI 1.1-3.5); and low self-reported adherence to hand hygiene recommendations (AOR 0.9, 95% CI 0.7-1.0). Contact with persons with acute respiratory illness, rather than workplace, was associated with influenza infection. Adherence to infection control recommendations may prevent influenza among HCWs. PMID- 23631833 TI - Health-related externalities: evidence from a choice experiment. AB - Health-related external benefits are of potentially large importance for public policy. This paper investigates health-related external benefits using a stated preference discrete-choice experiment framed in a health care context and including choice scenarios defined by six attributes related to a recipient and the recipient's condition: communicability, severity, medical necessity, relationship to respondent, location, and amount of contribution requested. Subjects also completed a set of own-treatment scenarios and a values-orientation instrument. We find evidence of substantial health-related external benefits that vary as expected with the scenario attributes and subjects' value orientations. The results are consistent with a number of hypotheses offered by the general theoretical analysis of health-related externalities and the analysis of externalities specific to health care. PMID- 23631834 TI - Dietary electrolyte balance affects the nutrient digestibility and maintenance energy expenditure of Nile tilapia. AB - Acid-base disturbances caused by environmental factors and physiological events including feeding have been well documented in several fish species, but little is known about the impact of dietary electrolyte balance (dEB). In the present study, we investigated the effect of feeding diets differing in dEB (-100, 200, 500 or 800 mEq/kg diet) on the growth, nutrient digestibility and energy balance of Nile tilapia. After 5 weeks on the test diet, the growth of the fish was linearly affected by the dEB levels (P< 0.001), with the lowest growth being observed in the fish fed the 800 dEB diet. The apparent digestibility coefficient (ADC) of fat was unaffected by dEB, whereas the ADC of DM and protein were curvilinearly related to the dEB levels, being lowest and highest in the 200 and 800 dEB diets, respectively. Stomach chyme pH at 3 h after feeding was linearly related to the dEB levels (P< 0.05). At the same time, blood pH of the heart (P< 0.05) and caudal vein (P< 0.01) was curvilinearly related to the dEB levels, suggesting the influence of dEB on postprandial metabolic alkalosis. Consequently, maintenance energy expenditure (MEm) was curvilinearly related to the dEB levels (P< 0.001), being 54 % higher in the 800 dEB group (88 kJ/kg(0.8) per d) than in the 200 dEB group (57 kJ/kg(0.8) per d). These results suggest that varying dEB levels in a diet have both positive and negative effects on fish. On the one hand, they improve nutrient digestibility; on the other hand, they challenge the acid-base homeostasis (pH) of fish, causing an increase in MEm, and thereby reduce the energy required for growth. PMID- 23631836 TI - Pedagogical goals for academic bioethics programs. PMID- 23631835 TI - Electronic medical records and the transgender patient: recommendations from the World Professional Association for Transgender Health EMR Working Group. AB - Transgender patients have particular needs with respect to demographic information and health records; specifically, transgender patients may have a chosen name and gender identity that differs from their current legally designated name and sex. Additionally, sex-specific health information, for example, a man with a cervix or a woman with a prostate, requires special attention in electronic health record (EHR) systems. The World Professional Association for Transgender Health (WPATH) is an international multidisciplinary professional association that publishes recognized standards for the care of transgender and gender variant persons. In September 2011, the WPATH Executive Committee convened an Electronic Medical Records Working Group comprised of both expert clinicians and medical information technology specialists, to make recommendations for developers, vendors, and users of EHR systems with respect to transgender patients. These recommendations and supporting rationale are presented here. PMID- 23631837 TI - Routine ultrasound examination by OB/GYN residents increase the accuracy of diagnosis for emergency surgery in gynecology. AB - INTRODUCTION: Diagnostic accuracy of first-line sonographic evaluation by obstetrics/gynecology residents in determining the need for emergency surgery in women with acute pelvic pain is unknown. Aim of this study was to evaluate the diagnostic accuracy of routine ultrasound evaluation by obstetrics/gynecology residents, available 24 hours a day, in patients with acute pelvic pain. METHODS: A cross-sectional retrospective study included consecutive patients who underwent emergency laparoscopy for acute pelvic pain at a teaching hospital gynecologic emergency unit, between January 1, 2004, and December 31, 2006. The laparoscopic diagnosis was the reference standard. Gynecologic and nongynecologic conditions requiring immediate surgery to avoid severe morbidity or death were defined as surgical emergencies. In all patients, obstetrics/gynecology residents routinely performed clinical examination and standardized ultrasonography was routinely recorded. Sonograms were re-interpreted for the study, blinded to physical examination and laparoscopic findings, according to evidence-based predetermined criteria. Sensitivity, specificity, and likelihood ratios were computed for clinical data alone, sonographic data alone, and the combination of both. RESULTS: Emergency laparoscopy was performed in 234 patients, diagnosing 139 (59%) surgical emergencies. Clinical and sonographic examinations performed by the residents each independently predicted a need for emergency surgery. Combining both examinations was superior over each examination alone and had an acceptable false-negative rate of 1%. CONCLUSIONS: First-line combined clinical and sonographic examination by obstetrics/gynecology residents is effective in ruling out surgical emergencies in patients with acute pelvic pain. PMID- 23631838 TI - Deaths associated with influenza pandemic of 1918-19, Japan. AB - Current estimates of deaths from the influenza pandemic of 1918-19 in Japan are based on vital records and range from 257,000 to 481,000. The resulting crude death rate range of 0.47%-0.88% is considerably lower than parallel and conservative worldwide estimates of 1.66%-2.77%. Because the accuracy of vital registration records for early 20th century Asia is questionable, to calculate the percentage of the population who died from the pandemic, we used alternative prefecture-level population count data for Japan in combination with estimation methods for panel data that were not available to earlier demographers. Our population loss estimates of 1.97-2.02 million are appreciably higher than the standing estimates, and they yield a crude rate of population loss of 3.62% 3.71%. This rate resolves a major puzzle about the pandemic by indicating that the experience of Japan was similar to that of other parts of Asia. PMID- 23631839 TI - Pathophysiological roles of nuclear factor kappaB (NF-kB) in pulmonary arterial hypertension: effects of synthetic selective NF-kB inhibitor IMD-0354. AB - AIMS: Proliferation of pulmonary arterial smooth muscle cells (PASMCs) is one histological sign of pulmonary arterial hypertension (PAH). We hypothesized that a signalling cascade from fibroblast growth factor 2 (FGF2) to plasminogen activator inhibitor 1 (PAI-1) and monocyte chemotactic protein-1 (MCP-1) via nuclear transcription factor nuclear factor kappaB (NF-kB) play a critical role in progression of PAH, and tested this hypothesis both in vivo and in vitro using a synthetic selective NF-kB inhibitor, N-(3,5-Bis-trifluoromethyl-phenyl)-5 chloro-2-hydroxy-benzamide (IMD-0354). METHODS AND RESULTS: Monocrotaline (MCT) was injected into 75 Sprague-Dawley rats. Starting at day 14 after MCT injection, we administered IMD-0354 (MCT + IMD group) or vehicle (MCT group) daily. At day 32, 65% of the MCT + IMD group were alive compared with 0% of the MCT group. IMD 0354 prevented increase of right ventricular pressure, and suppressed proliferation and induced apoptosis of PASMCs. mRNA transcript levels of FGF2, PAI-1, and tissue plasminogen activator (t-PA) were lower in MCT + IMD compared with MCT. In in vitro experiments, IMD-0354 inhibited p65 translocation to the nucleus promoted by FGF2 in PASMCs. Furthermore, the time courses of extracellular signal-regulated kinase (Erk) 1/2, MCP-1, and PAI-1 stimulated with FGF2 were each markedly shortened by IMD-0354. CONCLUSIONS: We speculate that the positive-feedback loop (Erk1/2-NF-kB-MCP-1-Erk1/2) is associated with progression of PAH by causing FGF2-induced inflammation in MCT rats. IMD-0354 has potential as a new therapeutic tool for PAH. PMID- 23631840 TI - Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations. AB - AIMS: Dilated cardiomyopathy (DCM) is characterized by ventricular dilation associated with systolic dysfunction, which could be caused by mutations in lamina/C gene (LMNA). LMNA-linked DCM is severe in males in both human patients and a knock-in mouse model carrying a homozygous p.H222P mutation (LmnaH222P/H222P). The aim of this study was to investigate the molecular mechanisms underlying the gender difference of LMNA-linked DCM. METHODS AND RESULTS: A whole-exome analysis of a multiplex family with DCM exhibiting the gender difference revealed a DCM-linked LMNA mutation, p.R225X. Immunohistochemical analyses of neonatal rat cardiomyocytes expressing mutant LMNA constructs and heart samples from the LMNA-linked DCM patients and LmnaH222P/H222P mice demonstrated a nuclear accumulation of androgen receptor (AR) and its co-activators, serum response factor, and four-and-a-half LIM protein-2. Role of sex hormones in the gender difference was investigated in vivo using the LmnaH222P/H222P mice, where male and female mice were castrated and ovariectomized, respectively, or treated with testosterone or an antagonist of AR. Examination of the mice by echocardiography, followed by the analyses of histological changes and gene/protein expression profiles in the hearts, confirmed the involvement of testicular hormone in the disease progression and enhanced cardiac remodelling in the LmnaH222P/H222P mice. CONCLUSION: These observations indicated that nuclear accumulation of AR was associated with the gender difference in LMNA-linked DCM. PMID- 23631841 TI - Group B Streptococcus pilus sortase regulation: a single mutation in the lid region induces pilin protein polymerization in vitro. AB - Gram-positive bacteria build pili on their cell surface via a class C sortase catalyzed transpeptidation mechanism from pilin protein substrates. Despite the availability of several crystal structures, pilus-related C sortases remain poorly characterized to date, and their mechanisms of transpeptidation and regulation need to be further investigated. The available 3-dimensional structures of these enzymes reveal a typical sortase fold, except for the presence of a unique feature represented by an N-terminal highly flexible loop known as the "lid." This region interacts with the residues composing the catalytic triad and covers the active site, thus maintaining the enzyme in an autoinhibited state and preventing the accessibility to the substrate. It is believed that enzyme activation may occur only after lid displacement from the catalytic domain. In this work, we provide the first direct evidence of the regulatory role of the lid, demonstrating that it is possible to obtain in vitro an efficient polymerization of pilin subunits using an active C sortase lid mutant carrying a single residue mutation in the lid region. Moreover, biochemical analyses of this recombinant mutant reveal that the lid confers thermodynamic and proteolytic stability to the enzyme. PMID- 23631842 TI - Acute myocardial infarction leads to acceleration of atherosclerosis. AB - Patients who experience acute myocardial infarction (AMI) are at increased risk of recurrent events in the weeks to months following the initial event. The underlying etiology for this vulnerable period following MI is unclear but could be related to the same underlying triggers responsible for the initial MI. Alternatively, the recurrent cardiac event could be promoted by the incident event. For example, several biomarkers reflecting inflammatory activity have been shown to be elevated for weeks to months following MI and this inflammatory response could aggravate existing atherosclerotic lesions by accelerating their growth and/or promoting plaque instability. The purpose of this review is to highlight recent preclinical and clinical studies supporting links between AMI and atherosclerosis and to consider potential therapeutic interventions. PMID- 23631843 TI - Bias and accuracy of resting metabolic rate equations in non-obese and obese adults. AB - BACKGROUND & AIMS: Consensus on the best equation for predicting metabolic rate in healthy people remains elusive. New equations continue to appear. The purpose of the current study was to validate several standard and new metabolic rate equations in obese and non-obese adults. METHODS: Resting metabolic rate was measured with indirect calorimetry and calculated using the Mifflin St. Jeor, Livingston, Harris Benedict, Muller, Vander Weg, WHO equations, and the Oxford variation of WHO. Each equation was compared for accuracy (percent of estimates falling within 10% of measured) and bias (95% confidence intervals of differences between estimate and measured expenditure that excluded zero). RESULTS: Three hundred thirty-seven ambulatory, community-living adults were measured. The Mifflin St. Jeor equation was unbiased (95% confidence interval -26 to +8 kcal/day), the Livingston equation tended to underestimate true metabolic rate (95% confidence interval -63 to -25 kcal/day), while all other equations tended to overestimate true metabolic rate. Accuracy rate was similar between Mifflin St. Jeor and Livingston (82 vs. 79%). Accuracy rate was lower in obese than non obese volunteers, no matter which equation was used (for example 87 vs. 75% for the Mifflin St. Jeor equation). CONCLUSION: The Mifflin St. Jeor equation is confirmed as a useful prediction equation for resting metabolic rate in community living ambulatory adults of various body sizes, though the Livingston equation is similar. Accuracy rate is lower in obese than non-obese people, and so an obesity specific equation is proposed. This equation needs validation before it is adopted for clinical use. PMID- 23631844 TI - Prevalence of and factors associated with sarcopenia in elderly patients with end stage renal disease. AB - BACKGROUND & AIMS: We investigated the prevalence of sarcopenia in elderly patients with end-stage renal disease (ESRD) and its relationship with various markers of nutrition, cognitive function, depressive symptoms, inflammation and beta2-microglobulin. METHODS: A cross-sectional study was conducted with 95 patients having ESRD aged over 50 years. Sarcopenia was defined as a decline in both muscle mass and strength. RESULTS: The mean age was 63.9 +/- 10.0 years; 56.8% were men and 52.6% had diabetes. Sarcopenia was highly prevalent in elderly patients with ESRD (37.0% in men and 29.3% in women). Subjective Global Assessment (SGA), inflammatory markers and beta2-microglobulin levels were significantly associated with sarcopenia, even after adjustment for age, gender, diabetes, and body mass index. Additionally, patients with depressive symptoms showed a higher risk of sarcopenia relative to those without depressive symptoms (odds ratio, OR = 6.87, 95% confidence interval, CI = 2.06-22.96) and sarcopenia was more likely to be present in patients with mild cognitive dysfunction (OR = 6.35, 95% CI = 1.62-34.96). CONCLUSIONS: Sarcopenia is highly prevalent in elderly patients with ESRD and is closely associated with SGA, inflammatory markers, beta2-microglobulin, depression and cognitive dysfunction. PMID- 23631845 TI - Hereditary cataract of the Nakano mouse: Involvement of a hypomorphic mutation in the coproporphyrinogen oxidase gene. AB - The Nakano cataract (NCT) is a recessive disorder in the mouse linked to the nct locus on chromosome 16. In this study, we positionally cloned the critical gene in the nct locus. Herein, we report that cataracts in the BALB/c-nct/nct mouse are caused by a hypomorphic mutation in the coproporphyrin oxidase gene (Cpox), encoding the enzyme responsible for catalyzing oxidative decarboxylation of the heme precursor, coproporphyrinogen III, in the heme biosynthetic pathway. BALB/c nct/nct mice are homozygous for a G to T nucleotide substitution in the Cpox gene, which results in a p.R380L amino acid substitution in the CPOX protein. The CPOX isoform with the p.R380L substitution retained only 15% of the activity of the wild type isoform. BALB/c-nct/nct mice had excessive accumulation of coproporphyrin III in the lens. The NCT phenotype was normalized by the introduction of a wild type Cpox transgene. The mechanisms by which impairment of CPOX leads to lens opacity in the NCT are elusive. However, our data illuminate a hitherto unanticipated involvement of the heme biosynthesis pathway in lens physiology. PMID- 23631846 TI - A novel ex vivo murine retina angiogenesis (EMRA) assay. AB - Pathological retinal angiogenesis results from the imbalance of pro-angiogenic and anti-angiogenic factors. In particular, vascular endothelial growth factor (VEGF) plays a pivotal role in retinal neovascularization and various therapeutic VEGF blockers have evolved over time. Nevertheless, new retinal angiogenesis models are crucial for investigating anti-angiogenic therapies and bringing them to patients. Here, we developed a novel ex vivo murine retina angiogenesis (EMRA) assay in which endothelial sprouts originate from mature and quiescent retinal vessels. In this model, retina fragments from adult mice are embedded in a three dimensional fibrin gel in the presence of human recombinant VEGF. Starting from the 3rd-4th day of incubation, endothelial cell sprouts invading the fibrin gel can be observed under an inverted microscope and measured at different time points thereafter. The effect of VEGF is dose-dependent, maximal stimulation being observed at day 7 for retina fragments stimulated with 25-75 ng/ml of the growth factor. To assess whether the EMRA assay is suitable for testing the activity of anti-angiogenic compounds, retina fragments were incubated with VEGF in the presence of the neutralizing anti-VEGF antibodies bevacizumab and ranibizumab. The results demonstrate that both antibodies inhibit VEGF activity in a dose-dependent manner. In conclusion, the EMRA assay represents a new ex vivo model of retinal neovascularization suitable for the rapid screening of novel anti-angiogenic therapeutics. PMID- 23631847 TI - Combination therapy with bevacizumab and temsirolimus in squamous cell carcinoma of the head and neck. PMID- 23631848 TI - Calcium dysregulation in ventricular myocytes from mice expressing constitutively active Rac1. AB - Increased Rac1 activity and its concomitant elevation of reactive oxygen species (ROS) levels is believed to be involved in the development of cardiac diseases such as hypertrophy and arrhythmia. To study the effects of activated Rac1 on the properties of isolated ventricular myocytes we used a transgenic mouse model (RacET) expressing constitutively active Rac1. Concurrent with dilated cardiomyopathy global Ca(2+) handling as well as single cell contractility was substantially decreased. Cellular ROS levels were assessed with two independent assays and unexpectedly depicted decreased ROS production in RacET that was uncoupled from hormonal stimulation. Western blot analysis illustrated a massive increase in cellular Rac1 activity concomitant with a reduction in NADPH-oxidase activity. Analysis of the Ca(2+) current, the ryanodine receptor and fractional Ca(2+) release uncovered defective excitation-contraction (ec) coupling and a substantial increase in sarcoplasmic reticulum Ca(2+) leak together with a larger Ca(2+) spark amplitude and frequency. We conclude that Rac1 activity plays an important role for cardiac diseases but can be uncoupled from NADPH-oxidase activity. Rac1-mediated partial uncoupling of the ec-coupling machinery results in a ROS-independent disarrayed cellular Ca(2+) handling, contractility and impaired cardiac function. PMID- 23631849 TI - Fast freeze-drying cycle design and optimization using a PAT based on the measurement of product temperature. AB - This paper is focused on the use of an innovative Process Analytical Technology for the fast design and optimization of freeze-drying cycles for pharmaceuticals. The tool is based on a soft-sensor, a device that uses the experimental measure of product temperature during freeze-drying, a mathematical model of the process, and the Extended Kalman Filter algorithm to estimate the sublimation flux, the residual amount of ice in the vial, and some model parameters (heat and mass transfer coefficients). The accuracy of the estimations provided by the soft sensor has been shown using as test case aqueous solutions containing different excipients (sucrose, polyvinylpyrrolidone), processed at various operating conditions, pointing out that the soft-sensor allows a fast estimation of model parameters and product dynamics without involving expensive hardware or time consuming analysis. The possibility of using the soft-sensor to calculate in-line (or off-line) the design space of the primary drying phase is here presented and discussed. Results evidences that by this way, it is possible to identify the values of the heating fluid temperature that maintain product temperature below the limit value, as well as the operating conditions that maximize the sublimation flux. Various experiments have been carried out to test the effectiveness of the proposed approach for a fast design of the cycle, evidencing that drying time can be significantly reduced, without impairing product quality. PMID- 23631850 TI - High levels of dietary phytosterols affect lipid metabolism and increase liver and plasma TAG in Atlantic salmon (Salmo salar L.). AB - Replacing dietary fishmeal (FM) and fish oil (FO) with plant ingredients in Atlantic salmon (Salmo salar L.) diets decreases dietary cholesterol and introduces phytosterols. The aim of the present study was to assess the effect of dietary sterol composition on cholesterol metabolism in Atlantic salmon. For this purpose, two dietary trials were performed, in which Atlantic salmon were fed either 100 % FM and FO (FM-FO) diet or one of the three diets with either high (80 %) or medium (40 %) plant protein (PP) and a high (70 %) or medium (35 %) vegetable oil (VO) blend (trial 1); or 70 % PP with either 100 % FO or 80 % of the FO replaced with olive, rapeseed or soyabean oil (trial 2). Replacing >= 70 % of FM with PP and >= 70 % of FO with either a VO blend or rapeseed oil increased plasma and liver TAG concentrations. These diets contained high levels of phytosterols and low levels of cholesterol. Fish fed low-cholesterol diets, but with less phytosterols, exhibited an increased expression of genes encoding proteins involved in cholesterol uptake and synthesis. The expression of these genes was, however, partially inhibited in rapeseed oil-fed fish possibly due to the high dietary and tissue phytosterol:cholesterol ratio. Atlantic salmon tissue and plasma cholesterol concentrations were maintained stable independent of the dietary sterol content. PMID- 23631851 TI - The fatty acid receptor FFA1/GPR40 a decade later: how much do we know? AB - Glucose homeostasis requires the highly coordinated regulation of insulin secretion by pancreatic beta cells. This is primarily mediated by glucose itself, but other nutrients, including free fatty acids (FFAs), potentiate the insulinotropic capacity of glucose. A decade ago, the seven-transmembrane domain receptor (7TMR) GPR40 was demonstrated to be predominantly expressed in beta cells and activated by long-chain FFAs. This discovery added a new dimension to our understanding of FFA-mediated control of glucose homeostasis. Furthermore, GPR40 has drawn considerable interest as a novel therapeutic target to enhance insulin secretion in type 2 diabetes. However, our understanding of the biology of GPR40 remains incomplete and its physiological role controversial. Here we summarize the current state of knowledge and emerging concepts regarding the role of GPR40 in regulating glucose homeostasis. PMID- 23631852 TI - Adaptive transfer of B10 cells: a novel therapy for chronic rejection after solid organ transplantation. AB - Chronic rejection occurs between almost all MHC-mismatched donors and recipients after transplantation. Immunosuppressive agents have been administrated indiscriminately to manage potential rejection, but complications from lifelong immunosuppressive therapy threaten transplant recipients. Recent studies demonstrated that a number of regulatory B cells (B10 cells) negatively regulate T cell mediated immune responses without inducing systemic immune suppression. Therefore, we propose that adaptive transfer of B10 cells suppresses alloreactive CD8(+) cytotoxic T cell activation induced by allogeneic solid organ transplantation, reduces T cell mediated rejection and prolongs allograft survival. PMID- 23631853 TI - Disruption of spine homeostasis causes depression. AB - Depression is one of the most burdensome diseases in the world. Although the exact pathogenesis remains unknown, stress is a well-known risk factor for the development of depression. Recently, stress has been known to induce loss of dendritic spines in neurons. Interestingly, also in human brains, higher levels of anxiety and depression scores are associated with decreased densities of spines in the hippocampus, supporting that the disturbance of spine homeostasis is deeply involved in the pathogenesis of depression. On the other hand, general serotonin vulnerability has been also proposed as a major risk factor in depression, where the paucity of available serotonin is involved in the pathogenesis of depression, indicating that the serotonergic system somehow possesses the ability to regulate spine homeostasis. However, the relationship between spine homeostasis and the serotonergic system is largely unknown. Thus, in this manuscript, I try to find the missing link between spine homeostasis and the serotonergic system. The hypothesis is as follows. First, stress reduces the number of spines. Since spine homeostasis is tightly regulated by the serotonergic system, the spine loss is compensated by activated serotonergic system in normal conditions. However, various factors, such as genetic predispositions and heavy stress, decrease the resilience of spine homeostasis. In such conditions, the serotonergic system cannot compensate spine homeostasis anymore, leading to disrupted spine homeostasis. Finally, disrupted spine homeostasis results in depression. The characteristic point of this hypothesis is that it can monistically explain the pathogenesis of depression, where disturbance of spine homeostasis is the main cause. PMID- 23631854 TI - Methicillin-resistant Staphylococcus aureus colonization of the groin and risk for clinical infection among HIV-infected adults. AB - Data on the interaction between methicillin-resistant Staphylococcus aureus (MRSA) colonization and clinical infection are limited. During 2007-2008, we enrolled HIV-infected adults in Atlanta, Georgia, USA, in a prospective cohort study. Nares and groin swab specimens were cultured for S. aureus at enrollment and after 6 and 12 months. MRSA colonization was detected in 13%-15% of HIV infected participants (n=600, 98% male) at baseline, 6 months, and 12 months. MRSA colonization was detected in the nares only (41%), groin only (21%), and at both sites (38%). Over a median of 2.1 years of follow-up, 29 MRSA clinical infections occurred in 25 participants. In multivariate analysis, MRSA clinical infection was significantly associated with MRSA colonization of the groin (adjusted risk ratio 4.8) and a history of MRSA infection (adjusted risk ratio 3.1). MRSA prevention strategies that can effectively prevent or eliminate groin colonization are likely necessary to reduce clinical infections in this population. PMID- 23631855 TI - Tensile strain increases expression of CCN2 and COL2A1 by activating TGF-beta Smad2/3 pathway in chondrocytic cells. AB - Physiologic mechanical stress stimulates expression of chondrogenic genes, such as multifunctional growth factor CYR61/CTGF/NOV (CCN) 2 and alpha1(II) collagen (COL2A1), and maintains cartilage homeostasis. In our previous studies, cyclic tensile strain (CTS) induces nuclear translocation of transforming growth factor (TGF)-beta receptor-regulated Smad2/3 and the master chondrogenic transcription factor Sry-type HMG box (SOX) 9. However, the precise mechanism of stretch mediated Smad activation remains unclear in transcriptional regulation of CCN2 and COL2A1. Here we hypothesized that CTS may induce TGF-beta1 release and stimulate Smad-dependent chondrogenic gene expression in human chondrocytic SW1353 cells. Uni-axial CTS (0.5Hz, 5% strain) stimulated gene expression of CCN2 and COL2A1 in SW1353 cells, and induced TGF-beta1 secretion. CCN2 synthesis and nuclear translocalization of Smad2/3 and SOX9 were stimulated by CTS. In addition, CTS increased the complex formation between phosphorylated Smad2/3 and SOX9. The CCN2 promoter activity was cooperatively enhanced by CTS and Smad3 in luciferase reporter assay. Chromatin immunoprecipitation revealed that CTS increased Smad2/3 interaction with the CCN2 promoter and the COL2A1 enhancer. Our results suggest that CTS epigenetically stimulates CCN2 transcription via TGF beta1 release associated with Smad2/3 activation and enhances COL2A1 expression through the complex formation between SOX9 and Smad2/3. PMID- 23631856 TI - Mechanics of hip dysplasia reductions in infants using the Pavlik harness: a physics-based computational model. AB - Biomechanical factors influencing the reduction of dislocated hips with the Pavlik harness in patients of Developmental Dysplasia of the Hip (DDH) were studied using a three-dimensional computer model simulating hip reduction dynamics in (1) subluxated and (2) fully dislocated hip joints. Five hip adductor muscles were identified as key mediators of DDH prognosis, and the non dimensional force contribution of each in the direction necessary to achieve concentric hip reductions was determined. Results point to the adductor muscles as mediators of subluxated hip reductions, as their mechanical action is a function of the degree of hip dislocation. For subluxated hips in abduction and flexion, the Pectineus, Adductor Brevis, Adductor Longus, and proximal Adductor Magnus contribute positively to reduction, while the rest of the Adductor Magnus contributes negatively. In full dislocations all muscles contribute detrimentally to reduction, elucidating the need for traction to reduce Graf IV type dislocations. Reduction of dysplastic hips was found to occur in two distinct phases: (a) release phase and (b) reduction phase. PMID- 23631857 TI - Dose-response effects of customised foot orthoses on lower limb kinematics and kinetics in pronated foot type. AB - Despite the widespread use of customised foot orthoses (FOs) for the pronated foot type there is a lack of reliable information on the dose-response effect on lower limb mechanics. This study investigated these effects in subjects with normal and pronated foot types. Customised FOs were administered to 12 participants with symptomatic pronated foot type and 12 age and gender matched controls. A computer-aided design (CAD) software was used to design nine FOs per participant with dose incrementally changed by varying only the rearfoot post angle. This was done in 2 degrees increments from 6 degrees lateral to 10 degrees medial posting. A 3D printing method was used to manufacture the FOs. Quantification of the dose-response effect was performed using three-dimensional gait analyses for selected rearfoot and knee kinematics and kinetics. Under these experimental conditions, significant and linear effects of posting were seen for the peak (p<0.001) and mean (p<0.001) rearfoot eversions, peak (p=0.003) and mean (p<0.001) ankle eversion moments and peak (p=0.017) and mean (p=0.005) knee adduction moment variables. Group effects were observed for the peak (p=0.007) and mean (p=0.007) forefoot abduction and for the peak (p=0.007) knee adduction moment. A significant interaction between posting and group was seen for internal tibial rotation (p=0.004). These data indicate that a dose-response effect, with a linear trend for both the rearfoot and knee, exists for customised FOs used to treat pronated foot type. PMID- 23631858 TI - Training and career development in palliative care and end-of-life research: opportunities for development in the U.S. AB - There has been a dramatic increase in attention to the field of palliative care and end-of-life (PCEOL) research over the past 20 years. This increase is particularly notable in the development of palliative care clinical and educational programs. However, there remain important shortcomings in the evidence base to ensure access to and delivery of effective palliative care for patients with life-limiting illness and their families. Development of this evidence base will require that we train the next generation of researchers to focus on issues in PCEOL. The purpose of this article was to explore the current status of the recruitment, training, and retention of future investigators in PCEOL research in the U.S. and propose recommendations to move us forward. Some key contextual issues for developing and supporting this research workforce are articulated, along with timely and important research areas that will need to be addressed during research training and career development. We provide targeted key recommendations to facilitate the nurturing and support of the future research workforce that is needed to ensure the development and implementation of the science necessary for providing high-quality, evidence-based palliative care to all who need and desire it. PMID- 23631860 TI - Disasters, catastrophes, and worse: a scalar taxonomy. PMID- 23631859 TI - Starvation actively inhibits splicing of glucose-6-phosphate dehydrogenase mRNA via a bifunctional ESE/ESS element bound by hnRNP K. AB - Regulated expression of glucose-6-phosphate dehydrogenase (G6PD) is due to changes in the rate of pre-mRNA splicing and not changes in its transcription. Starvation alters pre-mRNA splicing by decreasing the rate of intron removal, leading to intron retention and a decrease in the accumulation of mature mRNA. A regulatory element within exon 12 of G6PD pre-mRNA controls splicing efficiency. Starvation caused an increase in the expression of heterogeneous nuclear ribonucleoprotein (hnRNP) K protein and this increase coincided with the increase in the binding of hnRNP K to the regulatory element and a decrease in the expression of G6PD mRNA. HnRNP K bound to two C-rich motifs forming an ESS within exon 12. Overexpression of hnRNP K decreased the splicing and expression of G6PD mRNA, while siRNA-mediated depletion of hnRNP K caused an increase in the splicing and expression of G6PD mRNA. Binding of hnRNP K to the regulatory element was enhanced in vivo by starvation coinciding with a decrease in G6PD mRNA. HnRNP K binding to the C-rich motifs blocked binding of serine-arginine rich, splicing factor 3 (SRSF3), a splicing enhancer. Thus hnRNP K is a nutrient regulated splicing factor responsible for the inhibition of the splicing of G6PD during starvation. PMID- 23631861 TI - Checks and balances in membrane phospholipid class and acyl chain homeostasis, the yeast perspective. AB - Glycerophospholipids are the most abundant membrane lipid constituents in most eukaryotic cells. As a consequence, phospholipid class and acyl chain homeostasis are crucial for maintaining optimal physical properties of membranes that in turn are crucial for membrane function. The topic of this review is our current understanding of membrane phospholipid homeostasis in the reference eukaryote Saccharomyces cerevisiae. After introducing the physical parameters of the membrane that are kept in optimal range, the properties of the major membrane phospholipids and their contributions to membrane structure and dynamics are summarized. Phospholipid metabolism and known mechanisms of regulation are discussed, including potential sensors for monitoring membrane physical properties. Special attention is paid to processes that maintain the phospholipid class specific molecular species profiles, and to the interplay between phospholipid class and acyl chain composition when yeast membrane lipid homeostasis is challenged. Based on the reviewed studies, molecular species selectivity of the lipid metabolic enzymes, and mass action in acyl-CoA metabolism are put forward as important intrinsic contributors to membrane lipid homeostasis. PMID- 23631862 TI - Smoking ban in public areas is associated with a reduced incidence of hospital admissions due to ST-elevation myocardial infarctions in non-smokers. Results from the Bremen STEMI Registry. AB - INTRODUCTION: Laws banning tobacco smoking from public areas have been passed in several countries, including the region of Bremen, Germany at the end of 2007. The present study analyses the incidence of hospital admissions due to ST elevation myocardial infarctions (STEMIs) before and after such a smoking ban was implemented, focusing on differences between smokers and non-smokers. In this respect, data of the Bremen STEMI Registry (BSR) give a complete epidemiological overview of a region in northwest Germany with approximately 800,000 inhabitants since all STEMIs are admitted to one central heart centre. METHODS AND RESULTS: Between January 2006 and December 2010, data from the BSR was analysed focusing on date of admission, age, gender, and prior nicotine consumption. A total of 3545 patients with STEMI were admitted in the Bremen Heart Centre during this time period. Comparing 2006-2007 vs. 2008-2010, hence before and after the smoking ban, a 16% decrease of the number of STEMIs was observed: from a mean of 65 STEMI/month in 2006-2007 to 55/month in 2008-2010 (p < 0.01). The group of smokers showed a constant number of STEMIs: 25/month in 2006-2007 to 26/month in 2008-2010 (+4%, p = 0.8). However, in non-smokers, a significant reduction of STEMIs over time was found: 39/month in 2006-2007 to 29/month in 2008-2010 (-26%, p < 0.01). The decline of STEMIs in non-smokers was consistently observed in all age groups and both sexes. Adjusting for potentially confounding factors like hypertension, obesity, and diabetes mellitus did not explain the observed decline. CONCLUSIONS: In the BSR, a significant decline of hospital admissions due to STEMIs in non-smokers was observed after the smoking ban in public areas came into force. No reduction of STEMI-related admissions was found in smokers. These results may be explained by the protection of non-smokers from passive smoking and the absence of such an effect in smokers by the dominant effect of active smoking. PMID- 23631863 TI - Cost-effectiveness of universal and platelet reactivity assay-driven antiplatelet therapy in acute coronary syndrome. AB - Assays monitoring P2Y12 platelet reactivity can accurately predict which patients will have a poor response to clopidogrel. We sought to determine the cost effectiveness of using platelet reactivity assays (PRAs) to select a dual antiplatelet regimen for patients with acute coronary syndrome. A hybrid decision tree Markov model was developed to determine the cost-effectiveness of universal clopidogrel, ticagrelor, or prasugrel (given to all patients) or PRA-driven ticagrelor or prasugrel (given to patients with high platelet reactivity, defined as >230 on the VerifyNow P2Y12 assay; the others received generic clopidogrel). We assumed a cohort of 65-year-old patients with acute coronary syndrome and an incidence of high platelet reactivity of 32% and 13% at ~24 to 48 hours after revascularization and 1 month, respectively. The 5-year costs, quality-adjusted life-years, and incremental cost-effectiveness ratios were calculated for PRA driven ticagrelor and prasugrel compared with universal clopidogrel, ticagrelor, or prasugrel. PRA-driven ticagrelor and prasugrel were cost-effective compared with universal clopidogrel (incremental cost-effectiveness ratio $40,100 and $49,143/quality-adjusted life-year, respectively); however, universal ticagrelor and prasugrel were not (incremental cost-effectiveness ratio $61,651 and $96,261/quality-adjusted life-year, respectively). Monte Carlo simulation suggested PRA-driven ticagrelor, PRA-driven prasugrel, universal ticagrelor, and universal prasugrel would have an incremental cost-effectiveness ratio <$50,000/quality-adjusted life-year in 52%, 40%, 23%, and 2% of the iterations compared with universal clopidogrel, respectively. Universal ticagrelor and prasugrel were not cost-effective compared with their respective PRA-driven regimens (incremental cost-effectiveness ratio $68,182; $116,875/quality-adjusted life-year, respectively). Monte Carlo simulation suggested universal ticagrelor and prasugrel would have an incremental cost-effectiveness ratio <$50,000/quality adjusted life-year in 26% and 4% of iterations compared with their respective PRA driven regimens. The results were most sensitive to differences in agent costs and drug-specific relative risks of death. In conclusion, even with generic clopidogrel, PRA-driven selection of antiplatelet therapy appeared to be a cost effective strategy with the potential to decrease the overall acute coronary syndrome-associated healthcare costs. PMID- 23631865 TI - The relationship between low birth weight and socioeconomic status in Ireland. AB - There is now fairly substantial evidence of a socioeconomic gradient in low birth weight for developed countries. The standard summary statistic for this gradient is the concentration index. Using data from the recently published Growing Up in Ireland survey, this paper calculates this index for low birth weight arising from preterm and intrauterine growth retardation. It also carries out a decomposition of this index for the different sources of low birth weight and finds that income inequality appears to be less important for the case of preterm births, while father's education and local environmental conditions appear to be more relevant for intrauterine growth retardation. The application of the standard Blinder-Oaxaca decomposition also indicates that the socioeconomic gradient for low birth weight appears to arise owing to different characteristics between rich and poor, and not because the impact of any given characteristic on low birth weight differs between rich and poor. PMID- 23631867 TI - The risk of blindness following 'non-surgical rhinoplasty'. PMID- 23631866 TI - Feline origin of rotavirus strain, Tunisia, 2008. AB - In Tunisia in 2008, an unusual G6P[9] rotavirus, RVA/human wt/TUN/17237/2008/G6P[9], rarely found in humans, was detected in a child. To determine the origin of this strain, we conducted phylogenetic analyses and found a unique genotype constellation resembling rotaviruses belonging to the feline BA222-like genotype constellation. The strain probably resulted from direct cat to-human transmission. PMID- 23631864 TI - SN79, a sigma receptor ligand, blocks methamphetamine-induced microglial activation and cytokine upregulation. AB - Methamphetamine (METH) abuse is associated with several negative side effects including neurotoxicity in specific brain regions such as the striatum. The precise molecular mechanisms by which METH usage results in neurotoxicity remain to be fully elucidated, with recent evidence implicating the importance of microglial activation and neuroinflammation in damaged brain regions. METH interacts with sigma receptors which are found in glial cells in addition to neurons. Moreover, sigma receptor antagonists have been shown to block METH induced neurotoxicity in rodents although the cellular mechanisms underlying their neuroprotection remain unknown. The purpose of the current study was to determine if the prototypic sigma receptor antagonist, SN79, mitigates METH induced microglial activation and associated increases in cytokine expression in a rodent model of METH-induced neurotoxicity. METH increased striatal mRNA and protein levels of cluster of differentiation 68 (CD68), indicative of microglial activation. METH also increased ionized calcium binding adapter molecule 1 (IBA 1) protein expression, further confirming the activation of microglia. Along with microglial activation, METH increased striatal mRNA expression levels of IL-6 family pro-inflammatory cytokines, leukemia inhibitory factor (lif), oncostatin m (osm), and interleukin-6 (il-6). Pretreatment with SN79 reduced METH-induced increases in CD68 and IBA-1 expression, demonstrating its ability to prevent microglial activation. SN79 also attenuated METH-induced mRNA increases in IL-6 pro-inflammatory cytokine family members. The ability of a sigma receptor antagonist to block METH-induced microglial activation and cytokine production provides a novel mechanism through which the neurotoxic effects of METH may be mitigated. PMID- 23631868 TI - Cryptococcus neoformans constitutes an ideal model organism to unravel the contribution of cellular aging to the virulence of chronic infections. AB - Aging affects all organisms, from unicellular yeasts to multicellular humans. Studies in model organisms demonstrate that the pathways that mediate the two forms of aging, replicative and chronological, are highly conserved. Most studies are focused on the effect of aging on an individual cell rather than a whole population. Complex longevity regulation, however, makes aging a highly adaptive trait that is subject to natural selection. Recent studies have shed light on the potential relevance of aging in fungal pathogens, which undergo replicative aging when they expand in the host environment. Hence, pathogens causing chronic infections can constitute ideal model organisms in unraveling the contribution of selection to aging within a population and help elucidate the contribution of aging itself to the virulence of infections. PMID- 23631870 TI - Electronic properties of functionalized (5,5) beryllium oxide nanotubes. AB - Using the density functional theory (DFT) we study the structural and electronic properties of functionalized (5,5) chirality single wall beryllium oxide nanotubes (SW-BeONTs), i.e. armchair nanotubes. The nanotube surface and ends are functionalized by the hydroxyl (OH) functional group. Our calculations consider the Hamprecht-Cohen-Tozer-Handy functional in the generalized gradient approximation (HCTH-GGA) to deal with the exchange-correlation energies, and the base function with double polarization (DNP). The geometry optimization of both defects free and with point defects nanotubes is done applying the criterion of minimum energy. Six configurations are considered: The OH oriented toward the Be (on the surface and at the end), toward the O (on the surface and at the end) and placed at the nanotube ends. Simulation results show that the nanotube functionalization takes place at the nanotube ends with the BeO bond displaying hydrogen-like bridge bonds. Moreover the nanotube semiconductor behavior remains unchanged. The polarity is high (it shows a transition from covalent to ionic) favoring solvatation. On the other hand, the work function low value suggests this to be a good candidate for the device fabrication. When the nanotube contains surface point defects the work function is reduced which provides excellent possibilities for the use of this material in the electronic industry. PMID- 23631869 TI - Income received during treatment does not affect response to contingency management treatments in cocaine-dependent outpatients. AB - BACKGROUND: Prior studies find no effect of baseline income on response to contingency management (CM) interventions. However, income among substance disordered patients is variable, particularly at treatment entry. This study investigated the impact of during-treatment income, a more proximal estimate of economic resources at the time that CM is in effect, on response to standard treatment or the standard treatment plus CM. METHOD: These secondary analyses included 418 cocaine dependent participants initiating community intensive outpatient treatment. We examined whether differences were present in pretreatment and during-treatment overall income, as well as specific income sources. We then conducted a series of regression models to investigate the impact of during-treatment income on treatment outcome. RESULTS: Participants' during-treatment income was significantly lower compared to pretreatment income, and this difference was largely attributable to decreases in earned income, illegal income, and support from friends and family. Neither the main effect of income, nor the interaction of income and treatment condition, was significantly associated with treatment outcome. CM, however, was a significant predictor of improved treatment outcome relative to standard treatment. Income sources and some demographic characteristics were also significant predictors of outcomes; public assistance income was associated with improved outcomes and illegal income was associated with poorer outcomes. CONCLUSIONS: These results suggest that substance abusers benefit from CM regardless of their income level, and these data add to the growing literature supporting the generalizability of CM across a variety of patient characteristics. PMID- 23631871 TI - Alzheimer's disease biomarkers: correspondence between human studies and animal models. AB - Alzheimer's disease (AD) represents an escalating global threat as life expectancy and disease prevalence continue to increase. There is a considerable need for earlier diagnoses to improve clinical outcomes. Fluid biomarkers measured from cerebrospinal fluid (CSF) and blood, or imaging biomarkers have considerable potential to assist in the diagnosis and management of AD. An additional important utility of biomarkers is in novel therapeutic development and clinical trials to assess efficacy and side effects of therapeutic interventions. Because many biomarkers are initially examined in animal models, the extent to which markers translate from animals to humans is an important issue. The current review highlights many existing and pipeline biomarker approaches, focusing on the degree of correspondence between AD patients and animal models. The review also highlights the need for greater translational correspondence between human and animal biomarkers. PMID- 23631872 TI - NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: protection against impairments in axonal transport. AB - NAP (davunetide) is a novel neuroprotective compound with mechanism of action that appears to involve microtubule (MT) stabilization and repair. To evaluate, for the first time, the impact of NAP on axonal transport in vivo and to translate it to neuroprotection in a severe neurodegeneration, the SOD1-G93A mouse model for amyotrophic lateral sclerosis (ALS) was used. Manganese-enhanced magnetic resonance imaging (MRI), estimating axonal transport rates, revealed a significant reduction of the anterograde axonal transport in the ALS mice compared to healthy control mice. Acute NAP treatment normalized axonal transport rates in these ALS mice. Tau hyperphosphorylation, associated with MT dysfunction and defective axonal transport, was discovered in the brains of the ALS mice and was significantly reduced by chronic NAP treatment. Furthermore, in healthy wild type (WT) mice, NAP reversed axonal transport disruption by colchicine, suggesting drug-dependent protection against axonal transport impairment through stabilization of the neuronal MT network. Histochemical analysis showed that chronic NAP treatment significantly protected spinal cord motor neurons against ALS-like pathology. Sequential MRI measurements, correlating brain structure with ALS disease progression, revealed a significant damage to the ventral tegmental area (VTA), indicative of impairments to the dopaminergic pathways relative to healthy controls. Chronic daily NAP treatment of the SOD1-G93A mice, initiated close to disease onset, delayed degeneration of the trigeminal, facial and hypoglossal motor nuclei as was significantly apparent at days 90-100 and further protected the VTA throughout life. Importantly, protection of the VTA was significantly correlated with longevity and overall, NAP treatment significantly prolonged life span in the ALS mice. PMID- 23631873 TI - Enhanced neurotrophic distribution, cell signaling and neuroprotection following substantia nigral versus striatal delivery of AAV2-NRTN (CERE-120). AB - This paper reassesses the currently accepted viewpoint that targeting the terminal fields (i.e. striatum) of degenerating nigrostriatal dopamine neurons with neurotrophic factors in Parkinson's disease (PD) is sufficient for achieving an optimal neurotrophic response. Recent insight indicating that PD is an axonopathy characterized by axonal transport deficits prompted this effort. We tested whether a significantly greater neurotrophic response might be induced in SN neurons when the neurotrophic factor neurturin (NRTN) is also targeted to the substantia nigra (SN), compared to the more conventional, striatum-only target. While recognizing the importance of maintaining the integrity of nigrostriatal fibers and terminals (especially for achieving optimal function), we refocused attention to the fate of SN neurons. Under conditions of axonal degeneration and neuronal transport deficits, this component of the nigrostriatal system is most vulnerable to the lack of neurotrophic exposure following striatal-only delivery. Given the location of repair genes induced by neurotrophic factors, achieving adequate neurotrophic exposure to the SN neurons is essential for an optimal neurotrophic response, while the survival of these neurons is essential to the very survival of the fibers. Two separate studies were performed using the 6-OHDA model of nigrostriatal degeneration, in conjunction with delivery of the viral vector AAV2-NRTN (CERE-120) to continuously express NRTN to either striatum or nigra alone or combined striatal/nigral exposure, including conditions of ongoing axonopathy. These studies provide additional insight for reinterpreting past animal neurotrophic/6-OHDA studies conducted under conditions where axon transport deficiencies were generally not accounted for, which suggested that targeting the striatum was both necessary and sufficient. The current data demonstrate that delivering NRTN directly to the SN produces 1) expanded NRTN distribution within the terminal field and cell bodies of targeted nigrostriatal neurons, 2) enhanced intracellular neurotrophic factor signaling in the nigrostriatal neurons, and 3) produced greater numbers of surviving dopamine neurons against 6-OHDA-induced toxicity, particularly under the conditions of active axonopathy. Thus, these data provide empirical support that targeting the SN with neurotrophic factors (in addition to striatum) may help enhance the neurotrophic response in midbrain neurons, particularly under conditions of active neurodegeneration which occurs in PD patients. PMID- 23631874 TI - Synthesis of 1H-1,2,3-triazole linked beta-lactam-isatin bi-functional hybrids and preliminary analysis of in vitro activity against the protozoal parasite Trichomonas vaginalis. AB - Twenty-two different triazoles were prepared to examine the anti-Trichomonas vaginalis structure-activity relationships (SAR) within the beta-lactam-isatin triazole conjugate family. The compounds were synthesized by copper-catalyzed 'click chemistry.'In vitro activity against T. vaginalis was determined at 10 and 100 MUM for each compound, with eighteen of the synthesized hybrids showing 100% growth inhibition at 100 MUM. The compound 5i, with no cytotoxicity on cultured CHO-K1 cells, is considered a good compound for further analysis. PMID- 23631875 TI - Dismissing patients for health-based reasons. PMID- 23631876 TI - Liquid chromatography-mass spectrometry in metabolomics research: mass analyzers in ultra high pressure liquid chromatography coupling. AB - The present review gives an introduction into the concept of metabolomics and provides an overview of the analytical tools applied in non-targeted metabolomics with a focus on liquid chromatography (LC). LC is a powerful analytical tool in the study of complex sample matrices. A further development and configuration employing Ultra-High Pressure Liquid Chromatography (UHPLC) is optimized to provide the largest known liquid chromatographic resolution and peak capacity. Reasonably UHPLC plays an important role in separation and consequent metabolite identification of complex molecular mixtures such as bio-fluids. The most sensitive detectors for these purposes are mass spectrometers. Almost any mass analyzer can be optimized to identify and quantify small pre-defined sets of targets; however, the number of analytes in metabolomics is far greater. Optimized protocols for quantification of large sets of targets may be rendered inapplicable. Results on small target set analyses on different sample matrices are easily comparable with each other. In non-targeted metabolomics there is almost no analytical method which is applicable to all different matrices due to limitations pertaining to mass analyzers and chromatographic tools. The specifications of the most important interfaces and mass analyzers are discussed. We additionally provide an exemplary application in order to demonstrate the level of complexity which remains intractable up to date. The potential of coupling a high field Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (ICR-FT/MS), the mass analyzer with the largest known mass resolving power, to UHPLC is given with an example of one human pre-treated plasma sample. This experimental example illustrates one way of overcoming the necessity of faster scanning rates in the coupling with UHPLC. The experiment enabled the extraction of thousands of features (analytical signals). A small subset of this compositional space could be mapped into a mass difference network whose topology shows specificity toward putative metabolite classes and retention time. PMID- 23631877 TI - Local gentamicin application does not interfere with bone healing in a rat model. AB - For the prophylaxis and treatment of bony infections antibiotics are locally used. Since several decades antibiotics mixed with bone cement (methylmethacrylate) are successfully used in prosthetic surgery and a gentamicin coated tibial nail is approved in Europe for fracture stabilization. The goal of the present study was to investigate if gentamicin, locally applied from a polymeric coating of intramedullary nails, might interfere with the bone healing process. Female Sprague Dawley rats (n = 72) were used and the tibiae were intramedullary stabilized with Kirschner-wires (k-wires) after osteotomy. This model was established earlier and shows a delayed healing with a prolonged inflammatory reaction. The open approach is clinically more relevant compared to a closed one because it mimics the clinically critical case of an open fracture, which has a higher risk of infection. The k-wire was either coated with the polymer poly(d,l-lactide) (control group) or with 10% gentamicin incorporated into the polymer (gentamicin group). In vivo MUCT analyses were performed at days 10, 28, 42, and 84 after osteotomy. Mechanical torsional testing and histological evaluation were done at the days of sacrifice: 28, 42, and 84. The MUCT analyses revealed an increase in tissue mineral density (TMD) over the healing period in both groups. In the control group, the torsional stiffness and maximum load did not reach the values of the intact contralateral side at any time point. At day 84 the gentamicin treated tibiae, however, showed significantly better maximum load compared to the control group. The histology showed no bony bridging in the control, whereas in 2 of 5 calluses of the gentamicin group mineralized bridging occurred. Significantly more mineralized tissue was measured in the gentamicin group. This study shows that the local gentamicin application does not negatively interfere with the long term healing process. Local infection prophylaxis is effective without negative effects on bone healing. PMID- 23631878 TI - Dopamine D2-like receptor signaling suppresses human osteoclastogenesis. AB - Dopamine, a major neurotransmitter, transmits signals via five different seven transmembrane G protein-coupled receptors termed D1 to D5. Although the relevance of neuroendocrine system to bone metabolism has been emerging, the precise effects of dopaminergic signaling upon osteoclastogenesis remain unknown. Here, we demonstrate that human monocyte-derived osteoclast precursor cells express all dopamine-receptor subtypes. Dopamine and dopamine D2-like receptor agonists such as pramipexole and quinpirole reduced the formation of TRAP-positive multi nucleated cells, cathepsin K mRNA expression, and pit formation area in vitro. These inhibitory effects were reversed by pre-treatment with a D2-like receptor antagonist haloperidol or a Galphai inhibitor pertussis toxin, but not with the D1-like receptor antagonist SCH-23390. Dopamine and dopamine D2-like receptor agonists, but not a D1-like receptor agonist, suppressed intracellular cAMP concentration as well as RANKL-meditated induction of c-Fos and NFATc1 mRNA expression in human osteoclast precursor cells. Finally, the dopamine D2-like receptor agonist suppressed LPS-induced osteoclast formation in murine bone marrow culture ex vivo. These findings indicate that dopaminergic signaling plays an important role in bone homeostasis via direct effects upon osteoclast differentiation and further suggest that the clinical use of neuroleptics is likely to affect bone mass. PMID- 23631879 TI - Implication of CA repeated tracts on post-transcriptional regulation in Trypanosoma cruzi. AB - In Trypanosoma cruzi gene expression regulation mainly relays on post transcriptional events. Nevertheless, little is known about the signals which control mRNA abundance and functionality. We have previously found that CA repeated tracts (polyCA) are abundant in the vicinity of open reading frames and constitute specific targets for single stranded binding proteins from T. cruzi epimastigote. Given the reported examples of the involvement of polyCA motifs in gene expression regulation, we decided to further study their role in T. cruzi. Using an in silico genome-wide analysis, we identify the genes that contain polyCA within their predicted UTRs. We found that about 10% of T. cruzi genes carry polyCA therein. Strikingly, they are frequently concurrent with GT repeated tracts (polyGT), favoring the formation of a secondary structure exhibiting the complementary polydinucleotides in a double stranded helix. This feature is found in the species-specific family of genes coding for mucine associated proteins (MASPs) and other genes. For those polyCA-containing UTRs that lack polyGT, the polyCA is mainly predicted to adopt a single stranded structure. We further analyzed the functional role of such element using a reporter approach in T. cruzi. We found out that the insertion of polyCA at the 3' UTR of a reporter gene in the pTEX vector modulates its expression along the parasite's life cycle. While no significant change of the mRNA steady state of the reporter gene could be detected at the trypomastigote stage, significant increase in the epimastigote and reduction in the amastigote stage were observed. Altogether, these results suggest the involvement of polyCA as a signal in gene expression regulation in T. cruzi. PMID- 23631880 TI - The pediatric nurse practitioner workforce: meeting the health care needs of children. PMID- 23631881 TI - Match injury rates in professional soccer vary with match result, match venue, and type of competition. AB - BACKGROUND: Player activities in soccer matches are influenced by the match result and match venue. It is not known whether injury rates are influenced by these factors. PURPOSE: To investigate whether there are associations between injury rates and the match result, venue, and type of competition in male soccer. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Twenty-six professional clubs from 10 countries were followed prospectively during 9 seasons (2001-2002 to 2009-2010). All matches, and injuries occurring in these matches, were registered by the team's medical staff. An injury was registered if it resulted in player absence from training or matches. Information about match result, venue, and type of competition for all reported matches was gathered by the authors from online databases. Injury rates in matches with varying match characteristics were compared by use of generalized estimating equations. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 2738 injuries during 6010 matches were registered. There were no associations between odds of 1 injury occurrence and match result or type of competition, whereas the odds were decreased in matches played away compared with home matches (OR, 0.89; 95% CI, 0.80-0.99). The odds of 2 or more injury occurrences in a match were increased in matches resulting in a draw (OR, 1.39; 95% CI, 1.15-1.69) or loss (OR, 1.66; 95% CI, 1.38-1.98) compared with matches won and were decreased in other cup matches compared with league matches (OR, 0.57; 95% CI, 0.39-0.84) and in matches played away compared with home matches (OR, 0.70; 95% CI, 0.60-0.82). Finally, injuries with more than 1 week's absence occurred more frequently in Champions League matches compared with league matches both for matches with 1 injury (OR, 1.26; 95% CI, 1.09-1.45) and matches with 2 or more injuries (OR, 1.57; 95% CI, 1.13-2.20). CONCLUSION: The odds of 2 or more injury occurrences in professional soccer were higher in matches resulting in a loss or a draw compared with a win, whereas the odds of injury occurrences were lower in matches played away compared with home matches. The rate of moderate and severe injuries increased with the importance of the match. PMID- 23631882 TI - Symptomatic axillopectoral muscle in a swimmer: a case report. PMID- 23631883 TI - Arthroscopic repair of massive rotator cuff tears: outcome and analysis of factors associated with healing failure or poor postoperative function. AB - BACKGROUND: Many patients with an unhealed cuff after repair show functional improvement. PURPOSE: To evaluate outcomes of arthroscopically repaired massive rotator cuff tears and to identify prognostic factors affecting rotator cuff healing and functional outcome, especially in patients with failed rotator cuff healing. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Among 173 patients who underwent arthroscopic repair of a massive rotator cuff tear, 108 patients with a mean age of 63.7 years were included. Outcome evaluation was completed both anatomically (CT arthrography or ultrasonography) and functionally at a minimum of 1 year postoperatively; mean follow-up period was 31.68 +/- 15.81 months. Various factors affecting cuff healing were analyzed, and factors affecting functional outcome were evaluated in patients with failed repairs using both univariate and multivariate analyses. RESULTS: The anatomic failure rate was 39.8% in arthroscopically repaired massive rotator cuff tears; however, functional status significantly improved regardless of cuff healing (P < .05). Several factors were associated with failure of cuff healing in the univariate analysis, but only fatty infiltration (FI) of the infraspinatus was significantly related to healing failure in the multivariate analysis (P = .04). Among patients with failed rotator cuff healing, only reduced postoperative acromiohumeral distance (AHD) was related to poor functional outcome in the multivariate analysis (P = .01), with a cutoff value of 4.1 mm. CONCLUSION: Despite a high rate of healing failures, arthroscopic repair can be recommended in patients with massive rotator cuff tears because of the functional gain at midterm follow-up. Higher FI of the infraspinatus was the single most important factor negatively affecting cuff healing. In cases of failed massive rotator cuff repair, no preoperative factor was able to predict poor functional outcome; reduced postoperative AHD was the only relevant functional determinant in the patients' eventual functional outcome and should be considered when ascertaining a prognosis and planning further treatment strategies. PMID- 23631884 TI - Correlation between magnetic resonance imaging and clinical outcomes after cartilage repair surgery in the knee: a systematic review and meta-analysis. AB - BACKGROUND: Magnetic resonance imaging (MRI) is often used to assess cartilage after surgical repair. The correlation between MRI and clinical outcomes is not well understood. HYPOTHESIS: Postoperative MRI findings correlate with clinical outcome measures in patients after articular cartilage surgery of the knee. STUDY DESIGN: Meta-analysis. METHODS: A systematic review of the literature was performed to identify studies in which MRI and clinical outcomes were correlated after autologous chondrocyte implantation (ACI), osteochondral autograft transfer system (OATS), or microfracture. Studies that reported correlation coefficients (r) for different MRI parameters were then included in a meta-analysis. RESULTS: A total of 26 studies were identified for inclusion in this systematic review, 15 of which were included in the meta-analysis. Most of the studies (n = 19) involved ACI, although studies were available for OATS (n = 5) and microfracture (n = 4). The strongest MRI correlates with clinical outcomes after ACI were graft hypertrophy (r = 0.72) and repair tissue signal (r = 0.71). After microfracture, the strongest MRI correlates were the Henderson score (r = 0.97), subchondral edema (r = 0.77), and repair tissue signal (r = 0.76). Correlations after OATS were not as strong, with defect fill (r = 0.53) and repair tissue structure (r = 0.51) being the strongest. CONCLUSION: The MRI findings do correlate with clinical outcomes after cartilage repair surgery in the knee, although the specific parameters that correlate best vary by the type of procedure performed. No current MRI classification system has been shown to correlate with clinical outcomes after all types of cartilage repair surgery. PMID- 23631885 TI - Chronic electromyographic analysis of circadian locomotor activity in crayfish. AB - Animals generally exhibit circadian rhythms of locomotor activity. They initiate locomotor behavior not only reflexively in response to external stimuli but also spontaneously in the absence of any specific stimulus. The neuronal mechanisms underlying circadian locomotor activity can, therefore, be based on the rhythmic changes in either reflexive efficacy or endogenous activity. In crayfish Procambarus clarkii, it can be determined by analyzing electromyographic (EMG) patterns of walking legs whether the walking behavior is initiated reflexively or spontaneously. In this study, we examined quantitatively the leg muscle activity that underlies the locomotor behavior showing circadian rhythms in crayfish. We newly developed a chronic EMG recording system that allowed the animal to freely behave under a tethered condition for more than 10 days. In the LD condition in which the animals exhibited LD entrainment, the rhythmic burst activity of leg muscles for stepping behavior was preceded by non-rhythmic tonic activation that lasted for 1323+/-488ms when the animal initiated walking. In DD and LL free running conditions, the pre-burst activation lasted for 1779+/-31 and 1517+/-39ms respectively. In the mechanical stimulus-evoked walking, the pre-burst activation ended within 79+/-6ms. These data suggest that periodic changes in the crayfish locomotor activity under the condition of LD entrainment or free-running are based on activity changes in the spontaneous initiation mechanism of walking behavior rather than those in the sensori-motor pathway connecting mechanoreceptors with leg movements. PMID- 23631886 TI - Modulation of putative mirror neuron activity by both positively and negatively valenced affective stimuli: a TMS study. AB - Research indicates that mirror neurons are important for social cognition, including emotion processing. Emerging evidence, however, also reveals that emotional stimuli might be capable of modulating human mirror neuron system (MNS) activity. The current study used transcranial magnetic stimulation (TMS) to assess putative mirror neuron function following emotionally evocative images in twenty healthy adults. Participants observed videos of either a transitive hand action or a static hand while undergoing TMS of the primary motor cortex. In order to examine the effect of emotion on the MNS, each video was preceded by an image of either a positive, negative or neutral valence. MNS activity was found to be augmented by both the positive and negative (relative to neutral) stimuli, thus providing empirical support for a bi-directional link between emotion and the MNS, whereby both positively and negatively valenced stimuli are capable of facilitating mirror neuron activity. The potential adaptive significance of this finding is discussed. PMID- 23631887 TI - Women's attitude towards the use of complementary and alternative medicines (CAM) in pregnancy. AB - BACKGROUND: the popularity of non-prescription, over-the counter (OTC) medicines, vitamins, minerals, homoeopathic remedies and herbal supplements (CAM) has grown significantly in recent years. However, we have limited knowledge relating to why pregnant women use CAM and how this may relate to the provision of maternity care. Using an interview approach this study explored the nature of over-the counter and complementary medicines use in a sample of pregnant women. METHODS: this interview study formed part of a larger self-administered questionnaire survey on the extent of CAM use in pregnancy at large NHS Trust in England. The questionnaire provided the opportunity for women to complete a contact information reply slip if they were happy for follow-up interview. Audio recorded, face to face interviews were undertaken with a sample of 10 women. RESULTS: the reasons the women who were interviewed gave for using CAM broadly fell into two areas centred essentially on the contrasting advantages of CAM and disadvantages of conventional medicine. Doctors or midwives were rarely informed about the use of CAM medicines during pregnancy. CONCLUSION: the women saw CAM as outside of biomedicine and part of a holistic approach to health and well-being over which they are able to maintain their personal control. Non-disclosure of CAM use was common, a feature of which, appears to be some health-care professionals' lack of realisation of the importance, to women, of a holistic approach to their health, key to which is a desire to retain control over decisions associated with their well-being. PMID- 23631889 TI - Influence of psychosocial factors on the energy and protein intake of older people on dialysis. AB - OBJECTIVE: To explore the relationship between nutritional parameters and psychosocial factors in older people on dialysis. DESIGN: A cross-sectional observational study in prevalent older people on hemodialysis (HD) and peritoneal dialysis (PD). SETTING: A secondary analysis from a quality of life study in older people (Broadening Options for Long-term Dialysis in the Elderly). SUBJECTS: One-hundred and six patients 65 years of age or older and on dialysis for at least 90 days were purposively recruited (HD patients matched to PD patients by age, sex, dialysis vintage, ethnicity and Index of Deprivation). Half were on HD, the mean age was 72.7 years, 72% were male, 92% were from a White ethnic background, and 26% had diabetes. INTERVENTION: The patients attended one visit at which they completed nutritional assessments (3-day food diary, subjective global assessment, handgrip strength, and body mass index) and questionnaires: Short Form-12 (SF-12), the Hospital Anxiety and Depression Scale (HADS), the Mini Mental State Exam, and social networks. MAIN OUTCOME MEASURES: The differences in nutritional parameters between patients on PD and HD were determined by univariate analyses, and the relationships between nutritional intake and demographic, clinical, and psychosocial variables were determined by multivariate analyses. RESULTS: There was no difference in the energy and protein intake and nutritional status between older people on HD and PD. For the whole sample, multivariate analyses found that lower energy intake was related to fewer social networks (P = .002) and lower SF-12 Physical Component Scale (PCS) scores (P = .021). A lower protein intake was related to worsening Index of Deprivation scores (P = .028) and an interaction between SF-12 PCS and presence of possible depression (P = .015). CONCLUSION: Energy and protein intake in older people (regardless of modality) appears to be independently associated with psychosocial variables. PMID- 23631890 TI - Gender differences in intellectual performance persist at the limits of individual capabilities. AB - Males predominate at the top in chess, and chess is a useful domain to investigate possible causes of gender differences in high achievement. Opportunity, interest and extent of practice can be controlled for. Organized chess has objective performance measures, extensive longitudinal population-level data and little gatekeeper influence. Previous studies of gender differences in chess performance have not controlled adequately for females on average playing fewer rated games and dropping out at higher rates. The present study did so by examining performance of international chess players at asymptote and over equal numbers of rated games. Males still were very disproportionately represented at the top. Top female players showed signs of having less natural talent for chess than top males, such as taking more rated games to gain the grandmaster title. The hypothesis that males predominate because many more males play chess was tested by comparing gender performance differences in nations with varying percentages of female players. In well-practised participants, gender performance differences stayed constant even when the average national percentage of female international players increased from 4.2% to 32.3%. In Georgia, where women are encouraged strongly to play chess and females constitute nearly 32% of international players, gender performance differences are still sizeable. Males on average may have some innate advantages in developing and exercising chess skill. PMID- 23631888 TI - Association of serum phosphorus concentration with mortality in elderly and nonelderly hemodialysis patients. AB - OBJECTIVE: Hypo- and hyperphosphatemia have each been associated with increased mortality in maintenance hemodialysis (MHD) patients. There has not been previous evaluation of a differential relationship between serum phosphorus level and death risk across varying age groups in MHD patients. DESIGN AND SETTINGS: In a 6 year cohort of 107,817 MHD patients treated in a large dialysis organization, we examined the association between serum phosphorus levels with all-cause and cardiovascular mortality within 5 age categories (15 to <45, 45 to <65, 65 to <70, 70 to <75, and >=75 years old) using Cox proportional hazards models adjusted for case-mix covariates and malnutrition inflammation complex syndrome (MICS) surrogates. MAIN OUTCOME MEASURE: All-cause and cardiovascular mortality. RESULTS: The overall mean age of the cohort was 60 +/- 16 years, among whom there were 45% women, 35% Blacks, and 58% diabetics. The time-averaged serum phosphorus level (mean +/- SD) within each age category was 6.26 +/- 1.4, 5.65 +/- 1.2, 5.26 +/- 1.1, 5.11 +/- 1.0, and 4.88 +/- 1.0 mg/dL, respectively (P for trend <.001). Hyperphosphatemia (>5.5 mg/dL) was consistently associated with increased all cause and cardiovascular mortality risks across all age categories, including after adjustment for case-mix and MICS-related covariates. In fully adjusted models, a low serum phosphorus level (<3.5 mg/dL) was associated with increased all-cause mortality only in elderly MHD patients >=65 years old (hazard ratio [95% confidence interval]: 1.21 [1.07-1.37], 1.13 [1.02-1.25], and 1.28 [1.2 1.37] for patients 65 to <70, 70 to <75, and >=75 years old, respectively), but not in younger patients (<65 years old). A similar differential cardiovascular mortality risk for low serum phosphorus levels between old and young age groups was observed. CONCLUSIONS: The association between hyperphosphatemia and mortality is similar across all age groups of MHD patients, whereas hypophosphatemia is associated with increased mortality only in elderly MHD patients. Preventing very low serum phosphorus levels in elderly dialysis patients may be associated with better outcomes, which needs to be examined in future studies. PMID- 23631891 TI - Secondary vitellogenesis persists despite disrupted fecundity in amphipods maintained on metal-contaminated sediment: X-ray fluorescence assessment of oocyte metal content. AB - Melita plumulosa is an epibenthic, detritivorous amphipod found in estuaries along the eastern coast of Australia. It has been utilized as a test organism in rapid ten to thirteen days reproduction toxicity tests for sediment quality assessment. The fecundity of females in the toxicity test has been found to be inhibited by exposure of the amphipods to contaminated sediments enriched with zinc and other metals. This study investigated the proposal that interference in vitellogenesis is the cause of reproductive toxicity of metals in crustaceans. Inspection of the ovaries from amphipods on day 6 of the test either from control or Zn/Pb/Cd/Cu-spiked sediment, that were nearing completion of vitellogenesis, showed that the females in all treatments were producing similar numbers of oocytes undergoing secondary vitellogenesis. The distribution of the Zn, Cu and Pb in the oocytes and ventral caeca of females was examined by X-ray fluorescence microscopy. Elemental mapping revealed a dense accumulation of Zn in primary oocytes and a uniform distribution of Zn and Cu in the secondary oocytes in all treatments. Zn and Cu were also observed to be uniformly distributed in the ventral caeca. Pb was not detected in either of these tissues. The apparent normal morphology and the typical number of oocytes undergoing secondary vitellogenesis suggest that vitellogenesis was not being disrupted by Pb displacing Zn in the metal-binding domain of vitellogenin in amphipods exposed to the contaminated sediment during the test. Alternative mechanisms for the reproductive toxicity of amphipods exposed for six days to metal-contaminated sediment are discussed. PMID- 23631892 TI - Technique tip: percutaneous fixation of partial incongruous Lisfranc injuries in athletes. AB - Open reduction with screw fixation is considered the standard surgical approach for injuries of the Lisfranc complex in athletes. However, multiple incisions are required, which increase the risk for postoperative complications. We present a novel percutaneous reduction and solid screw fixation technique that may be a viable option to address partial incongruous injuries of the Lisfranc complex in athletes. At our institution, no intraoperative or postoperative complications have been encountered. Screw breakage did not occur. Reduction of the second metatarsal was considered anatomic across all patients. All patients have returned to their respective sport without limitation. The percutaneous approach appears to decrease complications while the targeting-reduction guide appears to precisely reduce the injury. Consequently, outcomes have been more consistent and predictable. The authors note that this percutaneous approach is specific to partial incongruous injuries of the Lisfranc complex. When presented with more extensive injuries, the authors advocate an open approach. PMID- 23631893 TI - Who does well where? Exploring how self-rated health differs across diverse people and neighborhoods. AB - This work establishes whether neighborhood disadvantage amplifies the impact of socioeconomic position (SEP) on a graded measure of self-rated health (SRH). SRH data were taken from 10,932 adults recruited across 200 Brisbane neighborhoods. After adjusting for demographics, those who lived in the most disadvantaged neighborhoods were more likely to report poor SRH than those living in the least disadvantaged neighborhoods (OR=2.67). Those with the lowest SEP and lived in the most advantaged neighborhoods had a similar probability of reporting excellent SRH as those with the highest SEP living in the most disadvantaged neighborhoods. This work highlights the importance of examining SEP and neighborhood-level disadvantage simultaneously when planning communities. PMID- 23631894 TI - Tick-borne encephalitis virus in horses, Austria, 2011. AB - An unexpectedly high infection rate (26.1%) of tick-borne encephalitis virus (TBEV) was identified in a herd of 257 horses of the same breed distributed among 3 federal states in Austria. Young age (p<0.001) and male sex (p=0.001) were positively associated with infection. PMID- 23631895 TI - The tiles make a puzzle but the single tile is not the puzzle: the need for a global assessment of the patient. PMID- 23631897 TI - Partial removal of pore and loosely bound water by low-energy drying decreases cortical bone toughness in young and old donors. AB - With an ability to quantify matrix-bound and pore water in bone, (1)H nuclear magnetic resonance (NMR) relaxometry can potentially be implemented in clinical imaging to assess the fracture resistance of bone in a way that is independent of current X-ray techniques, which assess bone mineral density as a correlate of bone strength. Working towards that goal, we quantified the effect of partial dehydration in air on the mechanical and NMR properties of human cortical bone in order to understand whether NMR is sensitive to water-bone interactions at low energy and whether such interactions contribute to the age-related difference in the toughness of bone. Cadaveric femurs were collected from male and female donors falling into two age groups: 21-60 years of age (young) and 74-99 years of age (old). After extracting two samples from the medial cortex of the mid-shaft, tensile tests were conducted on Wet specimens and paired, Partially Dry (PtlD) specimens (prepared by low-energy drying in air to remove ~3% of original mass before testing). Prior analysis by micro-computed tomography found that there were no differences in intra-cortical porosity between the Wet and PtlD specimens nor did an age-related difference in porosity exist. PtlD specimens from young and old donors had significantly less toughness than Wet specimens, primarily due to a dehydration-related decrease in post-yield strain. The low-energy drying protocol did not affect the modulus and yield strength of bone. Subsequent dehydration of the PtlD specimens in a vacuum oven at 62 degrees C and then 103 degrees C, with quantification of water loss at each temperature, revealed an age related shift from more loosely bound water to more tightly bound water. NMR detected a change in both bound and pore water pools with low-energy air-drying, and both pools were effectively removed when bone was oven-dried at 62 degrees C, irrespective of donor age. Although not strictly significant due to variability in the drying and testing conditions, the absolute difference in toughness between Wet and PtlD tended to be greater for the younger donors that had higher bone toughness and more bound water for the wet condition than did the older donors. With sensitivity to low-energy bone-water interactions, NMR, which underpins magnetic resonance imaging, has potential to assess fracture resistance of bone as it relates to bone toughness. PMID- 23631898 TI - Bioethics on the couch. PMID- 23631899 TI - Adsorptive removal of phosphorus from aqueous solution using sponge iron and zeolite. AB - Phosphorus adsorptive removal is an important and efficient treatment process in constructed subsurface flow wetlands. Many materials have been proposed for removal of excess phosphorus from wastewater. Selecting a substrate with a high phosphorus adsorption capacity is therefore important in obtaining significant phosphorus removal. In this study, the phosphorus removal capacities of sponge iron and zeolite were evaluated and related to their physico-chemical characteristics. The potential mechanisms affecting the adsorptive removal of phosphorus from aqueous solutions onto sponge iron and zeolite were investigated in batch experiments. The pseudo-second-order kinetics were useful since the adsorption rate data fitted well. The Freundlich and Langmuir models well described the adsorption isotherm data. The results of static experiments and dynamic experiments (column experiments) indicated that the adsorption of phosphorus onto sponge iron was more apt to chemical combination, but zeolite was more apt to electrostatic attraction or ion-exchange. For sponge iron, some iron (iii) (Fe(3+)) or iron (ii) (Fe(2+)) and phosphate ions (P) form Fe-P, the solid phases compound was fixed. For zeolite, aluminum oxide and silicon oxide formed complexes in aqueous solution. It was observed that positive or negative charge surface sites favored the adsorption of phosphate due to the electrostatic attraction or ion-exchange. PMID- 23631900 TI - Estrogen prevents cardiac and vascular failure in the 'listless' zebrafish (Danio rerio) developmental model. AB - The presence of a robust estrogen (E2) response system throughout heart and blood vessel tissues of vertebrates, including humans, has led to the speculation that this ubiquitous hormone may play a prominent role in the health and maintenance of the adult cardiovascular system (CVS). We previously established an embryonic zebrafish model called 'listless', which results from the inhibition of E2 synthesis by treatment with aromatase enzyme inhibitors (AI). These fish have outward symptoms similar to the human condition of congestive heart failure and tamponade. E2 replacement therapy (1) reduced the severity of cardiac sac abnormalities, (2) protected heart function, (3) prevented reduction in heart size, and (4) reduced blood vessel deterioration. Nitric oxide may be a critical downstream mediator of these events. We also demonstrate that removal of fluid around the heart increases survival of AI-treated fish. These results strongly indicate the importance of E2 in the developing CVS of the zebrafish and offer a potential model for the study of its role in CVS development, maintenance, and disease conditions. PMID- 23631901 TI - Avian circannual systems: persistence and sex differences. AB - Birds show adaptation in their physiology and behavior to daily and seasonal periodicities in the environment. A circannual clock system gates seasonal events in birds to happen at the most appropriate time of the year, since a mistiming will delay the event until the arrival of the favorable time next year. The circannual clocks, the self-sustained endogenous system, are expressed under aperiodic conditions with a period close to 12months. In stonechats, it has been shown that circannual rhythms in testicular and molt cycles persist for 12years; this suggests that circannual clocks are functional throughout the life of an individual. Circannual rhythms are synchronized with both the photoperiodic and non-photoperiodic cues, and a synchronized circannual rhythm provides information on annual timing of the physiological event. The integration of rigid circannual timekeeping with the cyclic environment ensures phenotypic plasticity that is required for successful survival of a species in its habitat. There can be however sex differences in the circannual rhythm characteristics and in the relationship between circannual rhythms and external environment. In few cases that have been investigated, females appear playing a larger role in defining the breeding season in the year in relation to the environment. There is no evidence for the involvement of circadian clock in the generation of circannual rhythms. Therefore, future researches need to focus on finding molecular gears that possibly form the neuroendocrine loop and are translated into a seasonal event. Here, we briefly review limited information that is available on circannual rhythms and their relationship with the external environment from a few bird species, inhabiting tropical and temperate environments. PMID- 23631896 TI - Splicing therapy for neuromuscular disease. AB - Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) are two of the most common inherited neuromuscular diseases in humans. Both conditions are fatal and no clinically available treatments are able to significantly alter disease course in either case. However, by manipulation of pre-mRNA splicing using antisense oligonucleotides, defective transcripts from the DMD gene and from the SMN2 gene in SMA can be modified to once again produce protein and restore function. A large number of in vitro and in vivo studies have validated the applicability of this approach and an increasing number of preliminary clinical trials have either been completed or are under way. Several different oligonucleotide chemistries can be used for this purpose and various strategies are being developed to facilitate increased delivery efficiency and prolonged therapeutic effect. As these novel therapeutic compounds start to enter the clinical arena, attention must also be drawn to the question of how best to facilitate the clinical development of such personalised genetic therapies and how best to implement their provision. PMID- 23631902 TI - The role of thyroid hormones in regulation of chicken ovarian steroidogenesis. AB - In all vertebrates, including birds, the normal development of the ovary and ovarian follicles is under the regulatory influence of hormones produced by the reproductive axis. In recent years, it has become clear that in birds an adequate level of thyroid hormones (THs), i.e. thyroxine (T4) and triiodothyronine (T3), in blood circulation is of primary importance for normal female reproductive functions. In avian species, characterized by seasonal reproduction, THs are involved in the photoperiodic regulation of reproduction acting at the mediobasal hypothalamus. In domestic fowl, where the seasonality of reproduction has been eliminated, the role of THs in ovarian function is not fully elucidated. Recent studies have revealed that ovarian follicles of the laying hen express mRNAs of TH nuclear receptors (TRalpha and TRbeta0) as well as integrin (alphaVbeta3) plasma membrane receptors, indicating genomic and nongenomic action of THs in the chicken ovary. In vivo experiments carried out on laying hens have showed that the bolus injection of T3 decreases levels of luteinizing hormone (LH) and estradiol (E2) in blood, and a hyperthyroid state evoked by administration of T3 for few days diminishes LH, E2 and progesterone (P4) levels, reduces the weight of the ovary, induces atresia of preovulatory follicles and eventually causes stoppage of egg laying. In vitro studies have demonstrated that T3 decreases E2 secretion from white nonhierarchical follicles and the theca layer of yellow preovulatory follicles, while on the other hand, it elevates P4 production from the granulosa layer of these follicles. These effects have been associated with steroidogenic enzyme expression and cyclic AMP synthesis. This review summarizes the current knowledge concerning the role of THs in regulation of steroidogenesis in chicken ovarian follicles. PMID- 23631903 TI - Update on ghrelin biology in birds. AB - Ghrelin is a peptide found in the mucosal layer of the rat stomach that exhibits growth hormone-releasing and appetite-stimulating activities. Since the discovery of ghrelin in chicken in 2002, information on its structure, distribution, function, and receptors has been accumulated, mainly in poultry. Here, we summarize the following findings since 2008 in birds: (1) central ghrelin acts as an anorexigenic neuropeptide, but the effect of peripheral ghrelin differs depending on the chicken strain and light conditions the birds are kept in; (2) central ghrelin inhibits not only food intake but also water drinking, and it may be mediated by urocortin, a member of the corticotropin-releasing factor family; (3) peripheral ghrelin acts as an anti-lipogenic factor in broiler chickens but not in rats; (4) the enzyme involved in ghrelin acylation (ghrelin-O acyltransferase [GOAT]) has been identified in chickens; (5) dietary lipids are used for ghrelin acylation; (6) des-acyl ghrelin administered alone or with ghrelin does not affect feeding behavior; (7) the existence and physiological function of obestatin must now be carefully examined in birds; (8) other than the growth hormone secretagogue receptors (GHS) R1a and 1b, GHS-R variants not found in mammals have been found in chicken and Japanese quail; and finally (9) little is known about the involvement of the ghrelin system in wild birds and in avian specific behavior such as brooding and migration. PMID- 23631904 TI - Stage-specific gene expression during spermatogenesis in the Senegalese sole (Solea senegalensis), a fish with semi-cystic type of spermatogenesis, as assessed by laser capture microdissection and absolute quantitative PCR. AB - Spermatogenesis is a complex process where hormonal signals regulate the interaction of different cell types in a tight spatial and temporal fashion. The Senegalese sole (Solea senegalensis) is a marine flatfish that, in contrast to many fish, exhibits a semi-cystic, asynchronous pattern of spermatogenesis progression. This pattern is characterized by the release of spermatids into the tubule lumen, where they transform into spermatozoa. In this study, we used laser capture microdissection (LCM) to isolate cells from cysts containing spermatogonia, spermatocytes, spermatids or spermatozoa in order to investigate developmental patterns of gene expression. Furthermore, we also analyzed the stage-specific expression of the same set of genes throughout spermatogenesis (early-mid, late and maturing spermatogenic stages) in tissue fragments of the Senegalese sole testis. Genes analyzed by absolute qPCR in cysts isolated by LCM and stage-specific testis samples included genes involved in steroid synthesis and action (3beta-hsd, 17beta-hsd, 20beta-hsd, star, star-like, progesterone receptor), gonadotropin action (fshr, lhr), the kisspeptin system (kiss2, kiss2r) and other genes important for the production of mature gametes (zona pellucida 2.2, claudin and clusterin). Our results show that, in general, steroidogenesis related genes tended to increase with spermatogenesis progression and that 3beta hsd and 20beta-hsd were expressed in germ cells but 17beta-hsd was not. Our results also show that fshr is expressed in most testicular cell types, including germ cells. In contrast, lhr is expressed only in late spermatogenesis and is not expressed in any of the germ cell types examined, indicating that, in contrast to fshr, lhr may be primarily expressed in non-germinal cells (e.g. Leydig cells). Furthermore, kisspeptin and its receptor were expressed in all germ cell types examined and, as expected, gamete maturation-related genes were more expressed in mature stages. These results illustrate that key factors that participate in the hormonal regulation of spermatogenesis in the Senegalese sole testis show complex cell type- and stage-specific patterns of gene expression. PMID- 23631905 TI - FPGA implementation of a configurable neuromorphic CPG-based locomotion controller. AB - Neuromorphic engineering is a discipline devoted to the design and development of computational hardware that mimics the characteristics and capabilities of neuro biological systems. In recent years, neuromorphic hardware systems have been implemented using a hybrid approach incorporating digital hardware so as to provide flexibility and scalability at the cost of power efficiency and some biological realism. This paper proposes an FPGA-based neuromorphic-like embedded system on a chip to generate locomotion patterns of periodic rhythmic movements inspired by Central Pattern Generators (CPGs). The proposed implementation follows a top-down approach where modularity and hierarchy are two desirable features. The locomotion controller is based on CPG models to produce rhythmic locomotion patterns or gaits for legged robots such as quadrupeds and hexapods. The architecture is configurable and scalable for robots with either different morphologies or different degrees of freedom (DOFs). Experiments performed on a real robot are presented and discussed. The obtained results demonstrate that the CPG-based controller provides the necessary flexibility to generate different rhythmic patterns at run-time suitable for adaptable locomotion. PMID- 23631906 TI - The effect of recent trends in vehicle design on U.S. societal fatality risk per vehicle mile traveled, and their projected future relationship with vehicle mass. AB - The National Highway Traffic Safety Administration (NHTSA) recently updated its 2003 and 2010 logistic regression analyses of the effect of a reduction in light duty vehicle mass on US fatality risk per vehicle mile traveled (VMT). The current NHTSA analysis is the most thorough investigation of this issue to date. LBNL's assessment of the analysis indicates that the estimated effect of mass reduction on risk is smaller than in the previous studies, and statistically non significant for all but the lightest cars. The effects three recent trends in vehicle designs and technologies have on societal fatality risk per VMT are estimated, and whether these changes might affect the relationship between vehicle mass and fatality risk in the future. Side airbags are found to reduce fatality risk in cars, but not necessarily light trucks or CUVs/minivans, struck in the side by another light-duty vehicle; reducing the number of fatalities in cars struck in the side is predicted to reduce the estimated detrimental effect of footprint reduction, but increase the detrimental effect of mass reduction, in cars on societal fatality risk. Better alignment of light truck bumpers with those of other vehicles appears to result in a statistically significant reduction in risk imposed on car occupants; however, reducing this type of fatality will likely have little impact on the estimated effect of mass or footprint reduction on risk. Finally, shifting light truck drivers into safer, car-based vehicles, such as sedans, CUVs, and minivans, would result in larger reductions in societal fatalities than expected from even substantial reductions in the masses of light trucks. A strategy of shifting drivers from truck-based to car-based vehicles would reduce fuel use and greenhouse gas emissions, while improving societal safety. PMID- 23631907 TI - A practical cost-effective management strategy for gallstone pancreatitis. AB - BACKGROUND: The purpose of this study was to evaluate the outcomes of various surgeon strategies used to evaluate and treat common duct stones (CDSs) in patients presenting with mild to moderate gallstone pancreatitis (GP). METHODS: We performed a retrospective review of patients admitted for mild to moderate GP. Data variables included laboratory values and radiology images, indications for and findings of intraoperative cholangiogram (IOC) and endoscopic retrograde cholangiopancreatography (ERCP), length of stay (LOS), and hospital charges. Data were stratified by 2 different management strategies: preoperative ERCP and then laparoscopic cholecystectomy (LC) or LC with IOC followed by selective postoperative ERCP. RESULTS: During this time period, 80 patients met the study criteria, 56 were treated by LC with IOC, and 24 had a preoperative ERCP performed. The incidence of CDS was 33% (n = 26). The presence of CDSs correlated with an elevated total bilirubin at admission (CDSs 3.5 mg/dL vs 2.1 mg/dL no CDSs, P < .01) and 24 hours after admission (CDS 3.2 mg/dL vs 1.5 mg/dL no CDS, P < .01). Patients who had an IOC compared with those who had preoperative ERCP had a shorter LOS (4.6 vs 5.9 days, P = .04) and lower hospital charges (US $28,510 vs US $38,620; P < .01). CONCLUSIONS: Elevated total bilirubin at admission and 24 hours after admission may predict a patient's risk for CDS. We found that the management of uncomplicated GP with early LC and IOC results in decreased LOS and total hospital charges when compared with preoperative ERCP. PMID- 23631908 TI - Comparison of two approaches for identification of haplotypes and point mutations in Candida albicans and Saccharomyces cerevisiae. AB - The human fungal pathogen Candida albicans displays a very high degree of plasticity, including the types of genomic changes frequently observed with cancer cells, such as gross chromosomal rearrangements, aneuploidy, and loss of heterozygosity. Despite its relevance to every aspect of genetics and evolution of this pathogen, our understanding of the mutation process and its bearing on organismal fitness remains quite limited. Here, we have evaluated and compared two approaches to estimate the mutation frequency at three ORFs/regions (HIS4, CEN4 and EST2) of the C. albicans genome. Sequencing of individual DNA molecules (clone-by-clone sequencing) identified de novo mutations at these DNA regions, whose frequency was similar to that observed for S. cerevisiae at homolog sites following the same approach. However, mutations were not detected when the same regions were directly sequenced from the pooled DNA. In addition, in the absence of the homologous recombination protein Rad52, mutation frequency within these sites remained unaltered. The use of an alternative polymerase also found mutations. These results suggest that at least some mutations are artifacts caused by the polymerase used, advising that post-PCR procedures might generate mutations which may become undistinguishable from the genuine mutations and thus may interfere with mutational analysis. Furthermore, we recommend that new mutations found in the sequences of cloned alleles used for the determination of haplotypes should be contrasted with the sequence yielded by the pooled DNA. PMID- 23631909 TI - A simple shotgun proteomics method for rapid bacterial identification. AB - Bacterial pathogens were rapidly identified by shotgun proteomics using a novel, easy to implement database search strategy. Peptide sequence data from nano-LC MS/MS was searched against a database represented by concatenated proteomes of completed genome sequences. Select bacterial species, including BSL-3 select agents, were used to demonstrate this method. PMID- 23631910 TI - The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis. AB - Tissue factor pathway inhibitor (TFPI) is the main inhibitor of tissue factor (TF)-mediated coagulation. In atherosclerotic plaques TFPI co-localizes with TF, where it is believed to play an important role in attenuating TF activity. Findings in animal models such as TFPI knockout models and gene transfer models are consistent on the role of TFPI in arterial thrombosis as they reveal an active role for TFPI in attenuating arterial thrombus formation. In addition, ample experimental evidence exists indicating that TFPI has inhibitory effects on both smooth muscle cell migration and proliferation, both which are recognized as important pathological features in atherosclerosis development. Nonetheless, the clinical relevance of these antithrombotic and atheroprotective effects remains unclear. Paradoxically, the majority of clinical studies find increased instead of decreased TFPI antigen and activity levels in atherothrombotic disease, particularly in atherosclerosis and coronary artery disease (CAD). Increased TFPI levels in cardiovascular disease might result from complex interactions with established cardiovascular risk factors, such as hypercholesterolemia, diabetes and smoking. Moreover, it is postulated that increased TFPI levels reflect either the amount of endothelial perturbation and platelet activation, or a compensatory mechanism for the increased procoagulant state observed in cardiovascular disease. In all, the prognostic value of plasma TFPI in cardiovascular disease remains to be established. The current review focuses on TFPI in clinical studies of asymptomatic and symptomatic atherosclerosis, coronary artery disease and ischemic stroke, and discusses potential atheroprotective actions of TFPI. PMID- 23631911 TI - Pan-genome and comparative genome analyses of propionibacterium acnes reveal its genomic diversity in the healthy and diseased human skin microbiome. AB - Propionibacterium acnes constitutes a major part of the skin microbiome and contributes to human health. However, it has also been implicated as a pathogenic factor in several diseases, including acne, one of the most common skin diseases. Its pathogenic role, however, remains elusive. To better understand the genetic landscape and diversity of the organism and its role in human health and disease, we performed a comparative genome analysis of 82 P. acnes strains, 69 of which were sequenced by our group. This collection covers all known P. acnes lineages, including types IA, IB, II, and III. Our analysis demonstrated that although the P. acnes pan-genome is open, it is relatively small and expands slowly. The core regions, shared by all the sequenced genomes, accounted for 88% of the average genome. Comparative genome analysis showed that within each lineage, the strains isolated from the same individuals were more closely related than the ones isolated from different individuals, suggesting that clonal expansions occurred within each individual microbiome. We also identified the genetic elements specific to each lineage. Differences in harboring these elements may explain the phenotypic and functional differences of P. acnes in functioning as a commensal in healthy skin and as a pathogen in diseases. Our findings of the differences among P. acnes strains at the genome level underscore the importance of identifying the human microbiome variations at the strain level in understanding its association with diseases and provide insight into novel and personalized therapeutic approaches for P. acnes-related diseases. IMPORTANCE: Propionibacterium acnes is a major human skin bacterium. It plays an important role in maintaining skin health. However, it has also been hypothesized to be a pathogenic factor in several diseases, including acne, a common skin disease affecting 85% of teenagers. To understand whether different strains have different virulent properties and thus play different roles in health and diseases, we compared the genomes of 82 P. acnes strains, most of which were isolated from acne or healthy skin. We identified lineage-specific genetic elements that may explain the phenotypic and functional differences of P. acnes as a commensal in health and as a pathogen in diseases. By analyzing a large number of sequenced strains, we provided an improved understanding of the genetic landscape and diversity of the organism at the strain level and at the molecular level that can be further applied in the development of new and personalized therapies. PMID- 23631913 TI - Genome sequencing of the plant pathogen Taphrina deformans, the causal agent of peach leaf curl. AB - Taphrina deformans is a fungus responsible for peach leaf curl, an important plant disease. It is phylogenetically assigned to the Taphrinomycotina subphylum, which includes the fission yeast and the mammalian pathogens of the genus Pneumocystis. We describe here the genome of T. deformans in the light of its dual plant-saprophytic/plant-parasitic lifestyle. The 13.3-Mb genome contains few identifiable repeated elements (ca. 1.5%) and a relatively high GC content (49.5%). A total of 5,735 protein-coding genes were identified, among which 83% share similarities with other fungi. Adaptation to the plant host seems reflected in the genome, since the genome carries genes involved in plant cell wall degradation (e.g., cellulases and cutinases), secondary metabolism, the hallmark glyoxylate cycle, detoxification, and sterol biosynthesis, as well as genes involved in the biosynthesis of plant hormones. Genes involved in lipid metabolism may play a role in its virulence. Several locus candidates for putative MAT cassettes and sex-related genes akin to those of Schizosaccharomyces pombe were identified. A mating-type-switching mechanism similar to that found in ascomycetous yeasts could be in effect. Taken together, the findings are consistent with the alternate saprophytic and parasitic-pathogenic lifestyles of T. deformans. IMPORTANCE: Peach leaf curl is an important plant disease which causes significant losses of fruit production. We report here the genome sequence of the causative agent of the disease, the fungus Taphrina deformans. The genome carries characteristic genes that are important for the plant infection process. These include (i) proteases that allow degradation of the plant tissues; (ii) secondary metabolites which are products favoring interaction of the fungus with the environment, including the host; (iii) hormones that are responsible for the symptom of severely distorted leaves on the host; and (iv) drug detoxification enzymes that confer resistance to fungicides. The availability of the genome allows the design of new drug targets as well as the elaboration of specific management strategies to fight the disease. PMID- 23631912 TI - STING-dependent recognition of cyclic di-AMP mediates type I interferon responses during Chlamydia trachomatis infection. AB - STING (stimulator of interferon [IFN] genes) initiates type I IFN responses in mammalian cells through the detection of microbial nucleic acids. The membrane bound obligate intracellular bacterium Chlamydia trachomatis induces a STING dependent type I IFN response in infected cells, yet the IFN-inducing ligand remains unknown. In this report, we provide evidence that Chlamydia synthesizes cyclic di-AMP (c-di-AMP), a nucleic acid metabolite not previously identified in Gram-negative bacteria, and that this metabolite is a prominent ligand for STING mediated activation of IFN responses during infection. We used primary mouse lung fibroblasts and HEK293T cells to compare IFN-beta responses to Chlamydia infection, c-di-AMP, and other type I IFN-inducing stimuli. Chlamydia infection and c-di-AMP treatment induced type I IFN responses in cells expressing STING but not in cells expressing STING variants that cannot sense cyclic dinucleotides but still respond to cytoplasmic DNA. The failure to induce a type I IFN response to Chlamydia and c-di-AMP correlated with the inability of STING to relocalize from the endoplasmic reticulum to cytoplasmic punctate signaling complexes required for IFN activation. We conclude that Chlamydia induces STING-mediated IFN responses through the detection of c-di-AMP in the host cell cytosol and propose that c-di-AMP is the ligand predominantly responsible for inducing such a response in Chlamydia-infected cells. IMPORTANCE: This study shows that the Gram negative obligate pathogen Chlamydia trachomatis, a major cause of pelvic inflammatory disease and infertility, synthesizes cyclic di-AMP (c-di-AMP), a nucleic acid metabolite that thus far has been described only in Gram-positive bacteria. We further provide evidence that the host cell employs an endoplasmic reticulum (ER)-localized cytoplasmic sensor, STING (stimulator of interferon [IFN] genes), to detect c-di-AMP synthesized by Chlamydia and induce a protective IFN response. This detection occurs even though Chlamydia is confined to a membrane-bound vacuole. This raises the possibility that the ER, an organelle that innervates the entire cytoplasm, is equipped with pattern recognition receptors that can directly survey membrane-bound pathogen-containing vacuoles for leaking microbe-specific metabolites to mount type I IFN responses required to control microbial infections. PMID- 23631914 TI - Fungal virulence in a lepidopteran model is an emergent property with deterministic features. AB - ABSTRACT Virulence has been proposed to be an emergent property, which by definition implies that it is not reducible to its components, but this application of a philosophical concept to the host-microbe interaction has not been experimentally tested. The goals of our study were to analyze the correlation of the phenotype with the ability to cause disease and to determine the dynamics of an experimental cryptococcal infection in Galleria mellonella and Acanthamoeba castellanii. By studying the outcome of infection as host death, we showed that the dynamics of virulence in the G. mellonella/Cryptococcus neoformans interaction follow a predictable pattern. We also found that the experimental temperature and not the presence of virulence factors was a critical parameter defining the pathogenic potential of cryptococcal species. Our results established that cryptococcal species not considered pathogenic could be pathogens given suitable conditions. Our results support the idea that virulence is an emergent property that cannot be easily predicted by a reductionist approach and yet it behaves as a deterministic system in a lepidopteran cryptococcal infection. These findings provide a road map for evaluating whether host-microbe interactions in other systems are chaotic, deterministic, or stochastic, including those with public health importance. IMPORTANCE: Virulence is a complex phenotype that cannot be easily studied by analyzing its individual components in isolation. By studying the outcome of infection as the death of the host, we found that a given microbial phenotype does not necessarily correlate with its ability to cause disease and that the presence of so-called virulence factors does not predict pathogenicity, consistent with the notion that virulence is an emergent property. This paper reports that the dynamics of virulence in Galleria mellonella larvae infected with the fungus Cryptococcus neoformans follows a predictable pattern. Establishing that virulence is an emergent property is important because it implies that it is not reducible to its components, and consequently, this phenomenon needs to be studied by a holistic approach. PMID- 23631915 TI - Generation of high current densities by pure cultures of anode-respiring Geoalkalibacter spp. under alkaline and saline conditions in microbial electrochemical cells. AB - Anode-respiring bacteria (ARB) generate electric current in microbial electrochemical cells (MXCs) by channeling electrons from the oxidation of organic substrates to an electrode. Production of high current densities by monocultures in MXCs has resulted almost exclusively from the activity of Geobacter sulfurreducens, a neutrophilic freshwater Fe(III)-reducing bacterium and the highest-current-producing member documented for the Geobacteraceae family of the Deltaproteobacteria. Here we report high current densities generated by haloalkaliphilic Geoalkalibacter spp., thus broadening the capability for high anode respiration rates by including other genera within the Geobacteraceae. In this study, acetate-fed pure cultures of two related Geoalkalibacter spp. produced current densities of 5.0 to 8.3 and 2.4 to 3.3 A m(-2) under alkaline (pH 9.3) and saline (1.7% NaCl) conditions, respectively. Chronoamperometric studies of halophilic Glk. subterraneus DSM 23483 and alkaliphilic Glk. ferrihydriticus DSM 17813 suggested that cells performed long-range electron transfer through electrode-attached biofilms and not through soluble electron shuttles. Glk. ferrihydriticus also oxidized ethanol directly to produce current, with maximum current densities of 5.7 to 7.1 A m(-2) and coulombic efficiencies of 84 to 95%. Cyclic voltammetry (CV) elicited a sigmoidal response with characteristic onset, midpoint, and saturation potentials, while CV performed in the absence of an electron donor suggested the involvement of redox molecules in the biofilm that were limited by diffusion. These results matched those previously reported for actively respiring Gb. sulfurreducens biofilms producing similar current densities (~5 to 9 A m(-2)). IMPORTANCE: This study establishes the highest current densities ever achieved by pure cultures of anode-respiring bacteria (ARB) under alkaline and saline conditions in microbial electrochemical cells (MXCs) and provides the first electrochemical characterization of the genus Geoalkalibacter. Production of high current densities among the Geobacteraceae is no longer exclusive to Geobacter sulfurreducens, suggesting greater versatility for this family in fundamental and applied microbial electrochemical cell (MXC) research than previously considered. Additionally, this work raises the possibility that different members of the Geobacteraceae have conserved molecular mechanisms governing respiratory extracellular electron transfer to electrodes. Thus, the capacity for high current generation may exist in other uncultivated members of this family. Advancement of MXC technology for practical uses must rely on an expanded suite of ARB capable of using different electron donors and producing high current densities under various conditions. Geoalkalibacter spp. can potentially broaden the practical capabilities of MXCs to include energy generation and waste treatment under expanded ranges of salinity and pH. PMID- 23631916 TI - Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. AB - A novel human coronavirus (HCoV-EMC) was recently identified in the Middle East as the causative agent of a severe acute respiratory syndrome (SARS) resembling the illness caused by SARS coronavirus (SARS-CoV). Although derived from the CoV family, the two viruses are genetically distinct and do not use the same receptor. Here, we investigated whether HCoV-EMC and SARS-CoV induce similar or distinct host responses after infection of a human lung epithelial cell line. HCoV-EMC was able to replicate as efficiently as SARS-CoV in Calu-3 cells and similarly induced minimal transcriptomic changes before 12 h postinfection. Later in infection, HCoV-EMC induced a massive dysregulation of the host transcriptome, to a much greater extent than SARS-CoV. Both viruses induced a similar activation of pattern recognition receptors and the interleukin 17 (IL-17) pathway, but HCoV EMC specifically down-regulated the expression of several genes within the antigen presentation pathway, including both type I and II major histocompatibility complex (MHC) genes. This could have an important impact on the ability of the host to mount an adaptive host response. A unique set of 207 genes was dysregulated early and permanently throughout infection with HCoV-EMC, and was used in a computational screen to predict potential antiviral compounds, including kinase inhibitors and glucocorticoids. Overall, HCoV-EMC and SARS-CoV elicit distinct host gene expression responses, which might impact in vivo pathogenesis and could orient therapeutic strategies against that emergent virus. IMPORTANCE: Identification of a novel coronavirus causing fatal respiratory infection in humans raises concerns about a possible widespread outbreak of severe respiratory infection similar to the one caused by SARS-CoV. Using a human lung epithelial cell line and global transcriptomic profiling, we identified differences in the host response between HCoV-EMC and SARS-CoV. This enables rapid assessment of viral properties and the ability to anticipate possible differences in human clinical responses to HCoV-EMC and SARS-CoV. We used this information to predict potential effective drugs against HCoV-EMC, a method that could be more generally used to identify candidate therapeutics in future disease outbreaks. These data will help to generate hypotheses and make rapid advancements in characterizing this new virus. PMID- 23631917 TI - Anthrax toxin-mediated delivery of the Pseudomonas exotoxin A enzymatic domain to the cytosol of tumor cells via cleavable ubiquitin fusions. AB - Anthrax toxin proteins from Bacillus anthracis constitute a highly efficient system for delivering cytotoxic enzymes to the cytosol of tumor cells. However, exogenous proteins delivered to the cytosol of cells are subject to ubiquitination on lysines and proteasomal degradation, which limit their potency. We created fusion proteins containing modified ubiquitins with their C-terminal regions fused to the Pseudomonas exotoxin A catalytic domain (PEIII) in order to achieve delivery and release of PEIII to the cytosol. Fusion proteins in which all seven lysines of wild-type ubiquitin were retained while the site cleaved by cytosolic deubiquitinating enzymes (DUBs) was removed were nontoxic, apparently due to rapid ubiquitination and proteasomal degradation. Fusion proteins in which all lysines of wild-type ubiquitin were substituted by arginine had high potency, exceeding that of a simple fusion lacking ubiquitin. This variant was less toxic to nontumor tissues in mice than the fusion protein lacking ubiquitin and was very efficient for tumor treatment in mice. The potency of these proteins was highly dependent on the number of lysines retained in the ubiquitin domain and on retention of the C-terminal ubiquitin sequence cleaved by DUBs. It appears that rapid cytosolic release of a cytotoxic enzyme (e.g., PEIII) that is itself resistant to ubiquitination is an effective strategy for enhancing the potency of tumor-targeting toxins. IMPORTANCE: Bacterial toxins typically have highly efficient mechanisms for cellular delivery of their enzymatic components. Cytosolic delivery of therapeutic enzymes and drugs is an important topic in molecular medicine. We describe anthrax toxin fusion proteins containing ubiquitin as a cytosolic cleavable linker that improves the delivery of an enzyme to mammalian cells. The ubiquitin linker allowed modulation of potency in cells and in mice. This effective strategy for enhancing the intracellular potency of an enzyme may be useful for the cytosolic delivery and release of internalized drugs. PMID- 23631918 TI - Clostridium difficile binary toxin CDT induces clustering of the lipolysis stimulated lipoprotein receptor into lipid rafts. AB - Clostridium difficile is the leading cause of antibiotics-associated diarrhea and pseudomembranous colitis. Hypervirulent C. difficile strains produce the binary actin-ADP-ribosylating toxin CDT (C. difficile transferase), in addition to the Rho-glucosylating toxins A and B. We recently identified the lipolysis-stimulated lipoprotein receptor (LSR) as the host receptor that mediates uptake of CDT into target cells. Here we investigated in H1-HeLa cells, which ectopically express LSR, the influence of CDT on the plasma membrane distribution of the receptor. We found by fluorescence microscopy that the binding component of CDT (CDTb) induces clustering of LSR into subcompartments of the plasma membrane. Detergent extraction of cells treated with CDTb, followed by sucrose gradient fractionation, uncovered accumulation of LSR in detergent-resistant membranes (DRMs) that contained typical marker proteins of lipid rafts. Membrane cholesterol depletion with methyl-beta-cyclodextrin inhibited the association of LSR with DRMs upon addition of CDTb. The receptor-binding domain of CDTb also triggered LSR clustering into DRMs. CDTb-triggered clustering of LSR into DRMs could be confirmed in Caco-2 cells. Our data suggest that CDT forces its receptor to cluster into lipid rafts and that oligomerization of the B component might enhance but is not essential for this process. IMPORTANCE: C. difficile binary toxin CDT is a member of the iota-like, actin ADP-ribosylating toxin family. The mechanism that mediates endocytic uptake of these toxins still remains elusive. Previous studies highlighted the importance of lipid rafts for oligomerization of the binding component of these toxins and for cell entry. Recently, the host cell receptor for this toxin family, namely, the lipolysis-stimulated lipoprotein receptor (LSR), has been identified. Our study now demonstrates that the binding component of CDT (CDTb) induces clustering of LSR into lipid rafts. Importantly, LSR clustering is efficiently induced also by the receptor-binding domain of CDTb, suggesting that oligomerization of the B component of CDT is not the main trigger of this process. The current work extends our knowledge on the cooperative play between iota-like toxins and their receptor. PMID- 23631920 TI - Light sensing in Aspergillus fumigatus highlights the case for establishing new models for fungal photobiology. AB - Microbes inhabit diverse environmental locations, and many species need to shift their physiology between different niches. To do this effectively requires the accurate sensing of and response to the environment. For pathogens, exposure to light is one major change between a free-living saprophyte lifestyle and causation of disease within the host. However, how light may act as a signal to influence pathogenesis, on the side of either the host or the pathogen, is poorly understood. Research during the last 2 decades has uncovered aspects about the machinery for light sensing in a small number of fungi. Now, Fuller et al. have initiated studies into the role that light and two photosensor homologs play in the behavior of the ubiquitous fungal pathogen Aspergillus fumigatus [K. K. Fuller, C. S. Ringelberg, J. J. Loros, and J. C. Dunlap, mBio 4(2):e00142-13, 2013, doi:10.1128/mBio.00142-13]. Light represses the germination of A. fumigatus spores and enhances resistance to ultraviolet light, oxidative stresses, and cell wall perturbations. The phenotypes of the strains with mutations in the LreA and FphA homologs revealed that these sensors control some, but not all, responses to light. Furthermore, interactions occur between blue and red light signaling pathways, as has been described for a related saprophytic species, Aspergillus nidulans. Genome-wide transcript analyses found that about 2.6% of genes increase or decrease their transcript levels in response to light. This use of A. fumigatus establishes common elements between model filamentous species and pathogenic species, underscoring the benefits of extending photobiology to new species of fungi. PMID- 23631919 TI - Opposing roles for two molecular forms of replication protein A in Rad51-Rad54 mediated DNA recombination in Plasmodium falciparum. AB - The bacterial RecA protein and its eukaryotic homologue Rad51 play a central role in the homologous DNA strand exchange reaction during recombination and DNA repair. Previously, our lab has shown that PfRad51, the Plasmodium falciparum homologue of Rad51, exhibited ATPase activity and promoted DNA strand exchange in vitro. In this study, we evaluated the catalytic functions of PfRad51 in the presence of putative interacting partners, especially P. falciparum homologues of Rad54 and replication protein A. PfRad54 accelerated PfRad51-mediated pairing between single-stranded DNA (ssDNA) and its homologous linear double-stranded DNA (dsDNA) in the presence of 0.5 mM CaCl2. We also present evidence that recombinant PfRPA1L protein serves the function of the bacterial homologue single stranded binding protein (SSB) in initiating homologous pairing and strand exchange activity. More importantly, the function of PfRPA1L was negatively regulated in a dose-dependent manner by PfRPA1S, another RPA homologue in P. falciparum. Finally, we present in vivo evidence through comet assays for methyl methane sulfonate-induced DNA damage in malaria parasites and accompanying upregulation of PfRad51, PfRad54, PfRPA1L, and PfRPA1S at the level of transcript and protein needed to repair DNA damage. This study provides new insights into the role of putative Rad51-interacting proteins involved in homologous recombination and emphasizes the physiological role of DNA damage repair during the growth of parasites. IMPORTANCE: Homologous recombination plays a major role in chromosomal rearrangement, and Rad51 protein, aided by several other proteins, plays a central role in DNA strand exchange reaction during recombination and DNA repair. This study reports on the characterization of the role of P. falciparum Rad51 in homologous strand exchange and DNA repair and evaluates the functional contribution of PfRad54 and PfRPA1 proteins. Data presented here provide mechanistic insights into DNA recombination and DNA damage repair mechanisms in this parasite. The importance of these research findings in future work will be to investigate if Rad51-dependent mechanisms are involved in chromosomal rearrangements during antigenic variation in P. falciparum. A prominent determinant of antigenic variation, the extraordinary ability of the parasite to rapidly change its surface molecules, is associated with var genes, and antigenic variation presents a major challenge to vaccine development. PMID- 23631921 TI - Are UK otorhinolaryngologists maintaining their research output? AB - BACKGROUND: In the general surgical and anaesthetic literature, there has been a decline in research output originating from the UK. This study analysed the 10 globally leading and 2 UK leading otorhinolaryngology journals to determine whether this trend was also reflected within otorhinolaryngology. METHODS: Citable research output was analysed from 4 individual years, over a 10-year period (2000-2010), to determine absolute output, geographical mix and article type. RESULTS: The proportion of research output from the UK and Ireland grew 22.8 per cent among the leading global otorhinolaryngology journals, but fell 28.6 per cent among the leading two UK otorhinolaryngology journals. The converse trend was true for the USA and Canada. Output from European and the rest of the world grew among both sets of journals, while Japanese output fell. 'Research' articles remained the most prevalent type. CONCLUSION: These results are encouraging as they refute the fall in UK research output observed by other authors. In the face of growing challenges, it is important to maintain published output so that the fate that has befallen other specialties is not mirrored within UK otorhinolaryngology. PMID- 23631922 TI - The role of university-based forensic clinics. AB - As forensic psychiatry and forensic psychology have grown and matured, the range of specialized services provided by each has expanded. In addition to traditional services such as forensic mental health assessments in criminal, family, and civil contexts, forensic specialists are now involved in delivering services in the community that include (in the criminal justice context) assessment for diversion into specialized probation or problem-solving courts, rehabilitation needs upon reentry (including specialized parole), and risk assessment for particular populations such as sexual offenders. Specialized forensic treatment services include those provided to clients under the jurisdiction of problem solving courts or parole/probation. Similar specialized assessment and treatment services may be provided for juveniles. The nature of such service needs underscores the importance of the university-based forensic clinic as one source of specialized forensic services in the community. Such clinics are based in universities, directed by supervising faculty, and offer services provided in part by forensic trainees (psychiatric residents and forensic fellows; psychology doctoral students, interns, and post-doctoral fellows). The structure and operations of such clinics are described, with different models provided. Implications for specialized training, forensic practice, and research are discussed. PMID- 23631923 TI - Hepatitis virus in long-fingered bats, Myanmar. AB - During an analysis of the virome of bats from Myanmar, a large number of reads were annotated to orthohepadnaviruses. We present the full genome sequence and a morphological analysis of an orthohepadnavirus circulating in bats. This virus is substantially different from currently known members of the genus Orthohepadnavirus and represents a new species. PMID- 23631924 TI - Occurrence of Treponema spp. in porcine skin ulcers and gingiva. AB - Porcine shoulder ulcers and ear necrosis are a significant animal welfare concern and impair efficient livestock production. Although spirochetes have been detected in both types of lesions the potential role of these bacteria in lesion propagation has received little attention. The objective of this study was to investigate the occurrence of spirochetes of the genus Treponema in shoulder ulcers or ear necrosis in pigs and compare these with treponemes from porcine gingiva. Samples were collected from gingiva and necrotic ulcers in 169 pigs. Presence of spirochetes was observed in silver stained histological sections and by phase contrast microscopy in scrapings from the necrotic lesions. Additionally, PCR of the 16SrRNA-tRNA(Ile) intergenic spacer region (ISR2) was used to detect Treponema spp. in all samples. Combined analysis showed that 73% of the shoulder ulcers and 53% of the ear necroses were positive for spirochetes. Treponema spp. were detected in 9.7% of the gingival samples. Comparative DNA sequence analysis of the ISR2 sequences revealed the presence of three distinct genetic phylotypes of Treponema spp. corresponding to Treponema pedis, and as yet two unnamed phylotypes represented by GenBank sequences C1UD1 (Acc. No. AY342041) and C1BT2-8 (Acc. No. AY342046). Detection of identical ISR2 sequences from gingiva and ulcer samples indicates that oral Treponema spp. are spread from mouth to ulcer. We conclude that Treponema spp. frequently occur in shoulder ulcers and ear necrosis in pigs, and suggest a possible infection route through biting and licking. PMID- 23631925 TI - Avian bornaviruses are widely distributed in canary birds (Serinus canaria f. domestica). AB - Avian bornavirus (ABV) was identified in 2008 as the causative agent of proventricular dilatation disease (PDD) in psittacine birds. In addition, ABV variants were detected in wild waterfowl and in a canary bird. PDD-like diseases were also reported in various other avian species, but it remains unknown whether ABV is involved. In this study we detected ABV in 12 of 30 tested canary bird flocks (40%), indicating a wide distribution of ABV in captive canary birds in Germany. Sequence analysis identified several distinct ABV genotypes which differ markedly from the genotypes present in psittacine birds. Some canaries naturally infected with ABV exhibited gastrointestinal and neurological symptoms which resembled PDD in psittacines, while others did not show signs of disease. Canaries experimentally inoculated with ABV developed infections of the brain and various other organs. The experimentally infected canaries transmitted the virus to sentinel birds kept in the same aviary, but did not show any clinical signs during a five month observation period. Embryonated eggs originating from ABV infected hens contained ABV-specific RNA, but virus could not be re-isolated from embryonic tissue. These results indicate that ABV is widely distributed in canary birds and due to its association to clinical signs should be considered as a potential pathogen of this species. PMID- 23631927 TI - Spatial memory deficits in maternal iron deficiency paradigms are associated with altered glucocorticoid levels. AB - "The goal of this study was to examine the effect of maternal iron deficiency on the developing hippocampus in order to define a developmental window for this effect, and to see whether iron deficiency causes changes in glucocorticoid levels. The study was carried out using pre-natal, post-natal, and pre+post-natal iron deficiency paradigm. Iron deficient pregnant dams and their pups displayed elevated corticosterone which, in turn, differentially affected glucocorticoid receptor (GR) expression in the CA1 and the dentate gyrus. Brain Derived Neurotrophic Factor (BDNF) was reduced in the hippocampi of pups following elevated corticosterone levels. Reduced neurogenesis at P7 was seen in pups born to iron deficient mothers, and these pups had reduced numbers of hippocampal pyramidal and granule cells as adults. Hippocampal subdivision volumes also were altered. The structural and molecular defects in the pups were correlated with radial arm maze performance; reference memory function was especially affected. Pups from dams that were iron deficient throughout pregnancy and lactation displayed the complete spectrum of defects, while pups from dams that were iron deficient only during pregnancy or during lactation displayed subsets of defects. These findings show that maternal iron deficiency is associated with altered levels of corticosterone and GR expression, and with spatial memory deficits in their pups." PMID- 23631926 TI - Expression and purification of Suid Herpesvirus-1 glycoprotein E in the baculovirus system and its use to diagnose Aujeszky's disease in infected pigs. AB - Suid Herpesvirus 1 (SHV-1) is the etiological agent of Aujeszky's disease (AD), which affects swine herds worldwide and causes substantial economic losses due to animal mortality and lost productivity. In order to eradicate SHV-1, vaccination programs using viruses lacking the gene encoding glycoprotein E (gE) are ongoing in several countries. These eradication programs have generated a currently unmet demand for affordable and sensitive tests that can detect SHV-1 infection, yet distinguish between infected and vaccinated pigs. To meet this demand, we used the baculovirus-insect cell system to produce immunologically authentic full length recombinant gE protein for use in a serum ELISA assay. As previous efforts to clone the gE gene had failed due to its extremely high GC-content (75% average), we used betaine as a PCR enhancer to facilitate amplification of the entire gE gene from the Argentinian CL15 strain of SHV-1. The cloned gE gene was expressed at high levels in recombinant baculovirus-infected insect cells and reacted strongly with sera from SHV-1 infected pigs. We used the recombinant gE protein to develop a local indirect ELISA test with sensitivity and specificity comparable to currently available commercial tests. Thus, recombinant gE produced in baculovirus-infected insect cells is a viable source of antigen for the detection of SHV-1 in ELISA tests. We also provide evidence supporting a potential application of this recombinant form of gE as a SHV-1 subunit vaccine. PMID- 23631928 TI - Individualized metacognitive therapy program for patients with psychosis (MCT+): introduction of a novel approach for psychotic symptoms. AB - BACKGROUND: Metacognitive Group Training for Schizophrenia Patients (MCTg) focuses on dysfunctional thinking styles (e.g. cognitive biases) putatively involved in the formation and maintenance of delusions. Recently, the Individualized Metacognitive Therapy Program for Patients with Psychosis (MCT+), an extension of the group training, was released. MCT+ sessions aim to correct false metacognitive beliefs, which in turn should challenge a patient's personal delusional convictions. AIMS: The present study demonstrates how MCT and MCT+ can be combined and how the contents are conveyed to the patient. METHOD: We present a single case study of a patient undergoing a combined treatment of MCT and MCT+. Before intervention and 4 weeks later the Positive and Negative Syndrome Scale (PANSS) and the Psychotic Symptom Rating Scales (PSYRATS) were administered. RESULTS: The patient showed a substantial symptom reduction after 4 weeks of combined therapy of MCTg and MCT+ as measured with PANSS and PSYRATS. CONCLUSIONS: The present case history lends preliminary evidence for the feasibility of this new treatment approach in psychosis. PMID- 23631930 TI - Cytotoxic and clastogenic activity of CdCl2 in human lymphocytes from different donors. AB - The sensitivity of human lymphocytes from different donors to CdCl2 using a complex of methods for determination of cytotoxicity and genotoxicity was studied. As endpoints for cytotoxicity the mitotic index (MI) and apoptosis were evaluated. To indicate genotoxicity chromosome aberrations test (CA) was used. The results indicate an individual sensitivity of lymphocytes to CdCl2-induced damage, which is directly depending on the concentration (10(-6), 10(-5), 5*10( 5), 10(-4)mol/l) applied. The assessment of the toxic and genotoxic effect using various endpoints allows more complete risk estimation for organisms exposed to heavy metals. The results have direct practical significance for threat evaluation in humans. PMID- 23631929 TI - Prospective memory predicts medication management ability and correlates with non adherence to medications in individuals with clinically stable schizophrenia. AB - BACKGROUND: Prospective memory (PM), the ability to remember to carry out an intended action in the future, is thought to relate closely to everyday functioning, such as medication adherence. PM impairment in schizophrenia may contribute to unintentional medication non-adherence. This study aimed to examine the relationship between PM, medication management and medication adherence. METHODS: Eighty-two stable patients with schizophrenia underwent assessment for PM and medication management ability by laboratory measures at baseline. Clinical symptoms, other neuropsychological functions and risk factors known to associate with non-adherence were also measured. Linear regression was used to identify predictors of medication management ability at baseline. Actual medication adherence was assessed three months later and logistic regression was used to identify predictors of non-adherence. RESULTS: In the linear regression model, time- and event-based PM together accounted for 72.3% of the variance in the performance of medication management at baseline. At three-month follow-up, the non-adherent group performed significantly more poorly in time- and event-based PM, and had poorer insight, more severe symptoms and poorer ability to manage medications, as compared to the adherent group. In the logistic regression model, insight and PANSS general score significantly predicted non-adherence in the community. Time- and event-based PM moderated the predictive power of insight and PANSS general score. CONCLUSIONS: Our results support that PM performance robustly predicts medication management ability and may influence medication adherence in the community by moderating the effect of insight and symptom severity. Optimizing PM performance may improve medication adherence in the community, particularly for unintentional non-adherence. PMID- 23631932 TI - Revisiting Bloodstein's Anticipatory Struggle Hypothesis from a psycholinguistic perspective: a Variable Release Threshold hypothesis of stuttering. AB - This paper reviews Bloodstein's (1975) Anticipatory Struggle Hypothesis of stuttering, identifies its weaknesses, and proposes modifications to bring it into line with recent advances in psycholinguistic theory. The review concludes that the Anticipatory Struggle Hypothesis provides a plausible explanation for the variation in the severity of stuttered disfluencies across speaking situations and conversation partners. However, it fails to explain the forms that stuttered disfluencies characteristically take or the subjective experience of loss of control that accompanies them. The paper then describes how the forms and subjective experiences of persistent stuttering can be accounted for by a threshold-based regulatory mechanism of the kind described in Howell's (2003) revision of the EXPLAN hypothesis. It then proposes that shortcomings of both the Anticipatory Struggle and EXPLAN hypotheses can be addressed by combining them together to create a 'Variable Release Threshold' hypothesis whereby the anticipation of upcoming difficulty leads to the setting of an excessively high threshold for the release of speech plans for motor execution. The paper also reconsiders the possibility that two stuttering subtypes exist: one related to formulation difficulty and other to difficulty initiating motor execution. It concludes that research findings that relate to the one may not necessarily apply to the other. LEARNING OUTCOMES: After reading this article, the reader will be able to: (1) summarize the key strengths and weaknesses of Bloodstein's Anticipatory Struggle Hypothesis; (2) describe two hypothesized mechanisms behind the production of stuttered disfluencies (tension and fragmentation & release threshold mechanisms); and (3) discuss why the notion of anticipation is relevant to current hypotheses of stuttering. PMID- 23631933 TI - Comparison of moped, scooter and motorcycle crash risk and crash severity. AB - The increased popularity of mopeds and motor scooters in Australia and elsewhere in the last decade has contributed substantially to the greater use of powered two-wheelers (PTWs) as a whole. As the exposure of mopeds and scooters has increased, so too has the number of reported crashes involving those PTW types, but there is currently little research comparing the safety of mopeds and, particularly, larger scooters with motorcycles. This study compared the crash risk and crash severity of motorcycles, mopeds and larger scooters in Queensland, Australia. Comprehensive data cleansing was undertaken to separate motorcycles, mopeds and larger scooters in police-reported crash data covering the five years to 30 June 2008. The crash rates of motorcycles (including larger scooters) and mopeds in terms of registered vehicles were similar over this period, although the moped crash rate showed a stronger downward trend. However, the crash rates in terms of distance travelled were nearly four times higher for mopeds than for motorcycles (including larger scooters). More comprehensive distance travelled data is needed to confirm these findings. The overall severity of moped and scooter crashes was significantly lower than motorcycle crashes but an ordered probit regression model showed that crash severity outcomes related to differences in crash characteristics and circumstances, rather than differences between PTW types per se. Greater motorcycle crash severity was associated with higher (>80km/h) speed zones, horizontal curves, weekend, single vehicle and nighttime crashes. Moped crashes were more severe at night and in speed zones of 90km/h or more. Larger scooter crashes were more severe in 70km/h zones (than 60km/h zones) but not in higher speed zones, and less severe on weekends than on weekdays. The findings can be used to inform potential crash and injury countermeasures tailored to users of different PTW types. PMID- 23631934 TI - The contribution of attention in virtual moped riding training of teenagers. AB - Riding a moped, like many other everyday activities, is a complex behavior in which attention plays a crucial role. This study aims to investigate the role of attention in enhancing the skills required to ride a moped simulator. Two experiments were conducted with 207 and 60 students (14-15 years old), respectively, using a moped simulator to ride on 12 different tracks. The assignment was to ride safely and avoid hazards. In experiment 1, we divided the hazard scenes of the tracks on the basis of the fact that a shift in attention was required to escape the danger. We showed that during the riding training, when no attentional shift was required, the ability to avoid hazards was constantly higher. In experiment 2, participants were asked to cope with the same basic experimental setting but with an additional attentive task. The results showed that they performed in such a way that not only did the attentive task not impair their performance, but it also produced an improvement in the ability to shift attentional focus, preserving performance efficiency. On the basis of these data, it can be claimed that, primarily, attentional shift plays a prominent role in accounting for accident circumstances. Secondarily, it can be claimed that attentional training contributes to improved processing efficiency so as to prevent mishaps. PMID- 23631935 TI - US commercial air tour crashes, 2000-2011: burden, fatal risk factors, and FIA Score validation. AB - INTRODUCTION: This study provides new public health data concerning the US commercial air tour industry. Risk factors for fatality in air tour crashes were analyzed to determine the value of the FIA Score in predicting fatal outcomes. METHODS: Using the Federal Aviation Administration's (FAA) General Aviation and Air Taxi Survey and National Transportation Safety Board data, the incidence of commercial air tour crashes from 2000 through 2010 was calculated. Fatality risk factors for crashes occurring from 2000 through 2011 were analyzed using regression methods. The FIA Score, Li and Baker's fatality risk index, was validated using receiver operating characteristic (ROC) curves. RESULTS: The industry-wide commercial air tour crash rate was 2.7 per 100,000 flight hours. The incidence rates of Part 91 and 135 commercial air tour crashes were 3.4 and 2.3 per 100,000 flight hours, respectively (relative risk [RR] 1.5, 95% confidence interval [CI] 1.1-2.1, P=0.015). Of the 152 air tour crashes that occurred from 2000 through 2011, 30 (20%) involved at least one fatality and, on average, 3.5 people died per fatal crash. Fatalities were associated with three major risk factors: fire (adjusted odds ratio [AOR] 5.1, 95% CI 1.5-16.7, P=0.008), instrument meteorological conditions (AOR 5.4, 95% CI 1.1-26.4, P=0.038), and off-airport location (AOR 7.2, 95% CI 1.6-33.2, P=0.011). The area under the FIA Score's ROC curve was 0.79 (95% CI 0.71-0.88). DISCUSSION: Commercial air tour crash rates were high relative to similar commercial aviation operations. Disparities between Part 91 and 135 air tour crash rates reflect regulatory disparities that require FAA action. The FIA Score appeared to be a valid measurement of fatal risk in air tour crashes. The FIA should prioritize interventions that address the three major risk factors identified by this study. PMID- 23631936 TI - Immunological Genome Project and systems immunology. AB - Immunological studies of single proteins in a single cell type have been complemented in recent years by larger studies, enabled by emerging high throughput technologies. This trend has recently been exemplified by the discovery of gene networks controlling regulatory and effector alphabeta T cell subset development and human hematopoiesis. The Immunological Genome Project (ImmGen) aims to decipher the gene networks underpinning mouse hematopoiesis. The first phase, completed in 2012, profiled the transcriptome of 249 immune cell types. We discuss the utilities of the datasets in high-resolution mapping of the hematopoietic system. The immune transcriptome compendium has revealed unsuspected cell lineage relations and the network reconstruction has identified novel regulatory factors of hematopoiesis. PMID- 23631937 TI - Codon optimization and woodchuck hepatitis virus posttranscriptional regulatory element enhance the immune responses of DNA vaccines against infectious bursal disease virus in chickens. AB - The present study was undertaken to evaluate the protective efficacy of DNA vaccines against infectious bursal disease virus (IBDV) in chickens and to determine whether codon optimization and the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) could improve the immunogenicity of the DNA vaccines. The VP2, VP243 and codon-optimized VP243 genes of IBDV were cloned into pCAGGS vector, and designated as pCAGVP2, pCAGVP243 and pCAGoptiVP243, respectively. Plasmids pCAGWVP243 and pCAGWoptiVP243 carrying the WPRE elements were also constructed as DNA vaccines. To evaluate vaccine efficacy, 2-week-old chickens were injected intramuscularly with the constructed plasmids twice at 2-week intervals and challenged with very virulent IBDV 2 weeks post-boost. Plasmid pCAGVP243 induced better immune responses than pCAGVP2. Chickens immunized with pCAGoptiVP243 and pCAGWVP243 had higher levels of antibody titers, lymphoproliferation responses and cytokine production compared with pCAGVP243. Furthermore, plasmid pCAGWoptiVP243 induced the highest levels of immune responses among the groups. After challenged, DNA vaccines pCAGVP2, pCAGVP243, pCAGoptiVP243, pCAGWVP243 and pCAGWoptiVP243 conferred protection for 33%, 60%, 80%, 87% and 100% of chickens, respectively, as evidenced by the absence of clinical signs, mortality, and bursal atrophy. These results indicate that codon optimization and WPRE could enhance the protective efficacy of DNA vaccines against IBDV and these two approaches could work together synergistically in a single DNA vaccine. PMID- 23631938 TI - Systems scale assessment of the sustainability implications of emerging green initiatives. AB - This paper demonstrates a systems framework for assessment of environmental impacts from 'green initiatives', through a case study of meso-scale, anthropogenic-biogenic interactions. The following cross-sectoral green initiatives, combining the emerging trends in the North East region of the United Kingdom, have been considered - increasing the vegetation cover; decarbonising road transport; decentralising energy production through biomass plants. Two future scenarios are assessed - Baseline_2020 (projected emissions from realisation of policy instruments); Aggressive_2020 (additional emissions from realisation of green initiatives). Resulting trends from the Aggressive_2020 scenario suggest an increase in emissions of pollutant precursors, including biogenic volatile organic compounds and nitrogen dioxide over the base case by up to 20% and 5% respectively. This has implications for enhanced daytime ozone and secondary aerosols formation by up to 15% and over 5% respectively. Associated land cover changes show marginal decrease of ambient temperature but modest reductions in ammonia and ambient particulates. PMID- 23631939 TI - Kinetic control of contaminant release from NAPLs--experimental evidence. AB - Mass transfer processes of pollutants from non-aqueous phase liquids (NAPL) may control groundwater pollution at abandoned industrial sites. We studied release kinetics of polycyclic aromatic hydrocarbons (PAHs) from fresh and aged tar phases using a dialysis tubing technique. Time for equilibration ranged from several days to more than three years. For fresh tar materials the release seems to be limited by retarded pore diffusion, while for two of three aged tars diffusion limited release influenced by dissolved organic matter (DOM) was assumed. The equilibration process was driven by solubilization thermodynamics expressed by Raoult's law. Yet, solubility enhancement was observed potentially due to the presence of organic mobile sorbents. The results show that the release of PAHs from tar phases is generally rate limited and partitioning according to Raoult's law is the driving mechanism of the exchanges process. PMID- 23631940 TI - Can citizen science produce good science? Testing the OPAL Air Survey methodology, using lichens as indicators of nitrogenous pollution. AB - Citizen science is having increasing influence on environmental monitoring as its advantages are becoming recognised. However methodologies are often simplified to make them accessible to citizen scientists. We tested whether a recent citizen science survey (the OPAL Air Survey) could detect trends in lichen community composition over transects away from roads. We hypothesised that the abundance of nitrophilic lichens would decrease with distance from the road, while that of nitrophobic lichens would increase. The hypothesised changes were detected along strong pollution gradients, but not where the road source was relatively weak, or background pollution relatively high. We conclude that the simplified OPAL methodology can detect large contrasts in nitrogenous pollution, but it may not be able to detect more subtle changes in pollution exposure. Similar studies are needed in conjunction with the ever-growing body of citizen science work to ensure that the limitations of these methods are fully understood. PMID- 23631941 TI - Design of systems for productivity and well being. AB - It has always been an ambition within the ergonomic profession to ensure that design or redesign of production systems consider both productivity and employee well being, but there are many approaches to how to achieve this. This paper identifies the basic issues to be addressed in light of some research activities at DTU, especially by persons responsible for facilitating design processes. Four main issues must be addressed: (1) determining the limits and scope of the system to be designed; (2) identifying stakeholders related to the system and their role in the system design; (3) handling the process' different types of knowledge; and (4) emphasizing that performance management systems, key performance indicators (KPIs), and leadership are also part of the system design and must be given attention. With the examples presented, we argue that knowledge does exist to help system design facilitators address these basic issues. PMID- 23631942 TI - The development of guidelines for the design and evaluation of warning signs for young children. AB - We report a study which aimed to provide further development and refinement of a set of guidelines (Waterson et al., 2012) for the design and evaluation of warning signs and other visual material for young children (i.e., aged 5-11 years). The study involved a set of semi-structured interviews and focus groups with the parents of young children, teachers, human factors experts and other groups (n = 38). The findings from the study provided broad support for the guidelines, as well as highlighting a number of issues which need to be addressed. These included the need to consider the target audience in more detail and provide additional guidance covering possible tie-ins with safety campaigns, sign location, age differences, gender and children's special needs. Similar findings were obtained with regard to the evaluation guidelines and their coverage of methods and activities for testing signs (e.g., simulation, role playing). We discuss our findings within the context of a revised set of guidelines and a set of suggestions aimed at working towards a more comprehensive approach to the design/evaluation of signs for young children. The paper concludes with a set of future topics for research including a discussion of ways forward in terms of improving support for design and evaluation including behavioural testing with children, their parents and other care givers. PMID- 23631943 TI - Hand, foot, and mouth disease caused by coxsackievirus A6, Thailand, 2012. AB - In Thailand, hand, foot, and mouth disease (HFMD) is usually caused by enterovirus 71 or coxsackievirus A16. To determine the cause of a large outbreak of HFMD in Thailand during June-August 2012, we examined patient specimens. Coxsackievirus A6 was the causative agent. To improve prevention and control, causes of HFMD should be monitored. PMID- 23631944 TI - Rapid assessment of neurovisual integrity using multiple rarebits. AB - OBJECTIVE: Rapid assessments of vision commonly rely on visual acuity testing alone. Although well suited for uncovering optical defects, visual acuity tests may fail to detect dysfunction of the neural substrate. There is a need for a rapid companion test sensitive to neural damage. DESIGN: Evaluation of diagnostic tests. PARTICIPANTS AND CONTROLS: Forty-seven patients with optic nerve or visual pathway lesions of low to moderate severities and 30 normal subjects. METHODS: A new computer-based quick test of neurovisual integrity was developed using segmented digits defined by rarebits, that is, receptive field-size bright dots briefly presented on a dark background. MAIN OUTCOME MEASURES: The test variable was the number of rarebits per segment; digit size was fixed. The test task was to call out verbally all digits that were seen during an 8-second presentation sequence. Test outcomes were contrasted with the results of an optotype acuity test and automated perimetry. RESULTS: All subjects easily grasped the test task. The normal subjects read, on average, 5.6 (+/- 0.5 standard deviation) of the 6 digits contained in the test sequence, whereas the patients averaged 3.3 +/- 1.8 digits. The numbers of digits read correlated modestly with the acuity and perimetry results. Analysis of receiver operating characteristic curves indicated that the multiple rarebit test provided the best discrimination. CONCLUSIONS: The multiple rarebit test seemed to be highly capable of detecting neurovisual dysfunction. Its simplicity and uniquely short duration indicate a useful role in screening settings. The test is available free on the Internet. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23631945 TI - Prevalence and severity of undetected manifest glaucoma: results from the early manifest glaucoma trial screening. AB - PURPOSE: To estimate the prevalence and severity of undetected glaucoma in the population. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 32 918 subjects aged 55 to 79 years from Malmo, Sweden, who were screened between 1992 and 1997. All subjects in the screened age groups living in the catchment area, and for whom there were no recent records at the Malmo University Hospital Ophthalmology department, were invited. The main purpose of the screening was to recruit subjects for the Early Manifest Glaucoma Trial. METHODS: We registered the age, sex, and amount of visual field loss in subjects with previously undiagnosed glaucoma identified at the screening. The disease was categorized into 5 stages based on perimetric mean deviation values. MAIN OUTCOME MEASURES: Prevalence of undetected glaucoma at various disease stages in different age groups expressed as percentages. RESULTS: Among the screened subjects, who were 77.5% of all invited subjects, a total of 406 subjects (1.23%) were identified with previously undetected glaucoma. Prevalence increased with age, from 0.55% at 55 to 59 years to 2.73% at 75 to 79 years. Unilateral disease accounted for 66% of all cases. Extent of visual field loss was similar in all age groups from 60 years and more. Most eyes had early (35%) or moderate (31%) glaucomatous visual field defects, but 134 subjects (33%) had advanced visual field loss in at least 1 eye. No subject was blind in both eyes, but 3.4% of the newly diagnosed patients were unilaterally blind because of glaucoma. CONCLUSIONS: Prevalence of undetected glaucoma increased with age, whereas disease severity did not increase in subjects older than 60 years of age. One third of subjects with previously undetected glaucoma had advanced or later-stage disease in at least 1 eye. Unilaterally blind subjects were present in all age groups. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23631946 TI - The economic burden of vision loss and eye disorders among the United States population younger than 40 years. AB - OBJECTIVE: To estimate the economic burden of vision loss and eye disorders in the United States population younger than 40 years in 2012. DESIGN: Econometric and statistical analysis of survey, commercial claims, and census data. PARTICIPANTS: The United States population younger than 40 years in 2012. METHODS: We categorized costs based on consensus guidelines. We estimated medical costs attributable to diagnosed eye-related disorders, undiagnosed vision loss, and medical vision aids using Medical Expenditure Panel Survey and MarketScan data. The prevalence of vision impairment and blindness were estimated using National Health and Nutrition Examination Survey data. We estimated costs from lost productivity using Survey of Income and Program Participation. We estimated costs of informal care, low vision aids, special education, school screening, government spending, and transfer payments based on published estimates and federal budgets. We estimated quality-adjusted life years (QALYs) lost based on published utility values. MAIN OUTCOME MEASURES: Costs and QALYs lost in 2012. RESULTS: The economic burden of vision loss and eye disorders among the United States population younger than 40 years was $27.5 billion in 2012 (95% confidence interval, $21.5-$37.2 billion), including $5.9 billion for children and $21.6 billion for adults 18 to 39 years of age. Direct costs were $14.5 billion, including $7.3 billion in medical costs for diagnosed disorders, $4.9 billion in refraction correction, $0.5 billion in medical costs for undiagnosed vision loss, and $1.8 billion in other direct costs. Indirect costs were $13 billion, primarily because of $12.2 billion in productivity losses. In addition, vision loss cost society 215 000 QALYs. CONCLUSIONS: We found a substantial burden resulting from vision loss and eye disorders in the United States population younger than 40 years, a population excluded from previous studies. Monetizing quality-of-life losses at $50 000 per QALY would add $10.8 billion in additional costs, indicating a total economic burden of $38.2 billion. Relative to previously reported estimates for the population 40 years of age and older, more than one third of the total cost of vision loss and eye disorders may be incurred by persons younger than 40 years. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23631947 TI - Wide-field fundus autofluorescence imaging of retinitis pigmentosa. AB - PURPOSE: To evaluate the clinical usefulness of wide-field fundus autofluorescence (FAF) imaging in patients with retinitis pigmentosa (RP). DESIGN: Cross-sectional case series. PARTICIPANTS: Seventy-five eyes of 75 patients with RP. METHODS: We examined the eyes of the RP patients using the Optos 200Tx imaging system (Optos PLC, Dunfermline, United Kingdom) and identified abnormal FAF patterns such as ring hyperautofluorescence and patchy hypoautofluorescent areas. Patients with hyperautofluorescent rings or foveal hyperautofluorescence were compared with those without such findings. We determined the percentage area occupied by the FAF abnormalities within a defined region of the eye and examined the relationship between the percentage area of these abnormalities and the visual field area. Moreover, we categorized the patients into 3 different groups based on the presence of a patchy hypoautofluorescent lesion larger than 1 disc diameter: Group A consisted of those with patchy lesions smaller than 1 disc diameter, group B consisted of those with patchy lesions larger than 1 disc diameter but present in only 1 quadrant, and group C consisted of those with patchy lesions larger than 1 disc diameter and present in more than 1 quadrant. In addition, various clinical characteristics were compared among these 3 groups. MAIN OUTCOME MEASURES: Predicting the visual field size and duration of the disease in RP patients based on FAF patterns. RESULTS: Patients without hyperautofluorescent rings or foveal hyperautofluorescence had better visual acuity or mean deviation measured with a Humphrey perimeter. The total area of the abnormal FAF image correlated with the visual field area measured with a Goldmann perimeter (R = -0.64, P<0.001). The individuals with the large patchy hypofluorescent areas (i.e., larger than 1 disc diameter) were older than those with small patchy hypofluorescent areas (group A vs. groups B and C, P = 0.002 and P<0.001, respectively) and had experienced the symptoms for longer durations (group A vs. groups B and C, P<0.05 and P<0.001, respectively). CONCLUSIONS: We can estimate the visual field in patients with RP using the objective measurements from wide-field FAF. The presence of patchy hypofluorescent lesions can be used an indicator of the duration of RP. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23631948 TI - Characterization of a clinician-scientist cohort in ophthalmology: a demographic analysis of k grant awardees in ophthalmology. AB - OBJECTIVE: To analyze ophthalmologists who are National Institutes of Health (NIH) K grant awardees to characterize clinician-scientists in ophthalmology. DESIGN: Cohort study. PARTICIPANTS: Ophthalmologists who have received a K award from 1996 through 2010. METHODS: K08 and K23 grant awardees were identified through the NIH Research Portfolio Online Reporter database. Information including gender, institution, educational degrees, and success in obtaining an R01 grant was analyzed. MAIN OUTCOME MEASURES: Receipt of an R01 grant. RESULTS: One hundred five ophthalmologists were identified who received K08 or K23 grants from the National Eye Institute from 1996 through 2010. Overall, 75% of these were male, although 43% of K awardees were women from 2006 through 2010. Sixty five percent (68/105) of individuals came from ophthalmology departments that ranked in the top 20 of NIH funding in 2010. The most predominant subspecialties represented were retina (32%), cornea (22%), and glaucoma (15%). Among the K awardees, 40% (42/105) had a doctor of philosophy (PhD) degree in addition to their medical doctor degree. From 1996 through 2000, 61% (23/38) were successful in obtaining an R01 grant, whereas only 13% (5/39) from 2001 through 2005 obtained R01 grants (P<0.001). CONCLUSIONS: Gender disparities exist among K awardees in ophthalmology, but these seem to be improving over time. None of the other variables studied-gender, PhD degree, specialty, or funding tier-was associated with obtaining R01 funding. This study helps to characterize the clinician-scientist cohort in ophthalmology and to identify areas to improve the recruitment of these individuals. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23631949 TI - Outcomes and predictive factors in bilateral macular holes. AB - PURPOSE: To evaluate the incidence, risk factors, outcomes, and visual prognosis in patients with bilateral macular holes repaired surgically with indocyanine green (ICG)-assisted internal limiting membrane (ILM) peeling in our population. DESIGN: Retrospective, multisurgeon, nonrandomized, noncomparative case series. PARTICIPANTS: Eighty-two patients were identified who underwent bilateral macular hole surgery with ILM peeling without other vision-limiting pathologic features. METHODS: All patients underwent bilateral macular hole surgery at a single-site, multisurgeon center with preoperative and postoperative optical coherence tomography (OCT) characterization and ICG-assisted ILM peeling during surgery with intraocular gas tamponade. MAIN OUTCOME MEASURES: Comparison of the closure and reopening rate, prognosis, change in visual acuity, and family history for patients undergoing bilateral surgery. RESULTS: Eight-two patients met the inclusion criteria (164 eyes). Nineteen patients (22.6%) had asymptomatic vitreomacular adhesion by OCT in the fellow eye at the time of presentation of macular hole in the first eye. There was a mean interval of 19.4 months between the first and fellow eye macular holes and a male-to-female ratio of 1:2.42. Surgical closure rate was 89% with the first macular hole surgery and 98.8% with the second surgery. Sex, family history, and duration of hole symptom were not found to be associated with risk of macular hole recurrence. Symptom duration of less than 1 year and earlier macular hole stage yielded the best visual acuity after successful surgical repair. CONCLUSIONS: Patients with bilateral macular holes may consider undergoing bilateral macular hole surgery to improve visual acuity. Successful closure rates of bilateral macular holes with ILM peeling in this series are better than those reported previously without consistent ILM peeling. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23631950 TI - Infant movement opportunities are related to early growth--GECKO Drenthe cohort. AB - BACKGROUND: Movement by an infant during the first year of life might influence its activity level and thereby influence growth in early childhood. AIM: To examine whether the time that an infant is able to move unrestrictedly and time spent in baby seats are related to weight and waist circumference at age 9 months and growth from 9 to 24 months. METHODS: In the GECKO Drenthe birth cohort, weight and height were measured in Well Baby Clinics at the ages of 9 and 24 months. Time spent moving unrestrictedly and time spent in baby seats were reported on a questionnaire at age 9 months. Children born <37 weeks or with a low birthweight (<2500 g) were excluded. Outcomes were defined as the Z-scores for weight-for-height, weight-for-age, and waist circumference-for-age at the ages of 9 and 24 months, and changes in Z-scores as between 9 and 24 months of age. RESULTS: The time an infant is able to move unrestrictedly at age 9 months was inversely related to Z-score waist circumference at 9 months, and the change in Z-scores weight-for-height and weight-for-age between the ages 9 and 24 months. For time spent in baby seats, 'never users' showed a decline in Z-score weight-for-height as compared to those who used baby seats. On the contrary, Z score waist circumference-for-age declined in children sitting for 1h or more in baby seats. CONCLUSION: More time spent moving unrestrictedly in infancy may contribute to a healthy growth pattern. PMID- 23631951 TI - A randomized controlled trial of the effectiveness of computer-assisted cognitive remediation (CACR) in adolescents with psychosis or at high risk of psychosis. AB - BACKGROUND: Computer assisted cognitive remediation (CACR) was demonstrated to be efficient in improving cognitive deficits in adults with psychosis. However, scarce studies explored the outcome of CACR in adolescents with psychosis or at high risk. AIMS: To investigate the effectiveness of a computer-assisted cognitive remediation (CACR) program in adolescents with psychosis or at high risk. METHOD: Intention to treat analyses included 32 adolescents who participated in a blinded 8-week randomized controlled trial of CACR treatment compared to computer games (CG). Cognitive abilities, symptoms and psychosocial functioning were assessed at baseline and posttreatment. RESULTS: Improvement in visuospatial abilities was significantly greater in the CACR group than in CG. Other cognitive functions, psychotic symptoms and psychosocial functioning improved significantly, but at similar rates, in the two groups. CONCLUSION: CACR can be successfully administered in this population; it proved to be effective over and above CG for the most intensively trained cognitive ability. PMID- 23631952 TI - Health-related quality of life before and after pediatric epilepsy surgery: the influence of seizure outcome on changes in physical functioning and social functioning. AB - Health-related quality of life (HRQOL) is an important outcome in pediatric epilepsy surgery, but there are few studies that utilize presurgical ratings to assess the effect of surgery on HRQOL. We collected parental ratings on the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire for 28 children who participated in neuropsychological assessment before and after epilepsy surgery. Our results revealed significant improvements in overall HRQOL after surgery, especially in physical and social activities. These changes were apparent despite generally unchanged intellectual and psychological functioning. Children with better seizure outcome had more improvement in HRQOL; however, improvements were not statistically different among children with Engel class I, II, and III outcomes. Our results suggest that children can experience significant improvements in HRQOL following epilepsy surgery even when neuropsychological functioning remains unchanged. Moreover, improvements in HRQOL appear evident in children who experience any worthwhile improvement in seizure control (Engel class III or better). PMID- 23631953 TI - Treatment of plasmapheresis refractory thrombotic thrombocytopenic purpura with double-filtration membrane plasmapheresis. AB - Thrombotic thrombocytic purpura (TTP) is a life-threatening disorder. Without plasma exchange treatment (PET) the mortality rate is quite high. Double filtration plasmapheresis is an alternative opportunity for TTP patients refractory to PET. Here we report our experience in a refractory TTP patient who was successfully treated by means of double-filtration plasmapheresis therapy. PMID- 23631954 TI - New insights into the roles of juvenile hormone and ecdysteroids in honey bee reproduction. AB - In workers of the Western honeybee, Apis mellifera, juvenile hormone (JH) and ecdysteroids regulate many aspects of age polyphenism. Here we investigated whether these derived functions in workers have developed by an uncoupling of endocrine mechanisms in adult queens and workers, or whether parallels can be found between the roles of the two hormones in both castes. We looked at yolk protein metabolism as a process central to the physiology of both queens and workers, and at sperm storage as a feature of the queen alone. Queens of differing fertility status (virgin, virgin but CO2-treated, inseminated, freshly laying and 1-2 years-old) were compared regarding vitellogenin (Vg), JH and ecdysteroid-titers in their hemolymph, as well as ovarian yolk protein and spermathecal gland composition. Our results showed that hormone titres were unrelated to the composition of spermathecal glands. JH-concentrations in the hemolymph were low in the groups of queens characterized by yolk uptake into the ovaries, and high in pre-vitellogenic queens or animals that were forced to interrupt egg-laying by caging. Ecdysteroid-concentrations were higher in untreated virgins than after insemination or during egg-laying. They were not affected by the caging of queens. These patterns of hormone changes were parallel to those known from worker bees. Together, these findings suggest a conserved role for JH as repressor of vitellogenin uptake into tissues, and for ecdysteroids in preparing tissues for this process. An involvement of the two hormones in the regulation of sperm storage seems unlikely. Our results add to the view that JH and ecdysteroids act similarly on the yolk protein metabolism of both castes of A. mellifera. This may imply that it was the biochemical versatility of Vg rather than that of hormonal regulatory circuits that allowed for the functional separation of the two castes. PMID- 23631955 TI - Two cases of nasopharyngeal branchial cleft cyst treated by powered instrument assisted marsupialisation. AB - OBJECTIVE: We report two extremely rare cases of symptomatic nasopharyngeal branchial cleft cyst treated by powered instrument assisted marsupialisation. METHODS: Case report and literature review concerning nasopharyngeal branchial cleft cyst and surgical treatment methods. RESULTS: The first case was a two-year old boy with a 1 * 2 cm, cystic, oropharyngeal mass, who also had severe snoring and sleep apnoea. The second case was a 56-year-old man with right nasal obstruction and a sensation of fullness in the right ear. In both cases, we performed endoscopic marsupialisation using a powered instrument. There was no recurrence in either case over two years of follow up. CONCLUSION: Powered instrument marsupialisation is a simple, effective and less invasive technique for the treatment of nasopharyngeal branchial cleft cyst. PMID- 23631956 TI - Fibrosing connective tissue disorders of the skin: molecular similarities and distinctions. AB - A variety of fibrosing connective tissue disorders of the skin have been described. They all share a characteristic activation of fibroblasts resulting in excessive production and deposition of extracellular matrix whereas their etiologies, incidence rates and clinical appearances differ dramatically in part. As effective treatment options are still not on hand, the understanding of cutaneous fibrogenesis needs to be improved. This review focuses on the molecular differences and similarities of the major fibrosing skin disorders namely systemic sclerosis, localized scleroderma, keloid and hypertrophic scars, Eosinophilic fasciitis, Lichen sclerosus and graft-versus-host-disease. Abnormalities in ECM turnover and the impact of matrix-metalloproteases were closely examined. It could be concluded, that besides increased collagen synthesis, modified ECM degradation is an as important factor in cutaneous fibrogenesis. The influence of immune components such as HLA haplotypes and the production of auto-antibodies is crucial for some of the diseases, but not decisive for skin fibrosis in general. A great number of cytokines was reported to be differentially regulated in the respective disorders among whom the components of the gp130/STAT3 signaling pathway seem to be of pivotal importance. Furthermore, the role of miRNAs in the pathogenesis of fibrosing connective tissue diseases of the skin was analyzed according to the current state of knowledge. In summary, this review gives an explicit overview of the various molecular mechanisms leading to fibrosis in the skin and the underlying connective tissue and reveals the most promising targets for future therapeutic approaches. PMID- 23631957 TI - The problem with predoctoral orthodontic education. PMID- 23631958 TI - Bonded lingual retainers. PMID- 23631959 TI - Authors' response. PMID- 23631960 TI - Informed consent or informed refusal? PMID- 23631962 TI - Intraoral distalizer effects with conventional and skeletal anchorage: a meta analysis. AB - INTRODUCTION: The aims of this meta-analysis were to quantify and to compare the amounts of distalization and anchorage loss of conventional and skeletal anchorage methods in the correction of Class II malocclusion with intraoral distalizers. METHODS: The literature was searched through 5 electronic databases, and inclusion criteria were applied. Articles that presented pretreatment and posttreatment cephalometric values were preferred. Quality assessments of the studies were performed. The averages and standard deviations of molar and premolar effects were extracted from the studies to perform a meta-analysis. RESULTS: After applying the inclusion and exclusion criteria, 40 studies were included in the systematic review. After the quality analysis, 2 articles were classified as high quality, 27 as medium quality, and 11 as low quality. For the meta-analysis, 6 studies were included, and they showed average molar distalization amounts of 3.34 mm with conventional anchorage and 5.10 mm with skeletal anchorage. The meta-analysis of premolar movement showed estimates of combined effects of 2.30 mm (mesialization) in studies with conventional anchorage and -4.01 mm (distalization) in studies with skeletal anchorage. CONCLUSIONS: There was scientific evidence that both anchorage systems are effective for distalization; however, with skeletal anchorage, there was no anchorage loss when direct anchorage was used. PMID- 23631963 TI - Factors related to the rate of orthodontically induced tooth movement. AB - INTRODUCTION: The purpose of this study was to investigate the variations of orthodontically induced tooth movement in the maxillary and mandibular arches between patients and the factors such as age, sex, and presence of an interference that might influence the amount of tooth displacement. METHODS: By using a standardized experimental orthodontic tooth movement in 30 subjects, 57 premolars were moved buccally during 8 weeks with the application of a 1-N force. Forty-four contralateral premolars not subjected to orthodontic tooth movement served as the controls. Plaster models from before and after the experimental tooth movement were digitized and superimposed to evaluate the amounts of tooth movement. Differences in tooth movement between the experimental and control groups were tested by an unpaired t test. For the experimental teeth, subject related factors (age and sex) and tooth-related factors (location in the maxillary or mandibular dental arch, and the presence or absence of an intra-arch or interarch obstacle such as neighboring touching teeth or teeth interfering with the occlusion) were examined with analysis of variance. Multiple linear regression analysis was performed to determine correlations between tooth displacement, age, sex, tooth location, and presence of an interference. RESULTS: Each subject contributed at least 2 experimental premolars and 1 control premolar. The displacement of the orthodontically moved teeth was 2.42 mm (range, 0.3-5.8 mm). Younger subjects (<16 years; n = 19; number of teeth, 36) had significantly greater amounts of tooth displacement compared with older subjects (>=16 years; n = 11; number of teeth, 21): 2.6 +/- 1.3 mm vs 1.8 +/- 0.8 mm; P <0.01. When an interarch or intra-arch obstacle was present, the amount of tooth movement was significantly less (2.6 +/- 1.3 mm vs 1.8 +/- 0.8 mm) (P <0.05). Neither sex nor the location of the experimental teeth in the mandible or the maxilla had any effect. CONCLUSIONS: Younger patients showed greater tooth movement velocity than did older ones. An interarch or intra-arch obstacle decreased the amount of tooth displacement. PMID- 23631964 TI - Associations between palatally displaced canines and maxillary lateral incisors. AB - INTRODUCTION: The purpose of this research was to investigate relationships among the location and orientation of palatally displaced canines and the dimension and orientation of the maxillary lateral incisor. METHODS: An experimental group of 40 patients with 46 palatally displaced canines (20 from boys, 26 from girls; mean age of the subjects, 13.9 years; age range, 10.5-15.9 years) was selected from the records of patients referred to a radiology practice specializing in cone-beam volumetric tomography imaging. This group was age- and sex-matched with 30 normal subjects with 60 canines (26 from boys, 34 from girls; mean age of the subjects, 13.8 years; age range, 10.4-15.7 years). Digital cone-beam volumetric tomography images were imported into an imaging software and were reoriented and reconstructed into several radiographic images in coronal and sagittal sections; a maxillary arch occlusal view was also produced. The angular and linear variables of the canines and the maxillary lateral incisors were measured by using software measurement tools. Independent t tests or Mann-Whitney U tests were used accordingly based on normality of the data to compare the variables between the palatally displaced canine and the control groups. Multiple linear regressions were used to examine the relationships between the canine variables (dependent variables) and the maxillary lateral incisor variables together with confounding variables (independent variables). RESULTS: The maxillary lateral incisors in the palatally displaced canine group tended to be more upright in the sagittal and coronal planes. Generally, the most significant independent variables according to backward examination of linear regression for canine variables (coronal and sagittal angulations, and distance to the occlusal plane of palatally displaced canines) were the coronal and sagittal angulations of the maxillary lateral incisors, the length and buccolingual root width of the maxillary lateral incisors, and age. CONCLUSIONS: The orientation and location of palatally displaced canines were associated with changes in the angulations of maxillary lateral incisors and small lateral incisors. PMID- 23631965 TI - Three-dimensional assessment of buccal alveolar bone after rapid and slow maxillary expansion: a clinical trial study. AB - INTRODUCTION: The purposes of this study were to analyze and compare the immediate effects of rapid and slow maxillary expansion protocols, accomplished by Haas-type palatal expanders activated in different frequencies of activation on the positioning of the maxillary first permanent molars and on the buccal alveolar bones of these teeth with cone-beam computerized tomography. METHODS: The sample consisted of 33 children (18 girls, 15 boys; mean age, 9 years) randomly distributed into 2 groups: rapid maxillary expansion (n = 17) and slow maxillary expansion (n = 16). Patients in the rapid maxillary expansion group received 2 turns of activation (0.4 mm) per day, and those in the slow maxillary expansion group received 2 turns of activation (0.4 mm) per week until 8 mm of expansion was achieved in both groups. Cone-beam computerized tomography images were taken before treatment and after stabilization of the jackscrews. Data were gathered through a standardized analysis of cone-beam computerized tomography images. Intragroup statistical analysis was accomplished with the Wilcoxon matched-pairs test, and intergroup statistical analysis was accomplished with analysis of variance. Linear relationships, among all variables, were determined by Spearman correlation. RESULTS AND CONCLUSIONS: Both protocols caused buccal displacement of the maxillary first permanent molars, which had more bodily displacement in the slow maxillary expansion group, whereas more inclination was observed in the rapid maxillary expansion group. Vertical and horizontal bone losses were found in both groups; however, the slow maxillary expansion group had major bone loss. Periodontal modifications in both groups should be carefully considered because of the reduction of spatial resolution in the cone-beam computerized tomography examinations after stabilization of the jackscrews. Modifications in the frequency of activation of the palatal expander might influence the dental and periodontal effects of palatal expansion. PMID- 23631967 TI - Influence of maxillary incisor edge asymmetries on the perception of smile esthetics among orthodontists and laypersons. AB - INTRODUCTION: Our objective was to determine the perception of smile esthetics among orthodontists and laypeople with respect to asymmetries on the maxillary incisor edges in a frontal smile analysis. METHODS: Two frontal close-up smile photos of 2 women, 1 white and 1 Afro-Brazilian, were selected for this study. Both smiles displayed healthy maxillary anterior dentitions. The images were digitally altered to create tooth wear on the maxillary left central and lateral incisors in 0.5-mm increments. The final images were randomly assembled into a photo album that was given to 120 judges, 60 orthodontists and 60 laypersons. Each rater was asked to evaluate the attractiveness of the images with visual analog scales. The data collected were statistically analyzed with 1-way analysis of variance with the Tukey post-hoc test and the unpaired Student t test. RESULTS: The most attractive smiles in both types of smiles were those without asymmetries and the 0.5-mm wear in the lateral incisor. In general, tooth wear was considered unattractive by both groups of raters following a pattern: the more tooth wear, the more unattractive the smile; tooth wear in the central incisor was considered more unattractive than in the lateral incisor. For both group of raters, 0.5 mm of wear in the central incisor was considered unattractive, whereas the thresholds for lateral incisor discrepancies were 0.5 mm for orthodontists and 1.0 mm for laypersons. CONCLUSIONS: The result of this study corroborates the clinical assumption that symmetry between the maxillary central incisors is a paramount goal for esthetic treatments. PMID- 23631966 TI - Three-dimensional deformation comparison of self-ligating brackets. AB - INTRODUCTION: Archwire rotation is used in orthodontic treatment to alter the labiolingual orientation of a tooth. Measurement of the 3-dimensional (3D) motion of the orthodontic brackets requires a new configuration of the orthodontic torque simulator. METHODS: The orthodontic torque simulator was coupled with a stereo microscope and 2 cameras to allow for the 3D bracket motion to be determined during wire twisting. The stereo camera images were processed with a 3D digital image correlation technique to determine the 3D deformation of the orthodontic brackets. Three self-ligating brackets (Damon Q, Ormco, Orange, Calif; In-Ovation R, GAC, Bohemia, NY; and Speed, Strite Industries, Cambridge, Ontario, Canada) were compared by using the 3D digital image correlation method to demonstrate the difference in 3D motion of self-ligating brackets components. RESULTS: Contour plots of the 3 brackets demonstrate the 3D motion of the bracket tie-wings and the archwire retentive component. The 3D motion of the bracket tie wings and archwire retentive component were quantified. The displacement values of the archwire retentive component measured with the 3D orthodontic torque simulator were found to be 2.0 and 3.5 times less for the In-Ovation and Damon Q brackets than the values in previous studies that examined the compliance of the archwire retentive component. CONCLUSIONS: The 3D digital image correlation method used to quantify bracket deformation showed the 3D motion of the bracket tie-wings and the motion of the archwire retentive component. The use of a 3D optical measurement system is useful to understand the motion of the archwire retentive component but is not necessary to quantify bracket tie-wing motion. This measurement technique can be used to evaluate brackets of varying designs. PMID- 23631968 TI - Impact of cone-beam computed tomography on orthodontic diagnosis and treatment planning. AB - INTRODUCTION: In this study, we measured the impact of cone-beam computed tomography (CBCT) on orthodontic diagnosis and treatment planning. METHODS: Participant orthodontists shown traditional orthodontic records for 6 patients were asked to provide a diagnostic problem list, a hypothetical treatment plan, and a clinical certainty. They then evaluated a CBCT scan for each patient and noted any changes, confirmations, or enhancements to their diagnosis and treatment plan. RESULTS: The number of diagnosis and treatment plan changes varied widely by patient characteristics. The most frequently reported diagnosis and treatment plan changes occurred in patients with unerupted teeth, severe root resorption, or severe skeletal discrepancies. We found no benefit in terms of changes in treatment plan for patients when the reason for obtaining a CBCT scan was to examine for abnormalities of the temporomandibular joint or airway, or crowding. Orthodontic participants who own CBCT machines or use CBCT scans frequently in practice reported significantly more diagnosis and treatment plan changes and greater confidence after viewing the CBCT scans during the study. CONCLUSIONS: The results of this study support obtaining a CBCT scan before orthodontic diagnosis and treatment planning when a patient has an unerupted tooth with delayed eruption or a questionable location, severe root resorption as diagnosed with a periapical or panoramic radiograph, or a severe skeletal discrepancy. We propose that CBCT scans should be ordered only when there is clear, specific, individual clinical justification. PMID- 23631969 TI - Mechanical properties of Opus closing loops, L-loops, and T-loops investigated with finite element analysis. AB - INTRODUCTION: The objective of this research was to investigate the mechanical properties at both sides of Opus closing loops by analyzing the effects of loop shape, loop position, coil position, and tipping of the vertical legs. METHODS: Opus loops were compared with L-loops (with and without a coil) and a T-loop by using finite element analysis. Both upright and tipped vertical loop legs (70 degrees ) were tested. Loop response to loop pulling was simulated at 5 loop positions for a 12-mm interbracket distance and 10-mm loop lengths and heights. Three-dimensional models of the closing loops were created by using beam elements with stainless steel properties. The L-loops and Opus loops were directed toward the anterior side. Loop properties (horizontal load/deflection, vertical force, and moment-to-force ratio) at both loop ends were recorded at activation forces of 100 and 200 g. RESULTS: Upright Opus loops and L-loops showed the highest moment-to-force ratios (8.5-9.3) on the canine bracket when the loop was centered. The Opus loops and L-loops with tipped vertical legs and the T-loop had slightly lower moment-to-force ratios (7.8-8.5), with the maximum values occurring when the loop was placed close to the canine bracket end. CONCLUSIONS: Upright L-loops showed the highest moment-to-force ratios on canine brackets, whereas backward tipping of the vertical legs shifted mechanical properties closer to those of a T-loop. Loop properties varied with loop configuration and position. Clinicians should understand the specific characteristics of each loop configuration to most effectively exploit them for the desired tooth movements. PMID- 23631970 TI - Dentoskeletal changes induced by the Jasper jumper and the activator-headgear combination appliances followed by fixed orthodontic treatment. AB - INTRODUCTION: The aim of this study was to compare the dentoskeletal changes of patients with Class II Division 1 malocclusion treated with either the Jasper jumper appliance or the activator-headgear combination, both associated with fixed appliances. METHODS: The sample comprised 72 subjects with Class II Division 1 malocclusion divided into 3 groups: group 1 included 25 subjects treated with fixed appliances and the force modules of the Jasper jumper at an initial mean age of 12.72 years, group 2 included 25 subjects treated with the activator-headgear combination followed by fixed appliances at an initial mean age of 11.07 years, and group 3 included 22 untreated subjects at an initial mean age of 12.67 years. Initial cephalometric characteristics and dentoskeletal changes were compared with analysis of variance. RESULTS: Both experimental groups had similar dentoskeletal changes: restrictive effect on the maxilla, clockwise mandibular rotation and a slight increase in anterior face height, retrusion of the maxillary incisors, distalization of the maxillary molars, protrusion of the mandibular incisors, extrusion of the mandibular molars, and significant improvements of the maxillomandibular relationship, overjet, overbite, and the molar relationship. CONCLUSIONS: The effects of the Jasper jumper and the activator-headgear combination followed by fixed orthodontic appliances were similar in Class II malocclusion treatment. PMID- 23631971 TI - Stability of quad-helix/crib therapy in dentoskeletal open bite: a long-term controlled study. AB - INTRODUCTION: The purpose of this study was to evaluate the long-term stability of quad-helix/crib treatment in subjects with dentoskeletal open bite. METHODS: Twenty-eight subjects (11 boys, 17 girls; mean age, 8.2 +/- 1.3 years) were treated consecutively with quad-helix/crib appliances. The patients were reevaluated at the end of active treatment with the quad-helix/crib (mean age, 9.7 +/- 1.6 years) and at least 5 years after the completion of treatment (mean age, 14.6 +/- 1.9 years). A control group of 20 untreated subjects with the same dentoskeletal disharmony was used for the statistical comparison (Mann-Whitney U test). RESULTS: In the long term, the quad-helix/crib group showed a significant reduction in the ANB angle (-1.3 degrees ), a downward rotation of the palatal plane (1.8 degrees ), a greater increase in overbite (2.1 mm), and a decrease in overjet (-1.5 mm) when compared with the controls. CONCLUSIONS: In the long term, the use of the quad-helix/crib appliance led to successful outcomes in about 93% of the patients considered. Correction of dentoskeletal open bite was associated with a clinically significant downward rotation of the palatal plane. PMID- 23631972 TI - Reconstruction of a collapsed dental arch in a patient with severe periodontitis. AB - This case report describes the significance of orthodontic treatment in reconstruction of a collapsed dental arch and a malocclusion associated with severe periodontitis. A Japanese man (age, 40 years 7 months) had an anterior crossbite, a collapsed occlusion, and severe periodontitis. Orthodontic treatment included the following steps: (1) correction of the anterior crossbite, labial movement of the maxillary incisors, and intrusion and retraction of the mandibular incisors; (2) correction of the posterior crossbite on the left side, buccal movement of the maxillary left canine and first premolars, and intrusion and retraction of the mandibular first premolar into the space of the mandibular left canine; (3) correction of the crowding of the mandibular right buccal segment and alignment of the teeth after extraction of the mandibular right first molar with a periapical lesion; and (4) improvement of the occlusion, with reconstruction of an acceptable occlusion. When combined with restorative and prosthodontic treatment, a fairly good occlusion was obtained. Reevaluation of the treatment after 11 years showed that the occlusion and periodontal condition were maintained well without deepening of the pockets and further bone loss. Orthodontic treatment with a systematic approach helped to recover the occlusion and prevented the recurrence of periodontitis by acquiring a good oral environment and motivating the patient to maintain oral health. PMID- 23631973 TI - Iatrogenic absence of maxillary canines: Bolton discrepancy treated with mandibular incisor extraction. AB - This case report describes the orthodontic treatment of an adult patient with iatrogenic absence of the maxillary canines, moderate maxillary and severe mandibular dental crowding, a Bolton discrepancy with a large mandibular anterior excess, a maxillary right lateral incisor crossbite, and Angle Class II molar relationships. The treatment consisted of fixed appliance therapy, mandibular incisor extraction, tooth bleaching, and dental recontouring. This method of treatment maintained the patient's good facial appearance, improved the dental esthetics, and provided a good functional occlusion, eliminating the arch length and Bolton discrepancies and providing a good outcome with minimal undesirable effects. PMID- 23631974 TI - Canine autotransplantation: effect of extraction site preservation with a titanium prosthesis and a bioresorbable membrane. AB - The permanent canine is the most frequently displaced or impacted tooth. The standard treatment for an impacted canine includes surgical exposure and orthodontic alignment. Autotransplantation is a treatment alternative for canines with complete root formation. The purpose of this article is to report a canine autotransplantation where the extraction site was preserved with a titanium prosthesis and a bioresorbable membrane. The autotransplanted canine had minimal root resorption and no ankylosis. PMID- 23631975 TI - Submandibular-space abscess from loss of a bonded molar tube during orthognathic surgery. AB - The use of bonded orthodontic molar tubes is becoming more prevalent in orthodontics because they have some advantages over conventional bonding. However, a bonded apparatus can become detached, leading to complications. This article presents the case of a submandibular-space abscess associated with a molar tube that detached during orthognathic surgery and became embedded in the soft tissues. The site became infected, and antibiotics were prescribed. Eventually, the molar tube migrated and could be removed under local anesthesia. PMID- 23631976 TI - Three-dimensional reproducibility of natural head position. AB - INTRODUCTION: Although natural head position has proven to be reliable in the sagittal plane, with an increasing interest in 3-dimensional craniofacial analysis, a determination of its reproducibility in the coronal and axial planes is essential. This study was designed to evaluate the reproducibility of natural head position over time in the sagittal, coronal, and axial planes of space with 3-dimensional imaging. METHODS: Three-dimensional photographs were taken of 28 adult volunteers (ages, 18-40 years) in natural head position at 5 times: baseline, 4 hours, 8 hours, 24 hours, and 1 week. Using the true vertical and horizontal laser lines projected in an iCAT cone-beam computed tomography machine (Imaging Sciences International, Hatfield, Pa) for orientation, we recorded references for natural head position on the patient's face with semipermanent markers. By using a 3-dimensional camera system, photographs were taken at each time point to capture the orientation of the reference points. By superimposing each of the 5 photographs on stable anatomic surfaces, changes in the position of the markers were recorded and assessed for parallelism by using 3dMDvultus (3dMD, Atlanta, Ga) and software (Dolphin Imaging & Management Solutions, Chatsworth, Calif). RESULTS: No statistically significant differences were observed between the 5 time points in any of the 3 planes of space. However, a statistically significant difference was observed between the mean angular deviations of 3 reference planes, with a hierarchy of natural head position reproducibility established as coronal > axial > sagittal. CONCLUSIONS: Within the parameters of this study, natural head position was found to be reproducible in the sagittal, coronal, and axial planes of space. The coronal plane had the least variation over time, followed by the axial and sagittal planes. PMID- 23631977 TI - Litigation and legislation: so let be written, so let it be done. PMID- 23631978 TI - Multiplicity 3: repeated measures. PMID- 23631979 TI - Chemically cross-linked and grafted cyclodextrin hydrogels: from nanostructures to drug-eluting medical devices. AB - The unique ability of cyclodextrins (CDs) to form inclusion complexes can be transmitted to polymeric networks in which CDs are chemically grafted or cross linked. Combination of CDs and hydrogels in a single material leads to synergic properties: the hydrophilic network enhances biocompatibility and prevents dilution in the physiological medium increasing the stability of the inclusion complexes, while CDs finely tune the mechanical features and the stimuli responsiveness and provide affinity-based regulation of drug loading and release. Therefore, CD-functionalized materials are opening new perspectives in pharmacotherapy, emerging as advanced delivery systems (DDS) for hydrophobic and hydrophilic drugs to be administered via almost any route. Medical devices (catheters, prosthesis, vascular grafts, bone implants) can also benefit from surface grafting or thermofixation of CDs. The present review focuses on the approaches tested to synthesize nano- to macro-size covalently cross-linked CD networks: i) direct cross-linking through condensation with di- or multifunctional reagents, ii) copolymerization of CD derivatives with acrylic/vinyl monomers, and iii) grafting of CDs to preformed medical devices. Examples of the advantages of having the CDs chemically bound among themselves and to substrates are provided and their applicability in therapeutics discussed. PMID- 23631980 TI - Cortical control of normal gait and precision stepping: an fNIRS study. AB - Recently, real time imaging of the cortical control of gait became possible with functional near-infrared spectroscopy (fNIRS). So far, little is known about the activations of various cortical areas in more complex forms of gait, such as precision stepping. From previous work on animals and humans one would expect precision stepping to elicit extra activity in the sensorimotor cortices (S1/M1), supplementary motor area (SMA), as well as in prefrontal cortices (PFC). In the current study, hemodynamic changes in the PFC, SMA, M1, and S1 were measured with fNIRS. In contrast to previous fNIRS gait studies, the technique was optimized by the use of reference channels (to correct for superficial hemodynamic interference). Eleven subjects randomly performed ten trials of treadmill walking at 3 km/h (normal walking) and ten trials of 3 km/h treadmill walking on predefined spots for the left and right foot presented on the treadmill (precision stepping). The walking trials of approximately 35 seconds were alternated with rest periods of 25-35 seconds consisting of quiet standing. The PFC revealed profound activation just prior to the onset of both walking tasks. There was also extra activation of the PFC during the first half of the task period for precision stepping. The SMA showed mainly increased activation prior to the start of both tasks. In contrast, the sensorimotor cortex did not show a change in activation during either task as compared to a condition of standing. The SMA, M1, and S1 revealed no significant differences between normal walking and precision stepping. It was concluded that fNIRS is suited to record the planning and initiation of gait. The lack of M1/S1 activation during gait suggests that even in the current precision stepping task the control of ongoing gait depended mostly on subcortical automatisms, while motor cortex contributions did not differ between standing and walking. PMID- 23631981 TI - Effect of long-term treatment with pramipexole or levodopa on presynaptic markers assessed by longitudinal [123I]FP-CIT SPECT and histochemistry. AB - A previous clinical trial studied the effect of long-term treatment with levodopa (LD) or the dopamine agonist pramipexole (PPX) on disease progression in Parkinson disease using SPECT with the dopamine transporter (DAT)-radioligand [(123)I]beta-CIT as surrogate marker. [(123)I]beta-CIT binding declined to significantly lower levels in patients receiving LD compared to PPX. However, the interpretation of this difference as LD-induced neurotoxicity, PPX-induced neuroprotection/-regeneration, or only drug-induced regulatory changes of DAT availability remained controversial. To address this question experimentally, we induced a subtotal lesion of the substantia nigra in mice by bilateral injection of the neurotoxin 6-hydroxydopamine. After 4 weeks, mice were treated for 20 weeks orally with LD (100mg/kg/day) or PPX (3mg/kg/day), or water (vehicle) only. The integrity of nigrostriatal projections was assessed by repeated [(123)I]FP CIT SPECT in vivo and by immunostaining for DAT and the dopamine-synthesizing enzyme tyrosine hydroxylase (TH) after sacrifice. In sham-lesioned mice, we found that both LD and PPX treatment significantly decreased the striatal FP-CIT binding (LD: -21%; PPX: -14%) and TH-immunoreactivity (LD: -42%; PPX: -45%), but increased DAT-immunoreactivity (LD: +42%; PPX: +33%) compared to controls without dopaminergic treatment. In 6-hydroxydopamine-lesioned mice, however, neither LD nor PPX significantly influenced the stably reduced FP-CIT SPECT signal (LD: 66%; PPX: -66%; controls -66%), TH-immunoreactivity (LD: -70%; PPX: -72%; controls: -77%) and DAT-immunoreactivity (LD: -70%; PPX: -75%; controls: -75%) in the striatum or the number of TH-positive cells in the substantia nigra (LD: 88%; PPX: -88%; controls: -86%), compared to lesioned mice without dopaminergic treatment. In conclusion, chronic dopaminergic stimulation with LD or PPX induced similar adaptive presynaptic changes in healthy mice, but no discernible changes in severely lesioned mice. These findings allow to more reliably interpret the results from clinical trials using neuroimaging of DAT as surrogate parameter. PMID- 23631982 TI - Correlated slow fluctuations in respiration, EEG, and BOLD fMRI. AB - Low-frequency temporal fluctuations of physiological signals (<0.1 Hz), such as the respiration and cardiac pulse rate, occur naturally during rest and have been shown to be correlated with blood-oxygenation-level-dependent (BOLD) signal fluctuation. Such physiological signal modulations have been considered as sources of noise and their effects on BOLD signal are commonly removed in functional magnetic resonance imaging (fMRI) studies. However, possible neural correlates of the physiological fluctuations have not been considered nor examined in detail. In the present study we investigated this possibility by simultaneously acquiring electroencephalogram (EEG) with BOLD fMRI data, respiratory and cardiac waveforms in healthy human subjects at eyes-closed and eyes-open resting. We quantified the concurrent changes of the EEG power in the alpha frequency band, the respiration volume, and the cardiac pulse rate, then assessed the temporal correlations between alpha EEG power and physiological signal fluctuations. In addition, time-shifted time courses of alpha EEG power or physiological data were included as regressors to examine their correlations with the whole-brain BOLD fMRI signals. We observed a significant correlation between alpha EEG global field power and respiration, particularly at eyes-closed resting condition. Similar spatial patterns were observed between the correlation maps of BOLD with alpha EEG power and respiration, with negative correlations coinciding in the visual cortex, superior/middle temporal gyrus, inferior frontal gyrus, and inferior parietal lobule and positive correlations in the thalamus and caudate. Regressing out the physiological variations in the BOLD signal resulted in reduced correlation between BOLD and alpha EEG power. These results suggest a mutual link of neuronal origin between alpha EEG power, respiration, and BOLD signals. PMID- 23631983 TI - Standardizing the intrinsic brain: towards robust measurement of inter-individual variation in 1000 functional connectomes. AB - As researchers increase their efforts to characterize variations in the functional connectome across studies and individuals, concerns about the many sources of nuisance variation present and their impact on resting state fMRI (R fMRI) measures continue to grow. Although substantial within-site variation can exist, efforts to aggregate data across multiple sites such as the 1000 Functional Connectomes Project (FCP) and International Neuroimaging Data-sharing Initiative (INDI) datasets amplify these concerns. The present work draws upon standardization approaches commonly used in the microarray gene expression literature, and to a lesser extent recent imaging studies, and compares them with respect to their impact on relationships between common R-fMRI measures and nuisance variables (e.g., imaging site, motion), as well as phenotypic variables of interest (age, sex). Standardization approaches differed with regard to whether they were applied post-hoc vs. during pre-processing, and at the individual vs. group level; additionally they varied in whether they addressed additive effects vs. additive+multiplicative effects, and were parametric vs. non parametric. While all standardization approaches were effective at reducing undesirable relationships with nuisance variables, post-hoc approaches were generally more effective than global signal regression (GSR). Across approaches, correction for additive effects (global mean) appeared to be more important than for multiplicative effects (global SD) for all R-fMRI measures, with the exception of amplitude of low frequency fluctuations (ALFF). Group-level post-hoc standardizations for mean-centering and variance-standardization were found to be advantageous in their ability to avoid the introduction of artifactual relationships with standardization parameters; though results between individual and group-level post-hoc approaches were highly similar overall. While post-hoc standardization procedures drastically increased test-retest (TRT) reliability for ALFF, modest reductions were observed for other measures after post-hoc standardizations-a phenomena likely attributable to the separation of voxel-wise from global differences among subjects (global mean and SD demonstrated moderate TRT reliability for these measures). Finally, the present work calls into question previous observations of increased anatomical specificity for GSR over mean centering, and draws attention to the near equivalence of global and gray matter signal regression. PMID- 23631984 TI - Functional connectivity of the cortex of term and preterm infants and infants with Down's syndrome. AB - Near-infrared spectroscopy (NIRS) imaging studies have revealed the functional development of the human brain in early infancy. By measuring spontaneous fluctuations in cerebral blood oxygenation with NIRS, we can examine the developmental status of the functional connectivity of networks in the cortex. However, it has not been clarified whether premature delivery and/or chromosomal abnormalities affect the development of the functional connectivity of the cortex. In the current study, we investigated the spontaneous brain activity of sleeping infants who were admitted to a neonatal intensive care unit at term age. We classified them into the 3 following infant groups: (i) term-or-late-preterm, (ii) early-preterm, and (iii) Down's syndrome (DS). We used multichannel NIRS to measure the spontaneous changes in oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin (deoxy-Hb) at 10 measurement channels, which covered the frontal, temporal, and occipital regions. In order to reveal the functional connectivity of the cortical networks, we calculated the temporal correlations of the time-course signals among all of the pairs of measurement channels. The functional connectivity was classified into the 4 following types: (i) short range, (ii) contralateral-transverse, (iii) ipsilateral-longitudinal, and (iv) control. In order to examine whether the local properties of hemodynamics reflected any pathological conditions, we calculated the phase differences between the oxy- and deoxy-Hb time-course signals in the 3 groups. The statistical analyses of the functional connectivity data showed main effects of group and the types of connectivity. For the group effect, the mean functional connectivity of the infants in the term-or-late-preterm group did not differ from that in the early-preterm group, and the mean functional connectivity of the infants in the DS group was lower than that in the other 2 groups. For the effect of types of connectivity, short-range connectivity was highest compared to any of the other types of connectivity, and the second highest connectivity was the contralateral-transverse one. The phase differences between the oxy- and deoxy-Hb changes showed that there were significant differences between the DS group and the other 2 groups. Our findings suggested that the development of the functional connectivity of cortical networks did not differ between term-or-late-preterm infants and early-preterm infants around term-equivalent ages, while DS infants had alterations in their functional connectivity development and local hemodynamics at term age. The highest short-range connectivity and the second highest contralateral-transverse connectivity suggested that the precursors for the basic cortical networks of functional connectivity were present at term age. PMID- 23631985 TI - Optimally-Discriminative Voxel-Based Morphometry significantly increases the ability to detect group differences in schizophrenia, mild cognitive impairment, and Alzheimer's disease. AB - Optimally-Discriminative Voxel-Based Analysis (ODVBA) (Zhang and Davatzikos, 2011) is a recently-developed and validated framework of voxel-based group analysis, which transcends limitations of traditional Gaussian smoothing in the forms of analysis such as the General Linear Model (GLM). ODVBA estimates the optimal non-stationary and anisotropic filtering of the data prior to statistical analyses to maximize the ability to detect group differences. In this paper, we extensively evaluate ODVBA to three sets of previously published data from studies in schizophrenia, mild cognitive impairment, and Alzheimer's disease, and evaluate the regions of structural difference identified by ODVBA versus standard Gaussian smoothing and other related methods. The experimental results suggest that ODVBA is considerably more sensitive in detecting group differences, presumably because of its ability to adapt the regional filtering to the underlying extent and shape of a group difference, thereby maximizing the ability to detect such difference. Although there is no gold standard in these clinical studies, ODVBA demonstrated highest significance in group differences within the identified voxels. In terms of spatial extent of detected area, agreement of anatomical boundary, and classification, it performed better than other tested voxel-based methods and competitively with the cluster enhancing methods. PMID- 23631986 TI - Neuropsychiatric deep brain stimulation for translational neuroimaging. AB - From a neuroimaging point of view, deep brain stimulation (DBS) in psychiatric disorders represents a unique source of information to probe results gained in functional, structural and molecular neuroimaging studies in vivo. However, the implementation has, up to now, been restricted by the heterogeneity of the data reported in DBS studies. The aim of the present study was therefore to provide a comprehensive and standardized database of currently used DBS targets in selected psychiatric disorders (obsessive-compulsive disorder (OCD), treatment-resistant depression (TRD), Gilles de la Tourette syndrome (GTS)) to enable topological comparisons between neuroimaging results and stimulation areas. A systematic literature research was performed and all peer-reviewed publications until the year 2012 were included. Literature research yielded a total of 84 peer-reviewed studies including about 296 psychiatric patients. The individual stimulation data of 37 of these studies meeting the inclusion criteria which included a total of 202 patients (63 OCD, 89 TRD, 50 GTS) was translated into MNI stereotactic space with respect to AC origin in order to identify key targets. The created database can be used to compare DBS target areas in MNI stereotactic coordinates with: 1) activation patterns in functional brain imaging (fMRI, phfMRI, PET, MET, EEG); 2) brain connectivity data (e.g., MR-based DTI/tractography, functional and effective connectivity); 3) quantitative molecular distribution data (e.g., neuroreceptor PET, post-mortem neuroreceptor mapping); 4) structural data (e.g., VBM for neuroplastic changes). Vice versa, the structural, functional and molecular data may provide a rationale to define new DBS targets and adjust/fine tune currently used targets in DBS based on this overview in stereotactic coordinates. Furthermore, the availability of DBS data in stereotactic space may facilitate the investigation and interpretation of treatment effects and side effect of DBS by comparing these to neuroimaging results. The present study thus improves comparability between functional, structural and molecular data in standard stereotactic space gained in neuroimaging studies with surgical targets for DBS, which is among other possible implications of crucial importance for the definition of new targets for effective DBS. PMID- 23631988 TI - Metabolic and structural connectivity within the default mode network relates to working memory performance in young healthy adults. AB - Studies of functional connectivity suggest that the default mode network (DMN) might be relevant for cognitive functions. Here, we examined metabolic and structural connectivity between major DMN nodes, the posterior cingulate (PCC) and medial prefrontal cortex (MPFC), in relation to normal working memory (WM). DMN was captured using independent component analysis of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) data from 35 young healthy adults (27.1 +/ 5.1 years). Metabolic connectivity, a correlation between FDG uptake in PCC and MPFC, was examined in groups of subjects with (relative to median) low (n=18) and high (n=17) performance on digit span backward test as an index of verbal WM. In addition, fiber tractography based on PCC and MPFC nodes as way points was performed in a subset of subjects. FDG uptake in the DMN nodes did not differ between high and low performers. However, significantly (p=0.01) lower metabolic connectivity was found in the group of low performers. Furthermore, as compared to high performers, low performers showed lower density of the left superior cingulate bundle. Verbal WM performance is related to metabolic and structural connectivity within the DMN in young healthy adults. Metabolic connectivity as quantified with FDG-PET might be a sensitive marker of the normal variability in some cognitive functions. PMID- 23631989 TI - The neural representation of sensorimotor transformations in a human perceptual decision making network. AB - Humans can quickly engage a neural network to transform complex visual stimuli into a motor response. Activity from a key region within this network, the intraparietal sulcus (IPS), has been associated with evidence accumulation and motor planning, thus implicating it in sensorimotor transformations. If such transformations occur within a brain region, a key and untested prediction is that neural activity reflecting both the parametric amount of evidence available and the timing of motor planning can be independently manipulated. To investigate these ideas, we constructed a dot motion discrimination task in which information about response modality (what to use) and response mapping (how to use it) was provided independently either before or after presentation of a dot motion coherence stimulus whose strength varied across trials. Consistent with our hypothesis, activity within IPS covaried with dot motion coherence during the stimulus phase, and as information necessary for the response was delayed, the peak of IPS activity shifted to the response phase. In contrast, areas such as the motion-sensitive region MT+ and the supplementary motor area demonstrated activity limited to the stimulus and response phases of the task, respectively. These results show that activity in IPS correlates with temporally dissociable representations consistent with both evidence accumulation and motor planning, and suggest that IPS is a core component for sensorimotor transformations within the perceptual decision-making network. PMID- 23631987 TI - Fiber clustering versus the parcellation-based connectome. AB - We compare two strategies for modeling the connections of the brain's white matter: fiber clustering and the parcellation-based connectome. Both methods analyze diffusion magnetic resonance imaging fiber tractography to produce a quantitative description of the brain's connections. Fiber clustering is designed to reconstruct anatomically-defined white matter tracts, while the parcellation based white matter segmentation enables the study of the brain as a network. From the perspective of white matter segmentation, we compare and contrast the goals and methods of the parcellation-based and clustering approaches, with special focus on reviewing the field of fiber clustering. We also propose a third category of new hybrid methods that combine the aspects of parcellation and clustering, for joint analysis of connection structure and anatomy or function. We conclude that these different approaches for segmentation and modeling of the white matter can advance the neuroscientific study of the brain's connectivity in complementary ways. PMID- 23631990 TI - Near-infrared spectroscopy versus magnetic resonance imaging to study brain perfusion in newborns with hypoxic-ischemic encephalopathy treated with hypothermia. AB - BACKGROUND: The measurement of brain perfusion may provide valuable information for assessment and treatment of newborns with hypoxic-ischemic encephalopathy (HIE). While arterial spin labeled perfusion (ASL) magnetic resonance imaging (MRI) provides noninvasive and direct measurements of regional cerebral blood flow (CBF) values, it is logistically challenging to obtain. Near-infrared spectroscopy (NIRS) might be an alternative, as it permits noninvasive and continuous monitoring of cerebral hemodynamics and oxygenation at the bedside. OBJECTIVE: The purpose of this study is to determine the correlation between measurements of brain perfusion by NIRS and by MRI in term newborns with HIE treated with hypothermia. DESIGN/METHODS: In this prospective cohort study, ASL MRI and NIRS performed during hypothermia were used to assess brain perfusion in these newborns. Regional cerebral blood flow (CBF) values, measured from 1-2 MRI scans for each patient, were compared to mixed venous saturation values (SctO2) recorded by NIRS just before and after each MRI. Analysis included groupings into moderate versus severe HIE based on their initial background pattern of amplitude integrated electroencephalogram. RESULTS: Twelve concomitant recordings were obtained of seven neonates. Strong correlation was found between SctO2 and CBF in asphyxiated newborns with severe HIE (r=0.88; p value=0.0085). Moreover, newborns with severe HIE had lower CBF (likely lower oxygen supply) and extracted less oxygen (likely lower oxygen demand or utilization) when comparing SctO2 and CBF to those with moderate HIE. CONCLUSIONS: NIRS is an effective bedside tool to monitor and understand brain perfusion changes in term asphyxiated newborns, which in conjunction with precise measurements of CBF obtained by MRI at particular times, may help tailor neuroprotective strategies in term newborns with HIE. PMID- 23631992 TI - Comparing connectomes across subjects and populations at different scales. AB - Brain connectivity can be represented by a network that enables the comparison of the different patterns of structural and functional connectivity among individuals. In the literature, two levels of statistical analysis have been considered in comparing brain connectivity across groups and subjects: 1) the global comparison where a single measure that summarizes the information of each brain is used in a statistical test; 2) the local analysis where a single test is performed either for each node/connection which implies a multiplicity correction, or for each group of nodes/connections where each subset is summarized by one single test in order to reduce the number of tests to avoid a penalizing multiplicity correction. We comment on the different levels of analysis and present some methods that have been proposed at each scale. We highlight as well the possible factors that could influence the statistical results and the questions that have to be addressed in such an analysis. PMID- 23631993 TI - Mapping interhemispheric connectivity using functional MRI after transcranial magnetic stimulation on the human auditory cortex. AB - Interhemispheric interactions can be important in transcranial magnetic stimulation (TMS) studies investigating motor or cognitive brain functions, but their role in predicting the outcome of TMS is not clear. Previously, we showed that individual differences in interhemispheric functional connectivity of auditory cortices influenced the behavioral effect of repetitive TMS (rTMS) applied over auditory cortex in a melody discrimination task. Here, functional magnetic resonance imaging (fMRI) scanning with the same task was carried out before and after rTMS applied over auditory cortex to determine how rTMS affects both behavior and neural function. After rTMS applied over the right auditory cortex, we found mean increases in activation in the contralateral auditory cortex. The degree and direction of modulation of the fMRI response were correlated with behavior: the higher the contralateral increase after stimulation, the faster the response times, whereas individuals with reduced contralateral activity showed no behavioral facilitation. We also found that higher interhemispheric connectivity between auditory cortices before TMS was associated with faster response times. This study shows directly the role of functional connectivity in the auditory network on TMS-induced modulation, which could explain its often variable effects on behavior. Combined TMS and fMRI is particularly useful to promote plastic reorganization in the auditory network and has implications for research on auditory-related disorders. PMID- 23631991 TI - Clinical applications of the functional connectome. AB - Central to the development of clinical applications of functional connectomics for neurology and psychiatry is the discovery and validation of biomarkers. Resting state fMRI (R-fMRI) is emerging as a mainstream approach for imaging based biomarker identification, detecting variations in the functional connectome that can be attributed to clinical variables (e.g., diagnostic status). Despite growing enthusiasm, many challenges remain. Here, we assess evidence of the readiness of R-fMRI based functional connectomics to lead to clinically meaningful biomarker identification through the lens of the criteria used to evaluate clinical tests (i.e., validity, reliability, sensitivity, specificity, and applicability). We focus on current R-fMRI-based prediction efforts, and survey R-fMRI used for neurosurgical planning. We identify gaps and needs for R fMRI-based biomarker identification, highlighting the potential of emerging conceptual, analytical and cultural innovations (e.g., the Research Domain Criteria Project (RDoC), open science initiatives, and Big Data) to address them. Additionally, we note the need to expand future efforts beyond identification of biomarkers for disease status alone to include clinical variables related to risk, expected treatment response and prognosis. PMID- 23631994 TI - Networks of task co-activations. AB - Recent progress in neuroimaging informatics and meta-analytic techniques has enabled a novel domain of human brain connectomics research that focuses on task dependent co-activation patterns across behavioral tasks and cognitive domains. Here, we review studies utilizing the BrainMap database to investigate data trends in the activation literature using methods such as meta-analytic connectivity modeling (MACM), connectivity-based parcellation (CPB), and independent component analysis (ICA). We give examples of how these methods are being applied to learn more about the functional connectivity of areas such as the amygdala, the default mode network, and visual area V5. Methods for analyzing the behavioral metadata corresponding to regions of interest and to their intrinsically connected networks are described as a tool for local functional decoding. We finally discuss the relation of observed co-activation connectivity results to resting state connectivity patterns, and provide implications for future work in this domain. PMID- 23631995 TI - High density of nicotinic receptors in the cingulo-insular network. AB - The nicotinic system plays an important role in ordinary cognition, particularly in attention. The main nicotinic receptor in the human brain is the heteromeric alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR), which is distributed throughout the brain, with an especially high density in the thalamus and brainstem. Despite the important role of alpha4beta2 nAChRs in various physiological functions and pathological conditions, their distribution in the human cortex remains poorly characterized. We assessed the in vivo distribution of alpha4beta2 nAChRs in the human cortex in a group of seven non-smoking healthy subjects, using 2-[(18)F]F-A-85380 PET and a volume-of-interest-based analysis. We showed that cortical nAChR density was highest in the insular and anterior cingulate cortices. In functional magnetic resonance imaging studies, these two cortical regions and the thalamus have been shown to be highly correlated during the resting state and various tasks. Here, we also directly assessed nAChR density in this cingulo-insular network as defined in an independent dataset using resting-state functional connectivity, and compared it to other control related networks, to the default mode network as well as to sensory and motor networks. Receptor density was significantly higher in the cingulo-insular network. This network has been suggested to maintain a variety of foundational capacities fundamental to cognitive function. The demonstration of a high nAChR density in the insular and anterior cingulate cortices reflects a particular neurochemical organization of the cingulo-insular network, and suggests an important role of the nicotinic receptors in its functions. PMID- 23631997 TI - Trends in hip fracture rates in US hemodialysis patients, 1993-2010. AB - BACKGROUND: Changes in mineral and bone disorder treatment patterns and demographic changes in the dialysis population may have influenced hip fracture rates in US dialysis patients in 1993-2010. STUDY DESIGN: Retrospective follow-up study analyzing trends over time in hospitalized hip fracture rates. SETTING & PARTICIPANTS: Using Medicare data, we created 2 point-prevalent study cohorts for each study year. Hemodialysis cohorts included patients with Medicare as primary payer receiving hemodialysis in the United States on January 1 of each year; non end-stage renal disease (ESRD) cohorts included Medicare beneficiaries 66 years or older on January 1 of each year. FACTORS: Age, sex, race, primary cause of ESRD, dual Medicare/Medicaid enrollment status, comorbid conditions. OUTCOMES: Hip fracture rates. MEASUREMENTS: Unadjusted hip fracture rates measured using number of events per 1,000 person-years in each year, then adjusted for patient characteristics. Poisson models estimated strata-specific event rates. RESULTS: The observed number of first hospitalized hip fracture events and the adjusted hip fracture rate increased steadily from 1993 (831 events; 11.9/1,000 person years), peaked in 2004 (3,256 events; 21.9/1,000 person-years), and decreased through 2010 (2,912 events; 16.6/1,000 person-years). The trend for the subset of hemodialysis patients 66 years or older was similar to the trend for the full hemodialysis cohort; however, it differed markedly in magnitude and pattern from the non-ESRD Medicare cohort, for which rates were substantially lower and slowly decreasing since 1996. LIMITATIONS: Unable to provide causal explanations for observed changes; hip fractures identified through inpatient episodes; results do not describe hemodialysis patients without Medicare Parts A and B; laboratory values unavailable in the Medicare data set. CONCLUSIONS: Temporal trends in hip fracture rates among Medicare hemodialysis patients differ markedly from the steadily decreasing trend in non-ESRD Medicare beneficiaries, showing a relatively rapid increase until 2004 and relatively rapid decrease thereafter. Further research is needed to define associated factors. PMID- 23631996 TI - Frequency specific interactions of MEG resting state activity within and across brain networks as revealed by the multivariate interaction measure. AB - Resting state networks (RSNs) are sets of brain regions exhibiting temporally coherent activity fluctuations in the absence of imposed task structure. RSNs have been extensively studied with fMRI in the infra-slow frequency range (nominally <10(-1)Hz). The topography of fMRI RSNs reflects stationary temporal correlation over minutes. However, neuronal communication occurs on a much faster time scale, at frequencies nominally in the range of 10(0)-10(2)Hz. We examined phase-shifted interactions in the delta (2-3.5 Hz), theta (4-7 Hz), alpha (8-12 Hz) and beta (13-30 Hz) frequency bands of resting-state source space MEG signals. These analyses were conducted between nodes of the dorsal attention network (DAN), one of the most robust RSNs, and between the DAN and other networks. Phase shifted interactions were mapped by the multivariate interaction measure (MIM), a measure of true interaction constructed from the maximization of imaginary coherency in the virtual channels comprised of voxel signals in source space. Non-zero-phase interactions occurred between homologous left and right hemisphere regions of the DAN in the delta and alpha frequency bands. Even stronger non-zero-phase interactions were detected between networks. Visual regions bilaterally showed phase-shifted interactions in the alpha band with regions of the DAN. Bilateral somatomotor regions interacted with DAN nodes in the beta band. These results demonstrate the existence of consistent, frequency specific phase-shifted interactions on a millisecond time scale between cortical regions within RSN as well as across RSNs. PMID- 23631998 TI - Cariogenic potential of commercial sweeteners in an experimental biofilm caries model on enamel. AB - OBJECTIVE: Scarce evidence is available on the cariogenic potential of the widely used commercial sweeteners. The aim of this study was to evaluate the effect of several sweeteners on enamel demineralisation and on the cariogenic properties of Streptococcus mutans biofilms in an artificial caries model. METHODS: S. mutans UA159 biofilms were cultured on bovine enamel slabs and exposed to one of the following commercial sweeteners in tablet or powder form: stevia, sucralose, saccharin, aspartame or fructose. Ten percent sucrose and 0.9% NaCl were used as caries-positive and caries-negative controls, respectively. Slabs/biofilms were exposed to the sweeteners three times per day for 5min each time. After 5 days, biofilms were recovered to determine: biomass, bacterial counts and intra- and extracellular polysaccharides. Surface microhardness was measured before and after the experiment to assess enamel demineralisation, expressed as percentage of surface hardness loss (%SHL). Data were analysed using analysis of variance (ANOVA) and Bonferroni (p<0.05). RESULTS: All tested commercial sweeteners, except fructose, showed less enamel demineralisation than sucrose (p<0.05). Only saccharine showed less biomass and intracellular polysaccharides than the rest of the groups (p<0.05). Stevia, sucralose and saccharine reduced the number of viable cells when compared with sucrose (p<0.05). All sugar alternatives reduced extracellular polysaccharide formation when compared with sucrose (p<0.05). CONCLUSIONS: Most commercial sweeteners appear to be less cariogenic than sucrose, but still retaining some enamel demineralisation potential. Products containing stevia, sucralose and saccharine showed antibacterial properties and seem to interfere with bacterial metabolism. Further studies are necessary to deepen these findings. PMID- 23632000 TI - Positive beliefs about rumination are associated with ruminative thinking and affect in daily life: evidence for a metacognitive view on depression. AB - BACKGROUND: Self-regulatory executive function theory (Wells and Matthews, 1994; Wells, 2008) stresses the role of metacognitions in the development of emotional disorders. Within this metacognitive model, positive beliefs about ruminative thinking are thought to be a risk factor for engaging in rumination and subsequently for depression. However, most of the existing research relies on retrospective self-report trait measures. AIMS: The aim of the present study was to examine the theory's predictions with an Ecological Momentary Assessment approach capturing rumination as it occurs in daily life. METHOD: Non-clinical participants (N = 93) were equipped with electronic diaries and completed four signal-contingent momentary self-reports per day for 4 weeks. A multilevel mediation model was computed to examine associations between positive beliefs about rumination and ruminative thinking and negative affect in daily life. RESULTS: Positive beliefs about rumination were significantly associated with ruminative thinking as it occurs in daily life. We further found evidence for a negative association with positive affect that was completely mediated via ruminative thinking in daily life occurring in response to negative emotions. CONCLUSIONS: Our results add ecologically valid corroborating evidence for the metacognitive model of emotional disorders within the framework of self regulatory executive function theory. PMID- 23631999 TI - Early introduction and delayed dissemination of pandemic influenza, Gabon. AB - Active surveillance in health care centers in Gabon during 2009-2011 detected 72 clinical cases of pandemic (H1N1) 2009 (pH1N1). We found that pH1N1 virus was introduced in mid-2009 but spread throughout the country in 2010. Thus, Gabon was also affected by pH1N1. PMID- 23632001 TI - Restoring stream habitat connectivity: a proposed method for prioritizing the removal of resident fish passage barriers. AB - Systematic methods for prioritizing the repair and removal of fish passage barriers, while growing of late, have hitherto focused almost exclusively on meeting the needs of migratory fish species (e.g., anadromous salmonids). An important but as of yet unaddressed issue is the development of new modeling approaches which are applicable to resident fish species habitat restoration programs. In this paper, we develop a budget constrained optimization model for deciding which barriers to repair or remove in order to maximize habitat availability for stream resident fish. Habitat availability at the local stream reach is determined based on the recently proposed C metric, which accounts for the amount, quality, distance and level of connectivity to different stream habitat types. We assess the computational performance of our model using geospatial barrier and stream data collected from the Pine-Popple Watershed, located in northeast Wisconsin (USA). The optimization model is found to be an efficient and practical decision support tool. Optimal solutions, which are useful in informing basin-wide restoration planning efforts, can be generated on average in only a few minutes. PMID- 23632002 TI - Degradation of chlorpyrifos in humid tropical soils. AB - The insecticide chlorpyrifos is extensively used in the humid tropics for insect control on crops and soils. Chlorpyrifos degradation and mineralization was studied under laboratory conditions to characterize the critical factors controlling the degradation and mineralization in three humid tropical soils from Malaysia. The degradation was fastest in moist soils (t1/2 53.3-77.0 days), compared to dry (t1/2 49.5-120 days) and wet soils (t1/2 63.0-124 days). Degradation increased markedly with temperature with activation energies of 29.0 76.5 kJ mol(-1). Abiotic degradation which is important for chlorpyrifos degradation in sub-soils containing less soil microbial populations resulted in t1/2 of 173-257 days. Higher chlorpyrifos dosages (5-fold) which are often applied in the tropics due to severe insects infestations caused degradation and mineralization rates to decrease by 2-fold. The mineralization rates were more sensitive to the chlorpyrifos application rates reflecting that degradation of metabolites is rate limiting and the toxic effects of some of the metabolites produced. Despite that chlorpyrifos is frequently used and often in larger amounts on tropical soils compared with temperate soils, higher temperature, moderate moisture and high activity of soil microorganisms will stimulate degradation and mineralization. PMID- 23632003 TI - Simultaneous serum nicotine, cotinine, and trans-3'-hydroxycotinine quantitation with minimal sample volume for tobacco exposure status of solid organ transplant patients. AB - Concentrations of nicotine and its metabolites in blood are indicative of patients' current tobacco exposure, and their quantifications have been clinically applied to multiple assessments including demonstration of abstinence prior to heart-lung transplantation. For the purpose of transplant evaluation, the laboratory work up is extensive; thereby an assay with minimal sample volume is preferred. We developed and validated a rapid LC-MS/MS assay to simultaneously quantitate nicotine and its major metabolites, Cotinine and trans-3'-OH-cotinine (3-OH-Cot), in serum. 100MUL of serum was spiked with deuterated internal standards and extracted by Oasis HLB solid phase extraction cartridge. Nicotine and metabolites in the reconstituted serum extract were separated by Agilent Eclipse XDB-C8 3.5MUm 2.1mm*50mm HPLC column within 4.7min, and quantified by MS/MS with positive mode electrospray ionization and multiple reaction monitoring. Ion suppression was insignificant, and extraction efficiency was 79 110% at 50ng/mL for all compounds. Limit of detection was 1.0ng/mL for nicotine and 3-OH-Cot, and <0.5ng/mL for Cotinine. Linearity ranges for nicotine, cotinine and 3-OH-Cot were 2-100, 2-1000, and 5-1000ng/mL with recoveries of 86-115%. Within-day and twenty-day imprecision at nicotine/cotinine/3-OH-Cot levels of 22/150/90, 37/250/150, and 50/800/500ng/mL were all 1.1-6.5%. The reconstituted serum extracts were stable for at least 7 days stored in the HPLC autosampler at 5 degrees C. Our method correlates well with alternative LC-MS/MS methods. We successfully developed and validated an LC-MS/MS assay to quantitate concentrations of nicotine and its metabolites in serum with minimal sample volume to assess tobacco exposure of heart-lung transplant patients. PMID- 23632004 TI - Role and mechanism of tissue plasminogen activator in venous wall fibrosis remodeling after deep venous thrombosis via the glycogen synthase kinase-3 beta signaling pathway. AB - BACKGROUND: Deep venous thrombosis (DVT) confers vein wall injury associated with fibrosis and extracellular matrix turnover. The activation of vascular smooth muscle cells (VSMCs) and phenotypic switching are postulated to be the significant contributing factors in the evolution of the pathogenic processes. This study investigated the effect of tissue plasminogen activator (tPA) on the phenotypic switching and collagen deposition of VSMCs, as well as related signaling pathway that leads to this activation. MATERIALS AND METHODS: The model of stasis-induced DVT was established by ligation of the femoral vein. VSMCs transfected with the plasmid vector carrying a rat recombinant tPA gene with an enhanced green fluorescent protein (EGFP) tag (AdtPA-EGFP). Fibrotic change, expression of collagen type I, the cell number of media, and intimal thickness score were evaluated; the comparisons were made among the AdtPA-EGFP-transfected group, an empty vector (AdNull-EGFP) transfected group, and a phosphate-buffered saline perfused group in vivo. tPA induced VSMCs phenotypic switching and collagen deposition in vitro. The related signaling pathway molecules and the cell cycle progression were also investigated by western blot and flow cytometry. RESULTS: In the AdtPA-EGFP stasis DVT model, early vein wall collagenolysis and deposition occurred more remarkable. Histological studies showed that the expression of vein wall collagen type I protein, cell number of media, and intimal thickness score was significantly increased (P < 0.05). In primary culture VSMCs, sustained stimulation with tPA induced collagen type I upregulation and triggered sequential signaling events involving Akt, extracellular signal-regulated kinases 1/2 (ERK1/2), glycogen synthase kinase-3 (GSK3)-beta phosphorylation, and cyclin D1 induction. Blockade of phosphatidylinositol 3-kinase-Akt and ERK1/2 activation suppressed tPA-induced GSK3beta phosphorylation, cyclin D1 expression, and the deposition of collagen type I. CONCLUSIONS: tPA was a profibrotic factor that potentiated the phenotypic switching and the deposition of collagen in VSMC. The effect of tPA on VSMCs involved activation of Akt and ERK1/2 pathways and inhibition of GSK3beta activity, which could promote a switch of the synthetic phenotype in VSMCs and lead to the remodeling of vascular injury. PMID- 23632005 TI - An investigation of the effect of thiamine pyrophosphate on cisplatin-induced oxidative stress and DNA damage in rat brain tissue compared with thiamine: thiamine and thiamine pyrophosphate effects on cisplatin neurotoxicity. AB - This study investigated the effects of thiamine pyrophosphate (TPP) at dosages of 10 and 20 mg/kg on oxidative stress induced in rat brain tissue with cisplatin and compared this with thiamine. Cisplatin neurotoxicity represents one of the main restrictions on the drug being given in effective doses. Oxidative stress is considered responsible for cisplatin toxicity. Our results showed that cisplatin increased the levels of oxidant parameters such as lipid peroxidation (thio barbituric acid reactive substance (TBARS)) and myeloperoxidase (MPO) in brain tissue and suppressed the effects of antioxidants such as total glutathione (GSH) and superoxide dismutase (SOD). TPP, especially at a dosage of 20 mg/kg, significantly reduced TBARS and MPO levels that increase with cisplatin administration compared with the thiamine group, while TPP significantly increases GSH and SOD levels. In addition, the level of 8-Gua (guanine), a product of DNA damage, was 1.7 +/- 0.12 8-hydroxyl guanine (8-OH Gua)/105 Gua in brain tissue in the control group receiving cisplatin, compared with 0.97 +/- 0.03 8-OH Gua/105 Gua in the thiamine pyrophosphate (20 mg/kg) group and 1.55 +/- 0.11 8-OH Gua/105 Gua in the thiamine (20 mg/kg) group. These results show that thiamine pyrophosphate significantly prevents oxidative damage induced by cisplatin in brain tissue, while the protective effect of thiamine is insignificant. PMID- 23632006 TI - Effect of subacute exposure to silver nanoparticle on some hematological and plasma biochemical indices in silver carp (Hypophthalmichthys molitrix). AB - The use of silver nanoparticles (Ag-NPs) is rapidly increasing, but there are limited data on their effects on the aquatic environment. The present study aimed to determine the acute toxicity and evaluate the effect of subacute concentrations of Ag-NPs (Nanocid(r): average particle size of 61 nm) on hematological and plasma biochemical indices of silver carp, Hypophthalmichthys molitrix, after 3, 7 and 14 days. The 24-, 48-, 72- and 96-h median lethal concentration (LC50) values of Nanocid for silver carp were estimated at 0.810, 0.648, 0.383 and 0.202 mg/L, respectively; 20% and 10% of the 96-h LC50 values (0.04 and 0.02 mg/L) were selected for subacute study. Red blood cell (RBC) count, hemoglobin (Hb) count and hematocrit (Hct) level were significantly reduced at both concentrations tested (p < 0.05). White blood cell (WBC), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), cortisol and glucose levels in Nanocid-treated groups were significantly higher than the controlled group at experimental periods (p < 0.05). In conclusion, Ag NPs intoxication resulted in erythrocyte reduction, hematological disturbances, leucocytosis and stress response in silver carp and offered a simple tool to evaluate toxicity-derived alterations. PMID- 23632007 TI - Development of a method for extraction and assay of human erythrocyte acetylcholinesterase and pesticide inhibition. AB - A method of extracting membranes from red blood cells (RBCs) is described, which were in turn used to assay acetylcholinesterase (AChE) activity. The evidence for the enzyme activity was established by selective inhibition using 1,5-bis(4 allyldimethylammoniumphenyl) pentan-3-one dibromide, tetraisopropyl pyrophosphoramide and neostigmine. Blood samples were exposed to three organophosphorus (dichlorvos, chlorpyrifos and diazinon) and two carbamate (carbaryl and carbofuran) pesticides. Afterwards AChE activities in RBC membranes were determined. The concentrations capable to inhibit the enzyme activity by 50% (IC50) for the pesticides were 10.66 uM (dichlorvos), 21.42 uM (chlorpyrifos), 109.98 uM (carbaryl) and 5.44 uM (carbofuran). The results related to 20% enzyme inhibition (level used in the estimation of threshold limits for anticholinesterase compounds) were below those acceptable daily intake values enacted by relevant national and international regulations. These results suggest that the proposed AChE extraction from RBC and assay could be a suitable method for monitoring occupational exposure to pesticides. PMID- 23632008 TI - Ethics by opinion poll? The functions of attitudes research for normative deliberations in medical ethics. AB - Empirical studies on people's moral attitudes regarding ethically challenging topics contribute greatly to research in medical ethics. However, it is not always clear in which ways this research adds to medical ethics as a normative discipline. In this article, we aim to provide a systematic account of the different ways in which attitudinal research can be used for normative reflection. In the first part, we discuss whether ethical judgements can be based on empirical work alone and we develop a sceptical position regarding this point, taking into account theoretical, methodological and pragmatic considerations. As empirical data should not be taken as a direct source for normative justification, we then delineate different ways in which attitudes research can be combined with theoretical accounts of normative justification in the second part of the article. Firstly, the combination of attitudes research with normative-ethical theories is analysed with respect to three different aspects: (a) The extent of empirical data which is needed, (b) the question of which kind of data is required and (c) the ways in which the empirical data are processed within the framework of an ethical theory. Secondly, two further functions of attitudes research are displayed which lie outside the traditional focus of ethical theories: the exploratory function of detecting and characterising new ethical problems, and the field of 'moral pragmatics'. The article concludes with a methodological outlook and suggestions for the concrete practice of attitudinal research in medical ethics. PMID- 23632009 TI - Significance of past statements: speech act theory. AB - In W v M, a judge concluded that M's past statements should not be given weight in a best interests assessment. Several commentators in the ethics literature have argued this approach ignored M's autonomy. In this short article I demonstrate how the basic tenets of speech act theory can be used to challenge the inherent assumption that past statements represent an individual's beliefs, choices or decisions. I conclude that speech act theory, as a conceptual tool, has a valuable contribution to make to this debate. PMID- 23632010 TI - What about the dentist-patient relationship in dental tourism? AB - Dental tourism is patients travelling across international borders with the intention of receiving dental care. It is a growing phenomenon that raises many ethical issues, particularly regarding the dentist-patient relationship. We discuss various issues related to this phenomenon, including patient autonomy over practitioner choice, patient safety, continuity of care, informed consent and doctor-patient communication, among other factors. In particular, patients partaking in medical tourism should be informed of its potential problems and the importance of proper planning and post-treatment care to guarantee high-quality treatment outcomes. PMID- 23632011 TI - Dietary exposure biomarker-lead discovery based on metabolomics analysis of urine samples. AB - Although robust associations between dietary intake and population health are evident from conventional observational epidemiology, the outcomes of large-scale intervention studies testing the causality of those links have often proved inconclusive or have failed to demonstrate causality. This apparent conflict may be due to the well-recognised difficulty in measuring habitual food intake which may lead to confounding in observational epidemiology. Urine biomarkers indicative of exposure to specific foods offer information supplementary to the reliance on dietary intake self-assessment tools, such as FFQ, which are subject to individual bias. Biomarker discovery strategies using non-targeted metabolomics have been used recently to analyse urine from either short-term food intervention studies or from cohort studies in which participants consumed a freely-chosen diet. In the latter, the analysis of diet diary or FFQ information allowed classification of individuals in terms of the frequency of consumption of specific diet constituents. We review these approaches for biomarker discovery and illustrate both with particular reference to two studies carried out by the authors using approaches combining metabolite fingerprinting by MS with supervised multivariate data analysis. In both approaches, urine signals responsible for distinguishing between specific foods were identified and could be related to the chemical composition of the original foods. When using dietary data, both food distinctiveness and consumption frequency influenced whether differential dietary exposure could be discriminated adequately. We conclude that metabolomics methods for fingerprinting or profiling of overnight void urine, in particular, provide a robust strategy for dietary exposure biomarker-lead discovery. PMID- 23632012 TI - The Jarisch-Herxheimer reaction: revisited. AB - The Jarisch-Herxheimer reaction (JHR) is a transient immunological phenomenon seen commonly in patients during treatment for syphilis, and it manifests clinically with short-term constitutional symptoms such as fever, chills, headache and myalgias, besides exacerbation of existing cutaneous lesions. The complex interplay of its underlying patho-physiological mechanisms continues to elude modern medicine, ever since it was described over a century ago. An increase in the incidence of JHR may be expected among patients co-infected with HIV and other infectious diseases including syphilis. Since this subject has not received much attention in recent literature except for brief mentions in standard textbooks, we felt it important to provide an overview of its various attributes including the current concepts in pathophysiology and management. PMID- 23632013 TI - Existence of lysogenic bacteriophages in Bacillus thuringiensis type strains. AB - We screened the existence of bacteriophages in 67 Bacillus thuringiensis type strains by phage DNA extraction and PCR using phage terminase small subunit (TerS)-specific primers to the supernatants and the precipitated pellets of Bt cultures, and by transmission electron microscopy. The various bacteriophages were observed from the supernatants of 22 type strains. Ten type strains showed the extracted phage DNAs and the amplified fragment by TerS PCR but 12 type strains showed only the phage DNAs. Their morphological characteristic suggests that they belong to Family Siphoviridae which had a long tail and symmetrical head. PMID- 23632015 TI - New trends in cytochrome p450 research at the half-century mark. AB - Cytochrome P450 enzymes have major roles in the metabolism of steroids, drugs, carcinogens, eicosanoids, and numerous other chemicals. The P450s are collectively considered the most diverse catalysts known in biochemistry, although they operate from a basic structural fold and catalytic mechanism. The four minireviews in this thematic series deal with the unusual aspects of catalytic reactions and electron transfer pathway organization, the structural diversity of P450s, and the expanding roles of P450s in disease and medicine. PMID- 23632014 TI - Large terminase conformational change induced by connector binding in bacteriophage T7. AB - During bacteriophage morphogenesis DNA is translocated into a preformed prohead by the complex formed by the portal protein, or connector, plus the terminase, which are located at an especial prohead vertex. The terminase is a powerful motor that converts ATP hydrolysis into mechanical movement of the DNA. Here, we have determined the structure of the T7 large terminase by electron microscopy. The five terminase subunits assemble in a toroid that encloses a channel wide enough to accommodate dsDNA. The structure of the complete connector-terminase complex is also reported, revealing the coupling between the terminase and the connector forming a continuous channel. The structure of the terminase assembled into the complex showed a different conformation when compared with the isolated terminase pentamer. To understand in molecular terms the terminase morphological change, we generated the terminase atomic model based on the crystallographic structure of its phage T4 counterpart. The docking of the threaded model in both terminase conformations showed that the transition between the two states can be achieved by rigid body subunit rotation in the pentameric assembly. The existence of two terminase conformations and its possible relation to the sequential DNA translocation may shed light into the molecular bases of the packaging mechanism of bacteriophage T7. PMID- 23632016 TI - Unusual cytochrome p450 enzymes and reactions. AB - Cytochrome P450 enzymes primarily catalyze mixed-function oxidation reactions, plus some reductions and rearrangements of oxygenated species, e.g. prostaglandins. Most of these reactions can be rationalized in a paradigm involving Compound I, a high-valent iron-oxygen complex (FeO(3+)), to explain seemingly unusual reactions, including ring couplings, ring expansion and contraction, and fusion of substrates. Most P450s interact with flavoenzymes or iron-sulfur proteins to receive electrons from NAD(P)H. In some cases, P450s are fused to protein partners. Other P450s catalyze non-redox isomerization reactions. A number of permutations on the P450 theme reveal the diversity of cytochrome P450 form and function. PMID- 23632017 TI - Reactive intermediates in cytochrome p450 catalysis. AB - Recently, we reported the spectroscopic and kinetic characterizations of cytochrome P450 compound I in CYP119A1, effectively closing the catalytic cycle of cytochrome P450-mediated hydroxylations. In this minireview, we focus on the developments that made this breakthrough possible. We examine the importance of enzyme purification in the quest for reactive intermediates and report the preparation of compound I in a second P450 (P450ST). In an effort to bring clarity to the field, we also examine the validity of controversial reports claiming the production of P450 compound I through the use of peroxynitrite and laser flash photolysis. PMID- 23632018 TI - Folding of a cyclin box: linking multitarget binding to marginal stability, oligomerization, and aggregation of the retinoblastoma tumor suppressor AB pocket domain. AB - The retinoblastoma tumor suppressor (Rb) controls the proliferation, differentiation, and survival of cells in most eukaryotes with a role in the fate of stem cells. Its inactivation by mutation or oncogenic viruses is required for cellular transformation and eventually carcinogenesis. The high conservation of the Rb cyclin fold prompted us to investigate the link between conformational stability and ligand binding properties of the RbAB pocket domain. RbAB unfolding presents a three-state transition involving cooperative secondary and tertiary structure changes and a partially folded intermediate that can oligomerize. The first transition corresponds to unfolding of the metastable B subdomain containing the binding site for the LXCXE motif present in cellular and viral targets, and the second transition corresponds to the stable A subdomain. The low thermodynamic stability of RbAB translates into a propensity to rapidly oligomerize and aggregate at 37 degrees C (T50 = 28 min) that is suppressed by human papillomavirus E7 and E2F peptide ligands, suggesting that Rb is likely stabilized in vivo through binding to target proteins. We propose that marginal stability and associated oligomerization may be conserved for function as a "hub" protein, allowing the formation of multiprotein complexes, which could constitute a robust mechanism to retain its cell cycle regulatory role throughout evolution. Decreased stability and oligomerization are shared with the p53 tumor suppressor, suggesting a link between folding and function in these two essential cell regulators that are inactivated in most cancers and operate within multitarget signaling pathways. PMID- 23632019 TI - Rapid accumulation of endogenous tau oligomers in a rat model of traumatic brain injury: possible link between traumatic brain injury and sporadic tauopathies. AB - Traumatic brain injury (TBI) is a serious problem that affects millions of people in the United States alone. Multiple concussions or even a single moderate to severe TBI can also predispose individuals to develop a pathologically distinct form of tauopathy-related dementia at an early age. No effective treatments are currently available for TBI or TBI-related dementia; moreover, only recently has insight been gained regarding the mechanisms behind their connection. Here, we used antibodies to detect oligomeric and phosphorylated Tau proteins in a non transgenic rodent model of parasagittal fluid percussion injury. Oligomeric and phosphorylated Tau proteins were detected 4 and 24 h and 2 weeks post-TBI in injured, but not sham control rats. These findings suggest that diagnostic tools and therapeutics that target only toxic forms of Tau may provide earlier detection and safe, more effective treatments for tauopathies associated with repetitive neurotrauma. PMID- 23632020 TI - Structural diversity of eukaryotic membrane cytochrome p450s. AB - X-ray crystal structures are available for 29 eukaryotic microsomal, chloroplast, or mitochondrial cytochrome P450s, including two non-monooxygenase P450s. These structures provide a basis for understanding structure-function relations that underlie their distinct catalytic activities. Moreover, structural plasticity has been characterized for individual P450s that aids in understanding substrate binding in P450s that mediate drug clearance. PMID- 23632021 TI - Cytochromes p450: roles in diseases. AB - The cytochrome P450 superfamily consists of a large number of heme-containing monooxygenases. Many human P450s metabolize drugs used to treat human diseases. Others are necessary for synthesis of endogenous compounds essential for human physiology. In some instances, alterations in specific P450s affect the biological processes that they mediate and lead to a disease. In this minireview, we describe medically significant human P450s (from families 2, 4, 7, 11, 17, 19, 21, 24, 27, 46, and 51) and the diseases associated with these P450s. PMID- 23632022 TI - Investigations of the contribution of a putative glycine hinge to ryanodine receptor channel gating. AB - Ryanodine receptor channels (RyR) are key components of striated muscle excitation-contraction coupling, and alterations in their function underlie both inherited and acquired disease. A full understanding of the disease process will require a detailed knowledge of the mechanisms and structures involved in RyR function. Unfortunately, high-resolution structural data, such as exist for K(+) selective channels, are not available for RyR. In the absence of these data, we have used modeling to identify similarities in the structural elements of K(+) channel pore-forming regions and postulated equivalent regions of RyR. This has identified a sequence of residues in the cytosolic cavity-lining transmembrane helix of RyR (G(4864)LIIDA(4869) in RyR2) analogous to the glycine hinge motif present in many K(+) channels. Gating in these K(+) channels can be disrupted by substitution of residues for the hinge glycine. We investigated the involvement of glycine 4864 in RyR2 gating by monitoring properties of recombinant human RyR2 channels in which this glycine is replaced by residues that alter gating in K(+) channels. Our data demonstrate that introducing alanine at position 4864 produces no significant change in RyR2 function. In contrast, function is altered when glycine 4864 is replaced by either valine or proline, the former preventing channel opening and the latter modifying both ion translocation and gating. Our studies reveal novel information on the structural basis of RyR gating, identifying both similarities with, and differences from, K(+) channels. Glycine 4864 is not absolutely required for channel gating, but some flexibility at this point in the cavity-lining transmembrane helix is necessary for normal RyR function. PMID- 23632023 TI - Matrix metalloproteinase 8 (collagenase 2) induces the expression of interleukins 6 and 8 in breast cancer cells. AB - Matrix metalloproteinase 8 (MMP-8) is a tumor-suppressive protease that cleaves numerous substrates, including matrix proteins and chemokines. In particular, MMP 8 proteolytically activates IL-8 and, thereby, regulates neutrophil chemotaxis in vivo. We explored the effects of expression of either a WT or catalytically inactive (E198A) mutant version of MMP-8 in human breast cancer cell lines. Analysis of serum-free conditioned media from three breast cancer cell lines (MCF 7, SK-BR-3, and MDA-MB-231) expressing WT MMP-8 revealed elevated levels of IL-6 and IL-8. This increase was mirrored at the mRNA level and was dependent on MMP-8 catalytic activity. However, sustained expression of WT MMP-8 by breast cancer cells was non-permissive for long-term growth, as shown by reduced colony formation compared with cells expressing either control vector or E198A mutant MMP-8. In long-term culture of transfected MDA-MB-231 cells, expression of WT but not E198A mutant MMP-8 was lost, with IL-6 and IL-8 levels returning to base line. Rare clonal isolates of MDA-MB-231 cells expressing WT MMP-8 were generated, and these showed constitutively high levels of IL-6 and IL-8, although production of the interleukins was no longer dependent upon MMP-8 activity. These studies support a causal connection between MMP-8 activity and the IL-6/IL-8 network, with an acute response to MMP-8 involving induction of the proinflammatory mediators, which may in part serve to compensate for the deleterious effects of MMP-8 on breast cancer cell growth. This axis may be relevant to the recognized ability of MMP-8 to orchestrate the innate immune system in inflammation in vivo. PMID- 23632024 TI - Isolation, characterization, and aggregation of a structured bacterial matrix precursor. AB - Biofilms are surface-associated groups of microbial cells that are embedded in an extracellular matrix (ECM). The ECM is a network of biopolymers, mainly polysaccharides, proteins, and nucleic acids. ECM proteins serve a variety of structural roles and often form amyloid-like fibers. Despite the extensive study of the formation of amyloid fibers from their constituent subunits in humans, much less is known about the assembly of bacterial functional amyloid-like precursors into fibers. Using dynamic light scattering, atomic force microscopy, circular dichroism, and infrared spectroscopy, we show that our unique purification method of a Bacillus subtilis major matrix protein component results in stable oligomers that retain their native alpha-helical structure. The stability of these oligomers enabled us to control the external conditions that triggered their aggregation. In particular, we show that stretched fibers are formed on a hydrophobic surface, whereas plaque-like aggregates are formed in solution under acidic pH conditions. TasA is also shown to change conformation upon aggregation and gain some beta-sheet structure. Our studies of the aggregation of a bacterial matrix protein from its subunits shed new light on assembly processes of the ECM within bacterial biofilms. PMID- 23632025 TI - A self-compartmentalizing hexamer serine protease from Pyrococcus horikoshii: substrate selection achieved through multimerization. AB - Oligopeptidases impose a size limitation on their substrates, the mechanism of which has long been under debate. Here we present the structure of a hexameric serine protease, an oligopeptidase from Pyrococcus horikoshii (PhAAP), revealing a complex, self-compartmentalized inner space, where substrates may access the monomer active sites passing through a double-gated "check-in" system, first passing through a pore on the hexamer surface and then turning to enter through an even smaller opening at the monomers' domain interface. This substrate screening strategy is unique within the family. We found that among oligopeptidases, a residue of the catalytic apparatus is positioned near an amylogenic beta-edge, which needs to be protected to prevent aggregation, and we found that different oligopeptidases use different strategies to achieve such an end. We propose that self-assembly within the family results in characteristically different substrate selection mechanisms coupled to different multimerization states. PMID- 23632026 TI - Atypical antigen recognition mode of a shark immunoglobulin new antigen receptor (IgNAR) variable domain characterized by humanization and structural analysis. AB - The immunoglobulin new antigen receptors (IgNARs) are a class of Ig-like molecules of the shark immune system that exist as heavy chain-only homodimers and bind antigens by their single domain variable regions (V-NARs). Following shark immunization and/or in vitro selection, V-NARs can be generated as soluble, stable, and specific high affinity monomeric binding proteins of ~12 kDa. We have previously isolated a V-NAR from an immunized spiny dogfish shark, named E06, that binds specifically and with high affinity to human, mouse, and rat serum albumins. Humanization of E06 was carried out by converting over 60% of non complementarity-determining region residues to those of a human germ line Vkappa1 sequence, DPK9. The resulting huE06 molecules have largely retained the specificity and affinity of antigen binding of the parental V-NAR. Crystal structures of the shark E06 and its humanized variant (huE06 v1.1) in complex with human serum albumin (HSA) were determined at 3- and 2.3-A resolution, respectively. The huE06 v1.1 molecule retained all but one amino acid residues involved in the binding site for HSA. Structural analysis of these V-NARs has revealed an unusual variable domain-antigen interaction. E06 interacts with HSA in an atypical mode that utilizes extensive framework contacts in addition to complementarity-determining regions that has not been seen previously in V-NARs. On the basis of the structure, the roles of various elements of the molecule are described with respect to antigen binding and V-NAR stability. This information broadens the general understanding of antigen recognition and provides a framework for further design and humanization of shark IgNARs. PMID- 23632028 TI - Epilepsy health consumer groups and charities; how representative of patients are they? (Grinton M., et al. Seizure J. (2012)). PMID- 23632027 TI - Tetraspanin CD63 promotes vascular endothelial growth factor receptor 2-beta1 integrin complex formation, thereby regulating activation and downstream signaling in endothelial cells in vitro and in vivo. AB - CD63 is a member of the transmembrane-4 glycoprotein superfamily (tetraspanins) implicated in the regulation of membrane protein trafficking, leukocyte recruitment, and adhesion processes. We have investigated the involvement of CD63 in endothelial cell (EC) signaling downstream of beta1 integrin and VEGF. We report that silencing of CD63 in primary ECs arrested capillary sprouting and tube formation in vitro because of impaired adhesion and migration of ECs. Mechanistically, CD63 associated with both beta1 integrin and the main VEGF receptor on ECs, VEGFR2. Our data suggest that CD63 serves to bridge between beta1 integrin and VEGFR2 because CD63 silencing disrupted VEGFR2-beta1 integrin complex formation identified using proximity ligation assays. Signaling downstream of beta1 integrin and VEGFR2 was attenuated in CD63-silenced cells, although their cell surface expression levels remained unaffected. CD63 was furthermore required for efficient internalization of VEGFR2 in response to VEGF. Importantly, systemic delivery of VEGF failed to potently induce VEGFR2 phosphorylation and downstream signaling in CD63-deficient mouse lungs. Taken together, our findings demonstrate a previously unrecognized role for CD63 in coordinated integrin and receptor tyrosine kinase signaling in vitro and in vivo. PMID- 23632029 TI - Pompe disease: early diagnosis and early treatment make a difference. AB - Pompe disease (glycogen storage disease type II or acid maltase deficiency) is a lysosomal disorder in which acid alpha-glucosidase (GAA) deficiencies lead to intralysosomal accumulation of glycogen in all tissues; most notably in skeletal muscles. Both the patient's age at the onset of Pompe disease symptoms and the rate of deterioration caused by the disease can vary considerably. In classical infant-onset Pompe disease (IOPD), symptoms start very early in life, and death occurs soon afterward if the disease remains untreated. In later-onset Pompe disease, symptoms are slower to appear, and patients often progress to wheelchair confinement and eventual respiratory failure. A diagnosis can be made by screening for GAA in dried blood samples, followed either by GAA assessment in lymphocytes or in fibroblasts or by the genetic analysis of mutations. Treatment by enzyme replacement therapy (ERT) with alglucosidase alfa was approved for human use in 2006. In classical IOPD, treatment significantly lengthens survival and improves motor development and cardiac function. The sooner ERT begins, the better are the results. Newborn screening aims to take advantage of different technologies for diagnosing and treating newborns early on and it yields better outcomes. However, newborns diagnosed early and other long-term survivors may encounter fresh problems, making up a new phenotype of IOPD patients. Further modifications of the treatment, such as a decrease in immune responses to ERT, a higher dosage, a better uptake formulation, and gene therapy delivered locally or systemically are being explored. PMID- 23632030 TI - Diversification of the yellow-shouldered bats, genus Sturnira (Chiroptera, Phyllostomidae), in the New World tropics. AB - The Yellow-shouldered bats, Genus Sturnira, are widespread, diverse, and abundant throughout the Neotropical Region, but little is known of their phylogeny and biogeography. We collected 4409 bp of DNA from three mitochondrial (cyt-b, ND2, D loop) and two nuclear (RAG1, RAG2) sequences from 138 individuals representing all but two recognized species of Sturnira and five other phyllostomid bats used as outgroups. The sequence data were subjected to maximum parsimony, maximum likelihood, and Bayesian inference analyses. Results overwhelmingly support the monophyly of the genus Sturnira but not continued recognition of Corvira as a subgenus; the two species (bidens and nana) allocated to that group constitute separate, basal branches on the phylogeny. A total of 21 monophyletic putatively species-level groups were recovered; pairs were separated by an average 7.09% (SD=1.61) pairwise genetic distance in cyt-b, and three of these groups are apparently unnamed. Several well-supported clades are evident, including a complex of seven species formerly confused with S. lilium, a species that is actually limited to the Brazilian Shield. We used four calibration points to construct a time-tree for Sturnira, using BEAST. Sturnira diverged from other stenodermatines in the mid-Miocene, and by the end of that epoch (5.3 Ma), three basal lineages were present. Most living species belong to one of two clades, A and B, which appeared and diversified shortly afterwards, during the Pliocene. Both parsimony (DIVA) and likelihood (Lagrange) methods for reconstructing ancestral ranges indicate that the radiation of Sturnira is rooted in the Andes; all three basal lineages (in order, bidens, nana, and aratathomasi) have strictly or mainly Andean distributions. Only later did Sturnira colonize the Pacific lowlands (Choco) and thence Central America. Sturnira species that are endemic to Central America appeared after the final emergence of the Panamanian landbridge ~3 Ma. Despite its ability to fly and to colonize the Antilles overwater, this genus probably accompanied the "legions" of South American taxa that moved overland during the Great American Biotic Interchange. Its eventual colonization of the Lesser Antilles and the appearance of two endemic lineages there did not take place until the Pleistocene. Because of its continual residence and diversification in South America, Andean assemblages of Sturnira contain both basal and highly derived members of the genus. PMID- 23632032 TI - Species tree reconstruction of a poorly resolved clade of salamanders (Ambystomatidae) using multiple nuclear loci. AB - The analysis of diverse data sets can yield different phylogenetic estimates that challenge systematists to explain the source of discordance. The mole salamanders (family Ambystomatidae) are a classic example of this phylogenetic conflict. Previous attempts to resolve the ambystomatid species tree using allozymic, morphological, and mitochondrial sequence data have yielded different estimates, making it unclear which data source best approximates ambystomatid phylogeny and which ones yield phylogenetically inaccurate reconstructions. To shed light on this conflict, we present the first multi-locus DNA sequence-based phylogenetic study of the Ambystomatidae. We utilized a range of analyses, including coalescent-based methods of species-tree estimation that account for incomplete lineage sorting within a locus and concordance-based methods that estimate the number of sampled loci that support a particular clade. We repeated these analyses with the removal of individual loci to determine if any locus has a disproportionate effect on our phylogenetic results. Collectively, these results robustly resolved many deep and relatively shallow clades within Ambystoma, including the placement of A. gracile and A. talpoideum as the sister clade to a clade containing all remaining ambystomatids, and the placement of A. maculatum as the sister lineage to all remaining ambystomatids excluding A. gracile and A. talpoideum. Both Bayesian coalescent and concordance methods produced similar results, highlighting strongly supported branches in the species tree. Furthermore, coalescent-based analyses that excluded loci produced overlapping species-tree posterior distributions, suggesting that no particular locus- including mtDNA--disproportionately contributed to our species-tree estimates. Overall, our phylogenetic estimates have greater similarity with previous allozyme and mitochondrial sequence-based phylogenetic estimates. However, intermediate depths of divergence in the ambystomatid species tree remain unresolved, potentially highlighting a region of rapid species radiation or a hard polytomy, which limits our ability to comment on previous morphologically based taxonomic groups. PMID- 23632033 TI - Response to a rabies epidemic, Bali, Indonesia, 2008-2011. AB - Emergency vaccinations and culling failed to contain an outbreak of rabies in Bali, Indonesia, during 2008-2009. Subsequent island-wide mass vaccination (reaching 70% coverage, >200,000 dogs) led to substantial declines in rabies incidence and spread. However, the incidence of dog bites remains high, and repeat campaigns are necessary to eliminate rabies in Bali. PMID- 23632034 TI - Is less always more? The effects of low-fat labeling and caloric information on food intake, calorie estimates, taste preference, and health attributions. AB - The present study examined whether low-fat labeling and caloric information affect food intake, calorie estimates, taste preference, and health perceptions. Participants included 175 female undergraduate students who were randomly assigned to one of four experimental conditions. A 2*2 between subjects factorial design was used in which the fat content label and caloric information of chocolate candy was manipulated. The differences in food intake across conditions did not reach statistical significance. However, participants significantly underestimated the calorie content of low-fat-labeled candy. Participants also rated low-fat-labeled candy as significantly better tasting when they had caloric information available. Participants endorsed more positive health attributions for low-fat-labeled candy than for regular-labeled candy, independent of caloric information. The inclusion of eating attitudes and behaviors as covariates did not alter the results. The study findings may be related to the "health halo" associated with low-fat foods and add to the research base by examining the interaction between low-fat and calorie labeling. PMID- 23632035 TI - Supplementation by thylakoids to a high carbohydrate meal decreases feelings of hunger, elevates CCK levels and prevents postprandial hypoglycaemia in overweight women. AB - Thylakoids are chlorophyll-containing membranes in chloroplasts that have been isolated from green leaves. It has been previously shown that thylakoids supplemented with a high-fat meal can affect cholecystokinin (CCK), ghrelin, insulin and blood lipids in humans, and can act to suppress food intake and prevent body weight gain in rodents. This study investigates the addition of thylakoids to a high carbohydrate meal and its effects upon hunger motivation and fullness, and the levels of glucose, insulin, CCK, ghrelin and tumour necrosis factor (TNF)-alpha in overweight women. Twenty moderately overweight female subjects received test meals on three different occasions; two thylakoid enriched and one control, separated by 1 week. The test meals consisted of a high carbohydrate Swedish breakfast, with or without addition of thylakoids. Blood samples and VAS-questionnaires were evaluated over a 4-h period. Addition of thylakoids suppressed hunger motivation and increased secretion of CCK from 180 min, and prevented postprandial hypoglycaemia from 90 min following food intake. These effects indicate that thylakoids may intensify signals of satiety. This study therefore suggests that the dietary addition of thylakoids could aid efforts to reduce food intake and prevent compensational eating later in the day, which may help to reduce body weight over time. PMID- 23632036 TI - Food neophobia and its relation with olfactory ability in common odour identification. AB - Food neophobia is strictly connected with many different aspects of human feeding, ranging from food preferences to food choice, from active chemosensory exploration of the world (sniffing and tasting) to physiological responses associated with alertness. Therefore in this study, we tested the ability of 167 participants (54 women and 113 men, aged between 20 and 59 years old) to correctly identify 36 common odours, and we verified whether such ability could be related to their level of neophobia toward food and to demographic parameters (i.e., age, gender, and smoking habits). In the analyses, an advantage in odour identification abilities for non-neophobic people over more-neophobic participants was observed. As for participants' demographic information, a smaller reluctance to try new food in older than younger people was highlighted. The results of the present study suggest a connection between the attitude toward the exploration of the chemosensory environment and the ability to identify odours. PMID- 23632037 TI - Reliability and validity of a short FFQ for assessing the dietary habits of 2-5 year-old children, Sydney, Australia. AB - OBJECTIVE: A simple FFQ which ranks young children's dietary habits is necessary for population-based monitoring and intervention programmes. The aim of the present study was to determine the reliability and validity of a short FFQ to assess the dietary habits of young children aged 2-5 years. DESIGN: Parents completed a seventeen-item FFQ for their children by telephone on two occasions, two weeks apart. Sixty-four parents also completed 3 d food records for their children. The FFQ included daily servings of fruit and vegetables, frequency of eating lean meat, processed meats, take-away food, snack foods (biscuits, cakes, doughnuts, muesli bars), potato crisps and confectionery, and cups of soft drinks/cordials, juice, milk and water. Weighted kappa and intra-class correlation coefficients were used to assess FFQ reliability and the Bland-Altman method was used to assess validity of the FFQ compared with the 3 d food record. SETTING: Seven pre-school centres in metropolitan Sydney, Australia. SUBJECTS: Seventy-seven children aged 2-5 years. RESULTS: The majority of questions had moderate to good reliability: kappa w ranged from 0.37 (lean meat) to 0.85 (take away food consumption). Validity analysis showed a significant increase in mean values from the food record with increasing ordered categories from the FFQ for servings of vegetables and fruit and cups of drinks (all trend P <= 0.01). Spearman rank correlation coefficient was >0.5 for vegetables, fruit, diet soft drinks and fruit juice. CONCLUSIONS: The FFQ provides reliable and moderately valid information about the dietary intakes and habits of children aged 2-5 years, in particular for fruit, vegetables and beverages. PMID- 23632038 TI - Management of women with systemic lupus erythematosus. AB - With improvements in survival rates for women with systemic lupus erythematosus (SLE) in the last few decades, the focus has now shifted towards the management of the associated complications. These include cancer, cardiovascular disease, osteoporosis and early menopause. These co-morbidities are believed to be the result of a complex interplay between the inflammatory process and disease treatment, and they complicate the management. A majority of women with SLE suffer considerable morbidity in the prime of their life. A team of multidisciplinary specialists is required to ensure aggressive and comprehensive management of risk factors, treatment of symptoms and prevention of complications to ensure successful outcomes. PMID- 23632039 TI - Pragmatics abilities in narrative production: a cross-disorder comparison. AB - We aimed to disentangle contributions of socio-pragmatic and structural language deficits to narrative competence by comparing the narratives of children with autism spectrum disorder (ASD; n = 25), non-autistic children with language impairments (LI; n = 23), and children with typical development (TD; n = 27). Groups were matched for age (61/2 to 15 years; mean: 10;6) and non-verbal ability; ASD and TD groups were matched on standardized language scores. Despite distinct clinical presentation, children with ASD and LI produced similarly simple narratives that lacked semantic richness and omitted important story elements, when compared to TD peers. Pragmatic errors were common across groups. Within the LI group, pragmatic errors were negatively correlated with story macrostructure scores and with an index of semantic-pragmatic relevance. For the group with ASD, pragmatic errors consisted of comments that, though extraneous, did not detract from the gist of the narrative. These findings underline the importance of both language and socio-pragmatic skill for producing coherent, appropriate narratives. PMID- 23632031 TI - Radically different phylogeographies and patterns of genetic variation in two European brown frogs, genus Rana. AB - We reconstruct range-wide phylogeographies of two widespread and largely co occurring Western Palearctic frogs, Rana temporaria and R. dalmatina. Based on tissue or saliva samples of over 1000 individuals, we compare a variety of genetic marker systems, including mitochondrial DNA, single-copy protein-coding nuclear genes, microsatellite loci, and single nucleotide polymorphisms (SNPs) of transcriptomes of both species. The two focal species differ radically in their phylogeographic structure, with R. temporaria being strongly variable among and within populations, and R. dalmatina homogeneous across Europe with a single strongly differentiated population in southern Italy. These differences were observed across the various markers studied, including microsatellites and SNP density, but especially in protein-coding nuclear genes where R. dalmatina had extremely low heterozygosity values across its range, including potential refugial areas. On the contrary, R. temporaria had comparably high range-wide values, including many areas of probable postglacial colonization. A phylogeny of R. temporaria based on various concatenated mtDNA genes revealed that two haplotype clades endemic to Iberia form a paraphyletic group at the base of the cladogram, and all other haplotypes form a monophyletic group, in agreement with an Iberian origin of the species. Demographic analysis suggests that R. temporaria and R. dalmatina have genealogies of roughly the same time to coalescence (TMRCA ~3.5 mya for both species), but R. temporaria might have been characterized by larger ancestral and current effective population sizes than R. dalmatina. The high genetic variation in R. temporaria can therefore be explained by its early range expansion out of Iberia, with subsequent cycles of differentiation in cryptic glacial refugial areas followed by admixture, while the range expansion of R. dalmatina into central Europe is a probably more recent event. PMID- 23632040 TI - External inorganic N source enhances the uptake of As species in garland chrysanthemum (C. coronarium) amended with chicken manure bearing roxarsone and its metabolites. AB - Roxarsone (ROX), a widely used feed organoarsenic additive, is excreted as itself and its metabolites in animal manure. Animal manure is commonly applied with N fertilizer to meet the N demand of crop. We investigated the accumulation of As species in garland chrysanthemum plants fertilized with chicken manure (CM) bearing ROX and its metabolites, combined with different inorganic N sources (NH4(+), NO3(-) and urea), respectively. The change of pH, N forms and As species in soils was examined as well. The results show that As(V), As(III) and dimethylarsinic acid (DMA) were detectable in soils, and conversions between As species were affected by three inorganic N sources, irrespective of N form and soil pH. As(III) was the sole As species in garland chrysanthemum shoots, and As(III) and As(V) could be detected in roots. Urea, superior to NH4(+), significantly enhanced the uptake of As species in plants by promoting plant growth, while NO3(-) slightly reduced the As accumulation due to decreased biomass. As(III) was the dominant As compound (86.9-89.7%) in plants. Therefore, inorganic N fertilizers may inadvertently increase the risk of As contamination in plant from ROX via the way ROX->chicken->CM->soil->crop. PMID- 23632041 TI - Micro-electrolysis of Cr (VI) in the nanoscale zero-valent iron loaded activated carbon. AB - In this paper we prepared a novel material of activated carbon/nanoscale zero valent iron (C-Fe(0)) composite. The C-Fe(0) was proved to possess large specific surface area and outstanding reducibility that result in the rapid and stable reaction with Cr (VI). The prepared composite has been examined in detail in terms of the influence of solution pH, concentration and reaction time in the Cr (VI) removal experiments. The results showed that the C-Fe(0) formed a micro electrolysis which dominated the reaction rate. The Micro-electrolysis reaches equilibrium is ten minutes. Its reaction rate is ten times higher than that of traditional adsorption reaction, and the removal rate of Cr reaches up to 99.5%. By analyzing the obtained profiles from the cyclic voltammetry, PXRD and XPS, we demonstrate that the Cr (VI) is reduced to insoluble Cr (III) compound in the reaction. PMID- 23632042 TI - Ultrasonic degradation of acetaminophen and naproxen in the presence of single walled carbon nanotubes. AB - Ultrasonic (US) and single-walled carbon nanotube (SWNT)-catalyzed ultrasonic (US/SWNT) degradation of a pharmaceutical (PhAC) mixture of acetaminophen (AAP) and naproxen (NPX) used as analgesics was carried out in water. In the absence of SWNTs, maximum degradations of AAP and NPX occurred at a high frequency (1000 kHz) and under acidic conditions (pH 3) and different solution temperatures (25 degrees C at 28 kHz and 35 degrees C at 1000 kHz) during US reactions. Rapid degradation of PhACs occurred within 10 min at 28 kHz (44.5% for AAP; 90.3% for NPX) and 1000 kHz (39.2% for AAP; 74.8% for NPX) at a SWNT concentration of 45 mgL(-1) under US/SWNT process, compared with 28 kHz (5.2% for AAP; 10.6% for NPX) and 1000 kHz (29.1% for AAP; 46.2% for NPX) under US process. Degradation was associated with the dispersion of SWNTs; small particles acted as nuclei during US reactions, enhancing the H2O2 production yield. NPX removal was greater than AAP removal under all US-induced reaction and SWNT adsorption conditions, which is governed by the chemical properties of PhACs. Based on the results, the optimal treatment performance was observed at 28 kHz with 45 mgL(-1) SWNTs (US/SWNT) within 10 min. PMID- 23632043 TI - Serum and cerebrospinal fluid heavy neurofilaments and antibodies against them in early multiple sclerosis. AB - Heavy neurofilaments (NFH) released from neurons during axonal injury induce a humoral immune response. We measured CSF and serum levels of NFH proteins and anti-NFH IgG antibodies in 19 patients with clinically isolated syndrome (CIS) converting to multiple sclerosis, in 20 stable CIS patients, 23 patients with multiple sclerosis (MS) and 32 control subjects using ELISA. CSF and intrathecal levels and CSF/serum ratios of anti-NFH antibodies were increased in the CIS patients early developing MS while NFH protein concentrations were similar among the groups. Changes associated with NFH are more pronounced for antibodies than for protein itself and may aid in prediction of CIS patients. PMID- 23632044 TI - Selective use of whole breast radiotherapy after breast conserving surgery for invasive breast cancer and DCIS. AB - BACKGROUND: Radiotherapy following breast conservation is routine in the treatment of invasive breast cancer and is commonly used in ductal carcinoma in situ to decrease local recurrence. However, adjuvant breast radiotherapy has significant short and longer-term side effects and consumes substantial health care resources. We aimed to review the randomised controlled trials and attempted to identify clinico-pathological factors and molecular markers associated with the risk of local recurrence. METHODS: A literature search using the Medline and Ovid databases between 1965 and 2011 was conducted using the terms 'breast conservation' and radiotherapy, and radiotherapy and DCIS. Only papers with randomised clinical trials published in English in adult were included. Only Level 2 evidence and above was included. RESULTS: Three meta-analyses and 17 randomised controlled trials have been published in invasive disease and one meta analysis and four randomised controlled trials for DCIS. Overall, adjuvant radiotherapy provides a 15.7% decrease in local recurrence and 3.8% decrease in 15-year risk of breast cancer death. The key clinico-pathological factors, which enable stratification into high, intermediate or low risk groups include age, oestrogen receptor positivity, use of tamoxifen and extent of surgery. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories are 7.8%, 1.1%, and 0.1% respectively Adjuvant radiotherapy provides a 60% risk reduction in local recurrence in DCIS with no impact on distal metastases or overall survival. Size, pathological subtype and margins are major risk factors for local recurrence in DCIS. CONCLUSIONS: Adjuvant radiotherapy consistently decreases local recurrence across all subtypes of invasive and in situ disease. While it has a survival advantage in those with invasive disease, this is not seen with DCIS and is minimal in invasive disease where the risk of local recurrence is low. This group includes women over 70 with node negative, ER positive tumours<2 cm. PMID- 23632045 TI - Yoga for the sinoatrial node: sarcoplasmic reticulum calcium release confers flexibility. PMID- 23632046 TI - Altered regional cardiac wall mechanics are associated with differential cardiomyocyte calcium handling due to nebulette mutations in preclinical inherited dilated cardiomyopathy. AB - Nebulette (NEBL) is a sarcomeric Z-disk protein involved in mechanosensing and force generation via its interaction with actin and tropomyosin-troponin complex. Genetic abnormalities in NEBL lead to dilated cardiomyopathy (DCM) in humans and animal models. The objectives of this study are to determine the earliest preclinical mechanical changes in the myocardium and define underlying molecular mechanisms by which NEBL mutations lead to cardiac dysfunction. We examined cardiac function in 3-month-old non-transgenic (non-Tg) and transgenic (Tg) mice (WT-Tg, G202R-Tg, A592E-Tg) by cardiac magnetic resonance (CMR) imaging. Contractility and calcium transients were measured in isolated cardiomyocytes. A592E-Tg mice exhibited enhanced in vivo twist and untwisting rate compared to control groups. Ex vivo analysis of A592E-Tg cardiomyocytes showed blunted calcium decay response to isoproterenol. CMR imaging of G202R-Tg mice demonstrated reduced torsion compared to non-Tg and WT-Tg, but conserved twist and untwisting rate after correcting for geometric changes. Ex vivo analysis of G202R-Tg cardiomyocytes showed elevated calcium decay at baseline and a conserved contractile response to isoproterenol stress. Protein analysis showed decreased alpha-actinin and connexin43, and increased cardiac troponin I phosphorylation at baseline in G202R-Tg, providing a molecular mechanism for enhanced ex vivo calcium decay. Ultrastructurally, G202R-Tg cardiomyocytes exhibited increased I band and sarcomere length, desmosomal separation, and enlarged t-tubules. A592E Tg cardiomyocytes also showed abnormal ultrastructural changes and desmin downregulation. This study showed distinct effects of NEBL mutations on sarcomere ultrastructure, cellular contractile function, and calcium homeostasis in preclinical DCM in vivo. We suggest that these abnormalities correlate with detectable myocardial wall motion patterns. PMID- 23632047 TI - A serine hydroxymethyltransferase from marine bacterium Shewanella algae: Isolation, purification, characterization and l-serine production. AB - Currently, l-serine is mainly produced by enzymatic conversion, in which serine hydroxymethyltransferase (SHMT) is the key enzyme, suggesting the importance of searching for a SHMT with high activity. Shewanella algae, a methanol-utilizing marine bacterium showing high SHMT activity, was selected based on screening bacterial strains and comparison of the activities of SHMTs. A glyA was isolated from the S. algae through thermal asymmetric interlaced PCR (TAIL-PCR) and it encoded a 417 amino acid polypeptide. The SaSHMT, encoded by the glyA, showed the optimal activity at 50 degrees C and pH 7.0, and retained over 45% of its maximal activity after incubation at 40 degrees C for 3h. The enzyme showed better stability under alkaline environment (pH 6.5-9.0) than Hyphomicrobium methylovorum GM2's SHMT (pH 6.0-7.5). The SaSHMT can produce 77.76mM of l-serine by enzymatic conversion, with the molecular conversion rate in catalyzing glycine to l-serine being 1.41-fold higher than that of Escherichia coli. Therefore, the SaSHMT has the potential for industrial applications due to its tolerance of alkaline environment and a relatively high enzymatic conversion rate. PMID- 23632048 TI - Conditional relative survival: a different perspective to measuring cancer outcomes. PMID- 23632050 TI - Case report: polyuria related to dexmedetomidine. AB - Dexmedetomidine has become a popular sedative in the intensive care unit for patients undergoing mechanical ventilation because of its highly selective alpha 2 agonism, which exerts a combination of anesthetic, analgesic, and anxiolytic effects. Bradycardia and hypotension have been reported as the most common side effects of its use in large studies. Dexmedetomidine has been reported to induce polyuria by suppressing vasopressin secretion and increasing permeability of the collecting ducts in a dose-dependent fashion. We report a case of dexmedetomidine related polyuria that occurred with a high-dose continuous infusion and subsequently resolved with discontinuation of the drug. (Anesth Analg 2013;117:150-2). PMID- 23632049 TI - Effects of polymorphisms in alcohol metabolism and oxidative stress genes on survival from head and neck cancer. AB - BACKGROUND: Heavy alcohol consumption increases risk of developing squamous cell carcinoma of the head and neck (SCCHN). Alcohol metabolism to cytotoxic and mutagenic intermediates acetaldehyde and reactive oxygen species is critical for alcohol-drinking-associated carcinogenesis. We hypothesized that polymorphisms in alcohol metabolism-related and antioxidant genes influence SCCHN survival. METHODS: Interview and genotyping data (64 polymorphisms in 12 genes) were obtained from 1227 white and African-American cases from the Carolina Head and Neck Cancer Epidemiology study, a population-based case-control study of SCCHN conducted in North Carolina from 2002 to 2006. Vital status, date and cause of death through 2009 were obtained from the National Death Index. Kaplan-Meier log rank tests and adjusted hazard ratios were calculated to identify alleles associated with survival. RESULTS: Most tested SNPs were not associated with survival, with the exception of the minor alleles of rs3813865 and rs8192772 in CYP2E1. These were associated with poorer cancer-specific survival (HRrs3813865, 95% CI=2.00, 1.33-3.01; HRrs8192772, 95% CI=1.62, 1.17-2.23). Hazard ratios for 8 additional SNPs in CYP2E1, GPx2, SOD1, and SOD2, though not statistically significant, were suggestive of differences in allele hazards for all-cause and/or cancer death. No consistent associations with survival were found for SNPs in ADH1B, ADH1C, ADH4, ADH7, ALDH2, GPx2, GPx4, and CAT. CONCLUSIONS: We identified some polymorphisms in alcohol and oxidative stress metabolism genes that influence survival in subjects with SCCHN. Previously unreported associations of SNPs in CYP2E1 warrant further investigation. PMID- 23632051 TI - A comparison of intraarticular lumbar facet joint steroid injections and lumbar facet joint radiofrequency denervation in the treatment of low back pain: a randomized, controlled, double-blind trial. AB - BACKGROUND: Lumbar facet joint degeneration is a source of chronic low back pain, with an incidence of 15% to 45% among patients with low back pain. Various therapeutic techniques in the treatment of facet-related pain have been described in the literature, including intraarticular lumbar facet joint steroid injections and radiofrequency denervation. In this study, we compared the effectiveness of intraarticular facet joint steroid injections and radiofrequency denervation. METHODS: Our randomized, double-blind, controlled study included patients who received intraarticular steroid infiltrations in the lumbar facet joints (L3/L4 L5/S1) and patients who underwent radiofrequency denervation of L3/L4-L5/S1 segments. The inclusion criteria were based first on magnetic resonance imaging findings showing hypertrophy of the facet joints L3/L4-L5/S1 and a positive response to an intraarticular test infiltration of the facet joints L3/L4-L5/S1 with local anesthetics. The primary end point was the Roland-Morris Questionnaire. Secondary end points were the visual analog scale and the Oswestry Disability Index. All outcome assessments were performed at baseline and at 6 months. RESULTS: Fifty-six patients were randomized; 24 of 29 patients in the steroid injection group and 26 of 27 patients in the denervation group completed the 6-month follow-up. Pain relief and functional improvement were observed in both groups. There were no significant differences between the 2 groups for the primary end point (95% confidence interval [CI], -3 to 4) and for both secondary end points (95% CI for visual analog scale, -2 to 1; 95% CI for Oswestry Disability Index, -18 to 0). CONCLUSIONS: Intraarticular steroid infiltration or radiofrequency denervation appear to be a managing option for chronic function limiting low back pain of facet origin with favorable short- and midterm results in terms of pain relief and function improvement, but improvements were similar in both groups. PMID- 23632052 TI - Guided paravertebral blocks with versus without clonidine for women undergoing breast surgery: a prospective double-blinded randomized study. AB - BACKGROUND: Paravertebral blocks (PVBs) have been introduced as an alternative to general anesthesia for breast cancer surgeries. The addition of clonidine as an adjuvant in PVBs may enhance quality and duration of analgesia and significantly reduce the consumption of analgesics after breast surgery. In this prospective randomized double-blind study, we assessed the significance of adding clonidine to the anesthetic mixture for women undergoing mastectomy. METHODS: Sixty patients were randomized equally into 2 groups, both of which received PVB block, either with or without clonidine. Analgesic consumption was noted up to 2 weeks after the operation. A visual analog scale was used to assess pain postoperatively during the hospital stay, and a numeric rating scale was used when patients were discharged. RESULTS: Analgesic consumption was significantly lower in the clonidine group 48 hours postoperatively with 95% confidence interval (CI) for the difference (-69.5% to -6.6%). Pain scores at rest showed significant reduction in the clonidine group during the period from 24 to 72 hours postoperatively with 95% CI for the ratios of 2 means (1.09-3.61), (2.04 9.04), and (2.54-16.55), respectively, with shoulder movement at 24, 48, and 72 hours postoperatively 95% CI for the ratio of 2 means (1.10-3.15), (1.32-6.38), and (1.33-8.42), respectively. The time needed to resume daily activity was shorter in the clonidine group compared with the control group with 95% CI for the ratio of 2 means (1.14-1.62). CONCLUSION: The addition of clonidine enhanced the analgesic efficacy of PVB up to 3 days postoperatively for patients undergoing breast surgery. PMID- 23632053 TI - Lateral parasagittal versus midline interlaminar lumbar epidural steroid injection for management of low back pain with lumbosacral radicular pain: a double-blind, randomized study. AB - BACKGROUND: Epidural steroid injections are commonly used for management of low back pain with lumbosacral radicular pain and can be administered by either interlaminar or transforaminal routes. The transforaminal route is reported to be more effective than the interlaminar route due to higher delivery of drug at the ventral epidural space. However, the transforaminal route has been associated with serious complications including spinal cord injury and permanent paralysis. Hence, there is a search for a technically better route with fewer complications for drug delivery into the ventral epidural space. Recently, a parasagittal interlaminar (PIL) approach of epidural contrast injection was reported to have 100% ventral epidural spread. However, the therapeutic efficacy of this route has never been investigated. We compared the therapeutic efficacy of the PIL approach and midline interlaminar (MIL) approach. We hypothesized that the PIL approach may produce a better clinical outcome because of better ventral epidural spread of the drug compared with MIL approach. METHODS: Thirty-seven patients were randomized to receive injection of 80 mg methylprednisolone either by the PIL (PIL group, n = 19) or MIL (MIL group, n = 18) approach under fluoroscopic guidance. Patients were evaluated for effective pain relief (>=50% from baseline) by visual analog scale and improvement in disability by the modified Oswestry Disability Questionnaire at intervals of 15 days, 1, 2, 3, and 6 months. Patients having <50% pain relief from baseline received additional epidural injection of the same drug, dosage, and route, a maximum of 3 injections at least 15 days apart. The primary outcome of our study was the incidence of effective pain relief at 6 months. RESULTS: The incidence of patients having effective pain relief was higher with the PIL approach (13/19 [68.4%]) vs MIL (3/18 [16.7%]) at the end of 6 months. A significantly higher relative success of effective pain relief was noted in the PIL group (relative risk, 4.10; 95% confidence interval, 1.40-12.05; P = 0.001) at the end of the 6-month follow up with the requirement of fewer total injections (29 vs 41 in MIL, P = 0.043). Visual analog scale and modified Oswestry Disability Questionnaire scores were significantly lower in the PIL group compared with the MIL group at all time intervals after the procedure. Ventral epidural spread of contrast was significantly higher in the PIL 89.7% vs 31.7% in the MIL group. The administration of epidural steroid injection was without any complications with an exact 95% Clopper-Pearson confidence interval of 0.0% to 17.6% in the PIL group and 0.0% to 18.5% in the MIL group. CONCLUSIONS: Epidural steroid injection administered with the PIL approach was significantly more effective for pain relief and improvement in disability than the MIL approach for 6 months in the management of low back pain with lumbosacral radicular pain. PMID- 23632054 TI - A comparison of ultrasound-guided and landmark-based approaches to saphenous nerve blockade: a prospective, controlled, blinded, crossover trial. AB - BACKGROUND: Blockade of the saphenous nerve is often used for surgeries below the knee. Depending on the approach, success rates vary widely ranging from 33% to 88%. In this prospective volunteer study, we compared 2 ultrasound-guided techniques, the modified vastus medialis and perifemoral saphenous nerve block with a below the knee field block. METHODS: Twenty volunteer adults, in a single blinded, crossover, prospective trial underwent 3 different saphenous nerve blocks. The primary end point of block success was loss of sensation in the distal two-thirds distribution of the saphenous nerve. Secondary variables included time to perform the block, time to sensory loss, pain during block, and motor weakness. RESULTS: Compared with the below the knee field block success rate (30%), both the modified vastus medialis and perifemoral techniques had significantly higher success rates (80%, difference 50% with confidence interval [CI], 23%-77%, P = 0.009, and 100%, difference 70% with CI, 41%-91%, P < 0.001, respectively). However, the difference when comparing the perifemoral ultrasound technique against the modified vastus medialis ultrasound technique did not show significance (difference 20% with CI, -7% to 49%, P = 0.125). Also, no statistical differences were found with the other variables measured, except the perifemoral technique showed faster block performance times than below the knee field block (P = 0.007). CONCLUSION: In our prospective study, we have demonstrated that ultrasound-guided above the knee saphenous nerve blocks have higher success rates than a below the knee field block and are easily performed in a short amount of time. PMID- 23632055 TI - The accuracy, precision and reliability of measuring ventilatory rate and detecting ventilatory pause by rainbow acoustic monitoring and capnometry. AB - BACKGROUND: Current methods for monitoring ventilatory rate have limitations including poor accuracy and precision and low patient tolerance. In this study, we evaluated a new acoustic ventilatory rate monitoring technology for accuracy, precision, reliability, and the ability to detect pauses in ventilation, relative to capnometry and a reference method in postsurgical patients. METHODS: Adult patients presenting to the postanesthesia care unit were connected to a Pulse CO Oximeter with acoustic monitoring technology (Rad-87, version 7804, Masimo, Irvine, CA) through an adhesive bioacoustic sensor (RAS-125, rev C) applied to the neck. Each subject also wore a nasal cannula connected to a bedside capnometer (Capnostream20, version 4.5, Oridion, Needham, MA). The acoustic monitor and capnometer were connected to a computer for continuous acoustic and expiratory carbon dioxide waveform recordings. Recordings were retrospectively analyzed by a trained technician in a setting that allowed for the simultaneous viewing of both waveforms while listening to the breathing sounds from the acoustic signal to determine inspiration and expiration reference markers within the ventilatory cycle without using the acoustic monitor- or capnometer calculated ventilatory rate. This allowed the automatic calculation of a reference ventilatory rate for each device through a software program (TagEditor, Masimo). Accuracy (relative to the respective reference) and precision of each device were estimated and compared with each other. Sensitivity for detection of pauses in ventilation, defined as no inspiration or expiration activity in the reference ventilatory cycle for >=30 seconds, was also determined. The devices were also evaluated for their reliability, i.e., the percentage of the time when each displayed a value and did not drop a measurement. RESULTS: Thirty-three adults (73% female) with age of 45 +/- 14 years and weight 117 +/- 42 kg were enrolled. A total of 3712 minutes of monitoring time (average 112 minutes per subject) were analyzed across the 2 devices, reference ventilatory rates ranged from 1.9 to 49.1 bpm. Acoustic monitoring showed significantly greater accuracy (P = 0.0056) and precision (P- = 0.0024) for respiratory rate as compared with capnometry. On average, both devices displayed data over 97% of the monitored time. The (0.95, 0.95) lower tolerance limits for the acoustic monitor and capnometer were 94% and 84%, respectively. Acoustic monitoring was marginally more sensitive (P = 0.0461) to pauses in ventilation (81% vs 62%) in 21 apneic events. CONCLUSIONS: In this study of a population of postsurgical patients, the acoustic monitor and capnometer both reliably monitored ventilatory rate. The acoustic monitor was statistically more accurate and more precise than the capnometer, but differences in performance were modest. It is not known whether the observed differences are clinically significant. The acoustic monitor was more sensitive to detecting pauses in ventilation. Acoustic monitoring may provide an effective and convenient means of monitoring ventilatory rate in postsurgical patients. PMID- 23632056 TI - Technical communication: stability of propofol in polystyrene-based tissue culture plates. AB - Propofol has been reported to have high stability in glass and relatively high stability up to 24 hours in polyvinyl chloride-based medical plastics. Recent publications have observed the effects of propofol on cells and tissues grown in culture. Many cell culture plastics are formulated from polystyrene but we could find little information on the stability of propofol exposed to these products. We observed very little change in the concentration of propofol diluted in cell culture medium over 24 hours when exposed to glass, but substantial loss of the drug when exposed to 96-well polystyrene cell culture plates. This decrease was most rapid in the first hour but continued until 24 hours. The type of plastic used in cell and tissue culture experiments with propofol may influence the results by increasing the apparent dose required to see an effect. PMID- 23632057 TI - The facilitatory effects of intravenous dexmedetomidine on the duration of spinal anesthesia: a systematic review and meta-analysis. AB - BACKGROUND: Central mechanisms have been proposed to explain the prolongation of effect reported with the off-label use of dexmedetomidine as an adjuvant in local anesthetic admixtures. We evaluated whether IV dexmedetomidine can prolong the duration of sensory block associated with spinal anesthesia. METHODS: The authors searched MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases for randomized controlled trials investigating the facilitatory effects of IV administration of dexmedetomidine (dexmedetomidine group) compared with placebo (control group) on single-injection local anesthetic-based spinal anesthesia. Durations of sensory and motor block, sensory and motor block onset times, postoperative pain scores, time to first analgesic request, analgesic consumption, and dexmedetomidine-related side effects were evaluated. Results were combined using random effects modeling when appropriate. RESULTS: A total of 364 patients were analyzed from 7 intermediate to high-quality randomized controlled trials. When IV dexmedetomidine accompanied spinal anesthesia, sensory block duration was prolonged by at least 34% (point estimate: 38%), P < 0.00001, motor block duration was prolonged by at least 17% (point estimate: 21%), P < 0.00001, and time to first analgesic request was increased by at least 53% (point estimate: 60%), P < 0.00001. The use of dexmedetomidine was associated with a 3.7-fold increase (95% confidence interval, 1.53-8.82, P = 0.004) in transient reversible bradycardia. There was no difference in the incidence of hypotension or postoperative sedation, and none of the patients experienced respiratory depression. CONCLUSION: IV dexmedetomidine can prolong the duration of sensory block, motor block, and time to first analgesic request associated with spinal anesthesia. PMID- 23632058 TI - Introduction to the special issues of mixed reality guidance of therapy-towards clinical implementation. PMID- 23632060 TI - Alleles and genotypes of polymorphisms of IL-18, TNF-alpha and IFN-gamma are associated with a higher risk and severity of hepatocellular carcinoma (HCC) in Brazil. AB - Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver. We evaluated the association of alleles and genotypes of polymorphisms of IL-18 ( 607C/A and -137G/C), IFN-gamma (+874T/A) and TNF-alpha (-238G/A and -308G/A) with the risk and severity of HCC. One-hundred-and-twelve patients with HCC and 202 healthy controls were studied. Single nucleotide polymorphisms (SNPs) were amplified by PCR with specific primers and the products were submitted to polyacrylamide gel electrophoresis and stained with silver. We evaluated tumor presentation, tumor size and presence of metastasis. Significant higher risk of HCC was associated with: alleles IL-18 -607(*)A (P=0.0235; OR=1.48; 95%CI=1.06 2.08); TNF-alpha -238(*)A (P=0.0025; OR=2.12; 95%CI=1.32-3.40) and TNF-alpha 308(*)A (P=0.0351; OR=1.82; 95%CI=1.07-3.08); and genotypes IL-18-607AA (P=0.0048; OR=3.03; 95%CI=1.40-6.55); TNF-alpha -238GA (P=0.0011; OR=2.44; 95%CI=1.45-4.12); and TNF-alpha -308GA (P=0.0031; OR=2.51; 95%CI=1.39-4.51). Significant association was found between multinodular HCC and IL-18 -607(*)C allele (P=0.029; OR=2.40, 95%CI: 1.09-5.28), and IL-18 -607CC genotype (P=0.028; OR=3.5, 95%CI: 1.24-9.86). Diffuse HCC was significantly associated with IFN gamma +874TA genotype (P=0.044; OR=3.6, 95%CI: 1.03-12.47). The IL-18 -137(*)C allele showed a significant association with the presence of metastasis. Thus, IL 18 -607(*)A and TNF-alpha (-238(*)A and -308(*)A) alleles may confer susceptibility to HCC, while IL-18 -607(*)C and -137(*)C alleles more severe disease. PMID- 23632061 TI - CCR2 and CCR5 genes polymorphisms in benign prostatic hyperplasia and prostate cancer. AB - Benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are two chronic conditions, very common in aged men, that have been associated to inflammatory process. Chemokines and their receptors are recognized as critical mediators of inflammatory responses, they regulate immune cell migration and are implicated in tumor pathogenesis. The impact of two chemokine receptor gene polymorphisms, CCR2 64I (rs1799864) and CCR5-Delta32 (rs333), was evaluated in BPH and PCa. 385 DNA samples (130 BPH, 136 PCa, 119 healthy control) were genotyped. The allele frequencies were similar among control, BPH and PCa groups. Median of serum PSA levels was different between groups: 0.79, 1.45 and 6.91 ng/mL in control, BPH and PCa groups, respectively (all p<0.001). The prostate volume median was 20.00 cm(3) in the control group, thus, lower than BPH (35.35 cm(3)) and PCa (35.80 cm(3)) (both p<0.001), nevertheless no statistical significant difference was observed between BPH and PCa patients (p=0.172). Remarkably, CCR2-64I was a protective factor to PCa when compared with BPH (OR=0.550; 95%CI=0.311-0.975), although the statistically significant difference was lost after correction for multiple comparisons. No significant associations of CCR5-Delta32 variant were observed with BPH, PCa or PCa clinicopathologic status. Our data suggest the influence of CCR2-64I variant in the development of prostate cancer. PMID- 23632062 TI - Distribution of KIR genes in the Croatian population. AB - The KIR locus with genes involved in immune processes is among the most polymorphic and structurally diverse human loci. KIR genes encode activating and inhibitory receptors that differ in specificity for HLA class I ligands and signaling potential. These receptors are expressed principally by natural killer (NK) cells and subpopulations of T cells. This study represents the first report of the distribution of KIR genes, KIR genotypes and KIR/HLA pairs in 121 unrelated healthy Croatian individuals. Twenty-three different genotypes were observed in the Croatian population and all 16 KIR genes known to date were found. The most frequent KIR genotype was the AA genotype. All individuals had at least one inhibitory KIR/HLA pair with the majority of individuals with three inhibitory KIR/HLA pairs. The most frequent KIR/HLA pair was the KIR2DL3/C1 group. Our results demonstrated the similarity of the Croatian population's KIR repertoire with other Caucasian populations reported so far. PMID- 23632059 TI - On mixed reality environments for minimally invasive therapy guidance: systems architecture, successes and challenges in their implementation from laboratory to clinic. AB - Mixed reality environments for medical applications have been explored and developed over the past three decades in an effort to enhance the clinician's view of anatomy and facilitate the performance of minimally invasive procedures. These environments must faithfully represent the real surgical field and require seamless integration of pre- and intra-operative imaging, surgical instrument tracking, and display technology into a common framework centered around and registered to the patient. However, in spite of their reported benefits, few mixed reality environments have been successfully translated into clinical use. Several challenges that contribute to the difficulty in integrating such environments into clinical practice are presented here and discussed in terms of both technical and clinical limitations. This article should raise awareness among both developers and end-users toward facilitating a greater application of such environments in the surgical practice of the future. PMID- 23632064 TI - Genetic relatedness of dengue viruses in Key West, Florida, USA, 2009-2010. AB - Sequencing of dengue virus type 1 (DENV-1) strains isolated in Key West/Monroe County, Florida, indicate endemic transmission for >2 years of a distinct and predominant sublineage of the American-African genotype. DENV-1 strains isolated elsewhere in Florida grouped within a separate Central American lineage. Findings indicate endemic transmission of DENV into the continental United States. PMID- 23632063 TI - Polyaminergic agents modulate the reconsolidation of conditioned fear. AB - When consolidated memories are reactivated, they become labile and, to persist, must undergo a new stabilization process called reconsolidation. During reactivation, memory is susceptible to pharmacological interventions that may improve or impair it. Spermidine (SPD) is an endogenous polyamine that physiologically modulates the N-methyl-d-aspartate (NMDA) receptor in mammals by binding on the polyamine-binding site at the NMDA receptor. While polyamine agonists and antagonists of the polyamine binding site on the NMDA receptor respectively improve and impair early consolidation, it has not been defined whether these agents alter memory reconsolidation. Male Wistar rats were trained in a fear conditioning apparatus using a 0.4 mA footshock as unconditioned stimulus. Twenty four hours after training, animals were re-exposed to the apparatus in the absence of shock (reactivation session). Immediately after the reactivation session, SPD (1-30 mg/kg, i.p.) or the antagonist of the polyamine binding site at the NMDA receptor, arcaine (0.1-10 mg/kg, i.p.), were injected, and the animals were tested in the same apparatus 24 h later. Freezing scores at testing were considered a measure of memory. While SPD (3 and 10mg/kg) improved, arcaine (1 and 10 mg/kg) impaired memory reconsolidation. These drugs had no effect on memory if they were administered in the absence of reactivation, or 6h after reactivation session. Arcaine (0.1 mg/kg, i.p.) prevented SPD (3 mg/kg) induced improvement of memory reconsolidation. Accordingly, SPD (1 mg/kg) prevented arcaine (10 mg/kg)-induced impairment of memory reconsolidation. The amnesic effect of arcaine was not reversed by arcaine administration prior to test, ruling out state dependence in this effect. These results suggest that systemic administration of polyamine binding site ligands modulate memory reconsolidation. PMID- 23632065 TI - Cs-corrected scanning transmission electron microscopy investigation of dislocation core configurations at a SrTiO(3)/MgO heterogeneous interface. AB - Heterostructures and interfacial defects in a 40-nm-thick SrTiO(3) (STO) film grown epitaxially on a single-crystal MgO (001) were investigated using aberration-corrected scanning transmission electron microscopy and geometric phase analysis. The interface of STO/MgO was found to be of the typical domain matching epitaxy with a misfit dislocation network having a Burgers vector of 1/2 a(STO) <100>. Our studies also revealed that the misfit dislocation cores at the heterogeneous interface display various local cation arrangements in terms of the combination of the extra-half inserting plane and the initial film plane. The type of the inserting plane, either the SrO or the TiO(2) plane, alters with actual interfacial conditions. Contrary to previous theoretical calculations, the starting film planes were found to be dominated by the SrO layer, i.e., a SrO/MgO interface. In certain regions, the starting film planes change to the TiO(2)/MgO interface because of atomic steps at the MgO substrate surface. In particular, four basic misfit dislocation core configurations of the STO/MgO system have been identified and discussed in relation to the substrate surface terraces and possible interdiffusion. The interface structure of the system in reverse- MgO/STO--is also studied and presented for comparison. PMID- 23632066 TI - Tibialis posterior recession for balancing varus ankle contracture during total ankle replacement. AB - Correction of soft tissue varus contracture with total ankle replacement is a challenge. In the present techniques report, I describe tibialis posterior recession using topographic anatomic landmarks that can be useful in correcting soft tissue contracture of the tibialis posterior musculotendinous unit associated with longstanding varus contractures during primary and revision total ankle replacement. PMID- 23632067 TI - Plantar pressure distribution in a hyperpronated foot before and after intervention with an extraosseous talotarsal stabilization device-a retrospective study. AB - Plantar pressure measurements have long been used by clinicians to provide information regarding potential impairments and disorders of the foot and ankle. Elevations in peak plantar pressures or a poor distribution of these pressures can be an indication of pathomechanics in the foot. Lower extremity deficits such as sensory impairment, foot deformities, limited joint mobility, and reduced plantar tissue thickness have been associated with high plantar pressures. The total pressures, pressure distribution, and peak pressures provide useful information to evaluate the abnormal functioning of the talotarsal joint. Instability of the talotarsal joint can result in excessive forces exerted on the joints and surrounding tissues in the foot that can then lead to dysfunction of the proximal musculoskeletal kinetic chain. In the present study, we performed a retrograde analysis of the pre- and postoperative measurements of the peak plantar pressures, peak forces, and area of contact between the foot and the ground during each phase of the gait cycle for 6 patients (12 feet) who had undergone a bilateral extraosseous talotarsal stabilization procedure using a type II extraosseous talotarsal stabilization device. After the procedure, a significant reduction was seen in the peak pressures (42%) over the entire foot and a significant increase in the contact area (19.7%) between the foot and the floor. This could imply that the extraosseous talotarsal stabilization procedure was effective in stabilizing the talotarsal joint complex, thus eliminating abnormal hindfoot motion and restoring the normal biomechanics of the foot and ankle complex, as indicated by a reduction and realignment of the peak plantar pressures and forces. PMID- 23632068 TI - Low-profile titanium plate construct for early weightbearing with first metatarsophalangeal joint arthrodesis. AB - First metatarsophalangeal joint arthrodesis is a useful procedure for various first ray pathologic entities. Multiple constructs for fixation have provided successful fusion. A retrospective study of 21 feet (18 patients) was performed after first metatarsophalangeal joint fusion using crossed Kirschner wires or compression fixation with cannulated screws followed by the application of a 2 hole low-profile partially locking titanium plate. The median age was 59 (range 41 to 76) years, and we had 4 smokers and 3 patients with diabetes in our series. Postoperatively, a compression dressing with a posterior splint was applied. The patients then transitioned to a controlled ankle motion walker, and all patients reported full weightbearing by 2 weeks postoperatively. The mean follow-up duration was 11.43 (range 6 to 27) months. The overall primary fusion rate was 95.24% (20 of 21). Two nonunions occurred; one was asymptomatic and successfully consolidated at 12 months. The second nonunion required revisional surgery with an autogenous bone graft to heal successfully. This patient was noncompliant with the postoperative regimen and had a 48-pack year history of tobacco usage. Our results have shown early weightbearing after first metatarsophalangeal joint arthrodesis can be successfully initiated with splintage or lag screw fixation and a 2-hole, low-profile, partially locking titanium plate. PMID- 23632069 TI - Reply: To PMID 22819617. PMID- 23632070 TI - Complications of distal tibiofibular syndesmotic screw stabilization: analysis of 236 patients. AB - The objective of the present study was to evaluate our complications of screw stabilization and to formulate recommendations for clinical practice. Using a prospectively collected fracture database, the data from 236 consecutive adult patients were analyzed who had undergone syndesmotic screw stabilization from January 1979 to December 2000 at our level I academic trauma center. We observed 16 complications in 15 patients. The average patient age was 37.5 years. Of the 15 patients, 1 had a Weber B fracture and 14 had a Weber C ankle fracture. These complications included tibiofibular synostosis in 11 patients, screw breakage in 4 patients, and late diastasis in 1 patient. All breakages occurred in Weber C fractures. In particular, the 3.5-mm screws, penetrating both tibial cortices, tended to break. Synostosis was observed in 3% of the Weber B fractures and 5% of the Weber C fractures. Weightbearing in a plaster cast during syndesmotic screw stabilization is a safe postoperative treatment. We suggest that the use of 3.5 mm screws and screws penetrating 2 tibial cortices have a greater risk of breakage. Because of the low complication rate and more difficult treatment of late syndesmotic diastasis, a syndesmotic screw should be placed when in doubt of the indication. PMID- 23632071 TI - Synovial sarcoma of the foot. AB - We report the case of a 75-year-old male who underwent lung lobectomy for presumed lung cancer. Thereafter, he presented with a painful mass between the third and fourth metatarsal heads in the foot that was assumed to be Morton's neuroma. After extensive oncologic evaluation, the foot mass was diagnosed as a synovial sarcoma. In retrospect, his lung lesion was understood to be metastatic disease. PMID- 23632072 TI - Sexual-risk behaviour and HIV testing among Canadian snowbirds who winter in Florida. AB - Rates of HIV (human immunodeficiency virus) and sexual-risk behaviour for those aged 50 and over in the United States are highest and increasing in Florida, where many Canadian "snowbirds" winter. This pilot study examined the sexual-risk behaviour and predictors of HIV testing in a convenience sample of Canadian snowbirds who winter in Florida (n = 265). Multivariate logistic regression analyses revealed that the odds of testing were increased for the unmarried, those aged 50-64, those who had talked to a doctor about sexual-risk behaviour since age 50, and those who agreed that sex was important in their lives. Dating males were more likely to test than non-dating males. Dating females were not more likely to test than non-dating females; and males who dated were 13.6 times more likely to test than females who dated. Further research will improve understanding of Canadian snowbirds' sexual interactions and HIV-testing behaviour. PMID- 23632073 TI - Radiofrequency on the liver remnant after liver resection to reach the haemostasis not otherwise achievable with conventional techniques. AB - INTRODUCTION: During liver resection, in same case of inflamed, steatotic or neo vascularized liver parenchyma, reaching of haemostasis on the liver resection surface could be very difficult for the surgeon because of the presence of fragile tissue that does not allows the proper placement of stitches, and the conventional method fail. PRESENTATION OF CASE: The authors describe a novel technique in which, after a formal liver resection, liver haemostasis is achieved using radiofrequency energy on the resected surface. A patient affected by a hystiocytic sarcoma localized on the VI-V and IVa segments was scheduled for liver resection. During the resection a diffuse bleeding from the resected surface started with little success obtained with conventional method. So we decided to use the coagulative necrosis generated by the radiofrequency, using a cool type cluster needle, hand-piece with 3 needle, bending 2 needles in a way resembling a "fork", to reach a complete and definitive haemostasis. DISCUSSION: Haemostasis remains a critical issue in liver surgery not only for the catastrophic effect of haemorrhage but also because it is correlated to complications rate and to survival. The coagulative necrosis generated by the radiofrequency could be used to facilitate the creation of a necrotic plane to be transacted. CONCLUSION: The use of the radiofrequency energy, delivered through needles, is suggested when the conventional techniques fail to reach a proper haemostasis after a liver resection or, to consider its use, prior to resect the liver in presence of fragile parenchyma. PMID- 23632074 TI - Tumor seeding incidentally found two years after robotic-Assisted radical nephrectomy for papillary renal cell carcinoma. A case report and review of the literature. AB - INTRODUCTION: Port-site metastasis or peritoneal spread after laparoscopic surgery for urological malignancies is a rare phenomenon accounting for 0.09% and 0.03% of the cases respectively. PRESENTATION OF CASE: We present a case of tumor seeding in the omentum found in a female patient after previous transperitoneal robotic-assisted radical nephrectomy (RARN) for papillary renal cell carcinoma (RCC). Two years after the robotic operation, the patient was diagnosed with cervical clear cell carcinoma and underwent radical hysterectomy with lymphadenectomy and omentectomy. A neoplastic omental nodule was incidentally identified intraoperatively. Pathological characteristics and immunohistochemistry revealed features of papillary RCC. Two years after the hysterectomy, the patient is clinically cancer free, without any adjuvant therapy for her cervical cancer. DISCUSSION: To the best of our knowledge, we report the first case of tumor seeding in the omentum following RARN for organ confined low grade papillary (T2aN0M0) RCC. No risk factors that could explain the tumor seeding were identified. The neoplastic cells had a low proliferative index (Ki 67<5%) and a decreased capability to metastasize. CONCLUSION: Tumor seeding as a result of robotic assisted laparoscopic nephrectomy, although rare, might represent a novel way of tumor inoculation deprived of or with low malignant potential. PMID- 23632075 TI - Sec62 protein mediates membrane insertion and orientation of moderately hydrophobic signal anchor proteins in the endoplasmic reticulum (ER). AB - Nascent chains are known to be targeted to the endoplasmic reticulum membrane either by a signal recognition particle (SRP)-dependent co-translational or by an SRP-independent post-translational translocation route depending on signal sequences. Using a set of model and cellular proteins carrying an N-terminal signal anchor sequence of controlled hydrophobicity and yeast mutant strains defective in SRP or Sec62 function, the hydrophobicity-dependent targeting efficiency and targeting pathway preference were systematically evaluated. Our results suggest that an SRP-dependent co-translational and an SRP-independent post-translational translocation are not mutually exclusive for signal anchor proteins and that moderately hydrophobic ones require both SRP and Sec62 for proper targeting and translocation to the endoplasmic reticulum. Further, defect in Sec62 selectively reduced signal sequences inserted in an N(in)-C(out) (type II) membrane topology, implying an undiscovered role of Sec62 in regulating the orientation of the signal sequence in an early stage of translocation. PMID- 23632077 TI - Building partnerships in community-based participatory research: budgetary and other cost considerations. AB - Community-based participatory research (CBPR) is an important framework for partnering with communities to reduce health disparities. Working in partnership with community incurs additional costs, some that can be represented in a budget summary page and others that are tied to the competing demands placed on community and academic partners. These cost considerations can inform development of community-academic partnerships. We calculated costs from a case study based on an ongoing CBPR project involving a Community Planning Group (CPG) of community co-researchers in rural Alaska and a bicultural liaison group who help bridge communication between CPG and academic co-researchers. Budget considerations specific to CBPR include travel and other communication-related costs, compensation for community partners, and food served at meetings. We also identified sources of competing demands for community and academic partners. Our findings can inform budget discussions in community-academic partnerships. Discussions of competing demands on community partners' time can help plan timelines for CBPR projects. Our findings may also inform discussions about tenure and promotion policies that may represent barriers to participation in CBPR for academic researchers. PMID- 23632076 TI - Dissection of the ATPase active site of P1 ParA reveals multiple active forms essential for plasmid partition. AB - The segregation, or partition, of bacterial plasmids is driven by the action of plasmid-encoded partition ATPases, which work to position plasmids inside the cell. The most common type of partition ATPase, generally called ParA, is represented by the P1 plasmid ParA protein. ParA interacts with P1 ParB (the site specific DNA binding protein that recognizes the parS partition site), and interacts with the bacterial chromosome via an ATP-dependent nonspecific DNA binding activity. ParA also regulates expression of the par genes by acting as a transcriptional repressor. ParA requires ATP for multiple steps and in different ways during the partition process. Here, we analyze the properties of mutations in P1 ParA that are altered in a key lysine in the Walker A motif of the ATP binding site. Four different residues at this position (Lys, Glu, Gln, Arg) result in four different phenotypes in vivo. We focus particularly on the arginine substitution (K122R) because it results in a worse-than-null and dominant-negative phenotype called ParPD. We show that ParAK122R binds and hydrolyzes ATP, although the latter activity is reduced compared with wild-type. ParAK122R interacts with ParB, but the consequences of the interaction are damaged. The ability of ParB to stimulate the ATPase activity of ParA in vitro and its repressor activity in vivo is defective. The K122R mutation specifically damages the disassembly of ParA-ParB-DNA partition complexes, which we believe explains the ParPD phenotype in vivo. PMID- 23632079 TI - Building tobacco cessation capacity in the U.S.-affiliated Pacific Islands. AB - Tobacco control stakeholders in priority populations are searching for culturally appropriate cessation training models to strengthen cessation capacity and infrastructure. We adapted the University of Arizona model for Brief Tobacco Cessation Interventions training for Pacific Islanders and pilot-tested it in four Pacific Islands-Palau, the Federated States of Micronesia, the Northern Mariana Islands and the Marshall Islands. All participants completed a posttraining knowledge assessment exam, pre- and posttraining confidence assessments, and a quality improvement evaluation. Of 70 participants, 65 (93%) completed the training. Forty-one (63%) passed the posttraining knowledge assessment exam at the first attempt; an additional 9 (14%) successfully passed on their second attempt, for a total pass rate of 77%. The pre- and posttraining confidence surveys demonstrated a statistically significant increase in confidence across all competency areas for delivering brief advice. The quality improvement survey revealed high acceptance and approval for the content and delivery of the locally adapted training model. As Pacific Island communities enact tobacco control policies, cessation demand is growing. The Guam cessation training model used culturally relevant data, materials, and training approaches and appeared effective in four different Pacific island countries. This underscores the importance of culturally competent adaptation of cessation training for priority populations such as Pacific Islanders. PMID- 23632078 TI - Environmental influences on tobacco use among Asian American and Pacific Islander youth. AB - There is growing interest in understanding individual and environmental influences on youth risk behaviors, including tobacco use. The purpose of this article is to describe the processes and findings from a study that sought to increase the capacity of Asian American and Pacific Islander (AAPI) community based organizations to understand and address the environmental influences on tobacco use among AAPI youth. Using a multimethod approach to data collection that included GIS (geographic information system) mapping, Photovoice, and individual youth surveys, a team of community and university researchers conducted a 3-year study to assess and address the environmental influences of tobacco use among youth. Community-based participatory research principles guided the study and facilitated unique capacity building and analyses throughout the study period. Results in Long Beach from all three methods highlighted the associations between youth smoking and environmental factors: GIS mapping identified at least 77 separate locations of pro-tobacco influences, photographs captured many of these locations and provided youth leaders with opportunities to identify how other influences contributed to smoking risk, and surveys of youth indicated that perceived community safety and proximity to pro-tobacco influences were associated with smoking in the past 30 days. Subsequent community-based organization activities undertaken by study partners are also discussed, and lessons learned summarized. PMID- 23632080 TI - Managing ethical dilemmas in community-based participatory research with vulnerable populations. AB - This article describes two ethical dilemmas encountered by our research team during a project working with undocumented immigrants in Toronto, Canada. This article aims to be transparent about the problems the research team faced, the processes by which we sought to understand these problems, how solutions were found, and how the ethical dilemmas were resolved. Undocumented immigrants are a vulnerable community of individuals residing in a country without legal citizenship, immigration, or refugee status. There are more than half a million undocumented immigrants in Canada. Through an academic-community partnership, a study was conducted to understand the experiences of undocumented immigrants seeking health care in Toronto. The lessons outlined in this article may assist others in overcoming challenges and ethical dilemmas encountered while doing research with vulnerable communities. PMID- 23632081 TI - Identification of an allosteric modulator of the serotonin transporter with novel mechanism of action. AB - Serotonin transporters (SERTs) play an essential role in the termination and regulation of serotonin signaling in the brain. SERT is also the target of antidepressants and psychostimulants. Molecules with novel activities and modes of interaction with regard to SERT function are of great scientific and clinical interest. We explored structural regions outside the putative serotonin translocation pathway to identify potential binding sites for allosteric transporter modulators (ATMs). Mutational studies revealed a pocket of amino acids outside the orthosteric substrate binding sites located in the interface between extracellular loops 1 and 3 that when mutated affect transporter function. Using the structure of the bacterial transporter homolog leucine transporter as a template, we developed a structural model of SERT. We performed molecular dynamics simulations to further characterize the allosteric pocket that was identified by site-directed mutagenesis studies and employed this pocket in a virtual screen for small-molecule modulators of SERT function. In functional transport assays, we found that one of the identified molecules, ATM7, increased the reuptake of serotonin, possibly by facilitating the interaction of serotonin with transport-ready conformations of SERT when concentrations of serotonin were low and rate limiting. In addition, ATM7 potentiates 3,4-methylenedioxy-N methylamphetamine (MDMA, "Ecstasy")-induced reversed transport by SERT. Taking advantage of a conformationally sensitive residue in transmembrane domain 6, we demonstrate that ATM7 mechanistically stabilizes an outward-facing conformation of SERT. Taken together these observations demonstrate that ATM7 acts through a novel mechanism that involves allosteric modulation of SERT function. PMID- 23632082 TI - GIRK-like and TRPC-like conductances mediate thyrotropin-releasing hormone induced increases in excitability in thalamic paraventricular nucleus neurons. AB - The thalamic paraventricular nucleus (PVT), reported to participate in arousal and motivated behaviors, contains abundant receptors for thyrotropin-releasing hormone (TRH), a neuropeptide also known to modulate arousal and mood. To test the hypothesis that TRH could influence the excitability of PVT neurons, whole cell patch-clamp recordings obtained in rat brain slice preparations were evaluated during bath applied TRH. In the majority of neurons tested, TRH induced reversible TTX-resistant membrane depolarization. Under voltage-clamp, TRH induced a concentration-dependent G protein- mediated inward current. The mean net TRH-induced current exhibited a decrease in membrane conductance. Further analyses identified two concurrent conductances contributing to the TRH-induced response. One conductance featured a Na(+)-independent and K(+)-dependent net current that displayed rectification and was suppressed by micromolar concentrations of Ba(2+) and two GIRK antagonists, tertiapin Q and SCH 23390. The second conductance featured a Na(+)-dependent net inward current with an I-V relationship that exhibited double rectification with a negative slope conductance below -40 mV. This conductance was suppressed by nonselective TRPC channel blockers 2-APB, flufenamic acid and ML204, enhanced by La(3+) in a subpopulation of cells, and unchanged by the TRPV1 antagonist capsazepine or a Na(+)/Ca(2+) exchanger blocker KB-R7943. TRH also enhanced hyperpolarization activated low threshold spikes, a feature that was sensitive to pretreatment with either 2-APB or ML204. Collectively, the data imply that TRH enhances excitability in PVT neurons via concurrently decreasing a G-protein-gated inwardly rectifying K(+) conductance and activating a cationic conductance with characteristics reminiscent of TRPC-like channels, possibly involving TRPC4/C5 subunits. PMID- 23632084 TI - Evaluation of anti-obesity effect of Aegle marmelos leaves. AB - The study was carried out to investigate the anti-obesity effects of Aegle marmelos leaves extracts and its phytochemical constituents in vitro and in vivo. The dichloromethane (DCM), ethyl acetate (EtOAc) and n-butanol extracts of A. marmelos leaves were studied for their lipolytic effect. Lipolysis was measured by determining the amount of glycerol released at 12 h and 24 h at 50 MUg/ml and 100 MUg/ml concentrations. Phytochemical investigation of the most active DCM extract yielded 14 compounds. The isolated compounds were evaluated for their lipolytic effects at 50 MUM and 100 MUM. The most active compounds, umbelliferone and esculetin were further screened for their antiobesity effects in vivo in the high fat diet (HFD) induced obese rat model. Umbelliferone and esculetin reduced body weight, total triglyceride (TG), total cholesterol (TC) and glucose level in their respective HFD groups. A. marmelos DCM extract and compounds isolated from it have the potential of counteracting the obesity by lipolysis in adipocytes. PMID- 23632085 TI - Anti-allergic actions of rottlerin from Mallotus philippinensis in experimental mast cell-mediated anaphylactic models. AB - Allergy is an acquired hypersensitivity reaction of the immune system mediated by cross-linking of the allergen-specific IgE-bound high-affinity IgE receptors, leading to immediate mast cell degranulation. Rottlerin is an active molecule isolated from Mallotus philippinensis, a medicinal plant used in Ayurvedic Medicine System for anti-allergic and anti-helminthic treatments. The present study investigated potential anti-allergic effects of rottlerin in animal models of IgE-dependent anaphylaxis and the anti-allergic mechanisms of action of rottlerin in mast cells. Anti-allergic actions of rottlerin were evaluated in passive cutaneous anaphylaxis and passive systemic anaphylaxis mouse models, and in anaphylactic contraction of bronchial rings isolated from sensitized guinea pigs. Direct mast cell-stabilizing effect of rottlerin was examined in RBL-2H3 mast cell line. Anti-allergic signaling mechanisms of action of rottlerin in mast cells were also examined. Rottlerin prevented IgE-mediated cutaneous vascular extravasation, hypothermia, elevation in plasma histamine level and tracheal tissue mast cell degranulation in mice in a dose-dependent manner. In addition, rottlerin suppressed ovalbumin-induced guinea pig bronchial smooth muscle contraction. Furthermore, rottlerin concentration-dependently blocked IgE mediated immediate release of beta-hexosaminidase from RBL-2H3 mast cells. Rottlerin was found to inhibit IgE-induced PLCgamma1 and Akt phosphorylation, production of IP3 and rise in cytosolic Ca2+ level in mast cells. We report here for the first time that rottlerin possesses anti-allergic activity by blocking IgE-induced mast cell degranulation, providing a foundation for developing rottlerin for the treatment of allergic asthma and other mast cell-mediated allergic disorders. PMID- 23632083 TI - Molecules and circuits involved in nicotine addiction: The many faces of smoking. AB - Tobacco smoking in humans is one of the most persistent and widespread addictions and is driven by nicotine in tobacco smoke. Over the last several decades, understanding of the molecular and cellular basis for nicotine addiction has increased tremendously as a result of pharmacological, molecular genetic, electrophysiological and behavioral studies of nicotine reinforcement. Studies of the biological basis for nicotine reinforcement has helped in the design of new treatments for smoking cessation such as varenicline; however, smokers report that they smoke for many reasons, including the ability to control symptoms of anxiety and depression or the desire to control appetite. Further, developmental exposure to tobacco smoke increases the likelihood of adult smoking. Here we review what is known about the molecular and circuit basis for a number of behaviors related to tobacco smoking. Leveraging the knowledge from studies of different behaviors mediated by nicotine receptors in multiple brain circuits could provide points of convergence that will inform future therapeutic development for smoking cessation. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23632087 TI - Increased liver apoptosis and tumor necrosis factor expression in Atlantic bluefin tuna (Thunnus thynnus) reared in the northern Adriatic Sea. AB - The Atlantic bluefin tuna Thunnus thynnus (ABFT) is intensely fished in the Mediterranean Sea to supply a prosperous capture-based mariculture industry. Liver apoptotic structures and tumor necrosis factor (TNF) gene expression were determined in: wild ABFT caught in the eastern Atlantic; juvenile ABFT reared in the central Adriatic Sea; juvenile ABFT reared in the northern Adriatic Sea; adult ABFT reared in the western Mediterranean. The highest density of liver apoptotic structures was found in the juveniles from the northern Adriatic. Two partial TNF cDNAs (TNF1 and TNF2) were cloned and sequenced. TNF1 gene expression was higher in juveniles than in adults. The highest expression of TNF2 was found in the juveniles from the northern Adriatic. These findings might be related to the juvenile exposure to environmental pollutants. PMID- 23632088 TI - Changes to chronic nitrogen loading from sewage discharges modify standing stocks of coastal phytoplankton. AB - Nutrient delivery in subtropical coastal systems is predominantly via acute episodic high flow events. However, continuous nutrient discharges from point sources alter these natural fluctuations in nutrient delivery, and are therefore likely to lead to different ecosystem responses. The aim of this study was to assess how a reduction in chronic sewage nutrient inputs affected chlorophyll a (chl a) concentrations in a subtropical bay, in the context of seasonal fluctuations in riverine nutrient inflows. Reduced nutrient inputs from a large sewage treatment plant (STP) resulted in lower mean dissolved inorganic nitrogen and phytoplankton chl a concentrations during both the austral summer wet and winter dry season. This was measurable within 10 y of nutrient reductions and despite the confounding effects of nutrient inflow events. Our study demonstrates that reductions in STP inputs can have significant effects on phytoplankton biomass despite confounding factors over relatively short time frames. PMID- 23632089 TI - Potential acidification impacts on zooplankton in CCS leakage scenarios. AB - Carbon capture and storage (CCS) technologies involve localized acidification of significant volumes of seawater, inhabited mainly by planktonic species. Knowledge on potential impacts of these techniques on the survival and physiology of zooplankton, and subsequent consequences for ecosystem health in targeted areas, is scarce. The recent literature has a focus on anthropogenic greenhouse gas emissions into the atmosphere, leading to enhanced absorption of CO2 by the oceans and a lowered seawater pH, termed ocean acidification. These studies explore the effects of changes in seawater chemistry, as predicted by climate models for the end of this century, on marine biota. Early studies have used unrealistically severe CO2/pH values in this context, but are relevant for CCS leakage scenarios. Little studied meso- and bathypelagic species of the deep sea may be especially vulnerable, as well as vertically migrating zooplankton, which require significant residence times at great depths as part of their life cycle. PMID- 23632086 TI - The prevalence, maintenance, and relevance of G protein-coupled receptor oligomerization. AB - Over the past decade, ideas and experimental support for the hypothesis that G protein-coupled receptors may exist as dimeric or oligomeric complexes moved initially from heresy to orthodoxy, to the current situation in which the capacity of such receptors to interact is generally accepted but the prevalence, maintenance, and relevance of such interactions to both pharmacology and function remain unclear. A vast body of data obtained following transfection of cultured cells is still to be translated to native systems and, even where this has been attempted, results often remain controversial and contradictory. This review will consider approaches that are currently being applied and why these might be challenging to interpret, and will suggest means to overcome these limitations. PMID- 23632090 TI - Phase II study of CD4+-guided pentostatin lymphodepletion and pharmacokinetically targeted busulfan as conditioning for hematopoietic cell allografting. AB - One limitation of reduced-intensity preparative regimens is potential for graft failure. We have developed a regimen that targets CD4(+) lymphodepletion to ensure early and durable engraftment. The primary endpoint was achievement of >=50% CD3(+) donor chimerism by day +28. Forty-two patients (median age, 53 years; range, 29 to 73 years) received pentostatin 4 mg/m(2) i.v. on days -28, 21, and -14 when the CD4(+) cell count was >100 cells/MUL and on days -4 and -3 regardless of CD4(+) level. Rituximab 375 mg/m(2) was administered to patients with CD20(+) malignancies on days -21, -14, -7, +1, and +8. Busulfan 200 mg/m(2) i.v. was administered on days -4 and -2 at a dose to target a cumulative AUC dose of 16,000 (+/-10%) MUmol.min/L. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 86% of patients. Donors were matched related (47%), matched unrelated (43%), or mismatched unrelated (10%). Chronic lymphocytic leukemia (45%) and follicular non-Hodgkin lymphoma (14%) were the most common diagnoses. Disease status at initiation of the preparative regimen was complete remission in 22%, partial response in 55%, and stable/progression in 24%. The median percent CD4(+) cell count decrease from baseline (day -28) was 52% to day -21, 66% to day -14, 62% to day -7, and 91% to day 0. At day +28, all 42 patients (100%) had >=50% CD3(+) donor chimerism. No patient experienced graft failure. Overall response rate was 82% (complete remisson, 67%). The day +100 cumulative incidence of grade II-IV acute GVHD was 59% (grade III-IV acute GVHD, 19%), and the 2 year cumulative incidence of chronic GVHD was 69% (moderate/severe, 58%). Nonrelapse mortality was 2% at day +100 and 17% at 2 years. Two-year PFS was 55%, and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse. PMID- 23632092 TI - Gender differences in the neurotoxicity of metals in children. AB - Gender-related differences in susceptibility to chemical exposure to neurotoxicants have not received sufficient attention. Although a significant number of epidemiological studies on the neurodevelopmental effects of metal exposure has been published in the last twenty years, not many of them have considered the possible gender-specific effects of such exposure. This review is focused on studies where the gender differences in pre- and/or postnatal exposure/s to five metals (mercury, lead, manganese, cadmium, and arsenic) and neurodevelopment were evaluated. We conducted a PubMed search in December 2012 and retrieved 20 studies that met the inclusion criteria. A large body of literature on potential neurodevelopment effects in children due to mercury exposure is available, but, a clear pattern regarding gender differences in neurotoxicity is not elucidated. There is also abundant available information on the gender-specific health effects of lead, and exposure to this metal seems to affect boys more than girls. Information regarding gender differences in susceptibility of manganese, cadmium, and arsenic is still too scarce to draw any definite conclusion. More research is highly warranted about this matter. Environmental epidemiological studies should be designed to quantify differential gender-based exposures and outcomes, and this may provide new insights into prevention strategies. PMID- 23632093 TI - Prediction of the energy values of feedstuffs for broilers using meta-analysis and neural networks. AB - Several researchers have developed prediction equations to estimate the metabolisable energy (ME) of energetic and protein concentrate feedstuffs used in diets for broilers. The ME is estimated by considering CP, ether extract, ash and fibre contents. However, the results obtained using traditional regression analysis methods have been inconsistent and new techniques can be used to obtain better estimate of the feedstuffs' energy value. The objective of this paper was to implement a multilayer perceptron network to estimate the nitrogen-corrected metabolisable energy (AMEn) values of the energetic and protein concentrate feeds, generally used by the poultry feed industry. The concentrate feeds were from plant origin. The dataset contains 568 experimental results, all from Brazil. This dataset was separated into two parts: one part with 454 data, which was used to train, and the other one with 114 data, which was used to evaluate the accuracy of each implemented network. The accuracy of the models was evaluated on the basis of their values of mean squared error, R 2, mean absolute deviation, mean absolute percentage error and bias. The 7-5-3-1 model presented the highest accuracy of prediction. It was developed an Excel(r) AMEn calculator by using the best model, which provides a rapid and efficient way to predict the AMEn values of concentrate feedstuffs for broilers. PMID- 23632091 TI - Unrelated donor allogeneic transplantation after failure of autologous transplantation for acute myelogenous leukemia: a study from the center for international blood and marrow transplantation research. AB - The survival of patients with relapsed acute myelogenous leukemia (AML) after autologous hematopoietic stem cell transplantation (auto-HCT) is very poor. We studied the outcomes of 302 patients who underwent secondary allogeneic hematopoietic cell transplantation (allo-HCT) from an unrelated donor (URD) using either myeloablative (n = 242) or reduced-intensity conditioning (RIC; n = 60) regimens reported to the Center for International Blood and Marrow Transplantation Research. After a median follow-up of 58 months (range, 2 to 160 months), the probability of treatment-related mortality was 44% (95% confidence interval [CI], 38%-50%) at 1-year. The 5-year incidence of relapse was 32% (95% CI, 27%-38%), and that of overall survival was 22% (95% CI, 18%-27%). Multivariate analysis revealed a significantly better overal survival with RIC regimens (hazard ratio [HR], 0.51; 95% CI, 0.35-0.75; P <.001), with Karnofsky Performance Status score >=90% (HR, 0.62; 95% CI, 0.47-0.82: P = .001) and in cytomegalovirus-negative recipients (HR, 0.64; 95% CI, 0.44-0.94; P = .022). A longer interval (>18 months) from auto-HCT to URD allo-HCT was associated with significantly lower riak of relapse (HR, 0.19; 95% CI, 0.09-0.38; P <.001) and improved leukemia-free survival (HR, 0.53; 95% CI, 0.34-0.84; P = .006). URD allo HCT after auto-HCT relapse resulted in 20% long-term leukemia-free survival, with the best results seen in patients with a longer interval to secondary URD transplantation, with a Karnofsky Performance Status score >=90%, in complete remission, and using an RIC regimen. Further efforts to reduce treatment-related mortaility and relapse are still needed. PMID- 23632094 TI - Control of foot-and-mouth disease during 2010-2011 epidemic, South Korea. AB - An outbreak of foot-and-mouth disease caused by serotype O virus occurred in cattle and pigs in South Korea during November 2010-April 2011. The highest rates of case and virus detection were observed 44 days after the first case was detected. Detection rates declined rapidly after culling and completion of a national vaccination program. PMID- 23632095 TI - Analysis of the efficacy of portal vein embolization for patients with extensive liver malignancy and very low future liver remnant volume, including a comparison with the associating liver partition with portal vein ligation for staged hepatectomy approach. AB - BACKGROUND: The primary reported indication for the associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) technique is in patients with very low future liver remnant volumes. Given the elevated incidence of major morbidity (40%) and liver-related mortality (12%) with ALPPS, we sought to determine the safety and efficacy of percutaneous portal vein embolization (PVE) in a similar patient population. STUDY DESIGN: Tumor resectability and morbidity and mortality rates were reviewed for 144 consecutive liver tumor patients with future liver remnant to body weight ratios (LR/BW) less than 0.5%. All patients were referred for preoperative percutaneous right plus segment IV PVE using embolic microspheres, with planned reassessment of the LR/BW 30 days after PVE. Post-PVE outcomes were compared with reported outcomes for ALPPS. RESULTS: Percutaneous PVE was successfully performed in 141 of the 144 study patients (97.9%). Adequate regeneration was observed in 139 patients (98.5%) with median post-PVE LR/BW rising from 0.33% to 0.52% (p < 0.0001), representing a per patient median regeneration rate of 62% (range 0.3% to 379%). In total, 104 patients underwent extended right hepatectomy (n = 102) or right hepatectomy (n = 2). The remaining 40 patients (27.8%) were not resectable due to short-interval disease progression (27 patients, 18.5%), insufficient liver regeneration (5 patients, 3.5%), and medical comorbidities (8 patients, 5.6%). After resection, the following outcomes were observed: major morbidity: 33.0% (34 of 104), liver insufficiency: 12.5% (13 of 104), and 90-day liver-related mortality: 5.8% (6 of 104). These oncologic and technical results compare favorably with those of ALPPS. CONCLUSIONS: Based on its ability to select oncologically resectable patients and superior safety and efficacy profiles, percutaneous right + segment IV PVE and interval surgery remains the standard of care for patients with very low future liver remnant volumes. PMID- 23632097 TI - Diminishing returns in bovine tuberculosis control. AB - Mycobacterium bovis causes bovine tuberculosis (bTB) in many mammals including cattle, deer and brushtail possum. The aim of this study was to estimate the strength of association, using model selection (AICc) regression analyses, between the proportion of cattle and farmed deer herds with bTB in New Zealand and annual costs of TB control, namely disease control in livestock, in wildlife or in a combination of the two. There was more support for curved (concave up) than linear models which related the proportion of cattle and farmed deer herds with bTB to the annual control costs. The curved, concave-up, best-fitting relationships showed diminishing returns with no positive asymptote and implied TB eradication is feasible in New Zealand. PMID- 23632096 TI - Family smoking history moderates the effect of expectancies on smoking initiation in college students. AB - AIMS: This report was designed to test the hypothesis that family history of smoking (FH) would moderate the effects of positive and negative smoking expectancies on initiation in a college sample. DESIGN: Secondary analysis of a study of college freshmen never-smokers (n=196; 46% male) who completed a baseline interview and quarterly online follow-up assessments for 15 months. FINDINGS: Analyses indicated that FH moderated the effect of negative outcome expectancies (p=.003) but not the effects of expectancies for positive or negative reinforcement on the probability of smoking initiation. Stronger negative expectancies were associated with a decreased risk of initiation for family history positive but not family history negative participants. CONCLUSIONS: Findings are consistent with previous tobacco research indicating that FH+adolescents have more negative expectancies about cigarette smoking. This suggests that adolescents observing negative consequences or receiving negative messages from their parents about cigarettes may be less likely to experiment with smoking. PMID- 23632098 TI - Genomic organization and transcription of the medaka and zebrafish cellular retinol-binding protein (rbp) genes. AB - In this study, we examined the evolutionary trajectories and the common ancestor of medaka rbp genes by comparing them to the well-studied rbp/RBP genes from zebrafish and other vertebrates. We describe here gene structure, sequence identity, phylogenetic analysis and conserved gene synteny of medaka rbp genes and their putative proteins as well as the tissue-specific distribution of rbp transcripts in adult medaka and zebrafish. Medaka rbp genes consist of four exons separated by three introns that encode putative polypeptides of 134-138 amino acids, a genomic organization characteristic of rbp genes. Medaka Rbp sequences share highest sequence identity and similarity with their orthologs in vertebrates, and form a distinct clade with them in phylogenetic analysis. Conserved gene synteny was evident among medaka, zebrafish and human rbp/RBP genes, which provides compelling evidence that the medaka rbp1, rbp2a, rbp2b, rbp5, rbp7a and rbp7b genes arose from a common ancestor of vertebrates. Moreover, the duplicated rbp2 and rbp7 genes most likely exist owing to a whole genome duplication (WGD) event specific to the teleost fish lineage. Selection pressure and the nonparametric relative rate test of the medaka and zebrafish duplicated rbp2 and rbp7 genes suggest that these duplicated genes are subjected to purifying selection and one paralog might have evolved at an accelerated rate compared to its sister duplicate since the WGD. The steady-state levels of medaka and zebrafish rbp1, rbp2a, rbp2b and rbp5 transcripts in various tissues suggest that medaka rbp1, rbp2a and rbp2b genes have retained the regulatory elements of an ancestral RBP1 and RBP2 genes, and the medaka rbp5 gene has acquired new function. Furthermore, the tissue-specific regulations of rbp7a and rbp7b genes have diverged markedly in medaka and zebrafish since the teleost-specific WGD. PMID- 23632099 TI - Non-classic congenital adrenal hyperplasia. AB - Non-classic or late-onset congenital adrenal hyperplasia (NCAH) due to 21 hydroxylase deficiency is one of the most common autosomal recessive disorders. Reported prevalence is approximately 1 in 1000. Affected individuals typically present due to signs and symptoms of androgen excess. The purpose of this review is to provide current information regarding the pathophysiology, molecular genetics, and management of this common disorder. The treatment of NCAH needs to be directed towards the symptoms. For affected children, goals of treatment include normal linear growth velocity, normal rate of skeletal maturation, "on time" puberty. For affected adolescent and adult women, goals of treatment include regular menstrual cycles, prevention or progression of hirsutism and acne, and fertility. Treatment needs to be individualized and should not be initiated merely to decrease abnormally elevated hormone concentrations. PMID- 23632100 TI - The utility of galactomannan antigen in the bronchial washing and serum for diagnosing pulmonary aspergillosis. AB - BACKGROUND: The diagnosis of pulmonary aspergillosis is difficult because the sensitivity of the conventional methods for the detection of Aspergillus such as culture and cytology, is poor. To improve the sensitivity for Aspergillus detection, the detection of galactomannan antigen has been investigated. The serum galactomannan (GM) antigen has been recognized to be a useful tool for the diagnosis of invasive pulmonary aspergillosis. However, the utility of the galactomannan antigen for the diagnosis of pulmonary aspergillosis other than invasive pulmonary aspergillosis (IPA) has been unclear. METHODS: The GM antigen using serum and bronchial washing (BW) using bronchofiberscopy for the diagnosis of pulmonary aspergillosis other than IPA were measured. RESULTS: In 45 enrolled patients, 7 patients had pulmonary aspergillosis, 5 of these patients had chronic necrotizing pulmonary aspergillosis and 2 patients had allergic bronchopulmonary aspergillosis. The area under the receiver operating characteristic (ROC) curve was 0.89 for the BW GM antigen detection test, and 0.41 for the serum GM antigen detection test, suggesting that the BW GM antigen detection test exhibits a better diagnostic performance than the serum GM antigen detection test. The BW GM antigen detection test had a sensitivity of 85.7% and a specificity of 76.3% at a cut-off level of >=0.5, which was the optimal cut-off level obtained by the ROC curve. CONCLUSION: The BW GM antigen detection test is thought to be a promising test for the diagnosis of pulmonary aspergillosis other than IPA. PMID- 23632101 TI - Factors associated with aerobic fitness in adolescents with asthma. AB - BACKGROUND: In adolescents with asthma, information on factors associated with cardiorespiratory fitness levels is limited. The present study aimed to determine if objectively measured physical activity as well as potential relevant factors such as lung function, asthma exacerbations, use of inhaled corticosteroids or skin fold thickness are associated with direct measurements of peak oxygen uptake (VO2peak) in adolescents with asthma. METHODS: From a nested case-control study at 13-years in the Environment and Childhood Asthma birth cohort study in Oslo, Norway, 86 13-years old adolescents with and 76 without asthma performed maximal running on a treadmill with VO2peak measured. The sum of four skin fold thicknesses was recorded, followed by wearing an activity monitor for four consecutive days. Lung function was measured by maximum forced expiratory flow volume curves and body plethysmography. Asthma exacerbations and use of medication were registered by parental structured interview. Data were analysed using multiple regression analysis. RESULTS: Vigorous physical activity (coefficients with 95% confidence intervals; 1.73 (0.32, 3.14)) and skin fold thickness -0.35 (-0.41, -0.28)) were significantly associated with VO2peak in adolescents with asthma. Neither use of inhaled corticosteroids, lung function nor number of asthma exacerbations was associated with VO2peak when taking physical activity and skin fold thickness into account. In the adolescents without asthma only skin fold thicknesses was negatively associated with VO2peak 3.5 (-4.1, -2.8). CONCLUSIONS: VO2peak appears to be determined by vigorous physical activity level in Norwegian adolescents with asthma and not by asthma related factors such as use of inhaled corticosteroids, lung function nor number of asthma exacerbations. PMID- 23632102 TI - Energy dissipation in brown adipose tissue: from mice to men. AB - In rodents, brown adipose tissue (BAT) is a metabolic organ that produces heat in response to cold and dietary intake through mitochondrial uncoupling. For long time, BAT was considered to be solely important in small mammals and infants, however recent studies have shown that BAT is also functional in adult humans. Interestingly, the presence and/or functionality of this thermogenic tissue is diminished in obese people, suggesting a link between human BAT and body weight regulation. In the last years, evidence has also emerged for the existence of adipocytes that may have an intermediate thermogenic phenotype between white and brown adipocytes, so called brite or beige adipocytes. Together, these findings have resulted in a renewed interested in (human) brown adipose tissue and pathways to increase the activity and recruitment of these thermogenic cells. Stimulating BAT hypertrophy and hyperplasia in humans could be a potential strategy to target obesity. Here we will review suggested pathways leading to BAT activation in humans, and discuss novel putative BAT activators in rodents into human perspective. PMID- 23632103 TI - Small RNAs in spermatogenesis. AB - Spermatogenesis is characterized by meiotic divisions and major morphological changes to produce spermatozoa that are capable of independent movement and fertilization of an egg. Male germ cell differentiation is governed by orchestrated, phase-specific gene expression patterns that are tightly controlled at transcriptional and post-transcriptional level. Post-transcriptional regulation of protein-coding mRNAs becomes prominent during the late steps of spermatogenesis when the compacting sperm nucleus becomes transcriptionally inhibited. Small non-coding RNAs are important regulators of gene expression that mainly function post-transcriptionally to control the properties of their target mRNAs. Male germ cells express several classes of small RNAs, including Dicer dependent microRNAs (miRNAs) and endogenous small interfering RNAs (endo-siRNAs), as well as Dicer-independent piwi-interacting RNAs (piRNAs). Increasing evidence supports the essential role of small RNA-mediated RNA regulation in normal spermatogenesis and male fertility. PMID- 23632104 TI - Non-classical mechanisms of steroid sensing in the ovary: lessons from the bovine oxytocin model. AB - Steroidogenic tissues such as the ovary, testes or adrenal glands are paradoxical in that they often indicate actions of steroid hormones within a dynamic range of ligand concentration in a high nanomolar or even micromolar level, i.e. at the natural concentrations existing within those organs. Yet ligand-activated nuclear steroid receptors act classically by direct interaction with DNA in the picomolar or low nanomolar range. Moreover, global genomic studies suggest that less than 40% of steroid-regulated genes involve classical responsive elements in gene promoter regions. The bovine oxytocin gene is a key element in the maternal recognition of pregnancy in ruminants and is regulated via an SF1 site in its proximal promoter. This gene is also regulated by steroids acting in a non classical manner, involving nuclear receptors which do not interact directly with DNA. Dose-response relationships for these actions are in the high nanomolar range. Similar 'steroid sensing' mechanisms may prevail for other SF1-regulated genes and predict alternative pathways by which environmental endocrine disruptors might influence the functioning of steroid-producing organs and hence indirectly the steroid-dependent control of physiology and development. PMID- 23632105 TI - Farmers' practices, motivators and barriers for adoption of treatments of digital dermatitis in dairy farms. AB - This study aimed to catalogue the digital dermatitis (DD) treatment practices used by French dairy farmers and to identify the motivators and barriers to the adoption of these treatments. A semi-structured survey was conducted involving 65 farmers in the main dairy production areas of France in the spring of 2009. The different treatment modalities implemented by farmers since the first diagnosis of DD in their herds were described. The reasons for adopting or abandoning these treatments were then investigated based on criteria of perceived effectiveness, labour, time, cost and toxicity related to their use. For individual treatments, farmers used 30 different products, applied through three different routes, for 1 to 21 consecutive days. For collective treatments, farmers used 31 products, applied through four different routes, at a rate ranging from once a day to once a year. Several products, especially antibiotics, were used without observing the manufacturer's instructions. The principal criteria for the adoption of a treatment was the perceived effectiveness in healing DD lesions and in limiting recurrence, while the principal barriers to adopting a treatment were the time and labour required for its application, followed by cost. Topical oxytetracycline treatments applied individually were used and adopted the most. They were perceived to be effective in healing DD lesions. However, these treatments were judged labour and time consuming, particularly when many animals had to be treated. Collective treatments combining formalin and copper sulphate often were applied topically using walk-though footbaths. These treatments often were judged to be insufficiently effective in healing DD lesions, difficult to implement, labour and time consuming and costly. The plethora of DD treatment practices and the misuse of some treatments could suggest that there is a lack of guidelines available to farmers on the optimal use and expected effectiveness of treatments. Clinical trials should be conducted to develop recommendations based on scientific rather than empirical data, and to identify the DD control measures which consume the least amount of time and labour. PMID- 23632106 TI - Pale horse, pale rider done taken my lover away. PMID- 23632107 TI - Significant influence of particular unsaturated fatty acids and pH on the volatile compounds in meat-like model systems. AB - The present study aimed to investigate the effects of particular unsaturated fatty acids and pH on volatile compounds in the meat-like model systems containing 21 amino acids and ribose. We have chosen oleic acid (C18:1n-9), linoleic acid (C18:2n-6) and linolenic acid (C18:3n-3) for the present investigation. The effect on the volatile compounds was evaluated at two different pH 5.5 and 6.2. The addition of C18:2n-6 and C18:3n-3 to the Maillard reaction mixtures inhibited the formation of many Maillard compounds or produced in low amount. Whereas, the addition of C18:1n-9 resulted in an increase in the amount of many Maillard compounds. The thiols and thiophenes were preferentially formed at pH 5.5 whereas pyrazines were preferentially favored at pH 6.2. Based on our results, it is suggested that a high level of C18:2n-6 and C18:3n-3 in meat probably causes an undesirable flavor. The pH value of 5.5 was found to be ideal for the formation of volatile compounds associated with desirable flavor of meat. PMID- 23632108 TI - Effects of high pressure treatment and temperature on lipid oxidation and fatty acid composition of yak (Poephagus grunniens) body fat. AB - Effects of high-pressure treatment (100 MPa to 600 MPa) on lipid oxidation and composition of fatty acids in yak body fat at 4 degrees C and 15 degrees C were investigated for up to 20 days storage. 400 and 600 MPa treatments increase the level of thiobarbituric acid-reactive substances (TBARS) 335% and 400% (p<0.05), respectively. Composition analysis shows that 600 MPa treatment induces a lower (p<0.05) percentage of polyunsaturated fatty acids, and C22:6 decreased significantly. A significant decrease in PUFA/SFA and n-6/n-3 PUFA values was observed at the end of storage. Samples treated at the lower pressures gave good sensory acceptability. It is concluded that a higher-pressure treatment is important in catalyzing lipid oxidation and the evolution of fatty acids in pressure-treated yak body fat. PMID- 23632109 TI - A motorway, bridge and bypass to an impaired left ventricle. PMID- 23632110 TI - A novel indicator for assessment of mitral regurgitation severity: pro adrenomedullin. PMID- 23632111 TI - Response to letter by Wang Q et al. regarding article "Serum soluble ST2 and interleukin-33 levels in patients with pulmonary arterial hypertension". PMID- 23632112 TI - Quality of life and cognitive function in Fontan patients, a population-based study. AB - BACKGROUND: After the Fontan procedure patients are at risk for reduced quality of life (QoL) and cognitive function. We aimed to assess these important factors in Danish Fontan patients and to compare the results with a group of healthy controls. METHODS: All Fontan patients living in Denmark were identified and invited to participate. QoL was evaluated using the Pediatric Quality of Life Inventory (PedsQL) version 4.0 generic core module in patients <16 years and the Short Form 36 questionnaire (SF-36) in patients >=16 years. Cognitive function was evaluated in all patients >=6 years using the Quick Test of Cognitive Speed. To evaluate if QoL correlated with exercise capacity, patients performed a symptom-limited bicycle test. RESULTS: 158 of 179 eligible patients (88%) consented to participate. Median age was 13.9 years (IQR: 10.2-19.3). PedsQL scores increased with age but were significantly lower among patients than among controls. SF-36 physical scores were significantly lower in patients compared to controls while psychosocial scores were similar. Cognitive speed was significantly reduced in patients at all ages compared to controls. No significant difference in PedsQL-/SF-36 scores or cognitive speed was found between hypoplastic left heart syndrome (HLHS) and non-HLHS Fontan patient. PedsQL-/SF-36 scores in patients >=10 years correlated significantly to cognitive speed but not to peak exercise capacity. CONCLUSION: QoL is reduced in Fontan children compared to their healthy counterparts whereas in patients >=16 years only physical, but not psychosocial QoL is reduced. Cognitive speed was significantly lower in patients at all ages compared to controls. PMID- 23632113 TI - Incidence, predictors, and clinical impact of tissue prolapse after stent implantation for saphenous vein graft disease: intravascular ultrasound study. PMID- 23632114 TI - CHA2DS2-VASc Score and risk for reobstruction after endovascular treatment of the superficial femoral artery: differences between balloon angioplasty and stenting. PMID- 23632115 TI - The role of Toll-like receptor 2 and hypoxia-induced transcription factor-1alpha in the atrial structural remodeling of non-valvular atrial fibrillation. PMID- 23632116 TI - Left ventricular site-directed biopsy guided by left ventricular voltage mapping: a proof of principle. PMID- 23632117 TI - Full text view of the included articles for meta-analysis is important for cardiology journals. PMID- 23632118 TI - The time course of paroxysmal atrial fibrillation and its implications: an analysis from a snapshot. PMID- 23632119 TI - Molecular basis of disturbed extracellular matrix homeostasis in stress cardiomyopathy. PMID- 23632120 TI - Cardiac biomarkers and high altitude pulmonary edema. PMID- 23632121 TI - Soluble lectin-like oxidized LDL receptor-1 (sLOX-1) as a valuable diagnostic marker for rupture of thin-cap fibroatheroma: verification by optical coherence tomography. AB - BACKGROUND: Relationships between plaque morphology on optical coherence tomography (OCT) and biomarker levels in the patients with acute coronary syndrome (ACS) have not been fully investigated. METHODS: ACS patients (n=128) were prospectively enrolled and their plasma levels of soluble lectin-like oxidized LDL receptor-1 (sLOX-1), high-sensitivity C-reactive protein (hs-CRP), and high-sensitivity troponin T (hs-TnT) were measured. Another set of 20 patients with stable angina pectoris (SAP) without plaque rupture or erosion served as controls. Among 128 ACS patients, 75 patients underwent OCT procedure to evaluate culprit plaque morphology, and were categorized into two groups; ACS with plaque rupture (ruptured ACS; R-ACS, n=54) and ACS without plaque rupture (non-ruptured ACS; N-ACS, n=21). RESULTS: Levels of sLOX-1 (p<0.001), hs-CRP (p=0.048) and hs-TnT (p<0.001) were significantly higher in R-ACS than SAP. Levels of sLOX-1 were also significantly higher in R-ACS than in N-ACS (p<0.001); whereas levels of hs-CRP (p=0.675), as well as those of hs-TnT (p=0.055), were comparable between R-ACS and N-ACS. Comparison of receiver operating characteristic (ROC) curves among sLOX-1, hs-CRP and hs-TnT to differentiate R ACS from N-ACS revealed that the area under the curve (AUC) values of sLOX-1, hs CRP and hs-TnT were 0.782, 0.531 and 0.643, respectively. ROC curves, generated for these biomarkers, to differentiate ACS with thin-cap fibroatheroma (TCFA) from those without demonstrated that the AUC values of sLOX-1, hs-CRP and hs-TnT were 0.718, 0.506 and 0.524, respectively. CONCLUSION: sLOX-1, but not hs-CRP or hs-TnT, can differentiate ACS with plaque rupture from those without, and ACS with TCFA from those without. PMID- 23632122 TI - The "PAC-MAN" sign: an insidious complication after transcatheter aortic valve deployment. PMID- 23632123 TI - A large waterborne gastroenteritis outbreak in central Greece, March 2012: challenges for the investigation and management. AB - In March 2012, there was an unusual increase of gastroenteritis cases in a district with 37,264 inhabitants in central Greece. It was estimated that more than 3600 people developed symptoms. A 1:1 case-control study showed that consumption of tap water was a risk factor for acquiring infection [odds ratio (OR) 2.18, 95% confidence interval (CI) 1.11-4.28]. Descriptive data, low gastroenteritis incidence in adjacent areas with different water supply systems, and water-quality data further supported the hypothesis of a waterborne outbreak. Thirty-eight stool samples were positive for rotavirus. Bacterial indicators of recent faecal contamination were detected in samples from the water source and ice cubes from a local production enterprise. Molecular epidemiology of rotavirus strains, apart from the common strain, G3[P8], identified the unusual G/P combination G2P[8]. Water sanitation measures contributed to the control of the outbreak. This outbreak demonstrated the need for the cooperation of laboratories with different expertise and the importance of early notification of waterborne gastroenteritis outbreaks. PMID- 23632124 TI - The acceptability of meadow plants to the slug Deroceras reticulatum and implications for grassland restoration. AB - BACKGROUND AND AIMS: Despite the selective pressure slugs may exert on seedling recruitment there is a lack of information in this context within grassland restoration studies. Selective grazing is influenced by interspecific differences in acceptability. As part of a larger study of how slug-seedling interactions may influence upland hay meadow restoration, an assessment of relative acceptability is made for seedlings of meadow plants to the slug, Deroceras reticulatum. METHODS: Slug feeding damage to seedling monocultures of 23 meadow species and Brassica napus was assessed in microcosms over 14 d. The severity and rate of damage incurred by each plant species was analysed with a generalized additive mixed model. Plant species were then ranked for their relative acceptability. KEY RESULTS: Interspecific variation in relative acceptability suggested seedlings of meadow species form a hierarchy of acceptability to D. reticulatum. The four most acceptable species were Achillea millefolium and the grasses Holcus lanatus, Poa trivialis and Festuca rubra. Trifolium pratense was acceptable to D. reticulatum and was the second highest ranking forb species. The most unacceptable species were mainly forbs associated with the target grassland, and included Geranium sylvaticum, Rumex acetosa, Leontodon hispidus and the grass Anthoxanthum odoratum. A strong positive correlation was found for mean cumulative feeding damage and cumulative seedling mortality at day 14. CONCLUSIONS: Highly unacceptable species to D. reticulatum are unlikely to be selectively grazed by slugs during the seedling recruitment phase, and were predominantly target restoration species. Seedlings of highly acceptable species may be less likely to survive slug herbivory and contribute to seedling recruitment at restoration sites. Selective slug herbivory, influenced by acceptability, may influence community-level processes if seedling recruitment and establishment of key functional species, such as T. pratense is reduced. PMID- 23632125 TI - Formation, signaling functions, and metabolisms of nitrated cyclic nucleotide. AB - 8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is a unique derivative of guanosine 3',5'-cyclic monophosphate (cGMP) formed in mammalian and plant cells in response to production of nitric oxide and reactive oxygen species. 8 Nitro-cGMP possesses signaling activity inherited from parental cGMP, including induction of vasorelaxation through activation of cGMP-dependent protein kinase. On the other hand, 8-nitro-cGMP mediates cellular signaling that is not observed for native cGMP, e.g., it behaves as an electrophile and reacts with protein sulfhydryls, which results in cGMP adduction to protein sulfhydryls (protein S guanylation). Several proteins have been identified as targets for endogenous protein S-guanylation, including Kelch-like ECH-associated protein 1 (Keap1), H Ras, and mitochondrial heat shock proteins. 8-Nitro-cGMP signaling via protein S guanylation of those proteins may have evolved to convey adaptive cellular stress responses. 8-Nitro-cGMP may not undergo conventional cGMP metabolism because of its resistance to phosphodiesterases. Hydrogen sulfide has recently been identified as a potent regulator for metabolisms of electrophiles including 8 nitro-cGMP, through sulfhydration of electrophiles, e.g., leading to the formation of 8-SH-cGMP. Better understanding of the molecular basis for the formation, signaling functions, and metabolisms of 8-nitro-cGMP would be useful for the development of new diagnostic approaches and treatment of diseases related to oxidative stress and redox metabolisms. PMID- 23632127 TI - Role of MRI in patient selection for surgical treatment of intractable epilepsy in infancy. AB - Epilepsy surgery is an effective treatment in selected patients with localization related intractable epilepsy. The success of epilepsy surgery is in part dependent upon identification of a lesion on MRI. In infants, the surgical epileptogenic substrates include focal cortical dysplasia (FCD), hemimegalencephaly, tuberous sclerosis complex, Sturge Weber syndrome, hypoxic ischemic or cerebrovascular injury and low-grade tumor. The sensitivity of MRI in identifying the epileptogenic substrate is influenced by the nature of the epileptogenic substrate, MRI technique and expertise of the interpreting physician. The MRI features of some lesions such as FCD may differ in infants compared to children and adults; the white matter adjacent to FCD may demonstrate lower T2 and higher T1 signal in some infants due to premature myelination, while in others, the white matter demonstrates higher T2 or lower T1 signal due to demyelination, dysmyelination or gliosis, similar to children and adults. The appearances of some lesions, such as FCD, may change with time, due to brain maturation or seizure related changes. MRI for patients with localization-related intractable epilepsy should have high-resolution, multiplanar and multisequence. In infants, volumetric T1 and high-resolution T2 imaging are recommended. FLAIR and proton density sequences are less helpful in infants due to lack of myelin in the white matter. The physician interpreting the scan should be familiar with the imaging appearances of epileptogenic substrates and may need to review the scan more than once if a lesion is not seen on initial inspection. PMID- 23632126 TI - Risk of incident diabetes in relation to long-term exposure to fine particulate matter in Ontario, Canada. AB - BACKGROUND: Laboratory studies suggest that fine particulate matter (<= 2.5 um in diameter; PM(2.5)) can activate pathophysiological responses that may induce insulin resistance and type 2 diabetes. However, epidemiological evidence relating PM2.5 and diabetes is sparse, particularly for incident diabetes. OBJECTIVES: We conducted a population-based cohort study to determine whether long-term exposure to ambient PM(2.5) is associated with incident diabetes. METHODS: We assembled a cohort of 62,012 nondiabetic adults who lived in Ontario, Canada, and completed one of five population-based health surveys between 1996 and 2005. Follow-up extended until 31 December 2010. Incident diabetes diagnosed between 1996 and 2010 was ascertained using the Ontario Diabetes Database, a validated registry of persons diagnosed with diabetes (sensitivity = 86%, specificity = 97%). Six-year average concentrations of PM2.5 at the postal codes of baseline residences were derived from satellite observations. We used Cox proportional hazards models to estimate the associations, adjusting for various individual-level risk factors and contextual covariates such as smoking, body mass index, physical activity, and neighborhood-level household income. We also conducted multiple sensitivity analyses. In addition, we examined effect modification for selected comorbidities and sociodemographic characteristics. RESULTS: There were 6,310 incident cases of diabetes over 484,644 total person years of follow-up. The adjusted hazard ratio for a 10-ug/m(3) increase in PM(2.5) was 1.11 (95% CI: 1.02, 1.21). Estimated associations were comparable among all sensitivity analyses. We did not find strong evidence of effect modification by comorbidities or sociodemographic covariates. CONCLUSIONS: This study suggests that long-term exposure to PM2.5 may contribute to the development of diabetes. PMID- 23632128 TI - Safety and efficacy of intravenous infusion of allogeneic cryopreserved mesenchymal stem cells for treatment of chronic kidney disease in cats: results of three sequential pilot studies. AB - INTRODUCTION: Administration of mesenchymal stem cells (MSCs) has been shown to improve renal function in rodent models of chronic kidney disease (CKD), in part by reducing intrarenal inflammation and suppressing fibrosis. CKD in cats is characterized by tubulointerstitial inflammation and fibrosis, and thus treatment with MSCs might improve renal function and urinary markers of inflammation in this disease. Therefore, a series of pilot studies was conducted to assess the safety and efficacy of intravenous administration of allogeneic adipose-derived MSCs (aMSCs) in cats with naturally occurring CKD. METHODS: Cats enrolled in these studies received an intravenous infusion of allogeneic aMSCs every 2 weeks collected from healthy, young, specific pathogen-free cats. Cats in pilot study 1 (six cats) received 2 * 106 cryopreserved aMSCs per infusion, cats in pilot study 2 (five cats) received 4 * 106 cryopreserved aMSCs per infusion, and cats in pilot study 3 (five cats) received 4 * 106 aMSCs cultured from cryopreserved adipose. Serum biochemistry, complete blood count, urinalysis, urine protein, glomerular filtration rate, and urinary cytokine concentrations were monitored during the treatment period. Changes in clinical parameters were compared statistically by means of repeated measures analysis of variance (ANOVA) followed by Bonferroni's correction. RESULTS: Cats in pilot study 1 had few adverse effects from the aMSC infusions and there was a statistically significant decrease in serum creatinine concentrations during the study period, however the degree of decrease seems unlikely to be clinically relevant. Adverse effects of the aMSC infusion in cats in pilot study 2 included vomiting (2/5 cats) during infusion and increased respiratory rate and effort (4/5 cats). Cats in pilot study 3 did not experience any adverse side effects. Serum creatinine concentrations and glomerular filtration rates did not change significantly in cats in pilot studies 2 and 3. CONCLUSIONS: Administration of cryopreserved aMSCs was associated with significant adverse effects and no discernible clinically relevant improvement in renal functional parameters. Administration of aMSCs cultured from cryopreserved adipose was not associated with adverse effects, but was also not associated with improvement in renal functional parameters. PMID- 23632130 TI - Key drug use, health and socio-economic characteristics of young crack users in two Brazilian cities. AB - BACKGROUND: Crack use constitutes a major problem in cities across Brazil. While existing data suggest that crack use is generally concentrated among disenfranchised young people with extensive health problems and crime involvement, extensive data gaps exist. To address this issue, this study aimed to assess key characteristics of young crack users in two Brazilian cities. METHODS: N=160 regular and young adult (ages 18-24) crack users were recruited by community-based methods in the cities of Rio de Janeiro (Southeast) and Salvador (Northeast). Assessments included an interviewer-administered questionnaire on key social, drug use, health and service use characteristics, as well as serological testing of HBV, HCV and HIV status, and were conducted anonymously between November 2010 and June 2011. Participants provided informed consent and received transportation vouchers following assessment completion. The study was approved by institutional ethics review boards. RESULTS: The majority of participants were: male, with less than high school education, unstably housed (Rio only); gained income from legal or illegal work; arrested by police in past year (Salvador only); had numerous daily crack use episodes and shared paraphernalia (Salvador only); co-used alcohol, tobacco, cannabis and cocaine; had no injection history; rated physical and mental health as 'fair' or lower (Salvador only); had unprotected sex; were never HIV tested; were not HIV, HBV or HCV positive; and did not use existing social or health services, but desired access to crack user specific services. CONCLUSION: Crack users in the two Brazilian sites featured extensive socio-economic marginalization, crack and poly drug use as well as sexual risk behaviours, and compromised health status. Social and health service utilization are low, yet needs are high. There is an urgent need for further research and for targeted interventions for crack use in Brazil. PMID- 23632129 TI - Largazole, a class I histone deacetylase inhibitor, enhances TNF-alpha-induced ICAM-1 and VCAM-1 expression in rheumatoid arthritis synovial fibroblasts. AB - In the present study, we evaluated the effect of largazole (LAR), a marine derived class I HDAC inhibitor, on tumor necrosis factor-alpha (TNF-alpha) induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and matrix metalloproteinase-2 (MMP-2) activity. LAR (1-5 MUM) had no adverse effect on the viability of RA synovial fibroblasts. Among the different class I HDACs screened, LAR (0.5-5 MUM) inhibited the constitutive expression of HDAC1 (0-30%). Surprisingly, LAR increased class II HDAC [HDAC6] by ~220% with a concomitant decrease in HDAC5 [30 58%] expression in RA synovial fibroblasts. SAHA (5 MUM), a pan-HDAC inhibitor, also induced HDAC6 expression in RA synovial fibroblasts. Pretreatment of RA synovial fibroblasts with LAR further enhanced TNF-alpha-induced ICAM-1 and VCAM 1 expression. However, LAR inhibited TNF-alpha-induced MMP-2 activity in RA synovial fibroblasts by 35% when compared to the TNF-alpha-treated group. Further, the addition of HDAC6 specific inhibitor Tubastatin A with LAR suppressed TNF-alpha+LAR-induced ICAM-1 and VCAM-1 expression and completely blocked MMP-2 activity, suggesting a role of HDAC6 in LAR-induced ICAM-1 and VCAM 1 expression. LAR also enhanced TNF-alpha-induced phospho-p38 and phospho-AKT expression, but inhibited the expression of phospho-JNK and nuclear translocation of NF-kappaBp65 in RA synovial fibroblasts. These results suggest that LAR activates p38 and Akt pathways and influences class II HDACs, in particular HDAC6, to enhance some of the detrimental effects of TNF-alpha in RA synovial fibroblasts. Understanding the exact role of different HDAC isoenzymes in RA pathogenesis is extremely important in order to develop highly effective HDAC inhibitors for the treatment of RA. PMID- 23632131 TI - The effect of a no-denial policy on imaging utilization. AB - PURPOSE: Seeking to control advanced diagnostic imaging costs, health insurance plans have instituted broad-based utilization management systems. Most processes ultimately contain denial provisions, meaning that the health plans will refuse to pay for requested studies if performed. The aim of this analysis was to determine whether removal of a denial provision would result in increased utilization of imaging services. METHODS: A major US health plan used a no-denial preauthorization system in all but 4 geographic markets for all CT, MRI, PET, and nuclear cardiac imaging studies, constituting the experimental group. This study consisted of a retrospective review of 247,117 advanced imaging requests 21 months before and 16 months after the elimination of the denial provision in the experimental group. A matched population with no such change in the review process served as the control group. Population-normalized utilization rates were measured for both pooled groups before and after the change. RESULTS: Utilization decreased slightly more in the experimental group than in the control group ( 0.10 requests per 1,000 covered lives; 95% confidence interval, -0.20 to 0.00; P = .050) after elimination of the denial provision. The rates of request approval, examination modification, withdrawal, and no consensus after peer-to-peer consultation did not significantly change. CONCLUSIONS: Eliminating denial provisions in utilization management for advanced diagnostic imaging does not result in increased utilization of such imaging. PMID- 23632132 TI - ACR appropriateness criteria jaundice. AB - A fundamental consideration in the workup of a jaundiced patient is the pretest probability of mechanical obstruction. Ultrasound is the first-line modality to exclude biliary tract obstruction. When mechanical obstruction is present, additional imaging with CT or MRI can clarify etiology, define level of obstruction, stage disease, and guide intervention. When mechanical obstruction is absent, additional imaging can evaluate liver parenchyma for fat and iron deposition and help direct biopsy in cases where underlying parenchymal disease or mass is found. Imaging techniques are reviewed for the following clinical scenarios: (1) the patient with painful jaundice, (2) the patient with painless jaundice, and (3) the patient with a nonmechanical cause for jaundice. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 23632133 TI - Analysis of radiologists' imaging workload trends by place of service. AB - PURPOSE: The aim of this study was to determine what proportion of noninvasive diagnostic imaging (NDI) work done by radiologists occurred in each of the 4 primary places of service where imaging is conducted. METHODS: Medicare's Physician/Supplier Procedure Summary Master Files for 2000 to 2011 were the data source. Specialty codes were used to identify radiologists, and place-of-service codes identified studies done in hospital outpatient facilities, hospital inpatient facilities, private offices, and emergency departments (EDs). The applicable total professional component relative value units (RVUs) were assigned to each NDI Current Procedural Terminology code, and RVU rates per 1,000 Medicare beneficiaries were calculated. RVU rates reflect workload and costs and are therefore a better metric than utilization rates based on volume. RESULTS: From 2000 to 2006, radiologists' RVU rates per 1,000 Medicare beneficiaries increased in each of the 4 primary venues. However, from 2006 to 2011, rates remained essentially flat in hospital outpatient and inpatient facilities and offices but continued to increase in EDs. Absolute RVU rate increases from 2000 through 2011 were 289 in hospital outpatient facilities, 218 in EDs, 194 in private offices, and 99 in inpatient facilities. In 2011, 19% of radiologists' workload occurred in offices; the remainder was conducted in the 3 hospital settings. Twice as much elective outpatient NDI work by radiologists was done in hospital outpatient facilities as in radiologists' private offices. CONCLUSIONS: Radiologists' workload in hospital outpatient and inpatient facilities and offices grew from 2000 through 2006, but no further growth occurred thereafter. EDs were the only venue where growth continued. The vast proportion of radiology NDI RVUs (81% in 2011) are produced in hospital settings. PMID- 23632134 TI - Measurement of depressive symptoms among cardiac patients: should sex differences be considered? AB - Confounding of depressive and cardiac symptoms may hold implications for assessment. This study investigated psychometric properties and sex differences in two depression scales among cardiac patients. Cardiac inpatients from 11 hospitals were recruited and completed a mailed survey including the Beck Depression Inventory-II and Gotland Scale of Male Depression 1 year later. The scales were significantly correlated and both were associated with social desirability. Females scored higher than males on the fatigue factor only (p < .001). Psychometric properties of the Beck Depression Inventory-II were more favorable in this population. Practitioners must not overlook reports of fatigue in female cardiac patients. PMID- 23632135 TI - Struggle with the divine in Swiss patients visited by chaplains: prevalence and correlates. AB - A body of evidence is developing that describes harmful effects of religious struggle that includes struggle with the divine (e.g. feeling abandoned or punished by God). We examined the prevalence and correlates of divine struggle among 540 Swiss hospital patients. Some divine struggle was reported by 46 percent of the sample. Unexpected hospital admission and scores on a measure of faith were associated with a greater likelihood of reporting any divine struggle. Higher levels of anxiety and depression were also associated with divine struggle. Screening for divine struggle or other forms of religious struggle will permit, where indicated, appropriate religious assessment and care to mitigate the harmful effects that may accompany religious struggle. PMID- 23632136 TI - The role of specific and core dysfunctional beliefs in breast cancer radiotherapy patients' fatigue. AB - The goal of the study was to examine the relationships among fatigue catastrophizing, core dysfunctional beliefs, and fatigue in breast cancer radiotherapy patients. Seventy-eight patients participated in the study (mean age = 56.3, standard deviation = 10.5). Patients completed questionnaires on fatigue catastrophizing, core dysfunctional beliefs, and fatigue in their last week of radiotherapy. Using bootstrapping procedures to obtain estimates and confidence intervals for indirect effects, results showed that core beliefs (Need for Comfort and Demandingness for Fairness) had significant indirect effects on fatigue through fatigue catastrophizing, as indicated by the 95 percent confidence interval (.02-.19 for Need for Comfort; .01-.16 for Demandingness for Fairness). PMID- 23632137 TI - In vitro reconstruction and functional development of the superior colliculus in the retinotectal pathway. AB - In order to examine the formation of a neural network and the functional development of a visual pathway, we performed in vitro reconstruction of the retinotectal pathway using organotypic explants and co-culture methods. Retinas and superior colliculus (SC) slices obtained from embryonic rats were co-cultured on microelectrode array (MEA) substrates for four weeks. We observed retinal ganglion cell neurites innervating SC slices that evoked responses in retinas or SC slices after applying electrical stimulation. Functional connections between retinas and SC slices were formed in the cultures. At the same time, spontaneous electrical activities were recorded from both the retinas and SC slices over the four weeks. In the co-cultured SC slices, sporadic firings were initially observed at 3-4 days in vitro (DIV), and thereafter the frequency of spontaneous firing increased and synchronized activities occurred after two weeks in vitro (WIV). In most of the single-cultured SC slices, however, only sporadic firings were observed over four weeks. In addition, the retinas and SC slices were co cultured to enable the exchange of soluble factors with each other via culture medium but not via direct neural connections. The activity patterns resembled ones of single-cultured SC slices. These results suggest that signal inputs from retinas through direct neural connections affect the development of SCs in the retinotectal pathway. PMID- 23632138 TI - Is the speed of chronic compression an important factor for chronic spinal cord injury rat model? AB - OBJECTIVE: To evaluate the effect of expansion speed on chronic compressive spinal cord injury in the rat. METHODS: Thirty-six Sprague-Dawley rats were divided into four groups: a control group, a group receiving compressor in the C5 C6 epidural space with instant compression (group 1), and two other groups receiving water-absorbing polyurethane polymer sheets with two expansion speeds, which reached maximum volume in 2 h (group 2: fast expansion) or 24 h (group 3: slow expansion). A C6 laminectomy was performed in the control group. Neurological function, MRI, large motoneuron number in the ventral horn, and myelin staining intensity in the posterior funiculus were evaluated. RESULTS: In the instant compression group, compression was confirmed on T2-weighted images by a hypointense signal change in the intramedulla. In the gradual compressive injury groups, large motoneuron number (p<0.001), but not myelin staining intensity, was significantly decreased in both the fast and slow expansion groups compared with the instant compression group. However, there was no difference in Basso Beattie Bresnahan score, cord distortion in T2-weighted image, large motoneuron numbers, or myelin staining between the fast and slow expansion groups. CONCLUSION: Instant spinal cord compression caused acute injury. Gradual expansion compression induced reliable pathology and MRI characteristics consistent with chronic compressive spinal cord injury. The speed of expansion is not a significant problem for establishing a reliable model if the chronic compression is induced by gradual expansion. PMID- 23632139 TI - Prioritizing investment in public health and health equity: what can commissioners do? AB - OBJECTIVES: To explore commissioners' views on prioritizing for investment in health. This study reviewed: methods for decision support; their relevance for prioritizing health and health equity in principle; and their adoption by decision makers in practice. METHODS: Decision makers' views were sought through semi-structured interviews and an online survey, and prioritization tools were reviewed. Interviews were held in 2008-2009 with a subsample followed up in 2009 2010. In late 2009, a national online survey was sent to 508 individuals across 146 primary care trusts (PCTs). The two phases of the interviews comprised 52 and 17 participants, respectively. Responses to the national survey were received from 138 decision makers in 95 (65%) PCTs. Prioritization tools were identified through interviews and the survey as above, a rapid review of literature and in consultation with health economists. A grounded theory approach was adopted for the qualitative interview analysis. RESULTS: Although most PCTs used a prioritization framework, few of the tools identified in this review were used by public health commissioners. This was partly a consequence of limitations of priority-setting tools in the context of public health investment, and partly a lack of relevant skills and data. Tensions in relation to developing strategies for disinvestment and in prioritizing a long-term public health agenda in a context of economic austerity were evident. CONCLUSIONS: The context for decision making appears to be more important than the deployment of specific tools and techniques. Commissioners need to recognize the limitations of priority-setting tools, but also know how to apply them to help maximize health gain and health equity over the longer term. Decision-support tools should be developed in collaboration with public health commissioners to ensure relevance and practicality of use. PMID- 23632140 TI - From the editors: Saul Steinberg's message. PMID- 23632141 TI - The association between teenage motherhood and poor offspring outcomes: a national cohort study across 30 years. AB - Teenage motherhood is associated with poor offspring outcomes but these associations may be influenced by offspring birth year because of substantial social changes in recent decades. Existing research also has not examined whether these associations are due to the specific effect of mother's age at childbirth or factors shared by siblings in a family. We used a population-based cohort study in Sweden comprising all children born from 1960 to 1989 (N = 3,162,239), and a subsample of siblings differentially exposed to maternal teenage childbearing (N = 485,259) to address these limitations. We examined the effect of teenage childbearing on offspring violent and non-violent criminal convictions, poor academic performance, and substance-related problems. Population-wide teenage childbearing was associated with offspring criminal convictions, poor academic performance, and substance-related problems. The magnitude of these associations increased over time. Comparisons of differentially exposed siblings indicated no within-family association between teenage childbearing and offspring violent and non-violent criminal convictions or poor academic performance, although offspring born to teenage mothers were more likely to experience substance-related problems than their later-born siblings. Being born to a teenage mother in Sweden has become increasingly associated with negative outcomes across time, but the nature of this association may differ by outcome. Teenage childbearing may be associated with offspring violent and non-violent criminal convictions and poor academic performance because of shared familial risk factors, but may be causally associated with offspring substance-related problems. The findings suggest that interventions to improve offspring outcomes should delay teenage childbearing and also target risk factors influencing all offspring of teenage mothers. PMID- 23632142 TI - Exercise for depression in care home residents: a randomised controlled trial with cost-effectiveness analysis (OPERA). AB - BACKGROUND: Many older people living in care homes (long term residential care or nursing homes) are depressed. Exercise is a promising non-drug intervention for preventing and treating depression in this population. OBJECTIVE: To evaluate the impact of a 'whole-home' intervention, consisting of training for residential and nursing home staff backed up with a twice-weekly, physiotherapist-led exercise class on depressive symptoms in care home residents. DESIGN: A cluster randomised controlled trial with a cost-effectiveness analysis to compare (1) the prevalence of depression in intervention homes with that in control homes in all residents contributing data 12 months after homes were randomised (cross-sectional analysis); (2) the number of depressive symptoms at 6 months between intervention and control homes in residents who were depressed at pre-randomisation baseline assessment (depressed cohort comparison); and (3) the number of depressive symptoms at 12 months between intervention and control homes in all residents who were present at pre-randomisation baseline assessment (cohort comparison). SETTING: Seventy-eight care homes in Coventry and Warwickshire and north-east London. PARTICIPANTS: Care home residents aged >= 65 years. INTERVENTIONS: Control intervention: Depression awareness training programme for care home staff. Active intervention: A 'whole-home' exercise intervention, consisting of training for care home staff backed up with a twice-weekly, physiotherapist-led exercise group. MAIN OUTCOME MEASURES: Geriatric Depression Scale-15, proxy European Quality of Life-5 Dimensions (EQ-5D), cost-effectiveness from an National Health Service perspective, peripheral fractures and death. RESULTS: We recruited a total of 1054 participants. Cross-sectional analysis: We obtained 595 Geriatric Depression Scale-15 scores and 724 proxy EQ-5D scores. For the cohort analyses we obtained 765 baseline Geriatric Depression Scale-15 scores and 776 proxy EQ-5D scores. Of the 781 who we assessed prior to randomisation, 765 provided a Geriatric Depression Scale-15 score. Of these 374 (49%) were depressed and constitute our depressed cohort. Resource-use and quality-adjusted life-year data, based on proxy EQ-5D, were available for 798 residents recruited prior to randomisation. We delivered 3191 group exercise sessions with 31,705 person attendances and an average group size of 10 (5.3 study participants and 4.6 non study participants). On average, our participants attended around half of the possible sessions. No serious adverse events occurred during the group exercise sessions. In the cross-sectional analysis the odds for being depressed were 0.76 [95% confidence interval (CI) 0.53 to 1.09] lower in the intervention group at 12 months. The point estimates for benefit for both the cohort analysis (0.13, 95% CI -0.33 to 0.60) and depressed cohort (0.22, 95% CI -0.52 to 0.95) favoured the control intervention. There was no evidence of differences in fracture rates or mortality (odds ratio 1.07, 95% CI 0.79 to 1.48) between the two groups. There was no evidence of differences in the other outcomes between the two groups. Economic analysis: The additional National Health Service cost of the OPERA intervention was L374 per participant (95% CI -L655 to L1404); the mean difference in quality-adjusted life-year was -0.0014 (95% CI -0.0728 to 0.0699). The active intervention was thus dominated by the control intervention, which was more effective and less costly. CONCLUSION: The results do not support the use of a whole-home physical activity and moderate-intensity exercise programme to reduce depression in care home residents. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43769277. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 18. See the Health Technology Assessment programme website for further project information. PMID- 23632143 TI - The new revised classification of acute pancreatitis 2012. AB - This study aims to update the 1991 Atlanta Classification of acute pancreatitis, to standardize the reporting of and terminology of the disease and its complications. Important features of this classification have incorporated new insights into the disease learned over the last 20 years, including the recognition that acute pancreatitis and its complications involve a dynamic process involving two phases, early and late. The accurate and consistent description of acute pancreatitis will help to improve the stratification and reporting of new methods of care of acute pancreatitis across different practices, geographic areas, and countries. PMID- 23632144 TI - Endoscopic management of acute pancreatitis. AB - Patients presenting with acute pancreatitis can be complex on different levels. Having a multifaceted approach to these patients is often necessary with radiographic, endoscopic, and surgical modalities all working to benefit the patient. Major surgical intervention can often be avoided or augmented by therapeutic and diagnostic endoscopic maneuvers. The diagnostic role of endoscopy in patients presenting with acute idiopathic pancreatitis can help define specific causative factors and ameliorate symptoms by endoscopic maneuvers. Etiologies of an acute pancreatitis episode, such as choledocholithiasis with or without concomitant cholangitis, microlithiasis or biliary sludge, and anatomic anomalies, such as pancreas divisum and pancreatobiliary ductal anomalies, often improve after endoscopic therapy. PMID- 23632145 TI - The role of antimicrobial therapy in severe acute pancreatitis. AB - The role of antimicrobial therapy in patients with severe acute pancreatitis is to treat secondary pancreatic infections to prevent systemic sepsis and death. Infected pancreatic necrosis is diagnosed using image-directed fine needle aspiration with culture and Gram's stain. Prophylactic antibiotics have not proven efficacious, while the precise timely detection of secondary pancreatic infections is often elusive. A high clinical index of suspicion should prompt the empiric initiation of antimicrobial therapy until culture results are available. Positive cultures should guide antimicrobial therapy, and for infected pancreatic necrosis, antibiotics should be used in conjunction with interventional techniques for source control. PMID- 23632146 TI - Operative management of acute pancreatitis. AB - Acute pancreatitis comprises a range of diseases. Clinical manifestations range from mild symptoms to a life-threatening or life-ending process. Operative management is focused on managing the acute complications, the long-term sequelae, or the prevention of recurrent pancreatitis. Using the least amount of intervention is the goal. However, the evolution of videoscopic and endoscopic techniques have greatly expanded the tools available. This article provides a review of the three major categories of operations: ameliorating the emergent problems associated with the inflammatory state, ameliorating chronic sequelae, and prevention of a subsequent episode. PMID- 23632147 TI - Management of pancreatic fistulas. AB - The management of pancreatic fistulas can be complex and mandates a multidisciplinary approach. Basic principles of fistula control/patient stabilization, delineation of ductal anatomy, and definitive therapy remain of paramount importance. PMID- 23632148 TI - Type 2 diabetes mellitus and pancreatic cancer. AB - Tumorigenesis of pancreatic cancer (PC) and the pathophysiology of type 2 diabetes mellitus (DM2) are emerging as intertwined pathways. As the operative morbidity and mortality of pancreatectomy has improved, incidence has increased and survival has remained mostly unchanged. The diagnosis of DM2 suggests pancreatic dysfunction and possible early carcinogenesis. DM2 is a significant comorbidity predicting worse outcomes in patients undergoing pancreatic resection as part of the treatment of PC. This article examines this phenomena and suggests possible approaches to screening and diagnosis. PMID- 23632149 TI - Screening and surgical outcomes of familial pancreatic cancer. AB - This article reviews the genetics and incipient pathology of familial pancreatic cancer and the screening modalities in current use, and summarizes the outcomes of reported screening programs. PMID- 23632150 TI - Resection margins in pancreatic cancer. AB - Controversy regarding various aspects of microscopic margin involvement (R1) in pancreatic cancer has resulted in conflicting published data on the R1 rate and the prognostic significance of margin involvement. This article discusses the current lack of consensus regarding the definition and diagnostic criteria of R1 resection, the terminology for the various surgical margins, and the pathology grossing technique. Recent developments in pathology examination that allow a more accurate margin assessment are described. Furthermore, the need of a quality assurance system that ensures robustness and comparability of data on resection margins in pancreatic cancer is highlighted. PMID- 23632151 TI - How to define and manage borderline resectable pancreatic cancer. AB - Historically, borderline resectable (BLR) pancreatic cancer has had many definitions, which has made interpretation of treatment data and outcomes difficult. Advances in imaging, surgical technique, and the potential benefit of neoadjuvant therapy have emphasized the need for uniform classification. Despite recent efforts to provide a clearer definition, prospective randomized trials are lacking in the literature. This article reviews current definitions, treatment sequences, outcomes, and prognostic factors associated with BLR pancreatic cancer. Further clarification and consensus on the definition of BLR pancreatic cancer will allow for further data collection and cooperation in future efforts to make progress and standardize treatment. PMID- 23632152 TI - Management of pancreatic neuroendocrine tumors. AB - Pancreatic neuroendocrine tumors account for 1% to 2% of pancreatic neoplasms and may occur sporadically or as part of a hereditary syndrome. Patients may present with symptoms related to hormone secretion by functional tumors or to locally advanced or metastatic nonfunctional tumors. Asymptomatic pancreatic neuroendocrine tumors are increasingly detected incidentally during abdominal imaging performed for other reasons. The management of localized pancreatic neuroendocrine tumors is surgical resection. Hepatic metastases are common and their management involves a variety of liver-directed therapies, which should be tailored according to extent of disease, symptoms, presence of extrahepatic metastases, and patient performance status. PMID- 23632153 TI - Quality metrics in pancreatic surgery. AB - As the practice of pancreatic surgery evolves to encompass a wider array of clinical indications, incorporate increasingly complex technologies, and provide care to an aging population with many comorbid conditions, systematic assessment of quality and outcomes in an effort to improve the quality of care is imperative. This article discusses the volume-outcomes relationship that exists in pancreatic surgery, trends in centralization of practice within the field, common outcomes measures, and the complexity of assessing quality metrics. It also highlights surgical outcomes from several high-volume institutions and recent developments in quality metrics within pancreatic surgery. PMID- 23632154 TI - The economics of pancreas surgery. AB - Pancreas surgery is a paradigm for high-acuity surgical specialization. Given the current intrigue over containing health care expenditures, pancreas surgery provides an ideal model to investigate the cost of care. This article explores the economics of this field from literature accrued over the last 2 decades. The cost of performing a pancreatic resection is established and then embellished with a discussion of the effects of clinical care paths. Then the influence of complications on costs is explored. Next, cost is investigated as an emerging outcome metric regarding variations in pancreatic surgical care. Finally, the societal-level fiscal impact is considered. PMID- 23632155 TI - Modern concepts in pancreatic surgery. PMID- 23632156 TI - Modern concepts in pancreatic surgery. PMID- 23632157 TI - Zebrafish scales respond differently to in vitro dynamic and static acceleration: analysis of interaction between osteoblasts and osteoclasts. AB - Zebrafish scales consist of bone-forming osteoblasts, bone-resorbing osteoclasts, and calcified bone matrix. To elucidate the underlying molecular mechanism of the effects induced by dynamic and static acceleration, we investigated the scale osteoblast- and osteoclast-specific marker gene expression involving osteoblast osteoclast communication molecules. Osteoblasts express RANKL, which binds to the osteoclast surface receptor, RANK, and stimulates bone resorption. OPG, on the other hand, is secreted by osteoblast as a decoy receptor for RANKL, prevents RANKL from binding to RANK and thus prevents bone resorption. Therefore, the RANK RANKL-OPG pathway contributes to the regulation of osteoclastogenesis by osteoblasts. Semaphorin 4D, in contrast, is expressed on osteoclasts, and binding to its receptor Plexin-B1 on osteoblasts results in suppression of bone formation. In the present study, we found that both dynamic and static acceleration at 3.0*g decreased RANKL/OPG ratio and increased osteoblast-specific functional mRNA such as alkaline phosphatase, while static acceleration increased and dynamic acceleration decreased osteoclast-specific mRNA such as cathepsin K. Static acceleration increased semaphorin 4D mRNA expression, while dynamic acceleration had no effect. The results of the present study indicated that osteoclasts have predominant control over bone metabolism via semaphorin 4D expression induced by static acceleration at 3.0*g. PMID- 23632159 TI - Detecting subarachnoid hemorrhage: comparison of combined FLAIR/SWI versus CT. AB - OBJECTIVES: Aim of this study was to compare the utility of susceptibility weighted imaging (SWI) with the established diagnostic techniques CT and fluid attenuated inversion recovery (FLAIR) in their detecting capacity of subarachnoid hemorrhage (SAH), and further to compare the combined SWI/FLAIR MRI data with CT to evaluate whether MRI is more accurate than CT. METHODS: Twenty-five patients with acute SAH underwent CT and MRI within 6 days after symptom onset. Underlying pathology for SAH was head trauma (n=9), ruptured aneurysm (n=6), ruptured arteriovenous malformation (n=2), and spontaneous bleeding (n=8). SWI, FLAIR, and CT data were analyzed. The anatomical distribution of SAH was subdivided into 8 subarachnoid regions with three peripheral cisterns (frontal-parietal, temporal occipital, sylvian), two central cisterns and spaces (interhemispheric, intraventricular), and the perimesencephalic, posterior fossa, superior cerebellar cisterns. RESULTS: SAH was detected in a total of 146 subarachnoid regions. CT identified 110 (75.3%), FLAIR 127 (87%), and SWI 129 (88.4%) involved regions. Combined FLAIR and SWI identified all 146 detectable regions (100%). FLAIR was sensitive for frontal-parietal, temporal-occipital and Sylvian cistern SAH, while SWI was particularly sensitive for interhemispheric and intraventricular hemorrhage. CONCLUSIONS: By combining SWI and FLAIR, MRI yields a distinctly higher detection rate for SAH than CT alone, particularly due to their complementary detection characteristics in different anatomical regions. Detection strength of SWI is high in central areas, whereas FLAIR shows a better detection rate in peripheral areas. PMID- 23632158 TI - Attack of the nervous system by Clostridium perfringens Epsilon toxin: from disease to mode of action on neural cells. AB - Epsilon toxin (ET), produced by Clostridium perfringens types B and D, ranks among the four most potent poisonous substances known so far. ET-intoxication is responsible for enterotoxaemia in animals, mainly sheep and goats. This disease comprises several manifestations indicating the attack of the nervous system. This review aims to summarize the effects of ET on central nervous system. ET binds to endothelial cells of brain capillary vessels before passing through the blood-brain barrier. Therefore, it induces perivascular oedema and accumulates into brain. ET binding to different brain structures and to different component in the brain indicates regional susceptibility to the toxin. Histological examination has revealed nerve tissue and cellular lesions, which may be directly or indirectly caused by ET. The naturally occurring disease caused by ET intoxication can be reproduced experimentally in rodents. In mice and rats, ET recognizes receptor at the surface of different neural cell types, including certain neurons (e.g. the granule cells in cerebellum) as well as oligodendrocytes, which are the glial cells responsible for the axons myelination. Moreover, ET induces release of glutamate and other transmitters, leading to firing of neural network. The precise mode of action of ET on neural cells remains to be determined. PMID- 23632160 TI - Blood lead levels and serum insulin-like growth factor 1 concentrations in peripubertal boys. AB - BACKGROUND: Childhood lead exposure has been associated with growth delay. However, the association between blood lead levels (BLLs) and insulin-like growth factor 1 (IGF-1) has not been characterized in a large cohort with low-level lead exposure. METHODS: We recruited 394 boys 8-9 years of age from an industrial Russian town in 2003-2005 and followed them annually thereafter. We used linear regression models to estimate the association of baseline BLLs with serum IGF-1 concentration at two follow-up visits (ages 10-11 and 12-13 years), adjusting for demographic and socioeconomic covariates. RESULTS: At study entry, median BLL was 3 MUg/dL (range, < 0.5-31 MUg/dL), most boys (86%) were prepubertal, and mean +/- SD height and BMI z-scores were 0.14 +/- 1.0 and -0.2 +/- 1.3, respectively. After adjustment for covariates, the mean follow-up IGF-1 concentration was 29.2 ng/mL lower (95% CI: -43.8, -14.5) for boys with high versus low BLL (>= 5 MUg/dL or < 5 MUg/dL); this difference persisted after further adjustment for pubertal status. The association of BLL with IGF-1 was stronger for mid-pubertal than prepubertal boys (p = 0.04). Relative to boys with BLLs < 2 MUg/dL, adjusted mean IGF-1 concentrations decreased by 12.8 ng/mL (95% CI: -29.9, 4.4) for boys with BLLs of 3-4 MUg/dL; 34.5 ng/mL (95% CI: -53.1, -16.0) for BLLs 5-9 MUg/dL; and 60.4 ng/mL (95% CI: -90.9, -29.9) for BLLs >= 10 MUg/dL. CONCLUSIONS: In peripubertal boys with low-level lead exposure, higher BLLs were associated with lower serum IGF-1. Inhibition of the hypothalamic-pituitary-growth axis may be one possible pathway by which lead exposure leads to growth delay. PMID- 23632161 TI - Exploring the relationship between mental health stigma, knowledge and provision of pharmacy services for consumers with schizophrenia. AB - BACKGROUND: Pharmacists' provision of medication counseling and medication review has been shown to improve adherence and resolve drug-related problems. Lack of knowledge of mental health conditions and negative beliefs may act as a barrier to the provision of pharmacy services. It is unclear how pharmacists' knowledge and attitudes impact their provision of pharmacy services. OBJECTIVES: To explore the relationship between pharmacists' level of mental health stigma, mental health literacy and behavioral intentions in relation to providing pharmacy services for consumers with schizophrenia. METHODS: A survey instrument containing a measure of mental health literacy, the 7-item social distance scale, and 16 items relating to the provision of pharmacy services for consumers with schizophrenia compared to cardiovascular disease, was mailed to a random sample of 1000 pharmacists registered with the Pharmacy Board of New South Wales in November 2009. Multiple linear regression models were used to assess the relationship between stigma, knowledge and behavior. RESULTS: Responses were received from 188 pharmacists. Pharmacists were significantly more confident and comfortable to provide services to consumers with a cardiovascular illness than a mental illness. Social distance, beta = -0.11 (95% CI: -0.22, -0.01, P = 0.03), and schizophrenia literacy scores, beta = 1.02, (95% CI: 0.54, 1.50, P < 0.001), were strongly associated with willingness to provide medication counseling. Schizophrenia literacy was also a predictor of identifying drug-related problems, beta = 1.09 (95% CI: 0.39, 1.79, P = 0.002). CONCLUSIONS: Low levels of mental health stigma and high levels of schizophrenia literacy were associated with pharmacists being more willing to provide medication counseling and identify drug related problems for consumers with schizophrenia. This demonstrates the importance of improving knowledge and stigma surrounding schizophrenia to improve service delivery for consumers taking medications for schizophrenia. PMID- 23632162 TI - PlantGSEA: a gene set enrichment analysis toolkit for plant community. AB - Gene Set Enrichment Analysis (GSEA) is a powerful method for interpreting biological meaning of a list of genes by computing the overlaps with various previously defined gene sets. As one of the most widely used annotations for defining gene sets, Gene Ontology (GO) system has been used in many enrichment analysis tools. EasyGO and agriGO, two GO enrichment analysis toolkits developed by our laboratory, have gained extensive usage and citations since their releases because of their effective performance and consistent maintenance. Responding to the increasing demands of more comprehensive analysis from the users, we developed a web server as an important component of our bioinformatics analysis toolkit, named PlantGSEA, which is based on GSEA method and mainly focuses on plant organisms. In PlantGSEA, 20 290 defined gene sets deriving from different resources were collected and used for GSEA analysis. The PlantGSEA currently supports gene locus IDs and Affymatrix microarray probe set IDs from four plant model species (Arabidopsis thaliana, Oryza sativa, Zea mays and Gossypium raimondii). The PlantGSEA is an efficient and user-friendly web server, and now it is publicly accessible at http://structuralbiology.cau.edu.cn/PlantGSEA. PMID- 23632164 TI - Synthesis of 18O-labeled RNA for application to kinetic studies and imaging. AB - Radioisotopes and fluorescent compounds are frequently used for RNA labeling but are unsuitable for clinical studies of RNA drugs because of the risk from radiation exposure or the nonequivalence arising from covalently attached fluorophores. Here, we report a practical phosphoramidite solid-phase synthesis of (18)O-labeled RNA that avoids these disadvantages, and we demonstrate its application to quantification and imaging. The synthesis involves the introduction of a nonbridging (18)O atom into the phosphate group during the oxidation step of the synthetic cycle by using (18)O water as the oxygen donor. The (18)O label in the RNA was stable at pH 3-8.5, while the physicochemical and biological properties of labeled and unlabeled short interfering RNA were indistinguishable by circular dichroism, melting temperature and RNA-interference activity. The (18)O/(16)O ratio as measured by isotope ratio mass spectrometry increased linearly with the concentration of (18)O-labeled RNA, and this technique was used to determine the blood concentration of (18)O-labeled RNA after administration to mice. (18)O-labeled RNA transfected into human A549 cells was visualized by isotope microscopy. The RNA was observed in foci in the cytoplasm around the nucleus, presumably corresponding to endosomes. These methodologies may be useful for kinetic and cellular-localization studies of RNA in basic and pharmaceutical studies. PMID- 23632163 TI - The Genomic HyperBrowser: an analysis web server for genome-scale data. AB - The immense increase in availability of genomic scale datasets, such as those provided by the ENCODE and Roadmap Epigenomics projects, presents unprecedented opportunities for individual researchers to pose novel falsifiable biological questions. With this opportunity, however, researchers are faced with the challenge of how to best analyze and interpret their genome-scale datasets. A powerful way of representing genome-scale data is as feature-specific coordinates relative to reference genome assemblies, i.e. as genomic tracks. The Genomic HyperBrowser (http://hyperbrowser.uio.no) is an open-ended web server for the analysis of genomic track data. Through the provision of several highly customizable components for processing and statistical analysis of genomic tracks, the HyperBrowser opens for a range of genomic investigations, related to, e.g., gene regulation, disease association or epigenetic modifications of the genome. PMID- 23632165 TI - QualitySNPng: a user-friendly SNP detection and visualization tool. AB - QualitySNPng is a new software tool for the detection and interactive visualization of single-nucleotide polymorphisms (SNPs). It uses a haplotype based strategy to identify reliable SNPs; it is optimized for the analysis of current RNA-seq data; but it can also be used on genomic DNA sequences derived from next-generation sequencing experiments. QualitySNPng does not require a sequenced reference genome and delivers reliable SNPs for di- as well as polyploid species. The tool features a user-friendly interface, multiple filtering options to handle typical sequencing errors, support for SAM and ACE files and interactive visualization. QualitySNPng produces high-quality SNP information that can be used directly in genotyping by sequencing approaches for application in QTL and genome-wide association mapping as well as to populate SNP arrays. The software can be used as a stand-alone application with a graphical user interface or as part of a pipeline system like Galaxy. Versions for Windows, Mac OS X and Linux, as well as the source code, are available from http://www.bioinformatics.nl/QualitySNPng. PMID- 23632167 TI - The characteristic expression pattern of BMI-1 and SALL4 genes in placenta tissue and cord blood. AB - INTRODUCTION: SALL4 and BMI-1 are important factors in hematopoiesis. Placental tissue (PT) and umbilical cord blood (CB) are rich in hematopoietic stem/progenitor cells (HSCs/HPCs), but their SALL4 and BMI-1 expression levels remain unknown. METHODS: Real-time PCR was used to determine the expression level of these genes in PT and CB from ten cases, and ten healthy donors were used as controls. RESULTS: A significantly higher BMI-1 and SALL4 gene expression level was found in PT (median: 17.548 and 34.362, respectively) than in cord blood mononuclear cells (CBMCs) (median: 2.071 and 11.300, respectively) (P = 0.0001 and P = 0.007) and healthy peripheral blood mononuclear cells (PBMCs) (median: 0.259 and 0.384, respectively) (P = 0.001 and P <0.0001), and their expression level was lower in PBMCs than in CBMCs (P = 0.029 and P = 0.002). A positive correlation between the BMI-1 and SALL4 genes was found in the PT and CB groups, while there was no significant correlation between these genes in the healthy group. There was also no significant correlation between the expression level of each gene in PT and CB. CONCLUSIONS: These results describe the characteristic features of the BMI-1 and SALL4 gene expression pattern in placental tissue and cord blood. Placental tissue with higher expression level of both genes may be considered as a potential resource for SALL4-related HPC expansion. PMID- 23632166 TI - Genome conformation capture reveals that the Escherichia coli chromosome is organized by replication and transcription. AB - To fit within the confines of the cell, bacterial chromosomes are highly condensed into a structure called the nucleoid. Despite the high degree of compaction in the nucleoid, the genome remains accessible to essential biological processes, such as replication and transcription. Here, we present the first high resolution chromosome conformation capture-based molecular analysis of the spatial organization of the Escherichia coli nucleoid during rapid growth in rich medium and following an induced amino acid starvation that promotes the stringent response. Our analyses identify the presence of origin and terminus domains in exponentially growing cells. Moreover, we observe an increased number of interactions within the origin domain and significant clustering of SeqA-binding sequences, suggesting a role for SeqA in clustering of newly replicated chromosomes. By contrast, 'histone-like' protein (i.e. Fis, IHF and H-NS) binding sites did not cluster, and their role in global nucleoid organization does not manifest through the mediation of chromosomal contacts. Finally, genes that were downregulated after induction of the stringent response were spatially clustered, indicating that transcription in E. coli occurs at transcription foci. PMID- 23632168 TI - Decisive role of Reelin signaling during early stages of Alzheimer's disease. AB - Alzheimer's disease (AD) is one of the largest unmet medical concerns of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles, the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiological characteristic of late-onset AD. PMID- 23632169 TI - Occipital somites guide motor axons of the accessory nerve in the avian embryo. AB - The accessory nerve (nervus accessorius) displays a unique organization in that its axons ascend along the rostrocaudal axis after exiting the cervical spinal cord and medulla oblongata and thereafter project ventrally into the periphery at the first somite level. Little is known about how this organization is achieved. We have investigated the role of somites in the guidance of motor axons of the accessory nerve using heterotopic transplantations of somites in avian embryos. The formation of not only accessory nerve but also the vagal nerve was affected, when a more caudal occipital somite (somites 2-4) was grafted to the position of the first occipital somite. Our study reveals that only the first occipital somite permits the development of ventral projection of accessory axons, a process that is inhibited by more caudal occipital somites. PMID- 23632170 TI - Training-induced cortical plasticity compared between three tongue-training paradigms. AB - The primary aim of this study was to investigate the effect of different training types and secondary to test gender differences on the training-related cortical plasticity induced by three different tongue-training paradigms: (1) therapeutic tongue exercises (TTE), (2) playing computer games with the tongue using the Tongue Drive System (TDS) and (3) tongue-protrusion task (TPT). Forty-eight participants were randomized into three groups with 1h of TTE, TDS, or TPT. Stimulus-response curves of motor evoked potentials (MEPs) and motor cortex mapping for tongue muscles and first dorsal interosseous (FDI) (control) were established using transcranial magnetic stimulation at three time-points: (1) before tongue-training, (2) immediately after training, (3) 1h after training. Subject-based reports of motivation, fun, pain and fatigue were evaluated on 0-10 numerical rating scales after training. The resting motor thresholds of tongue MEPs were lowered by training with TDS and TPT (P<0.011) but not by TTE (P=0.167). Tongue MEP amplitudes increased after training with TDS and TPT (P<0.030) but not with TTE (P=0.302). Men had higher MEPs than women in the TDS group (P<0.045) at all time-points. No significant effect of tongue-training on FDI MEPs was observed (P>0.335). The tongue cortical motor map areas were not significantly increased by training (P>0.142). Training with TDS was most motivating and fun (P<0.001) and TTE was rated the most painful (P<0.001). Fatigue level was not different between groups (P>0.071). These findings suggest a differential effect of tongue-training paradigms on training-induced cortical plasticity and subject-based scores of fun, motivation and pain in healthy participants. PMID- 23632171 TI - Bilateral anterior shoulder dislocation. AB - We describe a case of simultaneous bilateral anterior shoulder dislocation in a 70-year-old gentleman post-trauma. There was no associated motor, sensory or vascular deficit. Patient underwent closed reduction for both his dislocated shoulder joints under general anaesthesia followed by immobilisation for 4 weeks, and subsequent follow-up showed good functional outcomes. PMID- 23632172 TI - Acute coronary syndrome in congenitally corrected transposition of the great arteries. PMID- 23632173 TI - Poorly controlled type 2 diabetes complicated by an episode of severe hypertriglyceridaemia-induced pancreatitis. AB - A 23-year-old woman with a history of type 2 diabetes and non-compliance presented to the emergency department with abdominal epigastric pain and nausea. Laboratory examination revealed a mild ketoacidosis while an abdominal CT scan performed the following day demonstrated a severe acute pancreatitis of the body and tail (Balthazar grade E) despite normal amylase serum levels on admission. The presence of a lactescent serum was the clue to an extremely high triglyceride level (>10 000 mg/dl) causing the pancreatitis. The hypertriglyceridaemia itself was attributed mainly to the diabetic ketoacidosis. There was no family history of hypertriglyceridaemia. The triad consisting of diabetic ketoacidosis, hypertriglyceridaemia and acute pancreatitis is an unusual presentation of poorly controlled diabetes which can occur in type 1 as well as type 2 diabetic adults and children. Treatment with intravenous insulin and hydration successfully resolved the ketoacidosis and hypertriglyceridaemia and reversed the episode of acute pancreatitis. PMID- 23632174 TI - Alkaptonuria and Pompe disease in one patient: metabolic and molecular analysis. AB - Pompe disease is characterised by deficiency of acid alpha-glucosidase that results in abnormal glycogen deposition in the muscles. Alkaptonuria is caused by a defect in the enzyme homogentisate 1,2-dioxygenase with subsequent accumulation of homogentisic acid. We report the case of a 6-year-old boy diagnosed with Pompe disease and alkaptonuria. Urine organic acids and alpha-glucosidase were measured. Homogentisate 1,2-dioxygenase (HGO) and acid alpha-glucosidase (GAA) genes were sequenced by Sanger DNA sequencing. The level of alpha-glucosidase in white blood cells was markedly decreased (4 nm/mg) while the level of homogentisic acid was markedly increased (15 027 mmol/mol creatine). GAA sequencing detected two heterozygous GAA mutations (C.670C>T and C.1064T>C) while HGO sequencing revealed three polymorphisms in exons 4, 5 and 6, respectively. To the best of our knowledge, this is the first reported instance of Pompe disease and alkaptonuria occurring in the same individual. PMID- 23632175 TI - Reflections on mental capacity assessments in general hospitals. AB - Research suggests that a significant proportion of inpatients in general medical wards may lack capacity to make treatment decisions, a situation that often goes unrecognised by clinicians. We would like to briefly discuss two cases from a non psychiatric setting, where a mental disorder served to inhibit the individual's ability to weigh-up associated risks when deciding to refuse potentially life sustaining healthcare interventions. In both cases the history of mental disorder was well established yet, for markedly different reasons, the respective presentation was such that the influence of the disorder on decision-making was not evident to the treating teams. PMID- 23632176 TI - Polyglandular autoimmune syndrome disguised as mental illness. AB - Our case acts to highlight the numerous presentations of polyglandular autoimmune syndromes. A 62-year-old Taiwanese woman with a history of schizophrenia presented to our emergency department with a brain tumour causing her headaches. She was admitted due to severe anaemia, and after further investigation, the patient was discovered to have pernicious anaemia and autoimmune thyroiditis consistent with the diagnosis of polyglandular autoimmune syndrome IIIb. Her underlying primary psychiatric diagnosis was then questioned. The diagnosis of her endocrinopathies were likely delayed for many years due to the psychiatric disorder which may have been due to her long-standing autoimmune hypothyroidism and/or vitamin B12 deficiency. Initial treatment brought about major behavioural improvement, and encourages physicians to investigate secondary causes of psychosis and other coexisting autoimmune diseases when a patient presents with one endocrinopathy. PMID- 23632177 TI - Just a sore throat? Uncommon causes of significant respiratory disease. AB - We present two uncommon underlying causes of a sore throat which, if missed or delayed in diagnosis, can lead to disastrous consequences. Our first case is of Lemierre's syndrome diagnosed in a 21-year-old man presenting with a 5-day history of sore throat, fever, right-sided pleuritic chest pain and bilateral pulmonary nodules on CT imaging. Fusobacterium necrophorum cultured from peripheral blood and an occluded left internal jugular vein on ultrasound lead to an eventual diagnosis. Our second case presents a 29-year-old woman with a 5-day history of sore throat, fever and right-sided pleuritic chest pain. A left-sided quinsy was diagnosed and aspirated and the patient was discharged home. She represented shortly with worsening pleuritic pain and was found to have a right sided pleural effusion with descending mediastinitis originating from the tonsillar abscess. Delayed diagnosis resulted in open thoracotomy, decortication and prolonged intravenous antibiotics. PMID- 23632178 TI - Subarachnoid haemorrhage with orgasmic cephalgia. PMID- 23632179 TI - Fused primary supernumerary tooth associated with maxillary primary and permanent lateral incisors. PMID- 23632180 TI - Acute splenic infarction in a hiker with previously unrecognised sickle cell trait. PMID- 23632181 TI - A rare parapharyngeal space branchial cleft cyst. AB - The second branchial cleft cyst may arise anywhere from the tonsillar fossa to the supraclavicular area. It usually lies along the anterior border of the sternocleidomastoid muscle or deep into the muscle. Occurrence of the second branchial cleft cyst in the parapharyngeal space is extremely uncommon. We report one such case of second branchial cleft cyst arising from the parapharyngeal space and discuss its differential diagnosis and treatment modalities in detail. PMID- 23632182 TI - Silastic arthroplasty of the first metatarsophalangeal joint as salvage for failed revisional fusion with interpositional structural bone graft. AB - Silastic arthroplasty of the first metatarsophalangeal joint should be considered a viable salvage procedure either for cases of previously failed fusion with interpositional tricortical bone grafting, or for cases of painful previous Kellers, as it can restore length back to the toe, power, stability of gait and therefore reduce pain. PMID- 23632183 TI - Inhaled hypertonic saline+hyaluronic acid in cystic fibrosis with asthma-like symptoms: a new therapeutic chance. AB - The aim of the paper is to report the case of a boy affected by cystic fibrosis, with non-ABPA-related recurrent wheezing and frequent pulmonary exacerbation during childhood, who had been inhaling 7% NaCl+0.1% hyaluronic acid (HA) as a maintenance therapy. We reviewed patient database and, analysing a 7-year follow up, considered pulmonary exacerbation, antibiotic and steroid courses, pulmonary function (forced expiratory volume in one second; FEV1) and microbiological data. After starting 7% NaCl+0.1% HA treatment, we observed a dramatic decrease of oral antibiotic need (0.55 courses/month during the pretreatment period against 0.10 courses/month in the treatment period), associated with a good initial recovery and a stability of FEV1. In our opinion this case could suggest an extended indication for inhaled 7% NaCl+0.1% HA use in CF, not only in patients who did not tolerate hypertonic saline, but also in patients with coexistent asthma-like symptoms. PMID- 23632184 TI - Emphysematous cystitis: a tympanic bladder. AB - An 86-year-old woman with type 2 diabetes was admitted with increasing lethargy and hyperglycaemia. On examination she was noted to have a tender and tympanic bladder. CT revealed a distended bladder with gas locules in the bladder wall. She was diagnosed with hyperglycaemic hyperosmolar non-ketosis precipitated by emphysematous cystitis. After systemic antibiotics and bladder drainage via a urethral catheter, her symptoms readily improved. Radiographic appearances of the bladder were normal one week after instigating treatment. Emphysematous cystitis is characterized by gas within the bladder wall. Although rare it is increasingly more recognized with the advent of modern imaging. The mainstay of treatment is antibiotics and bladder drainage. Rarely surgical debridement and even cystectomy is required. PMID- 23632185 TI - Successful anticoagulation with fresh frozen plasma for cardiopulmonary bypass in a patient with heparin resistance: a cautionary tale. AB - Heparin resistance (HR) is an increasingly common occurrence due to a greater awareness of the benefits of antithrombosis prophylaxis in hospitalised patients with low molecular weight and unfractionated heparin. Furthermore as more high risk patients with prior heparin exposure undergo cardiac surgery we can expect to encounter more such cases. Adequate anticoagulation is essential for the safe conduct of any operation requiring cardiopulmonary bypass and is usually achieved with systemic heparinisation. We report a case of successful anticoagulation with the intraoperative administration of fresh frozen plasma in a high-risk coronary patient with HR and highlight the perils of unwitting overheparinisation in such cases. This case highlights the importance of clinical awareness of this phenomenon and the available alternative anticoagulants. PMID- 23632186 TI - Primary intracranial melanoma in a child with a giant congenital melanocytic naevus and normal MRI. AB - We present a case of a 10-year-old girl with a giant congenital melanocytic naevus, and malignant cerebral melanoma. PMID- 23632187 TI - Acquired urethral meatal stenosis: a rare sequel of an aggressive form of Behcet's disease. AB - Behcet's disease (BD) is characterised by the triad of recurrent oral and genital aphthous ulceration, skin lesions and ocular inflammation. This disease frequently affects other systems including neurological, locomotor, cardiac or vascular systems. Recurrent oral and genital aphthous ulcerations are the hallmarks of BD. We hereby report a case of rapidly evolving and aggressive form of BD in a young man presenting with extensive ulcerative lesions in orogenital region leading to obstructive uropathy resulting in acquired urethral meatal stenosis due to inflammatory activity. PMID- 23632188 TI - Lung hernia. PMID- 23632189 TI - 'Eye is a window to the pulse': bilateral ocular ischaemic syndrome as a presenting manifestation of Takayasu arteritis. AB - A 22-year-old lady presented with gradually progressive visual loss and chronic pain in both the eyes of 3 months duration. The clinical examination and fundus fluorescein angiography were suggestive of bilateral ocular ischaemic syndrome. Her upper limb pulses were feeble and blood pressure was not recordable in the same. Carotid Doppler revealed a bilateral carotid artery occlusion. Systemic markers for inflammation were elevated. Diagnosis of Takayasu arteritis was made on the basis of clinical and laboratory findings. Takayasu arteritis should be considered in the differential diagnosis of ocular ischaemic syndrome, particularly in young Asian women. PMID- 23632190 TI - Calcified embolism: a rare cause of cerebral infarction. AB - Calcified cerebral emboli (CCE) are a rare cause of stroke and these emboli can be identified on a CT scan of the brain performed for the initial evaluation of stroke. In this report we present a patient who developed a CCE following cardiac catheterisation that lodged in the left middle cerebral artery with resultant right hemiparesis and aphasia. The calcified embolus was seen on CT but could not be identified on MRI. Predisposing factors for CCE include angiography and valve or vessel wall calcification. The natural history and response to standard therapy in patients with CCE as compared with stroke of other aetiologies have not been studied until now. Increased awareness and ability to identify calcified emboli will help us to have an improved understanding of strokes resulting from CCE. PMID- 23632191 TI - Curative surgical management of isolated adrenal recurrence of oesophageal adenocarcinoma. AB - Adrenal metastases of oesophageal adenocarcinoma are rarely detected in the clinical setting, more frequently being found as an incidental postmortem finding in the presence of widespread metastases. With improvements in the sensitivity of radiological diagnostic modalities, the incidence of adrenal tumour detection is on the rise. We report herein a particularly rare case of primary operative management by adrenalectomy for an isolated right-sided adrenal metastasis secondary to oesophageal adenocarcinoma, with a long-term survival. PMID- 23632192 TI - Ulcerative colitis: a case of steroid refractory disease. AB - A 21-year-old lady was admitted to a hospital with an 8-week history of bloody diarrhoea. She had been diagnosed with ulcerative colitis 2 years previously and had remained in remission until the gradual onset of bloody diarrhoea. Her bowel frequency was 20 times per day and associated with significant abdominal pain and weight loss. She was started on intravenous steroids, topical therapy and anti tumour necrosis factor therapy; however, this failed to achieve symptom control. Histology of tissue obtained from flexible sigmoidoscopy eventually demonstrated cytomegalovirus (CMV)-associated colitis. Intravenous anti-viral valganciclovir was initiated and the patient made a rapid recovery. This case discusses the differentials for steroid-refractory ulcerative colitis, including the common pitfall of inflammatory bowel disease management and CMV infection. This case also discusses CMV pathophysiology including histological features, appropriate investigations and current management guidelines. PMID- 23632194 TI - The reasons of higher NT-proBNP depend on very different conditions. PMID- 23632193 TI - Treatment of lower extremity oedema by subcutaneous drainage in a home hospice patient. AB - Lower extremity oedema is common in patients with advanced illness and can normally be managed with oral diuretics and elevation of the involved extremities. The management of oedema can be more complicated in home hospice patients, however. They tend to be more frail and are often less able to tolerate usual interventions. We present a case of a home hospice patient with severe oedema treated by creating subcutaneous tracts in his legs to allow drainage of excess interstitial fluid. The procedure was very successful in improving the patient's quality of life. PMID- 23632195 TI - Deletion of the receptor tyrosine kinase Tyro3 inhibits synovial hyperplasia and bone damage in arthritis. AB - OBJECTIVE: To test whether the tyrosine kinase Tyro3 affects arthritis. Tyro3, the ligand of growth arrest-specific protein 6 (GAS6) is a receptor tyrosine kinase involved in cell survival. Tyro3 and GAS6 are expressed in the arthritic synovium, and in vitro studies have shown their role in osteoclast differentiation. METHODS: Bone was assessed by micro CT and histomorphometry in Tyro3-deficient (Tyro3(-/-)) and wild-type mice. Arthritis was induced in both genotypes, and Gas6 level was measured by ELISA. Synovitis, synovial hyperplasia, bone erosion, osteoclast activation and osteoclast gene expression were assessed by histomorphometry and reverse transcriptase-PCR, respectively. In vitro osteoclast differentiation assays were performed in Tyro3(-/-) and wild-type mice. Furthermore, effects of Tyro3 and GAS6 on human synovial fibroblast proliferation and osteoclastogenesis were assessed in human cells. RESULTS: Tyro3(-/-) mice had significantly higher bone mass than wild-type littermates. Induction of arthritis increased GAS6 serum levels. Arthritic Tyro3(-/-) mice showed less synovial hyperplasia, osteoclast numbers and bone damage compared with controls. In vivo expression of osteoclast-associated receptor and receptor activator of nuclear factor-kappaB and in vitro osteoclastogenesis were impaired in Tyro3(-/-) mice. GAS6 also induced synovial fibroblast proliferation and osteoclast differentiation in human cells in Tyro3-dependent manner. CONCLUSIONS: These findings indicate that Tyro3 is a critical signal for synovial hyperplasia, osteoclast differentiation and bone erosion during arthritis. GAS6 and Tyro3 therefore constitute therapeutic targets to inhibit synovial hyperplasia and associated bone erosion. PMID- 23632196 TI - Who do you think you are? Identity and childhood in Australian healthcare ethics. PMID- 23632197 TI - Effects of medetomidine and medetomidine-butorphanol on transcranial color-coded duplex ultrasonography in healthy dogs. AB - The study was designed to determine the effects of two protocols of sedation, medetomidine and medetomidine-butorphanol, on cerebral blood flow (CBF) by transcranial color-coded Duplex ultrasonography in healthy dogs. Transcranial Doppler ultrasonographic examination was performed in 20 dogs before and 20 min after sedation with either medetomidine (group 1) or medetomidine-butorphanol (group 2). The left and right middle cerebral arteries (LMCA and RMCA) were evaluated using the temporal windows, and the basilar artery (BA) was studied through the suboccipital window. Peak systolic velocity (PSV), mean velocity (MV), end diastolic velocity (EDV), resistance index (RI), and pulsatility index (PI) were measured for each vessel. Blood pressure (BP) and heart rate (HR) were also recorded before and after sedation in both groups. Statistically significant differences were found for PSV, MV and EDV when RMCA and LMCA were interrogated before and after sedation. PSV, RI and PI were found to be statistically significantly different when the study was performed on the BA. These results should be taken in account when a transcranial Doppler is performed in dogs sedated with the mentioned protocols and it might suggest some degree of neuroprotection. PMID- 23632198 TI - SNPs of bovine HGF gene and their association with growth traits in Nanyang cattle. AB - Hepatocyte growth factor (HGF) is one of the multifunctional cell factors that regulates cellular proliferation, motility and morphogenesis in mammalians. And its medical research has deep significance. In this paper, polymorphisms of HGF gene were investigated in 1433 health and irrelated Chinese cattle by PCR-RFLP and DNA sequencing approach. Ten novel Single nucleotide polymorphisms (SNPs) were identified, which included one missense mutation, g.72801G>A in the coding region, and the others in the intron. Association analysis between four of them, g.288T>C, g.72801G>A, g.77172G>T, and g.77408T>G, and growth traits in Nanyang, were performed. The results indicated that SNPs within bovine HGF gene were significantly associated with growth traits. Phylogenetic analysis showed that the genetic background of Caoyuan Red cattle was different from the others in the tested breeds. The findings will provide a background for application of bovine HGF gene in the selection program in Chinese cattle. PMID- 23632199 TI - Streptococcus equi ssp. zooepidemicus C5a peptidase, a putative invasin, induces protective immune response in mice. AB - Streptococcus equi ssp. zooepidemicus (Streptococcus zooepidemicus, SEZ) is responsible for septicemia, meningitis, arthritis and several other serious diseases in various species with adhesive and invasive properties. The absence of suitable vaccine confounds the control of SEZ infection. The highly conserved C5a peptidase was served as an invasin to host epithelial cells and involved in the pathogenicity in other streptococcus species. In the present study, the purified recombinant SEZ C5a peptidase (rSCPZ) could adhere to Hep-2 cells and interfere with the invasion of SEZ into Hep-2 cells confirmed by adherence and invasion assay. Immunization of BALB/c mice with rSCPZ could elicit a significant humoral antibody response and could confer significant protection against challenge with a lethal dose of SEZ. In addition, the hyperimmune sera against rSCPZ could efficiently inhibit bacterial growth in a whole blood assay and confer significant protection against SEZ infection in the experiment of passive immunization. The present study suggests that SCPZ could be useful for development of subunit vaccine against SEZ. PMID- 23632200 TI - Characterization of the use of liraglutide for glycemic control in healthy and Type 1 diabetes mellitus suffering dogs. AB - Glucagon-like peptide 1 (GLP-1) is a glucose-lowering, intestinal-derived factor with multiple physiological effects, making it attractive for diabetes therapy. However, the therapeutic potential of endogenous GLP-1 is limited, because of rapid inactivation by dipeptidyl peptidase-4. Recently, enhanced incretin preparations, such as liraglutide, have emerged, which are more resistant to degradation and longer lasting. Liraglutide is a long-acting acylated human GLP-1 receptor agonist, with a 97% amino acid sequence identity to endogenous human GLP 1, and 100% amino acid sequence homology with canine GLP-1. Since liraglutide has yet to be examined for use in dogs, and the incretin effect has been reported to exist in dogs, we sought to initially characterize liraglutide's ability for glycemic control in healthy dogs, under an oral glucose tolerance test (OGTT) environment initially. This was followed up a more realistic scenario involving food with insulin injection +/- liraglutide injection resulting in a glucose curve based study involving dogs suffering from Type 1 diabetes mellitus (T1DM). Overall, liraglutide had a stabilizing effect on glucose levels, maintaining circulating levels between 77.0 and 137.0mg/ml throughout the OGTT test period, resulting in a significant reduction of 13.8% in glucose AUC0-120 min (total area under the curve for 0-120 min) as compared to baseline control in healthy dogs (n=5). Interestingly, the liraglutide associated reduction in circulating glucose was not accompanied by any significant increase in insulin. Moreover, T1DM dogs (n=4) responded favorably to liraglutide treatment, which lead to a significant reduction of 46.0% in glucose AUC0-12h (total area under the curve for 0-12h), and a significant reduction of 66.5% in serum glucose as compared to baseline controls (insulin treatment only). Therefore, liraglutide's prandial glucagon suppressive ability appears to play a key role in its glucose-lowering capability, and offers great potential for use with dogs suffering from T1DM. PMID- 23632201 TI - The twin children of Auschwitz-Birkenau: conference on Nazi medicine. AB - The twin children who survived the Holocaust and the horrific medical experiments conducted by Nazi doctors are sometimes overlooked in the relevant literature. This topic and more were discussed as part of an annual conference hosted by students from Yeshiva University's Medical Ethics Society in October 2012. A selective summary of this meeting is followed by summaries of recent twin studies concerning genetic influences on twinning, in vitro fertilization versus spontaneous twin pregnancies, gender identity disorder, and royal support for twin registries. Several human interest stories are also worth noting. They include identical twin school principals, twin loss at Sandy Hook Elementary School, timely twin documentaries, new twin and twin-like reunions, and the passing of two prominent twins. PMID- 23632202 TI - The relationship between the motor system activation during action observation and adaptation in the motor system following repeated action observation. AB - Repeated action observation has been shown to alter the cortical representation of the observed movement in the motor system. This change in cortical representation is thought to reflect a motor adaptation to observational training (observational training effect). One factor that may impact the observational training effect is the degree of motor system activation that occurs during the observation of the action (i.e., individual differences in the responsiveness of the motor system during action observation). The present study was conducted to test this hypothesis by assessing the relationship between the change in motor system activity during action observation and the change in cortical representation of action following repeated action observation. To this end, transcranial magnetic stimulation (TMS) was used to evoke contractions of thumb muscles in two different protocols: 1) during the observation of thumb movements to assess the responsiveness of each individual's corticospinal system during action observation; and, 2) after the observation of 1800 thumb movements to assess the amount of adaptation in the representation of the thumb following repeated action observation. The key finding was the significant positive relationship between the level of corticospinal system activation during action observation and the amount of change in the direction of TMS evoked thumb movements. These data support the hypothesized relationship between motor system activation during action observation and the motor systems adaptation following observational training. They are also consistent with the notion that a common neural mechanism underlies these effects. PMID- 23632203 TI - Dietary approach to hypertension based on low glycaemic index and principles of DASH (Dietary Approaches to Stop Hypertension): a randomised trial in a primary care service. AB - Hypertension is one of the leading causes of morbidity and mortality in Brazil. Diet may play an important role in reducing blood pressure (BP), as has been shown for diets high in fruits, vegetables and low-fat dairy products and low in salt (Dietary Approaches to Stop Hypertension (DASH)-Na). A low-glycaemic index Brazilian diet combined with the principles of the DASH-Na diet was evaluated in a randomised study of 206 individuals who were followed for 6 months. In the control group (CG), counselling was based on standard care and mainly focused on salt intake reduction. An intention-to-treat analysis showed that, after 6 months, systolic BP was reduced by 14.4 mmHg and diastolic BP by 9.7 mmHg in the experimental group (EG), compared with 6.7 and 4.6 mmHg, respectively, in the CG. After adjusting for body weight, BP at baseline and age, these changes were 12.1 and 7.9 mmHg, respectively. Urinary Na excretion was also reduced by 43.4 mEq/24 h in the EG. Food intake was modified accordingly during the intervention with an increase in the consumption of vegetables (2.97-5.85 frequency of consumption measured in three non-consecutive days), fruits (4.09-7.18), beans (1.94-3.13) and fish (1.80-2.74) by the EG. The present study showed the feasibility of a Brazilian dietary approach to treating hypertension by reducing urinary Na excretion and BP, changes that may have a great impact on public health and promote the benefits of controlling hypertension. PMID- 23632204 TI - General practitioners and consultation drift: the effects of supply-side changes and reforms on service delivery patterns. AB - OBJECTIVES: To determine what types of supply-side change underpinned the recent decline in longer (Level C and D) consultation provision and to evaluate the impact of the May 2010 reforms in realigning Medicare with long-term health policy objectives. METHODS: Retrospective analysis of Level C and D consultation provision by general practitioners (GPs) across Australia. Outcome measures were extent (number of consultations per providing GP) and participation (proportion of GPs providing these consultations). RESULTS: The proportion of GPs participating in Level C consultation provision is substantial (96%) and constant; however, extent of provision per GP decreased by 21% between 2006 and 2010. Level D participation decreased from 72% during 2006 to a nadir of 62% in 2009, and extent of provision decreased by 26% between 2006 and 2010. CONCLUSION: Two distinct types of change underpinned the overall decline in Level C and D consultation provision. GPs appear to be providing Level C consultations less often, but the overwhelming majority still provide these consultations to some extent. The extent of provision of Level D consultations and the proportion of GPs providing them has decreased; an appreciable number of GPs simply stopped providing Level D consultations. Medicare reforms appear ineffective in realigning Medicare with long-term policy objectives. PMID- 23632206 TI - Prevalence of and factors contributing to missing lymph tissue in uterine cancer staging surgery. AB - OBJECTIVE: We wished to investigate the prevalence of missing lymph nodes (MLN), factors contributing to MLN, and the effect of MLN on progression free survival (PFS). METHODS: Patients with uterine cancer undergoing abdominal hysterectomy and lymphadenectomy were recruited. All surgeries adhered to the Gynecologic Oncology Group protocol in collecting all the lymph node tissues in paraaortic, common iliac, obturator fossa, and external and internal iliac bilaterally. Data regarding race, age, body mass index (BMI), lymph node counts, staging, location of missing lymph nodes, length of surgery, and estimated blood loss were collected and analyzed in reference to missing lymph nodes. The definition of missing lymph node was an incomplete nodal specimen obtained without actual lymph node tissue. RESULTS: Between April 2003 and January 2010, 235 consecutive patients were enrolled prospectively; 108 patients had missing lymph nodes post operatively (46%), and 127 patients had complete lymph nodes. We found no correlation between MLN relative to race (P = 0.97), age (P = 0.25), BMI (P = 0.09), estimated blood loss (P = 0.38), American Society of Anaesthesiologist physical status classification system (P = 0.18), surgery time (P = 0.22), hospital stay (P = 0.05), nodes without cancer (P =0.12), nodes with cancer (P = 0.99), stage (P = 0.90), grade (P = 0.17), or PFS (P = 0.29). CONCLUSION: In our study, although prevalence of missing lymph nodes seems relatively high, none of the perioperative variables studied appeared to contribute to missing lymph nodes. Finally, missing lymph nodes did not affect progression free survival. PMID- 23632205 TI - Endometrial cancer and a family history of cancer. AB - OBJECTIVE: Lynch Syndrome (LS), an inherited genetic syndrome, predisposes to cancers such as colorectal and endometrial. However, the risk for endometrial cancer (EC) in women not affected by LS, but with a family history of cancer, is currently unknown. We examined the association between a family history of cancer and the risk for EC in non-LS patients. METHODS: This population-based case control study included 519 EC cases and 1015 age-matched controls and took place in Alberta, Canada between 2002 and 2006. Information about risk factors, including family history of cancer in first and second degree relatives, was ascertained via in-person interviews. Microsatellite instability (MSI) status of tumor tissue was assessed to determine involvement of DNA mismatch repair (MMR) genes. RESULTS: A first or second degree family history of uterine cancer was modestly associated with the risk for overall EC [odds ratio (OR), 1.3; 95% confidence interval (CI), 0.9, 1.9], and the risks were similar for MSI+cancer (OR=1.5, 95%CI=0.7, 3.3) and MSI- cancer (OR=1.3, 95%CI=0.8, 2.4). Although consistent, these associations were modest and not significant. In contrast, the risk for MSI+cancer was elevated with a reported family history of colorectal cancer (OR=1.4, 95%CI=1.0, 2.2), but not for MSI- cancer. CONCLUSIONS: A family history of uterine cancer may be modestly associated with EC risk in non-LS patients regardless of MSI status, suggesting that risk was not related to inherited defects in the MMR gene pathway. These results provide preliminary support for an EC-specific genetic syndrome. PMID- 23632207 TI - Recurrence patterns after extended treatment with bevacizumab for ovarian, fallopian tube, and primary peritoneal cancers. AB - OBJECTIVE: To evaluate patterns of recurrence for ovarian, fallopian tube, and primary peritoneal cancer patients undergoing extended treatment with bevacizumab (BEV). METHODS: A retrospective review of patients with primary ovarian, fallopian tube, or peritoneal cancer treated with BEV alone or in combination with other chemotherapy from 2001 to 2011 was performed. Qualified patients were identified by chemotherapy records. Electronic medical records, labs, and imaging reports were reviewed and abstracted. RESULTS: Of 108 patients identified, 89 patients met study criteria by having disease progression either during treatment with BEV or after discontinuing BEV without initiating any other treatment. Patients on extended BEV therapy (>12 cycles) were more likely to recur in extra visceral sites (p=0.04), especially in lymph nodes (p=0.0002), and presented with fewer symptoms at time of recurrence (p=0.02), compared to patients who had received <= 12 cycles. CA-125 becomes less reliable for the detection of recurrent disease with extended BEV therapy (p=0.03 for <=12 cycles vs. p=0.08 for >12 cycles). Radiology was superior to CA-125, symptom, and physical exam, in detecting recurrence with extended BEV therapy (all p<0.0001). CONCLUSIONS: Extended treatment with BEV in ovarian, fallopian tube, and peritoneal cancers results in alterations in the patterns of recurrence. Radiologic imaging is more reliable than CA-125, symptoms, or physical exam, in identifying recurrent disease in patients undergoing BEV treatment. As novel targeted therapies continue to be employed, guidelines for gynecologic cancer surveillance must continue to be reexamined. PMID- 23632208 TI - The role of single nucleotide polymorphisms of the ERCC1 and MMS19 genes in predicting platinum-sensitivity, progression-free and overall survival in advanced epithelial ovarian cancer. AB - OBJECTIVE: This study aims to assess the role of polymorphisms in DNA repair genes, excision repair cross-complementation group 1 (ERCC1) and methyl methanesulfonate sensitivity 19 (MMS19), in tumor response to platinum-based chemotherapy and survival in advanced epithelial ovarian cancer (EOC). METHODS: Single nucleotide polymorphism (SNP) analysis was performed on the paraffin embedded tumor tissue of women with advanced EOC, treated with platinum-based chemotherapy at the University of Oklahoma Health Sciences Center. Polymorphisms from two ERCC1 (codon-118 and C8092A) and three MMS19 (rs2211243, rs2236575 and rs872106) gene loci were evaluated by real time PCR Allelic Discrimination Assay. RESULTS: Genotyping was performed in 107 patients, 45 platinum-sensitive and 62 platinum-resistant. ERCC1, codon-118 and C8092A genotyping was evaluable in 98 and 106 patients respectively and in all 107 patients for MMS19 polymorphisms. No differences were observed in genotype between platinum-sensitive and platinum resistant patients. Polymorphisms in the ERCC1, codon-118 and MMS19 genes did not correlate with overall survival (OS), although a trend toward improved progression free survival (PFS) was observed in patients expressing the minor (GG) alleles of the rs872106 MMS19 gene. Women homozygous for the ERCC1-C8092A minor (AA) alleles had a significant increase in PFS compared to AC and CC patients and both AA and AC genotypes conferred improved survival over the major (CC) genotype. CONCLUSIONS: Polymorphisms in ERCC1, codon-118 and MMS19 genes are not associated with clinical response to platinum or survival. The ERCC1-C8092A genotypes containing an "A" allele were associated with significant improvement in PFS and OS strengthening the value of this specific genotype in survival. PMID- 23632209 TI - Intensity modulated radiotherapy in gynecologic cancers: hope, hype or hyperbole? AB - Significant advances have occurred within the field of radiation oncology within the past few decades. Treatment with external beam radiotherapy has progressed from treatment fields planned from bony anatomy seen on planar X-rays, to 3 dimensional planning utilizing fused MRI's and PET images. Recently, intensity modulated radiotherapy (IMRT) has been integrated into many areas within radiation oncology, and its role in the treatment of gynecologic cancers is evolving. Potentials exist for improvements in both treatment toxicity, as well as improved efficacy through advances in treatment delivery. Unique challenges are also raised, however. With increased accuracy of treatment delivery comes the need for greater accuracy in target delineation and incorporation of motion to prevent marginal misses. The goal of this review is to evaluate the use of IMRT in cervical and endometrial cancers, including the results of dosimetric and clinical studies to date. In addition, potential disadvantages and challenges of IMRT integration are discussed. PMID- 23632210 TI - Principles for the risk assessment of genetically modified microorganisms and their food products in the European Union. AB - Genetically modified microorganisms (GMMs) are involved in the production of a variety of food and feed. The release and consumption of these products can raise questions about health and environmental safety. Therefore, the European Union has different legislative instruments in place in order to ensure the safety of such products. A key requirement is to conduct a scientific risk assessment as a prerequisite for the product to be placed on the market. This risk assessment is performed by the European Food Safety Authority (EFSA), through its Scientific Panels. The EFSA Panel on Genetically Modified Organisms has published complete and comprehensive guidance for the risk assessment of GMMs and their products for food and/or feed use, in which the strategy and the criteria to conduct the assessment are explained, as well as the scientific data to be provided in applications for regulated products. This Guidance follows the main risk assessment principles developed by various international organisations (Codex Alimentarius, 2003; OECD, 2010). The assessment considers two aspects: the characterisation of the GMM and the possible effects of its modification with respect to safety, and the safety of the product itself. Due to the existing diversity of GMMs and their products, a categorisation is recommended to optimise the assessment and to determine the extent of the required data. The assessment starts with a comprehensive characterisation of the GMM, covering the recipient/parental organism, the donor(s) of the genetic material, the genetic modification, and the final GMM and its phenotype. Evaluation of the composition, potential toxicity and/or allergenicity, nutritional value and environmental impact of the product constitute further cornerstones of the process. The outcome of the assessment is reflected in a scientific opinion which indicates whether the product raises any safety issues. This opinion is taken into account by the different European regulatory authorities prior to a decision regarding authorisation to commercialise the product. PMID- 23632212 TI - Hippocampal theta rhythm induced by rostral pontine nucleus stimulation in the conditions of pedunculopontine tegmental nucleus inactivation. AB - Theta rhythm in rat hippocampus occurs during cortical activation in different forms of waking as well as during paradoxical phase of sleep. The multi-level regulatory system of theta, based mainly on cholinergic transmission, includes structures from the forebrain to the medulla. Among them the most important are two reticular nuclei: the pedunculopontine tegmental nucleus (PPN) and rostral pontine tegmental nucleus (RPO). Functional relations between these two nuclei are still unidentified. It is known that cholinergic stimulation of these nuclei with carbachol leads to induction of theta in the hippocampus. Electrical stimulation has the same effect but only when applied to the RPO. In our experiments, performed on urethanized rats, each of these two methods was applied to the RPO with the PPN being inactivated in the contralateral hemisphere. We found that inactivation of the PPN does not suppress theta induced with carbachol microinjection into the RPO, but completely blocks theta induction with electrical stimulation of the RPO. The results suggest the important role of the PPN in theta rhythm generation from brainstem level, depending on the method of theta rhythm induction, i.e. cholinergic or electric stimulation of the RPO. PMID- 23632213 TI - WITHDRAWN: Epidemiological role of Phlebotomus papatasi and P. sergenti populations in Morocco: What we know and what can we learn from the field? AB - This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23632211 TI - Exercise attenuates PCB-induced changes in the mouse gut microbiome. AB - BACKGROUND: The gut microbiome, a dynamic bacterial community that interacts with the host, is integral to human health because it regulates energy metabolism and immune functions. The gut microbiome may also play a role in risks from environmental toxicants. OBJECTIVES: We investigated the effects of polychlorinated biphenyls (PCBs) and exercise on the composition and structure of the gut microbiome in mice. METHODS: After mice exercised voluntarily for 5 weeks, they were treated by oral gavage with a mixture of environmentally relevant PCB congeners (PCB153, PCB138, and PCB180; total PCB dose, 150 umol/kg) for 2 days. We then assessed the microbiome by determination of 16S rRNA using microarray analysis. RESULTS: Oral exposure to PCBs significantly altered the abundance of the gut microbiome in mice primarily by decreasing the levels of Proteobacteria. The activity level of the mice correlated with a substantial shift in abundance, biodiversity, and composition of the microbiome. Importantly, exercise attenuated PCB-induced changes in the gut microbiome. CONCLUSIONS: Our results show that oral exposure to PCBs can induce substantial changes in the gut microbiome, which may then influence their systemic toxicity. These changes can be attenuated by behavioral factors, such as voluntary exercise. PMID- 23632214 TI - Letter to the editor. PMID- 23632216 TI - 56-year-old man with pulmonary hypertension. PMID- 23632217 TI - Performance reviews: a saving grace or the devil? PMID- 23632219 TI - Speaking up. PMID- 23632220 TI - A 3-year retrospective audit of the use of noninvasive positive pressure ventilation via the Oxylog 3000 transport ventilator during air medical retrievals. AB - INTRODUCTION: The purpose of this study was to describe the safety profile of noninvasive positive pressure ventilation (NIPPV) using the Oxylog 3000 transport ventilator (Drager Medical, Lubeck, Germany) by air medical retrieval teams from the Queensland Section of the Royal Flying Doctor Service of Australia. METHODS: Over a 3-year period, patients identified in clinical transport records to have NIPPV via the Oxylog 3000 transport ventilator during air medical transfer were systematically reviewed on the clinical indication and adverse effects. RESULTS: A total of 29 patients were identified to have had treatment with NIPPV during air medical retrieval. Three patients suffered serious adverse effects of cardiorespiratory arrest during treatment. The main reported adverse event was intolerance of the facemask. There were no documented episodes of vomiting or hypotension. CONCLUSION: The use of NIPPV via the Oxylog 3000 transport ventilator during air medical retrieval requires careful patient selection. The application and management do not differ from standard hospital-based practice. PMID- 23632221 TI - Analyzing communication errors in an air medical transport service. AB - INTRODUCTION: Poor communication can result in adverse events. Presently, no standards exist for classifying and analyzing air medical communication errors. This study sought to determine the frequency and types of communication errors reported within an air medical quality and safety assurance reporting system. METHODS: Of 825 quality assurance reports submitted in 2009, 278 were randomly selected and analyzed for communication errors. Each communication error was classified and mapped to Clark's communication level hierarchy (ie, levels 1-4). Descriptive statistics were performed, and comparisons were evaluated using chi square analysis. RESULTS: Sixty-four communication errors were identified in 58 reports (21% of 278). Of the 64 identified communication errors, only 18 (28%) were classified by the staff to be communication errors. Communication errors occurred most often at level 1 (n = 42/64, 66%) followed by level 4 (21/64, 33%). Level 2 and 3 communication failures were rare (, 1%). CONCLUSION: Communication errors were found in a fifth of quality and safety assurance reports. The reporting staff identified less than a third of these errors. Nearly all communication errors (99%) occurred at either the lowest level of communication (level 1, 66%) or the highest level (level 4, 33%). An air medical communication ontology is necessary to improve the recognition and analysis of communication errors. PMID- 23632222 TI - Pneumothorax volume expansion in helicopter emergency medical services transport. AB - OBJECTIVE: In accordance with Boyle's law (as barometric pressure decreases, gas volume increases), thoracostomy is often recommended for patients with pneumothoraces before helicopter EMS (HEMS) transport. We sought to characterize altitude-related volume changes in a pneumothorax model, aiming to improve clinical decisions for preflight thoracostomy in HEMS patients. METHODS: This prospective study used 3 devices to measure air expansion at HEMS altitudes. The main device was an artificial pneumothorax model that mimicked a human pulmonary system with a 40 mL pneumothorax. In addition, volume changes were calculated in 2 spherical balloons (6 L and 25 L) by measuring equatorial circumferences. Measurements were recorded at 500-foot altitude increments from 1000 to 5000 feet above ground level. RESULTS: The 3 models exhibited volume increases of 12.7% 16.2% at 5000 feet compared to ground level. Univariate linear regression yielded similar increases, 1.27%-1.52%, in volume per 500-foot altitude increase for all 3 models. Bivariate indexed linear regression identified no association between volume increase and assessment model (P values .19 and .29). Locally weighted scatterplot smoothing (lowess) plots indicated linearity of the altitude-volume relationship. CONCLUSION: This study demonstrated predictable pneumothorax volume changes at typical HEMS altitudes. Increased understanding of altitude-related volume changes will aid decision making before transport. PMID- 23632223 TI - Helicopter transport effectiveness of patients for primary percutaneous coronary intervention. AB - BACKGROUND: For patients with ST-elevated myocardial infarction (STEMI), time to primary percutaneous coronary intervention (PCI) is an important factor in saving myocardium. Helicopter emergency medical service (HEMS) has become a vital component in regionalized cardiac care. The objective of this study is to assess the logistics of HEMS and ground EMS for interfacility transport of STEMI patients for primary PCI and to determine the effectiveness of HEMS transports in terms of the number of lives saved per 100 flights. METHODS: This is a retrospective database and records review of interfacility transports of STEMI patients for primary PCI to a single medical center. The study period consisted of 18 months (January 2010 through June 2011). RESULTS: Ninety-seven of 120 patients met the criteria for review. Of these, 66% were transported by HEMS. The pretransport patient handling times were similar for the HEMS and ground EMS groups. Door-to-PCI in < 120 minutes was achieved in 35.5% (11 of 31) of ground EMS and 24.2% (16 of 66) of HEMS. Patients transported by ground EMS were more likely to get to PCI in < 90 minutes (9.7%, 3 of 31). HEMS patients traveled significantly farther distances, 51 miles (IQR 43-68) than ground EMS, 37 miles (IQR 18-51). This equates to a 38% longer distance for patients transported by HEMS. An estimate of the driving time for HEMS-transported patients suggests HEMS transports saved a median of 41 minutes (IQR 33-48). The proportion of HEMS flights saving more than 30 minutes was 78.8% (95% CI 67.0-87.9%). CONCLUSION: The results did not show a time savings for HEMS- versus ground EMS-transported patients. When estimates of time spent for ground EMS of actual HEMS transported patients are analyzed, HEMS provides a median savings of 41 minutes, with a savings of at least 30 minutes in 78.8% of the HEMS patients. Based on estimates used in this study, conservative calculations arrived at a time-based mortality effectiveness of HEMS of about 1.2 lives saved per 100 flights. PMID- 23632224 TI - Feasibility of bedside thoracic ultrasound in the helicopter emergency medical services setting. AB - INTRODUCTION: Bedside thoracic ultrasound has been shown to be a valuable diagnostic tool in the emergency department. The purpose of this study was to evaluate the feasibility of bedside thoracic ultrasound in the prehospital HEMS setting. SETTING: Air ambulance helicopters during patient transportation. METHODS: This was a prospective pilot study. 71 consecutive, nonpregnant patients over 18 years old were enrolled. While in flight, providers completed limited bedside thoracic ultrasounds with the patient supine and recorded their interpretation of the presence or absence of the ultrasonographic sliding lung sign on a closed data-set instrument. RESULTS: 41 (58%) of the eligible patients had a recorded thoracic ultrasound acquired in flight. The level of agreement in image interpretation between the flight crew and expert reviewer was substantial (Kappa 0.67, CI 0.44-0.90). The reviewer rated 54% of all images as "good" in quality. The most common reason cited for not completing the ultrasound was lack of enough provider time or space limitations within the aircraft cabin. CONCLUSION: The results of this study suggest that, with limited training, bedside thoracic ultrasound image acquisition and interpretation for the sliding lung sign in the HEMS setting is feasible. PMID- 23632225 TI - Logistical concerns for helicopter emergency medical services response to the injured police officer. AB - INTRODUCTION: Although infrequent, helicopter emergency medical services (HEMS) have been activated to transport police officers injured in the line of duty. The purpose of this study was to query current industry operating procedures in terms of law enforcement training and operations, specifically in terms of firearms restrictions and cotransport of injured officers and suspects. METHODS: This is a survey-based study of air medical emergency medical services program managers in 2010. Descriptive statistics and the Fisher exact test were used to analyze the results. RESULTS: Fifty-eight programs (78.4%) reported transporting officers injured in the line of duty. Sixty-three respondents (85.1%) maintained a written policy addressing the presence of weapons aboard the aircraft; 58.8% of respondents replied that this restriction applied to sworn law enforcement personnel on active duty. Nearly a quarter of programs with written firearms policies have not informed the law enforcement agencies affected by these policies. Two programs reported having cotransported an injured officer and a suspect. CONCLUSION: HEMS will continue to play an important role in the care and transportation of injured officers. HEMS programs may have specific policies that impact law enforcement operations. Open communication of these policies and interagency training are critical to effective interaction during high-stress incidents. PMID- 23632226 TI - Stratification of patients in long-distance, international, fixed-wing aircraft. AB - INTRODUCTION: A growing number of individuals with significant medical histories travel for business and holidays. Precise anticipation and stratification of transport-relevant illness severity in the planning stage of an air medical evacuation is crucial for mission success and patient safety. METHODS: We developed a staging system (ie, Stratification of Air Medical Transport by Expression of Symptoms in Patients [STEP]) and applied it to 356 patients transported by a fixed wing aircraft between January 2010 and June 2011. Patients were stratified before transport, and the transport team performed independent staging of each patient during the actual transport. Data on transport modes, transport time, age, sex, diagnosis, the need for mechanical ventilation, and transport-related complications were collected. Data were analyzed for significant differences in STEP categories between operations staging and staging by the flight crew and for the correlation between operations STEP staging and actual transport acuity. RESULTS: Complete datasets were available in 353 of 356 patients. Differences between staging by operations and flight crew were documented in 31 cases (P = .809); in 18 of them, the flight crew considered the patient to be more severely affected than previously estimated. Decisions for specific transport mode and configuration were found to be adequate in all but 3 cases (99.15%). CONCLUSION: STEP is a useful tool to assess patient's illness/injury severity in the planning stage of a long distance, international, air ambulance transport and assists in choosing the appropriate mode and configuration of transport. PMID- 23632228 TI - Taxonomic evaluation of the genus Enterobacter based on multilocus sequence analysis (MLSA): proposal to reclassify E. nimipressuralis and E. amnigenus into Lelliottia gen. nov. as Lelliottia nimipressuralis comb. nov. and Lelliottia amnigena comb. nov., respectively, E. gergoviae and E. pyrinus into Pluralibacter gen. nov. as Pluralibacter gergoviae comb. nov. and Pluralibacter pyrinus comb. nov., respectively, E. cowanii, E. radicincitans, E. oryzae and E. arachidis into Kosakonia gen. nov. as Kosakonia cowanii comb. nov., Kosakonia radicincitans comb. nov., Kosakonia oryzae comb. nov. and Kosakonia arachidis comb. nov., respectively, and E. turicensis, E. helveticus and E. pulveris into Cronobacter as Cronobacter zurichensis nom. nov., Cronobacter helveticus comb. nov. and Cronobacter pulveris comb. nov., respectively, and emended description of the genera Enterobacter and Cronobacter. AB - The taxonomy of Enterobacter has a complicated history, with several species transferred to and from this genus. Classification of strains is difficult owing to its polyphyletic nature, based on 16S rRNA gene sequences. It has been previously acknowledged that Enterobacter contains species which should be transferred to other genera. In an attempt to resolve the taxonomy of Enterobacter, MLSA based on partial sequencing of protein-encoding genes (gyrB, rpoB, infB and atpD) was performed on the type strains and reference strains of Enterobacter, Cronobacter and Serratia species, as well as members of the closely related genera Citrobacter, Klebsiella, Kluyvera, Leclercia, Mangrovibacter, Raoultella and Yokenella. Phylogenetic analyses of the concatenated nucleotide sequences revealed that Enterobacter can be divided into five strongly supported MLSA groups, suggesting that the species should be reclassified into five different genera. Further support for this was provided by a concatenated amino acid tree, phenotypic characteristics and fatty acid profiles, enabling differentiation of the MLSA groups. Three novel genera are proposed: Lelliottia gen. nov., Pluralibacter gen. nov. and Kosakonia gen. nov. and the following new combinations: Lelliottia nimipressuralis comb. nov., Lelliottia amnigena comb. nov., Pluralibacter gergoviae comb. nov., Pluralibacter pyrinus comb. nov., Kosakonia cowanii comb. nov., Kosakonia radicincitans comb. nov., Kosakonia oryzae comb. nov., Kosakonia arachidis comb. nov., Cronobacter helveticus comb. nov. and Cronobacter pulveris comb. nov. Additionally, the novel epithet Cronobacter zurichensis nom. nov. is proposed for the reclassification of Enterobacter turicensis into the genus Cronobacter, as Cronobacter turicensis (Iversen et al., 2008) is already in use. PMID- 23632229 TI - Intracoronary imaging using attenuation-compensated optical coherence tomography allows better visualisation of coronary artery diseases. AB - PURPOSE: To allow an accurate diagnosis of coronary artery diseases by enhancing optical coherence tomography (OCT) images of atheromatous plaques using a novel automated attenuation compensation technique. BACKGROUND: One of the major drawbacks of coronary OCT imaging is the rapid attenuation of the OCT signal, limiting penetration in tissue to only few millimetres. Visualisation of deeper anatomy is however critical for accurate assessment of plaque burden in-vivo. METHODS: A compensation algorithm, previously developed to correct for light attenuation in soft tissues and to enhance contrast in ophthalmic OCT images, was applied to intracoronary plaque imaging using spectral-domain OCT. RESULTS: Application of the compensation algorithm significantly increased tissue contrast in the vessel wall and atherosclerotic plaque boundaries. Contrast enhancement allows a better differentiation of plaque morphology, which is particularly important for the identification of lipid rich fibro atheromatous plaques and to guide decision on treatment strategy. CONCLUSION: The analysis of arterial vessel structure clinically captured with OCT is improved when used in conjunction with automated attenuation compensation. This approach may improve the OCT-based interpretation of coronary plaque morphology in clinical practice. PMID- 23632230 TI - Subthalamic deep brain stimulation versus best medical therapy for L-dopa responsive pain in Parkinson's disease. AB - Pain is a frequently observed non-motor symptom of patients with Parkinson's disease. In some patients, Parkinson's-related pain responds to dopaminergic treatment. In the present study, we aimed to elucidate whether subthalamic deep brain stimulation has a similar beneficial effect on pain in Parkinson's disease, and whether this effect can be predicted by a pre-operative l-dopa challenge test assessing pain severity. We prospectively analyzed 14 consecutive Parkinson's patients with severe pain who underwent subthalamic deep brain stimulation. In 8 of these patients, pain severity decreased markedly with high doses of l-dopa, irrespective of the type and localization of the pain symptoms. In these patients, subthalamic deep brain stimulation provided an even higher reduction of pain severity than did dopaminergic treatment, and the majority of this group was pain-free after surgery. This effect lasted for up to 41 months. In the remaining 6 patients, pain was not improved by dopaminergic treatment nor by deep brain stimulation. Thus, we conclude that pain relief following subthalamic deep brain stimulation is superior to that following dopaminergic treatment, and that the response of pain symptoms to deep brain stimulation can be predicted by l-dopa challenge tests assessing pain severity. This diagnostic procedure could contribute to the decision on whether or not a Parkinson's patient with severe pain should undergo deep brain stimulation for potential pain relief. PMID- 23632231 TI - Characteristics of fatal child maltreatment associated with multiple births in Japan. AB - The purpose of the present study was to clarify the characteristics of fatal child maltreatment in families with multiple births in Japan. An exhaustive information search was performed to find multiple-birth cases between July 2003 and March 2011. There were 437 cases of fatal maltreatment of children aged 0-17 years during this period, including 14 involving multiple-birth children. A keyword search was performed to create a full profile for each multiple-birth case. The 14 multiple-birth victims were twins from 13 families. No significant difference between twins and singletons with fatal maltreatment was observed for most characteristics. However, in the case of twins, 0-month victims were rare, and the number of children per family was larger. One twin died from shaken baby syndrome. The victim's siblings were also maltreated in six out of 12 relevant cases, including all six co-twins. Premature birth, having a disabled co-twin, delay of growth or development, and parental disfavor tended to be factors of maltreatment when only one twin was maltreated. Four families were given suspended sentences in total, including three mothers who acted as solitary murderers (43% = 3/7). In conclusion, recent Japanese nationwide data suggests that the non-specific overburden of child rearing might be one possible reason for higher frequency of child maltreatment for multiples compared with singletons, and parental comparisons between two twins might be another. The penal sentences for fatal child maltreatment might be more lenient for perpetrators of this crime against twins than against singletons. PMID- 23632232 TI - The global organ trade: a case in point. PMID- 23632233 TI - Association of obesity with cardiovascular disease mortality in the PLCO trial. AB - OBJECTIVE: Obesity is a risk factor for cardiovascular disease (CVD) mortality, but the association between obesity and specific causes of CVD mortality is still under investigation. METHOD: We prospectively examined body-mass index (BMI) in relation to CVD-specific causes of death in approximately 86,000 US men and women in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, followed for up to 13 years. BMI was calculated from self-reported weight and height at baseline. Hazard ratios (HRs) were calculated overall and stratified by sex, smoking status, and educational level. RESULT: Overweight non-obese participants (BMI: 25.0-29.9) were not at excess risk for CVD mortality (HR and CIs are 1.02 [0.92-1.13]), compared to participants of normal BMI (18.5-24.9). Excess CVD mortality was observed for participants of BMI 30.0-34.9 (HR and CIs: 1.29 [1.13-1.48]), BMI 35.0-39.9 (HR and CIs: 1.87 [1.51-2.32]) and BMI 40.0+ (HR and CIs: 2.21 [1.57-3.21]) (p<0.001 for trend). BMI was unrelated to mortality due to stroke. The observed association of BMI with CVD was independent of gender, smoking status and educational level. CONCLUSION: Obesity is associated with increased mortality due to CVD. PMID- 23632234 TI - Spinal extradural solitary fibrous tumor with retiform and papillary features. AB - We report a 66-year-old man with a spinal, extradural solitary fibrous tumor showing unique retiform and papillary architecture. The patient presented in May 2008 with worsening right-sided lower back pain and urinary frequency. Magnetic resonance imaging of the spine documented a heterogeneously enhancing dumbbell shaped extradural lesion causing cord compression at T11/12 level. The tumor extended to the paravertebral soft tissue and invaded the right adjacent vertebral pedicles and laminae. An angiogram showed prominent vascular supply mainly from the right T11 radicular artery. The patient underwent surgery to relieve cord compression in May 2008 and a second operation following embolization with coils in October 2009. No recurrence was observed at the last neuroimaging follow-up in June 2012. The tumor was composed of vimentin, CD34, Bcl-2, and CD99-positive rounded or slightly elongated cells with scant cytoplasm and oval to spindle nuclei. Several pseudovascular spaces reminiscent of the rete testis were present, and several of them contained papillary projections. Cytologic atypia was minimal, and mitotic activity was low. Focal infiltration of the paraspinal adipose tissue was seen at microscopic level. To our knowledge, retiform and papillary features have never been reported in a solitary fibrous tumor. PMID- 23632235 TI - Effect of conjugated linoleic acid supplementation on inflammatory factors and matrix metalloproteinase enzymes in rectal cancer patients undergoing chemoradiotherapy. AB - OBJECTIVES: The aims of this study were to determine the effect of conjugated linoleic acid (CLA) supplementation on inflammatory factors and matrix metalloproteinase (MMP) enzymes in rectal cancer patients undergoing chemoradiothetrapy. METHOD AND MATERIAL: In this randomized, double-blind, placebo-controlled pilot study, 34 volunteer patients with rectal cancer undergoing chemoradiotherapy assigned into the CLA group (n = 16), receiving 3 g CLA/d, and placebo group (n = 18) receiving placebo capsules (sunflower oil) for 6 weeks. The supplementation began 1 week before starting RT (loading period) and continued every day during treatment. Before and after intervention, serum tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), IL-6, MMP-2, MMP 9, and high-sensitivity C-reactive protein (hsCRP) were measured by enzyme-linked immunosorbent assay (ELISA) kits and immunoturbidimetric method, respectively. Independent t tests and paired t tests were used to compare parameters between and within groups, respectively. RESULTS: In the CLA group, the mean serum TNF alpha, IL-1beta, hsCRP, MMP-9, and MMP-2 levels reduced insignificantly. However, significant changes in TNF-alpha (P = 0.04), hsCRP (P = 0.03), and MMP-9 (P = 0.04) concentrations were observed in the CLA group when compared with the placebo group. The mean serum IL-6 level remained unchanged in the CLA group but increased remarkably in the placebo group. CONCLUSION: According to our results, CLA supplementation improved inflammatory factors, MMP-2, and MMP-9 as biomarkers of angiogenesis and tumor invasion. It seems that CLA may provide new complementary treatment by reducing tumor invasion and resistance to cancer treatment in patients with rectal cancer. PMID- 23632236 TI - A systematic review of complementary and alternative medicine interventions for the management of cancer-related fatigue. AB - Fatigue, experienced by patients during and following cancer treatment, is a significant clinical problem. It is a prevalent and distressing symptom yet pharmacological interventions are used little and confer limited benefit for patients. However, many cancer patients use some form of complementary and alternative medicine (CAM), and some evidence suggests it may relieve fatigue. A systematic review was conducted to appraise the effectiveness of CAM interventions in ameliorating cancer-related fatigue. Systematic searches of biomedical, nursing, and specialist CAM databases were conducted, including Medline, Embase, and AMED. Included papers described interventions classified as CAM by the National Centre of Complementary and Alternative Medicine and evaluated through randomized controlled trial (RCT) or quasi-experimental design. Twenty studies were eligible for the review, of which 15 were RCTs. Forms of CAM interventions examined included acupuncture, massage, yoga, and relaxation training. The review identified some limited evidence suggesting hypnosis and ginseng may prevent rises in cancer-related fatigue in people undergoing treatment for cancer and acupuncture and that biofield healing may reduce cancer related fatigue following cancer treatments. Evidence to date suggests that multivitamins are ineffective at reducing cancer-related fatigue. However, trials incorporated within the review varied greatly in quality; most were methodologically weak and at high risk of bias. Consequently, there is currently insufficient evidence to conclude with certainty the effectiveness or otherwise of CAM in reducing cancer-related fatigue. The design and methods employed in future trials of CAM should be more rigorous; increasing the strength of evidence should be a priority. PMID- 23632237 TI - Lycopene supplementation modulates plasma concentrations and epididymal adipose tissue mRNA of leptin, resistin and IL-6 in diet-induced obese rats. AB - Obesity is characterised by chronic low-grade inflammation, and lycopene has been reported to display anti-inflammatory effects. However, it is not clear whether lycopene supplementation modulates adipokine levels in vivo in obesity. To determine whether lycopene supplementation can regulate adipokine expression in obesity, male Wistar rats were randomly assigned to receive a control diet (C, n 6) ora hyperenergetic diet (DIO, n 12) for 6 weeks. After this period, the DIO animals were randomised into two groups: DIO (n 6) and DIO supplemented with lycopene (DIO + L, n 6). The animals received maize oil (C and DIO) or lycopene (DIO + L, 10 mg/kg body weight(BW) per d) by oral administration for a 6-week period. The animals were then killed by decapitation, and blood samples and epididymal adipose tissue were collected for hormonal determination and gene expression evaluation (IL-6, monocyte chemoattractant protein-1(MCP-1), TNF alpha, leptin and resistin). There was no detectable lycopene in the plasma of the C and DIO groups. However, the mean lycopene plasma concentration was 24 nmol in the DIO + L group. Although lycopene supplementation did not affect BW or adiposity, it significantly decreased leptin, resistin and IL-6 gene expression in epididymal adipose tissue and plasma concentrations. Also, it significantly reduced the gene expression of MCP-1 in epididymal adipose tissue. Lycopene affects adipokines by reducing leptin, resistin and plasma IL-6 levels. These data suggest that lycopene may be an effective strategy in reducing inflammation in obesity. PMID- 23632238 TI - Mesodermal and neural crest derived ovine tibial and mandibular osteoblasts display distinct molecular differences. AB - Mandibular osteoblasts originate from the neural crest and deposit bone intramembranously, mesoderm derived tibial osteoblasts by endochondral mechanisms. Bone synthesized by both cell types is identical in structure, yet functional differences between the two cell types may exist. Thus, both matched juvenile and adult mandibular and tibial osteoblasts were studied regarding their proliferative capacity, their osteogenic potential and the expression of osteogenic and origin related marker genes. Juvenile tibial cells proliferated at the highest rate while juvenile mandibular cells exhibited higher ALP activity depositing more mineralized matrix. Expression of Hoxa4 in tibial cells verified their mesodermal origin, whereas very low levels in mandibular cells confirmed their ectodermal descent. Distinct differences in the expression pattern of bone development related genes (collagen type I, osteonectin, osteocalcin, Runx2, MSX1/2, TGF-beta1, BAMBI, TWIST1, beta-catenin) were found between the different cell types. The distinct dissimilarities in proliferation, alkaline phosphatase activity, the expression of characteristic genes, and mineralization may aid to explain the differences in bone healing time observed in mandibular bone when compared to long bones of the extremities. PMID- 23632239 TI - A 914-bp promoter is sufficient to reproduce the endogenous prolyl oligopeptidase gene localization in the mouse placenta if not subject to position effect. AB - Prolyl oligopeptidase (POP) is a widely distributed multifunctional protein which has an endopeptidase activity to cleave a Pro-X peptide bond. In spite of numerous studies about POP, the mechanism by which its transcription is controlled has not been well investigated. Here we generated transgenic mice bearing a transgene which contained a 914-bp POP gene promoter linked to the enhanced green fluorescent protein (EGFP) gene to assess the in vivo promoter activity. We established six transgenic lines with different copy numbers, but no EGFP signal was observed in four lines due to a high level of DNA methylation, which suggested that the transgene was subject to position effect. However, in the other two lines, we detected the EGFP expression in many tissues, and its placental localization showed a similar change to POP. A strong EGFP signal was observed in the junctional and labyrinthine zones of E10.5-E12.5 placentas and in the junctional zone and the maternal decidua after that. This placental gene activation might be attributed to AP-2gamma because we detected its binding to the POP promoter. In contrast, we did not obtain any evidence that EGFP was expressed in a similar pattern compared with POP in the ovary. The current data demonstrated that the 914-bp promoter had sufficient activity to reproduce the POP localization in the placenta if it was not subject to position effect and suggest that the regulatory mechanism of the POP gene expression differs between tissues. PMID- 23632240 TI - Promoter polymorphisms of pri-miR-34b/c are associated with hepatocellular carcinoma. AB - BACKGROUND: Numerous studies have focused on the association between miR-34 family members, which are direct p53 targets, and carcinogenesis of many cancers, including hepatocellular carcinoma (HCC). This study aimed to assess whether polymorphisms in the single-nucleotide polymorphism miR-34b/c T>C (rs4938723) and TP53 Arg72Pro (rs1042522) increase the risk of HCC and influence outcome in patients with HCC. PATIENTS AND METHODS: We enrolled 157 HCC patients and 201 cancer-free control subjects from the Korean population. MicroRNA polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: We found that the miR-34b/c TC+CC frequency was significantly higher in HCC patients than in controls (adjusted odds ratio [AOR]: 1.580; 95% confidence interval [CI]: 1.029-2.426). The miR 34b/c CC-TP53 Arg/Arg combination significantly increased the risk of HCC (AOR: 13.644; 95% CI: 1.451-128.301). The SNPs miR-34b/c T>C and TP53 Arg72Pro(G>C) had no influence on survival of HCC patients. CONCLUSIONS: Our findings suggest that loss of the T allele in miR-34b/c T>C, and the miR-34b/c CC-TP53 Arg/Arg combination increases the risk of HCC in the Korean population. PMID- 23632241 TI - Sperm morphology and phylogeny of lagriids (Coleoptera, Tenebrionidae). AB - The systematics of tenebrionids remain unclear, principally at the subfamily level, as is the case of the Lagriinae. Considering that sperm morphology has contributed to the various insect group phylogenies, in this work we describe the structure and ultrastructure of these cells in Lagria villosa. Sperm in this species exhibit a strong morphological similarity to those of Tenebrio molitor and Tribolium castaneum, the only two species of Tenebrionidae with previously described sperm. In tenebrionids, the flagellar components offer good diagnostic characters, e.g. the symmetry of mitochondrial derivatives in L. villosa differentiates sperm of this species from those of Te. molitor and Tr. castaneum. However, the lateral association of the nucleus with flagellar components, the form of accessory bodies, and the presence of material connecting the axoneme to the accessory bodies and mitochondrial derivatives indicate that the three species form a sister group. Therefore, the sperm morphology of L. villosa support lagriid beetles as a subfamily (Lagriinae) of Tenebrionidae. PMID- 23632243 TI - Re-endovascular recanalization for acute middle cerebral artery reocclusion after surgical embolectomy. AB - A 62-year-old woman with atrial fibrillation underwent burr hole trephination for a chronic subdural hematoma. Two days later the patient suddenly presented with motor dysphasia and slightly decreased motor power. Time of flight MR angiography revealed distal M1 occlusion without diffusion restriction. Stent-assisted mechanical thrombectomy was attempted but failed. Post-procedure MRI illustrated a small area of diffusion restriction within the peri-insular and parietal areas. Immediate surgical embolectomy was performed but reocclusion of M1 was documented in the postoperative angiography. Stent-assisted revascularization with a Solitaire stent was conducted and immediate restoration of blood flow was observed. The patient's motor weakness and motor dysphasia recovered fully. Re endovascular intervention can be beneficial in selected patients for acute middle cerebral artery reocclusion after surgical embolectomy when endovascular thrombectomy fails. PMID- 23632244 TI - Effects of sorption kinetics on the fate and transport of pharmaceuticals in estuaries. AB - Many current fate and transport models based on the assumption of instantaneous sorption equilibrium of contaminants in the water column may not be valid for certain pharmaceuticals with long times to reach sorption equilibrium. In this study, a sorption kinetics model was developed and incorporated into a water quality model for the Patuxent River Estuary to evaluate the effect of sorption kinetics. Model results indicate that the assumption of instantaneous sorption equilibrium results in significant under-prediction of water column concentrations for some pharmaceuticals. The relative difference between predicted concentrations for the instantaneous versus kinetic approach is as large as 150% at upstream locations in the Patuxent Estuary. At downstream locations, where sorption processes have had sufficient time to reach equilibrium, the relative difference decreases to roughly 25%. This indicates that sorption kinetics affect a model's ability to capture accumulation of pharmaceuticals into riverbeds and the transport of pharmaceuticals in estuaries. These results offer strong evidence that chemicals are not removed from the water column as rapidly as has been assumed on the basis of equilibrium-based analyses. The findings are applicable not only for pharmaceutical compounds, but also for diverse contaminants that reach sorption equilibrium slowly. PMID- 23632245 TI - Sorption and distribution of asphaltene, resin, aromatic and saturate fractions of heavy crude oil on quartz surface: molecular dynamic simulation. AB - The molecular scale sorption, diffusion and distribution of asphaltene, resin, aromatic and saturate fractions of heavy crude oil on quartz surface were studied using molecular dynamic simulation. Sorption of saturates on quartz decreased by 31% when temperature increased from 298 to 398K while opposite trend was observed for resins, but insignificant changes were found in asphaltenes and aromatics. Despite of this variety, the main contribution of interactions was van der Waals energy (>90%) irrespective of molecular components and temperatures. The diffusion coefficient of saturates was predicted as 10.8*10(-10)m(2)s(-1) while that of the remaining fractions was about 4*10(-10)m(2)s(-1) at 298K. The most likely oil distribution on quartz surface was that aromatics and saturates transported randomly into and out of the complex consisting of asphaltenes surrounded by resins, which was influenced by temperature. Overall, the knowledge on quartz-oil and oil-oil interactions gained in this study is essential for future risk assessment and remediation activities as previous studies on soil remediation either limited to light oil fractions with <40 carbons or treated the heavy crude oil as a single pseudo entity ignoring the interactions between oil fractions. PMID- 23632246 TI - Assessment of cytogenetic damage in bovine peripheral lymphocytes exposed to in vitro tebuconazole-based fungicide. AB - The tebuconazole-based fungicide was tested in vitro for its potential genotoxic and cytotoxic effects on cultured bovine peripheral lymphocytes. Following 24h and 48 h of incubation, several cytogenetic endpoints were investigated such as: Chromosome Aberrations (CAs); Sister Chromatid Exchanges (SCEs); Micronuclei (MN); Mitotic Index (MI); Proliferation Index (PI); and Cytokinesis Block Proliferation Index (CBPI). The cultured lymphocytes were exposed to the fungicide formulation at concentrations of 3, 6, 15, 30 and 60 MUg mL(-1). Statistical significant increases were seen in the CA assays at concentrations ranging from 6 to 30 MUg mL(-1) for 24h. The higher doses caused a decrease or total inhibition of chromosome damages in comparison to the last active dose, or the control values. The Fluorescence in situ Hybridisation (FISH) technique was also used for the study of stable/unstable structural chromosomal aberrations and numerical aberrations of aneuploidy/polyploidy at the concentrations of 6 and 15 MUg mL(-1). Under conditions of our study, no reciprocal translocations were detected. The more frequent types of aberrations were trisomies and monosomies; both have been identified in association with either bovine chromosome 5 or 7. No statistical significant value was seen in the induced MN; but, the clear, evident reduction of the CBPI was observed. Significant elevations of SCE were observed after the applications of the fungicide formulation at doses from 15 to 60 MUg mL(-1) in each donor for 24h. The highest concentrations also caused a statistical significant decrease in the PI. The treatment for 48 h failed to exhibit any genotoxic activity of the fungicide. PMID- 23632249 TI - Identification, clinical aspects, susceptibility pattern, and molecular epidemiology of beta-haemolytic group G Streptococcus anginosus group isolates from central Taiwan. AB - No literature is available on the prevalence and clinical aspects of beta haemolytic group G Streptococcus anginosus group in central Taiwan. In this study, we used 16S rRNA gene sequencing and 16S-23S rDNA intergenic spacer sequencing (where necessary) as the gold standard for molecular identification. Twenty-seven S. anginosus group isolates were identified from 273 beta-haemolytic GGS isolates collected from patients in central Taiwan between February 2007 and August 2011. Of the 27 isolates, 22 were S. anginosus and 5 were Streptococcus constellatus. The 3 commercial methods, Rapid ID 32 Strep, API 20 Strep, and Vitek 2 GP card, identified 77.8%, 40.7%, and 37.0% of S. anginosus group isolates, respectively, with acceptable %ID or probability level. All the S. constellatus isolates possessed the lmb gene (encoding laminin-binding protein); however, none of the S. anginosus isolates possessed this gene. All the 27 isolates were susceptible to penicillin. Five S. anginosus group isolates (18.5%) were resistant to erythromycin. The resistance genes, ermB and mefA, were detected in 3 (2 S. anginosus and 1 S. constellatus) and 2 (2 S. anginosus) isolates, respectively. Pulsed field gel electrophoresis showed that most S. anginosus group isolates were genetically diverse. This is the first study to evaluate 3 commercial methods for the identification of beta-haemolytic group G S. anginosus group species, and only the Rapid ID 32 Strep system showed considerable ability. The clinical aspects, susceptibility pattern, and molecular epidemiology of beta-haemolytic group G S. anginosus group isolates from central Taiwan were also first presented. PMID- 23632248 TI - Structural studies on the regulation of Ca2+/calmodulin dependent protein kinase II. AB - Ca(2+)/calmodulin dependent protein kinase II (CaMKII) is a broadly distributed metazoan Ser/Thr protein kinase that is important in neuronal and cardiac signaling. CaMKII forms oligomeric assemblies, typically dodecameric, in which the calcium-responsive kinase domains are organized around a central hub. We review the results of crystallographic analyses of CaMKII, including the recently determined structure of a full-length and autoinhibited form of the holoenzyme. These structures, when combined with other data, allow informed speculation about how CaMKII escapes calcium-dependence when calcium spikes exceed threshold frequencies. PMID- 23632250 TI - Comparison of LED and conventional fluorescence microscopy for detection of acid fast bacilli in an area with high tuberculosis incidence. AB - The objective of the study is to compare the performance of conventional fluorescence microscopy (CFM) and light-emitting diode (LED) fluorescence microscopy (FM) for detection of acid-fast bacilli (AFB) in clinical samples. We included AFB smears, stained using the auramine O method and blindly examined with both CFM and LED-FM. Culture results were used as reference for evaluating the reliability of the FM. We included 180 culture positive specimens and an equal number of culture negative specimens. Sensitivities for the CFM and LED-FM were 79.4% and 82.2%, respectively. Both microscopes had a high specificity (97.2%). The negative-positive (>1 cross) inter-reader agreement of LED-FM and CFM was excellent. Therefore, detection of scanty AFB was higher with LED-FM. Both microscopes were equivalent with respect to time required to read smears. Although it was not faster than CFM, the higher detection of scanty AFB smears combined with ease of use supports the consideration of LED microscopy by all tuberculosis diagnostic laboratories, as a replacement for conventional fluorescence microscopes. PMID- 23632251 TI - Soil moisture modulates the effects of the timing and amount of rainfall on faecal moisture and development of Haemonchus contortus and Trichostrongylus colubriformis to infective third stage larvae. AB - Recent experiments on the effects of rainfall and/or soil moisture (SM) on development of sheep gastro-intestinal nematodes to infective L3 stage have used soil of relatively low moisture content in small experimental samples that dry out faster than field soil. To determine whether higher and more sustained SM content modulates the effects of rainfall amount and timing on faecal moisture (FM) and development of H. contortus and T. colubriformis to infective third stage larvae (L3), a climate-controlled chamber experiment was conducted. It was designed to test the effects of rainfall amount (0, 12 and 24 mm), rainfall timing (days -1, 0 and 3 relative to faecal deposition) and soil moisture maintained at 10, 20 and 30% on these variables. Total recovery of L3 14 days after faecal deposition was significantly affected by SM, rainfall timing and their interaction (P<0.01), but not by rainfall amount or species or other two way interactions. Recovery of L3 was maximal (28%) with a SM treatment of 30% and simulated rainfall on day 3. Faecal moisture was significantly affected by collection day, SM treatment, rainfall amount and rainfall timing with significant interaction between many of these effects (P<0.05). A positive linear association between FM and total L3 recovery was strongest on day 4 after faecal deposition (R(2)=0.64, P<0.001) for H. contortus and day 6 (R(2)=0.78, P<0.001) for T. colubriformis. Overall the results show that SM is able to modulate the effects of rainfall timing and amount with increased SM acting to broaden the window of opportunity for the free-living stages to respond to post deposition rainfall to complete development to L3. If SM is maintained in the range 10-30%, the reported benefits of early rainfall (days -1 and 0) of up to 24 mm appear to be negated with later rainfall (day 3) proving more beneficial. These results require field confirmation. PMID- 23632252 TI - Identification, expression profiling of a grass carp TLR8 and its inhibition leading to the resistance to reovirus in CIK cells. AB - TLR8 (toll-like receptor 8), a homolog of TLR3, TLR7 and TLR9 as prototypical intracellular members of TLR family, is generally associated with sensing single stranded RNA and plays a pivotal role in antiviral immune response. In this study, a TLR8 gene from grass carp Ctenopharyngodon idella (designated as CiTLR8) was obtained and characterized. The full-length cDNA of CiTLR8 was of 3766 bp. The open reading frame was of 3072 bp and encoded a polypeptide of 1023 amino acids, including seventeen LRR (leucine-rich repeat) motifs, one transmembrane domain and one TIR (toll/interleukin-1 receptor) domain. A single intron with the size of 839 bp was found on the neck of start codon (ATG). CiTLR8 mRNA was ubiquitously expressed in the 15 tested tissues and the expression level in gas bladder, spleen, brain, hindgut and trunk kidney tissues was high. Besides, the CiTLR8 expression in spleen and head kidney was significantly up-regulated and reached peak at 24 h post-injection of grass carp reovirus (GCRV). CiTLR8 transcription reached peak at 8 h and then declined below the normal level post GCRV infection in the C. idella kidney (CIK) cell line; and it was rapidly and significantly down-regulated by the stimulation of the synthetic double-stranded RNA polyriboinosinic-polyribocytidylic acid sodium salt (poly I:C) in CIK cells in a dose and time-dependent manner. The inhibitor expression vectors were constructed and transfected into CIK cell line to obtain stably expressing shRNA targeting TLR8. In CiTLR8-knockdown cells, CiTLR7 transcript weakly increased, CiIFN-I mRNA was significantly down-regulated, and the expression of CiMyD88, CiIRF7 and CiMx1 scarcely changed. Post poly I:C stimulation, CiTLR8, CiTLR7 and CiMyD88 transcripts significantly increased, CiIRF7 was down-regulated after an initial phase of increase, and CiIFN-I and CiMx1 transcripts were up-regulated. After GCRV infection, the transcripts of CiTLR8, CiTLR7, CiMyD88 and CiIRF7 were up-regulated, but CiIFN-I and CiMx1 transcripts were inhibited. Nevertheless, cells transfected with pshTLR8 vectors had strong resistance against GCRV injection, suggesting CiTLR8 might play a negative role in antiviral immune response. These results collectively suggested that CiTLR8 was a novel member of TLR gene family, engaging in antiviral innate immune defense in C. idella, which laid a foundation for the further mechanism research of TLR8 in fishes. PMID- 23632254 TI - Identification of cathepsin B in the razor clam Sinonovacula constricta and its role in innate immune responses. AB - Cathepsin B, a lysosomal cysteine protease, has drawn much attention in vertebrates. However, very little is known about the functions of cathepsin B in bivalves. In this study, we identified the cathepsin B gene in the razor clam Sinonovacula constricta. The protein has a typical cysteine protease structure, comprising a 15-residue putative signal peptide, a 75-residue propeptide and a 249-residue mature domain. In the mature domain, there is an occluding loop, an oxyanion hole (Gln) and a catalytic triad (Cys, His and Asn). The cathepsin B gene is expressed in a wide range of tissues but appears to exhibit greatest level of expression in the liver. During the early developmental stages, the transcript could be detected widely. After the clam was infected with Vibrio anguillarum, the expression of the cathepsin B gene showed the most significant up-regulation in the liver and mantle tissues at 8h after infection. The fact that bacterial infection can induce the expression of the cathepsin B transcript suggests that cathepsin B could play an important role in the innate immunity of clams. PMID- 23632255 TI - Nonphysician-assisted suicide in Switzerland. PMID- 23632256 TI - Estimation of trochanteric soft tissue thickness from dual-energy X-ray absorptiometry. PMID- 23632253 TI - Conventional and non-conventional Drosophila Toll signaling. AB - The discovery of Toll in Drosophila and of the remarkable conservation in pathway composition and organization catalyzed a transformation in our understanding of innate immune recognition and response. At the center of that picture is a cascade of interactions in which specific microbial cues activate Toll receptors, which then transmit signals driving transcription factor nuclear localization and activity. Experiments gave substance to the vision of pattern recognition receptors, linked phenomena in development, gene regulation, and immunity into a coherent whole, and revealed a rich set of variations for identifying non-self and responding effectively. More recently, research in Drosophila has illuminated the positive and negative regulation of Toll activation, the organization of signaling events at and beneath membranes, the sorting of information flow, and the existence of non-conventional signaling via Toll-related receptors. Here, we provide an overview of the Toll pathway of flies and highlight these ongoing realms of research. PMID- 23632257 TI - An update to MitoTool: using a new scoring system for faster mtDNA haplogroup determination. AB - The determination of human mitochondrial DNA (mtDNA) haplogroups is not only crucial in anthropological and forensic studies, but is also helpful in the medical field to prevent establishment of wrong disease associations. In recent years, high-throughput technologies and the huge amounts of data they create, as well as the regular updates to the mtDNA phylogenetic tree, mean that there is a need for an automated approach which can make a speedier determination of haplogroups than can be made by using the traditional manual method. Here, we update the MitoTool (www.mitotool.org) by incorporating a novel scoring system for the determination of mtDNA into haplogroups, which has advantages on speed, accuracy and ease of implementation. In order to make the access to MitoTool easier, we also provide a stand-alone version of the program that will run on a local computer and this version is freely available at the MitoTool website. PMID- 23632259 TI - Echinococcus granulosus genotype G1 dominated in cattle and sheep during 2003 2006 in Buenos Aires province, an endemic area for cystic echinococcosis in Argentina. AB - Cystic echinococcosis (hydatidosis) is a severe and widespread disease, caused by the larval stage of the tapeworm Echinococcus granulosus; it affects large numbers of humans and farm animals annually, causing serious health and economic problems. Molecular studies have identified large genetic variation within the E. granulosus complex, with various hosts displaying different susceptibility to different genotypes. For the effective management of the disease, one of the most pressing tasks is to combine epidemiological and genetic data to better understand the role of different hosts and genotypes in the transmission of the parasite. The aim of the present study was to describe the epidemiology of cystic echinococcosis in cattle and sheep, and to characterise the genotypes of E. granulosus present in these farm animals. The study was carried out in the Pampa region of Argentina, with a particular focus on Buenos Aires province, where cystic echinococcosis represents an important human and veterinary health problem. Among 513 cattle and 792 sheep, 11.9% and 4.0%, respectively, were infected with E. granulosus. Genetic characterisation of 42 isolates from cattle and 34 isolates from sheep was carried out by sequencing mitochondrial cox1 and nad1 genes. The vast majority of isolates were identified as genotype G1, except for a single sheep isolate determined as genotype G2, and a single cattle isolate that corresponded to genotype G5. Genotype G1 has previously been found to be the most infectious genotype to humans. As G1 was also the genotype principally responsible for cystic echinococcosis in Buenos Aires province, these results have important implications for developing effective disease control programmes to improve human and animal healthcare in this region. PMID- 23632258 TI - Pilot field trial of the EG95 vaccine against ovine cystic echinococcosis in Rio Negro, Argentina: early impact and preliminary data. AB - Cystic echinococcosis is endemic in the Rio Negro province of Argentina. After 30 years of control using praziquantel in dogs the transmission rate to humans and sheep has decreased significantly, however transmission persists. The objective of the study is to assess the impact of the inclusion of the EG95 vaccine for sheep in the control programme, including analysis of the vaccine's operative feasibility in field conditions. The vaccine was applied in an area comprising four communities of native people including 79 farms with 3146 lambs and 311 dogs in total. Seventy one farms were designated as control areas where no vaccinations were undertaken while vaccinations of lambs undertaken on 91 farms. Lambs received two vaccinations with the EG95 vaccine followed by a single booster injection when the animals were 1-1.5 years of age. Farm locations were defined using GPS coordinates for the houses. Evidence for Echinococcus granulosus transmission was monitored by coproantigen ELISA on samples of dog faeces, by E. granulosus-specific PCR using soil samples, and anti-E. granulosus antibody assessments in sera from 2 to 4 teeth lambs, purgation of dogs to detect E. granulosus worms and necropsy on adult sheep. Before the vaccine was introduced, 26.2% of sheep with 2-4 teeth were positive using ELISA/WB, the prevalence decreased to 7.8% at the third year following use of the vaccine. Necropsy of animals older than 6 years (not vaccinated) showed that 66.1% of animals were infected with E. granulosus. In dogs, 4% was found positive for E. granulosus using arecoline purgation and 24.7% of the farms were infected using coproELISA/WB. During the first year of vaccination 2721 lambs received the first vaccine dose and 2448 received a booster. In the second year 2138 lambs were initially vaccinated and 1745 received a booster, and 1308 animals received the third dose. During the third year 1110 lambs received the first dose from which 539 received a booster and 723 animals received the third dose. An analysis of advantages and limitations of the diagnostic techniques used and the ability of the geospatial analysis to detect risk area are included. Based in the immunodiagnostic techniques, the EG95 vaccine has been able to prevent the infection in animals up to 3 years old. Also, the difficulties in the field for the correct vaccine administration and the social features and habits that may impact on echinococcosis control are included in the analysis. PMID- 23632260 TI - Oral propranolol versus placebo for retinopathy of prematurity: a pilot, randomised, double-blind prospective study. PMID- 23632261 TI - Influence of filter choice on 18F-FDG PET segmentation accuracy determined using generalized estimating equations. AB - This study aims to quantify how filter choice affects several fluoro-deoxy glucose (FDG)-positron emission tomography (PET) segmentation methods and present the use of model fitting via generalized estimating equations (GEEs) to appropriately account for the properties of a common segmentation quality metric (Dice similarity coefficient). Spherical and irregularly shaped 'hot' objects filled with 18F-FDG were placed in a medium with background activity and imaged for 1, 2 and 5 min durations at low and high contrasts. Images were filtered with Gaussian and bilateral filters of 5 and 7 mm full-width half maximum (FWHM), with and without 3 mm FWHM Gaussian pre-smoothing. Four segmentation methods were used: 40% thresholding, adaptive thresholding, k-means clustering and seeded region-growing. Segmentation accuracy was quantified by overlap (using Dice similarity coefficient (DSC)) and distance between surfaces (using symmetric-mean absolute-surface-distance (SMASD)) of the ground truth and segmented volumes. All segmentation methods showed mean DSC values between 0.71-0.87 and mean SMASD values between 0.72-2.10 mm across filters. The bilateral filter with 3 mm FWHM Gaussian pre-smoothing had mean DSC 0.80 +/- 0.17 and mean SMASD 1.17 +/- 1.51 mm displaying approximately equal performance to a 5 mm Gaussian filter with mean DSC 0.79 +/- 0.18 and mean SMASD 1.27 +/- 1.52 mm. Results from models fit using GEE with a binomial distribution and exchangeable correlation structure estimated the correlation between DSC values as 0.118 and 0.290 for spheres and irregular objects, respectively. The GEE approach accounts for several factors specific to the DSC metric that simpler statistical approaches do not, providing more accurate estimations of experimental effects commonly associated with nuclear medicine segmentation studies. PMID- 23632262 TI - Polyurethane-based drug delivery systems. AB - Polyurethanes (PUs) are formed by a reaction between isocyanates and diols to yield polymers with urethane bonds (-NH-COO-) in their main chain. A great variety of building blocks is commercially available that allows the chemical and physical properties of PUs to be tailored to their target applications, particularly for the biomedical and pharmaceutical fields. This article reviews the synthesis and characterization of PUs and PU-copolymers, as well as their in vitro and in vivo biodegradability and biocompatibility. Particular emphasis is placed on the use of PUs for the controlled release of drugs and for the (targeted) delivery of biotherapeutics. PMID- 23632263 TI - Development of PIK-75 nanosuspension formulation with enhanced delivery efficiency and cytotoxicity for targeted anti-cancer therapy. AB - PIK-75 is a phosphatidylinositol 3-kinase (PI3K) inhibitor that shows selectivity toward p110-alpha over the other PI3K class Ia isoforms p110-beta and p110-delta, but it lacks solubility, stability and other kinase selectivity. The purpose of this study was to develop folate-targeted PIK-75 nanosuspension for tumor targeted delivery and to improve therapeutic efficacy in human ovarian cancer model. High pressure homogenization was used to prepare the non-targeted and targeted PIK-75 nanosuspensions which were characterized for size, zeta potential, entrapment efficiency, morphology, saturation solubility and dissolution velocity. In vitro analysis of drug uptake, cell viability and cell survival was conducted in SKOV-3 cells. Drug pharmacokinetics and pAkt expression were determined in SKOV-3 tumor bearing mice. PIK-75 nanosuspensions showed an improvement in dissolution velocity and an 11-fold increase in saturation solubility over pre-milled PIK-75. In vitro studies in SKOV-3 cells indicated a 2 fold improvement in drug uptake and 0.4-fold decrease in IC50 value of PIK-75 following treatment with targeted nanosuspension compared to non-targeted nanosuspension. The improvement in cytotoxicity was attributed to an increase in caspase 3/7 and hROS activity. In vivo studies indicated a 5-10-fold increased PIK-75 accumulation in the tumor with both the nanosuspension formulations compared to PIK-75 suspension. The targeted nanosuspension showed an enhanced downregulation of pAkt compared to non-targeted formulation system. These results illustrate the opportunity to formulate PIK-75 as a targeted nanosuspension to enhance uptake and cytotoxicity of the drug in tumor. PMID- 23632264 TI - Retinal vascular calibers associate differentially with cerebral gray matter and white matter atrophy. AB - Cerebral small-vessel disease is thought to contribute to brain atrophy, but it remains unclear whether it affects the gray matter and white matter atrophy differentially. Retinal vessels provide a direct measure to study cerebral small vessel disease in vivo. In a cohort of 1065 persons (mean age, 67.5 y and 51% women), from the population-based Rotterdam Study, we investigated how retinal vascular calibers relate to brain atrophy and to gray matter and white matter atrophy separately. Retinal arteriolar and venular calibers were semiautomatically measured on digitized fundus transparencies. Using automated quantification of MRI scans, we obtained whole-brain volume and volumes of gray matter and white matter. Both narrower arteriolar and wider venular calibers were associated with smaller brain volume, independent from each other. These associations were primarily driven by smaller white matter volume, whereas no associations were seen for gray matter volume. Adjustments for cardiovascular risk factors attenuated the results, but wider venular caliber remained borderline significantly associated with smaller white matter volume. Our data provide evidence that cerebral small-vessel disease contributes to brain atrophy primarily by affecting the cerebral white matter. PMID- 23632266 TI - Determining the predictors of change in quality of life self-ratings and carer ratings for community-dwelling people with Alzheimer disease. AB - The aim of this study was to determine the factors that mediate changes in Health Related Quality of Life (HRQoL) ratings by community-dwelling people with Alzheimer disease (AD) and carers over a period of 18 months. We completed an 18 month longitudinal study of 80 community-dwelling older adults diagnosed with probable AD of mild or moderate severity (NINCDS-ADRD criteria) and their family carers. The primary outcome of interest was the 18-month change in HRQoL ratings as measured with the Quality of Life-AD (QoL-AD) (by carer and by self). Explanatory variables included demographics, lifestyle, cognition, awareness, psychopathology, burden-of-care, use of medication, and functionality in daily life. We found a significant decline (8.7%, P=0.003) in QoL-AD carer-ratings, but not in self-ratings. The final parsimonious model of predictors of changes in QoL AD self-ratings explained 22.6% of the variance; only changes on Hospital Anxiety and Depression Scale Anxiety retained significance. The final model of predictors of changes in carer-ratings explained 55.0% of the variance: that is, changes on Informant Questionnaire on Cognitive Decline in the Elderly, changes on Hospital Anxiety and Depression Scale Depression, practicing hobbies at 18 months, and number of visit(s) or admission(s) to hospital. HRQoL self-ratings and carer ratings of community-dwelling people with AD do not decline at same rate over 18 months and changes are associated with different factors. Interventions designed to optimize quality of life of people with AD should consider carefully whose HRQoL ratings they wish to change. PMID- 23632265 TI - Retrospective and prospective data collection compared in the Dutch End Of Life in Dementia (DEOLD) study. AB - Studying end of life in dementia patients is challenging because of ill-defined prognoses and frequent inability to self-report. We aim to quantify and compare (1) feasibility and (2) sampling issues between prospective and retrospective data collection specific to end-of-life research in long-term care settings. The observational Dutch End of Life in Dementia study (DEOLD; 2007 to 2011) used both prospective data collection (28 facilities; 17 nursing home organizations/physician teams; questionnaires between January 2007 and July 2010, survival until July 2011) and retrospective data collection (exclusively after death; 6 facilities; 2 teams, questionnaires between November 2007 and March 2010). Prospective collection extended from the time of admission to the time after death or conclusion of the study. Prospectively, we recruited 372 families: 218 residents died (59%) and 184 (49%) had complete physician and family after death assessments. Retrospectively, 119 decedents were enrolled, with 64 (54%) complete assessments. Cumulative data collection over all homes lasted 80 and 8 years, respectively. Per complete after-death assessments in a year, the prospective data collection involved 37.9 beds, whereas this was 7.9 for the retrospective data collection. Although age at death, sex, and survival curves were similar, prospectively, decedents' length of stay was shorter (10.3 vs. 31.4 mo), and fewer residents had advanced dementia (39% vs. 54%). Regarding feasibility, we conclude that prospective data collection is many fold more intensive and complex per complete after-death assessment. Regarding sampling, if not all are followed until death, it results in right censoring and in different, nonrepresentative samples of decedents compared with retrospective data collection. Future work may adjust or stratify for dementia severity and length of stay as key issues to promote comparability between studies. PMID- 23632267 TI - Pulse wave velocity and cognitive function in older adults. AB - Arterial stiffness may be associated with cognitive function. In this study, pulse wave velocity (PWV) was measured from the carotid to femoral (CF-PWV) and from the carotid to radial (CR-PWV) with the Complior SP System. Cognitive function was measured by 6 tests of executive function, psychomotor speed, memory, and language fluency. A total of 1433 participants were included (mean age 75 y, 43% men). Adjusting for age, sex, education, pulse rate, hemoglobin A1C, high-density lipoprotein cholesterol, hypertension, cardiovascular disease history, smoking, drinking, and depression symptoms, a CF-PWV>12 m/s was associated with a lower Mini-Mental State Examination score (coefficient: -0.31, SE: 0.11, P=0.005), fewer words recalled on Auditory Verbal Learning Test (coefficient: -1.10, SE: 0.43, P=0.01), and lower score on the composite cognition score (coefficient: -0.10, SE: 0.05, P=0.04) and marginally significantly associated with longer time to complete Trail Making Test-part B (coefficient: 6.30, SE: 3.41, P=0.06), CF-PWV was not associated with Trail Making Test-part A, Digit Symbol Substation Test, or Verbal Fluency Test. No associations were found between CR-PWV and cognitive performance measures. Higher large artery stiffness was associated with worse cognitive function, and longitudinal studies are needed to confirm these associations. PMID- 23632268 TI - A risk stratification model of acute pyelonephritis to indicate hospital admission from the ED. AB - OBJECTIVES: There are no guidelines regarding the hospitalization of female patients with acute pyelonephritis (APN); therefore, we performed a retrospective analysis to construct a clinical prediction model for hospital admission. METHODS: We conducted a retrospective analysis of a prospective database of women diagnosed as having APN in the emergency department between January 2006 and June 2012. Independent risk factors for admission were determined by multivariable logistic regression analysis in half of the patients in this database. The risk of admission was categorized into 5 groups. The internal and external validations were conducted using the remaining half of the patients and 192 independent patients, respectively. RESULTS: Independent risk factors for admission were age of 65 years or greater (odds ratio [OR], 2.62; 1 point), chill (OR, 2.40; 1 point), and the levels of segmented neutrophils greater than 90% (OR, 2.00; 1 point), serum creatinine greater than 1.5 mg/dL (OR, 2.41; 1 point), C-reactive protein greater than 10 mg/dL (OR, 2.37; 1 point), and serum albumin less than 3.3 g/dL (OR, 7.36; 2 points). The admission risk scores consisted of 5 categories, which were very low (0 points; 5.9%), low (1 point; 10.7%), intermediate (2 points; 20.7%), high (3-4 points; 51.9%), and very high (5-7 points; 82.8%) risk, showing an area under the curve of 0.770. The areas under the curve of the internal and external validation cohorts were 0.743 and 0.725, respectively. CONCLUSION: This model can provide a guideline to determine the admission of women with APN in the emergency department. PMID- 23632269 TI - Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)-1 oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BMS 742413): a potent human CGRP antagonist with superior safety profile for the treatment of migraine through intranasal delivery. AB - Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the potential to provide rapid onset of action through intranasal delivery. The compound displays excellent aqueous solubility, oxidative stability, and toxicological profile. BMS 742413 has good intranasal bioavailability in the rabbit and shows a robust, dose dependent inhibition of CGRP-induced increases in marmoset facial blood flow. PMID- 23632270 TI - Discovery of potent transient receptor potential vanilloid 1 antagonists: design and synthesis of phenoxyacetamide derivatives. AB - We aimed to discover a novel type of transient receptor potential vanilloid 1 (TRPV1) antagonist because such antagonists are possible drug candidates for treating various disorders. We modified the structure of hit compound 7 (human TRPV1 IC50=411 nM) and converted its pyrrolidino group to a (hydroxyethyl)methylamino group, which substantially improved inhibitory activity (15d; human TRPV1 IC50=33 nM). In addition, 15d ameliorated bladder overactivity in rats in vivo. PMID- 23632271 TI - Art promoting mental health literacy and a positive attitude towards people with experience of mental illness. AB - BACKGROUND: Exhibitions of art by people with experience of mental illness are increasingly being staged to improve awareness of mental health issues in the general community and to counter the stigma of mental illness. However, few exhibitions have incorporated research to ascertain their actual effectiveness. METHOD: This paper reports the results of a study that considered the responses of 10,000 people after they viewed exhibitions of art produced by people with experience of mental illness. These works were selected from the Cunningham Dax Collection, one of the world's most extensive collection of artworks by people with experience of mental illness and/or psychological trauma. RESULTS: More than 90% of respondents agreed with three propositions that the exhibitions helped them: (1) gain a better understanding of mental illness; (2) gain a more sympathetic understanding of the suffering of people with mental illness; and (3) appreciate the ability and creativity of people with mental illness. CONCLUSION: The results suggest that exhibitions can successfully promote mental health literacy and contribute to positive attitudes towards people with experience of mental illness. This paper explores these findings and raises questions about how the presentation of artworks in an exhibition influences their effectiveness in mental health promotion. PMID- 23632272 TI - Effects of a question prompt sheet on active patient behaviour: a randomized controlled trial with depressed outpatients. AB - BACKGROUND: A deeper engagement into medical decision-making is demanded by treatment guidelines for patients with affective disorders. There is to date little evidence on what facilitates active behaviour of patients with depression. In general medicine 'question prompt sheets' (QPSs) have been shown to change patients' behaviour in the consultation and improve treatment satisfaction but there is no evidence for such interventions for mental health settings. AIMS: To study the effects of a QPS on active patient behaviour in the consultation. METHODS: Randomized controlled trial (involving N = 100 outpatients with depression) evaluating the effects of a QPS on patients' behaviour in the consultation. RESULTS: The QPS showed no influence on the number of topics raised by patients (p = .13) nor on the external rater's perception of 'Who made the decisions in today's consultation?' (p = .50). CONCLUSIONS: A QPS did not change depressed patients' behaviour in the consultation. More complex interventions might be needed to change depressed patients' behaviour within an established doctor-patient dyad. Patient seminars addressing behavioural aspects have been shown to be effective in other settings and may also be feasible for outpatients with affective disorders. PMID- 23632273 TI - Pulmonary adenocarcinomas with micropapillary component significantly correlate with recurrence, but can be well controlled with EGFR tyrosine kinase inhibitors in the early stages. AB - Pulmonary adenocarcinoma with a micropapillary component (PA-MPC) is known to exhibit biologically aggressive behavior. The aim of this study was to evaluate the clinicopathological characteristics of early-stage PA-MPC and to investigate the correlation between PA-MPC and epidermal growth factor receptor (EGFR) or KRAS mutation status. We reviewed 440 PA patients who underwent resection. We defined PA-MPC as adenocarcinoma with MPC occupying at least 5% of the entire tumor. EGFR and KRAS mutations were detected using established methods. Of the 440 cases, 256 cases were classified as stage IA, of which 53 cases (20.7%) had MPC. The 5-year disease-free survival rates in the MPC-negative and MPC-positive groups of patients with stage IA tumors were 92.1% and 77.6%, respectively. The difference in these rates was statistically significant (p = 0.003), whereas the difference in overall survival between the groups was not statistically significant (p = 0.973). The mean percentage of MPC was 20.4% in the recurrent group and 18.3% in the non-recurrent group, with no significant correlation (p = 0.996). Of the 10 recurrent cases, 6 cases exhibited EGFR mutations; the 5 cases treated with a tyrosine kinase inhibitor (TKI) achieved long survival (median, 64.6 months). No KRAS mutations were detected in any of the 10 cases. PA-MPCs were strongly associated with recurrence, but were not influenced by the MPC percentage even in early-stage lesions. Moreover, PA-MPCs with recurrence were associated with relatively better survival. These findings indicate that PA-MPCs were biologically aggressive but could be controlled with EGFR-TKIs. PMID- 23632274 TI - The effect of telemonitoring at home on quality of life and self-care behaviors of patients with heart failure. AB - Heart failure (HF) is a costly chronic disease that affects 5.7 million people in the United States. Home healthcare agencies are implementing initiatives to reduce hospitalizations and manage HF patients at home. In this study, telemonitoring improved patients' perception of their quality of life and assisted them to sustain critical self-care behaviors. Patients who were monitored had fewer hospitalizations but telemonitoring was not statistically significant in lowering hospitalizations. PMID- 23632275 TI - Opening the door to improve visiting nurse safety: an initiative to collect and analyze protection practices and policies. AB - The number of home healthcare clinicians who have been harmed by workplace violence as the direct result of patient care is not known. An initiative in the form of a 36-question survey was sent to the nurse administrators of 156 visiting nurse organizations in the United States. The purpose was to describe workplace violence policies and practices and explore what agencies are doing to protect visiting nurses. PMID- 23632276 TI - F conjugation: back to the beginning. AB - Bacterial conjugation as mediated by the F plasmid has been a topic of study for the past 65 years. Early research focused on events that occur on the cell surface including the pilus and its phages, recipient cell receptors, mating pair formation and its prevention via surface or entry exclusion. This short review is a reminder of the progress made in those days that will hopefully kindle renewed interest in these subjects as we approach a complete understanding of the mechanism of conjugation. PMID- 23632277 TI - Characterisation of the stbD/E toxin-antitoxin system of pEP36, a plasmid of the plant pathogen Erwinia pyrifoliae. AB - pEP36 is a plasmid ubiquitously present in Erwinia pyrifoliae, a pathogen which causes black stem blight of Asian pear. pEP36 is highly stable in its host, even in the absence of selective pressure. The plasmid is closely related to pEA29, which is widespread in E. amylovora, the causative agent of fire blight of apple and pear trees. Here we report that pEP36 possesses a functional hybrid toxin antitoxin module, stbD/E(pEP36), with the toxin showing homology to the RelE/ParE proteins and the antidote belonging to the Phd/YefM antitoxin family. Bacteria expressing the StbE(pEP36) toxin arrest cell growth and enter a viable but non culturable stage. However, they maintain their typical cell length and do not show filamentation. Pulse-chase experiments revealed that StbE(pEP36) acts as a global inhibitor of protein synthesis while it does not interfere with DNA and RNA synthesis. The StbD(pEP36) antitoxin is capable of neutralising StbE(pEP36) toxicity. Additional experiments show that the stbD/E(pEP36) module can stabilise plasmids at least 20-fold. Thus the toxin-antitoxin system may contribute to the remarkable stability of pEP36. PMID- 23632278 TI - The French euthanasia debate: exception and solidarity. PMID- 23632279 TI - Electrically evoked compound action potential artifact rejection by independent component analysis: technique validation. AB - The electrically-evoked compound action potential (ECAP) is the synchronous whole auditory nerve activity in response to an electrical stimulus, and can be recorded in situ on cochlear implant (CI) electrodes. A novel procedure (ECAP ICA) to isolate the ECAP from the stimulation artifact, based on independent component analysis (ICA), is described here. ECAPs with artifact (raw-ECAPs) were sequentially recorded for the same stimulus on 9 different intracochlear recording electrodes. The raw-ECAPs were fed to ICA, which separated them into independent sources. Restricting the ICA projection to 4 independent components did not induce under-fitting and was found to explain most of the raw-data variance. The sources were identified and only the source corresponding to the neural response was retained for artifact-free ECAP reconstruction. The validity of the ECAP-ICA procedure was supported as follows: N1 and P1 peaks occurred at usual latencies; and ECAP-ICA and artifact amplitude-growth functions (AGFs) had different slopes. Concatenation of raw-ECAPs from multiple stimulus currents, including some below the ECAP-ICA threshold, improved the source separation process. The main advantage of ECAP-ICA is that use of maskers or alternating polarity stimulation are not needed. PMID- 23632280 TI - Rivoglitazone: a new thiazolidinedione for the treatment of type 2 diabetes mellitus. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of the thiazolidinedione rivoglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, to determine its potential role in the treatment of type 2 diabetes mellitus. DATA SOURCES: A MEDLINE search (1966-February 2013) was conducted for English-language studies in humans, using the terms rivoglitazone and CS011. Abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes annual meetings from 2007 to 2012 were also evaluated for relevant data. STUDY SELECTION AND DATA EXTRACTION: Articles pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of rivoglitazone were reviewed. DATA SYNTHESIS: Rivoglitazone has been shown, through small clinical studies, to decrease hemoglobin A(1c) (A1C) by 0.11-1.1% when compared with placebo and may provide greater A1C reduction than pioglitazone. Rivoglitazone reduces hyperglycemia, hyperinsulinemia, and hypertriglyceridemia by acting as an agonist of PPAR-gamma. Rivoglitazone is the most potent PPAR-gamma agonist; the initial recommended dose is 1 mg daily, with adjustment as needed to a maximum dose of 2 mg daily. Additionally, rivoglitazone has a longer half-life than other PPAR-gamma agonists. Similar to those of the other PPAR-gamma agonists, rivoglitazone's adverse effects include peripheral edema and weight gain. CONCLUSIONS: Rivoglitazone is the fourth agent in the thiazolidinedione class of antidiabetes drugs. Although rivoglitazone appears to be more potent in its ability to lower A1C levels compared with other thiazolidinediones, further studies of longer duration are needed to fully assess the risks associated with this drug. Until these can be completed, we cannot recommend rivoglitazone over currently approved drugs in this class. PMID- 23632281 TI - Proton pump inhibitor-associated hypomagnesemia: what do FDA data tell us? AB - BACKGROUND: Proton pump inhibitors (PPIs) are a class of medications indicated for the treatment of gastric acid-related diseases. Hypomagnesemia is a rare but serious adverse effect of PPIs. OBJECTIVE: To address the association between the use of different PPIs and hypomagnesemia by examining the frequency of occurrence of hypo magnesemia among the reported adverse drug reactions from the Food and Drug Administration (FDA) Adverse Event Reporting System database. METHODS: We conducted a cross-sectional study of PPI-associated adverse effect cases reported to the FDA between November 1, 1997, and April 1, 2012. Logistic regression was used to examine the association of sex, age, and different PPIs with hypomagnesemia. chi2 analysis was conducted to investigate the association of PPI associated hypomagnesemia with hypocalcemia and hypokalemia. RESULTS: Among 66,102 subjects identified as experiencing 1 or more adverse effects while taking a PPI, 1.0% (n = 693) were reported to have hypomagnesemia. The mean (SD) age of PPI users presenting with hypomagnesemia was 64.4 (12.9) years. Results from logistic regression indicated that, compared with esomeprazole, all other PPIs had a higher rate of hypomagnesemia, with pantoprazole having the highest rate (OR 4.3; 95% CI 3.3-5.7; p < 0.001). The risk of female subjects having hypo magnesemia (OR 0.83; 95% CI 0.71-0.97; p = 0.016) was significantly lower than that of males. Elderly subjects (age >65 years) were at increased risk of PPI associated hypomagnesemia (OR 1.5; 95% CI 1.2-1.7; p < 0.001). chi2 analysis showed strong association between hypomagnesemia and both hypocalcemia (p < 0.001) and hypokalemia (p < 0.001). CONCLUSIONS: All PPIs were associated with hypomagnesemia, with esomeprazole having the lowest risk and pantoprazole having the highest risk. The risk of PPI-associated hypomagnesemia was higher in males and the elderly population. Hypocalcemia and hypokalemia commonly coexisted with PPI-associated hypomagnesemia. PMID- 23632282 TI - Novel method for transdiaphragmatic pressure measurements in mice. AB - The diaphragm muscle (DIAm) is responsible for breathing and determines the ability to generate both ventilatory and non-ventilatory behaviors. Size limitations of the mouse make transdiaphragmatic pressure (Pdi) measurement using a dual balloon system untenable. Adult C57BL/6J mice (n=8) and C57BL/6*129 (n=9), underwent Pdi measurements using solid-state pressure catheters spanning the thoracic and abdominal surfaces of the DIAm. Measurements were conducted during eupnea, hypoxia (10% O2)-hypercapnia (5% CO2), chemical airway stimulation (i.e., sneezing), spontaneously occurring deep breaths, sustained tracheal occlusion, and bilateral phrenic nerve stimulation. There was a difference in the Pdi generated across the range of ventilatory and non-ventilatory behaviors (p=0.001). No difference in Pdi across behaviors was evident between mouse strains (p=0.161). This study establishes a novel method to determine Pdi across a range of DIAm behaviors in mice that may be useful in evaluating conditions associated with reduced ability to perform expulsive, non-ventilatory behaviors. PMID- 23632283 TI - Retraction. PMID- 23632285 TI - Postural control and fear of falling assessment in people with chronic obstructive pulmonary disease: a systematic review of instruments, international classification of functioning, disability and health linkage, and measurement properties. AB - OBJECTIVES: To systematically review the instruments used to assess postural control and fear of falling in people with chronic obstructive pulmonary disease (COPD), and to synthesize and evaluate their breadth of content and measurement properties. DATA SOURCES: MEDLINE, EMBASE, Web of Science, CINAHL, CENTRAL, PsycINFO, PEDro, and OTSeeker databases searched in September 2012. STUDY SELECTION: Two independent reviewers performed the selection of articles, the ICF linking process and quality assessment. Only quantitative studies were included, irrespective of language or publication date. DATA EXTRACTION: This systematic review comprised two phases. Phase 1 aimed to identify the commonly used instruments to assess postural control and fear of falling in the COPD literature. The breadth of content of each instrument was examined based on the International Classification of Functioning, Disability and Health (ICF). In phase 2, a measurement property search filter was adopted and used in four electronic databases to retrieve properties reported in the COPD population. The COSMIN checklist was used to assess the methodological quality of each measurement property reported. DATA SYNTHESIS: Seventeen out of 401 publications were eligible in phase 1. Seventeen instruments were identified including 15 for postural control and 2 for fear of falling assessment. The Berg Balance Scale, the Short Physical Performance Battery, and the Activities-specific Balance Confidence (ABC) scale were the most frequently used instruments to assess postural control and fear of falling respectively. The ICF categories covered varied considerably among instruments. The Balance Evaluation Systems test and ABC presented the greatest breadth of content. Measurement properties reported included criterion predictive validity (4 instruments), construct validity (11 instruments) and responsiveness (1 instrument), with inconsistent findings based on 'fair' and 'poor' quality studies. CONCLUSIONS: Different instruments with heterogeneous content have been used to assess postural control and fear of falling outcomes. Standardized assessment methods and best evidence on measurement properties is required in the COPD literature. PMID- 23632286 TI - Meta-analysis of botulinum toxin A detrusor injections in the treatment of neurogenic detrusor overactivity after spinal cord injury. AB - OBJECTIVE: To examine the effectiveness of botulinum toxin type A (BTX-A) on neurogenic detrusor overactivity (NDO) in individuals with spinal cord injury (SCI). DATA SOURCES: MEDLINE, CINAHL, EMBASE, and PsycINFO databases were searched for all relevant articles published from 1980 to June 2012. STUDY SELECTION: Trials examining the use of BTX-A injections into the detrusor wall in the treatment of NDO after SCI were included if (1) >= 50% of study sample comprised subjects post-SCI; (2) outcomes of interest were assessed before and after treatment with a single injection of BTX-A; and (3) the sample size was >= 3. DATA EXTRACTION: A standardized mean difference +/- SE (95% confidence interval) was calculated for at least 1 of the following outcomes in every study: postvoid residual urine volume, reflex detrusor volume, bladder capacity, bladder compliance, catheterization frequency, and maximum flow rate. Results from all studies were then pooled using a random-effects model. Treatment effect sizes were interpreted as small, >0.2; moderate, >0.5; or large, >0.8. DATA SYNTHESIS: Fourteen studies representing data from 734 subjects were included. After BTX-A injection, large treatment effects were observed in postvoid residual urine volume, reflex detrusor volume, bladder capacity, bladder compliance, and catheterization frequency (P<.01). Rate of incontinence episodes was reduced from 23% to 1.31% after BTX-A treatment. No significant decrease in max flow rate was observed (P=.403). CONCLUSIONS: Results of the meta-analysis indicate BTX-A is effective in treating NDO after SCI. The use of BTX-A was associated with a decrease in incontinence episodes, catheter use, and bladder pressures. PMID- 23632287 TI - Measurement of hyolaryngeal muscle activation using surface electromyography for comparison of two rehabilitative dysphagia exercises. AB - OBJECTIVE: To investigate the effects of a resistance-based chin-to-chest (CtC) exercise on measures of hyolaryngeal muscle activation compared with a head-lift exercise. DESIGN: Within-subject, repeated-measures design. SETTING: Academic research laboratory. PARTICIPANTS: Healthy young women (N=20) without a history of dysphagia, cervical spine conditions, neurologic disease, or head/neck cancer (mean age, 22.5y). INTERVENTIONS: All participants performed an isometric jaw opening exercise against resistance (CtC) and an isometric head-lift exercise, both targeting activation in the hyolaryngeal (suprahyoid) muscles. The CtC exercise required jaw opening into a chin brace secured against the upper torso for a duration of 10 seconds. The isometric head-lift exercise required lifting and holding the head from a supine position for 10 seconds. The degree to which each exercise activated the suprahyoid muscles was measured using surface electromyography (sEMG). MAIN OUTCOME MEASURES: Microvolts as measured from sEMG sensors placed on the skin surface above the hyolaryngeal muscles (surface of skin above geniohyoid, mylohyoid, and anterior digastric). Dependent variables included the peak microvolts during 10 seconds of sustained contraction and the difference in microvolts from rest to peak contraction for each exercise. RESULTS: Activation in the hyolaryngeal musculature as measured via sEMG was significantly greater when participants performed the CtC exercise compared with the head-lift exercise. Measures of peak microvolts during contraction were significantly greater for CtC (t=10.72, P<.001) compared with the head-lift exercise, and difference measures in microvolts calculated between rest and contraction for each exercise revealed a 2-fold increase in hyolaryngeal muscular activation for CtC (t=8.27, P<.001). CONCLUSIONS: The isometric CtC exercise resulted in greater activation of the hyolaryngeal muscles compared with an isometric head-lift exercise. Results support the need for further investigations to determine whether the CtC exercise has a positive effect as a rehabilitative exercise for clinical populations with dysphagia secondary to upper esophageal sphincter dysfunction where hyolaryngeal excursion is a physiological impairment. PMID- 23632288 TI - Predictors for relapse after antiepileptic drug withdrawal in seizure-free patients with epilepsy. AB - The objective of this study was to evaluate the timing of medication withdrawal and other clinical factors as potential predictors of seizure relapse after antiepileptic drug (AED) withdrawal in patients with epilepsy. A total of 99 patients who were seizure free for more than 2 years were recruited from the Neurology Clinics of Nanjing Brain Hospital between 2001 and 2009, and were followed prospectively for at least 2 years or until seizure relapse. Kaplan Meier survival analysis was used for calculating recurrence rates. Univariate and multivariate analyses for recurrence risk factors were performed using the Cox proportional hazards model. Thirteen patients were excluded due to loss of follow up or incomplete seizure records. Epileptiform electroencephalography (EEG) abnormality within the first year after AED withdrawal (hazard ratio [HR] = 4.810, 95% confidence interval [CI] = 2.220-10.420) was found on multivariate analysis to be a predictor of seizure recurrence. Early AED withdrawal after a seizure-free period of 2-3 years did not significantly increase the risk of recurrence (HR = 0.999, 95% CI = 0.969-1.029) as compared with delayed AED withdrawal (patients who were seizure-free for more than 3 years). AED can be withdrawn in patients who have been seizure-free for more than 2 years. As epileptiform EEG abnormality within the first year after AED withdrawal predicts seizure relapse, it is necessary to perform EEG for patients during the first year after AED withdrawal. PMID- 23632289 TI - Surgical treatment of spinal vascular malformations performed using intraoperative indocyanine green videoangiography. AB - This study aims to evaluate the benefits of intraoperative indocyanine green (ICG) videoangiography and associated surgical outcomes of patients with spinal vascular malformations. ICG videoangiography was used during 24 surgical interventions to treat spinal vascular malformations at the Beijing Tiantan Hospital from August 2009 to May 2011. The vascular malformations were removed or the fistulae were occluded with the assistance of ICG videoangiography. The completeness of fistula clipping or nidus extirpation and each patient's neurological status were evaluated. Among these 24 patients, there were seven with spinal dural arteriovenous fistulae, five glomus arteriovenous malformations, one juvenile arteriovenous malformation, nine perimedullary arteriovenous fistulae, and two perimedullary arteriovenous fistulae in combination with perimedullary arteriovenous malformations. Intraoperative ICG videoangiography confirmed the definite clipping of the fistulous points and complete removal of intramedullary arteriovenous malformations in all but one patient. All patients had satisfactory preservation of spinal cord blood supply and venous return. No adverse effects or complications related to ICG videoangiography occurred. Three patients were lost to follow up; 21 patients were followed clinically with a mean follow up of 7.5 months. The neurological deficits completely resolved in six patients, improved significantly in 10, remained stable in two, and were aggravated in three patients. Our experience shows that intraoperative ICG videoangiography offers useful information on the pathological and physiological vascular anatomy encountered during surgery for spinal vascular malformations. PMID- 23632290 TI - Adjuvant whole brain radiation following resection of brain metastases. AB - Brain metastasis is a common complication of systemic cancer and significant cause of suffering in oncology patients. Despite a plethora of available treatment modalities, the prognosis is poor with a median survival time of approximately one year. For patients with controlled systemic disease, good performance status, and a limited number of metastases, treatment typically entails surgical resection or radiosurgery, followed by whole brain radiotherapy (WBRT) to control microscopic disease. WBRT is known to control the progression of cancer in the brain, but it can also have toxic effects, particularly with regard to neurocognition. There is no consensus as to whether the benefit of WBRT outweighs the potential harm. We review the evidence related to the question of whether patients undergoing surgical resection of brain metastases should receive adjuvant WBRT. PMID- 23632291 TI - A deletion mutation of the VHL gene associated with a patient with sporadic von Hippel-Lindau disease. AB - Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited familial cancer syndrome resulting from mutations in the VHL tumor suppressor gene, which leads to the development of a variety of benign and malignant tumors, especially central nervous system hemangioblastomas, retinal angiomas, clear-cell renal cell carcinomas and pheochromocytomas, with age-dependent penetrance. To date, nearly 400 germline mutations have been found to be involved in VHL disease according to the public Human Gene Mutation Database (HGMD). Although most index cases have a positive family history of VHL, some do not and may represent de novo cases. Patients diagnosed without family histories of VHL have been reported in as many as 23% of affected individuals with VHL. In this paper, we report the presence of a heterozygous deletion mutation of c.227_229delTCT in the VHL gene, causing the deletion of phenylalanine at codon 76 (p.Phe76del) of the VHL protein in a patient with sporadic VHL with a benign prognosis. The mutation involved may be de novo or the seemingly unaffected parent may be mosaic for the disease. PMID- 23632292 TI - Cerebrovascular neurosurgery in 2012. AB - Considerable advances in our understanding of the natural history and treatment of cerebrovascular disease were made in 2012. The landmark Unruptured Cerebral Aneurysm Study in Japan was published, illustrating a significantly greater rupture risk than previously reported for small anterior and posterior communicating artery aneurysms, those with daughter domes, and giant aneurysms. Results from the Cerecyte (DePuy Synthes, West Chester, PN, USA) coil trial did not demonstrate a statistically significant positive impact of these bioactive coils on angiographic occlusion rates or outcome. The Clazosentan to Overcome Neurological Ischemia and Infarct Occurring after Subarachnoid Hemorrhage study was also published and unfortunately did not demonstrate an overall favorable long-term functional outcome rate for patients with aneurysmal subarachnoid hemorrhage receiving clazosentan. Studies furthering our understanding of the natural history and treatment of vascular malformations were also published, including large prospective natural history studies of cavernous malformations from the Mayo Clinic and the Scottish Audit of Intracranial Vascular Malformations database. Although pregnancy was found to be a significant risk factor for arteriovenous malformation hemorrhage, several studies did not demonstrate pregnancy as a significant risk factor for cavernous malformation hemorrhage. Finally, prospective randomized control trials illustrated significantly improved angiographic and clinical outcome results for both the Solitaire (ev3 Endovascular, Plymouth, MN, USA; SWIFT trial) and Trevo (Concentric Medical, Mountainview, CA, USA; TREVO 2 trial) stent retrievers as compared to the Merci (Concentric Medical) clot retriever. PMID- 23632293 TI - Horizontal visual search in a large field by patients with unilateral spatial neglect. AB - In this study, we investigated the horizontal visual search ability and pattern of horizontal visual search in a large space performed by patients with unilateral spatial neglect (USN). Subjects included nine patients with right hemisphere damage caused by cerebrovascular disease showing left USN, nine patients with right hemisphere damage but no USN, and six healthy individuals with no history of brain damage who were age-matched to the groups with brain right hemisphere damage. The number of visual search tasks accomplished was recorded in the first experiment. Neck rotation angle was continuously measured during the task and quantitative data of the measurements were collected. There was a strong correlation between the number of visual search tasks accomplished and the total Behavioral Inattention Test Conventional Subtest (BITC) score in subjects with right hemisphere damage. In both USN and control groups, the head position during the visual search task showed a balanced bell-shaped distribution from the central point on the field to the left and right sides. Our results indicate that compensatory strategies, including cervical rotation, may improve visual search capability and achieve balance on the neglected side. PMID- 23632294 TI - Web scraping technologies in an API world. AB - Web services are the de facto standard in biomedical data integration. However, there are data integration scenarios that cannot be fully covered by Web services. A number of Web databases and tools do not support Web services, and existing Web services do not cover for all possible user data demands. As a consequence, Web data scraping, one of the oldest techniques for extracting Web contents, is still in position to offer a valid and valuable service to a wide range of bioinformatics applications, ranging from simple extraction robots to online meta-servers. This article reviews existing scraping frameworks and tools, identifying their strengths and limitations in terms of extraction capabilities. The main focus is set on showing how straightforward it is today to set up a data scraping pipeline, with minimal programming effort, and answer a number of practical needs. For exemplification purposes, we introduce a biomedical data extraction scenario where the desired data sources, well-known in clinical microbiology and similar domains, do not offer programmatic interfaces yet. Moreover, we describe the operation of WhichGenes and PathJam, two bioinformatics meta-servers that use scraping as means to cope with gene set enrichment analysis. PMID- 23632295 TI - Peripheral baroreflex and chemoreflex function after eversion carotid endarterectomy. AB - OBJECTIVE: This study assessed the long-term effect of the eversion technique for carotid endarterectomy (e-CEA) on arterial baroreflex and peripheral chemoreflex function. METHODS: The study included 13 patients who underwent, between 2001 and 2006, bilateral e-CEA and 16 who underwent bilateral standard CEA (s-CEA) to eliminate the complicating effects of intact contralateral carotid sinus function. Exclusion criteria were age >70 years, diabetes mellitus, chronic pulmonary disease, ischemic cardiac disease or medical therapy with beta blockers, cardiac arrhythmia, neurologic deficits, carotid restenosis, and previous neck or chest surgery or irradiation. Young and aged-matched healthy individuals were recruited as controls. All patients underwent standard cardiovascular reflex tests, including lying-to-standing, orthostatic hypotension, deep breathing, and Valsalva maneuver. Autonomic cardiovascular modulation was indirectly evaluated by spectral analysis of heart rate variability and systolic arterial pressure variability. The chemoreflex sensitivity to hypoxia was obtained during classic rebreathing tests from the slopes of the linear regression of minute ventilation (VE) vs arterial oxygen saturation measured by pulse oximetry (SpO2%) and partial pressure of end-tidal oxygen (PetO2). RESULTS: Patients (16 men; age, 62.4 +/- 8.0 years) were enrolled after a mean interval of 24 +/- 17 months from the last CEA. All were asymptomatic, and results of standard tests were negative. Residual baroreflex performance was documented in both patient groups, although reduced, compared with young controls. Notably, baroreflex sensitivity (msec/mm Hg) was better maintained after e-CEA than after s-CEA at rest (young controls, 19.93 +/- 9.50; age-matched controls, 7.75 +/- 5.68; e-CEA, 13.85 +/- 14.54; and s-CEA, 3.83 +/- 1.15; analysis of variance [ANOVA], P = .001); and at standing (young controls, 7.83 +/- 2.55; age-matched controls, 3.71 +/- 1.59; e-CEA, 7.04 +/- 5.62; and s CEA 3.57 +/- 3.80; ANOVA, P = .001). Similarly, chemoreflex sensitivity to hypoxia was maintained in both patient groups, which did not differ from each other, and was reduced compared with controls (controls vs patient groups DeltaVE/DeltaSpO2: -1.37 +/- 0.33 vs -0.33 +/- 0.08 and SpO2% -0.29 +/- 0.13 L/min; P = .002; DeltaVE/DeltaPetO2: -0.20 +/- 0.1 vs -0.01 +/- 0.0 and -0.07 +/- 0.02 L/min/mm Hg; P = .04, ANOVA with least significant difference correction for multiple comparisons). CONCLUSIONS: Our data show that e-CEA, even when performed on both sides, preserves baroreflexes and chemoreflexes and, therefore, does not confer permanent carotid sinus denervation. Also, e-CEA does not increase long term arterial pressure variability, and this suggests that perioperative hemodynamic derangements can be attributed to the temporary effects of surgical trauma. PMID- 23632296 TI - Rapid polyclonal desensitization with antibodies to IgE and FcepsilonRIalpha. AB - BACKGROUND: Rapid desensitization, a procedure in which persons allergic to an antigen are treated at short intervals with increasing doses of that antigen until they tolerate a large dose, is an effective, but risky, way to induce temporary tolerance. OBJECTIVE: We wanted to determine whether this approach can be adapted to suppress all IgE-mediated allergies in mice by injecting serially increasing doses of monoclonal antibodies (mAbs) to IgE or FcepsilonRIalpha. METHODS: Active and passive models of antigen- and anti-IgE mAb-induced IgE mediated anaphylaxis were used. Mice were desensitized with serially increasing doses of anti-IgE mAb, anti-FcepsilonRIalpha mAb, or antigen. Development of shock (hypothermia), histamine and mast cell protease release, cytokine secretion, calcium flux, and changes in cell number and FcepsilonRI and IgE expression were evaluated. RESULTS: Rapid desensitization with anti-IgE mAb suppressed IgE-mediated immediate hypersensitivity; however, some mice developed mild anaphylaxis during desensitization. Rapid desensitization with anti FcepsilonRIalpha mAb that only binds FcepsilonRI that is not occupied by IgE suppressed both active and passive IgE-mediated anaphylaxis without inducing disease. It quickly, but temporarily, suppressed IgE-mediated anaphylaxis by decreasing mast cell signaling through FcepsilonRI, then slowly induced longer lasting mast cell unresponsiveness by removing membrane FcepsilonRI. Rapid desensitization with anti-FcepsilonRIalpha mAb was safer and longer lasting than rapid desensitization with antigen. CONCLUSION: A rapid desensitization approach with anti-FcepsilonRIalpha mAb safely desensitizes mice to IgE-mediated anaphylaxis by inducing mast cell anergy and later removing all mast cell IgE. Rapid desensitization with an anti-human FcepsilonRIalpha mAb may be able to prevent human IgE-mediated anaphylaxis. PMID- 23632298 TI - The challenge of treating preschool wheezing. PMID- 23632297 TI - Compartmentalized chemokine-dependent regulatory T-cell inhibition of allergic pulmonary inflammation. AB - BACKGROUND: Induction of endogenous regulatory T (Treg) cells represents an exciting new potential modality for treating allergic diseases, such as asthma. Treg cells have been implicated in the regulation of asthma, but the anatomic location in which they exert their regulatory function and the mechanisms controlling the migration necessary for their suppressive function in asthma are not known. Understanding these aspects of Treg cell biology will be important for harnessing their power in the clinic. OBJECTIVE: We sought to determine the anatomic location at which Treg cells exert their regulatory function in the sensitization and effector phases of allergic asthma and to determine the chemokine receptors that control the migration of Treg cells to these sites in vivo in both mice and human subjects. METHODS: The clinical efficacy and anatomic location of adoptively transferred chemokine receptor-deficient CD4(+)CD25(+) forkhead box protein 3-positive Treg cells was determined in the sensitization and effector phases of allergic airway inflammation in mice. The chemokine receptor expression profile was determined on Treg cells recruited into the human airway after bronchoscopic segmental allergen challenge of asthmatic patients. RESULTS: We show that CCR7, but not CCR4, is required on Treg cells to suppress allergic airway inflammation during the sensitization phase. In contrast, CCR4, but not CCR7, is required on Treg cells to suppress allergic airway inflammation during the effector phase. Consistent with our murine studies, human subjects with allergic asthma had an increase in CCR4-expressing functional Treg cells in the lungs after segmental allergen challenge. CONCLUSION: The location of Treg cell function differs during allergic sensitization and allergen-induced recall responses in the lung, and this differential localization is critically dependent on differential chemokine function. PMID- 23632300 TI - Approved and unapproved use of immunoglobulins in Iceland. PMID- 23632301 TI - The diagnostic and prognostic significance of SCUBE1 levels in Crimean-Congo hemorrhagic fever. AB - BACKGROUND: The new biochemical marker, signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1), is secreted and cell surface glycoprotein expressed during early embryogenesis. The protein is found in platelet and endothelial cells. Crimean-Congo hemorrhagic fever (CCHF), which is caused by a tick-borne virus belonging to the Bunyaviridae family, may present with a mild clinical course or may exhibit a severe profile with potentially fatal hemorrhaging. The aim of this study was to determine the diagnostic and prognostic significance of SCUBE1 levels in CCHF. METHODS: This study was conducted with patients with CCHF. SCUBE1 levels in patients with CCHF were determined using an ELISA. RESULTS: SCUBE1 titers of CCHF patients were significantly higher compared to those of the control group (p=0.0001). SCUBE1 levels of patients with hemorrhage were significantly higher than those of patients without hemorrhage (p=0.0001). SCUBE1 values of patients who died were significantly higher than those of the survivors (p=0.012). CONCLUSIONS: SCUBE1 levels are a new biomarker that can be used in the differential diagnosis and monitoring of patients hospitalized with suspected CCHF. These levels are also significant as potential predictors of mortality. PMID- 23632302 TI - Epidemiology of infections in a burn unit, Albania. AB - BACKGROUND: Many types of nosocomial infections (NIs) can be present in the burned patient. The purpose of this study is to calculate the rates for NI in the Intensive Care Unit of the Service of Burns and Plastic Surgery in University Hospital Centre (UHC) in Tirana, Albania. METHOD: The study is prospective, clinical and analytical. The study is continued/longitudinal because monitors all patients with severe burns during a specified time period (1year). For data analysis was used SPSS 19.0. RESULTS: The infection prevalence rate was 12 infected patients per 100 patients. The colonisation prevalence rate was 43 colonised patients for 100 patients. The most frequent infection microorganisms were Pseudomonas aeruginosa and Staphylococcus aureus (67% and 24%). Incidence of BSI was 3 BSI for 1000 hospitalization days. Incidence of catheter-related bloodstream infection (CRBSI) was 11.7 BSI for 1000 catheter days. Colonisation of the tip of the central catheter (CTC) was 15.6 for 1000 catheter days. CONCLUSIONS: The epidemiology of burn wound infections as well as the definitions have changed due to important changes in burn wound treatment but further studies should be done documented the factors that can reduce the burn wound infection rates. PMID- 23632299 TI - TNF-alpha-mediated bronchial barrier disruption and regulation by src-family kinase activation. AB - BACKGROUND: Because TNF-alpha is increased in severe asthma, we hypothesized that TNF-alpha contributes to barrier dysfunction and cell activation in bronchial epithelial cells. We further hypothesized that src-family kinase inhibition would improve barrier function in healthy cells in the presence of TNF-alpha and directly in cultures of severe asthmatic cells where the barrier is disrupted. OBJECTIVES: We assessed the effect of TNF-alpha, with or without src-family kinase inhibitor SU6656, on barrier properties and cytokine release in differentiated human bronchial epithelial cultures. Further, we tested the effect of SU6656 on differentiated primary cultures from severe asthma. METHODS: Barrier properties of differentiated human bronchial epithelial air-liquid interface cultures from healthy subjects and subjects with severe asthma were assessed with transepithelial electrical resistance and fluorescent dextran passage. Proteins were detected by immunostaining or Western blot analysis and cytokines by immunoassay. Mechanisms were investigated with src kinase and other inhibitors. RESULTS: TNF-alpha lowered transepithelial electrical resistance and increased fluorescent dextran permeability, caused loss of occludin and claudins from tight junctions with redistribution of p120 catenin and E-cadherin from adherens junctions, and also increased endogenous TNF-alpha, IL-6, IL-1beta, IL-8, thymic stromal lymphoprotein, and pro-matrix metalloprotease 9 release. SU6656 reduced TNF-alpha-mediated paracellular permeability changes, restored occludin, p120, and E-cadherin and lowered autocrine TNF-alpha release. Importantly, SU6656 improved the barrier properties of severe asthmatic air-liquid interface cultures. Redistribution of E-cadherin and p120 was observed in bronchial biopsies from severe asthmatic airways. CONCLUSIONS: Inhibiting TNF-alpha or src kinases may be a therapeutic option to normalize barrier integrity and cytokine release in airway diseases associated with barrier dysfunction. PMID- 23632303 TI - Combining gene expression and genetic analyses to identify candidate genes involved in cold responses in pea. AB - Cold stress affects plant growth and development. In order to better understand the responses to cold (chilling or freezing tolerance), we used two contrasted pea lines. Following a chilling period, the Champagne line becomes tolerant to frost whereas the Terese line remains sensitive. Four suppression subtractive hybridisation libraries were obtained using mRNAs isolated from pea genotypes Champagne and Terese. Using quantitative polymerase chain reaction (qPCR) performed on 159 genes, 43 and 54 genes were identified as differentially expressed at the initial time point and during the time course study, respectively. Molecular markers were developed from the differentially expressed genes and were genotyped on a population of 164 RILs derived from a cross between Champagne and Terese. We identified 5 candidate genes colocalizing with 3 different frost damage quantitative trait loci (QTL) intervals and a protein quantity locus (PQL) rich region previously reported. This investigation revealed the role of constitutive differences between both genotypes in the cold responses, in particular with genes related to glycine degradation pathway that could confer to Champagne a better frost tolerance. We showed that freezing tolerance involves a decrease of expression of genes related to photosynthesis and the expression of a gene involved in the production of cysteine and methionine that could act as cryoprotectant molecules. Although it remains to be confirmed, this study could also reveal the involvement of the jasmonate pathway in the cold responses, since we observed that two genes related to this pathway were mapped in a frost damage QTL interval and in a PQL rich region interval, respectively. PMID- 23632304 TI - Calcium pathways such as cAMP modulate clothianidin action through activation of alpha-bungarotoxin-sensitive and -insensitive nicotinic acetylcholine receptors. AB - Clothianidin is a neonicotinoid insecticide developed in the early 2000s. We have recently demonstrated that it was a full agonist of alpha-bungarotoxin-sensitive and -insensitive nicotinic acetylcholine receptors expressed in the cockroach dorsal unpaired median neurons. Clothianidin was able to act as an agonist of imidacloprid-insensitive nAChR2 receptor and internal regulation of cAMP concentration modulated nAChR2 sensitivity to clothianidin. In the present study, we demonstrated that cAMP modulated the agonist action of clothianidin via alpha bungarotoxin-sensitive and insensitive receptors. Clothianidin-induced current voltage curves were dependent to clothianidin concentrations. At 10 MUM clothianidin, increasing cAMP concentration induced a linear current-voltage curve. Clothianidin effects were blocked by 0.5 MUM alpha-bungarotoxin suggesting that cAMP modulation occurred through alpha-bungarotoxin-sensitive receptors. At 1 mM clothianidin, cAMP effects were associated to alpha-bungarotoxin-insensitive receptors because clothianidin-induced currents were blocked by 5 MUM mecamylamine and 20 MUM d-tubocurarine. In addition, we found that application of 1mM clothianidin induced a strong increase of intracellular calcium concentration. These data reinforced the finding that calcium pathways including cAMP modulated clothianidin action on insect nicotinic acetylcholine receptors. We proposed that intracellular calcium pathways such as cAMP could be a target to modulate the mode of action of neonicotinoid insecticides. PMID- 23632306 TI - Cost-effectiveness of rotavirus vaccines in British Columbia: Responding to: Fisman DN, Chan CH, Lowcock E, Naus M, Lee V. Effectiveness and cost effectiveness of pediatric rotavirus vaccination in British Columbia: A model based evaluation [Vaccine 2012 December 14]. PMID- 23632305 TI - CD4+ T-cell responses among adults and young children in response to Streptococcus pneumoniae and Haemophilus influenzae vaccine candidate protein antigens. AB - We characterized cytokine profiles of CD4(+) T-helper (h) cells in adults and young children to ascertain if responses occur to next-generation candidate vaccine antigens PspA, PcpA, PhtD, PhtE, Ply, LytB of Streptococcus pneumonia (Spn) and protein D and OMP26 of non-typeable Haemophilus influenzae (NTHi). Adults had vaccine antigen-specific Th1 and Th2 cells responsive to all antigens evaluated whereas young children had significant numbers of vaccine antigen specific CD4(+) T cells producing IL-2, (p=0.004). Vaccine antigen-specific CD4(+) T-cell populations in adults were largely of effector (TEM) and/or central memory (TCM) phenotypes as defined by CD45RA(-)CCR7(+) or CD45RA(-)CCR7(-) respectively; however among young children antigen-specific IL-2 producing CD4(+) T cells demonstrated CD45RA(+) expression (non-memory cells). We conclude that adults have circulating memory CD4(+) T cells (CD45RA(-)) that can be stimulated by all the tested Spn and NTHi protein vaccine candidate antigens, whereas young children have a more limited response. PMID- 23632307 TI - Population access to new vaccines in European countries. AB - Time from registration to population access to new vaccines can take considerable time in European countries. Reasons might be found in the regulatory framework, decision-making processes or the assessment of vaccines by evaluating bodies. The aim of this study was to determine whether some decision-making processes can explain between-country differences in the time to population access to new vaccination programs. Information gathered from a survey among European National Vaccine Industry Groups was combined with information from official health authorities, vaccine manufacturers and literature published. Firstly, a retrospective survey was conducted to measure access time to new vaccines against three diseases in 17 European countries. Secondly, qualitative information on the country-specific decision-making frameworks for the introduction of new "vaccination programs" was identified in a cross-sectional survey. Spearman's rank correlation coefficients (rho) were used for data analysis. The median access time to new vaccines was 6.4 years (95% confidence interval: 5.7-7.1 years) post marketing authorization. National assessments underlying immunization policy decisions (recommendation phase) absorbed most of the access time. Correlation analysis suggested that processes with established timelines and clarity in regard to vaccine evaluation criteria used could ameliorate the effectiveness of the decision-making process. In order to reduce the time to access for new, beneficial vaccines, the underlying vaccination recommendation, implementation and funding process needs to be understood and optimized, where necessary. PMID- 23632308 TI - In response to: scientific investigations into febrile reactions observed in the paediatric population following vaccination with a 2010 Southern Hemisphere Trivalent Influenza Vaccine. PMID- 23632309 TI - Investigation of in vivo metabolic profile of Abelmoschus Manihot based on pattern recognition analysis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Abelmoschus manihot (L.) Medik. var. manihot is one of the most commonly used Chinese medicines and has played an important role in treating chronic glomerulonephritis and diabetic nephropathy. AIM OF THE STUDY: Metabolites identification of traditional Chinese medicine (TCM) is a complex and time-consuming process due to the complicity of TCM and subsequent large number of detected ions. In this paper, UPLC-MS combined with pattern recognition analysis approach were used to simplify and quicken the identification of the metabolites of Abelmoschus Manihot. MATERIALS AND METHODS: Rat urine samples were collected before (as control sample) and after Abelmoschus Manihot administration. Pattern recognition analysis method was used to differentiate components between Abelmoschus Manihot-treated group and its controlled comparison. These components could be considered as Abelmoschus Manihot-related metabolites in vivo. RESULTS: LC-MS based metabolomics could be an advanced tool to help us find metabolites with regards to its capacity of processing large datasets, differentiating and classifying of sample groups, as well as its indiscriminative nature of biomarker and metabolite identification. Using this method, seven metabolites were identified, which are flavonoid aglycone glucuronidation, sulfatation, and methylation metabolites. CONCLUSION: Our results showed that UPLC-MS based- pattern recognition analysis approach can be used to quickly identify Abelmoschus Manihot related metabolites in biological fluids. Furthermore, this work demonstrates the potential application of combining the UPLC-MS approach with the metabolomics approach in identifying the metabolites of TCM. PMID- 23632310 TI - Immunoregulatory effects of glycyrrhizic acid exerts anti-asthmatic effects via modulation of Th1/Th2 cytokines and enhancement of CD4(+)CD25(+)Foxp3+ regulatory T cells in ovalbumin-sensitized mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrhizic acid (GA) is the main bioactive ingredient of licorice (Glycyrrhiza glabra), and has been found to be associated with multiple therapeutic properties. AIM OF THE STUDY: In this study, we investigated immunoregulatory effects of glycyrrhizic acid on anti-asthmatic effects and underlying mechanisms. MATERIALS AND METHODS: Asthma model was established by ovalbumin-induced. A total of 60 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2 mg/kg) and GA (10 mg/kg, 20 mg/kg, 40 mg/kg). Airway resistance (Raw) were measured by the forced oscillation technique, histological studies were evaluated by The hematoxylin and eosin (HE) staining, Th1/Th2 and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA), and CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) was evaluated by Flow Cytometry (FCM), the forkhead/winged helix transcription factor (Foxp3) was evaluated by western blotting. RESULTS: Our study demonstrated that, compared with model group, GA inhibited OVA-induced increases in Raw and eosinophil count; interleukin (IL)-4, IL-5, IL-13 levels were recovered in bronchoalveolar lavage fluid compared; increased IFN-gamma level in bronchoalveolar lavage fluid; histological studies demonstrated that GA substantially inhibited OVA-induced eosinophilia in lung tissue and airway tissue compared with model group. Flow cytometry studies demonstrated that GA substantially enhanced Tregs compared with model group. CONCLUSION: These findings suggest that GA may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma. PMID- 23632314 TI - Radiologically confirmed pneumonia among neonates and very young infants. PMID- 23632312 TI - Accessorizing the human mitochondrial transcription machinery. AB - The human genome comprises large chromosomes in the nucleus and mitochondrial DNA (mtDNA) housed in the dynamic mitochondrial network. Human cells contain up to thousands of copies of the double-stranded, circular mtDNA molecule that encodes essential subunits of the oxidative phosphorylation complexes and the rRNAs and tRNAs needed to translate these in the organelle matrix. Transcription of human mtDNA is directed by a single-subunit RNA polymerase, POLRMT, which requires two primary transcription factors, TFB2M (transcription factor B2, mitochondrial) and TFAM (transcription factor A, mitochondrial), to achieve basal regulation of the system. Here, we review recent advances in understanding the structure and function of the primary human transcription machinery and the other factors that facilitate steps in transcription beyond initiation and provide more intricate control over the system. PMID- 23632315 TI - Sequence microheterogeneity of parvalbumin, the major fish allergen. AB - The microheterogeneity of amino acid sequence observed in various allergens may affect immune response, but incidence of sequence microheterogeneity in allergens and its relation to their allergenicity are unclear. The occurrence of sequence microheterogeneity in major fish allergen, parvalbumin (PA), has been explored using bioinformatics approaches. 44% of 111 species with known PA sequence have PA isoforms. 41% of these species exhibit from 1 to 4 cases of PA sequence microheterogeneity, i.e. unique pairs of PA isoforms with sequence identity above 90%. 29% of 210 PA sequences studied are characterized by microheterogeneity. The occurrence of allergens among them is 2.5-fold higher than among other PAs. The incidence of sequence microheterogeneity within more allergenic beta isoform of PA is 2.0-fold lower than that for its less allergenic alpha isoform. 39 residues affected by PA microheterogeneity are concentrated in the region of helices A, B, F, while helices D and E are the most conservative region. 44% and 11% of the microheterogeneous substitutions are located in the species-specific and cross reactive IgE-binding epitopes of PAs, respectively. 45% and 48% of the substitution cases are predicted to cause notable changes in protein disorder propensity and protein stability, respectively. Hence, the increased allergenicity rate among PAs having microheterogeneous isoforms can be related to differences in their IgE-binding caused directly or in an allosteric manner. Overall, sequence microheterogeneity is shown to be inherent to many of PAs and likely contributes to PA allergenicity. PMID- 23632313 TI - Alternative cleavage and polyadenylation: the long and short of it. AB - Cleavage and polyadenylation (C/P) of nascent transcripts is essential for maturation of the 3' ends of most eukaryotic mRNAs. Over the past three decades, biochemical studies have elucidated the machinery responsible for the seemingly simple C/P reaction. Recent genomic analyses have indicated that most eukaryotic genes have multiple cleavage and polyadenylation sites (pAs), leading to transcript isoforms with different coding potentials and/or variable 3' untranslated regions (UTRs). As such, alternative cleavage and polyadenylation (APA) is an important layer of gene regulation impacting mRNA metabolism. Here, we review our current understanding of APA and recent progress in this field. PMID- 23632316 TI - Mass spectrometry investigation of glycosylation on the NXS/T sites in recombinant glycoproteins. AB - We used a targeted proteomics approach to investigate whether introduction of new N-linked glycosylation sites in a chimeric protein influence the glycosylation of the existing glycosylation sites. To accomplish our goals, we over-expressed and purified a chimeric construct that contained the Fc region of the IgG fused to the exons 7 & 8 of mouse ZP3 (IgG-Fc-ZP3E7 protein). Immunoglobulin heavy chain (IgG-HC protein) was used as control. We then analyzed the IgG-HC and IgG-Fc ZP3E7 proteins by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and by Western blotting (WB). We concluded that in control experiments, the glycosylation site was occupied as expected. However, in the IgG-Fc-ZP3E7 protein, we concluded that only one out of three NXS/T glycosylation sites is occupied by N-linked oligosaccharides. We also concluded that in the IgG-Fc-ZP3E7 protein, upon introduction of additional potential NXS/T glycosylation sites within its sequence, the original NST/S glycosylation site from the Fc region of the IgG-Fc-ZP3E7 protein is no longer glycosylated. The biomedical significance of our findings is discussed. PMID- 23632317 TI - Metallo-beta-lactamase: inhibitors and reporter substrates. AB - Metallo-beta-lactamases represent an emerging clinical threat due to their ability to render ineffective an entire class of antibiotics. Accordingly, this family of enzymes has been suggested as an attractive target for drug design. Progress toward developing effective inhibitors as well as the development of reporter substrates is reviewed. Inhibitors are classified into six classes and known binding interactions with metallo-beta-lactamases are summarized. The development of chromogenic and fluorogenic reporter substrates is also reviewed with respect to current and prospective applications to future inhibitor and diagnostic discovery, mechanistic studies, and biological imaging. Despite progress in molecular probe development, the sequence and structural diversity within the metallo-beta-lactamase family continue to present substantial hurdles for rational ligand design. PMID- 23632318 TI - An increasing use of defunctioning stomas after low anterior resection for rectal cancer. Is this the way to go? AB - BACKGROUND: The last decade there has been an increased awareness of the problem of anastomotic leakage after low anterior resection for rectal cancer, which may have led to more defunctioning stomas. In this study, current use of defunctioning stomas was assessed and compared to the use of defunctioning stomas at the time of the TME-trial together with associated outcomes. METHODS: Eligible patients with rectal cancer undergoing low anterior resection were selected from the Dutch Surgical Colorectal Audit (DSCA, n = 988). Similar patients were selected from the TME-trial (n = 891). The percentages of patients with a defunctioning stoma, anastomotic leakage and postoperative mortality rates were studied. Multivariable models were used to study possible confounding on the outcomes. RESULTS: At the time of the TME-trial, 57% of patients received a defunctioning stoma. At the time of the DSCA, 70% of all patients received a defunctioning stoma (p < 0.001). Anastomotic leakage rates were similar (11.4% and 12.1%; p = 0.640). The postoperative mortality rate differed (3.9% in the TME trial vs. 1.1% in the DSCA; p < 0.001), but was not associated with a more frequent use of a stoma (OR 1.80, 95% CI 0.91-3.58). CONCLUSION: In current surgical practice, 70% of patients undergoing LAR for rectal cancer receives a defunctioning stomas. This percentage seems increased when compared to data from the TME-trial. Clinically relevant anastomotic leakage rates remained similar. Therefore, current routine use of defunctioning stomas should be questioned. PMID- 23632319 TI - Validation of a technique using microbubbles and contrast enhanced ultrasound (CEUS) to biopsy sentinel lymph nodes (SLN) in pre-operative breast cancer patients with a normal grey-scale axillary ultrasound. AB - BACKGROUND: In patients with breast cancer, grey-scale ultrasound often fails to identify lymph node (LN) metastases. We aimed to validate the technique of contrast-enhanced ultrasound (CEUS) as a test to identify sentinel lymph node (SLN) metastases and reduce the numbers of patients requiring a completion axillary node clearance (ANC). METHODS: 371 patients with breast cancer and a normal axillary ultrasound were recruited. Patients received periareolar intra dermal injection of microbubble contrast agent. Breast lymphatics were visualised by CEUS and followed to identify and biopsy axillary SLN. Patients then underwent standard tumour excision and either SLN excision (benign biopsy) or axillary clearance (malignant biopsy) with subsequent histopathological analysis. RESULTS: The technique failed in 46 patients, 6 patients had indeterminate biopsy results and 24 patients were excluded. In 295 patients with a conclusive SLN biopsy, the sensitivity of the technique was 61% and specificity 100%. Given a benign SLN biopsy result, the post-test probability that a patient had SLN metastases was 8%. 35 patients were found to have SLN metastases and had a primary ANC (29 macrometastases and 6 micrometastases/ITC). There were 22 false negative results (10 macrometastases and 12 micrometastases). Macrometastases in core biopsy specimens correlated with LN macrometastases on surgical excision. CONCLUSION: Pre-operative biopsy of SLN reduced the numbers of patients requiring completion ANC. Despite the low sensitivity, only 22 patients (8%) with a benign SLN biopsy were subsequently found to have LN metastases. Without the confirmation of macrometastases on core biopsy specimens, patients with micrometastases/ITC may be inadvertently selected for primary ANC. PMID- 23632320 TI - Author's reply: To PMID 23148932. PMID- 23632321 TI - Anti-tumor effects in mice induced by survivin-targeted siRNA delivered through polysaccharide nanoparticles. AB - Recently, survivin has been attracting great attention because it plays an important role in inhibiting the apoptosis process of tumor cells. Down regulating the expression of survivin gene by small interfering RNA (siRNA) offers a promising method for anti-tumor therapy. However, lack of appropriate siRNA delivery vector has significantly hindered the successful application of survivin-targeted siRNA in anti-tumor therapy. The purpose of this study was to use polysaccharide vector TAT-g-CS we synthesized to deliver functional siRNA and evaluate its in vivo anti-tumor activity. TAT-g-CS vector was firstly synthesized and well structurally characterized. MTT assay showed that TAT-g-CS vector exhibited good biocompatibility. TAT-g-CS complexed with siRNA offering nanoparticles with an average particle size of 212.2 nm and a polydispersity index of 0.121, and the zeta potential of the nanoparticles was +18.58 mV. Results from reporter gene assay suggested that luciferase-targeted siRNA when delivered by TAT-g-CS could down-regulate the expression of luciferase gene with 75.3% reduction. Most importantly, we use siRNA(Sur) targeting survivin gene to assess the in vitro and in vivo delivery capacity of TAT-g-CS and its anti-tumor effects. Our results demonstrated that TAT-g-CS/siRNA(Sur) nanoparticles not only strongly inhibited the in vitro proliferation of 4T1-Luc tumor cells via inducing cell apoptosis, but also effectively inhibited the in vivo growth and metastasis of malignant breast tumor, which suggested that TAT-g-CS/siRNA nanoparticle was a highly efficient non-viral system for siRNA delivery, especially for anti-tumor therapy based on siRNA therapeutics. PMID- 23632322 TI - Bioinformatics-based selection of a model cell type for in vitro biomaterial testing. AB - Biomaterial properties can be tailored for specific applications via systematic and high-throughput screening of biomaterial-cell interactions. However, progress in material development is often hampered by the lack of adequate in vitro testing methods, frequently due to incomplete understanding of involved in vivo mechanisms. In line with drug discovery in pharmacology, a crucial step in assay development for biomaterial screening is the identification of a target to direct the screen against. Herein, the cell type to be used for screening is of essential importance and has to be carefully chosen. So far, few attention has been put on selecting a cell type specifically suitable for in vitro testing of materials for predefined applications. In this manuscript, we describe an approach to define a suitable cell type for screening assays, for which biomaterials for bone regeneration served as example. Using a bioinformatics methodology, different cell lines are compared on three well-characterized model materials. The transcriptional profiles of MG63, iMSC, SV-HFO, hPPCT, hBPCT and SW480 cells are assessed on 3 calcium phosphate-based materials to evaluate their potential application in a screening assay. We show that MG63 is the most suitable cell line to evaluate biomaterials for bone regeneration applications, evidenced by their robust gene expression differences between the 3 model materials. The gene expression differences between the cell lines were assessed based on the overall gene expression profiles and specific subsets of genes and pathways related to osteogenesis and bone homeostasis in response to the 3 materials tested. In the next phase, this cell line will be used to identify a target correlating with in vivo biomaterial performance and henceforth to develop an in vitro screening system. PMID- 23632323 TI - Affinity-selected heparan sulfate for bone repair. AB - Bone morphogenetic protein (BMP)-2 is a potent bone healing compound produced at sites of bone trauma. Here we present a therapeutic strategy to harness the activity of endogenously produced BMP-2 by delivery of an affinity-matched heparan sulfate (HS) glycos aminoglycan biomaterial that increases the bioavailability, bioactivity and half-life of this growth factor. We have developed a robust, cost effective, peptide-based affinity platform to isolate a unique BMP-2 binding HS variant from commercially available preparations of HS, so removing the manufacturing bottleneck for their translation into the clinic. This affinity-matched HS enhanced BMP-2-induced osteogenesis through improved BMP 2 kinetics and receptor modulation, prolonged pSMAD signaling and reduced interactions with its antagonist noggin. When co-delivered with a collagen implant, the HS was as potent as exogenous BMP-2 for the healing of critical sized bone defects in rabbits. This affinity platform can be readily tuned to isolate HS variants targeted ata range of clinically-relevant growth and adhesive factors. PMID- 23632324 TI - Tendon graft revitalization using adult anterior cruciate ligament (ACL)-derived CD34+ cell sheets for ACL reconstruction. AB - As a new strategy for enhancing recovery after anterior cruciate ligament (ACL) reconstruction, we developed a cell sheet wrapped graft using ACL-derived CD34+ cells. Our results from an ex vivo cell migration assay demonstrated gradual cell migration into the graft from the cell sheet, and an enzyme-linked immunosorbent assay indicated that the cell sheet cultures secreted a significantly greater amount of VEGF than typical monolayer cultures. In the in vivo study, the rats received one of three possible ACL reconstruction treatments; 1) a tendon graft wrapped in an ACL-derived CD34+ cell sheet, 2) a tendon graft and ACL-derived CD34+ cell injection, or 3) the control group that received just the tendon graft. The in vivo studies revealed that the ACL-derived CD34+ cell sheet wrapped grafts demonstrated a greater number of the cells derived from the cell sheets incorporated within the bone tunnel site and grafted tendon. We believe the incorporated CD34+ cells enhanced the healing of both the bone-tendon junction and the grafted tendon in the reconstructed rat ACLs by increasing proprioceptive recovery, graft maturation, and biomechanical strength. ACL-derived CD34+ cell sheet wrapped grafts could become a promising strategy to revitalize tendon autografts and recovery after ACL reconstruction resulting in superior and quicker recovery in patients requiring ACL reconstruction. PMID- 23632325 TI - Valproic acid-induced parkinsonism: levodopa responsiveness with dyskinesia. AB - BACKGROUND: Valproic acid is a drug used for the treatment of a variety of psychiatric and neurological disorders. While it is well known to cause postural tremor, hyperammonemia, slowness, and sedation, it has also been described to occasionally cause a reversible form of parkinsonism. MATERIALS AND METHODS: A series of five cases is reported. RESULTS: All patients were taking the drug for at least several months before onset of their parkinsonian symptoms. Parkinsonism was defined by the presence of bradykinesia, rigidity, postural instability, and resting tremor, but not postural or action tremor. After discontinuing their valproic acid, improvement was seen by all patients. The course of improvement took days to months after discontinuance. Two of these patients responded to dopaminergic therapy, with drug-induced dyskinesia observed in one. In another patient, valproic acid was thought to unmask underlying Parkinson's Disease; this patient benefited from levodopa as well. CONCLUSION: Valproic acid-induced parkinsonism can look identical to idiopathic parkinsonism. In all five cases, the relationship between the valproic acid use and parkinsonism was initially unclear because of the delayed and insidious onset. Our finding of levodopa responsiveness and dyskinesia added to the diagnostic confusion. This treatment responsiveness also set it apart from neuroleptic-induced parkinsonism. In all cases improvement of symptoms occurred after discontinuation of the offending medication. PMID- 23632326 TI - Magnification narrow-band imaging for the diagnosis of early gastric cancer: a review of the Japanese literature for the Western endoscopist. PMID- 23632327 TI - CD103-CD11b+ dendritic cells regulate the sensitivity of CD4 T-cell responses to bacterial flagellin. AB - Toll-like receptor 5 (TLR5) has been widely studied in an inflammatory context, but the effect of TLR5 on the adaptive response to bacterial flagellin has received considerably less attention. Here, we demonstrate that TLR5 expression by dendritic cells (DCs) allows a 1,000-fold enhancement of T-cell sensitivity to flagellin, and this enhancement did not require the expression of NLRC4 or Myd88. The effect of TLR5 on CD4 T-cell sensitivity was independent of the adjuvant effect of flagellin and TLR5 ligation did not alter the sensitivity of ovalbumin (OVA)-specific T cells to OVA. In the spleen, the exquisite T-cell sensitivity to flagellin was regulated by CD4-CD8alpha- DCs and was blocked by a monoclonal antibody to TLR5. In the mesenteric lymph nodes, flagellin-specific T-cell activation was regulated by a population of CD103-CD11b+ DCs. Thus, TLR5 expression by mucosal and systemic DC subsets controls the sensitivity of the adaptive immune response to flagellated pathogens. PMID- 23632329 TI - Newly developed glycogen synthase kinase-3 (GSK-3) inhibitors protect neuronal cells death in amyloid-beta induced cell model and in a transgenic mouse model of Alzheimer's disease. AB - Glycogen synthase kinase-3 (GSK-3) is emerging as a prominent therapeutic target of Alzheimer's disease (AD). A number of studies have been undertaken to develop GSK-3 inhibitors for clinical use. We report two novel GSK-3 inhibitors (C-7a and C-7b) showing good activity and pharmacokinetic (PK) profiles. IC50 of new GSK-3 inhibitors were in the range of 120-130 nM, and they effectively reduced the Abeta-oligomers induced neuronal toxicity. Also, new GSK-3 inhibitors decreased the phosphorylated tau at pThr231, pSer396, pThr181, and pSer202, and inhibited the GSK-3 activity against Abeta-oligomers induced neuronal cell toxicity. In B6;129-Psen1(tm1Mpm) Tg(APPSwe, tauP301L)1Lfa/Mmjax model of AD, oral administration of C-7a (20 mg/kg, 50 mg/kg) showed increased total arm entries and spontaneous alteration of Y-maze which was regarded as short-term memory. In particular, 50 mg/kg C-7a treated mice significantly decreased the level of phosphorylated tau (Ser396) in brain hippocampus. We suggest that new GSK-3 inhibitor (C-7a) is potential candidates for the treatment of AD. PMID- 23632330 TI - Major haplotypes of the human bitter taste receptor TAS2R41 encode functional receptors for chloramphenicol. AB - A complete understanding of bitterness perception requires identification of cognate bitter substances for all human bitter taste receptors (TAS2Rs). However, so far, no agonists have been identified for five of the 25 TAS2Rs, i.e., TAS2R41, TAS2R42, TAS2R45, TAS2R48 and TAS2R60. Due to substantial genetic variability several haplotypes exist for most bitter receptor genes. For some of the deorphaned TAS2Rs, haplotypes have been identified coding for proteins with severely impaired or even lacking receptor function, proposing that the use of non-functional receptor variants in previous investigations accounted for the failure to identify cognate bitter agonists for the orphan TAS2Rs. In the present report we reasoned that at least one out of the major genetically encoded TAS2R variants is functional. Therefore, we expressed the major haplotypes of the five orphan TAS2Rs in our functional assay and challenged the cells with 106 bitter compounds. Chloramphenicol was identified as agonist for TAS2R41. Further studies revealed that TAS2R41 is a 'specialist' receptor highly selective for this antibiotic. None of the other TAS2R variants responded to any of the 106 compounds, suggesting that the use of non-functional variants does not explain the failure to identify cognate agonists for the other four TAS2Rs. Probably, these TAS2Rs are highly selective for bitter substances absent in our compound library. PMID- 23632328 TI - Lung epithelial cells are essential effectors of inducible resistance to pneumonia. AB - Infectious pneumonias are the leading cause of death worldwide, particularly among immunocompromised patients. Therapeutic stimulation of the lungs' intrinsic defenses with a unique combination of inhaled Toll-like receptor (TLR) agonists broadly protects mice against otherwise lethal pneumonias. As the survival benefit persists despite cytotoxic chemotherapy-related neutropenia, the cells required for protection were investigated. The inducibility of resistance was tested in mice with deficiencies of leukocyte lineages due to genetic deletions and in wild-type mice with leukocyte populations significantly reduced by antibodies or toxins. Surprisingly, these serial reductions in leukocyte lineages did not appreciably impair inducible resistance, but targeted disruption of TLR signaling in the lung epithelium resulted in complete abrogation of the protective effect. Isolated lung epithelial cells were also induced to kill pathogens in the absence of leukocytes. Proteomic and gene expression analyses of isolated epithelial cells and whole lungs revealed highly congruent antimicrobial responses. Taken together, these data indicate that lung epithelial cells are necessary and sufficient effectors of inducible resistance. These findings challenge conventional paradigms about the role of epithelia in antimicrobial defense and offer a novel potential intervention to protect patients with impaired leukocyte-mediated immunity from fatal pneumonias. PMID- 23632331 TI - A putative bactoprenol glycosyltransferase, CsbB, in Bacillus subtilis activates SigM in the absence of co-transcribed YfhO. AB - Bacteria are equipped with complex cell surface structures, such as cell walls. How they maintain cell surface integrity through cell wall metabolism during growth and adaptation to unfavorable environmental conditions is still elusive. In the Gram-positive soil bacterium Bacillus subtilis, one extracytoplasmic function (ECF) sigma factor, SigM, is believed to play a primary role in cell surface integrity. Here, we find that expression of CsbB, which is known to be involved in the extracellular stress response, causes constitutive activation of SigM when YfhO, a membrane protein with unknown function, is lost. CsbB has similarity with the well-characterized bactoprenol glucosyltransferase GtrB found in Gram-negative bacteria. Substitution of a single amino acid residue at the putative catalytic site of CsbB abolishes this constitutive activation, and expression of Escherichia coli GtrB in B. subtilis causes similar effects as expression of CsbB, suggesting that SigM is activated by the glycosyltransferase activity of CsbB. A comparison with the Gtr system in Gram-negative bacteria suggests that accumulation of glycosylated bactoprenol catalyzed by CsbB reduces the bactoprenol pool in the absence of YfhO. Reduction of bactoprenol synthesis causes similar effects as expression of CsbB. We propose that it is the shortage of available bactoprenol within a cell that induces SigM activity. PMID- 23632332 TI - Fixation techniques for complex traumatic transverse sacral fractures: a systematic review. AB - STUDY DESIGN: Systematic review. OBJECTIVE: To identify and describe reconstruction methods for the treatment of transverse sacral fracture (TSF) and to evaluate outcomes based on treatment interventions. SUMMARY OF BACKGROUND DATA: A variety of surgical interventions for stabilization of TSFs exist, yet the optimal management remains unclear. Although there are many individual case reports and series describing techniques to stabilize TSF, prior reviews fail to provide a comprehensive summary of current and past surgical techniques and their individual outcomes. METHODS: Our systematic review searched the PubMed database using keywords identifying sacral fractures with a transverse component, requiring internal fixation for stabilization as well as a review of bibliographies and archives from meeting proceedings. RESULTS: Our search located 417 publications for abstract review, of which 27 (109 patients) with TSF were included. Average follow-up was 22 months (range, 0-82 mo). Thirty-eight patients (34%) underwent spinopelvic fixation (SPF), 53 (49%) underwent posterior pelvic ring fixation (PPRF), and 18 (17%) underwent both. PPRF included iliosacral screws (37 patients), transiliac screws (11 patients), transiliac screws with plating (3 patients), posterior plating (1 patient), and transiliac bar (1 patient). Additional injuries causing lumbosacral instability were seen in 8 patients (42%) who underwent SPF, 2 patients (18%) treated with PPRF, and 5 patients (45%) who were treated with both SPF and PPRF. Of those who presented with a neurological deficit, 5 patients (45%) with SPF, 9 (39%) with PPRF, and 3 (30%) with SPF and PPRF experienced full neurological recovery. Five patients (45%) with SPF, 7 (30%) with PPRF, and 5 (50%) with both regained partial neurological function. One patient (9%) with SPF, 7 (30%) with PPRF, and 2 (20%) with both experienced no neurological recovery. CONCLUSION: PPRF seems to be effective for stabilization of TSF. However, in the setting of further injuries causing additional lumbosacral instability, SPF should be used to ensure effective stabilization. PMID- 23632333 TI - Surgery and prognostic factors of patients with epidural spinal cord compression caused by hepatocellular carcinoma metastases: retrospective study of 36 patients in a single center. AB - STUDY DESIGN: A retrospective study of 36 patients with metastatic hepatocellular carcinoma (HCC) of the mobile spine was performed by survival analysis. OBJECTIVE: To discuss the factors that may affect outcomes of patients with HCC spinal metastases. SUMMARY OF BACKGROUND DATA: HCC is a rare tumor in Western countries. However, HCC is common in Far East (Taiwan, Korea, mainland China), where the hepatitis B virus is epidemic. As the mean survival time of patients with HCC has largely increased in recent years, it is now more common to encounter a patient with epidural spinal cord compression caused by HCC spinal metastases in clinic. METHODS: The univariate and multivariate analyses of various clinical factors were performed to identify independent variables that could predict prognosis. The survival rate was estimated by the Kaplan-Meier method, and differences were analyzed by the log-rank test. Factors with P values of 0.1 or less were subjected to multivariate analysis for survival rate by multivariate Cox proportional hazards analysis. RESULTS: A total of 36 patients with metastatic HCC of the mobile spine were included in the study. Age (<=45 yr/>45 yr), duration of preoperative symptoms (<6 mo/>=6 mo), preoperative Frankel score (A-C/D-E), Tomita score (5-7/8-10), and bisphosphonate treatment were suggested as the potential prognostic factors through univariate analysis. However, as they were submitted to the multivariate Cox regression model, only Tomita score was found as an independent prognostic factor. CONCLUSION: Tomita score no more than 7 is a favorable prognostic factor for HCC metastases in the mobile spine. LEVEL OF EVIDENCE: 4. PMID- 23632334 TI - Efficacy of diffusion-weighted magnetic resonance imaging in diagnosing spinal root disorders in lumbar disc herniation. AB - STUDY DESIGN: Prospective study based on magnetic resonance imaging for lumbar disc herniation. OBJECTIVE: In this study, we captured diffusion-weighted imaging (DWI) of dorsal root ganglion (DRG) of the affected nerve root in lumbar disc herniation and examined the relationship between apparent diffusion coefficient (ADC) and clinical symptoms to evaluate the efficacy of DWI in the diagnosis of lumbar spinal disorders. SUMMARY OF BACKGROUND DATA: DWI captures diffusion of water molecules in intracellular or extracellular fluid, allowing visualization of edematous changes, and is therefore used in diagnosis of hyper-acute cerebral infarction. In addition, it is possible to quantify the degree of diffusion using ADC calculated from the DWI data. Meanwhile in lumbar disc herniation, edematous changes occur in DRG of affected nerve root. If DWI enables visualization of these edematous changes, it will be possible to diagnose objectively the affected level. METHODS: The subjects were 30 patients who underwent surgery of unilateral radiculopathy and a single level lumbar disc herniation. We analyzed the relationship between morbidity duration, visual analogue scale (VAS) score of leg symptoms, and ADC. In addition, we investigated any correlation between VAS recovery ratio (i.e., VAS preoperative - VAS postoperative)/VAS preoperative * 100) with ADC. RESULTS: When compared with the contralateral side, ADC of the affected DRG was observed to increase in 18 and decrease in 12 subjects, and thus no definite trend was observed. The relationship between morbidity duration, VAS score, and ADC had no observed correlation. A positive correlation between ADC and VAS recovery ratio was statistically observed (P < 0.01, leg pain: r = 0.707, leg numbness: r = 0.738). CONCLUSION: This study showed that patients with decreased ADC tended to show poor improvement of leg symptoms, which may suggest the possibility that ADC of DRG is related to neuronal plasticity. LEVEL OF EVIDENCE: 2. PMID- 23632335 TI - Incidence and mortality of cardiac events in lumbar spine surgery. AB - STUDY DESIGN: Retrospective national database analysis. OBJECTIVE: A population based database was analyzed to characterize the incidence, mortality, and associated risk factors for cardiac events in lumbar spine surgery. SUMMARY OF BACKGROUND DATA: Cardiac events are a leading cause of perioperative mortality in spinal surgery. The incidence of these complications after lumbar surgery is not well characterized on a national level. METHODS: Data from the Nationwide Inpatient Sample was obtained from 2002 to 2009. Patients undergoing lumbar decompression or lumbar fusion for degenerative etiologies were identified. Patient demographics, incidence of cardiac complications, comorbidities, and mortality were assessed. Statistical analysis was performed using Student t test for discrete variables and chi test for categorical data. Logistic regression was used to identify independent predictors for cardiac complications. RESULTS: A total of 578,457 lumbar spine procedures were identified in the Nationwide Inpatient Sample from 2002 to 2009. The overall incidence of cardiac complications was 6.7 per 1000 cases. Cardiac events occurred more frequently in the lumbar fusion group, with a rate of 9.3 per 1000 cases, than in the lumbar decompression group, with a rate of 4.0 per 1000 (P < 0.0005). Patients with cardiac events were significantly older than patients without complications by 9.4 years (P < 0.0005). Patients with cardiac complications had statistically increased hospitalizations, costs, and mortality when a cardiac event was present (P < 0.0005). Logistic regression analysis demonstrated independent predictors for cardiac events to include age 65 years or older, acute blood loss anemia, and several comorbidities. CONCLUSION: Our results demonstrated an overall incidence of 6.7 cardiac complications per 1000 lumbar spine surgical procedures from 2002 to 2009. Patients undergoing lumbar fusion were more likely to experience cardiac events than lumbar decompression patients. Cardiac events tend to occur in patients with noted risk factors and result in increased hospitalizations, costs, and mortality. On the basis of these findings, we think that patients with specified risk factors should be monitored closely and medically optimized in the perioperative period. PMID- 23632336 TI - Selective thoracic fusion in Lenke 1C curves: prevalence and criteria. AB - STUDY DESIGN: Multicenter retrospective analysis of prospectively collected data. OBJECTIVE: Evaluate radiographical and clinical characteristics of patients undergoing a selective thoracic fusion (STF) for Lenke 1C curves. SUMMARY OF BACKGROUND DATA: STF of adolescent idiopathic scoliosis has been advocated for the so-called "false double major" curve (Lenke 1C/King type II). Despite these recommendations, many surgeons continue to perform nonselective fusions for this curve type. It is unknown to what extent other factors influence the surgeon's fusion-level selection. METHODS: A prospective multicenter database included 264 patients with surgically treated Lenke 1C curves and were divided into 2 groups. The STF group included patients with the lowest instrumented vertebra at or cephalad to L1, whereas the nonselective fusion group included patients with the lowest instrumented vertebra at or caudal to L3. Preoperative radiographical, clinical (scoliometer), Scoliosis Appearance Questionnaire (SAQ), and Scoliosis Research Society (SRS) questionnaires were analyzed and compared. RESULTS: Only 138 of 264 patients (49%) underwent an STF. Sex ratio (90% vs. 86% female), average age (14.7 vs. 14.8 yr), and preoperative main thoracic Cobb angles (56.0 degrees +/- 9.9 degrees vs. 55.3 degrees +/- 11.4 degrees ) were not significantly different (STF vs. nonselective fusion). However, the average thoracolumbar/lumbar (TL/L) preoperative Cobb angle was significantly smaller in the STF group (42.1 degrees +/- 8.6 degrees vs. 47.0 degrees +/- 9.0 degrees ; P < 0.001), whereas the main thoracic: TL/L Cobb ratio (1.35 +/- 0.20 vs. 1.18 +/ 0.15; P < 0.001), apical vertebral translation, and rotation (1.82 +/- 0.59 vs. 1.31 +/- 0.53; P < 0.001), (1.16 vs. 0.98; P < 0.001) ratios were significantly greater in the STF group. Preoperative coronal balance, sagittal Cobb angles (including T10-L2 kyphosis) and Risser Grade were not significantly different. Preoperative TL/L scoliometer measures were significantly less in the STF group (8.1 degrees +/- 3.7 degrees vs. 10.3 degrees +/- 5.4 degrees ; P = 0.001). On the SAQ, the STF group had less desire for an appearance change. CONCLUSION: Despite the recommendation to fuse only the structural thoracic curve in a 1C curve, only 49% of patients were treated with an STF. Those undergoing an STF had smaller TL/L Cobb angles, less TL/L clinical deformity, larger main thoracic: TL/L ratios, and less desire for an appearance change. LEVEL OF EVIDENCE: 3. PMID- 23632338 TI - Incidence and risk factors for gastrointestinal hemorrhage after lumbar fusion. AB - STUDY DESIGN: Retrospective database analysis. OBJECTIVE: To determine rates of gastrointestinal (GI) hemorrhage after lumbar fusions, a population-based database was analyzed to identify incidence, mortality, and risk factors associated with anterior (ALF), posterior (PLF), and simultaneous anterior/posterior (APLF) lumbar fusions. SUMMARY OF BACKGROUND DATA: GI hemorrhage after lumbar surgery is a rare complication that can have devastating consequences. Incidences of GI bleeding after lumbar fusion are not well characterized in the current literature. METHODS: Data from the Nationwide Inpatient Sample were obtained from 2002 to 2009. Patients undergoing ALF, PLF, and APLF for degenerative pathologies were identified and the incidence of GI hemorrhage was evaluated. Patient demographics, Charlson Comorbidity Index, length of stay, costs, and mortality were assessed. SPSS version 20 (IBM; Armonk, NY) was used to detect statistical differences between groups and perform logistic regression analyses to identify independent predictors of GI bleeding. A P value of <0.001 denoted significance. RESULTS: A total of 220,522 lumbar fusions were identified in the United States from 2002 to 2009. Of these, 19,762 were ALFs, 182,801 were PLFs, and 17,959 were APLFs. GI bleeding was noted in ALFs, with 1.1 events per 1000 cases, PLFs with 1.4 events, and APLFs with 1.7 events. Patients with GI bleeding demonstrated greater Charlson Comorbidity Index scores, length of stay, costs, and mortality (P < 0.001). Logistic regression analysis demonstrated independent predictors of GI hemorrhage including advanced age (>65 yr), male sex, blood loss anemia, fluid/electrolyte disorders, metastatic neoplasm, and weight loss (P < 0.001). CONCLUSION: The results of our study demonstrate very low complication rates of GI hemorrhage across ALFs, PLFs, and APLF cohorts. Across all surgical procedures, the presence of GI bleeding complications was associated with greater comorbidity, length of stay, cost, and mortality. We strongly advise physicians to perform stringent perioperative assessments of risk factors and to provide prompt medical attention to minimize the impact of GI bleeding complications. LEVEL OF EVIDENCE: 3. PMID- 23632337 TI - 10-second step test for quantitative evaluation of the severity of thoracic compressive myelopathy. AB - STUDY DESIGN: A clinical and cohort study. OBJECTIVE: To evaluate the efficacy of the 10-second step test as a measure of the severity of thoracic compressive myelopathy. SUMMARY OF BACKGROUND DATA: Objective measurement is essential for determining the severity of thoracic compressive myelopathy. Some useful measurements for cervical myelopathy have been identified; however, few reports have addressed the measurement of severity of thoracic myelopathy. METHODS: Twenty-five presurgical patients with thoracic compressive myelopathy were included. Patients with cervical myelopathy and concomitant lumbar canal stenosis were excluded from this analysis. The subjects included 14 males and 11 females, with a mean age of 58.8 years (range, 36-81). The 10-second step test was performed, and the number of steps in 10 seconds was recorded. The Japanese Orthopedic Association (JOA) score for thoracic myelopathy, which was adapted from the JOA score for cervical myelopathy, was also used for assessment. RESULTS: The average 10-second step test score in all patients was 9.6 +/- 1.3 before surgery, which significantly correlated with the total JOA score (r = 0.69, P < 0.01) and its lower extremity motor function score (r = 0.92, P < 0.01). They were retested 12 months after surgery, but the postoperative scores for 5 patients were not available. The average preoperative 10-second step test score of the remaining 20 patients was 9.5 +/- 1.5, which significantly improved to 15.1 +/- 1.2 12 months after surgery. The step test score in those 20 patients significantly correlated with the total JOA score and lower extremity motor function score before and after surgery (P < 0.01). CONCLUSION: The 10-second step test reflected the severity of thoracic compressive myelopathy. Moreover, this test was useful for evaluating surgical outcome in patients with thoracic compressive myelopathy. PMID- 23632339 TI - Safety of thromboembolic chemoprophylaxis in spinal trauma patients requiring surgical stabilization. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To determine the incidence of thromboembolic events, bleeding complications such as epidural hematomas, and wound complications in patients with spinal trauma requiring surgical stabilization. SUMMARY OF BACKGROUND DATA: Literature addressing the safety and efficacy of chemoprophylactic agents in postoperative patients with spinal trauma is sparse. As a result, significant variability exists regarding administration of thromboembolic chemoprophylaxis in this population. The risk of bleeding complications is particularly concerning. METHODS: Patients with spinal trauma who underwent surgical stabilization in 2009 and 2010 at a single level 1 trauma center were retrospectively reviewed. Exclusion criteria included patients who underwent solely decompressive procedures, noninstrumented fusions, kyphoplasty, or had incomplete medical records. Patients who received chemoprophylaxis were compared with patients who did not. Demographical information and injury data were collected. Primary outcome measures were prevalence of thromboembolic events, epidural hematomas, and persistent wound drainage requiring irrigation and debridement. RESULTS: Two hundred twenty-seven of 373 patients were included (56 in the untreated group, 171 in the treated group). Eight patients in the untreated group (14.3%) and 12 patients in the treated group (7%) developed postoperative thromboembolism (P = 0.096). There was 1 pulmonary embolism in the untreated group (1.8%), and 4 pulmonary embolisms in the treated group (2.3%). Surgical irrigation and debridement for wound drainage was required for 1.8% of patients in the untreated group and for 5.3% of patients in the treated group. No epidural hematomas were noted in either group. The treated group had more spinal levels fused (P = 0.46), higher injury severity scores (0.001), and longer hospitalizations (0.018). Patients who developed postoperative thromboembolism had significantly higher body mass indexes (P = 0.01), injury severity scores (0.001), number of spinal levels fused (P = 0.004), incidence of neurological deficits (0.001), and longer hospitalizations (0.16) compared with those who did not. CONCLUSION: The use of chemoprophylaxis appears to be safe in at-risk patients in the immediate postoperative period after spinal trauma surgery. No epidural hematomas occurred, and the risk of wound drainage is small. Body mass index, injury severity score, presence of neurological deficits, and number of spinal levels fused should be considered when determining which patients should receive chemoprophylaxis after surgical stabilization. PMID- 23632340 TI - Electronic structure analysis of multistate reactivity in transition metal catalyzed reactions: the case of C-H bond activation by non-heme iron(IV)-oxo cores. AB - This perspective discusses the principles of the multistate scenario often encountered in transition metal catalyzed reactions, and is organized as follows. First, several important theoretical concepts (physical versus formal oxidation states, orbital interactions, use of (spin) natural and corresponding orbitals, exchange enhanced reactivity and the connection between valence bond and molecular orbital based electronic structure analysis) are presented. These concepts are then used to analyze the electronic structure changes occurring in the reaction of C-H bond oxidation by Fe(IV)oxo species. The analysis reveals that the energy separation and the overlap between the electron donating orbitals and electron accepting orbitals of the Fe(IV)oxo complexes dictate the reaction stereochemistry, and that the manner in which the exchange interaction changes depends on the identity of these orbitals. The electronic reorganization of the Fe(IV)oxo species during the reaction is thoroughly analyzed and it is shown that the Fe(IV)oxo reactant develops oxyl radical character, which interacts effectively with the sigmaCH orbital of the alkane. The factors that determine the energy barrier for the reaction are discussed in terms of molecular orbital and valence bond concepts. PMID- 23632342 TI - The role of imaging in hepatocellular carcinoma: the present and future. AB - Imaging plays an important role in diagnosis and management of patients with hepatocellular carcinoma (HCC). Although ultrasound is the main surveillance imaging tool for HCC, dynamic contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are used primarily for diagnosis and staging of HCC. Recent advances in both CT and MRI technology have led to a decrease in ionizing radiation exposure and improved capabilities for evaluation of HCC, including, dynamic contrast-enhanced CT and MRI, perfusion CT and MRI, dual energy CT, radiation dose reduction strategies, diffusion-weighted imaging, MR elastography, iron and fat quantification, and intravenous hepatobiliary contrast agents. PMID- 23632341 TI - Characteristics of liver injury in drug-induced systemic hypersensitivity reactions. AB - BACKGROUND: The liver is the most commonly involved internal organ in drug induced systemic hypersensitivity. However, data obtained from these patients have yet to be analyzed in depth with respect to liver injury. METHODS: The medical records of 136 patients who developed delayed-type drug hypersensitivity were reviewed at a tertiary referral hospital. Culprit drugs, the pattern and degree of liver injury, and the effect of systemic corticosteroids were evaluated in the group of patients with drug-induced systemic hypersensitivity and liver dysfunction (aspartate aminotransferase or alanine aminotransferase >=80 IU/L). Clinical characteristics of patients with drug-induced systemic hypersensitivity and liver injury were analyzed. RESULTS: Among the 61 patients with drug-induced systemic hypersensitivity and liver dysfunction, the clinical phenotypes were drug reaction with eosinophilia and systemic symptoms (n = 29, 48%), Stevens Johnson syndrome/toxic epidermal necrolysis (n = 11, 18%), and maculopapular rash (n = 17, 28%). Antibiotics (n = 27, 44%) were the most common cause of drug induced systemic hypersensitivity with liver dysfunction. Whereas patients with Stevens-Johnson syndrome/toxic epidermal necrolysis had mild hepatocellular-type liver injury of relatively brief duration, those with drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome had more severe and prolonged hepatocellular injury in addition to moderate to severe cholestatic-type liver injury. The use of systemic corticosteroids did not significantly affect either recovery from liver injury or mortality. LIMITATIONS: This study was retrospective and the number of subjects was small. CONCLUSION: The results suggest that the severity, pattern, and duration of liver injury differ according to the drug-hypersensitivity phenotype. Further studies are needed to evaluate the role of systemic corticosteroids in drug-induced systemic hypersensitivity and liver injury. PMID- 23632343 TI - Anatomic considerations in the surgical resection of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is a common cause of cancer death worldwide. Treatment of HCC usually consists of combinations of locoregional therapy, surgical resection, orthotopic liver transplantation, and in advanced cases, systemic chemotherapy. The best rates of cure are achieved with surgical resection or orthotopic liver transplantation in well-selected patients. The success of surgical resection depends on the adequacy of the extent of resection, balanced with the need to preserve functional hepatic parenchyma. Nonanatomic resection for HCC has been proposed as a surgical technique to maximize residual liver mass, but has been shown by some to yield inferior oncologic outcomes compared with formal anatomic resection. This review discusses relevant surgical anatomy of the liver, classifications of hepatic resection, and the current literature regarding outcomes of anatomic and nonanatomic resection of the liver. PMID- 23632344 TI - Liver transplantation for hepatocellular carcinoma: a surgical perspective. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in the world. Early detection and timely treatment of HCC is critical for better patient outcomes. Curative therapy consists of surgical hepatic resection or liver transplantation (LTx); however, both are restricted to explicit selective criteria. Liver resection is the gold standard of treatment for noncirrhotic patients but can be done in only a small fraction of cirrhotic patients depending on synthetic dysfunction, degree of portal hypertension, and number and location(s) of tumor(s). Therefore, the best treatment modality in cirrhotic patients with HCC is LTx as it will cure both HCC and the underlying cirrhosis. The limitation to offer transplant to all cirrhotic patients with HCC is the shortage of available donor organs. While these patients are waiting for transplant, their tumors may progress and develop distant metastases and may lead to patients losing their candidacy for LTx. Various ablation therapies can be used to treat HCC, prevent tumor progression, and thus, avoid patients losing the option of LTx. Future directions to improve HCC patient outcomes include advancement in tumor gene analysis and histopathology for better prediction of tumor behavior, improved immunosuppression regimens to reduce tumor recurrence in the posttransplant setting, and efficient use of an expanded donor pool that includes living donor organs. This paper will review the current methods of HCC diagnosis, selection for either hepatic resection or LTx, and will also summarize posttreatment outcomes. We will suggest future directions for the field as we strive to improve outcomes for our HCC patients. PMID- 23632346 TI - Clinical implications of lactose malabsorption versus lactose intolerance. AB - The majority of the world's adult population and an estimated 80 million Americans are hypolactasic and hence malabsorb ingested lactose. Although lactose malabsorption is easily identified, less readily assessed is the clinically important question of how often does this malabsorption induce symptoms. This review summarizes: (1) knowledge concerning the etiology and diagnosis of hypolactasia and the pathophysiology of the symptoms of lactose malabsorption and (2) the results of well-controlled trials of the symptomatic response of lactose malabsorbers to varying dosages of lactose and the efficacy of therapeutic interventions to alleviate these symptoms. We conclude that the clinical significance of lactose malabsorption has been overestimated by both the lay public and physicians in that commonly ingested doses of lactose (ie, the quantity in a cup of milk) usually do not cause perceptible symptoms when ingested with a meal. Symptoms occur when the lactose dosage exceeds that in a cup of milk or when lactose is ingested without other nutrients. Simple dietary instruction, rather than the use of commercial products to reduce lactose intake, is recommended for the vast majority of lactose-malabsorbing subjects. PMID- 23632345 TI - Epidemiology of hepatocellular carcinoma: consider the population. AB - Hepatocellular carcinoma (HCC) is increasing in incidence and has a very high fatality rate. Cirrhosis due to chronic hepatitis B or hepatitis C is the leading risk factor for HCC. Global epidemiology of HCC is determined by the prevalence of dominant viral hepatitis and the age it is acquired in the underlying population. Upcoming risk factors include obesity, diabetes, and related nonalcoholic fatty liver disease. This review discusses the latest trends of HCC globally and in the United States. It also provides an evidence-based commentary on the risk factors and lists some of the preventive measures to reduce the incidence of HCC. PMID- 23632347 TI - Potential screening benefit of a colorectal imaging capsule that does not require bowel preparation. AB - INTRODUCTION: Check-Cap is a capsule device that images the colon using low-dose radiation (total dose equivalent to a plain abdominal radiograph) and does not require bowel preparation. Check-Cap is in development for colorectal cancer imaging. AIM: : To survey patients in a primary care setting for their preferences for Check-Cap versus fecal occult blood testing (FOBT), including among patients who decline colonoscopy. METHODS: Patients aged 50 and older presenting to the general medicine and family practice clinics of Indiana University Health sites within a 3-month period were approached during clinic visits. A total of 502 patients who agreed to participate were given the opportunity to complete an anonymous survey (Supplementary Appendix 1, http://links.lww.com/JCG/A71) regarding their preferences for colon cancer screening. The survey presented procedure descriptions and projected accuracies for colonoscopy, FOBT, and Check-Cap. For Check-Cap, projected sensitivity was 80% for cancer and 50% for large polyps. RESULTS: The mean age of the subjects was 61.6 years, 39% were males, 44% white, 62% of patients had prior colonoscopy, and 26% had prior polypectomy. We defined 3 groups of patients-those that had never had a colonoscopy (NC)-38%, those who had a colonoscopy but no polypectomy (CNP)-36%, and those who had a colonoscopy and polypectomy (CP)-26%. Overall, 284 patients (57%) were willing to undergo a future colonoscopy. Patients with prior colonoscopy and polypectomy were more willing to get another colonoscopy than the other 2 groups (CP:CNP:NC=78%:64%:38%; P<0.0001). Willingness to undergo colonoscopy decreased with age in all the 3 groups. Among those not willing to undergo colonoscopy, 30% were willing to undergo Check-Cap, 20% were willing for FOBT), 25% were willing to do both, and 24% were not willing for either test. Among those who declined future colonoscopy, 40% reported Check-Cap as their preferred screening test versus 22% for FOBT; P=0.0002. CONCLUSION: Our survey suggests that an imaging capsule like Check-Cap could contribute to screening adherence among patients who decline colonoscopy, provided that it can achieve projected sensitivities of 80% for cancer and 50% for large polyps. PMID- 23632348 TI - Development of the patient Harvey Bradshaw index and a comparison with a clinician-based Harvey Bradshaw index assessment of Crohn's disease activity. AB - GOALS AND BACKGROUND: The objective is to develop a patient-based Harvey Bradshaw Index (P-HBI) of Crohn's Disease (CD) activity and to compare it with the clinician-based HBI of CD activity in CD outpatients. STUDY: Consecutive patients with CD randomly completed the P-HBI either before or after the consultation. The gastroenterologist assessed patient's CD activity on the same day. Overall agreement between HBI and P-HBI was calculated with Spearman's rho and Mann Whitney U test. Agreement regarding active disease versus remission and agreement at item level was calculated by percent agreement and Cohen's kappa. RESULTS: One hundred eighty-one (response rate 88.3%) CD patients participated. P-HBI and HBI showed a large correlation (rs=0.82). The medians (interquartile range) of the total HBI (2; 0 to 4) and P-HBI (4; 1 to 7) were statistically significantly different (z=-8.411; P<0.001). Fortunately, in 82.6% of the cases this difference between clinicians and patients was not clinically significant (<3.2). The percentage agreement between clinician and patient, judging CD as active or as in remission, was 77%, rs=0.56, kappa=0.52, indicating a moderate agreement. P-HBI and HBI on frequent extraintestinal manifestations in CD varied from less than chance (kappa=-0.02) to a perfect agreement (kappa=1). Patients tended to report more symptoms while completing the patient-based questionnaire compared to what they reported to the clinician during consultation. CONCLUSIONS: The P-HBI is the first step in developing a potential promising tool given its adequate agreement with the original HBI and its feasibility, especially in patients with low scores. Future research is necessary to develop a validated patient-based version studied in several patient populations. PMID- 23632349 TI - The utility of esophagogastroduodenoscopy before endoscopic ultrasonography in patients undergoing endoscopic ultrasonography for pancreatico-biliary and mediastinal indications. AB - BACKGROUND: Oblique-viewing echoendoscopes may miss luminal lesions. There is no consensus on whether to routinely perform esophagogastroduodenoscopy (EGD) before endoscopic ultrasonography (EUS). Currently, practice patterns are variable and prospective data are needed. AIM: : To determine the proportion of clinically meaningful lesions detected when EGD is performed routinely before EUS. STUDY: This was a multicenter prospective cohort study conducted at tertiary referral center and large community practice. Patients undergoing EUS for pancreatico biliary and mediastinal indications were enrolled. MAIN OUTCOMES: The primary outcome was the proportion of patients with a clinically meaningful lesion found on EGD. This was a combined outcome defined as any lesion that would alter medical management, or impact the subsequent EUS examination. RESULTS: Two hundred four patients were included in the final analysis. Clinically meaningful lesions were found on EGD in 45 patients [22.1%; 95% confidence interval (CI), 16.4-27.8]. Lesions that altered medical management were found in 32 patients (15.7%; 95% CI, 10.7-20.7). Lesions impacting the subsequent EUS examination were found in 20 patients (9.8%; 95% CI, 5.7-13.9). Clinically meaningful lesions found were (number of patients): esophagitis (14), ulcer (9), ring/stricture (7), large hiatal hernia (6), hyperplastic gastric polyp (5), Barrett esophagus (3), surgically altered anatomy (2), neoplastic lesion (2), subepithelial mass/GIST (1), stenosis (1), diverticulum (1), and fistula (1). CONCLUSIONS: EGD before EUS may detect enough clinically meaningful lesions to support the routine performance of EGD before EUS. PMID- 23632350 TI - Consider the perspectives: interventional radiology. AB - Image-guided percutaneous local and regional modalities are major treatments for hepatocellular carcinoma. Patients having better liver function and performance are usually eligible and can gain significant survival benefit, especially with more limited tumor burden. The most common local therapies are ethanol and radiofrequency ablation, with the latter providing better local tumor control and survival. Radiofrequency ablation has also occasionally been found to be equivalent to surgical resection for appropriate tumors, with additionally lower morbidity. Chemoembolization is the prevalent transarterial therapy and has been shown to increase survival compared with conservative management. Chemoembolization using drug-eluting beads and radioembolization with beta emitting yttrium-90 microspheres seems to reduce side effects and expand the pool of eligible patients, whereas controversy remains regarding the role of bland particle embolization. Combinations of local and regional therapies may be appropriate for treating a particular tumor or different tumors over time and they may be combined with surgical and medical options. PMID- 23632351 TI - Endoscopic ultrasound-assisted bile duct access and drainage: multicenter, long term analysis of approach, outcomes, and complications of a technique in evolution. AB - BACKGROUND AND STUDY AIMS: When endoscopic retrograde cholangio-pancreatography fails, the bile duct is drained percutaneously or surgically. Evolution of endoscopic ultrasound (EUS) has provided the ability to visualize and also drain the biliary tree. The aim of this study was to review different techniques of EUS guided bile duct access and drainage, and compare extrahepatic (EH) and intrahepatic (IH) approaches and benign with malignant indications. PATIENTS AND METHODS: EUS-guided attempts at bile duct drainage from 6 international centers were reviewed. This is a multicenter, nonrandomized retrospective study. RESULTS: Two hundred forty patients underwent EUS-guided bile duct access and drainage (EUS-BD) with a mean age of 67.3 years. The IH approach was used in 60% of the cases. In 99% of the subjects, a 19-G needle was used. Success was achieved in 87% cases, with a similar success rate in EH and IH approaches (84.3% vs. 90.4%; P=0.15). Metal stents were placed in 60% and plastic stents in 27% of the cases. A higher success rate was noted in malignant diseases compared with benign diseases (90.2% vs. 77.3%; P=0.02). Complications for all techniques included pneumoperitoneum 5%, bleeding 11%, bile leak/peritonitis 10%, and cholangitis 5%. No significant difference was noted between the IH and the EH approaches (32.6% vs. 35.6%; P=0.64), with similar rates in benign and malignant diseases (26.7% vs. 37.1%; P=0.19). CONCLUSIONS: The EUS-BD technique is currently limited by a lack of dedicated devices and large data reporting outcomes and complications. Larger prospective and multicenter studies are needed to better define the indications, outcomes, and complications. With greater experience and dedicated devices, EUS-BD can be an effective alternative. PMID- 23632352 TI - Three-combination probiotics therapy in children with salmonella and rotavirus gastroenteritis. AB - GOALS: Quantitative Vesikari scales and qualitative severe diarrhea (Vesikari scale >=11) assessments were used to grade the Salmonella-induced and rotavirus induced gastroenteritis severity. A significant reduction in severe diarrhea (Vesikari score >=11) was used to evaluate the efficacy of three-combination probiotics (BIO-THREE). BACKGROUND: Several studies have shown that rotavirus and Salmonella infections are the leading causes of infectious gastroenteritis. Although probiotics have been effective in some studies, the use of 3-combination formulation probiotics is rare. STUDY: This single-center, open-label, randomized, controlled trial included 159 patients (age range, 3 mo to 14 y) hospitalized with infectious gastroenteritis between February 2009 and October 2010. RESULTS: Patients were grouped according to the pathogen identified (48, Salmonella; 42, rotavirus; and 69, unknown origin). The total diarrhea duration was significantly shorter for children who received BIO-THREE (P<0.0001). After BIO-THREE administration, there were significantly less intervention group patients with severe diarrhea at intervention day 3. Vesikari scale or diarrhea frequency results did not reveal significant differences between groups (except for day 5 in patients with rotavirus), and there were no significant changes in other clinical parameters or the length of hospital stay. CONCLUSIONS: Seven-day BIO-THREE administration demonstrated high efficacy and safety in infants and children with severe gastroenteritis. The incidence of severe gastroenteritis was significantly reduced in the rotavirus origin and BIO-THREE intervention groups. PMID- 23632353 TI - Gastroenterologists' practice patterns for positive fecal occult blood test. AB - GOALS: To evaluate gastroenterologists' use of esophagogastroduodenoscopy (EGD) for positive fecal occult blood test (FOBT). BACKGROUND: Colonoscopy is recommended when an FOBT performed for colorectal cancer screening is positive. Guidelines suggest no further evaluation if anemia and gastrointestinal (GI) symptoms are absent. METHODS: Online surveys included 4 vignettes: positive FOBT in average-risk adults 50 years of age or older with/without iron-deficiency anemia and with/without upper GI symptoms. For each scenario, respondents were asked if they would perform colonoscopy only, EGD only, colonoscopy+EGD on same day, or colonoscopy followed by EGD on different day if colonoscopy was negative. RESULTS: Surveys were returned by 778 (11%) of 7094 potential responders. In patients without anemia or upper GI symptoms, 65% performed colonoscopy only; 35% added EGD (9% same day, 25% different day). EGD was added in 91% with anemia, 96% with symptoms, and 100% with anemia+symptoms. In patients with positive FOBT alone (no symptoms or anemia), multivariate analysis revealed fear of litigation as the primary factor associated with adding EGD to colonoscopy (odds ratio=4.1; 95% confidence interval, 2.3-7.3). When EGD+colonoscopy were planned for positive FOBT, private practice was associated with performing EGD on a different day (odds ratio=6.3; 95% confidence interval, 2.9-13.5 for private versus academic setting). CONCLUSIONS: One third of gastroenterologists perform EGD in addition to colonoscopy for a positive FOBT alone. Fear of litigation is the most important factor in deciding whether to add EGD to colonoscopy. When both procedures are planned, they are more likely to be performed on different days in a private practice setting than in an academic setting. PMID- 23632354 TI - Ipilimumab-induced perforating colitis. AB - Recently, a monoclonal antibody to cytotoxic T-lymphocyte-associated antigen 4, ipilimumab, was approved for the treatment of metastatic melanoma. One of the most common side effects associated with this therapy is diarrhea and colitis. We report 3 cases of perforating colitis induced by ipilimumab requiring colectomy. The histologic findings of mucosal biopsies have been previously described. Herein, we describe novel associated histologic findings (pseudopolyp formation, fissuring ulcers, dilated crypts, and lack of intraepithelial lymphocytosis and epithelial apoptosis) of segmental resections in patients who required subtotal colectomy after perforation due to the severity of their ipilimumab-induced colitis. Although steroid therapy is the standard treatment for ipilimumab induced colitis, surgery may be necessary. In the setting of progressive or worsening diarrhea after steroid therapy in patients with colitis, bowel perforation should be considered. PMID- 23632355 TI - Prevalence and risk factors of functional dyspepsia: a nationwide multicenter prospective study in Korea. AB - GOALS: To evaluate the prevalence of functional dyspepsia (FD) and its risk factors. BACKGROUND: FD is a common disorder, but its negative influences greatly affect the quality of life. The predictive factors of FD are still ambiguous. STUDY: A total of 3399 participants underwent screening gastroscopy at one of 7 nationwide health care centers in Korea and who completed a questionnaire. Atrophic gastritis was defined by gastroscopy. Serologic Helicobacter pylori immunoglobulin G antibody was measured by enzyme-linked immunosorbent assay. RESULTS: Of the 3399 participants who did not have organic diseases, 694 (20.4%) had dyspeptic symptoms such as epigastric pain/soreness or postprandial discomfort. Among the 694 participants, atrophic gastritis and positive H. pylori serology were found in 282 (40.6%) and 422 (60.8%), respectively; these proportions were not different from the remaining asymptomatic subjects. Multivariate analysis showed that having relatives with gastric cancer [odds ratio (OR), 1.35; 95% confidence interval (CI), 1.01-1.81], education below college (OR, 1.32; 95% CI, 1.06-1.64), and high-salt diet (OR, 1.33; 95% CI, 1.05 1.68) were associated with FD symptoms. CONCLUSIONS: FD symptoms were frequently found in the health check-up subjects. Relatives of gastric cancer, education below college, and high-salt diet were risk factors of FD, suggesting that FD is a multifactorial disease. PMID- 23632356 TI - Identification of patients with developing ulcerative colitis-associated neoplasia by nitrative DNA damage marker 8-nitroguanin expression in rectal mucosa. AB - GOAL: To clarify whether the expression of nitrative and oxidative DNA damage markers in the rectal mucosa of patients with ulcerative colitis (UC) could be used to predict UC-associated neoplasia. BACKGROUND: A longer duration of UC can increase the risk of developing UC-associated cancer (UCAC). Effective diagnostic markers are being sought to provide more selective screening and treatment strategies for patients with long-standing UC. STUDY: A total of 141 patients with UC who underwent a proctocolectomy were enrolled in this study. The expression of 8-nitroguanine (8-NG), 8-oxo-7,8-dihydro-2'-deoxyguanosine (8 oxodG), and inducible nitric oxide synthase (iNOS) in the rectal mucosa were evaluated using immunohistochemistry (IHC) and assessed relative to the pathogenesis of UC-associated neoplasia. RESULTS: Eighteen patients (12.8%) had UC-associated neoplasia including low-grade or high-grade dysplasia and UCAC. IHC scores of 8-NG in UC-associated neoplasia group was significantly higher than in non-neoplasia group (P<0.0001). In contrast, IHC score of 8-oxodG in non neoplasia group was significantly decreased compared with UC-associated neoplasia group (P=0.0028). In logistic regression analysis, duration of disease >8 years, high IHC scores of 8-NG, and low 8-oxodG in the rectal mucosa were significantly associated with the development of UC-associated neoplasia (P<0.01). The expression of 8-NG was more frequently observed in patients with UCAC than in patients with sporadic colorectal cancer (P<0.01). CONCLUSION: These results suggest that evaluating the expression levels of 8-NG in the rectal mucosa may be a useful biomarker for detecting patients with UC-associated neoplasia. PMID- 23632358 TI - Resolution of severe Clostridium difficile infection following sequential fecal microbiota transplantation. PMID- 23632357 TI - Human leukocyte antigen genetics and clinical features of self-treated patients on a gluten-free diet. AB - BACKGROUND AND AIMS: Increasingly, people start a gluten-free diet (GFD) without a clear celiac disease (CD) diagnosis. Human leukocyte antigen (HLA) genotyping is useful in ruling out CD in patients with equivocal results of serologic testing or small-bowel biopsy (SBB), but its utility and the clinical features of patients on self-treated GFD (ST-GFD) are largely unknown. METHODS: Retrospective study of single tertiary care center cohort compared 137 patients on ST-GFD and 443 patients with well-defined CD. We compared HLA genotype, symptoms, serologic and SBB results, and response to GFD between the 2 groups. Analysis used univariate logistic regression modeling, adjusted for age and sex. RESULTS: Patients with ST-GFD presented more often with diarrhea (P<0.001), abdominal distention (P<0.001), flatulence (P=0.002), cramping (P=0.02), itchy skin (P=0.02), oral inflammation (P=0.04), and constipation (P=0.01) and less often with anemia (P<0.001) or malaise (P=0.02) than CD patients. In addition, 41% did not carry DQ2.5 and DQ8 versus 6% of CD patients (P<0.001). Only 2% of ST-GFD patients had SBB clearly consistent with CD. Family history of CD showed no difference between groups (P=0.77). Although CD patients had a statistically higher rate of GFD benefit, both groups had a high responsiveness rate (98% vs. 94%; P=0.03). CONCLUSIONS: HLA genotyping is useful in evaluating patients on an ST-GFD. Although confirmed CD is rare in self-treated patients, most still report benefit from GFD regardless of DQ2 and DQ8 status. Nonceliac gluten sensitivity may play a role. PMID- 23632359 TI - Decompensated cirrhotics have slower intestinal transit times as compared with compensated cirrhotics and healthy controls. AB - BACKGROUND: Altered small intestinal motility in cirrhotics may play a major role in the development of bacterial translocation (BT) by leading to small intestinal bacterial overgrowth. BT has been implicated in the development of several complications including spontaneous bacterial peritonitis, esophageal variceal hemorrhage, and hepatorenal syndrome. Prior studies using antroduodenal manometry to evaluate intestinal motility have shown discrepancies regarding the relationship between dysmotility and the severity of cirrhosis. OBJECTIVES: (1) To characterize the frequency of small bowel motility disturbances in cirrhotic patients using a wireless motility capsule (SmartPill); (2) To assess the relationship of intestinal dysmotility with liver disease severity and cirrhosis complications; and (3) To compare intestinal transit times and motility indices among cirrhotics and healthy controls. METHODS: We conducted a prospective study of 20 patients with cirrhosis (10 compensated, 10 decompensated) who were recruited from Yale New Haven Hospital and Hepatology clinics (February 2011 to July 2011). All patients underwent and completed SmartPill studies. Intestinal transit times were calculated, analyzed, and compared among compensated versus decompensated cirrhotics versus historical, healthy controls. Intestinal transit delays/motility indices were correlated with disease severity and complications. RESULTS: Decompensated cirrhotics had significantly longer small bowel transit times (SBTT) as compared with compensated cirrhotics (6.17 vs. 3.56 h, P=0.036). There was a significant correlation (r=0.77, P=0.0003) between SBTT and cirrhosis severity as assessed by Child-Pugh score. There were no statistical differences noted between the groups for gastric or colonic transit times, although there was a trend toward prolonged transit throughout the gut in decompensated. Cirrhotics with spontaneous bacterial peritonitis and ascites also had significantly longer SBTT as compared with those without. CONCLUSIONS: This study demonstrates that decompensated cirrhotics have slower intestinal transit times as compared with compensated cirrhotics and healthy controls. Additional prospective studies are needed to further characterize dysmotility in cirrhotics and its relationship to complications related to BT. This would aid in the identification of patients at risk for developing severe complications and who may benefit from prophylactic prokinetic and/or antimicrobial therapy. PMID- 23632360 TI - Significance of granulomatous inflammation found on endoscopic biopsies or surgical resections on the severity of Crohn's disease. PMID- 23632361 TI - Safety and efficacy of endoscopic excavation for gastric subepithelial tumors originating from the muscularis propria layer: results from a large study in China. AB - BACKGROUND AND AIM: In this retrospective study, we investigated the safety and efficacy of endoscopic excavation of gastric subepithelial tumors (SETs) originating from the muscularis propria (MP) layer. MATERIALS AND METHODS: Between November 2007 and June 2012, 212 patients with gastric SETs originating from the MP layer were treated via endoscopic excavation. The key procedures were: (1) injecting a mixture solution (100 mL saline+2 mL indigo carmine+1 mL epinephrine) into the submucosa around the tumor; (2) making a cross-incision of the mucosa and then excavating the tumor by the technique of endoscopic excavation. After the tumor was completely excavated from the MP layer, it was removed using a snare; (3) closing the artificial ulcer with clips. RESULTS: The mean diameter of the 212 tumors was 16.5 mm. Complete resection by endoscopic excavation was achieved in 204 cases (96.2%). The rate of complete resection was significantly higher for tumors <2 cm (98.0%) than for tumors >2 cm (91.9%) (P=0.035). Perforation occurred in 32 cases (15.1%), and massive bleeding occurred in 9 cases (4.2%) during the procedure. The rate of perforation was significantly higher for the fundus and the body than for antrum (21.5%, 11.5%, 0%, respectively; P=0.036), and also differed significantly in relation to histologic diagnosis (23.7% for gastrointestinal stromal tumors vs. 7.8% for leiomyoma; P=0.001). Histologic diagnosis showed that the density of gastrointestinal stromal tumors located in the fundus and the body of the stomach was significantly higher than in the antrum (44.1%, 51.9%, 13.3%, respectively; P=0.036). CONCLUSIONS: Endoscopic excavation is a safe and efficient method for resecting small (>3.5 cm) gastric SETs originating from the MP layer. PMID- 23632362 TI - Autoimmune hepatitis in association with ramelteon. AB - Ramelteon is a nonscheduled insomnia medication that lacks the abuse potential and residual effects common for other sedative-hypnotics. Distinct in its mechanism, the drug is a melatonin agonist with a high affinity for the membrane receptors MT1 and MT2. Although it therapeutically targets the suprachiasmatic nucleus of the hypothalamus, many organ systems have melatonin receptors and thus may be influenced by ramelteon. A growing body of research on melatonin indicates that it modulates the immune system. Indeed, immune cells have been shown to synthesize and to respond to this compound through receptors including MT1 and MT2. Melatonin's effects are generally immunostimulatory, and there is evidence to suggest that the chemical may potentiate autoimmunty. Here, we describe a case of autoimmune hepatitis that developed in a 50-year-old man after starting ramelteon for insomnia. The temporal association between ramelteon initiation and disease development, as well as the immunomodulatory properties of melatonergic compounds, suggest a role for ramelteon in the etiology of his illness. PMID- 23632363 TI - Hepatocellular carcinoma: histologic considerations: pure, mixed, and motley. AB - Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor seen in adults. The histopathologic diagnosis of classic or conventional differentiated HCC is seldom challenging, however, HCC is a particularly heterogeneous tumor. HCC often has a medley of morphologic features that are either challenging to recognize as hepatocellular, or represents components that are of complex histogenesis. This review focuses on the heterogeneous nature of HCC, with discussion of the histologic variants, some of which the clinical significance is unknown. In some cases, a lack of numbers precludes elucidating the clinical significance of these variants. Ultimately, larger studies are needed to determine the diagnostic and prognostic relevance of the phantasmagoria within HCC. PMID- 23632364 TI - A multidisciplinary approach: group dynamics. AB - Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer death in the United States. The field of liver cancer is evolving rapidly with the emergence of new therapies, the potential for combining local and systemic therapies, and a better understanding of the molecular pathways that drive the development of liver cancer. HCC is a heterogeneous cancer, most often arising in a diseased organ, with a dizzying array of potential therapies that depend upon liver function, burden of tumor, and institutional expertise. Unlike other cancers, the diagnosis can be made by dynamic imaging alone, and it is the only solid organ tumor for which transplant offers a cure. The management of HCC involves: a thorough understanding of the severity of the patient's underlying liver disease; the benefits, risks, limitations, and sometimes trade-offs of potentially curative, bridging, and palliative therapies; and the role of the many specialties involved in treating HCC. Proper patient selection and multidisciplinary cooperation are essential to arrive at a rational plan of care for each patient and to achieve the best outcomes. A multidisciplinary conference or tumor board provides a forum wherein specialists can engage in patient selection, match the patient to the appropriate therapy, and consider patients for enrollment in clinical trials. When there is controversy or no clear evidence based guidance, productive multidisciplinary teams will reach consensus and can often revisit challenging cases along the continuum of care. PMID- 23632365 TI - Anti-inflammatory secondary metabolites from the leaves of Rosa laevigata. AB - Bioassay-guided fractionation of a n-BuOH-soluble extract of the leaves of Rosa laevigata led to the isolation of three new 19-oxo-18,19-seco-ur-sane-type triterpenoids, laevigins A-C (1-3), a new oleanane-type triterpenoid saponin, laevigin D (4), a new geranylmethylbenzoate, 5-[(2"E,6"S)-6",7"-dihydroxy-3",7" dimethyl-2"-octen-1"-yl]-2-(beta-D-glucopyranosyloxy)-methyl benzoate (5), together with 9 known compounds (6-14). Their structures were elucidated by spectroscopic and chemical methods. Compounds 4, 9, 11, and 12 significantly suppressed the LPS-stimulated NF-kappaB transcriptional activity and the release of TNFalpha, IL-1beta, IL-6, and IL-10 in mouse RAW 264.7 macrophages. The compound 12 exhibited moderate inhibition on NF-kappaB transcriptional activity with an IC50 value of 23.21 MUM. The IC50 values of compound 12 were measured as 14.32, 8.53, 8.04, and 10.38 MUM for the inhibitory activity on TNFalpha-release, IL-1beta-release, IL-6-release, and IL-10-release, respectively. PMID- 23632366 TI - Design, synthesis and evaluation of 1,2-benzisothiazol-3-one derivatives as potent caspase-3 inhibitors. AB - A number of 1,2-benzisothiazol-3-one derivatives were prepared through structural modification of the original compound from high-throughput screening. Some analogues (e.g., 6b, 6r, 6s and 6w) were identified as novel and potent caspase inhibitors with IC50 of nanomolar. Structure-activity relationship (SAR) studies for caspase-3 inhibition were evaluated in vitro. Molecular modeling studies provided further insight into the interaction of this class of compounds with activated caspase-3. The present small molecule caspase-3 inhibitor with novel structures different from structures of known caspase inhibitors revealed a new direction for therapeutic strategies directed against diseases involving abnormally up-regulated apoptosis. PMID- 23632367 TI - Effect of plantar intrinsic muscle training on medial longitudinal arch morphology and dynamic function. AB - A specific training program emphasizing the neuromuscular recruitment of the plantar intrinsic foot muscles, colloquially referred to as "short foot" exercise (SFE) training, has been suggested as a means to dynamically support the medial longitudinal arch (MLA) during functional tasks. A single-group repeated measures pre- and post-intervention study design was utilized to determine if a 4-week intrinsic foot muscle training program would impact the amount of navicular drop (ND), increase the arch height index (AHI), improve performance during a unilateral functional reaching maneuver, or the qualitative assessment of the ability to hold the arch position in single limb stance position in an asymptomatic cohort. 21 asymptomatic subjects (42 feet) completed the 4-week SFE training program. Subject ND decreased by a mean of 1.8 mm at 4 weeks and 2.2 mm at 8 weeks (p < 0.05). AHI increased from 28 to 29% (p < 0.05). Intrinsic foot muscle performance during a static unilateral balancing activity improved from a grade of fair to good (p < 0.001) and subjects experienced a significant improvement during a functional balance and reach task in all directions with the exception of an anterior reach (p < 0.05). This study offers preliminary evidence to suggest that SFE training may have value in statically and dynamically supporting the MLA. Further research regarding the value of this exercise intervention in foot posture type or pathology specific patient populations is warranted. PMID- 23632368 TI - Normal kinematics of the neck: the interplay between the cervical and thoracic spines. AB - The movement coordination between the cervical and thoracic spine was examined in 34 asymptomatic participants (24 female and 10 male). Three-dimensional electromagnetic motion sensors were attached to the skin overlying the head, T1, T6, and T12 spinous processes to measure the angular displacement of the cervical, upper thoracic, and lower thoracic spine during active neck movements. These displacement measurements were found to have excellent reliability, with intraclass correlation coefficient ranging from 0.899 to 0.993. The angular displacement-time curves of the cervical and upper thoracic spine were also highly repeatable, with coefficient of multiple determinations ranging from 0.900 to 0.967. Both the cervical and thoracic spines were found to contribute to active neck motion, the greatest contribution being from the cervical region in all movement directions. The inter-regional movement coordination between the cervical spine and upper thoracic spine in all three planes of movement was found to be high, as determined by cross-correlation analysis of the movements of the regions. The current results suggest that the motion of the thoracic spine, in particular the upper thoracic spine, contributes to neck mobility, and that the upper thoracic spine should be included during clinical examination of neck dysfunction. PMID- 23632369 TI - What is slumped sitting? A kinematic and electromyographical evaluation. AB - Slumped sitting is a commonly used reference posture when comparing effects of upright sitting in both clinical and non-clinical populations alike. The exact nature of slumped sitting has not been clearly defined, including regional differences within the posture, and how the passive nature of slumped sitting compares to an active-flexion posture. Kinematic and electromyographical (EMG) data were collected from 12 males during three repeats of slumped sitting and seated maximum forward flexion. Spine angles were defined in four regions (three thoracic and lumbar) as well as for the pelvis, and EMG was collected from eight muscles bilaterally. Kinematic data were expressed as a range of motion (in degrees), and as a percent of full forward flexion while seated (%SIT-FF) and standing (%STAND-FF). EMG data were normalized to a percent maximum contraction (%MVC). Results showed that slumped sitting is characterized by 10 degrees posterior pelvis rotation, near end-range flexion of the mid- (90%SIT-FF) and lower- (81%SIT-FF) thoracic regions, and mid-range flexion of the upper-thoracic (51%SIT-FF) and lumbar (43%SIT-FF) regions. Comparison of slumped by %STAND-FF showed the upper- and mid-thoracic regions to have high variability and large values (over 100%STAND-FF). Muscle activation showed a significant 3%MVC reduction in the lower-thoracic erector spinae muscle when moving from upright to slumped sitting. These data highlight the postural differences occurring within different spine regions, and interpretations that could be drawn, depending on which normalization (sit or stand) method is used. PMID- 23632371 TI - No more hic sunt dracones: Portugal is in the COPD map. PMID- 23632370 TI - The influence of high and low heeled shoes on EMG timing characteristics of the lumbar and hip extensor complex during trunk forward flexion and return task. AB - BACKGROUND: Recent studies suggest that wearing high-heel shoes increases the risk of developing certain musculoskeletal pain conditions. In this study we sought to examine whether heel height alters lumbar and hip extensor muscle timing characteristics during a standardized trunk flexion task. METHODS: Thirty one young, healthy women (22-27 years; 168.6 +/- 5.1 cm; 57.1 +/- 11.8 kg) participated in this study. Lumbar erector spinae (ES), gluteus maximus (GM), and biceps femoris (BF) electromyographic (EMG) signals were recorded during a trunk flexion task where subjects were instructed to flex their trunk in the sagittal plane and then return to a neutral posture. The task was repeated under three footwear conditions: while wearing no footwear, while wearing shoes with 4-cm heels, and while wearing shoes with 10-cm heels. EMG onset and offset times, as well as EMG duration, were calculated for each muscle and compared across conditions. RESULTS: We observed a significantly earlier onset of the ES EMG activity (1.36 +/- 0.61 vs. 1.56 +/- 0.67 s), and significantly delayed onset of the GM EMG activity (1.72 +/- 0.66 vs. 1.28 +/- 0.58 s) during the flexion phase of movement in the 10-cm heeled compared to the no footwear condition. The GM muscle also exhibited an earlier offset time in the 10-cm heel condition compared to the no footwear condition during the flexion movement (2.57 +/- 0.67 vs. 3.30 +/- 0.61 s) as well as during the return from flexion movement phase (10.87 +/- 0.58 vs. 11.69 +/- 0.65 s). These alterations in timing characteristic resulted in an overall decrease in the EMG duration for the GM muscle during the flexion movement. CONCLUSION: The results of this study suggest that high-heels alter trunk and hip extensor muscle coordination patterns. These findings, when considered in combination with other recent findings on the biomechanical effects of wearing high-heels, raise concern about whether wearing high heels results in abnormal spine loading patterns and increases the risk for developing musculoskeletal injuries. PMID- 23632372 TI - Optimizing the structure and contractility of engineered skeletal muscle thin films. AB - An experimental system was developed to tissue engineer skeletal muscle thin films with well-defined tissue architecture and to quantify the effect on contractility. Using the C2C12 cell line, the authors tested whether tailoring the width and spacing of micropatterned fibronectin lines can be used to increase myoblast differentiation into functional myotubes and maximize uniaxial alignment within a 2-D sheet. Using a combination of image analysis and the muscular thin film contractility assay, it was demonstrated that a fibronectin line width of 100MUm and line spacing of 20MUm is able to maximize the formation of anisotropic, engineered skeletal muscle with consistent contractile properties at the millimeter length scale. The engineered skeletal muscle exhibited a positive force-frequency relationship, could achieve tetanus and produced a normalized peak twitch stress of 9.4+/-4.6kPa at 1Hz stimulation. These results establish that micropatterning technologies can be used to control skeletal muscle differentiation and tissue architecture and, in combination with the muscular thin film contractility, assay can be used to probe structure-function relationships. More broadly, an experimental platform is provided with the potential to examine how a range of microenvironmental cues such as extracellular matrix protein composition, micropattern geometries and substrate mechanics affect skeletal muscle myogenesis and contractility. PMID- 23632373 TI - Bioactivity in silica/poly(gamma-glutamic acid) sol-gel hybrids through calcium chelation. AB - Bioactive glasses and inorganic/organic hybrids have great potential as biomedical implant materials. Sol-gel hybrids with interpenetrating networks of silica and biodegradable polymers can combine the bioactive properties of a glass with the toughness of a polymer. However, traditional calcium sources such as calcium nitrate and calcium chloride are unsuitable for hybrids. In this study calcium was incorporated by chelation to the polymer component. The calcium salt form of poly(gamma-glutamic acid) (gammaCaPGA) was synthesized for use as both a calcium source and as the biodegradable toughening component of the hybrids. Hybrids of 40wt.% gammaCaPGA were successfully formed and had fine scale integration of Ca and Si ions, according to secondary ion mass spectrometry imaging, indicating a homogeneous distribution of organic and inorganic components. (29)Si magic angle spinning nuclear magnetic resonance data demonstrated that the network connectivity was unaltered with changing polymer molecular weight, as there was no perturbation to the overall Si speciation and silica network formation. Upon immersion in simulated body fluid a hydroxycarbonate apatite surface layer formed on the hybrids within 1week. The polymer molecular weight (Mw 30-120kDa) affected the mechanical properties of the resulting hybrids, but all hybrids had large strains to failure, >26%, and compressive strengths, in excess of 300MPa. The large strain to failure values showed that gammaCaPGA hybrids exhibited non-brittle behaviour whilst also incorporating calcium. Thus calcium incorporation by chelation to the polymer component is justified as a novel approach in hybrids for biomedical materials. PMID- 23632375 TI - Aptamers: molecules of great potential. AB - Aptamers emerged over 20 years ago as a class of nucleic acids able to recognize specific targets. Today, aptamer-related studies constitute a large and important field of biotechnology. Functional oligonucleotides have proved to be a versatile tool in biomedical research due to the ease of synthesis, a wide range of potentially recognized molecular targets and the simplicity of selection. Similarly to antibodies, aptamers can be used to detect or isolate specific molecules, as well as to act as targeting and therapeutic agents. In this review we present different approaches to aptamer application in nanobiotechnology, diagnostics and medicine. PMID- 23632374 TI - A predetermined first patient on the trauma list can improve theatre start times. AB - INTRODUCTION: The concept of the golden patient (GP) was introduced to our busy teaching hospital, in April 2009, with the aim of improving our trauma theatre start times. The GP is a pre-selected first patient on the following day trauma list who is medically fit with a clear surgical plan. METHODS: This prospective study compared the trauma theatre start times over a two month period following the introduction of the GP, with a similar two month period prior to the introduction of the GP. A two-sided t-test was used to evaluate statistical significance between groups. RESULTS: Of the 55 planned trauma lists analysed, 42 had a designated GP on it (76%), 37 of which remained first on the actual trauma list (88%). The mean operation start time for the pre-GP lists was 10:03 compared to 09:33 for the actual GP lists (P<0.001). The reception, anaesthetic and operation start times for pre-GP lists compared with lists where no GP was selected were not statistically significant suggesting that the GP was the cause of the significance. CONCLUSION: The introduction of the GP to our trauma lists has made a significant improvement to theatre start times and consequently surgical theatre efficiency. PMID- 23632376 TI - Methods of downstream processing for the production of biodiesel from microalgae. AB - Despite receiving increasing attention during the last few decades, the production of microalgal biofuels is not yet sufficiently cost-effective to compete with that of petroleum-based conventional fuels. Among the steps required for the production of microalgal biofuels, the harvest of the microalgal biomass and the extraction of lipids from microalgae are two of the most expensive. In this review article, we surveyed a substantial amount of previous work in microalgal harvesting and lipid extraction to highlight recent progress in these areas. We also discuss new developments in the biodiesel conversion technology due to the importance of the connectivity of this step with the lipid extraction process. Furthermore, we propose possible future directions for technological or process improvements that will directly affect the final production costs of microalgal biomass-based biofuels. PMID- 23632377 TI - Umbilical cord blood cells regulate endogenous neural stem cell proliferation via hedgehog signaling in hypoxic ischemic neonatal rats. AB - Umbilical cord blood mononuclear cells (UCBMC) transplantation may improve hypoxia-induced brain injury in neonatal rats, but the mechanism is unclear. This study examines whether UCBMC promote neural stem cell (NSC) proliferation via the Sonic hedgehog (Shh) signaling pathway. The rats underwent left carotid ligation followed by hypoxic stress. UCBMC were transplanted 24h after hypoxia ischemia (HI), and immunohistochemistry, immmunoblotting, and morphology analyses were performed at different time points after transplantation. Increased numbers of NSCs were observed in the subventrical zone (SVZ) of the HI+UCBMC group, but these increases were attenuated by cyclopamine treatment. There were significant increases in Shh and Gli1 protein levels after transplantation in the HI group treated with UCBMC compared to HI rats treated with phosphate-buffered solution (PBS). Significantly more Gli1(+)DAPI(+) cells were observed in the SVZ of the HI+UCBMC group compared to the HI+PBS and N+UCBMC groups, but few Gli1(+)DAPI(+) cells were found in the SVZ of the HI+cyclopamine+UCBMC group. The HI+UCBMC group had significantly less neuronal loss in the cortex and CA1 sector of the hippocampus compared to the HI+PBS group, but more neuron loss was observed in the HI+cyclopamine+UCBMC group compared to HI+UCBMC. These results indicate that UCBMC may promote NSC proliferation and alleviate brain injury in HI neonatal rats via Shh signaling. PMID- 23632378 TI - Pretreatment with rosuvastatin protects against focal cerebral ischemia/reperfusion injury in rats through attenuation of oxidative stress and inflammation. AB - This study aimed to examine the potential protective effect of rosuvastatin against cerebral ischemia/reperfusion injury and its mechanisms. Forty-eight male SD rats underwent 90 min of transient middle cerebral artery occlusion (tMCAO), followed by reperfusion. Rats were orally given (1) rosuvastatin 1mg/kg, (2) rosuvastatin 10mg/kg or (3) water (vehicle) once a day from 7 days before to 1 day after induction of tMCAO. Neurological score, infarct volume, and oxidative stress-related molecules (assessed by immunohistochemistry, dihydroethidium staining, or western blotting) were estimated at 24h after reperfusion. Rosuvastatin prevented the impairment of neurological function and decreased the infarct volume, compared with the vehicle group. The increases in activated microglia, macrophage, and superoxide levels usually caused by ischemia/reperfusion were significantly ameliorated by rosuvastatin. Rosuvastatin also inhibited the upregulation of gp91(phox) and p22phox, phosphorylation of nuclear factor-kappa B, and induction of cyclooxygenase 2 and inducible nitric oxide synthase, compared with vehicle. The results suggest that pretreatment with rosuvastatin may be a promising therapeutic strategy for cerebral ischemia/reperfusion injury, through attenuation of oxidative stress and inflammation. PMID- 23632379 TI - Neural correlates of familiarity and conceptual fluency in a recognition test with ancient pictographic characters. AB - Familiarity and conceptual priming refer to distinct memory expressions and are subtypes of explicit memory and implicit memory, respectively. Given that the neural events that produce conceptual priming may in some cases promote familiarity, distinguishing between neural signals of these two types of memory may further our understanding of recognition memory mechanisms. Although FN400 event-related potentials observed during recognition tests have often been ascribed to familiarity, much evidence suggests that they should instead be ascribed to conceptual fluency. To help resolve this controversy, we studied potentials elicited by unrecognizable ancient Chinese characters. These stimuli were categorized as high or low in meaningfulness based on subjective ratings. Conceptual priming was produced exclusively by repetition of characters high in meaningfulness. During a recognition test in which recollection was discouraged, FN400 old-new effects were observed, and amplitudes of the FN400 potentials varied inversely with familiarity confidence. However, these effects were absent for old items given low meaningfulness ratings. For both high and low meaningfulness, late positive (LPC) potentials were found in old-new comparisons, and LPC amplitudes were greater when higher familiarity confidence was registered during the recognition test. These findings linked familiarity and conceptual fluency with different brain potentials - LPC and FN400, respectively - and provide additional evidence that explicit memory and implicit memory have distinct neural substrates. PMID- 23632381 TI - Frequency of combined factor V and factor VIII deficiency in southern Iran. PMID- 23632380 TI - Distribution of CaMKIIalpha expression in the brain in vivo, studied by CaMKIIalpha-GFP mice. AB - To facilitate the study of the CaMKIIalpha function in vivo, a CaMKIIalpha-GFP transgenic mouse line was generated. Here, our goal is to provide the first neuroanatomical characterization of GFP expression in the CNS of this line of mouse. Overall, CaMKIIalpha-GFP expression is strong and highly heterogeneous, with the dentate gyrus of the hippocampus as the most abundantly expressed region. In the hippocampus, around 70% of granule and pyramidal neurons expressed strong GFP. In the neocortex, presumed pyramidal neurons were GFP positive: around 32% of layer II/III and 35% of layer VI neurons expressed GFP, and a lower expression rate was found in other layers. In the thalamus and hypothalamus, strong GFP signals were detected in the neuropil. GFP-positive cells were also found in many other regions such as the spinal trigeminal nucleus, cerebellum and basal ganglia. We further compared the GFP expression with specific antibody staining for CaMKIIalpha and GABA. We found that GFP+ neurons were mostly positive for CaMKIIalpha-IR throughout the brain, with some exceptions throughout the brain, especially in the deeper layers of neocortex. GFP and GABA-IR marked distinct neuronal populations in most brain regions with the exception of granule cells in the olfactory bulb, purkinje cells in the cerebellar, and some layer I cells in neocortex. In conclusion, GFP expression in the CaMKIIalpha-GFP mice is similar to the endogenous expression of CaMKIIalpha protein, thus these mice can be used in in vivo and in vitro physiological studies in which visualization of CaMKIIalpha- neuronal populations is required. PMID- 23632382 TI - Neonatal and childhood right atrial thrombosis: critical clot size. PMID- 23632386 TI - A single- and double-flash flash photolysis study of the sequential biphotonic photoprocesses of Cu(I) phenanthrolines. Comparison of the helicate complex, [Cu2(1,3-bis(9-methyl-1,10-phenanthrolin-2-yl)propane)2]2+, and [Cu(2,9-dimethyl 1,10-phenanthroline)2]+ photoprocesses. AB - Photochemical processes induced when two photons are sequentially absorbed by the helicate complex [Cu2(mphenpr)2](2+), where mphenpr = 1,3-bis(9-methyl-1,10 phenanthrolin-2-yl)propane, and [Cu(dmp)2](+) were investigated in CH2Cl2 containing solvents. A strong resemblance was observed between the fs-ns photophysics of [Cu2(mphenpr)2](2+) and Cu(I) phenanthroline complexes having a large steric hindrance. In the biphotonic regime, single-flash flash-photolyzed solutions were used for the determination of the product concentrations and quantum yields. The concentration of Cl(-) produced by the photoinduced decomposition of CH2Cl2 increases linearly with flash intensity as expected for a monophotonic process. In contrast, the concentration of a decomposed Cu(I) complex exhibits the quadratic dependence on flash intensity of a biphotonic process. Results of a sequential double-flash flash photolysis experiment are consistent with the decomposition of CH2Cl2 ahead of the flattened excited state formation and with the absorption of the second photon by the flattened MLCT excited state. PMID- 23632383 TI - Basic and applied uses of genome-scale metabolic network reconstructions of Escherichia coli. AB - The genome-scale model (GEM) of metabolism in the bacterium Escherichia coli K-12 has been in development for over a decade and is now in wide use. GEM-enabled studies of E. coli have been primarily focused on six applications: (1) metabolic engineering, (2) model-driven discovery, (3) prediction of cellular phenotypes, (4) analysis of biological network properties, (5) studies of evolutionary processes, and (6) models of interspecies interactions. In this review, we provide an overview of these applications along with a critical assessment of their successes and limitations, and a perspective on likely future developments in the field. Taken together, the studies performed over the past decade have established a genome-scale mechanistic understanding of genotype-phenotype relationships in E. coli metabolism that forms the basis for similar efforts for other microbial species. Future challenges include the expansion of GEMs by integrating additional cellular processes beyond metabolism, the identification of key constraints based on emerging data types, and the development of computational methods able to handle such large-scale network models with sufficient accuracy. PMID- 23632385 TI - Systematic identification of proteins that elicit drug side effects. AB - Side effect similarities of drugs have recently been employed to predict new drug targets, and networks of side effects and targets have been used to better understand the mechanism of action of drugs. Here, we report a large-scale analysis to systematically predict and characterize proteins that cause drug side effects. We integrated phenotypic data obtained during clinical trials with known drug-target relations to identify overrepresented protein-side effect combinations. Using independent data, we confirm that most of these overrepresentations point to proteins which, when perturbed, cause side effects. Of 1428 side effects studied, 732 were predicted to be predominantly caused by individual proteins, at least 137 of them backed by existing pharmacological or phenotypic data. We prove this concept in vivo by confirming our prediction that activation of the serotonin 7 receptor (HTR7) is responsible for hyperesthesia in mice, which, in turn, can be prevented by a drug that selectively inhibits HTR7. Taken together, we show that a large fraction of complex drug side effects are mediated by individual proteins and create a reference for such relations. PMID- 23632384 TI - Characterization of drug-induced transcriptional modules: towards drug repositioning and functional understanding. AB - In pharmacology, it is crucial to understand the complex biological responses that drugs elicit in the human organism and how well they can be inferred from model organisms. We therefore identified a large set of drug-induced transcriptional modules from genome-wide microarray data of drug-treated human cell lines and rat liver, and first characterized their conservation. Over 70% of these modules were common for multiple cell lines and 15% were conserved between the human in vitro and the rat in vivo system. We then illustrate the utility of conserved and cell-type-specific drug-induced modules by predicting and experimentally validating (i) gene functions, e.g., 10 novel regulators of cellular cholesterol homeostasis and (ii) new mechanisms of action for existing drugs, thereby providing a starting point for drug repositioning, e.g., novel cell cycle inhibitors and new modulators of alpha-adrenergic receptor, peroxisome proliferator-activated receptor and estrogen receptor. Taken together, the identified modules reveal the conservation of transcriptional responses towards drugs across cell types and organisms, and improve our understanding of both the molecular basis of drug action and human biology. PMID- 23632388 TI - Inoculation with microorganisms of Lolium perenne L.: evaluation of plant growth parameters and endophytic colonization of roots. AB - Turfgrasses are not only designed for recreation activities, but they also provide beneficial environmental effects and positively influence the human wellness. Their major problems are predisposition to tearing out and microbial diseases. The aim of this study was to investigate whether the inoculation of microorganisms can be effective to improve plant growth and root development of perennial ryegrass, to evaluate new sustainable practice for green preservation. A microorganism-based commercial product was used to amend hydroponically grown Lolium perenne L. and results compared with the use of the same filtered product, a phytohormone solution and an untreated control. Plants were grown for five weeks, shoots cut and measured at one-week interval and, at the end, roots were measured for length and weight. Shoot resistance to tearing out was also tested. Moreover, the main microbial groups present in the product were characterized and the microbial profile of sand and root samples was investigated by PCR-DGGE. The plants treated with the product showed an increased resistance to tearing out with respect to other treatments and roots were longer with respect to the control. Microbial analyses of the product evidenced bacterial and yeast species with plant growth promoting activity, such as Stenothrophomonas maltophilia, Candida utilis and several Lactobacillus species. Some Lactobacillus strains were also found to be able to colonize plant roots. In conclusion, the treatment with microorganisms has a great potential for the maintenance and increased performance of turfgrass surfaces. PMID- 23632389 TI - In situ XRD studies of nanocrystallization of Fe-based metallic glass: a comparative study by reciprocal and direct space methods. AB - Structural changes occurring in an Fe(72.5)Cu1Nb2Mo2Si(15.5)B7 alloy during a combination of constant rate heating (20 K min(-1)) and isothermal holding at 500 and 520 degrees C were investigated using in situ high-energy X-ray diffraction. We found that the ferromagnetic-to-paramagnetic transition of the amorphous phase is revealed as a change in the slope of the thermal expansion curve when heating a sample at a constant rate up to 520 degrees C. Real space analysis by means of the atomic pair distribution function (PDF) demonstrated that the rate and extent of the thermal expansion strongly depend on the interatomic separation. The PDF proved to be a reliable method for the description of crystallization kinetics. Further it allows determination of sizes of ultrafine nanocrystals with grain sizes well below 8 nm and thus makes observation of early stages of nanocrystallization possible. Following grain growth kinetics during isothermal annealing at 500 and 520 degrees C we found that the activation energy of the process is 357 +/- 12 kJ mol(-1). PMID- 23632390 TI - Expanding the Repertoire of Target Sites for Zinc Finger Nuclease-mediated Genome Modification. AB - Recent studies have shown that zinc finger nucleases (ZFNs) are powerful reagents for making site-specific genomic modifications. The generic structure of these enzymes includes a ZF DNA-binding domain and nuclease domain (Fn) are separated by an amino acid "linker" and cut genomic DNA at sites that have a generic structure (site1)-(spacer)-(site2) where the "spacer" separates the two binding sites. In this work, we compare the activity of ZFNs with different linkers on target sites with different spacer lengths. We found those nucleases with linkers' lengths of 2 or 4 amino acid (aa) efficiently cut at target sites with 5 or 6 base pair (bp) spacers, and that those ZFNs with a 5-aa linker length efficiently cut target sites with 6 or 7 bp spacers. In addition, we demonstrate that the Oligomerized Pool ENgineering (OPEN) platform used for making three fingered ZF proteins (ZFPs) can be modified to incorporate modular assembly fingers (including those recognizing ANNs, CNNs, and TNNs) and we were able to generate nucleases that efficiently cut cognate target sites. The ability to use module fingers in the OPEN platform at target sites of 5-7 bp spacer lengths increases the probability of finding a ZFN target site to 1 in 4 bp. These findings significantly expand the range of sites that can be potentially targeted by these custom-engineered proteins.Molecular Therapy - Nucleic Acids (2013) 2, e88; doi:10.1038/mtna.2013.13; published online 30 April 2013. PMID- 23632391 TI - Early versus late acute antibody-mediated rejection in renal transplant recipients. AB - BACKGROUND: Over the last decade, the diagnostic precision for acute antibody mediated rejection (aABMR) in kidney transplant recipients has improved significantly. The phenotypes of early and late aABMR may differ. We assessed the characteristics and outcomes of early versus late aABMR. METHODS: Between January 1, 2005 and December 31, 2010, aABMR was diagnosed in 67 grafts in 65 kidney recipients, with a median follow-up of 3.6 years (range, 61 days-7.3 years). Recipients were stratified by early aABMR (<3 months after transplantation; n=40) and late aABMR (>3 months after transplantation; n=27). The main outcome was kidney allograft loss. Outcome of aABMR was compared with recipients with acute early (n=276) or late (n=100) non-ABMR during the same period. RESULTS: Recipients with late aABMR had significantly reduced graft survival compared with recipients with early aABMR (P<0.001, log-rank test; 40% vs. 75% at 4 years; hazard ratio, 3.72; 95% confidence interval, 1.65-8.42). Graft survival in late aABMR was also inferior to late non-ABMR acute rejections (P=0.008). At transplantation, more patients were presensitized to human leukocyte antigens (22 [55%] vs. 4 [15%] in the early vs. late aABMR group). The late aABMR group was characterized by younger recipient age (37.9 +/- 12.9 vs. 50.9 +/- 11.6 years; P<0.001), increased occurrence of de novo donor-specific antibodies (52% vs. 13%; P=0.001), and nonadherence/suboptimal immunosuppression (56% vs. 0%; P<0.001). CONCLUSION: Compared with early aABMR, late aABMR had inferior graft survival and was characterized by young age, frequent nonadherence, or suboptimal immunosuppression and de novo donor-specific antibodies. PMID- 23632392 TI - Usefulness of liver biopsy in anti-hepatitis C virus antibody-positive and hepatitis C virus RNA-negative kidney transplant recipients. AB - BACKGROUND: Some guidelines recommend a liver biopsy to all anti-hepatitis C virus (HCV) antibody-positive kidney transplant (KT) recipients. However, in the case of HCV RNA-negative KT recipients, the benefit of a liver biopsy is unclear. We examined the usefulness of a liver biopsy for anti-HCV antibody-positive and HCV RNA-negative patients by analyzing the hepatic histologic findings and clinical outcomes. METHODS: A total of 30 anti-HCV antibody-positive patients who underwent liver biopsy before KT at Asan Medical Center were retrospectively recruited. The patients were divided into two groups based on HCV RNA positivity: 17 patients were positive and 13 patients were negative. Histologic evidence of hepatic inflammation and fibrosis was assessed using the METAVIR score, and clinical outcomes, including mortality, graft loss, and progression of liver disease, were compared. RESULTS: The mean histologic activity scores for inflammation and fibrosis for the HCV RNA-positive and HCV RNA-negative groups were significantly different (inflammation score 1.11 +/- 0.85 vs. 0.46 +/- 0.51; P=0.01 and fibrosis score 1.05 +/- 1.24 vs. 0.15 +/- 0.37; P=0.01, respectively). The overall rates of mortality and graft loss were not significantly different between the two groups. Progression of liver disease was noted in the HCV RNA positive group only. CONCLUSION: The HCV RNA-negative group showed no evidence of liver disease progression. Neither did they show any histologic evidence of liver inflammation and fibrosis before KT. Therefore, it appears that liver biopsy is not necessary in anti-HCV antibody-positive and HCV RNA-negative KT recipients. PMID- 23632393 TI - Magnolol treatment reversed the glial pathology in an unpredictable chronic mild stress-induced rat model of depression. AB - Growing evidence indicates that glia atrophy contributes to the pathophysiology and the pathogenesis of major depressive disorder. Magnolol is the main constituent identified in the bark of Magnolia officinalis, which has been used for the treatment of mental disorders, including depression, in Asian countries. In this study, we investigated the antidepressant-like effect and the possible mechanisms of magnolol in rats subjected to unpredictable chronic mild stress (UCMS). The ameliorative effect of magnolol on depression symptoms was investigated through behavior tests, including sucrose preference test, open field test and forced-swimming test. In addition, the levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in the hippocampus and prefrontal cortex were determined by immunohistochemistry, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR). Exposure to UCMS resulted in a decrease of behavioral activity, whereas magnolol (20, 40 mg/kg) and fluoxetine (20mg/kg) administration significantly reversed the depressive-like behaviors (P<0.05).Moreover, treatment with magnolol effectively increased GFAP mRNA and protein levels in UCMS rats. These results confirmed the antidepressant-like effect of magnolol, which maybe primarily mediated by reversing the glial atrophy in the UCMS rat brain. PMID- 23632394 TI - Sigma-1 receptor antagonism as opioid adjuvant strategy: enhancement of opioid antinociception without increasing adverse effects. AB - While opioids are potent analgesics widely used in the management of pain, a number of well-known adverse effects limit their use. The sigma-1 receptor is a ligand-regulated molecular chaperone involved in pain processing, including modulation of opioid antinociception. However, data supporting the potential use of sigma-1 receptor ligands as suitable opioid adjuvants are based on studies that use non selective ligands. Also, safety issues derived from combination therapy are poorly addressed. In this study we used the new selective sigma-1 receptor antagonist S1RA (E-52862) to characterize the effect of selective sigma 1 receptor blockade on opioid-induced efficacy- and safety-related outcomes in mice. S1RA (40 mg/kg) had no effect in the tail-flick test but did enhance the antinociceptive potency of several opioids by a factor between 2 and 3.3. The potentiating effect of S1RA on morphine antinociception did not occur in sigma-1 receptor knockout mice, which supports the selective involvement of the sigma-1 receptor. Interestingly, S1RA co-administration restored morphine antinociception in tolerant mice and reverted the reward effects of morphine in the conditioned place preference paradigm. In addition, enhancement of antinociception was not accompanied by potentiation of other opioid-induced effects, such as the development of morphine analgesic tolerance, physical dependence, inhibition of gastrointestinal transit, or mydriasis. The use of sigma-1 receptor antagonists as opioid adjuvants could represent a promising pharmacological strategy to enhance opioid potency and, most importantly, to increase the safety margin of opioids. S1RA is currently in phase II clinical trials for the treatment of several pain conditions. PMID- 23632395 TI - Intraindividual comparison of Canaloplasty versus trabeculectomy with mitomycin C in a single-surgeon series. AB - PURPOSE: To compare the safety, efficacy, and postoperative management of canaloplasty in one eye versus trabeculectomy with mitomycin C in the contralateral eye in patients with open-angle glaucoma. METHODS: This study was a consecutive case series of 30 eyes of 15 patients who had prior trabeculectomy with mitomycin C (group II) and later were treated with canaloplasty (group I) in the fellow eye. Primary outcome measures included intraocular pressure (IOP) and glaucoma medication after 6- and 12-month follow-up. Secondary outcome measures were number of postoperative interventions, hospitalization, and follow-up visits. RESULTS: Mean preoperative IOP+/-SD was 26.73+/-6.4 mm Hg in group I and 26.3+/-10.9 mm Hg in group II (P=0.9), which decreased to 13.21+/-2.83 mm Hg for canaloplasty (P<0.0001) and 11.64+/-5.2 mm Hg for trabeculectomy (P<0.0005) including 3 patients with hypotony at 12 months. Glaucoma medication decreased from 2.5 in group I and 2.7 in group II to no medication in group I and 0.36+/ 0.74 supplemental medication in group II 12 months postoperatively (P<0.0001). Best corrected visual acuity (+/-SD) was logMAR 0.06+/-0.09 (group I) and 0.28+/ 0.56 (group II) before and logMAR 0.07+/-0.09 (group I) and 0.31+/-0.58 (group II) after surgery. In group I, 2 interventions were necessary. In group II, 8 eyes needed 112 interventions for filtering bleb management. Although canaloplasty took significantly longer to perform, trabeculectomy group required a longer initial postoperative hospitalization (mean 10.4 vs. 5.4 d, P<0.0001) and more postoperative follow-up visits (mean 3.9 vs. 8.5, P<0.001). CONCLUSIONS: Canaloplasty and trabeculectomy were both effective in lowering IOP. However, less follow-up visits and significantly fewer complications and interventions were favorable for canaloplasty. PMID- 23632396 TI - Effect of refractive correction on the accuracy of frequency-doubling technology Matrix. AB - PURPOSE: To investigate the effect of refractive correction on the reliability and accuracy of frequency-doubling technology (FDT) Matrix examinations. METHODS: Forty-eight eyes of healthy people were submitted to the FDT Matrix 30/2 threshold program. They had experience in perimetry, normal eye examination, and negative history for glaucoma and/or neurological diseases. The subjects were randomized into groups A (24 subjects) and B (24 subjects). The FDT Matrix 30/2 examinations were carried out in 3 different sessions. At the first session, groups A and B underwent the examinations with their best refractive correction. In the second session, group A underwent the FDT 30/2 examination with best refractive correction and the group B without it. In the third session, the groups were matched and followed the same protocol. The perimetric and reliability indexes and the time of examination with or without correction were considered. The Student t test was used when the distribution of the data was normal, whereas Mann-Whitney when the distribution of the data was not normal. After a Bonferroni correction, a P value <0.001 was considered as statistically significant. RESULTS: Mean deviation reduced statistically significantly when refractive correction was used (-2.65+/-3.71 vs. -1.41+/-3.51 dB; P<0.006). All the other perimetric indexes and data considered did not change significantly when the subjects did the examination with or without the refractive correction. CONCLUSIONS: The statistically significant reduction of mean deviation obtained with corrective lens showed that a better general accuracy and reliability of FDT responses was obtained with refractive correction. Pattern standard deviation constancy with or without correction confirmed that a localized defect is the first sign of visual field defect and that the absence of differences of pattern standard deviation between the 2 sessions is related to the absence of pathologic conditions in the eyes studied. Finally, as FDT Matrix is less influenced by other nonconventional perimetric techniques by refractive errors, the use of corrective lens is advisable to improve the accuracy and reliability of the results obtained and to optimize their performance. PMID- 23632397 TI - Corneal endothelial abnormalities after selective laser trabeculoplasty (SLT). AB - PURPOSE: Whitish spots are sometimes observed in the corneal endothelium after selective laser trabeculoplasty (SLT). To evaluate the corneal endothelium after SLT, corneal specular microscopy was performed. METHODS: A total of 142 eyes with open angle glaucoma that underwent SLT during the period of 9 months from February 10 to November 10, 2012, had their corneal endothelium examined with specular microscopy before and after SLT. RESULTS: Dark spots were observed in the corneal endothelium on corneal specular microscopy immediately after SLT. Seventy-one of the 142 eyes had no significant dark spots or increase in dark spots after SLT. Thirty-seven of the 142 eyes showed few dark spots after SLT. Thirty-four of the 142 eyes showed numerous dark spots after SLT on specular microscopy imaging, which resolved by 1 month. The last group had the greatest decrease in the corneal endothelial cell count at 1 month after SLT, but this was not statistically significant in this study (P=0.1). CONCLUSIONS: The corneal endothelial abnormalities after SLT shown in this study may be transient, and long-term effects are probably negligible in normal corneas or single treatments. However, in corneas with reduced transparency of the endothelium, such as compromised corneas and corneas with pigment deposits on the endothelium, there may be a risk of further corneal endothelial compromise, especially after repeated SLT. Larger and longer term studies with histopathologic evaluation would be useful to evaluate the effect of SLT on normal and subnormal corneal endothelium. Until further studies are done, it would be wise to minimize the number and energy of SLT laser shots. PMID- 23632398 TI - Intracameral ranibizumab and subsequent mitomycin C augmented trabeculectomy in neovascular glaucoma. AB - PURPOSE: The purpose of this study is to evaluate the efficacy of intracameral ranibizumab (ICR) injections with subsequent mitomycin C (MMC) augmented trabeculectomy in the management of neovascular glaucoma (NVG). METHODS: This is a prospective, interventional study of NVG, with research conducted between January 2010 and February 2011, at the Ophthalmology Department of Kasr El-Aini Hospital and Petrol Medical Center (Cairo, Egypt). Fifteen patients with NVG were included in the study, all of whom received intracameral ranibizumab (ICR) injections (0.5 mg) into their eyes 4 weeks before MMC augmented trabeculectomies were performed. All patients were followed up for a period of 6 months. RESULTS: Thirteen eyes (86.7%) achieved absence of clinically apparent iris neovascularization after 1 ICR injection and 2 eyes (13.3%) after a second injection. Eight eyes (53.3%) achieved complete success [if the intraocular pressure (IOP) was between 10 and 21 mm Hg] without topical antiglaucoma medications, 6 eyes (40%) had qualified success (if the IOP was within the same range) but with topical antiglaucoma medications, and failure occurred in 1 eye (6.7%) (because the IOP was above 21 mm Hg) despite the use of topical antiglaucoma medications. CONCLUSIONS: An ICR injection with subsequent MMC augmented trabeculectomy seems to be an effective combined technique in controlling IOP in eyes with NVG. PMID- 23632399 TI - A comparison of false-negative responses for full threshold and SITA standard perimetry in glaucoma patients and normal observers. AB - PURPOSE: To compare false-negative (FN) rates for Full Threshold (FULL) and Swedish Interactive Threshold Algorithm (SITA) Standard automated perimetry in healthy control subjects and glaucoma patients. METHODS: One eye of 19 glaucoma patients and 5 normal control subjects underwent 5 visual field examinations within 6 weeks on the Humphrey Field Analyzer II using the 24-2 FULL and SITA testing procedures. The order of presentation of test procedures was counterbalanced across participants. We obtained FN response procedures that presented stimuli 9 dB greater than a previously determined threshold value at specific locations in the visual field (FULL) or up to 20 dB greater than the threshold value (SITA), and evaluated whether the patient responded to these suprathreshold stimuli. We compared the percentage of FN responses for the FULL and SITA tests before (Peridata output) and after postprocessing of data. RESULTS: The percentage of FNs was almost twice as high for FULL testing compared with the 2 SITA analyses. The SD of FN percentages was half as large for SITA postprocessing compared with FULL and SITA Peridata procedures. Because the distributions were not normally distributed, a Kruskal-Wallis analysis of variance was performed and revealed a statistically significant difference (H=13.094, P<0.001) for FN percentages among the 3 evaluations. CONCLUSIONS: FULL test procedures yield about twice as many FNs as SITA procedures. This may be related to the SITA method of testing for FN in relatively normal areas as opposed to any location (even if it has low sensitivity) with FULL. Because FN responses can be due to either high variability in damaged areas or pathologic variations, these revised FN procedures provide greater assistance in properly interpreting visual field results. PMID- 23632400 TI - Oral fluoroquinolones and risk of glaucoma. AB - OBJECTIVE: To evaluate the risk of developing glaucoma in patients taking systemic fluoroquinolones. METHODS: A case-control study was carried out among a cohort of subjects who had visited an ophthalmologist in the Province of British Columbia, Canada from 2000 to 2007. Cases were identified as those newly diagnosed with glaucoma (ICD-9 360). For each case, 5 controls were selected and matched to the cases by age and calendar time. Crude and adjusted rate ratios (RRs) for current, recent, past, and distant use of fluoroquinolones were calculated. RESULTS: From the cohort of 989,591 subjects, 178,264 subjects were diagnosed with glaucoma and 891,320 were corresponding controls. The 2 groups had same average age of 65 and comparable systemic comorbidities including hypertension, coronary artery disease, and diabetes. There was no statistically significant association between the use of systemic fluoroquinolones and the development of glaucoma for current use [RR=1.01 (95% confidence interval (CI), 0.95-1.07)], recent use [RR=1.00 (95% CI, 0.92-1.08)], or past use [RR=0.94 (95% CI, 0.90-1.00)]. Distant use of systemic fluoroquinolones had a small statistically significant increased risk of developing glaucoma [RR=1.12 (95% CI, 1.09-1.14)]. CONCLUSIONS: There was no detected increased association of the development of glaucoma with current, recent, or past use of systemic fluoroquinolone but a minimal statistically significant increased risk was associated with distant use. Future studies should further examine a potential delayed response with fluoroquinolones and glaucoma. PMID- 23632401 TI - Does intravitreal injections of bevacizumab for age-related macular degeneration affect long-term intraocular pressure? AB - PURPOSE: To evaluate the long-term intraocular pressure (IOP) changes after intravitreal injection of bevacizumab for age-related macular degeneration. PATIENTS AND METHODS: A total of 83 eyes that received intravitreal injections of bevacizumab for age-related macular degeneration were enrolled. IOP measurements at baseline, 6, 12, 18, and 24 months, and at the last follow-up after injection were analyzed. On the basis of the median number of injections, the changes in IOP were compared. RESULTS: The mean number of injections was 3.71+/-1.62. There was no significantly higher elevation than baseline IOP (14.11+/-2.76 mm Hg) after multiple intravitreal injections of bevacizumab (P>0.05). In the group which had >=4 injections, mean IOP measurements were not higher compared with the group which had <4 injections during the follow-up period (P>0.05). In the patients with preexisting glaucoma (3 eyes), there were no significant increases of IOP during the follow-up period. CONCLUSIONS: IOP elevation was not observed during the long-term follow-up period. In addition, the numbers of injection and preexisting glaucoma did not affect IOP changes. PMID- 23632402 TI - Evaluation of the effect of pan retinal photocoagulation on optic nerve head parameters using HRT3. AB - PURPOSE: To evaluate the optic disc topography after pan retinal photocoagulation (PRP) in diabetic retinopathy patients using confocal scanning laser ophthalmoscopy (HRT3). METHODS: Thirty eyes of 30 diabetic patients (non-insulin dependent diabetes mellitus) underwent PRP for proliferative diabetic retinopathy. Subjects with glaucoma or family history of glaucoma, any coexisting neuroophthalmic disease, uveitis, retinal artery or vein occlusion, corneal opacity or lasered previously were excluded from the study. Optic nerve head (ONH) of these patients were evaluated by confocal scanning laser ophthalmoscopy (HRT3) at baseline, 3, and 6 months after completion of PRP. RESULTS: There were 23 males and 7 females with a mean age of 51.8 years (36 to 67 y). The mean intraocular pressure was 13.1+/-2.57 mm Hg at baseline, 13.4+/-2.6 mm Hg at 3 months, and 13.3+/-2.2 mm Hg at 6 months (P=0.6). The global values of ONH parameters showed no significant change from baseline at 3 months. At 6 months, there was a significant increase in vertical cup:disc ratio (P=0.021), cup volume (P=0.036), mean cup depth (P=0.042), and maximum cup depth (P=0.05) as compared with baseline values. CONCLUSIONS: PRP induces significant changes in the ONH in patients with diabetic retinopathy as measured with HRT3. This is an important consideration in the diagnosis and evaluation of progression in glaucoma patients with diabetic retinopathy who have undergone PRP. PMID- 23632403 TI - Interocular asymmetry of the visual field defects in newly diagnosed normal tension glaucoma, primary open-angle glaucoma, and chronic angle-closure glaucoma. AB - PURPOSE: To compare the interocular asymmetry of visual field loss in newly diagnosed normal-tension glaucoma (NTG), primary open-angle glaucoma (POAG), and chronic angle-closure glaucoma (CACG) patients. METHODS: Visual field results of 117 newly diagnosed, treatment-naive glaucoma patients (42 NTG, 38 POAG, and 37 CACG) were studied retrospectively. The following 3 visual field defect parameters were used to evaluate the interocular asymmetry: (1) global indices; (2) local mean deviations (MDs) of 6 predefined visual field areas; and (3) stage designated by glaucoma staging system 2. The differences of the above parameters between the trial eye (the eye with greater MDs) and the fellow eye in each subject were defined as interocular asymmetry scores. RESULTS: Interocular asymmetry of visual field loss was presented in all the 3 groups (all P<0.05). CACG group had greater total MD interocular asymmetry score compared with the NTG and POAG groups (among groups, P=0.008; NTG vs. CACG, P=0.005; POAG vs. CACG, P=0.009). CACG also presented with significantly higher local MD interocular asymmetry scores at central, inferior, and temporal areas compared with those of the POAG group and at inferior area compared with that of NTG group. No significant difference in either total or local MDs was detected between NTG and POAG (all P>0.05). Interocular asymmetry scores of glaucoma staging system 2 had no significant difference among the 3 groups (P=0.068). CONCLUSIONS: All CACG, POAG, and NTG groups presented with interocular asymmetric visual field loss at the time of diagnosis. CACG had greater interocular asymmetry compared with NTG and POAG. No significant interocular asymmetry difference was observed between NTG and POAG. PMID- 23632405 TI - Delayed topiramate-induced bilateral angle-closure glaucoma. AB - PURPOSE: To report a unique case of delayed topiramate-induced bilateral angle closure. METHODS: A case report of a 40-year-old woman who experienced bilateral acute angle-closure glaucoma and induced myopia on a standard and consistent dose of topiramate for 262 days before the onset of symptoms. Initial and follow-up examination findings were reviewed. RESULTS: Initial examination revealed finger counting at one foot OU, intraocular pressures of 38 mm Hg OD and 37 mm Hg OS, and bilaterally closed angles with no view of anterior trabecular meshwork (Shaffer grade 0). Discontinuation of topiramate and administration of topical drops were able to break the attack. At 3 months of follow-up, the patient was 20/25 OU with deep angles open to the scleral spur (Shaffer grade III) and had intraocular pressures of 14 mm Hg in both the eyes. CONCLUSIONS: This case provides evidence of delayed bilateral angle closure from topiramate and raises questions as to the cellular mechanism of topiramate-induced angle closure, both immediate and delayed. PMID- 23632404 TI - Comparison of acetazolamide, brimonidine, and anterior chamber paracentesis for ocular hypertension control after initial intravitreal bevacizumab injection: a randomized clinical trial. AB - PURPOSE: To evaluate the effects of oral acetazolamide (ACZ), anterior chamber paracentesis (ACP), or topical brimonidine tartrate (BT) to reduce intraocular pressure (IOP) elevation after intravitreal bevacizumab injection (IVBI). PATIENTS AND METHODS: A total of 56 patients scheduled for IVBI (1.5 mg/0.06 mL) were randomly assigned to a pretreatment with ACZ (14 eyes), BT (14 eyes), as well as an immediately after ACP (14 eyes), or no treatment (control group-CG) (14 eyes). IOP was measured 90 minutes before injection (baseline), just before injection, and at 3, 10, 20, and 30 minutes after the procedure. RESULTS: IOP was increased at 3 minutes after injection in CG, 20.9+/-2.1 (mean+/-SE intraindividual change in mm Hg); BT, 15.5+/-2.3; ACZ, 13.7+/-1.7; but not in ACP, 0.3+/-1.2 (P<0.0001). At 30 minutes after injections, IOP difference to baseline was not significantly different in groups BT, 0.0+/-0.7; ACZ, -3.2+/ 0.8; and ACP, -2.5+/-3.9, but was kept higher in the CG, 4.0+/-4.3 (P<0.0001). CONCLUSIONS: ACP prevents IOP elevation after IVBI, whereas ACZ and BT caused a faster return to baseline than untreated nonglaucomatous eyes. Further studies with larger number of subjects, including glaucomatous patients, and the use of other topical glaucoma medications are warranted to establish a standard recommendation. PMID- 23632406 TI - Optic nerve diffusion tensor imaging parameters and their correlation with optic disc topography and disease severity in adult glaucoma patients and controls. AB - PURPOSE: To evaluate optic nerve diffusion tensor imaging (DTI) parameters in glaucoma patients and controls, and to correlate DTI parameters with the rim area obtained with Heidelberg retina tomography (HRT) and with the severity of glaucomatous damage using the Glaucoma Staging System. DESIGN: Pilot study. METHODS: Twenty-seven patients with glaucoma and 12 control subjects underwent DTI and HRT imaging. Main outcome measures included: fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity, HRT rim area, and Glaucoma Staging System stage. RESULTS: In group comparison, mean diffusivity (1.33 vs. 0.91 MUm/ms, P=0.0002), axial diffusivity (1.70 vs. 1.43 MUm/ms, P=0.036), and radial diffusivity (1.24 vs. 0.71 MUm/ms, P<0.0001) were significantly higher and fractional anisotropy (0.21 vs. 0.44, P<0.0001) was significantly lower in the glaucoma compared with those of control subjects. In glaucoma patients, mean, axial, and radial diffusivities increased and fractional anisotropy decreased as rim area decreases and the Glaucoma stage increased (P<0.05). However, there were no statistically significant differences in the DTI parameters when adjacent pairs of stages were compared (P>0.05). CONCLUSIONS: DTI may be a useful technique for detection and evaluation of glaucomatous damage in the optic nerve, particularly for patients in whom conventional imaging and perimetry are not possible. Future studies are needed to evaluate how DTI parameters change longitudinally with glaucomatous damage within the visual pathways and address cerebrospinal fluid partial volume effects in diffusion tensor quantification, especially for patients with advanced glaucoma stage. PMID- 23632407 TI - A comparison of applanation tonometry using conventional reusable goldmann prisms and disposable prisms. AB - PURPOSE: To determine the agreement between intraocular pressure (IOP) measurements using conventional Goldmann applanation tonometry (GAT) and Tonosafe disposable prisms, and also to provide a comprehensive cost analysis of the use of both types of prisms METHODS: : In this prospective observational study, 198 eyes of 100 glaucoma patients had their IOPs measured by 5 consultant ophthalmologists. Data were analyzed using the Bland-Altman method of differences, and correlation was measured using the Pearson coefficient. An analysis of the cost incurred using the 2 methods over a 6-month period was performed. RESULTS: The majority were Chinese (82%), with a male preponderance (57%). The range of IOPs as measured by GAT was 4 to 34 mm Hg. Using the Bland Altman method to compare GAT and disposable prisms, the bias was 0.2 mm Hg. Tonosafe overestimated the IOP by 0.2 mm Hg in the right eye and underestimated it by 0.2 mm Hg in the left eye. The Tonosafe IOP correlated well with GAT, with a Pearson coefficient of correlation(r) of 0.91 (P<0.0005) for the right eye and 0.92 (P<0.0005) for the left eye, respectively. For those with GAT IOP>=21 mm Hg (n=26), Tonosafe underestimated the IOP by 0.35 mm Hg. The cost incurred by Tonosafe prisms was approximately 8 times that of GAT, but the cost differential reverses when GAT had to be replaced after every 100 cycles of disinfection. CONCLUSIONS: We found a good correlation between Tonosafe prisms and conventional GAT in measuring the IOP. Tonosafe prisms may be of use, especially if the risk of transmission of infection is high. However, cost may limit its more widespread use. PMID- 23632408 TI - Ocular decompression with cotton swabs lowers intraocular pressure elevation after intravitreal injection. AB - OBJECTIVE: To determine the effect of preinjection ocular decompression by cotton swabs on the immediate rise in intraocular pressure (IOP) after intravitreal injections. METHODS: Forty-eight patients receiving 0.05 mL ranibizumab injections in a retina clinic were randomized to 2 anesthetic methods in each eye on the same day (if bilateral disease) or on consecutive visits (if unilateral disease). One method utilized cotton swabs soaked in 4% lidocaine applied to the globe with moderate pressure and the other 3.5% lidocaine gel applied without pressure. IOPs were recorded at baseline (before injection) and at 0, 5, 10, and 15 minutes after the injection until the IOP was <=30 mm Hg. The IOP elevations from baseline were compared after the 2 anesthetic methods. RESULTS: The preinjection mean IOP (SD, mm Hg) was 15.5 (3.3) before the cotton swabs and 15.9 (3.0) before the gel (P=0.28). Mean IOP (SD, mm Hg) change immediately after injection was 25.7 (9.2) after the cotton swabs and 30.9 (9.9) after the gel (P=0.001). Thirty-five percent of gel eyes had IOP>=50 mm Hg compared with only 10% of cotton swab eyes immediately after the injection (P<0.001). CONCLUSION: Decompressing the eye with cotton swabs during anesthetic preparation before an intravitreal injection produces a significantly lower IOP spike after the injection. PMID- 23632409 TI - A novel antiproliferative drug coating for glaucoma drainage devices. AB - PURPOSE: The implantation of a glaucoma drainage device (GDD) is often necessary for intractable cases of glaucoma. Currently, the success rate of GDD implants is relatively low because fibrosis that develops during the wound-healing process ultimately blocks fluid drainage. We describe herein a novel porous coating for Ahmed glaucoma valves based on biodegradable poly(lactic-co-glycolic acid) (PLGA). MATERIALS AND METHODS: Thin films of PLGA were fabricated using a spin coating technique. The procedure led to an asymmetric pore structure that was exploited to control the rate of dissolution. Double-layered porous films were constructed to achieve continuous drug release. A cell culture system was used to test the efficacy of these coatings. RESULTS: Double-layered films were manufactured to provide a burst of mitomycin C (MMC) release followed by a slow release of 5-fluorouracil (5-FU), which together prevented fibrosis over the most active period of postoperative wound healing (0 to 28 d). Double-layered films containing 5-FU only in the bottom layer showed a 3- to 5-day delay in drug release, followed by a sharp increase that continued for ~28 days. MMC was stable only when surface-loaded, and this drug was therefore surface-loaded onto the top PLGA layer to provide a continuous release of antifibrotics over the wound healing period. CONCLUSIONS: The combined use of both MMC and 5-FU in a biodegradable device inhibits cell proliferation in a tissue culture model and has the potential to reduce fibrosis and increase the success rate of GDD implants. The design is simple and can be scaled for commercial production. PMID- 23632410 TI - Clinical impact of 8 prospective, randomized, multicenter glaucoma trials. AB - PURPOSE: To determine the impact of 8 multicenter randomized clinical trials (RCTs) on glaucoma practice. METHODS: An electronic survey was distributed to the members of the American Glaucoma Society (AGS). Each participant was asked 2 study-specific questions and 1 standard question common to all 8 RCTs assessing the study's impact on clinical practice. RCTs included in the survey were the Advanced Glaucoma Intervention Study (AGIS), Collaborative Initial Glaucoma Treatment Study (CIGTS), Collaborative Normal Tension Glaucoma (CNTG) Study, European Glaucoma Prevention Study (EGPS), Early Manifest Glaucoma Trial (EMGT), Glaucoma Laser Trial (GLT), Ocular Hypertension Treatment Study (OHTS), and Tube Versus Trabeculectomy (TVT) Study. A 5-point Likert scale was used for rating all responses. The practice setting and duration of glaucoma practice was determined for all AGS members who responded. RESULTS: A total of 206 (23.0%) of 894 AGS members participated in the survey. Among those who responded, 46.4% were self classified as academic practitioners and 53.6% worked in a private practice setting. Mean Likert scores for the standard question evaluating the overall impact of the RCT were OHTS 4.47, CNTG Study 4.13, AGIS 3.78, TVT Study 3.53, EMGT 3.48, CIGTS 3.44, GLT 3.39, and 2.69 EGPS. CONCLUSIONS: Substantial differences were observed in the clinical impact of several RCTs in glaucoma. The reported impact of each study likely reflects several factors including study timing, design, conduct, and interpretation of results. PMID- 23632411 TI - "Toxic" glaucoma? A case of possible styrene-induced ocular hypertension. AB - This case report is the first, to our knowledge, to describe ocular hypertension in a patient with occupational exposure to styrene. The intraocular pressure then returned to normal levels with removal of exposure. PMID- 23632412 TI - Brimonidine allergy presenting as vernal-like keratoconjunctivitis. AB - PURPOSE: To report a brimonidone-induced allergic reaction that mimicked a limbal form of vernal keratoconjunctivitis in the setting of background ocular surface toxicity. PATIENTS AND METHODS: A 78-year-old male with a history of primary open angle glaucoma presented with symptoms of unilateral blurry vision, irritation, and redness shortly after starting brimonidine exclusively in the right eye. Examination revealed injected palpebral and bulbar conjunctiva, diffuse punctate epithelial erosion and discrete, non-staining corneal limbal infiltrates superiorly. RESULTS: Given the unilateral presentation, the patient was diagnosed with an allergic limbal keratoconjunctivitis secondary to bromonidine. Shortly after discontinuing the brimonidine, there was full resolution of the corneal limbal infiltrates. The punctate epithelial erosions and tear film abnormalities remained. CONCLUSION: Direct medication allergy and ocular surface disease are two distinct entities that often co-exist. Distinguishing between the two entities, sometimes by trial and error, is critical in the management of these patients. PMID- 23632413 TI - Juvenile onset of ocular hypertension associated with de novo nail-patellar syndrome. AB - PURPOSE: To report a rare case of juvenile-onset ocular hypertension (OHT) associated with nail-patellar syndrome (NPS). METHOD: Clinical data of the patient were reviewed retrospectively. RESULTS: A 29-year-old woman was referred due to uncontrollable OHT. The OHT was found to be associated with NPS, a disorder characterized by anomalies of nails and skeletal bones. The patient had a history of high recorded intraocular pressure (IOP), beginning when she was 13 years old. Trabeculotomy was performed in both eyes due to uncontrollable high IOP. Postoperatively, the IOP has been well controlled without deterioration of optic disc appearance or visual field defects. CONCLUSION: When evaluating patients presenting with juvenile-onset OHT, clinicians should be aware of NPS as a differential diagnosis. PMID- 23632414 TI - Systemic arterial stiffness in patients with pseudoexfoliation glaucoma. AB - AIM: : To evaluate carotid-femoral pulse wave velocity (CF-PWV) values of patients with pseudoexfoliation (PEX) glaucoma in comparison with healthy subjects. METHODS: Twenty-five consecutive patients with PEX glaucoma (PEXG group) and 25 controls (control group) were included in the study. CF-PWV was assessed by a noninvasive device by the measurements of pulse transmit time and the distance between 2 recording sites. RESULTS: The mean age was 64.7+/-7.3 (range, 55 to 79) years the in PEXG group and 63.8+/-6.6 (range, 51 to 77) years in the control group. There were 8 men (32%) and 17 women (68%) in the PEXG group and 11 men (44%) and 14 women (56%) in the control group. The CF-PWV of the PEX group was significantly higher than that of the control group (P<0.001). CONCLUSIONS: We have revealed an association between PEXG and increased CF-PWV. Also, increased CF-PWV may be considered as a risk factor for the development of PEXG. PMID- 23632415 TI - Introducing the systems biology of cell state regulation section of Physiological Genomics. PMID- 23632416 TI - miR-222 contributes to sex-dimorphic cardiac eNOS expression via ets-1. AB - It is well recognized that there is sex-dimorphic expression of mRNA and protein in the heart; however, the underlying mechanism is poorly understood. Endothelial nitric oxide synthase (eNOS) is an important regulator of cardiac function, and the expression levels of eNOS differ between male and female hearts. The aim of this study was to examine whether expression of specific microRNA (miRNA, miR) in males and females contributes to changes in the expression of eNOS. miRNA was extracted from the myocardium of male and female C57BL/6 mice and subjected to an Affymetrix miRNA array. Decreased expression of miR-222 was discovered in females and confirmed by qRT-PCR from whole heart or isolated cardiomyocytes. The transcription factor V-ets erythroblastosis virus E26 oncogene homolog-1 (ets-1) was identified as a potential target of miR-222 using TargetScan, and fivefold increased ets-1 protein expression in females was confirmed by Western blot. Targeting of ets-1 by miR-222 was determined in HEK293 cells overexpressing luciferase under regulation of either the ets-1 3'-UTR, a null 3'-UTR control, or a scrambled ets-1 3'-UTR and treated with a small molecule miR-222 mimic or inhibitor. Additionally qRT-PCR confirmed that mRNA levels of the ets-1 transcriptional target, eNOS, were 25% higher in females. Compared with untreated myocyte controls, 50% inhibition of eNOS expression was achieved by treatment with a miR-222 mimic, compared with a 25% increase due to miR-222 inhibitor. Our findings indicate that sex-dependent miR-222 regulation alters the expression of the cardiac regulatory protein eNOS. PMID- 23632418 TI - RNA-Seq reveals expression signatures of genes involved in oxygen transport, protein synthesis, folding, and degradation in response to heat stress in catfish. AB - Temperature is one of the most prominent abiotic factors affecting ectotherms. Most fish species, as ectotherms, have extraordinary ability to deal with a wide range of temperature changes. While the molecular mechanism underlying temperature adaptation has long been of interest, it is still largely unexplored with fish. Understanding of the fundamental mechanisms conferring tolerance to temperature fluctuations is a topic of increasing interest as temperature may continue to rise as a result of global climate change. Catfish have a wide natural habitat and possess great plasticity in dealing with environmental variations in temperature. However, no studies have been conducted at the transcriptomic level to determine heat stress-induced gene expression. In the present study, we conducted an RNA-Seq analysis to identify heat stress-induced genes in catfish at the transcriptome level. Expression analysis identified a total of 2,260 differentially expressed genes with a cutoff of twofold change. qRT-PCR validation suggested the high reliability of the RNA-Seq results. Gene ontology, enrichment, and pathway analyses were conducted to gain insight into physiological and gene pathways. Specifically, genes involved in oxygen transport, protein folding and degradation, and metabolic process were highly induced, while general protein synthesis was dramatically repressed in response to the lethal temperature stress. This is the first RNA-Seq-based expression study in catfish in response to heat stress. The candidate genes identified should be valuable for further targeted studies on heat tolerance, thereby assisting the development of heat-tolerant catfish lines for aquaculture. PMID- 23632417 TI - Chronic carvedilol treatment partially reverses the right ventricular failure transcriptional profile in experimental pulmonary hypertension. AB - Right ventricular failure (RVF) is the most frequent cause of death in patients with pulmonary arterial hypertension (PAH); however, specific therapies targeted to treat RVF have not been developed. Chronic treatment with carvedilol has been shown to reduce established maladaptive right ventricle (RV) hypertrophy and to improve RV function in experimental PAH. However, the mechanisms by which carvedilol improves RVF are unknown. We have previously demonstrated by microarray analysis that RVF is characterized by a distinct gene expression profile when compared with functional, compensatory hypertrophy. We next sought to identify the effects of carvedilol on gene expression on a genome-wide basis. PAH and RVF were induced in male Sprague-Dawley rats by the combination of VEGF receptor blockade and chronic hypoxia. After RVF was established, rats were treated with carvedilol or vehicle for 4 wk. RNA was isolated from RV tissue and hybridized for microarray analysis. An initial prediction analysis of carvedilol treated RVs showed that the gene expression profile resembled the RVF prediction set. However, a more extensive analysis revealed a small group of genes differentially expressed after carvedilol treatment. Further analysis categorized these genes in pathways involved in cardiac hypertrophy, mitochondrial dysfunction, and protein ubiquitination. Genes encoding proteins in the cardiac hypertrophy and protein ubiquitination pathways were downregulated in the RV by carvedilol, while genes encoding proteins in the mitochondrial dysfunction pathway were upregulated by carvedilol. These gene expression changes may explain some of the mechanisms that underlie the functional improvement of the RV after carvedilol treatment. PMID- 23632420 TI - Gene selection heuristic algorithm for nutrigenomics studies. AB - Large datasets from -omics studies need to be deeply investigated. The aim of this paper is to provide a new method (LEM method) for the search of transcriptome and metabolome connections. The heuristic algorithm here described extends the classical canonical correlation analysis (CCA) to a high number of variables (without regularization) and combines well-conditioning and fast computing in "R." Reduced CCA models are summarized in PageRank matrices, the product of which gives a stochastic matrix that resumes the self-avoiding walk covered by the algorithm. Then, a homogeneous Markov process applied to this stochastic matrix converges the probabilities of interconnection between genes, providing a selection of disjointed subsets of genes. This is an alternative to regularized generalized CCA for the determination of blocks within the structure matrix. Each gene subset is thus linked to the whole metabolic or clinical dataset that represents the biological phenotype of interest. Moreover, this selection process reaches the aim of biologists who often need small sets of genes for further validation or extended phenotyping. The algorithm is shown to work efficiently on three published datasets, resulting in meaningfully broadened gene networks. PMID- 23632419 TI - Cluster analysis reveals differential transcript profiles associated with resistance training-induced human skeletal muscle hypertrophy. AB - Using genomic microarray analysis, we sought to identify and annotate differences in the pretraining skeletal muscle transcriptomes among human subjects clustered as nonresponders (Non), modest responders (Mod), and extreme responders (Xtr) based on differential magnitudes of myofiber hypertrophy in response to progressive resistance training (RT) (Non-6 MUm2, Mod 1,111 MUm2, or Xtr 2,475 MUm2). In prior work, we noted differences among clusters in the prevalence of myogenic stem cells prior to and during RT (35), and in the translational signaling responses to the first bout of resistance exercise (30). Here we identified remarkable differences in the pretraining transcript profiles among clusters (8,026 gene transcripts differentially expressed between Xtr and Non, 2,463 between Xtr and Mod, and 1,294 between Mod and Non). Annotated functions and networks of differentially expressed genes suggest Xtr were "primed" to respond to RT through transcriptional regulation, along with a uniquely expressed network of genes involved in skeletal muscle development, while the failed response in Non may have been driven by excessive proinflammatory signaling. Protein follow-up analysis revealed higher basal levels of acetylated histone H3 (K36) in the two responder clusters (Mod, Xtr) compared with Non, and only the responders experienced alterations in the muscle content of select proteins (e.g., alpha-tubulin, p27(kip)) in response to the first resistance exercise stimulus. Overall, the widely disparate transcriptomes identified prior to RT among the three clusters support the notion that at least some of the interindividual heterogeneity in propensity for RT-induced myofiber hypertrophy is likely predetermined. PMID- 23632421 TI - A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics. AB - The past years have seen increasing interest in nonlinear optical microscopic imaging approaches for the investigation of diseases due to the method's unique capabilities of deep tissue penetration, 3D sectioning and molecular contrast. Its application in clinical routine diagnostics, however, is hampered by large and costly equipment requiring trained staff and regular maintenance, hence it has not yet matured to a reliable tool for application in clinics. In this contribution implementing a novel compact fiber laser system into a tailored designed laser scanning microscope results in a small footprint easy to use multimodal imaging platform enabling simultaneously highly efficient generation and acquisition of second harmonic generation (SHG), two-photon excited fluorescence (TPEF) as well as coherent anti-Stokes Raman scattering (CARS) signals with optimized CARS contrast for lipid imaging for label-free investigation of tissue samples. The instrument combining a laser source and a microscope features a unique combination of the highest NIR transmission and a fourfold enlarged field of view suited for investigating large tissue specimens. Despite its small size and turnkey operation rendering daily alignment dispensable the system provides the highest flexibility, an imaging speed of 1 megapixel per second and diffraction limited spatial resolution. This is illustrated by imaging samples of squamous cell carcinoma of the head and neck (HNSCC) and an animal model of atherosclerosis allowing for a complete characterization of the tissue composition and morphology, i.e. the tissue's morphochemistry. Highly valuable information for clinical diagnostics, e.g. monitoring the disease progression at the cellular level with molecular specificity, can be retrieved. Future combination with microscopic probes for in vivo imaging or even implementation in endoscopes will allow for in vivo grading of HNSCC and characterization of plaque deposits towards the detection of high risk plaques. PMID- 23632422 TI - Spectromicroscopy of pulses transporting alkali metal in a surface reaction. AB - The NO + H2 reaction on a potassium promoted Rh(110) surface is shown to sustain the formation of spatio-temporal periodic patterns leading to mass transport phenomena. The excitation of pulses and the mass transport mechanism are studied in the 10(-7) and 10(-6) mbar pressure range, with the potassium coverage varying between thetaK = 0.05 and thetaK = 0.12 ML. Using spectroscopic photoemission and spectroscopic low energy electron microscopy (SPELEEM) as well as related microprobe diffraction techniques, we show that the excitation mechanism comprises a cyclic structural transformation: K + O-coadsorbate -> (2 * 1)-N -> c(2 * 4)-2O,N -> K + O coadsorbate. Laterally resolved spectroscopy demonstrates that potassium is accumulated in front of the nitrogen pulses, suggesting that adsorbed nitrogen acts as a diffusion barrier for potassium. PMID- 23632423 TI - Glycoprotein IIb/IIIa antagonists in Takotsubo cardiomyopathy. PMID- 23632424 TI - [Stroke prevention in atrial fibrillation : old and new anticoagulants]. AB - Atrial fibrillation is the most common form of cardiac arrhythmia with an age dependent increase in prevalence. It is common clinical practice to treat patients with atrial fibrillation and who have a high risk for thromboembolic stroke with vitamin K antagonists. However, due to the many problems with vitamin K antagonist therapy many high risk patients are either not treated at all or receive insufficient anticoagulation treatment. The new oral anticoagulants, e.g. dabigatran as a direct thrombin antagonist or rivaroxaban and apixaban as factor Xa antagonists were tested in large scale clinical trials with respect to the efficacy in stroke prevention in atrial fibrillation patients. The therapeutic superiority over warfarin could be impressively proven either with respect to the efficacy in stroke prevention and/or to the safety of therapy with a significant decrease in cerebral bleeding complications. PMID- 23632425 TI - Treatment of acute silicoproteinosis by whole-lung lavage. AB - Acute silicoproteinosis is a rare disease that occurs following a heavy inhalational exposure to silica dusts. Clinically, it resembles pulmonary alveolar proteinosis (PAP); silica exposure is thought to be a cause of secondary PAP. We describe a patient with biopsy-confirmed acute silicoproteinosis whose course was complicated by acute hypoxemic respiratory failure requiring mechanical ventilation. Without clinical improvement despite antibiotic and steroid treatment, the patient was scheduled for whole-lung lavage under general anesthesia. Anesthetic challenges included double-lumen tube placement and single lung ventilation in a hypoxic patient, facilitating lung lavage, and protecting the contralateral lung from catastrophic spillage. PMID- 23632426 TI - Evaluating the built environment in inpatient psychiatric wards. AB - OBJECTIVE: Research on inpatient psychiatric care has paid little attention to the built environment of psychiatric wards. This study described the built environment in a sample of inpatient psychiatric wards in England and investigated relationships between staff satisfaction with the built environment of the ward and objective design features of the environment. METHODS: Trained researchers completed a checklist of built-environment characteristics of 98 inpatient wards in England in 2007-2009. Interrater reliability was assessed and confirmed. Staff on these wards completed a three-item measure assessing the ward for overall design, fitness for purpose, and role in ensuring safety. Multilevel modeling was used to test relationships between built-environment features and staff satisfaction. RESULTS: A total of 1,540 staff responded. The wards encompassed a wide variety of service types and built-environment features. Staff satisfaction with the built environment was associated with noncorridor design and with the provision of personal bathrooms for patients. No association with observability of patients, exterior views, or other facilities was found. There was no difference between nurses and other groups in satisfaction with overall design, but nurses rated ward environment lower on ensuring safety (p=.036) and on fitness for purpose (p=.012). CONCLUSIONS: Objective measurement of the built environment in inpatient psychiatric settings is feasible and can be used to identify features that increase user satisfaction. PMID- 23632428 TI - Demented and hearing loss patient. PMID- 23632427 TI - Molecular characterization and drug resistance of Escherichia coli strains isolated from urine from long-term care facility residents in Cracow, Poland. AB - BACKGROUND: The aim of this study was to assess the prevalence of multidrug resistant Escherichia coli and extended-spectrum a-lactamases (ESBL) pathogens isolated from asymptomatic bacteriuria and urinary tract infections (UTIs), and the relationship between the phylogeny, antimicrobial resistance, and virulence among isolates in residents of 3 long-term care facilities (LTCF) in Krakow, Poland. MATERIAL AND METHODS: This was point prevalence study and prospective infection control in a group of 217 people. Urine samples were examined with standard microbiological methods and screened for the presence of blaCTX-M, blaSHV, and blaTEM. E. coli isolates were screened for 6 common virulence factors (VFs) and classified according to the rapid phylogenetic grouping technique. RESULTS: Among all the strains tested, 14 isolates (13.9%) expressed ESBL activity. A significant proportion of isolates were resistant to ciprofloxacin (32.7%, n=33). Resistance to trimethoprim/sulfamethoxazole was identified among 45 isolates (44.5%). Independent risk factors for the presence of an ESBL producing strain were: UTI, urinary and/or fecal incontinence, bedridden, and low values of the Barthel and Katz Indexes. Gene sequencing identified 8 blaCTX-M-15, 1 blaCTX-M-3, 9 blaTEM-1, and 1 blaSHV-12. Among E. coli, no relationship between number of VF genes and phylogeny was found. The most prevalent virulence factor was fimH (82.1%). CONCLUSIONS: The findings of this study emphasize the need for further research on the epidemiology of multi-drug resistant organisms (MDRO) and ESBL in LTCF, including transmission patterns, rates of infection, and factors associated with infections. It may be necessary to extend the requirements and precautions to MDRO and ESBL-producers. PMID- 23632430 TI - Prevention and treatment of local anesthetics-induced complete atrioventricular block during awake craniotomy. PMID- 23632431 TI - A retrospective analysis of stridor after vestibular schwannoma surgery. AB - BACKGROUND: Transient lower cranial nerve deficits may occur after surgery in the posterior cranial fossa. Stridor has been reported after cerebellopontine angle epidermoid resection. The aim of this retrospective study is to find out whether any preoperative, intraoperative, and postoperative factors lead to stridor after resection of vestibular schwannoma. METHODS: Data of patients who underwent vestibular schwannoma resection from 2006 to 2011 were collected. We collected the following factors--age, sex, weight, diabetes, hypertension, preoperative cranial nerve deficits, tumor characteristics, intraoperative use of nitrous oxide, difficult endotracheal intubation, duration of surgery, postoperative cough and swallowing difficulty, limb weakness, and facial edema. Data of patients who developed stridor were compared with those who did not develop stridor. Odds ratio (OR) was used to assess the risk of developing stridor with each factor. RESULTS: Thirteen patients (4.65%) developed stridor in immediate postextubation period. The risk of stridor was significantly high in patients who had difficult intubation (OR=9.56), longer duration of surgery (P=0.034) and in patients who developed facial edema (OR=13.33), upperlimb weakness (OR=32.88), poor cough (OR=7.72), and swallowing difficulty (OR=24.97) in the postoperative period. CONCLUSIONS: The identification of the exact etiology of stridor often is difficult. Our results suggest that stridor may be more likely in patients who were difficult to intubate, had longer duration of surgery, who develop facial and neck edema and upperlimb weakness, poor cough, and swallowing after surgery. Establishing airway patency with intubation of the trachea may be required if patients develop oxygen desaturation due to stridor. PMID- 23632432 TI - Chemical and electrochemical oxidation of [Rh(beta diketonato)(CO)(P(OCH2)3CCH3)]: an experimental and DFT study. AB - An experimental and computational chemistry study of the reactivity of [Rh(beta diketonato)(CO)(P(OCH2)3CCH3)] complexes towards chemical and electrochemical oxidation shows that more electron withdrawing groups on the beta-diketonato ligand reduce electron density on the rhodium atom to a larger extent than electron donating groups. This leads to a slower second-order oxidative addition rate, k1, and a higher electrochemical oxidation potential, E(pa)(Rh), linearly related by ln k1 = -11(1) E(pa)(Rh) - 2.3(5). The reactivity of these complexes can be predicted by their DFT calculated HOMO energies: E(HOMO) = 0.34(8)E(pa)(Rh) - 5.04(4) = 0.032(5) ln k1- 4.96(4). k1 of [Rh(beta diketonato)(CO)(P(OCH2)3CCH3)] complexes is slower than that of related [Rh(beta diketonato)(CO)(PPh3)] and [Rh(beta-diketonato)(P(OPh)3)2] complexes due to the better pi-acceptor ability of the CO-phosphite-rhodium combination than that of CO-PPh3-rhodium or di-phosphite-rhodium. PMID- 23632433 TI - Multivariate curve resolution-alternating least squares assisted by voltammetry for simultaneous determination of betaxolol and atenolol using carbon nanotube paste electrode. AB - In the present work differential pulse voltammetry coupled with multivariate curve resolution-alternating least squares (MCR-ALS) was applied for simultaneous determination of betaxolol (Bet) and atenolol (Ate) in 0.20 M Britton-Robinson (B R) buffer solution at the surface of a multi-walled carbon nanotube modified carbon paste electrode (MWCNT/CPE). Characterization of the modified electrode was carried out by electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). A strategy based on experimental design was followed. Operating conditions were improved with central composite rotatable design (CCRD) and response surface methodology (RSM), involving several chemical and instrumental parameters. Then second order data were built from variable pulse heights of DPV and after correction in potential shift analyzed by MCR-ALS. Analytical parameters such as linearity, repeatability, and stability were also investigated and a detection limit (DL) of 0.19 and 0.29 MUM for Bet and Ate was achieved, respectively. The proposed method was successfully applied in simultaneous determining the two analytes in human plasma. PMID- 23632434 TI - Direct electrochemistry and electrocatalysis of heme proteins immobilised in carbon-coated nickel magnetic nanoparticle-chitosan-dimethylformamide composite films in room-temperature ionic liquids. AB - The direct electrochemistry and electrocatalysis of heme proteins entrapped in carbon-coated nickel magnetic nanoparticle-chitosan-dimethylformamide (CNN-CS DMF) composite films were investigated in the hydrophilic ionic liquid [bmim][BF4]. The surface morphologies of a representative set of films were characterised via scanning electron microscopy. The proteins immobilised in the composite films were shown to retain their native secondary structure using UV vis spectroscopy. The electrochemical performance of the heme proteins-CNN-CS-DMF films was evaluated via cyclic voltammetry and chronoamperometry. A pair of stable and well-defined redox peaks was observed for the heme protein films at formal potentials of -0.151 V (HRP), -0.167 V (Hb), -0.155 V (Mb) and -0.193 V (Cyt c) in [bmim][BF4]. Moreover, several electrochemical parameters of the heme proteins were calculated by nonlinear regression analysis of the square-wave voltammetry. The addition of CNN significantly enhanced not only the electron transfer of the heme proteins but also their electrocatalytic activity toward the reduction of H2O2. Low apparent Michaelis-Menten constants were obtained for the heme protein-CNN-CS-DMF films, demonstrating that the biosensors have a high affinity for H2O2. In addition, the resulting electrodes displayed a low detection limit and improved sensitivity for detecting H2O2, which indicates that the biocomposite film can serve as a platform for constructing new non-aqueous biosensors for real detection. PMID- 23632435 TI - Hyperbaric oxygen does not improve cerebral function when started 2 or 4 hours after cerebral arterial gas embolism in swine. AB - OBJECTIVE: Hyperbaric oxygenation is the accepted treatment for cerebral arterial gas embolism. Although earlier start of hyperbaric oxygenation is associated with better outcome, it is unknown how much delay can be tolerated before start of hyperbaric oxygenation. This study investigates the effect of hyperbaric oxygenation on cerebral function in swine when initiated 2 or 4 hours after cerebral arterial gas embolism. DESIGN: Prospective interventional animal study. SETTING: Surgical laboratory and hyperbaric chamber. SUBJECTS: Twenty-two Landrace pigs. INTERVENTIONS: Under general anesthesia, probes to measure intracranial pressure, brain oxygen tension (PbtO2), and brain microdialysis, and electrodes for electroencephalography were placed. The electroencephalogram (quantified using temporal brain symmetry index) was suppressed during 1 hour by repeated injection of air boluses through a catheter placed in the right ascending pharyngeal artery. Hyperbaric oxygenation was administered using U.S. Navy Treatment Table 6 after 2- or 4-hour delay. Control animals were maintained on an inspiratory oxygen fraction of 0.4. MEASUREMENTS AND MAIN RESULTS: Intracranial pressure increased to a mean maximum of 19 mm Hg (SD, 4.5 mm Hg) due to the embolization procedure. Hyperbaric oxygenation significantly increased PbtO2 in both groups treated with hyperbaric oxygenation (mean maximum PbtO2, 390 torr; SD, 177 torr). There were no significant differences between groups with regard to temporal brain symmetry index (control vs 2-hr delay, p = 0.078; control vs 4-hr delay, p = 0.150), intracranial pressure, and microdialysis values. CONCLUSIONS: We did not observe an effect of hyperbaric oxygenation on cerebral function after a delay of 2 or 4 hours. The injury caused in our model could be too severe for a single session of hyperbaric oxygenation to be effective. Our study should not change current hyperbaric oxygenation strategies for cerebral arterial gas embolism, but further research is necessary to elucidate our results. Whether less severe injury benefits from hyperbaric oxygenation should be investigated in models using smaller amounts of air and clinical outcome measures. PMID- 23632437 TI - Formation and photoinduced processes of the host-guest complexes of a beta cyclodextrin-conjugated aza-BODIPY and tetrasulfonated porphyrins. AB - A bis(permethylated beta-cyclodextrin)-substituted aza-BODIPY has been prepared, which forms stable 1 : 1 host-guest complexes with metal-free and zinc(II) tetrasulfonated porphyrins in water. The resulting complexes exhibit predominantly a photoinduced energy or electron transfer process depending on the porphyrin-based guest. PMID- 23632436 TI - Cocaine modulation of frontostriatal expression of Zif268, D2, and 5-HT2c receptors in high and low impulsive rats. AB - Impulsivity shares high comorbidity with substance abuse in humans, and high impulsivity (HI) in rats has been identified as a predictive factor for cocaine addiction-like behavior. Despite the evidence that high impulsivity is associated with altered function of corticostriatal networks, the specific neural substrates underlying the increased vulnerability of impulsive individuals to develop cocaine addiction remain unknown. We therefore investigated specific neural correlates of HI within the corticostriatal circuitry and determined how they interact with a protracted history of cocaine self-administration. We used in situ hybridization to map brain expression of two major genes implicated in impulsivity, encoding the dopamine D2 receptor (DA D2R) and the 5-HT2c receptor (5-HT2cR), and an immediate early gene associated with neuronal plasticity, zif268, in groups of rats selected for HI and low impulsivity (LI) on a 5-choice serial reaction time task (5-CSRTT) immediately after 5-CSRTT training, and following 10 or 50 days of cocaine self-administration. HI rats exhibited decreased DA D2R mRNA in the mesolimbic pathway, and increased 5-HT2cR mRNA in the orbitofrontal cortex compared with LI rats. HI rats also showed decreased zif268 mRNA in the ventral and dorsomedial striatum. Cocaine exposure decreased striatal D2R mRNA in both HI and LI rats, decreased 5-HT2cR mRNA differentially in striatal and prefrontal areas between HI and LI rats, and selectively decreased zif268 mRNA in the orbitofrontal and infralimbic cortices of HI animals. These findings implicate novel markers underlying the vulnerability of impulsive rats to cocaine addiction that localize to the OFC, infralimbic cortex, and striatum. PMID- 23632438 TI - Small-world networks in neuronal populations: a computational perspective. AB - The analysis of the brain in terms of integrated neural networks may offer insights on the reciprocal relation between structure and information processing. Even with inherent technical limits, many studies acknowledge neuron spatial arrangements and communication modes as key factors. In this perspective, we investigated the functional organization of neuronal networks by explicitly assuming a specific functional topology, the small-world network. We developed two different computational approaches. Firstly, we asked whether neuronal populations actually express small-world properties during a definite task, such as a learning task. For this purpose we developed the Inductive Conceptual Network (ICN), which is a hierarchical bio-inspired spiking network, capable of learning invariant patterns by using variable-order Markov models implemented in its nodes. As a result, we actually observed small-world topologies during learning in the ICN. Speculating that the expression of small-world networks is not solely related to learning tasks, we then built a de facto network assuming that the information processing in the brain may occur through functional small world topologies. In this de facto network, synchronous spikes reflected functional small-world network dependencies. In order to verify the consistency of the assumption, we tested the null-hypothesis by replacing the small-world networks with random networks. As a result, only small world networks exhibited functional biomimetic characteristics such as timing and rate codes, conventional coding strategies and neuronal avalanches, which are cascades of bursting activities with a power-law distribution. Our results suggest that small-world functional configurations are liable to underpin brain information processing at neuronal level. PMID- 23632440 TI - Ecological and spatial factors drive intra- and interspecific variation in exposure of subarctic predatory bird nestlings to persistent organic pollutants. AB - Top predators in northern ecosystems may suffer from exposure to persistent organic pollutants (POPs) as this exposure may synergistically interact with already elevated natural stress in these ecosystems. In the present study, we aimed at identifying biological (sex, body condition), ecological (dietary carbon source, trophic level) and spatial factors (local habitat, regional nest location) that may influence intra- and interspecific variation in exposure of subarctic predatory bird nestlings to polychlorinated biphenyl 153 (CB 153), polybrominated diphenyl ether 47 (BDE 47), dichlorodiphenyldichloroethylene (p,p' DDE) and hexachlorobenzene (HCB). During three breeding seasons (2008-2010), we sampled body feathers from fully-grown nestlings of three ecologically distinct predatory bird species in subarctic Norway: Northern Goshawk (Accipiter gentilis), White-tailed Eagle (Haliaeetus albicilla) and Golden Eagle (Aquila chrysaetos). The present study analysed, for the first time, body feathers for both POPs and carbon (delta(13)C) and nitrogen (delta(15)N) stable isotopes, thus integrating the dietary carbon source, trophic level and POP exposure for the larger part of the nestling stage. Intraspecific variation in exposure was driven by a combination of ecological and spatial factors, often different for individual compounds. In addition, combinations for individual compounds differed among species. Trophic level and local habitat were the predominant predictors for CB 153, p,p'-DDE and BDE 47, indicating their biomagnification and decreasing levels according to coast>fjord>inland. Variation in exposure may also have been driven by inter-annual variation arisen from primary sources (e.g. p,p'-DDE) and/or possible revolatilisation from secondary sources (e.g. HCB). Interspecific differences in POP exposure were best explained by a combination of trophic level (biomagnification), dietary carbon source (food chain discrimination) and regional nest location (historical POP contamination). In conclusion, the combined analysis of POPs and stable isotopes in body feathers from fully-grown nestlings has identified ecological and spatial factors that may drive POP exposure over the larger part of the nestling stage. This methodological approach further promotes the promising use of nestling predatory bird body feathers as a non-destructive sampling strategy to integrate various toxicological and ecological proxies. PMID- 23632442 TI - Disengagement from care: perspectives of individuals with serious mental illness and of service providers. AB - OBJECTIVE: This study sought to describe reasons for disengagement from services and practical guidelines to enhance engagement among individuals with serious mental illness and high need for treatment. METHODS: Qualitative interviews were conducted with 56 individuals with serious mental illness and 25 providers recruited from a larger project that used administrative data to identify individuals with serious mental illness who had disengaged from care. Individuals with serious mental illness and providers described reasons for disengagement and effective provider engagement strategies. RESULTS: Individuals with serious mental illness and providers differed in reported reasons for disengagement. Reasons reported by individuals with serious mental illness included services that were not relevant to their needs, inability to trust providers, and a belief that they were not ill. Providers cited lack of insight, stigma, and language and cultural barriers as common reasons for disengagement. Strategies for increasing engagement were grouped into a framework of acceptable, accessible, and available services. Acceptable services reflect a partnership model that fosters support and instills hope; accessible services minimize barriers related to transportation and intake procedures; and available services address recovery needs in addition to treatment of general medical and psychiatric problems. CONCLUSIONS: Individuals with serious mental illness and providers often do not agree on reasons for seeking care. The framework of acceptable, accessible, and available services identifies opportunities for providers to adjust practices and maximize engagement in services among individuals with serious mental illness who are in high need of treatment. PMID- 23632441 TI - Comparison of 21-gauge and 22-gauge aspiration needle in endobronchial ultrasound guided transbronchial needle aspiration: results of the American College of Chest Physicians Quality Improvement Registry, Education, and Evaluation Registry. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure originally performed using a 22 gauge (22G) needle. A recently introduced 21-gauge (21G) needle may improve the diagnostic yield and sample adequacy of EBUS-TBNA, but prior smaller studies have shown conflicting results. To our knowledge, this is the largest study undertaken to date to determine whether the 21G needle adds diagnostic benefit. METHODS: We retrospectively evaluated the results of 1,299 patients from the American College of Chest Physicians Quality Improvement Registry, Education, and Evaluation (AQuIRE) Diagnostic Registry who underwent EBUS-TBNA between February 2009 and September 2010 at six centers throughout the United States. Data collection included patient demographics, sample adequacy, and diagnostic yield. Analysis consisted of univariate and multivariate hierarchical logistic regression comparing diagnostic yield and sample adequacy of EBUS-TBNA specimens by needle gauge. RESULTS: A total of 1,235 patients met inclusion criteria. Sample adequacy was obtained in 94.9% of the 22G needle group and in 94.6% of the 21G needle group (P = .81). A diagnosis was made in 51.4% of the 22G and 51.3% of the 21G groups (P = .98). Multivariate hierarchical logistic regression showed no statistical difference in sample adequacy or diagnostic yield between the two groups. The presence of rapid onsite cytologic evaluation was associated with significantly fewer needle passes per procedure when using the 21G needle (P < .001). CONCLUSIONS: There is no difference in specimen adequacy or diagnostic yield between the 21G and 22G needle groups. EBUS-TBNA in conjunction with rapid onsite cytologic evaluation and a 21G needle is associated with fewer needle passes compared with a 22G needle. PMID- 23632443 TI - Evolution of structure and properties of neutral and negatively charged transition metal-coronene complexes: a comprehensive analysis. AB - The geometries, electronic and magnetic properties of neutral and negatively charged Mn(coronene)m (M = V and Ti; n, m = 1, 2) complexes were investigated using density functional theory. The results show that one V or Ti atom prefers to occupy the eta(6)-site in M(coronene)(0/-) complexes and to be sandwiched between the two coronene molecules in M(coronene)2(0/-) complexes. Two metal atoms always form a dimer and interact with one coronene molecule. The calculated vertical electron affinities and transition energies are in good agreement with experimental values. This lends considerable credence to the obtained ground state structure and validates the chosen computational method. The bond formation between metal atom and coronene is accounted for by 3d/4s-pi bonds, as revealed by the molecular orbitals plots. The reason why the peripheral ring site binds metal most effectively has been analyzed systematically by pi electron content, aromaticity and average charge on carbon atoms. The electron localization function shows that there is perfect electron delocalization in these complexes. Furthermore, the magnetic moments of V(coronene)(0/-) and Ti(coronene)(-) are found to be substantially enhanced over the corresponding free metal atom; the magnetic moment of the neutral Ti(coronene) remains unchanged; while the larger size clusters experience a reduction. PMID- 23632444 TI - Weaning of the patient with tracheostomy. Role of continuous positive airway pressure. PMID- 23632445 TI - Effect of volatile anesthetics on the ischemia-reperfusion injury. PMID- 23632446 TI - Can renin predict the mortality of patients in Intensive Care Unit? PMID- 23632448 TI - First principles intensity calculations of the methane rovibrational spectra in the infrared up to 9300 cm(-1). AB - We report global calculations of rovibrational spectra and dipole transition intensities of methane using our recent ab initio dipole moment and potential surfaces [Nikitin et al., Chem. Phys. Lett., 2011, 501, 179; 2013, 565, 5]. For the full symmetry account, a recently published variational tensor formalism in normal modes [Rey et al., J. Chem. Phys., 2012, 136, 244106] is applied, the convergence of high-J calculations being improved by the use of vibrational eigenfunctions to make a compressed basis set for solving the rovibrational problem. Comparisons of theoretical predictions up to J = 25 for various complex polyads of methane involving strongly coupled vibration-rotation bands support the validity of this new approach. For the first time, positions and line intensities at 80 K and 296 K are shown to be in excellent agreement with raw experimental data, even for high energy ranges. The theoretical predictions also correctly describe the isotopic effects in line positions and intensities due to the CH4 -> CD4 substitution which is considered as the test for the method. This work is a first step toward the theoretical interpretation of numerous methane bands which remain still unassigned and detailed line-by-line absorption/emission spectra analyses for atmospheric and planetological applications. PMID- 23632447 TI - Cecropia peltata accumulates starch or soluble glycogen by differentially regulating starch biosynthetic genes. AB - The branched glucans glycogen and starch are the most widespread storage carbohydrates in living organisms. The production of semicrystalline starch granules in plants is more complex than that of small, soluble glycogen particles in microbes and animals. However, the factors determining whether glycogen or starch is formed are not fully understood. The tropical tree Cecropia peltata is a rare example of an organism able to make either polymer type. Electron micrographs and quantitative measurements show that glycogen accumulates to very high levels in specialized myrmecophytic structures (Mullerian bodies), whereas starch accumulates in leaves. Compared with polymers comprising leaf starch, glycogen is more highly branched and has shorter branches--factors that prevent crystallization and explain its solubility. RNA sequencing and quantitative shotgun proteomics reveal that isoforms of all three classes of glucan biosynthetic enzyme (starch/glycogen synthases, branching enzymes, and debranching enzymes) are differentially expressed in Mullerian bodies and leaves, providing a system-wide view of the quantitative programming of storage carbohydrate metabolism. This work will prompt targeted analysis in model organisms and cross-species comparisons. Finally, as starch is the major carbohydrate used for food and industrial applications worldwide, these data provide a basis for manipulating starch biosynthesis in crops to synthesize tailor-made polyglucans. PMID- 23632449 TI - Evidence of diminished FEV1 and FVC in 6-year-olds followed in the European Cystic Fibrosis Patient Registry, 2007-2009. AB - BACKGROUND: Many infants with cystic fibrosis (CF) exhibit airway inflammation, gas trapping, bronchiectasis, and/or reduced flow, but by age 6 years have forced vital capacities (FVC) and expiratory volumes in 1 second (FEV1) within the variability range of the normal population. We sought evidence of diminished FVC and FEV1 in 6-year-olds with CF. METHODS: GLI 2012 FVC and FEV1 Z-scores for 6 year-olds from the European CF Patient Registry were plotted against theoretical values from the Normal distribution. RESULTS: Mean FVC and FEV1 Z-scores for 681 patients (322 females) were -0.43 (SD=1.41) and -0.65 (1.40). Z-scores were consistently lower than expected for the normative population by quantile quantile plot. CONCLUSIONS: Diminished FEV1, and to a lesser extent FVC, is found in a large majority of this population, consistent with an established body of evidence that loss of lung function begins early in life for most, if not all, children with CF. PMID- 23632450 TI - Elevated levels of miR-145 correlate with SMAD3 down-regulation in cystic fibrosis patients. AB - MicroRNAs (miRNAs) have recently emerged as important gene regulators in Cystic Fibrosis (CF), a common monogenic disease characterized by severe infection and inflammation, especially in the airway compartments. In the current study, we show that both miR-145 and miR-494 are significantly up-regulated in nasal epithelial tissues from CF patients compared with healthy controls (p<0.001 and p<0.01, respectively) by Quantitative Real-Time PCR. Only miR-494 levels showed a trend of correlation with reduced CFTR mRNA expression and positive sweat test values, supporting the negative regulatory role of this miRNA on CFTR synthesis. Using computational prediction algorithms and luciferase reporter assays, SMAD family member 3 (SMAD3), a key element of the TGF-beta1 inflammatory pathway, was identified as a target of miR-145. Indeed, miR-145 synthetic mimics suppressed by approximately 40% the expression of a reporter construct containing the SMAD3 3' UTR. Moreover, we observed an inverse correlation between SMAD3 mRNA expression and miR-145 in CF nasal tissues (r=-0.68, p=0.0018, Pearson's correlation). Taken together, these results confirm the pivotal role of miRNAs in the CF physio pathogenesis and suggest that miRNA deregulation play a role in the airway disease severity by modulating CFTR levels as well as the expression of important molecules involved in the inflammatory response. miR-494 and miR-145 may, therefore, be potential biomarker and therapeutic target to specific CF clinical manifestations. PMID- 23632451 TI - Development of culturally tailored educational brochures on HPV and pap tests for American Indian women. AB - PURPOSE: Participatory formative research guided the creation of a culturally tailored educational brochure about human papillomavirus (HPV) at an American Indian women's clinic. METHOD: A review of existing educational materials and in depth interviews were conducted. Nine steps for creating health communications messages that were patterned after National Cancer Institute guidelines guided the brochure development process. RESULTS: Of 95 women tested for HPV, 41% were positive, 32 (34%) agreed to the in-depth interview, and 9 agreed to the pretesting interview. Mean age was 41 years. Interviews revealed key themes concerning emotional reactions to abnormal Pap test results and HPV; need for basic information about HPV, Pap tests, and results; concerns about HPV stigma, sexual transmission, and communication with sexual partner; and the preferred source and format for HPV educational materials. A literature review revealed 12 areas of basic HPV content. CONCLUSIONS: A participatory process successfully engaged nursing staff and patients in creating culturally appropriate brochures for clinic use. IMPLICATIONS: This article provides specific steps for creating culturally tailored patient education materials. PMID- 23632452 TI - Physical activity behavior change in persons with neurologic disorders: overview and examples from Parkinson disease and multiple sclerosis. AB - Persons with chronic progressive neurologic diseases such as Parkinson disease (PD) and multiple sclerosis (MS) face significant declines in mobility and activities of daily living, resulting in a loss of independence and compromised health-related quality of life over the course of the disease. Such undesirable outcomes can be attenuated through participation in exercise and physical activity, yet there is profound and prevalent physical inactivity in persons with PD and MS that may initiate a cycle of deconditioning and worsening of disease consequences, independent of latent disease processes. This Special Interest article highlights the accruing evidence revealing the largely sedentary behaviors common among persons living with physically disabling conditions and summarizes the evidence on the benefits of physical activity in persons with PD and MS. We then examine the social cognitive theory as an approach to identifying the primary active ingredients for behavioral change and, hence, the targets of interventions for increasing physical activity levels. The design and efficacies of interventions based on the social cognitive theory for increasing physical activity in persons with PD and MS are discussed. Finally, a rationale for adopting a secondary prevention approach to delivering physical therapy services is presented, with an emphasis on the integration of physical activity behavior change interventions into the care of persons with chronic, progressive disabilities over the course of the disease.Video Abstract available (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A42) for more insights from the authors. PMID- 23632453 TI - Aerobic exercise to improve executive function in Parkinson disease: a case series. AB - BACKGROUND AND PURPOSE: Parkinson disease (PD) affects cognition, specifically executive function. In people with PD, impaired executive function has been identified as an indicator of fall risk and decreased quality of life. Therefore, it is important to consider impaired executive function in the physical therapy management of PD. It has been established that exercise improves cognition in older adults and emerging evidence suggests a similar effect in people with neurological conditions. We assessed changes in executive function in an aerobic exercise intervention in 2 people with cognitive impairments due to PD. CASE DESCRIPTION: Two individuals with PD participated in this case series. Participant 1 was a 61-year-old woman with PD dementia, who had PD for 14 years. Participant 2 was a 72-year-old man with mild cognitive impairments, who had PD for 7 years. INTERVENTION: The participants completed an 8-week program of aerobic exercise training on a stationary bicycle. Primary outcome measures examined executive function, and secondary measures examined disease severity, quality of life, and walking function. OUTCOMES: Both participants demonstrated improvements in all measures of executive function and quality of life. Participant 1 also made improvements in walking function. DISCUSSION: Our outcomes provide preliminary evidence of improved executive function following aerobic exercise in people with PD with cognitive impairments. Larger studies are needed to confirm these findings and investigate whether a causal relationship exists between exercise and improved executive function in persons with PD, and how these impact motor performance and quality of life measures.Video Abstract available (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A43) for more insights from the authors. PMID- 23632454 TI - Orbitofrontal cortex neurofeedback produces lasting changes in contamination anxiety and resting-state connectivity. AB - Anxiety is a core human emotion but can become pathologically dysregulated. We used functional magnetic resonance imaging (fMRI) neurofeedback (NF) to noninvasively alter patterns of brain connectivity, as measured by resting-state fMRI, and to reduce contamination anxiety. Activity of a region of the orbitofrontal cortex associated with contamination anxiety was measured in real time and provided to subjects with significant but subclinical anxiety as a NF signal, permitting them to learn to modulate the target brain region. NF altered network connectivity of brain regions involved in anxiety regulation: subjects exhibited reduced resting-state connectivity in limbic circuitry and increased connectivity in the dorsolateral prefrontal cortex. NF has been shown to alter brain connectivity in other contexts, but it has been unclear whether these changes persist; critically, we observed changes in connectivity several days after the completion of NF training, demonstrating that such training can lead to lasting modifications of brain functional architecture. Training also increased subjects' control over contamination anxiety several days after the completion of NF training. Changes in resting-state connectivity in the target orbitofrontal region correlated with these improvements in anxiety. Matched subjects undergoing a sham feedback control task showed neither a reorganization of resting-state functional connectivity nor an improvement in anxiety. These data suggest that NF can enable enhanced control over anxiety by persistently reorganizing relevant brain networks and thus support the potential of NF as a clinically useful therapy. PMID- 23632455 TI - Effects of NRG1 and DAOA genetic variation on transition to psychosis in individuals at ultra-high risk for psychosis. AB - Prospective studies have suggested genetic variation in the neuregulin 1 (NRG1) and D-amino-acid oxidase activator (DAOA) genes may assist in differentiating high-risk individuals who will or will not transition to psychosis. In a prospective cohort (follow-up=2.4-14.9 years) of 225 individuals at ultra-high risk (UHR) for psychosis, we assessed haplotype-tagging single-nucleotide polymorphisms (htSNPs) spanning NRG1 and DAOA for their association with transition to psychosis, using Cox regression analysis. Two NRG1 htSNPs (rs12155594 and rs4281084) predicted transition to psychosis. Carriers of the rs12155594 T/T or T/C genotype had a 2.34 (95% confidence interval (CI)=1.37 4.00) times greater risk of transition compared with C/C carriers. For every rs4281084 A-allele the risk of transition increased by 1.55 (95% CI=1.05-2.27). For every additional rs4281084-A and/or rs12155594-T allele carried the risk increased ~1.5-fold, with 71.4% of those carrying a combination of ?3 of these alleles transitioning to psychosis. None of the assessed DAOA htSNPs were associated with transition. Our findings suggest NRG1 genetic variation may improve our ability to identify UHR individuals at risk for transition to psychosis. PMID- 23632456 TI - ErbB inhibitors ameliorate behavioral impairments of an animal model for schizophrenia: implication of their dopamine-modulatory actions. AB - Ligands for ErbB receptors, including epidermal growth factor (EGF) and neuregulin-1, have a neurotrophic activity on midbrain dopaminergic neurons and are implicated in the pathophysiology of schizophrenia. Although ErbB kinase inhibitors ameliorate behavioral deficits of the schizophrenia model that was established by hippocampal lesioning of rat pups, the antipsychotic action of ErbB kinase inhibitors and its general applicability to other models are not fully characterized. Using a different animal model, here, we examined whether and how ErbB kinase inhibitors ameliorate the behavioral endophenotypes relevant to schizophrenia. The animal model for schizophrenia was prepared by exposing neonatal rats to the cytokine EGF. Intraventricular infusion of the ErbB1 inhibitors ZD1839 and PD153035 in these animals ameliorated the deficits in startle response and prepulse inhibition in a dose-dependent manner. The deficits of latent inhibition of fear learning were also alleviated by ZD1839 with its limited effects on body weight gain or locomotor activity. ZD1839 infusion also decreased the busting activity of nigral dopamine (DA) neurons and reduced pallidal DA metabolism, a result that mimics the anti-dopaminergic profile of risperidone and haloperidol in this brain region. ErbB inhibitors appear to have anti-dopaminergic actions to alleviate some of the behavioral deficits common to animal models for schizophrenia. PMID- 23632457 TI - BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities. AB - The therapeutic activity of selective serotonin (5-HT) reuptake inhibitors (SSRIs) relies on long-term adaptation at pre- and post-synaptic levels. The sustained administration of SSRIs increases the serotonergic neurotransmission in response to a functional desensitization of the inhibitory 5-HT1A autoreceptor in the dorsal raphe. At nerve terminal such as the hippocampus, the enhancement of 5 HT availability increases brain-derived neurotrophic factor (BDNF) synthesis and signaling, a major event in the stimulation of adult neurogenesis. In physiological conditions, BDNF would be expressed at functionally relevant levels in neurons. However, the recent observation that SSRIs upregulate BDNF mRNA in primary cultures of astrocytes strongly suggest that the therapeutic activity of antidepressant drugs might result from an increase in BDNF synthesis in this cell type. In this study, by overexpressing BDNF in astrocytes, we balanced the ratio between astrocytic and neuronal BDNF raising the possibility that such manipulation could positively reverberate on anxiolytic-/antidepressant-like activities in transfected mice. Our results indicate that BDNF overexpression in hippocampal astrocytes produced anxiolytic-/antidepressant-like activity in the novelty suppressed feeding in relation with the stimulation of hippocampal neurogenesis whereas it did not potentiate the effects of the SSRI fluoxetine on these parameters. Moreover, overexpressing BDNF revealed the anxiolytic-like activity of fluoxetine in the elevated plus maze while attenuating 5-HT neurotransmission in response to a blunted downregulation of the 5-HT1A autoreceptor. These results emphasize an original role of hippocampal astrocytes in the synthesis of BDNF, which can act through neurogenesis-dependent and independent mechanisms to regulate different facets of anxiolytic-like responses. PMID- 23632459 TI - Inspiration from old molecules: field-induced slow magnetic relaxation in three air-stable tetrahedral cobalt(II) compounds. AB - We have investigated the dynamics of the magnetization of three four-coordinate mononuclear cobalt(II) compounds, which are synthesized conveniently and are air stable. Slow magnetic relaxation effects were observed for the compounds in the presence of a dc magnetic field. PMID- 23632461 TI - [Liver transplantation]. PMID- 23632458 TI - A single gene defect causing claustrophobia. AB - Claustrophobia, the well-known fear of being trapped in narrow/closed spaces, is often considered a conditioned response to traumatic experience. Surprisingly, we found that mutations affecting a single gene, encoding a stress-regulated neuronal protein, can cause claustrophobia. Gpm6a-deficient mice develop normally and lack obvious behavioral abnormalities. However, when mildly stressed by single-housing, these mice develop a striking claustrophobia-like phenotype, which is not inducible in wild-type controls, even by severe stress. The human GPM6A gene is located on chromosome 4q32-q34, a region linked to panic disorder. Sequence analysis of 115 claustrophobic and non-claustrophobic subjects identified nine variants in the noncoding region of the gene that are more frequent in affected individuals (P=0.028). One variant in the 3'untranslated region was linked to claustrophobia in two small pedigrees. This mutant mRNA is functional but cannot be silenced by neuronal miR124 derived itself from a stress regulated transcript. We suggest that loosing dynamic regulation of neuronal GPM6A expression poses a genetic risk for claustrophobia. PMID- 23632460 TI - Synthesis, properties, and antitumor effects of a new mixed phosphine gold(I) compound in human colon cancer cells. AB - The antineoplastic potential of a new stable mixed phosphine gold(I) complex containing tris(tert-butyl)phosphine (tBu3P) and bis(diphenylphosphino)ethene (dppet), namely [Au(tBu3P)(dppet)Cl], has been investigated in the human colon cancer HCT-116 cell line. The (31)P NMR solution study, confirms the structural features observed in the solid state and, in addition, indicates partial formation of dinuclear cationic [Au(tBu3P)2](+) and [Au(dppet)2](+) species. The ionic character and strong Au-P bonds of this gold(I) species are similar to those of the most active antitumor gold compounds so far studied. The title compound was found to exhibit strong cytotoxicity, showing 85 fold greater toxicity than cisplatin (IC50=0.45MUM vs IC50=39.16 for cisplatin at 24h) on the HCT-116 line. The cytotoxic effects were, at least partly, mediated by the induction of apoptotic cell death as evidenced by the sub-G1 cell accumulation, oligonucleosomal DNA fragmentation, caspase-3 activation and the release of cytochrome c from the mitochondria. The gold(I) compound showed little interaction with DNA measured through fluorescence quenching studies with calf thymus DNA. The inhibitory effect of the gold(I) compound on intracellular redox proteins has been also observed in pretreated HCT-116 cells. The compound was particularly effective in inhibiting thioredoxin reductase, that is likely responsible for the increased ROS production, and subsequent apoptosis induction via the mitochondrial pathway. PMID- 23632462 TI - Dielectric phenomena associated with the keratin-glucose interactions of nail plate. AB - In this study, we analyzed the effect of water and frequency on the dielectric properties of the nail plate in healthy individuals and in diabetic patients. The temperature dependencies of the loss tangent for both healthy and diabetic nail represent the relation between the electrical energy lost and stored in keratin glucose-water complexes of this tissue. The differences between these materials concern the temperature ranges in which there appears the decomposition of loosely bound water. The effect of glycation on the loss tangent of the wet and the dry nail is supported by higher values of this parameter than in those describing the healthy samples in the whole temperature range and above 100 degrees C, respectively. In addition, glycation lead to distinct increase in the dielectric relaxation decrement in permittivity and dielectric loss between the frequency of 500 Hz and 100 kHz for the wet and the dry nail. The results of this study indicate that the dielectric spectroscopy may be useful in observing the decomposition of water in the diabetic nail plate. PMID- 23632463 TI - Charge carrier separation in nanostructured TiO2 photoelectrodes for water splitting. AB - There is intense interest in developing new novel nanostructured photoanodes for water splitting. It is therefore important that methods to analyze the effect of nanostructuring on water splitting yields are developed in order to rationalize the relative merits of this approach for different materials. In this study the dependence of charge separation efficiency (eta(sep)) on potential during photoelectrochemical water splitting at pH 2 has been quantified in a model electrode system (nanocrystalline, mesoporous TiO2) using two independent methods. These are (i) analysis of incident photon conversion efficiency (IPCE) measurements and (ii) transient absorption (TA) spectroscopy measurements. The techniques provide good agreement with each other and show that a low maximum value of eta(sep) (~0.18) is the primary cause of the low IPCE for water oxidation on these nc-TiO2 electrodes. PMID- 23632464 TI - Hierarchical hollow TiO2 spheres: facile synthesis and improved visible-light photocatalytic activity. AB - We demonstrate here a simple one-pot approach to directly fabricate hierarchical hollow anatase TiO2 spheres with a mesoporous shell architecture, which show improved visible light photocatalytic activity owing to their unique structure. PMID- 23632466 TI - Relationship between relapse and hospitalization in first-episode psychosis. AB - OBJECTIVE: Relapse is a frequently used outcome measure in schizophrenia research. However, difficulties in reliably measuring relapse diminish its usefulness. Hospitalization is a potential alternative, but its relationship to relapse has not been assessed. METHODS: This study used data from a two-year, prospective study to examine associations between relapse and hospitalization in a cohort of 200 Canadian patients with first-episode psychosis. First, the relationship between relapse and hospitalization was assessed by cross-tabulating relapse and hospitalization. Next, survival curves of time to first relapse or hospitalization were compared. Finally, to examine the convergent validity of relapse and hospitalization, the predictive capacity of three predictors were examined: a substance use disorder diagnosis, prior hospitalization, and medication adherence. RESULTS: Rates of both relapse and hospitalization were similar. During the two-year follow-up, 37% of the patients experienced a relapse, and 26% were hospitalized. As an indicator of relapse, hospitalization had a low sensitivity (47%) and high specificity (87%). A higher risk of hospitalization and relapse was associated with prior hospitalization, a substance use disorder diagnosis, and medication nonadherence. CONCLUSIONS: Results indicated that relapse and hospitalization are separate but related outcome measures. They had similar frequencies and were found to have similar relationships with some predictors. Relapse is a more useful outcome measure in smaller clinical studies in which routine standardized clinical measures can be used. Hospitalization is more relevant in larger studies or as a quality indicator for studies using administrative databases, and it serves as a good measure for quality management in health systems. PMID- 23632467 TI - The art of age-appropriate care: reflecting on a conceptual model of the cancer experience for teenagers and young adults. AB - BACKGROUND: There is recognition that teenagers and young adults with cancer merit age-appropriate specialist care. However, outcomes associated with such specialist care are not defined. Patient experience and patient-reported outcomes such as quality of life are gaining importance. Nevertheless, there is a lack of theoretical basis and patient involvement in experience surveys for young people. OBJECTIVE: We previously proposed a conceptual model of the lived experience of cancer. We aimed to refine this model adding to areas that were lacking or underreported. The proposed conceptual framework will inform a bespoke patient experience survey for young people. METHODS: Using participatory research, 11 young people aged 13 to 25 years at diagnosis, participated in a 1-day workshop consisting of semistructured peer-to-peer interviews. RESULTS: Eight core themes emerged: impact of cancer diagnosis, information provision, place of care, role of health professionals, coping, peers, psychological support, and life after cancer. CONCLUSIONS: The conceptual framework has informed survey development for a longitudinal cohort study examining patient experience and outcomes associated with specialist cancer care. IMPLICATIONS FOR PRACTICE: Young people must be kept at the center of interactions in recognition of their stated needs of engagement, of individually tailored information and support unproxied by parents/family. Age appropriate information and support services that help young people deal with the impact of cancer on daily life and life after cancer must be made available. If we are to develop services that meet need, patient experience surveys must be influenced by patient involvement. Young people can be successfully involved in planning research relevant to their experience. PMID- 23632469 TI - Adolescents' psychosocial health-related quality of life within 6 months after cancer treatment completion. AB - BACKGROUND: Health-related quality of life (HRQOL) may be affected by cure directed therapy given to pediatric oncology patients. Identification of HRQOL risk/protective factors may facilitate the development of clinical interventions. OBJECTIVE: The study purpose was to assess adolescents' psychosocial HRQOL soon after treatment completion using patient-reported outcome measures. METHODS: Subjects were recruited from May 2005 to February 2007 to participate in a structured interview that collected information on demographics, symptoms, HRQOL (PedsQL 4.0), and coping (Adolescent Coping Orientation for Problem Strategies Questionnaire). Disease/treatment information was abstracted from medical records. Data analysis included descriptive approaches for data summarization and regression modeling for estimation and testing. RESULTS: A total of 94 participants were included in the analyses. Their mean psychosocial functioning summary scores fell between the means reported for healthy children and children with cancer; 18% were more than 1 standard deviation below the mean. In the univariate analyses, lower psychosocial HRQOL was associated with central nervous system tumors (P = .01), radiation therapy (P = .01), and treatment duration of 13 to 24 months (P < .01). Protective factors identified in multivariable analyses included older age and use of humor for coping; risk factors included symptoms of pain, fatigue, and posttraumatic stress. CONCLUSION: Although most patients rated their psychosocial HRQOL as good, a subset (18%) may have increased risk for impaired HRQOL. IMPLICATIONS FOR PRACTICE: Clinical assessment of psychosocial HRQOL using patient-reported outcome measures during the early posttreatment phase is recommended. Longitudinal studies are needed to further explore risk/protective factors and to identify targeted interventions to minimize the adverse psychosocial effects of cancer treatment and maximize healthy survivorship. PMID- 23632468 TI - Correlates of colorectal cancer screening among South Asian immigrants in the United States. AB - BACKGROUND: South Asians are a rapidly increasing population in the United States. Little is known about influences on their cancer screening behaviors, an important prerequisite to designing culturally appropriate education. OBJECTIVE: The purpose of this study was to evaluate rates and correlates of colorectal cancer (CRC) screening, knowledge, and beliefs among South Asians. METHODS: A subsample of those 50 years or older (n = 275) was drawn from the South Asian Health Descriptor Study, an assessment of multiple health indicators conducted in Chicago, Illinois. RESULTS: Indians represented 87% of the sample; 2.2% of participants believed that they were at risk for CRC; 8% reported a past stool blood test (SBT); and 13.6% had had a sigmoidoscopy or colonoscopy. Language acculturation (adjusted odds ratio [AOR], 1.93; confidence interval [CI], 1.1 3.5) and medical mistrust (AOR, 0.243; CI, 0.091-0.650) were significantly related to SBT completion. Language acculturation (AOR, 3.30; CI, 1.8-5.5), income (AOR, 2.70; CI, 1.0-7.1), living in the United States for more than 5 years (AOR, 8.6; CI, 1.9-14.5), perception of CRC risk (AOR, 8.9; CI, 1.1-17.7), and past SBT (AOR, 5.0; CI, 1.8-14.0) were significantly related to endoscopic cancer screening. CONCLUSIONS: Facilitators and barriers to different CRC tests vary. Education to increase CRC screening may need to be targeted to culture and specific barriers to each screening test rather than generic messages for all screening tests. IMPLICATIONS FOR PRACTICE: Because barriers to CRC screening may differ among people based on the specific screening test being recommended. Primary care practitioners should recognize this fact and identify different barriers to enhance adherence to screening recommendations. PMID- 23632470 TI - Distress in patients with acute leukemia: a concept analysis. AB - BACKGROUND: Patients with acute leukemia (AL) require immediate and aggressive inpatient treatment that results in many weeks to months of hospitalization. Thus, it is not surprising that distress has been found in as many as 45.5% of patients. Although distress is a regularly reported outcome measure in clinical research, currently, there is a lack of a clear, consistent, and universal definition of this concept. OBJECTIVE: The purposes of this article were to examine the current state of the science surrounding the concept of distress and to propose a model of distress for patients with AL. INTERVENTIONS/METHODS: The Walker and Avant framework was used to guide the analysis of the concept of distress in patients with AL. The findings from this analysis were then used to generate a model guided by the current science. RESULTS: Distress in AL is generally accepted as multidimensional, quantifiable, subjective, and temporal. Antecedents to distress include demographics, intrinsic factors, social support, disease progression, treatment, and communication. Consequences to distress include decreased quality of life, patient outcomes, as well as the severity of physical and psychological symptoms. CONCLUSIONS: Distress is an outcome measure that is frequently assessed and reported within the literature. The operationalization of distress varies by investigator, limiting its generalizability. IMPLICATIONS FOR PRACTICE: The proposed conceptual model may be used to guide further research on distress in patients with AL at high risk for negative outcomes. Improved understanding of patient distress may guide interventions aimed at managing the psychosocial needs for patients receiving treatment for AL. PMID- 23632471 TI - The effects of patient participation-based dietary intervention on nutritional and functional status for patients with gastrectomy: a randomized controlled trial. AB - BACKGROUND: Patients undergoing gastrectomy because of stomach cancer often face weight loss in the perioperational period, which can lead to malnutrition and negative treatment outcomes. OBJECTIVE: The purpose of this study was to develop a patient participation-based dietary intervention (PPDI) and evaluate its effects on patient outcomes. INTERVENTIONS/METHODS: This was a prospective, randomized controlled trial in which the patients were recruited in a cancer center in South Korea. The participants (N = 56), who underwent gastrectomy with stomach cancer stage I to III, were randomly assigned into either the experimental or the control group. The PPDI, which was given on the day before the hospital discharge, comprised 2 face-to-face and 2 telephone interventions. The outcome variables included body weight, body mass index, muscle mass, the Patient-Generated Subjective Global Assessment, Dietary Symptom Scale, Functional Assessment Cancer Therapy-General, Karnofsky Performance Status, Adherence to Dietary Guidelines Scale, Scale of Dietary Knowledge, Patient Satisfaction Scale, and a 3-day food diary. RESULTS: Participants in the PPDI intervention demonstrated significant (P < .05) reductions in adverse dietary symptoms and significant improvements (P < .05) in functional status, performance status, dietary intake, adherence to dietary guidelines, dietary knowledge, and satisfaction with the intervention as compared with the control group over time. CONCLUSION: The PPDI was an effective dietary intervention for patients undergoing a gastrectomy for gastric cancer and deserves additional study in other populations of patients. IMPLICATIONS FOR PRACTICE: Incorporating patients' perspectives into a dietary intervention after gastrectomy for gastric cancer may contribute to improved patient outcomes and quality care. PMID- 23632473 TI - The impact of an external breast prosthesis on the gait parameters of women after mastectomy. AB - BACKGROUND: An integral part of the recovery process after mastectomy involves the consideration of restorative options, including external prosthesis use; however, only few studies regarding the influence of breast prostheses on functional status have been done. OBJECTIVE: This study aimed to determine whether wearing an external breast prosthesis affects gait in women after a mastectomy. METHODS: Spatiotemporal gait parameters were collected in 40 women, postmastectomy, aged 37 to 70 years, divided into age subgroups of 37 to 54 years and 55 to 70 years, and in 38 healthy controls, women aged 38 to 69 years. Gait parameters were assessed with and without the breast prosthesis, including walking velocity, cadence, step length, step time, and left-right step time asymmetry. RESULTS: Significant differences were found in the gait parameters of the younger age group with and without a prosthesis. No significant differences were found in the women of the older group with and without the prosthesis. CONCLUSION: Gait parameters of the younger age group were closer to those of the healthy control group when they were wearing an external prosthesis, as compared with when they were not. This suggests a positive influence of breast prosthesis use on the functional status of women after mastectomy. IMPLICATIONS FOR PRACTICE: Clinical practitioners should be aware of the study results suggesting a positive influence of breast prosthesis use on gait parameters after mastectomy surgery, which could improve the patient's functional status after surgery; however, further research is still needed on factors affecting changes in gait with a larger study population. PMID- 23632472 TI - Prevention and detection of prostate cancer: a pilot intervention in a resource- poor South African community. AB - BACKGROUND: Prostate cancer is a global health problem strongly linked to the Western lifestyle and its health risks. South Africa, like many African countries, has no population-based screening for this disease. OBJECTIVE: The purpose of this study was to develop and pilot test an intervention focused on the prevention and detection of prostate cancer in a resource-poor community in Tshwane, South Africa. INTERVENTION: Personal invitations for screening were extended to 122 men 40 years or older. Those presenting for screening received health education on prostate cancer and were screened using digital rectal examination and a prostate-specific antigen (PSA) test. Follow-up appointments were also arranged. RESULTS: Only 53.3% (n = 65) of the invitees reported for screening, with 38 (58.5%) returning to the clinic to learn the results of the PSA test. Knowledge of prostate cancer improved significantly after the intervention. Abnormal findings were detected in 6.2% (n = 4) of the participants, and elevations in PSA levels, in 12.3% (n = 8). CONCLUSIONS: Disappointing results in terms of screening uptake and the number of men lost to follow-up were achieved. The strategies to improve knowledge were successful and resulted in a significant increase in knowledge of prostate cancer. IMPLICATIONS FOR NURSING PRACTICE: The success of a cancer prevention and detection service is determined by participation and screening uptake. The reasons for not accepting the screening invitation and not returning to learn the findings of the PSA test should be explored. Preventative strategies should be developed and tested as part of a second pilot study testing the refined intervention. PMID- 23632475 TI - Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK. AB - BACKGROUND: We examined the potential of metformin (MET) to enhance non-small cell lung cancer (NSCLC) responses to ionising radiation (IR). METHODS: Human NSCLC cells, mouse embryonic fibroblasts from wild-type and AMP-activated kinase (AMPK) alpha1/2-subunit(-/-) embryos (AMPKalpha1/2(-/-)-MEFs) and NSCLC tumours grafted into Balb/c-nude mice were treated with IR and MET and subjected to proliferation, clonogenic, immunoblotting, cell cycle and apoptosis assays and immunohistochemistry (IHC). RESULTS: Metformin (2.5 MUM-5 mM) inhibited proliferation and radio-sensitised NSCLC cells. Metformin (i) activated the ataxia telengiectasia-mutated (ATM)-AMPK-p53/p21(cip1) and inhibited the Akt mammalian target of rapamycin (mTOR)-eIF4E-binding protein 1 (4EBP1) pathways, (ii) induced G1 cycle arrest and (iii) enhanced apoptosis. ATM inhibition blocked MET and IR activation of AMPK. Non-small cell lung cancer cells with inhibited AMPK and AMPKalpha1/2(-/-)-MEFs were resistant to the antiproliferative effects of MET and IR. Metformin or IR inhibited xenograft growth and combined treatment enhanced it further than each treatment alone. Ionising radiation and MET induced (i) sustained activation of ATM-AMPK-p53/p21(cip1) and inhibition of Akt-mTOR 4EBP1 pathways in tumours, (ii) reduced expression of angiogenesis and (iii) enhanced expression of apoptosis markers. CONCLUSION: Clinically achievable MET doses inhibit NSCLC cell and tumour growth and sensitise them to IR. Metformin and IR mediate their action through an ATM-AMPK-dependent pathway. Our results suggest that MET can be a clinically useful adjunct to radiotherapy in NSCLC. PMID- 23632474 TI - Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2 positive metastatic breast cancer. AB - INTRODUCTION: Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours. METHODS: This was a phase I/II, open label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer. RESULTS: Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m(-2) on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1-147.3 weeks). Common treatment-emergent adverse events (all grades/grade >=3) included diarrhoea (92%/29%; none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9 81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan-Meier median progression-free survival was 57.0 weeks (95% CI: 47.7-81.6 weeks). Pharmacokinetic analyses indicated no interaction between neratinib and paclitaxel. CONCLUSION: The combination of neratinib and paclitaxel was associated with higher toxicity than that of neratinib as a single agent, but was manageable with antidiarrhoeal agents and dose reductions in general. The combination therapy also demonstrated a high rate of response in patients with HER2-positive breast cancer. A phase III trial is ongoing to assess the benefit and risk of this combination in the first-line setting. PMID- 23632476 TI - Fluid intake, genetic variants of UDP-glucuronosyltransferases, and bladder cancer risk. AB - BACKGROUND: Results of studies of fluid consumption and its association with bladder cancer have been inconsistent. Few studies have considered modification effects from genetic variants that may interact with the type of consumed fluids. UDP-glucuronosyltransferases (UGTs), which are membrane-bound conjugating enzymes, catalyse the transformation of hydrophobic substrates to more water soluble glucuronides to facilitate renal or biliary excretion. Whether genetic variants in UGTs could modulate the association between fluid intake and bladder cancer has not been studied. METHODS: We conducted a case-control study with 1007 patients with histopathologically confirmed bladder cancer and 1299 healthy matched controls. Fluid intake and epidemiologic data were collected via in person interview. Multivariate unconditional logistic regression was used to estimate odds ratios (ORs) and the 95% confidence intervals (95% CI). RESULTS: After adjustment for potential confounders, high quantity of total fluid intake (> or =2789 vs. <1696 ml per day) conferred a 41% increased risk of bladder cancer (OR=1.41; 95% CI=1.10-1.81). Specific fluids such as regular soft drinks and decaffeinated coffee were also associated with increased risks, whereas tea, wine, and liquor were associated with decreased risks. Among 83 single-nucleotide polymorphisms in the UGT gene family, 18 were significantly associated with bladder cancer risk. The most significant one was rs7571337, with the variant genotype conferring a 29% reduction in risk (OR=0.71; 95% CI=0.56-0.90). CONCLUSIONS: Total and specific fluid intakes are associated with bladder cancer risk in the study population and that genetic variants of UGT genes could modulate the effects. These results facilitate identification of high-risk individuals and have important implications in bladder cancer prevention. PMID- 23632477 TI - Geographic analysis of RKIP expression and its clinical relevance in colorectal cancer. AB - BACKGROUND: This study evaluates the geographic expression pattern of Raf-1 Kinase Inhibitor Protein (RKIP) in colorectal cancer (CRC) in correlation with clinicopathological and molecular features, markers of epithelial-mesenchymal transition (EMT) and survival outcome. METHODS: Whole-tissue sections of 220 well characterised CRCs were immunostained for RKIP. NF-kappaB and E-Cadherin expression was assessed using a matched multi-punch tissue microarray. Analysis of mismatch repair (MMR) protein expression, B-Raf and KRAS mutations was performed. RKIP expression in normal mucosa, tumour centre, invasion front and tumour buds was each assessed for clinical relevance. RESULTS: RKIP was diffusely expressed in normal mucosa and progressively lost towards tumour centre and front (P<0.0001). Only 0.9% of tumour buds were RKIP-positive. In the tumour centre, RKIP deficiency predicted metastatic disease (P=0.0307), vascular invasion (P=0.0506), tumour budding (P=0.0112) and an invasive border configuration (P=0.0084). Loss of RKIP correlated with NF-kappaB activation (P=0.0002) and loss of E-Cadherin (P<0.0001). Absence of RKIP was more common in MMR-deficient cancers (P=0.0191), while no impact of KRAS and B-Raf mutation was observed. RKIP in the tumour centre was identified as a strong prognostic indicator (HR (95% CI): 2.13 (1.27-3.56); P=0.0042) independently of TNM classification and therapy (P=0.0474). CONCLUSION: The clinical relevance of RKIP expression as an independent prognostic factor is restricted to the tumour centre. Loss of RKIP predicts features of EMT and correlates with frequent distant metastasis. PMID- 23632478 TI - Paradoxical effect of lenalidomide on cytokine/growth factor profiles in multiple myeloma. AB - BACKGROUND: Lenalidomide is an active immunomodulatory and antiproliferative agent in multiple myeloma. However, the molecular mechanisms driving these activities are not yet fully elucidated. Therefore, we investigated the modulation of the cytokine/growth factor patterns of myeloma cells under LEN treatment. METHODS: Lenalidomide effect on myeloma cell proliferation was investigated in a myeloma cell line collection (n=23) by (3)H-thymidine incorporation. Modulation of the cytokine/growth factor patterns of myeloma cells under LEN treatment was analysed by real-time quantitative PCR. RESULTS: Lenalidomide inhibits the proliferation of two-thirds of myeloma cell lines independently of their genetic background. We demonstrated that LEN increased TNF alpha and IL-8 inflammatory cytokines and insulin-like growth factor-1 (IGF-1) growth factor in both sensitive and resistant myeloma cells to LEN. CONCLUSION: Lenalidomide favours a uniform TNF-alpha and IL-8 inflammatory and IGF-1 secretory profile of myeloma cells, an observation that raises important questions for therapeutic approaches incorporating the agent. PMID- 23632479 TI - Comment on 'Endocrine therapy in prostate cancer: time for re-appraisal of risks, benefits and cost-effectiveness?'. PMID- 23632481 TI - Reply: Endocrine therapy in prostate cancer: time for reappraisal of risks, benefits and cost-effectiveness? PMID- 23632480 TI - Melatonin-induced methylation of the ABCG2/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells. AB - BACKGROUND: Current evidence indicates that a stem cell-like sub-population within malignant glioblastomas, that overexpress members of the adenosine triphosphate-binding cassette (ABC) family transporters, is responsible for multidrug resistance and tumour relapse. Eradication of the brain tumour stem cell (BTSC) compartment is therefore essential to achieve a stable and long lasting remission. METHODS: Melatonin actions were analysed by viability cell assays, flow cytometry, quantitative PCR for mRNA expression, western blot for protein expression and quantitative and qualitative promoter methylation methods. RESULTS: Combinations of melatonin and chemotherapeutic drugs (including temozolomide, current treatment for malignant gliomas) have a synergistic toxic effect on BTSCs and A172 malignant glioma cells. This effect is correlated with a downregulation of the expression and function of the ABC transporter ABCG2/BCRP. Melatonin increased the methylation levels of the ABCG2/BCRP promoter and the effects on ABCG2/BCRP expression and function were prevented by preincubation with a DNA methyltransferase inhibitor. CONCLUSION: Our results point out a possible relationship between the downregulation of ABCG2/BCRP function and the synergistic toxic effect of melatonin and chemotherapeutic drugs. Melatonin could be a promising candidate to overcome multidrug resistance in the treatment of glioblastomas, and thus improve the efficiency of current therapies. PMID- 23632482 TI - 212Pb-radioimmunotherapy potentiates paclitaxel-induced cell killing efficacy by perturbing the mitotic spindle checkpoint. AB - BACKGROUND: Paclitaxel has recently been reported by this laboratory to potentiate the high-LET radiation therapeutic (212)Pb-TCMC-trastuzumab, which targets HER2. To elucidate mechanisms associated with this therapy, targeted alpha-particle radiation therapeutic (212)Pb-TCMC-trastuzumab together with paclitaxel was investigated for the treatment of disseminated peritoneal cancers. METHODS: Mice bearing human colon cancer LS-174T intraperitoneal xenografts were pre-treated with paclitaxel, followed by treatment with (212)Pb-TCMC-trastuzumab and compared with groups treated with paclitaxel alone, (212)Pb-TCMC-HuIgG, (212)Pb-TCMC-trastuzumab and (212)Pb-TCMC-HuIgG after paclitaxel pre-treatment. RESULTS: (212)Pb-TCMC-trastuzumab with paclitaxel given 24 h earlier induced increased mitotic catastrophe and apoptosis. The combined modality of paclitaxel and (212)Pb-TCMC-trastuzumab markedly reduced DNA content in the S-phase of the cell cycle with a concomitant increase observed in the G2/M-phase. This treatment regimen also diminished phosphorylation of histone H3, accompanied by an increase in multi-micronuclei, or mitotic catastrophe in nuclear profiles and positively stained gammaH2AX foci. The data suggests, possible effects on the mitotic spindle checkpoint by the paclitaxel and (212)Pb-TCMC-trastuzumab treatment. Consistent with this hypothesis, (212)Pb-TCMC-trastuzumab treatment in response to paclitaxel reduced expression and phosphorylation of BubR1, which is likely attributable to disruption of a functional Aurora B, leading to impairment of the mitotic spindle checkpoint. In addition, the reduction of BubR1 expression may be mediated by the association of a repressive transcription factor, E2F4, on the promoter region of BubR1 gene. CONCLUSION: These findings suggest that the sensitisation to therapy of (212)Pb-TCMC-trastuzumab by paclitaxel may be associated with perturbation of the mitotic spindle checkpoint, leading to increased mitotic catastrophe and cell death. PMID- 23632483 TI - Patient-reported genitourinary toxicity for long-term prostate cancer survivors treated with radiation therapy. AB - BACKGROUND: The objective of this study is to provide comprehensive overviews of patient-reported urinary symptoms for long-term prostate cancer survivors treated with radiation therapy and for untreated, healthy men. METHODS: We performed a population-based cross-sectional study using a study-specific postal questionnaire assessing symptoms among 1007 men consecutively treated at the Sahlgrenska University Hospital, Goteborg, Sweden from 1993-2006 (primary or salvage external beam radiation therapy (EBRT) or EBRT and high-dose rate brachytherapy). We also randomly recruited 350 non-pelvic-irradiated matched control men from the Swedish Total Population Register. Symptom prevalence and prevalence ratios were computed. RESULTS: Survey participation rate was 89% (874/985) for eligible survivors and 73% (243/332) for eligible controls. Median time from treatment to follow-up was 5 years (range, 1-14 years). Among the 21 investigated symptoms reflecting obstruction, frequency, urgency, pain and incontinence, we found significantly higher prevalence compared with controls for 9 symptoms in the EBRT group, 10 in the EBRT+brachytherapy group and 5 in the salvage EBRT group. The prevalence for a majority of the symptoms was stable over time. CONCLUSION: The presented toxicity profiles provide a thorough understanding of patient-reported urinary symptoms that can assist in developing personalised therapy for prostate cancer. PMID- 23632484 TI - Are the UK oncology trainees adequately informed about the needs of older people with cancer? AB - BACKGROUND: Outcomes for older people with cancer are poorer in the United Kingdom compared with that in other countries. Despite this, the UK oncology curricula do not have dedicated geriatric oncology learning objectives. This cross-sectional study of UK medical oncology trainees investigates the training, confidence level and attitudes towards treating older people with cancer. METHODS: A web-based survey link was sent to the delegates of a national medical oncology trainee meeting. Responses were collected in October 2011. RESULTS: The response rate was 93% (64 out of 69). The mean age of the respondents was 32.3 years (range 27-42 years) and 64.1% were female. A total of 66.1% of the respondents reported never receiving training on the particular needs of older people with cancer, 19.4% reported to have received this training only once. Only 27.1% of the trainees were confident in assessing risk to make treatment recommendations for older patients compared with 81.4% being confident to treat younger patients. Even fewer were confident with older patients with dementia (10.2%). CONCLUSION: This first study of the UK medical oncology trainees highlights the urgent need for change in curricula to address the complex needs of older people with cancer. PMID- 23632486 TI - Noncentral catadioptric camera calibration using a generalized unified model. AB - This Letter proposes a generalized unified model (GUM) for the calibration of noncentral catadioptric cameras. Releasing the constraint on the projection center and the orientation of the imaging plane that the traditional unified projection model has, the new model is able to well compensate the misalignment between the mirror and the camera. Being a compact and approximate central model, the GUM inherits the flexibility and simplicity from the unified model while maintaining accuracy even under severe misalignment. The calibration algorithm to compute the describing parameters of the model is also given. With the GUM, the calibration of central or noncentral systems could be treated with equal simplicity (or complexity). Experiments on both synthetic data and real images proved our success. PMID- 23632485 TI - Circulating microRNAs as potential new biomarkers for prostate cancer. AB - Since they were first described in the 1990s, circulating microRNAs (miRNAs) have provided an active and rapidly evolving area of current research that has the potential to transform cancer diagnostics and therapeutics. In particular, miRNAs could provide potential new biomarkers for prostate cancer, the most common cause of cancer in UK men. Current diagnostic tests for prostate cancer have low specificity and poor sensitivity. Further, although many prostate cancers are so slow growing as not to pose a major risk to health, there is currently no test to distinguish between these and cancers that will become aggressive and life threatening. Circulating miRNAs are highly stable and are both detectable and quantifiable in a range of accessible bio fluids, thus have the potential to be useful diagnostic, prognostic and predictive biomarkers. This review aims to summarise the current understanding of circulating miRNAs in prostate cancer patients and their potential role as biomarkers. PMID- 23632487 TI - Wavelength-multiplexing phase-sensitive surface plasmon imaging sensor. AB - A wavelength-multiplexing phase-sensitive surface plasmon resonance (SPR) imaging sensor offering wide dynamic detection range and microarray capability is reported. Phase detection is accomplished by performing self-interference between the s- and p- polarizations within the signal beam. A liquid crystal tunable filter is used to sequentially select the SPR excitation wavelength from a white light source. This wavelength-multiplexing approach enables fast detection of the sensor's SPR phase response over a wide range of wavelengths, thereby covering literally any regions of interest within the SPR dip and thus maintaining the highest sensitivity point at all times. The phase-sensitive approach is particularly important for imaging SPR sensing applications because of its less stringent requirements for intensity signal-to-noise ratio, which also means the possibility of using uncooled modest resolution analog-to-digital conversion imaging devices. Experimental results demonstrate a resolution of 2.7*10(-7) RIU with a dynamic range of 0.0138 RIU. PMID- 23632488 TI - Fast, optically controlled Kerr phase shifter for digital signal processing. AB - We demonstrate an optically controlled Kerr phase shifter using a room temperature 85Rb vapor operating in a Raman gain scheme. Phase shifts from zero to pi relative to an unshifted reference wave are observed, and gated operations are demonstrated. We further demonstrate the versatile digital manipulation of encoded signal light with an encoded phase-control light field using an unbalanced Mach-Zehnder interferometer. Generalizations of this scheme should be capable of full manipulation of a digitized signal field at high speed, opening the door to future applications. PMID- 23632489 TI - Influence of mounting on the hysteresis of polymer fiber Bragg grating strain sensors. AB - Fiber Bragg grating sensors recorded in poly(methyl methacrylate) fiber often exhibit hysteresis in the response of Bragg wavelength to strain, particularly when exposed to high levels of strain. We show that, when such a fiber grating sensor is bonded directly to a substrate, the hysteresis is reduced by more than 12 times, compared to the case where the sensor is suspended freely between two supports. PMID- 23632490 TI - Observation of electromagnetically induced transparency-like transmission in terahertz asymmetric waveguide-cavities systems. AB - Electromagnetically induced transparency (EIT)-like transmission was demonstrated in terahertz asymmetric parallel plate waveguides with two identical cavities. By shifting the position of the bottom cavity from the symmetric position in the propagation direction, both the phases of the propagating wave at resonances and the coupling strengths between two cavities are changed, resulting in exciting the additional asymmetric resonance and manipulating the detuning of two different resonant frequencies. The transparent peak between two resonances comes from the cancelation of symmetric and asymmetric resonances. We also use the physical picture of excitation of quasi-dark mode to explain this EIT-like transmission, which is similar to the metamaterial systems. PMID- 23632491 TI - Real-time prediction of structural and optical properties of hollow-core photonic bandgap fibers during fabrication. AB - We formulate a simple model based on mass conservation to accurately predict the structural parameters of hollow-core photonic bandgap fibers from knowledge of the second stage preforms from which they are drawn. We show that combining this model with precalculated property maps can allow real-time prediction of the optical properties of manufactured fibers. PMID- 23632492 TI - Ultrahigh birefringence index-guiding photonic crystal fiber and its application for pressure and temperature discrimination. AB - In this Letter, we reported on an ultrahigh birefringence photonic crystal fiber (PCF) with a germanium-doped elliptical core, which is fabricated in our lab using the stack-and-draw method. An ultrahigh birefringence of 1.1*10(-2) is obtained experimentally, which is close to the theoretical value of 1.4*10(-2) at the wavelength of 1550 nm. To our knowledge, this is the highest birefringence reported to date for fabricated index-guiding PCF. Fiber Bragg gratings (FBG) were written in the fiber to confirm its ultrahigh birefringence, and we demonstrated the capability to simultaneously measure the FBG's pressure and temperature experimentally. Because of the large separation of the two FBG peaks (>12 nm), such fiber is a promising candidate for a single polarization device. PMID- 23632494 TI - Multiview phase shifting: a full-resolution and high-speed 3D measurement framework for arbitrary shape dynamic objects. AB - This Letter presents a multiview phase shifting (MPS) framework for full resolution and high-speed reconstruction of arbitrary shape dynamic objects. Unlike conventional methods, this framework can directly find the corresponding points from the wrapped phase-maps. Therefore, only a minimum number of images are required for phase shifting to measure arbitrary shape objects, including discontinuous surfaces. Benefit from phase shifting MPS can achieve full spatial resolution and high, accurate 3D reconstruction. Benefit from multiview constraint MPS is also robust to discontinuities. Experimental results are presented to verify the performance of the proposed technique. PMID- 23632495 TI - Correction method for fisheye image based on the virtual small-field camera. AB - A distortion correction method for a fisheye image is proposed based on the virtual small-field (SF) camera. The correction experiment is carried out, and a comparison is made between the proposed method and the conventional global correction method. From the experimental results, the corrected image by this method satisfies the law of perspective projection, and the image looks as if it was captured by an SF camera with the optical axis pointing at the corrected center. This method eliminates the phenomena of center compression, edge stretch, and field loss, and the image character is more obvious, which benefits the afterward target detection and information extraction. PMID- 23632496 TI - Scintillation of nonuniformly correlated beams in atmospheric turbulence. AB - We investigated the scintillation properties of nonuniformly correlated (NUC) beams in atmospheric turbulence and have shown that NUC beams can not only have lower scintillation but also higher intensity than Gaussian-Schell model beams and even higher intensity than coherent Gaussian beams over certain propagation distances. PMID- 23632497 TI - Reflective colored image based on metal-dielectric-metal-coated gratings. AB - Subwavelength gratings coated with metal-dielectric-metal layers and embedded in a dielectric exhibit distinctive color properties in reflectance. The reflected color of incident unpolarized white light can be tuned by the modulation depth of the grating. It is shown that reflective colored images may be reproduced by this type of gratings having a laterally adapted modulation depth. Its lightness, as well as the angle tolerance of the image coloring, is even suitable for human observers in ambient light. The gratings with variable depth are manufactured by electron-beam lithography and by a subsequent direct laser writing process. These types of reflective images may be replicated by a simple nano-imprint process on plastic foil. This method is predestined for industrial mass production. PMID- 23632498 TI - Deep tissue flowmetry based on diffuse speckle contrast analysis. AB - Diffuse correlation spectroscopy (DCS) is an emerging modality for noninvasive deep tissue blood flow monitoring that is becoming increasingly popular; it conducts an autocorrelation analysis of fast fluctuating photon count signals from a single speckle. In this Letter, we show that the same level of deep tissue flow information can be obtained from a much simpler analysis on the spatial distribution of the speckles that is obtained by a CCD camera, which we named diffuse speckle contrast analysis (DSCA). Both the flow phantom experiment and in vivo cuff occlusion data are presented. DSCA can be considered a new optical modality that combines DCS and laser speckle contrast imaging (LSCI), which exploits simple instrumentation and analysis and yet is sensitive to deep tissue flow. PMID- 23632499 TI - Real-time handheld multispectral optoacoustic imaging. AB - Multispectral optoacoustic tomography (MSOT) of functional and molecular contrast has the potential to find broad deployment in clinical practice. We have developed the first handheld MSOT imaging device with fast wavelength tuning achieving a frame rate of 50 Hz. In this Letter, we demonstrate its clinical potential by dynamically resolving multiple disease-relevant tissue chromophores, including oxy-/deoxyhemoglobin, and melanin, in human volunteers. PMID- 23632500 TI - Negative refraction of a partially coherent electromagnetic beam. AB - A theory of usual (positive) refraction of partially coherent electromagnetic beams has been developed recently. In this Letter, we discuss the theory of negative refraction of a partially coherent electromagnetic beam. We show that negative refraction can produce change in spatial coherence of such a beam. PMID- 23632501 TI - Physically admissible parameterization for differential Mueller matrix of uniform media. AB - In this Letter, we address the question of physical validity of differential Mueller matrix. A parameterization of entries of this differential matrix is proposed. It ensures that the generators associated with depolarization terms lead to physical Mueller matrices as for the nondepolarizing terms. A general expression for the depolarizing part of the differential matrix is found and a way to compute the nonlinear relations between the parameters is proposed. PMID- 23632503 TI - Experimental demonstration of ultracompact air hole photonic crystal ring resonator fabricated on silicon-on-insulator wafer. AB - A photonic crystal ring resonator (PCRR) of air hole arrays is fabricated on a silicon-on-insulator wafer by using electron-beam lithography and inductively coupled plasma etching. The designed PCRR is modeled and its performance is simulated by the two-dimensional finite difference time domain method. The simulation results show that the PCRR has two resonant wavelengths, 1598 and 1606 nm, and their corresponding quality factors are 3994 and 4015, respectively. A sample of the PCRR structure is fabricated and tested by the established experimental setup. Compared with the simulation results, the experimental resonant wavelengths drift to some extent and the quality factors are reduced by about one order of magnitude. The fabrication error and irregularity are the main reasons for the above results, which can be further reduced by improving the process technology. In addition, one more resonant wavelength emerged for the PCRR sample, which can be attributed to the change of the coupling strength. PMID- 23632502 TI - Quantum-enhanced micromechanical displacement sensitivity. AB - We report on a hitherto unexplored application of squeezed light: for quantum enhancement of mechanical transduction sensitivity in microcavity optomechanics. Using a toroidal silica microcavity, we experimentally demonstrate measurement of the transduced phase modulation signal in the frequency range 4-5.8 MHz with a sensitivity -0.72(+/-0.01) dB below the shot noise level. This is achieved for resonant probing in the highly undercoupled regime, by preparing the probe in a weak coherent state with phase squeezed vacuum states at sideband frequencies. PMID- 23632504 TI - Experimental demonstration of superluminal space-to-time mapping in long period gratings. AB - We experimentally demonstrate a superluminal space-to-time mapping process in grating-assisted (GA) codirectional coupling devices, particularly fiber long period gratings (LPGs). Through this process, the grating complex (amplitude and phase) apodization profile is directly mapped into the device's temporal impulse response. In contrast to GA counterdirectional couplers, e.g., Bragg gratings, this mapping occurs with a space-to-time scaling factor that is much higher than the propagation speed of light in vacuum. This phenomenon has been used for synthesizing customized complex optical pulse data sequences with femtosecond features (3.5 Tbit/s data rate) using readily feasible fiber LPG designs, e.g., with subcentimeter resolutions. PMID- 23632505 TI - Silicon mode (de)multiplexer enabling high capacity photonic networks-on-chip with a single-wavelength-carrier light. AB - A small silicon mode (de)multiplexer with cascaded asymmetrical directional couplers is demonstrated experimentally. As an example, a four channel mode (de)multiplexer is designed and realized for TM polarization. The fabricated mode (de)multiplexer has a low excess loss (<1 dB) as well as low crosstalk (<=23 dB) over a broad wavelength range (~20 nm). More channels can be achieved with two sets of orthogonal-polarization modes (e.g., 2N=8) multiplexed when desired. PMID- 23632507 TI - Pd-based integrated optical hydrogen sensor on a silicon-on-insulator platform. AB - We have experimentally demonstrated a compact, integrated optical hydrogen sensor on a silicon-on-insulator platform. The sensor consists of silicon waveguide coated with a thin palladium film. The sensitivity and response time of the sensor was tested for volumetric hydrogen concentrations ranging from 0% to 4%. The proposed hydrogen sensor shows great potential as a building block for an optical nose capable of simultaneous detection of multiple gases as well as environmental effects such as temperature and humidity. PMID- 23632506 TI - Optical image encryption via ptychography. AB - Ptychography is combined with optical image encryption for the first time. Due to the nature of ptychography, not only is the interferometric optical setup that is usually adopted not required any more, but also the encryption for a complex valued image is achievable. Considering that the probes overlapping with each other is the crucial factor in ptychography, their complex-amplitude functions can serve as a kind of secret keys that lead to the enlarged key space and the enhanced system security. Further, since only introducing the probes into the input of common system is required, it is convenient to combine ptychography with many existing optical image encryption systems for varied security applications. PMID- 23632508 TI - Resonant cavity enhanced light harvesting in flexible thin-film organic solar cells. AB - Dielectric/metal/dielectric (DMD) electrodes have the potential to significantly increase the absorption efficiency and photocurrent in flexible organic solar cells. We demonstrate that this enhancement is attributed to a broadband cavity resonance. Silver-based semitransparent DMD electrodes with sheet resistances below 10 ohm/sq. are fabricated on flexible polyethylene terephthalate (PET) substrates in a high-throughput roll-to-roll sputtering tool. We carefully study the effect of the semitransparent DMD electrode (here composed of Zn(x)Sn(y)O(z)/Ag/In(x)Sn(y)O(z)) on the optical device performance of a copper phthalocyanine (CuPc)/fullerene (C60) bilayer cell and illustrate that a resonant cavity enhanced light trapping effect dominates the optical behavior of the device. PMID- 23632509 TI - Microchip solid-state cylindrical vector lasers with orthogonally polarized dual laser-diode end pumping. AB - We report a simple method for generating cylindrical vector beams directly from laser-diode (LD)-pumped microchip solid-state lasers by using dual end-pumping beams. Radially as well as azimuthally polarized vector field emissions have been generated from the common c-cut Nd:GdVO4 laser cavity merely by controlling the focus positions of orthogonally polarized LD off-axis pump beams. Hyperbolically polarized vector fields have also been observed, in which the cylindrical symmetry of vector fields is broken. Experimental results have been well reproduced by numerical simulations. PMID- 23632510 TI - A closed-form approximate expression for the optical conductivity of graphene. AB - A closed-form approximate expression for the optical conductivity of graphene is developed, which generates results with less than 0.8% maximum absolute error for lambda>250 nm. The expression takes wavelength, temperature, chemical potential, and hopping parameter into account and provides a fast, easy, and reliable alternative to well-known methods that include singular integrals. Numerical results confirm that the effective complex electrical permittivity derived from the optical conductivity successfully represents this one atom thick material in three-dimensional electromagnetic simulations and analyses. PMID- 23632511 TI - Fluorescence lifetime detection in turbid media using spatial frequency domain filtering of time domain measurements. AB - It is demonstrated that high spatial frequency filtering of time domain fluorescence signals can allow efficient detection of intrinsic fluorescence lifetimes from turbid media and the rejection of diffuse excitation leakage. The basis of this approach is the separation of diffuse fluorescence signals into diffuse and fluorescent components with distinct spatiotemporal behavior. PMID- 23632512 TI - Manipulation of Airy surface plasmon beams. AB - We demonstrate experimentally the manipulation of Airy surface plasmon beams in a linear potential. For this purpose, we fabricate dielectric-loaded plasmonic structures with a graded refractive index by negative-tone gray-scale electron beam lithography. Using such carefully engineered potentials, we show that the bending of an Airy surface plasmon beam can be fully reversed by the potential. PMID- 23632513 TI - Camera calibration with active phase target: improvement on feature detection and optimization. AB - The calibration of camera with intrinsic and extrinsic parameters is a procedure of significance in current imaging-based optical metrology. Improvement at two aspects, feature detection and overall optimization, are investigated here by using an active phase target and statistically constrained bundle adjustment (SCBA). From the observations in experiment and simulation, the feature detection can be enhanced by "virtual defocusing" and windowed polynomial fitting if sinusoidal fringe patterns are used as the active phase target. SCBA can be applied to avoid the difficult measurement of the active target. As a typical calibration result in our experiment, the root mean square of reprojection error can be reduced to 0.0067 pixels with the proposed method. PMID- 23632514 TI - Reflection measurements to reveal the absorption in nanowire arrays. AB - The absorption of light is at the core of photovoltaic applications. For many nanostructure-based devices, an assessment of the absorption in the nanostructures is complicated by a thick, opaque substrate that prohibits transmission measurements. Here, we show how a single reflection measurement can be used for approximating the amount of light absorbed in vertical semiconductor nanowire arrays. PMID- 23632515 TI - Through nanohole formation in thin metallic film by single nanosecond laser pulses using optical dielectric apertureless probe. AB - Separate nanoholes with the minimum size down to 35 nm (~lambda/15) and nanohole arrays with the hole size about 100 nm (~lambda/5) were fabricated in a 50 nm optically "thick" Au/Pd film, using single 532 nm pump nanosecond laser pulses focused to diffraction-limited spots by a specially designed apertureless dielectric fiber probe. Nanohole fabrication in the metallic film was found to result from lateral heat diffusion and center-symmetrical lateral expulsion of the melt by its vapor recoil pressure. The optimized apertureless dielectric microprobe was demonstrated to enable laser fabrication of deep through nanoholes. PMID- 23632516 TI - Multiple rings formation in cascaded conical refraction. AB - When a light beam passes through a cascade of biaxial crystals (BCs) with aligned optic axes, the resulting transverse intensity pattern consists of multiple concentric rings. We provide a simple formulation for the pattern formation for both circularly and linearly polarized input beams, that could be applied for a cascade of an arbitrary number of BCs. We have experimentally investigated multiple ring formation with up to three cascade BCs, showing that the theoretical formulation is in full agreement with the experimental results. PMID- 23632517 TI - Low-threshold whispering-gallery-mode microlasers fabricated in a Nd:glass substrate by three-dimensional femtosecond laser micromachining. AB - We report on fabrication of whispering-gallery-mode microlasers in a Nd:glass chip by femtosecond laser three-dimensional micromachining. The main fabrication procedures include the fabrication of freestanding microdisks supported by thin pillars by femtosecond laser ablation of the glass substrate immersed in water, followed by CO2 laser annealing for surface smoothing. The quality (Q) factor of the fabricated microcavity is measured to be 1.065*10(6). Lasing is observed at a pump threshold as low as ~69 MUW at room temperature with a continuous-wave laser diode operating at 780 nm. This technique allows for fabrication of microcavities of high Q factors in various dielectric materials, such as glasses and crystals. PMID- 23632518 TI - Single-step absorption and phase retrieval with polychromatic x rays using a spectral detector. AB - In this Letter, we present a single-step method to simultaneously retrieve x-ray absorption and phase images valid for a broad range of imaging energies and material properties. Our method relies on the availability of spectrally resolved intensity measurements, which is now possible using semiconductor x-ray photon counting detectors. The retrieval method is derived and presented, with results showing good agreement. PMID- 23632519 TI - Evaluation of the shadow effect in terahertz kinoform gratings. AB - The experimental and numerical evaluation of the shadow effect in kinoform diffractive gratings for the terahertz (THz) range is given. This effect limits the diffractive efficiency of dense gratings, which are the base of the elements suited for convenient beam focusing and imaging in THz. The observed effect of redirecting most of the incident energy into stray -1st diffractive order is observed and discussed. The presented results show the great significance of the shadow effect in selected kinoform gratings and prove the utility of the used methodology of numerical simulations. PMID- 23632520 TI - Brillouin scattering signal in polymer optical fiber enhanced by exploiting pulsed pump with multimode-fiber-assisted coupling technique. AB - A cost-effective technique for coupling a polymer optical fiber (POF) with 50 MUm core diameter to a silica single-mode fiber (SMF) with 8 MUm core diameter is proposed, which can, by exploiting a multimode fiber with 50 MUm core diameter, avoid the damage or burning at the butt-coupled POF/SMF interface. Using this coupling technique, we also show that the Brillouin signal in a POF can be enhanced by combined use of pulsed pump and an erbium-doped fiber amplifier. When the pulsed pump with average optical power of 18 dBm (63 mW), duty ratio of 15%, and pulse period of 2 MUs is launched into a 200 m-long POF, 4 dB enhancement of the Stokes power is obtained compared to that with 18 dBm continuous wave pump. The relatively small enhancement is probably caused by the high Brillouin threshold of POFs. The Stokes power dependence on duty ratio is nonmonotonic, which might originate from a longer phonon lifetime in POFs than that in silica SMFs. PMID- 23632521 TI - Demonstration of high-Q mid-infrared chalcogenide glass-on-silicon resonators. AB - We demonstrated high-index-contrast, waveguide-coupled As2Se3 chalcogenide glass resonators monolithically integrated on silicon fabricated using optical lithography and a lift-off process. The resonators exhibited a high intrinsic quality factor of 2*10(5) at 5.2 MUm wavelength, which is among the highest values reported in on-chip mid-infrared (mid-IR) photonic devices. The resonator can serve as a key building block for mid-IR planar photonic circuits. PMID- 23632522 TI - Photonic XOR with inherent loss compensation mechanism for memory cell implementation in a standard nanoscale very large-scale integrated fabrication process. AB - A multilayer photonic XOR gate is presented. The XOR is implemented by the interconnect layers of a microelectronic chip and is suitable for fabrication in a standard VLSI fabrication process. The proposed device features an inherent insertion loss compensation mechanism by utilization of nanometric holes, making it possible to implement an optic memory cell without the need of additional complex compensation devices. The structure of such a memory cell, implemented by utilization of two proposed XOR gates, configured to perform the NOT function, is shown. The unique structure of the proposed device allows us to significantly reduce sensitivity to process variations and therefore makes it possible to utilize the memory cell in state-of-the-art nanoscale processes. The proposed memory can be integrated with conventional electronics on the same VLSI chip. PMID- 23632523 TI - Collecting optical coherence elastography depth profiles with a micromachined cantilever probe. AB - We present an experimental setup that combines optical coherence elastography depth sensing with atomic force microscope indentation. The instrument relies on a miniaturized cantilever probe that compresses a sample with a small footprint force and simultaneously collects an optical coherence tomography (OCT) depth profile underneath the indenting point. The deflection of the cantilever can be monitored via optical fiber interferometry with a resolution of 2 nm. The OCT readout then provides depth profiles of the subsurface layer deformation with 15 nm resolution and depth range of a few millimeters. PMID- 23632525 TI - Optical double-sideband modulation to single-sideband modulation conversion using period-one nonlinear dynamics of semiconductor lasers for radio-over-fiber links. AB - To distribute microwaves over fibers, optical single-sideband (SSB) modulation signals are preferred to optical double-sideband (DSB) modulation signals. This study investigates an optically injected semiconductor laser at period-one nonlinear dynamics for optical DSB-to-SSB conversion. For the operating microwave frequencies up to 40 GHz investigated in this study, the proposed system regenerates or even enhances the microwave features of an optical DSB input while converting its optical feature into SSB with an intensity difference of at least 20 dB. The bit-error ratio at 622 Mb/s is down to 10(-9) with a sensitivity improvement of up to 3 dB. The proposed system can be self-adapted to certain changes in the operating microwave frequency and can operate stably under certain fluctuations in the input optical power and frequency. PMID- 23632524 TI - Stimulated Raman scattering imaging by continuous-wave laser excitation. AB - We demonstrate a low-cost-stimulated Raman scattering (SRS) microscope using continuous-wave (cw) lasers as excitation sources. A dual modulation scheme is used to remove the electronic background. The cw-SRS imaging of lipids in fatty liver is demonstrated by excitation of C?H stretch vibration. PMID- 23632526 TI - Backscattering reciprocity for large particles. AB - The backscattering reciprocity theorem is considered for large particles as compared with the incident wavelength particles of arbitrary shape. It is shown that, in the specific case of faceted particles, this theorem is provided by the appearance of pairs of conjugate backscattered beams. A parameter characterizing a deviation of any approximation from the reciprocity theorem is proposed, and it is used for estimation of reliability for the physical-optics approximation. PMID- 23632527 TI - Hybrid Bloch-Anderson localization of light. AB - We investigate the interplay of Bloch oscillations and Anderson localization in optics. Gradual washing out of Bloch oscillations and the formation of nearly stationary averaged intensity distributions, which are symmetric for narrow and strongly asymmetric for broad input excitations, are observed experimentally in laser-written waveguide arrays. At large disorder levels Bloch oscillations are completely destroyed and both narrow and wide excitations lead to symmetric stationary averaged intensity distributions with exponentially decaying tails. PMID- 23632528 TI - Air-ring microstructure arrays for enhanced light extraction from a face-up light emitting diode. AB - In this Letter, a light-emitting diode (LED) with prism-shaped-air-ring microstructures (PSAMs) formed on flat sapphire substrate is demonstrated as an alternative design to face-up LEDs on patterned sapphire substrate (PSS) for enhanced light extraction efficiency. In this LED design, the emitted photons can be deflected to the top of the chip for its effective extraction, contrary to the PSS-LED wherein photons are guided to sapphire and get absorbed by packaging materials. The PSAM-LED showed an enhancement in the radiometric power as high as 10% with a low far-field angle of 129 degrees over that of a PSS-LED under an injection current of 20 mA. PMID- 23632529 TI - In-line, fiber-optic polarimetric twist/torsion sensor. AB - This letter presents an optical fiber twist/torsion sensor that utilizes dissimilar polarization-preserving characteristics of standard single-mode and high-birefringence fibers. When only one polarization mode of the high birefringence fiber is excited, spatial orientation of the E-field vector follows the fiber's principal axis orientation, even when the fiber is twisted around its longitudinal axis. This is contrary to a standard single-mode fiber (SMF), where the E-field vector maintains its spatial orientation regardless of the fiber torsional twist. The proposed sensor consists of a short section of standard SMF inserted in between two lead-in polarization-mainlining fibers. Only one mode of the lead-in fiber is excited at the input, while the ratio of both polarization modes is measured at the output side of the fiber assembly in order to determine the torsional twist of a standard SMF. This sensor can be used for measuring unambiguously twist/torsion angles of between +/-95 degrees . The sensor demonstrated very low temperature dependence. PMID- 23632530 TI - Differential matrix physically admissible for depolarizing media: the case of diagonal matrices. AB - In this Letter, we address the question of the physical validity of a depolarizing differential matrix. A parameterization of the diagonal terms of these depolarizing differential matrices is proposed. It ensures that the generators associated with diagonal depolarization terms lead to physical Mueller matrices. The validity of this parameterization is discussed. A condition is derived and related to the spatial extension of inhomogeneities with respect to the optical path length as proposed by Ossikovski [Opt. Lett. 36, 2330 (2011)]. PMID- 23632531 TI - Unidirectional fiber optic sensor for angular acceleration measurement. AB - A concept of a fiber optic sensor consisting of a light source, a fiber coil, and a two-beam interferometer measuring angular acceleration is described. The principle differs essentially from common fiber optic gyroscopes (FOGs) still exploiting the Sagnac effect but sending light of the monochromatic source only unidirectionally into the fiber coil. A change in the optical path length in the fiber coil due to the Sagnac effect maintains proportionality to angular acceleration and could be detected by means of a subsequent two-beam interferometer. The sensitivity of this approach is in contrast to common FOGs determined not only by the total surface area enclosed by the fiber turns but also by the characteristics of the particular interferometer used. PMID- 23632532 TI - Differential photoacoustic microscopy technique. AB - Photoacoustic microscopy (PAM), whose image quality largely depends on the optical absorption of samples, provides endogenous information for structural and functional imaging. However, PAM technology in general can not provide edge enhancement imaging for absorbing objects. Therefore, PAM and differential microscopy are integrated for the first time in a single technique to obtain an edge enhancement image. The resolution test target RTA-07 and red blood cells are used as samples to achieve the desired spatial differential photoacoustic imaging. The feasible biomedical application of edge enhancement from the improved differential PAM was demonstrated. PMID- 23632533 TI - Phase shift extraction algorithm based on Euclidean matrix norm. AB - In this Letter, the character of Euclidean matrix norm (EMN) of the intensity difference between phase-shifting interferograms, which changes in sinusoidal form with the phase shifts, is presented. Based on this character, an EMN phase shift extraction algorithm is proposed. Both the simulation calculation and experimental research show that the phase shifts with high precision can be determined with the proposed EMN algorithm easily. Importantly, the proposed EMN algorithm will supply a powerful tool for the rapid calibration of the phase shifts. PMID- 23632534 TI - Soft x-ray low-pass filter with a square-pore microchannel plate. AB - A type of low-pass filter devices for soft x rays is investigated by using a microchannel plate (MCP) of small channels with square cross section. The measured transmission spectra on the Beijing Synchrotron Radiation Facility showed that the MCP has excellent bandpass effects below 1.5 keV by grazing incidence and internal multireflections. Combined with filters, the MCP energy bandwidth can be narrowed to 100 eV. In contrast to bandpass made of planar mirrors, the MCP has a much smaller size and better bandpass effects, and can be easily extended to high energy ranges. For low-resolution spectrometer applications of soft x rays, this method allows the monochromator to be replaced by a simple MCP filter and therefore significantly reduces alignment complexity in experiments. PMID- 23632535 TI - Noninvasive imaging of pulsatile movements of the optic nerve head in normal human subjects using phase-sensitive spectral domain optical coherence tomography. AB - We report use of high-speed spectral domain optical coherence tomography to noninvasively image pulsatile axial movement of the optic nerve head (ONH) in normal human subjects. Time-lapse B-scan mode is used to image the ONH at 500 frames per second. Capture of phase differences between adjacent B-scans permits extraction of axial ONH movement. We find the ONH experiences continuous oscillatory axial motion that is strongly correlated with simultaneously measured pulsatile blood flow in the central retinal artery. PMID- 23632536 TI - Flexible endoscope for continuous in vivo multispectral fluorescence lifetime imaging. AB - Fluorescence lifetime imaging (FLIM) offers a noninvasive approach for characterizing the biochemical composition of biological tissue. There has been an increasing interest in the application of multispectral FLIM for medical diagnosis. Central to the clinical translation of FLIM technology is the development of compact and high-speed endoscopy systems. Unfortunately, the predominant multispectral FLIM approaches suffer from limitations that impede the development of endoscopy systems that are suitable for in vivo tissue imaging. We present a compact wide-field time-gated FLIM flexible endoscope capable of continuous lifetime imaging of up to three fluorescence emission bands simultaneously. This endoscope design will facilitate the evaluation of FLIM for in vivo applications. PMID- 23632537 TI - Self-trapping threshold in disordered nonlinear photonic lattices. AB - We investigate numerically and experimentally the influence of coupling disorder on the self-trapping dynamics in nonlinear one-dimensional optical waveguide arrays. The existence of a lower and upper bound of the effective average propagation constant allows for a generalized definition of the threshold power for the onset of soliton localization. When compared to perfectly ordered systems, this threshold is found to decrease in the presence of coupling disorder. PMID- 23632538 TI - Single-molecule orientation measurements with a quadrated pupil. AB - This Letter presents a means of measuring the dipole orientation of a fluorescent, orientationally fixed single molecule, which uses a specially designed phase mask, termed a "quadrated pupil," conjugate to the back focal plane of a conventional wide-field microscope. The method leverages the spatial anisotropy of the far-field emission pattern of a dipole emitter and makes this anisotropy amenable to quantitative analysis at the image plane. In comparison to older image-fitting techniques that infer orientation by matching simulations to defocused or excessively magnified images, the quadrated pupil approach is more robust to minor modeling discrepancies and optical aberrations. Precision of 1 degrees -5 degrees is achieved in proof-of-concept experiments for both azimuthal (phi) and polar (theta) angles without defocusing. Since the phase mask is implemented on a liquid-crystal spatial light modulator that may be deactivated without any mechanical perturbation of the sample or imaging system, the technique may be readily integrated into clear aperture imaging studies. PMID- 23632540 TI - Directional single-mode emission from coupled whispering gallery resonators realized by using ZnS microbelts. AB - Ring microcavities were formed by wrapping ZnS microbelts, which act as the waveguide and gain region of the microcavities on the surface of optical fibers. The ring microcavities with the formation of whispering gallery modes have lasing threshold lower (Q-factor higher) than that of the ZnS microbelts. The excitation of TM modes could also be suppressed by the ring geometries of ZnS microbelts. Furthermore, directional single-mode lasing was realized from a coupled asymmetric ring microcavity. The Vernier coupling effect and deformed geometry of the asymmetric ring microcavity were contributed to the stable single-mode operation and directional emission, respectively. PMID- 23632539 TI - Use of hyperspectral imaging for label-free decoding and detection of biomarkers. AB - Detecting the existence of biomarkers is one of the most important issues in molecular diagnosis. This Letter presents a label-free decoding and detection method for biomarker tests based on hyperspectral imaging and interferometry. The decoding and detection results were extracted from a single hyperspectral image with different spectrum-to-thickness reconstructing algorithms, which made the testing procedure extremely fast and simple. The coding capacity of this method is more than 400, and the detection sensitivity can reach 2 ng/mm2 without fluorescent labeling. PMID- 23632541 TI - Multiphoton near-infrared quantum cutting luminescence of Yb3+ ion cooperative energy transferred from the oxyfluoride vitroceramics phosphor matrix. AB - In this Letter, we reported on an interesting multiphoton infrared quantum cutting phenomenon in Yb(3+)Tb3(+)-doped oxyfluoride vitroceramics phosphors. From the study results it is found that the absorption of one 288.0 nm photon of the matrix results in the emission of two 975.5 nm photons of the Yb3+ ion. In addition, it is found also that one 255.0 nm photon of the matrix may result in the emission of three 975.5 nm photons of the Yb3+ ion, due to the fact that their cooperative energy transfer rate is larger than multiphonon nonradiative relaxation rate. PMID- 23632542 TI - Twisted hi-bi fiber distributed-feedback lasers with controllable output state of polarization. AB - We demonstrate that single polarization, hi-bi fiber DFB lasers are, in general, characterized by elliptical state of polarization (SOP), due to the in-built fiber birefringence axis rotation. Externally applied birefringence axis twist is shown to provide accurate control of the output SOP. Continuous tuning from circular to linear polarization, with polarization extinction ratio of ~40 dB, has been demonstrated. PMID- 23632543 TI - Removing left-right asymmetry in a Sagnac interferometer applied to cancel its reflectance dependence on birefringence. AB - We present a left-right symmetry restoring method, which removes the detrimental birefringence in the single-mode fiber Sagnac interferometer, achieved with the aid of a half waveplate oriented at a specific angle. We show theoretically and demonstrate experimentally that adding a pi-shift between clockwise and counterclockwise propagating, horizontally (in fiber loop plane) polarized field components, the Sagnac loop mirror's reflection becomes independent on birefringence of an element placed in the loop. PMID- 23632544 TI - All-fiber magnetic field sensors based on magnetic fluid-filled photonic crystal fibers. AB - A method for measurement of a magnetic field by combining photonic crystal fibers (PCFs) and magnetic fluid is presented and experimentally demonstrated. The magnetic fluid is filled into the air holes of the cladding layer in the PCF. Due to the tunable refractive index property of the magnetic fluid, the refractive index difference between the fiber core and cladding layer is changed with the external magnetic field. The magnetic field can be directly detected by measuring the intensity of the transmission light. A series of magnetic fields with different strengths have been measured with the sensor. The experimental results show that a resolution of up to 0.09 Oe is achieved, and a good repetition is demonstrated experimentally. Compared with other expensive methods, the proposed method possesses high sensitivity and low cost. PMID- 23632545 TI - Internal modulation of a random fiber laser. AB - A characterization of a modulated random mirror laser has been experimentally carried out. Unlike conventional internally modulated fiber lasers, no distortion of the modulating frequency or self-mode-locking effects were measured. The behavior of the laser using pulsed and analog modulation up to 12 GHz is shown. PMID- 23632546 TI - Effects of source correlation on the spectral shift of light waves on scattering. AB - The far-zone scattered spectrum has been investigated for the scattering of two correlated sources from a deterministic medium. It is shown that red shift or blue shift can be produced in the far-zone scattered spectrum, and the spectral shift is influenced by the source correlation. PMID- 23632547 TI - Bandwidth-length trade-off figures of merit for electro-optic traveling wave modulators. AB - Closed-form expressions explicitly relating modulation bandwidth and active length in electro-optic traveling wave modulators are presented which fully account for skin-effect electrode loss and optical-electrical wave velocities mismatch. Four operative margins have been identified where the bandwidth-length trade-off figure of merit takes simple forms. PMID- 23632548 TI - Nonresonant background suppression in coherent anti-Stokes Raman spectroscopy through cascaded nonlinear optical interactions. AB - We propose and experimentally validate a technique for four-wave mixing background suppression in coherent anti-Stokes Raman spectroscopy. It is based on the interaction of the signals generated from the Kerr third-order nonlinearity and the cascaded quadratic process in a nonlinear crystal. Theoretical analysis agrees well with the experimental results, which provide a quantitative assessment of different contributions and allow extraction of the nonlinearity parameters. PMID- 23632549 TI - Mid-IR laser beam quality measurement through vanadium dioxide optical switching. AB - We present a beam characterization system for infrared lasers which can measure both wavefront and beam profile with visible detectors. While previous studies demonstrated the conversion from the visible to the near infrared, this device exploits the wavelength conversion from the infrared to the visible, which is based on the refractive index change because of the optical switching of a vanadium dioxide layer. This technique can be applied over a broad spectral range from the visible to the infrared and potentially to the terahertz. PMID- 23632550 TI - Polarization and polarization control of random lasers from dye-doped nematic liquid crystals. AB - A polarimetric study of random laser (RL) emitted from dye-doped nematic liquid crystals (NLCs) is presented. We observed linearly polarized light, the orientation of which is in proximity to the bisection between the polarization direction at the maximal scattering in NLCs and the nematic director. Any arbitrary linear polarization of RLs can be obtained by rotating the NLC sample. The efficiency and output uniformity over the complete direction angle of 2pi can be optimized by choosing a proper pump polarization. PMID- 23632551 TI - Computational superposition projector for extended depth of field and field of view. AB - This Letter describes a projection system with extended depth of field (DOF) and field of view (FOV). In the proposed system, an input image is projected with varying focusing distances and optical axis directions, and the projected images are superposed on a three-dimensional screen to realize a three-dimensionally space-invariant point spread function (PSF). A target image is deconvolved, and the result is used as the input image before projection by using the superposed PSF to generate a sharp output image on the screen. This concept for extended-DOF and -FOV projection was demonstrated experimentally. PMID- 23632552 TI - Direct measurement of the x-ray refractive index by Fresnel diffraction at a transparent edge. AB - We demonstrate the feasibility of measuring x-ray refractive indices by transparent edge diffraction without recourse to the Kramers-Kronig relations. The method requires a coherent x-ray source, a transparent sample with a straight edge, and a high resolution x-ray detector. Here, we use the aluminum Kalpha radiation originating from a laser-produced plasma to coherently illuminate the edge of thin aluminum and beryllium foils. The resulting diffraction patterns are recorded with an x-ray CCD camera. From least-squares fits of Fresnel diffraction modeling to the measured data we determine the refractive index of Al and Be at the wavelength of the Al Kalpha radiation (0.834 nm, 1.49 keV). PMID- 23632554 TI - Mid-infrared tunable optical polarization converter composed of asymmetric graphene nanocrosses. AB - We present a mid-IR highly tunable optical polarization converter composed of asymmetric graphene nanocrosses. It can convert linearly polarized light to circularly and elliptically polarized light or exhibit a giant optical activity at different wavelengths. The transmitted wavelength and polarization states can also be dynamically tuned by varying the Fermi energy of graphene, without reoptimizing and refabricating the nanostructures. This offers a further step in developing a controllable polarization converter. PMID- 23632555 TI - Observation of acoustically induced modulation instability in a Brillouin photonic crystal fiber laser. AB - We report the experimental observation of self-induced modulation instability (MI) in a Brillouin fiber laser made with a solid-core photonic crystal fiber (PCF) with strong anomalous dispersion. We identify this MI as the result of parametric amplification of optical sidebands generated by guided acoustic modes within the core of the PCF. It is further shown that MI leads to passive harmonic mode locking and to the generation of a picosecond pulse train at a repetition rate of 1.15 GHz which matches the acoustic frequency of the fundamental acoustic mode of the PCF. PMID- 23632556 TI - Improved AlGaInP vertical emitting light-emitting diodes using direct printing. AB - In this study, we fabricated a high-brightness AlGaInP light-emitting diode (LED) using the direct printing technique and dry etching. In general, wet etching is used for surface roughening to improve the light extraction of AlGaInP red LEDs. However, a structure fabricated by wet etching has limited height and shows a tiled cone shape after the etching process due to the AlGaInP crystal structure. These limitations reduce the light extraction of the LED. As a result, we fabricated a perfectly cone-shaped pattern with high aspect ratio using direct printing by etching to maximize the LED light extraction efficiency. Compared to the red LED with a wet-etched structure, the patterning enhanced the light output power by 12% without electrical degradation. This enhanced light output power was maintained even after the packaging process. PMID- 23632557 TI - Efficient spectral-step expansion of a filamenting laser pulse. AB - We report an efficient transfer of 800 nm energy into both the ultraviolet and the far infrared (IR) during the filamentation in air of an appropriately shaped laser pulse. The multiorder enhancement of the IR supercontinuum in the 3-5 MUm atmospheric transmission windows was achieved thanks to spectral-step cascaded four-wave mixing occurring within the spectrum of the shaped femtosecond laser pulse. These results also point out the limit of the self-phase modulation model to explain the spectral broadening of a filamenting laser pulse. PMID- 23632558 TI - Shaping optical beams with topological charge. AB - We show that by spatially arranging topological charges on a phase mask, it is possible to shape the spatial intensity profile of vortex beams in a controlled manner. As proof-of-principle experiments, we generated vortex beams with the spatial shape of straight lines, corners, and triangles. Potential applications for shaped beams include selective excitation of plasmonic modes, geometrically tunable Bose-Einstein condensates, and optical tweezers. PMID- 23632559 TI - State conversion based on terahertz plasmonics with vanadium dioxide coating controlled by optical pumping. AB - The state conversion and terahertz (THz) wave modulation based on a plasmonic device composed of silicon column arrays with vanadium dioxide (VO2) coating were experimentally demonstrated. For double 45 degrees tilted optical pumping, a state conversion from dielectric photonic crystal (PC) to metallic PC was demonstrated due to the insulator-metal transition (IMT) of VO2 with the pump power increasing. In this process, a broadband intensity modulation with 70% modulation depth was achieved. Furthermore, for normally incident optical pumping, another state conversion from dielectric PC to plasmonic device was also demonstrated due to the partial IMT of VO2, and the out of plane PC resonance gradually changed to be plasmonic resonances. This device and its modulation scheme will be of great significance for potential THz applications. PMID- 23632560 TI - High-uniformity multichannel plasmonic filter using linearly lengthened insulators in metal-insulator-metal waveguide. AB - A high-uniformity multichannel plasmonic filter based on metal-insulator-metal (MIM) waveguide is proposed. It consists of two metal layers and sandwiched multiple insulator super units structured by alternately stacking two insulators with different refractive indices. By linearly lengthening the high refractive index insulators in each super unit, the dispersion-induced loss coefficient can be reduced and flattened, leading to a high uniformity among multiple transmission channels of the plasmonic filter. The corresponding spectral characteristics are numerically investigated by using the finite-difference time domain method. Fourteen transmission channels with an excellent channel uniformity of +/-0.2 dB and a peak-to-notch contrast ratio greater than 14.8 dB in the range of 1-2 MUm, have been confirmed. PMID- 23632561 TI - Optical refrigeration to 119 K, below National Institute of Standards and Technology cryogenic temperature. AB - We report on bulk optical refrigeration of Yb:YLF crystal to a temperature of ~124 K, starting from the ambient. This is achieved by pumping the E4-E5 Stark multiplet transition at ~1020 nm. A lower temperature of 119+/-1 K (~-154C) with available cooling power of 18 mW is attained when the temperature of the surrounding crystal is reduced to 210 K. This result is within only a few degrees of the minimum achievable temperature of our crystal and signifies the bulk solid state laser cooling below the National Institute of Standards and Technology (NIST)-defined cryogenic temperature of 123 K. PMID- 23632562 TI - Optics letters to increase page limit to four pages. PMID- 23632563 TI - Site-selective effects on guest-molecular adsorption and fabrication of four component architecture by higher order networks. AB - 2D porous networks have attracted great attention as they can be used to immobilize functional units as guest molecules in a spatially ordered arrangement. In this work, a novel molecular hybrid network with two kinds of cavities was fabricated. Several kinds of guest molecules, such as coronene, copper(II) phthalocyanine (CuPc), triphenylene, heptanoic acid and fullerene molecules, can be immobilized into this template. Site- and size-selective effects can be observed. Furthermore, we have also fabricated interesting 2D crystal architecture with complex four-component structure at the liquid-solid interface, following investigation by scanning tunnelling microscopy (STM). The current findings provide a convenient approach towards the formation of more complex and functionalized surface nanopatterns, which can benefit the study of host-guest assembly behaviour within a monolayer composed by several components at interfaces. PMID- 23632564 TI - Solvent feedstock effect: the insights into the deactivation mechanism of Cu/SiO2 catalysts for hydrogenation of dimethyl oxalate to ethylene glycol. AB - The variation of the supports on the Cu/SiO2 catalyst plays an important role in the catalytic performance for hydrogenation of dimethyl oxalate. The loss of silica in the form of tetramethoxysilane from the support under the reaction conditions is responsible for the deactivation of the Cu/SiO2 catalyst. PMID- 23632565 TI - Measuring spatial proximity in mother-infant interaction: a kinematic approach for an examination of the effects of maternal postpartum depression. AB - A kinematic approach was used to measure mother-infant spatial proximity at 4 months. Maternal postpartum depression (PPD) impacts on mother-infant spatial interaction. We compared 28 dyads with mothers meeting criteria for PPD and 46 typical dyads. The PPD dyads had less variability in spatial proximity compared to typical dyads. PMID- 23632566 TI - Donation after circulatory death: current status. AB - PURPOSE OF REVIEW: Donor shortage has forced transplant teams to explore new methods to increase the potential donor pool. Donation after circulatory death (DCD) has opened new perspectives and could be a valuable option to expand the brain-dead donors. The purpose of this review is to provide an overview of current practice and to identify remaining questions related to ethical and medical issues that should be further addressed in the future. RECENT FINDINGS: Recent findings demonstrate acceptable outcomes after DCD kidney and lung transplantation but inferior graft survival for liver transplantation. The impact and importance of the agonal phase following withdrawal of treatment in controlled DCD is increasingly recognized. Premortem interventions are currently under debate related to preservation strategies or comfort therapy. New preservation strategies using in-situ/in-vivo extracorporeal membrane oxygenation or ex-vivo machine perfusion have large potential in the future. Finally, organizations and institutions are reporting more uniform guidelines related to declaration of death and DCD organ procurement. SUMMARY: DCD donation has regained much attention during the last decade and is now part of standard clinical practice albeit this type of donation should not be regarded as an equally acceptable alternative for donation after brain death. It will be important to further explore the potential of DCD, to monitor the long-term outcomes and to further optimize the quality of these grafts. Development and implementation of uniform guidelines will be necessary to guarantee the clinical use of these donor pools. PMID- 23632567 TI - Current world literature. PMID- 23632570 TI - A molecular conformational change induced self-assembly: from randomness to order. AB - From an interplay of high-resolution scanning tunneling microscopy (STM) imaging and density functional theory (DFT) calculations we reveal how a molecular conformational change induced self-assembly process can result in the conversion from a random molecular phase to the formation of two types of ordered surface nanostructures with different apparent heights. PMID- 23632571 TI - Listening to and involving consumers in research. PMID- 23632573 TI - Case studies in public-sector leadership: addressing the problem of appointment nonadherence with a plan for a walk-in clinic. PMID- 23632569 TI - [Neurobiology of behavioral addictions]. AB - Reward learning represents a crucial mechanism in the acquisition and maintenance of addictive behavior. The underlying neurobiological foundations and associated neurobiological pathways are identified in this review and similarities between substance abuse and behavioral addictions will be discussed. In the second section current neuroimaging findings on neurobiological mechanisms of pathological gambling and computer and internet addiction are discussed. The main focuses are on changes in neurocognitive processes, such as cue reactivity, reward and punishment processing and behavioral control. PMID- 23632574 TI - Research and services partnerships: the practice research network: a successful collaboration in Maryland. AB - The Practice Research Network (PRN) in Maryland, funded by a grant from the National Institute of Mental Health, extends the historically close collaborative relationship between the Department of Psychiatry at the University of Maryland and the Maryland Mental Hygiene Administration. The PRN focuses on the relationship between university-based investigators and participants in the public mental health system by using local mental health authorities (Core Service Agencies) as the point of contact. PRN staff serve as liaisons to foster partnerships between university researchers and practitioners. The PRN has identified a broader range of research participants by establishing contacts with provider agencies and stakeholder groups. It has addressed concerns about research participation by meeting with consumer and family groups and arranging for investigators to present research projects to stakeholders. This approach to developing a statewide network in support of mental health research can serve as a model for other state and university partnerships. PMID- 23632575 TI - Evergreen: creating a child and youth mental health framework for Canada. AB - Mental disorders affect many young Canadians, and most do not access care, partly because of lack of health policy-driven programs and services. Recognizing this policy need, the Child and Youth Advisory Committee of the Mental Health Commission of Canada created Evergreen: A Child and Youth Mental Health Framework for Canada. Evergreen was designed as a framework to guide development, implementation, and review of child and youth mental health policies, plans, and services across Canada. This Open Forum report describes the framework and the innovative features used to create Evergreen, including the advisory committee structure, application of qualitative research methods and tools, informed public input, and use of online collaborative writing technologies. PMID- 23632576 TI - A review of school mental health programs in SAMHSA's national registry of evidence-based programs and practices. AB - OBJECTIVE School programs provided by the Substance Abuse and Mental Health Services Administration's National Registry of Evidence-Based Programs and Practices (NREPP) were reviewed to describe program characteristics, costs, and ratings of research and dissemination. METHODS Data were gathered from the NREPP to identify mental health programs adaptable for schools. Program costs and quality and dissemination ratings were examined as a function of program characteristics. RESULTS School mental health programs constituted 32% of the registry, with 44% providing only materials at cost and 46% providing universal mental health promotion rather than intensive supports. Readiness for dissemination was poorer for programs providing only intensive supports, and quality of research increased as total costs of program implementation increased. CONCLUSIONS Mechanisms for tracking mental health promotion and treatment can be effective in disseminating information about evidence-based school programming. Assessing program transportability is necessary for decision making to match programs with the needs of particular schools and communities. PMID- 23632577 TI - A collaborative care approach to depression treatment for Asian Americans. AB - OBJECTIVE This study examined effectiveness of collaborative care for depression among Asians treated either at a community health center that focuses on Asians (culturally sensitive clinic) or at general community health centers and among a matched population of whites treated at the same general community clinics. METHODS For 345 participants in a statewide collaborative care program, use of psychotropic medications, primary care visits with depression care managers, and depression severity (as measured with the nine-item Patient Health Questionnaire) were tracked at baseline and 16 weeks. RESULTS After adjustment for differences in baseline demographic characteristics, all three groups had similar treatment process and depression outcomes. Asian patients served at the culturally sensitive clinic (N=129) were less likely than Asians (N=72) and whites (N=144) treated in general community health clinics to be prescribed psychotropic medications. CONCLUSIONS Collaborative care for depression showed similar response rates among all three groups. PMID- 23632578 TI - A case and care management program to reduce use of acute care by clients with substance use disorders. AB - OBJECTIVE The authors describe outcomes of a targeted case and care management program for persons with addictions utilizing a high level of acute services in Connecticut's system of care. METHODS Administrative and cost data were analyzed from five consecutive years (2004-2008) (N=165,305 clients). RESULTS In the year after enrollment, acute care episodes fell by 56% compared with the year before enrollment, with a 19% increase in engagement in nonacute care services. Paid units of acute care fell by 62%; paid units of nonacute care increased by 63%. Costs of care were approximately 46% lower in the year after enrollment. CONCLUSIONS Findings suggest that outcomes can be improved while costs and acute care demands can be reduced through combined use of care management to identify high users and case management to engage them in lower levels of care. The system was able to reallocate acute care resources to nonacute services and serve additional clients. PMID- 23632579 TI - A novel intervention for treatment of suicidal individuals. PMID- 23632580 TI - Rural or Remote Psychiatric Rehabilitation (rPSR). PMID- 23632581 TI - The need for appropriate use of involuntary commitment: in reply. PMID- 23632582 TI - The need for appropriate use of involuntary commitment. PMID- 23632583 TI - Training mental health professionals to treat tobacco dependence. PMID- 23632584 TI - Effects of point-of-choice prompts on stair usage in a psychiatric setting. PMID- 23632585 TI - CIHS updates integrated care framework. PMID- 23632586 TI - Kaiser Foundation marks third anniversary of ACA. PMID- 23632595 TI - Using patient-reported outcomes (PROs) to compare the providers of surgery: does the choice of measure matter? AB - BACKGROUND: Patient-reported outcomes (PROs) are being used to compare health care providers with little knowledge of how the choice of measure affects such comparisons. OBJECTIVES: To assess how much difference the choice of PRO makes to a provider's adjusted outcome and whether the choice affects a provider's rating. RESEARCH DESIGN: PROs collected in England from patients undergoing: hip replacement (243 providers; 52,692 patients); knee replacement (244; 60,118); varicose vein surgery (100; 11,163); and groin hernia repair (201; 31,714). Four case-mix-adjusted outcomes (mean postoperative disease-specific and generic PRO; proportion achieving a minimally important difference in disease-specific PRO; proportion reporting improvement on single transitional item). We calculated the associations between measures and for each measure, the proportion of providers rated as statistically above or below average and the level of agreement in ratings. RESULTS: For major surgery, disease-specific PROs were strongly correlated with the generic PRO (hip 0.90; knee 0.88), they rated high proportions of providers as above or below average (hip 25.1%; knee 19.3%) and there was agreement in ratings with the generic PRO. Even so, for a large proportion of providers (hip 30%; knee 16%) their rating depended on the choice of measure. For minor surgery, correlations between measures were mostly weak. The single transitional item identified the most outliers (varicose vein 20%, hernia 10%). CONCLUSIONS: Choice of outcome measure can determine a provider's rating. Measure selection depends on whether the priority is to avoid missing "poor" providers or avoid mislabeling average providers as "poor." PMID- 23632594 TI - The effect of weight loss on health, productivity, and medical expenditures among overweight employees. AB - OBJECTIVES: To test whether overweight or obese employees who achieve clinically significant weight loss of >= 5% have reduced medical expenditures, absenteeism, presenteeism, and/or improved Health-Related Quality Of Life (HRQOL). METHODS: The sample analyzed combines data from full-time overweight or obese employees who took part in one of the WAY to Health weight loss studies: 1 that took place in 17 community colleges (935 employees) and another in 12 universities (933), all in North Carolina. The estimations are performed using nonlinear difference in-difference models where groups are identified by whether the employee achieved a >= 5% weight loss (treated) or not (control) and the treatment variable indicates preweight and postweight loss intervention. The outcomes analyzed are the average quarterly (90 d) amount of medical claims paid by the health insurer, number of days missed at work during the past month, Stanford Presenteeism Scale SPS-6, and the EQ-5D-3L measure of HRQOL. RESULTS: We find statistical evidence supporting that >= 5% weight loss prevents deterioration in EQ-5D-3L scores by 0.026 points (P-value=0.03) and reduces both absenteeism by 0.258 d/mo (P value=0.093) and the likelihood of showing low presenteeism (Stanford SPS-6 score between 7 and 9) by 2.9 percentage points (P-value=0.083). No reduction in medical expenditures was observed. CONCLUSIONS: Clinically significant weight loss among overweight or obese employees prevents short-term deterioration in HRQOL and there is some evidence that employee productivity is increased. We find no evidence of a quick return on investment from reduced medical expenditures, although this may occur over longer periods. PMID- 23632596 TI - Trends and predictors of quality of care in VA nursing homes related to serious mental illness. AB - OBJECTIVE: Within Veterans Affairs (VA) nursing homes (NHs), quality issues have a tremendous impact on the population with serious mental illness (SMI), who are more likely than their non-SMI Veteran counterparts to use NH services. We examined recent trends in quality indicators (QIs) measuring poor performance of VA NHs and whether the facility-level QIs vary with SMI concentration within the facility. METHODS: From VA administrative records including Minimum Data Set assessments, we identified all residents in the 135 VA NHs between fiscal years 2005 (FY05) through FY07. We used a zero-inflated Poisson regression to assess trends in and facility-level predictors of 3 process-related QIs: depression without antidepressant therapy; bladder/bowel incontinence without a toileting plan; and physical restraint use. Facility-level predictors included collocated special care units, rurality, staffing, physical plant characteristics, SMI prevalence, and SMI admission volume. RESULTS: During FY05-FY07, restraint use declined from 1.2% to 1.1% and incontinence without a toileting plan from 25.8% to 22.1%, but untreated depression increased from 5.1% to 5.5%. Despite overall gains in quality, higher SMI prevalence was associated with higher odds of physical restraint use and lack of toileting plan. Higher SMI prevalence was also associated with higher frequency of untreated depression. Other characteristics such as complex building structure were predictive of variation in quality, but the relationships were not consistent across QI types. CONCLUSION: VA NHs had significant improvements in these examined QIs during the study period. Nonetheless, overall poorer quality was observed at sites with higher SMI concentrations. PMID- 23632597 TI - Opioid prescribing in emergency departments: the prevalence of potentially inappropriate prescribing and misuse. AB - OBJECTIVE: Emergency departments (EDs) routinely provide care for patients seeking treatment for painful conditions; however, they are also targeted by people seeking opioid analgesics for nonmedical use. This study determined the prevalence of indicators of potential ED opioid misuse and inappropriate prescription practices by ED providers in a large, commercially insured, adult population. RESEARCH DESIGN AND INDICATORS: We analyzed the 2009 Truven Health MarketScan Research Databases to examine the ED visits of enrollees aged 18-64 years. Indicators used to mark potential inappropriate use included opioid prescriptions overlapping by one week or more; overlapping opioid and benzodiazepine prescriptions; high daily doses (>=100 morphine milligram equivalents); long-acting/extended-release (LA/ER) opioids for acute pain, and overlapping LA/ER opioids. Analyses were stratified by sex. RESULTS: We identified 400,288 enrollees who received at least one ED opioid prescription. At least one indicator applied to 10.3% of enrollees: 7.7% had high daily doses; 2.0% had opioid overlap; 1.0% had opioid-benzodiazepine overlap. Among LA/ER opioid prescriptions, 21.7% were for acute pain, and 14.6% were overlapping. Females were more likely to have at least one indicator. CONCLUSIONS: In some instances, the prescribing of opioid analgesics in EDs might not be optimal in terms of minimizing the risk of their misuse. Guidelines for the cautious use of opioid analgesics in EDs and timely data from prescription drug monitoring programs could help EDs treat patients with pain while reducing the risk of nonmedical use. PMID- 23632598 TI - Medical homes versus individual practice in primary care: impact on health care expenditures. AB - BACKGROUND: The medical home (MH) model has prompted increasing attention given its potential to improve quality of care while reducing health expenditures. OBJECTIVES: We compare overall and specific health care expenditures in Belgium, from the third-party payer perspective (compulsory social insurance), between patients treated at individual practices (IP) and at MHs. We compare the sociodemographic profile of MH and IP users. RESEARCH DESIGN: This is a retrospective study using public insurance claims data. Generalized linear models estimate the impact on health expenditures of being treated at a MH versus IP, controlling for individual, and area-based sociodemographic characteristics. The choice of primary care setting is modeled using logistic regressions. SUBJECTS: A random sample of 43,678 persons followed during the year 2004. MEASURES: Third party payer expenditures for primary care, secondary care consultations, pharmaceuticals, laboratory tests, acute and long-term inpatient care. RESULTS: Overall third-party payer expenditures do not differ significantly between MH and IP users (?+27). Third-party payer primary care expenditures are higher for MH than for IP users (?+129), but this difference is offset by lower expenditures for secondary care consultations (?-11), drugs (?-40), laboratory tests (?-5) and acute and long-term inpatient care (?-53). MHs attract younger and more underprivileged populations. CONCLUSIONS: MHs induce a shift in expenditures from secondary care, drugs, and laboratory tests to primary care, while treating a less economically favored population. Combined with positive results regarding quality, MH structures are a promising way to tackle the challenges of primary care. PMID- 23632600 TI - Lipophilic bismuth phosphates: a molecular tetradecanuclear cage and a 1D coordination polymer. Synthesis, structure and conversion to BiPO4. AB - The reaction of the phosphate monoester {(ArO)PO(OH)2} (Ar = 2,6-i-Pr2C6H3) with BiPh3 in a 1 : 1 ratio in refluxing toluene afforded a tetradecabismuth-oxo phosphate cage [{(ArO)PO3}10{(ArO)PO2OH}2(Bi14O10).2(CH3OH)].3C6H12.3CH3OH.2H2O (Ar = 2,6-i-Pr2C6H3) (1). On the other hand the reaction of the phosphate diester {((t)BuO)2PO(OH)} with BiPh3 in a 1 : 1 ratio at room temperature in ethanol afforded the 1D-coordination polymer [Bi(C6H5)2((t)BuO)2PO2]n (2). The molecular structure of 1 reveals that the cage is comprised of a central planar Bi6 rim and two Bi4 poles. The entire aggregate is held together by multiple coordination of O(2-), [(ArO)P(O)(OH)](-), [(ArO)PO3](2-) and methanol ligands. 2 is a 1D coordination polymer where adjacent bismuth is bridged by isobidentate [((t)BuO)2PO2](-) ligands. In solution, however, 2 decomposes into the monomeric repeat unit [Ph2Bi{((t)BuO)2PO2}] which is indicated by ESI-MS studies. Thermolysis of 1 and 2 at 700 degrees C affords a pure phase of BiPO4. PMID- 23632601 TI - Chemically modified ribbon edge stimulated H2 dissociation: a first-principles computational study. AB - First-principles computational studies indicate that (B, N, or O)-doped graphene ribbon edges can substantially reduce the energy barrier for H2 dissociative adsorption. The low barrier is competitive with many widely used metal or metal oxide catalysts. This suggests that suitably functionalized graphene architectures are promising metal-free alternatives for low-cost catalytic processes. PMID- 23632602 TI - Intervention to reduce catheter-related bloodstream infections in an intensive care unit at a regional hospital in Southern Taiwan. PMID- 23632603 TI - Breakthrough disseminated cryptococcosis during micafungin therapy. AB - Echinocandins are not active against basidiomycetous yeasts, such as Cryptococcus neoformans, Trichosporon, and Rhodotorula species, and zygomycosis. We present a patient with renal failure and candidemia, who developed a breakthrough fungal infection with cryptococcemia and cryptococcuria while receiving micafungin therapy. PMID- 23632604 TI - Empirical antimicrobial therapy for critically ill patients with Acinetobacter baumannii bacteremia: combination is better. PMID- 23632605 TI - The Boston Marathon response: why did it work so well? PMID- 23632606 TI - Anaesthesia management for acute appendicitis in cases with Sjogren's syndrome accompanying autoimmune hepatitis. AB - Characterised by lymphocytic infiltration of exocrine glands, Sjogren's syndrome (SS) is a chronic autoimmune disease. Symptoms belonging to the involved systems may occur owing to the fact that it affects multiple systems. While rheumatoid arthritis is observed concomitantly, its co-occurrence with autoimmune hepatitis is astonishingly common. Through this case report, we intended to review issues that should be attended to while administering anaesthesia to a patient with SS accompanying autoimmune hepatitis. In the light of literature, we aimed to discuss anaesthesia management to the patient with SS and issues stemming from the clinical features of SS. In SS, the expected issues are liver problems related autoimmune hepatitis and respiratory problems related pulmonary fibrosis. A careful preoperative evaluation, a comprehensive preparation against difficulty in intubation, a selective anaesthesia management in terms of autoimmune hepatitis and close monitoring of postoperative respiration may prevent or decrease possible complications. PMID- 23632607 TI - A cholestatic diagnostic dilemma. AB - A 28-year-old man with hereditary spherocytosis presented with abdominal pain and jaundice. He had severe, mainly conjugated (642 MUmol/l), hyperbilirubinaemia (1033 MUmol/l), with elevated liver enzymes: alkaline phosphatase (ALP) (163 IU/l), gamma-glutamyltransferase (gGT) (277 IU/l) and aspartate transaminase (AST) (358 IU/l). Abdominal ultrasound and magnetic resonance cholangiopancreatography (MRCP) showed gallstones in the gallbladder but an absence of biliary duct dilation. Liver biopsy was consistent with cholestasis but showed no large duct obstruction. The cause of the cholestasis was unclear, was it a primary intrahepatic pathology or secondary to a posthepatic cause? He presented with similar symptoms days later with gallstones in the bile duct (choledocholithiasis) and underwent endoscopic retrograde cholangiopancreatography (ERCP) and cholecystectomy. This report guides one through the assessment of jaundice and serves as an example whereby the diagnosis of a common cause of illness is blurred by an atypical clinical presentation and relevant comorbidities. A diagnosis of benign recurrent intrahepatic cholestasis (BRIC) is also considered. PMID- 23632608 TI - Schwannoma of the brachial plexus: a rare cause of monoparesis. PMID- 23632609 TI - Aberration in the palatal root of the maxillary first molar. AB - Thorough knowledge of root canal morphology is essential for the endodontic therapy. Variations in the root and root canal morphology, especially in multirooted teeth, are a constant challenge for diagnosis and management. The dentist needs to be familiar with the various root canal configurations and their variations for successful endodontic therapy. There are rare variations in canal number and configuration in maxillary molars, which could affect treatment outcome. Two lingual root structures are occasionally found on human permanent maxillary molars. One of these is the normal lingual root, which is always present, the other is a supernumerary structure which can be located either mesiolingually (radix mesiolingualis) or distolingually (radix distolingualis). The purpose of this paper is to review the literature and to demonstrate a case report which describes the successful non-surgical endodontic management of an unusual maxillary first molar with four separate roots and four canals. PMID- 23632610 TI - Levonorgestrel intrauterine system as a treatment option for severe menorrhagia in adolescent with type III von Willebrand disease. AB - The authors describe a case of an adolescent with type III von Willebrand disease and severe menorrhagia since menarche. Antifibrinolytic, hormonal (estroprogestative pill in high doses, etonogestrel implant and gonadotropin releasing hormone agonist goserelin) and Von Willebrand Factor/Factor VIII replacement therapies were prescribed to the patient, but symptomatic control was only obtained with high doses of VWF/FVIII twice a week. In March 2012, a levonorgestrel intrauterine system was inserted in a 14-year-old. At present, the patient is asymptomatic without regular prophylaxis (VWF/FVIII replacement therapy) and has had a remarkable improvement in her quality of life. PMID- 23632611 TI - Improving outcomes for pancreatic cancer: radical surgery with patient-tailored, surgery-specific advanced haemodynamic monitoring. AB - Pancreatic cancer has poor prognoses, with a median survival after diagnosis of less than 6 months. For some patients radical surgery remains the only chance of long-term cure. We report the successful outcome of a patient with pancreatic cancer and portal vein encasement that underwent a biliary bypass procedure and chemoradiotherapy. He was reassessed 8 months later where a complete resection of the pancreatic cancer was undertaken. The patient required a total pancreatectomy, splenectomy, subtotal gastrectomy and partial colectomy. Portal and superior mesenteric vein resection was performed, with reconstitution using the splenic vein as conduit with its draining inferior mesenteric vein. We report novel aspects of the surgical technique and describe our institution's patient tailored, surgery-specific goal-directed strategy that was considered paramount for the successful perioperative outcome in this case. PMID- 23632612 TI - Localised normocalcaemic tetany secondary to dehydration in an individual with Gitelman syndrome. AB - Dehydration is a common presentation to any emergency department with symptoms ranging from lethargy, confusion, oliguria as well as those specific to the underlying cause. In this case we describe a young patient who following a short history of vomiting and abdominal pain developed carpopedal spasm and distal parasthesia on a background of Gitelman syndrome. Biochemical blood analysis showed a marked hypokalaemia, hypomagnesaemia and mild metabolic alkalosis in addition to a prolonged QTc interval of 592 ms seen on ECG. Following fluid replacement and electrolyte correction his clinical symptoms resolved along with QTc normalisation. This case demonstrates a patient with a rare and interesting renal disorder who presented with typical biochemical and ECG abnormalities in addition to tetany in the presence of normal plasma calcium. PMID- 23632613 TI - Spinal epidural abscess treated with antibiotics alone. AB - Spinal epidural abscess (SEA) is a rare clinical condition among children. Most patients do not present with classical signs. A 13-year-old boy without any predisposing factors presented with paraparesis, bladder and bowel involvement. MRI spine demonstrated an SEA at the C7 and D1 levels on both sides of the midline with cord oedema at the C2-3 to C6 level with minimal marrow oedema in the C6 vertebral body. We treated the patient with antibiotics (ceftriaxone and vancomycin) alone. The patient showed excellent response with only minimal residual gait disturbance at the end of 6 weeks of antibiotic therapy. This is the first paediatric report of complete recovery of a patient at clinical stage 4 following antibiotic treatment alone from India. However, caution should be exercised to closely monitor the patient's recovery as any progression in the neurological state warrants surgery. PMID- 23632614 TI - Wellens' syndrome in a 24-year-old woman. AB - Wellens' syndrome refers to specific ECG abnormalities in the precordial T-wave segment, which are associated with critical stenosis of the proximal left anterior descending (LAD) coronary artery culminating in an acute anterior wall myocardial infarction (MI) if the patient is not urgently revascularised. We describe the youngest reported presentation of Wellens' syndrome in a 24-year-old woman with unstable chest pain, characteristic ECG changes and slight troponin biomarker elevation. This was initially unrecognised by the emergency department as unstable coronary syndrome and she subsequently progressed to an anterior non ST elevation MI (NSTEMI). Her coronary angiogram showed critical narrowing of the proximal LAD which was successfully treated with a drug-eluting stent. PMID- 23632615 TI - Concertina effect: a subtle but specific marker. PMID- 23632616 TI - Primary intraocular central nervous system lymphoma masquerading as diffuse retinal vasculitis. AB - A 49-year-old woman had blurred vision and floaters of 4 days duration in the right eye. Ocular examination revealed granulomatous panuveitis, vitritis and diffuse retinal vasculitis. Following a strongly positive tuberculin skin test, she received antitubercular therapy with oral steroids and immunosuppressants. A year later, despite therapy, vitritis and vasculitis persisted. Additionally, yellowish white lesions appeared beneath the retinal pigment epithelium. Fluorescein angiography revealed a leopard skin appearance. Following a negative vitreous biopsy, she was subjected to a chorioretinal biopsy which revealed non Hodgkin's lymphoma. MRI was normal. The ocular lesions resolved following intravitreal methotrexate injections. MRI of the brain was repeated every 3 months to rule out central nervous system (CNS) involvement. About 2.5 years after initial presentation, she complained of ataxia, hypersomnia and speech difficulty. MRI of the brain now showed lesions in the thalamocapsular region and the corpus callosum splenium suggestive of CNS lymphoma. She underwent a whole brain radiation with symptomatic improvement followed by chemotherapy. PMID- 23632617 TI - Prostate adenocarcinoma with a rectal metastasis. PMID- 23632618 TI - Recurrent case of ibuprofen-induced aseptic meningitis in mixed connective tissue disease. AB - Although relatively uncommon, the incidence of non-steroidal anti-inflammatory drug-induced aseptic meningitis appears to be increasing among patients with connective tissue disease and also among the healthy population. Ibuprofen is the most common culprit identified. We report a case of a 28-year-old woman with mixed connective tissue disease and recent intake of ibuprofen, presenting with a recurrent episode of ibuprofen-induced aseptic meningitis. PMID- 23632619 TI - Hydranencephaly: a rare cause of delayed developmental milestones. PMID- 23632620 TI - Spindle cell carcinoma in maxilla. AB - Spindle cell carcinomas (sarcomatoid carcinomas) are rare tumours. It is a variant of squamous cell carcinoma which has spindled tumour cells, which simulate a true sarcoma, but are epithelial in origin. They are extremely uncommon in the head and neck region. Only five cases with maxillary origin have been discussed in the literature. As compared to squamous cell carcinoma of maxilla, this variant is associated with poor diagnosis and advanced disease at presentation, as is demonstrated in the case presented. There are no standard recommendations for management owing to the rarity of this histology. Surgery and radiotherapy form the mainstays of treatment. We report a rare case of spindle cell carcinoma involving the maxilla. PMID- 23632621 TI - Twin pedunculated intraoral submucosal lipoma. PMID- 23632622 TI - Biliary contents in the chest drain tube: a finding not to ignore. AB - A 45-year-old man presented with a left-sided pneumothorax following an episode of forceful vomiting. His chest drain revealed biliary contents and his CT chest with oral contrast confirmed the diagnosis of oesophageal rupture. He was transferred for surgical repair to a tertiary centre. Biliary contents within a chest tube are an important clinical finding and should raise suspicion of Boerhaave's syndrome. Any delays should be avoided due to the high mortality. PMID- 23632624 TI - Pointwise confidence intervals for a survival distribution with small samples or heavy censoring. AB - We propose a beta product confidence procedure (BPCP) that is a non-parametric confidence procedure for the survival curve at a fixed time for right-censored data assuming independent censoring. In such situations, the Kaplan-Meier estimator is typically used with an asymptotic confidence interval (CI) that can have coverage problems when the number of observed failures is not large, and/or when testing the latter parts of the curve where there are few remaining subjects at risk. The BPCP guarantees central coverage (i.e. ensures that both one-sided error rates are no more than half of the total nominal rate) when there is no censoring (in which case it reduces to the Clopper-Pearson interval) or when there is progressive type II censoring (i.e. when censoring only occurs immediately after failures on fixed proportions of the remaining individuals). For general independent censoring, simulations show that the BPCP maintains central coverage in many situations where competing methods can have very substantial error rate inflation for the lower limit. The BPCP gives asymptotically correct coverage and is asymptotically equivalent to the CI on the Kaplan-Meier estimator using Greenwood's variance. The BPCP may be inverted to create confidence procedures for a quantile of the underlying survival distribution. Because the BPCP is easy to implement, offers protection in settings when other methods fail, and essentially matches other methods when they succeed, it should be the method of choice. PMID- 23632625 TI - Estimation and selection of complex covariate effects in pooled nested case control studies with heterogeneity. AB - A major challenge in cancer epidemiologic studies, especially those of rare cancers, is observing enough cases. To address this, researchers often join forces by bringing multiple studies together to achieve large sample sizes, allowing for increased power in hypothesis testing, and improved efficiency in effect estimation. Combining studies, however, renders the analysis difficult owing to the presence of heterogeneity in the pooled data. In this article, motivated by a collaborative nested case-control (NCC) study of ovarian cancer in three cohorts from United States, Sweden, and Italy, we investigate the use of penalty regularized partial likelihood estimation in the context of pooled NCC studies to achieve two goals. First, we propose an adaptive group lasso (gLASSO) penalized approach to simultaneously identify important variables and estimate their effects. Second, we propose a composite agLASSO penalized approach to identify variables with heterogeneous effects. Both methods are readily implemented with the group coordinate gradient decent algorithm and shown to enjoy the oracle property. We conduct simulation studies to evaluate the performance of our proposed approaches in finite samples under various heterogeneity settings, and apply them to the pooled ovarian cancer study. PMID- 23632626 TI - Chronic hypoxic incubation blunts thermally dependent cholinergic tone on the cardiovascular system in embryonic American alligator (Alligator mississippiensis). AB - Environmental conditions play a major role in shaping reptilian embryonic development, but studies addressing the impact of interactions between chronic and acute environmental stressors on embryonic systems are lacking. In the present study, we investigated thermal dependence of cholinergic and adrenergic cardiovascular tone in embryonic American alligators (Alligator mississippiensis) and assessed possible phenotypic plasticity in a chronic hypoxic incubation treatment. We compared changes in heart rate (f H) and mean arterial blood pressure (P M) for chronically hypoxic and normoxic-incubated embryos after cholinergic and adrenergic blockade following three different acute temperature treatments: (1) 30 degrees C (control incubation temperature), (2) acute, progressive decrease 30-24 degrees C then held at 24 degrees C, and (3) acute, progressive increase 30-36 degrees C then held at 36 degrees C. f H progressively fell in response to decreasing temperature and rose in response to increasing temperature. P M did not significantly change with decreasing temperature, but was lowered significantly with increasing acute temperature in the normoxic group at 90 % of development only. Propranolol administration (beta adrenergic antagonist) produced a significant f H decrease at 24, 30, and 36 degrees C that was similar at all temperatures for all groups. For normoxic incubated embryos at 90 % of development, atropine administration (cholinergic antagonist) significantly increased f H in both 24 and 36 degrees C treatments, but not in the 30 degrees C control treatment. This atropine response at 24 and 36 degrees C demonstrated acute thermally dependent cholinergic tone on f H late in development for normoxic-incubated, but not chronically hypoxic-incubated embryos. Collectively, data indicated that cardiovascular control mechanisms in embryonic alligators may be activated by thermal extremes, and the maturation of control mechanisms was delayed by chronic hypoxia. PMID- 23632627 TI - The hemoglobin system of the serpent eel Ophisurus serpens: structural and functional characterization. AB - The hemoglobin system of the serpent eel Ophisurus serpens was structurally and functionally characterized with the aim of comparing it to the hemoglobin system of other fish species, as oxygen loading under the severe habitat conditions experienced by O. serpens could have necessitated specific adaptation mechanisms during evolution. The hemoglobin system of O. serpens includes one cathodic and four anodic components. The molecular mass of the alpha and beta chains of the cathodic component as well as the 2 alpha and 4 beta of the anodic components were determined. Analysis of the intact alpha and beta chains from cathodic hemoglobin and their proteolytic digestion products by high-resolution MS and MS/MS experiments resulted in 92 and 95 % sequence coverage of the alpha and beta globins, respectively. The oxygen binding properties of both hemoglobin components were analyzed with respect to their interactions with their physiological effectors. Stripped cathodic hemoglobin displayed the highest oxygen affinity among Anguilliformes with no significant effect of pH on O2 affinity. In the presence of both chloride and organic phosphates, O2-affinity was strongly reduced, and cooperativity was enhanced; moreover, cathodic hemoglobin contains two indistinguishable GTP-binding sites. Stripped anodic hemoglobins exhibited both low O2-affinity and low cooperativity and a larger Bohr effect than cathodic hemoglobin. The cathodic hemoglobin of O. serpens and the corresponding component of Conger conger share the greatest structural and functional similarity among hemoglobin systems of Anguilliformes studied to date, consistent with their phylogenetic relationship. PMID- 23632628 TI - Expression of lipogenic genes is upregulated in the heart with exercise training induced but not pressure overload-induced left ventricular hypertrophy. AB - Cardiac hypertrophy is accompanied by molecular remodeling that affects different cellular pathways, including fatty acid (FA) utilization. In the present study, we show that cardiac lipid metabolism is differentially regulated in response to physiological (endurance training) and pathological [abdominal aortic banding (AAB)] hypertrophic stimuli. Physiological hypertrophy was accompanied by an increased expression of lipogenic genes and the activation of sterol regulatory element-binding protein-1c and Akt signaling. Additionally, FA oxidation pathways regulated by AMP-activated protein kinase (AMPK) and peroxisome proliferator activated receptor-alpha (PPARalpha) were induced in trained hearts. Cardiac lipid content was not changed by physiological stimulation, underlining balanced lipid utilization in the trained heart. Moreover, pathological hypertrophy induced the AMPK-regulated oxidative pathway, whereas PPARalpha and expression of its downstream targets, i.e., acyl-CoA oxidase and carnitine palmitoyltransferase I, were not affected by AAB. In contrast, pathological hypertrophy leads to cardiac triglyceride (TG) and diacylglycerol (DAG) accumulation, although the expression of lipogenic genes and the levels of FA transport proteins (CD36 and FATP) were not changed or reduced compared with the sham group. A possible explanation for this phenomenon is a decrease in lipolysis, as evidenced by the increased content of adipose triglyceride lipase inhibitor G0S2, the increased phosphorylation of hormone-sensitive lipase at Ser(565), and the decreased protein levels of DAG lipase that attenuate TG and DAG contents. The increased TG and DAG accumulation observed in AAB-induced hypertrophy might have lipotoxic effects, thereby predisposing to cardiomyopathy and heart failure in the future. PMID- 23632629 TI - Resistance exercise induced mTORC1 signaling is not impaired by subsequent endurance exercise in human skeletal muscle. AB - The current dogma is that the muscle adaptation to resistance exercise is blunted when combined with endurance exercise. The suggested mechanism (based on rodent experiments) is that activation of adenosine monophosphate-activated protein kinase (AMPK) during endurance exercise impairs muscle growth through inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). The purpose of this study was to investigate potential interference of endurance training on the signaling pathway of resistance training [mTORC1 phosphorylation of ribosomal protein S6 kinase 1 (S6K1)] in human muscle. Ten healthy and moderately trained male subjects performed on two separate occasions either acute high-intensity and high-volume resistance exercise (leg press, R) or R followed by 30 min of cycling (RE). Muscle biopsies were collected before and 1 and 3 h post resistance exercise. Phosphorylation of mTOR (Ser2448) increased 2-fold (P < 0.05) and that of S6K1 (Thr389) 14-fold (P < 0.05), with no difference between R and RE. Phosphorylation of eukaryotic elongation factor 2 (eEF2, Thr56) was reduced ~70% during recovery in both trials (P < 0.05). An interesting finding was that phosphorylation of AMPK (Thr172) and acetyl-CoA carboxylase (ACC, Ser79) decreased ~30% and ~50%, respectively, 3 h postexercise (P < 0.05). Proliferator activated receptor-gamma coactivator-1 (PGC-1alpha) mRNA increased more after RE (6.5-fold) than after R (4-fold) (RE vs. R: P < 0.01) and was the only gene expressed differently between trials. These data show that the signaling of muscle growth through the mTORC1-S6K1 axis after heavy resistance exercise is not inhibited by subsequent endurance exercise. It is also suggested that prior activation of mTORC1 signaling may repress subsequent phosphorylation of AMPK. PMID- 23632630 TI - Hydrogen sulfide deficiency and diabetic renal remodeling: role of matrix metalloproteinase-9. AB - Matrix metalloproteinase-9 (MMP-9) causes adverse remodeling, whereas hydrogen sulfide (H2S) rescues organs in vascular diseases. The involvement of MMP-9 and H2S in diabetic renovascular remodeling is, however, not well characterized. We determined whether MMP-9 regulates H2S generation and whether H2S modulates connexin through N-methyl-d-aspartate receptor (NMDA-R)-mediated pathway in the diabetic kidney. Wild-type (WT, C57BL/6J), diabetic (Akita, C57BL/6J Ins2(Akita)), MMP-9(-/-) (M9KO), double knockout (DKO) of Akita/MMP-9(-/-) mice and in vitro cell culture were used in our study. Hyperglycemic Akita mice exhibited increased level of MMP-9 and decreased production of H2S. H2S synthesizing enzymes cystathionine-beta-synthase and cystathionine-gamma-lyase were also diminished. In addition, increased expressions of NMDA-R1 and connexin 40 and -43 were observed in diabetic kidney. As expected, MMP-9 mRNA was not detected in M9KO kidneys. However, very thin protein expression and activity were detected. No other changes were noticed in M9KO kidney. In DKO mice, all the above molecules showed a trend toward baseline despite hyperglycemia. In vitro, glomerular endothelial cells treated with high glucose showed induction of MMP-9, attenuated H2S production, NMDA-R1 induction, and dysregulated conexin-40 and -43 expressions. Silencing MMP-9 by siRNA or inhibition of NMDA-R1 by MK801 or H2S treatment preserved connexin-40 and -43. We conclude that in diabetic renovascular remodeling MMP-9 plays a major role and that H2S has therapeutic potential to prevent adverse diabetic renal remodeling. PMID- 23632632 TI - A CRY for help to fight fat. PMID- 23632631 TI - Antenatal glucocorticoid exposure enhances the inhibition of adrenal steroidogenesis by leptin in a sex-specific fashion. AB - Antenatal treatment with glucocorticoids (GC) poses long-lasting effects on endocrine and cardiovascular function. Given that leptin attenuates adrenal function and the reported sex differences in plasma leptin concentration, we hypothesized that antenatal GC will affect leptin levels and leptin modulation of adrenal function in a sex-specific manner. Pregnant sheep were randomly given betamethasone or vehicle at 80 days of gestational age, and offspring were allowed to deliver at term. Adrenocortical cells (ADC) were studied from male and female animals at 1.5 yr of age. Plasma leptin was increased 66% in male and 41% in female GC-treated animals (P < 0.05), but adrenal leptin mRNA was increased only in GC-treated males (P < 0.05). Whereas mRNA expression of adrenal leptin receptor isoforms showed sex (Ob-Ra and Ob-Rb) and treatment-dependent (Ob-Rb) differences, protein expression remained unchanged. GC-treated females showed greater plasma cortisol and greater ACTH-stimulated cortisol production (P < 0.05) in ADC. Leptin exerted a greater inhibitory effect on basal and stimulated cortisol by ADC from GC-treated males (P < 0.05), with no differences in females. Similarly, greater inhibitory effects on basal and ACTH-stimulated StAR and ACTH R mRNA expression by leptin were observed in cells from GC males (P < 0.05), with no changes in females. Persistent effects of antenatal GC on leptin levels and leptin modulation of adrenal function are expressed in a sex-specific manner; males are more sensitive than females to the inhibitory influences of leptin on adrenal function, and this effect appears to be mediated by a greater inhibition of StAR and ACTH-R expression in adrenals of adult GC-treated males. PMID- 23632633 TI - Lack of myostatin impairs mechanical performance and ATP cost of contraction in exercising mouse gastrocnemius muscle in vivo. AB - Although it is well established that the lack of myostatin (Mstn) promotes skeletal muscle hypertrophy, the corresponding changes regarding force generation have been studied mainly in vitro and remain conflicting. Furthermore, the metabolic underpinnings of these changes are very poorly documented. To clarify this issue, we have investigated strictly noninvasively in vivo the impact of the lack of Mstn on gastrocnemius muscle function and energetics in Mstn-targeted knockout (Mstn-/-) mice using 1H-magnetic resonance (MR) imaging and 31P-MR spectroscopy during maximal repeated isometric contractions induced by transcutaneous electrostimulation. In Mstn-/- animals, although body weight, gastrocnemius muscle volume, and absolute force were larger (+38, +118, and +34%, respectively) compared with wild-type (Mstn+/+) mice, specific force (calculated from MR imaging measurements) was significantly lower (-36%), and resistance to fatigue was decreased. Besides, Mstn deficiency did not affect phosphorylated compound concentrations and intracellular pH at rest but caused a large increase in ATP cost of contraction (up to +206% compared with Mstn+/+) throughout the stimulation period. Further, Mstn deficiency limits the shift toward oxidative metabolism during muscle activity despite the fact that oxidative ATP synthesis capacity was not altered. Our data demonstrate in vivo that the absence of Mstn impairs both mechanical performance and energy cost of contraction in hypertrophic muscle. These findings must be kept in mind when considering Mstn as a potential therapeutic target for increasing muscle mass in patients suffering from muscle-wasting disorders. PMID- 23632635 TI - Reproductive physiology of a humanized GnRH receptor mouse model: application in evaluation of human-specific analogs. AB - The human GnRH receptor (GNRHR1) has a specific set of properties with physiological and pharmacological influences not appropriately modeled in laboratory animals or cell-based systems. To address this deficiency, we have generated human GNRHR1 knock-in mice and described their reproductive phenotype. Measurement of pituitary GNRHR1 transcripts from homozygous human GNRHR1 knock-in (ki/ki) mice revealed a severe reduction (7- to 8-fold) compared with the mouse Gnrhr1 in wild-type mice. 125I-GnRH binding assays on pituitary membrane fractions corroborated reduced human GNRHR1 protein expression in ki/ki mice, as occurs with transfection of human GNRHR1 in cell lines. Female homozygous knock in mice displayed normal pubertal onset, indicating that a large reduction in GNRHR1 expression is sufficient for this process. However, ki/ki females exhibited periods of prolonged estrous and/or metestrous and reduced fertility. No impairment was found in reproductive maturity or adult fertility in male ki/ki mice. Interestingly, the serum LH response to GnRH challenge was reduced in both knock-in males and females, indicating a reduced GNRHR1 signaling capacity. Small molecules targeting human GPCRs usually have poor activities at homologous rodent receptors, thus limiting their use in preclinical development. Therefore, we tested a human-specific GnRH1 antagonist, NBI-42902, in our mouse model and demonstrated abrogation of a GnRH1-induced serum LH rise in ki/ki mice and an absence of effect in littermates expressing the wild-type murine receptor. This novel model provides the opportunity to study the human receptor in vivo and for screening the activity of human-specific GnRH analogs. PMID- 23632634 TI - Influence of fish oil on skeletal muscle mitochondrial energetics and lipid metabolites during high-fat diet. AB - Omega-3 polyunsaturated fatty acids (n-3 PUFAs) enhance insulin sensitivity and glucose homeostasis in rodent models of insulin resistance. These beneficial effects have been linked with anti-inflammatory properties, but emerging data suggest that the mechanisms may also converge on mitochondria. We evaluated the influence of dietary n-3 PUFAs on mitochondrial physiology and muscle lipid metabolites in the context of high-fat diet (HFD) in mice. Mice were fed control diets (10% fat), HFD (60% fat), or HFD with fish oil (HFD+FO, 3.4% kcal from n-3 PUFAs) for 10 wk. Body mass and fat mass increased similarly in HFD and HFD+FO, but n-3 PUFAs attenuated the glucose intolerance that developed with HFD and increased expression of genes that regulate glucose metabolism in skeletal muscle. Despite similar muscle triglyceride levels in HFD and HFD+FO, long-chain acyl-CoAs and ceramides were lower in the presence of fish oil. Mitochondrial abundance and oxidative capacity were similarly increased in HFD and HFD+FO compared with controls. Hydrogen peroxide production was similarly elevated in HFD and HFD+FO in isolated mitochondria but not in permeabilized muscle fibers, likely due to increased activity and expression of catalase. These results support a hypothesis that n-3 PUFAs protect glucose tolerance, in part by preventing the accumulation of bioactive lipid mediators that interfere with insulin action. Furthermore, the respiratory function of skeletal muscle mitochondria does not appear to be a major factor in sphingolipid accumulation, glucose intolerance, or the protective effects of n-3 PUFAs. PMID- 23632637 TI - Palladium-catalyzed Suzuki cross-coupling of N'-tosyl arylhydrazines. AB - The first palladium-catalyzed Suzuki cross-coupling of N'-tosyl arylhydrazines with various organoboron reagents has been developed for the preparation of biaryl compounds in high yields. N'-Tosyl arylhydrazine as a readily available and stable electrophile also demonstrated its generality in a number of coupling reactions. PMID- 23632638 TI - Devices and meshes for the surgical treatment of prolapse and incontinence. Foreword. PMID- 23632639 TI - Approval process for devices and mesh for surgical treatment of pelvic organ prolapse and urinary incontinence. AB - Most marketed devices in the United States, including most used to treat prolapse and incontinence, are marketed without FDA approval; instead, they gain "clearance" as a class II device through premarket notification [also known as the 510(k) process]. Under this process, the manufacturer states that the device is substantially equivalent to one already on the market. Thus, mesh kits for prolapse and incontinence were not required to undergo clinical testing before reaching the market. In January 2012, the FDA announced that it would require postmarket surveillance studies to address safety and effectiveness of mesh kits for prolapse and for single-incision slings. PMID- 23632636 TI - Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: role in maternal obesity. AB - Obesity is associated with low-grade chronic inflammation, which contributes to cellular dysfunction promoting metabolic disease. Obesity during pregnancy leads to a proinflammatory milieu in the placenta; however, the underlying causes for obesity-induced placental inflammation remain unclear. Here, we examine the mechanisms by which saturated fatty acids and inflammatory cytokines induce inflammation in placental trophoblasts. We conducted global transcriptomic profiling in BeWo cells following palmitate and/or TNFalpha treatment and gene/protein expression analyses of MAPK pathways and characterized downstream transcription factors directly regulating inflammatory cytokines. Microarray analysis revealed increased expression of genes regulating inflammation, stress response, and immediate early response in cytotrophoblasts in response to palmitic acid (PA), TNFalpha, or a combination of both (PA + TNFalpha). Both gene ontology and gene set enrichment analysis revealed MAPK and EGR-1 signaling to be upregulated in BeWo cells, which was confirmed via immunoblotting. Importantly, activation of JNK signaling was necessary for increased proinflammatory cytokine (IL-6, TNFalpha, and IL-8) and EGR1 mRNA. Consistent with the requirement of JNK signaling, ChIP analysis confirmed the recruitment of c-Jun and other MAPK responsive immediate early factors on the EGR1 promoter. Moreover, recruitment of EGR-1 on cytokine promoters (IL-6, TNFalpha, and IL-8) and an impaired proinflammatory response following knockdown of EGR-1 suggested it as a central component of the mechanism facilitating inflammatory gene expression. Finally, akin to in vitro findings, term placenta from obese women also had both increased JNK and p38 signaling and greater EGR-1 protein relative to lean women. Our results demonstrate that lipotoxic insults induce inflammation in placental cells via activation of JNK/EGR-1 signaling. PMID- 23632640 TI - Critical anatomic concepts for safe surgical mesh. AB - A comprehensive knowledge of the boundaries, contents, and interactions between surgical spaces is essential to safely and effectively perform mesh-augmented prolapse repairs and anti-incontinence procedures. This knowledge is also critical when managing intraoperative and postoperative complications such as bleeding, visceral injury, mesh erosion, exposure, or extrusion, and pelvic pain, groin pain, and dyspareunia. We present a detailed description of the surgical spaces entered during mesh augmented vaginal repair procedures and suggest strategies to avoid nerve and visceral injuries. PMID- 23632641 TI - Neurological diseases in pregnancy: an overview. Foreword. PMID- 23632642 TI - Multiple sclerosis and pregnancy. AB - Multiple sclerosis (MS) is a chronic neurological illness affecting adults at the time when they are most likely to consider starting a family. It is known that the risk of MS relapse declines during pregnancy but increases in the first 3 to 6 months postpartum. It is also known that this risk is not affected by delivery method, anesthesia type, or parity. Unanswered questions remain, including long term pregnancy effects on MS outcomes, effects of lactation on postpartum relapses, or the best management strategies of MS patients through reproductive cycle. This review provides information and guidelines for counseling patients with MS desiring motherhood. PMID- 23632643 TI - Stroke and pregnancy: clinical presentation, evaluation, treatment, and epidemiology. AB - Stroke is a neurological emergency that carries a risk of morbidity and mortality. Recent studies have shown that the incidence of stroke, although rare, is increasing in pregnant females. In this review, stroke and other vasculopathies in the pregnant and postpartum female are examined. A discussion of the symptoms and clinical presentation of stroke is provided and the current guideline for treatment of stroke in pregnancy. Finally, the data illustrating the recent increases in stroke incidence are outlined. PMID- 23632647 TI - Combination of gamma radiation and essential oils from medicinal plants in managing Tribolium castaneum contamination of stored products. AB - Effectiveness of management of insect infestation of stored products with essential oils as viable alternatives to synthetic insecticides can be enhanced with gamma radiation. We studied effects of sublethal doses of essential oils from Rosmarinus officinalis (L.) and Perovskia atriplicifolia (Benth) (safe natural insecticides) in combination with gamma radiation on mortality of adults of Tribolium castaneum (Herbst). The insects were subjected to two radiation doses and two concentrations of the essential oils in the air. This combined treatment increased the mortality, which was also 3-6 times higher than could be expected from the sum of the effects of each of the treatments. The synergistic effect was more pronounced in the case of R. officinalis (L.) than in the case of P. atriplicifolia (Benth). The experiments have shown that the known insecticidal effectiveness of the essential oils can be enhanced by preliminary irradiation. Possible approaches to implementation of the combined treatment are discussed. PMID- 23632648 TI - A new binuclear oxovanadium(V) complex as a catalyst in combination with pyrazinecarboxylic acid (PCA) for efficient alkane oxygenation by H2O2. AB - A new binuclear oxovanadium(V) complex [{VO(OEt)(EtOH)}2L] (1) where H4L is bis(2 hydroxybenzylidene)terephthalohydrazide has been synthesized and fully characterized. The combination of 1 with pyrazine-2-carboxylic acid (PCA; a cocatalyst) affords a catalytic system for the efficient oxidation of saturated hydrocarbons, RH, with hydrogen peroxide and air in acetonitrile solution at 50 degrees C to produce alkyl hydroperoxides, ROOH, as the main primary products. Very high turnover numbers (TONs) have been attained in this reaction: for example, after 2220 min, TON = 44,000 and initial TOF (turnover frequency) = 3300 h(-1) per molecule of complex 1. The estimated activation energy of the cyclohexane oxygenation in the presence of 1/PCA is E(a) = 16 +/- 2 kcal mol(-1). This value is identical to that obtained for the cyclohexane oxidation with H2O2 catalyzed by the (n-Bu4N)[VO3]/PCA combination (17 +/- 2 kcal mol(-1)). The dependences of initial oxidation rates W0 on the initial concentrations of all components of the reaction mixture have been determined. Based on these kinetic data and on the regio- and bond-selectivity parameters measured in the oxidation of linear and branched alkanes a mechanism of the oxidation has been proposed which includes the generation of hydroxyl radicals in the crucial stage. PMID- 23632649 TI - [Osteotomy for approaches to the knee joint. Tibial tubercle, lateral epicondyle of the femur and head of the fibula]. AB - The present article summarizes the different osteotomy techniques for an extension of standard surgical approaches to the knee joint in selected patients. The aim is to achieve satisfactory exposure and reduce potential postoperative complications compared to alternative techniques, such as the V-Y plasty or the quadriceps snip procedures. Osteotomy of the tibial tubercle is a reasonable extension of the anteromedial or the anterolateral surgical approach in selected patients undergoing revision total knee replacement. This osteotomy will provide excellent surgical exposure of the knee without the risk of avulsion of the patellar tendon and will preserve the blood supply of the patella and the surrounding soft tissue. Moreover, functional clinical outcome will be improved by minimizing damage to the extensor mechanism. Osteotomy of the lateral femoral condyle gives excellent exposure of the posterolateral aspect of the knee joint which might be necessary in some patients with fractures of the posterolateral tibial plateau as well as patients undergoing open allograft transplantation of the lateral meniscus. An alternative option for an extended exposure to the posterolateral knee joint is accomplished by osteotomy or partial resection of the fibular head which is also described as having good clinical results and a low complication rate. PMID- 23632650 TI - [Update on metal-on-metal hip joints]. AB - Increasing data are available describing risk factors for the development of local and systemic adverse events following operations using metal-on-metal (MoM) hip implants. The prevalence and clinical relevance of metal-associated problems are, however, still under debate. They can be influenced by type and position of implant as well as patient-specific factors. Patients with small MoM heads (maximum diameter 32 mm) and subgroups of resurfacing arthroplasty can achieve good long-term survival. The use of large head MoM implants (diameters greater than 36 mm), however, is currently not advised due to the unsatisfactory results. PMID- 23632652 TI - Morphology dependent oxygen reduction activity of titanium carbide: bulk vs. nanowires. AB - Titanium carbide (TiC) possesses fascinating properties like high electrical conductivity and high mechanical strength coupled with high corrosion resistance and stability in acidic and alkaline environments. The present study demonstrates the tunability of mechanistic aspects of oxygen reduction reaction (ORR) using TiC nanostructures. One dimensional TiC nanostructures (TiC-NW) have been synthesized using a simple, hydrothermal method and used as a catalyst for ORR. Shape dependent electroactivity is demonstrated by comparing the activity of TiC NW with its bulk counterparts. Comparative studies reveal higher ORR activities in the case of 1D TiC-NW involving ~4 electrons showing efficient reduction of molecular oxygen. Excellent stability and high methanol tolerance with good selectivity for ORR is reported. PMID- 23632653 TI - Androgen use for low sexual desire in midlife women. AB - CLINICAL SCENARIO: Andrea, a 53-year-old postmenopausal woman, is concerned about her loss of desire for sexual activity. Her last menstrual period occurred 2 years ago, and she has experienced minimal vasomotor symptoms. She has a loving relationship with her husband, to whom she has been married for 5 years and with whom she has previously enjoyed sexual intimacy, often initiating it. She is disturbed by the fact that not only has she no sexual desire but also that she has become unresponsive to her husband's sexual advances. The problem predates menopause by 1 to 2 years. She has recently heard that testosterone may be a treatment for this and wants to know what options are available. PMID- 23632651 TI - Modulation frequency discrimination with modulated and unmodulated interference in normal hearing and in cochlear-implant users. AB - Differences in fundamental frequency (F0) provide an important cue for segregating simultaneous sounds. Cochlear implants (CIs) transmit F0 information primarily through the periodicity of the temporal envelope of the electrical pulse trains. Successful segregation of sounds with different F0s requires the ability to process multiple F0s simultaneously, but it is unknown whether CI users have this ability. This study measured modulation frequency discrimination thresholds for half-wave rectified sinusoidal envelopes modulated at 115 Hz in CI users and normal-hearing (NH) listeners. The target modulation was presented in isolation or in the presence of an interferer. Discrimination thresholds were strongly affected by the presence of an interferer, even when it was unmodulated and spectrally remote. Interferer modulation increased interference and often led to very high discrimination thresholds, especially when the interfering modulation frequency was lower than that of the target. Introducing a temporal offset between the interferer and the target led to at best modest improvements in performance in CI users and NH listeners. The results suggest no fundamental difference between acoustic and electric hearing in processing single or multiple envelope-based F0s, but confirm that differences in F0 are unlikely to provide a robust cue for perceptual segregation in CI users. PMID- 23632654 TI - Patient Handout. What you should know about testosterone for midlife women with sexual problems. PMID- 23632655 TI - Menopause education: needs assessment of American obstetrics and gynecology residents. AB - OBJECTIVE: This study aims to understand the current teaching of menopause medicine in American obstetrics and gynecology residency programs. METHODS: A Web based survey was e-mailed to all American obstetrics and gynecology residency directors, with a request that they forward it to their residents. RESULTS: Of 258 residency program directors contacted, 79 (30.6%) confirmed forwarding the survey. In all, 1,799 people received the survey, with 510 completions, for a response rate of 28.3%. Most residents reported that they had limited knowledge and needed to learn more about these aspects of menopause medicine: pathophysiology of menopause symptoms (67.1%), hormone therapy (68.1%), nonhormone therapy (79.0%), bone health (66.1%), cardiovascular disease (71.7%), and metabolic syndrome (69.5%). Among fourth-year residents who will be entering clinical practice soon, a large proportion also reported a need to learn more in these areas: pathophysiology of menopause symptoms (45.9%), hormone therapy (54.2%), nonhormone therapy (69.4%), bone health (54.2%), cardiovascular disease (64.3%), and metabolic syndrome (63.8%). When asked to rate the most preferred modalities for learning about menopause, the top choice was supervised clinics (53.2%), followed by case presentations (22.2%), formal lectures (21.3%), small groups (14.7%), Web-based learning (7.8%), and independent reading (5.2%). Only 20.8% of residents reported that their program had a formal menopause medicine learning curriculum, and 16.3% had a defined menopause clinic as part of their residency. CONCLUSIONS: It seems that some American residency programs do not fulfill the educational goals of their residents in menopause medicine. A curriculum would be beneficial for increasing knowledge and clinical experience on menopause issues. PMID- 23632656 TI - Association between serum osteocalcin and insulin resistance in postmenopausal, but not premenopausal, women in Korea. AB - OBJECTIVE: Menopause is known to compound cardiometabolic disease risk factors, and a deeper understanding of the mechanism of this effect is needed. Recently, the osteoblast-derived protein osteocalcin was found to function as a regulator of glucose and fat metabolism. However, there is a lack of studies comparing the extent of association between osteocalcin and glucose metabolism in postmenopausal versus premenopausal women. METHODS: To examine the relationship between serum osteocalcin and glucose metabolism in premenopausal versus postmenopausal women, we identified well-balanced pairs of premenopausal and postmenopausal women matched on propensity score. The interactions between serum osteocalcin levels and menopause status on fasting glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) and the associations of these parameters with serum osteocalcin levels in premenopausal and postmenopausal women were statistically analyzed. RESULTS: Among the 61 matched pairs of premenopausal and postmenopausal women, significant interactions of menopause status and serum osteocalcin levels were observed for fasting insulin (P = 0.031) and HOMA-IR (P = 0.019). Furthermore, after logarithmical transformation for each variable, significant relationships between serum osteocalcin levels and fasting insulin (r = -0.307, P = 0.016) and HOMA-IR (r = 0.298, P = 0.019) were found in postmenopausal women, but no significant correlation was seen in premenopausal women (r = 0.002, P = 0.989 and r = 0.062, P = 0.633, respectively). CONCLUSIONS: Our study shows that the association between serum osteocalcin and insulin resistance varies according to menopause status, and that serum osteocalcin is associated with insulin resistance in postmenopausal women but not in premenopausal women. As postmenopausal women have a higher prevalence of obesity and other cardiac risk factors, the potential endocrine actions of osteocalcin may serve as a marker of metabolism in menopause status. Further studies are needed to define the precise nature of the relationship between osteocalcin and insulin resistance in postmenopausal women. PMID- 23632657 TI - Relationship between objectively recorded hot flashes and sleep disturbances among breast cancer patients: investigating hot flash characteristics other than frequency. AB - OBJECTIVE: The aim of this study was to evaluate the relationship between various characteristics of objectively recorded hot flashes and sleep disturbances in breast cancer patients. METHODS: Fifty-six women who had completed a similar treatment protocol for a first diagnosis of breast cancer within the previous 3 months wore ambulatory sternal skin conductance and polysomnography devices for a home-based nighttime recording of hot flashes and sleep. RESULTS: Hot flash frequency was not associated with polysomnographic variables (r = -0.18 to 0.21) or beta-I and beta-II electroencephalographic activities (r = -0.01 and 0.03) but was significantly correlated with increased slow (r = 0.28) and delta (r = 0.32) electroencephalographic activities. A slower hot flash onset and a longer hot flash duration were associated with greater polysomnographic impairments (r = 0.50 to 0.48). Greater sleep disturbances were found during hot flash onset or hot flash plateau as compared with the pre-hot flash period (greater percentage of wake time, lower percentage of stage II sleep, and lower percentage of rapid eye movement sleep, all P values < 0.05). The probability that a stage change to a lighter sleep occurred was significantly greater during hot flash onset (11%) than during hot flash plateau (6%; P = 0.02). CONCLUSIONS: This study suggests that the speed and duration of hot flashes would contribute more importantly to sleep alterations than hot flash frequency. Sleep disturbances tend to occur simultaneously with hot flashes, suggesting that these two nocturnal symptoms are manifestations of a higher-order mechanism involving the central nervous system. PMID- 23632658 TI - Adverse association between obesity and menopause in mice treated with bezafibrate, a pan peroxisome proliferator-activated receptor agonist. AB - OBJECTIVE: The goal of this study was to investigate the combined effects of ovariectomy (OVX) and high-fat diet (HF) on insulin sensitivity and pancreatic remodeling in C57BL/6 mice treated with bezafibrate. METHODS: Female C57BL/6 mice were subjected to OVX or surgical procedure without removal of the ovary (SHAM). Animals received standard chow (SC; 10% lipids) or HF (60% lipids). After 13 weeks on the diets, the animals were subdivided into six groups based on diet, bezafibrate treatment, or both: SHAM-SC, SHAM-HF, SHAM-HFBz, OVX-SC, OVX-HF, and OVX-HFBz. After treatment for 5 weeks, the pancreas was removed and analyzed using morphometry, stereological tools, immunostaining, and multiplex assay kits. RESULTS: SHAM-HF and OVX-HF mice showed increased fasting glucose levels, plasma insulin levels, homeostasis model of assessment for insulin resistance index, body mass, islet hypertrophy, beta-cell mass, and insulin immunostaining, but decreased GLUT2 immunostaining. Bezafibrate treatment prevented islet hypertrophy and reduced body mass, plasma insulin levels, and homeostasis model of assessment for insulin resistance index. CONCLUSIONS: OVX combined with HF accentuates the effects of menopause, leading to the development of insulin resistance. Bezafibrate treatment reduces body mass, plasma insulin levels, and pancreatic islet hypertrophy in mice fed HF. PMID- 23632659 TI - Changes in bone mineral density are correlated with bone markers and reductions in hot flush severity in postmenopausal women treated with bazedoxifene/conjugated estrogens. AB - OBJECTIVE: A post hoc exploratory analysis was conducted to examine correlations between changes in bone density, bone markers, and hot flushes after the treatment of postmenopausal women with bazedoxifene (BZA)/conjugated estrogens (CE). METHODS: In a 2-year phase 3 study, 3,397 postmenopausal women were randomized to BZA 10 mg/CE 0.45 mg, BZA 20 mg/CE 0.45 mg, BZA 40 mg/CE 0.45 mg, BZA 10 mg/CE 0.625 mg, BZA 20 mg/CE 0.625 mg, BZA 40 mg/CE 0.625 mg, raloxifene 60 mg, or placebo. In this analysis, bone density changes at 2 years were compared with baseline levels of the bone markers serum C-telopeptide and osteocalcin. Correlations between changes in bone density and changes in 12-week hot flush composite scores in symptomatic women were also analyzed. RESULTS: Treatment with BZA 20 mg/CE 0.45 mg or BZA 20 mg/CE 0.625 mg increased lumbar spine bone density more in women with higher bone resorption and formation, categorized by baseline levels of C-telopeptide and osteocalcin (P < 0.001, both BZA/CE doses). With placebo, larger decreases in lumbar spine bone density were seen in the highest tertile of serum C-telopeptide. There was no correlation between changes in total hip bone density and baseline bone markers. There were significant correlations between percent change in hot flush score at week 12 and percent changes in lumbar spine (r = -0.31, P = 0.006) and total hip (r = -0.23, P = 0.044) bone densities at month 24. CONCLUSIONS: With 2-year BZA/CE treatment, women with larger increases in lumbar spine and total hip densities also have higher baseline bone markers. Early reductions in hot flush score (12 wk) are predictive of long-term increases in bone density (24 mo). PMID- 23632660 TI - Characterization of blood lipoproteins and validation of cholesterol and triacylglycerol assays for free-ranging polar bears (Ursus maritimus). AB - Blood triacylglycerol (TG) and lipoproteins are important variables for evaluating nutritional status of wildlife, but measurements are often expensive and difficult. Performance of a small, portable blood analyzer intended for human medical diagnostics was evaluated in measuring these variables in plasma and serum from free-ranging polar bears (Ursus maritimus), which are experiencing nutritional stress related to sea ice loss. The analyzer accurately tracked changes in concentration of total cholesterol (Ctotal), cholesterol associated with high-density lipoprotein (CHDL), and TG during a validation protocol of diluting samples and spiking them with exogenous cholesterol and glycerol. Values of Ctotal and TG agreed well with values obtained by other methods (ultracentrifugation followed by colorimetric assays); agreement was variable for values of cholesterol associated with specific lipoproteins. Similar to a study of captive polar bears, ultracentrifugation methods revealed greater TG in very low-density lipoproteins than in low-density lipoprotein, which is unusual and merits additional study. PMID- 23632661 TI - Serum amyloid A as a prognostic marker in cats with various diseases. AB - Serum amyloid A (SAA) is reported not only as a marker for the presence of inflammation but also as a prognostic indicator in human beings. In cats, however, there is no report on the association between SAA concentration and prognosis. The objective of the current study was to evaluate SAA concentration as a prognostic marker in diseased cats. A total of 175 cats with neoplastic diseases, inflammatory diseases, and other diseases were retrospectively recruited, and the medical records of these cats, including follow-up data on mortality, were reviewed. Cats were divided into 2 groups according to SAA concentration, and differences in survival between each group were assessed. Median survival time of cats in the elevated SAA (>0.82 mg/l) group was significantly shorter than that in the nonelevated SAA (<=0.82 mg/l) group (P < 0.001). Furthermore, by multivariate analysis, SAA concentration was shown as a significant and independent prognostic marker in cats with various diseases (P = 0.015). Serum amyloid A concentration in diseased cats is a useful predictive indicator of prognosis regardless of diagnosis. PMID- 23632662 TI - Identification of pathogens in mastitis milk samples with fluorescent in situ hybridization. AB - Traditionally, the bacteriological examination of mastitis milk samples is performed by culture followed by biochemical tests on the cultured bacteria to allow identification of the causative pathogen. Depending on the species involved, this classic identification is time-consuming compared to other techniques such as fluorescent in situ hybridization (FISH), a culture independent method that utilizes oligonucleotides (labeled with a fluorophore) that are specific to a string of target DNA/RNA. In the current study, the applicability of FISH was evaluated for the detection of mastitis pathogens directly in milk samples. To remove interfering lipids and proteins from mastitis milk samples prior to FISH, a previously published enzymatic treatment with savinase was evaluated. FISH was performed using oligonucleotides specific for Staphylococcus aureus, Streptococcus agalactiae, Streptococcus uberis, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, and Trueperella (Arcanobacterium) pyogenes. The enzymatic pretreatment and the sensitivity of FISH were evaluated using spiked whole milk samples and mastitis milk samples with bacterial loads of less than 10(3) up to 10(8) colony-forming units (CFU)/ml. Bacteria were reliably detected in milk samples with bacterial numbers of 10(6) CFU/ml or higher. However, bacteria present in numbers below 10(6) CFU/ml were not detectable in all cases. The ability of FISH to identify mastitis causing pathogens directly in milk samples, and therefore earlier than classical culture methods, can supplement the classic diagnostic procedures for mastitis milk samples. PMID- 23632663 TI - Multiscale modelling approach combining a kinetic model of glutathione metabolism with PBPK models of paracetamol and the potential glutathione-depletion biomarkers ophthalmic acid and 5-oxoproline in humans and rats. AB - A key role of the antioxidant glutathione is detoxification of chemically reactive electrophilic drug metabolites within the liver. Therefore glutathione depletion can have severe toxic consequences. Ophthalmic acid and 5-oxoproline are metabolites involved in glutathione metabolism, which can be measured readily in the blood and urine and have been proposed as candidate biomarkers of hepatic glutathione content. However, currently it is unclear whether their concentrations in plasma exhibit a robust correlation with hepatic glutathione content. To explore this important question, we have developed a novel approach which combines a physiologically based pharmacokinetic (PBPK) model of metabolism and disposition of paracetamol (acetaminophen) with a previously developed mathematical systems model of hepatic glutathione homeostasis. Paracetamol is metabolised to reactive intermediates which deplete glutathione and cause toxicity when given at high doses. Our model correctly predicted that hepatic glutathione depletion following paracetamol administration resulted in elevated concentrations of 5-oxoproline and ophthalmic acid in blood and of 5-oxoproline in urine. However, we also found from the model that concentrations of both of the compounds were likely to be influenced by prolonged administration of paracetamol and by the concentrations of intracellular metabolites such as methionine. We conclude that care must be taken when extrapolating from concentrations of these biomarkers to hepatic glutathione status. PMID- 23632664 TI - What an editor seeks. PMID- 23632665 TI - Total hip replacement for patients with active tuberculosis of the hip: a systematic review and pooled analysis. AB - The timing of total hip replacement (THR) in patients with active tuberculosis (TB) of the hip is controversial, because of the potential risk of reactivation of infection. There is little information about the outcome of THR in these patients. We conducted a systematic review of published studies that evaluated the outcome of THR in patients with active TB of the hip. A review of multiple databases referenced articles published between 1950 and 2012. A total of six articles were identified, comprising 65 patients. TB was confirmed histologically in all patients. The mean follow-up was 53.2 months (24 to 108). Antituberculosis treatment continued post-operatively for between six and 15 months, after debridement and THR. One non-compliant patient had reactivation of infection. At the final follow-up the mean Harris hip score was 91.7 (56 to 98). We conclude that THR in patients with active TB of the hip is a safe procedure, providing symptomatic relief and functional improvement if undertaken in association with extensive debridement and appropriate antituberculosis treatment. PMID- 23632666 TI - Bone graft substitutes currently available in orthopaedic practice: the evidence for their use. AB - We reviewed 59 bone graft substitutes marketed by 17 companies currently available for implantation in the United Kingdom, with the aim of assessing the peer-reviewed literature to facilitate informed decision-making regarding their use in clinical practice. After critical analysis of the literature, only 22 products (37%) had any clinical data. Norian SRS (Synthes), Vitoss (Orthovita), Cortoss (Orthovita) and Alpha-BSM (Etex) had Level I evidence. We question the need for so many different products, especially with limited published clinical evidence for their efficacy, and conclude that there is a considerable need for further prospective randomised trials to facilitate informed decision-making with regard to the use of current and future bone graft substitutes in clinical practice. PMID- 23632667 TI - Development and prevalence of femoroacetabular impingement-associated morphology in a paediatric and adolescent population: a CT study of 225 patients. AB - We investigated the development of CT-based bony radiological parameters associated with femoroacetabular impingement (FAI) in a paediatric and adolescent population with no known orthopaedic hip complaints. We retrospectively reformatted and reoriented 225 abdominal CTs into standardised CT pelvic images with neutral pelvic tilt and inclination (244 female and 206 male hips) in patients ranging from two to 19 years of age (mean 10.4 years). The Tonnis angle, acetabular depth ratio, lateral centre-edge angle, acetabular version and alpha angle were assessed. Acetabular measurements demonstrated increased acetabular coverage with age and/or progressive ossification of the acetabulum. The alpha angle decreased with age and/or progressive cortical bone development and resultant narrowing of the femoral neck. Cam and pincer morphology occurred as early as ten and 12 years of age, respectively, and their prevalence in the adolescent patient population is similar to that reported in the adult literature. Future aetiological studies of FAI will need to focus on the early adolescent population. PMID- 23632668 TI - Ten-year RSA-measured migration of the Exeter femoral stem. AB - The Exeter femoral stem is a double-tapered highly polished collarless cemented implant with good long-term clinical results. In order to determine why the stem functions well we have undertaken a long-term radiostereometric analysis (RSA) study. A total of 20 patients undergoing primary Exeter total hip replacement for osteoarthritis using the Hardinge approach were recruited and followed with RSA for ten years. The stems progressively subsided and internally rotated with posterior head migration. The mean subsidence was 0.7 mm (95% confidence interval (CI) 0.5 to 0.9) at two years and 1.3 mm (95% CI 1.0 to 1.6) at ten years. The mean posterior migration of the head was 0.7 mm (95% CI 0.5 to 0.9) at two years and 1.2 mm (95% CI 1.0 to 1.4) at ten years. There was no significant cement restrictor migration. The Exeter stem continues to subside slowly into the cement mantle in the long term. This appears to compress the cement and the cement bone interface, contributing to secure fixation in the long term. PMID- 23632669 TI - A comparison of hemiarthroplasty with a novel polycarbonate-urethane acetabular component for displaced intracapsular fractures of the femoral neck: a randomised controlled trial in elderly patients. AB - We undertook a randomised controlled trial to compare bipolar hemiarthroplasty (HA) with a novel total hip replacement (THR) comprising a polycarbonate-urethane (PCU) acetabular component coupled with a large-diameter metal femoral head for the treatment of displaced fractures of the femoral neck in elderly patients. Functional outcome, assessed with the Harris hip score (HHS) at three months and then annually after surgery, was the primary endpoint. Rates of revision and complication were secondary endpoints. Based on a power analysis, 96 consecutive patients aged > 70 years were randomised to receive either HA (49) or a PCU-THR (47). The mean follow-up was 30.1 months (23 to 50) and 28.6 months (22 to 52) for the HA and the PCU group, respectively. The HHS showed no statistically significant difference between the groups at every follow-up. Higher pain was recorded in the PCU group at one and two years' follow-up (p = 0.006 and p = 0.019, respectively). In the HA group no revision was performed. In the PCU-THR group six patients underwent revision and one patient is currently awaiting re operation. The three-year survival rate of the PCU-THR group was 0.841 (95% confidence interval 0.680 to 0.926). Based on our findings we do not recommend the use of the PCU acetabular component as part of the treatment of patients with fractures of the femoral neck. PMID- 23632670 TI - Reduction of blood loss with the use of a new combined intra-operative and post operative autologous blood transfusion system compared with no drainage in primary total hip replacement. AB - Autologous retransfusion and no-drainage are both blood-saving measures in total hip replacement (THR). A new combined intra- and post-operative autotransfusion filter system has been developed especially for primary THR, and we conducted a randomised controlled blinded study comparing this with no-drainage. A total of 204 THR patients were randomised to autologous blood transfusion (ABT) (n = 102) or no-drainage (n = 102). In the ABT group, a mean of 488 ml (sd 252) of blood was retransfused. The mean lowest post-operative haemoglobin level during the hospital stay was higher in the autotransfusion group (10.6 g/dl (7.8 to 13.9) vs 10.2 g/dl (7.5 to 13.3); p = 0.01). The mean haemoglobin levels for the ABT and no-drainage groups were not significantly different on the first day (11.3 g/dl (7.8 to 13.9) vs 11.0 g/dl (8.1 to 13.4); p = 0.07), the second day (11.1 g/dl (8.2 to 13.8) vs 10.8 g/dl (7.5 to 13.3); p = 0.09) or the third day (10.8 g/dl (8.0 to 13.0) vs 10.6 g/dl (7.5 to 14.1); p = 0.15). The mean total peri operative net blood loss was 1464 ml (sd 505) in the ABT group and 1654 ml (sd 553) in the no-drainage group (p = 0.01). Homologous blood transfusions were needed in four patients (3.9%) in the ABT group and nine (8.8%) in the no drainage group (p = 0.15). No statistically significant difference in adverse events was found between the groups. The use of a new intra- and post-operative autologous blood transfusion filter system results in less total blood loss and a smaller maximum decrease in haemoglobin levels than no-drainage following primary THR. PMID- 23632671 TI - Reconstruction of the anterior cruciate ligament: association of graft choice with increased risk of early revision. AB - We examined the association of graft type with the risk of early revision of primary anterior cruciate ligament reconstruction (ACLR) in a community-based sample. A retrospective analysis of a cohort of 9817 ACLRs recorded in an ACLR Registry was performed. Patients were included if they underwent primary ACLR with bone-patellar tendon-bone autograft, hamstring tendon autograft or allograft tissue. Aseptic failure was the main endpoint of the study. After adjusting for age, gender, ethnicity, and body mass index, allografts had a 3.02 times (95% confidence interval (CI) 1.93 to 4.72) higher risk of aseptic revision than bone patellar tendon-bone autografts (p < 0.001). Hamstring tendon autografts had a 1.82 times (95% CI 1.10 to 3.00) higher risk of revision compared with bone patellar tendon-bone autografts (p = 0.019). For each year increase in age, the risk of revision decreased by 7% (95% CI 5 to 9). In gender-specific analyses a 2.26 times (95% CI 1.15 to 4.44) increased risk of hamstring tendon autograft revision in females was observed compared with bone-patellar tendon-bone autograft. We conclude that allograft tissue, hamstring tendon autografts, and younger age may all increase the risk of early revision surgery after ACLR. PMID- 23632672 TI - Analgesia after total knee replacement: local infiltration versus epidural combined with a femoral nerve blockade: a prospective, randomised pragmatic trial. AB - In a randomised controlled pragmatic trial we investigated whether local infiltration analgesia would result in earlier readiness for discharge from hospital after total knee replacement (TKR) than patient-controlled epidural analgesia (PCEA) plus femoral nerve block. A total of 45 patients with a mean age of 65 years (49 to 81) received a local infiltration with a peri-articular injection of bupivacaine, morphine and methylprednisolone, as well as adjuvant analgesics. In 45 PCEA+femoral nerve blockade patients with a mean age of 67 years (50 to 84), analgesia included a bupivacaine nerve block, bupivacaine/hydromorphone PCEA, and adjuvant analgesics. The mean time until ready for discharge was 3.2 days (1 to 14) in the local infiltration group and 3.2 days (1.8 to 7.0) in the PCEA+femoral nerve blockade group. The mean pain scores for patients receiving local infiltration were higher when walking (p = 0.0084), but there were no statistically significant differences at rest. The mean opioid consumption was higher in those receiving local infiltration. The choice between these two analgesic pathways should not be made on the basis of time to discharge after surgery. Most secondary outcomes were similar, but PCEA+femoral nerve blockade patients had lower pain scores when walking and during continuous passive movement. If PCEA+femoral nerve blockade is not readily available, local infiltration provides similar length of stay and similar pain scores at rest following TKR. PMID- 23632673 TI - Survival rates and causes of revision in cemented primary total knee replacement: a report from the Norwegian Arthroplasty Register 1994-2009. AB - We evaluated the rates of survival and cause of revision of seven different brands of cemented primary total knee replacement (TKR) in the Norwegian Arthroplasty Register during the years 1994 to 2009. Revision for any cause, including resurfacing of the patella, was the primary endpoint. Specific causes of revision were secondary outcomes. Three posterior cruciate-retaining (PCR) fixed modular-bearing TKRs, two fixed non-modular bearing PCR TKRs and two mobile bearing posterior cruciate-sacrificing TKRs were investigated in a total of 17 782 primary TKRs. The median follow-up for the implants ranged from 1.8 to 6.9 years. Kaplan-Meier 10-year survival ranged from 89.5% to 95.3%. Cox's relative risk (RR) was calculated relative to the fixed modular-bearing Profix knee (the most frequently used TKR in Norway), and ranged from 1.1 to 2.6. The risk of revision for aseptic tibial loosening was higher in the mobile-bearing LCS Classic (RR 6.8 (95% confidence interval (CI) 3.8 to 12.1)), the LCS Complete (RR 7.7 (95% CI 4.1 to 14.4)), the fixed modular-bearing Duracon (RR 4.5 (95% CI 1.8 to 11.1)) and the fixed non-modular bearing AGC Universal TKR (RR 2.5 (95% CI 1.3 to 5.1)), compared with the Profix. These implants (except AGC Universal) also had an increased risk of revision for femoral loosening (RR 2.3 (95% CI 1.1 to 4.8), RR 3.7 (95% CI 1.6 to 8.9), and RR 3.4 (95% CI 1.1 to 11.0), respectively). These results suggest that aseptic loosening is related to design in TKR. PMID- 23632674 TI - Reconstruction using femoral head allograft in revision total knee replacement: an experience in Asian patients. AB - Structural allografts may be used to manage uncontained bone defects in revision total knee replacement (TKR). However, the availability of cadaver grafts is limited in some areas of Asia. The aim of this study was to evaluate the mid-term outcome of the use of femoral head allografts for the reconstruction of uncontained defects in revision TKR, focusing on complications related to the graft. We retrospectively reviewed 28 patients (30 TKRs) with Anderson Orthopaedic Research Institute (AORI) type 3 bone defects, who underwent revision using femoral head allografts and stemmed components. The mean number of femoral heads used was 1.7 (1 to 3). The allograft-host junctions were packed with cancellous autograft. At a mean follow-up of 76 months (38 to 136) the mean American Knee Society knee score improved from 37.2 (17 to 60) pre-operatively to 90 (83 to 100) (p < 0.001). The mean function score improved from 26.5 (0 to 50) pre-operatively to 81 (60 to 100) (p < 0.001). All the grafts healed to the host bone. The mean time to healing of the graft was 6.6 months (4 to 16). There have been no complications of collapse of the graft, nonunion, infection or implant loosening. No revision surgery was required. The use of femoral head allografts in conjunction with a stemmed component and autogenous bone graft in revision TKR in patients with uncontained bone defects resulted in a high rate of healing of the graft with minimal complications and a satisfactory outcome. Longer follow-up is needed to observe the evolution of the graft. PMID- 23632675 TI - A comparison of proximal and distal chevron osteotomy for the correction of moderate hallux valgus deformity. AB - The purpose of this study was to compare the results of proximal and distal chevron osteotomy in patients with moderate hallux valgus. We retrospectively reviewed 34 proximal chevron osteotomies without lateral release (PCO group) and 33 distal chevron osteotomies (DCO group) performed sequentially by a single surgeon. There were no differences between the groups with regard to age, length of follow-up, demographic or radiological parameters. The clinical results were assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) scoring system and the radiological results were compared between the groups. At a mean follow-up of 14.6 months (14 to 32) there were no significant differences in the mean AOFAS scores between the DCO and PCO groups (93.9 (82 to 100) and 91.8 (77 to 100), respectively; p = 0.176). The mean hallux valgus angle, intermetatarsal angle and sesamoid position were the same in both groups. The metatarsal declination angle decreased significantly in the PCO group (p = 0.005) and the mean shortening of the first metatarsal was significantly greater in the DCO group (p < 0.001). We conclude that the clinical and radiological outcome after a DCO is comparable with that after a PCO; longer follow-up would be needed to assess the risk of avascular necrosis. PMID- 23632676 TI - Anatomical variations of the deltoid artery: relevance to the deltopectoral approach to the shoulder. AB - Despite the expansion of arthroscopic surgery of the shoulder, the open deltopectoral approach to the shoulder is still frequently used, for example in fracture fixation and shoulder replacement. However, it is sometimes accompanied by unexpected bleeding. The cephalic vein is the landmark for the deltopectoral interval, yet its intimate relationship with the deltoid artery, and the anatomical variations in that structure, have not previously been documented. In this study the vascular anatomy encountered during 100 consecutive elective deltopectoral approaches was recorded and the common variants described. Two common variants of the deltoid artery were encountered. In type I (71%) it crosses the interval and tunnels into the deltoid muscle without encountering the cephalic vein. However, in type II (21%) it crosses the interval, reaches the cephalic vein and then runs down, medial to and behind it, giving off several small arterial branches that return back across the interval to the pectoralis major. Several minor variations were also seen (8%). These variations in the deltoid artery have not previously been described and may lead to confusion and unexpected bleeding during this standard anterior surgical approach to the shoulder. PMID- 23632677 TI - Isolated latissimus dorsi transfer to restore shoulder external rotation in adults with brachial plexus injury. AB - In adults with brachial plexus injuries, lack of active external rotation at the shoulder is one of the most common residual deficits, significantly compromising upper limb function. There is a paucity of evidence to address this complex issue. We present our experience of isolated latissimus dorsi (LD) muscle transfer to achieve active external rotation. This is a retrospective review of 24 adult post-traumatic plexopathy patients who underwent isolated latissimus dorsi muscle transfer to restore external rotation of the shoulder between 1997 and 2010. All patients were male with a mean age of 34 years (21 to 57). All the patients underwent isolated LD muscle transfer using a standard technique to correct external rotational deficit. Outcome was assessed for improvement in active external rotation, arc of movement, muscle strength and return to work. The mean improvement in active external rotation from neutral was 24 degrees (10 degrees to 50 degrees ). The mean increase in arc of rotation was 52 degrees (38 degrees to 55 degrees ). Mean power of the external rotators was 3.5 Medical Research Council (MRC) grades (2 to 5). A total of 21 patients (88%) were back in work by the time of last follow up. Of these, 13 had returned to their pre-injury occupation. Isolated latissimus dorsi muscle transfer provides a simple and reliable method of restoring useful active external rotation in adults with brachial plexus injuries with internal rotational deformity. PMID- 23632678 TI - Surgical treatment of physeal injuries of the lateral aspect of the clavicle: a case series. AB - Lateral clavicular physeal injuries in adolescents are frequently misinterpreted as acromioclavicular dislocations. There are currently no clear guidelines for the management of these relatively rare injuries. Non-operative treatment can result in a cosmetic deformity, warranting resection of the non-remodelled original lateral clavicle. However, fixation with Kirschner (K)-wires may be associated with infection and/or prominent metalwork. We report our experience with a small series of such cases. Between October 2008 and October 2011 five patients with lateral clavicular physeal fractures (types III, IV and V) presented to our unit. There were four boys and one girl with a mean age of 12.8 years (9 to 14). Four fractures were significantly displaced and treated operatively using a tension band suture technique. One grade III fracture was treated conservatively. The mean follow-up was 26 months (6 to 42). All patients made an uncomplicated recovery. The mean time to discharge was three months. The QuickDASH score at follow-up was 0 for each patient. No patient developed subsequent growth disturbances. We advocate the surgical treatment of significantly displaced Grade IV and V fractures to avoid cosmetic deformity. A tension band suture technique avoids the problems of retained metalwork and the need for a secondary procedure. Excellent clinical and radiological results were seen in all our patients. PMID- 23632679 TI - Revision of an unstable hemiarthroplasty or anatomical total shoulder replacement using a reverse design prosthesis. AB - Instability after arthroplasty of the shoulder is difficult to correct surgically. Soft-tissue procedures and revision surgery using unconstrained anatomical components are associated with a high rate of failure. The purpose of this study was to determine the results of revision of an unstable anatomical shoulder arthroplasty to a reverse design prosthesis. Between 2004 and 2007, 33 unstable anatomical shoulder arthroplasties were revised to a reverse design. The mean age of the patients was 71 years (53 to 86) and their mean follow-up was 42 months (25 to 71). The mean time to revision was 26 months (4 to 164). Pain scores improved significantly (pre-operative visual analogue scale (VAS) of 7.2 (sd 1.6); most recent VAS 2.2 (sd 1.9); p = 0.001). There was a statistically significant increase in mean active forward elevation from 40.2 degrees (sd 27.3) to 97.0 degrees (sd 36.2) (p = 0.001). There was no significant difference in internal (p = 0.93) or external rotation (p = 0.40). Radiological findings included notching in five shoulders (15%) and heterotopic ossification of the inferior capsular region in three (9%). At the last follow-up 31 shoulders (94%) were stable. The remaining two shoulders dislocated at 2.5 weeks and three months post-operatively, respectively. According to the Neer rating system, there were 13 excellent (40%), ten satisfactory (30%) and ten unsatisfactory results (30%). Revision of hemiarthroplasty or anatomical total shoulder replacement for instability using a reverse design prosthesis gives good short-term results. PMID- 23632680 TI - The cost of outpatient venous thromboembolism prophylaxis following lower limb injuries. AB - This paper reports the cost of outpatient venous thromboembolism (VTE) prophylaxis following 388 injuries of the lower limb requiring immobilisation in our institution, from a total of 7408 new patients presenting between May and November 2011. Prophylaxis was by either self-administered subcutaneous dalteparin (n = 128) or oral dabigatran (n = 260). The mean duration of prophylaxis per patient was 46 days (6 to 168). The total cost (pay and non-pay) for prophylaxis with dalteparin was L107.54 and with dabigatran was L143.99. However, five patients in the dalteparin group required nurse administration (L23 per home visit), increasing the cost of dalteparin to L1142.54 per patient. The annual cost of VTE prophylaxis in a busy trauma clinic treating 12 700 new patients (2010/11), would be L92 526.33 in the context of an income for trauma of L1.82 million, which represents 5.3% of the outpatient tariff. Outpatient prophylaxis in a busy trauma clinic is achievable and affordable in the context of the clinical and financial risks involved. PMID- 23632682 TI - Blood loss in spinal tumour surgery and surgery for metastatic spinal disease: a meta-analysis. AB - There is currently no consensus about the mean volume of blood lost during spinal tumour surgery and surgery for metastatic spinal disease. We conducted a systematic review of papers published in the English language between 31 January 1992 and 31 January 2012. Only papers that clearly presented blood loss data in spinal surgery for metastatic disease were included. The random effects model was used to obtain the pooled estimate of mean blood loss. We selected 18 papers, including six case series, ten retrospective reviews and two prospective studies. Altogether, there were 760 patients who had undergone spinal tumour surgery and surgery for metastatic spinal disease. The pooled estimate of peri-operative blood loss was 2180 ml (95% confidence interval 1805 to 2554) with catastrophic blood loss as high as 5000 ml, which is rare. Aside from two studies that reported large amounts of mean blood loss (> 5500 ml), the resulting funnel plot suggested an absence of publication bias. This was confirmed by Egger's test, which did not show any small-study effects (p = 0.119). However, there was strong evidence of heterogeneity between studies (I(2) = 90%; p < 0.001). Spinal surgery for metastatic disease is associated with significant blood loss and the possibility of catastrophic blood loss. There is a need to establish standardised methods of calculating and reporting this blood loss. Analysis should include assessment by area of the spine, primary pathology and nature of surgery so that the amount of blood loss can be predicted. Consideration should be given to autotransfusion in these patients. PMID- 23632681 TI - Effects of selenium coating of orthopaedic implant surfaces on bacterial adherence and osteoblastic cell growth. AB - The aim of this study was to evaluate whether coating titanium discs with selenium in the form of sodium selenite decreased bacterial adhesion of Staphylococcus aureus and Staph. epidermidis and impeded osteoblastic cell growth. In order to evaluate bacterial adhesion, sterile titanium discs were coated with increasing concentrations of selenium and incubated with bacterial solutions of Staph. aureus (ATCC 29213) and Staph. epidermidis (DSM 3269) and stained with Safranin-O. The effect of selenium on osteoblastic cell growth was also observed. The adherence of MG-63 cells on the coated discs was detected by staining with Safranin-O. The proportion of covered area was calculated with imaging software. The tested Staph. aureus strain showed a significantly reduced attachment on titanium discs with 0.5% (p = 0.011) and 0.2% (p = 0.02) selenium coating. Our test strain from Staph. epidermidis showed a highly significant reduction in bacterial adherence on discs coated with 0.5% (p = 0.0099) and 0.2% (p = 0.002) selenium solution. There was no inhibitory effect of the selenium coating on the osteoblastic cell growth. Selenium coating is a promising method to reduce bacterial attachment on prosthetic material. PMID- 23632683 TI - Risk factors for the displacement of fractures of both bones of the forearm in children. AB - Forearm fractures in children have a tendency to displace in a cast leading to malunion with reduced functional and cosmetic results. In order to identify risk factors for displacement, a total of 247 conservatively treated fractures of the forearm in 246 children with a mean age of 7.3 years (sd 3.2; 0.9 to 14.9) were included in a prospective multicentre study. Multivariate logistic regression analyses were performed to assess risk factors for displacement of reduced or non reduced fractures in the cast. Displacement occurred in 73 patients (29.6%), of which 65 (89.0%) were in above-elbow casts. The mean time between the injury and displacement was 22.7 days (0 to 59). The independent factors found to significantly increase the risk of displacement were a fracture of the non dominant arm (p = 0.024), a complete fracture (p = 0.040), a fracture with translation of the ulna on lateral radiographs (p = 0.014) and shortening of the fracture (p = 0.019). Fractures of both forearm bones in children have a strong tendency to displace even in an above-elbow cast. Severe fractures of the non dominant arm are at highest risk for displacement. Radiographs at set times during treatment might identify early displacement, which should be treated before malunion occurs, especially in older children with less potential for remodelling. PMID- 23632684 TI - The value of ultrasonic diagnosis in the management of vascular complications of supracondylar fractures of the humerus in children. AB - Of 48 consecutive children with Gartland III supracondylar fractures, 11 (23%) had evidence of vascular injury, with an absent radial pulse. The hand was pink and warm in eight and white and cold in the other three patients. They underwent colour-coded duplex scanning (CCDS) and ultrasound velocimetry (UV) to investigate the patency of the brachial artery and arterial blood flow. In seven patients with a pink pulseless hand, CCDS showed a displaced, kinked and spastic brachial artery and a thrombosis was present in the other. In all cases UV showed reduced blood flow in the hand. In three patients with a white pulseless hand, scanning demonstrated a laceration in the brachial artery and/or thrombosis. In all cases, the fracture was reduced under general anaesthesia and fixed with Kirschner wires. Of the seven patients with a pink pulseless hand without thrombosis, the radial pulse returned after reduction in four cases. The remaining three underwent exploration, along with the patients with laceration in the brachial artery and/or thrombosis. We believe that the traditional strategy of watchful waiting in children in whom the radial pulse remains absent in spite of good peripheral perfusion should be revisited. Vascular investigation using these non-invasive techniques that are quick and reliable is recommended in the management of these patients. PMID- 23632686 TI - The operative correction of symptomatic flat foot deformities in children: the relationship between static alignment and dynamic loading. AB - At our institution surgical correction of symptomatic flat foot deformities in children has been guided by a paradigm in which radiographs and pedobarography are used in the assessment of outcome following treatment. Retrospective review of children with symptomatic flat feet who had undergone surgical correction was performed to assess the outcome and establish the relationship between the static alignment and the dynamic loading of the foot. A total of 17 children (21 feet) were assessed before and after correction of soft-tissue contractures and lateral column lengthening, using standardised radiological and pedobarographic techniques for which normative data were available. We found significantly improved static segmental alignment of the foot, significantly improved mediolateral dimension foot loading, and worsened fore-aft foot loading, following surgical treatment. Only four significant associations were found between radiological measures of static segmental alignment and dynamic loading of the foot. Weakness of the plantar flexors of the ankle was a common post operative finding. Surgeons should be judicious in the magnitude of lengthening of the plantar flexors that is undertaken and use techniques that minimise subsequent weakening of this muscle group. PMID- 23632685 TI - Intra-operative neurophysiological prediction of upper trunk recovery in obstetric brachial plexus palsy with neuroma in continuity. AB - We investigated the predictive value of intra-operative neurophysiological investigations in obstetric brachial plexus injuries. Between January 2005 and June 2011 a total of 32 infants of 206 referred to our unit underwent exploration of the plexus, including neurolysis. The findings from intra-operative electromyography, sensory evoked potentials across the lesion and gross muscular response to stimulation were evaluated. A total of 22 infants underwent neurolysis alone and ten had microsurgical reconstruction. Of the former, one was lost to follow-up, one had glenoplasty and three had subsequent nerve reconstructions. Of the remaining 17 infants with neurolysis, 13 (76%) achieved a modified Mallet score > 13 at a mean age of 3.5 years (0.75 to 6.25). Subluxation or dislocation of the shoulder is a major confounding factor. The positive predictive value and sensitivity of the intra-operative EMG for C5 were 100% and 85.7%, respectively, in infants without concurrent shoulder pathology. The positive and negative predictive values, sensitivity and specificity of the three investigations combined were 77%, 100%, 100% and 57%, respectively. In all, 20 infants underwent neurolysis alone for C6 and three had reconstruction. All of the former and one of the latter achieved biceps function of Raimondi grade 5. The positive and negative predictive values, sensitivity and specificity of electromyography for C6 were 65%, 71%, 87% and 42%, respectively. Our method is effective in evaluating the prognosis of C5 lesion. Neurolysis is preferred for C6 lesions. PMID- 23632687 TI - The 2012 ABC orthopaedic fellowship in North America: May 24 to July 2. AB - In May 2012, in airports across the globe, seven orthopaedic surgeons bravely said goodbye to their loved ones, and slowly turned towards their respective aircraft. Filled with expectation and mild trepidation they stepped into the unknown... the ABC fellowship of 2012. PMID- 23632688 TI - Response to: Costa ML, Stengel D, Griffin XL, Carey Smith R, Parsons N. Research methods and The Bone & Joint Journal Bone Joint J 2013;95-B:2-3. PMID- 23632689 TI - Exam corner - May 2013. PMID- 23632693 TI - The cover. Child health. PMID- 23632690 TI - Arrested growth and spontaneous tumor regression of partially resected low-grade cerebellar astrocytomas in children. AB - PURPOSE: The prognosis of children with low-grade cerebellar astrocytoma who have partial resection of tumor is largely unpredictable. The purpose of this study was to review the long-term outcome of such patients. METHODS: The medical charts, imaging findings, operative notes, histopathological reports, and survival times of 12 patients with cerebellar astrocytoma were reviewed. RESULTS: Five patients had total resection and seven had partial resection. Nine patients had grade I histology and three patients had grade II. Follow-up duration ranged from 3 to 25 years. Among the seven patients with residual tumor, five had tumor progression, one had arrested tumor growth, and one had spontaneous tumor regression. Five patients with partial resection received radiotherapy and three had malignant transformation of tumor during follow-up. Six patients, including five who had partial resection, underwent a second operation. One patient with partial resection died of pneumonia 23 years after surgery. CONCLUSIONS: Patients with complete tumor resection had a better prognosis than patients with partial resection. For patients with partial resection, we recommend a "wait and see" policy with surveillance using MRI. The phenomenon of arrested tumor growth and spontaneous tumor regression in patients with cerebellar astrocytoma who have subtotal resection warrants further study. PMID- 23632695 TI - Antityphoid vaccination in children. PMID- 23632696 TI - Programs aim to help schools identify and address mental illness in children. PMID- 23632697 TI - AAP: Consider blood disorders as well as abuse as cause of bleeding in children. PMID- 23632698 TI - Study ignites debate on new anticoagulant. PMID- 23632699 TI - Judge: No age restriction for emergency contraceptive. PMID- 23632709 TI - Differential effects of fructose and glucose on cerebral blood flow. PMID- 23632710 TI - Differential effects of fructose and glucose on cerebral blood flow. PMID- 23632711 TI - Differential effects of fructose and glucose on cerebral blood flow--reply. PMID- 23632712 TI - Falsification end points for observational studies. PMID- 23632713 TI - Falsification end points for observational studies--reply. PMID- 23632714 TI - Serologic markers of Lyme disease in children with autism. PMID- 23632717 TI - Restoring science to the National Children's Study. PMID- 23632718 TI - Shedding light on the long shadow of childhood adversity. PMID- 23632719 TI - The transformation of child health research: innovation, market failure, and the public good. PMID- 23632720 TI - Creation and retention of the next generation of physician-scientists for child health research. PMID- 23632721 TI - A piece of my mind. What is natural? PMID- 23632722 TI - Effect of different dosages of oral vitamin D supplementation on vitamin D status in healthy, breastfed infants: a randomized trial. AB - IMPORTANCE: Vitamin D supplementation in infancy is required to support healthy bone mineral accretion. A supplement of 400 IU of vitamin D per day is thought to support plasma 25-hydroxyvitamin D (25[OH]D) concentrations between 40 and 50 nmol/L; some advocate 75 to 150 nmol/L for bone health. OBJECTIVE: To investigate the efficacy of different dosages of vitamin D in supporting 25(OH)D concentrations in infants. DESIGN, SETTING, AND PARTICIPANTS: Double-blind randomized clinical trial conducted among 132 one-month-old healthy, term, breastfed infants from Montreal, Quebec, Canada, between March 2007 and August 2010. Infants were followed up for 11 months ending August 2011 (74% completed study). INTERVENTION: Participants were randomly assigned to receive oral cholecalciferol (vitamin D3) supplements of 400 IU/d (n=39), 800 IU/d (n=39), 1200 IU/d (n=38), or 1600 IU/d (n=16). MAIN OUTCOMES AND MEASURES: The primary outcome was a plasma 25(OH)D concentration of 75 nmol/L or greater in 97.5% of infants at 3 months. Secondary outcomes included 25(OH)D concentrations of 75 nmol/L or greater in 97.5% of infants at 6, 9, and 12 months; 25(OH)D concentrations of 50 nmol/L or greater across all times; growth; and whole body and regional bone mineral content. Data were analyzed by intention to treat using available data, logistic regression, and mixed-model analysis of variance. RESULTS: By 3 months, 55% (95% CI, 38%-72%) of infants in the 400-IU/d group achieved a 25(OH)D concentration of 75 nmol/L or greater vs 81%(95% CI, 65%-91%) in the 800-IU/d group, 92% (95% CI, 77%-98%) in the 1200-IU/d group, and 100% in the 1600-IU/d group. This concentration was not sustained in 97.5% of infants at 12 months in any of the groups. The 1600-IU/d dosage was discontinued prematurely because of elevated plasma 25(OH)D concentrations. All dosages established 25(OH)D concentrations of 50 nmol/L or greater in 97% (95% CI, 94%-100%) of infants at 3 months and sustained this in 98% (95% CI, 94%-100%) to 12 months. Growth and bone mineral content did not differ by dosage. CONCLUSIONS AND RELEVANCE: Among healthy, term, breastfed infants, only a vitamin D supplement dosage of 1600 IU/d (but not dosages of 400, 800, or 1200 IU/d) increased plasma 25(OH)D concentration to 75 nmol/L or greater in 97.5% of infants at 3 months. However, this dosage increased 25(OH)D concentrations to levels that have been associated with hypercalcemia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00381914. PMID- 23632723 TI - Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. AB - IMPORTANCE: Global use of human papillomavirus (HPV) vaccines to prevent cervical cancer is impeded by cost. A 2-dose schedule for girls may be possible. OBJECTIVE: To determine whether mean antibody levels to HPV-16 and HPV-18 among girls receiving 2 doses was noninferior to women receiving 3 doses. DESIGN, SETTING, AND PATIENTS: Randomized, phase 3, postlicensure, multicenter, age stratified, noninferiority immunogenicity study of 830 Canadian females from August 2007 through February 2011. Follow-up blood samples were provided by 675 participants (81%). INTERVENTION: Girls (9-13 years) were randomized 1:1 to receive 3 doses of quadrivalent HPV vaccine at 0, 2, and 6 months (n = 261) or 2 doses at 0 and 6 months (n = 259). Young women (16-26 years) received 3 doses at 0, 2, and 6 months (n = 310). Antibody levels were measured at 0, 7, 18, 24, and 36 months. MAIN OUTCOMES AND MEASURES: Primary outcome was noninferiority (95% CI, lower bound >0.5) of geometric mean titer (GMT) ratios for HPV-16 and HPV-18 for girls (2 doses) compared with young women (3 doses) 1 month after last dose. Secondary outcomes were noninferiority of GMT ratios of girls receiving 2 vs 3 doses of vaccine; and durability of noninferiority to 36 months. RESULTS: The GMT ratios were noninferior for girls (2 doses) to women (3 doses): 2.07 (95% CI, 1.62-2.65) for HPV-16 and 1.76 (95% CI, 1.41-2.19) for HPV-18. Girls (3 doses) had GMT responses 1 month after last vaccination for HPV-16 of 7736 milli-Merck units per mL (mMU/mL) (95% CI, 6651-8999) and HPV-18 of 1730 mMU/mL (95% CI, 1512 1980). The GMT ratios were noninferior for girls (2 doses) to girls (3 doses): 0.95 (95% CI, 0.73-1.23) for HPV-16 and 0.68 (95% CI, 0.54-0.85) for HPV-18. The GMT ratios for girls (2 doses) to women (3 doses) remained noninferior for all genotypes to 36 months. Antibody responses in girls were noninferior after 2 doses vs 3 doses for all 4 vaccine genotypes at month 7, but not for HPV-18 by month 24 or HPV-6 by month 36. CONCLUSIONS AND RELEVANCE: Among girls who received 2 doses of HPV vaccine 6 months apart, responses to HPV-16 and HPV-18 one month after the last dose were noninferior to those among young women who received 3 doses of the vaccine within 6 months. Because of the loss of noninferiority to some genotypes at 24 to 36 months in girls given 2 doses vs 3 doses, more data on the duration of protection are needed before reduced-dose schedules can be recommended. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00501137. PMID- 23632724 TI - Association between efavirenz-based compared with nevirapine-based antiretroviral regimens and virological failure in HIV-infected children. AB - IMPORTANCE: Worldwide, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are commonly used in first-line antiretroviral regimens in both adults and children with human immunodeficiency virus (HIV) infection. Data on the comparative effectiveness of these medications in children are limited. OBJECTIVE: To investigate whether virological failure is more likely among children who initiated 1 or the other NNRTI-based HIV treatment. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of children (aged 3-16 years) who initiated efavirenz-based (n = 421) or nevirapine-based (n = 383) treatment between April 2002 and January 2011 at a large pediatric HIV care setting in Botswana. MAIN OUTCOMES AND MEASURES: The primary outcome was time from initiation of therapy to virological failure. Virological failure was defined as lack of plasma HIV RNA suppression to less than 400 copies/mL by 6 months or confirmed HIV RNA of 400 copies/mL or greater after suppression. Cox proportional hazards regression analysis compared time to virological failure by regimen. Multivariable Cox regression controlled for age, sex, baseline immunologic category, baseline clinical category, baseline viral load, nutritional status, NRTIs used, receipt of single-dose nevirapine, and treatment for tuberculosis. RESULTS: With a median follow-up time of 69 months (range, 6 112 months; interquartile range, 23-87 months), 57 children (13.5%; 95% CI, 10.4% 17.2%) initiating treatment with efavirenz and 101 children (26.4%; 95% CI, 22.0% 31.1%) initiating treatment with nevirapine had virological failure. There were 11 children (2.6%; 95% CI, 1.3%-4.6%) receiving efavirenz and 20 children (5.2%; 95% CI, 3.2%-7.9%) receiving nevirapine who never achieved virological suppression. The Cox proportional hazard ratio for the combined virological failure end point was 2.0 (95% CI, 1.4-2.7; log rank P < .001, favoring efavirenz). None of the measured covariates affected the estimated hazard ratio in the multivariable analyses. CONCLUSIONS AND RELEVANCE: Among children aged 3 to 16 years infected with HIV and treated at a clinic in Botswana, the use of efavirenz compared with nevirapine as initial antiretroviral treatment was associated with less virological failure. These findings may warrant additional research evaluating the use of efavirenz and nevirapine for pediatric patients. PMID- 23632725 TI - Neurodevelopmental outcome in extremely preterm infants at 2.5 years after active perinatal care in Sweden. AB - IMPORTANCE: Active perinatal care increases survival of extremely preterm infants; however, improved survival might be associated with increased disability among survivors. OBJECTIVE: To determine neurodevelopmental outcome in extremely preterm children at 2.5 years (corrected age). DESIGN, SETTING, AND PARTICIPANTS: Population-based prospective cohort of consecutive extremely preterm infants born before 27 weeks of gestation in Sweden between 2004 and 2007. Of 707 live-born infants, 491 (69%) survived to 2.5 years. Survivors were assessed and compared with singleton control infants who were born at term and matched by sex, ethnicity, and municipality. Assessments ended in February 2010 and comparison estimates were adjusted for demographic differences. MAIN OUTCOMES AND MEASURES: Cognitive, language, and motor development was assessed with Bayley Scales of Infant and Toddler Development (3rd edition; Bayley-lll), which are standardized to mean (SD) scores of 100 (15). Clinical examination and parental questionnaires were used for diagnosis of cerebral palsy and visual and hearing impairments. Assessments were made by week of gestational age. RESULTS: At a median age of 30.5 months (corrected), 456 of 491 (94%) extremely preterm children were evaluated (41 by chart review only). For controls, 701 had information on health status and 366 had Bayley-lll assessments. Mean (SD) composite Bayley-III scores (cognition, 94 [12.3]; language, 98 [16.5]; motor, 94 [15.9]) were lower than the corresponding mean scores for controls (cognition, 104 [10.6]; P < .001; adjusted difference in mean scores, 9.2 [99% CI, 6.9-11.5]; language, 109 [12.3]; P < .001; adjusted difference in mean scores, 9.3 [99% Cl, 6.4-12.3]; and motor, 107 [13.7]; P < .001; adjusted difference in mean scores, 12.6 [99% Cl, 9.5-15.6]). Cognitive disability was moderate in 5% of the extremely preterm group vs 0.3% in controls (P < .001) and it was severe in 6.3% of the extremely preterm group vs 0.3% in controls (P < .001). Language disability was moderate in 9.4% of the extremely preterm group vs 2.5% in controls (P < .001) and severe in 6.6% of the extremely preterm group vs 0% in controls (P < .001). Other comparisons between the extremely preterm group vs controls were for cerebral palsy (7.0% vs 0.1%; P < .001), for blindness (0.9% vs 0%; P = .02), and for hearing impairment (moderate and severe, 0.9% vs 0%; P = .02, respectively). Overall, 42% (99% CI, 36%-48%) of extremely preterm children had no disability, 31% (99% CI, 25%-36%) had mild disability, 16% (99% CI, 12%-21%) had moderate disability, and 11% (99% CI, 7.2%-15%) had severe disability. Moderate or severe overall disability decreased with gestational age at birth (22 weeks, 60%; 23 weeks, 51%; 24 weeks, 34%; 25 weeks, 27%; and 26 weeks, 17%; P for trend < .001). CONCLUSIONS AND RELEVANCE: Of children born extremely preterm and receiving active perinatal care, 73% had mild or no disability and neurodevelopmental outcome improved with each week of gestational age. These results are relevant for clinicians counseling families facing extremely preterm birth. PMID- 23632727 TI - Abdominal swelling in a teenaged girl. PMID- 23632726 TI - Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. AB - IMPORTANCE: Neonatal abstinence syndrome (NAS) caused by in utero opioid exposure is a growing problem; genetic factors influencing the incidence and severity have not been previously examined. Single-nucleotide polymorphisms (SNPs) in the MU opioid receptor (OPRM1), multidrug resistance (ABCB1), and catechol-o methyltransferase (COMT) genes are associated with risk for opioid addiction in adults. OBJECTIVE: To determine whether SNPs in the OPRM1, ABCB1, and COMT genes are associated with length of hospital stay and the need for treatment of NAS. DESIGN, SETTING, AND PARTICIPANTS: Prospective multicenter cohort study conducted at 5 tertiary care centers and community hospitals in Massachusetts and Maine between July 2011 and July 2012. DNA samples were genotyped for SNPs, and then NAS outcomes were correlated with genotype. Eighty-six of 140 eligible mother infant dyads were enrolled. Infants were eligible if they were 36 weeks' gestational age or older and exposed to methadone or buprenorphine in utero . MAIN OUTCOMES AND MEASURES: Primary outcome measure was length of hospital stay, with between-group differences expressed as beta and calculated with linear regression models. Secondary outcome measures included need for any medical treatment for NAS and treatment with 2 or more medications. RESULTS: Infants with the OPRM1 118A>G AG/GG genotype had shortened length of stay (beta = -8.5 days; 95% CI, -14.9 to -2.1 days; P = .009) and were less likely to receive any treatment than AA infants (48% vs 72%; adjusted odds ratio, 0.76; 95% CI, 0.63 0.96; P = .006). The COMT 158A>G AG/GG genotype was associated with shortened length of stay (beta = -10.8 days; 95% CI, -18.2 to -3.4 days; P = .005) and less treatment with 2 or more medications (18% vs 56%; adjusted odds ratio, 0.68; 95% CI, 0.55-0.86; P = .001) than the AA genotype. Associations with the ABCB1 SNPs were not significant. CONCLUSIONS AND RELEVANCE: Among infants with NAS, variants in the OPRM1 and COMT genes were associated with a shorter length of hospital stay and less need for treatment. These preliminary findings may provide insight into the mechanisms underlying NAS. PMID- 23632728 TI - Targeting dietary vitamin D intakes and plasma 25-hydroxyvitamin D in healthy infants. PMID- 23632729 TI - HPV vaccination: too soon for 2 doses? PMID- 23632730 TI - Contrasts in child health care and child health research. PMID- 23632731 TI - JAMA patient page. Attention-deficit/hyperactivity disorder. PMID- 23632732 TI - Current world literature. Headache. PMID- 23632734 TI - Microscopic origin of the optical processes in blue sapphire. AB - Al2O3 changes from transparent to a range of intense colours depending on the chemical impurities present. In blue sapphire, Fe and Ti are incorporated; however, the chemical process that gives rise to the colour has long been debated. Atomistic modelling identifies charge transfer from Ti(III) to Fe(III) as being responsible for the characteristic blue appearance. PMID- 23632735 TI - Depressive symptoms and culture in Chinese patients. PMID- 23632736 TI - Phenylalanine--a biogenic ligand with flexible eta6- and eta6:kappa1-coordination at ruthenium(II) centres. AB - The reaction of (S)-2,5-dihydrophenylalanine 1 with ruthenium(III) chloride yields the MU-chloro-bridged dimeric eta(6)-phenylalanine ethyl ester complex 3, which can be converted into the monomeric analogue, eta(6):kappa(1)-phenylalanine ethyl ester complex 12, under basic conditions. Studies were carried out to determine the stability and reactivity of complexes bearing eta(6)- and eta(6):kappa(1)-chelating phenylalanine ligands under various conditions. Reaction of 3 with ethylenediamine derivatives N-p-tosylethylenediamine or 1,4-di N-p-tosylethylenediamine results in the formation of monomeric eta(6):kappa(1) phenylalanine ethyl ester complexes 14 and 15, which could be saponified yielding complexes 16 and 17 without changing the inner coordination sphere of the metal centre. The structure of eta(6):kappa(1)-phenylalanine complex 17 and an N kappa(1)-phenylalanine complex 13 resulting from the reaction of 3 with an excess of pyridine were confirmed by X-ray crystallography. PMID- 23632737 TI - Use of a decision support system improves the management of hemodynamic and respiratory events in orthopedic patients under propofol sedation and spinal analgesia: a randomized trial. AB - Decision support systems (DSSs) have been successfully implemented into clinical practice offering clinical suggestions and treatment options with excellent results in various clinical settings. Although their results appeared promising, showing that DSSs can increase anesthesiologists' vigilance and patient safety during surgery, DSSs have never been used before to help anesthesiologists in identifying critical events in patients under spinal analgesia with sedation. We have developed and clinically evaluated a DSS for this specific task. The DSS was developed with the ability to indicate respiratory and hemodynamic critical events via audio-visual alarms and give decisional aid. Critical respiratory events were defined as SpO2 <92 % and/or respiratory rate <8/min. Critical hemodynamic events were defined as mean arterial pressure (MAP) <60 mmHg and/or heart rate <40 bpm. The objective of this trial was to determine the duration to detect and treat these critical events with the help of the DSS (DSS Group) compared with a standard Control Group where the system was not in place. One hundred and fifty orthopedic patients undergoing spinal analgesia with propofol sedation were enrolled in this randomized control trial, 75 each group. All respiratory and hemodynamic critical events were detected in the DSS Group, while in the Control Group 26 % of the events were not detected.The delay to detect and treat critical events was significantly shorter (P < 0.0001) in the DSS Group at 9.1 +/- 3.6 s, whereas 27.5 +/- 18.9 s were necessary to identify them in the Control Group. There were no significant differences in physiological parameters in the two groups during surgery. The number of critical events/h occurring and the duration of surgery were similar in both groups. The number of hypoxemia episodes was significantly less (P = 0.036) in the DSS group (0.7 +/- 1.0 vs. 1.4 +/- 2.2 for the Control Group). The DSS tested in this trial could help the clinician to detect and treat critical events more efficiently and in a shorter length of time. PMID- 23632738 TI - Cardiac asynchrony in Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. Heart failure is a classical complication in this disease. Little data are available about systolic dyssynchrony in DMD. We sought to assess the prevalence of left ventricular dysfunction and systolic asynchrony in DMD patients using echocardiographic parameters. We performed electrocardiography and echocardiography for adult's patients with DMD. For systolic dyssynchrony assessment, echocardiography-Doppler was performed and completed by tissular Doppler imaging. 48 DMD were included in our study. Age ranged from 20 to 37 years. QRS duration >120 ms was present in 10 patients/48 and 1 patient disclosed a QRS duration >150 ms. Left ventricular (LV) ejection fraction (EF) ranged from 10 to 62 % with a median of 43 %. Inter ventricular asynchrony was found in 11.9 % of patients with EF < 35 % and in 2.6 % of patients with EF > 35 %. Intra-ventricular asynchrony was present in 6 % of patients with EF < 35 %. We found a high prevalence of LV dysfunction in DMD. Systolic ventricular asynchrony seems frequent particularly in patients with EF < 35 %. PMID- 23632739 TI - Identification of common gene networks responsive to mild hyperthermia in human cancer cells. AB - Hyperthermia (HT) has been used as a possible treatment modality for various types of malignant tumors. Due to its pleiotropic effects, its combined use with radiotherapy and/or chemotherapy has proven to be beneficial. However, the molecular mechanisms underling the cellular responses to heat stress remain unclear. Therefore, the aim of this study was to identify common gene expression patterns responsive to mild HT (MHT) in human cancer cells. HeLa human cervical squamous cell carcinoma (SCC) and HSC-3 human oral SCC cells were exposed to MHT at 41C for 30 min, followed by culture at 37C for 0-24 h. MHT did not affect cell viability or the cell cycle. GeneChip microarray analysis clearly revealed that many probe sets were differentially expressed by a factor of >=1.5 in both cell lines following exposure to MHT. Of the many differentially expressed probe sets, 114 genes were found to be commonly upregulated in both HeLa and HSC-3 cells, and two significant gene networks were obtained from the commonly upregulated genes. Gene network A included several heat shock proteins, as well as BCL2-associated athanogene 3 (BAG3), and was found to be mainly associated with the biological functions of cellular function and maintenance. Gene network B included several anti-cell death genes, such as early growth response 1 (EGR1) and endothelin 1 (EDN1) and was found to be associated with the biological functions of cell death and survival. Real-time quantitative polymerase chain reaction demonstrated that the gene expression patterns of the 12 genes selected were consistent with the microarray data in four cancer cell lines. These findings may provide further insight into the detailed molecular mechanisms of the MHT response in cancer cells. PMID- 23632741 TI - Elevated miR-29a expression is not correlated with disease activity index in PBMCs of patients with ankylosing spondylitis. AB - OBJECTIVES: Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by new bone formation. Recent evidence suggests that new bone formation in AS may be due to upregulation of Wnt signaling in the osteoblastic pathway secondary to low serum Dickkopf homolog 1 (Dkk-1) levels. And miR-29a orchestrates osteoblast differentiation through direct targeting and negative regulation of Dkk-1. METHODS: We initially validated the expression levels of miR 29a in the peripheral blood mononuclear cells (PBMCs) of AS patients (n = 30), rheumatoid arthritis (RA) patients (n = 30) and healthy controls (n = 30) using real-time quantitative reverse transcription PCR (qRT-PCR). Correlation analysis was assessed between miR-29a level in PBMCs of AS patients and disease activity indexes, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis function index (BASFI) and modified Stoke ankylosing spondylitis spinal score (mSASSS). RESULTS: Significantly higher expression of miR-29a was observed in PBMCs of AS patients (Ct 9.18 +/- 1.96) compared with that in RA patients (10.97 +/- 0.70, p < 0.001) and healthy controls (Ct 11.45 +/ 1.23, p < 0.001). There was no significant difference between RA patients and healthy controls in miR-29a expression (p > 0.05). Elevated miR-29a expression is not correlated with disease activity index (p > 0.05). A weak correlation was found between elevated miR-29a expression and mSASSS (r = -0.393, p = 0.032). CONCLUSIONS: We report for the first time elevated miR-29a expression in PBMCs of patients with ankylosing spondylitis, and miR-29a might be used as a useful diagnostic marker in new bone formation but cannot reflect disease activity. PMID- 23632740 TI - Early diffusion-weighted magnetic resonance imaging in children after cardiac arrest may provide valuable prognostic information on clinical outcome. AB - OBJECTIVE: We examined whether early diffusion-weighted magnetic resonance imaging (DW-MRI) abnormalities of the brain and variation of apparent diffusion coefficient (ADC) values can provide prognostic information on clinical outcome in children following cardiac arrest (CA). DESIGN: Retrospective study. SETTING: A 12-bed paediatric intensive care unit (PICU). PATIENTS: Children aged between 1 month and 18 years who had DW-MRI with ADC measurement within the first week following CA. Neurological outcomes were assessed using the Pediatric Cerebral Performance Category Scale (PCPC). Differences between the favourable (PCPC <=3) and unfavourable (PCPC >=4) groups were analysed with regard to clinical data, electrophysiological patterns as well as qualitative and quantitative DW-MRI abnormalities. RESULTS: Twenty children with a median age of 20 months (1.5-185) and a male/female sex ratio of 1.5 underwent DW-MRI after CA with a median delay of 3 days (1-7). Aetiologies of CA were (i) asphyxia (n = 10), (ii) haemodynamic (n = 5) or (iii) unknown (n = 5). With regard to DW-MRI findings, the unfavourable outcome group (n = 8) was associated with cerebral cortex (p = 0.02) and basal ganglia (p = 0.005) lesions, with a larger number of injured brain regions (p = 0.001) and a global decrease in measured ADC signal (p = 0.008). Normal DW-MRI (n = 5) was exclusively associated with the favourable outcome group (n = 12). CONCLUSION: Qualitative, topographic and quantitative analysis of early DW-MRI with ADC measurement in children following CA may provide valuable prognostic information on neurological outcomes. PMID- 23632742 TI - Cardiac peroxisome proliferator-activated receptor-gamma expression is modulated by oxidative stress in acutely infrasound-exposed cardiomyocytes. AB - The aim of the present study was to examine the effects of acute infrasound exposure on oxidative damage and investigate the underlying mechanisms in rat cardiomyocytes. Neonatal rat cardiomyocytes were cultured and exposed to infrasound for several days. In the study, the expression of CAT, GPx, SOD1, and SOD2 and their activities in rat cardiomyocytes in infrasound exposure groups were significantly decreased compared to those in the various time controls, along with significantly higher levels of O2 (-) and H2O2. Decreased cardiac cell viability was not observed in various time controls. A significant reduction in cardiac cell viability was observed in the infrasound group compared to the control, while significantly increased cardiac cell viability was observed in the infrasound exposure and rosiglitazone pretreatment group. Compared to the control, rosiglitazone significantly upregulated CAT, GPx, SOD1, and SOD2 expression and their activities in rat cardiomyocytes exposed to infrasound, while the levels of O2 (-) or H2O2 were significantly decreased. A potential link between a significant downregulation of PPAR-gamma expression in rat cardiomyocytes in the infrasound group was compared to the control and infrasound induced oxidative stress. These findings indicate that infrasound can induce oxidative damage in rat cardiomyocytes by inactivating PPAR-gamma. PMID- 23632743 TI - p300-mediated histone acetylation is essential for the regulation of GATA4 and MEF2C by BMP2 in H9c2 cells. AB - Histone acetylase (HAT) p300 plays an important role in the regulation of cardiac gene expression. During cardiac development, bone morphogenetic protein (BMP)-2 induces the expression of cardiac transcription factors. However, the underlying molecular mechanism(s) is not clear. In the present study, we tested the hypothesis that p300-mediated histone acetylation was essential for the regulation of cardiac transcription factors by BMP2. Cultured rat H9c2 embryonic cardiac myocytes (H9c2 cells) were transfected with recombinant adenoviruses expressing human BMP2 (AdBMP2) with or without curcumin, a specific p300-HAT inhibitor. Quantitative real-time RT-PCR analysis showed that curcumin substantially inhibited both AdBMP2-induced and basal expression levels of cardiac transcription factors GATA4 and MEF2C, but not Tbx5. Similarly, chromatin immunoprecipitation (ChIP) analysis showed that curcumin inhibited both AdBMP2 induced and basal histone H3 acetylation levels in the promoter regions of GATA4 and MEF2C, but not of Tbx5. In addition, curcumin selectively suppressed AdBMP2 induced expression of HAT p300, but not HAT GCN5 in H9c2 cells. The data indicated that inhibition of histone H3 acetylation with curcumin diminished BMP2 induced expression of GATA4 and MEF2C, suggesting that p300-mediated histone acetylation was essential for the regulation of GATA4 and MEF2C by BMP2 in H9c2 cells. PMID- 23632744 TI - Green space is associated with walking and moderate-to-vigorous physical activity (MVPA) in middle-to-older-aged adults: findings from 203 883 Australians in the 45 and Up Study. AB - BACKGROUND: Green space is widely hypothesised to promote physical activity. Few studies, however, examine whether this is the case for walking and moderate-to vigorous physical activity (MVPA). We investigated to what extent neighbourhood green space was associated with weekly participation and frequency of walking and MVPA in a large cross-sectional survey of Australian adults 45 years and older. METHODS: Logit and negative binomial regression were used to estimate the degree of association between walking, MVPA and neighbourhood green space in a sample of 203 883 adults from the Australian 45 and Up Study. Walking and MVPA were measured using the Active Australia Survey. Green space was measured as a percentage of the total land-use within 1 km radius of residence. We controlled for a range of individual and neighbourhood characteristics. RESULTS: 86.6% of the sample walked and 85.8% participated in MVPA at least once a week. These rates fell steeply with age. Compared with residents of neighbourhoods containing 0-20% green space, those in greener areas were significantly more likely to walk and participate in MVPAs at least once a week (trend for both p<0.001). Among those participating at least once a week, residents of neighbourhoods containing 80%+ green space participated with a greater frequency of walking (incidence rate ratio (IRR) 1.09, 95% CI 1.05 to 1.13) and MVPA (IRR 1.10, 95% CI 1.05 to 1.15). CONCLUSIONS: Our findings suggest that the amount of green space available to adults in middle-to-older age within their neighbourhood environments could help to promote walking and MVPA. PMID- 23632745 TI - Genomics of elite sporting performance: what little we know and necessary advances. AB - Numerous reports of genetic associations with performance-related phenotypes have been published over the past three decades but there has been limited progress in discovering and characterising the genetic contribution to elite/world-class performance, mainly owing to few coordinated research efforts involving major funding initiatives/consortia and the use primarily of the candidate gene analysis approach. It is timely that exercise genomics research has moved into a new era utilising well-phenotyped, large cohorts and genome-wide technologies- approaches that have begun to elucidate the genetic basis of other complex traits/diseases. This review summarises the most recent and significant findings from sports genetics and explores future trends and possibilities. PMID- 23632746 TI - Injury surveillance in the World Football Tournaments 1998-2012. AB - BACKGROUND: International sports bodies should protect the health of their athletes, and injury surveillance is an important pre-requisite for injury prevention. The Federation International de Football Association (FIFA) has systematically surveyed all football injuries in their tournaments since 1998. AIMS: Analysis of the incidence, characteristics and changes of football injury during international top-level tournaments 1998-2012. METHODS: All newly incurred football injuries during the FIFA tournaments and the Olympic Games were reported by the team physicians on a standardised injury report form after each match. The average response rate was 92%. RESULTS: A total of 3944 injuries were reported from 1546 matches, equivalent to 2.6 injuries per match. The majority of injuries (80%) was caused by contact with another player, compared with 47% of contact injuries by foul play. The most frequently injured body parts were the ankle (19%), lower leg (16%) and head/neck (15%). Contusions (55%) were the most common type of injury, followed by sprains (17%) and strains (10%). On average, 1.1 injuries per match were expected to result in absence from a match or training. The incidence of time-loss injuries was highest in the FIFA World Cups and lowest in the FIFA U17 Women's World Cups. The injury rates in the various types of FIFA World Cups had different trends over the past 14 years. CONCLUSIONS: Changes in the incidence of injuries in top-level tournaments might be influenced by the playing style, refereeing, extent and intensity of match play. Strict application of the Laws of the Games is an important means of injury prevention. PMID- 23632747 TI - Effects of whey proteins on glycaemia and insulinaemia to an oral glucose load in healthy adults; a dose-response study. AB - BACKGROUND/OBJECTIVES: Whey proteins have insulinogenic properties and the effect appears to be mediated from a postprandial plasma amino-acid (AA) response. The aim was to study the possible dose-response relationship between whey intake and glycaemic-, insulinaemic- and plasma AA responses. SUBJECTS/METHODS: Twelve healthy volunteers participated in the study. They were provided three whey protein drinks, containing 4.5, 9 or 18 g protein as breakfast meals in random order. All meals contained 25 g available carbohydrates (glucose). The same amount of glucose in water was used as reference. RESULTS: Linear dose-response relations were found between whey protein intake and postprandial glycaemia, insulinaemia and plasma AAs. The two highest doses, 18 g and 9 g, significantly reduced postprandial glycaemia (incremental area under the curve (iAUC) 0-120 min; P <= 0.05). The 18 g dose significantly increased the insulin response (iAUC 0-120 min; P <= 0.05). All measured plasma AAs (15 in total), except glutamic acid, responded in a dose-dependent way, and the 9 and 18 g doses resulted in significantly higher plasma levels of AAs compared with the reference. CONCLUSIONS: Whey protein affects glycaemia, insulinaemia and plasma AAs to a glucose load in a dose-dependent manner. Comparatively low doses of whey protein (9 g) reduced postprandial glycaemia significantly when added to a carbohydrate rich meal. PMID- 23632748 TI - Sodium intake of a city population in Korea estimated by 24-h urine collection method. AB - OBJECTIVES: Accurate estimation of sodium intake by a precise and reproducible method is crucial in sodium intake reduction policy. This study tested the feasibility of 24-h urine (24HU) collection method and estimated sodium intake of a major city population from a representative adult sample. SUBJECTS/METHODS: A representative population (aged 20-65 years) was selected by list-assisted random digit dialing method from a city with a population of one million. Sodium and potassium intakes (24HUNa and 24HUK, respectively) were measured with 24HU collection. RESULTS: Of those 496 individuals recruited, 24HU samples from 368 participants were determined to be properly collected and analyzed. The weighted mean of 24HUNa was 166.4 +/- 68.1 mmol per day, much lower than 208.2 mmol of 24HUNa measured in Pusan (Korea; 1988 INTERSALT). The 24HUNa was highest in population aged 40-49 years, with a decrease after 50 years. Men had higher 24HUNa than women (182.0 +/- 77.6 vs 151.4 +/- 55.0 mmol per day). The sodium intake is higher than that found in survey conducted in the United Kingdom/Scotland and Finland, similar to that of Spain and lower than that of Portugal, Slovenia and Turkey. In contrast to 24HUNa, 24HUK increased continuously as age increased. CONCLUSIONS: This study enables us to compare sodium intake with the results of other surveys even from other countries, and reinforce the recommended introduction of the 24HU collection method in Korea. Sodium intake of the studied population was higher than the World Health Organization recommendation, suggesting the needs for further efforts to reduce sodium intake. PMID- 23632749 TI - Metabolic and hormonal consequences of two different meals after a moderate intensity exercise bout in obese prepubertal children. AB - BACKGROUND/OBJECTIVES: To investigate the relationship between postprandial nutrient balance, satiety and hormone changes induced by two different meals taken after a moderate intensity exercise bout. SUBJECTS/METHODS: Ten prepubertal obese children participated in the study. The experiment was designed as a cross over study for repeated measures. Each test period lasted five consecutive hours during which the children were under medical supervision. The effects of two isocaloric meals were compared after a moderate intensity exercise (4 multiples of resting metabolic rate, 30 min, cycling): a low-fat/high-carbohydrate meal (meal A) and a high-fat/low-carbohydrate meal (meal B). Pre and postprandial (3 h) substrate oxidation, biochemical parameters, gastrointestinal hormone concentrations and appetite were measured. RESULTS: The main results were: (i) higher fat balance (5.1+/-5.0 vs -5.0+/-6.6 g, P=0.001) and lower carbohydrate balance after meal B than A (-9.7+/-13.3 vs 11.3+/-18.3 g, P<0.01); (ii) higher energy balance after meal B than after meal A (5.9+/-21.5 vs -13.9+/-20.2 kcal, P<0.05); (iii) higher plasma triglyceride concentrations (area under the curve) after meal B than after meal A (2962.5+/-2095.8 mg*180 min/dl vs -169.5+/-1633.7 mg*180 min/dl, P<0.01); (iv) higher serum glucagon-like peptide-1 concentrations after meal B than after meal A (1101.5+/-873.0 pmol*180 min/l vs 478.8+/-638.3 pmol*180 min/l, P<0.05). CONCLUSIONS: After a bout of moderate intensity exercise, a meal with a high-fat/low-carbohydrate ratio had a less favorable metabolic impact than an isoenergetic, isoproteic low-fat/high-carbohydrate meal. PMID- 23632750 TI - Validity of nutritional screening with MUST and SNAQ in hospital outpatients. AB - BACKGROUND/OBJECTIVES: The majority of hospital outpatients with undernutrition is unrecognized, and therefore untreated. There is a need for an easy and valid screening tool to detect undernutrition in this setting. The aim of this study was to determine the diagnostic accuracy of the MUST (Malnutrition Universal Screening Tool) and SNAQ (Short Nutritional Assessment Questionnaire) tools for undernutrition screening in hospital outpatients. METHODS: In a large multicenter hospital-outpatient population, patients were classified as: severely undernourished (body mass index (BMI) <18.5 (<65 years) or <20 ( >= 65 years) and/or unintentional weight loss >5% in the last month or >10% in the last 6 months), moderately undernourished (BMI 18.5-20 (<65 years) or 20-22 ( >= 65 years) and/or 5-10% unintentional weight loss in the last 6 months) or not undernourished. Diagnostic accuracy of the screening tools versus the reference method was expressed as sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Out of the 2236 outpatients, 6% were severely and 7% were moderately undernourished according to the reference method. MUST and SNAQ identified 9% and 3% as severely undernourished, respectively. MUST had a low PPV (Se=75, Sp=95, PPV=43, NPV=98), whereas SNAQ had a low Se (Se=43, Sp=99, PPV=78, NPV=96). CONCLUSIONS: The validity of MUST and SNAQ is insufficient for hospital outpatients. While SNAQ identifies too few patients as undernourished, MUST identifies too many patients as undernourished. We advise to measure body weight, height and weight loss, in order to define undernutrition in hospital outpatients. PMID- 23632751 TI - References and cutoffs for triceps and subscapular skinfolds in Norwegian children 4-16 years of age. AB - BACKGROUND/OBJECTIVES: To establish new reference values for triceps (TSF) and subscapular (SSF) skinfolds of Norwegian children 4-16 years of age, and to define cutoff values for overweight and obesity using the criteria of the International Obesity Task Force (IOTF). SUBJECTS/METHODS: A cross-sectional sample of 4606 children 4-16 years of age, part of a larger growth study, was used to estimate reference curves with the LMS method; suggested cutoffs were selected using receiver operating characteristic analyses. RESULTS: Reference values for TSF and SSF are presented as percentiles. Mean skinfold size increased with age. Girls had higher values than boys over the entire age range. There was a strong positive correlation between both skinfolds and body mass index (BMI). For all ages together, a cutoff of 1.0 standard deviation score (SDS) gave a sensitivity of 76% for SSF, and 70% for TSF to detect overweight, with a corresponding specificity of 92% for both. To detect obesity, a cutoff value of 1.3 SDS gave a sensitivity of 91% and specificity of 90% for SSF. Corresponding values for TSF were 86% for the sensitivity, and 91% for the specificity. CONCLUSIONS: This study presents new reference values for TSF and SSF skinfolds in Norwegian children 4-16 years of age. Both skinfolds had a high-discriminating power to detect overweight and obesity as defined by the IOTF BMI criteria. PMID- 23632752 TI - Ketosis and appetite-mediating nutrients and hormones after weight loss. AB - BACKGROUND/OBJECTIVES: Diet-induced weight loss is accompanied by compensatory changes, which increase appetite and encourage weight regain. There is some evidence that ketogenic diets suppress appetite. The objective is to examine the effect of ketosis on a number of circulating factors involved in appetite regulation, following diet-induced weight loss. SUBJECTS/METHODS: Of 50 non diabetic overweight or obese subjects who began the study, 39 completed an 8-week ketogenic very-low-energy diet (VLED), followed by 2 weeks of reintroduction of foods. Following weight loss, circulating concentrations of glucose, insulin, non esterified fatty acids (NEFA), beta-hydroxybutyrate (BHB), leptin, gastrointestinal hormones and subjective ratings of appetite were compared when subjects were ketotic, and after refeeding. RESULTS: During the ketogenic VLED, subjects lost 13% of initial weight and fasting BHB increased from (mean+/ s.e.m.) 0.07+/-0.00 to 0.48+/-0.07 mmol/l (P<0.001). BHB fell to 0.19+/-0.03 mmol/l after 2 weeks of refeeding (P<0.001 compared with week 8). When participants were ketotic, the weight loss induced increase in ghrelin was suppressed. Glucose and NEFA were higher, and amylin, leptin and subjective ratings of appetite were lower at week 8 than after refeeding. CONCLUSIONS: The circulating concentrations of several hormones and nutrients which influence appetite were altered after weight loss induced by a ketogenic diet, compared with after refeeding. The increase in circulating ghrelin and subjective appetite which accompany dietary weight reduction were mitigated when weight-reduced participants were ketotic. PMID- 23632753 TI - Clustering of multiple lifestyle behaviours and its association to cardiovascular risk factors in children: the IDEFICS study. AB - BACKGROUND/OBJECTIVES: Individual lifestyle behaviours have independently been associated with cardiovascular diseases (CVD) risk factors in children. This study aimed to identify clustered lifestyle behaviours (dietary, physical activity (PA) and sedentary indicators) and to examine their association with CVD risk factors in children aged 2-9 years. SUBJECTS/METHODS: Participants included 4619 children (51.6% boys) from eight European countries participating in the IDEFICS cross-sectional baseline survey (2007-2008). Insulin resistance, total cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, sum of two skinfolds and systolic blood pressure (SBP) z-scores were summed to compute a CVD risk score. Cluster analyses stratified by sex and age groups (2 to <6 years; 6-9 years) were performed using parental-reported data on fruit, vegetables and sugar sweetened beverages (SSB) consumption, PA performance and television video/DVD viewing. RESULTS: Five clusters were identified. Associations between CVD risk factors and score, and clusters were obtained by multiple linear regression using cluster 5 ('low beverages consumption and low sedentary') as the reference cluster. SBP was positively associated with clusters 1 ('physically active'; beta=1.34; 95% confidence interval (CI): 0.02, 2.67), 2 ('sedentary'; beta=1.84; 95% CI: 0.57, 3.11), 3 ('physically active and sedentary'; beta=1.45; 95% CI: 0.15, 2.75) and 4 ('healthy diet'; beta=1.83; 95% CI: 0.50, 3.17) in older boys. A positive association was observed between CVD risk score and clusters 2 (beta=0.60; 95% CI: 0.20, 1.01), 3 (beta=0.55; 95% CI: 0.14, 0.97) and 4 (beta=0.60, 95% CI: 0.18, 1.02) in older boys. CONCLUSIONS: Low television/video/DVD viewing levels and low SSB consumption may result in a healthier CVD profile rather than having a diet rich in fruits and vegetables or being physically active in (pre-)school children. PMID- 23632754 TI - Monolayer patterning using ketone dipoles. AB - The self-assembly of multi-component monolayers with designed patterns requires molecular recognition among components. Dipolar interactions have been found to influence morphologies of self-assembled monolayers and can affect molecular recognition functions. Ketone groups have large dipole moments (2.6 D) and are easily incorporated into molecules. The potential of ketone groups for dipolar patterning has been evaluated through synthesis of two 1,5-disubstituted anthracenes bearing mono-ketone side chains, STM characterization of monolayers self-assembled from their single and two component solutions and molecular mechanics simulations to determine their self-assembly energetics. The results reveal that (i) anthracenes bearing self-repulsive mono-ketone side chains assemble in an atypical monolayer morphology that establishes dipolar attraction, instead of repulsion, between ketones in adjacent side chains; (ii) pairs of anthracene molecules whose self-repulsive ketone side chains are dipolar complementary spontaneously assemble compositionally patterned monolayers, in which the two components segregate into neighboring, single component columns, driven by side chain dipolar interactions; (iii) compositionally patterned monolayers also assemble from dipolar complementary anthracene pairs that employ different dipolar groups (ketones or CF2 groups) in their side chains; (iv) the ketone group, with its larger dipole moment and size, provides comparable driving force for patterned monolayer formation to that of the smaller dipole, and smaller size, CF2 group. PMID- 23632755 TI - Interest in new heterodinuclear transition-metal/main-group-metal complexes: DFT study of electronic structure and mechanism of fluoride sensing function. AB - Systematic DFT calculations were carried out on a series of heterodinuclear complexes [(o-(Ph2P)C6H4)3M(1)M(2)Cl](+) (M(1) = As, Sb, or Bi; M(2) = Pd or Pt) to investigate the mechanism of colorimetric sensing function for the fluoride anion. The fluoride anion binds with the M(1) center to afford a hypervalent M(1) species with large stabilization energy. For instance, the stabilization energy by the fluoride adduct formation is -15.5 kcal mol(-1) for 3 (M(1) = Sb; M(2) = Pd) and -16.2 kcal mol(-1) for 6 (M(1) = Sb; M(2) = Pt), where a negative value represents stabilization. Interestingly, the allosteric coordination of the third phosphine with the M(2) center is induced by the fluoride adduct formation. For chloride, bromide, and thiocyanide anions, the binding energies are positive (~4.5 kcal mol(-1)), and the allosteric coordination does not occur. The allosteric coordination plays a crucial role in the absorption spectrum change induced by the fluoride adduct formation. For instance, the fluoride adduct formation quenches the absorption band of 3 around 400 nm and newly exhibits two absorption peaks at longer wavelength, 475 and 451 nm. These two peaks are assigned to ligand-field transitions (d(xy)-> d(z(2)) and d(x(2)-y(2))-> d(z(2))) including metal-to-ligand charge transfer character. We discussed the reasons why the allosteric coordination can occur only in the fluoride adduct and induces these two absorptions in the longer wavelength region. In addition, the Bi-Pd combination is also recommended for a fluoride sensing material, while the Sb-Pt combination is recommended for cyanide sensing. PMID- 23632756 TI - Comparison of percutaneous endoscopic, laparoscopic and open gastrostomy insertion in children. AB - PURPOSE: To compare the outcomes and complications between percutaneous endoscopic gastrostomy (PEG), laparoscopic gastrostomy (LAPG) and open gastrostomy (OG) in children. METHODS: Retrospective review of 369 patients from July 1998 to December 2010 who had their gastrostomies inserted at a single tertiary paediatric institution. Patients who were lost in follow-up (59) and had insufficient data (23) were excluded from this study. Results were analysed using descriptive statistics. RESULTS: Of the 369 included in our study, 260 patients underwent LAPG, 86 PEG and 23 open gastrostomy (OG) procedures. The early complication rate for PEGs was 10.5 %, and for LAPGS 2.7 % (p = 0.006). The late complication rate was 41.9 % for PEGs and 43.1 % for LAPGs (p = NS). The overall complication rate for PEG was 54.7 % and it was 44.6 % for LAPG (p = NS). Major complications occurred only in the PEG group: gastro-colonic fistula (1), peritonitis (1), and "buried bumper syndrome" (1). The overall complication rate for OG was 78.3 % (p = 0.01, when this was compared to LAPGs and PEGs together), although there were no early complications in the OG group. CONCLUSION: PEGs had a significantly higher early complication rate than LAPGs and the only major complications occurred in the PEG group. PEGs also had a higher overall complication rate than LAPGs, although the difference was not statistically significant. Both PEGs and LAPGs were significantly superior to OG in terms of overall complication rates. PMID- 23632757 TI - Can TKA design affect the clinical outcome? Comparison between two guided-motion systems. AB - PURPOSE: In a retrospective comparative analysis in patients undergoing primary guided-motion total knee arthroplasty (TKA), the authors have evaluated whether different TKA implant design would influence the clinical and functional outcomes. METHODS: Between 2007 and 2009, 227 computer-assisted primary TKAs were performed in 219 consecutive patients. Patients received one of the two different fixed-bearing guided-motion TKA designs assisted by navigation surgery: the Scorpio Non-Restrictive Geometry (NRG) knee system and the Journey Bi-Cruciate Stabilized (BCS) knee systems. RESULTS: Data were available for 180 patients (187 knees). No significant differences were observed between the two groups with respect to preoperative demographic characteristics, range of motion (ROM) and radiographic knee alignment. At a mean follow-up of 29 months, the Journey BCS group had higher mean Knee Injury and Osteoarthritis Outcome Score (KOOS) in all subscales and a greater ROM than the Scorpio NRG group. This difference was statistically significant for the KOOS subscales of pain (p = 0.007) and knee related quality of life (p = 0.045), as well as for postoperative ROM (p = 0.018). Considering the overall complications, 1 patient of Scorpio NRG group (0.5%) and 5 in Journey BCS (2.7%) had stiffness. Anterior knee pain was reported in 4 cases of Scorpio NRG group (2.1%). In the Journey BCS group were observed 2 cases (1.1%) of frontal plane instability and 1 case (0.5%) of synovitis pain. CONCLUSIONS: The bearing geometry and kinematic pattern of different guided motion prosthetic designs can affect the clinical-functional outcome and complications type in primary TKA. LEVEL OF EVIDENCE: Clinical study, Level III. PMID- 23632759 TI - An evidence-based approach to the efficient use of computed tomography imaging in the neurosurgical patient. AB - BACKGROUND: Computed tomography (CT) is the current standard for rapidly diagnosing some of the more common structural pathologies that affect the neurosurgical patient perioperatively. With this convenience comes the potential for its overuse. OBJECTIVE: To investigate the utility of head CT scans ordered for various clinical indications. METHODS: All head CT studies ordered by the UCLA Neurosurgery Department from August 15, 2011 through December 15, 2011, were prospectively studied. Variables collected included demographic information, diagnosis, surgical procedures, indication for CT, CT findings, and whether the study led to a documentable change in management. RESULTS: There were 801 head CT studies ordered for the 462 patients who were admitted to the neurosurgical service. The authors identified 14 indications for ordering a head CT with the following probabilities of a positive finding: examination change (17/56, 30.3%), follow-up (4-6 hours after intracerebral hemorrhage; 16/126, 12.7%), CT angiography (11/30, 36.7%), routine postoperative imaging (6/126, 4.7%), postventriculostomy placement (4/62, 6.5%), immediately before (4/31, 12.9%) or after removal of (2/42, 4.8%) a ventriculostomy, surveillance (>24 hours after intracerebral hemorrhage or external ventricular drain placement) (3/66, 4.5%), headaches (2/8, 25%), ground level fall (1/8, 12.5%), intracranial pressure spikes (2/6, 33.3%), and delayed (6-24 hours after intracerebral hemorrhage; 1/25, 4%). CONCLUSION: The probability of discovering a clinically significant finding varies widely for each of the listed study indications. This prospective analysis of all CT scans ordered at a single institution suggests that imaging studies obtained without a change in neurological status were unlikely to produce a positive finding, and even when there was a positive finding, it was extremely unlikely to result in any intervention. PMID- 23632760 TI - The impact of the body mass index on outcome after subarachnoid hemorrhage: is there an obesity paradox in SAH? A retrospective analysis. AB - BACKGROUND: Obesity is a risk factor for cardiovascular disease and associated with a poor outcome, especially for intensive care patients. However, recent studies have described favorable outcomes of obese patients after stroke, a phenomenon called the "obesity paradox." OBJECTIVE: To assess the impact of the body mass index (BMI) on outcome after subarachnoid hemorrhage (SAH). METHODS: We analyzed the data for 741 SAH patients. A BMI greater than 25 kg/m(2) was considered overweight and greater than 30 kg/m(2) obese. The outcome according to the Glasgow Outcome Scale at discharge and after 6 months was assessed using logistic regression analysis. RESULTS: According to the BMI, 268 patients (36.2%) were overweight and 113 (15.2%) were obese. A favorable outcome (Glasgow Outcome Scale score >3) was achieved in 53.0% of overweight patients. In contrast, 61.4% of the 360 patients with a normal BMI had a favorable outcome (P = .021). However, in the multivariate analysis, only age (odds ratio [OR]: 1.051, 95% confidence interval [CI]: 1.04-1.07, P < .001), World Federation of Neurological Surgeons grade (OR: 2.095, 95% CI: 1.87-2.35, P < .001), occurrence of vasospasm (OR: 2.90, 95% CI: 1.94-4.34, P < .001), and aneurysm size larger than 12 mm (OR: 2.215, 95% CI: 1.20-4.10, P = .011) were independent predictors of outcome after 6 months. Of the 321 poor grade patients (World Federation of Neurological Surgeons score >3), 171 (53.3%) were overweight. Of these, 21.6% attained a favorable outcome compared with 35.3% of normal-weight patients (P = .006). CONCLUSION: Although many physicians anticipate a worse outcome for obese patients, in our study, the BMI was not an independent predictor of outcome. Based on the BMI, obesity seems to be negligible for outcome after SAH compared with the impact of SAH itself, the patient's age, occurrence of vasospasm, or aneurysm size. PMID- 23632761 TI - Biopsy of the superficial cortex: predictors of effectiveness and outcomes. AB - BACKGROUND: Brain biopsies of superficial cortex are performed for diagnosis of neurological diseases, but preoperative predictors of successful diagnosis and risks are lacking. OBJECTIVE: We evaluated effectiveness and outcomes of superficial cortical biopsies and determined preoperative predictors of diagnosis, outcomes, morbidities, and mortality. METHODS: A single-institution retrospective analysis of 170 patients who underwent open brain biopsies of superficial cortex was performed. Clinical predictors of effectiveness and outcomes were determined using univariate/multivariate analyses and a system for risk-benefit stratification was created and tested. RESULTS: Brain biopsies led to successful diagnosis in 122 of 170 (71.8%) and affected management in 97 of 170 (57.1%) cases. Factors increasing the odds of diagnostic pathology included age older than 45 years (odds ratio [OR]: 2.67, 95% confidence interval [CI]: 1.34-5.27, P < .01), previous cancer diagnosis (OR: 3.64, 95% CI: 1.69-7.85, P < .001), focal (OR: 3.90, 95% CI: 1.91-8.00, P < .001) and enhancing (OR: 5.03, 95% CI: 2.41-10.52, P < .001) lesions on magnetic resonance imaging, biopsy of specific lesions on magnetic resonance imaging (OR: 9.34, 95% CI: 4.29-20.33, P < .001), and use of intraoperative navigation (OR: 6.59, 95% CI: 3.04-14.28, P < .001). Brain biopsies led to symptomatic intracranial hemorrhage, seizures, other significant morbidities, and perioperative mortality in 12.4%, 16.2%, 37.1%, and 8% of cases, respectively. Risk of postoperative intracranial hemorrhage was increased by a history of aspirin use (OR: 2.51, 95% CI: 1.23-5.28, P < .05) and age older than 60 years (OR: 2.66, 95% CI: 1.36-5.18, P < .01). CONCLUSION: Effectiveness and risk of morbidity/mortality can be estimated preoperatively for patients undergoing open brain biopsies of the superficial cortex. Older age and specific imaging characteristics increase the odds of diagnostic biopsy. Conversely, older age and aspirin use increases the risk of postoperative complications. PMID- 23632762 TI - Characterization of chronic subdural hematoma fluid proteome. AB - BACKGROUND: Chronic subdural hematoma (CSDH) is commonly caused by head injury, but the progression of CSDH is recognized as an inflammatory process. The protein composition of the CSDH fluid has not been fully elucidated, nor has the contribution of its components to the enlargement of the hematoma cavity and to its chronic manifestation. OBJECTIVE: To characterize the protein content of CSDH fluid and study the differences between CSDH fluid and serum to identify proteins putatively involved in the pathogenesis of CSDH. METHODS: CSDH fluid and serum of 5 patients were investigated with 2-dimensional gel electrophoresis followed by glycosylation-specific fluorescence staining and mass spectrometry. RESULTS: Two dimensional gel electrophoresis revealed approximately 1100 protein spots in the CSDH fluid. We identified 213 spots representing 57 different proteins, most of which were glycosylated. The comparison with serum revealed 11 proteins with elevated levels in the CSDH fluid including carbonic anhydrase I, catalase, ferritin light chain, fibrinogen (alpha, beta, gamma), hemoglobin (alpha, beta), malate dehydrogenase, peroxiredoxin 2, and transforming growth factor-beta induced protein ig-h3. The levels of haptoglobin and a fragment of complement C4 were decreased. Changes in spot positions were detected for apolipoprotein A1 and a fragment of complement C3. CONCLUSION: The hematoma fluid originates mainly from blood and the results suggest the involvement of coagulation and fibrinolysis cascades. However, proteins with a potential role in CSDH pathogenesis were detected including carbonic anhydrase I, transforming growth factor-beta-induced protein ig-h3, and the altered components of the complement system. Inflammation and fibrosis indicate targets for further studies in the pathogenesis of CSDH. PMID- 23632763 TI - Biomechanical comparison of transforaminal lumbar interbody fusion with 1 or 2 cages by finite-element analysis. AB - BACKGROUND: Anterior lumbar interbody fusion and posterior lumbar interbody fusion with 1 cage have been shown to have similar biomechanics compared with the use of 2 cages. However, there have been no reports on the biomechanical differences between using 1 or 2 cages in transforaminal lumbar interbody fusion (TLIF) surgery. OBJECTIVE: To determine the biomechanical differences between the use of 1 or 2 cages in TLIF by finite-element analysis. METHODS: Three validated finite-element models of the L3-L5 lumbar segment were created (intact model and single- and paired-cage TLIF models). To study the biomechanics, a compressive preload of 400 N over 7.5 N-m was applied to the superior surfaces of the L3 vertebral body to simulate flexion, extension, rotation, and lateral bending. RESULTS: There was no significant difference in the range of motion between single-cage and paired-cage TLIF models, < 1 degrees for all loading cases. Cage stress was high in the single-cage TLIF model under all loading conditions. Bone graft stress was high in the single-cage TLIF model. Pedicle screw stress was higher in the single-cage compared with the paired-cage TLIF. CONCLUSION: Single cage TLIF approximates biomechanical stability and increases the stress of the bone graft. The use of a single cage may simplify the standard TLIF procedure, shorten operative times, decrease cost, and provide satisfactory clinical outcomes. Thus, single-cage TLIF is a useful alternative to traditional 2-cage TLIF. PMID- 23632764 TI - Evolution of transoral surgery: three decades of change in patients, pathologies, and indications. AB - BACKGROUND: Transoral surgery may be used to approach pathologies at the craniocervical junction. However, the need for this approach has decreased over the past few decades. OBJECTIVE: To assess the outcome and complications of transoral surgery and extended transoral approaches at a single UK center between 1980 and 2011. METHODS: A retrospective review was performed of 495 ventral midline operations (between 1980 and 2004) and prospective review of 38 operations (2004-2011) in a total of 479 patients. Trends in surgery and factors associated with good or bad outcome were assessed over this 30-year period. RESULTS: Of 533 operations, the most frequently performed surgeries were simple transoral surgery (321 operations), transoral surgery with splitting of the palate (107 operations), open-door maxillotomy (58 operations), and mandibulotomy (11 operations). Since the 1990s, there has been a steady decrease in the number of operations performed, mainly due to the decrease in the number of patients with rheumatoid arthritis presenting for surgery. The incidence of craniocervical junction tumors remained constant. The number of complications was significantly associated with the preoperative neurological status, and more complications were seen in myelopathic rheumatoid patients as well as a greater trend in congenital basilar invagination. The rates of pharyngeal infection (0.6%) and cerebrospinal fluid leak (0.3%) for standard transoral surgery were extremely low. CONCLUSION: The number of transoral and associated operations has decreased over time. Transoral surgery is now mainly indicated for ventral midline tumors such as chordomas. Transnasal endoscopic techniques show promise, but a major advantage of standard transoral surgery is the low cerebrospinal fluid leak and infection rates. PMID- 23632765 TI - Simultaneous recording of single-neuron activities and broad-area intracranial electroencephalography: electrode design and implantation procedure. AB - BACKGROUND: There has been growing interest in clinical single-neuron recording to better understand epileptogenicity and brain function. It is crucial to compare this new information, single-neuronal activity, with that obtained from conventional intracranial electroencephalography during simultaneous recording. However, it is difficult to implant microwires and subdural electrodes during a single surgical operation because the stereotactic frame hampers flexible craniotomy. OBJECTIVE: To describe newly designed electrodes and surgical techniques for implanting them with subdural electrodes that enable simultaneous recording from hippocampal neurons and broad areas of the cortical surface. METHODS: We designed a depth electrode that does not protrude into the dura and pulsates naturally with the brain. The length and tract of the depth electrode were determined preoperatively between the lateral subiculum and the lateral surface of the temporal lobe. A frameless navigation system was used to insert the depth electrode. Surface grids and ventral strips were placed before and after the insertion of the depth electrodes, respectively. Finally, a microwire bundle was inserted into the lumen of the depth electrode. We evaluated the precision of implantation, the recording stability, and the recording rate with microwire electrodes. RESULTS: Depth-microwire electrodes were placed with a precision of 3.6 mm. The mean successful recording rate of single- or multiple unit activity was 14.8%, which was maintained throughout the entire recording period. CONCLUSION: We achieved simultaneous implantation of microwires, depth electrodes, and broad-area subdural electrodes. Our method enabled simultaneous and stable recording of hippocampal single-neuron activities and multichannel intracranial electroencephalography. PMID- 23632767 TI - A case of falcine sinus dural arteriovenous fistula. AB - BACKGROUND AND IMPORTANCE: The falcine sinus is an embryonic vessel that connects the superior and inferior sagittal sinuses and mostly closes after birth. Although some cases of persistent falcine sinus have been reported, dural arteriovenous fistula (dAVF) associated with the falcine sinus has not previously been reported. CLINICAL PRESENTATION: A 60-year-old man presented with asymptomatic dAVFs on digital subtraction angiography. The dAVFs were fed mainly by the cortical branch of the left anterior cerebral artery and drained into the falcine sinus. Intraoperatively, all veins draining in a retrograde manner into cortical veins were obstructed. However, cortical venous reflux did not disappear before removal of the falx cerebri, including the falcine sinus and inferior sagittal sinus. In this case, we considered falcine sinus dAVF as equivalent to olfactory groove dAVF because the medial olfactory artery, in its role as a common feeding artery in olfactory groove dAVF, is a rudiment of the anterior cerebral artery as the main feeding artery in this case. Intraoperative findings and the surgical specimen revealed a small vessel network in the falx cerebri communicating with the falcine and inferior sagittal sinuses, which was considered to represent a falcine venous plexus, not a vessel anomaly. CONCLUSION: Extensive removal of the falx cerebri including the falcine sinus or complete endovascular obliteration of the whole falcine sinus as early as possible represents an important strategy in the surgical treatment of falcine sinus dAVF. PMID- 23632768 TI - Commentary: Societal statement on recent acute stroke intervention trials: results and implications. PMID- 23632769 TI - Fluorescent and colorimetric magnetic microspheres as nanosensors for Hg2+ in aqueous solution prepared by a sol-gel grafting reaction and host-guest interaction. AB - Fluorescent sensing TSRh6G-beta-cyclodextrin fluorophore/adamantane-modified inclusion complex magnetic nanoparticles (TFIC MNPs) have been synthesized via the cooperation of a host-guest interaction and sol-gel grafting reaction. Powder X-ray diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, and UV-visible absorption and emission spectroscopy have been employed to characterize the material. Fluorescence and UV-visible spectra have shown that the resultant multifunctional nanoparticle sensors exhibit selective 'turn-on' type fluorescent enhancements and a clear color change from light brown to pink with Hg(2+). Owing to a larger surface area and high permeability, TFIC MNPs exhibit remarkable selectivity and sensitivity for Hg(2+), and its detection limit measures up to the micromolar level in aqueous solution. Most importantly, magnetic measurements have shown that TFIC magnetic nanoparticles are superparamagnetic and they can be separated and collected easily using a commercial magnet. These results not only solve the limitations in practical sensing applications of nanosensors, but also enable the fabrication of other multifunctional nanostructure-based hybrid nanomaterials. PMID- 23632770 TI - The urgent need for an effective biomarker for cytotoxic therapy-induced adverse effects. PMID- 23632771 TI - Current world literature. PMID- 23632774 TI - Bone refilling in cortical basic multicellular units: insights into tetracycline double labelling from a computational model. AB - Bone remodelling is carried out by 'bone multicellular units' ([Formula: see text]s) in which active osteoclasts and active osteoblasts are spatially and temporally coupled. The refilling of new bone by osteoblasts towards the back of the [Formula: see text] occurs at a rate that depends both on the number of osteoblasts and on their secretory activity. In cortical bone, a linear phenomenological relationship between matrix apposition rate and [Formula: see text] cavity radius is found experimentally. How this relationship emerges from the combination of complex, nonlinear regulations of osteoblast number and secretory activity is unknown. Here, we extend our previous mathematical model of cell development within a single cortical [Formula: see text] to investigate how osteoblast number and osteoblast secretory activity vary along the [Formula: see text]'s closing cone. The mathematical model is based on biochemical coupling between osteoclasts and osteoblasts of various maturity and includes the differentiation of osteoblasts into osteocytes and bone lining cells, as well as the influence of [Formula: see text] cavity shrinkage on osteoblast development and activity. Matrix apposition rates predicted by the model are compared with data from tetracycline double labelling experiments. We find that the linear phenomenological relationship observed in these experiments between matrix apposition rate and [Formula: see text] cavity radius holds for most of the refilling phase simulated by our model, but not near the start and end of refilling. This suggests that at a particular bone site undergoing remodelling, bone formation starts and ends rapidly, supporting the hypothesis that osteoblasts behave synchronously. Our model also suggests that part of the observed cross-sectional variability in tetracycline data may be due to different bone sites being refilled by [Formula: see text]s at different stages of their lifetime. The different stages of a [Formula: see text]'s lifetime (such as initiation stage, progression stage, and termination stage) depend on whether the cell populations within the [Formula: see text] are still developing or have reached a quasi-steady state whilst travelling through bone. We find that due to their longer lifespan, active osteoblasts reach a quasi-steady distribution more slowly than active osteoclasts. We suggest that this fact may locally enlarge the Haversian canal diameter (due to a local lack of osteoblasts compared to osteoclasts) near the [Formula: see text]'s point of origin. PMID- 23632773 TI - Variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives. AB - Variant ataxia telangiectasia (A-T) may be an underdiagnosed entity. We correlate data from radiosensitivity and kinase assays with clinical and molecular data from a patient with variant A-T and relatives. The coding region of ATM was sequenced. To evaluate the functional effect of the mutations, we performed kinase assays and developed a novel S-G2 micronucleus test. Our patient presented with mild dystonia, moderately dysarthric speech, increased serum alpha fetoprotein but no ataxia nor telangiectasias, no nystagmus or oculomotor dyspraxia. She has a severe IgA deficiency, but does not have recurrent infections. She is compound heterozygote for ATM c.8122G>A (p.Asp2708Asn) and c.8851-1G>T, leading to in frame loss of 63 nucleotides at the cDNA level. A trace amount of ATM protein is translated from both alleles. Residual kinase activity is derived only from the p.Asp2708Asn allele. The conventional G0 micronucleus test, based on irradiation of resting lymphocytes, revealed a radiosensitive phenotype for the patient, but not for the heterozygous relatives. As ATM is involved in homologous recombination and G2/M cell cycle checkpoint, we optimized an S-G2 micronucleus assay, allowing to evaluate micronuclei in lymphocytes irradiated in the S and G2 phases. This test showed increased radiosensitivity for both the patient and the heterozygous carriers. Intriguingly, heterozygous carriers of c.8851-1G>T (mutation associated with absence of kinase activity) showed a stronger radiosensitive phenotype with this assay than heterozygous carriers of p.Asp2708Asn (mutation associated with residual kinase activity). The modified S-G2 micronucleus assay provided phenotypic insight into complement the diagnosis of this atypical A-T patient. PMID- 23632775 TI - Infected aortic stent graft with Propionibacterium acnes. AB - An infected aortic endograft is an uncommon event, and when it happens it can be of significant morbidity and mortality to the patient. We present here a case of a patient with an infected aortic endograft following percutaneous translumbar sac embolization for a type II endoleak leading to sac expansion. The cultured pathogen was Propionibacterium acnes, a commonly occurring skin bacterium that leads to the clinical condition "acne vulgaris." The patient underwent graft explantation and reconstruction with autogenous femoral vein. To our knowledge, there are no previously published reports of aortic graft infections with P acnes. PMID- 23632776 TI - Ab initio and DFT analysis of the low-lying electronic states of metal dihalides: quantum chemical calculations on the neutral BrMCl (M = Cu, Ag, Au). AB - The electronic configuration of the electronic ground and low-lying doublet excited states of neutral metal dihalides BrMCl (M = Cu, Ag, Au) has been investigated on the basis of CASSCF/CASPT2 methods taking into account scalar relativistic effects. A preliminary study of the electronic problem in BrAgCl, based on DFT and CASSCF/CASPT2 approaches and using various basis sets, namely relativistic all-electron basis sets, effective core potentials and ab initio model potentials (AIMP), as well as non-relativistic AIMP is discussed. It is shown that single-determinant methods are not flexible enough to describe the bonding of the neutral species in the electronic ground state regardless of the basis set. The failure to allocate the single electron of BrAgCl correlates with a wrong charge distribution within the complex, which is more accentuated when using pseudopotential basis sets. The inclusion of static and dynamic correlation effects by means of CASSCF/CASPT2 methods using large relativistic all-electron basis sets provides a correct qualitative picture of the electronic structure of the BrMCl series (M = Cu, Ag, Au). The spin unrestricted KS-DFT approach leads to a reasonable description of the degenerate electronic ground state ((2)Sigma/(2)Pi) bonding in these complexes with negligible spin contamination providing comparative spin densities in the series of molecules under investigation. PMID- 23632777 TI - RNA interference-mediated knockdown of Livin suppresses cell proliferation and invasion and enhances the chemosensitivity to cisplatin in human osteosarcoma cells. AB - Livin is a novel member of the inhibitor of apoptosis protein (IAP) family that has been reported to be overexpressed in a variety of human malignancies, including osteosarcoma. However, the potential roles of Livin in tumorigenesis have not been elucidated. In the present study, we employed RNA interference (RNAi) technology to suppress endogenous Livin expression in osteosarcoma cells and successfully generated a U2-OS cell line with stably knockdown of Livin. Functional analysis showed that knockdown of Livin significantly reduced cell proliferation, colony formation, and invasion and migration capacities of U2-OS cells in vitro. Moreover, specific downregulation of Livin led to cell cycle arrest at the G0/G1 phase and eventual apoptosis. Meanwhile, western blot analysis revealed that cells with stably knockdown of Livin showed decreased expression levels of Cyclin D1, Bcl-2, matrix metalloproteinase (MMP)-2 and MMP 9, but increased expression levels of activated Caspase-3, Bax and cleaved poly (ADP-ribose) polymerase (PARP) compared to those transfected with a control vector. We also observed that suppression of Livin expression in osteosarcoma cells increased their chemosensitivity to cisplatin. Taken together, our data suggest that Livin is involved in tumorigenesis of human osteosarcoma and may serve as a promising therapeutic target for osteosarcoma. PMID- 23632778 TI - Technique of anatomical footprint reconstruction of the ACL with oval tunnels and medial portal aimers. AB - PURPOSE: The purpose of this article was to demonstrate an anterior cruciate ligament (ACL) reconstruction technique using oval tunnels. Aim of this single bundle technique is to fit the footprint anatomy of the ACL as closely as possible. TECHNIQUE AND PATIENTS: The presented technique is a single bundle technique using a semitendinosus graft. For femoral tunnel placement, a specific medial portal aimer (Karl Storz, Tuttlingen, Germany) is used. Aiming and drilling of the femoral tunnel are performed via the medial portal. Oval tunnels are created by stepwise dilatation with ovally shaped dilatators. The position of the femoral tunnel is visualized and controlled with the arthroscope via the medial portal. For the tibial tunnel placement, a specific aimer was used as well. With this technique, 24 patients were operated and all intra- and postoperative complications were analyzed prospectively. The tunnel position was documented postoperatively by CT scan. RESULTS: There were no significant intra- and postoperative complications associated with the oval tunnel technique. The postoperative 3D CT scan revealed that all femoral and tibial tunnels were located within the area of the anatomical ACL insertions. CONCLUSIONS: This article presents an ACL reconstruction technique using oval dilatators and medial portal aimers to create oval tunnels. These oval tunnels match the insertion site anatomy much closer than round tunnels do. LEVEL OF EVIDENCE: Level IV, case series. PMID- 23632779 TI - Management of acute acromioclavicular joint dislocations: current concepts. AB - Acromioclavicular joint (ACJ) injuries represent a common injury to the shoulder girdle. In the management algorithm of acute ACJ injuries complete radiological evaluation represents the key to a successful therapy. According to the classification of Rockwood the presence of a horizontal component in addition to vertical instability has to be detected. Using axillary functional views or Alexander views dynamic horizontal ACJ instability can be diagnosed in a simple, efficient and cost-effective manner reducing the number of mis-/underdiagnosed ACJ injuries. MRI should not be the imaging modality of first choice. The treatment of ACJ dislocations must consider two aspects. In addition to the correct type of injury therapy strategies should be adapted to patient's demands and compliance. Low grade AC injuries types I and II are treated non-operatively in terms of "skilful-neglect". High-grade injuries types IV-VI should be treated operatively within a time frame of 2-3 weeks after injury. A certain debate is still ongoing regarding type III injuries. Out from the literature, non-operative treatment of type III injuries results to provide at least equal functional outcomes as compared to surgical treatment associated with less complications and earlier return to professional and sports activities. If surgical treatment is indicated, open surgical procedures using pins, PDS-slings or hook plates are still widely used concurring with recently raising minimally invasive, arthroscopic techniques using new implants designed to remain in situ. Combined coracoclavicular and acromioclavicular repair are gaining in importance to restore horizontal as well as vertical ACJ stability. PMID- 23632780 TI - Heterotopic ossification in portal sites following hip arthroscopy. AB - Heterotopic ossification (HO) is a well-known condition that usually occurs after head trauma, burns and open surgical procedures, most commonly around the hip and elbow joints. It is a well-documented complication occurring after open hip surgery; however, there exists limited information regarding its prevalence and clinical importance following hip arthroscopy. We report a case of symptomatic HO formation in portal sites following arthroscopic rim decompression, femoroplasty and labral debridement that was successfully treated with arthroscopic removal. PMID- 23632781 TI - Computed tomography assessment of lateral pedicle wall perforation by free-hand subaxial cervical pedicle screw placement. AB - PURPOSE: To present the technique of free-hand subaxial cervical pedicle screw (CPS) placement without using intra-operative navigating devices, and to investigate the crucial factors for safe placement and avoidance of lateral pedicle wall perforation, by measuring and classifying perforations with postoperative computed tomography (CT) scan. The placement of CPS has generally been considered as technically demanding and associated with considerable lateral wall perforation rate. For surgeons without access to navigation systems, experience of safe free-hand technique for subaxial CPS placement is especially valuable. MATERIALS AND METHODS: A total of 214 consecutive traumatic or degenerative patients with 1,024 CPS placement using the free-hand technique were enrolled. In the operative process, the lateral mass surface was decorticated. Then a small curette was used to identify the pedicle entrance by touching the cortical bone of the medial pedicle wall. It was crucial to keep the transverse angle and make appropriate adjustment with guidance of the resistance of the thick medial cortical bone. The hand drill should be redirected once soft tissue breach was palpated by a slim ball-tip prober. With proper trajectory, tapping, repeated palpation, the 26-30 mm screw could be placed. After the procedure, the transverse angle of CPS trajectory was measured, and perforation of the lateral wall was classified by CT scan: grade 1, perforation of pedicle wall by screw placement, with the external edge of screw deviating out of the lateral pedicle wall equal to or less than 2 mm and grade 2, critical perforation of pedicle wall by screw placement, large than 2 mm. RESULTS: A total of 129 screws (12.64 %) were demonstrated as lateral pedicle wall perforation, of which 101 screws (9.86 %) were classified as grade 1, whereas 28 screws (2.73 %) as grade 2. Among the segments involved, C3 showed an obviously higher perforating rate than other (P < 0.05). The difference between the anatomical pedicle transverse angle and the screw trajectory angle was higher in patients of grade 2 perforation than the others. In the 28 screws of grade 2 perforation verified by axial CT, 26 screws had been palpated as abnormal during operation. However, only 19 out of the 101 screws of grade 1 perforation had shown palpation alarming signs during operation. The average follow-up was 36.8 months (range 5-65 months). There was no symptom and sign of neurovascular injuries. Two screws (0.20 %) were broken, and one screw (0.10 %) loosen. CONCLUSION: Placement of screw through a correct trajectory may lead to grade 1 perforation, which suggests transversal expansion and breakage of the thinner lateral cortex, probably caused by mismatching of the diameter of 3.5 mm screws and the tiny cancellous bone cavity of pedicle. Grade 1 perforation is deemed as relatively safe to the vertebral artery. Grade 2 perforation means obvious deviation of the trajectory angle of hand drill, which directly penetrates into the transverse foramen, and the risk of vertebral artery injury (VAI) or development of thrombi caused by the irregular blood flow would be much greater compared to grade 1 perforation. Moreover, there are two crucial maneuvers for increasing accuracy of screw placement: identifying the precise entry point using a curette or hand drill to touch the true entrance of the canal after decortication, and guiding CPS trajectory on axial plane by the resistant of thick medial wall. PMID- 23632782 TI - A multi-level rapid prototyping drill guide template reduces the perforation risk of pedicle screw placement in the lumbar and sacral spine. AB - INTRODUCTION: The method of free-hand pedicle screw placement is generally safe although it carries potential risks. For this reason, several highly accurate computer-assisted systems were developed and are currently on the market. However, these devices have certain disadvantages. We have developed a method of pedicle screw placement in the lumbar and sacral region using a multi-level drill guide template, created with the rapid prototyping technology and have validated it in a clinical study. The aim of the study was to manufacture and evaluate the accuracy of a multi-level drill guide template for lumbar and first sacral pedicle screw placement and to compare it with the free-hand technique under fluoroscopy supervision. MATERIALS AND METHODS: In 2011 and 2012, a randomized clinical trial was performed on 20 patients. 54 screws were implanted in the trial group using templates and 54 in the control group using the fluoroscopy supervised free-hand technique. Furthermore, applicability for the first sacral level was tested. Preoperative CT-scans were taken and templates were designed using the selective laser sintering method. Postoperative evaluation and statistical analysis of pedicle violation, displacement, screw length and deviation were performed for both groups. RESULTS: The incidence of cortex perforation was significantly reduced in the template group; likewise, the deviation and displacement level of screws in the sagittal plane. In both groups there was no significantly important difference in deviation and displacement level in the transversal plane as not in pedicle screw length. The results for the first sacral level resembled the main investigated group. CONCLUSIONS: The method significantly lowers the incidence of cortex perforation and is therefore potentially applicable in clinical practice, especially in some selected cases. The applied method, however, carries a potential for errors during manufacturing and practical usage and therefore still requires further improvements. PMID- 23632783 TI - The use of a dual-mobility concept in total hip arthroplasty patients with spastic disorders: no dislocations in a series of ten cases at midterm follow-up. AB - INTRODUCTION: Total hip arthroplasty (THA) is one of the treatment options in patients with cerebral palsy (CP) with painful osteoarthritis of the hip. However, the risk of dislocation of the prosthesis is higher in patients with CP when compared with physically normal patients. In this retrospective study of ten consecutive cases, we hypothesized that the use of a dual-mobility cup could reduce this risk of dislocation combined with good functional results. MATERIALS AND METHODS: From January 2008 until October 2010, eight patients (ten hips) with CP who consecutively received a THA using a dual-mobility cup were identified. At the time of surgery, the average age of the patient group was 54 years (range 43 61). Latest follow-up took place after on average 39 months (range 22-56 months). All patients or their caregivers were interviewed by telephone. They were asked if dislocation of the prosthesis had occurred. To evaluate quality of life and health in general, patients completed the SF-36 questionnaire. RESULTS: None of the prostheses had dislocated at the latest follow-up. Reoperation was needed in one patient after a periprosthetic fracture. Radiologic evaluation showed a mean cup inclination of 46 (range 27-58). On average, the quality of life of patients in this study was found to be limited in particular on the domains of physical health and functioning, while a fair to good score was measured at the six other different domains. CONCLUSION: The use of a dual-mobility cup in THA in patients with CP can lead to favourable results with respect to dislocation and clinical outcome. PMID- 23632784 TI - Quantification of electron transfer rates of different facets on single gold nanoparticles during catalytic reactions. AB - Rayleigh scattering spectra of high-index {730} elongated tetrahexahedral gold nanoparticles and low-index {100}, {110}, and {111} gold nanorods were collected in real time in the reduction of 4-nitrophenol. The high-index facets are capable of accepting electrons seven times faster and emitting electrons two-and-a-half times faster than low-index facets. PMID- 23632785 TI - Trigeminal schwannoma with extracranial extension and brainstem compression. PMID- 23632786 TI - Knowledge and education of primary care physicians on management of children with hearing loss and pediatric cochlear implantation. PMID- 23632787 TI - Spontaneous plugging of the horizontal semicircular canal with reversible canal dysfunction and recovery of vestibular evoked myogenic potentials. AB - OBJECTIVE: To evaluate the clinical pathophysiology of oculomotor changes in a patient presenting with a spontaneous semicircular horizontal canal plug. PATIENT: A 42-year-old man with acute spontaneous vertigo with spinning and persistent left-horizontal nystagmus, intensity but not direction dependent on head orientation with respect to gravity, indicating a benign paroxysmal positional vertigo due to otoconia causing a plug in the horizontal semicircular canal. INTERVENTION: Electrophysiological and video-oculographic testing; vestibular rehabilitation. MAIN OUTCOME MEASURES: Cervical and ocular vestibular evoked myogenic potentials (VEMPs); video head impulse testing. RESULTS: The video head-impulse test revealed an eye velocity cutoff at 80 degrees /s in the time interval from 40 to 90 ms after initiation of head impulses to the right. This normalized within 2 days after liberatory maneuvers, documenting for the first time a reversible deficiency of the cupular-endolymph high-frequency system dynamics. Cervical and ocular vestibular myogenic potentials were absent during stimulation of the affected side before the liberatory maneuvers but normalized within 30 to 80 days. CONCLUSION: This case is special in 4 respects: 1) nystagmus intensity, but not direction, was dependent on head orientation with respect to gravity, indicating a horizontal canal plug; 2) VEMPs were asymmetrical before liberatory maneuvers; 3) VEMPs recovered after Day 30; and 4) video head-impulse test asymmetry recovered. These observations challenge the common belief that VEMPs are evoked by otolith stimulation only. Instead, the assumption of a reversible canal dysfunction by a plug offers a more plausible explanation for all effects. PMID- 23632788 TI - Congenital cholesteatoma is predominantly found in the posterior-superior quadrant in the Asian population: systematic review and meta-analysis, including our clinical experience. AB - OBJECTIVE: The study compares the clinical features of patients with congenital cholesteatoma seen in our institution over the most recent 10 years versus those seen in the previous decade. Furthermore, this study includes a systematic review and meta-analysis investigating whether differences in site predilection of congenital cholesteatoma exist between patients from Asian and Western countries. DATA SOURCES: The retrospective review consisted of 31 cases encountered from 2001 to 2011 as compared with 40 cases previously described. For systematic review, data were retrieved from PubMed, EmBase, and the Japan Medical Abstracts Society Database (January 1995 through May 2012). STUDY SELECTIONS: Articles addressing site predilection of congenital cholesteatoma were selected with no language preference. DATA EXTRACTION: The database was searched using the keywords "congenital cholesteatoma." After critical review of 408 studies, 27 studies were eligible for quantitative synthesis. DATA SYNTHESIS: A retrospective analysis of our departmental cases showed that more than 70% (8/11) of the Potsic's stage I or II cases had a predilection for the anterior-superior quadrant (ASQ). None of the Stage III (17) or IV (3) cases had a similar site predilection. Consistent with our previous chart review, Stage III was the most common, comprising more than 60% of cases. Meta-analysis of the 27 eligible studies provided sufficient information regarding locations of congenital cholesteatoma, and Asian studies showed less frequent ASQ involvement (overall estimate, 0.54; 95% confident interval [CI], 0.49-0.59) when compared with Western studies (overall estimate, 0.76; 95% CI, 0.73-0.80). Moreover, the involvement of posterior-superior quadrant (PSQ) in Asian studies was estimated as 0.69 (95% CI, 0.64-0.73), which was higher than that associated with involvement of ASQ. CONCLUSION: In contrast to Western studies, PSQ was more frequently involved than ASQ in Asian studies of congenital cholesteatoma. The posteriorly located lesions might have a completely distinct pathophysiologic origin when compared with lesions originating from the ASQ. PMID- 23632789 TI - A vibration investigation of a flat surface contact to skull bone for direct bone conduction transmission in sheep skulls in vivo. AB - HYPOTHESIS: Bone conduction implant (BCI) attached with a flat surface contact will offer efficient and linear vibration transmission over time. BACKGROUND: Despite that percutaneous bone conduction devices (PBCD) are successful in treating patients with conductive hearing loss, there are some drawbacks related to the need of a permanent skin penetration. The BCI system is designed as an alternative to the PBCD because it leaves the skin intact. METHODS: BCI dummy implants were installed in 3 sheep skulls in vivo to study the vibration transmission characteristics over time. Mechanical point impedances and vibration transfer response functions of the BCI implants were measured at the time of surgery and after a healing period of 8 months. RESULTS: In 1 sheep both implants healed without complications. In the other 2 sheep, the implants were either partially loose or lost to follow up. In the sheep with stable implants, it was found by the resonance frequency shift of the mechanical point impedance that a firmer integration between the implant and bone tissue as seen in osseointegrated surfaces developed over time. It was also shown that the transcranial vibration transmission remains stable and linear. Providing bone chips in the contact between the implant and the bone did not enhance vibration transmission. The surgical procedure for installing the BCI dummy implants was uneventful. CONCLUSION: The mechanical point impedances and vibration transfer response functions indicate that the BCI implants integrate and that transmission conditions remain stable over time. PMID- 23632790 TI - Platelet defects in congenital variant of Rett syndrome patients with FOXG1 mutations or reduced expression due to a position effect at 14q12. AB - The Forkhead box G1 (FOXG1) gene encodes a transcriptional repressor essential for early development of the telencephalon. Intragenic mutations and gene deletions leading to haploinsufficiency cause the congenital variant of Rett syndrome. We here describe Rett syndrome-like patients, three of them carrying a balanced translocation with breakpoint in the chromosome 14q12 region, and one patient having a 14q12 microdeletion excluding the FOXG1 gene. The hypothesis of long-range FOXG1-regulatory elements in this region was supported by our finding of reduced FOXG1 mRNA and protein levels in platelets and skin fibroblasts from these cases. Given that FOXG1 is not only expressed in brain but also in platelets, we have studied platelet morphology in these patients and two additional patients with FOXG1 mutations. Electron microscopy of their platelets showed some enlarged, rounder platelets with often abnormal alpha, and fewer dense granules. Platelet function studies were possible in one 14q12 translocation patient with a prolonged Ivy bleeding time and a patient with a heterozygous FOXG1 c.1248C>G mutation (p.Tyr416X). Both have a prolonged PFA-100 occlusion time with collagen and epinephrine and reduced aggregation responses to low dose of ADP and epinephrine. Dense granule ATP secretion was normal for strong agonists but absent for epinephrine. In conclusion, our study shows that by using platelets functional evidence of cis-regulatory elements in the 14q12 region result in reduced FOXG1 levels in patients' platelets having translocations or deletions in that region. These platelet functional abnormalities deserve further investigation regarding a non-transcriptional regulatory role for FOXG1 in these anucleated cells. PMID- 23632791 TI - The KCNJ8-S422L variant previously associated with J-wave syndromes is found at an increased frequency in Ashkenazi Jews. AB - J-wave syndromes have been associated with increased risk of ventricular fibrillation and sudden cardiac death. Previous studies have identified the KCNJ8 S422L variant in heterozygous form in individuals with J-wave syndromes. Its absence in over 1500 controls, coupled with in vitro analysis, have led to the conclusion that S422L is pathogenic. We previously performed whole-genome sequencing in a family quartet of Ashkenazi Jewish decent with no history of J wave syndrome. Re-examination of these data reveals that both parents are heterozygous for the S422L variant, while the 12-year old son carries two copies- thus representing the first reported case of a S422L homozygote. In order to examine whether the S422L mutation might segregate at appreciable frequencies in specific populations, we genotyped the variant in a panel consisting of 722 individuals from 22 European, Middle Eastern non-Jewish, Ashkenazi Jewish, and non-Ashkenazi Jewish populations. We found that the S422L allele was at a significantly higher frequency in Ashkenazi Jews (~4%) compared with other populations in our survey, which have frequencies <0.25%. We also performed ECGs in both male members of the family quartet. The homozygous boy demonstrated no clinically significant ECG abnormalities, while the heterozygous father presented with a subtle J-wave point elevation. Our results suggest that either (a) previous studies implicating S422L as pathogenic for J-wave syndromes failed to appropriately account for European population structure and the variant is likely benign, or (b) Ashkenazi Jews may be at significantly increased risk of J-wave syndromes and ultimately sudden cardiac death. PMID- 23632792 TI - Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder. AB - Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development. PMID- 23632793 TI - Pre-symptomatic genetic testing for inherited cardiac conditions: a qualitative exploration of psychosocial and ethical implications. AB - Inherited cardiac conditions (ICCs) can lead to sudden cardiac death at any age, yet are often asymptomatic and clinically undetected. Prophylactic interventions are available and cascade testing is recommended to identify family members at risk. When a disease-causing mutation has been identified in a family, pre symptomatic genetic testing (PSGT) is available. This study explores perceptions of the cascade process, impact of PSGT and attitudes towards direct contact as an alternative to family-mediated dissemination for ICCs. In depth, interviews were conducted with 22 participants eligible for PSGT for Hypertrophic Cardiomyopathy or Long QT syndrome. Data were analysed using an inductive, thematic approach. Risk is perceived to be low pre-test in the absence of symptoms, and participants frequently test with the aim of ruling out risk to self and children. Testing of children is a complex decision; although older participants have concerns about possible adverse effects of genetic testing early in the life course, young participants are pragmatic about their result. The meaning of a positive genetic test result may be difficult to conceptualise in the absence of clinical evidence of disease, and this may deter further dissemination to at-risk family members. A majority of participants see advantages in direct contact from health professionals and support it in principle. Implications for practice include addressing risk perception pre-test, and presenting genetic test information as part of a risk stratification process rather than a binary outcome. Families may require more support or intervention in cascading genetic test information. PMID- 23632794 TI - Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders. AB - Copy number variants (CNVs) have repeatedly been found to cause or predispose to autism spectrum disorders (ASDs). For diagnostic purposes, we screened 194 individuals with ASDs for CNVs using Illumina SNP arrays. In several probands, we also analyzed candidate genes located in inherited deletions to unmask autosomal recessive variants. Three CNVs, a de novo triplication of chromosome 15q11-q12 of paternal origin, a deletion on chromosome 9p24 and a de novo 3q29 deletion, were identified as the cause of the disorder in one individual each. An autosomal recessive cause was considered possible in two patients: a homozygous 1p31.1 deletion encompassing PTGER3 and a deletion of the entire DOCK10 gene associated with a rare hemizygous missense variant. We also identified multiple private or recurrent CNVs, the majority of which were inherited from asymptomatic parents. Although highly penetrant CNVs or variants inherited in an autosomal recessive manner were detected in rare cases, our results mainly support the hypothesis that most CNVs contribute to ASDs in association with other CNVs or point variants located elsewhere in the genome. Identification of these genetic interactions in individuals with ASDs constitutes a formidable challenge. PMID- 23632797 TI - The Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-revised (PISQ IR). PMID- 23632795 TI - Controlling complexity: the clinical relevance of mouse complex genetics. AB - Experimental animal models are essential to obtain basic knowledge of the underlying biological mechanisms in human diseases. Here, we review major contributions to biomedical research and discoveries that were obtained in the mouse model by using forward genetics approaches and that provided key insights into the biology of human diseases and paved the way for the development of novel therapeutic approaches. PMID- 23632796 TI - Whole-exome sequencing, without prior linkage, identifies a mutation in LAMB3 as a cause of dominant hypoplastic amelogenesis imperfecta. AB - The conventional approach to identifying the defective gene in a family with an inherited disease is to find the disease locus through family studies. However, the rapid development and decreasing cost of next generation sequencing facilitates a more direct approach. Here, we report the identification of a frameshift mutation in LAMB3 as a cause of dominant hypoplastic amelogenesis imperfecta (AI). Whole-exome sequencing of three affected family members and subsequent filtering of shared variants, without prior genetic linkage, sufficed to identify the pathogenic variant. Simultaneous analysis of multiple family members confirms segregation, enhancing the power to filter the genetic variation found and leading to rapid identification of the pathogenic variant. LAMB3 encodes a subunit of Laminin-5, one of a family of basement membrane proteins with essential functions in cell growth, movement and adhesion. Homozygous LAMB3 mutations cause junctional epidermolysis bullosa (JEB) and enamel defects are seen in JEB cases. However, to our knowledge, this is the first report of dominant AI due to a LAMB3 mutation in the absence of JEB. PMID- 23632798 TI - A new measure of sexual function in women with pelvic floor disorders (PFD): the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR). AB - INTRODUCTION AND HYPOTHESIS: The objective of this study was to create a valid, reliable, and responsive sexual function measure in women with pelvic floor disorders (PFDs) for both sexually active (SA) and inactive (NSA) women. METHODS: Expert review identified concept gaps and generated items evaluated with cognitive interviews. Women underwent Pelvic Organ Prolapse Quantification (POPQ) exams and completed the Incontinence Severity Index (ISI), a prolapse question from the Epidemiology of Prolapse and Incontinence Questionnaire (ISI scores), the Pelvic Floor Distress Inventory-20 (PFDI-20), and the Female Sexual Function Index (FSFI). Principle components and orthogonal varimax rotation and principle factor analysis with oblique rotation identified item grouping. Cronbach's alpha measured internal consistency. Factor correlations evaluated criterion validation. Change scores compared to change scores in other measures evaluated responsiveness among women who underwent surgery. RESULTS: A total of 589 women gave baseline data, 200 returned surveys after treatment, and 147 provided test retest data. For SA women, 3 subscales each in 2 domains (21 items) and for NSA women 2 subscales in each of 2 domains (12 items) emerged with robust psychometric properties. Cronbach's alpha ranged from .63 to .91. For SA women, correlations were in the anticipated direction with PFDI-20, ISI, and FSFI scores, POPQ, and EPIQ question #35 (all p < .05). PFDI-20, ISI, and FSFI subscale change scores correlated with Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire International Urogynecological Association-revised (PISQ-IR) factor change scores and with mean change scores in women who underwent surgery (all p < .05). For NSA women, PISQ-IR scores correlated with PFDI-20, ISI scores, and with EPIQ question #35 (all p < .05). No items demonstrated differences between test and retest (all p >= .05), indicating stability over time. CONCLUSIONS: The PISQ-IR is a valid, reliable, and responsive measure of sexual function. PMID- 23632799 TI - The PISQ-IR: considerations in scale scoring and development. AB - INTRODUCTION: This paper provides a detailed discussion of the psychometric analysis and scoring of a revised measure of sexual function in women with pelvic floor disorders (PFD): the Pelvic Organ Prolapse Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR). METHODS: Standard tools for evaluating item distributions, relationships, and psychometric properties were used to identify sub-scales and determine how the sub-scales should be scored. The evaluation of items included a nonresponse analysis, the nature of missingness, and imputation methods. The minimum number of items required to be answered and three different scoring methods were evaluated: simple summation, mean calculation, and transformed summation. RESULTS: Item nonresponse levels are low in women who are sexually active and the psychometric properties of the scales are robust. Moderate levels of item nonresponse are present for women who are not sexually active, which presents some concerns relative to the robustness of the scales. Single imputation for missing items is not advisable and multiple imputation methods, while plausible, are not recommended owing to the complexity of their application in clinical research. The sub-scales can be scored using either mean calculation or transformed summation. Calculation of a summary score is not recommended. CONCLUSION: The PISQ-IR demonstrates strong psychometric properties in women who are sexually active and acceptable properties in those who are not sexually active. To score the PISQ-IR sub-scales, half of the items must be answered, imputation is not recommended, and either mean calculation or transformed sum methods are recommended. A summary score should not be calculated. PMID- 23632801 TI - The improvement of pelvic floor muscle function in POP patients after the Prolift procedure: results from surface electromyography. AB - INTRODUCTION AND HYPOTHESIS: Patients with pelvic organ prolapse (POP) have lower pelvic floor muscle (PFM) function. We hypothesized that pelvic reconstructive surgery could improve PFM function and strength. METHODS: The controlled, nonrandomized study recruited 37 POP patients in the Prolift group and 30 non-POP patients in the control group. Two urogynecologists performed the Prolift procedure. One experienced physiotherapist who was blinded to the grouping conducted the surface electromyography (SEMG) evaluation using an intravaginal probe. The patient was considered objectively cured if she had stage 0 or I according to the Pelvic Organ Prolapse Quantification system (POP-Q) at the 3rd month postoperatively. Two types of contractions, namely maximum voluntary contraction (MVC) and short, fast contractions (SFC) in 6 s were performed at each SEMG measurement. The SEMG data were collected once in the control group on admission and twice in the Prolift group (on admission and at the 3rd month postoperatively). The t test, Mann-Whitney U test, and Wilcoxon test were used for statistical analysis. RESULTS: A total of 36 POP patients were cured by the Prolift procedure. At the 3-month follow-up, the voltage and duration of MVC as well as the numbers and voltage of SFC increased significantly in the Prolift group. These variables were lower in POP patients compared to women without POP. CONCLUSIONS: The restoration of pelvic anatomy may account for the improved PFM function with increased electrical activity in POP patients verified by SEMG. Evaluation of PFM function may be used as a clinical tool in the overall assessment of pelvic reconstructive surgeries. PMID- 23632800 TI - The use of transvaginal synthetic mesh for anterior vaginal wall prolapse repair: a randomized controlled trial. AB - INTRODUCTION AND HYPOTHESIS: The aim of the study was to compare the efficacy and safety of transvaginal trocar-guided polypropylene mesh insertion with traditional colporrhaphy for treatment of anterior vaginal wall prolapse. METHODS: This is a randomized controlled trial in which women with advanced anterior vaginal wall prolapse, at least stage II with Ba >= +1 cm according to the Pelvic Organ Prolapse Quantification (POP-Q) classification, were randomly assigned to have either anterior colporrhaphy (n = 39) or repair using trocar guided transvaginal mesh (n = 40). The primary outcome was objective cure rate of the anterior compartment (point Ba) assessed at the 12-month follow-up visit, with stages 0 and I defined as anatomical success. Secondary outcomes included quantification of other vaginal compartments (POP-Q points), comparison of quality of life by the prolapse quality of life (P-QOL) questionnaire, and complication rate between the groups after 1 year. Study power was fixed as 80% with 5% cutoff point (p < 0.05) for statistical significance. RESULTS: The groups were similar regarding demographic and clinical preoperative parameters. Anatomical success rates for colporrhaphy and repair with mesh placement groups were 56.4 vs 82.5% (95% confidence interval 0.068-0.54), respectively, and the difference between the groups was statistically significant (p = 0.018). Similar total complication rates were observed in both groups, with tape exposure observed in 5% of the patients. There was a significant improvement in all P-QOL domains as a result of both procedures (p < 0.001), but they were not distinct between groups (p > 0.05). CONCLUSIONS: Trocar-guided transvaginal synthetic mesh for advanced anterior POP repair is associated with a higher anatomical success rate for the anterior compartment compared with traditional colporrhaphy. Quality of life equally improved after both techniques. However, the trial failed to detect differences in P-QOL scores and complication rates between the groups. PMID- 23632802 TI - High-energy supercapacitors based on hierarchical porous carbon with an ultrahigh ion-accessible surface area in ionic liquid electrolytes. AB - A very important yet really challenging issue to address is how to greatly increase the energy density of supercapacitors to approach or even exceed those of batteries without sacrificing the power density. Herein we report the fabrication of a new class of ultrahigh surface area hierarchical porous carbon (UHSA-HPC) based on the pore formation and widening of polystyrene-derived HPC by KOH activation, and highlight its superior ability for energy storage in supercapacitors with ionic liquid (IL) as electrolyte. The UHSA-HPC with a surface area of more than 3000 m(2) g(-1) shows an extremely high energy density, i.e., 118 W h kg(-1) at a power density of 100 W kg(-1). This is ascribed to its unique hierarchical nanonetwork structure with a large number of small-sized nanopores for IL storage and an ideal meso-/macroporous network for IL transfer. PMID- 23632803 TI - A cartography of the van der Waals territories. AB - The distribution of distances from atoms of a particular element E to a probe atom X (oxygen in most cases), both bonded and intermolecular non-bonded contacts, has been analyzed. In general, the distribution is characterized by a maximum at short E...X distances corresponding to chemical bonds, followed by a range of unpopulated distances--the van der Waals gap--and a second maximum at longer distances--the van der Waals peak--superimposed on a random distribution function that roughly follows a d(3) dependence. The analysis of more than five million interatomic "non-bonded" distances has led to the proposal of a consistent set of van der Waals radii for most naturally occurring elements, and its applicability to other element pairs has been tested for a set of more than three million data, all of them compared to over one million bond distances. PMID- 23632804 TI - Acute alcohol intoxication characteristics in children. AB - AIMS: To describe clinical, mental and physical signs in children with different severity acute alcohol intoxication (AAI) determined either by serum alcohol concentration (SAC) or by blood alcohol concentration (BAC) to study the diagnostic performance characteristics of clinical assessment and to establish the ratio of SAC:BAC in children. METHODS: Data were analysed from 256 children aged 8.4-17.9 years who were hospitalized at Estonia's two children's hospitals over a 3-year period. In each case, the on-call paediatrician completed a special form about the clinical, mental (consciousness, balance and speech) and physical (muscle tone, blood pressure, pulse and body temperature) signs of AAI. Blood samples were drawn for measurements of SAC and BAC. Diagnostic performance characteristics (sensitivity, specificity, efficiency) of the clinical assessments and the SAC:BAC ratio were calculated. RESULTS: The most correctly described signs in children in different SAC groups were consciousness (rs = 0.16) and speech (rs = 0.13) (P < 0.0001). The severity of alteration of consciousness and degrees of disturbance in balance and speech were positively correlated with SAC (P < 0.001). The clinical judgment matched better with AAI determined by SAC rather than by BAC with the mean efficiency. The mean ratio between SAC and BAC was 1.19 +/- 0.13 (P < 0.001) in children. CONCLUSION: The level of consciousness is the leading sign in the clinical evaluation of children with AAI and correlates well with SAC. The severity of AAI judged by clinical assessment matched better with AAI severity stages determined by SAC than by BAC. For legal cases where BAC is required, the SAC:BAC ratio of 1.19:1 should be used in children regardless of their gender or age. PMID- 23632805 TI - Brain structure in adolescents and young adults with alcohol problems: systematic review of imaging studies. AB - AIMS: Alcohol-dependent people who are middle-aged or older have a widespread loss of cortical grey and white matter, particularly in the prefrontal cortex (PFC). We examine if brain abnormalities are detectable in alcohol use disorders before the fifth decade (i.e., <40), and the brain structural differences associated with alcohol abuse/dependence in adolescence. METHODS: Case-control studies comparing brain structure in alcohol-abusing/-dependent individuals with normal controls in which the mean age of participants was <40 were identified using Medline, EMBASE and PsychInfo. Studies in which mean age was over and under 21 were considered separately. RESULTS: Twelve papers fulfilled inclusion criteria, five in the adolescent (14-21) and seven in the young adult age range. Two independent groups reported hippocampal and prefrontal volume reductions in adolescents, although this was consistently observed only in females. In young adults (aged 21-40), there were grey matter deficits in the PFC in both sexes. Adult women appeared to, particularly, exhibit white matter differences, evident as reduced area of the corpus callosum. Hippocampal volume reduction was observed in one study of young adults study but not another. CONCLUSION: The available data suggest that quantitative structural abnormalities of the brain are detectable in young alcohol abusers. There is overlap between the abnormalities seen in adolescents and young adults, although hippocampal volume loss is most consistently seen in the former group. The adolescent hippocampus may be particularly susceptible to alcohol, potentially because of an interaction between adolescent brain development and alcohol exposure. PMID- 23632806 TI - Improved drinking behaviour improves quality of life: a follow-up in alcohol dependent subjects 7 years after treatment. AB - AIM: The present study relates alcohol-dependent patients' Quality of Life (QoL) 7 years after treatment to drinking status as the conventional endpoint of trials. Potential moderating factors such as patients' smoking status, additional healthcare usage and stressful life events were accounted for. METHODS: Seven years after being treated for alcoholism, n = 127 alcohol-dependent patients filled out the Munich List of Quality of Life Dimensions (MLDL), a generic QoL questionnaire and were re-examined in telephone interviews. Patients' drinking and smoking behaviours during the previous year and additional healthcare usage and whether or not they had experienced stressful life events during the whole follow-up period were assessed. RESULTS: Patients reporting abstinence or improved drinking showed significantly higher QoL ratings than patients whose drinking had not improved. Smoking status had no significant effect on QoL. Patients who used additional healthcare during the follow-up period reported lower QoL. The same was true of those who had experienced stressful life events. CONCLUSIONS: Improved drinking after a 7-year follow-up is associated with improved QoL even when considering other factors such as additional healthcare use and stressful life events. We conclude that QoL can be an additional endpoint in treatment trials. PMID- 23632807 TI - Nativity and level of need: toward an integrative perspective of Asian American mental health. AB - This study uses data from the NLAAS to investigate the relationship between culture and the level of psychiatric needs. Contrary to trends, those U.S. born with non-serious disorders were less likely to use mental health services. Results indicate that in order to effectively treat Asian Americans with mental health disorders, interventions need to take into account service use patterns that are impacted by both acculturation and the level of need. PMID- 23632808 TI - Prospective associations between bilingualism and executive function in Latino children: sustained effects while controlling for biculturalism. AB - The study purpose was to test 1-year prospective associations between English Spanish bilingualism and executive function in 5th to 6th grade students while controlling for biculturalism. Participants included 182 US Latino students (50 % female). Self-report surveys assessed biculturalism, bilingualism, and executive function (i.e., working memory, organizational skills, inhibitory control, and emotional control, as well as a summary executive function score). General linear model regressions demonstrated that bilingualism significantly predicted the summary executive function score as well as working memory such that bilingual proficiency was positively related to executive function. Results are the first to demonstrate (a) prospective associations between bilingualism to executive function while controlling for the potential third variable of biculturalism, and (b) a principal role for working memory in this relationship. Since executive function is associated with a host of health outcomes, one implication of study findings is that bilingualism may have an indirect protective influence on youth development. PMID- 23632809 TI - Mineralization of dense collagen hydrogel scaffolds by human pulp cells. AB - While advances in biomineralization have been made in recent years, unanswered questions persist on bone- and tooth-cell differentiation, on outside-in signaling from the extracellular matrix, and on the link between protein expression and mineral deposition. In the present study, we validate the use of a bioengineered three-dimensional (3D) dense collagen hydrogel scaffold as a cell culture model to explore these questions. Dental pulp progenitor/stem cells from human exfoliated deciduous teeth (SHEDs) were seeded into an extracellular matrix like collagen gel whose fibrillar density was increased through plastic compression. SHED viability, morphology, and metabolic activity, as well as scaffold mineralization, were investigated over 24 days in culture. Additionally, measurements of alkaline phosphatase enzymatic activity, together with immunoblotting for mineralized tissue cell markers ALPL (tissue-non-specific alkaline phosphatase), DMP1 (dentin matrix protein 1), and OPN (osteopontin), demonstrated osteo/odontogenic cell differentiation in the dense collagen scaffolds coincident with mineralization. Analyses of the mineral phase by electron microscopy, including electron diffraction and energy-dispersive x-ray spectroscopy, combined with Fourier-transform infrared spectroscopy and biochemical analyses, were consistent with the formation of apatitic mineral that was frequently aligned along collagen fibrils. In conclusion, use of a 3D dense collagen scaffold promoted SHED osteo/odontogenic cell differentiation and mineralization. PMID- 23632810 TI - Hydrogen peroxide diffusion dynamics in dental tissues. AB - The aim of this study was to investigate the diffusion dynamics of 25% hydrogen peroxide (H2O2) through enamel-dentin layers and to correlate it with dentin's structural alterations. Micro-Raman Spectroscopy (MRS) and Fourier Transform Infrared Photoacoustic Spectroscopy (FTIR-PAS) were used to measure the spectra of specimens before and during the bleaching procedure. H2O2 was applied to the outer surface of human enamel specimens for 60 minutes. MRS measurements were performed on the inner surface of enamel or on the subsurface dentin. In addition, H2O2 diffusion dynamics from outer enamel to dentin, passing through the dentin-enamel junction (DEJ) was obtained with Raman transverse scans. FTIR PAS spectra were collected on the outer dentin. MRS findings revealed that H2O2 (O-O stretching u-Raman band) crossed enamel, had a more marked concentration at DEJ, and accumulated in dentin. FTIR-PAS analysis showed that H2O2 modified dentin's organic compounds, observed by the decrease in amides I, II, and III absorption band intensities. In conclusion, H2O2 penetration was demonstrated to be not merely a physical passage through enamel interprismatic spaces into the dentinal tubules. H2O2 diffusion dynamics presented a concentration gradient determined by the chemical affinity of the H2O2 with each specific dental tissue. PMID- 23632811 TI - Water use by a warm-temperate deciduous forest under the influence of the Asian monsoon: contributions of the overstory and understory to forest water use. AB - The warm temperate deciduous forests in Asia have a relatively dense understory, hence, it is imperative that we understand the dynamics of transpiration in both the overstory (E O) and understory (E U) of forest stands under the influence of the Asian monsoon in order to improve the accuracy of forest water use budgeting and to identify key factors controlling forest water use under climate change. In this study, E O and E U of a temperate deciduous forest stand located in South Korea were measured during the growing season of 2008 using sap flow methods. The objectives of this study were (1) to quantify the total transpiration of the forest stand, i.e., overstory and understory, (2) to determine their relative contribution to ecosystem evapotranspiration (E eco), and (3) to identify factors controlling the transpiration of each layer. E O and E U were 174 and 22 mm, respectively. Total transpiration accounted for 55 % of the total E eco, revealing the importance of unaccounted contributions to E eco (i.e., soil evaporation and wet canopy evaporation). During the monsoon period, there was a strong reduction in the total transpiration, likely because of reductions in photosynthetic active radiation, vapor pressure deficit and plant area index. The ratio of E U to E O declined during the same period, indicating an effect of monsoon on the partitioning of E eco in its two components. The seasonal pattern of E O was synchronized with the overstory canopy development, which equally had a strong regulatory influence on E U. PMID- 23632812 TI - Overexpression of retinoic acid-induced protein 3 predicts poor prognosis for hepatocellular carcinoma. AB - AIM: To investigate clinical significance of retinoic acid-induced protein 3 (RAI3) in hepatocellular carcinoma (HCC). METHODS: Expression of RAI3 at both mRNA and protein levels in tumor, para-tumor and normal liver tissues was detected in 106 HCC patients by real-time quantitative RT-PCR, Western blot and immunohistochemistry. Then, the correlation of RAI3 expression with clinicopathological characteristics and survivals of HCC patients was analyzed. RESULTS: Our data first found that RAI3 mRNA and protein expression were both significantly higher in HCC than in para-tumor (both P < 0.001) and normal liver tissues (both P < 0.001). The correlation analysis showed a positive correlation between RAI3 mRNA level and RAI3 protein level in HCC tissues (r = 0.8, P < 0.001). Immunohistochemistry data also revealed that overexpression of RAI3 was present in 73.6 % (78/106) of HCC tissues. In addition, high RAI3 protein expression was correlated with advanced TNM stage (P = 0.001), high serum AFP (P = 0.008), vascular invasion (P = 0.01) and tumor recurrence (P = 0.008). Moreover, HCC patients with overexpression of RAI3 had significantly shorter overall (P = 0.01) and disease-free survival (P = 0.01). Furthermore, multivariate analysis showed that overexpression of RAI3 was an independent prognostic factor for both overall (P = 0.02) and disease-free survival (P = 0.03) in HCC. CONCLUSION: Our data for the first time provide a basis for the concept that overexpression of RAI3 may contribute to the malignant progression of HCC and predict poor prognosis for patients with this deadly disease after curative hepatectomy. RAI3 might be an important marker for tumor progression and prognosis, as well as a potential therapeutic target of HCC. PMID- 23632813 TI - Statin use and peripheral blood progenitor cells mobilization in patients with multiple myeloma. AB - PURPOSE: Statins have beneficial effects in patients after myocardial infarction and at least part of the benefit results from mobilization of marrow endothelial progenitors to repopulate damaged myocardial tissues. This study examines if statins may have the same effect in mobilizing marrow progenitors to be harvested and subsequently used in high-dose chemotherapy with progenitor cell rescue in multiple myeloma. METHODS: From 2006 to 2012, 86 patients with multiple myeloma were mobilized with the use of G-CSF and were retrospectively analyzed. Patients with other malignancies or mobilized with the use of chemotherapy or with plerixafor were excluded. RESULTS: The median age of the patients was 60 years. 72 patients had received one line of chemotherapy and 14 patients two or more lines of chemotherapy. Twenty patients were taking statins at the time of the harvest while 66 patients were not. In the group of patients taking statins the success rate of first leukapheresis (obtaining the target number of 4 * 10(6) CD34+ cells/kg) was 85 % while in the group not taking statins this rate was 63.6 %. Despite the comparatively small number of patients this difference approached statistical significance (chi (2) = 0.07). CONCLUSION: This retrospective analysis of 86 patients shows for the first time a possible benefit of statins for peripheral blood progenitor cells mobilization in patients with multiple myeloma. Larger studies would be required to clarify the issue. If their effectiveness is confirmed, statins could be a safe and cheaper addition to chemotherapy and plerixafor for peripheral hematopoietic stem cell mobilization. PMID- 23632814 TI - Outcome and toxicity using helical tomotherapy for craniospinal irradiation in pediatric medulloblastoma. AB - PURPOSE: The objective of this study is to evaluate the tolerability and outcome of craniospinal irradiation (CSI) with helical tomotherapy (HT) in the treatment of medulloblastoma. METHODS: We evaluated 19 consecutive patients with primary medulloblastoma who were treated with HT from 2007 through 2010. HT regimens to the neuroaxis included: 23.4 Gy at 1.8 Gy/fraction (N = 10), 36 Gy at 1.8 Gy/fraction (N = 7), and 39 Gy bid at 1.3 Gy/fraction (N = 2). The tumor bed received 54-60 Gy. Potential associations between patient, treatment, and toxicity factors and overall survival (OS) were assessed in univariate analyses using the Cox proportional hazards model. Spearman's rank correlation coefficient was used to correlate potential risk factors with the grade of acute toxicity. RESULTS: The median age at diagnosis was 5 years (range 2-14) and the median follow-up for alive patients (N = 14) 40 months (range 10-62). Two- and three year overall survival was 75 and 68 %, respectively. The most common acute toxicity was hematological (79 %), being grade 2 and grade 3 in 4 (21 %) and 11 (58 %) cases, respectively. No grade >=2 late toxicities were observed. Higher grades of acute body toxicity were found in older children (P = 0.004). Longer time between diagnosis and radiation therapy was correlated with shorter OS (P = 0.03). In addition, higher grades of acute thrombocytopenia were associated with shorter OS (P = 0.03). CONCLUSIONS: CSI delivered with HT for medulloblastoma is well tolerated with low rates of severe acute toxicity. Further research is necessary to assess late toxicity with a longer follow-up. PMID- 23632815 TI - Natural history of colorectal adenomas: birth cohort analysis among 3.6 million participants of screening colonoscopy. AB - BACKGROUND: Most colorectal cancers (CRC) develop from adenomas. Knowledge of the natural history of colorectal adenomas, which is not directly observable for ethical reasons, is crucial for designing cost-effective CRC screening strategies. METHODS: We derived transition rates from carriage of nonadvanced adenoma to carriage of advanced adenoma to carriage of CRC by sex and age in birth cohort analyses among 3,593,420 participants in the German screening colonoscopy program in 2003-2010. RESULTS: Transition rates from advanced adenoma to CRC carriage were similar in men and women, but monotonically and significantly increased with age. Estimated annual transition percentages [(95% confidence interval (CI)] in age groups 55-59, 60-64, 65-69, 70-74, and 75-79 years were 2.6 (2.4-2.9), 3.1 (2.8-3.3), 3.8 (3.5-4.1), 5.1 (4.8-5.5), and 5.2 (4.6-5.8) among men, and 2.5 (2.2-2.7), 2.7 (2.4-3.0), 3.8 (3.5-4.1), 5.0 (4.5 5.4), and 5.6 (4.9-6.3) among women. Estimated annual transitions from carriage of nonadvanced to carriage of advanced adenoma were in a narrow range from 3.6% to 4.7% for all age and sex groups. CONCLUSIONS: Despite low annual transition rates, cumulative transition rates from advanced adenoma to CRC carriage are expected to exceed by 60%, 50%, and 40% for age intervals 55-80, 65-80, and 70-80 years, respectively, in both sexes. Cumulative transition rates from nonadvanced adenoma to CRC carriage are expected to be close to 30% for age interval 55-80 years, but less than 2% for age interval 75-80 years. IMPACT: Our results enhance the empirical basis for modeling CRC screening strategies. PMID- 23632816 TI - Age-specific occurrence of HPV16- and HPV18-related cervical cancer. AB - The age-specific occurrence of cervical cancer related to human papillomavirus (HPV) genotypes HPV16 and HPV18, the two targeted by current HPV vaccines, is not well described. We therefore used data from two large, tissue-based HPV genotyping studies of cervical cancer, one conducted in New Mexico (n = 744) and an International study restricted to cancers (n = 1,729) from Europe, North America, and Australia to represent those regions with widely available cervical cancer screening facilities. HPV results were categorized as HPV16- or HPV18 positive (HPV16/18) versus other HPV genotype. We observed a decreasing proportion of HPV16/18-positive cancers with increasing age in the International study (Ptrend < 0.001) and New Mexico study (Ptrend < 0.001). There was no heterogeneity in the relationship between age of diagnosis and the proportion of HPV16/18-positive cancers between studies (P = 0.8). Combining results from the two studies (n = 2,473), the percentages of HPV16/18-positive cases were 77.0% [95% confidence interval (CI): 75.1%-78.9%] for women less than 65 years old and 62.7% [95% confidence interval (CI): 58.4%-66.9%] for women aged 65 and older (P < 0.001). In women who are under the age of 25 and have been vaccinated before becoming sexually active, the cervical cancer incidence is expected to be approximately 3.5 per million by 2020. HPV vaccination against HPV16/18 may have a greater impact on cervical cancers in women under 65 than in women aged 65 and older. These data will inform the age-specific impact of HPV vaccination and its integration with cervical cancer screening activities. PMID- 23632817 TI - Meat-related mutagens and pancreatic cancer: null results from a clinic-based case-control study. AB - BACKGROUND: Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. The study objective was to evaluate risk of pancreatic cancer associated with meat preparation methods and meat-related mutagen consumption using a clinic-based case-control design. METHODS: There were 384 cases and 983 controls; subjects provided demographic information and completed a 144-item food frequency questionnaire, which was used to estimate meat mutagen intake using the National Cancer Institute's CHARRED database (Bethesda, MD). Logistic regression was used to calculate ORs and 95% confidence intervals (CI), adjusted for factors including age, sex, cigarette smoking, body mass index, and diabetes mellitus. RESULTS: Overall, the findings were null with respect to meat mutagen intake and pancreatic cancer. CONCLUSIONS: The results do not support an association between well-done meat or meat-related mutagen intake and pancreatic cancer and contrast with generally increased risks reported in previous studies. IMPACT: These data contribute to evidence about pancreatic cancer and potentially carcinogenic compounds in meat. PMID- 23632818 TI - The increased risk of colon cancer due to cigarette smoking may be greater in women than men. AB - BACKGROUND: Smoking is a recently established risk factor for colon cancer. We wanted to explore the hypothesis that women may be more susceptible to smoking attributed colon cancer than men as one of the possible explanations for the high colon cancer risk of Norwegian women. METHODS: We followed 602,242 participants aged 19 to 67 years at enrollment in 1972-2003, by linkage to national registries through December 2007. We used Cox proportional hazard models to estimate HRs and 95% confidence intervals (CI). RESULTS: During a mean follow-up of 14 years, altogether 3,998 (46% women) subjects developed colon cancer. Female ever-smokers had a 19% (HR = 1.19, 95% CI = 1.09-1.32) and male ever-smokers an 8% (HR = 1.08, CI = 0.97-1.19) increased risk of colon cancer compared with never smokers. For all the four dose-response variables examined, female ever-smokers in the most exposed category of smoking initiation, (HR = 1.48, 95% CI = 1.21-1.81), of daily cigarette consumption (HR = 1.28, 95% CI = 1.06-1.55), of smoking duration (HR = 1.47, 95% CI = 1.11-1.95), and of pack-years of smoking (HR = 1.33, 95% CI = 1.11 1.57) had a significantly increased risk of more than 20% for colon cancer overall and of more than 40% for proximal colon cancer, compared with never smokers. A test for heterogeneity by gender was statistically significant only for ever smoking and risk of proximal colon cancer (Wald chi(2), P = 0.02). CONCLUSIONS: Female smokers may be more susceptible to colon cancer and especially to proximal colon cancer than male smokers. IMPACT: Women who smoke are more vulnerable to colon cancer than men. PMID- 23632819 TI - The effect of ultraviolet radiation on the transforming growth factor beta 1/Smads pathway and p53 in actinic keratosis and normal skin. AB - Ultraviolet (UV) radiation is considered to be essential for the progression of actinic keratosis (AK) to squamous cell carcinoma (SCC); however, the mechanisms have not been fully elucidated. To understand this process, the effects of UV radiation on the transforming growth factor beta 1 (TGFbeta1)/Smads pathway and p53 in normal skin and AK were studied. Normal human skin and AK tissues were cultured and divided into the following four groups according to the UV radiation dose: 0 (control group), 5, 10, and 20 J/cm2. The tissues were radiated for four consecutive days; 24 h after radiation, the tissues were collected for investigation. Compared with the control group, greater proliferative inhibition and apoptosis were induced by UV radiation in normal skin than AK. The expression of TGFbeta1, Smad7, and p53 was increased in AK and normal skin, while the level of TbetaRII was decreased. Smad2 was reduced in AK only. The expressions of TbetaRI, Smad3, and Smad4 were not significantly changed. The results demonstrated that although p53 was induced, suppression of the TGFbeta1/Smads pathway by UV radiation might contribute to the progression of AK to SCC. PMID- 23632820 TI - Stimuli responsive synthetic polypeptides derived from N-carboxyanhydride (NCA) polymerisation. AB - The progress in NCA polymerisation combined with advanced orthogonal functionalization techniques as well as the integration with other controlled polymerisation techniques significantly widened the scope of polypeptide building blocks in a variety of material designs. Well-defined synthetic stimuli responsive polypeptides ("smart" polypeptides) with incorporated different functionalities have been extensively explored over the past decades. Their significant potential lies in the fact that they combine natural and synthetic elements both contributing to their properties. These novel materials have potential applications in biomedicine and biotechnology including tissue engineering, drug delivery and biodiagnostics. Responsive polypeptides are capable of undergoing conformational changes and phase transition accompanied by variations in the chemical and physical changes of the polypeptides in response to an external stimulus such as biologically relevant species (i.e. biomolecules), the environment (i.e. temperature, pH), irradiation with light or exposure to a magnetic field. In this review, the recent developments including synthetic strategies and applications of synthetic stimuli-responsive homo- and block polypeptides are reviewed. PMID- 23632821 TI - [Seasonal and pandemic influenza vaccination: coverage and attitude among private physicians in Germany]. AB - BACKGROUND: General practitioners serve as important multipliers for seasonal influenza vaccination in risk groups such as elderly or chronically ill persons, for whom vaccination is recommended in Germany by the Standing Committee on Vaccination (STIKO). Moreover, physicians are a target group for influenza vaccination themselves. METHODS: Data from 1 590 telephone interviews were analysed. The study population comprised private physicians from 4 different disciplines (general and internal medicine, gynaecology, paediatrics). We assessed seasonal and pandemic vaccination coverage, attitudes and informational needs related to vaccination in general, and opinions about the pandemic situation 2009. RESULTS: Of the interviewed physicians, 61% stated that they have been vaccinated against seasonal influenza regularly. Main reasons for not/only occasionally having received a flu shot were: the belief that seasonal influenza vaccination is not necessary for them (78%) or having forgotten about the vaccination (28%). The interviewed physicians expressed a great demand for active information on STIKO recommendations and certain aspects of the seasonal influenza vaccination. There was a significant association between physicians' own influenza vaccination status and the provision of vaccination information materials, utilisation of a data management system for the vaccination of patients, and active vaccination reminders in the physicians' office. In 2009/10, almost 60% had received a pandemic influenza A(H1N1) vaccination. A major barrier to vaccine uptake was the mistrust in the safety of H1N1 vaccines (stated by 54% of non-vaccinees). Information for the public and physicians by the German public health authorities during the pandemic was rather critically appraised by the respondents. CONCLUSION: Compared to other subgroups of health-care workers, among private physicians seasonal and pandemic vaccine uptake was rather high. The physicians' need for more information on vaccination topics can be met by intensified publishing and communication activities of STIKO and by using existing physician-information channels. PMID- 23632822 TI - [Profitability analysis of clinical risk management]. AB - INTRODUCTION: Medical treatment entails many risks. Increasingly, the negative impact of these risks on patients' health is revealed and corresponding cases are reported to hospital insurances. A systematic clinical risk management can reduce risks. This analysis is designed to demonstrate the financial profitability of implementing a clinical risk management. METHODS: The decision analysis of a clinical risk management includes information from published articles and studies, publicly available data from the Federal Statistical Office and expert interviews and was conducted in 2 scenarios. The 2 scenarios result from a maximum and minimum value of preventable adverse events reported in Germany. The planning horizon was a 1-year -period. The analysis was performed from a hospital's perspective. Subsequently, a threshold-analysis of the reduction of preventable adverse events as an effect of clinical risk management was executed. Furthermore, a static capital budgeting over a 5-year period was added, complemented by a risk analysis. RESULTS: Regarding the given assumptions, the implementation of clinical risk management would save about 53 000 ? or 175 000 ?, respectively, for an average hospital within the first year. Only if the reduction of preventable adverse events is as low as 5.6 or 2.8%, respectively, will the implementation of clinical risk management produce losses. According to a comprehensive risk simulation this happens in less than one out of 1 million cases. The investment in a clinical risk management, based on a 5-year period and an interest rate of 5%, has an annually pay off of 81 000 ? or 211 000 ?, respectively. CONCLUSIONS: The implementation of clinical risk management in a hospital pays off within the first year. In the subsequent years the surplus is even higher due to the elimination of implementation costs. PMID- 23632823 TI - Synthesis and structures of Co bis-trifluoromethylpyrazolate complexes. AB - Reactions of Co(PMe3)3Cl or CoCl2 with 3,5-(CF3)2-PzNa in hexane give Co(PMe3)3(3,5-(CF3)2-Pz) (1) and Co(PMe3)3(3,5-(CF3)2-Pz)2 (2) respectively (3,5 (CF3)2-PzNa = sodium bis-trifluoromethylpyrazolate). Reaction of (3,5-(CF3)2-PzH) with Co(PMe3)4 produces the unusual complex [cis-Co(PMe3)4H2][Co(PMe3)(3,5-(CF3)2 Pz)3] (3) which formally contains a [Co(III)](+)[Co(II)](-) complex ion pair. Reaction of 3,5-(CF3)2-PzLi with an oxygenated suspension of CoCl2 and 3 equivalents of PMe3 gives (3,5-(CF3)2-Pz)2Co(MU-3,5-(CF3)2-Pz)(MU OPMe3)Li(OPMe3)2 (4), while 2 reacts with LiOH to give [(PMe3)Co(MU-3,5-(CF3)2 Pz)2(MU(3)-OH)Li]2 (5). Both 2 and 3 react with O2 in toluene solution to give Co(OPMe3)2(3,5-(CF3)2-Pz)2 (6). All compounds have been characterized spectroscopically and by single crystal X-ray diffraction studies. PMID- 23632824 TI - Activation of CO2 by tBuZnOH species: efficient routes to novel nanomaterials based on zinc carbonates. AB - We report on the activation of CO2 by the well-defined alkylzinc hydroxide (tBuZnOH)6 in the absence and presence of tBu2Zn as an external proton acceptor. The slight modifications in reaction systems involving organozinc precursors enable control of the reaction products with high selectivity leading to the isolation of the mesoporous solid based on ZnCO3 nanoparticles or an unprecedented discrete alkylzinc carbonate [(tBuZn)2(MU5-CO3)]6 cluster with the Zn-C bond intact, respectively. PMID- 23632825 TI - Correlation between 25-hydroxyvitamin D levels and latitude in Brazilian postmenopausal women: from the Arzoxifene Generations Trial. AB - SUMMARY: We investigated vitamin D status in Brazilian cities located at different latitudes. Insufficiency (<50 nmol/L) was common (17 %), even in those living in a tropical climate. Vitamin D insufficiency increased as a function of latitude. Mean 25-hydroxyvitamin D (25(OH)D) levels in each site and latitude correlation were very high (r = -0.88; p=0.02). [corrected]. INTRODUCTION: Inadequate vitamin D, determined by low levels of 25(OH)D, has become very common despite the availability of sunlight at some latitudes. National data from a country that spans a wide range of latitudes would help to determine to what extent latitude or other factors are responsible for vitamin D deficiency. We investigated vitamin D status in cities located at different latitudes in Brazil, a large continental country. METHODS: The source is the Brazilian database from the Generations Trial (1,933 osteopenic or osteoporotic postmenopausal women (60 to 85 years old) with 25(OH)D measurements). 25(OH)D below 25 nmol/L (10 ng/mL) was an exclusion criterion. Baseline values were between fall and winter. The sites included Recife, Salvador, Rio de Janeiro, Sao Paulo, Curitiba, and Porto Alegre. Mean and standard deviation of 25(OH)D, age, spine and femoral neck T score, calcium, creatinine, and alkaline phosphatase were calculated for each city. Pearson correlation was used for 25(OH)D and latitude. RESULTS: Insufficiency (<50 or <20 ng/mL) was common (329 subjects, 17 %). Vitamin D insufficiency increased as a function of latitude, reaching 24.5 % in the southernmost city, Porto Alegre. The correlation between mean 25(OH)D levels in each site and latitude was very high (r = -0.88, p < 0.0001). CONCLUSION: There is a high percentage of individuals with vitamin D insufficiency in Brazil, even in cities near the equator, and this percentage progressively increases with more southern latitudes. PMID- 23632827 TI - The impact of decreasing U.S. hip fracture rates on future hip fracture estimates. AB - SUMMARY: We examined age- and sex-specific hip fracture hospitalization rates among people aged 65 and older using 1990-2010 National Hospital Discharge Survey data. Trends calculated using Joinpoint regression analysis suggest that future increases in hip fractures due to the aging population will be largely offset by decreasing hip fracture rates among women. However, this trend will be counterbalanced by rising numbers of hip fractures among men. INTRODUCTION: From 1990 to 2006, age-adjusted U.S. hip fracture rates among people aged 65 years and older declined significantly. We wanted to determine whether decreasing age group specific hip fracture rates might offset increases in hip fractures among the aging population over the next two decades. METHODS: This study used data from the National Hospital Discharge Survey, a national probability survey of inpatient discharges from nonfederal U.S. hospitals, to analyze hip fracture hospitalizations, defined as cases with first diagnosis coded ICD-9 CM 820. We analyzed trends in rates by sex and 10-year age groups using Joinpoint analysis software and used the results and projected population estimates to obtain the expected number of hip fractures in 2020 and 2050. RESULTS: Based on current age- and sex-specific trends in hip fracture hospitalization rates, the number of hip fractures is projected to rise 11.9 %-from 258,000 in 2010 to 289,000 (Projection Interval [PI] = 193,000-419,000) in 2030. The number of hip fractures among men is expected to increase 51.8 % (PI = 15.9-119.4 %) while the number among women is expected to decrease 3.5 % (PI = -44.3-37.3 %). These trends will affect the future distribution of hip fractures among the older population. CONCLUSIONS: Although the number of older people in the U.S.A. will increase appreciably over the next 20 years, the expected increase in the total number of hip fractures will be largely offset by decreasing hip fracture rates among women. However, this trend will be counterbalanced by rising numbers of hip fractures among men. PMID- 23632826 TI - Micro-morphological properties of osteons reveal changes in cortical bone stability during aging, osteoporosis, and bisphosphonate treatment in women. AB - SUMMARY: We analyzed morphological characteristics of osteons along with the geometrical indices of individual osteonal mechanical stability in young, healthy aged, untreated osteoporotic, and bisphosphonate-treated osteoporotic women. Our study revealed significant intergroup differences in osteonal morphology and osteocyte lacunae indicating different remodeling patterns with implications for fracture susceptibility. INTRODUCTION: Bone remodeling is the key process in bone structural reorganization, and its alterations lead to changes in bone mechanical strength. Since osteons reflect different bone remodeling patterns, we hypothesize that the femoral cortices of females under miscellaneous age, disease and treatment conditions will display distinct osteonal morphology and osteocyte lacunar numbers along with different mechanical properties. METHODS: The specimens used in this study were collected at autopsy from 35 female donors (young group, n = 6, age 32 +/- 8 years; aged group, n = 10, age 79 +/- 9 years; osteoporosis group, n = 10, age 81 +/- 9 years; and bisphosphonate group, n = 9, age 81 +/- 7 years). Von Kossa-modified stained femoral proximal diaphyseal sections were evaluated for osteonal morphometric parameters and osteocyte lacunar data. Geometrical indices of osteonal cross-sections were calculated to assess the mechanical stability of individual osteons, in terms of their resistance to compression, bending, and buckling. RESULTS: The morphological assessment of osteons and quantification of their osteocyte lacunae revealed significant differences between the young, aged, osteoporosis and bisphosphonate treated groups. Calculated osteonal geometric indices provided estimates of the individual osteons' resistance to compression, bending and buckling based on their size. In particular, the osteons in the bisphosphonate-treated group presented improved osteonal geometry along with increased numbers of osteocyte lacunae that had been formerly impaired due to aging and osteoporosis. CONCLUSIONS: The data derived from osteons (as the basic structural units of the cortical bone) in different skeletal conditions can be employed to highlight structural factors contributing to the fracture susceptibility of various groups of individuals. PMID- 23632828 TI - Associations between social anxiety and emotional intelligence within clinically depressed patients. AB - Impairments in emotional intelligence (EI) have been found in individuals with high general and social anxiety; however, no studies have examined this relationship in a clinically depressed population. Thirty-one patients (11 male, 20 female) with a DSM-IV-TR diagnosis of a major affective disorder and 28 non clinical controls (5 male, 23 female) completed self-report instruments assessing EI, depression and social anxiety. Compared to a control group, the clinical group scored lower on the EI dimensions of Emotional Recognition and Expression, Understanding Emotions, Emotional Management, and Emotional Control. Regression analyses revealed Emotional Control was a significant predictor of interaction, performance, and generalised social anxiety. Self-report measures of EI may have predictive value in terms of early identification of those at risk of developing social anxiety and depression. The current study points to the potential value of conducting further studies of a prospective nature. PMID- 23632830 TI - Chronic disabling fatigue in adolescents. PMID- 23632829 TI - The maximum limiting performance improved counter electrode based on a porous fluorine doped tin oxide conductive framework for dye-sensitized solar cells. AB - A novel porous fluorine doped tin oxide (PFTO) conductive framework was introduced to counter electrodes (CEs) for dye-sensitized solar cells (DSSCs). When modified by platinum (Pt) or carbon (C), the PFTO conductive framework displays high catalytic activity to I(-)/I3(-) redox couples. Power conversion efficiencies of 6.09% and 5.81% were obtained in the DSSCs based on Pt and C modified PFTO CEs respectively, which were close to that of DSSCs with Pt coated FTO glass (6.05%) and Pt sheet (6.26%) CEs. Maximum limiting performances of the CEs were obtained from the polarization curves. The CE based on PFTO showed higher maximum limiting power conversion efficiency (~20%) compared with the planar FTO substrate Pt CE (~18%), with the increase of its surface area and electrocatalytic activity. PMID- 23632831 TI - The neuroepigenetics of suicide. PMID- 23632832 TI - Protecting confidentiality in human research. PMID- 23632833 TI - Loss of libido in a woman with schizophrenia. AB - Sexual dysfunction is common among women with schizophrenia treated with antipsychotic medication. Multiple factors influence sexual function and reproductive health in this patient population, including the effects of medications on prolactin secretion and the complexities of making contraceptive decisions in the context of a serious mental illness. The author explores the causes and management of loss of libido as illustrated by a case vignette and describes the course and outcome of a clinical intervention that was implemented to alleviate the sexual dysfunction. Possible approaches and potential pitfalls of the intervention are described. Clinicians must be open to discussions regarding sexual concerns, relationships with sexual partners, and reproductive issues with women suffering from schizophrenia. Both patients and clinicians need to be aware of unintended effects of intervention. Opportunities exist for improved education among clinicians to achieve a more proactive approach to sexual health in women receiving antipsychotic medication. PMID- 23632834 TI - Saint Anthony of Qozhaya's cave: a pioneering shelter for the mentally ill in the Middle East. PMID- 23632835 TI - Prevalence and correlates of prolonged fatigue in a U.S. sample of adolescents. AB - OBJECTIVE: Prolonged fatigue in adolescents has a major impact on social functioning and school attendance. In adults, prolonged fatigue substantially overlaps with mood and anxiety disorders. Extending the data to adolescents, the authors studied the prevalence and correlates of fatigue in a representative U.S. sample. METHOD: The participants were 10,123 adolescents ages 13-18 years from the National Comorbidity Survey Adolescent Supplement. They were interviewed about prolonged fatigue, defined as extreme fatigue with at least one associated symptom (pains, dizziness, headache, sleep disturbance, inability to relax, irritability) that does not resolve by resting or relaxing and lasting at least 3 months. RESULTS: The prevalence of prolonged fatigue was 3.0% (SE=0.3), with 1.4% (SE=0.2) for prolonged fatigue only and 1.6% (SE=0.2) for prolonged fatigue concomitant with a depressive or anxiety disorder. Nearly 60% of the adolescents with prolonged fatigue only had severe or very severe disability, and their rates of poor physical and mental health were comparable to those of adolescents with mood or anxiety disorders only. Adolescents with prolonged fatigue and comorbid mood or anxiety disorders had significantly greater disability, poorer mental health, and more health service use than those with either condition alone. CONCLUSIONS: These findings suggest that prolonged fatigue is associated with disability and is an important clinical entity independent of mood and anxiety disorders in adolescents. Persistent fatigue with a comorbid mood or anxiety state is related to even more functional impairment, suggesting that prolonged fatigue may reflect greater severity of mood and anxiety disorders in adolescents. PMID- 23632836 TI - Defective processing speed and nonclinical psychotic experiences in children: longitudinal analyses in a large birth cohort. AB - OBJECTIVE: Psychotic experiences in children are associated with an elevated risk of developing psychosis. The authors investigated whether the pattern of cognitive deficits present in psychosis also exists in children with psychotic experiences within the general population. METHOD: The authors examined the longitudinal relationships between key cognitive domains, selected a priori based on their association with schizophrenia, and onset of psychotic experiences in children from the Avon Longitudinal Study of Parents and Children and whether these associations were independent of one another. RESULTS: Lower performance in the domains of processing speed at age 8 years (odds ratio=1.24, 95% CI=1.12 1.36) and attention at age 11 (odds ratio=1.14, 95% CI=1.04-1.25) and decline of processing speed between the ages of 8 and 11 (odds ratio=1.29, 95% CI=1.15-1.45) were associated with higher risk of psychotic experiences at age 12. When adjusting for the other cognitive domains, processing speed at age 8 (odds ratio=1.20, 95% CI=1.09-1.33) was the measure most strongly associated with psychotic experiences. CONCLUSIONS: Defective processing speed is a particularly strong predictor of psychotic experiences in children. Furthermore, the pattern of associations between cognition and psychotic experiences in children within the general population is similar to the one between cognition and schizophrenia. These findings have potentially important implications for understanding the pathogenesis of psychotic disorders and the specific deficits that seem to place children at higher risk of psychopathology. PMID- 23632837 TI - Relapse of major depression in women who continue or discontinue antidepressant medication during pregnancy. PMID- 23632838 TI - In whom does lithium work? PMID- 23632839 TI - Methylfolate as adjunctive treatment in major depression. PMID- 23632840 TI - Response to Li and Su letter. PMID- 23632846 TI - Response to Guille and Epperson letter. PMID- 23632847 TI - Response to Carlson letter. PMID- 23632848 TI - Up-regulation of NOTCH4 gene expression in bipolar disorder: future studies. PMID- 23632851 TI - The lived experience of anxiety among late adolescents during high school: an interpretive phenomenological inquiry. AB - PURPOSE: To gain an understanding of everyday anxiety among late adolescents during high school. DESIGN: An interpretive phenomenological approach was utilized. A purposive sample of eight males and females in late adolescence with everyday anxiety were interviewed. METHOD: Individual interviews were conducted. Data analysis was undertaken throughout the research study by utilizing a thematic analysis of text in which themes emerged to understand the lived experience of everyday anxiety among late adolescents during high school. FINDINGS: The study revealed themes reflective of the lived body in time and space and in relation with others. The three themes were (a) the embodied experience of anxiety with the subtheme of the body and mind responds; (b) feeling uncomfortable in the lived space of school with the subthemes of the lived relations of bullying, the internal/external space of isolation, and the constant pressure to perform well; and (c) life at home with the subthemes of the lived space of home, the lived relations of pressure from parents, and life will get better. CONCLUSIONS: Nurses need to provide holistic care for late adolescents experiencing everyday anxiety by focusing on healing the whole person through the unity of body, mind, emotion, spirit, and environment. PMID- 23632852 TI - Sporopollenin biosynthetic enzymes interact and constitute a metabolon localized to the endoplasmic reticulum of tapetum cells. AB - The sporopollenin polymer is the major constituent of exine, the outer pollen wall. Recently fatty acid derivatives have been shown to be the precursors of sporopollenin building units. ACYL-COA SYNTHETASE, POLYKETIDE SYNTHASE A (PKSA) and PKSB, TETRAKETIDE alpha-PYRONE REDUCTASE1 (TKPR1) and TKPR2 have been demonstrated to be involved in sporopollenin biosynthesis in Arabidopsis (Arabidopsis thaliana). Here all these sporopollenin biosynthetic enzymes but TKPR2 have been immunolocalized to endoplasmic reticulum of anther tapetal cells. Pull-down experiments demonstrated that tagged recombinant proteins interacted to form complexes whose constituents were characterized by immunoblotting. In vivo protein interactions were evidenced by yeast (Saccharomyces cerevisiae) two hybrid analysis and by fluorescence lifetime imaging microscopy/Forster resonance energy transfer studies in transgenic Nicotiana benthamiana, which were used to test the possibility that the enzymes interact to form a biosynthetic metabolon. Various pairs of proteins fused to two distinct fluorochromes were coexpressed in N. benthamiana leaf tissues and fluorescence lifetime imaging microscopy/Forster resonance energy transfer measurements demonstrated that proteins interacted pairwise in planta. Taken together, these results suggest the existence of a sporopollenin metabolon. PMID- 23632853 TI - Negative feedback control of jasmonate signaling by an alternative splice variant of JAZ10. AB - The plant hormone jasmonate (JA) activates gene expression by promoting ubiquitin dependent degradation of jasmonate ZIM domain (JAZ) transcriptional repressor proteins. A key feature of all JAZ proteins is the highly conserved Jas motif, which mediates both JAZ degradation and JAZ binding to the transcription factor MYC2. Rapid expression of JAZ genes in response to JA is thought to attenuate JA responses, but little is known about the mechanisms by which newly synthesized JAZ proteins exert repression in the presence of the hormone. Here, we show in Arabidopsis (Arabidopsis thaliana) that desensitization to JA is mediated by an alternative splice variant (JAZ10.4) of JAZ10 that lacks the Jas motif. Unbiased protein-protein interaction screens identified three related basic helix-loop helix transcription factors (MYC2, MYC3, and MYC4) and the corepressor NINJA as JAZ10.4-binding partners. We show that the amino-terminal region of JAZ10.4 contains a cryptic MYC2-binding site that resembles the Jas motif and that the ZIM motif of JAZ10.4 functions as a transferable repressor domain whose activity is associated with the recruitment of NINJA. Functional studies showed that the expression of JAZ10.4 from the native JAZ10 promoter complemented the JA hypersensitive phenotype of a jaz10 mutant. Moreover, treatment of these complemented lines with JA resulted in the rapid accumulation of JAZ10.4 protein. Our results provide an explanation for how the unique domain architecture of JAZ10.4 links transcription factors to a corepressor complex and suggest how JA induced transcription and alternative splicing of JAZ10 premessenger RNA creates a regulatory circuit to attenuate JA responses. PMID- 23632854 TI - A chloroplast ABC1-like kinase regulates vitamin E metabolism in Arabidopsis. AB - In bacteria and mitochondria, ABC1 (for Activity of bc1 complex)-like kinases regulate ubiquinone synthesis, mutations causing severe respiration defects, including neurological disorders in humans. Little is known about plant ABC1-like kinases; in Arabidopsis (Arabidopsis thaliana), five are predicted in mitochondria but, surprisingly, six are located at lipid droplets in chloroplasts. These are a known site of prenylquinone (including tocopherol [vitamin E], phylloquinone [vitamin K] and plastoquinone) metabolism and contain a large proportion of the tocopherol cyclase (VTE1) required for vitamin E synthesis and recycling. Therefore, ABC1-like kinases may be involved in the regulation of chloroplast prenylquinone metabolism. Using a nontargeted lipidomics approach, we demonstrate that plants lacking the plastoglobule ABC1 like kinase ABC1K3 are defective both for the production of plastochromanol-8 (a plastoquinone-derived lipid antioxidant) and the redox recycling of alpha tocopherol, whereas tocopherol production is not affected. All of these pathways require VTE1 activity. However, in the abc1k3 mutant, VTE1 levels are strongly reduced posttranscriptionally. We provide evidence that the ABC1-like kinase ABC1K3 phosphorylates VTE1, possibly stabilizing it at plastoglobules. However, ABC1K3 may also have other targets and be involved in a wider chloroplast regulatory network. PMID- 23632855 TI - EMBRYONIC FLOWER1 and ULTRAPETALA1 Act Antagonistically on Arabidopsis Development and Stress Response. AB - Epigenetic regulation of gene expression is of fundamental importance for eukaryotic development. EMBRYONIC FLOWER1 (EMF1) is a plant-specific gene that participates in Polycomb group-mediated transcriptional repression of target genes such as the flower MADS box genes AGAMOUS, APETALA3, and PISTILLATA. Here, we investigated the molecular mechanism underlying the curly leaf and early flowering phenotypes caused by reducing EMF1 activity in the leaf primordia of LFYasEMF1 transgenic plants and propose a combined effect of multiple flower MADS box gene activities on these phenotypes. ULTRAPETALA1 (ULT1) functions as a trithorax group factor that counteracts Polycomb group action in Arabidopsis (Arabidopsis thaliana). Removing ULT1 activity rescues both the abnormal developmental phenotypes and most of the misregulated gene expression of LFYasEMF1 plants. Reducing EMF1 activity increases salt tolerance, an effect that is diminished by introducing the ult1-3 mutation into the LFYasEMF1 background. EMF1 is required for trimethylating lysine-27 on histone 3 (H3K27me3), and ULT1 associates with ARABIDOPSIS TRITHORAX1 (ATX1) for trimethylating lysine-3 on histone 4 (H3K4me3) at flower MADS box gene loci. Reducing EMF1 activity decreases H3K27me3 marks and increases H3K4me3 marks on target gene loci. Removing ULT1 activity has the opposite effect on the two histone marks. Removing both gene activities restores the active and repressive marks to near wild-type levels. Thus, ULT1 acts as an antirepressor that counteracts EMF1 action through modulation of histone marks on target genes. Our analysis indicates that, instead of acting as off and on switches, EMF1 and ULT1 mediate histone mark deposition and modulate transcriptional activities of the target genes. PMID- 23632856 TI - The Pseudomonas syringae type III effector AvrRpt2 promotes pathogen virulence via stimulating Arabidopsis auxin/indole acetic acid protein turnover. AB - To accomplish successful infection, pathogens deploy complex strategies to interfere with host defense systems and subvert host physiology to favor pathogen survival and multiplication. Modulation of plant auxin physiology and signaling is emerging as a common virulence strategy for phytobacteria to cause diseases. However, the underlying mechanisms remain largely elusive. We have previously shown that the Pseudomonas syringae type III effector AvrRpt2 alters Arabidopsis (Arabidopsis thaliana) auxin physiology. Here, we report that AvrRpt2 promotes auxin response by stimulating the turnover of auxin/indole acetic acid (Aux/IAA) proteins, the key negative regulators in auxin signaling. AvrRpt2 acts additively with auxin to stimulate Aux/IAA turnover, suggesting distinct, yet proteasome dependent, mechanisms operated by AvrRpt2 and auxin to control Aux/IAA stability. Cysteine protease activity is required for AvrRpt2-stimulated auxin signaling and Aux/IAA degradation. Importantly, transgenic plants expressing the dominant axr2 1 mutation recalcitrant to AvrRpt2-mediated degradation ameliorated the virulence functions of AvrRpt2 but did not alter the avirulent function mediated by the corresponding RPS2 resistance protein. Thus, promoting auxin response via modulating the stability of the key transcription repressors Aux/IAA is a mechanism used by the bacterial type III effector AvrRpt2 to promote pathogenicity. PMID- 23632858 TI - Life(span) in balance: oxygen fuels a sophisticated neural network for lifespan homeostasis in C. elegans. PMID- 23632857 TI - Function of oncogenes in cancer development: a changing paradigm. AB - Tumour-associated oncogenes induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, therapeutic strategies that block oncogene activity are likely to selectively target tumour cells. However, recent evidences have revealed that oncogenes are only essential for the proliferation of some specific tumour cell types, but not all. Indeed, the latest studies of the interactions between the oncogene and its target cell have shown that oncogenes contribute to cancer development not only by inducing proliferation but also by developmental reprogramming of the epigenome. This provides the first evidence that tumorigenesis can be initiated by stem cell reprogramming, and uncovers a new role for oncogenes in the origin of cancer. Here we analyse these evidences and propose an updated model of oncogene function that can explain the full range of genotype-phenotype associations found in human cancer. Finally, we discuss how this vision opens new avenues for developing novel anti-cancer interventions. PMID- 23632859 TI - SUMO wrestling with Drp1 at mitochondria. PMID- 23632860 TI - [Diagnosis of lymphedema]. AB - "Edema" is only symptom of a disease, so edema treatment is only treating the symptoms. Therefore the aim of a step-by-step diagnostic approach is to determine the cause and severity of the lymphedema, as well as to distinguish the lymphedema from other edema-associated diseases. "Lymphedema" is a genuine disease, so lymphedema treatment is causal disease treatment! Due to improved diagnostic and therapeutic possibilities and not least by a growing majority of patients with their demand for adequate therapy, also the physicians awareness of lymphatic diseases has increased. Nevertheless, there is still a clear deficit in the knowledge of the very simple diagnostic steps to confirm the diagnosis and also of the appropriate stage-related treatment of lymphedema. PMID- 23632861 TI - Proteotyping for the rapid identification of influenza virus and other biopathogens. AB - The influenza virus is one of the most deadly infectious agents known to man and has been responsible for the deaths of some hundred million lives throughout human history. The need to rapidly and reliably survey circulating virus strains down to the molecular level is ever present. This tutorial describes the development and application of a new proteotyping approach that harnesses the power of high resolution of mass spectrometry to characterise the influenza virus, and by extension other bacterial and viral pathogens. The approach is shown to be able to type, subtype, and determine the lineage of human influenza virus strains through the detection of one or more signature peptide ions in the mass spectrum of whole virus digests. Pandemic strains can be similarly distinguished from seasonal ones, and new computer algorithms have been written to allow reassorted strains that pose the greatest pandemic risk to be rapidly identified from such datasets. The broader application of the approach is further demonstrated here for the parainfluenza virus, a virus which can be life threatening to children and presents similar clinical symptoms to influenza. PMID- 23632862 TI - The first palladium-catalyzed 1,4-addition of terminal alkenes to acrylate esters. AB - A novel and efficient procedure for the synthesis of delta,gamma-alkenyl esters with complete E-stereochemistry by the 1,4-addition of alkenes to acrylate esters in the presence of a catalytic amount of palladium chloride has been developed. This method provides a rapid and efficient access to substituted delta,gamma alkenyl esters. PMID- 23632863 TI - A new, simple method for estimating pleural effusion size on CT scans. AB - BACKGROUND: There is no standardized system to grade pleural effusion size on CT scans. A validated, systematic grading system would improve communication of findings and may help determine the need for imaging guidance for thoracentesis. METHODS: CT scans of 34 patients demonstrating a wide range of pleural effusion sizes were measured with a volume segmentation tool and reviewed for qualitative and simple quantitative features related to size. A classification rule was developed using the features that best predicted size and distinguished among small, moderate, and large effusions. Inter-reader agreement for effusion size was assessed on the CT scans for three groups of physicians (radiology residents, pulmonologists, and cardiothoracic radiologists) before and after implementation of the classification rule. RESULTS: The CT imaging features found to best classify effusions as small, moderate, or large were anteroposterior (AP) quartile and maximum AP depth measured at the midclavicular line. According to the decision rule, first AP-quartile effusions are small, second AP-quartile effusions are moderate, and third or fourth AP-quartile effusions are large. In borderline cases, AP depth is measured with 3-cm and 10-cm thresholds for the upper limit of small and moderate, respectively. Use of the rule improved interobserver agreement from kappa = 0.56 to 0.79 for all physicians, 0.59 to 0.73 for radiology residents, 0.54 to 0.76 for pulmonologists, and 0.74 to 0.85 for cardiothoracic radiologists. CONCLUSIONS: A simple, two-step decision rule for sizing pleural effusions on CT scans improves interobserver agreement from moderate to substantial levels. PMID- 23632864 TI - The relationship between structural/MHC changes in upper airway palatopharyngeal muscle morphology and obstructive sleep apnea/hypopnea syndrome. AB - The aim of this study is to explore the relationship between structural/MHC changes in upper airway palatopharyngeal muscle morphology and obstructive sleep apnea/hypopnea syndrome. Palatopharyngeal muscle specimens were taken from 51 patients with obstructive sleep apnea hypopnea syndrome (OSAHS) who underwent uvulopalatopharyngoplasty (UPPP) resection. Patients were divided into light, medium and severe in terms of the severity of their OSAHS. There were 17 patients in each severity group. Palatopharyngeal muscle specimens were also taken from 17 patients suffering from chronic tonsillitis for comparison as the control group. All specimens were stained using Masson and observed for structural changes, especially in muscle fiber morphology, density and arrangement, as well as intermuscular connective tissues, under light microscopy. All specimens were also analyzed for MHC-I, MHC-IIa and MHC-IIb phenotype and protein expression differences using mRNA quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining. The results from each group were then statistically analyzed using semi-quantitative analysis. Light microscopy with Masson staining revealed that in the control group, the muscle fibers are closely connected and arranged neatly. In specimens from patients suffering from OSAHS, the palatopharyngeal muscle fibers are larger with obvious hypertrophy and there was an increase in elastic fibers. The mucosal lamina propria was thickened, and the density of muscle fibers was reduced. Muscle fibers are not neatly arranged and degeneration was observed. The amount of muscular pathology and fibrosis corresponds to the severity of disease in the patients. In patients with severe OSAHS, the proportion of collagen to muscle fibers was increased significantly. Immunofluorescence results reveal that there were significantly more fast muscle fibers and less slow muscle fibers in the study group than the control group. mRNA quantitative reverse transcription polymerase chain reaction (RT-PCR) revealed similar results, i.e., the proportion of MHC-II palatopharyngeal muscle fibers is higher in the study group than the control group, and increases with the severity of OSAHS. Pathological change occurs in both the collagen and muscle of OSAHS patients and corresponds to the degree of severity of OSAHS. Pathological change in palatopharyngeal muscle tissues is therefore, likely to be related to the occurrence and development of OSAHS. The increase in the proportion of the MHC-1I type fibers in OSAHS patients is likely to have an effect on the amount of airway support conferred by the muscle. This is likely the reason behind the lack of clinical improvement in some patients with severe OSAHS despite surgical treatment. PMID- 23632865 TI - Comparison of two cochlear implantation techniques and their effects on the preservation of residual hearing. Is the surgical approach of any importance? AB - The goal of this work was to review the pre-and postsurgical auditory thresholds of two surgical implantation techniques, namely the mastoidectomy with posterior tympanotomy approach (MPTA) and suprameatal approach (SMA), to determine whether there is a difference in the degree of preservation of residual hearing. In a series of 430 consecutive implanted patients 227 patients had measurable pre operative hearing thresholds at 250, 500, and 1,000 Hz. These patients were divided into two groups according to the surgical technique that was used for implantation. The SMA approach was followed for 84 patients in Amsterdam, whereas the MPTA technique was adhered to 143 patients in Maastricht. The outcome variables of interest were alteration of pre-and postoperative auditory thresholds after cochlear implantation. Complete or partial preservation of residual hearing was obtained in 21.4 and 21.7% in the SMA and MPTA group, respectively. No statistical differences could be found between the SMA and MPTA group (p = 0.96; Chi-square test). The SMA technique is correlated with a similar degree of hearing loss after cochlear implantation compared to the MPTA technique. However, both techniques were not able to conserve a measurable amount of hearing in patients with a substantial degree of residual hearing. Therefore, both surgical techniques need to be refined for patients in which residual acoustical hearing is pursued. PMID- 23632866 TI - Venous thromboembolism in ENT surgery: a review of the literature and completed audit cycle of adherence to national guidance. AB - Venous thromboembolism (VTE) risk assessment of elective ENT patients is essential to minimize the risk of mortality and morbidity. The study is standard based audit of VTE risk assessment against the ENT UK guidelines and intervention includes instructional poster and departmental presentation. 23 patients on eight operating lists were audited in the first cycle (C1). A total of 27 patients on ten operating lists were re-audited in the second cycle (C2). There were marked improvements in the number of VTE risk assessments completed (C1 = 3/23; C2 = 26/27; p < 0.0001), the number of patients encouraged to mobilize (C1 = 0/23; C2 = 26/27; p < 0.0001), and the number of VTE leaflets provided upon discharge (C1 = 1/23; C2 = 27/27; p < 0.0001) following the intervention. The introduction of a poster and a departmental presentation proved to be simple, cheap, and effective measures to improve adherence of national VTE guidelines. PMID- 23632867 TI - Age-adjusted normality patterns for posturography by Sway Star system. AB - Technological advances have led to the development of new measurement techniques that have improved the evaluation, diagnosis, and treatment of patients with vertigo, dizziness and balance disorders. The objective of this study was to propose population normality patterns, adjusted for age, for summary option (balance control summary, BCS) of Sway Star system. Prospective study involving 70 healthy individuals (average age 44.9 years) evenly distributed in seven age groups and who underwent a postural study with the Sway Star system. The normality patterns for the BCS are presented in Tables 2, 3 and 4. No influence of the gender variable was found. Age had an influence in the more sensorially complex stance tests, and the sensory analysis (visual and vestibular contributions). No influence of age in gait tests or in balance control indexes was found. The BCS option is the most feasible way of systematically using the Sway Star, because it provides complete information of the patient's postural capacity in sensorially complex settings. Establishing normality patterns is the initial and essential step to validate the usefulness of Sway Star in the study of patients with balance disorder. Gait test results were not influenced by age because of their greater capacity to reproduce physiological situations; these could be the tests of choice for detecting elderly patients with a tendency to fall. PMID- 23632868 TI - The predictive value of Muller maneuver in REM-dependent obstructive sleep apnea. AB - To our knowledge, no studies up to date have investigated the correlation of rapid eye movement (REM) dependent obstructive sleep apnea syndrome (OSAS) and Muller maneuver. The aim of this study is to investigate whether REM-dependent OSAS is predicted by the findings of the Muller maneuver. The study was conducted on 149 patients with witnessed apnea and daytime sleepiness. Muller maneuver was performed to all patients and the obstruction site was determined using a five point scale. Then, polysomnography of the patient was obtained and the apnea hypopnea indexes were determined in total sleep time, REM-dependent sleep and non REM-dependent sleep. The correlations between the Muller maneuver findings and polysomnographic data were analyzed. The ages of the patients included in the study ranged between 25 and 73 years with a mean age of 49.3 +/- 10.1 years. Their mean body mass index was 30.8 +/- 5.1 kg/m(2) (range 21.9-55.4 kg/m(2)). The patients' mean apnea-hypopnea indexes in total sleep time was 28.1 and ranged between 5.4 and 124.3. REM-dependent OSAS was determined in 49 patients. When the data were analyzed, it was determined that there were no statistically significant correlations between tongue base or lateral pharyngeal band obstruction at the level of hypopharynx and the REM-dependent OSAS. At the level of the soft palate, the obstruction caused by the lateral pharyngeal bands or soft palate and REM dependency did not show any statistically significant correlation (p > 0.05). In conclusion, Muller maneuver does not provide useful data to predict REM dependency of OSAS. PMID- 23632870 TI - Feminization laryngoplasty: assessment of surgical pitch elevation. AB - The aim of this study is to analyze change in pitch following feminization laryngoplasty, a technique to alter the vocal tract of male to female transgender patients. This is a retrospective review of 94 patients undergoing feminization laryngoplasty between June 2002 and April 2012 of which 76 individuals completed follow-up audio recordings. Feminization laryngoplasty is a procedure removing the anterior thyroid cartilage, collapsing the diameter of the larynx as well as shortening and tensioning the vocal folds to raise the pitch. Changes in comfortable speaking pitch, lowest vocal pitch and highest vocal pitch are assessed before and after surgery. Acoustic parameters of speaking pitch and vocal range were compared between pre- and postoperative results. The average comfortable speaking pitch preoperatively, C3# (139 Hz), was raised an average of six semitones to G3 (196 Hz), after surgical intervention. The lowest attainable pitch was raised an average of seven semitones and the highest attainable pitch decreased by an average of two semitones. One aspect of the procedure, thyrohyoid approximation (introduced in 2006 to alter resonance), did not affect pitch. Feminization laryngoplasty successfully increased the comfortable fundamental frequency of speech and removed the lowest notes from the patient's vocal range. It does not typically raise the upper limits of the vocal range. PMID- 23632869 TI - Expression of selected regulatory molecules on the CD83+ monocyte-derived dendritic cells generated from patients with laryngeal cancer and their clinical significance. AB - B7H1 and B7H4 overexpression is associated with inhibition of the immune system in many solid tumors, and altogether with CD200 molecule plays an important role in tumor invasion by promoting malignant transformation. However, there is no report about impact of these molecules on laryngeal squamous cell carcinoma. The objective of the present study was to assess by means of flow cytometry the expression of B7H1, B7H4, CD200, and CD200R on CD83+ monocyte-derived dendritic cells (Mo-DC), pulsed with autologous tumor cell lysates (aTCL) in patients who suffer from G1, G2, or G3 laryngeal carcinoma (LC, n = 60) in comparison to healthy donors (HD, n = 15). It has been demonstrated that median value of the percentages of CD83+ B7H1+, CD83+ B7H4+, and CD83+ CD200+ cells were higher in LC patients than HD (p = 0.041, p <= 0.0001, and p = 0.02, respectively). Mean fluorescence intensity (MFI) of CD200, CD200R, B7H1, and B7H4 on the Mo-DC pulsed with aTCL of the patients was also higher than on the Mo-DC of HD (p <= 0.0001, p <= 0.0001, p = 0.002, and p <= 0.0001, respectively). The highest MFI levels of all molecules were noted in grade 3 LC. The aforementioned results prove that there is a relation between the presence of laryngeal cancer and the expression of B7H1, B7H4, CD200, and CD200R regulatory molecules on the CD83+ Mo-DC pulsed with autologous cancer cell lysates. Strong association of LC grade and the tested antigens expression suggests a critical role for these proteins in LC biology. PMID- 23632872 TI - IgE reactivity profiles among house dust mite allergic patients in Bavaria. AB - Recombinant allergen diagnostics have become increasingly important in daily allergological routine, made possible by inroads into the understanding of major and minor allergens accomplished within the last decade. Recombinant allergen diagnostics will, however, only provide correct diagnoses when sufficient knowledge of the regional IgE reactivity profile to a specific allergen source is available. A variety of studies in different European countries revealed reactivity profiles, where a sensitization to house dust mite could be recognized in more than 97 % of cases in which Der p1 and Der p2 were measured. The aim of this study was to investigate the IgE reactivity profiles of house dust mite allergic patients in southern Germany. Sera of house dust mite allergic patients (positive intranasal provocation) were screened for IgE antibodies against commercially available D pter., nDer p1, rDer p2 and rDer p10. IgE antibodies against D pter. could be found in 98 out of 98 sera (100 %). Seventy-five patients (76.5 %) reacted to nDer p1. In 72 patients (73.4 %), IgE antibodies against rDer p2 could be found, while IgE antibodies against rDer p10 were present in only 4 patients (4.1 %). Seventeen patients (17.3 %) had no IgE antibodies against nDer p1, rDer p2 and nDer p10, but displayed reactions to D pter. Knowledge of IgE regional reactivity profiles is necessary when using recombinant allergen diagnostics. In the case of our house dust mite allergic patients 17 would have remained undiagnosed based on a diagnostic method utilizing only the two major allergens nDerp1 and rDerp2. PMID- 23632873 TI - Response to "Letter to the Editor" by Antonio Pirodda entitled "Idiopathic sudden hearing loss: another kind of circulatory risk should not be neglected". PMID- 23632871 TI - Syndromes of hearing loss associated with visual loss. AB - Patients with hearing loss depend more on their vision on their communication and vice versa. ENT physician faces difficult situation when he or she consults a patient complaining of hearing loss with a problem of vision. The prevalence of ophthalmic abnormalities in deaf population is also higher compared to their hearing peers. This paper is to summarize the common syndromes associated with visual defect according to the site of affection in the eye. STUDY DESIGN: Review article. Syndromes which result in deaf blind person are different among adults compared to among children. Rubella syndrome and Down syndrome are the main causes of deaf blind people above 18 years of age. While in children, CHARGE syndrome is the main cause of deaf blind children. ENT physician should be aware of these syndromes for earlier detection of deaf blind persons. Deaf blind people need a great deal of help. Communication and education are crucial for them and need to be properly supported. PMID- 23632874 TI - Controversial issues of optimal surgical timing and patient selection in the treatment planning of otosclerosis. AB - The aim of this study was to analyze the impact of clinical factors on the outcomes of otosclerosis surgery and support patients' access to evidence-based information in pre-operative counseling to optimize their choices. A total of 109 ears in 93 patients undergoing stapes surgery in a tertiary referral center were included. Variables with a potential impact on hearing outcomes were recorded, with an emphasis on factors that were readily available pre-operatively. Hearing success was defined as a post-operative air-bone gap <=10 dB. Logistic regression analysis was used to determine the factors independently contributing to the prediction of hearing success. The mean follow-up period was 18.0 months. Univariate and multivariate analyses indicated that none of the pre-operative factors (piston type, age, sex, affected side, tinnitus, vertigo, and pre operative hearing thresholds) affected hearing success significantly (all p > 0.05). In conclusion, self-crimping Nitinol piston provides comparable hearing outcomes with conventional manual-crimping prostheses. However, Nitinol piston offers a technical simplification of a surgical procedure and an easier surgical choice for patients. In addition, age is not a detriment to hearing gain and instead might result in better use of hearing aids in older adults, thus facilitating social hearing recovery. Finally, hearing success does not depend on the extent of pre-operative hearing loss. Hence, patients with poor cochlear function should not be considered poor candidates for surgery. The predictive model has established recommendations for otologists for better case selection, and factors that are readily available pre-operatively may inform patients more explicitly about expected post-operative audiometric results. PMID- 23632875 TI - Searching for the cheese: does ethmoid pneumatization affect the location of the anterior ethmoid artery? AB - Endoscopic sinus surgery is a widely used technique in otolaryngologic practice. To avoid complications, the locations of important anatomical structures, such as the anterior ethmoid artery (AEA), should be determined preoperatively. We want to evaluate the effect of ethmoid cavity pneumatization on the location of the AEA and to determine consistent landmark(s) for locating the AEA. 524 consecutive patients undergoing sinus CT scans between February and October 2012 were reviewed retrospectively. After the exclusion criteria were applied, 150 CT scans (300 sides) were selected for the study. A statistically significant positive correlation was found between ethmoid pneumatization and the distance of the AEA to the attachment of the inferior turbinate to the lateral nasal wall (Spearman's rho = 0.305; p < 0.001). Likewise, a statistically significant positive correlation was found between ethmoid pneumatization and the distance between the AEA and the frontonasal junction (Spearman's rho = 0.219; p < 0.001). We found that the artery was located mostly between the second and third lamellae [n 211 (71 %) cases]. There was no statistically significant correlation between ethmoid pneumatization and AEA location in terms of the lamellae. Increased ethmoid volume increases the distance of the AEA from the frontonasal junction and the lateral attachment of the inferior turbinate. However, increased pneumatization of the ethmoid cavity did not affect AEA localization in terms of the lamellae. Based on our findings, we suggest that using the lamellae to locate the AEA is reliable. PMID- 23632876 TI - Mini-endoscopy of the frontal sinus to guide endonasal frontal sinus surgery. AB - Endoscopic frontal sinus surgery requires special attention to the numerous anatomical variations. Additionally, in situations of revision surgery, endonasal frontal sinus identification may be challenging. Numerous strategies have been described to access the frontal sinus in endonasal endoscopic frontal sinus surgery including an additional external approach. A pilot study is presented using a newly designed modular mini-endoscope (1.1 mm, 10.000 pixel, 2 working channels and 120 degrees lens) to assist the frontal sinus surgery through a transcutaneous puncture of the frontal sinus. We used this mini-endoscope for primary frontal sinus surgery on 3 patients and for revision frontal sinus surgery on 4 patients. In all patients, the mini-endoscope could be placed in the frontal sinus without side effects. The visible illumination at the frontal sinus floor, caused by the mini-endoscope being in the frontal sinus, guided the surgeon endonasally directly to the frontal sinus floor. Frontal sinus drainage was achieved by the described guidance on all patients. In conclusion, mini endoscopy of the frontal sinus might be an interesting option in endoscopic frontal sinus surgery to guide the surgeon by illumination in complex anatomical situations to the frontal sinus. This technique will contribute to further improvement in endonasal endoscopic frontal sinus surgery. PMID- 23632877 TI - Medical nowcasting using Google Trends: application in otolaryngology. AB - Google Trends is a valuable new additional tool for medical research, mainly for epidemiological and economical issues, which is fast and inexpensive to use and may be especially helpful when analyzing patient collectives who go to general practitioners or specialists in private practice rather than public or university clinics, where data for statistics are most often collected from. PMID- 23632878 TI - Comparison of field portable measurements of ultrafine TiO2: X-ray fluorescence, laser-induced breakdown spectroscopy, and Fourier-transform infrared spectroscopy. AB - Laboratory measurements of ultrafine titanium dioxide (TiO2) particulate matter loaded on filters were made using three field portable methods (X-ray fluorescence (XRF), laser-induced breakdown spectroscopy (LIBS), and Fourier transform infrared (FTIR) spectroscopy) to assess their potential for determining end-of-shift exposure. Ultrafine TiO2 particles were aerosolized and collected onto 37 mm polycarbonate track-etched (PCTE) filters in the range of 3 to 578 MUg titanium (Ti). Limit of detection (LOD), limit of quantification (LOQ), and calibration fit were determined for each measurement method. The LOD's were 11.8, 0.032, and 108 MUg Ti per filter, for XRF, LIBS, and FTIR, respectively and the LOQ's were 39.2, 0.11, and 361 MUg Ti per filter, respectively. The XRF calibration curve was linear over the widest dynamic range, up to the maximum loading tested (578 MUg Ti per filter). LIBS was more sensitive but, due to the sample preparation method, the highest loaded filter measurable was 252 MUg Ti per filter. XRF and LIBS had good predictability measured by regressing the predicted mass to the gravimetric mass on the filter. XRF and LIBS produced overestimations of 4% and 2%, respectively, with coefficients of determination (R(2)) of 0.995 and 0.998. FTIR measurements were less dependable due to interference from the PCTE filter media and overestimated mass by 2% with an R(2) of 0.831. PMID- 23632879 TI - The distribution of interstitial cells of Cajal in congenital ureteropelvic junction obstruction. AB - PURPOSE: The authors analysed the distribution of c-kit-positive interstitial cells of Cajal (ICCs) in obstructed ureteropelvic junction (UPJ) and its age related changes. METHODS: Twenty specimens were obtained from children with intrinsic ureteropelvic junction obstruction (UPJO), at the average age of 8.1 years (8 months-16.8 years), fixed in formalin and embedded in paraffin. Five control samples were taken from children at the average age of 2.3 years (2.4 months-7.4 years). All specimens were analysed by the immunohistochemistry test with light microscopy with respect to c-kit expression. The distribution of c-kit positive ICCs in the two groups was compared and the correlation between the distribution of c-kit-positive ICCs and the patients' age in UPJO cases was analysed. The results were examined by Yates' chi(2) test, Mann-Whitney U test, and t test for Pearson's correlation coefficient. A P value < 0.05 was considered as statistically significant. RESULTS: No statistically significant differences were found in the distribution of c-kit-positive ICCs between UPJO and the control group. No correlation was established between the age of patients with UPJO and the distribution of c-kit-positive ICCs. CONCLUSION: No distributional difference found in obstructed and unobstructed UPJ seems to indicate that UPJO is not associated with anomalous distribution of c-kit-positive ICCs. Age-related changes in the expression of c-kit-positive ICCs are equally distributed in obstructed UPJ. PMID- 23632880 TI - Choline PET/CT for imaging prostate cancer: an update. AB - Whole-body positron emission tomography/computed tomography (PET/CT) with [(11)C] and [(18)F]-labeled choline derivates has emerged as a promising molecular imaging modality for the evaluation of prostate cancer. (11)C- and (18)F-choline PET/CT are used successfully for restaging prostate cancer in patients with biochemical recurrence of disease after definitive therapy, especially when the serum prostate-specific antigen level is >1.0 ng/mL. (11)C- and (18)F-choline PET/CT have more limited roles for the initial staging of prostate cancer and for the detection of tiny lymph node metastases due to the low spatial resolution inherent to PET. Overall, these modalities are most useful in patients with a high pre-test suspicion of metastatic disease. The following is a review of the current clinical roles of (11)C- and (18)F-choline PET/CT in the management of prostate cancer. PMID- 23632881 TI - Analysis of differences in oxygen sensitivity of Fe-S clusters. AB - Many but not all iron-sulphur clusters in metalloproteins are known to be sensitive to molecular oxygen with dramatic consequences for their biological function. We performed a systematic quantum chemical investigation that sheds light on the differences in oxygen sensitivity depending on charge and spin states of these clusters as well as on their spatial fixation by the enzyme's scaffold. We find that significant structural distortions are required to bind O2 exothermically to [Fe2S2] and [Fe3S4] clusters, while only small conformational changes allow for the thermodynamically favorable coordination of molecular oxygen to [Fe4S4] cubanes and [Fe4S3] clusters. PMID- 23632882 TI - 2-Acyl-dimedones as UV-active protective agents for chiral amino acids: enantiomer separations of the derivatives on chiral anion exchangers. AB - 2-Acetyldimedone and 12 related compounds were employed as UV-active pre-column derivatizing agents for amino acids. Direct enantioseparation of the products was achieved using chiral anion exchanger stationary phases in polar-organic mobile phase mode. Under basic conditions, the reagents' cyclic beta-tricarbonyl motifs can give rise to exo- and endocyclic enols through tautomerization. However, with primary amines (proteinogenic and unusual amino acids, aminosulfonic and aminophosphonic acids), we exclusively observed the formation of exocyclic enamine-type products. Reaction yields depended strongly on the 2-acyl modification of the reagent; in particular, we observed a significant decrease when electronegative or sterically demanding substituents were present in alpha position to the exocyclic carbonyl group. In addition to improving UV detectability of the products, the introduction of this protective group facilitated successful enantiomer separations of the amino acid derivatives on Cinchona-based chiral anion exchangers. Particularly high enantiomer selectivity was observed in combination with stationary phases bearing a new variation of selectors with pi-acidic (electron-poor) bis(trifluoromethyl)phenyl groups. No racemization of the analytes occurred at any stage of the analytical method including the deprotection, which was achieved with hydrazine. PMID- 23632883 TI - Enabling luminescence decay time-based sensing using integrated organic photodiodes. AB - The use of organic photodiodes (OPDs) for measuring phosphorescent lifetimes of optochemical oxygen sensors is described. Phosphorescent indicators with lifetimes ranging from ~5 to 60 MUs have been studied using light-emitting diodes as the excitation source and organic photodiodes integrated into the sensor substrate for detection. A measurement system using an adjusted electronic circuitry to detect photocurrents in the nanoampere range is presented. The response behaviour of the organic photodiodes has been characterized, and it was found that a forward (positive) bias had to be applied in order to decrease the response time of the OPDs to a range suitable for phosphorescence decay time measurements. A modulation cutoff frequency of ~100 kHz has been determined, corresponding to a response time of the organic photodiodes of 1.6 MUs. Two sensor dyes have been characterized regarding their lifetimes upon exposure to 0 20% oxygen, and it was shown that results comparable to literature data and inorganic photodetectors can be achieved. PMID- 23632884 TI - Simultaneous electrical and plasmonic monitoring of potential induced ion adsorption on metal nanowire arrays. AB - Simultaneous LSPR and electronic sensing of potential induced ion adsorption onto gold nanowire arrays is presented. The formation of a Stern layer upon applying an electrochemical potential generated a complex optical response. Simulation of a lossy atomic layer on the nanowire array using the Multiple Multipole Program (MMP) corresponded very well to the experimentally observed peak position, intensity, and radius of curvature changes. Additionally, a significant voltage dependent change in the resistance of the gold nanowire array was observed during the controlled formation of the electrical double layer. The results demonstrated that an applied electrochemical potential induces measurable changes in the optical and electrical properties of the gold nanowire surface. This is the first demonstration of combined plasmonic and nanowire resistance-based sensing of a surface process in the literature. PMID- 23632885 TI - Pinpointing a highly specific pathological functional connection that turns phantom sound into distress. AB - It has been suggested that an auditory phantom percept is the result of multiple, parallel but overlapping networks. One of those networks encodes tinnitus loudness and is electrophysiologically separable from a nonspecific distress network. The present study investigates how these networks anatomically overlap, what networks are involved, and how and when these networks interact. Electroencephalography data of 317 tinnitus patients and 256 healthy subjects were analyzed, using independent component analysis. Results demonstrate that tinnitus is characterized by at least 2 major brain networks, each consisting of multiple independent components. One network reflects tinnitus distress, while another network reflects the loudness of the tinnitus. The component coherence analysis shows that the independent components that make up the distress and loudness networks communicate within their respective network at several discrete frequencies in parallel. The distress and loudness networks do not intercommunicate for patients without distress, but do when patients are distressed by their tinnitus. The obtained data demonstrate that the components that build up these 2 separable networks communicate at discrete frequencies within the network, and only between the distress and loudness networks in those patients in whom the symptoms are also clinically linked. PMID- 23632886 TI - Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG). AB - In this study, we evaluated the frequency and prognostic impact of DNMT3A mutations (DNMT3A(mut)) in 1770 younger adult patients with acute myeloid leukemia (AML) in the context of other genetic alterations and the European LeukemiaNet (ELN) classification. DNMT3A(mut) were found in 20.9% of AMLs and were associated with older age (P < .0001), higher white blood cell counts (P < .0001), cytogenetically normal AML (CN-AML; P < .0001), NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and IDH1/2 mutations (P < .0001). In univariable and multivariable analyses, DNMT3A(mut) did not impact event-free, relapse-free (RFS), or overall survival (OS) in either the entire cohort or in CN-AML; a negative prognostic effect was found only in the ELN unfavorable CN-AML subset (OS, P = .011). In addition, R882 mutations vs non-R882 mutations showed opposite clinical effects-unfavorable for R882 on RFS (all: hazard ratio [HR], 1.29 [P = .026]; CN-AML: HR, 1.38 [P = .018]) and favorable for non-R882 on OS (all: HR, 0.77 [P = .057]; CN-AML: HR, 0.73 [P = .083]). In our statistically high-powered study with minimized selection bias, DNMT3A(mut) represent a frequent genetic lesion in younger adults with AML but have no significant impact on survival end points; only moderate effects on outcome were found, depending on molecular subgroup and DNMT3A(mut) type. PMID- 23632887 TI - ASB2alpha regulates migration of immature dendritic cells. AB - The actin-binding protein filamins (FLNs) are major organizers of the actin cytoskeleton. They control the elasticity and stiffness of the actin network and provide connections with the extracellular microenvironment by anchoring transmembrane receptors to the actin filaments. Although numerous studies have revealed the importance of FLN levels, relatively little is known about the regulation of its stability in physiological relevant settings. Here, we show that the ASB2alpha cullin 5-ring E3 ubiquitin ligase is highly expressed in immature dendritic cells (DCs) and is down-regulated after DC maturation. We further demonstrate that FLNs are substrates of ASB2alpha in immature DCs and therefore are not stably expressed in these cells, whereas they exhibit high levels of expression in mature DCs. Using ASB2 conditional knockout mice, we show that ASB2alpha is a critical regulator of cell spreading and podosome rosette formation in immature DCs. Furthermore, we show that ASB2(-/-) immature DCs exhibit reduced matrix-degrading function leading to defective migration. Altogether, our results point to ASB2alpha and FLNs as newcomers in DC biology. PMID- 23632888 TI - GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. AB - Granulocyte-macrophage-colony-stimulating factor (GM-CSF) hypersensitivity is a hallmark of juvenile myelomonocytic leukemia (JMML) but has not been systematically shown in the related human disease chronic myelomonocytic leukemia (CMML). We find that primary CMML samples demonstrate GM-CSF-dependent hypersensitivity by hematopoietic colony formation assays and phospho-STAT5 (pSTAT5) flow cytometry compared with healthy donors. Among CMML patients, the pSTAT5 hypersensitive response positively correlated with high-risk disease, peripheral leukocytes, monocytes, and signaling-associated mutations. When compared with IL-3 and G-CSF, GM-CSF hypersensitivity was cytokine specific and thus a possible target for intervention in CMML. To explore this possibility, we treated primary CMML cells with KB003, a novel monoclonal anti-GM-CSF antibody, and JAK2 inhibitors. We found that an elevated proportion of immature GM-CSF receptor-alpha(R) subunit-expressing cells were present in the bone marrow myeloid compartment of CMML. In survival assays, we found that myeloid and monocytic progenitors were sensitive to GM-CSF signal inhibition. Our data indicate that a committed myeloid precursor expressing CD38 may represent the progenitor population with enhanced GM-CSF dependence in CMML, consistent with results in JMML. These preclinical data indicate that GM-CSF signaling inhibitors merit further investigation in CMML and that GM-CSFR expression on myeloid progenitors may be a biomarker for this therapy. PMID- 23632889 TI - Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes. AB - Pericytes and vascular smooth muscle cells (VSMCs), which are recruited to developing blood vessels by platelet-derived growth factor BB, support endothelial cell survival and vascular stability. Here, we report that imatinib, a tyrosine kinase inhibitor of platelet-derived growth factor receptor beta (PDGFRbeta), impaired growth of lymphoma in both human xenograft and murine allograft models. Lymphoma cells themselves neither expressed PDGFRbeta nor were growth inhibited by imatinib. Tumor growth inhibition was associated with decreased microvascular density and increased vascular leakage. In vivo, imatinib induced apoptosis of tumor-associated PDGFRbeta(+) pericytes and loss of perivascular integrity. In vitro, imatinib inhibited PDGFRbeta(+) VSMC proliferation and PDGF-BB signaling, whereas small interfering RNA knockdown of PDGFRbeta in pericytes protected them against imatinib-mediated growth inhibition. Fluorescence-activated cell sorter analysis of tumor tissue revealed depletion of pericytes, endothelial cells, and their progenitors following imatinib treatment. Compared with imatinib, treatment with an anti-PDGFRbeta monoclonal antibody partially inhibited lymphoma growth. Last, microarray analysis (Gene Expression Omnibus database accession number GSE30752) of PDGFRbeta(+) VSMCs following imatinib treatment showed down-regulation of genes implicated in vascular cell proliferation, survival, and assembly, including those representing multiple pathways downstream of PDGFRbeta. Taken together, these data indicate that PDGFRbeta(+) pericytes may represent a novel, nonendothelial, antiangiogenic target for lymphoma therapy. PMID- 23632890 TI - LAMP1/CD107a is required for efficient perforin delivery to lytic granules and NK cell cytotoxicity. AB - Secretory lysosomes of natural killer (NK) cells, containing perforin and granzymes, are indispensable for NK-cell cytotoxicity because their release results in the induction of target-cell apoptosis. Lysosome-associated membrane protein (LAMP) 1/CD107a is used as a marker for NK-cell degranulation, but its role in NK-cell biology is unknown. We show that LAMP1 silencing causes inhibition of NK-cell cytotoxicity, as LAMP1 RNA interference (RNAi) cells fail to deliver granzyme B to target cells. Reduction of LAMP1 expression affects the movement of lytic granules and results in decreased levels of perforin, but not granzyme B, in the granules. In LAMP1 RNAi cells, more perforin is retained outside of lysosomal compartments in trans-Golgi network-derived transport vesicles. Disruption of expression of LAMP1 binding partner, adaptor protein 1 (AP-1) sorting complex, also causes retention of perforin in the transport vesicles and inhibits cytotoxicity, indicating that the interaction between AP-1 sorting complex and LAMP1 on the surface of the transport vesicles is important for perforin trafficking to lytic granules. We conclude that the decreased level of perforin in lytic granules of LAMP1-deficient cells, combined with disturbed motility of the lytic granules, leads to the inability to deliver apoptosis inducing granzyme B to target cells and to inhibition of NK-cell cytotoxicity. PMID- 23632892 TI - Efficacy of intradiscal hepatocyte growth factor injection for the treatment of intervertebral disc degeneration. AB - A poor nutritional supply to the cells of the avascular intervertebral discs, caused by dehydration of the extracellular matrix, is a major cause of intervertebral disc degeneration (IDD). Since hepatocyte growth factor (HGF) has been shown to exert antifibrotic effects, we hypothesized that HGF treatment may be capable of retarding IDD. The present study aimed to evaluate the efficacy of HGF treatment in retarding IDD in a rat tail model of disc degeneration. The disc degeneration models were induced by needle puncture of the rat tail discs. Four weeks following needle puncture, a triblock poly(lactide-co-glycolide) poly(ethyleneglycol)-poly(lactide-co-glycolide; PLGA-PEG-PLGA) polymer gel loaded with HGF or the gel alone was injected into rat tail discs. The efficacy of HGF in retarding IDD was assessed by magnetic resonance imaging (MRI), histological and immunohistochemical evaluation of the type I collagen, type II collagen and bone morphogenetic protein-2 (BMP-2) expression levels. Following injection of the HGF-loaded gel into the nucleus pulposus (NP), a significant trend towards an increase in T2 signal intensity (P=0.028), type II collagen staining in the NP and the number of BMP-2-positive cells in the annulus fibrosus was observed. In addition, the results demonstrated a significant trend towards a decrease in the histological score (P=0.025) and type I collagen staining in the NP compared with segments treated with the gel alone, following the induction of disc degeneration by stab injury. Following treatment with HGF, a tendency for the level of disc height to be maintained was also observed (no statistical significance). By MRI, histological and immunohistochemical evaluation, the present study demonstrated that HGF-loaded PLGA-PEG-PLGA gel was able to retard disc degeneration when injected into the degenerative discs of rat tail models. PMID- 23632891 TI - Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-kappaB activation in diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Aberrant activation of Hedgehog (Hh) and nuclear factor (NF)-kappaB pathways is ubiquitously observed and known to mediate tumor growth, survival, and chemoresistance in DLBCL. Here, we find that activation of Hh signaling is positively correlated with NF-kappaB pathway in DLBCL tumors, and that smoothened (SMO), the signal transducer subunit of Hh pathway, contributes to NF-kappaB activation through recruiting G protein subunits Galphai and Galpha12 to activate PKCbeta/CARMA1/TRAF6/NEMO signaling axis followed by assembling of the CARMA1/BCL10/MALT1/TRAF6 complex to SMO. Moreover, functional inhibition of SMO enhances the cytotoxic effects of NF-kappaB inhibitor. Altogether, our study reveals a noncanonical Hh signaling pathway in which SMO activates trimeric G proteins and CARMA1-associated signaling complex, leading to NF-kappaB activation. This signaling cascade contributes to the survival of DLBCL and may serve as a potential target for combination therapies in DLBCL. PMID- 23632893 TI - Genetic and host-associated differentiation within Thrips tabaci Lindeman (Thysanoptera: Thripidae) and its links to Tomato spotted wilt virus-vector competence. AB - Of eight thelytokous populations of onion thrips (Thrips tabaci) collected from potato (three populations), onion (four) or Chrysanthemum (one) hosts from various regions of Australia, only those from potato were capable of transmitting Tomato spotted wilt virus (TSWV) in controlled transmission experiments. Genetic differentiation of seven of these eight populations, and nine others not tested for TSWV vector competence, was examined by comparison of the DNA sequences of mitochondrial cytochrome oxidase subunit 1 (COI) gene. All Australian populations of T. tabaci grouped within the European 'L2' clade of Brunner et al. (2004). Within this clade the seven populations from potato, the three from onion, and the four from other hosts (Chrysanthemum, Impatiens, lucerne, blackberry nightshade) clustered as three distinct sub-groupings characterised by source host. Geographical source of thrips populations had no influence on genetic diversity. These results link genetic differentiation of thelytokous T. tabaci to source host and to TSWV vector capacity for the first time. PMID- 23632894 TI - A sequential coalescent algorithm for chromosomal inversions. AB - Chromosomal inversions are common in natural populations and are believed to be involved in many important evolutionary phenomena, including speciation, the evolution of sex chromosomes and local adaptation. While recent advances in sequencing and genotyping methods are leading to rapidly increasing amounts of genome-wide sequence data that reveal interesting patterns of genetic variation within inverted regions, efficient simulation methods to study these patterns are largely missing. In this work, we extend the sequential Markovian coalescent, an approximation to the coalescent with recombination, to include the effects of polymorphic inversions on patterns of recombination. Results show that our algorithm is fast, memory-efficient and accurate, making it feasible to simulate large inversions in large populations for the first time. The SMC algorithm enables studies of patterns of genetic variation (for example, linkage disequilibria) and tests of hypotheses (using simulation-based approaches) that were previously intractable. PMID- 23632895 TI - Global spread and genetic variants of the two CYP9M10 haplotype forms associated with insecticide resistance in Culex quinquefasciatus Say. AB - Insecticide resistance develops as a genetic factor (allele) conferring lower susceptibility to insecticides proliferates within a target insect population under strong positive selection. Intriguingly, a resistance allele pre-existing in a population often bears a series of further adaptive allelic variants through new mutations. This phenomenon occasionally results in replacement of the predominating resistance allele by fitter new derivatives, and consequently, development of greater resistance at the population level. The overexpression of the cytochrome P450 gene CYP9M10 is associated with pyrethroid resistance in the southern house mosquito Culex quinquefasciatus. Previously, we have found two genealogically related overexpressing CYP9M10 haplotypes, which differ in gene copy number (duplicated and non-duplicated). The duplicated haplotype was derived from the non-duplicated overproducer probably recently. In the present study, we investigated allelic series of CYP9M10 involved in three C. quinquefasciatus laboratory colonies recently collected from three different localities. Duplicated and non-duplicated overproducing haplotypes coexisted in African and Asian colonies indicating a global distribution of both haplotype lineages. The duplicated haplotypes both in the Asian and African colonies were associated with higher expression levels and stronger resistance than non-duplicated overproducing haplotypes. There were slight variation in expression level among the non-duplicated overproducing haplotypes. The nucleotide sequences in coding and upstream regions among members of this group also showed a little diversity. Non-duplicated overproducing haplotypes with relatively higher expression were genealogically closer to the duplicated haplotypes than the other non-duplicated overproducing haplotypes, suggesting multiple cis-acting mutations before duplication. PMID- 23632896 TI - Basal metabolic rate can evolve independently of morphological and behavioural traits. AB - Quantitative genetic analyses of basal metabolic rate (BMR) can inform us about the evolvability of the trait by providing estimates of heritability, and also of genetic correlations with other traits that may constrain the ability of BMR to respond to selection. Here, we studied a captive population of zebra finches (Taeniopygia guttata) in which selection lines for male courtship rate have been established. We measure BMR in these lines to see whether selection on male sexual activity would change BMR as a potentially correlated trait. We find that the genetic correlation between courtship rate and BMR is practically zero, indicating that the two traits can evolve independently of each other. Interestingly, we find that the heritability of BMR in our population (h(2)=0.45) is markedly higher than was previously reported for a captive zebra finch population from Norway. A comparison of the two studies shows that additive genetic variance in BMR has been largely depleted in the Norwegian population, especially the genetic variance in BMR that is independent of body mass. In our population, the slope of BMR increase with body mass differs not only between the sexes but also between the six selection lines, which we tentatively attribute to genetic drift and/or founder effects being strong in small populations. Our study therefore highlights two things. First, the evolvability of BMR may be less constrained by genetic correlations and lack of independent genetic variation than previously described. Second, genetic drift in small populations can rapidly lead to different evolvabilities across populations. PMID- 23632897 TI - Understanding the meaning of short-term, yiyeqing relationships and how they are formed: implications for condom use in Liuzhou, China. AB - Yiyeqing (YYQ) ("one night love", i.e., having sex only once with a non commercial partner) has increased in China, concomitant with the increase in heterosexual transmission of sexually transmitted infections/human immunodeficiency virus (STI/HIV). Our study explored how participants who had experienced YYQ understood these relationships and characterized YYQ's links to sexual risk behaviors. We conducted in-depth interviews with 45 adults in Liuzhou, a city in southwest China, who had YYQ experience. We analyzed the findings using social construction to interpret the participants' understandings of YYQ. Participants reported that they tend to select YYQ partners whom they trust, which is built through introductions from social connections and within entertainment venues, resulting in the belief that their partners are free of STI/HIV and do not require protected sex. As YYQ relationships become more common, understanding the nature of these relationships is critical for developing public health messages that convey the risks associated with sex in short-term relationships and the need for condoms. PMID- 23632898 TI - Multivalent scaffolds in glycoscience: an overview. PMID- 23632899 TI - A cellular logic circuit for the detection of bacterial pore-forming toxins. AB - We present a cellular logic circuit for deciphering the profiles of toxin production in B. cereus, using multiple readout techniques based on the pore formation on the cell membrane. This new assay enables the simultaneous detection of seven biomarkers in pathogenic strains from various samples. PMID- 23632900 TI - From qualitative work to intervention development in pediatric oncology palliative care research. AB - Qualitative methods can be particularly useful approaches to use with individuals who are experiencing a rare disease and thus who comprise a small sample (such as children with cancer) and are at points in care that few experience (such as end of life). This data-based methods article describes how findings from a qualitative study were used to guide and shape a pediatric oncology palliative care intervention. Qualitative data can lay a strong foundation for subsequent pilot intervention work by facilitating the development of an underlying study conceptualization, providing recruitment feasibility estimates, helping establish clinically meaningful inclusion criteria, establishing staff acceptability of a research intervention, and providing support for face validity of newly developed interventions. These benefits of preliminary qualitative research are described in the context of this study on legacy-making, which involves reports of children (7-12 years of age) living with advanced cancer and of their parent caregivers. PMID- 23632902 TI - A prognostic model for 6-month mortality in elderly survivors of critical illness. AB - BACKGROUND: Although 1.4 million elderly Americans survive hospitalization involving intensive care annually, many are at risk for early mortality following discharge. No models that predict the likelihood of death after discharge exist explicitly for this population. Therefore, we derived and externally validated a 6-month postdischarge mortality prediction model for elderly ICU survivors. METHODS: We derived the model from medical record and claims data for 1,526 consecutive patients aged >= 65 years who had their first medical ICU admission in 2006 to 2009 at a tertiary-care hospital and survived to discharge (excluding those patients discharged to hospice). We then validated the model in 1,010 patients from a different tertiary-care hospital. RESULTS: Six-month mortality was 27.3% and 30.2% in the derivation and validation cohorts, respectively. Independent predictors of mortality (in descending order of contribution to the model's predictive power) were a do-not-resuscitate order, older age, burden of comorbidity, admission from or discharge to a skilled-care facility, hospital length of stay, principal diagnoses of sepsis and hematologic malignancy, and male sex. For the derivation and external validation cohorts, the area under the receiver operating characteristic curve was 0.80 (SE, 0.01) and 0.71 (SE, 0.02), respectively, with good calibration for both (P = 0.31 and 0.43). CONCLUSIONS: Clinical variables available at hospital discharge can help predict 6-month mortality for elderly ICU survivors. Variables that capture elements of frailty, disability, the burden of comorbidity, and patient preferences regarding resuscitation during the hospitalization contribute most to this model's predictive power. The model could aid providers in counseling elderly ICU survivors at high risk of death and their families. PMID- 23632903 TI - Innovative potential treatment strategies for schizophrenia and biomarkers for Alzheimer's disease. PMID- 23632904 TI - The efficacy and safety of long-term Norditropin(r) treatment in children with Prader-Willi syndrome. AB - Prader-Willi syndrome is a genetic disorder that is associated with short stature, partial growth hormone deficiency, small hands and feet, learning and behavioural problems, and hyperphagia leading to severe, often morbid, obesity. Growth hormone therapy is associated with an improvement in height and body composition. We evaluated the efficacy and safety of long-term growth hormone treatment in a retrospective observational multinational study of 41 prepubertal children (mean age 3.8+/-3.0 years) with genetically diagnosed Prader-Willi syndrome treated with growth hormone (0.03-0.06 mg/kg/day) for >12 months [mean duration 4.1 (range 0.9-9.5) years]. Height, weight, and body composition measurements were recorded at baseline and at 6 month intervals until last observation. Mean (SD) gain in height at 12 months was 0.9 (0.2) SD score (p<0.0001). At last observation (after approximately 6 years) mean gain in height was 1.3 (0.3) (p=0.0001) with 85% of children achieving height>- 2 SD score. Body composition improved during treatment with an estimated 9.1% increase in lean body mass and 9.1% decrease in fat mass at last observation (p=0.019). Scoliosis was reported in 3 patients at baseline and 8 patients at last observation. Sleep apnoea was recorded in 3 (7.3%) patients. There were no other severe adverse events reported. Long-term growth hormone treatment of prepubertal children with Prader-Willi syndrome was associated with significant improvements in height and body composition. Treatment was well tolerated. The development of scoliosis warrants monitoring by an orthopaedic specialist. PMID- 23632905 TI - Clock gene expression in the liver of streptozotocin-induced and spontaneous type 1 diabetic rats. AB - Several investigations have shown a relation between diabetes and alterations of the liver circadian clock. We investigated the diurnal expression of clock genes and clock-controlled genes (CCGs) in 3-hour intervals for a 24-h period in the livers of male streptozotocin (STZ)-treated rats, male spontaneous type 1 diabetic LEW.1AR1-iddm (Iddm) rats, and Iddm rats treated for 10 days with insulin. Hepatic mRNA was extracted, and the relative expression of clock genes (Per1, Per2, Bmal1, Clock, Cry1), as well as CCGs (Dbp, E4bp4, RevErbalpha, Roralpha, Ppargamma), was analyzed by reverse transcription followed by real-time polymerase chain reaction. Diabetic STZ and Iddm rats, as well as insulin substituted Iddm rats, exhibited a significant diurnal expression pattern of clock genes as determined by Cosinor analysis; however, the MESOR (midline estimating statistic of rhythm) of Bmal1, Per2, and Clock transcript expression was altered in Iddm and insulin-substituted Iddm rats. The hepatic expression of the CCGs Dbp and RevErbalpha revealed a diurnal rhythm in all investigated groups. Insulin administration to Iddm rats normalized the enhanced MESOR in the expression of Dbp, RevErbalpha, and E4bp4 to the levels of normoglycemic controls. Cosinor analysis indicated no diurnal rhythm of Ppargamma expression in the livers of diabetic STZ or Iddm rats or in those of insulin-substituted Iddm rats. Also, insulin substitution could not reverse the decreased MESOR of Ppargamma expression in Iddm rats. In consequence of the diabetic disease, changes in the expression of clock genes and CCGs suggest alterations in the hepatic peripheral clock mechanism. PMID- 23632907 TI - Purification, molecular cloning, and antimicrobial activity of peptides from the skin secretion of the black-spotted frog, Rana nigromaculata. AB - Antimicrobial peptides from a wide range of amphibian species, especially frogs of the genus Rana, have been characterised and are potential therapeutic agents. Here we describe the isolation, purification, and structural and biological characterisation of three novel antimicrobial peptides from the skin secretions of the black spotted frog, Rana nigromaculata, from Northeastern China. The peptides were identified as belonging to two known families: the temporin, which was first identified in R. nigromaculata from China, and the brevinin-2. Temporin 1RNa and temporin-1RNb both containing three positive charges and have a high potency against microorganisms (MIC: 3.13-8.3 MUM against Gram-positive bacteria, 12.5-25.0 MUM against Gram-negative bacteria, and 6.25-12.5 MUM against Candida albicans) and a high haemolytic activity against human erythrocytes (HC50: 100 150 MUM). Brevinin-2RNa contains a single intra-disulphide bridge at the C terminus that is active towards the tested Gram-positive bacteria but is not active against E. coli and P. aeruginosa. The cDNAs encoding three novel peptide precursors were also subsequently cloned from an R. nigromaculata skin cDNA library and sequenced. The precursors contain 58-72 amino acid residues, which include a conserved signal peptide, acidic propeptide, and the mature temporin 1RNa, temporin-1RNb and brevinin-2RNa. The CD spectra of temporin-1RNa and temporin-1RNb in water, 30 mM SDS and 50 % trifluoroethanol (TFE) indicated that both peptides adopted an aperiodic structure in water and an organised structure with an alpha-helical conformation in TFE and SDS solution. The conformational transition induced by TFE or SDS reflects the potential ability of temporin-1RNa and temporin-1RNb to interact with anionic membranes. PMID- 23632906 TI - Rhizosphere colonization and arsenic translocation in sunflower (Helianthus annuus L.) by arsenate reducing Alcaligenes sp. strain Dhal-L. AB - In the present study, six arsenic-resistant strains previously isolated were tested for their plant growth promoting characteristics and heavy metal resistance, in order to choose one model strain as an inoculum for sunflower plants in pot experiments. The aim was to investigate the effect of arsenic resistant strain on sunflower growth and on arsenic uptake from arsenic contaminated soil. Based on plant growth promoting characteristics and heavy metal resistance, Alcaligenes sp. strain Dhal-L was chosen as an inoculum. Beside the ability to reduce arsenate to arsenite via an Ars operon, the strain exhibited 1-amino-cyclopropane-1-carboxylic acid deaminase activity and it was also able to produce siderophore and indole acetic acid. Pot experiments were conducted with an agricultural soil contaminated with arsenic (214 mg kg-1). A real time PCR method was set up based on the quantification of ACR3(2) type of arsenite efflux pump carried by Alcaligenes sp. strain Dhal-L, in order to monitor presence and colonisation of the strain in the bulk and rhizospheric soil. As a result of strain inoculation, arsenic uptake by plants was increased by 53 %, whereas ACR3(2) gene copy number in rhizospheric soil was 100 times higher in inoculated than in control pots, indicating the colonisation of strain. The results indicated that the presence of arsenate reducing strains in the rhizosphere of sunflower influences arsenic mobilization and promotes arsenic uptake by plant. PMID- 23632908 TI - Remarkable impact of PAHs and TPHs on the richness and diversity of bacterial species in surface soils exposed to long-term hydrocarbon pollution. AB - Nowadays, because of substantial use of petroleum-derived fuels the number and extension of hydrocarbon polluted terrestrial ecosystems is in growth worldwide. In remediation of aforementioned sites bioremediation still tends to be an innovative, environmentally attractive technology. Although huge amount of information is available concerning the hydrocarbon degradation potential of cultivable hydrocarbonoclastic bacteria little is known about the in situ long term effects of petroleum derived compounds on the structure of soil microbiota. Therefore, in this study our aim was to determine the long-term impact of total petroleum hydrocarbons (TPHs), volatile petroleum hydrocarbons (VPHs), total alkyl benzenes (TABs) as well as of polycyclic aromatic hydrocarbons (PAHs) on the structure of bacterial communities of four different contaminated soil samples. Our results indicated that a very high amount of TPH affected positively the diversity of hydrocarbonoclastic bacteria. This finding was supported by the occurrence of representatives of the alpha-, beta-, gamma-Proteobacteria, Actinobacteria, Flavobacteriia and Bacilli classes. High concentration of VPHs and TABs contributed to the predominance of actinobacterial isolates. In PAH impacted samples the concentration of PAHs negatively correlated with the diversity of bacterial species. Heavily PAH polluted soil samples were mainly inhabited by the representatives of the beta-, gamma-Proteobacteria (overwhelming dominance of Pseudomonas sp.) and Actinobacteria. PMID- 23632909 TI - Investigation of the FeFe-hydrogenase gene diversity combined with phylogenetic microbial community analysis of an anaerobic domestic sewage sludge. AB - Biological hydrogen production through the anaerobic digestion is an environmental friendly alternative for satisfying future hydrogen demands. Microorganisms residing into waste water treatment plants are far from being exhaustively characterized and surveys on hydrogen production through FeFe hydrogenase in such ecosystems are scarce. This study combined the analysis of 16S rRNA and [FeFe]-hydrogenase (hydA) genes with statistical tools to estimate richness and diversity of the microbial community of a domestic sewage treatment plant at the phylogenetic and functional levels. Archaeal groups were represented by 69 % of sequences assigned to Methanosarcinales and the remaining belonged to Methanomicrobiales. Within the bacterial library, 136 operational taxonomic units (OTUs) were distributed into 9 phyla, being 86 OTUs related to uncultivated bacteria. From these, 25 OTUs represented potential novel taxa within Synergistetes. Proteobacteria was the most predominant (36 % of the OTUs) and diversified phylogenetic group in the bacterial library, most of them assigned to the class Betaproteobacteria. Twenty-two putative hydA sequences were recovered into four distinct clusters and most of them were more closely related to each other than with sequences retrieved from databases, indicating they are hitherto undetected [Fe-Fe]-hydrogenase gene sequences. The richness estimates revealed that the number of sampled sequences was enough for full coverage of the archaeal diversity but not sufficient to cover both bacterial and hydA gene diversities. The results confirmed a great richness and diversity of bacterial and hydA sequences retrieved from the sewage sludge sample, suggesting such environment as a potential reservoir of new hydrogenase genes for biotechnological exploration. PMID- 23632910 TI - Tubeless procedure reduces hospitalization and pain after percutaneous nephrolithotomy: results of a multivariable analysis. AB - The objective of the study was to assess the efficacy and safety of tubeless percutaneous nephrolithotomy (t-PCNL) in comparison with standard PCNL (s-PCNL). We retrospectively evaluated 317 consecutive PCNL and compared perioperative results, time of hospitalization and analgesic requirement of t-PCNL (114; 36.0 %) to s-PCNL (203; 64.0 %). The decision to perform a tubeless PCNL was made at the end of the procedures depending on the surgeon's preference and according to the following inclusion criteria: (a) no serious bleeding or perforation in the collecting system during the procedure; (b) patients with no more than one access; and (c) residual stone burden needing a second-stage nephroscopy. Staghorn stones and anatomic anomalies were not considered as exclusion criteria for t-PCNL. Univariate analyses were conducted with one-way ANOVA, Fisher's exact test, Pearson's Chi-square and linear-by-linear association test as appropriate. Stepwise multivariable regression analyses were used to assess the independent correlation between demographics and clinical variables and the clinical outcomes. There were no significant differences between the two groups in terms of stone-free rate, hemoglobin decrease, blood transfusion and complication rate. Mean hospital stay was significantly shorter in the t-PCNL group (3.3 vs. 4.6 days; P < 0.001). Tubeless PCNL was associated with less analgesia requirement (68.4 vs. 86.7 %; P < 0.001) and with lower analgesic dose requirement (1.6 vs. 2.1 mean doses; P = 0.010). Multivariable analyses showed that t-PCNL (P < 0.001), postoperative fever (P < 0.001), transfusions (P < 0.001), operative time (P = 0.002), postoperative hydronephrosis (P = 0.005) and residual fragment dimension (P = 0.024) were independently correlated with duration of hospitalization, while analgesic dose requirement was independently influenced by hemoglobin decrease (P < 0.001), t-PCNL (P = 0.005) and stone number (P = 0.044). Our study confirmed that t-PCNL has similar outcomes to s-PCNL in terms of stone free rate without increasing complications in selected cases. t-PCNL is a factor independently associated with shorter hospitalization and lower analgesic requirement. PMID- 23632911 TI - The genetic composition of Oxalobacter formigenes and its relationship to colonization and calcium oxalate stone disease. AB - Oxalobacter formigenes is a unique intestinal organism that relies on oxalate degradation to meet most of its energy and carbon needs. A lack of colonization is a risk factor for calcium oxalate stone disease. Protection against calcium oxalate stone disease appears to be due to the oxalate degradation that occurs in the gut on low calcium diets with a possible further contribution from intestinal oxalate secretion. Much remains to be learned about how the organism establishes and maintains gut colonization and the precise mechanisms by which it modifies stone risk. The sequencing and annotation of the genomes of a Group 1 and a Group 2 strain of O. formigenes should provide the informatic tools required for the identification of the genes and pathways associated with colonization and survival. In this review we have identified genes that may be involved and where appropriate suggested how they may be important in calcium oxalate stone disease. Elaborating the functional roles of these genes should accelerate our understanding of the organism and clarify its role in preventing stone formation. PMID- 23632912 TI - The association between the incidence of urolithiasis and nutrition based on Japanese National Health and Nutrition Surveys. AB - To clarify the association between regional variations in urolithiasis incidence and nutrition intake, we evaluated associated data from Japanese national surveys. The incidence of urolithiasis in 12 regions of Japan was calculated from 2005 patient data obtained from 430 hospitals (n = 92,797). Nutrition intake data were obtained from the National Health and Nutrition Survey. We examined the association between urolithiasis incidence and average intake of various types of food or nutrients by region. Continuing surveys in Japan reveal fixed variations in urolithiasis incidence among geographic regions. The national average of patients with urolithiasis was estimated as 203.1 per 100,000 citizens. Regarding food, intake of fruit correlated negatively with the incidence of urolithiasis (r = -0.721, p = 0.008), while intake of eggs (r = 0.537, p = 0.072) and sugar (r = 0.475, p = 0.119) tended to positively correlate with incidence. Regarding nutrients, intake of potassium (r = -0.500, p = 0.098), vitamin K (r = -0.562, p = 0.057), and pantothenic acid (r = -0.560, p = 0.058) tended to negatively correlate with incidence. The incidence of urolithiasis is higher in geographic areas with populations having low fruit and high sugar intake. PMID- 23632914 TI - Transition metal-catalyzed functionalization of pyrazines. AB - Transition metal-catalyzed reactions are generally used for carbon-carbon bond formation on pyrazines and include, but are not limited to, classical palladium catalyzed reactions like Sonogashira, Heck, Suzuki, and Stille reactions. Also a few examples of carbon-heteroatom bond formation in pyrazines are known. This perspective reviews recent progress in the field of transition metal-catalyzed cross-coupling reactions on pyrazine systems. It deals with the most important C C- and C-X-bond formation methodologies. PMID- 23632913 TI - Feasibility of an online mindfulness program for stress management--a randomized, controlled trial. AB - BACKGROUND: Chronic stress affects many Americans. Stress management programs may be prohibitively expensive or have limited access. PURPOSE: This study aims to determine feasibility of an 8-week Internet-based stress management program (ISM) based on mindfulness principles in reducing stress in a 12-week, parallel, randomized, controlled trial. METHODS: Participants were randomly allocated to ISM, ISM plus online message board (ISM+), or control groups. Perceived stress, mindfulness, self-transcendence, psychological well-being, vitality, and quality of life were measured at baseline, week 8, and week 12 using standard validated questionnaires. RESULTS: ISM and ISM+ groups demonstrated statistically significant improvements compared with control on all measures except vitality and physical health. CONCLUSIONS: The ISM program effectively and sustainably reduced measures of stress. The magnitude of improvement is comparable to traditional mindfulness programs, although fewer participants were engaged. This feasibility study provides strong support for online stress management programs, which increase access at a fraction of cost of traditional programs. PMID- 23632915 TI - Genetic, functional, and phenotypic diversity in TAS2R38-mediated bitter taste perception. AB - Mutational polymorphism in the TAS2R38 bitter taste receptor is a key determinant of threshold taste detection of isolated compounds, such as phenylthiocarbamide (PTC) and propylthiouracil (PROP), as well as complex orosensation-mediated traits such as diet choice and smoking habits. These relationships are accounted for, in part, by 2 common alleles differing in functionality, TAS2R38-PAV and TAS2R38-AVI. However, TAS2R38 harbors extensive additional polymorphism whose functional significance remains unknown. To examine this variation, we ascertained genetic diversity in 56 Caucasian subjects via whole-gene sequencing, analyzed allele-specific responses to 5 TAS2R38 agonists (PTC, PROP, goitrin, methimazole, and sinigrin) using in vitro assays, and assessed genotypic associations with threshold detection phenotypes. Sequencing identified 3 single nucleotide substitutions encoding 3 amino acid changes (C145G/P49A, C785T/A262V, and A886G/I296V), which combined to form 6 haplotypes in our sample. In vitro assays revealed a continuous range of response across alleles, and associations with threshold were significant for all single nucleotide polymorphisms (P < 0.002) and PAV/AVI haplotypes (P < 0.001). Haplotypes other than PAV and AVI did not exhibit phenotypic associations in our sample, possibly as a result of their low frequencies. However, prior studies have indicated that these alleles are common in some global regions, suggesting that alleles rare in our sample may be phenotypically relevant in other populations. PMID- 23632916 TI - High p53 and MAP1 light chain 3A co-expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. AB - p53 and microtubule-associated protein 1 light chain 3A (LC3A) are regulators of apoptosis and autophagy and are expressed at high levels in a number of human tumors. The purpose of the current study was to evaluate the clinicopathological and prognostic significance of p53 and LC3A expression levels in esophageal squamous cell carcinomas (ESCCs). p53 and LC3A expression levels were measured by immunohistochemistry in 114 patients with stage II/III (Tany N+M0 or T3,4 Nany M0) ESCCs treated with surgery followed by adjuvant concurrent chemoradiotherapy. The overexpression of p53 and LC3A was observed in 57 and 54% of ESCC samples, respectively. p53 staining was nuclear and LC3A was localized to the cytoplasm of tumor cells. p53 overexpression was more frequently observed in ESCCs with positive lymph nodes (P=0.017). Patients with ESCCs overexpressing p53 and LC3A were associated with a lower 5-year overall survival rate than those with low p53 and LC3A expression (18.0 vs. 54.4%; P=0.001). Univariate and multivariate analyses revealed that the overexpression of p53 or LC3A was not associated with poor patient outcome (P>0.05). However, patients with high levels of p53 and LC3A co-expression had poor clinical prognoses (P=0.027). Thus, p53 and LC3A co expression is an independent prognostic marker for patients with ESCC. PMID- 23632917 TI - An integrated study reveals diverse methanogens, Thaumarchaeota, and yet uncultivated archaeal lineages in Armenian hot springs. AB - Culture-independent and enrichment techniques, with an emphasis on members of the Archaea, were used to determine the composition and structure of microbial communities inhabiting microbial mats in the source pools of two geothermal springs near the towns of Arzakan and Jermuk in Armenia. Amplification of small subunit rRNA genes using "universal" primers followed by pyrosequencing (pyrotags) revealed highly diverse microbial communities in both springs, with >99 % of pyrosequences corresponding to members of the domain Bacteria. The spring in Arzakan was colonized by a photosynthetic mat dominated by Cyanobacteria, in addition to Proteobacteria, Bacteroidetes, Chloroflexi, Spirochaeta and a diversity of other Bacteria. The spring in Jermuk was colonized by phylotypes related to sulfur, iron, and hydrogen chemolithotrophs in the Betaproteobacteria and Epsilonproteobacteria, along with a diversity of other Bacteria. Analysis of near full-length small subunit rRNA genes amplified using Archaea-specific primers showed that both springs are inhabited by a diversity of methanogens, including Methanomicrobiales and Methanosarcinales and relatives of Methanomassiliicoccus luminyensis, close relatives of the ammonia-oxidizing archaeon (AOA) "Candidatus Nitrososphaera gargensis", and the yet-uncultivated Miscellaneous Crenarchaeotal Group and Deep Hydrothermal Vent Crenarchaeota group 1. Methanogenic enrichments confirmed the predicted physiological diversity, revealing methylotrophic, acetoclastic, and hydrogenotrophic methanogenesis at 45 and 55 degrees C, but not 65 degrees C. This is one of only a few studies combining cultivation-independent and -dependent approaches to study archaea in moderate-temperature (37-73 degrees C) terrestrial geothermal environments and suggests important roles for methanogenic archaea and AOA in the carbon and nitrogen biogeochemical cycles in these environments. PMID- 23632918 TI - Waldiomycin, a novel WalK-histidine kinase inhibitor from Streptomyces sp. MK844 mF10. AB - WalK, a histidine kinase, and WalR, a response regulator, make up a two-component signal transduction system that is indispensable for the cell-wall metabolism of low GC Gram-positive bacteria. WalK inhibitors are likely to show bactericidal effects against methicillin-resistant Staphylococcus aureus . We discovered a new WalK inhibitor, designated waldiomycin, by screening metabolites from actinomycetes. Waldiomycin belongs to the family of angucycline antibiotics and is structurally related to dioxamycin. Waldiomycin inhibits WalK from S. aureus and Bacillus subtilis at IC50s 8.8 and 10.2 MUM, respectively, and shows antibacterial activity with MICs ranging from 4 to 8 MUg ml(-1) against methicillin-resistant S. aureus and B. subtilis. PMID- 23632919 TI - Intervenolin, a new antitumor compound with anti-Helicobacter pylori activity, from Nocardia sp. ML96-86F2. AB - Because stromal cells can regulate the growth and metastasis of tumor cells, a compound that modulates the interaction between the stromal cells and the tumor cells can control the tumor progression. In the course of our screening for such a compound, we have isolated a new compound, intervenolin, from the culture broth of Nocardia sp. ML96-86F2. Intervenolin inhibits the growth of human gastric and colorectal cancer cell lines in the coculture with the respective organ-derived stromal cells more strongly than that of the cancer cells cultured alone. Intervenolin shows antitumor effect against a xenograft model of human colorectal cancer cells in vivo. Furthermore, intervenolin exerts selective anti Helicobacter pylori effect. PMID- 23632920 TI - Infection control team activity and recent antibiograms in the Kobe University Hospital. AB - The hospital infection control team (ICT) has a major role in suppressing or preventing infectious diseases. The purpose of this study was to investigate whether the work of the ICT had affected the antibiograms at the Kobe University Hospital in the past 3 years. The ICT's works are as follows: (1) to monitor whether physicians are instructed in the use of broad-spectrum antibiotics; (2) to check whether measures for preventing the occurrence or spread of infectious disease are performed along with appropriate standard precautions; (3) to provide rapid communication with physicians in bacteremia cases and (4) reporting the antibiograms in the hospital. In addition, we investigated changes in the antibiograms every 6 months based on all materials. There were 193 physician interventions in 2010 and 491 in 2011. The representative isolated bacteria included no additional bacteria with lower susceptibilities found over the past 1.5 years compared with the initial 1.5 years in the 3-year investigation period. The ratio for performing two sets of blood culture tests in all blood culture tests showed an upward tendency from 58.1% in 2009 to 71.1% in 2010 and 80.3% in 2011 (r=0.995, P=0.063, b=0.089). In conclusion, since the introduction of an expanded ICT role, our data showed an increased antibiotic susceptibilities in bacteria such as Enteroccus faecalis and the total amount of hand disinfectant agents tended to increase year by year, even though direct statistical analyses could not easily be performed. Further observation may be necessary for a definitive evaluation of ICT activities. PMID- 23632921 TI - Xanthone derivatives could be potential antibiotics: virtual screening for the inhibitors of enzyme I of bacterial phosphoenolpyruvate-dependent phosphotransferase system. AB - The phosphoenolpyruvate phosphotransferase system (PTS) is ubiquitous in eubacteria and absent from eukaryotes. The system consists of two phosphoryl carriers, enzyme I (EI) and the histidine-containing phosphoryl carrier protein (HPr), and several PTS transporters, catalyzing the concomitant uptake and phosphorylation of several carbohydrates. Since a deficiency of EI in bacterial mutants lead to severe growth defects, EI could be a drug target to develop antimicrobial agents. We used the 3D structure PDB 1ZYM of Escherichia coli EI as the target to virtually screen the potential tight binders from NPPEDIA (Natural Product Encyclopedia), ZINC and Super Natural databases. These databases were screened using the docking tools of Discovery Studio 2.0 and the Integrated Drug Design System IDDS. Among the many interesting hits, xanthone derivatives with reasonably high Dock scores received more attentions. Two of the xanthone derivatives were obtained to examine their capabilities to inhibit cell growth of both Gram-positive and Gram-negative bacterial strains. The results indicate that they may exert the inhibition effects by blocking the EI activities. We have demonstrated for the first time that the xanthone derivatives have high potential to be developed as future antibiotics. PMID- 23632922 TI - An argument for conducting methodologically strong, randomized, controlled trials in educational research. PMID- 23632923 TI - Attitudes of medical students toward psychiatry and psychiatry as a career: a systematic review. AB - OBJECTIVE: The discipline of psychiatry, and psychiatry as a career option, have been negatively regarded by medical students for decades. There is a large amount of literature on attitudes of students and the factors that attract them to and detract from psychiatry. The aim of this article is to systematically review this literature from 1990 to the present time. METHOD: The author undertook a systematic review searching a number of electronic databases using the following key words: medical students, attitudes, psychiatry, career. Studies were included in the review if they had been published in an English-language, peer-reviewed journal. Data extracted included year of publication, country where the study was conducted, study design and aim, sample size and response rate, year of study that students were in when they participated in the research, and main results. RESULTS: A total of 32 papers from 22 different countries were selected for inclusion; 12,144 students from 74 medical schools were surveyed. A mix of positive and negative attitudes toward psychiatry were identified, and, overall, attitudes were found to be positive. However, psychiatry as a career choice was rated poorly and found to be unpopular for many students. CONCLUSION: The studies undertaken to-date have identified and raised awareness of a wide range of negative and positive factors toward psychiatry. In order to encourage more students to consider psychiatry as a career, attention needs to focus more closely on the psychiatry curriculum and the development of innovative teaching strategies. This may overcome the negativity that students express toward psychiatry, improve recruitment rates to training programs, and put psychiatry on a more positive foundation for the future. PMID- 23632924 TI - Web-streamed didactic instruction on substance use disorders compares favorably with live-lecture format. AB - OBJECTIVE: Education about substance use disorders in medical schools and, subsequently, physicians' identification of and intervention in these diagnoses lag behind that of most other disabling disorders. To reduce barriers and improve access to education about this major public health concern, medical schools are increasingly adopting web-based instruction on substance use and other psychiatric disorders as part of their curricula; however, it is not well known how a web-streamed lecture compares with a traditional one. The authors hypothesized that both these formats would be equally efficacious in terms of knowledge acquisition and student satisfaction. METHOD: Authors conducted a prospective study to test this hypothesis among third-year medical students who received web-streamed lecture on substance use/addiction versus those who received a traditional live lecture. RESULTS: Of the 243 students, significantly more students completed the on-line lecture series. Of the 216 students in the final study sample, 130 (60%) were assigned to the web-streamed lecture and 86 (40%) to the live lecture. Within-subject comparisons of pre- and post-lecture scores for the entire cohort indicated a significant improvement in the percentage of correct answers (21.0% difference). Although no differences in improved scores between the two groups were found, students in the live-lecture group reported small, but significantly higher levels of satisfaction. CONCLUSIONS: This preliminary work supports the hypothesis that a web-streamed lecture can be at least equally efficacious as a traditional lecture in terms of knowledge acquisition. However, attention needs to be paid to the lower satisfaction levels associated with using the web-streamed format. PMID- 23632925 TI - Academic performance in the context of a "three excused absences" psychiatry clerkship policy. AB - OBJECTIVE: In order to better manage medical student absences during the psychiatry clerkship, a policy allowing students to miss up to 3 days without penalty was developed. The purpose of this study was to describe absence patterns and compare academic performance between students with and without absences. METHOD: Authors reviewed the academic record of 3rd-year medical students rotating through the psychiatry clerkship between July 1, 2009 and June 30, 2011. The number of clerkship absences during the 6-week rotation, NBME shelf performance, and clinical evaluation scores were extracted. The sample was dichotomized into "absent" and "non-absent" groupings, and mean NBME shelf exam and subjective grades were compared by Student's t-test. RESULTS: During this period of observation, 249 students (57.5%) had no absences; 96 (22.1%) had one absence; 62 (14.3%) had two absences; 25 (5.8%) had three absences; and 1 (0.2%) had four absences. Students with no absences had higher mean NBME psychiatry shelf exam scores than students with >=1 absences. Mean clinical grades, which include a professionalism component, and final course letter grade distribution did not differ significantly between absent and non-absent students. CONCLUSION: Given that students with absences seemed as academically successful as students who were not absent, we conclude that this policy may effectively manage commonly expressed attendance concerns. PMID- 23632927 TI - Psychiatry student interest groups: what they are and what they could be. AB - OBJECTIVE: Medical student interest groups across all specialties help students explore various specialties. There are no published reports on psychiatry student interest group (PSIG) curricula. The aim was to develop elements of a curriculum for such groups, based on data elicited from medical students and faculty members through a multi-institutional online survey. METHOD: The authors electronically surveyed 172 United States psychiatric residency training directors to determine the activities they felt to be important for inclusion in PSIG curricula. Similarly, they surveyed U.S. medical student PSIG leaders to ascertain the activities they felt important to include in such groups, and the current content of their groups. RESULTS: Authors received responses from 64 program directors and 44 PSIG leaders. Based on integration of the results of both surveys, and the practices of existing groups, they propose elements of a curriculum for PSIGs. Medical student PSIG leaders are particularly interested in activities that involve residents. Other curricular topics of interest both to students and training directors include those that focus on student/physician mental health and various psychiatry subspecialties or practice settings. Training directors are willing to be involved with a wide variety of PSIG activities. CONCLUSIONS: The results of these surveys should help to guide PSIG leaders and faculty members in optimizing their PSIG curricula by helping them to include those activities felt to be of most interest by students and of most relevance by training directors. PMID- 23632928 TI - Subspecialty exposure in a psychiatry clerkship does not improve student performance in the subject examination. AB - OBJECTIVE: The authors compared the NBME subject examination scores and subspecialty profiles of 3rd-year medical students who were assigned to psychiatry subspecialties during their clerkship with those who were not. METHOD: The authors collated and analyzed the shelf examination scores, the clinical grades, and the child psychiatry and emergency psychiatry shelf profiles of 361 junior medical students in two medical schools during their psychiatry clerkship. RESULTS: There were no significant differences on these parameters between the students assigned to subspecialty sites and those who were not. CONCLUSION: This study, like some similar previous studies in other clerkships, calls attention to the lack of measurable academic benefit of fragmenting and compartmentalizing the psychiatry clerkship experience for 3rd-year medical students. PMID- 23632929 TI - Telemedicine for peer-to-peer psychiatry learning between U.K. and Somaliland medical students. AB - OBJECTIVE: The proportion of U.K. medical students applying for psychiatry training continues to decline, whereas, in Somaliland, there are no public-sector psychiatrists. This pilot study assessed the usefulness and feasibility of online, instant messenger, peer-to-peer exchange for psychiatry education between cultures. METHOD: Twenty medical students from King's College, London, and Hargeisa University (Somaliland) met online in pairs every 2 weeks to discuss prearranged psychiatric topics, clinical cases, and treatment options, completing online evaluations throughout. RESULTS: Average ratings of the enjoyment, academic helpfulness, and interest of sessions were 4.31, 3.56, and 4.54 (of a maximum of 5), respectively; 83% would recommend the partnership to a friend. CONCLUSION: This partnership enabled students on both sides to exploit psychiatry learning resources at the other's disposal, outside the standard medical education context, illustrating the benefits to medical students in dramatically different locations of partnership through telemedicine. This pilot study presents an innovative, cost-effective, under-used approach to international medical education. PMID- 23632931 TI - Influence of clerkship on attitudes of medical students toward psychiatry across cultures: United States and Qatar. AB - OBJECTIVE: To assure adequate treatment for patients with mental illness worldwide, medical schools must impart positive attitudes toward psychiatry. The authors examined the effect of culture on changes in attitudes toward psychiatry among medical students receiving the same psychiatry clerkship curriculum in two different countries. METHODS: A group of 74 students from Weill Cornell Medical College-New York and 32 from Weill Cornell Medical College-Qatar completed pre- and post-clerkship questionnaires assessing their attitudes toward psychiatry. RESULTS: On the pretest, the Qatar students had less positive attitudes than the New York students, as evidenced by lower group mean total scores. During the clerkship, the attitudes of students at both schools improved, but more markedly in Qatar, narrowing the group differences. CONCLUSION: A psychiatry clerkship with a U.S.-derived curriculum had a positive effect on medical students' attitudes toward psychiatry in Qatar, suggesting the usefulness of applying such curricula across cultures. PMID- 23632932 TI - Substance use and attitudes on professional conduct among medical students: a single-institution study. AB - OBJECTIVE: This study sought to examine how specific substance-use behavior, including nonmedical prescription stimulant (NPS) use, among U.S. medical students correlates with their attitudes and beliefs toward professionalism. METHOD: An anonymous survey was distributed to all medical students at a private medical university (46% response rate). Participants were asked to report alcohol and marijuana use patterns, NPS use, stress levels, and history of suicidal ideation. RESULTS: Over one-third of medical students reported excessive drinking during the past month, and 5% reported NPS use during the past year. Students who endorsed such behavior were significantly less likely to view it as unprofessional and warranting intervention. A large number of students seemed unfamiliar with how to help a classmate with an NPS use problem. CONCLUSIONS: Medical students' substance use behaviors appear to influence attitudes and beliefs toward professional issues regarding substance use. PMID- 23632933 TI - Senior medical students' attitudes toward psychiatry as a career choice before and after an undergraduate psychiatry internship in Iran. AB - OBJECTIVES: The study aimed to assess 1) the attitudes of medical students in the sixth and seventh years (known as interns in Iran) toward psychiatry as a career choice, and 2) the degree of attractiveness of psychiatry as a career choice, with regard to various defined aspects, before and after an undergraduate psychiatry internship (similar to the medical school psychiatry rotation in the United States, but mandatory in Iran) in three major medical schools in Tehran, the capital of Iran. METHOD: Sixth- and seventh-year medical students (locally called interns, N=347) at Tehran, Shahid Beheshti, and Iran Universities of Medical Sciences were consecutively invited to complete anonymous self-report questionnaires designed to assess their perceptions of careers in psychiatry before and after internship in psychiatry wards. Also, students evaluated psychiatry in terms of the factors that reflected the degree of attractiveness of this specialty. RESULTS: Positive responses toward choosing psychiatry as a career were seen in 18.8% before and 20.0% after psychiatry rotation. No significant differences were observed in the positive responses before and after psychiatry internship. The students' opinions changed to a more attractive degree in terms of only 3 out of the 13 defined aspects. There was also no significant difference in the total score on attractiveness of psychiatry before and after the psychiatry internship. CONCLUSIONS: The study indicated that undergraduate psychiatry internship might not induce more students to consider psychiatry as a possible career. The present pattern of psychiatry education in Iran seems not to positively affect most aspects of medical students' attitudes toward psychiatry. PMID- 23632934 TI - Nigerian medical students' opinions about the undergraduate curriculum in psychiatry. AB - OBJECTIVE: The number of psychiatrists in Nigeria is inadequate to meet the treatment needs for neuropsychiatric disorders. Developing mental health competency in the future Nigerian physician workforce is one approach to filling the treatment gap. The authors aimed to assess medical students' attitudes to this training and its relevance to their future practice and to assess whether they are getting adequate or relevant training. METHOD: A cross-sectional, questionnaire-based survey was undertaken among a sample (N=375) of 5th- and 6th year students across four medical schools in Nigeria. RESULTS: Over one-tenth (12%) chose psychiatry as a future career choice. Most expressed positive attitudes toward psychiatry and its relevance to their future careers. A majority were enthusiastic about receiving training in psychiatry in primary-care settings and welcomed a curriculum that emphasized the learning and management of common psychiatric disorders seen in general practice. CONCLUSION: Medical students surveyed would welcome an undergraduate curriculum that integrates the learning of psychiatry with other specialties and skills-training relevant for primary care. Efforts to modify the current curriculum in psychiatry in Nigerian medical schools should be encouraged. PMID- 23632936 TI - An approach to improving psychiatry NBME and USMLE performance. PMID- 23632937 TI - Using mutual invitation in educational and professional small-group settings. PMID- 23632939 TI - Resident and medical student viewpoints on their participation in a telepsychiatry rotation. PMID- 23632941 TI - Half sandwich complexes of chalcogenated pyridine based bi-(N, S/Se) and terdentate (N, S/Se, N) ligands with (eta6-benzene)ruthenium(II): synthesis, structure and catalysis of transfer hydrogenation of ketones and oxidation of alcohols. AB - The half sandwich complexes [(eta(6)-C6H6)Ru(L)Cl][PF6] (1-5) have been synthesized by the reactions of (2-arylchalcogenomethyl)pyridine [L = L1-L3] and bis(2-pyridylmethyl)chalcogenide [L = L4-L5] (chalcogen = S, Se; Ar = Ph/2 pyridyl for S, Ph for Se) with [(eta(6)-C6H6)RuCl2]2, at room temperature followed by treatment with NH4PF6. Their HR-MS, (1)H, (13)C{(1)H} and (77)Se{(1)H} NMR spectra have been found characteristic. The single crystal structures of 1-5 have been established by X-ray crystallography. The Ru has pseudo-octahedral half sandwich "piano-stool" geometry. The complexes 1-5 have been found efficient for catalytic oxidation of alcohols with N-methylmorpholine N-oxide (NMO) and transfer hydrogenation of ketones with 2-propanol (at moderate temperature 80 degrees C) as TON values are up to 9.9 * 10(3) and 9.8 * 10(3) respectively for the two catalytic reactions. On comparing the required catalyst loading for good conversions and reaction time for the present complexes with those reported in literature for other transfer hydrogenation/oxidation catalysts, it becomes apparent that 1-5 have good promise. The complexes of Se ligands have been found more efficient than their sulphur analogues. The complexes of bidentate ligands are more efficient than those of terdentate, due to difficult bond cleavage in the case of latter. These orders of efficiency are supported by DFT calculations. The calculated bond lengths/angles by DFT are generally consistent with the experimental ones. PMID- 23632942 TI - Chiral recognition of a 3D chiral nanoporous metal-organic framework. AB - Some racemates including alcohol, ketone, flavone, phenol, base, and amide racemates etc. were successfully separated by using a 3D chiral nanoporous metal organic framework (MOF) as a new chiral stationary phase in HPLC. The experimental results show that the chiral MOF possesses excellent recognition ability for various racemates, and indicate that enantioseparation on the chiral MOF column is practicable. PMID- 23632943 TI - Characteristics of perimenstrual asthma and its relation to asthma severity and control: data from the Severe Asthma Research Program. AB - BACKGROUND: Although perimenstrual asthma (PMA) has been associated with severe and difficult-to-control asthma, it remains poorly characterized and understood. The objectives of this study were to identify clinical, demographic, and inflammatory factors associated with PMA and to assess the association of PMA with asthma severity and control. METHODS: Women with asthma recruited to the National Heart, Lung, and Blood Institute Severe Asthma Research Program who reported PMA symptoms on a screening questionnaire were analyzed in relation to basic demographics, clinical questionnaire data, immunoinflammatory markers, and physiologic parameters. Univariate comparisons between PMA and non-PMA groups were performed. A severity-adjusted model predicting PMA was created. Additional models addressed the role of PMA in asthma control. RESULTS: Self-identified PMA was reported in 17% of the subjects (n = 92) and associated with higher BMI, lower FVC % predicted, and higher gastroesophageal reflux disease rates. Fifty two percent of the PMA group met criteria for severe asthma compared with 30% of the non-PMA group. In multivariable analyses controlling for severity, aspirin sensitivity and lower FVC % predicted were associated with the presence of PMA. Furthermore, after controlling for severity and confounders, PMA remained associated with more asthma symptoms and urgent health-care utilization. CONCLUSIONS: PMA is common in women with severe asthma and associated with poorly controlled disease. Aspirin sensitivity and lower FVC % predicted are associated with PMA after adjusting for multiple factors, suggesting that alterations in prostaglandins may contribute to this phenotype. PMID- 23632944 TI - Thalamic-hypothalamic infarction presenting as first-order Horner syndrome. PMID- 23632945 TI - Clinical phenotype, muscle MRI and muscle pathology of LGMD1F. AB - Of the seven autosomal dominant genetically distinct forms of LGMD so far described, in only four the causative gene has been identified (LGMD1A-1D). We describe clinical, histopathological and muscle MRI features of a large Italo Spanish kindred with LGMD1F presenting proximal-limb and axial muscle weakness. We obtained complete clinical data and graded the progression of the disease in 29 patients. Muscle MRI was performed in seven patients. Three muscle biopsies from two patients were investigated. Patients with age at onset in the early teens, had a more severe phenotype with a rapid disease course; adult onset patients presented a slow course. Muscle MRI showed prominent atrophy of lower limb muscles, involving especially the vastus lateralis. Widening the patients population resulted in the identification of previously unreported features, including dysphagia, arachnodactyly and respiratory insufficiency. Muscle biopsies showed diffuse fibre atrophy, which evolved with time, chronic myopathic changes, basophilic cytoplasmic areas, autophagosomes and accumulation of myofibrillar and cytoskeletal proteins. The LGMD1F is characterized by a selective involvement of limb muscles with respiratory impairment in advanced stages, and by different degrees of clinical progression. Novel clinical features emerged from the investigation of additional patients. PMID- 23632946 TI - Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS. AB - In the 12-month phase 3 TRANSFORMS study, fingolimod showed greater efficacy than intramuscular interferon beta (IFNbeta)-1a in patients with relapsing-remitting multiple sclerosis (RRMS). This study analyzed fingolimod efficacy compared with IFNbeta-1a in patient subgroups from TRANSFORMS. Patients were randomized to receive fingolimod or weekly IM IFNbeta-1a for 12 months. Analyses of efficacy included annualized relapse rate (ARR), and magnetic resonance imaging (MRI) measures [gadolinium (Gd)-enhancing T1 lesions, new/newly enlarged (active) T2 lesions, brain volume change]. Subgroups were defined based on demographics, disease characteristics (baseline EDSS score, relapse rate, and MRI parameters), and response to previous therapy. Fingolimod 0.5 mg reduced ARR over 12 months by 32-59 % relative to IFNbeta-1a in all subgroups defined by demographic factors or baseline disease characteristics. Fingolimod also reduced the number of new Gd enhancing lesions, active T2 lesions, and the rate of brain volume loss, versus IFNbeta-1a in most (95 %) subgroups. In patients with high disease activity despite IFNbeta treatment in the year before study, fingolimod 0.5 mg reduced ARR by 61 % relative to IFNbeta-1a. Reductions in lesion counts and brain volume loss also favored fingolimod in these patients. In conclusion, consistently better efficacy was observed for fingolimod compared with IFNbeta-1a across different subgroups of patients with RRMS. PMID- 23632947 TI - Age-dependent yield of screening for undetected atrial fibrillation in stroke patients: the Find-AF study. AB - Diagnosis of paroxysmal atrial fibrillation (AF) in stroke patients is challenging, but highly clinically relevant. The percentage of stroke patients with permanent AF increases with age, but limited data are available for the age dependent yield of paroxysmal AF by Holter monitoring. Patients with acute cerebral ischemia were included into the prospective observational Find-AF study. Patients free from AF at presentation received 7 day Holter monitoring. We calculated the percentage of otherwise undetected paroxysmal AF and the number needed to screen for age groups under 60 years, and in 5 year clusters from the age of 60 up to 85 and older. 272 patients were included, 43 (15.8 %) had AF at admission, 33 patients with paroxysmal AF were identified by 7 day Holter (n = 29) or medical history (n = 4).The yield of 7 day Holter ECG clearly increased with older age (p = 0.004): <60 years: 5 %, 60-64 years: 5 %, 65-69 years: 7 %, 70-74 years: 11 %, 75-79 years: 13 %, 80-84 years: 25 %, >= 85 years: 39 %. The number needed to screen (NNS) to find one patient with paroxysmal AF decreased with age: <= 60 years: 18, 60-64 years: 20, 65-69 years: 14, 70-74 years: 9, 75 79 years: 8, 80-84 years: 4, >= 85 years: 3, respectively. In patients <65 years, all AF cases were detected by Holter ECG. The percentage of paroxysmal AF in stroke patients increases with age. The 7 day Holter ECG is most efficient in elderly patients. PMID- 23632948 TI - Allogeneic stem cell transplantation using alemtuzumab-containing regimens in severe aplastic anemia. AB - Alemtuzumab, a humanized anti-CD52, IgG1 monoclonal antibody, is used to reduce graft-versus- host disease (GVHD) and aid engraftment after allogeneic haemopoietic stem cell transplant (HSCT). Its associated low incidence of GVHD makes it an attractive alternative to anti-thymocyte globulin (ATG) in transplant conditioning regimen for severe aplastic anaemia (SAA). We have reviewed the use of alemtuzumab-based conditioning regimen for HSCT in SAA and show that it results in sustained haematological engraftment, a very low incidence of chronic GVHD without an increase in viral infections. Intriguingly, alemtuzumab appears to induce tolerance post-HSCT with the findings of stable mixed T cell chimerism with full donor myeloid chimerism and the absence of chronic GVHD, and which persist on withdrawal of post-graft immunosuppression. Finally, its low toxicity profile may permit future application of HSCT to older patients with SAA who fail to respond to immunosuppressive therapy. PMID- 23632949 TI - Post-transplant gastric antral vascular ectasia after intra-venous busulfan regimen. AB - Gastric antral vascular ectasia (GAVE) is an angiodysplastic disorder that causes gastric bleeding. GAVE can develop as a complication of hematopoietic stem cell transplantation (HSCT-GAVE), and it has been suggested that it may be associated with oral administration of busulfan. We report two cases of HSCT-GAVE after a conditioning regimen containing intra-venous busulfan (ivBu), not oral busulfan. The first case, a 42-year-old woman with blastic plasmacytoid dendritic cell neoplasm, underwent second allogeneic HSCT with conditioning regimen consisting of cyclophosphamide (120 mg/kg) and ivBu (12.8 mg/kg). HSCT-GAVE developed on day 84 post-transplant, and argon plasma coagulation (APC) was performed successfully. The second case, a 60-year-old woman with acute myelogenous leukemia, underwent allogeneic HSCT with the conditioning regimen consisting of ivBu (12.8 mg/kg) and fludarabine (150 mg/kg). She developed melena and was diagnosed with GAVE by endoscopy on day 145 post-transplant. Although complete hemostasis was not achieved despite four administrations of APCs, the melena spontaneously terminated on day 235 post-transplant. To our knowledge, this is the first report describing HSCT-GAVE after ivBU-based HSCT. Although there is no established therapy for HSCT-GAVE, APC may be an option for HSCT-GAVE. PMID- 23632950 TI - Late-onset hemorrhagic cystitis after haploidentical hematopoietic stem cell transplantation in patients with advanced leukemia: differences in ATG dosage are key. AB - Late-onset hemorrhagic cystitis (LOHC) is a common complication following allogeneic hematopoietic stem cell transplantation (HSCT), but its cause remains obscure. More attention to risk factors for LOHC is needed. We retrospectively analyzed patients with advanced leukemia who had been treated with ATG-containing conditioning regimens to evaluate the influence of different doses of ATG on LOHC after haploidentical HSCT. Seventy-five patients undergoing haploidentical HSCT from January 2003 to February 2011 were evaluated. A total of 39 patients receiving transplantation before June 2008 were treated with high-dose ATG (10 mg/kg), whereas 36 patients received low-dose ATG (6 mg/kg) thereafter. LOHC occurred in 16.7% of the patients with low-dose ATG, and in 38.5% of the patients with high-dose ATG (P = 0.027). Univariate analysis showed high-dose ATG, male gender and cytomegalovirus reactivation to be significant risk factors for LOHC. However, only high-dose ATG (HR 2.96, 95% CI 1.143-7.663, P = 0.025) and male gender (HR 4.033, 95% CI 1.355-12.008, P = 0.012) were independent risk factors, as shown by multivariate analysis. In the setting of haploidentical HSCT, we concluded that LOHC is more prevalent in recipients of high-dose ATG and male patients. Future studies should focus on immune reconstitution and virus infection after haploidentical HSCT with 6 mg/kg or 10 mg/kg ATG. PMID- 23632951 TI - Comparison of standardized uptake values in normal structures between PET/CT and PET/MRI in an oncology patient population. AB - PURPOSE: The purpose of this study was to compare and correlate standardized uptake values (SUV) derived from magnetic resonance attenuation correction (MRAC) with those derived from computed tomography attenuation correction (CTAC) in an oncology patient population. PROCEDURES: The HIPAA-compliant study was approved by the Internal Review Board and all subjects gave written informed consent prior to inclusion in the study. Forty patients (mean age 61 +/- 15.1; 20 male) referred for clinically indicated 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) scans also underwent a PET/magnetic resonance imaging (MRI) examination. MRAC was performed using an automatic three-segment model. Regions of interest were drawn over eight normal structures in order to obtain SUVmax and SUVmean values. Spearman rank correlation coefficients (r) were calculated and two-tailed paired t tests were performed to compare the SUVmax and SUVmean values obtained from CTAC with those from MRAC. RESULTS: The mean time after FDG injection was 66 +/- 7 min for PET/CT and 117 +/- 15 min for PET/MRI examination. MRAC SUV values were significantly lower than the CTAC SUV values in mediastinal blood pool (p < 0.001 for both SUVmax and SUVmean) and liver (p = 0.01 for SUVmean). The MRAC SUV values were significantly higher in bone marrow (p < 0.001 for both SUVmax and SUVmean), psoas major muscle (p < 0.001 for SUVmax), and left ventricular myocardium (p < 0.001 for SUVmax and p = 0.01 for SUVmean). For the other normal structures, no significant difference was observed. When comparing SUV values generated from CTAC versus MRAC, high correlations between CTAC and MRAC were observed in myocardium (r = 0.96/0.97 for SUVmax/mean), liver (r = 0.68 for SUVmax), bone marrow (r = 0.80/0.83 for SUVmax/mean), lung tissue (r = 0.70 for SUVmax), and mediastinal blood pool (r = 0.0.68/.069 for SUVmax/mean). Moderate correlations were found in lung tissue (r = 0.67 for SUV mean), liver (r = 0.66 for SUVmean), fat (r = 0.48/0.53 for SUVmax/mean), psoas major muscle (r = 0.54/0.58 for SUVmax/mean), and iliacus muscle (r = 0.41 for SUVmax). Low correlation was found in iliacus muscle (r = 0.32 for SUVmean). CONCLUSIONS: Using the automatic three segment model, our study showed high correlation for measurement of SUV values obtained from MRAC compared to those from CTAC, as the reference standard. Differences observed between MRAC and CTAC derived SUV values may be attributed to the time-delay between the PET/CT and PET/MRI scans or biologic clearance of radiotracer. Further studies are required to assess SUV measurements when performing different MR attenuation correction techniques. PMID- 23632952 TI - Synchrotron radiation X-ray phase micro-computed tomography as a new method to detect iron oxide nanoparticles in the brain. AB - PURPOSE: The purpose of this study was to introduce synchrotron radiation X-ray phase computed tomography (SR-PCT) as a new method of visualizing ultrasmall superparamagnetic particles of iron oxide (USPIO) distribution into the brains of mice with neuroinflammation. PROCEDURES: The sensitivity of the technique was assessed by performing back-to-back SR-PCT and magnetic resonance imaging (MRI) in mice stereotaxically injected with a range of USPIO concentrations. Eight mice with cerebral ischemia were then intravenously injected with USPIOs and imaged back-to-back with MRI and SR-PCT. RESULTS: SR-PCT proved sensitive enough to detect iron in nanomolar quantities. In stroke-induced animals, SR-PCT showed hyperintense areas in the regions of MR signal loss and immunostaining for macrophages. SR-PCT, moreover, identified brain anatomy as clearly as histology, without the need for sectioning or staining, with an examination time of 44 min per brain at an isotropic spatial resolution of 8 MUm. CONCLUSION: SR-PCT has potential for cellular imaging in intact brain, with unequaled neuroanatomy. PMID- 23632953 TI - Macromolecule extravasation-xenograft size matters: a systematic study using probe-based confocal laser endomicroscopy (pCLE). AB - PURPOSE: Profound changes of the vasculature in tumors critically impact drug delivery and therapy response. We aimed at developing a procedure to monitor morphological and functional parameters of the vasculature in subcutaneous xenograft models commonly applied for therapy testing by using probe-based confocal laser endomicroscopy. PROCEDURES: By monitoring various normal and diseased tissues, we established an experimental and analytical set-up to systematically analyze tracer extravasation from the microvasculature. Application of the approach in two xenograft models (HCT-116 and SW620) was realized consecutively throughout tumor growth. RESULTS: The incidence of dilated vessels increased with xenograft size in both models while macromolecule extravasation and tracer accumulation in the tumor tissue, respectively, was significantly reduced throughout growth. The development of dilated/ultradilated vessels correlated with tracer extravasation only in the HCT-116 but not the SW620 model. The underlying mechanisms are still ambiguous and discussed. CONCLUSIONS: Our findings clearly indicate that both xenograft type and size matter for drug delivery and therapy testing. PMID- 23632954 TI - Reticular macular disease is associated with multilobular geographic atrophy in age-related macular degeneration. AB - PURPOSE: To investigate the incidence of reticular macular disease (RMD), a subphenotype of age-related macular degeneration, in multilobular geographic atrophy (GA) and its relation to GA progression. METHODS: One hundred and fifty seven eyes of 99 subjects with age-related macular degeneration, primary GA, and good quality autofluorescence, and/or infrared images were classified into unilobular GA (1 lesion) or multilobular GA (>= 2 distinct and/or coalescent lesions). Thirty-four subjects (50 eyes) had serial imaging. The authors determined the spatiotemporal relationships of RMD to GA and GA progression rates in five macular fields. RESULTS: 91.7% eyes (144 of 157) had multilobular GA, 95.8% of which exhibited RMD. In subjects with serial imaging, the mean GA growth rate significantly differed between the unilobular and multilobular groups (0.40 vs. 1.30 mm2/year, P < 0.001). Of the macular fields in these eyes, 77.1% of fields with RMD at baseline showed subsequent GA progression, while 53.4% of fields without RMD showed progression (P < 0.001). Percentage of fields with RMD significantly correlated with GA progression rate (P = 0.01). CONCLUSION: Autofluorescence and infrared imaging demonstrates that RMD is nearly always present with multilobular GA in age-related macular degeneration. Furthermore, GA lobules frequently develop in areas of RMD, suggesting progression of a single underlying disease process. PMID- 23632955 TI - Diagnostic and therapeutic challenges. PMID- 23632956 TI - Amaurosis fugax in ocular vascular occlusive disorders: prevalence and pathogeneses. AB - PURPOSE: To investigate systematically the prevalence of amaurosis fugax (AF) in various ocular vascular occlusive disorders individually and to discuss the pathogeneses of each. METHODS: The study comprised patients with central retinal artery occlusion (271 eyes), branch retinal artery occlusion (169 eyes), ocular ischemic syndrome (39 eyes), central retinal vein occlusion (864 eyes), hemi central retinal vein occlusion (67 eyes), branch retinal vein occlusion (285 eyes), nonarteritic anterior ischemic optic neuropathy (946 eyes), and giant cell arteritis with visual loss (147 eyes). At first visit, all patients had a detailed ophthalmic and medical history and comprehensive ophthalmic evaluation and systemic evaluation. RESULTS: Prevalence of AF was 12.18% in central retinal artery occlusion, 14.20% in branch retinal artery occlusion, 15.38% in ocular ischemic syndrome, 4.86% in central retinal vein occlusion, 37.84% in central retinal vein occlusion with cilioretinal artery occlusion, 13.43% in hemi-central retinal vein occlusion, 0.35% in branch retinal vein occlusion, and 2.54% in nonarteritic anterior ischemic optic neuropathy. In giant cell arteritis, 32.4% of patients with ocular involvement had a history of AF or 26.5% of the involved eyes. Amaurosis fugax in central retinal artery occlusion, branch retinal artery occlusion, and nonarteritic anterior ischemic optic neuropathy is mostly because of transient embolism. The pathogenesis of AF in each ocular vascular occlusive disorder is discussed. CONCLUSION: Prevalence and pathogenesis of AF in various ocular vascular occlusive disorders varies widely. Amaurosis fugax may be the presenting symptom in these disorders and that always requires urgent evaluation. PMID- 23632958 TI - A series of noninvasive evaluations for bilateral adrenal tumor. PMID- 23632957 TI - PET-based delineation of tumour volumes in lung cancer: comparison with pathological findings. AB - PURPOSE: The objective of the study was to validate an adaptive, contrast oriented thresholding algorithm (COA) for tumour delineation in (18)F fluorodeoxyglucose (FDG) positron emission tomography (PET) for non-small cell lung cancer (NSCLC) in comparison with pathological findings. The impact of tumour localization, tumour size and uptake heterogeneity on PET delineation results was also investigated. METHODS: PET tumour delineation by COA was compared with both CT delineation and pathological findings in 15 patients to investigate its validity. Correlations between anatomical volume, metabolic volume and the pathology reference as well as between the corresponding maximal diameters were determined. Differences between PET delineations and pathological results were investigated with respect to tumour localization and uptake heterogeneity. RESULTS: The delineated volumes and maximal diameters measured on PET and CT images significantly correlated with the pathology reference (both r > 0.95, p < 0.0001). Both PET and CT contours resulted in overestimation of the pathological volume (PET 32.5 +/- 26.5%, CT 46.6 +/- 27.4%). CT volumes were larger than those delineated on PET images (CT 60.6 +/- 86.3 ml, PET 48.3 +/- 61.7 ml). Maximal tumour diameters were similar for PET and CT (51.4 +/- 19.8 mm for CT versus 53.4 +/- 19.1 mm for PET), slightly overestimating the pathological reference (mean difference CT 4.3 +/- 3.2 mm, PET 6.2 +/- 5.1 mm). PET volumes of lung tumours located in the lower lobe were significantly different from those determined from pathology (p = 0.037), whereas no significant differences were observed for tumours located in the upper lobe (p = 0.066). Only minor correlation was found between pathological tumour size and PET heterogeneity (r = -0.24). CONCLUSION: PET tumour delineation by COA showed a good correlation with pathological findings. Tumour localization had an influence on PET delineation results. The impact of tracer uptake heterogeneity on PET delineation should be considered carefully and individually in each patient. Altogether, PET tumour delineation by COA for NSCLC patients is feasible and reliable with the potential for routine clinical application. PMID- 23632959 TI - Microscopic polyangiitis on 18F-FDG PET/CT of a patient with fever of unknown origin presenting as isolated diffuse renal hypermetabolism. PMID- 23632961 TI - Ethical, green and sustainable nuclear medicine. PMID- 23632960 TI - Molecular subtypes of breast cancer: metabolic correlation with 18F-FDG PET/CT. AB - PURPOSE: To determine whether the metabolic features of breast tumours differ among molecular subtypes. METHODS: This prospective study included 168 women diagnosed with locally advanced breast cancer. PET/CT was requested in the initial staging before neoadjuvant treatment (multicentre study, FISCAM grant). All patients underwent an 18F-FDG PET/CT scan with a dual time-point acquisition. Both examinations (PET-1 and PET-2) were evaluated qualitatively and semiquantitatively with calculation of SUVmax (SUV-1 and SUV-2, respectively), and the percentage variation in the SUVs and retention indexes (RI) between PET-1 and PET-2 in the breast tumour were calculated. Biological prognostic parameters, including the steroid receptor status, HER-2 expression, proliferation rate (Ki 67) and grading, were determined from primary tumour tissue. Tumour subtypes were classified following the recommendations of the 12th International Breast Conference, by immunohistochemical surrogates as luminal A, luminal B-HER2(-), luminal B-HER2(+), HER2(+) or basal. Metabolic semiquantitative parameters and molecular subtypes were correlated. RESULTS: Of the 168 tumours, 151 were classified: 16 were luminal A, 53 were luminal B-HER2(-), 29 were luminal B HER2(+), 18 were HER2(+) and 35 were basal. There were significant differences between SUV-1 and SUV-2 and the different subtypes, with higher SUVs in HER2(+) and basal tumours. No significant differences were found with respect to RI. CONCLUSION: Semiquantitative metabolic parameters showed statistically significant differences among the molecular subtypes of the tumours evaluated. Therefore, there seems to be a relationship between molecular and glycolytic phenotypes. PMID- 23632962 TI - On some misconceptions about tumor heterogeneity quantification. PMID- 23632963 TI - Improved quantification of small hearts for gated myocardial perfusion imaging. AB - PURPOSE: In patients with a small heart, defined as an end-systolic volume (ESV) of <=20 mL calculated using the Quantitative Gated SPECT (QGS) program, underestimation of ESV and overestimation of ejection fraction (EF) using gated myocardial perfusion imaging are considered errors caused by inappropriate delineation of the left ventricle (LV). The aim of this study was to develop a new method for delineation of the LV and to evaluate it in studies using a digital phantom, normal subjects and patients. METHODS: The active shape-based method for LV delineation, EXINI heart (ExH), was adjusted to more accurately process small hearts. In small hearts, due to the partial volume effect and the short distance to the opposite ventricular wall, the endocardial and the epicardial surfaces are shifted in the epicardial direction depending on the midventricular volume. The adjusted method was evaluated using digital XCAT phantoms with Monte Carlo simulation (8 virtual patients), a Japanese multicentre normal database (69 patients) and consecutive Japanese patients (116 patients). The LV volumes, EF and diastolic parameters derived from ExH and QGS were compared. RESULTS: The digital phantom studies showed a mean ESV of 87% +/- 9% of the true volume calculated using ExH and 22 % +/- 18% calculated using QGS. In the normal database, QGS gave higher EFs in women than in men (71.4 +/- 6.0 % vs. 67.2 +/- 6.0%, p = 0.0058), but ExH gave comparable EFs (70.7 +/- 4.9% and 71.4 +/- 5 % in men and women, respectively, p = ns). QGS gave higher EFs in subjects with a small heart than in those with a normal-sized heart (74.5 +/- 5.1% vs. 66.1 +/- 4.9%), but ExH gave comparable values (70.0 +/- 5.9% vs. 71.6 +/- 4.2%, respectively, p = ns). In consecutive patients, the average EFs with QGS in patients with ESV >20 mL, 11-20 mL and <=10 mL were 57.9%, 71.9% and 83.2%, but with ExH the differences among these groups were smaller (65.2%, 67.8% and 71.5%, respectively). CONCLUSION: The volume-dependent edge correction algorithm was able to effectively reduce the effects on ESV and EF of a small heart. The uniform normal values might be applicable to both men and women and to both small and normal-sized hearts. PMID- 23632964 TI - Impact of school flu vaccine program on student absences. AB - Literature provides evidence that school attendance correlates with academic performance and student success. Influenza is a contributing factor to school absences. Primary prevention for influenza includes immunization. School-located influenza vaccine (SLIV) programs provide greater access for students to be immunized. A retrospective review of preexisting data from four academic years was conducted to examine the relationship between SLIV participation and absenteeism among students at eight public elementary schools in Effingham County, Georgia. Results identified differences in average frequency of absences between SLIV and non-SLIV years as well as between SLIV participants and nonparticipants for the 2 SLIV years. Implications for practice include the potential for increased herd immunity among students, which may also extend to other parties within the school community and at home, thus promoting overall wellness and future student success. PMID- 23632965 TI - Ghrelin induces apoptosis in colon adenocarcinoma cells via proteasome inhibition and autophagy induction. AB - Ghrelin is a metabolism-regulating hormone recently investigated for its role in cancer survival and progression. Controversially, ghrelin may act as either anti apoptotic or pro-apoptotic factor in different cancer cells, suggesting that the effects are cell type dependent. Limited data are currently available on the effects exerted by ghrelin on intracellular proteolytic pathways in cancer. Both the lysosomal and the proteasomal systems are fundamental in cellular proliferation and apoptosis regulation. With the aim of exploring if the proteasome and autophagy may be possible targets of ghrelin in cancer, we exposed human colorectal adenocarcinoma cells to ghrelin. Preliminary in vitro fluorimetric assays evidenced for the first time a direct inhibition of 20S proteasomes by ghrelin, particularly evident for the trypsin-like activity. Moreover, 1 MUM ghrelin induced apoptosis in colorectal adenocarcinoma cells by inhibiting the ubiquitin-proteasome system and by activating autophagy, with p53 having an "interactive" role. PMID- 23632967 TI - Prostaglandin E2 type 1 receptors contribute to neuronal apoptosis after transient forebrain ischemia. AB - Cyclooxygenase-2-derived prostaglandin E2 (PGE2) contributes to excitotoxic and ischemic neuronal cell death by engaging neuronal PGE2 type 1 receptors (EP1R). Our previous studies have shown that EP1R signaling resulted in disturbances of intracellular Ca(2+) homeostasis and suppression of the pro-survival protein kinase AKT. The aim of this study was to investigate whether these pathophysiological mechanism have a role in the neuronal cell death after transient forebrain ischemia. Mice were subjected to ischemia/reperfusion by bilateral common carotid artery occlusion. Hippocampal cornu ammonis area 1 (CA1) neuronal cell death was determined 5 days after reperfusion. Animals treated with the EP1R antagonist SC51089 or EP1R-deficient mice (EP1(-/-)) showed significantly less neuronal injury as compared to vehicle-treated wild-type controls. Benefits of EP1R blockage were still evident 14 days after injury. Better neuronal survival was correlated with reduced neuronal caspase-3 activity and decreased nuclear translocation of the apoptosis-inducing factor . Neuroprotection could be reverted by intracerebroventricular administration of the phosphoinositide 3-kinase inhibitor LY294002 and was not further increased by the calcineurin inhibitor FK506. These data implicate EP1R in postischemic neuronal apoptosis possibly by facilitating AKT inhibition. PMID- 23632968 TI - Loss of miR-29b following acute ischemic stroke contributes to neural cell death and infarct size. AB - Glutathione depletion and 12-lipoxygenase-dependent metabolism of arachidonic acid are known to be implicated in neurodegeneration associated with acute ischemic stroke. The objective of this study was to investigate the significance of miR-29 in neurodegeneration associated with acute ischemic stroke. Neural cell death caused by arachidonic acid insult of glutathione-deficient cells was preceded by a 12-lipoxygenase-dependent loss of miR-29b. Delivery of miR-29b mimic to blunt such loss was neuroprotective. miR-29b inhibition potentiated such neural cell death. 12-Lipoxygenase knockdown and inhibitors attenuated the loss of miR-29b in challenged cells. In vivo, stroke caused by middle-cerebral artery occlusion was followed by higher 12-lipoxygenase activity and loss of miR-29b as detected in laser-captured infarct site tissue. 12-Lipoxygenase knockout mice demonstrated protection against such miR loss. miR-29b gene delivery markedly attenuated stroke-induced brain lesion. Oral supplementation of alpha tocotrienol, a vitamin E 12-lipoxygenase inhibitor, rescued stroke-induced loss of miR-29b and minimized lesion size. This work provides the first evidence demonstrating that loss of miR-29b at the infarct site is a key contributor to stroke lesion. Such loss is contributed by activity of the 12-lipoxygenase pathway providing maiden evidence linking arachidonic acid metabolism to miR dependent mechanisms in stroke. PMID- 23632969 TI - Inhibition of CXCL12 signaling attenuates the postischemic immune response and improves functional recovery after stroke. AB - After stroke, brain inflammation in the ischemic hemisphere hampers brain tissue reorganization and functional recovery. Housing rats in an enriched environment (EE) dramatically improves recovery of lost neurologic functions after experimental stroke. We show here that rats housed in EE after stroke induced by permanent occlusion of the middle cerebral artery (pMCAO), showed attenuated levels of proinflammatory cytokines in the ischemic core and the surrounding peri infarct area, including a significant reduction in the stroke-induced chemokine receptor CXCR4 and its natural ligand stromal cell-derived factor-1 (CXCL12). To mimic beneficial effects of EE, we studied the impact of inhibiting CXCL12 action on functional recovery after transient MCAO (tMCAO). Rats treated with the specific CXCL12 receptor antagonist 1-[4-(1,4,8,11-tetrazacyclotetradec-1 ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclo-tetradecan (AMD3100) showed improved recovery compared with saline-treated rats after tMCAO, without a concomitant reduction in infarct size. This was accompanied by a reduction of infiltrating immune cells in the ischemic hemisphere, particularly cluster of differentiation 3-positive (CD3(+)) and CD3(+)/CD4(+) T cells. Spleen atrophy and delayed death of splenocytes, induced by tMCAO, was prevented by AMD3100 treatment. We conclude that immoderate excessive activation of the CXCL12 pathway after stroke contributes to depression of neurologic function after stroke and that CXCR4 antagonism is beneficial for the recovery after stroke. PMID- 23632971 TI - Microglia is an active player in how glibenclamide improves stroke outcome. PMID- 23632970 TI - Combined antiapoptotic and antioxidant approach to acute neuroprotection for stroke in hypertensive rats. AB - We hypothesized that targeting key points in the ischemic cascade with combined neuroglobin (Ngb) overexpression and c-jun N-terminal kinase (JNK) inhibition (SP600125) would offer greater neuroprotection than single treatment after in vitro hypoxia/reoxygenation and in a randomized, blinded in vivo experimental stroke study using a clinically relevant rat strain. Male spontaneously hypertensive stroke-prone rats underwent transient middle cerebral artery occlusion (tMCAO) and were divided into the following groups: tMCAO; tMCAO+control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO+Ngb-expressing CAV-2, CAVNgb; tMCAO+SP600125; tMCAO+CAVNgb+SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression+SP600125 significantly reduced oxidative stress and apoptosis compared with single treatment(s) after hypoxia/reoxygenation in B50 cells. In vivo, infarct volume was significantly reduced by CAVNgb, SP600125, and further by CAVNgb+SP600125. The number of Ngb positive cells in the peri-infarct cortex and striatum was significantly increased 14 days after tMCAO in animals receiving CAVNgb. Neurologic outcome, measured using a 32-point neurologic score, significantly improved with CAVNgb+SP600125 compared with single treatments at 14 days after tMCAO. Combined Ngb overexpression with JNK inhibition reduced hypoxia/reoxygenation-induced oxidative stress and apoptosis in cultured neurons and reduced infarct and improved neurologic outcome more than single therapy after in vivo experimental stroke in hypertensive rats. PMID- 23632972 TI - Adaptation of scoring methods for testing cochlear implant users using the Cantonese Hearing In Noise Test (CHINT). AB - OBJECTIVES: It is often difficult to use an adaptive approach to evaluate speech reception in noise in cochlear implant (CI) users, because of variations in performance. Thus, two studies were conducted to develop an alternative method for scoring the Cantonese Hearing In Noise Test (CHINT) and to use this method for evaluating speech reception in CI users. DESIGN: In Study 1, 20 normal hearing adults were tested using four scoring methods, including three modified and the standard HINT scoring method. The speech was presented in the front, and noise originated from the front, the right, or the left loudspeakers, as a standard HINT protocol. Threshold signal-to-noise ratio (S/N) and word intelligibility percent score (word score) were measured in each CHINT noise condition using each rule. In Study 2, depending on the word score of the individual CI user in the quiet CHINT condition, different adaptive rules were selected to score the responses from 12 CI users in the three noise conditions. The percentage of CI users who could successfully be tested using these scoring methods was evaluated. RESULTS: In Study 1, threshold S/Ns obtained using different rules were significantly different and consistent with expectations. The slopes of the performance-intensity function relating mean word scores and threshold S/Ns were linear and agreed well with previous findings. These results showed that the modified rules could be used to adaptively measure CHINT thresholds in noise. In Study 2, these modified rules were successful in measuring CHINT thresholds in 10 of the 12 participants, whose word scores in quiet exceeded 40%. CONCLUSIONS: These modified rules could be used in CI users whose speech reception ability could not have been measured otherwise. PMID- 23632974 TI - Factors associated with length of hospitalization in patients admitted with transient ischemic attack in United States. AB - BACKGROUND AND PURPOSE: Approximately 70% of all patients presenting with transient ischemic attack are admitted to the hospital in United States. The duration and cost of hospitalization and associated factors are poorly understood. This article seeks to identify the proportion and determinants of prolonged hospitalization and to determine the impact on hospital charges using nationally representative data. METHODS: We determined the national estimates of length of stay, mortality, and charges incurred in patients admitted with transient ischemic attack (diagnosis-related code 524 or 069) using Nationwide Inpatient Sample data from 2002 to 2010. Nationwide Inpatient Sample is the largest all-payer inpatient care database in the United States and contains data from ~1000 hospitals, which is a 20% stratified sample of US community hospitals. All the variables pertaining to hospitalization were compared in 3 groups on the basis of length of hospital stay (<= 1, 2-6, and >= 7 days). RESULTS: A total of 949 558 patients were admitted with the diagnosis of transient ischemic attack during the study period. The length of hospitalization was <= 1, 2 to 6, and >= 7 days in 232 732 (24.4%), 662 909 (70%), and 53 917 (5.6%) patients, respectively. The mean hospitalization charges were $10 876, $17 187, and $38 200 for patients hospitalized for <= 1, 2 to 6, and >= 7 days, respectively. The use of thrombolytics (0.03%, 0.09%, and 0.1%; P<0.0001) for ischemic stroke was very low among the 3 strata defined by length of hospitalization. In the multivariate analysis, the following factors were associated with length of hospitalization of >= 2 days: age >65 years (odds ratio [OR], 1.5), women (OR, 1.2), admission to teaching hospitals (OR, 1.1), renal failure (OR, 1.7), hypertension (OR, 1.1), diabetes mellitus (OR, 1.2), chronic lung disease (OR, 1.4), congestive heart failure (OR, 1.4), atrial fibrillation (OR, 1.5), ischemic stroke occurrence (OR, 1.4), Medicare/Medicaid insurance (OR, 1.3), and hospital location in Northeast US region (OR, 1.5; all P values <0.025). CONCLUSIONS: Approximately 75% of patients admitted with transient ischemic attack stay in the hospital for >= 2 days, with the most important determinants being pre-existing medical comorbidities. Longer duration of hospital stay is associated with 2- to 5-fold greater hospitalization charges. PMID- 23632973 TI - Effect of hearing aid bandwidth on speech recognition performance of listeners using a cochlear implant and contralateral hearing aid (bimodal hearing). AB - OBJECTIVES: The purpose of this study was to determine how the bandwidth of the hearing aid (HA) fitting affects bimodal speech recognition of listeners with a cochlear implant (CI) in one ear and severe-to-profound hearing loss in the unimplanted ear (but with residual hearing sufficient for wideband amplification using National Acoustic Laboratories Revised, Profound [NAL-RP] prescriptive guidelines; unaided thresholds no poorer than 95 dB HL through 2000 Hz). DESIGN: Recognition of sentence material in quiet and in noise was measured with the CI alone and with CI plus HA as the amplification provided by the HA in the high and mid-frequency regions was systematically reduced from the wideband condition (NAL RP prescription). Modified bandwidths included upper frequency cutoffs of 2000, 1000, or 500 Hz. RESULTS: On average, significant bimodal benefit was obtained when the HA provided amplification at all frequencies with aidable residual hearing. Limiting the HA bandwidth to only low-frequency amplification (below 1000 Hz) did not yield significant improvements in performance over listening with the CI alone. CONCLUSIONS: These data suggest the importance of providing amplification across as wide a frequency region as permitted by audiometric thresholds in the HA used by bimodal users. PMID- 23632975 TI - External validation of the SEDAN score for prediction of intracerebral hemorrhage in stroke thrombolysis. AB - BACKGROUND AND PURPOSE: The SEDAN score is a prediction rule for assessment of the risk of symptomatic intracerebral hemorrhage (SICH) per the European Cooperative Acute Stroke Study (ECASS) II definition in patients with acute ischemic stroke treated with intravenous thrombolysis. We assessed the performance of the score in predicting SICH per the ECASS II and Safe Implementation of Treatments in Stroke Monitoring Study (SITS-MOST) definitions in the SITS-International Stroke Thrombolysis Register (SITS-ISTR). METHODS: We calculated the SEDAN score in 34 251 patients with complete data, enrolled into the SITS-ISTR. The risk for SICH by both definitions was calculated per score category. Odds ratios for SICH per point increase of the score were obtained using logistic regression. The predictive performance was assessed using area under the curve of the receiver operating characteristic (AUC-ROC). RESULTS: The predictive capability for SICH per ECASS II was moderate at AUC-ROC=0.66. With rising scores, there was a moderate increase in risk for SICH per ECASS II (odds ratio, 1.65 per point; 95% confidence interval, 1.59-1.72; P<0.001), with SICH rates between 1.6% for 0 points and 16.9% for >= 5 points, average 5.1%. The predictive capability for SICH per SITS-MOST was weaker, AUC-ROC=0.60, with lower increase per score point (odds ratio, 1.36 per point; 95% confidence interval, 1.28-1.46; P<0.001), and SICH rates between 0.8% for 0 points and 5.4% for >= 5 points, average 1.8%. CONCLUSIONS: In this very large data set, the predictive and discriminatory performances of the SEDAN score were only moderate for SICH per ECASS II and low for SICH per SITS-Monitoring Study. PMID- 23632976 TI - Constraint-induced movement therapy overcomes the intrinsic axonal growth inhibitory signals in stroke rats. AB - BACKGROUND AND PURPOSE: Constraint-induced movement therapy (CIMT) improves functional outcome in patients with stroke possibly through structural plasticity. We hypothesized that CIMT could enhance axonal growth by overcoming the intrinsic growth-inhibitory signals, leading eventually to improved behavioral performance in stroke rats. METHODS: Focal cerebral ischemia was induced by intracerebral injection of endothelin-1. Adult Wistar rats were divided into a sham-operated group, an ischemic group, and an ischemic group treated with CIMT. CIMT started at postoperative day 7 and continued for 3 weeks. Biotinylated dextran amine was injected into the contralateral sensorimotor cortex at postoperative day 14 to trace crossing axons at the cervical spinal cord. The expressions of Nogo-A, Nogo receptor, RhoA, and Rho-associated kinase in the peri-infarct cortex, and the expressions of biotinylated dextran amine, growth associated protein-43, synaptophysin, vGlut1, and postsynaptic density-95 in the denervated spinal cord were measured by immunohistochemistry and Western blots. Behavioral recovery was analyzed at postoperative days 29 to 32. RESULTS: Infarct volumes were not different between groups after stroke. CIMT significantly increased the length and the number of midline crossings of contralateral corticospinal axons to the denervated cervical spinal cord. CIMT significantly decreased the expressions of Nogo-A/Nogo receptor and RhoA/Rho associated kinase in the peri-infarct cortex, and increased the expressions of growth associated protein-43, synaptophysin, vGlut1, and postsynaptic density-95 in the denervated cervical spinal cord. Behavioral performances assessed by the beam-walking test and the water maze test were improved significantly by CIMT. CONCLUSIONS: CIMT promoted poststroke synaptic plasticity and axonal growth at least partially by overcoming the intrinsic growth-inhibitory signaling, leading to improved behavioral outcome. PMID- 23632977 TI - Vascular endothelial growth factor promotes pericyte coverage of brain capillaries, improves cerebral blood flow during subsequent focal cerebral ischemia, and preserves the metabolic penumbra. AB - BACKGROUND AND PURPOSE: Therapeutic angiogenesis aims at improving cerebral blood flow by amplification of vascular sprouting, thus promoting tissue survival under conditions of subsequent ischemia. It remains unknown whether induced angiogenesis leads to the formation of functional vessels that indeed result in hemodynamic improvements. Observations of hemodynamic steal phenomena and disturbed neurovascular integrity after vascular endothelial growth factor delivery questioned the concept of therapeutic angiogenesis. METHODS: Mice were treated with recombinant human vascular endothelial growth factor (0.02 MUg/d; intracerebroventricular) for 3 to 21 days and subsequently exposed to 90-minute middle cerebral artery occlusion. Angiogenesis, histological brain injury, IgG extravasation, cerebral blood flow, protein synthesis and energy state, and pericyte coverage on brain capillaries were evaluated in a multiparametric approach combining histochemical, autoradiographic, and regional bioluminescence techniques. RESULTS: Vascular endothelial growth factor increased brain capillary density within 10 days and reduced infarct volume and inflammation after subsequent middle cerebral artery occlusion, and, when delivered for prolonged periods of 21 days, enhanced postischemic blood-brain barrier integrity. Increased cerebral blood flow was noted in ischemic brain areas exhibiting enhanced angiogenesis and was associated with preservation of the metabolic penumbra, defined as brain tissue in which protein synthesis has been suppressed but ATP preserved. Vascular endothelial growth factor enhanced pericyte coverage of brain endothelial cells via mechanisms involving increased N-cadherin expression on cerebral microvessels. CONCLUSIONS: That cerebral blood flow is increased during subsequent ischemic episodes, leading to the stabilization of cerebral energy state, fosters hope that by promoting new vessel formation brain tissue survival may be improved. PMID- 23632978 TI - Differences and similarities between spontaneous dissections of the internal carotid artery and the vertebral artery. AB - BACKGROUND AND PURPOSE: To compare potential risk factors, clinical symptoms, diagnostic delay, and 3-month outcome between spontaneous internal carotid artery dissection (sICAD) and spontaneous vertebral artery dissection (sVAD). METHODS: We compared patients with sICAD (n=668) and sVAD (n=302) treated in 3 university hospitals. RESULTS: Patients with sICAD were older (46.3 +/- 9.6 versus 42.0 +/- 10.2 years; P<0.001), more often men (62.7% versus 53.0%; P=0.004), and presented more frequently with tinnitus (10.9% versus 3.4%; P<0.001) and more severe ischemic strokes (median National Institutes of Health Stroke Scale, 10 +/- 7.1 versus 5 +/- 5.9; P<0.001). Patients with sVAD had more often bilateral dissections (15.2% versus 7.6%; P<0.001) and were more often smokers (36.0% versus 28.7%; P=0.007). Thunderclap headache (9.2% versus 3.6%; P=0.001) and neck pain were more common (65.8% versus 33.5%; P<0.001) in sVAD. Subarachnoid hemorrhage (6.0% versus 0.6%; P<0.001) and ischemic stroke (69.5% versus 52.2%; P<0.001) were more frequent in sVAD. After multivariate analysis, sex difference lost its significance (P=0.21), and all other variables remained significant. Time to diagnosis was similar in sICAD and sVAD and improved between 2001 and 2012 compared with the previous 10-year period (8.0 +/- 10.5 days versus 10.7 +/- 13.2 days; P=0.004). In sVAD, favorable outcome 3 months after ischemic stroke (modified Rankin Scale, 0-2: 88.8% versus 58.4%; P<0.001), recurrent transient ischemic attack (4.8% versus 1.1%; P=0.001), and recurrent ischemic stroke (2.8% versus 0.7%; P=0.02) within 3 months were more frequent. CONCLUSIONS: sICAD and sVAD patients differ in many aspects. Future studies should perform separate analyses of these 2 entities. PMID- 23632979 TI - Comparison of risk-scoring systems in predicting symptomatic intracerebral hemorrhage after intravenous thrombolysis. AB - BACKGROUND AND PURPOSE: Various risk score models have been developed to predict symptomatic intracerebral hemorrhage (SICH) after intravenous thrombolysis for acute ischemic stroke. In this study, we aimed to determine the prediction performance of these risk scores in a Taiwanese population METHODS: Prospectively collected data from 4 hospitals were used to calculate probability of SICH with the scores developed by Cucchiara et al, the Hemorrhage After Thrombolysis (HAT) score, the Safe Implementation of Thrombolysis in Stroke-SICH risk score, the Glucose Race Age Sex Pressure Stroke Severity score, and the Stroke Prognostication using Age and National Institutes of Health Stroke Scale-100 index. We used logistic regression to evaluate the effectiveness of each risk model in predicting SICH and the c statistic to assess performance. RESULTS: A total of 548 patients were included. The rates of SICH were 7.3% by the National Institute of Neurological Diseases and Stroke definition, 5.3% by the European Australasian Cooperative Acute Stroke Study II definition, and 3.5% by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study definition. The Cucchiara score, the HAT score, and the Safe Implementation of Thrombolysis in Stroke-SICH risk score were significant predictors of SICH for all 3 definitions, whereas the Glucose Race Age Sex Pressure Stroke Severity score and the Stroke Prognostication using Age and National Institutes of Health Stroke Scale-100 index predicted well only for 1 or 2 definitions of SICH. The c statistic was highest for the HAT score (range, 0.69-0.73) across the definitions of SICH. CONCLUSIONS: The Cucchiara score, the HAT score, and the Safe Implementation of Thrombolysis in Stroke-SICH risk score predicted SICH reasonably well regardless of which SICH definition was used. However, only the HAT score had an acceptable discriminatory ability. PMID- 23632980 TI - Risk of stroke from new carotid artery occlusion in the Asymptomatic Carotid Surgery Trial-1. AB - BACKGROUND AND PURPOSE: In the Asymptomatic Carotid Surgery Trial-1 (ACST-1), 3120 patients with tight asymptomatic carotid stenosis were randomly assigned to medical treatment alone or to carotid endarterectomy and appropriate medication. Successful carotid endarterectomy significantly reduced 10-year stroke risk in younger patients. This study was undertaken to determine the risk of new occlusion and stroke during trial follow-up. METHODS: Patients with contralateral occlusion at trial entry (n=276) or incomplete duplex follow-up (n=137) were excluded. Risk of occlusion and stroke in patients with occlusion was estimated by Kaplan-Meier analysis. Cox proportional hazard regression models were used to determine risk factors for developing new occlusion and stroke. RESULTS: Median follow-up in 2707 patients was 80.0 months (interquartile range, 52.0-115.0). New occlusions occurred in 197 patients (1.1% per annum) but were more likely to occur in arteries with tight stenosis and in unoperated patients. Overall risk of stroke was 7.6% (95% confidence interval [CI], 6.6-8.7) and 15.5% (95% CI, 13.6 17.4) at 5 and 10 years, respectively; for patients with new occlusion, this significantly increased to 17.0% (95% CI, 11.6-22.4) and 20.8% (95% CI, 14.1 26.2), respectively (P<0.001). Stroke was significantly more likely to occur in patients developing occlusion (hazard ratio, 1.78; 95% CI, 1.26-2.51) irrespective of allocated treatment. CONCLUSIONS: New occlusions were uncommon after carotid endarterectomy in ACST-1. During long-term follow-up, occlusion and stroke were commoner among patients with >= 70% stenosis, most of whom had not undergone carotid endarterectomy. Occlusion was an independent prognostic risk factor for occurrence of stroke. PMID- 23632981 TI - Comparison of short-term outcomes of thrombolysis for in-hospital stroke and out of-hospital stroke in United States. AB - BACKGROUND AND PURPOSE: In-hospital stroke (IHS) differs from out-of-hospital stroke (OHS) in risk factors and outcomes. We compared IHS and OHS treated with thrombolysis from a large national cohort in a cross-sectional study to further clarify these differences. METHODS: The Nationwide Inpatient Sample for the years 2005-2010 was searched for adult acute ischemic stroke cases treated with intravenous or intra-arterial thrombolysis. Patients treated on the day of admission were classified as OHS. We compared the demographic and hospital characteristics, comorbidities, and short-term outcomes of thrombolysed IHS and OHS. RESULTS: IHS included 8.7% of 11 750 thrombolysed stroke cases in this study. IHS was associated with a higher comorbidity profile and higher rates of acute medical conditions compared with OHS. IHS had higher inpatient mortality (15.7% versus 9.6%; P<0.001) and lower rate of discharge to home/self-care (22.8% versus 30.0%; P<0.001). IHS was also associated with higher mortality among endovascular treatment group (19.3% versus 13.8%; P=0.010). The difference in the rate of all intracerebral hemorrhage was not significant (5.3% versus 4.7%; P=0.361). In the multivariate analysis, inpatient mortality (adjusted odds ratio, 1.59; 95% confidence interval, 1.32-1.92; P<0.001) and favorable discharge outcome (adjusted odds ratio, 0.79; 95% confidence interval, 0.67-0.93; P=0.005) remained significantly worse in IHS. CONCLUSIONS: Thrombolysed IHS is associated with worse discharge outcomes compared with thrombolysed OHS, likely because of their higher comorbidities and additional medical reasons for the index admission. Thrombolysis is not associated with a higher rate of intracerebral hemorrhage among IHS. PMID- 23632982 TI - Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. AB - BACKGROUND AND PURPOSE: It is unknown whether supraventricular arrhythmias other than atrial fibrillation or flutter are associated with stroke. METHODS: To examine the association between paroxysmal supraventricular tachycardia (PSVT) and stroke, we performed a retrospective cohort study using administrative claims data from all emergency department encounters and hospitalizations at California's nonfederal acute care hospitals in 2009. Our cohort comprised all adult patients with >= 1 emergency department visit or hospitalization from which they were discharged alive and without a diagnosis of stroke. Our primary exposure was a diagnosis of PSVT recorded at an encounter before stroke or documented as present-on-admission at the time of stroke. To reduce confounding, we excluded patients with diagnoses of atrial fibrillation. We defined PSVT, stroke, and atrial fibrillation using International Classification of Diseases, Ninth Revision, Clinical Modification codes previously validated by detailed chart review. RESULTS: Of 4 806 830 eligible patients, 14 121 (0.29%) were diagnosed with PSVT and 14 402 (0.30%) experienced a stroke. The cumulative rate of stroke after PSVT diagnosis (0.94%; 95% confidence interval, 0.76%-1.16%) significantly exceeded the rate among patients without a diagnosis of PSVT (0.21%; 95% confidence interval, 0.21%-0.22%). In Cox proportional hazards analysis controlling for demographic characteristics and potential confounders, PSVT was independently associated with a higher risk of subsequent stroke (hazard ratio, 2.10; 95% confidence interval, 1.69-2.62). CONCLUSIONS: In a large and demographically diverse sample of patients, we found an independent association between PSVT and ischemic stroke. PSVT seems to be a novel risk factor that may account for some proportion of strokes that are currently classified as cryptogenic. PMID- 23632983 TI - Effect of the chemokine receptor CCR5 in the development of American cutaneous leishmaniasis in a Southern Brazilian population. AB - American cutaneous leishmaniasis (ACL) shows a wide spectrum of clinical and immunopathological manifestations. The CCR5 chemokine receptor directs the immune response to a Th1 pattern and the mutant allele of this genotype (Delta32/Delta32) results in a less effective response, thus leading to a milder inflammation. The objective of the present study was to investigate the effect of the CCR5 chemokine receptor in the pathogenesis of ACL in a population of Southern Brazil. The frequency of the genotypes and their association with ACL were studied in 111 patients and compared with 218 control subjects. Genotyping was performed using samples amplified by polymerase chain reaction with sequence specific primers (PCR-SSP). The groups varied in chronological age (P<0.00001), but showed no differences in gender (P=0.0696) or ethnicity (P=0.2944). The frequency of the CCR5/Delta32 genotype did not differ between the patient and control groups (P=0.3009). The Delta32/Delta32 deletion was not observed in any individual involved in the study. The analysis of the genotypes observed no significant difference in the frequency of the CCR5/Delta32 genotype between the ACL and control groups, however the subgroup of patients with a recurrence of the lesion showed a higher frequency of the CCR5/Delta32 mutation (P=0.020), indicating a possible effect of this allele in the pathogenesis of ACL. Nevertheless, more studies are required to elucidate the role of CCR5 in the pathogenesis of ACL. PMID- 23632984 TI - Nocturnal hypoxemia biomarker predicts sleepiness in patients with severe obstructive sleep apnea. AB - PURPOSE: This study aims to assess the association between excessive daytime sleepiness (EDS) and variables extracted from the pulse-oximetry signal obtained during overnight polysomnography. METHODS: A cross-sectional design was used to study the relation between four hypoxemia variables and EDS as determined by Epworth Sleepiness Scale scores (ESSS) in 200 consecutive patients, newly diagnosed with obstructive sleep apnea (OSA), as defined by an apnea-hypopnea index (AHI)>= 15. Hypoxemia measurements were compared between sleepy (ESSS >= 10) and nonsleepy (ESSS<10) patients before and after dichotomizing the cohort for each hypoxemia variable (and for AHI) such that there were 35 (165) patients in each of the corresponding higher (lower) subcohorts. The hypoxemia variables were combined into a biomarker, and its accuracy for predicting sleepiness in individual patients was evaluated. We planned to interpret prediction accuracy above 80 % as evidence that hypoxemia predicted EDS. RESULTS: Hypoxemia was unassociated with sleepiness in OSA patients with AHI in the range of 15 to 50. In patients with AHI>50, the hypoxemia biomarker (but not individual hypoxemia variables) predicted sleepiness with 82 % accuracy. CONCLUSION: Nocturnal hypoxemia as determined by a polyvariable biomarker reliably predicted EDS in patients with severe OSA (AHI>50), indicating that oxygen fluctuation had a direct role in the development of EDS in patients with severe OSA. PMID- 23632985 TI - Levels of urinary isoflavones and lignan polyphenols in Japanese women. AB - OBJECTIVES: High consumption of soybean products has been associated with a reduced risk of hormone-sensitive tumors. Soybean products contain phytoestrogens, such as daidzein, and sesame seeds contain secoisolariciresinol. These compounds are further metabolized to equol, enterodiol, and enterolactone by intestinal bacteria. However, individual differences in the metabolizing potential remain unclear. The aim of this study was to evaluate the urinary daidzein, equol, enterodiol, and enterolactone concentrations in women from several different regions of Japan according to age group. METHODS: Five hundred urine samples collected from Japanese women living in Sapporo, Sendai, Kyoto, Kochi, and Naha were analyzed for daidzein, equol, enterodiol, and enterolactone concentration by gas chromatography-mass spectrometry. RESULTS: The urinary isoflavone and lignan polyphenol levels did not differ significantly among the sampling sites, except for daidzein, which was highest in urine collected at Naha. The prevalence of equol producers was 39 % in the total study cohort. In equol producers, a positive correlation was observed between the urinary daidzein and equol levels (r = 0.399, p < 0.001). However, there was no significant difference between daidzein concentrations in equol producers and non-producers. Moreover, the levels of enterodiol and enterolactone were higher in equol producers than in equol non-producers. In the multivariate logistic analyses, two factors, Sendai dwelling and current smoking, were found to be significant [equol producers to non-producers: odds ratio 2.15 (95 % confidence interval: 1.17-4.02) and odds ratio 0.32 (0.15-0.63), respectively]. CONCLUSIONS: Our data suggest that geographic factors and smoking status should be considered during the evaluation of equol in urine samples and that the same pathway may be responsible for the metabolism of both isoflavones and lignan polyphenols. PMID- 23632986 TI - Photoluminescent poly(ether ether ketone)-quantum dot composite films. AB - A fluoropoly(ether ether ketone) (FPEEK) demonstrating blue fluorescence was developed as a flexible, transparent membranous matrix for the incorporation of quantum dots (QDs) to fabricate a composite photoluminescent film which is promising as a self-referenced temperature sensor. PMID- 23632987 TI - Clinical and radiological outcomes of treatment of avascular necrosis of the femoral head using autologous osteochondral transfer (mosaicplasty): preliminary report. AB - PURPOSE: The purpose of this study was to evaluate clinical and radiological outcomes of autologous osteochondral transfer (OATS) for femoral head osteonecrosis. METHODS: Twenty-one hips in 20 patients (one woman and 19 men), average patients' age at the time of surgery of 35.4 (range 20-56) years, were treated with OATS for osteonecrosis of the femoral head (ONFH). Seven patients at pre-collapse ARCO stages IIA and IIB were treated with OATS alone. Thirteen patients with large pre-collapse ARCO IIC and post-collapse ARCO III and IV were treated with OATS and morselised bone allografts (OATS/allograft). Harris hip score (HHS) was used for clinical evaluation of outcomes; X-rays were performed to examine the evolution of the disease. Kaplan-Meier survival curves were used to determine the failure of the procedures with conversion to THR defined as endpoint. RESULTS: Follow-up of patients treated with OATS alone was 46.14 (range 18-75) months with HHS improvement from a preoperative mean of 42 to 87.85 points at the latest follow-up examination. Only one patient in this group needed a revision operation with THR. The survival for this group of patients was 85.71 % at four years. Follow-up of patients treated with AOTS/allograft was 32.7 (range 7-84) months with HHS improvement from a preoperative mean of 35.2 to 65.7 points at the latest follow-up examination. One patient died six months after the surgery. There were five conversions to THR because of femoral head collapse in this group of patients with survival of 61.54 % at three years. CONCLUSION: The use of osteochondral grafts offers the possibility of successful treatment for ONFH at small and medium pre-collapse stages. The outcomes of large pre-collapse and post-collapse stages were below our expectations. OATS is a time buying procedure for young patients as it may defer total hip replacement. PMID- 23632988 TI - Regulation of ClC-2 gating by intracellular ATP. AB - ClC-2 is a voltage-dependent chloride channel that activates slowly at voltages negative to the chloride reversal potential. Adenosine triphosphate (ATP) and other nucleotides have been shown to bind to carboxy-terminal cystathionine-beta synthase (CBS) domains of ClC-2, but the functional consequences of binding are not sufficiently understood. We here studied the effect of nucleotides on channel gating using single-channel and whole-cell patch clamp recordings on transfected mammalian cells. ATP slowed down macroscopic activation and deactivation time courses in a dose-dependent manner. Removal of the complete carboxy-terminus abolishes the effect of ATP, suggesting that CBS domains are necessary for ATP regulation of ClC-2 gating. Single-channel recordings identified long-lasting closed states of ATP-bound channels as basis of this gating deceleration. ClC-2 channel dimers exhibit two largely independent protopores that are opened and closed individually as well as by a common gating process. A seven-state model of common gating with altered voltage dependencies of opening and closing transitions for ATP-bound states correctly describes the effects of ATP on macroscopic and microscopic ClC-2 currents. To test for a potential pathophysiological impact of ClC-2 regulation by ATP, we studied ClC-2 channels carrying naturally occurring sequence variants found in patients with idiopathic generalized epilepsy, G715E, R577Q, and R653T. All naturally occurring sequence variants accelerate common gating in the presence but not in the absence of ATP. We propose that ClC-2 uses ATP as a co-factor to slow down common gating for sufficient electrical stability of neurons under physiological conditions. PMID- 23632989 TI - Rituximab in the treatment of resistant lupus nephritis: therapy failure in rapidly progressive crescentic lupus nephritis. AB - OBJECTIVE: The objective of this paper is to report the clinical outcome of B cell depletion therapy in 18 patients with refractory lupus nephritis (LN). METHODS: Eighteen patients received rituximab on an open-label basis with prospective evaluations. All patients had renal disease refractory to conventional immunosuppressive therapy, including intravenous cyclophosphamide (CyC). All patients fulfilled the revised ACR classification criteria for SLE. Rituximab was given as 2 * 1 g infusions with 500 mg iv CyC and 500 mg iv methylprednisolone, two weeks apart. Complete remission (CR) of nephritis at six months was defined as normal serum creatinine and serum albumin levels, inactive urine sediment, and proteinuria < 0.5 g/day; partial remission (PR) was defined as a >=50% improvement in all renal parameters that were abnormal at baseline. Clinical response was assessed by the British Isles Lupus Assessment Group (BILAG) score pre- and post-rituximab treatment, and efficacy was recorded by extent and duration of B lymphocyte depletion (normal range 0.100-0.500 * 10(9)/l). Follow-up data were collected at six months, one year post-treatment and at the most recent clinic visit. RESULTS: At six months, 11/18 patients reached renal CR and two of 18 PR. The mean global BILAG scores for responders decreased from 15 (SD 10) to 5 (SD 3), and a total of ten A scores disappeared. Five patients failed to show complete or partial renal response despite peripheral B lymphocyte count depletion, and progressed to end-stage renal failure (ESRF) and dialysis. Four of these patients had severe proliferative, crescentic nephritis, of whom three had Class IV-G, one Class III and one late membranous glomerulonephritis. One patient died six years after rituximab therapy from overwhelming sepsis while on long-term haemodialysis. CONCLUSION: Rituximab therapy achieved a response in 13/18 patients with refractory LN. However, in patients with rapidly progressive crescentic LN, when there is already evidence of significant renal impairment, rituximab therapy may not prevent progression to ESRF and dialysis. Our data also suggest that severe Class IV-G LN may be associated with a poor response to therapy. PMID- 23632991 TI - Impact of microenvironments and personal activities on personal PM2.5 exposures among asthmatic children. AB - Personal activity patterns have often been suggested as a source of unexplained variability when comparing personal particulate matter (PM2.5) exposure to modeled data using central site or microenvironmental data. To characterize the effect of personal activity patterns on asthmatic children's personal PM2.5 exposure, data from the Windsor, Ontario Exposure Assessment Study were analyzed. The children spent on an average 67.1+/-12.7% (winter) and 72.3+/-22.6% (summer) of their time indoors at home where they received 51.7+/-14.8% and 66.3+/-19.0% of their PM2.5 exposure, respectively. In winter, 17.7+/-5.9% of their time was spent at school where they received 38.6+/-11.7% of their PM2.5 exposure. In summer, they spent 10.3+/-11.8% 'indoors away from home', which represented 23.4+/-18.3% of their PM2.5 exposure. Personal activity codes adapted from those of the National Human Activity Pattern Survey and the Canadian Human Activity Pattern Survey were assigned to the children's activities. Of the over 100 available activity codes, 19 activities collectively encompassed nearly 95% of their time. Generalized estimating equation (GEE) models found that, while indoors at home, relative to daytime periods when sedentary activities were conducted, several personal activities were associated with significantly elevated personal PM2.5 exposures. Indoor playing represented a mean increase in PM2.5 of 10.1 MUg/m(3) (95% CI 6.3-13.8) and 11.6 MUg/m(3) (95% CI 8.1-15.1) in winter and summer, respectively, as estimated by a personal nephelometer. PMID- 23632992 TI - Air pollution exposure prediction approaches used in air pollution epidemiology studies. AB - Epidemiological studies of the health effects of outdoor air pollution have traditionally relied upon surrogates of personal exposures, most commonly ambient concentration measurements from central-site monitors. However, this approach may introduce exposure prediction errors and misclassification of exposures for pollutants that are spatially heterogeneous, such as those associated with traffic emissions (e.g., carbon monoxide, elemental carbon, nitrogen oxides, and particulate matter). We review alternative air quality and human exposure metrics applied in recent air pollution health effect studies discussed during the International Society of Exposure Science 2011 conference in Baltimore, MD. Symposium presenters considered various alternative exposure metrics, including: central site or interpolated monitoring data, regional pollution levels predicted using the national scale Community Multiscale Air Quality model or from measurements combined with local-scale (AERMOD) air quality models, hybrid models that include satellite data, statistically blended modeling and measurement data, concentrations adjusted by home infiltration rates, and population-based human exposure model (Stochastic Human Exposure and Dose Simulation, and Air Pollutants Exposure models) predictions. These alternative exposure metrics were applied in epidemiological applications to health outcomes, including daily mortality and respiratory hospital admissions, daily hospital emergency department visits, daily myocardial infarctions, and daily adverse birth outcomes. This paper summarizes the research projects presented during the symposium, with full details of the work presented in individual papers in this journal issue. PMID- 23632993 TI - Disappearance of congenital noncompaction in hereditary cobalamin-C-deficiency 2.5 years after birth. PMID- 23632994 TI - Knockdown of TRB3 induces apoptosis in human lung adenocarcinoma cells through regulation of Notch 1 expression. AB - The upregulation of tribbles homolog 3 (TRB3), a pseudokinase in mammals, has been observed in several types of malignant cancer, including thyroid, ovarian, liver and colorectal cancer. However, the pathological role and the regulatory mechanism of TRB3 in cancer remain unknown. In the current study, we demonstrated that the expression of TRB3 was upregulated in non-small cell lung cancer (NSCLC), correlating with tumor metastasis, disease recurrence and poor survival in patients. Knocking down TRB3 in aggressive lung cancer cell lines was demonstrated to significantly inhibit their malignant behaviors, including in vitro invasion and cell proliferation, as well as in vivo metastasis and tumor growth. The correlation between TRB3 and Notch 1 expression revealed that Notch 1 was downregulated by the knockdown of TRB3 in the lung adenocarcinoma cell lines. These results have provided insights into the correlation between TRB3 expression and lung cancer progression, and thus may have potential for the prognosis and therapy of lung cancer. PMID- 23632995 TI - Hydrogen bonding versus hyperconjugation in condensed-phase carbocations. AB - Hyperconjugative stabilization of positive charge in tertiary carbocations is the textbook explanation for their stability and low frequency nuCH bands in their IR spectra have long been taken as confirming evidence. While this is substantiated in the gas phase by the very close match of the IR spectrum of argon-tagged t butyl cation with that calculated under C(s) symmetry, the situation in condensed phases is much less clear. The congruence of nuCH(max) of t-Bu(+) in superacid media (2830 cm(-1)) with that in the gas phase (2834 cm(-1)) has recently been shown to be accidental. Rather, nuCH(max) varies considerably as a function of counterion in a manner that reveals the presence of significant C-H...anion hydrogen bonding. This paper addresses the question of the relative importance of hyperconjugation versus H-bonding. We show by assigning IR spectra in the nuCH region to specific C-H bonds in t-butyl cation that the low frequency nuCH(max) band in the IR spectrum of t-butyl cation, long taken as direct evidence for hyperconjugation, appears to be due mostly to H-bonding. The appearance of similar low frequency nuCH bands in the IR spectra of secondary alkyl carboranes such as i-Pr(CHB11Cl11), which have predominant sp(3) centres rather than sp(2) centres (and are therefore less supportive of hyperconjugation), also suggests the dominance of H-bonding over hyperconjugation. PMID- 23632996 TI - Microwave-assisted synthesis and high dechlorination activity of magnetic FeNi broom-like nanostructures. AB - A three-dimensional (3D) broom-like nanostructured magnetic FeNi catalyst was synthesized using inexpensive Fe and Ni as precursors in a controllable microwave assisted route. In this 3D broom-like nanostructure, the length of an FeNi nanorod, which serves as a building block, depends on the molar content of Fe. With a decrease in the Fe content from 100 to 45% in the Fe(x)Ni(96-x) system, the length varies from 8 MUm to 1 MUm, which is corroborated by SEM, TEM, XRD, EDS and XPS. The magnetic behavior measurement results show that the magnetic saturation and coercivity are strongly influenced by the length of the nanorods and the Fe content. The sample of Fe nanorods gives a maximum magnetization saturation at 196 emu g(-1), and a maximum coercivity of 241.23 Oe is obtained for Fe78Ni22. These economical 3D FeNi broom-like nanostructures, with large surface areas and dispersed active sites, can dramatically facilitate the diffusion and transportation of a reactant to improve the reactivity. In particular, Fe89Ni11 broom-like nanostructures exert an excellent reactivity towards the reductive dechlorination of 1,1,2,2-tetrachloroethane. PMID- 23632997 TI - Exploration of NaVOPO4 as a cathode for a Na-ion battery. AB - Monoclinic NaVOPO4 is explored as a cathode material for a sodium ion battery. It exhibits electrochemical activity operating at an average potential of 3.6 V (vs. Na(+)/Na) and delivers a reversible capacity of 90 mA h g(-1) at 1/15 C. PMID- 23632999 TI - alpha1-Antitrypsin phenotypes and associated serum protein concentrations in a large clinical population. AB - BACKGROUND: alpha1-Antitrypsin (AAT) deficiency variants reduce the concentration of serum AAT protease inhibitor and can lead to the development of pulmonary and hepatic disease. Relative frequencies of rare AAT variant phenotypes (non-M, Z, and S) and associated serum concentrations in the clinical population have not been thoroughly described. METHODS: Protein phenotypes were determined by isoelectric focusing electrophoresis for 72,229 consecutive samples. Phenotype frequencies, median serum concentrations, and central 95% concentration intervals were determined for observed phenotypes. Concurrent AAT phenotype and concentration data were used to evaluate the efficacy of using serum AAT concentration alone to detect AAT deficiency. RESULTS: Age, race, and sex had only slight effects on the median 95% serum protein concentration intervals of the 58,087 PiMM (wild type) phenotype specimens. Positive predictive values were calculated for the detection of potential deficiency phenotypes at different serum cutoff concentrations, aiding potential screening effort design. For example, the PiZZ deficiency phenotype (n = 814) could be detected at 99.5% sensitivity and 96.5% specificity using a cutoff of <= 85 mg/dL. However, at-risk specimens with two putative deleterious variants (Z, S, I, F, P, T, and Null variants) were detected with only 85.9% sensitivity at this cutoff (n = 1,661). Rare phenotype variants were observed in 2.5% of samples. CONCLUSIONS: This analysis provides novel information on serum AAT concentrations associated with different AAT phenotypes and provides insight into the severity of depression of AAT concentration in the presence of rare deficiency variants. Additionally, it allows for evaluation of efficacy of testing algorithms incorporating AAT serum concentration determination. PMID- 23632998 TI - Occult breast tumor reservoir: biological properties and clinical significance. AB - Small, occult, undiagnosed breast cancers are found at autopsy in up to 15.6 % of women dying from unrelated causes with an average of 7 % from eight separate studies. The mammographic detection threshold of breast tumors ranges from 0.88 to 1.66 cm in diameter based on the patient's age. Tumor growth rates, expressed as "effective doubling times," vary from 10 to >700 days. We previously reported two models, based on iterative analysis of these parameters, to describe the biologic behavior of undiagnosed, occult breast tumors. Our models facilitate interpretation of the Women's Health Initiative (WHI) and antiestrogen breast cancer prevention studies. A nude mouse xenograft model was used to validate our assumption that breast tumors grow in a log-linear fashion. We then used our previously reported occult tumor growth (OTG) and computer-simulated tumor growth models to analyze various clinical trial data. Parameters used in the OTG model included a 200-day effective doubling time, 7 % prevalence of occult tumors, and 1.16 cm detection threshold. These models had been validated by comparing predicted with observed incidence of breast cancer in eight different populations of women. Our model suggests that menopausal hormone therapy with estrogens plus a progestogen (E + P) in the WHI trial primarily promoted the growth of pre existing, occult lesions and minimally initiated de novo tumors. We provide a potential explanation for the lack of an increase in breast cancer incidence in the subgroup of women in the WHI who had not received E + P prior to randomization. This result may have reflected a leftward skew in the distribution of occult tumor doublings and insufficient time for stimulated tumors to reach the detection threshold. Our model predicted that estrogen alone reduced the incidence of breast cancer as a result of apoptosis. Understanding of the biology of occult tumors suggests that breast cancer "prevention" with antiestrogens or aromatase inhibitors represents early treatment rather than a reduction in de novo tumor formation. Our models suggest that occult, undiagnosed tumors are prevalent, grow slowly, and are the biologic targets of a hormone therapy in menopausal women and of antiestrogen therapy for prevention. PMID- 23633000 TI - Impact of Zn-Pb mining in the Olkusz ore district on the Permian aquifer (SW Poland). AB - Long-term extensive mining of Zn-Pb ores in the Olkusz area resulted in significant changes of water table levels and chemical composition of water in all aquifers in this area. Within the Permian aquifer, hydrochemical type of water evolved in two general stages. Short-term effect was freshening in the zones of contact with overlying the Triassic limestones and dolomites. Long-term effect was a change in flow pattern and, as a consequence, an inflow of naturally altered and antropogenically contaminated water from the Triassic aquifer into the Permian complex. This was especially intensive in densely fissured and fault zones. As a result of all these processes, hydrochemical type of water shifted from multi-ion types with various combinations of ions towards higher shares of sulphates, calcium and magnesium. PMID- 23633001 TI - Brief communication: beyond the South African cave paradigm--Australopithecus africanus from Plio-Pleistocene paleosol deposits at Taung. AB - Following the discovery of the "Taung Child" (Australopithecus africanus) in 1924 in the Buxton-Norlim Limeworks near Taung, the fossil-bearing deposits associated with the Dart and Hrdlicka pinnacles have been interpreted as the mined remnants of cave sediments that formed within the Plio-Pleistocene Thabaseek Tufa: either as a younger cave-fill or as contemporaneous carapace caves. When combined with the Plio-Pleistocene dolomitic cave deposits from the "Cradle of Humankind," a rather restricted view emerges that South African early hominins derived from cave deposits, whereas those of east and central Africa are derived from fluvio lacustrine and paleosol deposits. We undertook a sedimentological and paleomagnetic analysis of the pink-colored deposit (PCS) from which the "Taung Child" is purported to have derived and demonstrate that it is a calcrete, a carbonate-rich pedogenic sediment, which formed on the paleo-land surface. The deposit extends 100 s of meters laterally beyond the Dart and Hrdlicka Pinnacles where it is interbedded with the Thabaseek Tufa, indicating multiple episodes of calcrete development and tufa growth. The presence of in situ rhizoconcretions and insect trace fossils (Celliforma sp. and Coprinisphaera sp.) and the distinctive carbonate microfabric confirm that the pink deposit is a pedogenic calcrete, not a calcified cave sediment. Paleomagnetic and stratigraphic evidence indicates that a second, reversed polarity, fossil-bearing deposit (YRSS) is a younger fissure-fill formed within a solutional cavity of the normal polarity tufa and pink calcrete (PCS). These observations have implications for the dating, environment, and taphonomy of the site, and increase the likelihood of future fossil discoveries within the Buxton-Norlim Limeworks. PMID- 23633002 TI - Accessing local knowledge to identify where species of conservation concern occur in a tropical forest landscape. AB - Conventional biodiversity surveys play an important role in ensuring good conservation friendly management in tropical forest regions but are demanding in terms of expertise, time, and budget. Can local people help? Here, we illustrate how local knowledge can support low cost conservation surveys. We worked in the Malinau watershed, East Kalimantan, Indonesia, an area currently at risk of extensive forest loss. We selected eight species of regional conservation interest: rafflesia (Rafflesia spp.), black orchid (Coelogyne pandurata), sun bear (Helarctos malayanus), tarsier (Tarsius bancanus), slow loris (Nycticebus coucang), proboscis monkey (Nasalis larvatus), clouded leopard (Neofelis diardi/N. nebulosa), and orang-utan (Pongo pygmaeus). We asked 52 informants in seven villages if, where and when they had observed these species. We used maps, based on both geo-referenced and sketched features, to record these observations. Verification concerns and related issues are discussed. Evaluations suggest our local information is reliable. Our study took 6 weeks and cost about USD 5000. Extensive expert based field surveys across the same region would cost one or two orders of magnitude more. The records extend the known distribution for sun bear, tarsier, slow loris, and clouded leopard. Reports of rafflesia, proboscis monkey, and orang-utan are of immediate conservation significance. While quality concerns should never be abandoned, we conclude that local people can help expand our knowledge of large areas in an effective, reliable, and low cost manner and thus contribute to improved management. PMID- 23633003 TI - Impact of diabetes on overall and cancer-specific mortality in colorectal cancer patients. AB - PURPOSE: Diabetes is associated with increased risk of developing colorectal cancer (CRC), but its effect on overall and cancer-specific mortality in CRC patients has been little investigated. The aim of this study was to assess the influence of diabetes on overall and cancer-specific mortality in Italian CRC patients. METHODS: Cases of adult (>=15 years) CRC, diagnosed in 2003-2005, most followed-up to the end of 2008, were randomly selected from the Italian Cancer Registries database. Diabetic status, sex, age, tumor stage, subsite, treatment, morphology, and grade were obtained by consultation of patient clinical records. Poisson multivariable regression models, adjusted for potential confounding variables, were used to estimate hazard ratios (HRs) for all-cause and CRC specific mortality, according to diabetic status. RESULTS: A total of 1,039 CRC cases with known fasting glucose or diabetic status, archived in 7 cancer registries, was analyzed. Compared to non-diabetics, diabetics (specific diagnosis or glucose >=126 mg/dl) were older and less likely to receive adjuvant therapy. Diabetics were at higher risk of all-cause death [HR 1.41; 95 % confidence interval (CI) 1.18-1.70] and CRC death (HR 1.36; 95 % CI 1.11-1.67), with no differences by sex or subsite. CONCLUSIONS: Diabetes was significantly associated with increased overall and CRC-specific mortality. Our findings indicate that diabetes is a negative prognostic factor for CRC and suggest that in patients with CRC, diabetes prevention and treatments that stabilize the condition and control its complications might reduce mortality. Further studies are required to ascertain the mechanisms linking diabetes to greater mortality in CRC patients. PMID- 23633004 TI - Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. AB - BACKGROUND: CD22 expression occurs in >90% of patients with acute lymphocytic leukemia (ALL). Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, is active in ALL. METHODS: Patients with refractory-relapsed ALL received treatment with inotuzumab. The first 49 patients received single-dose, intravenous inotuzumab at doses of 1.3 to 1.8 mg/m2 every 3 to 4 weeks. In the next 41 patients, the schedule was modified to inotuzumab weekly at a dose of 0.8 mg/m2 on day 1 and at a dose of 0.5 mg/m2 on days 8 and 15, every 3 to 4 weeks, based on higher in vitro efficacy with more frequent exposure. RESULTS: Ninety patients were treated; 68% were in salvage 2 or beyond. Overall, 17 patients (19%) achieved a complete response (CR), 27 (30%) had a CR with no platelet recovery (CRp), and 8 (9%) had a bone marrow CR (no recovery of counts), for an overall response rate of 58%. Response rates were similar for single-dose and weekly dose inotuzumab (57% vs 59%, respectively). The median survival was 6.2 months overall, 5.0 months with the single-dose schedule, and 7.3 months with the weekly dose schedule. The median survival was 9.2 months for patients in salvage 1 (37% at 1 year), 4.3 months for patients in salvage 2, and 6.6 months for patients in salvage 3 or later. The median remission duration was 7 months. Reversible bilirubin elevation, fever, and hypotension were observed less frequently on the weekly dose. In total, 36 of 90 patients (40%) underwent allogeneic stem cell transplantation. Veno-occlusive disease was noted in 6 of 36 patients after stem cell transplantation (17%), was less frequent after the weekly schedule (7%), and with less alkylators in the preparative regimen. CONCLUSIONS: Inotuzumab single-agent therapy was highly active, safe, and convenient in patients with refractory-relapsed ALL. A weekly dose schedule appeared to be equally effective and less toxic than a single-dose schedule. PMID- 23633006 TI - Adolescent idiopathic scoliosis. PMID- 23633005 TI - Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: diagnostic study. AB - OBJECTIVES: To quantify the diagnostic accuracy of selected inflammatory markers in addition to symptoms and signs for predicting pneumonia and to derive a diagnostic tool. DESIGN: Diagnostic study performed between 2007 and 2010. Participants had their history taken, underwent physical examination and measurement of C reactive protein (CRP) and procalcitonin in venous blood on the day they first consulted, and underwent chest radiography within seven days. SETTING: Primary care centres in 12 European countries. PARTICIPANTS: Adults presenting with acute cough. MAIN OUTCOME MEASURES: Pneumonia as determined by radiologists, who were blind to all other information when they judged chest radiographs. RESULTS: Of 3106 eligible patients, 286 were excluded because of missing or inadequate chest radiographs, leaving 2820 patients (mean age 50, 40% men) of whom 140 (5%) had pneumonia. Re-assessment of a subset of 1675 chest radiographs showed agreement in 94% (kappa 0.45, 95% confidence interval 0.36 to 0.54). Six published "symptoms and signs models" varied in their discrimination (area under receiver operating characteristics curve (ROC) ranged from 0.55 (95% confidence interval 0.50 to 0.61) to 0.71 (0.66 to 0.76)). The optimal combination of clinical prediction items derived from our patients included absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever, with an ROC area of 0.70 (0.65 to 0.75). Addition of CRP at the optimal cut off of >30 mg/L increased the ROC area to 0.77 (0.73 to 0.81) and improved the diagnostic classification (net reclassification improvement 28%). In the 1556 patients classified according to symptoms, signs, and CRP >30 mg/L as "low risk" (<2.5%) for pneumonia, the prevalence of pneumonia was 2%. In the 132 patients classified as "high risk" (>20%), the prevalence of pneumonia was 31%. The positive likelihood ratio of low, intermediate, and high risk for pneumonia was 0.4, 1.2, and 8.6 respectively. Measurement of procalcitonin added no relevant additional diagnostic information. A simplified diagnostic score based on symptoms, signs, and CRP >30 mg/L resulted in proportions of pneumonia of 0.7%, 3.8%, and 18.2% in the low, intermediate, and high risk group respectively. CONCLUSIONS: A clinical rule based on symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough performed best in patients with mild or severe clinical presentation. Addition of CRP concentration at the optimal cut off of >30 mg/L improved diagnostic information, but measurement of procalcitonin concentration did not add clinically relevant information in this group. PMID- 23633007 TI - German transplant group fights to regain public trust. PMID- 23633008 TI - Orlistat: should we worry about liver inflammation? PMID- 23633009 TI - New trials of gene therapy for heart failure are announced. PMID- 23633011 TI - Biotinyl moiety-selective polymer films with highly ordered macropores. AB - Macroporous polymer films with long-range uniformity and biotinyl-moiety selective recognition sites have been developed. A hierarchical molecular imprinting strategy afforded significant enhancements in quartz crystal microbalance (QCM) sensitivities towards biotinylated compounds. PMID- 23633012 TI - Glycosylation profiling of therapeutic antibodies in serum samples using a microfluidic CD platform and MALDI-MS. AB - The serum clearance rate of therapeutic antibodies is important as it affects the clinical efficacy, required dose, and dose frequency. The glycosylation of antibodies has in some studies been shown to have an impact on the elimination rates in vivo. Monitoring changes to the glycan profiles in pharmacokinetics studies can reveal whether the clearance rates of the therapeutic antibodies depend on the different glycoforms, thereby providing useful information for improvement of the drugs. In this paper, a novel method for glycosylation analysis of therapeutic antibodies in serum samples is presented. A microfluidic compact-disc (CD) platform in combination with MALDI-MS was used to monitor changes to the glycosylation profiles of samples incubated in vitro. Antibodies were selectively purified from serum using immunoaffinity capture on immobilized target antigens. The glycans were enzymatically released, purified, and finally analyzed by MALDI-TOF-MS. To simulate changes to glycan profiles after administration in vivo, a therapeutic antibody was incubated in serum with the enzyme alpha1-2,3 mannosidase to artificially reduce the amount of the high mannose glycoforms. Glycan profiles were monitored at specific intervals during the incubation. The relative abundance of the high mannose 5 glycoform was clearly found to decrease and, simultaneously, that of high mannose 4 increased over the incubation period. The method can be performed in a rapid, parallel, and automated fashion for glycosylation profiling consuming low amounts of samples and reagents. This can contribute to less labor work and reduced cost of the studies of therapeutic antibodies glycosylation in vitro and in vivo. PMID- 23633014 TI - Kinetic and thermodynamic control of protonation in atmospheric pressure chemical ionization. AB - For p-(dimethylamino)chalcone (p-DMAC), the N atom is the most basic site in the liquid phase, whereas the O atom possesses the highest proton affinity in the gas phase. A novel and interesting observation is reported that the N- and O protonated p-DMAC can be competitively produced in atmospheric pressure chemical ionization (APCI) with the change of solvents and ionization conditions. In neat methanol or acetonitrile, the protonation is always under thermodynamic control to form the O-protonated ion. When methanol/water or acetonitrile/water was used as the solvent, the protonation is kinetically controlled to form the N protonated ion under conditions of relatively high infusion rate and high concentration of water in the mixed solvent. The regioselectivity of protonation of p-DMAC in APCI is probably attributed to the bulky solvent cluster reagent ions (S(n)H(+)) and the analyte having different preferred protonation sites in the liquid phase and gas phase. PMID- 23633013 TI - Unusual fragmentation pathways in collagen glycopeptides. AB - Collagens are the most abundant glycoproteins in the body. One characteristic of this protein family is that the amino acid sequence consists of repeats of three amino acids -(X-Y-Gly)n. Within this motif, the Y residue is often 4 hydroxyproline (HyP) or 5-hydroxylysine (HyK). Glycosylation in collagen occurs at the 5-OH group in HyK in the form of two glycosides, galactosylhydroxylysine (Gal-HyK) and glucosyl galactosylhydroxylysine (GlcGal-HyK). In collision induced dissociation (CID), collagen tryptic glycopeptides exhibit unexpected gas-phase dissociation behavior compared to typical N- and O-linked glycopeptides (i.e., in addition to glycosidic bond cleavages, extensive cleavages of the amide bonds are observed). The Gal- or GlcGal- glycan modifications are largely retained on the fragment ions. These features enable unambiguous determination of the amino acid sequence of collagen glycopeptides and the location of the glycosylation site. This dissociation pattern was consistent for all analyzed collagen glycopeptides, regardless of their length or amino acid composition, collagen type or tissue. The two fragmentation pathways-amide bond and glycosidic bond cleavage-are highly competitive in collagen tryptic glycopeptides. The number of ionizing protons relative to the number of basic sites (i.e., Arg, Lys, HyK, and N-terminus) is a major driving force of the fragmentation. We present here our experimental results and employ quantum mechanics calculations to understand the factors enhancing the labile character of the amide bonds and the stability of hydroxylysine glycosides in gas phase dissociation of collagen glycopeptides. PMID- 23633015 TI - N-terminal peptide sequence repetition influences the kinetics of backbone fragmentation: a manifestation of the Jahn-Teller effect? AB - Analysis of large (>10,000 entries) databases consisting of high-resolution tandem mass spectra of peptide dications revealed with high statistical significance (P < 1[Symbol: see text]10(-3)) that peptides with non-identical first two N-terminal amino acids undergo cleavages of the second peptide bond at higher rates than repetitive sequences composed of the same amino acids (i.e., in general AB- and BA- bonds cleave more often than AA- and BB- bonds). This effect seems to depend upon the collisional energy, being stronger at lower energies. The phenomenon is likely to indicate the presence of the diketopiperazine structure for at least some b2 (+) ions. When consisting of two identical amino acids, these species should form through intermediates that have a symmetric geometry and, thus, must be subject to the Jahn-Teller effect that reduces the stability of such systems. PMID- 23633017 TI - Particle production in reflection and transmission mode laser ablation: implications for laserspray ionization. AB - Particles were ablated from laser desorption and inlet ionization matrix thin films with a UV laser in reflection and transmission geometries. Particle size distributions were measured with a combined scanning mobility particle sizer (SMPS) and aerodynamic particle sizer (APS) system that measured particles in the size range from 10 nm to 20 MUm. The matrixes investigated were 2,5 dihydroxybenzoic acid (DHB), alpha-cyano-4-hydroxycinnamic acid (CHCA), sinapic acid (SA), 2,5-dihydroxy-acetophenone (DHAP), and 2-nitrophloroglucinol (NPG). Nanoparticles with average diameters between 20 and 120 nm were observed in both transmission and reflection geometry. The particle mass distribution was significantly different in reflection and transmission geometry. In reflection geometry, approximately equal mass was distributed between particles in the 20 to 450 nm range of diameters and particles in the 450 nm to 1.5 MUm diameter range. In transmission mode, the particle mass distribution was dominated by large particles in the 2 to 20 MUm diameter range. Ablation of inlet ionization matrices DHAP and NPG produced particles that were 3 to 4 times smaller compared with the other matrices. The results are consistent with ion formation by nanoparticle melting and breakup or melting and breakup of the large particles through contact with heated inlet surfaces. ? PMID- 23633016 TI - Electron transfer dissociation of photolabeled peptides. Backbone cleavages compete with diazirine ring rearrangements. AB - Gas-phase conformations and electron transfer dissociations of pentapeptide ions containing the photo-Leu residue (L*) were studied. Exhaustive conformational search including molecular dynamics force-field, semi-empirical, ab initio, and density functional theory calculations established that the photo-Leu residue did not alter the gas-phase conformations of (GL*GGK + 2H)(2+) and (GL*GGK-NH2 + H)(+) ions, which showed the same conformer energy ranking as the unmodified Leu containing ions. This finding is significant in that it simplifies conformational analysis of photo-labeled peptide ions. Electron transfer dissociation mass spectra of (GL*GGK + 2H)(2+), (GL*GGK-NH2 + 2H)(2+),(GL*GGKK + 2H)(2+), (GL*GLK + 2H)(2+), and (GL*LGK + 2H)(2+) showed 16 %-21 % fragment ions originating by radical rearrangements and cleavages in the diazirine ring. These side-chain dissociations resulted in eliminations of N2H3, N2H4, [N2H5], and [NH4O] neutral fragments and were particularly abundant in long-lived charge-reduced cation radicals. Deuterium labeling established that the neutral hydrazine molecules mainly contained two exchangeable and two nonexchangeable hydrogen atoms from the peptide and underwent further H/D exchange in an ion-molecule complex. Electron structure calculations on the charge-reduced ions indicated that the unpaired electron was delocalized between the diazirine and amide pi* electronic systems in the low electronic states of the cation-radicals. The diazirine moiety in GL*GGK-NH2was calculated to have an intrinsic electron affinity of 1.5 eV, which was further increased by the Coulomb effect of the peptide positive charge. Mechanisms are proposed for the unusual elimination of hydrazine from the photo labeled peptide ions. PMID- 23633018 TI - Collision-induced dissociation fragmentation inside disulfide C-terminal loops of natural non-tryptic peptides. AB - Collision-induced dissociation (CID) spectra of long non-tryptic peptides are usually quite complicated and rather difficult to interpret. Disulfide bond formed by two cysteine residues at C-terminus of frog skin peptides precludes one to determine sequence inside the forming loop. Thereby, chemical modification of S-S bonds is often used in "bottom up" sequencing approach. However, low-energy CID spectra of natural non-tryptic peptides with C-terminal disulfide cycle demonstrate an unusual fragmentation route, which may be used to elucidate the "hidden" C-terminal sequence. Low charge state protonated molecules experience peptide bond cleavage at the N-terminus of C-terminal cysteine. The forming isomeric acyclic ions serve as precursors for a series of b-type ions revealing sequence inside former disulfide cycle. The reaction is preferable for peptides with basic lysine residues inside the cycle. It may also be activated by acidic protons of Asp and Glu residues neighboring the loop. The observed cleavages may be quite competitive, revealing the sequence inside disulfide cycle, although S-S bond rupture does not occur in this case. PMID- 23633019 TI - Minimization of fragmentation and aggregation by laser desorption laser ionization mass spectrometry. AB - Measuring average quantities in complex mixtures can be challenging for mass spectrometry, as it requires ionization and detection with nearly equivalent cross-section for all components, minimal matrix effect, and suppressed signal from fragments and aggregates. Fragments and aggregates are particularly troublesome for complex mixtures, where they can be incorrectly assigned as parent ions. Here we study fragmentation and aggregation in six aromatic model compounds as well as petroleum asphaltenes (a naturally occurring complex mixture) using two laser-based ionization techniques: surface assisted laser desorption ionization (SALDI), in which a single laser desorbs and ionizes solid analytes; and laser ionization laser desorption mass spectrometry (L(2)MS), in which desorption and ionization are separated spatially and temporally with independent lasers. Model compounds studied include molecules commonly used as matrices in single laser ionization techniques such as matrix assisted laser desorption ionization (MALDI). We find significant fragmentation and aggregation in SALDI, such that individual fragment and aggregate peaks are typically more intense than the parent peak. These fragment and aggregate peaks are expected in MALDI experiments employing these compounds as matrices. On the other hand, we observe no aggregation and only minimal fragmentation in L(2)MS. These results highlight some advantages of L(2)MS for analysis of complex mixtures such as asphaltenes. PMID- 23633020 TI - Genome-wide association analysis implicates elastic microfibrils in the development of nonsyndromic striae distensae. PMID- 23633021 TI - Transcriptome profiling identifies HMGA2 as a biomarker of melanoma progression and prognosis. AB - The genetic alterations contributing to melanoma pathogenesis are incompletely defined, and few independent prognostic features have been identified beyond the clinicopathological characteristics of the primary tumor. We used transcriptome profiling of 46 primary melanomas, 12 melanoma metastases, and 16 normal skin (N) samples to find genes associated with melanoma development and progression. Results were confirmed using immunohistochemistry and real-time PCR and replicated in an independent set of 330 melanomas using AQUA analysis of tissue microarray (TMA). Transcriptome profiling revealed that transcription factor HMGA2, previously unrecognized in melanoma pathogenesis, is significantly upregulated in primary melanoma and metastases (P-values=1.2 * 10(-7) and 9 * 10( 5)) compared with N. HMGA2 overexpression is associated with BRAF/NRAS mutations (P=0.0002). Cox proportional hazard regression model and log-rank test showed that HMGA2 is independently associated with disease-free survival (hazard ratio (HR)=6.3, 95% confidence interval (CI)=1.8-22.3, P=0.004), overall survival (OS) (stratified log-rank P=0.008), and distant metastases-free survival (HR=6.4, 95% CI=1.4-29.7, P=0.018) after adjusting for American Joint Committee on Cancer (AJCC) stage and age at diagnosis. Survival analysis in an independent replication TMA of 330 melanomas confirmed the association of HMGA2 expression with OS (P=0.0211). Our study implicates HMGA2 in melanoma progression and demonstrates that HMGA2 overexpression can serve as an independent predictor of survival in melanoma. PMID- 23633022 TI - Barrier abnormality due to ceramide deficiency leads to psoriasiform inflammation in a mouse model. AB - It has been recognized that ceramides are decreased in the epidermis of patients with psoriasis and atopic dermatitis. Here, we generated Sptlc2 (serine palmitoyltransferase long-chain base subunit 2)-targeted mice (SPT-cKO mice), thereby knocking out serine palmitoyltransferase (SPT), the critical enzyme for ceramide biosynthesis, in keratinocytes. SPT-cKO mice showed decreased ceramide levels in the epidermis, which impaired water-holding capacity and barrier function. From 2 weeks of age, they developed skin lesions with histological aberrations including hyperkeratosis, acanthosis, loss of the granular layer, and inflammatory cell infiltrates. Epidermal Langerhans cells showed persistent activation and enhanced migration to lymph nodes. Skin lesions showed upregulation of psoriasis-associated genes, such as IL-17A, IL-17F, IL-22, S100A8, S100A9, and beta-defensins. In the skin lesions and draining lymph nodes, there were increased numbers of gammadelta T cells that produced IL-17 (gammadelta-17 cells), most of which also produced IL-22, as do Th17 cells. Furthermore, IL-23-producing CD11c(+) cells were observed in the lesions. In vivo treatment of SPT-cKO mice with an anti-IL-12/23p40 antibody ameliorated the skin lesions and reduced the numbers of gammadelta-17 cells. Therefore, we conclude that a ceramide deficiency in the epidermis leads to psoriasis-like lesions in mice, probably mediated by IL-23-dependent IL-22-producing gammadelta-17 cells. PMID- 23633023 TI - ST2 regulates allergic airway inflammation and T-cell polarization in epicutaneously sensitized mice. AB - IL-33 is an inducer of proinflammatory and T-helper type 2 (Th2) cytokines, which have an important role in atopic dermatitis (AD) and allergic asthma. ST2 is a specific receptor for IL-33 and is expressed on Th2 cells, eosinophils and mast cells. A murine model of AD was used to characterize the role of ST2 in allergen induced skin inflammation and allergic asthma. ST2-/- and wild-type (WT) mice were epicutaneously sensitized with ovalbumin (OVA) and staphylococcal enterotoxin B, and intranasally challenged with OVA. ST2-/- mice exhibited increased production of IFNgamma and increased number of CD8(+) T cells in the sensitized skin and in the airways compared with WT mice. The number of eosinophils was decreased, and Th2 cytokines were downregulated in the airways of epicutaneously sensitized ST2-/- mice compared with WT controls. However, dermal eosinophil numbers were as in WT, and the levels of Th2 cytokines were even elevated in the sensitized skin of ST2-/- mice. ST2-/- mice had elevated numbers of neutrophils and macrophages and increased levels of proinflammatory cytokines in the sensitized skin. The role of ST2 differs between different target tissues: ST2 is dispensable for the development of Th2 response in the sensitized skin, whereas it is a main inducer of Th2 cytokines in asthmatic airways. PMID- 23633024 TI - Six mutations in AAGAB confirm its pathogenic role in Chinese punctate palmoplantar keratoderma patients. PMID- 23633025 TI - Efficient photo-driven hydrogen evolution by binuclear nickel catalysts of different coordination in noble-metal-free systems. AB - Exploration of the complex Ni2(MBD)4 (MBD = 2-mercaptobenzimidazole) (C1) having different coordinated Ni atoms as a photocatalyst for hydrogen evolution is made. For comparison, the bimetallic Ni2(MBT)4 (MBT = 2-mercaptobenthiazole) (C2) complex with the same coordinated Ni atoms was synthesized. Both of the complexes have been successfully constructed for photo-induced hydrogen production using organic dyes as photosensitizers and triethanolamine (TEOA) as the effective electron donor by visible light (>400 nm) in acetonitrile-water solution. The time-dependence of H2 generation and DFT computational studies demonstrate that the complex C1 is more active than C2 for H2 evolution. The mechanisms of photocatalytic hydrogen generation for C1 and C2 involve different protonation sites resulting from the differences between the two structures. PMID- 23633026 TI - Smoking duration before first childbirth: an emerging risk factor for breast cancer? Results from 302,865 Norwegian women. AB - PURPOSE: Recently, The International Agency for Research on Cancer classified cigarette smoking as possibly carcinogenic to the human breast. Since some new cohort studies have suggested that this risk is confined to women who started to smoke before first childbirth, we wanted to examine the association between smoking and breast cancer, with a focus on time of smoking initiation in relation to the first childbirth. METHODS: We followed 302,865 Norwegian women born between 1899 and 1975, recruited from 1974 to 2003, by linkage to national registries through December 2007. We used Cox proportional hazard models to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: During more than 4.1 million person-years of follow-up, we ascertained 7,490 cases of primary invasive breast cancer. Compared with never smokers, ever smokers had a 15% (HR = 1.15, 95% CI 1.10-1.21) increased risk of breast cancer overall and also a significantly increased risk of breast cancer in the three most exposed categories of age at smoking initiation (parous women), number of cigarettes smoked per day, years of smoking duration and number of pack-years. Ever smokers who started to smoke more than 1 year after the first childbirth had not an increased risk (HR = 0.93, 95% CI 0.86-1.02), while those who initiated smoking more than 10 years before their first childbirth had a 60% (HR = 1.60, 95% CI 1.42-1.80) increased risk of breast cancer, compared with never smokers. CONCLUSION: Smoking initiation before the first childbirth increases the risk of breast cancer. PMID- 23633029 TI - Dissecting the structural determinants for the difference in mechanical stability of silk and amyloid beta-sheet stacks. AB - Stacking of beta-sheets results in a protein super secondary structure with remarkable mechanical properties. beta-Stacks are the determinants of a silk fiber's resilience and are also the building blocks of amyloid fibrils. While both silk and amyloid-type crystals are known to feature a high resistance against rupture, their structural and mechanical similarities and particularities are yet to be fully understood. Here, we systematically compare the rupture force and stiffness of amyloid and spider silk poly-alanine beta-stacks of comparable sizes using Molecular Dynamics simulations. We identify the direction of force application as the primary determinant of the rupture strength; beta-sheets in silk are orientated along the fiber axis, i.e. the pulling direction, and consequently require high forces in the several nanoNewton range for shearing beta-strands apart, while beta-sheets in amyloid are oriented vertically to the fiber, allowing a zipper-like rupture at sub-nanoNewton forces. A secondary factor rendering amyloid beta-stacks softer and weaker than their spider silk counterparts is the sub-optimal side-chain packing between beta-sheets due to the sequence variations of amyloid-forming proteins as opposed to the perfectly packed poly-alanine beta-sheets of silk. Taken together, amyloid fibers can reach the stiffness of silk fibers in spite of their softer and weaker beta-sheet arrangement as they are missing a softening amorphous matrix. PMID- 23633027 TI - Intrathecal administration of cyclic AMP response element-binding protein antisense oligonucleotide attenuates neuropathic pain after peripheral nerve injury and decreases the expression of N-methyl-D-aspartic receptors in mice. AB - The aim of the present study was to determine whether the cAMP response element binding protein (CREB) contributes to neuropathic pain during development stage. Adult (7-8 weeks old) male C57BL/6 mice weighing 20-25 g were used. Intrathecal catheter implantation and chronic constriction of the sciatic nerve of the animals were performed. Western blotting and reverse transcription PCR experiments were carried out. Our study demonstrated that the expression of spinal NMDAR after peripheral nerve injury was modulated by central CREB. Chronic constriction nerve injury (CCI) in mice induced thermal hyperalgesia and mechanical allodynia. The increase of NR1 and NR2B subunits of the NMDAR was significantly diminished by intrathecal administration of the CREB antisense oligonucleotide against CREB and pCREB. Additionally, nociceptive behavior induced by CCI was attenuated by intrathecal administration of the CREB antisense oligonucleotide during the period of injection, and the above effects of relieving pain lasted at least 12 days following the last injection. Our results suggested that central functional pCREB may contribute to the development of neuropathic pain and regulate the expression of the NR1 and NR2B subunits of the NMDAR in the process. PMID- 23633030 TI - Hospital variation in patient-reported outcomes at the level of EQ-5D dimensions: evidence from England. AB - BACKGROUND: The English Department of Health has introduced routine collection of patient-reported outcome data for selected surgical procedures to facilitate patient choice and increase hospital accountability. However, using aggregate health outcome scores, such as EQ-5D utilities, for performance assessment purposes causes information loss and raises statistical and normative concerns. OBJECTIVES: . For hip replacement surgery, we explore a) the change in patient reported outcomes between baseline and follow-up on 5 health dimensions (EQ-5D), b) the extent to which treatment impact varies across hospitals, and c) the extent to which hospital performance on EQ-5D dimensions is correlated with performance on the EQ-5D utility index. METHODS: . We combine information on pre- and postoperative EQ-5D outcomes with routine inpatient data for the financial year 2009-2010. The sample consists of 21,000 patients in 153 hospitals. We employ hierarchical ordered probit risk-adjustment models that recognize the multilevel nature of the data and the response distributions. The treatment impact is modeled as a random coefficient that varies at the hospital level. We obtain hospital-specific empirical Bayes (EB) estimates of this coefficient. We estimate separate models for each EQ-5D dimension and the EQ-5D utility index and analyze correlations of EB estimates across these. RESULTS: . Hospital treatment is associated with improvements in all EQ-5D dimensions. Variability in treatment impact is most pronounced on the mobility and usual activities dimensions. Conversely, only pain/discomfort and anxiety/depression correlate well with performance measures based on utilities. This leads to different assessments of hospital performance across metrics. CONCLUSIONS: . Our results indicate which hospitals are better than others in improving health across particular EQ-5D dimensions. We demonstrate the importance of evaluating dimensions of the EQ-5D separately for the purposes of hospital performance assessment. PMID- 23633031 TI - Species identification of Chinese medicinal plant Fallopia multiflora (Thunb.) Haraldson by suppression subtraction hybridization. AB - Fallopia multiflora (Thunb.) Haraldson, a traditional Chinese medicinal plant, has been extensively used in preparations of herbal medicine, health products and personal hygiene products. However, the clinical safety and efficiency of F. multiflora (Thunb.) Haraldson is impaired because of the existence of various adulterants. In this study, genomic DNA (gDNA) suppression subtraction hybridization (SSH) was used to authenticate F. multiflora (Thunb.) Haraldson from its adulterants. First, differential gDNA fragments between F. multiflora (Thunb.) Haraldson and its most closely related species F. multiflora var. ciliinervis (Nakai) Yonek. & H. Ohashi by SSH were identified. The differential fragments were then hybridized with arrays constructed from multiple whole genomes of several species (adulterants and/or closely related plants) to screen for the unique gDNA fragments representing F. multiflora (Thunb.) Haraldson. The unique gDNA fragments could be used to design species-specific primers for the identification of F. multiflora (Thunb.) Haraldson. Using SSH, we obtained four differential gDNA fragments, and four pairs of primers were designed. The designed primers could differentiate F. multiflora (Thunb.) Haraldson from its adulterants and/or closely related species via PCR. The results confirmed that the SSH is an efficient method for screening and designing species-specific primers. PMID- 23633032 TI - Differing effects of adjuvant chemotherapy according to BRCA1 nuclear expression in gastric cancer. AB - BACKGROUND: We aimed to investigate the role of BRCA1 nuclear expression in sporadic gastric cancer; currently, the role remains unknown. METHODS: Patients with gastric cancer who received curative operation with D2 dissection were enrolled in this study. Adjuvant chemotherapy was administered at the discretion of the physician. According to BRCA1 nuclear expression analysis by immunohistochemistry (IHC) on tissue microarrays using anti-BRCA1 antibody MS110, BRCA1 expression was classified as negative, low expression, and high expression. RESULTS: Among 318 cases, 155 cases (48.7 %) were identified as BRCA1-negative by IHC and 96 cases (30.2 %) revealed BRCA1 low expression, 67 cases (21.0 %) showed BRCA1 high expression. The negative or reduced expression of BRCA1 was more frequent in more advanced-stage disease (p < 0.001) and was associated with perineural invasion (p = 0.032). Disease-free survival (DFS) was significantly decreased with reduced BRCA1 expression (p = 0.027). This tendency was also observed in overall survival (OS), although the difference was not significant. The poorer prognosis of BRCA1-negative tumors was overcome through adjuvant chemotherapy. The benefit of adjuvant chemotherapy for DFS and OS in stage III was enhanced only in BRCA1-negative tumors (p < 0.001, p < 0.001, respectively), but not in BRCA1-positive tumors (p = 0.236, p = 0.148, respectively). CONCLUSION: The reduction of BRCA1 nuclear expression is associated with advanced stage and perineural invasion. Moreover, negative BRCA1 nuclear expression is a predictive marker regarding the benefit of adjuvant chemotherapy in sporadic gastric cancer; these novel findings are of great importance, and further, larger studies are warranted. PMID- 23633033 TI - Anticipatory behavior in captive bottlenose dolphins (Tursiops truncatus): a preliminary study. AB - This study examined whether a group of captive dolphins displayed anticipatory behaviors before shows. In general, anticipation occurs when an event is being predicted. Anticipatory behavior is defined by Spruijt et al. as "responses elicited by rewarding stimuli that lead to and facilitate consummatory behavior (Spruijt et al., 2001, Appl Anim Behav Sci 72: 145-171)." Using behavioral recording techniques, the behaviors, breathing rates, space use, and activity levels of all dolphins was recorded both before and after shows. Analysis compared pre- and post-show data in addition to looking at gradual changes in behavior prior to show sessions. Significant changes were found in the behavior and space use prior to sessions with the dolphins decreasing their activity levels, spending more time at the surface and moving towards the starting point of a session before it took place. There was a significant increase in the vigilant behavior before sessions, indicating that the dolphins were becoming more alert towards their trainers and other activities around the pool. This result mirrors previous research with other captive species; as feeding time was approaching, the animals seemed to "wait" and look for the handlers. Any behavioral change that may be regarded as anticipatory behavior was not evidently abnormal or stereotypic in nature, and breathing rates remained stable indicating that the animals do not perceive the shows as stressful or as an aversive experience. Additionally, behavior and level of activity remained stable following the sessions. PMID- 23633035 TI - [Reconstruction of perforations of the nasal septum with a modified dorsal pedicled nasal floor transposition graft]. PMID- 23633036 TI - West Nile virus polyradiculitis with good prognosis. PMID- 23633034 TI - The detection and implication of genome instability in cancer. AB - Genomic instability is a hallmark of cancer that leads to an increase in genetic alterations, thus enabling the acquisition of additional capabilities required for tumorigenesis and progression. Substantial heterogeneity in the amount and type of instability (nucleotide, microsatellite, or chromosomal) exists both within and between cancer types, with epithelial tumors typically displaying a greater degree of instability than hematological cancers. While high-throughput sequencing studies offer a comprehensive record of the genetic alterations within a tumor, detecting the rate of instability or cell-to-cell viability using this and most other available methods remains a challenge. Here, we discuss the different levels of genomic instability occurring in human cancers and touch on the current methods and limitations of detecting instability. We have applied one such approach to the surveying of public tumor data to provide a cursory view of genome instability across numerous tumor types. PMID- 23633037 TI - Treatment outcome of late steroid-resistant nephrotic syndrome: a study by the Midwest Pediatric Nephrology Consortium. AB - BACKGROUND: Idiopathic nephrotic syndrome (NS) in children is classified as steroid sensitive or steroid resistant. Steroid sensitivity typically portends a low risk of permanent renal failure. However, some initially steroid-sensitive patients later develop steroid resistance. These patients with late steroid resistance (LSR) are often treated with immunosuppressant medications, but the effect of these additional drugs on the long-term prognosis of LSR is still unknown. METHODS: A retrospective chart review was performed on patients diagnosed with idiopathic NS and subsequent LSR during the 8-year study period from 2002 up to and including 2009, with a minimum of 2 years of follow-up. Primary outcome measures were proteinuria and renal function. RESULTS: A total of 29 patients were classified as having LSRNS. The majority of patients received treatment with calcineurin inhibitors and/or mycophenolate mofetil. Seven patients received three or more non-steroid immunosuppressant medications. Sustained complete or partial remission was achieved in 69 % of patients. Three developed end-stage renal disease, and all others maintained normal renal function. There were 13 episodes of serious adverse events, none of which were fatal or irreversible. CONCLUSION: Most patients with LSRNS responded to immunosuppressive therapy by reduction or resolution of proteinuria and preservation of renal function. The results suggest that immunosuppressive treatment is a viable option in NS patients who develop LSR. PMID- 23633040 TI - High-efficiency removal of phytic acid in soy meal using two-stage temperature induced Aspergillus oryzae solid-state fermentation. AB - BACKGROUND: Phytic acid of soy meal (SM) could influence protein and important mineral digestion of monogastric animals. Aspergillus oryzae (ATCC 9362) solid state fermentation was applied to degrade phytic acid in SM. Two-stage temperature fermentation protocol was investigated to increase the degradation rate. The first stage was to maximize phytase production and the second stage was to realize the maximum enzymatic degradation. RESULTS: In the first stage, a combination of 41% moisture, a temperature of 37 degrees C and inoculum size of 1.7 mL in 5 g substrate (dry matter basis) favored maximum phytase production, yielding phytase activity of 58.7 U, optimized via central composite design. By the end of second-stage fermentation, 57% phytic acid was degraded from SM fermented at 50 degrees C, compared with 39% of that fermented at 37 degrees C. The nutritional profile of fermented SM was also studied. Oligosaccharides were totally removed after fermentation and 67% of total non-reducing polysaccharides were decreased. Protein content increased by 9.5%. CONCLUSION: Two-stage temperature protocol achieved better phytic acid degradation during A. oryzae solid state fermentation. The fermented SM has lower antinutritional factors (phytic acid, oligosaccharides and non-reducing polysaccharides) and higher nutritional value for animal feed. PMID- 23633041 TI - "It's just a muscle sprain". PMID- 23633038 TI - Ginseng saponin metabolite 20(S)-protopanaxadiol inhibits tumor growth by targeting multiple cancer signaling pathways. AB - Plant-derived active constituents and their semi-synthetic or synthetic analogs have served as major sources of anticancer drugs. 20(S)-protopanaxadiol (PPD) is a metabolite of ginseng saponin of both American ginseng (Panax quinquefolius L.) and Asian ginseng (Panax ginseng C.A. Meyer). We previously demonstrated that ginsenoside Rg3, a glucoside precursor of PPD, exhibits anti-proliferative effects on HCT116 cells and reduces tumor size in a xenograft model. Our subsequent study indicated that PPD has more potent antitumor activity than that of Rg3 in vitro although the mechanism underlying the anticancer activity of PPD remains to be defined. Here, we investigated the mechanism underlying the anticancer activity of PPD in human cancer cells in vitro and in vivo. PPD was shown to inhibit growth and induce cell cycle arrest in HCT116 cells. The in vivo studies indicate that PPD inhibits xenograft tumor growth in athymic nude mice bearing HCT116 cells. The xenograft tumor size was significantly reduced when the animals were treated with PPD (30 mg/kg body weight) for 3 weeks. When the expression of previously identified Rg3 targets, A kinase (PRKA) anchor protein 8 (AKAP8L) and phosphatidylinositol transfer protein alpha (PITPNA), was analyzed, PPD was shown to inhibit the expression of PITPNA while upregulating AKAP8L expression in HCT116 cells. Pathway-specific reporter assays indicated that PPD effectively suppressed the NF-kappaB, JNK and MAPK/ERK signaling pathways. Taken together, our results suggest that the anticancer activity of PPD in colon cancer cells may be mediated through targeting NF-kappaB, JNK and MAPK/ERK signaling pathways, although the detailed mechanisms underlying the anticancer mode of PPD action need to be fully elucidated. PMID- 23633047 TI - Parathyroid hormone-related protein and regulation of cell survival in the kidney. AB - Parathyroid hormone-related protein (PTHrP) is a pleiotropic factor with multiple physiological functions in morphogenesis, cell proliferation, differentiation, apoptosis, and calcium homeostasis. In the kidney, PTHrP is known to be expressed abundantly and to be upregulated in various experimental nephropathies, showing growth-modulatory and proinflammatory properties. Ardura et al. demonstrate a possible link between PTHrP-induced Runx2 expression and an antiapoptotic effect in tubular epithelial cells. PMID- 23633042 TI - Dynamics of stochastic epidemics on heterogeneous networks. AB - Epidemic models currently play a central role in our attempts to understand and control infectious diseases. Here, we derive a model for the diffusion limit of stochastic susceptible-infectious-removed (SIR) epidemic dynamics on a heterogeneous network. Using this, we consider analytically the early asymptotic exponential growth phase of such epidemics, showing how the higher order moments of the network degree distribution enter into the stochastic behaviour of the epidemic. We find that the first three moments of the network degree distribution are needed to specify the variance in disease prevalence fully, meaning that the skewness of the degree distribution affects the variance of the prevalence of infection. We compare these asymptotic results to simulation and find a close agreement for city-sized populations. PMID- 23633048 TI - Need to quickly excrete K(+)? Turn off NCC. AB - Renal K(+) excretion is increased rapidly following dietary K(+) intake, but the underlying molecular mechanisms are largely unknown. Sorensen and colleagues show that K(+) intake in mice provoked rapid and near-complete dephosphorylation of the renal distal convoluted tubule NaCl cotransporter, temporally associated with increases in both Na(+) and K(+) excretion. This response was independent of aldosterone and may be a crucial component of the acute homeostatic adaptation of the kidney to K(+) intake. PMID- 23633049 TI - Vitamin K: key vitamin in controlling vascular calcification in chronic kidney disease. AB - Vascular calcification has emerged as an independent risk factor for cardiovascular morbidity and mortality, especially in chronic kidney disease. Deficiencies in calcium-regulatory proteins directly relate to development of calcifications. McCabe and colleagues report that vitamin K is a key regulator of vascular calcification, via carboxylation of vitamin K-dependent proteins such as matrix Gla protein. Knowledge about vitamin K status may propel therapeutic strategies to prevent and treat vascular calcification with high vitamin K supplementation. PMID- 23633050 TI - Synthetic oleanane triterpenoids: magic bullets or not? AB - A recent clinical trial in patients with chronic kidney disease (CKD) and diabetic nephropathy demonstrated that bardoxolone methyl (CDDO-ME) increases estimated glomerular filtration rate (eGFR) by an unknown mechanism. The paper by Ding et al. suggests that short-term administration of a CDDO-ME analog increases GFR by increasing glomerular surface area. However, changes in other renal hemodynamic parameters cannot be excluded. Vigorous testing of CDDO-ME and highly purified analogs is warranted to determine their physiology, pharmacology, and efficacy and to exclude serious side effects. PMID- 23633051 TI - Commentary for 'effect of frequent hemodialysis on residual kidney function': Frequent Hemodialysis Network (FHN) Trials. AB - This post hoc analysis of the recently reported Frequent Hemodialysis Network Trials suggests that frequent nocturnal treatment, unlike frequent daily treatment, may be associated with more rapid loss of residual kidney function than conventional hemodialysis. Differences in blood pressure control, among other factors, may be implicated. The study invites reflection on our current concepts of the importance of preserving residual kidney function and on the indications for frequent treatments, particularly nocturnal. PMID- 23633052 TI - A balanced view of calcium and phosphate homeostasis in chronic kidney disease. AB - The association of abnormalities of calcium and phosphate homeostasis with adverse clinical outcomes in chronic kidney disease (CKD) has generated interest in developing therapeutic strategies to target mineral metabolism early in the course of CKD. Hill et al. present results from a classic balance study of CKD stage 3-4 patients that challenge existing paradigms and suggest a need to rethink our understanding of calcium and phosphate homeostasis in CKD. PMID- 23633053 TI - Balancing transition to dialysis: the urgent need for more intensive hemodialysis. PMID- 23633054 TI - Cyclophosphamide versus mycophenolate mofetil for initial treatment of lupus nephritis. PMID- 23633055 TI - The authors reply. PMID- 23633056 TI - How do we balance the risk in starting dialysis? PMID- 23633057 TI - The authors reply. PMID- 23633058 TI - Arteriovenous fistula infection as a cause of vascular access hemorrhage. PMID- 23633059 TI - The authors reply:. PMID- 23633060 TI - Normality test is needed in data description: a neglectful but vital problem. PMID- 23633061 TI - Extracellular Hsp27 in patients with chronic kidney disease. PMID- 23633062 TI - Chloride-liberal fluids and intracellular acidosis. PMID- 23633065 TI - Pathologic cervical fracture in a patient with secondary hyperparathyroidism. PMID- 23633066 TI - The case | a 69-year-old-woman with polyuria. PMID- 23633067 TI - Risk factors for falls in multiple sclerosis: an observational study. AB - BACKGROUND: People with multiple sclerosis (MS) experience frequent falls, which are associated with impairments and limitations to activities and participations. OBJECTIVE: The objective of this paper is to evaluate falls risk factors using robust clinical measures. METHODS: A total of 150 individuals (confirmed MS diagnosis, Expanded Disability Status Scale (EDSS) 3.5-6.5) were recruited, with 148 participants included in the final analysis. Demographic data were collected and performance assessed in eight predictor measures (Physiological Profile Assessment (PPA), Brief Ataxia Rating scale, Ashworth scale (Ashworth), Modified Falls Efficacy scale, Symbol Digit Modalities Test, dual-task interference, lying/standing blood pressure, static/dynamic visual acuity). Participants prospectively recorded falls over three months using a daily diary. People were classified as "fallers" based on reports of >= two falls. RESULTS: A total of 104 participants recorded 672 falls; 78 (52.7%) reported >= two falls. Continence issues, previous falls history and use of prescribed medications were each associated with increased risk of being a "faller". Ashworth and PPA risk score contributed significantly to a logistic regression model predicting faller/non faller classification. The reduced model (Ashworth, PPA, EDSS) showed fair-to good predictive ability (ROC c-statistic 0.73, sensitivity 70%, specificity 69%). CONCLUSION: This study confirms the high prevalence of falls in ambulant people with MS. Important potentially modifiable risk factors are identified, suggesting aspects to target in falls interventions. PMID- 23633069 TI - Immune selection, senescence and adjuvant. PMID- 23633070 TI - Medullary thymic epithelial cells, the indispensable player in central tolerance. AB - Crosstalk between thymocytes and thymic epithelial cells is critical for T cell development and the establishment of central tolerance. Medullary thymic epithelial cells (mTECs) play important roles in the late stage of T cell development, especially negative selection and Treg generation. The function of mTECs is highly dependent on their characteristic features such as ectopic expression of peripheral tissue restricted antigens (TRAs) and their master regulator-autoimmune regulator (Aire), expression of various chemokines and cytokines. In this review, we summarize the current understanding of cellular and molecular mechanisms of mTEC development and its functions in T cell development and the establishment of central tolerance. The open questions in this field are also discussed. Understanding the function and underlying mechanisms of mTECs will contribute to the better control of autoimmune diseases and the improvement of immune reconstitution during aging or after infection, chemotherapy or radiotherapy. PMID- 23633071 TI - Immunosenescence and age-related viral diseases. AB - Immunosenescence is described as a decline in the normal functioning of the immune system associated with physiologic ageing. Immunosenescence contributes to reduced efficacy to vaccination and increased susceptibility to infectious diseases in the elderly. Extensive studies of laboratory animal models of ageing or donor lymphocyte analysis have identified changes in immunity caused by the ageing process. Most of these studies have identified phenotypic and functional changes in innate and adaptive immunity. However, it is unclear which of these defects are critical for impaired immune defense against infection. This review describes the changes that occur in innate and adaptive immunity with ageing and some age-related viral diseases where defects in a key component of immunity contribute to the high mortality rate in mouse models of ageing. PMID- 23633072 TI - Salivary IgA enhancement strategy for development of a nasal-spray anti-caries mucosal vaccine. AB - Dental caries remains one of the most common global chronic diseases caused by Streptococcus mutans, which is prevalent all over the world. The caries prevalence of children aged between 5-6 years old in China is still in very high rate. A potent and effective anti-caries vaccine has long been expected for caries prevention but no vaccines have been brought to market till now mainly due to the low ability to induce and maintain protective antibody in oral fluids. This review will give a brief historical retrospect on study of dental caries and pathogenesis, effective targets for anti-caries vaccines, oral immune system and immunization against dental caries. Then, salivary IgA antibodies and the protective responses are discussed in the context of the ontogeny of mucosal immunity to indigenous oral streptococcal. The methods and advancement for induction of specific anti-caries salivary sIgA antibodies and enhancement of specific anti-caries salivary sIgA antibodies by intranasal immunization with a safe effective mucosal adjuvant are described. The progress in the enhancement of salivary sIgA antibodies and anti-caries protection by intranasal immunization with flagellin-PAc fusion protein will be highlighted. Finally, some of the main strategies that have been used for successful mucosal vaccination of caries vaccine are reviewed, followed by discussion of the mucosal adjuvant choice for achieving protective immunity at oral mucosal membranes for development of a nasal-spray or nasal-drop anti-caries vaccine for human. PMID- 23633073 TI - Different quasispecies with great mutations hide in the same subgroup J field strain of avian leukosis virus. AB - Blood samples were collected from a local strain of chickens associated with serious tumor cases in Shandong Province. The samples were inoculated into chicken embryo fibroblast and DF-1 cells for virus isolation and identification, respectively. The inoculated cells were screened for three common chicken tumor viruses. Nine strains of avian leukosis virus subgroup J (ALV-J) were identified, and were designated LY1201-LY1209. The env gene from the LY1201 strain was amplified and cloned. All nine resultant env clones (clones 01-09) were sequenced, and the gp85 and gp37 amino acid regions were subjected to homology analysis. Clones 01 and 03 had 10 amino acid deletions in the gp85 region compared to the other seven clones, suggesting that at least two quasispecies with obvious mutations coexist in the same field strain. Among these nine clones, three had identical gp85 and gp37 sequences, and were recognized as the dominant LY1201 quasispecies. The amino acid sequence homology of gp37 and gp85 among the nine clones was 98.5%-100.0% and 96.6%-100.0% respectively, suggesting that the gp85 region of the env gene can better display the quasispecies diversity of ALV J than gp37. PMID- 23633074 TI - Electron microscopy: essentials for viral structure, morphogenesis and rapid diagnosis. AB - Electron microscopy (EM) should be used in the front line for detection of agents in emergencies and bioterrorism, on accounts of its speed and accuracy. However, the number of EM diagnostic laboratories has decreased considerably and an increasing number of people encounter difficulties with EM results. Therefore, the research on viral structure and morphologyant in EM diagnostic practice. EM has several technological advantages, and should be a fundamental tool in clinical diagnosis of viruses, particularly when agents are unknown or unsuspected. In this article, we review the historical contribution of EM to virology, and its use in virus differentiation, localization of specific virus antigens, virus-cell interaction, and viral morphogenesis. It is essential that EM investigations are based on clinical and comprehensive pathogenesis data from light or confocal microscopy. Furthermore, avoidance of artifacts or false results is necessary to exploit fully the advantages while minimizing its limitations. PMID- 23633075 TI - MiRNA-711-SP1-collagen-I pathway is involved in the anti-fibrotic effect of pioglitazone in myocardial infarction. AB - Although microRNAs (miRNAs) have been intensively studied in cardiac fibrosis, their roles in drug-mediated anti-fibrotic therapy are still unknown. Previously, Pioglitazone attenuated cardiac fibrosis and increased miR-711 experimentally. We aimed to explore the role and mechanism of miR-711 in pioglitazone-treated myocardial infarction in rats. Our results showed that pioglitazone significantly reduced collagen-I levels and increased miR-711 expression in myocardial infarction heart. Pioglitazone increased the expression of miR-711 in cardiac fibroblasts, and overexpression of miR-711 suppressed collagen-I levels in angiotensin II (Ang II)-treated or untreated cells. Transfection with antagomir 711 correspondingly abolished the pioglitazone-induced reduction in collagen-I levels. Bioinformatics analysis identified SP1, which directly promotes collagen I synthesis, as the putative target of miR-711. This was confirmed by luciferase assay and western blot analysis. Additionally, increased SP1 expression was attenuated by pioglitazone in myocardial infarction heart. Furthermore, transfection of antagomir-711 attenuated pioglitazone-reduced SP1 expression in cardiac fibroblasts with or without Ang II stimulation. We conclude that pioglitazone up-regulated miR-711 to reduce collagen-I levels in rats with myocardial infarction. The miR-711-SP1-collagen-I pathway may be involved in the anti-fibrotic effects of pioglitazone. Our findings may provide new strategies for miRNA-based anti-fibrotic drug research. PMID- 23633076 TI - Mitochondrial genome sequences of Artemia tibetiana and Artemia urmiana: assessing molecular changes for high plateau adaptation. AB - Brine shrimps, Artemia (Crustacea, Anostraca), inhabit hypersaline environments and have a broad geographical distribution from sea level to high plateaus. Artemia therefore possess significant genetic diversity, which gives them their outstanding adaptability. To understand this remarkable plasticity, we sequenced the mitochondrial genomes of two Artemia tibetiana isolates from the Tibetan Plateau in China and one Artemia urmiana isolate from Lake Urmia in Iran and compared them with the genome of a low-altitude Artemia, A. franciscana. We compared the ratio of the rate of nonsynonymous (Ka) and synonymous (Ks) substitutions (Ka/Ks ratio) in the mitochondrial protein-coding gene sequences and found that atp8 had the highest Ka/Ks ratios in comparisons of A. franciscana with either A. tibetiana or A. urmiana and that atp6 had the highest Ka/Ks ratio between A. tibetiana and A. urmiana. Atp6 may have experienced strong selective pressure for high-altitude adaptation because although A. tibetiana and A. urmiana are closely related they live at different altitudes. We identified two extended termination-associated sequences and three conserved sequence blocks in the D-loop region of the mitochondrial genomes. We propose that sequence variations in the D-loop region and in the subunits of the respiratory chain complexes independently or collectively contribute to the adaptation of Artemia to different altitudes. PMID- 23633077 TI - Protein array of Coxiella burnetii probed with Q fever sera. AB - Coxiella burnetii is the etiological agent of Q fever. To identify its major seroreactive proteins, a subgenomic protein array was developed. A total of 101 assumed virulence-associated recombinant proteins of C. burnetii were probed with sera from mice experimentally infected with C. burnetii and sera from Q fever patients. Sixteen proteins were recognized as major seroreactive antigens by the mouse sera. Seven of these 16 proteins reacted positively with at least 45% of Q fever patient sera. Notably, HspB had the highest fluorescence intensity value and positive frequency of all the proteins on the array when probed with both Q fever patient sera and mouse sera. These results suggest that these seven major seroreactive proteins, particularly HspB, are potential serodiagnostic and subunit vaccine antigens of Q fever. PMID- 23633078 TI - PyrG is required for maintaining stable cellular uracil level and normal sporulation pattern under excess uracil stress in Aspergillus nidulans. AB - Tight control of the intracellular uracil level is believed to be important to reduce the occurrence of uracil incorporation into DNA. The pyrG gene of Aspergillus nidulans encodes orotidine 5'-phosphate decarboxylase, which catalyzes the conversion of orotidine monophosphate (OMP) to uridine monophosphate (UMP). In this study, we found that pyrG is critical for maintaining uracil at a low concentration in A. nidulans cells in the presence of exogenous uracil. Excess uracil and its derivatives had a stronger inhibitory effect on the growth of the pyrG89 mutant with defective OMP decarboxylase activity than on the growth of wild type, and induced sexual development in the pyrG89 mutant but not in wild type. Analysis of transcriptomic responses to excess uracil by digital gene expression profiling (DGE) revealed that genes related to sexual development were transcriptionally activated in the pyrG89 mutant but not in wild type. Quantitative analysis by HPLC showed that the cellular uracil level was 6.5 times higher in the pyrG89 mutant than in wild type in the presence of exogenous uracil. This study not only provides new information on uracil recycling and adaptation to excess uracil but also reveals the potential effects of OMP decarboxylase on fungal growth and development. PMID- 23633079 TI - Habitat suitability modeling of amphibian species in southern and central China: environmental correlates and potential richness mapping. AB - Successful wildlife management must take into account suitable habitat areas. Information on the correlation between distribution ranges and environmental conditions would, therefore, improve the efficacy of in-situ conservation of wildlife. In this contribution, correlations between environmental factors and the distribution of 51 amphibians in southern and central China were investigated. Ecological niche factor analysis (ENFA) at a spatial resolution of 1 degrees latitude*1 degrees longitude identified a mixture of climatic and habitat factors as important predictors of the occurrence of individual species. The aims of the present work were (i) to evaluate potential distributions of amphibians based on the suitability of areas; (ii) to identify the major environmental descriptors upon which they depend; and (iii) to identify areas of potential high richness that have been overlooked in available inventories. Most of the predicted species ranges of species covered the majority of southern and central China. Six richness hotspots were predicted, of which four have been described previously, but two overlooked (SE Fujian and SE Qinghai). The prediction model was considered to be relatively accurate and it is recommended that these two new potential hotspots should be subjected to further evaluation and sampling efforts. Amphibians have high ecological preference for high humidity and precipitation, and low annual frost days. ENFA is a useful tool in wildlife conservation assessment because it is able to identify potential hotspots where studies on the correlations between environmental descriptors and the occurrence of particular species could be focused. PMID- 23633080 TI - Silica sacrificial layer-assisted in-plane incorporation of Au nanoparticles into mesoporous titania thin films through different reduction methods. AB - This study focuses on the incorporation of gold nanoparticles (Au NPs) into our previously synthesized mesoporous titania thin films consisting of titania nanopillars and inverse mesospace (C. W. Wu, T. Ohsuna, M. Kuwabara and K. Kuroda, J. Am. Chem. Soc., 2006, 128, 4544-4545, denoted as MTTFs). Recently, mesoporous titania materials doped with noble metals such as gold have attracted considerable attention because noble metals can enhance the efficiency of mesoporous titania-based devices. In this research, we attempted to use four different reduction methods (i.e., thermal treatment, photo irradiation, liquid immersion, and vapor contacting) to introduce gold nanoparticles (Au NPs) into MTTFs. The synthesized Au@MTTFs were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). We further systematically investigated the formation mechanism of gold nanoparticles on the external and internal surfaces of the MTTFs. With the assistance of a silica sacrificial layer, well-dispersed Au NPs with sizes of 4.1 nm were obtained inside the MTTF by photo irradiation. The synthesized Au@MTTF materials show great potential in various photo-electronic and photo-catalytic applications. PMID- 23633082 TI - Tuning size and magnetic thermal hysteresis in a new near room temperature spin crossover compound. AB - A mononuclear spin crossover compound Fe(AP-Mesal)2, which exhibits spin transitions near room temperature and light induced excited spin state trapping (LIESST) effects at low temperature, was synthesized and substructured in the form of micro- and nanoscaled particles. A thermal hysteresis loop was detected with particle size reduction to microscale and nanoscale. PMID- 23633083 TI - Technical note: comparing von Luschan skin color tiles and modern spectrophotometry for measuring human skin pigmentation. AB - Prior to the introduction of reflectance spectrophotometry into anthropological field research during the 1950s, human skin color was most commonly classified by visual skin color matching using the von Luschan tiles, a set of 36 standardized, opaque glass tiles arranged in a chromatic scale. Our goal was to establish a conversion formula between the tile-based color matching method and modern reflectance spectrophotometry to make historical and contemporary data comparable. Skin pigmentation measurements were taken on the forehead, inner upper arms, and backs of the hands using both the tiles and a spectrophotometer on 246 participants showing a broad range of skin pigmentation. From these data, a second-order polynomial conversion formula was derived by jackknife analysis to estimate melanin index (M-index) based on tile values. This conversion formula provides a means for comparing modern data to von Luschan tile measurements recorded in historical reports. This is particularly important for populations now extinct, extirpated, or admixed for which tile-based measures of skin pigmentation are the only data available. PMID- 23633081 TI - Circulating microRNAs: a novel class of potential biomarkers for diagnosing and prognosing central nervous system diseases. AB - As a class of important endogenous small noncoding RNAs that regulate gene expression at the posttranscriptional level, microRNAs (miRNAs) play a critical role in many physiological and pathological processes. It is believed that miRNAs contribute to the development, differentiation, and synaptic plasticity of the neurons, and their dysregulation has been linked to a series of diseases. MiRNAs exist in the tissues and as circulating miRNAs in several body fluids, including plasma or serum, cerebrospinal fluid, urine, and saliva. There are significant differences between the circulating miRNA expression profiles of healthy individuals and those of patients. Consequently, circulating miRNAs are likely to become a novel class of noninvasive and sensitive biomarkers. Although little is known about the origin and functions of circulating miRNAs at present, their roles in the clinical diagnosis and prognosis of diseases make them attractive markers, particularly for tumors and cardiovascular diseases. Until now, however, there have been limited data regarding the roles of circulating miRNAs in central nervous system (CNS) diseases. This review focuses on the characteristics of circulating miRNAs and their values as potential biomarkers in CNS diseases, particularly in Alzheimer's disease, Huntington's disease, multiple sclerosis, schizophrenia, and bipolar disorder. PMID- 23633084 TI - Genetic relationship between multiple squamous cell carcinomas arising in the oral cavity. AB - BACKGROUND: Histological and clinical criteria are generally used to differentiate second primary tumors (SPTs) from local recurrences. The purpose of the present study was to apply mitochondrial DNA (mtDNA) D-loop analysis to differentiate SPTs from local recurrences and to validate the clinical classification. METHODS: The study population consisted of 20 consecutive patients presenting multiple oral neoplastic lesions for a total of 25 paired lesions. The mtDNA D-loop analysis was performed by direct sequencing and phylogenetic clusterization. RESULTS: Agreement between mtDNA analysis and clinical classification was found in 19 cases. Discrepancies arose in 6 cases in which the clinical criteria based only on the spatial or temporal distance of the second lesion from the index tumor had led to a diagnosis of SPT (2 cases) or local recurrence (4 cases). CONCLUSION: The present data highlight the value of mtDNA analysis in establishing the clonal relationship between the index tumor and the second neoplastic lesion. PMID- 23633085 TI - Tranexamic acid for reducing blood transfusions in arthroplasty interventions: a cost-effective practice. AB - BACKGROUND: Tranexamic acid (TXA) administered during arthroplasty intervention can prevent blood loss and blood transfusions. The purpose of the present study is to evaluate the benefit of TXA administration on blood transfusion rates in patients undergoing joint arthroplasty, and to perform cost-benefit analysis. METHODS: The study population included 100 patients admitted for arthroplasty intervention between 1st June 2008 and 31st October 2008 who did not receive TXA, and 98 patients admitted between 1st June 2009 and 31st October 2009 receiving TXA during the intervention. Blood transfusion was the main outcome. Risk factors for transfusion were evaluated in logistic regression models. Costs of autologous blood donation, TXA administration, autotransfusion and homologous blood transfusion were used to perform a cost-benefit evaluation. RESULTS: In the multivariate adjusted analysis, high preoperative haemoglobin level and TXA administration were significantly associated with a reduced risk of transfusion. Seventy-five percent of patients not receiving TXA required at least one transfusion versus 40.8% of patients receiving TXA, with a reduction of 45.6%. The mean number of blood units transfused was reduced of 26%. The reduction in transfusions was higher in hip arthroplasty. Among patients receiving TXA, the reduction in Hb level was lower both at days 1 and 2 after the intervention. The mean saving related to TXA administration was of 138 per patient. CONCLUSIONS: The administration of TXA during arthroplasty intervention reduces the need of transfusion among patients undertaking arthroplasty interventions and can be considered a cost-effective practice for the National Health System. PMID- 23633086 TI - Comparison of the change in patellar height between opening and closed wedge high tibial osteotomy: measurement with a new method. AB - PURPOSE: The purposes of this study were to examine patellar height at preoperation and postoperation, and compare the change of patellar height between opening wedge high tibial osteotomy (HTO) and closed wedge HTO by using Insall Salvati (IS) ratio and our original method. METHODS: Twenty patients (26 knees) were included. There were 6 males (6 knees) and 14 females (20 knees). Sixteen knees underwent closed method and 10 knees underwent opening method. Patellar height was measured at preoperation, immediately after the operation (postoperation) and 1 year after the operation according to IS ratio and modified Blumensaat (MB) ratio. We defined MB ratio as the ratio of distance from Blumensaat line to the midpoint of patellofemoral joint of patella against the length of Blumensaat line. RESULTS: In opening wedge HTO, though IS ratio significantly increased postoperatively compared with preoperative IS ratio, IS ratio at 1 year after operation was not significantly different from preoperative values. MB ratio at postoperation and that at 1 year after the operation significantly decreased compared with preoperative MB ratio. In closed wedge HTO, there was no difference between preoperative and postoperative values of both IS ratio and MB ratio. CONCLUSIONS: In the postoperative period after opening wedge HTO, IS ratio was significantly increased, whereas MB ratio was decreased. We recommend that patients with low preoperative MB ratio must be treated with closed wedge HTO. PMID- 23633087 TI - A pulled sutures technique for bony Bankart lesion. AB - In an attempt to present a new surgical technique for arthroscopic bony Bankart fixation, the authors developed the pulled sutures technique. In executing the new method, the authors first passed several non-absorbable sutures through labroligamentous tissue with displaced articular fragment by mimicking transglenoid suture technique. Aimed at achieving a safe and stable fixation, using a knotless anchor rather than transglenoid suture, was deployed. Overall, this pulled sutures technique was shown to be effective with the result of direct reduction, stable, and safe fixation for bony Bankart's lesion. PMID- 23633088 TI - Investigation of the clinicopathological features of fallopian tube malignancy. AB - The present study investigated the clinico-pathological features of fallopian tube malignancy (FTM) and elucidated the biological behavior of this disorder. Data were compiled concerning FTM from 68 patients from 7 institutes. The patients included 60 cases with fallopian tube carcinoma and 8 cases with fallopian tube carcinosarcoma. The clinical stage was stage III or higher in 72% of the cases. A complete response or partial response was achieved in 56 and 10 of the 68 patients with FTM, respectively, indicating a response rate of 97.1%. The median observation period for FTM was 41 months (3 to 126 months). Three of the 19 patients with stage I/II disease (16%) and 31 of the 49 patients with stage III/IV disease (63%) experienced recurrence, with a median progression-free survival of 17.5 months, and a 3-year overall survival of 77.2%. Regarding the site of recurrence, local intraperitoneal recurrence (26.2%) and solitary recurrences in lymph nodes (19.0%) and in the liver (16.7%) were relatively frequent. Secondary debulking surgery (SDS) was performed in 15 patients (44%) out of the 34 recurrent FTMs. Conversely, recurrence was associated with ascites (carcinomatous peritonitis) in 4 of the 34 recurrent patients, but all 4 patients died. The median survival period after recurrence was 28 months: 7.5 and 30 months with and without ascites, respectively (P<0.001). A univariate analysis showed that prognosis was significantly correlated only with whether SDS could be performed. These results suggest that since FTM frequently results in solitary recurrence, aggressive recurrence treatment including SDS could improve prognosis. PMID- 23633089 TI - Bacterial infection in elderly nursing home and community-based patients: a prospective cohort study. AB - PURPOSE: The aim of the study was to assess differences between elderly nursing home (NH) residents and elderly patients living in the community admitted to hospital for bacterial infection. METHODS: We conducted a prospective cohort study with manual data collection. Patients aged 65 years and older from NHs and from the community admitted to hospital for bacterial infection were included in the study. Patient characteristics, site of infection, microorganism profile, and final outcome were assessed and compared between these two subgroups of patients. RESULTS: Two hundred and sixty-two patients were from NHs and 707 were from the community. Patients from NHs were older, had more underlying chronic illnesses, and more often showed characteristics indicating advanced debility. In both groups, the most common site of infection was the respiratory tract. In comparison to the community group, patients from NHs had a higher fatality rate (23.3 vs. 10.9%) and more often experienced functional decline at discharge (27.5 vs. 16.8%). After adjustment for age, sex, presence of comorbidity, and debility, NH residence remained associated with increased in-hospital mortality but not with functional decline. CONCLUSIONS: Elderly patients from NHs admitted to hospital for bacterial infection are older and more debilitated than their counterparts from the community. Microorganisms found in the NH residents are somewhat different from those in the community dwellers. The community dwellers had a better survival rate than those admitted from the NHs after adjusting for age, sex, presence of any comorbidity, and debility. PMID- 23633092 TI - Confirming the factor structure of the alcohol and alcohol problems questionnaire (AAPPQ) in a sample of baccalaureate nursing students. AB - The Alcohol and Alcohol Problems Perception Questionnaire (AAPPQ) is a multi dimensional measure of clinicians' attitudes toward working with patients with alcohol problems. In the past 35 years, five- and six-subscale versions and a short version of the AAPPQ have been published. While the reliability of the AAPPQ subscales has remained acceptable, the factor structure has not been verified using confirmatory techniques. In the current study, we split a sample of 299 baccalaureate nursing students to use exploratory (EFA) and confirmatory factor analyses (CFA). When compared to the original six-factor solution and an imposed six-factor structure in CFA, the EFA seven-factor solution with three original items (19, 20, and 25) removed had the best model fit. PMID- 23633090 TI - Take-home emergency naloxone to prevent heroin overdose deaths after prison release: rationale and practicalities for the N-ALIVE randomized trial. AB - The naloxone investigation (N-ALIVE) randomized trial commenced in the UK in May 2012, with the preliminary phase involving 5,600 prisoners on release. The trial is investigating whether heroin overdose deaths post-prison release can be prevented by prior provision of a take-home emergency supply of naloxone. Heroin contributes disproportionately to drug deaths through opiate-induced respiratory depression. Take-home emergency naloxone is a novel preventive measure for which there have been encouraging preliminary reports from community schemes. Overdoses are usually witnessed, and drug users themselves and also family members are a vast intervention workforce who are willing to intervene, but whose responses are currently often inefficient or wrong. Approximately 10% of provided emergency naloxone is thought to be used in subsequent emergency resuscitation but, as yet, there have been no definitive studies. The period following release from prison is a time of extraordinarily high mortality, with heroin overdose deaths increased more than sevenfold in the first fortnight after release. Of prisoners with a previous history of heroin injecting who are released from prison, 1 in 200 will die of a heroin overdose within the first 4 weeks. There are major scientific and logistical challenges to assessing the impact of take-home naloxone. Even in recently released prisoners, heroin overdose death is a relatively rare event: hence, large numbers of prisoners need to enter the trial to assess whether take-home naloxone significantly reduces the overdose death rate. The commencement of pilot phase of the N-ALIVE trial is a significant step forward, with prisoners being randomly assigned either to treatment-as-usual or to treatment-as-usual plus a supply of take-home emergency naloxone. The subsequent full N-ALIVE trial (contingent on a successful pilot) will involve 56,000 prisoners on release, and will give a definitive conclusion on lives saved in real-world application. Advocates call for implementation, while naysayers raise concerns. The issue does not need more public debate; it needs good science. PMID- 23633094 TI - [Recurrent left sided sinusitis with hearing loss and occipital headache]. PMID- 23633095 TI - [Lip edema of unknown origin and gingival hyperplasia in an 11-year-old boy]. PMID- 23633096 TI - [From the expert's office: Evaluation of beginning NIHL (noise induced hearing loss)--a new recommendation]. PMID- 23633097 TI - [Functional soft-palate reconstruction with radial forearm free flaps]. AB - Oropharyngeal cancer of the soft palate is a therapeutic challenge. This is due to crucial importance of velopharyngeal competence for articulation and swallowing. Patient counseling must present the whole therapeutic spectrum in order to receive informed consent. Basically, in primary therapy of oropharyngeal cancer multimodal concepts have to be considered including surgical resection and radiochemotherapy. With regard to the occasional difficulties predicting the functional outcome after primary therapy the ladder of reconstructive options has to be discussed a priori. Among numerous pedicled flaps the radial forearm free flap nowadays belongs definitely in the surgical armoury, which offers almost ideal reconstructive possibilities after extensive resections. This implies some additional aspects in pre- and postoperative workup that are reviewed in this article. PMID- 23633098 TI - Amino Acid deprivation-induced expression of asparagine synthetase regulates the growth and survival of cultured silkworm cells. AB - Expression of Bombyx mori Asparagine synthetase (BmASNS), one gene that encodes an enzyme catalyzing asparagine biosynthesis, is transcriptionally induced following amino acid deprivation. Previous transcriptional analysis of the BmASNS gene showed the involvement of Polycomb proteins, epigenetic repressors, in suppressing BmASNS expression in a cell cycle-dependent manner. However, the role of BmAsns protein in these cellular processes remains unclear. The present study thus exploited the potential function of BmAsns protein in cultured silkworm cells. Our results showed that ectopic overexpression of BmASNS gene effectively inhibited cell growth in silkworm cells, whereas its overexpression could rescue cell growth upon amino acid deprivation treatment. We found that the cells expressing BmAsns protein were capable of influencing the formation of autophagic vacuoles stimulated by amino acid deprivation. We speculated that the recovery of cell growth by overexpressed BmAsns protein is due to the rapid turnover of autophagic vacuoles in the cells. To further assess the effects of BmAsns on cell development, we used RNA interference to silence BmASNS expression in silkworm cells in the presence or absence of amino acids. Our results revealed a significant change of cell proliferation as well as cell cycle distribution after knockdown of BmASNS. Importantly, silkworm cells lacking BmASNS under the condition of amino acid deprivation showed severely impaired proliferation. Altogether, we concluded that the up-regulated expression of BmASNS would be able to protect cells from impairment induced by amino acid deprivation, which in turn facilitates cell growth and survival. PMID- 23633100 TI - A resampling approach and implications for estimating the phalangeal index from unassociated hand bones in fossil primates. AB - Primate fossil assemblages often have metacarpals and phalanges from which functional/behavioral interpretations may be inferred. For example, intrinsic hand proportions can indicate hand function and substrate use. But, estimates of intrinsic hand proportions from unassociated hand elements can be imperfect due to digit misattribution. Although isolated metacarpals can be identified to a specific digit, phalanges are difficult to assign to a specific ray. We used a resampling approach to evaluate how estimates of intrinsic hand proportions are affected by such uncertainty. First, the phalangeal index-intermediate phalanx length plus proximal phalanx length divided by metacarpal length-for the third digit was calculated for associated specimens of terrestrial, semiterrestrial, and arboreal taxa. We then used resampling procedures to generate distributions of "composite digits" based on resampled ratios in which phalanges from the second, fourth, and fifth rays, and from different individuals, were chosen randomly. Results confirm that the phalangeal index for associated third digits significantly discriminates groups. We also found that resampled ratios had significantly lower means, indicating that using composite digits is prone to systematic underestimation. Resampled ratios also generated distributions with greater variance around the means that obscured distinctions between groups, although significant differences between the most arboreal and terrestrial taxa are maintained. We conclude that using unassociated phalanges to calculate a phalangeal index is prone to sampling bias. Nevertheless, a resampling approach has the potential to inform estimates of hand proportions for fossil taxa, provided that the comparative sample is constrained to mimic the fossil composition. PMID- 23633099 TI - Posterior reversible encephalopathy syndrome in neuroblastoma patients receiving anti-GD2 3F8 monoclonal antibody. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) comprises clinical and radiologic findings with rapid onset and potentially dire consequences. Patients experience hypertension, seizures, headache, visual disturbance, and/or altered mentation. Magnetic resonance imaging reveals edematous changes in the brain (especially in the parietal and occipital lobes). In this report, the authors describe PRES associated with antidisialoganglioside (anti-GD2 ) monoclonal antibody (MoAb) immunotherapy, which is now standard for high-risk neuroblastoma but has not previously been implicated in PRES. METHODS: Successive clinical trials using the anti-GD2 MoAb 3F8 (a murine immunoglobulin 3 MoAb specific for GD2) for patients with neuroblastoma involved multiple cycles of standard-dose 3F8 (SD-3F8) (20 mg/m2 daily for 5 days per cycle) or 2 cycles of high-dose 3F8 (HD-3F8) (80 mg/m2 daily for 5 days per cycle) followed by cycles of SD-3F8. RESULTS: PRES was diagnosed in 5 of 215 patients (2.3%), including 3 of 160 (1.9%) who received SD-3F8 and 2 of 55 (3.6%) who received HD 3F8 (P = .6). All 5 patients had a rapid return to clinical-radiologic baseline. PRES occurred in 3 of 26 patients (11.5%) whose prior treatment included external beam radiotherapy to the brain (2 of 6 patients status-post total body irradiation and 1 of 20 patients status-post craniospinal irradiation) compared with 2 of 189 patients (1.1%) who had not received prior brain irradiation (P = .01). Hypertension, which is strongly linked to PRES, reached grade 3 toxicity in 12 of 215 patients (5.6%), including the 5 patients with PRES and 7 patients without PRES. CONCLUSIONS: Patients who receive anti-GD2 MoAb immunotherapy should be closely monitored for, and undergo urgent treatment or evaluation of, symptoms that may herald PRES (eg, hypertension or headaches). Prior brain irradiation may be a predisposing factor for PRES with this immunotherapy. PMID- 23633101 TI - Do headache and abdominal pain in childhood predict suicides and severe suicide attempts? Finnish nationwide 1981 birth cohort study. AB - This study investigated associations between pain symptoms in mid-childhood and severe suicidality in adolescence and early adulthood. Severe suicidality was defined as completed suicide or suicidal attempt requiring hospital admission. In a nationwide prospective population-based study (n = 6,017), parents and children were asked about the child's headache and abdominal pain at age eight. The outcome was register-based data on suicide or suicidal attempt requiring hospital treatment by age 24. Family composition, parental educational level, and the child's psychiatric symptoms reported by the child, parents and teacher at baseline were included as covariates in statistical analyses. Boys' abdominal pain reported by the parents was associated with later severe suicidality after adjusting for family composition, parental educational level, and childhood psychiatric symptoms at baseline. In addition, the association between boys' own report of headache and later severe suicidality reached borderline significance in unadjusted analysis. Girls' pain symptoms did not predict later severe suicidality. PMID- 23633102 TI - Child-mother and child-father attachment security: links to internalizing adjustment among children with learning disabilities. AB - The study examined the unique role of children's attachment with the father and with the mother, in explaining differences in internalizing features (i.e., loneliness, sense of coherence, hope and effort, and internalizing behavior syndrome) among 107 children with learning disabilities (LD) versus 98 children with typical development ages 8-12. Preliminary analyses yielded significant group differences on most measures. SEM analysis indicated high fit between the theoretical model and empirical findings, and different patterns of relations among the model's components for the two populations. As hypothesized, child father and child-mother attachment contributed differently to children's internalizing features for the two subgroups. Discussion focused on understanding unique and complementary roles of attachment relations with fathers versus mothers among children with and without LD. PMID- 23633103 TI - Association of Pro12Ala (rs1801282) variant of PPAR gamma with rheumatoid arthritis in a Pakistani population. AB - Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) belongs to a receptor superfamily of ligand-activated transcription factors, encoded by PPARG gene. Role of PPARgamma has been well established in variety of metabolic disorders and in regulation of inflammation. In the present study, we aimed to investigate the association of PPARG (Pro12Ala; rs1801282) in clinically definite Pakistani Rheumatoid Arthritis (RA) patients and matching controls. The genotypes of the Pro12Ala variant in the PPARG were determined in a sample of 300 Pakistanis, including 150 RA cases and 150 controls. The genotyping was performed using Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS PCR) method, and the data was analyzed through Graphpad Prism 5 V software. Allele-specific primer set (two forward: PPARG-F1, PPARG-F2 and a common reverse primer: PPARG-R) was used for amplification, and the product was resolved on 2 % agarose gel. The CC (ProPro) genotype has higher frequency in controls than RA cases [75 (50.0 %) vs. 51 (34.0 %)], whereas the CG (ProAla) genotype has relatively same frequencies in both cases and controls [72 (48.0 %) vs. 70 (46.6 %)]. However, significantly higher frequency of GG (AlaAla) genotype was observed in cases [27 (18.0 %) vs. 5 (3.3 %); chi2 18.54; p < 0.0001]. Furthermore, the minor allele G has significantly higher allele frequency in cases having same trend and direction of association (OR 1.991(1.412-2.808); p < 0.0001). These observations suggest that Pro12Ala (rs1801282), a coding variant in the PPARG gene, is associated with Rheumatoid Arthritis in Pakistanis. PMID- 23633105 TI - The human environment interface: applying ecosystem concepts to health. AB - One Health approaches have tended to focus on closer collaboration among veterinarians and medical professionals, but remain unclear about how ecological approaches could be applied or how they might benefit public health and disease control. In this chapter, we review ecological concepts, and discuss their relevance to health, with an emphasis on emerging infectious diseases (EIDs). Despite the fact that most EIDs originate in wildlife, few studies account for the population, community, or ecosystem ecology of the host, reservoir, or vector. The dimensions of ecological approaches to public health that we propose in this chapter are, in essence, networks of population dynamics, community structure, and ecosystem matrices incorporating concepts of complexity, resilience, and biogeochemical processes. PMID- 23633104 TI - Molecular profiling of sinonasal undifferentiated carcinoma. AB - BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) remains a poorly characterized malignancy at both the clinical and molecular level, and, consequently, the optimal treatment strategy remains undefined. METHODS: We used a mass spectroscopy-based approach (Sequenom) to evaluate 95 hallmark single nucleotide variations (SNVs) within 12 oncogenes or tumor suppressor genes (AKT, BRAF, CDK4, Beta-catenin, epidermal growth factor receptor [EGFR], FBXW7, JAK2, c KIT, KRAS, PDGFR, PI3K, and vascular endothelial growth factor [VEGF]) in 13 histologically confirmed SNUC cases. RESULTS: None of the samples demonstrated activating mutations in any of the 95 SNVs. CONCLUSION: Select clinically relevant activating genomic mutations were not identified in the 13 patient samples. However, polymorphisms were noted within the promoter region of VEGF. These may merit future studies as predictive biomarkers for treatment response or overall survival. Additionally, future studies focusing on larger tumor sets and utilizing whole genome or exome sequencing may help define genetic aberrations in SNUC that can be clinically targeted with available or emerging biological agents. PMID- 23633106 TI - DNA metabolism in mycobacterial pathogenesis. AB - Fundamental aspects of the lifestyle of Mycobacterium tuberculosis implicate DNA metabolism in bacillary survival and adaptive evolution. The environments encountered by M. tuberculosis during successive cycles of infection and transmission are genotoxic. Moreover, as an obligate pathogen, M. tuberculosis has the ability to persist for extended periods in a subclinical state, suggesting that active DNA repair is critical to maintain genome integrity and bacterial viability during prolonged infection. In this chapter, we provide an overview of the major DNA metabolic pathways identified in M. tuberculosis, and situate key recent findings within the context of mycobacterial pathogenesis. Unlike many other bacterial pathogens, M. tuberculosis is genetically secluded, and appears to rely solely on chromosomal mutagenesis to drive its microevolution within the human host. In turn, this implies that a balance between high versus relaxed fidelity mechanisms of DNA metabolism ensures the maintenance of genome integrity, while accommodating the evolutionary imperative to adapt to hostile and fluctuating environments. The inferred relationship between mycobacterial DNA repair and genome dynamics is considered in the light of emerging data from whole genome sequencing studies of clinical M. tuberculosis isolates which have revealed the potential for considerable heterogeneity within and between different bacterial and host populations. PMID- 23633107 TI - Expanded Prader-Willi syndrome due to chromosome 15q11.2-14 deletion: report and a review of literature. AB - We report on a male infant with de novo unbalanced t(5;15) translocation resulting in a 17.23 Mb deletion within 15q11.2-q14 and a 25.12 kb deletion in 5pter. The 15q11.2-q14 deletion encompassed the 15q11.2-q13 Prader-Willi syndrome (PWS) critical region and the recently described 15q13.3 microdeletion syndrome region while the 5pter deletion contained no RefSeq genes. From our literature review, patients with similar deletions in chromosome 15q exhibit expanded phenotype of severe developmental delay, protracted feeding problem, absent speech, central visual impairment, congenital malformations and epilepsy in addition to those typical of PWS. The patient reported herein had previously unreported anomalies of mega cisterna magna, horseshoe kidney and the rare neonatal interstitial lung disease known as pulmonary interstitial glycogenosis. Precise breakpoint delineation by microarray is useful in patients with atypical PWS deletions to guide investigation and prognostication. PMID- 23633108 TI - Epidemiologic characteristics of cases for influenza A(H7N9) virus infections in China. PMID- 23633109 TI - Testing antimicrobial drugs. PMID- 23633110 TI - Editorial commentary: local treatments for cutaneous leishmaniasis. PMID- 23633111 TI - Travelers with cutaneous leishmaniasis cured without systemic therapy. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is a disfiguring but not life threatening disease. Because antileishmanial drugs are potentially toxic, the World Health Organization (WHO) recommends simple wound care or local therapy as first-line treatment, followed or replaced by systemic therapy if local therapy fails or cannot be performed. METHODS: To determine the feasibility and impact of the recommended approach, we analyzed the results of a centralized referral treatment program in 135 patients with parasitologically proven CL. RESULTS: Infections involved 10 Leishmania species and were contracted in 29 different countries. Eighty-four of 135 patients (62%) were initially treated without systemic therapy. Of 109 patients with evaluable charts, 23 of 25 (92%) treated with simple wound care and 37 of 47 (79%) treated with local antileishmanial therapy were cured by days 42-60. In 37 patients with large or complex lesions, or preexisting morbidities, or who had not been cured with local therapy, the cure rate with systemic antileishmanial agents was 60%. Systemic adverse events were observed in 15 patients, all receiving systemic therapy. CONCLUSIONS: In this population of CL patients displaying variable degrees of complexity and severity, almost two-thirds of patients could be initially managed without systemic therapy. Of these, 60 were cured before day 60. The WHO-recommended stepwise approach favoring initial local therapy therefore resulted in at least 44% of all patients being cured without exposure to the risk of systemic adverse events. Efforts are needed to further simplify local therapy of CL and to improve the management of patients with complex lesions and/or preexisting comorbidities. PMID- 23633113 TI - Validation of minimally invasive, image-guided cochlear implantation using Advanced Bionics, Cochlear, and Medel electrodes in a cadaver model. AB - PURPOSE: Validation of a novel minimally invasive, image-guided approach to implant electrodes from three FDA-approved manufacturers-Medel, Cochlear, and Advanced Bionics-in the cochlea via a linear tunnel from the lateral cranium through the facial recess to the cochlea. METHODS: Custom microstereotactic frames that mount on bone-implanted fiducial markers and constrain the drill along the desired path were utilized on seven cadaver specimens. A linear tunnel was drilled from the lateral skull to the cochlea followed by a marginal, round window cochleostomy and insertion of the electrode array into the cochlea through the drilled tunnel. Post-insertion CT scan and histological analysis were used to analyze the results. RESULTS: All specimens ([Formula: see text]) were successfully implanted without visible injury to the facial nerve. The Medel electrodes ([Formula: see text]) had minimal intracochlear trauma with 8, 8, and 10 (out of 12) electrodes intracochlear. The Cochlear lateral wall electrodes (straight research arrays) ([Formula: see text]) had minimal trauma with 20 and 21 of 22 electrodes intracochlear. The Advanced Bionics electrodes ([Formula: see text]) were inserted using their insertion tool; one had minimal insertion trauma and 14 of 16 electrodes intracochlear, while the other had violation of the basilar membrane just deep to the cochleostomy following which it remained in scala vestibuli with 13 of 16 electrodes intracochlear. CONCLUSIONS: Minimally invasive, image-guided cochlear implantation is possible using electrodes from the three FDA-approved manufacturers. Lateral wall electrodes were associated with less intracochlear trauma suggesting that they may be better suited for this surgical technique. PMID- 23633112 TI - Three-dimensional histological specimen preparation for accurate imaging and spatial reconstruction of the middle and inner ear. AB - PURPOSE: This paper presents a highly accurate cross-sectional preparation technique. The research aim was to develop an adequate imaging modality for both soft and bony tissue structures featuring high contrast and high resolution. Therefore, the advancement of an already existing micro-grinding procedure was pursued. The central objectives were to preserve spatial relations and to ensure the accurate three-dimensional reconstruction of histological sections. METHODS: Twelve human temporal bone specimens including middle and inner ear structures were utilized. They were embedded in epoxy resin, then dissected by serial grinding and finally digitalized. The actual abrasion of each grinding slice was measured using a tactile length gauge with an accuracy of one micrometre. The cross-sectional images were aligned with the aid of artificial markers and by applying a feature-based, custom-made auto-registration algorithm. To determine the accuracy of the overall reconstruction procedure, a well-known reference object was used for comparison. To ensure the compatibility of the histological data with conventional clinical image data, the image stacks were finally converted into the DICOM standard. RESULTS: The image fusion of data from temporal bone specimens' and from non-destructive flat-panel-based volume computed tomography confirmed the spatial accuracy achieved by the procedure, as did the evaluation using the reference object. CONCLUSION: This systematic and easy-to-follow preparation technique enables the three-dimensional (3D) histological reconstruction of complex soft and bony tissue structures. It facilitates the creation of detailed and spatially correct 3D anatomical models. Such models are of great benefit for image-based segmentation and planning in the field of computer-assisted surgery as well as in finite element analysis. In the context of human inner ear surgery, three-dimensional histology will improve the experimental evaluation and determination of intra-cochlear trauma after the insertion of an electrode array of a cochlear implant system. PMID- 23633115 TI - Expression of human full-length MUC1 inhibits the proliferation and migration of a B16 mouse melanoma cell line. AB - Mucin 1 (MUC1) is a large transmembrane glycoprotein that is aberrantly overexpressed in most adenocarcinomas and certain hematological malignancies. MUC1 is known to function as an oncogene with roles in both tumor formation and progression, making it a potential target for immunotherapy. B16-MUC1 cells with human full-length MUC1 are frequently used to study the antitumor activities of MUC1-based vaccines. However, we found that the growth of B16-MUC1 cells was significantly reduced in vitro. Therefore, in this study, we established two MUC1 positive clones, B16-MUC1 9-12 and B16-MUC1 9-23, and one empty vector control clone, B16-neo, to investigate the effects of MUC1 on the cancer-related characteristics of B16 cells in vitro and in vivo. Our results demonstrated that, compared with MUC1-negative cells, cells expressing MUC1 exhibited decreased cell proliferation, increased cell cycle arrest and reduced cell migratory and invasive capacities. We further investigated several MUC1-related molecules of the beta-catenin pathway, and found that the expression of MUC1 decreased the translocation of beta-catenin into the nucleus, reduced the activity of T cell factor (TCF) and blocked the expression of cyclin D1 and c-Myc. Moreover, when inoculated into BALB/c nude mice, cells expressing MUC1 developed smaller tumors compared with the control cells. These results demonstrate that MUC1 expression negatively affects the malignancy of B16 cells, and suggest that the regulatory mechanisms of MUC1 as an oncoprotein are more complex than previously appreciated. PMID- 23633117 TI - [Latent classes of personality disorders: group comparisons and course of psychotherapy]. AB - Using latent class analysis the Personality Disorder Screening (PDS) classifies patients into 4 groups: personality disordered (PD) patients (PDS+), healthy patients (PDS -) and 2 hybrid classes with exaggerated personality styles (histrionic/dependent and avoidant/obsessive-compulsive). The present study investigated if the PDS groups differ concerning sociodemographic and clinical variables, psychological distress and treatment outcome. We analyzed the PDS response patterns of 555 outpatients. PDS+ group membership is associated with typical PD characteristics, chronic depression and a high level of general psychological distress. Patients of both hybrid classes are found to show average psychological distress. The treatment was effective for all patients. Membership in the histrionic/dependent hybrid class is associated with early drop out from outpatient therapy. PMID- 23633116 TI - Sleep loss and its effects on health of family caregivers of individuals with primary malignant brain tumors. AB - Sleep loss places caregivers at risk for poor health. Understanding correlates of sleep loss and relationships to health may enable improvement of health of caregivers of individuals with primary malignant brain tumors (PMBT). In this cross-sectional, descriptive study of 133 caregivers, relationships were examined between sleep loss and physical, mental, emotional, and social health at time of patient diagnosis. Sleep loss was not related to physical health. Shorter total sleep time was associated with greater fatigue and social support. Sleep quality was positively associated with quality of life. Further study is needed of the role of sleep loss in the PMBT caregiving trajectory and its long-term relationship with health outcomes. PMID- 23633118 TI - Evidence that CXCL16 is a potent mediator of angiogenesis and is involved in endothelial progenitor cell chemotaxis : studies in mice with K/BxN serum-induced arthritis. AB - OBJECTIVE: To examine the possibility that CXCL16 recruits endothelial cells (ECs) to developing neovasculature in rheumatoid arthritis (RA) synovium. METHODS: We utilized the RA synovial tissue SCID mouse chimera system to examine human microvascular EC (HMVEC) and human endothelial progenitor cell (EPC) recruitment into engrafted human synovium that was injected intragraft with CXCL16-immunodepleted RA synovial fluid (SF). CXCR6-deficient and wild-type (WT) C57BL/6 mice were primed to develop K/BxN serum-induced arthritis and evaluated for angiogenesis. HMVECs and EPCs from human cord blood were also examined for CXCR6 expression, by immunofluorescence and assessment of CXCL16 signaling activity. RESULTS: CXCR6 was prominently expressed on human EPCs and HMVECs, and its expression on HMVECs could be up-regulated by interleukin-1beta. SCID mice injected with CXCL16-depleted RA SF exhibited a significant reduction in EPC recruitment. In experiments using the K/BxN serum-induced inflammatory arthritis model, CXCR6(-/-) mice showed profound reductions in hemoglobin levels, which correlated with reductions in monocyte and T cell recruitment to arthritic joint tissue compared to that observed in WT mice. Additionally, HMVECs and EPCs responded to CXCL16 stimulation, but exhibited unique signal transduction pathways and homing properties. CONCLUSION: These results indicate that CXCL16 and its receptor CXCR6 may be a central ligand/receptor pair that is closely associated with EPC recruitment and blood vessel formation in the RA joint. PMID- 23633121 TI - A four-component synthetic attractant for Drosophila suzukii (Diptera: Drosophilidae) isolated from fermented bait headspace. AB - BACKGROUND: A mixture of wine and vinegar is more attractive than wine or vinegar to spotted wing drosophila, Drosophila suzukii (Matsumura) (Diptera: Drosophilidae), and ethanol and acetic acid are considered key to that attractiveness. In addition to ethanol and acetic acid, 13 other wine and vinegar volatiles are antennally active to D. suzukii and might be involved in food finding. RESULTS: Out of the 13 antennally active chemicals, acetoin, ethyl lactate and methionol increased fly response to a mixture of acetic acid and ethanol in field trapping experiments. A five-component blend of acetic acid, ethanol, acetoin, ethyl lactate and methionol was as attractive as the starting mixture of wine and vinegar in field tests conducted in the states of Oregon and Mississippi. Subtracting ethyl lactate from the five-component blend did not reduce the captures of flies in the trap. However, subtracting any other compound from the blend significantly reduced the numbers of flies captured. CONCLUSION: These results indicate that acetic acid, ethanol, acetoin and methionol are key olfactory cues for D. suzukii when attracted to wine and vinegar, which may be food-finding behavior leading flies to fermenting fruit in nature. It is anticipated that this four-component blend can be used as a highly attractive chemical lure for detection and management of D. suzukii. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. PMID- 23633122 TI - PTSD as a mediator between lifetime sexual abuse and substance use among jail diversion participants. AB - OBJECTIVE: Many of the individuals with serious mental illness involved in the criminal justice system have experienced interpersonal victimization, such as sexual abuse, and have high rates of alcohol and drug use disorders. Little attention has been paid to the prevalence of posttraumatic stress disorder (PTSD) and its potential role in the substance misuse of offenders with mental illness. METHODS: The study used a path analytic framework to test the hypothesis that PTSD mediates the relationship between sexual abuse and level of alcohol and drug use among individuals (N=386) with mental illness enrolled in a multisite (N=7) jail diversion project. RESULTS: Sexual abuse was strongly associated with PTSD, which was in turn associated with both heavy drug use and heavy drinking. CONCLUSIONS: These findings suggest that PTSD may be an important target for jail diversion programs. PMID- 23633123 TI - A new single gene deletion on 2q34: ERBB4 is associated with intellectual disability. AB - We report on a 15-year-old patient with hyperactivity, intellectual disability and severe speech developmental delay. An array CGH analysis revealed de novo 2q34 deletion, 958 kb in size, involving a single protein coding gene ERBB4 (position 212,505,294-213,463,152; NCBI build 36). The ERBB4 gene is important in numerous neurobiological processes in both the developing and the adult brain. The NRG1-ERBB4 signaling pathway has been recently implicated in the pathophysiology of schizophrenia and epilepsy. Many risk haplotypes were identified in several studies across different populations. The severe clinical consequences in our patient demonstrate that the haploinsufficiency of ERBB4 is crucial for intellectual and cognitive function. These observations are compatible with previously reported results. PMID- 23633119 TI - Multidrug resistance-associated protein 2 (MRP2/ABCC2) haplotypes significantly affect the pharmacokinetics of tacrolimus in kidney transplant recipients. AB - BACKGROUND AND OBJECTIVE: Tacrolimus is an immunosuppressive drug used for the prevention of the allograft rejection in kidney transplant recipients. It exhibits a narrow therapeutic index and large pharmacokinetic variability. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) 3A4 and 3A5 and effluxed via ATP-binding cassette (ABC) transporters such as P-glycoprotein (P gp), encoded by ABCB1 gene. The influence of CYP3A5*3 on the pharmacokinetics of tacrolimus has been well characterized. On the other hand, the contribution of polymorphisms in other genes is controversial. In addition, the involvement of other efflux transporters than P-gp in tacrolimus disposition is uncertain. The present study was designed to investigate the effects of genetic polymorphisms of CYP3As and efflux transporters on the pharmacokinetics of tacrolimus. SUBJECTS AND METHODS: A total of 500 blood concentrations of tacrolimus from 102 adult stable kidney transplant recipients were included in the analyses. Genetic polymorphisms in CYP3A4 and CYP3A5 genes were determined. In addition, the genes of efflux transporters including P-gp (ABCB1), multidrug resistance-associated protein (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2) were genotyped. For ABCC2 gene, haplotypes were determined as follows: H1 (wild type), H2 (1249G>A), H9 (3972C>T) and H12 (-24C>T and 3972C>T). Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. RESULTS: Analyses revealed that the CYP3A5 expressers (CYP3A5*1 carriers) and MRP2 high-activity group (ABCC2 H2/H2 and H1/H2) showed a decreased dose normalized trough concentration of tacrolimus by 2.3-fold (p < 0.001) and 1.5 fold (p = 0.007), respectively. The pharmacokinetics of tacrolimus were best described using a two-compartment model with first order absorption and an absorption lag time. In the population pharmacokinetic analysis, CYP3A5 expressers and MRP2 high-activity groups were identified as the significant covariates for tacrolimus apparent clearance expressed as 20.7 * (age/50)(-0.78) * 2.03 (CYP3A5 expressers) * 1.40 (MRP2 high-activity group). No other CYP3A4, ABCB1 or ABCG2 polymorphisms were associated with the apparent clearance of tacrolimus. CONCLUSIONS: This is the first report showing that MRP2/ABCC2 has a crucial impact on the pharmacokinetics of tacrolimus in a haplotype-specific manner. Determination of the ABCC2 as well as CYP3A5 genotype may be useful for more accurate tacrolimus dosage adjustment. PMID- 23633124 TI - Efficient two-step testing of gene-gene interactions in genome-wide association studies. AB - Exhaustive testing of all possible SNP pairs in a genome-wide association study (GWAS) generally yields low power to detect gene-gene (G * G) interactions because of small effect sizes and stringent requirements for multiple-testing correction. We introduce a new two-step procedure for testing G * G interactions in case-control GWAS to detect interacting single nucleotide polymorphisms (SNPs) regardless of their marginal effects. In an initial screening step, all SNP pairs are tested for gene-gene association in the combined sample of cases and controls. In the second step, the pairs that pass the screening are followed up with a traditional test for G * G interaction. We show that the two-step method is substantially more powerful to detect G * G interactions than the exhaustive testing approach. For example, with 2,000 cases and 2,000 controls, the two-step method can have more than 90% power to detect an interaction odds ratio of 2.0 compared to less than 50% power for the exhaustive testing approach. Moreover, we show that a hybrid two-step approach that combines our newly proposed two-step test and the two-step test that screens for marginal effects retains the best power properties of both. The two-step procedures we introduce have the potential to uncover genetic signals that have not been previously identified in an initial single-SNP GWAS. We demonstrate the computational feasibility of the two-step G * G procedure by performing a G * G scan in the asthma GWAS of the University of Southern California Children's Health Study. PMID- 23633125 TI - A new and automated method for objective analysis of detrusor rhythm during the filling phase. AB - INTRODUCTION: There is growing acceptance that the detrusor muscle is not silent during the filling phase of the micturition cycle but displays low-amplitude phasic contractions that have been associated with urinary urgency. Unfortunately, there is currently no standardized methodology to quantify detrusor rhythm during the filling phase. Therefore, the purpose of this study was to develop an automated computer algorithm to analyze rat detrusor rhythm in a quick, accurate, and reproducible manner. MATERIALS AND METHODS: Strips of detrusor smooth muscle from rats (n = 17) were placed on force transducers and subjected to escalating doses of PGE2 to generate contractile rhythm tracings. An automated computer algorithm was developed to analyze contractile frequency, amplitude, and tone on the generated rhythm tracings. Results of the automated computerized analysis were compared to human (n = 3) interpretations. Human interpreters manually counted contractions and then recounted the same data two weeks later. Intra-observer, inter-observer, and human-to-computer comparisons were performed. RESULTS: The computer algorithm quantified concentration dependent changes in contractile frequency, amplitude, and tone after administration of PGE2 (10(-9)-10(-6)M). Concentration-response curves were similar for all contractile components with increases in frequency identified mainly at physiologic concentrations of PGE2 and increases in amplitude at supra physiologic concentrations. The computer algorithm consistently over-counted the human interpreters, but with less variability. Differences in inter-observer consistency were statistically significant. CONCLUSIONS: Our computerized algorithm accurately and consistently identified changes in detrusor muscle contractile frequency, amplitude, and tone with varying doses of PGE2. Frequency counts were consistently higher than those obtained by human interpreters but without variability or bias. Refinements of this method may allow for more standardized approach in the study of pharmacologic agents on filling phase rhythmic activity. PMID- 23633126 TI - Outcome of female urethral reconstruction: a 12-year experience. AB - INTRODUCTION AND HYPOTHESIS: To report our experience over 12 years in female urethral reconstruction with either anterior bladder tube (Tanagho) or labia minora pedicled tube. PATIENTS AND METHODS: This retrospective study included 16 patients with posttraumatic urethral loss. The patients were divided into two groups. Group I: included 6 patients managed with combined vaginal and abdominal approach using a proximally based anterior bladder tube (Tanagho) and Group II: included 10 patients underwent repair with labial fat pad flap with concomitant TOT sling. Outcomes included the success or failure of anatomical repair and continence, which was assessed during patient follow up by voiding diary, 24-h pad test and uroflowmetry. RESULTS: A total of 15 patients were followed for a mean of 42 months postoperatively, and only one patient was lost to follow up. Total continence was achieved in 10 patients (66.6 %) [4/6 patients (66.6 %) in group I and 6/9 patients (66.6 %) in group II]. Partial continence (i.e., one or two pad per day) was achieved in 2 patients (13.3 %). Failure occurs in 3 cases (20 %) [one case in group I and two cases in group II]. All our patients had a smooth postoperative course. In the labia pedicled tube, meatal stenosis was encountered in one patient and transient postoperative urine retention in 2 patients. Successful anatomical repair was achieved in all our patients. CONCLUSION: Both Bladder tube and labia minora pedicled tube with sling procedure have high success rate with only minor complications and are equally effective in the management of females with total urethral loss. Due to the small number of patients in this study, we still need to extend our study to verify our results. PMID- 23633127 TI - Lichen sclerosus in men is associated with elevated body mass index, diabetes mellitus, coronary artery disease and smoking. AB - PURPOSE: To elucidate disease associations and possible etiology of lichen sclerosus (LS), we identified comorbidities present in men with LS. LS is a chronic inflammatory disease of unknown etiology affecting genitals and urethra of men commonly resulting in strictures. METHODS: Men with LS of the urethra, penis, prepuce and scrotum were identified. A control population was generated from men seen in the Department of Urology matched by age and race in a 5:1 ratio. A case-control study was performed and comorbidities identified by ICD9, CPT codes and medication use via systematic electronic medical record review. Subgroup analysis of men with urethral strictures was performed based on their LS status. RESULTS: Men with LS had a significantly higher mean body mass index [31.0 (range 18.9-52.6)] compared to controls [28.1 (16.8-64.1), p = 0.001], significantly increased rate of coronary artery disease (CAD) (15.3 vs. 8.9%, p = 0.05) as well as a twofold higher rate of diabetes mellitus (15.5 vs. 8.3%, p = 0.02). Of men with LS and stricture disease, 11/19 (58%) were current or former smokers, compared to 28% of men with strictures without LS (p = 0.006). No association of LS with other morbidities like hyperlipidemia, hypertension, cerebrovascular disease, peripheral vascular disease or dermatologic disorders was found. CONCLUSIONS: Men suffering from LS have an increased BMI and a higher prevalence of concomitant CAD, diabetes mellitus and tobacco use. Development and chronicity of LS may not be a purely dermatologic condition, but be associated or confounded by systemic or vascular compromise from disorders of CAD, DM and smoking. PMID- 23633128 TI - D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. AB - PURPOSE: To test whether D-mannose powder is effective for recurrent urinary tract infection (UTI) prevention. MATERIALS AND METHODS: After initial antibiotic treatment of acute cystitis, 308 women with history of recurrent UTI and no other significant comorbidities were randomly allocated to three groups. The first group (n = 103) received prophylaxis with 2 g of D-mannose powder in 200 ml of water daily for 6 months, the second (n = 103) received 50 mg Nitrofurantoin daily, and the third (n = 102) did not receive prophylaxis. RESULTS: Overall 98 patients (31.8%) had recurrent UTI: 15 (14.6) in the D-mannose group, 21 (20.4) in Nitrofurantoin group, and 62 (60.8) in no prophylaxis group, with the rate significantly higher in no prophylaxis group compared to active groups (P < 0.001). Patients in D-mannose group and Nitrofurantoin group had a significantly lower risk of recurrent UTI episode during prophylactic therapy compared to patients in no prophylaxis group (RR 0.239 and 0.335, P < 0.0001). In active groups, 17.9% of patients reported side effects but they were mild and did not require stopping the prophylaxis. Patients in D-mannose group had a significantly lower risk of side effects compared to patients in Nitrofurantoin group (RR 0.276, P < 0.0001), but the clinical importance of this finding is low because Nitrofurantoin was well tolerated. CONCLUSIONS: In our study, D-mannose powder had significantly reduced the risk of recurrent UTI which was no different than in Nitrofurantoin group. More studies will be needed to validate the results of this study, but initial findings show that D-mannose may be useful for UTI prevention. PMID- 23633129 TI - Vesicular glutamate transporter-3 in the rodent brain: vesicular colocalization with vesicular gamma-aminobutyric acid transporter. AB - Vesicular glutamate transporters (VGLUT1-3) carry glutamate into synaptic vesicles. VGLUT3 has been reported to be localized in nonglutamatergic neuronal populations in the brain. However, detailed subcellular localization of VGLUT3 has not been shown. In particular, the identity of synaptic vesicles expressing VGLUT3 remains to be revealed. Here we present novel electron microscopic postembedding immunogold data from mouse and rat brains showing that small, clear, and round synaptic vesicles in gamma-aminobutyric acid (GABA)-ergic nerve terminals contain labeling for both VGLUT3 and the vesicular GABA transporter (VGAT). Immunoisolation of synaptic vesicles confirmed the immunogold data and showed vesicular colocalization of VGLUT3 and VGAT. Moreover, we show that gold particles signaling VGLUT3 are present in synaptic vesicles in acetylcholinergic nerve terminals in the striatum. Quantitative immunogold analyses reveal that the density of VGLUT3 gold particles is similar in GABAergic terminals in the hippocampus and the neocortex to that in cholinergic terminals in the striatum. In contrast to in the hippocampus and the neocortex, VGLUT3 was absent from VGAT positive terminals in the striatum. The labeling pattern produced by the VGLUT3 antibodies was found to be specific; there was no labeling in VGLUT3 knockout tissue, and the observed labeling throughout the rat brain corresponds to the known light-microscopic distribution of VGLUT3. From the present results, we infer that glutamate is released with GABA from inhibitory terminals and acetylcholine from cholinergic terminals. PMID- 23633130 TI - The CURB-65 scoring system in severity assessment of Eastern Nigerian patients with community-acquired pneumonia: a prospective observational study. AB - BACKGROUND: Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality in Nigeria. Severity assessment is a major starting point in the proper management of CAP. The BTS guideline for managing this condition is simple and does not require sophisticated equipment. Adherence to this guideline will improve CAP management in Nigeria. AIMS: To assess the usefulness of the CURB-65 score in the management of CAP patients in Nigeria and to determine the outcome in relation to the degree of severity using CURB-65. METHODS: A prospective observational study of 80 patients with CAP was carried out in the University of Nigeria Teaching Hospital Enugu, Nigeria from December 2008 to June 2009. The patients were classified into three risk groups and the ability of the CURB-65 score to predict the 30-day mortality rate and the need for ICU admission was determined. RESULTS: Eighty patients were recruited, 39 of whom were men, giving a male to female ratio of 1:1.05. The mean age was 56 +/- 18 years. Thirty-seven patients (46.3%) were outpatients, 13 with CURB score 0, 21 with CURB score 1, two with CURB score 2, and one with CURB score 3. Of the 43 patients (53.7%) admitted to hospital, six, 13, 14, and 10 had scores of 4, 3, 2, and 1, respectively. The ICU admission rate was 10%. Twelve patients died, 2.2% in the low-risk group, 12.5% in the intermediate-risk group, and 45% in the high-risk group. CONCLUSIONS: The CURB-65 score is a simple method of assessing and risk stratifying CAP patients. It is particularly useful in a busy emergency department because of its ability to identify a reasonable proportion of low-risk patients for potential outpatient care. PMID- 23633131 TI - Analysis of quantitative magnetic resonance imaging and biomechanical parameters on human discs with different grades of degeneration. AB - PURPOSE: To establish relationships between quantitative MRI (qMRI) and biomechanical parameters in order to help inform and interpret alterations of human intervertebral discs (IVD) with different grades of degeneration. MATERIALS AND METHODS: The properties of the nucleus pulposus (NP) and annulus fibrosus (AF) of each IVD of 10 lumbar spines (range, 32-77 years) were analyzed by qMRI (relaxation times T1 and T2, magnetization transfer ratio [MTR], and apparent diffusion coefficient [ADC]), and tested in confined compression and dynamic shear. RESULTS: T1 and T2 significantly decreased in both the NP and AF with increasing degeneration grades while the MTR increased significantly with grade 4. In contrast to the other qMRI parameters, the ADC had a tendency to decrease with increasing grade. Disc degeneration caused a decrease in the aggregate modulus, hydraulic permeability and shear modulus magnitude along with an increase in phase angle in the AF. In contrast, disc degeneration of NPs demonstrated decreases in shear modulus and phase angle. CONCLUSION: Our studies indicate that qMRI can be used as a noninvasive diagnostic tool in the detection of IVD properties with the potential to help interpret and detect early, middle, and late stages of degeneration. QMRI of human IVD can therefore become a very important diagnostic assessment tool in determining the functional state of the disc. PMID- 23633132 TI - Percutaneous mitral valve repair in the initial EVEREST cohort: evidence of reverse left ventricular remodeling. AB - BACKGROUND: Percutaneous repair of mitral regurgitation (MR) permits examination of the effect of MR reduction without surgery and cardiopulmonary bypass on left ventricular (LV) dimensions and function. The goal of this analysis was to determine the extent of reverse remodeling at 12 months after successful percutaneous reduction of MR with the MitraClip device. METHODS AND RESULTS: Of 64 patients with 3 and 4+ MR who achieved acute procedural success after treatment with the MitraClip device, 49 patients had moderate or less MR at 12 month follow-up. Their baseline and 12-month echocardiograms were compared between the group with and without LV dysfunction. In patients with persistent MR reduction and pre-existing LV dysfunction, there was a reduction in LV wall stress, reduced LV end-diastolic volume, LV end-systolic volume and increase in LV ejection fraction in contrast to those with normal baseline LV function, who showed reduction in LV end-diastolic volume, LV wall stress, no change in LV end systolic volume, and a fall in LV ejection fraction. CONCLUSIONS: Patients with pre-existing LV dysfunction demonstrate reverse remodeling and improved LV ejection fraction after percutaneous mitral valve repair. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00209339, NCT00209274. PMID- 23633133 TI - The 2013 Thomas Hunt Morgan Medal: Thomas Douglas Petes. AB - The Genetics Society of America annually honors members who have made outstanding contributions to genetics. The Thomas Hunt Morgan Medal recognizes a lifetime contribution to the science of genetics. The Genetics Society of America Medal recognizes particularly outstanding contributions to the science of genetics over the past 32 years. The George W. Beadle Award recognizes distinguished service to the field of genetics and the community of geneticists. The Elizabeth W. Jones Award for Excellence in Education recognizes individuals or groups who have had a significant, sustained impact on genetics education at any level, from kindergarten through graduate school and beyond. The Novitski Prize recognizes an extraordinary level of creativity and intellectual ingenuity in solving significant problems in biological research through the application of genetic methods. We are pleased to announce the 2013 awards. PMID- 23633134 TI - The 2013 Genetics Society of America Medal: Elaine A. Ostrander. PMID- 23633135 TI - The 2013 George W. Beadle Award: R. Scott Hawley. PMID- 23633136 TI - The 2013 Genetics Society of America Elizabeth W. Jones Award for Excellence in Education: A. Malcolm Campbell. PMID- 23633137 TI - The 2013 Novitski Prize: Jonathan Pritchard. PMID- 23633139 TI - Charles Darwin's mitochondria. AB - Charles Darwin's long-term illness has been the subject of much speculation. His numerous symptoms have led to conclusions that his illness was essentially psychogenic in nature. These diagnoses have never been fully convincing, however, particularly in regard to the proposed underlying psychological background causes of the illness. Similarly, two proposed somatic causes of illness, Chagas disease and arsenic poisoning, lack credibility and appear inconsistent with the lifetime history of the illness. Other physical explanations are simply too incomplete to explain the range of symptoms. Here, a very different sort of explanation will be offered. We now know that mitochondrial mutations producing impaired mitochondrial function may result in a wide range of differing symptoms, including symptoms thought to be primarily psychological. Examination of Darwin's maternal family history supports the contention that his illness was mitochondrial in nature; his mother and one maternal uncle had strange illnesses and the youngest maternal sibling died of an infirmity with symptoms characteristic of mitochondrial encephalomyopathy, lactic acidosis, and stroke like episodes (MELAS syndrome), a condition rooted in mitochondrial dysfunction. Darwin's own symptoms are described here and are in accord with the hypothesis that he had the mtDNA mutation commonly associated with the MELAS syndrome. PMID- 23633140 TI - New roles for old characters: an educational primer for use with "Vps factors are required for efficient transcription elongation in budding yeast". AB - An article from Alan Hinnebusch's laboratory in the March 2013 issue of GENETICS establishes an exciting new link between proteins with well-established roles in the endomembrane system and the process of transcription elongation. This Primer article provides tools needed for students to fully appreciate, analyze, and critically evaluate the experiments and interpretations of Gaur et al. (2013). The primer includes detailed descriptions of techniques used in the study, such as the chromatin immunoprecipitation assay and assays for transcription elongation, and it provides a framework to facilitate an understanding of how a combination of genetic, biochemical, and cell microscopy experimental approaches were used by the authors to converge on a single major conclusion. Suggestions for using this Primer article in an undergraduate or graduate-level course in conjunction with the original article to promote student learning are also presented. PMID- 23633141 TI - UNC-16/JIP3/sunday driver: a new cop on the organelle highway. PMID- 23633142 TI - The color genes of speciation in plants. PMID- 23633146 TI - Pharmacokinetic dose proportionality between two strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate film-coated tablets in fasting state: a single dose, randomized, two-period crossover study in healthy volunteers. AB - BACKGROUND: Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. No data on the dose proportionality of the pharmacokinetics of doxylamine are available, although this drug has been marketed in European countries for more than 50 years. OBJECTIVE: The objective of this study was to evaluate and compare the dose proportionality between two marketed strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate after a single oral dose administration under fasting conditions in healthy human subjects. STUDY DESIGN: This was a single center, randomized, single dose, laboratory-blinded, two-period, two-sequence, crossover study. SETTING: The study was conducted in a phase I clinical unit. SUBJECTS AND METHODS: A single oral dose of doxylamine hydrogen succinate of 12.5 mg (equivalent to 8.7 mg of doxylamine base) or 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under fasting conditions in each study period. The drug administrations were separated by a wash-out period of 7 calendar days. Blood samples were collected for up to 60 h post-dose, and plasma doxylamine levels were determined by an ultra high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using non-compartmental analysis. Dose proportionality was assessed based on the parameter area under the concentration-time curve (AUCt normalized). Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs and 12-lead electrocardiogram (ECG). RESULTS: In total, 12 healthy volunteers (3 male; 9 female) were included in the study. Mean maximum observed plasma concentration (Cmax) and area under the concentration-time curve from time zero to time t (AUCt ) of doxylamine hydrogen succinate 12.5 mg and 25 mg tablets increased linearly and dose-dependently [12.5 mg: mean Cmax 61.94 ng/mL, coefficient of variation (CV) 23.2%; mean AUCt 817.33 ng.h/mL, CV 27.4%; and 25 mg: mean Cmax 124.91 ng/mL, CV 18.7%; mean AUCt 1630.85 ng.h/mL, CV 22.8%]. Mean AUCt normalized was 815.43 ng.h/mL, CV 22.8% for 25 mg. The dose-normalized geometric mean ratio (%, 12.5 mg/25 mg) of AUCt was 98.92 (90% CI: 92.46, 105.83). The most common adverse event was somnolence. CONCLUSIONS: Exposure to doxylamine was proportional over the therapeutic dose range of 12.5-25 mg in healthy volunteers. Based on the results, a predictable and linear increase in systemic exposure can be expected. Doxylamine hydrogen succinate was safe and well tolerated. PMID- 23633144 TI - An organelle gatekeeper function for Caenorhabditis elegans UNC-16 (JIP3) at the axon initial segment. AB - Neurons must cope with extreme membrane trafficking demands to produce axons with organelle compositions that differ dramatically from those of the cell soma and dendrites; however, the mechanism by which they accomplish this is not understood. Here we use electron microscopy and quantitative imaging of tagged organelles to show that Caenorhabditis elegans axons lacking UNC-16 (JIP3/Sunday Driver) accumulate Golgi, endosomes, and lysosomes at levels up to 10-fold higher than wild type, while ER membranes are largely unaffected. Time lapse microscopy of tagged lysosomes in living animals and an analysis of lysosome distributions in various regions of unc-16 mutant axons revealed that UNC-16 inhibits organelles from escaping the axon initial segment (AIS) and moving to the distal synaptic part of the axon. Immunostaining of native UNC-16 in C. elegans neurons revealed a localized concentration of UNC-16 at the initial segment, although UNC 16 is also sparsely distributed in distal regions of axons, including the synaptic region. Organelles that escape the AIS in unc-16 mutants show bidirectional active transport within the axon commissure that occasionally deposits them in the synaptic region, where their mobility decreases and they accumulate. These results argue against the long-standing, untested hypothesis that JIP3/Sunday Driver promotes anterograde organelle transport in axons and instead suggest an organelle gatekeeper model in which UNC-16 (JIP3/Sunday Driver) selectively inhibits the escape of Golgi and endosomal organelles from the AIS. This is the first evidence for an organelle gatekeeper function at the AIS, which could provide a regulatory node for controlling axon organelle composition. PMID- 23633147 TI - [Negative emotions and understanding - patients' perspective on coercion]. AB - OBJECTIVE: This study evaluated involuntarily admitted psychiatric patients' and their perception of coercive measures (i. e. involuntary admission and physical or pharmacological restraint) by asking retrospectively which emotions were induced during the process of coercion. METHOD: Interviews were carried out around 3 weeks after coercion. The interview consisted of 31 items categorized into demographic, nosological and coercion-related themes. Patients were also asked about their subjective experiences of the coercion. 40 patients were recruited, with 72 % suffering from psychosis-related and 21 % with affective disorders. For 22.5 % of the patients, this was their first psychiatric hospitalization. The most frequently reported emotions were rage, anger and despair. Patients who were more stable, according to the Clinical Global Impressions scale (CGI), generally evaluated the coercion as being worse. CONCLUSION: More than half of the patients were satisfied with the treatment received during hospitalization. The potential suffering caused as a result of patients' perceptions of the coercion, and the impact of this on the course of the disease should be taken into account when developing new treatment strategies. PMID- 23633148 TI - ["That you stay free, but always know there is this support rod that I need"]. AB - OBJECTIVE: Models of integrated care (IC) have a high potential to improve psychiatric care in a sectored health care system. The present study aims to delineate differences in the perception of psychiatric care after introduction of a regional IC-model in schizophrenic patients and family caregivers. METHODS: Six focus group interviews with n = 32 schizophrenic patients and three with n = 17 family caregivers either from the region with IC-model or a nearby control region were conducted. Categories of the contents of transcribed interviews were developed and subsequently compared between persons with and without experience of IC. RESULTS: Most participants of the IC-group were not aware to participate in an IC-model. Differences between IC- vs. non-IC groups were primarily related to feelings of security and experiences of flexibility of care which was ensured by the outpatient nursing service in the IC-model. This was noticeable both in daily living and in coping with crisis. No substantial differences were found with regard to the experience of cooperation of professionals, information and psychoeducation of patients as well as support for family caregivers, amongst others. CONCLUSIONS: IC will play an important part in the psychiatric care of schizophrenic patients. It has the potential to integrate sustainable relations, general availability and needs-related care provision. PMID- 23633143 TI - Transfer RNA post-transcriptional processing, turnover, and subcellular dynamics in the yeast Saccharomyces cerevisiae. AB - Transfer RNAs (tRNAs) are essential for protein synthesis. In eukaryotes, tRNA biosynthesis employs a specialized RNA polymerase that generates initial transcripts that must be subsequently altered via a multitude of post transcriptional steps before the tRNAs beome mature molecules that function in protein synthesis. Genetic, genomic, biochemical, and cell biological approaches possible in the powerful Saccharomyces cerevisiae system have led to exciting advances in our understandings of tRNA post-transcriptional processing as well as to novel insights into tRNA turnover and tRNA subcellular dynamics. tRNA processing steps include removal of transcribed leader and trailer sequences, addition of CCA to the 3' mature sequence and, for tRNA(His), addition of a 5' G. About 20% of yeast tRNAs are encoded by intron-containing genes. The three-step splicing process to remove the introns surprisingly occurs in the cytoplasm in yeast and each of the splicing enzymes appears to moonlight in functions in addition to tRNA splicing. There are 25 different nucleoside modifications that are added post-transcriptionally, creating tRNAs in which ~15% of the residues are nucleosides other than A, G, U, or C. These modified nucleosides serve numerous important functions including tRNA discrimination, translation fidelity, and tRNA quality control. Mature tRNAs are very stable, but nevertheless yeast cells possess multiple pathways to degrade inappropriately processed or folded tRNAs. Mature tRNAs are also dynamic in cells, moving from the cytoplasm to the nucleus and back again to the cytoplasm; the mechanism and function of this retrograde process is poorly understood. Here, the state of knowledge for tRNA post-transcriptional processing, turnover, and subcellular dynamics is addressed, highlighting the questions that remain. PMID- 23633149 TI - Effects of 940 Hz EMF on luciferase solution: structure, function, and dielectric studies. AB - We designed a rectangular waveguide exposure system to study the effects of mobile phone frequency (940 MHz) electromagnetic fields (EMF) on luciferase structure and activity. The luciferase activity of exposed samples was significantly higher than that of unexposed samples. Dynamic light scattering of the exposed samples showed smaller hydrodynamic radii compared to unexposed samples (20 nm vs. 47 nm +/- 5%). The exposed samples also showed less tendency to form aggregates, monitored by turbidity measurements at l = 360 nm. A microwave dielectric measurement was performed to study the hydration properties of luciferase solutions with a precision network analyzer over frequency ranges from 0.2 to 20 GHz before and after exposure. The change in the dielectric properties of the exposed luciferase solution was related to the disaggregation potency of the applied field. Together, our results suggested that direct interactions with luciferase molecules and its dipole moment were responsible for the reduced aggregation and enhanced luciferase activity upon exposure to the EMF. PMID- 23633150 TI - Clearance of ingested neonicotinoid pesticide (imidacloprid) in honey bees (Apis mellifera) and bumblebees (Bombus terrestris). AB - BACKGROUND: Bees in agricultural landscapes are exposed to dietary pesticides such as imidacloprid when they feed from treated mass-flowering crops. Concern about the consequent impact on bees makes it important to understand their resilience. In the laboratory, the authors therefore fed adult worker bees on dosed syrup (125 MUg L(-1) of imidacloprid, or 98 MUg kg(-1)) either continuously or as a pulsed exposure and measured their behaviour (feeding and locomotory activity) and whole-body residues. RESULTS: On dosed syrup, honey bees maintained much lower bodily levels of imidacloprid than bumblebees (<0.2 ng versus 2.4 ng of imidacloprid per bee). Dietary imidacloprid did not affect the behaviour of honey bees, but it reduced feeding and locomotory activity in bumblebees. After the pulsed exposure, bumblebees cleared bodily imidacloprid after 48 h and recovered behaviourally. CONCLUSION: The differential behavioural resilience of the two species can be attributed to the observed differential in bodily residues. The ability of bumblebees to recover may be environmentally relevant in wild populations that face transitory exposures from the pulsed blooming of mass flowering crops. PMID- 23633151 TI - Testing for modes of inheritance involving compound heterozygotes. AB - Functional variants change the protein product or the expression of genes. Due to the latest advances in sequencing technology, most known functional variants can now be assayed in a cost-effective manner. However, to fully use the information from functional variants, researchers need to model the joint effect of these variants. In this article, we propose methods that model the action/interaction of loss-of-function (LOF) mutations, i.e., those mutations that eliminate the protein product of a gene. When multiple LOFs occur in the same causal gene/region, their effect on a phenotype might depend on whether these mutations lie on the same DNA strand/haplotype. When compared to LOFs occurring on the same strand, if these mutations lie on different strands, both copies of the gene are impaired and the impact on the relevant phenotypes is likely to be more severe. To use the information from LOF strand colocalization, we propose three methods that utilize the information from the estimated number of affected strands. We compare the performance of the proposed and competing methods by using simulations of common and rare LOF variants. Two of the proposed methods exhibited desirable power profiles, the first for both common and rare LOFs and the second only for common LOFs. One of the existing methods, collapsed double heterozygosity, exhibits good power to detect compound models for rare variants, especially when no haplotype harbors two or more rare alleles. Consequently, we recommend these three methods to be used for the analysis of functional variants coming from sequencing studies. PMID- 23633153 TI - A familial deletion of 16q21 characterized by an SNP array and associated with a normal phenotype. PMID- 23633152 TI - Promotive effects of cell proliferation and chromosomal instability induced by tribbles-related protein 3 in mouse mammary tumor cells. AB - Tribbles-related protein 3 (TRB3) has been shown to be a crucial modulator of tumorigenesis. However, the precise role and the functional morphology of TRB3 are not clearly understood. To elucidate these enigmas we established the cell line, M2TRB3, by introducing the human TRB3 gene and protein in Cl66M2 (M2) mouse mammary tumor cells. This cell line stably expressed the TRB3 gene and protein. After 72 h of cell culture, there was a 34% increase in the growth of M2TRB3 cells compared to the control M2 mock cells. The mean volume of the tumors originating from the M2TRB3 cells was significantly increased by 38% when compared to the mean volume of the M2 mock tumors, and the proliferating cell nuclear antigen (PCNA) labeling index in the M2TRB3 tumors was higher when compared to that of the M2 and M2 mock cells. In the tumor tissue samples, the mean diameter of nuclei in the M2TRB3 tumor cells (9.4+/-0.3 um) showed a significant increase compared to that of the M2 mock tumor cells (7.0+/-0.2 um). M2TRB3 cells also showed a marked increase in the population of tetraploid or octaploid nuclei compared to M2 mock cells bearing mainly either diploid or tetraploid nuclei. Western blot analysis revealed the overexpression of cyclin B1 and cyclin D1 in M2TRB3 cells when compared to that in the M2 mock cells. These novel findings provide further evidence that TRB3 promotes cell proliferation and chromosomal instability by causing polyploidization during development. PMID- 23633154 TI - Losartan supports liver regrowth via distinct boost of portal vein pressure in rodents with 90 % portal branch ligation. AB - OBJECTIVES: The study used a model of 90 % portal branch ligation (PBL) in rats to study the effect of losartan on portal vein pressure (PVP) and liver regeneration in rats after PBL. METHODS: A total of 144 male Sprague-Dawley rats were arbitrarily designated into three treatment method groups: a sham operation group (Sham), a PBL treatment group (PBL), and a PBL plus losartan treatment group (PBL + L). Losartan (2 mg/day) was intragastrically gavaged 3 days before the PBL or sham operation to time points of study. RESULTS: Both the PBL and PBL + L groups showed an intense surge in PVP after PBL treatment, peaking at 12 h postsurgery, then lessening progressively afterwards. PVP was substantially greater in these two groups compared with the Sham group at 6-72 h postsurgery (p < 0.01). Compared with the PBL group, the PBL + L group showed a noticeable reduction in PVP 6-48 h postsurgery (p < 0.05); the PBL group showed considerably raised levels of plasma ALT and AST 6-72 h postsurgery (p < 0.01). Compared to the PBL group, the PBL + L group showed drastically reduced plasma ALT and AST levels 12-72 h postsurgery (p < 0.05). CONCLUSIONS: Losartan supports liver regeneration in 90 % of rats that underwent PBL. The mechanism may be related to losartan's ability to regulate PVP and increase serum hepatocyte growth factor levels. PMID- 23633155 TI - Disrupted circadian rhythmicity of the intestinal glucose transporter SGLT1 in Zucker diabetic fatty rats. AB - BACKGROUND: Intestinal absorptive capacity shows a circadian rhythm synchronized with eating patterns. Disrupting these coordinated rhythms, e.g., with shift work, may contribute to metabolic disease. Circadian expression of nutrient transporters has not been studied in metabolic disease. We studied the circadian rhythm of intestinal transporter sodium glucose co-transporter type 1 (SGLT1) in an obese diabetic rat. METHODS: We compared obese Zucker diabetic fatty (ZDF) rats to lean ZDF littermates. Temporal feeding patterns were assessed, then rats were harvested at Zeitgeber (ZT, ZT0 = 7:00 a.m.) 3, 9, or 15 to measure insulin resistance, SGLT1 expression and intestinal glucose absorption capacity. Regulators of SGLT1 (sweet taste receptor T1R2/3; clock genes) were measured to elucidate underlying mechanisms. RESULTS: Both groups exhibited altered circadian food intake. Obese ZDF rats lost circadian rhythmicity of SGLT1 mRNA expression and functional activity. Lean ZDF rats maintained rhythmicity of SGLT1 mRNA expression but that of functional glucose absorption was blunted. Circadian rhythms of intestinal clock genes were maintained in both groups. Neither group had discernible rhythms of intestinal GLUT2 (glucose transporter) or T1R2 (sweet taste receptor component) mRNA expression. In summary, lean and obese ZDF rats exhibited similar disruptions in circadian feeding. Glucose intolerance was evident in lean rats, but only obese rats further developed diabetes and exhibited disrupted circadian rhythmicity of both SGLT1 mRNA expression and function. CONCLUSIONS: Our findings suggest that disrupted circadian feeding rhythms contribute to glucose intolerance, but additional factors (genetics, changes in nutrient sensing/transport) are needed to lead to full diabetes. PMID- 23633156 TI - Relationship between neutrophil gelatinase-associated lipocalin (NGAL) levels and inflammatory bowel disease type and activity. AB - BACKGROUND AND AIM: Neutrophil gelatinase associated lipocalin (NGAL) is a recently identified molecule, which is bacteriostatic, has tissue destructive effects and is pro-inflammatory with chemoattractant molecule binding properties. Our aim was to investigate the relationship between serum NGAL levels and the type and level of disease activity of IBD. METHODS: A total of 92 patients [43 with Crohn's disease (CD) and 49 with ulcerative colitis (UC)], and 30 age- and sex-matched healthy controls (HC) were included in this study. Serum NGAL levels were measured using ELISA. RESULTS: Serum NGAL levels were elevated in the IBD group [median 171, range (57-312) ng/mL] compared to the HC group [107 (45-234) ng/mL] (p<0.0001) and were elevated in UC patients [188 (74-312) ng/mL] compared to CD patients [168 (57-279) ng/mL] (p=0.006). When NGAL levels were further analysed based on localization of the CD and UC, the levels in ulcerative pancolitis [233 (144-312) ng/mL] were significantly higher (p=0.004) than the left-sided colitis [156 (103-309) ng/mL]. Similarly, NGAL levels were significantly higher in colonic CD [207 (125-249) ng/mL] than ileal CD [114 (78 210) ng/mL], and also in ileocolonic CD [198 (57-279) ng/mL] than ileal CD (p=0.033). When CD and UC groups were further categorized as active and inactive according to clinical and endoscopic activity indices, serum NGAL concentrations did not differ between inquiescent versus active stages. When a cut-off level of 129 ng/mL was used to distinguish IBD from HC, a sensitivity of 76.1% and a specificity of 60.9% was reached. CONCLUSIONS: The serum NGAL levels in the IBD group was significantly higher than the HC group. Serum NGAL levels were higher in more extensive colonic involvement. PMID- 23633157 TI - Gastrointestinal stromal tumor: an unusual cause of gastrointestinal bleeding. PMID- 23633158 TI - Endoscopic mucosal resection results in change of histologic diagnosis in Barrett's esophagus patients with visible and flat neoplasia: a multicenter cohort study. AB - BACKGROUND: There are limited data on the effect of endoscopic mucosal resection (EMR) on changes of histopathologic diagnosis for Barrett's esophagus (BE) patients undergoing endoscopic eradication therapy (EET); especially those without visible lesions. AIM: To compare the frequency of changes of diagnosis by EMR compared with pre-EMR biopsy diagnosis for patients with and without visible lesions. METHODS: In this multicenter outcomes project, patients with Barrett's related neoplasia undergoing EET at three tertiary-care centers were included. Patients undergoing biopsies followed by EMR within six months were included. The main outcome measures were frequency of overall change of histopathologic diagnosis, change based on pre-EMR biopsy diagnosis, and change based on the presence of visible lesions. RESULTS: One-hundred and thirty-eight BE patients (low-grade dysplasia (LGD) 15 (10.9 %), high-grade dysplasia (HGD) 87 (63 %), esophageal adenocarcinoma (EAC) 36 (26.1 %)) were included; 114 (82.6 %) patients had visible lesions. EMR resulted in a change of diagnosis for 43 (31.1 %) patients (upgrade 14 (10.1 %); downgrade 29 (21 %)). For HGD patients, EMR downstaged dysplasia grade for 17 (19.5 %) cases and upstaged it to EAC for nine (10.3 %) cases. There was a change of diagnosis for 26 (29.9 %) HGD patients, irrespective of the presence or absence of visible lesions (p = 0.76). For EAC patients, EMR downstaged dysplasia grade in 10 (27.8 %) cases. There was a change of diagnosis for 10 (27.8 %) EAC patients, irrespective of the presence or absence of endoscopically visible lesions (p = 0.48). CONCLUSIONS: EMR results in a change of diagnosis for approximately 30 % of BE patients with early neoplasia (with and without visible lesions) referred for EET. PMID- 23633159 TI - A high level of TM4SF5 is associated with human esophageal cancer progression and poor patient survival. AB - PURPOSE: We investigated expression of TM4SF5 and its involvement in human esophageal cancer (HEC). METHODS: We analyzed TM4SF5 expression in normal esophageal epithelial cells (HEEC), in four HEC cell lines, and in 20 HEC clinical tissue samples and matched nontumor samples. The effect of TM4SF5 on HEC cell proliferation and metastasis and invasion was assessed, and the relationship between TM4SF5 and integrin beta1 was determined. Finally, TM4SF5 and integrin beta1 expression were further examined by use of immunohistochemistry (IHC) and tissue microarray analysis, and the prognostic use of TM4SF5 and integrin beta1 in HEC was evaluated. RESULTS: TM4SF5 was more highly expressed in HEC cells and in HEC tissues than in HEEC and matched nontumor tissues. Down-regulation of TM4SF5 in KYSE150 cells reduced cell proliferation and metastasis and invasion whereas metastasis and invasion by KYSE510 increased after TM4SF5 cDNA transfection. In HEC cells, TM4SF5 formed a complex with integrin beta1, and interference with integrin beta1 in KYSE510-TM4SF5 cells markedly inhibited cell invasion on laminin 5. Our findings also showed that TM4SF5 and integrin beta1 overexpression correlated with low differentiation and high stage (p<0.05, respectively). Postoperative 5-year overall survival of patients with TM4SF5low and/or integrin beta1low was higher than for patients with TM4SF5high and/or integrin beta1high. Multivariate analysis demonstrated that TM4SF5 and integrin beta1 co-overexpression was an independent prognostic marker for HEC. CONCLUSION: TM4SF5 is positively associated with HEC invasiveness. The combination of TM4SF5 with integrin beta1 could potentially serve as a novel marker for predicting HEC prognosis. PMID- 23633160 TI - Vessel-encoded arterial spin labeling (VE-ASL) reveals elevated flow territory asymmetry in older adults with substandard verbal memory performance. AB - PURPOSE: To evaluate how flow territory asymmetry and/or the distribution of blood through collateral pathways may adversely affect the brain's ability to respond to age-related changes in brain function. These patterns have been investigated in cerebrovascular disease; however, here we evaluated how flow territory asymmetry related to memory generally in older adults. MATERIALS AND METHODS: A multi-faceted MRI protocol, including vessel-encoded arterial spin labeling capable of flow territory mapping, was applied to assess how flow territory asymmetry; memory performance (CERAD-Immediate Recall); cortical cerebral blood flow (CBF), white matter lesion (WML) count, and cortical gray matter volume were related in older healthy control volunteers (HC; n = 15; age = 64.5 +/- 7 years) and age-matched mild cognitive impairment volunteers (MCI; n = 7; age = 62.7 +/- 3.7 years). RESULTS: An inverse relationship was found between memory performance and flow territory asymmetry in HC volunteers (P = 0.04), which reversed in MCI volunteers (P = 0.04). No relationship was found between memory performance and cortical tissue volume in either group (P > 0.05). Group level differences for HC volunteers performing above versus below average on CERAD-I were observed for flow territory asymmetry (P < 0.02) and cortical volume (P < 0.05) only. CONCLUSION: Findings suggest that flow territory asymmetry may correlate more sensitively with memory performance than CBF, atrophy and WML count in older adults. PMID- 23633161 TI - Generalizability in the family-to-family education program randomized waitlist control trial. AB - OBJECTIVE: Randomized controlled trials (RCTs) may have limited generalizability for the community when a high proportion of individuals refuse randomization or otherwise do not participate-a not uncommon phenomenon. A randomized waitlist control trial of the Family-to-Family (FTF) education program, a 12-week course offered by the National Alliance on Mental Illness for family members of adults with mental illness, was previously reported. This study assessed whether the RCT derived estimates of effectiveness of FTF were generalizable to individuals who participated in FTF but declined participation in the RCT. METHODS: Propensity score matching was used to create five quintiles, each containing scores for individuals in FTF or waitlist conditions and for decliners; scores were matched on multiple baseline characteristics (N=442) within each quintile. Effectiveness estimates, with standard errors, were derived for the decliner population on the basis of effectiveness estimates derived from participants in the RCT; estimates were weighted to the baseline distribution of quintiles for the decliners. RESULTS: For each outcome, estimates of the effect sizes observed in the RCT were very similar to the effect sizes observed for the decliner population; confidence intervals also had a high degree of overlap. CONCLUSIONS: This study suggests that the benefits of FTF observed in the RCT are generalizable to the group of individuals who declined RCT participation, providing further evidence of FTF's effectiveness. Propensity score matching was a useful statistical tool for addressing selection bias resulting from high rates of nonconsent in randomized waitlist-control trials. PMID- 23633162 TI - Prolonged benzodiazepine coma as a complication of morbid obesity. PMID- 23633163 TI - Intracranial malignant triton tumor in a patient with neurofibromatosis type 1: case report and review of the literature. AB - We report the fourth case of an intracranial malignant triton tumor not associated with a cranial nerve in a 26-year-old male with a clinical history of neurofibromatosis type 1. The patient was found unresponsive and displayed confusion, lethargy, hyperreflexia, and dysconjugate eye movements upon arrival at the emergency room. MRI revealed a large bifrontal mass. Biopsy demonstrated a high-grade spindle cell tumor with focal areas of rhabdomyoblasts that stained positive for desmin, myogenin, and muscle-specific actin. Electron microscopy showed skeletal muscle differentiation. Based on the clinical history of NF1 and the pathologic results, a diagnosis of malignant triton tumor was made. The differential diagnosis, immunohistochemistry, molecular genetics, and treatment of malignant triton tumor are reviewed. PMID- 23633164 TI - The effects of chlordiazepoxide and d-amphetamine during a three-component multiple schedule. AB - Multiple schedules have been used in behavioral pharmacology research to show that a drug's effect on behavior can be a function of the schedule of reinforcement that supports that behavior. However, less research has examined whether the context of the schedule of reinforcement in a multiple schedule can change the drug's effect on behavior. We examined the effects of acute chlordiazepoxide and d-amphetamine injections on the behavior of two groups of pigeons trained on a three-component multiple schedule with identical schedules of reinforcement in the first and last components. For one group of pigeons reinforcement was unavailable during the middle component (decreased-middle component). For the second group reinforcement rate was higher during the middle component than during the first or third components (increased-middle-component). In the decreased-middle-component group, chlordiazepoxide (3.2-32 mg/kg) decreased third-component response rates less than it decreased responding in the first component. Conversely, in the increased-middle-component group, chlordiazepoxide (3.2-10 mg/kg) decreased third-component response rates more than in the first component. In both groups, d-amphetamine did not differentially affect response rates across components. These results are consistent with previous research showing that drugs can differentially affect responding to two different schedules of reinforcement during the same session, and suggest that pharmacological preparations may be helpful in elucidating the mechanisms that control multiple schedule interactions. PMID- 23633165 TI - Training transfer: scientific background and insights for practical application. AB - Training transfer as an enduring, multilateral, and practically important problem encompasses a large body of research findings and experience, which characterize the process by which improving performance in certain exercises/tasks can affect the performance in alternative exercises or motor tasks. This problem is of paramount importance for the theory of training and for all aspects of its application in practice. Ultimately, training transfer determines how useful or useless each given exercise is for the targeted athletic performance. The methodological background of training transfer encompasses basic concepts related to transfer modality, i.e., positive, neutral, and negative; the generalization of training responses and their persistence over time; factors affecting training transfer such as personality, motivation, social environment, etc. Training transfer in sport is clearly differentiated with regard to the enhancement of motor skills and the development of motor abilities. The studies of bilateral skill transfer have shown cross-transfer effects following one-limb training associated with neural adaptations at cortical, subcortical, spinal, and segmental levels. Implementation of advanced sport technologies such as motor imagery, biofeedback, and exercising in artificial environments can facilitate and reinforce training transfer from appropriate motor tasks to targeted athletic performance. Training transfer of motor abilities has been studied with regard to contralateral effects following one limb training, cross-transfer induced by arm or leg training, the impact of strength/power training on the preparedness of endurance athletes, and the impact of endurance workloads on strength/power performance. The extensive research findings characterizing the interactions of these workloads have shown positive transfer, or its absence, depending on whether the combinations conform to sport-specific demands and physiological adaptations. Finally, cross-training as a form of concurrent exercising in different athletic disciplines has been examined in reference to the enhancement of general fitness, the preparation of recreational athletes, and the preparation of athletes for multi-sport activities such as triathlon, duathlon, etc. PMID- 23633166 TI - Activity of chlorantraniliprole and thiamethoxam seed treatments on life stages of the rice water weevil as affected by the distribution of insecticides in rice plants. AB - BACKGROUND: The systemic insecticides chlorantraniliprole (CAP) and thiamethoxam (TMX), applied to rice as seed treatments, may affect multiple life stages of the rice water weevil, Lissorhoptrus oryzophilus. Effects of CAP and TMX on adult survival, egg-laying and first- and late-instar survivals were determined by infesting plants treated as seeds with different rates of insecticides. The biological activity was related to insecticidal concentrations in leaves, shoots and roots. RESULTS: CAP did not affect adult survival but decreased egg numbers and reduced the survival of the first and late instars. The greatest reduction in weevil population occurred in late instars feeding on roots. In contrast, TMX reduced adult survival and egg and larval numbers. The high biological activity of CAP on root-feeding stages was consistent with the accumulation of CAP in roots, whereas in TMX-treated plants the high activity on adults correlated with high concentrations of TMX in leaves and stems. CONCLUSIONS: The differential activity of insecticides on adults suggests poor inherent potency of CAP as an adulticide and/or its limited systemicity in foliage. The distribution of insecticide in specific plant parts can be attributed to the different physicochemical properties of CAP and TMX. The field implications of this research on management of L. oryzophilus are discussed. PMID- 23633168 TI - Pediatric voice. PMID- 23633167 TI - Kyphosis and decline in physical function over 15 years in older community dwelling women: the Study of Osteoporotic Fractures. AB - BACKGROUND: Maintaining physical function is an important prerequisite for preserving independence in later life. Greater degrees of kyphosis in the thoracic spine are prevalent in older persons and accompanied by reduced physical function in multiple cross-sectional studies. It is unknown whether kyphosis predicts worse physical function over time. METHODS: We retrospectively assessed whether greater magnitude of kyphosis is associated with decline in self-reported and objectively measured physical function over 15 years. Digitized Cobb angle kyphosis (T4-T12) was derived from supine lateral thoracic spine radiographs in a cohort of 1,196 women aged 65 and older (mean = 69.3 years [SD = 4.0]). Using regression models, we evaluated associations of baseline kyphosis with both self reported functional status and objectively measured gait speed, grip strength, and timed chair stands cross-sectionally and as change assessed over 15 years. RESULTS: In cross-sectional multivariate analyses, with each 10-degree increment of kyphosis, grip strength was 0.24 kg lower (p = .02), but there were no significant associations between kyphosis and functional status, gait speed, or timed chair stand, likely reflecting the high functioning study participants. In multivariate longitudinal analysis, with each 10-degree increment in baseline kyphosis, there was 0.07 point additional decline in functional status (p = .09), 0.01 m/s more decline in gait speed (p = .07), and 0.32 s greater decline in time to complete five chair stands (p = .004), but no association with decline in grip strength. CONCLUSIONS: Greater magnitude of kyphosis may predict worsening lower extremity function over time in older women. Early recognition and preventative measures against kyphosis progression may help preserve physical function over the long term. PMID- 23633169 TI - The role of the speech-language pathologist in the schools for the treatment of voice disorders: working within the framework of the individuals with disabilities education improvement act. AB - The role of the speech-language pathologist (SLP) has developed considerably over the past 20 years given the medical and technological advances in life-sustaining procedures. Children born with congenital, surgical, or "medically fragile" conditions become mainstreamed into regular school-based settings, thus extending the traditional role of the treating SLP and multidisciplinary team. Understanding the impact of associated voice disorders on educational performance requires dissemination of additional and important information, as eligibility decisions for students in school-based settings must be made within the framework of the federal legislation and regulations governing the provision of services for students with disabilities. This article discusses how to identify children with voice disorders under the Individuals with Disabilities Education Improvement Act (IDEA), the role of the SLP in various triaging scenarios, and how models of voice therapy can be integrated in a school-based setting. PMID- 23633170 TI - Care of the child's voice: a pediatric otolaryngologist's perspective. AB - Children with voice problems are encountered by speech-language pathologists working in schools but not with sufficient frequency to yield a great experience in managing them. Their evaluation and treatment now are best handled by a team of specialists in pediatric otolaryngology and speech-language pathology with expertise in voice and resonance disorders. The voice team uses a variety of assessment tools, including perceptual, parent- and patient-based, instrumental, and imaging measures. The most important component of the diagnostic assessment is laryngoscopy in the awake child, to visualize the vocal folds while the child phonates. This review covers the pediatric otolaryngologist's approach to dysphonia in children. The common causes of dysphonia are reviewed, including vocal nodules and other lesions, reflux laryngitis, laryngeal paralysis, congenital glottic webs, laryngeal papillomatosis, functional voice disorders, and velopharyngeal incompetence. Current treatment options are continually being modified. These are discussed by highlighting recently published research. PMID- 23633171 TI - Children's voice and voice disorders. AB - This article discusses the differences between children's voices and adult voices. We give an overview of the anatomy in the head and neck and specifically the anatomy of the respiratory system and the larynx. We also describe the development of children's voices including different physiological measures and voice quality. The development and consequences for voice production and voice quality are addressed and related to gender differences in the growing child. We also discuss the prevalence of voice problems and hoarseness in children. Environmental and other factors contributing to voice problems in children are described, and finally, issues related to intervention and evidence-based practice are discussed. PMID- 23633172 TI - Some guiding principles in emerging models of voice therapy for children. AB - Voice disorders are the most common communication disorder across the life span, affecting more than five million school-aged children annually in the United States alone. Although such disorders are commonly associated with benign pathology, medically malicious conditions cannot be ruled out without proper medical examination by an otolaryngologist. Many children with voice disorders are otherwise healthy. However, some are not. Moreover, children with voice problems of any origin often experience distinctly negative consequences in quality of life and academic participation as a result of them. Regrettably, this population is badly underserved by speech-language pathology. In this article, possible reasons are suggested, among them the relative unattractiveness of traditional therapy that emphasizes voice conservation using a Skinnerian paradigm. Alternatives are presented in terms of foundational principles of biomechanics, biology, and learning and factors affecting children's compliance with health care directives, which may help to shape the next generation of pediatric voice therapies. The article concludes with discussion of challenges surrounding voice therapy in the school setting and possible solutions. PMID- 23633173 TI - Talk it out: a conflict resolution program for preschool children with speech and language impairments. AB - Talk It Out was developed by speech-language pathologists to teach young children, especially those with speech and language impairments, to recognize problems, use words to solve them, and verbally negotiate solutions. One of the very successful by-products is that these same strategies help children avoid harming their voice. Across a school year, Talk It Out provides teaching and practice in predictable contexts so that children become competent problem solvers. It is especially powerful when implemented as part of the tier 1 preschool curriculum. The purpose of this article is to help school-based speech language pathologists (1) articulate the need and rationale for early implementation of conflict resolution programs, (2) develop practical skills to implement Talk It Out strategies in their programs, and (3) transfer this knowledge to classroom teachers who can use and reinforce these strategies on a daily basis with the children they serve. PMID- 23633174 TI - The association of a preschool voice education program with changes in yelling frequency. AB - Voice problems in children can occur as early as infancy. Early onset of voice problems can carry social and academic penalties, and negatively affect voice in adolescence or adulthood. Unfortunately, only 1% of school-aged children receive voice therapy despite a 6 to 24% prevalence of voice disorders in school-aged children. One alternative may be to use a classroom-based voice education curriculum to effectively reduce yelling frequency, the most common behavior associated with phonotrauma-related voice problems in children. A classroom-based voice education curriculum was administered to preschool children by the preschool speech-language pathologists in a university-affiliated program. Classroom teachers provided cueing and reinforcement of curriculum strategies for 8 weeks following the program. Baseline frequencies of participant yelling behaviors were compared with postprogram frequencies. Results demonstrated significant reduction in yelling frequencies from pre- to postprogram, particularly in those judged as high-frequency yellers prior to the program. Important factors for future consideration are discussed. PMID- 23633175 TI - Nonspecific chronic cough and paradoxical vocal fold motion disorder in pediatric patients. AB - Paradoxical vocal fold motion disorder and nonspecific chronic cough are laryngeal disorders that are newly identified within the speech-language pathologist's scope of practice. Recognizing the signs and symptoms of these disorders and providing practical and evidenced-based treatment is the focus of this article. Defining the role of the speech-language pathologist in treating these low incidence yet quickly remediated disorders provides the pediatric or school-based speech-language pathologist a unique service delivery challenge. A model that utilizes an interdisciplinary team to provide efficient and effective treatment outcomes is discussed. PMID- 23633178 TI - Evaluation of hepatic focal lesions using diffusion-weighted MR imaging: comparison of apparent diffusion coefficient and intravoxel incoherent motion derived parameters. AB - PURPOSE: To determine whether parameters obtained from intravoxel incoherent motion (IVIM)-diffusion-weighted imaging (DWI) using multiple b-values can improve characterization of common focal liver lesions (FLLs), compared with the apparent diffusion coefficient (ADCtotal ). MATERIALS AND METHODS: Our Institutional Review Board approved this retrospective study and informed consent was waived. In all, 142 patients with 169 FLLs underwent liver magnetic resonance imaging (MRI) including IVIM-DWI with multiple b factors at 3.0T. ADCtotal and IVIM-DWI-derived parameters including true diffusion (Dt ), pseudodiffusion (Dp ), and perfusion fraction (f) were calculated for each lesion and compared using dedicated software. RESULTS: Dt and ADCtotal were significantly lower in malignancies (0.95 +/- 0.21, 1.14 +/- 0.24, (*10(-3) mm(2) /sec)) than in benign FLLs (1.61 +/- 0.34, 1.72 +/- 0.37, (*10(-3) mm(2) /sec)). In the differential diagnosis of malignancies from benign lesions, Dt (Az value: 0.971) showed better diagnostic performance than ADCtotal (Az: 0.933) (P < 0.0005). Dt (Az: 0.961) also showed better diagnostic performance than ADCtotal (Az: 0.919) in differentiating hypervascular malignancies from benign hypervascular FLLs (P < 0.0005). In addition, Dp and f were significantly higher in hypervascular FLLs (35.74 +/- 20.08 (*10(-3) mm(2) /sec), 28.14 +/- 11.82 (%)) than hypovascular FLLs (21.87 +/- 13.8 (*10(-3) mm(2) /sec), 12.2 +/- 5.92 (%)) (P < 0.0001). CONCLUSION: Dt provided better diagnostic performance than ADCtotal in differentiating benign from malignant lesions. Dp and f were significant parameters for diagnosing hypervascular FLLs. PMID- 23633177 TI - Strategy to control type I error increases power to identify genetic variation using the full biological trajectory. AB - Genome-wide association studies have been successful in identifying loci that underlie continuous traits measured at a single time point. To additionally consider continuous traits longitudinally, it is desirable to look at SNP effects at baseline and over time using linear-mixed effects models. Estimation and interpretation of two coefficients in the same model raises concern regarding the optimal control of type I error. To investigate this issue, we calculate type I error and power under an alternative for joint tests, including the two degree of freedom likelihood ratio test, and compare this to single degree of freedom tests for each effect separately at varying alpha levels. We show which joint tests are the optimal way to control the type I error and also illustrate that information can be gained by joint testing in situations where either or both SNP effects are underpowered. We also show that closed form power calculations can approximate simulated power for the case of balanced data, provide reasonable approximations for imbalanced data, but overestimate power for complicated residual error structures. We conclude that a two degree of freedom test is an attractive strategy in a hypothesis-free genome-wide setting and recommend its use for genome-wide studies employing linear-mixed effects models. PMID- 23633179 TI - Stimulus specificity and dishabituation of operant responding in humans. AB - Habituation has recently been addressed within the operant conditioning paradigm. While the literature on this topic is growing, the examination of dishabituation, a fundamental characteristic of habituation, remains limited. This study expanded research on habituation of operant responding in non-human animals to research involving humans. Specifically, dishabituation and stimulus specificity were examined under a variety of conditions involving changes in the reinforcer type, reinforcement schedule, reinforcer amount, and selected properties of the antecedent stimuli for a computerized task with 46 undergraduate students. An additional 3 participants were exposed to a control condition. Evaluation of within session patterns of responding indicates that the introduction of stimulus changes into the operant context reliably produced dishabituation of operant responding in humans. PMID- 23633180 TI - Utilizing high-fidelity crucial conversation simulation in genetic counseling training. AB - Genetics professionals are often required to deliver difficult news to patients and families. This is a challenging task, but one that many genetics trainees have limited opportunity to master during training. This is true for several reasons, including relative scarcity of these events and an understandable hesitation of supervisors allowing a trainee to provide such high stakes information. Medical simulation is effective in other health care disciplines giving trainees opportunities of "hands on" education in similar high stakes situations. We hypothesized that crucial conversations simulation would be effective for genetics trainees to gain experience in communication and counseling skills in a realistic clinical scenario. To test this hypothesis, we designed a prenatal counseling scenario requiring disclosure of an abnormal amniocentesis result and discussion of pregnancy management options; we challenged participants to address common counseling questions. Three medical genetics resident physicians and five genetic counseling students participated. Genetics and simulation experts observed the session via live video feed from a different room. A behavioral checklist was completed in real time assessing trainee's performance and documenting medical information discussed. Debriefing immediately followed the session and included simulation and genetics experts and the actor parents. Participants completed open-ended post evaluations. There was a trend towards participants being more likely to discuss issues the child could have while an infant/toddler rather than issues that could emerge as the child with Down Syndrome transitions to adulthood and end of life (P=.069). All participants found the simulation helpful, notably that it was more realistic than role-playing with colleagues. PMID- 23633181 TI - Trauma care in Germany: an inclusive system. AB - BACKGROUND: Development of trauma systems is a demanding process. The United States and Germany both have sophisticated trauma systems. This manuscript is a summary of political, economic, and medical changes that have led to the development of both trauma systems and the current high-quality standards. QUESTIONS/PURPOSES: We specifically asked three questions: (1) What tasks are involved in developing a modern trauma system? (2) What is the approach to achieve this task? (3) Do these systems work? METHODS: We conducted a systematic review of relevant articles by searching electronic databases (PubMed, Embase, Cochrane library) using the following search terms: "trauma system", "polytrauma", "trauma networks", and "trauma registry". Of 2573 retrieved manuscripts, the authors made a personal selection of studies. A personal study selection from our experiences was added when their contribution to the topic was judged important. RESULTS: Worldwide, similar tasks concerning trauma care have to be addressed. In most societies, traffic accidents and firearm-related injuries contribute to a high number of trauma victims. The German approach has been to decrease the number of accidents through injury prevention and to provide better care by establishing an emergency medical system. For in-hospital treatment, clinical care has constantly improved and a close interaction with members from the American Association for the Surgery of Trauma and the Orthopaedic Trauma Association has helped a great deal to achieve these improvements. The German healthcare system was developed as a powerful healthcare tool covering patients from injury to rehabilitation. In addition, trauma and injury research has been strengthened to deal with various questions of trauma care. CONCLUSIONS: Organized injury prevention programs and systematized professional patient care can address the issues associated with the global burden of trauma. These trauma systems require constant monitoring and improvement. PMID- 23633182 TI - Impact of socioeconomic factors on outcome of total knee arthroplasty. AB - BACKGROUND: Few data exist regarding the impact of socioeconomic factors on results of current TKA in young patients. Predictors of TKA outcomes have focused primarily on surgical technique, implant details, and individual patient clinical factors. The relative importance of these factors compared to patient socioeconomic status is not known. QUESTIONS/PURPOSES: We determined whether (1) socioeconomic factors, (2) demographic factors, or (3) implant factors were associated with satisfaction and functional outcomes after TKA in young patients. METHODS: We surveyed 661 patients (average age, 54 years; range, 18-60 years; 61% female) 1 to 4 years after undergoing modern primary TKA for noninflammatory arthritis at five orthopaedic centers. Data were collected by an independent third party with expertise in collecting healthcare data for state and federal agencies. We examined specific questions regarding satisfaction, pain, and function after TKA and socioeconomic (household income, education, employment) and demographic (sex, minority status) factors. Multivariable analysis was conducted to examine the relative importance of these factors for each outcome of interest. RESULTS: Patients reporting incomes of less than USD 25,000 were less likely to be satisfied with TKA outcomes and more likely to have functional limitations after TKA than patients with higher incomes; no other socioeconomic factors were associated with satisfaction. Women were less likely to be satisfied and more likely to have functional limitations than men, and minority patients were more likely to have functional limitations than nonminority patients. Implants were not associated with outcomes after surgery. CONCLUSIONS: Socioeconomic factors, in particular low income, are more strongly associated with satisfaction and functional outcomes in young patients after TKA than demographic or implant factors. Future studies should be directed to determining the causes of this association, and studies of clinical results after TKA should consider stratifying patients by socioeconomic status. PMID- 23633183 TI - Total hip arthroplasty for the sequelae of Legg-Calve-Perthes disease. AB - BACKGROUND: The durability and risks associated with total hip arthroplasty (THA) for patients with a history of Legg-Calve-Perthes disease (LCPD) are not well known. QUESTIONS/PURPOSE: We sought to (1) determine the survivorship of THAs performed for LCPD; (2) assess hip scores and complications associated with THA in this patient population; and (3) compare results between patients who had undergone surgery in childhood with patients who had conservative treatment. METHODS: We reviewed 99 primary THAs performed in 95 patients with a history of LCPD with minimum 2-year followup (mean +/- SD, 8 +/- 5 years). Mean age at THA was 48 +/- 15 years. RESULTS: A total of 10 revisions were performed. Using revision for any reason as the end point, the 8-year survival rate was 90% (95% confidence interval [CI], 76%-96%) for cementless implants compared with 86% (95% CI, 57%-96%) for hybrid implants. The mean Harris hip score improved by 31 +/- 16 (n = 76). Complications occurred in 16% of hips. The most common major complication was intraoperative fracture (eight femoral, one acetabular). Three patients developed sciatic nerve palsy after a mean lengthening of 2.2 +/- 1 cm compared with a mean of 1.4 +/- 1 cm in patients with intact sciatic nerve (p = 0.3). CONCLUSIONS: Cementless THAs for the sequelae of LCPD demonstrate 90% survival from any revision at 8 years followup. THAs for the sequelae of LCPD can be complicated and technically difficult. Intraoperative fractures and nerve injuries are common. Care should be taken to avoid excessive limb lengthening. PMID- 23633184 TI - What is the success of treatment of hip and knee candidal periprosthetic joint infection? AB - BACKGROUND: Fungal infection at an arthroplasty site is rare and poses a therapeutic challenge. To the best of our knowledge, no reports have been published thus far on the success rate of prosthesis reimplantation after fungal prosthetic joint infections. QUESTIONS/PURPOSES: We asked: (1) What is the success rate in terms of infection eradication using a two-stage exchange arthroplasty in patients with hip or knee fungal periprosthetic joint infections, particularly focusing on Candida infections? (2) What patient-, infection-, and treatment-related variables are associated with the success or failure of treatment? METHODS: From January 2000 to December 2010, 16 patients with hip or knee candidal periprosthetic joint infections were treated with two-stage exchange arthroplasty at our institute. Treatment success was defined as a well functioning joint without relapse of candidal infection after prosthesis reimplantation, while treatment failure was defined as uncontrolled or relapse of candidal infection or mortality. Variables, including age, sex, comorbidities, microbiology, antimicrobial agents used, and operative methods, were analyzed. Minimum followup was 28 months (mean, 41 months; range, 28-90 months). RESULTS: At latest followup, the treatment failed to eradicate the infection in eight of the 16 patients, and there were four deaths related to fungemia. Four patients required permanent resection arthroplasty owing to uncontrolled or recurrent candidal infections. All eight patients (50% successful rate) who had their infections eradicated and successful prosthesis reimplantation had prolonged treatment with oral fluconazole before (mean, 8 months) and after (mean, 2.2 months) prosthesis reimplantation. The antifungal therapy correlated with successful treatment. Renal insufficiency, hypoalbuminemia, anemia, and chronic obstructive pulmonary disease were significantly more prevalent in the treatment failure group than in the treatment-success group. CONCLUSIONS: Half of the patients treated with two-stage exchange arthroplasty for fungal periprosthetic joint infections had recurrence or lack of control of the infection. A prolonged antifungal therapy appeared to be essential for successful treatment of candidal periprosthetic joint infections. The presence of renal insufficiency, hypoalbuminemia, anemia, or chronic obstructive pulmonary disease might be associated with a poor outcome. PMID- 23633185 TI - The classic. Review article: Traffic accidents. 1966. AB - This Classic Article is a translation of the original work by Prof. Harald Tscherne, Der Strabetaenunfall [Traffic Accidents]. An accompanying biographical sketch of Prof. Tscherne is available at DOI 10.1007/s11999-013-3011-x . An online version of the original German article is available as supplemental material. The Classic Article is reproduced with permission from Bruder Hollinek & Co. GesmbH, Purkersdorf, Austria. The original article was published in Wien Med Wochenschr. 1966;116:105-108. (Translated by Dr. Roman Pfeifer.). PMID- 23633187 TI - The Chitranjan Ranawat Award: Should prophylactic antibiotics be withheld before revision surgery to obtain appropriate cultures? AB - BACKGROUND: Preoperative antibiotics are known to be critical for decreasing the risk of periprosthetic joint infection (PJI) in primary THA and TKA. However, antibiotics often are withheld before revision surgery, as there is concern that even a single dose of prophylactic antibiotics may affect intraoperative cultures. QUESTIONS/PURPOSES: In this prospective randomized controlled trial, we determined the effect of a single dose of prophylactic antibiotics on cultures obtained at the time of revision arthroplasty. METHODS: We randomized 65 patients with known PJI after 37 TKAs and 28 THAs at three centers. Patients were included in the trial if they had a culture-positive aspiration and had not taken antibiotics within 2 weeks of the procedure. Patients were randomized to receive prophylactic antibiotics either before the skin incision or after a minimum of three sets of intraoperative cultures were obtained. Preoperative and intraoperative cultures were then compared. Results between patients who did and did not receive antibiotics were compared using an equivalence test for proportion differences (two one-sided t-tests [TOST]) with a 0.2 margin. RESULTS: Intraoperative cultures yielded the same organisms as preoperative cultures in 28 of 34 patients (82%) randomized to receive antibiotics before the skin incision compared to 25 of 31 patients (81%) randomized to receive antibiotics after obtaining operative cultures (statistically equivalent by TOST estimate: p = 0.0290). CONCLUSIONS: In this randomized controlled trial, there was no effect on the results of cultures obtained intraoperatively when prophylactic antibiotics were administered before skin incision. Given the known benefits of prophylactic antibiotics in preventing PJI, preoperative prophylaxis should not be withheld in revision surgery for fear of affecting cultures. PMID- 23633188 TI - Toxicity risk of insecticides to the insect egg parasitoid Trichogramma evanescens Westwood (Hymenoptera: Trichogrammatidae). AB - BACKGROUND: Natural populations of Trichogramma evanescens contribute to the control of lepidopterous pests. The toxic effects of insecticides have been extensively reported on trichogrammatids, but are largely unknown on T. evanescens. In this study, the toxicities of seven classes of chemicals against the parasitoid were investigated. RESULTS: Among these classes, organophosphates and carbamates exhibited the highest levels of intrinsic toxicity, with LC50 values ranging from 0.025 (0.023-0.028) to 2.20 (1.71-3.09) and from 0.040 (0.032 0.053) to 1.84 (1.53-2.30) mg AI L(-1) respectively. Among the phenylpyrazoles, only ethiprole can be considered to be less toxic in the group. Avermectins, pyrethroids and neonicotinoids were less toxic, with LC50 values ranging from 1.29 to 2.57, from 2.26 to 14.03 and from 1.12 to 239.1 mg AI L(-1) respectively. In contrast, insect growth regulators (IGRs) showed the lowest toxicity to the parasitoid, with LC50 values ranging from 3383 (2406-5499) to 5650 (4228-8579) mg AI L(-1) . CONCLUSION: The results of risk quotient analysis indicated that neonicotinoids, avermectins, pyrethroids and IGRs were less hazardous, but phenylpyrazoles (except for ethiprole), organophosphates and carbamates were slightly to moderately or dangerously toxic to T. evanescens. The present results provide informative data for implementing biological and chemical control strategies in integrated pest management of lepidopterans. PMID- 23633186 TI - Measuring expectations in orthopaedic surgery: a systematic review. AB - BACKGROUND: Advances in the surgical treatment of musculoskeletal conditions have resulted in an interest in better defining and understanding patients' expectations of these procedures, but the best ways to do this remain a topic of considerable debate. QUESTIONS/PURPOSES: (1) What validated instruments for the assessment of patient expectations of orthopaedic surgery have been used in published studies to date? (2) How were these expectation measures developed and validated? (3) What unvalidated instruments for the assessment of patient expectations have been used in published studies to date? METHODS: A systematic literature search was performed using the OVID Medline and EMBASE databases, in duplicate, to identify all studies that assessed patient expectations in orthopaedic surgery. Sixty-six studies were ultimately included in the present review. RESULTS: Seven validated expectation instruments were identified, all of which use patient-reported questionnaires. Five were specific to a particular procedure or affected anatomic location, whereas two were broadly applicable. Details of reliability and validity testing were available for all but one of these instruments. Forty additional unvalidated expectation assessment tools were identified. Thirteen were based on existing clinical outcome tools, and the others were study-specific, custom-developed tools. Only one of the unvalidated tools was used in more than one study. CONCLUSIONS: Several validated expectation instruments have been developed for use by patients undergoing orthopaedic surgery. However, many tools have been reported without evidence of testing and validation. The wide range of untested instruments used in single studies substantially limits the interpretation and comparison of data concerning patient expectations. PMID- 23633189 TI - Involvement of PARP-1 Val762Ala polymorphism in the onset of cervical cancer in caucasian women. AB - BACKGROUND AND OBJECTIVE: Data on the Val762Ala (rs1136410) polymorphism in the poly(adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP-1) gene as a risk factor for various types of cancers in different ethnicities are inconsistent. We studied this association in a Caucasian population. METHODS: Using high resolution melting curve analysis (HRM), we studied the distribution of the PARP 1 Val762Ala polymorphism in patients with cervical cancer (n = 446) and in controls (n = 491). RESULTS: Logistic regression analysis adjusting for age, pregnancy, oral contraceptive use, tobacco smoking, and menopausal status demonstrated that the PARP-1 Val762Ala polymorphism was associated with an increased risk of cervical cancer. The adjusted odds ratio (OR) for patients with the Ala/Val genotype versus the Val/Val genotype was 1.381 (95 % CI = 1.025 1.859, p = 0.033), and the adjusted OR for the Ala/Ala or Ala/Val genotype versus the Val/Val genotype was 1.403 (95 % CI = 1.057-1.863, p = 0.019). The p value from the chi-square test of the trend observed for the PARP-1 Val762Ala polymorphism was statistically significant (p trend = 0.0123). Stratified analyses of the PARP-1 Val762Ala genotype distribution and cervical cancer risk showed that the age-adjusted OR of Ala/Ala or Ala/Val vs Val/Val for pregnancy was 1.388 (95 % CI = 1.027-1.877, p = 0.0328), 1.773 (95 % CI = 1.145-2.745, p = 0.0100) for contraceptive use, and 1.604 (95 % CI = 1.132-2.272, p = 0.0077) for postmenopausal women. The age-adjusted OR of Ala/Val vs Val/Val for contraceptive use was 1.769 (95 % CI = 1.114-2.809, p = 0.0154) and for postmenopausal women was 1.577 (95 % CI = 1.094-2.272, p = 0.0143). CONCLUSION: Our studies suggest that the PARP-1 Val762Ala polymorphism may be a genetic risk factor for cervical cancer. PMID- 23633191 TI - Pregnancy and venous thromboembolism. AB - Pregnancy and the postpartum period are associated with an increased risk of venous thromboembolism (VTE), which complicates 1 to 2 of 1,000 pregnancies and represents a leading cause of mortality during pregnancy in developed countries. Strong evidence for the management of pregnancy-related VTE is missing, mostly because pregnant women have been excluded from all major trials investigating different diagnostic tools and treatment regimens. Nevertheless, proper evaluation of the involved risk factors is mandatory to reduce the incidence of pregnancy-related VTE and improve outcomes. Low-molecular-weight heparins are considered as a first-line option in the management of pregnancy-related VTE. With regard to future research, there is a need for methodologically strong studies in pregnant women, especially with respect to risk stratification, optimal heparin doses, usefulness of anti-FXa levels and their correlation with clinical outcomes, and correct management of anticoagulation during delivery. PMID- 23633192 TI - Arterial and venous thrombosis in endocrine diseases. AB - Endocrine diseases have been associated with cardiovascular events. Both altered coagulation and fibrinolysis markers and thrombotic disorders have been described in several endocrine diseases. This review summarizes the evidence on the influence of thyroid diseases, cortisol excess and deficiency, pheochromocytoma, hyperparathyroidism, hyperaldosteronism, hyperprolactinemia, and growth hormone excess and deficiency; on parameters of hemostasis; and on arterial and venous thrombotic events. All these endocrine diseases do have, or may have, influence either on hemostasis or on the risk of thrombotic events. Future studies are needed to establish the clinical relevance of these associations. PMID- 23633193 TI - JAK2 mutation-related disease and thrombosis. AB - A recurrent JAK2V617F mutation is typically associated with chronic myeloproliferative neoplasms (MPNs) that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis. This mutation results in a gain of function that is credited to underlie most of the pathogenesis and phenotypic characteristics of these disorders; it serves as a key diagnostic marker and represents a suitable target for JAK2 inhibitors. Because cardiovascular events represent the main cause of morbidity and mortality in PV and ET, current patients' risk stratification is based on variables predicting individual thrombotic risk (age and previous thrombotic history). However, evidence is accumulating that supports a role of JAK2V617F mutation as a novel risk factor for thrombosis, although prospective validation has not been provided yet. In this review, we discuss about potential mechanisms that link mutated JAK2 with the thrombotic propensity of MPN and the clinical correlates; hopefully, novel information could result in better patient management. PMID- 23633194 TI - The DPP-4 inhibitor linagliptin restores beta-cell function and survival in human isolated islets through GLP-1 stabilization. AB - CONTEXT: Inhibition of dipeptidyl peptidase-4 (DPP-4) is a potent strategy to increase glucose-dependent insulinotropic polypeptide and glucagon like peptide 1 (GLP-1) induced insulin secretion in diabetes. It is important to know whether new drugs approved for the treatment of type 2 diabetes have direct effects on the beta-cell. OBJECTIVE: Herein we investigated the effect of linagliptin, a novel DPP-4 inhibitor, on beta-cell function and survival. DESIGN: Human islets were exposed to a diabetic milieu (11.1-33.3 mM glucose, 0.5 mM palmitate, the mixture of 2 ng/mL IL-1beta+1000 U/mL interferon-gamma, or 50 MUM H2O2) with or without 500 ng/mL IL-1 receptor antagonist (IL-1Ra) or 30-50 nM linagliptin. RESULTS: Linagliptin restored beta-cell function and turnover, which was impaired when islets were exposed to elevated glucose, palmitate, cytokines, or H2O2. Pretreatment with IL-1Ra was similarly effective, except against H2O2 treatment. Nitrotyrosine concentrations in islet lysates, an indicator of oxidative stress, were highly elevated under diabetic conditions but not in islets treated with linagliptin or IL-1Ra. Linagliptin also reduced cytokine secretion and stabilized GLP-1 in islet supernatants. CONCLUSIONS: We show that the novel DPP-4 inhibitor linagliptin protected from gluco-, lipo-, and cytokine-toxicity and stabilized active GLP-1 secreted from human islets. This provides a direct GLP-1 mediated protective effect of linagliptin on beta-cell function and survival. PMID- 23633195 TI - Association of glypican-4 with body fat distribution, insulin resistance, and nonalcoholic fatty liver disease. AB - CONTEXT AND OBJECTIVE: Glypican-4 was identified as a novel adipokine capable of enhancing insulin signaling and modulating adipocyte differentiation. We investigated associations between glypican-4 and body composition, insulin resistance, arterial stiffness, and nonalcoholic fatty liver disease (NAFLD) in nondiabetic Asian subjects. DESIGN AND PARTICIPANTS: We analyzed baseline cross sectional data from the Korean Sarcopenic Obesity Study, an ongoing prospective cohort study. NAFLD was diagnosed by unenhanced computed tomography using the liver attenuation index. We also examined the effects of a 3-month combined aerobic and resistance exercise program on glypican-4 levels and cardiometabolic risk factors. RESULTS: Circulating glypican-4 levels were higher in men than in women (1.83 [1.19, 2.78] ng/mL vs 1.17 [0.66, 2.00] ng/mL, P < .001) and had a significant positive relationship with the waist-to-hip ratio (WHR) (r = 0.20, P = .014) and the ratio of visceral to sc fat area (r = 0.30, P < .001). Furthermore, glypican-4 levels in women were correlated with cardiometabolic risk factors, including insulin resistance and arterial stiffness, and were independently associated with NAFLD by multiple logistic regression analysis (P = .017, R2 = 0.33). The 3-month combined exercise training program significantly improved several cardiometabolic parameters and reduced retinol binding protein-4 levels. Changes in glypican-4 levels after the exercise program were significantly different between subjects with an increased WHR compared with those with a decreased WHR (P = .034). CONCLUSION: A gender-based difference in circulating glypican-4 levels was apparent as these were increased in women with NAFLD and related to body fat distribution, insulin resistance, and arterial stiffness. PMID- 23633196 TI - Joint effect of insulin signaling genes on insulin secretion and glucose homeostasis. AB - CONTEXT: Reduced insulin signaling in insulin secreting beta-cells causes defective insulin secretion and hyperglycemia in mice. OBJECTIVE: We investigated whether functional polymorphisms affecting insulin signaling (ie, ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; and TRIB3 Q84R, rs2295490) exert a joint effect on insulin secretion and abnormal glucose homeostasis (AGH). DESIGN: Insulin secretion was evaluated by 1) the disposition index (DI) from an oral glucose tolerance test (OGTT) in 829 individuals; 2) insulin secretion stimulation index (SI) in islets from nondiabetic donors after glucose (n = 92) or glibenclamide (n = 89) stimulation. AGH (including impaired fasting glucose and/or impaired glucose tolerance or type 2 diabetes; T2D) was evaluated in case-control studies from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) Consortium (n = 6607). RESULTS: Genotype risk score, obtained by totaling individual weighted risk allele effects, was associated with the following: 1) DI (P = .005); 2) glucose and glibenclamide SI (P = .046 and P = .009); or 3) AGH (odds ratio 1.08, 95% confidence interval 1.03-1.13; P = .001). We observed an inverse relationship between genetic effect and age at AGH onset, as indicated by a linear correlation between AGH-genotype risk score odds ratios and age-at diagnosis cutoffs (R(2) = 0.80, P < .001). CONCLUSIONS: Functional polymorphisms affecting insulin signaling exert a joint effect on both in vivo and in vitro insulin secretion as well as on early-onset AGH. Our data provide further evidence that abnormal insulin signaling reduces beta-cell function and impairs glucose homeostasis. PMID- 23633198 TI - Gender difference in the relationship between passive smoking exposure and HDL cholesterol levels in late adolescence. AB - BACKGROUND: High-density lipoprotein-cholesterol (HDL-C) levels are influenced by gender and by genetic and environmental factors. We aimed to assess the impact of passive smoking exposure since birth on HDL-C levels of nonsmoking adolescents at age 17 years and to determine whether there was a gender difference in the relationship between smoking exposure and HDL-C. METHODS: A total of 804 nonsmoking adolescents with biochemical, anthropometric, and lifestyle data from a cohort of 1754 adolescents (mean age, 17 +/- 0.25 y) of the Western Australian Pregnancy Cohort (Raine) Study had data of maternal smoking during pregnancy and smoking exposure in the household over 17 years. HDL-C was analyzed using multivariable linear regression, with adjustment for early-life, adiposity, and current lifestyle confounders. RESULTS: HDL-C levels were significantly lower in girls exposed to passive smoking compared to those not exposed (regression coefficient b = -0.09 [95% confidence interval, -0.15, -0.03]); this was not observed in boys (b = 0.02 [95% confidence interval, -0.04, 0.08]), with a significant sex interaction P = .009. The effects of passive smoking in girls persisted after adjusting for oral contraceptive use. CONCLUSIONS: This study has shown a gender difference in the relationship between passive smoking exposure since birth and HDL-C in late adolescence. Exposure to passive smoking in girls could have adverse consequences on their risk of cardiovascular disease in adulthood. These findings reinforce the need for future public health measures to reduce children's exposure to passive smoking. PMID- 23633190 TI - Mechanisms of heat shock response in mammals. AB - Heat shock (HS) is one of the best-studied exogenous cellular stresses. The cellular response to HS utilizes ancient molecular networks that are based primarily on the action of stress-induced heat shock proteins and HS factors. However, in one way or another, all cellular compartments and metabolic processes are involved in such a response. In this review, we aimed to summarize the experimental data concerning all aspects of the HS response in mammalian cells, such as HS-induced structural and functional alterations of cell membranes, the cytoskeleton and cellular organelles; the associated pathways that result in different modes of cell death and cell cycle arrest; and the effects of HS on transcription, splicing, translation, DNA repair, and replication. PMID- 23633197 TI - Comparisons of immunoassay and mass spectrometry measurements of serum estradiol levels and their influence on clinical association studies in men. AB - CONTEXT: Immunoassay-based techniques, routinely used to measure serum estradiol (E2), are known to have reduced specificity, especially at lower concentrations, when compared with the gold standard technique of mass spectrometry (MS). Different measurement techniques may be responsible for the conflicting results of associations between serum E2 and clinical phenotypes in men. OBJECTIVE: Our objective was to compare immunoassay and MS measurements of E2 levels in men and evaluate associations with clinical phenotypes. DESIGN AND SETTING: Middle-aged and older male subjects participating in the population-based Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2599), MrOS US (n = 688), and the European Male Aging Study (n = 2908) were included. MAIN OUTCOME MEASURES: Immunoassay and MS measurements of serum E2 were compared and related to bone mineral density (BMD; measured by dual energy x-ray absorptiometry) and ankle brachial index. RESULTS: Within each cohort, serum E2 levels obtained by immunoassay and MS correlated moderately (Spearman rank correlation coefficient rS 0.53-0.76). Serum C-reactive protein (CRP) levels associated significantly (albeit to a low extent, rS = 0.29) with immunoassay E2 but not with MS E2 levels. Similar associations of immunoassay E2 and MS E2 were seen with lumbar spine and total hip BMD, independent of serum CRP. However, immunoassay E2, but not MS E2, associated inversely with ankle-brachial index, and this correlation was lost after adjustment for CRP. CONCLUSIONS: Our findings suggest interference in the immunoassay E2 analyses, possibly by CRP or a CRP-associated factor. Although associations with BMD remain unaffected, this might imply for a reevaluation of previous association studies between immunoassay E2 levels and inflammation-related outcomes. PMID- 23633199 TI - Subclinical hypothyroidism and cardiovascular risk: how to end the controversy. PMID- 23633201 TI - Effects of ingestion routes on hormonal and metabolic profiles in gastric bypassed humans. AB - CONTEXT: Gastric bypass surgery (GBP) results in the rapid resolution of type 2 diabetes. Most studies aiming to explain the underlying mechanisms are limited to data obtained after a postsurgical recovery period, making assessment of confounding influences from, for example, weight loss and altered nutrient intake difficult. OBJECTIVE: To examine the impact of GBP on hormonal and metabolite profiles under conditions of identical nutrient intake independent of weight loss, we studied GBP patients fitted with a gastrostomy tube to enable the administration of nutrients to bypassed segments of the gut. Thus, this model allowed us to simulate partially the preoperative condition and compare this with the postoperative situation in the same patient. DESIGN: Patients (n = 4) were first given a mixed meal test (MMT) orally and then via the gastrostomy tube, preceded by overnight and 2-hour fasting, respectively. Blood samples were assessed for hormones and metabolites. RESULTS: The oral MMT yielded 4.6-fold increase in plasma insulin (P < .05), 2-fold in glucagon-like peptide-1 (P < .05), and 2.5-fold in glucose-dependent insulinotropic peptide (P < .05) plasma levels, compared with the gastrostomy MMT. The changes in hormone levels were accompanied by elevated branched-chain amino acid levels (1.4-2-fold, P < .05) and suppressed fatty acid levels (~50%, P < .05). CONCLUSIONS: These data, comparing identical nutrient delivery, demonstrate markedly higher incretin and insulin responses after oral MMT than after gastric MMT, thereby providing a potential explanation for the rapid remission of type 2 diabetes observed after GBP. The simultaneous increase in branched-chain amino acid questions its role as a marker for insulin resistance. PMID- 23633200 TI - Coexistence of THRB and TBG gene mutations in a Turkish family. AB - OBJECTIVE: Resistance to thyroid hormone is a syndrome characterized by high serum free T4 levels and unsuppressed serum TSH concentration. Thyroxine-binding globulin complete deficiency manifests with low serum total T4 and T3 levels and normal serum TSH concentration. Our objective is to describe a family with the coexistence of resistance to thyroid hormone and thyroxine-binding globulin complete deficiency. METHODS: We conducted clinical studies and genetic analyses. RESULTS: The proband presented with mental retardation, hearing loss, and recurrent upper respiratory tract infections accompanied by high serum levels of TSH, T3, T4, and high thyroglobulin antibody titers. His elder sister presented with normal TSH and T3 and high serum T4 levels. Both patients were found to be heterozygous for the mutation P453A in the thyroid hormone receptor beta (THRB) gene. One of the proband's brothers had low serum total T3 and T4 and normal TSH concentrations, without any clinical manifestations. He was hemizygous for the mutation P50fs51X in the TBG gene. The proband's mother showed slightly elevated TSH, normal total T3 and T4, and elevated titers of thyroperoxidase antibodies and thyroglobulin antibodies. She was heterozygous for both THRB and TBG genes mutations. CONCLUSIONS: To our knowledge, this is the first report of the coexistence of THRB and TBG gene mutations in the same individual (mother of the proband), whereas other affected family members had only 1 of the 2 genes mutated. The case illustrates the difficulty that might be encountered in the interpretation of thyroid function tests when different genetic defects affecting thyroid function coexist. PMID- 23633202 TI - Relation between circulating levels of 25(OH) vitamin D and parathyroid hormone in chronic kidney disease: quest for a threshold. AB - CONTEXT: Vitamin D deficiency is common in patients with chronic kidney disease (CKD). Current guidelines recommend treatment strategies in these patients similar to those for the general population, but the vitamin D nutritional status sufficient to prevent PTH levels from increasing in CKD is unknown. OBJECTIVE, MAIN OUTCOME MEASURE: Our aim was to study the relation between circulating PTH and 25(OH)D levels and to search for a 25(OH)D threshold associated with a significant PTH increase. DESIGN, SETTING, AND PATIENTS: In the hospital-referred NephroTest cohort study, we measured 25(OH)D, PTH, and glomerular filtration rate (mGFR) by 51Cr-EDTA renal clearance in 929 adult patients with nondialysis CKD stages 1 to 5 and no vitamin D supplementation. Patients' mean age was 60.1 +/- 14.7 years; 71% were men, and 9% were black. Their median mGFR was 37.8 mL/min/1.73 m2. RESULTS: We found a 25(OH)D threshold of 8 ng/mL with an upper limit of 20 ng/mL (95% confidence interval) by linear piecewise regression modeling of log-PTH for 25(OH)D adjusted for mGFR, age, race, and ionized calcium level. The smoothed curve confirmed that PTH concentration rose steeply when circulating 25(OH)D levels fell to less than 20 ng/mL. CONCLUSIONS: Spontaneous 25(OH)D levels greater than 20 ng/mL seem sufficient to control serum PTH in CKD patients. This result reinforces guidelines to supplement vitamin D only if less than 30 ng/mL. PMID- 23633203 TI - Familial SDHA mutation associated with pituitary adenoma and pheochromocytoma/paraganglioma. AB - CONTEXT: Reports of the coexistence of pituitary adenomas and pheochromocytoma/paraganglioma are uncommon. Recently germline mutations in 2 of the genes encoding succinate dehydrogenase, SDHC and SDHD, were associated with pituitary tumors. OBJECTIVE: Our aim was to determine whether the development of a pituitary adenoma was associated with SDHA mutation. PATIENTS: A 46-year-old female presented with carotid body paraganglioma (proband). Subsequently the proband's son was diagnosed with a nonfunctioning pituitary macroadenoma at age 30 years. RESULTS: An immunohistochemical analysis of the resected paraganglioma and pituitary adenoma revealed the loss of succinate dehydrogenase subunit B and succinate dehydrogenase subunit A (SDHA) expression in both tumors, with the preservation of staining in nonneoplastic tissue. Mutation analysis showed a novel SDHA mutation (c.1873C>T, p.His625Tyr) in the germline of the proband as well as in the proband's son. In the paraganglioma of the proband, in addition to the germline mutation, a somatic mutation was observed (c.1865G>A, p.Trp622*). In the pituitary adenoma of the proband's son, loss of SDHA immunoreactivity was paradoxically accompanied by loss of the mutant allele. CONCLUSIONS: This is the first report of a pituitary adenoma arising in the setting of germline SDHA mutation. The loss of SDHA protein expression in both the paraganglioma (proband) and pituitary adenoma (proband's son) argues strongly for a causative role of SDHA mutation. This report further strengthens the link between pituitary neoplasia and germline SDH mutation. Although pituitary adenomas appear rare among patients carrying SDH subunit mutations, they may have been underrecognized due to the low penetrance of disease and lack of systematic surveillance. PMID- 23633204 TI - Mild iodine deficiency during pregnancy is associated with reduced educational outcomes in the offspring: 9-year follow-up of the gestational iodine cohort. AB - CONTEXT: Severe iodine deficiency (ID) during gestation is associated with neurocognitive sequelae. The long-term impact of mild ID, however, has not been well characterized. OBJECTIVE: The purpose of this study was to determine whether children born to mothers with urinary iodine concentrations (UICs) <150 MUg/L during pregnancy have poorer educational outcomes in primary school than peers whose mothers did not have gestational ID (UIC >=150 MUg/L). DESIGN: This was a longitudinal follow-up (at 9 years old) of the Gestational Iodine Cohort. Pregnancy occurred during a period of mild ID in the population, with the children subsequently growing up in an iodine-replete environment. SETTING AND PARTICIPANTS: Participants were children whose mothers attended The Royal Hobart Hospital (Tasmania) antenatal clinics between 1999 and 2001. MAIN OUTCOME MEASURES: Australian national curriculum and Tasmanian state curriculum educational assessment data for children in year 3 were analyzed. RESULTS: Children whose mothers had UIC <150 MUg/L had reductions of 10.0% in spelling ( 41.1 points, 95% confidence interval [CI], -68.0 to -14.3, P = .003), 7.6% in grammar (-30.9 points, 95% CI, -60.2 to -1.7, P = .038), and 5.7% in English literacy (-0.33 points, 95% CI, -0.63 to -0.03, P = .034) performance compared with children whose mothers' UICs were >=150 MUg/L. These associations remained significant after adjustment for a range of biological factors (maternal age at birth of child, gestational length at time of birth, gestational age at time of urinary iodine collection, birth weight, and sex). Differences in spelling remained significant after further adjustment for socioeconomic factors (maternal occupation and education). CONCLUSIONS: This study provides preliminary evidence that even mild iodine deficiency during pregnancy can have long-term adverse impacts on fetal neurocognition that are not ameliorated by iodine sufficiency during childhood. PMID- 23633205 TI - Molecular diagnosis of 5alpha-reductase deficiency in 4 elite young female athletes through hormonal screening for hyperandrogenism. AB - CONTEXT: Although a rare occurrence, previously undiagnosed disorders of sex development (DSD) with hyperandrogenism are sometimes detected by hormonal screening during the international sports competitions. Identifying the cause of XY,DSD raises medical and ethical concerns, especially with regard to issues of the eligibility to compete. OBJECTIVE: The aim of this study was to determine whether the detection of high plasma T in young elite female athletes during hormonal screening would reveal an unsuspected XY DSD. SETTING: The study was performed in the Nice and Montpellier University Hospitals (France), which collaborate as reference centers for DSD in elite athletes on behalf of sports governing bodies. PATIENTS: Four cases of elite young athletes with female phenotypes but high plasma T detected during hormonal screening were investigated for undiagnosed XY DSD. MAIN OUTCOME MEASURES: Evaluation of clinical, biological, radiological (magnetic resonance imaging and dual-energy x-ray absorptiometry) and genetic characteristics was conducted. RESULTS: The 4 athletes presented as tall, slim, muscular women with a male bone morphotype, no breast development, clitoromegaly, partial or complete labial fusion, and inguinal/intralabial testes. All reported primary amenorrhea. The hormonal analysis evidenced plasma T within the male range, the karyotype was 46, XY, and molecular analysis of the 5alpha-reductase type 2 (srd5A2) gene identified a homozygotic mutation in 2 cases, a heterozygotic compound in 1 case, and a deletion in 1 case. CONCLUSION: 5alpha-Reductase deficiency should be investigated in elite young female athletes with primary amenorrhea and high male T levels detected during antidoping programs to identify undiagnosed XY DSD. PMID- 23633207 TI - Visceral fat accumulation and postdexamethasone serum cortisol levels in patients with adrenal incidentaloma. AB - OBJECTIVE: Visceral fat is a significant cardiovascular risk factor. Because visceral fat has not been measured systematically in patients with adrenal incidentalomas, we have tested the hypothesis that visceral fat volume may be associated with cutoffs for serum cortisol levels post dexamethasone. DESIGN: This was a retrospective, cross-sectional study. SETTING: The study was conducted at the Endocrine Investigation Unit, University Teaching Hospital. PARTICIPANTS: Seventy-three women and 52 men diagnosed with adrenal incidentalomas and 9 patients with overt Cushing's syndrome participated in this study. MAIN OUTCOME MEASURES: The following was measured for serum cortisol level after dexamethasone suppression and visceral fat ratios: visceral-subcutaneous (V:S) and visceral total volume (V:TV) measured by computed tomography. RESULTS: Sixty-eight patients with a postdexamethasone serum cortisol greater than 1.8 MUg/dL (50 nmol/L) showed a significantly higher mean V:S and V:TV fat ratio compared with those whose serum cortisol was less than 1.8 MUg/dL: women, lnV:S, -0.45 vs -0.69 [mean difference 0.24 (95% confidence interval [CI] 0.08-0.41); P = .004] and V:TV, 0.39 vs 0.34 [mean difference 0.05 (95% CI 0.02-0.09); P = .004]; men, lnV:S, 0.64 vs 0.29 [mean difference 0.35 95% CI 0.08-0.63); P = .01] and V:TV, 0.65 vs 0.57 [mean difference 0.08 (95% CI 0.02-0.14); P = .02]. By ANOVA and post hoc analysis (Fisher's least significant differences), there was no difference in fat ratios between the postdexamethasone serum cortisol groups [1.8 2.9 MUg/dL (50-82 nmol/L), 3.0-5.0 MUg/dL (83-137 nmol/L), > 5.0 MUg/dL (>138 nmol/L) and Cushing's syndrome (mean V:TV: 0.38, 0.40, 0.40, 0.41, respectively)], but they all differed significantly from the less than the 1.8 MUg/dL group (V:TV: 0.34, P = .03). CONCLUSION: Visceral fat is increased in patients with adrenal incidentalomas and a postdexamethasone serum cortisol of greater than 1.8 MUg/dL and is similar to that found in patients with overt Cushing's syndrome. PMID- 23633206 TI - Divergent expression of IL-1 receptor antagonists in CD34+ fibrocytes and orbital fibroblasts in thyroid-associated ophthalmopathy: contribution of fibrocytes to orbital inflammation. AB - CONTEXT: Thyroid-associated ophthalmopathy (TAO) manifests as inflammation of orbital connective tissue. Bone marrow-derived CD34+ fibrocytes infiltrate the orbit in TAO where they become CD34+ orbital fibroblasts. They express thyroid specific antigens and thus may contribute to inflammation. Evidence suggests that orbital susceptibility to TAO may involve IL-1, which is modulated by IL-1 receptor antagonists, designated secreted (sIL-1RA) and intracellular (icIL-1RA). OBJECTIVE: We sought to characterize the expression of sIL-1RA and icIL-1RA in TAO orbital fibroblasts compared to CD34+ fibrocytes. DESIGN/SETTING/PARTICIPANTS: Patients with TAO and healthy donors were recruited from an academic medical center clinical practice. MAIN OUTCOME MEASURES: Real time PCR, cytokine-specific ELISA, gene promoter activities, transcriptional analysis, mRNA stability, and cytometric cell sorting were performed. RESULTS: Orbital fibroblasts treated with IL-1beta exhibit greater inductions of IL 1alpha, IL-1beta, and prostaglandin endoperoxide H synthase-2 transcripts than do fibrocytes. Fibrocytes express dramatically higher basal levels of both icIL-1RA and sIL-1RA. When treated with IL-1beta, icIL-1RA is induced in orbital fibroblasts but not sIL-1RA, whereas in fibrocytes, sIL-1RA is dominantly up regulated. These inductions result from increased steady-state levels of respective mRNAs, enhanced transcript stabilities, and modestly increased gene transcription. CONCLUSIONS: Robust responses of TAO orbital fibroblasts to IL 1beta are a consequence of low-level sIL-1RA expression. This results in poorly opposed actions of IL-1beta. In contrast, circulating fibrocytes express high levels of sIL-1RA, which are diminished as these cells transition to orbital fibroblasts. These findings identify an explanation for the inflammatory phenotype exhibited by TAO orbital fibroblasts and provide a potential target for altering disease susceptibility. PMID- 23633208 TI - Childhood craniopharyngioma: hypothalamus-sparing surgery decreases the risk of obesity. AB - CONTEXT: Craniopharyngioma is a brain tumor whose high local recurrence rate has for a long time led to a preference for extensive surgery. Limited surgery minimizing hypothalamic damage may decrease the severe obesity rate at the expense of the need for radiotherapy to complete the treatment. OBJECTIVE: We compared weight gain and local recurrence rates after extensive resection surgery (ERS) and hypothalamus-sparing surgery (HSS). DESIGN: Our observational study compared a historical cohort managed with ERS between 1985 and 2002 to a prospective cohort managed with HSS between 2002 and 2010. SETTING: The patients were treated in a pediatric teaching hospital in Paris, France. PATIENTS: Thirty seven boys and 23 girls were managed with ERS (median age, 8 years); 38 boys and 27 girls were managed with HSS (median age, 9.3 years). MAIN OUTCOME MEASURES: Data were collected before and 6 months to 7 years after surgery. Body mass index (BMI) Z-score was used to assess obesity and the number of surgical procedures to assess local recurrence rate. RESULTS: Mean BMI Z-score before surgery was comparable in the 2 cohorts (0.756 after ERS vs 0.747 after HSS; P = .528). At any time after surgery, mean BMI Z-score was significantly lower after HSS (eg, 1.889 SD vs 2.915 SD, P = .004 at 1 year). At last follow-up, the HSS cohort had a significantly lower prevalence of severe obesity (28% vs 54%, P < .05) and higher prevalence of normal BMI (38% vs 17%, P < .01). Mean number of surgical procedures was not significantly different in the 2 cohorts. CONCLUSIONS: Hypothalamus-sparing surgery decreases the occurrence of severe obesity without increasing the local recurrence rate. PMID- 23633209 TI - Aryl hydrocarbon receptor interacting protein (AIP) mutations occur rarely in sporadic parathyroid adenomas. AB - CONTEXT: The molecular pathogenesis of primary hyperparathyroidism is still largely unknown. The aryl hydrocarbon receptor interacting protein (AIP) gene has a major role in the pathogenesis of familial isolated pituitary adenoma. OBJECTIVE: We evaluated the involvement of the AIP gene in sporadic parathyroid adenomas. PATIENTS AND DESIGN: We performed direct sequencing and multiplex ligation-dependent probe amplification analyses of the AIP gene in a large series of sporadic parathyroid adenomas. Loss of heterozygosity (LOH) at the AIP locus was studied, and aryl hydrocarbon receptor interacting protein immunostaining was also performed. In addition, alterations in the MEN1 gene were studied. RESULTS: A somatic AIP mutation, substitution of arginine with glutamine at codon 304 (R304Q), was identified in 2 of 132 tumors. The mutation was germline in both cases despite the nonfamilial presentation. Heterozygous AIP large deletions were detected in 29 cases including 1 of the 2 mutated tumors, confirming a biallelic inactivation of the AIP gene. The AIP-mutated tumor with LOH showed decreased AIP immunostaining compared with normal parathyroid. LOH at the MEN1 locus, which often shared LOH at the AIP locus, was found in one third of tumors. Somatic MEN1 mutations were found in the 1 of the 2 AIP-mutated tumors and in 22 parathyroid adenomas. In addition, multiplex ligation-dependent probe amplification analysis revealed 1 large deletion of the MEN1 gene in 1 patient. CONCLUSIONS: The AIP gene is rarely involved in parathyroid adenomas, but the germline nature of the mutations suggests that it might predispose to primary hyperparathyroidism. MEN1 gene alterations occur in a substantial proportion of sporadic parathyroid adenomas. PMID- 23633210 TI - Metabolic signature shift in type 2 diabetes mellitus revealed by mass spectrometry-based metabolomics. AB - OBJECTIVE: Metabolic profiling of small molecules offers a snapshot of physiological processes. To identify metabolic signatures associated with type 2 diabetes and impaired fasting glucose (IFG) beyond differences in glucose, we used mass spectrometry-based metabolic profiling. RESEARCH DESIGN AND METHODS: Individuals attending an institutional health screen were enrolled. IFG (n = 24) was defined as fasting glucose (FG) of 6.1 to 6.9 mmol/L and 2-hour post glucose load <11.1 mmol/L or glycosylated hemoglobin <6.5%, type 2 diabetes (n = 27), FG >=7.0 mmol/L, or 2-hour post glucose load >=11.1 mmol/L, or glycosylated hemoglobin >=6.5%, and healthy controls (n = 60), FG <6.1 mmol/L. Fasting serum metabolomes were profiled and compared using gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry. RESULTS: Compared to healthy controls, those with IFG and type 2 diabetes had significantly raised fructose, alpha-hydroxybutyrate, alanine, proline, phenylalanine, glutamine, branched-chain amino acids (leucine, isoleucine, and valine), low carbon number lipids (myristic, palmitic, and stearic acid), and significantly reduced pyroglutamic acid, glycerophospohlipids, and sphingomyelins, even after adjusting for age, gender, and body mass index. CONCLUSIONS: Using 2 highly sensitive metabolomic techniques, we report distinct serum profile change of a wide range of metabolites from healthy persons to type 2 diabetes mellitus. Apart from glucose, IFG and diabetes mellitus are characterized by abnormalities in amino acid, fatty acids, glycerophospholipids, and sphingomyelin metabolism. These early broad spectrum metabolic changes emphasize the complex abnormalities present in a disease defined mainly by elevated blood glucose levels. PMID- 23633211 TI - Production and release of acylcarnitines by primary myotubes reflect the differences in fasting fat oxidation of the donors. AB - CONTEXT: Acylcarnitines are biomarkers of incomplete beta-oxidation and mitochondrial lipid overload but indicate also high rates of mitochondrial fatty acid oxidation. It is unknown whether the production of acylcarnitines in primary human myotubes obtained from lean, metabolically healthy subjects reflects the fat oxidation in vivo. OBJECTIVE: Our objective was to quantify the acylcarnitine production in myotubes obtained from subjects with low and high fasting respiratory quotient (RQ). METHODS: Fasting RQ was determined by indirect calorimetry. Muscle biopsies from the vastus lateralis muscle were taken from 6 subjects with low fasting RQ (mean 0.79 +/- 0.03) and 6 with high fasting RQ (0.90 +/- 0.03), and satellite cells were isolated, cultured, and differentiated to myotubes. Myotubes were cultivated with 125 MUM (13)C-labeled palmitate for 30 minutes and 4 and 24 hours. Quantitative profiling of 42 intracellular and 31 extracellular acylcarnitines was performed by stable isotope dilution-based metabolomics analysis by liquid chromatography coupled to mass spectrometry. RESULTS: Myotubes from donors with high fasting RQ produced and released significant higher amounts of medium-chain acylcarnitines. High (13)C8 and (13)C10 acylcarnitine levels in the extracellular compartment correlated with high fasting RQ. The decreased expression of medium-chain acyl-coenzyme A dehydrogenase (MCAD) in these myotubes can explain the higher rate of incomplete fatty acid oxidation. A lower intracellular [(13)C]acetylcarnitine to carnitine and lower intracellular (13)C16/(13)C18 acylcarnitine to carnitine ratio indicate reduced fatty acid oxidation capacity in these myotubes. Mitochondrial DNA content was not different. CONCLUSION: Acylcarnitine production and release from primary human myotubes of donors with high fasting RQ indicate a reduced fatty acid oxidation capacity and a higher rate of incomplete fatty acid oxidation. Thus, quantitative profiling of acylcarnitine production in human myotubes can be a suitable tool to identify muscular determinants of fat oxidation in vivo. PMID- 23633212 TI - Genome-wide association of single-nucleotide polymorphisms with weight loss outcomes after Roux-en-Y gastric bypass surgery. AB - CONTEXT: Roux-en-Y gastric bypass (RYGB) is among the most effective treatments for extreme obesity and obesity-related complications. However, despite its potential efficacy, many patients do not achieve and/or maintain sufficient weight loss. OBJECTIVE: Our objective was to identify genetic factors underlying the variability in weight loss outcomes after RYGB surgery. DESIGN: We conducted a genome-wide association study using a 2-stage phenotypic extreme study design. SETTING: Patients were recruited from a comprehensive weight loss program at an integrated health system. PATIENTS: Eighty-six obese (body mass index >35 kg/m(2)) patients who had the least percent excess body weight loss (%EBWL) and 89 patients who had the most %EBWL at 2 years after surgery were genotyped using Affymetrix version 6.0 single-nucleotide polymorphism (SNP) arrays. A second group from the same cohort consisting of 164 patients in the lower quartile of %EBWL and 169 from the upper quartile were selected for evaluation of candidate regions using custom SNP arrays. INTERVENTION: We performed RYGB surgery. MAIN OUTCOME MEASURES: We assessed %EBWL at 2 years after RYGB and SNPs. RESULTS: We identified 111 SNPs in the first-stage analysis whose frequencies were significantly different between 2 phenotypic extremes of weight loss (allelic chi(2) test P < .0001). Linear regression of %EBWL at 2 years after surgery revealed 17 SNPs that approach P < .05 in the validation stage and cluster in or near several genes with potential biological relevance including PKHD1, HTR1A, NMBR, and IGF1R. CONCLUSIONS: This is the first genome-wide association study of weight loss response to RYGB. Variation in weight loss outcomes after RYGB may be influenced by several common genetic variants. PMID- 23633213 TI - Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRalpha1 receptor: consequences of LT4 treatment. AB - CONTEXT: Recently the first patients with inactivating mutations in T3 receptor (TR)-alpha1 have been identified. These patients have low free T4, low T4, high T3, low rT3, and normal TSH serum levels, in combination with growth retardation, delayed bone development, and constipation. OBJECTIVE: The aim of the current study was to report the effects of levothyroxine (LT4) treatment on the clinical phenotype of 2 patients (father and daughter) with a heterozygous inactivating mutation in TRalpha1. SETTING AND PARTICIPANTS: Both patients were treated with LT4 for the last 5 years. To evaluate the effect of LT4 treatment, LT4 was withdrawn for 35 days and subsequently reinitiated. Data were collected from medical records, by reanalysis of serum collected over the last 6 years, and by a detailed clinical evaluation. RESULTS: Treatment with LT4 resulted in a suppression of serum TSH and normalization of serum free T4 and rT3, whereas T3 levels remained elevated in both patients. In addition, there was a normalization of the dyslipidemia as well as a response in serum IGF-I, SHBG, and creatine kinase in the index patient. All these parameters returned to pretreatment values when LT4 was briefly stopped. LT4 also resulted in an improvement of certain clinical features, such as constipation and nerve conductance. However, cognitive and fine motor skill defects remained. CONCLUSION: This study reports the consequences of LT4 treatment over a prolonged period of time in 2 of the first patients with a heterozygous mutation in TRalpha1. LT4 therapy leads to an improvement of certain but not all features of the clinical phenotype. PMID- 23633214 TI - Circulating serotonin and bone density, structure, and turnover in carcinoid syndrome. AB - CONTEXT: Gut-derived serotonin has been proposed as a regulator of bone formation, and inhibition of gut serotonin synthesis increases bone formation in rodents. Carcinoid neuroendocrine tumors can produce very high levels of circulating serotonin and so offer a model of serotonin excess in humans. OBJECTIVES: The objective of the study was to determine whether patients with carcinoid syndrome have lower bone formation markers, lower bone density, or poor bone structure compared with healthy controls. DESIGN: We conducted a cross sectional study of 25 patients with carcinoid syndrome and 25 healthy controls, individually matched to carcinoid patients by gender, age, height, and body mass index. OUTCOME MEASURES: We measured circulating serotonin in blood and plasma and 5-hydroxyindoleacetic acid (5HIAA) in plasma and urine. We measured lumbar spine and hip bone mineral density by dual-energy x-ray absorptiometry, the distal radius and tibia with high-resolution peripheral quantitative computed tomography, and bone turnover with serum osteocalcin, amino-terminal propeptide of type I procollagen (PINP) and C-terminal telopeptide of type I collagen (CTX). RESULTS: All measures of serotonin and 5HIAA were higher in carcinoid patients than in controls. No measures of bone density or bone structure differed significantly between cases and controls. Osteocalcin was higher in the cases than controls (26.0 vs 21.1 ng/mL, P = .02). PINP and CTX did not differ between cases and controls. In patients with carcinoid syndrome, plasma 5HIAA was positively correlated with osteocalcin. In controls, whole-blood serotonin was positively correlated with osteocalcin, PINP, and CTX (R values = 0.40-0.47, all P < .05.). CONCLUSIONS: High circulating serotonin in carcinoid syndrome is not associated with clinically significant lower bone density, poorer bone structure, or lower bone formation markers. PMID- 23633215 TI - Deep brain stimulation of the subthalamic nucleus regulates postabsorptive glucose metabolism in patients with Parkinson's disease. AB - OBJECTIVE: Subthalamic nucleus-deep brain stimulation (STN-DBS) is an alternative treatment for patients with uncontrolled symptoms of Parkinson's disease (PD), but it has other nonmotor impact. Because STN-DBS alters the energy expenditure in humans, we hypothesized that STN-DBS may affect postabsorptive glucose metabolism in patients with PD. RESEARCH DESIGN AND METHODS: Endogenous glucose production (EGP) and whole-body glucose disposal rates (GDRs) were assessed in the postabsorptive state during a primed continuous iv infusion of D-[6,6 (2)H2]glucose for 5 hours in 8 STN-DBS-treated patients with PD, without (Stim OFF) and during STN-DBS (Stim-ON) treatment. EGP and GDR in PD patients were compared with glucose kinetics of 8 matched healthy control subjects. Plasma concentrations of insulin, glucagon, and free fatty acids were also determined. RESULTS: EGP and GDR were higher in PD patients in Stim-OFF conditions than in the control group (2.62 +/- 0.09 vs 2.27 +/- 0.10 mg/kg.min, P < .05). Despite no significant changes in blood glucose throughout the kinetic study, a significant and consistent 22% decrease in EGP occurred in PD patients during Stim-ON (2.04 +/- 0.07 mg/kg(-1).min(-1); P < .01), and whole-body glucose kinetics in Stim-ON patients were no more different from those of the control subjects (P = NS). No difference in insulin, glucagon, or free fatty acid concentrations was observed in the patients between Stim-OFF and Stim-ON conditions. CONCLUSIONS: Deep brain stimulation in patients with PD affects EGP glucose disposal, suggesting that a cross talk between the central nervous system and peripheral tissues may regulate glucose homeostasis. PMID- 23633216 TI - Path toward economic resilience for family caregivers: mitigating household deprivation and the health care talent shortage at the same time. AB - Rising costs and a workforce talent shortage are two of the health care industry's most pressing challenges. In particular, serious illnesses often impose significant costs on individuals and their families, which can place families at an increased risk for multigenerational economic deprivation or even an illness-poverty trap. At the same time, family caregivers often acquire a wide variety of health care skills that neither these caregivers nor the health care industry typically use. As these skills are marketable and could be paired with many existing medical certifications, this article describes a possible "path toward economic resilience" (PER) through a program whereby family caregivers could find meaningful employment using their new skills. The proposed program would identify ideal program candidates, assess and supplement their competencies, and connect them to the health care industry. We provide a set of practical steps and recommended tools for implementation, discuss pilot data on the program's appeal and feasibility, and raise several considerations for program development and future research. Our analysis suggests that this PER program could appeal to family caregivers and the health care industry alike, possibly helping to address two of our health care system's most pressing challenges with one solution. PMID- 23633217 TI - Walking impairment questionnaire improves mortality risk prediction models in a high-risk cohort independent of peripheral arterial disease status. AB - BACKGROUND: The Walking Impairment Questionnaire (WIQ) is a subjective measure of patient-reported walking performance developed for peripheral arterial disease. The purpose of this study is to examine whether this simple tool can improve the predictive capacity of established risk models and whether the WIQ can be used in patients without peripheral arterial disease. METHODS AND RESULTS: At baseline we assessed the walking distance, stair-climbing, and walking speed WIQ category scores among individuals who were undergoing coronary angiography. During a median follow-up of 5.0 years, there were 172 mortalities among 1417 study participants. Adjusted Cox proportional hazards models showed that all 3 WIQ categories independently predicted future all-cause and cardiovascular mortality, including among individuals without peripheral arterial disease (P<0.001). Compared with the cardiovascular risk factors model, we observed significantly increased risk discrimination with a C-index of 0.741 (change in C-index, 0.040; 95% confidence interval, 0.011-0.068) and 0.832 (change in C-index, 0.080; 95% confidence interval, 0.034-0.126) for all-cause and cardiovascular mortality, respectively. Examination of risk reclassification using the net reclassification improvement index showed a 48.4% (P<0.001) improvement for all-cause mortality and a 77.4% (P<0.001) improvement for cardiovascular mortality compared with the cardiovascular risk factors model. CONCLUSIONS: All 3 WIQ categories independently predicted future all-cause and cardiovascular mortality. Importantly, we found that this subjective measure of walking ability could be extended to patients without peripheral arterial disease. The addition of the WIQ scores to established cardiovascular risk models significantly improved risk discrimination and reclassification, suggesting broad clinical use for this simple, inexpensive test. PMID- 23633218 TI - Patterns of emergency medical services use and its association with timely stroke treatment: findings from Get With the Guidelines-Stroke. AB - BACKGROUND: Prior studies found that only about half of stroke patients arrived at hospitals via emergency medical services (EMSs), yet since then, there have been efforts to increase public awareness that time is brain. Using contemporary Get With the Guidelines-Stroke data, we assessed nationwide EMS use by stroke patients. METHODS AND RESULTS: We analyzed data from 204 591 patients with ischemic and hemorrhagic stroke admitted to 1563 Get With the Guidelines-Stroke participating hospitals with data on National Institute of Health Stroke Score and insurance status. Hospital arrival by EMSs was observed in 63.7% of patients. Older patients, those with Medicaid and Medicare insurance, and those with severe stroke were more likely to activate EMSs. In contrast, minority race and ethnicity and living in rural communities were associated with decreased odds of EMS use. EMS transport was independently associated with earlier arrival (onset to-door time, <=3 hours; adjusted odds ratio, 2.00; 95% confidence interval, 1.93 2.08), prompter evaluation (more patients with door-to-imaging time, <=25 minutes; odds ratio, 1.89; 95% confidence interval, 1.78-2.00), more rapid treatment (more patients with door-to-needle time, <=60 minutes; odds ratio, 1.44; 95% confidence interval, 1.28-1.63), and more eligible patients to be treated with tissue-type plasminogen activator if onset is <=2 hours (67% versus 44%; odds ratio, 1.47; 95% confidence interval, 1.33-1.64). CONCLUSIONS: Although EMS use is independently associated with more rapid evaluation and treatment of stroke, more than one third of stroke patients fail to use EMSs. Interventions aimed at increasing EMS activation should target populations at risk, particularly younger patients and those of minority race and ethnicity. PMID- 23633221 TI - Indian medical curriculum is to get "long overdue" ethics training. PMID- 23633220 TI - Distal-less regulates eyespot patterns and melanization in Bicyclus butterflies. AB - Butterfly eyespots represent novel complex traits that display substantial diversity in number and size within and across species. Correlative gene expression studies have implicated a large suite of transcription factors, including Distal-less (Dll), Engrailed (En), and Spalt (Sal), in eyespot development in butterflies, but direct evidence testing the function of any of these proteins is still missing. Here we show that the characteristic two-eyespot pattern of wildtype Bicyclus anynana forewings is correlated with dynamic progression of Dll, En, and Sal expression in larval wings from four spots to two spots, whereas no such decline in gene expression ensues in a four-eyespot mutant. We then conduct transgenic experiments testing whether over-expression of any of these genes in a wild-type genetic background is sufficient to induce eyespot differentiation in these pre-patterned wing compartments. We also produce a Dll-RNAi transgenic line to test how Dll down-regulation affects eyespot development. Finally we test how ectopic expression of these genes during the pupal stages of development alters adults color patters. We show that over expressing Dll in larvae is sufficient to induce the differentiation of additional eyespots and increase the size of eyespots, whereas down-regulating Dll leads to a decrease in eyespot size. Furthermore, ectopic expression of Dll in the early pupal wing led to the appearance of ectopic patches of black scales. We conclude that Dll is a positive regulator of focal differentiation and eyespot signaling and that this gene is also a possible selector gene for scale melanization in butterflies. PMID- 23633222 TI - Doctors who take on leadership roles are considered to have gone over to "dark side," report says. PMID- 23633224 TI - Makers of anticancer drugs are "profiteering," say 100 specialists from around the world. PMID- 23633219 TI - Structure-based DNA-targeting strategies with small molecule ligands for drug discovery. AB - Nucleic acids are the molecular targets of many clinical anticancer drugs. However, compared with proteins, nucleic acids have traditionally attracted much less attention as drug targets in structure-based drug design, partially because limited structural information of nucleic acids complexed with potential drugs is available. Over the past several years, enormous progresses in nucleic acid crystallization, heavy-atom derivatization, phasing, and structural biology have been made. Many complicated nucleic acid structures have been determined, providing new insights into the molecular functions and interactions of nucleic acids, especially DNAs complexed with small molecule ligands. Thus, opportunities have been created to further discover nucleic acid-targeting drugs for disease treatments. This review focuses on the structure studies of DNAs complexed with small molecule ligands for discovering lead compounds, drug candidates, and/or therapeutics. PMID- 23633225 TI - US drug control efforts have made little progress, report finds. PMID- 23633226 TI - Seriously ill woman expecting a baby with anencephaly has waited a month to learn whether she can have an abortion. PMID- 23633223 TI - "Troika" mandated austerity and the emerging healthcare crisis in Greece: an open letter to the Greek government. PMID- 23633229 TI - Highly accelerated cardiac cine phase-contrast MRI using an undersampled radial acquisition and temporally constrained reconstruction. AB - PURPOSE: To evaluate a method to enable single-slice or multiple-slice cine phase contrast (cine-PC) acquisition during a single breath-hold using a highly sparsified radial acquisition ordering and temporally constrained image reconstruction with a spatially varying temporal constraint. MATERIALS AND METHODS: Simulated and in vivo cine-PC datasets of the proximal ascending aorta were obtained at different acceleration factors using a view projection acquisition order optimized for temporally constrained reconstruction (TCR). Reconstruction of the sparse cine-PC data performed with TCR was compared to reconstructions using zero-filled regridding and temporal interpolation. RESULTS: TCR resulted in more accurate velocity measurements than regridding or temporal interpolation. In one dataset, TCR of undersampled in vivo data (16 views per cardiac phase) resulted in a peak systolic velocity within 3.3% of the value measured by Doppler ultrasound while shortening the scan time to 13 seconds. High temporal-resolution undersampled TCR was also compared lower temporal-resolution, more highly sampled, regridding in three normal volunteers. CONCLUSION: TCR proved to be an effective method for reconstructing undersampled radial PC data. Although TCR utilizes a temporal constraint, temporal blurring was minimized by using appropriate constraint weights in addition to a spatially varying temporal constraint. TCR allowed for the acquisition time to be reduced to the duration of a breath-hold, while still resulting in accurate velocity measurements. PMID- 23633228 TI - Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation. AB - Autophagy is a conserved lysosomal degradation process that has important roles in both normal human physiology and disease. However, the function of autophagy in bone homeostasis is not well understood. Here, we report that autophagy is activated during osteoblast differentiation. Ablation of focal adhesion kinase family interacting protein of 200 kD (FIP200), an essential component of mammalian autophagy, led to multiple autophagic defects in osteoblasts including aberrantly increased p62 expression, deficient LC3-II conversion, defective autophagy flux, absence of GFP-LC3 puncta in FIP200-null osteoblasts expressing transgenic GFP-LC3, and absence of autophagosome-like structures by electron microscope examination. Osteoblast-specific deletion of FIP200 led to osteopenia in mice. Histomorphometric analysis revealed that the osteopenia was the result of cell-autonomous effects of FIP200 deletion on osteoblasts. FIP200 deletion led to defective osteoblast terminal differentiation in both primary bone marrow and calvarial osteoblasts in vitro. Interestingly, both proliferation and differentiation were not adversely affected by FIP200 deletion in early cultures. However, FIP200 deletion led to defective osteoblast nodule formation after initial proliferation and differentiation. Furthermore, treatment with autophagy inhibitors recapitulated the effects of FIP200 deletion on osteoblast differentiation. Taken together, these data identify FIP200 as an important regulator of bone development and reveal a novel role of autophagy in osteoblast function through its positive role in supporting osteoblast nodule formation and differentiation. PMID- 23633230 TI - What studies are appropriate and necessary for staging gastric adenocarcinoma? Results of an international RAND/UCLA expert panel. AB - BACKGROUND: The approach for staging gastric adenocarcinoma (GC) has not been well defined, with heterogeneity in the application of staging modalities. METHODS: Utilizing a RAND/UCLA appropriateness methodology (RAM), a multidisciplinary expert panel of 16 physicians scored 84 GC staging scenarios. Appropriateness was scored from 1 to 9. Median appropriateness scores from 1 to 3 were considered inappropriate, 4-6 uncertain, and 7-9 appropriate. Agreement was reached when 12 or more of 16 panelists scored the scenario similarly. Appropriate scenarios were subsequently scored for necessity. RESULTS: Pretreatment TNM stage determination is necessary. Necessary staging maneuvers include esophagogastroduodenoscopy (EGD); biopsy of the tumor; documentation of tumor size, description, location, distance from gastroesophageal junction (GEJ), and any GEJ, esophageal, or duodenal involvement; if an EGD report is unclear, surgeons should repeat it to confirm tumor location. Pretreatment radiologic assessment should include computed tomography (CT)-abdomen and CT-pelvis, performed with multidetector CT scanners with 5-mm slices. Laparoscopy should be performed before resection of cT3-cT4 lesions or multivisceral resections. Laparoscopy should include inspection of the stomach, diaphragm, liver, and ovaries. CONCLUSIONS: Using a RAM, we describe appropriate and necessary staging tests for the pretreatment staging evaluation of GC, as well as how some of these staging maneuvers should be conducted. PMID- 23633231 TI - Low-temperature conditioning induces chilling tolerance in 'Hayward' kiwifruit by enhancing antioxidant enzyme activity and regulating en-dogenous hormones levels. AB - BACKGROUND: To understand the mechanisms leading to the enhanced chilling tolerance of kiwifruit by low-temperature conditioning (LTC, 12 degrees C for 3 days), this study investigated the effect of LTC on chilling tolerance and changes in antioxidant enzyme activities and endogenous hormones. RESULTS: LTC significantly alleviated chilling injury in kiwifruit. Fruits treated with LTC maintained lower respiration and ethylene production and higher firmness. Furthermore, this treatment inhibited the accumulation of malondialdehyde, superoxide radicals and hydrogen peroxide and the increase in membrane permeability and increased the activities of superoxide dismutase, catalase, ascorbate peroxidase and peroxidase under chilling stress. The treatment also maintained higher levels of endogenous abscisic acid (ABA), indole-3-acetic acid (IAA) and zeatin riboside (ZR), lower gibberellic acid (GA3) levels and higher ABA/GA3 and ABA/IAA ratios. CONCLUSION: The results suggested that LTC alleviated chilling injury in kiwifruit by improving antioxidant enzyme activities and maintaining higher levels of endogenous ABA, IAA and ZR, lower GA3 levels and higher ABA/GA3 and ABA/IAA ratios. PMID- 23633232 TI - Acute care of pediatric patients with sickle cell disease: a simulation performance assessment. AB - BACKGROUND: Sickle cell disease (SCD) is a rare disorder with cardinal features including hospitalization for vaso-occlusive pain episodes, acute pulmonary injury, and increased infection rates. For physician-trainees, learning optimal SCD management is challenging because of limited exposure to life threatening complications requiring timely interventions. PROCEDURE: To create, demonstrate reliability, and validate simulation-based, acute care SCD scenarios for physician-trainees, seven scenarios were derived from SCD patient cases. For each scenario, participants had 5 minutes to complete diagnostic and treatment interventions. Participants were divided into two groups based on clinical experience: interns or residents/fellows. Two raters scored performances using diagnostic and therapeutic checklists--indicating whether specific actions were performed and a global, 1 (poor) to 9 (excellent), rating. Scenario scores were calculated by averaging rater scores on each metric. Reliability was defined through uniformity in rater scoring and consistency of participant performance over scenarios. Validity was demonstrated by the performance gradient where the more experienced trainees outperform those early in training. RESULTS: Twenty eight pediatric residents and hematology fellows took part in the study. Reliability for assessment scores overall was moderate. Performance on all but one scenario was moderately predictive of overall performance. Senior resident/fellows performed significantly better than interns. Positive associations existed between overall performance scores (P < 0.01) and months of postgraduate training (P < 0.01). CONCLUSIONS: Mannequin-based simulation is a novel method for teaching pediatric residents SCD-specific acute care skills. The assessment provided reliable and valid measures of trainees' performance. Further studies are needed to determine simulation's utility in education and evaluation. PMID- 23633233 TI - Aggressive ameloblastic fibro-odontoma assessment with CBCT and treatment. AB - BACKGROUND: Ameloblastic fibro-odontomas (AFO) are rare lesions and defined by the World Health Organisation as a tumour composed of a proliferation of odontogenic epithelium immersed in ectomesenchyme reminiscent of the interdental papilla. It also presents inductive processes leading to formation of enamel and dentine, confusing, histopathologically, with odontoma. Despite numerous efforts, there is still considerable confusion over its controversial aetiopathogenesis and treatment. A brief review of the literature on the clinical, pathological and therapeutic features of this lesion is reported. CASE REPORT: A case of aggressive AFO in a 3-year-old boy was referred to the Oral Diagnostics Service of Hospital General de Fortaleza for evaluation following a 3-months painless swelling in the right mandibular and facial regions. During anamnesis, the patient's carers reported no systemic problem and his medical history was non contributory. Intra-orally there was a swelling of the right lateral portion of the mandible, adjacent teeth were not mobile and the oral mucosa appeared normal and showed no signs of ulceration. Radiographic examination, with panoramic radiography and cone beam computed tomography with three-dimensional (3D) reconstruction, was better able to identify the extent of bone involvement and showed an expansive hypodense image in the right mandibular region. 3D reconstruction showed expansion of buccal and lingual cortical bone and the preservation of basal bone. TREATMENT: Enucleation and curettage of the lesion were carried out and care was taken not to fracture the basal bone during the surgical procedure. Tissue specimens were sent for histopathologic analysis. Aspiration performed during surgery was negative for blood and other exudates. FOLLOW-UP: No recurrence has occurred during a follow-up period of 11 months. CONCLUSION: A comprehensive diagnosis including all clinical, radiographic and histopathologic features is necessary for the success of therapy, which varies from case to case, thus, improving the quality of life of patients with AFO. PMID- 23633235 TI - Cardiac and respiratory dysfunction in Duchenne muscular dystrophy and the role of second messengers. AB - Duchenne muscular dystrophy (DMD) affects young boys and is characterized by the absence of dystrophin, a large cytoskeletal protein present in skeletal and cardiac muscle cells and neurons. The heart and diaphragm become necrotic in DMD patients and animal models of DMD, resulting in cardiorespiratory failure as the leading cause of death. The major consequences of the absence of dystrophin are high levels of intracellular Ca(2+) and the unbalanced production of NO that can finally trigger protein degradation and cell death. Cytoplasmic increase in Ca(2+) concentration directly and indirectly triggers different processes such as necrosis, fibrosis, and activation of macrophages. The absence of the neuronal isoform of nitric oxide synthase (nNOS) and the overproduction of NO by the inducible isoform (iNOS) further increase the intracellular Ca(2+) via a hypernitrosylation of the ryanodine receptor. NO overproduction, which further induces the expression of iNOS but decreases the expression of the endothelial isoform (eNOS), deregulates the muscle tissue blood flow creating an ischemic situation. The high levels of Ca(2+) in dystrophic muscles and the ischemic state of the muscle tissue would culminate in a positive feedback loop. While efforts continue toward optimizing cardiac and respiratory care of DMD patients, both Ca(2+) and NO in cardiac and respiratory muscle pathways have been shown to be important to the etiology of the disease. Understanding the mechanisms behind the fine regulation of Ca(2+) -NO may be important for a noninterventional and noninvasive supportive approach to treat DMD patients, improving the quality of life and natural history of DMD patients. PMID- 23633236 TI - Improving the accuracy of pancreatobiliary tract cytology with fluorescence in situ hybridization: a molecular test with proven clinical success. AB - The detection of aneuploidy by fluorescence in situ hybridization (FISH) has revolutionized how laboratories diagnose cholangiocarcinoma and pancreatic adenocarcinoma using cytology specimens. Numerous clinical studies have demonstrated that FISH increases the diagnostic sensitivity of routine cytology for detecting pancreatobiliary tract malignancy with minimal decreases in clinical specificity. FISH also provides useful information in difficult clinical scenarios, including the assessment of patients with biliary strictures who have equivocal cytology results and the assessment of patients with primary sclerosing cholangitis who have clinical features suggestive of malignancy. The improved ability to detect pancreatobiliary tract cancers offers the possibility of earlier detection when patients are amenable to surgical intervention and can decrease health care costs by reducing the amount of clinical evaluation required to arrive at a cancer diagnosis. Cytopathology personnel should maintain familiarity with molecular cytology testing methodologies, because morphologic and aneuploidy assessment of tumors will continue to be an integral part of large scale genome analyses of individual tumors. PMID- 23633234 TI - The usefulness of cone beam computed tomography for treatment of complex odontoma. AB - BACKGROUND: Odontomas are odontogenic tumours, resulting from epithelial growth and differentiated mesenchymal cells, clinically asymptomatic, and often associated with changes to the eruption of the permanent dentition. In recent years, cone beam computed tomography (CBCT) has been used in the diagnosis and treatment planning of this condition. CASE REPORT: A 9-year-old male patient, with an unerupted permanent maxillary right central incisor (tooth 11) presented to our clinic. The panoramic radiograph showed impaction of tooth 11 with incomplete root development and the suspicion of an odontome and supernumerary tooth. CBCT was performed and enabled the visualisation of a radiopaque image compatible with an odontome, confirming the presence of an impacted supernumerary tooth on the palatal surface of tooth 11. TREATMENT: Surgical excision of the odontome and the supernumerary tooth was performed. FOLLOW-UP: Clinical and radiographic evaluations 2 months after the removal of the lesion showed lack of space for the eruption of tooth 11. The patient was referred for orthodontic treatment and a Hyrax appliance was fitted. The patient has been followed for 12 months. CONCLUSION: CBCT is an important auxiliary tool, aiding in both correct diagnosis and accurate treatment planning. It is currently a technology accessible to most paediatric dentists and should be beneficial considering the diagnostic information provided as well as the cost-benefit ratio for the patient. PMID- 23633237 TI - Development and validation of a reverse phase liquid chromatography method for the simultaneous quantification of eserine and pralidoxime chloride in drugs-in adhesive matrix type transdermal patches. AB - BACKGROUND: In the present study, a simple, precise, specific, fast, accurate and reliable reverse phase high performance liquid chromatographic (RP-HPLC) method has been developed and validated for the simultaneous determination and quantification of eserine and pralidoxime chloride in drugs-in-adhesive matrix type transdermal patches. METHODS: The chromatographic separation was achieved by C18 column, using a mobile phase consisting of acetonitrile: 10 mM potassium dihydrogen phosphate, 10 mM heptane-1-sulfonic acid sodium salt monohydrate in water (30:70, v/v) adjusted at pH 3.0 with ortho-phosphoric acid. Flow rate was 1.0 mL/min and UV detection at 238 nm. The method was validated according to the International Conference on Harmonization (ICH) guidelines. RESULTS: The calibration curves were linear over the different concentration ranges of 0.5-10 MUg/ml for eserine and 5-25 MUg/mL for 2PAM. Relative standard deviation for precision was less than 2.0%. Limit of detection values of eserine and 2-PAM were 0.018 ug/mL and 0.008 ug/mL, respectively. The limit of quantification of eserine and 2-PAM were 0.055 ug/mL and 0.026 ug/mL, respectively. CONCLUSION: The developed method was applied for the routine analysis of these 2 drugs in drugs in-adhesive matrix type transdermal patches in order to evaluate the drug content of different formulations. It could be also used with reliability for the determination of the drug in other pharmaceutical dosage forms. PMID- 23633238 TI - Muscle size, strength, and physical performance and their associations with bone structure in the Hertfordshire Cohort Study. AB - Sarcopenia is associated with a greater fracture risk. This relationship was originally thought to be explained by an increased risk of falls in sarcopenic individuals. However, in addition, there is growing evidence of a functional muscle-bone unit in which bone health may be directly influenced by muscle function. Because a definition of sarcopenia encompasses muscle size, strength, and physical performance, we investigated relationships for each of these with bone size, bone density, and bone strength to interrogate these hypotheses further in participants from the Hertfordshire Cohort Study. A total of 313 men and 318 women underwent baseline assessment of health and detailed anthropometric measurements. Muscle strength was measured by grip strength, and physical performance was determined by gait speed. Peripheral quantitative computed tomography (pQCT) examination of the calf and forearm was performed to assess muscle cross-sectional area (mCSA) at the 66% level and bone structure (radius 4% and 66% levels; tibia 4% and 38% levels). Muscle size was positively associated with bone size (distal radius total bone area beta = 17.5 mm2 /SD [12.0, 22.9]) and strength (strength strain index (beta = 23.3 mm3 /SD [18.2, 28.4]) amongst women (p < 0.001). These associations were also seen in men and were maintained after adjustment for age, height, weight-adjusted-for-height, limb-length adjusted-for-height, social class, smoking status, alcohol consumption, calcium intake, physical activity, diabetes mellitus, and in women, years since menopause and estrogen replacement therapy. Although grip strength showed similar associations with bone size and strength in both sexes, these were substantially attenuated after similar adjustment. Consistent relationships between gait speed and bone structure were not seen. We conclude that although muscle size and grip strength are associated with bone size and strength, relationships between gait speed and bone structure and strength were not apparent in this cohort, supporting a role for the muscle-bone unit. PMID- 23633239 TI - Body awareness: differentiating between sensitivity to and monitoring of bodily signals. AB - Sensitivity to bodily signals is the tendency to be aware of bodily states and to identify subtle bodily reactions to internal and environmental conditions. Monitoring these signals is a top-down process, describing individuals' tendency to actively scan their bodies in order to detect cues for their physical condition. Two studies examined the relations between these constructs and their adaptivity among young adults. In Study 1, 180 young adults completed questionnaires assessing sensitivity, monitoring, and hypochondriac tendency. In Study 2, 205 students reported their levels of sensitivity, monitoring, pain catastrophizing, and trait anxiety. Although monitoring and sensitivity were correlated, when controlling for their shared variance, only monitoring was associated with high hypochondriac tendency and anxiety. In addition, the adaptivity of sensitivity to bodily signals was dependent on both level of monitoring of bodily signals and pain catastrophizing. That is, pain catastrophizing moderated the effect of sensitivity and monitoring on anxiety. These findings suggest that the adaptivity of sensitivity is determined by the mode of attention characterizing the individual engaged in this process. PMID- 23633240 TI - Identification of anastomotic leakage after colorectal surgery using microdialysis of the peritoneal cavity. AB - BACKGROUND: Early detection of colorectal anastomotic leakage (AL) may lead to better outcome. AL may be preceded by change in local metabolism and local ischaemia. Microdialysis of the peritoneal cavity is able to measure these changes in real-time and is minimally invasive. The aim of this prospective cohort study was to compare values of intraperitoneal microdialysis in patients with AL to patients without AL after open and laparoscopic colorectal surgery. METHODS: Twenty-four patients underwent surgery for left-sided, sigmoid and rectal carcinoma with creation of an anastomosis. Intraoperatively a juxta anastomotical intraperitoneal and subcutaneous microdialysis catheter was placed. The levels of lactate, pyruvate, glucose and glycerol in the dialysate were measured every 4 h during the first 5 post-operative days, and mean values and area under the curve (AUC) were calculated. RESULTS: Mortality was 0 % and morbidity 38 %. In 3 patients (17 %), AL occurred. In patients with AL, post operative peritoneal lactate level was 3.2 mmol/l (standard deviation (SD) 0.9) for patients without AL, compared to 4.4 mmol/l (SD 1.5) in case of AL (p = 0.03 for AUC). Intraperitoneal glucose levels were 8.1 mmol/l (SD 1.3), compared to 7.8 mmol/l (SD 2.2) in the complicated course (ns for AUC). Mean intraperitoneal lactate/pyruvate-ratio was 19.2 (SD 3) after colorectal surgery without AL compared to 25 (SD 4.7) in case of AL (non-significant (ns) for AUC). No significant differences were observed between patients who underwent laparoscopic resection and those who underwent open resection. CONCLUSIONS: Anastomotic leakage was preceded by a significantly higher AUC and mean value of lactate levels during the first 5 post-operative days. To identify cut-off values for clinical use, pooling of data is necessary. PMID- 23633242 TI - Early detection and the prevention of serious complications of anastomotic leakage in rectal cancer surgery. PMID- 23633241 TI - Hybrid seton for the treatment of high anal fistulas: results of 128 consecutive patients. AB - BACKGROUND: The aim of this study was to evaluate our experience in managing high anal fistulas with a simple modification of the cutting seton. METHODS: We performed a retrospective review of standardized patient charts and of prospectively collected scores and questionnaires. Surgical outcomes of 128 consecutive, well-documented patients with high anal fistulas, including anterior transsphincteric fistulas in females, treated using a hybrid seton, were analyzed. RESULTS: No significant complications occurred. The mean postoperative pain scores on a visual analog scale were 3.23 and 0.61, on days 1 and 7, respectively. Complete healing was achieved in 67 cases (52.3 %) at 1 month and in all cases (100 %) at 3 months. Recurrent fistula was noted in 2 patients (1.5 %) at 6 and 12 months. The mean postoperative incontinence scores at 3 and 12 months did not differ significantly from the preoperative score (p = 0.061, Wilcoxon's test). The depression, life style, and embarrassment item scores of the fecal incontinence quality of life index improved significantly after surgical treatment. CONCLUSIONS: The results of this series suggest that the hybrid seton might be a valid alternative for the treatment of high anal fistulas, eliminating the need for postoperative adjustments. The slow and stable cutting of the sphincter seems to have a positive effect on the maintenance of continence. The successful outcome is associated with significant improvement in quality of life. PMID- 23633243 TI - My favourite flowering image: Maryland Mammoth tobacco. AB - Almost 100 years ago, the study of Maryland Mammoth tobacco by Garner and Allard was one in a long series of studies that have led to a better understanding of how plants "decide" when to flower. deciphering how plants "decide" when to flower. The extreme phenotype of Maryland Mammoth tobacco, in which a single recessive mutation changes a day-neutral to a strictly photoperiod-requiring plant, impressively illustrates the action of the photoperiodic pathway of flowering. PMID- 23633244 TI - Intra- and interscan reproducibility using Fourier Analysis of STimulated Echoes (FAST) for the rapid and robust quantification of left ventricular twist. AB - PURPOSE: To assess the intra- and interscan reproducibility of LV twist using FAST. Assessing the reproducibility of the measurement of new MRI biomarkers is an important part of validation. Fourier Analysis of STimulated Echoes (FAST) is a new MRI tissue tagging method that has recently been shown to compare favorably with conventional estimates of left ventricular (LV) twist from cardiac tagged images, but with significantly reduced user interaction time. MATERIALS AND METHODS: Healthy volunteers (N = 10) were scanned twice using FAST over 1 week. On day 1, two measurements of LV twist were collected for intrascan comparisons. Measurements for LV twist were again collected on day 8 for interscan assessment. LV short-axis tagged images were acquired on a 3 Tesla (T) scanner to ensure detectability of tags during early and mid-diastole. Peak LV twist is reported as mean +/- SD. Reproducibility was assessed using the concordance correlation coefficient (CCC) and the repeatability coefficient (RC) (95% confidence interval [CI] range). RESULTS: Mean peak twist measurements were 13.4 +/- 4.3 degrees (day 1, scan 1), 13.6 +/- 3.7 degrees (day 1, scan 2), and 13.0 +/- 2.7 degrees (day 8). Bland-Altman analysis resulted in intra- and interscan bias and 95% CI of -0.6 degrees [-1.0 degrees , 1.6 degrees ] and 1.4 degrees (-1.0 degrees , 3.0 degrees ), respectively. The Bland-Altman RC for peak LV twist was 2.6 degrees and 4.0 degrees for intra- and interscan, respectively. The CCC was 0.9 and 0.6 for peak LV twist for intra- and interscan, respectively. CONCLUSION: FAST is a semi-automated method that provides a quick and quantitative assessment of LV systolic and diastolic twist that demonstrates high intrascan and moderate interscan reproducibility in preliminary studies. PMID- 23633245 TI - Nutrient composition of selected indigenous fruits from sub-Saharan Africa. AB - Indigenous fruits constitute an important part of human diets in many sub-Saharan African countries, particularly in rural areas and during droughts. In order to promote and expand the utilisation of these fruits, knowledge on their nutritional composition is essential. This review presents the results of a literature research of the nutritional composition of ten selected indigenous fruits from sub-Saharan Africa. Species were selected based on their current importance as well as their future potential for nutrition, processing and cash income generation. Compositional data were compiled and mean values of components per species were calculated. Most papers were compiled for Adansonia digitata (26) and Dacryodes edulis (16), followed by Tamarindus indica (ten), Balanites aegyptiaca (nine), Sclerocarya birrea (nine), Ziziphus mauritiana (nine), Vitex doniana (seven) and Irvingia gabonensis (five), and least for Uapaca kirkiana (three) and Syzygium guineense (three). Fruits were found to be mainly analysed for macronutrients and minerals. Vitamins, apart from vitamin C, were rarely reported. Substantial compositional differences were found among as well as within the different fruit species. The results of this study emphasise the need to generate more high-quality data on a wider spectrum of components of the selected indigenous fruits in sub-Saharan Africa. PMID- 23633246 TI - Fundamentals of balanced steady state free precession MRI. AB - Balanced steady state free precession (balanced SSFP) has become increasingly popular for research and clinical applications, offering a very high signal-to noise ratio and a T2 /T1 -weighted image contrast. This review article gives an overview on the basic principles of this fast imaging technique as well as possibilities for contrast modification. The first part focuses on the fundamental principles of balanced SSFP signal formation in the transient phase and in the steady state. In the second part, balanced SSFP imaging, contrast, and basic mechanisms for contrast modification are revisited and contemporary clinical applications are discussed. PMID- 23633247 TI - Environmental exposure assessment of engineered nanoparticles: why REACH needs adjustment. AB - Engineered nanomaterials (ENMs) possess novel properties making them attractive for application in a wide spectrum of fields. These novel properties are not accounted for in the environmental risk assessment methods that the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) proposes in their guidance on environmental exposure estimation, although ENMs are already applied in a variety of consumer and industrial products. It is thus necessary to evaluate the guidance document REACH provides on environmental exposure estimation on its applicability to ENMs. This is most urgently the case for engineered nanoparticles (ENPs), as the novel properties are most often only applicable to them. The environmental fate of ENPs was reviewed and compared to the environmental fate of chemicals according to the REACH guidance. Major deviations between the fate of ENPs and predicted fate by REACH were found. They were related to at least 1 of 3 major assumptions made in REACH guidance: 1) in REACH, environmental alteration processes are all thought of as removal processes, whereas alterations of ENPs in the environment may greatly affect their properties, environmental effects, and behavior, 2) in REACH, chemicals are supposed to dissolve instantaneously and completely on release into the environment, whereas ENPs should be treated as nondissolved nanosized solids, and 3) in REACH, partitioning of dissolved chemicals to solid particles in air, water, and soil is estimated with thermodynamic equilibrium coefficients, but in the case of ENPs thermodynamic equilibrium between "dispersed" and "attached" states is generally not expected. The environmental exposure assessment of REACH therefore needs adjustment to cover the specific environmental fate of ENPs. Incorporation of the specific environmental fate processes of ENPs into the environmental risk assessment framework of REACH requires a pragmatic approach. PMID- 23633248 TI - [The ambulance attendant comes - what's up?]. PMID- 23633250 TI - [Definitions, decision-making and documentation in end of life situations in the intensive care unit]. AB - The present work provides assistance for physicians concerning decision making in clinical borderline situations in the ICU. Based on a structured checklist the two fundamental aspects of any medical decision, the medical indication and the patient's preference are queried in a systematic way. Four possible steps of withholding and/or withdrawing therapy are discussed. Finally, recommendations regarding appropriate documentation of end of life decisions are provided. PMID- 23633251 TI - [Flight and altitude medicine for anesthetists-part 3: emergencies on board commercial aircraft]. AB - The demographic trend of industrialized societies is also reflected in commercial airlines' passengers: passengers are older nowadays and long-haul flights are routine mode of transport despite considerable chronic and acute medical conditions. Moreover, duration of non-stop flight routes and the number of passengers on board increase. Thus, the probability of a medical incident during a particular flight event increases, too.Due to international regulations minimum standards for medical equipment on board, and first aid training of the crews are set. However, it is often difficult to assess whether a stopover at a nearby airport can improve the medical care of a critically ill passenger. Besides flight operations and technical aspects, the medical infrastructure on the ground has to be considered carefully.Regardless of the amount of experience of a physician medical emergencies on board an aircraft usually represent a particular challenge. This is mainly due to the unfamiliar surroundings, the characteristics of the cabin atmosphere, the often existing cultural and language barriers and legal liability concerns. PMID- 23633252 TI - [Declaration of Helsinki on patient safety in anesthesiology--part 4: SOP for perioperative anaphylaxis]. PMID- 23633253 TI - [Pssst...AINS secrets! Today in the general surgery]. PMID- 23633254 TI - [Pediatric anesthesia--practice makes perfect]. PMID- 23633255 TI - [Does anesthesia harm children's brain?]. AB - Animal data, that could show a correlation between anesthetic exposure and longterm damage to the developing brain, have raised concern within the international anesthesiology community, but also in patients, parents and media. The evaluation of the available literature does not provide evidence for changes in routine anesthetic practice associated with the order, to establish evidence through increased basic and clinical research about the mechanisms and possible effects in humans. PMID- 23633256 TI - [Supraglottic airways in infants and children]. AB - The development of the LMA-ClassicTM revolutionized anaesthesia practice as its wide-spread use led to the establishment of a unique form of airway management, the "supraglottic airway management", besides the existing classical airway management with the face mask or endotracheal tube. Today, 25 years later, along with the original prototype of supraglottic airways quite a few numbers of different devices exist that can be used to secure the airway "above the glottis". After initially primarily marketing adult sizes many suppliers offer paediatric sizes nowadays. However, the scientific evidence in terms of superiority or at a least equality to the original LMA-Classic( of any of these airway devices must be considered insufficient except for the LMA-ProSealTM. Consequently, the routine use of these devices outside controlled clinical studies must be considered questionable. The following article aims at providing a critical appraisal of currently available supraglottic airway devices for neonates and infants. PMID- 23633257 TI - [Clinical basics of supraglottic airway management in paediatric anaesthesia]. AB - The low invasiveness and simplicity of use of the LMA-ClassicTM contributed substantially to the supraglottic airway management acquiring a special role in the anaesthesia care of neonates and children. Due to the introduction of new supraglottic airway devices and the expansion of indications, this form of airway management has a predominant role in paediatric anaesthesia in many institutions nowadays. As securing the airway "above the glottis" differs substantially in some aspects from securing the airway using the endotracheal tube it is mandatory to acknowledge special aspects in routine clinical practice in order to avoid complications. The following article describes basic aspects of supraglottic airway management in paediatric anaesthesia and illustrates, where possible, the available scientific evidence in the use of different supraglottic airway devices in this regard. PMID- 23633258 TI - [The difficult venous access]. AB - Venipunctures in children are difficult. Some factors can hardly be influenced, for example, a well-developed subcutaneous fat tissue. Technical devices may help to identify invisible veins. With the help of ultrasound deep peripheral veins on the wrists and ankles can be presented and punctured. Stiff resistance of a child thwarts any successful puncture. Children should therefore be adequately sedated, if cannot be induced by mask. Missing practice venipuncture and inadequate knowledge of appropriate puncture sites can be met easily by practicing and reading.The possibility of intraosseous puncture today is standard of anesthesia care for children. Within in a few seconds, a secure access to the vein system can be created. PMID- 23633259 TI - [Perioperative fluid management in infants and toddlers]. AB - The more than 50 years ago of Holiday and Segar created fundamentals of fluid therapy with sodium hypotonic solutions require revision. Hypotonic electrolyte solutions should not be longer used perioperatively. To maintain the water balance in the perioperative phase stable, children need balanced electrolyte solutions, corresponding to the composition of the extracellular space. Routine glucose supply is not required, only children with an increased risk of hypoglycemia, such as newborns, need a supply of glucose as well as a monitoring of serum glucose. The historic 4-2-1-rule should be replaced by a simpler approach. Fasting deficit and intraoperative maintenance requirement will be covered by an increased rate of infusion of a balanced electrolyte solution. Intraoperative losses and correction needs to be replaced according to clinical criteria. Balanced electrolyte solution with and without 1% glucose are very safe with respect to hyponatremia, hypo-and hyperglycemia, and accidental overinfusion. PMID- 23633260 TI - [Regional anaesthesia in children--caudal anaesthesia and trunk blocks]. AB - In children, elective surgery is often performed in the trunk region. Regional anaesthetic techniques allow good analgesia with reduced opioid consumption, and enhance rapid discharge of the small patients. This review focuses on indication, anatomic structures, puncture techniques and potential complications of caudal anaesthesia, transversus abdominis plane block, ilioinguinal/iliohypogastric nerve block and rectus sheath block. PMID- 23633261 TI - [Perioperative thermal management in children]. AB - Perioperative temperature monitoring is a pre-requisite for successful prevention of inadvertent hypothermia in children. To achieve this goal, besides of pre warming, active warming measures have to be intensified the younger and immature infants are. Intraoperatively incubators can be used. Forced-air warming in combination with fluid warming has been proven effective in children. Postoperative shivering should be treated, e.g. with pethidin or clonidine. PMID- 23633265 TI - Statin use in relation to prostate cancer outcomes in a population-based patient cohort study. AB - BACKGROUND: We investigated associations between statin use begun before prostate cancer (PCa) diagnosis and PCa recurrence/progression and PCa-specific mortality (PCSM) in a prospective, population-based cohort study. METHODS: The analysis included 1,001 PCa patients diagnosed in 2002-2005 in King County, Washington. Statin use was assessed at the time of diagnosis using a detailed in-person interview. Prostate cancer recurrence/progression events and cause-specific survival were ascertained from a follow-up survey and the SEER registry. Multivariable competing risk and Cox proportional hazards regression models were used to assess the risk of PCa outcomes according to categories of statin use. RESULTS: Of the 1,001 PCa patients in our study, 289 men were ever users of statin drugs. During follow-up, we identified 151 PCa recurrence/progression events and 123 total deaths, including 39 PCa-specific deaths. In unadjusted analysis, the risk of PCSM was significantly lower for statin users compared to non-users (1% vs. 5% at 10 years; P < 0.01). In multivariable analysis, the adjusted hazard ratio of PCSM for statin users versus non-users was 0.19 (95% CI: 0.06, 0.56). Statin use was not associated with overall PCa recurrence/progression and other-cause mortality. CONCLUSIONS: Statin use begun before PCa diagnosis was unrelated to PCa recurrence/progression but was associated with a decrease in risk of PCSM. PMID- 23633266 TI - Comparison of 3D reconstructive technologies used for morphometric research and the translation of knowledge using a decision matrix. AB - The use of three-dimensional (3D) models for education, pre-operative assessment, presurgical planning, and measurement have become more prevalent. With the increase in prevalence of 3D models there has also been an increase in 3D reconstructive software programs that are used to create these models. These software programs differ in reconstruction concepts, operating system requirements, user features, cost, and no one program has emerged as the standard. The purpose of this study was to conduct a systematic comparison of three widely available 3D reconstructive software programs, Amira((r)), OsiriX, and Mimics((r)) , with respect to the software's ability to be used in two broad themes: morphometric research and education to translate morphological knowledge. Cost, system requirements, and inherent features of each program were compared. A novel concept selection tool, a decision matrix, was used to objectify comparisons of usability of the interface, quality of the output, and efficiency of the tools. Findings indicate that Mimics was the best-suited program for construction of 3D anatomical models and morphometric analysis, but for creating a learning tool the results were less clear. OsiriX was very user-friendly; however, it had limited capabilities. Conversely, although Amira had endless potential and could create complex dynamic videos, it had a challenging interface. These results provide a resource for morphometric researchers and educators to assist the selection of appropriate reconstruction programs when starting a new 3D modeling project. PMID- 23633267 TI - Extrinsic factors promoting in vitro differentiation of insulin-secreting cells from human adipose tissue-derived mesenchymal stem cells. AB - Understanding of beta cell regeneration is needed to develop new treatment modalities in diabetes mellitus. We present our experience of glucose-sensitive insulin-secreting mesenchymal stem cells (IS-MSC) generated and differentiated from human adipose tissue (h-AD) with application of specific differentiation media, sans xenogenic material. h-AD from donor abdominal wall was collected in proliferation medium composed of alpha-Minimum Essential Media, albumin, fibroblast-growth factor and antibiotics, minced, incubated in collagenase I at 37 degrees C with shaker and centrifuged. Supernatant and pellets were separately cultured in proliferation medium on cell + plates at 37 degrees C with 5 % CO(2) for 10 days. Cells were harvested, checked for viability, sterility, quantification, flow-cytometry (CD45(-)/90(+)/73(+)), and differentiated into insulin-expressing cells using medium composed of Dulbecco's modified eagle's medium, gene expressing upregulators and antibiotics for 3 days. They were studied for transcriptional factors paired box genes-6(Pax-6), islet 1 transcriptional factor (Isl-1), pancreatic and duodenal homobox-1(Pdx-1). C peptide and insulin were measured by chemiluminescence. IS-MSC showed presence of all three transcriptional factors and showed rise in insulin and c-peptide level in presence of glucose stimuli. It can be concluded that the specific extrinsic factors used in the defined differentiation media effectively and safely promote differentiation of glucose-sensitive insulin-secreting cells from human adipose tissue, without any genetic modulation. PMID- 23633268 TI - Food legislation and its harmonization in Russia. AB - Bringing Russian legislation into compliance with international norms and standards is necessary after its accession to the World Trade Organization. Harmonization of food legislation and of sanitary and phytosanitary measures are among the problems that had to be solved first. Many Russian food and trade regulations had been changed or are still in the process of being reformed, largely owing to a policy of integration pursued by the Customs Union of Russia, Belarus and Kazakhstan. However, as a member of the Eurasian Economic Community, Russia is also engaged not only in harmonization throughout the Customs Union but also Kirgizstan and Tajikistan, and Armenia, Moldova and Ukraine as observer countries. Russia also continues to coordinate policy reforms closely with the European Union, its primary trade partner, ultimately bringing Russian food and sanitary norms closer to international standards (e.g. Codex). Today, all participants in the Russian food production chain, processing and sale of foods have to deal with growing numbers of security standards. Many organizations are certified under several schemes, which leads to unnecessary costs. Harmonization of standards has helped promote solutions in the domestic market as well as import-export of foods and raw materials for production. Priorities have included food safety for human health, consumer protection, removal of hazardous and/or adulterated products and increased competition within the domestic food market as well as mutual recognition of certification in bilateral and multilateral (inter)national agreements. PMID- 23633269 TI - Lipoproteins are an important bacterial component responsible for bone destruction through the induction of osteoclast differentiation and activation. AB - Bacterial infection can cause inflammatory bone diseases accompanied by the bone destruction resulting from excess generation of osteoclasts. Although lipoproteins are one of the major immunostimulating components of bacteria, little is known about their effects on bone metabolism. In this study, we investigated the role of lipoproteins in bacteria-induced bone destruction using Staphylococcus aureus wild type, its lipoprotein-deficient mutant, and synthetic lipopeptides Pam2CSK4 and Pam3CSK4 known to mimic bacterial lipoproteins. Formaldehyde-inactivated S. aureus or the synthetic lipopeptides induced severe bone loss in the femurs of mice after intraperitoneal administration and in a calvarial bone implantation model, whereas the lipoprotein-deficient S. aureus did not show such effects. Mechanism studies further identified three action mechanisms for the lipopeptide-induced osteoclast differentiation and bone resorption via (i) enhancement of osteoclast differentiation through Toll-like receptor 2 and MyD88-dependent signaling pathways; (ii) induction of pro inflammatory cytokines, TNF-alpha and IL-6; and (iii) upregulation of RANKL expression with downregulation of osteoprotegerin expression in osteoblasts. Taken together, these results suggest that lipoprotein might be an important bacterial component responsible for bone destruction during bacterial infections through augmentation of osteoclast differentiation and activation. PMID- 23633270 TI - Mortality and sudden death in pediatric left ventricular noncompaction in a tertiary referral center. AB - BACKGROUND: Left ventricular noncompaction is a cardiomyopathy characterized by excessive trabeculation of the left ventricle, progressive myocardial dysfunction, and early mortality. Left ventricular noncompaction has a heterogeneous clinical presentation that includes arrhythmia and sudden cardiac death. METHODS AND RESULTS: We retrospectively reviewed all children diagnosed with left ventricular noncompaction at Texas Children's Hospital from January 1990 to January 2009. Patients with congenital cardiac lesions were excluded. Two hundred forty-two children were diagnosed with isolated left ventricular noncompaction over the study period. Thirty-one (12.8%) died, and 13 (5.4%) were received a transplant. One hundred fifty (62%) presented with or developed cardiac dysfunction. The presence of cardiac dysfunction was strongly associated with mortality (hazard ratio, 11; P<0.001). ECG abnormalities were present in 87%, with ventricular hypertrophy and repolarization abnormalities occurring most commonly. Repolarization abnormalities were associated with increased mortality (hazard ratio, 2.1; P=0.02). Eighty children (33.1%) had an arrhythmia, and those with arrhythmias had increased mortality (hazard ratio, 2.8; P=0.002). Forty-two (17.4%) had ventricular tachycardia, with 5 presenting with resuscitated sudden cardiac death. In total, there were 15 cases of sudden cardiac death in the cohort (6.2%). Nearly all patients with sudden death (14 of 15) had abnormal cardiac dimensions or cardiac dysfunction. No patient with normal cardiac dimensions and function without preceding arrhythmias died. CONCLUSIONS: Left ventricular noncompaction has a high mortality rate and is strongly associated with arrhythmias in children. Preceding cardiac dysfunction or ventricular arrhythmias are associated with increased mortality. Children with normal cardiac dimensions and normal function are at low risk for sudden death. PMID- 23633271 TI - Efficacy of the CCR5 antagonist maraviroc in reducing early, ritonavir-induced atherogenesis and advanced plaque progression in mice. AB - BACKGROUND: CCR5 plays an important role in atherosclerosis and ischemic cardiovascular diseases, as well as in HIV replication and diffusion. HIV infection is characterized by a high burden of cardiovascular diseases, particularly in subjects exposed to ritonavir-boosted protease inhibitors. Maraviroc, a CCR5 antagonist antiretroviral drug, might provide benefit for patients with M-tropic HIV infections at high risk for cardiovascular diseases. METHODS AND RESULTS: Exposure to maraviroc limits the evolution and associated systemic inflammation of ritonavir-induced atherosclerotic in ApoE(-/-) mice and inhibits plaques development in a late model of atherosclerosis in which dyslipidemia plays the main pathogenic role. In ritonavir-treated mice, maraviroc reduced plaque areas and macrophage infiltration; downregulated the local expression of vascular cell adhesion molecule-1, intercellular adhesion molecule 1, monocyte chemoattractant protein-1, and interleukin-17A; and reduced tumor necrosis factor-alpha and RANTES (regulated on activation, normal T cell expressed, and secreted). Moreover, maraviroc counterregulated ritonavir-induced lipoatrophy and interlelukin-6 gene expression in epididymal fat, along with the splenic proinflammatory profile and expression of CD36 on blood monocytes. In the late model, maraviroc inhibited atherosclerotic progression by reducing macrophage infiltration and lowering the expression of adhesion molecules and RANTES inside the plaques. However, limited systemic inflammation was observed. CONCLUSIONS: In a mouse model of genetic dyslipidemia, maraviroc reduced the atherosclerotic progression by interfering with inflammatory cell recruitment into plaques. Moreover, in mice characterized by a general ritonavir-induced inflammation, maraviroc reversed the proinflammatory profile. Therefore, maraviroc could benefit HIV-positive patients with residual chronic inflammation who are at a high risk of acute coronary disease despite a suppressive antiretroviral therapy. To determine these benefits, large clinical studies are needed. PMID- 23633272 TI - Short-term alcohol consumption may have detrimental effect on fibrinolysis and endothelial function: preliminary report of prospective randomised study. AB - BACKGROUND AND AIM: This study was designed to clarify the impact of the short term consumption of different types of alcoholic beverages on haemostatic factors, C-reactive protein (hsCRP) and endothelin-1 (E-1) plasma levels. METHODS: The study group consisted of 57 healthy male volunteers, aged 20-29 years. Subjects were randomised to consume 300 mL of red wine, white wine, 12% ethanol, black currant juice or water for five days. Blood samples were collected for CRP, tissue type plasminogen activator antigen (t-PA:Ag), plasminogen activator inhibitor antigen (PAI-1:Ag) and E-1 at baseline, on day 2, and on day 6. RESULTS: A significant increase in PAI-1:Ag concentration was observed in the red wine drinking group (day 1: 44.98; day 2:56.86; day 6: 47.44 ng/mL; p = 0.05). A similar increase of E-1 level was found in the 12% ethanol group (day 1: 0.53; day 2:1.65; day 6: 1.11 fmol/mL; p = 0.01). Dividing the whole study group according to ethanol content of consumed beverages revealed significant changes in tPA:Ag, PAI-1:Ag and E-1 levels. In the alcohol drinking group, significant increases of PAI-1:Ag (day 1: 44.75; day 2: 54.07; day 6: 44.80 ng/mL; p < 0.05); tPA:Ag level (day 1: 3.65; day 2: 4.17; day 6: 5.03 ng/mL;p < 0.02) and E-1 (day 1: 0.42; day 2: 1.01; day 6: 0.97 fmol/mL; p < 0.002) were observed. CONCLUSIONS: Short-term alcohol consumption increases tPA:Ag, PAI:Ag and E-1 plasma levels. This effect may have an unfavourable impact on the fibrinolytic system and endothelial function. PMID- 23633273 TI - Prognostic value of serum resistin levels in patients with acute myocardial infarction. AB - BACKGROUND: Resistin is a novel adipokine that is suggested to be involved in inflammatory conditions and atherosclerosis. AIM: To investigate the prognostic importance of resistin in acute myocardial infarction (AMI) patients. METHODS: Resistin levels were measured in a population of 132 patients with AMI, of whom 72 (54%) had a diagnosis of ST elevation myocardial infarction (STEMI), and 60 (46%) had non-ST elevation myocardial infarction (NSTEMI). Thirty-three consecutive subjects who were referred to elective coronary angiography due to chest pain evaluation with normal coronary angiograms served as controls. All patients were followed-up for the occurrence of major adverse cardiac events (MACE). RESULTS: There was a significant increase in serum resistin levels in patients with AMI compared to controls (3.71 +/- 4.20 vs. 2.00 +/- 1.05, p = 0.001, respectively). However, serum resistin levels were similar in patients with STEMI and NSTEMI. (4.26 +/- 5.11 vs. 3.06 +/- 2.64, p = 0.49, respectively). The patients with MACE had significantly higher levels of serum resistin levels compared to either the AMI or the control group (6.35 +/- 5.47, p = 0.005, respectively). Logistic regression analysis revealed that resistin, left ventricular ejection fraction, and coronary artery bypass graft were independent predictors of MACE in AMI patients (OR = 1.11, 95% CI 1.01-1.22, p = 0.03 and OR = 3.84, 95% CI 1.26-11.71, p = 0.018, respectively). CONCLUSIONS: Serum resistin level was increased in patients with AMI and constituted a risk factor for MACE in this group. PMID- 23633274 TI - Blood pressure load in adults with treated hypertension. AB - BACKGROUND AND AIM: To assess blood pressure (BP) load in a population of treated hypertensive patients. METHODS: The study group consisted of 137 hypertensive adults, including 75 (54.75%) men and 62 (45.25%) women, with either formerly or newly diagnosed hypertension based on office BP measurements. The median age in the whole study group was 52 years (47 and 56 years among men and women, respectively). The mean body mass index (BMI) was 27 +/- 4 kg/m2, and median duration of hypertension was 3 years. We divided the study group into subgroups depending on age, gender, BMI, and duration of hypertension. All patients underwent single 24-h ambulatory BP monitoring. We calculated 24-h, daytime and nighttime BP loads separately for systolic and diastolic BP. Statistical analysis was carried out using the SPSS 15.0 environment. RESULTS: Men were significantly younger than women (48.17 vs. 55.48 years, p < 0.02). Mean BMI was higher in men than women (28 vs. 26 kg/m2, p < 0.044). There were no differences in the mean values of BP load depending on gender, BMI and, duration of hypertension (p = NS). Twenty-four hour and daytime diastolic BP load was higher in patients aged 41-65 years than in patients above 65 years (32.4 vs. 20.8%, p < 0.04; and 29.6 vs. 17.5%, p < 0.03). A negative correlation was found between daytime diastolic BP load and age (r = -0.19, p < 0.026) and a positive correlation was found between night time systolic BP load and age (r = 0.24, p < 0.005). CONCLUSIONS: There was no relationship between BP load and gender, BMI, and duration of hypertension. Diastolic BP load was age-related. Middle-aged patients were characterised by significantly higher values of 24-h and daytime diastolic BP load than the elderly patients. PMID- 23633275 TI - [Do repeating MRI studies in patients with sciatica make sense? MRI is still recommended]. PMID- 23633276 TI - [Diagnostic studies with molecular biomarkers--individualized medicine comes under scrutiny]. PMID- 23633277 TI - [Weight reduction: evaluation of the possibilities in primary care and patient satisfaction. Results from a weight reduction trial]. AB - BACKGROUND: Commercial weight loss programs offer support to overweight and obese patients to reduce excess bodyweight. Many patients seek advice for weight loss from their general practitioners. PATIENTS AND METHODS: In the framework of a randomized controlled 1-year trial the effectiveness and safety of a commercial weight loss program was compared with a primary care intervention. At the end of the trial the participating general practitioners and study participants were asked to answer specific questions about their offered weight loss management. This paper relates to the German study part (268 participants, 40 general practitioners). RESULTS: More than half of the general practitioners reported to offer a dietary concept which varied strongly across general practitioners. About one third of the general practitioners considered commercial weight loss programs as an alternative to support weight reduction. Participants reported that they considered weight loss advice by their general practitioners as helpful. But patients in the commercial weight loss program assessed the advice as more positive and achieved twice as much weight loss as patients in the primary care intervention. CONCLUSION: Evaluated commercial weight loss programs can be effective and safe alternatives for general practitioners to achieve weight loss in overweight and obese patients. PMID- 23633278 TI - [Right lower quadrant abdominal pain--the usual suspects? Diagnosis and therapy of a symptomatic mesenteric cyst]. AB - HISTORY AND CLINICAL FINDINGS: A 17-year-old male sought medical attention for right lower abdominal pain. At clinical examination an abdominal mass in the right lower abdominal quadrant was accompanied by pain and tenderness in this very region. The febrile patient (temperature axillary: 37.5 degrees C, rectal: 38.6 degrees C) was in reduced general health. INVESTIGATIONS: Except for an elevated C-reactive protein (CRP: 14.3 mg/dl, normal: < 0.5) laboratory tests were inconspicuous. Abdominal ultrasound showed a hypoechogenic/anechogenic septated mass measuring 7.2 * 10.4 * 15 cm as well as small amounts of fluid. Abdominal computed tomography confirmed these findings. Radiographically there was evidence for appendicitis. TREATMENT AND COURSE: Empiric antibiotic therapy was immediately commenced. Within 48 hours laparotomy was performed showing an abdominal mass which seemed to infiltrate the transverse colon, the ileocolic artery and the mesenteric root. No signs of appendicitis were found. A radical resection of the abdominal mass was performed meeting current standards of oncologic surgery. The postoperative course was favourable. Histopathological investigation showed a mesenteric cyst incorporating a hematoma and tissue with signs of chronic inflammation and granulation. CONCLUSION: Mesenteric cysts are rare pathologies occurring most frequently during childhood. They may become clinically overt in case of infection, haemorrhage or secondary intestinal obstruction. In the presented case presented hematoma formation and chronic inflammation had presumably induced peritonitis and clinical signs of appendicitis. Abdominal ultrasound and computed tomography facilitated diagnostic work-up. The patient thereby benefited from a scheduled laparotomy allowing a complete recovery. PMID- 23633279 TI - [23-year-old woman with ventriculoperitoneal shunt and lower abdominal pain]. PMID- 23633280 TI - [Ultrasound for abdominal lymphadenopathy]. AB - This CME-review is about the clinical importance of the abdominal lymph node diagnostic with special attention to various ultrasound techniques. This includes innovative techniques like contrast enhanced ultrasound and elastography. The clinical importance of ultrasound in relation to cross sectional imaging will be the target of the article as well as anatomic- topographic aspects. The article deals as well with endosonographic techniques because of the upmost importance of the technique for diagnosing mediastinal and abdominal lymphnode swellings. In conclusion of the article different clinical scenarios and clinical algorithms are presented to help the reader to diagnose abdominal lymphadenopathy correctly in an efficient way. PMID- 23633281 TI - [ARDS--an update]. AB - The acute respiratory distress syndrome (ARDS) is characterized by severe impairment of gas exchange and remains a challenge for modern intensive care medicine. The most common causes of ARDS are pneumonia and sepsis. The mortality in severe ARDS is as high as 50 %. The new definition of ARDS differentiates three levels of severity depending on the degree of hypoxaemia. The fundamental basis of therapy is to treat the underlying cause of ARDS. Furthermore, lung protective mechanical ventilation must be applied using low tidal volumes and limiting inspiratory pressures. Intermittent prone positioning can reduce mortality in severe cases of ARDS. In extreme, life threatening cases extracorporeal membrane oxygenation can stabilize gas exchange and serve as a bridge to recovery and means to enable lung protective ventilation. PMID- 23633283 TI - Challenges in planning and conducting diagnostic studies with molecular biomarkers. AB - Biomarkers are of increasing importance for personalized medicine in many areas of application, such as diagnosis, prognosis, or the selection of targeted therapies. In many molecular biomarker studies, intensity values are obtained from large scale -omics experiments. These intensity values, such as protein concentrations, are often compared between at least two groups of subjects to determine the diagnostic ability of the molecular biomarker. Various prospective or retrospective study designs are available for molecular biomarker studies, and the biomarker used may be univariate or may even consist in a multimarker rule. In this work, several challenges are discussed for the planning and conduct of biomarker studies. The phases of diagnostic biomarker studies are closely related to levels of evidence in diagnosis, and they are therefore discussed upfront. Different study designs for molecular biomarker studies are discussed, and they primarily differ in the way subjects are selected. Using two systematic reviews from the literature, common sources of bias of molecular diagnostic studies are illustrated. The extreme selection of patients and controls and verification bias are specifically discussed. The pre-analytical and technical variability of biomarker measurements is usually expressed in terms of the coefficient of variation, and is of great importance for subsequent validation studies for molecular biomarkers. It is finally shown that the required sample size for biomarker validation quadratically increases with the coefficient of variation, and the effect is illustrated using real data from different laboratory technologies. PMID- 23633284 TI - Purine derivate content and amino acid profile in larval stages of three edible insects. AB - BACKGROUND: Considering their high content of protein, insects are a valuable alternative protein source. However, no evaluation of their purine content has so far been done. High content of purine derivates may lead to the exclusion of such food from the diet of people with specific diseases. The aim of this study was to analyse the content of selected purine derivates and amino acid profile in the three insect species most often used for entomophagy in Europe and compare them with the purine content in egg white and chicken breast. RESULTS: The content of individual purine derivates and their total content were significantly dependent on insect species. The purine content in all three species was significantly higher (P < 0.05) than in egg white, but some values were significantly lower (P < 0.05) than in chicken breast. The total protein content was 548.9 g kg(-1) dry matter (DM) in mealworm (Tenebrio molitor), 551.6 g kg(-1) DM in superworm (Zophobas atratus) and 564.9 g kg(-1) DM in cricket (Gryllus assimilis). CONCLUSION: Larvae of mealworm and superworm are protein-rich and purine-low meat alternatives. In contrast, cricket nymphs are protein-rich and purine-rich and cannot be recommended for people with hyperuricemia or gout. PMID- 23633285 TI - Presence of a hypovascular hepatic nodule showing hypointensity on hepatocyte phase image is a risk factor for hypervascular hepatocellular carcinoma. AB - PURPOSE: To determine whether the presence of a hypovascular nodule in the liver showing hypointensity on hepatocyte-phase of gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) is a risk factor for hypervascular hepatocellular carcinoma (HCC) in patients with chronic liver disease. MATERIALS AND METHODS: Forty-one patients with pathologically confirmed hypervascular HCC and 41 age- and gender-matched controls were retrospectively selected. These patients had undergone EOB-MRI at least twice: the latest EOB-MRI and EOB-MRI performed more than 6 months earlier. History of hypervascular HCC, presence of a hypointense hypovascular nodule in previous hepatocyte-phase MR images, percent prothrombin time, platelet count, serum levels of albumin, total bilirubin, aspartate aminotransferase, alanine aminotransferase, alpha-fetoprotein, and protein induced by vitamin K absence-II (PIVKA-II) were variables evaluated by multivariate logistic regression analysis. RESULTS: Multivariate analysis revealed that serum albumin level (odds ratio [95% confidence interval], 0.19 [0.06-0.57]; P = 0.0024), history of hypervascular HCC (8.62 [2.71-32.8]; P = 0.0001), and presence of a hypointense hypovascular nodule (4.18 [1.18-17.2]; P = 0.0256) were significant risk factors for hypervascular HCC. CONCLUSION: Patients with chronic liver disease showing a hypointense hypovascular nodule in the liver on hepatocyte-phase EOB-MRI have a high risk of HCC development. PMID- 23633286 TI - Non-invasive in situ monitoring and quantification of TOL plasmid segregational loss within Pseudomonas putida biofilms. AB - Methods for the detection of plasmid loss in natural environments have typically relied on replica plating, selective markers and PCR. However, these traditional methods have the limitations of low sensitivity, underestimation of specific cell populations, and lack of insightful data for non-homogeneous environments. We have developed a non-invasive microscopic analytical method to quantify local plasmid segregational loss from a bacterial population within a developing biofilm. The probability of plasmid segregational loss in planktonic and biofilm cultures of Pseudomonas putida carrying the TOL plasmid (pWWO::gfpmut3b) was determined directly in situ, in the absence of any applied selection pressure. Compared to suspended liquid culture, we report that the biofilm mode of growth enhances plasmid segregational loss. Results based on a biofilm-averaged analysis reveal that the probability of plasmid loss in biofilm cultures (0.016 +/- 0.004) was significantly greater than that determined in planktonic cultures (0.0052 +/- 0.0011). Non-invasive assessments showed that probabilities of plasmid segregational loss at different locations in a biofilm increased dramatically from 0.1% at the substratum surface to 8% at outside layers of biofilm. Results suggest that higher nutrient concentrations and subsequentially higher growth rates resulted in higher probability of plasmid segregational loss at the outer layers of the biofilm. PMID- 23633287 TI - Estrogen receptor-beta ligand treatment after disease onset is neuroprotective in the multiple sclerosis model. AB - Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation and neurodegeneration. Current MS treatments were designed to reduce inflammation in MS rather than directly to prevent neurodegeneration. Estrogen has well documented neuroprotective effects in a variety of disorders of the CNS, including experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model of MS. Treatment with an estrogen receptor-beta (ERbeta) ligand is known to ameliorate clinical disease effectively and provide neuroprotection in EAE. However, the protective effects of this ERbeta ligand have been demonstrated only when administered prior to disease (prophylactically). Here we tested whether ERbeta ligand treatment could provide clinical protection when treatment was initiated after onset of disease (therapeutically). We found that therapeutic treatment effectively ameliorated clinical disease in EAE. Specifically, ERbeta ligand-treated animals exhibited preserved axons and myelin compared with vehicle treated animals. We observed no difference in the number of T lymphocytes, macrophages, or microglia in the CNS of vehicle- vs. ERbeta ligand-treated animals. Our findings show that therapeutically administered ERbeta ligand successfully treats clinical EAE, bearing translational relevance to MS as a candidate neuroprotective agent. PMID- 23633289 TI - Proposal for a "Harmonized" strategy for the assessment of the HP 14 property. AB - In Europe, the decision whether waste is hazardous or not is based on 15 properties, among them the HP 14 property ("ecotoxic": waste that presents or may present immediate or delayed risks for 1 or more sectors of the environment). This document describes a strategy for assessing the HP 14 property, based on a combination of 2 approaches: the summation of classified compounds in the waste carried out according to the regulation on Classification, Labeling and Packaging (CLP) of substances and mixtures and the usage of the results of biotests performed on waste eluates and solid wastes. The proposal is based mainly on recommendations of a European ring test carried out in 2007, the work performed in the CEN/TC 292/WG 7 standardization working group, and the results of various research projects regarding the ecotoxicological characterization of waste carried out mainly in France and Germany. Examples are provided showing that, using this approach, a distinction between hazardous and nonhazardous wastes is possible, independent of which type of threshold values is used (currently, both effect concentrations [EC] or lowest ineffective dilutions [LID] values have been used successfully). Furthermore, a battery of tests (3 using waste eluates and 3 using solid waste samples, plus, under certain conditions, a genotoxicity test) is recommended for the ecotoxicological testing of wastes. We propose to consider this combined approach when defining the legal requirements for the ecotoxicological classification of wastes. PMID- 23633290 TI - Superparamagnetic iron oxide nanoparticles for MRI: contrast media pharmaceutical company R&D perspective. AB - Superparamagnetic iron oxide (SPIO) nanoparticles are a relatively large class of contrast agents for magnetic resonance imaging. According to their biodistribution, distinct classes of SPIO nanoparticles have been investigated for clinical applications either as macrophage imaging agents or blood pool agents. Contrast agents which are pharmaceutics followed the same development rules as therapeutic drugs. Several drawbacks such as clinical development difficulties, organization of market access and imaging technological developments have limited the widespread use of these products. SPIO nanoparticles that are composed of thousands iron atoms providing large T2* effects are particularly suitable for theranostic. Stem cell migration and immune cell trafficking, as well as targeted SPIO nanoparticles for molecular imaging studies are mainly at the stage of proof of concept. A major economic challenge in the development of molecular imaging associated with a therapeutic treatment/procedure is to define innovative business models compatible with the needs of all players taking into account that theranostic solutions are promising to optimize resource allocation and ensure that expensive treatments are prescribed to responding patients. PMID- 23633291 TI - Alternatives to steroids?! Beneficial effects of immunosuppressant drugs in autoimmune pancreatitis. PMID- 23633292 TI - Helicobacter pylori is associated with lower androgen activity among men in NHANES III. PMID- 23633288 TI - How stem cells speak with host immune cells in inflammatory brain diseases. AB - Advances in stem cell biology have raised great expectations that diseases and injuries of the central nervous system (CNS) may be ameliorated by the development of non-hematopoietic stem cell medicines. Yet, the application of adult stem cells as CNS therapeutics is challenging and the interpretation of some of the outcomes ambiguous. In fact, the initial idea that stem cell transplants work only via structural cell replacement has been challenged by the observation of consistent cellular signaling between the graft and the host. Cellular signaling is the foundation of coordinated actions and flexible responses, and arises via networks of exchanging and interacting molecules that transmit patterns of information between cells. Sustained stem cell graft-to-host communication leads to remarkable trophic effects on endogenous brain cells and beneficial modulatory actions on innate and adaptive immune responses in vivo, ultimately promoting the healing of the injured CNS. Among a number of adult stem cell types, mesenchymal stem cells (MSCs) and neural stem/precursor cells (NPCs) are being extensively investigated for their ability to signal to the immune system upon transplantation in experimental CNS diseases. Here, we focus on the main cellular signaling pathways that grafted MSCs and NPCs use to establish a therapeutically relevant cross talk with host immune cells, while examining the role of inflammation in regulating some of the bidirectionality of these communications. We propose that the identification of the players involved in stem cell signaling might contribute to the development of innovative, high clinical impact therapeutics for inflammatory CNS diseases. PMID- 23633293 TI - Association of Helicobacter pylori seropositivity with all-cause mortality: fact or fiction? PMID- 23633295 TI - Re-evaluation of traditional Mediterranean foods. The local landraces of 'Cipolla di Giarratana' (Allium cepa L.) and long-storage tomato(Lycopersicon esculentum L.): quality traits and polyphenol content. AB - BACKGROUND: The heightened consumer awareness for food safety is reflected in the demand for products with well-defined individual characteristics due to specific production methods, composition and origin. In this context, of pivotal importance is the re-evaluation of folk/traditional foods by properly characterizing them in terms of peculiarity and nutritional value. The subjects of this study are two typical Mediterranean edible products. The main morphological, biometrical and productive traits and polyphenol contents of three onion genotypes ('Cipolla di Giarratana', 'Iblea' and 'Tonda Musona') and three long-storage tomato landraces ('Montallegro', 'Filicudi' and 'Principe Borghese') were investigated. RESULTS: Sicilian onion landraces were characterized by large bulbs, with 'Cipolla di Giarratana' showing the highest bulb weight (605 g), yield (151 t ha(-1)) and total polyphenol content (123.5 mg kg(-1)). Landraces of long-storage tomato were characterized by low productivity (up to 20 t ha(-1)), but more than 70% of the total production was obtained with the first harvest, allowing harvest costs to be reduced. High contents of polyphenols were found, probably related to the typical small fruit size and thick skin characterizing these landraces. CONCLUSION: The present study overviews some of the most important traits that could support traditional landrace characterization and their nutritional value assessment. PMID- 23633296 TI - Background parenchymal enhancement on breast MRI: influence of menstrual cycle and breast composition. AB - PURPOSE: To evaluate the menstrual cycle and breast composition influence on background parenchymal enhancement of breast magnetic resonance imaging (MRI) and to investigate the optimal time for breast MR examinations. MATERIALS AND METHODS: We evaluated the dynamic contrast-enhanced breast MR images of 238 women who had completed a questionnaire survey about menstrual status. On MRI, the degree of enhancement (DE) of normal parenchyma was measured in the images 2 minutes and 6 minutes after contrast injection. A comparison between premenopausal and postmenopausal women and a separate comparison between dense breasts and fatty breasts were analyzed according to the premenopausal women's menstrual cycle. RESULTS: Premenopausal women showed significantly higher DE than the postmenopausal women (P<0.001). In premenopausal women, overall DE of fatty breasts and dense breasts was not different. However, fatty breasts showed the highest DE in the 4th week and lowest DE in the 2nd week, while dense breasts showed the highest DE in the 3rd week and the lowest DE in the 4th week of menstrual cycle. CONCLUSION: The influence of menstrual cycle on the enhancement of breast parenchyma is different according to the breast composition. The optimal time for breast MRI could be different for dense and fatty breasts. PMID- 23633298 TI - Isolation of fully synthetic promoters for high-level gene expression in Corynebacterium glutamicum. AB - Corynebacterium glutamicum is an important industrial organism that is widely used in the production of amino acids, nucleotides and vitamins. To extend its product spectrum and improve productivity, C. glutamicum needs to undergo further engineering, including the development of applicable promoter system. Here, we isolated new promoters from the fully synthetic promoter library consisting of 70 bp random sequences in C. glutamicum. Using green fluorescent protein (GFP) as a reporter, highly fluorescent cells were screened from the library by fluorescent activated cell sorting (FACS). Twenty potential promoters of various strengths were isolated and characterized through extensive analysis of DNA sequences and mRNA transcripts. Among 20 promoters, 6 promoters which have different strengths were selected and their activities were successfully demonstrated using two model proteins (antibody fragment and endoxylanase). Finally, the strongest promoter (P(H36)) was employed for the secretory production of endoxylanase in fed-batch cultivation, achieving production levels of 746 mg/L in culture supernatant. This is the first report of synthetic promoters constructed in C. glutamicum, and our screening strategy together with the use of synthetic promoters of various strengths will contribute to the future engineering of C. glutamicum. PMID- 23633297 TI - Conditioned medium from human amniotic epithelial cells may induce the differentiation of human umbilical cord blood mesenchymal stem cells into dopaminergic neuron-like cells. AB - Dopaminergic (DA) neuron therapy has been established as a new clinical tool for treating Parkinson's disease (PD). Prior to cell transplantation, there are two primary issues that must be resolved: one is the appropriate seed cell origin, and the other is the efficient inducing technique. In the present study, human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) were used as the available seed cells, and conditioned medium from human amniotic epithelial cells (ACM) was used as the inducing reagent. Results showed that the proportion of DA neuron-like cells from hUCB-MSCs was significantly increased after cultured in ACM, suggested by the upregulation of DAT, TH, Nurr1, and Pitx3. To identify the process by which ACM induces DA neuron differentiation, we pretreated hUCB-MSCs with k252a, the Trk receptor inhibitor of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), and found that the proportion of DA neuron like cells was significantly decreased compared with ACM-treated hUCB-MSCs, suggesting that NGF and BDNF in ACM were involved in the differentiation process. However, we could not rule out the involvement of other unidentified factors in the ACM, because ACM + k252a treatment does not fully block DA neuron-like cell differentiation compared with control. The transplantation of ACM-induced hUCB MSCs could ameliorate behavioral deficits in PD rats, which may be associated with the survival of engrafted DA neuron-like cells. In conclusion, we propose that hUCB-MSCs are a good source of DA neuron-like cells and that ACM is a potential inducer to obtain DA neuron-like cells from hUCB-MSCs in vitro for an ethical and legal cell therapy for PD. PMID- 23633300 TI - A newly recognized autosomal recessive syndrome affecting neurologic function and vision. AB - Genetic factors represent an important etiologic group in the causation of intellectual disability. We describe a Saudi Arabian family with closley related parents in which four of six children were affected by a congenital cognitive disturbance. The four individuals (aged 18, 16, 13, and 2 years when last examined) had motor and cognitive delay with seizures in early childhood, and three of the four (sparing only the youngest child) had progressive, severe cognitive decline with spasticity. Two affected children had ocular malformations, and the three older children had progressive visual loss. The youngest had normal globes with good functional vision when last examined but exhibited the oculodigital sign, which may signify a subclinical visual deficit. A potentially deleterious nucleotide change (c.1A>G; p.Met1Val) in the C12orf57 gene was homozygous in all affected individuals, heterozygous in the parents, and absent in an unaffected sibling and >350 normal individuals. This gene has no known function. This family manifests a autosomal recessive syndrome with some phenotypic variability that includes abnormal development of brain and eyes, delayed cognitive and motor milestones, seizures, and a severe cognitive and visual decline that is associated with a homozygous variant in a newly identified gene. PMID- 23633299 TI - Siglec-h on activated microglia for recognition and engulfment of glioma cells. AB - Sialic-acid-binding immunoglobulin-like lectin-h (Siglec-h) is a recently identified mouse-specific CD33-related Siglec that signals via DAP12/TYROBP. Expression of Siglec-h has been observed on plasmacytoid dendritic cells and microglia, but the ligand and the function of Siglec-h remained elusive. Here, we demonstrate gene transcription and protein expression of Siglec-h by mouse microglia after interferon-gamma treatment or polarization into a M1-subtype. Microglial Siglec-h acted as phagocytosis receptor since targeting of microsphere beads to Siglec-h triggered their uptake into the microglia. The extracellular domain of Siglec-h protein bound to mouse glioma lines, but not to astrocytes or other normal mouse cells. Microglial cells stimulated to express Siglec-h engulfed intact glioma cells without prior induction of apoptosis and slightly reduced glioma cell number in culture. Phagocytosis of glioma cells by activated microglia was dependent on Siglec-h and its adapter molecule DAP12. Thus, data show that M1-polarized microglial cells can engulf glioma cells via a DAP12 mediated Siglec-h dependent mechanism. PMID- 23633301 TI - Why I believe nanoparticles are crucial as a carrier for targeted drug delivery. AB - Nanoparticles are the only materials small enough to target cells in the body, and therefore are crucial to targeted drug delivery. Issues with the synthesis, consistency, and bioactivity of these molecules are still being addressed, but base on current proof of concept studies there is a reason to believe that the 'holy grail' of targeted drug delivery might someday be achieved using nanoparticle-based systems. PMID- 23633302 TI - Optimization of the cultivation conditions for mushroom production with European wild strains of Agaricus subrufescens and Brazilian cultivars. AB - BACKGROUND: The almond mushroom Agaricus subrufescens (formerly Agaricus blazei or Agaricus brasiliensis) is cultivated at commercial level in Brazil and some Asian countries on local substrates and casing mixtures. Despite its tropical origin, A. subrufescens might be a seasonal option for mushroom growers in western countries, where some wild strains have been isolated. For this purpose, cultivation conditions were developed starting from the substrate and casing mixture commonly used for commercial production of the button mushroom Agaricus bisporus in France. RESULTS: The commercial compost, based on wheat straw and horse manure, used for A. bisporus and the casing mixture (peat and limestone) supplemented with fine sand proved efficient to grow A. subrufescens. Increasing the depth of the casing layer improved significantly the yield and time to fruiting. Daily variations in temperature did not markedly modify the yield. Significantly higher mushroom biomass was obtained with three wild European strains compared with three Brazilian cultivars. The very productive wild strain CA438-A gave mushrooms of size and dry matter content comparable to those of a cultivar. CONCLUSION: Commercial production of A. subrufescens can be developed in western countries on the wheat straw-based substrate commonly used for A. bisporus in these regions, by a simple modification of the casing mixture and maintaining the incubation temperature throughout the crop, which is expected to save energy during summer. Good yields were obtained cultivating European strains under optimised parameters. PMID- 23633303 TI - Garlic for peripheral arterial occlusive disease. AB - BACKGROUND: Commercially available preparations of garlic have been reported to have beneficial effects on some of the risk factors associated with atherosclerosis. OBJECTIVES: To assess the effects of garlic (both dried and non powdered preparations) for the treatment of peripheral arterial occlusive disease. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2013) and CENTRAL (2012, Issue 12). SELECTION CRITERIA: Randomised trials of garlic therapy in patients with lower limb atherosclerosis were included. The main outcomes were objective measures of progression of underlying atherosclerosis (e.g. ankle pressure measurements, treadmill testing) and subjective measures (e.g. symptom progression). DATA COLLECTION AND ANALYSIS: Two review authors (RJ and JK) independently extracted data and assessed trial quality. One author (RJ) contacted investigators to obtain information needed for the review that could not be found in published reports. MAIN RESULTS: One eligible trial with 78 participants was found. Both men and women (aged 40 to 75) were included. The follow-up period was short, 12 weeks only.After twelve weeks of treatment, pain-free walking distance increased from 161 to 207 metres in the group receiving garlic and from 172 to 203 metres in the placebo group. This was not a statistically significant difference. There was no difference in change of systolic or diastolic blood pressure, heart rate, ankle and brachial pressures. No severe side effects were observed and nine patients taking garlic (28%) and four patients taking placebo (12%) complained of a noticeable garlic smell.Three trials were excluded from the review because they did not include any clinical measurements. AUTHORS' CONCLUSIONS: One small trial of short duration found no statistically significant effect of garlic on walking distance. PMID- 23633304 TI - Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. AB - BACKGROUND: The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease have been conflicting and controversial. An updated meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease. OBJECTIVES: The primary objective was to determine the efficacy and safety of azathioprine and 6-mercaptopurine for induction of remission in active Crohn's disease. SEARCH METHODS: A literature search for relevant studies (inception to June 13, 2012) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) of oral azathioprine or 6 mercaptopurine compared to placebo or active therapy involving adult patients with active Crohn's disease were selected for inclusion. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent observers based on the intention to-treat principle. Outcomes of interest included: clinical remission, clinical improvement, fistula improvement or healing, steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. We calculated the pooled relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria. MAIN RESULTS: Thirteen RCTs (n = 1211 patients) of azathioprine and 6-mercaptopurine therapy in adult patients were identified: nine included placebo comparators and six included active comparators. The majority of included studies were rated as low risk of bias. There was no statistically significant difference in clinical remission rates between azathioprine or 6-mercaptopurine and placebo. Forty-eight per cent (95/197) of patients receiving antimetabolites achieved remission compared to 37% (68/183) of placebo patients (5 studies, 380 patients; RR 1.23, 95% CI 0.97 to 1.55). There was no statistically significant difference in clinical improvement rates between azathioprine or 6-mercaptopurine and placebo. Forty-eight per cent (107/225) of patients receiving antimetabolites achieved clinical improvement or remission compared to 36% (75/209) of placebo patients (8 studies, 434 patients; RR 1.26, 95% CI 0.98 to 1.62). There was a statistically significant difference in steroid sparing (defined as prednisone dose < 10 mg/day while maintaining remission) between azathioprine and placebo. Sixty-four per cent (47/163) of azathioprine patients were able to reduce their prednisone dose to < 10 mg/day compared to 46% (32/70) of placebo patients (RR 1.34, 95% CI 1.02 to 1.77). GRADE analyses rated the overall quality of the evidence for the outcomes clinical remission, clinical improvement and steroid sparing as moderate due to sparse data. There was no statistically significant difference in withdrawals due to adverse events or serious adverse events between antimetabolites and placebo. Ten percent of patients in the antimetabolite group withdrew due to adverse events compared to 5% of placebo patients (8 studies, 510 patients; RR 1.70, 95% CI 0.94 to 3.08). Serious adverse events were reported in 14% of patients receiving azathioprine compared to 4% of placebo patients (2 studies, 216 patients; RR 2.57, 95% CI 0.92 to 7.13). Common adverse events reported in the placebo controlled studies included: allergic reactions. leukopenia, pancreatitis and nausea. Azathioprine was significantly inferior to infliximab for induction of steroid-free clinical remission. Thirty per cent (51/170) of azathioprine patients achieved steroid-free remission compared to 44% (75/169) of infliximab patients (1 study, 339 patients; RR 0.68, 95% CI 0.51 to 0.90). The combination of azathioprine and infliximab was significantly superior to infliximab alone for induction of steroid-free clinical remission. Sixty per cent (116/194) of patients in the combined azathioprine and infliximab group achieved steroid-free remission compared to 48% (91/189) of infliximab patients (2 studies, 383 patients; RR 1.23, 95% CI 1.02 to 1.47). Azathioprine or 6-mercaptopurine therapy was found to be no better at inducing steroid free clinical remission compared to methotrexate (RR 1.13, 95% CI 0.85 to 1.49) and 5-aminosalicylate or sulfasalazine (RR 1.24, 95% CI 0.80 to 1.91). There were no statistically significant differences in withdrawals due to adverse events between azathioprine or 6-mercaptopurine and methotrexate (RR 0.78, 95% CI 0.23 to 2.71); between azathioprine or 6-mercaptopurine and 5-aminosalicylate or sulfasalazine (RR 0.98, 95% CI 0.38 to 2.54); between azathioprine and infliximab (RR 1.47, 95% CI 0.96 to 2.23); or between the combination of azathioprine and infliximab and infliximab (RR 1.16, 95% CI 0.75 to 1.80). Common adverse events in the active comparator trials included nausea, abdominal pain, pyrexia and headache. AUTHORS' CONCLUSIONS: Azathioprine and 6-mercaptopurine offer no advantage over placebo for induction of remission or clinical improvement in active Crohn's disease. Antimetaboilte therapy may allow patients to reduce steroid consumption. Adverse events were more common in patients receiving antimetabolites although differences with placebo were not statistically significant. Azathioprine therapy is inferior to infliximab for induction of steroid-free remission. However, the combination of azathioprine and infliximab was superior to infliximab alone for induction of steroid-free remission. PMID- 23633305 TI - Prostanoids for intermittent claudication. AB - BACKGROUND: Peripheral arterial disease (PAD) is a common cause of morbidity in the general population. While numerous studies have established the efficacy of prostanoids in PAD stages III and IV, the question of the role of prostanoids as an alternative or additive treatment in patients suffering from intermittent claudication (PAD II) has not yet been clearly answered. This is an update of a Cochrane Review first published in 2004. OBJECTIVES: To determine the effects of prostanoids in patients with intermittent claudication (IC) Fontaine stage II. SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched January 2013) and CENTRAL (2012, Issue 12). Clinical trials databases were searched for details of ongoing or unpublished studies. In addition, reference lists of relevant articles were checked. SELECTION CRITERIA: Randomised clinical trials of prostanoids versus placebo or alternative ('control') treatment in people with intermittent claudication were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Primary outcomes included pain-free walking distance (PFWD) and maximum walking distance (MWD), presented as mean change in walking distance during the course of the trial (% improvement) and as final walking distance (that is walking distance, in metres, after treatment) for the prostanoid and control groups. MAIN RESULTS: Eighteen trials with a total of 2773 patients were included (16 in the original review and a further two in this update). As the majority of trials did not report standard deviations for the primary PFWD and MWD outcomes, it was often not possible to test for the statistical significance of any improvements in walking distance between groups. The quality of individual trials was variable and usually unclear due to insufficient reporting information. Comparison between trials was hampered by the use of different treadmill testing protocols, including different walking speeds and gradients. Such limitations in the data and the trial heterogeneity meant it was not possible to meaningfully pool results by meta-analysis.Four trials compared prostaglandin E1 (PGE1) with placebo; individual trials showed significant increases in walking distances with administration of PGE1 and in several trials the walking capacity remained increased after termination of treatment. Compared with pentoxifylline, PGE1 was associated with a higher final PFWD and MWD but these results were based on final walking distances rather than changes in walking distance from baseline. When PGE1 was compared with other treatments including laevadosin, naftidrofuryl and L-arginine, improvements in walking distances over time were observed for both PGE1 and the alternative treatment, but it was not possible from the data available to analyse statistically whether or not one treatment was more effective than the other.Six studies compared various preparations of prostacyclins (PGI2) with placebo. In one study using three different dosages of iloprost, PFWD and MWD appeared to increase in a dose dependent manner; iloprost was associated with headache, pain, nausea and diarrhoea, leading to a higher rate of treatment withdrawal. Of three studies using beraprost sodium, one showed an improvement in PFWD and MWD compared with placebo while two showed no significant benefit. Beraprost sodium was associated with an increased incidence of drug-related adverse events. Of two studies on taprostene, the results of one in particular must be interpreted with caution due to an imbalance in walking capacity at baseline.Comprehensive, high quality data on outcomes such as quality of life, ankle brachial index, venous occlusion plethysmography and haemorrheological parameters were lacking. AUTHORS' CONCLUSIONS: Whilst results from some individual studies suggested a beneficial effect of PGE1, the quality of these studies and of the overall evidence available is insufficient to determine whether or not patients with intermittent claudication derive clinically meaningful benefit from the administration of prostanoids. Further well-conducted randomised, double blinded trials with a sufficient number of participants to provide statistical power are required to answer this question. PMID- 23633306 TI - School-based programmes for preventing smoking. AB - BACKGROUND: Helping young people to avoid starting smoking is a widely endorsed public health goal, and schools provide a route to communicate with nearly all young people. School-based interventions have been delivered for close to 40 years. OBJECTIVES: The primary aim of this review was to determine whether school smoking interventions prevent youth from starting smoking. Our secondary objective was to determine which interventions were most effective. This included evaluating the effects of theoretical approaches; additional booster sessions; programme deliverers; gender effects; and multifocal interventions versus those focused solely on smoking. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Tobacco Addiction Group's Specialised Register, MEDLINE, EMBASE, PsycINFO, ERIC, CINAHL, Health Star, and Dissertation Abstracts for terms relating to school-based smoking cessation programmes. In addition, we screened the bibliographies of articles and ran individual MEDLINE searches for 133 authors who had undertaken randomised controlled trials in this area. The most recent searches were conducted in October 2012. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) where students, classes, schools, or school districts were randomised to intervention arm(s) versus a control group, and followed for at least six months. Participants had to be youth (aged 5 to 18). Interventions could be any curricula used in a school setting to deter tobacco use, and outcome measures could be never smoking, frequency of smoking, number of cigarettes smoked, or smoking indices. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed studies for inclusion, extracted data and assessed risk of bias. Based on the type of outcome, we placed studies into three groups for analysis: Pure Prevention cohorts (Group 1), Change in Smoking Behaviour over time (Group 2) and Point Prevalence of Smoking (Group 3). MAIN RESULTS: One hundred and thirty-four studies involving 428,293 participants met the inclusion criteria. Some studies provided data for more than one group.Pure Prevention cohorts (Group 1) included 49 studies (N = 142,447). Pooled results at follow-up at one year or less found no overall effect of intervention curricula versus control (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.85 to 1.05). In a subgroup analysis, the combined social competence and social influences curricula (six RCTs) showed a statistically significant effect in preventing the onset of smoking (OR 0.49, 95% CI 0.28 to 0.87; seven arms); whereas significant effects were not detected in programmes involving information only (OR 0.12, 95% CI 0.00 to 14.87; one study), social influences only (OR 1.00, 95% CI 0.88 to 1.13; 25 studies), or multimodal interventions (OR 0.89, 95% CI 0.73 to 1.08; five studies). In contrast, pooled results at longest follow-up showed an overall significant effect favouring the intervention (OR 0.88, 95% CI 0.82 to 0.96). Subgroup analyses detected significant effects in programmes with social competence curricula (OR 0.52, 95% CI 0.30 to 0.88), and the combined social competence and social influences curricula (OR 0.50, 95% CI 0.28 to 0.87), but not in those programmes with information only, social influence only, and multimodal programmes.Change in Smoking Behaviour over time (Group 2) included 15 studies (N = 45,555). At one year or less there was a small but statistically significant effect favouring controls (standardised mean difference (SMD) 0.04, 95% CI 0.02 to 0.06). For follow-up longer than one year there was a statistically nonsignificant effect (SMD 0.02, 95% CI -0.00 to 0.02).Twenty-five studies reported data on the Point Prevalence of Smoking (Group 3), though heterogeneity in this group was too high for data to be pooled.We were unable to analyse data for 49 studies (N = 152,544).Subgroup analyses (Pure Prevention cohorts only) demonstrated that at longest follow-up for all curricula combined, there was a significant effect favouring adult presenters (OR 0.88, 95% CI 0.81 to 0.96). There were no differences between tobacco-only and multifocal interventions. For curricula with booster sessions there was a significant effect only for combined social competence and social influences interventions with follow-up of one year or less (OR 0.50, 95% CI 0.26 to 0.96) and at longest follow-up (OR 0.51, 95% CI 0.27 to 0.96). Limited data on gender differences suggested no overall effect, although one study found an effect of multimodal intervention at one year for male students. Sensitivity analyses for Pure Prevention cohorts and Change in Smoking Behaviour over time outcomes suggested that neither selection nor attrition bias affected the results. AUTHORS' CONCLUSIONS: Pure Prevention cohorts showed a significant effect at longest follow-up, with an average 12% reduction in starting smoking compared to the control groups. However, no overall effect was detected at one year or less. The combined social competence and social influences interventions showed a significant effect at one year and at longest follow-up. Studies that deployed a social influences programme showed no overall effect at any time point; multimodal interventions and those with an information only approach were similarly ineffective.Studies reporting Change in Smoking Behaviour over time did not show an overall effect, but at an intervention level there were positive findings for social competence and combined social competence and social influences interventions. PMID- 23633307 TI - Hormone therapy for preventing cardiovascular disease in post-menopausal women. AB - BACKGROUND: Evidence from systematic reviews of observational studies suggest that hormone replacement therapy (HT) may have beneficial effects in reducing the incidence of cardiovascular disease (CVD) events in post-menopausal women. This is an updated version of a Cochrane review first published in 2005 (Gabriel Sanchez 2005). OBJECTIVES: To assess the effects of HT for the prevention of CVD in post-menopausal women, and whether there are differential effects between use of single therapy alone compared to combination HT and use in primary or secondary prevention. SEARCH METHODS: We searched the following databases to April 2010: Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE and LILACS. SELECTION CRITERIA: Randomised controlled trials (RCTs) of women comparing orally administered HT with placebo with a minimum of six-months follow-up. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Risk Ratios (RR) with 95% confidence intervals were calculated for each outcome. Results were combined using fixed-effect meta-analyses, and where possible, further stratified analyses conducted to assess the effect of time on treatment. Additionally, univariate meta-regression analyses were undertaken to assess whether length of trial follow up, single or combination treatment, or whether treatment for primary or secondary prevention were potential predictors for a number of CVD outcomes in the trials. MAIN RESULTS: Four new trials were identified through the update; one trial included in the previous review was excluded. Therefore the review included 13 trials with a total of 38,171 post-menopausal women. Overall, single and combination HT in both primary and secondary prevention conferred no protective effects for all cause mortality, CVD death, non-fatal MI, or angina. There were no significant differences in the number of coronary artery by-pass procedures or angioplasties performed between the trial arms. However there was an increased risk of stroke for both primary and secondary prevention when combination and single HT was combined, RR 1.26 (95% CI 1.11 to 1.43), in venous thromboembolic events, RR 1.89 (95% CI 1.58 to 2.26) and in pulmonary embolism RR 1.84 (95% CI 1.42 to 2.37) relative to placebo. The associated numbers needed-to-harm (NNH) were 164, 109 and 243 for stroke, venous thromboembolism and pulmonary embolism respectively. AUTHORS' CONCLUSIONS: Treatment with HT in post-menopausal women for either primary or secondary prevention of CVD events is not effective, and causes an increase in the risk of stroke, and venous thromboembolic events. HT should therefore only be considered for women seeking relief from menopausal symptoms. Short-term HT treatment should be at the lowest effective dose, and used with caution in women with predisposing risk factors for CVD events. PMID- 23633308 TI - Non-invasive ventilation for cystic fibrosis. AB - BACKGROUND: Non-invasive ventilation may be a means to temporarily reverse or slow the progression of respiratory failure in cystic fibrosis. OBJECTIVES: To compare the effect of non-invasive ventilation versus no non-invasive ventilation in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We searched the reference lists of each trial for additional publications possibly containing other trials.Most recent search: 22 February 2013. SELECTION CRITERIA: Randomised controlled trials comparing a form of pressure preset or volume preset non invasive ventilation to no non-invasive ventilation in people with acute or chronic respiratory failure in cystic fibrosis. DATA COLLECTION AND ANALYSIS: Three reviewers independently assessed trials for inclusion criteria and methodological quality, and extracted data. MAIN RESULTS: Fifteen trials were identified; seven trials met the inclusion criteria with a total of 106 participants. Six trials evaluated single treatment sessions and one evaluated a six-week intervention.Four trials (79 participants) evaluated non-invasive ventilation for airway clearance compared with an alternative chest physiotherapy method and showed that airway clearance may be easier with non-invasive ventilation and people with cystic fibrosis may prefer it. We were unable to find any evidence that NIV increases sputum expectoration, but it did improve some lung function parameters.Three trials (27 participants) evaluated non-invasive ventilation for overnight ventilatory support, measuring lung function, validated quality of life scores and nocturnal transcutaneous carbon dioxide. Due to the small numbers of participants and statistical issues, there were discrepancies in the results between the RevMan and the original trial analyses. No clear differences were found between non-invasive ventilation compared with oxygen or room air except for exercise performance, which significantly improved with non invasive ventilation compared to room air over six weeks. AUTHORS' CONCLUSIONS: Non-invasive ventilation may be a useful adjunct to other airway clearance techniques, particularly in people with cystic fibrosis who have difficulty expectorating sputum. Non-invasive ventilation, used in addition to oxygen, may improve gas exchange during sleep to a greater extent than oxygen therapy alone in moderate to severe disease. These benefits of non-invasive ventilation have largely been demonstrated in single treatment sessions with small numbers of participants. The impact of this therapy on pulmonary exacerbations and disease progression remain unclear. There is a need for long-term randomised controlled trials which are adequately powered to determine the clinical effects of non invasive ventilation in cystic fibrosis airway clearance and exercise. PMID- 23633309 TI - Benzodiazepines for psychosis-induced aggression or agitation. AB - BACKGROUND: Acute psychotic illness, especially when associated with agitated or violent behaviour, can require urgent pharmacological tranquillisation or sedation. In several countries, clinicians often use benzodiazepines (either alone or in combination with antipsychotics) for this outcome. OBJECTIVES: To estimate the effects of benzodiazepines, alone or in combination with antipsychotics, when compared with placebo or antipsychotics, alone or in combination with antihistamines, to control disturbed behaviour and reduce psychotic symptoms. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's register (January 2012), inspected reference lists of included and excluded studies and contacted authors of relevant studies. SELECTION CRITERIA: We included all randomised clinical trials (RCTs) comparing benzodiazepines alone or in combination with any antipsychotics, versus antipsychotics alone or in combination with any other antipsychotics, benzodiazepines or antihistamines, for people with acute psychotic illnesses. DATA COLLECTION AND ANALYSIS: We reliably selected studies, quality assessed them and extracted data. For binary outcomes, we calculated standard estimates of relative risk (RR) and their 95% confidence intervals (CI) using a fixed-effect model. For continuous outcomes, we calculated the mean difference (MD) between groups. If heterogeneity was identified, this was explored using a random-effects model. MAIN RESULTS: We included 21 trials with a total of n = 1968 participants. There was no significant difference for most outcomes in the one trial that compared benzodiazepines with placebo, although there was a higher risk of no improvement in people receiving placebo in the medium term (one to 48 hours) (n = 102, 1 RCT, RR 0.62, 95% CI 0.40 to 0.97, very low quality evidence). There was no difference in the number of participants who had not improved in the medium term when benzodiazepines were compared with antipsychotics (n = 308, 5 RCTs, RR 1.10, 95% CI 0.85 to 1.42, low quality evidence); however, people receiving benzodiazepines were less likely to experience extrapyramidal effects (EPS) in the medium term (n = 536, 8 RCTs, RR 0.15, 95% CI 0.06 to 0.39, moderate quality of evidence). Data comparing combined benzodiazepines and antipsychotics versus benzodiazepines alone did not yield any significant results. When comparing combined benzodiazepines/antipsychotics (all studies compared haloperidol) with the same antipsychotics alone (haloperidol), there was no difference between groups in improvement in the medium term (n = 155, 3 RCTs, RR 1.27, 95% CI 0.94 to 1.70, very low quality evidence) but sedation was more likely in people who received the combination therapy (n = 172, 3 RCTs, RR 1.75, 95% CI 1.14 to 2.67, very low quality evidence). However, more participants receiving combined benzodiazepines and haloperidol had not improved by medium term when compared to participants receiving olanzapine (n = 60,1 RCT, RR 25.00, 95% CI 1.55 to 403.99, very low quality evidence) or ziprasidone (n = 60, 1 RCT, RR 4.00, 95% CI 1.25 to 12.75 very low quality evidence). When haloperidol and midazolam were compared with olanzapine, there was some evidence the combination was superior in terms of improvement, sedation and behaviour. AUTHORS' CONCLUSIONS: The evidence from trials for the use of benzodiazepines alone is not good. There were relatively little good data and most trials are too small to highlight differences in either positive or negative effects. Adding a benzodiazepine to other drugs does not seem to confer clear advantage and has potential for adding unnecessary adverse effects. Sole use of older antipsychotics unaccompanied by anticholinergic drugs seems difficult to justify. Much more high quality research is needed in this area. PMID- 23633310 TI - Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. AB - BACKGROUND: Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer side effects. OBJECTIVES: To determine the efficacy and safety of ibuprofen for closing a PDA in preterm and/or low birth weight infants. Seperate comparisons are presented for 1. ibuprofen (iv) compared with placebo; 2. ibuprofen (oral) compared with placebo; 3. ibuprofen (oral or iv) compared with other cyclo-oxygenase inhibitors (given iv or orally); 4. ibuprofen (oral) versus indomethacin (given iv or orally); 5. ibuprofen (oral) versus iv ibuprofen; 6. high dose versus standard dose of iv ibuprofen; 7. early versus expectant administration of iv ibuprofen. SEARCH METHODS: We searched The Cochrane Library, MEDLINE, EMBASE, Clincialtrials.gov, Controlled-trials.com, www.abstracts2view.com/pas, and personal files in July 2012. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of ibuprofen for the treatment of a PDA in newborn infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group. MAIN RESULTS: Twenty-seven studies are included in this review. One study (n = 136) compared iv ibuprofen versus placebo. Ibuprofen reduced the composite outcome of infant deaths, infants who dropped out or required rescue treatment; risk ratio (RR) 0.58 (95% confidence interval (CI) 0.38 to 0.89); risk difference (RD) -0.22 (95% CI -0.38 to -06); number needed to benefit (NNTB) 5 (95% CI 3 to 17). One study (n = 64) compared oral ibuprofen with placebo. There was a significant reduction in the failure rate to close a PDA; RR 0.26 (95% CI 0.11 to 0.62); RD 0.44 (95% CI -0.65 to -0.23); NNTB 2 (95% CI 2 to 4). Failure rates for PDA closure with ibuprofen (oral or iv) compared with indomethacin (oral or iv) was reported in 20 studies (n = 1019 infants). There was no significant difference between the groups; typical RR 0.98 (95% CI 0.80 to 1.20) I(2) = 0%; typical RD 0.01 (95% CI -0.06 to 0.05); I(2) = 0%. The risk of developing necrotising enterocolitis (NEC) was reduced for ibuprofen (15 studies (n = 865); typical RR 0.68 (95% CI 0.47 to 0.99); typical RD -0.04 (95% CI -0.08 to -0.00; (P = 0.04); NNTB 25 (95% CI 13, infinity); I(2) = 0%). The duration of ventilatory support was reduced with ibuprofen (oral or iv) compared with iv or oral indomethacin (six studies, n = 471) mean difference (MD) -2.35 days (95% CI -3.71 to -0.99); I(2) = 19%. Failure rates for PDA closure with oral ibuprofen compared with indomethacin (oral or iv) were reported in seven studies (n = 189 infants). There was no significant difference between the groups; typical RR 0.82 (95% CI 0.52 to 1.29); typical RD -0.06 (95% CI -0.18 to 0.06). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (oral or iv) six studies (n = 166); typical RR 0.44 (95% CI 0.23 to 0.82); RD -0.15 (95% CI -0.25 to -0.04); NNTB 7 (95% CI 4 to 25). There was no heterogeneity for this outcome. There was a decreased risk of failure to close a PDA with oral ibuprofen compared with iv ibuprofen, three studies (n = 236) typical RR 0.37 (95% CI 0.23 to 0.61); typical RD -0.24 (95% CI -0.35 to -0.13); NNTB 4 (95% CI 3 to 8). There was less evidence of transient renal insufficiency in infants who received ibuprofen compared with indomethacin. High dose versus standard dose of iv ibuprofen and early versus expectant administration of iv ibuprofen have only been studied in two trials. AUTHORS' CONCLUSIONS: Ibuprofen is as effective as indomethacin in closing a PDA and reduces the risk of NEC and transient renal insufficiency. Given the reduction in NEC ibuprofen currently appears to be the drug of choice. Oro gastric administration of ibuprofen appears at least as effective as iv administration. Too few patients have been enrolled in studies assessing the effectiveness of a high dose of ibuprofen versus the standard dose and early versus expectant administration of ibuprofen to make recommendations. Studies are needed to evaluate the effect of ibuprofen compared with indomethacin treatment on longer-term outcomes in infants with PDA. PMID- 23633311 TI - Lung lavage for meconium aspiration syndrome in newborn infants. AB - BACKGROUND: Meconium aspiration syndrome (MAS) can occur when a newborn infant inhales a mixture of meconium and amniotic fluid into the lungs around the time of delivery. Other than supportive measures, little effective therapy is available. Lung lavage may be a potentially effective treatment for MAS by virtue of removing meconium from the airspaces and altering the natural course of the disease. OBJECTIVES: To evaluate the effects of lung lavage on morbidity and mortality in newborn infants with MAS. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, and EMBASE up to December 2012; previous reviews including cross-references, abstracts, and conference proceedings; and expert informants. We contacted authors directly to obtain additional data. We used the following subject headings and text words: meconium aspiration, pulmonary surfactants, fluorocarbons, bronchoalveolar lavage, lung lavage, pulmonary lavage. SELECTION CRITERIA: Randomised controlled trials that evaluated the effects of lung lavage in infants with MAS, including those intubated for the purpose of lavage. Lung lavage was defined as any intervention in which fluid is instilled into the lung that is followed by an attempt to remove it by suctioning and/or postural drainage. DATA COLLECTION AND ANALYSIS: The review authors extracted from the reports of the clinical trial, data regarding clinical outcomes, including mortality, requirement for extracorporeal membrane oxygenation (ECMO), pneumothorax, duration of mechanical ventilation and oxygen therapy, length of hospital stay, indices of pulmonary function, and adverse effects of lavage. Data analysis was done in accordance with the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Only four small randomised controlled trials fulfilled the selection criteria. For one of these trials, no data are available for the control group. Two studies compared lavage using diluted surfactant with standard care. Meta-analysis of these two studies did not show a significant effect on mortality (typical relative risk 0.42, 95% confidence interval [CI] 0.12 to 1.46; typical risk difference -0.10, 95% CI -0.24 to 0.04) or the use of ECMO (typical relative risk 0.27, 95% CI 0.04 to 1.86; typical risk difference 0.15, 95% CI -0.35 to 0.04). For the composite outcome of death or use of ECMO, a significant effect favoured the lavage group (typical relative risk 0.33, 95% CI 0.11 to 0.96; typical risk difference -0.19, 95% CI -0.34 to -0.03; number needed to benefit [NNTB] 5). No other benefits were reported. The other published study compared surfactant lavage followed by a surfactant bolus with surfactant bolus therapy alone in MAS complicated by pulmonary hypertension. No significant improvements in mortality, pneumothorax, duration of mechanical ventilation. or duration of hospitalisation were observed. AUTHORS' CONCLUSIONS: In infants with meconium aspiration syndrome, lung lavage with diluted surfactant may be beneficial, but additional controlled clinical trials of lavage therapy should be conducted to confirm the treatment effect, to refine the method of lavage treatment, and to compare lavage treatment with other approaches, including surfactant bolus therapy. Long-term outcomes should be evaluated in further clinical trials. PMID- 23633313 TI - Interventions to improve antibiotic prescribing practices for hospital inpatients. AB - BACKGROUND: The first publication of this review in Issue 3, 2005 included studies up to November 2003. This update adds studies to December 2006 and focuses on application of a new method for meta-analysis of interrupted time series studies and application of new Cochrane Effective Practice and Organisation of Care (EPOC) Risk of Bias criteria to all studies in the review, including those studies in the previously published version. The aim of the review is to evaluate the impact of interventions from the perspective of antibiotic stewardship. The two objectives of antibiotic stewardship are first to ensure effective treatment for patients with bacterial infection and second support professionals and patients to reduce unnecessary use and minimize collateral damage. OBJECTIVES: To estimate the effectiveness of professional interventions that, alone or in combination, are effective in antibiotic stewardship for hospital inpatients, to evaluate the impact of these interventions on reducing the incidence of antimicrobial-resistant pathogens or Clostridium difficile infection and their impact on clinical outcome. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE from 1980 to December 2006 and the EPOC specialized register in July 2007 and February 2009 and bibliographies of retrieved articles. The main comparison is between interventions that had a restrictive element and those that were purely persuasive. Restrictive interventions were implemented through restriction of the freedom of prescribers to select some antibiotics. Persuasive interventions used one or more of the following methods for changing professional behaviour: dissemination of educational resources, reminders, audit and feedback, or educational outreach. Restrictive interventions could contain persuasive elements. SELECTION CRITERIA: We included randomized clinical trials (RCTs), controlled clinical trials (CCT), controlled before-after (CBA) and interrupted time series studies (ITS). Interventions included any professional or structural interventions as defined by EPOC. The intervention had to include a component that aimed to improve antibiotic prescribing to hospital inpatients, either by increasing effective treatment or by reducing unnecessary treatment. The results had to include interpretable data about the effect of the intervention on antibiotic prescribing or microbial outcomes or relevant clinical outcomes. DATA COLLECTION AND ANALYSIS: Two authors extracted data and assessed quality. We performed meta-regression of ITS studies to compare the results of persuasive and restrictive interventions. Persuasive interventions advised physicians about how to prescribe or gave them feedback about how they prescribed. Restrictive interventions put a limit on how they prescribed; for example, physicians had to have approval from an infection specialist in order to prescribe an antibiotic. We standardized the results of some ITS studies so that they are on the same scale (percent change in outcome), thereby facilitating comparisons of different interventions. To do this, we used the change in level and change in slope to estimate the effect size with increasing time after the intervention (one month, six months, one year, etc) as the percent change in level at each time point. We did not extrapolate beyond the end of data collection after the intervention. The meta-regression was performed using standard weighted linear regression with the standard errors of the coefficients adjusted where necessary. MAIN RESULTS: For this update we included 89 studies that reported 95 interventions. Of the 89 studies, 56 were ITSs (of which 4 were controlled ITSs), 25 were RCT (of which 5 were cluster-RCTs), 5 were CBAs and 3 were CCTs (of which 1 was a cluster-CCT).Most (80/95, 84%) of the interventions targeted the antibiotic prescribed (choice of antibiotic, timing of first dose and route of administration). The remaining 15 interventions aimed to change exposure of patients to antibiotics by targeting the decision to treat or the duration of treatment. Reliable data about impact on antibiotic prescribing data were available for 76 interventions (44 persuasive, 24 restrictive and 8 structural). For the persuasive interventions, the median change in antibiotic prescribing was 42.3% for the ITSs, 31.6% for the controlled ITSs, 17.7% for the CBAs, 3.5% for the cluster-RCTs and 24.7% for the RCTs. The restrictive interventions had a median effect size of 34.7% for the ITSs, 17.1% for the CBAs and 40.5% for the RCTs. The structural interventions had a median effect of 13.3% for the RCTs and 23.6% for the cluster-RCTs. Data about impact on microbial outcomes were available for 21 interventions but only 6 of these also had reliable data about impact on antibiotic prescribing.Meta-analysis of 52 ITS studies was used to compare restrictive versus purely persuasive interventions. Restrictive interventions had significantly greater impact on prescribing outcomes at one month (32%, 95% confidence interval (CI) 2% to 61%, P = 0.03) and on microbial outcomes at 6 months (53%, 95% CI 31% to 75%, P = 0.001) but there were no significant differences at 12 or 24 months. Interventions intended to decrease excessive prescribing were associated with reduction in Clostridium difficile infections and colonization or infection with aminoglycoside- or cephalosporin-resistant gram-negative bacteria, methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. Meta analysis of clinical outcomes showed that four interventions intended to increase effective prescribing for pneumonia were associated with significant reduction in mortality (risk ratio 0.89, 95% CI 0.82 to 0.97), whereas nine interventions intended to decrease excessive prescribing were not associated with significant increase in mortality (risk ratio 0.92, 95% CI 0.81 to 1.06). AUTHORS' CONCLUSIONS: The results show that interventions to reduce excessive antibiotic prescribing to hospital inpatients can reduce antimicrobial resistance or hospital-acquired infections, and interventions to increase effective prescribing can improve clinical outcome. This update provides more evidence about unintended clinical consequences of interventions and about the effect of interventions to reduce exposure of patients to antibiotics. The meta-analysis supports the use of restrictive interventions when the need is urgent, but suggests that persuasive and restrictive interventions are equally effective after six months. PMID- 23633314 TI - Skin patch and vaginal ring versus combined oral contraceptives for contraception. AB - BACKGROUND: The delivery of combination contraceptive steroids from a transdermal contraceptive patch or a contraceptive vaginal ring offers potential advantages over the traditional oral route. The transdermal patch and vaginal ring could require a lower dose due to increased bioavailability and improved user compliance. OBJECTIVES: To compare the contraceptive effectiveness, cycle control, compliance (adherence), and safety of the contraceptive patch or the vaginal ring versus combination oral contraceptives (COCs). SEARCH METHODS: Through February 2013, we searched MEDLINE, POPLINE, CENTRAL, LILACS, ClinicalTrials.gov, and ICTRP for trials of the contraceptive patch or the vaginal ring. Earlier searches also included EMBASE. For the initial review, we contacted known researchers and manufacturers to identify other trials. SELECTION CRITERIA: We considered randomized controlled trials comparing a transdermal contraceptive patch or a contraceptive vaginal ring with a COC. DATA COLLECTION AND ANALYSIS: Data were abstracted by two authors and entered into RevMan. For dichotomous variables, the Peto odds ratio (OR) with 95% confidence intervals (CI) was calculated. For continuous variables, the mean difference was computed. We also assessed the quality of evidence for this review. MAIN RESULTS: We found 18 trials that met our inclusion criteria. Of six patch studies, five examined the marketed patch containing norelgestromin plus ethinyl estradiol (EE); one studied a patch in development that contains levonorgestrel (LNG) plus EE. Of 12 vaginal ring trials, 11 examined the same marketing ring containing etonogestrel plus EE; one studied a ring being developed that contains nesterone plus EE.Contraceptive effectiveness was not significantly different for the patch or ring versus the comparison COC. Compliance data were limited. Patch users showed better compliance than COC users in three trials. For the norelgestromin plus EE patch, ORs were 2.05 (95% CI 1.83 to 2.29) and 2.76 (95% CI 2.35 to 3.24). In the levonorgestrel plus EE patch report, patch users were less likely to have missed days of therapy (OR 0.36; 95% CI 0.25 to 0.51). Of four vaginal ring trials, one found ring users had more noncompliance (OR 3.99; 95% CI 1.87 to 8.52), while another showed more compliance with the regimen (OR 1.67; 95% CI 1.04 to 2.68).More patch users discontinued early than COC users. ORs from two meta analyses were 1.59 (95% CI 1.26 to 2.00) and 1.56 (95% CI 1.18 to 2.06) and another trial showed OR 2.57 (95% CI 0.99 to 6.64). Patch users also had more discontinuation due to adverse events than COC users. Users of the norelgestromin containing patch reported more breast discomfort, dysmenorrhea, nausea, and vomiting. In the levonorgestrel-containing patch trial, patch users reported less vomiting, headaches, and fatigue.Of 11 ring trials with discontinuation data, two showed the ring group discontinued less than the COC group: OR 0.32 (95% CI 0.16 to 0.66) and OR 0.52 (95% CI 0.31 to 0.88). Ring users were less likely to discontinue due to adverse events in one study (OR 0.32; 95% CI 0.15 to 0.70). Compared to the COC users, ring users had more vaginitis and leukorrhea but less vaginal dryness. Ring users also reported less nausea, acne, irritability, depression, and emotional lability than COC users.For cycle control, only one trial study showed a significant difference. Women in the patch group were less likely to have breakthrough bleeding and spotting. Seven ring studies had bleeding data; four trials showed the ring group generally had better cycle control than the COC group. AUTHORS' CONCLUSIONS: Effectiveness was not significantly different for the methods compared. Pregnancy data were available from half of the patch trials but two-thirds of ring trials. The patch could lead to more discontinuation than the COC. The patch group had better compliance than the COC group. Compliance data came from half of the patch studies and one-third of the ring trials. Patch users had more side effects than the COC group. Ring users generally had fewer adverse events than COC users but more vaginal irritation and discharge.The quality of the evidence for this review was considered low for the patch and moderate for the ring. The main reasons for downgrading were lack of information on the randomization sequence generation or allocation concealment, the outcome assessment methods, high losses to follow up, and exclusions after randomization. PMID- 23633315 TI - Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants. AB - BACKGROUND: Invasive fungal infection is an important cause of mortality and morbidity in very low birth weight infants. Early diagnosis is difficult and treatment is often delayed. Systemic antifungal agents (usually azoles) are increasingly used as prophylaxis against invasive fungal infection. OBJECTIVES: To assess the effect of prophylactic systemic antifungal therapy on mortality and morbidity in very low birth weight infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 3), MEDLINE, EMBASE, and CINAHL (to August 2012), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised controlled trials or quasi-randomised controlled trials that compared the effect of prophylactic systemic antifungal therapy versus placebo or no drug or another antifungal agent or dose regimen in very low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two review authors. MAIN RESULTS: We identified 11 eligible trials enrolling a total of 1136 infants. Seven trials (involving 880 infants) compared systemic antifungal prophylaxis versus placebo or no drug. These trials were generally small but of good methodological quality. Meta-analysis found a statistically significant reduction in the incidence of invasive fungal infection in infants who received systemic antifungal prophylaxis (typical risk ratio (RR) 0.41, 95% confidence interval (CI) 0.27 to 0.61; risk difference (RD) -0.09, 95% CI -0.14 to -0.05). The average incidence of invasive fungal infection in the control groups of the trials (16%) was much higher than that generally reported from large cohort studies (< 5%). Meta-analysis did not find a statistically significant difference in the risk of death prior to hospital discharge (typical RR 0.74, 95% CI 0.52 to 1.05; RD -0.04, 95% CI -0.08 to 0.01). Very limited data on long-term neurodevelopmental outcomes were available. Two trials that compared systemic versus oral or topical non-absorbed antifungal prophylaxis did not detect any statistically significant effects on invasive fungal infection or mortality. Two trials that compared different dose regimens of prophylactic intravenous fluconazole did not detect any significant differences in infection rates or mortality. AUTHORS' CONCLUSIONS: Prophylactic systemic antifungal therapy reduces the incidence of invasive fungal infection in very low birth weight infants. This finding should be interpreted and applied cautiously since the incidence of invasive fungal infection was very high in the control groups of most of the included trials. Meta-analysis does not demonstrate a statistically significant effect on mortality. There are currently only limited data on the long-term neurodevelopmental consequences for infants exposed to this intervention. In addition, there is a need for further data on the effect of the intervention on the emergence of organisms with antifungal resistance. PMID- 23633316 TI - Surgical management of pelvic organ prolapse in women. AB - BACKGROUND: Pelvic organ prolapse may occur in up to 50% of parous women. A variety of urinary, bowel and sexual symptoms may be associated with the prolapse. OBJECTIVES: To determine the effects of the many different surgeries used in the management of pelvic organ prolapse. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In Process and handsearching of journals and conference proceedings, healthcare-related bibliographic databases, handsearched conference proceedings (searched 20 August 2012), and reference lists of relevant articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that included surgical operations for pelvic organ prolapse. DATA COLLECTION AND ANALYSIS: Trials were assessed and data extracted independently by two review authors. Six investigators were contacted for additional information with five responding. MAIN RESULTS: Fifty-six randomised controlled trials were identified evaluating 5954 women. For upper vaginal prolapse (uterine or vault) abdominal sacral colpopexy was associated with a lower rate of recurrent vault prolapse on examination and painful intercourse than with vaginal sacrospinous colpopexy. These benefits must be balanced against a longer operating time, longer time to return to activities of daily living and increased cost of the abdominal approach. In single studies the sacral colpopexy had a higher success rate on examination and lower reoperation rate than high vaginal uterosacral suspension and transvaginal polypropylene mesh.Twenty-one trials compared a variety of surgical procedures for anterior compartment prolapse (cystocele). Ten compared native tissue repair with graft (absorbable and permanent mesh, biological grafts) repair for anterior compartment prolapse. Native tissue anterior repair was associated with more recurrent anterior compartment prolapse than when supplemented with a polyglactin (absorbable) mesh inlay (RR 1.39, 95% CI 1.02 to 1.90) or porcine dermis mesh inlay (RR 2.08, 95% CI 1.08 to 4.01), however there was no difference in post operative awareness of prolapse after absorbable mesh (RR 0.96, 95% CI 0.33 to 2.81) or a biological graft (RR 1.21, 95% CI 0.64 to 2.30). Data on morbidity and other clinical outcomes were lacking. Standard anterior repair was associated with more anterior compartment prolapse on examination than for any polypropylene (permanent) mesh repair (RR 3.15, 95% CI 2.50 to 3.96). Awareness of prolapse was also higher after the anterior repair as compared to polypropylene mesh repair (28% versus 18%, RR 1.57, 95% CI 1.18 to 2.07). However, the reoperation rate for prolapse was similar at 14/459 (3%) after the native tissue repair compared to 6/470 (1.3%) (RR 2.18, 95% CI 0.93 to 5.10) after the anterior polypropylene mesh repair and no differences in quality of life data or de novo dyspareunia were identified. Blood loss (MD 64 ml, 95% CI 48 to 81), operating time (MD 19 min, 95% CI 16 to 21), recurrences in apical or posterior compartment (RR 1.9, 95% CI 1.0 to 3.4) and de novo stress urinary incontinence (RR 1.8, 95% CI 1.0 to 3.1) were significantly higher with transobturator meshes than for native tissue anterior repair. Mesh erosions were reported in 11.4% (64/563), with surgical interventions being performed in 6.8% (32/470).Data from three trials compared native tissue repairs with a variety of total, anterior, or posterior polypropylene kit meshes for vaginal prolapse in multiple compartments. While no difference in awareness of prolapse was able to be identified between the groups (RR 1.3, 95% CI 0.6 to 1.7) the recurrence rate on examination was higher in the native tissue repair group compared to the transvaginal polypropylene mesh group (RR 2.0, 95% CI 1.3 to 3.1). The mesh erosion rate was 35/194 (18%), and 18/194 (9%) underwent surgical correction for mesh erosion. The reoperation rate after transvaginal polypropylene mesh repair of 22/194 (11%) was higher than after the native tissue repair (7/189, 3.7%) (RR 3.1, 95% CI 1.3 to 7.3).Data from three trials compared posterior vaginal repair and transanal repair for the treatment of posterior compartment prolapse (rectocele). The posterior vaginal repair had fewer recurrent prolapse symptoms (RR 0.4, 95% CI 0.2 to 1.0) and lower recurrence on examination (RR 0.2, 95% CI 0.1 to 0.6) and on defecography (MD 1.2 cm, 95% CI -2.0 to -0.3).Sixteen trials included significant data on bladder outcomes following a variety of prolapse surgeries. Women undergoing prolapse surgery may have benefited from having continence surgery performed concomitantly, especially if they had stress urinary incontinence (RR 7.4, 95% CI 4.0 to 14) or if they were continent and had occult stress urinary incontinence demonstrated pre-operatively (RR 3.5, 95% CI 1.9 to 6.6). Following prolapse surgery, 12% of women developed de novo symptoms of bladder overactivity and 9% de novo voiding dysfunction. AUTHORS' CONCLUSIONS: Sacral colpopexy has superior outcomes to a variety of vaginal procedures including sacrospinous colpopexy, uterosacral colpopexy and transvaginal mesh. These benefits must be balanced against a longer operating time, longer time to return to activities of daily living, and increased cost of the abdominal approach.The use of mesh or graft inlays at the time of anterior vaginal wall repair reduces the risk of recurrent anterior wall prolapse on examination. Anterior vaginal polypropylene mesh also reduces awareness of prolapse, however these benefits must be weighted against increased operating time, blood loss, rate of apical or posterior compartment prolapse, de novo stress urinary incontinence, and reoperation rate for mesh exposures associated with the use of polypropylene mesh.Posterior vaginal wall repair may be better than transanal repair in the management of rectocele in terms of recurrence of prolapse. The evidence is not supportive of any grafts at the time of posterior vaginal repair. Adequately powered randomised, controlled clinical trials with blinding of assessors are urgently needed on a wide variety of issues, and they particularly need to include women's perceptions of prolapse symptoms. Following the withdrawal of some commercial transvaginal mesh kits from the market, the generalisability of the findings, especially relating to anterior compartment transvaginal mesh, should be interpreted with caution. PMID- 23633317 TI - Prevention and treatment of postpartum hypertension. AB - BACKGROUND: Postpartum blood pressure (BP) is highest three to six days after birth when most women have been discharged home. A significant rise in BP may be dangerous (e.g., can lead to stroke), but there is little information about how to prevent or treat postpartum hypertension. OBJECTIVES: To assess the relative benefits and risks of interventions to: (1) prevent postpartum hypertension, by assessing whether 'routine' postpartum medical therapy is better than placebo/no treatment; and (2) treat postpartum hypertension, by assessing whether (i) one antihypertensive therapy is better than placebo/no therapy for mild-moderate postpartum hypertension; and (ii) one antihypertensive agent offers advantages over another for mild-moderate or severe postpartum hypertension. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2013), bibliographies of retrieved papers, and personal files. SELECTION CRITERIA: For women with antenatal hypertension, trials comparing a medical intervention with placebo/no therapy. For women with postpartum hypertension, trials comparing one antihypertensive with either another or placebo/no therapy. DATA COLLECTION AND ANALYSIS: We extracted the data independently and were not blinded to trial characteristics or outcomes. We contacted authors for missing data when possible. MAIN RESULTS: Nine trials are included. PREVENTION: Four trials (358 women) compared furosemide, nifedipine capsules, or L-arginine with placebo/no therapy. For women with antenatal pre-eclampsia, postnatal furosemide is associated with a strong trend towards reduced use of antihypertensive therapy in hospital. TREATMENT: For treatment of mild-moderate postpartum hypertension, three trials (189 women) compared timolol, oral hydralazine, or oral nifedipine with methyldopa. Use of additional antihypertensive therapy did not differ between groups (risk ratio (RR) 0.92, 95% confidence interval (CI) 0.20 to 4.20; three trials), but the trials were not consistent in their effects. The drugs were well tolerated.For treatment of severe postpartum hypertension, two trials (120 women) compared intravenous hydralazine with either sublingual nifedipine or intravenous labetalol. There were no maternal deaths or hypotension. Use of additional antihypertensive therapy did not differ between groups (RR 0.58, 95% CI 0.04 to 9.07; two trials), but the trials were not consistent in their effects. AUTHORS' CONCLUSIONS: For women with pre-eclampsia, postnatal furosemide may decrease the need for postnatal antihypertensive therapy in hospital, but more data are needed on substantive outcomes before this practice can be recommended. There are no reliable data to guide management of women who are hypertensive postpartum. Any antihypertensive agent used should be based on a clinician's familiarity with the drug. Future studies should include data on postpartum analgesics, severe maternal hypertension, breastfeeding, hospital length of stay, and maternal satisfaction with care. PMID- 23633318 TI - Different antibiotic treatments for group A streptococcal pharyngitis. AB - BACKGROUND: Antibiotics provide only modest benefit in treating sore throat, although effectiveness increases in participants with positive throat swabs for group A beta-haemolytic streptococci (GABHS). It is unclear which antibiotic is the best choice if antibiotics are indicated. OBJECTIVES: To assess the evidence on the comparative efficacy of different antibiotics in: (a) alleviating symptoms (pain, fever); (b) shortening the duration of the illness; (c) preventing relapse; and (d) preventing complications (suppurative complications, acute rheumatic fever, post-streptococcal glomerulonephritis). To assess the evidence on the comparative incidence of adverse effects and the risk-benefit of antibiotic treatment for streptococcal pharyngitis. SEARCH METHODS: We searched CENTRAL 2012, Issue 10, MEDLINE (1966 to October week 2, 2012), EMBASE (1974 to October 2012) and Web of Science (2010 to October 2012). SELECTION CRITERIA: Randomised, double-blind trials comparing different antibiotics and reporting at least one of the following: clinical cure, clinical relapse, complications, adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently screened trials for inclusion and extracted data. MAIN RESULTS: Seventeen trials (5352 participants) were included; 16 compared with penicillin (six with cephalosporins, six with macrolides, three with carbacephem and one with sulfonamides), one trial compared clindamycin and ampicillin. Randomisation reporting, allocation concealment and blinding were poor.There was no difference in symptom resolution between cephalosporins and penicillin (intention-to-treat (ITT) analysis; N = 5; n = 2018; odds ratio for absence of resolution of symptoms (OR) 0.79, 95% confidence interval (CI) 0.55 to 1.12). Clinical relapse was lower with cephalosporins (N = 4; n = 1386; OR 0.55, 95% CI 0.31 to 0.99; overall number needed to treat to benefit (NNTB) 50), but found only in adults (OR 0.42, 95% CI 0.20 to 0.88; NNTB 33). There were no differences between macrolides and penicillin. Carbacephem showed better symptom resolution post-treatment (N = 3; n = 795; OR 0.70, 95% CI 0.49 to 0.99; NNTB 14), but only in children (N = 2; n = 233; OR 0.57, 95% CI 0.33 to 0.99; NNTB 8.3). Children experienced more adverse events with macrolides (N = 1, n = 489; OR 2.33; 95% CI 1.06 to 5.15). AUTHORS' CONCLUSIONS: Evidence is insufficient to show clinically meaningful differences between antibiotics for GABHS tonsillopharyngitis. Limited evidence in adults suggests cephalosporins are more effective than penicillin for relapse, but the NNTB is high. Limited evidence in children suggests carbacephem is more effective for symptom resolution. Data on complications are too scarce to draw conclusions. Based on these results and considering the low cost and absence of resistance, penicillin can still be recommended as first choice. PMID- 23633319 TI - Oral evening primrose oil and borage oil for eczema. AB - BACKGROUND: Eczema is a chronic inflammatory skin condition, which usually develops in early childhood. Many children outgrow this disorder as they reach secondary school age, and although It may improve with age, there is no cure. Constant itch makes life uncomfortable for those with this condition, no matter what age they are, so it may have a significant effect on a person's quality of life. Its prevalence seems to be increasing as populations move from rural locations to cities. Some people, who do not see an adequate improvement or fear side-effects of conventional medical products, try complementary alternatives to conventional treatment. This is a review of evening primrose oil (EPO) and borage oil (BO) taken orally (by mouth); these have been thought to be beneficial because of their gamma-linolenic acid content. OBJECTIVES: To assess the effects of oral evening primrose oil or borage oil for treating the symptoms of atopic eczema. SEARCH METHODS: We searched the following databases up to August 2012: Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 1946), EMBASE (from 1974), AMED (from 1985), and LILACS (from 1982). We also searched online trials registers and checked the bibliographies of included studies for further references to relevant trials. We corresponded with trial investigators and pharmaceutical companies to try to identify unpublished and ongoing trials. We performed a separate search for adverse effects of evening primrose oil and borage oil in November 2011. SELECTION CRITERIA: All randomised controlled, parallel, or cross-over trials investigating oral intake of evening primrose oil or borage oil for eczema. DATA COLLECTION AND ANALYSIS: Two review authors independently applied eligibility criteria, assessed risk of bias, and extracted data. We pooled dichotomous outcomes using risk ratios (RR), and continuous outcomes using the mean difference (MD). Where possible, we pooled study results using random-effects meta-analysis and tested statistical heterogeneity using both the Chi(2) test and the I(2) statistic test. We presented results using forest plots with 95% confidence intervals (CI). MAIN RESULTS: A total of 27 studies (1596 participants) met the inclusion criteria: 19 studies assessed evening primrose oil, and 8 studies assessed borage oil. For EPO, a meta-analysis of results from 7 studies showed that EPO failed to significantly increase improvement in global eczema symptoms as reported by participants on a visual analogue scale of 0 to 100 (MD -2.22, 95% CI -10.48 to 6.04, 176 participants, 7 trials) and a visual analogue scale of 0 to 100 for medical doctors (MD -3.26, 95% CI -6.96 to 0.45, 289 participants, 8 trials) compared to the placebo group.Treatment with BO also failed to significantly improve global eczema symptoms compared to placebo treatment as reported by both participants and medical doctors, although we could not conduct a meta-analysis as studies reported results in different ways. With regard to the risk of bias, the majority of studies were of low risk of bias; we judged 67% of the included studies as having low risk of bias for random sequence generation; 44%, for allocation concealment; 59%, for blinding; and 37%, for other biases. AUTHORS' CONCLUSIONS: IMPLICATIONS FOR PRACTICE: Oral borage oil and evening primrose oil lack effect on eczema; improvement was similar to respective placebos used in trials. Oral BO and EPO are not effective treatments for eczema.In these studies, along with the placebos, EPO and BO have the same, fairly common, mild, transient adverse effects, which are mainly gastrointestinal.The short-term studies included here do not examine possible adverse effects of long-term use of EPO or BO. A case report warned that if EPO is taken for a prolonged period of time (more than one year), there is a potential risk of inflammation, thrombosis, and immunosuppression; another study found that EPO may increase bleeding for people on Coumadin(r) (warfarin) medication. IMPLICATIONS FOR RESEARCH: Noting that the confidence intervals between active and placebo treatment are narrow, to exclude the possibility of any clinically useful difference, we concluded that further studies on EPO or BO for eczema would be hard to justify.This review does not provide information about long-term use of these products. PMID- 23633320 TI - Delayed antibiotics for respiratory infections. AB - BACKGROUND: Concerns exist regarding antibiotic prescribing for acute respiratory tract infections (ARTIs) owing to adverse reactions, cost and antibacterial resistance. One strategy to reduce antibiotic prescribing is to provide prescriptions but to advise delay in the hope symptoms will resolve first. This is an update of a Cochrane Review originally published in 2007 and updated in 2010. OBJECTIVES: To evaluate the use of delayed antibiotics compared to immediate or no antibiotics as a prescribing strategy for ARTIs. We evaluated clinical outcomes including duration and severity measures for pain, malaise, fever, cough and rhinorrhoea in sore throat, acute otitis media, bronchitis (cough) and the common cold. We also evaluated the outcomes of antibiotic use, patient satisfaction, antibiotic resistance and re-consultation rates and use of alternative therapies. SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2013, Issue 2), which includes the Acute Respiratory Infection Group's Specialised Register; Ovid MEDLINE (January 1966 to February Week 3 2013); Ovid MEDLINE In-Process & Other Non-Indexed Citations (28 February 2013); EMBASE (1990 to 2013 Week 08); Science Citation Index - Web of Science (2007 to May 2012) and EBSCO CINAHL (1982 to 28 February 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) involving participants of all ages defined as having an ARTI, where delayed antibiotics were compared to antibiotics used immediately or no antibiotics. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted and collected data. Important adverse effects, including adverse effects of antibiotics and complications of disease, were included as secondary outcomes. We assessed the risk of bias of all included trials. We contacted trial authors to obtain missing information where available. MAIN RESULTS: Ten studies, with a total of 3157 participants, were included in this review. Heterogeneity of the 10 included studies and their results generally precluded meta-analysis with patient satisfaction being an exception.There was no difference between delayed, immediate and no prescribed antibiotics for the clinical outcomes evaluated in cough and common cold. In patients with acute otitis media (AOM) and sore throat immediate antibiotics were more effective than delayed for fever, pain and malaise in some studies. There were only minor differences in adverse effects with no significant difference in complication rates.Delayed antibiotics resulted in a significant reduction in antibiotic use compared to immediate antibiotics. A strategy of no antibiotics resulted in least antibiotic use.Patient satisfaction favoured immediate antibiotics over delayed (odds ratio (OR) 0.52; 95% confidence interval (CI) 0.35 to 0.76). Delayed and no antibiotics had similar satisfaction rates with both strategies achieving over 80% satisfaction (OR 1.44; 95% CI 0.99 to 2.10).There was no difference in re-consultation rates for immediate and delayed groups.None of the included studies evaluated antibiotic resistance. AUTHORS' CONCLUSIONS: Most clinical outcomes show no difference between strategies. Delay slightly reduces patient satisfaction compared to immediate antibiotics (87% versus 92%) but not compared to none (87% versus 83%). In patients with respiratory infections where clinicians feel it is safe not to prescribe antibiotics immediately, no antibiotics with advice to return if symptoms do not resolve is likely to result in the least antibiotic use, while maintaining similar patient satisfaction and clinical outcomes to delayed antibiotics. PMID- 23633321 TI - Effect of longer-term modest salt reduction on blood pressure. AB - BACKGROUND: A reduction in salt intake lowers blood pressure (BP) and, thereby, reduces cardiovascular risk. A recent meta-analysis by Graudal implied that salt reduction had adverse effects on hormones and lipids which might mitigate any benefit that occurs with BP reduction. However, Graudal's meta-analysis included a large number of very short-term trials with a large change in salt intake, and such studies are irrelevant to the public health recommendations for a longer term modest reduction in salt intake. We have updated our Cochrane meta-analysis. OBJECTIVES: To assess (1) the effect of a longer-term modest reduction in salt intake (i.e. of public health relevance) on BP and whether there was a dose response relationship; (2) the effect on BP by sex and ethnic group; (3) the effect on plasma renin activity, aldosterone, noradrenaline, adrenaline, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides. SEARCH METHODS: We searched MEDLINE, EMBASE, Cochrane Hypertension Group Specialised Register, Cochrane Central Register of Controlled Trials, and reference list of relevant articles. SELECTION CRITERIA: We included randomised trials with a modest reduction in salt intake and duration of at least 4 weeks. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers. Random effects meta-analyses, subgroup analyses and meta-regression were performed. MAIN RESULTS: Thirty-four trials (3230 participants) were included. Meta-analysis showed that the mean change in urinary sodium (reduced salt vs usual salt) was -75 mmol/24-h (equivalent to a reduction of 4.4 g/d salt), the mean change in BP was -4.18 mmHg (95% CI: -5.18 to -3.18, I (2)=75%) for systolic and -2.06 mmHg (95% CI: -2.67 to -1.45, I (2)=68%) for diastolic BP. Meta regression showed that age, ethnic group, BP status (hypertensive or normotensive) and the change in 24-h urinary sodium were all significantly associated with the fall in systolic BP, explaining 68% of the variance between studies. A 100 mmol reduction in 24 hour urinary sodium (6 g/day salt) was associated with a fall in systolic BP of 5.8 mmHg (95%CI: 2.5 to 9.2, P=0.001) after adjusting for age, ethnic group and BP status. For diastolic BP, age, ethnic group, BP status and the change in 24-h urinary sodium explained 41% of the variance between studies. Meta-analysis by subgroup showed that, in hypertensives, the mean effect was -5.39 mmHg (95% CI: -6.62 to -4.15, I (2)=61%) for systolic and -2.82 mmHg (95% CI: -3.54 to -2.11, I (2)=52%) for diastolic BP. In normotensives, the mean effect was -2.42 mmHg (95% CI: -3.56 to -1.29, I (2)=66%) for systolic and -1.00 mmHg (95% CI: -1.85 to -0.15, I (2)=66%) for diastolic BP. Further subgroup analysis showed that the decrease in systolic BP was significant in both whites and blacks, men and women. Meta-analysis of hormone and lipid data showed that the mean effect was 0.26 ng/ml/hr (95% CI: 0.17 to 0.36, I (2)=70%) for plasma renin activity, 73.20 pmol/l (95% CI: 44.92 to 101.48, I (2)=62%) for aldosterone, 31.67 pg/ml (95% CI: 6.57 to 56.77, I (2)=5%) for noradrenaline, 6.70 pg/ml (95% CI: -0.25 to 13.64, I (2)=12%) for adrenaline, 0.05 mmol/l (95% CI: -0.02 to 0.11, I (2)=0%) for cholesterol, 0.05 mmol/l (95% CI: -0.01 to 0.12, I (2)=0%) for LDL, -0.02 mmol/l (95% CI: -0.06 to 0.01, I (2)=16%) for HDL, and 0.04 mmol/l (95% CI: -0.02 to 0.09, I (2)=0%) for triglycerides. AUTHORS' CONCLUSIONS: A modest reduction in salt intake for 4 or more weeks causes significant and, from a population viewpoint, important falls in BP in both hypertensive and normotensive individuals, irrespective of sex and ethnic group. With salt reduction, there is a small physiological increase in plasma renin activity, aldosterone and noradrenaline. There is no significant change in lipid levels. These results provide further strong support for a reduction in population salt intake. This will likely lower population BP and, thereby, reduce cardiovascular disease. Additionally, our analysis demonstrates a significant association between the reduction in 24-h urinary sodium and the fall in systolic BP, indicating the greater the reduction in salt intake, the greater the fall in systolic BP. The current recommendations to reduce salt intake from 9 12 to 5-6 g/d will have a major effect on BP, but are not ideal. A further reduction to 3 g/d will have a greater effect and should become the long term target for population salt intake. PMID- 23633322 TI - Treatment for superficial thrombophlebitis of the leg. AB - BACKGROUND: The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is the second update of a review first published in 2007. OBJECTIVES: To assess the efficacy and safety of topical, medical, and surgical treatments in patients presenting with ST of the legs. SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched November 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 11). We handsearched the reference lists of relevant papers and conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs that included participants with a clinical diagnosis of ST of the legs or an objective diagnosis of a thrombus in a superficial vein. DATA COLLECTION AND ANALYSIS: Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus. MAIN RESULTS: We identified four additional trials (986 patients), so this update considered 30 studies involving 6507 participants with ST of the legs.Treatment ranged from fondaparinux, low molecular weight heparin (LMWH), unfractionated heparin (UFH), non-steroidal anti-inflammatory agents (NSAIDs), topical treatment, oral treatment, intramuscular treatment, and intravenous treatment to surgery. Only a minority of trials compared treatment with placebo rather than an alternative treatment, none evaluated the same treatment comparisons on the same study outcomes (which precluded meta-analysis), and many of the studies were small and of poor quality. In one large, placebo-controlled RCT of about 3000 patients, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (RR 0.15; 95% CI 0.04 to 0.50), ST extension (RR 0.08; 95% CI 0.03 to 0.22), and ST recurrence (RR 0.21; 95% CI 0.08 to 0.54) with comparable rates of major bleeding (RR 0.99; 95% CI 0.06 to 15.86) relative to placebo. In a further placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (RR 0.40; 95% CI 0.22 to 0.72 and RR 0.42; 95% CI 0.23 to 0.75, respectively) and NSAIDs (RR 0.41; 95% CI 0.23 to 0.75) reduced the extension and recurrence of ST in comparison to placebo, with no significant effects on symptomatic VTE nor major bleeding. Overall, topical treatments improved local symptoms compared with placebo but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatment, topical treatment, or surgery did not report VTE, ST progression, adverse events, or treatment side effects. AUTHORS' CONCLUSIONS: Prophylactic dose fondaparinux given for six weeks appears to be a valid therapeutic option for ST of the legs. The evidence on oral treatments, topical treatment, or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE and ST progression. Further research is needed to assess the role of the new oral direct thrombin and activated factor-X inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments. PMID- 23633323 TI - Massage for promoting mental and physical health in typically developing infants under the age of six months. AB - BACKGROUND: Infant massage is increasingly being used in the community with babies and their primary caregivers. Anecdotal reports suggest benefits for sleep, respiration and elimination, the reduction of colic and wind, and improved growth. Infant massage is also thought to reduce infant stress and promote positive parent-infant interaction. OBJECTIVES: The aim of this review was to assess whether infant massage is effective in promoting infant physical and mental health in low-risk, population samples. SEARCH METHODS: Relevant studies were identified by searching the following electronic databases up to June 2011: CENTRAL; MEDLINE; EMBASE; CINAHL; PsycINFO; Maternity and Infant Care; LILACS; WorldCat (dissertations); ClinicalTrials.gov; China Masters' Theses; China Academic Journals; China Doctoral Dissertations; China Proceedings of Conference. We also searched the reference lists of relevant studies and reviews. SELECTION CRITERIA: We included studies that randomised healthy parent-infant dyads (where the infant was under the age of six months) to an infant massage group or a 'no treatment' control group. Studies had to have used a standardised outcome measure of infant mental or physical development. DATA COLLECTION AND ANALYSIS: Mean differences (MD) and standardised mean differences (SMD) and 95% confidence intervals (CIs) are presented. Where appropriate, the results have been combined in a meta-analysis using a random-effects model. MAIN RESULTS: We included 34 studies, which includes one that was a follow-up study and 20 that were rated as being at high risk of bias.We conducted 14 meta-analyses assessing physical outcomes post-intervention. Nine meta-analyses showed significant findings favouring the intervention group for weight (MD -965.25 g; 95% CI -1360.52 to 569.98), length (MD -1.30 cm; 95% CI -1.60 to -1.00), head circumference (MD 0.81 cm; 95% CI -1.18 to -0.45), arm circumference (MD -0.47 cm; 95% CI -0.80 to 0.13), leg circumference (MD -0.31 cm; 95% CI -0.49 to -0.13), 24-hour sleep duration (MD -0.91 hr; 95% CI -1.51 to -0.30), time spent crying/fussing (MD 0.36; 95% CI -0.52 to -0.19), deceased levels of blood bilirubin (MD -38.11 mmol/L; 95% CI -50.61 to -25.61), and there were fewer cases of diarrhoea, RR 0.39; 95% CI 0.20 to 0.76). Non-significant results were obtained for cortisol levels, mean increase in duration of night sleep, mean increase in 24-hour sleep and for number of cases of upper respiratory tract disease and anaemia.Sensitivity analyses were conducted for weight, length and head circumference, and only the finding for length remained significant following removal of studies judged to be at high risk of bias. These three outcomes were the only ones that could also be meta-analysed at follow-up; although both weight and head circumference continued to be significant at 6-month follow-up, these findings were obtained from studies conducted in Eastern countries only. No sensitivity analyses were possible.We conducted 18 meta-analyses measuring aspects of mental health and development. A significant effect favouring the intervention group was found for gross motor skills (SMD -0.44; 95% CI -0.70 to 0.18), fine motor skills (SMD -0.61; 95% CI -0.87 to -0.35), personal and social behaviour (SMD -0.90; 95% CI -1.61 to -0.18) and psychomotor development (SMD 0.35; 95% CI -0.54 to -0.15); although the first three findings were obtained from only two studies, one of which was rated as being at high risk of bias, and the finding for psychomotor development was not maintained following following removal of studies judged to be at high risk of bias in a sensitivity analysis. No significant differences were found for a range of aspects of infant temperament, parent-infant interaction and mental development. Only parent-infant interaction could be meta-analysed at follow-up, and the result was again not significant. AUTHORS' CONCLUSIONS: These findings do not currently support the use of infant massage with low-risk groups of parents and infants. Available evidence is of poor quality, and many studies do not address the biological plausibility of the outcomes being measured, or the mechanisms by which change might be achieved. Future research should focus on the impact of infant massage in higher-risk groups (for example, demographically and socially deprived parent infant dyads), where there may be more potential for change. PMID- 23633324 TI - Chinese herbal medicines for induction of remission in advanced or late gastric cancer. AB - BACKGROUND: Gastric cancer is difficult to cure once it progresses to an advanced or late stage. Although some chemotherapies or bio-therapies have made progress in the remission of this disease, the mortality from gastric cancer remains high. A variety of Chinese medicinal herbs have been used to treat gastric cancer. OBJECTIVES: To assess the effectiveness of Chinese medicinal herbs in the short term remission of advanced or late gastric cancer. SEARCH METHODS: We searched the The Cochrane Library, MEDLINE, EMBASE, AHMED (Allied and Complementary Medicine Database) and CBM (Chinese Biomedical Database) from the first year of the databases to June 2011. We handsearched a number of journals. SELECTION CRITERIA: All randomised clinical trials of Chinese herbs for advanced or late gastric cancer were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data, which were analysed using RevMan 5.1 software (RevMan 2011). For dichotomous data, we estimated the relative risk. For continuous data, we calculated the weighted mean difference. MAIN RESULTS: Eighty five trials with 6857 advanced or late gastric cancer patients were identified for inclusion, most were of low quality and used traditional Chinese medicinal herbs (TCMHs) plus chemotherapy compared with the same chemotherapy alone (65 trials). Apart from 23 trials of four different kinds of TCMHs, we could not pool the results because no more than two used the same intervention or outcomes.TCMHs with or without chemotherapy, in 57 trials, showed statistically significant differences for the improvement of mortality in nine trials, quality of life in 16 trials, rate of remission in 11 trials, and leukopenia in five trials. The pooled results from the four injected TCMHs, Huachansu, Aidi, Fufangkushen, and Shenqifuzheng showed statistically significant differences for the improvement of leukopenia, but no significant difference in the rate of short-term remission. AUTHORS' CONCLUSIONS: This review did not provide assured evidence concerning the effectiveness of TCMHs in improving quality of life or rate of remission, alleviating the toxicity or side effects of chemotherapy, or reducing short-term mortality. Limited, weak evidence showed that Huachansu, Aidi, Fufangkushen, and Shenqifuzheng improved leukopenia when used together with chemotherapy; and Huachansu, Aidi, and Fufangkushen were of benefit for adverse events in the digestive system caused by chemotherapy. These TCMHs did not improve the rate of short-term remissions. Large, well designed clinical trials are required urgently before any definite conclusions can be drawn about the value of TCMHs for advanced or late stage gastric cancer. PMID- 23633325 TI - Antenatal perineal massage for reducing perineal trauma. AB - BACKGROUND: Perineal trauma following vaginal birth can be associated with significant short-term and long-term morbidity. Antenatal perineal massage has been proposed as one method of decreasing the incidence of perineal trauma. OBJECTIVES: To assess the effect of antenatal digital perineal massage on the incidence of perineal trauma at birth and subsequent morbidity. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (22 October 2012), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2012, Issue 10), PubMed (1966 to October 2012), EMBASE (1980 to October 2012) and reference lists of relevant articles. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials evaluating any described method of antenatal digital perineal massage undertaken for at least the last four weeks of pregnancy. DATA COLLECTION AND ANALYSIS: Both review authors independently applied the selection criteria, extracted data from the included studies and assessed study quality. We contacted study authors for additional information. MAIN RESULTS: We included four trials (2497 women) comparing digital perineal massage with control. All were of good quality. Antenatal digital perineal massage was associated with an overall reduction in the incidence of trauma requiring suturing (four trials, 2480 women, risk ratio (RR) 0.91 (95% confidence interval (CI) 0.86 to 0.96), number needed to treat to benefit (NNTB) 15 (10 to 36)) and women practicing perineal massage were less likely to have an episiotomy (four trials, 2480 women, RR 0.84 (95% CI 0.74 to 0.95), NNTB 21 (12 to 75)). These findings were significant for women without previous vaginal birth only. No differences were seen in the incidence of first- or second-degree perineal tears or third-/fourth-degree perineal trauma. Only women who have previously birthed vaginally reported a statistically significant reduction in the incidence of pain at three months postpartum (one trial, 376 women, RR 0.45 (95% CI 0.24 to 0.87) NNTB 13 (7 to 60)). No significant differences were observed in the incidence of instrumental deliveries, sexual satisfaction, or incontinence of urine, faeces or flatus for any women who practised perineal massage compared with those who did not massage. AUTHORS' CONCLUSIONS: Antenatal digital perineal massage reduces the likelihood of perineal trauma (mainly episiotomies) and the reporting of ongoing perineal pain, and is generally well accepted by women. As such, women should be made aware of the likely benefit of perineal massage and provided with information on how to massage. PMID- 23633327 TI - The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. AB - BACKGROUND: The use of cannabis (marijuana) or of its psychoactive ingredient delta-9-tetrahydrocannabinol (THC) as a medicine has been highly contested in many settings.There have been claims that smoked or ingested cannabis, either in its natural form or artificial form (pharmaceutically manufactured drug such as dronabinol), improves the appetites of people with AIDS, results in weight gain and lifts mood, thus improving the quality of life. OBJECTIVES: The objectives of this review were to assess whether cannabis (in its natural or artificially produced form), either smoked or ingested, decreases the morbidity or mortality of patients infected with HIV. SEARCH METHODS: The search strategy was conducted to July 2012 and was based on that of the Cochrane HIV/AIDS Review Group. We searched the following databases: CENTRAL/CCTR, MEDLINE and EMBASE. In addition, searching was performed where necessary of journals, reference lists of articles, and conference proceedings. SELECTION CRITERIA: The review included randomised controlled trials (RCTs) of any cannabis intervention, in any form, and administered by any route, in adults with HIV or AIDS, compared with placebo or with a known effective treatment, and conducted in a hospital, outpatient clinic, or home care setting. Quasi-randomised studies using any form of cannabis as an intervention in patients with HIV or AIDS were also included. DATA COLLECTION AND ANALYSIS: Data from the eligible studies were extracted and coded independently by two researchers, using a standardised data extraction form. Data were then analysed using RevMan 5.0. No meta-analyses were performed. MAIN RESULTS: A total of seven relevant studies were included in the review, reported in eight publications. All were randomised controlled studies, with four utilising a parallel group design, two a within-subject randomisation and two a cross-over design. All of the studies were of a fairly short duration, ranging from 21 days to 84 days. In only four papers (in effect, three studies) were sequence generation and allocation concealment judged to be adequate. The use of cannabis and rapidly acting cannabinoids posed considerable challenges for blinding, as the psychoactive effects are expected to be quickly discernible to study participants, particularly those who have been previous users of such products. Dronabinol was expected to be more easily blinded. The outcomes measured were variable, including change in weight, change in body fat (measured as a percentage of total body weight), change in appetite (measured on a visual analogue scale), change in caloric intake (measured in kcals/kg/24hr), change in nausea and vomiting (measured on a visual analogue scale), change in performance (measured by Karnofsky performance score or specific tests for memory and dexterity) and change in mood (measured on a visual analogue scale).The evidence for substantial effects on morbidity and mortality is currently limited. Data from only one relatively small study (n=139, of which only 88 were evaluable), conducted in the period before access to highly-active antiretroviral therapy (HAART), showed that patients administered dronabinol were twice as likely to gain 2kg or more in body weight (RR 2.09), but the confidence interval for this measure (95% CI 0.72 - 6.06) included unity. The mean weight gain in the dronabinol group was only 0.1kg, compared with a loss of 0.4kg in the placebo group. However, the quality of sequence generation and allocation concealment in this study, in which participants were randomised by centre, could not be assessed. AUTHORS' CONCLUSIONS: Despite dronabinol being registered by at least some medicines regulatory authorities for the treatment of AIDS-associated anorexia, and some jurisdictions making allowances for the "medical" use of marijuana by patients with HIV/AIDS, evidence for the efficacy and safety of cannabis and cannabinoids in this setting is lacking. Such studies as have been performed have been of short duration, in small numbers of patients, and have focused on short-term measures of efficacy. Long-term data, showing a sustained effect on AIDS-related morbidity and mortality and safety in patients on effective antiretroviral therapy, has yet to be presented. Whether the available evidence is sufficient to justify a wide-ranging revisiting of medicines regulatory practice remains unclear. PMID- 23633328 TI - Sequencing of chemotherapy and radiotherapy for early breast cancer. AB - BACKGROUND: After surgery for localised breast cancer, radiotherapy (RT) improves both local control and breast cancer-specific survival. In patients at risk of harbouring micro-metastatic disease, adjuvant chemotherapy (CT) improves 15-year survival. However, the best sequence of administering these two types of adjuvant therapy for early-stage breast cancer is unclear. OBJECTIVES: To determine the effects of different sequencing of adjuvant CT and RT for women with early breast cancer. SEARCH METHODS: An updated search was carried out in the Cochrane Breast Cancer Group's Specialised Register (20 May 2011), MEDLINE (14 December 2011), EMBASE (20 May 2011) and World Health Organization (WHO) International Clinical Trials Registry Platform (20 May 2011). Details of the search strategy and methods of coding for the Specialised Register are described in the Group's module in The Cochrane Library. We extracted studies that had been coded as 'early', 'chemotherapy' and 'radiotherapy'. SELECTION CRITERIA: We included randomised controlled trials evaluating different sequencing of CT and RT. DATA COLLECTION AND ANALYSIS: We assessed the eligibility and quality of the identified studies and extracted data from the published reports of the included trials. We derived odds ratios (OR) and hazard ratios (HR) from the available numerical data. Toxicity data were extracted, where reported. We used a fixed effect model for meta-analysis and conducted analyses on the basis of the method of sequencing of the two treatments. MAIN RESULTS: Three trials reporting two different sequencing comparisons were identified. There were no significant differences between the various methods of sequencing adjuvant therapy for local recurrence-free survival, overall survival, relapse-free survival and metastasis free survival based on 1166 randomised women in three trials. Concurrent chemoradiation increased anaemia (OR 1.54; 95% confidence interval (CI) 1.10 to 2.15), telangiectasia (OR 3.85; 95% CI 1.37 to 10.87) and pigmentation (OR 15.96; 95% CI 2.06 to 123.68). Treated women did not report worse cosmesis with concurrent chemoradiation but physician-reported assessments did (OR 1.14; 95% CI 0.42 to 3.07). Other measures of toxicity did not differ between the two types of sequencing. On the basis of one trial (244 women), RT before CT was associated with an increased risk of neutropenic sepsis (OR 2.96; 95% CI 1.26 to 6.98) compared with CT before RT, but other measures of toxicity did not differ. AUTHORS' CONCLUSIONS: The data included in this review, from three well-conducted randomised trials, suggest that different methods of sequencing CT and RT do not appear to have a major effect on recurrence or survival for women with breast cancer if RT is commenced within seven months after surgery. PMID- 23633329 TI - Herbal preparations for uterine fibroids. AB - BACKGROUND: Uterine fibroids are the most common non-malignant growths in women of childbearing age. They are associated with heavy menstrual bleeding and subfertility. Herbal preparations are commonly used as alternatives to surgical procedures. OBJECTIVES: To evaluate the effectiveness and safety of Chinese herbal medicine for treatment of uterine fibroids. SEARCH METHODS: The authors with the guidance of the Trials Search Coordinator searched the following electronic databases: the Trials Registers of the Cochrane Menstrual Disorders and Subfertility Group and the Cochrane Complementary Medicine Field, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), MEDLINE, EMBASE, the Chinese Biomedical Database, the Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS), AMED, and LILACS. The searches were up to 11 September 2012. SELECTION CRITERIA: Randomised controlled trials comparing herbal preparations with no intervention, placebo, medical treatment, or surgical procedures in women with uterine fibroids. We included trials of herbal preparations with or without conventional therapy. DATA COLLECTION AND ANALYSIS: Two review authors collected data independently. We assessed trial risk of bias according to our methodological criteria. We presented dichotomous data as risk ratios (RR) and continuous outcomes as mean differences (MD), both with 95% confidence intervals (CI). MAIN RESULTS: We included 21 randomised trials (involving 2222 women) and the majority of them had unclear or high risk of bias. There were several different herbal preparations used within the included trials. The average treatment duration was three to six months. The primary outcome of uterine fibroid related symptoms was not reported in any of the included trials. The majority of the trials reported fibroid volume and size of the uterus.Compared with mifepristone, Tripterygium wilfordii extract was associated with a greater reduction in the fibroid volume (MD -23.03 cm(3), 95% CI -28.39 to -17.67; 2 trials) and in uterine size (MD -51.25 cm(3), 95% CI 77.70 to -24.80; 2 trials). There was no evidence of a significant difference between Nona Roguy herbal product and gonadotropin-releasing hormone (GnRH) agonist on the average fibroid volume or the uterine size. The combination of Guizhi Fuling formula and mifepristone was associated with a greater reduction in the fibroid volume (-1.72 [-2.42, -1.02] 7 trials) and in uterine size (MD -31.63 [95% CI -54.58, -8.68] 3 trials)) compared with mifepristone alone. Only 13/21 trials reported on adverse events and no serious adverse effects from herbal preparations were reported. AUTHORS' CONCLUSIONS: Current evidence does not support or refute the use of herbal preparations for treatment of uterine fibroids due to insufficient studies with large sample sizes and of high quality. Further high quality trials evaluating clinically relevant outcomes are warranted. PMID- 23633330 TI - Rutosides for treatment of post-thrombotic syndrome. AB - BACKGROUND: Post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterised by pain, swelling, and skin changes in the affected limb. One in three patients with DVT will develop post-thrombotic sequelae within five years. Rutosides are a group of compounds derived from horse chestnut (Aesculus hippocastanum), a traditional herbal remedy for treating oedema formation in chronic venous insufficiency (CVI). However, it is not known whether rutosides are effective and safe in the treatment of PTS. OBJECTIVES: To determine the effectiveness and safety of rutosides for treatment of PTS in patients with DVT compared to placebo, no intervention, elastic compression stockings (ECS) or any other treatment. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2012) and CENTRAL (2012, Issue 9). Clinical trials databases were searched for details of ongoing and unpublished studies. SELECTION CRITERIA: Two authors (JM and DNK) independently assessed studies for inclusion. Studies were included to allow the comparison of rutosides versus placebo or no treatment, rutosides versus ECS, and rutosides versus any other treatment. Two authors (JM and SEY) extracted information from the trials. Disagreements were resolved by discussion. DATA COLLECTION AND ANALYSIS: Data were extracted using designated data extraction forms. The Cochrane risk of bias tool was used for all included studies to assist in the assessment of quality. Primary outcome measures were the occurrence of leg ulceration over time (yes or no) and any improvement or deterioration of post-thrombotic syndrome (yes or no). Secondary outcomes included reduction of oedema, pain, recurrence of deep venous thrombosis or pulmonary embolism, compliance with therapy, and adverse effects. All of the outcome measures were analysed using Mantel-Haenzel fixed-effect model odds ratios. The unit of analysis was the number of patients. MAIN RESULTS: Ten reports of nine studies were identified following searching and three studies with a total of 233 participants met the inclusion criteria. One study compared rutoside with placebo, one study compared rutosides with ECS and rutosides plus ECS versus ECS alone, and one study compared rutosides with an alternative venoactive remedy. Occurrence of leg ulceration was not reported in any of the included studies. There was a 29% odds of an improvement in PTS in the rutoside treated group versus placebo or no treatment, and lower rates of improvement in PTS in the rutoside treated group when compared with ECS, however these were statistically non-significant. Lower rates of improvement in PTS were shown in the rutoside treated group when compared with an alternative venoactive remedy. More PTS deterioration was shown in the placebo or no treatment group when compared with rutosides but this was not statistically significant. Compared with ECS, rutosides showed higher odds of PTS deterioration but this was also not statistically significant. One study reported on adverse effects showing higher odds of mild adverse effects in the rutoside treated group compared to placebo but this was not statistically significant. AUTHORS' CONCLUSIONS: There was no evidence that rutosides were superior to the use of placebo or ECS. Overall, there is currently limited evidence that 'venoactive' or 'phlebotonic' remedies such as rutosides reduce symptoms of PTS. Mild side effects were noted in one study. The three studies included in this review provide no evidence for the use of rutosides in the treatment of PTS. PMID- 23633331 TI - Rutosides for prevention of post-thrombotic syndrome. AB - BACKGROUND: Post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterised by pain, swelling, and skin changes in the affected limb. One in three patients with DVT will develop post-thrombotic sequelae within five years. The current standard care for the prevention of PTS following DVT is elastic compression stockings. Rutosides are a group of compounds derived from horse chestnut (Aesculus hippocastanum), a traditional herbal remedy for treating oedema formation in chronic venous insufficiency (CVI). However, it is not known whether rutosides are effective and safe in the prevention of post-thrombotic syndrome. OBJECTIVES: To determine the effectiveness and safety of rutosides for prevention of PTS in patients with DVT, compared to placebo, no intervention, or reference medication. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2012) and CENTRAL (2012, Issue 9). Clinical trials databases were searched for details of ongoing and unpublished studies. SELECTION CRITERIA: We planned to include trials of rutosides versus any alternative (placebo, no intervention, or reference medication) in the prevention of PTS in patients with DVT. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion and intended to extract information from the trials. MAIN RESULTS: No studies were identified comparing rutosides versus any alternative in the prevention of PTS. AUTHORS' CONCLUSIONS: As there were no studies identified in this review it is not possible to support the use of rutosides in the prevention of PTS. Some studies suggest that rutosides may provide short-term relief of PTS symptoms. However, there is nothing published on their use as a preventative therapy for PTS. High quality randomised controlled trials of rutoside versus any alternative are required to build the evidence base in this area. PMID- 23633333 TI - Interventions for improving adherence to ocular hypotensive therapy. AB - BACKGROUND: Poor adherence to therapy is a significant healthcare issue, particularly in patients with chronic disease such as open-angle glaucoma. Treatment failure may necessitate unwarranted changes of medications, increased healthcare expenditure and risk to the patient if surgical intervention is required. Simplifying eye drop regimes, providing adequate information, teaching drop instillation technique and ongoing support according to the patient need may have a positive effect on improving adherence. OBJECTIVES: To summarise the effects of interventions for improving adherence to ocular hypotensive therapy in people with ocular hypertension (OHT) or glaucoma. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 6), MEDLINE (June 1946 to June 2012), EMBASE (June 1980 to June 2012), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (June 1937 to June 2012), PsycINFO (1806 to June 2012), PsycEXTRA (1908 to June 2012), Web of Science (1970 to June 2012), ZETOC (1993 to June 2012), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 26 June 2012. We did not search the National Research Register (NNR) as this resource has now been now archived. We contacted pharmaceutical manufacturers to request unpublished data and searched conference proceedings for the Association for Research in Vision and Ophthalmology (ARVO), and the Annual Congress for the Royal College of Ophthalmologists (RCO). SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that compared interventions to improve adherence to ocular hypotensive therapy for patients with OHT or glaucoma. DATA COLLECTION AND ANALYSIS: At least two authors independently assessed the search results for eligibility and extracted data for included trials onto specifically designed forms. We did not pool data due to clinical and methodological heterogeneity. MAIN RESULTS: Sixteen trials (1565 participants) met the inclusion criteria. Seven studies investigated some form of patient education. In six of these studies this education was combined with other behavioural change interventions including tailoring daily routines to promote adherence to eye drops. Eight studies compared different drug regimens (one of these trials also compared open and masked monitoring) and one study investigated a reminder device. The studies were of variable quality and some were at considerable risk of bias; in general, the length of follow-up was short at less than six months with only two studies following up to 12 months. Different interventions and outcomes were reported and so it was not possible to produce an overall estimate of effect. There was some evidence from three studies that education combined with personalised interventions, that is, more complex interventions, improved adherence to ocular hypotensive therapy. There was less information on other outcomes such as persistence and intraocular pressure, and no information on visual field defects, quality of life and cost. There was weak evidence as to whether people on simpler drug regimens were more likely to adhere and persist with their ocular hypotensive therapy. A particular problem was the interpretation of cross-over studies, which in general were not reported correctly. One study investigated a reminder device and monitoring but the study was small and inconclusive. AUTHORS' CONCLUSIONS: Although complex interventions consisting of patient education combined with personalised behavioural change interventions, including tailoring daily routines to promote adherence to eye drops, may improve adherence to glaucoma medication, overall there is insufficient evidence to recommend a particular intervention. The interventions varied between studies and none of the included studies reported on the cost of the intervention. Simplified drug regimens also could be of benefit but again the current published studies do not provide conclusive evidence. Future studies should follow up for at least one year, and could benefit from standardised outcomes. PMID- 23633334 TI - Interventions for treating traumatised permanent front teeth: luxated (dislodged) teeth. AB - BACKGROUND: Dental trauma is common especially in children and young adults. One group of dento-alveolar injuries is classified as luxation. This group includes a subgroup of severe injuries where the tooth is displaced from its original position. These injuries are classified further by the direction in which the tooth has been displaced, namely: intrusion, extrusion and lateral luxation. OBJECTIVES: To evaluate the effects of a range of interventions for treating displaced luxated permanent front teeth. SEARCH METHODS: Search strategies were developed for MEDLINE via OVID and revised appropriately for the following databases: Cochrane Oral Health Group's Trials Register (to 20 August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 8), MEDLINE via OVID (1966 to August 2012), EMBASE via Elsevier (1974 to August 2012), and LILACS via BIREME (1982 to August 2012). Dissertations, Theses and Abstracts were searched as were reference lists from articles. There were no language restrictions. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of treatment interventions for displaced luxated permanent front teeth. Included trials had to have a minimum follow-up period of 12 months. DATA COLLECTION AND ANALYSIS: Two review authors independently and in duplicate assessed the eligibility of all reports identified in the searches. Authors were contacted for additional information where required. MAIN RESULTS: No randomised or quasi-randomised controlled trials were found. AUTHORS' CONCLUSIONS: We found no randomised or quasi-randomised trials of interventions to treat displaced luxated permanent front teeth. Current clinical guidelines are based on available information from case series studies and expert opinions. Randomised controlled trials in this area of dental trauma are required to robustly identify the benefits of different treatment strategies. PMID- 23633332 TI - Interval debulking surgery for advanced epithelial ovarian cancer. AB - BACKGROUND: Interval debulking surgery (IDS), following induction or neoadjuvant chemotherapy, may have a role in treating advanced epithelial ovarian cancer (stage III to IV) where primary debulking surgery is not an option. OBJECTIVES: To assess the effectiveness and complications of IDS for women with advanced stage epithelial ovarian cancer. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group's Specialised Register to June 2012, the Cochrane Central Register of Controlled Trials (CENTRAL) 2012, Issue 6, MEDLINE to June 2012 and EMBASE to June 2012. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing survival of women with advanced epithelial ovarian cancer, who had IDS performed between cycles of chemotherapy after primary surgery with survival of women who had conventional treatment (primary debulking surgery and adjuvant chemotherapy). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Searches for additional information from study authors were attempted. We performed meta-analysis of overall and progression-free survival (PFS), using random-effects models. MAIN RESULTS: Three RCTs randomising 853 women, of whom 781 were evaluated, met the inclusion criteria. Meta-analysis of three trials for overall survival (OS) found no statistically significant difference between IDS and chemotherapy alone (hazard ratio (HR) = 0.80, 95% confidence interval (CI) 0.61 to 1.06, I2 = 58%). Subgroup analysis for OS in two trials, where the primary surgery was not performed by gynaecologic oncologists or was less extensive, showed a benefit of IDS (HR = 0.68, 95% CI 0.53 to 0.87, I2 = 0%). Meta-analysis of two trials for PFS found no statistically significant difference between IDS and chemotherapy alone (HR = 0.88, 95% CI 0.57 to 1.33, I2 = 83%). Rates of toxic reactions to chemotherapy were similar in both arms (risk ratio = 1.19, 95% CI 0.53 to 2.66, I2 = 0%), but little information was available for other adverse events or quality or life (QoL). AUTHORS' CONCLUSIONS: We found no conclusive evidence to determine whether IDS between cycles of chemotherapy would improve or decrease the survival rates of women with advanced ovarian cancer, compared with conventional treatment of primary surgery followed by adjuvant chemotherapy. IDS appeared to yield benefit only in women whose primary surgery was not performed by gynaecologic oncologists or was less extensive. Data on QoL and adverse events were inconclusive. PMID- 23633335 TI - Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. AB - BACKGROUND: Polycythaemia vera and essential thrombocythaemia are chronic Philadelphia-negative myeloproliferative neoplasms that increase the risk of arterial and venous thrombosis, as well as bleeding. In addition to the different therapeutic strategies available, an antiplatelet drug is often used to reduce thrombotic risk. OBJECTIVES: To quantify the benefit and harm of antiplatelet drugs for long-term primary and secondary prophylaxis of arterial and venous thrombotic events in patients with polycythaemia vera or essential thrombocythaemia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library (Issue 1 2012), MEDLINE (1966 to 2012), and EMBASE (1980 to 2012), as well as online registers of ongoing trials and conference proceedings. The date of the last search was October 2012. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing long-term (>6 months) use of an antiplatelet drug versus placebo or no treatment in participants with polycythaemia vera or essential thrombocythaemia, as diagnosed by established international criteria, with data for at least one of the selected outcomes. DATA COLLECTION AND ANALYSIS: Using a pre-defined extraction form, two review authors independently screened results, extracted data, and assessed quality. We planned to analyse the following outcomes: mortality from arterial and venous thrombotic events (primary efficacy outcome), mortality from bleeding episodes (primary safety outcome), fatal and non-fatal arterial thrombotic events, fatal and non-fatal venous thrombotic events, micro circulation events, transient neurological and ocular manifestations, major and minor bleeding episodes, and all-cause mortality and any adverse events. We based quantitative analysis of outcome data on an intention-to-treat principle. We used the pooled odds ratio (OR) with 95% confidence interval (CI) with a fixed-effect model (Mantel-Haenszel) to estimate the overall treatment effect. MAIN RESULTS: We identified no new studies from the updated searches. We included in this review two RCTs for a total of 630 participants. Both RCTs included participants with an established diagnosis of polycythaemia vera and with no clear indication or contraindication to aspirin therapy. We judged both studies to be of moderate quality. Published data from both studies were insufficient for a time-to-event data analysis and for some of the primary and secondary outcomes that we planned. The use of low-dose aspirin, compared with placebo, was associated with a lower risk of fatal thrombotic events (although this benefit was not statistically significant (OR 0.20, 95% CI 0.03 to 1.14; P = 0.07). No data on mortality from bleeding episodes were available. A non-significant benefit of aspirin was shown for all-cause mortality (OR 0.46, 95% CI 0.21 to 1.01; P = 0.05). No increase in the risk of major bleeding was reported in participants taking aspirin compared with those given placebo (OR 0.99, 95% CI 0.23 to 4.36; P = 0.99), and a non significant increase with aspirin treatment was shown for minor bleeding (OR 1.85, 95% CI 0.90 to 3.79; P = 0.09). No published studies have reported findings in participants with essential thrombocythaemia or in the study of other antiplatelet drugs. AUTHORS' CONCLUSIONS: For patients with polycythaemia vera who have no clear indication or contraindication to aspirin therapy, available evidence suggests that the use of low-dose aspirin, when compared with no treatment, is associated with a statistically non-significant reduction in the risk of fatal thrombotic events and all-cause mortality, without an increased risk of major bleeding. PMID- 23633336 TI - Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. AB - BACKGROUND: Respiratory syncytial virus (RSV) is one of the most important viral pathogens causing acute respiratory infections in children. It results in about 3.4 million hospitalisations annually in children under five. Palivizumab is an anti-RSV monoclonal antibody, administered intramuscularly at a dose of 15 mg/kg once every 30 days. The efficacy and safety of palivizumab has been evaluated in multicentre, randomised controlled trials (RCTs) and a large number of economic evaluations (EEs) have tested its cost-effectiveness. OBJECTIVES: To assess the effectiveness and safety of palivizumab prophylaxis compared with placebo, or another type of prophylaxis, in reducing the risk of complications (hospitalisation due to RSV infection) in high-risk infants and children. To assess the cost-effectiveness (or cost-utility) of palivizumab prophylaxis compared with no prophylaxis in infants and children in different risk groups. SEARCH METHODS: We searched CENTRAL 2012, Issue 7, MEDLINE (1996 to July week 4, 2012), EMBASE (1996 to August 2012), CINAHL (1996 to August 2012) and LILACS (1996 to August 2012) for studies of effectiveness and safety. We searched the NHS Economic Evaluations Database (NHS EED 2012, Issue 4), Health Economics Evaluations Database (HEED, 9 August 2012) and Paediatric Economic Database Evaluations (PEDE, 1980 to 2009), MEDLINE (1996 to July week 4, 2012) and EMBASE (1996 to August 2012) for economic evaluations. SELECTION CRITERIA: We included RCTs comparing palivizumab prophylaxis with a placebo, no prophylaxis or another type of prophylaxis in preventing serious lower respiratory tract disease caused by RSV in paediatric patients at high risk. We included cost-effectiveness analyses and cost-utility analyses comparing palivizumab prophylaxis with no prophylaxis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias for the included studies and extracted data for both the RCTs and EEs. We calculated risk ratios (RRs) and their associated 95% confidence intervals (CIs) for dichotomous outcomes and for adverse events (AEs). We provided a narrative summary of results for continuous outcomes, due to missing data on standard deviations. We performed fixed-effect meta-analyses for the estimation of pooled effects whenever there was no indication of heterogeneity between included RCTs. We summarised the results reported in included EEs, such as incremental costs, incremental effectiveness, and incremental cost effectiveness and/or cost-utility ratios (ICERs), and we calculated ICER present values in 2011 Euros for all studies. MAIN RESULTS: Of the seven available RCTs, three compared palivizumab with a placebo in a total of 2831 patients, and four compared palivizumab with motavizumab in a total of 8265 patients. All RCTs were sponsored by the drug manufacturing company. The overall quality of RCTs was good, but for most of the outcomes assessed only data from two studies contributed to the analysis. Palivizumab prophylaxis was associated with a statistically significant reduction in RSV hospitalisations (RR 0.49, 95% CI 0.37 to 0.64) when compared to placebo. When compared to motavizumab, palivizumab recipients showed a non-significant increase in the risk of RSV hospitalisations (RR 1.36, 95% CI 0.97 to 1.90). In both cases, the proportion of children with any AE or any AE related to the study drug was similar between the two groups.In terms of economic evidence, we included 34 studies that reported cost effectiveness and/or cost-utility data for palivizumab prophylaxis compared with no prophylaxis, in high-risk children with different underlying medical conditions. The overall quality of EEs was good, but the variations in modelling approaches were considerable across the studies, leading to big differences in cost-effectiveness results. The cost-effectiveness of palivizumab prophylaxis depends on the consumption of resources taken into account by the study authors; and on the cost-effectiveness threshold set by the healthcare sector in each country. AUTHORS' CONCLUSIONS: There is evidence that palivizumab prophylaxis is effective in reducing the frequency of hospitalisations due to RSV infection, i.e. in reducing the incidence of serious lower respiratory tract RSV disease in children with chronic lung disease, congenital heart disease or those born preterm.Results from economic evaluations of palivizumab prophylaxis are inconsistent, implying that economic findings must be interpreted with caution. ICER values varied considerably across studies, from highly cost-effective to not cost-effective. The availability of low-cost palivizumab would reduce its inequitable distribution, so that RSV prophylaxis would be available to the poorest countries where children are at greatest risk. PMID- 23633337 TI - Strategies for communicating contraceptive effectiveness. AB - BACKGROUND: Knowledge of contraceptive effectiveness is crucial to making an informed choice. The consumer has to comprehend the pros and cons of the contraceptive methods being considered. Choice may be influenced by understanding the likelihood of pregnancy with each method and factors that influence effectiveness. OBJECTIVES: To review all randomized controlled trials comparing strategies for communicating to consumers the effectiveness of contraceptives in preventing pregnancy. SEARCH METHODS: Through February 2013, we searched the computerized databases of MEDLINE, POPLINE, CENTRAL, PsycINFO and CINAHL, ClinicalTrials.gov, and ICTRP. Previous searches also included EMBASE. We also examined references lists of relevant articles. For the initial review, we wrote to known investigators for information about other published or unpublished trials. SELECTION CRITERIA: We included randomized controlled trials that compared methods for communicating contraceptive effectiveness to consumers. The comparison could be usual practice or an alternative to the experimental intervention.Outcome measures were knowledge of contraceptive effectiveness, attitude about contraception or toward any particular contraceptive, and choice or use of contraceptive method. DATA COLLECTION AND ANALYSIS: For the initial review, two authors independently extracted the data. One author entered the data into RevMan, and a second author verified accuracy. For the update, an author and a research associate extracted, entered, and checked the data.For dichotomous variables, we calculated the Mantel-Haenszel odds ratio with 95% confidence intervals (CI). For continuous variables, we computed the mean difference (MD) with 95% CI. MAIN RESULTS: Seven trials met the inclusion criteria and had a total of 4526 women. Five were multi-site studies. Four trials were conducted in the USA, while Nigeria and Zambia were represented by one study each, and one trial was done in both Jamaica and India.Two trials provided multiple sessions for participants. In one study that examined contraceptive choice, women in the expanded program were more likely to choose sterilization (OR 4.26; 95% CI 2.46 to 7.37) or use a modern contraceptive method (OR 2.35; 95% CI 1.82 to 3.03), i.e., sterilization, pills, injectable, intrauterine device or barrier method. For the other study, the groups received educational interventions with differing format and intensity. Both groups reportedly had increases in contraceptive use, but they did not differ significantly by six months in consistent use of an effective contraceptive, i.e., sterilization, IUD, injectable, implant, and consistent use of oral contraceptives, diaphragm, or male condoms.Five trials provided one session and focused on testing educational material or media. In one study, knowledge gain favored a slide-and-sound presentation versus a physician's oral presentation (MD -19.00; 95% CI -27.52 to -10.48). In another trial, a table with contraceptive effectiveness categories led to more correct answers than a table based on pregnancy numbers [ORs were 2.42 (95% CI 1.43 to 4.12) and 2.19 (95% CI 1.21 to 3.97)] or a table with effectiveness categories and pregnancy numbers [ORs were 2.58 (95% CI 1.5 to 4.42) and 2.03 (95% CI 1.13 to 3.64)]. Still another trial provided structured counseling with a flipchart on contraceptive methods. The intervention and usual-care groups did not differ significantly in choice of contraceptive method (by effectiveness category) or in continuation of the chosen method at three months. Lastly, a study with couples used videos to communicate contraceptive information (control, motivational, contraceptive methods, and both motivational and methods videos). The analyses showed no significant difference between the groups in the types of contraceptives chosen. AUTHORS' CONCLUSIONS: These trials varied greatly in the types of participants and interventions to communicate contraceptive effectiveness. Therefore, we cannot say overall what would help consumers choose an appropriate contraceptive method. For presenting pregnancy risk data, one trial showed that effectiveness categories were better than pregnancy numbers. In another trial, audiovisual aids worked better than the usual oral presentation. Strategies should be tested in clinical settings and measured for their effect on contraceptive choice. More detailed reporting of intervention content would help in interpreting results. Reports could also include whether the instruments used to assess knowledge or attitudes were tested for validity or reliability. Follow up should be incorporated to assess retention of knowledge over time. The overall quality of evidence was considered to be low for this review, given that five of the seven studies provided low or very low quality evidence. PMID- 23633338 TI - Screening women for intimate partner violence in healthcare settings. AB - BACKGROUND: Intimate partner violence (IPV) damages individuals, their children, communities, and the wider economic and social fabric of society. Some governments and professional organisations recommend screening all women for intimate partner violence rather than asking only women with symptoms (case finding); however, what is the evidence that screening interventions will increase identification, and referral to support agencies, or improve women's subsequent wellbeing and not cause harm? OBJECTIVES: To assess the effectiveness of screening for intimate partner violence conducted within healthcare settings for identification, referral to support agencies and health outcomes for women. SEARCH METHODS: We searched the following databases in July 2012: CENTRAL (2012, Issue 6), MEDLINE (1948 to September Week June Week 3 2012), EMBASE (1980 to Week 28 2012), MEDLINE In-Process (3 July 2012), DARE (2012, Issue 2), CINAHL (1937 to current), PsycINFO (1806 to June Week 4 2012), Sociological Abstracts (1952 to current) and ASSIA (1987 to October 2010). In addition we searched the following trials registers: metaRegister of Controlled Trials (mRCT) (to July 2012), and International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, Australian New Zealand Clinical Trials Registry and the International Standard Randomised Controlled Trial Number Register to August 2010. We also searched the reference lists of articles and websites of relevant organisations. SELECTION CRITERIA: Randomised or quasi-randomised trials assessing the effectiveness of IPV screening where healthcare professionals screened women face-to-face or were informed of results of screening questionnaires, compared with usual care ( which included screening for other purposes). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias in the trials and undertook data extraction. For binary outcomes, we calculated a standardised estimation of the risk ratio (RR) and for continuous data, either a mean difference (MD) or standardised mean difference (SMD). All are presented with a 95% confidence interval (CI). MAIN RESULTS: We included 11 trials that recruited 13,027 women overall. Six of 10 studies were assessed as being at high risk of bias.When data from six comparable studies were combined (n = 3564), screening increased identification of victims/survivors (RR 2.33; 95% CI 1.40 to 3.89), particularly in antenatal settings (RR 4.26; 95% CI 1.76 to 10.31).Only three studies measured referrals to support agencies (n = 1400). There is no evidence that screening increases such referrals, as although referral numbers increased in the screened group, actual numbers were very small and crossed the line of no effect (RR 2.67; 95% CI 0.99 to 7.20).Only two studies measured women's experience of violence after screening (one at three months, the other at six, 12 and 18 months after screening) and found no significant reduction of abuse.Only one study measured adverse effects and data from this study suggested that screening may not cause harm. This same study showed a trend towards mental health benefit, but the results did not reach statistical significance.There was insufficient evidence on which to judge whether screening increases take up of specialist services, and no studies included economic evaluation. AUTHORS' CONCLUSIONS: Screening is likely to increase identification rates but rates of referral to support agencies are low and as yet we know little about the proportions of false measurement (negatives or positives). Screening does not appear to cause harm, but only one study examined this outcome. As there is an absence of evidence of long-term benefit for women, there is insufficient evidence to justify universal screening in healthcare settings. Studies comparing screening versus case finding (with or without advocacy or therapeutic interventions) for women's long-term wellbeing would better inform future policies in healthcare settings. PMID- 23633339 TI - Interventions for the prevention of mycobacterium avium complex in adults and children with HIV. AB - BACKGROUND: Mycobacterium avium complex (MAC) infection is a common complication of advanced acquired immunodeficiency syndrome (AIDS) disease and is an independent predictor of mortality and shortened survival. OBJECTIVES: To determine the effectiveness and safety of interventions aimed at preventing MAC infection in adults and children with HIV infection. SEARCH METHODS: We searched MEDLINE, EMBASE, and The Cochrane Library (search date December 2012). SELECTION CRITERIA: Randomised controlled trials comparing different strategies for preventing MAC infection in HIV-infected individuals. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility and quality, and extracted data. Where data were incomplete or unclear, a third reviewer resolved conflicts and/or trial authors were contacted for further details. Development of MAC infection and survival were compared using risk ratios (RR) and 95% confidence intervals (CI). The quality of evidence has been assessed using the GRADE methodology. MAIN RESULTS: Eight studies met the inclusion criteria. Placebo-controlled trials: There was no statistically significant difference between clofazimine and no treatment groups in the number of patients that developed MAC infection (RR 1.01; 95% CI 0.37 to 2.80). Rifabutin (one study; RR 0.48; 95% CI 0.35 to 0.67), azithromycin (three studies; RR 0.37; 95% CI 0.19 to 0.74) and clarithromycin (one study; RR 0.35; 95% CI 0.21 to 0.58) were more effective than placebo in preventing the development of MAC infection. There was no statistically significant difference between those treated with clofazimine (one study; RR 0.98; 95% CI 0.41 to 2.32), rifabutin (one study RR 0.91; 95% CI 0.78 to 1.05), azithromycin (three studies, pooled RR 0.96; 95% CI 0.69 to 1.32) and placebo in number of reported deaths. One study found that the risk of death was reduced by 22% in patients treated with clarithromycin compared to those treated with placebo (RR 0.78; 95% CI 0.64 to 0.96). Monotherapy vs. monotherapy: Patients treated with clarithromycin (RR 0.60; 95% CI 0.41 to 0.89) and azithromycin (RR 0.60; 95% CI 0.40 to 0.89) were 40% less likely to develop MAC infection than those treated with rifabutin. There was no statistically significant difference between those treated with clarithromycin (RR 0.98; 95% CI 0.83 to 1.15), azithromycin (RR 0.98; 95% CI 0.77 to 1.24) and rifabutin in the number of reported deaths. Combination therapy versus monotherapy: There was no statistically significant difference between patients treated with a combination of rifabutin and clarithromycin and those treated with clarithromycin alone (RR 0.74; 95% CI 0.46 to 1.20); and those treated with combination of rifabutin and azithromycin and those treated with azithromycin alone (RR 0.59; 95% CI 1.03). Patients treated with a combination of rifabutin plus clarithromycin were 56% less likely to develop MAC infection than those treated with rifabutin alone (RR 0.44; 95% CI 0.29 to 0.69). Patients treated with a combination of rifabutin plus azithromycin were 65% less likely to develop MAC infection than those treated with rifabutin alone (RR 0.35; 95% CI 0.21 to 0.59). There was no statistically significant difference in the number of reported deaths in all the four different comparisons of prophylactic agents. AUTHORS' CONCLUSIONS: Based on limited data, azithromycin or clarithromycin appeared to be a prophylactic agent of choice for MAC infection. Further studies are needed, especially direct comparison of clarithromycin and azithromycin. In additions, studies that will compare different doses and regimens are needed. PMID- 23633340 TI - Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children. AB - BACKGROUND: Traditionally inhaled treatment for asthma has used separate preventer and reliever therapies. The combination of formoterol and budesonide in one inhaler has made possible a single inhaler for both prevention and relief of symptoms (single inhaler therapy or SiT). OBJECTIVES: To assess the efficacy and safety of budesonide and formoterol in a single inhaler for maintenance and reliever therapy in asthma compared with maintenance with inhaled corticosteroids (ICS) (alone or as part of current best practice) and any reliever therapy. SEARCH METHODS: We searched the Cochrane Airways Group trials register in February 2013. SELECTION CRITERIA: Parallel, randomised controlled trials of 12 weeks or longer in adults and children with chronic asthma. Studies had to assess the combination of formoterol and budesonide as SiT, against a control group that received inhaled steroids and a separate reliever inhaler. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 13 trials involving 13,152 adults and one of the trials also involved 224 children (which have been separately reported). All studies were sponsored by the manufacturer of the SiT inhaler. We considered the nine studies assessing SiT against best practice to be at a low risk of selection bias, but a high risk of detection bias as they were unblinded.In adults whose asthma was not well-controlled on ICS, the reduction in hospital admission with SiT did not reach statistical significance (Peto odds ratio (OR) 0.81; 95% confidence interval (CI) 0.45 to 1.44, eight trials, N = 8841, low quality evidence due to risk of detection bias in open studies and imprecision). The rates of hospital admission were low; for every 1000 people treated with current best practice six would experience a hospital admission over six months compared with between three and eight treated with SiT. The odds of experiencing exacerbations needing treatment with oral steroids were lower with SiT compared with control (OR 0.83; 95% CI 0.70 to 0.98, eight trials, N = 8841, moderate quality evidence due to risk of detection bias). For every 100 adults treated with current best practice over six months, seven required a course of oral steroids, whilst for SiT there would be six (95% CI 5 to 7). The small reduction in time to first severe exacerbation needing medical intervention was not statistically significant (hazard ratio (HR) 0.94; 95% CI 0.85 to 1.04, five trials, N = 7355). Most trials demonstrated a reduction in the mean total daily dose of ICS with SiT (mean reduction was based on self-reported data from patient diaries and ranged from 107 to 385 ug/day). Withdrawals due to adverse events were more common in people treated with SiT (OR 2.85; 95% CI 1.89 to 4.30, moderate quality evidence due to risk of detection bias).Three studies including 4209 adults compared SiT with higher dose budesonide maintenance and terbutaline for symptom relief. The studies were considered as low risk of bias. The run-in for these studies involved withdrawal of LABA, and patients were recruited who were symptomatic during run-in. The reduction in the odds of hospitalisation with SiT compared with higher dose ICS did not reach statistical significance (Peto OR; 0.56; 95% CI 0.28 to 1.09, moderate quality evidence due to imprecision). Fewer patients on SiT needed a course of oral corticosteroids (OR 0.54; 95% CI 0.45 to 0.64, high quality evidence). For every 100 adults treated with ICS over 11 months, 18 required a course of oral steroids, whilst for SiT there would be 11 (95% CI 9 to 12). Withdrawals due to adverse events were more common in people treated with SiT (OR 0.57; 95% CI 0.35 to 0.93, high quality evidence).One study included children (N = 224), in which SiT was compared with higher dose budesonide. There was a significant reduction in participants who needed an increase in their inhaled steroids with SiT, but there were only two hospitalisations for asthma and no separate data on courses of oral corticosteroids. Less inhaled and oral corticosteroids were used in the SiT group and the annual height gain was also 1 cm greater in the SiT group, (95% CI 0.3 cm to 1.7 cm).The results for fatal serious adverse events were too rare to rule out either treatment being harmful. There was no significant difference found in non fatal serious adverse events for any of the comparisons. AUTHORS' CONCLUSIONS: Single inhaler therapy has now been demonstrated to reduce exacerbations requiring oral corticosteroids against current best practice strategies and against a fixed higher dose of inhaled steroids. The strength of evidence that SiT reduces hospitalisation against these same treatments is weak. There were more discontinuations due to adverse events on SiT compared to current best practice, but no significant differences in serious adverse events. Our confidence in these conclusions is limited by the open-label design of the trials, and by the unknown adherence to treatment in the current best practice arms of the trials.Single inhaler therapy can reduce the risk of asthma exacerbations needing oral corticosteroids in comparison with fixed dose maintenance ICS and separate relief medication. The reduced odds of exacerbations with SiT compared with higher dose ICS should be viewed in the context of the possible impact of LABA withdrawal during study run-in. This may have made the study populations more likely to respond to SiT.Single inhaler therapy is not currently licensed for children under 18 years of age in the United Kingdom and there is currently very little research evidence for this approach in children or adolescents. PMID- 23633341 TI - Temozolomide for high grade glioma. AB - BACKGROUND: High grade glioma (HGG) is an aggressive form of brain cancer. Treatment of HGG usually entails biopsy, or resection if safe, followed by radiotherapy. Temozolomide is a novel oral chemotherapy drug that penetrates into the brain and purportedly has a low incidence of adverse events. OBJECTIVES: To assess whether temozolomide has any advantage for treating HGG in either primary or recurrent disease settings. SEARCH METHODS: The following databases were searched: CENTRAL (Issue 10, 2012), MEDLINE, EMBASE, Science Citation Index, Physician Data Query and the Meta-Register of Controlled Trials in October, 2012. Reference lists of identified studies were searched. The Journal of Neuro Oncology and Neuro-oncology were handsearched from 1999 to 2012 including conference abstracts. We contacted neuro-oncologists regarding ongoing and unpublished trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) where the interventions were the use of temozolomide during primary therapy or for recurrent disease. Comparisons included no chemotherapy, non-temozolomide chemotherapy or different dosing schedules of temozolomide. Patients included those of all ages with histologically proven HGG. DATA COLLECTION AND ANALYSIS: Two review authors undertook the quality assessment and data extraction. Outcome measures included: overall survival (OS); progression-free survival (PFS); quality of life (QoL); and adverse events. MAIN RESULTS: For primary therapy three RCTs were identified, enrolling a total of 745 patients, that investigated temozolomide in combination with radiotherapy versus radiotherapy alone for glioblastoma multiforme (GBM). Temozolomide increased OS (hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.46 to 0.79, P value 0.0003) and increased PFS (HR 0.63, 95% CI 0.43 to 0.92, P value 0.02), when compared with radiotherapy alone, although these benefits only appear to emerge when therapy is given in both concomitant and adjuvant phases of treatment. A single RCT found that temozolomide did not have a statistically significant effect on QoL. Risk of haematological complications, fatigue and infections were increased with temozolomide.In recurrent HGG, two RCTs enrolling 672 patients in total found that temozolomide did not increase OS compared to standard chemotherapy (HR 0.9, 95% CI 0.76 to 1.06, P value 0.2) but it did increase PFS in a subgroup analysis of grade IV GBM tumours (HR 0.68, 95% CI 0.51 to 0.90, P value 0.008). Adverse events were similar between arms.In the elderly, 2 RCTs of 664 patients found OS and PFS was similar with temozolomide alone versus radiotherapy alone. QoL did not appear to differ between arms in a single trial but certain adverse events were significantly more common with temozolomide. AUTHORS' CONCLUSIONS: Temozolomide when given in both concomitant and adjuvant phases is an effective primary therapy in GBM compared to radiotherapy alone. It prolongs survival and delays progression without impacting on QoL but it does increase early adverse events. In recurrent GBM, temozolomide compared with standard chemotherapy improves time-to-progression (TTP) and may have benefits on QoL without increasing adverse events but it does not improve overall. In the elderly, temozolomide alone appears comparable to radiotherapy in terms of OS and PFS but with a higher instance of adverse events. PMID- 23633343 TI - Physical tests for shoulder impingements and local lesions of bursa, tendon or labrum that may accompany impingement. AB - BACKGROUND: Impingement is a common cause of shoulder pain. Impingement mechanisms may occur subacromially (under the coraco-acromial arch) or internally (within the shoulder joint), and a number of secondary pathologies may be associated. These include subacromial-subdeltoid bursitis (inflammation of the subacromial portion of the bursa, the subdeltoid portion, or both), tendinopathy or tears affecting the rotator cuff or the long head of biceps tendon, and glenoid labral damage. Accurate diagnosis based on physical tests would facilitate early optimisation of the clinical management approach. Most people with shoulder pain are diagnosed and managed in the primary care setting. OBJECTIVES: To evaluate the diagnostic accuracy of physical tests for shoulder impingements (subacromial or internal) or local lesions of bursa, rotator cuff or labrum that may accompany impingement, in people whose symptoms and/or history suggest any of these disorders. SEARCH METHODS: We searched electronic databases for primary studies in two stages. In the first stage, we searched MEDLINE, EMBASE, CINAHL, AMED and DARE (all from inception to November 2005). In the second stage, we searched MEDLINE, EMBASE and AMED (2005 to 15 February 2010). Searches were delimited to articles written in English. SELECTION CRITERIA: We considered for inclusion diagnostic test accuracy studies that directly compared the accuracy of one or more physical index tests for shoulder impingement against a reference test in any clinical setting. We considered diagnostic test accuracy studies with cross-sectional or cohort designs (retrospective or prospective), case-control studies and randomised controlled trials. DATA COLLECTION AND ANALYSIS: Two pairs of review authors independently performed study selection, assessed the study quality using QUADAS, and extracted data onto a purpose designed form, noting patient characteristics (including care setting), study design, index tests and reference standard, and the diagnostic 2 x 2 table. We presented information on sensitivities and specificities with 95% confidence intervals (95% CI) for the index tests. Meta-analysis was not performed. MAIN RESULTS: We included 33 studies involving 4002 shoulders in 3852 patients. Although 28 studies were prospective, study quality was still generally poor. Mainly reflecting the use of surgery as a reference test in most studies, all but two studies were judged as not meeting the criteria for having a representative spectrum of patients. However, even these two studies only partly recruited from primary care.The target conditions assessed in the 33 studies were grouped under five main categories: subacromial or internal impingement, rotator cuff tendinopathy or tears, long head of biceps tendinopathy or tears, glenoid labral lesions and multiple undifferentiated target conditions. The majority of studies used arthroscopic surgery as the reference standard. Eight studies utilised reference standards which were potentially applicable to primary care (local anaesthesia, one study; ultrasound, three studies) or the hospital outpatient setting (magnetic resonance imaging, four studies). One study used a variety of reference standards, some applicable to primary care or the hospital outpatient setting. In two of these studies the reference standard used was acceptable for identifying the target condition, but in six it was only partially so. The studies evaluated numerous standard, modified, or combination index tests and 14 novel index tests. There were 170 target condition/index test combinations, but only six instances of any index test being performed and interpreted similarly in two studies. Only two studies of a modified empty can test for full thickness tear of the rotator cuff, and two studies of a modified anterior slide test for type II superior labrum anterior to posterior (SLAP) lesions, were clinically homogenous. Due to the limited number of studies, meta-analyses were considered inappropriate. Sensitivity and specificity estimates from each study are presented on forest plots for the 170 target condition/index test combinations grouped according to target condition. AUTHORS' CONCLUSIONS: There is insufficient evidence upon which to base selection of physical tests for shoulder impingements, and local lesions of bursa, tendon or labrum that may accompany impingement, in primary care. The large body of literature revealed extreme diversity in the performance and interpretation of tests, which hinders synthesis of the evidence and/or clinical applicability. PMID- 23633342 TI - Corticosteroids as adjuvant therapy for ocular toxoplasmosis. AB - BACKGROUND: Ocular infestation with Toxoplasma gondii, a parasite, may result in inflammation in the retina, choroid, and uvea and consequently lead to complications such as glaucoma, cataract, and posterior synechiae. OBJECTIVES: The objective of this systematic review was to assess the effects of adjunctive use of corticosteroids for ocular toxoplasmosis. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to October 2012), EMBASE (January 1980 to October 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to October 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We searched the reference lists of included studies for any additional studies not identified by the electronic searches. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 11 October 2012. SELECTION CRITERIA: We planned to include randomized and quasi randomized controlled trials. Eligible trials would have enrolled participants of any age who were immunocompetent and were diagnosed with active ocular toxoplasmosis. Included trials would have compared anti-parasitic therapy plus corticosteroids versus anti-parasitic therapy alone, or different doses or times of initiation of corticosteroids. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles and abstracts retrieved from the electronic searches. We retrieved full-text articles of studies categorized as 'unsure' or 'include' after review of the abstracts. Two authors independently reviewed each full-text article. Discrepancies were resolved through discussion. MAIN RESULTS: The electronic searches retrieved 368 titles and abstracts. We reviewed 20 full text articles. We identified no trials eligible for inclusion in this systematic review. AUTHORS' CONCLUSIONS: Although research has identified wide variation in practices regarding use of corticosteroids, our systematic review did not identify evidence from randomized controlled trials for the role of corticosteroids in the management of ocular toxoplasmosis. Several questions remain unanswered by well-conducted randomized trials in this context, including whether use of corticosteroids is more effective than use of anti-parasitic therapy alone, when corticosteroids should be initiated in the treatment regimen (early versus late course of treatment), and which dosage and duration of steroid use is best. These questions are easily amenable to research using a randomized controlled design and they are ethical due to the absence of evidence to support or discourage use of corticosteroids for this condition. The question of foremost importance, however, is whether they should be used as adjunct therapy (that is, additional) to anti-parasitic agents. PMID- 23633344 TI - Nebuliser systems for drug delivery in cystic fibrosis. AB - BACKGROUND: Nebuliser systems are used to deliver medications to control the symptoms and the progression of lung disease in people with cystic fibrosis. Many types of nebuliser systems are available for use with various medications; however, there has been no previous systematic review which has evaluated these systems. OBJECTIVES: To evaluate effectiveness, safety, burden of treatment and adherence to nebulised therapy using different nebuliser systems for people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching of relevant journals and abstract books of conference proceedings. We searched the reference lists of each study for additional publications and approached the manufacturers of both nebuliser systems and nebulised medications for published and unpublished data. Date of the most recent search: 15 Oct 2012. SELECTION CRITERIA: Randomised controlled trials or quasi-randomised controlled trials comparing nebuliser systems including conventional nebulisers, vibrating mesh technology systems, adaptive aerosol delivery systems and ultrasonic nebuliser systems. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion. They also independently extracted data and assessed the risk of bias. A third author assessed studies where agreement could not be reached. MAIN RESULTS: The search identified 40 studies with 20 of these (1936 participants) included in the review. These studies compared the delivery of tobramycin, colistin, dornase alfa, hypertonic sodium chloride and other solutions through the different nebuliser systems. This review demonstrates variability in the delivery of medication depending on the nebuliser system used. Conventional nebuliser systems providing higher flows, higher respirable fractions and smaller particles decrease treatment time, increase deposition and may be preferred by people with CF, as compared to conventional nebuliser systems providing lower flows, lower respirable fractions and larger particles. Nebulisers using adaptive aerosol delivery or vibrating mesh technology reduce treatment time to a far greater extent. Deposition (as a percentage of priming dose) is greater than conventional with adaptive aerosol delivery. Vibrating mesh technology systems may give greater deposition than conventional when measuring sputum levels, but lower deposition when measuring serum levels or using gamma scintigraphy. The available data indicate that these newer systems are safe when used with an appropriate priming dose, which may be different to the priming dose used for conventional systems. There is an indication that adherence is maintained or improved with systems which use these newer technologies, but also that some nebuliser systems using vibrating mesh technology may be subject to increased failures. AUTHORS' CONCLUSIONS: Clinicians should be aware of the variability in the performance of different nebuliser systems. Technologies such as adaptive aerosol delivery and vibrating mesh technology have advantages over conventional systems in terms of treatment time, deposition as a percentage of priming dose, patient preference and adherence. There is a need for long-term randomised controlled trials of these technologies to determine patient-focused outcomes (such as quality of life and burden of care), safe and effective dosing levels of medications and clinical outcomes (such as hospitalisations and need for antibiotics) and an economic evaluation of their use. PMID- 23633345 TI - Interventions for acute internal hordeolum. AB - BACKGROUND: Hordeolum is a common, painful inflammation of the eyelid margin that is usually caused by bacterial infection. The infection affects oil glands of the eyelid and can be internal or external. In many cases, the lesion drains spontaneously and resolves untreated; however, the inflammation can spread to other ocular glands or tissues, and recurrences are common. If unresolved, acute internal hordeolum can become chronic or can develop into a chalazion. External hordeola, also known as styes, were not included in the scope of this review. OBJECTIVES: The objective of this review was to investigate the effectiveness and safety of nonsurgical treatments for acute internal hordeolum compared with observation or placebo. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to July 2012), EMBASE (January 1980 to July 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to July 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 26 July 2012. SELECTION CRITERIA: The selection criteria for this review included randomized or quasi-randomized clinical trials of participants diagnosed with acute internal hordeolum. Studies of participants with external hordeolum (stye), chronic hordeolum, or chalazion were excluded. Nonsurgical interventions of interest included the use of hot or warm compresses, lid scrubs, antibiotics, or steroids compared with observation, placebo, or other active interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the references identified by electronic searches for inclusion in this review. No relevant studies were found. The reasons for exclusion were documented. MAIN RESULTS: No trials were identified for inclusion in this review. Most of the references identified from our search reported on external hordeola or chronic internal hordeola. The few references specific to acute internal hordeolum reported mostly recommendations for treatment or were reports of interventional case series, case studies, or other types of observational study designs and were published more than 20 years ago. AUTHORS' CONCLUSIONS: We did not find any evidence for or against the effectiveness of nonsurgical interventions for the treatment of hordeolum. Controlled clinical trials would be useful in determining which interventions are effective for the treatment of acute internal hordeolum. PMID- 23633346 TI - Clinically-indicated replacement versus routine replacement of peripheral venous catheters. AB - BACKGROUND: US Centers for Disease Control guidelines recommend replacement of peripheral intravenous (IV) catheters no more frequently than every 72 to 96 hours. Routine replacement is thought to reduce the risk of phlebitis and bloodstream infection. Catheter insertion is an unpleasant experience for patients and replacement may be unnecessary if the catheter remains functional and there are no signs of inflammation. Costs associated with routine replacement may be considerable. This is an update of a review first published in 2010. OBJECTIVES: To assess the effects of removing peripheral IV catheters when clinically indicated compared with removing and re-siting the catheter routinely. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases (PVD) Group Trials Search Co-ordinator searched the PVD Specialised Register (December 2012) and CENTRAL (2012, Issue 11). We also searched MEDLINE (last searched October 2012) and clinical trials registries. SELECTION CRITERIA: Randomised controlled trials that compared routine removal of peripheral IV catheters with removal only when clinically indicated in hospitalised or community dwelling patients receiving continuous or intermittent infusions. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: Seven trials with a total of 4895 patients were included in the review. Catheter-related bloodstream infection (CRBSI) was assessed in five trials (4806 patients). There was no significant between group difference in the CRBSI rate (clinically-indicated 1/2365; routine change 2/2441). The risk ratio (RR) was 0.61 but the confidence interval (CI) was wide, creating uncertainty around the estimate (95% CI 0.08 to 4.68; P = 0.64). No difference in phlebitis rates was found whether catheters were changed according to clinical indications or routinely (clinically-indicated 186/2365; 3-day change 166/2441; RR 1.14, 95% CI 0.93 to 1.39). This result was unaffected by whether infusion through the catheter was continuous or intermittent. We also analysed the data by number of device days and again no differences between groups were observed (RR 1.03, 95% CI 0.84 to 1.27; P = 0.75). One trial assessed all-cause bloodstream infection. There was no difference in this outcome between the two groups (clinically indicated 4/1593 (0.02%); routine change 9/1690 (0.05%); P = 0.21). Cannulation costs were lower by approximately AUD 7.00 in the clinically-indicated group (mean difference (MD) -6.96, 95% CI -9.05 to -4.86; P <= 0.00001). AUTHORS' CONCLUSIONS: The review found no evidence to support changing catheters every 72 to 96 hours. Consequently, healthcare organisations may consider changing to a policy whereby catheters are changed only if clinically indicated. This would provide significant cost savings and would spare patients the unnecessary pain of routine re-sites in the absence of clinical indications. To minimise peripheral catheter-related complications, the insertion site should be inspected at each shift change and the catheter removed if signs of inflammation, infiltration, or blockage are present. PMID- 23633347 TI - Initial arch wires for tooth alignment during orthodontic treatment with fixed appliances. AB - BACKGROUND: Initial arch wires are the first arch wires to be inserted into the fixed appliance at the beginning of orthodontic treatment and are used mainly for the alignment of teeth by correcting crowding and rotations. With a number of different types of orthodontic arch wires available for initial tooth alignment, it is important to understand which wire is most efficient, as well as which wires cause the least amount of root resorption and pain during the initial aligning stage of treatment. This is an update of the review 'Initial arch wires for alignment of crooked teeth with fixed orthodontic braces' first published in the Cochrane Database of Systematic Reviews 2010, Issue 4. OBJECTIVES: To assess the effects of initial arch wires for alignment of teeth with fixed orthodontic braces in relation to alignment speed, root resorption and pain intensity. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group's Trials Register (to 2 August 2012), CENTRAL (The Cochrane Library 2012, Issue 7), MEDLINE via OVID (1950 to 2 August 2012) and EMBASE via OVID (1980 to 2 August 2012). We also searched the reference lists of relevant articles. There was no restriction with regard to publication status or language of publication. We contacted all authors of included studies to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of initial arch wires to align teeth with fixed orthodontic braces. Only studies involving participants with upper and/or lower full arch fixed orthodontic appliances were included. DATA COLLECTION AND ANALYSIS: Two review authors were responsible for study selection, validity assessment and data extraction. All disagreements were resolved by discussion amongst the review team. Corresponding authors of included studies were contacted to obtain missing information. MAIN RESULTS: Nine RCTs with 571 participants were included in this review. All trials were at high risk of bias and a number of methodological limitations were identified. All trials had at least one potentially confounding factor (such as bracket type, slot size, ligation method, extraction of teeth) which is likely to have influenced the outcome and was not controlled in the trial. None of the trials reported the important adverse outcome of root resorption.Three groups of comparisons were made.(1) Multistrand stainless steel initial arch wires compared to superelastic nickel titanium (NiTi) initial arch wires. There were four trials in this group, with different comparisons and outcomes reported at different times. No meta analysis was possible. There is insufficient evidence from these trials to determine whether or not there is a difference in either rate of alignment or pain between stainless steel and NiTi initial arch wires.(2) Conventional (stabilised) NiTi initial arch wires compared to superelastic NiTi initial arch wires. There were two trials in this group, one reporting the outcome of alignment over 6 months and the other reporting pain over 1 week. There is insufficient evidence from these trials to determine whether or not there is any difference between conventional (stabilised) and superelastic NiTi initial arch wires with regard to either alignment or pain.(3) Single-strand superelastic NiTi initial arch wires compared to other NiTi (coaxial, copper NiTi (CuNiTi) or thermoelastic) initial arch wires. The three trials in this comparison each compared a different product against single-strand superelastic NiTi. There is very weak unreliable evidence, based on one very small study (n = 24) at high risk of bias, that coaxial superelastic NiTi may produce greater tooth movement over 12 weeks, but no information on associated pain or root resorption. This result should be interpreted with caution until further research evidence is available. There is insufficient evidence to determine whether or not there is a difference between either thermoelastic or CuNiTi and superelastic NiTi initial arch wires. AUTHORS' CONCLUSIONS: There is no reliable evidence from the trials included in this review that any specific initial arch wire material is better or worse than another with regard to speed of alignment or pain. There is no evidence at all about the effect of initial arch wire materials on the important adverse effect of root resorption. Further well-designed and conducted, adequately-powered, RCTs are required to determine whether the performance of initial arch wire materials as demonstrated in the laboratory, makes a clinically important difference to the alignment of teeth in the initial stage of orthodontic treatment in patients. PMID- 23633348 TI - Ibuprofen with or without an antiemetic for acute migraine headaches in adults. AB - BACKGROUND: This is an updated version of the original review published in Issue 10, 2010 (Rabbie 2010). Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers do not seek professional help, relying instead on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce symptoms commonly associated with migraine headaches. OBJECTIVES: To determine efficacy and tolerability of ibuprofen, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Relief Database, ClinicalTrials.gov, and reference lists for studies through 22 April 2010 for the original review and to 14 February 2013 for the update. SELECTION CRITERIA: We included randomised, double-blind, placebo- or active-controlled studies using self-administered ibuprofen to treat a migraine headache episode, with at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and number needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment. MAIN RESULTS: No new studies were found for this update. Nine included studies (4373 participants, 5223 attacks) compared ibuprofen with placebo or other active comparators; none combined ibuprofen with a self-administered antiemetic. All studies treated attacks with single doses of medication. For ibuprofen 400 mg versus placebo, NNTs for 2-hour pain-free (26% versus 12% with placebo), 2-hour headache relief (57% versus 25%) and 24-hour sustained headache relief (45% versus 19%) were 7.2, 3.2 and 4.0, respectively. For ibuprofen 200 mg versus placebo, NNTs for 2-hour pain-free (20% versus 10%) and 2-hour headache relief (52% versus 37%) were 9.7 and 6.3, respectively. The higher dose was significantly better than the lower dose for 2-hour headache relief. Soluble formulations of ibuprofen 400 mg were better than standard tablets for 1-hour, but not 2-hour headache relief.Similar numbers of participants experienced adverse events, which were mostly mild and transient, with ibuprofen and placebo.Ibuprofen 400 mg did not differ from rofecoxib 25 mg for 2-hour headache relief or 24-hour headache relief. AUTHORS' CONCLUSIONS: We found no new studies since the last version of this review. Ibuprofen is an effective treatment for acute migraine headaches, providing pain relief in about half of sufferers, but complete relief from pain and associated symptoms for only a minority. NNTs for all efficacy outcomes were better with 400 mg than 200 mg in comparisons with placebo, and soluble formulations provided more rapid relief. Adverse events were mostly mild and transient, occurring at the same rate as with placebo. PMID- 23633349 TI - Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 11, 2010 (Derry 2010). Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce nausea and vomiting, which are commonly associated with migraine. OBJECTIVES: To determine the efficacy and tolerability of paracetamol (acetaminophen), alone or in combination with an antiemetic, compared with placebo and other active interventions in the treatment of acute migraine in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 4 October 2010 for the original review, and to 13 February 2013 for the update. Two clinical trials registers (ClinicalTrials.gov and gsk-clinicalstudyregister.com) were also searched on both occasions. SELECTION CRITERIA: We included randomised, double blind, placebo- or active-controlled studies using self-administered paracetamol to treat a migraine headache episode, with at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared with placebo or other active treatment. MAIN RESULTS: Searches for the update identified one additional study for inclusion. Eleven studies (2942 participants, 5109 attacks) compared paracetamol 1000 mg, alone or in combination with an antiemetic, with placebo or other active comparators, mainly sumatriptan 100 mg. For all efficacy outcomes paracetamol was superior to placebo, with NNTs of 12 (19% response with paracetamol, 10% with placebo), 5.0 (56% response with paracetamol, 36% with placebo) and 5.2 (39% response with paracetamol, 20% with placebo) for 2-hour pain-free and 2- and 1-hour headache relief, respectively, when medication was taken for moderate to severe pain.Paracetamol 1000 mg plus metoclopramide 10 mg was not significantly different from oral sumatriptan 100 mg for 2-hour headache relief; there were no 2-hour pain-free data.Adverse event rates were similar between paracetamol and placebo, and between paracetamol plus metoclopramide and sumatriptan. No serious adverse events occurred with paracetamol alone, but more serious and/or severe adverse events occurred with sumatriptan than with the combination therapy (NNH 32). AUTHORS' CONCLUSIONS: Paracetamol 1000 mg alone is statistically superior to placebo in the treatment of acute migraine, but the NNT of 12 for pain-free response at two hours is inferior to at of other commonly used analgesics. Given the low cost and wide availability of paracetamol, it may be a useful first choice drug for acute migraine in those with contraindications to, or who cannot tolerate, non steroidal anti-inflammatory drugs (NSAIDs) or aspirin. The addition of 10 mg metoclopramide gives short-term efficacy equivalent to oral sumatriptan 100 mg. Adverse events with paracetamol did not differ from placebo; serious and/or severe adverse events were slightly more common with sumatriptan than with paracetamol plus metoclopramide. PMID- 23633350 TI - Aspirin with or without an antiemetic for acute migraine headaches in adults. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 4, 2010 (Kirthi 2010). Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce nausea and vomiting commonly associated with migraine headaches. OBJECTIVES: To determine the efficacy and tolerability of aspirin, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Relief Database, ClinicalTrials.gov, and reference lists for studies through 10 March 2010 for the original review and to 31 January 2013 for the update. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled or active-controlled studies, or both, using aspirin to treat a migraine headache episode, with at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment. MAIN RESULTS: No new studies were found for this update. Thirteen studies (4222 participants) compared aspirin 900 mg or 1000 mg, alone or in combination with metoclopramide 10 mg, with placebo or other active comparators, mainly sumatriptan 50 mg or 100 mg. For all efficacy outcomes, all active treatments were superior to placebo, with NNTs of 8.1, 4.9 and 6.6 for 2 hour pain-free, 2-hour headache relief, and 24-hour headache relief with aspirin alone versus placebo, and 8.8, 3.3 and 6.2 with aspirin plus metoclopramide versus placebo. Sumatriptan 50 mg did not differ from aspirin alone for 2-hour pain-free and headache relief, while sumatriptan 100 mg was better than the combination of aspirin plus metoclopramide for 2-hour pain-free, but not headache relief; there were no data for 24-hour headache relief.Adverse events were mostly mild and transient, occurring slightly more often with aspirin than placebo.Additional metoclopramide significantly reduced nausea (P < 0.00006) and vomiting (P = 0.002) compared with aspirin alone. AUTHORS' CONCLUSIONS: We found no new studies since the last version of this review. Aspirin 1000 mg is an effective treatment for acute migraine headaches, similar to sumatriptan 50 mg or 100 mg. Addition of metoclopramide 10 mg improves relief of nausea and vomiting. Adverse events were mainly mild and transient, and were slightly more common with aspirin than placebo, but less common than with sumatriptan 100 mg. PMID- 23633351 TI - Cholesterol-reducing agents for aneurysmal subarachnoid haemorrhage. AB - BACKGROUND: Cerebral vasospasm and related delayed ischaemic deficits (DIDs) occur in about 17% to 40% of patients with aneurysmal subarachnoid haemorrhage (SAH) and lead to a poor outcome. Cholesterol-reducing agents might improve unfavourable outcomes. OBJECTIVES: To assess the effects of cholesterol-reducing agents for improving outcomes in patients with aneurysmal SAH. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (May 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5), MEDLINE (1948 to May 2012) and EMBASE (1980 to May 2012). We also searched three Chinese databases: SinoMed, CNKI and VIP (May 2012). In an effort to identify further published, ongoing and unpublished trials we searched relevant clinical trials and research registers (May 2012), contacted pharmaceutical companies and investigators known to be involved in previous trials and screened the reference lists of all relevant articles identified. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared cholesterol-reducing agents with control or placebo treatment in participants with aneurysmal SAH. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria, reviewed the relevant trials and extracted data. We did not perform meta-analysis as we only included one RCT in the review. MAIN RESULTS: We included one study in which 39 patients received either simvastatin (80 mg daily; n = 19) or placebo (n = 20) for 14 days. The incidence of DIDs (secondary outcome) was 26% (5/19) in the simvastatin group versus 60% (12/20) in the placebo group (risk ratio (RR) 0.44, 95% confidence interval (CI) 0.19 to 1.01, P = 0.05). This means that, in this study, simvastatin had no effect on DIDs. Two patients in the simvastatin group and one patient in the placebo group had elevated levels of aspartate transaminase or alanine transaminase. One patient in the simvastatin group had a raised creatine phosphokinase. There were no results from this trial for the primary outcome of death or dependency at six months. AUTHORS' CONCLUSIONS: We cannot draw any conclusions about the effectiveness and safety of lowering cholesterol in aneurysmal SAH because of insufficient reliable evidence from only one small trial. More RCTs are needed. PMID- 23633352 TI - Topical nasal steroids for treating nasal polyposis in people with cystic fibrosis. AB - BACKGROUND: Nasal polyps frequently occur in people with cystic fibrosis. Sinus infections have been shown to be a factor in the development of serious chest complications in these people. Nasal polyps have been linked to a higher risk of lower respiratory tract infections with Pseudomonas aeruginosa . Topical nasal steroids are of proven efficacy for treating nasal polyposis in the non-cystic fibrosis population. There is no clear current evidence for the efficacy of topical steroids for nasal polyps in people with cystic fibrosis. OBJECTIVES: To assess the effectiveness of topical nasal steroids for treating symptomatic nasal polyps in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Latest search: 25 January 2013. SELECTION CRITERIA: Randomised and quasi-randomised controlled comparing the effects of topical nasal steroids to placebo in people with nasal polyps with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias in the included trial and extracted data. MAIN RESULTS: One single-centred trial (46 participants) was identified comparing a topical steroid (betamethasone) to placebo. Twenty-two participants received the active drug.Subjective symptom scores, change in polyp size, and side effects were assessed. There was no difference in nasal symptom scores between the treatment and placebo groups. Betamethasone was effective in reducing the size of polyps, but was associated with increased reports of mild side effects, nasal bleeding and discomfort.Risk of bias was high since over 50% of people enrolled did not complete the study. Follow-up of patients was short (six weeks) also reducing the significance of the results for clinical practice. AUTHORS' CONCLUSIONS: This review suggests topical steroids for nasal polyposis in patients with cystic fibrosis have no demonstrable effect on subjective nasal symptom scores. They have some effect in reducing the size of the polyps, but due to the small sample size, poor study completion rates and lack of follow-up, the study is at high risk of bias and evidence for efficacy is limited. Overall there is no clear evidence for using topical steroids in people with cystic fibrosis and nasal polyposis.A well-designed randomised controlled trial of adequate power and long-term follow-up is needed. Validated measures of symptoms and physical findings should be performed and quality of life issues addressed. PMID- 23633353 TI - Somatostatin analogues for pancreatic surgery. AB - BACKGROUND: Pancreatic resections are associated with high morbidity (30% to 60%) and mortality (5%). Synthetic analogues of somatostatin are advocated by some surgeons to reduce complications following pancreatic surgery; however, their use is controversial. OBJECTIVES: To determine whether prophylactic somatostatin analogues should be used routinely in pancreatic surgery. SEARCH METHODS: We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 1), MEDLINE, EMBASE and Science Citation Index Expanded to February 2013. SELECTION CRITERIA: We included randomised controlled trials comparing prophylactic somatostatin or one of its analogues versus no drug or placebo during pancreatic surgery (irrespective of language or publication status). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and independently extracted data. We analysed data with both the fixed-effect and random-effects models using Review Manager (RevMan). We calculated the risk ratio (RR), mean difference (MD) or standardised mean difference (SMD) with 95% confidence intervals (CI) based on an intention-to treat or available case analysis. When it was not possible to perform either of the above, we performed a per protocol analysis. MAIN RESULTS: We identified 21 trials (19 trials of high risk of bias) involving 2348 people. There was no significant difference in the perioperative mortality (RR 0.80; 95% CI 0.56 to 1.16; n = 2210) or the number of people with drug-related adverse effects between the two groups (RR 2.09; 95% CI 0.83 to 5.24; n = 1199). Quality of life was not reported in any of the trials. The overall number of participants with postoperative complications was significantly lower in the somatostatin analogue group (RR 0.70; 95% CI 0.61 to 0.80; n = 1903) but there was no significant difference in the re-operation rate (RR 1.26; 95% CI 0.58 to 2.70; n = 687) or hospital stay (MD -1.29 days; 95% CI -2.60 to 0.03; n = 1314) between the groups. The incidence of pancreatic fistula was lower in the somatostatin analogue group (RR 0.66; 95% CI 0.55 to 0.79; n = 2206). The proportion of these fistulas that were clinically significant was not mentioned in most trials. On inclusion of trials that clearly distinguished clinically significant fistulas, there was no significant difference between the two groups (RR 0.69; 95% CI 0.38 to 1.28; n = 292). AUTHORS' CONCLUSIONS: Somatostatin analogues may reduce perioperative complications but do not reduce perioperative mortality. Further adequately powered trials with low risk of bias are necessary. Based on the current available evidence, somatostatin and its analogues are recommended for routine use in people undergoing pancreatic resection. PMID- 23633354 TI - Cognitive rehabilitation for executive dysfunction in adults with stroke or other adult non-progressive acquired brain damage. AB - BACKGROUND: Executive functions are the controlling mechanisms of the brain and include the processes of planning, initiation, organisation, inhibition, problem solving, self monitoring and error correction. They are essential for goal oriented behaviour and responding to new and novel situations. A high number of people with acquired brain injury, including around 75% of stroke survivors, will experience executive dysfunction. Executive dysfunction reduces capacity to regain independence in activities of daily living (ADL), particularly when alternative movement strategies are necessary to compensate for limb weakness. Improving executive function may lead to increased independence with ADL. There are various cognitive rehabilitation strategies for training executive function used within clinical practice and it is necessary to determine the effectiveness of these interventions. OBJECTIVES: To determine the effects of cognitive rehabilitation on executive dysfunction for adults with stroke or other non progressive acquired brain injuries. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (August 2012), the Cochrane Central Register of Controlled Trials (The Cochrane Library, August 2012), MEDLINE (1950 to August 2012), EMBASE (1980 to August 2012), CINAHL (1982 to August 2012), PsycINFO (1806 to August 2012), AMED (1985 to August 2012) and 11 additional databases. We also searched reference lists and trials registers, handsearched journals and conference proceedings, and contacted experts. SELECTION CRITERIA: We included randomised trials in adults after non-progressive acquired brain injury, where the intervention was specifically targeted at improving cognition including separable executive function data (restorative interventions), where the intervention was aimed at training participants in methods to compensate for lost executive function (compensative interventions) or where the intervention involved the training in the use of an adaptive technique for improving independence with ADL (adaptive interventions). The primary outcome was global executive function and the secondary outcomes were specific components of executive function, working memory, ADL, extended ADL, quality of life and participation in vocational activities. We included studies in which the comparison intervention was no treatment, a placebo intervention (i.e. a rehabilitation intervention that should not impact on executive function), standard care or another cognitive rehabilitation intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts, extracted data and appraised trials. We undertook an assessment of methodological quality for allocation concealment, blinding of outcome assessors, method of dealing with missing data and other potential sources of bias. MAIN RESULTS: Nineteen studies (907 participants) met the inclusion criteria for this review. We included 13 studies (770 participants) in meta-analyses (417 traumatic brain injury, 304 stroke, 49 other acquired brain injury) reducing to 660 participants once non included intervention groups were removed from three and four group studies. We were unable to obtain data from the remaining six studies. Three studies (134 participants) compared cognitive rehabilitation with sensorimotor therapy. None reported our primary outcome; data from one study was available relating to secondary outcomes including concept formation and ADL. Six studies (333 participants) compared cognitive rehabilitation with no treatment or placebo. None reported our primary outcome; data from four studies demonstrated no statistically significant effect of cognitive rehabilitation on secondary outcomes. Ten studies (448 participants) compared two different cognitive rehabilitation approaches. Two studies (82 participants) reported the primary outcome; no statistically significant effect was found. Data from eight studies demonstrated no statistically significant effect on the secondary outcomes. We explored the effect of restorative interventions (10 studies, 468 participants) and compensative interventions (four studies, 128 participants) and found no statistically significant effect compared with other interventions. AUTHORS' CONCLUSIONS: We identified insufficient high-quality evidence to reach any generalised conclusions about the effect of cognitive rehabilitation on executive function, or other secondary outcome measures. Further high-quality research comparing cognitive rehabilitation with no intervention, placebo or sensorimotor interventions is recommended. PMID- 23633355 TI - Multimedia educational interventions for consumers about prescribed and over-the counter medications. AB - BACKGROUND: Health consumers increasingly want access to accurate, evidence-based information about their medications. Currently, education about medications (that is, information that is designed to achieve health or illness related learning) is provided predominantly via spoken communication between the health provider and consumer, sometimes supplemented with written materials. There is evidence, however, that current educational methods are not meeting consumer needs. Multimedia educational programs offer many potential advantages over traditional forms of education delivery. OBJECTIVES: To assess the effects of multimedia patient education interventions about prescribed and over-the-counter medications in people of all ages, including children and carers. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2011, Issue 6), MEDLINE (1950 to June 2011), EMBASE (1974 to June 2011), CINAHL (1982 to June 2011), PsycINFO (1967 to June 2011), ERIC (1966 to June 2011), ProQuest Dissertation & Theses Database (to June 2011) and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of multimedia-based patient education about prescribed or over-the-counter medications in people of all ages, including children and carers, if the intervention had been targeted for their use. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias of included studies. Where possible, we contacted study authors to obtain missing information. MAIN RESULTS: We identified 24 studies that enrolled a total of 8112 participants. However, there was significant heterogeneity in the comparators used and the outcomes measured, which limited the ability to pool data. Many of the studies did not report sufficient information in their methods to allow judgment of their risk of bias. From the information that was reported, three of the studies had a high risk of selection bias and one was at high risk of bias due to lack of blinding of the outcome assessors. None of the included studies reported the minimum clinically important difference for the outcomes that were measured. We have therefore reported results from the studies but have been unable to interpret whether differences were of clinical importance.The main findings of the review are as follows.Knowledge: There is low quality evidence that multimedia education was more effective than usual care (non-standardised education provided as part of usual clinical care) or no education (standardised mean difference (SMD) 1.04, 95% confidence interval (CI) 0.49 to 1.58, six studies with 817 participants). There was considerable statistical heterogeneity (I(2) = 89%), however, all but one of the studies favoured the multimedia group. There is moderate quality evidence that multimedia education was not more effective at improving knowledge than control multimedia interventions (i.e. multimedia programs that do not provide information about the medication) (mean difference (MD) of knowledge scores 2.78%, 95% CI -1.48 to 7.0, two studies with 568 participants). There is moderate quality evidence that multimedia education was more effective when added to a co-intervention (written information or brief standardised instructions provided by a health professional) compared with the co intervention alone (MD of knowledge scores 24.59%, 95% CI 22.34 to 26.83, two studies with 381 participants).Skill acquisition: There is moderate quality evidence that multimedia education was more effective than usual care or no education (MD of inhaler technique score 18.32%, 95% CI 11.92 to 24.73, two studies with 94 participants) and written education (risk ratio (RR) of improved inhaler technique 2.14, 95% CI 1.33 to 3.44, two studies with 164 participants). There is very low quality evidence that multimedia education was equally effective as education by a health professional (MD of inhaler technique score 1.01%, 95% CI -15.75 to 13.72, three studies with 130 participants).Compliance with medications: There is moderate quality evidence that there was no difference between multimedia education and usual care or no education (RR of complying 1.02, 95% CI 0.96 to 1.08, two studies with 4552 participants).We could not determine the effect of multimedia education on other outcomes, including patient satisfaction, self-efficacy and health outcomes, due to an inadequate number of studies from which to draw conclusions. AUTHORS' CONCLUSIONS: This review provides evidence that multimedia education about medications is more effective than usual care (non-standardised education provided by health professionals as part of usual clinical care) or no education, in improving both knowledge and skill acquisition. It also suggests that multimedia education is at least equivalent to other forms of education, including written education and education provided by a health professional. However, this finding is based on often low quality evidence from a small number of trials. Multimedia education about medications could therefore be considered as an adjunct to usual care but there is inadequate evidence to recommend it as a replacement for written education or education by a health professional. Multimedia education may be considered as an alternative to education provided by a health professional, particularly in settings where provision of detailed education by a health professional is not feasible. More studies evaluating multimedia educational interventions are required in order to increase confidence in the estimate of effect of the intervention.Conclusions regarding the effect of multimedia education were limited by the lack of information provided by study authors about the educational interventions, and variability in their content and quality. Studies testing educational interventions should provide detailed information about the interventions and comparators. Research is required to establish a framework that is specific for the evaluation of the quality of multimedia educational programs. Conclusions were also limited by the heterogeneity in the outcomes reported and the instruments used to measure them. Research is required to identify a core set of outcomes which should be measured when evaluating patient educational interventions. Future research should use consistent, reliable and validated outcome measures so that comparisons can be made between studies. PMID- 23633356 TI - Hormonal contraceptives for contraception in overweight or obese women. AB - BACKGROUND: Obesity has reached epidemic proportions around the world. Effectiveness of hormonal contraceptives may be related to metabolic changes in obesity or greater body mass or body fat. Hormonal contraceptives mainly include oral contraceptives, injectables and implants, the transdermal patch, and the vaginal ring. We systematically reviewed the evidence on the effectiveness of hormonal contraceptives among overweight and obese women. OBJECTIVES: To examine the effectiveness of hormonal contraceptives in preventing unplanned pregnancies among women who are overweight or obese versus women of lower weight or body mass index (BMI). SEARCH METHODS: Through January 2013, we searched MEDLINE, CENTRAL, POPLINE, ClinicalTrials.gov, and ICTRP. The previous search also included EMBASE. We contacted investigators to identify other trials. SELECTION CRITERIA: All study designs were eligible. Any type of hormonal contraceptive could have been examined. Reports had to contain information on the specific contraceptive method(s). The primary outcome was pregnancy. Overweight or obese women must have been identified by an analysis cutoff for weight or BMI (kg/m(2)). DATA COLLECTION AND ANALYSIS: Data were abstracted by two authors. Life-table rates were included where available. For dichotomous variables, we computed an odds ratio with 95% confidence interval (CI). We used reported pregnancy rates or relative risk (RR) when those were the only results provided. The main comparisons were between overweight or obese women and women of lower weight or BMI. We assessed the quality of evidence for this review. MAIN RESULTS: We found nine reports with data from 13 trials that included a total of 49,712 women. Five reports from 2002 to 2012 compared BMI groups; of those, one reported a higher pregnancy risk for overweight or obese women. In that trial, women assigned to an oral contraceptive containing norethindrone acetate 1.0 mg plus EE 20 ug and having a BMI at least 25 had greater pregnancy risk compared to those with BMI less than 25 (reported RR 2.49; 95% CI 1.01 to 6.13). The comparisons reported in the other four studies were not significantly different for pregnancy. These included studies of a combined oral contraceptive (COC), a transdermal patch, an implant, and an injectable. The COC study showed no trend by BMI or weight. With the transdermal patch, body weight was associated with pregnancy (reported P < 0.001) but BMI was not. The implant study had one pregnancy and the injectable study reported no pregnancies.Four studies from the 1990s used weight alone rather than BMI. Results were mixed. Studies of a vaginal ring (never marketed) and a six-rod implant showed higher pregnancy rates for women weighing at least 70 kg versus those weighing less than 70 kg (reported P values: 0.0013 and < 0.05, respectively). However, two implant studies showed no trend by body weight. AUTHORS' CONCLUSIONS: The evidence did not generally show an association of BMI with effectiveness of hormonal contraceptives. However, the evidence was limited for any individual contraceptive method. Studies using BMI (rather than weight alone) can provide more information about whether body composition is related to contraceptive effectiveness. The efficacy of subdermal implants and injectable contraceptives may be unaffected by body mass. The contraceptive methods examined here are among the most effective when the recommended regimen is followed.The overall quality of evidence was low for this review. More recent reports provided moderate quality evidence, while the older studies provided evidence of low or very low quality for our purposes. Investigators should consider adjusting for potential confounding related to BMI. Trials should be designed to include sufficient numbers of overweight or obese women to adequately examine effectiveness and side effects of hormonal contraceptives within those groups. PMID- 23633357 TI - Vitamin K supplementation for cystic fibrosis. AB - BACKGROUND: Cystic fibrosis is a genetic disorder which can lead to multiorgan dysfunction. Malabsorption of fat and fat-soluble vitamins (A, D, E, K) may occur and can cause subclinical deficiencies of some of these vitamins. Vitamin K is known to play an important role in both blood coagulation and bone formation. Supplementation with vitamin K appears to be one way of addressing the deficiency, but there is very limited agreement on the appropriate dose and frequency of use of these supplements. OBJECTIVES: To assess the effects of vitamin K supplementation in people with cystic fibrosis and to determine the optimal dose and route of administration of vitamin K for both routine and therapeutic use. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 11 October 2012. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of all preparations of vitamin K used as a supplement compared to either no supplementation (or placebo) at any dose or route and for any duration, in children or adults diagnosed with cystic fibrosis (by sweat test or genetic testing). DATA COLLECTION AND ANALYSIS: Two authors independently screened papers, extracted trial details and assessed their risk of bias. MAIN RESULTS: Two trials (total of 32 participants) were included in the review and were assessed as having a moderate risk of bias. One was a dose-ranging parallel group trial; and the other had a cross-over design, but no separate data were reported for the first intervention period. Neither of the trials addressed any of the primary outcomes (coagulation, bone formation and quality of life). Both trials reported the restoration of serum vitamin K and undercarboxylated osteocalcin levels to the normal range after one month of daily supplementation with 1 mg of vitamin K. AUTHORS' CONCLUSIONS: Evidence from randomised controlled trials on the benefits of routine vitamin K supplementation for people with CF is currently weak and limited to two small trials of short duration. However, no harm was found and until further evidence is available, the present recommendations should be adhered to. PMID- 23633358 TI - Interventions for the prevention of postoperative ear discharge after insertion of ventilation tubes (grommets) in children. AB - BACKGROUND: Grommets are frequently inserted in children's ears for acute otitis media and otitis media with effusion. A common complication is postoperative ear discharge (otorrhoea). A wide range of treatments are used to prevent the discharge, but there is no consensus on whether or not intervention is necessary nor which is the most effective intervention. OBJECTIVES: To assess the effectiveness of prophylactic interventions, both topical and systemic, in reducing the incidence of otorrhoea following the surgical insertion of grommets in children. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 3 July 2012. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared the efficacy of prophylactic interventions against placebo/control and/or with other prophylactic interventions for postoperative otorrhoea in children. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and risk of bias, and extracted data. The outcome data were dichotomous for all the included trials. We calculated individual and pooled risk ratios (RR) using the Mantel Haenszel fixed-effect method. We also calculated the numbers needed to treat to benefit (NNTB). MAIN RESULTS: We found 15 eligible RCTs (2476 children, aged from four months to 17 years). We graded seven RCTs as being at a low risk of bias (n = 926 children) and for an eighth RCT we also graded two of the arms as being at a low risk of bias. We graded the other seven trials as being at a high risk of bias.For a single application at surgery, there was evidence from two low risk of bias trials that at two weeks postoperatively the risk of otorrhoea was reduced by multiple saline washouts (from 30% to 16%; RR 0.52, 95% confidence interval (CI) 0.27 to 1.00; NNTB 7; one RCT; 140 children) and antibiotic/steroid ear drops (from 9% to 1%; RR 0.13, 95% CI 0.03 to 0.57; NNTB 13; one RCT; 322 ears). A meta-analysis of two low risk of bias trials (222 ears) failed to find an effect of a single application of antibiotic/steroid ear drops at four to six weeks postoperatively.For a prolonged application of an intervention, there was evidence from four low risk of bias trials that the risk of otorrhoea was reduced two weeks postoperatively by antibiotic ear drops (from 15% to 8%; RR 0.54, 95% CI 0.30 to 0.97; NNTB 15; one RCT; 372 children), antibiotic/steroid ear drops (from 39% to 5%; RR 0.13, 95% CI 0.05 to 0.31; NNTB 3; one RCT; 200 children), aminoglycoside/steroid ear drops (from 15% to 5%; RR 0.37, 95% CI 0.18 to 0.74; NNTB 11; one RCT; 356 children) or oral antibacterial agents/steroids (from 39% to 5%; RR 0.13, 95% CI 0.03 to 0.51; NNTB 3; one RCT; 77 children).Only one trial assessed the secondary outcome of ototoxicity, but no effect was found. There were no trials that assessed quality of life. AUTHORS' CONCLUSIONS: Our review found that each of the following were effective at reducing the rate of otorrhoea up to two weeks following surgery: (1) multiple saline washouts at surgery, (2) a single application of topical antibiotic/steroid drops at surgery, (3) a prolonged application of topical drops (namely antibiotic ear drops, antibiotic/steroid eardrops or aminoglycoside/steroid ear drops) and (4) a prolonged application of oral antibacterial agents/steroids. However, the rate of otorrhoea between RCTs varied greatly and the higher the rates of otorrhoea within a RCT, the smaller the NNTB for therapy.We conclude that if a surgeon has a high rate of postoperative otorrhoea in children then either saline irrigation or antibiotic ear drops at the time of surgery would significantly reduce that rate. If topical drops are chosen, it is suggested that to reduce the cost and potential for ototoxic damage this be a single application at the time of surgery and not prolonged thereafter. PMID- 23633359 TI - Conservative interventions for treating diaphyseal fractures of the forearm bones in children. AB - BACKGROUND: Diaphyseal forearm fractures in children are common injuries, the vast majority of which are treated conservatively. There is a need to assess the role of modifiable factors such as techniques of reduction and casting in order to optimise functional recovery. OBJECTIVES: To assess the effects of different conservative interventions for diaphyseal forearm fractures in children, including adolescents. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (to November 2012), the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2012 Issue 11), MEDLINE (1950 to November 2012), EMBASE (1980 to November 2012), CINAHL (1982 to November 2012), trial registries (to November 2012), conference proceedings and reference lists of articles. SELECTION CRITERIA: Randomised or quasi-randomised trials comparing conservative interventions for diaphyseal forearm fractures in children were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently examined search results to identify eligible trials. MAIN RESULTS: After screening 493 citations, 17 potentially eligible studies were identified. Of these 13 studies were excluded, two studies, both reported incompletely in conference abstracts only, await assessment and two are ongoing trials whose recruitment status is unknown. AUTHORS' CONCLUSIONS: This review found no usable evidence from randomised trials to make recommendations concerning different conservative interventions for the treatment of diaphyseal fractures of the forearm bones in children. Publication in full of trials that have already been performed on this topic would be a useful start to changing this unsatisfactory situation. PMID- 23633360 TI - Diclofenac with or without an antiemetic for acute migraine headaches in adults. AB - BACKGROUND: This review is an update of a previously published review in Issue 2, 2012 (Derry 2012a). Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter (OTC) analgesics. Diclofenac is an established analgesic, and new formulations using the potassium or epolamine salts, which can be dissolved in water, have been developed for rapid absorption, which may be beneficial in acute migraine. Co-therapy with an antiemetic should help to reduce the nausea and vomiting commonly associated with migraine. OBJECTIVES: To determine the efficacy and tolerability of diclofenac, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Relief Database, ClinicalTrials.gov, and reference lists for studies through 27 September 2011 for the original review and 15 February 2013 for the update. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled or active-controlled studies, or both, using self administered diclofenac to treat a migraine headache episode, with at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate relative risk (or 'risk ratio') and numbers needed to treat to benefit (NNT) or harm (NNH) compared to placebo or a different active treatment. MAIN RESULTS: Five studies (1356 participants, 2711 attacks) compared oral diclofenac with placebo, and one also compared it with sumatriptan; none combined diclofenac with a self administered antiemetic. Four studies treated attacks with single doses of medication, and two allowed an optional second dose for inadequate response. Only two studies, with three active treatment arms, provided data for pooled analysis of primary outcomes. For single doses of diclofenac potassium 50 mg versus placebo (two studies), the NNTs were 6.2, 8.9, and 9.5 for pain-free at two hours, headache relief at two hours, and pain-free responses at 24 hours, respectively.Similar numbers of participants experienced adverse events, which were mostly mild and transient, with diclofenac and placebo.There were insufficient data to evaluate other doses of oral diclofenac, or to compare different formulations or different dosing regimens; only one study compared oral diclofenac with an active comparator (oral sumatriptan 100 mg). AUTHORS' CONCLUSIONS: Oral diclofenac potassium 50 mg is an effective treatment for acute migraine, providing relief from pain and associated symptoms, although only a minority of patients experience pain-free responses. Adverse events are mostly mild and transient and occur at the same rate as with placebo. PMID- 23633361 TI - Physical exercise training interventions for children and young adults during and after treatment for childhood cancer. AB - BACKGROUND: A decreased physical fitness and impaired social functioning has been reported in patients and survivors of childhood cancer. This is influenced by the negative effects of disease and treatment of childhood cancer and by behavioural and social elements. Exercise training for adults during or after cancer therapy has frequently been reported to improve physical fitness and social functioning. More recently, literature on this subject became available for children and young adults with cancer, both during and after treatment. OBJECTIVES: This review aimed to evaluate the effect of a physical exercise training intervention (at home, at a physical therapy centre, or hospital based) on the physical fitness of children with cancer, in comparison with the physical fitness in a care as usual control group. The intervention needed to be offered within the first five years from diagnosis.The second aim was to assess the effects of a physical exercise training intervention in this population on fatigue, anxiety, depression, self efficacy, and health-related quality of life and to assess the adverse effects of the intervention. SEARCH METHODS: For this review the electronic databases of CENTRAL, MEDLINE, EMBASE, CINAHL, PEDro, and ongoing trial registries were searched on 6 September 2011. In addition, a handsearch of reference lists and conference proceedings was performed in that same month. SELECTION CRITERIA: The review included randomised controlled trials (RCTs) and clinical controlled trials (CCTs) that compared the effects of physical exercise training with no training, in people who were within the first five years of their diagnosis of childhood cancer. DATA COLLECTION AND ANALYSIS: By the use of standardised forms two review authors independently identified studies meeting the inclusion criteria, performed the data extraction, and assessed the risk of bias. Quality of the studies was rated by using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) criteria. MAIN RESULTS: Five articles were included in this review: four RCTs (14, 14, 28, and 51 participants) and one CCT (24 participants). In total 131 participants (74 boys, 54 girls, three unknown) were included in the analysis, all being treated for childhood acute lymphoblastic leukaemia (ALL). The study interventions were all implemented during chemotherapy treatment.The duration of the training sessions ranged from 15 to 60 minutes per session. Both the type of intervention, as well as the intervention period, which ranged from 10 weeks to two years, varied in all the included studies. In all included studies the control group received care as usual.All studies had methodological limitations, such as small numbers of participants, unclear randomisation methods, and single-blind study designs in case of an RCT.Cardiorespiratory fitness was studied by the use of the nine minute run-walk test, the timed up-and-down stairs test, and the 20-m shuttle run test. Only the up-and-down stairs test showed significant differences between the intervention and the control group, in favour of the intervention group (P value = 0.05, no further information available).Bone mineral density was assessed in one study, in which a statistically significant difference in favour of the exercise group was identified (standardised mean difference (SMD) 1.07; 95% confidence interval (CI) 0.48 to 1.66; P value < 0.001). Body mass index was assessed in two studies. The pooled data on this item did not show a statistically significant difference between the intervention and control study group.Flexibility was assessed in three studies. In one study the active ankle dorsiflexion method was used to assess flexibility and the second study they used the passive ankle dorsiflexion test. No statistically significant difference between the intervention and control group was identified with the active ankle dorsiflexion test, whereas with the passive test method a statistically significant difference in favour of the exercise group was found (SMD 0.69; 95% CI 0.12 to 1.25; P value = 0.02). The third study assessed body flexibility by the use of the sit-and-reach distance test; no statistically significant difference between the intervention and control group was identified.One study assessed the effects of an inspiratory muscle training programme aimed to train the lung muscles and increase physical fitness. This study reported no significant effect on either inspiratory or expiratory muscle strength. Two other studies using either knee and ankle strength changes by hand-held dynamometry or the number of completed push-ups (with knees on the ground) and a peripheral quantitative computed tomography of the tibia to determine the muscle mass did not identify statistically significant differences in muscle strength/endurance.The level of daily activity, health-related quality of life, fatigue, and adverse events were assessed in one study only; for all these items no statistically significant differences between the intervention and control group were found.None of the included studies evaluated the outcomes activity energy expenditure, time spent exercising, anxiety and depression, or self efficacy. AUTHORS' CONCLUSIONS: The effects of physical exercise training interventions for childhood cancer participants are not yet convincing due to small numbers of participants and insufficient study methodology. Despite that, first results show a trend towards an improved physical fitness in the intervention group compared to the control group. Changes in physical fitness were seen by improved body composition, flexibility, and cardiorespiratory fitness. However, the evidence is limited and these positive effects were not found for the other assessed outcomes, such as muscle strength/endurance, the level of daily activity, health-related quality of life, and fatigue. There is a need for more studies with comparable aims and interventions, using higher numbers of participants and for studies with another childhood cancer population than ALL only. PMID- 23633363 TI - Phyllanthus species versus antiviral drugs for chronic hepatitis B virus infection. AB - BACKGROUND: Phyllanthus species for patients with chronic hepatitis B virus (HBV) infection have been assessed in clinical trials, but no consensus regarding their usefulness exists. When compared with placebo or no intervention, we were unable to identify convincing evidence that phyllanthus species are beneficial in patients with chronic hepatitis B. Some randomised clinical trials have compared phyllanthus species versus antiviral drugs. OBJECTIVES: To evaluate the benefits and harms of phyllanthus species compared with antiviral drugs for patients with chronic HBV infection. SEARCH METHODS: Searches were performed in The Cochrane Hepato-Biliary Gorup Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expended, and the Chinese Biomedical CD Database, China Network Knowledge Information, Chinese Science Journal Database, TCM Online, and Wanfang Database. Conference proceedings in Chinese were handsearched. All searches were conducted until 31st October 2012. SELECTION CRITERIA: Randomised clinical trials comparing phyllanthus species with antiviral drugs for patients with chronic HBV infection. We included trials irrespective of blinding, publication status, or language. DATA COLLECTION AND ANALYSIS: Two authors selected the trials and extracted the data independently. The RevMan software was used for statistical analysis of dichotomous data with risk ratio (RR) with 95% confidence intervals (CI). We assessed the risk of bias to control for systematic errors. We calculated the number of patients needed (required information size) to be randomised in order to make reliable conclusions. We assessed the cumulative findings with trial sequential analysis to control for random errors. MAIN RESULTS: We identified five randomised clinical trials with 290 patients. All trials were considered to have high risk of bias. Patients in the experimental group received compound phyllanthus for three months to 12 months. Patients in the antiviral drug group received lamivudine, interferon alpha, thymosin, or thymosin alpha 1. None of the trials reported mortality, hepatitis B-related morbidity, quality of life, or liver histology. Phyllanthus seemed to have a superior effect on clearance of serum HBeAg at the end of treatment in conventional meta-analysis (RR 0.76; 95% CI 0.64 to 0.91, P = 0.002; I(2) = 0%), but not when trial sequential analysis was applied. Phyllanthus had no significant effect on clearance of serum HBsAg (RR 1.00; 95% CI 0.93 to 1.08, P = 0.92; I(2) = 0%) or HBV DNA (RR 0.83; 95% CI 0.53 to 1.31, P = 0.43; I(2) = 70%) when compared with antiviral drugs. Data on HBeAg seroconversion was reported in one trial and no significant difference was found comparing phyllanthus versus lamivudine (RR 0.89; 95% CI 0.71 to 1.11). No data were reported on adverse events in the five trials. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to support or refute the use of phyllanthus for patients with chronic hepatitis B virus infection. Researchers who are interested in conducting further randomised clinical trials on phyllanthus ought to monitor both beneficial and harmful effects and should primarily test the herb against placebo in addition to antiviral drugs that are known to offer more benefit than harm. Only in this way new interventions can be assessed without compromising personal ethical considerations. PMID- 23633364 TI - Sulphonylurea monotherapy for patients with type 2 diabetes mellitus. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a growing health problem worldwide. Whether sulphonylureas show better, equal or worse therapeutic effects in comparison with other antidiabetic interventions for patients with T2DM remains controversial. OBJECTIVES: To assess the effects of sulphonylurea monotherapy versus placebo, no intervention or other antidiabetic interventions for patients with T2DM. SEARCH METHODS: We searched publications in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS and CINAHL (all until August 2011) to obtain trials fulfilling the inclusion criteria for our review. SELECTION CRITERIA: We included clinical trials that randomised patients 18 years old or more with T2DM to sulphonylurea monotherapy with a duration of 24 weeks or more. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias. The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes were other patient-important outcomes and metabolic variables. Where possible, we used risk ratios (RR) with 95% confidence intervals (95% CI) to analyse the treatment effect of dichotomous outcomes. We used mean differences with 95% CI to analyse the treatment effect of continuous outcomes. We evaluated the risk of bias. We conducted trial sequential analyses to assess whether firm evidence could be established for a 10% relative risk reduction (RRR) between intervention groups. MAIN RESULTS: We included 72 randomised controlled trials (RCTs) with 22,589 participants; 9707 participants randomised to sulphonylureas versus 12,805 participants randomised to control interventions. The duration of the interventions varied from 24 weeks to 10.7 years. We judged none of the included trials as low risk of bias for all bias domains. Patient important outcomes were seldom reported.First-generation sulphonylureas (FGS) versus placebo or insulin did not show statistical significance for all-cause mortality (versus placebo: RR 1.46, 95% CI 0.87 to 2.45; P = 0.15; 2 trials; 553 participants; high risk of bias (HRB); versus insulin: RR 1.18, 95% CI 0.88 to 1.59; P = 0.26; 2 trials; 1944 participants; HRB). FGS versus placebo showed statistical significance for cardiovascular mortality in favour of placebo (RR 2.63, 95% CI 1.32 to 5.22; P = 0.006; 2 trials; 553 participants; HRB). FGS versus insulin did not show statistical significance for cardiovascular mortality (RR 1.36, 95% CI 0.68 to 2.71; P = 0.39; 2 trials; 1944 participants; HRB). FGS versus alpha-glucosidase inhibitors showed statistical significance in favour of FGS for adverse events (RR 0.63, 95% CI 0.52 to 0.76; P = 0.01; 2 trials; 246 participants; HRB) and for drop-outs due to adverse events (RR 0.28, 95% CI 0.12 to 0.67; P = 0.004; 2 trials; 246 participants; HRB).Second-generation sulphonylureas (SGS) versus metformin (RR 0.98, 95% CI 0.61 to 1.58; P = 0.68; 6 trials; 3528 participants; HRB), thiazolidinediones (RR 0.92, 95% CI 0.60 to 1.41; P = 0.70; 7 trials; 4955 participants; HRB), insulin (RR 0.96, 95% CI 0.79 to 1.18; P = 0.72; 4 trials; 1642 participants; HRB), meglitinides (RR 1.44, 95% CI 0.47 to 4.42; P = 0.52; 7 trials; 2038 participants; HRB), or incretin-based interventions (RR 1.39, 95% CI 0.52 to 3.68; P = 0.51; 2 trials; 1503 participants; HRB) showed no statistically significant effects regarding all cause mortality in a random-effects model. SGS versus metformin (RR 1.47; 95% CI 0.54 to 4.01; P = 0.45; 6 trials; 3528 participants; HRB), thiazolidinediones (RR 1.30, 95% CI 0.55 to 3.07; P = 0.55; 7 trials; 4955 participants; HRB), insulin (RR 0.96, 95% CI 0.73 to 1.28; P = 0.80; 4 trials; 1642 participants; HRB) or meglitinide (RR 0.97, 95% CI 0.27 to 3.53; P = 0.97; 7 trials, 2038 participants, HRB) showed no statistically significant effects regarding cardiovascular mortality. Mortality data for the SGS versus placebo were sparse. SGS versus thiazolidinediones and meglitinides did not show statistically significant differences for a composite of non-fatal macrovascular outcomes. SGS versus metformin showed statistical significance in favour of SGS for a composite of non fatal macrovascular outcomes (RR 0.67, 95% CI 0.48 to 0.93; P = 0.02; 3018 participants; 3 trials; HRB). The definition of non-fatal macrovascular outcomes varied among the trials. SGS versus metformin, thiazolidinediones and meglitinides showed no statistical significance for non-fatal myocardial infarction. No meta-analyses could be performed for microvascular outcomes. SGS versus placebo, metformin, thiazolidinediones, alpha-glucosidase inhibitors or meglitinides showed no statistical significance for adverse events. SGS versus alpha-glucosidase inhibitors showed statistical significance in favour of SGS for drop-outs due to adverse events (RR 0.48, 95% CI 0.24 to 0.96; P = 0.04; 9 trials; 870 participants; HRB). SGS versus meglitinides showed no statistical significance for the risk of severe hypoglycaemia. SGS versus metformin and thiazolidinediones showed statistical significance in favour of metformin (RR 5.64, 95% CI 1.22 to 26.00; P = 0.03; 4 trials; 3637 participants; HRB) and thiazolidinediones (RR 6.11, 95% CI 1.57 to 23.79; P = 0.009; 6 trials; 5660 participants; HRB) for severe hypoglycaemia.Third-generation sulphonylureas (TGS) could not be included in any meta-analysis of all-cause mortality, cardiovascular mortality or non-fatal macro- or microvascular outcomes. TGS versus thiazolidinediones showed statistical significance regarding adverse events in favour of TGS (RR 0.88, 95% CI 0.78 to 0.99; P = 0.03; 3 trials; 510 participants; HRB). TGS versus thiazolidinediones did not show any statistical significance for drop-outs due to adverse events. TGS versus other comparators could not be performed due to lack of data.For the comparison of SGS versus FGS no meta-analyses of all-cause mortality, cardiovascular mortality, non-fatal macro- or microvascular outcomes, or adverse events could be performed.Health related quality of life and costs of intervention could not be meta-analysed due to lack of data.In trial sequential analysis, none of the analyses of mortality outcomes, vascular outcomes or severe hypoglycaemia met the criteria for firm evidence of a RRR of 10% between interventions. AUTHORS' CONCLUSIONS: There is insufficient evidence from RCTs to support the decision as to whether to initiate sulphonylurea monotherapy. Data on patient-important outcomes are lacking. Therefore, large-scale and long-term randomised clinical trials with low risk of bias, focusing on patient-important outcomes are required. PMID- 23633365 TI - Interventions for hiring, retaining and training district health systems managers in low- and middle-income countries. AB - BACKGROUND: District managers are playing an increasingly important role in determining the performance of health systems in low- and middle-income countries as a result of decentralization. OBJECTIVES: To assess the effectiveness of interventions to hire, retain and train district health systems managers in low- and middle-income countries. SEARCH METHODS: We searched a wide range of international databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. We also searched online resources of international agencies, including the World Bank, to find relevant grey literature. Searches were conducted in December 2011. SELECTION CRITERIA: District health systems managers are those persons who are responsible for overseeing the operations of the health system within a defined, subnational geographical area that is designated as a district. Hiring and retention interventions include those that aim to increase the attractiveness of district management positions, as well as those related to hiring and retention processes, such as private contracting. Training interventions include education programs to develop future managers and on-the-job training programs for current managers. To be included, studies needed to use one of the following study designs: randomized controlled trial, nonrandomized controlled trial, controlled before-and-after study, and interrupted time series analysis. DATA COLLECTION AND ANALYSIS: We report measures of effect in the same way that the primary study authors have reported them. Due to the varied nature of interventions included in this review we could not pool data across studies. MAIN RESULTS: Two studies met our inclusion criteria. The findings of one study conducted in Cambodia provide low quality evidence that private contracts with international nongovernmental organizations (NGOs) for district health systems management ('contracting-in') may improve health care access and utilization. Contracting-in increased use of antenatal care by 28% and use of public facilities by 14%. However, contracting in was not found to have an effect on population health outcomes. The findings of the other study provide low quality evidence that intermittent training courses over 18 months may improve district health system managers' performance. In three countries in Latin America, managers who did not receive the intermittent training courses had between 2.4 and 8.3 times more management deficiencies than managers who received the training courses. No studies that aimed to investigate interventions for retaining district health systems managers met our study selection criteria for inclusion in this review. AUTHORS' CONCLUSIONS: There is low quality evidence that contracting-in may improve health care accessibility and utilization and that intermittent training courses may improve district health systems managers' performance. More evidence is required before firm conclusions can be drawn regarding the effectiveness of these interventions in diverse settings. Other interventions that might be promising candidates for hiring and retaining (e.g., government regulations, professional support programs) as well as training district health systems managers (e.g., in-service workshops with on-site support) have not been adequately investigated. PMID- 23633366 TI - Pharmacological interventions for self-injurious behaviour in adults with intellectual disabilities. AB - BACKGROUND: Self-injurious behaviour among people with intellectual disability is relatively common and often persistent. Self-injurious behaviour continues to present a challenge to clinicians. It remains poorly understood and difficult to ameliorate despite advances in neurobiology and psychological therapies. There is a strong need for a better evidence base in prescribing and monitoring of drugs in this population, especially since none of the drugs are actually licensed for self-injurious behaviour. OBJECTIVES: To determine clinical effectiveness of pharmacological interventions in management of self-injurious behaviour in adults with intellectual disability. SEARCH METHODS: We searched the following databases on 19 February 2012: CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, Science Citation Index, Social Science Citation Index, Conference Proceedings Citation Index - Science, Conference Proceedings Citation Index - Social Science and Humanities, ZETOC and WorldCat. We also searched ClinicalTrials.gov, ICTRP and the reference lists of included trials. SELECTION CRITERIA: We included randomised controlled trials that examined drug interventions versus placebo for self-injurious behaviour (SIB) in adults with intellectual disability. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias for each trial using a data extraction form. We present a narrative summary of the results is presented. We did not consider meta-analysis was appropriate due to differences in study designs, differences between interventions and heterogeneous outcome measures. MAIN RESULTS: We found five double-blind placebo controlled trials that met our inclusion criteria. These trials assessed effectiveness and safety of drugs in a total of 50 people with intellectual disability demonstrating SIB. Four trials compared the effects of naltrexone versus placebo and one trial compared clomipramine versus placebo.One of the naltrexone versus placebo trials reported that naltrexone had clinically significant effects (>= 33% reduction) on the daily rates of three of the four participants' most severe form of SIB and modest to substantial reductions in SIB for all participants; however, this study did not report on statistical significance. Another trial reported that naltrexone attenuated SIB in all four participants, with 25 mg and 50 mg doses producing a statistically significant decrease in SIB (P value < 0.05). Another trial (eight people) indicated that naltrexone administration was associated with significantly fewer days of high frequency self injury and significantly more days with low frequency self injury. Naltrexone had different effects depending on the form and location of self injury. Another trial with only 26 participants found that neither single-dose (100 mg) nor long-term (50 and 150 mg) naltrexone treatment had any therapeutic effect on SIB.Comparison of clomipramine versus placebo found no statistically significant benefit for any outcome measure, which included SIB rate and intensity, stereotypy and adverse events. However, it showed clinically significant improvement in the rate and intensity of SIB and stereotypy.There were very few noteworthy adverse events to report in any of the four trials in which these were reported.All trials were at high risk of bias, apart from one trial (Lewis 1996), which was probably at low risk of bias. The short period of follow-up was a significant drawback in the design of all five trials, as it did not allow long-term assessment of behaviour over time.We were unable to examine the efficacy of antidepressants other than clomipramine, antipsychotics, mood stabilisers or beta-blockers as we did not identify any relevant placebo controlled trials. AUTHORS' CONCLUSIONS: There was weak evidence in included trials that any active drug was more effective than placebo for people with intellectual disability demonstrating SIB. Due to sparse data, an absence of power and statistical significance, and high risk of bias for four of the included trials, we are unable to reach any definite conclusions about the relative benefits of naltrexone or clomipramine compared to placebo. PMID- 23633368 TI - Workplace pedometer interventions for increasing physical activity. AB - BACKGROUND: The World Health Organization and the World Economic Forum have recommended further research to strengthen current knowledge of workplace health programmes, particularly on effectiveness and using simple instruments. A pedometer is one such simple instrument that can be incorporated in workplace interventions. OBJECTIVES: To assess the effectiveness of pedometer interventions in the workplace for increasing physical activity and improving subsequent health outcomes. SEARCH METHODS: Electronic searches of the Cochrane Central Register of Controlled Trials (671 potential papers), MEDLINE (1001), Embase (965), CINAHL (1262), OSH UPDATE databases (75) and Web of Science (1154) from the earliest record to between 30th January and 6th February 2012 yielded 3248 unique records. Reference lists of articles yielded an additional 34 papers. Contact with individuals and organisations did not produce any further records. SELECTION CRITERIA: We included individual and cluster-randomised controlled trials of workplace health promotion interventions with a pedometer component in employed adults. The primary outcome was physical activity and was part of the eligibility criteria. We considered subsequent health outcomes, including adverse effects, as secondary outcomes. DATA COLLECTION AND ANALYSIS: Two review authors undertook the screening of titles and abstracts and the full-text papers independently. Two review authors (RFP and MC) independently completed data extraction and risk of bias assessment. We contacted authors to obtain additional data and clarification. MAIN RESULTS: We found four relevant studies providing data for 1809 employees, 60% of whom were allocated to the intervention group. All studies assessed outcomes immediately after the intervention had finished and the intervention duration varied between three to six months. All studies had usual treatment control conditions; however one study's usual treatment was an alternative physical activity programme while the other three had minimally active controls. In general, there was high risk of bias mainly due to lack of blinding, self reported outcome measurement, incomplete outcome data due to attrition, and most of the studies had not published protocols, which increases the likelihood of selective reporting.Three studies compared the pedometer programme to a minimally active control group, but the results for physical activity could not be combined because each study used a different measure of activity. One study observed an increase in physical activity under a pedometer programme, but the other two did not find a significant difference. For secondary outcomes we found improvements in body mass index, waist circumference, fasting plasma glucose, the quality of life mental component and worksite injury associated with the pedometer programmes, but these results were based on limited data from one or two small studies. There were no differences between the pedometer programme and the control group for blood pressure, a number of biochemical outcomes and the quality of life physical component. Sedentary behaviour and disease risk scores were not measured by any of the included studies.One study compared a pedometer programme and an alternative physical activity programme, but baseline imbalances made it difficult to distinguish the true improvements associated with either programme.Overall, there was insufficient evidence to assess the effectiveness of pedometer interventions in the workplace.There is a need for more high quality randomised controlled trials to assess the effectiveness of pedometer interventions in the workplace for increasing physical activity and improving subsequent health outcomes. To improve the quality of the evidence available, future studies should be registered in an online trials register, publish a protocol, allocate time and financial support to reducing attrition, and try to blind personnel (especially those who undertake measurement). To better identify the effects of pedometer interventions, future studies should report a core set of outcomes (total physical activity in METs, total time sitting in hours and minutes, objectively measured cardiovascular disease and type II diabetes risk factors, quality of life and injury), assess outcomes in the long term and undertake subgroup analyses based upon demographic subgroups (e.g. age, gender, educational status). Future studies should also compare different types of active intervention to test specific intervention components (eligibility, duration, step goal, step diary, settings), and settings (occupation, intervention provider). AUTHORS' CONCLUSIONS: There was limited and low quality data providing insufficient evidence to assess the effectiveness of pedometer interventions in the workplace for increasing physical activity and improving subsequent health outcomes. PMID- 23633369 TI - Biopsy versus resection for the management of low-grade gliomas. AB - BACKGROUND: Low-grade gliomas (LGG) constitute a class of slow-growing primary brain neoplasms. Patients with clinically and radiographically suspected LGG have two initial surgical options, biopsy or resection. Biopsy can provide a histological diagnosis with minimal risk but does not offer a direct treatment. Resection may have additional benefits such as increasing survival and delaying recurrence, but is associated with a higher risk for surgical morbidity. There remains controversy about the role of biopsy versus resection and the relative clinical outcomes for the management of LGG. OBJECTIVES: To assess the clinical effectiveness of biopsy compared to surgical resection in patients with a new lesion suspected to be a LGG. SEARCH METHODS: The following electronic databases were searched: Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 11), MEDLINE (1950 to week 3 November 2012), EMBASE (1980 to Week 46 2012). Unpublished and grey literature including Metaregister, Physicians Data Query, www.controlled-trials.com/rct, www.clinicaltrials.gov, and www.cancer.gov/clinicaltrials were also queried for ongoing trials. SELECTION CRITERIA: Patients of any age with a suspected intracranial LGG receiving biopsy or resection within a randomized clinical trial (RCT) or controlled clinical trial (CCT) were included. Patients with prior resections, radiation therapy, or chemotherapy for LGG were excluded. Outcome measures included overall survival (OS), progression free survival (PFS), functionally independent survival (FIS), adverse events, symptom control, and quality of life (QoL). DATA COLLECTION AND ANALYSIS: A total of 2764 citations were searched and critically analyzed for relevance. This effort was undertaken by three independent review authors. MAIN RESULTS: No RCTs of biopsy or resection for LGG were identified. Twenty other studies were retrieved for analysis based on pre-specified selection criteria. Ten studies were retrospective or literature reviews. Three studies were prospective but were limited to tumor recurrence or the extent of resection. One study was a population-based parallel cohort and not an RCT. Four studies were RCTs, however patients were randomized with respect to varying radiotherapy regimens to assess timing and dose of radiation. One RCT was focused on high grade gliomas and not LGG. One last RCT evaluated diffusion tensor imaging (DTI) based neuro-navigation for surgical resection. AUTHORS' CONCLUSIONS: Currently there are no randomized clinical trials or controlled clinical trials available on which to base clinical decisions. Therefore, physicians must approach each case individually and weigh the risks and benefits of each intervention until further evidence is available. Future research could focus on randomized clinical trials to determine outcomes benefits for biopsy versus resection. PMID- 23633367 TI - Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples. AB - BACKGROUND: Antiretroviral drugs have been shown to reduce risk of mother-to child transmission of human immunodeficiency virus (HIV) and are also widely used for post-exposure prophylaxis for parenteral and sexual exposures. Sexual transmission may be lower in couples in which one partner is infected with HIV and the other is not and the infected partner is on antiretroviral therapy (ART). OBJECTIVES: To determine if ART use in an HIV-infected member of an HIV discordant couple is associated with lower risk of HIV transmission to the uninfected partner compared to untreated discordant couples. SEARCH METHODS: We used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language. SELECTION CRITERIA: Randomised controlled trials (RCT), cohort studies and case-control studies of HIV-discordant couples in which the HIV-infected member of the couple was being treated or not treated with ART DATA COLLECTION AND ANALYSIS: Abstracts of all trials identified by electronic or bibliographic scanning were examined independently by two authors. We initially identified 3,833 references and examined 87 in detail for study eligibility. Data were abstracted independently using a standardised abstraction form. MAIN RESULTS: One RCT and nine observational studies were included in the review. These ten studies identified 2,112 episodes of HIV transmission, 1,016 among treated couples and 1,096 among untreated couples. The rate ratio for the single randomised controlled trial was 0.04 [95% CI 0.00, 0.27]. All index partners in this study had CD4 cell counts at baseline of 350-550 cells/uL. Similarly, the summary rate ratio for the nine observational studies was 0.58 [95% CI 0.35, 0.96], with substantial heterogeneity (I(2)=64%). After excluding two studies with inadequate person-time data, we estimated a summary rate ratio of 0.36 [95% CI 0.17, 0.75] with substantial heterogeneity (I(2)=62%). We also performed subgroup analyses among the observational studies to see if the effect of ART on prevention of HIV differed by the index partner's CD4 cell count. Among couples in which the infected partner had >=350 CD4 cells/uL, we estimated a rate ratio of 0.12 [95% CI 0.01, 1.99]. In this subgroup, there were 247 transmissions in untreated couples and 30 in treated couples. AUTHORS' CONCLUSIONS: ART is a potent intervention for prevention of HIV in discordant couples in which the index partner has <=550 CD4 cells/uL. A recent multicentre RCT confirms the suspected benefit seen in earlier observational studies and reported in more recent ones. Questions remain about durability of protection, the balance of benefits and adverse events associated with earlier therapy, long-term adherence and transmission of ART-resistant strains to partners. Resource limitations and implementation challenges must also be addressed.Counselling, support, and follow up, as well as mutual disclosure, may have a role in supporting adherence, so programmes should be designed with these components. In addition to ART provision, the operational aspects of delivering such programmes must be considered. PMID- 23633370 TI - Brief co-incubation of sperm and oocytes for in vitro fertilization techniques. AB - BACKGROUND: The in vitro fertilization (IVF) technique is commonly used and is the only treatment option for a proportion of infertile couples. To obtain better outcomes of IVF, it is important to enhance embryo quality by optimizing IVF techniques. In IVF procedures, oocytes and sperm are routinely co-incubated overnight, which may expose oocytes and zygotes to suboptimal culture conditions with increased reactive oxygen species (ROS) produced by sperm in this long term culture. As an attempt to avoid possible detrimental effects on the oocytes from long exposure to sperm, the brief co-incubation insemination protocol was developed. However, despite a number of studies in this area, it is unclear whether brief co-incubation improves the IVF outcomes compared with the standard overnight insemination protocol. OBJECTIVES: This Cochrane review aimed to determine whether brief co-incubation of sperm and oocytes improves outcomes compared with the standard overnight insemination protocol for women undergoing IVF. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group Register (14 June 2012), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, 1st quarter), MEDLINE (1948 to 14 June 2012), EMBASE (1989 to 14 June 2012), PsycINFO (1806 to 14 June 2012) and CINAHL (1980 to 26 July 2012). In addition, we searched trials registers, reference lists of articles, conference proceedings (American Society for Reproductive Medicine (ASRM), European Society of Human Reproduction and Embryology (ESHRE)) and contacted experts in the field. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing brief co-incubation of gametes with the standard overnight insemination protocol. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and trial quality, and extracted data. Disagreements were resolved by discussion with a third author. Statistical analysis was performed using RevMan software. MAIN RESULTS: Eight RCTs with 733 women in total that compared brief co-incubation and the standard insemination protocol were included. Live birth was not reported in the included studies. For ongoing pregnancy rate, there were 127 ongoing pregnancies in two trials including 426 women. The low quality evidence showed that brief co-incubation was associated with an increased ongoing pregnancy rate compared to the standard insemination protocol (pooled odds ratio (OR) 2.42, 95% confidence interval (CI) 1.55 to 3.77; P < 0.0001, I(2) = 0%). Measuring clinical pregnancy rate, there were 93 clinical pregnancies in three trials including 372 women. The low quality evidence showed that brief co-incubation was associated with a significantly higher clinical pregnancy rate than the overnight insemination protocol (pooled OR 2.36, 95% CI 1.45 to 3.85; P = 0.0006, I(2) = 0%). For the miscarriage rate, there were six miscarriages in one trial including 167 women. This low quality evidence suggested no significant difference in the odds of miscarriage between brief co-incubation and standard insemination (OR 1.98, 95% CI 0.35 to 11.09; P = 0.44). AUTHORS' CONCLUSIONS: This review has provided evidence that brief co-incubation of sperm and oocytes may improve the ongoing pregnancy and clinical pregnancy rates for infertile women undergoing IVF cycles. More RCTs are required to assess whether brief co-incubation would contribute to a higher live birth rate and a lower miscarriage rate compared to the standard overnight insemination protocol. PMID- 23633371 TI - Interventions for treating pain and disability in adults with complex regional pain syndrome. AB - BACKGROUND: There is currently no strong consensus regarding the optimal management of complex regional pain syndrome although a multitude of interventions have been described and are commonly used. OBJECTIVES: To summarise the evidence from Cochrane and non-Cochrane systematic reviews of the effectiveness of any therapeutic intervention used to reduce pain, disability or both in adults with complex regional pain syndrome (CRPS). METHODS: We identified Cochrane reviews and non-Cochrane reviews through a systematic search of the following databases: Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Ovid MEDLINE, Ovid EMBASE, CINAHL, LILACS and PEDro. We included non-Cochrane systematic reviews where they contained evidence not covered by identified Cochrane reviews. The methodological quality of reviews was assessed using the AMSTAR tool.We extracted data for the primary outcomes pain, disability and adverse events, and the secondary outcomes of quality of life, emotional well being and participants' ratings of satisfaction or improvement. Only evidence arising from randomised controlled trials was considered. We used the GRADE system to assess the quality of evidence. MAIN RESULTS: We included six Cochrane reviews and 13 non-Cochrane systematic reviews. Cochrane reviews demonstrated better methodological quality than non-Cochrane reviews. Trials were typically small and the quality variable.There is moderate quality evidence that intravenous regional blockade with guanethidine is not effective in CRPS and that the procedure appears to be associated with the risk of significant adverse events.There is low quality evidence that bisphosphonates, calcitonin or a daily course of intravenous ketamine may be effective for pain when compared with placebo; graded motor imagery may be effective for pain and function when compared with usual care; and that mirror therapy may be effective for pain in post-stroke CRPS compared with a 'covered mirror' control. This evidence should be interpreted with caution. There is low quality evidence that local anaesthetic sympathetic blockade is not effective. Low quality evidence suggests that physiotherapy or occupational therapy are associated with small positive effects that are unlikely to be clinically important at one year follow up when compared with a social work passive attention control.For a wide range of other interventions, there is either no evidence or very low quality evidence available from which no conclusions should be drawn. AUTHORS' CONCLUSIONS: There is a critical lack of high quality evidence for the effectiveness of most therapies for CRPS. Until further larger trials are undertaken, formulating an evidence-based approach to managing CRPS will remain difficult. PMID- 23633372 TI - Levomepromazine for nausea and vomiting in palliative care. AB - BACKGROUND: Nausea and vomiting are common, distressing symptoms for patients receiving palliative care. There are several agents which can be used to treat these symptoms. Levomepromazine is an antipsychotic drug which is commonly used to alleviate nausea and vomiting in palliative care settings. OBJECTIVES: To evaluate the efficacy of and adverse events (both minor and serious) associated with the use of levomepromazine for the treatment of nausea and vomiting in palliative care patients. SEARCH METHODS: We searched the electronic databases including CENTRAL, MEDLINE, and EMBASE using relevant search terms and synonyms in March 2013. SELECTION CRITERIA: Randomised controlled trials of levomepromazine for the treatment of nausea or vomiting, or both, for adults receiving palliative care. Studies where symptoms were thought to be due to pregnancy or surgery were excluded. DATA COLLECTION AND ANALYSIS: The potential relevance of studies was assessed based on titles and abstracts. Any study reports which appeared to meet the inclusion criteria were obtained for further assessment. All three authors read these papers to determine their suitability for inclusion and discussed discrepancies to achieve a consensus. MAIN RESULTS: The search strategy identified 421 abstracts from which eight studies were considered but all were excluded from the review. AUTHORS' CONCLUSIONS: No randomised controlled trials were identified examining the use of levomepromazine for nausea and vomiting in palliative care. Further studies of levomepromazine and other antiemetic agents are needed to provide better evidence for their use in this setting. PMID- 23633373 TI - Transarterial (chemo)embolisation versus no intervention or placebo intervention for liver metastases. AB - BACKGROUND: Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. Chemoembolisation is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery. Therefore, embolisation of the hepatic artery can lead to selective necrosis of the liver tumour while it may leave normal parenchyma virtually unaffected. OBJECTIVES: To study the beneficial and harmful effects of transarterial (chemo)embolisation compared with no intervention or placebo intervention in patients with liver metastases. SEARCH METHODS: We searched the Cochrane Hepato Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012. SELECTION CRITERIA: We included all randomised clinical trials assessing beneficial and harmful effects of transarterial (chemo)embolisation compared with no intervention or placebo intervention in patients with liver metastases, no matter the location of the primary tumour. DATA COLLECTION AND ANALYSIS: We extracted relevant information on participant characteristics, interventions, study outcome measures, and data on the outcome measures for our review as well as information on the design and methodology of the studies. Bias risk assessment of the trials, fulfilling the inclusion criteria, and data extraction from the retrieved final evaluation trials were done by one author and checked by a second author. MAIN RESULTS: One randomised clinical trial fulfilled the inclusion criteria of the review. Sixty one patients with colorectal liver metastases were randomised into three intervention groups: 22 received hepatic artery embolisation, 19 received hepatic artery infusion chemotherapy, and 20 were randomised to control, described as "no active therapeutic intervention, although symptomatic treatment was provided whenever necessary". As hepatic artery infusion chemotherapy is not in the scope of this review, we have not included the data from this intervention group. In the remaining two groups that were of interest to the review, 43 of the participants were men and 18 women. Most tumours were synchronous metastases involving up to 75% of the liver and non-resectable. The risk of bias in the trial was judged to be high.Patients were followed-up for a minimum of seven months. Mortality at last follow-up was 86% (19/22) in the hepatic artery embolisation group versus 95% (19/20) in the control group (RR 0.91; 95% CI 0.75 to 1.1), that is, no statistically significant difference was observed. Median survival after trial entry was 7.0 months (range 2 to 44) in the hepatic artery embolisation group and 7.9 months (range 1 to 26) in the control group. Nine out of 22 (41%) in the hepatic artery embolisation group and five out of 20 (25%) in the control group developed evidence of extrahepatic disease (RR 1.64; 95% CI 0.60 to 4.07). Local recurrence was reported for 10 patients in the trial without details about the trial group. Most patients in the embolisation group experienced post-embolic syndrome (82%), and one patient had local haematoma. No other adverse events were reported. The authors did not report if there were any adverse events in the control group. AUTHORS' CONCLUSIONS: On the basis of one small randomised trial that did not describe sequence generation, allocation concealment or blinding, it can be concluded that in patients with liver metastases no significant survival benefit or benefit on extrahepatic recurrence was found in the embolisation group in comparison with the palliation group. The probability for selective outcome reporting bias in the trial is high. At present, transarterial (chemo)embolisation cannot be recommended outside randomised clinical trials. PMID- 23633374 TI - Effectiveness of systematic screening for the detection of atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is a leading cause of morbidity and mortality. Screening for AF in asymptomatic patients has been proposed as a way of reducing the burden of the disease by detecting people who would benefit from prophylactic anticoagulation therapy prior to the onset of symptoms. However, for screening to be an effective intervention it must improve the detection of AF and provide benefit for those who are detected earlier as a result of screening. OBJECTIVES: The primary objective of this review was to examine whether screening programmes increase the detection of new cases of AF compared to routine practice. The secondary objectives were to identify which combination of screening strategy and patient population is most effective, as well as assessing any safety issues associated with screening, its acceptability within the target population and the costs involved. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE (Ovid) and EMBASE (Ovid) up to March 2012. Other relevant research databases, trials registries and websites were searched up to June 2012. Reference lists of identified studies were also searched for potentially relevant studies and we contacted corresponding authors for information about additional published or unpublished studies that may be relevant. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials, controlled before and after studies and interrupted time series studies comparing screening for AF with routine practice in people aged 40 years and over were eligible. Two authors (PM, CT or MF) independently selected the trials for inclusion. DATA COLLECTION AND ANALYSIS: Assessment of risk of bias and data extraction were performed independently by two authors (PM, CT). Odds ratios (OR) and 95% confidence intervals (CI) were used to present the results for the primary outcome, which is a dichotomous variable. Since only one included study was identified, no meta-analysis was performed. MAIN RESULTS: One cluster randomised controlled trial met the inclusion criteria for this review. This study compared systematic screening (by invitation to have an electrocardiogram (ECG)) and opportunistic screening (pulse palpation during a general practitioner (GP) consultation for any reason followed by an ECG if pulse was irregular) to routine practice (normal case finding on the basis of clinical presentation) in people aged 65 years or older. The risk of bias in the included study was judged to be low.Both systematic and opportunistic screening of people over the age of 65 years are more effective than routine practice (OR 1.57, 95% CI 1.08 to 2.26 and OR 1.58, 95% CI 1.10 to 2.29, respectively). The number needed to screen in order to detect one additional case compared to routine practice was 172 (95% CI 94 to 927) for systematic screening and 167 (95% CI 92 to 806) for opportunistic screening. Both systematic and opportunistic screening were more effective in men (OR 2.68, 95% CI 1.51 to 4.76 and OR 2.33, 95% CI 1.29 to 4.19, respectively) than in women (OR 0.98, 95% CI 0.59 to 1.62 and OR 1.2, 95% CI 0.74 to 1.93, respectively). No data on the effectiveness of screening in different ethnic or socioeconomic groups were available. There were insufficient data to compare the effectiveness of screening programmes in different healthcare settings.Systematic screening was associated with a better overall uptake rate than opportunistic screening (53% versus 46%) except in the >= 75 years age group where uptake rates were similar (43% versus 42%). In both screening programmes men were more likely to participate than women (57% versus 50% in systematic screening, 49% versus 41% in opportunistic screening) and younger people (65 to 74 years) were more likely to participate than people aged 75 years and over (61% versus 43% systematic, 49% versus 42% opportunistic). No adverse events associated with screening were reported.The incremental cost per additional case detected by opportunistic screening was GBP 337, compared to GBP 1514 for systematic screening. All cost estimates were based on data from the single included trial, which was conducted in the UK between 2001 and 2003. AUTHORS' CONCLUSIONS: Systematic and opportunistic screening for AF increase the rate of detection of new cases compared with routine practice. While both approaches have a comparable effect on the overall AF diagnosis rate, the cost of systematic screening is significantly more than that of opportunistic screening from the perspective of the health service provider. The lack of studies investigating the effect of screening in other health systems and younger age groups means that caution needs to be exercised in relation to the transferability of these results beyond the setting and population in which the included study was conducted.Additional research is needed to examine the effectiveness of alternative screening strategies and to investigate the effect of the intervention on the risk of stroke for screened versus non-screened populations. PMID- 23633375 TI - Swimming training for asthma in children and adolescents aged 18 years and under. AB - BACKGROUND: Asthma is the most common chronic medical condition in children and a common reason for hospitalisation. Observational studies have suggested that swimming, in particular, is an ideal form of physical activity to improve fitness and decrease the burden of disease in asthma. OBJECTIVES: To determine the effectiveness and safety of swimming training as an intervention for asthma in children and adolescents aged 18 years and under. SEARCH METHODS: We searched the Cochrane Airways Group's Specialised Register of trials (CENTRAL), MEDLINE , EMBASE, CINAHL, in November 2011, and repeated the search of CENTRAL in July 2012. We also handsearched ongoing Clinical Trials Registers. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) and quasi-RCTs of children and adolescents comparing swimming training with usual care, a non-physical activity, or physical activity other than swimming. DATA COLLECTION AND ANALYSIS: We used standard methods specified in the Cochrane Handbook for Systematic reviews of Interventions. Two review authors used a standard template to independently assess trials for inclusion and extract data on study characteristics, risk of bias elements and outcomes. We contacted trial authors to request data if not published fully. When required, we calculated correlation coefficients from studies with full outcome data to impute standard deviation of changes from baseline. MAIN RESULTS: Eight studies involving 262 participants were included in the review. Participants had stable asthma, with severity ranging from mild to severe. All studies were randomised trials, three studies had high withdrawal rates. Participants were between five to 18 years of age, and in seven studies swimming training varied from 30 to 90 minutes, two to three times a week, over six to 12 weeks. The programme in one study gave 30 minutes training six times per week. The comparison was usual care in seven studies and golf in one study. Chlorination status of swimming pool was unknown for four studies. Two studies used non-chlorinated pools, one study used an indoor chlorinated pool and one study used a chlorinated but well-ventilated pool.No statistically significant effects were seen in studies comparing swimming training with usual care or another physical activity for the primary outcomes; quality of life, asthma control, asthma exacerbations or use of corticosteroids for asthma. Swimming training had a clinically meaningful effect on exercise capacity compared with usual care, measured as maximal oxygen consumption during a maximum effort exercise test (VO2 max) (two studies, n = 32), with a mean increase of 9.67 mL/kg/min; 95% confidence interval (CI) 5.84 to 13.51. A difference of equivalent magnitude was found when other measures of exercise capacity were also pooled (four studies, n = 74), giving a standardised mean difference (SMD) 1.34; 95% CI 0.82 to 1.86. Swimming training was associated with small increases in resting lung function parameters of varying statistical significance; mean difference (MD) for FEV1 % predicted 8.07; 95% CI 3.59 to 12.54. In sensitivity analyses, by risk of attrition bias or use of imputed standard deviations, there were no important changes on effect sizes. Unknown chlorination status of pools limited subgroup analyses.Based on limited data, there were no adverse effects on asthma control or occurrence of exacerbations. AUTHORS' CONCLUSIONS: This review indicates that swimming training is well tolerated in children and adolescents with stable asthma, and increases lung function (moderate strength evidence) and cardio-pulmonary fitness (high strength evidence). There was no evidence that swimming training caused adverse effects on asthma control in young people 18 years and under with stable asthma of any severity. However whether swimming is better than other forms of physical activity cannot be determined from this review. Further adequately powered trials with longer follow-up periods are needed to better assess the long-term benefits of swimming. PMID- 23633376 TI - Mammography in combination with breast ultrasonography versus mammography for breast cancer screening in women at average risk. AB - BACKGROUND: Breast cancer is the most common malignant disease diagnosed in women worldwide. Screening with mammography has the ability to detect breast cancer at an early stage. The diagnostic accuracy of mammography screening largely depends on the radiographic density of the imaged breasts. In radiographically dense breasts, non-calcified breast cancers are more likely to be missed than in fatty breasts. As a consequence, some cancers are not detected by mammography screening. Supporters of adjunct ultrasonography to the screening regimen for breast cancer argue that it might be a safe and inexpensive approach to reduce the false negative rates of the screening process. Critics, however, are concerned that performing supplemental ultrasonography on women at average risk will also increase the rate of false positive findings and can lead to unnecessary biopsies and treatments. OBJECTIVES: To assess the comparative effectiveness and safety of mammography in combination with breast ultrasonography versus mammography for breast cancer screening for women at average risk of breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's Specialised Register, MEDLINE (via OvidSP) and EMBASE up until February 2012.To detect ongoing or unpublished studies, we searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov and the National Cancer Institute's clinical trial database until June 2012. In addition, we conducted grey literature searches using the following sources: OpenGrey; National Institute of Health RePORTER; Health Services Research Projects in Progress (HSRPROJ); Hayes, Inc. Health Technology Assessment; The New York Academy of Medicine's Grey Literature Index and Conference Papers Index. SELECTION CRITERIA: For efficacy, we considered randomised controlled trials (RCTs), with either individual or cluster randomisation, and prospective, controlled non-randomised studies with a low risk of bias and a sample size of at least 500 participants.In addition to studies eligible for efficacy, we considered any controlled, non-randomised study with a low risk of bias and a study size of at least 500 participants for the assessment of harms.Our population of interest were women between the ages of 40 and 75 years who were at average risk for breast cancer. DATA COLLECTION AND ANALYSIS: Two review authors screened abstracts and full-text publications against the inclusion criteria. None of the studies met our inclusion criteria. MAIN RESULTS: Our review did not detect any controlled studies on the use of adjunct ultrasonography for screening in women at average risk for breast cancer. One ongoing randomised controlled trial was identified (J-START, Japan). AUTHORS' CONCLUSIONS: Presently, there is no methodologically sound evidence available justifying the routine use of ultrasonography as an adjunct screening tool in women at average risk for breast cancer. PMID- 23633377 TI - Parent-mediated early intervention for young children with autism spectrum disorders (ASD). AB - BACKGROUND: Young children with autism spectrum disorders (ASD) have impairments in the areas of communication and social interaction and often display repetitive or non-compliant behaviour. This early pattern of difficulties is a challenge for parents. Therefore, approaches that help parents develop strategies for interaction and management of behaviour are an obvious route for early intervention in ASD. This review updates a Cochrane review first published in 2002 but is based on a new protocol. OBJECTIVES: To assess the effectiveness of parent-mediated early interventions in terms of the benefits for both children with ASD and their parents and to explore some potential moderators of treatment effect. SEARCH METHODS: We searched a range of psychological, educational and biomedical databases including CENTRAL, MEDLINE, Embase, PsycINFO and ERIC in August 2012. As this is an update of a previous review, we limited the search to the period following the original searches in 2002. Bibliographies and reference lists of key articles were searched, field experts were contacted and key journals were handsearched. SELECTION CRITERIA: We included only randomised controlled trials of early intervention for children with ASD. The interventions in the experimental condition were mediated by parents; the control conditions included no treatment, treatment as usual, waiting list, alternative child centred intervention not mediated by parents, or alternative parent-mediated intervention of hypothesised lesser effect than the experimental condition. DATA COLLECTION AND ANALYSIS: Two review authors (HM and IPO) independently screened articles identified in the search and decided which articles should be retrieved in full. For each included study, two review authors (IPO and EH) extracted and recorded data, using a piloted data collection form. Two review authors (IPO and HM) assessed the risk of bias in each study. We performed data synthesis and analysis using The Cochrane Collaboration's Review Manager 5.1 software. MAIN RESULTS: The review includes 17 studies from six countries (USA, UK, Australia, Canada, Thailand and China), which recruited 919 children with ASD. Not all 17 studies could be compared directly or combined in meta-analyses due to differences in the theoretical basis underpinning interventions, the duration and intensity of interventions, and the outcome measurement tools used. Data from subsets of 10 studies that evaluated interventions to enhance parent interaction style and thereby facilitate children's communication were included in meta analyses. The largest meta-analysis combined data from 316 participants in six studies and the smallest combined data from 55 participants in two studies. Findings from the remaining seven studies were reported narratively.High risk of bias was evident in the studies in relation to allocation concealment and incomplete outcome data; blinding of participants was not possible.Overall, we did not find statistical evidence of gains from parent-mediated approaches in most of the primary outcomes assessed (most aspects of language and communication - whether directly assessed or reported; frequency of child initiations in observed parent-child interaction; child adaptive behaviour; parents' stress), with findings largely inconclusive and inconsistent across studies. However, the evidence for positive change in patterns of parent-child interaction was strong and statistically significant (shared attention: standardised mean difference (SMD) 0.41; 95% confidence interval (CI) 0.14 to 0.68, P value < 0.05; parent synchrony: SMD 0.90; 95% CI 0.56 to 1.23, P value < 0.05). Furthermore, there is some evidence suggestive of improvement in child language comprehension, reported by parents (vocabulary comprehension: mean difference (MD 36.26; 95% CI 1.31 to 71.20, P value < 0.05). In addition, there was evidence suggesting a reduction in the severity of children's autism characteristics (SMD -0.30, 95% CI -0.52 to 0.08, P value < 0.05). However, this evidence of change in children's skills and difficulties as a consequence of parent-mediated intervention is uncertain, with small effect sizes and wide CIs, and the conclusions are likely to change with future publication of high-quality RCTs. AUTHORS' CONCLUSIONS: The review finds some evidence for the effectiveness of parent-mediated interventions, most particularly in proximal indicators within parent-child interaction, but also in more distal indicators of child language comprehension and reduction in autism severity. Evidence of whether such interventions may reduce parent stress is inconclusive. The review reinforces the need for attention to be given to early intervention service models that enable parents to contribute skilfully to the treatment of their child with autism. However, practitioners supporting parent mediated intervention require to monitor levels of parent stress. The ability to draw conclusions from studies would be improved by researchers adopting a common set of outcome measures as the quality of the current evidence is low. PMID- 23633378 TI - Desmopressin acetate (DDAVP) for preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders. AB - BACKGROUND: Congenital bleeding disorders can cause obstetric haemorrhage during pregnancy, labour and following delivery. Desmopressin acetate is found to be an effective drug which can reduce the risk of haemorrhage and can also stop bleeding in certain congenital bleeding disorders. Its use in pregnancy has been controversial. Hence beneficial and adverse effects of desmopressin acetate in these groups of pregnant women should be evaluated. OBJECTIVES: To determine the efficacy of desmopressin acetate in preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coaguopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant and abstract books of conferences proceedings. We also searched for any randomised controlled trials in a registry of ongoing trials and the reference lists of relevant articles and reviews.Date of most recent search: 28 February 2013. SELECTION CRITERIA: Randomised and quasi randomised controlled trials investigating the efficacy of desmopressin acetate versus tranexamic acid or factor VIII or rFactor VII or fresh frozen plasma in preventing and treating congenital bleeding disorders during pregnancy were eligible. DATA COLLECTION AND ANALYSIS: No trials matching the selection criteria were eligible for inclusion. MAIN RESULTS: No trials matching the selection criteria were eligible for inclusion. AUTHORS' CONCLUSIONS: The review did not identify any randomised controlled trials investigating the relative effectiveness of desmopressin acetate for bleeding during pregnancy in women with congenital bleeding disorders. In the absence of high quality evidence, clinicians need to use their clinical judgement and lower level evidence (e.g. from observational trials) to decide whether or not to treat women with congenital bleeding disorders with desmopressin acetate.Given the ethical considerations, future randomised controlled trials are unlikely. However, other high quality controlled studies (such as risk allocation designs, sequential design, parallel cohort design) to investigate the risks and benefits of using desmopressin acetate in this population are needed. PMID- 23633379 TI - Intra-articular glucocorticoids for acute gout. AB - BACKGROUND: Although intra-articular glucocorticoids are a commonly used intervention in the treatment of acute gout, there is little evidence to support their safety and efficacy in this setting. OBJECTIVES: To evaluate the safety and efficacy of intra-articular glucocorticoids in the treatment of acute gout. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), Ovid MEDLINE and Ovid EMBASE for studies to 16th October 2012. We also searched the 2010 to 2011 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts and performed a handsearch of the reference lists of articles considered for inclusion. SELECTION CRITERIA: Studies were eligible for inclusion if they were randomised controlled trials (RCTs) or controlled clinical trials (CCTs) that used quasi-randomisation methods to allocate participants to treatment and compared intra-articular glucocorticoids to another therapy (active or placebo) in adults with acute gout. Outcomes selected for inclusion were pain, the proportion of participant withdrawals due to adverse events, inflammation, function, patient global assessment of treatment success, quality of life and proportion of particpants with serious adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies for inclusion and planned to extract the data and perform a risk of bias assessment. MAIN RESULTS: No trials were identified that evaluated the efficacy and safety of intra articular glucocorticoids for acute gout. AUTHORS' CONCLUSIONS: There is presently no evidence from randomised trials to support the use of intra articular glucocorticoid treatment in acute gout. Evidence suggests intra articular glucocorticoids may be a safe and effective treatment in osteoarthritis and rheumatoid arthritis. These results may be generalisable to people with acute gout, and the treatment may be especially useful in people when non-steroidal anti-inflammatory drugs or colchicine are contraindicated. PMID- 23633380 TI - Deflation of gastric band balloon in pregnancy for improving outcomes. AB - BACKGROUND: In line with the rise in the prevalence of obesity, an increasing number of women of childbearing age are undergoing laparoscopic adjustable gastric banding (LAGB), resulting in an increasing number of pregnancies with a band in place. Currently, there is no consensus on optimal band management in pregnancy. Some clinicians advocate leaving the band balloon inflated to reduce gestational weight gain and associated adverse perinatal outcomes. However, there are concerns that maintaining balloon inflation during pregnancy might increase the risk of band complications and adversely affect fetal development and/or growth as a result of reduced nutritional intake. OBJECTIVES: To compare maternal and perinatal outcomes for elective gastric band balloon deflation versus intention to maintain balloon inflation during pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2012) and the Web of Science database (1940 to September 2012). SELECTION CRITERIA: Randomised-controlled trials comparing elective deflation of the gastric band balloon with intention to maintain balloon inflation in pregnant women who have undergone LAGB. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion. MAIN RESULTS: No studies met the criteria for inclusion in the review. AUTHORS' CONCLUSIONS: To date no randomised controlled trials exist that compare elective deflation of the gastric band balloon in pregnancy versus intention to maintain balloon inflation. Further research is needed to define the optimum management of the gastric band balloon in pregnancy. PMID- 23633381 TI - Alginate dressings for venous leg ulcers. AB - BACKGROUND: Venous leg ulcers are a common and recurring type of chronic, complex wound associated with considerable cost to patients and healthcare providers. To aid healing, primary wound contact dressings are usually applied to ulcers beneath compression devices. Alginate dressings are used frequently and there is a variety of alginate products on the market, however, the evidence base to guide dressing choice is sparse. OBJECTIVES: To determine the effects of alginate dressings compared with alternative dressings, non-dressing treatments or no dressing, with or without concurrent compression therapy, on the healing of venous leg ulcers. SEARCH METHODS: We searched The Cochrane Wounds Group Specialised Register (searched 30 November 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 11); The NHS Economic Evaluation Database (NHS EED) (The Cochrane Library 2012, Issue 5); Ovid MEDLINE (1946 to November Week 2 2012); Ovid MEDLINE (In-Process & Other Non Indexed Citations November 29, 2012); Ovid EMBASE (1980 to 2011 Week 11); and EBSCO CINAHL (1982 to 23 November 2012). There were no restrictions based on language or date of publication. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) that evaluated the effects of any type of alginate dressing in the treatment of venous ulcers were included. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction and risk of bias assessment. Meta-analysis was undertaken when deemed feasible and appropriate. MAIN RESULTS: Five RCTs (295 participants) were included in this review. Overall risk of bias was high for two RCTs and unclear for three. One RCT compared different proprietary alginate dressings (20 participants), three compared alginate and hydrocolloid dressings (215 participants), and one compared alginate and plain non-adherent dressings (60 participants). Follow-up periods were six weeks in three RCTs and 12 weeks in two. No statistically significant between-group differences were detected for any comparison, for any healing outcome. Meta-analysis was feasible for one comparison (alginate and hydrocolloid dressings), with data from two RCTs (84 participants) pooled for complete healing at six weeks: risk ratio 0.42 (95% confidence interval 0.14 to 1.21). Adverse event profiles were generally similar between groups (not assessed for alginate versus plain non-adherent dressings). AUTHORS' CONCLUSIONS: The current evidence base does not suggest that alginate dressings are more or less effective in the healing of venous leg ulcers than hydrocolloid or plain non-adherent dressings, and there is no evidence to indicate a difference between different proprietary alginate dressings. However, the RCTs in this area are considered to be of low or unclear methodological quality. Further, good quality evidence is required from well designed and rigorously conducted RCTs that employ - and clearly report on - methods to minimise bias, prior to any definitive conclusions being made regarding the efficacy of alginate dressings in the management of venous leg ulcers. PMID- 23633384 TI - Improved MRI quantification of spinal cord atrophy in multiple sclerosis. AB - PURPOSE: To identify an improved method for measuring spinal cord cross-sectional area (CSA) using magnetic resonance imaging (MRI) in multiple sclerosis (MS). MATERIALS AND METHODS: MRI was performed on 15 controls and 15 MS patients and repeated in nine controls and nine patients after 6 months. At this timepoint, an additional scan was acquired to evaluate scan-rescan reproducibility. Two sequences were acquired in the cervical cord: 3D phase sensitive inversion recovery (PSIR) and 3D magnetization prepared rapid acquisition T1-weighted gradient echo. CSA was outlined at C2-C3 using two methods: a semiautomated edge detection method and active surface model (ASM). We evaluated reproducibility for all combinations of sequences and analysis methods using coefficient of variation (COV) and intraclass correlation coefficient and performed sample size calculations for clinical trials to reduce longitudinal cord atrophy. RESULTS: PSIR/ASM combination provided the lowest values of COV for intrarater, interrater, scan-rescan reproducibility (0.002%, 0.03%, and 0.1% respectively). At 6-month follow-up no significant changes were seen in CSA of controls, and a trend towards significance was observed in patients. CONCLUSION: PSIR/ASM proved more reproducible than established methods of evaluating CSA in MS and also provides the lowest number of subjects per arm for 6-month and 1-year clinical trials. PMID- 23633385 TI - A tandem laboratory scale protein purification process using Protein A affinity and anion exchange chromatography operated in a weak partitioning mode. AB - A significant consequence of scaling up production of high titer monoclonal antibody (mAb) processes in existing facilities is the generation of in-process pools that exceed the capacity of storage vessels. A semi-continuous downstream process where columns and filters are linked and operated in tandem would eliminate the need for intermediate holding tanks. This study is a bench-scale demonstration of the feasibility of a tandem process for the purification of mAbs employing an affinity Protein A capture step, followed by a flow-through anion exchange (AEX) step with the possibility of adding an in-line virus filtration step (VF). All three steps were linked sequentially and operated as one continuous process using an AKTA FPLC equipped with two pumps and a system of valves and bypasses that allowed the components to be engaged at different stages of the process. The AEX column was operated in a weak partitioning (WP) mode enabled by a precise in-line titration of Protein A effluent. In order to avoid complex control schemes and facilitate validation, quality and robustness were built into the system through selection of buffers based on thermodynamic and empirical models. The tandem system utilized the simplest possible combination of valves, pumps, controls, and automation, so that it could easily be implemented in a clinical or commercial production facility. Linking the purification steps in a tandem process is expected to generate savings in time and production costs and also reduce the size of quality systems due to reduced documentation requirements, microbial sampling, and elimination of hold time validation. PMID- 23633386 TI - Polarized distribution of AMPA, but not GABAA , receptors in radial glia-like cells of the adult dentate gyrus. AB - Glial fibrillary acidic protein (GFAP)-positive astrocytes with radial processes [radial glia (RG)-like cells] in the postnatal dentate gyrus share many of the characteristics of embryonic radial glia and appear to act as precursor cells for adult dentate neurogenesis, a process important for pattern separation and hippocampus-dependent learning. Although much work has delineated the mechanisms underlying activity-neurogenesis coupling via gamma-amino butyric acid (GABA)ergic neurotransmission on GFAP-negative transient-amplifying cells and neuroblasts, little is known regarding the effects of neurotransmitters on RG like cells. Conflicting evidence exists for both GABA and glutamate receptors on these cells. Here, using GFAP reporter mice, we show that the somatic membrane of RG-like cells carries GABAA receptors and glutamate transporters but not ionotropic glutamate receptors, whereas 2-amino-3-(hydroxyl-5-methylisoxazole-4 yl) propionic acid (AMPA) and GABAA receptors are expressed on the processes of these cells. Almost all RG-like cells expressed the GluA2 subunit, which restricts the Ca(2+) permeability of AMPA receptors. The glial GABAA receptors mainly comprised alpha2/alpha4, beta1, and gamma1/gamma3. The selective presence of AMPA receptors on the radial processes may be important for sensing and responding to local activity-driven glutamate release and supports the concept that RG-like astrocytes are composed of functional and structural domains. PMID- 23633387 TI - Glycogen function in adult central and peripheral nerves. AB - We studied the roles of glycogen in axonal pathways of the central nervous system (CNS) and peripheral nervous system (PNS). By using electrophysiological recordings, in combination with biochemical glycogen assay, it was possible to determine whether glycogen was crucial to axon function under different conditions. Glycogen was present both in mouse optic nerve (MON) and in mouse sciatic nerve (MSN). Aglycemia caused loss of the compound action potential (CAP) in both pathways after a latency of 15 min (MON) and 120 min for myelinated axons (A fibers) in the MSN. With the exception of unmyelinated axons (C fibers) in the MSN, CAP decline began when usable glycogen was exhausted. Glycogen was located in astrocytes in the MON and in myelinating Schwann cells in the MSN; it was absent from the Schwann cells surrounding unmyelinated C fibers. In MON, astrocytic glycogen is metabolized to lactate and "shuttled" to axons to support metabolism. The ability of lactate to support A fiber conduction in the absence of glucose suggests a common pathway in both the CNS and the PNS. Lactate is released from MON and MSN in substantial quantities. That lactate levels fall in MSN in the presence of diaminobenzidine, which inhibits glycogen phosphorylase, strongly suggests that glycogen metabolism contributes to lactate release under resting conditions. Glycogen is a "backup" energy substrate in both the CNS and the PNS and, beyond sustaining excitability during glucose deprivation, has the capacity to subsidize the axonal energy demands during times of intense activity in the presence of glucose. PMID- 23633388 TI - A de novo GLI3 mutation in a patient with acrocallosal syndrome. AB - Acrocallosal syndrome is characterized by postaxial polydactyly, macrocephaly, agenesis of the corpus callosum, and severe developmental delay. In a few patients with this disorder, a mutation in the KIF7 gene has been reported, which was associated with impaired GLI3 processing and dysregulaton of GLI3 transcription factors. A single patient with acrocallosal syndrome and a de novo p.Ala934Pro mutation in GLI3 has been reported, whereas diverse and numerous GLI3 mutations have also been described in syndromes with overlapping clinical manifestations, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, trigonocephaly with craniosynostosis and polydactyly, oral-facial digital syndrome, and non-syndromic polydactyly. Here, we describe a second patient with acrocallosal syndrome, who has a de novo, novel c.2786T>C mutation in GLI3, which predicts p.Leu929Pro. This mutation is in the same domain as the mutation in the previously reported patient. These data confirm that mutations in GLI3 are a cause of the acrocallosal phenotype. PMID- 23633389 TI - Tracking and evaluation of dendritic cell migration by cellular magnetic resonance imaging. AB - Cellular magnetic resonance imaging (MRI) is a means by which cells labeled ex vivo with a contrast agent can be detected and tracked over time in vivo. This technology provides a noninvasive method with which to assess cell-based therapies in vivo. Dendritic cell (DC)-based vaccines are a promising cancer immunotherapy, but its success is highly dependent on the injected DC migrating to a secondary lymphoid organ such as a nearby lymph node. There the DC can interact with T cells to elicit a tumor-specific immune response. It is important to verify DC migration in vivo using a noninvasive imaging modality, such as cellular MRI, so that important information regarding the anatomical location and persistence of the injected DC in a targeted lymph node can be provided. An understanding of DC biology is critical in ascertaining how to label DC with sufficient contrast agent to render them detectable by MRI. While iron oxide nanoparticles provide the best sensitivity for detection of DC in vivo, a clinical grade iron oxide agent is not currently available. A clinical grade (19) Fluorine-based perfluorcarbon nanoemulsion is available but is less sensitive, and its utility to detect DC migration in humans remains to be demonstrated using clinical scanners presently available. The ability to quantitatively track DC migration in vivo can provide important information as to whether different DC maturation and activation protocols result in improved DC migration efficiency which will determine the vaccine's immunogenicity and ultimately the tumor immunotherapy's outcome in humans. PMID- 23633390 TI - Antioxidant activity, volatile composition and sensory profile of four new very early apricots (Prunus armeniaca L.). AB - BACKGROUND: Very-early apricot cultivars are interesting owing to the fact that they will be available in markets before any other cultivar. In order to achieve good fruit quality, very-early apricots require appropriate size, weight and color, good balance of sugars and organic acids, proper content of bioactive compounds, relatively strong apricot aroma as well as acceptable sensory quality. RESULTS: Physical, chemical, antioxidant and sensory properties showed important variations among apricot cultivars. These differences were basically attributed to genetic reasons. Four very-early apricot cultivars were studied, namely 'Mirlo Blanco', 'Mirlo Anaranjado', 'Colorao' and 'Mogador'. All of them showed proper size and weight, but their contents of organic acids, sugars and bioactive compounds were low and the number of volatile compounds was also low. However, very-early apricots showed an appropriate sensory profile for fresh consumption. CONCLUSION: Regarding physical, chemical and volatile composition and sensory properties, very-early apricot cultivars could be recommended for fresh consumption. However, future research must be focused on increasing their contents of sugars, organic acids and bioactive and volatile compounds, perhaps via cultural practices such as deficit irrigation and/or mulching. PMID- 23633391 TI - Impact of omega-6 polyunsaturated fatty acid supplementation and gamma aminobutyric acid on astrogliogenesis through the endocannabinoid system. AB - Neural stem cells express cannabinoid CB1 and CB2 receptors and the enzymes for the biosynthesis and metabolism of endocannabinoids (eCBs). Here we have studied the role of neural stem cell-derived eCBs as autonomous regulatory factors during differentiation. First, we examined the effect of an indirect eCB precursor linoleic acid (LA), a major dietary omega-6 fatty acid, on the eCB system in neural stem/progenitor cells (NSPCs) cultured in DMEM/F12 supplemented with N2 (N2/DF) as monolayer cells. LA upregulated eCB system-related genes and 2 arachidonoylglycerol (2-AG), but not anandamide (AEA), levels. Glial fibrillary acidic protein (GFAP) was significantly higher under LA-enriched conditions, and this effect was inhibited by the cannabinoid receptor type-1 (CB1) antagonist AM251. Second, the levels of AEA and 2-AG, as well as of the mRNA of eCB system related genes, were measured in NSPCs after gamma-aminobutyric acid (GABA) treatment. GABA upregulated AEA levels significantly in LA-enriched cultures and increased the mRNA expression of the 2-AG-degrading enzyme monoacylglycerol lipase. These effects of GABA were reproduced under culture conditions using neurobasal media supplemented with B27, which is commonly used for neurosphere culture. GABA stimulated astroglial differentiation in this medium as indicated by increased GFAP levels. This effect was abolished by AM251, suggesting the involvement of AEA and CB1 in GABA-induced astrogliogenesis. This study highlights the importance of eCB biosynthesis and CB1 signalling in the autonomous regulation of NSPCs and the influence of the eCB system on astrogliogenesis induced by nutritional factors or neurotransmitters, such as LA and GABA. PMID- 23633392 TI - Phase 1/1b study of lonafarnib and temozolomide in patients with recurrent or temozolomide refractory glioblastoma. AB - BACKGROUND: Lonafarnib is an oral selective farnesyltransferase inhibitor, a class of drugs which have shown activity in preclinical glioma models. Temozolomide (TMZ) is an alkylating agent that is the first-line chemotherapy for glioblastoma. METHODS: The current study combined the cytotoxic agent TMZ with the cytostatic agent lonafarnib for patients with recurrent glioblastoma to establish a maximum tolerated dose (MTD) of the combination and its preliminary efficacy. Three dose cohorts of lonafarnib were studied in the phase 1 component of the trial (100 mg twice daily [bid], 150 mg bid, and 200 bid) with dose-dense schedule of TMZ (150 mg/m2 daily) administered in an alternating weekly schedule. After establishing the MTD of lonafarnib, a subsequent expansion phase 1b was undertaken to evaluate efficacy, primarily measured by 6-month progression-free survival (PFS-6). RESULTS: Fifteen patients were enrolled into the phase 1 component and 20 patients into the phase 1b component. The MTD of lonafarnib in combination with TMZ was 200 mg bid. Among the patients enrolled into the study, 34 were eligible for 6-month progression evaluation and 35 patients were evaluable for time-to-progression analysis. The PFS-6 rate was 38% (95% confidence interval [CI] = 22%, 56%) and the median PFS was 3.9 months (95% CI = 2.5, 8.4). The median disease-specific survival was 13.7 months (95% CI = 8.9, 22.1). Hematologic toxicities, particularly lymphopenia, were the most common grade 3 and 4 adverse events. There were no treatment-related deaths. CONCLUSIONS: These results demonstrate that TMZ can be safely combined with a farnesyltransferase inhibitor and that this regimen is active, although the current study cannot determine the relative contributions of the 2 agents or the contribution of the novel administration schedule. PMID- 23633394 TI - Boron-phenylpyrrin dyes: facile synthesis, structure, and pH-sensitive properties. AB - Boron-phenylpyrrin dyes: In the presence of BF3?OEt2, 4 (diethylamino)salicylaldehyde reacts with substituted pyrroles to give boron phenylpyrrin dyes, which contain a central boron-containing seven-membered ring. Upon protonation in acidic solution, the complexes, with a large Stokes shift, exhibit a color change and a unique red shift in both the electronic absorption and fluorescence emission spectra (see picture), thus rendering them new analogues of boron-dipyrrin dyes that can be used as pH sensors. PMID- 23633393 TI - Recurrent compartment syndrome in a patient with clinical features of a connective tissue disorder. AB - Arterial complications are common in vascular type Ehlers-Danlos syndrome (EDS), accounting for 66% of first complications. Several cases in the literature have documented acute compartment syndrome (ACS) following vascular rupture in vascular type EDS. Other disorders of connective tissue have also demonstrated vascular fragility, leading to arterial aneurysm and rupture, but there have been no documented cases of ACS. Here, we report on a female patient with a history of recurrent compartment syndrome who exhibits some clinical findings seen in hypermobile and vascular EDS; however she does not meet clinical and molecular diagnostic criteria for either of them. We further review the literature on ACS in heritable connective tissue disorders and suggest that compartment syndrome may rarely complicate other heritable disorders of connective tissue. PMID- 23633395 TI - Scaling of Haversian canal surface area to secondary osteon bone volume in ribs and limb bones. AB - Studies of secondary osteons in ribs have provided a great deal of what is known about remodeling dynamics. Compared with limb bones, ribs are metabolically more active and sensitive to hormonal changes, and receive frequent low-strain loading. Optimization for calcium exchange in rib osteons might be achieved without incurring a significant reduction in safety factor by disproportionally increasing central canal size with increased osteon size (positive allometry). By contrast, greater mechanical loads on limb bones might favor reducing deleterious consequences of intracortical porosity by decreasing osteon canal size with increased osteon size (negative allometry). Evidence of this metabolic/mechanical dichotomy between ribs and limb bones was sought by examining relationships between Haversian canal surface area (BS, osteon Haversian canal perimeter, HC.Pm) and bone volume (BV, osteonal wall area, B.Ar) in a broad size range of mature (quiescent) osteons from adult human limb bones and ribs (modern and medieval) and various adult and subadult non-human limb bones and ribs. Reduced major axis (RMA) and least-squares (LS) regressions of HC.Pm/B.Ar data show that rib and limb osteons cannot be distinguished by dimensional allometry of these parameters. Although four of the five rib groups showed positive allometry in terms of the RMA slopes, nearly 50% of the adult limb bone groups also showed positive allometry when negative allometry was expected. Consequently, our results fail to provide clear evidence that BS/BV scaling reflects a rib versus limb bone dichotomy whereby calcium exchange might be preferentially enhanced in rib osteons. PMID- 23633396 TI - Evaluating the potential of artificial neural network and neuro-fuzzy techniques for estimating antioxidant activity and anthocyanin content of sweet cherry during ripening by using image processing. AB - BACKGROUND: This paper presents a versatile way for estimating antioxidant activity and anthocyanin content at different ripening stages of sweet cherry by combining image processing and two artificial intelligence (AI) techniques. In comparison with common time-consuming laboratory methods for determining these important attributes, this new way is economical and much faster. The accuracy of artificial neural network (ANN) and adaptive neuro-fuzzy inference system (ANFIS) models was studied to estimate the outputs. Sensitivity analysis and principal component analysis were used with ANN and ANFIS respectively to specify the most effective attributes on outputs. RESULTS: Among the designed ANNs, two hidden layer networks with 11-14-9-1 and 11-6-20-1 architectures had the highest correlation coefficients and lowest error values for modeling antioxidant activity (R = 0.93) and anthocyanin content (R = 0.98) respectively. ANFIS models with triangular and two-term Gaussian membership functions gave the best results for antioxidant activity (R = 0.87) and anthocyanin content (R = 0.90) respectively. CONCLUSION: Comparison of the models showed that ANN outperformed ANFIS for this case. By considering the advantages of the applied system and the accuracy obtained in somewhat similar studies, it can be concluded that both techniques presented here have good potential to be used as estimators of proposed attributes. PMID- 23633397 TI - Detection of miRNA in live cells by using templated RuII-catalyzed unmasking of a fluorophore. AB - Reactions templated by cellular nucleic acids are attractive for nucleic acid sensing or responsive systems. Herein we report the use of a photocatalyzed reductive cleavage of an immolative linker to unmask a rhodamine fluorophore, and its application to miRNA imaging. The reaction was found to proceed with a very high turnover (>4000) and provided reliable detection down to 5 pM of template by using gamma-serine-modified peptide nucleic acid (PNA) probes. The reaction was used for the selective detection of miR-21 in BT474 cells and miR-31 in HeLa cells following irradiation for 30 min. The probes were introduced by using reversible permeation with streptolysin-O (SLO) or a transfection technique. PMID- 23633398 TI - Do reductions in brain N-acetylaspartate levels contribute to the etiology of some neuropsychiatric disorders? AB - N-acetylaspartate (NAA) is recognized as a noninvasive diagnostic neuronal marker for a host of neuropsychiatric disorders using magnetic resonance spectroscopy (MRS). Numerous correlative clinical studies have found significant decreases in NAA levels in specific neuronal systems in an array of neuropsychiatric and substance-abuse disorders. We have recently identified the methamphetamine induced neuronal protein known as "shati" as the NAA biosynthetic enzyme (aspartate N-acetyltransferase [Asp-NAT]; gene Nat8l). We have generated an Nat8l transgenic knockout mouse line to study the functions of NAA in the nervous system. We were unable to breed homozygous Nat8l knockout mice successfully for study and so used the heterozygous mice (Nat8l(+/-) ) for initial characterization. MRS analysis of the Nat8l(+/-) mice indicated significant reductions in NAA in cortex (-38%) and hypothalamus (-29%) compared with wild type controls, which was confirmed using HPLC (-29% in forebrain). The level of the neuromodulator N-acetylaspartylglutamate (NAAG), which is synthesized from NAA, was decreased by 12% in forebrain as shown by HPLC. Behavioral analyses of the heterozygous animals indicated normal behavior in most respects but reduced vertical activity in open-field tests compared with age- and sex-matched wild type mice of the same strain. Nat8l(+/-) mice also showed atypical locomotor responses to methamphetamine administration, suggesting that NAA is involved in modulating the hyperactivity effect of methamphetamine. These observations add to accumulating evidence suggesting that NAA has specific regulatory functional roles in mesolimbic and prefrontal neuronal pathways either directly or indirectly through impact on NAAG synthesis PMID- 23633399 TI - Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer. AB - BACKGROUND: Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5 fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. METHODS: Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). RESULTS: The proportions of patients in the 4 subgroups were comparable in both treatment arms (P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P < .0001) and OS (P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively. CONCLUSIONS: Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy. PMID- 23633400 TI - Development of the human heart. AB - Molecular and genetic studies around the turn of this century have revolutionized the field of cardiac development. We now know that the primary heart tube, as seen in the early embryo contains little more than the precursors for the left ventricle, whereas the precursor cells for the remainder of the cardiac components are continuously added, to both the venous and arterial pole of the heart tube, from a single center of growth outside the heart. While the primary heart tube is growing by addition of cells, it does not show significant cell proliferation, until chamber differentiation and expansion starts locally in the tube, by which the chambers balloon from the primary heart tube. The transcriptional repressors Tbx2 and Tbx3 locally repress the chamber-specific program of gene expression, by which these regions are allowed to differentiate into the distinct components of the conduction system. Molecular genetic lineage analyses have been extremely valuable to assess the distinct developmental origin of the various component parts of the heart, which currently can be unambiguously identified by their unique molecular phenotype. Despite the enormous advances in our knowledge on cardiac development, even the most common congenital cardiac malformations are only poorly understood. The challenge of the newly developed molecular genetic techniques is to unveil the basic gene regulatory networks underlying cardiac morphogenesis. PMID- 23633401 TI - Study on a biomimetic enzyme-linked immunosorbent assay method for rapid determination of trace acrylamide in French fries and cracker samples. AB - BACKGROUND: Acrylamide has attracted worldwide concern due to its neurotoxicity, genotoxicity, reproductive-development toxicity. It is necessary to develop an accurate and reliable analytical method to prevent the harm on the human health. RESULTS: In this study, a sensitive and fast analytical method of direct competitive biomimetic enzyme-linked immunosorbent assay (BELISA) was developed using a hydrophilic imprinted membrane as biomimetic antibody. This novel imprinted membrane was directly synthesised on the well surface of MaxiSorp polystyrene 96-well plates in an aqueous environment, and it exhibited high binding ability and specificity toward acrylamide. Under the optimal conditions, the established BELISA method had a good sensitivity (IC50, 8.0 +/- 0.4 mg L(-1)) and a low limit of detection (IC15, 85.0 +/- 4.2 ug L(-1)). The blank potato samples spiked with acrylamide at three levels of 100, 250 and 500 ug L(-1) were extracted and determinate by the proposed method, and good recoveries ranging from 90.0% to 110.5% were obtained. This presented method was applied to the quantitative detection of the acrylamide in French fries and cracker samples. Also, the results were correlated well with that obtained by the gas chromatography method. CONCLUSION: With good properties of high sensitivity, simple pre-treatment and low cost, this BELISA could be a promising screening method in food sample analysis. PMID- 23633402 TI - Prophylactic efficacy of oral emtricitabine and tenofovir disoproxil fumarate combination therapy against a tenofovir-resistant simian/human immunodeficiency virus containing the K65R mutation in macaques. AB - Daily preexposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) is a novel strategy for preventing human immunodeficiency virus infection. We investigated in macaques whether FTC/TDF prevents transmission of a tenofovir-resistant simian/human immunodeficiency virus (SHIV) containing the K65R mutation. Six macaques received weekly a dose of FTC/TDF 3 days before rectal SHIV exposures and a second dose 2 hours after. Six untreated animals were controls. Animals were exposed rectally to escalating virus doses weekly for up to 28 weeks. PrEP significantly delayed infection with SHIVK65R (P = .028), although 4 of 6 FTC/TDF-treated macaques were infected at the end of the challenges. These findings highlight the need to closely monitor PrEP efficacy in areas with prevalent K65R. PMID- 23633404 TI - DNA priming prior to inactivated influenza A(H5N1) vaccination expands the antibody epitope repertoire and increases affinity maturation in a boost-interval dependent manner in adults. AB - DNA priming improves the response to inactivated influenza A(H5N1) vaccination. We compared the immunogenicity of an H5 DNA prime (using strain A/Indonesia/5/2005) followed by an H5N1 monovalent inactivated vaccine boost at 4, 8, 12, 16, or 24 weeks to that of 2 doses of H5N1 monovalent inactivated vaccine in adults. Antibody epitope repertoires were elucidated by genome fragment phage-display library analysis, and antibody avidities for HA1 and HA2 domains were measured by surface plasmon resonance. H5 DNA priming expanded the H5-specific antibody epitope repertoire and enhanced antibody avidity to the HA1 (but not the HA2) domain in an interval-dependent manner. Enhanced HA1 binding and avidity after an interval of >=12 weeks between prime and boost correlated with improved neutralization of homologous and heterologous H5N1 strains. Clinical trials registration NCT01086657. PMID- 23633403 TI - Clinical evaluation of a loop-mediated amplification kit for diagnosis of imported malaria. AB - BACKGROUND: Diagnosis of malaria relies on parasite detection by microscopy or antigen detection; both fail to detect low-density infections. New tests providing rapid, sensitive diagnosis with minimal need for training would enhance both malaria diagnosis and malaria control activities. We determined the diagnostic accuracy of a new loop-mediated amplification (LAMP) kit in febrile returned travelers. METHODS: The kit was evaluated in sequential blood samples from returned travelers sent for pathogen testing to a specialist parasitology laboratory. Microscopy was performed, and then malaria LAMP was performed using Plasmodium genus and Plasmodium falciparum-specific tests in parallel. Nested polymerase chain reaction (PCR) was performed on all samples as the reference standard. Primary outcome measures for diagnostic accuracy were sensitivity and specificity of LAMP results, compared with those of nested PCR. RESULTS: A total of 705 samples were tested in the primary analysis. Sensitivity and specificity were 98.4% and 98.1%, respectively, for the LAMP P. falciparum primers and 97.0% and 99.2%, respectively, for the Plasmodium genus primers. Post hoc repeat PCR analysis of all 15 tests with discrepant results resolved 4 results in favor of LAMP, suggesting that the primary analysis had underestimated diagnostic accuracy. CONCLUSIONS: Malaria LAMP had a diagnostic accuracy similar to that of nested PCR, with a greatly reduced time to result, and was superior to expert microscopy. PMID- 23633405 TI - Highly sensitive detection of malaria parasitemia in a malaria-endemic setting: performance of a new loop-mediated isothermal amplification kit in a remote clinic in Uganda. AB - BACKGROUND: Current malaria diagnostic tests, including microscopy and antigen detecting rapid tests, cannot reliably detect low-density infections. Molecular methods such as polymerase chain reaction (PCR) are highly sensitive but remain too complex for field deployment. A new commercial molecular assay based on loop mediated isothermal amplification (LAMP) was assessed for field use. METHODS: Malaria LAMP (Eiken Chemical, Japan) was evaluated for samples from 272 outpatients at a rural Ugandan clinic and compared with expert microscopy, nested PCR, and quantitative PCR (qPCR). Two technicians performed the assay after 3 days of training, using 2 alternative blood sample-preparation methods and visual interpretation of results by fluorescence assay. RESULTS: Compared with 3-well nested PCR, the sensitivity of both LAMP and single-well nested PCR was 90%; the microscopy sensitivity was 51%. For samples with a Plasmodium falciparum qPCR titer of >= 2 parasites/uL, LAMP sensitivity was 97.8% (95% confidence interval, 93.7%-99.5%). Most false-negative LAMP results involved samples with parasitemia levels detectable by 3-well nested PCR but very low or undetectable by qPCR. CONCLUSIONS: Malaria LAMP in a remote Ugandan clinic achieved sensitivity similar to that of single-well nested PCR in a United Kingdom reference laboratory. LAMP dramatically lowers the detection threshold achievable in malaria-endemic settings, providing a new tool for diagnosis, surveillance, and screening in elimination strategies. PMID- 23633408 TI - Asymmetric Mannich reaction of alpha-keto imines catalyzed by diarylprolinol silyl ether. AB - Synthetic methods: An asymmetric catalytic, desulfonylative Mannich reaction of alpha-keto imines with aldehydes, as catalyzed by diarylprolinol silyl ether 1, was developed. It gave the Mannich product in good yield with excellent anti and enantioselectivity (see scheme; Boc = tert-butoxycarbonyl, TMS = trimethylsilyl). PMID- 23633406 TI - Safety of zoster vaccine in elderly adults following documented herpes zoster. AB - BACKGROUND: After completion of the Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Studies Program Number 403), SPS participants who had initially received placebo were offered investigational zoster vaccine without charge. This provided an opportunity to determine the relative safety of zoster vaccine in older adults following documented herpes zoster (HZ). METHODS: A total of 13 681 SPS placebo recipients who elected to receive zoster vaccine were followed for serious adverse events (SAE) for 28 days after vaccination. In contrast to the SPS, a prior episode of HZ was not a contraindication to receiving zoster vaccine. The SPS placebo recipients who received zoster vaccine included 420 who had developed documented HZ during the SPS. RESULTS: The mean interval between the onset of HZ and the receipt of zoster vaccine in the 420 recipients with prior HZ was 3.61 years (median interval, 3.77 years [range, 3-85 months]); the interval was <5 years for approximately 80% of recipients. The proportion of vaccinated SPS placebo recipients with prior HZ who developed >= 1 SAE (0.95%) was not significantly different from that of vaccinated SPS placebo recipients with no prior history of HZ (0.66%), and the distribution of SAEs in the 2 groups was comparable. CONCLUSIONS: These results demonstrate that the general safety of zoster vaccine in older persons is not altered by a recent history of documented HZ, supporting the safety aspect of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommendation to administer zoster vaccine to all persons >= 60 years of age with no contraindications, regardless of a prior history of HZ. PMID- 23633409 TI - Outcomes in stage I testicular seminoma: a population-based study of 9193 patients. AB - BACKGROUND: Few studies have quantified temporal patterns of cause-specific mortality in contemporary cohorts of men with early-stage seminoma. Given that several management strategies can be applied in these patients, each resulting in excellent long-term survival, it is important to evaluate associated long-term sequelae. In particular, data describing long-term risks of cardiovascular disease (CVD) are conflicting. METHODS: We identified 9193 men diagnosed with stage I seminoma (ages 15-70 years) in the population-based SEER registries (1973 2001). We calculated survival estimates, standardized mortality ratios (SMRs), and adjusted hazard rates (AHRs). RESULTS: During 121,037 person-years of follow up (median, 12.3 years), 915 deaths (SMR, 1.23; 95% CI, 1.16-1.32) were reported, with significant excesses for suicide (n = 39; SMR, 1.45; 95% CI, 1.06-1.98), infection (n = 58; SMR, 2.32; 95% CI, 1.80-3.00), and second malignant neoplasms (SMNs; n = 291; SMR, 1.81; 95% CI, 1.61-2.03), but not CVD (n = 201; SMR, 0.91; 95% CI, 0.80-1.05). After radiotherapy (78% patients), CVD deaths were not increased (n = 158; SMR, 0.89; 95% CI, 0.76-1.04), in contrast to SMN deaths (n = 246; SMR, 1.89; 95% CI, 1.67-2.14). SMN mortality was higher among patients administered radiotherapy than among those not given radiotherapy (AHR, 1.36; 95% CI, 0.99-1.88; P = .059), with a cumulative 15-year risk of 2.64% (95% CI, 2.19 3.16). Suicide, although rare, accounted for 1 in 230 deaths. CONCLUSIONS: Modern radiotherapy as applied in this large population-based study is not associated with excess CVD mortality. Although increased all-cause mortality exists, cumulative SMN risk is considerably smaller than reported in historical series, but additional follow-up will be required to characterize long-term trends. The increased risk of suicide, previously unreported in men with stage I seminoma, requires confirmation. PMID- 23633410 TI - Ring chromosome 9 in a girl with developmental delay and dysmorphic features: case report and review of the literature. AB - In this report, we describe a female child with dysmorphic features and developmental delay. Chromosome microarray analysis followed by conventional karyotyping revealed a ring chromosome 9 with a 12 Mb deletion at 9pter-p23 and a 540 kb deletion at 9q34.3-qter. Four percent of the analyzed cells had monosomy 9. The patient has the features of both the Kleefstra syndrome and the chromosome 9p-syndrome, including trigonocephaly, long philtrum, hypertelorism, and retro /micronagthia. The deletion of the patient overlaps with several of the proposed critical regions for the 9p deletion syndrome. PMID- 23633407 TI - Prime-boost interval matters: a randomized phase 1 study to identify the minimum interval necessary to observe the H5 DNA influenza vaccine priming effect. AB - BACKGROUND: H5 DNA priming was previously shown to improve the antibody response to influenza A(H5N1) monovalent inactivated vaccine (MIV) among individuals for whom there was a 24-week interval between prime and boost receipt. This study defines the shortest prime-boost interval associated with an improved response to MIV. METHODS: We administered H5 DNA followed by MIV at intervals of 4, 8, 12, 16, or 24 weeks and compared responses to that of 2 doses of MIV (prime-boost interval, 24 weeks). RESULTS: H5 DNA priming with an MIV boost >=12 weeks later showed an improved response, with a positive hemagglutination inhibition (HAI) titer in 91% of recipients (geometric mean titer [GMT], 141-206), compared with 55%-70% of recipients with an H5 DNA and MIV prime-boost interval of <=8 weeks (GMT, 51-70) and 44% with an MIV-MIV prime-boost interval of 24 weeks (GMT, 27). CONCLUSION: H5 DNA priming enhances antibody responses after an MIV boost when the prime-boost interval is 12-24 weeks. Clinical Trials Registration. NCT01086657. PMID- 23633411 TI - Divergent regulation of the Osteopontin promoter by the estrogen receptor-related receptors is isoform- and cell context dependent. AB - We sought to determine whether the estrogen receptor-related receptor gamma (mEsrrg) regulated the Osteopontin (Opn) promoter through the same AP1/CAAT box element that we have previously described for mEsrra. In HeLa cells mEsrrg used an additional site present in the 5'UTR, while in ROS17/2.8 cells the AP1/CAAT site was not used, but a completely novel site surrounding the transcription start site was used. We also find that in ROS17/2.8 cells mEsrra repressed, while mEsrrg activated the Opn promoter. None of the sites identified conform to established Esrr response elements (ERREs). Additionally, the two reported mEsrrg protein isoforms showed differences in their activation potential. Mutations in the activation function 2 (AF2) of mEsrra, predicted to abolish activation, surprisingly turned mEsrra into a better activator. In contrast, similar AF2 mutations in Esrrg2 abolished its ability to activate the Opn promoter. Mutation of the DNA binding domain of mEsrra/g2 abolished transcriptional activity in HeLa and ROS17/2.8 cells. Our data indicate, first, that the two Esrr isoforms regulate Opn in a cell context-dependent manner. Second, they suggest that although the DNA binding domains of mEsrra and mEsrrg are 93% identical and required for regulation, the receptors bind to distinct Opn promoter elements, suggesting that the two isoforms may co-regulate Opn, and perhaps other genes, without competing for the same site in the promoter. Finally, the results suggest that each isoform interacts differently with co-activators and co-repressors, as highlighted by the AF2 mutation that turns mEsrra into a better activator but abolishes activity of Esrrg2. PMID- 23633412 TI - Expertise modulates local regional homogeneity of spontaneous brain activity in the resting brain: an fMRI study using the model of skilled acupuncturists. AB - Studies on training/expertise-related effects on human brain in context of neuroplasticity have revealed that plastic changes modulate not only task activations but also patterns and strength of internetworks and intranetworks functional connectivity in the resting state. Much has known about plastic changes in resting state on global level; however, how training/expertise-related effect affects patterns of local spontaneous activity in resting brain remains elusive. We investigated the homogeneity of local blood oxygen level-dependent fluctuations in the resting state using a regional homogeneity (ReHo) analysis among 16 acupuncturists and 16 matched nonacupuncturists (NA). To prove acupuncturists' expertise, we used a series of psychophysical tests. Our results demonstrated that, acupuncturists significantly outperformed NA in tactile-motor and emotional regulation domain and the acupuncturist group showed increased coherence in local BOLD signal fluctuations in the left primary motor cortex (MI), the left primary somatosensory cortex (SI) and the left ventral medial prefrontal cortex/orbitofrontal cortex (VMPFC/OFC). Regression analysis displayed that, in the acupuncturists group, ReHo of VMPFC/OFC could predict behavioral outcomes, evidenced by negative correlation between unpleasantness ratings and ReHo of VMPFC/OFC and ReHo of SI and MI positively correlated with the duration of acupuncture practice. We suggest that expertise could modulate patterns of local resting state activity by increasing regional clustering strength, which is likely to contribute to advanced local information processing efficiency. Our study completes the understanding of neuroplasticity changes by adding the evidence of local resting state activity alterations, which is helpful for elucidating in what manner training effect extends beyond resting state. PMID- 23633413 TI - Digestive recovery of sulfur-methyl-L-methionine and its bioaccessibility in Kimchi cabbages using a simulated in vitro digestion model system. AB - BACKGROUND: Sulfur-methyl-L-methionine (SMM) has been known to provide various biological functions such as radical scavenging effect, inhibition of adipocyte differentiation, and prevention of gastric mucosal damage. Kimchi cabbages are known to be a major food source providing SMM but its bioaccessibility has not been studied. The objective of current study was to determine both the digestive stability of SMM and the amount released from Kimchi cabbages under a simulated in vitro digestion model system. RESULTS: The in vitro digestion model system simulating a human gastrointestinal tract was carried out for measuring digestive recovery and bioaccessibility of SMM. SMM was quantified by using high performance liquid chromatography with a fluorescence detector. Recovery of an SMM standard after digestion was 0.68 and 0.65% for fasted and fed conditions, respectively, indicating that the digestive stability of the SMM standard was not affected by dietary energy or co-ingested food matrix. The SMM standard was also significantly stable in acidic pH (P < 0.05). The bioaccessibility of SMM from Kimchi cabbages was measured under a fasted condition, resulted in 8.83, 14.71 and 10.88%, for salivary, gastric and small intestinal phases, respectively. CONCLUSION: Results from our study suggest that SMM from Kimchi cabbages, a component of food sources, is more bioavailable than SMM by itself. PMID- 23633414 TI - A leading role for the immune system in the pathophysiology of preeclampsia. AB - Preeclampsia syndrome is characterized by inadequate placentation, because of deficient trophoblastic invasion of the uterine spiral arteries, leading to placental hypoxia, secretion of proinflammatory cytokines, the release of angiogenic and antiangiogenic factors and miRNAs. Although immune-system alterations are associated with the origin of preeclampsia, other factors, including proinflammatory cytokines, neutrophil activation, and endothelial dysfunction, are also related to the pathophysiology of this syndrome. The pathophysiology of preeclampsia may involve several factors, including persistent hypoxia at the placental level and the release of high amounts of STBMs. DAMP molecules released under hypoxic conditions and STBMs, which bind TLRs, may activate monocytes, DCs, NK cells, and neutrophils, promoting persistent inflammatory conditions in this syndrome. The development of hypertension in preeclamptic women is also associated with endothelial dysfunction, which may be mediated by various mechanisms, including neutrophil activation and NET formation. Furthermore, preeclamptic women have higher levels of nonclassic and intermediate monocytes and lower levels of lymphoid BDCA-2(+) DCs. The cytokines secreted by these cells may contribute to the inflammatory process and to changes in adaptive-immune system cells, which are also modulated in preeclampsia. The changes in T cell subsets that may be seen in preeclampsia include low Treg activity, a shift toward Th1 responses, and the presence of Th17 lymphocytes. B cells can participate in the pathophysiology of preeclampsia by producing autoantibodies against adrenoreceptors and autoantibodies that bind the AT1-R. PMID- 23633415 TI - Real-world outcomes of US employees with type 2 diabetes mellitus treated with insulin glargine or neutral protamine Hagedorn insulin: a comparative retrospective database study. AB - OBJECTIVES: To compare real-world outcomes of initiating insulin glargine (GLA) versus neutral protamine Hagedorn (NPH) insulin among employees with type 2 diabetes mellitus (T2DM) who had both employer-sponsored health insurance and short-tem-disability coverages. DESIGN: Retrospective cohort study. SETTING: MarketScan Commercial Claims and Encounters/Health and Productivity Management Databases 2003-2009. PARTICIPANTS: Adult employees with T2DM who were previously treated with oral antidiabetic drugs and/or glucagon-like-peptide 1 receptor agonists and initiated GLA or NPH were included if they were continuously enrolled in healthcare and short-term-disability coverages for 3 months before (baseline) and 1 year after (follow-up) initiation. Treatment selection bias was addressed by 2:1 propensity score matching. Sensitivity analyses were conducted using different matching ratios. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcomes during 1-year follow-up were measured and compared: insulin treatment persistence and adherence; hypoglycaemia rates and daily average consumption of insulin; total and diabetes-specific healthcare resource utilisation and costs and loss in productivity, as measured by short-term disability, and the associated costs. RESULTS: A total of 534 patients were matched and analysed (GLA: 356; NPH 178) with no significant differences in baseline characteristics. GLA patients were more persistent and adherent (both p<0.05), had lower rates of hospitalisation (23% vs 31.4%; p=0.036) and endocrinologist visits (19.1% vs 26.9%; p=0.038), similar hypoglycaemia rates (both 4.4%; p=1.0), higher diabetes drug costs ($2031 vs $1522; p<0.001), but similar total healthcare costs ($14 550 vs $16 093; p=0.448) and total diabetes-related healthcare costs ($4686 vs $5604; p=0.416). Short-term disability days and costs were numerically lower in the GLA cohort (16.0 vs 24.5 days; p=0.086 and $2824 vs $4363; p=0.081, respectively). Sensitivity analyses yielded similar findings. CONCLUSIONS: Insulin GLA results in better persistence and adherence, compared with NPH insulin, with no overall cost disadvantages. Better persistence and adherence may lead to long-term health benefits for employees with T2DM. PMID- 23633416 TI - The association of alcohol drinking pattern and self-inflicted intentional injury in Korea: a cross-sectional WHO collaborative emergency room study. AB - OBJECTIVES: Self-inflicted intentional injuries are increasing at an alarming rate in the Republic of Korea, yet few reports describe their relationship with alcohol consumption. The aim of this study was to characterise the association of alcohol drinking patterns and self-inflicted intentional injury in Korean emergency departments (EDs) using WHO collaborative study protocol. DESIGN: Cross sectional study. SETTING: Data were collected from four general hospital EDs in four geographically diverse regions of Korea: Seoul, Suwon, Chuncheon and Gwangju. PARTICIPANTS: Information was collected on 1989 patients aged 18 and above. A representative probability sample was drawn from patients admitted to each ED for the first time within 6 h of injury. PRIMARY AND SECONDARY OUTCOME MEASURES: Alcohol-related non-fatal injuries. RESULTS: Among 467 persons with alcohol-related injuries, 33 (7.1%), were self-inflicted intentional injuries and 137 (29.3%) were intentional injuries caused by someone else. The adjusted odds of self-inflicted intentional injury verses unintentional injury were calculated for heavy (OR 1.764; 95% CI 0.783 to 3.976), binge (OR 2.125; 95% CI 0.930 to 4.858) and moderate drinking (OR 3.039; 95% CI 1.129 to 8.178) after controlling for demographic variables. Similar odds were reported for pooled intentional injury data (self-inflicted and caused by someone else) and drinking patterns. CONCLUSIONS: These data show a strong association between all patterns of acute alcohol consumption and self-inflicted intentional injury in the Republic of Korea. PMID- 23633417 TI - Correction. PMID- 23633418 TI - Semen quality of 1559 young men from four cities in Japan: a cross-sectional population-based study. AB - OBJECTIVES: To provide information of semen quality among normal young Japanese men and indicate the frequency of reduced semen quality. DESIGN: Cross-sectional, coordinated studies of Japanese young men included from university areas. The men had to be 18-24 years, and both the man and his mother had to be born in Japan. Background information was obtained from questionnaires. Standardised and quality controlled semen analyses were performed, reproductive hormones analysed centrally and results adjusted for confounding factors. SETTING: Four study centres in Japan (Kawasaki, Osaka, Kanazawa and Nagasaki). PARTICIPANTS: 1559 men, median age 21.1 years, included during 1999-2003. OUTCOME MEASURES: Semen volume, sperm concentration, total sperm count, sperm motility, sperm morphology and reproductive hormone levels. RESULTS: Median sperm concentration was 59 (95% CI 52 to 68) million/ml, and 9% and 31.9% had less than 15 and 40 million/ml, respectively. Median percentage of morphologically normal spermatozoa was 9.6 (8.8 to 10.3)%. Small, but statistically significant, differences were detected for both semen and reproductive hormone variables between men from the four cities. Overall, the semen values were lower than those of a reference population of 792 fertile Japanese men. CONCLUSIONS: Assuming that the investigated men were representative for young Japanese men, a significant proportion of the population had suboptimal semen quality with reduced fertility potential, and as a group they had lower semen quality than fertile men. However, the definitive role-if any-of low semen quality for subfertility and low fertility rates remain to be investigated. PMID- 23633419 TI - The eye response test alone is sufficient to predict stroke outcome- reintroduction of Japan Coma Scale: a cohort study. AB - OBJECTIVES: Prompt assessment of consciousness levels is vitally important during the emergency care of stroke patients. The Japan Coma Scale (JCS) is a one-axis coma scale published in 1974 with outstanding simplicity. The hypothesis is that JCS is sufficient to predict stroke outcome. The aim of the study was to verify the predictability of JCS, which should help JCS attain international recognition. DESIGN: A cohort study. SETTING: A prefectural stroke registry. PARTICIPANTS: We analysed 13 788 stroke patients identified from January 1999 to December 2009 inclusive in the entire Kyoto prefecture and registered in the Kyoto Stroke Registry (KSR). MAIN OUTCOME MEASURES: We investigated the relationship between consciousness levels, based on JCS at stroke onset and activities of daily living (ADL) at 30 days or deaths within 30 days in a large population-based stroke registry. We calculated Spearman's coefficient for the correlation between JCS and the ADL scale, generated estimated survival curves by the Kaplan-Meier method and finally compared HRs for death within 30 days after onset, comparing patients with different conscious levels based on JCS. RESULTS: A total of 13 406 (97.2%) patients were graded based on JCS. JCS correlated to the ADL scale with Spearman's correlation coefficient of 0.61. HRs for death within 30 days were 1 (reference) (95% CIs), 5.55 (4.19 to 7.37), 9.54 (7.16 to 12.71) and 35.21 (26.10 to 44.83) in those scored as JCS0, JCS1, JCS2 and JCS3, respectively. CONCLUSIONS: Using a single test of eye response, JCS has outstanding merits as a coma scale, that is, simplicity and applicability. The present study adds predictability for early outcome in stroke patients. JCS is valuable, especially in an emergency setting, when a prompt assessment of consciousness levels is needed. PMID- 23633420 TI - The benefits of thermal clothing during winter in patients with heart failure: a pilot randomised controlled trial. AB - OBJECTIVES: To examine whether providing thermal clothing to heart failure patients improves their health during winter. DESIGN: A randomised controlled trial with an intervention group and a usual care group. SETTING: Heart failure clinic in a large tertiary referral hospital in Brisbane, Australia. PARTICIPANTS: Eligible participants were those with known systolic heart failure who were over 50 years of age and lived in Southeast Queensland. Participants were excluded if they lived in a residential aged care facility, had incontinence or were unable to give informed consent. Fifty-five participants were randomised and 50 completed. INTERVENTIONS: Participants randomised to the intervention received two thermal hats and tops and a digital thermometer. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the mean number of days in hospital. Secondary outcomes were the number of general practitioner (GP) visits and self-rated health. RESULTS: The mean number of days in hospital per 100 winter days was 2.5 in the intervention group and 1.8 in the usual care group, with a mean difference of 0.7 (95% CI -1.5 to 5.4). The intervention group had 0.2 fewer GP visits on average (95% CI -0.8 to 0.3), and a higher self-rated health, mean improvement -0.3 (95% CI -0.9 to 0.3). The thermal tops were generally well used, but even in cold temperatures the hats were only worn by 30% of the participants. CONCLUSIONS: Thermal clothes are a cheap and simple intervention, but further work needs to be done on increasing compliance and confirming the health and economic benefits of providing thermals to at-risk groups. TRIAL REGISTRATION: The study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000378820). PMID- 23633421 TI - Determining immunisation status of children from history: a diagnostic accuracy study. AB - OBJECTIVES: Children presenting unplanned to healthcare services are routinely asked about previous immunisations as part of their assessment. We aimed to assess the accuracy of screening children for immunisation status by history. DESIGN: Diagnostic accuracy study. We compared information from patient history by a retrospective review of notes and used a central database of child immunisation records as the reference standard. SETTING: Paediatric emergency department in a tertiary hospital in Oxford, UK. PARTICIPANTS: Consecutive children aged 6 months to 6 years presenting over a 2-month period. OUTCOME MEASURES: Proportion of children with documented immunisation history; sensitivity and specificity of detecting overdue immunisations by history compared to central records. RESULTS: 1166 notes were surveyed. 76.3% children were asked about immunisations. The proportion of children who were fully immunised on central records was 93.1%. History had a sensitivity of 41.3% (95% CI 27% to 56.8%) and a specificity of 98.7% (95% CI 97.5% to 99.4%) for detecting those who were overdue. Negative predictive value was 95.8% (95% CI 93.9% to 97.2%). Only around a third of children with overdue immunisations are detected by the current screening methods, and approximately 1 in 20 children stated as being up to date are in fact overdue. CONCLUSIONS: History had poor sensitivity for identifying overdue immunisation. Strategies to improve detection of children overdue with immunisation should focus on alternative strategies for alerting clinicians, such as linkage of community and hospital electronic records. PMID- 23633422 TI - Influence of societal and practice contexts on health professionals' clinical reasoning: a scoping study protocol. AB - INTRODUCTION: In a context of constrained resources, the efficacy of interventions is a pivotal aim of healthcare systems worldwide. Efficacy of healthcare interventions is highly compromised if clinical reasoning (CR), the process that practitioners use to plan, direct, perform and reflect on client care, is not optimal. The CR process of health professionals is influenced by the institutional dimension (ie, legal, regulatory, administrative and organisational aspects) of their societal and practice contexts. Although several studies have been conducted with respect to the institutional dimension influencing health professionals' CR, no clear integration of their results is yet available. The aim of this study is to synthesise and disseminate current knowledge on the influence of the institutional dimension of contexts on health professionals' CR. METHODS AND ANALYSIS: A scoping study of the scientific literature from January 1980 to March 2013 will be undertaken to summarise and disseminate research findings about the influence of the institutional dimension on CR. Numerous databases (n=18) from three relevant fields (healthcare, health law and politics and management) will be searched. Extended search strategies will include the manual search of bibliographies, health-related websites, public registries and journals of interest. Data will be collected and analysed using a thematic chart and content analysis. A systematic multidisciplinary team approach will allow optimal identification of relevant studies, as well as effective and valid content analysis and dissemination of the results. DISCUSSION: This scoping study will provide a rigorous, accurate and up-to-date synthesis of existing knowledge regarding: (1) those aspects of the institutional dimension of health professionals' societal and practice contexts that impact their CR and (2) how these aspects influence health professionals' CR. Through the synergy of a multidisciplinary research team from a wide range of expertise, clinical pertinence and an exhaustive dissemination of results to knowledge-users will be ensured. PMID- 23633423 TI - Portrait of rural emergency departments in Quebec and utilisation of the Quebec Emergency Department Management Guide: a study protocol. AB - INTRODUCTION: Emergency departments are important safety nets for people who live in rural areas. Moreover, a serious problem in access to healthcare services has emerged in these regions. The challenges of providing access to quality rural emergency care include recruitment and retention issues, lack of advanced imagery technology, lack of specialist support and the heavy reliance on ambulance transport over great distances. The Quebec Ministry of Health and Social Services published a new version of the Emergency Department Management Guide, a document designed to improve the emergency department management and to humanise emergency department care and services. In particular, the Guide recommends solutions to problems that plague rural emergency departments. Unfortunately, no studies have evaluated the implementation of the proposed recommendations. METHODS AND ANALYSIS: To develop a comprehensive portrait of all rural emergency departments in Quebec, data will be gathered from databases at the Quebec Ministry of Health and Social Services, the Quebec Trauma Registry and from emergency departments and ambulance services managers. Statistics Canada data will be used to describe populations and rural regions. To evaluate the use of the 2006 Emergency Department Management Guide and the implementation of its various recommendations, an online survey and a phone interview will be administered to emergency department managers. Two online surveys will evaluate quality of work life among physicians and nurses working at rural emergency departments. Quality of-care indicators will be collected from databases and patient medical files. Data will be analysed using statistical (descriptive and inferential) procedures. ETHICS AND DISSEMINATION: This protocol has been approved by the CSSS Alphonse Desjardins research ethics committee (Project MP-HDL-1213-011). The results will be published in peer-reviewed scientific journals and presented at one or more scientific conferences. PMID- 23633424 TI - Discordant chromosome placental mosaicism in a dichorionic twin pregnancy. PMID- 23633425 TI - Assessment of tonotopically organised subdivisions in human auditory cortex using volumetric and surface-based cortical alignments. AB - Although orderly representations of sound frequency in the brain play a guiding role in the investigation of auditory processing, a rigorous statistical evaluation of cortical tonotopic maps has so far hardly been attempted. In this report, the group-level significance of local tonotopic gradients was assessed using mass-multivariate statistics. The existence of multiple fields on the superior surface of the temporal lobe in both hemispheres was shown. These fields were distinguishable on the basis of tonotopic gradient direction and may likely be identified with the human homologues of the core areas AI and R in primates. Moreover, an objective comparison was made between the usage of volumetric and surface-based registration methods. Although the surface-based method resulted in a better registration across subjects of the grey matter segment as a whole, the alignment of functional subdivisions within the cortical sheet did not appear to improve over volumetric methods. This suggests that the variable relationship between the structural and the functional characteristics of auditory cortex is a limiting factor that cannot be overcome by morphology-based registration techniques alone. Finally, to illustrate how the proposed approach may be used in clinical practice, the method was used to test for focal differences regarding the tonotopic arrangements in healthy controls and tinnitus patients. No significant differences were observed, suggesting that tinnitus does not necessarily require tonotopic reorganisation to occur. PMID- 23633426 TI - Catalytic enantioselective allylation of ketimines by using palladium pincer complexes with chiral bis(imidazoline)s. AB - Get selective! Enantioselective allylation of ketimines derived from isatins by using chiral 1,3-bis(imidazolin-2-yl)benzene (Phebim)-Pd(II) complexes afforded products with good enantioselectivity (see scheme). The reaction was applied to a wide variety of ketimines. The obtained product can be converted to homoallylic amines and a spirocyclic amine without the loss of enantiopurity. PMID- 23633427 TI - Occurrence and degree of intersex (testis-ova) in darters (Etheostoma SPP.) across an urban gradient in the Grand River, Ontario, Canada. AB - The variability and extent of the intersex condition (oocytes in testes, or testis-ova) was documented in fish along an urban gradient in the Grand River, Ontario, Canada, that included major wastewater treatment plant outfalls. A method for rapid enumeration of testis-ova was developed and applied that increased the capacity to quantify intersex prevalence and severity. Male rainbow darters (Etheostoma caeruleum) sampled downstream of the first major wastewater outfall (Waterloo) had a significant increase, relative to 4 upstream reference sites, in the mean proportion of fish with at least 1 testis-oocyte per lobe of testes (9-20% proportion with <= 1 testis-oocyte/lobe vs 32-53% and >1.4 testis oocyte/lobe). A much higher mean incidence of intersex proportion and degree was observed immediately downstream of the second wastewater outfall (Kitchener; 73 100% and 8-70 testis-oocyte/lobe); but only 6.3 km downstream of the Kitchener outfall, the occurrence of intersex dropped to those of the reference sites. In contrast, downstream of a tertiary treated wastewater outfall on a small tributary, intersex was similar to reference sites. Estrogenicity, measured using a yeast estrogen screen, followed a similar pattern, increasing from 0.81 +/- 0.02 ng/L 17b-estradiol equivalents (EEq) (Guelph), to 4.32 +/- 0.07 ng/L (Waterloo), and 16.99 +/- 0.40 ng/L (Kitchener). Female rainbow darter downstream of the Kitchener outfall showed significant decreases in gonadosomatic index and liver somatic index, and increases in condition factor (k) relative to corresponding reference sites. The prevalence of intersex and alterations in somatic indices suggest that exposure to municipal wastewater effluent discharges can impact endocrine function, energy use, and energy storage in wild fish. PMID- 23633428 TI - Effect of organic, conventional and mixed cultivation practices on soil microbial community structure and nematode abundance in a cultivated onion crop. AB - BACKGROUND: Responses of the soil microbial and nematode community to organic and conventional agricultural practices were studied using the Teagasc Kinsealy Systems Comparison trial as the experimental system. The trial is a long-term field experiment which divides conventional and organic agriculture into component pest-control and soil treatment practices. We hypothesised that management practices would affect soil ecology and used community level physiological profiles, microbial and nematode counts, and denaturing gradient gel electrophoresis (DGGE) to characterise soil microbial communities in plots used for onion (Allium cepa L.) cultivation. RESULTS: Microbial activity and culturable bacterial counts were significantly higher under fully organic management. Culturable fungi, actinomycete and nematode counts showed a consistent trend towards higher numbers under fully organic management but these data were not statistically significant. No differences were found in the fungal/bacterial ratio. DGGE banding patterns and sequencing of excised bands showed clear differences between treatments. Putative onion fungal pathogens were predominantly sequenced under conventional soil treatment practices whilst putative soil suppressive bacterial species were predominantly sequenced from the organic pest-control treatment plots. CONCLUSION: Organic management increased microbial activity and diversity. Sequence data was indicative of differences in functional groups and warrants further investigation. PMID- 23633429 TI - Intensity-modulated radiotherapy (IMRT) in pediatric low-grade glioma. AB - BACKGROUND: The objective of this study was to evaluate local control and patterns of failure in pediatric patients with low-grade glioma (LGG) who received treatment with intensity-modulated radiation therapy (IMRT). METHODS: In total, 39 children received IMRT after incomplete resection or disease progression. Three methods of target delineation were used. The first was to delineate the gross tumor volume (GTV) and add a 1-cm margin to create the clinical target volume (CTV) (Method 1; n = 19). The second was to add a 0.5-cm margin around the GTV to create the CTV (Method 2; n = 6). The prescribed dose to the GTV was the same as dose to the CTV for both Methods 1 and 2 (median, 50.4 grays [Gy]). The final method was dose painting, in which a GTV was delineated with a second target volume (2TV) created by adding 1 cm to the GTV (Method 3; n = 14). Different doses were prescribed to the GTV (median, 50.4 Gy) and the 2TV (median, 41.4 Gy). RESULTS: The 8-year progression-free and overall survival rates were 78.2% and 93.7%, respectively. Seven failures occurred, all of which were local in the high-dose (>=95%) region of the IMRT field. On multivariate analysis, age <=5 years at time of IMRT had a detrimental impact on progression free survival. CONCLUSIONS: IMRT provided local control rates comparable to those provided by 2-dimensional and 3-dimensional radiotherapy. Margins >=1 cm added to the GTV may not be necessary, because excellent local control was achieved by adding a 0.5-cm margin (Method 2) and by dose painting (Method 3). PMID- 23633430 TI - A novel inverted 17p13.3 microduplication disrupting PAFAH1B1 (LIS1) in a girl with syndromic lissencephaly. AB - We describe a female patient with mild lissencephaly (pachygyria), severe intellectual disability, and facial dysmorphisms with an inverted 1.4 Mb microduplication of chromosome 17p13.3. The 17p13.3 microduplication syndrome is associated with mild intellectual disabiltiy and contains, among others, the PAFAH1B1 (LIS1) gene, whereas microdeletions of the same segment cause Miller Dieker syndrome (MDS) with severe to profound retardation. The duplication identified in our patient encompasses 29 genes, including CRK and YWHAE. The proximal breakpoint of the duplication is located in the first intron of the PAFAH1B1 gene. Analysis of total RNA showed that only one PAFAH1B1 allele is expressed. Therefore, this patient has a unique alteration: a duplication including YWHAE and CRK and haploinsufficiency of PAFAH1B1. Overexpression of YWHAE is associated with macrosomia, mild developmental delay, autism and facial dysmorphisms, and deletion of PAFAH1B1 alone leads to isolated lissencephaly (ILS). The patient described here shares features with MDS, but she is affected to a lesser degree. Her facial features are similar to MDS, and she has manifestations seen in other cases with YWHAE duplication. PMID- 23633431 TI - Intrahemispheric and interhemispheric structural network abnormalities in PLS and ALS. AB - Using diffusion tensor (DT) magnetic resonance imaging (MRI), damage to brain intrahemispheric and interhemispheric connections was assessed in 26 sporadic primary lateral sclerosis (PLS) patients compared with 28 sporadic amyotrophic lateral sclerosis (ALS) patients with similar disability and 35 healthy controls. DT MRI diagnostic accuracy in distinguishing the two motor neuron disease (MND) variants was tested. PLS and ALS patients showed a distributed pattern of abnormalities of the motor system, including the corticospinal tracts and corpus callosum (CC). PLS versus ALS patients showed a more severe damage to the motor CC fibers and subcortical white matter (WM) underlying the primary motor cortices. Both patient groups showed an extra-motor damage, which was more severe in PLS. This did not appear to be driven by longer disease duration in PLS. In PLS patients, damage to the CC mid-body correlated with the severity of upper motor neuron clinical burden. CC fractional anisotropy values had the highest accuracy in distinguishing PLS from controls and ALS. PLS and ALS share an overlapped pattern of WM abnormalities. This underscores that PLS, despite its distinct clinical phenotype and long survival, still lies within the wider MND spectrum. Whether CC diffusivity may be a novel marker to increase confidence in an early diagnostic separation of PLS from ALS still needs to be investigated. PMID- 23633434 TI - Tobacco use and external beam radiation therapy for prostate cancer: Influence on biochemical control and late toxicity. AB - BACKGROUND: The objective of this study was to examine the effect of tobacco use on disease control and late gastrointestinal and genitourinary toxicity in men undergoing external beam radiotherapy (EBRT) for prostate cancer. METHODS: In total, 633 men with known tobacco history at consultation underwent definitive EBRT between 1988 and 2008. Tobacco use was defined as positive (current or prior) or negative (never). The median EBRT dose was 74 gray (Gy). In univariate analysis, tobacco use and other prognostic factors were compared with disease control and toxicity. Multivariable analysis included tobacco use and the covariates that were associated with outcome on univariate analysis (P < .1). RESULTS: The rate of 5-year freedom from biochemical failure (FFBF) was 76% for current smokers, 81% for prior smokers, and 87% for never smokers (P < .02). Risk group, the percentage of involved cores, and EBRT dose >=74 Gy were associated with FFBF (all P < .01). On multivariable analysis, smoking was not associated with FFBF (P = .19). Factors that were associated with late grade >=2 genitourinary toxicity on univariate analysis included positive tobacco history, intensity-modulated radiotherapy, and EBRT dose >=74 Gy (all P < .05). Prior transurethral resection of the prostate (P < .01) and current smoking status (P = .06) were associated with grade >=3 toxicity. On multivariable analysis, a positive tobacco history was associated with grade >=2 toxicity (hazard ratio, 1.45; P < .02), and current smoking status was associated with grade >=3 toxicity (hazard ratio, 3.02; P < .05). Tobacco use was not associated with late gastrointestinal toxicity. CONCLUSIONS: In men who are receiving EBRT for prostate cancer, tobacco use may be associated with higher rates of late grade >=2 toxicity, and current smokers may have higher rates of late grade >=3 genitourinary toxicity. PMID- 23633432 TI - Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. AB - Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow-derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations, the otherwise prometastatic Gr1(+) myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. Bone marrow specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by bone marrow transplant from Tsp-1(+) donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacologic inducer of Tsp-1 in Gr1(+) bone marrow cells, which dramatically suppressed metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1(+) myeloid cells as the main source of Tsp 1. The results underscore the plasticity of Gr1(+) cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer. SIGNIFICANCE: The mechanisms of metastasis suppression are poorly understood. Here, we have identified a novel mechanism whereby metastasis-incompetent tumors generate metastasis-suppressive microenvironments in distant organs by inducing Tsp-1 expression in the bone marrow-derived Gr1+myeloid cells. A 5-amino acid peptide with Tsp-1-inducing activity was identified as a therapeutic agent against metastatic cancer. PMID- 23633435 TI - Reproductive success of belted kingfishers on the upper Hudson River. AB - Belted kingfishers (Megaceryle alcyon) are predators in many North American aquatic ecosystems; as such, they are prone to bioaccumulation of certain environmental contaminants. In 2002 and 2004, kingfisher eggs collected near the upper Hudson River in New York had elevated concentrations of polychlorinated biphenyls (PCBs), and the kingfisher population in this area was reported to be at risk because of PCB exposure. From 2007 to 2009, the authors monitored 69 kingfisher nests on the Hudson River to track both nest success and survival of individual nestlings. The study site consisted of 2 adjacent sections of the Hudson River, 1 upstream and 1 downstream of a historic PCB source. The authors compared models of nest success that differentially incorporated the following 4 variables that they deemed most likely to affect reproductive output: 1) river section (upstream vs downstream of PCB source), 2) year, 3) hatch date, and 4) abandonment by 1 parent. After ranking models according to Akaike's information criterion for small sample sizes, it was clear that parental abandonment was the most important of the factors examined. River section was not an important parameter, and overall nesting success was slightly higher in the PCB contaminated section than in the upstream area. These findings support the conclusion that kingfisher productivity is not adversely impacted by PCB contamination in the upper Hudson River. PMID- 23633436 TI - A sampling approach for predicting the eating quality of apples using visible near infrared spectroscopy. AB - BACKGROUND: Visible-near infrared spectroscopy remains a method of increasing interest as a fast alternative for the evaluation of fruit quality. The success of the method is assumed to be achieved by using large sets of samples to produce robust calibration models. In this study we used representative samples of an early and a late season apple cultivar to evaluate model robustness (in terms of prediction ability and error) on the soluble solids content (SSC) and acidity prediction, in the wavelength range 400-1100 nm. RESULTS: A total of 196 middle early season and 219 late season apples (Malus domestica Borkh.) cvs 'Aroma' and 'Holsteiner Cox' samples were used to construct spectral models for SSC and acidity. Partial least squares (PLS), ridge regression (RR) and elastic net (EN) models were used to build prediction models. Furthermore, we compared three sub sample arrangements for forming training and test sets ('smooth fractionator', by date of measurement after harvest and random). Using the 'smooth fractionator' sampling method, fewer spectral bands (26) and elastic net resulted in improved performance for SSC models of 'Aroma' apples, with a coefficient of variation CVSSC = 13%. The model showed consistently low errors and bias (PLS/EN: R(2) cal = 0.60/0.60; SEC = 0.88/0.88 degrees Brix; Biascal = 0.00/0.00; R(2) val = 0.33/0.44; SEP = 1.14/1.03; Biasval = 0.04/0.03). However, the prediction acidity and for SSC (CV = 5%) of the late cultivar 'Holsteiner Cox' produced inferior results as compared with 'Aroma'. CONCLUSION: It was possible to construct local SSC and acidity calibration models for early season apple cultivars with CVs of SSC and acidity around 10%. The overall model performance of these data sets also depend on the proper selection of training and test sets. The 'smooth fractionator' protocol provided an objective method for obtaining training and test sets that capture the existing variability of the fruit samples for construction of visible-NIR prediction models. The implication is that by using such 'efficient' sampling methods for obtaining an initial sample of fruit that represents the variability of the population and for sub-sampling to form training and test sets it should be possible to use relatively small sample sizes to develop spectral predictions of fruit quality. Using feature selection and elastic net appears to improve the SSC model performance in terms of R(2), RMSECV and RMSEP for 'Aroma' apples. PMID- 23633438 TI - Population-based evaluation of incidence trends in oropharyngeal cancer focusing on socioeconomic status, sex, and race/ethnicity. AB - BACKGROUND: The influences of socioeconomic status (SES) on the incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) are unclear. METHODS: Data from the California Cancer Registry and U.S. Census were used to compare incidence rates and trends of OPSCC and other human papillomavirus-related and -unrelated cancer sites by neighborhood SES, race/ethnicity, and sex. RESULTS: The incidence of OPSCC rose in both higher and lower SES neighborhoods. Absolute rates were greater in the latter. Only non-Hispanic white males with OPSCC demonstrated a significant increase in the incidence rate of squamous cell carcinoma of the head and neck (SCCHN). The incidence rate for this group increased from 4.5/100,000 person-years between 1988 and 1992 to 7.1 between 2003 and 2009. Regression analysis demonstrated an annual percentage change of 1% from 1988 to 1997 and 4% thereafter. CONCLUSIONS: Increases in incidence rates are SES independent. Incidence rates are higher in lower-SES groups. The rise in OPSCC incidence is limited to non-Hispanic white males. PMID- 23633437 TI - Mucopolysaccharidosis type VI: a predominantly cardiac phenotype associated with homozygosity for p.R152W mutation in the ARSB gene. AB - Mucopolysaccharidosis type VI (MPS VI) is a rare lysosomal, autosomal recessive storage disorder caused by deficient activity of N-acetylgalactosamine-4 sulfatase (ARSB). Approximately, 140 ARSB gene mutations have been identified; however, most are private mutations making genotype-phenotype correlation for most MPS VI patients difficult. The aim of this study was to describe the natural clinical course in patients homozygous for the p.R152W mutation from eight unrelated families. From our database of 70 patients with MPS VI, we selected 10 patients homozygous for the p.R152W mutant allele (median age 27.5 years, range 18-38 years). We performed a cross-sectional observational study characterizing the onset and prevalence of clinical manifestations. First signs of the disease, such as cardiac valve disease, slightly decreased joint range of motion and mild growth retardation, were observed in mid-adolescent years (median 15 years). Within the disease course, the most common clinical feature in all the patients was progressive heart disease of predominantly valve origin leading to symptoms of heart failure. Other typical MPS VI features were subtle and not present in all the patients. Delays up to 23 years (median 8.5 years) intervened between symptom onset and disease diagnosis. Patients homozygous for the p.R152W mutation present a cardiac variant of MPS VI characterized by progressive cardiac valve disease leading to serious cardiac complications including abrupt death due to cardiac failure. PMID- 23633439 TI - On the planum temporale lateralization in suprasegmental speech perception: evidence from a study investigating behavior, structure, and function. AB - This study combines functional and structural magnetic resonance imaging to test the "asymmetric sampling in time" (AST) hypothesis, which makes assertions about the symmetrical and asymmetrical representation of speech in the primary and nonprimary auditory cortex. Twenty-three volunteers participated in this parametric clustered-sparse fMRI study. The availability of slowly changing acoustic cues in spoken sentences was systematically reduced over continuous segments with varying lengths (100, 150, 200, 250 ms) by utilizing local time reversion. As predicted by the hypothesis, functional lateralization in Heschl's gyrus could not be observed. Lateralization in the planum temporale and posterior superior temporal gyrus shifted towards the right hemisphere with decreasing suprasegmental temporal integrity. Cortical thickness of the planum temporale was automatically measured. Participants with an L > R cortical thickness performed better on the in-scanner auditory pattern-matching task. Taken together, these findings support the AST hypothesis and provide substantial novel insight into the division of labor between left and right nonprimary auditory cortex functions during comprehension of spoken utterances. In addition, the present data yield support for a structural-behavioral relationship in the nonprimary auditory cortex. PMID- 23633440 TI - Spondyloepimetaphyseal dysplasia Pakistani type: expansion of the phenotype. AB - Spondyloepimetaphyseal dysplasia (SEMD), Pakistani type, is a skeletal dysplasia characterized by platyspondyly, delayed epiphyseal ossification, mild metaphyseal abnormalities, short stature, and short and bowed legs, and is caused by mutations in PAPSS2. In a single Turkish patient also hyperandrogenism was reported. We describe five patients from a Turkish family with SEMD Pakistani type with homozygosity for a nonsense mutation (p.R329X) leading to a stop codon in PAPSS2. Plasma levels of dehydroepiandrosterone (DHEA) and androstenedione were normal, but DHEA sulfate levels were low in four of the patients. Two patients and a mother had history of pubertal hyperandrogenism. Testosterone level was mildly elevated in one of the female patients, and insulin resistance was not detected in any of the patients. The patients also had precocious costal calcification, small iliac bones, short femoral necks, coxa vara, short halluces and fused vertebral bodies, none of which has been reported previously in this entity. PMID- 23633441 TI - Outcome of older patients with acute myeloid leukemia: an analysis of SEER data over 3 decades. AB - BACKGROUND: Acute myeloid leukemia (AML) is the common form of acute leukemia in adults, accounting for over 80% of all acute leukemias in individuals aged >18 years. Overall 5-year survival remains poor in older AML patients; it is <5% in patients aged >65 years. In this study, the authors examined whether survival has improved for subsets of geriatric AML patients over 3 successive decades. METHODS: Surveillance, Epidemiology and End Results (SEER) data were used to determine trends in relative survival by age among 19,000 patients with AML over 3 successive decades (1977-1986, 1987-1996, and 1997-2006). Relative survival rates (RRs) with 95% confidence intervals (CIs) were calculated as measures of survival. RESULTS: Overall, the RRs increased for each successive decade (1977 1986, 1987-1996, and 1997-2006) in patients ages 65 to 74 years, with improvements in 12-month survival from 20%, to 25%, to 30%, respectively. Findings were similar for 24-month, 36-month, 48-month, and 60-month survival. However, survival rates did not improve in patients aged >=75 years. The oldest old patients (aged >=85 years) had the lowest survival rates, with no apparent improvement. CONCLUSIONS: This analysis of a large data set demonstrated that, although overall survival remained unsatisfactory among older patients, it improved in the younger old (ages 65-74 years). Survival of older old AML patients has not been favorably impacted by available AML therapies or supportive care, and intervention in this age group is best undertaken on a clinical trial. PMID- 23633442 TI - An on-site comparative study of yield factors during glume removal, a primary step in the traditional processing of hulled wheats. AB - BACKGROUND: Glume removal represents the preliminary step of hulled wheat grain processing for human consumption. Einkorn and emmer wheat are two hulled species, cultivated in marginal areas, from the Mediterranean to the Caucasian region, and the subject of investigation in this paper. An experiment has been carried out to compare the yield of the traditional process, used in Turkey and Armenia, and an updated Italian procedure, by means of on-plant samplings. RESULTS: Crushed grains represent a product from all the plants examined. However, the relative amounts of fractions of different size and use, according to each country, varied consistently. The main Italian product is whole pearled grain. The calculated yield factors varied in the following ranges: dehulling: 0.73-0.81 kg kg(-1); food product: 0.82-0.96 kg kg(-1); overall yield: 0.56-0.95 kg kg(-1) excluding unwanted losses, and 0.42-0.74 kg kg(-1) including unwanted losses. CONCLUSIONS: This first comparative assay of hulled wheat processing showed that, not considering the kind of product obtained, glume removal can be carried out with good efficiency in continuously operating traditional plants. Modern schemes, however, allow yielding of intact kernels. Some yield factors were highly affected by the available technology, especially when the process was operating discontinuously. PMID- 23633443 TI - The polychaete worm Nereis diversicolor increases mercury lability and methylation in intertidal mudflats. AB - The polychaete worm Nereis diversicolor engineers its environment by creating oxygenated burrows in anoxic intertidal sediments. The authors carried out a laboratory microcosm experiment to test the impact of polychaete burrowing and feeding activity on the lability and methylation of mercury in sediments from the Bay of Fundy, Canada. The concentration of labile inorganic mercury and methylmercury in burrow walls was elevated compared to worm-free sediments. Mucus secretions and organic detritus in worm burrows increased labile mercury concentrations. Worms decreased sulfide concentrations, which increased Hg bioavailability to sulfate-reducing bacteria and increased methylmercury concentrations in burrow linings. Because the walls of polychaete burrows have a greater interaction with organisms, and the overlying water, the concentrations of mercury and methylmercury they contain is more toxicologically relevant to the base of a coastal food web than bulk samples. The authors recommend that researchers examining Hg in marine environments account for sediment dwelling invertebrate activity to more fully assess mercury bioavailability. PMID- 23633444 TI - Radiotherapy for a repeatedly recurrent ameloblastoma with malignant transformation. AB - BACKGROUND: The role of radiation therapy (RT) for ameloblastoma remains controversial and undetermined due to the rarity of the disease. METHODS: A case of repeatedly recurrent ameloblastoma with malignant transformation is presented. The clinical course and managements are described. RESULTS: The 63-year-old man had a recurrent ameloblastoma in the left mandible. Five years after the first surgical resection, he underwent 8 more rounds of surgical excision of the recurrent tumors. The malignant transformation occurred and the unresectable tumor invaded the masticator space, parapharyngeal space, and skull base. He received 3-dimensional conformal RT, at the dose of 66 Gray (Gy) in 33 fractions. The ulcerative exophytic mass had regressed gradually. After follow-up of 28 months, the tumor was well controlled. CONCLUSIONS: RT seems to be a feasible treatment option for recurrent ameloblastoma with malignant transformation. PMID- 23633445 TI - Sudden gains in prolonged exposure and sertraline for chronic PTSD. AB - BACKGROUND: Sudden gains are significant, rapid improvements in symptoms, larger than typical between-session symptom reduction.([8]) Sudden gains in a large sample of individuals with posttraumatic stress disorder (PTSD) have not been studied, and only one study has looked at it in pharmacotherapy, but not in PTSD. In the present study, we examined the occurrence of sudden gains in psychotherapy, specifically prolonged exposure (PE), and pharmacotherapy, specifically sertraline, for chronic PTSD. METHOD: Sudden gains in PTSD symptoms (PTSD symptom scale self-report([25]) ) were assessed in 200 individuals with PTSD during 10 weeks of PE or sertraline. RESULTS: Individuals in both PE (42.2%) and sertraline (31%) exhibited sudden gains. Individuals in PE made more gains toward the end of treatment (7.2%) than sertraline (2%, OR = 3.82). However, individuals in sertraline made larger gains during early treatment (M = 18.35, SD = 8.15) than PE (M = 12.53, SD = 5.16, d = .85). Notably, those on sertraline were more likely to exhibit a reversal of sudden gains than those in PE (OR = .23). Pointing to clinical significance, the presence of a sudden gain was associated with better reduction in symptoms from pre- to posttreatment (beta = .49). CONCLUSIONS: Individuals in both PE and sertraline experienced gains, though sertraline was associated with earlier large but reversible gains, and PE was associated with later gains. This differential pattern of discontinuous change highlights potential differential mechanism for these therapies and marks important transition points for further detailed analyses of change mechanisms. PMID- 23633446 TI - Clinical and genetic study of a family with a paternally inherited 15q11-q13 duplication. AB - Interstitial chromosome 15q11-q13 duplications are associated with developmental delay, behavioral problems and additional manifestations, including epilepsy. In most affected individuals the duplicated chromosome is maternally derived, whereas paternal inheritance is more often associated with a normal phenotype. Seizures have not been described in patients with paternal dup 15q11-q13. We describe a family with five individuals in three generations with a paternally inherited 15q11-q13 duplication, four of whom exhibited abnormal phenotypic characteristics, including seizures. The 18-year-old female proband presented with moderate intellectual disability, obesity, and epilepsy. Her brother manifested learning disability and behavioral problems. They both inherited the 15q11-q13 dup from their father who had a normal phenotype. Their paternal uncle and grandfather also had the duplication and were reported to have had seizures. Array-CGH and MLPA analyses showed that the duplication included the TUBGCP5, CYFIP1, MKRN3, MAGEL2, NDN, SNRPN, UBE3A, ATP10A, GABRB3, GABRA5, GABRG3, and OCA2 genes. This report provides evidence for intrafamilial phenotypic variability of paternal dup 15q11-q13, ranging from normal to intellectual disability and seizures, and potentially expanding the phenotype of paternal 15q11-q13 interstitial duplications. PMID- 23633447 TI - Influence of heavy metals on glyceraldehyde-3-phosphate dehydrogenase interactions in Chironomus riparius larvae. AB - Some aquatic organisms can live in contaminated environment due to their adaptable defense mechanism related to their inducible detoxification and excretion. A recent study showed glyceraldehyde-3-phosphate dehydrogenase (GAPDH) can modulate different cellular activities including transcription activation and detoxification. In the present study, the authors report on experiments to test the GAPDH activity of Chironomus riparius toward heavy metals. Glyceraldehyde-3 phosphate dehydrogenase was isolated and purified from C. riparius. The kinetics of the enzyme was measured. The results showed that GAPDH was inhibited by heavy metals including Co(2+) , Cu(2+) , Fe(2+) , Ni(2+) , Pb(2+) , but was activated by zinc ions. The kinetics study of the enzyme showed maximum initial velocity (Vmax) of GAPDH increased by 50%. In addition, the substrate and cofactor affinity increased in the presence of zinc. The GAPDH from C. riparius had maximum activities at pH 8.5 and 37 degrees C. The protein sequence analysis shows that there are 2 additional cysteine and histidine residues in the conserved region of GAPDH from C. riparius, which is believed to play an important role in the interactions with heavy metals. The results suggest that exposure to zinc could modulate GAPDH, which could be related to response of antioxidant defense to other heavy metals. PMID- 23633448 TI - CD22 monoclonal antibody therapies in relapsed/refractory acute lymphoblastic leukemia. PMID- 23633449 TI - Breast cancer genomics: challenges in interpretation and application. PMID- 23633450 TI - Debate: The biology of breast cancer in young women is unique. PMID- 23633451 TI - Interpreting cancer biology: refining our therapeutic algorithm in breast cancer. PMID- 23633452 TI - Cap-translation inhibitor, 4EGI-1, restores sensitivity to ABT-737 apoptosis through cap-dependent and -independent mechanisms in chronic lymphocytic leukemia. AB - PURPOSE: The lymph node microenvironment promotes resistance to chemotherapy in chronic lymphocytic leukemia (CLL), partly through induction of BCL2 family prosurvival proteins. Currently available inhibitors do not target all BCL2 family prosurvival proteins and their effectiveness is also modified by proapoptotic BCL2 homology domain 3 (BH3) only protein expression. The goal of this study was to evaluate synergy between the eIF4E/eIF4G interaction inhibitor, 4EGI-1, and the BH3 mimetic, ABT-737. EXPERIMENTAL DESIGN: CLL cells were cultured in conditions to mimic the lymph node microenvironment. Protein synthesis and cap-complex formation were determined. Polysome association of mRNAs from BCL2 family survival genes was analyzed by translational profiling. The effects of 4EGI-1 and the BCL2/BCL2L1 antagonist, ABT-737, on CLL cell apoptosis were determined. RESULTS: Protein synthesis was increased approximately 6-fold by stromal cell/CD154 culture in a phosphoinositide 3-kinase alpha (PI3Kalpha)-specific manner and was reduced by 4EGI-1. PI3K inhibitors and 4EGI-1 also reduced cap-complex formation but only 4EGI-1 consistently reduced BCL2L1 and BCL2A1 protein levels. 4EGI-1, but not PI3K inhibitors or rapamycin, induced an endoplasmic reticulum stress response including proapoptotic NOXA and the translation inhibitor phosphorylated eIF2alpha. 4EGI-1 and ABT-737 synergized to cause apoptosis, independent of levels of prosurvival protein expression in individual patients. CONCLUSIONS: Overall protein synthesis and cap-complex formation are induced by microenvironment stimuli in CLL. Inhibition of the cap complex was not sufficient to repress BCL2 family prosurvival expression, but 4EGI-1 inhibited BCL2A1 and BCL2L1 while inducing NOXA through cap-dependent and independent mechanisms. 4EGI-1 and ABT-737 synergized to produce apoptosis, and these agents may be the basis for a therapeutically useful combination. PMID- 23633453 TI - Disrupting protein NEDDylation with MLN4924 is a novel strategy to target cisplatin resistance in ovarian cancer. AB - PURPOSE: Ovarian cancer has the highest mortality rate of all female reproductive malignancies. Drug resistance is a major cause of treatment failure and novel therapeutic strategies are urgently needed. MLN4924 is a NEDDylation inhibitor currently under investigation in multiple phase I studies. We investigated its anticancer activity in cisplatin-sensitive and -resistant ovarian cancer models. EXPERIMENTAL DESIGN: Cellular sensitivity to MLN4924/cisplatin was determined by measuring viability, clonogenic survival, and apoptosis. The effects of drug treatment on global protein expression, DNA damage, and reactive oxygen species generation were determined. RNA interference established natural born killer/bcl 2-interacting killer (NBK/BIK) as a regulator of therapeutic sensitivity. The in vivo effects of MLN4924/cisplatin on tumor burden and key pharmacodynamics were assessed in cisplatin-sensitive and -resistant xenograft models. RESULTS: MLN4924 possessed significant activity against both cisplatin-sensitive and -resistant ovarian cancer cells and provoked the stabilization of key NEDD8 substrates and regulators of cellular redox status. Notably, MLN4924 significantly augmented the activity of cisplatin against cisplatin-resistant cells, suggesting that aberrant NEDDylation may contribute to drug resistance. MLN4924 and cisplatin cooperated to induce DNA damage, oxidative stress, and increased expression of the BH3-only protein NBK/BIK. Targeted NBK/BIK knockdown diminished the proapoptotic effects of the MLN4924/cisplatin combination. Administration of MLN4924 to mice bearing ovarian tumor xenografts significantly increased the efficacy of cisplatin against both cisplatin-sensitive and -resistant tumors. CONCLUSIONS: Our collective data provide a rationale for the clinical investigation of NEDD8 activating enzyme (NAE) inhibition as a novel strategy to augment cisplatin efficacy in patients with ovarian cancer and other malignancies. PMID- 23633454 TI - Conjunctival melanomas harbor BRAF and NRAS mutations and copy number changes similar to cutaneous and mucosal melanomas. AB - PURPOSE: Conjunctival melanoma is a rare but potentially deadly tumor of the eye. Despite effective local therapies, recurrence and metastasis remain frequent. Once the tumor has metastasized, treatment options are limited and the prognosis is poor. To date, little is known of the genetic alterations in conjunctival melanomas. EXPERIMENTAL DESIGN: We conducted genetic analysis of 78 conjunctival melanomas, to our knowledge the largest cohort reported to date. An oncogene hotspot array was run on 38 samples, screening for a panel of known cancer relevant mutations. Thirty tumors were analyzed for genome-wide copy number alterations (CNA) using array-based comparative genomic hybridization. Sanger sequencing of selected target mutations was conducted in all samples. RESULTS: BRAF mutations were identified in 23 of 78 (29%) tumors. NRAS mutations, previously not recognized as relevant in conjunctival melanoma, were detected in 14 of 78 (18%) tumors. We found CNAs affecting various chromosomes distributed across the genome in a pattern reminiscent of cutaneous and mucosal melanoma but differing markedly from uveal melanoma. CONCLUSIONS: The presence of NRAS or BRAF mutations in a mutually exclusive pattern in roughly half (47%) of conjunctival melanomas and the pattern of CNAs argue for conjunctival melanoma being closely related to cutaneous and mucosal melanoma but entirely distinct from uveal melanoma. Patients with metastatic conjunctival melanoma should be considered for therapeutic modalities available for metastatic cutaneous and mucosal melanoma including clinical trials of novel agents. PMID- 23633456 TI - PIK3CA and PTEN gene and exon mutation-specific clinicopathologic and molecular associations in colorectal cancer. AB - PURPOSE: PIK3CA and PTEN mutations are prevalent in colorectal cancer and potential markers of response to mitogen-activated protein/extracellular signal regulated kinase inhibitors and anti-EGF receptor antibody therapy. Relationships between phosphoinositide 3-kinase (PI3K) pathway mutation, clinicopathologic characteristics, molecular features, and prognosis remain controversial. EXPERIMENTAL DESIGN: A total of 1,093 stage I-IV colorectal cancers were screened for PIK3CA (exons 9 and 20), KRAS (codons 12-13), BRAF (codon 600) mutations, and microsatellite instability (MSI). PTEN (exons 3-8) and CpG island methylator phenotype (CIMP) status were determined in 744 and 489 cases. PIK3CA data were integrated with 17 previous reports (n = 5,594). RESULTS: PIK3CA and PTEN mutations were identified in 11.9% and 5.8% of colorectal cancers. PTEN mutation was associated with proximal tumors, mucinous histology, MSI-high (MSI-H), CIMP high (CIMP-H), and BRAF mutation (P < 0.02). PIK3CA mutation was related to older age, proximal tumors, mucinous histology, and KRAS mutation (P < 0.04). In integrated cohort analysis, PIK3CA exon 9 and 20 mutations were overrepresented in proximal, CIMP-low (CIMP-L), and KRAS-mutated cancers (P <= 0.011). Comparing PIK3CA exonic mutants, exon 20 mutation was associated with MSI-H, CIMP-H, and BRAF mutation, and exon 9 mutation was associated with KRAS mutation (P <= 0.027). Disease-free survival for stage II/III colorectal cancers did not differ by PI3K pathway status. CONCLUSION: PI3K pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile-serrated pathway (MSI-H/CIMP-H/BRAF(mut)), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-L/KRAS(mut)) of tumorigenesis. Our data highlight the PI3K pathway as a therapeutic target in distinct colorectal cancer subtypes. PMID- 23633457 TI - Molecular pathways: Fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer. AB - Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for development of cutaneous and uterine leiomyomas and an aggressive form of type II papillary kidney cancer. HLRCC is characterized by germline mutation of the tricarboxylic acid (TCA) cycle enzyme, fumarate hydratase (FH). FH-deficient kidney cancer is characterized by impaired oxidative phosphorylation and a metabolic shift to aerobic glycolysis, a form of metabolic reprogramming referred to as the Warburg effect. Increased glycolysis generates ATP needed for increased cell proliferation. In FH-deficient kidney cancer, levels of AMP-activated protein kinase (AMPK), a cellular energy sensor, are decreased resulting in diminished p53 levels, decreased expression of the iron importer, DMT1, leading to low cellular iron levels, and to enhanced fatty acid synthesis by diminishing phosphorylation of acetyl CoA carboxylase, a rate-limiting step for fatty acid synthesis. Increased fumarate and decreased iron levels in FH-deficient kidney cancer cells inactivate prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor (HIF)-1alpha and increased expression of genes such as VEGF and glucose transporter 1 (GLUT1) to provide fuel needed for rapid growth demands. Several therapeutic approaches for targeting the metabolic basis of FH-deficient kidney cancer are under development or are being evaluated in clinical trials, including the use of agents such as metformin, which would reverse the inactivation of AMPK, approaches to inhibit glucose transport, lactate dehydrogenase A (LDHA), the antioxidant response pathway, the heme oxygenase pathway, and approaches to target the tumor vasculature and glucose transport with agents such as bevacizumab and erlotinib. These same types of metabolic shifts, to aerobic glycolysis with decreased oxidative phosphorylation, have been found in a wide variety of other cancer types. Targeting the metabolic basis of a rare cancer such as FH-deficient kidney cancer will hopefully provide insights into the development of effective forms of therapies for other, more common forms of cancer. PMID- 23633459 TI - A survey of the opinions of recent veterinary graduates and employers regarding early career business skills. AB - A questionnaire was designed to assess recent veterinary graduates' proficiency in early career business skills, from the perspectives of graduates of 2006-2008 and employers of recent graduates in the UK. Recent graduates perceived themselves to be generally more competent in financial matters than employers considered them to be. However, when specific skills were assessed, graduates felt less prepared than employers considered them to be competent. Overall, graduates and employers rated recent graduates' preparedness/competence as poor to average for all skills, which were regarded as having average to high importance. Both groups commented on the difficulties faced by new graduates in terms of client communication (generally and financially), and having the confidence to charge clients appropriately for veterinary services. The results of this study indicate that veterinary schools need to take a more active role in the teaching of basic finance skills in order to equip graduates with essential early career competencies. It is anticipated that the information reported will help inform undergraduate curriculum development and highlight the need for increased training at the continuing education level. PMID- 23633460 TI - Histological response to and immunogenicity of different material patches implanted in rabbit abdominal walls. AB - The high failure rate of traditional procedures of repairing pelvic organ prolapse by using sutures pushes multiple transvaginal mesh delivery systems into the marketplace; however, these are currently without optimal clinical results. We observed the short-term histological changes and the effects of Th1/Th2 cytokines after the implantation in rabbit abdominal walls of five materials, i.e., porcine urinary bladder matrix (UBM), cross-linked UBM, polypropylene mesh, composite cross-linked UBM, and composite UBM, and explored the feasibility of their application to pelvic reconstructive surgery. Grafts were harvested at 1, 2, 4, 8, and 12 weeks after surgery and were processed for histology in order to evaluate the host inflammatory response and the degree of tissue incorporation. Additionally, graft site cytokine levels were determined by reverse transcriptase polymerase chain reaction. The results demonstrate that the two composite groups were associated with an erosion response, whereas the other groups induced a milder response than the composite groups. The Th1/Th2 cytokine mRNA expression levels of the cross-linked UBM group at each time point were similar to that of the sham group, whereas the other groups elicited a more variable expression. The cross-linked UBM showed slow degradation, mild inflammatory response, and low immunogenicity. This suggests that cross-linked UBM is a better material of choice for pelvic reconstructive surgery. PMID- 23633458 TI - Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. AB - PURPOSE: We set out to identify Stearoyl-CoA desaturase 1 (SCD1) as a novel molecular target in clear cell renal cell carcinoma (ccRCC) and examine its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current U.S. Food and Drug Administration (FDA)-approved regimens. EXPERIMENTAL DESIGN: Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor, A939572, were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus. RESULTS: Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real time PCR, and protein analysis of A939572-treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of A939572 with temsirolimus synergistically inhibited tumor growth in vitro and in vivo. CONCLUSIONS: Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease. PMID- 23633461 TI - Polymorphisms in the activin A receptor type 2A gene affect the onset time and severity of preeclampsia in the Turkish population. AB - AIM: To investigate the possible roles of selected single nucleotide gene polymorphisms (SNPs) of the activin A receptor type 2A (ACVR2A) gene in the pathogenesis of preeclampsia. METHODS: Ninety-four patients with preeclampsia and 166 healthy pregnant women were included in this study. Genomic DNA was extracted from venous blood and were stored at -80 degrees C before the analysis. Selected ACVR2A SNPs (rs10497025, rs1128919, rs13430086) were determined in an ABI 7900 HT Real-Time PCR instrument. RESULTS: For all three SNPs, no statistically significant difference was found between preeclampsia and control groups in terms of genotype and allele frequencies. In the late preeclampsia group, with regard to the rs1128919 SNP, the frequency of GG genotype was found to be significantly lower (P=0.02). Although the frequency of "A" allele was found to be higher (P=0.05; OR=1.54), and the "G" allele was found to be lower (P=0.05; OR=0.65), the results did not reach statistical significance in late preeclamptic patients. For the rs1128919 SNP, the frequency of the AA genotype was found to be significantly higher in both mild (P=0.004) and severe (P=0.0001) preeclampsia groups, whereas the frequency of GG genotype was found to be significantly lower (P=0.008, and P=0.0001, respectively). For the rs13430086 SNP, while the frequency of the AA genotype was found to be significantly lower in both mild (P=0.02) and severe (P=0.0001) preeclamptic patients, the frequency of TT genotype was found to be significantly higher in only severe preeclampsia group (P=0.0001). CONCLUSION: ACVR2A gene polymorphisms may play a role in the development of preeclampsia. PMID- 23633455 TI - Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. AB - PURPOSE: High-grade serous carcinoma (HGSC) accounts for the majority of epithelial ovarian cancer deaths. Genomic and functional data suggest that approximately half of unselected HGSC have disruption of the BRCA pathway and defects in homologous recombination repair (HRR). Pathway disruption is regarded as imparting a BRCAness phenotype. We explored the molecular changes in HGSC arising in association with specific BRCA1/BRCA2 somatic or germline mutations and in those with BRCA1 DNA promoter methylation. EXPERIMENTAL DESIGN: We describe gene expression and copy number analysis of two large cohorts of HGSC in which both germline and somatic inactivation of HRR has been measured. RESULTS: BRCA1 disruptions were associated with the C2 (immunoreactive) molecular subtype of HGSC, characterized by intense intratumoral T-cell infiltration. We derived and validated a predictor of BRCA1 mutation or methylation status, but could not distinguish BRCA2 from wild-type tumors. DNA copy number analysis showed that cases with BRCA1 mutation were significantly associated with amplification both at 8q24 (frequencies: BRCA1 tumors 50%, BRCA2 tumors 32%, and wild-type tumors 9%) and regions of the X-chromosome specifically dysregulated in basal-like breast cancer (BLBC; BRCA1 62%, BRCA2 34%, and wild-type 35%). Tumors associated with BRCA1/BRCA2 mutations shared a negative association with amplification at 19p13 (BRCA1 0%, BRCA2 3%, and wild-type 20%) and 19q12 (BRCA1 6%, BRCA2 3%, and wild-type 29%). CONCLUSION: The molecular differences between tumors associated with BRCA1 compared with BRCA2 mutations are in accord with emerging clinical and pathologic data and support a growing appreciation of the relationship between HGSC and BLBC. PMID- 23633462 TI - A polymorphism in an autophagy-related gene, ATG16L1, influences time to delivery in women with an unfavorable cervix who require labor induction. AB - Autophagy is an intracellular process that maintains homeostasis by the removal of damaged organelles and proteins. A single nucleotide polymorphism (SNP) in the autophagy-related 16-like 1 (ATG16L1) gene results in decreased autophagy. We evaluated whether the ATG16L1 polymorphism influenced the time to delivery during labor induction in pregnant women with an unfavorable cervix. DNA from 69 women with an unfavorable cervix who required labor induction due to post-term (>294 days) (n=26), oligohydramnios (n=17), hypertension or pre-eclampsia (n=10), abnormal fetal heart rate (n=8), diabetes (n=3) or other reasons (n=5) was tested by gene amplification and endonuclease digestion for a SNP in ATG16L1 (rs2241880). The mean hours (SD) from induction to delivery was 20.8 (9.7) for women who were A,A homozygotes, 19.2 (8.8) for A,G heterozygotes and 14.3 (6.6) for homozygote carriers of the G,G variant (P=0.03 A,A vs. G,G, P=0.04 A,A/A,G vs. G,G). The G,G prevalence was 24.4% and 4.2% for those who delivered in <=24 and >24 h, respectively (P=0.04). There was no difference in genotype distribution by indication for induction. A decreased genetic capacity for autophagy may be beneficial in women with an unfavorable cervix whose labor has to be induced. PMID- 23633463 TI - Unusual cause of urethral bleeding in an adolescent: a case in dilemma. AB - Numerous cases of self-inflicted foreign bodies in the male urethra have been reported. A case of a self-inflicted urethral injury or hemangioma in an adolescent that presented a dilemma is described here. An adolescent male of 14 years presented with a complaint of intermittent urethral bleeding for a week. He attributed this to blunt trauma sustained while playing in school. On examination, there was no sign suggestive of any trauma or any abnormal lesion on the genitalia or surrounding area. On cystourethroscopy, there was a solitary hemorrhagic lesion of 0.5 cm with a bluish base on the ventral surface of the pendular urethra, 1 cm proximal to the fossa navicularis, which was ablated using Ho:YAG laser fiber (365 MUm) through a working channel mounted in an OIU (optical internal urethrotomy) sheath. The absence of any sign of external trauma or presentation after 1 week of the incident suggests an element of falseness in the history. It may be due to embarrassment or fear, which contributes to self insertion of foreign bodies into the urethra as the primary cause, especially in adolescent males. However, the trauma can be coincidental, with the bleeding of the urethra caused by a urethral lesion like a hemangioma and might present after a long gap of 1 week due to a lack of understanding or lack of severe symptoms. Most patients of self-inflicted injuries are too ashamed to admit that they inserted any object. A psychiatric evaluation is recommended for all these adolescents, with appropriate medical therapy when indicated. PMID- 23633464 TI - Adolescents with anorectal malformation: physical outcome, sexual health and quality of life. AB - BACKGROUND: The necessity of referring adolescents with anorectal malformation (ARM) from pediatric units to adult care is unclear. The issue requires knowledge about the health of the adolescent. OBJECTIVE: To examine the physical outcome, sexual health and quality of life (QoL) in adolescents with ARM. METHODS: At medical counseling, 24 adolescents with ARM, 15-21 years of age, answered questionnaires about physical outcome according to the Krickenbeck follow-up and QoL according to SF 36 and gastrointestinal quality of life (Giqli). Matched control groups were used; 15 adolescents participated in deep interviews about sexual health and body imaging. RESULTS: Fecal soiling, constipation and gas incontinence were much higher for ARM patients compared with controls (p<0.05). QoL regarding large bowel function was lower for both genders compared with controls (p<0.05). Females scored lower in physically related QoL (p<0.05). Social and sexual adaption to the symptoms was obvious in the deep interviews. CONCLUSION: Adolescents with ARM have considerable intestinal symptoms, which influence QoL and require adaption in intimate situations. A referral to adult care seems to be important, and continuous cooperation between the pediatric surgeon and adult care is suggested. PMID- 23633465 TI - Clinical implications of a recent adjustment to the high-sensitivity cardiac troponin T assay: some results. PMID- 23633466 TI - Interindividual variability of hemolysis in plasma samples during pneumatic tube system transport. PMID- 23633467 TI - Efficient use of basic biochemical methods to prove the presence of monoclonal protein in the clinical diagnosis of malignant monoclonal gammopathy. PMID- 23633468 TI - Utility of a panel of sera for the alignment of test results in the worldwide multicenter study on reference values. AB - BACKGROUND: In a planned International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) worldwide study on reference intervals (RIs), a common panel of serum samples is to be measured by laboratories from different countries, and test results are to be compared through conversion using linear regression analysis. This report presents a validation study that was conducted in collaboration with four laboratories. METHODS: A panel composed of 80 sera was prepared from healthy individuals, and 45 commonly tested analytes (general chemistry, tumor markers, and hormones) were measured on two occasions 1 week apart in each laboratory. Reduced major-axis linear regression was used to convert reference limits (LL and UL). Precision was expressed as a ratio of the standard error of converted LL or UL to the standard deviation (SD) comprising RI (approx. 1/4 of the RI width corresponding to between-individual SD). The allowable and optimal levels of error for the SD ratio (SDR) were set as <=0.250 and <=0.125, respectively, in analogy to the common method of setting limits for analytical bias based on between-individual SD. RESULTS: The values for the calculated SDRs depended upon the distribution patterns of test results: skewness toward higher values makes SDRLL lower and SDRUL higher. However, the CV of the regression line slope, CV(b), is less affected by skewness. The average of SDRLL and SDRUL (aveSDR) correlates closely with CV(b) (r=0.995). The aveSDRs of <=0.25 and <=0.125 corresponds approximately to CV(b) values of <=11% and <=5.5%, respectively. For all results (i.e., n=80), conversion was allowable (optimal) in 98% (89%) of the analytes, as judged by CV(b). Resampling studies using random subsets of data with a data size (n) of 70 to 20 revealed that SDRs and CV(b) gradually increase with reduction of n, especially with n <=30. CONCLUSIONS: CV(b) is a robust estimator for judging the convertibility of reference values among laboratories, even with a skewed distribution. Assuming 40 sera to be a practical size for the panel, reference values of 89% (80%) of analytes examined were made comparable by regression analysis with the allowable (optimal) level of precision. PMID- 23633469 TI - Protocol and standard operating procedures for common use in a worldwide multicenter study on reference values. AB - The reference intervals (RIs) given in laboratory reports have an important role in aiding clinicians in interpreting test results in reference to values of healthy populations. In this report, we present a proposed protocol and standard operating procedures (SOPs) for common use in conducting multicenter RI studies on a national or international scale. The protocols and consensus on their contents were refined through discussions in recent C-RIDL meetings. The protocol describes in detail (1) the scheme and organization of the study, (2) the target population, inclusion/exclusion criteria, ethnicity, and sample size, (3) health status questionnaire, (4) target analytes, (5) blood collection, (6) sample processing and storage, (7) assays, (8) cross-check testing, (9) ethics, (10) data analyses, and (11) reporting of results. In addition, the protocol proposes the common measurement of a panel of sera when no standard materials exist for harmonization of test results. It also describes the requirements of the central laboratory, including the method of cross-check testing between the central laboratory of each country and local laboratories. This protocol and the SOPs remain largely exploratory and may require a reevaluation from the practical point of view after their implementation in the ongoing worldwide study. The paper is mainly intended to be a basis for discussion in the scientific community. PMID- 23633473 TI - Self-organized broadband light trapping in thin film amorphous silicon solar cells. AB - Nanostructured glass substrates endowed with high aspect ratio one-dimensional corrugations are prepared by defocused ion beam erosion through a self-organized gold (Au) stencil mask. The shielding action of the stencil mask is amplified by co-deposition of gold atoms during ion bombardment. The resulting glass nanostructures enable broadband anti-reflection functionality and at the same time ensure a high efficiency for diffuse light scattering (Haze). It is demonstrated that the patterned glass substrates exhibit a better photon harvesting than the flat glass substrate in p-i-n type thin film a-Si:H solar cells. PMID- 23633474 TI - Temperature-dependent electron mobility in InAs nanowires. AB - Effective electron mobilities are obtained by transport measurements on InAs nanowire field-effect transistors at temperatures ranging from 10 to 200 K. The mobility increases with temperatures below ~30-50 K, and then decreases with temperatures above 50 K, consistent with other reports. The magnitude and temperature dependence of the observed mobility can be explained by Coulomb scattering from ionized surface states at typical densities. The behaviour above 50 K is ascribed to the thermally activated increase in the number of scatterers, although nanoscale confinement also plays a role as higher radial subbands are populated, leading to interband scattering and a shift of the carrier distribution closer to the surface. Scattering rate calculations using finite element simulations of the nanowire transistor confirm that these mechanisms are able to explain the data. PMID- 23633475 TI - Generation of substrate-free III-V nanodisks from user-defined multilayer nanopillar arrays for integration on Si. AB - High material quality InP-based multilayer nanopillar (NP) arrays are fabricated using a combination of self-assembly of silica particles for mask generation and dry etching. In particular, the NP arrays are made from user-defined epitaxial multilayer stacks with specific materials and layer thicknesses. An additional degree of flexibility in the structures is obtained by changing the lateral diameters of the NP multilayer stacks. Pre-defined NP arrays made from InGaAsP/InP and InGaAs/InP NPs are then used to generate substrate-free nanodisks of a chosen material from the stack by selective etching. A soft-stamping method is demonstrated to transfer the generated nanodisks with arbitrary densities onto Si. The transferred nanodisks retain their smooth surface morphologies and their designed geometrical dimensions. Both InP and InGaAsP nanodisks display excellent photoluminescence properties, with line-widths comparable to unprocessed reference epitaxial layers of similar composition. The multilayer NP arrays are potentially attractive for broad-band absorption in third-generation solar cells. The high optical quality, substrate-free InP and InGaAsP nanodisks on Si offer a new path to explore alternative ways to integrate III-V on Si by bonding nanodisks to Si. The method also has the advantage of re-usable III-V substrates for subsequent layer growth. PMID- 23633476 TI - Spatially selective Au nanoparticle growth in laser-quality glass controlled by UV-induced phosphate-chain cross-linkage. AB - Herein we describe how UV excitation of localized electronic states in phosphate glasses can activate structural rearrangements that influence the kinetics of Au nanoparticle (NP) thermal growth in Au-doped glass. The results suggest a novel strategy to address the problem of controlling nano-assembly processes of metal NP patterns in fully inorganic and chemically stable hard materials, such as laser-quality glasses. We show that the mechanism is promoted by opening and subsequent cross-linkage of phosphate chains under UV excitation of non-bridging groups in the amorphous network of the glass, with a consequent modification of Au diffusion and metal NP growth. Importantly, the micro-Raman mapping of the UV induced modifications demonstrates that the process is restricted within the beam waist region of the focused UV laser beam. This fact is consistent with the need for more than one excitation event, close in time and in space, in order to promote structural cross-linkage and Au diffusion confinement. The stability of the photo-induced modifications makes it possible to design new metal patterning approaches for the fabrication of three-dimensional metal structures in laser quality materials for high-power nonlinear applications. PMID- 23633472 TI - Cell death sensitization of leukemia cells by opioid receptor activation. AB - Cyclic AMP (cAMP) regulates a number of cellular processes and modulates cell death induction. cAMP levels are altered upon stimulation of specific G-protein coupled receptors inhibiting or activating adenylyl cyclases. Opioid receptor stimulation can activate inhibitory Gi-proteins which in turn block adenylyl cyclase activity reducing cAMP. Opioids such as D,L-methadone induce cell death in leukemia cells. However, the mechanism how opioids trigger apoptosis and activate caspases in leukemia cells is not understood. In this study, we demonstrate that downregulation of cAMP induced by opioid receptor activation using the opioid D,L-methadone kills and sensitizes leukemia cells for doxorubicin treatment. Enhancing cAMP levels by blocking opioid-receptor signaling strongly reduced D,L-methadone-induced apoptosis, caspase activation and doxorubicin-sensitivity. Induction of cell death in leukemia cells by activation of opioid receptors using the opioid D,L-methadone depends on critical levels of opioid receptor expression on the cell surface. Doxorubicin increased opioid receptor expression in leukemia cells. In addition, the opioid D,L methadone increased doxorubicin uptake and decreased doxorubicin efflux in leukemia cells, suggesting that the opioid D,L-methadone as well as doxorubicin mutually increase their cytotoxic potential. Furthermore, we found that opioid receptor activation using D,L-methadone alone or in addition to doxorubicin inhibits tumor growth significantly in vivo. These results demonstrate that opioid receptor activation via triggering the downregulation of cAMP induces apoptosis, activates caspases and sensitizes leukemia cells for doxorubicin treatment. Hence, opioid receptor activation seems to be a promising strategy to improve anticancer therapies. PMID- 23633478 TI - Editorial: Early and late endothelial progenitor cells are miR-tually exclusive. PMID- 23633477 TI - Surface free-carrier screening effect on the output of a ZnO nanowire nanogenerator and its potential as a self-powered active gas sensor. AB - The output of a piezoelectric nanogenerator (NG) fabricated using ZnO nanowire arrays is largely influenced by the density of the surface charge carriers at the nanowire surfaces. Adsorption of gas molecules could modify the surface carrier density through a screening effect, thus, the output of the NG is sensitive to the gas concentration. Based on such a mechanism, we first studied the responses of an unpackaged NG to oxygen, H2S and water vapor, and demonstrated its sensitivity to H2S to a level as low as 100 ppm. Therefore, the piezoelectric signal generated by a ZnO NWs NG can act not only as a power source, but also as a response signal to the gas, demonstrating a possible approach as a self-powered active gas sensor. PMID- 23633479 TI - Editorial: Leukocytes in tularemia--so many cells, so little time. PMID- 23633480 TI - Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors. AB - Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC. PMID- 23633481 TI - Dynamic mast cell-stromal cell interactions promote growth of pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) exists in a complex desmoplastic microenvironment, which includes cancer-associated fibroblasts [also known as pancreatic stellate cells (PSC)] and immune cells that provide a fibrotic niche that impedes successful cancer therapy. We have found that mast cells are essential for PDAC tumorigenesis. Whether mast cells contribute to the growth of PDAC and/or PSCs is unknown. Here, we tested the hypothesis that mast cells contribute to the growth of PSCs and tumor cells, thus contributing to PDAC development. Tumor cells promoted mast cell migration. Both tumor cells and PSCs stimulated mast cell activation. Conversely, mast cell-derived interleukin (IL) 13 and tryptase stimulated PSC proliferation. Treating tumor-bearing mice with agents that block mast cell migration and function depressed PDAC growth. Our findings suggest that mast cells exacerbate the cellular and extracellular dynamics of the tumor microenvironment found in PDAC. Therefore, targeting mast cells may inhibit stromal formation and improve therapy. PMID- 23633482 TI - Cancer stem-like cell marker CD44 promotes bone metastases by enhancing tumorigenicity, cell motility, and hyaluronan production. AB - CD44, an adhesion molecule that binds to the extracellular matrix, primarily to hyaluronan (HA), has been implicated in cancer cell migration, invasion, and metastasis. CD44 has also recently been recognized as a marker for stem cells of several types of cancer. However, the roles of CD44 in the development of bone metastasis are unclear. Here, we addressed this issue by using bone metastatic cancer cell lines, in which CD44 was stably knocked down. Tumor sphere formation and cell migration and invasion were significantly inhibited by CD44 knockdown. Furthermore, the downregulation of CD44 markedly suppressed tumorigenicity and bone metastases in nude mice. Of note, the number of osteoclasts decreased in the bone metastases. Microarray analysis revealed that the expression of HA synthase 2 was downregulated in CD44-knockdown cells. The localization of HA in the bone metastatic tumors was also markedly reduced. We then examined the roles of CD44 HA interaction in bone metastasis using 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis. 4-MU decreased tumor sphere and osteoclast-like cell formation in vitro. Moreover, 4-MU inhibited bone metastases in vivo with reduced number of osteoclasts. These results collectively suggest that CD44 expression in cancer cells promotes bone metastases by enhancing tumorigenicity, cell migration and invasion, and HA production. Our results also suggest the possible involvement of CD44-expressing cancer stem cells in the development of bone metastases through interaction with HA. CD44-HA interaction could be a potential target for therapeutic intervention for bone metastases. PMID- 23633483 TI - SENP1 deSUMOylates and regulates Pin1 protein activity and cellular function. AB - The Pin1 prolyl isomerase regulates phosphorylation signaling by controlling protein conformation after phosphorylation, and its upregulation promotes oncogenesis via acting on numerous oncogenic molecules. SUMOylation and deSUMOylation are dynamic mechanisms regulating a spectrum of protein activities. The SUMO proteases (SENP) remove SUMO conjugate from proteins, and their expression is deregulated in cancers. However, nothing is known about the role of SUMOylation in regulating Pin1 function. Here, we show that Pin1 is SUMOylated on Lys6 in the WW domain and on Lys63 in the PPIase domain. Pin1 SUMOylation inhibits its protein activity and oncogenic function. We further identify that SENP1 binds to and deSUMOylates Pin1. Importantly, either overexpression of SENP1 or disruption of Pin1 SUMOylation promotes the ability of Pin1 to induce centrosome amplification and cell transformation. Moreover, SENP1 also increases Pin1 protein stability in cell cultures, and Pin1 levels are positively correlated with SENP1 levels in human breast cancer specimens. These results not only uncover Pin1 SUMOylation on Lys6/63 as a novel mechanism to inhibit its activity and function but also identify a critical role for SENP1-mediated deSUMOylation in promoting Pin1 function during tumorigenesis. PMID- 23633484 TI - Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. AB - Tumor progression is facilitated by regulatory T cells (Treg) and restricted by effector T cells. In this study, we document parallel regulation of CD8(+) T cells and Foxp3(+) Tregs by programmed death-1 (PD-1, PDCD1). In addition, we identify an additional role of CTL antigen-4 (CTLA-4) inhibitory receptor in further promoting dysfunction of CD8(+) T effector cells in tumor models (CT26 colon carcinoma and ID8-VEGF ovarian carcinoma). Two thirds of CD8(+) tumor infiltrating lymphocytes (TIL) expressed PD-1, whereas one third to half of CD8(+) TIL coexpressed PD-1 and CTLA-4. Double-positive (PD-1(+)CTLA-4(+)) CD8(+) TIL had characteristics of more severe dysfunction than single-positive (PD-1(+) or CTLA-4(+)) TIL, including an inability to proliferate and secrete effector cytokines. Blockade of both PD-1 and CTLA-4 resulted in reversal of CD8(+) TIL dysfunction and led to tumor rejection in two thirds of mice. Double blockade was associated with increased proliferation of antigen-specific effector CD8(+) and CD4(+) T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs, and upregulation of key signaling molecules critical for T cell function. When used in combination with GVAX vaccination (consisting of granulocyte macrophage colony-stimulating factor-expressing irradiated tumor cells), inhibitory pathway blockade induced rejection of CT26 tumors in 100% of mice and ID8-VEGF tumors in 75% of mice. Our study indicates that PD-1 signaling in tumors is required for both suppressing effector T cells and maintaining tumor Tregs, and that PD-1/PD-L1 pathway (CD274) blockade augments tumor inhibition by increasing effector T-cell activity, thereby attenuating Treg suppression. PMID- 23633486 TI - Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. AB - Tumors can suppress the host immune system by employing a variety of cellular immune modulators, such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSC). In the peripheral blood of patients with advanced stage melanoma, there is an accumulation of CD14(+)HLA-DR(lo/-) MDSC that suppress autologous T cells ex vivo in a STAT-3-dependent manner. However, a precise mechanistic basis underlying this effect is unclear, particularly with regard to whether the MDSC induction mechanism relies on cell-cell contact of melanoma cells with CD14(+) cells. Here, we show that early-passage human melanoma cells induce phenotypic changes in CD14(+) monocytes, leading them to resemble MDSCs characterized in patients with advanced stage melanoma. These MDSC like cells potently suppress autologous T-cell proliferation and IFN-gamma production. Notably, induction of myeloid-suppressive functions requires contact or close proximity between monocytes and tumor cells. Further, this induction is largely dependent on production of cyclooxygenase-2 (COX-2) because its inhibition in these MDSC-like cells limits their ability to suppress T-cell function. We confirmed our findings with CD14(+) cells isolated from patients with advanced stage melanoma, which inhibited autologous T cells in a manner relying up prostaglandin E2 (PGE2), STAT-3, and superoxide. Indeed, PGE2 was sufficient to confer to monocytes the ability to suppress proliferation and IFN gamma production by autologous T cells ex vivo. In summary, our results reveal how immune suppression by MDSC can be initiated in the tumor microenvironment of human melanoma. PMID- 23633485 TI - Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling. AB - Mutations in PIK3CA, the gene encoding the p110alpha catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding of mutant p110alpha via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CA-mediated transformation of MECs. Conditional loss of ErbB3 in mammary epithelium resulted in a delay of PIK3CA(H1047R)-dependent mammary gland hyperplasia, but tumor latency, gene expression, and PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with several tyrosyl phosphoproteins, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Similarly, inhibition of ErbB RTKs with lapatinib did not affect PI3K signaling in PIK3CA(H1047R)-expressing tumors. However, the p110alpha-specific inhibitor BYL719 in combination with lapatinib impaired mammary tumor growth and PI3K signaling more potently than BYL719 alone. Furthermore, coinhibition of p110alpha and ErbB3 potently suppressed proliferation and PI3K signaling in human breast cancer cells harboring PIK3CA(H1047R). These data suggest that PIK3CA(H1047R) driven tumor growth and PI3K signaling can occur independently of ErbB RTKs. However, simultaneous blockade of p110alpha and ErbB RTKs results in superior inhibition of PI3K and mammary tumor growth, suggesting a rational therapeutic combination against breast cancers harboring PIK3CA activating mutations. PMID- 23633487 TI - BMP-6 in renal cell carcinoma promotes tumor proliferation through IL-10 dependent M2 polarization of tumor-associated macrophages. AB - Dysregulated bone morphogenetic proteins (BMP) may contribute to the development and progression of renal cell carcinoma (RCC). Herein, we report that BMP-6 promotes the growth of RCC by interleukin (IL)-10-mediated M2 polarization of tumor-associated macrophages (TAM). BMP-6-mediated IL-10 expression in macrophages required Smad5 and STAT3. In human RCC specimens, the three-marker signature BMP-6/IL-10/CD68 was associated with a poor prognosis. Furthermore, patients with elevated IL-10 serum levels had worse outcome after surgery. Together, our results suggest that BMP-6/macrophage/IL-10 regulates M2 polarization of TAMs in RCC. PMID- 23633488 TI - Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer. AB - Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here, we describe a novel tumor stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of hypoxia-inducible factor-1alpha (HIF-1alpha) by tumor hypoxia strongly activates secretion of the sonic hedgehog (SHH) ligand by cancer cells, which in turn causes stromal fibroblasts to increase fibrous tissue deposition. In support of this finding, elevated levels of HIF-1alpha and SHH in pancreatic tumors were determined to be markers of decreased patient survival. Repeated cycles of hypoxia and desmoplasia amplified each other in a feed forward loop that made tumors more aggressive and resistant to therapy. This loop could be blocked by HIF-1alpha inhibition, which was sufficient to block SHH production and hedgehog signaling. Taken together, our findings suggest that increased HIF-1alpha produced by hypoxic tumors triggers the desmoplasic reaction in pancreatic cancer, which is then amplified by a feed forward loop involving cycles of decreased blood flow and increased hypoxia. Our findings strengthen the rationale for testing HIF inhibitors and may therefore represent a novel therapeutic option for pancreatic cancer. PMID- 23633489 TI - Critical role of STAT3 in IL-6-mediated drug resistance in human neuroblastoma. AB - Drug resistance is a major cause of treatment failure in cancer. Here, we have evaluated the role of STAT3 in environment-mediated drug resistance (EMDR) in human neuroblastoma. We determined that STAT3 was not constitutively active in most neuroblastoma cell lines but was rapidly activated upon treatment with interleukin (IL)-6 alone and in combination with the soluble IL-6 receptor (sIL 6R). Treatment of neuroblastoma cells with IL-6 protected them from drug-induced apoptosis in a STAT3-dependent manner because the protective effect of IL-6 was abrogated in the presence of a STAT3 inhibitor and upon STAT3 knockdown. STAT3 was necessary for the upregulation of several survival factors such as survivin (BIRC5) and Bcl-xL (BCL2L1) when cells were exposed to IL-6. Importantly, IL-6 mediated STAT3 activation was enhanced by sIL-6R produced by human monocytes, pointing to an important function of monocytes in promoting IL-6-mediated EMDR. Our data also point to the presence of reciprocal activation of STAT3 between tumor cells and bone marrow stromal cells including not only monocytes but also regulatory T cells (Treg) and nonmyeloid stromal cells. Thus, the data identify an IL-6/sIL-6R/STAT3 interactive pathway between neuroblastoma cells and their microenvironment that contributes to drug resistance. PMID- 23633490 TI - Coevolution of solid stress and interstitial fluid pressure in tumors during progression: implications for vascular collapse. AB - The stress harbored by the solid phase of tumors is known as solid stress. Solid stress can be either applied externally by the surrounding normal tissue or induced by the tumor itself due to its growth. Fluid pressure is the isotropic stress exerted by the fluid phase. We recently showed that growth-induced solid stress is on the order of 1.3 to 13.0 kPa (10-100 mmHg)--high enough to cause compression of fragile blood vessels, resulting in poor perfusion and hypoxia. However, the evolution of growth-induced stress with tumor progression and its effect on cancer cell proliferation in vivo is not understood. To this end, we developed a mathematical model for tumor growth that takes into account all three types of stresses: growth-induced stress, externally applied stress, and fluid pressure. First, we conducted in vivo experiments and found that growth-induced stress is related to tumor volume through a biexponential relationship. Then, we incorporated this information into our mathematical model and showed that due to the evolution of growth-induced stress, total solid stress levels are higher in the tumor interior and lower in the periphery. Elevated compressive solid stress in the interior of the tumor is sufficient to cause the collapse of blood vessels and results in a lower growth rate of cancer cells compared with the periphery, independently from that caused by the lack of nutrients due to vessel collapse. Furthermore, solid stress in the periphery of the tumor causes blood vessels in the surrounding normal tissue to deform to elliptical shapes. We present histologic sections of human cancers that show such vessel deformations. Finally, we found that fluid pressure increases with tumor growth due to increased vascular permeability and lymphatic impairment, and is governed by the microvascular pressure. Crucially, fluid pressure does not cause vessel compression of tumor vessels. PMID- 23633491 TI - Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8. AB - Triple-negative breast cancers (TNBC) are aggressive with no effective targeted therapies. A combined database analysis identified 32 inflammation-related genes differentially expressed in TNBCs and 10 proved critical for anchorage independent growth. In TNBC cells, an LPA-LPAR2-EZH2 NF-kappaB signaling cascade was essential for expression of interleukin (IL)-6, IL-8, and CXCL1. Concurrent inhibition of IL-6 and IL-8 expression dramatically inhibited colony formation and cell survival in vitro and stanched tumor engraftment and growth in vivo. A Cox multivariable analysis of patient specimens revealed that IL-6 and IL-8 expression predicted patient survival times. Together these findings offer a rationale for dual inhibition of IL-6/IL-8 signaling as a therapeutic strategy to improve outcomes for patients with TNBCs. PMID- 23633492 TI - Myeloid cell receptor LRP1/CD91 regulates monocyte recruitment and angiogenesis in tumors. AB - Recruitment of monocytes into sites of inflammation is essential in the immune response. In cancer, recruited monocytes promote invasion, metastasis, and possibly angiogenesis. LDL receptor-related protein (LRP1) is an endocytic and cell-signaling receptor that regulates cell migration. In this study, we isografted PanO2 pancreatic carcinoma cells into mice in which LRP1 was deleted in myeloid lineage cells. Recruitment of monocytes into orthotopic and subcutaneous tumors was significantly increased in these mice, compared with control mice. LRP1-deficient bone marrow-derived macrophages (BMDM) expressed higher levels of multiple chemokines, including, most prominently, macrophage inflammatory protein-1alpha/CCL3, which is known to amplify inflammation. Increased levels of CCL3 were detected in LRP1-deficient tumor-associated macrophages (TAM), isolated from PanO2 tumors, and in RAW 264.7 macrophage-like cells in which LRP1 was silenced. LRP1-deficient BMDMs migrated more rapidly than LRP1-expressing cells in vitro. The difference in migration was reversed by CCL3 neutralizing antibody, by CCR5-neutralizing antibody, and by inhibiting NF-kappaB with JSH-23. Inhibiting NF-kappaB reversed the increase in CCL3 expression associated with LRP1 gene silencing in RAW 264.7 cells. Tumors formed in mice with LRP1-deficient myeloid cells showed increased angiogenesis. Although VEGF mRNA expression was not increased in LRP1-deficient TAMs, at the single-cell level, the increase in TAM density in tumors with LRP1-deficient myeloid cells may have allowed these TAMs to contribute an increased amount of VEGF to the tumor microenvironment. Our results show that macrophage density in tumors is correlated with cancer angiogenesis in a novel model system. Myeloid cell LRP1 may be an important regulator of cancer progression. PMID- 23633493 TI - Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double-strand breaks. AB - Deregulation of the mTOR pathway is closely associated with tumorigenesis. Accordingly, mTOR inhibitors such as rapamycin and mTOR-selective kinase inhibitors have been tested as cancer therapeutic agents. Inhibition of mTOR results in sensitization to DNA-damaging agents; however, the molecular mechanism is not well understood. We found that an mTOR-selective kinase inhibitor, AZD8055, significantly enhanced sensitivity of a pediatric rhabdomyosarcoma xenograft to radiotherapy and sensitized rhabdomyosarcoma cells to the DNA interstrand cross-linker (ICL) melphalan. Sensitization correlated with drug induced downregulation of a key component of the Fanconi anemia pathway, FANCD2 through mTOR regulation of FANCD2 gene transcripts via mTORC1-S6K1. Importantly, we show that FANCD2 is required for the proper activation of ATM-Chk2 checkpoint in response to ICL and that mTOR signaling promotes ICL-induced ATM-Chk2 checkpoint activation by sustaining FANCD2. In FANCD2-deficient lymphoblasts, FANCD2 is essential to suppress endogenous and induced DNA damage, and FANCD2 deficient cells showed impaired ATM-Chk2 and ATR-Chk1 activation, which was rescued by reintroduction of wild-type FANCD2. Pharmacologic inhibition of PI3K mTOR-AKT pathway in Rh30 rhabdomyosarcoma cells attenuated ICL-induced activation of ATM, accompanied with the decrease of FANCD2. These data suggest that the mTOR pathway may promote the repair of DNA double-strand breaks by sustaining FANCD2 and provide a novel mechanism of how the Fanconi anemia pathway modulates DNA damage response and repair. PMID- 23633495 TI - The stray capacitance effect in Kelvin probe force microscopy using FM, AM and heterodyne AM modes. AB - The effect of stray capacitance on potential measurements was investigated using Kelvin probe force microscopy (KPFM) at room temperature under ultra-high vacuum (UHV). The stray capacitance effect was explored in three modes, including frequency modulation (FM), amplitude modulation (AM) and heterodyne amplitude modulation (heterodyne AM). We showed theoretically that the distance-dependence of the modulated electrostatic force in AM-KPFM is significantly weaker than in FM- and heterodyne AM-KPFMs and that the stray capacitance of the cantilever, which seriously influences the potential measurements in AM-KPFM, was almost completely eliminated in FM- and heterodyne AM-KPFMs. We experimentally confirmed that the contact potential difference (CPD) in AM-KPFM, which compensates the electrostatic force between the tip and the surface, was significantly larger than in FM- and heterodyne AM-KPFMs due to the stray capacitance effect. We also compared the atomic scale corrugations in the local contact potential difference (LCPD) among the three modes on the surface of Si(111)-7 * 7 finding that the LCPD corrugation in AM-KPFM was significantly weaker than in FM- and heterodyne AM-KPFMs under low AC bias voltage conditions. The very weak LCPD corrugation in AM-KPFM was attributed to the artefact induced by topographic feedback. PMID- 23633494 TI - Simultaneous targeting of tumor antigens and the tumor vasculature using T lymphocyte transfer synergize to induce regression of established tumors in mice. AB - Most systemic cancer therapies target tumor cells directly, although there is increasing interest in targeting the tumor stroma that can comprise a substantial portion of the tumor mass. We report here a synergy between two T-cell therapies, one directed against the stromal tumor vasculature and the other directed against antigens expressed on the tumor cell. Simultaneous transfer of genetically engineered syngeneic T cells expressing a chimeric antigen receptor targeting the VEGF receptor-2 (VEGFR2; KDR) that is overexpressed on tumor vasculature and T cells specific for the tumor antigens gp100 (PMEL), TRP-1 (TYRP1), or TRP-2 (DCT) synergistically eradicated established B16 melanoma tumors in mice and dramatically increased the tumor-free survival of mice compared with treatment with either cell type alone or T cells coexpressing these two targeting molecules. Host lymphodepletion before cell transfer was required to mediate the antitumor effect. The synergistic antitumor response was accompanied by a significant increase in the infiltration and expansion and/or persistence of the adoptively transferred tumor antigen-specific T cells in the tumor microenvironment and thus enhanced their antitumor potency. The data presented here emphasize the possible beneficial effects of combining antiangiogenic with tumor-specific immunotherapeutic approaches for the treatment of patients with cancer. PMID- 23633496 TI - Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy. AB - Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events. We examined the effect of rare genetic variants in the APOA5 gene region on plasma HDL-C, apolipoprotein A-I (apoA-I), and TG response to fenofibric acid monotherapy and in combination with statins. The APOA5 gene region was sequenced in 1,612 individuals with mixed dyslipidemia in a randomized trial of fenofibric acid alone and in combination with statins. Student's t-test and rare variant burden tests were used to examine plasma HDL-C, apoA-I, and TG response. Rare APOA5 promoter region variants were associated with decreased HDL-C and apoA-I levels in response to fenofibric acid therapy; rare missense variants were associated with increased TG response to combination therapy. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofibric acid monotherapy or combined with statins. PMID- 23633497 TI - Distributed approximation of Pareto surfaces in multicriteria radiation therapy treatment planning. AB - We consider multicriteria radiation therapy treatment planning by navigation over the Pareto surface, implemented by interpolation between discrete treatment plans. Current state of the art for calculation of a discrete representation of the Pareto surface is to sandwich this set between inner and outer approximations that are updated one point at a time. In this paper, we generalize this sequential method to an algorithm that permits parallelization. The principle of the generalization is to apply the sequential method to an approximation of an inexpensive model of the Pareto surface. The information gathered from the model is sub-sequently used for the calculation of points from the exact Pareto surface, which are processed in parallel. The model is constructed according to the current inner and outer approximations, and given a shape that is difficult to approximate, in order to avoid that parts of the Pareto surface are incorrectly disregarded. Approximations of comparable quality to those generated by the sequential method are demonstrated when the degree of parallelization is up to twice the number of dimensions of the objective space. For practical applications, the number of dimensions is typically at least five, so that a speed-up of one order of magnitude is obtained. PMID- 23633498 TI - Pneumolabyrinth following Eustachian tube insufflation. PMID- 23633499 TI - Response to letter to the editor of Kohui and Ghazavi. PMID- 23633500 TI - Letter to the editor on "Cerebellar infarctions mimicking acute peripheral vertigo: how to avoid misdiagnosis?". PMID- 23633501 TI - Response to: "Cerebellar infarctions mimicking acute peripheral vertigo," from Yeo et al. PMID- 23633502 TI - Further concerns regarding opioids after tonsillectomy in children. PMID- 23633503 TI - Response to "Further concerns regarding opioids after tonsillectomy in children". PMID- 23633504 TI - Improper citation of previously published work in Ghosh et al. PMID- 23633505 TI - Re: Improper citation of previously published work in Ghosh et al. PMID- 23633506 TI - A novel measurement and delivery system for synchronizing oxygen gas flow with blood flow during cardiopulmonary bypass. AB - Monitoring the blood pump and the oxygen gas flow meter are important maneuvers at the initiation of cardiopulmonary bypass (CPB). We present a novel system, designed to improve safety in the heart-lung machine by linking the control of blood flow and the oxygen gas flow meter. This system uses a mass flow controller to provide and control oxygen flow based on the ventilation-perfusion (V/Q) ratio, using the electronic signal of the blood flow. We tested the system, in vitro and in vivo, and examined the resulting level of blood oxygenation. When extracorporeal circulation was initiated, the oxygen flow was instantly linked to the circulating blood flow, providing an adequate V/Q ratio; the partial pressure of oxygen in the blood was maintained at a normal level. Although we have yet to confirm the safety of this system in clinical trials, the new safety assist device can automatically supply oxygen to the oxygenator at the beginning of CPB. PMID- 23633507 TI - An intracellular partitioning-based framework for tissue cell polarity in plants and animals. AB - Tissue cell polarity plays a major role in plant and animal development. We propose that a fundamental building block for tissue cell polarity is the process of intracellular partitioning, which can establish individual cell polarity in the absence of asymmetric cues. Coordination of polarities may then arise through cell-cell coupling, which can operate directly, through membrane-spanning complexes, or indirectly, through diffusible molecules. Polarity is anchored to tissues through organisers located at boundaries. We show how this intracellular partitioning-based framework can be applied to both plant and animal systems, allowing different processes to be placed in a common evolutionary and mechanistic context. PMID- 23633509 TI - ProNGF promotes neurite growth from a subset of NGF-dependent neurons by a p75NTR dependent mechanism. AB - The somatosensory and sympathetic innervation of the vertebrate head is derived principally from the neurons of trigeminal and superior cervical ganglia (SCG), respectively. During development, the survival of both populations of neurons and the terminal growth and branching of their axons in the tissues they innervate is regulated by the supply of nerve growth factor (NGF) produced by these tissues. NGF is derived by proteolytic cleavage of a large precursor protein, proNGF, which is recognised to possess distinctive biological functions. Here, we show that proNGF promotes profuse neurite growth and branching from cultured postnatal mouse SCG neurons. In marked contrast, proNGF does not promote the growth of trigeminal neurites. Studies using compartment cultures demonstrated that proNGF acts locally on SCG neurites to promote growth. The neurite growth-promoting effect of proNGF is not observed in SCG neurons cultured from p75(NTR)-deficient mice, and proNGF does not phosphorylate the NGF receptor tyrosine kinase TrkA. These findings suggest that proNGF selectively promotes the growth of neurites from a subset of NGF-responsive neurons by a p75(NTR)-dependent mechanism during postnatal development when the axons of these neurons are ramifying within their targets in vivo. PMID- 23633511 TI - Bithorax-complex genes sculpt the pattern of leucokinergic neurons in the Drosophila central nervous system. AB - Although the Hox genes are the main factors involved in the generation of diversity along the anterior/posterior body axis of segmented organisms, it is still largely unknown how these genes act in single cells to determine specific traits at precise developmental stages. The aim of this study was to understand the mechanisms by which Hox genes of the Bithorax complex (Bx-C) of Drosophila act to define segmental differences in the ventral nerve cord of the central nervous system. To achieve this, we have focused on the specification of the leucokinin-expressing neurons. We find that these neurons are specified from the same progenitor neuroblast at two different developmental stages: embryonic and larval neurogenesis. We show that genes of the Bx-C acted in postmitotic cells to specify the segment-specific appearance of leucokinergic cells in the larval and adult ventral nerve cord. PMID- 23633508 TI - C. elegans GATA factors EGL-18 and ELT-6 function downstream of Wnt signaling to maintain the progenitor fate during larval asymmetric divisions of the seam cells. AB - The C. elegans seam cells are lateral epithelial cells arrayed in a single line from anterior to posterior that divide in an asymmetric, stem cell-like manner during larval development. These asymmetric divisions are regulated by Wnt signaling; in most divisions, the posterior daughter in which the Wnt pathway is activated maintains the progenitor seam fate, while the anterior daughter in which the Wnt pathway is not activated adopts a differentiated hypodermal fate. Using mRNA tagging and microarray analysis, we identified the functionally redundant GATA factor genes egl-18 and elt-6 as Wnt pathway targets in the larval seam cells. EGL-18 and ELT-6 have previously been shown to be required for initial seam cell specification in the embryo. We show that in larval seam cell asymmetric divisions, EGL-18 is expressed strongly in the posterior seam-fated daughter. egl-18 and elt-6 are necessary for larval seam cell specification, and for hypodermal to seam cell fate transformations induced by ectopic Wnt pathway overactivation. The TCF homolog POP-1 binds a site in the egl-18 promoter in vitro, and this site is necessary for robust seam cell expression in vivo. Finally, larval overexpression of EGL-18 is sufficient to drive expression of a seam marker in other hypodermal cells in wild-type animals, and in anterior hypodermal-fated daughters in a Wnt pathway-sensitized background. These data suggest that two GATA factors that are required for seam cell specification in the embryo independently of Wnt signaling are reused downstream of Wnt signaling to maintain the progenitor fate during stem cell-like divisions in larval development. PMID- 23633510 TI - Decoupling the function of Hox and Shh in developing limb reveals multiple inputs of Hox genes on limb growth. AB - Limb development relies on an exquisite coordination between growth and patterning, but the underlying mechanisms remain elusive. Anterior-posterior and proximal-distal specification initiates in early limb bud concomitantly with the proliferative expansion of limb cells. Previous studies have shown that limb bud growth initially relies on fibroblast growth factors (FGFs) produced in the apical ectodermal ridge (AER-FGFs), the maintenance of which relies on a positive feedback loop involving sonic hedgehog (Shh) and the BMP antagonist gremlin 1 (Grem1). The positive cross-regulation between Shh and the HoxA and HoxD clustered genes identified an indirect effect of Hox genes on the maintenance of AER-FGFs but the respective function of Shh and Hox genes in this process remains unknown. Here, by uncoupling Hox and Shh function, we show that HoxA and HoxD genes are required for proper AER-FGFs expression, independently of their function in controlling Shh expression. In addition, we provide evidence that the Hox-dependent control of AER-FGF expression is achieved through the regulation of key mesenchymal signals, namely Grem1 and Fgf10, ensuring proper epithelial mesenchymal interactions. Notably, HoxA and HoxD genes contribute to both the initial activation of Grem1 and the subsequent anterior expansion of its expression domain. We propose that the intricate interactions between Hox genes and the FGF and Shh signaling pathways act as a molecular network that ensures proper limb bud growth and patterning, probably contributing to the coordination of these two processes. PMID- 23633512 TI - Klumpfuss controls FMRFamide expression by enabling BMP signaling within the NB5 6 lineage. AB - A number of transcription factors that are expressed within most, if not all, embryonic neuroblast (NB) lineages participate in neural subtype specification. Some have been extensively studied in several NB lineages (e.g. components of the temporal gene cascade) whereas others only within specific NB lineages. To what extent they function in other lineages remains unknown. Klumpfuss (Klu), the Drosophila ortholog of the mammalian Wilms tumor 1 (WT1) protein, is one such transcription factor. Studies in the NB4-2 lineage have suggested that Klu functions to ensure that the two ganglion mother cells (GMCs) in this embryonic NB lineage acquire different fates. Owing to limited lineage marker availability, these observations were made only for the NB4-2 lineage. Recent findings reveal that Klu is necessary for larval neuroblast growth and self-renewal. We have extended the study of Klu to the well-known embryonic NB5-6T lineage and describe a novel role for Klu in the Drosophila embryonic CNS. Our results demonstrate that Klu is expressed specifically in the postmitotic Ap4/FMRFa neuron, promoting its differentiation through the initiation of BMP signaling. Our findings indicate a pleiotropic function of Klu in Ap cluster specification in general and particularly in Ap4 neuron differentiation, indicating that Klu is a multitasking transcription factor. Finally, our studies indicate that a transitory downregulation of klu is crucial for the specification of the Ap4/FMRFa neuron. Similar to WT1, klu seems to have either self-renewal or differentiation promoting functions, depending on the developmental context. PMID- 23633514 TI - Mechanisms of tentacle morphogenesis in the sea anemone Nematostella vectensis. AB - Evolution of the capacity to form secondary outgrowths from the principal embryonic axes was a crucial innovation that potentiated the diversification of animal body plans. Precisely how such outgrowths develop in early-branching metazoan species remains poorly understood. Here we demonstrate that three fundamental processes contribute to embryonic tentacle development in the cnidarian Nematostella vectensis. First, a pseudostratified ectodermal placode forms at the oral pole of developing larvae and is transcriptionally patterned into four tentacle buds. Subsequently, Notch signaling-dependent changes in apicobasal epithelial thickness drive elongation of these primordia. In parallel, oriented cell rearrangements revealed by clonal analysis correlate with shaping of the elongating tentacles. Taken together, our results define the mechanism of embryonic appendage development in an early-branching metazoan, and thereby provide a novel foundation for understanding the diversification of body plans during animal evolution. PMID- 23633513 TI - Fascin 1 is transiently expressed in mouse melanoblasts during development and promotes migration and proliferation. AB - Fascins, a family of actin-bundling proteins, are expressed in a spatially and temporally restricted manner during development and often in cancer. Fascin 1 has a clear role in cell migration in vitro, but its role in vivo in mammals is not well understood. Here, we investigate the role of fascin 1 in the melanocyte lineage and in melanoma cells. Fascin 1 knockout causes hypopigmentation in adult mice owing to migration and cell cycle progression defects in melanoblasts, the melanocyte precursor cell. Study of live embryo skin explants reveals that E14.5 fascin 1-null melanoblasts migrate slower, and generate fewer and thinner pseudopods. By contrast, fascin 1 expression drives faster migration and lamellipodia protrusion in melanocytes in vitro. In addition, fascin 1 depletion retards melanoblast proliferation in vivo and melanoma cell growth in vitro. These data indicate that fascin 1 not only promotes cell migration in mouse melanocytes but it also has a role in growth and cell cycle progression. PMID- 23633515 TI - An inducible transgene expression system for zebrafish and chick. AB - We have generated an inducible system to control the timing of transgene expression in zebrafish and chick. An estrogen receptor variant (ERT2) fused to the GAL4 transcriptional activator rapidly and robustly activates transcription within 3 hours of treatment with the drug 4-hydroxy-tamoxifen (4-OHT) in tissue culture and transgenic zebrafish. We have generated a broadly expressed inducible ERT2-GAL4 zebrafish line using the ubiquitin (ubi) enhancer. In addition, use of ERT2-GAL4 in conjunction with tissue-specific enhancers enables the control of transgene expression in both space and time. This spatial restriction and the ability to sustain forced expression are important advantages over the currently used heat-shock promoters. Moreover, in contrast to currently available TET and LexA systems, which require separate constructs with their own unique recognition sequences, ERT2-GAL4 is compatible with the growing stock of UAS lines being generated in the community. We also applied the same inducible system to the chick embryo and find that it is fully functional, suggesting that this strategy is generally applicable. PMID- 23633516 TI - p53 dysfunction precedes the activation of nuclear factor-kappaB during disease progression in mice expressing Tax, a human T-cell leukemia virus type 1 oncoprotein. AB - Transgenic (Tg) mice expressing Tax, a human T-cell leukemia virus type 1 (HTLV 1) oncoprotein, develop mature T-cell leukemia/lymphoma. The leukemic cells in Tg mice expressing Tax show p53 dysfunction and nuclear factor-kappaB (NF-kappaB) activation, similar to that seen in adult T-cell leukemia/lymphoma (ATLL) cells from patients infected with HTLV-1. However, it is unclear when these effects occur in HTLV-1 carriers during the development of ATLL. Here, we examined p53 function and NF-kappaB activity before the onset of leukemia in Tax-expressing Tg (Tax-Tg) mice between 4 and 25 months of age. At 4-10 months of age, 71% of mice showed p53 inactivation, without evidence for NF-kappaB activation, even though tax expression was consistent from 4 to 25 months of age. The decline in p53 function resulted from decreased p53 accumulation after DNA damage. From 11 months of age onward, 75% of mice showed p53 dysfunction and 37.5% showed constitutive NF-kappaB activation with the components of p50 and RelB. An NF kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced NF-kappaB activity (i.e. p50/RelB) but did not restore p53 function. In vivo, treatment with DHMEQ until 24 months of age prevented the onset of T-cell leukemia in Tax Tg mice. These results suggest that the Tax-induced decline in p53 function, which is independent of NF-kappaB activation in the early stage, might be the first stage in the onset of ATLL. NF-kappaB activity is involved in the later stages of ATLL onset. PMID- 23633517 TI - RIP1 potentiates BPDE-induced transformation in human bronchial epithelial cells through catalase-mediated suppression of excessive reactive oxygen species. AB - Cell survival signaling is important for the malignant phenotypes of cancer cells. Although the role of receptor-interacting protein 1 (RIP1) in cell survival signaling is well documented, whether RIP1 is directly involved in cancer development has never been studied. In this report, we found that RIP1 expression is substantially increased in human non-small cell lung cancer and mouse lung tumor tissues. RIP1 expression was remarkably increased in cigarette smoke-exposed mouse lung. In human bronchial epithelial cells (HBECs), RIP1 was significantly induced by cigarette smoke extract or benzo[a]pyrene diol epoxide (BPDE), the active form of the tobacco-specific carcinogen benzo(a)pyrene. In RIP1 knockdown HBECs, BPDE-induced cytotoxicity was significantly increased, which was associated with induction of cellular reactive oxygen species (ROS) and activation of mitogen-activated protein kinases (MAPKs), including c-jun N terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38. Scavenging ROS suppressed BPDE-induced MAPK activation and inhibiting ROS or MAPKs substantially blocked BPDE-induced cytotoxicity, suggesting ROS-mediated MAPK activation is involved in BPDE-induced cell death. The ROS-reducing enzyme catalase is destabilized in an ERK- and JNK-dependent manner in RIP1 knockdown HBECs and application of catalase effectively blocked BPDE-induced ROS accumulation and cytotoxicity. Importantly, BPDE-induced transformation of HBECs was significantly reduced when RIP1 expression was suppressed. Altogether, these results strongly suggest an oncogenic role for RIP1, which promotes malignant transformation through protecting DNA-damaged cells against carcinogen-induced cytotoxicity associated with excessive ROS production. PMID- 23633518 TI - Depletion of 4E-BP1 and regulation of autophagy lead to YXM110-induced anticancer effects. AB - Natural products have always been a profuse database for developing new chemotherapeutics. YXM110 is a newly synthesized phenanthroquinolizidines that exhibits excellent anticancer activity in numerous cancer cells. In this study, we examined the anticancer mechanisms of YXM110 both in vitro and in vivo. Protein level of 4E-binding protein 1, which is crucial in cap-independent translation, was decreased significantly after YXM110 treatment via c-Jun N terminal kinases-mediated proteasomal degradation. Moreover, the effects of YXM110 were associated with several characteristics of autophagy, including accumulation of autophagic vacuoles, elevation of Atg12-Atg5 and light chain 3 (LC3)-II, and levels of GFP-LC3 puncta. The results suggested that depletion of Mcl-1 contributes to YXM110-triggered autophagy, whereas downregulation of lysosomal-related genes could cause autophagy impairment. Furthermore, YXM110 induced cell death was prevented by autophagy inhibitor 3-methyladenine and Atg5 silencing, indicating that YXM110-mediated autophagy impairment leads to cancer cell death. These data reveal key mechanisms that support the further development of YXM110 as a promising anticancer agent. PMID- 23633519 TI - Polyunsaturated fatty acids affect the localization and signaling of PIP3/AKT in prostate cancer cells. AB - AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. In spite of extensive research on AKT, one aspect has been largely overlooked, namely the role of the fatty acid chains on PIPs. PIPs are phospholipids composed of a glycerol backbone with fatty acids at the sn-1 and sn-2 position and inositol at the sn-3 position. Here, we show that polyunsaturated fatty acids (PUFAs) modify phospholipid content. Docosahexaenoic acid (DHA), an omega3 PUFA, can replace the fatty acid at the sn-2 position of the glycerol backbone, thereby changing the species of phospholipids. DHA also inhibits AKT(T308) but not AKT(S473) phosphorylation, alters PI(3,4,5)P3 (PIP3) and phospho-AKT(S473) protein localization, decreases pPDPK1(S241)-AKT and AKT BAD interaction and suppresses prostate tumor growth. Our study highlights a potential novel mechanism of cancer inhibition by omega3 PUFA through alteration of PIP3 and AKT localization and affecting the AKT signaling pathway. PMID- 23633520 TI - Manual experience shapes object representations. AB - How do people represent object meaning? It is now uncontentious that thinking about manipulable objects (e.g., pencils) activates brain regions underlying action. But is this activation part of the meaning of these objects, or is it merely incidental? The research we report here shows that when the hands are engaged in a task involving motions that are incompatible with those used to interact with frequently manipulated objects, it is more difficult to think about those objects--but not harder to think about infrequently manipulated objects (e.g., bookcases). Critically, the amount of manual experience with the object determines the amount of interference. These findings show that brain activity underlying manual action is part of, not peripheral to, the representation of frequently manipulated objects. Further, they suggest that people's ability to think about an object changes dynamically on the basis of the match between their (experience-based) mental representation of its meaning and whatever they are doing at that moment. PMID- 23633521 TI - Loss of Kruppel-like factor 3 (KLF3/BKLF) leads to upregulation of the insulin sensitizing factor adipolin (FAM132A/CTRP12/C1qdc2). AB - Kruppel-like factor 3 (KLF3) is a transcriptional regulator that we have shown to be involved in the regulation of adipogenesis in vitro. Here, we report that KLF3 null mice are lean and protected from diet-induced obesity and glucose intolerance. On a chow diet, plasma levels of leptin are decreased, and adiponectin is increased. Despite significant reductions in body weight and adiposity, wild-type and knockout animals show equivalent energy intake, expenditure, and excretion. To investigate the molecular events underlying these observations, we used microarray analysis to compare gene expression in Klf3(+/+) and Klf3(-/-) tissues. We found that mRNA expression of Fam132a, which encodes a newly identified insulin-sensitizing adipokine, adipolin, is significantly upregulated in the absence of KLF3. We confirmed that KLF3 binds the Fam132a promoter in vitro and in vivo and that this leads to repression of promoter activity. Further, plasma adipolin levels were significantly increased in Klf3(-/ ) mice compared with wild-type littermates. Boosting levels of adipolin via targeting of KLF3 offers a novel potential therapeutic strategy for the treatment of insulin resistance. PMID- 23633522 TI - Casein-coated iron oxide nanoparticles for high MRI contrast enhancement and efficient cell targeting. AB - Surface properties, as well as inherent physicochemical properties, of the engineered nanomaterials play important roles in their interactions with the biological systems, which eventually affect their efficiency in diagnostic and therapeutic applications. Here we report a new class of MRI contrast agent based on milk casein protein-coated iron oxide nanoparticles (CNIOs) with a core size of 15 nm and hydrodynamic diameter ~30 nm. These CNIOs exhibited excellent water solubility, colloidal stability, and biocompatibility. Importantly, CNIOs exhibited prominent T2 enhancing capability with a transverse relaxivity r2 of 273 mM(-1) s(-1) at 3 tesla. The transverse relaxivity is ~2.5-fold higher than that of iron oxide nanoparticles with the same core but an amphiphilic polymer coating. CNIOs showed pH-responsive properties, formed loose and soluble aggregates near the pI (pH ~4.0). The aggregates could be dissociated reversibly when the solution pH was adjusted away from the pI. The transverse relaxation property and MRI contrast enhancing effect of CNIOs remained unchanged in the pH range of 2.0-8.0. Further functionalization of CNIOs can be achieved via surface modification of the protein coating. Bioaffinitive ligands, such as a single chain fragment from the antibody of epidermal growth factor receptor (ScFvEGFR), could be readily conjugated onto the protein coating, enabling specific targeting to MDA-MB-231 breast cancer cells overexpressing EGFR. T2-weighted MRI of mice intravenously administered with CNIOs demonstrated strong contrast enhancement in the liver and spleen. These favorable properties suggest CNIOs as a class of biomarker targeted magnetic nanoparticles for MRI contrast enhancement and related biomedical applications. PMID- 23633523 TI - The relationship between diabetic retinopathy and cognitive impairment. AB - OBJECTIVE: Recent studies have shown an increased risk for cognitive impairment and dementia in patients with diabetes. An association between diabetic retinopathy (DR) and retinal microvasculature disease and cognitive impairment has been reported as potential evidence for a microvascular component to the cognitive impairment. It was hypothesized that severity of DR would be associated with cognitive impairment in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Three hundred eighty patients with type 2 diabetes were recruited from a population-based eye screening program and grouped by severity of DR as follows: no/mild DR (n=252) and proliferative diabetic retinopathy (PDR) (n=128). Each participant underwent psychosocial assessment; depression screening; ophthalmic and physical examination, including blood assays; and cognitive assessment with the Addenbrooke's Cognitive Examination-Revised (ACE-R), Mini Mental State Examination (MMSE), and the Mini-Cog. General linear modeling was used to examine severity of DR and cognitive impairment, adjusting for confounders. RESULTS: Severity of DR demonstrated an inverse relationship with cognitive impairment (fully adjusted R2=0.415, P<0.001). Ethnicity contributed most to the variance observed (16%) followed by education (7.3%) and retinopathy status (6.8%). The no/mild DR group had lower cognitive impairment scores on ACE R (adjusted mean+/-SE 77.0+/-1.9) compared with the PDR group (82.5+/-2.2, P<0.001). The MMSE cutoff scores showed that 12% of the no/mild DR group (n=31) had positive screening results for dementia or significant cognitive impairment compared with 5% in the PDR group (n=6). CONCLUSIONS: Patients with minimal DR demonstrated more cognitive impairment than those with advanced DR. Therefore, the increased prevalence of cognitive impairment in diabetes may be associated with factors other than evident retinal microvascular disease. PMID- 23633524 TI - Sucralose affects glycemic and hormonal responses to an oral glucose load. AB - OBJECTIVE: Nonnutritive sweeteners (NNS), such as sucralose, have been reported to have metabolic effects in animal models. However, the relevance of these findings to human subjects is not clear. We evaluated the acute effects of sucralose ingestion on the metabolic response to an oral glucose load in obese subjects. RESEARCH DESIGN AND METHODS: Seventeen obese subjects (BMI 42.3 +/- 1.6 kg/m(2)) who did not use NNS and were insulin sensitive (based on a homeostasis model assessment of insulin resistance score <= 2.6) underwent a 5-h modified oral glucose tolerance test on two separate occasions preceded by consuming either sucralose (experimental condition) or water (control condition) 10 min before the glucose load in a randomized crossover design. Indices of beta-cell function, insulin sensitivity (SI), and insulin clearance rates were estimated by using minimal models of glucose, insulin, and C-peptide kinetics. RESULTS: Compared with the control condition, sucralose ingestion caused 1) a greater incremental increase in peak plasma glucose concentrations (4.2 +/- 0.2 vs. 4.8 +/- 0.3 mmol/L; P = 0.03), 2) a 20 +/- 8% greater incremental increase in insulin area under the curve (AUC) (P < 0.03), 3) a 22 +/- 7% greater peak insulin secretion rate (P < 0.02), 4) a 7 +/- 4% decrease in insulin clearance (P = 0.04), and 5) a 23 +/- 20% decrease in SI (P = 0.01). There were no significant differences between conditions in active glucagon-like peptide 1, glucose dependent insulinotropic polypeptide, glucagon incremental AUC, or indices of the sensitivity of the beta-cell response to glucose. CONCLUSIONS: These data demonstrate that sucralose affects the glycemic and insulin responses to an oral glucose load in obese people who do not normally consume NNS. PMID- 23633526 TI - Adsorption of Polycyclic aromatic hydrocarbons (fluoranthene and anthracenemethanol) by functional graphene oxide and removal by pH and temperature-sensitive coagulation. AB - A new kind of functional graphene oxide with fine stability in water was fabricated by mixing graphene oxide (GO) and brilliant blue (BB) with a certain weight ratio. The adsorption performance of this mixture of BB and GO (BBGO) to polycyclic aromatic hydrocarbons (anthracenemethanol (AC) and fluoranthene (FL)) was investigated, and the results indicated BBGO possessed adsorption capacity of 1.676 mmol/g and removal efficiency of 72.7% as to AC and adsorption capacity of 2.212 mmol/g and removal efficiency of 93.2% as to FL. After adsorption, pH and temperature-sensitive coagulation (PTC) method was used to remove the AC/BBGO or FL/BBGO complex and proved to be an effective approach to flocculate the AC/BBGO or FL/BBGO complex into large flocs, which tended to be removed from the aqueous solution. PMID- 23633525 TI - Association between metformin therapy and mortality after breast cancer: a population-based study. AB - OBJECTIVE: Metformin has been associated with a reduction in breast cancer risk and may improve survival after cancer through direct and indirect tumor suppressing mechanisms. The purpose of this study was to evaluate the effect of metformin therapy on survival in women with breast cancer using methods that accounted for the duration of treatment with glucose-lowering therapies. RESEARCH DESIGN AND METHODS: This population-based study, using Ontario health care databases, recruited women aged 66 years or older diagnosed with diabetes and breast cancer between 1 April 1997 and 31 March 2008. Using Cox regression analyses, we explored the association between cumulative duration of past metformin use and all-cause and breast cancer-specific mortality. We modeled cumulative duration of past metformin use as a time-varying exposure. RESULTS: Of 2,361 breast cancer patients identified, mean (+/-SD) age at cancer diagnosis was 77.4+/-6.3 years, and mean follow-up was 4.5+/-3.0 years. There were 1,101 deaths (46.6%), among which 386 (16.3%) were breast cancer-specific deaths. No significant association was found between cumulative duration of past metformin use and all-cause mortality (adjusted hazard ratio 0.97 [95% CI 0.92-1.02]) or breast cancer-specific mortality (0.91 [0.81-1.03]) per additional year of cumulative use. CONCLUSIONS: Our findings failed to show an association between improved survival and increased cumulative metformin duration in older breast cancer patients who had recent-onset diabetes. Further research is needed to clarify this association, accounting for effects of cancer stage and BMI in younger populations or those with differing stages of diabetes as well as in nondiabetic populations. PMID- 23633527 TI - Highly efficient blue-green quantum dot light-emitting diodes using stable low cadmium quaternary-alloy ZnCdSSe/ZnS core/shell nanocrystals. AB - High-quality blue-green emitting ZnxCd(1-x)S(1-y)Se(y)/ZnS core/shell quantum dots (QDs) have been synthesized by a phosphine-free method. The quantum yields of as-synthesized ZnxCd(1-x)S(1-y)Se(y)/ZnS core/shell QDs can reach 50-75% with emissions between 450 and 550 nm. The emissions of such core/shell QDs are not susceptible to ligand loss through the photostability test. Blue-green light emitting diodes (LEDs) based on the low-cadmium ZnxCd(1-x)S(1-y)Se(y)/ZnS core/shell QDs have been successfully demonstrated. Composite films of poly[9,9 dioctylfluorene-co-N-[4-(3-methylpropyl)]-diphenylamine] (TFB) and ZnO nanoparticle layers were chosen as the hole-transporting and the electron transporting layers, respectively. Highly bright blue-green QD-based light emitting devices (QD-LEDs) showing maximum luminance up to 10000 cd/m(2), in particular, the blue QD-LEDs show an unprecedentedly high brightness over 4700 cd/m(2) and peak external quantum efficiency (EQE) of 0.8%, which is the highest value ever reported. These results signify a remarkable progress in QD-LEDs and offer a practicable platform for the realization of QD-based blue-green display and lighting. PMID- 23633528 TI - Acrolein, an alpha,beta-unsaturated aldehyde, irreversibly inhibits the acetylation of aromatic amine xenobiotics by human arylamine N-acetyltransferase 1. AB - Acrolein is an electrophilic alpha,beta-unsaturated aldehyde of industrial, pharmaceutic, and toxicologic importance to which we are exposed in environmental, occupational, and therapeutic situations. Acrolein is known to exert different biologic effects through reactions with cellular macromolecules such as DNA, certain proteins, or glutathione. In many situations (such as in tobacco smoke or other fumes), exposure to acrolein occurs concomitantly with other compounds such as aromatic amine chemicals. Interestingly, it has been shown that acrolein could impact the cellular metabolism of aromatic xenobiotics through an indirect mechanism based on the transcriptional induction of phase II xenobiotic-metabolizing enzymes. Here we report a novel mechanism by which acrolein acts on the metabolism of aromatic foreign chemicals. We provide molecular, kinetic, and cellular evidence that acrolein can react directly and irreversibly with arylamine N-acetyltransferases, a major family of xenobiotic metabolizing enzymes involved in the metabolization of aromatic amine chemicals. Formation of an acrolein adduct with a catalytic cysteine residue in the active site is responsible for the impairment of aromatic amine acetylation by the enzyme. This biochemical process may represent an additional mechanism by which acrolein impacts the metabolism and fate of aromatic amine drugs and pollutants. PMID- 23633529 TI - Characterization of recombinantly expressed rat and monkey intestinal alkaline phosphatases: in vitro studies and in vivo correlations. AB - Intestinal alkaline phosphatases (IALPs) are widely expressed in the brush border of epithelial cells of the intestinal mucosa. Although their physiologic role is unclear, they are very significant when it comes to the release of bioactive parent from orally dosed phosphate prodrugs. Such prodrugs can be resistant to cleavage by IALP, or alternatively undergo rapid cleavage leading to the release and precipitation of the less soluble parent. Because purified IALPs from preclinical species are not commercially available, and species differences have not been investigated to date, an effort was made to recombinantly express, purify, and characterize rat and cynomolgus monkey IALP (rIALP). Specifically, recombinant IALP (rIALP)-catalyzed cleavage of five prodrugs (fosphenytoin, clindamycin phosphate, dexamethasone phosphate, ritonavir phosphate, and ritonavir oxymethyl phosphate) was tested in vitro and parent exposure was assessed in vivo (rat only) following an oral dose of each prodrug. It was determined that the rate of phosphate cleavage in vitro varied widely; direct phosphates were more resistant to bioconversion, whereas faster conversion was observed with oxymethyl-linked prodrugs. Overall, the rat rIALP-derived data were qualitatively consistent with in vivo data; prodrugs that were readily cleaved in vitro rendered higher parent drug exposure in vivo. Of the five prodrugs tested, one (ritonavir phosphate) showed no conversion in vitro and no in vivo parent exposure. Finally, the apparent K(m) values obtained for fosphenytoin and clindamycin phosphate in vitro suggest that IALP is not likely to be saturated at therapeutic doses. PMID- 23633530 TI - Thermostable DNA ligase-mediated PCR production of circular plasmid (PPCP) and its application in directed evolution via in situ error-prone PCR. AB - Polymerase chain reaction (PCR) is a powerful method to produce linear DNA fragments. Here we describe the Tma thermostable DNA ligase-mediated PCR production of circular plasmid (PPCP) and its application in directed evolution via in situ error-prone PCR. In this thermostable DNA ligase-mediated whole plasmid amplification method, the resultant DNA nick between the 5' end of the PCR primer and the extended newly synthesized DNA 3' end of each PCR cycle is ligated by Tma DNA ligase, resulting in circular plasmid DNA product that can be directly transformed. The template plasmid DNA is eliminated by 'selection marker swapping' upon transformation. When performed under an error-prone condition with Taq DNA polymerase, PPCP allows one-step construction of mutagenesis libraries based on in situ error-prone PCR so that random mutations are introduced into the target gene without altering the expression vector plasmid. A significant difference between PPCP and previously published methods is that PPCP allows exponential amplification of circular DNA. We used this method to create random mutagenesis libraries of a xylanase gene and two cellulase genes. Screening of these libraries resulted in mutant proteins with desired properties, demonstrating the usefulness of in situ error-prone PPCP for creating random mutagenesis libraries for directed evolution. PMID- 23633531 TI - Functionally relevant microsatellite markers from chickpea transcription factor genes for efficient genotyping applications and trait association mapping. AB - We developed 1108 transcription factor gene-derived microsatellite (TFGMS) and 161 transcription factor functional domain-associated microsatellite (TFFDMS) markers from 707 TFs of chickpea. The robust amplification efficiency (96.5%) and high intra-specific polymorphic potential (34%) detected by markers suggest their immense utilities in efficient large-scale genotyping applications, including construction of both physical and functional transcript maps and understanding population structure. Candidate gene-based association analysis revealed strong genetic association of TFFDMS markers with three major seed and pod traits. Further, TFGMS markers in the 5' untranslated regions of TF genes showing differential expression during seed development had higher trait association potential. The significance of TFFDMS markers was demonstrated by correlating their allelic variation with amino acid sequence expansion/contraction in the functional domain and alteration of secondary protein structure encoded by genes. The seed weight-associated markers were validated through traditional bi-parental genetic mapping. The determination of gene-specific linkage disequilibrium (LD) patterns in desi and kabuli based on single nucleotide polymorphism microsatellite marker haplotypes revealed extended LD decay, enhanced LD resolution and trait association potential of genes. The evolutionary history of a strong seed-size/weight-associated TF based on natural variation and haplotype sharing among desi, kabuli and wild unravelled useful information having implication for seed-size trait evolution during chickpea domestication. PMID- 23633532 TI - Regulation of lipid metabolism by glucocorticoids and 11beta-HSD1 in skeletal muscle. AB - The prevalences of insulin resistance and type 2 diabetes mellitus are rising dramatically, and, as a consequence, there is an urgent need to understand the pathogenesis underpinning these conditions to develop new and more efficacious treatments. We have tested the hypothesis that glucocorticoid (GC)-mediated changes in insulin sensitivity may be associated with changes in lipid flux. Furthermore, prereceptor modulation of GC availability by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) may represent a critical regulatory step. Dexamethasone (DEX) decreased lipogenesis in both murine C2C12 and human LHC-NM2 myotubes. Inactivating p-Ser-79/218 of acetyl-CoA carboxylase 1/2 and activating p-Thr-172 of AMP-activated protein kinase were both increased after DEX treatment in C2C12 myotubes. In contrast, DEX increased beta-oxidation. Selective 11beta HSD1 inhibition blocked the 11-dehydrocorticosterone (11DHC)-mediated decrease in lipogenic gene expression and increase in lipolytic gene expression. Lipogenic gene expression was decreased, whereas lipolytic and beta-oxidative gene expression increased in corticosterone (CORT)- and 11DHC-treated wild-type mice and CORT (but not 11DHC)-treated 11beta-HSD1(-/-) mice. Furthermore, CORT- and 11DHC-treated wild-type mice and CORT (but not 11DHC)-treated 11beta-HSD1(-/-) mice had increased p-Ser-79/218 acetyl-CoA carboxylase 1/2, p-Thr-172 AMP activated protein kinase and intramyocellular diacylglyceride content. In summary, we have shown that GCs have potent actions on intramyocellular lipid homeostasis by decreasing lipid storage, increasing lipid mobilization and utilization, and increasing diacylglyceride content. It is plausible that dysregulated intramyocellular lipid metabolism may underpin GC-induced insulin resistance of skeletal muscle. PMID- 23633537 TI - Cure trends in acute lymphoblastic leukemia: is it time for a revised concept of cure? PMID- 23633533 TI - Previous history of chronic stress changes the transcriptional response to glucocorticoid challenge in the dentate gyrus region of the male rat hippocampus. AB - Chronic stress is a risk factor for several neuropsychiatric diseases, such as depression and psychosis. In response to stress glucocorticoids (GCs) are secreted that bind to mineralocorticoid and glucocorticoid receptors, ligand activated transcription factors that regulate the transcription of gene networks in the brain necessary for coping with stress, recovery, and adaptation. Chronic stress particularly affects the dentate gyrus (DG) subregion of the hippocampus, causing several functional and morphological changes with consequences for learning and memory, which are likely adaptive but at the same time make DG neurons more vulnerable to subsequent challenges. The aim of this study was to investigate the transcriptional response of DG neurons to a GC challenge in male rats previously exposed to chronic restraint stress (CRS). An intriguing finding of the current study was that having a history of CRS had profound consequences for the subsequent response to acute GC challenge, differentially affecting the expression of several hundreds of genes in the DG compared with challenged nonstressed control animals. This enduring effect of previous stress exposure suggests that epigenetic processes may be involved. In line with this, CRS indeed affected the expression of several genes involved in chromatin structure and epigenetic processes, including Asf1, Ash1l, Hist1h3f, and Tp63. The data presented here indicate that CRS alters the transcriptional response to a subsequent GC injection. We propose that this altered transcriptional potential forms part of the molecular mechanism underlying the enhanced vulnerability for stress-related disorders like depression caused by chronic stress. PMID- 23633538 TI - To respond or not to respond to hydroxyurea in thalassemia: a matter of stress adaptation? PMID- 23633539 TI - Lenalidomide in the treatment of plasma cell dyscrasia: state of the art and perspectives. PMID- 23633540 TI - High-dose chemotherapy and autologous stem cell transplantation for secondary central nervous system lymphoma: many are called, but few are chosen. PMID- 23633541 TI - T315I, more or less, predicts for major molecular response: the devil is in the details! PMID- 23633542 TI - Principles of care for the diagnosis and treatment of von Willebrand disease. AB - Von Willebrand disease is a common autosomal inherited bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor, a multi-adhesive protein that binds platelets to exposed subendothelium and carries factor VIII in circulation. As a result of von Willebrand factor deficiency or abnormality, levels of factor VIII, the protein deficient in hemophilia A, may be variably reduced. Clinical manifestations are mainly represented by mucous membrane and of soft tissue bleeding. Their severity is variable depending on the degree of von Willebrand factor and factor VIII reduction. While a clear-cut diagnosis is easy in severe von Willebrand factor reductions, the advantage of pursuing a definite diagnosis in mild or dubious cases should be weighed against the risk of over medicalization. The aim of treatment is to correct the dual defect of hemostasis caused by the abnormal/reduced von Willebrand factor and the concomitant deficiency of factor VIII. Desmopressin is the treatment of choice for type 1 von Willebrand disease patients with factor VIII and von Willebrand factor levels of 10 U/dL or over who have proved responsive to a test-infusion with the compound. Von Willebrand factor/factor VIII concentrates are needed when desmopressin is ineffective (mainly type 2 and 3 von Willebrand disease). PMID- 23633544 TI - Clonal analyses reveal associations of JAK2V617F homozygosity with hematologic features, age and gender in polycythemia vera and essential thrombocythemia. AB - Subclones homozygous for JAK2V617F are more common and larger in patients with polycythemia vera compared to essential thrombocythemia, but their role in determining phenotype remains unclear. We genotyped 4564 erythroid colonies from 59 patients with polycythemia vera or essential thrombocythemia to investigate whether the proportion of JAK2V617F -homozygous precursors, compared to heterozygous precursors, is associated with clinical or demographic features. In polycythemia vera, a higher proportion of homozygous-mutant precursors was associated with more extreme blood counts at diagnosis, consistent with a causal role for homozygosity in polycythemia vera pathogenesis. Larger numbers of homozygous-mutant colonies were associated with older age, and with male gender in polycythemia vera but female gender in essential thrombocythemia. These results suggest that age promotes development or expansion of homozygous-mutant clones and that gender modulates the phenotypic consequences of JAK2V617F homozygosity, thus providing a potential explanation for the long-standing observations of a preponderance of men with polycythemia vera but of women with essential thrombocythemia. PMID- 23633543 TI - Clinical implications of the molecular genetics of chronic lymphocytic leukemia. AB - Genetics and molecular genetics have contributed to clarify the biological bases of the clinical heterogeneity of chronic lymphocytic leukemia. In recent years, our knowledge of the molecular genetics of chronic lymphocytic leukemia has significantly broadened, offering potential new clinical implications. Mutations of TP53 and ATM add prognostic information independently of fluorescence in situ hybridization cytogenetic stratification. In addition, next generation sequencing technologies have allowed previously unknown genomic alterations in chronic lymphocytic leukemia to be identified. Mutations of NOTCH1, SF3B1 and BIRC3 have been associated with short time to progression and survival. Each of these lesions recognizes a different distribution across different clinical phases and biological subgroups of the disease. The clinical implications of these molecular lesions are in some instances well established, such as in the case of patients with TP53 disruption, who should be considered for alternative therapies/allogeneic stem cell transplant upfront, or in patients with ATM disruption, who are candidates to rituximab-based immunochemotherapy. On the contrary, NOTCH1, SF3B1 and BIRC3 mutations appear to have a specific significance, the clinical value of which is currently being validated, i.e. association to Richter syndrome transformation for NOTCH1 mutations, and short progression-free survival after treatment for SF3B1 mutations. Certainly, these new lesions have helped clarify the molecular bases of chronic lymphocytic leukemia aggressiveness beside TP53 disruption. This review covers the recent advancements in our understanding of the molecular genetics of chronic lymphocytic leukemia and discusses how they are going to translate into clinical implications for patient management. PMID- 23633545 TI - Predictors of survival in thrombotic thrombocytopenic purpura. PMID- 23633546 TI - Swedish nurses encounter barriers when promoting healthy habits in children. AB - To increase the understanding of difficulties in promoting healthy habits to parents, we explore barriers in health-care provision. The aim of this study is to describe nurses' perceived barriers when discussing with parents regarding healthy food habits, physical activity and their child's body weight. A mixed method approach was chosen. Nurses (n = 76) working at 29 different Child Health Care Centers' in an area in west Sweden were included in the study. Three focus group interviews were conducted and 17 nurses were selected according to maximum variation. Data were categorized and qualitative content analysis was the chosen analysis method. In the second method, data were obtained from a questionnaire distributed to all 76 nurses. The latent content was formulated into a theme: even with encouragement and support, the nurses perceive barriers of both an external and internal nature. The results identified four main barriers: experienced barriers in the workplace-internal and external; the nurse's own fear and uncertainty; perceived obstacles in nurse-parent interactions and modern society impedes parents' ability to promote healthy habits. The nurses' perceived barriers were confirmed by the results from 62 of the nurses who completed the questionnaire. Despite education and professional support, the health professionals perceived both external and internal barriers in promoting healthy habits to parents when implementing a new method of health promotion in primary care. Further qualitative studies are needed to gain deeper understanding of the perceived barriers when promoting healthy habits to parents. PMID- 23633547 TI - Diagnostic approach and differential diagnosis in patients with hypertrophied left ventricles. PMID- 23633548 TI - Dronedarone for the treatment of non-permanent atrial fibrillation: National Institute for Health and Clinical Excellence guidance. PMID- 23633550 TI - Discontinuous gradient centrifugation (DGC) decreases the proportion of chromosomally unbalanced spermatozoa in chromosomal rearrangement carriers. AB - STUDY QUESTION: Can the proportion of unbalanced spermatozoa in chromosomal rearrangement carriers be decreased through the use of discontinuous gradient centrifugation (DGC)? SUMMARY ANSWER: DGC significantly decreases the proportion of genetically unbalanced spermatozoa in chromosomal rearrangement carriers. WHAT IS KNOWN ALREADY: Chromosomal rearrangement carriers present with a certain proportion of unbalanced gametes, which can lead to miscarriages or malformations in the offspring. There is presently no known way to select the balanced spermatozoa and use them for IVF. STUDY DESIGN, SIZE, DURATION: The proportion of unbalanced spermatozoa after DGC was compared with that before DGC in 21 patients with a chromosomal rearrangement. At least 500 spermatozoa were analysed per observation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-one male patients with a chromosomal rearrangement were included in this prospective study. They initially consulted for infertility, recurrent miscarriages or a history of abnormal pregnancy. The samples were split into two, with one part undergoing DGC and the other being immediately fixed. Fluorescence in situ hybridization was performed to establish the chromosome segregation pattern of each spermatozoon. MAIN RESULTS AND THE ROLE OF CHANCE: DGC significantly decreased the proportion of unbalanced spermatozoa in all but 1 of the 21 chromosomal rearrangement carriers (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Although DGC reduces the proportion of unbalanced spermatozoa in ejaculates from patients with chromosome rearrangements this elimination is only partial and some abnormal spermatozoa remain. Means to exclude these spermatozoa to ensure that only balanced ones are used in IVF remain to be discovered. The motility and morphology of the sperm before and after DGC were not measured. WIDER IMPLICATIONS OF THE FINDINGS: Used in IVF or intrauterine insemination, DGC could decrease the chance that a man carrying a chromosomal rearrangement will father an abnormal fetus. PMID- 23633551 TI - Tetraploidy in hydatidiform moles. AB - STUDY QUESTION: How does tetraploidy develop in hydatidiform moles (HMs), and what is the frequency of the different origins? SUMMARY ANSWER: Most molar pregnancies with tetraploid cells appear to be produced by somatic endoreduplications, while a minority originate from a tetraploid zygote. The frequency of zygotic tetraploidy was estimated to be 0.7%. WHAT IS KNOWN ALREADY: The parental origin of the genome in tetraploid HMs has only been evaluated in a few cases, most showing three genome sets from the father (PPPM). Estimates of the proportion of HMs that are tetraploid vary between 2 and 28%. STUDY DESIGN, SIZE, DURATION: From 1986 to 2010, unfixed samples of clinically suspected molar pregnancies were forwarded to the Danish Mole Project. For this cohort study 442 samples fulfilled the following criteria for inclusion: macroscopic appearance of HM and >= 10 vesicular chorionic villi with a diameter of >= 1 mm. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of 403 karyotyped samples, 21 cases disclosed >= 2 tetraploid metaphases. The 21 cases were scrutinized by karyotyping, flow cytometry (FC) and DNA-marker analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Among 20 HMs, 3 showed the genotype PPPM: one with the sex chromosomes XXYY and two with XXXY, indicating that they originated in tetraploid zygotes. In 14 androgenetic, one likely androgenetic and two mosaics, the tetraploid cells likely developed by endoreduplications of diploid cells. One case did not fulfil the histopathological criteria for HM. LIMITATIONS, REASONS FOR CAUTION: As an inclusion criterion was the macroscopic observation of vesicular chorionic villi, some non-molar hydropic placentas may have been included and some early moles may have been excluded. WIDER IMPLICATIONS OF THE FINDINGS: In future, studies to determine that an HM is tetraploid and discriminate cases of mosaicism and to deduce the origin of the tetraploidy must use the techniques of karyotyping, DNA-marker analysis and FC in combination. PMID- 23633549 TI - Venous malformation-causative TIE2 mutations mediate an AKT-dependent decrease in PDGFB. AB - Mutations in the endothelial cell (EC) tyrosine kinase receptor TIE2 cause inherited and sporadic forms of venous malformation. The recurrent somatic mutation L914F and common germline mutation R849W differ in terms of phosphorylation level, as well as sub-cellular localization and trafficking of the receptor. Previous studies have shed light on certain pathogenic properties of R849W, but the mechanisms of action of L914F are unknown. We used global gene expression profiling to study the effects of L914F on ECs. We found that L914F strongly dysregulates genes involved in vascular development, cell migration and extracellular matrix processing, while R849W has weak effects. We also demonstrate, for the first time, that TIE2-mutant ECs are deficient in the production of PDGFB, both in vitro and ex vivo in patient tissues. This defect is mediated by the chronic, ligand-independent activation of AKT by the mutant receptors. Inadequate secretion of the major mural cell attractant likely plays an important role in the development of abnormal vascular channels, contributing to the characteristic paucity of surrounding vascular smooth muscle cells. PMID- 23633552 TI - Minimal residual disease detection of leukemic cells in ovarian cortex by eight color flow cytometry. AB - STUDY QUESTION: How can leukemic cells be detected in cryopreserved ovarian tissue? SUMMARY ANSWER: Multicolor flow cytometry (FCM) is useful to evaluate the presence of viable leukemic cells in the ovarian cortex with a high specificity and a robust sensitivity. WHAT IS KNOWN ALREADY: Storing ovarian tissue is an option to preserve fertility before gonadotoxic radiotherapy or chemotherapy treatments. However, transplantation of cryopreserved ovarian cortex to women cured of leukemia is currently not possible due to the risk of cancer re-seeding. STUDY DESIGN, SIZE, DURATION: We developed an automated ovarian cortex dissociation technique and we used eight-color FCM to identify leukemic cells with a series of dilutions added to ovarian single cell suspensions obtained from healthy cortex. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Healthy ovarian cortex originated from women between 23 and 39 years of age undergoing laparoscopic ovarian drilling for polycystic ovary syndrome. Blood or bone marrow cells were collected in acute lymphoblastic leukemia (ALL) patients at diagnosis. MAIN RESULTS AND THE ROLE OF CHANCE: The tissue dissociation technique yield was 1.83 +/- 1.49 * 10(6) viable nucleated cells per 100 mg of ovarian cortex. No cell exhibiting a leukemic phenotype was present in the normal ovarian cortex. Added leukemic cells were detected using their leukemia-associated phenotype up to a dilution of 10(-4). When specific gene rearrangements were present, they were detected by real-time quantitative PCR at the same dilution. The ovarian cortex from two leukemia patients was then used, respectively, as positive and negative controls. LIMITATIONS, REASONS FOR CAUTION: Making available minimal residual disease (MRD) detection techniques (multicolor FCM, PCR and xenograft), that can be used either alone or together, is essential to add a fail-safe oncological dimension to pre-autograft monitoring. WIDER IMPLICATIONS OF THE FINDINGS: This approach can be performed on fresh ovarian tissue during cryopreservation or on frozen/thawed tissue before reimplantation and it is currently the only available technique in cases of ALL where no molecular markers are identified. This new perspective should lead to studies on ovarian tissue from leukemia patients, for whom the presence of MRD should be established before autograft. STUDY FUNDINGS/COMPETING INTEREST(S): The study was supported by the BioMedicine Agency, the Committee of the League against Cancer, the Besancon University Hospital, DGOS/INSERM/INCa and the regional Council of Franche-Comte. There were no conflicts of interest to declare. PMID- 23633553 TI - Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG. AB - STUDY QUESTION: Is severe early ovarian hyperstimulation syndrome (OHSS) completely prevented with the GnRH agonist trigger and 1500 IU hCG luteal rescue protocol? SUMMARY ANSWER: Severe early OHSS can occur even after the GnRH agonist trigger and 1500 IU hCG luteal rescue protocol. WHAT IS KNOWN ALREADY: Prior studies including over 200 women who received the GnRH agonist trigger and 1500 hCG luteal rescue protocol have reported complete prevention of severe early OHSS. Only a few late OHSS cases have been reported and it has been suggested that this protocol can be safely applied to any women under risk. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included all women who were at high risk of OHSS and were given the GnRH agonist trigger plus hCG luteal rescue protocol between December 2008 and August 2012 in the two participating centers. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 23 women with a mean estradiol level of 4891 +/- 2214 pg/ml and a mean number of >12 mm follicles of 20 +/- 6 on the day of ovulation triggering. OHSS was categorized according to the Golan criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Overall 6 of the 23 (26%) women developed severe OHSS. Five women had severe early OHSS requiring ascites drainage and hospitalization and three of these women did not undergo embryo transfer. The number of follicles measuring 10-14 mm on the day of triggering was significantly different between women who developed severe early OHSS and those who did not. LIMITATIONS, REASONS FOR CAUTION: The small number of women with severe early OHSS may have prevented identification of other significant risk factors. WIDER IMPLICATIONS OF THE FINDINGS: Although the GnRH agonist plus 1500 IU hCG luteal rescue protocol significantly decreases the risk of severe OHSS, this life threatening complication can still occur in high-risk patients. It would be prudent to avoid hCG luteal rescue and freeze all embryos for future transfer in such women particularly when there are >=18 follicles with 10-14 mm diameters even with few larger follicles. PMID- 23633554 TI - Low-dose hCG supplementation after GnRH agonist triggering: Don't be too quick on the trigger. PMID- 23633555 TI - Solving tough problems with games. PMID- 23633556 TI - Seeking sailors to help measure phytoplankton populations. PMID- 23633558 TI - Oncological outcomes of thoracoscopic thymectomy for the treatment of stages I III thymomas. AB - OBJECTIVES: Thoracoscopic thymectomy has gradually replaced conventional sternotomy for resection of thymoma; however, a thoracoscopic approach for thymoma remains controversial. We evaluated the oncological outcomes of thoracoscopic thymectomy for the treatment of stages I-III thymomas. METHODS: Sixty-two patients who underwent thoracoscopic thymectomy for the treatment of thymoma were retrospectively reviewed between July 2005 and September 2011 at Jikei University Hospital. Surgical outcomes and pathological results between stages I+II and stage III were compared. RESULTS: Twenty-nine patients had Masaoka stage I, 28 had stage II and 5 had stage III. Three stage III patients needed conversions to open surgery. Masaoka stage III comprised pathological type B3 in 3 patients and thymic carcinoma in 2. For all patients, the 5-year overall survival rate was 100%. Three recurrences, diagnosed as thymic carcinoma, were observed in the Masaoka stage II or III patients. The 5-year disease-free survival rate was 94.2% for all patients, 100% for Masaoka stage I, 96.1% for stage II and 37.5% (55 months) for stage III (P=0.002). The 5-year disease-free survival rate was 100% for the World Health Organization classification types A, AB and B1-3 and 0% for thymic carcinoma (P<0.0001). Significant differences were found in the 5-year disease-free survival stratified by the Masaoka stage or WHO classification, but not by surgical procedures. CONCLUSIONS: Thoracoscopic thymectomy for Masaoka stages I and II thymomas presented acceptable oncological outcomes. Further investigation in a large series with longer follow-up is required. Masaoka stage III thymoma requires careful consideration of the approaches, including median sternotomy. PMID- 23633559 TI - Two-stage operation for isolated pulmonary valve infectious endocarditis with Candida parapsilosis. AB - We report a case of isolated pulmonary infectious endocarditis (IE) with Candida parapsilosis. A 66-year-old man presented with fever and cough. Echocardiography showed severe pulmonary regurgitation and vegetations on the pulmonary valves. Initially, antibiotics were prescribed against bacterial IE, and the vegetations disappeared; however, the pulmonary vegetations relapsed, and C. parapsilosis was grown from blood cultures. We performed a debridement without a pulmonary valve replacement. There was no recurrence of IE for 3 years, and then the patient developed right ventricular enlargement and severe tricuspid regurgitation due to severe pulmonary regurgitation. Pulmonary valve replacement was performed. Now the patient is free from infection. PMID- 23633560 TI - Adverse events of pulmonary vascular stapling in thoracic surgery. AB - OBJECTIVES: The use of staplers for thoracic surgery has been widely accepted and regarded as a safe procedure. However, adverse events (AEs) of stapling are occasionally experienced. The aim of this retrospective study was to analyse the AEs of stapling in pulmonary vascular surgery. METHODS: A retrospective multi institutional review was conducted by the 29 institutions of the Central Japan Lung Cancer Surgery Study Group. All staplings of the pulmonary artery (PA) and vein in thoracic surgery were reviewed during the research period. RESULTS: Stapling of the PA and vein was performed 3393 times. The total number of AEs related to stapling was nine (0.27%). Eight events occurred intraoperatively and one occurred immediately after the operation. Intraoperative AE occurred more frequently than postoperative AE. AE in the PA occurred more frequently than in the pulmonary vein. The intraoperative AEs were oozing (n=3), stapling failure (n=2), laceration of the peripheral vasculature at compression (n=2) and technical injury of the vasculature at insertion (n=1). The causes of AEs were reported to be tissue fragility (n=3), stapler rocking during stapling (n=2), stapler-tissue thickness mismatch (n=2) and technical failure (n=1). The only postoperative AE was staple line rupture of the PV stump. No relationship was seen between the incidence of AE and cartridge colours, compression types of staplers or numbers of staple lines. CONCLUSIONS: Generally, stapling of the pulmonary vasculatures in recent thoracic surgery has been safe. Furthermore, the knowledge of the possible risks of pulmonary vascular stapling may help to decrease the AEs of stapling. PMID- 23633561 TI - PET/MR imaging consensus paper: a joint paper by the Society of Nuclear Medicine and Molecular Imaging Technologist Section and the Section for Magnetic Resonance Technologists. PMID- 23633562 TI - Time to onset of secondary progression as an outcome in MS trials: a new paradigm? PMID- 23633563 TI - Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver X receptor. AB - Epidemiological studies demonstrate that the link between impaired fetal development and glucose intolerance in later life is exacerbated by postnatal catch-up growth. Maternal protein restriction (MPR) during pregnancy and lactation in the rat has been previously demonstrated to lead to impaired glucose tolerance in adulthood, however the effects of protein restoration during weaning on glucose homeostasis are largely unknown. Recent in vitro studies have identified that the liver X receptor alpha (LXRalpha) maintains glucose homeostasis by inhibiting critical genes involved in gluconeogenesis including G6pase (G6pc), 11beta-Hsd1 (Hsd11b1) and Pepck (Pck1). Therefore, we hypothesized that MPR with postnatal catch-up growth would impair LXRalpha in vivo, which in turn would lead to augmented gluconeogenic LXRalpha-target gene expression and glucose intolerance. To examine this hypothesis, pregnant Wistar rats were fed a control (20%) protein diet (C) or a low (8%) protein diet during pregnancy and switched to a control diet at birth (LP). At 4 months, the LP offspring had impaired glucose tolerance. In addition, LP offspring had decreased LXRalpha expression, while hepatic expression of 11beta-HSD1 and G6Pase was significantly higher. This was concomitant with decreased binding of LXRalpha to the putative LXRE on 11beta-Hsd1 and G6pase. Finally, we demonstrated that the acetylation of histone H3 (K9,14) surrounding the transcriptional start site of hepatic Lxralpha (Nr1h3) was decreased in LP offspring, suggesting MPR-induced epigenetic silencing of the Lxralpha promoter. In summary, our study demonstrates for the first time the important role of LXRalpha in mediating enhanced hepatic gluconeogenic gene expression and consequent glucose intolerance in adult MPR offspring. PMID- 23633564 TI - A new member of the 4-methylideneimidazole-5-one-containing aminomutase family from the enediyne kedarcidin biosynthetic pathway. AB - 4-Methylideneimidazole-5-one (MIO)-containing aminomutases catalyze the conversion of L-alpha-amino acids to beta-amino acids with either an (R) or an (S) configuration. L-phenylalanine and L-tyrosine are the only two natural substrates identified to date. The enediyne chromophore of the chromoprotein antitumor antibiotic kedarcidin (KED) harbors an (R)-2-aza-3-chloro-beta-tyrosine moiety reminiscent of the (S)-3-chloro-5-hydroxy-beta-tyrosine moiety of the C 1027 enediyne chromophore, the biosynthesis of which uncovered the first known MIO-containing aminomutase, SgcC4. Comparative analysis of the KED and C-1027 biosynthetic gene clusters inspired the proposal for (R)-2-aza-3-chloro-beta tyrosine biosynthesis starting from 2-aza-L-tyrosine, featuring KedY4 as a putative MIO-containing aminomutase. Here we report the biochemical characterization of KedY4, confirming its proposed role in KED biosynthesis. KedY4 is an MIO-containing aminomutase that stereospecifically catalyzes the conversion of 2-aza-L-tyrosine to (R)-2-aza-beta-tyrosine, exhibiting no detectable activity toward 2-aza-L-phenylalanine or L-tyrosine as an alternative substrate. In contrast, SgcC4, which stereospecifically catalyzes the conversion of L-tyrosine to (S)-beta-tyrosine in C-1027 biosynthesis, exhibits minimal activity with 2-aza-L-tyrosine as an alternative substrate but generating (S)-2 aza-beta-tyrosine, a product with the opposite stereochemistry of KedY4. This report of KedY4 broadens the scope of known substrates for the MIO-containing aminomutase family, and comparative studies of KedY4 and SgcC4 provide an outstanding opportunity to examine how MIO-containing aminomutases control substrate specificity and product enantioselectivity. PMID- 23633566 TI - Fe-carbonyl is a key player in planetary magmas. PMID- 23633565 TI - Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. AB - Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from BRAF kinase mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. We performed high-resolution copy-number analysis on 44 formalin-fixed, paraffin-embedded diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gain, was observed in 28% of diffuse astrocytoma grade IIs and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene v-myb avian myeloblastosis viral oncogene homolog (MYB) on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged diffuse astrocytoma grade II demonstrated MYBL1 tandem duplication and few other events. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas. PMID- 23633567 TI - Expression of TEX101, regulated by ACE, is essential for the production of fertile mouse spermatozoa. AB - Formation of spermatozoa of normal shape, number, and motility is insufficient for the male siring of pups. The spermatozoa must be accompanied by sound fertilizing ability. We found that males with disrupted testis-expressed gene 101 (Tex101) produce normal-looking but fertilization-incompetent spermatozoa, which were accompanied by a deficiency of a disintegrin and metallopeptidase domain 3 (ADAM3) on sperm plasma membrane. It was also found that the existence of TEX101 on spermatozoa was regulated by angiotensin-converting enzyme (ACE). The removal of GPI-anchored protein TEX101 by ACE was essential to produce fertile spermatozoa, and the function of ACE was not depending on its well-known peptidase activity. The finding of TEX101 as a unique specific substrate for ACE may provide a potential target for the production of an awaited contraceptive medicine for men. PMID- 23633568 TI - Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behcet disease. AB - Genome-wide association studies (GWAS) are a powerful means of identifying genes with disease-associated common variants, but they are not well-suited to detecting genes with disease-associated rare and low-frequency variants. In the current study of Behcet disease (BD), nonsynonymous variants (NSVs) identified by deep exonic resequencing of 10 genes found by GWAS (IL10, IL23R, CCR1, STAT4, KLRK1, KLRC1, KLRC2, KLRC3, KLRC4, and ERAP1) and 11 genes selected for their role in innate immunity (IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4) were evaluated for BD association. A differential distribution of the rare and low-frequency NSVs of a gene in 2,461 BD cases compared with 2,458 controls indicated their collective association with disease. By stringent criteria requiring at least a single burden test with study-wide significance and a corroborating test with at least nominal significance, rare and low-frequency NSVs in one GWAS-identified gene, IL23R (P = 6.9 * 10(-5)), and one gene involved in innate immunity, TLR4 (P = 8.0 * 10(-4)), were associated with BD. In addition, damaging or rare damaging NOD2 variants were nominally significant across all three burden tests applied (P = 0.0063-0.045). Furthermore, carriage of the familial Mediterranean fever gene (MEFV) mutation Met694Val, which is known to cause recessively inherited familial Mediterranean fever, conferred BD risk in the Turkish population (OR, 2.65; P = 1.8 * 10(-12)). The disease-associated NSVs in MEFV and TLR4 implicate innate immune and bacterial sensing mechanisms in BD pathogenesis. PMID- 23633569 TI - Limits to upward movement of subalpine forests in a warming climate. PMID- 23633570 TI - Juvenile hormone and its receptor, methoprene-tolerant, control the dynamics of mosquito gene expression. AB - Juvenile hormone III (JH) plays a key role in regulating the reproduction of female mosquitoes. Microarray time-course analysis revealed dynamic changes in gene expression during posteclosion (PE) development in the fat body of female Aedes aegypti. Hierarchical clustering identified three major gene clusters: 1,843 early-PE (EPE) genes maximally expressed at 6 h PE, 457 mid-PE (MPE) genes at 24 h PE, and 1,815 late-PE (LPE) genes at 66 h PE. The RNAi microarray screen for the JH receptor Methoprene-tolerant (Met) showed that 27% of EPE and 40% of MPE genes were up-regulated whereas 36% of LPE genes were down-regulated in the absence of this receptor. Met repression of EPE and MPE and activation of LPE genes were validated by an in vitro fat-body culture experiment using Met RNAi. Sequence motif analysis revealed the consensus for a 9-mer Met-binding motif, CACG(C)/TG(A)/G(T)/AG. Met-binding motif variants were overrepresented within the first 300 bases of the promoters of Met RNAi-down-regulated (LPE) genes but not in Met RNAi-up-regulated (EPE) genes. EMSAs using a combination of mutational and anti-Met antibody supershift analyses confirmed the binding properties of the Met consensus motif variants. There was a striking temporal separation of expression profiles among major functional gene groups, with carbohydrate, lipid, and xenobiotics metabolism belonging to the EPE and MPE clusters and transcription and translation to the LPE cluster. This study represents a significant advancement in the understanding of the regulation of gene expression by JH and its receptor Met during female mosquito reproduction. PMID- 23633571 TI - Fast neurotransmitter release regulated by the endocytic scaffold intersectin. AB - Sustained fast neurotransmission requires the rapid replenishment of release ready synaptic vesicles (SVs) at presynaptic active zones. Although the machineries for exocytic fusion and for subsequent endocytic membrane retrieval have been well characterized, little is known about the mechanisms underlying the rapid recruitment of SVs to release sites. Here we show that the Down syndrome associated endocytic scaffold protein intersectin 1 is a crucial factor for the recruitment of release-ready SVs. Genetic deletion of intersectin 1 expression or acute interference with intersectin function inhibited the replenishment of release-ready vesicles, resulting in short-term depression, without significantly affecting the rate of endocytic membrane retrieval. Acute perturbation experiments suggest that intersectin-mediated vesicle replenishment involves the association of intersectin with the fissioning enzyme dynamin and with the actin regulatory GTPase CDC42. Our data indicate a role for the endocytic scaffold intersectin in fast neurotransmitter release, which may be of prime importance for information processing in the brain. PMID- 23633572 TI - Surface display of a massively variable lipoprotein by a Legionella diversity generating retroelement. AB - Diversity-generating retroelements (DGRs) are a unique family of retroelements that confer selective advantages to their hosts by facilitating localized DNA sequence evolution through a specialized error-prone reverse transcription process. We characterized a DGR in Legionella pneumophila, an opportunistic human pathogen that causes Legionnaires disease. The L. pneumophila DGR is found within a horizontally acquired genomic island, and it can theoretically generate 10(26) unique nucleotide sequences in its target gene, legionella determinent target A (ldtA), creating a repertoire of 10(19) distinct proteins. Expression of the L. pneumophila DGR resulted in transfer of DNA sequence information from a template repeat to a variable repeat (VR) accompanied by adenine-specific mutagenesis of progeny VRs at the 3'end of ldtA. ldtA encodes a twin-arginine translocated lipoprotein that is anchored in the outer leaflet of the outer membrane, with its C-terminal variable region surface exposed. Related DGRs were identified in L. pneumophila clinical isolates that encode unique target proteins with homologous VRs, demonstrating the adaptability of DGR components. This work characterizes a DGR that diversifies a bacterial protein and confirms the hypothesis that DGR mediated mutagenic homing occurs through a conserved mechanism. Comparative bioinformatics predicts that surface display of massively variable proteins is a defining feature of a subset of bacterial DGRs. PMID- 23633573 TI - Quantifying primary loops in polymer gels by linear viscoelasticity. PMID- 23633574 TI - Inadequate methods and questionable conclusions in atmospheric life study. PMID- 23633575 TI - The transition in southern Iberia: insights from paleoclimatology and the Early Upper Palaeolithic. PMID- 23633576 TI - Towards a structural biology work bench. AB - This is an introduction to four papers based on presentations given at a workshop entitled Integrated Software for Integrative Structural Biology. The use of hybrid techniques, and other trends in structural research, pose new challenges to software developers. A structural biology work bench that meets these needs would provide seamless data transfer between processing steps, and accumulate archival data and metadata without intruding into the scientist's work process. PMID- 23633577 TI - On the usefulness of ion-mobility mass spectrometry and SAXS data in scoring docking decoys. AB - Scoring, the process of selecting the biologically relevant solution from a pool of generated conformations, is one of the major challenges in the field of biomolecular docking. A prominent way to cope with this challenge is to incorporate information-based terms into the scoring function. Within this context, low-resolution shape data obtained from either ion-mobility mass spectrometry (IM-MS) or SAXS experiments have been integrated into the conventional scoring function of the information-driven docking program HADDOCK. Here, the strengths and weaknesses of IM-MS-based and SAXS-based scoring, either in isolation or in combination with the HADDOCK score, are systematically assessed. The results of an analysis of a large docking decoy set composed of dimers generated by running HADDOCK in ab initio mode reveal that the content of the IM-MS data is of too low resolution for selecting correct models, while scoring with SAXS data leads to a significant improvement in performance. However, the effectiveness of SAXS scoring depends on the shape and the arrangement of the complex, with prolate and oblate systems showing the best performance. It is observed that the highest accuracy is achieved when SAXS scoring is combined with the energy-based HADDOCK score. PMID- 23633578 TI - On the development of three new tools for organizing and sharing information in three-dimensional electron microscopy. AB - Electron microscopy is a valuable tool for elucidating the three-dimensional structures of macromolecular complexes. As the field matures and the number of solved structures increases, the existence of infrastructures that keep this information organized and accessible is crucial. At the same time, standards and clearly described conventions facilitate software maintenance, benefit interoperability with other packages and allow data interchange. This work describes three developments promoting integrative biology, standardization and workflow processing, namely PeppeR, the EMX initiative and Scipion. PMID- 23633579 TI - OpenStructure: an integrated software framework for computational structural biology. AB - Research projects in structural biology increasingly rely on combinations of heterogeneous sources of information, e.g. evolutionary information from multiple sequence alignments, experimental evidence in the form of density maps and proximity constraints from proteomics experiments. The OpenStructure software framework, which allows the seamless integration of information of different origin, has previously been introduced. The software consists of C++ libraries which are fully accessible from the Python programming language. Additionally, the framework provides a sophisticated graphics module that interactively displays molecular structures and density maps in three dimensions. In this work, the latest developments in the OpenStructure framework are outlined. The extensive capabilities of the framework will be illustrated using short code examples that show how information from molecular-structure coordinates can be combined with sequence data and/or density maps. The framework has been released under the LGPL version 3 license and is available for download from http://www.openstructure.org. PMID- 23633581 TI - The structure of cardiac troponin C regulatory domain with bound Cd2+ reveals a closed conformation and unique ion coordination. AB - The amino-terminal domain of cardiac troponin C (cNTnC) is an essential Ca(2+) sensor found in cardiomyocytes. It undergoes a conformational change upon Ca(2+) binding and transduces the signal to the rest of the troponin complex to initiate cardiac muscle contraction. Two classical EF-hand motifs (EF1 and EF2) are present in cNTnC. Under physiological conditions, only EF2 binds Ca(2+); EF1 is a vestigial site that has lost its function in binding Ca(2+) owing to amino-acid sequence changes during evolution. Proteins with EF-hand motifs are capable of binding divalent cations other than calcium. Here, the crystal structure of wild type (WT) human cNTnC in complex with Cd(2+) is presented. The structure of Cd(2+)-bound cNTnC with the disease-related mutation L29Q, as well as a structure with the residue differences D2N, V28I, L29Q and G30D (NIQD), which have been shown to have functional importance in Ca(2+) sensing at lower temperatures in ectothermic species, have also been determined. The structures resemble the overall conformation of NMR structures of Ca(2+)-bound cNTnC, but differ significantly from a previous crystal structure of Cd(2+)-bound cNTnC in complex with deoxycholic acid. The subtle structural changes observed in the region near the mutations may play a role in the increased Ca(2+) affinity. The 1.4 A resolution WT cNTnC structure, which is the highest resolution structure yet obtained for cardiac troponin C, reveals a Cd(2+) ion coordinated in the canonical pentagonal bipyramidal geometry in EF2 despite three residues in the loop being disordered. A Cd(2+) ion found in the vestigial ion-binding site of EF1 is coordinated in a noncanonical 'distorted' octahedral geometry. A comparison of the ion coordination observed within EF-hand-containing proteins for which structures have been solved in the presence of Cd(2+) is presented. A refolded WT cNTnC structure is also presented. PMID- 23633582 TI - Structural and functional characterization of HP0377, a thioredoxin-fold protein from Helicobacter pylori. AB - Maturation of cytochrome c is carried out in the bacterial periplasm, where specialized thiol-disulfide oxidoreductases provide the correct reduction of oxidized apocytochrome c before covalent haem attachment. HP0377 from Helicobacter pylori is a thioredoxin-fold protein that has been implicated as a component of system II for cytochrome c assembly and shows limited sequence similarity to Escherichia coli DsbC, a disulfide-bond isomerase. To better understand the role of HP0377, its crystal structures have been determined in both reduced and partially oxidized states, which are highly similar to each other. Sedimentation-equilibrium experiments indicate that HP0377 is monomeric in solution. HP0377 adopts a thioredoxin fold but shows distinctive variations as in other thioredoxin-like bacterial periplasmic proteins. The active site of HP0377 closely resembles that of E. coli DsbC. A reductase assay suggests that HP0377 may play a role as a reductase in the biogenesis of holocytochrome c553 (HP1227). Binding experiments indicate that it can form a covalent complex with HP0518, a putative L,D-transpeptidase with a catalytic cysteine residue, via a disulfide bond. Furthermore, physicochemical properties of HP0377 and its R86A variant have been determined. These results suggest that HP0377 may perform multiple functions as a reductase in H. pylori. PMID- 23633580 TI - The role of structural bioinformatics resources in the era of integrative structural biology. AB - The history and the current state of the PDB and EMDB archives is briefly described, as well as some of the challenges that they face. It seems natural that the role of structural biology archives will change from being a pure repository of historic data into becoming an indispensable resource for the wider biomedical community. As part of this transformation, it will be necessary to validate the biomacromolecular structure data and ensure the highest possible quality for the archive holdings, to combine structural data from different spatial scales into a unified resource and to integrate structural data with functional, genetic and taxonomic data as well as other information available in bioinformatics resources. Some recent developments and plans to address these challenges at PDBe are presented. PMID- 23633583 TI - Mechanism for controlling the monomer-dimer conversion of SARS coronavirus main protease. AB - The Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (M(pro)) cleaves two virion polyproteins (pp1a and pp1ab); this essential process represents an attractive target for the development of anti-SARS drugs. The functional unit of M(pro) is a homodimer and each subunit contains a His41/Cys145 catalytic dyad. Large amounts of biochemical and structural information are available on M(pro); nevertheless, the mechanism by which monomeric M(pro) is converted into a dimer during maturation still remains poorly understood. Previous studies have suggested that a C-terminal residue, Arg298, interacts with Ser123 of the other monomer in the dimer, and mutation of Arg298 results in a monomeric structure with a collapsed substrate-binding pocket. Interestingly, the R298A mutant of M(pro) shows a reversible substrate-induced dimerization that is essential for catalysis. Here, the conformational change that occurs during substrate-induced dimerization is delineated by X-ray crystallography. A dimer with a mutual orientation of the monomers that differs from that of the wild-type protease is present in the asymmetric unit. The presence of a complete substrate binding pocket and oxyanion hole in both protomers suggests that they are both catalytically active, while the two domain IIIs show minor reorganization. This structural information offers valuable insights into the molecular mechanism associated with substrate-induced dimerization and has important implications with respect to the maturation of the enzyme. PMID- 23633584 TI - Atomic resolution structures of the c-Src SH3 domain in complex with two high affinity peptides from classes I and II. AB - The atomic resolution crystal structures of complexes between the SH3 domain of the c-Src tyrosine kinase and two high-affinity peptides belonging to class I and class II have been solved. The crystals of the Thr98Asp and Thr98Glu mutants in complex with the APP12 peptide (APPLPPRNRPRL) belonged to the trigonal space group P3121 and in both cases the asymmetric unit was composed of one molecule of the SH3-APP12 complex. The crystals of the Thr98Glu mutant in complex with the VSL12 peptide (VSLARRPLPLP) belonged to the trigonal space group P3221 and the asymmetric unit was also composed of a single molecule of the SH3-VSL12 complex. All crystals were obtained in the presence of PEG 300 under the same conditions as reported for the intertwined dimeric structure of the c-Src SH3 domain, but the presence of the peptide stabilizes the monomeric form of the domain. These structures allow a detailed analysis of the role of salt bridges, cation-pi interactions and hydrogen bonds in the binding of proline-rich motifs to the c Src SH3 domain. Moreover, these crystallographic structures allow the role of water molecules in the binding of these motifs to the c-Src SH3 domain to be studied for the first time. PMID- 23633585 TI - The 1.6 A resolution structure of a FRET-optimized Cerulean fluorescent protein. AB - Genetically encoded cyan fluorescent proteins (CFPs) bearing a tryptophan-derived chromophore are commonly used as energy-donor probes in Forster resonance energy transfer (FRET) experiments useful in live cell-imaging applications. In recent years, significant effort has been expended on eliminating the structural and excited-state heterogeneity of these proteins, which has been linked to undesirable photophysical properties. Recently, mCerulean3, a descendant of enhanced CFP, was introduced as an optimized FRET donor protein with a superior quantum yield of 0.87. Here, the 1.6 A resolution X-ray structure of mCerulean3 is reported. The chromophore is shown to adopt a planar trans configuration at low pH values, indicating that the acid-induced isomerization of Cerulean has been eliminated. beta-Strand 7 appears to be well ordered in a single conformation, indicating a loss of conformational heterogeneity in the vicinity of the chromophore. Although the side chains of Ile146 and Leu167 appear to exist in two rotamer states, they are found to be well packed against the indole group of the chromophore. The Ser65 reversion mutation allows improved side-chain packing of Leu220. A structural comparison with mTurquoise2 is presented and additional engineering strategies are discussed. PMID- 23633586 TI - The structure of the caspase recruitment domain of BinCARD reveals that all three cysteines can be oxidized. AB - The caspase recruitment domain (CARD) is present in death-domain superfamily proteins involved in inflammation and apoptosis. BinCARD is named for its ability to interact with Bcl10 and inhibit downstream signalling. Human BinCARD is expressed as two isoforms that encode the same N-terminal CARD region but which differ considerably in their C-termini. Both isoforms are expressed in immune cells, although BinCARD-2 is much more highly expressed. Crystals of the CARD fold common to both had low symmetry (space group P1). Molecular replacement was unsuccessful in this low-symmetry space group and, as the construct contains no methionines, first one and then two residues were engineered to methionine for MAD phasing. The double-methionine variant was produced as a selenomethionine derivative, which was crystallized and the structure was solved using data measured at two wavelengths. The crystal structures of the native and selenomethionine double mutant were refined to high resolution (1.58 and 1.40 A resolution, respectively), revealing the presence of a cis-peptide bond between Tyr39 and Pro40. Unexpectedly, the native crystal structure revealed that all three cysteines were oxidized. The mitochondrial localization of BinCARD-2 and the susceptibility of its CARD region to redox modification points to the intriguing possibility of a redox-regulatory role. PMID- 23633587 TI - Structural analysis of malaria-parasite lysyl-tRNA synthetase provides a platform for drug development. AB - Aminoacyl-tRNA synthetases are essential enzymes that transmit information from the genetic code to proteins in cells and are targets for antipathogen drug development. Elucidation of the crystal structure of cytoplasmic lysyl-tRNA synthetase from the malaria parasite Plasmodium falciparum (PfLysRS) has allowed direct comparison with human LysRS. The authors' data suggest that PfLysRS is dimeric in solution, whereas the human counterpart can also adopt tetrameric forms. It is shown for the first time that PfLysRS is capable of synthesizing the signalling molecule Ap4a (diadenosine tetraphosphate) using ATP as a substrate. The PfLysRS crystal structure is in the apo form, such that binding to ATP will require rotameric changes in four conserved residues. Differences in the active site regions of parasite and human LysRSs suggest the possibility of exploiting PfLysRS for selective inhibition. These investigations on PfLysRS further validate malarial LysRSs as attractive antimalarial targets and provide new structural space for the development of inhibitors that target pathogen LysRSs selectively. PMID- 23633588 TI - AutoDrug: fully automated macromolecular crystallography workflows for fragment based drug discovery. AB - AutoDrug is software based upon the scientific workflow paradigm that integrates the Stanford Synchrotron Radiation Lightsource macromolecular crystallography beamlines and third-party processing software to automate the crystallography steps of the fragment-based drug-discovery process. AutoDrug screens a cassette of fragment-soaked crystals, selects crystals for data collection based on screening results and user-specified criteria and determines optimal data collection strategies. It then collects and processes diffraction data, performs molecular replacement using provided models and detects electron density that is likely to arise from bound fragments. All processes are fully automated, i.e. are performed without user interaction or supervision. Samples can be screened in groups corresponding to particular proteins, crystal forms and/or soaking conditions. A single AutoDrug run is only limited by the capacity of the sample storage dewar at the beamline: currently 288 samples. AutoDrug was developed in conjunction with RestFlow, a new scientific workflow-automation framework. RestFlow simplifies the design of AutoDrug by managing the flow of data and the organization of results and by orchestrating the execution of computational pipeline steps. It also simplifies the execution and interaction of third-party programs and the beamline-control system. Modeling AutoDrug as a scientific workflow enables multiple variants that meet the requirements of different user groups to be developed and supported. A workflow tailored to mimic the crystallography stages comprising the drug-discovery pipeline of CoCrystal Discovery Inc. has been deployed and successfully demonstrated. This workflow was run once on the same 96 samples that the group had examined manually and the workflow cycled successfully through all of the samples, collected data from the same samples that were selected manually and located the same peaks of unmodeled density in the resulting difference Fourier maps. PMID- 23633589 TI - Structural basis of L-phosphoserine binding to Bacillus alcalophilus phosphoserine aminotransferase. AB - Phosphoserine aminotransferase is a vitamin B6-dependent enzyme that catalyzes the reversible conversion of 3-phosphohydroxypyruvate to L-phosphoserine using glutamate as an amine donor. In an effort to gain insight into the substrate recognition mechanism of the enzyme, crystal structures of Bacillus alcalophilus phosphoserine aminotransferase in the presence or absence of L-phosphoserine were determined to resolutions of 1.5 and 1.6 A, respectively. Local conformational changes induced upon substrate binding were identified. However, in contrast to other aminotransferases, no domain or subunit movements were observed. Two Arg residues (Arg42 and Arg328) and two His residues (His41 and His327) were found to form a tight binding site for the phosphate group of L-phosphoserine. Comparison with Escherichia coli phosphoserine aminotransferase in complex with the substrate analogue alpha-methylglutamate revealed more extensive structural changes in the case of L-phosphoserine binding. Based on the structural analysis, the flexibility of Arg328 is proposed to be critical for substrate recognition. PMID- 23633590 TI - Inhibition of a type III secretion system by the deletion of a short loop in one of its membrane proteins. AB - The membrane protein FlhB is a highly conserved component of the flagellar secretion system. It is composed of an N-terminal transmembrane domain and a C terminal cytoplasmic domain (FlhBC). Here, the crystal structures of FlhBC from Salmonella typhimurium and Aquifex aeolicus are described at 2.45 and 2.55 A resolution, respectively. These flagellar FlhBC structures are similar to those of paralogues from the needle type III secretion system, with the major difference being in a linker that connects the transmembrane and cytoplasmic domains of FlhB. It was found that deletion of a short flexible loop in a globular part of Salmonella FlhBC leads to complete inhibition of secretion by the flagellar secretion system. Molecular-dynamics calculations demonstrate that the linker region is the most flexible part of FlhBC and that the deletion of the loop reduces this flexibility. These results are in good agreement with previous studies showing the importance of the linker in the function of FlhB and provide new insight into the relationship between the different parts of the FlhBC molecule. PMID- 23633591 TI - Structure of a complete four-domain chitinase from Moritella marina, a marine psychrophilic bacterium. AB - X-ray crystallography reveals chitinase from the psychrophilic bacterium Moritella marina to be an elongated molecule which in addition to the catalytic beta/alpha-barrel domain contains two Ig-like domains and a chitin-binding domain, all linked in a chain. A ligand-binding study using NAG oligomers showed the enzyme to be active in the crystal lattice and resulted in complexes of the protein with oxazolinium ion (the reaction intermediate) and with NAG2, a reaction product. The characteristic motif DXDXE, containing three acidic amino acid residues, which is a signature of type 18 chitinases, is conserved in the enzyme. Further analysis of the unliganded enzyme with the two protein-ligand complexes and a comparison with other known chitinases elucidated the roles of other conserved residues near the active site. Several features have been identified that are probably important for the reaction mechanism, substrate binding and the efficiency of the enzyme at low temperatures. The chitin-binding domain and the tryptophan patch on the catalytic domain provide general affinity for chitin, in addition to the affinity of the binding site; the two Ig-like domains give the protein a long reach over the chitin surface, and the flexible region between the chitin-binding domain and the adjacent Ig-like domain suggests an ability of the enzyme to probe the surface of the substrate, while the open shallow substrate-binding groove allows easy access to the active site. PMID- 23633592 TI - The structures of Arabidopsis Deg5 and Deg8 reveal new insights into HtrA proteases. AB - Plant Deg5 and Deg8 are two members of the HtrA proteases, a family of oligomeric serine endopeptidases that are involved in a variety of protein quality-control processes. These two HtrA proteases are located in the thylakoid lumen and participate in high-light stress responses by collaborating with other chloroplast proteins. Deg5 and Deg8 degrade photodamaged D1 protein of the photosystem II reaction centre, allowing its in situ replacement. Here, the crystal structures of Arabidopsis thaliana Deg5 (S266A) and Deg8 (S292A) are reported at 2.6 and 2.0 A resolution, respectively. The Deg5 trimer contains two calcium ions in a central channel, suggesting a link between photodamage control and calcium ions in chloroplasts. Previous structures of HtrA proteases have indicated that their regulation usually requires C-terminal PDZ domain(s). Deg5 is unique in that it contains no PDZ domain and the trimeric structure of Deg5 (S266A) reveals a novel catalytic triad conformation. A similar triad conformation is observed in the hexameric structure of the single PDZ-domain containing Deg8 (S292A). These findings suggest a novel activation mechanism for plant HtrA proteases and provide structural clues to their function in light stress response. PMID- 23633593 TI - Anomalous signal from S atoms in protein crystallographic data from an X-ray free electron laser. AB - X-ray free-electron lasers (FELs) enable crystallographic data collection using extremely bright femtosecond pulses from microscopic crystals beyond the limitations of conventional radiation damage. This diffraction-before-destruction approach requires a new crystal for each FEL shot and, since the crystals cannot be rotated during the X-ray pulse, data collection requires averaging over many different crystals and a Monte Carlo integration of the diffraction intensities, making the accurate determination of structure factors challenging. To investigate whether sufficient accuracy can be attained for the measurement of anomalous signal, a large data set was collected from lysozyme microcrystals at the newly established 'multi-purpose spectroscopy/imaging instrument' of the SPring-8 Angstrom Compact Free-Electron Laser (SACLA) at RIKEN Harima. Anomalous difference density maps calculated from these data demonstrate that serial femtosecond crystallography using a free-electron laser is sufficiently accurate to measure even the very weak anomalous signal of naturally occurring S atoms in a protein at a photon energy of 7.3 keV. PMID- 23633595 TI - Imaging protein three-dimensional nanocrystals with cryo-EM. AB - Flash-cooled three-dimensional crystals of the small protein lysozyme with a thickness of the order of 100 nm were imaged by 300 kV cryo-EM on a Falcon direct electron detector. The images were taken close to focus and to the eye appeared devoid of contrast. Fourier transforms of the images revealed the reciprocal lattice up to 3 A resolution in favourable cases and up to 4 A resolution for about half the crystals. The reciprocal-lattice spots showed structure, indicating that the ordering of the crystals was not uniform. Data processing revealed details at higher than 2 A resolution and indicated the presence of multiple mosaic blocks within the crystal which could be separately processed. The prospects for full three-dimensional structure determination by electron imaging of protein three-dimensional nanocrystals are discussed. PMID- 23633594 TI - Towards protein-crystal centering using second-harmonic generation (SHG) microscopy. AB - The potential of second-harmonic generation (SHG) microscopy for automated crystal centering to guide synchrotron X-ray diffraction of protein crystals was explored. These studies included (i) comparison of microcrystal positions in cryoloops as determined by SHG imaging and by X-ray diffraction rastering and (ii) X-ray structure determinations of selected proteins to investigate the potential for laser-induced damage from SHG imaging. In studies using beta2 adrenergic receptor membrane-protein crystals prepared in lipidic mesophase, the crystal locations identified by SHG images obtained in transmission mode were found to correlate well with the crystal locations identified by raster scanning using an X-ray minibeam. SHG imaging was found to provide about 2 um spatial resolution and shorter image-acquisition times. The general insensitivity of SHG images to optical scatter enabled the reliable identification of microcrystals within opaque cryocooled lipidic mesophases that were not identified by conventional bright-field imaging. The potential impact of extended exposure of protein crystals to five times a typical imaging dose from an ultrafast laser source was also assessed. Measurements of myoglobin and thaumatin crystals resulted in no statistically significant differences between structures obtained from diffraction data acquired from exposed and unexposed regions of single crystals. Practical constraints for integrating SHG imaging into an active beamline for routine automated crystal centering are discussed. PMID- 23633596 TI - Effects of cryoprotectants on the structure and thermostability of the human carbonic anhydrase II-acetazolamide complex. AB - Protein X-ray crystallography has seen a progressive shift from data collection at cool/room temperature (277-298 K) to data collection at cryotemperature (100 K) because of its ease of crystal preparation and the lessening of the detrimental effects of radiation-induced crystal damage, with 20-25%(v/v) glycerol (GOL) being the preferred choice of cryoprotectant. Here, a case study of the effects of cryoprotectants on the kinetics of carbonic anhydrase II (CA II) and its inhibition by the clinically used inhibitor acetazolamide (AZM) is presented. Comparative studies of crystal structure, kinetics, inhibition and thermostability were performed on CA II and its complex with AZM in the presence of either GOL or sucrose. These results suggest that even though the cryoprotectant GOL was previously shown to be directly bound in the active site and to interact with AZM, it affects neither the thermostability of CA II nor the binding of AZM in the crystal structure or in solution. However, addition of GOL does affect the kinetics of CA II, presumably as it displaces the water proton transfer network in the active site. PMID- 23633598 TI - On optimal placement of molecules in the unit cell. AB - There are currently no rules for a unified, standard way of placing macromolecular structures in the crystal lattice. An analysis of all possible symmetry-equivalent representations of molecular structures in various space groups leads to the concept of the anti-Cheshire symmetry and suggests that the center of a unique structural motif can always be placed within the selected asymmetric unit of the anti-Cheshire cell. The placement of structures according to this suggestion will ensure uniformity of presentation of all structurally equivalent Protein Data Bank models and will therefore diminish the possibility of confusing less crystallographically knowledgeable users of the PDB. The anti Cheshire cells and their asymmetric units are defined and tabulated for all 65 space groups relevant to macromolecular crystallography that exhibit only rotational symmetry operations. PMID- 23633597 TI - Structures of Enterovirus 71 3C proteinase (strain E2004104-TW-CDC) and its complex with rupintrivir. AB - The crystal structure of 3C proteinase (3C(pro)) from Enterovirus 71 (EV71) was determined in space group C2221 to 2.2 A resolution. The fold was similar to that of 3C(pro) from other picornaviruses, but the difference in the beta-ribbon reported in a previous structure was not observed. This beta-ribbon was folded over the substrate-binding cleft and constituted part of the essential binding sites for interaction with the substrate. The structure of its complex with rupintrivir (AG7088), a peptidomimetic inhibitor, was also characterized in space group P212121 to 1.96 A resolution. The inhibitor was accommodated without any spatial hindrance despite the more constricted binding site; this was confirmed by functional assays, in which the inhibitor showed comparable potency towards EV71 3C(pro) and human rhinovirus 3C(pro), which is the target that rupintrivir was designed against. PMID- 23633599 TI - The structure of the SBP-Tag-streptavidin complex reveals a novel helical scaffold bridging binding pockets on separate subunits. AB - The 38-residue SBP-Tag binds to streptavidin more tightly (K(d) -/= 2.5-4.9 nM) than most if not all other known peptide sequences. Crystallographic analysis at 1.75 A resolution shows that the SBP-Tag binds to streptavidin in an unprecedented manner by simultaneously interacting with biotin-binding pockets from two separate subunits. An N-terminal HVV peptide sequence (residues 12-14) and a C-terminal HPQ sequence (residues 31-33) form the bulk of the direct interactions between the SBP-Tag and the two biotin-binding pockets. Surprisingly, most of the peptide spanning these two sites (residues 17-28) adopts a regular alpha-helical structure that projects three leucine side chains into a groove formed at the interface between two streptavidin protomers. The crystal structure shows that residues 1-10 and 35-38 of the original SBP-Tag identified through in vitro selection and deletion analysis do not appear to contact streptavidin and thus may not be important for binding. A 25-residue peptide comprising residues 11-34 (SBP-Tag2) was synthesized and shown using surface plasmon resonance to bind streptavidin with very similar affinity and kinetics when compared with the SBP-Tag. The SBP-Tag2 was also added to the C terminus of beta-lactamase and was shown to be just as effective as the full length SBP-Tag in affinity purification. These results validate the molecular structure of the SBP-Tag-streptavidin complex and establish a minimal bivalent streptavidin-binding tag from which further rational design and optimization can proceed. PMID- 23633600 TI - Structural analysis of coniferyl alcohol 9-O-methyltransferase from Linum nodiflorum reveals a novel active-site environment. AB - Coniferyl alcohol 9-O-methyltransferase from Linum nodiflorum (Linaceae) catalyzes the unusual methylation of the side-chain hydroxyl group of coniferyl alcohol. The protein was heterologously expressed in Escherichia coli as a hexahistidine derivative and purified for crystallization. Diffracting crystals were obtained of the pure protein and of its selenomethionine derivative, as well as of complexes with coniferyl alcohol and with S-adenosyl-L-homocysteine together with coniferyl alcohol 9-O-methyl ether (PDB entries 4ems, 4e70 and 4evi, respectively). The X-ray structures show that the phenylpropanoid binding mode differs from other phenylpropanoid O-methyltransferases such as caffeic acid O-methyltransferase. Moreover, the active site lacks the usually conserved and catalytic histidine residue and thus implies a different reaction mode for methylation. Site-directed mutagenesis was carried out to identify critical amino acids. The binding order of coniferyl alcohol and S-adenosyl-L-methionine was investigated by isothermal titration calorimetry experiments. PMID- 23633601 TI - Camel and bovine chymosin: the relationship between their structures and cheese making properties. AB - Bovine and camel chymosin are aspartic peptidases that are used industrially in cheese production. They cleave the Phe105-Met106 bond of the milk protein kappa casein, releasing its predominantly negatively charged C-terminus, which leads to the separation of the milk into curds and whey. Despite having 85% sequence identity, camel chymosin shows a 70% higher milk-clotting activity than bovine chymosin towards bovine milk. The activities, structures, thermal stabilities and glycosylation patterns of bovine and camel chymosin obtained by fermentation in Aspergillus niger have been examined. Different variants of the enzymes were isolated by hydrophobic interaction chromatography and showed variations in their glycosylation, N-terminal sequences and activities. Glycosylation at Asn291 and the loss of the first three residues of camel chymosin significantly decreased its activity. Thermal differential scanning calorimetry revealed a slightly higher thermal stability of camel chymosin compared with bovine chymosin. The crystal structure of a doubly glycosylated variant of camel chymosin was determined at a resolution of 1.6 A and the crystal structure of unglycosylated bovine chymosin was redetermined at a slightly higher resolution (1.8 A) than previously determined structures. Camel and bovine chymosin share the same overall fold, except for the antiparallel central beta-sheet that connects the N terminal and C-terminal domains. In bovine chymosin the N-terminus forms one of the strands which is lacking in camel chymosin. This difference leads to an increase in the flexibility of the relative orientation of the two domains in the camel enzyme. Variations in the amino acids delineating the substrate-binding cleft suggest a greater flexibility in the ability to accommodate the substrate in camel chymosin. Both enzymes possess local positively charged patches on their surface that can play a role in interactions with the overall negatively charged C-terminus of kappa-casein. Camel chymosin contains two additional positive patches that favour interaction with the substrate. The improved electrostatic interactions arising from variation in the surface charges and the greater malleability both in domain movements and substrate binding contribute to the better milk-clotting activity of camel chymosin towards bovine milk. PMID- 23633602 TI - Integrated database of information from structural genomics experiments. AB - Information from structural genomics experiments at the RIKEN SPring-8 Center, Japan has been compiled and published as an integrated database. The contents of the database are (i) experimental data from nine species of bacteria that cover a large variety of protein molecules in terms of both evolution and properties (http://database.riken.jp/db/bacpedia), (ii) experimental data from mutant proteins that were designed systematically to study the influence of mutations on the diffraction quality of protein crystals (http://database.riken.jp/db/bacpedia) and (iii) experimental data from heavy atom-labelled proteins from the heavy-atom database HATODAS (http://database.riken.jp/db/hatodas). The database integration adopts the semantic web, which is suitable for data reuse and automatic processing, thereby allowing batch downloads of full data and data reconstruction to produce new databases. In addition, to enhance the use of data (i) and (ii) by general researchers in biosciences, a comprehensible user interface, Bacpedia (http://bacpedia.harima.riken.jp), has been developed. PMID- 23633603 TI - Using high-throughput in situ plate screening to evaluate the effect of dehydration on protein crystals. AB - Crystal dehydration is a post-crystallization technique that can potentially improve the diffraction of macromolecular crystals. There are currently several ways of undertaking this process; however, dehydration experiments are often limited in their throughput and require prior manipulation of the samples. In the present study, a novel method is proposed that uses in situ plate screening to assess the effect of dehydration by combining the throughput of 96-well crystallization plates with direct X-ray feedback on crystal diffraction quality. PMID- 23633605 TI - The World Trade Center disaster: a tragic source of medical advancement. PMID- 23633606 TI - Pulmonary hypertension at exercise in COPD: does it matter? PMID- 23633607 TI - T'ai chi for individuals with COPD: an ancient wisdom for a 21st century disease? PMID- 23633608 TI - How children with asthma breathe: have we been overlooking a problem? PMID- 23633609 TI - Are statins beneficial for viral pneumonia? PMID- 23633610 TI - Eosinophilic bronchiolitis: is it a new syndrome? PMID- 23633611 TI - Oestrogen and the sexual dimorphism of pulmonary arterial hypertension: a translational challenge. PMID- 23633612 TI - A peculiar squamous dysplastic lesion presenting as a ground-glass opacity: a case report. PMID- 23633613 TI - Paediatric lung transplant outcomes vary with Mycobacterium abscessus complex species. PMID- 23633614 TI - Previous general practitioner consulting behaviour as a predictor of pneumonia in children. PMID- 23633615 TI - Asymmetric dimethylarginine and asthma: results from the Childhood Asthma Prevention Study. PMID- 23633616 TI - Natural course of sleep disordered breathing after acute myocardial infarction. PMID- 23633619 TI - Impact of movement sequencing on sciatic and tibial nerve strain and excursion during the straight leg raise test in embalmed cadavers. AB - STUDY DESIGN: Laboratory study, repeated-measures design. OBJECTIVES: To quantify differences in sciatic and tibial nerve biomechanics (strain and excursion) during common variations of the straight leg raise (SLR) test. BACKGROUND: Hip flexion and ankle dorsiflexion are the primary movement components of the SLR. It has been suggested that the nervous system is loaded differently when ankle dorsiflexion is added before or after hip flexion. There are, however, no data to either support or refute this suggestion. METHODS: Strain and excursion in the sciatic and tibial nerve were measured in the hip, knee, and ankle regions during 2 movement sequences for the SLR test in 10 embalmed cadavers. The proximal-to distal sequence consisted of hip flexion followed by ankle dorsiflexion; the distal-to-proximal sequence consisted of ankle dorsiflexion followed by hip flexion. RESULTS: In the SLR end position, strain and excursion were comparable for both sequences for the sciatic and tibial nerve at the knee (P>.24). Strain in the tibial nerve at the ankle was greater with the proximal-to-distal sequence (P = .008), but the actual difference was small (0.8%). The pattern of strain increase and nerve excursion varied between sequences (P<=.009), with nerve strain increasing earlier and being maintained longer in regions closest to the joint that was moved first in the movement sequence. CONCLUSION: Varying the movement sequence does not substantially impact excursion and strain in the end position of the SLR. Therefore, if neurodynamic test sequencing is useful in the differential diagnosis of neuropathies, it is not likely due to differences in strain in the end position of testing. PMID- 23633618 TI - A structural snapshot of CYP2B4 in complex with paroxetine provides insights into ligand binding and clusters of conformational states. AB - An X-ray crystal structure of CYP2B4 in complex with the drug paroxetine [(3S,4R) 3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine] was solved at 2.14 A resolution. The structure revealed a conformation intermediate to that of the recently solved complex with amlodipine and that of the more compact complex with 4-(4-chlorophenyl)imidazole in terms of the placement of the F-G cassette. Moreover, comparison of the new structure with 15 previously solved structures of CYP2B4 revealed some new insights into the determinants of active site size and shape. The 2B4-paroxetine structure is nearly superimposable on a previously solved closed structure in a ligand-free state. Despite the overall conformational similarity among multiple closed structures, the active-site cavity volume of the paroxetine complex is enlarged. Further analysis of the accessible space and binding pocket near the heme reveals a new subchamber that resulted from the movement of secondary structural elements and rearrangements of active-site side chains. Overall, the results from the comparison of all 16 structures of CYP2B4 demonstrate a cluster of protein conformations that were observed in the presence or absence of various ligands. PMID- 23633620 TI - Clinical factors related to recurrence after hepatic arterial concurrent chemoradiotherapy for advanced but liver-confined hepatocellular carcinoma. AB - Before the sorafenib era, advanced but liver-confined hepatocellular carcinoma (HCC) was treated by liver-directed therapy. Hepatic arterial concurrent chemoradiotherapy (CCRT) has been performed in our group, giving substantial local control but frequent failure. The aim of this study was to analyze patterns of failure and find out predictive clinical factors in HCC treated with a liver directed therapy, CCRT. A retrospective analysis was done for 138 HCC patients treated with CCRT between May 2001 and November 2009. Protocol-based CCRT was performed with local radiotherapy (RT) and concurrent 5-fluorouracil (5-FU) hepatic arterial infusion chemotherapy (HAIC), followed by monthly HAIC (5-FU and cisplatin). Patterns of failure were categorized into three groups: infield, intrahepatic-outfield and extrahepatic failure. Treatment failure occurred in 34.0% of patients at 3 months after RT. Infield, intrahepatic-outfield and extrahepatic failure were observed in 12 (8.6%), 26 (18.7%) and 27 (19.6%) patients, respectively. Median progression-free survival for infield, outfield and extrahepatic failure was 22.4, 18 and 21.5 months, respectively. For infield failure, a history of pre-CCRT treatment was a significant factor (P = 0.020). Pre-CCRT levels of alpha-fetoprotein and prothrombin induced by vitamin K absence or antagonist-II were significant factors for extrahepatic failure (P = 0.029). Treatment failures after CCRT were frequent in HCC patients, and were more commonly intrahepatic-outfield and extrahepatic failures than infield failure. A history of pre-CCRT treatment and levels of pre-CCRT tumor markers were identified as risk factors that could predict treatment failure. More intensified treatment is required for patients presenting risk factors. PMID- 23633622 TI - Fine-tuning evolution: germ-line epigenetics and inheritance. AB - In mice, epiblast cells found both the germ-line and somatic lineages in the developing embryo. These epiblast cells carry epigenetic information from both parents that is required for development and cell function in the fetus and during post-natal life. However, germ cells must establish an epigenetic program that supports totipotency and the configuration of parent-specific epigenetic states in the gametes. To achieve this, the epigenetic information inherited by the primordial germ cells at specification is erased and new epigenetic states are established during development of the male and female germ-lines. Errors in this process can lead to transmission of epimutations through the germ-line, which have the potential to affect development and disease in the parent's progeny. This review discusses epigenetic reprogramming in the germ-line and the transmission of epigenetic information to the following generation. PMID- 23633621 TI - Association between changes in electromyographic signal amplitude and abdominal muscle thickness in individuals with and without lumbopelvic pain. AB - STUDY DESIGN: Validation study. OBJECTIVES: To investigate the association between changes in electromyographic (EMG) signal amplitude and sonographic measures of muscle thickness of 4 abdominal muscles, during 2 clinical tests, in adults with and without lumbopelvic pain. BACKGROUND: There is a trend in rehabilitation to use ultrasound imaging (USI) to determine the extent of abdominal muscle contraction. However, the literature investigating the relationship between abdominal muscle thickness change and level of activation is inconclusive and has not included clinically relevant tasks. METHODS: Simultaneous recording from fine-wire EMG and USI was performed for 4 abdominal muscles, in 7 adults with lumbopelvic pain (mean +/- SD age, 29.7 +/- 12.0 years) and 7 adults without lumbopelvic pain (32.0 +/- 10.6 years), during an active straight leg raise (ASLR) test and an abdominal drawing-in maneuver (ADIM). Cross correlation functions and linear regression analyses were used to describe the relationship between the 2 measures. Analyses of variance were used to compare individuals with and without lumbopelvic pain, with an alpha set at .05. RESULTS: Across all muscles, peak cross-correlation values were low (ASLR, r = 0.28 +/- 0.09; ADIM, r = 0.35 +/- 0.11), and there was large variability in associated time lags (ASLR, tau = 0.69 +/- 2.56 seconds; ADIM, tau = 0.53 +/- 3.75 seconds). Regression analyses did not detect a systematic pattern of association between EMG signal amplitude and USI measurements, and analyses of variance revealed no differences between cohorts. CONCLUSION: These results suggest a weak relationship between EMG amplitude and abdominal muscle thickness change measured with USI during the ADIM and ASLR, and raise questions about thickness change derived from USI as a measure of muscular activity for the abdominal musculature. PMID- 23633623 TI - SMAD7 antagonizes key TGFbeta superfamily signaling in mouse granulosa cells in vitro. AB - Transforming growth factor beta (TGFbeta) superfamily signaling is essential for female reproduction. Dysregulation of the TGFbeta signaling pathway can cause reproductive diseases. SMA and MAD (mothers against decapentaplegic) (SMAD) proteins are downstream signaling transducers of the TGFbeta superfamily. SMAD7 is an inhibitory SMAD that regulates TGFbeta signaling in vitro. However, the function of SMAD7 in the ovary remains poorly defined. To determine the signaling preference and potential role of SMAD7 in the ovary, we herein examined the expression, regulation, and function of SMAD7 in mouse granulosa cells. We showed that SMAD7 was expressed in granulosa cells and subject to regulation by intraovarian growth factors from the TGFbeta superfamily. TGFB1 (TGFbeta1), bone morphogenetic protein 4, and oocyte-derived growth differentiation factor 9 (GDF9) were capable of inducing Smad7 expression, suggesting a modulatory role of SMAD7 in a negative feedback loop. Using a small interfering RNA approach, we further demonstrated that SMAD7 was a negative regulator of TGFB1. Moreover, we revealed a link between SMAD7 and GDF9-mediated oocyte paracrine signaling, an essential component of oocyte-granulosa cell communication and folliculogenesis. Collectively, our results suggest that SMAD7 may function during follicular development via preferentially antagonizing and/or fine-tuning essential TGFbeta superfamily signaling, which is involved in the regulation of oocyte-somatic cell interaction and granulosa cell function. PMID- 23633624 TI - Uterine secretome and its modulation in rat (Rattus norvegicus). AB - The present study identifies uterine fluid (UF) proteins that display differential abundance during the embryo-permissive phase in nonconception and conception cycles in rats. UF samples were collected from nonpregnant rats in the proestrous (n=17) and metestrous (n=18) phases and also from pregnant (n=17) and pseudopregnant (n=17) rats on day 4 post coitus. UF protein profile in the metestrous phase was compared with that in the proestrous phase. Similarly, UF protein profile of the pregnant rats was compared with that of the pseudopregnant rats. Two-dimensional PAGE, followed by densitometric analysis of the paired protein spots, revealed differential abundance of 44 proteins in the metestrous phase, compared with that in the proestrous phase. Of these, 29 proteins were identified by matrix-assisted laser desorption/ionization time-of-flight or liquid chromatography-tandem mass spectrometry. Functional groups such as proteases, protease inhibitors, and oxidoreductases were enriched in differentially abundant proteins. Total protease activity in UF was found to be significantly (P<0.05; t-test) higher in the proestrous phase, compared with that in the metestrous phase. Furthermore, 41 UF proteins were found to be differentially abundant in pregnant rats, compared with pseudopregnant rats. Of these, 11 proteins could be identified. Immunoblotting analysis confirmed significantly higher (P<0.05; t-test) abundance of beta-actin, Rho-specific guanine nucleotide dissociation inhibitor alpha (Rho-GDIalpha), and peroxiredoxin 2 and -6 in the metestrous phase, compared with that in the proestrous phase. Compared with pseudopregnant rats, pregnant rats had significantly higher (P<0.05; t-test) levels of UF beta-actin and Rho-GDIalpha. Furthermore, these proteins could be detected in the culture supernatants of endometrial epithelial cell lines, thereby providing an evidence of their secretion from endometrial epithelial cells. Data obtained from the study expand our knowledge on the uterine milieu that favours embryo implantation. PMID- 23633625 TI - Concurrent validity of calipers and ultrasound imaging to measure interrecti distance. AB - STUDY DESIGN: Clinical measurement, concurrent validity criterion standard. OBJECTIVE: To determine the concurrent validity of digital nylon calipers in comparison to ultrasound imaging (USI) for the measurement of interrecti distance (IRD). BACKGROUND: Diastasis rectus abdominis is the abnormal increase in the width of the linea alba, measured as IRD. A diastasis rectus abdominis can compromise mechanical trunk function in both genders. IRD has been accurately measured with USI but requires costly equipment and extensive examiner training. Digital nylon calipers are inexpensive and easy to use, but their use to measure IRD has not been validated. METHODS: A sample of convenience of 56 individuals (11 men, 45 women) was measured. A single examiner was assigned to each tool (calipers or USI), and IRD was measured at 2 locations (above and below the umbilicus) under 2 conditions (abdominal muscles at rest and abdominal muscles contracted). All measurements were made during a single session, and examiners were blinded to measurements with the other tool. RESULTS: Above the umbilicus, the measurements of IRD with calipers were similar to those made with USI, with intraclass correlation coefficients (model 3,2) of 0.79 with abdominal muscles at rest and 0.71 with abdominal muscles contracted. The absolute mean difference between the caliper and USI measurements of IRD above the umbilicus was 0.03 cm larger with the calipers when the abdominal muscles were at rest and 0.03 cm smaller when the abdominal muscles were contracted. The values of IRD obtained with the caliper and USI techniques were not comparable when obtained below the umbilicus. CONCLUSION: The calipers are a valid tool for measuring IRD above the umbilicus in males and females. Measuring IRD with calipers below the umbilicus should not be considered valid, using USI as the criterion standard. This may reflect anatomical variation of the linea alba or a limitation of the calipers to assess IRD at the same depth as USI. PMID- 23633626 TI - Baseline characteristics of patients with nerve-related neck and arm pain predict the likely response to neural tissue management. AB - STUDY DESIGN: Planned secondary analysis of a randomized controlled trial comparing neural tissue management (NTM) to advice to remain active. OBJECTIVE: To develop a model that predicts the likelihood of patient-reported improvement following NTM. BACKGROUND: Matching patients to an intervention they are likely to benefit from potentially improves outcomes. However, baseline characteristics that predict patients' responses to NTM are unknown. METHODS: Data came from 60 consecutive adults who had nontraumatic, nerve-related neck and unilateral arm pain for at least 4 weeks. Participants were assigned to a group that received NTM (n = 40), which involved brief education, manual therapy, and nerve gliding exercises for 4 treatments over 2 weeks, or to a group that was given advice to remain active (n = 20), which involved instruction to continue their usual activities. The participants' global rating of change at a 3- to 4-week follow-up defined improvement. Penalized regression of NTM data identified the best prediction model. A medical nomogram was created for prediction model scoring. Post hoc analysis determined whether the model predicted a specific response to NTM. RESULTS: Absence of neuropathic pain qualities, older age, and smaller deficits in median nerve neurodynamic test range of motion predicted improvement. Prediction model cutoffs increased the likelihood of improvement from 53% to 90% (95% confidence interval: 56%, 98%) or decreased the likelihood of improvement to 9% (95% confidence interval: 1%, 42%). The model did not predict the outcomes of the advice to remain active group. CONCLUSION: Baseline characteristics of patients with nerve-related neck and arm pain predicted the likelihood of improvement with NTM. Model performance needs to be validated in a new sample using different comparison interventions and longer follow-up. Australian New Zealand Clinical Trials Registry (ACTRN 12610000446066). LEVEL OF EVIDENCE: Prognosis, level 2b-. PMID- 23633627 TI - Size and symmetry of trunk muscles in ballet dancers with and without low back pain. AB - STUDY DESIGN: Cross-sectional, observational study. OBJECTIVES: To investigate the cross-sectional area (CSA) of trunk muscles in professional ballet dancers with and without low back pain (LBP). BACKGROUND: LBP is the most prevalent chronic injury in classical ballet dancers. Research on nondancers has found changes in trunk muscle size and symmetry to be associated with LBP. There are no studies that examine these changes in ballet dancers. METHODS: Magnetic resonance imaging was performed in 14 male and 17 female dancers. The CSAs of 4 muscles (multifidus, lumbar erector spinae, psoas, and quadratus lumborum) were measured and compared among 3 groups of dancers: those without LBP or hip pain (n = 8), those with LBP only (n = 13), and those with both hip-region pain and LBP (n = 10). RESULTS: Dancers with no pain had larger multifidus muscles compared to those with LBP at L3-5 (P<.024) and those with both hip-region pain and LBP at L3 and L4 on the right side (P<.027). Multifidus CSA was larger on the left side at L4 and L5 in dancers with hip-region pain and LBP compared to those with LBP only (P<.033). Changes in CSA were not related to the side of pain (all, P>.05). The CSAs of the other muscles did not differ between groups. The psoas (P<.0001) and quadratus lumborum (P<.01) muscles were larger in male dancers compared to female dancers. There was a positive correlation between the size of the psoas muscles and the number of years of professional dancing (P = .03). CONCLUSION: In classical ballet dancers, LBP and hip-region pain and LBP are associated with a smaller CSA of the multifidus but not the erector spinae, psoas, or quadratus lumborum muscles. PMID- 23633628 TI - [Clinical consideration of percutaneous renal biopsy for renal tumor]. AB - We performed ultrasound-guided biopsies on 14 patients having tumors that were difficult to distinguish as benign or malignant on computed tomography. The study took place from January 2004 to December 2011. Of the 14 tumors biopsied, 12 were malignant, 1 was benign, and 1 was a sampling error. Of the 12 malignant tumors, 7 were primary kidney carcinomas. Six patients received radical or partial nephrectomies, and all had a good prognosis. Three patients with metastatic kidney cancers died of the primary disease. Eleven patients (85.5%) were diagnosed pathologically by biopsies, allowing us to decide the course of treatment. However, because our tests also revealed one sampling error and one unspecified cancer, we determined that there are limitations to a renal biopsy. PMID- 23633629 TI - [Efficacy and safety of maintenance intravesical instillation therapy with bacillus Calmette-Guerin and epirubicin for non-muscle invasive bladder cancer]. AB - The objectives of this study were to evaluate the efficacy and toxicity of maintenance intravesical instillation therapy with bacillus Calmette-Guerin (BCG) and epirubicin for non-muscle invasive bladder cancer. From April 1999 to March 2010, 27 eligible patients were enrolled in this study. After receiving one cycle of epirubicin (100 mg/100 ml) by intravesical instillation, all patients received 6 weekly alternate intravesical instillation of BCG (80 mg/50 ml) and epirubicin (50 mg/50 ml), followed by 10 monthly instillations. Among the 27 patients, 19 were men and 8 were women, with a median age of 62.4 years (range, 37-78 years). Tumor pathologic stage was pTa in 25 patients, pT1 in 2 and there were no concomitant carcinoma in situ cases. Median follow-up was 37.1 months (range, 11 82 months). The 3- year recurrence-free and progression-free survival rates were 75.3% and 96.1%, respectively. Furthermore, a high completion rate of 81.5% was achieved in this study. Adverse events of grade 3 or higher occurred in 3 patients (11.1%), 1 patient had anaphylaxis. There were no treatment-related deaths. Maintenance intravesical instillation therapy with BCG and epirubicin is a favorable therapeutic option for non-muscle invasive bladder cancer. Given the safety and benefit profile found in this study, appropriate patient selection is warranted in the future. PMID- 23633630 TI - [Socioeconomic advantages of longer screening intervals for men with low prostate specific antigen levels in prostate cancer mass screening]. AB - In prostate specific antigen (PSA) -based prostate cancer mass screening, the optimal re-screening interval is still in question, although guidelines suggest that a prolonged interval would be safe and cost-saving. We examined the socioeconomic feasibility of prolonged re-screening interval based on individual baseline PSA values. Markov decision-analytic models of prostate cancer screening were established for cost-effectiveness comparison of prolonged re-screening in men with low (?1 ng/ml) PSA level (meta-interval strategy) and annual re screening in every participant (control strategy). Effectiveness and socioeconomic feasibility were evaluated according to quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER ; Deltacost per DeltaQALY), respectively. As a result, outcomes including cancer detection rates and stage shift suggested that these models well recapitulated actual prostate cancer mass screening. The meta-interval strategy was more cost-effective than the control strategy. The ICER for the control strategy with respect to the meta interval strategy exceeded US$62, 000/QALY through the sensitivity analyses for every assumption. The meta-interval strategy was more effective and less expensive if the trade-off of impaired clinical outcomes caused by delayed detection was small. In conclusion, our models suggest that the meta-interval strategy is more cost-effective than annual screening. It can be even more effective if the interval is determined appropriately such that cancer can be detected within the therapeutic window. PMID- 23633631 TI - [IgG4-related idiopathic segmental ureteritis which was difficult to distinguish from ureteral cancer: a case report]. AB - A 79-year-old woman was admitted with a chief complaint of gross hematuria, pollakisuria, lower abdominal pain. Urine cytology, intravenous pyelography, and cystoscopy were performed but showed no abnormal findings. About 6 months later, abdominal computed tomography (CT) revealed a 5cm long segment of ureteral narrowing with wall thickening, hydronephrosis, para-aortic lymph node swelling. Retrogradepyelography (RP) was done. Pelvic urine cytology was class IV. Under the clinical diagnosis of ureteral carcinoma and lymph node metastasis, a left nephroureterectomy with lymph node dissection was performed. The pathological diagnosis was IgG4-related idiopathic segmental ureteritis. PMID- 23633632 TI - [A case of endosalpingiosis in submucosa of the urinary bladder]. AB - A 39-year-old woman showed thickening of the bladder wall on magnetic resonance imaging (MRI). Since transurethral resection to the lesion revealed that the histological structure of the lesion was compatible with that of the fallopian tube and endometrium, we considered that the tumor was derived from mullerian tissue. Subsequently, partial cystectomy was performed to remove the tumor. Immunohistochemical examination indicated a diagnosis of endosalpingiosis involving endometriosis. The concept of endosalpingiosis was proposed in 1930, and only 9 cases of urinary bladder endosalpingiosis have been reported worldwide. Surgical procedures such as transurethral resection and partial cystectomy were performed in all reported cases. None of the reported cases, including the present case, showed recurrence. PMID- 23633633 TI - [Endocervicosis/endosalpingiosis of the bladder: a case report]. AB - Endocervicosis/ endosalpingiosis of the bladder is a very rare benign condition, with a total of 34 documented cases found in the literature. Herein, we report a 35-year-old woman with suspected bladder cancer following a cystoscopic examination, which revealed a mass on the right posterior bladder wall. Transurethral resection of the lesion was performed, and both pathological and immunohistochemical findings confirmed a diagnosis of endocervicosis/ endosalpingiosis. Recurrence was seen 6 months later in a follow-up cystoscopic examination and a partial cystectomy was performed. Since endocervicosis/ endosalpingiosis tends to recur, a partial cystectomy is the best therapeutic option for patients with persistent symptoms or recurrence. PMID- 23633634 TI - [A case of urachal abscess accompanied by a stone]. AB - A 64-year-old woman presented to our hospital with the chief complaints of abdominal pain and appetite loss, and she was admitted to the internal medicine department. Kidney, ureter and bladder X-ray revealed intrapelvic calcification near the bladder, and so, the patient consulted our department. Computed tomography and magnetic resonance imaging revealed an urachal abscess accompanied by a stone. Open surgery was performed under general anesthesia. The mass adhered tightly to the intestine and bladder. The urachal abscess ruptured during the operation, and pus leaked into the intraabdominal cavity. Partial cystectomy was performed to remove the mass completely. The stone existed in the urachal abscess, and its constituents were CaOxa (51%) and CaP (49%). The pathological diagnosis was urachal abscess without malignancy. PMID- 23633635 TI - [Recrudescent prostate cancer with a low serum PSA level and a high serum CEA level treated with docetaxel : a case report]. AB - A 63-year-old man was hospitalized with an increased serum prostate specific antigen (PSA) level (72 ng/ml). A prostate biopsy was performed, and histological examinations indicated moderately and poorly differentiated adenocarcinoma with positive staining for carcinoembryonic antigen (CEA). The patient was diagnosed as having prostate cancer (clinical stage : T3bN0M0) and received radiotherapy and hormonal therapy. Five years after the diagnosis, the serum CEA level increased to 153.8 ng/dl, and the patient complained of abdominal pain. His serum PSA level remained normal (<0.1 ng/dl). Computed topography indicated multiple bone metastasis and the involvement of multiple lymph glands. A biopsy of a cervical lymph gland revealed poorly differentiated adenocarcinoma with positive staining for CEA. Gastrointestinal examination showed no evidence of abnormality. The diagnosis of metastatic prostate cancer was made, and docetaxel (60-70 mg/m2) was administered. Eight courses of docetaxel therapy led to an approximately 20% reduction in lymph volume, and the serum CEA level decreased. However, liver metastases developed 12 months later, and the patient died at 18 months after the diagnosis of metastatic prostate cancer with a high serum CEA level. We encountered a case of recrudescence of prostate cancer positive for CEA with a low serum PSA level and report the effect of docetaxel therapy for atypical prostatic carcinoma. PMID- 23633636 TI - [Testicular tumor arising in intra-abdominal testis which was not detected at prior orchidopexy : a case report]. AB - A 35-year-old man with an intra-abdominal testicular tumor arising from the right unresolved intraabdominal testis is reported. At 10 years old, left orchidopexy was successfully performed for bilateral undescended testes. However, the right testis was not detected during the operation, and it was diagnosed as vanishing testis. Twenty-five years later, he was referred to our hospital with the complaint of right lower abdominal pain. Computed tomography revealed huge pelvic tumors and bulky para-aortic lymph node swellings. Histopathologic examination of the needle biopsy specimen obtained from the pelvic tumor revealed seminomatous germ cell tumor. Taking the results with a tumor marker study into consideration, the patient was tentatively diagnosed with non-seminomatous germ cell tumor NSGCT (stage IIB) arising from the unresolved intra-abdominal testis or extragonadal germ cell tumor. He received 3 courses of bleomycin, etoposide, cisplatin (BEP), and 4 courses of VP-16, ifosfamide, cisplatin (VIP). After chemotherapy, we performed tumorectomy and retroperitoneal lymphadenectomy because tumor markers were normalized and 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)-CT revealed normalization. We identified the pelvic tumor as an intra abdominal testicular tumor arising from right unresolved intra-abdominal testis. Pathological examination revealed no residual tumor cells. There has been no recurrence 17 months after surgery. PMID- 23633637 TI - [A case of metastatic tumor of the spermatic cord from gastric cancer]. AB - A 52-year-old man underwent distal gastrectomy for gastric cancer in November, 2007. In November, 2009, he visited our department with chief complaint of swelling of right intrascrotum and an inguinal mass. The tumor was suspected to be a primary tumor of the spermatic cord or metastasis of the gastric cancer. An operation was performed and histopathological examination revealed adenocarcinoma in the spermatic cord. Microscopic appearance of the surgical specimen of the right spermatic code demonstrated a CK7+/ CK20- expression pattern, which is the same as that of past gastric cancer. These results suggested that the spermatic cord tumor was a metastatic lesion from the gastric cancer. The patient died 12 months later. Metastatic tumor of the spermatic cord resulting from gastric cancer is rare. We should take metastatic tumor into consideration the possibility of tumor of the spermatic code or tumor in the scrotum particularly when the patient has had an operation for cancer of the digestive system. PMID- 23633638 TI - Retinol-binding protein 4 is elevated and is associated with free testosterone and TSH in postmenopausal women. AB - The aim of this study was to understand the relationship of retinol-binding protein 4 (RBP4) with hormonal and biochemical parameters in pre- and postmenopausal women. We included 69 postmenopausal women and 27 regularly menstruating premenopausal women. Postmenopausal women had statistically significantly higher RBP4 levels when compared to premenopausal women. RBP4 levels were negatively associated with free testosterone and positively associated with thyroid stimulating hormone in postmenopausal women. In premenopausal women RBP4 was positively associated with body mass index. RBP4 levels were increased in postmenopausal women. Although the mechanism is not clear, these findings suggest that RBP4 has a role in the regulation of hormonal and metabolic parameters. PMID- 23633640 TI - Factors influencing the selection of standardized tests for the diagnosis of specific language impairment. AB - PURPOSE: Standardized tests are one of the primary assessment tools used by speech-language pathologists (SLPs) to diagnose child language impairment. Numerous child language tests are commercially available; however, it is unknown what factors lead clinicians to select particular tests to use in clinical practice. This study investigated whether the quality of standardized tests, as measured by the test's psychometric properties, is related to how frequently the tests are used in clinical practice. METHOD: A total of 364 SLPs completed a survey regarding how frequently they used specific standardized tests when diagnosing suspected specific language impairment (SLI). The test manuals for 55 tests were reviewed to determine whether test characteristics, such as test reliability, validity, and accuracy, correlated with the frequency of test use. RESULTS: The most frequently used standardized tests were omnibus measures (e.g., Clinical Evaluation of Language Fundamentals-Fourth Edition [Semel, Wiig, & Secord, 2003], Preschool Language Scale, Fourth Edition [Zimmerman, Steiner, & Pond, 2002]) and single-word vocabulary measures (e.g., Peabody Picture Vocabulary Test, Fourth Edition [Dunn & Dunn, 2007]). Publication year was the only test characteristic that correlated significantly with the frequency of test use. CONCLUSION: The quality of a standardized test, as measured by the test's psychometric properties, does not appear to influence how frequently a test is used. These results highlight the need for increased evidence-based practice when diagnosing children with language impairment. PMID- 23633641 TI - Morphological awareness intervention with kindergartners and first- and second grade students from low socioeconomic status homes: a feasibility study. AB - PURPOSE: The effect of a morphological awareness intervention on the morphological awareness and literacy skills of students from low socioeconomic status homes was investigated. METHOD: A 9-week intervention designed to increase awareness of affixes and the relations between base words and their inflected and derived forms was conducted with students in kindergarten (n = 19), 1st grade (n = 21), and 2nd grade (n = 21). Groups of 4-5 students were provided with instruction 4 times a week for 25 min a day. RESULTS: Results showed medium to very large clinically significant gains in morphological awareness and literacy abilities (ds = 0.29-2.96) across all participants. CONCLUSION: The results of this feasibility study suggest that morphological awareness instruction that requires students to analyze, recognize, orally produce, and determine the spelling patterns of multimorphemic words leads to therapeutic effects within a population of young students who are at risk for future reading difficulties. Initial clinical implications, limitations of the study, and research suggestions are discussed. PMID- 23633642 TI - Teachers' perceptions of adolescent females with voice disorders. AB - PURPOSE: The purpose of this study was to explore teachers' attitudes toward, and perceptions of personality traits of, female adolescents who presented with voice disorders. METHOD: For this comparative study consisting of a 25-item web-based semantic differential survey, teachers rated voice recordings of 4 female adolescents (considered normophonic, mildly, moderately, and severely dysphonic, respectively) on 18 personality traits and 6 teacher attitude parameters. A flyer with a link to the survey was distributed via e-mail to teachers at 8 middle and high schools in Ohio. RESULTS: Thirty-two teachers completed the survey. Results revealed differences in teachers' perceptions of female adolescents with a normal voice compared to those with voice disorders. CONCLUSION: Adolescent female students with voice disorders may be at risk for academic, social, and vocational difficulties. These results highlight and support the need to inform teachers, speech-language pathologists, students, and families about the potential for subtle biases and negative perceptions of students with voice disorders by teachers. Furthermore, teaching self-advocacy to students who have voice disorders may help them obtain an optimal education experience. PMID- 23633643 TI - The impact of reading expressiveness on the listening comprehension of storybooks by prekindergarten children. AB - PURPOSE: The purpose of this study was to determine the effect of oral reading expressiveness on the comprehension of storybooks by 4- and 5-year-old prekindergarten children. The possible impact of prosody on listening comprehension was explored. METHOD: Ninety-two prekindergarten children (M age = 57.26 months, SD = 3.89 months) listened to an expressive or inexpressive recording of 1 of 2 similar stories. Story comprehension was tested using assessments of both free recall and cued recall. RESULTS: Children showed statistically significantly better cued recall for the expressive readings of stories compared to the inexpressive readings of stories. This effect generalized across stories and when story length was controlled across both expressive and inexpressive versions. The effect of expressiveness on children's free recall was not significant. CONCLUSION: Highly expressive readings resulted in better comprehension of storybooks by prekindergarten children. Further, because recordings were used, this effect might be attributed to the facilitation of language processing rather than to enhanced social interaction between the reader and the child. PMID- 23633644 TI - Severe speech sound disorders: an integrated multimodal intervention. AB - PURPOSE: This study introduces an integrated multimodal intervention (IMI) and examines its effectiveness for the treatment of persistent and severe speech sound disorders (SSD) in young children. The IMI is an activity-based intervention that focuses simultaneously on increasing the quantity of a child's meaningful productions of target words and providing supports to shape the quality of natural speech productions of target sounds by systematically incorporating the full range of each child's communicative repertoire, including augmentative and alternative communication (AAC) systems and natural speech and language. METHOD: A multiple-probe single-subject research design was used to assess the effectiveness of the IMI for 3 boys (ages 4 to 8) with moderate to severe SSD, all of whom used speech-generating AAC. RESULTS: All 3 participants demonstrated an increase in the amount of speech they produced (i.e., quantity) and an increase in the production accuracy of their target speech sounds (i.e., quality). CONCLUSION: This study demonstrated that simultaneously targeting natural speech and AAC speech using an integrated multimodal approach was effective in producing positive changes in both communication and speech production goals. These findings strongly suggest that integrating multimodal speech-generating AAC with traditional speech intervention was effective at supporting natural speech production for these children. PMID- 23633646 TI - Predictors of treatment failure, incipient hypothyroidism, and weight gain following radioiodine therapy for Graves' thyrotoxicosis. AB - BACKGROUND: Following radioiodine ((131)I) therapy, both late recognition of hypothyroidism and treatment failure may result in adverse outcomes. AIM: We sought to assess indicators of both incipient hypothyroidism and treatment failure following (131)I and determine factors predictive of weight gain. SUBJECTS AND METHODS: Retrospective study of 288 patients receiving (131)I for treatment of Graves' thyrotoxicosis. Primary outcome measures were thyroid status and weight change at 1 yr following (131)I. RESULTS: The treatment failure rate at 1 yr was 13.5%. Hypothyroidism developed in 80.9%, with 58.5% of patients having levels of free T4 (fT4) <6 pmol/l at diagnosis. Patients receiving thionamides before and after (131)I had significantly higher levels of treatment failure (23.3%) than those with no thionamide exposure (6.3%, p=0.003), but also had more active Graves' disease. Following (131)I, development of a detectable TSH or low-normal fT4 levels was not associated with recurrent thyrotoxicosis. Median weight gain was 5.3 kg, although patients with nadir fT4 levels <6 pmol/l gained an average 2 kg more than those with levels >6 pmol/l (p=0.05). The main predictor of weight gain was fT4 level immediately prior to treatment; those in the lowest tertile gained a median 3.1 kg whilst those in the highest tertile gained 7.4 kg (median difference 4.3 kg; 95% confidence interval: 2.5-6.2). CONCLUSIONS: Marked hypothyroidism following (131)I is common and often occurs early. Simple biochemical parameters may help identify incipient hypothyroidism and potentially limit excess weight gain. Treatment failure is common in patients with severe thyrotoxicosis and in such cases larger doses of (131)I may be warranted. PMID- 23633645 TI - Structural and dialectal characteristics of the fictional and personal narratives of school-age African American children. AB - PURPOSE: To report preliminary comparisons of developing structural and dialectal characteristics associated with fictional and personal narratives in school-age African American children. METHOD: Forty-three children, Grades 2-5, generated a fictional narrative and a personal narrative in response to a wordless-book elicitation task and a story-prompt task, respectively. Narratives produced in these 2 contexts were characterized for macrostructure, microstructure, and dialect density. Differences across narrative type and grade level were examined. RESULTS: Statistically significant differences between the 2 types of narratives were found for both macrostructure and microstructure but not for dialect density. There were no grade-related differences in macrostructure, microstructure, or dialect density. CONCLUSION: The results demonstrate the complementary role of fictional and personal narratives for describing young children's narrative skills. Use of both types of narrative tasks and descriptions of both macrostructure and microstructure may be particularly useful for characterizing the narrative abilities of young school-age African American children, for whom culture-fair methods are scarce. Further study of additional dialect groups is warranted. PMID- 23633647 TI - Natural radioactivity, radon exhalation rates and indoor radon concentration of some granite samples used as construction material in Turkey. AB - It is very important to determine the levels of the natural radioactivity in construction materials and radon exhalation rate from these materials for assessing potential exposure risks for the residents. The present study deals with 22 different granite samples employed as decoration stones in constructions in Turkey. The natural radioactivity in granite samples was measured by gamma-ray spectrometry with an HPGe detector. The activity concentrations of (226)Ra, (232)Th and (40)K were found to be in the range of 10-187, 16-354 and 104-1630 Bq kg(-1), respectively. The radon surface exhalation rate and the radon mass exhalation rate estimated from the measured values of (226)Ra content and material properties varied from 1.3 to 24.8 Bq m(-2) h(-1) with a mean of 10.5+/ 1.5 Bq m(-2) h(-1) and 0.03-0.64 Bq kg(-1) h(-1) with a mean of 0.27+/-0.04 Bq kg(-1) h(-1), respectively. Radon concentrations in the room caused from granite samples estimated using a mass balance equation varied from 23 to 461 Bq m(-3) with a mean of 196+/-27 Bq m(-3). Also the gamma index (Igamma), external indoor annual effective dose (Egamma) and annual effective dose due to the indoor radon exposure (ERn) were estimated as the average value of 1.1+/-0.1, 0.16+/-0.02 mSv and 5.0+/-0.7 mSv, respectively, for the granite samples. PMID- 23633648 TI - BACKGROUND RADIATION MEASUREMENTS AND CANCER RISK ESTIMATES FOR SEBINKARAHISAR, TURKEY. AB - This paper presents the measurement results of environmental radioactivity levels for Sebinkarahisar district (uranium-thorium area), Giresun, Turkey. The radioactivity concentrations of 238U, 232Th, 40K and the fission product 137Cs in soil samples collected from 73 regions from the surroundings of the study area were determined. In situ measurements of the gamma dose rate in air were performed in the same 73 locations where the soil samples were collected using a portable NaI detector. Also the mean radioactivity concentrations of 238U, 232Th and 40K in rock samples collected from 50 regions were determined. The mean estimated cancer risk value was found. The seasonal variations of the indoor radon activity concentrations were determined in the 30 dwellings in the study area. In addition, the mean gross alpha, gross beta and radon activities in tap water samples were determined in the same 30 dwellings. The excess lifetime cancer risk was calculated using the risk factors of International Commission on Radiological Protection and Biological Effects of Ionizing Radiation. Radiological maps of the Sebinkarahisar region were composed using the results obtained from this study. PMID- 23633649 TI - Neural network modelling of dose distribution and dose uniformity in the Tunisian Gamma Irradiator. AB - In this paper an approach to model dose distributions, isodose curves and dose uniformity in the Tunisian Gamma Irradiation Facility using artificial neural networks (ANNs) are described. For this purpose, measurements were carried out at different points in the irradiation cell using polymethyl methacrylate dosemeters. The calculated and experimental results are compared and good agreement is observed showing that ANNs can be used as an efficient tool for modelling dose distribution in the gamma irradiation facility. Monte Carlo (MC) photon-transport simulation techniques have been used to evaluate the spatial dose distribution for extensive benchmarking. ANN approach appears to be a significant advance over the time-consuming MC or the less accurate regression methods for dose mapping. As a second application, a detailed dose mapping using two different product densities was carried out. The minimum and maximum dose locations and dose uniformity as a function of the irradiated volume for each product density were determined. Good agreement between ANN modelling and experimental results was achieved. PMID- 23633650 TI - Radiation exposure received by the medical radiation workers in Lithuania at the Institute of Oncology, Vilnius University, 2004-2011. AB - The occupational radiation exposure of medical radiation workers at the Institute of Oncology, Vilnius University (IOVU) was analysed. Quartile dose measurements were collected and routinely analysed for a period of 8 y from 1 January 2004 to 31 December 2011. A total of 193 medical radiation workers were monitored, comprising 34 % physicians (radiologists and radiotherapists), 8 % physicists, 42 % radiological technologists and 16 % ancillary staff. A statistically significant decrease by 18 % has been detected when comparing the annual average effective doses (AAEDs) received by medical radiation workers at the IOVU during periods 2004-2007 and 2008-2011 (p < 0.0001). The main occupation categories responsible for this reduction were of Nuclear Medicine (p < 0.028) and Radiology (p < 0.0001) departments. The values of AAED in Radiology, Radiotherapy and Nuclear Medicine departments are quite low and well below the annual limit of 20 mSv, averaged over a period of 5 consecutive years. PMID- 23633651 TI - Prevalence of male accessory gland inflammations/infections in patients with Type 2 diabetes mellitus. AB - BACKGROUND: MAGI is an acronym that identifies the "male accessory gland inflammations/infections", a potential cause of male infertility. Type 2 diabetes mellitus (DM2) prevalence is going to increase among men of reproductive age. Due to the high prevalence of these two conditions, we could suppose that they might appear together in the same patient. AIM: To evaluate MAGI prevalence in patients with DM2 in fertile age. SUBJECTS AND METHODS: A cross-sectional study carried out on patients with DM2 of fertile age. All patients underwent andrological evaluation for the identification of conventional MAGI diagnostic criteria. RESULTS: DM2 patients showed a frequency of MAGI about 43%, significantly lower (p<0.05) than in infertile patients of the same age without diabetes, which showed a MAGI overall frequency of 61%. Among examined diabetic patients the prevalence of MAGI did not significantly differ between patients attending for diabetes care problems (glycemic control) and patients with andrological disorders. Finally, no significant difference in seminal inflammatory signs frequency was detected between patients with DM2 and infertile patients without diabetes. Finally, the correlation analysis showed a significant direct correlation between duration of diabetes and glycemic control with the prevalence of MAGI. CONCLUSION: MAGI prevalence in DM2 is lower than the one detected in age matched infertile non-diabetic patients, however, as in infertile patients, there is a high frequency of seminal inflammatory signs. Moreover, the observed prevalence among diabetic patients with diabetes care problems and diabetic patients with andrological problems is not statistically different. PMID- 23633652 TI - Intraocular biomarker identification in uveitis associated with juvenile idiopathic arthritis. AB - PURPOSE: To investigate the presence of biomarkers in aqueous humor (AH) from patients with uveitis associated with juvenile idiopathic arthritis (JIA). METHODS: AH (N = 73) AND SERUM (N = 105) SAMPLES FROM 116 CHILDREN WERE ANALYZED USING SURFACE ENHANCED LASER DESORPTION/IONIZATION TIME OF FLIGHT MASS SPECTROMETRY (SELDI-TOF MS). THE SAMPLES WERE DIVIDED INTO THE FOLLOWING GROUPS: JIA, silent chronic anterior uveitis (AU), other uveitis entities, and noninflammatory controls. Statistical biomarker identification was performed using the SELDI-ToF Biomarker Analysis Cluster Wizard followed by multivariate statistical analysis. Biochemical identification of biomarkers was performed by polyacrylamide gel protein separation, followed by liquid chromatography tandem mass spectrometry. ELISA was performed in a number of AH samples representing all four study groups. RESULTS: In the JIA group, one AH protein peak at mass/charge (m/z) 13,762 had qualitative and quantitative differences in expression compared with the other uveitis entities and the controls, but not to the group of silent chronic AU. Its quantitative expression in AH of patients with JIA and other silent chronic AU was positively associated with uveitis activity. The protein at m/z 13,762 in AH was identified as transthyretin (TTR). The TTR concentration in AH differed significantly between the study groups (P = 0.006) with considerably higher TTR concentrations in JIA and silent chronic AU samples positive for m/z 13,762 than those of the other uveitis and control groups. CONCLUSIONS: TTR is a potential intraocular biomarker of JIA- associated uveitis. Its role in the pathogenesis of silent chronic AU with and without arthritis needs further investigation. PMID- 23633654 TI - The continuum of detection and awareness of visual stimuli within the blindfield: from blindsight to the sighted-sight. AB - PURPOSE: We investigated systematically the effect of repeated exposure on detection and reported awareness of visual stimuli presented deep within the field defect of 5 hemianopic patients. METHODS: An objective measure of sensitivity (detection in a temporal two-alternative forced-choice paradigm) and subjective reports of awareness were recorded on trial by trial bases. Visual stimulus to be detected was a temporally modulated (10 Hz) circular patch (6 degrees diameter) of vertical grating (1 c/ degrees ). Hemianopic patients took part in the study 8 to 15 months after injury, so that the findings could not be attributed to spontaneous recovery. RESULTS: Initially, high contrast (90%) target stimuli were detected at or near chance level with little reported awareness. In 4 of 5 cases, repeated stimulation led to improved sensitivity, indicated by increased detection scores and higher incidence of awareness. In a fifth case, there was no change in sensitivity despite extensive exposure (>22,000 trials). CONCLUSIONS: At retinal locations deep within the field defect, repeated stimulation can lead to blindsight performance (type I detection without awareness), followed by detection with reported awareness (type II blindsight), and eventual reported visual experiences. The findings indicate that conscious awareness of stimuli lies on a continuous spectrum and repeated systematic training can lead to improved visual sensitivity. PMID- 23633653 TI - A CNS-specific hypomorphic Pdgfr-beta mutant model of diabetic retinopathy. AB - PURPOSE: A mouse mutant identified during a recessive N-ethyl-N-nitrosourea (ENU) mutagenesis screen exhibited ocular hemorrhaging resulting in a blood-filled orbit, and hence was named "redeye." We aimed to identify the causal mutation in redeye, and evaluate it as a model for diabetic retinopathy (DR). METHODS: The causative gene mutation in redeye was identified by haplotype mapping followed by exome sequencing. Glucose tolerance tests, detailed histologic and immunofluorescence analyses, and vascular permeability assays were performed to determine the affect of redeye on glucose metabolism, pericyte recruitment, and the development of the retinal vasculature and blood-retinal barrier (BRB). RESULTS: A mutation was identified in the Pdgfrb gene at position +2 of intron 6. We show that this change causes partial loss of normal splicing resulting in a frameshift and premature termination, and, therefore, a substantial reduction in normal Pdgfrb transcript. The animals exhibit defective pericyte recruitment restricted to the central nervous system (CNS) causing basement membrane and vascular patterning defects, impaired vascular permeability, and aberrant BRB development, resulting in vascular leakage and retinal ganglion cell apoptosis. Despite exhibiting classic features of diabetic retinopathy, redeye glucose tolerance is normal. CONCLUSIONS: The Pdgfrb(redeye/redeye) mice exhibit all of the features of nonproliferative DR, including retinal neurodegeneration. In addition, the perinatal onset of the CNS-specific vascular phenotype negates the need to age animals or manage diabetic complications in other organs. Therefore, they are a more useful model for diseases involving pericyte deficiencies, such as DR, than those currently being used. PMID- 23633656 TI - The relationship between cord blood cytokine levels and perinatal factors and retinopathy of prematurity: a gestational age-matched case-control study. AB - PURPOSE: To investigate the relationship between cytokine levels in cord blood and perinatal factors and retinopathy of prematurity (ROP) in gestational age matched, preterm, newborn infants. METHODS: Each of 20 premature singleton infants with ROP (gestational age < 32 weeks) was matched for gestational age, birth weight, and sex with two control infants without ROP. The concentration of 10 cytokines in cord blood extracted at birth was measured using a multiplex bead array assay. Data on maternal factors, labor and delivery characteristics, and neonatal parameters were also collected from both groups. The variables obtained were compared using the conditional logistic regression model. RESULTS: No differences in the levels of inflammatory cytokines (IL-1beta, IL-4, IL-6, IL-8, IL-10, IL-12, interferon-gamma, and TNF-alpha) and growth factors (insulin-like growth factor-1 and VEGF) were detected between the two groups. Multivariate conditional logistic regression analysis indicated that elevated maternal leukocyte count on admission and low Apgar scores at 5 minutes were significantly associated with an increased risk of ROP. CONCLUSIONS: Cytokine levels in cord blood are not associated with the risk of ROP, whereas elevated maternal blood leukocyte count and low Apgar score are associated with ROP. These data suggest that the determination of cytokine levels in cord blood samples in premature infants may be of little value for predicting ROP. PMID- 23633655 TI - Roles for redox signaling by NADPH oxidase in hyperglycemia-induced heme oxygenase-1 expression in the diabetic retina. AB - PURPOSE: The antioxidant response element (ARE)-mediated antioxidant pathway has an important role in maintaining the redox status of the retina. The expression of ARE-mediated antioxidants, such as heme oxygenase-1 (HO-1), remains unclear in the db/db mice. We evaluated the expression of HO-1 in the retinas of db/db mice and investigated a possible role for NADPH oxidase. METHODS: Fresh retinas were harvested from 8-, 12-, and 20-week db/db or db/m mice. Reactive oxygen species were detected by dihydroethidium. The expression levels of HO-1, Nox2, and Nox4 were evaluated by immunohistochemistry and Western blotting. In vitro retina explants culture was used to assess the role of NADPH oxidase in high glucose induced HO-1 expression. RESULTS: The expression of HO-1 was increased in the retinas of 8-week db/db mice, while it was decreased in 20-week db/db mice compared to age-matched controls. Similarly, the activation of Nox4 was increased in the retinas at 8 weeks and returned to basal levels at 20 weeks in db/db mice compared to age-matched controls. The activation of Nox2 was increased in the retinas of 8-, 12-, and 20-week db/db mice compared to age-matched controls. The NADPH oxidase inhibitors apocynin and DPI significantly blocked the HO-1 expression that was induced by high glucose levels in cultured retina explants. CONCLUSIONS: The expression patterns of HO-1, Nox2, Nox4 in db/db mouse retinas, and the suppressive effects of NADPH oxidase inhibitors on the expression of HO-1 induced by high glucose levels in cultured retina explants suggest that the expression of HO-1 is, at least partially, mediated by NADPH oxidase in this diabetic animal model. PMID- 23633657 TI - Longitudinal analysis of progression in glaucoma using spectral-domain optical coherence tomography. AB - PURPOSE: To compare the longitudinal loss of RNFL thickness measurements by SD OCT in healthy individuals and glaucoma patients with or without progression concerning optic disc morphology. METHODS: A total of 62 eyes, comprising 38 glaucomatous eyes with open angle glaucoma and 24 healthy controls, were included in the study (Erlangen Glaucoma Registry, NTC00494923). All patients were investigated annually over a period of 3 years by Spectralis SD-OCT measuring peripapillary RNFL thickness. By masked comparative analysis of photographs, the eyes were classified into nonprogressive and progressive glaucoma cases. Longitudinal loss of RNFL thickness was compared with morphological changes of optic disc morphology. RESULTS: Mixed model analysis of annual OCT scans revealed an estimated annual decrease of the RNFL thickness by 2.12 MUm in glaucoma eyes with progression, whereas glaucoma eyes without progression in optic disc morphology lost 1.18 MUm per year in RNFL thickness (P = 0.002). The rate of change in healthy eyes was 0.60 MUm and thereby also significantly lower than in glaucoma eyes with progression (P < 0.001). The intrasession variability of three successive measurements without head repositioning was 1.5 +/- 0.7 MUm. The loss of mean RNFL thickness exceeded the intrasession variability in 60% of nonprogressive eyes, and in 85% of progressive eyes after 3 years. CONCLUSIONS: LONGITUDINAL MEASUREMENTS OF RNFL THICKNESS USING SD-OCT SHOW A MORE PRONOUNCED REDUCTION OF RNFL THICKNESS IN PATIENTS WITH PROGRESSION COMPARED WITH PATIENTS WITHOUT PROGRESSION IN GLAUCOMATOUS OPTIC DISC CHANGES. (www.clinicaltrials.gov number, NTC00494923.). PMID- 23633658 TI - Dry eye syndrome, posttraumatic stress disorder, and depression in an older male veteran population. AB - PURPOSE: To evaluate whether veterans with posttraumatic stress disorder (PTSD) or depression have differences in dry eye symptoms and signs compared to a population without these conditions. METHODS: Male patients aged >=50 years with normal eyelid, conjunctival, and corneal anatomy were recruited from the Miami Veterans Affairs Eye Clinic (N = 248). We compared dry eye symptoms (determined by the Dry Eye Questionnaire 5 [DEQ5] score) to tear film indicators obtained by clinical examination (i.e., tear osmolarity, corneal staining, tear breakup time, Schirmer's, meibomian gland quality, orifice plugging, lid vascularity) between patients with PTSD or depression and those without these conditions. Student's t tests, chi(2) analyses, and linear and logistic regressions were used to assess differences between the groups. RESULTS: DEQ5 scores were higher in the PTSD (mean = 13.4; standard error [SE] = 1.1; n = 22) and depression (mean = 12.0; SE = 0.8; n = 40) groups compared to the group without these conditions (mean = 9.8; SE = 0.4; n = 186; P < 0.01 and P = 0.02, respectively). More patients in the PTSD and depression groups had severe dry eye symptoms, defined as a DEQ5 score >= 12 (77% and 63% vs. 41%; P < 0.01 and P = 0.02, respectively). No significant differences in tear film indicators were found among the three groups. Multivariable logistic regression indicated that a PTSD diagnosis (odds ratio [OR] = 4.08; 95% confidence interval [CI] = 1.10-15.14) and use of selective serotonin reuptake inhibitors (OR = 2.66; 95% CI = 1.01-7.00) were significantly associated with severe symptoms. CONCLUSIONS: Patients with PTSD have ocular surface symptoms that are not solely explained by tear indicators. Identifying underlying conditions associated with ocular discomfort is essential to better understand the mechanisms behind ocular pain in dry eye syndrome. PMID- 23633660 TI - Size threshold perimetry performs as well as conventional automated perimetry with stimulus sizes III, V, and VI for glaucomatous loss. AB - PURPOSE: It is thought that large perimetric stimuli are insensitive for demonstrating visual field defects. To test the hypothesis that there is no difference in the total number of abnormal test locations with total deviation empiric probability plots in glaucoma patients, we compared results of glaucoma patients tested with sizes III (0.43 degrees diameter), V (1.72 degrees ), and VI (3.44 degrees ), and size threshold perimetry (STP), a method that finds threshold by changing stimulus size. METHODS: We derived normative limits for total deviation probability plots using the second test from 60 age-matched normals. We analyzed the probability plots of 120 glaucoma patients (mean deviation was -9.3 +/- 6.1 dB with a range of -0.2 to -31.6) at the 42 nonblind spot locations common to the tests. We compared the number of abnormal test locations at the 5% level among the tests using one-way repeated measures ANOVA on ranks. We stratified the results by mean deviation. RESULTS: There was a statistically significant difference in the number of abnormal test locations among the tests: III, 28.5; V, 29.7; VI, 27.0; and STP, 28.8, P = 0.001; Tukey pairwise comparisons were statistically significant for the assessments between sizes V and VI and between STP and size VI. When stratifying by mean deviation, with mild visual loss, size V was most sensitive, followed by STP; size VI appeared slightly less sensitive. CONCLUSIONS: Size V and STP provide favorable stimulus methodology for detection of mild to moderate glaucoma. Size VI appears slightly less sensitive for glaucoma with mild loss. PMID- 23633659 TI - Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy. AB - PURPOSE: Increase in reactive oxygen species (ROS) is one of the major retinal metabolic abnormalities associated with the development of diabetic retinopathy. NF-E2-related factor 2 (Nrf2), a redox sensitive factor, provides cellular defenses against the cytotoxic ROS. In stress conditions, Nrf2 dissociates from its cytosolic inhibitor, Kelch like-ECH-associated protein 1 (Keap1), and moves to the nucleus to regulate the transcription of antioxidant genes including the catalytic subunit of glutamylcysteine ligase (GCLC), a rate-limiting reduced glutathione (GSH) biosynthesis enzyme. Our aim is to understand the role of Nrf2 Keap1-GCLC in the development of diabetic retinopathy. METHODS: Effect of diabetes on Nrf2-Keap1-GCLC pathway, and subcellular localization of Nrf2 and its binding with Keap1 was investigated in the retina of streptozotocin-induced diabetic rats. The binding of Nrf2 at GCLC was quantified by chromatin immunoprecipitation technique. The results were confirmed in isolated retinal endothelial cells, and also in the retina from human donors with diabetic retinopathy. RESULTS: Diabetes increased retinal Nrf2 and its binding with Keap1, but decreased DNA-binding activity of Nrf2 and also its binding at the promoter region of GCLC. Similar impairments in Nrf2-Keap1-GCLC were observed in the endothelial cells exposed to high glucose and in the retina from donors with diabetic retinopathy. In retinal endothelial cells, glucose-induced impairments in Nrf2-GCLC were prevented by Nrf2 inducer tBHQ and also by Keap1-siRNA. CONCLUSIONS: Due to increased binding of Nrf2 with Keap1, its translocation to the nucleus is compromised contributing to the decreased GSH levels. Thus, regulation of Nrf2-Keap1 by pharmacological or molecular means could serve as a potential adjunct therapy to combat oxidative stress and inhibit the development of diabetic retinopathy. PMID- 23633661 TI - Pretreatment with TLR2 and TLR4 ligand modulates innate immunity in corneal fibroblasts challenged with Aspergillus fumigatus. AB - PURPOSE: To study the innate immunity in telomerase-immortalized human stroma fibroblasts (THSFs) challenged with Aspergillus fumigatus hyphae after copretreatment with TLR2 and TLR4 ligand. METHODS: THSFs were pretreated with different concentrations of zymosan and/or lipopolysaccharide (LPS) at different time periods, and challenged with high-dose Aspergillus fumigatus hyphae. The gene expression and protein secretion of inflammatory cytokines (TNF-alpha, IL-6, and IL-8) were detected by RT-PCR and ELISA. The effects of stimulation or pretreatment of TLR ligands on proliferation of THSFs were measured by MTT analysis. RESULTS: In the certain concentration range, pretreatment of THSFs with zymosan suppressed gene expression of inflammatory cytokines (TNF-alpha and IL 6). Copretreatment with zymosan and LPS suppressed gene expression and protein secretion more strongly compared with pretreatment with zymosan or LPS alone. Zymosan and/or LPS pretreatment suppressed lethal effect of A. fumigatus to THSFs in a certain period. CONCLUSIONS: Pretreatment of THSFs with TLR2-specific ligand zymosan results in a state of A. fumigatus hyphae tolerance. Copretreatment with TLR2 and -4 ligands (zymosan and LPS) leads to a stronger state of A. fumigatus hyphae tolerance, and suppresses the lethal effect of A. fumigatus. PMID- 23633662 TI - Comparison of iris insertion classification among american caucasian and ethnic Chinese using ultrasound biomicroscopy. AB - PURPOSE: To qualitatively classify and compare types of iris insertion among American Caucasians, American Chinese, and mainland Chinese. METHODS: Prospective multicenter cross-sectional study. Sex- and age-matched Caucasian, American Chinese, and mainland Chinese cohorts were enrolled. Ultrasound biomicroscopy (UBM) images of the anterior chamber were acquired. Qualitative classification of iris insertion into basal, middle, and apical categories was performed. Proportions of each type of insertion were compared among racial groups. Multivariate logistic regression was carried out adjusting for potential confounders. RESULTS: data from 117, 129, and 112 subjects were available for american caucasian, american chinese, and mainland chinese subjects, respectively. The most common type of iris insertion in the superior quadrant was basal insertion in both ethnic Chinese and Caucasians. In the inferior, nasal, and temporal quadrants, chinese showed significantly higher proportions of nonbasal insertion (P = 0.048, P 0.0001, P 0.0001, respectively). After adjusting for confounders, nonbasal insertion was significantly associated with Chinese ethnicity in nasal and temporal quadrants (nasal, OR: 3.1, temporal, OR: 4.8). Increasing proportions of nonbasal insertion were found with advancing age in both Chinese and Caucasians. CONCLUSIONS: Chinese have significantly higher proportions of nonbasal iris insertion in the nasal and temporal quadrants when compared with Caucasians, even after adjusting for ASOCT-measured anterior segment biometry and iris characteristics. Longitudinal studies in patients who have PAC/PACG are needed to fully elucidate the relationship between iris insertion and angle closure development. PMID- 23633663 TI - Longitudinal analysis of reticular drusen associated with geographic atrophy in age-related macular degeneration. AB - PURPOSE: To characterize longitudinal changes of reticular drusen (RDR) in subjects with geographic atrophy (GA) secondary to age-related macular degeneration in the multicenter, prospective natural history Geographic Atrophy Progression Study. METHODS: Three-field confocal scanning laser ophthalmoscopy fundus autofluorescence (cSLO FAF, excitation [exc.] = 488 nm; emission [em.] 500 800 nm, Heidelberg Retina Angiograph/Spectralis) of 44 eyes of 22 patients with RDR (median age 77.6 years; range, 61-90 years) at baseline were identified in the study population and included for further analysis. Two independent readers determined the presence, topographic distribution, and pattern of RDR at baseline and at 18 months. Furthermore, the convex hull of the extent of RDR as the minimum polygon encompassing the entire area of RDR involvement was quantified. RESULTS: RDR lesion boundaries were clearly detectable in all directions within three-field FAF composite images in 16 eyes of 10 patients at both baseline and final visits. Over time, RDR-affected retinal area and RDR density increased. Quantitative analysis showed a mean average RDR extent of 53.7 mm(2) (95% confidence interval [95% CI]; 40.7; 66.8) at baseline. The mean differences for intraobserver agreements were 2.4 mm(2) (95% CI; -0.1; 4.9) for reader 1 and -0.6 mm(2) (95% CI; -2.3; 1.1) for reader 2. The mean difference of interobserver agreement was 0.9 mm(2) (95% CI; -0.8; 2.7). A mean growth rate of the RDR extent within the three-field FAF composite image of 4.4 mm(2)/y (95% CI; 1.9; 6.9) was measured. CONCLUSIONS: In vivo cSLO FAF imaging allows for both qualitative and quantitative mapping of longitudinal changes of RDR areas within a relatively short time period. Continuous enlargement of the affected retinal area indicates disease progression with regard to this phenotypic characteristic associated with GA in AMD. Systematic recordings of RDR progression appears warranted in future natural history and interventional studies in dry AMD. (ClinicalTrials.gov number, NCT00599846.). PMID- 23633664 TI - Noninvasive investigation of deep vascular pathologies of exudative macular diseases by high-penetration optical coherence angiography. AB - PURPOSE: A newly developed high-penetration Doppler optical coherence angiography (HP-OCA) with a 1-MUm probe beam for noninvasive investigation of vascular pathology of exudative macular diseases is introduced. A descriptive case series is presented to discuss the clinical utility of HP-OCA. METHODS: Eleven eyes of 10 subjects with exudative macular disease, including two eyes with myopic choroidal neovascularization (mCNV); four eyes with AMD; and five eyes with polypoidal choroidal vasculopathy (PCV) were investigated. Two Doppler scanning modes (bidirectional and high-sensitive) of HP-OCA were used for the investigation. HP-OCA provides depth-resolved and en face angiograms and a structural OCT noninvasively. The HP-OCA images were compared with fluorescein angiography (FA); indocyanine green angiography (ICGA); and color fundus images. RESULTS: The abnormal vasculature patterns observed with high-sensitive HP-OCA presented high similarity to the midphase of ICGA. Several abnormal Doppler signals were observed in the en face high-sensitive HP-OCA and were colocated with FA leakage. This colocation was found in one eye with mCNV, four eyes with AMD, and one eye with PCV. Doppler tomogram of the bidirectional mode showed abnormal Doppler signals in three of five PCV cases beneath the pigment epithelium detachment. With the high-sensitive mode, Doppler signals were found beneath the elevated retinal pigment epithelium in all untreated cases. CONCLUSIONS: HP-OCA revealed depth-resolved abnormal vasculatures in exudative macular diseases. The en face HP-OCA images showed high similarity with FA and ICGA images. These results suggest HP-OCA can be used for noninvasive and three dimensional angiography in a clinical routine. PMID- 23633665 TI - Human photoreceptor outer segments shorten during light adaptation. AB - PURPOSE: Best disease is a macular dystrophy caused by mutations in the BEST1 gene. Affected individuals exhibit a reduced electro-oculographic (EOG) response to changes in light exposure and have significantly longer outer segments (OS) than age-matched controls. The purpose of this study was to investigate the anatomical changes in the outer retina during dark and light adaptation in unaffected and Best disease subjects, and to compare these changes to the EOG. METHODS: Unaffected (n = 11) and Best disease patients (n = 7) were imaged at approximately 4-minute intervals during an approximately 40-minute dark-light cycle using spectral domain optical coherence tomography (SD-OCT). EOGs of two subjects were obtained under the same conditions. Automated three-dimensional (3 D) segmentation allowed measurement of light-related changes in the distances between five retinal surfaces. RESULTS: In normal subjects, there was a significant decrease in outer segment equivalent length (OSEL) of -2.14 MUm (95% confidence interval [CI], -1.77 to -2.51 MUm) 10 to 20 minutes after the start of light adaptation, while Best disease subjects exhibited a significant increase in OSEL of 2.07 MUm (95% CI, 1.79-2.36 MUm). The time course of the change in OS length corresponded to that of the EOG waveform. CONCLUSIONS: Our results strongly suggest that the light peak phase of the EOG is temporally related to a decreased OSEL in normal subjects, and the lack of a light peak phase in Best disease subjects is associated with an increase in OSEL. One potential role of Bestrophin-1 is to trigger an increase in the standing potential that approximates the OS to the apical surface of the RPE to facilitate phagocytosis. PMID- 23633666 TI - Influence of macular pigment on retinal straylight in healthy eyes. AB - PURPOSE: To study the influence of macular pigment on retinal straylight in healthy eyes. METHODS: This prospective study included 150 eyes of 75 healthy subjects between 12 and 81 years of age (mean, 46.1 years) without a history of ocular surgery or ocular disease known to influence straylight (e.g., cataract). Retinal straylight was measured with the compensation comparison technique, and the known influence of age and axial length was compensated by calculating the base, age, and axial length-corrected (BALC) straylight. Macular pigment optical density (MPOD) was measured using light-emitting diode (LED) heterochromatic flicker photometry. Axial length was determined with a partial coherence biometer and iris color by visual inspection. Data analysis consisted of studying the predictive values between these parameters, after correction for the symmetry between left and right eyes, using linear mixed models. RESULTS: Mean retinal straylight was 1.05 +/- 0.18 log units, and the mean MPOD was 0.37 +/- 0.19. Age and axial length were found to be important predictors of retinal straylight (P < 0.001 and P = 0.010, respectively) but not of MPOD (P > 0.05). The mean BALC straylight was -0.07 +/- 0.13 log units. No significant relationship was found between retinal straylight and MPOD (P > 0.05), even after correction for age and axial length. Also, no significant correlation was found between iris color and BALC straylight or MPOD. CONCLUSIONS: In healthy human eyes, retinal straylight values measured with the compensation comparison technique are not significantly correlated with macular pigment optical density. PMID- 23633667 TI - Harnessing autophagy for cell fate control gene therapy. AB - We hypothesized that rapamycin, through induction of autophagy and promotion of an antiapoptotic phenotype, would permit lentiviral (LV)-based transgene delivery to human T-Rapa cells, which are being tested in phase II clinical trials in the setting of allogeneic hematopoietic cell transplantation. Manufactured T-Rapa cells were exposed to supernatant enriched for a LV vector encoding a fusion protein consisting of truncated CD19 (for cell surface marking) and DTYMK/TMPKDelta, which provides "cell-fate control" due to its ability to phosphorylate (activate) AZT prodrug. LV-transduction in rapamycin-treated T-Rapa cells: (1) resulted in mitochondrial autophagy and a resultant antiapoptotic phenotype, which was reversed by the autophagy inhibitor 3-MA; (2) yielded changes in MAP1LC3B and SQSTM1 expression, which were reversed by 3-MA; and (3) increased T-Rapa cell expression of the CD19-DTYMKDelta fusion protein, despite their reduced proliferative status. Importantly, although the transgene expressing T-Rapa cells expressed an antiapoptotic phenotype, they were highly susceptible to cell death via AZT exposure both in vitro and in vivo (in a human into-mouse xenogeneic transplantation model). Therefore, rapamycin induction of T cell autophagy can be used for gene therapy applications, including the CD19 DTYMKDelta cell-fate control axis to improve the safety of T cell immuno-gene therapy. PMID- 23633668 TI - Association of Trichomonas vaginalis with its symbiont Mycoplasma hominis synergistically upregulates the in vitro proinflammatory response of human monocytes. AB - OBJECTIVES: Trichomonas vaginalis is the causative agent of trichomoniasis, one of the most common sexually transmitted diseases worldwide. In recent years we have described the symbiotic relationship between T vaginalis and Mycoplasma hominis. How this biological association might affect the pathogenicity of one or both the microorganisms is still unknown. Since local inflammation is thought to play a central role in T vaginalis infection, we investigated the in vitro response of human macrophages to naturally mycoplasma-free T vaginalis, as compared to a mycoplasma-infected trichomonad isolate. METHODS: THP-1 cells were stimulated with two isogenic T vaginalis isolates, one naturally mycoplasma-free and one stably associated with M hominis, and secreted cytokines measured by ELISA. Nuclear factor kappaB (NFkappaB) involvement in THP-1 response to T vaginalis and M hominis was evaluated by means of a reporter system based on detection of alkaline phosphatase activity. RESULTS: We found that the presence of M hominis upregulates the expression of a panel of proinflammatory cytokines in a synergistic fashion. We also found that the upregulation of the proinflammatory response by THP-1 cells involves the transcription factor NFkappaB. CONCLUSIONS: These findings suggest that the presence of M hominis in T vaginalis isolates might play a key role in inflammation during trichomoniasis, thus affecting the severity of the disease. The synergistic upregulation of the macrophage proinflammatory response might also affect some important clinical conditions associated with T vaginalis infection, such as the increased risk of acquiring cervical cancer or HIV, which are thought to be affected by the inflammatory milieu during trichomoniasis. PMID- 23633669 TI - Modern diagnosis of Trichomonas vaginalis infection. AB - Recent advances in tests for the sexually transmitted protozoan parasite Trichomonas vaginalis have increased opportunities for diagnosis and treatment of this important sexually transmitted infection. This review summarises currently available tests, highlighting their performance characteristics, advantages and limitations. The recent development of molecular tests for the detection of T vaginalis, including rapid antigen detection and nucleic acid amplification tests, has significantly improved the quality of diagnostics for trichomoniasis, particularly in women. In light of the expanded menu of testing options now available, improved recognition and better control of trichomoniasis are in sight, which should enable the eventual reduction of adverse reproductive consequences associated with T vaginalis infection. PMID- 23633670 TI - Patterns and trends in Pakistan's heterogeneous HIV epidemic. AB - BACKGROUND: Considerable HIV transmission occurs among injection drug users (IDUs) in Pakistan and recently the HIV prevalence has been increasing among male (MSW), hijra (transgender; HSW) and female (FSW) sex workers. We describe past and estimate future patterns of HIV emergence among these populations in several cities in Pakistan. METHODS: The density of these key populations per 1000 adult men was calculated using 2011 mapping data from Karachi, Lahore, Faisalabad, Larkana, Peshawar and Quetta, and surveillance data were used to assess bridging between these key populations. We used the UNAIDS Estimation and Projection Package model to estimate and project HIV epidemics among these key populations in Karachi, Lahore, Faisalabad and Larkana. RESULTS: The density and bridging of key populations varied across cities. Lahore had the largest FSW population (11.5/1000 adult men) and the smallest IDU population (1.7/1000 adult men). Quetta had the most sexual and drug injection bridging between sex workers and IDUs (6.7%, 7.0% and 3.8% of FSW, MSW and HSW, respectively, reported injecting drugs). Model evidence suggests that by 2015 HIV prevalence is likely to reach 17 22% among MSWs/HSWs in Karachi, 44-49% among IDUs in Lahore and 46-66% among IDUs in Karachi. Projection suggests the prevalence may reach as high as 65-75% among IDUs in Faisalabad by 2025. HIV prevalence is also estimated to increase among FSWs, particularly in Karachi and Larkana. CONCLUSIONS: There is a need to closely monitor regional and subpopulation epidemic patterns and implement prevention programmes customised to local epidemics. PMID- 23633671 TI - Infectious particles, stress, and induced prion amyloids: a unifying perspective. AB - Transmissible encephalopathies (TSEs) are believed by many to arise by spontaneous conversion of host prion protein (PrP) into an infectious amyloid (PrP-res, PrP (Sc) ) without nucleic acid. Many TSE agents reside in the environment, with infection controlled by public health measures. These include the disappearance of kuru with the cessation of ritual cannibalism, the dramatic reduction of epidemic bovine encephalopathy (BSE) by removal of contaminated feed, and the lack of endemic scrapie in geographically isolated Australian sheep with susceptible PrP genotypes. While prion protein modeling has engendered an intense focus on common types of protein misfolding and amyloid formation in diverse organisms and diseases, the biological characteristics of infectious TSE agents, and their recognition by the host as foreign entities, raises several fundamental new directions for fruitful investigation such as: (1) unrecognized microbial agents in the environmental metagenome that may cause latent neurodegenerative disease, (2) the evolutionary social and protective functions of different amyloid proteins in diverse organisms from bacteria to mammals, and (3) amyloid formation as a beneficial innate immune response to stress (infectious and non-infectious). This innate process however, once initiated, can become unstoppable in accelerated neuronal aging. PMID- 23633672 TI - Mechanisms and consequence of bacteria detection by the Drosophila gut epithelium. AB - Since insect mostly developed on decaying matter and contaminated fruits, they are constantly ingesting bacteria. The insect model, Drosophila, is therefore well adapted to study the interactions that take place between the gut epithelia and either resident or infectious bacteria. In order to provide an ad hoc immune response, gut epithelial cells must detect the presence of bacteria. In a recent report, Bosco-Drayon et al. identify the main receptors by which Drosophila sense gut associated bacteria and analyze how this bacteria-receptor interaction translate into gene activation. PMID- 23633673 TI - Design, dissemination, and evaluation of an advanced communication elective at seven U.S. medical schools. AB - PURPOSE: To test educational methods that continue communication training into the fourth year of medical school. METHOD: The authors disseminated and evaluated an advanced communication elective in seven U.S. medical schools between 2007 and 2009; a total of 9 faculty and 22 fourth-year students participated. The elective emphasized peer learning, practice with real patients, direct observation, and applications of video technology. The authors used qualitative and quantitative survey methods and video review to evaluate the experience of students and faculty. RESULTS: Students reported that the elective was better than most medical school clerkships they had experienced. Their self-confidence in time management and in the use of nine communication skills improved significantly. The most valued course components were video review, repeated practice with real patients, and peer observation. Analysis of student videos with real patients and in role-plays showed that some skills (e.g., agenda setting, understanding the patient perspective) were more frequently demonstrated than others (e.g., exploring family and cultural values, communication while using the electronic health record). Faculty highly valued this learner-centered model and reported that their self-awareness and communication skills grew as teachers and as clinicians. CONCLUSIONS: Learner-centered methods such as peer observation and video review and editing may strengthen communication training and reinforce skills introduced earlier in medical education. The course design may counteract a "hidden curriculum" that devalues respectful interactions with trainees and patients. Future research should assess the impact of course elements on skill retention, attitudes for lifelong learning, and patients' health outcomes. PMID- 23633674 TI - Histone demethylases set the stage for cancer metastasis. AB - Metastasis is the major cause of cancer-related mortality. It is increasingly evident that epigenetic alterations in tumor cells enable them to overcome various barriers in this multistage process of cell spreading, and insight into the molecular roles of epigenetic regulators in tumor metastasis are just beginning to emerge. Histone demethylases appear to have critical roles in creating suitable epigenetic states for tumor cells to gain metastatic potential. These studies shed light on the roles of histone demethylases in tumor metastasis and highlight the importance of targeting these enzymes to suppress metastatic disease. PMID- 23633676 TI - Spatial control of Epac2 activity by cAMP and Ca2+-mediated activation of Ras in pancreatic beta cells. AB - The cAMP (adenosine 3',5'-monophosphate)-activated guanine nucleotide exchange factor (GEF) Epac2 is an important mediator of cAMP-dependent processes in multiple cell types. We used real-time confocal and total internal reflection fluorescence microscopy to examine the spatiotemporal regulation of Epac2, which is a GEF for the guanosine triphosphatase (GTPase) Rap. We demonstrated that increases in the concentration of cAMP triggered the translocation of Epac2 from the cytoplasm to the plasma membrane in insulin-secreting beta cells. Glucose induced oscillations of the submembrane concentration of cAMP were associated with cyclic translocation of Epac2, and this translocation could be amplified by increases in the cytoplasmic Ca(2+) concentration. Analyses of Epac2 mutants identified the high-affinity cAMP-binding and the Ras association domains as crucial for the translocation. Expression of a dominant-negative Ras mutant reduced Epac2 translocation, and Ca(2+)-dependent oscillations in Ras activity synchronized with Epac2 translocation in single beta cells. The cyclic translocation of Epac2 was accompanied by oscillations of Rap GTPase activity at the plasma membrane, and expression of an inactive Rap1B mutant decreased insulin secretion. Thus, Epac2 localization is dynamically controlled by cAMP as well as by Ca(2+)-mediated activation of Ras. These results help to explain how oscillating signals can produce pulses of insulin release from pancreatic beta cells. PMID- 23633675 TI - Epigenetic activation of AP1 promotes squamous cell carcinoma metastasis. AB - The transcription factor AP1 (activating protein 1), a heterodimer of the JUN and FOS proteins, promotes the invasive growth and metastasis of various tumors such as squamous cell carcinoma (SCC), breast cancer, and melanoma. AP1 activity is transcriptionally induced through a positive feedback loop. We identified the histone demethylase KDM4A (lysine-specific demethylase 4A) as a key epigenetic priming factor in this positive feedback loop. KDM4A contributed to the induction of genes encoding the AP1 transcription factors and the invasive growth and metastasis of SCC. KDM4A knockdown decreased the growth factor-induced messenger RNA expression and protein abundance of AP1 family members, including JUN and FOSL1. Mechanistically, histone demethylation by KDM4A facilitated the binding of the AP1 complex to the promoters of JUN and FOSL1, thereby promoting the positive feedback loop that maintains activation of AP1. In a mouse model of SCC, KDM4A knockdown inhibited lymph node metastasis. Moreover, the abundance of KDM4A correlated with the abundance of JUN and FOSL1 in human SCC tissues, and KDM4A expression was increased in human lymph node metastases. Our studies provide insights into the epigenetic control of AP1 and tumor invasion and suggest that KDM4A could be an important therapeutic target for inhibiting invasive SCC growth and metastasis. PMID- 23633677 TI - beta-arrestin-dependent activation of the cofilin pathway is required for the scavenging activity of the atypical chemokine receptor D6. AB - Chemokines promote the recruitment of leukocytes to sites of infection and inflammation by activating conventional heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). Chemokines are also recognized by a set of atypical chemokine receptors (ACRs), which cannot induce directional cell migration but are required for the generation of chemokine gradients in tissues. ACRs are presently considered "silent receptors" because no G protein dependent signaling activity is observed after their engagement by cognate ligands. We report that engagement of the ACR D6 by its ligands activates a beta arrestin1-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin through the Rac1-p21 activated kinase 1 (PAK1)-LIM kinase 1 (LIMK1) cascade. This signaling pathway is required for the increased abundance of D6 protein at the cell surface and for its chemokine-scavenging activity. We conclude that D6 is a signaling receptor that exerts its regulatory function on chemokine-mediated responses in inflammation and immunity through a distinct signaling pathway. PMID- 23633680 TI - Influence of the eye-tracking-based follow-up function in retinal nerve fiber layer thickness using fourier-domain optical coherence tomography. PMID- 23633679 TI - A randomized, placebo-controlled trial of selenium supplementation in patients with type 2 diabetes: effects on glucose homeostasis, oxidative stress, and lipid profile. AB - Selenium is an antioxidant trace element. Patients with diabetes are shown to have increased oxidative stress together with decreased selenium concentrations. Whether raising serum selenium will improve blood glucose management in diabetes is largely unknown. In this randomized, double-blind placebo-controlled trial, we assessed the effects of selenium on blood glucose, lipid profile, and oxidative stress in 60 patients with type 2 diabetes. Selenium 200 ug/d or placebo was administered orally for 3 months. Serum concentrations of fasting plasma glucose, glycosylated hemoglobin A1c (HbA1c), insulin, and lipid profile, as well as ferric-reducing ability of plasma and thiobarbituric acid-reactive substances were determined in the fasting state at baseline and after 3 months. Mean (SD) serum selenium at baseline was 42.69 (29.47) ug/L and 47.11 (42.86) ug/L in selenium and placebo groups, respectively. At endpoint, selenium concentration reached to 71.98 (45.08) ug/L in selenium recipients compared with 45.38 (46.45) ug/L in placebo recipients (P<0.01). Between-group comparison showed that fasting plasma glucose, glycosylated hemoglobin A1c, and high-density lipoprotein cholesterol were statistically significantly higher in the selenium recipient arm. Other endpoints changes during the course of trial were not statistically different across the 2 treatment arms. This study suggests that selenium supplementation in patients with type 2 diabetes may be associated with adverse effects on blood glucose homeostasis, even when plasma selenium concentration is raised from deficient status to the optimal concentration of antioxidant activity. Until results of further studies become available, indiscriminate use of selenium supplements in patients with type 2 diabetes warrants caution. PMID- 23633681 TI - Consequences of revised CLSI and EUCAST guidelines for antibiotic susceptibility patterns of ESBL- and AmpC beta-lactamase-producing clinical Enterobacteriaceae isolates. AB - OBJECTIVES: This study aimed to: (i) analyse the antibiotic susceptibility testing (AST) profiles of extended spectrum beta-lactamase (ESBL)- and AmpC beta lactamase-producing clinical Enterobacteriaceae isolates applying EUCAST 2013 AST guidelines; and (ii) evaluate discrepancies in AST profiles according to EUCAST 2010 guidelines, EUCAST 2013 guidelines, CLSI 2009 guidelines and CLSI 2013 guidelines. METHODS: The 195 ESBL- and/or AmpC beta-lactamase-producing Enterobacteriaceae isolates used in this study were systematically characterized by disc diffusion AST interpreted according to the 2013 guidelines of EUCAST and CLSI, the EUCAST 2010 guidelines and the CLSI 2009 guidelines. RESULTS: Individual cephalosporin AST patterns according to EUCAST 2013 guidelines were described for individual ESBL and AmpC beta-lactamase genotypes. Significant differences in the susceptibility rates of important cephalosporins such as cefepime, ceftazidime and cefotaxime applying EUCAST 2013 and CLSI 2013 AST guidelines were demonstrated for ESBL- and AmpC beta-lactamase-producing isolates. CONCLUSIONS: The confirmation of ESBL and/or AmpC beta-lactamase production can support the selection of an adequate antibiotic drug therapy. Despite a harmonized CLSI and EUCAST 'report as found' strategy for cephalosporins and ESBL-producing isolates, AST interpretation according to the CLSI 2013 and EUCAST 2013 guidelines shows significant differences in susceptibility rates for mainstay cephalosporins such as cefepime, ceftazidime and cefotaxime. Thus, further harmonization of clinical breakpoints is warranted. PMID- 23633678 TI - Child maltreatment victimization and subsequent perpetration of young adult intimate partner violence: an exploration of mediating factors. AB - This study examined whether young adults with documented histories of child maltreatment had higher records of documented severe intimate partner violence (IPV) perpetration than an income-matched control group. It also examined whether this association was mediated by juvenile violent delinquency, problematic substance use, or mental health problems. Study data came from one state's administrative public sector records of child welfare, juvenile court, mental health, income maintenance, and birth records. The study employed a prospective longitudinal design to follow children for 16 years (N = 5,377). The IPV was measured by police arrests and temporary restraining order petitions. Multiple group path analysis was used to examine mediation hypotheses and determine whether they differed by gender. The study found that IPV perpetration rates were higher among maltreated than control participants and higher in maltreated men than in women. For men, maltreatment had both direct and mediated effects on IPV perpetration through violent delinquency. For women, maltreatment did not directly or indirectly predict IPV perpetration, though low power makes these findings tentative. The study highlights the importance of child maltreatment prevention as a way to reduce violence later in life and suggests that the juvenile justice system may also provide a point of intervention for the maltreated youth. PMID- 23633682 TI - Comment on: The national burden of infections after prostate biopsy in England and Wales: a wake-up call for better prevention. PMID- 23633683 TI - High concordance of genotypic coreceptor prediction in plasma-viral RNA and proviral DNA of HIV-1 subtype C: implications for use of whole blood DNA in resource-limited settings. AB - OBJECTIVES: Genotypic tropism testing (GTT) of HIV is increasingly used prior to the initiation of CCR5 antagonist therapy in HIV-infected individuals. Normally performed on plasma-derived virus, the test is challenging when performed in patients with suppressed viraemia. We aimed to evaluate the performance of cell associated proviral DNA against plasma-derived viral RNA as the genetic material for GTT in an Indian clinical setting. METHODS: From 52 HIV-1-infected individuals, the env V3 region was successfully amplified and sequenced from both proviral DNA and plasma RNA paired samples having a viral load >2500 copies/mL (n = 42) and from proviral DNA only in 10 antiretroviral therapy (ART)-experienced patients with a viral load <500 copies/mL. GTT was performed using the Geno2Pheno algorithm with the interpretative false positive rate (FPR) cut-off of 10%. RESULTS: Among paired samples, 40 of 42 patients harboured subtype C strains. Plasma RNA tropism prediction revealed X4 tropism in 4 of 42 (9.5%). A high concordance of 97.6% in tropism prediction was noted in simultaneous RNA/DNA samples (38 R5 and 3 X4). Discordance was observed in one sample showing R5 tropism in proviral DNA and X4 tropism in plasma RNA. Comparison of Geno2Pheno FPRs in both the plasma and proviral compartments showed good correlation (overall, r = 0.87; ART-naive patients, r = 0.79; ART-failing patients, r = 0.97). GTT was successfully performed in all 10 whole blood DNA samples having a viral load <500 copies/mL, all showing R5 tropism. CONCLUSIONS: High concordance in tropism prediction from proviral DNA and plasma-viral RNA suggests that prediction of viral tropism using proviral DNA is accurate and feasible in resource-limited clinical settings, particularly in patients with low or suppressed viraemia. PMID- 23633684 TI - Rifampicin-resistant and rifabutin-susceptible Mycobacterium tuberculosis strains: a breakpoint artefact? AB - OBJECTIVES: It has long been assumed that some rifampicin-resistant Mycobacterium tuberculosis strains are susceptible to, and thus treatable with, rifabutin. However, clinical breakpoints for susceptibility testing of rifabutin as well as the evidence for a clinical effect of rifabutin in rifampicin-resistant strains remains poorly defined. The objective of this study was to re-evaluate the breakpoint for rifabutin in relation to its MIC wild-type distribution and the presence of mutations in rpoB. METHODS: The MIC in 7H10 Middlebrook medium was determined for clinical isolates of M. tuberculosis (n = 95), where a majority were multidrug resistant. Additionally, all strains were screened for rpoB mutations by sequencing and the GenoType MTBDRplus assay. RESULTS: Rifampicin resistance was confirmed by genotypical and/or phenotypical tests in 73 isolates (76.8%). Nineteen isolates, defined as rifampicin resistant and rifabutin susceptible according to the present breakpoint, exhibited significantly higher MICs of rifabutin (0.064-0.5 mg/L) than rifabutin-susceptible isolates without any detectable mutations in rpoB (P < 0.001). These 19 isolates were clearly resistant to rifampicin (MIC 2-256 mg/L) and all but one had mutations in rpoB, with 9 (47.4%) specifically in Asp516Val. CONCLUSIONS: Our results indicate that rifampicin-resistant but rifabutin-susceptible isolates according to the present breakpoints harbour rpoB mutations and have a rifabutin MIC significantly higher than strains without any detectable mutations in rpoB. So far there are no clinical, pharmacological or microbiological data to confirm that such isolates can be treated with rifabutin and we suggest a revision of the current breakpoints. PMID- 23633685 TI - Delivery of the endolysin Cpl-1 by inhalation rescues mice with fatal pneumococcal pneumonia. AB - OBJECTIVES: Pneumonia is associated with a high morbidity and mortality worldwide. Streptococcus pneumoniae remains the most common cause of pneumonia, and pneumococcal antibiotic resistance is increasing. The purified bacteriophage endolysin Cpl-1 rapidly and specifically kills pneumococci. We tested the hypothesis that a single dose of recombinant aerosolized Cpl-1 would rescue mice with severe pneumococcal pneumonia. METHODS: Female C57Bl/6 mice (aged 8-12 weeks) were transnasally infected with pneumococci. When severe pneumonia was established 24 h after infection, mice were treated with 25 MUL of aerosolized Cpl-1. Survival was monitored for 10 days and the pulmonary and systemic bacterial burdens were assessed. Furthermore, cytokines were quantified in bronchoalveolar lavage fluid, and lung morphology was analysed histologically. RESULTS: The endolysin efficiently reduced pulmonary bacterial counts and averted bacteraemia. Although concentrations of inflammatory cytokines were increased shortly after Cpl-1 inhalation, mice recovered rapidly, as shown by increasing body weight, and inflammatory infiltrates resolved in the lungs, leading to a reduction in mortality of 80%. CONCLUSIONS: Administration of Cpl-1 by inhalation may offer a new therapeutic perspective for the treatment of pneumococcal lung infection. PMID- 23633686 TI - Rapid in vivo assessment of drug efficacy against Mycobacterium tuberculosis using an improved firefly luciferase. AB - OBJECTIVES: In vivo experimentation is costly and time-consuming, and presents a major bottleneck in anti-tuberculosis drug development. Conventional methods rely on the enumeration of bacterial colonies, and it can take up to 4 weeks for Mycobacterium tuberculosis to grow on agar plates. Light produced by recombinant bacteria expressing luciferase enzymes can be used as a marker of bacterial load, and disease progression can be easily followed non-invasively in live animals by using the appropriate imaging equipment. The objective of this work was to develop a bioluminescence-based mouse model of tuberculosis to assess antibiotic efficacy against M. tuberculosis in vivo. METHODS: We used an M. tuberculosis strain carrying a red-shifted derivative of the firefly luciferase gene (FFlucRT) to infect mice, and monitored disease progression in living animals by bioluminescence imaging before and after treatment with the frontline anti tuberculosis drug isoniazid. The resulting images were analysed and the bioluminescence was correlated with bacterial counts. RESULTS: Using bioluminescence imaging we detected as few as 1.7 * 10(3) and 7.5 * 10(4) reporter bacteria ex vivo and in vivo, respectively, in the lungs of mice. A good correlation was found between bioluminescence and bacterial load in both cases. Furthermore, a marked reduction in luminescence was observed in living mice given isoniazid treatment. CONCLUSIONS: We have shown that an improved bioluminescent strain of M. tuberculosis can be visualized by non-invasive imaging in live mice during an acute, progressive infection and that this technique can be used to rapidly visualize and quantify the effect of antibiotic treatment. We believe that the model presented here will be of great benefit in early drug discovery as an easy and rapid way to identify active compounds in vivo. PMID- 23633687 TI - FDA advisory panel assesses hydrocodone prescription writing: every dentist's responsibility. PMID- 23633688 TI - Midlevel providers. PMID- 23633689 TI - Cost of education. PMID- 23633690 TI - CBCT findings. PMID- 23633691 TI - Authors' response. PMID- 23633692 TI - Xylitol for adult caries. PMID- 23633693 TI - Author's response. PMID- 23633694 TI - How the development of the high-speed turbine handpiece changed the practice of dentistry. PMID- 23633695 TI - Diabetes and tooth loss: an analysis of data from the National Health and Nutrition Examination Survey, 2003-2004. AB - BACKGROUND: The authors conducted an analysis of data from the National Health and Nutrition Examination Survey (NHANES) to understand the association between diabetes and tooth loss in the United States. METHODS: The authors analyzed the oral examination and self-reported diabetes data obtained from the NHANES 2003 2004 cycle and included 2,508 participants representing a civilian, noninstitutionalized U.S. population 50 years and older. The authors calculated the prevalence of edentulism and the number of missing teeth among dentate people, and they used multiple regression analyses to assess the association between diabetes and tooth loss. RESULTS: The prevalence of edentulism was 28 percent and 14 percent among people with and without diabetes, respectively. The multiple logistic regression analysis revealed that people with diabetes were more likely to be edentulous than were those without diabetes (adjusted odds ratio = 2.25; 95 percent confidence interval, 1.19-4.21). Among dentate adults, those with diabetes had a higher number of missing teeth than did adults without diabetes (mean [standard error {SE}] = 9.8 [0.67]), mean [SE] = 6.7 [0.29]); P < .01). CONCLUSIONS: These study results revealed that adults with diabetes are at higher risk of experiencing tooth loss and edentulism than are adults without diabetes. One of every five cases of edentulism in the United States is linked to diabetes. Practical Implications. Although the association between diabetes and periodontal disease is well established, health care professionals also need to recognize the risk of tooth loss and its effect on quality of life among people with diabetes. PMID- 23633696 TI - The prevalence of temporomandibular disorders in patients with late whiplash syndrome who experience orofacial pain: a case-control series study. AB - BACKGROUND: The authors conducted a study to compare the frequency of specific temporomandibular disorder (TMD) diagnoses in patients who had late whiplash syndrome (LWS) with that in a control group. METHODS: The authors recruited 65 patients who had orofacial pain and a previous diagnosis of LWS and 65 age- and sex-matched control patients who had chronic orofacial pain without a history of whiplash injury (WI) for a case-control series study. All patients completed a questionnaire pertaining to the Research Diagnostic Criteria for Temporomandibular Disorders and underwent a clinical examination. RESULTS: The authors compared the frequency of TMD diagnoses in case patients with that in control patients by using a chi(2) test; they set the alpha level a priori at .05. The number of patients diagnosed with myofascial pain (MP) and disk displacement with reduction (DDWR) was significantly higher in the case group than in the control group (P = .002 and P = .001, respectively). CONCLUSIONS: The results of this study show a higher frequency of MP and DDWR in patients with LWS than in patients with chronic orofacial pain and no history of WI. Practical Implications. Clinicians should be knowledgeable about the correlation between WI and TMD so they can inform and treat patients accurately. PMID- 23633697 TI - A chronic nonhealing gingival mass. Histoplasmosis. PMID- 23633698 TI - Treatments for hypersensitive noncarious cervical lesions: a Practitioners Engaged in Applied Research and Learning (PEARL) Network randomized clinical effectiveness study. AB - BACKGROUND: The Practitioners Engaged in Applied Research and Learning (PEARL) Network conducted a three-armed randomized clinical study to determine the comparative effectiveness of three treatments for hypersensitive noncarious cervical lesions (NCCLs): use of a potassium nitrate dentifrice for treatment of hypersensitivity, placement of a resin-based composite restoration and placement of a sealant. METHODS: Seventeen trained practitioner-investigators (P-Is) in the PEARL Network enrolled participants (N = 304) with hypersensitive posterior NCCLs who met enrollment criteria. Participants were assigned to treatments randomly. Evaluations were conducted at baseline and at one, three and six months thereafter. Primary outcomes were the reduction or elimination of hypersensitivity as measured clinically and by means of patient-reported outcomes. RESULTS: Lesion depth and pretreatment sensitivity (mean, 5.3 on a 0- to 10-point scale) were balanced across treatments, as was sleep bruxism (present in 42.2 percent of participants). The six-month participant recall rate was 99 percent. Treatments significantly reduced mean sensitivity (P < .01), with the sealant and restoration groups displaying a significantly higher reduction (P < .01) than did the dentifrice group. The dentifrice group's mean (standard deviation) sensitivity at six months was 2.1 (2.1); those of the sealant and restoration groups were 1.0 (1.6) and 0.8 (1.4), respectively. Patient-reported sensitivity (to cold being most pronounced) paralleled clinical measurements at each evaluation. CONCLUSIONS: Sealing and restoration treatments were effective overall in reducing NCCL hypersensitivity. The potassium nitrate dentifrice reduced sensitivity with increasing effectiveness through six months but not to the degree offered by the other treatments. Practical Implications. Sealant or restoration placement is an effective method of immediately reducing NCCL sensitivity. Although a potassium nitrate dentifrice did reduce sensitivity slowly across six months, at no time was the reduction commensurate with that of sealants or restorations. PMID- 23633701 TI - A practitioner's guide to developing critical appraisal skills: reviews of research. AB - BACKGROUND: and overview. This article describes the different types of reviews of research that are available in the literature: systematic reviews and traditional reviews. Systematic reviews have become the reference standard for evidence to inform clinical practice. In this article, the authors set out guidance on appraising the quality and relevance of systematic reviews to help readers make decisions about their clinical practice. CONCLUSIONS: and practical implications. Systematic reviews are of variable quality, although evaluations of reviews by the Cochrane Collaboration generally are of the highest quality. An assessment tool described in this article appears currently to be the most useful tool to guide clinicians to assess systematic reviews and therefore to decide whether the evidence is appropriate to change practice. PMID- 23633699 TI - Correlates of root caries experience in middle-aged and older adults in the Northwest Practice-based REsearch Collaborative in Evidence-based DENTistry research network. AB - BACKGROUND: The authors examined the correlates of root caries experience for middle-aged adults (aged 45-64 years) and older adults (65 years and older) to test the hypothesis that the factors related to root caries are different for middle-aged adults than they are for older adults. METHODS: The authors conducted an observational cross-sectional study that focused on adult patients aged 45 to 97 years recruited from the Northwest Practice-based REsearch Collaborative in Evidence-based DENTistry research network (N = 775). The outcome variable was any root caries experience (no/yes). The authors hypothesized that sociodemographic, intra- oral and behavioral factors were root caries correlates. The authors used Poisson regression models to generate overall and age-stratified prevalence ratios (PRs) of root caries, and they used generalized estimating equations to account for practice-level clustering of participants. RESULTS: A total of 19.6 percent of adults had any root caries. A dentist's assessment that the patient was at high risk of developing any caries was associated with greater prevalence of root caries experience in both middle-aged adults (PR, 2.70; 95 percent confidence interval [CI], 1.63-4.46) and older adults (PR, 1.87; 95 percent CI, 1.19-2.95). The following factors were associated significantly with increased root caries prevalence but only for middle-aged adults: male sex (P = .02), self reported dry mouth (P < .001), exposed roots (P = .03) and increased frequency of eating or drinking between meals (P = .03). No other covariates were related to root caries experience for older adults. CONCLUSIONS: Within a practice-based research network, the factors associated with root caries experience were different for middle-aged adults than they were for older adults. Research is needed to identify relevant root caries correlates for adults 65 years and older. Practical Implications. Interventions aimed at preventing root caries are likely to be different for middle-aged adults than for older adults. Dentists should use root caries prevention programs that address appropriate aged-based risk factors. PMID- 23633702 TI - Smokers may experience poorer bone regeneration than nonsmokers after periodontal treatment. PMID- 23633700 TI - An evaluation of 10 percent and 20 percent benzocaine gels in patients with acute toothaches: efficacy, tolerability and compliance with label dose administration directions. AB - BACKGROUND: The authors evaluated the efficacy and tolerability of 10 percent and 20 percent benzocaine gels compared with those of a vehicle (placebo) gel for the temporary relief of toothache pain. They also assessed the compliance with the label dose administration directions on the part of participants with toothache pain. METHODS: Under double-masked conditions, 576 participants self-applied study gel to an open tooth cavity and surrounding oral tissues. Participants evaluated their pain intensity and pain relief for 120 minutes. The authors determined the amount of gel the participants applied. RESULTS: The responders' rates (the primary efficacy parameter), defined as the percentage of participants who had an improvement in pain intensity as exhibited by a pain score reduction of at least one unit on the dental pain scale from baseline for two consecutive assessments any time between the five- and 20-minute points, were 87.3 percent, 80.7 percent and 70.4 percent, respectively, for 20 percent benzocaine gel, 10 percent benzocaine gel and vehicle gel. Both benzocaine gels were significantly (P <= .05) better than vehicle gel; the 20 percent benzocaine gel also was significantly (P <= .05) better than the 10 percent benzocaine gel. The mean amount of gel applied was 235.6 milligrams, with 88.2 percent of participants applying 400 mg or less. CONCLUSIONS: Both 10 percent and 20 percent benzocaine gels were more efficacious than the vehicle gel, and the 20 percent benzocaine gel was more efficacious than the 10 percent benzocaine gel. All treatments were well tolerated by participants. Practical Implications. Patients can use 10 percent and 20 percent benzocaine gels to temporarily treat toothache pain safely. PMID- 23633703 TI - What are the ethical implications of having more than one fee schedule? PMID- 23633704 TI - Salivary characteristics and dental caries: evidence from general dental practices. AB - BACKGROUND: Saliva is one of the intraoral host factors that influence caries development. The authors conducted a study to investigate whether salivary characteristics are associated with recent dental caries experience. METHODS: Dentist-investigators and dental staff members collected data pertaining to a two year cumulative incidence of dental caries (previous 24 months) and salivary characteristics during baseline assessment in an ongoing longitudinal study. The systematic random sample consisted of patients (n = 1,763) visiting general dental practices (n = 63) within the Northwest Practice-based REsearch Collaborative in Evidence-based DENTistry (PRECEDENT). The authors estimated adjusted rate ratios (RRs) by using generalized estimating equations log-linear regression to relate salivary characteristics to coronal carious lesions into dentin. RESULTS: Low resting pH (<= 6.0) in the overall sample and low stimulated salivary flow rate (<= 0.6 milliliter/minute) in older adults (>= 65 years old) were associated with increased dental caries (RR, 1.6; 95 percent confidence interval [CI], 1.1-2.2; RR, 2.4; 95 percent CI, 1.5-3.8, respectively). Low buffering capacity was associated with decreased dental caries in children and adolescents (RR, 0.3; 95 percent CI, 0.1-1.0; RR, 0.2; 95 percent CI, 0.1-0.7, respectively). A thick, sticky or frothy salivary consistency also was associated with decreased dental caries in adults (RR, 0.6; 95 percent CI, 0.4-1.0). Associations between other salivary characteristics and dental caries for the overall sample and within each age group were not statistically significant. CONCLUSIONS: Salivary characteristics were associated weakly with previous dental caries experience, but the authors did not find consistent trends among the three age groups. Different salivary characteristics were associated with an increased caries experience in older adults and a lowered caries experience in children and adolescents and adults. Practical Implications. Further investigations are needed in this population setting to understand the study's conflicting results. The study findings cannot support the use of salivary tests to determine caries risk in actual clinical settings. PMID- 23633705 TI - Race/Ethnic and Nativity Disparities in Child Overweight in the United States and England. AB - Child overweight is a growing problem in wealthy countries. There is also evidence that child overweight varies by race/ethnicity and socioeconomic status. In this article, the authors use data from two recent birth cohort studies in the United States and England to address four questions: (1) Are race/ethnic and immigrant status associated with child overweight? (2) Is the association between socioeconomic status and child overweight similar across race/ethnic and nativity subgroups? (3) Does the age of immigrant mothers at migration moderate the association between immigrant status and child overweight? and (4) Does maternal obesity mediate the association between race/ethnicity and nativity and child overweight? Findings indicate that (1) race/ethnicity and immigrant status are risk factors for child overweight in both countries, (2) the influence of socioeconomic status differs by subgroup, (3) mother's age at migration does not moderate the association, and (4) mother's obesity mediates some of the race/ethnic disparities in child overweight. PMID- 23633706 TI - "Convenience" euthanasia -- a comment. PMID- 23633707 TI - "Convenience" euthanasia -- a comment. PMID- 23633708 TI - Member wellness -- the art of maintaining your sanity. PMID- 23633709 TI - Veterinary medical ethics. An ethicist's commentary on prolonging the life of cancer patient. PMID- 23633710 TI - Explanatory model of cattle death by starvation in Manitoba: forensic evaluation. AB - Cattle death by starvation is a persistent annual event in Manitoba. Herds with more than 10% overwinter death loss are usually identified in the late winter or early spring. Field and postmortem findings suggest that there is complete mobilization of fat followed by inability to maintain adequate thermoregulation and death by cardiac arrest. Carcasses show only mild evidence of muscle catabolism and are in excellent preservation if located prior to or around the time of spring thaw. A forensic diagnosis of death by starvation-induced exposure can be made with a high level of confidence when considering field data, whole carcass appearance, and postmortem evaluation of residual fat stores. PMID- 23633711 TI - Owner-perceived signs and veterinary diagnosis in 50 cases of feline osteoarthritis. AB - Veterinarians contacted to identify cats diagnosed with osteoarthritis (OA) provided information on signalment, method of diagnosis, treatment and concurrent disease. Owners of 50 cats were interviewed to collect information on specific OA signs observed in the home, relating to mobility, self-maintenance, social and exploratory behavior, and activity and habits at diagnosis and after treatment. Mean age at diagnosis was 12 y; concurrent diseases were common (44%). Owner reported abnormalities led to OA diagnosis in most cases; either as the primary finding (30%), or combined with abnormal physical examination or radiographic findings (64%). Owners frequently reported changes in mobility, particularly gait, jumping, and use of stairs. Oral or injectable disease-modifying osteoarthritis drugs were the most common treatments (71%). Feline OA diagnosis and therapeutic monitoring appear to rely heavily on owner-perceived signs; physical examination abnormalities may not be detected. Questioning of owners revealed various observable signs potentially useful in OA detection and monitoring. PMID- 23633712 TI - Ultrasound-guided percutaneous antegrade pyelography with computed tomography for the diagnosis of spontaneous partial ureteral rupture in a dog. AB - A 10-year-old spayed female dalmatian dog developed acute vomiting and abdominal pain. Ultrasound examination of the abdomen showed right hydronephrosis and proximal ureter dilation with mild retroperitoneal free fluid. Computed tomography (CT) of the abdomen confirmed the ultrasonographic findings and revealed, additionally, a right ureteral stone. Spontaneus rupture of the right ureter was confirmed with CT post ultrasound-guided percutaneous antegrade pyelography. Pyeloureteral rupture and the presence of a ureteral stone were confirmed at surgery. PMID- 23633714 TI - An unusual case of urinary incontinence in an intersex West Highland white terrier. AB - A 5-year-old neutered female West Highland white terrier dog was presented with a history of congenital urinary incontinence that had become refractory to medical management. Complex urogenital anomalies including urethrovestibular and vestibuloperineal fistulae with low vulvar position along with a penoclitoris were present. Vaginectomy with perineal urethral reconstruction resolved the incontinence. PMID- 23633713 TI - Spontaneous intradural disc herniation with focal distension of the subarachnoid space in a dog. AB - Myelo-computed tomography of a paraparetic 14-year-old dog revealed subarachnoid distension with an intradural filling defect above the T13-L1 disc space. T12-L1 hemilaminectomy followed by durotomy allowed removal of a large piece of degenerated disc material that compressed the spinal parenchyma. Full return to function was achieved 10 days post-surgery. The distension was likely secondary to the intradural herniation, and is a rare and distinct finding. PMID- 23633715 TI - Premature parturition, edema, and ascites in an alpaca infected with Anaplasma phagocytophilum. AB - An 8-year-old alpaca was presented for fever, anorexia, edema, ascites, and premature parturition. She was determined to have Anaplasma phagocytophilum infection based on positive blood polymerase chain reaction (PCR) and positive acute and convalescent serum titers. Antibiotics and supportive therapies were administered and the alpaca made a complete recovery. PMID- 23633716 TI - Putative peanut allergy-induced urticaria in a dog. AB - A 9-year-old, spayed male schnauzer dog was presented with vomiting, diarrhea, generalized erythema, pruritic urticaria and conjunctival hyperemia after ingestion of peanut. The history, clinical signs, and histopathology of the lesions were compatible with a hypersensitivity reaction. The clinical signs resolved rapidly after treatment with prednisolone and antihistamine. This is the first report of urticaria caused by peanut ingestion in a dog. PMID- 23633717 TI - Necrotizing fasciitis caused by methicillin-resistant Staphylococcus pseudintermedius at a previously irradiated site in a dog. AB - A great Dane dog was presented with a small, superficial wound on the left tarsus that rapidly progressed to a large necrotic area. The dog had undergone radiation therapy in the left tarsal region 33 months previously. Necrotizing fasciitis was diagnosed on histopathological examination, and bacterial culture revealed methicillin-resistant Staphylococcus pseudintermedius. PMID- 23633718 TI - Granulomatous giant cell submandibular sialadenitis in a dog. AB - A 4-month-old dog was presented with a progressive swelling of the submandibular area. The history, course, cytological, and sialographic findings were consistent with an aseptic pyogranulomatous sialadenitis with concurrent duct blockage. This rare entity, responsive to medical treatment, appears to be similar to the granulomatous giant cell sialadenitis of humans. PMID- 23633719 TI - Primary peri-aortic hemangiosarcoma in a dog. AB - A 10-year-old intact male Norwich terrier dog was evaluated for progressive, intermittent increased respiratory effort. Thoracic radiographs, ultrasonography, and computed tomography were used to identify a caudodorsal thoracic extrapulmonary mass and the presence of pulmonary metastasis. Blood transfusion and stabilization measures were not successful and the patient died. Necropsy confirmed the origin of the mass to be the adventitial layer of the aorta and determined it to be hemangiosarcoma. This is a rare site for the primary lesion. PMID- 23633721 TI - Diagnostic ophthalmology. PMID- 23633720 TI - Infectious canine hepatitis associated with prednisone treatment. AB - An 11-week-old, female Alaskan husky dog housed outdoors in the Yukon, Canada, was diagnosed with infectious canine hepatitis. The predisposing factors in this puppy for such a rare disease included inappropriate vaccination program, potential contact with endemic wildlife, and immunosuppression due to prednisone treatment. PMID- 23633722 TI - Practices values fall. PMID- 23633723 TI - Tobacco Industry Influence on the American Law Institute's Restatements of Torts and Implications for Its Conflict of Interest Policies. AB - The American Law Institute ("ALI") is a prestigious and influential organization that creates treatises on the current state of the law, including "Restatements" of case law that guide judicial decisions and legislation. This paper uses previously secret tobacco industry documents made available as the result of state and federal litigation against the industry to describe how the tobacco companies, acting both indirectly through their trade organization, the Tobacco Institute, and directly, using influential lawyers, quietly influenced the ALI's writing of the Restatements. The tobacco industry's ease of access to the ALI calls into question the Institute's independence, the preparation of major policy documents such as the Restatements, as well as the Institute's ability to monitor and control conflicts of interest. The ALI's conflict of interest policies lag behind comparable organizations such as the National Academy of Sciences and the Institute of Medicine, and are insufficient to protect Institute projects from significant outside influence. Because of the undisclosed influence of the tobacco industry over the ALI, courts and legislatures should not apply the principles embodied in the Restatements in tort cases against the tobacco companies for injuries suffered from tobacco use. Until the ALI implements strong conflict of interest policies to ensure independence from private-interest manipulation, courts and legislatures should not rely on Institute reports and recommendations as neutral scholarly summaries of the law that should guide judicial and legislative decision-making. PMID- 23633724 TI - Effect of the Pt buffer layer on perpendicular exchange bias based on collinear/non-collinear coupling in a Cr2O3/Co3Pt interface. AB - In this study, we fabricated a Cr2O3 (0001) film without and with a Pt buffer layer and investigated its effect on perpendicular exchange coupling in a Cr2O3/Co3Pt interface. The results showed that the exchange bias field (MU0Hex) and blocking temperature (TB) of a Cr2O3 film without and with Pt were very different. The Cr2O3 film without Pt had a lower MU0Hex of 176 Oe and a lower TB of 75 K, whereas that with Pt had a higher MU0Hex of 436 Oe and a higher TB of 150 K. We discussed this difference in MU0Hex and TB values based on collinear/non-collinear coupling in a ferromagnetic and antiferromagnetic interface using Meiklejohn and Bean's exchange anisotropy model. PMID- 23633725 TI - A message from the editor. PMID- 23633727 TI - The face of occupational safety and health: 2020 and beyond. PMID- 23633728 TI - Achieving pharmacy-based public health: a call for public health engagement. PMID- 23633729 TI - Risk of substance abuse and dependence among young adult sexual minority groups using a multidimensional measure of sexual orientation. AB - OBJECTIVE: We examined associations between two definitions of sexual minority status (SMS) and substance abuse and/or dependence among young adults in a national population. METHODS: A total of 14,152 respondents (7,529 women and 6,623 men) interviewed during wave four of the National Longitudinal Study of Adolescent Health were included in the study (age range: 24-32 years). We used two definitions of SMS based on self-reported attraction, behavior, and identity: 1-indicator SMS (endorsing any dimension) and 3-indicator SMS (endorsing all dimensions). Outcomes included nicotine dependence as well as >=3 signs of substance dependence, any sign of substance abuse, and lifetime diagnosis of abuse or dependence for alcohol, marijuana, and a composite measure of other drugs. Weighted logistic regression models were fit to estimate the odds of each outcome for each of the sexual minority groups (compared with the heterosexual majority), controlling for sociodemographic covariates. RESULTS: SMS women were more likely than exclusively heterosexual women to experience substance abuse and dependence, regardless of substance or SMS definition. In adjusted models for women, 3-indicator SMS was most strongly associated with abuse/dependence (adjusted odds ratio [AOR] range: 2.74-5.17) except for >=3 signs of cannabis dependence, where 1-indicator SMS had the strongest association (AOR=3.35). For men, the 1-indicator SMS group had higher odds of nicotine dependence (AOR=1.35) and the 3-indicator SMS group had higher odds of >=3 signs of alcohol dependence (AOR=1.64). CONCLUSIONS: Young adult female sexual minority groups, regardless of how defined, are at a higher risk than their heterosexual peers of developing alcohol, drug, or tobacco abuse and dependence. PMID- 23633730 TI - Correlates of HIV risk behaviors among homeless and unstably housed young adults. AB - OBJECTIVES: Homeless young adults are exposed to multiple risk factors for HIV infection. We identified HIV risk behaviors and their correlates among homeless young adults in Portland, Oregon. METHODS: We conducted a community-based, cross sectional survey of HIV risk behaviors among homeless young adults aged 18-25 years in 2010. Participants completed three study components: (1) an interviewer administered survey of HIV risk behaviors; (2) a brief, client-centered HIV risk based counseling session; and (3) rapid HIV testing. RESULTS: Among 208 participants, 45.8% identified as racial/ethnic minority groups, 63.8% were male, and 35.7% self-identified as nonheterosexual. Six participants, all from sexual minority groups, had positive HIV screening results (two newly identified, four previously known) for a seropositivity rate of 2.9%. Female sex, belonging to a sexual minority group, frequent traveling between cities, depression, and alcohol use to intoxication were significantly associated with unprotected sex in univariate analysis. Female sex and high perceived risk of HIV were significantly associated with unprotected sex in multivariate analysis. CONCLUSIONS: Our findings support the need for enhanced HIV prevention interventions for homeless young adults. PMID- 23633731 TI - HIV screening practices and hospital characteristics in the US, 2009-2010. AB - OBJECTIVES: The Centers for Disease Control and Prevention recommends HIV screening in U.S. health-care settings unless providers document a yield of undiagnosed HIV infections of <1 per 1,000 population. However, implementation of this guidance has not been widespread and little is known of the characteristics of hospitals with screening practices in place. We assessed how screening practices vary with hospital characteristics. METHODS: We used a national hospital survey of HIV testing practices, linked to HIV prevalence for the county, parish, borough, or city where the hospital was located, to assess HIV screening of some or all patients by hospitals. We used multivariate logistic regression analysis to assess the association between screening practices and hospital characteristics that were significantly associated with screening in bivariate analyses. RESULTS: Of 376 hospitals in areas of prevalence >=0.1%, only 25 (6.6%) reported screening all patients for HIV and 131 (34.8%) reported screening some or all patients. Among 638 hospitals included, screening some or all patients was significantly (p<0.05) more common at teaching hospitals, hospitals with higher numbers of annual admissions, and hospitals with a high proportion of Medicaid admissions. In multivariable analysis, screening some or all patients was independently associated with admitting more than 15% of Medicaid patients and receiving resources or reimbursement for screening tests. CONCLUSION: We found that few hospitals surveyed reported screening some or all patients, and failure to screen is common across all types of hospitals in all regions of the country. Expanded reimbursement for screening may increase compliance with the recommendations. PMID- 23633732 TI - Cardiovascular disease among Black Americans: comparisons between the U.S. Virgin Islands and the 50 U.S. states. AB - OBJECTIVES: Consistent findings show that black Americans have high rates of cardiovascular disease (CVD) and related behavioral risk factors. Despite this body of work, studies on black Americans are generally limited to the 50 U.S. states. We examined variation in CVD and related risk factors among black Americans by comparing those residing within the U.S. Virgin Islands (USVI) with those residing in the 50 U.S. states and Washington, D.C. (US 50/DC) and residing in different regions of the US 50/DC (Northeast, Midwest, South, and West). METHODS: Using data from the 2007 and 2009 Behavioral Risk Factor Surveillance System, we compared CVD and CVD risk factor prevalence in non-Hispanic black people (>=20 years of age) in the USVI and US 50/DC, examining the relative contributions of health behaviors, health insurance, and socioeconomic status (SES). RESULTS: Accounting for age, sex, education, health insurance, and health behaviors, US 50/DC black Americans were significantly more likely than USVI black people to report ever having a stroke and coronary heart disease, and to be hypertensive, diabetic, or obese. While there was heterogeneity by region, similar patterns emerged when comparing the USVI with different regions of the US 50/DC. CONCLUSION: USVI black people have lower CVD and risk factor prevalence than US 50/DC black people. These lower rates are not explained by differences in health behaviors or SES. Understanding health in this population may provide important information on the etiology of racial/ethnic variation in health in the U.S. and elsewhere, and highlight relevant public health policies to reduce racial/ethnic group disparities. PMID- 23633733 TI - Estimates of smoking before and during pregnancy, and smoking cessation during pregnancy: comparing two population-based data sources. AB - OBJECTIVES: We compared three measures of maternal smoking status--prepregnancy, during pregnancy, and smoking cessation during pregnancy-between the Pregnancy Risk Assessment Monitoring System (PRAMS) questionnaire and the 2003 revised birth certificate (BC). METHODS: We analyzed data from 10,485 women with live births in eight states from the 2008 PRAMS survey, a confidential, anonymous survey administered in the postpartum period that is linked to select BC variables. We calculated self-reported prepregnancy and prenatal smoking (last trimester only) prevalence based on the BC, the PRAMS survey, and the two data sources combined, and the percentage of smoking cessation during pregnancy based on the BC and PRAMS survey. We used two-sided t-tests to compare BC and PRAMS estimates. RESULTS: Prepregnancy smoking prevalence estimates were 17.3% from the BC, 24.4% from PRAMS, and 25.4% on one or both data sources. Prenatal smoking prevalence estimates were 11.3% from the BC, 14.0% from PRAMS, and 15.2% on one or both data sources. The percentages of prepregnancy smokers who indicated that they quit smoking by the last trimester were 35.1% from the BC and 42.6% from PRAMS. The PRAMS estimates of prepregnancy and prenatal smoking, and smoking cessation during pregnancy were statistically higher than the corresponding BC estimates (t-tests, p<0.05). CONCLUSIONS: PRAMS captured more women who smoked before and during the last trimester than the revised BC. States implementing PRAMS and the revised BC should consider information from both sources when developing population-based estimates of smoking before pregnancy and during the last trimester of pregnancy. PMID- 23633734 TI - Preschool vision screening in primary care pediatric practice. AB - OBJECTIVES: We determined the efficacy of pediatric-based preschool vision screening, as knowledge of vision screening effectiveness in primary care pediatrics is incomplete. METHODS: Pediatricians and staff at nine primary care pediatric practices were trained in vision screening, and practices screened children aged 3-5 years from May 2007 through July 2008. Children failing or considered untestable were referred for pediatric ophthalmology examinations. We determined rates of testability, failure, referral, and ophthalmologic examination completion, as well as positive predictive values (PPVs) of screening failure and untestability. We also surveyed practices to assess the ease and accuracy of preschool vision screening. RESULTS: Of 2,933 children screened, 93 (3.2%) failed the vision screening and 349 (11.9%) were untestable. Untestability was highest (27.1%) among 3-year-olds. The PPV for failing any aspect of the vision screening was 66.7%; for children aged 3, 4, and 5 years, the PPVs for failing were 30.0%, 77.8%, and 87.5%, respectively. However, only 38.7% of children who failed the vision screening received ophthalmologic examinations, despite multiple follow-up attempts. Pediatricians rated the ease and accuracy of screening 3-year-old children lower than for screening older children. CONCLUSIONS: Visual acuity-based screening had good PPV for vision loss for 4- and 5-year-old children but was less successful for 3-year-olds. Rates of referral and ophthalmologic examination completion were low, especially among children from low-income families. PMID- 23633735 TI - Partners in immunization: 2010 survey examining differences among H1N1 vaccine providers in Washington state. AB - OBJECTIVES: Emergency response involving mass vaccination requires the involvement of traditional vaccine providers as well as other health-care providers, including pharmacists, obstetricians, and health-care providers at correctional facilities. We explored differences in provider experiences administering pandemic vaccine during a public health emergency. METHODS: We conducted a cross-sectional survey of H1N1 vaccine providers in Washington State, examining topics regarding pandemic vaccine administration, participation in preparedness activities, and communication with public health agencies. We also examined differences among provider types in responses received (n=619, 80.9% response rate). RESULTS: Compared with other types of vaccine providers (e.g., family practitioners, obstetricians, and specialists), pharmacists reported higher patient volumes as well as higher patient-to-practitioner ratios, indicating a broad capacity for community reach. Pharmacists and correctional health-care providers reported lower staff coverage with seasonal and H1N1 vaccines. Compared with other vaccine providers, pharmacists were also more likely to report relying on public health information from federal sources. They were less likely to report relying on local health departments (LHDs) for pandemic-related information, but indicated a desire to be included in LHD communications and plans. While all provider types indicated a high willingness to respond to a public health emergency, pharmacists were less likely to have participated in training, actual emergency response, or surge capacity initiatives. No obstetricians reported participating in surge capacity initiatives. CONCLUSIONS: Results from this survey suggest that efforts to increase communication and interaction between public health agencies and pharmacy, obstetric, and correctional health-care vaccine providers may improve future preparedness and emergency response capability and reach. PMID- 23633736 TI - Using GIS and secondary data to target diabetes-related public health efforts. AB - OBJECTIVES: To efficiently help communities prevent and manage diabetes, health departments need to be able to target populations with high risk but low resources. To aid in this process, we mapped county-level diabetes-related rates and resources/use using publicly available secondary data to identify Michigan counties with high diabetes prevalence and low or no medical and/or community resources. METHODS: We collected county-level diabetes-related rates and resources from Web-based sources and mapped them using geographic information systems (GIS) software. Data included age-adjusted county diabetes rates, diabetes-related medical resource and resource use (i.e., the number of endocrinologists and percentage of Medicare patients with diabetes who received hemoglobin A1c testing in the past year), community resources (i.e., the number of certified diabetes self-management education and diabetes support groups), as well as population estimates and demographics (e.g., rural residence, education, poverty, and race/ethnicity). We created GIS maps highlighting areas that had higher-than-median rates of disease and lower-than-median resources. We also conducted linear, logistic, and Poisson regression analyses to confirm GIS findings. RESULTS: There were clear regional trends in resource distribution across Michigan. The 15 counties in the Upper Peninsula were lacking in medical resources but higher in community resources compared with the 68 counties in the Lower Peninsula. There was little apparent association between need (diabetes prevalence) and diabetes-related resources/use. Specific counties with high diabetes prevalence and low resources were easily identified using GIS mapping. CONCLUSION: Using public data and mapping tools identified diabetes health service shortage areas for targeted public health programming. PMID- 23633737 TI - Correlation between aerial insecticide spraying to interrupt west nile virus transmission and emergency department visits in Sacramento County, California. AB - OBJECTIVES: Insecticides reduce vector-borne pathogen transmission but also pose health risks. In August 2005, Sacramento County, California, underwent emergency aerial ultralow-volume (ULV) application of pyrethrin insecticide to reduce the population of West Nile virus (WNV)-infected mosquitoes and thereby interrupt enzootic and tangential transmission. We assessed the association between aerially applied pyrethrin insecticide and patterns of emergency department (ED) visit diagnoses. METHODS: We used geographic information systems software to determine ZIP Code-level exposure to pyrethrin. We used logistic regression models to examine the relationship between exposure status and three-digit International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes (785 in total) for all ED visits (n=253,648) within Sacramento County in 2005 and for specific diagnostic clusters (e.g., respiratory, gastrointestinal, skin, eye, and neurologic). All models were adjusted for age, gender, race/ethnicity (individual level), median income, ozone, and temperature (ZIP Code level). RESULTS: Exposure to aerially applied insecticide was not associated with clusters of respiratory, gastrointestinal, skin, eye, and neurologic complaints in adjusted models but was inversely associated with ICD-9 CM code 799 ("other ill-defined morbidity and mortality"), with adjusted odds ratios (AORs) ranging from 0.31 to 0.36 for 0-3 lag days (95% confidence interval 0.17, 0.68). Spraying was also directly associated with ICD-9-CM code 553 ("other abdominal hernia"), with AORs ranging from 2.34 to 2.96 for 2-3 lag days. CONCLUSIONS: The observed significant ICD-9-CM code associations likely represented chance findings. Aerial ULV pyrethrin applications were not associated with ED visits for specific diagnoses or clusters of diagnoses. PMID- 23633739 TI - Health system transformation and the role of health information law. PMID- 23633741 TI - Weight Loss and obstructive sleep apnea: what lies AHEAD? PMID- 23633742 TI - Prefrontal dysfunction in obstructive sleep apnea: a biomarker of disease severity? PMID- 23633743 TI - Nonrestorative sleep: a new perspective. PMID- 23633744 TI - A new pharmacological treatment to treat obstructive sleep apnea? PMID- 23633745 TI - The brain in obstructive sleep apnea: the chickens coming home to roost? PMID- 23633746 TI - Long-term effect of weight loss on obstructive sleep apnea severity in obese patients with type 2 diabetes. AB - STUDY OBJECTIVES: To examine whether the initial benefit of weight loss on obstructive sleep apnea (OSA) severity at 1 year is maintained at 4 years. DESIGN: Randomized controlled trial with follow-up at 1, 2, and 4 years. SETTING: 4 Look AHEAD clinical centers. PARTICIPANTS: Two hundred sixty-four obese adults with type 2 diabetes and OSA. INTERVENTIONS: Intensive lifestyle intervention with a behavioral weight loss program or diabetes support and education. MEASUREMENTS: Change in apnea-hypopnea index on polysomnogram. RESULTS: The intensive lifestyle intervention group's mean weight loss was 10.7 +/- 0.7 (standard error), 7.4 +/- 0.7, and 5.2 +/- 0.7 kg at 1, 2, and 4 years respectively, compared to a less than 1-kg weight loss for the control group at each time (P < 0.001). Apnea-hypopnea index difference between groups was 9.7 +/- 2.0, 8.0 +/- 2.0, and 7.7 +/- 2.3 events/h at 1, 2 and 4 years respectively (P < 0.001). Change in apnea-hypopnea index over time was related to the amount of weight loss (P < 0.0001) and intervention, independent of weight loss (P = 0.001). Remission of OSA at 4 years was 5 times more common with intensive lifestyle intervention (20.7%) than diabetes support and education (3.6%). CONCLUSIONS: Among obese adults with type 2 diabetes and OSA, intensive lifestyle intervention produced greater reductions in weight and apnea-hypopnea index over a 4 year period than did diabetes support and education. Beneficial effects of intensive lifestyle intervention on apneahypopnea index at 1 year persisted at 4 years, despite an almost 50% weight regain. Effect of intensive lifestyle intervention on apnea-hypopnea index was largely, but not entirely, due to weight loss. PMID- 23633747 TI - Altered resting-state brain activity in obstructive sleep apnea. AB - STUDY OBJECTIVES: Structural and functional brain changes may contribute to neural dysfunction in patients with obstructive sleep apnea (OSA). However, the effect of OSA on resting-state brain activity has not been established. The objective of this study was to investigate alterations in resting-state functional connectivity (rsFC) of the common brain networks in patients with OSA and their relationships with changes in gray matter volume (GMV) in the corresponding brain regions. DESIGNS: Resting-state functional and structural MRI data were acquired from patients with OSA and healthy controls. Seven brain networks were identified by independent component analysis. The rsFC in each network was compared between groups and the GMV of brain regions with significant differences in rsFC was also compared. SETTING: University hospital. PATIENTS AND PARTICIPANTS: Twenty-four male patients with untreated OSA and 21 matched healthy controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: OSA specifically affected the cognitive and sensorimotor-related brain networks but not the visual and auditory networks. The medial prefrontal cortex and left dorsolateral prefrontal cortex (DLPFC) showed decreased rsFC and GMV in patients with OSA, suggesting structural and functional deficits. The right DLPFC and left precentral gyrus showed decreased rsFC and unchanged GMV, suggesting a functional deficit. The right posterior cingulate cortex demonstrated increased rsFC and unchanged GMV, suggesting functional compensation. In patients with OSA, the rsFC of the right DLPFC was negatively correlated with the apnea-hypopnea index. CONCLUSIONS: OSA specifically affects resting-state functional connectivity in cognitive and sensorimotor-related brain networks, which may be related to the impaired cognitive and motor functions in these patients. PMID- 23633748 TI - Mirtazapine provokes periodic leg movements during sleep in young healthy men. AB - STUDY OBJECTIVES: Recent evidence suggests that certain antidepressants are associated with an increase of periodic leg movements (PLMS) that may disturb sleep. So far, this has been shown in patients clinically treated for depression and in cross-sectional studies for various substances, but not mirtazapine. It is unclear whether antidepressants induce the new onset of PLMS or only increase preexisting PLMS, and whether this is a general property of the antidepressant or only seen in depressed patients. We report here the effect of mirtazapine on PLMS in young healthy men. DESIGN: Open-labeled clinical trial (NCT00878540) including a 3-week preparatory phase with standardized food, physical activity, and sleep wake behavior, and a 10-day experimental inpatient phase with an adaptation day, 2 baseline days, and 7 days with mirtazapine. SETTING: Research institute. PARTICIPANTS: Twelve healthy young (20-25 years) men. INTERVENTIONS: Seven days of nightly intake (22:00) of 30 mg mirtazapine. MEASUREMENTS AND RESULTS: Sleep was recorded on 2 drug-free baseline nights, the first 2 drug nights, and the last 2 drug nights. Eight of the 12 subjects showed increased PLMS after the first dose of mirtazapine. Frequency of PLMS was highest on the first drug night and attenuated over the course of the next 6 days. Three subjects reported transient restless legs symptoms. CONCLUSIONS: Mirtazapine provoked PLMS in 67% of young healthy males. The effect was most pronounced in the first days. The possible role of serotonergic, noradrenergic and histaminergic mechanisms in mirtazapine-induced PLMS is discussed. PMID- 23633750 TI - Associations of self-reported sleep duration and snoring with colorectal cancer risk in men and women. AB - STUDY OBJECTIVES: We assessed the relationship between sleep duration, snoring and colorectal cancer risk. DESIGN: Prospective cohort studies. SETTING: United States. PARTICIPANTS: A total of 30,121 men aged 41 to 79 years in the Health Professionals Follow-up Study and 76,368 women aged 40 to 73 years in the Nurses' Health Study. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We queried information on sleep duration and snoring in 1986/87. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs, 95% CIs). We documented 1,973 incident colorectal cancer cases (709 men and 1,264 women) over a 22-year follow-up period. Compared to sleep an average 7 h, >= 9 h of sleep was significantly associated with a higher risk of colorectal cancer among men (HR = 1.35, 95% CI: 1.00, 1.82), and to a lesser degree, among women (HR = 1.11, 95% CI: 0.85, 1.44). The risk associated with longer sleep was restricted to individuals who regularly snored (men: HR = 1.80, 95% CI: 1.14, 2.84; women: HR = 2.32, 95% CI: 1.24, 4.36) and to overweight individuals (i.e., BMI >= 25 kg/m2) (men: HR = 1.52, 95% CI: 1.04, 2.21; women: HR = 1.37, 95% CI: 0.97, 1.94). Short sleep duration (<= 5 h) was not associated with an increased risk of colorectal cancer in the entire sample or in subgroups stratified by snoring or BMI. CONCLUSIONS: Longer sleep duration was associated with an increased risk of developing colorectal cancer among individuals who were overweight or snored regularly. This observation raises the possibility that sleep apnea and its attendant intermittent hypoxemia may contribute to cancer risk. PMID- 23633751 TI - Caenorhabditis-in-drop array for monitoring C. elegans quiescent behavior. AB - STUDY OBJECTIVES: To develop a method, called Caenorhabditis-in-Drop (CiD), encapsulating single worms in aqueous drops, for parallel analysis of behavioral quiescence in C. elegans nematodes. DESIGN: We designed, constructed, and tested a device that houses an array of aqueous droplets laden with individual worms. The droplets are separated and covered by immiscible, biocompatible oil. We modeled gas exchange across the aqueous/oil interface and tested the viability of the encapsulated animals. We studied the behavior of wild-type animals; of animals with a loss of function mutation in the cGMP-dependent protein kinase gene egl-4; of animals with a loss of function mutation in the gene kin-2, which encodes a cAMP-dependent protein kinase A regulatory subunit; of animals with a gain-of-function mutation in the gene acy-1, which encodes an adenylate cyclase; and of animals that express high levels of the EGF protein encoded by lin-3. MEASUREMENTS AND RESULTS: We used CiD to simultaneously monitor the behavior of 24 worms, a nearly 5-fold improvement over the prior best methodology. In support of our gas exchange models, we found that worms remain viable on the chip for 4 days, past the 12-h period needed for observation, but show reduced longevity to that measured on an agar surface. Measurements of duration of lethargus quiescence and total leth-argus quiescence showed reduced amounts as well as reduced variability relative to prior methods. There was reduced lethargus quiescence in animals that were mutant for kin-2 and for acy-1, supporting a wake promoting effect of PKA in C. elegans, but no change in lethargus quiescence in egl-4 mutants. There was increased quiescence in animals that expressed kin-2 in the nervous system or over-expressed EGF. CONCLUSIONS: CiD is useful for the analysis of behavioral quiescence during lethargus as well as during the adult stage C. elegans. The method is expandable to parallel simultaneous monitoring of hundreds of animals and for other studies of long-term behavior. Using this method, we were successful in measuring, for the first time, quiescence in kin 2(ce179) and in acy-2(ce2) mutants, which are hyperactive. Our observations also highlight the impact of environmental conditions on quiescent behavior and show that longevity is reduced in CiD in comparison to agar surfaces. PMID- 23633749 TI - Differentiating nonrestorative sleep from nocturnal insomnia symptoms: demographic, clinical, inflammatory, and functional correlates. AB - STUDY OBJECTIVES: Recent studies have suggested that nonrestorative sleep (NRS) symptoms may be distinct from nocturnal insomnia symptoms (NIS). However, there is limited information on the demographic, medical, and biologic correlates of NRS independent from NIS in the general population. This report presents the sociodemographic correlates, patterns of comorbidity with other sleep and physical disorders, C-reactive protein (CRP) levels, and general productivity associated with NIS and NRS in a nationally representative sample of US adults. DESIGN: National Health and Nutrition Examination Survey (NHANES). SETTING: The 2005-2008 surveys of the general population in the United States. PARTICIPANTS: There were 10,908 individuals (20 years or older). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Respondents were classified by the presence or absence of NIS and NRS. Compared with those without insomnia symptoms, respondents with NIS were older and had lower family income and educational levels than those with NRS. In addition, there was a significant association between NIS and cardiovascular disease, whereas NRS was associated with other primary sleep disorders (including habitual snoring, sleep apnea, and restless legs syndrome), respiratory diseases (emphysema and chronic bronchitis), thyroid disease, and cancer as well as increased CRP levels. In addition, the study participants with NRS only reported poorer scores on the Functional Outcomes of Sleep Questionnaire (FOSQ) than those without insomnia symptoms or those with NIS only. CONCLUSIONS: These findings suggest that there are substantial differences between NIS and NRS in terms of sociodemographic factors, comorbidity with other sleep and physical disorders, increased CRP level, and functional impairment. An inflammatory response might play a unique role in the pathogenesis of NRS. PMID- 23633752 TI - Sensitization of upper airway mechanoreceptors as a new pharmacologic principle to treat obstructive sleep apnea: investigations with AVE0118 in anesthetized pigs. AB - STUDY OBJECTIVES: Drug treatment for obstructive sleep apnea (OSA) is desirable because at least 30% of patients do not tolerate continuous positive airway pressure (CPAP) treatment. The negative pressure reflex (NPR) involving superficially located mechanoreceptors in the upper airway (UA) is an important mechanism for UA patency inhibitable by topical UA anesthesia (lidocaine). The NPR may serve as a target for pharmacological intervention for a topical treatment of OSA. The objective was to determine the effect of pharmacological augmentation of the NPR on UA collapsibility. DESIGN: We developed a model of UA collapsibility in which application of negative pressures caused UA collapses in spontaneously breathing alpha-chloralose-urethane anesthetized pigs as indicated by characteristic tracheal pressure and air flow changes. SETTING: N/A. PATIENTS OR PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The potassium channel blocker AVE0118 administered topically to the UA in doses of 1, 3, and 10 mg per nostril sensitized the NPR, shifting the mechanoreceptor response threshold for the genioglossus muscle to more positive pressures (P < 0.001; n = 6 per group) and dose-dependently inhibited UA collapsibility. Ten mg of AVE0118 prevented UA collapses against negative pressures of -150 mbar (P < 0.01) for > 4 h in all pigs, while in control pigs the UA collapsed at -50 mbar or less negative pressures. The effect of AVE0118 was abolished by UA lidocaine anesthesia. Acute intravenous administration of naloxone or acetazolamide was ineffective; paroxetine and mirtazepine were weakly effective and fluoxetine was moderately effective in line with reported clinical efficacy. CONCLUSION: Topical administration of AVE0118 to the UA is a promising pharmacologic approach for the treatment of OSA. PMID- 23633753 TI - Obstructive sleep apnea as a risk factor for cerebral white matter change in a middle-aged and older general population. AB - STUDY OBJECTIVE: Obstructive sleep apnea (OSA) contributes to the development of systemic hypertension, and hypertension strongly predicts the development of white matter change (WMC). Thus, it is plausible that OSA mediates WMC. The goal of the current study is to determine whether a contextual relationship exists between OSA and cerebral WMC. DESIGN: Cross-sectional analyses conducted in a population-based study. SETTING: Korean community-based sample from the Korean Genome and Epidemiology Study (KoGES) who attended examinations in 2011 at a medical center. PARTICIPANTS: There were 503 individuals (mean +/- SD, age 59.63 +/- 7.48 y) who were free of previously diagnosed cardiovascular and neurologic diseases. MEASUREMENTS AND RESULTS: Participants underwent 1-night polysomnography and were classified as no OSA (obstructive apnea-hypopnea index [AHI] < 5, n = 289), mild OSA (AHI 5-15, n = 161), and moderate to severe OSA (AHI >= 15, n = 53). WMC was identified with brain magnetic resonance imaging (MRI) and was found in 199 individuals (39.56%). Multivariate logistic regression analyses adjusted for covariates revealed that moderate to severe OSA was significantly associated with the presence of WMC (odds ratio [OR] 2.08, 95%, confidence interval [CI] 1.05-4.13) compared with no OSA. Additional adjustment of hypertension to the model did not alter the significance of the association (OR 2.03, 95% CI 1.02-4.05). CONCLUSIONS: Moderate to severe OSA is an independent risk factor for WMC in middle-aged and older individuals. Thus, early recognition and treatment of OSA could reduce the risk of stroke and vascular dementia. PMID- 23633754 TI - Sleep disordered breathing and gestational hypertension: postpartum follow-up study. AB - BACKGROUND: Gestational hypertension (GH) is a newly recognized risk factor for adverse cardiovascular events later in life. Sleep disordered breathing (SDB) is an established risk factor for adverse cardiovascular events. Recent research has suggested that women with GH may have an increased rate of SDB during pregnancy, but it is not known if this higher rate of SDB persists into the postpartum state. OBJECTIVE: To assess whether women with GH continue to have an increased rate of SDB compared to healthy pregnant women, after the physiologic changes of pregnancy resolve. METHODS: We previously studied women with GH and uncomplicated pregnancies with sleep questionnaires and level 1 polysomnography. Participants were invited to participate in repeat testing 1-2 years postpartum. Respiratory disturbance index (RDI) differences were assessed. RESULTS: Eighteen subjects (11 GH and 7 healthy) had complete follow-up data available for comparison with antepartum data. This group was representative of the initial antepartum cohort. Women with GH experienced a decrease in mean RDI from antepartum to postpartum (12.0 +/- 12.3 vs. 2.9 +/- 2.9; P = 0.02). Healthy women did not experience the same change (2.8 +/- 5.3 vs. 2.1 +/- 3.2; P = 0.81). Postpartum comparisons showed the mean RDI of women with GH had decreased to be similar to that of healthy women (P = 0.75). CONCLUSIONS: SDB in women with gestational hypertension improved in the postpartum state to levels indistinguishable from our healthy subjects. This suggests that the physiologic effects of pregnancy may have had a pathologic role in the development of antepartum SDB in women with GH. PMID- 23633755 TI - Short sleep duration combined with obstructive sleep apnea is associated with visceral obesity in Korean adults. AB - STUDY OBJECTIVES: To determine whether short sleep duration alone or combined with obstructive sleep apnea (OSA) is associated with regional body fat including abdominal visceral fat area (VFA) among Korean adults. DESIGN: Cross-sectional study. SETTING: Ansan, South Korea. PARTICIPANTS: There were 838 community participants age 40-69 y from the Korean Genome and Epidemiology Study. MEASUREMENTS AND RESULTS: Subjective habitual sleep duration and OSA were defined based on a structured sleep questionnaire and a home portable sleep study, respectively. Abdominal VFA and hepatic fat components were assessed by computed tomography. Adjusted mean VFA and hepatic fat were highest in the shortest sleep duration group (< 5 h) and decreased linearly with increasing sleep duration. Individuals with OSA (apnea-hypopnea index >= 5) had a higher body mass index, waist circumference, percent body fat, VFA, and hepatic fat than those without OSA after adjusting for age and sex. The adjusted odds ratio (OR) for visceral obesity (VFA >= 100 cm2) was 2.05 (95% confidence interval [CI], 1.09-3.86) in individuals sleeping less than 5 h compared with those sleeping longer than 7 h, and 1.57 (95% CI, 1.08-2.26) in individuals with OSA compared with those without OSA, after adjusting for all confounding factors including body mass index. A combination of short sleep duration (< 5 h) and OSA substantially increased the OR for visceral obesity (OR, 4.40, 95% CI, 1.80-10.77) compared with those who slept longer (>= 7 h) without OSA. CONCLUSION: Short sleep duration and OSA are independently associated with visceral obesity in adults. The association is particularly strong in short sleepers with OSA. PMID- 23633757 TI - A randomized controlled trial of problem-solving therapy compared to cognitive therapy for the treatment of insomnia in adults. AB - STUDY OBJECTIVES: To compare the efficacy of problem-solving therapy (PST) combined with behavioral sleep strategies to standard cognitive therapy (CT) combined with behavioral sleep strategies in the treatment of insomnia. DESIGN: A six-week randomized controlled trial with one month follow-up. SETTING: The Australian National University Psychology Clinic, Canberra, Australia. PARTICIPANTS: Forty-seven adults aged 18-60 years recruited from the community meeting the Research Diagnostic Criteria for insomnia. INTERVENTIONS: Participants received 6 weeks of treatment including one group session (sleep education and hygiene, stimulus control instructions and progressive muscle relaxation) followed by 5 weeks of individual treatment of PST or CT. MEASUREMENTS AND RESULTS: Primary outcomes included sleep efficiency (SE) from sleep diaries, the Insomnia Severity Index (ISI), and the Pittsburgh Sleep Quality Index (PSQI). Secondary measures assessed dysfunctional sleep beliefs, problem-solving skills and orientations, and worry. Both treatments produced significant post therapy improvements in sleep which were maintained at 1 month follow-up (on SE Cohen d = 1.42, 95% CI 1.02-1.87 for PST; d = 1.26, 95% CI 0.81 1.65 for CT; on ISI d = 1.46, 95% CI 1.03-1.88 for PST; d = 1.95, 95% CI 0.52 2.38 for CT; for PSQI d = 0.97, 95% CI 0.55-1.40 for PST and d = 1.34, 95% CI 0.90-1.79 for the CT). There were no differences in PST and CT in the size or rate of improvement in sleep although CT produced a significant faster rate of decline in negative beliefs about sleep than PST and there was a trend (P = 0.08) for PST to produce a faster rate of improvement in negative problem orientation than CT. CONCLUSIONS: The results provide preliminary support for problem solving treatment as an equally efficacious alternative component to cognitive therapy in psychological interventions for insomnia. PMID- 23633756 TI - Insomnia does not appear to be associated with substantial structural brain changes. AB - STUDY OBJECTIVES: Sleep has been demonstrated to significantly modulate brain plasticity and the manifestation of mental disorders. However, previous studies on the effect of disrupted sleep on brain structure have reported inconsistent results. The goal of the current study was to investigate brain morphometry in a well-characterized large sample of patients with primary insomnia (PI) in comparison with good sleeper controls. DESIGN: Automated parcellation and pattern recognition approaches were supplemented by voxelwise analyses of gray and white matter volumes to analyze magnetic resonance images. All analyses included age, sex, and total intracranial volume as covariates. SETTING: Department of Psychiatry and Psychotherapy of the University of Freiburg Medical Center. PARTICIPANTS: There were 28 patients with PI (10 males; 18 females; age 43.7 +/- 14.2 y) and 38 healthy, good sleepers (17 males; 21 females; age 39.6 +/- 8.9 y). INTERVENTIONS: N/A. RESULTS: No significant between-group differences were observed in any of the investigated brain morphometry variables. CONCLUSIONS: Altered brain function in insomnia does not appear to have a substantial effect on brain morphometry on a macroscopic level. PMID- 23633758 TI - Regular exercise prevents sleep deprivation associated impairment of long-term memory and synaptic plasticity in the CA1 area of the hippocampus. AB - STUDY OBJECTIVES: The present study aimed to investigate the effects of treadmill exercise on sleep deprivation (S-D)-induced impairment of hippocampal dependent long-term memory, late phase long-term potentiation (L-LTP) and its signaling cascade in the cornu ammonis 1 (CA1) area. EXPERIMENTAL DESIGN: Animals were conditioned to run on treadmills for 4 weeks then deprived of sleep for 24 h using the columns-in-water method. We tested the effect of exercise and/or S-D on behavioral performance using a post-learning paradigm in the radial arm water maze (RAWM) and in vivo extracellular recording in the CA1 area. The levels of L LTP-related molecules in the CA1 area were then assessed both before and after L LTP induction. MEASUREMENTS AND RESULTS: After 24 h of S-D, spatial long-term memory impairment in the RAWM and L-LTP suppression was prevented by 4 weeks of regular exercise. Regular exercise also restored the S-D-associated decreases in the basal levels of key signaling molecules such as: calcium/calmodulin kinase IV (CaMKIV), mitogen-activated protein kinase (MAPK/ERK), phosphorylated cAMP response element-binding protein (P-CREB) and brain derived neurotrophic factor (BDNF), in the CA1 area. After L-LTP induction, regular exercise also prevented the S-D-induced down regulation of BDNF and P-CREB protein levels. CONCLUSIONS: The results suggest that our exercise protocol may prevent 24-h S-D-induced impairments in long-term memory and LTP by preventing deleterious changes in the basal and post-stimulation levels of P-CREB and BDNF associated with S-D. PMID- 23633759 TI - Vascular inflammation and sleep disordered breathing in a community-based cohort. AB - STUDY OBJECTIVES: Sleep disordered breathing is associated with cardiovascular disease. The pathophysiologic mechanisms remain unclear, but enhanced vascular inflammation is implicated. We sought to evaluate the association of sleep disordered breathing with biomarkers of inflammation. DESIGN: Cross-sectional, observational. SETTING: Community-based. PARTICIPANTS: There were 900 participants from the Framingham Heart Study site of the Sleep Heart Health Study (52% females, mean age 60 y, 23% ethnic minorities). INTERVENTIONS: None. MEASUREMENTS: We assessed circulating levels of nine inflammatory biomarkers in relation to polysomnographically-derived apnea-hypopnea index and hypoxemia index (% sleep time with oxyhemoglobin saturation < 90%). Multivariable models were adjusted for demographics, smoking, cardiovascular diseases, diabetes, and other potential confounders, without and with adjustment for body mass index. RESULTS: With multivariable adjustment not including body mass index, the apnea-hypopnea index was associated with C-reactive protein, inter-leukin-6, fibrinogen, intercellular adhesion molecule-1, and P-selectin levels and hypoxemia index was associated with C-reactive protein, interleukin-6, and fibrinogen levels. After adjustment for body mass index, only the association of interleukin-6 with sleep disordered breathing remained significant: the adjusted mean serum interleukin-6 level was 2.93, 3.14, 3.34, and 4.62 pg/mL, respectively, in participants with apnea-hypopnea index < 5, 5-14.9, 15-29.9, and >= 30 events/h (P = 0.01 for trend) and 2.97, 3.01, 3.35, and 4.85 pg/mL, respectively, in participants with hypoxemia index < 0.5, 0.5-4.9, 5-9.9, and >= 10% of sleep time (P = 0.02 for trend). CONCLUSIONS: In a community-based sample, sleep disordered breathing is associated with higher levels of interleukin-6, a marker of myocardial infarction risk and mortality. Adiposity may mediate the increased levels of C-reactive protein, fibrinogen, intercellular adhesion molecule-1, and P-selectin observed in sleep disordered breathing. PMID- 23633762 TI - It's getting better all the time...! PMID- 23633761 TI - Sleep estimates using microelectromechanical systems (MEMS). AB - STUDY OBJECTIVES: Although currently more affordable than polysomnography, actigraphic sleep estimates have disadvantages. Brand-specific differences in data reduction impede pooling of data in large-scale cohorts and may not fully exploit movement information. Sleep estimate reliability might improve by advanced analyses of three-axial, linear accelerometry data sampled at a high rate, which is now feasible using microelectromechanical systems (MEMS). However, it might take some time before these analyses become available. To provide ongoing studies with backward compatibility while already switching from actigraphy to MEMS accelerometry, we designed and validated a method to transform accelerometry data into the traditional actigraphic movement counts, thus allowing for the use of validated algorithms to estimate sleep parameters. DESIGN: Simultaneous actigraphy and MEMS-accelerometry recording. SETTING: Home, unrestrained. PARTICIPANTS: Fifteen healthy adults (23-36 y, 10 males, 5 females). INTERVENTIONS: None. MEASUREMENTS: Actigraphic movement counts/15-sec and 50-Hz digitized MEMS-accelerometry. ANALYSES: Passing-Bablok regression optimized transformation of MEMS-accelerometry signals to movement counts. Kappa statistics calculated agreement between individual epochs scored as wake or sleep. Bland-Altman plots evaluated reliability of common sleep variables both between and within actigraphs and MEMS-accelerometers. RESULTS: Agreement between epochs was almost perfect at the low, medium, and high threshold (kappa = 0.87 +/ 0.05, 0.85 +/- 0.06, and 0.83 +/- 0.07). Sleep parameter agreement was better between two MEMS-accelerometers or a MEMS-accelerometer and an actigraph than between two actigraphs. CONCLUSIONS: The algorithm allows for continuity of outcome parameters in ongoing actigraphy studies that consider switching to MEMS accelerometers. Its implementation makes backward compatibility feasible, while collecting raw data that, in time, could provide better sleep estimates and promote cross-study data pooling. PMID- 23633760 TI - Extreme sleep durations and increased C-reactive protein: effects of sex and ethnoracial group. AB - STUDY OBJECTIVES: We hypothesize that extremes of sleep duration are associated with elevated C-reactive protein (CRP), a pro-inflammatory marker for cardiovascular disease risk. DESIGN: Cross-sectional. SETTING: Population-based research. PARTICIPANTS: Nationally representative sample of 2007-2008 National Health and Nutrition Examination Survey participants (n = 5,587 adults). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Associations between CRP and self reported total sleep time (TST) were examined. Explanatory models considered contributions of sex, age, race/ethnicity, body mass index (BMI), and BMI squared (BMI2). Models also explored the role of insomnia symptoms, sleep apnea, active medical illness, and antidiabetic/antihypertensive treatment. Differential patterns among race/ethnicity groups were examined using interactions and stratified analyses. Nonlinear relationships between CRP and TST were assessed using polynomial and multinomial regression models (< 5, 5, 6, 7, 8, 9, and > 9 h). Linear and squared terms were significant in all models in the complete sample, with notable differences by sex and ethnoracial group. Overall, in models adjusted for sociodemographics and BMI, different patterns were observed for non Hispanic white (elevated CRP for < 5 h and > 9 h), black/African-American (elevated CRP for < 5 h and 8 h), Hispanic/Latino (elevated CRP for > 9 h), and Asian/ Other (higher in 9 and > 9 h and lower in 5 h and 6 h) groups. Ethnoracial groups also demonstrated patterning by sex. CONCLUSION: In a representative sample of American adults, elevated CRP was associated with extreme sleep durations. Sex, race/ethnicity, sleep disorders, and medical comorbidity influenced these associations. Differences in CRP along these dimensions should be considered in future research on sleep related disparities influencing cardiometabolic disease risk. PMID- 23633763 TI - Where there is a will there is a way. PMID- 23633764 TI - Biofilm and dental implant: The microbial link. AB - Mouth provides a congenial environment for the growth of the microorganisms as compared to any other part of the human body by exhibiting an ideal nonshedding surface. Dental plaque happens to be a diverse community of the microorganisms found on the tooth surface. Periodontal disease and the peri-implant disease are specific infections that are originating from these resident microbial species when the balance between the host and the microbial pathogenicity gets disrupted. This review discusses the biofilms in relation to the peri-implant region, factors affecting its presence, and the associated treatment to manage this complex microbial colony. Search Methodology: Electronic search of the medline was done with the search words: Implants and biofilms/dental biofilm formation/microbiology at implant abutment interface/surface free energy/roughness and implant, periimplantitis/local drug delivery and dental implant. Hand search across the journals - clinical oral implant research, implant dentistry, journal of dental research, international journal of oral implantology, journal of prosthetic dentistry, perioodntology 2000, journal of periodontology were performed. The articles included in the review comprised of in vivo studies, in vivo (animal and human) studies, abstracts, review articles. PMID- 23633765 TI - An overview of frenal attachments. AB - Frenal attachments are thin folds of mucous membrane with enclosed muscle fibers that attach the lips to the alveolar mucosa and underlying periosteum. Most often, during the oral examination of the patient the dentist gives very little importance to the frenum, for assessing its morpholology and attachment. However, it has been seen that an abnormal frenum can be an indicator of a syndrome. This paper highlights the different frenal attachments seen in association with various syndromic as well as non-syndromic conditions. PMID- 23633766 TI - Cellular response within the periodontal ligament on application of orthodontic forces. AB - During application of controlled orthodontic force on teeth, remodeling of the periodontal ligament (PDL) and the alveolar bone takes place. Orthodontic forces induce a multifaceted bone remodeling response. Osteoclasts responsible for bone resorption are mainly derived from the macrophages and osteoblasts are produced by proliferations of the cells of the periodontal ligament. Orthodontic force produces local alterations in vascularity, as well as cellular and extracellular matrix reorganization, leading to the synthesis and release of various neurotransmitters, cytokines, growth factors, colony-stimulating factors, and metabolites of arachidonic acid. Although many studies have been reported in the orthodontic and related scientific literature, research is constantly being done in this field resulting in numerous current updates in the biology of tooth movement, in response to orthodontic force. Therefore, the aim of this review is to describe the mechanical and biological processes taking place at the cellular level during orthodontic tooth movement. PMID- 23633767 TI - Antioxidant therapy as monotherapy or as an adjunct to treatment of periodontal diseases. AB - BACKGROUND: Treatment of periodontal diseases by nonsurgical debridement has been considered as a gold standard procedure. Various other treatment modalities have been tried and tested to treat periodontal diseases. The aim of this study was to investigate the effect of antioxidant therapy on the progression of periodontal disease as monotherapy and/or as an adjunct to nonsurgical debridement. MATERIALS AND METHODS: 70 subjects were divided into three groups, i.e. clinically healthy, gingivitis and periodontitis group on the basis of Community Periodontal Index of Treatment Needs score. Gingivitis and periodontitis groups were further subdivided into three subgroups. At the baseline, periodontal attachment loss was recorded and scaling and root planing was performed in two subgroups. 6 mg antioxidant was administered in three divided doses for 2 weeks. Saliva samples were collected at baseline, 15(th) day, 30(th) day and 45(th) day for evaluation of uric acid levels. RESULTS: Uric acid levels were significantly low in patients with more periodontal attachment loss as compared to clinically healthy and gingivitis groups. As the treatment was initiated, significant increase in uric acid levels was observed. CONCLUSION: Rise in salivary antioxidant levels was observed on the administration of antioxidant therapy. Hence, antioxidant therapy can be used as an adjunct to the nonsurgical periodontal therapy. PMID- 23633768 TI - Prevalence and severity of periodontal disease in type 2 diabetes mellitus (non insulin-dependent diabetes mellitus) patients in Bangalore city: An epidemiological study. AB - BACKGROUND: Our objective was to study the prevalence and severity of periodontal disease in type 2 diabetes mellitus (DM) patients in Bangalore city. MATERIALS AND METHODS: Four hundred and eight type 2 DM patients (Study Group) and 100 non diabetic patients (Control Group) among the age group of 35-75 years were included in the study. The study group was divided based on Glycated hemoglobin levels into well, moderately and poorly controlled. Relevant information regarding age, oral hygiene habits and personal habits was obtained from the patients. Diabetic status and mode of anti-diabetic therapy of the study group was obtained from the hospital records with consent from the patient. Community periodontal index (CPI) was used to assess the periodontal status. The results were statistically evaluated. RESULTS: The mean CPI score and the number of missing teeth was higher in diabetics compared with non-diabetics, and was statistically significant (P=0.000), indicating that prevalence and extent of periodontal disease was more frequent and more severe in diabetic patients. The risk factors like Glycated hemoglobin, duration of diabetes, fasting blood sugar, personal habits and oral hygiene habits showed a positive correlation with periodontal destruction, whereas mode of anti-diabetic therapy showed a negative correlation according to the multiple regression analysis. The odds ratio of a diabetic showing periodontal destruction in comparison with a non-diabetic was 1.97, 2.10 and 2.42 in well, moderately and poorly controlled diabetics, respectively. CONCLUSION: Our study has made an attempt to determine the association between type 2 DM (NIDDM) and periodontal disease in Bangalore city. It was found that type 2 DM (non-insulin-dependent diabetes mellitus [NIDDM]) subjects manifested relatively higher prevalence and severity of periodontal disease as compared with non-diabetics. PMID- 23633769 TI - Assessment of serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol in periodontitis patients. AB - BACKGROUND AND OBJECTIVES: Periodontal disease is a destructive inflammatory disease inducing profound changes in the plasma concentrations of cytokines leading to a catabolic state characterized by altered lipid metabolism and hypertriglyceridemia. The main objective of the present study was to evaluate the effect of periodontal infection on serum levels of triglycerides (TGL), total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. MATERIALS AND METHODS: A sample of 90 subjects; 30 periodontally healthy individuals, 30 chronic gingivitis cases (n=30), and 30 chronic periodontitis cases (n=30) with an age range of 25 to 65 years were included in the study. Periodontal parameters including Plaque Index, Gingival Index, Probing Depth, and Clinical Attachment Level were recorded. Venous blood samples were obtained after 12 hours fasting period from antecubital vein and serum levels of TGL, TC, HDL, and LDL cholesterol were measured. RESULTS: The levels of TGL, TC, and LDL cholesterol were significantly higher for periodontitis group (P<0.05) as compared to gingivitis and periodontally healthy groups. HDL cholesterol levels were significantly lower in periodontitis group (P<0.05) as compared to periodontally healthy and gingivitis groups. CONCLUSION: The results of the present study indicate that periodontal infection has a definite role in altering lipid metabolism leading to hyperlipidemia. However, further studies are required to clarify the relationship between periodontitis and serum lipid levels and to determine whether oral healthcare has the potential to reduce serum lipid levels in otherwise systemically healthy individuals. PMID- 23633770 TI - The short-term effects of non-surgical periodontal therapy on the circulating levels of interleukin-6 and C-reactive protein in patients with chronic periodontitis. AB - BACKGROUND: Recent epidemiological studies have shown that periodontal infection is a risk factor for a number of systemic diseases and conditions. In addition to the conventional risk factors, chronic infection and the subsequent generation of a systemic inflammatory response may be associated with this increased risk. AIMS: This study was conducted to determine whether the presence of chronic periodontitis and subsequent non-surgical periodontal therapy could influence the serum levels of interleukin-6 and C-reactive protein (CRP) in patients with severe chronic generalized periodontitis. SETTINGS AND DESIGN: Participants were selected from subjects who attended the Department of Periodontics and Oral Implantololgy, Government Dental College, Thiruvananthapuram. MATERIALS AND METHODS: Sera were obtained from 25 patients with periodontitis for baseline examination and reassessment after completion of treatment. As a control, sera were also obtained from 20 subjects without periodontitis. Interleukin-6 was determined by sensitive enzyme-linked immunosorbent assay, and high-sensitivity CRP (hsCRP) was measured using latex turbidometric immunoassay. STATISTICAL ANALYSIS: Data were analyzed using computer software, Statistical Package for Social Sciences (SPSS) version 10. RESULTS: The level of interleukin-6 and hsCRP in the sera of periodontitis patients was seen to be higher than those of healthy controls. Interleukin-6 level tended to decrease with improvement of the periodontal condition following treatment and approached that of control subjects, and this decline was statistically significant. The hsCRP levels also showed a decreasing trend following periodontal treatment. CONCLUSIONS: In this study, we were able to show that periodontal disease significantly affects the serum levels of systemic inflammatory markers and that non-surgical periodontal therapy could bring about a decrease in the levels of these inflammatory markers. PMID- 23633771 TI - Salivary protein concentration, flow rate, buffer capacity and pH estimation: A comparative study among young and elderly subjects, both normal and with gingivitis and periodontitis. AB - BACKGROUND: To evaluate the salivary protein concentration in gingivitis and periodontitis patients and compare the parameters like salivary total protein, salivary albumin, salivary flow rate, pH, buffer capacity and flow rate in both young and elderly patients with simple methods. MATERIALS AND METHODS: One hundred and twenty subjects were grouped based on their age as young and elderly. Each group was subgrouped (20 subjects) as controls, gingivitis and periodontitis. Unstimulated whole saliva was collected from patients and flow rate was noted down during collection of the sample. Salivary protein estimation was done using the Biuret method and salivary albumin was assessed using the Bromocresol green method. pH was estimated with a pHmeter and buffering capacity was analyzed with the titration method. Student's t-test, Fisher's test (ANOVA) and Tukey HSD (ANOVA) tests were used for statistical analysis. RESULTS: A very highly significant rise in the salivary total protein and albumin concentration was noted in gingivitis and periodontitis subjects of both young and elderly. An overall decrease in salivary flow rate was observed among the elderly, and also the salivary flow rate of women was significantly lower than that of men. CONCLUSION: Significant associations between salivary total protein and albumin in gingivitis and periodontitis were found with simple biochemical tests. A decrease in salivary flow rate among elderly and among women was noted. PMID- 23633772 TI - Comparative evaluation of subgingival plaque microflora in pregnant and non pregnant women: A clinical and microbiologic study. AB - CONTEXT: Gingival changes in pregnancy have been attributed to changes in the subgingival biofilm related to hormonal variations. AIMS: To evaluate the subgingival plaque microflora in pregnant and nonpregnant women to determine if pregnancy induces any alterations in the subgingival plaque and to associate these changes with changes in periodontal status. SETTINGS AND DESIGN: Thirty pregnant and 10 nonpregnant women within the age group of 20-35 years having a probing pocket depth (PPD) of 3-4 mm were included in the study. The pregnant women were equally divided into 3 groups of 10, each belonging to I, II, and III trimester. MATERIALS AND METHODS: Plaque index, gingival index, PPD, and microbiologic evaluation for specific bacterial counts for Prevotella intermedia, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Parvimonas micra, and Fusobacterium nucleatum were carried out for all subjects. STATISTICAL ANALYSIS: Mann-Whitney U test. RESULTS: Increase in gingival inflammation was observed in II and III trimester as compared with I trimester and control. Plaque scores did not show any significant difference between pregnant and nonpregnant women. Specific bacterial examination revealed an increase in proportion of P. intermedia in pregnant women of both II and III trimester as compared with I trimester and nonpregnant women. CONCLUSIONS: A definite increase in proportions of P. intermedia occurs in subgingival plaque microflora in pregnancy that may be responsible for the exaggerated gingival response. PMID- 23633773 TI - Evaluation of socio-demographic variables affecting the periodontal health of pregnant women in Chandigarh, India. AB - BACKGROUND: The literature is replete with reports that pregnant women have an increased level of periodontal disease as compared with non-pregnant women of the same age. There are many studies correlating the effect of periodontal disease on the adverse pregnancy outcomes. The development of periodontal diseases during pregnancy can be influenced by factors such as preexisting oral conditions, general health, and socio-cultural background. There is very little data studying the effect of socio-demographic factors on the periodontal health of pregnant women. This study evaluated the periodontal status of a sample of pregnant women of Chandigarh and adjoining areas. The study also investigated the relationship between these variables and a series of demographic and clinical variables. MATERIALS AND METHODS: The participants were 190 pregnant women attending Gynecology and Obstetrics outpatient department of Government Medical College and Hospital, Chandigarh. The participants were examined for their periodontal health and various socio-demographic variables were recorded on performas designed for the purpose of study. Statistical analysis was done. RESULTS: The results revealed that the mean bleeding index scores and probing depth increased with statistical significance when the socio-economic status was lower (P<0.05). No significant differences were found in bleeding index scores and mean probing depth among different categories of profession, education, place of residence, and trimester of pregnancy (P>0.1). The plaque index was not significantly associated with the socio-economic status, profession, place of residence, and trimester of pregnancy (P>0.1). CONCLUSION: In the population of pregnant women investigated under this study, the clinical and socio-demographic characteristics showed non-significant correlation except socio-economic status which showed statistically significant correlation with bleeding on probing and pocket depth. Further studies may be required in Indian population to determine the association of periodontal diseases in pregnant women with socio-demographic variables. PMID- 23633774 TI - Influence of personality traits on gingival health. AB - BACKGROUND: The maintenance of good oral hygiene is considered a salient issue in dental health promotion. Personality is the combination of characteristics or qualities that form an individual's distinctive character. Various personality traits have been proposed to influence the oral health. The purpose of the present study was to assess the influence of personality characteristics using questionnaire on oral hygiene performance and gingival health. MATERIALS AND METHODS: In total, 155 patients were subjected to personality questionnaire using Eysenck Personality Questionnaire. Clinical parameters such as Patient oral hygiene performance index and gingival index were recorded. Based on Eysenck Personality Questionnaire, the subjects were divided into three groups: Psychoticism, extroversion, and neuroticism. RESULTS: Data analysis showed that subjects in psychoticism and neuroticism groups displayed moderate gingivitis, whereas subjects in extroversion group had severe gingivitis. Subjects in all the three groups demonstrated poor oral hygiene status. No statistically significant relation was found. CONCLUSIONS: A considerable clinical correlation was observed between the different personality traits and gingival health status of the subjects. It was not statistically significant. Further trials need to be conducted so as to ascertain this association so that psychological interventions may be undertaken to improve the oral hygiene condition of the population. PMID- 23633775 TI - Correlation of mast cells in periodontal diseases. AB - BACKGROUND: Among the cells involved in immune and inflammatory responses in periodontal disease, mast cells have been shown to be capable of generating a large number of biologically active substances. Mast cells are mobile, bone marrow-derived, granule-containing immune cells that are found in all connective tissue and mucosal environments and in the peripheral and central nervous systems. Mast cells are able to phagocytose, process and present antigens as effectively as macrophages. The present study was undertaken to quantify the mast cells in health and disease, whether they correlate degree of inflammation and clinical features of periodontium. MATERIALS AND METHODS: Ten cases of localized chronic periodontitis (CP), 10 cases of dental plaque-induced gingivitis (DPIG) and 10 cases of clinically healthy gingival tissues were selected. Samples were obtained from patients undergoing for periodontal surgery in CP and DPIG. In health group third molar impacted and covered with operculum without any inflammation were selected. Sample fixed in 10% buffered formalin and stained with Toludine blue stain and observed under binocular microscope. CONCLUSION: In human periodontal disease there is an increase in the number of mast cells that may be participating either in the destructive events or in the defense mechanism of periodontal disease via secretion of cytokines. PMID- 23633776 TI - Mathematical analysis of furcation angle in extracted mandibular molars. AB - BACKGROUND: Multi-rooted teeth with furcation involvement exhibit a poorer prognosis when compared to single rooted teeth. The furcation angle (formed by the divergent roots and the roof) may exert a considerable influence on the accessibility for both home care maintenance and instrumentation during periodontal therapy. As there are few anatomy based reports, the furcation angle has not yet been delineated. MATERIALS AND METHODS: Furcation angle (FA) was mathematically evaluated in extracted mandibular first and second molar teeth, using the Computer-aided design - computer-aided manufacturing technology. RESULTS: THE FURCATIONS WERE DIVIDED INTO THREE GROUPS (GROUP I: <30 degrees , Group II: 30 degrees -60 degrees , Group III: >60 degrees ) based on the furcation angle and their prevalence. The first molar showed greater prevalence of group II FA, while second molar showed a greater prevalence of group III FA. CONCLUSION: Linear, two dimensional measurements may not accurately reflect the complexities of the furcation area which exhibits considerable intermolar and intramolar (buccal and lingual furcations of second molar) variation. PMID- 23633777 TI - Comparative evaluation of anti-plaque efficacy of herbal and 0.2% chlorhexidine gluconate mouthwash in a 4-day plaque re-growth study. AB - BACKGROUND: Chlorhexidine gluconate mouthwash has earned eponym of gold standard to treat and/or prevent periodontal disease. However, it has been reported to have local side-effects on long-term use. To explore a herbal alternative, the present study was carried out with an aim to compare the anti-plaque efficacy of a herbal mouthwash with 0.2% chlorhexidine gluconate mouthwash and normal saline. MATERIALS AND METHODS: It was an examiner-blinded, parallel designed clinical trial, in which 90 pre-clinical dental students with gingival index (GI) <=1 were enrolled. To begin with, GI and plaque index (PI) were recorded. Then, baseline plaque scores were brought to zero by professionally cleaning the teeth with scaling and polishing. After that, randomized 3 groups were made (of 30 subjects each - after excluding the drop-outs) who were refrained from regular mechanical oral hygiene measures. Subjects were asked to swish with respective mouthwash (0.2% chlorhexidine gluconate mouthwash, herbal mouthwash, or normal saline) as per therapeutic dose for 4 days. Then, GI and PI scores were re-evaluated on 5(th) day by the same investigator, and the differences were compared statistically by ANOVA and Student's 't'-test. RESULTS AND OBSERVATIONS: Least post-rinsing GI and PI scores were demonstrated with 0.2% chlorhexidine gluconate mouthwash, followed by herbal mouthwash and highest scores with normal saline. The difference of post-rinsing PI scores between the chlorhexidine and herbal mouthwash groups was statistically non-significant, whereas this difference was significant between chlorhexidine and saline groups, and the difference between herbal and saline groups was non-significant. It was concluded that 0.2% chlorhexidine gluconate mouthwash remains the best anti-plaque agent. However, when socio-economic factor and/or side-effects of chlorhexidine need consideration, presently tested herbal mouthwash may be considered as a good alternative. PMID- 23633778 TI - A comparative evaluation of the effectiveness of subpedicle acellular dermal matrix allograft with subepithelial connective tissue graft in the treatment of isolated marginal tissue recession: A clinical study. AB - INTRODUCTION: The most common problem encountered in our day to day practice is exposed root surface or a tooth getting long. The main indication for root coverage procedures are esthetics and/or cosmetic demands followed by the management of root hypersensitivity, root caries or when it hampers proper plaque removal. Over the years, various techniques have been used to achieve root coverage. AIM AND OBJECTIVES: The aim of this study was to compare the effectiveness of subpedicle acellular dermal matrix allograft (ADMA) with subepithelial connective tissue graft (SCTG) in the treatment of isolated marginal tissue recession. MATERIALS AND METHODS: Twenty systemically healthy patients aged between 18 to 50 years (mean age29.7+/-4.35 years) with a recession defect on the labial and the buccal surfaces of any teeth were selected for the study. Ten patients received the test treatment (ADMA), ten patients received the control treatment (SCTG). Clinical recordings assessed at baseline, three months and six months post surgery, included Plaque index (PI), Papillary bleeding index (PBI), Gingival recession (REC), Probing pocket depth (PPD), Clinical attachment level (CAL) and Width of keratinized gingival (WKG). RESULTS: Test group (ADMA) showed 86.93% mean root coverage while control group (SCTG) showed 84.72% at six months post surgery. Mean increase in the width of keratinized gingiva was significantly greater in the SCTG group (3.3+/-0.48mm) compared to ADMA group (2.4+/-0.51mm). CONCLUSION: Both the treatment produced a significant reduction in gingival recession and probing pocket depth and significant gain in clinical attachment level and width of keratinised gingiva. PMID- 23633779 TI - An in-office, cost effective technique for measuring width of bone using intra oral periapical radiographs in occlusal projection. AB - BACKGROUND: The aim of this in vitro study was to determine the dimensions of ridge/width of bone and deviation of center of ridge using Intra Oral Periapical Radiographs (IOPA) in occlusal projection as a preprosthetic diagnostic method. MATERIALS AND METHODS: Mandibles with edentulous space were procured and cold cure acrylic stents were fabricated. Three holes were drilled occlusally, buccally, lingually and filled with gutta percha. Then mandibles were tied to menaquine model which was fitted to a dental chair. IOPA radiographs in occlusal projection were taken. Radiographs were scanned to obtain a digital image which was analyzed using computerized software. Direct measurements were taken and compared. The position of center of ridge was compared in vitro and radiographically using student unpaired t test and width of bone was compared using Karl Pearson's coefficient test. RESULTS: Comparisons of bucco-lingual ridge width using radiographical measurement versus in vitro method showed a mean value of 4.1930 with deviation of 0.5934 and the proposed position of center of ridge for both the methods gave a mean value of 0.2738 with deviation of 0.1164. CONCLUSION: The findings in this study suggested that IOPA radiographs in occlusal projection can be used as a preprosthetic diagnostic method to assess the width of the alveolar bone for future flapless implant placement. PMID- 23633780 TI - Comparative study between two techniques for alveolar bone loss assessment: A pilot study. AB - OBJECTIVE: To conduct a comparative study between two techniques for assessment of alveolar bone loss. MATERIALS AND METHODS: Absolute and relative techniques were evaluated. The sample consisted of 16 radiographs supposed to meet a single criterion: The reference points applied (Cementum-enamel junction (CEJ) alveolar bone crest and root apex) should be visible. Bone height was measured in the selected radiographs as the percentage of root length through both techniques. Data were submitted to the Statistical Package for Social Science software. Results obtained by both methods were converted into bone loss index values and then categorized. Sensitivity and specificity of the relative technique, compared to the absolute technique, were calculated. Wilcoxon test and the Bland and Altman's method were employed for comparisons. Significance level was set at 5%. RESULTS: For the absolute and relative techniques, means of bone loss index were respectively of 4.81 (+/-2.25) and 4.75 (+/-1.80). Bone loss index >=6 (alveolar bone loss >=50%) was found in 5 (31.2%) teeth, in the absolute technique, and in 4 (25%) teeth, according to the relative technique. There was no statistically significant difference between both methods (P>0.05). According to the Bland and Altman's method, it was verified a bias of 0.06, and limits of upper and lower agreement of, respectively, 1.58 and -1.45. Sensitivity of 0.8 and specificity of 1 were found for the relative technique compared to the absolute one. CONCLUSION: There was no significant difference between the techniques evaluated, and the relative technique was found to be reliable for measuring alveolar bone loss. PMID- 23633781 TI - The comparative efficacy of decalcified allogenic bone matrix and intra-oral free osseous autografts in the treatment of periodontal intrabony defects. AB - BACKGROUND AND OBJECTIVES: The primary goal of periodontal treatment is the maintenance of the natural dentition in health and comfortable function. The shift in therapeutic concepts from resection to regeneration has significantly impacted the practice of periodontology. The objective of the present study is to compare the relative efficacy of intra-oral autogenous graft and decalcified allogenic bone matrix (DABM) in the treatment of periodontal intrabony defects. MATERIALS AND METHODS: In the present study, 30 patients in the age group of 30 50 years with two almost identical intrabony defects, on either side of the mouth/upper and lower jaw, based upon the radiographic observations were selected from amongst the patients visiting the Department of Periodontology and Oral Medicine, Punjab Government Dental College and Hospital, Amritsar. One of the defect was selected randomly and filled with autogenous cancellous graft and the other with DABM. Post-operative assessment was done by taking radiographs, 12 weeks and 24 weeks post-operatively. RESULTS: Definite bone fill was achieved both with intra-oral free osseous autograft and with DABM at 12 weeks observation, which further increased significantly at 24 weeks observation. The bone fill obtained with intra-oral free osseous autograft was found to be significantly higher than that with DABM both at 12 weeks and 24 weeks post operative observation. CONCLUSION: Within the limitations of this study, it establishes the superiority of the intra-oral free osseous autograft over that of DABM graft in correcting the intrabony defects. PMID- 23633782 TI - Evaluation of hydroxyapatite (Periobone-G) as a bone graft material and calcium sulfate barrier (Capset) in treatment of interproximal vertical defects: A clinical and radiologic study. AB - BACKGROUND: This study has been undertaken to assess treatment response of interproximal vertical defects using an alloplast (Periobone-G) and calcium sulfate (Capset) as a barrier both clinically and radiographically. MATERIALS AND METHODS: Eight patients were selected with 16 sites that were divided into control and experimental sites based on split mouth study design. Plaque index, gingival index, probing depth, clinical attachment level, gingival margin position were recorded at baseline and 9 months and radiographic assessment was done at baseline and 9 months after recording clinical parameters, the sites were randomly treated either with hydroxyapatite granules Periobone-G or hydroxyapatite granules (control group) was used to fill the osseous defect and calcium sulfate (Capset) (experiment group) barrier was placed. RESULT: The plaque score reduction was statistically highly significant within control and experimental groups. The gingival score reduction was significant within control and experimental groups, although there were no significant difference between the 2 groups. The pocket depth reduction was significant within control and experimental group, however, the hydroxyapatite + capset group showed significant reduction as compared with hydroxyapatite alone group. The clinical attachment gain and gingival margin position was significant within control and experimental groups, although there was no significant difference between the 2 groups. The amount of defect fill was significant in both control and experimental groups but the difference between the 2 groups was not significant. The mean change in alveolar crest level between control and experimental groups was significant (P=0.02). The percentage of original defect resolved was not significant. CONCLUSION: The use of calcium sulfate as a barrier proved its role in the treatment of interproximal defects. The application of calcium sulfate (Capset) barrier is easy and simple. The multifaceted properties of calcium sulfate demonstrate its usefulness in periodontal practice. PMID- 23633784 TI - Amelogenesis imperfecta and localised aggressive periodontitis: A rare clinical entity. AB - This case report presents two female patients whose chief complaint was discoloration of teeth. On careful clinical examination it was found that the patients had features of amelogenesis imperfecta and localised aggressive periodontitis. This article will give an insight of clinical and radiographic features of amelogenesis imperfecta with localised aggressive periodontitis, which is a rare clinical entity. PMID- 23633783 TI - Evaluation of the efficacy of a bioactive synthetic graft material in the treatment of intrabony periodontal defects. AB - BACKGROUND: Bioactive ceramic fillers are synthetic materials which have shown the potential to enhance bone formation. The purpose of this study was to evaluate the efficacy of a bioactive synthetic graft material in the treatment of intrabony periodontal defects. MATERIALS AND METHODS: Fourteen intrabony defects in twelve systemically healthy subjects having moderate to severe chronic periodontitis were evaluated after bone grafting with bioactive ceramic filler for a period of 6 months. Clinical and radiographic evaluations were made at baseline, at 3 and 6 months following surgery. RESULTS: Mean radiographic defect fill of 64.76% (2.49+/-0.5 mm) was observed in 6 months, which was statistically significant. A statistically significant relative attachment level gain of 2.71+/ 1.13 mm and probing pocket depth reduction of 4.21+/-1.18 mm was recorded at the end of the study. A significant decrease in mobility and gingival index was observed. CONCLUSIONS: Bioactive glass is an efficacious treatment option for the reconstruction of intrabony periodontal defects as it led to statistically significant improvements in the clinical and radiographic parameters. PMID- 23633785 TI - Severe gingival enlargement associated with aggressive periodontitis. AB - Enlargement of the gingiva can be due to various causes. Most prevalent are the inflammatory type and drug-induced type of gingival hyperplasia. However, sever enlargement associated with an aggressive type of periodontitis is an infrequent finding. Reported here is a case of a female patient aged 18 years who presented with severe enlargement of the maxillary and mandibular gingiva. Examination revealed enlargement extending up to the incisal edge of all the teeth and also an associated generalized loss of attachment with radiographic evidence of reduced bone height resembling an aggressive type of periodontitis. There were no associated systemic signs and symptoms or any family history except that there was generalized vitiligo of the skin and oral mucous membrane. The case was treated by gross electrosection of the gingiva. PMID- 23633786 TI - Root coverage with bridge flap. AB - Gingival recession in anterior teeth is a common concern due to esthetic reasons or root sensitivity. Gingival recession, especially in multiple anterior teeth, is of huge concern due to esthetic reasons. Various mucogingival surgeries are available for root coverage. This case report presents a new bridge flap technique, which allows the dentist not only to cover the previously denuded root surfaces but also to increase the zone of attached gingiva at a single step. In this case, a coronally advanced flap along with vestibular deepening technique was used as root coverage procedure for the treatment of multiple recession-type defect. Here, vestibular deepening technique is used to increase the width of the attached gingiva. The predictability of this procedure results in an esthetically healthy periodontium, along with gain in keratinized tissue and good patient's acceptance. PMID- 23633787 TI - Modified semilunar coronally advanced flap: A case series. AB - Dentists traditionally think of periodontal treatment as a means of saving the teeth while leaving the patient with an esthetic problem. The goal of gingival esthetics is to maintain normal healthy gingival appearance around teeth that must be restored. Gingival recession represents a significant concern for patients and a therapeutic problem for the clinician. Root coverage is the goal of periodontal plastic surgery when treating gingival recessions in the esthetic zone. Correction of mucogingival recession deformities with a variety of periodontal plastic surgical procedures have been described each demonstrating a variable degree of success. This case report presents to you the treatment outcomes and predictability of modified semilunar coronally advanced flap (Kamran Haghighat) techniques described for the treatment of recession defects on single and multiple adjacent teeth, respectively. PMID- 23633788 TI - Severe periodontitis associated with chronic kidney disease. AB - The data on Indian population with regard to severity/prevalence of chronic periodontitis in association with chronic kidney disease (CKD) is scarce. We are describing an interesting case of severe periodontitis associated with CKD. The patient had unusual inflammatory gingival overgrowth which persisted even after treatment. By describing this case we want to highlight our current lack of understanding with regard to etiopathogenesis of periodontal disease in CKD patients and need for further research in this area. PMID- 23633790 TI - Knowledge, attitude, and practice of medical doctors towards periodontal disease. AB - The study aimed to assess the knowledge of medical doctors on the association between periodontal disease and general health and their willingness to advise their patients to seek dental treatment. In a cross-sectional survey, randomly selected medical doctors (n = 267) practicing in Nellore District were interviewed through a questionnaire survey about their knowledge of periodontal diseases and the bidirectional relationship between general health and periodontal diseases. Data were analyzed through percentages. All the medical doctors (100%) were aware that there existed a relation between oral health and general health. But only 10% of respondents refer their patients to dentists without patients asking for referral. Very few respondents (21.3%) knew about different branches of dentistry. Screening and referral by healthcare professionals may benefit their patients by improving access to dental care. Therefore, there is a need to educate doctors about oral health and general health. PMID- 23633789 TI - Treatment of an early failing implant by guided bone regeneration using resorbable collagen membrane and bioactive glass. AB - Implant failure can be divided into early (prior to prosthetic treatment) or late (after prosthetic rehabilitation). Early failure is generally due to interference in the healing process after implant placement. Implants undergoing early failure will show progressive bone loss on radiographs during the healing period (4 to 6 weeks). In the present case report, early progressive bone loss was seen at 6 weeks, after placement of a non-submerged single piece mini implant. Clinical examination revealed peri-implant bleeding on probing and pocket and grade-1 mobility. Treatment protocol included mechanical debridement (plastic curettes), chemical detoxification with supersaturated solution of citric acid, antibiotics and guided bone regeneration therapy using the collagen membrane as guided bone regeneration barrier in combination with bioactive glass as bone grafting material. The 6 month postoperative examination showed complete resolution of the osseous defect, thus suggesting that this technique may hold promise in the treatment of implants undergoing early failure. PMID- 23633791 TI - Cancer: Show your care, be aware. PMID- 23633792 TI - Evaluation of the effect of enamel preparation on retention rate of fissure sealant. AB - BACKGROUND: Prevention from caries is a principle in dentistry and fissure sealant therapy is being used as a preventive method success of sealants is directly depending on their retention. AIM: The Aim of the present study is to evaluate effects of enamel preparation on sealant retention. SETTINGS AND DESIGN: Clinical trial. MATERIALS AND METHODS: About 57 children aged 6-8 year old took part in this study. 200 first molar teeth of these children has been randomly separated into two groups: A case group (Mechanically preparation of enamel) and a control group (conventional method, without preparation). After applying fissure sealants children were followed up 6 months later. STATISTICAL ANALYSIS USED: Mann- U- Whitney Test was used. RESULTS: Complete retention after 6 month follow up was 86.7% in case group and 82.8% in control group. No significant difference was seen between the groups after 6 month follow up. (P = 0.508). CONCLUSION: Although statistical evaluation didn't show significant difference, but sealant retention was more after preparation technique. PMID- 23633793 TI - A clinico-radiographic analysis of sagittal condylar guidance determined by protrusive interocclusal registration and panoramic radiographic images in humans. AB - PURPOSE: To evaluate the correlation between sagittal condylar guidance obtained by protrusive interocclusal records and panoramic radiograph tracing methods in human dentulous subjects. MATERIALS AND METHODS: The sagittal condylar guidance was determined in 75 dentulous subjects by protrusive interocclusal records using Aluwax through a face bow transfer (HANAUTM Spring Bow, Whip Mix Corporation, USA) to a semi-adjustable articulator (HANAUTM Wide-Vue Articulator, Whip Mix Corporation, USA). In the same subjects, the sagittal outline of the articular eminence and glenoid fossa was traced in panoramic radiographs. The sagittal condylar path inclination was constructed by joining the heights of curvature in the glenoid fossa and the corresponding articular eminence. This was then related to the constructed Frankfurt's horizontal plane to determine the radiographic angle of sagittal condylar guidance. RESULTS: A strong positive correlation existed between right and left condylar guidance by the protrusive interocclusal method (P 0.000) and similarly by the radiographic method (P 0.013). The mean difference between the condylar guidance obtained using both methods were 1.97 degrees for the right side and 3.18 degrees for the left side. This difference between the values by the two methods was found to be highly significant for the right (P 0.003) and left side (P 0.000), respectively. The sagittal condylar guidance obtained from both methods showed a significant positive correlation on right (P 0.000) and left side (P 0.015), respectively. CONCLUSION: Panoramic radiographic tracings of the sagittal condylar path guidance may be made relative to the Frankfurt's horizontal reference plane and the resulting condylar guidance angles used to set the condylar guide settings of semi-adjustable articulators. PMID- 23633794 TI - A comparative microbiological study to assess caries excavation by conventional rotary method and a chemo-mechanical method. AB - AIMS: This study was aimed to determine the effectiveness of Papacarie((r)) for caries removal as compared to the conventional method with respect to microbial flora, time, the amount of tissue removal, child's behavior, pain perception, and preference of treatment. MATERIALS AND METHODS: Sixty primary molars of 30 children of age 4-9 years were selected randomly and divided into two groups of 30 teeth each: Group A treated by conventional method and group B with Papacarie((r)) method. RESULTS: Comparatively, no statistical difference was seen in microbial growth, total bacterial count, and lactobacilli count in both the groups (P = 0.36). The mean cavity entrance size with group A was 0.98133 mm and group B was 0.26083 mm (P < 0.001). The mean preparation time for group A was 4.7 Mins (minutes) and group B was 17.96 min s (P < 0.001). Majority of kids of both group A and B scored 3 (Frankl Behavior Rating Scale) before and after the treatment showing no statistical difference in their behavioral score (P = 1). In group A 50% of children experienced no pain as compared to 86.7% in group B (P = 0.01). There was no statistical difference in the preference of treatment (P = 0.12). CONCLUSION: Thus, the Chemo mechanical caries removal method can be considered as an effective method to control pain and preserve sound tooth structure during caries excavation. PMID- 23633795 TI - Retraction notice. PMID- 23633796 TI - Tooth loss, chewing ability and quality of life. AB - OBJECTIVES: The aim of this study was to observe the tooth loss over age in a sample of Brazilian patients and analyze their ability to chew, relating it to how much is the loss of oral function impact over the quality of life (QoL). MATERIALS AND METHODS: This is a single center, observational study and the data were collected through clinical examination followed of questionnaires to obtain sociodemographic information, the ability to chew (through the index of chewing ability [ICA]) and QoL (through Oral Health Impact Profile, OHIP-14). RESULTS: The sample was composed by 171 random volunteers with mean age of 47 (SD 15.2). Low number of natural teeth was associated with an increase of age (Spearman's rho correlation coefficient-0.7, P < 0.001, 2-tailed) and chew disability (ICA: chew's ability vs. disability) (Mann-Whitney U-Test, P < 0.001). Chew disability showed a negative impact over the QoL (overall OHIP; Mann-Whitney U Test P < 0.001) and in five of seven OHIP domains (Functional Limitation, Physical Pain, Psychological Discomfort, Physical Disability, Psychological Disability). Age over than 40 years, was also associated with chewing disability (Pearson Chi Square P < 0.001) and poorer QoL (Mann-Whitney U test P = 0.01). CONCLUSION: This study observed that the chewing disability produces a significant and negative impact over oral-health related QoL and both, poor QoL and chewing disability are related with the decrease of the number of natural teeth. PMID- 23633797 TI - Effect of oral health education and fluoridated dentifrices on the oral health status of visually impaired children. AB - Visually impaired children are challenged everyday in their everyday skills. Oral hygiene practices among visually impaired children require a special approach with time and patience. The purpose of this study was to evaluate the effect of oral health education and fluoridated dentifrices on the oral health status of visually impaired children. MATERIALS AND METHODS: Fifty visually impaired children between 8 and 12 years of age formed the study group. Oral health education and motivation was done with the help of Braille. Modified Bass method of brushing was taught to the children and the required dental treatment was done. Subjects were randomly divided into two equal groups fluoridated and non fluoridated. Oral hygiene index -simplified, DMFT, deft index, and Streptococcus mutans and Lactobacillus count were assessed at baseline, immediately after the treatment and at 3, 6, and 12 month intervals. The oral health awareness was assessed using a questionnaire at the beginning and end of the study. RESULTS: At baseline, the mean OHI-S, DMFT and deft scores were 2.72, 0.47, and 0.51 respectively. At the end of 12 months there was a significant decrease in OHI-S scores in the fluoridated group. No significant difference was seen in DMFT and deft between the fluoridated and non-fluoridated groups at the different time interval. After the oral health education and comprehensive treatment there was a reduction in Streptococcus mutans and Lactobacillus counts in both groups; however, at the end of 3, 6, 12 months there was a significant decrease in fluoridated group as compared to the non-fluoridated. The oral health awareness increased significantly at the end of the study. CONCLUSION: The oral health education and motivation formulated for the visually impaired children was effective in improving their oral health status. Fluoridated dentifrices decreased the Streptococcus mutans and Lactobacillus counts and improved the oral hygiene status. PMID- 23633798 TI - Relation of caries status on the salivary total antioxidant levels in asthmatic children. AB - AIM: To study the correlation between the caries status and the salivary antioxidant levels among asthmatic children. SETTINGS AND DESIGN: One hundred children within the age group of 6 12 years were selected and equally subdivided into children having a history of asthma and their healthy siblings. MATERIALS AND METHODS: Salivary antioxidant levels were assessed using spectrophotometric method, and the caries status was recorded using DMFT (Decayed, missing and Filled Teeth Index) and dft (decayed, filled teeth index) index. RESULT: The salivary antioxidant levels were reduced among the asthmatic children which was statistically highly significant, whereas the caries prevalence was reduced, but not statistically significant. PMID- 23633799 TI - Gore-tex((r)) versus resolut adapt((r)) GTR membranes with perioglas((r)) in periodontal regeneration. AB - BACKGROUND: Successful reconstruction of periodontal tissues destroyed due to periodontitis has been an evasive goal for the periodontists. Several GTR materials and bone grafts have been tried with varied success rates. AIMS AND OBJECTIVES: The aim of the present study was to evaluate and compare the efficacy of non-resorbable (GoreTex((r))) and bioabsorbable (Resolut Adapt((r))) membranes in combination with bioactive glass (PerioGlas((r))) in the treatment of periodontal intrabony defects. MATERIALS AND METHODS: Ten chronic periodontitis patients having bilateral matched intrabony defects were treated with non resorbable membrane (GoreTex((r))) and bioactive glass or the bioresorbable membrane (Resolut Adapt((r))) and bioactive glass in split mouth design. Clinical parameters like plaque index, gingival index, probing pocket depth, clinical attachment level, and gingival recession were recorded at baseline and 9 months post-operatively. Similarly, radiographic (linear CADIA) and intra-surgical (re entry) measurements were evaluated at baseline and 9 months post-operatively). RESULTS: Both the membrane groups showed clinically and statistically significant improvement in clinical parameters i.e., reduction in probing depth (4.6 +/- 1.4 mm) vs. 3.7 +/- 1.3 mm) and gain in clinical attachment level (4.6 + 1.6 vs. 3.2 +/- 1.5 mm) for non-resorbable and bioresorbable membrane groups, respectively. Similar trend was observed when radiographical and intra-surgical (re-entry) measurements were evaluated and compared, pre- and post-operatively at 9 months. However, on comparison between the two groups, the difference was statistically not significant. CONCLUSION: Both the barrier membranes i.e., non-resorbable (Gore-Tex((r))) and bioabsorbable (Resolut Adapt((r))) membranes in combination with bioactive glass (PerioGlas((r))) were equally effective in enhancing the periodontal regeneration. PMID- 23633800 TI - Placement of single tooth implant in healed socket with immediate temporization: Clinical study. AB - INTRODUCTION: Edentulous condition inadequately compensated for, by dentures, impair oral function and is accompanied by reduced self-confidence. In a continued effort to achieve these goals, implant dentistry was introduced. Immediate temporization is somehow a recent concept, which allows the maintenance of soft tissue contours, along with interdental alveolar contours. AIMS AND OBJECTIVES: Aims of the present study were to study the placement of implant in the post-extracted healed tooth socket of anterior maxilla and to evaluate the feasibility of early function on implants placed. MATERIALS AND METHODS: In the present study, HI-TECH IMPLANTS TRX-OP one-piece immediate loading implant system with the built on abutment has been used. Immediate temporisation has been done and results have been evaluated in terms of stability, gingival health, esthetics, marginal bone loss, patient's psychological attitude, and satisfaction. RESULTS: Out of eight implants, 6 successfully healed whereas 2 implants suffered failure. CONCLUSION: Overall conclusion drawn from the study is, immediate temporization is a successful method providing psychological, financial and emotional benefits to the patient. PMID- 23633801 TI - A comparative evaluation of electronic and radiographic determination of root canal length in primary teeth: An in vitro study. AB - AIMS: The purpose of this in vitro study was to compare the root canal length determination by Electronic apex locator (EAL) (Raypex 5) and conventional radiography, and then compare them with the actual measurements obtained by direct visualization. SETTINGS AND DESIGN: This study was conducted at the Department of Pedodontics and Preventive Dentistry, Government Dental College, Thiruvananthapuram, Kerala, India. SUBJECTS AND METHODS: One hundred single rooted primary teeth extracted due to extensive caries, trauma, serial extraction or unwillingness of the parent to save the teeth were selected. The teeth were numbered and root canal length was determined using the visual, electronic and the radiographic methods. The actual, electronic and the radiographic measurements were recorded. STATISTICAL ANALYSIS USED: Data were analyzed using Intraclass correlation test and linear regression analysis. RESULTS: The accuracy of EAL and radiographic methods were 92% and 72%, respectively within + 0.5 mm. Both the electronic and conventional radiographic methods showed a high correlation and agreement (ICC intraclass correlation coefficient = 0.99 and 0.98 respectively) with the actual measurements. CONCLUSIONS: EALs proved to be more accurate in determining the root canal length than the radiographic method. PMID- 23633802 TI - Coronal microleakage with five different temporary restorative materials following walking bleach technique: An ex-vivo study. AB - CONTEXT: Walking bleach technique uses 30% hydrogen peroxide and sodium perborate, and this paste mixture causes loosening of the coronal temporary restorative materials and thus decreasing its clinical effectiveness and causing irritation to the patients oral tissues. In the present study, sealing ability of hygroscopic coronal temporary restorative materials were compared with the other commonly used temporary restorative materials. AIM: To evaluate the effects of walking bleach material on the marginal sealing ability and coronal microleakage of the hydrophilic temporary restorative materials with that of the other commonly used temporary restorative materials in endodontic practice. MATERIALS AND METHODS: Seventy-five extracted human maxillary central incisor teeth were prepared chemo-mechanically and obturated with gutta-percha in lateral condensation technique. Surface of each tooth was double coated with cyanoacrylate glue. All the teeth were randomly divided in to five groups. Out of 15 teeth in each group, 10 teeth served as experimental specimens, in which bleaching agent was placed in the pulp chamber and 5 teeth served as control, in which no bleaching agent was placed. The access cavities were restored with temporary restorative materials being tested per each group respectively. The specimens were then immersed in 1% India ink dye and subjected to thermo cycling for 7 days. All the teeth were longitudinally sectioned and observed with stereomicroscope and were graded according to the depth of linear dye penetration. STATISTICAL ANALYSIS USED: Mann-Whitney U test and Kruskal-Wallis test. RESULTS: Hydrophilic temporary restorative materials Cavit G and Coltosol F have shown minimal coronal dye leakage with better sealing ability when exposed to walking bleach paste mixture in the dye penetration tests compared to other commonly used temporary restorative materials. CONCLUSION: Marginal sealing ability of Cavit G and Coltosol F were not influenced by the effects of bleaching agent compared to other temporary restorative materials used in the study. PMID- 23633803 TI - Oral health-related quality of life following non-surgical (routine) tooth extraction: A pilot study. AB - AIM: The study was designed to explore the changes in oral health-related quality of life (QoL) in the immediate postoperative period following routine (non surgical) dental extraction. SETTING AND DESIGN: A prospective study carried out at the Oral and Maxillofacial Surgery clinic of the Lagos University Teaching Hospital, Nigeria. MATERIALS AND METHODS: Subjects attending who required non surgical removal of one or two teeth under local anesthesia were included in the study. A baseline QoL questionnaire (oral health impact profile-14 [OHIP-14]) was filled by each patient just before surgery, and only those who were considered to have their QoL "not affected" (total score 14 or less) were included in the study. After the extraction, each subject was given a modified form of "health related QoL" [OHIP-14]-instrument to be completed by the 3(rd) day-after surgery, and were given the opportunity to review the questionnaire on the 7(th) day postoperative review. RESULTS: Total OHIP-14 scores ranged between 14 and 48 (mean +/- SD, 26.2 +/- 8.3). Majority of the subjects (60%) reported, "a little affected." Only few subjects (5.8%) reported, "not at all affected," and about 32% reported, "quite a lot." Summation of OHIP-14 scores revealed that QoL was "affected" in 41 subjects (34.2%) and "not affected" in 79 subjects (65.8%). More than 30% of subjects reported that their ability to chew, ability to open the mouth and enjoyment of food were affected following tooth extraction. Few subjects (14-34%) reported deterioration in their speech and less than 20% of subjects reported that change in their appearance was "affected." Only few subjects (12.5-15.1%) reported sleep and duty impairment. Thirty-percent of subjects reported their inability to keep social activities, and 41% were not able to continue with their favorite sports and hobbies. Multiple regression analysis revealed no significant association between age, sex, indications for extraction, duration of extraction, intra-operative complications, and deterioration in QoL (P < 0.05). Consumption of analgesics beyond postoperative day 1 (POD1) was more common in subjects with socket healing complications than those without (P = 0.000). About 33% of subjects reported, "inability to work" (1 3 days). CONCLUSION: About a third of subjects experienced significant deterioration in QoL. The most affected domains were eating/diet variation and speech variation. Therefore, patients should be informed of possible deterioration in their QoL following non-surgical tooth extraction. PMID- 23633804 TI - Enamel surface remineralization: Using synthetic nanohydroxyapatite. AB - OBJECTIVE: The purpose of this study was to evaluate the effects of synthetically processed hydroxyapatite particles in remineralization of the early enamel lesions in comparison with 2% sodium fluoride. MATERIALS AND METHODS: Thirty sound human premolars were divided into nanohydroxyapatite group (n = 15) and the sodium fluoride group (n = 15). The specimens were subjected to demineralization before being coated with 10% aqueous slurry of 20 nm nanohydroxyapatite or 2% sodium fluoride. The remineralizing efficacy of the materials was evaluated using surface microhardness (SMH) measurements, scanning microscopic analysis and analysis of the Ca/P ratio of the surface enamel. Data analysis was carried out using paired t-test and independent t-test. RESULTS: The results showed that the nanohydroxyapatite group produced a surface morphology close to the biologic enamel, the increase in mineral content (Ca/P ratio) was more significant in the nanohydroxyapatite group (P < 0.05) and the SMH recovery was closer to the baseline level in the nanohydroxyapatite group (P < 0.05). Both the groups did not show any significant difference in thickness (P > 0.05). CONCLUSION: The use of biomimetic nanohydroxyapatite as a remineralizing agent holds promise as a new synthetic enamel biocompatible material to repair early carious lesions. PMID- 23633805 TI - Autogenous bone block in the treatment of teeth with hopeless prognosis. AB - BACKGROUND: Autogenous bone graft, although considered as a gold standard, has been relegated to background because of limited quantity and donor site morbidity. Revival of interest in its use has been reflected by its tremendous capacity for regeneration in less than ideal situation. Bone blocks have been used for implant site augmentation, with varied success. AIM: Aim of the study was to evaluate the efficacy of autogenous bone block in the regeneration of bone, for saving teeth with a hopeless prognosis. SETTINGS AND DESIGN: A total of six patients and 12 sites with grade II and III mobile teeth were treated with autogenous bone blocks and fiber splinting. SUBJECTS AND METHODS: Attachment loss, probing depths, and radiographic bone loss were recorded at baseline and at 12 months interval. STATISTICAL ANALYSIS USED: The Student paired t test was used for evaluation of the changes from baseline to 12 months. RESULTS: At 12 months post-operatively, there was a highly significant amount of bone gain as compared to the baseline. The mean amount of bone loss reduced from 9.41 +/- 1.16 to 5.41 +/- 1.01. The clinical attachment loss reduced from 7.37 +/- 1.24 mm to 3.79 +/- 0.89 mm and probing depth reduced from 7 +/- 1.67 mm to 5.5 +/- 0.63 mm. The grafted bone was observed to have been incorporated with the host bone in most of the sites as evidenced by radiographs. CONCLUSIONS: For teeth with hopeless prognosis, this method can be considered to be a very viable alternative to extraction and replacement by costly implants. PMID- 23633806 TI - Occlusal traits of deciduous dentition of preschool children of Indian children. AB - OBJECTIVES: To assess the occlusal relationship, canine relationship, crowding, primate spaces, and anterior spacing in both maxillary and mandibular arches of primary dentition of Indian children of Wardha District and also to study the age wise differences in occlusal characteristics. MATERIALS AND METHODS: A total of 1053 (609 males and 444 females) children of 3-5 year age group with complete primary dentition were examined for occlusal relationship, canine relationship, crowding, primate spaces, and anterior spacing in both maxillary and mandibular arches. RESULTS: The data after evaluation showed significant values for all parameters except mandibular anterior spacing, which was 47.6%. Mild crowding was prevalent at 5 year age group and moderate crowding was common at 3 year-age group. CONCLUSION: Evaluated parameters such as terminal molar relationship and canine relationship were predominantly progressing toward to normal but contacts and crowding status were contributing almost equal to physiologic anterior spacing. Five-year-age group showed higher values with respect to all the parameters. PMID- 23633807 TI - Estimation of serum malondialdehyde in potentially malignant disorders and post antioxidant treated patients: A biochemical study. AB - BACKGROUND: Tobacco causes the generation of free radicals and reactive oxygen species (ROS) which are responsible for the high rate of lipid peroxidation. Malondialdehyde (MDA) is the most widely used agent to estimate the extent of lipid peroxidation. Timely diagnosis of the condition followed by supplementation with antioxidants like beta-carotene, pro-vitamin A, vitamin A, vitamin C, vitamin E, lipoic acid, zinc, selenium, and spirulina can prevent potentially malignant disorders. MATERIALS AND METHODS: In this study, serum MDA was measured according to the method of Buege, in 15 normal samples and 15 patients who were histopathologically diagnosed with potentially malignant disordered and they were prescribed with antioxidants for a period of 4 week-time following which potentially malignant patients serum MDA was analyzed again to determine the extent of peroxidation reactions. RESULTS: The mean serum MDA level in Group C1 was 0.7900 +/- 0.2336 MUM/L were as the mean serum MDA level of Group S1 was 2.478 +/- 0.50756 MUM/L and the values between them were highly significant. The values between C1 and S2 were found to be statistically significant. The mean serum MDA of S2 was 2.160 +/- 0.41252 MUM/L and the values were significant when compared to S1. CONCLUSION: Serum MDA estimation in oral pre-cancer would serve in determining the extent of lipid peroxidation. Diagnosis of patients and administration of antioxidants has proven to be effective in declining the ROS and thus reducing the extent of damage on the cells. MDA may serve as a diagnostic tool in the estimation of oral pre-cancer and in evaluation of post treated cases. PMID- 23633808 TI - Stress distribution among periodontally compromised abutments: A comparative study using three-dimensional finite element analysis. AB - AIMS: The aim of the study was to evaluate the stress distribution patterns in teeth and supporting structures of fixed prosthesis and design modifications in a fixed prosthesis with either normal or reduced bone support of an additional abutment. Study was also undertaken to disprove Ante's law. MATERIALS AND METHODS: Main models and variations of main models (modification 1, 2, 3, 4, 5, 6, 7, 8) were subjected to 200 N at angulations of 90 degrees and 15 degrees on functional cusps. Results for each loading were obtained as stress distribution color images and numerical values were recorded. A three-dimensional finite element analysis study of variations of normal models was performed using two finite element softwares, namely PRO-Engineer wildfire version 1.0 manufacturer: Parametric technology corporation, Needham, MA 02494 U.S.A. RESULTS: When periodontal compromised abutment teeth was splinted with an additional abutment an increase of stress was observed in periodontally compromised abutments so an additional abutment is not required. Eventhough the pericemental area of compromised abutments with an additional abutment (canine) was more than the combined pericemental area of pontics to be replaced, stress generated was more on abutments. This disproves Ante's law. Hence, it may be a reference, but should not be the ultimate criterion in determining the number of multiple abutments. CONCLUSIONS: When periodontal compromised abutment teeth was splinted with an additional abutment an increase of stress was observed in periodontally compromised abutments so an additional abutment is not required. Even though the pericemental area of compromised abutments with an additional abutment (canine) was more than combined pericemental area of pontics to be replaced, stress generated was more on abutments. This disproves Ante's law. Hence, it may be a reference, but should not be the ultimate criterion in determining the number of multiple abutments. PMID- 23633809 TI - Prevalence of and factors affecting post-obturation pain following single visit root canal treatment in Indian population: A prospective, randomized clinical trial. AB - AIM: This prospective randomized clinical study (1) investigated the prevalence of post-obturation pain after single visit root canal treatment and (2) evaluated the influence of factors affecting the pain experience. MATERIALS AND METHODS: One thousand three hundred and twenty eight (1328) patients were included in this study. Conventional single visit root canal treatment was carried out. The chemicomechanical preparation of root canals was done by a rotary protaper system with a combination of hand instruments. Post-operative pain was recorded by each patient by using visual analogue scale in well-defined categories at three time intervals, 12 h, 24 h, and 48 h. The data were analyzed using Fisher's exact test. RESULTS: The prevalence of post-obturation pain (severe) within 48 h after treatment was 4% (n = 54) but less as compared to the pain experienced after 12 h (9%) and 24 h (8.6%). The factors that significantly influenced post-obturation pain experience were: Age (Fishers exact test = 46.387, P = 0.0), gender (Fishers exact test = 23.730, P = 0.0), arch (Fishers exact test = 11.710, P = 0.001), and presence of pre-operative pain (Fishers exact test = 67.456, P = 0.0). CONCLUSION: The presence of post-operative pain was low (4%). The important prognostic determinants of post-obturation pain were: Old age, female, mandibular teeth, and presence of pre-operative pain. The vital condition of the tooth does not affect the intensity and frequency of post-obturation pain. PMID- 23633810 TI - An asymptomatic tongue nodule. AB - Cysticercosis is a major health concern in developing countries, as it is a major cause of seizures in these countries. The tissues commonly affected are the neural tissues, muscle, heart, lungs, liver, subcutaeneous layers and peritoneum, but oral manifestations are rare. Present case is of an asymptomatic tongue nodule which was diagnosed as cysticercosis on histologic examination. Thus, emphasizing the importance of routine microscopic examination and diagnosis of apparently innocuous lesions of the oral cavity. PMID- 23633811 TI - A novel surgical procedure for papilla reconstruction using platelet rich fibrin. AB - Loss of interdental papilla predisposes to phonetic, functional, and esthetic problem. Surgical techniques are manifold, but are challenging and very unpredictable. The purpose of this case report is to present the use of platelet rich fibrin (PRF) in the reconstruction of papilla in the maxiallry anterior region of a forty year old woman who presented with loss of interdental papillae in 11, 12 and 11, 21 region. PRF was tucked in to the pouch created with a semilunar pedicle flap and the entire gingivopapillary unit was displaced coronally. Optimal fill was noted at 3 and 6 months postoperatively. Use of PRF may thus be the panacea for interdental papilla augmentation. PMID- 23633812 TI - Placement of implants in an ossifying fibroma defect obliterated with demineralized, freeze-dried bone allograft and Plasma-rich growth factor. AB - There has been considerable clinical interest in combining the grafts, particularly bone allografts for support for dental implants, soft-tissue support, periodontal maintenance, and ovate pontic formation. The use of demineralized, freeze-dried bone allograft (DFDBA) offers certain advantages over other graft materials and can avoid the need for a second-site surgery for autogenous donor bone. The advantages of DFDBA include handling properties, osteoinductivity, membrane tenting, and less susceptibility to migration after placement. This article will review available grafting materials and demonstrate a case of ossifying fibroma of the mandible, which was treated by curettage and hollow cavity filled with DFDBA. Six months follow-up period showed successful graft result and this grafted bone form was utilized for implant supported prosthesis. PMID- 23633813 TI - Unusual imaging appearance of unicystic ameloblastoma. AB - Unicystic ameloblastoma (UA) refers to those cystic lesions that show clinical, radiographic, or gross features of a mandibular cyst, but on histologic examination show a typical ameloblastous epithelium lining part of the cystic cavity, with or without luminal and/or mural tumor growth. It accounts for 5-15% of all intraosseous ameloblastomas. We report a case of UA in a 35-year-old female with an unusual large multilocular (tennis racket) appearance on the right body of mandible and illustrate the importance and complexity of differential diagnosis with a brief review of recent literature. PMID- 23633814 TI - Use of ribbond and panavia F cement in reattaching fractured tooth fragments of vital maxillary anterior teeth. AB - Coronal fractures of the anterior teeth are a common form of dental trauma that mainly affects children and adolescents. One of the options for managing coronal tooth fractures when the tooth fragment is available and there is no or minimal violation of the biological width is the reattachment of the fragment. This article presents a novel technique for reattachment of oblique fractured fragment of vital maxillary central and lateral incisor with pulp exposure. Pulp capping was done using mineral trioxide aggregate. Orthodontic extrusion was done to expose the sub gingival fractured site. Polyethylene fiber (ribbond) and panavia F cement were used to reattach the fractured fragment using an internal groove technique to provide high fracture strength to restored tooth. Ribbond fibers can be used to give additional strength to the reattached tooth fragment so that the tooth obtains fracture resistance equal to an intact tooth. PMID- 23633815 TI - Autogenous bonding of tooth fragment retained in lower lip after trauma. AB - In cases of trauma, dental fragments occasionally penetrate into the soft-tissues and may cause severe complications, if neglected. Clinical and radiographic examinations can provide a diagnosis and help in the surgical removal of any dental fragment embedded in soft-tissue. This case report concerns an 8-year-old boy who was diagnosed with a fragment of a fractured permanent central incisor crown located in the lower lip. The patient was seen initially at a general hospital, where the dental fragment went unnoticed. After 2 days, the patient was seen at the pediatric dentistry clinic, where a fragment embedded in the lower lip, causing a large swelling, was diagnosed. The fragment was removed surgically and bonded to the fractured tooth. A mouth guard was prescribed for sports. The importance of soft-tissue exploration even post-trauma was highlighted in this paper. PMID- 23633817 TI - Traumatic pseudo-lipoma in 3-year-old child. AB - The buccal fat pad is relatively large and prominent in neonates, infants and young children. The main function of this fat pad is considered as a cushioning tissue and sucking pad. A minor tear of buccal mucosa and buccinator muscle can result in herniation of large volume of fat into oral cavity that is termed as "pseudolipoma." The young children tend to be very playful while brushing their teeth. Improper brushing technique resulted in severe trauma to the buccal fat, including soft-tissue between buccinator and retromolar area. This article presents a case-report of a female child who developed traumatic pseudolipoma after faulty tooth brushing for long duration and its management along with its detail review of literature. PMID- 23633816 TI - Addison's disease. AB - Addison's disease is a rare endocrinal disorder, with several oral and systemic manifestations. A variety of pathological processes may cause Addison's disease. Classically, hyperpigmentation is associated with the disease, and intraoral pigmentation is perceived as the initial sign and develops earlier than the dermatological pigmentation. The symptoms of the disease usually progress slowly and an event of illness or accident can make the condition worse and may lead to a life-threatening crisis. In this case, several oral as well as systemic manifestation of the Addison's disease was encountered. PMID- 23633818 TI - Mineral trioxide aggregate pulpotomy: An ideal treatment option for management of talon cusp. AB - To use mineral trioxide aggregate (MTA) in prophylactic management of talon cusp. Talon cusp is an endodontic oddity that possesses a treatment challenge to the clinician, especially when it causes esthetic and functional problems. Management ranges from periodic gradual reduction to radical removal followed by vital pulp/endodontic therapy. MTA has replaced calcium hydroxide as pulp capping material because of its superior properties. A 12-year-old boy reported with a complaint of irregular teeth. Clinical and radiographic examination revealed talon cusp on maxillary left central incisor. Radical removal of talon cusp and MTA pulpotomy was performed. The 4-year follow-up showed the positive pulp vitality test without any radiographic changes, emphasizing the use of MTA pulpotomy in successful management of talon cusp. PMID- 23633819 TI - Ewing's sarcoma of mandible: A case report and review of Indian literature. AB - Ewing's sarcoma (ES) is a rare malignancy primarily affecting skeletal system and it is commonly diagnosed in children and young adults. It seldom occurs in the head and neck region. ES has poor prognosis because of uncontrolled metastatic potential making early diagnosis and intervention critical for survival of the patient. This paper reports a rare case of ES involving mandible in an 8-year-old girl with clinical, radiological, histopathological and immunohistochemical features. PMID- 23633820 TI - Genetics and presence of non-syndromic supernumerary teeth: A mystery case report and review of literature. AB - Presence of supernumerary teeth is well-recognized clinical phenomenon. However, it is uncommon to find multiple supernumeraries in individuals with no other associated disease or syndrome. Presence of multiple supernumerary teeth is thought to have genetic component. We report a rare case where multiple supernumerary teeth were seen without presence of any other syndrome in 3 generations; father, son, and two grandsons. We also present a review of similar cases published in literature till date. The role of genetics in development of supernumerary teeth is highlighted. PMID- 23633821 TI - Stylocarotid syndrome: An unusual case report. AB - Patients presenting with vague head and neck pain can lead to wide-ranging differential diagnosis. Elongation of styloid process (SP) should also be considered as one of the etiological factors for cervical pain radiating to jaws, pharyngodynia, and difficulty in swallowing. Symptomatic elongation of SP or mineralization of stylohyoid ligament is referred as Eagle's syndrome. It is a rare entity presenting with an array of symptoms like recurrent throat pain, dysphagia, otalgia, and neck pain. History and physical examination play a vital role in diagnosing this condition and further radiological investigation confirms the diagnosis. The preferred radiologic modality is 3D-computed tomography, which gives accurate information about length, angulation, type of elongation, and relation to vital structures and hence helps in execution of treatment planning. This paper describes clinical approach, imaging investigations, and management of a case of Eagle's syndrome. PMID- 23633822 TI - Huge lipoma of tongue. AB - Lipoma is the commonest benign tumor occurring at any anatomical site, where fat is present. In oral cavity and oropharynx, it is a relatively uncommon neoplasm. Tongue, which is totally devoid of fat cell is also a site for lipoma but very rarely. We report one such rare case of the universal tumor, of 20 years of duration and 9 cm in size, presenting at the lateral margin, dorsal and ventral surface of the tongue, for which complete tumor excision was done. PMID- 23633823 TI - Multidisciplinary management of an unusual case of multiple developmental defects in lateral incisor followed by intrusive injury to primary incisors. AB - Dental traumatic injuries occur frequently in children. The close relationship between the apices of primary teeth and germ of the permanent successors can lead to developmental disturbances in the permanent dentition. Developmental disorder can occur in any tooth. One of the most common teeth affected is lateral incisor. These developmental anomalies can cause various clinical problems. Clinical and radiographic characteristics of these anomalies may sometime present confusing picture. Therefore, recognition of this condition, early diagnosis, and treatment are important to avoid complications. High prevalence of dental trauma in young children emphasizes the need of educational and preventive programs in schools. Dentist plays important role in early diagnosis of disturbances in the permanent successor teeth by rigorous clinical and radiographic follow-up examination. PMID- 23633824 TI - Nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome). AB - The Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome (NBCCS), is an infrequent multisystemic disease inherited in a dominant autosomal way, which shows a high level of penetrance and variable expressiveness. It is characterized by odontogenic keratocysts in the jaw, multiple basal cell nevi carcinomas and skeletal abnormalities. This syndrome may be diagnosed early by a dentist by routine radiographic exams in the first decade of life, since the odontogenic keratocysts are usually one of the first manifestations of the syndrome. This case report presents a patient diagnosed as NBCCS by clinical, radiographic and histological findings in a 13-year-old boy. This paper highlights the importance of early diagnosis of NBCCS which can help in preventive multidisciplinary approach to provide a better prognosis for the patient. PMID- 23633825 TI - Maxillary lateral incisors with two canals and two separate curved roots. AB - Variation in the roots and root canal anatomy seems to be the norm rather than an exception. For a successful endodontic treatment, a clinician should have a thorough knowledge of the internal and external dental anatomy and its variations. Maxillary lateral incisors usually exhibit single canal with a single root. In this case, clinical examination and radiographs clearly demonstrates the presence of two root canals with two separate curved roots. This case report emphasizes the need for attention during endodontic management of maxillary lateral incisors. PMID- 23633826 TI - The fear and fever of publication? PMID- 23633827 TI - Digitization of DNA: Miniaturization of information storage moving toward data in DNA! PMID- 23633828 TI - Role of curcumin in systemic and oral health: An overview. AB - Various modalities of treatment are available for different dental diseases, but the major drawback of these conventional drug therapies is the numerous side effects associated with their use. This has led to renewed interest in the discovery of novel anti-infective natural compounds derived from plants. Plants have been the major source of medicine since the time immemorial. Turmeric has been attributed a number of medicinal properties in the traditional system of medicine. The objective of this article is to review the efficacy of turmeric herb in maintenance of oral health, in particular, and overall health, in general. Turmeric, a rhizome of Curcuma longa, is a herb known for its medicinal properties and is a more acceptable and viable option for a common man. It has proven properties like anti-inflammatory, antioxidant, antimicrobial, hepatoprotective, immunostimulant, antiseptic, and antimutagenic. Due to these properties, it is quite useful in dentistry as well. It has a role in the treatment of periodontal diseases and oral cancers. Turmeric can also be used as a pit and fissure sealant, mouth wash, and subgingival irrigant in different preparations. It can also be used as a component in local drug delivery system in gel form. PMID- 23633829 TI - Vagal nerve stimulator: Evolving trends. AB - Over three decades ago, it was found that intermittent electrical stimulation from the vagus nerve produces inhibition of neural processes, which can alter brain activity and terminate seizures. This paved way for the concept of vagal nerve stimulator (VNS). We describe the evolution of the VNS and its use in different fields of medicine. We also review the literature focusing on the mechanism of action of VNS producing desired effects in different conditions. PUBMED and EMBASE search was performed for 'VNS' and its use in refractory seizure management, depression, obesity, memory, and neurogenesis. VNS has been in vogue over for the past three decades and has proven to reduce the intensity and frequency of seizure by 50% in the management of refractory seizures. Apart from this, VNS has been shown to promote neurogenesis in the dentate gyrus of rat hippocampus after 48 hours of stimulation of the vagus nerve. Improvement has also been observed in non-psychotic major depression from a randomized trial conducted 7 years ago. The same concept has been utilized to alter behavior and cognition in rodents, and good improvement has been observed. Recent studies have proven that VNS is effective in obesity management in patients with depression. Several hypotheses have been postulated for the mechanism of action of VNS contributing to its success. VNS has gained significant popularity with promising results in epilepsy surgery and treatment-resistant depression. The spectrum of its use has also extended to other fields of medicine including obesity, memory, and neurogenesis, and there is still a viable scope for its utility in the future. PMID- 23633830 TI - Halitosis: From diagnosis to management. AB - Halitosis is formed by volatile molecules which are caused because of pathological or nonpathological reasons and it originates from an oral or a non oral source. It is very common in general population and nearly more than 50% of the general population have halitosis. Although halitosis has multifactorial origins, the source of 90% cases is oral cavity such as poor oral hygiene, periodontal disease, tongue coat, food impaction, unclean dentures, faulty restorations, oral carcinomas, and throat infections. Halitosis affects a person's daily life negatively, most of people who complain about halitosis refer to the clinic for treatment but in some of the people who can suffer from halitosis, there is no measurable halitosis. There are several methods to determine halitosis. Halitosis can be treated if its etiology can be detected rightly. The most important issue for treatment of halitosis is detection etiology or determination its source by detailed clinical examination. Management may include simple measures such as scaling and root planning, instructions for oral hygiene, tongue cleaning, and mouth rinsing. The aim of this review was to describe the etiological factors, prevalence data, diagnosis, and the therapeutic mechanical and chemical approaches related to halitosis. PMID- 23633831 TI - Bioterrorism: Health sector alertness. AB - The global events of the last two decades indicate that the threat of biological warfare is not a myth, but a harsh reality. The successive outbreaks caused by newly recognized and resurgent pathogens and the risk that high-consequence pathogens might be used as bioterrorism agents amply demonstrate the need to enhance capacity in clinical and public health management of highly infectious diseases. This review article provides a concise overview of bioterrorism, the agents used, and measures to counteract it, with a relevant note on India's current scenario of surveillance systems, laboratory response network, and the need for preparedness. PMID- 23633833 TI - The nano era in dentistry. AB - Nanotechnology is a new transnational and transcultural development that is growing rapidly and pervasively. The potential impact of novel Nanodentistry Applications in disease diagnosis, therapy and prevention is foreseen to change oral health care in a fundamental way. This review presents a general overview of the novel nanomaterial and relevant advances of nanotechnology, focusing on promising dental applications. In particular, relevant applications are reported in Restorative dentistry, minimally invasive dental procedures, cancer diagnosis and treatment, molecular imaging and implant dentistry. Many applications are still in their infancy. An increasing number of products are currently under clinical investigation while some are commercially available. PMID- 23633834 TI - Electrostatic interaction between dipoles and side chains in the voltage sensor domain of K(+) channel. AB - BACKGROUND: It is well known that alpha-helices of protein, possessing equal and opposite charged ends, behaves like a macrodipole, but the relative importance of such macrodipoles to the aggregation of a pair of helix in the voltage sensor domain (VSD) of K+ ion channel, has not been assessed. In the VSD, importance has been given primarily to the helically arranged Arginine residues of helix, but the role of the charged residues of S3b is less focused. METHOD AND OBJECTIVE: Applying electrostatic theory, we have studied the interaction between the charges of S3b-S4 alpha-helix pair of KvAP through virtual mutagenesis. RESULT AND CONCLUSION: We have shown that the terminal charges arising from the inherent dipolar property of alpha-helices play an important role in affecting the stability of the S3b-S4 pair, and in determining its spatial position at zero transmembrane potential. Moreover, the negatively charged side chain of S3b was found to be the primary stabilizing factor in holding S3b-S4 pair together as a "paddle". Comparison of sequences of S3b helix of K+ channels from different species showed a previously unreported positional conservation of negative residues, highlighting their functional importance. These charges may contribute to the energetic of alpha-helix movements in an electric field. PMID- 23633832 TI - Early childhood caries update: A review of causes, diagnoses, and treatments. AB - Dental caries (decay) is an international public health challenge, especially amongst young children. Early childhood caries (ECC) is a serious public health problem in both developing and industrialized countries. ECC can begin early in life, progresses rapidly in those who are at high risk, and often goes untreated. Its consequences can affect the immediate and long-term quality of life of the child's family and can have significant social and economic consequences beyond the immediate family as well. ECC can be a particularly virulent form of caries, beginning soon after dental eruption, developing on smooth surfaces, progressing rapidly, and having a lasting detrimental impact on the dentition. Children experiencing caries as infants or toddlers have a much greater probability of subsequent caries in both the primary and permanent dentitions. The relationship between breastfeeding and ECC is likely to be complex and confounded by many biological variables, such as mutans streptococci, enamel hypoplasia, intake of sugars, as well as social variables, such as parental education and socioeconomic status, which may affect oral health. Unlike other infectious diseases, tooth decay is not self-limiting. Decayed teeth require professional treatment to remove infection and restore tooth function. In this review, we give detailed information about ECC, from its diagnosis to management. PMID- 23633835 TI - Search of potential inhibitor against New Delhi metallo-beta-lactamase 1 from a series of antibacterial natural compounds. AB - BACKGROUND: New Delhi metallo-beta-lactamase-1 (NDM-1)-producing Gram-negative bacteria are today's major worldwide health concern. The enzyme NDM-1 provides bacterial resistance by its hydrolytic activity against the beta-lactam ring of antibiotics. Inhibition of NDM-1 may prevent the hydrolysis of beta-lactam ring of the antibiotics, and therefore, plays an important role against antibacterial resistance. MATERIALS AND METHODS: Here we made an attempt to design suitable inhibitors against NDM-1 from different natural antibacterial compounds using molecular docking approach. RESULTS: We observed that natural compounds such as Nimbolide and Isomargololone are showing an appreciable IC50 value as well as significant binding energy value for NDM-1. We further observed these compounds showing better affinity to NDM-1 on comparison with 14 beta-lactam antibiotics. CONCLUSION: Finally, our study provides a platform for the development of a potent inhibitor of NDM-1, which may be considered as a potential drug candidate against bacterial resistance. PMID- 23633836 TI - Incidence of metabolic syndrome and its characteristics of patients attending a diabetic outpatient clinic in a tertiary care hospital. AB - OBJECTIVE: We sought to evaluate the incidence of metabolic syndrome and non metabolic syndrome among type 2 diabetic patients attending the diabetic outpatient clinic at tertiary care hospital, Warangal. MATERIALS AND METHODS: A cross-sectional study was conducted in a period of 6 months from January 2011 to June 2011. The study group consisted of 75 type 2 diabetic patients. They were screened for hypertension, hyperlipidemia, obesity, and clinical characteristics, and other co-morbidities were recorded. Metabolic syndrome diagnosis was made as per ATP III guidelines. RESULTS: The prevalence of metabolic syndrome was significant in men (54.8%) compared to women (45.2%). Incidence of metabolic syndrome was found to be more in normal weight patients (43.56%). Low high density lipoprotein (HDL) levels were observed in both rural (90.63%) and urban (95.65%) patients with metabolic syndrome, followed by increase in waist circumference. The mean HDL level was found to be 23.77 mg/dl. Patients in the age group 51-60 years were found to be more affected with metabolic syndrome. Sedentary household female patients (58.3%) and illiterates (41.8%) were suffering from metabolic syndrome. Patients with metabolic syndrome had been suffering with diabetes (duration of diabetes) from 1 to 5 years. In summary, this cross-sectional study characterizes the metabolic and non-metabolic syndromes of type 2 diabetes patients living in Telangana regions, using ATP III guidelines, and generates a biological resource that enables further investigation of numerous hypotheses related to genetic exposure of both in a population. CONCLUSION: These results suggest that higher prevalence of metabolic syndrome was observed in non-obese male patients and was significantly associated with aging. Nevertheless, further studies are required to confirm the metabolic syndrome in larger population. PMID- 23633837 TI - Evaluation of the protective role of vitamin C in imidacloprid-induced hepatotoxicity in male Albino rats. AB - In the present study, the effects of oral administration of imidacloprid for 4 weeks on serum biochemical, oxidative stress, histopathological and ultrastructural alterations were assessed in the liver of male rats. This study also aimed to investigate whether vitamin C could protect against the imidacloprid-induced oxidative stress. Forty-eight male Sprague dawley rats were divided into four groups of 12 animals each. Group 1 served as the control, while groups 2 and 4 were administered with imidacloprid (80 mg/kg body weight) daily by oral gavage for 28 days. In addition to imidacloprid, group 4 also received vitamin C at 10 mg/kg daily by oral gavage for 28 days. Group 3 was maintained as the vitamin C control (dose as above). The serum biochemical assays revealed a significant (P < 0.05) increase in alanine transaminase and aspartate transaminase and decrease in total protein in group 2. The tissue biochemical profile revealed a significant (P < 0.05) reduction in reduced glutathione concentration in the liver of group 2 animals. Histologically, the liver showed marked dilation, congestion of central vein, portal vein and sinusoidal spaces, vacuolation/fatty change and degenerated hepatocytes. Ultra thin sections of the liver revealed swollen nuclei, varied size and shape of mitochondria, disrupted chromatin and rough endoplasmic reticulum. Co-treatment with vitamin C significantly (P < 0.05) reversed the imidacloprid-induced changes. PMID- 23633838 TI - Ameliorating effect of mother tincture of Syzygium jambolanum on carbohydrate and lipid metabolic disorders in streptozotocin-induced diabetic rat: Homeopathic remedy. AB - BACKGROUND: Syzygium jambolanum (S jambolanum) is widely used in homeopathy for treating patients with diabetes mellitus. In the present study, an attempt has been made to investigate the remedial effect of homeopathic drug S jambolanum on carbohydrate and lipid metabolic disorders on streptozotocin induced diabetic rat. MATERIALS AND METHODS: Diabetes induction in Wistar strain rat was performed as per standard method using streptozotocin at the dose of 4 mg/100 gm body weight. Activities of carbohydrate metabolic enzymes in hepatic tissue, and glycogen content in hepatic and muscular tissues were assessed biochemically following the standard protocols. Serum lipid profile level and activities of GOT and GPT in serum were measured as per standard method using specific kits. RESULTS: The homeopathic drug, mother tincture of S jambolanum significantly decreased fasting blood glucose levels and improved carbohydrate metabolic key enzyme activities in hepatic tissue i.e., hexokinase, glucose-6-phosphate dehydrogenase and glucose-6-phosphatase in diabetic rats. Alongside, serum lipid profile biomarkers i.e., triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDLc), very low density lipoprotein cholesterol (VLDLc) and high density lipoprotein cholesterol (HDLc) levels were significantly ameliorated in homeopathic drug supplemented diabetic animals in compared with the untreated diabetic animal. Side by side, the S jambolanum has the capacity to attenuate diabetes induced hepatic injury in model animal, which has been assessed here by the recovery of GOT and GPT activities in serum of drug treated diabetic animal. CONCLUSION: The result of the present study indicated that the homeopathic drug S jambolanum (mother tincture) has a protective effect on diabetic induced carbohydrate and lipid metabolic disorders in STZ-induced diabetic animal. PMID- 23633839 TI - A comparison between cervical vertebrae and modified MP3 stages for the assessment of skeletal maturity. AB - OBJECTIVE: Evaluation of skeletal maturity in human individuals is an important aspect in orthodontics and dentofacial orthopedics because, growth guidance and fundamental structural changes are essential for treatment of skeletal discrepancies in all the three planes. Among various growth assessment methods, cervical vertebra maturation stages and hand wrist have been correlated with the individual growth changes during puberty. The purpose of this study is to determine correlation of the CVM index with the modified median phalanx index (MP3) as described by Rajagopal and Kansal. MATERIALS AND METHODS: 200 subjects (100 males and 100 females) of Nellore, Indian origin boys aged between 10 to 19 years and girls of 8 to 16 years were selected for the study. The subjects are selected randomly from patients visiting the Departments of Orthodontics and Dentofacial Orthopedics, Pediatric dentistry and Oral medicine and Radiology at Narayana Dental College and Hospital. Nellore. Radiographs of left hand MP3 and lateral cephalogram were taken. RESULTS: Cohen's kappa statistic was used to assess the agreement between the two measurements based on categorical variables. CONCLUSIONS: There was a good concordance between 6 stages of CVMI (Hassel and Farman) and the 6 stages of MP3 (Rajagopal and Kansal). Physiological maturity was earlier in females than in males when compared to the individuals of opposite sex of same chronological age. Chronological age was not a valid predictor of assessing the skeletal maturity because of significant variations in the distribution of CVMI and MP3 stages with respect to individual chronological age distribution. PMID- 23633840 TI - Human immunodeficiency virus/acquired immunodeficiency syndrome knowledge among high school students in Kirikkale province of Turkey. AB - BACKGROUND: The purpose of the present study was to assess the existing level of knowledge of high school children about human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and the sources of their information. MATERIALS AND METHODS: A cross-sectional survey was conducted in two high schools in Kirikkale, Turkey and data were collected by a self-administered questionnaire. Multi-stage sampling technique was used to obtain a representative sample. RESULTS: Four hundred and seventy three participants; 230 males and 243 females were analyzed. Their ages ranged from 15 to 19 years with a mean age of 16.81 +/- 1.27. 92.2% of the students claimed to have heard about HIV/AIDS prior to the study with slightly more females than males. Although with some misconceptions, majority of the participants knew that HIV is not transmitted by sharing meals, casual contact, and sleeping in the same room and using the same bathroom. 93.4% identified HIV/AIDS as a life-threatening disease and 27% believe that there is a cure for AIDS. 64% and 22.8% respectively believed that the people can protect themselves by using condoms and by avoiding sexual contact. Internet was preponderantly claimed as the most important source of information about HIV/AIDS. CONCLUSION: Empirical evidence from this study suggests that the students have a fairly high knowledge of HIV/AIDS. This is not without some misconceptions about the prognosis of the disease. Internet was the major source of HIV/AIDS information. PMID- 23633841 TI - Evaluation of protective action of alpha-tocopherol in chromium-induced oxidative stress in female reproductive system of rats. AB - The present study was aimed to investigate whether alpha-tocopherol could protect the chromium (Cr) VI-induced oxidative stress in female reproductive system of rats and to explore the underlying mechanisms of the same. A total of 24 Wistar adult female rats were equally divided into four groups. Group 1 served as control, while groups 2 and 3 were administered K2Cr2O7 (10 mg/kg b.wt. s.c. single dose). In addition to Cr, group 3 also received alpha-tocopherol @ 125 mg/kg daily by oral gavage for 14 days. Group 4 was maintained as alpha tocopherol control (dose as above). Body weights were recorded at the beginning and at the end of experiment. Further, the rats were observed for occurrence of estrus cycle. At the end of 14 days, blood samples were drawn for sero biochemical analysis. Subsequently, all the rats were sacrificed to collect uterus along with ovaries for assay of tissue peroxidation, anti-oxidant and functional markers, and histopathology. Administration of chromium (Cr) VI to rats revealed a significant (P < 0.05) accumulation of cholesterol and a prolonged diestrus phase leading to impaired fertility in rats. Administration of chromium (Cr) VI significantly (P < 0.05) reduced the antioxidant markers such as superoxide dismutase (SOD) and reduced glutathione (GSH), along with significant (P < 0.05) increase in peroxidation markers such as malondialdehyde and protein carbonyls in ovaries. The functional marker in serum such as total protein was decreased, whereas other functional markers viz alanine transaminase (ALT), blood urea nitrogen (BUN) and creatinine were increased. Prominent pathological changes were observed in the uterus and ovaries of Cr-treated group. Co-treatment with alpha-tocopherol significantly (P < 0.05) reversed the (Cr) VI induced changes. PMID- 23633842 TI - Evaluation of arch width variations among different skeletal patterns in South Indian population. AB - BACKGROUND: Anterior cranial base can be taken as a reference line (SN) to determine the steepness of mandibular plane. Subjects with high mandibular plane angle tend to have a long face and one with low MP-SN angle has a shorter face. OBJECTIVE: This study was done to investigate if dental arch widths correlated with vertical facial types and if there are any differences in arch widths between untreated male and female adults in South Indian population. MATERIALS AND METHODS: Lateral cephalogram and dental casts were obtained from 180 untreated South Indian adults (90 males and 90 females) above 18 year old with no cross bite, minimal crowding and spacing. The angle between the anterior cranial base and the mandibular plane was measured on lateral cephalogram of each patient. Dental casts were used to obtain comprehensive dental measurements including maxillary and mandibular inter canine, inter premolar and inter molar widths, as well as amount of crowding or spacing. RESULTS: The results showed that male arch widths were significantly larger than those of females (P < 0.05) and there was a significant decrease in inter arch width as the MP-SN angle increased in untreated adult South Indian population. The results obtained in our study when compared with studies done in other population groups showed that there is difference in inter arch widths according to ethnicity and race. CONCLUSION: It was concluded that the dental arch width is associated with gender, race and vertical facial morphology. Thus using individualized arch wires according to each patient's pre treatment arch form and width is suggested during orthodontic treatment. PMID- 23633843 TI - Objective structured practical examination in biochemistry: An experience in Medical College, Kolkata. AB - BACKGROUND: Undergraduate medical examination is undergoing extensive re evaluation with new core educational objectives being defined. Consequently, new exam systems have also been designed to test the objectives. Objective structured practical examination (OSPE) is one of them. OBJECTIVES: To introduce OSPE as a method of assessment of practical skills and learning and to determine student satisfaction regarding the OSPE. Furthermore, to explore the faculty perception of OSPE as a learning and assessment tool. MATERIALS AND METHODS: The first M.B.B.S students of 2011 12 batch of Medical College, Kolkata, were the subjects for the study. OSPE was organized and conducted on "Identification of Unknown Abnormal Constituents in Urine." Coefficient of reliability of questions administered was done by calculating Cronbach's alpha. A questionnaire on various components of the OSPE was administered to get the feedback. RESULTS: 16 students failed to achieve an average of 50% or above in the assessment. However, 49 students on an average achieved >75%, 52 students achieved between 65% and 75%, and 29 students scored between 50% and 65%. Cronbach's alpha of the questions administered showed to be having high internal consistency with a score of 0.80. Ninety nine percent of students believed that OSPE helps them to improve and 81% felt that this type of assessment fits in as both learning and evaluation tools. Faculty feedback reflected that such assessment tested objectivity, measured practical skills better, and eliminated examiner bias to a greater extent. CONCLUSION: OSPE tests different desired components of competence better and eliminated examiner bias. Student feedback reflects that such assessment helps them to improve as it is effective both as teaching and evaluation tools. PMID- 23633844 TI - Conservative management of Beta-thalassemia major cases in the sub-division level hospital of rural West Bengal, India. AB - BACKGROUND: The ideal management of thalassemia involves a multidisciplinary therapeutic team approach and should be preferably done at a comprehensive thalassemia care center with all sorts of specialists and the backup of a well equipped blood bank. However, in developing country like ours, these facilities are not available in rural set up. So, a situation where conservative therapy with regular blood transfusion is the only choice left to innumerable thalassemic children. OBJECTIVE: To evaluate the existing conservative management protocol of Beta-thalassemia major patients in the setup of a subdivision level Government Hospital of rural West Bengal, India. MATERIALS AND METHODS: The study was performed between December 2009 and December 2011. Beta-thalassemia major patients, registered in blood bank for moderate transfusion regimen, were taken in study. All the patients were screened for Transfusion Transmittable Infections at the time of registration and thereafter periodically every six months. Iron chelation therapy was given simultaneously with transfusion at a dose of 20 to 40 mg/kg/day for six days. The patients were advised to follow up with chelation therapy at home by daily infusion with a goal of maintaining serum ferritin level below 1000 ng/ml. Over this long period of study, the patients were periodically evaluated for complications. RESULTS: The average blood requirement (ml/kg/year) in 1-5 years, 6-10 years, and 11-15 years were 110, 150, and 180, respectively. Incidence of Hepatitis C Virus infection in 1-5 years and 6-10 years were 1.75% and 2.08%, respectively. It is well seen that serum ferritin level increase with ascending age as does the blood consumption. CONCLUSION: Conservative management may be the best alternative and at times the only hope for patients in developing country like ours. However, in order to decrease the disease load, steps need to be taken to introduce preventive measures. PMID- 23633845 TI - Serum magnesium levels in patients with diabetic retinopathy. AB - BACKGROUND: Diabetic retinopathy is one of the leading causes of blindness in the world. Hypomagnesemia has been reported to occur at an increased frequency among patients with type 2 diabetes compared with their counterparts without diabetes. Hypomagnesemia has been linked to poor glycemic control. Many studies have been undergone to find out the precipitated factors of retinopathy such as duration and type of diabetes, hyperglycemia, hypomagnesemia and increased urinary total protein levels. AIM: This study was carried out to study the correlation between serum magnesium levels, glycosylated hemoglobin and urinary total protein levels in diabetic patients with retinopathy. MATERIALS AND METHODS: The study population comprised of 30 type 2 diabetic patients without retinopathy as Group 2, 30 type 2 diabetic patients with retinopathy as Group 3 in the age group 45-75 years as cases and 60 age and sex matched healthy individuals as controls (Group 1). Determination of Serum Magnesium (photometric xylidyl blue method), glycosylated hemoglobin, Hb1C (IFCC), fasting blood glucose, postprandial blood glucose (glucose oxidase method) and urine total protein (Pyrogallol red method) was carried out. The statistical software SPSS 11.0 and Systat 8.0 were used for the analysis of the data. RESULTS: Hypomagnesemia was observed in cases compared with both Group 2 and Group 3. FBS, PPBS, HbA1c, Urine total protein levels were increased in cases (without retinopathy and with retinopathy) compared with controls. CONCLUSION: Hypomagnesemia and albuminuria individually or in conjunction serve as indicators for dysglycemia and could be used as marker for the risk of development of diabetic retinopathy. PMID- 23633846 TI - Evaluation of the lateral orbital approach in management of zygomatic bone fractures. AB - Zygomatic maxillary fractures, also known as tripod fractures, are usually the result of a direct blow to the body of the zygoma. Tripod fracture consists of (a) zygomatic arch fracture, (b) fracture of the lateral orbital wall, and (c) fracture of the inferior orbital floor. The purpose of this study is to evaluate the functional and esthetic outcome following this lateral orbital approach in the management of zygoma fracture. This study was carried out in VMS Dental College, Salem, and in a private hospital. This study was based on the experience gained from a retrospective study of the 30 lateral orbital approaches that were used in 30 patients with fractures of the zygomatic complex, which were conducted for a period of 8 years between January 2003 and January 2011. In the retrospective study, all the 30 patients were able to open the mouth completely; eyeball movements were normal; esthetically, all patients appeared normal. There were no sinusitis or visual problems in any of the studied patients. We conclude that the lateral orbital approach is an ideal option in reduction and treatment of zygomatic bone and arch fractures. PMID- 23633847 TI - Quantitative evaluation and correlation of serum glycoconjugates: Protein bound hexoses, sialic acid and fucose in leukoplakia, oral sub mucous fibrosis and oral cancer. AB - BACKGROUND: Cancer is one of the most common causes of mortality and morbidity today, with more than 10 million new cases and more than 6 million deaths each year worldwide. Globally Oral Cancer is the sixth most common cause of cancer related death. India accounts for 86% of the world's oral cancer cases. Often it proceeds by pre cancerous conditions and lesions. In search for biological markers with diagnostic value, we investigated serum glycoconjugates like protein bound hexoses, fucose and sialic acid in these diseases. MATERIALS AND METHODS: For this Study 27 newly diagnosed Oral leukoplakia, 27 OSMF and 26 Oral Cancer patients, 40 healthy controls who are non tobacco users and 40 healthy controls who are tobacco users were selected. In all these groups we estimated serum glycoconjugates. RESULTS: We observed no difference in serum glycoconjugates levels between tobacco and non tobacco controls (P > 0.05), but very high levels in oral cancer, Leukoplakia and oral sub mucous fibrosis (OSMF) patients (P < 0.001) when compared to control groups. Fucose levels were significant (P < 0.05) of all the glycoconjugates between OSMF and Leukoplakia. CONCLUSION: The serum glycoconjugates whose levels were very high in OSMF, Leukoplakia and Oral Cancer, do have a significant diagnostic and prognostic value in these diseases. PMID- 23633848 TI - Influence of limonin on Wnt signalling molecule in HepG2 cell lines. AB - OBJECTIVE: The role of limonin as potent anti carcinogenic, apoptosis and chemotherapeutic agents has been supported by limited studies. MATERIALS AND METHODS: In this study, limonin is identified as a potent anti proliferative agent against human hepatoma HepG2 cells based on the cell viability study, LDH leakage assay. Induction of apoptosis in HepG2 cells by limonin was evidenced by western blot analysis of Bax, Cyclin D1, Caspase 3 and Caspase9. RESULTS: Since Wnt signalling is involved in the initiation and sustaining of hepatocellular carcinoma we studied differential expression of LRP5, LRP6 and DKK wnt players. CONCLUSION: Limonin found to down regulate these players which forms a rationale for further investigation on effect on limonin in cancer therapy. PMID- 23633849 TI - Prevention of post-partum hemorrhage by rectal Misoprostol: A randomized clinical trial. AB - BACKGROUND: Post-partum hemorrhage (PPH) is a common cause of maternal mortality in developing countries. This trial was conducted to study the effectiveness and safety of rectal misoprostol for PPH. AIM: To assess the effectiveness and safety of misoprostol and comparing with oxytocin for prevention of PPH. MATERIALS AND METHODS: Women were randomized to receive either two 200 MUg rectal misoprostol tablets (study group) or 20 units oxytocin in 1000 cc normal saline intravenously (control group). The outcomes were incidence of PPH, amount of blood loss, duration of labor, incidence of side effects, pre- and post-delivery hemoglobin, and use of additional uterotonics. FINDING: The incidence of PPH was 12% in the study group and 10% in the control group (P > 0.05). No significant difference was observed between the groups hematocrit (P > 0.05). Other variables including severe PPH and duration of the third stage of labor were similar in both groups. CONCLUSION: Rectal misoprostol was as effective as intravenous oxytocin for preventing post-partum hemorrhage with the same incidence of side effects and is recommended to be use as an uterotonic agent to manage third stage of labor routinely. PMID- 23633850 TI - Reversal of dental fluorosis: A clinical study. AB - AIM: This study was conducted to evaluate the clinical reversal of dental fluorosis with various combinations of calcium, vitamin D3, and ascorbic acid, along with changes in levels of certain biochemical parameters concerned with dental fluorosis. The role of fluoride level of drinking water in the etiology of dental fluorosis and the prevalence of dental fluorosis in both dentitions and teeth were also assessed. MATERIALS AND METHODS: A total number of 50 patients with clinical features of dental fluorosis without trauma and any adverse habits were selected. Of these, in 30 co-operative patients, estimation of water fluoride level and pretreatment and post-treatment serum and urine fluoride levels were done with ion selective electrode method. The selected 30 patients were divided into three groups, that is, group A, group B, and group C, and were given various combinations of medications like calcium with vitamin D3 supplements, ascorbic acid with vitamin D3 supplements, and chlorhexidine mouthwash (placebo) for three months, respectively. These 30 patients were assessed for any change in the clinical grading of dental fluorosis. RESULTS: No change in clinical grading of dental fluorosis was noted. Considerable reduction in serum and urine fluoride levels was noted in both group A and group B patients. Dental fluorosis was noted in permanent teeth more commonly than deciduous teeth, and permanent maxillary central incisors had the highest prevalence rate. CONCLUSION: This study comprises only 30 patients with three months of follow-up. So, this sample of patients and duration of follow-up period are conclusive to observe changes in biochemical parameters but not sufficient to observe changes in clinical grading. PMID- 23633851 TI - Pediatric idiopathic dilated cardiomyopathy: A single center experience. AB - CONTEXT: Idiopathic dilated cardiomyopathy (IDCM) is a severe illness with high mortality in the pediatric population. AIMS: To highlight our experience about clinical course and outcome of IDCM. SETTINGS AND DESIGN: Patients' files were reviewed retrospectively for diagnosed cases of IDCM in the pediatric cardiology unit of King Abdul Aziz University Hospital, Jeddah, Saudi Arabia, from Jan 2003 to Jun 2011. MATERIALS AND METHODS: Data about full history, clinical examination and investigations were recorded and grouped according to outcome as alive and well (group 1), alive and symptomatic (group 2) and worsened or dead (group 3). STATISTICAL ANALYSIS: Data was subjected to descriptive analysis. Chi-square and Student's paired t-test techniques were used where appropriate. Spearman rank correlation and survival analysis was done. RESULTS: Eighty three patients were included with presenting age median (range), i.e.,14 (2 months-12 years) with females predominance 53 (63.9%). On presentation; cardiomegaly was noted in 72 (86.7%) with increased lung vascularity in 45 (54%). Sixty-one (74%) patients had ST segment and T-wave changes on electrocardiogram, while the same number had left ventricular hypertrophy, and 15 (18%) had arrhythmias. Echocardiography records on presentation and at last follow-up showed significant difference in several areas. Group 1 had 40 (48.2%), Group 2 had 23 (27.7%) while 20 (24.1%) were in Group 3 including nine cases who died. Survival rate over three years was 78%. Older the age, worse was the outcome (Spearman's rho = 0.3, P = 0.04). CONCLUSION: Majority of subjects were presented during first year of life; the three year survival rate was 78%. Favorable outcome was correlated with younger age at presentation. PMID- 23633852 TI - Oxidative status in rat kidney exposed to petroleum hydrocarbons. AB - OBJECTIVE: The study investigates the possible role of oxidative stress on renal tissues in association with petroleum hydrocarbon-induced nephrotoxicity. MATERIALS AND METHODS: Rats of comparable weights were randomly distributed into 10 groups: Control and groups exposed to kerosene, petrol, and diesel via inhalation, contamination by food, and contamination by water. The exposure lasted for eight weeks. RESULTS: Exposure to petroleum hydrocarbon led to significant rise in serum urea and creatinine, and renal tissue malondialdehyde. It also caused significant reduction in urinary urea and creatinine, and reduced glutathione, superoxide dismutase, and catalase activities of renal tissue homogenate. However, serum and urine concentrations of albumin and total protein were comparable in all groups. CONCLUSION: Results from this study shows that exposure to petroleum hydrocarbon led to renal dysfunction via oxidative stress, increasing lipid peroxidation and reducing the antioxidant defense mechanism. PMID- 23633853 TI - Birth audit. AB - OBJECTIVE: To describe profile of births occurring in teaching institution on selected parameters. MATERIALS AND METHODS: Considering feasibility, four months were systematically chosen for two-year time frame over a decade to gather selected information of consecutive singleton intramural births from log books of labor room on structured pro-forma. Data management was done using software package and analysis carried out by computing descriptive statistics (%) and Chi square test. RESULTS: It was observed that there were a total of 2862 and 1527 singleton births (>28 weeks) recorded for the sampled time-frame of 2009 and 1999 respectively reflecting increased quantum of institutional deliveries over time span. Out of 2862 births, monthly distribution was 21.8% (Jan), 20% (Apr), 37.2% (July) and 21.1% (Oct) with similar picture for 1999. The birth according to 8 hourly timeframe was computed to be 31.6% (12 am-8 am), 34.3% (8 am-4 pm) and 34.0% (4 pm to 12 am) for 2009 while it was 28.6%, 38.6% and 32.8% for 1999 (P < 0.05). Births took place through-out seven days of week; however, Sunday (12.0%) was the least popular day while Thursday (18.7%) recorded maximum proportion of births during 2009. Slightly higher proportion of pre-term births were recorded during 2009 (21.76%) in comparison to 1999 (18.53%). The caesarian section rose to 26.1% from 20.2% (P < 0.05) while M:F ratio at birth was 1.28 and 1.17 with similar proportion (92.3%; 93.0%) of newborns being discharged live during 2009 and 1999 respectively. CONCLUSION: It provides snapshots of birth occurring in a teaching hospital and within study constraints finding could be utilized for improving quality of care, health communication, better utilization of human resource and logistics. PMID- 23633854 TI - Comparison of two purification products of shankha bhasma: A prospective randomized control trial. AB - BACKGROUND: Shankha bhasma is widely used in the treatment of gastroesophageal reflux disease (GERD) patients. AIM: To compare the efficacy of two purification methods of shankha bhasma in relieving GERD symptoms. In method A, purification was done with lemon juice and method B with sour gruel. MATERIALS AND METHODS: Patients with heartburn since at least four days/week but who did undergo endoscopy to assess esophageal mucosa could participate. In this single-phase, single-center, prospective, randomized control trial, the patients were randomized to receive either shankha bhasma purified by method A or by method B. The primary efficacy variable was the proportion of patients with resolution of heartburn at week 4 and week 8. DESIGN: Single-phase, single-center, prospective, randomized control trial in a hospital setting. RESULTS: Of the total 70 patients who received samples A and B in a randomized double-blind manner, 65% of the patients showed resolution of symptoms in sample A and 28% in sample B at the end of four weeks, whereas, 71% of the patients showed resolution of symptoms in sample A and 31% in sample B at the end of eight weeks; P value was statistically significant for resolution of symptoms (P <0.005). CONCLUSION: Purification of shankha bhasma by lemon juice method is better than sour gruel method in terms of clinical outcome in GERD patients and is hence recommended. PMID- 23633855 TI - Prevalence and pattern of utilization of voluntary counseling and testing services and HIV infection in Ogbomoso, southwestern Nigeria. AB - OBJECTIVE: Human immunodeficiency virus, HIV, infection has been a major problem across the globe with a high socioeconomic burden. Voluntary Counseling and Testing (VCT) is a measure put in place to encourage people to know their HIV status with essential counseling support to help them cope with a positive or a negative test result. This study was carried out to determine the utilization of VCT services, prevalence of HIV among VCT attendees, and the distribution of the viral infection based on gender and age in Ogbomoso, an urban community, southwestern Nigeria. MATERIALS AND METHODS: The health records of patients in Adebayo Alata Primary Health Centre, Ogbomoso South, Nigeria, between 2008 and 2011, were used. RESULTS: A total of 1,490 patients used the VCT services during the period of study, out of which 271 (18.19%) were males and 1,219 (81.81%) were females. A consistent number of people used the VCT service throughout the period of study. HIV infection was higher in females (2.15%) than males (0.54%). The viral infection was more prevalent in people above 14 years of age (2.62%). However, none of these differences observed in gender and age were statistically significant (P < 0.05). CONCLUSION: It was concluded that HIV infection has neither gender nor age bias. Efforts should be made to increase the provision of VCT services and ensure its continued utilization in an attempt to maintain a healthy social and reproductive health culture, improve maternal and child health in the context of HIV transmission, and improve global child survival. PMID- 23633856 TI - Relationship between anthropometric measures and dental caries among adolescent National Cadets Corps of Udupi district, south India. AB - OBJECTIVE: To evaluate the relationship between anthropometric measures and dental caries among National Cadets Corps of Udupi district, India. MATERIALS AND METHODS: Demographic information like age, sex, and parental education were collected. Various anthropometric measures like weight, height, mid-upper arm circumference, waist circumference and hip circumference, and dental caries were recorded as per standard guidelines. RESULTS: A total of 211 cadets with age range of 12-19 years constituted the final sample. Caries experience was significantly different with respect to age and gender (P = 0.049 and 0.05, respectively). Multivariate analysis was performed using Poisson regression with DMFT as dependent variable. Height, weight, BMI, and WC showed significant association with dental caries status (OR = 10.61, 1.03, 1.09, and 1.02, respectively). Stratified analysis showed no association with anthropometric measures (Height, weight, BMI, and WC) and dental caries in 12-14 years. Among 15 19 years age group, there was a significant association between anthropometric measures (Height, weight, and BMI) and dental caries. CONCLUSION: There was a significant association between anthropometric measures and caries status in 15 19 years age group while no association was found in 12-14 years age group. PMID- 23633857 TI - Transmission electron microscopy of ameloblastoma: A study on six cases. AB - BACKGROUND: Ameloblastoma is a rare, benign tumor of odontogenic epithelium, but with an aggressive clinical behavior. AIM: The present study aims to assess the ultramicroscopic features of the epithelial and connective tissue components of ameloblastoma. MATERIALS AND METHODS: Six cases of ameloblastoma were subjected to electron microscopy. They included three cases of follicular type and three cases of plexiform type. RESULTS: The study reveals that the ameloblastoma contains the full complement of cells normally found during odontogenesis. However, these cells resemble the enamel organ in an undifferentiated stage. CONCLUSION: Ultramicroscopy revealed the presence of different cell types among follicular type. The morphology of plexiform variants and correlation with odontogenesis could be elicited. The electron microscopic differences between follicular and plexiform types could help us in better understanding its pathogenesis. PMID- 23633858 TI - Evaluation of postoperative analgesic efficacy of transversus abdominis plane block after abdominal surgery: A comparative study. AB - BACKGROUND: The transversus abdominis plane (TAP) block is an effective method of providing postoperative analgesia in patients undergoing midline abdominal wall incisions, by blocking the abdominal wall neural afferents via the bilateral lumbar triangles of Petit. We evaluated its analgesic efficacy in patients during the first 48 postoperative hours after abdominal surgery, in a randomized, controlled single-blind clinical trial. MATERIALS AND METHODS: Sixty patients (mean age 36.2 +/- 9.6 years) of either sex of ASA grade 1 and 2 who underwent major gynecological or surgical operation were randomized either to receive standard care, including patient-controlled tramadol analgesia (n = 30), or to undergo TAP block (n = 30) in addition to standard care. After completion of surgery, 20 ml of 0.375% levobupivacaine was deposited into the transversus abdominis neurofascial plane via the bilateral lumbar triangles of Petit. Each patient was assessed in the postanesthesia care unit and at 2, 4, 6, 12, 24, and 48 h postoperatively. RESULTS: The TAP block reduced Visual Analog Scale pain scores at most (2, 4, 6, 12, 24 h), but not at all time (36, 48 h) points assessed. Patients undergoing TAP block had reduced tramadol requirement in 24 h (210.05 +/- 20.5 vs. 320.05 +/- 10.6; P < 0.01) and 48 h (508.25 +/- 20.6 vs. 550.25 +/- 20.6; P < 0.01), and a longer time to the first PCA tramadol request (in minutes), compared to the control group (178.5 +/- 45.6 vs. 23.5 +/- 3.8; P < 0.001). CONCLUSION: The TAP block provided highly effective postoperative analgesia in the first 24 postoperative hours after major abdominal surgery, and no complications due to the TAP block were detected. PMID- 23633859 TI - Role of Imipenem-resistant metallo-beta-lactamase positive pseudomonas aeruginosa carriers in nosocomial infections. AB - BACKGROUND: Imipenem-resistant metallo-beta-lactamase Positive Pseudomonas aeruginosa (IR-MBLP-PA) infections occur as outbreaks and epidemics with a potential to spread within and between hospitals and intercontinentally. Limited data is available on IR-MBLP-PA carriers and their role as source and/or reservoir of nosocomial infection. OBJECTIVES: Detection and antibiogram typing of IR-MBLP-PA from healthy healthcare workers (HCW) from different areas of hospital and to assess role of carriers as source and/or reservoir of nosocomial infections. MATERIAL AND METHODS: Specimens from 200 HCWs [ICUs (120), General wards (40) and OPDs (40)] were collected from axilla, hands, stool and throat and processed by standard laboratory procedures. IR-MBLP-PA detection is done by IMIPENEM+EDTA combined disc test. Antibiogram typing is done. Association of carriers with clinical cases is done by IR-MBLP-PA with identical antibiogram type from carriers and cases. Distribution of carriers was assessed by Chi-square test. RESULTS: Incidence of P. aeruginosa and IR-MBLP-PA carriers among HCWs was 25%, 3.21% in ICUs, 10% from general wards and 0% from OPDs. A total of five IR MBLP-PA antibiogram types were observed from four carriers and none from general wards and OPDs. Distribution of P. aeruginosa and IR-MBLP-PA carriers in different areas of hospital was not statistically significant with P values of 0.058 and 0.76, respectively. CONCLUSIONS: Role of IR-MBLP-PA carriers as source and/or reservoirs of infections could not be assessed with certainty; however, the possibility cannot be ruled out. Periodic carrier studies in targeted high risk areas of hospital should be undertaken. PMID- 23633860 TI - Outcome of nucleoplasty in patients with radicular pain due to lumbar intervertebral disc herniation. AB - BACKGROUND: Nucleoplasty (percutaneous lumbar disc decompression) is a minimally invasive procedure that utilizes radiofrequency energy as a treatment for symptomatic lumbar disc herniation, against open microdiscectomy, which would be the mainstay treatment modality. The literature reports a favorable outcome in up to 77% of patients at 6 months. AIM: To evaluate the effectiveness of nucleoplasty in the management of discogenic radicular pain. MATERIALS AND METHODS: The medical notes of 33 patients, admitted for nucleoplasty between June 2006 and September 2007, were reviewed retrospectively. All had radicular pain, and contained herniated disc as seen on magnetic resonance imaging (MRI) of lumbosacral spine. Patients were followed up at 1 and 3 months post-procedure. The outcome measures employed in this study were satisfaction with symptoms and self-reported improvement. RESULTS: Thirty-three cases were examined (18 males and 15 females). Twenty-seven procedures were performed with no complications and six were abandoned due to anatomical reasons. There were 18 and 15 cases of disc herniation at L5/S1 and L4/5 levels, respectively. Four weeks following the procedure, 13 patients reported improvement in symptoms, and 14 remained symptomatically the same and subsequently had open microdiscectomy. CONCLUSION: Nucleoplasty has been shown to be a safe and minimal-access procedure. Less than half of our selected cohort of patients reported symptomatic improvement at 1 month follow-up. We no longer offer this procedure to our patients. Possible reasons are discussed. PMID- 23633861 TI - Knowledge, attitudes, and practice of doctors to adverse drug reaction reporting in a teaching hospital in India: An observational study. AB - BACKGROUND: Underreporting of spontaneous adverse drug reaction (ADR) is a threat to pharmacovigilance. Various factors related with the knowledge and attitudes are responsible for underreporting of ADRs. AIMS: The study was aimed at investigating the knowledge and attitudes of doctors to ADR reporting. MATERIALS AND METHODS: It was a questionnaire-based cross-sectional study. One hundred and eight questionnaires were administered to doctors working in a teaching hospital with an ADR monitoring center. STATISTICAL ANALYSIS USED: The descriptive statistics were used for responses to evaluate the knowledge and attitudes toward ADR reporting. Pearson's Chi-square test was used to observe the association of knowledge and attitude with experience and position. RESULTS: The response rate was 62.9%. Spontaneous reporting rate was found to be 19.1%. The major factors found to be responsible for underreporting of ADR include inadequate risk perception about newly marketed drugs (77.9%), fear factor (73.5%), diffidence (67.7%), lack of clarity of information on ADR form about reporting (52.9%), lethargy (42.7%), insufficient training to identify ADRs (41.2%), lack of awareness about existence of pharmacovigilance program (30.9%) and ADR monitoring center in the institute (19.1%), and inadequate risk perception of over-the counter (OTC) product (20.6%) and herbal medicines (13.2%). Experience and position did not influence the knowledge and attitudes of doctors. CONCLUSION: The deficiencies in knowledge and attitudes require urgent attention not only to improve the rate of spontaneous reporting, but also for enhanced safety of the patients and society at large. PMID- 23633862 TI - Safety and efficacy of low-molecular-weight heparins in prophylaxis of deep vein thrombosis in postoperative/ICU patients: A comparative study. AB - BACKGROUND: Venous thromboembolism (VTE), although a very common problem in everyday clinical practice, remains asymptomatic in most cases. Clinical diagnosis helps identify those who are going to have thromboembolic episode. A combination of clinical scoring systems like Wells' score and D-dimer assay provide a useful diagnostic tool. Trauma (surgical or accidental) and critically ill patients are found to have greatest risk. Enoxaparin and dalteparin are amongst the most common low-molecular-weight heparins (LMWHs) used for deep venous thrombosis (DVT) prophylaxis in such patients. AIM: The present study is designed to compare their role in preventing DVT in postoperative or critically ill patients and to determine their relative safety profiles. MATERIALS AND METHODS: The study included 36 critically ill adult patients. All the patients were allocated into three groups of 12 patients each. Group I patients received no prophylaxis, group II received inj. enoxaparin s/c 0.6-0.8 mg/kg twice daily, and group III received inj. dalteparin s/c 125-250 units/kg once daily. Routine investigations and coagulation profile were recorded on admission to intensive care unit (ICU) and at every third day thereafter. Patients were daily assessed for pretest probability of DVT using Wells' scoring, and D-dimer test was done on the 7(th) day. Occurrence of any bleeding (visible or occult) was noted, and incidence of DVT was determined in each group using positive results of D-dimer test and the clinical assessment with Wells' score. RESULTS: A significant difference in Wells' score (P < 0.05) was found between groups I and III on day 5 and day 7. A lower, but insignificant difference in the incidence of DVT was found between the study and control groups. No significant difference in major bleeding or other side effects was found. Better hemodynamic status and arterial blood gases in the study groups may indirectly refer to absence of asymptomatic DVT or silent pulmonary embolism in this group. CONCLUSION: The present study suggests that LMWHs, namely, enoxaparin and dalteparin, provide effective means of preventing DVT in high-risk, critically ill or postoperative patients, without causing any significant increase in the risk of bleeding or other side effects. Dalteparin appears to be unaffected by low creatinine clearance as explained by its clearance by a non-saturable mechanism. Still, a more extensive study with larger population is needed to make the outcomes worthwhile. PMID- 23633863 TI - Effect of beta-cyclodextrin complexation on solubility and enzymatic hydrolysis rate of icariin. AB - OBJECTIVE: The aim of this work was to investigate the effect of beta cyclodextrin complexation on the solubility and hydrolysis rate of icariin. MATERIAL AND METHODS: The inclusion complex of icariin at the molar ratio of 1:1 was obtained by the dropping method and was characterized by differential scanning calorimetry. The solubility of icariin complex in water at 37 degrees C was 36 times greater than that of free icariin. Enzymatic hydrolysis conditions were tested for the bioconversion of icariin by mono-factor experimental design. METHODS: The inclusion complex of icariin at the molar ratio of 1:1 was obtained by the dropping method and was characterized by differential scanning calorimetry. The solubility of icariin complex in water at 37 degrees C was 36 times greater than that of free icariin. Enzymatic hydrolysis conditions were tested for the bioconversion of icariin by mono-factor experimental design. RESULTS: The enzymatic hydrolysis experiment showed that icariin can be transformed into baohuoside I. The optimum conditions determined were as follows: pH 5.0, 50 degrees C, the ratio of cellulase/substrate (0.6), the concentration of icariin 20 mg/ml, and reaction time 12 h. Under these enzymatic conditions, 98.2% transforming rate of baohuoside I from icariin in inclusion complexes was obtained. CONCLUSION: The aqueous solubility and enzymatic hydrolysis rate of icariin were improved owing to the inclusion complexation. PMID- 23633864 TI - Evaluation of protective action of fenugreek, insulin and glimepiride and their combination in diabetic Sprague Dawley rats. AB - The present study was conducted to assess the effect of fenugreek, insulin and glimepiride alone and their combination in diabetic rat liver. Fifty six male Sprague dawley rats of uniform age were randomly divided into seven groups. Group 1: Non-diabetic control; Group 2: Streptozotocin (40 mg/Kg i/p single dose) induced diabetic control; Group 3: Insulin (4 U/kg once daily for 8 weeks) treatment in diabetic rats; Group 4: Glimepiride (4 mg/Kg orally once daily for 8 weeks) treatment in diabetic rats; Group 5: Fenugreek seed powder treatment (1 g/kg orally once daily for 8 weeks) in diabetic rats; Group 6: Insulin + Fenugreek seed powder treatment (once daily for 8 weeks) in diabetic rats; Group 7: Glimepiride + Fenugreek seed powder treatment (once daily for 8 weeks) in diabetic rats. Livers were collected at the end of experiment for histopathology and estimation of reduced glutathione (GSH), thiobarbituric acid reacting substances (TBARS), protein carbonyls, glutathione S-transferase (GST), glucose-6 phosphate dehydrogenase (G6PD), Na(+)/K(+) ATPase and Mg(2)+ ATPase, cytochrome P450 (CYP) and glycogen. There was an increase in the concentration of TBARS and protein carbonyls, and decrease in the concentration of GSH and glycogen, and the activity of GST, G6PD, Na(+)/K(+) ATPase and Mg(2)+ ATPase in diabetic livers, while treatment groups showed significant (P < 0.05) increase in the above parameters. The histology of liver revealed marked changes in diabetic rats and mild changes in combination treatment groups. The treatment with fenugreek, insulin and glimepiride improved the liver parameters in diabetic rats and their combination showed a beneficial effect on liver. PMID- 23633865 TI - The study of the effects of ionizing and non-ionizing radiations on birth weight of newborns to exposed mothers. AB - OBJECTIVES: Life evolved in an environment filled with a wide variety of ionizing and non-ionizing radiation. It was previously reported that medical exposures to pregnant women increases the risk of low birth weight. This study intends to investigate the relationship between exposure to ionizing and non-ionizing radiation and the risk of low birth weight. MATERIALS AND METHODS: One thousand two hundred mothers with their first-term labor (vaginal or cesarean) whose newborns' history had been registered in neonates' screening program in Shiraz were interviewed and surveyed. Data collection was performed by the assessment of mother's history of radiography before and during pregnancy, physical examination of the mother for height and weight and weighing and examining the newborn for any diagnosis of disease and anomalies. RESULTS: There were no statistical significant differences between the mean weight of newborns whose mothers had been exposed to some common sources of ionizing and non-ionizing radiations such as dental or non dental radiographies, mobile phone, cordless phone and cathode ray tube (CRT) and those of non-exposed mothers. CONCLUSIONS: The findings of this study cast doubt on previous reports, which indicated that exposure to ionizing radiation during pregnancy increased the risk of low birth weight. PMID- 23633866 TI - The effects of residence duration in high background radiation areas on immune surveillance. AB - PURPOSE: The effective dose received by humans from natural sources is about 2.4 mSv y(-1), but this is 10.2 mSv y(-1) for inhabitants of Ramsar, a city in northern Iran. Carcinogenesis is one of the most studied effects of radiation, especially in high doses. Nonetheless carcinogenesis of low doses is uncertain. A recent epidemiological study in high background radiation areas of Ramsar showed that the cancer incidence in this era is lower than neighbors. The reason of this different behavior is under study yet. NK cells, helper, and Cytotoxic T cells are most important components of the tumor immune surveillance. The counts and activities of these cells and also leukocytes, lymphocyte, neutrophil cells, and other important parameters were studied in the residents of Ramsar with different duration of exposure to chronic low dose radiation. MATERIALS AND METHODS: Fifty residents of high background radiation areas, who were between 25 and 35 years and fully healthy, were selected randomly and their consent was obtained. Then, 2 cc fresh peripheral bloods were taken in sterile conditions. Complete blood cell counts were performed by an automatic hematology analyzer and CD4+, CD8+, NK, and CD107a+ cell counts were determined by monoclonal antibodies and flowcytometry. CD4+ and CD8+ percentages and the CD4/CD8 ratio were determined and the data were analyzed using SPSS 16. RESULTS: The percentages of CD4+ cells increase, but the counts of CD107a+ cells decline in higher exposure durations. The other parameters did not have significant regression with exposure duration. CONCLUSIONS: These confirm that living in high background radiation areas may induce changes in the immune system gradually and address more investigations. PMID- 23633867 TI - External jugular venous aneurysm: A clinical curiosity. AB - Jugular venous aneurysm is an extremely rare condition. The patients presented with a painless swelling in the neck that appears while coughing, straining, bending, or breath holding. Detection of a soft and compressible swelling in the course of an external jugular vein (EJV) superficial to the sternomastoid muscle, non-filling on compression of the EJV during Valsalva maneuver clinches the diagnosis of EJV aneurysm. Color Doppler ultrasound allows precise delineation of the lesion and is considered the gold standard for confirming the diagnosis. Surgical excision is indicated mostly for cosmetic reasons and symptomatic aneurysms. We, herein, report a patient with saccular external jugular venous aneurysm to highlight the typical clinical presentation and diagnosis of this rare entity. PMID- 23633868 TI - First case report of human myiasis with Sarcophaga species in Makkah city in the wound of a diabetic patient. AB - We have reported a case of a 40-year-old male diabetic patient, resident of a rural area, who visited the outpatient clinic of the diabetic center in Alnoor Specialist Hospital, Makkah, Saudi Arabia. He came to seek medical advice for a single wound in the back of the shoulder since 1 month. After examination, a larva was eliminated and sent to laboratory for confirmation. It was confirmed as the third-stage larva of Sarcophaga species after macroscopic and microscopic examination. This is the first case of a patient having diabetic wound myiasis with the larva of Sarcophaga species reported in the Makkah region of Saudi Arabia. PMID- 23633869 TI - Unilateral acute conjunctivitis due to Oestrus ovis in a veterinary doctor. AB - Myiasis is the infestation of tissues and organs of animals or man by fly larvae. We report a human case of external ophthalmomyiasis caused by the larvae of a sheep nasal botfly, Oestrus ovis, for the first time in a veterinary doctor. A 25 year-old veterinary doctor presented with severe symptoms of conjunctivitis. The larvae, 3 in number, were observed in the bulbar conjunctiva and the symptoms of the eye improved within a few hours of their removal. It is important for ophthalmologists to be aware of larval conjunctivitis as a significant possibility in the veterinary fraternity especially during the summer season. PMID- 23633870 TI - Idiopathic chronic calcific pancreatitis in a child: An uncommon entity. AB - Inflammatory disease of pancreas can be acute or chronic. Acute pancreatitis is a reversible process whereas chronic pancreatitis produces irreversible changes in the architecture and function of pancreas. Although pancreatitis is less common in children than in adults it still occurs with regularity and should be considered in any child with acute or chronic abdominal pain. The main difference between chronic pancreatitis in children and adults is in the etiology. We present a case of idiopathic chronic calcific pancreatitis in a child thereby signifying the importance of this entity at this age. PMID- 23633871 TI - Primary testicular lymphoma with rupture: An unusual presentation. AB - Primary testicular lymphoma usually presents as a unilateral testicular mass with occasional bilateral involvement. The tumor show contiguous spread to rete testis, epididymis spermatic cord and rarely to tunica albuginea. We report a case of primary testicular lymphoma which showed rupture of tunica albuginea with involvement of inguinal lymph node which is unusual. A 50-year-old male patient presented with right inguinal swelling and right side scrotal swelling of five months' duration. Fine needle aspiration of the right inguinal lymph node was done and was suggestive for lymphoma/seminoma. Histopathology of right orchiectomy revealed non-Hodgkin's lymphoma (NHL). Further investigations did not reveal any other organs involved with non-Hodgkin's lymphoma. Primary testicular lymphoma usually shows spread to extranodal sites like skin, central nervous system and Waldeyer's ring at presentation and at relapse. Whereas, less common sites are lung, bone, liver, gastrointestinal system and nodal sites, especially the paraaortic lymph nodes. Testicular lymphoma with involvement of the inguinal lymph node is unusual. Clinical presentation of such cases may mimic germ cell tumors. PMID- 23633872 TI - Unilateral fusion of mandibular permanent lateral incisor with canine: A report of a rare case. AB - Fusion is a developmental anomaly which occurs due to a union of one or more adjacent teeth during morpho-differentiation of the dental germs. Early diagnosis of this condition is important because it may cause clinical problems, such as esthetic concerns and arch asymmetry. These anomalies may be unilateral or bilateral and may affect either dentition, although the deciduous teeth are more commonly affected. This report describes a rare case of unilateral fusion between the mandibular permanent lateral incisors and the canine. Only few cases have been previously reported in the English literature. Hence this article aimed at reporting a case of this rare condition and evaluating the presence of any associated pathology. PMID- 23633873 TI - Recurrent subcutaneous trunk leiomyosarcoma: Management and review of the literature. AB - Superficial leiomyosarcomas are rare malignant smooth-muscle tumors accounting for 4-6.5% of all soft-tissue sarcomas, less than 2-3% of cutaneous soft-tissue neoplasms and 0.04% of all cancers. They are divided into cutaneous or dermal and subcutaneous leiomyosarcomas. Subcutaneous tumors have been reported to be associated with an increased risk of local recurrences and distant metastases, compared to their cutaneous counterparts. In this study, we describe a rare case of a recurrent subcutaneous trunk leiomyosarcoma in a 68-year-old male patient. Local recurrence developed two years after the complete surgical resection with wide margins and adjuvant postoperative radiotherapy. The management of the patient is discussed along with a review of the literature. We conclude that subcutaneous leiomyosarcoma is a rare clinical entity which may be associated with an atypical clinical presentation. Physicians should be aware of the misleading features of this tumor in order to avoid delay in diagnosis and treatment. Early complete surgical resection with wide margins of at least 2 cm is the cornerstone of treatment and has been reported to mostly influence the prognosis. However, the tumor has a high tendency to recur locally and metastasize. Recurrence may develop despite wide resection and radiotherapy. Long term follow-up is mandatory. PMID- 23633874 TI - Maxillary tuberosity fracture and subconjunctival hemorrhage following extraction of maxillary third molar. AB - Extraction of teeth is the most common minor surgical procedure performed. Complication of extraction ranges from periodontal injury to fracture of jaw in the mandible and fracture of tuberosity and oroantral communication in the maxilla. Subconjunctival hemorrhage after extraction of maxillary molar is a very rare complication, and so far, only one case is reported in the literature. We report a case of subconjunctival hemorrhage with maxillary tuberosity fracture after maxillary third molar extraction. PMID- 23633875 TI - Cleidocranial dysplasia with hearing loss. AB - Cleidocranial dysplasia is an inherited skeletal anomaly that affects primarily the skull, clavicle, and dentition, which can occur spontaneously, but most are inherited in autosomal dominant mode. The skull findings are brachycephaly, delayed or failed closure of the fontanelles, presence of open skull sutures and multiple wormian bones with pronounced frontal bossing. The syndrome is notable for aplasia or hypoplasia of the clavicles. The neck appears long and narrow and the shoulders markedly droop. Oral manifestations exhibit a hypoplastic maxilla with high-arched palate. Crowding of teeth is produced by retention of deciduous teeth, delayed eruption of permanent teeth, and the presence of a large number of unerupted supernumerary teeth. We report a case of CCD in a 12-year-old girl who presented with an unaesthetic facial appearance, unerupted permanent dentition with hearing loss. PMID- 23633876 TI - Adenoid cystic carcinoma of palate. AB - Adenoid cystic carcinoma is a rare tumor arising from the minor salivary glands;, the palate being the commonest site. Distant metastasis and perineural invasion areis common in adenoid cystic carcinoma. Diagnosis of adenoid cystic carcinoma is made usually with the help of clinical features, radiographic features and histologic features. We reported a case of adenoid cystic carcinoma of palate involving left maxillary sinus. The diagnosis of the case and brief review of literature of adenoid cystic carcinoma is discussed. The aim here is to highlight the importance of diagnosis, treatment and long-term follow-up of the patients with adenoid cystic carcinoma. PMID- 23633877 TI - Infiltrating lipomatosis of the face: A case series. AB - Infiltrating lipomatosis of the face is a very rare entity which is characterized by the collection of non-encapsulated mature adipocytes infiltrating local tissues, resulting in craniofacial deformities. Psychomotor development of the patients is normal, esthetics often being the primary concern to seek treatment. The presentation is always unilateral with hypertrophy of hard and soft structures on the affected side of the face. The pathogenesis of the condition is unclear. This condition shows a wide phenotypic range, uncertain prognosis with high rates of recurrence after surgery, and variable post-op cosmetic improvement. The condition shows no gender predilection, with most of the cases presenting in and beyond the second decade of life. Here, we present a series of four cases presenting in varying age groups with history of recurrence in three cases. PMID- 23633878 TI - Intraoperative anaphylaxis to ranitidine during cesarean section. AB - Ranitidine, a widely used drug, is known to be well tolerated. This case report illustrates a severe anaphylactic reaction after a single intravenous dose of 50 mg ranitidine during the emergency cesarean section under spinal anesthesia. Anaphylaxis was successfully managed with Inj. adrenaline, Inj. hydrocortisone, ventilatory, and inotropic support following which she had a full recovery. Awareness of this rare but fatal adverse reaction to this commonly used drug could help in early recognition of the event if faced suddenly. PMID- 23633879 TI - Oral myiasis in an adult associated with filariasis and Hansen's disease. AB - Oral myiasis is a common parasitic infestation of live human and animals caused by species of dipteran fly larvae known as maggots which may be secondary to medical disease. This case involves a 51-year-old female, poorly debilitated with advanced periodontal disease infected by the dipteral larvae in the anterior maxillary region which belonged to the family Calliphoridae and Chrysomya bezziana species. This lady was neglected from her family and presented oral myiasis with the previous history of filariasis and Hansen's disease. Secondary infestations may occur in cancrum oris, oral extraction wounds, jaw bone wounds, oral leprosy lesion, filariasis, and carcinoma. Hansen's disease (leprosy) is bacterial in origin whereas filariasis (elephantiasis) is parasitic in origin like-myiasis. The treatment consisted of manual removal of the larvae by topical application of turpentine oil, oral therapy, and surgical debridement of the oral wound. PMID- 23633880 TI - Symmetrical peripheral gangrene with Plasmodium falciparum malaria. AB - Symmetric peripheral gangrene is rare and relatively uncommon complication of malaria. We report a case of a 50-year-old male who survived Plasmodium falciparum infection with disseminated intravascular coagulation. Symmetric peripheral gangrene in our case, which ultimately required amputation of the toes, was most likely due to interaction between parasitic factors and host factors. PMID- 23633881 TI - Oral presentation in dengue hemorrhagic fever: A rare entity. AB - One of the major health hazards which is prevalent and dangerous is the dengue fever which causes the death of many people. This may be associated with a variety of mucocutaneous manifestations which may be of help in early diagnosis. Many biochemical assays and hematological investigations may aid in the further diagnosis and treatment of the fatal disease. Oral lesions are rare to occur and if present, are often mistaken for platelet abnormality. This case report highlights the importance of oral lesions and it is the first of its kind to be reported as dengue hemorrhagic fever. PMID- 23633882 TI - Inform, conform, reform and do not deform: A four axons' framework for the Hellenic academic institutions facing the Greek crisis challenge. PMID- 23633883 TI - Publication fraud, dishonesty, and deceit. PMID- 23633884 TI - A literature review reveals that trials evaluating treatment of non-specific low back pain use inconsistent criteria to identify serious pathologies and nerve root involvement. AB - OBJECTIVES: The broad aim of this study was to assess the homogeneity of patients included in trials of non-specific low back pain (NSLBP). To do this, we investigated the consistency and clarity of criteria used to identify and exclude participants with serious pathologies and nerve root compromise in randomized controlled trials, investigating interventions for NSLBP. METHODS: We searched Medline database for randomized controlled trials of low back pain (LBP). published between 2000 and 2009. We then randomly selected and screened trials for inclusion until we had 50 eligible trials. Data were extracted on the criteria used to identify cases of serious conditions (e.g. cancer, fracture) and nerve root involvement. RESULTS: The majority of papers (35/50) explicitly excluded patients with serious pathology. However, the terminology used and examples given were highly variable. Nerve root involvement was an exclusion criterion in the majority but not all studies. The criteria used for excluding patients with nerve root involvement varied greatly between studies. The most common criteria were 'motor, sensory or reflex changes' (nine studies), followed by 'pain radiating below the knee' (five studies) and 'reduced straight leg raise which reproduces leg pain' (five studies). In half of the included studies, the criteria used, while alluding to nerve root involvement, were not explained adequately for us to determine the types of patients included or excluded. DISCUSSION: The inconsistent and unclear criteria used to identify cases of serious pathology and nerve root compromise means that published trials of LBP likely include heterogeneous patient populations. This trait limits our ability to make comparisons across trials or pool studies. Standardization and consensus is important for future research. PMID- 23633886 TI - The influence of scapular depression on upper limb neurodynamic test responses. AB - OBJECTIVES: Upper limb neurodynamic testing (ULNT) can be used clinically to assist in identifying neural tissue involvement in patients with upper quarter pain and dysfunction. Consideration for scapular positioning is a crucial component of ULNT standardization, as variations in positioning may dramatically impact sensory and motor responses. This study aimed to determine if there was a meaningful difference in test outcomes when the ULNT was performed in alternative scapular positions. METHODS: This cross-sectional study included 40 asymptomatic individuals. Repeated ULNT testing was performed on the dominant limb with the scapula blocked in neutral (ULNTb) and in scapular depression (ULNTd). Sensory responses, muscle activity, and range of motion outcomes were compared between the two test variations. RESULTS: Pre-positioning in scapular depression (ULNTd) led to reduced elbow extension range of motion, provoked greater upper trapezius muscle activity and an earlier onset and broader area of sensory responses compared to ULNTb. DISCUSSION: During ULNTb, the limbs were taken further into range and elicited reduced muscle activation and more localized sensory response providing a less vigorous version of the test. This study demonstrates that scapular positioning has a meaningful impact on ULNT test outcomes in healthy, asymptomatic individuals. The ULNTd can be considered a more vigorous version that may be appropriate when the cervical motions commonly utilized for structural differentiation are limited or contraindicated. PMID- 23633885 TI - Safety of cervical spine manipulation: are adverse events preventable and are manipulations being performed appropriately? A review of 134 case reports. AB - BACKGROUND: Cervical spine manipulation (CSM) is a commonly utilized intervention, but its use remains controversial. PURPOSE: To retrospectively analyze all available documented case reports in the literature describing patients who had experienced severe adverse events (AEs) after receiving CSM to determine if the CSM was used appropriately, and if these types of AEs could have been prevented using sound clinical reasoning on the part of the clinician. DATA SOURCES: PubMed and the Cumulative Index to Nursing and Allied Health were systematically searched for case reports between 1950 and 2010 of AEs following CSM. STUDY SELECTION: Case reports were included if they were peer-reviewed; published between 1950 and 2010; case reports or case series; and had CSM as an intervention. Articles were excluded if the AE occurred without CSM (e.g. spontaneous); they were systematic or literature reviews. Data extracted from each case report included: gender; age; who performed the CSM and why; presence of contraindications; the number of manipulation interventions performed; initial symptoms experienced after the CSM; and type of resultant AE. DATA SYNTHESIS: Based on the information gathered, CSMs were categorized as appropriate or inappropriate, and AEs were categorized as preventable, unpreventable, or unknown. Chi-square analysis with an alpha level of 0.05 was used to determine if there was a difference in proportion between six categories: appropriate/preventable, appropriate/unpreventable, appropriate/unknown, inappropriate/preventable, inappropriate/unpreventable, and inappropriate/unknown. RESULTS: One hundred thirty four cases, reported in 93 case reports, were reviewed. There was no significant difference in proportions between appropriateness and preventability, P = .46. Of the 134 cases, 60 (44.8%) were categorized as preventable, 14 (10.4%) were unpreventable and 60 (44.8%) were categorized as 'unknown'. CSM was performed appropriately in 80.6% of cases. Death resulted in 5.2% (n = 7) of the cases, mostly caused by arterial dissection. LIMITATIONS: There may have been discrepancies between what was reported in the cases and what actually occurred, since physicians dealing with the effects of the AE, rather than the clinician performing the CSM, published many of the cases. CONCLUSIONS: This review showed that, if all contraindications and red flags were ruled out, there was potential for a clinician to prevent 44.8% of AEs associated with CSM. Additionally, 10.4% of the events were unpreventable, suggesting some inherent risk associated with CSM even after a thorough exam and proper clinical reasoning. PMID- 23633887 TI - The assessment of function. Part II: clinical perspective of a javelin thrower with low back and groin pain. AB - Assessment of an individual's functional ability can be complex. This assessment should also be individualized and adaptable to changes in functional status. In the first article of this series, we operationally defined function, discussed the construct of function, examined the evidence as it relates to assessment methods of various aspects of function, and explored the multi-dimensional nature of the concept of function. In this case report, we aim to demonstrate the utilization of a multi-dimensional assessment method (functional performance testing) as it relates to a high-level athlete presenting with pain in the low back and groin. It is our intent to demonstrate how the clinician should continually adapt their assessment dependent on the current functional abilities of the patients. PMID- 23633888 TI - Medical diagnosis of cubital tunnel syndrome ameliorated with thrust manipulation of the elbow and carpals. AB - This case report describes the effectiveness of thrust manipulation to the elbow and carpals in the management of a patient referred with a medical diagnosis of cubital tunnel syndrome (CuTS). The patient was a 45-year-old woman with a 6-week history of right medial elbow pain, ulnar wrist pain, and intermittent paresthesia in the ulnar nerve distribution. Upon initial assessment, she presented with a positive elbow flexion test and upper limb neurodynamic test with ulnar nerve bias. A biomechanical assessment of the elbow and carpals revealed a loss of lateral glide of the humerus on the ulna and a loss of palmar glide of the triquetral on the hamate. After the patient received two thrust manipulations of the elbow and one thrust manipulation of the carpals over the course of four sessions, her pain and paresthesia were resolved. This case demonstrates that the use of thrust manipulation to the elbow and carpals may be an effective approach in the management of insidious onset CuTS. This patient was successfully treated with thrust manipulation when joint dysfunction of the elbow and wrist were appropriately identified. This case report may shed light on the examination and management of insidious onset CuTS. PMID- 23633889 TI - Differential diagnosis and early management of rapidly progressing hip pain in a 59-year-old male. AB - OBJECTIVE AND IMPORTANCE: Rapidly progressing degeneration of the hip joint is an uncommon condition presenting to physical therapy. Differential diagnosis can often be difficult, as clinical and radiographic findings do not always coincide leaving clinicians with difficult decision making regarding course of treatment. The purpose of this case report was to describe the differential diagnosis and early management of a patient with rapidly progressing hip pain. CLINICAL PRESENTATION: A 59-year-old male with a complicated medical history was referred with a diagnosis of severe bilateral hip osteoarthritis. Clinical presentation of insidious onset, severe bilateral groin and anterior thigh pain with rapid progression of functional decline lead to the differential diagnosis of bilateral avascular necrosis. INTERVENTION: The patient received seven manual physical therapy sessions over the course of one month. CONCLUSION: During this time, the patient's Lower Extremity Functional Scale score worsened from 33 to 21. The persistence of the patient's painful symptoms and continued functional decline helped determine cessation of manual therapy and referral back to his GP for further diagnostic testing and eventual correct diagnosis. This case highlights the importance of monitoring patient prognosis using outcome measures leading to a change in patient management strategies. PMID- 23633890 TI - In response to: Cook C. How about a little love for non-thrust manipulation? PMID- 23633891 TI - Manual therapy: process or product? PMID- 23633892 TI - Sludge Retention Time as a Suitable Operational Parameter to Remove Both Estrogen and Nutrients in an Anaerobic-Anoxic-Aerobic Activated Sludge System. AB - Estrogen in wastewater are responsible for a significant part of the endocrine disrupting effects observed in the aquatic environment. The effect of sludge retention time (SRT) on the removal and fate of 17beta-estradiol (E2) and 17alpha ethinylestradiol (EE2) in an anaerobic-anoxic-oxic activated sludge system designed for nutrient removal was investigated by laboratory-scale experiments using synthetic wastewater. With a hydraulic retention time of 8 h, when SRT ranged 10-25 days, E2 was almost completely removed from water, and EE2 removal efficiency was 65%-81%. Both estrogens were easily sorbed onto activated sludge. Distribution coefficients (Kd) of estrogens on anaerobic sludge were greater than those on anoxic and aerobic sludges. Mass balance calculation indicated that 99% of influent E2 was degraded by the activated sludge process, and 1% remained in excess sludge; of influent EE2, 62.0%-80.1% was biodegraded; 18.9%-34.7% was released in effluent; and 0.88%-3.31% remained in excess sludge. Optimal SRT was 20 days for both estrogen and nutrient removal. E2 was almost completely degraded, and EE2 was only partly degraded in the activated sludge process. Residual estrogen on excess sludge must be considered in the sludge treatment and disposal processes. The originality of the work is that removal of nutrients and estrogens were linked, and optimal SRT for both estrogen and nutrient removal in an enhanced biological phosphorus removal system was determined. This has an important implication for the design and operation of full-scale wastewater treatment plants. PMID- 23633893 TI - Model Simulation of Diurnal Vertical Migration Patterns of Different-Sized Colonies of Microcystis Employing a Particle Trajectory Approach. AB - Microcystis, a genus of potentially harmful cyanobacteria, is known to proliferate in stratified freshwaters due to its capability to change cell density and regulate buoyancy. In this study, a trajectory model was developed to simulate the cell density change and spatial distribution of Microcystis cells with nonuniform colony sizes. Simulations showed that larger colonies migrate to the near-surface water layer during the night to effectively capture irradiation and become heavy enough to sink during daytime. Smaller-sized colonies instead took a longer time to get to the surface. Simulation of the diurnally varying Microcystis population profile matched the observed pattern in the field when the radii of the multisized colonies were in a beta distribution. This modeling approach is able to take into account the history of cells by keeping track of their positions and properties, such as cell density and the sizes of colonies. It also serves as the basis for further developmental modeling of phytoplanktons that are forming colonies and changing buoyancy. PMID- 23633894 TI - Dissolution-Driven Permeability Reduction of a Fractured Carbonate Caprock. AB - Geochemical reactions may alter the permeability of leakage pathways in caprocks, which serve a critical role in confining CO2 in geologic carbon sequestration. A caprock specimen from a carbonate formation in the Michigan sedimentary Basin was fractured and studied in a high-pressure core flow experiment. Inflowing brine was saturated with CO2 at 40 degrees C and 10 MPa, resulting in an initial pH of 4.6, and had a calcite saturation index of -0.8. Fracture permeability decreased during the experiment, but subsequent analyses did not reveal calcite precipitation. Instead, experimental observations indicate that calcite dissolution along the fracture pathway led to mobilization of less soluble mineral particles that clogged the flow path. Analyses of core sections via electron microscopy, synchrotron-based X-ray diffraction imaging, and the first application of microbeam Ca K-edge X-ray absorption near edge structure, provided evidence that these occlusions were fragments from the host rock rather than secondary precipitates. X-ray computed tomography showed a significant loss of rock mass within preferential flow paths, suggesting that dissolution also removed critical asperities and caused mechanical closure of the fracture. The decrease in fracture permeability despite a net removal of material along the fracture pathway demonstrates a nonintuitive, inverse relationship between dissolution and permeability evolution in a fractured carbonate caprock. PMID- 23633895 TI - Transfusion-related acute lung injury in the Canadian paediatric population. AB - BACKGROUND: The incidence of transfusion-related acute lung injury (TRALI) in adults is approximately one per 5000 transfusions. The Canadian Paediatric Surveillance Program undertook the present study to determine the incidence of TRALI in the paediatric population and to describe the characteristics and outcomes of children with TRALI. METHODS: The present surveillance study was conducted over a three-year period. RESULTS: Four TRALI cases were reported, yielding an incidence rate of 1.8 per 100,000 transfusions. The degree of severity varied: in two patients, only supplemental oxygen was necessary, while the other two required mechanical ventilation. CONCLUSION: TRALI was reported much less often in the present study compared with adult studies; therefore, it needs to be determined whether TRALI occurs less frequently in children, or alternatively, whether TRALI is recognized less often in children. The possibility that neonates who undergo cardiac surgery are at greater risk of TRALI than other patients should be addressed in future studies. PMID- 23633897 TI - Conversion disorder: Not a malingering matter. PMID- 23633896 TI - Fish consumption by children in Canada: Review of evidence, challenges and future goals. AB - Fish consumption is of great importance to children's health and is essential for neurodevelopment, which begins in pregnancy and continues throughout early childhood and into adolescence. However, fish consumption presents conflicting health outcomes associated with its nutritional benefits and its adverse contaminant risks, because both avoiding fish as well as the consumption of contaminated fish can potentially harm children. This may be challenging to communicate. The present review was performed to assess the current knowledge and recommendations around 'smart' fish-consumption decisions. Health Canada advises, as well as other advisories and guides, that fish should be consumed for its health benefits, while also informing consumers, especially women and children, to limit certain fish consumption. The current literature must attempt to handle the challenges inherent in communicating the dilemmas of children's fish consumption. Incorporation of new knowledge translation strategies are proposed as a means to raise the level of knowledge about optimal fish consumption practices. PMID- 23633898 TI - Case 1: Recurrent acute liver dysfunction in a 19-month-old boy. PMID- 23633899 TI - Case 2: A pain in the neck. PMID- 23633900 TI - Managing the paediatric patient with an acute asthma exacerbation. AB - Children with acute asthma exacerbations frequently present to an emergency department with signs of respiratory distress. The most severe episodes are potentially life-threatening. Effective treatment depends on the accurate and rapid assessment of disease severity at presentation. This statement addresses the assessment, management and disposition of paediatric patients with a known diagnosis of asthma who present with an acute asthma exacerbation, especially preschoolers at high risk for persistent asthma. Guidance includes the assessment of asthma severity, treatment considerations, proper discharge planning, follow up, and prescription for inhaled corticosteroids to prevent exacerbation and decrease chronic morbidity. PMID- 23633901 TI - Gambling in children and adolescents. AB - Despite the fact that minors in Canada are prohibited from legalized gambling, adolescents commonly engage in both legalized (lottery products, casino, video lottery terminals) and self-organized (cards, sports betting, dice) gambling activities both at home and in school. Lifetime prevalence rates of pathological gambling for adults range from 1% to 2%, and existing data suggest that the prevalence among adolescents may be two to four times higher. Very little is known about risk factors in the development and perpetuation of problematic and pathological gambling. This statement is intended to educate paediatricians, family physicians and other health care providers about the emerging knowledge around gambling in childhood and adolescence and the potential serious consequences of this activity. It also urges federal, provincial and territorial governments to include this specific issue in their agendas and to address the socio-political factors associated with gambling. PMID- 23633902 TI - Paediatricians, social media and blogs: Ethical considerations. AB - The use of blogs, Facebook and similar social networking sites is rapidly expanding and, when compared with e-mail, may be having a significantly different impact on the traditional doctor-patient relationship. Characteristics specific to these online platforms have major implications for professional relationships, including the 'Facebook effect' (the relative permanence of postings) and the 'online disinhibition effect'. The present practice point illustrates relevant ethical considerations and provides guidance to paediatricians and others concerning the prudent professional and personal use of social networking media. PMID- 23633903 TI - Prevalence of hypothalamic-pituitary-adrenal axis suppression in children treated for asthma with inhaled corticosteroid. AB - OBJECTIVE: To determine the prevalence of hypothalamic-pituitary-adrenal (HPA) axis suppression in asthmatic children on inhaled corticosteroids (ICS). METHODS: Clinical and demographic variables were recorded on preconstructed, standardized forms. HPA axis suppression was measured by morning serum cortisol levels and confirmed by low-dose adrenocorticotropic hormone stimulation testing. RESULTS: In total, 214 children participated. Twenty children (9.3%, 95% CI 5.3% to 13.4%) had HPA axis suppression. Odds of HPA axis suppression increased with ICS dose (OR 1.005, 95% CI 1.003 to 1.009, P<0.001). All children with HPA axis suppression were on a medium or lower dose of ICS for their age (200 MUg/day to 500 MUg/day). HPA axis suppression was not predicted by drug type, dose duration, concomitant use of long-acting beta-agonist or nasal steroid, or clinical features. CONCLUSION: Laboratory evidence of HPA axis suppression exists in children taking ICS for asthma. Children should be regularly screened for the presence of HPA axis suppression when treated with high-dose ICS (>500 MUg/day). Consideration should be given to screening children on medium-dose ICS. PMID- 23633904 TI - Neonatal withdrawal syndrome due to maternal codeine use. AB - Neonatal withdrawal from maternal drugs and medications is not uncommon. Codeine containing analgesic preparations given to pregnant mothers for headache have been identified as a cause of neonatal withdrawal syndrome. The present case highlights the importance of obtaining a detailed maternal drug history including prescription and nonprescription drugs, and highlights the need for prenatal counselling for women who are taking narcotic-containing analgesics. PMID- 23633906 TI - Impact and influence: valedictory editorial. PMID- 23633907 TI - Erratum: Folding wrinkles of a thin film stiff layer on a soft substrate. AB - [This corrects the article DOI: 10.1098/rspa.2011.0567.]. PMID- 23633908 TI - Asymptotics for metamaterials and photonic crystals. AB - Metamaterial and photonic crystal structures are central to modern optics and are typically created from multiple elementary repeating cells. We demonstrate how one replaces such structures asymptotically by a continuum, and therefore by a set of equations, that captures the behaviour of potentially high-frequency waves propagating through a periodic medium. The high-frequency homogenization that we use recovers the classical homogenization coefficients in the low-frequency long wavelength limit. The theory is specifically developed in electromagnetics for two-dimensional square lattices where every cell contains an arbitrary hole with Neumann boundary conditions at its surface and implemented numerically for cylinders and split-ring resonators. Illustrative numerical examples include lensing via all-angle negative refraction, as well as omni-directive antenna, endoscope and cloaking effects. We also highlight the importance of choosing the correct Brillouin zone and the potential of missing interesting physical effects depending upon the path chosen. PMID- 23633905 TI - Parametric study of effects of collagen turnover on the natural history of abdominal aortic aneurysms. AB - Abdominal aortic aneurysms (AAAs) are characterized by significant changes in the architecture of the aortic wall, notably, loss of functional elastin and smooth muscle. Because collagen is the principal remaining load-bearing constituent of the aneurysmal wall, its turnover must play a fundamental role in the natural history of the lesion. Nevertheless, detailed investigations of the effects of different aspects of collagen turnover on AAA development are lacking. A finite element membrane model of the growth and remodelling of idealized AAAs was thus used to investigate parametrically four of the primary aspects of collagen turnover: rates of production, half-life, deposition stretch (prestretch) and material stiffness. The predicted rates of aneurysmal expansion and spatio temporal changes in wall thickness, biaxial stresses and maximum collagen fibre stretch at the apex of the lesion depended strongly on all four factors, as did the predicted clinical endpoints (i.e. arrest, progressive expansion or rupture). Collagen turnover also affected the axial expansion, largely due to mechanical changes within the shoulder region of the lesion. We submit, therefore, that assessment of rupture risk could be improved by future experiments that delineate and quantify different aspects of patient-specific collagen turnover and that such understanding could lead to new targeted therapeutics. PMID- 23633909 TI - Genomics and genetics of aging. PMID- 23633910 TI - Genome-scale studies of aging: challenges and opportunities. AB - Whole-genome studies involving a phenotype of interest are increasingly prevalent, in part due to a dramatic increase in speed at which many high throughput technologies can be performed coupled to simultaneous decreases in cost. This type of genome-scale methodology has been applied to the phenotype of lifespan, as well as to whole-transcriptome changes during the aging process or in mutants affecting aging. The value of high throughput discovery-based science in this field is clearly evident, but will it yield a true systems-level understanding of the aging process? Here we review some of this work to date, focusing on recent findings and the unanswered puzzles to which they point. In this context, we also discuss recent technological advances and some of the likely future directions that they portend. PMID- 23633911 TI - Genome-Wide RNAi Longevity Screens in Caenorhabditis elegans. AB - Progress in aging research has identified genetic and environmental factors that regulate longevity across species. The nematode worm Caenorhabditis elegans is a genetically tractable model system that has been widely used to investigate the molecular mechanisms of aging, and the development of RNA interference (RNAi) technology has provided a powerful tool for performing large-scale genetic screens in this organism. Genome-wide screens have identified hundreds of genes that influence lifespan, many of which fall into distinct functional classes and pathways. The purpose of this review is to summarize the results of large-scale RNAi longevity screens in C. elegans, and to provide an in-depth comparison and analysis of their methodology and most significant findings. PMID- 23633912 TI - Mitochondria and organismal longevity. AB - Mitochondria are essential for various biological processes including cellular energy production. The oxidative stress theory of aging proposes that mitochondria play key roles in aging by generating reactive oxygen species (ROS), which indiscriminately damage macromolecules and lead to an age-dependent decline in biological function. However, recent studies show that increased levels of ROS or inhibition of mitochondrial function can actually delay aging and increase lifespan. The aim of this review is to summarize recent findings regarding the role of mitochondria in organismal aging processes. We will discuss how mitochondria contribute to evolutionarily conserved longevity pathways, including mild inhibition of respiration, dietary restriction, and target of rapamycin (TOR) signaling. PMID- 23633914 TI - MicroRNA in Aging: From Discovery to Biology. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively regulate gene expression of their targets at the post-transcriptional levels. A single miRNA can target up to several hundred mRNAs, thus capable of significantly altering gene expression regulatory networks. In-depth study and characterization of miRNAs has elucidated their critical functions in development, homeostasis, and disease. A link between miRNAs and longevity has been demonstrated in C. elegans, implicating their role in regulation of lifespan and in the aging process. Recent years have witnessed unprecedented technological advances in studies of miRNAs, including ultra-high throughput sequencing technologies that allow comprehensive discovery of miRNAs and their targets. Here we review the latest experimental approaches from the perspective of understanding miRNA gene expression regulatory networks in aging. We provide a methodological work flow that can be employed to discover aging-related miRNAs and their targets, and to functionally validate their roles in aging. Finally, we review the links between miRNAs known to act in the conserved pathways of aging and major aging-related diseases. Taken together, we hope to provide a focused review to facilitate future endeavor of uncovering the functional role of miRNA in aging. PMID- 23633915 TI - Systems biology in aging: linking the old and the young. AB - Aging can be defined as a process of progressive decline in the physiological capacity of an organism, manifested by accumulated alteration and destabilization at the whole system level. Systems biology approaches offer a promising new perspective to examine the old problem of aging. We begin this review by introducing the concepts of systems biology, and then illustrate the application of systems biology approaches to aging research, from gene expression profiling to network analysis. We then introduce the network that can be constructed using known lifespan and aging regulators, and conclude with a look forward to the future of systems biology in aging research. In summary, systems biology is not only a young field that may help us understand aging at a higher level, but also an important platform that can link different levels of knowledge on aging, moving us closer to a more comprehensive control of systematic decline during aging. PMID- 23633916 TI - Genetic association studies: an information content perspective. AB - The availability of high-density single nucleotide polymorphisms (SNPs) data has made the human genetic association studies possible to identify common and rare variants underlying complex diseases in a genome-wide scale. A handful of novel genetic variants have been identified, which gives much hope and prospects for the future of genetic association studies. In this process, statistical and computational methods play key roles, among which information-based association tests have gained large popularity. This paper is intended to give a comprehensive review of the current literature in genetic association analysis casted in the framework of information theory. We focus our review on the following topics: (1) information theoretic approaches in genetic linkage and association studies; (2) entropy-based strategies for optimal SNP subset selection; and (3) the usage of theoretic information criteria in gene clustering and gene regulatory network construction. PMID- 23633917 TI - On the limitations of biological knowledge. AB - Scientific knowledge is grounded in a particular epistemology and, owing to the requirements of that epistemology, possesses limitations. Some limitations are intrinsic, in the sense that they depend inherently on the nature of scientific knowledge; others are contingent, depending on the present state of knowledge, including technology. Understanding limitations facilitates scientific research because one can then recognize when one is confronted by a limitation, as opposed to simply being unable to solve a problem within the existing bounds of possibility. In the hope that the role of limiting factors can be brought more clearly into focus and discussed, we consider several sources of limitation as they apply to biological knowledge: mathematical complexity, experimental constraints, validation, knowledge discovery, and human intellectual capacity. PMID- 23633918 TI - PTEN deficiency contributes to the development and progression of head and neck cancer. AB - The sequencing of the head and neck cancer has provided a blueprint of the most frequent genetic alterations in this cancer type. They include inactivating mutations in Notch, p53, and p16(ink4a) tumor suppressor genes, in addition to nonoverlapping activating mutations of the PIK3CA and RAS oncogenes or inactivation of the tumor suppressor gene PTEN. Notably, these genetic alterations, along with epigenetic changes, result in increased activity of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, which is present in most head and neck squamous cell carcinomas (HNSCCs). Moreover, we show here that approximately 30% of HNSCCs exhibit reduced PTEN expression. We challenged the biologic relevance of this finding by combining the intraoral administration of a tobacco surrogate, 4-nitroquinoline 1 oxide, with a genetically defined animal model displaying reduced PTEN expression, achieved by the conditional deletion of Pten using the keratin promoter 14 CRE-lox system. This provided a specific genetic and environmentally defined animal model for HNSCC that resulted in the rapid development of oral specific carcinomas. Under these experimental conditions, control mice did not develop HNSCC lesions. In contrast, most mice harboring Pten deficiency developed multiple SCC lesions in the lateral border and ventral part of the tongue and floor of the mouth, which are the preferred anatomic sites for human HNSCC. Overall, our study highlights the likely clinical relevance of reduced PTEN expression and/or inactivation in HNSCC progression, while the combined Pten deletion with exposure to tobacco carcinogens or their surrogates may provide a unique experimental model system to study novel molecular targeted treatments for HNSCC patients. PMID- 23633913 TI - Chromatin remodeling, DNA damage repair and aging. AB - Cells are constantly exposed to a variety of environmental and endogenous conditions causing DNA damage, which is detected and repaired by conserved DNA repair pathways to maintain genomic integrity. Chromatin remodeling is critical in this process, as the organization of eukaryotic DNA into compact chromatin presents a natural barrier to all DNA-related events. Studies on human premature aging syndromes together with normal aging have suggested that accumulated damages might lead to exhaustion of resources that are required for physiological functions and thus accelerate aging. In this manuscript, combining the present understandings and latest findings, we focus mainly on discussing the role of chromatin remodeling in the repair of DNA double-strand breaks (DSBs) and regulation of aging. PMID- 23633919 TI - Restoring KLF5 in esophageal squamous cell cancer cells activates the JNK pathway leading to apoptosis and reduced cell survival. AB - Esophageal cancer is the eighth most common cancer in the world and has an extremely dismal prognosis, with a 5-year survival of less than 20%. Current treatment options are limited, and thus identifying new molecular targets and pathways is critical to derive novel therapies. Worldwide, more than 90% of esophageal cancers are esophageal squamous cell cancer (ESCC). Previously, we identified that Kruppel-like factor 5 (KLF5), a key transcriptional regulator normally expressed in esophageal squamous epithelial cells, is lost in human ESCC. To examine the effects of restoring KLF5 in ESCC, we transduced the human ESCC cell lines TE7 and TE15, both of which lack KLF5 expression, with retrovirus to express KLF5 upon doxycycline induction. When KLF5 was induced, ESCC cells demonstrated increased apoptosis and decreased viability, with up-regulation of the proapoptotic factor BAX. Interestingly, c-Jun N-terminal kinase (JNK) signaling, an important upstream mediator of proapoptotic pathways including BAX, was also activated following KLF5 induction. KLF5 activation of JNK signaling was mediated by KLF5 transactivation of two key upstream regulators of the JNK pathway, ASK1 and MKK4, and inhibition of JNK blocked apoptosis and normalized cell survival following KLF5 induction. Thus, restoring KLF5 in ESCC cells promotes apoptosis and decreases cell survival in a JNK-dependent manner, providing a potential therapeutic target for human ESCC. PMID- 23633920 TI - Multitargeted low-dose GLAD combination chemoprevention: a novel and promising approach to combat colon carcinogenesis. AB - Preclinical studies have shown that gefitinib, licofelone, atorvastatin, and alpha-difluoromethylornithine (GLAD) are promising colon cancer chemopreventive agents. Because low-dose combination regimens can offer potential additive or synergistic effects without toxicity, GLAD combination was tested for toxicity and chemopreventive efficacy for suppression of intestinal tumorigenesis in adenomatous polyposis coli (APC)(Min/+) mice. Six-week-old wild-type and APC(Min/+) mice were fed modified American Institute of Nutrition 76A diets with or without GLAD (25 + 50 + 50 + 500 ppm) for 14 weeks. Dietary GLAD caused no signs of toxicity based on organ pathology and liver enzyme profiles. GLAD feeding strongly inhibited (80-83%, P < .0001) total intestinal tumor multiplicity and size in APC(Min/+) mice (means +/- SEM tumors for control vs GLAD were 67.1 +/- 5.4 vs. 11.3 +/- 1.1 in males and 72.3 +/- 8.9 vs 14.5 +/- 2.8 in females). Mice fed GLAD had >95% fewer polyps with sizes of >2 mm compared with control mice and showed 75% and 85% inhibition of colonic tumors in males and females, respectively. Molecular analyses of polyps suggested that GLAD exerts efficacy by inhibiting cell proliferation, inducing apoptosis, decreasing beta-catenin and caveolin-1 levels, increasing caspase-3 cleavage and p21, and modulating expression profile of inflammatory cytokines. These observations demonstrate that GLAD, a novel cocktail of chemopreventive agents at very low doses, suppresses intestinal tumorigenesis in APC(Min/+) mice with no toxicity. This novel strategy to prevent colorectal cancer is an important step in developing agents with high efficacy without unwanted side effects. PMID- 23633921 TI - The role of sarcosine metabolism in prostate cancer progression. AB - Metabolomic profiling of prostate cancer (PCa) progression identified markedly elevated levels of sarcosine (N-methyl glycine) in metastatic PCa and modest but significant elevation of the metabolite in PCa urine. Here, we examine the role of key enzymes associated with sarcosine metabolism in PCa progression. Consistent with our earlier report, sarcosine levels were significantly elevated in PCa urine sediments compared to controls, with a modest area under the receiver operating characteristic curve of 0.71. In addition, the expression of sarcosine biosynthetic enzyme, glycine N-methyltransferase (GNMT), was elevated in PCa tissues, while sarcosine dehydrogenase (SARDH) and pipecolic acid oxidase (PIPOX), which metabolize sarcosine, were reduced in prostate tumors. Consistent with this, GNMT promoted the oncogenic potential of prostate cells by facilitating sarcosine production, while SARDH and PIPOX reduced the oncogenic potential of prostate cells by metabolizing sarcosine. Accordingly, addition of sarcosine, but not glycine or alanine, induced invasion and intravasation in an in vivo PCa model. In contrast, GNMT knockdown or SARDH overexpression in PCa xenografts inhibited tumor growth. Taken together, these studies substantiate the role of sarcosine in PCa progression. PMID- 23633922 TI - Biologic effects of dopamine on tumor vasculature in ovarian carcinoma. AB - Chronic sympathetic nervous system activation results in increased angiogenesis and tumor growth in orthotopic mouse models of ovarian carcinoma. However, the mechanistic effects of such activation on the tumor vasculature are not well understood. Dopamine (DA), an inhibitory catecholamine, regulates the functions of normal and abnormal blood vessels. Here, we examined whether DA, an inhibitory catecholamine, could block the effects of chronic stress on tumor vasculature and tumor growth. Exogenous administration of DA not only decreased tumor microvessel density but also increased pericyte coverage of tumor vessels following daily restraint stress in mice. Daily restraint stress resulted in significantly increased tumor growth in the SKOV3ip1 and HeyA8 ovarian cancer models. DA treatment blocked stress-mediated increases in tumor growth and increased pericyte coverage of tumor endothelial cells. Whereas the antiangiogenic effect of DA is mediated by dopamine receptor 2 (DR2), our data indicate that DA, through DR1, stimulates vessel stabilization by increasing pericyte recruitment to tumor endothelial cells. DA significantly stimulated migration of mouse 10T1/2 pericyte-like cells in vitro and increased cyclic adenosine mono-phosphate (cAMP) levels in these cells. Moreover, DA or the DR1 agonist SKF 82958 increased platinum concentration in SKOV3ip1 tumor xenografts following cisplatin administration. In conclusion, DA stabilizes tumor blood vessels through activation of pericyte cAMP-protein kinase A signaling pathway by DR1. These findings could have implications for blocking the stimulatory effects of chronic stress on tumor growth. PMID- 23633923 TI - Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex. AB - BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL) cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2) corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIM epigenetic silencing but is able to act as an inducer of BIM methylation. PMID- 23633924 TI - Inauhzin sensitizes p53-dependent cytotoxicity and tumor suppression of chemotherapeutic agents. AB - Toxicity and chemoresistance are two major issues to hamper the success of current standard tumor chemotherapy. Combined therapy of agents with different mechanisms of action is a feasible and effective means to minimize the side effects and avoid the resistance to chemotherapeutic drugs while improving the antitumor effects. As the most essential tumor suppressor, p53 or its pathway has been an attractive target to develop a new type of molecule-targeting anticancer therapy. Recently, we identified a small molecule, Inauhzin (INZ), which can specifically activate p53 by inducing its deacetylation. In this study, we tested if combination with INZ could sensitize tumor cells to the current chemotherapeutic drugs, cisplatin (CIS) and doxorubicin (DOX). We found that compared with any single treatment, combination of lower doses of INZ and CIS or DOX significantly promoted apoptosis and cell growth inhibition in human non small lung cancer and colon cancer cell lines in a p53-dependent fashion. This cooperative effect between INZ and CIS on tumor suppression was also confirmed in a xenograft tumor model. Therefore, this study suggests that specifically targeting the p53 pathway could enhance the sensitivity of cancer cells to chemotherapeutic agents and markedly reduce the doses of the chemotherapy, possibly decreasing its adverse side effects. PMID- 23633925 TI - Inhibition of SUR1 decreases the vascular permeability of cerebral metastases. AB - Inhibition of sulfonylurea receptor 1 (SUR1) by glyburide has been shown to decrease edema after subarachnoid hemorrhage. We investigated if inhibiting SUR1 reduces cerebral edema due to metastases, the most common brain tumor, and explored the putative association of SUR1 and the endothelial tight junction protein, zona occludens-1 (ZO-1). Nude rats were intracerebrally implanted with small cell lung carcinoma (SCLC) LX1 or A2058 melanoma cells (n = 36). Rats were administered vehicle, glyburide (4.8 ug twice, orally), or dexamethasone (0.35 mg, intravenous). Blood-tumor barrier (BTB) permeability (K (trans)) was evaluated before and after treatment using dynamic contrast-enhanced magnetic resonance imaging. SUR1 and ZO-1 expression was evaluated using immunofluorescence and Western blots. In both models, SUR1 expression was significantly increased (P < .05) in tumors. In animals with SCLC, control mean K (trans) (percent change +/- standard error) was 101.8 +/- 36.6%, and both glyburide (-21.4 +/- 14.2%, P < .01) and dexamethasone (-14.2 +/- 13.1%, P < .01) decreased BTB permeability. In animals with melanoma, compared to controls (117.1 +/- 43.4%), glyburide lowered BTB permeability increase (3.2 +/- 15.4%, P < .05), while dexamethasone modestly lowered BTB permeability increase (63.1 +/- 22.1%, P > .05). Both glyburide (P < .001) and dexamethasone (P < .01) decreased ZO-1 gap formation. By decreasing ZO-1 gaps, glyburide was at least as effective as dexamethasone at halting increased BTB permeability caused by SCLC and melanoma. Glyburide is a safe, inexpensive, and efficacious alternative to dexamethasone for the treatment of cerebral metastasis-related vasogenic edema. PMID- 23633926 TI - Cellular immunotherapy for carcinoma using genetically modified EGFR-specific T lymphocytes. AB - Epidermal growth factor receptor (EGFR) is overexpressed in a variety of human malignancies, including pancreatic cancer, breast cancer, colon cancer, and non small cell lung cancer. Overexpression of EGFR is a predictive marker of therapeutic response and several lines of evidence suggest that EGFR is an excellent target for tumor therapy. However, the effective antitumor capacity of EGFR-specific T cells against EGFR-overexpressing tumor cells has not been fully elucidated. In our previous study, we identified an anti-EGFR single-chain variable fragment (scFv) with specific and high affinity after screening by ribosome display. In this study, the anticancer potential of anti-EGFR scFv was investigated on the basis of cell-targeted therapy. A chimeric antigen receptor (CAR) targeting EGFR was constructed and expressed on the cell membrane of T lymphocytes. These CAR-modified T cells demonstrated antitumor efficacy both in vitro and in vivo. In addition, the safety evaluation showed that CAR-modified lymphocytes have no or very minimal acute systemic toxicity. Taken together, our study provided the experimental basis for clinical application of genetically engineered lymphocytes; moreover, we also evaluate a new and interesting cell therapy protocol. PMID- 23633927 TI - IGFBP-4 anti-angiogenic and anti-tumorigenic effects are associated with anti cathepsin B activity. AB - Insulin-like growth factor-binding protein 4 (IGFBP-4/IBP-4) has potent IGF independent anti-angiogenic and antitumorigenic effects. In this study, we demonstrated that these activities are located in the IGFBP-4 C-terminal protein fragment (CIBP-4), a region containing a thyroglobulin type 1 (Tg1) domain. Proteins bearing Tg1 domains have been shown to inhibit cathepsins, lysosomal enzymes involved in basement membrane degradation and implicated in tumor invasion and angiogenesis. In our studies, CIBP-4 was shown to internalize and co localize with lysosomal-like structures in both endothelial cells (ECs) and glioblastoma U87MG cells. CIBP-4 also inhibited both growth factor-induced EC tubulogenesis in Matrigel and the concomitant increases in intracellular cathepsin B (CatB) activity. In vitro assays confirmed CIBP-4 capacity to block recombinant CatB activity. Biodistribution analysis of intravenously injected CIBP-4-Cy5.5 in a glioblastoma tumor xenograft model indicated targeted accumulation of CIBP-4 in tumors. Most importantly, CIBP-4 reduced tumor growth in this animal model by 60%. Pleiotropic anti-angiogenic and anti-tumorigenic activities of CIBP-4 most likely underlie its observed therapeutic potential against glioblastoma. PMID- 23633929 TI - BEREAVEMENT BY TRAUMATIC MEANS: THE COMPLEX SYNERGY OF TRAUMA AND GRIEF. AB - When people lose intimates unexpectedly, in particular from malicious acts of violence, they are at risk for chronic grief reactions. The phenomenology, clinical symptoms, clinical needs, and risk factors associated with loss by traumatic means and the combined influences of loss and trauma exposure are yet to be systematically studied. We review the complex interplay between trauma and loss by traumatic means. The distinctions between normal and traumatic loss, and complicated and traumatic grief, are contrasted with the traditional conceptualization of posttraumatic stress disorder. The role of various mediators such as concurrent or life-span trauma exposure and interpersonal factors, particularly the degree of attachment to the individual or group traumatically lost, is discussed. We offer a more integrated and focused view of traumatic grief, its predictors, and future directions for the integrative study of trauma and loss outcomes. PMID- 23633930 TI - Edward p. Buchanan. PMID- 23633928 TI - Sabutoclax (BI97C1) and BI112D1, putative inhibitors of MCL-1, induce mitochondrial fragmentation either upstream of or independent of apoptosis. AB - Owing to the high levels of antiapoptotic B-cell lymphoma 2 (BCL-2) family members observed in several cancers, there has been a major effort to develop inhibitors of the BCL2-family as chemotherapeutic agents. Of the different members in the BCL-2 family, myeloid cell leukemia sequence 1 (MCL-1) is commonly amplified in human tumors and is associated with their relapse and chemoresistance. As a result, specific inhibitors of MCL-1 are being designed to treat resistant tumors. However, there is increasing evidence for other nonapoptotic roles of the BCL-2 family, ranging from ionic homeostasis and autophagy to the regulation of fission-fusion dynamics in subcellular organelles, including the endoplasmic reticulum and mitochondria. In this study, we characterize the specificity of two novel putative MCL-1 inhibitors, BI97C1 (Sabutoclax) and BI112D1, in inducing apoptosis in a BAX/BAK-dependent manner and in an MCL-1-dependent system. In addition to their being proapoptotic, these inhibitors also cause enhanced mitochondrial fragmentation that accompanies a time-dependent loss of optic atrophy 1 (OPA1), suggesting an impairment of mitochondrial fusion. This mitochondrial fragmentation occurs independently of dynamin-related protein 1 (DRP1)-mediated fission activity and, unlike most apoptotic stimuli, occurs upstream of and/or independent of BAX, BAK, and other BH3-only proteins. Furthermore, this mitochondrial fragmentation occurred rapidly and preceded other hallmarks of apoptosis, including the loss in mitochondrial membrane potential and the release of cytochrome c. Although such mitochondrial fragmentation did not deplete total cellular adenosine triphosphate (ATP) or alter other mitochondrial complexes, there was significant accumulation of reactive oxygen species. PMID- 23633931 TI - Craniofacial surgery. PMID- 23633932 TI - Nonsyndromic craniosynostosis. AB - Nonsyndromic craniosynostosis is more commonly encountered than syndromic cases in pediatric craniofacial surgery. Affected children display characteristic phenotypes according to the suture or sutures involved. Restricted normal growth of the skull can lead to increased intracranial pressure and changes in brain morphology, which in turn may contribute to neurocognitive deficiency. Management has primarily focused on surgical correction of fused sutures prior to 12 months of age to optimize correction of the deformity and to ameliorate the effects of increased intracranial pressure. However, emphasis has recently shifted to better understanding the pathogenesis of neurocognitive impairment observed in these children, along with genetic mutations that contribute to premature suture fusion. Such understanding will provide opportunities for earlier and more specific neurocognitive interventions and for the development of targeted genetic therapy to prevent pathologic suture fusion. The authors review the common types of nonsyndromic craniosynostosis and the epidemiological, genetic, and neurodevelopmental details that are currently known from the literature. In addition, they present the rationale for surgical correction, offer suggestions for timing of intervention, and present some nuances of techniques that they find important in producing consistent results. PMID- 23633933 TI - Syndromic craniosynostosis. AB - Although most cases of craniosynostosis are nonsyndromic, craniosynostosis is known to occur in conjunction with other anomalies in well-defined patterns that make up clinically recognized syndromes. Patients with syndromic craniosynostoses are much more complicated to care for, requiring a multidisciplinary approach to address all of their needs effectively. This review describes the most common craniosynostosis syndromes, their characteristic features and syndrome-specific functional issues, and new modalities utilized in their management. General principles including skull development, the risk of developing increased intracranial pressure in craniosynostosis syndromes, and techniques to measure intracranial pressure are discussed. Evolving techniques of the established operative management of craniosynostosis are discussed together with more recent techniques including spring cranioplasty and posterior cranial vault distraction osteogenesis. PMID- 23633934 TI - Pierre robin sequence. AB - Pierre Robin sequence (PRS) is classically described as a triad of micrognathia, glossoptosis, and airway obstruction. Infants frequently present at birth with a hypoplastic mandible and difficulty breathing. The smaller mandible displaces the tongue posteriorly, resulting in obstruction of the airway. Typically, a wide U shaped cleft palate is also associated with this phenomenon. PRS is not a syndrome in itself, but rather a sequence of disorders, with one abnormality resulting in the next. However, it is related to several other craniofacial anomalies and may appear in conjunction with a syndromic diagnosis, such as velocardiofacial and Stickler syndromes. Infants with PRS should be evaluated by a multidisciplinary team to assess the anatomic findings, delineate the source of airway obstruction, and address airway and feeding issues. Positioning will resolve the airway obstruction in ~70% of cases. In the correct position, most children will also be able to feed normally. If the infant continues to show evidence of desaturation, then placement of a nasopharyngeal tube is indicated. Early feeding via a nasogastric tube may also reduce the amount of energy needed and allow for early weight gain. A proportion of PRS infants do not respond to conservative measures and will require further intervention. Prior to considering any surgical procedure, the clinician should first rule out any sources of obstruction below the base of the tongue that would necessitate a tracheostomy. The two most common procedures for treatment, tongue-lip adhesion and distraction osteogenesis of the mandible, are discussed. PMID- 23633935 TI - Treacher collins syndrome. AB - Treacher Collins syndrome is a genetic disorder resulting in congenital craniofacial malformation. Patients typically present with downslanting palpebral fissures, lower eyelid colobomas, microtia, and malar and mandibular hypoplasia. This autosomal dominant disorder has a variable degree of phenotypic expression, and patients have no associated developmental delay or neurologic disease. Care for these patients requires a multidisciplinary team from birth through adulthood. Proper planning, counseling and surgical techniques are essential for optimizing patient outcomes. Here the authors review the features, genetics, and treatment of Treacher Collins syndrome. PMID- 23633936 TI - Craniofacial microsomia. AB - Craniofacial microsomia (CFM) is one of the most common congenital conditions treated in craniofacial centers worldwide. This condition is variably associated with anomalies of the jaws, ears, facial soft tissue, orbits, and facial nerve function and can be associated with extracranial anomalies. The cause of this condition is unknown, though CFM has been associated withprenatalexposures and genetic abnormalities. Diagnosis, treatment, and outcome assessment in CFM is challenging due to the wide phenotypic spectrum observed in this condition. Surgical treatment requires a coordinated team approach involving multiple specialties, which can include plastic surgery, craniofacial surgery, orthognathic surgery, and microsurgery. A wide variety of surgical options exist, and individual treatment plans should be based on the patient's needs. Although CFM can be challenging to treat, successful outcomes are rewarding. We provide a review of the common craniofacial surgical treatments for individuals with CFM. PMID- 23633937 TI - Applying an ESSENCE framework to understanding adult autism spectrum disorder and ADHD: retrospective parent reports of childhood problems. AB - Diagnoses of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are increasingly being made in adulthood. However, assessments can fail to address the diverse range of problems that patients have experienced. The current study applied an early symptomatic syndromes eliciting neurodevelopmental clinical examinations (ESSENCE) framework to explore retrospectively reported childhood developmental and behavioral problems. It examined if adult ASD and ADHD patients would show problems outside those reflected in the respective diagnostic criteria, and also if these patient groups would show more extensive childhood problems than other psychiatric patients. Parents of adults with ADHD (n = 130), ASD (n = 57), coexisting ADHD and ASD (n = 38), and other psychiatric disorders (n = 56) reported on a range of childhood problems. Descriptions of the ADHD, ASD, and ADHD+ASD groups reflected greater impairment than descriptions for patients with other psychiatric disorders in most problem areas. Although differences were observed between ADHD and ASD patients in the core diagnostic areas, these syndromes also shared a number of childhood difficulties. The ESSENCE approach can assist in understanding the symptom history of adult ADHD and ASD patients and can be helpful to distinguish their childhood experiences from other psychiatric patients' experiences. PMID- 23633939 TI - The interaction of vinculin with actin. AB - Vinculin can interact with F-actin both in recruitment of actin filaments to the growing focal adhesions and also in capping of actin filaments to regulate actin dynamics. Using molecular dynamics, both interactions are simulated using different vinculin conformations. Vinculin is simulated either with only its vinculin tail domain (Vt), with all residues in its closed conformation, with all residues in an open I conformation, and with all residues in an open II conformation. The open I conformation results from movement of domain 1 away from Vt; the open II conformation results from complete dissociation of Vt from the vinculin head domains. Simulation of vinculin binding along the actin filament showed that Vt alone can bind along the actin filaments, that vinculin in its closed conformation cannot bind along the actin filaments, and that vinculin in its open I conformation can bind along the actin filaments. The simulations confirm that movement of domain 1 away from Vt in formation of vinculin 1 is sufficient for allowing Vt to bind along the actin filament. Simulation of Vt capping actin filaments probe six possible bound structures and suggest that vinculin would cap actin filaments by interacting with both S1 and S3 of the barbed-end, using the surface of Vt normally occluded by D4 and nearby vinculin head domain residues. Simulation of D4 separation from Vt after D1 separation formed the open II conformation. Binding of open II vinculin to the barbed-end suggests this conformation allows for vinculin capping. Three binding sites on F actin are suggested as regions that could link to vinculin. Vinculin is suggested to function as a variable switch at the focal adhesions. The conformation of vinculin and the precise F-actin binding conformation is dependent on the level of mechanical load on the focal adhesion. PMID- 23633938 TI - Chapter 15: disease gene prioritization. AB - Disease-causing aberrations in the normal function of a gene define that gene as a disease gene. Proving a causal link between a gene and a disease experimentally is expensive and time-consuming. Comprehensive prioritization of candidate genes prior to experimental testing drastically reduces the associated costs. Computational gene prioritization is based on various pieces of correlative evidence that associate each gene with the given disease and suggest possible causal links. A fair amount of this evidence comes from high-throughput experimentation. Thus, well-developed methods are necessary to reliably deal with the quantity of information at hand. Existing gene prioritization techniques already significantly improve the outcomes of targeted experimental studies. Faster and more reliable techniques that account for novel data types are necessary for the development of new diagnostics, treatments, and cure for many diseases. PMID- 23633940 TI - Distinct types of disorder in the human proteome: functional implications for alternative splicing. AB - Intrinsically disordered regions have been associated with various cellular processes and are implicated in several human diseases, but their exact roles remain unclear. We previously defined two classes of conserved disordered regions in budding yeast, referred to as "flexible" and "constrained" conserved disorder. In flexible disorder, the property of disorder has been positionally conserved during evolution, whereas in constrained disorder, both the amino acid sequence and the property of disorder have been conserved. Here, we show that flexible and constrained disorder are widespread in the human proteome, and are particularly common in proteins with regulatory functions. Both classes of disordered sequences are highly enriched in regions of proteins that undergo tissue-specific (TS) alternative splicing (AS), but not in regions of proteins that undergo general (i.e., not tissue-regulated) AS. Flexible disorder is more highly enriched in TS alternative exons, whereas constrained disorder is more highly enriched in exons that flank TS alternative exons. These latter regions are also significantly more enriched in potential phosphosites and other short linear motifs associated with cell signaling. We further show that cancer driver mutations are significantly enriched in regions of proteins associated with TS and general AS. Collectively, our results point to distinct roles for TS alternative exons and flanking exons in the dynamic regulation of protein interaction networks in response to signaling activity, and they further suggest that alternatively spliced regions of proteins are often functionally altered by mutations responsible for cancer. PMID- 23633941 TI - Bayesian computation emerges in generic cortical microcircuits through spike timing-dependent plasticity. AB - The principles by which networks of neurons compute, and how spike-timing dependent plasticity (STDP) of synaptic weights generates and maintains their computational function, are unknown. Preceding work has shown that soft winner take-all (WTA) circuits, where pyramidal neurons inhibit each other via interneurons, are a common motif of cortical microcircuits. We show through theoretical analysis and computer simulations that Bayesian computation is induced in these network motifs through STDP in combination with activity dependent changes in the excitability of neurons. The fundamental components of this emergent Bayesian computation are priors that result from adaptation of neuronal excitability and implicit generative models for hidden causes that are created in the synaptic weights through STDP. In fact, a surprising result is that STDP is able to approximate a powerful principle for fitting such implicit generative models to high-dimensional spike inputs: Expectation Maximization. Our results suggest that the experimentally observed spontaneous activity and trial to-trial variability of cortical neurons are essential features of their information processing capability, since their functional role is to represent probability distributions rather than static neural codes. Furthermore it suggests networks of Bayesian computation modules as a new model for distributed information processing in the cortex. PMID- 23633942 TI - Localization of protein aggregation in Escherichia coli is governed by diffusion and nucleoid macromolecular crowding effect. AB - Aggregates of misfolded proteins are a hallmark of many age-related diseases. Recently, they have been linked to aging of Escherichia coli (E. coli) where protein aggregates accumulate at the old pole region of the aging bacterium. Because of the potential of E. coli as a model organism, elucidating aging and protein aggregation in this bacterium may pave the way to significant advances in our global understanding of aging. A first obstacle along this path is to decipher the mechanisms by which protein aggregates are targeted to specific intercellular locations. Here, using an integrated approach based on individual based modeling, time-lapse fluorescence microscopy and automated image analysis, we show that the movement of aging-related protein aggregates in E. coli is purely diffusive (Brownian). Using single-particle tracking of protein aggregates in live E. coli cells, we estimated the average size and diffusion constant of the aggregates. Our results provide evidence that the aggregates passively diffuse within the cell, with diffusion constants that depend on their size in agreement with the Stokes-Einstein law. However, the aggregate displacements along the cell long axis are confined to a region that roughly corresponds to the nucleoid-free space in the cell pole, thus confirming the importance of increased macromolecular crowding in the nucleoids. We thus used 3D individual-based modeling to show that these three ingredients (diffusion, aggregation and diffusion hindrance in the nucleoids) are sufficient and necessary to reproduce the available experimental data on aggregate localization in the cells. Taken together, our results strongly support the hypothesis that the localization of aging-related protein aggregates in the poles of E. coli results from the coupling of passive diffusion-aggregation with spatially non-homogeneous macromolecular crowding. They further support the importance of "soft" intracellular structuring (based on macromolecular crowding) in diffusion-based protein localization in E. coli. PMID- 23633943 TI - Chapter 17: bioimage informatics for systems pharmacology. AB - Recent advances in automated high-resolution fluorescence microscopy and robotic handling have made the systematic and cost effective study of diverse morphological changes within a large population of cells possible under a variety of perturbations, e.g., drugs, compounds, metal catalysts, RNA interference (RNAi). Cell population-based studies deviate from conventional microscopy studies on a few cells, and could provide stronger statistical power for drawing experimental observations and conclusions. However, it is challenging to manually extract and quantify phenotypic changes from the large amounts of complex image data generated. Thus, bioimage informatics approaches are needed to rapidly and objectively quantify and analyze the image data. This paper provides an overview of the bioimage informatics challenges and approaches in image-based studies for drug and target discovery. The concepts and capabilities of image-based screening are first illustrated by a few practical examples investigating different kinds of phenotypic changes caEditorsused by drugs, compounds, or RNAi. The bioimage analysis approaches, including object detection, segmentation, and tracking, are then described. Subsequently, the quantitative features, phenotype identification, and multidimensional profile analysis for profiling the effects of drugs and targets are summarized. Moreover, a number of publicly available software packages for bioimage informatics are listed for further reference. It is expected that this review will help readers, including those without bioimage informatics expertise, understand the capabilities, approaches, and tools of bioimage informatics and apply them to advance their own studies. PMID- 23633944 TI - Chapter 16: text mining for translational bioinformatics. AB - Text mining for translational bioinformatics is a new field with tremendous research potential. It is a subfield of biomedical natural language processing that concerns itself directly with the problem of relating basic biomedical research to clinical practice, and vice versa. Applications of text mining fall both into the category of T1 translational research-translating basic science results into new interventions-and T2 translational research, or translational research for public health. Potential use cases include better phenotyping of research subjects, and pharmacogenomic research. A variety of methods for evaluating text mining applications exist, including corpora, structured test suites, and post hoc judging. Two basic principles of linguistic structure are relevant for building text mining applications. One is that linguistic structure consists of multiple levels. The other is that every level of linguistic structure is characterized by ambiguity. There are two basic approaches to text mining: rule-based, also known as knowledge-based; and machine-learning-based, also known as statistical. Many systems are hybrids of the two approaches. Shared tasks have had a strong effect on the direction of the field. Like all translational bioinformatics software, text mining software for translational bioinformatics can be considered health-critical and should be subject to the strictest standards of quality assurance and software testing. PMID- 23633945 TI - HCV-induced miR-21 contributes to evasion of host immune system by targeting MyD88 and IRAK1. AB - Upon recognition of viral components by pattern recognition receptors, such as the toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like helicases, cells are activated to produce type I interferon (IFN) and proinflammatory cytokines. These pathways are tightly regulated by the host to prevent an inappropriate cellular response, but viruses can modulate these pathways to proliferate and spread. In this study, we revealed a novel mechanism in which hepatitis C virus (HCV) evades the immune surveillance system to proliferate by activating microRNA-21 (miR-21). We demonstrated that HCV infection upregulates miR-21, which in turn suppresses HCV-triggered type I IFN production, thus promoting HCV replication. Furthermore, we demonstrated that miR 21 targets two important factors in the TLR signaling pathway, myeloid differentiation factor 88 (MyD88) and interleukin-1 receptor-associated kinase 1 (IRAK1), which are involved in HCV-induced type I IFN production. HCV-mediated activation of miR-21 expression requires viral proteins and several signaling components. Moreover, we identified a transcription factor, activating protein-1 (AP-1), which is partly responsible for miR-21 induction in response to HCV infection through PKCepsilon/JNK/c-Jun and PKCalpha/ERK/c-Fos cascades. Taken together, our results indicate that miR-21 is upregulated during HCV infection and negatively regulates IFN-alpha signaling through MyD88 and IRAK1 and may be a potential therapeutic target for antiviral intervention. PMID- 23633947 TI - Have it your way: how polymorphic, injected kinases and pseudokinases enable Toxoplasma to subvert host defenses. PMID- 23633946 TI - The Mnn2 mannosyltransferase family modulates mannoprotein fibril length, immune recognition and virulence of Candida albicans. AB - The fungal cell wall is the first point of interaction between an invading fungal pathogen and the host immune system. The outer layer of the cell wall is comprised of GPI anchored proteins, which are post-translationally modified by both N- and O-linked glycans. These glycans are important pathogen associated molecular patterns (PAMPs) recognised by the innate immune system. Glycan synthesis is mediated by a series of glycosyl transferases, located in the endoplasmic reticulum and Golgi apparatus. Mnn2 is responsible for the addition of the initial alpha1,2-mannose residue onto the alpha1,6-mannose backbone, forming the N-mannan outer chain branches. In Candida albicans, the MNN2 gene family is comprised of six members (MNN2, MNN21, MNN22, MNN23, MNN24 and MNN26). Using a series of single, double, triple, quintuple and sextuple mutants, we show, for the first time, that addition of alpha1,2-mannose is required for stabilisation of the alpha1,6-mannose backbone and hence regulates mannan fibril length. Sequential deletion of members of the MNN2 gene family resulted in the synthesis of lower molecular weight, less complex and more uniform N-glycans, with the sextuple mutant displaying only un-substituted alpha1,6-mannose. TEM images confirmed that the sextuple mutant was completely devoid of the outer mannan fibril layer, while deletion of two MNN2 orthologues resulted in short mannan fibrils. These changes in cell wall architecture correlated with decreased proinflammatory cytokine induction from monocytes and a decrease in fungal virulence in two animal models. Therefore, alpha1,2-mannose of N-mannan is important for both immune recognition and virulence of C. albicans. PMID- 23633948 TI - Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity. AB - The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5' triphosphate (5'ppp) terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5'pppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, and induction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN) signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5'pppRNA, and not by IFNalpha-2b, that included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5'pppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5'pppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach provides transcriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5'pppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents. PMID- 23633949 TI - Vpu binds directly to tetherin and displaces it from nascent virions. AB - Tetherin (Bst2/CD317/HM1.24) is an interferon-induced antiviral host protein that inhibits the release of many enveloped viruses by tethering virions to the cell surface. The HIV-1 accessory protein, Vpu, antagonizes Tetherin through a variety of proposed mechanisms, including surface downregulation and degradation. Previous studies have demonstrated that mutation of the transmembrane domains (TMD) of both Vpu and Tetherin affect antagonism, but it is not known whether Vpu and Tetherin bind directly to each other. Here, we use cysteine-scanning mutagenesis coupled with oxidation-induced cross-linking to demonstrate that Vpu and Tetherin TMDs bind directly to each other in the membranes of living cells and to map TMD residues that contact each other. We also reveal a property of Vpu, namely the ability to displace Tetherin from sites of viral assembly, which enables Vpu to exhibit residual Tetherin antagonist activity in the absence of surface downregulation or degradation. Elements in the cytoplasmic tail domain (CTD) of Vpu mediate this displacement activity, as shown by experiments in which Vpu CTD fragments were directly attached to Tetherin in the absence of the TMD. In particular, the C-terminal alpha-helix (H2) of Vpu CTD is sufficient to remove Tetherin from sites of viral assembly and is necessary for full Tetherin antagonist activity. Overall, these data demonstrate that Vpu and Tetherin interact directly via their transmembrane domains enabling activities present in the CTD of Vpu to remove Tetherin from sites of viral assembly. PMID- 23633951 TI - A refined model of the prototypical Salmonella SPI-1 T3SS basal body reveals the molecular basis for its assembly. AB - The T3SS injectisome is a syringe-shaped macromolecular assembly found in pathogenic Gram-negative bacteria that allows for the direct delivery of virulence effectors into host cells. It is composed of a "basal body", a lock-nut structure spanning both bacterial membranes, and a "needle" that protrudes away from the bacterial surface. A hollow channel spans throughout the apparatus, permitting the translocation of effector proteins from the bacterial cytosol to the host plasma membrane. The basal body is composed largely of three membrane embedded proteins that form oligomerized concentric rings. Here, we report the crystal structures of three domains of the prototypical Salmonella SPI-1 basal body, and use a new approach incorporating symmetric flexible backbone docking and EM data to produce a model for their oligomeric assembly. The obtained models, validated by biochemical and in vivo assays, reveal the molecular details of the interactions driving basal body assembly, and notably demonstrate a conserved oligomerization mechanism. PMID- 23633950 TI - Parallel exploitation of diverse host nutrients enhances Salmonella virulence. AB - Pathogen access to host nutrients in infected tissues is fundamental for pathogen growth and virulence, disease progression, and infection control. However, our understanding of this crucial process is still rather limited because of experimental and conceptual challenges. Here, we used proteomics, microbial genetics, competitive infections, and computational approaches to obtain a comprehensive overview of Salmonella nutrition and growth in a mouse typhoid fever model. The data revealed that Salmonella accessed an unexpectedly diverse set of at least 31 different host nutrients in infected tissues but the individual nutrients were available in only scarce amounts. Salmonella adapted to this situation by expressing versatile catabolic pathways to simultaneously exploit multiple host nutrients. A genome-scale computational model of Salmonella in vivo metabolism based on these data was fully consistent with independent large-scale experimental data on Salmonella enzyme quantities, and correctly predicted 92% of 738 reported experimental mutant virulence phenotypes, suggesting that our analysis provided a comprehensive overview of host nutrient supply, Salmonella metabolism, and Salmonella growth during infection. Comparison of metabolic networks of other pathogens suggested that complex host/pathogen nutritional interfaces are a common feature underlying many infectious diseases. PMID- 23633952 TI - Guanylate-binding protein 1 (Gbp1) contributes to cell-autonomous immunity against Toxoplasma gondii. AB - IFN-gamma activates cells to restrict intracellular pathogens by upregulating cellular effectors including the p65 family of guanylate-binding proteins (GBPs). Here we test the role of Gbp1 in the IFN-gamma-dependent control of T. gondii in the mouse model. Virulent strains of T. gondii avoided recruitment of Gbp1 to the parasitophorous vacuole in a strain-dependent manner that was mediated by the parasite virulence factors ROP18, an active serine/threonine kinase, and the pseudokinase ROP5. Increased recruitment of Gbp1 to Deltarop18 or Deltarop5 parasites was associated with clearance in IFN-gamma-activated macrophages in vitro, a process dependent on the autophagy protein Atg5. The increased susceptibility of Deltarop18 mutants in IFN-gamma-activated macrophages was reverted in Gbp1(-/-) cells, and decreased virulence of this mutant was compensated in Gbp1(-/-) mice, which were also more susceptible to challenge with type II strain parasites of intermediate virulence. These findings demonstrate that Gbp1 plays an important role in the IFN-gamma-dependent, cell-autonomous control of toxoplasmosis and predict a broader role for this protein in host defense. PMID- 23633953 TI - Complex structure of OspI and Ubc13: the molecular basis of Ubc13 deamidation and convergence of bacterial and host E2 recognition. AB - Ubc13 is an important ubiquitin-conjugating (E2) enzyme in the NF-kappaB signaling pathway. The Shigella effector OspI targets Ubc13 and deamidates Gln100 of Ubc13 to a glutamic acid residue, leading to the inhibition of host inflammatory responses. Here we report the crystal structure of the OspI-Ubc13 complex at 2.3 A resolution. The structure reveals that OspI uses two differently charged regions to extensively interact with the alpha1 helix, L1 loop and L2 loop of Ubc13. The Gln100 residue is bound within the hydrophilic catalytic pocket of OspI. A comparison between Ubc13-bound and wild-type free OspI structures revealed that Ubc13 binding induces notable structural reassembly of the catalytic pocket, suggesting that substrate binding might be involved in the catalysis of OspI. The OspI-binding sites in Ubc13 largely overlap with the binding residues for host ubiquitin E3 ligases and a deubiquitinating enzyme, which suggests that the bacterial effector and host proteins exploit the same surface on Ubc13 for specific recognition. Biochemical results indicate that both of the differently charged regions in OspI are important for the interaction with Ubc13, and the specificity determinants in Ubc13 for OspI recognition reside in the distinct residues in the alpha1 helix and L2 region. Our study reveals the molecular basis of Ubc13 deamidation by OspI, as well as a convergence of E2 recognition by bacterial and host proteins. PMID- 23633955 TI - The Chlamydia pneumoniae invasin protein Pmp21 recruits the EGF receptor for host cell entry. AB - Infection of mammalian cells by the strictly intracellular pathogens Chlamydiae requires adhesion and internalization of the infectious Elementary Bodies (EBs). The components of the latter step were unknown. Here, we identify Chlamydia pneumoniae Pmp21 as an invasin and EGFR as its receptor. Modulation of EGFR surface expression evokes correlated changes in EB adhesion, internalization and infectivity. Ectopic expression of EGFR in EGFR-negative hamster cells leads to binding of Pmp21 beads and EBs, thus boosting the infection. EB/Pmp21 binding and invasion of epithelial cells results in activation of EGFR, recruitment of adaptors Grb2 and c-Cbl and activation of ERK1/2, while inhibition of EGFR or MEK kinase activity abrogates EB entry, but not attachment. Binding of Grb2 and c-Cbl by EGFR is essential for infection. This is the first report of an invasin receptor interaction involved in host-cell invasion by any chlamydial species. PMID- 23633954 TI - Early apoptosis of macrophages modulated by injection of Yersinia pestis YopK promotes progression of primary pneumonic plague. AB - Yersinia pestis causes pneumonic plague, a disease characterized by inflammation, necrosis and rapid bacterial growth which together cause acute lung congestion and lethality. The bacterial type III secretion system (T3SS) injects 7 effector proteins into host cells and their combined activities are necessary to establish infection. Y. pestis infection of the lungs proceeds as a biphasic inflammatory response believed to be regulated through the control of apoptosis and pyroptosis by a single, well-conserved T3SS effector protein YopJ. Recently, YopJ-mediated pyroptosis, which proceeds via the NLRP3-inflammasome, was shown to be regulated by a second T3SS effector protein YopK in the related strain Y. pseudotuberculosis. In this work, we show that for Y. pestis, YopK appears to regulate YopJ-mediated apoptosis, rather than pyroptosis, of macrophages. Inhibition of caspase-8 blocked YopK-dependent apoptosis, suggesting the involvement of the extrinsic pathway, and appeared cell-type specific. However, in contrast to yopJ, deletion of yopK caused a large decrease in virulence in a mouse pneumonic plague model. YopK-dependent modulation of macrophage apoptosis was observed at 6 and 24 hours post-infection (HPI). When YopK was absent, decreased populations of macrophages and dendritic cells were seen in the lungs at 24 HPI and correlated with resolution rather than progression of inflammation. Together the data suggest that Y. pestis YopK may coordinate the inflammatory response during pneumonic plague through the regulation of apoptosis of immune cells. PMID- 23633956 TI - Immunodomination during peripheral vaccinia virus infection. AB - Immunodominance is a fundamental property of CD8(+) T cell responses to viruses and vaccines. It had been observed that route of administration alters immunodominance after vaccinia virus (VACV) infection, but only a few epitopes were examined and no mechanism was provided. We re-visited this issue, examining a panel of 15 VACV epitopes and four routes, namely intradermal (i.d.), subcutaneous (s.c.), intraperitoneal (i.p.) and intravenous (i.v.) injection. We found that immunodominance is sharpened following peripheral routes of infection (i.d. and s.c.) compared with those that allow systemic virus dissemination (i.p. and i.v.). This increased immunodominance was demonstrated with native epitopes of VACV and with herpes simplex virus glycoprotein B when expressed from VACV. Responses to some subdominant epitopes were altered by as much as fourfold. Tracking of virus, examination of priming sites, and experiments restricting virus spread showed that priming of CD8(+) T cells in the spleen was necessary, but not sufficient to broaden responses. Further, we directly demonstrated that immunodomination occurs more readily when priming is mainly in lymph nodes. Finally, we were able to reduce immunodominance after i.d., but not i.p. infection, using a VACV expressing the costimulators CD80 (B7-1) and CD86 (B7-2), which is notable because VACV-based vaccines incorporating these molecules are in clinical trials. Taken together, our data indicate that resources for CD8(+) T cell priming are limiting in local draining lymph nodes, leading to greater immunodomination. Further, we provide evidence that costimulation can be a limiting factor that contributes to immunodomination. These results shed light on a possible mechanism of immunodomination and highlight the need to consider multiple epitopes across the spectrum of immunogenicities in studies aimed at understanding CD8(+) T cell immunity to viruses. PMID- 23633961 TI - Tissue homeostasis in the wing disc of Drosophila melanogaster: immediate response to massive damage during development. AB - All organisms have developed mechanisms to respond to organ or tissue damage that may appear during development or during the adult life. This process of regeneration is a major long-standing problem in Developmental Biology. We are using the Drosophila melanogaster wing imaginal disc to study the response to major damage inflicted during development. Using the Gal4/UAS/Gal80(TS) conditional system, we have induced massive cell killing by forcing activity of the pro-apoptotic gene hid in two major regions of the disc as defined by Gal4 inserts in the genes rotund (rn) and spalt (sal). The procedure ensures that at the end of a 40-48 hrs of ablation period the great majority of the cells of the original Rn or Sal domains have been eliminated. The results indicate that the damage provokes an immediate response aimed to keep the integrity of the epithelium and to repair the region under ablation. This includes an increase in cell proliferation to compensate for the cell loss and the replacement of the dead cells by others from outside of the damaged area. The response is almost contemporaneous with the damage, so that at the end of the ablation period the targeted region is already reconstructed. We find that the proliferative response is largely systemic, as the number of cells in division increases all over the disc. Furthermore, our results indicate that the Dpp and Wg pathways are not specifically involved in the regenerative response, but that activity of the JNK pathway is necessary both inside and outside the ablated domain for its reconstruction. PMID- 23633957 TI - IL-1beta production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease. AB - Chronic hepatitis C virus (HCV) infection is a leading cause of liver disease. Liver inflammation underlies infection-induced fibrosis, cirrhosis and liver cancer but the processes that promote hepatic inflammation by HCV are not defined. We provide a systems biology analysis with multiple lines of evidence to indicate that interleukin-1beta (IL-1beta) production by intrahepatic macrophages confers liver inflammation through HCV-induced inflammasome signaling. Chronic hepatitis C patients exhibited elevated levels of serum IL-1beta compared to healthy controls. Immunohistochemical analysis of healthy control and chronic hepatitis C liver sections revealed that Kupffer cells, resident hepatic macrophages, are the primary cellular source of hepatic IL-1beta during HCV infection. Accordingly, we found that both blood monocyte-derived primary human macrophages, and Kupffer cells recovered from normal donor liver, produce IL 1beta after HCV exposure. Using the THP-1 macrophage cell-culture model, we found that HCV drives a rapid but transient caspase-1 activation to stimulate IL-1beta secretion. HCV can enter macrophages through non-CD81 mediated phagocytic uptake that is independent of productive infection. Viral RNA triggers MyD88-mediated TLR7 signaling to induce IL-1beta mRNA expression. HCV uptake concomitantly induces a potassium efflux that activates the NLRP3 inflammasome for IL-1beta processing and secretion. RNA sequencing analysis comparing THP1 cells and chronic hepatitis C patient liver demonstrates that viral engagement of the NLRP3 inflammasome stimulates IL-1beta production to drive proinflammatory cytokine, chemokine, and immune-regulatory gene expression networks linked with HCV disease severity. These studies identify intrahepatic IL-1beta production as a central feature of liver inflammation during HCV infection. Thus, strategies to suppress NLRP3 or IL-1beta activity could offer therapeutic actions to reduce hepatic inflammation and mitigate disease. PMID- 23633960 TI - High-resolution mapping of h1 linker histone variants in embryonic stem cells. AB - H1 linker histones facilitate higher-order chromatin folding and are essential for mammalian development. To achieve high-resolution mapping of H1 variants H1d and H1c in embryonic stem cells (ESCs), we have established a knock-in system and shown that the N-terminally tagged H1 proteins are functionally interchangeable to their endogenous counterparts in vivo. H1d and H1c are depleted from GC- and gene-rich regions and active promoters, inversely correlated with H3K4me3, but positively correlated with H3K9me3 and associated with characteristic sequence features. Surprisingly, both H1d and H1c are significantly enriched at major satellites, which display increased nucleosome spacing compared with bulk chromatin. While also depleted at active promoters and enriched at major satellites, overexpressed H1(0) displays differential binding patterns in specific repetitive sequences compared with H1d and H1c. Depletion of H1c, H1d, and H1e causes pericentric chromocenter clustering and de-repression of major satellites. These results integrate the localization of an understudied type of chromatin proteins, namely the H1 variants, into the epigenome map of mouse ESCs, and we identify significant changes at pericentric heterochromatin upon depletion of this epigenetic mark. PMID- 23633964 TI - Building better oncology data systems and workforce models in a rapidly changing health care system. PMID- 23633963 TI - Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1. AB - Vertebrate limb outgrowth is driven by a positive feedback loop that involves Sonic hedgehog (Shh) and Gremlin1 (Grem1) in the posterior limb bud mesenchyme and Fibroblast growth factors (Fgfs) in the overlying epithelium. Proper spatio temporal control of these signaling activities is required to avoid limb malformations such as polydactyly. Here we show that, in Tbx2-deficient hindlimbs, Shh/Fgf4 signaling is prolonged, resulting in increased limb bud size and duplication of digit 4. In turn, limb-specific Tbx2 overexpression leads to premature termination of this signaling loop with smaller limbs and reduced digit number as phenotypic manifestation. We show that Tbx2 directly represses Grem1 in distal regions of the posterior limb mesenchyme allowing Bone morphogenetic protein (Bmp) signaling to abrogate Fgf4/9/17 expression in the overlying epithelium. Since Tbx2 itself is a target of Bmp signaling, our data identify a growth-inhibiting positive feedback loop (Bmp/Tbx2/Grem1). We propose that proliferative expansion of Tbx2-expressing cells mediates self-termination of limb bud outgrowth due to their refractoriness to Grem1 induction. PMID- 23633962 TI - Genetic requirements for signaling from an autoactive plant NB-LRR intracellular innate immune receptor. AB - Plants react to pathogen attack via recognition of, and response to, pathogen specific molecules at the cell surface and inside the cell. Pathogen effectors (virulence factors) are monitored by intracellular nucleotide-binding leucine rich repeat (NB-LRR) sensor proteins in plants and mammals. Here, we study the genetic requirements for defense responses of an autoactive mutant of ADR1-L2, an Arabidopsis coiled-coil (CC)-NB-LRR protein. ADR1-L2 functions upstream of salicylic acid (SA) accumulation in several defense contexts, and it can act in this context as a "helper" to transduce specific microbial activation signals from "sensor" NB-LRRs. This helper activity does not require an intact P-loop. ADR1-L2 and another of two closely related members of this small NB-LRR family are also required for propagation of unregulated runaway cell death (rcd) in an lsd1 mutant. We demonstrate here that, in this particular context, ADR1-L2 function is P-loop dependent. We generated an autoactive missense mutation, ADR1 L2D484V, in a small homology motif termed MHD. Expression of ADR1-L2D848V leads to dwarfed plants that exhibit increased disease resistance and constitutively high SA levels. The morphological phenotype also requires an intact P-loop, suggesting that these ADR1-L2D484V phenotypes reflect canonical activation of this NB-LRR protein. We used ADR1-L2D484V to define genetic requirements for signaling. Signaling from ADR1-L2D484V does not require NADPH oxidase and is negatively regulated by EDS1 and AtMC1. Transcriptional regulation of ADR1 L2D484V is correlated with its phenotypic outputs; these outputs are both SA dependent and -independent. The genetic requirements for ADR1-L2D484V activity resemble those that regulate an SA-gradient-dependent signal amplification of defense and cell death signaling initially observed in the absence of LSD1. Importantly, ADR1-L2D484V autoactivation signaling is controlled by both EDS1 and SA in separable, but linked pathways. These data allows us to propose a genetic model that provides insight into an SA-dependent feedback regulation loop, which, surprisingly, includes ADR1-L2. PMID- 23633965 TI - Tracking the workforce: the American Society of Clinical Oncology workforce information system. AB - PURPOSE: In anticipation of oncologist workforce shortages projected as part of a 2007 study, the American Society of Clinical Oncology (ASCO) worked with a contractor to create a workforce information system (WIS) to assemble the latest available data on oncologist supply and cancer incidence and prevalence. ASCO plans to publish findings annually, reporting on new data and tracking trends over time. METHODS: THE WIS REPORT IS COMPOSED OF THREE SECTIONS: supply, new entrants, and cancer incidence and prevalence. Tabulations of the number of oncologists in the United States are derived mainly from the American Medical Association Physician Masterfile. Information on fellows and residents in the oncology workforce pipeline come from published sources such as Journal of the American Medical Association. Incidence and prevalence estimates are published by the American Cancer Society and National Cancer Institute. RESULTS: The WIS reports a total of 13,084 oncologists working in the United States in 2011. Oncologists are defined as those physicians who designate hematology, hematology/oncology, or medical oncology as their specialty. The WIS compares the characteristics of these oncologists with those of all physicians and tracks emerging trends in the physician training pipeline. CONCLUSION: Observing characteristics of the oncologist workforce over time allows ASCO to identify, prioritize, and evaluate its workforce initiatives. Accessible figures and reports generated by the WIS can be used by ASCO and others in the oncology community to advocate for needed health care system and policy changes to help offset future workforce shortages. PMID- 23633966 TI - American Society of Clinical Oncology National Census of Oncology Practices: preliminary report. AB - In response to reports of increasing financial and administrative burdens on oncology practices and a lack of systematic information related to these issues, American Society of Clinical Oncology (ASCO) leadership started an effort to collect key practice-level data from all oncology practices in the United States. The result of the effort is the ASCO National Census of Oncology Practices (Census) launched in June 2012. The initial Census work involved compiling an inventory of oncology practices from existing lists of oncology physicians in the United States. A comprehensive, online data collection instrument was developed, which covered a number of areas, including practice characteristics (staffing configuration, organizational structure, patient mix and volume, types of services offered); organizational, staffing, and service changes over the past 12 months; and an assessment of the likelihood that the practice would experience organizational, staffing, and service changes in the next 12 months. More than 600 practices participated in the Census by providing information. In this article, we present preliminary highlights from the data gathered to date. We found that practice size was related to having experienced practice mergers, hiring additional staff, and increasing staff pay in the past 12 months, that geographic location was related to having experienced hiring additional staff, and that practices in metropolitan areas were more likely to have experienced practice mergers in the past 12 months than those in nonmetropolitan areas. We also found that practice size and geographic location were related to higher likelihoods of anticipating practice mergers, sales, and purchases in the future. PMID- 23633967 TI - Who does not receive treatment for cancer? AB - PURPOSE: Little has been published on nontreatment of cancer, yet the National Cancer Data Base (NCDB) indicates that 9.2% of patients receive no first course of treatment. Because the NCDB is limited to accredited cancer programs, there is potential for the actual rate to differ. We sought to understand the rate and characteristics of patients with cancer who receive no first course of treatment in a more population-representative data source. MATERIALS AND METHODS: The Iowa Cancer Registry (ICR) strives to capture 100% of newly diagnosed cancer cases among Iowa residents, regardless of where they are diagnosed or treated. RESULTS: In the ICR from 2004 to 2010, 12.3% of newly diagnosed patients with cancer did not receive a first course of treatment, which is 48% higher than the NCDB data for the state of Iowa (8.3%) during the same time period. Logistic regression indicated that nontreatment was more common in certain cancers (ie, small-cell and non-small-cell lung/bronchial cancers and low-grade non-Hodgkin lymphoma), advanced stages, older patients, those receiving treatment recommendations at nonaccredited cancer programs, and patients who never consulted an oncologist, radiation therapist, or surgeon. Distance to treatment facilities was not related to nontreatment. CONCLUSION: The rate of nontreatment varies by cancer type and stage and is higher in patients receiving initial treatment recommendations in nonaccredited cancer programs than in accredited cancer programs. This pattern seems to be correlated with patient characteristics but also may be related to provider and facility characteristics available to people locally that influence both patient and provider decision making. PMID- 23633968 TI - Association between the availability of medical oncologists and initiation of chemotherapy for patients with stage III colon cancer. AB - PURPOSE: Although the number of medical oncologists (MOs) has steadily increased over time, and adjuvant chemotherapy provides significant survival benefit for patients with stage III colon cancer, many patients still do not receive chemotherapy. Uneven geographic distribution of MOs may contribute to decreasing access to cancer care. This study explored the association of MO availability by hospital service area (HSA) of patient residence and access to chemotherapy treatment. METHODS: Using the linked SEER-Medicare database, the study identified 9,262 patients who were age >=66 years and underwent colectomy for stage III colon cancer diagnosed from 2000 to 2005. MOs were identified by physician specialty codes. HSAs are geographic areas that are relatively self-contained with respect to routine hospital care. Multivariate logistic regression was used to investigate the association between MO availability by HSA of patient residence and initiation of chemotherapy. RESULTS: Within 3 months after colectomy, 5,622 patients (60.7%) initiated chemotherapy. Adjusting for clinical and patient characteristics, patients residing in an HSA with >= one MO had an increased likelihood of initiating chemotherapy within 3 months after colectomy compared with those living in areas with no MOs (one to two MOs: OR, 1.451 [P < .01]; three to eight MOs: OR, 1.497 [P < .01]; >= nine MOs: OR, 1.322 [P < .01]). CONCLUSION: Results suggest that the availability of >= one MO within the HSA in which a patient resides was associated with greater access to chemotherapy after surgery. PMID- 23633969 TI - Prevalence and correlates of postdiagnosis initiation of complementary and alternative medicine among patients at a comprehensive cancer center. AB - PURPOSE: Patients with cancer increasingly use complementary and alternative medicine (CAM) in conjunction with conventional oncology treatments. Previous studies have not investigated postdiagnosis initiation of CAM therapies or independent correlates of use of individual CAM modalities. The purpose of this study was to determine the prevalence and correlates of individual CAM modalities initiated after cancer diagnosis. METHODS: A cross-sectional survey was conducted of a random sample of adults with a cancer diagnosis (N = 1,228) seeking care at a National Cancer Institute-designated comprehensive cancer center within a 12 month period. RESULTS: The majority of patients were female (64.7%), white (86.9%), and married (72.8%).Three-quarters (75.2%) used at least one CAM modality, and 57.6% of those using CAM initiated use after cancer diagnosis. For all CAM therapies combined, women were 1.7 times more likely than men to initiate any CAM therapy after cancer diagnosis. However, when CAM modalities were differentiated by type, men and women were equally likely to initiate all therapies except for psychotherapy and mind-body approaches. Postdiagnosis initiation of every CAM modality, except mind-body therapies, differed by cancer type. CONCLUSION: A significant proportion of patients initiated CAM use after diagnosis. However, specific type of CAM initiated varied by demographics and cancer type, suggesting there is not a "typology" of CAM user. Optimal comprehensive cancer treatment, palliation, and survivorship care will require patient and provider education regarding CAM use by modality type; improved provider-patient communication regarding potential benefits, limitations, and risks; and institutional policies to support integrated conventional and CAM treatment. PMID- 23633970 TI - Referral and treatment patterns among patients with stages III and IV non-small cell lung cancer. AB - PURPOSE: Little is known about how referrals to different cancer specialists influence cancer care for non-small-cell lung cancer (NSCLC). Among Medicare enrollees, we identified factors of patients and their primary care physician that were associated with referrals to cancer specialists, and how the types of cancer specialists seen correlated with delivery of guideline-based therapies (GBTs). METHODS: Data from patients with stages III and IV NSCLC included in the SEER-Medicare database were linked to their physicians in the American Medical Association Masterfile database. Using logistic regression, we (1) identified patient and physician factors that were associated with referrals to cancer specialists (medical oncologists, radiation oncologists, and surgeons); (2) identified the types of referral to cancer specialists that predicted greater likelihood of receiving GBT (per National Comprehensive Cancer Network guidelines). RESULTS: A total of 28,977 patients with NSCLC diagnosed from January 1, 2000 to December 31, 2005 met eligibility criteria. Younger age, white race, higher income, and primary physician specialty other than family practice predicted higher likelihood of referrals to medical oncologists (P < .01 for all predictors). Seeing the three types of cancer specialists predicted higher likelihood of GBT (stage IIIA: odds ratio [OR] = 20.6; P < .001; IIIB: OR = 77.2; P < .001; and IV: OR = 1.2; P = .011), compared with seeing a medical oncologist only. Use of GBTs increased over the study period (42% to 48% from 2000 to 2005; P < .001). CONCLUSION: Referrals to all types of cancer specialists increased the likelihood of treatment with standard therapies, particularly in stage III patients. However, racial and income disparities still prevent optimal referrals to cancer specialists. PMID- 23633971 TI - Inpatient hospitalization of oncology patients: are we missing an opportunity for end-of-life care? AB - INTRODUCTION: Despite advances in the care of patients with cancer over the last 10 years, cancer remains the second leading cause of death in the United States. Many patients receive aggressive, in-hospital end-of-life care at high cost. There are few data on outcomes after unplanned hospitalization of patients with metastatic cancer. METHODS: In 2000 and 2010, data were collected on admissions, interventions, and survival for patients admitted to an academic inpatient medical oncology service. RESULTS: The 2000 survey included 191 admissions of 151 unique patients. The 2010 survey assessed 149 admissions of 119 patients. Lung, GI, and breast cancers were the most common cancer diagnoses. In the 2010 assessment, pain was the most common chief complaint, accounting for 28%. Although symptoms were the dominant reason for admission in 2010, procedures and imaging were common in both surveys. The median survival of patients after discharge was 4.7 months in 2000 and 3.4 months in 2010. Despite poor survival in this patient population, hospice was recommended in only 23% and 24% of patients in 2000 and 2010, respectively. Seventy percent of patients were discharged home without additional services. CONCLUSION: On the basis of our data, an unscheduled hospitalization for a patient with advanced cancer strongly predicts a median survival of fewer than 6 months. We believe that hospital admission represents an opportunity to commence and/or consolidate appropriate palliative care services and end-of-life care. PMID- 23633972 TI - If palliative care is the answer, what is the question? PMID- 23633973 TI - Accuracy of marketing claims by providers of stereotactic radiation therapy. AB - PURPOSE: Direct-to-consumer advertising by industry has been criticized for encouraging overuse of unproven therapies, but advertising by health care providers has not been as carefully scrutinized. Stereotactic radiation therapy is an emerging technology that has sparked controversy regarding the marketing campaigns of some manufacturers. Given that this technology is also being heavily advertised on the Web sites of health care providers, the accuracy of providers' marketing claims should be rigorously evaluated. METHODS: We reviewed the Web sites of all U.S. hospitals and private practices that provide stereotactic radiation using two leading brands of stereotactic radiosurgery technology. Centers were identified by using data from the manufacturers. Centers without Web sites were excluded. The final study population consisted of 212 centers with online advertisements for stereotactic radiation. Web sites were evaluated for advertisements that were inconsistent with advertising guidelines provided by the American Medical Association. RESULTS: Most centers (76%) had individual pages dedicated to the marketing of their brand of stereotactic technology that frequently contained manufacturer-authored images (50%) or text (55%). Advertising for the treatment of tumors that have not been endorsed by professional societies was present on 66% of Web sites. Centers commonly claimed improved survival (22%), disease control (20%), quality of life (17%), and toxicity (43%) with stereotactic radiation. Although 40% of Web sites championed the center's regional expertise in delivering stereotactic treatments, only 15% of Web sites provided data to support their claims. CONCLUSION: Provider advertisements for stereotactic radiation were prominent and aggressive. Further investigation of provider advertising, its effects on quality of care, and potential oversight mechanisms is needed. PMID- 23633974 TI - Is a half-truth a whole lie? PMID- 23633975 TI - Breast cancer surveillance guidelines. PMID- 23633976 TI - Multisite parent-centered risk assessment to reduce pediatric oral chemotherapy errors. AB - PURPOSE: Observational studies describe high rates of errors in home oral chemotherapy use in children. In hospitals, proactive risk assessment methods help front-line health care workers develop error prevention strategies. Our objective was to engage parents of children with cancer in a multisite study using proactive risk assessment methods to identify how errors occur at home and propose risk reduction strategies. METHODS: We recruited parents from three outpatient pediatric oncology clinics in the northeast and southeast United States to participate in failure mode and effects analyses (FMEA). An FMEA is a systematic team-based proactive risk assessment approach in understanding ways a process can fail and develop prevention strategies. Steps included diagram the process, brainstorm and prioritize failure modes (places where things go wrong), and propose risk reduction strategies. We focused on home oral chemotherapy administration after a change in dose because prior studies identified this area as high risk. RESULTS: Parent teams consisted of four parents at two of the sites and 10 at the third. Parents developed a 13-step process map, with two to 19 failure modes per step. The highest priority failure modes included miscommunication when receiving instructions from the clinician (caused by conflicting instructions or parent lapses) and unsafe chemotherapy handling at home. Recommended risk assessment strategies included novel uses of technology to improve parent access to information, clinicians, and other parents while at home. CONCLUSION: Parents of pediatric oncology patients readily participated in a proactive risk assessment method, identifying processes that pose a risk for medication errors involving home oral chemotherapy. PMID- 23633977 TI - Reducing clinical trial monitoring resource allocation and costs through remote access to electronic medical records. AB - PURPOSE: With electronic medical records (eMRs), the option now exists for clinical trial monitors to perform source data verification (SDV) remotely. We report on a feasibility study of remote access to eMRs for SDV and the potential advantages of such a process in terms of resource allocation and cost. METHODS: The Clinical Trials Unit at the Peter MacCallum Cancer Centre, in collaboration with Novartis Pharmaceuticals Australia, conducted a 6-month feasibility study of remote SDV. A Novartis monitor was granted dedicated software and restricted remote access to the eMR portal of the cancer center, thereby providing an avenue through which perform SDV. RESULTS: Six monitoring visits were conducted during the study period, four of which were performed remotely. The ability to conduct two thirds of the monitoring visits remotely in this complex phase III study resulted in an overall cost saving to Novartis. Similarly, remote monitoring eased the strain on internal resources, particularly monitoring space and hospital computer terminal access, at the cancer center. CONCLUSION: Remote access to patient eMRs for SDV is feasible and is potentially an avenue through which resources can be more efficiently used. Although this feasibility study involved limited numbers, there is no limit to scaling these processes to any number of patients enrolled onto large clinical trials. PMID- 23633980 TI - Upper extremity venous thrombosis in patients with cancer with peripherally inserted central venous catheters: a retrospective analysis of risk factors. AB - PURPOSE: Peripherally inserted central catheters (PICCs) are often used in place of mediport catheters because of cost and lack of operating room time and to prevent delays in therapy. One common complication associated with their use is upper extremity venous thrombosis (UEVT). The purpose of this study was to ascertain risk factors associated with an increased risk of PICC-associated UEVT in patients with cancer. METHODS: Retrospective analysis identified 237 patients with cancer who received PICCs at the Dallas Veterans Affairs Medical Center from 2006 to 2009. We analyzed many risk factors, including PICC infection (PI), use of erythropoiesis-stimulating agents (ESAs), antiplatelet agents (APAs), treatment dose anticoagulation (TDA), and bevacizumab. RESULTS: Of 237 patients, 36 (15%) were found to have UEVT. Stepwise logistic regression analysis showed risk factors positively associated with UEVT were use of ESAs (odds ratio [OR], 10.66; 95% CI, 2.25 to 50.49), hospitalization (OR, 2.38; 95% CI, 1.05 to 5.39), PI (OR, 2.46; 95% CI, 1.03 to 5.86), and TDA (OR, 8.34; 95% CI, 2.98 to 23.33), whereas patients receiving APAs had a lower risk of UEVT (OR, 0.25; 95% CI, 0.07 to 0.92). CONCLUSION: Specific factors significantly increase the risk of UEVT in patients with cancer with PICCs, whereas use of APAs seems to have a protective effect against UEVT. These results may aid in the development of a predictive model for identifying patients at high risk of UEVT who may benefit from APAs, as well as in determining preventive strategies for reducing the risk of PICC associated UEVT. PMID- 23633981 TI - Redetermination of Nd2Ti2O7: a non-centrosymmetric structure with perovskite-type slabs. AB - Single crystals of dineodymium(III) dititanium(IV) hepta-oxide, Nd2Ti2O7, were synthesized by the flux method and found to belong to the family of compounds with perovskite-type structural motifs. The asymmetric unit contains four Nd, four Ti and 14 O-atom sites. The perovskite-type slabs are stacked parallel to (010) with a thickness corresponding to four corner-sharing TiO6 octa-hedra. The Nd and Ti ions are displaced from the geometrical centres of respective coordin ation polyhedra so that the net polarization occurs along the c axis. The investigated crystals were all twinned and have a halved monoclinic unit cell in comparison with the first structure determination of this compound [Scheunemann & Muller-Buschbaum (1975 ?). J. Inorg. Nucl. Chem. 37, 2261-2263]. PMID- 23633982 TI - Dipotassium hydrogencarbonate fluoride monohydrate. AB - Single crystals of the title compound, K2(HCO3)F.H2O, were obtained as a secondary product after performing flux synthesis experiments aimed at the preparation of potassium rare earth silicates. The basic building unit of the structure is an [(HCO3)(H2O)F](2-) zigzag chain running parallel to [001]. Both types of anions as well as the water mol-ecules reside on mirror planes perpendicular to [010] at y = 0.25 and y = 0.75, respectively. Linkage between the different constituents of the chains is provided by O-H?O and O-H?F hydrogen bonding. The K(+) cations are located between the chains and are coordinated by two F and five O atoms in form of a distorted monocapped trigonal prism. PMID- 23633983 TI - Ammonium diphosphitoindate(III). AB - The crystal structure of the title compound, NH4[In(HPO3)2], is built up from In(III) cations (site symmetry 3m.) adopting an octa-hedral environment and two different phosphite anions (each with site symmetry 3m.) exhibiting a triangular pyramidal geometry. Each InO6 octa-hedron shares its six apices with hydrogen phosphite groups. Reciprocally, each HPO3 group shares all its O atoms with three different metal cations, leading to [In(HPO3)2](-) layers which propagate in the ab plane. The ammonium cation likewise has site symmetry 3m.. In the structure, the cations are located between the [In(HPO3)2](-) layers of the host framework. The sheets are held together by hydrogen bonds formed between the NH4 (+) cations and the O atoms of the framework. PMID- 23633984 TI - Poly[[diaqua-bis-(MU2-4,4'-bipyrid-yl)cobalt(II)] dinitrate tetra-hydrate]. AB - The title compound, {[Co(C10H8N2)2(H2O)2](NO3)2.4H2O} n , (C10H8N2 = 4,4' bipyridine = 4,4'-bpy) is a layered coordination polymer built up from a cationic square grid extending in (101) enclosing uncoordinating nitrate ions and water mol-ecules. The Co(II) ion has site symmetry 2 and one of the 4,4'-bpy ligands is generated by twofold symmetry [two N atoms and two C atoms lie on the rotation axis and the dihedral angle between the pyridine rings is 45.66 (5) degrees ]. The other 4,4'-bpy ligand is generated by a crystallographic inversion center. The Co(II) ion exhibits a slightly distorted octa-hedral coordination geometry defined by two O atoms of two coordinating water mol-ecules and four N atoms from four bridging 4,4'-bpy ligands. The structure is consolidated by O-H?O, C-H?O and C-H?N hydrogen bonds. PMID- 23633985 TI - Bromido(1,4,7,10,13-penta-aza-cyclo-hexa-deca-ne)cobalt(III) dibromide dihydrate. AB - The title salt, [CoBr(C11H27N5)]Br2.2H2O, contains a complex cation with mirror symmetry and two Br(-) counter-anions that are likewise located on the mirror plane. The central Co(III) atom of the complex cation has one Br(-) ion in an axial position, one N atom of the penta-dentate macrocyclic ligand in the other axial position and four N atoms of the ligand in equatorial positions, defining a distorted octa-hedral coordination geometry. The macrocyclic ligand is coordinated to the Co(III) atom within a 5, 6, 5 arrangement of chelate rings in the equatorial plane of the four N atoms. Due to symmetry, the configuration of the chiral N atoms is 1RS, 4SR, 10RS, 13SR. In the crystal, N-H?Br, O-H?Br and N H?O hydrogen bonds between the complex cation, anions and lattice water mol ecules generate a three-dimensional network. PMID- 23633986 TI - Bis[1,2-bis-(eth-oxy-carbon-yl)ethene-1,2-dithiol-ato-kappa(2) S,S']bis-(eta(5) penta-methyl-cyclo-penta-dien-yl)tetra-MU3-sulfido-diiron(IV)diiron(III)(3 Fe Fe). AB - The title compound, [Fe4(C10H15)2(C8H10O4S2)2S4], contains a twisted Fe4S4 cubane like core. A twofold rotation axis passes through the Fe4S4 core, completing the coordination of the four Fe atoms with two penta-methyl-cyclo-penta-dienyl ligands and two chelating dithiol-ate ligands. There are three short Fe-Fe and three long Fe?Fe contacts in the Fe4S4 core, suggesting bonding and non-bonding inter-actions, respectively. The Fe-S bonds in the Fe4S4 core range from 2.1523 (5) to 2.2667 (6) A and are somewhat longer than the Fe-S bonds involving the dithiol-ate ligand. PMID- 23633987 TI - [(2R,3S)-Butane-1,2,3,4-tetraol-kappa(3) O (1),O (2),O (3)](ethanol-kappaO)tris (nitrato-kappa(2) O,O')samarium(III). AB - The title Sm(III)-erythritol complex, [Sm(NO3)3(C2H6O)(C4H10O4)], is isotypic with its Nd, Eu, Y, Gd, Tb and Ho analogues. The Sm(III) cation exhibits a coordination number of ten and is chelated by a tridentate erythritol ligand and three bidentate nitrate anions. It is additionally coordinated by an O atom of an ethanol mol-ecule, completing an irregular coordination sphere. The Sm-O bond lengths range from 2.416 (2) to 2.611 (2) A. In the crystal, extensive O-H?O hydrogen bonding involving all hy-droxy groups and some of the nitrate O atoms links the mol-ecules into a three-dimensional network. PMID- 23633988 TI - Bis{1-[(1H-benzimidazol-1-yl)meth-yl]-1H-imidazole-kappaN (3)}bis-(3,5-dicarb-oxy benzoato-kappa(2) O (1),O (1'))nickel(II) octa-hydrate. AB - In the title complex, [Ni(C9H5O6)2(C11H10N4)2].8H2O, the Ni(II) ion exhibits site symmetry 2. It has a distorted octa-hedral coordination defined by two N atoms from two symmetry-related 1-[(1H-benzimidazol-1-yl)meth-yl]-1H-imidazole ligands and four O atoms from two symmetry-related 3,5-dicarb-oxy-benzoate anions. In the crystal, the complex mol-ecules and solvent water mol-ecules are linked via O H?O, O-H?N and N-H?O hydrogen bonds, forming a three-dimensional structure. There are also a number of C-H?O inter-actions present. PMID- 23633989 TI - Poly[[(MU4-1,3,5-triamino-1,3,5-tride-oxy-cis-inositol)sodium] bromide]. AB - In the structure of the title compound, {[Na(C6H15N3O3)]Br} n , the sodium cation and the bromide anion are both located on threefold rotation axes. The sodium cation is bonded to the three hy-droxy groups of one 1,3,5-triamino-1,3,5-tride oxy-cis-inositol (taci) ligand, with the taci ligand residing around the same threefold rotation axis as the sodium ion. The coordination sphere of the sodium ion is completed by three amino groups of three neighbouring taci mol-ecules. Hence, this type of coordination constitutes a three-dimensional open framework with channels along the c axis which are filled with the bromide counter-anions. Each bromide ion forms three symmetry-related hydrogen bonds to both the hy-droxy and the amino groups of neighbouring taci ligands. PMID- 23633990 TI - 2-Meth-oxy-anilinium trichlorido-stannate(II). AB - The title compound, (C7H10NO)[SnCl3], is a new compound with non-linear optical (NLO) properties. The structure is pseudocentrosymmetric; the absence of an inversion centre was proved by the Kurtz and Perry method showing a significant second harmonic generation (SHG) signal about ten times lower than that from potassium dihydrogenphosphate. The crystal structure exhibits alternating organic and inorganic layers parallel to the ab plane, which are stabilized by inter molecular N-H?Cl inter-actions. PMID- 23633991 TI - Tetra-aqua-(pyrimidine-4,6-dicarboxyl-ato-kappa(2) N (1),O (6))magnesium monohydrate. AB - In the title compound, [Mg(C6H2N2O4)(H2O)4].H2O, the Mg(II) ion is coordinated by a fully deprotonated pyrimidine-4,6-dicarboxyl-ate mol-ecule, via a ring N and a carboxyl-ate O atom, and by four water O atoms at the apices of a slightly distorted octa-hedron. In the crystal, mol-ecules are linked by O-H?O and O-H?N hydrogen bonds, forming a three-dimensional network. PMID- 23633992 TI - 4-(Dimethyl-amino)-pyridinium tetra-chloridoferrate(III). AB - The title salt, (C7H11N2)[FeCl4], consists of one essentially planar (the r.m.s. deviation for all non-H atoms being 0.004 A) 4-(dimethyl-amino)-pyridinium cation and a tetra-hedral tetra-chloridoferrate(III) anion. The cations and anions are arranged in layers parallel to (010). Besides electrostatic inter-actions, the crystal packing features N-H?Cl and C-H?Cl hydrogen bonds between cations and anions, forming a three-dimensional network. PMID- 23633993 TI - Diaqua-bis-(2-hy-droxy-benzoato-kappaO (1))bis-(nicotinamide-kappaN (1))cadmium diaqua-bis-(2-hy-droxy-benzoato-kappa(2) O (1),O (1'))(nico-tin-amide kappaN)cadmium-water (1/2/4). AB - The crystal structure of the title compound, [Cd(C7H5O3)2(C6H6NO)2(H2O)2].2[Cd(C7H5O3)2(C6H6NO)(H2O)2].4H2O, consists of two kinds of Cd(II) complexes (A and B) and lattice water mol-ecules. In complex A, [Cd(C7H5O3)2(C6H6NO)2(H2O)2], the Cd(II) cation is located on an inversion center and is coordinated by two salicylate anions, two nicotinamide (NA) ligands and two water mol-ecules in a slightly distorted octa-hedral geometry. In complex B, [Cd(C7H5O3)2(C6H6NO)(H2O)2], the Cd(II) cation is coordinated by two salicylate anions, one nicotinamide (NA) ligand and two water mol-ecules in an irregular seven-coordinate geometry. There are extensive intra-molecular O-H?O and weak C H?O hydrogen bonds as well as extensive inter-molecular O-H?O and N-H?O hydrogen bonding in the crystal structure. pi-pi stacking between the pyridine and benzene rings, between the benzene rings, between the benzene and pyridine rings and between the pyridine rings [centroid-centroid distances = 3.5989 (10), 3.6005 (10), 3.5800 (9) and 3.5205 (10) A, respectively] further stabilize the crystal structure. A weak N-H?pi inter-action also occurs. One of the lattice water mol ecules is disordered over two positions with an occupancy ratio of 0.70:0.30. PMID- 23633994 TI - (2-Amino-7-methyl-4-oxidopteridine-6-carboxyl-ato-kappa(3) O (4),N (5),O (6))(ethane-1,2-diamine-kappa(2) N,N')(1H-imidazole-kappaN (3))nickel(II) dihydrate. AB - In the title complex, [Ni(C8H5N5O3)(C2H8N2)(C3N2H4)].2H2O, a tridentate 2-amino-7 methyl-4-oxidopteridine-6-carboxyl-ate (pterin) ligand, a bidentate ancillary ethane-1,2-diamine (en) ligand and a monodentate 1H-imidazole (im) ligand complete a distorted octa-hedral geometry around the Ni(II) atom. The pterin ligand forms two chelate rings. Both the en and im ligands are arranged nearly orthogonally relative to the pterin ligand [dihedral angles between the mean planes of the en and pterin ligands and of the im and pterin ligands are 84.62 (9) and 85.14 (9) degrees , respectively]. N-H?N, N-H?O, O-H?N and O-H?O hydrogen bonds link the complex mol-ecules and lattice water mol-ecules into a three dimensional network. PMID- 23633995 TI - catena-Poly[[bis-(2-chloro-pyrazine-kappaN (4))cadmium]-di-MU-thio-cyanato kappa(2) N:S;kappa(2) S:N]. AB - Reaction of cadmium thio-cyanate with 2-chloro-pyrazine leads to the polymeric title compound, [Cd(NCS)2(C4H3ClN2)2] n . The Cd(II) cation, which is located on a center of inversion, is coordinated by two N-bonded and two S-bonded thio cyanate anions and by two N-bonded 2-chloro-pyrazine ligands within a slightly distorted octa-hedron. The Cd(II) cations are linked into chains along the a axis by bridging thio-cyanate anions. PMID- 23633996 TI - Diaqua-bis-[bis-(pyrazin-2-yl) sulfide-kappaN (4)]bis-(thio-cyanato kappaN)iron(II) monohydrate. AB - In the title compound [Fe(NCS)2(C8H6N4S)2(H2O)2].H2O, the Fe(II) cation is coordinated by two N-bonded thio-cyanate anions, two N (4)-bonded bis-(pyrazin-2 yl) sulfide ligands and two water mol-ecules in an slightly distorted octa-hedral geometry. The Fe(II) cation is located on a center of inversion and the lattice water mol-ecule on a twofold rotation axis. The thio-cyanate anions, the coordinating water mol-ecules and the sulfide ligands occupy general positions. The complex mol-ecules and lattice water mol-ecules are linked into a three dimensional network by O-H-N and O-H?O hydrogen bonds. PMID- 23633997 TI - catena-Poly[[[diaqua-(tetra-methyl-ethylenediamine-kappa(2) N,N')nickel(II)]-MU sulfato-kappa(2) O:O'] monohydrate]. AB - The title compound, {[Ni(SO4)(C6H16N2)(H2O)2].H2O} n , contains a Ni(II) atom that is coordinated nearly octa-hedrally by a chelating tetra-ethyl-enediamine (tmeda) ligand, two water mol-ecules in a cis arrangement and two O atoms of two sulfate anions in a trans arrangement. The sulfate anions act as MU2-bridging ligands leading to a chain structure of alternating NiO4N2 octa-hedra and SO4 tetra-hedra parallel to [001]. The polymeric chains are linked by O-H?O hydrogen bonds between coordinating water mol-ecules and sulfate anions to give double strands. There is a lattice water mol-ecule which is also involved in O-H?O hydrogen bonding between adjacent [Ni(SO4)(tmeda)(H2O)2] chains. PMID- 23633998 TI - trans-Tetra-aqua-bis-(isonicotinamide-kappaN (1))zinc bis-(3-hy-droxy-benzoate) tetra-hydrate. AB - The asymmetric unit of the title compound, [Zn(C6H6N2O)2(H2O)4](C7H5O3)2.4H2O, contains half of the complex cation with the Zn(II) ion located on an inversion center, a 3-hy-droxy-benzoate counter-anion and two uncoordinating water mol ecules. Four water O atoms in the equatorial plane around the Zn(II) ion [Zn-O = 2.089 (2) and 2.128 (2) A] form a slightly distorted square-planar arrangement and the distorted octa-hedral geometry is completed by the two N atoms [Zn-N = 2.117 (2) A] from two isonicotinamide ligands. In the anion, the carboxyl-ate group is twisted from the attached benzene ring at 9.0 (2) degrees . In the crystal, a three-dimensional hydrogen-bonding network, formed by classical O-H?O and N-H?O and weak C-H?O hydrogen bonds, consolidates the crystal packing, which exhibits pi-pi stacking between the benzene and pyridine rings, with centroid centroid distances of 3.458 (2) and 3.609 (2) A. One of the two H atoms of each uncoordinating water mol-ecule is disordered over two orientations with an occupancy ratio of 0.60:0.40. PMID- 23633999 TI - [1,2-Bis(diisopropyl-phosphan-yl)ethane-kappa(2) P,P'](carbonato-kappa(2) O,O')nickel(II). AB - In the crystal of the title compound, [Ni(CO3)(C14H32P2)], the metal center in each of three independent mol-ecules shows slight tetra-hedral distortion from ideal square-planar coordination geometry, with angles between the normals to the planes defined by the cis-P-Ni-P and cis-O-Ni-O fragments of 3.92 (17), 0.70 (16) and 2.17 (14) degrees in the three mol-ecules. In the crystal, there are inter molecular C-H?O hydrogen bonds that show a laminar growth in the ab plane. PMID- 23634000 TI - Poly[[diaqua-bis-{MU-4-[6-(4-carb-oxy-phen-yl)-4,4'-bipyridin-2-yl]benzoato kappa(2) O:N (1')}copper(II)] dimethyl-formamide tetra-solvate]. AB - In the title compound, {[Cu(C24H15N2O4)2(H2O)2].4C3H7NO} n , the Cu(II) ion, lying on an inversion center, is six-coordinated by two N atoms from two 4-[6-(4 carb-oxy-phen-yl)-4,4'-bipyridin-2-yl]benzoate (L) ligands, two deprotonated carboxyl-ate O atoms from two other symmetry-related L ligands and two water mol ecules in a slightly distorted octa-hedral geometry. The Cu(II) atoms are linked by the bridging ligands into a layer parallel to (101). The presence of intra layer O-H?O hydrogen bonds and pi-pi inter-actions between the pyridine and benzene rings [centroid-centroid distances = 3.808 (2) and 3.927 (2) A] stabilizes the layer. Further O-H?O hydrogen bonds link the layers and the dimethyl-formamide solvent mol-ecules. PMID- 23634001 TI - [2-(2,2':4',2''-Terpyridin-6'-yl-kappa(2) N (1),N (1'))benzoato kappaO]manganese(II) trihydrate. AB - In the title complex, [Mn(C22H14N3O2)2].3H2O, the Mn(II) ion is coordinated by two N,N',O-tridentate 2-(2,2':4',2''-terpyridin-6'-yl-kappa(2) N (1),N (1'))benzoate ligands in a distorted cis-MnO2N4 octa-hedral geometry. In one ligand, the dihedral angles between the central pyridine ring, the other bonded pyridine ring, the terminal pyridine ring and the benzene ring are 14.3 (15), 18.3 (18) and 43.9 (16) degrees , respectively. The equivalent angles in the second ligand are 5.8 (18), 6.3 (18), and 47.0 (17) degrees , respectively. In the crystal, the complex molecules and lattice water molecules are linked by O H?O and O-H?N hydrogen bonds, generating a three-dimensional network. PMID- 23634002 TI - cis-Chlorido(methyl-amine)-bis-(propane-1,3-diamine)-cobalt(III) dichloride monohydrate. AB - In the title compound, [CoCl(CH5N)(C3H10N2)2]Cl2.H2O, the Co(III) ion has an octa hedral coordination environment and is surrounded by four N atoms of two propane 1,3-diamine ligands in the equatorial plane, with another N atom of the methylamine ligand and a Cl atom occupying the axial positions. The crystal packing is stabilized by inter-molecular N-H?O, N-H?Cl, and O-H?Cl inter-actions, generating a three-dimensional network. PMID- 23634003 TI - Poly[diaqua-bis-(MU-4,4'-bipyridine-kappa(2) N:N')bis-(ethane-1,2-diol kappaO)bis(MU-sulfato-kappa(2) O:O')dicobalt(II)]. AB - In the title compound, [Co2(SO4)2(C10H8N2)2(C2H6O2)2(H2O)2] n , there are two crystallographically independent Co(II) ions, each of which lies on a twofold rotation axis and has a slightly distorted octa-hedral environment. One Co(II) ion is coordinated by two N atoms from two bridging 4,4'-bipyridine (4,4'-bipy) ligands, two O atoms from two sulfate ions and two O atoms from aqua ligands. The second Co(II) ion is similar but with ethane-1,2-diol ligands in place of water mol-ecules. The sulfate anions act as bridging ligands to link two adjacent Co(II) ions together, leading to the formation of linear ?Co1Co2Co1Co2?chains along the a axis. Adjacent chains are further bridged by 4,4'-bipy ligands, which are also located on the twofold rotation axis, resulting in a two-dimensional layered polymer extending parallel to (001). In the crystal, the layers are linked by extensive O-H?O hydrogen-bonding inter-actions involving the O atoms of the water mol-ecules and ethane-1,2-diol mol-ecules, resulting in a three dimensional supra-molecular network. PMID- 23634004 TI - cis-Dichloridobis(ethyl methyl sulfide-kappaS)oxidovanadium(IV). AB - The mononuclear title complex, [VCl2O(C3H8S)2], features a V(IV)=O double bond [1.5845 (15) A] in an overall trigonal-bipyramidal coordination environment defined by two Cl(-) and the S atoms of two (CH3CH2)(CH3)S ligands. In the crystal, pairs of mol-ecules form centrosymmetric dimers via C-H?O hydrogen bonds between the methyl C-H group and the oxidovanadium O atom of a neighbouring mol ecule. PMID- 23634005 TI - Aqua-bis-(4-chloro-benzoato)-kappa(2) O,O';kappaO-bis-(pyridine kappaN)cobalt(II). AB - In the title compound, [Co(C7H4ClO2)2(C5H5N)2(H2O)], the Co(II) atom is six coordinated by three O atoms from a bidentate and a monodentate 4-chloro-benzoate ligand, two N atoms from two pyridine ligands and a water O atom, giving a distorted octa-hedral geometry. In the crystal, the complex mol-ecules are connected by O-H?O hydrogen bonds and pi-pi interactions between the benzene rings [centroid-centroid distance = 3.8924 (17) A] into a chain along [010]. Between adjacent chains, pi-pi inter-actions occur between the pyridine rings [centroid-centroid distance = 3.898 (2) A], giving an overall two-dimensional architecture. PMID- 23634006 TI - Dichloridobis(1,3-diisopropyl-4,5-di-methyl-1H-imidazol-3-ium-2-thiol-ate kappaS)copper(II). AB - The mol-ecular structure of the title compound, [CuCl2(C11H20N2S)2], shows the Cu(II) atom with a distorted tetra-hedral geometry from two Cl atoms [Cu-Cl = 2.2182 (6) A] and two thione S atoms [Cu-S = 2.3199 (6) A]. The angles at the copper cation, which lies on a twofold rotation axis, are Cl-Cu-Cl = 142.84 (4) degrees , Cl-Cu-S = 94.80 (2) and 99.97 (2) degrees , and S-Cu-S = 132.46 (4) degrees . The planes of the two imidazolium rings make a dihedral angle of 76.92 (8) degrees . PMID- 23634007 TI - Tris(2,2'-bipyridine)-copper(II) penta-cyanido-nitro-soferrate(II) methanol disolvate monohydrate. AB - The title complex [Cu(C10H8N2)3][Fe(CN)5(NO)].2CH3OH.H2O, consists of discrete [Cu(bpy)3](2+) cations (bpy is 2,2'-bipyridine), [Fe(CN)5NO](2-) anions and solvent mol-ecules of crystallization (two methanol mol-ecules and one water mol ecules per asymmetric unit). The Cu(II) ion adopts a distorted octa-hedral environment, coordinated by six N atoms from three bpy ligands. The cation charge is balanced by a nitro-prusside counter-anion, which has a slightly distorted octa-hedral coordination geometry. In the crystal, anions and solvent mol-ecules are involved in O-H?N and O-H?O hydrogen bonds, which form chains along [100]. The cations are located between these chains. PMID- 23634008 TI - Diaqua-bis-{5-(pyridin-2-yl-kappaN)-3-[4-(pyri-din-4-yl)phenyl]-1H-1,2,4-triazol 1-ido-kappaN (1)}zinc. AB - The asymmetric unit of the title compound, [Zn(C18H12N5)2(H2O)2], consists a Zn(II) ion, located on an inversion center, a deprotonated 5-pyridin-2-yl-3-[4 (pyridin-4-yl)phen-yl]-1H-1,2,4-triazol-1-ido ligand and a water mol-ecule. The whole mol-ecule is generated by inversion symmetry. The Zn(II) ion has a distorted octa-hedral coordination geometry, defined by four N atoms from the two deprotonated organic ligands and two water O atoms. In the crystal, O-H?N hydrogen bonds link the mol-ecules, forming a three-dimensional network. PMID- 23634009 TI - Tetra-aqua-bis-(3,5-dinitro-benzoato-kappaO (1))magnesium tetra-hydrate. AB - In the structure of the title compound, [Mg(C7H3N2O6)2(H2O)4].4H2O, the slightly distorted octa-hedral MgO6 coord-in-ation polyhedron comprises two trans-related carboxyl-ate O-atom donors from mononodentate 3,5-dinitro-benzoate ligands, and four water mol-ecules. The coordinating water mol-ecules and the four water mol ecules of solvation give both intra- and inter-unit O-H?O hydrogen-bonding inter actions with carboxyl-ate, water and nitro O-atom acceptors, forming a three dimensional structure. PMID- 23634010 TI - catena-Poly[[[bis-(4-pyridine-aldoxime-kappaN (1))zinc]-MU-benzene-1,4-dicarboxyl ato-kappa(2) O (1):O (4)] 4-pyridine-aldoxime monosolvate]. AB - In the title compound, {[Zn(C8H4O4)(C6H6N2O)2].C6H6N2O} n , the Zn(II) ion exhibits a tetra-hedral coordination environment defined by two benzene-1,4 dicarboxylate dianions and two 4-pyridinealdoxime ligands. The dianions bridge the Zn(II) ions, giving a zigzag chain along the b axis. Adjacent chains are connected by O-H?O hydrogen bonds, forming a cavity in which an uncoordinating 4 pyridine-aldoxime mol-ecule is located; this mol-ecule is linked by O-H?O and O H?N hydrogen bonds to the zigzag chain. PMID- 23634011 TI - Bis(3-aza-niumylpyridin-1-ium) hexa-chloridostannate(IV) dichloride. AB - The asymmetric unit of the title compound, (C5H8N2)2[SnCl6]Cl2, consists of one 3 aza-niumylpyridin-1-ium dication and one chloride ion in a general position and a hexa-chloridostannate(IV) dianion lying about a centre of inversion. The [SnCl6](2-) anion exhibits almost perfect octa-hedral geometry. The 3-aza niumylpyridin-1-ium and chloride ions are connected via medium-strong charge supported N-H?Cl hydrogen bonds, forming undulating layers in the (110) plane. The [SnCl6](2-) ions are located between these layers and occupy cavities formed by two facing layer puckers. PMID- 23634012 TI - Chlorido[1,1'-(5-methyl-1,3-phenyl-ene)bis-(3,5-dimethyl-1H-imidazol-2-yl idene)]platinum(II). AB - In the title compound, [Pt(C17H19N4)Cl], the Pt(II) cation is C,C',C''-chelated by the 1,1'-(5-methyl-1,3-phenyl-ene)bis-(3,5-dimethyl-1H-imidazolyl-idene) anion and coordinated by a Cl(-) anion in a distorted square-planar coordination geometry. pi-pi stacking is observed between nearly parallel imidazole and benzene rings of adjacent mol-ecules, the centroid-centroid distance being 3.802 (4) A. PMID- 23634013 TI - Poly[MU-aqua-aqua-MU4-naphthalene-1,8-dicarboxyl-ato-barium]: a layer structure. AB - The title compound, [Ba(C12H6O4)(H2O)2] n , is represented by a layer-like structure built of BaO8 polyhedra. The asymmetric unit contains a Ba(2+) ion, half a coordinating water mol-ecule and half a MU4-bridging naphthalene-1,8 dicarboxyl-ate (1,8-nap) ligand, the whole structure being generated by twofold rotational symmetry. The carboxyl-ate groups of the 1,8-nap ligands act as bridges linking four Ba(2+) ions, while each Ba(2+) ion is eight-coordinated by O atoms from four 1,8-nap ligands and two coordinating water mol-ecules. In the crystal, there are O-H?O hydrogen bonds involving the water mol-ecules and carboxyl-ate O atoms in the BaO8 polyhedra. Each BaO8 polyhedron is connected via corner-sharing water O atoms or edge-sharing ligand O atoms, forming a sheet parallel to the bc plane. These sheets stack along the a-axis direction and are connected via van der Waals forces only. The naphthalene groups protrude above and below the layers of the BaO8 polyhedra and there are voids of ca 208 A(3) bounded by these groups. No residual electron density was found in this region. The crystal studied was twinned by pseudo-merohedry, with a refined twin component ratio of 0.5261 (1):0.4739 (1). PMID- 23634014 TI - Tetra-kis(MU-4-chloro-benzoato-kappa(2) O:O')bis-[(ethanol-kappaO)copper(II)](Cu Cu). AB - In the centrosymmetric dinuclear title Cu(II) complex, [Cu2(C7H4ClO2)(C2H5OH)2], the Cu-Cu distance is 2.5905 (4) A. The two metal atoms are bridged by four 4 chloro-benzoate ligands and each has an ethanol mol-ecule in the axial position of the overall octahedral coordination environment. The crystal packing features O-H?O hydrogen bonds. PMID- 23634015 TI - Bis{2,2'-[methyl-aza-nediylbis(methyl-ene)]bis-(4,6-dimethyl-phenolato)-kappa(3) O,N,O'}titanium(IV) toluene sesquisolvate. AB - The title compound, [Ti(C19H23NO2)2].1.5C7H8, crystallizes with one titanium complex mol-ecule per asymmetric unit together with one and a half toluene mol ecules. The Ti(IV) atom is coordinated by two fully deprotonated O,N,O' tridentate phen-oxy-amine ligands in a distorted octa-hedral environment. Within this arrangement the O atoms occupy the equatorial sites and the N atoms the axial sites. One of the toluene mol-ecules is disordered over two sets of sites in a 0.628 (18):0.372 (18) ratio. PMID- 23634016 TI - catena-Poly[[[bis-(methanol-kappaO)bis-(seleno-cyanato-kappaN)manganese(II)]-MU 1,2-bis-(pyridin-4-yl)ethane-kappa(2) N:N'] 1,2-bis-(pyridin-4-yl)ethane monosolvate]. AB - The reaction of manganese seleno-cyanate with 1,2-bis-(pyridin-4-yl)ethane (bpa) leads to the title compound, {[Mn(NCSe)2(C12H12N2)(CH3OH)2].C12H12N2} n . The Mn(II) cation is coordinated by two N-bonded seleno-cyanate anions, two bpa ligands and two O-bonded methanol mol-ecules, within a slightly distorted octa hedral geometry. The Mn(II) cations and the non-coordinating N-donor ligands are located on centers of inversion while the coordinating N-donor co-ligands are located on a twofold rotation axis. In the crystal, the Mn(II) cations are linked into chains along the c-axis direction by the bpa ligands. The chains are further connected via a non-coordinating bpa ligand into layers parallel to (3-10) via O H?N hydrogen-bonding inter-actions. PMID- 23634017 TI - Chlorido[1-(2-oxidophen-yl)ethyl-idene][tris-(3,5-dimethyl-pyrazol-1-yl)hydro borato]iridium(III) chloro-form monosolvate. AB - In the title compound, [Ir(C15H22BN6)(C8H7O)Cl].CHCl3, the Ir atom is formally trivalent and is coordinated in a slightly distorted octa-hedral geometry by three facial N atoms, one C atom, one O atom and one Cl atom. The Ir=Ccarbene bond is strong and short and exerts a notable effect on the trans-Ir-N bond, which is about 0.10 A longer than the two other Ir-N bonds. The chloro-form solvent mol-ecule is anchored via a weak C-H?Cl hydrogen bond to the Cl atom of the Ir complex mol-ecule. In the crystal, the constituents adopt a layer-like arrangement parallel to (010) and are held together by weak inter-molecular C H?Cl hydrogen bonds, as well as weak Cl?Cl [3.498 (2) A] and Cl?pi [3.360 (4) A] inter-actions. A weak intra-molecular C-H?O hydrogen bond is also observed. PMID- 23634018 TI - cis,cis,cis-(Acetato-kappa(2) O,O')bis-[1,2-bis-(diphenyl-phosphan-yl)ethane kappa(2) P,P']ruthenium(II) 0.75-trifluoro-methane-sulfonate 0.25-chloride. AB - In the title Ru(II) carboxyl-ate compound, [Ru(C2H3O2)(C26H24P2)2](CF3O3S)0.75Cl0.25, the distorted tris-bidentate octa hedral stereochemistry about the Ru(II) atom in the complex cation comprises four P-atom donors from two 1,2-bis-(diphenyl-phosphan-yl)ethane ligands [Ru-P = 2.2881 (13)-2.3791 (13) A] and two O-atom donors from the acetate ligand [Ru-O = 2.191 (3) and 2.202 (3) A]. The disordered counter-anions are located on the same site in the structure in a 3:1 ratio, the expanded formula comprising four complex cations, three trifluoro-methane-sulfonate anions and one chloride anion, with two such formula units in the unit cell. PMID- 23634019 TI - Bis[1,2-bis-(meth-oxy-carbon-yl)ethene-1,2-dithiol-ato-kappa(2) S,S']bis-(eta(5) penta-methyl-cyclo-penta-dien-yl)tetra-MU3-sulfido-tetra-iron(4 Fe-Fe) hexa fluoridophosphate. AB - The asymmetric unit of the title compound, [Fe4(C6H6O4S2)2(C10H15)2S4]PF6, contains two different complex cations and two PF6 (-) anions. The two complex cations have similar conformations with the butterfly-like Fe4S4 core surrounded by two penta-methyl-cyclo-penta-dienyl ligands and the S atoms of two dithiol-ate ligands. In each Fe4S4 core, there are four short Fe-Fe and two long Fe?Fe contacts, suggesting bonding and non-bonding inter-actions, respectively. The Fe S distances range from 2.1287 (13) to 2.2706 (16) A for one and from 2.1233 (13) to 2.2650 (16) A for the other Fe4S4 core. The Fe-S distances involving the dithiol-ate ligands are in a more narrow range [2.1764 (16)-2.1874 (13) A for one and 2.1743 (14)-2.1779 (16) A for the other cation]. There are no significant inter-actions between cations and anions. PMID- 23634020 TI - Hexaaqua-copper(II) bis-(tetra-fluorido-borate)-pyrazine 1,4-dioxide (1/3). AB - The crystal structure of the title compound, [Cu(H2O)6](BF4)2.3C4H4N2O2, comprises discrete [Cu(H2O)6](2+) cations and BF4 (-) anions along with three equivalents of pyrazine 1,4-dioxide (pzdo). The hexa-aqua-copper(II) ion and all three pzdo mol-ecules lie about crystallographic inversion centers. The lattice is supported by an extensive hydrogen-bonding network. O-H?O hydrogen bonding between the [Cu(H2O)6](2+) and pzdo units creates a pseudo-hexa-gonal lattice parallel to the bc plane. The BF4 (-) anions lie in the voids of that lattice, held in place by O-H?F hydrogen bonds, and also generate BF4 (-)-pzdo-BF4 (-) pzdo stacks via short F?N contacts [2.866 (3)-3.283 (4) A]. PMID- 23634021 TI - catena-Poly[[copper(I)-MU-2,6-bis-[4-(pyridin-2-yl)thia-zol-2-yl]pyridine] hexa fluoridophosphate acetonitrile monosolvate] from single-crystal synchrotron data. AB - The title complex, {[Cu(C21H13N5S2)]PF6.CH3CN} n , was formed immediately on adding together a methanol solution containing copper(I) ions and a methanol solution of 2,6-bis-[4-(pyridin-2-yl)thia-zol-2-yl]pyridine. Crystallographic studies of the complex reveal a coordination polymer with the ligand acting as a bis-(bidentate) ligand with the pyridine N atom not coordinating a metal centre. The Cu(I) atom is four-coordinate with approximately tetra-hedral stereochemistry: the N4 donor set is provided by bipyridine-like moieties of the two heterocyclic ligands. Parallel chains of the coordination polymer run along the b-axis direction with the disordered (0.50:0.50 occupancy ratio) PF6 (-) anions and acetonitrile solvent mol-ecules located between the chains. PMID- 23634022 TI - Poly[diaqua-[MU6-4,4'-(1,4-phenyl-ene)bis-(2,6-dimethyl-pyridine-3,5-dicarboxyl ato)]dilead(II)]. AB - The asymmetric unit of the title Pb-based coordination polymer, [Pb2(C24H16N2O8)(H2O)2] n , consists of one Pb(II) cation, half of a 4,4'-(1,4 phenyl-ene)bis-(2,6-dimethyl-pyridine-3,5-di-carb-oxyl-ate (L (4-)) ligand and one coordinating water mol-ecule. The centers of the benzene ring of the ligand and the four-membered Pb/O/Pb/O ring are located on centers of inversion. The Pb(II) ion is coordinated in form of a distorted polyhedron by seven O atoms from four separate L (4-) ligands and by one water O atom. The PbO7 polyhedra share O atoms, forming infinite zigzag [PbO4(H2O)] n chains along [100] that are bridged by L (4-) ligands, forming a two-dimensional coordination network parallel to (001). O-H?O hydrogen bonds involving the water mol-ecule are observed. PMID- 23634023 TI - 2-Amino-4-(4-chloro-phen-yl)-4H-chromeno[8,7-b]pyridine-3-carbonitrile. AB - The asymmetric unit of the title compound, C19H12ClN3O, contains two mol-ecules with similar conformations. The 14 non-H atoms comprising the 4H-chromeno[8,7 b]pyridine residue are essentially coplanar (r.m.s. deviations = 0.037 and 0.042 A for the two mol-ecules) and the main difference between them is seen in the twist about the bond linking the main residue to the attached chloro-benzene rings [dihedral angles = 79.01 (12) and 76.22 (11) degrees for the two mol ecules]. Zigzag supra-molecular chains along the a-axis direction mediated by amino-pyridine N-H?N hydrogen bonds feature in the crystal packing; these are connected into a three-dimensional architecture by C-H?pi inter-actions and Cl?Cl contacts [Cl?Cl = 3.3896 (14) A]. PMID- 23634024 TI - 3-(4-Chloro-phen-yl)-5-(4-eth-oxy-phen-yl)-4,5-dihydro-1H-pyrazole-1-carbothio amide ethanol monosolvate. AB - The asymmetric unit of the title compound, C18H18ClN3OS.C2H5OH, comprises a pyrazoline derivative and an ethanol solvent mol-ecule. In the mol-ecule of the pyrazoline derivative, the pyrazole ring adopts an envelope conformation with the C atom bearing the eth-oxy-phenyl substituent as the flap. The dihedral angle between the benzene rings is 74.22 (7) degrees . The eth-oxy group is coplanar with the attached benzene ring [C-O-C-Cmeth-yl = 175.50 (11) degrees and r.m.s. deviation = 0.0459 (1) A for the nine non-H atoms]. In the crystal, the pyrazoline mol-ecules are linked by N-H?Oeth-oxy hydrogen bonds into chains along the c axis and are further linked with the solvent ethanol mol-ecules by N H?Oethanol and Oethanol-H?S hydrogen bonds. C-H?pi inter-actions are also present. PMID- 23634025 TI - (1'S,12'R,13'S,17'S)-15',15'-Dimethyl-1,2-dihydro-11',14',16',18'-tetra-oxa-7' aza-spiro-[indole-3,8'-penta-cyclo-[10.6.0.0(2,9).0(3,7).0(13,17)]octa-deca-ne] 2,10'-dione. AB - In the title compound, C22H24N2O6, the indole ring has a twist conformation and the tetra-hydro-2H-pyran-2-one ring a half-chair conformation. One of the pyrrolidine rings adopts an envelope conformation on the N atom, while the other has a twist conformation; the 'butterfly' angle between their mean planes is 62.98 (11) degrees . The dioxolane ring adopts a twist conformation and the tetra hydro-furan ring has an envelope conformation on the C atom in the fused tetra hydro-2H-pyran-2-one ring adjacent to the O atom of the tetra-hydro-furan ring. The 'butterfly' angle between the mean planes of these two five-membered rings is 69.14 (10) degrees . In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, forming chains along the a axis. PMID- 23634027 TI - (E)-N-(2,4-Dichloro-benzyl-idene)-2,5-dimeth-oxy-aniline. AB - In the title compound, C15H13Cl2NO2, which was obtained by a condensation reaction of 2,5-dimeth-oxy-aniline and 2,4-dichloro-benzaldehyde, the dihedral angle between the benzene rings is 51.94 (2) degrees . The 2,5-dimeth-oxy-phenyl and 2,4-dichloro-phenyl groups are attached to the ends of the N=C group in an E conformation. Intra-molecular C-H?Cl and C-H?N contacts are observed. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming chains parallel to the b axis. PMID- 23634026 TI - The furan-osteroid viridiol. AB - The asymmetric unit of the title compound, C20H18O6 (systematic name: 1beta,3beta dihy-droxy-2beta-meth-oxyfuro[4',3',2':4,5,6]-18-norandrosta-8,11,13-triene-7,17 dione), a dihydro derivative of the fungal steroid viridin, contains two mol ecules with similar conformations. The rings bearing the hy-droxy groups adopt boat conformations. The absolute structure was assigned based on the known chirality of a precursor compound. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds, generating a three-dimensional network and weak C-H?O inter actions consolidate the packing. PMID- 23634028 TI - d-Phenyl-glycinium bromide. AB - In the crystal of the title salt, C8H10NO2 (+).Br(-), the bromide anions and the phenylglycinium cations are -linked through N-H?Br, O-H?Br and C-H?O hydrogen bonds, generating sheets lying parallel to (001). PMID- 23634029 TI - Phenazin-5-ium hydrogen sulfate monohydrate. AB - The crystal structure of the title salt, C12H9N2 (+).HSO4 (-).H2O, comprises inversion-related pairs of phenazinium ions linked by C-H?N hydrogen bonds. The phenazinium N-H atoms are hydrogen bonded to the bis-ulfate anions. The bis ulfate anions and water mol-ecules are linked by O-H?O hydrogen-bonding inter actions into a structural ladder motif parallel to the a axis. PMID- 23634030 TI - 2-(4-Amino-benzene-sulfonamido)-4,6-dimethyl-pyrimidin-1-ium 2-carb-oxy-4,6 dinitro-phenolate. AB - In the structure of the phenolate salt of the sulfa drug sulfamethazine with 3,5 dinitro-salicylic acid, C12H15N4O2S(+).C7H3N2O7 (-), the dihedral angle between the pyrimidine and benzene rings of the cation is 59.70 (17) degrees . In the crystal, cation-anion hydrogen-bonding inter-actions involving pyrim-idine-carb oxy N(+)-H?O and amine-carb-oxy N-H?O pairs give a cyclic R 2 (2)(8) motif while secondary N-H?O hydrogen bonds between the aniline group and both sulfone and nitro O-atom acceptors give a two-dimensional structure extending in (001). PMID- 23634031 TI - 3-Bromo-chroman-4-one. AB - The heterocyclic ring of the title compound, C9H7BrO2, obtained by bromination of 4-chromanone with copper bromide, adopts a half-chair conformation. The supramol ecular structure is governed by a weak C-H?O hydrogen bond. There is also pi-pi stacking between symmetry-related benzene rings; the centroid-centroid distance is 3.9464 (18), the perpendicular distance between the rings is 3.4703 (11) and the offset is 1.879 A. PMID- 23634032 TI - 2-[2-(4-Meth-oxy-phen-yl)-4,5-diphenyl-1H-imidazol-1-yl]ethanol. AB - In the title compound, C24H22N2O2, the central imidazole ring makes dihedral angles of 49.45 (8), 88.94 (9) and 19.43 (8) degrees with the benzene ring and the two phenyl rings, respectively. The dihedral angle between the phenyl rings is 77.86 (9) degrees , and they form dihedral angles of 49.06 (9) and 67.31 (8) degrees with the benzene ring. In the crystal, mol-ecules are linked by O-H?N hydrogen bonds, forming chains along the b axis. These chains are connected by C H?O hydrogen bonds, forming a two-dimensional network parallel to (100). In addition, C-H?pi inter-actions are also observed. The terminal C and O atoms of the ethanol group are disordered over two sets of sites with an occupancy ratio of 0.801 (5):0.199 (5). PMID- 23634033 TI - 3-Amino-1-(4-fluoro-phen-yl)-8-meth-oxy-1H-benzo[f]chromene-2-carbonitrile. AB - The title compound, C21H15FN2O2, features an approximately planar 1H benzo[f]chromene fused-ring system (r.m.s. deviation for the 14 non-H atoms = 0.052 A), with the fluoro-benzene ring being almost perpendicular to this [dihedral angle = 85.30 (7) degrees ]. The furan ring has a flattened half-chair conformation, with the methine C atom deviating by 0.132 (2) A from the plane of the remaining atoms (r.m.s. deviation = 0.0107 A). In the crystal, inversion dimers are formed via pairs of amine-cyano N-H?N hydrogen bonds. The dimers are connected into a three-dimensional architecture by C-H?N(cyano), C-H?pi and pi-pi [inter-centroid distance = 3.6671 (10) A] inter-actions. PMID- 23634034 TI - 3-Amino-1-(4-fluoro-phen-yl)-7-meth-oxy-1H-benzo[f]chromene-2-carbonitrile. AB - In the title compound, C21H15FN2O2, the furan ring has a flattened half-chair conformation [the methine C atom lies 0.136 (2) A above the C5 plane which has an r.m.s. deviation of 0.0229 A]. Overall, the 1H-benzo[f]chromene fused-ring system approximates a plane (r.m.s. deviation of the 14 non-H atoms = 0.049 A). The fluoro-benzene ring is almost perpendicular to this plane [dihedral angle = 89.58 (8) degrees ]. Zigzag supra-molecular tapes along the b axis are the most notable feature of the crystal packing. This arises through an alternating sequence of 12 membered {?HNC3N}2 and eight-membered {?HNCO}2 synthons. These are connected into a three-dimensional architecture by pi-pi [inter-centroid distance for centrosymmetrically related fluoro-benzene rings = 3.5181 (10) A] and C-H?pi inter-actions. PMID- 23634035 TI - 2-Amino-4-(4-bromo-phen-yl)-6-meth-oxy-4H-benzo[h]chromene-3-carbonitrile. AB - In the title compound, C21H15BrN2O2, the 14 non-H atoms of the 4H benzo[h]chromene fused-ring system are approximately coplanar (r.m.s. deviation = 0.129 A). Within this system, the 4H-pyran ring adopts a flattened half-chair conformation with the methine C atom lying 0.281 (4) A above the plane of the remaining atoms (r.m.s. deviation = 0.0446 A). The bromo-benzene ring is almost perpendicular to the fused-ring system [dihedral angle = 85.34 (13) degrees ]. In the crystal, supra-molecular layers parallel to (101) are sustained by amine cyano N-H?N and amine-meth-oxy N-H?O hydrogen bonds. The layers stack with inter actions of the type (bromo-benzene)C-H?pi(outer-C6 ring of the fused-ring system) connecting them. PMID- 23634036 TI - N'-[3-Cyano-4-(4-fluoro-phen-yl)-6-meth-oxy-4H-benzo[h]chromen-2-yl]-N,N-dimethyl methanimidamide. AB - In the title compound, C24H20FN3O2, despite the 4H-pyran ring having a flattened half-chair conformation [the methine C atom lies 0.257 (3) A above the plane of the remaining atoms with an r.m.s. deviation of 0.0295 A], the 14 non-H atoms of the 4H-benzo[h]chromene residue are approximately coplanar (r.m.s. deviation = 0.081 A). The benzene ring is nearly perpendicular to this plane [dihedral angle = 76.18 (10) degrees ], but the planar (r.m.s. deviation = 0.033 A) dimethyl methanimidamide substituent is coplanar [dihedral angle = 1.96 (12) degrees ]. In the crystal, centrosymmetric dimeric aggregates arise from C-H?N inter-actions, and these are connected into supra-molecular layers in the ab plane by C-H?pi and pi-pi [inter-centroid (central C6 ring)?(outer C6 ring)(i) distance = 3.8564 (14) A] inter-actions. PMID- 23634037 TI - 1-(5-Hy-droxy-2,2,8,8-tetra-methyl-2H,8H-pyrano[2,3-f]chromen-6-yl)-3-(4-meth-oxy phen-yl)prop-2-en-1-one. AB - In the biologically active title compound, C26H26O5, the pyran ring of the chromene unit adopts a half-chair conformation. The C=C double bond of the propenone unit exhibits a trans conformation and the carbonyl group is syn conformation to the double bond. The dihedral angle between the benzene ring and the benzopyran-one moiety is 31.54 (4) degrees . The mol-ecular structure is stabilized by an intra-molecular C=O?H-O hydrogen bond. PMID- 23634038 TI - Cinnarizinium bis-(p-toluene-sulfonate) dihydrate. AB - THE ASYMMETRIC UNIT OF THE TITLE SALT [SYSTEMATIC NAME: 1-benzhydryl-4 cinnamylpiperazine-1,4-diium bis-(p-toluene-sulfonate) dihydrate], C26H30N2 (2+).2C7H7O3S(-).2H2O, consists of a diprotonated cinnarizinium cation hydrogen bonded through two water mol-ecules to two independent p-toluene-sulfonate anions, one which is disordered over two sets of sites in a 0.793 (3):0.207 (3) ratio. In the cation, the piperazine ring adopts a chair configuration and contains two positively charged N atoms with quarternery character. The dihedral angle between the two benzene rings in the benzhydr-yl group is 71.8 (1) degrees . The benzene ring flanked opposite the piperazine ring is twisted by 75.9 (9) and 8.8 (3) degrees from these two benzene rings. In the crystal, the [N H?Owater-H?O( S)]2 hydrogen-bonded asymmetric unit is connected by further O-H?O hydrogen bonds linking the components into chains along [100]. PMID- 23634039 TI - 3-Methyl-2-vinyl-pyridinium phosphate. AB - In the title salt, C8H10N(+).H2PO4 (-), the cation is essentially planar (r.m.s. deviation = 0.063 A). In the crystal, the phosphate anions form inversion R 2 (2)(8) dimers via pairs of O-H?O hydrogen bonds. These dimers are further linked by pairs of O-H?O hydrogen bonds, also enclosing R 2 (2)(8) loops, forming chains running along [001]. The cations are bonded to the anions via N-H?O hydrogen bonds and C-H?O contacts. PMID- 23634040 TI - Ethyl (2E,4E)-5-(3-bromo-phenyl-sulfon-yl)penta-2,4-dienoate. AB - In the title compound, C13H13BrO4S, both C=C double bonds adopt an E conformation. The S atom has a distorted tetra-hedral geometry with bond angles ranging from 102.17 (13) to 119.77 (14) degrees . The ethyl acrylate substituent adopts an extented conformation with all torsion angles close to 180 degrees . In the crystal, mol-ecules are linked into centrosymmetric R 2 (2)(14) dimers via pairs of C-H?O hydrogen bonds. PMID- 23634041 TI - N-(7-Methyl-1,8-naphthyridin-2-yl)acetamide-acetic acid (1/1). AB - In the title adduct, C11H11N3O.C2H4O2, all non-H atoms of the acetamide mol-ecule are roughly coplanar, with an r.m.s. deviation of 0.0720 A. The dihedral angle between the ring plane and the acetamide group is 8.5 (2) degrees . In the crystal, O-H?N and N-H?O hydrogen bonds link the acetamide and acetic acid mol ecules. PMID- 23634042 TI - (E)-N'-(3,4-Dihy-droxy-benzyl-idene)-2,4-dimethyl-benzohydrazide monohydrate. AB - In the title compound, C16H16N2O3.H2O, the dihedral angle between the benzene rings is 30.27 (7) degrees . In the crystal, the components are linked by N-H?O, O-H?O and C-H?O inter-actions into a three-dimensional network. PMID- 23634043 TI - 2-Amino-6-methyl-5-{5-[(naphthalen-2-yl-oxy)meth-yl]-1,3,4-oxadiazol-2-ylsulfan yl}-4-(3-nitro-phen-yl)pyridine-3-carbonitrile. AB - The asymmetric unit of the title compound, C26H18N6O4S, contains two independent mol-ecules (A and B). The dihedral angles between the oxadiazole ring and naphthalene ring system are 42.59 (14) and 6.88 (14) A in mol-ecules A and B, respectively. The dihedral angles between the pyridine and benzene rings in A and B are 65.53 (13 )and 87.67 (13) A, respectively. In the crystal, mol-ecules A and B are linked through a pair of N-H?N hydrogen bonds involving one -NH2 group H atom and second pair of N-H?N hydrogen bonds involving the other -NH2 group H atom, forming an -ABAB- ribbon along [100] containing R 2 (2)(8) and R 2 (2)(12) ring motifs. These ribbons are further connected by weak C-H?N, C-H?O and C-H?pi inter-actions, resulting in a three-dimensional network. The crystal studied was a non-merohedral twin with refined components 0.906 (1):0.094 (1). PMID- 23634044 TI - (6'R*,7'R*)-7'-(1,3,-Diphenyl-1H-pyrazol-4-yl)-1,2,5',6',7',7a',3'',4''-octa hydro-1'H,2''H-dispiro-[acenaphthyl-ene-1,5'-pyrrolo-[1,2-c][1,3]thia-zole-6',3'' [1]benzopyran]-2,4''-dione. AB - In the title compound, C40H29N3O3S, the pyran ring adopts a sofa conformation, the thia-zolidine ring adopts a twisted conformation and the pyrrolidine ring adopts an envelope conformation with the N atom as the flap. The pyrazole ring is essentially planar [maximum deviation = 0.002 (2) A] and forms dihedral angles of 4.8 (1) and 39.0 (1) degrees , respectively, with the benzene rings attached to the N and C atoms. The acenapthylene ring system is approximately planar [maximum deviation = 0.058 (2) A] and forms dihedral angles of 85.9 (1) and 48.5 (1) degrees , respectively, with the pyrollothia-zole and chromene ring systems. The mol-ecular conformation is stabilized by three weak intra-molecular C-H?O hydrogen bonds, which generate one S(8) and two S(6) ring motifs. In the crystal, pairs of C-H?O hydrogen bonds link centrosymmetrically related mol-ecules into dimers, generating R 2 (2)(14) ring motifs. The crystal packing also features pairs of C-H?pi inter-actions, which link the dimers into a supra-molecular chain along the b axis. PMID- 23634045 TI - {2,7-Dieth-oxy-8-[(naphthalen-1-yl)carbon-yl]naph-thalen-1-yl}(naphthalen-1 yl)methanone. AB - In the title compound, C36H28O4, the 1-naphthoyl groups at the 1- and 8-positions of the central 2,7-dieth-oxy-naphthalene ring system are aligned almost anti parallel and make a dihedral angle of 76.59 (4) degrees . The dihedral angles between the central 2,7-dieth-oxy-naphthalene ring system and the terminal naphthalene ring systems are 86.48 (4) and 83.97 (4) degrees . In the crystal, C H?pi inter-actions between the central naphthalene ring systems and the naphthoyl groups are observed along the a axis, with the mol-ecules forming a columnar structure. The columns are linked into chains parallel to the b axis by C-H?O inter-actions. PMID- 23634046 TI - 2-[(2-Aza-niumyleth-yl)carbamo-yl]phenolate-phenol (1/1). AB - In the title 1:1 adduct, C9H12N2O2.C6H6O, the dihedral angle between the benzene ring and the salicylic amide group is 6.68 (6) degrees . The conformation of the amide group is supported by two intra-molecular N-H?O hydrogen bonds, which close S(6) and S(7) rings. In the crystal, the components are linked by O-H?O and N-H?O hydrogen bonds, generating (100) sheets. PMID- 23634047 TI - Dimethyl 1-(4-methyl-phen-yl)-8-(thio-phen-2-yl)-11-oxatricyclo [6.2.1.0(2,7)]undeca-2,4,6,9-tetra-ene-9,10-dicarboxy-late. AB - The title compound, C25H20O5S, is the product of a Diels-Alder reaction. The mol ecule consists of a fused tricyclic system containing two five-membered rings and one six-membered ring. The five-membered rings both show an envelope conformation with the O atom at the flap, whereas the six-membered ring adopts a boat conformation. The thio-phene ring is disordered over two sets of sites with an occupancy ratio of 0.53 (1):0.47 (1). The dihedral angles between the 4-methyl phenyl ring and the major and minor components of the thio-phene ring are 66.3 (1) and 67.9 (1) degrees , respectively, while the dihedral angle between the disordered thio-phenyl components is 3.1 (1) degrees . The mean plane of the tricyclic ring system makes dihedral angles of 35.8 (1), 30.8 (1) and 32.8 (1) degrees , respectively, with the 4-methyl-phenyl ring and the major and minor components of the thio-phenyl ring. In the crystal, inversion dimers are formed through pairs of C-H?pi inter-actions. In addition, C-H?O inter-actions are observed. PMID- 23634048 TI - Diethyl 1,8-bis-(4-methyl-phen-yl)-11-oxatricyclo-[6.2.1.0(2,7)]undeca-2,4,6 triene-9,10-dicarboxyl-ate. AB - The title compound, C30H30O5, is the Diels-Alder adduct from 1,3-diphenyl benzo[c]furan and diethyl maleate. The mol-ecule comprises a fused tricyclic system containing two five-membered rings, which are in envelope conformations with the O atom at the flap, and a six-membered ring adopting a boat conformation. The dihedral angle between the 4-methyl-phenyl substituents in the 1- and 8-positions is 62.1 (1) degrees . The ethyl group of one ester group and the eth-oxy group of the other ester group are disordered over two sets of sites, with occupancy ratios of 0.43 (2):0.57 (2) and 0.804 (7):0.196 (7), respectively. In the crystal, inversion dimers are formed through pairs of C-H?O inter-actions. PMID- 23634049 TI - 5-Chloro-quinolin-8-yl furan-2-carboxyl-ate. AB - In the title compound, C14H8ClNO3, the central ester CO2 group is twisted away from the quinoline and furoyl rings by 57.46 (5) and 2.0 (1) degrees , respectively. In the crystal, mol-ecules are linked by weak C-H?O inter-actions, forming chains in [001]. PMID- 23634050 TI - Ethyl 2-[(2-oxo-2H-chromen-7-yl)-oxy]acetate. AB - In the title compound, C13H12O5, the mean plane of the 2H-chromene ring system (r.m.s deviation = 0.026 A) forms a dihedral angle of 81.71 (6) degrees with the mean plane of ethyl 2-hy-droxy-acetate moiety (r.m.s deviation = 0.034 A). In the crystal, C-H?O hydrogen bonds result in the formation of zigzag layers parallel to the bc plane. PMID- 23634051 TI - 7-Hy-droxy-methyl-2-pivaloyl-amino-1,8-naphthyridine. AB - In the title compound, C14H17N3O2, the mean plane of the 1,8-naphthyridine ring system (r.m.s deviation = 0.020 A) forms a dihedral angle of 23.4 (1) degrees with the acetamide moiety (r.m.s deviation = 0.001 A). The mol-ecular structure is stabilized by an intra-molecular O-H?N hydrogen bond, which generates an S(5) ring motif. In the crystal, mol-ecules are linked into inversion dimers by pairs of N-H?O hydrogen bonds, generating 18-membered R 2 (2)(18) ring motifs. PMID- 23634052 TI - Ethyl 2-(4-methyl-benzo-yl)-2,3-dihydro-1H-indene-2-carboxyl-ate. AB - The title compound, C20H20O3, contains two fused rings with a quaternary carbon centre connecting p-toluoyl and eth-oxy-carbonyl groups. The dihedral angle between the fused benzene ring and the three-C-atom plane (derived from O=C-C C=O) is 82.5 (4) degrees , whereas the dihedral angle between the planes of the benzene rings is 53.4 (2) degrees . In the crystal, molecules are linked via C H?Oester hydrogen bonds, forming chains propagating along [010]. PMID- 23634053 TI - 2-(2-Chloro-phen-yl)-N-cyclo-hexyl-2-oxoacetamide. AB - In the title compound, C14H16ClNO2, the cyclo-hexyl ring has a chair conformation. The dihedral angle between the benzene ring and the mean plane of the four planar C atoms of the cyclo-hexyl ring is 45.2 (3) degrees . The two carbonyl groups are trans to one another, with an O=C-C=O torsion angle of -137.1 (3) degrees . In the crystal, mol-ecules are linked by N-H?O hydrogen bonds forming chains propagating along [001]. A region of disordered electron density, situated near the unit-cell corners, was treated using the SQUEEZE routine in PLATON [Spek (2009 ?). Acta Cryst. D65, 148-155]. It gave a solvent-accessible void of ca 400 A(3) for only 21 electrons. It is probably due to traces of the solvent of crystallization and was not taken into account during structure refinement. PMID- 23634054 TI - Ethyl 2,6-bis-(4-chloro-phen-yl)-4-(4-fluoro-anilino)-1-(4-fluoro-phen-yl) 1,2,5,6-tetra-hydro-pyridine-3-carboxyl-ate. AB - In the title compound, C32H26Cl2F2N2O2, the tetra-hydro-pyridine ring adopts a distorted boat conformation. The chlorophenyl rings are inclined to one another by 55.2 (1) degrees , while for the fluorophenyl rings the dihedral angle is 80.7 (1) degrees . The amino group and carbonyl O atom are involved in an intra molecular N-H?O hydrogen bond. In the crystal, weak C-H?O, C-H?F and C-H?Cl inter actions link the mol-ecules into a three-dimensional network. PMID- 23634055 TI - 5-Iodo-3-phenyl-2,1-benzoxazole. AB - The title compound, C13H8INO, was prepared by a condensation reaction of 4-nitro benzene with phenyl-acetonitrile in NaOH-ethanol solution. There are two independent mol-ecules in the asymmetric unit, in which the dihedral angles between the benzene ring and the benzoisoxazole unit are 4.2 (3) and 4.1 (3) degrees . The crystal packing is governed by C-H?N, C-I?pi and C-I?O inter actions. PMID- 23634056 TI - 2,4-Dichloro-benzyl 2-meth-oxy-benzoate. AB - In the title compound, C15H12Cl2O3, the aromatic rings make a dihedral angle of 10.78 (4) degrees . In the molecule, there is a short C-H?O contact. In the crystal, C-H?O contacts connect the mol-ecules into C(7)C(8) chains along the b axis. The shortest inter-centroid distance between two benzoic acid aromatic systems is 3.7416 (8) A. PMID- 23634057 TI - 3,5-Dimeth-oxy-4'-methyl-biphen-yl. AB - The title compound, C15H16O2, crystallizes with three independent mol-ecules in the asymmetric unit. The intra-molecular torsion angle between the aromatic rings of each mol-ecule are -36.4 (3), 41.3 (3) and -37.8 (3) degrees . In the crystal, the complicated packing of the mol-ecules forms wave-like layers along the b and c axes. The mol-ecules are connected via extensive meth-oxy-phenyl C-H?pi inter actions. A weak C-H?O hydrogen-bonding network also exists between meth-oxy O atoms and aromatic or meth-oxy H atoms. PMID- 23634058 TI - [2-Acet-oxy-3-(naphthalen-1-yl-oxy)prop-yl](propan-2-yl)aza-nium chloride monohydrate. AB - The title compound, C18H24NO3 (+).Cl(-).H2O, was synthesized by the reaction of propranolol hydro-chloride with acetyl chloride in chloro-form followed by slow evaporation in air. In the cation, the dihedral angle between the planes of the naphthalene ring system and the acetate group is 71.1 (2) degrees . An intra molecular N-H?O hydrogen bond results in the formation of a non-planar pseudo ring, with the ether O and the H atom displaced by -1.328 (2) and 0.65 A, respectively, from the plane of the other ring atoms. The cation and anion are linked by an N-H?Cl hydrogen bond. The water molecule is linked to a methyl H atom by C-H?O hydrogen bond. PMID- 23634059 TI - 3-(4-Nitro-benz-yl)-4H-chromen-4-one. AB - In the title compound, C16H11NO4, the dihedral angle between the ten-membered chromen-4-one ring system (r.m.s. deviation = 0.0095 A) and the benzene ring is 86.16 (5) degrees . In the crystal, mol-ecules are linked into a three dimensional network by weak C-H?O hydrogen bonds. The crystal studied was a non merohedral twin, with the minor twin component refining to 0.093 (1). PMID- 23634060 TI - (E)-3-(3,5-Dimeth-oxy-phen-yl)-1-(2-meth-oxy-phen-yl)prop-2-en-1-one. AB - In the title mol-ecule, C18H18O4, the dihedral angle between the benzene rings is 52.52 (7) degrees . The C=C bond of the central enone group adopts a trans conformation. The relative conformation of the two double bonds in the enone group is s-transoid. In the crystal, mol-ecules are linked by pairs of weak C-H?O hydrogen bonds, forming inversion dimers. PMID- 23634061 TI - 2-(4-Fluoro-benzyl-idene)propane-dinitrile: monoclinic polymorph. AB - The title compound, C10H5FN2, is a monoclinic (P21/c) polymorph of the previously reported triclinic (P-1) form [Anti-pin et al. (2003 ?). J. Mol. Struct. 650, 1 20]. The 13 non-H atoms in the title polymorph are almost coplanar (r.m.s. deviation = 0.020 A); a small twist between the fluoro-benzene and dinitrile groups [C-C-C-C torsion angle = 175.49 (16) degrees ] is evident in the triclinic polymorph. In the crystal, C-H?N inter-actions lead to supra-molecular layers parallel to (-101); these are connected by C-F?pi inter-actions. PMID- 23634062 TI - Bis{(R)-1-(3-amino-sulfonyl-4-meth-oxy-phen-yl)-N-[2-(2-eth-oxy-phen-oxy)eth yl]propan-2-aminium} adipate tetra-hydrate. AB - The title compound, 2C20H29N2O5S(+).C6H8O4 (2-).4H2O, which was found to be optically active, is a relatively rare example of a chiral compound crystallizing in the triclinic crystal system. The dihedral angles between the phenyl rings of the cations are 60.03 (15) and 62.03 (16) degrees , while the C atoms of the anion are almost coplanar (r.m.s. deviation 0.085 A) and all trans to each other. In the crystal, the components are connected by an extensive network of N-H?O and O-H?O hydrogen bonds. The sulfonamide groups link the cations into pairs via two N-H?O hydrogen bonds about the pseudo-inversion centre, leading to the formation of R 2 (2)(8) rings. The anions are stacked in between four cationic pairs. Pairs of water mol-ecules bridge the larger building units, forming hydrogen bonds with the remaining two O atoms of the anion. PMID- 23634063 TI - 2-(4-Bromo-anilino)-6-(4-chloro-phen-yl)-5-meth-oxy-carbonyl-4-methyl-3,6-dihydro pyrimidin-1-ium chloride. AB - In the title molecular salt, C19H18BrClN3O2 (+).Cl(-), the dihedral angles between the pyrimidine ring and the chlorobenzene and bromobenzene rings are 72.4 (2) and 45.5 (2) degrees , respectively. The dihedral angle between the chlorobenzene and bromobenzene rings is 27.5 (2) degrees . The conformation of the mol-ecule is stabilized by an intra-molecular C-H?O inter-action. In the crystal, the anion and cation are linked by an N-H?Cl hydrogen bond. Pairs of weak C-H?O and C-H?Cl hydrogen bonds form inversion dimers. Further N-H?Cl hydrogen bonds form R 2 (1)(6) motifs and link the dimers into chains along [101]. Br?Cl short contacts [3.482 (2) A] inter-link the hydrogen-bonded chains along the b-axis direction. PMID- 23634064 TI - N-Cyclo-hexyl-3-methyl-benzamidine. AB - The title amidine compound, C14H20N2, prepared by a one-pot reaction, is asymmetric as only one N atom has an alkyl substituent. The terminal cyclo-hexyl group connected to the amino N atom is located on the other side of the N-C-N skeleton to the 4-methylbenzene ring and has a chair conformation. The dihedral angle between the phenyl ring and the NCN plane is 47.87 (12) degrees . In the crystal, mol-ecules are linked via N-H?N hydrogen bonds, forming chains propagating along the a-axis direction. PMID- 23634065 TI - (1S,3R,8R,9R,10S)-2,2-Dibromo-3,7,7,10-tetra-methyl-9beta,10beta-ep-oxy-3,7,7,10 tetra-methyl-tricyclo-[6.4.0.0(1,3)]dodeca-ne. AB - The title compound, C16H24Br2O, was synthesized from beta-himachalene (3,5,5,9 tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzocyclo-heptene), which was isolated from the essential oil of the Atlas cedar (Cedrus atlantica). The mol-ecule contains fused six- and seven-membered rings, each linked to a three-membered ring. The six-membered ring has a half-chair conformation, while the seven membered ring displays a chair conformation. The dihedral angle between the mean planes through the six- and seven-membered rings is 39.55 (12) degrees . The two three-membered rings, linked to the six- and seven-membered rings, are nearly perpendicular to the six-membered ring, making dihedral angles of 78.6 (2) and 80.5 (2) degrees , respectively. The absolute structure was established unambiguously from anomalous dispersion effects. In the crystal, each mol-ecule is linked to its symmetry-equivalent partner by C-H?O hydrogen bonds, forming zigzag chains parallel to [100]. PMID- 23634066 TI - 2-(2,6-Dichloro-phen-yl)-N-(1,3-thia-zol-2-yl)acetamide. AB - In the title compound, C11H8Cl2N2OS, the mean plane of the dichloro-phenyl ring is twisted by 79.7 (7) degrees from that of the thia-zole ring. In the crystal, molecules are linked via pairs of N-H?N hydrogen bonds, forming inversion dimers which stack along the a-axis direction. PMID- 23634067 TI - 4-Hy-droxy-6-methyl-3-[3-(thio-phen-2-yl)acrylo-yl]-2H-pyran-2-one. AB - The title compound, C13H10O4S, crystallizes with two mol-ecules in the asymmetric unit in which the rings make dihedral angles of 3.9 (1) and 6.0 (1) degrees ; this planarity is due in part to the presence of an intra-molecular O-H?O hydrogen bond, which generates an S(6) ring in each mol-ecule. Both mol-ecules represent E isomers with respect to the central C=C bond. In the crystal, mol ecules are linked by C-H?O inter-actions into a three-dimensional network. PMID- 23634068 TI - N-(4-Hy-droxy-phen-yl)-4-nitro-benzamide. AB - The mol-ecular structure of the title compound, C13H10N2O4, shows an almost planar conformation as the benzene rings make a dihedral angle of 2.31 (7) degrees . The nitro group lies in plane with the benzamide ring, with a C-C-N-O torsion angle of 0.6 (2) degrees . In the crystal, N-H?O and O-H?O hydrogen bonds link mol-ecules into sheets stacked along [10-1]. PMID- 23634069 TI - 4-(1-Allyl-4,5-diphenyl-1H-imidazol-2-yl)-N,N-dimethyl-aniline. AB - The title compound, C26H25N3, crystallizes with four independent mol-ecules, 1-4, in the asymmetric unit of the triclinic unit cell. The allyl substituents on the imidazole rings adopt similar conformations in all four mol-ecules. The imadazole and the 4-and 5-substituted phenyl rings of two pairs of molecules in the asymmetric unit stack parallel to (110). In contrast, the dimethyl-aniline systems in these pairs of mol-ecules are almost normal to one another, with dihedral angles of 85.84 (10) and 85.65 (10) degrees between the benzene rings of the two dimethyl-aniline fragments of mol-ecules 1 and 2, and 3 and 4, respectively. The crystal structure features an extensive series of C-H?pi inter actions that link the mol-ecules into undulating rows along the c axis. The crystal studied was a pseudo-merohedral twin with twin law [-100, 0-10, 111] and the BASF parameter refined to 0.513 (3). PMID- 23634070 TI - 2-Amino-4-methyl-pyrimidinium dihydrogen phosphate. AB - A charge-assisted hydrogen-bonding network involving N-H?O and O-H?O hydrogen bonds stabilizes the crystal of the title salt, C5H8N3 (+).H2PO4 (-). The dihydrogen phosphate anions form one-dimensional chains along [100], via O-H?O hydrogen bonds. The 2-amino-4-methyl-pyrimidinium cations are linked to these chains by means of two different kinds of N-H?O hydrogen bonds. Neighbouring chains are linked via C-H?N and C-H?O hydrogen bonds forming two-dimensional slab like networks lying parallel to (01-1). PMID- 23634071 TI - (2E,5E)-2,5-Bis(4-hy-droxy-3-meth-oxy-benzyl-idene)cyclo-penta-none ethanol monosolvate. AB - In the title structure, C21H20O5.C2H5OH, the curcumine-type mol-ecule has a double E conformation for the two benzyl-idene double bonds [C=C = 1.342 (4) and 1.349 (4) A] and is nearly planar with respect to the non-H atoms (r.m.s. deviation from planarity = 0.069 A). The two phenolic OH groups form bifurcated hydrogen bonds with intra-molecular branches to adjacent meth-oxy O atoms and inter-molecular branches to either a neighbouring mol-ecule or an ethanol solvent mol-ecule. The ethanol O atom donates a hydrogen bond to the keto O atom. These hydrogen bonds link the constituents into layers parallel to (101) in the crystal structure. PMID- 23634072 TI - 3-Bromo-7-meth-oxy-2-phenyl-imidazo[2,1-b][1,3]benzothia-zole. AB - In the title mol-ecule, C16H11BrN2OS, the central imidazo[2,1-b][1,3]benzothia zole tricycle is essentially planar (r.m.s. deviation = 0.021 A). The terminal phenyl ring is twisted at 36.18 (5) degrees from the mean plane of the tricycle. In the crystal, pairs of eak C-H?O hydrogen bonds link mol-ecules into centrosymmetric dimers, which are further packed into stacks along the a axis. PMID- 23634073 TI - (Z)-4-[2-(2,4-Dimethyl-phen-yl)hydrazinyl-idene]-3-methyl-pyrazol-5(1H)-one. AB - The mol-ecule of the title compound, C12H14N4O, is roughly planar, with a dihedral angle of 8.0 (8) degrees between the benzene and pyrazole rings, and an intra-molecular N-H?O hydrogen bond forms an S(6) ring motif. In the crystal, mol ecules are linked into an inversion dimer by a pair of N-H?O hydrogen bonds, which form an R 2 (2)(8) ring motif. PMID- 23634074 TI - 6-(3,5-Dimeth-oxy-benzyl-amino)-9-(oxan-2-yl)-9H-purine. AB - The mol-ecule of the title compound, C19H23N5O3, contains six-membered pyrimidine and five-membered imidazole rings merged into the essentially planar purine skeleton (r.m.s. deviation = 0.01 A). In the crystal, pairs of N-H?N hydrogen bonds link mol-ecules into inversion dimers. The dimers are linked via C-H?O hydrogen bonds, forming double-stranded chains propagating along [001]. These chains are linked via C-H?pi and parallel slipped pi-pi inter-actions [centroid centroid distance = 3.467 (1) A; slippage 0.519 A], forming a three-dimensional network. PMID- 23634075 TI - (E)-2-Hy-droxy-cinnamaldehyde. AB - The asymmetric unit of the title compound, C9H8O2, contains two independent mol ecules, both of which are essentially planar (r.m.s. deviations = 0.0294 and 0.0284 A). The C=C double bond is in an E conformation and the vinyl-aldehyde groups adopt extended conformations. In the crystal, mol-ecules are linked by O H?O hydrogen bonds, forming infinite chains parallel to [101]. PMID- 23634076 TI - 1-{(E)-[4-Bromo-2-(trifluoro-meth-oxy)phen-yl]imino-meth-yl}naphthalen-2-ol. AB - The title compound, C18H11BrF3NO2, crystallizes in the phenol-imine tautomeric form, with a strong intra-molecular O-H?N hydrogen bond. The dihedral angle between the naphthalene ring system and the benzene ring is 28.54 (10) degrees . PMID- 23634077 TI - 2-Hy-droxy-7-nitro-cyclo-hepta-2,4,6-trien-1-one. AB - The title compound, also known as 7-nitro-tropolone, C7H5NO4, exists in the crystalline state as the 2-hy-droxy-7-nitro-cyclo-hepta-2,4,6-trien-1-one tautomer and not as 2-hy-droxy-3-nitro-cyclo-hepta-2,4,6-trien-1-one. The dihedral angle between the ring and the nitro group is 70.3 (2) degrees . In the crystal, neighbouring mol-ecules are linked into dimers by a pair of O-H?O hydrogen bonds. In addition, the crystal is stabilized by O?pi [3.4039 (14) A] and O?O [3.073 (2) A] inter-actions. PMID- 23634078 TI - 2-Amino-5-bromo-pyridinium 5-chloro-2-hy-droxy-benzoate. AB - In the 5-chloro-salicylate anion of the title salt, C5H6BrN2 (+).C7H4ClO3 (-), an intra-molecular O-H?O hydrogen bond with an S(6) graph-set motif is formed, so that the anion is essentially planar with a dihedral angle of 1.3 (5) degrees between the benzene ring and the carboxyl-ate group. In the crystal, the protonated N atom and the 2-amino group of the cation are hydrogen bonded to the carboxyl-ate O atoms via a pair of N-H?O hydrogen bonds, forming an R 2 (2)(8) ring motif. The crystal structure also features N-H?O and weak C-H?O inter actions, resulting in a layer parallel to the (10-1) plane. PMID- 23634080 TI - Ethyl 4-(5-bromo-2-hy-droxy-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro quinoline-3-carboxyl-ate. AB - In the title compound, C21H24BrNO4, the dihedral angle between the heterocyclic ring and the pendant aromatic ring is 80.20 (13) degrees . The hexahydroquinone [i.e. the one with the C=O group] ring adopts a sofa conformation. An intra molecular O-H?O hydrogen bond generates an S(6) ring motif. The ethyl group is disordered over two sets of sites with a refined site occupancy ratio of 0.633 (10):0.366 (10). In the crystal, mol-ecules are linked by N-H?O inter-actions, forming chains parallel to [101]. There are no significant C-H?pi or pi-pi inter actions in the crystal structure. PMID- 23634079 TI - 5-Amino-6-methyl-quinolin-1-ium 3-carb-oxy-propano-ate. AB - The asymmetric unit of the title salt, C10H11N2 (+).C4H5O4 (-), consists of two independent 5-amino-6-methyl-quinolin-1-ium cations and two 3-carb-oxy-propano ate anions. Both cations are protonated at the pyridine N atoms and are essentially planar, with maximum deviations of 0.026 (3) and 0.016 (2) A. In the crystal, the cations and anions are linked via N-H?O and O-H?O hydrogen bonds, forming a layer parallel to the ab plane. In the layer, weak C-H?O hydrogen bonds and pi-pi stacking inter-actions, with centroid-to-centroid distances of 3.7283 (15) and 3.8467 (15) A, are observed. The crystal structure also features weak C H?O hydrogen bonds between the layers. PMID- 23634081 TI - (E)-1-(1-Hy-droxy-naphthalen-2-yl)-3-(2,4,5-trimeth-oxy-phen-yl)prop-2-en-1-one. AB - In the title mol-ecule, C22H20O5, the C=C bond of the central enone group adopts an E conformation. The dihedral angle formed by the benzene ring and the naphthalene ring system is 12.6 (4) degrees . The hy-droxy group attached to the naphthalene ring is involved in an intra-molecular O-H?O hydrogen bond. In the crystal, weak C-H?O hydrogen bonds link the mol-ecules into chains along [010]. In addition, pi-pi stacking inter-actions are present, with centroid-centroid distances of 3.6648 (15) and 3.8661 (15) A between the benzene and two naphthalene rings. PMID- 23634082 TI - 4-[5-(4-Benzoyl-oxyphen-yl)-1,2,4-oxa-diazol-3-yl]phenyl benzoate. AB - In the title compound, C28H18N2O5, the dihedral angle between the terminal benzoate rings is 20.67 (12) degrees . The central oxadiazole ring is almost coplanar with its two benzene ring substituents, making dihedral angles of 4.80 (16) and 5.82 (16) degrees . In the crystal, pairs of C-H?O hydrogen bonds form inversion dimers with R 2 (2)(40) ring motifs. The structure also features C-H?O, C-H?pi and pi-pi inter-actions [centroid-centroid separation = 3.695 (4) A]. PMID- 23634083 TI - 1,8-Bis(4-fluoro-benzo-yl)naphthalen-2,7-diyl dimethane-sulfonate. AB - The mol-ecule of the title compound, C26H18F2O8S2, lies across a crystallographic twofold rotation axis. The benzene rings of the 4-fluorobenzoyl groups make dihedral angles of 78.93 (12) degrees with the naphthalene ring system. An intra molecular C-H?pi inter-action occurs. In the crystal, a number of C-H?O inter actions link the mol-ecules, forming a three-dimensional structure. PMID- 23634084 TI - 1-(4-Bromo-3,5,5,6,8,8-hexa-methyl-5,6,7,8-tetra-hydro-naphthalen-2-yl)ethan-1 one: a precursor for phase-I metabolite of AHTN. AB - The title compound, C18H25BrO, crystallized as a racemate with four independent mol-ecules in the asymmetric unit. In the crystal, three of these four mol-ecules are linked via C-Br?Br-C halogen bonds [Br?Br = 3.662 (2) and 3.652 (2) A], forming dimers. PMID- 23634085 TI - 1-(2-Carb-oxy-eth-yl)-3-(carboxyl-atometh-yl)-2-ethyl-benzimidazol-1-ium monohydrate. AB - In the title compound, C14H16N2O4.H2O, three substituent groups are located on the same side of the benzimidazole ring plane. In the crystal, O-H?O hydrogen bonds and pi-pi stacking between parallel imidazole rings [centroid-centroid distance = 3.858 (4) A] link the mol-ecules into a three-dimensional supra molecular structure. PMID- 23634086 TI - 1,2-Bis(4-meth-oxy-phen-oxy)ethane. AB - The whole mol-ecule of the title compound, C16H18O4, is generated by twofold rotational symmetry; the twofold axis bis-ects the central C-C bond. The O-C-C-O torsion angle about the central C-C bond is 69.45 (16) degrees . Symmetry-related benzene rings are inclined to one another by 64.91 (8) degrees . In the crystal, mol-ecules are connected by C-H?O hydrogen bonds, forming a three-dimensional network. PMID- 23634087 TI - (E)-N-[(E)-3-(4-Nitro-phen-yl)allyl-idene]naphthalen-1-amine. AB - In the title compound, C19H14N2O2, the dihedral angle between the mean planes of the 4-nitro-phenyl ring and the naphthalene ring system is 12.79 (2) degrees . The imine group displays a C-C-N=C torsion angle of 41.0 (2) degrees and the C=N group has an E conformation. In the crystal, weak C-H?O hydrogen bonds link molecules into layers parallel to the b axis. PMID- 23634088 TI - 1,3-Bis(6-methyl-pyridin-2-yl)-1H-imidazol-3-ium hexa-fluoro-phosphate. AB - In the title salt, C17H19N4 (+).PF6 (-), the two pyridine rings of the cation are inclined to one another by 15.89 (8) degrees , and inclined to the imidazole ring by 65.05 (10) and 64.07 (10) degrees . In the crystal, the cations and anions are linked via a series of C-H?N and C-H?F hydrogen bonds, forming two-dimensional networks lying parallel to (001). PMID- 23634089 TI - 4-(6-Benzyl-7-oxo-1,2,3,4,5,5a,5a(1),6,7,7a,8,12b-dodeca-hydro-benzo[f]cyclo-octa [cd]isoindol-8-yl)benzonitrile. AB - In the title compound, C31H30N2O, the cis-fused cyclo-hexene and cyclo-octane rings adopt boat and boat-chair conformations, respectively. The essentially planar five-membered N-heterocyclic ring [r.m.s. deviation = 0.017 (1) A] is cis- and trans-fused, respectively, with the cyclo-hexene and cyclo-octane rings. In the crystal, mol-ecules are linked into inversion dimers through pairs of weak C H?O inter-actions. PMID- 23634090 TI - 2-(4-Chloro-phen-yl)-2-oxoethyl naphthalene-1-carboxyl-ate. AB - In the title compound, C19H13ClO3, an ester of 1-naphthoic acid with an aromatic alcohol, the least-squares planes defined by the C atoms of the respective aromatic systems enclose an angle of 77.16 (3) degrees . In the crystal, C-H?O contacts connect the mol-ecules into undulating sheets parallel to the bc plane. PMID- 23634092 TI - 4-Bromo-2-(dieth-oxy-meth-yl)phenyl benzoate. AB - In the title compound, C18H19BrO4, the aromatic rings enclose a dihedral angle of 81.9 (7) degrees . There are no short directional contacts in the crystal structure. PMID- 23634091 TI - 1-(2-Methyl-5-nitro-1H-imidazol-1-yl)acetone. AB - In the mol-ecule of the title compound, C7H9N3O3, the nitro and carbonyl groups are tilted with respect to the imidazole ring by 9.16 (6) and 65.47 (7) degrees , respectively. Neighbouring chains are linked via C-H?N and C-H?O hydrogen bonds forming two-dimensional slab-like networks lying parallel to (01-1). PMID- 23634093 TI - 2-Benzyl-sulfanyl-N-(1,3-dimethyl-imidazolidin-2-yl-idene)aniline. AB - The mol-ecular structure of the title compound, C18H21N3S, shows a twisted conformation with a dihedral angle of 67.45 (4) degrees between the aromatic ring planes and an N-C-C-S torsion angle of -5.01 (13) degrees . The imidazolidine ring and the aniline moiety make a dihedral angle of 56.03 (4) degrees and the asscociated C-N-C angle is 125.71 (10) degrees . The guanidine like C=N double bond is clearly localized, with a bond length of 1.2879 (14) A. The C-S-C angle is 102.12 (5) degrees and the S-C(aromatic) and S-C bond lengths are 1.7643 (11) and 1.8159 (12) A. PMID- 23634094 TI - (Z)-9-(1,2-Dichloro-vin-yl)-9H-carbazole. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C14H9Cl2N, in which the dihedral angles between the dichloro-vinyl unit (r.m.s. deviations = 0.0003 and 0.0009 A), and the carbazole ring are 87.77 (3) and 72.90 (3) degrees . PMID- 23634095 TI - 3,3-Bis(4-bromo-phenyl-sulfan-yl)-1-methyl-piperidin-2-one. AB - In the title compound, C18H17Br2NOS2, the conformation of the piperidin-2-one ring is based on a half-chair with the methyl-ene C atom diagonally opposite the N atom being 0.649 (3) A above the plane of the remaining five atoms (r.m.s. deviation = 0.1205 A). The S atoms occupy axial and bis-ectional positions, and the dihedral angle between the benzene rings of 59.95 (11) degrees indicates a splayed disposition. Helical supra-molecular chains along the b axis sustained by C-H?O inter-actions is the major feature of the crystal packing. The chains are connected into a three-dimensional architecture by C-H?Br and C-H?pi inter actions. PMID- 23634096 TI - Bis(1-benzoyl-7-meth-oxy-naphthalen-2-yl) terephthalate. AB - The title molecule, C44H30O8, lies about a crystallographic inversion centre located at the centre of the central benzene ring. The benzene rings in the benzoyl and the terephthalate units make dihedral angles of 67.05 (7) degrees and 57.57 (7) degrees , respectively, with the naphthalene ring system. There is an intra-molecular C-H?O inter-action between the ketonic carbonyl O atom and an H atom on the naphthalene ring system. In the crystal, C-H?O inter-action of the benzene ring in the benzoyl group and weak C=O?pi inter-action [O?centroid = 3.375 (2) A] of the naphthalene ring with the O atom in the ketonic carbonyl group are observed. These inter-actions form layers parallel to the bc plane. PMID- 23634097 TI - The chalcone derivative (E)-1-(4-fluoro-phen-yl)-3-(4-hy-droxy-3-meth-oxy-phen yl)prop-2-en-1-one monohydrate. AB - The title compound, C16H13FO3.H2O, has a cis disposition of the carbonyl and olefin bonds about the enone single bond. The arene rings are inclined to one another by 10.05 (6) A. In the crystal, mol-ecules are linked via O-H?O hydrogen bonds involving the water mol-ecules, forming loops which are, in turn, linked via O-H..O and C-H?F hydrogen bonds, forming sheets lying parallel to (103). These networks are linked via pi-pi inter-actions [centroid-centroid distance = 3.641 (1) A] involving inversion-related 4-fluoro-phenyl and 4-hy-droxy-3-meth oxy-phenyl rings. PMID- 23634098 TI - N,N'-Bis(pyridin-3-yl)oxamide. AB - The title mol-ecule, C12H10N4O2, located about an inversion centre, is roughly planar, with an r.m.s. deviation from the least-squares plane of all non-H atoms of 0.019 A. In the crystal, N-H?N hydrogen bonds between the amide N-H group and the pyridine N atom connect the mol-ecules into a corrugated layer parallel to (10-1). PMID- 23634099 TI - (4-Chlorobenzoyl)(4-chlorophenyl)amino 3-(2-nitrophenyl)propanoate. AB - In the title hydroxamic acid derivate, C22H16Cl2N2O5, the nitro-substituted benzene ring forms dihedral angles of 14.11 (15) and 16.08 (15) degrees , with the 4-chloro-benzoyl and 4-chloro-phenyl benzene rings, respectively. The dihedral angle between the chloro-substituted benzene rings is 2.28 (13) degrees . In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds, forming chains along [100]. PMID- 23634100 TI - (Z)-3-(3,4-Dimeth-oxy-benzyl-idene)-2,3-dihydro-1,5-benzothia-zepin-4(5H)-one. AB - In the title compound, C18H17NO3S, the seven-membered thia-zepine ring adopts a slightly distorted sofa conformation. The dihedral angle between the mean plane of the benzothia-zepine ring system and the benzene ring is 5.9 (1) degrees . The mol-ecular conformation is stabilized by an intra-molecular C-H?S hydrogen bond, which generates an S(7) ring motif. In the crystal, N-H?O and C-H?O hydrogen bonds link inversion-related mol-ecules into dimers, incorporating R 1 (2)(6) and R 2 (2)(8) ring motifs; the acceptor O atom is bifurcated. These dimers are further linked by C-H?O hydrogen bonds, forming supra-molecular tapes running along the a axis. These are connected into the three-dimensional architecture by C-H?pi inter-actions. PMID- 23634101 TI - (Z)-3-(2,4-Dichloro-benz-yl)-1,5-benzo-thia-zepin-4(5H)-one. AB - In the title compound, C16H11Cl2NOS, the seven-membered thia-zepine ring adopts a distorted twist-boat conformation. The dihedral angle between the mean plane of the benzothia-zepine ring system and the benzene ring is 78.6 (1) degrees . The mol-ecular conformation is stabilized by a weak intra-molecular C-H?Cl hydrogen bond, which generates an S(5) ring motif. In the crystal, pairs of N-H?O hydrogen bonds link inversion-related mol-ecules into dimers, generating R 2 (2)(8) ring motifs. The crystal packing also features alternating pi-pi inter-actions between benzothia-zepine benzene rings [inter-centroid distance = 3.740 (3) A] and dichloro-benzene rings [inter-centroid distance = 3.882 (3) A] to consolidate a three-dimensional architecture. PMID- 23634102 TI - Ethyl 23-benzyl-8,11,14-trioxa-23,28,29-triaza-penta-cyclo [19.7.1.0(2,7).0(15,20).0(22,27)]nona-cosa-2,4,6,15(20),16,18,21,26-octa-ene-26 carboxyl-ate. AB - The title compound, C33H35N3O5, is the product of the multicomponent condensation of 1-benzyl-4-eth-oxy-carbonyl-piperidin-3-one with 1,5-bis-(2-formyl-phen-oxy)-3 oxapentane and ammonium acetate. The mol-ecule comprises a penta-cyclic system containing the aza-14-crown-4-ether macrocycle, tetra-hydro-pyrimidine, tetra hydro-pyridine and two benzene rings. The aza-14-crown-4-ether ring adopts a bowl conformation with a dihedral angle of 62.37 (5) degrees between the benzene rings. The tetra-hydro-pyrimidine ring has an envelope conformation with the chiral C atom as the flap, whereas the tetra-hydro-pyridine ring adopts a distorted chair conformation. Two amino groups are involved in intra-molecular N H?O hydrogen bonds. In the crystal, weak C-H?O hydrogen bonds link the mol-ecules into layers parallel to the ab plane. PMID- 23634103 TI - N-But-oxy-carbonyl-5-oxo-l-proline ethyl ester. AB - The mol-ecular structure of the title compound, C12H19NO5, may be visualized as made up of two nearly perpendicular planes [dihedral angle = 87.39 (12) degrees ] and its crystal structure is a good example of C-H?O inter-actions assuming significance in optimizing supra-molecular aggregation in crystals in a mol-ecule which is severely imbalanced in terms of donors to acceptor atoms. The pyrrolidine ring adopts a ((3) T 2) twist conformation with puckering parameters Q = 0.2630 (4) A and phi = 59 (9) degrees . The crystal structure features R 2 (4)(10) and R 3 (4)(26) ring motifs formed by four weak C-H?O inter-actions, leading to supra-molecular sheets lying parallel to the bc plane. PMID- 23634104 TI - 2,2-Bis(pyridin-2-yl)-1,3-diazinane. AB - In the title compound, C14H16N4, the six-membered hexa-hydro-pyrimidine ring adopts a chair conformation. In the crystal, one of the two pyrimidine N atoms engages in N-H?N hydrogen bonding with one of the pyridine N atoms, generating a helical chain running along the c axis. The helical pitch is the length of the c axis. PMID- 23634105 TI - 2,4,6-Trinitro-phenyl 4-chloro-benzoate. AB - In the title benzoate derivative, C13H6ClN3O8, the planes of the benzene rings form a dihedral angle of 63.46 (5) degrees . The dihedral angles between the benzene ring and its nitro groups are 12.78 (16) degrees for the first ortho, 28.4 (4) and 17.4 (4) degrees for the second (disordered) ortho and 3.58 (16) degrees for the para nitro group. The central ester moiety, -C-(C=O)-O-, is essentially planar (r.m.s. deviation for all non-H atoms = 0.0229 A) and forms dihedral angles of 7.37 (14) degrees with the chloro-substituted benzene ring and 69.85 (6) degrees with the trinitro-substituted benzene ring. One of the nitro groups was refined as disordered over two sets of sites with fixed site occupancies of 0.61 and 0.39. In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds, forming a three-dimensional network. PMID- 23634106 TI - (E)-[2-(1,3-Dithio-lan-2-yl-idene)hydrazinyl-idene](3-fluoro-phen-yl)methyl 3 fluoro-benzoate. AB - In the title compound, C17H12F2N2O2S2, the conformation of the dithia-cyclo pentane ring is a half-chair, with a total puckering amplitude Q T = 0.460 (1) A. pi-pi inter-actions [centroid-centroid distance = 3.585 (9) A between the fluoro phenyl rings of neighbouring mol-ecules] and C-H?N and C-H?O inter-actions help to stabilize the crystal structure and form ladders along the c axis. PMID- 23634107 TI - Methyl (2Z)-2-bromo-methyl-3-(2,4-dichloro-phen-yl)prop-2-enoate. AB - In the title compound C11H9BrCl2O2, which represents the Z isomer, the methyl acrylate moiety is essentially planar within 0.039 (2) A and has an extended trans configuration. The benzene ring makes a dihedral angle of 28.3 (1) degrees with the mean plane of the methyl-acrylate moiety. The crystal packing is characterized by C-H?O hydrogen bonding and halogen-halogen inter-actions [Cl?Cl = 3.486 (3) A], resulting in the formation of R 2 (2)(11) ring motifs and connecting the mol-ecules into chains propagating along the b axis. PMID- 23634108 TI - 4,4,6a,6b,11,12,14b-Heptamethyl-16-oxo 1,2,3,4,4a,5,6,6a,6b,7,8,9,10,11,12,12a,14a,14b-octa-deca-hydro-12b,8a-(epoxy methano)-picen-3-yl acetate. AB - The title compound, C32H48O4, which was extracted from the bark of Rhododendron arboreum, consists of five fused rings to which an acetate and seven methyl groups are attached. The A, D and E rings adopt chair conformations, the B ring is in a distorted chair and the C ring is in a half-chair conformation. The five membered ring formed by the lactone group, which bridges from the A/B to the B/C ring junctions, is an approximate envelope with the C atom of the methyne group as the flap [displacement from the other four atoms = 0.753 (2) A]. There are no identified directional inter-actions in the crystal structure. PMID- 23634109 TI - Piperazine-1,4-diium bis-(2,4,5-tricarb-oxy-benzoate) dihydrate. AB - In the title hydrated salt, C4H12N2 (2+).2C10H5O8 (-).2H2O, the piperazinediium cation, lying about an inversion center, adopts a chair conformation. The benzene ring of the anion makes dihedral angles of 25.17 (8) degrees with the carboxyl ate group and angles of 8.50 (7), 20.07 (7) and 80.86 (8) degrees with the three carb-oxy-lic acid groups. In the crystal, the cations, anions and water mol ecules are connected by O-H?O and N-H?O hydrogen bonds into double layers parallel to (110). PMID- 23634110 TI - 2-[3-(4-Chloro-phen-yl)-5-(4-fluoro-phenyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-phenyl 1,3-thia-zole. AB - In the title compound, C24H17ClFN3S, the pyrazole ring is almost planar (r.m.s. deviation = 0.030 A). With the exception of the methine-bound benzene ring, which forms a dihedral angle of 85.77 (13) degrees with the pyrazole ring, the remaining non-C atoms lie in an approximate plane (r.m.s. deviation = 0.084 A) so that overall the mol-ecule has a T-shape. In the crystal, centrosymmetrically related mol-ecules are connected via pi-pi inter-actions between pyrazole rings [centroid-centroid distance = 3.5370 (15) A] and these stack along the a axis with no specific inter-actions between them. PMID- 23634111 TI - 5-Methyl-N'-[(3Z)-2-oxo-2,3-dihydro-1H-indol-3-yl-idene]-1-phenyl-1H-1,2,3 triazole-4-carbohydrazide. AB - In the title compound, C18H14N6O2, the benzene ring is slightly twisted out of the plane of the 1,2,3-triazole ring (r.m.s. deviation = 0.010 A), forming a dihedral angle of 6.20 (13) degrees . The nine non-H ring atoms of the fused five and six-membered ring system are almost coplanar (r.m.s. deviation = 0.032 A). The near coplanarity in the central residue is consolidated by an intra-molecular bifurcated N-H?(O,N) hydrogen bond. The conformation about the N=C bond is Z. In the crystal, supra-molecular chains along [101] are sustained by N-H?O hydrogen bonds and C-H?O inter-actions. These are consolidated into a three-dimensional architecture by C-H?pi and pi-pi inter-actions; the latter occur between centrosymmetrically related 1,2,3-triazole rings [centroid-centroid distance = 3.6056 (14) A]. PMID- 23634112 TI - 5,7-Dihy-droxy-2-(3-hy-droxy-4,5-dimeth-oxy-phen-yl)-6-meth-oxy-4H-chromen-4-one. AB - The title compound, C18H16O8, was isolated from the plant Artemisia baldshuanica Krasch et Zarp. The mol-ecule is approximately planar, with the exception of the terminal methyl groups, the C atoms of which devitate from their attached ring planes by 1.243 (5) and 1.168 (5) A. The dihedral angle between the substituted benzopyran and benzene rings is 5.8 (1) degrees ; this near planarity could be due to conjugation or a packing effect. Intra-molecular O-H?O and C-H?O hydrogen bonds occur. In the crystal, mol-ecules are connected by O-H?O hydrogen bonds involving the hy-droxy and carbonyl groups, forming hydrogen-bonded chains along [001] and [1-10]. The chains are linked by C-H?O inter-actions. PMID- 23634113 TI - 1,3-Bis(2,3,5,6-tetra-fluoro-4-iodo-phen-oxy)-2,2-bis-[(2,3,5,6-tetra-fluoro-4 iodo-phen-oxy)meth-yl]propane. AB - In the crystal structure of the title compound, C29H8F16I4O4, short I?I and I?F contacts, which can be understood as halogen bonds (XBs), represent the strongest inter-molecular inter-actions, consistent with the presence of I and F atoms, and the absence of H atoms, at the periphery of the mol-ecule. In addition, pi-pi stacking inter-actions between tetra-fluoro-iodo-phenyl (TFIP) groups and five short F?F inter-actions are present. PMID- 23634114 TI - 1-{[4-(4-{[(2-Oxidonaphthalen-1-yl)methyl-idene]aza-nium-yl}phen-oxy)phen yl]iminiumylmeth-yl}naphthalen-2-olate. AB - The title Schiff base compound, C34H24N2O3, was prepared by a condensation reaction of bifunctional aromatic diamine (4,4'-diamino-diphenyl ether) with hy droxy-naphtaldehyde. The asymmetric unit contains two independent mol-ecules with similar conformations. The compound contains a central oxygen bridge and two functionalized [(E)-(phenyl-iminio)meth-yl]naphthalen-2-olate units. The dihedral angles between the benzene rings linking to the central O atom are 74.64 (19) and 69.85 (18) degrees in the two independent mol-ecules. Intra-molecular O-H?O hydrogen bonding occurs between the protonated imino N atoms and deprotonated hy droxy O atoms in both mol-ecules. In the crystal, weak C-H?O hydrogen bonds are observed. PMID- 23634115 TI - 5-Bromo-2-chloro-pyrimidin-4-amine. AB - In the title compound, C4H3BrClN3, the pyrimidine ring is essentially planar (r.m.s. deviation from the plane = 0.087 A). In the crystal, pairs of N-H?N hydrogen bonds connect the mol-ecules into inversion dimers; these are connected by further N-H?N hydrogen bonds into a two-dimensional framework parallel to the bc plane. PMID- 23634116 TI - N-(2,6-Dimeth-oxy-pyridin-3-yl)-9-methyl-9H-carbazole-3-sulfonamide. AB - In the title compound, C20H19N3O4S, a novel tubulin ligand active against human cancer, the dihedral angle between the pyridine ring and the carbazole ring system is 42.87 (10) degrees . In the crystal, the mol-ecules are held together by N-H?O and C-H?O hydrogen bonds into layers, which are assembled into a three dimensional network via pi-pi stacking inter-actions between inversion-related pyridine rings, with centroid-centroid distances of 3.5101 (12) A. PMID- 23634117 TI - 7-Iodo-3,3-diphenyl-octa-hydro-benzo-furan. AB - The title compound, C20H21IO, was synthesized by cyclo-haloetherification of 2 (cyclo-hex-2-en-yl)-2,2-diphenyl-ethanol in CH2Cl2, and crystallized with two independent mol-ecules in the asymmetric unit. The six-membered cyclo-hexane ring adopts a chair conformation, while the five-membered ring adopts an envelope conformation with the fused C atom opposite the O atom as the flap in each case [displacements of the flap atoms = 0.6813 (3) and 0.6679 (3) A]. In the crystal, mol-ecules are linked via pairs of C-H?pi inter-actions, forming inversion dimers. PMID- 23634118 TI - (2E)-2-(3-Eth-oxy-2-hy-droxy-benzyl-idene)hydrazinecarboxamide. AB - The title compound, C10H13N3O3, adopts an E conformation with respect to the azomethine bond and crystallizes in the amide form. A classical intra-molecular O H?N hydrogen bond is present. The two N atoms of the hydrazinecarboxamide unit are also involved in inter-molecular N-H?O hydrogen bonds, with the O atom of the hydrazinecarboxamide group acting as the acceptor. Pairs of N-H?O hydrogen bond link the mol-ecules into centrosymmetric dimers, which are linked by further N H?O hydrogen bonds into chains along the b axis. The chains are linked by C-H?pi inter-actions. PMID- 23634119 TI - N-(2-Meth-oxy-benz-yl)-9-(oxolan-2-yl)-9H-purin-6-amine. AB - The title compound, C17H19N5O2, features an almost planar purine skeleton (r.m.s. deviation = 0.009 A) substituted by a tetra-hydro-furan ring, which adopts an envelope conformation. The purine and benzene rings subtend a dihedral angle of 66.70 (3) degrees . In the crystal, pairs of N-H?N hydrogen bonds connect adjacent mol-ecules into inversion dimers. C-H?N, C-H?O, C-H?pi and pi-pi inter actions [pyrimidine ring centroid-centroid distance = 3.3909 (1) A] connect the dimers into a three-dimensional architecture. PMID- 23634120 TI - 2,2-Dichloro-3,7,7,11-tetra-methyl-10-aza-tetra-cyclo [6.5.0.0(1,3).0(9,11)]trideca-ne. AB - The title compound, C16H25Cl2N, was synthesized from beta-himachalene (3,5,5,9 tetra-methyl-2,4a,5,6,7,8-hexa-hydro-1H-benzocyclo-heptene), which was isolated from the essential oil of the Atlas cedar (Cedrus Atlantica). The mol-ecule is built up from fused six- and seven-membered rings linked to two three-membered rings. The six-membered ring shows a half-chair conformation, whereas the seven membered ring displays a boat conformation. The dihedral angle between the mean planes through the six- and seven-membered rings is 59.8 (2) degrees . The two three-membered rings lie to one side and each is nearly perpendicular to the six membered ring, forming dihedral angles of 83.2 (2) and 86.0 (2) degrees . The absolute structure was established unambiguously from anomalous dispersion effects. No specific inter-molecular inter-actions are noted in the crystal structure. PMID- 23634121 TI - Cyclo-hexane-1,4-dicarb-oxy-lic acid-pyridinium-4-olate (1/1). AB - In the title adduct, C5H5NO.C8H12O4, the heterocycle exists in its zwitterionic form. The cyclo-hexane ring exhibits a chair conformation with the carb-oxy-lic acid groups in equatorial and axial orientations. In the crystal, mol-ecules are linked through charge-assisted O-H?O(-), N(+)-H?O(-) and N(+)-H?O hydrogen bonds, and an additional series of C-H?O contacts, giving a pleated two-dimensional hydrogen-bonded network parallel to (-204). PMID- 23634122 TI - Trimethyl-ammonium 5-(2,4-dinitro-phenyl)-2,6-dioxo-1,2,3,6-tetra-hydro-pyrimidin 4-olate 0.125-hydrate. AB - The asymmetric unit of the title salt C3H10N(+).C10H5N4O7 (-).0.125H2O [trivial name: trimethyl-ammonium 5-(2,4-dinitro-phen-yl)barbiturate 0.125-hydrate], contains two independent cations, two independent anions and a 0.25-occupancy solvent water mol-ecule. In one of the cations, the C atoms are disordered over two sets of sites with refined occupancies of 0.538 (8) and 0.462 (8). In the anions, the dihedral angles between the pyrimidine and benzene rings are 42.77 (6) and 46.55 (7) degrees . In the crystal, N-H?O hydrogen bonds connect anions and cations into chains along [010]. Within these chains, R 2 (2)(8) ring motifs are formed by inversion-related barbiturate anions. The H atoms of the partial occupancy water mol-ecule were not located nor included in the refinement. PMID- 23634123 TI - (E)-3-(4-Meth-oxy-phen-yl)-3-[3-(4-meth-oxy-phen-yl)-1H-pyrazol-1-yl]prop-2-enal. AB - In the title mol-ecule, C20H18N2O3, the pyrazole ring forms a dihedral angle of 2.2 (1) degrees with its meth-oxy-phenyl substituent and a dihedral angle of 67.2 (1) degrees with the benzene substituent on the propenal unit. In the crystal, mol-ecules are connected by weak C-H?O hydrogen bonds, forming R 2 (2)(26) and R 2 (2)(28) cyclic dimers that lie about crystallographic inversion centres. These dimers are further linked through C-H?O and C-H?N hydrogen bonds, forming C(8), C(9), C(10) and C(16) chain motifs. These primary motifs are further linked to form secondary C 2 (2)(15) chains and R 2 (2)(18) rings. PMID- 23634125 TI - 5-(3-Meth-oxy-phen-yl)-3-phenyl-1,2-oxazole. AB - In the title compound, C16H13NO2, the isoxazole ring makes dihedral angles of 17.1 (1) degrees with the 3-meth-oxy-phenyl ring and 15.2 (1) degrees with the phenyl group. Centrosymmetric dimers that are realised by pairs of C-H?pi inter actions are observed in the crystal structure. PMID- 23634124 TI - Bis(4-sulfamoylanilinium) sulfate. AB - In the title salt, 2C6H9N2O2S(+).SO4 (2-), the sulfate S atom is situated on a crystallographic twofold axis (the symmetry of the anion is 2). The anion exerts intense libration, which is manifested by shortening of the observed sulfate S-O bonds, as well as by features in the electron-density map. The crystal structure is stabilized through a three-dimensional hydrogen-bonding network formed by strong N-H?O hydrogen bonds. PMID- 23634126 TI - 3,9-Dimethyl-2,3-dihydro-spiro-[carb-az-ole-1,2'-[1,3]dithio-lan]-4(9H)-one. AB - The title compound, C16H17NOS2, consists of a carbazole skeleton with methyl and dithiol-ane groups as substituents. In the indole ring system, the benzene and pyrrole rings are nearly coplanar, forming a dihedral angle of 1.02 (11) degrees . The cyclo-hexenone ring has a twisted conformation, while the dithiol-ane ring adopts an envelope conformation with one of the CH2 C atoms at the flap. In the crystal, weak C-H?O hydrogen bonds link the mol-ecules into supra-molecular chains nearly parallel to the c axis. These hydrogen bonds together with weak C H?pi inter-actions link the molecules into a three-dimensional supramolecular network. PMID- 23634127 TI - o-Phenyl-enediaminium chloride nitrate. AB - In the title mol-ecular salt, C6H10N2 (2+).NO3 (-).Cl(-), the complete cation is generated by a crystallographic mirror plane. The complete nitrate ion is also generated by reflection, with the N atom and one O atom lying on the mirror plane; the chloride ion also lies on the reflection plane. In the crystal, the components are linked by N-H?Cl and N-H?(N,O) hydrogen bonds, forming (001) layers with the benzene rings projecting into the inter-layer regions. The layers are linked by weak C-H?O hydrogen bonds, generating a three-dimensional network. PMID- 23634128 TI - (3R,4S)-1-(4-Meth-oxy-phen-yl)-2-oxo-4-(3-vinyl-phen-yl)azetidin-3-yl acetate. AB - In the title compound, C20H19NO4, the absolute configuration (3R,4S) for the two chiral centres of the mol-ecule has been determined. PMID- 23634129 TI - 3-Methyl-1,5-diphenyl-4,5-dihydro-1H-pyrazole. AB - In the title compound, C16H16N2, the dihydro-pyrazole ring adopts a shallow envelope conformation, with the C atom bearing the phenyl group displaced by 0.298 (2) A from the other atoms (r.m.s. deviation = 0.015 A). The dihedral angles between the four near coplanar atoms of the central ring and the N- and C bonded phenyl groups are 13.49 (13) and 82.22 (16) degrees , respectively. PMID- 23634130 TI - Amicarbazone. AB - Three independent mol-ecules comprise the asymmetric unit of the title compound, C10H19N5O2, (systematic name: 4-amino-N-tert-butyl-3-isopropyl-5-oxo-4,5-dihydro 1H-1,2,4-triazole-1-carboxamide) . In all three mol-ecules, the triazole ring and the carboxamide group are almost coplanar [within 4.0-5.9 (9) degrees ], particularly because of the formation of an intra-molecular N-H?O hydrogen bond. On other hand, the orientation of the isopropyl group varies significantly from mol-ecule to mol-ecule. The crystal packing is dominated by N-H?O and N-H?N hydrogen bonds, which connect the mol-ecules into infinite chains along [010]. PMID- 23634131 TI - (Z)-1-(2-Hy-droxy-eth-yl)-4-(2-meth-oxy-benzyl-idene)-2-methyl-1H-imidazol-5(4H) one. AB - In the title compound, C14H16N2O3, an analog of the chromophore in green fluorescent protein, the meth-oxy-phenyl substituent and the imidazole N adopt a Z conformation with respect to the C=C bond. Aside from the hy-droxy-ethyl group, the mol-ecule is approximately planar, with the five- and six-membered ring planes forming a dihedral angle of 9.3 (1) degrees . An intra-molecular C-H?N contact occurs. In the crystal, O-H?N hydrogen bonds link the mol-ecules, forming chains along the b-axis direction. C-H?O hydrogen bonds are also observed. PMID- 23634132 TI - Bis(1,2,3-benzotriazolium) sulfate dihydrate. AB - In the asymmetric unit of the title hydrated salt, 2C6H6N3 (+).SO4 (2-).2H2O, there are two independent sulfate ions, one lying on a twofold axis, and the other in a general position. There are three independent benzotriazolium cations and three independent water mol-ecules. The sulfate ion in a general position forms hydrogen-bonded chains of stoichiometry SO4 (2-).3H2O in the b-axis direction. The sulfate on the twofold axis is unhydrated and accepts hydrogen bonds from four surrounding benzotriazoles. The benzotriazolium cations form two types of stacks along b. One stack contains only one type of independent cation, related by inversion centers. The other stack contains two alternating independent cations and no symmetry. The two types of stacks have orientations which are rotated by about 79 degrees in the ac plane. 12 symmetrically distinct hydrogen bonds of type N-H?O(sulfate), N-H?O(water), O-H?O(sulfate) and O H?O(water), with donor-acceptor distances in the range 2.5490 (13)-2.7871 (12) A, form a three-dimensional array. PMID- 23634133 TI - A new polymorph of 1,3-bis-(penta-fluoro-phen-yl)urea. AB - The title compound, C13H2F10N2O, has been previously described in the space group Pbca with Z = 8 [Jai-nhuknan et al. (1997 ?). Acta Cryst. C53, 455-457]. The current P212121 polymorph was obtained from a tetra-hydro-furan solution. The penta-fluoro-phenyl rings make dihedral angles of 50.35 (6) and 54.94 (6) degrees with the urea fragment, in close accord with those reported for the first polymorph. In the crystal, both of the N-H groups donate H atoms to the same carbonyl O atom, forming a one-dimensional mol-ecular array along the a axis. There are close contacts between perfluoro-phenyl C atoms within the array [3.228 (3) A] and halogen bonds are also observed between the arrays [F?F = 2.709 (2) and 2.7323 (18) A]. PMID- 23634134 TI - 1-Dichloro-acetyl-t-3,t-5-dimethyl-r-2,c-6-diphenyl-piperidin-4-one. AB - In the title compound, C21H21Cl2NO2, the piperidine ring adopts a distorted boat conformation. The phenyl rings substituted at the 2- and 6-positions of the piperidine ring subtend angles of 87.9 (7) and 70.8 (9) degrees , respectively, with the best plane through the piperidine ring. In the crystal, mol-ecules are connected by C-H?O and C-H?Cl inter-actions into layers in the ab plane. PMID- 23634135 TI - 2-Amino-6-methyl-pyridinium 4-hy-droxy-benzoate. AB - In the title mol-ecular salt, C6H9N2 (+).C7H5O3 (-), the dihedral angle between the benzene ring and the CO2 group in the anion is 6.1 (2) degrees . In the crystal, the cation and anion are linked by N-H?O and C-H?O hydrogen bonds, and the anions are connected by O-H?O hydrogen bonds, forming a three-dimensional network. PMID- 23634136 TI - 1,4-Bis(3-chloro-pyrazin-2-yl-oxy)benzene. AB - In the title compound, C14H8Cl2N4O2, the pyrazine rings are orthogonal to the benzene ring, making dihedral angles of 88.42 (8) and 89.22 (8) degrees . The Cl atoms attached to the pyrazine rings deviate by -0.0597 (5) and 0.0009 (5) A from the ring plane. The crystal structure features C-H?N hydrogen bonds. PMID- 23634137 TI - N-tert-Butyl-2-[4-(dimethyl-amino)-phen-yl]imidazo[1,2-a]pyrazin-3-amine. AB - In the title compound, C18H23N5, the imidazole ring makes a dihedral angles of 3.96 (8) and 19.02 (8) degrees , respectively, with the pyrazine and benzene rings while the dihedral angle between the pyrazine and benzene rings is 16.96 (7) degrees . In the crystal, mol-ecules are linked via N-H?N hydrogen bonds, forming chains along [010]. These chains are linked by C-H?N hydrogen bonds, forming two-dimensional networks lying parallel to (001). PMID- 23634138 TI - 5,11-Ditosyl-5H,11H-dibenzo[b,f][1,5]diazo-cine-6,12-dione acetic acid hemisolvate. AB - The mol-ecular structure of the title compound, C28H22N2O6S2.0.5CH3COOH, is built up from three fused rings, two six and one eight membered. The eight-membered ring shows a boat conformation and the dihedral angle between the two benzene groups attached thereto is 66.43 (11) degrees , resulting in a V-shaped geometry. Two tosyl substituents are bound to the N atoms. The planes through the tolyl rings are roughly perpendicular, as indicated by the dihedral angle of 82.44 (12) degrees . In the crystal, the mol-ecule and its inversion-related symmetry equivalent are linked to the acetic acid solvent mol-ecule by non-classical O-H?O and C-H?O hydrogen bonds. Two half-occupied acetic acid solvent mol-ecules are disordered at the same site and linked by a center of symmetry. PMID- 23634139 TI - 9-(2-Hy-droxy-6-oxocyclo-hex-1-en-1-yl)-2,3,4,9-tetra-hydro-1H-xanthen-1-one. AB - In the xanthene ring system in the title compound, C19H18O4, the 4H-pyran ring has a maximum deviation of 0.110 (2) A from planarity and the cyclo-hexene ring exhibits a puckered conformation [puckering parameters Q T = 0.452 (3) A, theta = 57.0 (4) and phi = 131.7 (4) degrees ]. The cyclo-hexene ring attached to the xanthene system adopts an envelope conformation, with the middle of the three methylene C atoms as the flap atom. In the crystal, O-H?O and C-H?O hydrogen bonds form infinite chains of R 1 (2)(6) ring motifs along [100] with the xanthene groups arranged in an alternating zigzag manner. PMID- 23634140 TI - 4-[5-(4-Fluoro-phen-yl)-1-(4-phenyl-1,3-thia-zol-2-yl)-4,5-dihydro-1H-pyrazol-3 yl]-5-methyl-1-(4-methyl-phenyl)-1H-1,2,3-triazole. AB - In the title compound, C28H23FN6S, the pyrazole ring adopts an envelope conformation, with the methine C atom being the flap atom. With respect to this ring, the 2-thienyl, triazole and fluoro-benzene rings are approximately coplanar, coplanar and perpendicular, respectively [dihedral angles = 8.56 (17), 6.03 (19) and 73.1 (2) degrees , respectively] so that to a first approximation the mol-ecule has a T-shape. In the crystal, mol-ecules are consolidated into a three-dimensional architecture by C-H?F (involving a bifurcated F atom), C-H?S and C-H?pi inter-actions. PMID- 23634141 TI - 5-(4-Fluoro-phen-yl)-3-[5-methyl-1-(4-methyl-phen-yl)-1H-1,2,3-triazol-4-yl]-N phenyl-4,5-dihydro-1H-pyrazole-1-carbothio-amide. AB - In the title compound, C26H23FN6S, the pyrazole ring has an envelope conformation, with the methine C atom being the flap atom. The thio-urea group is close to being coplanar with the pyrazole N atoms [N-N-C-S torsion angle = 176.78 (15) degrees ], which allows for an intra-molecular N-H?N hydrogen bond; the connected triazole ring is nearly coplanar with this ring [N-C-C-N = -172.65 (19) degrees ]. There is a significant twist between the pyrazole ring and attached fluoro-benzene ring [N-C-C-C = -18.8 (3) degrees ] and a greater twist between triazole and attached tolyl ring [dihedral angle = 58.25 (14) degrees ]. In the crystal, supra-molecular chains aligned along [40,10] are consolidated by pi-pi inter-actions between the triazole and phenyl rings [centroid-centroid distance = 3.7053 (13) A]. PMID- 23634142 TI - 3,4',5-Trichloro-biphenyl-4-yl 2,2,2-trichloro-ethyl sulfate. AB - Crystals of the title compound, C14H8Cl6O4S, are twinned by inversion, with unequal components [0.85 (3):0.15 (3)]. The asymmetric unit contains two independent mol-ecules that are related by a pseudo-inversion center. The Car-O [1.393 (9) and 1.397 (9) A] and ester S-O bond lengths [1.600 (5) and 1.590 (5) A] of both mol-ecules are comparable to the structurally related 2,3,5,5 trichloro-biphenyl-4-yl 2,2,2-trichloro-ethyl sulfate. The dihedral angles between the benzene rings in the two mol-ecules are 37.8 (2) and 35.0 (2) degrees . PMID- 23634143 TI - 4-(Dec-yloxy)phenyl 2-oxo-7-trifluoro-methyl-2H-chromene-3-carboxyl-ate. AB - The title compound, C27H29F3O5, is a liquid crystal (LC) and exhibits enanti otropic SmA phase transitions. In the crystal, the dihedral angle between the 2H chromene ring system and the benzene ring is 62.97 (2) degrees . The three F atoms of the -CF3 group are disordered over two sets of sites with occupancy factors 0.71 (4):0.29 (4). In the crystal, pairs of C-H?O hydrogen bonds form inversion dimers and generate R 2 (2)(10) rings. The structure also features C H?F and C-H?pi inter-actions along [100] and [010], respectively. PMID- 23634144 TI - Ethyl 2-(quinolin-8-yl-oxy)acetate monohydrate. AB - In the title compound, C13H13NO3.H2O, the dihedral angle between the ethyl ester group [C-C-O-C(=O); maximum deviation = 0.003 (2) A] and the quinoline ring system is 7.94 (12) degrees . The water solvent mol-ecule is linked to the title mol-ecule via O-H?O and O-H?N hydrogen bonds. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming chains propagating along [100]. PMID- 23634145 TI - Selective determinants of low bone mineral mass in adult women with anorexia nervosa. AB - We investigated the relative effect of amenorrhea and insulin-like growth factor I (sIGF-I) levels on cancellous and cortical bone density and size. We investigated 66 adult women with anorexia nervosa. Lumbar spine and proximal femur bone mineral density was measured by DXA. We calculated bone mineral apparent density. Structural geometry of the spine and the hip was determined from DXA images. Weight and BMI, but not height, as well as bone mineral content and density, but not area and geometry parameters, were lower in patients with anorexia nervosa as compared with the control group. Amenorrhea, disease duration, and sIGF-I were significantly associated with lumbar spine and proximal femur BMD. In a multiple regression model, we found that sIGF-I was the only significant independent predictor of proximal femur BMD, while duration of amenorrhea was the only factor associated with lumbar spine BMD. Finally, femoral neck bone mineral apparent density, but not hip geometry variables, was correlated with sIGF-I. In anorexia nervosa, spine BMD was related to hypogonadism, whereas sIGF-I predicted proximal femur BMD. The site-specific effect of sIGF-I could be related to reduced volumetric BMD rather than to modified hip geometry. PMID- 23634146 TI - Gene expression of leptin and long leptin receptor isoform in endometriosis: a case-control study. AB - In this study, leptin/BMI ratio in serum and peritoneal fluid and gene expression of leptin and long form leptin receptor (OB-RL) were assessed in eutopic and ectopic endometria of women with endometriosis and controls. Increased serum leptin/BMI ratio was found in endometriosis patients. Leptin and OB-RL gene expression was significantly higher in ectopic versus eutopic endometrium of patients and controls. A positive, significant correlation was observed between leptin and OB-RL transcripts in ectopic endometria and also in eutopic endometria in endometriosis and control groups. A negative and significant correlation was found between OB-RL mRNA expression and peritoneal fluid leptin/BMI ratio only in endometriosis. These data suggest that, through a modulatory interaction with its active receptor, leptin might play a role in the development of endometrial implants. PMID- 23634147 TI - Tuberculous pyomyositis: a rare but serious diagnosis. AB - Tuberculous pyomyositis is a rare clinical entity with serious consequences if a diagnosis is not established early. A 53-year-old female with a past medical history of sarcoidosis and pulmonary fibrosis presented from an outside hospital with persistent fevers and a rash. She had been hospitalized multiple times at an outside hospital without any improvement in her symptoms. On examination, she was noted to have a large area of left upper lower extremity (LUE) tenderness with superimposed erythema. Laboratory data revealed a white blood cell count of 22,300. Computed tomography (CT) scans of the LUE, chest, and left lower extremity (LLE) showed multiple intramuscular abscesses in those regions without evidence of osteomyelitis. Subsequent drainage of the abscesses and resulting cultures revealed Mycobacterium tuberculosis. The patient was started on therapy with rifampin, isoniazid, pyrazinamide, and ethambutol. However, the patient developed hepatitis on these agents and subsequently went into septic shock with multiorgan failure. Care was eventually withdrawn as a result of a poor prognosis. This case illustrates the severe consequences of TB pyomyositis if not diagnosed promptly. While tuberculosis is uncommon in the United States, it should be an important consideration in the differential diagnosis of immunocompromised patients. PMID- 23634148 TI - Post-Kala-Azar Dermal Leishmaniasis: A Paradigm of Paradoxical Immune Reconstitution Syndrome in Non-HIV/AIDS Patients. AB - Visceral leishmaniasis (VL) is a parasitic disease characterized by immune suppression. Successful treatment is usually followed by immune reconstitution and a dermatosis called post-Kala-azar dermal leishmaniasis (PKDL). Recently, PKDL was described as one of the immune reconstitution syndromes (IRISs) in HIV/VL patients on HAART. This study aimed to present PKDL as a typical example of paradoxical IRIS in non-HIV/AIDS individuals. Published and new data on the pathogenesis and healing of PKDL was reviewed and presented. The data suggested that PKDL is a typical example of paradoxical IRIS, being a new disease entity that follows VL successful treatment and immune recovery. PKDL lesions are immune inflammatory in nature with granuloma, adequate response to immunochemotherapy, and an ensuing hypersensitivity reaction, the leishmanin skin test (LST). The data also suggested that the cytokine patterns of PKDL pathogenesis and healing are probably as follows: an active disease state dominated by IL-10 followed by spontaneous/treatment-induced IL-12 priming, IL-2 stimulation, and INF- gamma production. INF- gamma -activated macrophages eliminate the Leishmania parasites/antigen to be followed by LST conversion and healing. In conclusion, PKDL is a typical example of paradoxical IRIS in non-HIV/AIDS individuals with anti-inflammatory cytokine patterns that are superseded by treatment-induced proinflammatory cytokines and lesions healing. PMID- 23634149 TI - Effect of bladder distension on dosimetry of organs at risk in computer tomography based planning of high-dose-rate intracavitary brachytherapy for cervical cancer. AB - PURPOSE: Distension and shape of urinary bladder may vary during intracavitary brachytherapy (ICBT) for cervical cancer, significantly affecting doses to bladder, rectum, sigmoid colon and small intestine and consequently late radiation toxicities. This study is to evaluate the effects of different fixed volume bladder distention on dosimetry, assessed by three dimensional image based planning, in different organs at risk during the treatment of cervical cancer with ICBT. MATERIAL AND METHODS: Forty seven cervical cancer patients (stage IB to IVA) were qualified for ICBT following external beam radiotherapy. Urinary bladder was distended with different volumes of normal saline instilled by a Foley's catheter. Planning CT scans were performed after insertion of applicators and three dimensional treatment planning was done on Brachyvision((r)) treatment planning system (Varian Medical Systems, Palo Alto, CA). Dose volume histograms were analyzed. Bladder, rectum, sigmoid colon and small intestine doses were collected for individual plans and compared, based on the amount of bladder filling. RESULTS: Mean dose to the bladder significantly decreased with increased bladder filling. However, doses to the small volumes (0.1 cc, 1 cc, 2 cc) which are relevant for brachytherapy, did not change significantly with bladder filling for bladder, rectum or sigmoid colon. Nevertheless, all dose values of small intestine are decreased significantly with bladder filling. CONCLUSIONS: Bladder distension has no significant effect on doses received during brachytherapy by relevant volumes of bladder, rectum and sigmoid colon except intestine where values are decreased with bladder distension. A larger study with clinical correlation of late toxicities is essential for proper evaluation of this strategy. PMID- 23634150 TI - Image-guided brachytherapy (IGBT) combined with whole pelvic intensity-modulated radiotherapy (WP-IMRT) for locally advanced cervical cancer: a prospective study from Chiang Mai University Hospital, Thailand. AB - PURPOSE: A report of preliminary results and toxicity profiles using image-guided brachytherapy (IGBT) combined with whole pelvic intensity-modulated radiation therapy (WP-IMRT) for locally advanced cervical cancer. MATERIAL AND METHODS: Fifteen patients with locally advanced cervical cancer were enrolled into the study. WP-IMRT was used to treat the Clinical Target Volume (CTV) with a dose of 45 Gy in 25 fractions. Concurrent cisplatin (40 mg/m(2)) was prescribed during radiotherapy (RT) on weekly basis. IGBT using computed tomography was performed at the dose of 7 Gy * 4 fractions to the High-Risk Clinical Target Volume (HR CTV). RESULTS: The mean cumulative doses - in terms of equivalent dose of 2 Gy (EQD2) - of IGBT plus WP-IMRT to HR-CTV, bladder, rectum, and sigmoid colon were 88.3, 85.0, 68.2 and 73.6 Gy, respectively. In comparison with standard (point A prescription) dose-volume histograms, volume-based image-guided brachytherapy improved the cumulative doses for bladder of 67%, rectum of 47% and sigmoid of 46%. At the median follow-up time of 14 months, the local control, metastasis free survival and overall survival rates were 93%, 100% and 93%, respectively. No grade 3-4 acute and late toxicities were observed. CONCLUSION: The combination of image-guided brachytherapy and intensity-modulated radiotherapy improved the dose distribution to tumor volumes and avoided overdose in OARs which could be converted in excellent local control and toxicity profiles. PMID- 23634151 TI - The dosimetric impact of vaginal balloon-packing on intracavitary high-dose-rate brachytherapy for gynecological cancer. AB - PURPOSE: We perform a clinical retrospective study to determine whether a vaginal balloon-packing system provides a dosimetric reduction to organs at risk (OARs) versus traditional gauze packing for gynecological high-dose-rate brachytherapy (HDR-BT). We also test various balloon filling materials for optimizing imaging quality. MATERIAL AND METHODS: Filling materials for balloon-packing were evaluated based on imaging quality with X-ray, computerized tomography, and magnetic resonance imaging modalities. We then retrospectively reviewed 45 HDR-BT plans of 18 patients performed with gauze packing and 39 plans of 16 patients performed with balloon-packing. Twelve patients received both gauze and balloon packing. HDR-BT was delivered with an iridium-192 afterloader and a Fletcher-Suit Declos-style T&O applicator. At each fraction, 3D imaging was obtained. The D2cc values of OARs were calculated, as well as ICRU-defined point doses. RESULTS: In the 84 HDR fractions reviewed, vaginal balloon-packing provides statistically equivalent doses to rectum, bladder, and sigmoid compared to gauze packing. On average balloon-packing produced average reductions of 3.3% and 6.9% in the rectal and sigmoid D2cc doses and an increase of 3.2% to the bladder D2cc dose (normalized to prescription dose), although none of these values were statistically significant for the twelve patients who received both gauze and balloon-packing (32 and 40 total fractions, respectively). CONCLUSIONS: In the 84 HDR fractions analyzed, vaginal balloon-packing is as effective as gauze packing for dose sparing to the rectum, bladder, and sigmoid. A 1: 1 solution of saline and contrast for filling material enables easy contouring for image-guided HDR with minimal artefacts. PMID- 23634152 TI - The retina dose-area histogram: a metric for quantitatively comparing rival eye plaque treatment options. AB - PURPOSE: Episcleral plaques have a history of over a half century in the delivery of radiation therapy to intraocular tumors such as choroidal melanoma. Although the tumor control rate is high, vision-impairing complications subsequent to treatment remain an issue. Notable, late complications are radiation retinopathy and maculopathy. The obvious way to reduce the risk of radiation damage to the retina is to conform the prescribed isodose surface to the tumor base and to reduce the dose delivered to the surrounding healthy retina, especially the macula. Using a fusion of fundus photography, ultrasound and CT images, tumor size, shape and location within the eye can be accurately simulated as part of the radiation planning process. In this work an adaptation of the dose-volume histogram (DVH), the retina dose-area histogram (RDAH) is introduced as a metric to help compare rival plaque designs and conformal treatment planning options with the goal of reducing radiation retinopathy. MATERIAL AND METHODS: The RDAH is calculated by transforming a digitized fundus-photo collage of the tumor into a rasterized polar map of the retinal surface known as a retinal diagram (RD). The perimeter of the tumor base is digitized on the RD and its area computed. Area and radiation dose are calculated for every pixel in the RD. RESULTS: The areal resolution of the RDAH is a function of the pixel resolution of the raster image used to display the RD and the number of polygon edges used to digitize the perimeter of the tumor base. A practical demonstration is presented. CONCLUSIONS: The RDAH provides a quantitative metric by which episcleral plaque treatment plan options may be evaluated and compared in order to confirm adequate dosimetric coverage of the tumor and margin, and to help minimize dose to the macula and retina. PMID- 23634153 TI - Low-dose-rate or high-dose-rate brachytherapy in treatment of prostate cancer - between options. AB - PURPOSE: Permanent low-dose-rate (LDR-BT) and temporary high-dose-rate (HDR-BT) brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never to be conducted comparing these two forms of brachytherapy, a comparative analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. The aim of this paper is to look for possible similarities and differences between both brachytherapy modalities. Indications and contraindications for monotherapy and for brachytherapy as a boost to external beam radiation therapy (EBRT) are presented. It is suggested that each of these techniques has attributes that advocates for one or the other. First, they represent the extreme ends of the spectrum with respect to dose rate and fractionation, and therefore have inherently different radiobiological properties. Low-dose-rate brachytherapy has the great advantage of being practically a one-time procedure, and enjoys a long-term follow-up database supporting its excellent outcomes and low morbidity. Low-dose-rate brachytherapy has been a gold standard for prostate brachytherapy in low risk patients since many years. On the other hand, HDR is a fairly invasive procedure requiring several sessions associated with a brief hospital stay. Although lacking in significant long-term data, it possesses the technical advantage of control over its postimplant dosimetry (by modulating the source dwell time and position), which is absent in LDR brachytherapy. This important difference in dosimetric control allows HDR doses to be escalated safely, a flexibility that does not exist for LDR brachytherapy. CONCLUSIONS: Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy, using current dose regimens. At present, all available clinical data regarding these two techniques suggests that they are equally effective, stage for stage, in providing high tumor control rates. PMID- 23634154 TI - Intraluminal urethral brachytherapy for recurrence of transitional cell carcinoma of urinary bladder in urethral stump. AB - We report a unique case of successfully performed intraluminal brachytherapy for low volume urethral mucosal recurrence of transitional cell carcinoma urinary bladder, initially treated by transurethral resection of bladder tumor, followed by radical cystectomy. Since the patient was unwilling to undergo any other operational interventions, intraluminal brachytherapy of urethra was attempted. Fluroscopy guided intraluminal HDR brachytherapy using Lumencath((r)) catheter under local anesthesia, and remote afterloading system (Nucletron, an Elekta company, Elekta AB, Stockholm, Sweden) was performed. A fraction dose of 7 Gy in seven weekly fractions was prescribed at 0.5 cm from the single applicator. The result was promising in terms of local control and symptomatic relief. Therefore, intraluminal brachytherapy in low volume superficial local disease in urethra may play a potential role, and should be applied when repeated surgery is not feasible due to technical or medical reasons. PMID- 23634155 TI - Individual applicator for brachytherapy for various sites of superficial malignant lesions. AB - The aim of this paper is to discuss brachytherapy treatment and individual applicators suitable for unfavorably localized superficial malignant lesions. Techniques for manufacturing an individual applicator and clinical examples of its use for various locations of cancer are presented. This techniques are based on individual size and shape of the tumour. CT-planning make the technique adequate for individual patient history and type of tumour. Featured techniques seems to be very useful and easy to performed. PMID- 23634157 TI - Another milestone. PMID- 23634156 TI - Optimizing parametrial aperture design utilizing HDR brachytherapy isodose distribution. AB - Treatment of cervical cancer includes combination of external beam radiation therapy (EBRT) and brachytherapy (BRT). Traditionally, coronal images displaying dose distribution from a ring and tandem (R&T) implant aid in construction of parametrial boost fields. This research aimed to evaluate a method of shaping parametrial fields utilizing contours created from the high-dose-rate (HDR) BRT dose distribution. Eleven patients receiving HDR-BRT via R&T were identified. The BRT and EBRT CT scans were sent to FocalSim (v4.62)((r)) and fused based on bony anatomy. The contour of the HDR isodose line was transferred to the EBRT scan. The EBRT scan was sent to CMS-XIO (v4.62)((r)) for planning. This process provides an automated, potentially more accurate method of matching the medial parametrial border to the HDR dose distribution. This allows for a 3D-view of dose from HDR-BRT for clinical decision-making, utilizes a paperless process and saves time over the traditional technique. PMID- 23634158 TI - Drug shortages: searching for a cure. AB - Shortages of prescription generic drugs have recently made headlines in Canada and elsewhere. The causes and possible solutions for these shortages are still unclear. With the failure of "market forces," has the time come to establish a Crown corporation to ensure the supply of essential drugs? PMID- 23634159 TI - Making Canada a destination for medical tourists: why Canadian provinces should not try to become "Mayo Clinics of the North". AB - When Canadian researchers examine the subject of medical tourism, they typically focus on ethical, social, public health and health policy issues related to Canadians seeking health services in other countries. They emphasize study of Canada as a departure point for medical tourists rather than as a potential destination for international patients. Several influential voices have recently argued that provincial healthcare systems in Canada should market health services to international patients. Proponents of marketing Canada as a destination for medical tourists argue that attracting international patients will generate revenue for provincial healthcare systems. Responding to such proposals, I argue that there are at least seven reasons why provincial health systems in Canada should not dedicate institutional, financial and health human resources to promoting themselves as destinations for medical tourists. PMID- 23634160 TI - How many patients should a family physician have? Factors to consider in answering a deceptively simple question. AB - The ratio of patients to physicians has long been used as a tool for measuring and planning healthcare resources in Canada. Some current changes in primary care, such as enrolment of patients with physicians, make this ratio easier to calculate, while others, such as changing practice structure, make it more complex to interpret. Based on information gleaned from a review of the literature, we argue that before panel size can be used as an accountability measure for individual physicians or practices in primary care, we must understand its relationship to quality and outcomes at individual and population levels, as well as the contextual factors that affect it. PMID- 23634161 TI - The politics of access to expensive drugs: INESSS and the innovative pharmaceutical industry. AB - The innovative pharmaceutical industry employs thousands of people in Quebec and so has the ability to exert strong political pressure; the public statements of Sanofi-Aventis concerning the provincial reimbursement of certain expensive drugs are an example. "Maintaining a dynamic biopharmaceutical industry" is one of four main axes of the drug policy of Quebec's ministry of health. However, this role of government should not take precedence over the efficient and equitable management of health resources. We defend the legitimate and responsible choice of the Institut national d'excellence en sante et en services sociaux du Quebec (INESSS) to require an acceptable cost-effectiveness ratio from expensive new drugs. PMID- 23634162 TI - Acute care alternate-level-of-care days due to delayed discharge for traumatic and non-traumatic brain injuries. AB - Alternate-level-of-care (ALC) days represent hospital beds that are taken up by patients who would more appropriately be cared for in other settings. ALC days have been found to be costly and may result in worse functional outcomes, reduced motor skills and longer lengths of stay in rehabilitation. This study examines the factors that are associated with acute care ALC days among patients with acquired brain injury (ABI). We used the Discharge Abstract Database to identify patients with ABI using International Classification of Disease-10 codes. From fiscal years 2007/08 to 2009/10, 17.5% of patients with traumatic and 14% of patients with non-traumatic brain injury had at least one ALC day. Significant predictors include having a psychiatric co-morbidity, increasing age and length of stay in acute care. These findings can inform planning for care of people with ABI in a publicly funded healthcare system. PMID- 23634163 TI - Health technology assessment and the media: more compatible than one may think? AB - While the Health Technology Assessment (HTA) community has acknowledged the importance of public and consumer involvement in the HTA process, very few studies have examined how technology-related findings may be reported by the media to the broader public. This paper compares the content of press articles with the content of three Canadian HTA reports that respectively assess electroconvulsive therapy, first-trimester prenatal screening for Down syndrome, and prostate-specific antigen screening for prostate cancer. We qualitatively and quantitatively analyzed 186 press articles addressing the same technologies. Our results show that beyond stylistic emphasis, there is an important overlap between media coverage of these technologies and the content of HTA reports. Findings also highlight shared interests on which both researchers and journalists could build to enhance the communication of health information to the public. PMID- 23634164 TI - Residential long-term care capacity planning: the shortcomings of ratio-based forecasts. AB - This paper uses observations from two British Columbia studies to illustrate the shortcomings of widely used ratio-based approaches for residential long-term care capacity planning. It shows that capacity plans based on a fixed ratio of beds per population over age 75 may result in either excess capacity or long wait times for admission. It then investigates the use of linear regression models to obtain a "best" ratio by relating optimal plans derived by rigorous analytical methods to population characteristics and shows that no single ratio applies broadly. While the use of regression is promising, finding these "best" ratios is too analytically complex for general practice. The paper concludes by providing and evaluating an easy-to-use planning method, which we call the average flow model (AFM). The AFM combines demand forecasts with length-of-stay estimates to produce enhanced capacity plans. The AFM is transparent, easily implemented in a spreadsheet and well suited for "what if?" analyses. PMID- 23634165 TI - Canadian return-for-service bursary programs for medical trainees. AB - Return-for-service (RFS) bursaries for physicians have been in use in Canada for many years, yet little is known about the programs that are currently available or the features of the RFS bursary that are particularly important to potential participants. Using document analysis, we found that RFS programs were available in nearly all provinces and territories. A survey of medical trainees from Memorial University showed that the most important factors in their decision to accept an RFS bursary were the location they would be required to work, the monetary value of the bursary and the return time required to repay the service commitment. RFS bursaries fund trainees who plan to remain in the province rather than attract new trainees to the province. These bursaries may nonetheless serve to reinforce the decisions of physicians who are predisposed to work in an underserved community. PMID- 23634166 TI - Benchmarking: a method for continuous quality improvement in health. AB - Benchmarking, a management approach for implementing best practices at best cost, is a recent concept in the healthcare system. The objectives of this paper are to better understand the concept and its evolution in the healthcare sector, to propose an operational definition, and to describe some French and international experiences of benchmarking in the healthcare sector. To this end, we reviewed the literature on this approach's emergence in the industrial sector, its evolution, its fields of application and examples of how it has been used in the healthcare sector. Benchmarking is often thought to consist simply of comparing indicators and is not perceived in its entirety, that is, as a tool based on voluntary and active collaboration among several organizations to create a spirit of competition and to apply best practices. The key feature of benchmarking is its integration within a comprehensive and participatory policy of continuous quality improvement (CQI). Conditions for successful benchmarking focus essentially on careful preparation of the process, monitoring of the relevant indicators, staff involvement and inter-organizational visits. Compared to methods previously implemented in France (CQI and collaborative projects), benchmarking has specific features that set it apart as a healthcare innovation. This is especially true for healthcare or medical-social organizations, as the principle of inter-organizational visiting is not part of their culture. Thus, this approach will need to be assessed for feasibility and acceptability before it is more widely promoted. PMID- 23634167 TI - The efficacy of guanxinning injection in treating angina pectoris: systematic review and meta-analysis of randomized controlled trials. AB - Objective. The randomized controlled trials (RCTs) on Guanxinning injection (GXN) in treating angina pectoris were published only in Chinese and have not been systematically reviewed. This study aims to provide a PRISMA-compliant and internationally accessible systematic review to evaluate the efficacy of GXN in treating angina pectoris. Methods. The RCTs were included according to prespecified eligibility criteria. Meta-analysis was performed to evaluate the symptomatic (SYMPTOMS) and electrocardiographic (ECG) improvements after treatment. Odds ratios (ORs) were used to measure effect sizes. Subgroup analysis, sensitivity analysis, and metaregression were conducted to evaluate the robustness of the results. Results. Sixty-five RCTs published between 2002 and 2012 with 6064 participants were included. Overall ORs comparing GXN with other drugs were 3.32 (95% CI: [2.72, 4.04]) in SYMPTOMS and 2.59 (95% CI: [2.14, 3.15]) in ECG. Subgroup analysis, sensitivity analysis, and metaregression found no statistically significant dependence of overall ORs upon specific study characteristics. Conclusion. This meta-analysis of eligible RCTs provides evidence that GXN is effective in treating angina pectoris. This evidence warrants further RCTs of higher quality, longer follow-up periods, larger sample sizes, and multicentres/multicountries for more extensive subgroup, sensitivity, and metaregression analyses. PMID- 23634168 TI - Complementary and Alternative Medicine Use among Physicians in Oriental Medicine Hospitals in Vietnam: A Hospital-Based Survey. AB - Interest in complementary and alternative medicine (CAM) is growing worldwide, even in Vietnam where traditional medicine is considered mainstream. We conducted a survey of the knowledge, attitudes, and practices of CAM therapies among physicians in oriental medicine (OM) hospitals in Vietnam. A two-stage random selection process selected 337 physicians who were interviewed using a face-to face method with a standardized structured questionnaire. Data from 312 physicians who completed the questionnaire suggested that oriental herbal medicine and acupuncture (Vietnamese OM version) were the more commonly used CAM modalities compared with Vietnamese folk medicine and other forms of CAM. A broad range of CAM modalities, particularly chiropractice, diet supplements, and dietary therapy, and an excessive proportion of western medication were employed in conjunction with OM in the physicians' daily practice. Their daily practice was influenced by the source of knowledge, education level, medical specialty, and working environment. These findings suggest that physicians in OM hospitals in Vietnam have interests in various forms of CAM therapies besides traditional modes. PMID- 23634169 TI - alpha -Mangostin from Cratoxylum arborescens (Vahl) Blume Demonstrates Anti Ulcerogenic Property: A Mechanistic Study. AB - Cratoxylum arborescens (Vahl) Blume is an Asian herbal medicine with versatile ethnobiological properties including treatment of gastric ulcer. This study evaluated the antiulcerogenic mechanism(s) of alpha -mangostin (AM) in a rat model of ulcer. AM is a prenylated xanthone derived through biologically guided fractionation of C. arborescens. Rats were orally pretreated with AM and subsequently exposed to acute gastric lesions induced by ethanol. Following treatment, ulcer index, gastric juice acidity, mucus content, histological and immunohistochemical analyses, glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO), and nonprotein sulfhydryl groups (NP-SH) were evaluated. The anti Helicobacter pylori, cyclooxygenase-2 (COX-2) inhibitory effect, and antioxidant activity of AM were also investigated in vitro. AM (10 and 30 mg/kg) inhibited significantly (P < 0.05) ethanol-induced gastric lesions by 66.04% and 74.39 %, respectively. The compound induces the expression of Hsp70, restores GSH levels, decreases lipid peroxidation, and inhibits COX-2 activity. The minimum inhibitory concentration (MIC) of AM showed an effective in vitro anti-H. pylori activity. The efficacy of the AM was accomplished safely without presenting any toxicological parameters. The results of the present study indicate that the antioxidant properties and the potent anti-H. pylori, in addition to activation of Hsp70 protein, may contribute to the gastroprotective activity of alpha mangostin. PMID- 23634170 TI - Multicomponent therapeutics of berberine alkaloids. AB - Although berberine alkaloids (BAs) are reported to be with broad-spectrum antibacterial and antiviral activities, the interactions among BAs have not been elucidated. In the present study, methicillin-resistant Staphylococcus aureus (MRSA) was chosen as a model organism, and modified broth microdilution was applied for the determination of the fluorescence absorption values to calculate the anti-MRSA activity of BAs. We have initiated four steps to seek the optimal combination of BAs that are (1) determining the anti-MRSA activity of single BA, (2) investigating the two-component combination to clarify the interactions among BAs by checkerboard assay, (3) investigating the multicomponent combination to determine the optimal ratio by quadratic rotation-orthogonal combination design, and (4) in vivo and in vitro validation of the optimal combination. The results showed that the interactions among BAs are related to their concentrations. The synergetic combinations included "berberine and epiberberine," "jatrorrhizine and palmatine" and "jatrorrhizine and coptisine"; the antagonistic combinations included "coptisine and epiberberine". The optimal combination was berberine : coptisine : jatrorrhizine : palmatine : epiberberine = 0.702 : 0.863 : 1 : 0.491 : 0.526, and the potency of the optimal combination on cyclophosphamide immunocompromised mouse model was better than the natural combinations of herbs containing BAs. PMID- 23634171 TI - Antinociceptive and anti-inflammatory effects of orally administrated denatured naja naja atra venom on murine rheumatoid arthritis models. AB - To investigate the antinociceptive and anti-inflammatory activities of the denatured Naja Naja atra venom (NNAV) in rheumatoid arthritis-associated models, the denatured NNAV (heat treated; 30, 90, 270 MU g/kg), the native NNAV (untreated with heat; 90 MU g/kg), and Tripterygium wilfordii polyglycoside (TWP, 15 mg/kg) were administrated orally either prophylactically or therapeutically. We measured time of licking the affected paw in formaldehyde induced inflammatory model, paw volume in egg-white-induced inflammation, and granuloma weight in formalin-soaked filter paper-induced granuloma. For adjuvant induced arthritis (AIA) rats, paw edema, mechanical withdrawal threshold, serum levels of TNF- alpha and IL-10, and histopathological changes of the affected paw were assessed. We found that the denatured NNAV (90, 270 MU g/kg) significantly reduced time of licking paw, paw volume, and granuloma weight in above inflammatory models and also attenuated paw edema, mechanical hyperalgesia, and histopathology changes in AIA rats. Additionally, the increase in serum TNF- alpha and the decrease in serum IL-10 in AIA rats were reversed by the denatured NNAV. Although the native NNAV and TWP rendered the similar pharmacological actions on the above four models with less potency than that of the denatured NNAV, these findings demonstrate that oral administration of the denatured NNAV produces antinociceptive and anti-inflammatory activities on rheumatoid arthritis. PMID- 23634173 TI - The Accumulation of Crocin and Geniposide and Transcripts of Phytoene Synthase during Maturation of Gardenia jasminoides Fruit. AB - Gardenia fruit (fruit of Gardenia jasminoides Ellis) is used as a natural pigment resource and a Chinese traditional medicine. The white mesocarp turning orange or red that occurs during gardenia fruit maturation arises from the production and accumulation of the apocarotenoids, especially crocin-1, which is derived from carotenoid. Meanwhile, the major medical component geniposide is accumulated in gardenia fruit. To further our understanding of the synthetic and accumulation mechanism for crocin-1 and geniposide in gardenia fruit, the contents of crocin-1 and geniposide and the transcripts of phytoene synthase (GjPSY) profiles in gardenia fruits were examined at various stages of maturation. The concentration of crocin-1 and geniposide in gardenia fruit was determined by reversed-phase high-performance liquid chromatography (HPLC). The results showed that the concentration of crocetin-1 was increased during fruit development and the concentration of geniposide does not change significantly during maturing. The expression levels of GjPSY mRNA were examined by RT-PCR. It was revealed that GjPSY was constitutively expressed during fruit development, suggesting that the primary mechanism that controls crocin accumulation in G. jasminoides fruits during development is not correlated to the differential regulation of transcript levels of GjPSY gene. PMID- 23634172 TI - New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics. AB - With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM) therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is "experience driven," the search for a therapeutically useful synthetic drug, like "looking for a needle in a haystack," is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development. PMID- 23634174 TI - Experimental and Clinical Pharmacology of Andrographis paniculata and Its Major Bioactive Phytoconstituent Andrographolide. AB - Andrographis paniculata (Burm. F) Nees, generally known as "king of bitters," is an herbaceous plant in the family Acanthaceae. In China, India, Thailand, and Malaysia, this plant has been widely used for treating sore throat, flu, and upper respiratory tract infections. Andrographolide, a major bioactive chemical constituent of the plant, has shown anticancer potential in various investigations. Andrographolide and its derivatives have anti-inflammatory effects in experimental models asthma, stroke, and arthritis. In recent years, pharmaceutical chemists have synthesized numerous andrographolide derivatives, which exhibit essential pharmacological activities such as those that are anti inflammatory, antibacterial, antitumor, antidiabetic, anti-HIV, antifeedant, and antiviral. However, what is noteworthy about this paper is summarizing the effects of andrographolide against cardiovascular disease, platelet activation, infertility, and NF- kappa B activation. Therefore, this paper is intended to provide evidence reported in relevant literature on qualitative research to assist scientists in isolating and characterizing bioactive compounds. PMID- 23634175 TI - Superficial collagen fibril modulus and pericellular fixed charge density modulate chondrocyte volumetric behaviour in early osteoarthritis. AB - The aim of this study was to investigate if the experimentally detected altered chondrocyte volumetric behavior in early osteoarthritis can be explained by changes in the extracellular and pericellular matrix properties of cartilage. Based on our own experimental tests and the literature, the structural and mechanical parameters for normal and osteoarthritic cartilage were implemented into a multiscale fibril-reinforced poroelastic swelling model. Model simulations were compared with experimentally observed cell volume changes in mechanically loaded cartilage, obtained from anterior cruciate ligament transected rabbit knees. We found that the cell volume increased by 7% in the osteoarthritic cartilage model following mechanical loading of the tissue. In contrast, the cell volume decreased by 4% in normal cartilage model. These findings were consistent with the experimental results. Increased local transversal tissue strain due to the reduced collagen fibril stiffness accompanied with the reduced fixed charge density of the pericellular matrix could increase the cell volume up to 12%. These findings suggest that the increase in the cell volume in mechanically loaded osteoarthritic cartilage is primarily explained by the reduction in the pericellular fixed charge density, while the superficial collagen fibril stiffness is suggested to contribute secondarily to the cell volume behavior. PMID- 23634177 TI - Normality index of ventricular contraction based on a statistical model from FADS. AB - Radionuclide-based imaging is an alternative to evaluate ventricular function and synchrony and may be used as a tool for the identification of patients that could benefit from cardiac resynchronization therapy (CRT). In a previous work, we used Factor Analysis of Dynamic Structures (FADS) to analyze the contribution and spatial distribution of the 3 most significant factors (3-MSF) present in a dynamic series of equilibrium radionuclide angiography images. In this work, a probability density function model of the 3-MSF extracted from FADS for a control group is presented; also an index, based on the likelihood between the control group's contraction model and a sample of normal subjects is proposed. This normality index was compared with those computed for two cardiopathic populations, satisfying the clinical criteria to be considered as candidates for a CRT. The proposed normality index provides a measure, consistent with the phase analysis currently used in clinical environment, sensitive enough to show contraction differences between normal and abnormal groups, which suggests that it can be related to the degree of severity in the ventricular contraction dyssynchrony, and therefore shows promise as a follow-up procedure for patients under CRT. PMID- 23634178 TI - The role of surgical resection in patients with brain metastases. AB - Brain metastasis is a devastating complication of systemic malignancy that affects a considerable number of cancer patients. The appearance of brain metastases is often considered to be a sign of poor prognosis; in patients with brain metastases poor survival time has been reported in the literature. Therefore, treatment of these brain lesions in cancer patients is important for quality of life, providing local tumour control, preventing death from neurological causes, and improving survival, although potentially only in a minority of patients. Surgical resection of brain metastases has been the cornerstone treatment in select patients. Careful patient selection, the use of appropriate surgical techniques, and surgical adjuncts are the major determinants of favourable outcome in patients undergoing resection of brain metastases. In this review, we explain the role of surgical resection in the treatment of patients with brain metastases with consideration of patient selection, surgical techniques and the use of intraoperative adjuncts. PMID- 23634179 TI - Outcome and clinico-biological characteristics of advanced breast cancer patients with surgically resected brain metastases: a multidisciplinary approach. AB - BACKGROUND: Despite improvements in brain surgery and radiotherapy, patients with brain metastases (BM) from breast cancer still have a poor prognosis. The aim of the present study is to evaluate the outcome of a multimodal therapeutic strategy in an unselected cohort of patients. METHODS: We retrospectively reviewed 24 breast cancer patients who developed BM and were treated with brain surgery, radiotherapy, and/or systemic therapy in the same institutions. RESULTS: Primary treatment for BM was surgery in the whole cohort, radiotherapy in 11 patients, radiotherapy combined with systemic therapy in nine patients, and systemic therapy as single treatment in six patients (chemo/targeted therapy n= 4; hormonal therapy n=2). The median time from breast cancer diagnosis to brain surgery was 57.6 months (range 1.8-130.7 months). The overall survival from surgery for BM was 22 months and the overall survival from BM surgery by presence of other metastatic sites at surgery was 25 months for patients with BM only and 11 months for patients with other metastatic sites (p=0.046). CONCLUSION: Although this study is retrospective and limited by the small number of patients, the overall survival of 22 months from the time of brain surgery represents an excellent outcome. The multidisciplinary approach that combines the efforts of specialists from different disciplines leads to satisfactory results for patients in terms of survival in the current clinical practice and prospective subtype oriented trials are urgently required in this category of patients. PMID- 23634176 TI - A review on the computational methods for emotional state estimation from the human EEG. AB - A growing number of affective computing researches recently developed a computer system that can recognize an emotional state of the human user to establish affective human-computer interactions. Various measures have been used to estimate emotional states, including self-report, startle response, behavioral response, autonomic measurement, and neurophysiologic measurement. Among them, inferring emotional states from electroencephalography (EEG) has received considerable attention as EEG could directly reflect emotional states with relatively low costs and simplicity. Yet, EEG-based emotional state estimation requires well-designed computational methods to extract information from complex and noisy multichannel EEG data. In this paper, we review the computational methods that have been developed to deduct EEG indices of emotion, to extract emotion-related features, or to classify EEG signals into one of many emotional states. We also propose using sequential Bayesian inference to estimate the continuous emotional state in real time. We present current challenges for building an EEG-based emotion recognition system and suggest some future directions. PMID- 23634180 TI - Incidence and management of infections in patients with acute leukemia following chemotherapy in general wards. AB - We hypothesise that treating patients with acute leukaemia in general wards, with proper hygienic and sanitary practices, would result in the minimum utilisation of resources as compared with the corresponding patients receiving ICU support. For this study, the acute leukaemia patients on induction chemotherapy were kept in general wards and observed for the incidence of neutropenia, resultant neutropenic febriles, the causative organism, and the effect of empirical antimicrobial treatment protocol on the outcome of such infections. Prophylactic anti-fungal therapy and cotrimoxazole therapy improved the outcome of infections. The therapy of neutropenic fever and infections must be adapted according to the risk factors and should include early empiric antifungal therapy. It was observed that the treatment of such patients in general wards could be managed effectively, with the added advantage of optimum utilisation of resources and in a patient-friendly environment, at a reasonable cost to the patients. PMID- 23634181 TI - Clear cell sarcoma of the kidney misdiagnosed as mesoblastic nephroma: a case report and review of the literature. AB - Clear cell sarcoma of the kidney (CCSK) is a rare renal neoplasm of paediatrics, making up about 3% of all renal tumours in paediatrics, with a high tendency for developing bone metastasis. A seven year-old boy was referred to our clinic with two firm, large masses over the manubrium of the sternum and right frontal area, which pathologically were confirmed as a metastatic CCSK. The patient had a history of a renal mass three years earlier, for which radical nephrectomy had been performed, and histopathologic diagnosis was compatible with mesoblastic nephroma. Thus, no further investigation and therapy had been applied for the patient. CCSK is a rare but malignant and aggressive paediatric renal tumour, with a high tendency for developing distant bone metastases, leading to its poor prognosis. CCSK could be misdiagnosed as several other renal tumours such as mesoblastic nephroma, and thus CCSK should be taken carefully into consideration in the diagnosis of renal tumours. PMID- 23634182 TI - Colonoscopy and colorectal cancer mortality: both sides of the story. PMID- 23634183 TI - Pillcam ESO((r)) is more accurate than clinical scoring systems in risk stratifying emergency room patients with acute upper gastrointestinal bleeding. AB - BACKGROUND: Upper gastrointestinal bleeding (UGIB) accounts for 400,000 hospital admissions in the US each year. Despite advances, mortality rates remain high and are estimated to be 5-10%. Early therapeutic endoscopy is widely recommended as a means of reducing morbidity and mortality. The Rockall and Blatchford scores are clinical scoring systems devised to assist in risk stratifying patients with UGIB. In a prior study we found that rapid live bedside video capsule endoscopy (VCE) utilizing Pillcam ESO((r)) correctly identified patients with high-risk stigmata of bleeding seen on upper endoscopy. In this study, we compare the accuracy of the Rockall and Blatchford scores with Pillcam ESO((r)) in predicting high-risk endoscopic stigmata. METHODS: Pre-endoscopy Blatchford and Rockall scores were calculated for 25 patients (14 males, 11 females) presenting to the emergency room with acute UGIB. The average patient was 66 years of age. A total of 24 out of 25 patients underwent upper endoscopy within 24 hours. One patient did not undergo endoscopy due to clinical instability. The timing of endoscopy was based on clinical parameters in 12 patients, and on live view VCE with Pillcam ESO((r)) in the other 13 patients. Positive VCE was defined as red blood, clot or coffee grounds. Mean Rockall and Blatchford scores for all 24 patients were compared to determine potential differences between high- and low-risk patients. Rockall and Blatchford scores were also compared with VCE findings. RESULTS: Of 24 patients, 13 had high-risk stigmata on upper endoscopy. The mean Rockall and Blatchford scores were 3 and 13, respectively. In the 11 patients without stigmata, the mean Rockall and Blatchford scores were 2 and 11, respectively. There was no statistically significant difference between the Blatchford scores of the two groups (95% confidence interval [CI] -5.1 to 1.3; p = 0.22). There was no statistically significant difference between the Rockall scores of the two groups (95% CI -2.3 to 0.3; p = 0.11). In the subgroup of 12 patients who underwent VCE prior to endoscopy, 8/12 had positive findings, which were all confirmed at endoscopy. All 4 patients with negative VCE had no high risk stigmata at endoscopy. CONCLUSION: In emergency room patients with acute UGIB, neither the Rockall nor the Blatchford scores were able to differentiate high- and low-risk patients identified at endoscopy. Live view VCE, however, was accurate in predicting high-risk endoscopic stigmata, and may be better suited as a risk stratification tool. Additional studies with a larger cohort will be required to validate these findings. PMID- 23634184 TI - Health resource utilization and multidisciplinary impact of endoscopic ultrasonography in a tertiary referral medical center. AB - BACKGROUND: Endoscopic ultrasound (EUS) is a resource-intensive endoscopic procedure, but may result in high downstream health resource utilization and multispecialty impact. Our aim was to examine the downstream impact of EUS by specialty and by indication. METHODS: A retrospective chart review was performed at an academic medical center for patients for whom EUS represented the first point of contact at the study institution within a 20-month period. RESULTS: A total of 552 EUS procedures were reviewed and 208 represented the first point of contact. The most common principle indication involved the pancreas (n = 117, 56%). Downstream health utilization was calculated for an average of 313 days postprocedure (range: 35-632 days). Following unique referral for endoscopic ultrasound, 52% of the patients in the study were retained within the institution for further management and, of these, 34% had a major intervention in the form of surgery or chemoradiotherapy. Compared with other indications, patients presenting with a pancreatic mass were significantly more likely to remain in the study institution for further management (62% versus 39%, p = 0.005), were more likely to have a downstream surgery (29% versus 14%, p = 0.020) and were more likely to have downstream chemo-radiotherapy (11% versus 3%, p = 0.012). CONCLUSIONS: EUS represents a unique portal of entry into tertiary referral medical centers. First point of contact EUS referrals are associated with major downstream health resource utilization and significantly increased utilization for mass lesions of the pancreas. PMID- 23634185 TI - New strategies for the management of diverticular disease: insights for the clinician. AB - Diverticulosis is one of the most common gastrointestinal conditions affecting the general population in the Western world. It is estimated that over 2.5 million people are affected by diverticular disease in the United States. The spectrum of clinical manifestations of diverticulosis ranges from asymptomatic diverticulosis to complicated diverticulitis. Treatment for symptomatic diverticular disease is largely based on symptoms. Traditional therapy includes fiber, bowel rest, antibiotics, pain control and surgery for selected cases. This review discusses recent advances in the medical treatment of diverticular disease such as the use of mesalamine, rifaximin and probiotics as our understanding of the disease evolves. PMID- 23634186 TI - Microbial dysbiosis and colon carcinogenesis: could colon cancer be considered a bacteria-related disease? AB - Colorectal cancer (CRC) is posing an increasingly important burden on the health care system, with western countries seeing a growing incidence of the disease. Except for germline DNA mutations which have been attributed to less than 5% of patients, little is known about the main causes of CRC. However, environment factors such as food, lifestyle and medication are now suspected to have a major influence on inducing cancers. Today, exhaustive quantitative and qualitative evaluation of all environmental factors is not possible. Various environment induced diseases have been characterized based on colon microflora, also called microbiota, analyses. Growing data have shown specific changes in microflora (i.e. dysbiosis) in the stools of patients with colon cancer or those adherent to the colonic mucosa. Thus, it appears that microbiota may be considered a platform offering host and environment interactions for studying CRCs. The hypothesis that colon cancer might be a bacteria-related disease is suggested and perspectives are discussed. PMID- 23634187 TI - Nutritional management of Crohn's disease. AB - Nutritional care and therapy forms an integral part of the management of patients with Crohn's disease (CD). Nutritional deficiencies result from reduced oral intake, malabsorption, medication side effects and systemic inflammation due to active disease. Enteral nutrition has a role in support for the malnourished patient, as well as in primary therapy to induce and maintain remission. The use of parenteral nutrition in CD is mainly limited to the preoperative setting or for patients with intestinal failure, but does not offer any additional advantage over EN in disease control. Dietary modifications, including elimination reintroduction diets and a low fermentable, oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet may improve symptoms but there are currently no data to suggest that these approaches have any role in the induction or maintenance of remission. PMID- 23634188 TI - Recent developments in the treatment of Duchenne muscular dystrophy and spinal muscular atrophy. AB - Pediatric neuromuscular disorders comprise a large variety of disorders that can be classified based on their neuroanatomical localization, patterns of weakness, and laboratory test results. Over the last decade, the field of translational research has been active with many ongoing clinical trials. This is particularly so in two common pediatric neuromuscular disorders: Duchenne muscular dystrophy and spinal muscular atrophy. Although no definitive therapy has yet been found, numerous active areas of research raise the potential for novel therapies in these two disorders, offering hope for improved quality of life and life expectancy for affected individuals. PMID- 23634189 TI - Targeting B cells in the treatment of multiple sclerosis: recent advances and remaining challenges. AB - Recent years have substantially broadened our view on the pathogenesis of multiple sclerosis (MS). While earlier concepts focused predominantly on T lymphocytes as the key cell type to mediate inflammatory damage within central nervous system (CNS) lesions, emerging evidence suggests that B lymphocytes may play a comparably important role both as precursors of antibody-secreting plasma cells and as antigen-presenting cells (APCs) for the activation of T cells. With greater appreciation of this pathogenic B-cell function in MS, B-cell-directed therapies, and in particular B-cell-depleting monoclonal antibodies targeting the CD20 molecule, have gained enormous interest over recent years. Clinical trials demonstrated that anti-CD20 treatment, which depletes immature and mature B cells but spares CD20 negative plasma cells, rapidly reduces formation of new inflammatory CNS lesions. While these findings clearly corroborate a pathogenic contribution of B cells, recent experimental but also clinical findings indicate that not all B cells contribute in an equally pathogenic manner and that certain subsets may in contrast mediate anti-inflammatory effects. In this review, we summarize current findings in support of pathogenic B-cell function in MS, including the encouraging clinical data which derived from anti-CD20 MS trials. Further, we review novel findings suggestive of regulatory properties of B-cell subsets which may be collaterally abolished by pan-CD20 depletion. In conclusion, we aim to provide an outlook on how this currently differentiating concept of pro and anti-inflammatory B-cell function could be harnessed to further improve safety and effectiveness of B-cell-directed therapeutic approaches in MS. PMID- 23634190 TI - Diagnosis and treatment of impulse control disorders in patients with movement disorders. AB - Impulse control disorders are a psychiatric condition characterized by the failure to resist an impulsive act or behavior that may be harmful to self or others. In movement disorders, impulse control disorders are associated with dopaminergic treatment, notably dopamine agonists (DAs). Impulse control disorders have been studied extensively in Parkinson's disease, but are also recognized in restless leg syndrome and atypical Parkinsonian syndromes. Epidemiological studies suggest younger age, male sex, greater novelty seeking, impulsivity, depression and premorbid impulse control disorders as the most consistent risk factors. Such patients may warrant special monitoring after starting treatment with a DA. Various individual screening tools are available for people without Parkinson's disease. The Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease has been developed specifically for Parkinson's disease. The best treatment for impulse control disorders is prevention. However, after the development of impulse control disorders, the mainstay intervention is to reduce or discontinue the offending anti-Parkinsonian medication. In refractory cases, other pharmacological interventions are available, including neuroleptics, antiepileptics, amantadine, antiandrogens, lithium and opioid antagonists. Unfortunately, their use is only supported by case reports, small case series or open-label clinical studies. Prospective, controlled studies are warranted. Ongoing investigations include naltrexone and nicotine. PMID- 23634192 TI - Treatment failure of intrathecal baclofen and supra-additive effect of nabiximols in multiple sclerosis-related spasticity: a case report. AB - Multiple sclerosis (MS)-related spasticity is associated with disability and impairment in quality of life. We report on a patient with secondary progressive MS and spastic tetraparesis (Expanded Disability Status Scale score 8.5). The right arm exhibited flexor spasticity resulting in functional disability despite multimodal symptomatic treatment. Intrathecal baclofen led to side effects despite decreasing efficacy. Low-dose nabiximols improved spasticity and function with recovery of daily-life activities and spasticity-related symptoms. Reduction of intrathecal baclofen ameliorated adverse drug reactions. Add-on cannabinoid therapy was effective in therapy-refractory spasticity with supra-additive effect in combining intrathecal baclofen and nabiximols, hypothetically explained by mutually complementing mechanisms of action. PMID- 23634193 TI - Timing of cigarette smoking as a risk factor for multiple sclerosis. PMID- 23634191 TI - Efficacy and safety of rufinamide in pediatric epilepsy. AB - Rufinamide is a novel anticonvulsant medication approved by the US Food and Drug Administration (FDA) in 2008 for the treatment of seizures associated with Lennox Gastaut syndrome in patients 4 years of age and older, based upon clinical trials demonstrating clinical efficacy and tolerability. Rufinamide is especially effective for tonic-atonic seizures in Lennox-Gastaut syndrome, but is subsequently proving to be safe and effective in clinical practice for a broad patient population with refractory epilepsy. Although further research and clinical experience is needed, rufinamide holds the promise to positively impact the care of children with epilepsy. In this review, we review the use of rufinamide in pediatric epilepsy, with a focus on efficacy and safety. PMID- 23634194 TI - A phase II single-arm study of induction chemotherapy with cisplatin and gemcitabine followed by concurrent cisplatin and gemcitabine with thoracic radiation for unresectable locally advanced non-small cell lung cancer. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy and tolerability of the combination of cisplatin-gemcitabine with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: This was a phase II, multicenter, open-label, single-arm trial in treatment-naive patients with stage IIIA and IIIB LA-NSCLC. After three induction cycles with gemcitabine 1250 mg/m(2) plus cisplatin 80 mg/m(2), two concurrent chemoradiotherapy cycles with gemcitabine 300 mg/m(2), cisplatin 80 mg/m(2), and radiotherapy (63 Gy) were administered. The primary endpoint was response rate after induction chemotherapy followed by concurrent chemoradiotherapy. Secondary endpoints included time to progressive disease (TtPD), overall survival (OS), and safety. RESULTS: Overall, 49 patients (median age 63.4 years; 73.5% male; Karnofsky performance status scores of 80, 85, 90, and 100 [16.3%, 2.0%, 49.0%, and 32.7%, respectively]; disease stage IIIA or IIIB 28.6% and 71.4%, respectively) were enrolled and treated. Response rate was 38.8% (95% confidence interval [CI] 25.2-53.8%). Median TtPD was 11.4 months (95% CI 9.4-12.9). Median OS was 21.8 months (95% CI 17.5-26.0), with 1- and 2-year survival rates of 70.8% and 43.7%, respectively. Overall, six patients discontinued from study treatment due to adverse events (AEs), of which two were serious AEs. The most relevant grade 3/4 AEs were neutropenia and thrombocytopenia in induction chemotherapy and chemoradiotherapy, and grade 3 events related to radiation in acute chemoradiotherapy, e.g. dysphagia, radiation pneumonitis, and radiation esophagitis. CONCLUSIONS: Induction chemotherapy followed by concurrent chemoradiotherapy with gemcitabine (300 mg/m(2)) and cisplatin was associated with acceptable toxicity. The observed median OS time was 21.8 months. Response evaluation was difficult as in many cases it was not possible to differentiate tumor progression from local radiofibrosis. PMID- 23634195 TI - Immunotherapeutic approaches in triple-negative breast cancer: latest research and clinical prospects. AB - Triple-negative breast cancer (TNBC), as defined by the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression, is a challenging disease with the poorest prognosis of all breast cancer subtypes. Importantly, there are currently no known molecular targets for this subgroup of patients. Recent advances in genomics and gene expression profiling have shed new light on the molecule heterogeneity of TNBC. We present an overview of the scientific evidence suggesting that clinical outcome in TNBC is affected by tumor-infiltrating immune cells. We also describe tumor-associated antigens recently identified in TNBC. Finally, we review the current literature on promising immunotherapies for TNBC, including tumor vaccine approaches, immune checkpoint inhibitors, antagonists of immunosuppressive molecules and adoptive cell therapies. It is our contention that selected patients with TNBC with lymphocytic tumor infiltrates at diagnosis may benefit from immune-based therapies and that these immunotherapies will be most beneficial in combination with cytotoxic drugs that potentiate adaptive anti-tumor immunity. PMID- 23634196 TI - Management of patients with vulvar cancer: a perspective review according to tumour stage. AB - Treatment of patients with vulvar cancer is challenging for gynaecologic oncologists. Owing to the localization in a sensitive area, surgical radicality and the indication for adjuvant treatment have to be balanced with psychosocial aspects to treat patients adequately. Clinical management is therefore highly dependent on the tumour stage. For patients with early-stage disease (FIGO I-II) therapy mainly concentrates on surgery with resection of the primary tumour and staging of the groin lymph nodes. In intermediate-stage vulvar cancer (FIGO III), advanced disease is expressed by affected inguinofemoral lymph nodes bringing radical lymphadenectomy and adjuvant therapy as well as radiation or chemoradiation into the focus of treatment. For locally advanced or metastatic vulvar cancer (FIGO IV) neoadjuvant or definitive chemoradiation has to be considered besides surgery. Owing to the low incidence of the disease, the level of evidence for different treatment modalities is poor. This review therefore puts different recommendations of clinical management in context and highlights the need for future trials. PMID- 23634197 TI - Systemic treatment of liver metastases from colorectal cancer. AB - Patients presenting with synchronous or metachronous colorectal cancer liver metastases (CLM) should be evaluated for multimodal management with curative intent. Preoperative systemic chemotherapy shows beneficial impact on adjuvant progression-free survival and also borderline on overall survival, without significantly increasing initially R0 resectable patients postoperative complication rates. Postoperative chemotherapy recommended based on the perioperative trial experience for those patients achieving at least stable disease during preoperative chemotherapy, or based on the adjuvant trials for patients receiving upfront resection. 'Borderline' resectable CLM, preoperative chemotherapy plays an important role in both in achievement of a resectable status and improvement of prognosis. Recent 4 drug combinations demonstrated response rates up to 80% even for advanced disease and are thus promising regimens for further evaluation in patients with resectable or unresectable liver limited (+/- lung) disease. PMID- 23634198 TI - Inhibition of Factor XII-Mediated Activation of Factor XI Provides Protection Against Experimental Acute Ischemic Stroke in Mice. AB - Blood coagulation factor XI (FXI) is an established risk factor for acute ischemic stroke (AIS) and thrombosis, but is also needed for normal hemostasis. Contact factor XII (FXII), an upstream activator of FXI, also contributes to experimental stroke, but is not required for hemostasis. We investigated whether selectively inhibiting FXII-mediated FXI activation, while leaving other FXI and FXII functions intact, could improve the outcome of experimental AIS in mice. Twenty-four hours before induction of AIS by placement of a filament into the internal carotid artery for 60 min, mice were anticoagulated with an antibody directed against the apple 2 domain of FXI. This antibody selectively reduces the prothrombotic activation of FXI by FXIIa but does not affect activated FXI or hemostatic activation of FXI by thrombin, thus leaving hemostasis intact in mice and primates. In this model of AIS/reperfusion injury, mice that received the antibody before AIS displayed less ischemic damage, manifested as reduced cerebral infarction and fibrin deposition (thrombosis), increased cortical reperfusion, and improved neurological behavior. Further, the antibody anticoagulated mice had no detectable hemostasis impairment. Consistent with the neuroprotective phenotype of FXII-deficient mice, our data suggest that a single molecular event, FXII-mediated FXI activation, contributes to the development of experimental AIS. PMID- 23634200 TI - Towards neuronal organoids: a method for long-term culturing of high-density hippocampal neurons. AB - One of the goals in neuroscience is to obtain tractable laboratory cultures that closely recapitulate in vivo systems while still providing ease of use in the lab. Because neurons can exist in the body over a lifetime, long-term culture systems are necessary so as to closely mimic the physiological conditions under laboratory culture conditions. Ideally, such a neuronal organoid culture would contain multiple cell types, be highly differentiated, and have a high density of interconnected cells. However, before these types of cultures can be created, certain problems associated with long-term neuronal culturing must be addressed. We sought to develop a new protocol which may further prolong the duration and integrity of E18 rat hippocampal cultures. We have developed a protocol that allows for culturing of E18 hippocampal neurons at high densities for more than 120 days. These cultured hippocampal neurons are (i) well differentiated with high numbers of synapses, (ii) anchored securely to their substrate, (iii) have high levels of functional connectivity, and (iv) form dense multi-layered cellular networks. We propose that our culture methodology is likely to be effective for multiple neuronal subtypes-particularly those that can be grown in Neurobasal/B27 media. This methodology presents new avenues for long-term functional studies in neurons. PMID- 23634199 TI - Characterization of sex determination and sex differentiation genes in Latimeria. AB - Genes involved in sex determination and differentiation have been identified in mice, humans, chickens, reptiles, amphibians and teleost fishes. However, little is known of their functional conservation, and it is unclear whether there is a common set of genes shared by all vertebrates. Coelacanths, basal Sarcopterygians and unique "living fossils", could help establish an inventory of the ancestral genes involved in these important developmental processes and provide insights into their components. In this study 33 genes from the genome of Latimeria chalumnae and from the liver and testis transcriptomes of Latimeria menadoensis, implicated in sex determination and differentiation, were identified and characterized and their expression levels measured. Interesting findings were obtained for GSDF, previously identified only in teleosts and now characterized for the first time in the sarcopterygian lineage; FGF9, which is not found in teleosts; and DMRT1, whose expression in adult gonads has recently been related to maintenance of sexual identity. The gene repertoire and testis-specific gene expression documented in coelacanths demonstrate a greater similarity to modern fishes and point to unexpected changes in the gene regulatory network governing sexual development. PMID- 23634201 TI - Prevalence of HIV, STIs, and risk behaviors in a cross-sectional community- and clinic-based sample of men who have sex with men (MSM) in Lima, Peru. AB - BACKGROUND: Further research is necessary to understand the factors contributing to the high prevalence of HIV/STIs among men who have sex with men (MSM) in Peru. We compared HIV/STI prevalence and risk factors between two non-probability samples of MSM, one passively enrolled from an STI clinic and the other actively enrolled from community venues surrounding the clinic in Lima, Peru. METHODS: A total of 560 self-identified MSM were enrolled between May-December, 2007. 438 subjects enrolled from a municipal STI clinic and 122 subjects enrolled during community outreach visits. All participants underwent screening for HIV, syphilis, HSV-2, gonorrhoea, and chlamydia and completed a survey assessing their history of HIV/STIs, prior HIV testing, and sexual behavior. RESULTS: HIV prevalence was significantly higher among MSM enrolled from the clinic, with previously undiagnosed HIV identified in 9.1% compared with 2.6% of community participants. 15.4 % of all MSM screened were infected with >= 1 curable STI, 7.4% with early syphilis (RPR >= 1:16) and 5.5% with urethral gonorrhoea and/or chlamydia. No significant differences between populations were reported in prevalence of STIs, number of male sex partners, history of unprotected anal intercourse, or alcohol and/or drug use prior to sex. Exchange of sex for money or goods was reported by 33.5% of MSM enrolled from the clinic and 21.2% of MSM from the community (p = 0.01). CONCLUSIONS: Our data demonstrate that the prevalence of HIV and STIs, including syphilis, gonorrhoea, and chlamydia are extremely high among MSM enrolled from both clinic and community venues in urban Peru. New strategies are needed to address differences in HIV/STI epidemiology between clinic- and community-enrolled samples of MSM. PMID- 23634202 TI - Linkage of presumptive multidrug resistant tuberculosis (MDR-TB) patients to diagnostic and treatment services in Cambodia. AB - SETTING: National Tuberculosis Programme, Cambodia. OBJECTIVE: In a cohort of TB patients, to ascertain the proportion of patients who fulfil the criteria for presumptive MDR-TB, assess whether they underwent investigation for MDR-TB, and the results of the culture and drug susceptibility testing (DST). METHODS: A cross sectional record review of TB patients registered for treatment between July-December 2011. RESULTS: Of 19,236 TB patients registered, 409 (2%) fulfilled the criteria of presumptive MDR-TB; of these, 187 (46%) were examined for culture. This proportion was higher among relapse, failure, return after default (RAD) and non-converters at 3 months of new smear positive TB patients (>60%) as compared to non-converters at 2 months of new TB cases (<20%). Nearly two thirds (n = 113) of the samples were culture positive; of these, three-fourth (n = 85) grew Mycobacterium tuberculosis complex (MTBc) and one-fourth (n = 28) grew non tuberculous Mycobacteria. DST results were available for 96% of the MTBc isolates. Overall, 21 patients were diagnosed as MDR-TB (all diagnosed among retreatment TB cases and none from non-converters) and all of them were initiated on MDR-TB treatment. CONCLUSION: There is a need to strengthen mechanisms for linking patients with presumptive MDR-TB to culture centers. The policy of testing non-converters for culture and DST needs to be reviewed. PMID- 23634203 TI - Increased expression of pregnancy up-regulated non-ubiquitous calmodulin kinase is associated with poor prognosis in clear cell renal cell carcinoma. AB - PURPOSE: The aims of this study were to evaluate the clinical significance and potential prognostic value of pregnancy up-regulated non-ubiquitous calmodulin kinase (PNCK) in clear cell renal cell carcinoma (ccRCC) patients. MATERIALS AND METHODS: The expression of PNCK mRNA was determined in 24 paired samples of ccRCCs and adjacent normal tissues using real-time RT-PCR. The expression of PNCK was determined in 248 samples of ccRCCs and 92 paired samples of adjacent normal tissues by immunohistochemical analysis. Statistical analysis was performed to define the relationship between PNCK expression and the clinical features of ccRCC. RESULTS: The mRNA level of PNCK was significantly higher in tumorous tissues than in the adjacent non-tumorous tissues (p<0.001). An immunohistochemical analysis of 92 paired tissue specimens showed that PNCK expression was higher in tumorous tissues than in the adjacent non-tumorous tissues (p<0.001). Moreover, there was a significant correlation between the PNCK expression and various clinicopathological parameters such as Fuhrman grade (p = 0.011), tumor size (p<0.001), T stage (p<0.001) and N stage (p = 0.015). Patients with higher PNCK expression had shorter overall survival time than those with lower PNCK expression (p<0.001). Multivariate analysis indicated that PNCK expression was an independent predictor for poor survival of ccRCC patients. CONCLUSIONS: To our knowledge, this is the first study that determines the relationship between PNCK and prognosis in ccRCC. We found that increased PNCK expression is associated with poor prognosis in ccRCC. PNCK may represent a novel prognostic marker for ccRCC. PMID- 23634204 TI - Dynamical models explaining social balance and evolution of cooperation. AB - Social networks with positive and negative links often split into two antagonistic factions. Examples of such a split abound: revolutionaries versus an old regime, Republicans versus Democrats, Axis versus Allies during the second world war, or the Western versus the Eastern bloc during the Cold War. Although this structure, known as social balance, is well understood, it is not clear how such factions emerge. An earlier model could explain the formation of such factions if reputations were assumed to be symmetric. We show this is not the case for non-symmetric reputations, and propose an alternative model which (almost) always leads to social balance, thereby explaining the tendency of social networks to split into two factions. In addition, the alternative model may lead to cooperation when faced with defectors, contrary to the earlier model. The difference between the two models may be understood in terms of the underlying gossiping mechanism: whereas the earlier model assumed that an individual adjusts his opinion about somebody by gossiping about that person with everybody in the network, we assume instead that the individual gossips with that person about everybody. It turns out that the alternative model is able to lead to cooperative behaviour, unlike the previous model. PMID- 23634205 TI - The role of serine-type serine repeat antigen in Plasmodium yoelii blood stage development. AB - A key step for the survival of the malaria parasite is the release from and subsequent invasion of erythrocytes by the merozoite. Differences in the efficiency of these two linked processes have a direct impact on overall parasite burden in the host and thereby virulence. A number of parasite proteases have recently been shown to play important roles during both merozoite egress as well as merozoite invasion. The rodent malaria parasite Plasmodium yoelii has been extensively used to investigate the mechanisms of parasite virulence in vivo and a number of important proteins have been identified as being key contributors to pathology. Here we have utilized transcriptional comparisons to identify two protease-like SERAs as playing a potential role in virulence. We show that both SERAs are non-essential for blood stage development of the parasite though they provide a subtle but important growth advantage in vivo. In particular SERA2 appears to be an important factor in enabling the parasite to fully utilize the whole age repertoire of circulating erythrocytes. This work for the first time demonstrates the subtle contributions different protease-like SERAs make to provide the parasite with a maximal capacity to successfully maintain an infection in the host. PMID- 23634206 TI - Risk factors for inadequate TB case finding in Rural Western Kenya: a comparison of actively and passively identified TB patients. AB - BACKGROUND: The findings of a prevalence survey conducted in western Kenya, in a population with 14.9% HIV prevalence suggested inadequate case finding. We found a high burden of infectious and largely undiagnosed pulmonary tuberculosis (PTB), that a quarter of the prevalent cases had not yet sought care, and a low case detection rate. OBJECTIVE AND METHODS: We aimed to identify factors associated with inadequate case finding among adults with PTB in this population by comparing characteristics of 194 PTB patients diagnosed in a health facility after self-report, i.e., through passive case detection, with 88 patients identified through active case detection during the prevalence survey. We examined associations between method of case detection and patient characteristics, including HIV-status, socio-demographic variables and disease severity in univariable and multivariable logistic regression analyses. FINDINGS: HIV-infection was associated with faster passive case detection in univariable analysis (crude OR 3.5, 95% confidence interval (CI) 2.0-5.9), but in multivariable logistic regression this was largely explained by the presence of cough, illness and clinically diagnosed smear-negative TB (adjusted OR (aOR) HIV 1.8, 95% CI 0.85-3.7). Among the HIV-uninfected passive case detection was less successful in older patients aOR 0.76, 95%CI 0.60-0.97 per 10 years increase), and women (aOR 0.27, 95%CI 0.10-0.73). Reported current or past alcohol use reduced passive case detection in both groups (0.42, 95% CI 0.23-0.79). Among smear-positive patients median durations of cough were 4.0 and 6.9 months in HIV infected and uninfected patients, respectively. CONCLUSION: HIV-uninfected patients with infectious TB who were older, female, relatively less ill, or had a cough of a shorter duration were less likely found through passive case detection. In addition to intensified case finding in HIV-infected persons, increasing the suspicion of TB among HIV-uninfected women and the elderly are needed to improve TB case detection in Kenya. PMID- 23634207 TI - Serological evidence of an early seroconversion to Simian virus 40 in healthy children and adolescents. AB - At present Simian virus 40 (SV40) infection in humans appears to be transmitted independently from early contaminated vaccines. In order to test the spread of SV40 infection in children, an immunologic assay employing specific SV40 synthetic peptides corresponding to its viral protein (VP) antigens was employed to estimate the seroprevalence of this polyomavirus in Italian infants and adolescents. Serum samples from 328 children and adolescents, up to 17 years, were investigated. Serum antibodies against SV40 VPs were detected by indirect enzyme-linked immunosorbent assays. The seroprevalence of this polyomavirus was calculated after stratifying the subjects by age. Anti-viral capsid protein 1-2-3 SV40 IgG antibodies were detected in 16% of the study participants. The prevalence of antibodies against SV40 VPs tended to increase with age in children, up to 10 year old (21%). Then, in the cohort of individuals aged 11-17 years, the prevalence decreased (16%). A higher prevalence rate (23%) of SV40 VP antibodies was detected in the cohorts of 1-3 year and 7-10 year old children, than in children and adolescents of the other age groups. This age corresponds to children starting nursery and primary school, respectively, in Italy. IgM antibodies against SV40 VP mimotopes were detected in 6-8 month old children suggesting that SV40 seroconversion can occur early in life. SV40 VP antibodies are present at low prevalence in Italian children (16%), suggesting that SV40 infection, although acquired early in life, probably through different routes, is not widespread. The low SV40 seroprevalence suggests that SV40 is less transmissible than other common polyomaviruses, such as BKV and JCV. Alternatively, our immunologic data could be due to another, as yet undiscovered, human polyomavirus closely related to SV40. PMID- 23634208 TI - A genetic screen using the PiggyBac transposon in haploid cells identifies Parp1 as a mediator of olaparib toxicity. AB - Genetic perturbation screens have the potential to dissect a wide range of cellular phenotypes. Such screens have historically been difficult in diploid mammalian cells. The recent derivation of haploid embryonic stem cells provides an opportunity to cause loss of function mutants with a random mutagen in a mammalian cell with a normal genetic background. We describe an approach to genetic screens that exploits the highly active piggyBac transposon in haploid mammalian cells. As an example of haploid transposon (HTP) screening, we apply this approach to identifying determinants of cancer drug toxicity and resistance. In a screen for 6-thioguanine resistance we recovered components of the DNA mismatch repair pathway, a known requirement for toxicity. In a further screen for resistance to the clinical poly(ADP-ribose) polymerase (PARP) inhibitor olaparib we recovered multiple Parp1 mutants. Our results show that olaparib toxicity to normal cells is mediated predominantly via Parp1, and suggest that the clinical side effects of olaparib may be on target. The transposon mutant libraries are stable and can be readily reused to screen other drugs. The screening protocol described has several advantages over other methods such as RNA interference: it is rapid and low cost, and mutations can be easily reverted to establish causality. PMID- 23634209 TI - Place of preoperative treatment of acromegaly with somatostatin analog on surgical outcome: a systematic review and meta-analysis. AB - CONTEXT: Transsphenoidal neurosurgery is the accepted first-line treatment of acromegaly in the majority of patients. Previous studies addressing preoperative somatostatin analog (SSA) treatment and subsequent surgical cure rates are conflicting, reporting either benefits or no significant differences. OBJECTIVE: The aim of this study, based on a meta-analysis of all published reports, was to investigate whether treatment with SSA before surgery improves the surgical outcome of acromegaly. DATA SOURCES: All studies of preoperative treatment of acromegaly with SSA were systematically reviewed up to December 2011. We searched the Medline, Embase, Cochrane and Google Scholar electronic databases. STUDY SELECTION: The primary endpoint was the biochemical postoperative cure rate. We identified 286 studies, out of which 10 studies (3.49%) fulfilling the eligibility criteria were selected for analysis; five retrospective studies with a control group, two prospective non-randomized trials, and three prospective controlled trials. The meta-analysis was conducted using the random-effects model. DATA EXTRACTION: Data were extracted from published reports by two independent observers. DATA SYNTHESIS: A borderline effect was detected in the analysis of all of the trials with control groups, with a pooled odds ratio (OR) for biochemical cure with SSA treatment of 1.62 (95% CI, 0.93-2.82). In the analysis of the three prospective controlled trials, a statistically significant effect was identified OR: 3.62 (95% CI, 1.88-6.96). CONCLUSIONS: Preoperative treatment with SSA og GH-secreting pituitary adenomas shows a significant improvement on surgical results. This meta-analysis suggests that in centers without optimal results all patients with a GH-secreting pituitary macroadenoma should be treated with a long-acting SSA prior to surgical treatment. PMID- 23634210 TI - Genetic Characterization of Legionella pneumophila Isolated from a Common Watershed in Comunidad Valenciana, Spain. AB - Legionella pneumophila infects humans to produce legionellosis and Pontiac fever only from environmental sources. In order to establish control measures and study the sources of outbreaks it is essential to know extent and distribution of strain variants of this bacterium in the environment. Sporadic and outbreak related cases of legionellosis have been historically frequent in the Comunidad Valenciana region (CV, Spain), with a high prevalence in its Southeastern-most part (BV). Environmental investigations for the detection of Legionella pneumophila are performed in this area routinely. We present a population genetics study of 87 L. pneumophila strains isolated in 13 different localities of the BV area irrigated from the same watershed and compare them to a dataset of 46 strains isolated in different points of the whole CV. Our goal was to compare environmental genetic variation at two different geographic scales, at county and regional levels. Genetic diversity, recombination and population structure were analyzed with Sequence-Based Typing data and three intergenic regions. The results obtained reveal a low, but detectable, level of genetic differentiation between both datasets, mainly, but not only, attributed to the occurrence of unusual variants of the neuA locus present in the BV populations. This differentiation is still detectable when the 10 loci considered are analyzed independently, despite the relatively high incidence of the most common genetic variant in this species, sequence type 1 (ST-1). However, when the genetic data are considered without their associated geographic information, four major groups could be inferred at the genetic level which did not show any correlation with sampling locations. The overall results indicate that the population structure of these environmental samples results from the joint action of a global, widespread ST-1 along with genetic differentiation at shorter geographic distances, which in this case are related to the common watershed for the BV localities. PMID- 23634211 TI - Impact of implementing evidence-based acute stroke interventions on survival: the South London Stroke Register. AB - BACKGROUND: Studies examining the impact of organised acute stroke care interventions on survival in subgroups of stroke patients remain limited. AIMS: This study examined the effects of a range of evidence-based interventions of acute stroke care on one year survival post-stroke and determined the size of the effect across different socio-demographic and clinical subgroups of patients. METHODS: Data on 4026 patients with a first-ever stroke recruited to the population-based South London Stroke Register between 1995 and 2010 were used. In uni-variable analyses, one year cumulative survival rates in socio-demographic groups and by care received was determined. Survival functions were compared using Log-rank tests. Multivariable Cox models were used to test for interactions between components of care and age group, sex, ethnic group, social class, stroke subtype and level of consciousness. RESULTS: 1949 (56.4%) patients were admitted to a stroke unit. Patients managed on a stroke unit, those with deficits receiving specific rehabilitation therapies and those with ischaemic stroke subtype receiving aspirin in the acute phase had better one year survival compared to those who did not receive these interventions. The greatest reduction in the hazards of death among patients treated on a stroke unit were in the youngest patients aged <65 years, (HR 0.39; 95% CI: 0.25-0.62), and those with reduced levels of consciousness, GCS <9, (HR: 0.44; CI: 0.33-0.58). CONCLUSIONS: There was evidence of better one year survival in patients receiving specific acute interventions after stroke with a significantly greater effect in stroke subgroups, suggesting the possibility of re-organising stroke services to ensure that the most appropriate care is made accessible to patients likely to derive the most benefits from such interventions. PMID- 23634212 TI - Prehypertension is not associated with all-cause mortality: a systematic review and meta-analysis of prospective studies. AB - OBJECTIVES: Quantitative associations between prehypertension or its two separate blood pressure (BP) ranges and cardiovascular disease (CVD) or all-cause mortality have not been reliably documented. In this study, we performed a comprehensive systematic review and meta-analysis to assess these relationships from prospective cohort studies. METHODS: We conducted a comprehensive search of PubMed (1966-June 2012) and the Cochrane Library (1988-June 2012) without language restrictions. This was supplemented by review of the references in the included studies and relevant reviews identified in the search. Prospective studies were included if they reported multivariate-adjusted relative risks (RRs) and corresponding 95% confidence intervals (CIs) of CVD or all-cause mortality with respect to prehypertension or its two BP ranges (low range: 120-129/80-84 mmHg; high range: 130-139/85-89 mmHg) at baseline. Pooled RRs were estimated using a random-effects model or a fixed-effects model depending on the between study heterogeneity. RESULTS: Thirteen studies met our inclusion criteria, with 870,678 participants. Prehypertension was not associated with an increased risk of all-cause mortality either in the whole prehypertension group (RR: 1.03; 95% CI: 0.91 to 1.15, P = 0.667) or in its two separate BP ranges (low-range: RR: 0.91; 95% CI: 0.81 to 1.02, P = 0.107; high range: RR: 1.00; 95% CI: 0.95 to 1.06, P = 0.951). Prehypertension was significantly associated with a greater risk of CVD mortality (RR: 1.32; 95% CI: 1.16 to 1.50, P<0.001). When analyzed separately by two BP ranges, only high range prehypertension was related to an increased risk of CVD mortality (low-range: RR: 1.10; 95% CI: 0.92 to 1.30, P = 0.287; high range: RR: 1.26; 95% CI: 1.13 to 1.41, P<0.001). CONCLUSIONS: From the best available prospective data, prehypertension was not associated with all cause mortality. More high quality cohort studies stratified by BP range are needed. PMID- 23634213 TI - Reciprocal complementation of the tumoricidal effects of radiation and natural killer cells. AB - The tumor microenvironment is a key determinant for radio-responsiveness. Immune cells play an important role in shaping tumor microenvironments; however, there is limited understanding of how natural killer (NK) cells can enhance radiation effects. This study aimed to assess the mechanism of reciprocal complementation of radiation and NK cells on tumor killing. Various tumor cell lines were co cultured with human primary NK cells or NK cell line (NK-92) for short periods and then exposed to irradiation. Cell proliferation, apoptosis and transwell assays were performed to assess apoptotic efficacy and cell viability. Western blot analysis and immunoprecipitation methods were used to determine XIAP (X linked inhibitor of apoptosis protein) and Smac (second mitochondria-derived activator of caspase) expression and interaction in tumor cells. Co-culture did not induce apoptosis in tumor cells, but a time- and dose-dependent enhancing effect was found when co-cultured cells were irradiated. A key role for caspase activation via perforin/granzyme B (Grz B) after cell-cell contact was determined, as the primary radiation enhancing effect. The efficacy of NK cell killing was attenuated by upregulation of XIAP to bind caspase-3 in tumor cells to escape apoptosis. Knockdown of XIAP effectively potentiated NK cell-mediated apoptosis. Radiation induced Smac released from mitochondria and neutralized XIAP and therefore increased the NK killing. Our findings suggest NK cells in tumor microenvironment have direct radiosensitization effect through Grz B injection while radiation enhances NK cytotoxicity through triggering Smac release. PMID- 23634214 TI - Associations between dru Types and SCCmec cassettes. AB - Molecular typing is an important tool in the investigation of methicillin resistant Staphylococcus aureus (MRSA) outbreaks and in following the evolution of MRSA. The staphylococcal cassette chromosome mec (SCCmec) contains a hypervariable region with a variable number of 40 bp repeats named direct repeat units (dru). The dru region has been suggested as a supplementary typing method for MRSA and an international nomenclature exists. The purpose of this study was to investigate the diversity and variability of the dru region in a diverse collection of MRSA. We studied 302 MRSA isolates harbouring SCCmec types I to VI. The isolates represented a broad genetic background based on Staphylococcal protein A (spa) typing and multilocus sequence typing (MLST) and included 68 isolates (68 patients) from an outbreak with t024-ST8-IVa and 26 isolates from the same patient. Sequencing identified 53 dru types (dt) in 283 isolates, while eighteen isolates contained no dru repeats and one isolate resisted sequencing. The most common dru type, dt10a, was present in 53% of the sequenced isolates and was found in all SCCmec types, except type II. Seven (10%) of the 68 epidemiologically related patients had isolates with dru type variants indicating that dru typing is not useful as a first line epidemiological typing tool. However, MRSA isolates cultured from a single patient over a three year period exhibited a single dru type. The finding of dt10a in most SCCmec types suggests that dru and mecA originate from the same Staphylococcus species. PMID- 23634215 TI - Effect of alanine replacement of l17 and f19 on the aggregation and neurotoxicity of arctic-type abeta40. AB - Alzheimer's disease is the most common form of neurodegenerative disease. Beta amyloid peptides (Abeta) are responsible for neuronal death both in vitro and in vivo. Previously, L17 and F19 residues were identified as playing key roles in the stabilization of the Abeta40 conformation and in the reduction of its neurotoxicity. In this study, the effects of L17A/F19A mutations on the neurotoxicity of Abeta genetic mutant Arctic-type Abeta40(E22G) were tested. The results showed that compared to Abeta40(E22G), Abeta40(L17A/F19A/E22G) reduced the rate of conformation conversion, aggregation, and cytotoxicity, suggesting that L17 and F19 are critical residues responsible for conformational changes which may trigger the neurotoxic cascade of Abeta. Abeta40(L17A/F19A/E22G) also had decreased damage due to reactive oxygen species. The results are consistent with the discordant helix hypothesis, and confirm that residues 17-25 are in the discordant helix region. Compared to Abeta40(L17A/F19A), reduction in aggregation of Abeta40(L17A/F19A/E22G) was less significantly decreased. This observation provides an explanation based on the discordant helix hypothesis that the mutation of E22 to G22 of Abeta40(E22G) alters the propensity of the discordant helix. Arctic-type Abeta40(E22G) aggregates more severely than wild-type Abeta40, with a consequential increase in toxicity. PMID- 23634216 TI - Water oxidation by a cytochrome p450: mechanism and function of the reaction. AB - P450(cam) (CYP101A1) is a bacterial monooxygenase that is known to catalyze the oxidation of camphor, the first committed step in camphor degradation, with simultaneous reduction of oxygen (O2). We report that P450(cam) catalysis is controlled by oxygen levels: at high O2 concentration, P450(cam) catalyzes the known oxidation reaction, whereas at low O2 concentration the enzyme catalyzes the reduction of camphor to borneol. We confirmed, using (17)O and (2)H NMR, that the hydrogen atom added to camphor comes from water, which is oxidized to hydrogen peroxide (H2O2). This is the first time a cytochrome P450 has been observed to catalyze oxidation of water to H2O2, a difficult reaction to catalyze due to its high barrier. The reduction of camphor and simultaneous oxidation of water are likely catalyzed by the iron-oxo intermediate of P450(cam) , and we present a plausible mechanism that accounts for the 1:1 borneol:H2O2 stoichiometry we observed. This reaction has an adaptive value to bacteria that express this camphor catabolism pathway, which requires O2, for two reasons: 1) the borneol and H2O2 mixture generated is toxic to other bacteria and 2) borneol down-regulates the expression of P450(cam) and its electron transfer partners. Since the reaction described here only occurs under low O2 conditions, the down regulation only occurs when O2 is scarce. PMID- 23634217 TI - Selective selC-independent selenocysteine incorporation into formate dehydrogenases. AB - The formate dehydrogenases (Fdh) Fdh-O, Fdh-N, and Fdh-H, are the only proteins in Escherichia coli that incorporate selenocysteine at a specific position by decoding a UGA codon. However, an excess of selenium can lead to toxicity through misincorporation of selenocysteine into proteins. To determine whether selenocysteine substitutes for cysteine, we grew Escherichia coli in the presence of excess sodium selenite. The respiratory Fdh-N and Fdh-O enzymes, along with nitrate reductase (Nar) were co-purified from wild type strain MC4100 after anaerobic growth with nitrate and either 2 uM or 100 uM selenite. Mass spectrometric analysis of the catalytic subunits of both Fdhs identified the UGA specified selenocysteine residue and revealed incorporation of additional, 'non specific' selenocysteinyl residues, which always replaced particular cysteinyl residues. Although variable, their incorporation was not random and was independent of the selenite concentration used. Notably, these cysteines are likely to be non-essential for catalysis and they do not coordinate the iron sulfur cluster. The remaining cysteinyl residues that could be identified were never substituted by selenocysteine. Selenomethionine was never observed in our analyses. Non-random substitution of particular cysteinyl residues was also noted in the electron-transferring subunit of both Fdhs as well as in the subunits of the Nar enzyme. Nar isolated from an E. coli selC mutant also showed a similar selenocysteine incorporation pattern to the wild-type indicating that non specific selenocysteine incorporation was independent of the specific selenocysteine pathway. Thus, selenide replaces sulfide in the biosynthesis of cysteine and misacylated selenocysteyl-tRNA(Cys) decodes either UGU or UGC codons, which usually specify cysteine. Nevertheless, not every UGU or UGC codon was decoded as selenocysteine. Together, our results suggest that a degree of misincorporation of selenocysteine into enzymes through replacement of particular, non-essential cysteines, is tolerated and this might act as a buffering system to cope with excessive intracellular selenium. PMID- 23634218 TI - Inhibition of nuclear factor-kappa B activation decreases survival of Mycobacterium tuberculosis in human macrophages. AB - Nuclear factor-kappa B (NFkappaB) is a ubiquitous transcription factor that mediates pro-inflammatory responses required for host control of many microbial pathogens; on the other hand, NFkappaB has been implicated in the pathogenesis of other inflammatory and infectious diseases. Mice with genetic disruption of the p50 subunit of NFkappaB are more likely to succumb to Mycobacterium tuberculosis (MTB). However, the role of NFkappaB in host defense in humans is not fully understood. We sought to examine the role of NFkappaB activation in the immune response of human macrophages to MTB. Targeted pharmacologic inhibition of NFkappaB activation using BAY 11-7082 (BAY, an inhibitor of IkappaBalpha kinase) or an adenovirus construct with a dominant-negative IkappaBalpha significantly decreased the number of viable intracellular mycobacteria recovered from THP-1 macrophages four and eight days after infection. The results with BAY were confirmed in primary human monocyte-derived macrophages and alveolar macrophages. NFkappaB inhibition was associated with increased macrophage apoptosis and autophagy, which are well-established killing mechanisms of intracellular MTB. Inhibition of the executioner protease caspase-3 or of the autophagic pathway significantly abrogated the effects of BAY. We conclude that NFkappaB inhibition decreases viability of intracellular MTB in human macrophages via induction of apoptosis and autophagy. PMID- 23634219 TI - Bacterial community profiling of milk samples as a means to understand culture negative bovine clinical mastitis. AB - Inflammation and infection of bovine mammary glands, commonly known as mastitis, imposes significant losses each year in the dairy industry worldwide. While several different bacterial species have been identified as causative agents of mastitis, many clinical mastitis cases remain culture negative, even after enrichment for bacterial growth. To understand the basis for this increasingly common phenomenon, the composition of bacterial communities from milk samples was analyzed using culture independent pyrosequencing of amplicons of 16S ribosomal RNA genes (16S rDNA). Comparisons were made of the microbial community composition of culture negative milk samples from mastitic quarters with that of non-mastitic quarters from the same animals. Genomic DNA from culture-negative clinical and healthy quarter sample pairs was isolated, and amplicon libraries were prepared using indexed primers specific to the V1-V2 region of bacterial 16S rRNA genes and sequenced using the Roche 454 GS FLX with titanium chemistry. Evaluation of the taxonomic composition of these samples revealed significant differences in the microbiota in milk from mastitic and healthy quarters. Statistical analysis identified seven bacterial genera that may be mainly responsible for the observed microbial community differences between mastitic and healthy quarters. Collectively, these results provide evidence that cases of culture negative mastitis can be associated with bacterial species that may be present below culture detection thresholds used here. The application of culture independent bacterial community profiling represents a powerful approach to understand long-standing questions in animal health and disease. PMID- 23634220 TI - The effectiveness of public health interventions to reduce the health impact of climate change: a systematic review of systematic reviews. AB - BACKGROUND: Climate change is likely to be one of the most important threats to public health in the coming years. Yet despite the large number of papers considering the health impact of climate change, few have considered what public health interventions may be of most value in reducing the disease burden. We aimed to evaluate the effectiveness of public health interventions to reduce the disease burden of high priority climate sensitive diseases. METHODS AND FINDINGS: For each disease, we performed a systematic search with no restriction on date or language of publication on Medline, Web of Knowledge, Cochrane CENTRAL and SCOPUS up to December 2010 to identify systematic reviews of public health interventions. We retrieved some 3176 records of which 85 full papers were assessed and 33 included in the review. The included papers investigated the effect of public health interventions on various outcome measures. All interventions were GRADE assessed to determine the strength of evidence. In addition we developed a systematic review quality score. The interventions included environmental interventions to control vectors, chemoprophylaxis, immunization, household and community water treatment, greening cities and community advice. For most reviews, GRADE showed low quality of evidence because of poor study design and high heterogeneity. Also for some key areas such as floods, droughts and other weather extremes, there are no adequate systematic reviews of potential public health interventions. CONCLUSION: In conclusion, we found the evidence base to be mostly weak for environmental interventions that could have the most value in a warmer world. Nevertheless, such interventions should not be dismissed. Future research on public health interventions for climate change adaptation needs to be concerned about quality in study design and should address the gap for floods, droughts and other extreme weather events that pose a risk to health. PMID- 23634221 TI - Cavin1; a regulator of lung function and macrophage phenotype. AB - Caveolae are cell membrane invaginations that are highly abundant in adipose tissue, endothelial cells and the lung. The formation of caveolae is dependent on the expression of various structural proteins that serve as scaffolding for these membrane invaginations. Cavin1 is a newly identified structural protein whose deficiency in mice leads to loss of caveolae formation and to development of a lipodystrophic phenotype. In this study, we sought to investigate the functional role of Cavin1 in the lung. Cavin1 deficient mice possessed dramatically altered distal lung morphology and exhibited significant physiological alterations, notably, increased lung elastance. The changes in distal lung architecture were associated with hypercellularity and the accumulation of lung macrophages. The increases in lung macrophages occurred without changes to circulating numbers of mononuclear cells and without evidence for increased proliferation. However, the increases in lung macrophages were associated with higher levels of macrophage chemotactic factors CXCL2 and CCL2 in BAL fluid from Cavin1-/- mice suggesting a possible mechanism by which these cells accumulate. In addition, lung macrophages from Cavin1-/- mice were larger and displayed measurable differences in gene expression when compared to macrophages from wild-type mice. Interestingly, macrophages were also increased in adipose tissue but not in liver, kidney or skeletal muscle from Cavin1-/- mice, and similar tissue specificity for macrophage accumulation was observed in lungs and adipose tissue from Caveolin1-/ mice. In conclusion, this study demonstrates an important role for Cavin1 in lung homeostasis and suggests that caveolae structural proteins are necessary for regulating macrophage number and phenotype in the lung. PMID- 23634222 TI - Role of activation-induced cytidine deaminase in the development of oral squamous cell carcinoma. AB - PURPOSE: In humans, activation-induced cytidine deaminase (AID) expression results due to inflammation and this deaminase activity is also involved in carcinogenesis. The aim of this study is to investigate the correlation between AID expression and the clinical classification of oral cancer tissues. EXPERIMENTAL DESIGN: The current study investigated the correlation between AID expression and the clinical classification of oral cancer tissues from 27 patients who underwent surgical resection using immunohistochemistry. Specific AID expression and its induction by cytokine stimulation were investigated in cultured HSC oral cancer cell lines by reverse transcriptase PCR. RESULTS: AID expression was detected in 10 of 27 specimens (37.0%). AID expression was more frequently detected in early-stage cancer, especially in early stage T, than in late-stage cancer (T1/T2 vs. T3/4; P = 0.0493, N0 vs. N1/2/3; P = 0.0793). HSC-2, a nonmetastatic oral cancer cell line, abundantly expressed endogenous AID, whereas no such expression was observed in HSC-3, a metastatic oral cancer cell line. Moreover, AID expression was substantially induced in HSC-2 cells by stimulation of an inflammation-related cytokine, TNF-alpha. CONCLUSIONS: Aberrant AID expression in the oral epithelium would contribute to the initiation of oral squamous cell carcinoma. Avoiding persistent AID inducible condition such as frequent cleaning of oral cavity would play an important role for the prevention of developing oral cancer. PMID- 23634223 TI - Role of the human endogenous retrovirus HERV-K18 in autoimmune disease susceptibility: study in the Spanish population and meta-analysis. AB - BACKGROUND: Human endogenous retroviruses (HERVs) are genomic sequences that resulted from ancestral germ-line infections by exogenous retroviruses and therefore are transmitted in a Mendelian fashion. Increased HERV expression and antibodies to HERV antigens have been found in various autoimmune diseases. HERV K18 in chromosome 1 was previously associated with type one diabetes and multiple sclerosis (MS). The etiology of these complex conditions has not been completely elucidated even after the powerful genome wide association studies (GWAS) performed. Nonetheless, this approach does not scrutinize the repetitive sequences within the genome, and part of the missing heritability could lie behind these sequences. We aimed at evaluating the role of HERV-K18 in chromosome 1 on autoimmune disease susceptibility. METHODS: Two HERV-K18 SNPs (97Y/C and 154W/Stop substitutions) conforming three haplotypes were genotyped in Spanish cohorts of multiple sclerosis (n = 942), rheumatoid arthritis (n = 462) and ethnically matched controls (n = 601). Our findings were pooled in a meta analysis including 5312 autoimmune patients and 4032 controls. RESULTS: Significant associations of both HERV-K18 polymorphisms in chromosome 1 with MS patients stratified by HLA-DRB1*15:01 were observed [97Y/C p = 0.02; OR (95% CI) = 1.5 (1.04-2.17) and 154W/Stop: p = 0.001; OR (95% CI) = 1.6 (1.19-2.16)]. Combined meta-analysis of the previously published association studies of HERV K18 with different autoimmune diseases, together with data derived from Spanish cohorts, yielded a significant association of the HERV-K18.3 haplotype [97Y-154W: p(M-H) = 0.0008; OR(M-H) (95% CI) = 1.22 (1.09-1.38)]. CONCLUSION: Association of the HERV-K18.3 haplotype in chromosome 1 with autoimmune-disease susceptibility was confirmed through meta-analysis. PMID- 23634224 TI - Pigmentation and sporulation are alternative cell fates in Bacillus pumilus SF214. AB - Bacillus pumilus SF214 is a spore forming bacterium, isolated from a marine sample, able to produce a matrix and a orange-red, water soluble pigment. Pigmentation is strictly regulated and high pigment production was observed during the late stationary growth phase in a minimal medium and at growth temperatures lower than the optimum. Only a subpopulation of stationary phase cells produced the pigment, indicating that the stationary culture contains a heterogeneous cell population and that pigment synthesis is a bimodal phenomenon. The fraction of cells producing the pigment varied in the different growth conditions and occurred only in cells not devoted to sporulation. Only some of the pigmented cells were also able to produce a matrix. Pigment and matrix production in SF214 appear then as two developmental fates both alternative to sporulation. Since the pigment had an essential role in the cell resistance to oxidative stress conditions, we propose that within the heterogeneous population different survival strategies can be followed by the different cells. PMID- 23634225 TI - Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis. AB - alpha-synuclein dysregulation is a critical aspect of Parkinson's disease pathology. Recent studies have observed that alpha-synuclein aggregates are cytotoxic to cells in culture and that this toxicity can be spread between cells. However, the molecular mechanisms governing this cytotoxicity and spread are poorly characterized. Recent studies of viruses and bacteria, which achieve their cytoplasmic entry by rupturing intracellular vesicles, have utilized the redistribution of galectin proteins as a tool to measure vesicle rupture by these organisms. Using this approach, we demonstrate that alpha-synuclein aggregates can induce the rupture of lysosomes following their endocytosis in neuronal cell lines. This rupture can be induced by the addition of alpha-synuclein aggregates directly into cells as well as by cell-to-cell transfer of alpha-synuclein. We also observe that lysosomal rupture by alpha-synuclein induces a cathepsin B dependent increase in reactive oxygen species (ROS) in target cells. Finally, we observe that alpha-synuclein aggregates can induce inflammasome activation in THP 1 cells. Lysosomal rupture is known to induce mitochondrial dysfunction and inflammation, both of which are well established aspects of Parkinson's disease, thus connecting these aspects of Parkinson's disease to the propagation of alpha synuclein pathology in cells. PMID- 23634226 TI - Associations between genetic polymorphisms in IL-33, IL1R1 and risk for inflammatory bowel disease. AB - BACKGROUND: Recent evidence suggests that the IL-33/IL1RL1 axis plays a critical role in several autoimmune and inflammatory disorders; however, its mechanistic role in inflammatory bowel disease (IBD) has not been clearly defined. We investigated the contribution of IL-33 and IL1RL1 polymorphisms to IBD risk, and possible correlations with phenotype in an Italian cohort of adult and pediatric patients. METHODS: We evaluated the association of six SNPs in IL-33 and IL1RL1 genes, in 805 Crohn's disease (CD), 816 ulcerative colitis (UC), and 752 controls, using Taqman. IL-33 and IL1RL1 mRNA expression was also analyzed. RESULTS: Significant allele and genotype associations with IL-33 rs3939286 were found in CD (P = 0.004; P = 0.035) and UC patients (P = 0.002; P = 0.038). After stratifying the cohort for age at diagnosis, the differences remained significant only in the IBD adult-onset. Significant associations were also obtained in CD patients with two IL1RL1 polymorphisms (rs13015714 and rs2058660, P<0.015). By combining homo- and heterozygous carriers of the rs13015714 risk allele, differences were still significant for both CD adult- and pediatric-onset. Upon genotype-phenotype evaluation, an increased frequency of extensive colitis in adult UC (P = 0.019) and in steroid-responsive pediatric patients (P = 0.024) carrying the IL-33 rs3939286 risk genotype, was observed. mRNA expression of IL 33 and IL1RL1 in inflamed IBD biopsy samples was significantly increased. CONCLUSIONS: Common IL-33 and IL1RL1 polymorphisms contribute to the risk of IBD in an Italian cohort of adult and pediatric patients, with some influence on sub phenotypes. PMID- 23634227 TI - Tzfp represses the androgen receptor in mouse testis. AB - The testis zinc finger protein (Tzfp), also known as Repressor of GATA, belongs to the BTB/POZ zinc finger family of transcription factors and is thought to play a role in spermatogenesis due to its remarkably high expression in testis. Despite many attempts to find the in vivo role of the protein, the molecular function is still largely unknown. Here, we address this issue using a novel mouse model with a disrupted Tzfp gene. Homozygous Tzfp null mice are born at reduced frequency but appear viable and fertile. Sertoli cells in testes lacking Tzfp display an increase in Androgen Receptor (AR) signaling, and several genes in the testis, including Gata1, Aie1 and Fanc, show increased expression. Our results indicate that Tzfp function as a transcriptional regulator and that loss of the protein leads to alterations in AR signaling and reduced number of apoptotic cells in the testicular tubules. PMID- 23634228 TI - Low genetic diversity in wide-spread Eurasian liver fluke Opisthorchis felineus suggests special demographic history of this trematode species. AB - Opisthorchis felineus or Siberian liver fluke is a trematode parasite (Opisthorchiidae) that infects the hepato-biliary system of humans and other mammals. Despite its public health significance, this wide-spread Eurasian species is one of the most poorly studied human liver flukes and nothing is known about its population genetic structure and demographic history. In this paper, we attempt to fill this gap for the first time and to explore the genetic diversity in O. felineus populations from Eastern Europe (Ukraine, European part of Russia), Northern Asia (Siberia) and Central Asia (Northern Kazakhstan). Analysis of marker DNA fragments from O. felineus mitochondrial cytochrome c oxidase subunit 1 and 3 (cox1, cox3) and nuclear rDNA internal transcribed spacer 1 (ITS1) sequences revealed that genetic diversity is very low across the large geographic range of this species. Microevolutionary processes in populations of trematodes may well be influenced by their peculiar biology. Nevertheless, we suggest that lack of population genetics structure observed in O. felineus can be primarily explained by the Pleistocene glacial events and subsequent sudden population growth from a very limited group of founders. Rapid range expansion of O. felineus through Asian and European territories after severe bottleneck points to a high dispersal potential of this trematode species. PMID- 23634229 TI - Genetic polymorphism of the kinesin-like protein KIF1B gene and the risk of hepatocellular carcinoma. AB - BACKGROUND: Frequent deletions of the kinesin-like protein gene 1B (KIF1B) have been reported in neural tumors. Recently, a genome-wide association study revealed an association between polymorphisms in the KIF1B gene and the risk of hepatocellular carcinoma (HCC), and several case-control studies have further investigated this relationship. However, these studies have yielded controversial results. We therefore performed a meta-analysis to derive a more precise estimation of the association between the KIF1B gene polymorphisms and HCC risk. METHODOLOGY/PRINCIPAL FINDING: PubMed, EMBASE, the ISI Web of Science and the CNKI databases were systematically searched to identify relevant studies. A total of 5 studies containing 13 cohorts with 5,773 cases and 6,404 controls were included. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the strength of the associations. Subgroup analyses were conducted based on ethnicities, sample sizes and quality scores. Overall, the G allele at rs17401966 of the KIF1B gene was associated with a significantly decreased risk for HCC (OR = 0.81, 95%CI: 0.70-0.93; P = 0.003). Furthermore, subgroup analyses showed that the G allele at rs17401966 of the KIF1B gene significantly reduced the risk for HCC in Chinese cohorts (OR = 0.76, 95%CI: 0.64 0.90; P = 0.002), large-sample-size cohorts (OR = 0.80, 95%CI: 0.73-0.88, P<0.01) and high-quality cohorts (OR = 0.78, 95%CI: 0.71-0.87, P<0.01). However, no significant associations were found in small-sample-size cohorts, studies with low-quality scores and when excluding the cohorts from the study reporting the original discovery. CONCLUSION/SIGNIFICANCE: These findings demonstrate that the presence of the G allele at rs17401966 of the KIF1B gene may decrease the risk for HCC and suggest that KIF1B may play a critical role in the development of HCC. High-quality studies with larger sample sizes and different ethnic populations will be of great value to further confirm these findings. PMID- 23634230 TI - Inhibition of mitogen-activated protein kinase Erk1/2 promotes protein degradation of ATP binding cassette transporters A1 and G1 in CHO and HuH7 cells. AB - Signal transduction modulates expression and activity of cholesterol transporters. We recently demonstrated that the Ras/mitogen-activated protein kinase (MAPK) signaling cascade regulates protein stability of Scavenger Receptor BI (SR-BI) through Proliferator Activator Receptor (PPARalpha) -dependent degradation pathways. In addition, MAPK (Mek/Erk 1/2) inhibition has been shown to influence liver X receptor (LXR) -inducible ATP Binding Cassette (ABC) transporter ABCA1 expression in macrophages. Here we investigated if Ras/MAPK signaling could alter expression and activity of ABCA1 and ABCG1 in steroidogenic and hepatic cell lines. We demonstrate that in Chinese Hamster Ovary (CHO) cells and human hepatic HuH7 cells, extracellular signal-regulated kinase 1/2 (Erk1/2) inhibition reduces PPARalpha-inducible ABCA1 protein levels, while ectopic expression of constitutively active H-Ras, K-Ras and MAPK/Erk kinase 1 (Mek1) increases ABCA1 protein expression, respectively. Furthermore, Mek1/2 inhibitors reduce ABCG1 protein levels in ABCG1 overexpressing CHO cells (CHO-ABCG1) and human embryonic kidney 293 (HEK293) cells treated with LXR agonist. This correlates with Mek1/2 inhibition reducing ABCG1 cell surface expression and decreasing cholesterol efflux onto High Density Lipoproteins (HDL). Real Time reverse transcriptase polymerase chain reaction (RT-PCR) and protein turnover studies reveal that Mek1/2 inhibitors do not target transcriptional regulation of ABCA1 and ABCG1, but promote ABCA1 and ABCG1 protein degradation in HuH7 and CHO cells, respectively. In line with published data from mouse macrophages, blocking Mek1/2 activity upregulates ABCA1 and ABCG1 protein levels in human THP1 macrophages, indicating opposite roles for the Ras/MAPK pathway in the regulation of ABC transporter activity in macrophages compared to steroidogenic and hepatic cell types. In summary, this study suggests that Ras/MAPK signaling modulates PPARalpha- and LXR-dependent protein degradation pathways in a cell-specific manner to regulate the expression levels of ABCA1 and ABCG1 transporters. PMID- 23634232 TI - Release-recapture studies confirm dispersal of Glossina palpalis gambiensis between river basins in Mali. PMID- 23634231 TI - A novel effect of MARCKS phosphorylation by activated PKC: the dephosphorylation of its serine 25 in chick neuroblasts. AB - MARCKS (Myristoylated Alanine-Rich C Kinase Substrate) is a peripheral membrane protein, especially abundant in the nervous system, and functionally related to actin organization and Ca-calmodulin regulation depending on its phosphorylation by PKC. However, MARCKS is susceptible to be phosphorylated by several different kinases and the possible interactions between these phosphorylations have not been fully studied in intact cells. In differentiating neuroblasts, as well as some neurons, there is at least one cell-type specific phosphorylation site: serine 25 (S25) in the chick. We demonstrate here that S25 is included in a highly conserved protein sequence which is a Cdk phosphorylatable region, located far away from the PKC phosphorylation domain. S25 phosphorylation was inhibited by olomoucine and roscovitine in neuroblasts undergoing various states of cell differentiation in vitro. These results, considered in the known context of Cdks activity in neuroblasts, suggest that Cdk5 is the enzyme responsible for this phosphorylation. We find that the phosphorylation by PKC at the effector domain does not occur in the same molecules that are phosphorylated at serine 25. The in situ analysis of the subcellular distribution of these two phosphorylated MARCKS variants revealed that they are also segregated in different protein clusters. In addition, we find that a sustained stimulation of PKC by phorbol-12-myristate-13 acetate (PMA) provokes the progressive disappearance of phosphorylation at serine 25. Cells treated with PMA, but in the presence of several Ser/Thr phosphatase (PP1, PP2A and PP2B) inhibitors indicated that this dephosphorylation is achieved via a phosphatase 2A (PP2A) form. These results provide new evidence regarding the existence of a novel consequence of PKC stimulation upon the phosphorylated state of MARCKS in neural cells, and propose a link between PKC and PP2A activity on MARCKS. PMID- 23634233 TI - Peripheral blood mononuclear cells of mycetoma patients react differently to Madurella mycetomatis antigens than healthy endemic controls. PMID- 23634234 TI - Uncertainty surrounding projections of the long-term impact of ivermectin treatment on human onchocerciasis. AB - BACKGROUND: Recent studies in Mali, Nigeria, and Senegal have indicated that annual (or biannual) ivermectin distribution may lead to local elimination of human onchocerciasis in certain African foci. Modelling-based projections have been used to estimate the required duration of ivermectin distribution to reach elimination. A crucial assumption has been that microfilarial production by Onchocerca volvulus is reduced irreversibly by 30-35% with each (annual) ivermectin round. However, other modelling-based analyses suggest that ivermectin may not have such a cumulative effect. Uncertainty in this (biological) and other (programmatic) assumptions would affect projected outcomes of long-term ivermectin treatment. METHODOLOGY/PRINCIPAL FINDINGS: We modify a deterministic age- and sex-structured onchocerciasis transmission model, parameterised for savannah O. volvulus-Simulium damnosum, to explore the impact of assumptions regarding the effect of ivermectin on worm fertility and the patterns of treatment coverage compliance, and frequency on projections of parasitological outcomes due to long-term, mass ivermectin administration in hyperendemic areas. The projected impact of ivermectin distribution on onchocerciasis and the benefits of switching from annual to biannual distribution are strongly dependent on assumptions regarding the drug's effect on worm fertility and on treatment compliance. If ivermectin does not have a cumulative impact on microfilarial production, elimination of onchocerciasis in hyperendemic areas may not be feasible with annual ivermectin distribution. CONCLUSIONS/SIGNIFICANCE: There is substantial (biological and programmatic) uncertainty surrounding modelling projections of onchocerciasis elimination. These uncertainties need to be acknowledged for mathematical models to inform control policy reliably. Further research is needed to elucidate the effect of ivermectin on O. volvulus reproductive biology and quantify the patterns of coverage and compliance in treated communities. PMID- 23634235 TI - Gamma-tocotrienol modulated gene expression in senescent human diploid fibroblasts as revealed by microarray analysis. AB - The effect of gamma -tocotrienol, a vitamin E isomer, in modulating gene expression in cellular aging of human diploid fibroblasts was studied. Senescent cells at passage 30 were incubated with 70 MU M of gamma -tocotrienol for 24 h. Gene expression patterns were evaluated using Sentrix HumanRef-8 Expression BeadChip from Illumina, analysed using GeneSpring GX10 software, and validated using quantitative RT-PCR. A total of 100 genes were differentially expressed (P < 0.001) by at least 1.5 fold in response to gamma -tocotrienol treatment. Amongst the genes were IRAK3, SelS, HSPA5, HERPUD1, DNAJB9, SEPR1, C18orf55, ARF4, RINT1, NXT1, CADPS2, COG6, and GLRX5. Significant gene list was further analysed by Gene Set Enrichment Analysis (GSEA), and the Normalized Enrichment Score (NES) showed that biological processes such as inflammation, protein transport, apoptosis, and cell redox homeostasis were modulated in senescent fibroblasts treated with gamma -tocotrienol. These findings revealed that gamma tocotrienol may prevent cellular aging of human diploid fibroblasts by modulating gene expression. PMID- 23634238 TI - Invasive catheterization of the hepatic artery for preclinical investigation of liver-directed therapies in rodent models of liver cancer. AB - PURPOSE: This study demonstrated invasive and reproducible hepatic artery catheterization in rats. A rigorously documented guide and pictorial essay describes the performance of an invasive hepatic artery catheterization technique suitable for the study of liver-targeted interventional procedures in rodent models of liver cancer. The goal was to produce a well-illustrated guide to hepatic artery catheterization under direct visualization via the gastroduodenal artery (GDA). MATERIALS AND METHODS: 20 Sprague Dawley rats were inoculated with McA-RH7777 HCC cells in the left lateral liver lobe. Magnetic resonance imaging (MRI) was used to measure tumor growth. Catheter placement in the hepatic artery proper was performed by entry through the GDA under direct visualization after laparotomy. Digital subtraction angiography confirmed catheter placement in the hepatic artery proper. Antegrade blood flow to the liver was restored after catheter removal. Rats were euthanized after procedures; livers were harvested for hematoxylin and eosin (H&E) staining. RESULTS: 85.0% of inoculated animals developed measurable tumors on MRI; average tumor size was 6.3 +/- 2.3 mm * 4.3 +/- 1.5 mm (mean +/- SD). 94.1% of animals with tumors were successfully catheterized. H&E staining demonstrated tumor growth in all inoculated animals, including those with no measurable tumors on MRI. CONCLUSION: Invasive catheter placement in the hepatic artery of a rodent model of HCC can be performed reproducibly according to the techniques described in this tutorial. These catheterization techniques are ideal for a broad range of preclinical IR studies intending to evaluate the efficacy of intra-arterial therapies for the treatment of primary and metastatic liver tumors. PMID- 23634237 TI - Emergence of ETS transcription factors as diagnostic tools and therapeutic targets in prostate cancer. AB - The discovery of chromosomal translocations in prostate cancer has greatly enhanced our understanding of prostate cancer biology. Genomic rearrangements involving the ETS family of transcription factors are estimated to be present in 50-70% of prostate cancer cases. These rearrangements fuse the ETS factors with promoters of genes that are androgen regulated. Thus, the expression of ETS factors, such as ERG, ETV1, ETV4 and ETV5, is mediated by androgen. In-vitro and in-vivo studies suggest that overexpression of ETS proteins increase cell proliferation and confer an invasive phenotype to prostate cancer cells. Epidemiological studies demonstrate that ETS-fusion positive patients exhibit tumors corresponding to a more advanced disease. The ability of ETS factors to serve as markers for screening and diagnosing prostate cancer patients is being investigated, and the results have been largely positive to date. Additionally, ETS factors present an excellent opportunity as therapeutic targets and several strategies have been devised to directly target ETS proteins or their binding partners and downstream effectors. PMID- 23634236 TI - Mitochondrial mechanisms of neuroglobin's neuroprotection. AB - Neuroglobin (Ngb) is an oxygen-binding globin protein that has been demonstrated to be neuroprotective against stroke and related neurological disorders. However, the underlying mechanisms of Ngb's neuroprotection remain largely undefined. Mitochondria play critical roles in multiple physiological pathways including cell respiration, energy production, free radical generation, and cellular homeostasis and apoptosis. Mitochondrial dysfunction is widely involved in the pathogenesis of stroke and neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's diseases. Accumulating evidence showed that elevated Ngb level is associated with preserved mitochondrial function, suggesting that Ngb may play neuroprotective roles through mitochondria-mediated pathways. In this paper we briefly discuss the mitochondria-related mechanisms in Ngb's neuroprotection, especially those involved in ATP production, ROS generation and scavenging, and mitochondria-mediated cell death signaling pathways. PMID- 23634240 TI - HaloTag as a reporter gene: positron emission tomography imaging with (64)Cu labeled second generation HaloTag ligands. AB - THE GOAL OF THIS STUDY IS TO EMPLOY THE HALOTAG TECHNOLOGY FOR POSITRON EMISSION TOMOGRAPHY (PET), WHICH INVOLVES TWO COMPONENTS: the HaloTag protein (a modified hydrolase which covalently binds to synthetic ligands) and HaloTag ligands (HTLs). 4T1 murine breast cancer cells were stably transfected to express HaloTag protein on the surface (termed as 4T1-HaloTag-ECS, ECS denotes extracellular surface). Two new HTLs were synthesized and termed NOTA-HTL2G-S and NOTA-HTL2G-L (2G indicates second generation, S stands for short, L stands for long, NOTA denotes 1,4,7-triazacyclononane-N,N'N''-triacetic acid). Microscopy studies confirmed surface expression of HaloTag in 4T1-HaloTag-ECS cells, which specifically bind NOTA-HTL2G-S/L. Uptake of (64)Cu-NOTA-HTL2G-L in 4T1-HaloTag ECS tumors (4.3 +/- 0.5, 4.1+/- 0.2, 4.0 +/- 0.2, 2.3 +/- 0.1, and 2.2 +/- 0.1 %ID/g at 0.5, 3, 6, 18, and 24 h post-injection respectively; n = 4) was significantly higher than that in the 4T1 tumors (3.0 +/- 0.3, 3.0+/- 0.1, 3.0 +/ 0.2, 2.0 +/- 0.4, and 2.4 +/- 0.3 %ID/g at 0.5, 3, 6, 18, and 24 h post injection respectively; n = 4) at early time points. In comparison, (64)Cu-NOTA HTL2G-S did not demonstrate significant uptake in either 4T1-HaloTag-ECS or 4T1 tumors. Blocking studies and autoradiography of tumor lysates confirmed that (64)Cu-NOTA-HTL2G-L binds specifically to HaloTag protein in the 4T1-HaloTag-ECS tumors, corroborated by histology. HaloTag protein-specific targeting and PET imaging in vivo with (64)Cu-NOTA-HTL2G-L serves as a proof-of-principle for future non-invasive and sensitive tracking of HaloTag-transfected cells with PET, as well as many other studies of gene/protein/cell function in vivo. PMID- 23634239 TI - TJ0711, a novel vasodilatory beta-blocker, protects SHR rats against hypertension induced renal injury. AB - Previous studies suggested that beta-blockers with adjunctive alpha1-blocking activities warrant renoprotective function other than the therapeutic effect on hypertension. The current report is designed to dissect the role of TJ0711, a novel beta-blocker with a 1:1 ratio for the beta1/alpha1 blocking activities, in renoprotection in SHR rats. It was noted that TJ0711 possesses similar potency for control of blood pressure as that of Carvedilol. However, TJ0711 is much more potent in terms of protecting SHR rats against hypertension induced renal injury. Specifically, SHR rats treated with 20mg/kg/day of TJ0711 manifested significantly lower levels for urine albumin and total protein. In line with these result, TJ0711 treated rats displayed much less severe pathological changes in the kidneys. Mechanistic studies revealed that TJ0711 improves kidney perfusion during the course of hypertensive insult by enhancing eNOS expression through suppressing inflammatory cytokine secretion. TJ0711 also attenuates Vasohibin-1 expression to prevent HIF-1alpha from signal-induced degradation, and by which it promotes HO-1 expression to protect SHR rats against oxidative stress induced by hypertension in the kidneys. Together, our data suggest that TJ0711 possesses higher potency for renoprotection while manifesting the similar effect on hypertension therapy as Carvedilol. PMID- 23634241 TI - The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters. AB - AIM: The present study describes the assessment of true formation of type III collagen in different pathologies using a neo-epitope specific competitive Enzyme linked immunosorbent assay (ELISA) towards the N-terminal propeptide of type III collagen (PRO-C3). METHODS: The monoclonal antibody was raised against the N protease mediated cleavage site of the N-terminal propeptide of type III collagen and a competitive ELISA was developed using the selected antibody. The assay was evaluated in relation to neo-epitope specificity, technical performance, and as a marker for liver fibrosis and muscle mass using the rat carbon tetrachloride (CCl4) model and a study of immobilization induced muscle loss in humans, respectively. RESULTS: The ELISA was neo-epitope specific, technically stable and can be assessed in serum and plasma samples. In the CCl4 liver fibrosis model it was observed that serum PRO-C3 were significantly elevated in rats with liver fibrosis as seen by histology (56% elevated in the highest quartile of total hepatic collagen compared to control rats, p<0.001) and correlated significantly to total hepatic collagen in the diseased rats (r=0.46, p<0.01) and not in control rats, suggesting the pathological origin of the epitope. Human plasma PRO C3 correlated significantly to muscle mass at baseline (R(2)=0.44, p=0.036). CONCLUSION: The developed neo-epitope specific serum ELISA for type III procollagen (PRO-C3) reflects true formation as it is specific for the propeptide cleaved off the intact collagen molecule. In a clinical and in a rodent study we showed that this marker was highly related to liver fibrosis and muscle mass. PMID- 23634242 TI - Erythropoietin facilitates resuscitation from ventricular fibrillation by signaling protection of mitochondrial bioenergetic function in rats. AB - OBJECTIVE: We previously reported beneficial myocardial effects during chest compression after administration of high-dose erythropoietin. We hypothesized that erythropoietin also elicits post-resuscitation myocardial benefits partly linked to protection of mitochondrial bioenergetic function. METHODS: Two series of 10 rats each underwent ventricular fibrillation for 10 minutes (series-1) and 8 minutes (series-2) and were randomized to erythropoietin (5,000 U/kg) or 0.9% NaCl before chest compression. Dobutamine was infused post-resuscitation in series-2 harvesting their hearts at 120 minutes. RESULTS: During chest compression, a statistically insignificant trend showing progressively higher coronary perfusion pressure in the erythropoietin group was observed consistent with previously reported preservation of left ventricular distensibility. Post resuscitation, in the absence of dobutamine (series-1) erythropoietin failed to improve post-resuscitation myocardial function or survival; in the presence of dobutamine (series-2) all rats survived and those treated with erythropoietin reversed post-resuscitation myocardial dysfunction yielding higher cardiac work index (CWI; 39+/-3 vs 25+/-10 mmHg.ml/kg, p<0.01) and higher mean aortic pressure (MAP; 99+/-4 vs 83+/-16, p<0.01) at 120 minutes post-resuscitation. Better myocardial function was associated with lesser increases in plasma cytochrome c, attaining levels which inversely correlated with CWI (p=0.026) and MAP (p=0.025). Hearts from erythropoietin-treated rats had higher phosphorylation levels of cytosolic Akt and higher phosphorylation levels of cytosolic and mitochondrial PKCepsilon and maintained cytochrome c oxidase activity. CONCLUSION: Erythropoietin activated mitochondrial protective mechanisms that helped maintain bioenergetic function enabling reversal of post-resuscitation myocardial dysfunction in the presence of dobutamine. PMID- 23634244 TI - VCAM1 expression correlated with tumorigenesis and poor prognosis in high grade serous ovarian cancer. AB - High expression of vascular cell adhesion molecule 1 (VCAM1) has been shown to be associated with several cancers although its role in ovarian cancer development is largely undefined. The purpose of this study is to investigate its role in ovarian cancer using the epithelial cells and ovarian cancer cell lines and correlate its expression with clinicopathologic parameters in ovarian cancer patients. VCAM1 expression was examined via immunohistochemical staining of 251 high grade serous carcinoma samples using tissue microarray. The expression of VCAM1 was silenced in RAS-transformed ovarian epithelial cell lines and two high grade ovarian cancer cell lines. Cell migration was analyzed in vitro and effect on tumor growth was analyzed in nude mice. High VCAM1 expression was found to be was related with response to surgery and chemotherapy drugs (P = 0.025) and elder age at diagnosis (P = 0.008). Cox regression multivariable analysis showed that VCAM1 expression in tumor cells was an independent prognostic factor. Ovarian cancer cells with VCAM1 overexpression, compared with corresponding control cells, had increased cell migration and enhanced growth of xenograft tumors in mice. Our data provide strong evidence that VCAM1 plays an important role in ovarian tumor growth, and it may be used as a prognostic factor and novel therapeutic target for ovarian cancer. PMID- 23634243 TI - Acute myocardial infarction induced functional cardiomyocytes to re-enter the cell cycle. AB - BACKGROUND: Loss of cardiomyocytes after myocardial infarction (MI) causes heart failure. In this study, we investigate whether the in situ cardiomyocytes can re enter the cell cycle and to what extent cell division of cardiomyocytes occurs after acute MI (AMI) in rats. METHODS: Sprague Dawley (SD) rats were used in this study; the left anterior descending coronary artery was ligated. At time points (3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks) after the operation, five rats were euthanized, respectively. An additional five sham-operated rats serves as a control group and were euthanized at 3 days post-operation. The expressions of cyclin A2, Ki-67, phospho-histone H3 (H3P), and Aurora B in myocardial tissues were detected by Western blot and immunofluorescence. RESULTS: The expression levels of cyclin A2 were significantly higher in all groups with AMI except the 4 week group than those found in the sham-operated group (P < 0.01). The percentage of Ki-67-positive nuclei in the border zones was significantly higher than the percentage in the distant normal myocardium (P < 0.01). CONCLUSIONS: our results demonstrate that cardiomyocytes re-enter the cell cycle after AMI and that cyclin A2 is a reliable marker for the detection of cell cycle activity in cardiomyocytes. PMID- 23634245 TI - Novel insight into the distribution of L-cells in the rat intestinal tract. AB - BACKGROUND: Gut secreted incretin hormones and gastric bypass surgery currently provides some of the most successful treatments for diabetes and obesity respectively. However, despite the evident importance of the gut endocrine system no information exists on the total number and distribution of different types of endocrine cells in the gut. Here we have used the established preclinical Zucker Diabetic Fatty (ZDF) rat model which displays elevated levels of GLP-1 to assess L-cell distribution and L-cell dynamics in the full rostro-caudal extension of the rat intestinal tract. METHODS: Using mathematically unbiased stereology we provide total and regional estimates of gut volume, gut surface area and the total number of L-cells throughout the intestinal tract in obese ZDF rats and lean controls. RESULTS: The total number of L-cells in the lean and obese ZDF gut is estimated to 4.8 and 10.9 million, respectively, coupled with a corresponding near doubling in total gut volume and total surface area. L-cell numbers were found to be distributed rather evenly throughout the jejunum, ileum and colon. CONCLUSION: The present study provides the first stereological report of total L cell number and L-cell distribution throughout the rat intestinal tract. In contrast to the currently held view, the majority of L-cells are actually located proximal to the traditionally defined ileum and colon. PMID- 23634246 TI - AURKA suppression induces DU145 apoptosis and sensitizes DU145 to docetaxel treatment. AB - The palliative therapy effect by docetaxel for CRPC patients makes it urgent to improve the therapy. It was suggested that PI3K and androgen receptor-directed combination therapy may be effective for prostate cancer (PCa) patients PTEN negative. However, for those patients PTEN positive, the mechanism of anti apoptosis survival of cancer cells is not yet well defined. Amplification of AURKA has been detected in 5% of PCa. In this work, Du145, a PTEN positive PCa cell model, was employed to investigate the role of aurora kinase a (AURKA) on cell growth. Inhibition of AURKA expression by shRNA markedly reduced prostate cancer cell viability. Furthermore, we demonstrate that AURKA inhibition induced a remarkable downregulation of AKT activity and Bax induction. Moreover, specific inhibition of the activity of AURKA, but not other aurora family members, by small molecular chemical inhibitors induced significant cell killing effects. Notably, AURKA inhibition sensitized prostate cancer cells to docetaxel treatment. Our work suggests that AURKA-directed monotherapy or combination therapy with docetaxel could be a potent treatment for PCa patients in future. PMID- 23634249 TI - Monographs editor. PMID- 23634247 TI - Elevated Jagged-1 and Notch-1 expression in high grade and metastatic prostate cancers. AB - BACKGROUND: Emerging evidence has suggested that Notch signaling pathway may be involved in the development, progression and metastasis of prostate cancer (PCa). In the present study, we investigated the expression levels of Jagged-1 and Notch 1 in human prostate tumors and their associations with PCa progression and metastasis. METHODS: Immunohistochemistry (IHC) for Jagged-1 and Notch-1 was performed on tissue microarray (TMA) slides containing 286 formalin-fixed and paraffin-embedded (FFPE) tissue specimens with various prostatic pathologies, including benign changes, high grade prostatic intraepithelial neoplasia (HGPIN), low- and high-grade PCas as well as metastatic PCa. RESULTS: Cytoplasmic and membranous IHC scores for Jagged-1 in both metastatic PCa and high grade PCa were significantly higher than those in low grade PCa and in benign prostatic tissues. Similarly, cytoplasmic IHC scores of Notch-1 in both metastatic PCa and high grade PCa were significantly elevated compared with those observed in low grade PCa and in benign prostatic tissues. A statistically significant correlation was identified between the expression of Jagged-1 and Notch-1 in human prostatic tissues. Furthermore, significantly more highly expressed Jagged-1 in membrane was observed in Caucasian patients with high-grade or metastatic PCa (vs. African Americans) and in PCa patients with positive surgical margins (vs. negative surgical margins). CONCLUSION: Our results provide strong evidence that up regulation of Jagged1-Notch1 signaling plays a role in PCa progression and metastasis and suggest that Jagged-1 and Notch-1 may be useful markers in distinguishing indolent and aggressive PCas. PMID- 23634248 TI - Identification of clinical biomarkers for pre-analytical quality control of blood samples. AB - BACKGROUND: Pre-analytical conditions are key factors in maintaining the high quality of biospecimens. They are necessary for accurate reproducibility of experiments in the field of biomarker discovery as well as achieving optimal specificity of laboratory tests for clinical diagnosis. In research at the National Biobank of Korea, we evaluated the impact of pre-analytical conditions on the stability of biobanked blood samples by measuring biochemical analytes commonly used in clinical laboratory tests. METHODS: We measured 10 routine laboratory analytes in serum and plasma samples from healthy donors (n = 50) with a chemistry autoanalyzer (Hitachi 7600-110). The analyte measurements were made at different time courses based on delay of blood fractionation, freezing delay of fractionated serum and plasma samples, and at different cycles (0, 1, 3, 6, 9) of freeze-thawing. Statistically significant changes from the reference sample mean were determined using the repeated-measures ANOVA and the significant change limit (SCL). RESULTS: The serum levels of GGT and LDH were changed significantly depending on both the time interval between blood collection and fractionation and the time interval between fractionation and freezing of serum and plasma samples. The glucose level was most sensitive only to the elapsed time between blood collection and centrifugation for blood fractionation. Based on these findings, a simple formula (glucose decrease by 1.387 mg/dL per hour) was derived to estimate the length of time delay after blood collection. In addition, AST, BUN, GGT, and LDH showed sensitive responses to repeated freeze-thaw cycles of serum and plasma samples. CONCLUSION: These results suggest that GGT and LDH measurements can be used as quality control markers for certain pre-analytical conditions (eg, delayed processing or repeated freeze-thawing) of blood samples which are either directly used in the laboratory tests or stored for future research in the biobank. PMID- 23634250 TI - Mammalian interphase cdks: dispensable master regulators of the cell cycle. AB - Cyclin-dependent kinases (Cdks) drive cell cycle progression in all eukaryotes. Yeasts have a single major Cdk that mediates distinct cell cycle transitions via association with different cyclins. The closest homolog in mammals, Cdk1, drives mitosis. Mammals have additional Cdks-Cdk2, Cdk4, and Cdk6-that represent the major Cdks activated during interphase (iCdks). A large body of evidence has accrued that suggests that activation of iCdks dictates progression though interphase. In apparent contradiction, deficiency in each individual iCdk, respectively, in knockout mice proved to be compatible with live birth and in some instances fertility. Moreover, murine embryos could be derived with Cdk1 as the only functional Cdk. Thus, none of the iCdks is strictly essential for mammalian cell cycle progression, raising the possibility that Cdk1 is the dominant regulator in interphase. However, an absence of iCdks has been accompanied by major shifts in cyclin association to Cdk1, suggesting gain in function. After considerable tweaking, a chemical genetic approach has recently been able to examine the impact of acute inhibition of Cdk2 activity without marked distortion of cyclin/Cdk complex formation. The results suggest that, when expressed at its normal levels, Cdk2 performs essential roles in driving human cells into S phase and maintaining genomic stability. These new findings appear to have restored order to the cell cycle field, bringing it full circle to the view that iCdks indeed play important roles. They also underscore the caveat in knockdown and knockout approaches that protein underexpression can significantly perturb a protein interaction network. We discuss the implications of the new synthesis for future cell cycle studies and anti-Cdk-based therapy of cancer and other diseases. PMID- 23634251 TI - Posttranslational modifications of the retinoblastoma tumor suppressor protein as determinants of function. AB - The retinoblastoma tumor suppressor protein (pRB) plays an integral role in G1-S checkpoint control and consequently is a frequent target for inactivation in cancer. The RB protein can function as an adaptor, nucleating components such as E2Fs and chromatin regulating enzymes into the same complex. For this reason, pRB's regulation by posttranslational modifications is thought to be critical. pRB is phosphorylated by a number of different kinases such as cyclin dependent kinases (Cdks), p38 MAP kinase, Chk1/2, Abl, and Aurora b. Although phosphorylation of pRB by Cdks has been extensively studied, activities regulated through phosphorylation by other kinases are just starting to be understood. As well as being phosphorylated, pRB is acetylated, methylated, ubiquitylated, and SUMOylated. Acetylation, methylation, and SUMOylation play roles in pRB mediated gene silencing. Ubiquitinylation of pRB promotes its degradation and may be used to regulate apoptosis. Recent proteomic data have revealed that pRB is posttranslationally modified to a much greater extent than previously thought. This new information suggests that many unknown pathways affect pRB regulation. This review focuses on posttranslational modifications of pRB and how they influence its function. The final part of the review summarizes new phosphorylation sites from accumulated proteomic data and discusses the possibilities that might arise from this data. PMID- 23634252 TI - Flipping the switch from g1 to s phase with e3 ubiquitin ligases. AB - The cell cycle ensures genome maintenance by coordinating the processes of DNA replication and chromosome segregation. Of particular importance is the irreversible transition from the G1 phase of the cell cycle to S phase. This transition marks the switch from preparing chromosomes for replication ("origin licensing") to active DNA synthesis ("origin firing"). Ubiquitin-mediated proteolysis is essential for restricting DNA replication to only once per cell cycle and is the major mechanism regulating the G1 to S phase transition. Although some changes in protein levels are attributable to regulated mRNA abundance, protein degradation elicits very rapid changes in protein abundance and is critical for the sharp and irreversible transition from one cell cycle stage to the next. Not surprisingly, regulation of the G1-to-S phase transition is perturbed in most cancer cells, and deregulation of key molecular events in G1 and S phase drives not only cell proliferation but also genome instability. In this review we focus on the mechanisms by which E3 ubiquitin ligases control the irreversible transition from G1 to S phase in mammalian cells. PMID- 23634253 TI - Cyclins and cell cycle control in cancer and disease. AB - Cyclin D1 overexpression is found in more than 50% of human breast cancers and causes mammary cancer in transgenic mice. Dysregulation of cyclin D1 gene expression or function contributes to the loss of normal cell cycle control during tumorigenesis. Recent studies have demonstrated that cyclin D1 conducts additional specific functions to regulate gene expression in the context of local chromatin, promote cellular migration, and promote chromosomal instability. It is anticipated that these additional functions contribute to the pathology associated with dysregulated cyclin D1 abundance. This article discusses evidence that examines the functional roles that cyclin D1 may play in cancer with an emphasis on other cyclin family members that also may contribute to cancer and disease in a similar fashion. PMID- 23634254 TI - CDK4: A Key Player in the Cell Cycle, Development, and Cancer. AB - The cell cycle is regulated in part by cyclins and their associated serine/threonine cyclin-dependent kinases, or CDKs. CDK4, in conjunction with the D-type cyclins, mediates progression through the G1 phase when the cell prepares to initiate DNA synthesis. Although CDK4-null mutant mice are viable and cell proliferation is not significantly affected in vitro due to compensatory roles played by other CDKs, this gene plays a key role in mammalian development and cancer. This review discusses the role that CDK4 plays in cell cycle control, normal development, and tumorigenesis as well as how small molecule inhibitors of CDK4 can be used to treat disease. PMID- 23634255 TI - Bridges between Cell Cycle Regulation and Self-Renewal Maintenance. AB - Stem cells are a unique population that lies at the summit of any, or at least most, biological systems. They can differentiate in a variety of mature cell types, but they also have the ability to self-renew, that is, the capacity to divide and retain all the features of the mother cell. The regulation of self renewal has been studied for many years, but several aspects of this regulation are still vague. The combined decision to divide and self-renew or differentiate suggests that the mechanisms that regulate self-renewal and cell cycle activity are intermingled. While inactivation of many cell cycle regulators impacts the physiological and pathological biology of stem cells, the exact mechanisms that link the decision to enter the cell cycle and the choice of the cellular fate are poorly understood. The multiplicity of signals and pathways regulating self renewal add to the complexity of the phenomenon. Here, I will review the described links between the cell cycle and self-renewal and discuss the role of the niche in the regulation of both mechanisms. PMID- 23634258 TI - Deciphering the New Role of the Greatwall/PP2A Pathway in Cell Cycle Control. AB - Mitotic division is induced by protein phosphorylation. For a long time the supported hypothesis was that mitotic entry and exit were the exclusive result of cyclin B-Cdk1 kinase activation and inactivation, whereas the phosphatase activity required to dephosphorylate mitotic substrates was thought to be constant during mitosis. Recent data demonstrate that phosphatase activity must also be tightly regulated to promote correct cell division. Here we describe the new pathway involved in phosphatase regulation and the questions that this discovery raises concerning the classic view of cell cycle regulation. PMID- 23634259 TI - Mitotic Stress and Chromosomal Instability in Cancer: The Case for TPX2. AB - Cell cycle deregulation is a common motif in human cancer, and multiple therapeutic strategies are aimed to prevent tumor cell proliferation. Whereas most current therapies are designed to arrest cell cycle progression either in G1/S or in mitosis, new proposals include targeting the intrinsic chromosomal instability (CIN, an increased rate of gain or losses of chromosomes during cell division) or aneuploidy (a genomic composition that differs from diploid) that many tumor cells display. Why tumors cells are chromosomally unstable or aneuploid and what are the consequences of these alterations are not completely clear at present. Several mitotic regulators are overexpressed as a consequence of oncogenic alterations, and they are likely to alter the proper regulation of chromosome segregation in cancer cells. In this review, we propose the relevance of TPX2, a mitotic regulator involved in the formation of the mitotic spindle, in oncogene-induced mitotic stress. This protein, as well as its partner Aurora-A, is frequently overexpressed in human cancer, and its deregulation may participate not only in chromosome numeric aberrations but also in other forms of genomic instability in cancer cells. PMID- 23634256 TI - Back to the origin: reconsidering replication, transcription, epigenetics, and cell cycle control. AB - In bacteria, replication is a carefully orchestrated event that unfolds the same way for each bacterium and each cell division. The process of DNA replication in bacteria optimizes cell growth and coordinates high levels of simultaneous replication and transcription. In metazoans, the organization of replication is more enigmatic. The lack of a specific sequence that defines origins of replication has, until recently, severely limited our ability to define the organizing principles of DNA replication. This question is of particular importance as emerging data suggest that replication stress is an important contributor to inherited genetic damage and the genomic instability in tumors. We consider here the replication program in several different organisms including recent genome-wide analyses of replication origins in humans. We review recent studies on the role of cytosine methylation in replication origins, the role of transcriptional looping and gene gating in DNA replication, and the role of chromatin's 3-dimensional structure in DNA replication. We use these new findings to consider several questions surrounding DNA replication in metazoans: How are origins selected? What is the relationship between replication and transcription? How do checkpoints inhibit origin firing? Why are there early and late firing origins? We then discuss whether oncogenes promote cancer through a role in DNA replication and whether errors in DNA replication are important contributors to the genomic alterations and gene fusion events observed in cancer. We conclude with some important areas for future experimentation. PMID- 23634257 TI - Decoding ubiquitin for mitosis. AB - Conjugation of ubiquitin (ubiquitination) to substrate proteins is a widespread modification that ensures fidelity of many cellular processes. During mitosis, different dynamic morphological transitions have to be coordinated in a temporal and spatial manner to allow for precise partitioning of the genetic material into two daughter cells, and ubiquitination of key mitotic factors is believed to provide both directionality and fidelity to this process. While directionality can be achieved by a proteolytic type of ubiquitination signal, the fidelity is often determined by various types of ubiquitin conjugation that does not target substrates for proteolysis by the proteasome. An additional level of complexity is provided by various ubiquitin-interacting proteins that act downstream of the ubiquitinated substrate and can serve as "decoders" for the ubiquitin signal. They may, specifically reverse ubiquitin attachment (deubiquitinating enzymes, DUBs) or, act as a receptor for transfer of the ubiquitinated substrate toward downstream signaling components and/or subcellular compartments (ubiquitin binding proteins, UBPs). In this review, we aim at summarizing the knowledge and emerging concepts about the role of ubiquitin decoders, DUBs, and UBPs that contribute to faithful regulation of mitotic division. PMID- 23634260 TI - The CDK Network: Linking Cycles of Cell Division and Gene Expression. AB - Cyclin-dependent kinases (CDKs) play essential roles in cell proliferation and gene expression. Although distinct sets of CDKs work in cell division and transcription by RNA polymerase II (Pol II), they share a CDK-activating kinase (CAK), which is itself a CDK-Cdk7-in metazoans. Thus a unitary CDK network controls and may coordinate cycles of cell division and gene expression. Recent work reveals decisive roles for Cdk7 in both pathways. The CAK function of Cdk7 helps determine timing of activation and cyclin-binding preferences of different CDKs during the cell cycle. In the transcription cycle, Cdk7 is both an effector kinase, which phosphorylates Pol II and other proteins and helps establish promoter-proximal pausing; and a CAK for Cdk9 (P-TEFb), which releases Pol II from the pause. By governing the transition from initiation to elongation, Cdk7, Cdk9 and their substrates influence expression of genes important for developmental and cell-cycle decisions, and ensure co-transcriptional maturation of Pol II transcripts. Cdk7 engaged in transcription also appears to be regulated by phosphorylation within its own activation (T) loop. Here I review recent studies of CDK regulation in cell division and gene expression, and propose a model whereby mitogenic signals trigger a cascade of CDK T-loop phosphorylation that drives cells past the restriction (R) point, when continued cell-cycle progression becomes growth factor-independent. Because R-point control is frequently deregulated in cancer, the CAK-CDK pathway is an attractive target for chemical inhibition aimed at impeding the inappropriate commitment to cell division. PMID- 23634262 TI - Isoflurane Induces Transient Anterograde Amnesia through Suppression of Brain Derived Neurotrophic Factor in Hippocampus. AB - OBJECTIVE: Transient anterograde amnesia is occasionally observed in a number of conditions, including migraine, focal ischemia, venous flow abnormalities, and after general anesthesia. The inhalation anesthetic, isoflurane, is known to induce transient anterograde amnesia. We examined the involvement of brain derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) in the underlying mechanisms of the isoflurane-induced transient anterograde amnesia. METHODS: Adult male Sprague-Dawley rats were divided into three groups : the control group, the 10 minutes after recovery from isoflurane anesthesia group, and the 2 hours after recovery from isoflurane anesthesia group (n=8 in each group). The rats in the isoflurane-exposed groups were anesthetized with 1.2% isoflurane in 75% nitrous oxide and 25% oxygen for 2 hours in a Plexiglas anesthetizing chamber. Short-term memory was determined using the step-down avoidance task. BDNF and TrkB expressions in the hippocampus were evaluated by immunofluorescence staining and western blot analysis. RESULTS: Latency in the step-down avoidance task was decreased 10 minutes after recovery from isoflurane anesthesia, whereas it recovered to the control level 2 hours after isoflurane anesthesia. The expressions of BDNF and TrkB in the hippocampus were decreased immediately after isoflurane anesthesia but were increased 2 hours after isoflurane anesthesia. CONCLUSION: In this study, isoflurane anesthesia induced transient anterograde amnesia, and the expressions of BDNF and TrkB in the hippocampus might be involved in the underlying mechanisms of this transient anterograde amnesia. PMID- 23634263 TI - Clinical and radiologic analysis of posterior apophyseal ring separation associated with lumbar disc herniation. AB - OBJECTIVE: We analyzed the clinical and radiologic features of posterior apophyseal ring separation (PARS) with lumbar disc herniation and suggest the proper management options according to the PARS characteristics. METHODS: We reviewed case series of patients with PARS who underwent surgery of lumbar disc herniation. Preoperative symptoms, neurologic status, Body Mass Index, preoperative and postoperative Visual Analogue Scale (VAS) and Korean-Oswestry Disability Index (K-ODI) scores, operation types were obtained. PARS size, locations, the degree of resection were assessed. RESULTS: PARS was diagnosed in 109 (7.5%) patients among 1448 patients given surgical treatment for single level lumbar disc herniation. There were 55 (50.5%) small PARS and 54 (49.5%) large PARS. Among the large PARS group, 15 (27.8%) had lower endplate PARS of upper vertebra at the level of disc herniation. Thirty-nine (72.2%) were upper endplate PARS of lower vertebra. Among the group with upper endplate PARS of lower vertebra, unresected PARS was diagnosed in 12 (30.8%) cases and resected PARS was diagnosed in 27 (69.2%) cases. VAS and K-ODI scores changes were 3.6+/-2.9 and 5.4+/-6.4 in the unresected PARS group, 5.8+/-2.1 and 11.3+/-7.1 in the resected PARS group. The group with upper endplate PARS of lower vertebra showed significant difference of VAS (p=0.01) and K-ODI (p=0.013) score changes between unresected and resected PARS groups. CONCLUSION: The large PARS of upper endplate in lower vertebra should be removed during the surgery of lumbar disc herniation. High level or bilateral side of PARS should be widely decompressed and arthrodesis procedures are necessary if there is a possibility of secondary instability. PMID- 23634261 TI - PP2A Counterbalances Phosphorylation of pRB and Mitotic Proteins by Multiple CDKs: Potential Implications for PP2A Disruption in Cancer. AB - Protein Phosphatase 2A (PP2A) consists of a collection of heterotrimeric serine/threonine phosphatase holoenzymes that play multiple roles in cell signaling via dephosphorylation of numerous substrates of a large family of serine/threonine kinases. PP2A substrate specificity is mediated by B regulatory subunits of four different families, which selectively recognize diverse substrates by mechanisms that are not well understood. Among the many signaling pathways with critical PP2A functions are several deregulated in cancer cells, and PP2A is a know tumor suppressor. However, the precise composition of the heterotrimeric PP2A complexes with tumor supressor activity is not well understood. This review is centered on the emerging role of the B regulatory subunit B55alpha and related subfamilly members in the modulation of the phosphorylation state of pocket proteins and mitotic CDK substrates, as well as the implications of PP2A function disruption in cancer in the context of these activities. PMID- 23634264 TI - Effect of electromagnetic navigated ventriculoperitoneal shunt placement on failure rates. AB - OBJECTIVE: To evaluate the effect of electromagnetic (EM) navigation system on ventriculoperitoneal (VP) shunt failure rate through comparing the result of standard shunt placement. METHODS: All patients undergoing VP shunt from October 2007 to September 2010 were included in this retrospective study. The first group received shunt surgery using EM navigation. The second group had catheters inserted using manual method with anatomical landmark. The relationship between proximal catheter position and shunt revision rate was evaluated using postoperative computed tomography by a 3-point scale. 1) Grade I; optimal position free-floating in cerebrospinal fluid, 2) Grade II; touching choroid or ventricular wall, 3) Grade III; tip within parenchyma. RESULTS: A total of 72 patients were participated, 27 with EM navigated shunts and 45 with standard shunts. Grade I was found in 25 patients from group 1 and 32 patients from group 2. Only 2 patients without use of navigation belonged to grade III. Proximal obstruction took place 7% in grade I, 15% in grade II and 100% in grade III. Shunt revision occurred in 11% of group 1 and 31% of group 2. Compared in terms of proximal catheter position, there was growing trend of revision rate according to increase of grade on each group. Although infection rate was similar between both groups, the result had no statistical meaning (p=0.905, chi-square test). CONCLUSION: The use of EM navigation in routine shunt surgery can eliminate poor shunt placement resulting in a dramatic reduction in failure rates. PMID- 23634265 TI - Risk factors for developing large emboli following carotid artery stenting. AB - OBJECTIVE: The introduction and development of the embolic protecting device (EPD) has resulted in a decreased rate of stroke after carotid artery stenting (CAS). The authors performed a retrospective study to investigate the risk factors for developing large emboli after CAS which can lead to ischemic events. METHODS: A total of 35 consecutive patients who underwent CAS between January 2009 and March 2012 were included in this study. Patients were divided into two groups including those with small emboli (group A; grade 1, 2) and those with large emboli (group B; grade 3, 4). The size and number of emboli were assigned one of four grades (1=no clots, 2=1 or 2 small clots, 3=more than 3 small clots, 4=large clots) by microscopic observation of the EPD after CAS. We compared demographic characteristics, medical history, and angiographic findings of each group. RESULTS: Thirty-five patients underwent CAS, and technical success was achieved in all cases. Twenty-three patients were included in group A and 12 patients in group B. Our results demonstrated that advanced age [odds ratio (OR) 1.24; 95% confidence interval (CI) 1.01-1.52; p=0.044] and smoking (OR 42.06; CI 2.828-625.65, p=0.006) were independent risk factors for developing large emboli after CAS. CONCLUSION: In patients with carotid artery stenosis treated with CAS, advanced age and smoking increased the number and size of emboli. Although use of an EPD is controversial, it may be useful in CAS in patients with risk factors for large emboli in order to reduce the risk of ischemic events. PMID- 23634266 TI - The usefulness of electromagnetic neuronavigation in the pediatric neuroendoscopic surgery. AB - OBJECTIVE: Neuroendoscopy is applied to various intracranial pathologic conditions. But this technique needs informations for the anatomy, critically. Neuronavigation makes the operation more safe, exact and lesser invasive procedures. But classical neuronavigation systems with rigid pinning fixations were difficult to apply to pediatric populations because of their thin and immature skull. Electromagnetic neuronavigation has used in the very young patients because it does not need rigid pinning fixations. The usefulness of electromagnetic neuronavigation is described through our experiences of neuroendoscopy for pediatric groups and reviews for several literatures. METHODS: Between January 2007 and July 2011, nine pediatric patients were managed with endoscopic surgery using electromagnetic neuronavigation (AxiEM, Medtronics, USA). The patients were 4.0 years of mean age (4 months-12 years) and consisted of 8 boys and 1 girl. Totally, 11 endoscopic procedures were performed. The cases involving surgical outcomes were reviewed. RESULTS: The goal of surgery was achieved successfully at the time of surgery, as confirmed by postoperative imaging. In 2 patients, each patient underwent re-operations due to the aggravation of the previous lesion. And one had transient mild third nerve palsy due to intraoperative manipulation and the others had no surgery related complication. CONCLUSION: By using electromagnetic neuronavigation, neuroendoscopy was found to be a safe and effective technique. In conclusion, electromagnetic neuronavigation is a useful adjunct to neuroendoscopy in very young pediatric patients and an alternative to classical optical neuronavigation. PMID- 23634267 TI - Prevalence of disc degeneration in asymptomatic korean subjects. Part 3 : cervical and lumbar relationship. AB - OBJECTIVE: There are many cases in which degenerative changes are prevalent in both the cervical and lumbar spine, and the relation between both spinal degenerative findings of MRI is controversial. The authors analyzed the prevalence of abnormal findings on MRI, and suggested a model to explain the relationship between cervical and lumbar disc in asymptomatic Korean subjects. METHODS: We performed 3 T MRI sagittal scans on 102 asymptomatic subjects (50 men and 52 women) who visited our hospital between the ages of 14 and 82 years (mean age 46.3 years). Scores pertaining to herniation (HN), annular fissure (AF), and nucleus degeneration (ND) were analyzed. The total scores for the cervical and lumbar spine were analyzed using correlation coefficients and multiple linear regression with various predictive parameters, including weight, height, sex, age, smoking, occupation, and sedentary fashion. RESULTS: The correlation coefficients of HN, AF, and ND were 0.44, 0.50, and 0.59, respectively. We made the best model for relationship by using multiple linear regression. CONCLUSION: The results of the current study showed that there was a close relationship between the cervical score (CS) and lumbar score (LS). In addition, the correlation between CS and LS, as well as the LS value itself, can be altered by other explanatory variables. Although not absolute, there was also a linear relationship between degenerative changes of the cervical and lumbar spine. Based on these results, it can be inferred that degenerative changes of the lumbar spine will be useful in predicting the degree of cervical spine degeneration in an actual clinical setting. PMID- 23634268 TI - Back muscle changes after pedicle based dynamic stabilization. AB - OBJECTIVE: Many studies have investigated paraspinal muscle changes after posterior lumbar surgery, including lumbar fusion. However, no study has been performed to investigate back muscle changes after pedicle based dynamic stabilization in patients with degenerative lumbar spinal diseases. In this study, the authors compared back muscle cross sectional area (MCSA) changes after non-fusion pedicle based dynamic stabilization. METHODS: Thirty-two consecutive patients who underwent non-fusion pedicle based dynamic stabilization (PDS) at the L4-L5 level between February 2005 and January 2008 were included in this retrospective study. In addition, 11 patients who underwent traditional lumbar fusion (LF) during the same period were enrolled for comparative purposes. Preoperative and postoperative MCSAs of the paraspinal (multifidus+longissimus), psoas, and multifidus muscles were measured using computed tomographic axial sections taken at the L4 lower vertebral body level, which best visualize the paraspinal and psoas muscles. Measurements were made preoperatively and at more than 6 months after surgery. RESULTS: Overall, back muscles showed decreases in MCSAs in the PDS and LF groups, and the multifidus was most affected in both groups, but more so in the LF group. The PDS group showed better back muscle preservation than the LF group for all measured muscles. The multifidus MCSA was significantly more preserved when the PDS-paraspinal-Wiltse approach was used. CONCLUSION: Pedicle based dynamic stabilization shows better preservation of paraspinal muscles than posterior lumbar fusion. Furthermore, the minimally invasive paraspinal Wiltse approach was found to preserve multifidus muscles better than the conventional posterior midline approach in PDS group. PMID- 23634269 TI - Urgent intracranial carotid artery decompression after penetrating head injury. AB - We describe a case of intracranial carotid artery occlusion due to penetrating craniofacial injury by high velocity foreign body that was relieved by decompressive surgery. A 46-year-old man presented with a penetrating wound to his face. A piece of an electric angular grinder disc became lodged in the anterior skull base. Computed tomography revealed that the disc had penetrated the unilateral paraclinoid and suprasellar areas without flow of the intracranial carotid artery on the lesion side. The cavernous sinus was also compromised. Removal of the anterior clinoid process reopened the carotid blood flow, and the injection of glue into the cavernous sinus restored complete hemostasis during extraction of the fragment from the face. Digital subtraction angiography revealed complete recanalization of the carotid artery without any evidence of dissection. Accurate diagnosis regarding the extent of the compromised structures and urgent decompressive surgery with adequate hemostasis minimized the severity of penetrating damage in our patient. PMID- 23634270 TI - Fatal septic internal jugular vein-sigmoid sinus thrombosis associated with a malpositioned central venous catheter. AB - Septic internal jugular vein-sigmoid sinus thrombosis (IJV-SST) associated with a malpositioned central venous catheter is a rare condition. It is potentially life threatening and necessitates early diagnosis and rapid administration of appropriate medications. Unfortunately, it is difficult to diagnose due to vague clinical presentations. Several studies such as CT, MRI, and cerebral angiography should be performed and carefully examined to help make the diagnosis. We report a case of septic IJV-SST due to a malpositioned central venous catheter. PMID- 23634271 TI - A Case of Cerebral Aneurysmal Subarachnoid Hemorrhage in Fabry's Disease. AB - We report an unusual case of cerebral aneurysmal subarachnoid hemorrage (SAH) with Fabry's disease. A 42-year-old woman presented with aneurysmal SAH originated from a saccular aneurysm of the right posterior communicating artery. The patient was treated by an endovascular coil embolization of aneurysm. Postoperatively the patient recovered favorably without any neurological deficit. During her admission, the patient had a sign of proteinuria in urine analysis. The pathologic findings of kidney needle biopsy implied nephrosialidosis (mucolipidosis of lysosomal stroage disease), which is consistent with a Fabry's disease. It is uncommon that Fabry's disease is presented with aneurysmal SAH, especially in middle-aged patients, but could be a clinical concern. Further investigations are needed to reveal risk factors, vascular anatomy, and causative mechanisms of Fabry's disease with aneurysmal SAH. PMID- 23634273 TI - Dissecting aneurysm of vertebral artery manifestating as contralateral abducens nerve palsy. AB - Isolated abducens nerve paresis related to ruptured vertebral artery (VA) aneurysm is rare. It usually occurs bilaterally or ipsilaterally to the pathologic lesions. We report the case of a contralateral sixth nerve palsy following ruptured dissecting VA aneurysm. A 38-year-old man was admitted for the evaluation of a 6-day history of headache. Abnormalities were not seen on initial computed tomography (CT). On admission, the patient was alert and no signs reflecting neurologic deficits were noted. Time of flight magnetic resonance angiography revealed a fusiform dilatation of the right VA involving origin of the posterior inferior cerebellar artery. The patient suddenly suffered from severe headache with diplopia the day before the scheduled cerebral angiography. Neurologic examination disclosed nuchal rigidity and isolated left abducens nerve palsy. Emergent CT scan showed high density in the basal and prepontine cistern compatible with ruptured aneurismal hemorrhage. Right vertebral angiography illustrated a right VA dissecting aneurysm with prominent displaced vertebrobasilar artery to inferiorly on left side. Double-stent placement was conducted for the treatment of ruptured dissecting VA aneurysm. No diffusion restriction signals were observed in follow-up magnetic resonance imaging of the brain stem. Eleven weeks later, full recovery of left sixth nerve palsy was documented photographically. In conclusion, isolated contralateral abducens nerve palsy associated with ruptured VA aneurysm may develop due to direct nerve compression by displaced verterobasilar artery triggered by primary thick clot in the prepontine cistern. PMID- 23634272 TI - Malignant peripheral nerve sheath tumor of non-neurofibromatosis type I metastasized to the cerebrospinal axis. AB - A malignant peripheral nerve sheath tumor (MPNST) is a type of sarcoma that arises from peripheral nerves or cells of the associated nerve sheath. This tumor most commonly metastasizes to the lung and metastases to the spinal cord and brain are very rare. We describe a case of young patient with spinal cord and brain metastases resulting from MPNST. An 18-year-old man presented with a 6 month history of low back pain and radiating pain to his anterior thigh. Magnetic resonance imaging showed a paraspinal mass that extended from the central space of L2 to right psoas muscle through the right L2-3 foraminal space. The patient underwent surgery and the result of the histopathologic study was diagnostic for MPNST. Six months after surgery, follow-up images revealed multiple spinal cord and brain metastases. The patient was managed with chemotherapy, but died several months later. Despite complete surgical excision, the MPNST progressed rapidly and aggressively. Thus, patients with MPNST should be followed carefully to identify local recurrence or metastasis as early as possible. PMID- 23634274 TI - Cerebral syphilitic gumma mimicking a brain tumor in the relapse of secondary syphilis in a human immunodeficiency virus-negative patient. AB - Diagnosis of cerebral syphilitic gumma is frequently determined at the time of surgery, because imaging and laboratory findings demonstrate the elusive results. A 59-year-old woman presenting dysarthria showed a mass on her brain computed tomography. She was first suspected of brain tumor, but histological results from surgical resection revealed cerebral gumma due to neurosyphilis. After operation, she presented fever and rash with an infiltration on a chest X-ray. Histological assessment of skin was consistent with syphilis. Fluorescent treponemal antibody absorbed test IgG in cerebrospinal fluid was positive. She was successfully treated with ceftriaxone for 14 days. PMID- 23634275 TI - Spontaneous chronic subdural hematoma in an adolescent girl. AB - In most cases, subdural hematoma (SDH) is regarded as a complication of head injury and nontraumatic causes are rare. Moreover, spontaneous chronic SDH in child or adolescent is very unusual. Here, we present the case of a healthy 14 year-old girl who was diagnosed as a spontaneous chronic SDH. The patient presented with severe headache following blurring of vision two weeks ago without any history of trivial head injury. Computed tomography and magnetic resonance imaging depicted a chronic SDH. The cause of the hematoma was not established. After performing burr hole drainage of the hematoma, the patient made an uneventful recovery. We explore the potential risk factors and pathophysiology implicated in this condition. Possible pathogenic mechanisms of this unique case are discussed and a review of the pertinent literature is included. PMID- 23634276 TI - Increasing trend of low birth weight in rural areas of iran: a warning. PMID- 23634277 TI - Alemtuzumab in multiple sclerosis: latest evidence and clinical prospects. AB - Alemtuzumab was first used in multiple sclerosis in 1991. It is a monoclonal antibody which is directed against CD52, a protein of unknown function on lymphocytes. Alemtuzumab causes a lymphopenia, following which homeostatic reconstitution leads to prolonged alteration of the immune repertoire. This reduces the risk of relapse and disability accumulation in multiple sclerosis; it is the only drug to show superiority over interferon beta-1a in disability outcomes in a monotherapy phase III trial. It should be used with a parallel risk management programme to identify the principal adverse effects of alemtuzumab, especially secondary autoimmunity months or years later, mainly against the thyroid but also immune thrombocytopenia. This review charts the development of alemtuzumab as a drug for multiple sclerosis and summarizes the latest clinical trial data. PMID- 23634278 TI - Exercise training in chronic heart failure. AB - The syndrome of heart failure (HF) is a growing epidemic that causes a significant socio-economic burden. Despite considerable progress in the management of patients with HF, mortality and morbidity remain a major healthcare concern and frequent hospital admissions jeopardize daily life and social activities. Exercise training is an important adjunct nonpharmacological treatment modality for patients with HF that has proven positive effects on mortality, morbidity, exercise capacity and quality of life. Different training modalities are available to target the problems with which HF patients are faced. It is essential to tailor the prescribed exercise regimen, so that both efficiency and safety are guaranteed. Electrical implanted devices and mechanical support should not exclude patients from exercise training; however, particular precautions and a specialized approach are advised. At least 50% of patients with HF, older than 65 years of age, present with HF with preserved ejection fraction (HFPEF). Although the study populations included in studies evaluating the effect of exercise training in this population are small, the results are promising and seem to support the idea that exercise training is beneficial for HFPEF patients. Both the short- and especially long-term adherence to exercise training remain a major challenge that can only be tackled by a multidisciplinary approach. Efforts should be directed towards closing the gap between recommendations and the actual implementation of training programmes. PMID- 23634279 TI - Treatment of autoimmune liver disease: current and future therapeutic options. AB - Autoimmune liver disease spans three predominant processes, from the interface hepatitis of autoimmune hepatitis to the lymphocytic cholangitis of primary biliary cirrhosis, and finally the obstructive fibrosing sclerotic cholangiopathy of primary sclerosing cholangitis. Although all autoimmune in origin, they differ in their epidemiology, presentation and response to immunosuppressive therapy and bile acid based treatments. With an ongoing better appreciation of disease aetiology and pathogenesis, treatment is set ultimately to become more rational. We provide an overview of current and future therapies for patients with autoimmune liver disease, with an emphasis placed on some of the evidence that drives current practice. PMID- 23634281 TI - Novel humanized anti-CD20 antibody BM-ca binds to a unique epitope and exerts stronger cellular activity than others. AB - Cellular activity of BM-ca, a novel humanized anti-CD20 antibody, was quantitatively compared with that of two other anti-CD20 antibodies used for clinical practice, rituximab and ofatumumab. The results of a complement dependent cytotoxicity (CDC) assay revealed that the strongest antibody was ofatumumab, followed by BM-ca, with rituximab being the weakest. Ofatumumab and BM-ca were effective not only against rituximab-sensitive SU-DHL-4 cells but also against rituximab-resistant RC-K8 cells. In an antibody-dependent cell-mediated cytotoxicity (ADCC) assay, although the effective concentrations against SU-DHL-4 cells were almost the same among these three antibodies, the maximum cytotoxic level was the highest for BM-ca. In an anti-cell proliferation assay using SU-DHL 4 cells, BM-ca was the most effective and ofatumumab, the weakest. Against RC-K8 cells, only BM-ca was effective. When combined with each of four cancer chemotherapeutics (prednisolone, vincristine, hydroxydaunorubicin, and cisplatin), BM-ca exerted the most effective combinatorial anti-cell proliferation activity. To assess the in vivo effect of BM-ca, we intravenously administered BM-ca into cynomolgus monkeys and found that the peripheral B-cell levels did not decrease in half of the animals. Sequencing of cDNA encoding CD20 of cynomolgus monkeys revealed that the responders and nonresponders had Leu/Pro (hetero) and Leu/Leu (homo) at amino acid (a.a.) position 160, respectively, suggesting that the epitope recognized by BM-ca was around this a.a. By analyzing reactivity to synthetic peptides, the epitope recognized by BM-ca was estimated to be a.a.'s 156-166, not shared with rituximab and ofatumumab. These results suggest BM-ca to be a promising anti-CD20 antibody having superior properties and recognizing a unique epitope. PMID- 23634280 TI - GM-CSF enhances tumor invasion by elevated MMP-2, -9, and -26 expression. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes tumor progression in different tumor models in an autocrine and paracrine manner. However, at the same time GM-CSF is used in cancer therapies to ameliorate neutropenia. We have previously shown in GM-CSF and G-CSF expressing or negative skin or head and neck squamous cell carcinoma that GM-CSF expression is associated with a highly angiogenic and invasive tumor phenotype. To determine the functional contribution of GM-CSF to tumor invasion, we stably transfected a GM-CSF negative colon adenocarcinoma cell line HT-29 with GM-CSF or treated the same cell line with exogenous GM-CSF. While GM-CSF overexpression and treatment reduced tumor cell proliferation and tumor growth in vitro and in vivo, respectively, it contributed to tumor progression. Together with an enhanced migratory capacity in vitro, we observed a striking increase in tumor cell invasion into the surrounding tissue concomitant with the induction of an activated tumor stroma in GM-CSF overexpressing or GM-CSF treated tumors. In a complex 3D in vitro model, enhanced GM-CSF expression was associated with a discontinued basement membrane deposition that might be mediated by the increased expression and activation of MMP-2, -9, and -26. Treatment with GM-CSF blocking antibodies reversed this effect. The increased presence and activity of these tumor cell derived proteases was confirmed in vivo. Here, expression of MMP-26 protein was predominantly located in pre- and early-invasive areas suggesting MMP 26 expression as an early event in promoting GM-CSF dependent tumor invasion. PMID- 23634282 TI - Slug increases sensitivity to tubulin-binding agents via the downregulation of betaIII and betaIVa-tubulin in lung cancer cells. AB - Transcription factor Slug/SNAI2 (snail homolog 2) plays a key role in the induction of the epithelial mesenchymal transition in cancer cells; however, whether the overexpression of Slug mediates the malignant phenotype and alters drug sensitivity in lung cancer cells remains largely unclear. We investigated Slug focusing on its biological function and involvement in drug sensitivity in lung cancer cells. Stable Slug transfectants showed typical morphological changes compared with control cells. Slug overexpression did not change the cellular proliferations; however, migration activity and anchorage-independent growth activity with an antiapoptotic effect were increased. Interestingly, stable Slug overexpression increased drug sensitivity to tubulin-binding agents including vinorelbine, vincristine, and paclitaxel (5.8- to 8.9-fold increase) in several lung cancer cell lines but did not increase sensitivity to agents other than tubulin-binding agents. Real-time RT-PCR (polymerase chain reaction) and western blotting revealed that Slug overexpression downregulated the expression of betaIII and betaIVa-tubulin, which is considered to be a major factor determining sensitivity to tubulin-binding agents. A luciferase reporter assay confirmed that Slug suppressed the promoter activity of betaIVa-tubulin at a transcriptional level. Slug overexpression enhanced tumor growth, whereas Slug overexpression increased drug sensitivity to vinorelbine with the downregulation of betaIII and betaIV-tubulin in vivo. Immunohistochemistry of Slug with clinical lung cancer samples showed that Slug overexpression tended to be involved in response to tubulin-binding agents. In conclusion, our data indicate that Slug mediates an aggressive phenotype including enhanced migration activity, anoikis suppression, and tumor growth, but increases sensitivity to tubulin-binding agents via the downregulation of betaIII and betaIVa-tubulin in lung cancer cells. PMID- 23634283 TI - Characterization of the melanoma brain metastatic niche in mice and humans. AB - Brain metastases occur in 15% of patients with melanoma and are associated with a dismal prognosis. Here, we investigate the architectural phenotype and stromal reaction of melanoma brain metastasis in mice and humans. A syngeneic, green fluorescence protein (GFP)-expressing murine B16-F1 melanoma clone was introduced via intracardiac injection, and was examined in vivo in comparison with human specimens. Immunofluorescence analyses of the brain metastases revealed that F4/80(+) macrophages/microglia were most abundant at the tumor front, but rare in its core, where they were found only around blood vessels (P = 0.01). Similar pattern of infiltration was found in CD3(+) T cells (P < 0.01). Infiltrating T cells were prominently CD4(+) compared with CD8(+) T cells (P < 0.001). Blood vessels (CD31(+)) were less abundant at the tumor front than in its center (12 +/ 1 vs. 4 +/- 0.6 vessels per high-power field [HPF], P < 0.001). In contrast, there were few vessels at the tumor front, but their diameter was significantly larger at the front (8236 MUm(2) vs. 4617 MUm(2) average cross-sectional area, P < 0.005). This is the first comparative analysis of melanoma brain metastases showing similar stromal reaction in murine models and human specimens. Our results validate the utility of this murine model of melanoma brain metastases for investigating the mechanism of the human disease. PMID- 23634285 TI - Assessment of diagnosis of inflammatory breast cancer cases at two cancer centers in Egypt and Tunisia. AB - The diagnosis of inflammatory breast cancer (IBC) is largely clinical and therefore inherently somewhat subjective. The objective of this study was to evaluate the diagnosis of IBC at two centers in North Africa where a higher proportion of breast cancer is diagnosed as IBC than in the United States (U.S.). Physicians prospectively enrolled suspected IBC cases at the National Cancer Institute (NCI) - Cairo, Egypt, and the Institut Salah Azaiz (ISA), Tunisia, recorded extent and duration of signs/symptoms of IBC on standardized forms, and took digital photographs of the breast. After second-level review at study hospitals, photographs and clinical information for confirmed IBC cases were reviewed by two U.S. oncologists. We calculated percent agreement between study hospital and U.S. oncologist diagnoses. Among cases confirmed by at least one U.S. oncologist, we calculated median extent and duration of signs and Spearman correlations. At least one U.S. oncologist confirmed the IBC diagnosis for 69% (39/50) of cases with photographs at the NCI-Cairo and 88% (21/24) of cases at the ISA. All confirmed cases had at least one sign of IBC (erythema, edema, peau d'orange) that covered at least one-third of the breast. The median duration of signs ranged from 1 to 3 months; extent and duration of signs were not statistically significantly correlated. From the above-mentioned outcomes, it can be concluded that the diagnosis of a substantial proportion of IBC cases is unambiguous, but a subset is difficult to distinguish from other types of locally advanced breast cancer. Among confirmed cases, the extent of signs was not related to delay in diagnosis. PMID- 23634284 TI - Complexity in cancer biology: is systems biology the answer? AB - Complex phenotypes emerge from the interactions of thousands of macromolecules that are organized in multimolecular complexes and interacting functional modules. In turn, modules form functional networks in health and disease. Omics approaches collect data on changes for all genes and proteins and statistical analysis attempts to uncover the functional modules that perform the functions that characterize higher levels of biological organization. Systems biology attempts to transcend the study of individual genes/proteins and to integrate them into higher order information. Cancer cells exhibit defective genetic and epigenetic networks formed by altered complexes and network modules arising in different parts of tumor tissues that sustain autonomous cell behavior which ultimately lead tumor growth. We suggest that an understanding of tumor behavior must address not only molecular but also, and more importantly, tumor cell heterogeneity, by considering cancer tissue genetic and epigenetic networks, by characterizing changes in the types, composition, and interactions of complexes and networks in the different parts of tumor tissues, and by identifying critical hubs that connect them in time and space. PMID- 23634286 TI - Phase II trial of upfront bevacizumab and temozolomide for unresectable or multifocal glioblastoma. AB - Patients with unresectable glioblastomas have a poor prognosis, with median survival of 6-10 months. We conducted a phase II trial of upfront 5-day temozolomide (TMZ) and bevacizumab (BV) in patients with newly diagnosed unresectable or multifocal glioblastoma. Patients received up to four cycles of TMZ at 200 mg/m(2) on days 1-5, and BV at 10 mg/kg on days 1 and 15 of a 28-day cycle. Brain magnetic resonance imaging (MRI) was performed monthly. Therapy was continued as long as there was no tumor progression, grade 4 nonhematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary end point was best tumor response as measured on MRI. Forty-one patients were accrued over 12 months; 39 had a full set of MRI scans available for evaluation. Assessment for best radiographic responses was as follows: partial responses in 24.4%, stable disease in 68.3%, and progressive disease in 2.4%. Treatment-related toxicities included seven grade 4 toxicities and one grade 5 toxicity (myocardial infarction). From this study, it was concluded that an upfront regimen of TMZ and BV for unresectable glioblastoma was well tolerated and provided a significant level of disease stabilization. Therapeutic toxicities were consistent with those seen in the adjuvant setting using these agents. The upfront approach to treatment of glioblastoma in the unresectable population warrants further investigation in randomized controlled phase III trials. PMID- 23634287 TI - Expression of adrenomedullin in human colorectal tumors and its role in cell growth and invasion in vitro and in xenograft growth in vivo. AB - Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). In this study, real-time quantitative reverse transcription demonstrated a significant expression of AM mRNA in tumor samples from colorectal cancer (CRC) patients in clinical stage II, III, and IV when compared with normal colorectal tissue. AM, CLR, RAMP2, and RAMP3 proteins were immunohistochemically localized in the carcinomatous epithelial compartment of CRC tissue. Tissue microarray analysis revealed a clear increase of AM, CLR, RAMP2, and RAMP3 staining in lymph node and distant metastasis when compared with primary tumors. The human colon carcinoma cells HT-29 expressed and secreted AM into the culture medium with a significant increase under hypoxia. Treatment of HT-29 cells with synthetic AM stimulated cell proliferation and invasion in vitro. Incubation with anti-AM antibody (alphaAM), anti-AM receptors antibodies (alphaAMR), or AM antagonist AM22-52 inhibited significantly basal levels of proliferation of HT-29 cells, suggesting that AM may function as an autocrine growth factor for CRC cells. Treatment with alphaAM significantly suppressed the growth of HT-29 tumor xenografts in vivo. Histological examination of alphaAM treated tumors showed evidence of disruption of tumor vascularity with decreased microvessel density, depletion of endothelial cells and pericytes, and increased tumor cell apoptosis. These findings highlight the potential importance of AM and its receptors in the progression of CRC and support the conclusion that alphaAM treatment inhibits tumor growth by suppression of angiogenesis and tumor growth, suggesting that AM may be a useful therapeutic target. PMID- 23634288 TI - Ultradeep sequencing detects GNAQ and GNA11 mutations in cell-free DNA from plasma of patients with uveal melanoma. AB - Elevated levels of cell-free DNA (cfDNA) are frequently observed in tumor patients. Activating mutations in exon 4 (R183) and exon 5 (Q209) of GNAQ and GNA 11 are almost exclusively found in uveal melanoma, thus providing a highly specific marker for the presence of circulating tumor DNA (ctDNA). To establish a reliable, noninvasive assay that might allow early detection and monitoring of metastatic disease, we determined the proportion of GNAQ or GNA 11 mutant reads in cfDNA of uveal melanoma patients by ultradeep sequencing. Cell-free DNA from 28 uveal melanoma patients with metastases or extraocular growth was isolated and quantified by real-time polymerase chain reaction (PCR) (7-1550 ng DNA/mL plasma). GNAQ and GNA 11 regions of interest were amplified in 22 of 28 patients and ultradeep sequencing of amplicons was performed to detect even low proportions of mutant reads. We detected Q209 mutations (2-38% mutant reads) in either GNAQ or GNA 11 in the plasma of 9 of 22 metastasized patients. No correlation between the proportion of mutant reads and the concentration of cfDNA could be detected. Among the nine ctDNA-positive patients, four had metastases in bone, whereas no metastases were detected in the 13 ctDNA-negative patients at this location (P = 0.025). Furthermore, ctDNA-positive patients tended to be younger at initial diagnosis and show larger metastases. The results show that ultradeep amplicon sequencing can be used to detect tumor DNA in plasma of metastasized uveal melanoma patients. It remains to be shown if this approach can be used for early detection of disseminated tumor disease. PMID- 23634289 TI - Evaluation of 5-year imatinib treatment of 458 patients with CP-CML in routine clinical practice and prognostic impact of different BCR-ABL cutoff levels. AB - We evaluated responses to the treatment and long-term outcomes of chronic myeloid leukemia patients treated with imatinib as first-line treatment in routine clinical setting from two countries with centralized tyrosine kinase inhibitors (TKIs) treatment. We assessed prognostic significance of European LeukemiaNet (ELN) 2006- and 2009-defined responses and the prognostic value of molecular responses at defined time points on 5-year survivals. Among the cumulative rates of incidence of hematologic, cytogenetic, and molecular responses and all important survival parameters, we evaluated the prognostic significance of different BCR-ABL transcript-level ratios (<=1%; >1%-<=10%; >10%) at 3, 6, 12, and 18 months (n = 199). The ELN optimal response criteria and their predictive role were significantly beneficial for event-free survival at all given time points. We found significant improvement in survivals of patients with BCR-ABL lower than 10% in the 6th and 12th months. Significantly better outcome was found in patients who achieved major molecular response (MMR) in the 12th month. The cumulative incidences of complete cytogenetic response (CCyR) and MMR were significantly associated with the molecular response in the 3rd month. The ELN response criteria and their predictive role were helpful at given time points; however, the 2009 definition did not significantly alter the prognostic accuracy compared with that of the 2006 definition. The significant value was observed for cytogenetic responses at the 6th and 12th month. Moreover, progression-free and event-free survivals were improved with MMR at the 12th month. PMID- 23634290 TI - Discordance in HER2 gene amplification in circulating and disseminated tumor cells in patients with operable breast cancer. AB - Human epidermal growth factor receptor 2 (HER2) gene amplification in circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) might be useful for modifying Herceptin therapy in breast cancer. In the process of investigating the utility of a microfluidic platform for detecting HER2 gene amplification in these cells, we observed novel results on discordance of HER2 status. Peripheral blood (8.5 mL) and bone marrow (BM) (7.5-10 mL) were collected prospectively from patients with clinical stages I-IV breast cancer. Mononuclear cells were recovered, stained with cytokeratin (CK), CD45, and DAPI, and processed through microfluidic channels for fluorescence in situ hybridization (FISH). A ratio of HER2:CEP17 >2 in any CK+/CD45 or CK-/CD45 cell was regarded as positive for HER2 gene amplification. Peripheral blood from 95 patients and BM from 78 patients were studied. We found CK+/CD45-/DAPI+ CTCs in 27.3% of patients. We evaluated HER2 gene amplification by FISH in 88 blood and 78 BM specimens and found HER2+ CTCs in 1 of 9 (11.1%) and HER2+ DTCs (27.2%) in 3 of 11 patients with HER2+ primary tumor. Among patients with a HER2- primary tumor, 5 of 79 had HER2+ CTCs (6.3%) and 14 of 67 had HER2+ DTCs (20.8%). The overall rate of discordance in HER2 status was 15% between primary tumor and CTCs and 28.2% between primary tumor and DTCs. HER2 was amplified in CTCs and DTCs in a portion of both HER2+ and HER2- primary tumors. HER2 discordance was more frequent for DTCs. The clinical implications of evaluating HER2 status in CTCs and DTCs in breast cancer needs to be established in prospective clinical trials. The cell enrichment and extraction microfluidic technology provides a sensitive platform for evaluation of HER2 gene amplification in CTCs and DTCs. PMID- 23634292 TI - Is there a role for immune checkpoint blockade with ipilimumab in prostate cancer? AB - Treatment for advanced prostate cancer has and will continue to grow increasingly complex, owing to the introduction of multiple new therapeutic approaches with the potential to substantially improve outcomes for this disease. Agents that modulate the patient's immune system to fight prostate cancer - immunotherapeutics - are among the most exciting of these new approaches. The addition of antigen-specific immunotherapy to the treatment of castration resistant prostate cancer (CRPC) has paved the way for additional research that seeks to augment the activity of the immune system itself. The monoclonal antibody ipilimumab, approved in over 40 countries to treat advanced melanoma and currently under phase 2 and 3 investigation in prostate cancer, is thought to act by augmenting immune responses to tumors through blockade of cytotoxic T lymphocyte antigen 4, an inhibitory immune checkpoint molecule. Ipilimumab has been studied in seven phase 1 and 2 clinical trials that evaluated various doses, schedules, and combinations across the spectrum of patients with advanced prostate cancer. The CRPC studies of ipilimumab to date suggest that the agent is active in prostate cancer as monotherapy or in combination with radiotherapy, docetaxel, or other immunotherapeutics, and that the adverse event profile is as expected given the safety data in advanced melanoma. The ongoing phase 3 program will further characterize the risk/benefit profile of ipilimumab in chemotherapy naive and -pretreated CRPC. PMID- 23634295 TI - Review of the bat flies of honduras, central america (Diptera: streblidae). AB - Streblid bat flies are obligate and host-specific blood-feeding ectoparasites of bats. While the bat flies of some American countries are well studied (e.g., Panama, Venezuela), little is known about Honduran Streblidae. Accumulation of substantial numbers of specimens, from several different collections, has enabled a relatively thorough treatment of the fauna. This study is based on 2,236 specimens representing 17 genera and 43 species of Streblidae. Of those presently reported, 11 genera and 32 species are new records for Honduras, increasing the number of known genera and species by 65% and 74%, respectively. Collection and host data are listed for all known Honduran streblid bat fly species. Comments regarding host associations and specificity, geographic distribution, and taxonomic problems are given in the species accounts. PMID- 23634291 TI - Correlation of angiogenic biomarker signatures with clinical outcomes in metastatic colorectal cancer patients receiving capecitabine, oxaliplatin, and bevacizumab. AB - A novel combination of capecitabine, oxaliplatin, and bevacizumab was evaluated in colorectal cancer patients enrolled in a phase II clinical trial. In this retrospective analysis, plasma samples from patients receiving capecitabine, oxaliplatin, and bevacizumab were analyzed to investigate biomarkers of clinical benefit. Forty-one protein biomarkers were tested in 38 patients at baseline and after two cycles of drug administration. Correlations among analytes were evaluated by Spearman analysis. Analyte levels at baseline and changes on treatment were correlated with progression-free survival (PFS) and overall survival (OS) by univariate analysis. Multivariate analyses were determined using the Cox proportional hazard model. Time to event analyses were evaluated by Kaplan-Meier analysis and compared by log-rank test. Baseline levels of vWF and Ang-2 significantly correlated with PFS, while levels of VCAM-1, vWF, TSP-2, IL 8, MMP-2, and Ang-2 correlated with OS (P < 0.05). The fold change of IGF-1 levels from baseline to the end of cycle 2 was correlated with PFS, while fold changes of Ang-2, TSP-2, and TGF-beta2 correlated with OS. A baseline signature of Ang-2, IGFBP-3, IL-6, and VCAM-1 identified a low-risk and high-risk group of patients (OS: 33.9 months vs. 18.1 months, respectively, P = 0.016). For treatment-related changes, a signature consisting of Ang-2, E-Cadherin, IL-6, MCP 1, OPN, and TGF-beta1 was able to stratify patients into high- and low-risk groups (PFS: 7.7 months vs. 15.5 months, P = 0.004). Multiplex analysis of patient plasma in this trial identified several baseline- and treatment-related biomarkers associated with clinical outcome. These findings merit further exploration in larger, controlled clinical trials. PMID- 23634293 TI - Identification of potential biomarkers from microarray experiments using multiple criteria optimization. AB - Microarray experiments are capable of determining the relative expression of tens of thousands of genes simultaneously, thus resulting in very large databases. The analysis of these databases and the extraction of biologically relevant knowledge from them are challenging tasks. The identification of potential cancer biomarker genes is one of the most important aims for microarray analysis and, as such, has been widely targeted in the literature. However, identifying a set of these genes consistently across different experiments, researches, microarray platforms, or cancer types is still an elusive endeavor. Besides the inherent difficulty of the large and nonconstant variability in these experiments and the incommensurability between different microarray technologies, there is the issue of the users having to adjust a series of parameters that significantly affect the outcome of the analyses and that do not have a biological or medical meaning. In this study, the identification of potential cancer biomarkers from microarray data is casted as a multiple criteria optimization (MCO) problem. The efficient solutions to this problem, found here through data envelopment analysis (DEA), are associated to genes that are proposed as potential cancer biomarkers. The method does not require any parameter adjustment by the user, and thus fosters repeatability. The approach also allows the analysis of different microarray experiments, microarray platforms, and cancer types simultaneously. The results include the analysis of three publicly available microarray databases related to cervix cancer. This study points to the feasibility of modeling the selection of potential cancer biomarkers from microarray data as an MCO problem and solve it using DEA. Using MCO entails a new optic to the identification of potential cancer biomarkers as it does not require the definition of a threshold value to establish significance for a particular gene and the selection of a normalization procedure to compare different experiments is no longer necessary. PMID- 23634296 TI - Body image dissatisfaction is increased in male and overweight/obese adolescents in Botswana. AB - INTRODUCTION: The purpose of this study was to examine linkages between obesity, physical activity, and body image dissatisfaction, with consideration of socioeconomic status (SES) and urbanization in adolescents in Botswana. MATERIALS AND METHODS: A nationally representative, cross-sectional survey in 707 secondary school students included measured height and weight to determine overweight (OW) or obesity (OB) using World Health Organization standards; physical activity (PA) using the International Physical Activity Questionnaire; and body image satisfaction using the Body Ideals Questionnaire. SES was described by private school versus public school attendance. RESULTS AND DISCUSSION: OW/OB students felt farther from ideal and greater dissatisfaction with their weight and body proportions than optimal weight students. Boys felt greater difference from ideal and more dissatisfaction with muscle tone, chest size, and strength than girls. Lower SES students and those from rural villages had more minutes of PA than higher SES or urban students. In this rapidly developing African country, these trends reflect the nutrition transition and offer opportunity to motivate OW/OB students and boys for PA as a health promotion obesity prevention behavior. CONCLUSIONS: As urbanization and improved SES are desirable and likely to continue, the public health system will be challenged to prevent obesity while preserving a healthy body image. PMID- 23634298 TI - Depression in the spousally bereaved elderly: correlations with subjective sleep measures. AB - Complaints of poor sleep and symptoms of depression are likely to coexist in the spousally bereaved elderly. This study was concerned with the correlation between depressive symptoms and various measures of subjectively reported sleep using questionnaire and diary instruments in 38 bereaved seniors (60y+). Correlations between the sleep measures and days since loss and grief intensity were also calculated. All sleep disruption measures correlated significantly with depression score, but only sleep duration correlated with grief intensity, and no sleep measure correlated with days since loss. Therapies which address both sleep and depression are likely to be of benefit to bereaved seniors. PMID- 23634297 TI - Predictors of metabolic syndrome in the Iranian population: waist circumference, body mass index, or waist to hip ratio? AB - This study aimed to investigate whether body mass index (BMI), waist circumference (WC), or waist to hip ratio (WHR) could be a better predictor of metabolic syndrome and, if so, what would be the cutoff points for these surrogates to appropriately differentiate metabolic syndrome in different age and sex subgroups. Methods. The present cross-sectional study was conducted on a sample of Isfahan Cohort Study (ICS). In total, 468 individuals (194 with and 274 subjects without metabolic syndrome) according to the National Cholesterol Education Program's Adult Treatment Panel III (ATP-III) criteria were selected. Anthropometric indices were measured and plotted using receiver-operating characteristic (ROC) curves. Results. According to ROC curve analysis, WC and WHR parameters were better indicators of metabolic syndrome compared to BMI in women, whereas in men WHR had a lower discriminating value compared to the other two parameters. Among these three anthropometric parameters, BMI had a lower sensitivity and WC and WHR both had a higher sensitivity for predicting metabolic syndrome in women compared with in men. The cut points for WC were nearly equal in men and women, 90.3 versus 90.0, respectively. Women had higher cut points for BMI (28.5 kg/m(2)) compared to men (26.0 kg/m(2)). Our results showed the highest sensitivity and specificity for WC cut points specially in women. To predict metabolic syndrome, we looked into optimal age-specific cut points for BMI, WC, and WHR. The results indicated that WC had the highest discriminating value compared to other indicators in the different age subgroups. The optimal cut points for all three parameters gradually increased with age. Conclusion. Our results demonstrated that regardless of gender and age variables, WC could be a preferred parameter for predicting metabolic syndrome compared to BMI and WHR in Iranian population. PMID- 23634299 TI - How older female spouses cope with partners' coronary artery bypass graft surgery. AB - This research sought to better understand how older female spouses cope with a partner's coronary artery bypass graft surgery and to explore coping's relationships with life-change stress, cognitive appraisal, resilience, social support, and aspects of spouse's surgery. A sample of 96 women, aged from 55 to 81 years, completed surveys after their partner's surgery. Folkman and Lazarus' ways of coping (WCQ) scales yielded two factors in this sample-reactive coping and adaptive coping. Reactive coping, including more emotion-focused ways of coping from the WCQ, was associated only with more time spent anticipating spouses' surgeries. Women described the greatest use of ways of coping labeled adaptive, which in turn had significant relationships with greater resilience, social support, and positive appraisal of the surgical experience. Stepwise multiple regression found greater resilience, more frequent religious participation, and fewer children to be distinct predictors of adaptive coping. Nursing staff are encouraged to accept and normalize reactive coping, while facilitating adaptive coping with surgical stresses. PMID- 23634300 TI - Cytokine Polymorphisms, Their Influence and Levels in Brazilian Patients with Pulmonary Tuberculosis during Antituberculosis Treatment. AB - Cytokines play an essential role during active tuberculosis disease and cytokine genes have been described in association with altered cytokine levels. Therefore, the aim of this study was to verify if IFNG, IL12B, TNF, IL17A, IL10, and TGFB1 gene polymorphisms influence the immune response of Brazilian patients with pulmonary tuberculosis (PTB) at different time points of antituberculosis treatment (T1, T2, and T3). Our results showed the following associations: IFNG +874 T allele and IFNG +2109 A allele with higher IFN- gamma levels; IL12B +1188 C allele with higher IL-12 levels; TNF -308 A allele with higher TNF- alpha plasma levels in controls and mRNA levels in PTB patients at T1; IL17A A allele at rs7747909 with higher IL-17 levels; IL10 -819 T allele with higher IL-10 levels; and TGFB1 +29 CC genotype higher TGF- beta plasma levels in PTB patients at T2. The present study suggests that IFNG +874T/A, IFNG +2109A/G, IL12B +1188A/C, IL10 -819C/T, and TGFB1 +21C/T are associated with differential cytokine levels in pulmonary tuberculosis patients and may play a role in the initiation and maintenance of acquired cellular immunity to tuberculosis and in the outcome of the active disease while on antituberculosis treatment. PMID- 23634301 TI - Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis. AB - We design here new nanomolar antituberculotics, inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), by means of structure-based molecular design. 3D models of TMPKmt-inhibitor complexes have been prepared from the crystal structure of TMPKmt cocrystallized with the natural substrate deoxythymidine monophosphate (dTMP) (1GSI) for a training set of 15 thymidine analogues (TMDs) with known activity to prepare a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. Subsequent validation of the predictability of the model has been performed with a 3D QSAR pharmacophore generation. The structural information derived from the model served to design new subnanomolar thymidine analogues. From molecular modeling investigations, the agreement between free energy of complexation (DeltaDeltaG com) and K i values explains 94% of the TMPKmt inhibition (pK i = -0.2924DeltaDeltaG com + 3.234; R (2) = 0.94) by variation of the computed DeltaDeltaG com and 92% for the pharmacophore (PH4) model (pK i = 1.0206 * pK i (pred) - 0.0832, R (2) = 0.92). The analysis of contributions from active site residues suggested substitution at the 5-position of pyrimidine ring and various groups at the 5'-position of the ribose. The best inhibitor reached a predicted K i of 0.155 nM. The computational approach through the combined use of molecular modeling and PH4 pharmacophore is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antituberculotic agents. PMID- 23634302 TI - Liposomal Doxorubicin in the treatment of breast cancer patients: a review. AB - Drug delivery systems can provide enhanced efficacy and/or reduced toxicity for anticancer agents. Liposome drug delivery systems are able to modify the pharmacokinetics and biodistribution of cytostatic agents, increasing the concentration of the drug released to neoplastic tissue and reducing the exposure of normal tissue. Anthracyclines are a key drug in the treatment of both metastatic and early breast cancer, but one of their major limitations is cardiotoxicity. One of the strategies designed to minimize this side effect is liposome encapsulation. Liposomal anthracyclines have achieved highly efficient drug encapsulation and they have proven to be effective and with reduced cardiotoxicity, as a single agent or in combination with other drugs for the treatment of either anthracyclines-treated or naive metastatic breast cancer patients. Of particular interest is the use of the combination of liposomal anthracyclines and trastuzumab in patients with HER2-overexpressing breast cancer. In this paper, we discuss the different studies on liposomal doxorubicin in metastatic and early breast cancer therapy. PMID- 23634304 TI - Achieving accurate ligament balancing using robotic-assisted unicompartmental knee arthroplasty. AB - Unicompartmental knee arthroplasty (UKA) allows replacement of a single compartment in patients with limited disease. However, UKA is technically challenging and relies on accurate component positioning and restoration of natural knee kinematics. This study examined the accuracy of dynamic, real-time ligament balancing using a robotic-assisted UKA system. Surgical data obtained from the computer system were prospectively collected from 51 patients (52 knees) undergoing robotic-assisted medial UKA by a single surgeon. Dynamic ligament balancing of the knee was obtained under valgus stress prior to component implantation and then compared to final ligament balance with the components in place. Ligament balancing was accurate up to 0.53 mm compared to the preoperative plan, with 83% of cases within 1 mm at 0 degrees , 30 degrees , 60 degrees , 90 degrees , and 110 degrees of flexion. Ligamentous laxity of 1.31 +/- 0.13 mm at 30 degrees of flexion was corrected successfully to 0.78 +/- 0.17 mm (P < 0.05). Robotic-assisted UKA allows accurate and precise reproduction of a surgical balance plan using dynamic, real-time soft-tissue balancing to help restore natural knee kinematics, potentially improving implant survival and functional outcomes. PMID- 23634305 TI - Gross hematuria in patients with prostate cancer: etiology and management. AB - The objective of the study is to assess the etiology and prognosis of gross hematuria (GH) in patients with carcinoma of the prostate (CAP). From 1991 to 2011, 81 men (mean age 74.3 years, SD 6.5) with CAP were hospitalized with GH. Primary treatment of CAP was radical surgery in 13 patients (group 1) and nonsurgical therapy in 68 (group 2), mostly radiotherapy (35 cases) and hormonal treatment (25 cases). The common etiologies of GH in group 1 were bladder cancer (38.5%) and urinary infection (23%). In contrast, CAP itself caused GH in 60% of the patients in group 2. Thirty-nine patients (48%) required transurethral surgery to manage GH which was effective in all cases; nevertheless, the prognosis of group 2 patients was dismal with median overall survival of 13 months after sustaining hematuria, compared to 50 months in group 1 (P = 0.0015). We conclude that the etiology of GH in patients with CAP varies according to primary treatment. After radical prostatectomy, it is habitually caused by bladder cancer or infection. When the primary treatment is not surgical, GH is most commonly due to CAP itself. Although surgical intervention is effective in alleviating hematuria of these patients, their prognosis is dismal. PMID- 23634303 TI - Gene therapy for advanced melanoma: selective targeting and therapeutic nucleic acids. AB - Despite recent advances, the treatment of malignant melanoma still results in the relapse of the disease, and second line treatment mostly fails due to the occurrence of resistance. A wide range of mutations are known to prevent effective treatment with chemotherapeutic drugs. Hence, approaches with biopharmaceuticals including proteins, like antibodies or cytokines, are applied. As an alternative, regimens with therapeutically active nucleic acids offer the possibility for highly selective cancer treatment whilst avoiding unwanted and toxic side effects. This paper gives a brief introduction into the mechanism of this devastating disease, discusses the shortcoming of current therapy approaches, and pinpoints anchor points which could be harnessed for therapeutic intervention with nucleic acids. We bring the delivery of nucleic acid nanopharmaceutics into perspective as a novel antimelanoma therapeutic approach and discuss the possibilities for melanoma specific targeting. The latest reports on preclinical and already clinical application of nucleic acids in melanoma are discussed. PMID- 23634307 TI - Foreign body in the oral cavity mimicking a benign connective tissue tumor. AB - Foreign bodies may be embedded in the oral cavity either by traumatic injury or iatrogenically. The commonly encountered iatrogenic foreign bodies are restorative materials like amalgam, obturation materials, broken instruments, needles, and impression materials. This paper describes an asymptomatic presentation of a foreign body in the oral mucosa which clinically appeared like a benign connective tissue tumor. PMID- 23634308 TI - Condylar aplasia and hypoplasia: a rare case. AB - Aplasia of condyle is very rare, when this condition not seen as a part of a syndrome. We report a case of condylar aplasia on the right side and hypoplasia on the left side in a 21-year-old female. The patient reported to the department with a chief complaint of underdeveloped lower jaw. Clinical examination, conventional radiographs, and 3D CBCT images revealed complete absence of condyle on the right side and hypoplasia on the left side. PMID- 23634309 TI - Duodenal wedge resection for large gastrointestinal stromal tumour presenting with life-threatening haemorrhage. AB - Background. Duodenal gastrointestinal stromal tumours (GISTs) are an uncommon malignancy of the gastrointestinal (GI) tract. We present a case of life threatening haemorrhage caused by a large ulcerating duodenal GIST arising from the third part of the duodenum managed by a limited duodenal wedge resection. Case Presentation. A 61-year-old patient presented with acute life-threatening gastrointestinal bleeding. After oesophagogastroduodenoscopy failed to demonstrate the source of bleeding, a 5 cm ulcerating exophytic mass originating from the third part of the duodenum was identified at laparotomy. A successful limited wedge resection of the tumour mass was performed. Histopathology subsequently confirmed a duodenal GIST. The patient remained well at 12-month followup with no evidence of local recurrence or metastatic spread. Conclusion. Duodenal GISTs can present with life-threatening upper GI haemorrhage. In the context of acute haemorrhage, even relatively large duodenal GISTs can be treated by limited wedge resection. This is a preferable alternative to duodenopancreatectomy with lower morbidity and mortality but comparable oncological outcome. PMID- 23634310 TI - Late onset atypical pantothenate-kinase-associated neurodegeneration. AB - Introduction. Pantothenate-kinase-associated neurodegeneration (PKAN) is a rare genetic disease and a form of neurodegeneration with brain iron accumulation (NBIA). It most commonly begins in the first two decades of life but should be considered in the differential diagnosis of patients at any age with an atypical progressive extrapyramidal disorder and cognitive impairment. Few late-adult cases have been reported. Case Report. A 50-year-old woman presented with a history of progressive dysarthria and dysphagia secondary to orolingual dystonia. Initial work-up was normal. There was no family history. Her initial symptoms were followed by the onset of blepharospasm, cervical dystonia, Parkinsonism, and cognitive impairment. Follow-up MRI four years after presentation revealed the diagnostic "eye-of-the-tiger" sign. Genetic testing confirmed a homozygous missense mutation consistent with the diagnosis of PKAN. Conclusion. Although PKAN is a rare genetic disorder most commonly seen in childhood, it should be considered in adult patients with a history of progressive focal dystonia or atypical Parkinsonism. As the radiographic findings are quite characteristic, genetic testing should be performed if the MRI shows evidence of iron accumulation. Optimal treatment strategies are not known, and at the current time therapies should be directed at the specific manifestations of the disease. PMID- 23634312 TI - Trigger finger appearing as gradually increasing digital nerve disorder after surgical treatment. AB - Trigger finger is a common disease, and operative treatments are often applied for it. Digital nerve injury is one of the complications of this surgical treatment, and paresthesia and sensory disturbance occur early after the operation. This paper presents a case of trigger finger appearing gradually as increasing digital nerve disorder after surgical treatment. In the second surgery, scar tissue covered the palmar MP joint where the A1 pulley had existed before, and palmar digital neurovascular tissue of the ulnar side was found on the inside of the scar. The ulnar digital nerve showed swelling like a neuroma, and bilateral digital nerves existed nearer to the center of the flexor pollicis longus tendon than normal digital nerves. Even when we operate on trigger finger by open release, we should create an appropriate surgical space for observation and be careful of digital nerve injury. PMID- 23634311 TI - Ovarian metastasis from lung cancer: a rare entity. AB - This paper describes a case of ovarian metastasis from lung carcinoma along with its diagnostic challenges, clinical management, and review of the literature. A 49-year-old woman was admitted to our emergency department with complaints of abdominal pain and vomiting. A laparoscopic appendectomy was performed due to acute appendicitis, and a unilateral oophorectomy (left side) via laparoscopy was performed due to the detection of an ovarian mass. Immunohistochemical staining of the ovarian mass revealed that it was reactive to cytokeratin-7 (CK-7) but negative for CK-20. The immunohistochemical and pathological features of the tumor indicated an ovarian metastasis of non-small-cell lung cancer. The patient underwent chemotherapy and was followed up by the oncology department. Her postoperative regular followup of 6 months showed that her condition was stable with no recurrence. The management of female patients with acute abdominal pain and pelvic masses should consist of a multidisciplinary approach to include the diagnosis of any distant organ metastasis. PMID- 23634313 TI - Missing screw as a rare complication of anterior cervical instrumentation. AB - Although anterior cervical arthrodesis is an effective procedure for the treatment of cervical disorders, the method has some complications. Here, we describe this rare complication of cervical instrumentation with a literature review. A 23-year-old male patient was operated for a C6-C7 dislocation. At postoperative month 10, he presented with hemoptysis and dysphagia. Cervical roentgenograms showed anterior migrations of one broken screw and a plate-locking screw at the C6 corpus. One screw was missing. We concluded that the missing screw had perforated the esophagus and had been eliminated spontaneously through the gastrointestinal tract. No screw should migrate. Even loose screws should be noted in follow-up X-ray studies. If such findings are detected, a second operation for revision should be considered as soon as possible to prevent potentially fatal complications. PMID- 23634306 TI - The visual callosal connection: a connection like any other? AB - Recent work about the role of visual callosal connections in ferrets and cats is reviewed, and morphological and functional homologies between the lateral intrinsic and callosal network in early visual areas are discussed. Both networks selectively link distributed neuronal groups with similar response properties, and the actions exerted by callosal input reflect the functional topography of those networks. This supports the notion that callosal connections perpetuate the function of the lateral intrahemispheric circuit onto the other hemisphere. Reversible deactivation studies indicate that the main action of visual callosal input is a multiplicative shift of responses rather than a changing response selectivity. Both the gain of that action and its excitatory-inhibitory balance seem to be dynamically adapted to the feedforward drive by the visual stimulus onto primary visual cortex. Taken together anatomical and functional evidence from corticocortical and lateral circuits further leads to the conclusion that visual callosal connections share more features with lateral intrahemispheric connections on the same hierarchical level and less with feedback connections. I propose that experimental results about the callosal circuit in early visual areas can be interpreted with respect to lateral connectivity in general. PMID- 23634314 TI - Acute lumbar burst fracture treated by minimally invasive lateral corpectomy. AB - Burst fractures in acute spinal traumas are a difficult problem to solve. Different approaches and techniques have been utilized, but with high incidence of morbidity and mortality, besides unsatisfactory clinical and radiological results. Mini-open approaches recently emerged and have been shown to be safe and effective in the treatment of several spinal conditions. Here we report a case of acute lumbar burst fracture at L2 treated by minimally invasive true lateral approach posteriorly instrumented with percutaneous pedicle screws. The minimum disruptive access in addition to a rigid construction allowed a lumbar corpectomy without the morbidity of standard open approaches, lowering surgery costs and accelerating the patient recovery with successfully clinical and radiological results. PMID- 23634316 TI - Unusual esophageal foreign body: a table fork. AB - The presence of an esophageal foreign body (EFB) is a medical emergency requiring urgent evaluation and treatment. Swallowing of foreign bodies is most common in children aged between 6 months and 6 years, in whom it usually occurs during games. In adults, foreign bodies tend to be ingested accidentally together with food. The authors report an unusual case of EFB (a table fork) in an adult and briefly report the clinical presentation and the therapeutic procedures adopted in this case and similar cases. PMID- 23634315 TI - Eosinophilic angiocentric fibrosis of the nasal septum. AB - Background. Eosinophilic angiocentric fibrosis (EAF) is a rare benign condition of unknown aetiology that causes stenosis of the upper respiratory tract. It is most commonly found at the nasal septum and sinus mucosa causing mucosal thickening and nasal obstructive symptoms. The diagnosis is mainly based on characteristic histologic findings. Case Report. A 27-year-old young woman presented with a slow growing mass at her anterior nasal septum for over eight years. She complained of persistent nasal obstruction, epistaxis, sometimes diffused facial pain, and chronic headache. 3 years ago, the tumor was partially resected for ventilation and a nasal septum perforation was left. Imaging findings indicated soft-tissue thickening of the anterior part of septum and adjacent lateral nasal walls. Pathological examination showed numerous inflammatory cells infiltrates containing eosinophils, fibroinflammatory lesion with a whorled appearance fibrosis which typically surrounded vessels. A diagnosis of eosinophilic angiocentric fibrosis was made. All laboratory tests were unremarkable. Skin prick test was positive. The tumor-like lesion was totally resected. Conclusions. EAF is a rare benign and progressive disorder causing destruction. Combined with radiological imaging of EAF historical findings contribute to the diagnosis. It is important to prevent tumor from recurrence by total resection of the lesion. PMID- 23634317 TI - Drosophila melanogaster Selection for Survival after Infection with Bacillus cereus Spores: Evolutionary Genetic and Phenotypic Investigations of Respiration and Movement. AB - Laboratory populations of D. melanogaster have been subjected to selection for survival after live spores of B. cereus were introduced as a pathogenic agent. The present study was designed to investigate correlated traits: respiration as a metabolic trait and movement as a behavioral trait. An underlying hypothesis was that the evolution of increased survival after B. cereus infection exerts a metabolic cost associated with elevated immunity and this would be detected by increased respiration rates. There was support for this hypothesis in the male response to selection, but not for selected-line females. Two phenotypic effects were also observed in the study. Females especially showed a marked increase in respiration after mating compared to the other assay stages regardless of whether respiration was measured per fly or adjusted by lean mass or dry weight. Given that mating stimulates egg production, it is feasible that elevated metabolism was needed to provision oocytes with yolk. Females also moved less than males, perhaps due to behaviors related to oviposition whereas elevated male activity might be due to behaviors associated with seeking females and courtship. Relatively low movement of females indicated that their elevated respiration after mating was not due to a change in locomotion. PMID- 23634318 TI - Diagnosis of follicular lesions of undetermined significance in fine-needle aspirations of thyroid nodules. AB - Aim. We aimed to analyze the diagnostic criteria proposed by the Bethesda System for Reporting Thyroid Cytopathology for follicular lesions of undetermined significance (FLUS), the risk of cancer and diagnostic improvement with use of immunocytochemistry. Methods. For each FLUS diagnosis, we analyzed the cytological criteria (9 Bethesda criteria), secondary fine-needle aspiration (FNA) results, surgical procedures, contribution of immunocytochemistry with the antibodies cytokeratin 19 (CK19) and monoclonal anti-human mesothelial cell (HBME1). Results. Among patients with 2,210 thyroid FNAs, 244 lesions (337 nodules) were classified as FLUS (11% of all thyroid FNAs). The 3 criteria most often applied were cytological atypia suggesting papillary carcinoma (36%), microfollicular architecture but sparse cellularity (23.1%), cytological atypia (21.5%). With secondary FNA, 48.8% of nodules were reclassified as benign. For about half of all cases (41.4% for the first FNA, 57.6% for the second FNA), immunocytochemistry helped establishing a diagnosis favoring malignant or benign. No benign immunocytochemistry results were associated with a malignant lesion. In all, 22.5% of the 39 removed nodules were malignant. Conclusion. The FLUS category is supported by well-described criteria. The risk of malignancy in our series was 22.5%. Because we had no false-negative immunocytochemistry results, immunocytochemistry could be helpful in FLUS management. PMID- 23634319 TI - The impact of experimental preconditioning using vascular endothelial growth factor in stroke and subarachnoid hemorrhage. AB - Vascular endothelial growth factor (VEGF) stimulating angiogenesis was shown to be a potential novel therapeutic approach for the treatment of ischemic vascular diseases. The goal of the present study was to examine whether transfection of VEGF before occurrence of major stroke (part I) and cerebral vasospasm after experimental subarachnoid hemorrhage (SAH; part II) develops neuroprotective qualities. A total of 25 (part I) and 26 (part II) brains were analyzed, respectively. In part one, a significant reduction of infarct volume in the VEGF treated stroke animals (43% reduction, P < 0.05) could be detected. In part two, significant vasospasm was induced in all hemorrhage groups (P < 0.02). Analyzing microperfusion, a significant higher amount of perfused vessels could be detected (P < 0.01), whereas no significant effect could be detected towards macroperfusion. Histologically, no infarctions were observed in the VEGF-treated SAH group and the sham-operated group. Minor infarction in terms of vasospasm induced small lesions could be detected in the control vector transduced group (P = 0.05) and saline-treated group (P = 0.09). The present study demonstrates the preconditioning impact of systemic intramuscular VEGF injection in animals after major stroke and induced severe vasospasm after SAH. PMID- 23634320 TI - Development of an HPLC-UV Method for the Analysis of Drugs Used for Combined Hypertension Therapy in Pharmaceutical Preparations and Human Plasma. AB - A simple, rapid, and selective HPLC-UV method was developed for the determination of antihypertensive drug substances: amlodipine besilat (AML), olmesartan medoxomil (OLM), valsartan (VAL), and hydrochlorothiazide (HCT) in pharmaceuticals and plasma. These substances are mostly used as combinations. The combinations are found in various forms, especially in current pharmaceuticals as threesome components: OLM, AML, and HCT (combination I) and AML, VAL, and HCT (combination II). The separation was achieved by using an RP-CN column, and acetonitrile-methanol-10 mmol orthophosphoric acid pH 2.5 (7 : 13 : 80, v/v/v) was used as a mobile phase; the detector wavelength was set at 235 nm. The linear ranges were found as 0.1-18.5 MU g/mL, 0.4-25.6 MU g/mL, 0.3-15.5 MU g/mL, and 0.3-22 MU g/mL for AML, OLM, VAL, and HCT, respectively. In order to check the selectivity of the method for pharmaceutical preparations, forced degradation studies were carried out. According to the validation studies, the developed method was found to be reproducible and accurate as shown by RSD <=6.1%, 5.7%, 6.9%, and 4.6% and relative mean error (RME) <=10.6%, 5.8%, 6.5%, and 6.8% for AML, OLM, VAL, and HCT, respectively. Consequently, the method was applied to the analysis of tablets and plasma of the patients using drugs including those substances. PMID- 23634321 TI - Noise-induced hearing loss still a problem in shipbuilders: a cross-sectional study in goa, India. AB - BACKGROUND: Workplace safety regulations seek to mitigate noise-induced hearing loss (NIHL), conventionally associated with the shipbuilding industry. Despite this, are workers still predisposed to NIHL? AIMS: To study the prevalence of NIHL among noise-exposed subjects in the shipbuilding industry in Goa and to compare it with that among the non-exposed population working in the same industry in relation to certain relevant factors. SUBJECTS AND METHODS: This is a cross-sectional study in the shipbuilding industry, Goa This study examined 552 workers: 276 shipbuilders and 276 office staff, of similar age, duration of employment and socio-economic status working at a shipbuilding enterprise. An interviewer-administered questionnaire was followed by audiometry. Values were presented as percentages, Mean (SD) and odds ratio (OR) and its 95% confidence interval (CI) (Woolfe's method). Fisher's exact test and binary logistic regression were used. P value of < 0.05 was taken as significant. SPSS version 16 was used. RESULTS: NIHL was found in 17 (6%) shipbuilders, while no office staff was detected to have this condition (OR = 37.29, 95% CI 22.42-62.18). The shipbuilders with NIHL were 52.5 years of age and had been employed for 30.4 years, on an average. None of the 17 cases of NIHL were found to be using earplugs consistently; 11 reported using them "sometimes" and six "never" used them. CONCLUSIONS: NIHL continues to affect shipbuilders, owing their non compliance to workplace regulation. Health education is the need of the hour. PMID- 23634322 TI - Awareness and Practice of Breast Self-Examination among Market Women in Abakaliki, South East Nigeria. AB - BACKGROUND: Breast cancer is the most common female malignancy and commonly associated with high levels of morbidity and mortality in developing countries due to late presentation. Breast self-examination (BSE) can help in early detection of the disease. AIMS: This study aims to determine the awareness and practice of BSE among market women in Abakailiki, Southeast Nigeria. SUBJECTS AND METHODS: This cross-sectional descriptive study involved the use of questionnaire among market women in Abakaliki. Inclusion criteria were women from the age of 18 years and above who own or sell in a shop, while females less than 18 years of age and women who came to the market to buy products were excluded. Questionnaires were distributed randomly among women who met the criteria in every shop visited based on willingness to participate. Analysis was done using Epi info version 3:5:3 (Atlanta Geogia USA.2008). The association between variables was tested using Chi square for trend statistics. Significance was set at P < 0.05. Binomial logistic regression analysis was used to test for relationship between the age group categories against ever heard of BSE. RESULTS: The age range of participants was between 20 and 65 years, with a mean age of 34.3 (10.8) years. The age range between 20 and 29 years constituted the highest age group 35.3% (84/238). Majority 54.2% (129/238) had a maximum of secondary education. Of the 238 participants, 77.7% have heard of breast cancer, of which 73.9% thought that early detection would aid treatment. Only 38.9% (6/195), 13% and 13.4% have heard of BSE, clinical breast examination and mammography, respectively. Just 23.9% have been taught how to perform BSE, while 21.8% had done it in the past. One person 0.4% knew the correct frequency of BSE, and also did it regularly. There was a statistically significant difference between the level of education and awareness of BSE. However, there was no statistical significant difference between participants age and awareness of BSE. CONCLUSION: There was a low level of awareness of BSE among market women in Abakiliki, and there is a need to increase the level of awareness through campaigns. PMID- 23634323 TI - Overweight and Obesity, Lipid Profile and Atherogenic Indices among Civil Servants in Abakaliki, South Eastern Nigeria. AB - BACKGROUND: The association between dyslipidaemia, obesity and hypertension is well established, and all have been found to be risk factors for cardiovascular disease (CVD). AIM: To determine the prevalence of overweight and obesity, plasma lipid profile and atherogenic indices as markers for CVD among civil servants. SUBJECTS AND METHODS: Two hundred and five (205) apparently healthy civil servants (106, 51.7% males) aged 21-60 years, mean and standard deviation (SD) 40.9 (11.3) years, enrolled between February and April 2008 were assessed for their plasma lipid profile and anthropometrics (body weight and height) using standard methods and techniques. RESULTS: Prevalent rates of overweight and obesity were 34.2% (70/205) and 6.8% (14/205), respectively, with more men affected than women. Abnormal lipids observed were: Elevated total cholesterol 37.1% (76/205), low-density lipoprotein-cholesterol (LDL-C) 37.1% (76/205), triglyceride 6.8% (14/205), reduced high-density lipoprotein-cholesterol (HDL-C) 8.8% (18/205) and elevated Atherogenic Index 10.7% (22/205) and Coronary Risk Index 9.8% (20/205), with the older age groups and higher Body Mass Index (BMI) groups being the most affected. Male subjects were found to have more favorable plasma lipid profile (lower LDL-C and higher HDL-C) than the females. Plasma lipids were positively correlated with BMI and artherogenic indices, except for HDL-C, which was negatively correlated with artherogenic indices and LDL-C but positively correlated with BMI. CONCLUSION: The findings show that civil servants in Abakaliki, particularly the females, those with higher BMI and advanced in age, exhibited unfavorable plasma lipids and social habits with a low level of physical activity, which may predispose them to CVD. In addition to epidemiological study of the general population, there is a need for education on healthier lifestyles such as good nutrition, weight reduction, smoking and alcohol cessation, greater physical activity and regular medical check-up. PMID- 23634324 TI - Health problems among the elderly: a cross-sectional study. AB - BACKGROUND: Estimates of health problems of the elderly in developing countries are required from time to time to predict trends in disease burden and plan health care for the elderly. Developing countries have a poor track record of equitable distribution of health care. Marginalized groups living in urban slums and rural villages have poor penetration of health services. AIMS: To identify the geriatric health problems in samples drawn from a slum and a village, and also to explore any gender and urban-rural difference morbidity. SUBJECT AND METHODS: A community-based cross-sectional study was carried out by house to house survey of all people aged over 60 years in an urban slum and a village in the field practice area of a teaching hospital. The total elderly population in these two areas was 407, with an almost equal representation from urban slum and rural area. Information (most of them self-reported) was collected in a pre tested instrument, which has been used earlier in a World Health Organization multicentric study in India. Categorical variables were summarized by percentages. Associations were explored with odds ratio (OR) and 95% confidence intervals (CIs). RESULTS: Female elders outnumbered the male elders; widows outnumbered widowers. Tobacco use was very high at 58.97% (240/407). Visual impairment (including uncorrected presbyopia) was the most common handicap with prevalence of 83.29% (339/407), with males more affected than females (OR = 2.52, 95% CI 1.32-4.87). Uncorrected hearing impairment was also common. Urinary complaints were also more common in males (OR = 1.68, 95% CI = 0.93-3.04). More rural elders were living alone than their urban counterpart (OR = 2.87, 95% CI 1.23-6.86). History of weight loss was higher in the rural areas, while tendency to obesity was higher in the urban areas. An appreciable number 29.2% (119/407) had unoperated cataract. Prevalence of hypertension was 30.7% (125/407); 12% (49/407) had diabetes; 7.6% (31/407) gave history of ischemic heart disease, males more than females (OR = 3.75, 95% CI 1.62-8.82). A large proportion, 32.6%, (133/407) had dental problems. Almost half of the population gave history of depression. CONCLUSION: A large number of unmet health needs, such as unoperated cataract, uncontrolled hypertension, uncorrected hearing impairment and tobacco use, exist in marginalized groups. Health interventions for these are needed in developing countries. Preventive services such as tobacco cessation campaigns among the elderly should also get priority. PMID- 23634325 TI - Lipid Profile of Anti-Retroviral Treatment-Naive HIV-Infected Patients in Jos, Nigeria. AB - BACKGROUND: Human immunodeficiency virus (HIV) infection and its treatment are associated with lipid abnormalities. Data on lipid profile of treatment-naive HIV infected patients in Nigeria are limited, and available studies did not exclude the role of major host-related risk factors for dyslipidemia. AIM: We assessed the lipid profile of normotensive, non-diabetic, and non-obese treatment-naive HIV-infected patients to identify their abnormalities in comparison with age- and sex-matched HIV-negative control. SUBJECTS AND METHODS: One hundred and six normotensive, non-diabetic, and non-obese HIV positive patients and 98 age-and sex-matched HIV-negative controls had lipid profile estimation in the fasting state. The CD4+ cell count of the HIV-infected patients was also quantified. RESULTS: The median (IQR) triglyceride was significantly higher in HIV-positive patients than in the controls [1.75 (1.30-2.40) mmol/L vs. 1.55 (1.30-1.90) mmol/L, P = 0.01]. HIV-positive patients also had significantly lower mean total cholesterol, TC [4.18 (1.04) mmol/L vs. 4.64 (1.01) mmol/L, P = 0.001] and HDL-C [1.17 (0.35) mmol/L vs. 1.29 (0.43) mmol/L, P = 0.03]. The mean LDL-C [2.20 (0.87) mmol/L vs. 2.19 (0.75) mmol/L, P = 0.97] and TC/HDL-C ratio [3.95 (1.42) vs. 3.84 (1.14) mmol/L, P = 0.52] were similar between the HIV-positive patients and controls. The HIV-infected patients had a significantly higher proportion of subjects with low HDL-C [36.8% (39/106) vs. 23.5% (23/98), P = 0.04] and hypertriglyceridemia [31.1% (33/106) vs. 11.2% (11/98), P = 0.001] while the controls had significantly higher proportion of subjects with hypercholesterolemia [22.4% (22/98) vs. 10.4% (11/106), P = 0.02]. Lower HDL-C was associated with CD4+ cell count < 200 cells/MUL (P = 0.02). CONCLUSION: Lipid abnormalities are common in treatment-naive HIV-infected patients even in the absence of major host-related risk factors for dyslipidemia. HIV-infected patients should, therefore, be routinely screened for lipid disorders before commencement of anti-retroviral therapy. PMID- 23634326 TI - Satisfaction with Quality of Care Received by Patients without National Health Insurance Attending a Primary Care Clinic in a Resource-Poor Environment of a Tertiary Hospital in Eastern Nigeria in the Era of Scaling up the Nigerian Formal Sector Health Insurance Scheme. AB - BACKGROUND: The increasing importance of the concept of patients' satisfaction as a valuable tool for assessing quality of care is a current global healthcare concerns as regards consumer-oriented health services. AIM: This study assessed satisfaction with quality of care received by patients without national health insurance (NHI) attending a primary care clinic in a resource-poor environment of a tertiary hospital in South-Eastern Nigeria. SUBJECT AND METHODS: This was a cross-sectional study carried out on 400 non-NHI patients from April 2011 to October 2011 at the primary care clinic of Federal Medical Centre, Umuahia, Nigeria. Adult patients seen within the study period were selected by systematic sampling using every second non-NHI patient that registered to see the physicians and who met the selection criteria. Data were collected using pretested, structured interviewer administered questionnaire designed on a five points Likert scale items with 1 and 5 indicating the lowest and highest levels of satisfaction respectively. Satisfaction was measured from the following domains: patient waiting time, patient-staff communication, patient-staff relationship, and cost of care, hospital bureaucracy and hospital environment. Operationally, patients who scored 3 points and above in the assessed domain were considered satisfied while those who scored less than 3 points were dissatisfied. RESULTS: The overall satisfaction score of the respondents was 3.1. Specifically, the respondents expressed satisfaction with patient-staff relationship (3.9), patient staff communication (3.8), and hospital environment (3.6) and dissatisfaction with patient waiting time (2.4), hospital bureaucracy (2.5), and cost of care (2.6). CONCLUSION: The overall non-NHI patient's satisfaction with the services provided was good. The hospital should set targets for quality improvement in the current domains of satisfaction while the cost of care has implications for government intervention as it mirrors the need to make NHI universal for all Nigerians irrespective of the employment status. PMID- 23634327 TI - Respiratory symptoms and lung function patterns in workers exposed to wood smoke and cooking oil fumes (mai suya) in Nigeria. AB - BACKGROUND: 'Mai suya' is a common job in the most northern Nigeria in which there is significant exposures to wood smoke and oil fumes. The respiratory impact of these dual exposures on workers engaged in this work has not been previously documented, hence this study was carried out. AIM: The aim is to study the prevalence, patterns and respiratory function assessment among this group. SUBJECT AND METHODS: This is a case controlled study involving mai suya and workers who are not exposed to wood smoke and oil fumes in an occupational setting. All consenting mai suya and matched controls were recruited. Both groups underwent an interviewer administered questionnaire followed by on spot spirometric test measuring forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR). Results are presented using descriptive statistics. Chi square was used to test for association between respiratory symptoms and the job categories. Student's t-test was used to compare values of continuous variables. Odd ratios were determined for the risk of respiratory symptoms and exposure to wood smoke and oil fumes. RESULTS: Both groups are similar in their demographic characters except in their smoking status, so current smokers were excluded from further analysis. The test group had significantly increased occurrence of chest tightness: 59% (19/32), nasal congestion: 37% (12/32), cough: 32% (10/32), and wheeze: 12% (4/32) compared with the control group, odds ratio (OR) 3.1, 95% confidence interval CI (0.1-5.8), P value 0.04, OR 1.2,95% CI (1.04-1.8), P value = 0.02, OR 0.9 95% CI (0.9-1.4), P value = 0.3, and OR 1.2,95% CI (1-1.3), P value = 0.04, respectively. Occurrences of some respiratory symptoms were associated with duration on the job, while a positive family history of asthma is not associated with increased occurrence of symptoms. The mean (SD) FEV1 and FVC were significantly lower among the test group compared with the control group; 2.5L/s (0.55) versus 3.02L/s (0.51), P value = 0.007 and 2.7L (0.7) versus 3.16L (0.51), P value = 0.04. CONCLUSION: Mai suya' have increased risk of respiratory symptoms and altered pulmonary functions. There is a need for protective equipment and periodic evaluation. PMID- 23634328 TI - Correlation of thyroid functions with severity and outcome of pregnancy. AB - BACKGROUND: During normal pregnancy, changes in thyroid function are well documented; however, information regarding thyroid function in preeclampsia is scanty. AIM: The present study was planned to study thyroid hormones in mild and severe preeclamptic women and normotensive women and correlate them with outcome of pregnancy. SUBJECT AND METHODS: Thyroid hormones were analyzed in mild (n = 50) and severe (n = 50) cases of preeclamptic women and normotensive women (n = 100). RESULTS: Thyroid-stimulating hormone (TSH) and TT4 levels were higher in mild preeclampsia as compared with severe preeclampsia (P < 0.001 and P < 0.01, respectively). TT3 levels were lower in preeclampsia (more so in severe preeclamptics as compared with normotensive pregnant and non-pregnant women). Preeclamptic with raised TSH levels had significantly higher mean arterial blood pressure and low birth weight (BW). A negative correlation was observed between BW and TSH levels (r = 0.296, P < 0.001) and BW and TT4 levels. A positive correlation was observed between BW and TT3 levels. CONCLUSION: These findings indicate that there is a state of biochemical hypothyroidism that correlates with severity of preeclampsia and influences obstetric outcome in these women. Identification of thyroid hormone in pregnancy might be of help in predicting occurrence of preeclampsia. PMID- 23634329 TI - Postpartum practices of parturient women in enugu, South East Nigeria. AB - BACKGROUND: Postpartum period is an important and interesting period in the life of the nursing mothers. It is a medically neglected period that receives relatively less attention than pregnancy and delivery. AIM: To describe the postpartum practices of women in Enugu, South East Nigeria. SUBJECT AND METHODS: This was a cross sectional study of women attending the postnatal care clinic at the UNTH, Enugu. Data was abstracted and analyzed with statistical software for social sciences version 12.0. The results were presented by percentages. Binomial logistic regression was used to determine the association between some socio demographic variables and resumption of coitus. P value less than 0.05 was considered statistically significant. RESULTS: Out of the 420 mothers, 68.9% (289/420) resumed coitus within 6 weeks of delivery. Only 14.7% (62/420) used contraception before resumption of coitus. There was no significant association when the model was adjusted for age (OR, 1.132, 95% CI (0.691-1.867), P = 0.612.), Parity (OR, 1.273, 95% CI (0.812-1.996), P = 0.292) and education (OR, 0.713, 95% CI (0.433-1.173), P = 0.183). Twenty five percent [25.2% (106/420)] of the women drank various forms of alcoholic beverages to induce lactation while 80.2% (337/420) of the women applied hot compresses on the lower abdomen to aid lochia drainage and involution of the uterus, 75% (315/420) of the women sat in hot water salt (Nacl) solution (sitz bath) in the immediate postpartum to aid lochia drainage, aid perineal wound healing and improve vaginal tone. CONCLUSION: There is need for medical attention and education on beneficial postpartum practices among women in Enugu, South East Nigeria. Thus, to reduce the associated maternal morbidities in the postpartum period. PMID- 23634331 TI - Increased Virus Replication and Cytotoxicity of Non-pathogenic Simian Human Immuno Deficiency Viruses-NM-3rN After Serial Passage in a Monkey-Derived Cell Line. AB - BACKGROUND: Infection and disease induction of variants of HIV type 1 (HIV-1) in vivo, especially their persistence, replication and rate of disease progression, have been found to depend on phenotypic characteristics. However, the mechanism (s) underlying these diverse phenotypic characteristics remain poorly understood. AIM: It was aimed at determining whether a SHIV that had been adapted to a monkey derived cell line could be used to explain the mechanism that underlies adaptive evolution of a virus to its host cell environment. MATERIALS AND METHODS: Standard procedures in virology such as cell culturing, FACS analysis and ELISA were employed to measure virus replication and growth kinetics, cell viability, reverse transcriptase (RT) activity assay and CD4 cells down-regulation. RESULTS: After about 20 passages, LT efficiently adapted to the monkey-derived cell line and replicated much better than the parent virus. LT accumulated a number of mutations in its entire genome with a majority of them being monkey cell specific. CONCLUSION: Thus we think we have obtained a virus that may enable studies to determine which of these mutations are specifically related to in vitro viral replication and which are specifically related to cytotoxicity so as to explain the mechanism associated with viral cytotoxicity and host cell specificity. PMID- 23634330 TI - Study of sleep habits and sleep problems among medical students of pravara institute of medical sciences loni, Western maharashtra, India. AB - BACKGROUND: Good quality sleep and adequate amount of sleep are important in order to have better cognitive performance and avoid health problems and psychiatric disorders. AIM: The aim of this study was to describe sleep habits and sleep problems in a population of undergraduates, interns and postgraduate students of Pravara Institute of Medical Sciences (Deemed University), Loni, Maharashtra, India. SUBJECT AND METHODS: Sleep habits and problems were investigated using a convenience sample of students from Pravara Institute of Medical Sciences (Deemed University), Loni, Maharashtra, India. The study was carried out during Oct. to Dec. 2011 with population consisted of total 150 medical students. A self-administered questionnaire developed based on Epworth Daytime Sleepiness Scale and Pittsburgh Sleep Quality Index was used. Data was analyzed by using Statistical Package of Social Sciences (SPSS) version 16.0. RESULTS: In this study, out of 150 medical students, 26/150 (17.3%) students had abnormal levels of daytime sleepiness while 20/150 (13.3%) were border line. Sleep quality in females was better than the male. CONCLUSION: Disorders related to poor sleep qualities are significant problems among medical students in our institution. Caffeine and alcohol ingestion affected sleep and there was high level of daytime sleepiness. Sleep difficulties resulted in irritability and affected lifestyle and interpersonal relationships. PMID- 23634332 TI - Prevalence and correlates of "high dose" antipsychotic prescribing: findings from a hospital audit. AB - BACKGROUND: High dose antipsychotic prescribing is common in psychiatric care, despite a lack of its benefit from research evidence. While several studies have explored the prevalence and factors associated with high dose antipsychotic prescribing, no such report has emanated from a developing country like Nigeria. AIM: The aims of this study were to determine the prevalence of high dose prescribing among in-patients at a tertiary psychiatric hospital and to determine the pattern of antipsychotic drugs prescribed. MATERIALS AND METHODS: An audit of in-patients at a regional tertiary psychiatric facility was carried out. We examined case notes and conducted oral interviews where necessary, on all patients receiving antipsychotics using a proforma designed for the study. RESULTS: The prevalence of high dose prescribing was 38% (65/171) using a prescribed daily dose/defined daily dose ratio of 1.5. The rate of antipsychotic polypharmacy was 7% (12/171). The atypical antipsychotic, olanzapine was the most commonly prescribed antipsychotic in monotherapy. Predictors of high dose prescribing were diagnoses (P = 0.04), polypharmacy (P = 0.04), a history of previous in-patient care (P = 0.02), and use of anticholinergic drugs (P = 0.01). CONCLUSIONS: High dose prescribing was common among in-patients audited. Further studies are needed to examine factors that promote "high dose" prescribing. PMID- 23634333 TI - Non-adherence of new pulmonary tuberculosis patients to anti-tuberculosis treatment. AB - BACKGROUND: Non-adherence to anti-tuberculosis (TB) treatment adversely affects treatment success rate. It increases disease morbidity and mortality. Also, it contributes significantly to the development of drug resistance. AIM: To identify risk factors for non-adherence to anti-TB treatment by new pulmonary TB patients. SUBJECTS AND METHODS: It is a prospective cohort study at 21 TB treatment centres in E ward of Mumbai Municipal Corporation. All sputum smear positive new pulmonary TB patients initiated on treatment regimen of short course chemotherapy fro 1(st) January to 30(th) June of a calendar year were enrolled and followed up till any final outcome as per revised national TB control program. Non-adherence was defined as interruption of anti-TB treatment for >= 1 month. The factors were identified by univariate and logistic regression analysis. RESULTS: We studied 156 newly diagnosed pulmonary TB patients. Out of these 78 (50%) were non adherent to anti-tuberculosis treatment (ATT). Independent risk factors for non adherence were identified as male gender (P = 0.035) and lack of knowledge of importance of regular treatment (P = 0.001). Being female sex worker (FSW) was also an absolute risk factor for non-adherence. CONCLUSIONS: There is immense need for continuous, effective and reinforcing health education to the patient and his family. Special groups like males in the age group of 15-49 years, patients who do not have any family support like migrants, FSW need special attention to ensure adherence to ATT. PMID- 23634334 TI - Investigating maternal mortality in a public teaching hospital, abakaliki, ebonyi state, Nigeria. AB - BACKGROUND: Maternal mortality in sub-Saharan Africa has remained high and this is a reflection of the poor quality of maternal services. AIM: To determine the causes, trends, and level of maternal mortality rate in Abakaliki, Ebonyi. MATERIALS AND METHODS: This was a review of the records of all maternal deaths related to pregnancy over a ten-year period, that is, January 1999 to December 2008. Relevant information on number of deaths, booking status, age, parity, educational level of women, mode of delivery, and causes of death were extracted and analyzed. RESULTS: During the study period, there were 12,587 deliveries and 171 maternal deaths. The maternal mortality ratio (MMR) was 1,359 per 100,000 live births. The trend over the period was lowest in 2008 and highest in 1999 with an MMR of 757 per 100,000 live births and 4,000 per 100,000 live births, respectively. There was a progressive decline in the MMR over the period of study except in the years 2003 and 2006, when the ratio spiked a little, giving an MMR of 1,510 per 100,000 live births and 1,290 per 100,000 live births, respectively. The progressive decline in maternal mortality corresponded with the time that free maternal services were introduced. Hemorrhage was the most important cause of maternal death, accounting for 23.0% (38/165), whereas diabetic ketoacidosis, congestive cardiac failure, and asthma in pregnancy were the least important causes of maternal deaths, each accounting for 0.6% (1/165). Majority of the maternal deaths occurred in unbooked patients (82.4% (136/165)), whereas 17.6% (29/165) of the deaths occurred in booked cases. Forty-seven (28.5% (47/165)) patients died following a cesarean section, 8.5% (14/165) died as a result of abortion complications, and 10.9% (18/165) died undelivered. Seventy-seven (46.7% (77/165)) of the maternal death patients had no formal education. Low socioeconomic status, poor educational level, and grand multiparity were some of the risk factors for maternal mortality. CONCLUSION: There was a decline in MMR during the period of study. The free maternal health services and adequate staff recruitment, which may have contributed to the observed decline in maternal mortality, should be sustained in developing countries. PMID- 23634335 TI - Role of patients' demographic characteristics and spatial orientation in predicting operative difficulty of impacted mandibular third molar. AB - BACKGROUND: The influence of patient factors such as age, sex, weight, body mass index (BMI) and spatial orientation on operative difficulty of impacted mandibular third molar (M3) surgery is a subject of controversy in the literature. AIM: To assess the risk indicators of operative difficulty of mandibular third molar surgery at our institution. SUBJECTS AND METHODS: A descriptive cross-sectional study involving patients that presented for wisdom tooth extraction between January 2010 and December 2011. The correlation between patients' factors such as age, sex, weight, height, BMI, radiographic spatial relationship of the impacted tooth and operation time was determined with Spearman's rank correlation coefficient. Statistically significant variables were selected for multiple regression analysis to determine which factors contribute most to operative difficulty of M3. P value was set at 0.05. Statistical analysis used SPSS 17.0. RESULTS: Only patients' age and radiographic spatial relationship showed a statistically significant correlation with operation time (P = 0.038 and 0.008, respectively). Linear regression analysis of patients' age and angulation of M3 showed that both contribute 44.8% risk of increased operation time (regression coefficient = 0.448), with M3 angulation contributing more significantly to increase in operation time (P = 0.001) than increasing age of the patient (P = 0.005). CONCLUSIONS: Findings from this study have shown that increasing age of the patient and the angulation of M3 impaction increases the risk of operative difficulty of the impacted M3 significantly. PMID- 23634336 TI - Developing and organizing a trauma system and mass casualty management: some useful observations from the israeli trauma model. AB - A trauma system is a chain of arrangements and preparedness to provide quality response to injured from the site of injury to the appropriate hospital for the full range of care. Israel has a unique trauma system developed from the experience gained in peace and in war. The system is designed to fit the state's current health system, which is different from the European and American systems. An effective trauma system may potentially manage mass casualty incidence better. The aim of this paper is to discuss learning points to develop a trauma system based on the Israeli trauma model. After participating in a course on developing a trauma system organized by a top Israeli trauma center, a literature search on the topic on the Internet was done using relevant key words like trauma system and disaster management in Israel using the Google search engine in the pubmed, open access journals and websites of trauma organizations. Israel has a unique trauma system of organizing and managing an emergency event, characterized by a central national organization responsible for management, coordination and ongoing quality control. Because of its unique geopolitical situation, the armed forces has a significant role in the system. Investing adequate resources on continuous education, manpower training, motivation, team-work and creation of public volunteers through advocacy is important for capacity building to develop a trauma system. Wisdom, motivation and pragmatism of the Israeli model may be useful to streamline work in skeletal trauma services of developing countries having fewer resources to bring consistency and acceptable standards in trauma care. PMID- 23634337 TI - Premature menopause. AB - Premature menopause affects 1% of women under the age of 40 years. The women are at risk of premature death, neurological diseases, psychosexual dysfunction, mood disorders, osteoporosis, ischemic heart disease and infertility. There is need to use simplified protocols and improved techniques in oocyte donation to achieve pregnancy and mother a baby in those women at risk. Review of the pertinent literature on premature menopause, selected references, internet services using the PubMed and Medline databases were included in this review. In the past, pregnancy in women with premature menopause was rare but with recent advancement in oocyte donation, women with premature menopause now have hoped to mother a child. Hormone replacement therapy is beneficial to adverse consequences of premature menopause. Women with premature menopause are at risk of premature death, neurological diseases, psychosexual dysfunction, mood disorders, osteoporosis, ischemic heart disease and infertility. Public enlightenment and education is important tool to save those at risk. PMID- 23634338 TI - Publication of research article: an art or science? AB - The publication process is a shared responsibility. Besides the writing, reviewing, publishing, and editorial teams, readers are one of the most important pillars of this process. Readers and authors cannot be dealt with separately, because most of the readers are authors. The varieties of articles and improvement in presentations reflect the rising interest and enthusiasm of writers and readers. Increasing number in critical comments and author's reply can be considered as a post-publication peer review process. Impact Factor, which was used as a proxy for the relative importance of a journal, is now being considered a misleading tool in assessing the quality of a paper or the researcher. Here, we are trying to discuss in brief the points which should be kept in mind before manuscript preparation and submission, so that our research should reach to maximum readers in an unbiased form. PMID- 23634339 TI - Ethical Dilemma and Management of Infertility in HIV Seropositive Discordant Couples: A Case Study in Nigeria. AB - The traditional African society places an invaluable premium on procreation and, in some communities, a woman's place in her matrimony is only confirmed on positive reproductive outcome. Infertility is rife in Nigeria, and HIV/acquired immunodeficiency syndrome (AIDS) infection is a global pandemic, which has led to a drop in life expectancy across the world. In Nigeria, a number of cultural norms relating to gender roles and power dynamics constitute a serious barrier to issues of sexuality and infertility. Couples are concerned about their infertility diagnostic test being disclosed to each other, especially before marriage. This concern is understandable, especially in an environment that lacks the modern concepts and attitude toward sexual matters. This is complicated by the advent of HIV/AIDS infection and the societal mind-set that look at seropostive individuals as transgressors. At present, sexual and reproductive health rights are currently not in place because ethical issues are not given prominence by many physicians in Nigeria. A case of an infertile and seropostive discordant couple, which raised a lot of medical and ethical concerns, is presented here to awaken the consciousness of Nigerian physicians and stimulate discussions on the ethical matters such as this in clinical practice. PMID- 23634340 TI - Foreign body in vagina: an uncommon cause of vaginitis in children. AB - Vaginal discharge in children may result from a variety of causes. A long standing intra-vaginal foreign body can pose both diagnostic and therapeutic challenges in children. Treatment failure may occur because of alteration of the normal vaginal flora. A 6-year-old girl, who lived with her parents, presented with a foul-smelling, blood-stained vaginal discharge as well as dysuria for 2 years. There was no history of sexual abuse. Initial evaluation that excluded gynecologic examination revealed lower abdominal tenderness. Vaginal swab and urine cultures yielded Staphylococcus aureus sensitive to ceftriaxone only. She was commenced on this antibiotic for 2 weeks, but the discharge persisted, necessitating referral to the gynecologist. Examination under anesthesia by the gynecologist revealed shreds of toilet tissue paper extracted from the vagina and slight excoriations on the wall of the vagina. Vaginal foreign body can present with diverse symptoms. It should be considered in any young female patient presenting with recurrent or persistent vaginal discharge. PMID- 23634341 TI - Multiple peripheral osteomas of forehead: report of a rare case. AB - Osteoma is a benign slow growing osteogenic lesion, composed of well differentiated mature bone tissue, characterized by the proliferation of compact or cancellous bone, almost exclusively found in the head and neck region. Central, peripheral and extra skeletal are the three variants of osteoma. Trauma, inflammation, developmental disorders and genetic defects are considered as the etiologic factors. Paranasal sinuses are the favourite locations of peripheral osteoma of the craniofacial region; frontal and ethmoidal sinuses being the common ones. Although, peripheral osteomas are usually benign, innocuous lesions, their size and prominent location on the visible parts of the face makes the surgical intervention necessary. We report case of multiple peripheral osteomas of forehead, without involvement of the frontal sinus, which is a rare variety. PMID- 23634342 TI - Ruptured seminoma of undescended testis presenting as acute abdomen: case report with literature review. AB - We present a case of a 28-year-old male who presented with acute abdomen and was later diagnosed to be having ruptured intra-abdominal seminoma with hemoperitoneum, where the pre-operative diagnosis was not made. Laprotomy and complete excision were carried out. Rupture of intra-abdominal testicular seminoma is a rare cause of acute abdomen and hemoperitoneum. The pre-operative diagnosis is often difficult because history of cryptorchidism is not provided and imaging findings may be non-specific. In a male patient with acute abdomen and without previous history of orchidectomy, a testicular aetiology of acute abdomen should be kept as the differential diagnosis. PMID- 23634344 TI - Managing a live advanced abdominal twin pregnancy. AB - Advanced abdominal pregnancies with live twin fetuses are extremely rare and are misdiagnosed in up to 60% of the cases. Such a case is presented here, highlighting the diagnostic and management challenges encountered. A high index of suspicion in making the diagnosis of this rare variety of ectopic pregnancy, emphasizing adherence to basic imaging principles, and appropriate placental management is very important in reducing the associated morbidity and mortality. PMID- 23634343 TI - Primary breast tuberculosis presenting as a lump: a rare modern disease. AB - Breast tuberculosis is an uncommon form of entity especially in the infra-mammary area. A 25- year-old female, presented with a lump in the breast and infra mammary area. She was having off and on fever without any other complaints. There was no positive family history. Primary breast tuberculosis was diagnosed on fine needle aspiration cytology wherein ZN stain for acid fast bacilli was positive. The patient received antitubercular drugs and at 3 month follow up the swelling had resolved and the patient was asymptomatic. Breast tuberculosis is a rare disease with non-specific clinical, radiological, and histological findings. Misdiagnosis is common as biopsy specimens are pauci-bacillary and investigations such as microscopy and culture are frequently negative. PMID- 23634345 TI - Splenic tuberculosis presenting as ascites in immunocompetant patient. AB - Tuberculosis can involve any part of the gastrointestinal tract from mouth to anus, the peritoneum and the pancreatobiliary system. Here we report a case of splenic tuberculosis in a 60-year-old man who presented with ascitis. Splenic tuberculosis is an unusual clinical presentation, especially in immunocompetent patients. No primary focus of infection was detected in the lungs or any other organs. The postulated mechanisms by which the tubercule bacilli reach the peritoneum is through direct spread from adjacent organs like spleen in this case. PMID- 23634346 TI - Revisiting plummer vinson syndrome. AB - Plummer Vinson syndrome is a rare association of postcricoid dysphagia, upper esophageal webs, and iron deficiency anemia. Iron deficiency state has been hypothesized to play an etiological role. While literature review elucidates the resolution of dysphagia in most cases with iron therapy, we discuss our case where the dysphagia was resistant to such therapy and necessitated a mechanical dilatation. PMID- 23634347 TI - Asyndromic bilateral transverse facial cleft. AB - Bilateral transverse facial cleft, Tessier no 7 also known as bilateral congenital macrostomia are very rare clefts. We present an eight months old female with bilateral transverse facial cleft, third child of three siblings in a monogamous setting born to parents of Delta origin who resides in effurun Delta state of Nigeria. Mother ingested postinor several times in an attempt to abort pregnancy. Pregnant women should be encouraged to have adequate folic acid diet or supplements. PMID- 23634348 TI - Rarer in a rare. AB - Though moya moya disease is a disease of Asian origin, it is one of the very rare causes of stroke in India. It is a rare disease mainly characterized by progressive cerebrovascular episode due to the slowly progressive stenosis of supraclinoid segment of bilateral internal carotid arteries, the anterior and the middle cerebral arteries, and very rarely, posterior cerebral arteries. We hereby report a case of a young female who presented to us with the psychiatric complaints and refractory headache since her childhood. Therefore, we are reporting rarer (headache and neuropsychiatric) manifestations in the rare (moya moya) disease. PMID- 23634349 TI - A rare case of zosteriform cutaneous metastases from squamous cell carcinoma of hard palate. AB - A 70-year-old woman presented with painful nodules on the left side of the neck of 1 month duration. Upon questioning, the patient gave history of reverse smoking since 50 years. On examination, the patient had a superficial ulcer over the hard palate. A provisional diagnosis of zosteriform cutaneous metastases was made. Fine needle aspiration cytology of the nodule performed showed metastatic squamous cell carcinoma deposits. Later, biopsy was performed from the neck lesion and oral lesion, and it confirmed the diagnosis. Histopathology of the oral biopsy was suggestive of infiltrating squamous cell carcinoma. Biopsy of neck lesion was suggestive of squamous cell carcinoma secondaries. Majority of these cases can be misdiagnosed as herpes zoster and were treated with antiviral drugs. Distant metastases from oral squamous cell carcinoma are unusual, but generally occur in lungs, bone, and liver. Cutaneous metastasis is extremely rare, and it often reflects an advanced stage with sinister prognosis. Therefore, metastatic diseases should be considered in the differential diagnosis of zosteriform rash in the elderly. PMID- 23634350 TI - Role of botox in efficient muscle relaxation and treatment outcome: an overview. PMID- 23634351 TI - Pattern and determinants of antenatal booking at abakaliki southeast Nigeria. PMID- 23634352 TI - Author's Response. PMID- 23634354 TI - Advising patients about obtaining genomic profiles. AB - Neurologists, as all physicians, should begin to familiarize themselves with elements of genomic medicine to help their patients navigate the promises and pitfalls of obtaining genomic profiles. The neurologist should encourage a realistic assessment of the patient's expectations regarding the genetic information to be provided and apprise the patient of the challenges involved in obtaining interpretable, clinically useful information. A review of risks of obtaining genomic information is equally important. Discrimination, loss of privacy, receiving inaccurate or unwanted information, and learning information that may create obligations to disclose to others are all possibilities. As genomic research and direct-to-consumer opportunities to obtain genomic information expand, reliance on personal physicians for ethical advice based on current advancements in genomic profiling should be anticipated. PMID- 23634355 TI - Treating patients with medically resistant epilepsy. AB - Recent evidence suggests that medically resistant epilepsy can be identified if seizures persist despite adequate doses of 2 appropriate first-line antiepileptic drugs (AEDs). Patients with medically resistant epilepsy should have their seizures carefully characterized in order to confirm their diagnosis, select treatment, and assist in determining prognosis. Patients should be counseled about factors that aggravate epilepsy and the importance of adhering to treatments. Physicians should carefully inquire about side effects and alter therapy to eliminate or minimize these symptoms. Uncontrolled seizures cause injuries, disability, and increased mortality, so surgery should be considered as soon as seizures are proven to be medically resistant. Patients with incomplete response to AEDs and who are not surgical candidates may benefit from additional medication trials or from palliative nonmedical therapies, such as vagal nerve stimulation. PMID- 23634356 TI - The evaluation of a patient with dizziness. AB - Dizziness is the quintessential symptom presentation in all of clinical medicine. It can stem from a disturbance in nearly any system of the body. Patient descriptions of the symptom are often vague and inconsistent, so careful probing is essential. The physical examination is performed by observing the patient at rest and following simple movements or bedside tests. In general, no special tools are required. The causes of dizziness range from benign to life-threatening disorders, and features that distinguish among these may be subtle. When diagnostic testing is considered, parsimony should be the rule. Identifying common peripheral vestibular disorders is a priority. Picking this "low hanging fruit" can be the key component to excluding more serious central causes of dizziness. PMID- 23634357 TI - Multiple sclerosis therapeutic strategies: Start safe and effective, reassess early, and escalate if necessary. PMID- 23634358 TI - Practice patterns of US neurologists in patients with CIS, RRMS, or RIS: A consensus study. AB - We assess current practice patterns of US neurologists in patients with clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and radiologically isolated syndrome (RIS) using case-based surveys. For CIS, 87% recommended initiation of disease-modifying therapy (DMT) with MRI brain lesions. An injectable DMT was recommended by 90%-98% for treatment-naive, mild RRMS patients. There was 97% consensus to treat highly active RRMS, but no consensus on therapy choice. With RIS, there was consensus not to initiate treatment with brain but no spinal MRI lesions. Current US treatment patterns emphasize MRI in MS diagnosis and subsequent treatment decisions, treatment of early disease, aggressive initial treatment of highly active MS, and close patient monitoring. PMID- 23634359 TI - Practice patterns of US neurologists in patients with SPMS and PPMS: A consensus study. AB - A modified Delphi process assessed current multiple sclerosis (MS) practice patterns for secondary and primary progressive MS (secondary progressive MS [SPMS] and primary progressive MS [PPMS]). In early 2011, 2 sequential, case based surveys were administered to 75 US MS specialists to assess treatment practices and patient management. Respondents were from geographically diverse US academic (42%) and community (58%) treatment centers. There was consensus (>=75% agreement in responses) to switch disease-modifying therapies for a patient with SPMS with both MRI activity and disability progression (95%), but no consensus on treatment selection. For PPMS, responses supported diagnosis using spinal MRI (100%) and lumbar puncture (75%) and treatment initiation in patients with brain gadolinium-enhancing lesions with or without spinal cord lesions (85%); however, there was no consensus on treatment initiation with spinal cord lesions alone or initial therapy. The lack of agreement among US MS experts on the best treatment approaches for SPMS or PPMS highlights the need for effective therapies. PMID- 23634360 TI - Treatment for routine symptomatic carotid bulb atherosclerosis: Carotid endarterectomy is better than stenting. PMID- 23634361 TI - Approach to the elderly patient with gait disturbance. AB - The prevalence of gait disturbances and falls increases dramatically with age, but these problems are not universal in the elderly. They should trigger a systematic search for underlying disease states, many of which can be treated medically or surgically, or significantly ameliorated through provision of physical therapy focused on gait training and aids to ambulation, removal of safety hazards in the environment, and the elimination of polypharmacy. While cardiovascular, orthopedic, and rheumatologic diseases account for the majority of gait disturbances in the elderly, the aim here is to outline an approach to the diagnosis and treatment of a broad array of neurologic conditions causing gait disturbance in the elderly. PMID- 23634362 TI - Neuro-ophthalmology: Five new things. AB - The field of neuro-ophthalmology is broad and interacts with other disciplines in neurology and ophthalmology along with neurosurgery, neuroradiology, rheumatology, and infectious disease. A number of interesting advances in diagnostic criteria, monitoring ability, and disease etiology have occurred in the last year that will improve our ability to take care of patients. PMID- 23634363 TI - Diagnostic tests for Alzheimer disease: FDG-PET imaging is a player in search of a role. PMID- 23634364 TI - Diagnostic tests for Alzheimer disease: Judicious use can be helpful in clinical practice. PMID- 23634365 TI - Cauda equina syndrome secondary to intravascular lymphoma. PMID- 23634366 TI - Approach to the patient with transient alteration of consciousness. AB - Evaluating transient impairment of consciousness is critical to diagnose epileptic seizures, syncope, parasomnias, organic encephalopathies, and psychogenic nonepileptic seizures. Effective evaluation of episodic unconscious events demands interactive interviewing of the patient and witnesses of the events, with judgment as to historians' observational abilities. When generalized tonic-clonic seizures have been witnessed by medical staff or other reliable observers, a search for concomitant nonconvulsive events and for comorbid illnesses often elucidates diagnoses unsuspected by the referring physician. Consultation for stupor-coma should not miss a potentially reversible acute severe encephalopathy, particularly when reversibility requires timely therapy. Perspicacious analyses of complex cognitive-motor phenomena support judicious application of diagnostic procedures, including brief or prolonged EEG and video EEG, EKG tilt-table testing, EKG loop monitoring, and brain imaging. PMID- 23634367 TI - Diagnosis and treatment of rapidly progressive dementias. AB - Rapidly progressive dementias are conditions that typically cause dementia over weeks or months. They are a particular challenge to neurologists as the differential diagnosis often is different from the more typical, slowly progressive dementias. Early and accurate diagnosis is essential, as many of the etiologies are treatable. The information in this review is in part based on experience through our rapidly progressive dementia program at the University of California San Francisco, Memory and Aging Center. As treatment of a rapidly progressive dementia is entirely dependent on the diagnosis, we present a comprehensive, structured, but pragmatic approach to diagnosis, including key clinical, laboratory, and radiologic features. For the 2 most common causes of rapid dementia, treatment algorithms for the autoimmune encephalopathies and symptomatic management for the neurodegenerative causes are discussed. PMID- 23634368 TI - Paraneoplastic syndromes and autoimmune encephalitis: Five new things. AB - We review novel findings in paraneoplastic syndromes including the Lambert-Eaton myasthenic syndrome, and then focus on the novel disorders associated with antibodies against cell surface antigens, discussing the importance and caveats of antibody testing, and providing an algorithm for interpretation of results. In anti-NMDAR encephalitis 2 novel findings include the recognition of a characteristic EEG pattern ("extreme delta brush") in 30% of patients and the demonstration of a fronto-temporo-occipital gradient of glucose metabolism that correlates with disease activity. In limbic encephalitis, antibodies to GABA(B) receptor are the most frequently detected in patients with small-cell lung cancer who are anti-Hu negative, and antibodies to mGluR5 distinctively associate with Hodgkin lymphoma (Ophelia syndrome). We also address the syndromes associated with "VGKC-complex antibodies," a problematic term that groups well-characterized immune-mediated disorders (LGI1, Caspr2) with others that lack syndrome specificity, are less responsive to treatment, and for which the target antigens are unknown. PMID- 23634369 TI - Mechanical thrombectomy devices for treatment of stroke. AB - Mechanical thrombectomy devices comprise a wide array of endovascular tools cleared for removing thrombi from the neurovasculature in acute ischemic stroke patients. In the United States, 3 classes of mechanical thrombectomy devices have been cleared by the Food and Drug Administration: coil retrievers in 2004, aspiration devices in 2008, and stent retrievers in 2012. Available evidence and fundamental physiologic principles suggest that mechanical thrombectomy is appropriate for patients with large, proximal intracranial artery occlusions due to emboli of cardiac or arterial origin and is most effective when performed as soon as feasible after onset in patients known to still be harboring salvageable penumbral tissue. This review summarizes the mechanism of action of these devices, clinical trial results for efficacy and safety, and clinical use. PMID- 23634370 TI - Oculopalatal tremor in multiple sclerosis with spontaneous resolution. PMID- 23634371 TI - Impulse control disorders and compulsive behaviors associated with dopaminergic therapies in Parkinson disease. AB - Impulse control disorders (ICD) (most commonly pathologic gambling, hypersexuality, and uncontrollable spending) and compulsive behaviors can be triggered by dopaminergic therapies in Parkinson disease (PD). ICD are especially prevalent in patients receiving a dopamine agonist as part of their treatment regimen for PD, and have also been reported when dopamine agonists are used for other indications (e.g., restless legs syndrome). Although these iatrogenic disorders are common, affecting 1 in 7 patients with PD on dopamine agonists, they often elude detection by the treating physician. ICD lead to serious consequences, causing significant financial loss and psychosocial morbidity for many patients and families. ICD can appear at any time during treatment with dopamine agonists, sometimes within the first few months, but most often after years of treatment, particularly when patients receive dopamine agonists and levodopa together. In most cases ICD resolve if the dopamine agonist is withdrawn, and PD motor symptoms are managed with levodopa monotherapy. Familiarity with the clinical aspects, risk factors, pathophysiology, and management of ICD is essential for physicians using dopaminergic therapies to treat PD and other disorders. PMID- 23634372 TI - What is the standard approach to assessment of an unprovoked seizure in an adult?: UNITED STATES. AB - A 34-year-old man experienced a single unprovoked generalized tonic-clonic seizure in the earlier morning hours while asleep. His spouse was awakened during the respiratory alteration and the repetitive movements. The patient was in excellent health without a prior history of seizures or remote symptomatic neurologic disease. There was a history of migraine headaches and mild closed head trauma as a child. He was receiving no prescription drugs. The family history was negative for epilepsy. Upon evaluation in the emergency department, a CT of the head was normal. The patient was described as being "postictal" on examination. An EEG study several hours after the seizure showed bitemporal, nonspecific slowing without definite epileptiform activity. An MRI head was performed the following day and was unremarkable. The patient was referred by the emergency room physician for an outpatient neurologic consultation. PMID- 23634373 TI - What is the standard approach to assessment of an unprovoked seizure in an adult?: BRAZIL. AB - The information era has narrowed the "conceptual" gap as to how to evaluate patients with medical problems. Nonetheless, countries differ in critical mass of expert practitioners, accessibility to resources, and level of medical and general education. Therefore, particularly in large countries like Brazil, specific approaches relate to socioeconomic, geographic, and cultural constraints. PMID- 23634374 TI - What is the standard approach to assessment of an unprovoked seizure in an adult?: HONG KONG. AB - Since Hong Kong is highly urbanized and acute public hospitals have been established across the city, most patients with unprovoked seizures not already receiving antiepileptic drug (AED) therapy, particularly convulsive seizures, will be admitted as emergency for assessment. A thorough history is taken from the patient and any witnesses to the seizure. This includes the circumstance of the seizures, detailed symptoms and signs experienced by the patient and witnessed by others before, during, and after the seizure, any potential precipitating factors, history of previous seizures (that the patient might have overlooked), and history of previous brain insults that might have increased the risk of epilepsy later in life, including gestational and birth history, history of childhood febrile seizure, significant head trauma, any family history of epilepsy or seizures, comorbidities, current medications, drug and alcohol abuse, and social history including employment, driving, and living circumstances. A detailed physical and neurologic examination is performed. PMID- 23634375 TI - Pediatric movement disorders: Five new things. AB - There is increasing need for both consensus definitions and continued research into the causes, clinical spectrum, and treatment of pediatric movement disorders. Treatment has been largely based on experience rather than evidence because clinical trials are limited. With development of consensus definitions, identification of causative genes, understanding of the clinical spectrum of disease, and clinical trials, we can provide overall better care for children with movement disorders. This review highlights 5 areas where progress is being made to achieve these goals in pediatric movement disorders. PMID- 23634376 TI - Patient assessment of physician performance of epilepsy quality-of-care measures. AB - To identify gaps in physician practice of epilepsy care, an online survey was sent to members of a Web-based epilepsy community to ascertain whether their physician performed 8 quality measures for epilepsy care. A total of 221 of 348 recently active epilepsy patients (64%) completed the survey. More than 80% of patients agreed they knew their seizure type, epilepsy syndrome, current seizure frequency, and had an EEG and neuroimaging. Fewer (60%) recalled being asked about medication side effects at each visit and safety issues annually. Only 48% report referral to an epilepsy surgery specialist and only 46% of appropriate patients had discussed reproductive issues with epilepsy. This demonstrates some potential gaps in epilepsy care and these data have been submitted to the American Academy of Neurology and the National Quality Forum. PMID- 23634377 TI - Personalized medicine: The return of the house call? AB - Personalized medicine is a new mantra evolving in health care. Harnessing each person's clinical, genetic, genomic, and environmental information drives the concept. The idea is simple. We can maximize a patient's chances of a better outcome if we base treatments on what we know. However, isn't this in many ways the way it's always been? Isn't this in part the basis for that old-time house call? To see how a disease or condition is being cared for in the home environment? Clinicians have long used personalized medicine, without overt use of single nucleotide polymorphisms, but certainly not totally void of genetic information. Of course, physicians of the past did not have gene chips, but they did have family histories often informing their decisions. Today as we raise the hopes for targeted therapies to break us free from the algorithmic treatments often followed by hit and miss approaches, there is a renewed fervor for personalized medicine. How do we get there and how does the average clinician or researcher understand the burgeoning array of information, talking heads, and latest hype of subgroup benefits? A key aspect is to trust your training, your experience, and your instincts, coupled with a few repeated doses of biostatistics. PMID- 23634378 TI - Donepezil 23 mg: An empty suit. AB - Donepezil 10 mg/day has been a modestly successful therapeutic agent for the palliative treatment of Alzheimer disease dementia. In 2011, seeking greater efficacy and an extension of the Aricept brand, a 23-mg formulation of donepezil was introduced. A large-scale trial, organized by Eisai, the sponsor, failed to show superiority in their primary analyses of donepezil 23 mg/day in patients with moderate to severe Alzheimer disease dementia vs 10 mg, but the published report used post hoc analyses to claim "statistically significant benefits." There was greater than a 3 times higher rate of gastrointestinal side effects with 23 mg of donepezil compared to 10 mg. Thus, not only does donepezil 23 mg/day increase the likelihood of unacceptable gastrointestinal side effects, it provides no clinical benefits. Aricept 23 mg is about 10 times more costly per pill than donepezil 10 mg. PMID- 23634379 TI - Acute encephalopathy as the initial manifestation of CADASIL. AB - A 29-year-old right-handed G1P1 Caucasian woman presented with acute bifrontal headache (which resolved within 1 day), confusion, and difficulty using her right hand on postpartum day 10. She did not report nausea, vomiting, or visual complaints. The patient was previously healthy except for her recent preeclampsia, which required emergent cesarean section. On examination, the patient was afebrile, awake, alert, and apathetic. She was able to follow few one step midline commands (e.g., eye opening and closing) inconsistently but not appendicular commands. Her neurologic deficits were remarkable for expressive aphasia, intermittent receptive aphasia, and hyperreflexia with bilateral extensor plantar responses. No meningismus or other focal neurologic deficits were present. Routine laboratory testing including urine toxicology screen was normal. C-reactive protein was 23 mg/L (reference range: <5 mg/L), and erythrocyte sedimentation rate (ESR) was 38 mm/h (reference range: 0-20 mm/h). Rheumatologic panel was negative. Brain MRI showed extensive non-contrast enhancing T2/fluid-attenuated inversion recovery hyperintensities involving periventricular and deep white matter, especially the centrum semiovale, corpus callosum, bilateral anterior temporal lobes, bilateral caudate nucleus, and globus pallidus (figure, A-C). No evidence of acute or previous stroke was found. CT angiogram and venogram revealed no cerebral sinus thrombosis or large vessel vasculitis. Lumbar puncture opening pressure was 18.5 cm H2O. CSF showed normal cell counts, protein, and glucose levels without oligoclonal bands. EEG recorded in awake, drowsy, and sleep state was normal. Dilated ophthalmic examination showed no microangiopathy or retinal branch arterial occlusion. Audiologic examination was normal. PMID- 23634380 TI - Restricted diffusion preceding gadolinium enhancement in large or tumefactive demyelinating lesions. AB - Although restricted diffusion without coincident contrast enhancement is most commonly associated with cerebral ischemia, large or tumefactive multiple sclerosis (MS) lesions may demonstrate this pattern initially, followed by subsequent gadolinium (Gd) enhancement. The clinical and MRI characteristics of 3 patients with MS with this imaging pattern are reviewed. All patients had brain MRI lesions >1 cm in diameter, in locations consistent with new neurologic symptoms, and with prominent restricted diffusion but no Gd enhancement. Demyelinating lesion etiologies were supported by CSF findings, laboratory exclusion of alternative diagnoses, lesion evolution, or additional lesions characteristic of MS on brain MRI. Follow-up imaging within 2-4 weeks showed decreased restricted diffusion with patchy Gd enhancement which resolved on subsequent imaging. This imaging evolution may reflect early demyelination prior to inflammation-associated blood-brain barrier disruption. PMID- 23634381 TI - Non-Parkinson movement disorders: Five new things. AB - SOLUTIONS TO THE MAJOR RIDDLES IN MOVEMENT DISORDERS ARE APPEARING AT A BREATHTAKING PACE: 1) loss-of-function mutations in PRRT2, which encodes a cell surface protein expressed in neurons, have been found in many patients with paroxysmal kinesigenic dyskinesias; 2) mutations in CIZ1, which encodes a protein involved in cell-cycle control at the G1-S checkpoint, have been identified in a small percentage of patients with cervical dystonia; and 3) finally, after many years of genetics and identification of more than 25 disease-associated genes, cellular studies related to the pathobiology of hereditary spastic paraplegia are converging on defects in modeling the endoplasmic reticulum and membrane trafficking. On the treatment front, the distinctive syndromes of faciobrachial dystonic seizures with anti-LRI1 antibodies and anti-N-methyl-d-aspartic acid encephalitis with orobuccolingual dyskinesias are becoming increasingly recognized by clinicians as imminently treatable conditions. Also on the treatment front, the first phase I trial of MRI-guided high-intensity focused ultrasound for essential tremor has been completed and intraoperative MRI is currently being used to place electrodes in the brains of patients with medically intractable dystonia. Definitive etiologies and efficacious treatments for non Parkinson disease movement disorders are no longer wishful thinking. PMID- 23634382 TI - A personal journey in advocacy. AB - Over the past decade, neurology advocacy has caught the attention of neurologists feeling increasingly frustrated about the health care environment in which they practice. We describe our experience in practicing advocacy at the national and local levels. Neurologists can participate in many levels of advocacy to benefit their patients and their profession. PMID- 23634383 TI - Quality measures for neurologists: Financial and practice implications. AB - Measuring and reporting health care quality is increasingly becoming part of clinical practice and reimbursement for specialists, including neurologists. The goal is to improve the value of care. Current major programs tie quality measurements to reimbursement, including programs from the Centers for Medicare and Medicaid Services: the Physician Quality Reporting System, the Electronic Health Record Incentive Program (and Meaningful Use), and Accountable Care Organizations. Many specialty boards, including the American Board of Psychiatry and Neurology, now require clinical practice quality measurements for maintenance of certification. Practitioners may find these programs confusing, overlapping, burdensome, and not clearly relevant to promoting better patient care. Yet, integrating quality metrics into practice has entered the mainstream and is increasingly tied to reimbursement. Further, over the next few years, most programs will switch from bonus incentives for participation to penalties for nonparticipation. This article aims to clarify current and rising quality measurement programs relevant to neurologists. PMID- 23634384 TI - Formularies, costs, and quality of care: Formulary restrictions are not the answer, especially for epilepsy. AB - The goal of treating an individual with epilepsy is to have no seizures and no side effects. Limiting availability of medications appears to be a simple way of controlling costs of patient care. This approach potentially jeopardizes both efficacy and safety. We argue, in this edition of Current Controversies, that limiting costs by restricting formularies is detrimental to the patients from an efficacy, safety, and cost perspective. PMID- 23634385 TI - Brain and spinal manifestations of Miller-Dieker syndrome. AB - A 6-month-old infant with LIS1 17p13.3 deletion-positive Miller-Dieker syndrome (MDS) presented with increased seizures in the setting of a Pseudomonal and Enterococcal urinary tract infection and a buttock abscess associated with a lumbosacral dermal sinus tract. MRI of the neuraxis revealed lissencephaly (figure 1), a tethered cord without lipoma or other mass (figure 2A), and an infected lumbosacral dermal sinus tract. Communication with the spinal canal could not be appreciated (figure 2B). The dermal sinus was explored and found not to extend into the spinal canal. This tract was excised and the lateral abscess drained. Tethered cord release is planned upon resolution of infection. PMID- 23634386 TI - Anatomical variations in the emergence of the cutaneous nerves from the nerve point in the neck and identification of the landmarks to locate the nerve point with its clinical implications: a cadaveric study on South Indian human foetuses. AB - OBJECTIVE: The cutaneous nerves from the cervical plexuses are anaesthetized by using local anaesthetics for pain relief or when minor surgical operations are performed. Knowing the variations in these nerves is important for anaestheticists to administer an effective anaesthesia to a particular nerve. So, the aim of this study was to look for the variations in the emerging patterns of the cervical cutaneous nerves in the neck and to locate the nerve point in the neck by using the superficial landmarks. MATERIALS AND METHODS: The neck was dissected in 16 foetal cadavers (total 32). The foetuses were divided into 2 groups, depending upon their ages- group 1 (13-24wks) and group 2 (24-38wks). The cervical cutaneous nerves were dissected. Measurements for locating the nerve point, were taken in both the groups. RESULTS: The statistical analysis of the measurements was done. In group 1, the mean distances of the nerve point from the External Acoustic Meatus (EAM), on the right and left sides, were 2.06cm and1.85cm and in group 2, the distances on the right and left sides were 2.32cm and 2.08cm. The mean distance of the nerve point from the clavicle in group 1, on both the right and the left sides was 1.85cm, and in group 2, the mean distances on the right and left sides were 2.67cm and 2.62cm. The variations in the cutaneous nerves which emerged from the nerve point were recorded and photographed. CONCLUSION: These landmarks will help the anaestheticists in locating the nerve point. These variations in the branches of the cervical plexus should be known to the anaestheticists while they give anaesthesia to a particular nerve during a nerve block. PMID- 23634387 TI - A Study on the Accessory Head of the Flexor Pollicis Longus Muscle (Gantzer's Muscle). AB - INTRODUCTION: The present study was planned to analyze the Accessory Head of the Flexor Pollicis Longus muscle' (AHFPL) or Gantzer's muscle and its incidence. It is an additional muscle in the forearm which might cause pressure symptoms to the underlying structures, especially to the anterior interosseus nerve. MATERIALS AND METHODS: This study was performed on 180 upper limbs (90 right and 90 left). The morphology and the morphometry of AHFPL was done. In this investigation, we observed the various shapes, origins, insertions, nerve supplies and relations of the muscle. OBSERVATIONS AND RESULTS: The incidence of the accessory head of the flexor pollicis longus muscle was seen in 92 cases (51.11%). It was found bilaterally in 66 (71.73%) cases and unilaterally in 26 cases (28.26%), among which, in 16, it was seen on the right side and in 10 on the left side. With the increasing incidence of the Gantzer's muscle, one can call it as an evolutionary muscle. CONCLUSION: The present study supplements the knowledge on the morphology of AHFPL muscle and its relationship with the anterior interosseus nerve. An increased incidence of this muscle may be the causative factor for the complete anterior interosseous nerve syndrome. PMID- 23634388 TI - Morphometry of the iliolumbar artery and the iliolumbar veins and their correlations with the lumbosacral trunk and the obturator nerve. AB - OBJECTIVES: To reveal the variations of the iliolumbar artery and the iliolumabar veins and their correlation with the surrounding important structures. METHODS: We dissected the iliolumbar region bilaterally in 20 formalin-fixed adult cadavers. The diameter of the iliolumbar artery at its origin, its length up to the branching point, the distance between the iliolumbar artery and the inferior margin of the fifth lumbar vertebra and the distance between the iliolumbar artery and the bifurcation point of the common iliac artery, were measured. The pattern of drainage, the dimensions, the points of confluence with the common iliac vein and the obliquity of the iliolumbar vein were noted. The correlation between the iliolumbar artery and the veins to the obturator nerve and the lumbosacral trunk was recorded. RESULTS: The iliolumbar artery originated from the posterior trunk of the internal iliac artery or from the internal iliac artery. The mean diameter of the iliolumbar artery, at its origin, was 3.5+/-0.5 mm. The mean distance between the origin of the iliolumbar artery and the bifurcation point to the iliac and the lumbar branches was 12.2+/-5.5 mm. The distance between the origin of the iliolumbar artery and the lower edge of the fifth lumbar vertebra was 43.2+/-11.6 mm. The distance between the origin of the iliolumbar artery and the bifurcation point of the common iliac artery was 38.7+/ 10.6 mm. The mean distance of the iliolumbar veins from the inferior vena cava, overall, was 35+/- 9.9 mm. The mean width of the mouth of the iliolumbar vein was10.7 +/- 5.1 mm and the mean angle of obliquity of the vein with respect to the long axis of the common iliac vein was 75.50. The tributaries which drained into the main iliolumbar vein were variable. The iliolumbar artery passed anterior in 70% and it passed posterior to the obturator nerve in 30%. The veins were lying anterior to the obturator nerve in 45% and they were lying posterior in 55%. The multiple tributaries which drained into the iliolumbar vein relation of the tributaries were variable, few passed anterior and few passed posterior. The iliolumbar artery was seen anterior to the lumbosacral trunk in 30%, it was posterior in 54%, it was cleaved in 8% and the branches of the artery were passing on either side of the lumbosacral trunk to enclose it like a clasp in 8%. The veins were anterior to the lumbosacral trunk in 40% and they were posterior in 60%. CONCLUSION: The anatomical features of the iliolumbar artery, the iliolumbar veins and their correlation with the anatomical landmarks, which were presented here, would be helpful in decreasing the iatrogenic trauma to the neurovascular structures in the iliolumbar region. PMID- 23634389 TI - An anatomical study on the foramen ovale and the foramen spinosum. AB - INTRODUCTION: An anatomical study was undertaken to note the shape of the foramen ovale(FO), foramen spinosum (FS) & presence or absence of canalis innominatus. FO is present in the posterior part of the greater wing of sphenoid. FS is located posterolareral to foramen ovale. Aims & Objective: We attempted this study to find out the variations in shape, bony growth & divisions of FO & FS in available dry human skulls. MATERIAL & METHODS: We studied 100 human skulls available in the Department of Anatomy MVPS Medical College, Nashik. This study of FO & FS was done in both male & female skulls. OBSERVATION & RESULTS: We found oval, round, almond, triangular shaped FO. Variations in the shape of FO showed the maximum as oval shaped followed by almond, round & slit like. CONCLUSION: FO is of great surgical & diagnostic importance in procedures like percutaneous trigeminal rizotomy in trigeminal neuralgia, transfacial fine needle aspiration technique etc. Considering such clinical importance of FO & FS, this study was worthwhile as far as neurosurgeons are concerned. PMID- 23634390 TI - Semmelweis's Forgotten Gift: Has Handwashing Lost Its Importance? AB - BACKGROUND AND OBJECTIVES: The hands harbour a kaleidoscope of bacteria, thus making hand washing an essential attribute in preventing the transmission of nosocomial pathogens. Medical students, as a part of their curriculum, are taught about handwashing. However, their adherence to it is doubtful. This study was carried out to ascertain the impact of educating medical students about the correct technique of handwashing and its role in reducing the bacterial contamination of their hands. METHODS: The hands of 50 medical students who attended the clinical postings were screened for bacterial colonisation. Following their screening, 30 students who had the highest colonization of bacteria were followed up for a second round of sampling. They were further allotted into two arbitrary groups: the control group and the test group. The procedure for an adequate handwash was taught to the test group, whereas the control group had been taught it as a part of their clinical curriculum during their postings. Each student's hands were sampled, both preceding and following a handwash. RESULTS: Following the handwashing, the students of the test group had a significantly (p=0.011) lower mean bacterial colonization on their hands, in contrast to the control group. Moreover, 86.7% of the students from the control group harboured Staphylococcus aureus even after handwashing, whereas only 40% of the test group students had it. The preliminary screening concluded that: (i) Females harboured a significantly greater (p=0.038) bacterial colonization on their hands than males.(ii) The students who wore rings showed a higher contamination (p=0.05). INTERPRETATION AND CONCLUSION: This study revealed that the students of the test group were at an advantage, as they had been given immediate prior instructions, whereas the control group had been taught the same technique at their clinical postings and were not instructed preceding the handwash and the sample collection. It can be concluded that a prior instruction in the form of teaching or visual aids such as posters etc., regarding the method of handwashing, is essential for an effective handwash, regardless of the past teaching. The instruction that is imparted to the students as a part of their curriculum needs reinforcement. PMID- 23634391 TI - The baseline widal titre among the healthy individuals of the hilly areas in the garhwal region of uttarakhand, India. AB - INTRODUCTION: Typhoid fever is endemic in all parts of India and the Widal test is widely used for its diagnosis. In the endemic areas, the healthy people may contain antibodies which are capable of reacting upto a variable titre in the Widal test, due to a past exposure, TAB vaccination and cross reacting antigens. Therefore it varies widely from place to place and is referred to as the baseline titre of that area. The aim of this study was to determine the average baseline titre of the apparently healthy population in the Garhwal region of Uttarakhand, India. MATERIAL AND METHODS: Blood samples were collected from healthy volunteers over the period from February 2011 to January 2012 and they were analyzed for the presence of the Salmonella antibodies by carrying out the Widal tube agglutination test. RESULTS: Among the 2164 serum specimens which were tested, 922 (42.6%) sera were found to be positive for the Widal test and 1242 were negative. The most frequently recorded titre of the reactive sera was 1:40 for the anti-O antibodies and it was 1:80 for the anti-H antibodies and this was the baseline titre for this region. CONCLUSION: Based on the above results of our study, it has been recommended that the cut-off titre of 1:80 for the anti-O antibodies and of 1:160 for the anti-H antibodies may be considered as diagnostic for enteric fever in the Garhwal region of Uttarakhand, India. PMID- 23634392 TI - The bacteriology of diabetic foot ulcers, with a special reference to multidrug resistant strains. AB - INTRODUCTION: A diabetic foot infection is one of the most feared complications of Diabetes mellitus. Many studies have reported on the bacteriology of Diabetic Foot Infections (DFIs) over the past 25 years, but the results have been varied and often contradictory. AIMS AND OBJECTIVES: This study was carried out to determine the bacterial profiles of infected ulcers and the antibiotic resistance pattern of the isolates. MATERIALS AND METHODS: Samples were collected from 50 patients with diabetic foot ulcers by using sterile swabs and they were processed. RESULTS: A total of 75 bacterial isolates were obtained from 50 patients with diabetic foot ulcers. The age group of these patients ranged from 35 to 80 years and the maximum number of patients was in the age group of 60 to 65 years. Gram negative bacilli were more prevalent (65.1%) than gram positive cocci (34.9%). The commonest isolate was Pseudomonas spp (16%), followed by Escherichia coli (14.6%) and Staphylococcus aureus (13.3%).The antibiotic sensivity profiles of the bacteria were also studied. 37.5% of the gram negative bacilli were ESBL producers and 31% were carbapenemase producers. CONCLUSION: This study showed a preponderance of gram negative bacilli among the isolates from the diabetic foot ulcers. Knowledge on the antibiotic sensitivity pattern of the isolates will be helpful in determining the drugs for the empirical treatment of diabetic ulcers. PMID- 23634393 TI - The prevalence of group a streptococci carriers among asymptomatic school children. AB - AIM: The Group A Streptococci (GAS) cause several suppurative and nonsuppurative infections. GAS frequently gets colonized in the throat of asymptomatic school children. A preliminary study was conducted to identify the GAS carrier state in apparently healthy children who belonged to various schools which were located in and around the rural village, B.G.Nagara, Mandya Dist, Karnataka state, India. MATERIAL AND METHODS: Throat swabs were collected from 2000 asymptomatic school children who were aged 5-15 years. The beta haemolytic streptococci isolates were sero-grouped by agglutination tests by using specific antisera (HiStrep Latex Test, Hi-Media, Mumbai, India). RESULTS: Out of the 44 (2.2%) beta haemolytic which were isolated, 38 (86.36%) were GAS, 5 (11.36%) were Group C Streptococci and one (2.27%) was Group G Streptococcus. Among the 38 GAS positive children, 24 (63.16%) were transient carriers, 10(26.32%) were recurrent carriers and 4 (10.52%) were chronic carriers. The GAS chronic carriers were of the age group of 9-12 years. CONCLUSION: The present study showed the prevalence of GAS among the asymptomatic school children in this location. The chronic carriers were treated with azithromycin for 3 days. A bacteriological cure was confirmed by doing throat swab cultures at intervals of one month and four months after the treatment. Identification of the GAS carriers and treating them, not only prevents them from developing non -suppurative complications, but they also prevent the spread of GAS to their family members and other children. PMID- 23634394 TI - Multidrug-Resistance and Extended Spectrum Beta-Lactamase Production in Uropathogenic E. Coli which were Isolated from Hospitalized Patients in Kolkata, India. AB - BACKGROUND AND OBJECTIVE: Urinary Tract Infections (UTIs) are mostly caused by Escherichia coli. The appropriate therapy demands a current knowledge on the antimicrobial susceptibility pattern amongst these pathogens, as an inappropriate use of antibiotics may lead to complications and treatment failure. The UTIs which are caused by multidrug resistant Extended-Spectrum Beta-Lactamase (ESBL) producing bacteria further pose a severe problem, as the treatment options are limited. The aim of this study was to identify the pattern of multi drug resistance amongst the uropathogenic E. coli (UPEC) isolates which were obtained from hospitalized patients. MATERIALS AND METHODS: Forty UPEC were isolated from 200 urine samples of hospitalized patients who were clinically suspected for UTIs. Antimicrobial susceptibility screening was performed by using 16 antibiotics, by the Kirby Bauer disk diffusion technique. The isolates which were resistant to the third generation cephalosporins were subjected to the ESBL confirmatory test by using drug and drug-inhibitor combination disks by following the CLSI guidelines. RESULTS: All the 40 isolates except three were multidrug resistant. They showed the highest sensitivities for nitrofurantoin (72.5%) and amikacin (70%). A high level of resistance was observed against ampicillin (97.5%), nalidixic acid and cefelexin (95%), amoxicillin (92.5%), cotrimoxazole (82.5%) and ciprofloxacin (80%) respectively. Thirty different antibiotic resistance patterns were observed against the different antibiotics. Twenty-eight out of the 40 isolates were resistant to the third generation cephalosporins. However, the phenotypic test for the ESBL confirmation indicated that eighteen out of the twenty-eight isolates were ESBL producers and that eleven different drug resistance patterns were observed amongst them. CONCLUSIONS: Therefore, this study accounts for the varied multidrug resistance pattern amongst the uropathogenic E. coli which were isolated from hospitalized patients in Kolkata, an eastern region of India. Nitrofurantoin and amikacin should be assigned as potent drugs to treat this infection in this region of the country. These varied resistance patterns present major therapeutic and infection control challenges and they suggest a heterogeneous population of the uropathogenic E. coli isolates which circulate in this sector of India. PMID- 23634395 TI - The Prevalence of Intestinal Parasitic Infestation and the Related Profile of the CD4 (+) Counts in HIV/AIDS People with Diarrhoea in Jaipur City. AB - INTRODUCTION: Gastrointestinal Tract (GIT) infections are among the most frequent infections in HIV/AIDS patients. The intestinal opportunistic parasitic infections in HIV-infected subjects present most commonly as diarrhoea. A study was conducted to determine the prevalence of enteric parasitic infections in HIV infected patients with diarrhoea, with different levels of immunity. METHODS: This study was carried out at the HIV Lab of the Microbiology Department of a tertiary care teaching hospital in Jaipur, Rajasthan, between June-October 2009 among consecutively enrolled 75 HIV infected patients who presented with diarrhoea. Stool samples were collected and examined for enteric parasites by using microscopy and special staining methods. The CD4 (+) cell counts were estimated by using the FACS count system. RESULTS: Intestinal parasitic pathogens were detected in 38.66% patients, Cryptosporidium species was the most common enteric opportunistic parasite which accounted for 37.93 % of the total parasites, followed by Isospora belli 31.03 %. In the HIV infected patients with CD4 (+) counts of < 200 cells/MUl, parasites were identified in 56.25 % patients and in HIV patients with CD4 (+) counts between 200-499 cells /MUl, parasites could be identified in 27.5 % of the patients . No parasite was detected in the patients with CD4 (+) counts of >500 cells/ MUl. CONCLUSION: Parasitic infections were detected in 38.66% HIV infected patients with diarrhoea and a low CD4 (+) count was significantly associated with opportunistic infections. Identification of the aetiological agent of diarrhoea in an HIV patient is very important, as it can help in the institution of the appropriate therapy and the reduction of the morbidity and the mortality in these patients. PMID- 23634397 TI - The Patients' Adherence and Adverse Drug Reactions (ADRs) which are Caused by Helicobacter pylori Eradication Regimens. AB - BACKGROUND: Helicobacter pylori is a major cause of upper gastrointestinal disorders. The eradication of H. pylori has been recommended for the treatment of different gastrointestinal diseases. Notwithstanding, a combination therapy is needed for Helicobacter pylori eradication, but using these medications can be the cause, the incidence risk of patients' adherence to treatment regimens reduction and probably increase risk of Adverse Drug Reactions (ADRS), so, it is seem that evaluation the out come of combination therapy is need more than the past. AIM: The aim of present study was to determine the patients' adherence to the treatment and the ADRs with five eradiation regimens. SETTING AND DESIGN: A cross sectional study was done in a well known referral clinic of gastrointestinal disorders in Tehran, Iran. METHODS AND MATERIALS: Ninety patients were evaluated the study (18 in each of the five regimens). The adherence to the treatment and the ADRs of the patients were asked during the treatment, twice, by doing telephone assays. STATISTICAL ANALYSIS USED: The data were analyzed by using the SPSS, 17 software and the statistical significance was accepted for the P values of 0.05. RESULTS: 81% of the patients had a good adherence and there was no significant difference between the types of regimens (triple or quadruple therapy) and the adherence to the treatment regimens by the patients (p=0.6). Also, we found that there was no significant relationship between the types of regimens and the sex (p=0.99), education level (p=0.99), accommodation (p=0.93), an existence of underlying disease (p=0.86) and the concurrent use other medications (p=0.93). But there was a significant relationship between the patients' age and adherence to the treatment regimens (p=0.008). The most reported ADRs belonged to gastrointestinal (GI) disorders (an abnormal taste had the most prevalence (36.6%) among the GI disorders). There was no significant relationship between the regimen type and the GI ADRs, (p=0.48). CONCLUSION: The findings of this study showed that the patients' adherence to the treatment regimens and the ADRs did not have a significant relationship with the various eradication regimens for H. pylori. It seems that the type of H. pylori eradication regimen may not be an important factor in the patients' adherence to the treatment regimens and the ADRs. PMID- 23634396 TI - The clinical, serological and molecular diagnosis of emerging dengue infection at a tertiary care institute in southern, India. AB - INTRODUCTION: Dengue is an acute viral infection which presents as uneventful pyrexia to a fatal complication. This infection is increasingly being recognized as the world's major emerging tropical disease and an important public health problem. This article highlights the clinical manifestations of Dengue virus infection and the various molecular tests that were used for its laboratory diagnosis. METHODS: Serum samples from 713 suspected cases of Dengue were collected between August and December 2007. The clinical profiles of 123 hospitalized patients were analyzed. Serology, RT- PCR, virus isolation and sequencing were done. RESULTS: The most common clinical symptoms were fever, thrombocytopenia, rash and elevated liver enzymes. The demonstration of the Dengue RNA in 5.16% samples, the detection of Dengue specific IgM antibodies in 18% samples and the isolation of the DENV-4 and the DENV-3 viruses from the clinical samples confirmed this Dengue outbreak. A co -infection with Chikungunya was observed in 2.06% of the cases. The phylogenetic analysis revealed that the Indian Dengue-4 isolates from this outbreak belonged to the genotype I. This study clearly indicated the sudden dominance of DENV-4 in an Indian Dengue outbreak. CONCLUSION: The surveillance of the Dengue viruses needs to be closely monitored for the emergence of newer serotype(s) in hitherto unknown areas. PMID- 23634398 TI - The Pattern of Drug Use in Acute Fever by General Practitioners (GPs) in Pune City, India. AB - OBJECTIVES: 1) To determine the WHO Prescribing Core Drug Use (PCDU) indicators in the management of acute fever (of less than 2 weeks duration) of the MBBS (allopathic) and BAMS (ayurvedic) General Practitioners (GPs) in Pune city. 2) To verify the appropriateness of the treatment. and 3) To compare the above parameters of the MBBS and the BAMS practitioners. METHODS: Pune city was divided in five zones, north, south, east, west and central. A list of doctors was obtained from the Indian Medical Association and it was divided zone wise. 2 MBBS and 2 BAMS GPs. were selected per zone. An informed consent was obtained from the GPs. The sample size was 20 encounters per GP. The patients of all ages and both sexes, who suffered from fever of less than 2 weeks duration, were included in the study. The indicators which were studied were 1) the WHO Prescribing Core Drug Use indicators and 2) the complimentary drug use indicators for the appropriateness of the treatment. RESULTS: 1) The age, sex and diagnosis wise distribution of the patients was comparable in both the groups. 2) Among the WHO PCDU indicators, a highly significant difference was observed in the average number of drugs which was prescribed, the antibiotic usage and in the injections which were prescribed among the MBBS and the BAMS GPs 3) The use of the drugs from EDL and that of the generic drugs were comparable in both the groups.4) A marked irrationality was found in the injectable antimicrobials by the BAMS GPs.5) The selection of the antimicrobials was inappropriate in 64.14% and 17.5% of the encounters which were made by the BAMS and the MBBS GPs respectively. CONCLUSION: Among the BAMS GPs: the WHO prescribing core drug use indicators were all significantly abnormal and the percentage of the inappropriate prescriptions was alarmingly high (92%). Among the MBBS GPs: There was more use of the antimicrobials but the proportion of the inappropriate prescriptions was less (42%). PMID- 23634399 TI - Changes in megakaryocytes in cases of thrombocytopenia: bone marrow aspiration and biopsy analysis. AB - BACKGROUND: Thrombocytopenia (platelet counts less than 150,000/MUl) is commonly encountered in various hematological disorders including myelodysplastic syndromes as well as various non-myelodysplastic hematological conditions. AIM: The present study was undertaken to calculate the prevalence of various conditions associated with thrombocytopenia and to record the megakaryocytic alterations in various cases of thrombocytopenia. Apart from this by means of statistical analysis it was tried to analyze whether a significant difference existed in megakaryocytic alteration noted in myelodysplastic versus non- myelodysplastic conditions. MATERIALS AND METHODS: A prospective series of 60 bone marrow aspirations along with concomitant bone marrow biopsies was conducted in a tertiary care centre catering to both urban as well as rural population in north India. STATISTICAL ANALYSIS: The distribution of morphological changes in cases of non myelodysplastic conditions and myelodysplastic were compared using Chi-Square test. A p-value less than 0.05 was considered significant. RESULTS: The commonest cause of thrombocytopenia for which bone marrow examination was sought was dimorphic anaemia (18 cases, 30%), followed by myelodysplastic syndrome (06 cases, 10%) which was followed equally by acute lymphocytic leukemia and blast crisis of chronic myeloid leukemia (CML). Of all the non-MDS conditions apart from dimorphic anaemia, idiopathic thrombocytopenic purpura and chronic myeloid leukemia (blast crisis); megakaryocytic dysplastic forms were not noted in any other condition. In cases of myelodysplasia; dysplastic forms, bare megakaryocytic nuclei, hypogranular forms and micromegakaryocytes were seen. Comparison between frequencies of normal, high and low number of nuclear lobes among MDS (n=9) and non MDS (n=68) conditions were found to be statistically significant. CONCLUSION: Further studies on the evaluation of megakaryocytic alteration and their contribution to thrombocytopenia can provide growing knowledge to the pathogenesis of numerous hematopoietic disorders that may identify broader clinical applications of the newer strategies to regulate platelet count and functioning. PMID- 23634400 TI - The diagnostic significance of the holter monitoring in the evaluation of palpitation. AB - PURPOSE: To determine the diagnostic yield of the 24-hour Holter monitoring in the patients who were evaluated for palpitations. METHODS: A prospective, single centre study was performed to evaluate the diagnostic yield of the Holter monitoring. The inclusion criteria was age greater then 18 years with the symptom of unexplained recurrent palpitations. The exclusion criteria was patients with known medical causes of palpitation, a history of documented arrhythmias, or a history of or the current use of anti-arrhythmic drugs. The outcomes included a diagnostic Holter monitor recording. RESULTS: The data analysis of the 335 patients who were studied, showed that there were 160 (47.8%) females and 175 (52.2%) males with a mean age of 55+/- 18.85 years (18 to 90 years). Ventricular ectopics as bigeminy in 36.7% patients and as couplets in 20% patients, were detected. Non-sustained VT was detected in 5.7% patients, VT was detected in 0.9% cases and SVT was detected in 12.5% cases. 3.58% cases had paraxosymal atrial flutter/fibrillation. The ST segment shift which is suggestive of silent ischaemia, was present in 17.6% of the study population. Second or higher degrees of AV blocks were noted in 2 cases, while one patient had the WPW syndrome. Ventricular bigeminy, couplets, VT,SVT and AF were statistically significant in the patients who were over the age of 50 years as compared to those who were less than 50 years. CONCLUSION: In patients with non-specific symptoms, Holter monitoring has a significant role in the primary diagnosis of myocardial ischaemia or arrhythmia as a cause of such symptoms in the older age groups. PMID- 23634401 TI - The use of the mini-mental state examination and the clock-drawing test for dementia in a tertiary hospital. AB - INTRODUCTION: An early and a quick identification of dementia is desirable to improve the overall care to the affected persons in the developing countries. The aim of this study was to evaluate the discriminative abilities of the Mini Mental State Examination (MMSE) and the Clock Drawing Test (CDT) in differentiating the demented patients from the controls and also the differentiation between the different types of dementia. PATIENTS AND METHODS: This study was designed to evaluate the patients with varied types and severities of dementia, who were diagnosed by using the Clinical Dementia Rating (CDR) scale. All the patients completed the MMSE and the simplified CDT. RESULTS: This study included 197 patients with an age range of 43-79 years. Fifty-one patients (25.9%) were diagnosed with Alzheimer Dementia (AD), 37 patients (18.8%) with Vascular Dementia (VD), 23 patients (11.7%) with Parkinson's Disease Dementia (PDD) and 86 patients (43.6%) with other variants of dementia. The total MMSE score of the enrolled patients was significantly lower as compared to that of the control subjects, with a non-significant difference between the varied diagnoses. The total CDT scores were significantly lower in the patients as compared to those in the controls, with significantly lower scores in the PDD group as compared to those in the AD group. The patients who had AD showed non-significantly higher CDT scores as compared to the patients who had vascular and other types of dementia. CONCLUSION: A combined application of both MMSE and CDT can identify the persons with a cognitive affection and this may be a useful tool for the diagnosis of the non Alzheimer's type of dementia. PMID- 23634402 TI - Alcohol expectancy responses from teenagers: the early forewarning signals. AB - BACKGROUND: The Indian population is overwhelmed by the rapid developmental activities in the new millennium. This has brought in urbanization and several banes of the faster life. Alcoholism is one among the menaces which have to be tackled at an early stage. OBJECTIVE: To assess the subjective expectancies from alcohol intake in young college students. METHODS: We carried out a survey on the expectancy from youth of the alcohol effects, which in fact is known as the principal motivator of alcohol intake. We chose the pre-university students (n= 200; 100 males and 100 females) of one of the oldest and prestigious colleges of Mangalore (south India). The survey used the Comprehensive Effect of Alcohol (CEOA) where the students had to respond to two sets of 38 questions, in which they would mention whether they agreed or disagreed to the statement regarding the effects of alcohol intake. RESULTS: From the results, we found that these young students were in agreement of the view that alcohol could cause a positive reinforcement. They also strongly agreed that alcohol consumption could cause negative effects. This was significantly more pronounced among the girls. Strikingly, only 25% of the boys and 14.5% of girls had consumed alcohol before, who indicated a stronger positive reinforce response as compared to those who had not tasted alcohol. CONCLUSIONS: The results reveal that the first exposure to alcohol consumption is the key factor which leads to alcoholism. If the experience of alcohol intake and the effects of alcohol are liked with the subjects, that becomes a motivating factor for future attempts. This needs a closer look by the clinicians, counselors and the parents, who need to actively interfere in educating the youth and in guiding them in the right direction during their formative ages. PMID- 23634403 TI - Survey of the attitude to, the knowledge and the practice of contraception and medical abortion in women who attended a family planning clinic. AB - OBJECTIVE: To assess the attitude to, the knowledge and practice of contraception and medical abortion in women attending the family planning clinic at the mvj medical college , hosakote , Bangalore, India. MATERIALS AND METHODS: Between 1(st) of August, 2011 and 31st of July, 2012 200 women attending family planning clinic of the mvj medical college, hosakote, Bangalore India of which 105 requested for medical termination of pregnancy (mtp), 95 for family planning advice, were interrogated on a structured questionnaire. The age of women ranged in between 20-45 years, 71 (35.5%) were illiterate, 30 (15%) had primary school education and 99 (49.5%) had diplomas from high school and above. Patients were grouped into low and high socio-economic status according to modified kuppuswamy socio-economic status scale: (i). upper class, (ii). Upper middle class, (iii). Middle class, (iv). Lower middle class, (v). lower class.consent of both husband and wife was taken. They were counseled about the various contraceptives available and allowed to choose whichever suited them best. RESULTS: Among the 200 women 85 (42%) did not use contraception; 51 (25.5 %) were on the barrier method; 49 (18.31%) used intrauterine devices (iud); 12 (6%) used oral pills and and 3 (1.5%) used other methods. the request for mtp was on grounds of unplanned pregnancy in 55.25% cases or failure of contraception in 44.7%. there was no eugenic indication of the women, 3 (1.5%) had heard about emergency contraceptives, however none had used them; 20 (10%) had heard of medical abortion and 12 (6%) had previously undergone mtp with satisfaction. the various methods of contraception accepted by the women post abortion were ocps by 11 (10.47%), iuds by 54 (51.5%) and female sterilization by 26 (24.71%). in the other group, 23 (24.2%) had iuds removed and reinserted; 37.8% had iuds inserted; 26 (27.36%) women underwent sterilization operation; and 6 (6.31%) had iuds removed opting for pregnancy. statistical analysis was done using spss software (Chicago) with chi(2) test taking p value of 0.05 as significant. CONCLUSION: There is lack of awareness of emergency contraception and medical abortion in the women community under study. PMID- 23634404 TI - Utilization Article of CHC (Complete Health Checkup) Type Charts to Improve the Students' Understanding of Clinical Pathology. AB - BACKGROUND: Second year undergraduate medical students lack an integrated approach towards the basic laboratory data. So, they find it difficult when analytical exercises are asked for in pathology practical examinations. A Complete Health Checkup (CHC) is one exercise where an individual undergoes a clinical examination, followed by various basic laboratory tests, along with other tests like ECG, X-ray and USG of the abdomen. A critical analysis of such charts would help in developing higher cognitive skills in the form of integration of all the data which is available, in order to arrive at a final diagnosis. We hypothesized that facilitating the students to analyze a set of clinical pathology tests by using CHC charts as modules would enhance their integrated approach towards the laboratory data. AIM: To evaluate the use of pre designed complete health charts which were designed to enhance the students' ability to apply and integrate their knowledge on the clinical pathology data. MATERIALS AND METHODS: Two batches of 44 students each (Group 1 and Group 2), who attended the clinical pathology postings, were included in the study (totally 88 students). Informed consents were obtained from all of them. In addition to their routine posting schedules, the students in Group 2 were exposed to fifteen CHC charts, one at a time, with the subsequent analysis of each chart by using an objective test and a discussion. At the end of their clinical pathology postings, an OSPE was conducted for all the students and the test scores were analyzed. The statistical analysis was done using SPSS, version 15. RESULTS: Group 1 obtained a score which ranged from 48% to 78%, with a mean+/-SE (mean) of 62.0% +/- 1.21 and Group 2 obtained a score which ranged from 65% to 94%, with a mean+/-SE (mean) of 86.2% +/- 0.96. The Student's-t-test for the equality of means with a value of 15.59 (p=0.000), implied a statistical significance in the mean score, as was observed between the two groups. CONCLUSION: Facilitating the students' learning by using CHC charts helps in improving the students' capacity to analyze and interpret the clinical pathology data and so, it can be utilized on a routine basis. PMID- 23634405 TI - Distribution of glaucoma in the major religious communities of a north Indian town: a hospital survey. AB - INTRODUCTION: Glaucoma is the leading cause of blindness in India and the numbers of the patients are increasing every day. The prevalence of glaucoma depends upon various factors like racial and ethnic factors, the socioeconomic status, etc. AIM: To study the pattern of glaucoma distribution among the patients in a tertiary care hospital. MATERIALS AND METHODS: A retrospective analysis of 1500 glaucoma patients was done, who presented between 2007 and 2012 in TMMC and RC, Moradabad, U.P, India. The age and the gender distribution of glaucoma was studied along with its subtypes in different religious groups (mainly among Hindus and Muslims). RESULTS: The mean age of the glaucoma patients was 52.7 years. Glaucoma was diagnosed in 882(58.8%) Muslim and in 561(37.4%) Hindu patients. The prevalence of POAG (33.0%) was almost equal to that of PACG (32.7%). POAG was the most common type of glaucoma in males (16.8%), while PACG was very common among females (18.8%). In Hindu patients, POAG (40.8%) was the commonest form of glaucoma, while in Muslims, PACG (40.1%) was the highest form of glaucoma. CONCLUSION: Glaucoma is a major ocular disease which is prevalent in the Muslim population of the western Uttar Pradesh region. PMID- 23634406 TI - A clinico-pathological study on benign breast diseases. AB - BACKGROUND: To study the patterns of clinically benign breast disease in females and to co-relate them with the pathological findings. METHODS: One hundred females who attended the Surgery Outpatients Department in Indira Gandhi Medical College and Research Institute, Pondicherry, with various forms of benign breast diseases during the period from October 2011 to September 2012, were studied. Early diagnoses by doing a triple assessment like a clinical examination, FNAC or a core needle biopsy and imaging methods like ultrasonography or mammography, were made within 72 hrs from the first consultation. The clinical diagnoses were compared with the cytological or histological findings wherever possible and their accuracies were evaluated. RESULTS: Out of the 100 female patients who were studied, 87 patients who presented with breast lumps and fibroadenoma, accounted for 48% of the cases, which was the highest number of patients. Fibrocystic changes and breast abscesses came next with 18% and 12% cases respectively. We detected 3 cases of proliferative disease with atypia and one case with florid hyperplasia, which had high and low risk factors respectively, for developing invasive carcinoma. The oldest lady of the group who was clinically diagnosed to have benign disease, was detected to have invasive ductal carcinoma. They were treated in our hospital and were advised follow up. CONCLUSION: Benign breast diseases are common in female patients and fibroadenoma is the commonest of them all. Triple assessment provided a quick diagnosis and it alleviated unnecessary anxiety from the patients about breast cancer. The clinical diagnosis of a breast lump, as confirmed by cytology and histology, was accurate in 91.95 % of the cases. PMID- 23634407 TI - The impact of the broadcasting mistake management culture in a healthy organization on the quality of the personnel work life. AB - BACKGROUND: Today, healthy organizations such as hospital have found out the importance of quality of work life (QWL) of their personnel. QWL direct to increase job satisfaction, improve the quality of services to patient of hospital, and create high performance. One of factors that impact QWL is mistake management culture (MMC) when contribute different organization aspects such as QWL and cover its needs and finally promote job performance. MATERIAL AND METHOD: A questionnarie was designed with items involve five-item Likert-type scale items and it distribute samong a sample of 207 nurses of four hospitals that voluntarily participated in research plan in Mashhad city. Two hospitals were private and two hospitals were public. RESULT: There are significant relationships between MMC, QWL and performance. CONCLUSION: According to importance of enhancement of QWL and job performance in organizations such as hospital, broadcasting culture of mistake management plays positive role and promotes quality level of work life of employees. Therefore, we can improve job satisfaction by changing and manipulating QWL factors, and thus move toward the development of the organization. PMID- 23634408 TI - Pathological Fractures in Primary Non-Hodgkin's Lymphoma of the Bone: A Case Series with Review of the Literature. AB - Primary non-Hodgkin's lymphoma of bone (PLB) is a rare entity. Patients generally present with localized bone pain and, less frequently, soft-tissue swelling or a palpable mass. Pathological fracture of the proximal femur and proximal humerus secondary to soft-tissue tumours is well documented in the literature; however, lymphomas presenting primarily at these sites with pathological fracture is unusual. A review of the world literature shows that the incidence of skeletal manifestation from NHL is less than 5%, and in all these cases, bony involvement was reported many years after presentation of the primary cancer. Histopathologically, PLB usually represents diffuse large B-cell lymphoma. We report our experience with two cases of Primary non-Hodgkin's lymphoma of proximal femur and proximal humerus with pathological fracture and their management. PMID- 23634409 TI - A rare presentation of the double inferior vena cava with an anomalous retrocaval right ureter: embryogenesis and clinical implications. AB - On dissection of the abdomen of an adult male cadaver, in addition to the normal inferior vena cava on the right side, an unusual venous channel which connected the left renal vein with the left common iliac vein was found; (probably the left inferior vena cava). The left testicular and the left suprarenal veins were opening into the left renal vein as usual. Other than this, a retrocaval ureter was found on the right side. The works of previous authors have highlighted the incidence of a venacaval duplication and its surgical implications, but here, we are presenting a unique case of a double inferior vena cava with an anomalous retrocaval ureter. A conglomeration of such vascular malformations is of immense surgical importance, and it is indicative of a grossly defective angiogenesis. Keeping in mind the clinical relevance of the variations which were observed, an attempt was made to explain them in the light of the embryogenic development. PMID- 23634410 TI - A case report of a spontaneous oesophageal pleural fistula. AB - We are reporting a case of an asthmatic patient who presented to us with retrosternal chest pain, constipation, and shortness of breath, with features which were suggestive of a hydropneumothorax and shock. On recovery from the shock, the patient was found to have increased chest tube drainage, which was suggestive of an oesophageal rupture. The Computerized Tomography (CT) scan showed a fistulous track. The patient was diagnosed as a case of a spontaneous oesophageal pleural fistula (Spontaneous EPF) on the basis of her clinical and radiological findings. PMID- 23634411 TI - A case of bone marrow necrosis of an idiopathic aetiology: the report of a rare entity with review of the literature. AB - Bone Marrow Necrosis (BMN) is regarded as a rare entity in the aspirates and the trephine biopsies which are obtained from living patients and it is a rare antemortem diagnosis. Usually, BMN is associated with a poor prognosis and it has a 90% association with malignancies (mainly haematological). Its other causes include infections, drugs and other non malignant haematological causes. BMN which occurs due to unknown causes (idiopathic), is very rare. The present case report describes a case of BMN in a 14 year old male child from rural background, who came to the medicine outpatient department of a tertiary care centre in north India, with the complaints of generalized weakness, severe bone pains, especially in the ribcage area and fatigue. His peripheral blood film revealed pancytopaenia. His bone marrow aspiration yielded a watery, sero-sanguinous fluid from 2 different sites. Microscopy revealed "ghost like" haematopoietic cells lying in eosinophilic, proteinaceous material. Bone marrow biopsies from both the sites revealed extensive foci of gelatinous transformation and necrosis. A diagnosis of BMN was rendered. No underlying neoplastic / non neoplastic cause was identified, even after a thorough systematic investigation (haematological/biochemical/ radiological and immunological). Thus, a final diagnosis of BMN due to an idiopathic cause, was finally given. The patient was given supportive treatment, after which he was referred to a higher centre. BMN which arises idiopathically is usually very rare and often precedes the aetiological diagnosis and obscures the diagnosis. Traditionally, the prognoses of the patients with BMN were considered as poor, but with better treatment aids (chemotherapy and supportive treatment), the prognoses of these patients have been found to improve. Vigorous supportive care, along with a disease specific treatment, is the key to its management. This case was worth reporting, as no cause of BMN was elicited in it and we have summarized the signs and symptoms, the associations, haematological and other lab investigations and the role of radiology, which helped in its diagnosis. PMID- 23634412 TI - The Appropriate DOTS Regimen Greatly Reduces the Disabilities in Polyarticular EPTB. AB - The placement of cases of Extrapulmonary Tuberculosis (EPTB) on the appropriate Directly Observed Treatment Short Course (DOTS) regimen remains a problematic issue in India and often, consultants delay this, leading to significant avoidable pain, discomfort and reduction in the quality of life of the patients. In contrast, a prompt institution of the DOTS regimen can regress such problems, even at a delayed stage. The following case report on polyarticular tuberculosis which involved the bilateral knee and ankle joints without a pulmonary or disseminated form of tuberculosis, amply highlights these facts. PMID- 23634413 TI - Fahr's Syndrome- An Interesting Case Presentation. AB - Fahr's syndrome refers to a rare syndrome which is characterized by symmetrical and bilateral intracranial calcification. We are presenting a 63 year old male, who complained of progressive dysarthria of 6 months, which was associated with slowness of movements. His neurological examination revealed Parkinsonian features. His CT scan revealed a symmetrical large area of calcification over the basal ganglia, the thalamus and the cerebellum. The secondary causes of the bilateral calcification were ruled out to make the clinical diagnosis of Idiopathic Bilateral Striopallidodentate Calcinosis, which is otherwise called as the Fahr's syndrome. Deposits of calcium and minerals cannot be linked to a single chromosomal locus and further genetic studies are in progress for identifying the chromosomal locus of the disease. PMID- 23634414 TI - An Interesting Case of Dysphagia in a HIV Patient. AB - Oesophageal tuberculosis is a rare disease. Tuberculosis (TB) can cause dysphagia due to oesophageal ulcers, Tracheo-Oesophageal Fistulas (TOFs) and an extrinsic compression which is caused by the mediastinal lymph nodes. A 33-year-old gentleman was admitted to our hospital for the evaluation of fever, dysphagia and cough. His chest X-ray was suggestive of miliary tuberculosis. A CT scan of his chest revealed miliary tuberculosis, mediastinal lymphadenopathy and pneumomediastinum. His sputum AFB (acid-fast bacilli) test was positive. An upper gastrointestinal endoscopy revealed a large ulcer in the oesophagus with a fistulous opening which was suggestive of a tracheo-oesophageal fistula. A biopsy from the ulcer was positive for AFB. The test for HIV-1 was positive. A nasogastric feeding tube was placed and the Anti Tubercular Therapy ( ATT) was started. The main aim of this case report is to sensitize the clinicians about the fact that Tuberculosis can present with dysphagia, especially in HIV patients. PMID- 23634415 TI - A Splenic Abscess which was Caused by Salmonella Typhi in a Non Sickler Patient: A Rare Case Finding. AB - A splenic abscess which is caused by Salmonella typhi is a very rare complication of typhoid fever. We are reporting a case of a 14 year old female who presented with fever and pain in the abdomen. She was treated for fever of unknown origin in a rural hospital and was then admitted to our hospital after 15 days . She complained of fever and pain in the abdomen. On ultrasound, multiple splenic abscesses were seen. A USG guided aspiration was done and the aspirated material was received for culture, which was found to be positive for Salmonella typhi. A blood and stool culture which were done were negative and the Widal test showed a positive result with titres of TO 1:320 and TH 1:320. No predisposing factor was found in our case. Sickling was negative and HIV and HBsAg screening showed negative results. She responded favourably to the antibiotics which were given as per our antibiotic sensitivity report. PMID- 23634416 TI - External Ophthalmomyiasis which was Caused by Sheep Botfly (Oestrus ovis) Larva: A Report of 10 Cases. AB - Myiasis is the infestation of the tissues and organs of animals or man by fly larvae. Ophthalmic myiasis has been reported from various world regions. In this study, we are presenting the clinical manifestations of external ophthalmomyiasis which was caused by the larvae of the sheep nasal botfly, Oestrus ovis, in 10 patients in the Tirunelveli and the Tuticorin districts of Tamil Nadu state India. All the patients were farmers, who worked in close contact with sheep and goats. All the patients presented with severe conjunctivitis. The larvae were observed in the bulbar conjunctiva and following their removal, the symptom of eye inflammation improved in a few hours. PMID- 23634417 TI - The Limb-Abdominal Wall Complex Defects, a form of Amniotic Band Sydrome: A Rare Case Report. AB - The limb-body wall complex defects a form of amniotic band syndrome which consists of a polymal formation with a thoracic and /or an abdominal-schisis, eventration of the internal organ and anomalies of the extremities. We are presenting a case of a limb-body wall complex defect with the phenotype of a placenta-abdominal attachment, anomalies of the abdominal wall defect, absence of the right lower limb and genitourinary defects. PMID- 23634418 TI - CRAO in Moyamoya Disease. AB - Moyo Moya Disease (MMD) is a rare, progressively stenotic condition of the intracranial arteries with various cerebrovascular manifestations. Ocular manifestations are seen very rarely and there are only few case reports of ocular perfusion anomalies. Central Retinal Artery Occlusion (CRAO) can be caused by atherosclerosis related thrombosis, carotid embolism, cardiac embolism, thrombophilic disorders, giant cell arteritis, etc. We are reporting a 26 years old patient with CRAO in the right eye, who was found to have the typical features of MMD on cerebral angiography. CRAO with MMD is a rare occurrence. PMID- 23634419 TI - The spontaneous prelabour rupture of anunscarred uterus at 34 weeks of pregnancy. AB - Uterine rupture is an obstetric emergency needs immediate surgery and is associated with poor fetal & maternal outcome. Usually uterine rupture occurs at the lower segment (weakest part) if there is no history of uterine surgery. We hereby are reporting a case of spontaneous uterine rupture at fundus, at 34 weeks of gestation in a patient who has never had uterine surgery. Only uterine curettage was done once for missed abortion. In this case, diagnosis was delayed until the patient went into massive hemorrhagic shock; because, there was no history of previous uterine surgery. However, clinical picture of the ruptured uterus at the fundus suggests there was some weakness at the fundus. Thereafter, D & C operation was taken into account. Subtotal hysterectomy was done as the rupture was irreparable damage to the fundus. Her one month follow up was uneventful. PMID- 23634420 TI - A Rare Case of an Epidermoid Cyst in the Parotid Gland - which was Diagnosed by Fine Needle Aspiration Cytology. AB - Cystic lesions are common in the head and neck. The most common are the cutaneous cysts, which are referred to as epidermal cysts. These cysts present as nodular and fluctuant subcutaneous lesions and they are seen most commonly in the acne - prone areas like the head, neck and the back. They arise following a localized inflammation of the hair follicle and occasionally after the implantation of the epithelium, following a trauma or surgery. The presence of benign cystic lesions in the salivary glands is rare.We are presenting a rare case of a 55-year-old male who presented with a soft swelling on the left side of the face. A diagnosis of an epidermoid cyst was given on cytology. A superficial parotidectomy was performed and the histopathology confirmed the above diagnosis. PMID- 23634421 TI - Huge dedifferentiated liposarcoma of the left thigh with a high grade fibrosarcomatous differentiation and a local recurrence. AB - Dedifferentiated liposarcoma is one of the variants of liposarcoma which has a more aggressive course. It constitutes less than 10% of all the liposarcomas and is often found in the retroperitoneum and the mediastinum. We are reporting a rare case of a 60 years old female who presented with a huge, soft tissue mass in the left thigh with a past history of an operation which was done15 years back. The histopathological examination showed a well differentiated liposarcoma with a high grade fibrosarcomatous differentiation. Immunohistochemical studies confirmed the dedifferentiated liposarcoma with the high grade fibrosarcomatous differentiation. To the best of our knowledge, this is the 11th case in the literature with rare findings. PMID- 23634422 TI - Myfibroma which was Associated with A Rudimentary Eyeball, which Masqueraded as an Ocular Palpebral Cyst. AB - Myofibroma, a benign neoplasm of the myofibroblasts, is most commonly encountered in the head and neck region, which includes the scalp, the forehead, the parotid region and the oral cavity. It is most rarely reported in the eyelids. Ocular myofibroma typically presents during childhood and it is rare in older patients. One such rare case which occurred in a 26 year old female with a clinical diagnosis of a palperbral orbital cyst, which was associated with a rudimentary eyeball, has been presented here. Rudimentary eyeballs which are associated with other congenital anomalies of the central nervous system, the female genital system and the skeletal system, have been frequently reported, but the occurrence of myofibroma in a rudimentary eyeball, as was seen in the present case, is an exceptional feature and an extensive review of literature did not reveal any report of such an occurrence. PMID- 23634423 TI - Carcinosarcoma of the gallbladder: a case report and review of the literature. AB - A carcinosarcoma is a rare type of gallbladder malignancy, the diagnosis of which requires the presence of both malignant epithelial and mesenchymal components. The prognosis of this disease is extremely poor because it normally presents at advanced stages.We are reporting a case of carcinosarcoma of the gallbladder in a 45 year-old woman who was treated by cholecystectomy, as the tumour was confined to the gall bladder only. PMID- 23634424 TI - A secondary carcinomatous lesion masquerading as a primary osteosarcoma - a case report. AB - Penile carcinomas account for 10% of all the malignancies in men with a predominant regional lymph node involvement, but a distant metastasis of such a carcinoma via the haematogenous route is rare (2.3%), with the common sites being the kidneys, adrenal glands, retroperitoneal lymph nodes, lungs, brain and the dorsal spine. The pattern of the metastatic spread from carcinomas of the penis has been well described in the literature, with the inguinal and the iliac nodes being the commonest sites. The distant metastases are uncommon and delayed, even in advanced disease. Although metastases to the liver and lungs have been reported, the osseous metastases are exceptionally rare. We are presenting a case of carcinoma of the penis which metastasized to the tibia. PMID- 23634425 TI - Organic mania in dengue. AB - Dengue fever is considered to be one of the major health problems in south east Asia. In the recent past, epidemic outbreaks of Dengue have also been noticed in India. Initially, the neurological manifestations which were associated with Dengue received little attention, but now, there have been several reports of encephalitis and encephalopathy . However, nowhere in the literature has Dengue fever been mentioned as a cause of acute psychosis or mania. Here, we are reporting a 21-year-old male, a resident of Delhi, India who after the Dengue infection, developed an episode of classical mania. PMID- 23634426 TI - Intracystic papillary carcinoma of the breast in males: a case report and review of the literature. AB - Carcinoma of the male breast is a relatively rare disease that accounts for less than 1% of all the cases of cancer in men. Intracystic Papillary Carcinoma (IPC) is an extremely rare disease of the male breast, with a few case reports. The prognosis is excellent for the patients who are diagnosed with IPC, regardless of whether the tumour is in-situ or of an invasive type. We are reporting the case of a 50 year old man who presented with a painless cystic lump in the left breast. Ultrasonography revealed an intracystic tumour. Fine needle aspiration suggested a papillary tumour. The patient underwent simple mastectomy without a sentinel lymph node biopsy. The final pathologic examination revealed an intracystic papillary carcinoma of a low nuclear grade without an invasion. PMID- 23634427 TI - Vascular leiomyoma of foot. AB - Vascular leiomyomas of the foot are relatively rare benign soft tissue tumours which arise from the tunica media and present as painful or painless solitary subcutaneous nodules. We are reporting a rare case of vascular leiomyoma with a dystrophic calcification and a myxoid change. PMID- 23634428 TI - Unicentric Mesenteric Castleman's Disease- A Diagnostic Quandary-A Case Report. AB - Castleman's Disease (CD) is a rare lymphoproliferative disorder and a mesenteric location is unusual. The unicentric variety is more difficult to diagnose clinically and it requires a histopathological confirmation. The excision biopsy itself will help both in the diagnosis and in planning the treatment. Here, we are presenting a case of unicentric mesenteric Castleman's disease which we suspected to be lymphoma. PMID- 23634429 TI - Increasing antimicrobial resistance and narrowing therapeutics in typhoidal salmonellae. AB - Multidrug-resistant typhoid fever (MDRTF) is a major public health problem in developing countries and is an emerging problem in the developed world. Because of the difficulties in preventing typhoid by public health measures or immunization in developing countries, great reliance is placed on antimicrobial chemotherapy. The treatment should commence as soon as the clinical diagnosis is made rather than after the results of antimicrobial susceptibility tests but the existence of MDRTF poses a serious clinical dilemma in the selection of empiric antimicrobial therapy. With the widespread emergence and spread of strains resistant to chloramphenicol, ampicillin and trimethoprim, ciprofloxacin became the drug of choice for the treatment of typhoid fever. However, of late the efficacy of fluoroquinolones too has been questioned, mainly due to increasing reports of increasing defervescence time and poor patient response. This indicates that the organism has begun to develop resistance to fluoroquinolones, and is corroborated by a steady increase in Minimum Inhibitory Concentration (MIC) of ciprofloxacin. The therapeutics of ciprofloxacin-resistant enteric fever narrows down to third- and fourth-generation cephalosporins and azithromycin. However, the emergence of extended-spectrum b-lactamases (ESBLs) in typhoidal Salmonellae poses a new challenge and would greatly limit the therapeutic options leaving only tigecycline and carbepenems as secondary antimicrobial drugs. This increasing resistance is alarming and emphasizes the need of effective preventive measures to control typhoid and to limit the unnecessary use of antibiotics. PMID- 23634431 TI - Planning an objective and need based curriculum: the logistics with reference to the undergraduate medical education in biochemistry. AB - PURPOSE: The medical education is recently being transformed into several domains in order to adapt to the need and the value based academics which is required for the quality doctors who serve the community. Presently, the biochemistry curricula for the graduate students of medicine have been questioned by as many experts, because of their multiple lacunae. In this review, we would like to highlight the scenario which is related to the existing biochemistry curricula for graduate medical students, which have been followed in several medical schools and universities and we also hope to share our ideas for implementing objective and pragmatic curricula. Evidence based research, wherein the articles which are related to innovative teaching-learning tools are collected and the pros and cons which are related to the different methods analyzed in biochemistry point of view. CONCLUSION: Rapid changes in the content of the curriculum may not be required, but a gradual introduction of the novel approach and the methods of teaching biochemistry can be adopted into the curriculum. PMID- 23634432 TI - Evaluation of the effect of probiotic (inersan(r)) alone, combination of probiotic with doxycycline and doxycycline alone on aggressive periodontitis - a clinical and microbiological study. AB - INTRODUCTION: The purpose of the present study was to evaluate the effect of a probiotic (Inersan(r)) alone, a combination of the probiotic with doxycycline and doxycycline alone on aggressive periodontitis patients. METHODS: Thirty patients who satisfied the inclusion and exclusion criteria, were assigned to one of the above mentioned three groups by using block randomization. The clinical and the microbiological parameters were recorded on day 0, at 2 weeks and at 2 months. On day 0, before recording the clinical parameters, 0.5 ml of unstimulated saliva was collected for the evaluation of the microbiological parameters. The clinical parameters which were recorded were the plaque index, the gingival index, the probing pocket depth and the clinical attachment level. The microbiological parameters which were recorded were Lactobacilli and Aggregatibacter actinomycetemcomitans. After this, Scaling and Root Planing (SRP) was performed on day 0. Two weeks after the SRP, the patients were recalled for the saliva sample collection and for the evaluation of the clinical parameters. On the same day, medications were given to the patients to be taken for fourteen days according to the group which they belonged to (Group A - probiotic alone, Group B - a combination of the probiotic with doxycycline, Group C - doxycycline alone). The patients were then recalled at two months for the saliva sample collection and for the evaluation of the clinical parameters. RESULTS: The administration of the probiotic alone, a combination of the probiotic with doxycycline and doxycycline alone, resulted in a decrease in the plaque index, the gingival index, the probing pocket depth and the clinical attachment level at 2 months, which was statistically significant (p < 0.05). The A. actinomycetemcomitans count tended to decrease in all the three groups at 2 months, which was statistically non-significant (p > 0.05). The Lactobacilli count tended to increase significantly in the probiotic alone group (p < 0.05). CONCLUSION: Probiotics have a future in the treatment of aggressive periodontitis, as antibiotics are prescribed most of the time. These antibiotics can lead to the emergence of drug resistant micro-organisms and they can also disturb the beneficial microflora of the body. Thus, as an alternative to antibiotics, probiotics can be used, as they repopulate the beneficial microflora and reduce the pathogenic bacteria. PMID- 23634434 TI - Crystallizing galactocele - an unusual diagnosis on fine needle aspiration cytology. PMID- 23634433 TI - The mandibular first molar with three canals in the mesial root- a case report. AB - The dynamic concept of the root canal system, which describes a variable morphology of the multiple root canals which are inter-connected by anastomoses, has been established as the prevailing state in the mandibular molars. The aim of this case report was to describe the unusual root canal anatomy that was detected in the mandibular first molar during the routine endodontic treatment. The clinical and the radiographic examinations allowed the detection of the middle mesial root canal between the mesiobuccal and the mesiolingual root canals. This report highlights the importance of such examinations and the need to find and treat the additional canals, to achieve a successful endodontic treatment. PMID- 23634436 TI - Plasmonics and spectroscopy. PMID- 23634435 TI - Aberrant adrenal tissue in omentum: an incidental finding on ovarian cystectomy. PMID- 23634437 TI - Malaria during pregnancy with parasite sequestration in the villous chamber. PMID- 23634438 TI - In response. PMID- 23634430 TI - Oxidative/Nitrosative stress and the pathobiology of chronic obstructive pulmonary disease. AB - The understanding of the pathobiology of Chronic Obstructive Pulmonary Disease (COPD) has undergone a major change in the past three decades. The classical 'protease-antiprotease' hypothesis still holds true, nevertheless, the sequence of the biochemical events which lead to the protease/antiprotease imbalance have been unraveled. For instance, tobacco smoke, a primary risk factor for COPD, contains a plethora of reactive Oxygen/Nitrogen Species (ROS/RNS) that serve to initiate the oxidant/antioxidant imbalance in the respiratory tract of chronic smokers, a phenomenon that is amplified if certain other risk factors co-exist (e.g. a genetic deficiency of the major antiproteases, a suboptimal antioxidant defense system, airway hyper responsiveness etc.). The inflammatory response that ensues as a result of the initial occult exogenous oxidative/ nitrosative stress becomes a secondary endogenous source of ROS/RNS. This perpetuates the ongoing lung damage, even though the primary insult may no longer be present (abstinence). Depletion of the pulmonary antioxidants, damage to the local antiprotease protective screen, a decreased immune response, hypersecretion of mucus, superadded infections, oxygen therapy-induced oxidant production, etc. are some of the critical factors which account for the oxidative/ nitrosative stress mediated pulmonary as well as extrapulmonary features of COPD. In the light of the recent developments, remarkable efforts are being made, either to develop novel therapeutic strategies or to improve the existing ones, which are aimed at treating different aspects of the disease. Thus, it is reasonable to recommend antioxidants as a useful adjunct to the more conventional treatment options, keeping in view the 'oxidant/antioxidant' hypothesis as a unifying theme for the 'protease/antiprotease' theory of COPD. PMID- 23634439 TI - The regulation of vascular tetrahydrobiopterin bioavailability. AB - 6R l-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for several enzymes including phenylalanine hydroxylase and the nitric oxide synthases (NOS). Oral supplementation of BH4 has been successfully employed to treat subsets of patients with hyperphenylalaninaemia. More recently, research efforts have focussed on understanding whether BH4 supplementation may also be efficacious in cardiovascular disorders that are underpinned by reduced nitric oxide bioavailability. Whilst numerous preclinical and clinical studies have demonstrated a positive association between enhanced BH4 and vascular function, the efficacy of orally administered BH4 in human cardiovascular disease remains unclear. Furthermore, interventions that limit BH4 bioavailability may provide benefit in diseases where nitric oxide over production contributes to pathology. This review describes the pathways involved in BH4 bio-regulation and discusses other endogenous mechanisms that could be harnessed therapeutically to manipulate vascular BH4 levels. PMID- 23634440 TI - In response. PMID- 23634441 TI - Message from Editor-in-Chief. PMID- 23634442 TI - Evolving new types of enzymes. PMID- 23634444 TI - [Radial diffusivity important in assessing subtle changes]. PMID- 23634445 TI - [Can tumor type be estimated by means of diffusion-weighted imaging?]. PMID- 23634443 TI - Cris Kuhlemeier. PMID- 23634446 TI - [Connective tissue disorders: is MRI a suitable predictor of mortality in patients with PAH?]. PMID- 23634448 TI - Zonal analysis of facial asymmetry and its clinical significance in facial plastic surgery. AB - OBJECTIVES: To describe common patterns of facial asymmetry and to augment the facial analysis paradigm for improved preoperative counseling and surgical planning. METHODS: We conducted a frontal photographic analysis of 50 patients who were seeking various types of facial cosmetic surgical procedures. The horizontal zonal thirds of the face were analyzed, and the bilateral data points were compared in regard to brow height, width of midface at maximum distance, malar eminence height,nasal alar height, and mandible width measured from the oral commissure to the gonial angle. RESULTS: Forty-five patients demonstrated measurable asymmetry of the midface. The malar eminence was found to be more superiorly positioned and defined on the narrower side of the face in all cases. In contrast, the contralateral wider side of the face appeared flatter, with a more hypoplastic, inferiorly positioned malar eminence.Also, the wider side of the face more often demonstrated a wider mandibular dimension and a superiorly displaced ala. The upper third of the face, in regard to brow height, was the most variable and showed little correlation to the lower two-thirds of the face. CONCLUSION: This facial analysis exercise can assist the surgeon in (1) preoperative counseling, (2) managing expectations,(3) choosing appropriate-sized implants for improved symmetry, and (4) offering a more detailed assessment during the counseling of patients before faceliftsurgery PMID- 23634450 TI - Disclosure of records without consent of or notice to patient may violate the Health Insurance Portability and Accountability Act. In the matter of Miguel M. PMID- 23634449 TI - The man who "listened" to noses: a past artisan's secret revealed. PMID- 23634451 TI - Medical negligence: Potential liability exists for policy formulation. Deya v. Hiawatha Hospital Association, Inc. PMID- 23634452 TI - General liability policy does not cover misleading recommendation. Preau v. St. Paul Fire & Marine Insurance Co. PMID- 23634453 TI - Healthcare providers may be liable for failing to report child abuse in Washington State. Beggs v. The State of Washington. PMID- 23634454 TI - The authors' reply. PMID- 23634455 TI - Communication,collaboration and education. PMID- 23634457 TI - Integrative medicine. Foreword. PMID- 23634456 TI - The experiences of nurses who insert central venous access devices. AB - There has been much role expansion in nursing in the last two decades, with advanced nurses now performing minimally invasive surgery such as central venous access device insertion. However, there is a lack of research exploring the perceptions of nurses performing these procedures. This study explored the lived experiences of nurses who perform minimally invasive surgery, namely central venous access device insertion. Three key themes emerged from this analysis:stress associated with the unpredictable nature of the procedure,coping with responsibility and a patient-focused approach. Although the practitioners experience a degree of stress in the role, they also experience job satisfaction and feel that their roles have a positive impact on the patients in their care. The study findings provide information to managers and nurses performing these roles, and suggest how stress and burnout can be prevented. PMID- 23634458 TI - Safe patient care when using vascular access devices. AB - Any health professional providing care and treatment should first do no harm. With many serious infections affecting hospitals, patient scan be fearful. Education and competency processes specific to vascular access devices (VADs) ensure staff have knowledge of the pathophysiology of infection, basic aseptic techniques for cannulation,device management, methods of flushing, assessing device functions,and dressing and securement techniques (Coopersmith et al, 2002;Centers for Disease Control and Prevention (CDC), 2011; Infusion Nurses Society (INS), 2011; Pratt et al, 2007). However, knowledge in these areas is often taken for granted and it is assumed that health professionals are applying such knowledge in practice. Staff education is effective in reducing infection and complications (Coopersmith et al, 2002). Through teaching the Clean, Assess and Clear model, which applies to intravenous access, patient assessment and flushing catheters until clear, the basics of safe intravenous care can be consistently understood and applied, and competency assessed (Moureau, 2012).Education on the principles of aseptic technique. is a necessary for all nurses and doctors to establish a culture of safety in all healthcare settings. Establishing consistent, simple and clear health professional education on the care and maintenance of intravenous devices, in compliance with guidelines and recommendations, is necessary to achieve the best outcomes. PMID- 23634459 TI - Intravenous cannula placement: getting it right. PMID- 23634466 TI - Uncertainty has been the hallmark of scientific endeavour. PMID- 23634460 TI - Integrative medicine. Common chronic pain conditions. PMID- 23634465 TI - Deaf patient could have been discriminated against because interpreter was not made available. Abernathy v. Valley Medical Center, No. C06-001MJP (W.D. Wash. May 25, 2006). PMID- 23634464 TI - Forging community partnerships to improve health care: the experience of four Medicaid managed care organizations. AB - Some managed care organizations (MCOs) serving Medicaid beneficiaries are actively engaging in community partnerships to meet the needs of vulnerable members and nonmembers. We found that the history, leadership, and other internal factors of four such MCOs primarily drive that focus. However, external factors such as state Medicaid policies and competition or collaboration among MCOs also play a role. The specific strat-egies of these MCOs vary but share common goals: (1) improve care coordination, access, and delivery; (2) strengthen the community and safety-net infrastructure; and (3) prevent illness and reduce disparities. The MCOs use data to identify gaps in care, seek community input in designing interventions, and commit resources to engage community organiza-tions. State Medicaid programs can promote such work by establishing goals, priorities, and guidelines; providing data analysis and technical assistance to evaluate local needs and community engagement efforts; and convening stakeholders to collaborate and share best practices. PMID- 23634462 TI - Integrative medicine. Cardiovascular health. PMID- 23634463 TI - Integrative medicine. Oncology: focus on breast cancer. PMID- 23634461 TI - Nurses' perceptions of transfusion training: an evaluation. AB - Within Scottish hospitals transfusion education is mandatory for all staff involved in the process of transfusion. Currently two modes of delivery exist, face-to-face and e-learning. The researcher,a transfusion practitioner, wished to evaluate the perceptions of registered nurses within her local children's hospital to the transfusion education available. The aim of the evaluation was to ascertain whether there were perceived benefits, whether expectations were met and whether nurses perceived that there were any barriers to undertaking the education. Both quantitative and qualitative data were obtained by means of a questionnaire; all registered nurses in the hospital were invited to participate. The study indicates a high level of compliance with mandatory transfusion education and suggests both satisfaction and perceived benefits with transfusion education among those who responded. Some barriers were highlighted, but it was noted that these were not exclusive to transfusion education and in the current challenging environment with conflicting priorities on time, resolution may be complex. PMID- 23634447 TI - The diced cartilage glue graft for nasal augmentation. Morphometric evidence of longevity. AB - BACKGROUND: A grafting technique that uses diced cartilage without fascia, which improves formability while maintaining long-term stability, would be a welcome addition to the rhinoplasty armamentarium. METHODS: A diced cartilage glue graft was recently introduced as the Tasman technique. The technique has been used by one of us (A.-J.T.) in 28 patients who were monitored clinically for 4 to 26 months. Sonographic morphometry of the graft was used in 10 patients with a maximum follow-up of 15 months, and 2 biopsies were obtained for histologic examination. RESULTS: Fashioning the diced cartilage glue graft reduced operating time compared with the diced cartilage fascia graft and allowed for a wide variety of transplant shapes and sizes, depending on the mold used. All grafts were used for augmentation of the nasal dorsum or radix and healed uneventfully. Sonographic cross-section measures of the grafts changed between 6% and 29%(median, -5%) in the early postoperative phase and 8%and -7% (median, -2%) between 3 and 15 months after insertion. Histologic examination of the graft biopsies revealed viable cartilage with signs of regeneration. CONCLUSION: The diced cartilage glue graft may become an attractive alternative to accepted methods for dorsal augmentation, the diced cartilage fascia graft in particular. PMID- 23634467 TI - Duty to stabilize newborn continues after admission. Lima-Rivera v. UHS of Puerto Rico, Civil No. 04-1798 (GAG) (D.P.R. Feb. 22, 2007). PMID- 23634468 TI - Evidence of verbal discussions admissible to show peroperative agreement. Juckett v. Elluru, _____ Mich. App. _____, _____ N.W. 2d _____, No. 260350 (Ct. App. Mich. Oct. 12, 2006). PMID- 23634469 TI - Breach of confidentiality must be within scope of employment to hold hospital liable. Bagent v. Blessing Care Corp., _____ Ill. 2d _____, No. 102430 (Ill. Jan. 19, 2007). PMID- 23634470 TI - The Uniformed Services University of the Health Sciences. PMID- 23634471 TI - Henry M. Jackson Foundation for the Advancement of Military Medicine: fostering research and education to protect and care for our nation's warriors. PMID- 23634472 TI - Military pain management in 21st century war. AB - Morphine and other opioid drugs have played a major role in austere environment pain management since the Civil War, particularly in the military. While the pre eminence and success of such medications is without question, their use is accompanied by significant side effects that are undesirable in the most advanced medical settings, and are potentially devastating in the field environment. Recently, there have been significant improvements in pain care for America's wounded service members, along with a shift in how many care providers view pain management. An increasing number of healthcare providers are seeing pain not merely as a symptom, but as a disease process. In addition to dramatically improving care for wounded service members, the evolution in the military's approach to pain is enhancing care for civilians. PMID- 23634473 TI - Overview of the rehabilitation of the combat casualty. AB - Current military conflicts, including Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF), have presented unique challenges in the medical, surgical, and rehabilitation care of service members injured in a combat setting. Although modern body armor and advances in medical and surgical capabilities have resulted in a significant improvement in survival rates from severe injuries, rehabilitation strategies must adapt to keep pace with these advances. Rehabilitation of the combat casualty requires the integration of multiple professional disciplines to optimally address the complex medical and surgical conditions, challenging geographic limitations and unique psychosocial factors to meet the expectations of patients, families, government, and society. PMID- 23634475 TI - Pulse!!: a model for research and development of virtual-reality learning in military medical education and training. AB - Pulse!! The Virtual Clinical Learning Lab at Texas A&M University-Corpus Christi, in collaboration with the United States Navy, has developed a model for research and technological development that they believe is an essential element in the future of military and civilian medical education. The Pulse!! project models a strategy for providing cross-disciplinary expertise and resources to educational, governmental, and business entities challenged with meeting looming health care crises. It includes a three-dimensional virtual learning platform that provides unlimited, repeatable, immersive clinical experiences without risk to patients, and is available anywhere there is a computer. Pulse!! utilizes expertise in the fields of medicine, medical education, computer science, software engineering, physics, computer animation, art, and architecture. Lab scientists collaborate with the commercial virtual-reality simulation industry to produce research-based learning platforms based on cutting-edge computer technology. PMID- 23634477 TI - Defense and Veterans Brain Injury Center: program overview and research initiatives. AB - For more than 16 years, the Defense and Veterans Brain Injury Center (at one time known is the Defense and Veterans Head Injury Program) has served to develop and disseminate clinical guidelines and undertake innovative clinical research initiatives and educational programs to serve active duty personnel, their dependents, and veterans with traumatic brain injury (TBI). Through educational initiatives and collaboration with civilian institution, the center is ensuring that critical discoveries surrounding TBI prevention, screening, and treatment are made available to preserve and improve the health of those within and outside the military health system. PMID- 23634476 TI - Military and civilian disaster response and resilience: from gene to policy. AB - Disasters, such as war, terrorism, and natural disasters, affect individuals, groups, and communities. Although the focus is often on post-traumatic stress disorder (PTSD), it is only one of many potential responses to traumatic experiences. Fostering community and individual resilience can help mitigate the effects of disaster. Research, education, and early intervention are integral tools to inform an effective response. The Center for the Study of Traumatic Stress (CSTS) at the Uniformed Services University of the Health Sciences ascribes to such a model in its approach. Recent studies confirm that appreciation of biology and its relation to trauma response are necessary to our understanding of trauma's effects on humans, including trauma-associated disorders, resiliency, and recovery. PMID- 23634478 TI - U.S. Military HIV Research Program: successfully integrating HIV vaccine research with prevention, care, and treatment. AB - In 1986, Congress mandated the U.S. Military HIV Research Program (MHRP) to protect service personnel and serve the global community by reducing the risk of HIV-1 infection. More than 20 years later, MHRP has become a leader in international HIV vaccine development efforts, with five research sites in Africa and Asia. The program's growth has been achieved through the combination of strong HIV vaccine science, the careful development of international research sites, and partnerships with key research institutions in the host countries and within the United States. In addition, the integration of prevention, care, and treatment services has helped MHRP build strong and trusting relationships with the communities in which research is conducted, while providing an ethical framework for the conduct of HIV clinical research. PMID- 23634474 TI - Combat Wound Initiative program. AB - The Combat Wound Initiative (CWI) program is a collaborative, multidisciplinary, and interservice public-private partnership that provides personalized, state-of the-art, and complex wound care via targeted clinical and translational research. The CWI uses a bench-to-bedside approach to translational research, including the rapid development of a human extracorporeal shock wave therapy (ESWT) study in complex wounds after establishing the potential efficacy, biologic mechanisms, and safety of this treatment modality in a murine model. Additional clinical trials include the prospective use of clinical data, serum and wound biomarkers, and wound gene expression profiles to predict wound healing/failure and additional clinical patient outcomes following combat-related trauma. These clinical research data are analyzed using machine-based learning algorithms to develop predictive treatment models to guide clinical decision-making. Future CWI directions include additional clinical trials and study centers and the refinement and deployment of our genetically driven, personalized medicine initiative to provide patient-specific care across multiple medical disciplines, with an emphasis on combat casualty care. PMID- 23634480 TI - 21st century paradigm of tissue banking: the Clinical Breast Care Project. AB - The Clinical Breast Care Project (CBCP) is a congressionally mandated program that began in the year 2000. The military-civilian collaboration was founded on five pillars: (1) center of excellence in clinical care, (2) risk reduction for women at risk for developing breast cancer, (3) tissue banking to develop and maintain the world's finest repository of human biospecimens of breast diseases, (4) targeted research into the molecular signatures of breast diseases and cancer, and (5) biomedical informatics core to support the data warehouse needs of the project. Now in its eighth year of operation, these efforts have resulted in more than 300 peer-reviewed scientific publications and dozens of collaborations with world leaders in cancer research. In this short time, CBCP has created what is believed to be the world's largest breast tissue biorepository. PMID- 23634479 TI - The Infectious Diseases Clinical Research Program: addressing the challenge of infections related to war injuries and skin and soft tissues. AB - The Infectious Diseases Clinical Research Program (IDCRP) at the Uniformed Services University of the Health Sciences (USU) is a National Institute of Allergy and Infectious Diseases (NIAID)-funded network of military treatment and research facilities coordinated through USU and the Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF). IDCRP functions in collaboration with the NIAID, universities, and industry to address infectious diseases threats to the U.S. military and to the nation. Although IDCRP has projects in diseases from HIV to tuberculosis, a major focus has been on skin, soft-tissue, and war related infections. PMID- 23634481 TI - Cancer Vaccine Development Program collaborations. AB - Immunotherapy for cancer, which uses the body's immune system to fight the disease, is an increasingly active area of research. Successful therapies such as trastuzamab (Herceptin) for breast cancer and cytokine therapy for renal cell carcinoma and melanoma have validated the field as a viable area of investigation. However, the goal of developing an effective cancer vaccine has not yet been achieved. The military's Cancer Vaccine Development Program (CVDP) is collaborating with other military programs, along with civilian institutions, to advance scientific research surrounding cancer vaccines. PMID- 23634482 TI - [Epidemiological study of penile cancer in Brazil]. PMID- 23634483 TI - [Surgical pathology of cancer of the penis]. PMID- 23634484 TI - [Conservative surgery in penile cancer]. PMID- 23634485 TI - [Foundation for the realization of lymphadenectomy in penile cancer: applied anatomy of the inguinal-crural region]. PMID- 23634486 TI - [Role of sentinel lymph nodes in penile cancer research]. PMID- 23634487 TI - [Inguinal lymphadenectomy in penile cancer]. PMID- 23634488 TI - Wise friends: after nearly 300 years of diabetes experience, these women are still going strong. PMID- 23634489 TI - Biggest winner: Channelle Washington took a crash course to make herself healthier. PMID- 23634490 TI - Freezing pay is no way to male efficiency savings. PMID- 23634491 TI - Anger as employers' boss says 1 per cent pay award is too costly. PMID- 23634492 TI - Guidance aims to support nurse directors in ensuring safe staffing. PMID- 23634495 TI - Benefit cuts will directly affect our profession. PMID- 23634493 TI - Mid Staffs chief nurse faces NMC fitness to practise panel hearing. PMID- 23634494 TI - CQC criticises lack of privacy and dignity in England's care homes. PMID- 23634496 TI - Never enough staff to care. AB - Low staffing levels risk creating a culture of 'accepted indignity' in nursing homes. Despite the fact that staffing levels are often so low that nursing staff can barely provide essential care, minimum staff-to-patient ratios remain controversial. This article considers the case for ratios and invites readers' responses. PMID- 23634497 TI - Health for all. AB - From April 1, public health will become the responsibility of local government. Here, experts explain how this shift--overseen by the new health and wellbeing boards--could ease bottlenecks in health services and change how nurses work. PMID- 23634498 TI - Champion of nursing. AB - Baroness Emerton has worked tirelessly for patients in her 60-year career. Her ambition was to be a ward sister but she went on to play a leading role in the profession. She received a special accolade at our Nurse Awards in recognition of her efforts. PMID- 23634499 TI - Examining the evidence for the use of probiotics in clinical practice. AB - This article reviews the use of probiotics in clinical practice, including explanations of what they are and how they work. Evidence for the health benefits of consuming probiotic bacteria and yeast are examined in several clinical conditions. The problems associated with making recommendations for the use of probiotics in clinical practice are also discussed. PMID- 23634500 TI - Integrating quality improvement into pre-registration education. AB - Healthcare organisations around the world are adopting new strategies to improve the quality of patient care in response to reports of negative patient outcomes and cuts to public service expenditure. However, many nurses lack the knowledge, skills and attitude to improve the systems within which they work, calling for a radical redesign of nursing education to integrate quality improvement science. This article describes the integration of quality improvement education within undergraduate nursing education programmes in Wales through collaboration between higher education institutions, NHS Wales and the UK Institute for Healthcare Improvement Open School. PMID- 23634501 TI - Penile cancer: diagnosis, clinical features and management. AB - This article aims to provide the reader with an overview of penile cancer. The focus is on clinical and medical aspects to help nurses understand incidence, aetiology, diagnosis and treatment, to enable them educate and support patients affected by this disease. Psychological support of patients and their partners is also emphasised as the effects of penile cancer can be significant. PMID- 23634502 TI - Spiritual care needs. PMID- 23634504 TI - Roster planning made easy. PMID- 23634503 TI - Caribbean challenge. PMID- 23634505 TI - Staying the course. PMID- 23634508 TI - Prevention is the name of the game when it comes to chronic disease. PMID- 23634507 TI - Prevention and wellness across the lifespan. AB - Life expectancy in the United States is more than 30 years longer than in 1900, thanks to a number of health care and public health interventions. Yet with that success come both benefits and challenges. As we live longer, we continue to age. New chronic diseases emerge as our body parts wear out or as the result of our lifestyle. However, aging does not necessarily mean that getting sicker is inevitable. It is possible to live longer with a high quality of life--even for those with chronic diseases. To do so takes an early investment in wellness and an approach to life that centers on prevention, as pointed out in the 2012 American Public Health Association Annual Meeting. PMID- 23634506 TI - The transformative promise of aging science. PMID- 23634509 TI - National plan to address Alzheimer's disease offers hope for new home care and hospice provisions. PMID- 23634510 TI - Role of the diabetes educator in home care. PMID- 23634512 TI - Men redefining the roles of caregivers. PMID- 23634513 TI - Serving as an expert. PMID- 23634511 TI - Providing caregiver support for individuals living with chronic conditions. PMID- 23634514 TI - Time to take the next step. PMID- 23634515 TI - What to say to grandchildren who ask, "what is wrong with grandma or grandpa"? PMID- 23634516 TI - Raising kids, not murderers. PMID- 23634517 TI - Creating a national policy on long-term care. PMID- 23634518 TI - [A centenarian is always young]. PMID- 23634519 TI - [Report on end of life care in France]. PMID- 23634520 TI - [Assuring the care and accompaniment of the elderly ]. PMID- 23634521 TI - [Screening for rheumatoid arthritis by a simple clinical exam]. PMID- 23634522 TI - [HIV infection in the elderly]. PMID- 23634525 TI - ["I'm trying to create an exchange for relational care"]. PMID- 23634524 TI - [Nursing practice in nursing homes]. AB - This article launches a new section devoted to care homes for dependent elderly people (EHPAD). Created in 2001, these homes accommodate around 685 000 people. They must be more and more medicalised to meet the needs of an increasingly dependent population. This first article provides an overview of this form of accommodation. PMID- 23634526 TI - [Supervising unqualified staff]. AB - In care homes for dependent elderly people, unqualified members of staff sometimes provide care for the residents. It is essential that the necessary tools and training for these carers are available within these structures. PMID- 23634523 TI - [Transfusions in the elderly: peculiarities and the role of nurses]. AB - Given the prevalence of anaemia in elderly people and its consequences in terms of morbidity and mortality, transfusions are common procedures in geriatrics. A survey was carried out of 41 nurses working in geriatrics to discover the conditions in which these transfusions are carried out and the particularities of a transfusion in an elderly person. PMID- 23634527 TI - [Planning for the aging global population]. PMID- 23634529 TI - [A universalist approach to the elderly in Sweden]. AB - Sweden has one of the oldest populations in Europe. For almost a century, it has built its old-age policy on principles of centrality of the state, universalism and equality. Its challenge for the years ahead will be to reconcile these principles with economic demands. PMID- 23634530 TI - [Care of the elderly in Lebanon]. AB - Of the Arab countries, Lebanon is the nation with the highest number of people aged 65 and over. Most live in the community, within their families, and only 4 000 elderly people are homed in institutions. PMID- 23634528 TI - [Geriatrics and sustainable development]. AB - Faced with the ageing of the population and the provision of care for the elderly people, there is a disparity in old-age policies across the world. This article looks at the situation across all five continents in terms of the challenges to be faced and future perspectives. PMID- 23634531 TI - [The accelerated aging of the population in Brazil]. AB - Formerly a young country, Brazil is now undergoing a period of acceleration in the ageing of its population. The Brazilian geriatric heathcare sector must prepare itself to advocate and optimise the care of elderly patients. The training of professionals in gerontology must be a priority and public policies need to evolve. PMID- 23634532 TI - [Geriatrics and gerontology in Senegal]. AB - Senegal is dealing positively with its demographic transition. On September 1st 2006, the Senegalese government introduced the "Plan Sesame", a national free health care program for elderly people aged 60 years and over. The University of Dakar academic authorities support the Sesame plan through an innovative training program in geriatrics and gerontology. Such programs aim to address the challenge of ageing in a developing country. PMID- 23634533 TI - [Nursing and the elderly]. AB - Nurses have a decisive role to play with regard to the provision of care to populations and in particular the most fragile among them such as the elderly. The guarantors of the quality and the safety of care provided to the elderly, nurses must be at the heart of healthcare policies. An overview of the situation across the world. PMID- 23634534 TI - [Bibliography. The aging global population]. PMID- 23634536 TI - [Pharmacokinetics and aging]. PMID- 23634535 TI - [Squamous cell carcinoma in the elderly: a case report]. PMID- 23634537 TI - [Techniques for transferring patients]. PMID- 23634538 TI - [Autumnal edition in the spring]. PMID- 23634540 TI - [DGA trains angiology assistants. Graduate education now also for medical assistant personnel]. PMID- 23634539 TI - [Using persons with mental disability in the nursing home. "They can contribute especially much on an emotional level"]. PMID- 23634541 TI - [Expert standard for prevention of accidental falls: scientific leader reports what will change and indicates where need for research exists. Counterproductive restriction of freedom (interview by Christian Heinemeyer)]. PMID- 23634542 TI - [Recommendations for skin care in advanced age and need for nursing care. Assessing the current status of the skin]. PMID- 23634543 TI - [Nursing care of patients with dementia in the acute hospital. Turning barriers into chances]. PMID- 23634544 TI - [Persons with dementia in the nursing home: family caregivers provide information on grounds for admission and how they experience the situation afterward. Accompaniment and support in the transition phase]. PMID- 23634545 TI - [Dementia and immobility in geriatric long-term nursing care. Not focusing on the deficits]. PMID- 23634546 TI - [Understanding persons with dementia. Achieving trust]. PMID- 23634547 TI - [Routine nursing care of persons with dementia - work with the memory journal. There is someone interested in a life review]. PMID- 23634550 TI - [Training and physical activity have a positive effect on psychiatric disorders]. PMID- 23634548 TI - [Improving palliative care in nursing homes. Are palliative care nursing interventions with the elderly effective in nursing homes?]. PMID- 23634552 TI - [Secure employment in inpatient geriatric nursing through age appropriate work organization. Relieving temporal and physical stresses]. PMID- 23634556 TI - [Metastatic colorectal carcinoma: bevacizumab extends total survival]. PMID- 23634555 TI - [Logical management of persons with dementia. Determining the causes]. PMID- 23634551 TI - [The image of geriatric nursing in graduating students. Altruism alone does not motivate]. PMID- 23634549 TI - [Intensive care and home artificial ventilation. How do nurses experience artificial respiratory care in the home of patients?]. AB - In Germany, the number of patients who receive artificial respiration in their own home is increasing. One reason for long time ventilation is the rise of technical possibilities. Bringing "intensive care" to the home of people challenges original understandings of home care. While intensive care and artificial respiration are technology-oriented, home-care is social-oriented, respecting the familiar environment of the patient. An international literature review reveals that research has been done by investigating the experiences of relatives and patients but not those of nurses. The few studies with a focus on nurses relate to themes of privacy and how to set limits. In Germany, not one study could be found that dealt with the question of how nurses experience artificial respiratory care in patients' homes. Considering the involved changes of care, the question rises, how nurses experience artificial respiratory care in the home of patients. This research is explorative and allows an insight into what home care is like when technology comes in. The exploration is based on eight narrative interviews with nurses who are experiencing respiratory care for patients in their home. The findings reveal professional challenges nurses have to face when caring for patients who are dependent on technological devices. The relatives are included in the caring activities and cooperating with them is crucial. PMID- 23634553 TI - [Guardianship law in routine nursing care. Determining mental competence]. PMID- 23634554 TI - [Memorandum: of the problems of society with uncooperative and peculiar elderly persons. The right of the elderly to autonomy]. PMID- 23634557 TI - [Subcutaneous administration of MabThera for therapy of non-Hodgkin lymphomas frees patients and medical personnel]. PMID- 23634558 TI - Prevention and management of complications of regional orbital anesthesia. AB - The majority of ophthalmic procedures are performed under regional anesthesia, but the proximity of important structures such as the blood vessels, optic nerve and the brainstem lead to increased risks associated with these blocks. The most serious of these complications is brainstem anesthesia. As the number of outpatient freestanding surgical centers increase, the significance of these potential complications is expected to increase from orbital blocks for ocular surgical procedures such as cataract removal and vitrectomy. An understanding of these complications, which may sometimes be life-threatening, are thus vital to the anesthesia practitioner. Procedural improvements include a close evaluation of the precise anatomy of the region, with particular attention to injection sites, depth of injection, position of the globe, and techniques to avoid nerve damage and accidental injection into surrounding structures, including blood vessels, globe and cerebrospinal fluid. This literature review emphasizes the importance of the prevention, recognition and management of these complications, which includes the extremely serious complication of brainstem anesthesia. PMID- 23634559 TI - Aids for facilitation of difficult tracheal intubation review and recent advances. AB - Management of difficult tracheal intubation has been facilitated by different techniques which include the use of stylets, introducers, intubating laryngeal mask airway, as well as by the development of special laryngoscope blades and fiberoptic laryngoscopes. The most recent advances for facilitation of difficult tracheal intubation is the introduction of the video-assisted laryngoscopes. The management of difficult tracheal intubation by video-assisted laryngoscopy can be further facilitated by using suspension laryngoscopy which frees the hands of the anesthesiologist to handle the insertion of the endotracheal tube with the aid of an endotracheal tube introducer, and a curved pipe stylet, under an umbrella of pharyngeal oxygen insufflation. PMID- 23634565 TI - Ultrasonographic modification of Cormack Lehane classification for pre-anesthetic airway assessment. AB - BACKGROUND: The major drawback of Cormack Lehane classification for airway assessment is its dependence on invasive direct laryngoscopy and hence it is inapplicable for pre-anesthetic assessment of airway in patients with no prior history of tracheal intubation. STUDY OBJECTIVES: The purpose of the study was to compare and correlate the ultrasound view of the airway and the Cormack Lehane classification of the direct laryngoscopy. METHODS/STUDY PROCEDURES: The present study was conducted on patients scheduled for elective surgery and requiring general anesthesia with direct laryngoscopy and endotracheal intubation. In the pre-operative holding area, the following measurements were obtained with the oblique-transverse ultrasound view of the airway: (a) the distance from the epiglottis to the midpoint of the distance between the vocal folds, (b) the depth of the pre-epiglottic space, and (c) the total time taken by the operator to achieve the final ultrasonic image. The data was then compared with the Cormack Lehane classification during direct laryngoscopy in the operating room. Subsequently based on the correlation data, the ultrasonographic modification of Cormack-Lehane Classification was developed. RESULTS: It was observed that there was a correlation of the distance between the epiglottis and the vocal cords (E VC) with the Cormack Lehane Grading; correlation was strong negative with regression coefficient of -0.966 (95% CI -1.431 to -0.501; p = 0.0001). Subsequently, the correlation of the pre-epiglottis space (Pre-E) with the Cormack Lehane Grading was strong in positive direction with regression coefficient of0.595 (95% CI 0.261 to 0.929; p = 0.0008). Finally the ratio of Pre E and E-VC distances with the Cormack Lehane Grading had the strongest positive correlation with regression coefficient of 0.495 (95% CI 0.319 to 0.671; p < 0.0001). Based on these statistical calculations and after rearranging the data, we found that prediction of Cormack Lehane (CL) grades can be adequately (67%-68% sensitivity) made by the ratio of Pre-E and E-VC distances (Pre-E/E-VC) {0 < [Pre E/E-VC] < 1 approximately CL grade 1; 1 < [Pre-E/E-VC] < 2 approximately CL grade 2; and 2 < [Pre-E/E-VC] < 3 approximately CL grade 3}. The average time taken to complete the ultrasound examination of airway in the preoperative area was 31.7 +/- 12.4 seconds. CONCLUSION: The non-invasive ultrasonographic modification of invasive Cormack Lehane classification for pre-anesthetic airway assessment can supplement the presently available noninvasive modalities of pre-anesthetic airway assessment including the Mallampati Classification. PMID- 23634561 TI - Cerebral oximetry: a replacement for pulse oximetry? AB - Cerebral oximetry has been around for some 3 decades but has had a somewhat checkered history regarding application and reliability. More recently several monitors have been approved in the United States and elsewhere and the technique is emerging as a useful tool for assessing not only adequate cerebral oxygenation but also tissue oxygenation and perfusion in other organs. PMID- 23634566 TI - Videolaryngoscopic endotracheal intubation (GlideScope) of morbidly obese patients in semi-erect position: a comparison with rapid sequence induction in supine position. AB - BACKGROUND: In regards to peri-anesthetic morbidity considerations, morbidly obese patients often have full stomach for extended periods secondary to delayed gastric emptying. Additionally, they may have difficulty lying supine because of multiple reasons. STUDY OBJECTIVES: The purpose of the study was to compare endotracheal intubation of morbidly obese patients placed in semi-erect position with the rapid sequence induction in the supine position using GlideScope video laryngoscopy. METHODS: A prospective randomized study was conducted in ASA I-III patients aged 18-65 years who were scheduled for bariatric surgery. Group A (Study Group): General anesthesia was induced in the semi-erect position, and endotracheal intubation was performed by the investigator positioned in front of the patient. The GlideScope blade was held in the right hand of the investigator during intubation and endotracheal tube with rigid stylet was inserted using the left hand. Group B (Control Group): General anesthesia was induced and patient's trachea intubated in the standard supine position. RESULTS: 39 patients underwent endotracheal intubation in semi-erect position (Study Group) and 37 patients underwent endotracheal intubation in supine position (Control Group). No differences were observed in the intubation parameters or patient safety. Intubation times required to secure patients' airways were not significantly insignificant (p = 0.42) between the two groups; desaturation episodes occurred 50% less frequently (though insignificant p = 0.42) in the semierect group. CONCLUSION: This is the first prospective study demonstrating endotracheal intubation with GlideScope in the semi-erect position as comparable to standard supine position intubation. Moreover, gravity-directed and aligned biomechanics in the semi-erect position may be ergonomically more efficient for intubating morbidly obese patients. PMID- 23634568 TI - Long-term use of intrathecal droperidol as an excellent antiemetic in nonmalignant pain--a retrospective study. AB - Over the past five years our pain practice encountered eight patients (5 female, 3 male) with chronic non-malignant pain syndromes, in whom any meaningful pain reduction via opioid analgesics (either by oral or systemic and/or intraspinal route) had resulted in profound nausea and/or vomiting despite generous use of available and/or affordable anti-emetics. After obtaining proper consents, small, incremental doses of intrathecal droperidol were added to these patients having implanted intrathecal narcotic drug delivery system. Significant reduction of nausea and vomiting without any side effects from droperidol was obtained while adequate pain reduction is achieved. PROCEDURE: All patients had implanted programmable Medtronic Synchromed pumps with intrathecal access catheters. The intrathecal catheter tip placement varied depending on the pain pathology of the patient. Six of eight patients were started and remained on morphine sulfate intrathecally for their opioids. Two patients with contraindications to morphine had fentanyl and hydramorphone as their intrathecal opioid respectively. The intrathecal dose of droperidol was started low (22.7 +/- 18.6 micrograms/day). All patients were on simple continuous pump dosing during the study. RESULTS: All patients achieved statistically significant antiemesis (77 +/- 10% P < 0.001) as well as statistically significant pain relief (84 +/- 7% P < 0.005) early on (within two pump refills). As the intrathecal dose/day of droperidol was increased to 124.7 +/- 114.8 micrograms/day as well as their intrathecal pain medication use, the degree of significance of antiemesis improved to 86 +/- 9% (P < .001) which was a statistically significant improvement of P < or = 0.05 level from the starting dose of droperidol in each patient. For the six patients on morphine the antiemesis improved to 88 +/- 10% (P < or = .003), also statistically significantly different at P < or = 0.05 level from the starting antiemesis level. During this period the intrathecal morphine dose was doubled from 4.76 +/- 2.43 mg/day to 9.5 +/- 6.5 mg/day (P < or = .001). Patients had no adverse effects from the use of droperidol at these doses (no sedation, changes in mental status, no signs or symptoms of arachnoiditis, no new sensory or motor disturbance, or any other indications of nerve toxicity detected.). Serial neurological studies involving MRI and CT, with contrast, EMG every 6-12 month showed no intrathecal catheter tip irritation sequelae in our patients either. CONCLUSIONS: We find droperidol in microgram doses of 5-300/day intrathecally a safe antiemetic to use along with opioid analgesics. We did not use droperidol intrathecally alone as its use systemically without an opioid companion base is fraught with concern in anesthesia literature ("calm looking on the outside agitated on the inside"). We would suggest a minimal starting dose of 20-30 micrograms/day of droperidol, adjust most probably upwards by 25-50% on subsequent pump refills until the desired effect is established. The scientific literature is rich with references to the brainstem chemoreceptor trigger zone, the floor of the fourth ventricle, and other nausea center locations (area postrema, the circumventricular organ, etc.). We would like to suggest that droperidol's direct actions on these centers are involved with antiemesis at these small doses. PMID- 23634570 TI - Incorrect fixation of endotracheal tube: a cause of non-inflation of the cuff. PMID- 23634571 TI - Ketamine infusion as a treatment for major depressive disorder: a new role for anesthesiologists? PMID- 23634569 TI - Inhalational induction with "vasoparalytic" sevoflurane: are we "hyperoxygenating" while anesthetizing developing brains? A case series discussion. AB - BACKGROUND: The concerns for hyperoxia-related brain tissue injury are well known to the medical community. The cerebro-vasodilatory properties of sevoflurane may create relative cerebral tissue "hyperoxia" during inhalational induction as compared to a propofol-based intravenous induction of anesthesia. STUDY OBJECTIVES: The objective for this case series discussion was to identify any differences in cerebral tissue oxygenation secondary to induction of anesthesia with sevoflurane versus propofol. METHODS/STUDY PROCEDURES: After institutional review board approval, the computer data of tissue cerebral oximetry of pediatric patients (1-18 years age group) undergoing non-cardiac surgeries was comparatively analyzed for changes over time between the groups of children who received sevoflurane induction versus propofol induction of anesthesia. "Hyperoxia" ("hyperoxygenation") was defined as significant percent changes from the baseline values as recorded in tissue cerebral oximetry. RESULTS: In this case series, seven patients underwent inhalational (INH) induction with high concentrations (8%) sevoflurane with nitrous oxide in 33% oxygen and four patients underwent intravenous (i.v.) induction with 2 mg/kg propofol and nitrous oxide in 33% oxygen. As compared to propofol, significant cerebral tissue "hyperoxia" occurred with sevoflurane induction (p = 0.003). This did not resolve over time. CONCLUSION: As compared to intravenous induction with propofol, inhalational induction with "vasoparalytic" sevoflurane "hyperoxygenates" developing brains. This observation requires validation in larger trials to conclude appropriate effect on our practice of pediatric anesthesia and pediatric patient safety under anesthesia. PMID- 23634567 TI - Naloxone versus metoclopramide for the treatment of established postoperative nausea and vomiting in patients following general anesthesia with fentanyl supplementation--pilot study. PMID- 23634562 TI - TENS compared to opioids in postoperative analgesic therapy after major spinal surgery with regard to cognitive function. AB - BACKGROUND: Long-term use of opioids causes cognitive decline. Transcutaneous nerve stimulation (TENS) applied preincisionally and postoperatively reduces postoperative opioid requirement and provides sufficient analgesia after major spinal surgery. Aim of this study was to find out the impact of TENS compared to opioids, prescribed for postoperative analgesia on early postoperative cognitive function. METHODS: This study was prospective and randomised-controlled. Patients and observers were blinded to the study design. Forty-one patients of both sexes planned for lumbar interbody fusion were admitted and divided randomly into 2 groups. 35 Patients finished the study. Group A received TENS preincisionally and postoperatively, group B received piritramide intravenously (i.v.) by patient controlled analgesia pump. The adjuvant analgesic therapy diclofenac 75 mg i.v. and the rescue medication paracetamol 1g i.v. was the same for all patients. Pain intensity was assessed by visual analogue scale (VAS). A battery of objective, standardized psychological tests was administered in the same order the day before surgery and 24 to 30 hours postoperatively. RESULTS: The two groups were compared by pairs. Pre- and postoperative attention and memory differed significantly in both groups (p < 0.05). The postoperative fatigue was lower in group A (p < 0.05). Neither age, sex, body mass index, duration of operation, the need of rescue medication nor the incidents of hypotensive phases showed any significant association with postoperative cognitive decline. CONCLUSIONS: Augmentation of fatigue in early postoperative phase was less in patients treated with TENS than with opioids for analgesic therapy after major spinal surgery. Further investigations on the duration of opioid therapy when cognitive functions decline are necessary. PMID- 23634564 TI - Combined use of metoclopramide and dexamethasone as a prophylactic antiemetic in elective cesarean section under spinal anesthesia. AB - BACKGROUND: Nausea and vomiting during regional anesthesia for cesarean section still remain a major problem. We compared the efficacy of dexamethasone plus metoclopramide with dexamethasone alone for preventing nausea and vomiting during and after spinal anesthesia for cesarean section in parturients. METHODS: The study was performed in 72 full-term parturient women of ASA I & II (American Society of Anesthesiology Grade I & II), aged between 19 and 37 years with uncomplicated pregnancies. The group I (n = 36) received 8 mg of dexamethasone intravenously immediately when the surgery started, while group II (n = 36) received 8 mg of dexamethasone plus 10 mg of metoclopramide. The type and number of episodes of nausea and emesis were recorded, as well as any other adverse effects. RESULTS: During the intraoperative period, a complete response (no emesis, no rescue) was noticed in 83% of patients in Group I and in 86% of patients in Group II. The incidence of nausea during both intra and postoperative periods was not different between the two groups. Metoclopramide was associated with impaired taste and smell and hot flushes. CONCLUSIONS: 10 mg of metoclopramide did not improve the incidence of emetic symptoms in patients undergoing cesarean section when combined with 8 mg of dexamethasone. PMID- 23634560 TI - Left-to-right cardiac shunt: perioperative anesthetic considerations. AB - Congenital heart disease (CHD) affects roughly 8/1000 live births. Improvements in medical and surgical management in recent decades have resulted in significantly more children with left-to-right cardiac shunts surviving into adulthood. Surgical care of these patients for their original cardiac defect(s) or other non-cardiac medical conditions requires thorough understanding of cardiopulmonary changes and mastery of treatment options. Commonly encountered CHD with left-to-right shunt include atrial septal defect (ASD), ventricular septal defect (VSD), endocardial cushion defect (ECD) and patent ductus arteriosus (PDA). The key pathological change is increased pulmonary vascular resistance (PVR) and pressure secondary to increased blood flow from the left-to right shunt. Increasing PVR and pulmonary arterial hypertension (PAH) will lead to reversed direction of blood flow through the cardiac defect (Eisenmenger Syndrome) and heart failure. Cardiac defects with left-to-right shunt generally require surgical or trans-catheter repair at an early age. We review the current concepts and general principles of perioperative anesthetic management of CHD, including neuraxial anesthesia. Current techniques and unique pharmacodynamic and pharmacokinetic effects of some commonly used anesthetic agents in patients with left-to-right shunt are also reviewed. PMID- 23634563 TI - Interobserver variability for non-invasive prediction of difficult intubation in different years of anesthesiology residency. AB - BACKGROUND: The incidence of a difficult laryngoscopy/intubation, which could lead to failed intubation is in the range of 1.5%-13%. Failed intubation may lead to hypoxia, brain damage or death. Preoperative evaluation of the airway can be accomplished by non-invasive bedside clinical tests during physical examination. We studied interobserver variability for non-invasive prediction of difficult intubation in different anesthesiology residency years. METHODS: Three hundred eighty four adult patients undergoing elective surgery with general anesthesia and endotracheal intubation were enrolled this study. The investigators were divided in to two groups: three of them were in 4th (Group 1) and the other three were in 1st (Group 2) year of their anesthesiology residency. The variables evaluated were age, weight, height, submental-cervical angle, measurements of mandibular space, deviation of trachea, jaw-hyomental distance, swelling or scar tissue at neck, limited mouth opening, small mouth cavity, macroglossia, cleft lip-palate, long teeth and modified Mallampati score. RESULTS: The incidence of difficult intubation is 4.9%. Group 1 is more successful than Group 2 in predicting difficult intubation. CONCLUSIONS: Regarding Mallampati score, measurements of mandibular space, jaw-hyomental distance, mouth opening and mouth cavity; interobserver variability is detected in predicting difficult intubation among different years of anesthesiology residency. In means of submental-cervical angle, tracheal deviation, swelling or scar tissue at neck and macroglossia, similar results which are statistically significant, are obtained. PMID- 23634572 TI - A case of severe SAM following a David procedure. AB - We report a case of hemodynamically significant systolic anterior motion of the mitral valve following a David procedure. Although systolic anterior motion of the mitral valve has been reported following mitral valve repair or replacement and aortic valve replacement, it has not been previously described following isolated ascending aortic surgery. PMID- 23634573 TI - Respiratory support including emergent extracorporeal membrane oxygenation as a bridge to airway dilatation following perioperative bronchial occlusion. AB - During the perioperative period, various factors may lead to intraoperative and postoperative respiratory failure including upper airway obstruction, bronchospasm, acid aspiration, laryngospasm, and pulmonary hypertension. Regardless of the etiology, prompt recognition with treatment of the inciting event is required to ensure a successful recovery. We report the intraoperative development of respiratory insufficiency and failure in a 17-year-old girl who was status post lung transplant undergoing bronchoscopy. During bronchoscopy, complete left main stem obstruction occurred due to a fibrinous mass near the bronchial anastomosis site. Various modalities were used to support the patient intraoperatively and then postoperatively including low tidal volume/high PEEP ventilation, inhaled nitric oxide (iNO), and high frequency oscillatory ventilation (HFOV). In the CTICU, emergent bedside venovenous extracorporeal membrane oxygenation (ECMO) was used as a bridge to the recovery of respiratory function which was achieved with removal of the occluding fibrinous airway tissue followed by balloon dilatation and stenting of the left main stem bronchus. The potential perioperative causes of respiratory failure are reviewed and support techniques including conventional ventilator strategies, iNO, HFOV and ECMO discussed. PMID- 23634575 TI - Acute quadriplegia after interscalene block secondary to cervical body erosion and epidural abscess. AB - Although the incidence of neurological complications after shoulder surgery with regional anesthesia remains low but serious negative outcomes have been reported in the literature. Here we report a case of acute quadriplegia secondary to cervical epidural abscess and possible neck manipulation. PMID- 23634577 TI - Endotracheal tube cuff leak with mysterious laryngotracheal pathology. AB - A 63 year-old obese man with gastroesophageal reflux disease, hiatal hernia, and no known history of airway pathology was to undergo a total knee arthroplasty. After intubation, however, repeated cuff leaks, decreasing tidal volumes, and desaturations prompted five additional endotracheal tube placements. Findings on radiography, computed tomography, and fiberoptic laryngoscopy and tracheoscopy were equivocal. Factors contributing to this challenge of persistent and repeated cuff leaks in the absence of known airway pathology could include various laryngotracheal abnormalities. PMID- 23634578 TI - Safe removal of epidural catheter--a dilemma, in patients who are started on dual anti platelet therapy postoperatively for acute coronary syndrome--a case report. AB - Epidural catheter insertion or removal in patients receiving antiplatelet therapy for acute coronary syndrome poses a high risk for epidural hematoma. Though practice guidelines suggest stopping clopidogrel for at least 7 days before such intervention. Withholding anti-platelet drugs for such a long duration represents a great risk to these patients. We present a case of a 53 year old male patient who underwent an exploratory laparotomy. He had an epidural catheter inserted for analgesia. He developed acute myocardial infarction on the first postoperative day, which was treated with dual antiplatelet therapy and percutaneous coronary angioplasty. The removal of epidural catheter in this patient required a clinical decision, balancing the risk of epidural hematoma with continuation of antiplatelet therapy against the risk of coronary re-thrombosis with discontinuation of the medication. We followed a strategy that combined a short duration of discontinuation of therapy, assessment of platelet functions by laboratory test, transfusion of platelets and removal of catheter, followed by restart of anticoagulation, which proved safe for the patient. PMID- 23634574 TI - General anesthesia in a patient with cleidocranial dysplasia. PMID- 23634579 TI - Cricothyroid approximation using a silastic sheath: a new approach. AB - Transsexualism is a gender identity disorder in which affected individuals believe themselves to be born into the wrong sex. Hormonal therapy and many surgical interventions were adopted in order to change their appearances. Cricothyroid approximation is the most acceptable surgical intervention to raise the vocal pitch in male to female transsexuals. Long-term follow up of this surgery revealed some failure partially due to cutting of the sutures through the cricoid and thyroid cartilages. In this report we would like to describe the first case of cricothyroid approximation using a silastic sheath interposed between the cartilages and the mattress suture to circumvent such a complication. PMID- 23634580 TI - Linking science and policy to prevent the spread of invasive species from the ballast water discharge of ships. PMID- 23634581 TI - Ballast water regulations and the move toward concentration-based numeric discharge limits. AB - Ballast water from shipping is a principal source for the introduction of nonindigenous species. As a result, numerous government bodies have adopted various ballast water management practices and discharge standards to slow or eliminate the future introduction and dispersal of these nonindigenous species. For researchers studying ballast water issues, understanding the regulatory framework is helpful to define the scope of research needed by policy makers to develop effective regulations. However, for most scientists, this information is difficult to obtain because it is outside the standard scientific literature and often difficult to interpret. This paper provides a brief review of the regulatory framework directed toward scientists studying ballast water and aquatic invasive species issues. We describe different approaches to ballast water management in international, U.S. federal and state, and domestic ballast water regulation. Specifically, we discuss standards established by the International Maritime Organization (IMO), the U.S. Coast Guard and U.S. Environmental Protection Agency, and individual states in the United States including California, New York, and Minnesota. Additionally, outside the United States, countries such as Australia, Canada, and New Zealand have well established domestic ballast water regulatory regimes. Different approaches to regulation have recently resulted in variations between numeric concentration based ballast water discharge limits, particularly in the United States, as well as reliance on use of ballast water exchange pending development and adoption of rigorous science-based discharge standards. To date, numeric concentration-based discharge limits have not generally been based upon a thorough application of risk-assessment methodologies. Regulators, making decisions based on the available information and methodologies before them, have consequently established varying standards, or not established standards at all. The review and refinement of ballast water discharge standards by regulatory agencies will benefit from activity by the scientific community to improve and develop more precise risk-assessment methodologies. PMID- 23634576 TI - Inferior wall diverticulum of left ventricle coexisting with mental retardation and atrial septal defect. AB - We report a case of congenital inferior wall left ventricular diverticulum (LVD), atrial septal defect and mental retardation detected by intraoperative transesophageal echocardiography. The combination of three features strongly suggests that genetic factors play important role in the pathogenesis of the disorder. Most LVDs are asymptomatic. Echocardiographers and cardiac anesthesiologists should be aware of this anomaly, and include it in the differential diagnosis of abnormally shaped ventricular wall and seek other congenital abnormalities if LVD is detected. PMID- 23634582 TI - Approaches to setting organism-based ballast water discharge standards. AB - As a vector by which foreign species invade coastal and freshwater waterbodies, ballast water discharge from ships is recognized as a major environmental threat. The International Maritime Organization (IMO) drafted an international treaty establishing ballast water discharge standards based on the number of viable organisms per volume of ballast discharge for different organism size classes. Concerns that the IMO standards are not sufficiently protective have initiated several state and national efforts in the United States to develop more stringent standards. We evaluated seven approaches to establishing discharge standards for the > 50-microm size class: (1) expert opinion/management consensus, (2) zero detectable living organisms, (3) natural invasion rates, (4) reaction-diffusion models, (5) population viability analysis (PVA) models, (6) per capita invasion probabilities (PCIP), and (7) experimental studies. Because of the difficulty in synthesizing scientific knowledge in an unbiased and transparent fashion, we recommend the use of quantitative models instead of expert opinion. The actual organism concentration associated with a "zero detectable organisms" standard is defined by the statistical rigor of its monitoring program; thus it is not clear whether such a standard is as stringent as other standards. For several reasons, the natural invasion rate, reaction-diffusion, and experimental approaches are not considered suitable for generating discharge standards. PVA models can be used to predict the likelihood of establishment of introduced species but are limited by a lack of population vital rates for species characteristic of ballast water discharges. Until such rates become available, PVA models are better suited to evaluate relative efficiency of proposed standards rather than predicting probabilities of invasion. The PCIP approach, which is based on historical invasion rates at a regional scale, appears to circumvent many of the indicated problems, although it may underestimate invasions by asexual and parthenogenic species. Further research is needed to better define propagule dose-responses, densities at which Allee effects occur, approaches to predicting the likelihood of invasion from multi-species introductions, and generation of formal comparisons of approaches using standardized scenarios. PMID- 23634583 TI - Geographic variation in marine invasions among large estuaries: effects of ships and time. AB - Coastal regions exhibit strong geographic patterns of nonnative species richness. Most invasions in marine ecosystems are known from bays and estuaries, where ship mediated transfers (on hulls or in ballasted materials) have been a dominant vector of species introductions. Conspicuous spatial differences in nonnative species richness exist among bays, but the quantitative relationship between invasion magnitude and shipping activity across sites is largely unexplored. Using data on marine invasions (for invertebrates and algae) and commercial shipping across 16 large bays in the United States, we estimated (1) geographic variation in nonnative species richness attributed to ships, controlling for effects of salinity and other vectors, (2) changes through time in geographic variation of these ship-mediated invasions, and (3) effects of commercial ship traffic and ballast water discharge magnitude on nonnative species richness. For all nonnative species together (regardless of vector, salinity, or time period), species richness differed among U.S. coasts, being significantly greater for Pacific Coast bays than Atlantic or Gulf Coast bays. This difference also existed when considering only species attributed to shipping (or ballast water), controlling for time and salinity. Variation in nonnative species richness among Pacific Coast bays was strongly affected by these same criteria. San Francisco Bay, California, had over 200 documented nonnative species, more than twice that reported for other bays, but many species were associated with other (non shipping) vectors or the extensive low-salinity habitats (unavailable in some bays). When considering only ship- or ballast-mediated introductions in high salinity waters, the rate of newly detected invasions in San Francisco Bay has converged increasingly through time on that for other Pacific Coast bays, appearing no different since 1982. Considering all 16 bays together, there was no relationship between either (1) number of ship arrivals (from foreign ports) and number of introductions attributed to ships since 1982 or (2) volume of foreign ballast water discharge and number of species attributed to ballast water since 1982. These shipping measures are likely poor proxies for propagule supply, although they are sometimes used as such, highlighting a fundamental gap in data needed to evaluate invasion dynamics and management strategies. PMID- 23634584 TI - Per capita invasion probabilities: an empirical model to predict rates of invasion via ballast water. AB - Ballast water discharges are a major source of species introductions into marine and estuarine ecosystems. To mitigate the introduction of new invaders into these ecosystems, many agencies are proposing standards that establish upper concentration limits for organisms in ballast discharge. Ideally, ballast discharge standards will be biologically defensible and adequately protective of the marine environment. We propose a new technique, the per capita invasion probability (PCIP), for managers to quantitatively evaluate the relative risk of different concentration-based ballast water discharge standards. PCIP represents the likelihood that a single discharged organism will become established as a new nonindigenous species. This value is calculated by dividing the total number of ballast water invaders per year by the total number of organisms discharged from ballast. Analysis was done at the coast-wide scale for the Atlantic, Gulf, and Pacific coasts, as well as the Great Lakes, to reduce uncertainty due to secondary invasions between estuaries on a single coast. The PCIP metric is then used to predict the rate of new ballast-associated invasions given various regulatory scenarios. Depending upon the assumptions used in the risk analysis, this approach predicts that approximately one new species will invade every 10 100 years with the International Maritime Organization (IMO) discharge standard of < 10 organisms with body size > 50 microm per m3 of ballast. This approach resolves many of the limitations associated with other methods of establishing ecologically sound discharge standards, and it allows policy makers to use risk based methodologies to establish biologically defensible discharge standards. PMID- 23634585 TI - Global ballast water management and the "same location" concept: a clear term or a clear issue? AB - The United Nations recognized the transfer of harmful organisms and pathogens across natural barriers as one of the four greatest pressures to the world's oceans and seas, causing global environmental changes, while also posing a threat to human health, property, and resources. Ballast water transferred by vessels was recognized as a prominent vector of such species and was regulated by the International Convention for the Control and Management of Ship's Ballast Water and Sediments (2004). Permanent exceptions from ballast water management requirements may apply when the uptake and discharge of ballast water occur at the "same location." However, the "same location" concept may be interpreted differently, e.g., a port basin, a port, an anchorage, or a larger area even with more ports inside. Considering that the Convention is nearing the beginning of enforcement, national authorities all around the world will soon be exposed to applications for exceptions. Here we consider possible effects of different interpretations of the "same location" concept. We have considered different possible extensions of the same location through environmental, shipping, and legal aspects. The extension of such areas, and the inclusion of more ports, may compromise the Convention's main purpose. We recommend that "same location" mean the smallest practicable unit, i.e., the same harbor, mooring, or anchorage. An entire smaller port, possibly also including the anchorage, could be considered as same location. For larger ports with a gradient of environmental conditions, "same location" should mean a terminal or a port basin. We further recommend that IMO consider the preparation of a guidance document to include concepts, criteria, and processes outlining how to identify "same location," which limits should be clearly identified. PMID- 23634586 TI - Counting at low concentrations: the statistical challenges of verifying ballast water discharge standards. AB - Discharge from the ballast tanks of ships is one of the primary vectors of nonindigenous species in marine environments. To mitigate this environmental and economic threat, international, national, and state entities are establishing regulations to limit the concentration of living organisms that may be discharged from the ballast tanks of ships. The proposed discharge standards have ranged from zero detectable organisms to < 10 organisms/ m3. If standard sampling methods are used, verifying whether ballast discharge complies with these stringent standards will be challenging due to the inherent stochasticity of sampling. Furthermore, at low concentrations, very large volumes of water must be sampled to find enough organisms to accurately estimate concentration. Despite these challenges, adequate sampling protocols comprise a critical aspect of establishing standards because they help define the actual risk level associated with a standard. A standard that appears very stringent may be effectively lax if it is paired with an inadequate sampling protocol. We describe some of the statistical issues associated with sampling at low concentrations to help regulators understand the uncertainties of sampling as well as to inform the development of sampling protocols that ensure discharge standards are adequately implemented. PMID- 23634587 TI - Priority setting for invasive species management: risk assessment of Ponto Caspian invasive species into Great Britain. AB - Invasive species drive important ecological and economic losses across wide geographies, with some regions supporting especially large numbers of nonnative species and consequently suffering relatively high impacts. For this reason, integrated risk assessments able to screen a suite of multiple invaders over large geographic areas are needed for prioritizing the allocation of limited resources. A total of 16 Ponto-Caspian aquatic species (10 gammarids, one isopod, two mysids, and three fishes) have been short-listed as recent or potential future invaders of British waters, whose introduction and spread is of high concern. In this study, we use multiple modeling techniques to assess their risk of establishment and spread into Great Britain. Climate suitability maps for these 16 species differed depending on the eastern and western distribution of species in continental Europe, which was related to their respective migration corridor: southern (Danube-Rhine rivers), and northern (Don and Volga rivers and Baltic lakes). Species whose suitability was high across large parts of Great Britain included four gammarids (Cheliorophium robustum, Dikerogammarus bispinosus, D. villosus, and Echinogammarus trichiatus) and a mysid (Hemimysis anomala). A climatic "heat map" combining the results of all 16 species together pointed to the southeast of England as the area most vulnerable to multiple invasions, particularly the Thames, Anglian, Severn, and Humber river basin districts. Regression models further suggested that alkalinity concentration > 120 mg/L in southeast England may favor the establishment of Ponto-Caspian invaders. The production of integrated risk maps for future invaders provides a means for the scientifically informed prioritization of resources toward particular species and geographic regions. Such tools have great utility in helping environmental managers focus efforts on the most effective prevention, management, and monitoring programs. PMID- 23634588 TI - High population density enhances recruitment and survival of a harvested coral reef fish. AB - A negative relationship between population growth and population density (direct density dependence) is necessary for population regulation and is assumed in most models of harvested populations. Experimental tests for density dependence are lacking for large-bodied, harvested fish because of the difficulty of manipulating population density over large areas. We studied a harvested coral reef fish, Lutjanus apodus (schoolmaster snapper), using eight large, isolated natural reefs (0.4-1.6 ha) in the Bahamas as replicates. An initial observational test for density dependence was followed by a manipulation of population density. The manipulation weakened an association between density and shelter-providing habitat features and revealed a positive effect of population density on recruitment and survival (inverse density dependence), but no effect of density on somatic growth. The snappers on an individual reef were organized into a few shoals, and we hypothesize that large shoals on high-density reefs were less vulnerable to large piscivores (groupers and barracudas) than the small shoals on low-density reefs. Reductions in predation risk for individuals in large social groups are well documented, but because snapper shoals occupied reefs the size of small marine reserves, these ecological interactions may influence the outcome of management actions. PMID- 23634589 TI - Rebuilding fish communities: the ghost of fisheries past and the virtue of patience. AB - The ecosystem approach to management requires the status of individual species to be considered in a community context. We conducted a comparative ecosystem analysis of the Georges Bank and North Sea fish communities to determine the extent to which biological diversity is restored when fishing pressure is reduced. First, fishing mortality estimates were combined to quantify the community-level intensity and selectivity of fishing pressure. Second, standardized bottom-trawl survey data were used to investigate the temporal trends in community metrics. Third, a size-based, multispecies model (LeMans) was simulated to test the response of community metrics to both hypothetical and observed changes in fishing pressure in the two communities. These temperate North Atlantic fish communities have much in common, including a history of overfishing. In recent decades fishing pressure has been reduced, and some species have started to rebuild. The Georges Bank fishery has been more selective, and fishing pressure was reduced sooner. The two communities have similar levels of size diversity and biomass per unit area, but fundamentally different community structure. The North Sea is dominated by smaller species and has lower evenness than Georges Bank. These fundamental differences in community structure are not explained by recent fishing patterns. The multispecies model was able to predict the observed changes in community metrics better on Georges Bank, where rebuilding is more apparent than in the North Sea. Model simulations predicted hysteresis in rebuilding community metrics toward their unfished levels, particularly in the North Sea. Species in the community rebuild at different rates, with smaller prey species outpacing their large predators and overshooting their pre-exploitation abundances. This indirect effect of predator release delays the rebuilding of community structure and biodiversity. Therefore community rebuilding is not just the sum of single-species rebuilding plans. Management strategies that account for interspecific interactions will be needed to restore biodiversity and community structure. PMID- 23634590 TI - Fishers' knowledge identifies environmental changes and fish abundance trends in impounded tropical rivers. AB - The long-term impacts of large hydroelectric dams on small-scale fisheries in tropical rivers are poorly known. A promising way to investigate such impacts is to compare and integrate the local ecological knowledge (LEK) of resource users with biological data for the same region. We analyzed the accuracy of fishers' LEK to investigate fisheries dynamics and environmental changes in the Lower Tocantins River (Brazilian Amazon) downstream from a large dam. We estimated fishers' LEK through interviews with 300 fishers in nine villages and collected data on 601 fish landings in five of these villages, 22 years after the dam's establishment (2006-2008). We compared these two databases with each other and with data on fish landings from before the dam's establishment (1981) gathered from the literature. The data obtained based on the fishers' LEK (interviews) and from fisheries agreed regarding the primary fish species caught, the most commonly used type of fishing gear (gill nets) and even the most often used gill net mesh sizes but disagreed regarding seasonal fish abundance. According to the interviewed fishers, the primary environmental changes that occurred after the impoundment were an overall decrease in fish abundance, an increase in the abundance of some fish species and, possibly, the local extinction of a commercial fish species (Semaprochilodus brama). These changes were corroborated by comparing fish landings sampled before and 22 years after the impoundment, which indicated changes in the composition of fish landings and a decrease in the total annual fish production. Our results reinforce the hypothesis that large dams may adversely affect small-scale fisheries downstream and establish a feasible approach for applying fishers' LEK to fisheries management, especially in regions with a low research capacity. PMID- 23634591 TI - Meta-modeling soil organic carbon sequestration potential and its application at regional scale. AB - Upscaling the results from process-based soil-plant models to assess regional soil organic carbon (SOC) change and sequestration potential is a great challenge due to the lack of detailed spatial information, particularly soil properties. Meta-modeling can be used to simplify and summarize process-based models and significantly reduce the demand for input data and thus could be easily applied on regional scales. We used the pre-validated Agricultural Production Systems sIMulator (APSIM) to simulate the impact of climate, soil, and management on SOC at 613 reference sites across Australia's cereal-growing regions under a continuous wheat system. We then developed a simple meta-model to link the APSIM modeled SOC change to primary drivers, i.e., the amount of recalcitrant SOC, plant available water capacity of soil, soil pH, and solar radiation, temperature, and rainfall in the growing season. Based on high-resolution soil texture data and 8165 climate data points across the study area, we used the meta model to assess SOC sequestration potential and the uncertainty associated with the variability of soil characteristics. The meta-model explained 74% of the variation of final SOC content as simulated by APSIM. Applying the meta-model to Australia's cereal-growing regions reveals regional patterns in SOC, with higher SOC stock in cool, wet regions. Overall, the potential SOC stock ranged from 21.14 to 152.71 Mg/ha with a mean of 52.18 Mg/ha. Variation of soil properties induced uncertainty ranging from 12% to 117% with higher uncertainty in warm, wet regions. In general, soils in Australia's cereal-growing regions under continuous wheat production were simulated as a sink of atmospheric carbon dioxide with a mean sequestration potential of 8.17 Mg/ha. PMID- 23634592 TI - An innovative aerial assessment of Greater Yellowstone Ecosystem mountain pine beetle-caused whitebark pine mortality. AB - An innovative aerial survey method called the Landscape Assessment System (LAS) was used to assess mountain pine beetle (MPB; Dendroctonus ponderosae)-caused mortality of whitebark pine (Pinus albicaulis) across the species distribution in the Greater Yellowstone Ecosystem (GYE; 894 774 ha). This large-scale implementation of the LAS method consisted of 8673 km of flight lines, along which 4653 geo-tagged, oblique aerial photos were captured at the catchment level (a subset of 12-digit USGS hydrologic units) and geographic information system (GIS) processed. The Mountain Pine Beetle-caused Mortality Rating System, a landscape-scale classification system designed specifically to measure the cumulative effects of recent and older MPB attacks on whitebark pine, was used to classify mortality with a rating from 0 to 6 based on the amount of red (recent attack) and gray (old attack) trees visible. The approach achieved a photo inventory of 79% of the GYE whitebark pine distribution. For the remaining 21%, mortality levels were estimated based on an interpolated surface. Results that combine the photo-inventoried and interpolated mortality indicate that nearly half (46%) of the GYE whitebark pine distribution showed severe mortality (3-4 or 5.3-5.4 rating), 36% showed moderate mortality (2-2.9 rating), 13% showed low mortality (1-1.9 rating), and 5% showed trace levels of mortality (0-0.9). These results reveal that the proliferation of MPB in the subalpine zone of the GYE due to climate warming has led to whitebark pine mortality that is more severe and widespread than indicated from either previous modeling research or USDA Forest Service Aerial Detection surveys. Sixteen of the 22 major mountain ranges of the GYE have experienced widespread moderate-to-severe mortality. The majority of catchments in the other six mountain ranges show low-to-moderate mortality. Refugia from MPB outbreaks, at least for now, also exist and correspond to locations that have colder microclimates. The spatially explicit mortality information produced by this project has helped forest managers develop and implement conservation strategies that include both preservation and restoration efforts. Future research aimed at documenting and quantifying the ecological impacts of widespread decline and collapse of this foundation and keystone species is warranted. PMID- 23634593 TI - The worldwide "wildfire" problem. AB - The worldwide "wildfire" problem is headlined by the loss of human lives and homes, but it applies generally to any adverse effects of unplanned fires, as events or regimes, on a wide range of environmental, social, and economic assets. The problem is complex and contingent, requiring continual attention to the changing circumstances of stakeholders, landscapes, and ecosystems; it occurs at a variety of temporal and spatial scales. Minimizing adverse outcomes involves controlling fires and fire regimes, increasing the resistance of assets to fires, locating or relocating assets away from the path of fires, and, as a probability of adverse impacts often remains, assisting recovery in the short-term while promoting the adaptation of societies in the long-term. There are short- and long term aspects to each aspect of minimization. Controlling fires and fire regimes may involve fire suppression and fuel treatments such as prescribed burning or non-fire treatments but also addresses issues associated with unwanted fire starts like arson. Increasing the resistance of assets can mean addressing the design and construction materials of a house or the use of personal protective equipment. Locating or relocating assets can mean leaving an area about to be impacted by fire or choosing a suitable place to live; it can also mean the planning of land use. Assisting recovery and promoting adaptation can involve insuring assets and sharing responsibility for preparedness for an event. There is no single, simple, solution. Perverse outcomes can occur. The number of minimizing techniques used, and the breadth and depth of their application, depends on the geographic mix of asset types. Premises for policy consideration are presented. PMID- 23634594 TI - Protein supplementation reduces non-grass foraging by a primary grazer. AB - It is believed that wildlife and livestock can coexist in semiarid savanna rangelands. However, this coexistence is threatened by intense competition for scarce, but nutritionally vital, forage resources. Specifically, there is evidence that grazing livestock seasonally compete for protein-rich forbs (non grasses) with browsing and mixed-feeding wildlife. While this has been attributed to protein needs, there are no experimental tests of whether grazers in such a context alter their diet selection when supplemented with protein. We compared forage selection between cattle supplemented with protein (cotton seedcake) and those not supplemented during dry and wet periods, in a semiarid African savanna rangeland where they have been demonstrated to compete with wildlife for forage. We further evaluated whether such dietary alteration affected the overall biting and movement behavior, nutrition, and performance of cattle, by comparing bite and step rates, diet quality (crude protein and digestible organic matter), forage intake, and live mass change between these treatment groups. During the dry period, relative consumption of forbs was 76% lower in supplemented cattle than in non-supplemented cattle. Notably, supplemented cattle significantly avoided forbs relative to their abundance in the environment, while non supplemented cattle over-sampled this herbage type. Conversely, selection and relative use of Brachiaria lachnantha, the most abundant grass species, and Bothriochloa insculpta, a grass species otherwise avoided, increased following protein supplementation. These patterns were similar but nonsignificant during the wet period. Bite and step rates, diet quality, forage intake, and performance were not significantly affected by protein supplementation in either period. Our study shows that foraging cattle partially trade off protein-rich forbs for protein-poor grasses when supplemented with protein, without suffering detrimental behavioral, nutritional, or performance consequences. These results broaden our understanding of the role of non-grasses in the diets of "grazers" and suggest protein supplementation as a potential tool in managing coexistence between grazing livestock and browsing (forb-consuming) wildlife. PMID- 23634595 TI - Repeated burning of eastern tallgrass prairie increases richness and diversity, stabilizing late successional vegetation. AB - Understanding temporal effects of fire frequency on plant species diversity and vegetation structure is critical for managing tallgrass prairie (TGP), which occupies a mid-continental longitudinal precipitation and productivity gradient. Eastern TGP has contributed little information toward understanding whether vegetation-fire interactions are uniform or change across this biome. We resampled 34 fire-managed mid- and late-successional ungrazed TGP remnants occurring across a dry to wet-mesic moisture gradient in the Chicago region of Illinois, USA. We compared hypotheses that burning acts either as a stabilizing force or causes change in diversity and structure, depending upon fire frequency and successional stage. Based on western TGP, we expected a unimodal species richness distribution across a cover-productivity gradient, variable functional group responses to fire frequency, and a negative relationship between fire frequency and species richness. Species diversity was unimodal across the cover gradient and was more strongly humpbacked in stands with greater fire frequency. In support of a stabilizing hypothesis, temporal similarity of late-successional vegetation had a logarithmic relationship with increasing fire frequency, while richness and evenness remained stable. Temporal similarity within mid successional stands was not correlated with fire frequency, while richness increased and evenness decreased over time. Functional group responses to fire frequency were variable. Summer forb richness increased under high fire frequency, while C4 grasses, spring forbs, and nitrogen-fixing species decreased with fire exclusion. On mesic and wet-mesic sites, vegetation structure measured by the ratio of woody to graminoid species was negatively correlated with abundance of forbs and with fire frequency. Our findings that species richness responds unimodally to an environmental-productivity gradient, and that fire exclusion increases woody vegetation and leads to loss of C4 and N-fixing species, suggest that these processes are uniform across the TGP biome and not affected by its rainfall-productivity gradient. However, increasing fire frequency in eastern TGP appears to increase richness of summer forbs and stabilize late-successional vegetation in the absence of grazing, and these processes may differ across the longitudinal axis of TGP. Managing species diversity in ungrazed eastern TGP may be dependent upon high fire frequency that removes woody vegetation and prevents biomass accumulation. PMID- 23634596 TI - Interactive effects of wildfire, forest management, and isolation on amphibian and parasite abundance. AB - Projected increases in wildfire and other climate-driven disturbances will affect populations and communities worldwide, including host-parasite relationships. Research in temperate forests has shown that wildfire can negatively affect amphibians, but this research has occurred primarily outside of managed landscapes where interactions with human disturbances could result in additive or synergistic effects. Furthermore, parasites represent a large component of biodiversity and can affect host fitness and population dynamics, yet they are rarely included in studies of how vertebrate hosts respond to disturbance. To determine how wildfire affects amphibians and their parasites, and whether effects differ between protected and managed landscapes, we compared abundance of two amphibians and two nematodes relative to wildfire extent and severity around wetlands in neighboring protected and managed forests (Montana, USA). Population sizes of adult, male long-toed salamanders (Ambystoma macrodactylum) decreased with increased burn severity, with stronger negative effects on isolated populations and in managed forests. In contrast, breeding population sizes of Columbia spotted frogs (Rana luteiventris) increased with burn extent in both protected and managed protected forests. Path analysis showed that the effects of wildfire on the two species of nematodes were consistent with differences in their life history and transmission strategies and the responses of their hosts. Burn severity indirectly reduced abundance of soil-transmitted Cosmocercoides variabilis through reductions in salamander abundance. Burn severity also directly reduced C. variabilis abundance, possibly though changes in soil conditions. For the aquatically transmitted nematode Gyrinicola batrachiensis, the positive effect of burn extent on density of Columbia spotted frog larvae indirectly increased parasite abundance. Our results show that effects of wildfire on amphibians depend upon burn extent and severity, isolation, and prior land use. Through subsequent effects on the parasites, our results also reveal how changes in disturbance regimes can affect communities across trophic levels. PMID- 23634597 TI - Population impacts of Wolbachia on Aedes albopictus. AB - Prior studies have demonstrated that Wolbachia, a commonly occurring bacterium capable of manipulating host reproduction, can affect life history traits in insect hosts, which in turn can have population-level effects. Effects on hosts at the individual level are predicted to impact population dynamics, but the latter has not been examined empirically. Here, we describe a biological model system based on Aedes albopictus (Asian tiger mosquito) that allows for measurement of population dynamics, which has not been accomplished in prior field trials or laboratory designs. The results demonstrate the studied populations to be robust and allow for persistent, closed populations with overlapping generations, which are regulated solely through density-dependent, intraspecific competition for limited resources. Using a novel experimental design, we compare populations that are either uninfected or infected with Wolbachia. The results show differences that include population size, eclosion rates, adult survivorship, and fecundity. The aposymbiotic populations were generally larger and adults longer lived relative to the infected populations. The outcome is discussed in context with naturally occurring Wolbachia invasions, proposed autocidal strategies, and the utility of the developed system as a biological platform for hypothesis testing and improved parameterization. PMID- 23634598 TI - Hibernation site requirements of bats in man-made hibernacula in a spatial context. AB - Bat hibernacula selection depends on various spatial and nonspatial variables that differ widely between sites. However, previous studies have focused mainly on nonspatial variables. This research investigated factors that determined the abundance and species richness of hibernating bats in hibernation objects of the New Dutch Waterline, The Netherlands, and determined the relevant scales over which spatial factors operate using regression techniques and ecological-niche factor analyses. The effects of 32 predictor variables on several response variables, i.e., the total bat abundance, species richness, and abundance and presence of bat species, were investigated. Predictor variables were classified as internal variables (e.g., building size, climatic conditions, and human access) or external variables (e.g., ground and vegetation cover and land cover type) that were measured at different spatial scales to study the influence of the spatial context. The internal building variables (mainly the size of hibernacula and the number of hiding possibilities) affected the hibernating bat abundance and species richness. Climatic variables, such as changes in temperature and humidity, were less important. The hibernation site suitability was also influenced by spatial variables at a variety of scales, thereby indicating the importance of scale-dependent species-environment relationships. The absence of human use and public access enhanced hibernation site suitability, but the internal size-related variables had the greatest positive effect on hibernation site suitability. These results demonstrate the importance of considering the different spatial scales of the surrounding landscape to better understand habitat selection, and they offer directives to managers to optimize objects for hibernating bats and to improve management and bat conservation. The analyses have wider applications to other wildlife-habitat studies. PMID- 23634599 TI - [The issues of assessment of medical support of patients with pathology of blood circulation system]. AB - The analysis of report forms No 12 "The information about number of diseases registered in patients residing in the area of medical institution supports" and No14 "The information about functioning of hospital" demonstrated that in conditions of ambulatory policlinic institutions there is no active monitoring of patients with diseases of blood circulation system. These diseases are the major causes of population mortality. PMID- 23634600 TI - [About the legal regulation of health care]. AB - The adoption of the law "About foundations of population health care in the Russian Federation" in absence of concept of health care development determining the major targets and tasks of the sector gives rise in citizen incomprehension and rejection of innovations of health policy. To determine the vector of development of Russian health care as compared with Soviet system of health care the analysis of particular positions of the Federal law "On foundations of population health care" (2011) and the USSR law "On approval of foundations of legislation of USSR and Union republics on health care" (1969) is made. PMID- 23634601 TI - [The medical social stipulation of reproductive behavior of female patients with inflammatory diseases of genitals]. AB - The article presents the characteristics of reproductive behavior of women aged 18-27 years with inflammatory diseases of genitals. It is established that according the sociological survey, female patients with mentioned diseases and having low level of medical sanitary knowledge are characterized by unsatisfactory material conditions of life and living, early age of sexual debuts, sexual promiscuity, frequent premarital conceptions, low indicator of nuptiality, low culture of family planning and reproductive activity. PMID- 23634603 TI - [The availability of particular types of medical social care to persons of elderly and senile age]. AB - The article presents the results of sociological survey of respondents of elderly and senile age living with their families or in senior centers. The comparative analysis was applied to availability of particular types of medical social care of contingent of interest depending on place of its residence. The age and ability of self-support of respondents were taken into account. PMID- 23634604 TI - [The students' awareness of prevention of sexually transmitted infections]. AB - The article analyzes the questionnaire data concerning the issues of awareness of sexually transmitted infections in students' milieu exemplified by specialized secondary educational institutions of Ryazan. PMID- 23634602 TI - [The prevalence of traumatism in population of rural industrial region]. AB - The rate of traumas and accidents in population of the Altai kray demonstrates the trend to insignificant increase. The prevalence of this occurrence among urban citizen is statistically much higher in comparison with rural dwellers (p < 0.05). The medical care appealability among male patients is higher than among female patients both in urban and rural territories. The maximum number of visits is conditioned by superficial traumas, open wounds, traumas of blood vessels, dislocations and strains, fractures of bones of upper and lower extremities. Among male patients as compared with female patients both in urban and rural areas, the percentage of open wounds, traumas of blood vessels and intra cerebral traumas was higher. In turn, in female patients the percentage of fractures of upper extremities, thermal and chemical burns were higher. PMID- 23634605 TI - [The healthy life-style as one of components of human safety]. AB - The technique of single-step anonymous questionnaire was applied to sampling of students of technical university to study propagation of health risk factors. The very high propagation of behavioral factors of life-style among students is noted. The model of healthy life-style is considered with emphasis on internal and external aspects of its functioning. It is established that particular steps in implementation of this model are ultimately individual. PMID- 23634606 TI - [About quality of life of patients with leprosy]. AB - The article deals with medical social and psychological aspects of impact of disease on quality of life of patients with leprosy. The focus is made upon predominantly elder age of registered patients with leprosy. The elaborated approach to treatment and dispensary monitoring of leprosy patients is proposed. The necessity of using techniques of evaluation of quality of life, enhancement of effectiveness of rehabilitation activities applied to leprosy patients is demonstrated. PMID- 23634607 TI - [The dynamics of morbidity of population of the city of Ufa]. AB - The article deals with analysis of general and primary morbidity of population of Ufa in all age groups according the data of form N 12 of state statistical supervision "The information of number of diseases registered in patients residing in the district of medical institution support" of Minzdrav of Republic of Bashkortostan in 2000-2008. It is established that during the mentioned period of time, an increase occurred of general and primary morbidity. The particular classes of diseases and age groups are detected which are characterized by a significant increase of indicators of morbidity. PMID- 23634608 TI - [The structural analysis of network of ambulatory polyclinic institutions in the Russian Federation]. AB - The article presents the results of structural analysis of statistic data concerning network, capacity and manpower support of institutions providing ambulatory polyclinic care to population of the Russian Federation. The structure of ambulatory polyclinic institutions including their planning capacity, physicians' and paramedical personnel manpower support and depending on type and administrative subordination level are demonstrated. The mean planning capacity of one conditional ambulatory polyclinic institution is estimated for comparative evaluation of intensity of changes in number of institutions and their capacity. PMID- 23634609 TI - [The prevention of complaints concerning quality of medical services: the role of communicative skills of medical personnel]. AB - The effective monitoring and prevention of complaints are obligatory elements of management of medical institution. The training of physicians to communicative skills has and additional positive potential in the process of prevention of occurrence of complaints. The training of physicians to communicative skills following procedure of patient-centered counseling makes it possible to significantly decrease number of complaints about quality of medical care in ambulatory medical institution. The training technology is to be convenient for simultaneous training of large amount of physicians. PMID- 23634610 TI - [About the formation of patients' flow in multi-type hospital]. AB - The analysis was applied concerning distribution of patients' flow depending on nosology forms of diseases and departments of hospital. The integrated value included number of treated patients and duration of treatment. The study established that the main groups of diseases determining the load on corresponding departments of hospital are cerebro-vascular diseases in neurologic department; diabetes mellitus in endocrinology department; pneumonia, chronic bronchitis and asthma in pulmonology department; urolithiasis in urology department; abnormal bleedings of female genitals in gynecology department; trauma of femur in traumatology department; cholelithiasis and cholecystitis in general surgery department. The developed differentiation of patients' flows makes it possible to determine the demand of diagnostic and treatment technologies in the particular hospital. PMID- 23634611 TI - [The development of management of clinical laboratory]. AB - The implementation of monitoring of main indicators of activities of the centralized laboratory developed in the counseling diagnostic center N1 makes it possible to assess the effectiveness of its functioning with the view of development of management. PMID- 23634613 TI - [The control of sanitary preventive measures in the framework of sanitary epidemiologic expertise of medical activities]. AB - The procedure of control of sanitary preventive, disinfection and sterilization measures during pre-licensing expertise of organization medical activities is discussed. PMID- 23634612 TI - [The main approaches to the public regulation of private system of health care of the Russian Federation]. AB - The article deals with the issues of public regulation of private system of health care. It is demonstrated that public control has to be of general character without meddling in operative economic activities of private medical organizations. The need in re-orientation of public tasks in the area of private health care is emphasized. The targets of public regulation of private health care are and forms of its implementation on different levels as well are marked. PMID- 23634614 TI - [About the history of gastroenterology in the USSR: the scientific school of M.I. Pevzner]. AB - The article deals with the for the first time presented reliable scientific biography of M. I. Pevzner, one of the founders of gastroenterology and scientific school in the USSR. PMID- 23634615 TI - [The significance of activities in the Imperial Orthodox Palestine Society for progression of medicine in the Middle East (to the 130th anniversary of foundation)]. AB - The article deals with the history of foundation of the Imperial Orthodox Palestine Society in Jerusalem and its input into progression of medicine in the Middle east. The medical activity of Russian physicians in medical institutions of the Society is reflected too. PMID- 23634616 TI - [To the 25th anniversary of commencement of perestroika of national public health]. AB - The process of modernization of public health of the Russian Federation requires the application of experience of resent past. In 2012, is 25 years from the day of approval of the decree "The main directions of development of population health protection and perestroika of public health of the USSR in 12th five-year plan and to the period up to 2000". Many items of this document remained unrealized due to the change of social political course of country progression. Nevertheless, these items can be used presently to enhance the legislation in public health sector. PMID- 23634617 TI - [Jean Alfred Fournier: to 180th anniversary]. AB - Jean Alfred Fournier was professor in dermatology in Universite de Paris and the director of the world-wide known venereology hospital of Saint Louisio. He is the author of many publications about clinical and social aspects of syphilidology. Fournier introduced the concept of "parasyphilis" (tabes dorsalis and general paralysis) and he was the first one who specified the relationship between these diseases and syphilis. He pointed out the significance of congenital syphilisio. In 1901 Fournier founded the French Society of sanitary and moral prevention. His ideas concerning syphilis control were implemented on the territories of many European countries. PMID- 23634618 TI - [The activities of the Red Cross Society during the Russia Japan war 1904-1905]. AB - The Red Cross Society actively participated in the organization of caring of ill and wounded soldiers at the Far East front during the Russia Japan war 1904-1905. The Red Cross units were not the supporting group of military sanitary institutions but independent organization providing serious assistance to medical service of Russian army through medical supply, transport and medical personnel. PMID- 23634619 TI - [Wanted: Politics against heart attacks]. PMID- 23634620 TI - [New European guidelines for acute and chronic heart failure]. PMID- 23634621 TI - [Navigated Transcranial Magnetic Stimulation (nTMS). Technology for more precise diagnosis and therapy of central nervous system dysfunctions]. PMID- 23634622 TI - [Benign prostatic hyperplasia with bladder outflow obstruction. A systematic review]. PMID- 23634623 TI - [Prioritization of funds for medical education and research favorable for clinical researchers]. PMID- 23634624 TI - [Nasal dilator astray led to severe pain]. PMID- 23634625 TI - [Applying for funding--tips for a successful applications]. PMID- 23634626 TI - [HPV test replaces Pap test in Uppsala]. PMID- 23634627 TI - [Mapping of severe injuries in Sweden]. PMID- 23634628 TI - [How to communicate difficult information? Let the patient decide]. PMID- 23634629 TI - [Can palliative sedation be an alternative to euthanasia?]. PMID- 23634630 TI - [The hospital library can save time for the researching physician]. PMID- 23634631 TI - [ Sad assault on "My records online"]. PMID- 23634633 TI - Time to abandon screening for depression in chronic disease. PMID- 23634632 TI - [Swedish laws applies here too]. PMID- 23634634 TI - Diagnosis and treatment of ectopic pregnancy. AB - The most common site of localisation of an ectopic pregnancy is the fallopian tube. Rarely an ectopic pregnancy can be found in the ovary, a caesarean section scar, the abdomen or the cervix. Risk factors are previous ectopic pregnancy, PID, endometriosis, previous pelvic surgery, the presence of a coil and infertility. However, a third of women with an ectopic pregnancy have no known risk factors. NICE recommends a low threshold for offering a pregnancy test to women of childbearing age when they attend the surgery. Symptoms and signs appear when the tube starts to tear. When the tube ruptures, the woman will quickly become unwell and haemodynamically unstable because of rapid intra-abdominal blood loss. The most common symptoms of ectopic pregnancy are pelvic or abdominal pain, amenorrhoea, missed period or abnormal period and vaginal bleeding. A positive diagnosis of a urinary tract infection or gastroenteritis does not exclude an ectopic pregnancy. Signs of suspected ectopic pregnancy include pelvic, abdominal, adnexal or cervical motion tenderness, rebound tenderness and abdominal distension. Women who are haemodynamically unstable, or in whom there is significant concern about the degree of pain or bleeding, should be referred directly to A&E, irrespective of the result of the pregnancy test. Stable patients with bleeding who have pain or a pregnancy of six weeks gestation or more or a pregnancy of uncertain gestation should be referred immediately to an early pregnancy assessment (EPA) service, or out-of-hours gynaecology service if the EPA service is not available. Diagnosis is confirmed by transvaginal ultrasound scan to identify the location of the pregnancy. PMID- 23634635 TI - Optimising the management of patients with infertility. AB - The main causes of infertility are female factor (anovulation, tubal damage, endometriosis and ovarian failure), male factor (low or absent numbers of motile sperm in the ejaculate, and erectile dysfunction), or unexplained infertility. More than 80% of couples will conceive within one year if the woman is aged under 40 and they have regular sexual intercourse. Of those who fail to conceive in the first year, around half will do so in the second year, giving a cumulative pregnancy rate > 90%. A woman of reproductive age who has not conceived after a year of regular sexual intercourse, and has no known cause of infertility, should be offered referral for further clinical assessment and investigation with her partner. Women who have a BMI > or = 30 are likely to take longer to conceive. Those with a BMI < 19 who have irregular or absent menstruation should be advised that putting on weight is likely to improve their chance of conception. The best test of ovulation is an appropriately timed mid-luteal serum progesterone level. Women with irregular or absent menstrual cycles should be offered a blood test to measure serum gonadotrophin levels (FSH and LH). Women with no known comorbidities should be screened for tubal occlusion. Those who are thought to have comorbidities should be offered laparoscopy and dye testing. PMID- 23634637 TI - Skin conditions affecting the elderly. PMID- 23634636 TI - Psychotic symptoms in young people warrant urgent referral. AB - There is a worse prognosis for psychosis and schizophrenia when onset is in childhood or adolescence. However, outcomes are improved with early detection and treatment. Psychotic symptoms can be associated with a variety of disorders including schizophrenia, schizoaffective disorder, drug-induced psychosis, personality disorder, epilepsy and autistic spectrum disorder. Positive symptoms include hallucinations and delusions. Negative symptoms include apathy, lack of drive, poverty of speech, social withdrawal and self-neglect. The DSM IV criteria for schizophrenia include two or more of the following: hallucinations, delusions, disorganised speech, grossly disorganised or catatonic behaviour and negative symptoms. Adults may raise concerns about social withdrawal, bizarre ideas, a change in behaviour or a decline in achievement. Most children and young people with psychotic symptoms will not go on to develop psychosis or schizophrenia. Direct enquiry may be needed to elicit suspected unusual beliefs or hallucinations. To distinguish unusual ideas from delusions the ideas should be tested for fixity. For example by asking: 'Are you sure? Could there be another explanation?' Mood and anxiety symptoms should be explored. The assessment should include a developmental history with particular attention to premorbid functioning. Failure to make expected progress whether personal, social or academic is significant. Better outcomes in terms of symptoms and social function are associated with a shorter duration of untreated psychosis. The detection of psychotic symptoms in primary care therefore warrants an urgent referral to secondary care mental health services for assessment and treatment. PMID- 23634638 TI - I'll never forget that advice you gave me, doctor.... PMID- 23634639 TI - Rapid quantification of yeast lipid using microwave-assisted total lipid extraction and HPLC-CAD. AB - We here present simple and rapid methods for fast screening of yeast lipids in Saccharomyces cerevisiae. First we introduced a microwave-assisted technique for fast lipid extraction that allows the extraction of lipids within 10 min. The new method enhances extraction rate by 27 times, while maintaining product yields comparable to conventional methods (n = 14, P > 0.05). The recovery (n = 3) from spiking of synthetic standards were 92 +/- 6% for cholesterol, 95 +/- 4% for triacylglycerol, and 92 +/- 4% for free fatty acids. Additionally, the new extraction method combines cell disruption and extraction in one step, and the approach, therefore, not only greatly simplifies sample handling but also reduces analysis time and minimizes sample loss during sample preparation. Second, we developed a chromatographic separation that allowed separation of neutral and polar lipids from the extracted samples within a single run. The separation was performed based on a three gradient solvent system combined with hydrophilic interaction liquid chromatography-HPLC followed by detection using a charged aerosol detector. The method was shown to be highly reproducible in terms of retention time of the analytes (intraday; 0.002-0.034% RSD; n = 10, interday; 0.04-1.35% RSD; n = 5) and peak area (intraday; 0.63-6% RSD; n = 10, interday; 4 12% RSD; n = 5). PMID- 23634640 TI - Anti-oxidant activity and attenuation of bladder hyperactivity by the flavonoid compound kaempferol. AB - OBJECTIVES: To evaluate the anti-oxidant activity of the flavonoid compound, kaempferol, and to examine its role in the suppression of oxidative stress and attenuation of bladder hyperactivity in a rat model of bladder injury. METHODS: The anti-oxidative activity of kaempferol was examined in lipopolysaccharide treated RAW264.7 macrophages by using flow cytometry. For in vivo studies, rats were pretreated with kaempferol or vehicle for 24 h. The rat urothelium was injured by the administration of protamine sulfate for 1.5 h and irritated by the subsequent infusion of potassium chloride for 4 h. Oxidative stress in the bladder tissue was assessed using chemiluminescence assay, and the bladder pressure was determination by cystomertrogram. RESULTS: Kaempferol significantly suppressed lipopolysaccharide-induced reactive oxygen species production in RAW264.7 rat macrophages. Exposure of the rat bladder to sequential infusion of protamine sulfate and potassium chloride induced bladder hyperactivity. Pretreatment with kaempferol, prevented the formation of reactive oxygen species and prolonged the intercontraction interval. CONCLUSION: Kaempferol suppresses oxidative stress and attenuates bladder hyperactivity caused by potassium chloride after protamine sulfate-induced bladder injury. PMID- 23634641 TI - Sintering of catalytic nanoparticles: particle migration or Ostwald ripening? AB - Metal nanoparticles contain the active sites in heterogeneous catalysts, which are important for many industrial applications including the production of clean fuels, chemicals and pharmaceuticals, and the cleanup of exhaust from automobiles and stationary power plants. Sintering, or thermal deactivation, is an important mechanism for the loss of catalyst activity. This is especially true for high temperature catalytic processes, such as steam reforming, automotive exhaust treatment, or catalytic combustion. With dwindling supplies of precious metals and increasing demand, fundamental understanding of catalyst sintering is very important for achieving clean energy and a clean environment, and for efficient chemical conversion processes with atom selectivity. Scientists have proposed two mechanisms for sintering of nanoparticles: particle migration and coalescence (PMC) and Ostwald ripening (OR). PMC involves the mobility of particles in a Brownian-like motion on the support surface, with subsequent coalescence leading to nanoparticle growth. In contrast, OR involves the migration of adatoms or mobile molecular species, driven by differences in free energy and local adatom concentrations on the support surface. In this Account, we divide the process of sintering into three phases. Phase I involves rapid loss in catalyst activity (or surface area), phase II is where sintering slows down, and phase III is where the catalyst may reach a stable performance. Much of the previous work is based on inferences from catalysts that were observed before and after long term treatments. While the general phenomena can be captured correctly, the mechanisms cannot be determined. Advancements in the techniques of in situ TEM allow us to observe catalysts at elevated temperatures under working conditions. We review recent evidence obtained via in situ methods to determine the relative importance of PMC and OR in each of these phases of catalyst sintering. The evidence suggests that, in phase I, OR is responsible for the rapid loss of activity that occurs when particles are very small. Surprisingly, very little PMC is observed in this phase. Instead, the rapid loss of activity is caused by the disappearance of the smallest particles. These findings are in good agreement with representative atomistic simulations of sintering. In phase II, sintering slows down since the smallest particles have disappeared. We now see a combination of PMC and OR, but do not fully understand the relative contribution of each of these processes to the overall rates of sintering. In phase III, the particles have grown large and other parasitic phenomena, such as support restructuring, can become important, especially at high temperatures. Examining the evolution of particle size and surface area with time, we do not see a stable or equilibrium state, especially for catalysts operating at elevated temperatures. In conclusion, the recent literature, especially on in situ studies, shows that OR is the dominant process causing the growth of nanoparticle size. Consequently, this leads to the loss of surface area and activity. While particle migration could be controlled through suitable structuring of catalyst supports, it is more difficult to control the mobility of atomically dispersed species. These insights into the mechanisms of sintering could help to develop sinter-resistant catalysts, with the ultimate goal of designing catalysts that are self-healing. PMID- 23634642 TI - Studies on the Himbert intramolecular arene/allene Diels-Alder cycloaddition. Mechanistic studies and expansion of scope to all-carbon tethers. AB - The unusual intramolecular arene/allene cycloaddition described 30 years ago by Himbert permits rapid access to strained polycyclic compounds that offer great potential for the synthesis of complex scaffolds. To more fully understand the mechanism of this cycloaddition reaction, and to guide efforts to extend its scope to new substrates, quantum mechanical computational methods were employed in concert with laboratory experiments. These studies indicated that the cycloadditions likely proceed via concerted processes; a stepwise biradical mechanism was shown to be higher in energy in the cases studied. The original Himbert cycloaddition chemistry is also extended from heterocyclic to carbocyclic systems, with computational guidance used to predict thermodynamically favorable cases. Complex polycyclic scaffolds result from the combination of the cycloaddition and subsequent ring-rearrangement metathesis reactions. PMID- 23634643 TI - Conformation-specific self-assembly of thermo-responsive poly(ethylene glycol)-b polypeptide diblock copolymer. AB - Poly(ethylene glycol)-block-poly(gamma-(2-methoxyethoxy)esteryl-L-glutamate) (PEG b-poly-L-EG2Glu) was synthesized via ring-opening polymerization (ROP) of L EG2Glu N-carboxyanhydride (NCA) using PEG-NH2 as macroinitiator. This diblock contained a thermo-responsive poly-L-EG2Glu block, which adopted primarily helical conformation in pristine aqueous solution. We found that PEG-b-poly-L EG2Glu diblock can display two levels of self-assembly behaviors associated with hydrophobic interactions and conformation-specific reassembly, respectively. Upon temperature increase, the PEG-b-poly-L-EG2Glu diblock formed wormlike micelles, in which the poly-L-EG2Glu formed the micelle core and maintained helical conformation. However, extension of thermal annealing time drove the secondary structure transformation of the poly-L-EG2Glu block from helical conformation to beta-sheet, which accounted for an assembly structure transition from wormlike micelles to nanoribbons. The critical factor was that poly-L-EG2Glu block can undergo thermo-induced hydrophobicity and conformation transformation, which offered an additional parameter to tune the nature of molecular interactions, i.e., intermolecular versus intramolecular hydrogen bonding interactions. The corresponding conformation and assembly structure changes were characterized using FTIR and electron microscopy, respectively. PMID- 23634644 TI - A population-based study of tumours of the renal pelvis and ureter: incidence, aetiology and histopathological findings. AB - OBJECTIVE: Carcinoma of the renal pelvis and ureter are unusual tumours and our limited knowledge comes mainly from case reports and small series from large academic hospitals, as a rule without histopathological review. This study reports aetiological and demographical factors as well as clinicopathological findings of all patients in a large geographical region. MATERIAL AND METHODS: All patients in western Sweden with a renal pelvic or ureteral tumour diagnosed between 1971 and 1998 (n = 930) were included. Untreated cases were not excluded. Demographic data and results of preoperative examinations were retrieved from the original clinical records. The histopathological slides were reviewed and tumour stage, grade, configuration, presence of carcinoma in situ and angiolymphatic invasion were determined. RESULTS: The majority of patients (80%) had invasive or high-grade tumours. Carcinoma in situ was present among 30% of patients with non invasive high-grade tumours. Angiolymphatic invasion (62%) and solid (non papillary) growth pattern (84%) were very common among patients with stage T2-T4 tumours. Twenty-three women out of 138 (16.7%) with ureteral carcinoma had a history of abdominal radiotherapy for gynaecological cancer 22 years (median) earlier. Forty-one patients out of 930 (4.4%) had a history of abuse of phenacetin-containing analgesics. CONCLUSIONS: This study demonstrates a very high incidence of high-grade upper tract tumours with carcinoma in situ, angiolymphatic invasion and solid (non-papillary) growth pattern, which underscores the malignant character of the disease. The possible association between pelvic radiotherapy and ureteral carcinoma warrants further study. PMID- 23634645 TI - CE verbal episodic memory impairment in schizophrenia: a comparison with frontal lobe lesion patients. AB - Schizophrenia (SCZ)-related verbal memory impairment is hypothesized to be mediated, in part, by frontal lobe (FTL) dysfunction. However, little research has contrasted the performance of SCZ patients with that of patients exhibiting circumscribed frontal lesions. The current study compared verbal episodic memory in patients with SCZ and focal FTL lesions (left frontal, LF; right frontal, RF; and bi-frontal, BF) on a four-trial list learning task consisting of three lists of varying semantic organizational structure. Each dependent variable was examined at two levels: scores collapsed across all four trials and learning scores (i.e., trial 4-trial 1). Performance deficits were observed in each patient group across most dependent measures at both levels. Regarding patient group differences, SCZ patients outperformed LF/BF patients (i.e., either learning scores or scores collapsed across trial) on free recall, primacy, primary memory, secondary memory, and subjective organization, whereas they only outperformed RF patients on the semantically blocked list on recency and primary memory. Collectively, these results indicate that the pattern of memory performance is largely similar between patients with SCZ and those with RF lesions. These data support tentative arguments that verbal episodic memory deficits in SCZ may be mediated by frontal dysfunction in the right hemisphere. PMID- 23634646 TI - Fish oil administration in older adults: is there potential for adverse events? A systematic review of the literature. AB - BACKGROUND: Omega-3 (n-3) fatty acid supplementation is becoming increasingly popular. However given its antithrombotic properties the potential for severe adverse events (SAE) such as bleeding has safety implications, particularly in an older adult population. A systematic review of randomized control trials (RCT) was conducted to explore the potential for SAE and non-severe adverse events (non SAE) associated with n-3 supplementation in older adults. METHODS: A comprehensive search strategy using Medline and a variety of other electronic sources was conducted. Studies investigating the oral administration of n-3 fish oil containing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or both against a placebo were sourced. The primary outcome of interest included reported SAE associated with n-3 supplementation. Chi-square analyses were conducted on the pooled aggregate of AEs. RESULTS: Of the 398 citations initially retrieved, a total of 10 studies involving 994 older adults aged >=60 years were included in the review. Daily fish oil doses ranged from 0.03 g to 1.86 g EPA and/or DHA with study durations ranging from 6 to 52 weeks. No SAE were reported and there were no significant differences in the total AE rate between groups (n-3 intervention group: 53/540; 9.8%; placebo group: 28/454; 6.2%; p = 0.07). Non-SAE relating to gastrointestinal (GI) disturbances were the most commonly reported however there was no significant increase in the proportion of GI disturbances reported in participants randomized to the n-3 intervention (n-3 intervention group: 42/540 (7.8%); placebo group: 24/454 (5.3%); p = 0.18). CONCLUSIONS: The potential for AEs appear mild-moderate at worst and are unlikely to be of clinical significance. The use of n-3 fatty acids and the potential for SAE should however be further researched to investigate whether this evidence is consistent at higher doses and in other populations. These results also highlight that well documented data outlining the potential for SAE following n-3 supplementation are limited nor adequately reported to draw definitive conclusions concerning the safety associated with n-3 supplementation. A more rigorous and systematic approach for monitoring and recording AE data in clinical settings that involve n 3 supplementation is required. PMID- 23634648 TI - Diagnostic accuracy of HbA1c in diabetes between Eastern and Western. AB - BACKGROUND: In 2010, the American Diabetes Association recommended the use of HbA1c as a diagnostic criterion for diabetes. However, HbA1c is not an accepted diagnostic tool for diabetes in Eastern Asia, because genetic differences compromise the standardization of the diagnostic cut-off point. OBJECTIVES: This study evaluated differences in the use of HbA1c for diagnosing diabetes in Eastern and Western populations and investigated whether HbA1c cut-off point of >= 6.5% is diagnostic of diabetes in patients from Eastern Asia. METHODS: Literature was obtained from MEDLINE, EMBASE and Cochrane databases. The pooled sensitivity and specificity of each HbA1c cut-off point were extracted and compared between Western and Eastern populations. Differences in the cut-off point for diagnosing diabetes in each region were compared by examining differences in the area under summary receiver operating characteristic (SROC) curves. RESULTS: Twelve publications from Eastern countries (n = 59,735) and 13 from Western countries (n = 22,954) were included in the analysis. Areas under SROC curves in the Eastern and Western groups were 0.9331 and 0.9120, respectively (P = 0.98). The cut-off point of the highest Youden index was 6.0%. At the HbA1c cut-off point of 6.5%, the pooled sensitivity and specificity were 58.7% and 98.4% for Eastern countries and 65.5% and 98.1% for Western countries, respectively. CONCLUSIONS: HbA1c exhibits the same diagnostic value for diabetes in Eastern and Western populations. In both populations, HbA1c levels > 6.0% identify the population at high risk of diabetes, and HbA1c > 6.5% is diagnostic of clinically established diabetes. PMID- 23634649 TI - Room-temperature polariton lasing from GaN nanowire array clad by dielectric microcavity. AB - Room-temperature polariton lasing from a GaN-dielectric microcavity is demonstrated with optical excitation. The device is fabricated with a GaN nanowire array clad by Si3N4/SiO2-distributed Bragg reflectors. The nanowire array is initially grown on silicon substrate by molecular beam epitaxy. A distinct nonlinearity in the lower polariton emission is observed at a threshold optical energy density of 625 nJ/cm(2), accompanied by significant line width narrowing to 5 meV and a small blue shift of ~1 meV. The measured polariton dispersion is characterized by a Rabi splitting of 40 meV and a cavity exciton detuning of -17 meV. The device described here is a demonstration of exciton photon strong coupling phenomenon in an array of light emitters and paves the way for the realization of a room temperature electrically injected polariton laser. PMID- 23634647 TI - Purification of pregnancy-associated glycoproteins from late-pregnancy Bubalus bubalis placentas and development of a radioimmunoassay for pregnancy diagnosis in water buffalo females. AB - BACKGROUND: Pregnancy-associated glycoproteins (PAGs) were first described as placental antigens present in the blood serum of the mother soon after implantation. Here, we describe the purification of several pregnancy-associated glycoproteins from water buffalo placenta (wbPAGs). A specific radioimmunoassay (RIA) was developed for early pregnancy diagnosis in buffalo species. RESULTS: Amino-terminal microsequencing of immunoreactive placental proteins allowed the identification of eleven wbPAGs sequences [Swiss-Prot accession numbers: P86369 to P86379]. Three polyclonal antisera (AS#858, AS#859 and AS#860) were raised in rabbits against distinct wbPAG fractions. A new RIA (RIA-860) was developed and used to distinguish between pregnant (n=33) and non-pregnant (n=26) water buffalo females. CONCLUSIONS: Our results confirmed the multiplicity of PAG expression in buffalo placenta. In addition, the RIA-860 system was shown to be sensitive, linear, reproducible, accurate and specific in measuring PAG concentrations in buffalo plasma samples from Day 37 of gestation onwards. PMID- 23634650 TI - Long distance travelling and financial burdens discourage tuberculosis DOTs treatment initiation and compliance in Ethiopia: a qualitative study. AB - BACKGROUND: Timely tuberculosis treatment initiation and compliance are the two key factors for a successful tuberculosis control program. However, studies to understand patents' perspective on tuberculosis treatment initiation and compliance have been limited in Ethiopia. The aim of this study is to attempt to do that in rural Ethiopia. METHODS: This qualitative, phenomenological study conducted 26 in-depth interviews with tuberculosis patients. A thematic content analysis of the interviews was performed using the Open Code software version 3.1. RESULTS: We found that lack of geographic access to health facilities, financial burdens, use of traditional healing systems and delay in diagnosis by health care providers were the main reasons for not initiating tuberculosis treatment timely. Lack of geographic access to health facilities, financial burdens, quality of health services provided and social support were also identified as the main reasons for failing to fully comply with tuberculosis treatments. CONCLUSIONS: This study highlighted complexities surrounding tuberculosis control efforts in Dabat District. Challenges of geographic access to health care facilities and financial burdens were factors that most influenced timely tuberculosis treatment initiation and compliance. Decentralization of tuberculosis diagnosis and treatment services to peripheral health facilities, including health posts is of vital importance to make progress toward achieving tuberculosis control targets in Ethiopia. PMID- 23634651 TI - New computerized indices for quantitative evaluation of depression and asymmetry in patients with chest wall deformities. AB - An evaluation index that can quantitatively assess the severity of chest wall deformities is essential to prepare and assess corrective surgical operations for patients with these deformities, including funnel chest patients. In previous studies, our group proposed several automatically calculated indices that represent the severity of depression and asymmetry in the chest wall. These indices showed sufficient performance in most cases of deformities, including those involving asymmetric and symmetric depression; however, their linearity declined when assessing complex deformities. The purpose of this study is to propose two automated indices that provide linear evaluation output for all types of chest wall deformities, including complex deformities, and to evaluate their performance and clinical feasibility. Six reference chest wall boundary curves were obtained from 60 computed tomography (CT) images of a normal chest. Next, an active contour model-based image processing technique was used to extract boundary curves from images of patients with real chest wall deformities. Third, the required parameters were extracted from the boundary curves and the targeted indices were calculated. Finally, the performance of the proposed indices was evaluated using 33 synthetic images and 60 real chest CT images of patients with chest wall deformities. The newly proposed indices can be automatically calculated from the original CT images and showed sufficient performance for all types of chest wall deformities. We believe that the newly proposed indices can facilitate pre- and postoperative evaluation of chest wall deformities in clinical practice. PMID- 23634652 TI - Beyond the Born-Oppenheimer approximation: a treatment of electronic flux density in electronically adiabatic molecular processes. AB - Intuition suggests that a molecular system in the electronic ground state Phi0 should exhibit an electronic flux density (EFD) in response to the motion of its nuclei. If that state is described by the Born-Oppenheimer approximation (BOA), however, a straightforward calculation of the EFD yields zero, since the electrons are in a stationary state, regardless of the state of the nuclear motion. Here an alternative pathway to a nonzero EFD from a knowledge of only the BOA ground-state wave function is proposed. Via perturbation theory a complete set of approximate vibronic eigenfunctions of the whole Hamiltonian is generated. If the complete non-BOA wave function is expressed in the basis of these vibronic eigenfunctions, the ground-state contribution to the EFD is found to involve a summation over excited states. Evaluation of this sum through the so-called "average excitation energy approximation" produces a nonzero EFD. An explicit formula for the EFD for the prototypical system, namely, oriented H2+ vibrating in the electronic ground state, is derived. PMID- 23634653 TI - Global transport and deposition of 137Cs following the Fukushima nuclear power plant accident in Japan: emphasis on Europe and Asia using high-resolution model versions and radiological impact assessment of the human population and the environment using interactive tools. AB - The earthquake and the subsequent tsunami that occurred offshore of Japan resulted in an important loss of life and a serious accident at the nuclear facility of Fukushima. The "hot spots" of the release are evaluated here applying the model LMDZORINCA for (137)Cs. Moreover, an assessment is attempted for the population and the environment using the dosimetric scheme of the WHO and the interactive tool ERICA, respectively. Cesium-137 was deposited mostly in Pacific and Atlantic Oceans and North Pole (80%), whereas the rest in the continental areas of North America and Eurasia contributed slightly to the natural background (0.5-5.0 kBq m(-2)). The effective dose from (137)Cs and (134)Cs (radiocesium) irradiation during the first 3 months was estimated between 1-5 mSv in Fukushima and the neighboring prefectures. In the rest of Japan, the respective doses were found to be less than 0.5 mSv, whereas in the rest of the world it was less than 0.1 mSv. Such doses are equivalent with the obtained dose from a simple X-ray; for the highly contaminated regions, they are close to the dose limit for exposure due to radon inhalation (10 mSv). The calculated dose rates from radiocesium exposure on reference organisms ranged from 0.03 to 0.18 MUGy h(-1), which are 2 orders of magnitude below the screening dose limit (10 MUGy h(-1)) that could result in obvious effects on the population. However, these results may underestimate the real situation, since stable soil density was used in the calculations, a zero radiocesium background was assumed, and dose only from two radionuclides was estimated, while more that 40 radionuclides have been deposited in the vicinity of the facility. When monitoring data applied, much higher dose rates were estimated certifying ecological risk for small mammals and reptiles in terms of cytogenetic damage and reproduction. PMID- 23634655 TI - Periesophageal vagal nerve injury post-AF ablation: the esophagus a vulnerable neighbor? PMID- 23634654 TI - Malaria is an uncommon cause of adult sepsis in south-western Uganda. AB - BACKGROUND: Malaria is often considered a cause of adult sepsis in malaria endemic areas. However, diagnostic limitations can make distinction between malaria and other infections challenging. Therefore, the objective of this study was to determine the relative contribution of malaria to adult sepsis in south western Uganda. METHODS: Adult patients with sepsis were enrolled at the Mbarara Regional Referral Hospital between February and May 2012. Sepsis was defined as infection plus >=2 of the following: axillary temperature >37.5 degrees C or <35.5 degrees C, heart rate >90 or respiratory rate >20. Severe sepsis was defined as sepsis plus organ dysfunction (blood lactate >4 mmol/L, confusion, or a systolic blood pressure <90 mmHg). Sociodemographic, clinical and laboratory data, including malaria PCR and rapid diagnostic tests, as well as acid fast bacteria sputum smears and blood cultures were collected. Patients were followed until in-patient death or discharge. The primary outcome of interest was the cause of sepsis. Multivariable logistic regression was performed to assess predictors of mortality. RESULTS: Enrollment included 216 participants who were 51% female with a median age of 32 years (IQR 27-43 years). Of these, 122 (56%) subjects were HIV-seropositive of whom 75 (66%) had a CD4+ T cell count <100 cells/MUL. The prevalence of malaria was 4% (six with Plasmodium falciparum, two with Plasmodium vivax). Bacteraemia was identified in 41 (19%) patients. In hospital mortality was 19% (n = 42). In multivariable regression analysis, Glasgow Coma Score <9 (IRR 4.81, 95% CI 1.80-12.8) and severe sepsis (IRR, 2.07, 95% CI 1.03-4.14), but no specific diagnoses were statistically associated with in-hospital mortality. CONCLUSION: Malaria was an uncommon cause of adult sepsis in a regional referral hospital in south-western Uganda. In this setting, a thorough evaluation for alternate causes of disease in patients presenting with sepsis is recommended. PMID- 23634656 TI - Racial variations in booking haemoglobin of primigravidae in Malaysia: a prospective study. AB - BACKGROUND: Variations in racial haemoglobin had been previously described in multiple studies locally and abroad. This study was conducted to quantify the differences in haemoglobin of booking primigravidae amongst the three major races in Malaysia at the antenatal clinic of University Malaya Medical Centre, Kuala Lumpur. FINDINGS: One year prospective study of booking full blood count sample of primigravidae taken in one centre was conducted. Multiple comparative analyses of the booking haemoglobin were performed using the One-way ANOVA comparative mean test in each trimester. 622 primigravidae without any known history of haematological disorders were recruited into the study. The mean haemoglobin for the Indian race was the lowest compared to the two other races in the second and the third trimesters, and it was found to be statistically significant lower (p- value 0.001) than the Malay race in the second trimester. It was also found that the Indian race had a significantly higher incidence of moderate to severe anaemia (p- value: 0.029). The prevalence of anaemia in our study population is also significantly higher in the Indian population (p- value: 0.01). CONCLUSIONS: The findings from this study have established that there is racial preponderance to anaemia in pregnancy. The Indian race is at a higher risk of having anaemia in pregnancy particularly in the second trimester. PMID- 23634657 TI - A protocol for a systematic review on the impact of unpublished studies and studies published in the gray literature in meta-analyses. AB - BACKGROUND: Meta-analyses are particularly vulnerable to the effects of publication bias. Despite methodologists' best efforts to locate all evidence for a given topic the most comprehensive searches are likely to miss unpublished studies and studies that are published in the gray literature only. If the results of the missing studies differ systematically from the published ones, a meta-analysis will be biased with an inaccurate assessment of the intervention's effects.As part of the OPEN project (http://www.open-project.eu) we will conduct a systematic review with the following objectives:? To assess the impact of studies that are not published or published in the gray literature on pooled effect estimates in meta-analyses (quantitative measure).? To assess whether the inclusion of unpublished studies or studies published in the gray literature leads to different conclusions in meta-analyses (qualitative measure). METHODS/DESIGN: INCLUSION CRITERIA: Methodological research projects of a cohort of meta-analyses which compare the effect of the inclusion or exclusion of unpublished studies or studies published in the gray literature. LITERATURE SEARCH: To identify relevant research projects we will conduct electronic searches in Medline, Embase and The Cochrane Library; check reference lists; and contact experts. OUTCOMES: 1) The extent to which the effect estimate in a meta analyses changes with the inclusion or exclusion of studies that were not published or published in the gray literature; and 2) the extent to which the inclusion of unpublished studies impacts the meta-analyses' conclusions. DATA COLLECTION: Information will be collected on the area of health care; the number of meta-analyses included in the methodological research project; the number of studies included in the meta-analyses; the number of study participants; the number and type of unpublished studies; studies published in the gray literature and published studies; the sources used to retrieve studies that are unpublished, published in the gray literature, or commercially published; and the validity of the methodological research project. DATA SYNTHESIS: DATA SYNTHESIS will involve descriptive and statistical summaries of the findings of the included methodological research projects. DISCUSSION: Results are expected to be publicly available in the middle of 2013. PMID- 23634658 TI - Fly-in/Fly-out nursing: is it for us? New graduate nurses' perspectives. AB - Fly-in/Fly-out models of health care for rural-remote communities are currently the focus of evaluation and debate, as the health inequalities of rural and remote communities continue to challenge both health service providers and healthcare consumers. At first glance, these models of health care may attract new graduate nurses transitioning to practice, because they appear to resolve some of the tensions in career planning and aspirations. However, FIFO models may also present significant tensions between healthcare services and the communities they serve. This article presents the thoughts and perceptions of new graduate nurses as they explore future career pathways in rural-remote nursing. It draws on the rural and remote health literature, in recognition of the enduring inequalities of rural and remote health in Australia. PMID- 23634659 TI - Female ejaculation orgasm vs. coital incontinence: a systematic review. AB - INTRODUCTION: Women may expel various kinds of fluids during sexual arousal and at orgasm. Their origins, quantity, compositions, and expulsion mechanisms depend on anatomical and pathophysiological dispositions and the degree of sexual arousal. These are natural sexual responses but may also represent symptoms of urinary incontinence. AIM: The study aims to clarify the etiology of fluid leakage at orgasm, distinguish between associated physiological sexual responses, and differentiate these phenomena from symptoms of illness. METHODS: A systematic literature review was performed. EMBASE (OvidSP) and Web of Science databases were searched for the articles on various phenomena of fluid expulsions in women during sexual arousal and at orgasm. MAIN OUTCOME MEASURES: Articles included focused on female ejaculation and its variations, coital incontinence (CI), and vaginal lubrication. RESULTS: Female ejaculation orgasm manifests as either a female ejaculation (FE) of a smaller quantity of whitish secretions from the female prostate or a squirting of a larger amount of diluted and changed urine. Both phenomena may occur simultaneously. The prevalence of FE is 10-54%. CI is divided into penetration and orgasmic forms. The prevalence of CI is 0.2-66%. Penetration incontinence occurs more frequently and is usually caused by stress urinary incontinence (SUI). Urodynamic diagnoses of detrusor overactivity (DOA) and SUI are observed in orgasmic incontinence. CONCLUSIONS: Fluid expulsions are not typically a part of female orgasm. FE and squirting are two different physiological components of female sexuality. FE was objectively evidenced only in tens of cases but its reported high prevalence is based mostly on subjective questionnaire research. Pathophysiology of squirting is rarely documented. CI is a pathological sign caused by urethral disorder, DOA, or a combination of both, and requires treatment. An in-depth appreciation of these similar but pathophysiologically distinct phenomena is essential for distinguishing normal, physiological sexual responses from signs of illness. PMID- 23634660 TI - The engagement of CTLA-4 on primary melanoma cell lines induces antibody dependent cellular cytotoxicity and TNF-alpha production. AB - BACKGROUND: CTLA-4 (Cytotoxic T lymphocyte antigen-4) is traditionally known as a negative regulator of T cell activation. The blocking of CTLA-4 using human monoclonal antibodies, such as Ipilimumab, is currently used to relieve CTLA-4 mediated inhibition of anti-tumor immune response in metastatic melanoma. Herein, we have analyzed CTLA-4 expression and Ipilimumab reactivity on melanoma cell lines and tumor tissues from cutaneous melanoma patients. Then, we investigated whether Ipilimumab can trigger innate immunity in terms of antibody dependent cellular cytotoxicity (ADCC) or Tumor Necrosis Factor (TNF)-alpha release. Finally, a xenograft murine model was set up to determine in vivo the effects of Ipilimumab and NK cells on melanoma. METHODS: CTLA-4 expression and Ipilimumab reactivity were analyzed on 17 melanoma cell lines (14 primary and 3 long-term cell lines) by cytofluorimetry and on 33 melanoma tissues by immunohistochemistry. CTLA-4 transcripts were analyzed by quantitative RT-PCR. Soluble CTLA-4 and TNF-alpha were tested by ELISA. Peripheral blood mononuclear cells (PBMC), NK and gammadeltaT cells were tested in ADCC assay with Ipilimumab and melanoma cell lines. TNF-alpha release was analyzed in NK-melanoma cell co cultures in the presence of ipilimumab. In vivo experiments of xenotransplantation were carried out in NOD/SCID mice. Results were analyzed using unpaired Student's t-test. RESULTS: All melanoma cell lines expressed mRNA and cytoplasmic CTLA-4 but surface reactivity with Ipilimumab was quite heterogeneous. Accordingly, about 2/3 of melanoma specimens expressed CTLA-4 at different level of intensity.Ipilimumab triggered, via FcgammaReceptorIIIA (CD16), ex vivo NK cells as well as PBMC, IL-2 activated NK and gammadeltaT cells to ADCC of CTLA-4+ melanoma cells. No ADCC was detected upon interaction with CTLA-4- FO-1 melanoma cell line. TNF-alpha was released upon interaction of NK cells with CTLA-4+ melanoma cell lines. Remarkably, Ipilimumab neither affected proliferation and viability nor triggered ADCC of CTLA-4+ T lymphocytes. In a chimeric murine xenograft model, the co-engraftment of Ipilimumab-treated melanoma cells with human allogeneic NK cells delayed and significantly reduced tumor growth, as compared to mice receiving control xenografts. CONCLUSIONS: Our studies demonstrate that Ipilimumab triggers effector lymphocytes to cytotoxicity and TNF-alpha release. These findings suggest that Ipilimumab, besides blocking CTLA-4, can directly activate the elimination of CTLA-4+ melanomas. PMID- 23634661 TI - Hippocampal gene expression dysregulation of Klotho, nuclear factor kappa B and tumor necrosis factor in temporal lobe epilepsy patients. AB - BACKGROUND: Previous research in animal seizure models indicates that the pleiotropic cytokine TNF is an important effector/mediator of neuroinflammation and cell death. Recently, it has been demonstrated that TNF downregulates Klotho (KL) through the nuclear factor kappa B (NFkB) system in animal models of chronic kidney disease and colitis. KL function in the brain is unclear, although Klotho knockout (Kl-/-) mice exhibit neural degeneration and a reduction of hippocampal synapses. Our aim was to verify if the triad KL-NFKB1-TNF is also dysregulated in temporal lobe epilepsy associated with hippocampal sclerosis (TLE(HS)) patients. FINDINGS: We evaluated TNF, NFKB1 and KL relative mRNA expression levels by reverse transcription quantitative PCR (RT-qPCR) in resected hippocampal tissue samples from 14 TLE(HS) patients and compared them to five post mortem controls. Four reference genes were used: GAPDH, HPRT1, ENO2 and TBP. We found that TNF expression was dramatically upregulated in TLE(HS) patients (P <0.005). NFKB1 expression was also increased (P <0.03) while KL was significantly downregulated (P <0.03) in TLE(HS) patients. Hippocampal KL expression had an inverse correlation with NFKB1 and TNF. CONCLUSIONS: Our data suggest that, similar to other inflammatory diseases, TNF downregulates KL through NFkB in TLE(HS) patients. The remarkable TNF upregulation in patients is a strong indication of hippocampal chronic inflammation. Our finding of hippocampal KL downregulation has wide implications not only for TLE(HS) but also for other neuronal disorders related to neurodegeneration associated with inflammation. PMID- 23634663 TI - On-chip enrichment and analysis of peptide subsets using a maleimide functionalized fluorous affinity biochip and nanostructure initiator mass spectrometry. AB - A new nanostructure initiator mass spectrometry (NIMS) methodology is presented that uses the strategy of fluorous-phase immobilization and capture by a maleimide-functionalized affinity tag to selectively enrich peptide subsets containing cysteine residues. This surface-based approach allows complex protein digests to be analyzed. The proposed platform makes use of a chemically unmodified porous silicon (pSi)-based NIMS chip. Unlike matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS), the approach described in this paper does not require analytes to be incorporated or cocrystallized with an initiator. The mass spectra generated by the approach in this work are characterized by low background noise and, therefore, high analyte detection sensitivity. Experiments were also conducted that show the potential the approach described in this work has for generating simplified mass spectra for MS/MS analyses. PMID- 23634662 TI - Quantifying variances in comparative RNA secondary structure prediction. AB - BACKGROUND: With the advancement of next-generation sequencing and transcriptomics technologies, regulatory effects involving RNA, in particular RNA structural changes are being detected. These results often rely on RNA secondary structure predictions. However, current approaches to RNA secondary structure modelling produce predictions with a high variance in predictive accuracy, and we have little quantifiable knowledge about the reasons for these variances. RESULTS: In this paper we explore a number of factors which can contribute to poor RNA secondary structure prediction quality. We establish a quantified relationship between alignment quality and loss of accuracy. Furthermore, we define two new measures to quantify uncertainty in alignment-based structure predictions. One of the measures improves on the "reliability score" reported by PPfold, and considers alignment uncertainty as well as base-pair probabilities. The other measure considers the information entropy for SCFGs over a space of input alignments. CONCLUSIONS: Our predictive accuracy improves on the PPfold reliability score. We can successfully characterize many of the underlying reasons for and variances in poor prediction. However, there is still variability unaccounted for, which we therefore suggest comes from the RNA secondary structure predictive model itself. PMID- 23634665 TI - Carbide cluster metallofullerenes: structure, properties, and possible origin. AB - Endohedral metallofullerenes (EMFs) are hybrid molecules with different metallic species encapsulated inside the fullerene cages. In addition to conventional EMFs that contain only metal ions, researchers have constructed novel compounds that encapsulate metallic clusters of nitride, carbide, oxide, cyanide, and sulfide. Among these structures, carbide cluster metallofullerenes (CCMFs) are unique because their synthesis requires only graphite and the metal source. As a result the molecular structures of CCMFs are particularly difficult to characterize. Two carbon atoms are encapsulated inside the cage, but they do not participate in constructing the cage framework. Recent X-ray crystallographic studies of EMFs have allowed researchers to unambiguously identify CCMFs (MxC2@C2n). Previously most of these structures had been described as conventional EMFs Mx@C2n+2. Most of these species are scandium-containing compounds such as Sc3C2@Ih(7)-C80 [not Sc3@C3v(7)-C82], Sc2C2@C2v(5)-C80 [not Sc2@C82], Sc2C2@Cs(6)-C82 [not Sc2@Cs(10) C84], Sc2C2@C2v(9)-C82 [not Sc2@C2v(17)-C84], Sc2C2@C3v(8)-C82 [not Sc2@D2d(23) C84], and Sc2C2@D2d(23)-C84 [not Sc2@C86]. Additional examples of CCMFs include Gd2C2@D3(85)-C92, Sc2C2@C2v(6073)-C68, Ti2C2@D3h(5)-C78, M2C2@C3v(8)-C82, M2C2@Cs(6)-C82 (M = Y, Er, etc.), Y2C2@C84, Y2C2@D3(85)-C92, Y2C2@D5(450)-C100, and Lu3C2@D2(35)-C88. The existence of so many CCMF species reminds us that the symbol '@' (which denotes the encapsulation status of EMFs) should be used with caution with species whose molecular structures have not been determined unambiguously. This Account presents a detailed summary of all aspects of CCMFs, including historically erroneous assignments and corrected structural characterizations, along with their intrinsic properties such as electrochemical and chemical properties. We emphasize structural issues, features that are fundamental for understanding their intrinsic properties. Finally, we discuss the formation mechanism and possible origin of cluster EMFs, not just CCMFs. PMID- 23634666 TI - Directional migration of vascular smooth muscle cells guided by a molecule weight gradient of poly(2-hydroxyethyl methacrylate) brushes. AB - Directional migration of cells mediated by gradient cues in vitro can mimic the corresponding biological events in vivo and thereby provides a way to disclose the cascade responses in tissue regeneration processes and to develop novel criteria for design of tissue-inductive biomaterials. In this work, a molecular weight gradient of poly(2-hydroxyethyl methacrylate) (PHEMA) brushes with a thickness ranging from 3 to 30 nm and slopes of 0.8-3.2 nm/mm were fabricated by using surface-initiated atom transfer radical polymerization (ATRP) and a dynamically controlled reaction process. The PHEMA gradients were characterized by X-ray photoelectron spectrometry (XPS) and ellipsometry. The adhesion number, spreading area, adhesion force, and expression of focal adhesion and actin fibers of vascular smooth muscle cells (VSMCs) decreased along with the increase of the PHEMA brushes length. The VSMCs exhibited preferential orientation and enhanced directional migration toward the direction of reduced PHEMA thickness, whose extent was dependent on the gradient slope and polymer thickness. Most of the cells were oriented, and 87% of the cells moved directionally at the optimal conditions. PMID- 23634667 TI - High energy density asymmetric quasi-solid-state supercapacitor based on porous vanadium nitride nanowire anode. AB - To push the energy density limit of asymmetric supercapacitors (ASCs), a new class of anode materials is needed. Vanadium nitride (VN) holds great promise as anode material for ASCs due to its large specific capacitance, high electrical conductivity, and wide operation windows in negative potential. However, its poor electrochemical stability severely limits its application in SCs. In this work, we demonstrated high energy density, stable, quasi-solid-state ASC device based on porous VN nanowire anode and VOx nanowire cathode for the first time. The VOx//VN-ASC device exhibited a stable electrochemical window of 1.8 V and excellent cycling stability with only 12.5% decrease of capacitance after 10,000 cycles. More importantly, the VOx//VN-ASC device achieved a high energy density of 0.61 mWh cm(-3) at current density of 0.5 mA cm(-2) and a high power density of 0.85 W cm(-3) at current density of 5 mA cm(-2). These values are substantially enhanced compared to most of the reported quasi/all-solid-state SC devices. This work constitutes the first demonstration of using VN nanowires as high energy anode, which could potentially improve the performance of energy storage devices. PMID- 23634669 TI - Has the time come for routine imaging studies in diabetes? PMID- 23634668 TI - Pyridinylquinazolines selectively inhibit human methionine aminopeptidase-1 in cells. AB - Methionine aminopeptidases (MetAPs), which remove the initiator methionine from nascent peptides, are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (1-4), but all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 1-4 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells. PMID- 23634671 TI - Comparison of glycemic variability in patients with type 2 diabetes given sitagliptin or voglibose: a continuous glucose monitoring-based pilot study. AB - OBJECTIVE: This study compared glycemic variability in patients with type 2 diabetes given sitagliptin or voglibose. PATIENTS AND METHODS: Seventeen type 2 diabetes patients were given sitagliptin 50 mg/day or voglibose 0.9 mg/day for 2 months and were hospitalized for a 4-day evaluation by continuous glucose monitoring (CGM). On discharge, they were crossed over to the other regimen for 2 months of treatment/4 days of evaluation. The CGM data were used to compare each parameter for glycemic variability. RESULTS: The average glucose levels with sitagliptin and voglibose were significantly different at 138.6 and 152.6 mg/dL for 24 h (P=0.014) and 147.2 and 160.9 mg/dL for during daytime (P=0.050), respectively. The patients' glucose levels with sitagliptin and voglibose were significantly different at 125.3 and 139.7 mg/dL before breakfast (P=0.015) and 112.7 and 131.4 mg/dL before lunch (P=0.049), respectively. The time from before meal to postprandial peak glucose levels was significantly longer after dinner with voglibose than with sitagliptin (91.5 and 122.3 min, respectively; P=0.012). All of the slopes of glucose elevation were significantly lower with voglibose after each meal, with that after breakfast, lunch, and dinner being 1.16 and 0.86 mg/dL/min (P=0.031), 0.70 and 0.45 mg/dL/min (P=0.048), and 1.06 and 0.73 mg/dL/min (P=0.028), respectively. CONCLUSIONS: This CGM-based pilot study revealed that sitagliptin significantly lowered 24-h and daytime mean glucose levels and glucose levels before breakfast and lunch compared with voglibose, whereas the time from before dinner to peak postprandial glucose levels was significantly longer, and the slope of postprandial elevation of glucose level was significantly lower after each meal, with voglibose compared with sitagliptin. PMID- 23634670 TI - Obesity and diabetes: newer concepts in imaging. AB - Quantifying body fat is currently an area of active research. Recent studies have shown that the quantity and location of fat in different compartments have varying clinical significance. This information can now be obtained from computed tomography (CT) or magnetic resonance (MR), and it can inform clinical decision making for patient management. Diabetes patients with insulin resistance and hyperinsulinemia have nonalcoholic fatty liver disease (NAFLD) ranging from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis, typically diagnosed by liver biopsy or serum markers. There is now an emerging role of noninvasive imaging tests such as MR imaging or MR spectroscopy or elastography, which can provide quantitative information and have potential to avoid biopsy. Obese patients with diabetes are also at risk for cardiovascular disease and cancer. There is an emerging role for imaging in early detection of not only structural but also functional abnormalities of myocardium at a subclinical stage. Screening for cancer is currently recommended only for breast, colon, prostate, and cervix. Given wider availability and advances in imaging techniques such as positron emission tomography/CT (faster scans with higher resolution and less ionizing radiation) and better understanding of molecular biology and risk stratification, more and more cancers are being detected in early stages with better clinical outcomes. Concerns related to cost, overdiagnosis, and unnecessary interventions must be addressed before population-based screening for other cancers is recommended. Based on ongoing imaging research, it is expected that it will be possible to provide more precise measurement of body fat and detect cardiovascular disease and cancers earlier in their course. PMID- 23634672 TI - Standardization versus customization of glucose reporting. AB - Bergenstal et al. (Diabetes Technol Ther 2013;15:198-211) described an important approach toward standardization of reporting and analysis of continuous glucose monitoring and self-monitoring of blood glucose (SMBG) data. The ambulatory glucose profile (AGP), a composite display of glucose by time of day that superimposes data from multiple days, is perhaps the most informative and useful of the many graphical approaches to display glucose data. However, the AGP has limitations; some variations are desirable and useful. Synchronization with respect to meals, traditionally used in glucose profiles for SMBG data, can improve characterization of postprandial glucose excursions. Several other types of graphical display are available, and recently developed ones can augment the information provided by the AGP. There is a need to standardize the parameters describing glycemic variability and cross-validate the available computer programs that calculate glycemic variability. Clinical decision support software can identify and prioritize clinical problems, make recommendations for modifications of therapy, and explain its justification for those recommendations. The goal of standardization is challenging in view of the diversity of clinical situations and of computing and display platforms and software. Standardization is desirable but must be done in a manner that permits flexibility and fosters innovation. PMID- 23634673 TI - Vice president's message to students is one of care. Threlfall assures students AVMA is working on solutions to their problems. PMID- 23634674 TI - Animal welfare continues improving with demands from buyers. PMID- 23634675 TI - The father of veterinary public health. PMID- 23634676 TI - What is your diagnosis? Acute hematoma. PMID- 23634677 TI - Pathology in practice. Mycoplasma bovis. PMID- 23634678 TI - Pathology in practice. Telangiectatic osteosarcoma. PMID- 23634679 TI - Differences in behavioral characteristics between dogs obtained as puppies from pet stores and those obtained from noncommercial breeders. AB - OBJECTIVE: To compare the owner-reported prevalence of behavioral characteristics in dogs obtained as puppies from pet stores with that of dogs obtained as puppies from noncommercial breeders. DESIGN: Cross-sectional study. Animals-Dogs obtained as puppies from pet stores (n = 413) and breeder-obtained dogs (5,657). PROCEDURES: Behavioral evaluations were obtained from a large convenience sample of current dog owners with the online version of the Canine Behavioral Assessment and Research Questionnaire, which uses ordinal scales to rate either the intensity or frequency of the dogs' behavior. Hierarchic linear and logistic regression models were used to analyze the effects of source of acquisition on behavioral outcomes when various confounding and intervening variables were controlled for. RESULTS: Pet store-derived dogs received significantly less favorable scores than did breeder-obtained dogs on 12 of 14 of the behavioral variables measured; pet store dogs did not score more favorably than breeder dogs in any behavioral category. Compared with dogs obtained as puppies from noncommercial breeders, dogs obtained as puppies from pet stores had significantly greater aggression toward human family members, unfamiliar people, and other dogs; greater fear of other dogs and nonsocial stimuli; and greater separation-related problems and house soiling. CONCLUSIONS AND CLINICAL RELEVANCE: Obtaining dogs from pet stores versus noncommercial breeders represented a significant risk factor for the development of a wide range of undesirable behavioral characteristics. Until the causes of the unfavorable differences detected in this group of dogs can be specifically identified and remedied, the authors cannot recommend that puppies be obtained from pet stores. PMID- 23634680 TI - Short-term and long-term outcomes for overweight dogs with cranial cruciate ligament rupture treated surgically or nonsurgically. AB - OBJECTIVE: To determine short- and long-term rates of successful outcomes of surgical and nonsurgical treatments for overweight dogs with cranial cruciate ligament rupture (CCLR). DESIGN: Prospective, randomized, clinical trial. Animals 40 client-owned overweight dogs with unilateral CCLR. PROCEDURES: Dogs were randomly assigned to nonsurgical (physical therapy, weight loss, and NSAID administration) or surgical (tibial plateau leveling osteotomy) treatment groups; dogs in both groups received the same nonsurgical treatments. Dogs were evaluated immediately before and 6, 12, 24, and 52 weeks after initiation of treatments via owner questionnaires, gait analysis, and dual-energy x-ray absorptiometry. A successful outcome was defined as an affected limb net ground reaction force > 85% of the value for healthy dogs and a >= 10% improvement in values of questionnaire variables. RESULTS: Owner questionnaire responses indicated dogs in both groups improved during the study, but dogs in the surgical treatment group seemed to have greater improvement. Body fat percentages for dogs in both treatment groups significantly decreased during the study. Surgical treatment group dogs had significantly higher peak vertical force for affected limbs versus nonsurgical treatment group dogs at the 24- and 52-week evaluation times. Surgical treatment group dogs had a higher probability of a successful outcome (67.7%, 92.6%, and 75.0% for 12-, 24-, and 52-week evaluations, respectively) versus nonsurgical treatment group dogs (47.1%, 33.3%, and 63.6% for 12-, 24-, and 52-week evaluations, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Overweight dogs with CCLR treated via surgical and nonsurgical methods had better outcomes than dogs treated via nonsurgical methods alone. However, almost two thirds of the dogs in the nonsurgical treatment group had a successful outcome at the 52-week evaluation time. PMID- 23634681 TI - Evaluation of the diagnostic value of serologic microagglutination testing and a polymerase chain reaction assay for diagnosis of acute leptospirosis in dogs in a referral center. AB - OBJECTIVE: To determine the diagnostic value of a serologic microagglutination test (MAT) and a PCR assay on urine and blood for the diagnosis of leptospirosis in dogs with acute kidney injury (AKI). DESIGN: Cross-sectional study. Animals-76 dogs with AKI in a referral hospital (2008 to 2009). PROCEDURES: Dogs' leptospirosis status was defined with a paired serologic MAT against a panel of 11 Leptospira serovars as leptospirosis-associated (n = 30) or nonleptospirosis associated AKI (12). In 34 dogs, convalescent serologic testing was not possible, and leptospirosis status was classified as undetermined. The diagnostic value of the MAT single acute or convalescent blood sample was determined in dogs in which leptospirosis status could be classified. The diagnostic value of a commercially available genus-specific PCR assay was evaluated by use of 36 blood samples and 20 urine samples. RESULTS: Serologic acute testing of an acute blood sample had a specificity of 100% (95% CI, 76% to 100%), a sensitivity of 50% (33% to 67%), and an accuracy of 64% (49% to 77%). Serologic testing of a convalescent blood sample had a specificity of 92% (65% to 99%), a sensitivity of 100% (87% to 100%), and an accuracy of 98% (88% to 100%). Results of the Leptospira PCR assay were negative for all samples from dogs for which leptospirosis status could be classified. CONCLUSIONS AND CLINICAL RELEVANCE: Serologic MAT results were highly accurate for diagnosis of leptospirosis in dogs, despite a low sensitivity for early diagnosis. In this referral setting of dogs pretreated with antimicrobials, testing of blood and urine samples with a commercially available genus-specific PCR assay did not improve early diagnosis. PMID- 23634682 TI - Association between previous splenectomy and gastric dilatation-volvulus in dogs: 453 cases (2004-2009). AB - OBJECTIVE: To evaluate the association between previous splenectomy and gastric dilatation-volvulus (GDV) in dogs. DESIGN: Multi-institutional retrospective case control study. Animals-151 dogs treated surgically for GDV and 302 control dogs with no history of GDV. PROCEDURES: Computerized records of dogs evaluated via exploratory laparotomy or abdominal ultrasonography were searched, and dogs with GDV and dogs without GDV (control dogs) were identified. Two control dogs were matched with respect to age, body weight, sex, neuter status, and breed to each dog with GDV. Data were collected on the presence or absence of the spleen for both dogs with GDV and control dogs. Conditional logistic regression analysis was used to investigate the association of previous splenectomy with GDV. RESULTS: 6 (4%) dogs in the GDV group and 3 (1%) dogs in the control group had a history of previous splenectomy. The odds of GDV in dogs with a history of previous splenectomy in this population of dogs were 5.3 times those of dogs without a history of previous splenectomy (95% confidence interval, 1.1 to 26.8). CONCLUSIONS AND CLINICAL RELEVANCE: For the patients in the present study, there was an increased odds of GDV in dogs with a history of splenectomy. Prophylactic gastropexy may be considered in dogs undergoing a splenectomy, particularly if other risk factors for GDV are present. PMID- 23634683 TI - Perioperative outcome in dogs with hemoperitoneum: 83 cases (2005-2010). AB - OBJECTIVE: To characterize the clinical course of dogs with hemoperitoneum in the perioperative setting and to determine risk factors that may affect short-term outcome. DESIGN: Retrospective case series. ANIMALS: 83 client-owned dogs. PROCEDURES: The medical records of dogs with hemoperitoneum that underwent surgery between 2005 and 2010 were reviewed. Data were analyzed to determine risk factors associated with perioperative outcome. The perioperative period was defined as the time from admission to the hospital for treatment of hemoperitoneum until the time of discharge or euthanasia (within the same visit). RESULTS: 13 of 83 (16%) dogs died or were euthanized in the perioperative period. The median hospitalization time for surviving dogs was 2 days (range, 1 to 5 days). The requirement for a massive transfusion with blood products was a negative prognostic indicator for hospital discharge. The source of bleeding was isolated to the spleen in 75 of 83 (90%) dogs; a splenic source of hemorrhage was determined to be a positive predictor of survival to discharge from the hospital. CONCLUSIONS AND CLINICAL RELEVANCE: In the present study, factors associated with death and failure to be discharged from the hospital included tachycardia, a requirement for massive transfusion with blood products, and the development of respiratory disease secondary to suspected pulmonary thromboembolism or acute respiratory distress syndrome. The presence of disease within the spleen was positively associated with survival to discharge. Surgical intervention for treatment of hemoperitoneum, regardless of etiology, resulted in discharge from the hospital for 70 of the 83 (84%) dogs in this series. PMID- 23634684 TI - Results of surgical excision and evaluation of factors associated with survival time in dogs with lingual neoplasia: 97 cases (1995-2008). AB - OBJECTIVE: To describe the clinical characteristics, treatments, outcomes, and factors associated with survival time in a cohort of dogs with lingual neoplasia that underwent surgical excision. DESIGN: Retrospective case series. Animals-97 client-owned dogs. PROCEDURES: Medical records of dogs with a lingual tumor examined between 1995 and 2008 were reviewed. Records were included if a lingual tumor was confirmed by histologic examination and surgical excision of the mass was attempted. Data were recorded and analyzed to identify prognostic factors. RESULTS: Clinical signs were mostly related to the oral cavity. For 93 dogs, marginal excision, subtotal glossectomy, and near-total glossectomy were performed in 35 (38%), 55 (59%), and 3 (3%), respectively. Surgery-related complications were rare, but 27 (28%) dogs had tumor recurrence. The most common histopathologic diagnoses for the 97 dogs were squamous cell carcinoma (31 [32%]) and malignant melanoma (29 [30%]). Eighteen (19%) dogs developed metastatic disease, and the overall median survival time was 483 days. Median survival time was 216 days for dogs with squamous cell carcinoma and 241 days for dogs with malignant melanoma. Dogs with lingual tumors >= 2 cm in diameter at diagnosis had a significantly shorter survival time than did dogs with tumors < 2 cm. CONCLUSIONS AND CLINICAL RELEVANCE: Similar to previous studies, results indicated that lingual tumors are most commonly malignant, and squamous cell carcinoma and malignant melanoma predominate. A thorough physical examination to identify lingual tumors at an early stage and surgical treatment after tumor identification are recommended because tumor size significantly affected survival time. PMID- 23634685 TI - Adrenal gland function in a dog following unilateral complete adrenalectomy and contralateral partial adrenalectomy. AB - CASE DESCRIPTION: A 40.3-kg (88.7-lb) 6-year-old spayed female Labrador Retriever was evaluated because of acute unilateral epistaxis. CLINICAL FINDINGS: During the initial evaluation of the dog, systemic hypertension and a left adrenal gland mass were detected. The left adrenal gland mass was surgically removed; results of histologic examination of the mass indicated it was a pheochromocytoma. Ten months later, the dog was evaluated because of persistent systemic hypertension and development of polyuria, polydipsia, and excessive panting. Abdominal ultrasonography revealed a mass in the cranial aspect of the right adrenal gland; results of MRI suggested the mass was a malignant tumor. TREATMENT AND OUTCOME: Epistaxis resolved after treatment and resolution of severe systemic hypertension. A partial right adrenalectomy was performed to remove the right adrenal gland mass. Results of histologic examination of the mass indicated it was a well-differentiated carcinoma of the cortex of the adrenal gland. Results of ACTH stimulation tests after surgery indicated the dog had adequate adrenal gland function. CLINICAL RELEVANCE: Partial adrenalectomy may be a safe and feasible treatment option to preserve adrenal gland function in dogs with small eccentrically located adrenal gland masses, particularly for dogs that have undergone removal of the contralateral adrenal gland. PMID- 23634686 TI - Idiopathic sterile inflammation of the epidural fat and epaxial muscles causing paraplegia in a mixed-breed dog. AB - CASE DESCRIPTION: A 4-year-old sexually intact male mixed-breed dog was evaluated because of clinical signs of acute-onset pelvic limb ataxia, rapidly progressing to paraplegia with severe spinal hyperesthesia. CLINICAL FINDINGS: General physical examination revealed pyrexia, tachycardia, and tachypnea. Neurologic examination demonstrated severe spinal hyperesthesia and paraplegia with decreased nociception. Magnetic resonance imaging revealed extradural spinal cord compression at T13-L1 and hyperintense lesions on T1- and T2-weighted images in the epaxial musculature and epidural space. TREATMENT AND OUTCOME: Decompressive surgery, consisting of a continuous dorsal laminectomy, with copious lavage of the vertebral canal was performed. Cultures of blood, urine, and surgical site samples were negative. Histologic examination results for samples obtained during surgery demonstrated suppurative myositis and steatitis. These findings confirmed a diagnosis of sterile idiopathic inflammation of the epidural fat and epaxial muscles with spinal cord compression. The dog's neurologic status started to improve 1 week after surgery. After surgery, the dog received supportive care including antimicrobials and NSAIDs. The dog was ambulatory 1 month after surgery and was fully ambulatory despite signs of mild bilateral pelvic limb ataxia 3 years after surgery. CLINICAL RELEVANCE: Although idiopathic sterile inflammation of adipose tissue, referred to as panniculitis, more commonly affects subcutaneous tissue, its presence in the vertebral canal is rare. Specific MRI findings described in this report may help in reaching a presumptive diagnosis of this neurologic disorder. A definitive diagnosis and successful long-term outcome in affected patients can be achieved by decompressive surgery and histologic examination of surgical biopsy samples. PMID- 23634687 TI - Staphylococcus aureus shedding pattern throughout lactation in dairy cows with naturally occurring intramammary infection. AB - OBJECTIVE: To evaluate shedding patterns of Staphylococcus aureus, specifically the association between clonal relatedness and shedding patterns of S aureus for cows with naturally occurring S aureus intramammary infection. DESIGN: Longitudinal field study. SAMPLE: Milk samples from 22 lactating cows (29 mammary glands) of varied numbers of lactations on 2 dairies. Procedures-Foremilk samples were collected weekly for 26 to 44 weeks during lactation from individual mammary glands. Milk samples were cultured bacteriologically with a 0.01-mL inoculum. Samples were considered culture positive for S aureus if >= 1 colony-forming units were obtained. Milk samples from known S aureus-positive mammary glands that were culture negative for S aureus or culture positive with a single colony of S aureus were cultured bacteriologically a second time with a 0.1-mL inoculum. Longitudinal shedding patterns of S aureus and the effect of strain type on ln(colony forming unit count) were examined. RESULTS: With the 0.01-mL inoculum, 914 of 1,070 (85%) samples were culture positive. After reculturing of negative samples with a 0.1-mL inoculum, 1,011 (95%) of the samples were culture positive. There was no significant difference in the detection of S aureus between genotypic clusters when either the 0.01- or 0.1-mL inoculum was used. There was no significant difference in the amount of shedding between mammary glands infected with isolates in genotypic cluster 1 or 2. No consistent shedding patterns were identified among or within cows. There was a significant difference in mammary gland linear score and test day (composite) linear score between mammary glands infected with isolates in genotypic clusters 1 and 2. CONCLUSIONS AND CLINICAL RELEVANCE: S aureus was shed consistently in cows with naturally occurring intramammary infection in cows, and regardless of the pulsotype, variations in the amount of S aureus shedding had no significant effect on the ability to detect S aureus with a 0.1-mL inoculum. PMID- 23634688 TI - Spiral colon impaction in juvenile alpacas: 12 cases (2006-2010). AB - OBJECTIVE: To describe clinical signs and treatment outcomes for juvenile alpacas with spiral colon impaction (SCI). DESIGN: Retrospective case series. Animals-12 juvenile (< 6 months old) camelids with SCI. PROCEDURES: Crias with SCI were identified by searching the medical records database of the Cornell University Equine and Farm Animal Hospital. A keyword-based search method was used. Inclusion required confirmation of SCI on the basis of surgical or necropsy findings. History, signalment, examination findings, diagnostic test results, medical treatments, and surgical reports as well as short- and long-term outcomes were reviewed. Peritoneal fluid parameters were compared with those of age matched comparison crias in which SCI was suspected but ruled out at necropsy or exploratory celiotomy. RESULTS: 12 crias with confirmed SCI were identified. Common clinical signs included lethargy and diarrhea. Abdominal distention was observed in 9 crias. In 3 crias, a mass in the region of the spiral colon was palpated. Seven crias underwent peritoneal fluid analysis; compared with age matched comparison crias, SCI-affected crias had higher peritoneal fluid nucleated cell counts and nucleated cell count-to-total protein concentration ratios. A ventral midline celiotomy was performed in 9 crias; 7 underwent an enterotomy, and 2 underwent transmural infusion of saline (0.9% NaCl) solution with manual breakdown of ingesta; 3 of these crias survived for at least 6 months. CONCLUSIONS AND CLINICAL RELEVANCE: Crias with SCI that were not resolved by medical management had a poor prognosis. During celiotomy, transmural infusion of saline solution with manual breakdown of ingesta provided a less invasive alternative to enterotomy. PMID- 23634689 TI - Dyslipidemia is associated with tunneled-cuffed catheter-related central venous thrombosis in hemodialysis patients: a retrospective, multicenter study. AB - The aim of this study was to explore the risk factors of tunneled-cuffed catheter (TCC)-related central venous thrombosis (CVT) for the maintenance of hemodialysis patients. In this study, 285 patients on maintenance hemodialysis were enrolled who had received their first TCC in the right jugular vein. Patients were divided into CVT and control groups according to the diagnosis of TCC-related CVT 6 months after catheterization. Patients with CVT had a higher prevalence of dyslipidemia (50.74 vs. 26.85%, respectively) and low protein store compared with the control group. After adjusting for confounders, serum triglycerides (OR: 3.632; 95% CI: 2.105-6.267), non-HDL cholesterol (OR: 1.463; 95% CI:1.067-2.007), and low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio (OR: 2.904; 95% CI: 1.797-4.692) were positively correlated with TCC-related CVT, while serum HDL cholesterol (OR: 0.097; 95% CI: 0.037-0.257) and serum albumin (OR: 0.922; 95% CI: 0.864-0.985) were negatively correlated. Dyslipidemia and low serum albumin levels were significantly associated with TCC-related CVT in hemodialysis patients. PMID- 23634690 TI - Bioreduction of hydrogen uranyl phosphate: mechanisms and U(IV) products. AB - The mobility of uranium (U) in subsurface environments is controlled by interrelated adsorption, redox, and precipitation reactions. Previous work demonstrated the formation of nanometer-sized hydrogen uranyl phosphate (abbreviated as HUP) crystals on the cell walls of Bacillus subtilis, a non-U(VI) reducing, Gram-positive bacterium. The current study examined the reduction of this biogenic, cell-associated HUP mineral by three dissimilatory metal-reducing bacteria, Anaeromyxobacter dehalogenans strain K, Geobacter sulfurreducens strain PCA, and Shewanella putrefaciens strain CN-32, and compared it to the bioreduction of abiotically formed and freely suspended HUP of larger particle size. Uranium speciation in the solid phase was followed over a 10- to 20-day reaction period by X-ray absorption fine structure spectroscopy (XANES and EXAFS) and showed varying extents of U(VI) reduction to U(IV). The reduction extent of the same mass of HUP to U(IV) was consistently greater with the biogenic than with the abiotic material under the same experimental conditions. A greater extent of HUP reduction was observed in the presence of bicarbonate in solution, whereas a decreased extent of HUP reduction was observed with the addition of dissolved phosphate. These results indicate that the extent of U(VI) reduction is controlled by dissolution of the HUP phase, suggesting that the metal-reducing bacteria transfer electrons to the dissolved or bacterially adsorbed U(VI) species formed after HUP dissolution, rather than to solid-phase U(VI) in the HUP mineral. Interestingly, the bioreduced U(IV) atoms were not immediately coordinated to other U(IV) atoms (as in uraninite, UO2) but were similar in structure to the phosphate-complexed U(IV) species found in ningyoite [CaU(PO4)2.H2O]. This indicates a strong control by phosphate on the speciation of bioreduced U(IV), expressed as inhibition of the typical formation of uraninite under phosphate-free conditions. PMID- 23634691 TI - Early maladaptive cognitive schemas in child sexual offenders compared with sexual offenders against adults and nonsexual violent offenders: an exploratory study. AB - INTRODUCTION: Although there is a growing body of research on the role of offense supporting cognitive distortions in child sexual offending, little is known about the origins of these distortions. According to cognitive theory, maladaptive cognitive schemas originating in adverse childhood experiences with caregivers have been hypothesized to underlie these cognitive distortions. AIM: This exploratory study investigates early maladaptive schemas (EMSs) in child sexual offenders compared with sexual offenders against adults and nonsexual offenders. MAIN OUTCOME MEASURES: EMSs were measured with the Young Schema Questionnaire, and psychopathy was measured with the Psychopathy Checklist-Revised. METHODS: Three groups of forensic inpatients-23 child sexual offenders, 19 sexual offenders against adults, and 24 nonsexual violent offenders-were assessed. Multivariate analyses of covariance were used to examine the hypothesized group differences in EMSs. RESULTS: Results showed that, after controlling for level of psychopathy, EMSs related to Abandonment (M = 2.61 vs. M = 1.73, P < 0.01), Social Isolation (M = 2.50 vs. M = 1.62, P < 0.01), Defectiveness/Shame (M = 2.05 vs. M = 1.42, P < 0.05), Subjugation (M = 2.28 vs. M = 1.57, P < 0.05), and Self Sacrifice (M = 3.29 vs. M = 2.41, P < 0.05) were more prevalent in child sexual offenders compared with nonsexual violent offenders. Compared with sexual offenders against adults, child sexual offenders showed a trend to have higher scores on EMSs related to Social Isolation (M = 2.50 vs. M = 1.88, P = 0.066). CONCLUSIONS: Our findings suggest that EMSs may play a role in offending behavior in child sexual offenders and offer the possibility of informing treatment strategies. PMID- 23634693 TI - Urban-rural differences in Spanish menopausal women. AB - INTRODUCTION: Most women spend one-third to half of their lifespan in the postmenopausal phase. As menopause involves biological and psychosocial changes that may significantly impair quality of life, the objectives of this study were to: (1) evaluate the prevalence of risk factors for osteoporosis and cardiovascular disease and the prevalence and severity of the appearance of menopausal symptoms among rural and urban Spanish menopausal women; (2) identify the main factors responsible for severity of symptoms; and (3) detect symptom differences between rural and urban women. METHODS: This cross-sectional descriptive study included 10,514 random-sampled women aged 45-65 years from Spain. Sociodemographic information, medical history and lifestyle data were assessed by survey. The Kupperman scale was used to assess severity of menopausal symptoms. RESULTS: Urban women had a higher prevalence of cardiovascular and osteoporosis risk factors than rural women, although this was not statistically significant. There was a greater frequency of menopausal symptoms in urban women although rural women experienced more hot flushes (p<0.05), depression, joint pain and tingling. In rural women menopausal symptoms were less severe (p<0.01). CONCLUSIONS: A high prevalence of risk factors for osteoporosis, and cardiovascular disease in particular, was observed. There were statistically significant differences between urban and rural women for some cardiovascular risk factors, frequency of hot flushes and severity of menopausal symptoms. PMID- 23634692 TI - Examination of osteoarthritis and subchondral bone alterations within the stifle joint of an ovariectomised ovine model. AB - The exact relationship between osteoporosis and osteoarthritis is still a matter for debate for many. The ovariectomised ewe is frequently used as a model for osteoporosis, resulting in significant alterations in bone morphometry and turnover in both trabecular and subchondral bone after 1 year. This study examines whether ovariectomy has any impact on development of osteoarthritis within the ovine stifle joint at the same time point. In addition, we investigate whether there are any significant correlations present between articular cartilage degeneration and alterations in microstructural parameters or turnover rates in the underlying bone. Twenty-two sheep were examined in this study; 10 of the sheep underwent ovariectomy and 12 were kept as controls. Five distinctive fluorochrome dyes were administered intravenously at 12-week intervals to both groups, to label sites of bone turnover. All animals were then sacrificed 12 months postoperatively. Although most specimens showed some evidence of osteoarthritis, no measurable difference between the two study groups was detected. Osteoarthritis was associated with a thinning of the subchondral plate, specifically the subchondral cortical bone; however, whereas previous studies have suggested a link between trabecular thinning and osteoarthritis, this was not confirmed. No correlation was found between osteoarthritis and bone turnover rates of either the subchondral trabecular bone or bone plate. In conclusion, despite the fact that ovariectomy results in marked morphological and structural changes in the ovine stifle joint at 1-year postoperatively, no evidence was found to suggest that it plays a direct role in the aetiology of osteoarthritis. PMID- 23634694 TI - Rectal temperature as an indicator for heat tolerance in chickens. AB - High environmental temperature is perhaps the most important inhibiting factor to poultry production in hot regions. The objective of this study was to test adaptive responses of chickens to high ambient temperatures and identify suitable indicators for selection of heat-tolerant individuals. Full-sib or half-sib Anak 40 pullets (n = 55) with similar body weights were raised in a room with a temperature ranging from 24 degrees C to 28 degrees C, and relative humidity of 50% from 61 to 65 days of age. On day 66, the ambient temperature was increased within 60 min to 35 +/- 1 degrees C which was defined as the initial of heat stress (0 h). Rectal temperature (RT) was measured on each pullet at 0, 6, 18, 30, 42, 54 and 66 h. After 66 h the ambient temperature was increased within 30 min to 41 +/- 1 degrees C and survival time (HSST) as well as lethal rectal temperatures (LRT) were recorded for each individual. The gap between the RT and initial RT was calculated as DeltaTn (DeltaT6, DeltaT18, DeltaT30, DeltaT42, DeltaT54 and DeltaT66), and the interval between LRT and initial RT as DeltaTT, respectively. A negative correlation was found between HSST and DeltaTn as well as DeltaTT (rDelta T 18 = -0.28 and rDelta TT = -0.31, respectively, P < 0.05; rDeltaT30 = -0.36, rDelta T 42 = -0.38, rDeltaT54 = -0.56, P < 0.01). Importantly, pullets with low DeltaT18 showed a longer HSST (256.0 +/- 208.4 min) than those with high DeltaT18 (HSST = 123.7 +/- 78.3 min). This observation suggested that the DeltaT18 or early increment of RT under heat stress might be considered as a reliable indicator for evaluation of heat resistance in chickens. PMID- 23634695 TI - Expression profiling of metastatic renal cell carcinoma using gene set enrichment analysis. AB - OBJECTIVE: To identify complex changes in cell biology occurring during metastatic progression of renal cell carcinoma using a novel gene expression analysis algorithm. METHODS: Whole genome expression profiling was carried out on 32 snap-frozen samples of clear-cell renal cell carcinoma metastases, 29 primary tumors (14 low grade, 15 high grade) and 14 samples of normal kidney tissue using oligonucleotide microarrays. These data were analyzed with the gene set enrichment analysis method, which is able to detect even small, but significant, expression changes in functionally connected genes that cannot be shown by gene by-gene comparisons. RESULTS: There were 95 gene sets (pathways) with significant upregulation in metastases compared with normal kidney tissue (P < 0.01), and 77 gene sets with significant downregulation, respectively. Low-grade and high-grade tumors showed deregulation of various pathways that have previously not been described in renal cell carcinoma. There were significant changes of genes involved in cell cycle control, apoptosis, cell motility, metabolism, cell adhesion and cytoskeleton. Some promising new potential therapy targets were identified in renal cell carcinoma metastases; for example, aurora-kinase A and flap structure-specific endonuclease 1. CONCLUSION: Expression profiling of metastatic renal cell carcinoma using the gene set enrichment analysis pathway analysis method provides new and detailed insights in alterations occurring in renal cell carcinoma during malignant transformation and progression. These data can help to develop new and specifically targeted renal cell carcinoma therapies. PMID- 23634696 TI - Impact of positive chest X-ray findings and blood cultures on adverse outcomes following hospitalized pneumococcal lower respiratory tract infection: a population-based cohort study. AB - BACKGROUND: Little is known about the clinical presentation and outcome of pneumococcal lower respiratory tract infection (LRTI) without positive chest X ray findings and blood cultures. We investigated the prognostic impact of a pulmonary infiltrate and bacteraemia on the clinical course of hospitalized patients with confirmed pneumococcal LRTI. METHODS: We studied a population-based multi-centre cohort of 705 adults hospitalized with LRTI and Streptococcus pneumoniae in LRT specimens or blood: 193 without pulmonary infiltrate or bacteraemia, 250 with X-ray confirmed pneumonia, and 262 with bacteraemia. We compared adverse outcomes in the three groups and used multiple regression analyses to adjust for differences in age, sex, comorbidity, and lifestyle factors. RESULTS: Patients with no infiltrate and no bacteraemia were of similar age but had more comorbidity than the other groups (Charlson index score >=1: no infiltrate and no bacteraemia 81% vs. infiltrate without bacteraemia 72% vs. bacteraemia 61%), smoked more tobacco, and had more respiratory symptoms. In contrast, patients with a pulmonary infiltrate or bacteraemia had more inflammation (median C-reactive protein: no infiltrate and no bacteraemia 82 mg/L vs. infiltrate without bacteraemia 163 mg/L vs. bacteraemia 316 mg/L) and higher acute disease severity scores. All adverse outcomes increased from patients with no infiltrate and no bacteraemia to those with an infiltrate and to those with bacteraemia: Length of hospital stay (5 vs. 6 vs. 8 days); intensive care admission (7% vs. 20% vs. 23%); pulmonary complications (1% vs. 5% vs. 14%); and 30-day mortality (5% vs. 11% vs. 21%). Compared with patients with no infiltrate and no bacteraemia, the adjusted 30-day mortality rate ratio was 1.9 (95% confidence interval (CI) 0.9-4.1) in patients with an infiltrate without bacteraemia and 4.1 (95% CI 2.0-8.5) in bacteraemia patients. Adjustment for acute disease severity and inflammatory markers weakened these associations. CONCLUSIONS: Hospitalization with confirmed pneumococcal LRTI is associated with substantial morbidity and mortality even without positive chest X-ray findings and blood cultures. Still, there is a clinically important outcome gradient from LRTI patients with pneumococcal isolation only to those with detected pulmonary infiltrate or bacteraemia which is partly mediated by higher acute disease severity and inflammation. PMID- 23634698 TI - Normative performance on the Brief Smell Identification Test (BSIT) in a multi ethnic bilingual cohort: a Project FRONTIER study. AB - The Brief Smell Identification Test (BSIT) is a commonly used measure of olfactory functioning in elderly populations. Few studies have provided normative data for this measure, and minimal data are available regarding the impact of sociodemographic factors on test scores. This study presents normative data for the BSIT in a sample of English- and Spanish-speaking Hispanic and non-Hispanic Whites. A Rasch analysis was also conducted to identify the items that best discriminated between varying levels of olfactory functioning, as measured by the BSIT. The total sample included 302 older adults seen as part of an ongoing study of rural cognitive aging, Project FRONTIER. Hierarchical regression analyses revealed that BSIT scores require adjustment by age and gender, but years of education, ethnicity, and language did not significantly influence BSIT performance. Four items best discriminated between varying levels of smell identification, accounting for 59.44% of total information provided by the measure. However, items did not represent a continuum of difficulty on the BSIT. The results of this study indicate that the BSIT appears to be well-suited for assessing odor identification deficits in older adults of diverse backgrounds, but that fine-tuning of this instrument may be recommended in light of its items' difficulty and discrimination parameters. Clinical and empirical implications are discussed. PMID- 23634699 TI - Impact of TBT on the vitellogenesis and sex hormones in freshwater prawn Macrobrachium rosenbergii (De Man, 1879). AB - BACKGROUND: Tributyltin (TBT) is a ubiquitous persistent xenobiotic that can be found in freshwater, estuarine and marine ecosystem. TBT is a strong endocrine disrupting compound (EDC) that can cause toxic threat to aquatic organisms. Imposex, sexual deformities and endocrine dysfunctions are the causes of TBT to most of the aquatic organisms. Effect of TBT on the vitellogenesis and sex hormonal changes in Macrobrachium rosenbergii has never been reported. Hence, the present investigation was undertaken to find out the impact of TBT on histological changes in the different reproductive tissues, sex hormonal alterations and level of biomarkers like vitellogenin and vitellin in M. rosenbergii. RESULTS: The present investigation documents the possible impact of tributyltin (TBT) on the vitellogenesis in freshwater female prawn M. rosenbergii. TBT at 10 ng/l, 100 ng/l and 1000 ng/l concentrations were exposed individually to prawns for a period of three months. At higher concentration of 1000 ng/l, the ovarian development was arrested and ovary remained at spent stage. At lower concentration of TBT (10 ng/l), the development proceeded up to early vitellogenic stage. At intermediate concentration of 100 ng/l TBT, the ovary remained at pre vitellogenic stage and thereafter no development was noticed. Histological results indicated the normal ovarian development with vitellogenic oocytes, filled with yolk globules in control prawn. On the other hand, the TBT treated groups showed reduction in yolk globules, fusion of developing oocytes and abundance of immature oocytes. Immunofluorescence staining denoted the remarkable reduction in vitellin content in ovary of TBT treated prawn. Hence, TBT had conspicuously inhibited the vitellogenesis by causing hormonal imbalance in M. rosenbergii. CONCLUSION: TBT had notably inhibited the vitellogenesis due to hormonal imbalance. This endocrine dysfunction ultimately impaired the oogenesis in the freshwater female prawn M. rosenbergii. PMID- 23634697 TI - Discovery of undefined protein cross-linking chemistry: a comprehensive methodology utilizing 18O-labeling and mass spectrometry. AB - Characterization of protein cross-linking, particularly without prior knowledge of the chemical nature and site of cross-linking, poses a significant challenge, because of their intrinsic structural complexity and the lack of a comprehensive analytical approach. Toward this end, we have developed a generally applicable workflow-XChem-Finder-that involves four stages: (1) detection of cross-linked peptides via (18)O-labeling at C-termini; (2) determination of the putative partial sequences of each cross-linked peptide pair using a fragment ion mass database search against known protein sequences coupled with a de novo sequence tag search; (3) extension to full sequences based on protease specificity, the unique combination of mass, and other constraints; and (4) deduction of cross linking chemistry and site. The mass difference between the sum of two putative full-length peptides and the cross-linked peptide provides the formulas (elemental composition analysis) for the functional groups involved in each cross linking. Combined with sequence restraint from MS/MS data, plausible cross linking chemistry and site were inferred, and ultimately confirmed, by matching with all data. Applying our approach to a stressed IgG2 antibody, 10 cross-linked peptides were discovered and found to be connected via thioethers originating from disulfides at locations that had not been previously recognized. Furthermore, once the cross-link chemistry was revealed, a targeted cross-link search yielded 4 additional cross-linked peptides that all contain the C-terminus of the light chain. PMID- 23634700 TI - Interleukin-1 beta converting enzyme is necessary for development of depression like behavior following intracerebroventricular administration of lipopolysaccharide to mice. AB - BACKGROUND: Interleukin-1 beta converting enzyme (ICE, caspase 1) is a cysteine protease that processes immature pro-IL-1beta into active mature IL-1beta. IL 1beta is a pro-inflammatory cytokine that mediates many of the physiological and behavioral responses to inflammation. Genetic deletion of ICE has previously been shown to prevent some negative physiologic responses to lipopolysaccharide (LPS) induced inflammation. METHODS: Here we used a preclinical murine model to test the hypothesis that ICE is necessary for development of depression-like behaviors following intracerebroventricular (ICV) treatment with LPS. Adult male ICE knockout (ICE KO) and congenic wild-type C57BL/6 J (WT) mice were administered LPS either ICV at 100 ng/mouse or intraperitoneally (IP) at 830 MUg/kg body weight or an equal volume of saline as controls. Mice were monitored up to 48 h after treatment for both sickness and depression-like behaviors. RESULTS: LPS given ICV induced a loss of body weight in both WT and ICE KO mice. This sickness response was similar between WT and ICE KO mice. As expected, LPS administered ICV increased immobility in the forced swim test (FST) and decreased sucrose preference in WT mice but no change in either of these two depression-like behaviors was observed in ICE KO mice. Expression of TNF-alpha and CD11b in brain was lower in ICE-KO mice at 24 h following ICV administration of LPS compared to WT mice. In contrast, when LPS was given systemically, sickness response, depression-like behaviors, and expression of these genes were similar between the two strains of mice. CONCLUSIONS: These findings indicate that ICE plays a specific role in depression-like behavior induced by a central inflammatory stimuli even though it is not required when LPS is administered systemically. PMID- 23634701 TI - Services just for men? Insights from a national study of the Well Men Services Pilots. AB - BACKGROUND: Men continue to have a lower life expectancy in most countries compared to women. Explanations of this gendered health inequality tend to focus on male risk taking, unhealthy lifestyle choices and resistance to seeking help from health services. In the period 2005-2008 the Scottish Government funded a nationwide community health promotion programme aimed at improving men's health, called Well Men Service Pilots (henceforth WMS). METHOD: This paper explores WMS programme users' perspectives and experiences of health help-seeking against theories of hegemonic masculinity as explanatory frameworks for men's behaviour around health and illness, and their views on a male-specific focus of the programme. It is based on a secondary analysis of 43 semi-structured interviews with men who engaged with this programme. RESULTS: We challenge the commonly held notion of men as being disinterested in their health, and point to their heterogeneity in relation to their views about health and notions of health seeking. Moreover, men in our study were largely ambivalent about the need for gender specific services, despite their positive reactions to the programme in general. CONCLUSIONS: Our findings question the utility of some theories of masculinity that posit somewhat simplistic explanations for men's reluctance to seek help from formal healthcare services. They also suggest that providing male specific health services may not significantly address men's supposed reluctance to seek help from formal health services. Essentially, age seemed to be more important than gender. All encompassing health programmes are likely to fail to meet their health improvement objectives if they attempt to engage with men on the simple basis that they are male. PMID- 23634702 TI - Nutrition in calcium nephrolithiasis. AB - Idiopathic calcium nephrolithiasis is a multifactorial disease with a complex pathogenesis due to genetic and environmental factors. The importance of social and health effects of nephrolithiasis is further highlighted by the strong tendency to relapse of the disease. Long-term prospective studies show a peak of disease recurrence within 2-3 years since onset, 40-50% of patients have a recurrence after 5 years and more than 50-60% after 10 years. International nutritional studies demonstrated that nutritional habits are relevant in therapy and prevention approaches of nephrolithiasis. Water, right intake of calcium, low intake of sodium, high levels of urinary citrate are certainly important for the primary and secondary prevention of nephrolithiasis. PMID- 23634703 TI - CNV-TV: a robust method to discover copy number variation from short sequencing reads. AB - BACKGROUND: Copy number variation (CNV) is an important structural variation (SV) in human genome. Various studies have shown that CNVs are associated with complex diseases. Traditional CNV detection methods such as fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (aCGH) suffer from low resolution. The next generation sequencing (NGS) technique promises a higher resolution detection of CNVs and several methods were recently proposed for realizing such a promise. However, the performances of these methods are not robust under some conditions, e.g., some of them may fail to detect CNVs of short sizes. There has been a strong demand for reliable detection of CNVs from high resolution NGS data. RESULTS: A novel and robust method to detect CNV from short sequencing reads is proposed in this study. The detection of CNV is modeled as a change-point detection from the read depth (RD) signal derived from the NGS, which is fitted with a total variation (TV) penalized least squares model. The performance (e.g., sensitivity and specificity) of the proposed approach are evaluated by comparison with several recently published methods on both simulated and real data from the 1000 Genomes Project. CONCLUSION: The experimental results showed that both the true positive rate and false positive rate of the proposed detection method do not change significantly for CNVs with different copy numbers and lengthes, when compared with several existing methods. Therefore, our proposed approach results in a more reliable detection of CNVs than the existing methods. PMID- 23634704 TI - Detection of capripoxvirus DNA using a novel loop-mediated isothermal amplification assay. AB - BACKGROUND: Sheep poxvirus (SPPV), Goat poxvirus (GTPV) and Lumpy skin disease virus (LSDV) are the most serious poxviruses of ruminants. They are double stranded DNA viruses of the genus Capripoxvirus, (subfamily Chordopoxvirinae) within the family Poxviridae. The aim of this study was to develop a Loop mediated isothermal AMPlification (LAMP) assay for the detection of Capripoxvirus (CaPV) DNA. RESULTS: A single LAMP assay targeting a conserved region of the CaPV P32 gene was selected from 3 pilot LAMP assays and optimised by adding loop primers to accelerate the reaction time. This LAMP assay successfully detected DNA prepared from representative CaPV isolates (SPPV, GTPV and LSDV), and did not cross-react with DNA extracted from other mammalian poxviruses. The analytical sensitivity of the LAMP assay was determined to be at least 163 DNA copies/MUl which is equivalent to the performance reported for diagnostic real-time PCR currently used for the detection of CaPV. LAMP reactions were monitored with an intercalating dye using a real-time PCR machine, or by agarose-gel electrophoresis. Furthermore, dual labelled LAMP products (generated using internal LAMP primers that were conjugated with either biotin or fluorescein) could be readily visualised using a lateral-flow device. CONCLUSIONS: This study provides a simple and rapid approach to detect CaPV DNA that may have utility for use in the field, or in non-specialised laboratories where expensive equipment is not available. PMID- 23634706 TI - Influences of surface charge, size, and concentration of colloidal nanoparticles on fabrication of self-organized porous silica in film and particle forms. AB - Studies on preparation of porous material have attracted tremendous attention because existence of pores can provide material with excellent performances. However, current preparation reports described successful production of porous material with only partial information on charges, interactions, sizes, and compositions of the template and host materials. In this report, influences of self-assembly parameters (i.e., surface charge, size, and concentration of colloidal nanoparticles) on self-organized porous material fabrication were investigated. Silica nanoparticles (as a host material) and polystyrene (PS) spheres (as a template) were combined to produce self-assembly porous materials in film and particle forms. The experimental results showed that the porous structure and pore size were controllable and strongly depended on the self assembly parameters. Materials containing highly ordered pores were effectively created only when process parameters fall within appropriate conditions (i.e., PS surface charge <= -30 mV; silica-to-PS size ratio <=0.078; and silica-to-PS mass ratio of about 0.50). The investigation of the self-assembly parameter landscape was also completed using geometric considerations. Because optimization of these parameters provides significant information in regard to practical uses, results of this report could be relevant to other functional properties. PMID- 23634705 TI - Prevalence of the molecular marker of Plasmodium falciparum resistance to chloroquine and sulphadoxine/pyrimethamine in Benin seven years after the change of malaria treatment policy. AB - BACKGROUND: In Benin, the National Malaria Control Programme (NMCP) changed the policy of malaria treatment in 2004 following increasing of failure rate of treatment with chloroquine (CQ) and sulphadoxine-pyrimethamine (SP). The objective of this study was to determinate the prevalence of Plasmodium falciparum molecular markers that are associated with resistance to CQ and SP in Benin seven years after the new policy was instituted. METHODS: The study was conducted in southern Benin, a region characterized by a perennial malaria transmission. Blood samples were collected in 2011 from children presenting with symptomatic and asymptomatic P. falciparum infections and living in the same area. The prevalence of critical point mutations in the genes of pfcrt (codon 76), pfmdr1 (codon 86), pfdhfr (codons, 51, 59 and 108) and pfdhps (codons 437, 540) was examined in parasite isolates by mutation-specific restriction enzyme digestion of nested PCR products. RESULTS: A high prevalence of parasites carrying point mutations in all studied targets was found: T76: 93.9% [89.8; 96.7], I51: 96.2% [92.7; 98.4], R59: 93, 9% [89.7; 96.7], N108: 97.6% [94.6; 99.2] and G437: 71.4% [64.8; 77.4]. No mutation was found at codon 540 of the pfdhps gene. The proportion of parasite isolates carrying triple mutation in the pfdhfr gene IRN (I51, R59 andN108) and quadruple mutation on the combination of pfdhfr/pfdhps IRNG (I51, R59, N108 and G437) was 91.5% [86.9; 94.9] and 65.7% [58.9; 72.1], respectively. Analysis of mutation in relation to the clinical status (symptomatic or asymptomatic) and according to age (younger or older than 10 years) showed similar very high frequencies in each category without significant difference between two groups. CONCLUSIONS: These results suggest a persistence level of resistance of P. falciparum to CQ and SP, seven years after the recommendation of the change of malaria treatment policy in Benin. The distribution of mutations studied was neither related to age nor to clinical status. PMID- 23634707 TI - Single ion channel recordings with CMOS-anchored lipid membranes. AB - We present single-ion-channel recordings performed with biomimetic lipid membranes which are directly attached to the surface of a complementary metal oxide-semiconductor (CMOS) preamplifier chip. With this system we resolve single channel currents from several types of bacterial ion channels, including fluctuations of a single alamethicin channel at a bandwidth of 1 MHz which represent the fastest single-ion-channel recordings reported to date. The platform is also used for high-resolution alpha-hemolysin nanopore recordings. These results illustrate the high signal fidelity, fine temporal resolution, small geometry, and multiplexed integration which can be achieved by leveraging integrated semiconductor platforms for advanced ion channel interfaces. PMID- 23634708 TI - Why do water and sanitation systems for the poor still fail? Policy analysis in economically advanced developing countries. AB - The results of an independent evaluation of 60 case studies of water and sanitation infrastructure projects in India, Mexico, and South Africa, most of them implemented since 2000, demonstrate an ongoing problem of failing infrastructure even in economically advanced developing countries. This paper presents a meta-analysis of those project case study results and analyses whether the design of existing policies or other factors contribute to failures. It concludes that the observed failures are due to well-known reasons and recommends how the implementation of the Dublin-Rio Principles can be improved. (They were introduced twenty years ago to avoid such failures by means of more sustainable planning.). PMID- 23634709 TI - The effect of chorionicity and twin-to-twin delivery time interval on short-term outcome of the second twin. AB - OBJECTIVES: To investigate the effect of chorionicity and twin-to-twin delivery time interval on short-term outcome in the second twin as well as to investigate the predictors of adverse outcome in both twins. METHODS: Data included vaginally delivered twins (>=36 weeks) from Copenhagen University Hospitals (2001-2009). The association between delivery interval and adverse outcome parameters was compared for monochorionic (MC) and dichorionic (DC) twins by multiple linear regression. Predictors were studied by logistic regression. RESULTS: There were 554 twin pairs, of which 57 were MC and 485 DC. We found no difference in the decrease of pH (p = 0.912) and Apgar (p = 0.609) in relation to increasing time interval. Neonatal unit (NICU) admissions did not differ (p = 0.167). Apgar <=7 (p < 0.001) and pH <= 7.20 (p = 0.002) increased first twin risk of NICU admission, whereas first (p = 0.001) or second (p < 0.001) twin Apgar <=7 and second twin pH <=7.00 (p = 0.003) increased second twin risk of NICU admission. CONCLUSIONS: Increasing delivery interval was associated with a significant decrease in pH and Apgar, but there was no difference between MC and DC twins. Low Apgar of the first twin increased the risk of second twin NICU admission. PMID- 23634711 TI - Preliminary validation of a new magnetic wireless blood pump. AB - In general, a blood pump must be small, have a simple configuration, and have sufficient hydrodynamic performance. Herein, we introduce new mechanisms for a wireless blood pump that is small and simple and provides wireless and battery free operation. To achieve wireless and battery-free operation, we implement magnetic torque and force control methods that use two external drivers: an external coil and a permanent magnet with a DC-motor, respectively. Power harvesting can be used to drive an electronic circuit for wireless monitoring (the observation of the pump conditions and temperature) without the use of an internal battery. The power harvesting will be used as a power source to drive other electronic devices, such as various biosensors with their driving circuits. To have both a compact size and sufficient pumping capability, the fully magnetic impeller has five stages and each stage includes four backward-curved blades. The pump has total and inner volumes of 20 and 9.8 cc, respectively, and weighs 52 g. The pump produces a flow rate of approximately 8 L/min at 80 mm Hg and the power generator produces 0.3 W of electrical power at 120 Omega. The pump also produces a minimum flow rate of 1.5 L/min and a pressure of 30 mm Hg for circulation at a maximum distance of 7.5 cm. PMID- 23634713 TI - Evaluation of potential protein biomarkers in patients with high sperm DNA damage. AB - The laboratory evaluation of male infertility remains an essential area of research as 40-60% of infertility cases are attributable to male-related factors. Current sperm analysis methods add only partial information on sperm quality and fertility outcomes. The specific underlying cause of infertility in most cases is unknown, while a proportion of male infertility could be caused by molecular factors such as the absence or abnormal expression of some essential sperm proteins. The objective of this study was to screen for associations between sperm protein profiles and sperm concentration, motility, and DNA fragmentation index in patients undergoing fertility evaluation in a clinical setting. Based on those parameters, semen samples were categorized as either normal or abnormal. We screened 34 semen samples with various abnormal parameters and compared them to 24 normal control samples by using one dimensional (1-D) gel electrophoresis and mass-spectrometry. In this study, we anticipated to establish a normal sperm parameter profile which would be compared to abnormal sperm samples and reveal candidate proteins. Our preliminary results indicate that no normal uniform profile could be established, which affirms the complexity of male fertility and confirms the limitations of standard semen analysis. Four main protein groups were identified in correlation with abnormal DNA fragmentation and/or motility. The first group included sperm nuclear proteins such as the SPANX (sperm protein associated with the nucleus on the X chromosome) isoforms and several types of histones. The second group contained mitochondria-related functions and oxidative stress proteins including Mitochondrial Ferritin, Mitochondrial Single-Stranded DNA Binding Protein, and several isoforms of Peroxiredoxins. Two other protein groups were related to sperm motility such as microtubule-based flagellum and spindle microtubule as well as proteins related to the ubiquitin-proteasome pathway. Further research is required in order to characterize these potential biomarkers of male fertility potential. PMID- 23634710 TI - Expression and cellular trafficking of GP82 and GP90 glycoproteins during Trypanosoma cruzi metacyclogenesis. AB - BACKGROUND: The transformation of noninfective epimastigotes into infective metacyclic trypomastigotes (metacyclogenesis) is a fundamental step in the life cycle of Trypanosoma cruzi, comprising several morphological and biochemical changes. GP82 and GP90 are glycoproteins expressed at the surface of metacyclic trypomastigote, with opposite roles in mammalian cell invasion. GP82 is an adhesin that promotes cell invasion, while GP90 acts as a negative regulator of parasite internalization. Our understanding of the synthesis and intracellular trafficking of GP82 and GP90 during metacyclogenesis is still limited. Therefore, we decided to determine whether GP82 and GP90 are expressed only in fully differentiated metacyclic forms or they start to be expressed in intermediate forms undergoing differentiation. METHODS: Parasite populations enriched in intermediate forms undergoing differentiation were analyzed by quantitative real time PCR, Western blot, flow cytometry and immunofluorescence to assess GP82 and GP90 expression. RESULTS: We found that GP82 and GP90 mRNAs and proteins are expressed in intermediate forms and reach higher levels in fully differentiated metacyclic forms. Surprisingly, GP82 and GP90 presented distinct cellular localizations in intermediate forms compared to metacyclic trypomastigotes. In intermediate forms, GP82 is localized in organelles at the posterior region and colocalizes with cruzipain, while GP90 is localized at the flagellar pocket region. CONCLUSIONS: This study discloses new aspects of protein expression and trafficking during T. cruzi differentiation by showing that the machinery involved in GP82 and GP90 gene expression starts to operate early in the differentiation process and that different secretion pathways are responsible for delivering these glycoproteins toward the cell surface. PMID- 23634714 TI - Adulteration of purported herbal and natural sexual performance enhancement dietary supplements with synthetic phosphodiesterase type 5 inhibitors. AB - INTRODUCTION: Many products labeled "herbal" or "all natural" (herbal/natural) that claim to enhance sexual performance and imply use for the treatment of erectile dysfunction (ED) are marketed as over-the-counter (OTC) dietary supplements. However, adulteration with undeclared phosphodiesterase type 5 (PDE5) inhibitors appears widespread. AIM: To assess the availability, cost, origin, categorical content, and adulteration with PDE5 inhibitors of purported herbal/natural OTC dietary supplements claiming to naturally enhance sexual performance. METHODS: Pfizer Global Security coordinated sample collection (all from convenience stores and filling stations in two U.S. metropolitan areas except for seven from U.S. Customs seizures) and liquid chromatography/mass spectrometry examination. MAIN OUTCOME MEASURE: Adulteration with synthetic PDE5 inhibitors. RESULTS: Ninety-one samples labeled as 58 distinct products and priced from $2.99 to $17.99 were evaluated. Origin/manufacture was claimed as United States (n = 62), apparently Asian (n = 15), and not clearly identified (n = 14). Although no sample claimed to include synthetic substances, 74 (81%) contained PDE5-inhibitor pharmaceutical ingredients, including tadalafil and/or sildenafil (n = 40, of which 18 contained >110% of the highest approved drug product strength) or PDE5-inhibitor analogs (n = 34). Pronounced heterogeneity of contents between samples within individual products indicated minimal quality control during manufacture. Labeling was inadequate (e.g., lacking lot number and/or expiry date) for 17 products (23 samples) and inconsistent between samples within a given product (e.g., in manufacturer, lot number, and/or expiry date) for seven of 17 products having multiple samples. Only 14 samples warned against concomitant nitrate use. CONCLUSIONS: Ethical pharmaceutical companies are concerned for an unsuspecting public when their products are counterfeited, mislabeled, and illegally offered for sale in an unsafe manner. Because of the dangers of adulteration with synthetic PDE5 inhibitors, absent safety warnings, and lack of quality or consistent manufacture, men with ED unknowingly risk their health by using OTC herbal/natural products that claim to enhance sexual performance. PMID- 23634715 TI - RHD variants in Polish blood donors routinely typed as D-. AB - BACKGROUND: Blood donors exhibiting a weak D or DEL phenotypical expression may be mistyped D- by standard serology hence permitting incompatible transfusion to D- recipients. Molecular methods may overcome these technical limits. Our aim was to estimate the frequency of RHD alleles among the apparently D- Polish donor population and to characterize its molecular background. STUDY DESIGN AND METHODS: Plasma pools collected from 31,200 consecutive Polish donors typed as D- were tested by real-time polymerase chain reaction (PCR) for the presence of RHD specific markers located in Intron 4 and Exons 7 and 10. RHD+ individuals were characterized by PCR or cDNA sequencing and serology. RESULTS: Plasma cross-pool strategy revealed 63 RHD+ donors harboring RHD*01N.03 (n = 17), RHD*15 (n = 12), RHD*11 (n = 7), RHD*DEL8 (n = 3), RHD*01W.2 (n = 3), RHD-CE(10) (n = 3), RHD*01W.3, RHD*01W.9, RHD*01N.05, RHD*01N.07, RHD*01N.23, and RHD(IVS1-29G>C) and two novel alleles, RHD*(767C>G) (n = 3) and RHD*(1029C>A). Among 47 cases available for serology, 27 were shown to express the D antigen CONCLUSION: 1) Plasma cross-pool strategy is a reliable and cost-effective tool for RHD screening. 2) Only 0.2% of D- Polish donors carry some fragments of the RHD gene; all of them were C or E+. 3) Almost 60% of the detected RHD alleles may be potentially immunogenic when transfused to a D- recipient. PMID- 23634716 TI - Effect of L-carnitine on maturation, cryo-tolerance and embryo developmental competence of bovine oocytes. AB - In this study, the effects of the addition of L-carnitine in in vitro maturation (IVM) medium for bovine oocytes on their nuclear maturation and cryopreservation were investigated; they were matured in IVM medium supplemented with 0.0, 0.3, 0.6 and 1.2 mg/mL of L-carnitine (control, 0.3, 0.6 and 1.2 groups, respectively) and some of them were vitrified by Cryotop. Moreover, the effects of L-carnitine during in vitro fertilization (IVF) and in vitro culture (IVC) on the developmental potential and quality of IVF embryos were also examined. A significantly higher maturation rate of oocytes was obtained for 0.3 and 0.6 mg/mL groups compared with the control (P < 0.05). The blastocyst formation rate in the 0.6 group was significantly improved, whereas the rate in the 1.2 group was significantly decreased when compared with the control group (P < 0.05). No significant difference was found in embryo development between the control and the L-carnitine group after oocyte vitrification. Supplementation of IVF and IVC media with L-carnitine had no effect on development to the blastocyst stage of IVM oocytes treated with 0.6 mg/mL L-carnitine. In conclusion, the supplementation of L-carnitine during IVM of bovine oocytes improved their nuclear maturation and subsequent embryo development after IVF, but when they were vitrified the improving effects were neutralized. PMID- 23634717 TI - Randomized controlled trial: comparison of two surgical techniques for closing the wound following ileostomy closure: purse string vs direct suture. AB - AIM: Surgical site infection (SSI) is a common complication following ileostomy closure with a frequency of up to 40%. This prospective randomized controlled trial was initiated to compare two surgical techniques - direct suture (DS) and purse-string suture (PSS) - used to close the wound following ileostomy closure. The primary end-point was the SSI rate. Secondary end-points were cosmetic outcome [using two validated scales: the Patient and Observer Scar Assessment Scale (POSAS) and the Body Image Questionnaire (BIQ)] and the influence of other factors on the SSI rate. METHOD: Of a total of 99 patients screened, 84 were included in this study. Forty-three patients were randomized into the PSS group and 41 were randomized into the DS group. Follow up was performed within 3 days after surgery, at discharge, and 30 days and 6 months after the operation. RESULTS: In the PSS group there were no cases of SSI compared with 10 (24%) cases in the DS group (P = 0.0004). There were no statistically significant differences in cosmetic outcome between the two groups. No other statistically significant factors influencing the incidence of SSI could be identified. CONCLUSION: The rate of SSI is significantly lower following PSS than following DS, and both techniques have a similar cosmetic outcome. PSS closure should be considered as standard of care for wound closure after ileostomy reversal. PMID- 23634718 TI - Deletion Xq27.3q28 in female patient with global developmental delays and skewed X-inactivation. AB - BACKGROUND: Global developmental delay and mental retardation are associated with X-linked disorders including Hunter syndrome (mucopolysaccharidosis type II) and Fragile X syndrome (FXS). Single nucleotide mutations in the iduronate 2 sulfatase (IDS) gene at Xq28 most commonly cause Hunter syndrome while a CGG expansion in the FMR1 gene at Xq27.3 is associated with Fragile X syndrome. Gene deletions of the Xq27-28 region are less frequently found in either condition with rare reports in females. Additionally, an association between Xq27-28 deletions and skewed X-inactivation of the normal X chromosome observed in previous studies suggested a primary role of the Xq27-28 region in X inactivation. CASE PRESENTATION: We describe the clinical, molecular and biochemical evaluations of a four year-old female patient with global developmental delay and a hemizygous deletion of Xq27.3q28 (144,270,614 154,845,961 bp), a 10.6 Mb region that contains >100 genes including IDS and FMR1. A literature review revealed rare cases with similar deletions that included IDS and FMR1 in females with developmental delay, variable features of Hunter syndrome, and skewed X-inactivation of the normal X chromosome. In contrast, our patient exhibited skewed X-inactivation of the deleted X chromosome and tested negative for Hunter syndrome. CONCLUSIONS: This is a report of a female with a 10.6 Mb Xq27-28 deletion with skewed inactivation of the deleted X chromosome. Contrary to previous reports, our observations do not support a primary role of the Xq27-28 region in X-inactivation. A review of the genes in the deletion region revealed several potential genes that may contribute to the patient's developmental delays, and sequencing of the active X chromosome may provide insight into the etiology of this clinical presentation. PMID- 23634719 TI - Development of an online microbore hollow fiber enzyme reactor coupled with nanoflow liquid chromatography-tandem mass spectrometry for global proteomics. AB - In this study, we report the development of a microbore hollow fiber enzyme reactor (mHFER) coupled to nanoflow liquid chromatography-tandem mass spectrometry (nLC-ESI-MS/MS) for the online digestion or selective enrichment of glycopeptides and analysis of proteins. With mHFER, enzymatic digestion of protein could be achieved by continuous flow within a very small volume (~10 MUL) of mHF inserted in a PEEK tube. Digested peptides exited through the pores of the hollow fiber membrane wall to external single or multiplexed trap columns for nLC ESI-MS/MS analysis. Evaluation of online mHFER-nLC-ESI-MS/MS system was made with bovine serum albumin (BSA) by varying the temperature of digestion and the amount of protein injected. We evaluated the ability of the mHFER system to enrich glycopeptides by injecting a mixture of lectin (concanavalin A) and digested peptides from alpha-1-acid glycoprotein (AGP) into the mHFER, followed by delivery of PNGase F for endoglycosidic digestion. Nonglycosylated peptides unbound to lectins eluted at the first breakthrough run while N-linked glycopeptides eluted after the endoglycosidic digestion. The developed method was applied to urine samples from patients with prostate cancer and controls; 67 N linked glycopeptides were identified and relative differences in glycopeptide content between patient and control samples were determined. PMID- 23634720 TI - Botulinum toxin treatment for bladder dysfunction. AB - Botulinum toxin A is available under three different protein complexes that are not interchangeable until appropriate comparative studies are undertaken. The best studied for the treatment of urinary incontinence as a result of neurogenic detrusor overactivity and overactive bladder/idiopathic detrusor overactivity is onabotulinum toxin A. This brand is only approved for the treatment of urinary incontinence as a result of neurogenic detrusor overactivity at a dose of 200 U and idiopathic detrusor overactivity at a dose of 100 U. In patients with detrusor overactivity as a result of spinal cord injury or multiple sclerosis, 200 U of onabotulinum toxin A should be injected in 30 different sites above the trigone. It was shown to be highly effective in curing or decreasing urinary symptoms of incontinence, increasing quality of life, increasing bladder capacity and decreasing maximal detrusor pressure. This effect was independent of the concomitant use of oral anticholinergic drugs. Adverse events were mild, mainly urinary tract infections and high postvoid residual requiring clean intermittent catheterization. In patients with overactive bladder/idiopathic detrusor overactivity, 100 U of onabotulinum toxin A should be injected in 20 sites above the trigone. It markedly decreases urinary incontinence and improves quality of life. Frequency and urgency episodes are also decreased. Adverse events are mild, mainly urinary tract infections and urinary retention. The latter occurred in just 5% of the patients. Candidates for onabotulinum toxin A treatment should be warned that the effect of the toxin is transient and that repeated injections will be required to maintain the effect in the long term. There is no evidence that repeated injections will have a decreased efficacy. PMID- 23634721 TI - Quantifying the use of bioresources for promoting their sharing in scientific research. AB - An increasing portion of biomedical research relies on the use of biobanks and databases. Sharing of such resources is essential for optimizing knowledge production. A major obstacle for sharing bioresources is the lack of recognition for the efforts involved in establishing, maintaining and sharing them, due to, in particular, the absence of adequate tools. Increasing demands on biobanks and databases to improve access should be complemented with efforts of end-users to recognize and acknowledge these resources. An appropriate set of tools must be developed and implemented to measure this impact.To address this issue we propose to measure the use in research of such bioresources as a value of their impact, leading to create an indicator: Bioresource Research Impact Factor (BRIF). Key elements to be assessed are: defining obstacles to sharing samples and data, choosing adequate identifier for bioresources, identifying and weighing parameters to be considered in the metrics, analyzing the role of journal guidelines and policies for resource citing and referencing, assessing policies for resource access and sharing and their influence on bioresource use. This work allows us to propose a framework and foundations for the operational development of BRIF that still requires input from stakeholders within the biomedical community. PMID- 23634723 TI - Vive la difference: naming structural variants in the human reference genome. AB - The HUGO Gene Nomenclature Committee has approved gene symbols for the majority of protein-coding genes on the human reference genome. To adequately represent regions of complex structural variation, the Genome Reference Consortium now includes alternative representations of some of these regions as part of the reference genome. Here, we describe examples of how we name novel genes in these regions and how this nomenclature is displayed on our website, http://genenames.org. PMID- 23634722 TI - Origin, evolution and classification of type-3 copper proteins: lineage-specific gene expansions and losses across the Metazoa. AB - BACKGROUND: Tyrosinases, tyrosinase-related proteins, catechol oxidases and hemocyanins comprise the type-3 copper protein family and are involved in a variety of biological processes, including pigment formation, innate immunity and oxygen transport. Although this family is present in the three domains of life, its origin and early evolution are not well understood. Previous analyses of type 3 copper proteins largely have focussed on specific animal and plant phyla. RESULTS: Here, we combine genomic, phylogenetic and structural analyses to show that the original type-3 copper protein possessed a signal peptide and may have been secreted (we designate proteins of this type the alpha subclass). This ancestral type-3 copper protein gene underwent two duplication events, the first prior to the divergence of the unikont eukaryotic lineages and the second before the diversification of animals. The former duplication gave rise to a cytosolic form (beta) and the latter to a membrane-bound form (gamma). Structural comparisons reveal that the active site of alpha and gamma forms are covered by aliphatic amino acids, and the beta form has a highly conserved aromatic residue in this position. The subsequent evolution of this gene family in modern lineages of multicellular eukaryotes is typified by the loss of one or more of these three subclasses and the lineage-specific expansion of one or both of the remaining subclasses. CONCLUSIONS: The diversity of type-3 copper proteins in animals and other eukaryotes is consistent with two ancient gene duplication events leading to alpha, beta and gamma subclasses, followed by the differential loss and expansion of one or more of these subclasses in specific kingdoms and phyla. This has led to many lineage-specific type-3 copper protein repertoires and in some cases the independent evolution of functionally-classified tyrosinases and hemocyanins. For example, the oxygen-carrying hemocyanins in arthropods evolved from a beta-subclass tyrosinase, whilst hemocyanins in molluscs and urochordates evolved independently from an alpha-subclass tyrosinase. Minor conformational changes at the active site of alpha, beta and gamma forms can produce type-3 copper proteins with capacities to either carry oxygen (hemocyanins), oxidize diphenols (catechol oxidase) or o-hydroxylate monophenols (tyrosinases) and appear to underlie some functional convergences. PMID- 23634724 TI - Hydration status of underground miners in a temperate Australian region. AB - BACKGROUND: Dehydration is a health risk for miners in tropical regions of Australia. However, it is not known whether dehydration poses a health risk to miners working in temperate regions of Australia. METHODS: A cross-sectional study of 88 miners from two underground mines was undertaken in south-eastern New South Wales, Australia. Participants had their height, weight, waist circumference and hydration status measured and completed a self-administered questionnaire on fluid intake, access to water, and socio-demographic characteristics. Health and Safety managers were surveyed about guidelines relating to healthy work and lifestyle behaviours which impact/influence hydration. RESULTS: Hydration tests indicated that more than half of the miners (approximately 58%) were dehydrated (Urinary Specific Gravity (USG) >1.020) both before and after their shift, with three workers pre-shift and four workers post shift displaying clinical dehydration (USG>1.030). Overall, 54.0% of participants were overweight and 36.8% were obese. Miners who commenced the shift with poor hydration status were 2.6 times more likely to end the shift with poor hydration, compared to those who commenced the shift with good hydration (OR 2.6, 95% CI 1.06, 6.44). Miners who had a mean USG result for the entire shift indicating dehydration were more likely to be obese (42.9%) and have a waist measurement in the high risk range for metabolic complications (40.8%) than those workers that were adequately hydrated for their entire shift (29.4% and 14.7% respectively). Some guidelines promoting healthy lifestyles and supportive work environments were in place, but there were limited guidelines on healthy weight and hydration. CONCLUSIONS: Dehydration, being overweight and obesity were linked issues in this cohort of miners. Strategies are needed to: adapt the workplace environment to increase water accessibility; encourage appropriate consumption of water both at work and at home; and to promote physical activity and good nutrition to maintain healthy weight. PMID- 23634726 TI - Indirect molecular epitaxy: deposition of n-alkane thin films on Au coated NaCl(001) and HOPG(0001) surfaces. AB - The epitaxial growth of organic molecules can lead to the formation of complex orientated morphologies. In previous work, we studied the kinetic and thermodynamic factors that drive the epitaxial growth of n-alkane thin films on HOPG(0001) and NaCl(001) by physical vapor deposition. A wide variety of morphologies are observed as a function of deposition conditions (substrate temperature, n-alkane chain length, etc.). In the current study we examine how a modified substrate (Au deposited on a HOPG(0001) or NaCl(001) substrate) affects the epitaxial growth of n-C36H74 (50 nm thick) relative to the uncoated substrates. This "indirect epitaxy", in which the patterned attractive forces of the substrate are transferred through a thin metal film, can tailor the conditions for epitaxial growth. The observation of fourfold symmetry for n alkane growth on Au/NaCl(001) and sixfold symmetry for n-alkane growth on Au/HOPG(0001) demonstrates indirect epitaxy over a wide range of substrate temperatures during deposition. PMID- 23634725 TI - Bilateral elevation of interleukin-6 protein and mRNA in both lumbar and cervical dorsal root ganglia following unilateral chronic compression injury of the sciatic nerve. AB - BACKGROUND: Current research implicates interleukin (IL)-6 as a key component of the nervous-system response to injury with various effects. METHODS: We used unilateral chronic constriction injury (CCI) of rat sciatic nerve as a model for neuropathic pain. Immunofluorescence, ELISA, western blotting and in situ hybridization were used to investigate bilateral changes in IL-6 protein and mRNA in both lumbar (L4-L5) and cervical (C7-C8) dorsal root ganglia (DRG) following CCI. The operated (CCI) and sham-operated (sham) rats were assessed after 1, 3, 7, and 14 days. Withdrawal thresholds for mechanical hyperalgesia and latencies for thermal hyperalgesia were measured in both ipsilateral and contralateral hind and fore paws. RESULTS: The ipsilateral hind paws of all CCI rats displayed a decreased threshold of mechanical hyperalgesia and withdrawal latency of thermal hyperalgesia, while the contralateral hind and fore paws of both sides exhibited no significant changes in mechanical or thermal sensitivity. No significant behavioral changes were found in the hind and fore paws on either side of the sham rats, except for thermal hypersensitivity, which was present bilaterally at 3 days. Unilateral CCI of the sciatic nerve induced a bilateral increase in IL-6 immunostaining in the neuronal bodies and satellite glial cells (SGC) surrounding neurons of both lumbar and cervical DRG, compared with those of naive control rats. This bilateral increase in IL-6 protein levels was confirmed by ELISA and western blotting. More intense staining for IL-6 mRNA was detected in lumbar and cervical DRG from both sides of rats following CCI. The DRG removed from sham rats displayed a similar pattern of staining for IL-6 protein and mRNA as found in naive DRG, but there was a higher staining intensity in SGC. CONCLUSIONS: Bilateral elevation of IL-6 protein and mRNA is not limited to DRG homonymous to the injured nerve, but also extended to DRG that are heteronymous to the injured nerve. The results for IL-6 suggest that the neuroinflammatory reaction of DRG to nerve injury is propagated alongside the neuroaxis from the lumbar to the remote cervical segments. This is probably related to conditioning of cervical DRG neurons to injury. PMID- 23634727 TI - Serum amyloid A (SAA) concentration after training sessions in Arabian race and endurance horses. AB - BACKGROUND: Serum amyloid A (SAA) is the major acute phase protein in horses. Its concentration increases in various pathologies but also in response to prolonged, strenuous effort. The purpose of this study was to establish whether routine race and endurance training produces changes in the SAA level in Arabian horses. Additionally, the differences between SAA response in experienced endurance horses and endurance horses that were beginning their career were investigated. RESULTS: There were no changes in SAA concentrations after race training and endurance training in experienced horses. In horses that were beginning their endurance training, exercise produced an increase in SAA level as compared with rest level. CONCLUSION: In Arabians, the SAA concentration seems to be a good indicator of endurance training but is useless in race training. The routine training of experienced horses, which were prepared for long distance rides, did not promote any changes in the SAA level. In contrast, a significant increase in the SAA concentration was observed in horses that were beginning their endurance training and were only prepared for moderate distance rides and underwent the same effort. Further research is needed to elucidate whether this difference reflects too heavy training or adaptation to an increasing workload. Additionally, the adaptation to long distance rides in Arabians may include a reduced acute phase response. PMID- 23634729 TI - Flexible piezoelectric PMN-PT nanowire-based nanocomposite and device. AB - Piezoelectric nanocomposites represent a unique class of materials that synergize the advantageous features of polymers and piezoelectric nanostructures and have attracted extensive attention for the applications of energy harvesting and self powered sensing recently. Currently, most of the piezoelectric nanocomposites were synthesized using piezoelectric nanostructures with relatively low piezoelectric constants, resulting in lower output currents and lower output voltages. Here, we report a synthesis of piezoelectric (1 - x)Pb(Mg1/3Nb2/3)O3 xPbTiO3 (PMN-PT) nanowire-based nanocomposite with significantly improved performances for energy harvesting and self-powered sensing. With the high piezoelectric constant (d33) and the unique hierarchical structure of the PMN-PT nanowires, the PMN-PT nanowire-based nanocomposite demonstrated an output voltage up to 7.8 V and an output current up to 2.29 MUA (current density of 4.58 MUA/cm(2)); this output voltage is more than double that of other reported piezoelectric nanocomposites, and the output current is at least 6 times greater. The PMN-PT nanowire-based nanocomposite also showed a linear relationship of output voltage versus strain with a high sensitivity. The enhanced performance and the flexibility of the PMN-PT nanowire-based nanocomposite make it a promising building block for energy harvesting and self-powered sensing applications. PMID- 23634728 TI - Severe Plasmodium falciparum and Plasmodium vivax malaria among adults at Kassala Hospital, eastern Sudan. AB - BACKGROUND: There have been few published reports on severe Plasmodium falciparum and Plasmodium vivax malaria among adults in Africa. METHODS: Clinical pattern/manifestations of severe P. falciparum and P. vivax (according to World Health Organization 2000 criteria) were described in adult patients admitted to Kassala Hospital, eastern Sudan. RESULTS: A total of 139 adult patients (80 males, 57.6%) with a mean (SD) age of 37.2 (1.5) years presented with severe P. falciparum (113, 81.3%) or P. vivax (26, 18.7%) malaria. Manifestations among the 139 patients included hypotension (38, 27.3%), cerebral malaria (23, 16.5%), repeated convulsions (18, 13.0%), hypoglycaemia (15, 10.8%), hyperparasitaemia (14, 10.1%), jaundice (14, 10.1%), severe anaemia (10, 7.2%), bleeding (six, 4.3%), renal impairment (one, 0.7%) and more than one criteria (27, 19.4%). While the geometric mean of the parasite count was significantly higher in patients with severe P. vivax than with severe P. falciparum malaria (5,934.2 vs 13,906.6 asexual stage parasitaemia per MUL, p = 0.013), the different disease manifestations were not significantly different between patients with P. falciparum or P. vivax malaria. Three patients (2.2%) died due to severe P. falciparum malaria. One had cerebral malaria, the second had renal impairment, jaundice and hypoglycaemia, and the third had repeated convulsions and hypotension. CONCLUSIONS: Severe malaria due to P. falciparum and P. vivax malaria is an existing entity among adults in eastern Sudan. Patients with severe P. falciparum and P. vivax develop similar disease manifestations. PMID- 23634730 TI - Dabigatran bleed risk with closed head injuries: are we prepared? AB - OBJECT: The direct thrombin inhibitor dabigatran has recently been approved in the US as an alternative to warfarin. The lack of guidelines, protocols, and an established specific antidote to reverse the anticoagulation effect of dabigatran potentially increases the rates of morbidity and mortality in patients with closed head injury (CHI). Confronted with this new problem, the authors reviewed their initial clinical experience. METHODS: The authors retrospectively reviewed all cases of adult patients (age >= 18 years) who sustained CHI secondary to ground-level falls and who presented to the authors' provisional regional Level I trauma center between February 2011 and May 2011. The authors divided these patients into 3 groups based on anticoagulant therapy: dabigatran, warfarin, and no anticoagulants. RESULTS: Between February 2011 and May 2011, CHIs from ground level falls were sustained by 5 patients while on dabigatran, by 15 patients on warfarin, and by 25 patients who were not on anticoagulants. The treatment of the patients on dabigatran at the authors' institution had great diversity. Repeat CT scans obtained during reversal showed 4 of 5 patients with new or expanded hemorrhages in the dabigatran group, whereas the warfarin group had 3 of 15 (p = 0.03). The overall mortality rate for patients sustaining CHI on dabigatran was 2 (40%) of 5, whereas that of the warfarin group was 0 (0%) of 15 (p = 0.05). CONCLUSIONS: It is critical for physicians involved in the care of patients with CHI on dabigatran to be aware of an elevated mortality rate if no treatment protocol or guideline is in place. The authors will soon implement a reversal management protocol for patients with CHI on dabigatran at their institution in an attempt to improve efficacy and safety in their treatment approach. PMID- 23634731 TI - Hydrophobic high surface area zeolites derived from fly ash for oil spill remediation. AB - Fly ash, a coal combustion byproduct with a predominantly aluminosilicate composition, is modified to develop an inexpensive sorbent for oil spill remediation. The as-produced fly ash is a hydrophilic material with poor sorption capacity. A simple two-step chemical modification process is designed to improve the oil sorption capacity. First, the fly ash was transformed to a zeolitic material via an alkali treatment, which increased the specific surface area up to 404 m(2) g(-1). Then, the material was surface functionalized to form a hydrophobic material with high contact angle up to 147 degrees that floats on the surface of an oil-water mixture. The reported oil sorption capacities of X type zeolite sorbent with different surface functionalization (propyl-, octyl-, octadecyl-trimethoxysilane and esterification) were estimated to 1.10, 1.02, 0.86, and 1.15 g g(-1), respectively. Oil sorption was about five times higher than the as-received fly ash (0.19 g g(-1)) and also had high buoyancy critical for economic cleanup of oil over water. PMID- 23634732 TI - Immune monitoring of children with respiratory syncytial virus infection. PMID- 23634734 TI - Study suggests link between high vitamin D levels at pregnancy and pediatric allergy. PMID- 23634733 TI - Vitamins and systemic lupus erythematosus: to D or not to D. PMID- 23634735 TI - Targeting IL-15 in large granular lymphocyte leukemia. AB - IL-15 is a cytokine that stimulates the proliferation of NK and T cells. Previous studies have shown that IL-15 is critical to the induction of T-cell large granular lymphocyte (T-LGL) leukemia. A Phase I trial of a humanized antibody (Hu Mikbeta1) to the IL2/IL15Rbeta receptor, expressed on T-LGL, is explored in this trial to evaluate the safety, pharmacokinetics, specificity and clinical efficacy of Hu-Mikbeta1. The study demonstrated no toxicity and favorable saturation of IL2/IL15Rbeta receptor, but no clinical efficacy in this Phase I study. PMID- 23634736 TI - Host-microbiota interaction and intestinal stem cells in chronic inflammation and colorectal cancer. AB - Inflammatory bowel disease (IBD) and colorectal cancer (CRC) are the major diseases of the lower gastrointestinal tract. The intestinal epithelium plays a critical role in the host's interactions with the large communities of resident luminal bacteria. Epithelial cells recognize the bacterial components via pattern recognition receptors. Toll-like receptors (TLRs) are a major class of pattern recognition receptors that are present on intestinal epithelial cells, including putative stem cells. Stem cells are responsible for tissue homeostasis and regeneration after injury including IBD. Stem cells are also implicated in the pathogenesis of CRC. In susceptible individuals, disruption of normal homeostatic balance between the host's mucosal cells and enteric microflora is believed to result in aberrant immune responses against the resident commensal bacteria, leading to IBD. Microbiological analyses have revealed that the composition and localization of microbiota is altered in CRC and IBD. It is plausible that stem cells directly sense and respond to microbiota. This review aims to summarize the current knowledge on the effect of microbiota and TLR signaling on intestinal stem cells. It also describes how TLR signaling could affect the stem cell regulatory pathways. PMID- 23634737 TI - New findings and old controversies in the research of multiple sclerosis and its model experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS that is heterogeneous in its clinical manifestation and progression, as well as in its pathological mechanisms. Animal models, in particular the various forms of experimental autoimmune encephalomyelitis, have been highly valuable for studying both disease pathology and drug development. Novel technologies, such as advanced imaging systems, as well as systematic research of CNS biopsies and postmortem samples from MS patients, have brought major progress in disease understanding. Consequently, in addition to the sclerotic demyelinated plaques in the white matter, changes in normal-appearing white matter tissue ('pre-plaque') and gray matter pathology are currently regarded as central disease components. This review aims to provide current insights on several central aspects in MS research. In particular, the interplay between inflammation and neurodegeneration mediating the disease, and therapeutic strategies attempting to induce immunomodulation and neuroprotective repair processes, are discussed. PMID- 23634738 TI - Jejunoileal bypass as the main procedure in the onset of immune-related conditions: the model of BADAS. AB - Bariatric surgery represents a common approach for the control of severe morbid obesity, reducing caloric intake by modifying the anatomy of the gastrointestinal tract. Following jejunoileal bypass, a large spectrum of complications has been described, with rheumatic manifestation present in up to 20% of cases. Although bowel bypass syndrome, also called blind loop syndrome, is a well-recognized complication of jejunoileal bypass, the same syndrome was recognized in patients who had not had intestinal bypass surgery, and the term the 'bowel-associated dermatosis-arthritis syndrome' (BADAS) was coined. The pathogenesis of BADAS is as yet poorly understood and only few data concerning this issue have been published in the literature. The aim of the present paper is to review the literature and to discuss putative pathogenic mechanisms of BADAS, focusing on the immune system. PMID- 23634739 TI - Vitamin D and systemic lupus erythematosus: an update. AB - Vitamin D is a steroid hormone that, in addition to its actions on calcium and bone metabolism, exhibits a plethora of regulatory effects on growth, proliferation, apoptosis and function of the cells of the immune system that are relevant to the pathophysiology of systemic lupus erythematosus (SLE). Hypovitaminosis D is highly prevalent in SLE as a result of avoidance of sunshine, photoprotection, renal insufficiency and the use of medications such as glucocorticoids, anticonvulsants, antimalarials and the calcineurin inhibitors, which alter the metabolism of vitamin D or downregulate the functions of the vitamin D receptor. Low levels of vitamin D correlate with disease activity, and is associated with osteoporosis, fatigue and certain cardiovascular risk factors in SLE patients. This review updates the recent evidence on the relationship between vitamin D status and the onset, activity and complications of SLE, and summarizes the recommendations for vitamin D supplementation. PMID- 23634740 TI - A comparison of immunotherapy delivery methods for allergen immunotherapy. AB - BACKGROUND: Allergic diseases are among the most common diseases in humans. Besides allergen avoidance, allergen-specific immunotherapy is the only causative treatment option. During recent years, many innovations of this therapy have emerged. METHODS: Selective literature research in Medline and PubMed, under the inclusion of national and international guidelines and Cochrane meta analyses. RESULTS: In several meta-analyses, the clinical efficacy of subcutaneous immunotherapy (SCIT) has been largely demonstrated. Recently, major research activities in mucosal immunotherapies focused on the sublingual application route. There are well-documented clinical data on the efficacy and safety of this form of immunotherapy. New application routes as well as new immune-modifying agents such as virus-like particles or CpG-motifs have also been investigated. CONCLUSION: SIT is accepted to be the only causative treatment option for allergies. New application routes and new immune-modifying agents will allow for different delivery methods in the future. PMID- 23634741 TI - Therapeutic management of hereditary angioedema due to C1 inhibitor deficiency. AB - Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a rare genetic disease characterized by recurrent swellings of the subcutaneous and submucosal tissues that can manifest as cutaneous edema, abdominal pain and laryngeal edema with airway obstruction. These symptoms have a significant impact on patients' quality of life. The reduction in C1-INH function leads to uncontrolled activation of the contact system and generation of bradykinin, the mediator of increased vascular permeability and edema formation. In the past, few treatment options were available; however, several new therapies with proven efficacy have recently become available to treat and prevent HAE attacks, such as plasma-derived and recombinant C1-INHs that replace the deficient protein, bradykinin receptor antagonist (icatibant) that blocks bradykinin activity and kallikrein inhibitor (ecallantide) that prevents bradykinin release. Such therapies can improve disease outcome. This article reviews the therapeutic management of HAE, which involves the treatment of acute attacks and prophylaxis. PMID- 23634743 TI - Babesia lengau associated with cerebral and haemolytic babesiosis in two domestic cats. AB - BACKGROUND: Although reported sporadically from various countries, feline babesiosis appears to be a significant clinical entity only in South Africa, where Babesia felis is usually incriminated as the causative agent. Babesia lengau, recently described from asymptomatic cheetahs, has now possibly been incriminated as the causative agent in two severe clinical cases in domestic cats. FINDINGS: Both cats were euthanised in extremis. While typical feline babesiosis in South Africa is an afebrile disease with a chronic manifestation, there was acute onset of severe clinical signs in both cats and their body temperatures were above the normal range when they were presented for treatment. Haemolytic anaemia was confirmed in one case. To our knowledge, this is the first report of cerebral babesiosis in cats.On reverse line blot 18S rDNA PCR products obtained from both cats showed positive hybridization profiles with the B. lengau species-specific probe. The two partial parasite 18S rRNA gene sequences obtained, showed high sequence similarity (99.9%) to B. lengau. In a representative tree constructed by the neighbor-joining method using the two parameter model of Kimura the two obtained partial 18S rDNA sequences and that of B. lengau formed a monophyletic group with B. conradae and sequences previously isolated from humans and wildlife in the western USA. CONCLUSION: All clinical cases of feline babesiosis in South Africa are not necessarily caused by B. felis. Other piroplasms, e.g. B. lengau, may be incriminated in clinical cases, especially those occurring outside the known endemic area. PMID- 23634745 TI - Attentional processing in bulbar- and spinal-onset amyotrophic lateral sclerosis: insights from event-related potentials. AB - Our objective was to evaluate attentional processing with respect to the clinical onset subtype in amyotrophic lateral sclerosis (ALS) using event-related potentials (ERPs). Thirty-three non-demented ALS patients (22 spinal onset, 11 bulbar onset) and 32 age- and gender-matched controls underwent a psychophysiological evaluation. Mismatch Negativity (MMN), P300 components and Contingent Negative Variation (CNV) were obtained. Latencies and amplitudes of the MMN, P3a and P3b waves and CNV amplitude were then evaluated. Clinical parameters were correlated with ERP data. No differences emerged between ALS patients and controls with regard to the MMN and P3b components. N1-P3a inter peak latency (Fz, p = 0.003; Cz, p = 0.001; Pz, p = 0.002) was longer in ALS-b than in ALS-s. Total CNV area (Cz, p = 0.01) and W1-CNV area were significantly reduced (Cz, p = 0.05; Pz, p = 0.03) in ALS-b with respect to the one of the controls, while no differences were found between ALS-s patients and controls. In conclusion, automatic pre-attentive processing of stimuli seems to be preserved in ALS. However, a significant delay in the time-course of selective attentive processing and a difficulty in initiating and sustaining attention may be present in ALS-b, which points to a possible dysfunction in the frontal neural network that responds to novelty and to abnormal integration of associative functions. This attentional impairment should be taken in account while developing alternative communicative strategies in ALS patients. PMID- 23634746 TI - Nonheme iron-mediated amination of C(sp3)-H bonds. Quinquepyridine-supported iron imide/nitrene intermediates by experimental studies and DFT calculations. AB - The 7-coordinate complex [Fe(qpy)(MeCN)2](ClO4)2 (1, qpy = 2,2':6',2":6",2''':6''',2''''-quinquepyridine) is a highly active nonheme iron catalyst for intra- and intermolecular amination of C(sp(3))-H bonds. This complex effectively catalyzes the amination of limiting amounts of not only benzylic and allylic C(sp(3))-H bonds of hydrocarbons but also the C(sp(3))-H bonds of cyclic alkanes and cycloalkane/linear alkane moieties in sulfamate esters, such as those derived from menthane and steroids cholane and androstane, using PhI?NR or "PhI(OAc)2 + H2NR" [R = Ts (p-toluenesulfonyl), Ns (p nitrobenzenesulfonyl)] as nitrogen source, with the amination products isolated in up to 93% yield. Iron imide/nitrene intermediates [Fe(qpy)(NR)(X)](n+) (CX, X = NR, solvent, or anion) are proposed in these amination reactions on the basis of experimental studies including ESI-MS analysis, crossover experiments, Hammett plots, and correlation with C-H bond dissociation energies and with support by DFT calculations. Species consistent with the formulations of [Fe(qpy)(NTs)2](2+) (CNTs) and [Fe(qpy)(NTs)](2+) (C) were detected by high-resolution ESI-MS analysis of the reaction mixture of 1 with PhI?NTs (4 equiv). DFT calculations revealed that the reaction barriers for H-atom abstraction of cyclohexane by the ground state of 7-coordinate CNTs and ground state of C are 15.3 and 14.2 kcal/mol, respectively, in line with the observed high activity of 1 in catalyzing the C-H amination of alkanes under mild conditions. PMID- 23634744 TI - Motivated behaviors and levels of 3alpha,5alpha-THP in the midbrain are attenuated by knocking down expression of pregnane xenobiotic receptor in the midbrain ventral tegmental area of proestrous rats. AB - INTRODUCTION: Progesterone (P4 ) and its product, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), act in the midbrain ventral tegmental area (VTA) to alter motivated behaviors, such as mating, and motor and anxiety behavior. Of interest is whether 3alpha,5alpha-THP formation requires the pregnane xenobiotic receptor (PXR), which is expressed in the midbrain of rats. AIM: The role of PXR in the midbrain for 3alpha,5alpha-THP formation, which precedes modulation of motivated behaviors, was investigated. METHODS: Rats had estrous cycle phase determined and were assessed when they were in diestrus or proestrus. Diestrous and proestrous rats were infused with control or antisense oligodeoxyribonucleotides (AS-ODNs) targeted against PXR to the VTA. MAIN OUTCOME MEASURES: In pilot studies, PXR gene and protein expression in the midbrain were determined with quantitative reverse transcriptase polymerase chain reaction and Western blotting, respectively. Diestrous and proestrous rats infused with control or AS-ODNs to the VTA were tested for anxiety (open field and plus maze), social (social interaction), and sexual (paced mating) behavior. Expression of PXR in the midbrain was verified with Western blotting. Plasma estradiol, P4 , dihydroprogesterone (DHP), and 3alpha,5alpha-THP levels, and brain P4 , DHP, and 3alpha,5alpha-THP levels were measured. We predicted that proestrous rats infused with PXR AS-ODNs would have decreased anti-anxiety, social, and sexual behavior, lower midbrain expression of PXR, and lower midbrain levels of 3alpha,5alpha-THP compared with controls. RESULTS: Results supported the hypothesis that formation of 3alpha,5alpha-THP requires PXR and may be important for motivated behaviors. PXR AS-ODN, compared with control, infusions to the VTA reduced PXR expression and 3alpha,5alpha-THP levels in the midbrain and attenuated sexual receptivity of proestrous rats. CONCLUSIONS: Knockdown of PXR in the midbrain reduces 3alpha,5alpha-THP levels and sexual receptivity of proestrous rats. Thus, PXR in the midbrain may be required for the observed increase in 3alpha-5alpha-THP during proestrus, which has subsequent effects on motivated, reproductive behaviors. PMID- 23634747 TI - Comparison of the lipid properties of healthy and pansteatitis-affected African sharptooth catfish, Clarias gariepinus (Burchell), and the role of diet in pansteatitis outbreaks in the Olifants River in the Kruger National Park, South Africa. AB - Pansteatitis has been identified in wild populations of sharptooth catfish, Clarias gariepinus (Burchell), and Nile crocodiles, Crocodylus niloticus Laurenti, inhabiting the same waters in the Olifants River Gorge in the Kruger National Park, South Africa. Mesenteric and pectoral fat tissue was investigated microscopically and by fatty acid analysis in healthy and pansteatitis-affected catfish from both captive and wild populations. Variation in fatty acid composition between pectoral and mesenteric fat was noted. Composition of mesenteric fat differed between fish from various localities as a result of differences in diet. Pansteatitis in the captive population, resulting from ingestion of high amounts of dietary oxidized fat, reflected higher levels of unsaturated fatty acids within the mesenteric fat. Mesenteric fat of pansteatitis affected wild catfish was characterized by an increase in moisture content, a decrease in fat content and a decrease in stearic and linoleic acids. The n-3 to n-6 fatty acid ratio of mesenteric fat was higher in pansteatitis-affected wild catfish than in healthy catfish from the same locality, reflecting higher polyunsaturated fat intake by pansteatitis-affected fish. The possible role of alien, invasive, phytoplankton-feeding silver carp, Hypophthalmichthys molitrix (Valenciennes), in the aetiology of pansteatitis in both catfish and crocodiles in the Olifants Gorge is discussed. PMID- 23634748 TI - Risk factors and outcomes associated with acute kidney injury following ruptured abdominal aortic aneurysm. AB - BACKGROUND: Current data describing the epidemiology of acute kidney injury (AKI) following repair of ruptured abdominal aortic aneurysm (rAAA) are limited and long-term outcomes are largely unknown. Our objectives were to describe the incidence rate, risk factors, clinical course and long-term outcomes of AKI following rAAA repair. METHODS: Retrospective population-based cohort study of all referrals undergoing emergency repair of rAAA in Northern Alberta from January 1, 2002 to December 31 2009. Demographic, clinical, physiologic and laboratory data were extracted. AKI was defined and classified according to the AKIN criteria. RESULTS: In total, 140 patients survived to receive emergent rAAA repair. Post-operative AKI occurred in 75.7% of patients (n = 106), 78.3% (n = 83) of which occurred during the initial 24 hours of ICU admission. AKIN stage 1, 2, and 3 occurred in 47 (33.6%), 36 (25.7%) and 23 (16.4%), respectively, with 19 patients receiving renal replacement therapy (RRT). Several clinical and biochemical patient factors were associated with incident AKI, including baseline estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (odds ratio [OR] 2.94; 95% CI, 1.15-7.51, p = 0.03), need for mechanical ventilation (OR 22.7; 95% CI, 7.0-72.1, p < 0.0001) and vasoactive therapy (OR 9.9; 95% CI, 3.0-32.2, p < 0.0001) and higher mean APACHE II scores (25.7 [8.2] vs. 16.3 [4.9], p < 0.0001). AKI was associated with a higher ICU (28.3% vs. 0%; p = 0.0008) and in-hospital case-fatality rate (35.9% vs. 0%, p = 0.0001). Of 102 survivors to discharge, 65.7% (n = 67) recovered to baseline kidney function. In multivariable analysis, greater severity of AKI (OR 5.01; 95% CI, 2.34-10.7, p < 0.001) and lower baseline eGFR (OR 0.96; 95% CI, 0.93-0.99, p = 0.03) were associated with non recovery. AKI remained independently associated with 1-year mortality after adjusting for age, sex, comorbidity, and illness severity (OR 5.21; 95% CI, 1.04 26.2, p = 0.045; AUC 0.83; H-L GoF, p = 0.26). Among survivors at 1-year, only 63.4% (n = 55) had complete kidney recovery. CONCLUSIONS: Following rAAA repair, AKI is a common complication independently associated with long-term post operative mortality. A significant proportion of AKI sufferers in this setting fail to recover to baseline kidney function. PMID- 23634749 TI - Patterns of recurrence of obstructing colon cancers after surgery for cure: a population-based study. AB - AIM: Little is known about patterns of recurrence in obstructing colon cancer (OCC) at a population level. The aim of this study was to determine the risk of recurrence following potentially curative surgery in OCC compared with that in uncomplicated colon cancer (CC). METHOD: Data were obtained from the population based digestive cancer registry of Burgundy (France). Local and distant failure rates were calculated using actuarial methods. A multivariate analysis was performed using a Cox model. RESULTS: Obstructing colon cancer represented 8.5% of all colon cancers resected with curative intent (n = 3375). The 5-year cumulative local recurrence rate was 14.2% for OCC and 7.6% for nonobstructing CC (P = 0.003). In the multivariate analysis, obstruction was an independent risk factor for local recurrence [hazard ratio 1.53 (1.01-2.34), P = 0.047]. The risk of local recurrence increased with advanced stage and age at diagnosis. The 5 year cumulative rate for distant metastases was also higher in OCC than in nonobstructing CC (36.1 vs 23.1%; P < 0.001). The relative risk of distant metastasis was borderline significant in the multivariate analysis [hazard ratio 1.25 (0.99-1.59), P = 0.057]. Stage at diagnosis, macroscopic type of growth, period of diagnosis and sex were also significant prognostic factors. Age and subsite were not significant in the multivariate analysis. CONCLUSION: It is possible to conduct special surveys in population-based registries to determine the recurrence rate of CC. Recurrence remains a substantial problem and is more frequent in OCC than in nonobstructing CC. Efforts must be made to diagnose CC earlier. Mass screening is a promising approach. PMID- 23634751 TI - Editorial comment from Dr. Ishidoya to "Laparoscopic simultaneous bilateral adrenalectomy for testosterone-secreting bilateral adrenal tumors". PMID- 23634750 TI - Clinical significance of combined detection of human papilloma virus infection and human telomerase RNA component gene amplification in patients with squamous cell carcinoma of the esophagus in northern China. AB - BACKGROUND: The aim of the study was to test for human papilloma virus (HPV) infection and human telomerase RNA component (hTERC) gene amplification in tissues derived from esophageal cancer, in esophagus displaying atypical hyperplasia and in normal tissue, and to analyze the relationship between them and discuss whether HPV infection and hTERC gene amplification play a role in the duration of survival of esophageal cancer patients. METHODS: To test for HPV infection, surface plasma resonance was used after extracting and subjecting the DNA to PCR amplification. Measurement of hTERC gene amplification was performed by the fluorescence in situ hybridization technique. RESULTS: The rates of HPV infection in the normal group, the atypical esophageal hyperplasia group and the cancer group were 0% (0/40), 10.00% (1/10) and 20.65% (19/92), respectively, with a statistically significant difference of P < 0.01. The hTERC gene amplification rate in normal tissue, grade I atypical hyperplastic tissue, grade II/III atypical hyperplastic tissue and esophageal cancer tissue were 0% (0/89), 15.38% (4/26), 47.06% (8/17) and 89.13% (82/92), respectively, with a statistically significant difference of P < 0.01. On follow-up of 92 patients, survival curves of the HPV-positive and HPV-negative groups were not significantly different (P > 0.05). Survival curves of the hTERC gene amplification-positive and hTERC gene amplification-negative groups were statistically significant (P < 0.05). A matching chi-square test showed that there was no correlation between HPV infection and hTERC gene amplification (P > 0.05). CONCLUSION: HPV infection may be one of many factors contributing to the development of esophageal cancer, but it does not influence prognosis. Amplification of the hTERC gene appears to influence certain features associated with postoperative survival in esophageal carcinoma patients. PMID- 23634752 TI - What do we tell patients about elective total hip replacement in the UK? An analysis of patient literature. AB - BACKGROUND: Although hip information literature is given to people following total hip replacement (THR) almost routinely, little evaluation has been conducted on it to date. Our aim was therefore to analyse and evaluate the literature provided to patients by occupational therapists concerning elective hip surgery in the UK. METHODS: This was a pragmatic, descriptive analysis of information leaflets routinely given to patients undergoing primary total hip replacement (THR). The literature was collected as part of a national survey of occupational therapy practice. In the absence of a suitable evaluation tool, the patient leaflets were compared using a checklist devised by the researchers. The three areas of interest were: accessibility including presentation of information, breadth of information covered and specific activities of daily living described. RESULTS: 111 information leaflets and booklets were examined. These ranged from hospital publications which were professionally printed to those produced by individual departments. There was a variation in the readability of the leaflets ranging from 13% to 83%; the mean was 45% (SD 15). There was also variation in the content ranging from those covering surgery and possible complications, to those including diet and hip exercises. The most commonly covered activity of daily living was advice on sitting (99; 89%); the least commonly covered was work (26; 23%). Only 3 (2.7%) booklets had involved patients in their production and only 22 (20%) signposted obtaining information in another language or in Braille. CONCLUSIONS: There was a range of literature in terms of presentation and content given to people who had a total hip replacement (THR). Although some booklets and leaflets scored highly, some did not meet basic standards such as providing contact details for help, using good quality diagrams, suggesting further reading or involving patients in their design. These results highlight important and fundamental deficiencies in the literature routinely provided. PMID- 23634754 TI - Combination of submicroemulsion and phospholipid complex for novel delivery of ursodeoxycholic acid. AB - The objective of this study was to prepare and characterize ursodeoxycholic acid submicron emulsion (UA-SME) loaded with ursodeoxycholic acid phytosomes (UA-PS) and optimize the process variables. A screening experiment with response surface methodology with Box-Behnken design (BBD) was used to optimize the process parameters of UA-SME. The blood concentrations of UA after oral administration of UA-SME and UA coarse drug were assayed. The optimum process conditions were finally obtained by using a desirability function. It was found that stirring velocity, homogenization pressure and homogenization cycles were the most important variables that affected the particles size, polydispersity index and entrapment efficiency of UA-SME. Results showed that the optimum stirring velocity, homogenization pressure and cycles were 16 000 rpm, 60 MPa and 10 cycles, respectively. The mean diameter, polydispersity index and entrapment efficiency of UA-SME were 251.9 nm, 0.241 and 74.36%, respectively. Pharmacokinetic parameters of UA and UA-SME in rats were Tmax 2.215 and 1.489 h, Cmax 0.0364 and 0.1562 MUg/mL, AUC0-infinity 3.682 and 13.756 MUg h/mL, respectively. The bioavailability of UA in rats was significantly different (p < 0.05) after oral administration of UA-SME compared to those of UA coarse drug. This was due to improvement of the hydrophilicity and lipophilic property of UA SME. PMID- 23634753 TI - Standardized image interpretation and post processing in cardiovascular magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR) board of trustees task force on standardized post processing. AB - With mounting data on its accuracy and prognostic value, cardiovascular magnetic resonance (CMR) is becoming an increasingly important diagnostic tool with growing utility in clinical routine. Given its versatility and wide range of quantitative parameters, however, agreement on specific standards for the interpretation and post-processing of CMR studies is required to ensure consistent quality and reproducibility of CMR reports. This document addresses this need by providing consensus recommendations developed by the Task Force for Post Processing of the Society for Cardiovascular MR (SCMR). The aim of the task force is to recommend requirements and standards for image interpretation and post processing enabling qualitative and quantitative evaluation of CMR images. Furthermore, pitfalls of CMR image analysis are discussed where appropriate. PMID- 23634755 TI - Development of a three-dimensional model of the human respiratory system for dosimetric use. AB - BACKGROUND: Determining the fate of inhaled contaminants in the human respiratory system has challenged scientists for years. Human and animal studies have provided some data, but there is a paucity of data for toxic contaminants and sensitive populations (such as children, elderly, diseased). METHODS: Three dimensional modeling programs and publicly available human physiology data have been used to develop a comprehensive model of the human respiratory system. RESULTS: The in silico human respiratory system model, which includes the extrathoracic region (nasal, oral, pharyngeal, and laryngeal passages), the upper airways (trachea and main bronchi), the tracheobronchial tree, and branching networks through alveolar region, allows for virtually any variation of airway geometries and disease states. The model allows for parameterization of variables that define the subject's airways by integrating morphological changes created by disease, age, etc. with a dynamic morphology. CONCLUSIONS: The model can be used for studies of sensitive populations and the homeland security community, in cases where inhalation studies on humans cannot be conducted with toxic contaminants of interest. PMID- 23634756 TI - Investigation of gene-by-sex interactions for lipid traits in diverse populations from the population architecture using genomics and epidemiology study. AB - BACKGROUND: High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels are influenced by both genes and the environment. Genome-wide association studies (GWAS) have identified ~100 common genetic variants associated with HDL-C, LDL-C, and/or TG levels, mostly in populations of European descent, but little is known about the modifiers of these associations. Here, we investigated whether GWAS-identified SNPs for lipid traits exhibited heterogeneity by sex in the Population Architecture using Genomics and Epidemiology (PAGE) study. RESULTS: A sex-stratified meta-analysis was performed for 49 GWAS-identified SNPs for fasting HDL-C, LDL-C, and ln(TG) levels among adults self-identified as European American (25,013). Heterogeneity by sex was established when phet < 0.001. There was evidence for heterogeneity by sex for two SNPs for ln(TG) in the APOA1/C3/A4/A5/BUD13 gene cluster: rs28927680 (p(het) = 7.4 x 10(-7)) and rs3135506 (p(het) = 4.3 x 10(-4)one SNP in PLTP for HDL levels (rs7679; p(het) = 9.9 x 10(-4)), and one in HMGCR for LDL levels (rs12654264; p(het) = 3.1 x 10(-5)). We replicated heterogeneity by sex in five of seventeen loci previously reported by genome-wide studies (binomial p = 0.0009). We also present results for other racial/ethnic groups in the supplementary materials, to provide a resource for future meta-analyses. CONCLUSIONS: We provide further evidence for sex-specific effects of SNPs in the APOA1/C3/A4/A5/BUD13 gene cluster, PLTP, and HMGCR on fasting triglyceride levels in European Americans from the PAGE study. Our findings emphasize the need for considering context-specific effects when interpreting genetic associations emerging from GWAS, and also highlight the difficulties in replicating interaction effects across studies and across racial/ethnic groups. PMID- 23634757 TI - Treatment of nasopharyngeal carcinoma by tomotherapy: five-year experience. AB - PURPOSE: To analyze of survival curve and toxicity outcomes for patients treated for nasopharyngeal carcinoma (NPC) by intensity-modulated radiotherapy (IMRT) delivered by helical TomoTherapy (HT). MATERIALS AND METHODS: Since May 2006, 72 patients with primary NPC were treated. In 67 cases PET-CT was used to help delineate the gross tumor volume (GTV); in 4 of these cases distant metastases in bone, mediastinal lymph nodes and unexpected small neck nodes were detected by high SUV uptake. 3, 22, 19, and 27 patients, respectively, had AJCC stage I to IV disease. Patients received a median total dose of 72 Gy to the GTV, 64.8 Gy to the elective PTV, and 54 Gy to the clinically negative neck region. RESULTS: At a median follow-up of 41 months (range 0.2 to 67 months), no patient has recurred locally. Two patients with stage IIb disease, both of whom received chemotherapy, recurred regionally. Ten patients developed distant metastases. One died from progressive disease with initial proved bony metastasis. Two patients with stage IIb disease, both of whom received chemotherapy, experienced neck node recurrence. 5-year locoregional control rate was 97%; freedom from distant metastases was 84.6% at 5 years. No evidence of disease was detected in 13 early stage (I/IIa/IIb) patients who did not receive chemotherapy. Acute grade 3 toxicity occurred in four patients and grade 4 in two patients. Late toxicities were low, with no grade 3+ xerostomia, grade 2 xerostomia in two patients (3%), and grade 3 hearing loss in two patients (3%). CONCLUSIONS: HT resulted in excellent long-term disease control and survival in heterogeneous NPC patients. Generally mild acute and late toxicity, with low rates of xerostomia, were obtained. Image-guided HT offers the ability to deliver conformal, OAR-sparing dose distributions to a wide variety of NPC patients with good long-term clinical outcomes. PMID- 23634758 TI - Thickening agents used for dysphagia management: effect on bioavailability of water, medication and feelings of satiety. AB - Dysphagia is the medical term for difficulty swallowing. Thickened liquids are often used in the management of dysphagia to improve bolus control and to help prevent aspiration. A range of starches and gums has historically been used to thicken liquids. Although thickened liquids improve swallow safety, they appear to have a great potential for unintended physiological consequences. Initial concerns were raised about the impact of thickeners on water binding due to the high prevalence of dehydration amongst individuals with dysphagia. Thankfully, regardless of thickening agent, thickeners do not affect water bioavailability. This effect holds true even for extremely thick fluids. However, bioavailability of medication is impaired with viscous substances. Liquids thickened to as little as 150 mPa.s retards drug release. In addition, feelings of satiety and thirst increase with increasingly viscous fluids. Flavour deteriorates with increasing thickness regardless of thickening agent. Therapeutically clinicians often prescribe small volumes of thickened liquids, consumed often. Yet small volumes of thick substances consumed with a long oral processing time, which is common for individuals with dysphagia, reduces the amount consumed. A combination of poor flavour, and increasing feelings of fullness result in little motivation and poor physiologic drive to consume thickened liquids. PMID- 23634760 TI - Droplet dynamics in controlled InAs nanowire interconnections. AB - Semiconductor nanowires offer a versatile platform for the fabrication of new nanoelectronic and nanophotonic devices. These devices will require a high level of control of the nanowire position in relation to both other components of the device and to other nanowires. We demonstrate unprecedented control of the position of InAs nanowires using selective-area vapor-liquid-solid epitaxy (VLS) on an InP ridge template. The high level of control allows us to design structures which connect individual nanowires through coalescence of their catalyst particles. The interconnection process acts as a perturbation to the geometry of the nanowire system that can contribute to the understanding of droplet dynamics in VLS growth. Postgrowth imaging reveals a complex sequence of droplet configurations, including predicted geometries that have not previously been observed. PMID- 23634759 TI - Indazole-based potent and cell-active Mps1 kinase inhibitors: rational design from pan-kinase inhibitor anthrapyrazolone (SP600125). AB - Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively. PMID- 23634761 TI - Open-source LCA tool for estimating greenhouse gas emissions from crude oil production using field characteristics. AB - Existing transportation fuel cycle emissions models are either general and calculate nonspecific values of greenhouse gas (GHG) emissions from crude oil production, or are not available for public review and auditing. We have developed the Oil Production Greenhouse Gas Emissions Estimator (OPGEE) to provide open-source, transparent, rigorous GHG assessments for use in scientific assessment, regulatory processes, and analysis of GHG mitigation options by producers. OPGEE uses petroleum engineering fundamentals to model emissions from oil and gas production operations. We introduce OPGEE and explain the methods and assumptions used in its construction. We run OPGEE on a small set of fictional oil fields and explore model sensitivity to selected input parameters. Results show that upstream emissions from petroleum production operations can vary from 3 gCO2/MJ to over 30 gCO2/MJ using realistic ranges of input parameters. Significant drivers of emissions variation are steam injection rates, water handling requirements, and rates of flaring of associated gas. PMID- 23634762 TI - Comment and reply on: ME is a distinct diagnostic entity, not part of a chronic fatigue spectrum. PMID- 23634763 TI - Predicting Culex pipiens/restuans population dynamics by interval lagged weather data. AB - BACKGROUND: Culex pipiens/restuans mosquitoes are important vectors for a variety of arthropod borne viral infections. In this study, the associations between 20 years of mosquito capture data and the time lagged environmental quantities daytime length, temperature, precipitation, relative humidity and wind speed were used to generate a predictive model for the population dynamics of this vector species. METHODS: Mosquito population in the study area was represented by averaged time series of mosquitos counts captured at 6 sites in Cook County (Illinois, USA). Cross-correlation maps (CCMs) were compiled to investigate the association between mosquito abundances and environmental quantities. The results obtained from the CCMs were incorporated into a Poisson regression to generate a predictive model. To optimize the predictive model the time lags obtained from the CCMs were adjusted using a genetic algorithm. RESULTS: CCMs for weekly data showed a highly positive correlation of mosquito abundances with daytime length 4 to 5 weeks prior to capture (quantified by a Spearman rank order correlation of rS = 0.898) and with temperature during 2 weeks prior to capture (rS = 0.870). Maximal negative correlations were found for wind speed averaged over 3 week prior to capture (rS = -0.621). Cx. pipiens/restuans population dynamics was predicted by integrating the CCM results in Poisson regression models. They were used to simulate the average seasonal cycle of the mosquito abundance. Verification with observations resulted in a correlation of rS = 0.899 for daily and rS = 0.917 for weekly data. Applying the optimized models to the entire 20 years time series also resulted in a suitable fit with rS = 0.876 for daily and rS = 0.899 for weekly data. CONCLUSIONS: The study demonstrates the application of interval lagged weather data to predict mosquito abundances with a feasible accuracy, especially when related to weekly Cx. pipiens/restuans populations. PMID- 23634764 TI - A statistical strategy to identify recombinant viral ribonucleoprotein of avian, human, and swine influenza A viruses with elevated polymerase activity. AB - OBJECTIVES: Reassortment of influenza A viruses can give rise to viral ribonucleoproteins (vRNPs) with elevated polymerase activity and the previous three pandemic influenza viruses contained reassorted vRNPs of different origins. These suggest that reassorted vRNP may be one of the factors leading to a pandemic virus. In this study, we reconstituted chimeric vRNPs with three different viral strains isolated from avian, human and swine hosts. We applied a statistical strategy to identify the effect that the origin of a single vRNP protein subunit or the interactions between these subunits on polymerase activity. DESIGN: Eighty one chimeric vRNPs were reconstituted in 293T cells at different temperatures. Polymerase activity was determined by luciferase reporter assay and the results were analysed by multiway anova and other statistical methods. RESULTS: It was found that PB2, PB1, NP, PB2-PB1 interaction, PB2-PA interaction and PB1-NP interaction had significant effect on polymerase activity at 37 degrees C and several single subunits and interactions were identified to lead to elevation of polymerase activity. Furthermore, we studied 27 out of these 81 different chimieric vRNPs in different combinations via fractional factorial design approach. Our results suggested that the approach can identify the major single subunit or interaction factors that affect the polymerase activity without the need to experimentally reproduce all possible vRNP combinations. CONCLUSIONS: Statistical approach and fractional factorial design are useful to identify the major single subunit or interaction factors that can modulate viral polymerase activity. PMID- 23634765 TI - The choosing wisely((r)) campaign and nurses' role in dissemination. PMID- 23634769 TI - Too old for telemedicine? PMID- 23634770 TI - Meningothelial cells as part of the central nervous system host defence. AB - BACKGROUND INFORMATION: Meningothelial cells (MECs) are the cellular components of the meninges protecting the brain and as such provide important barrier function for the central nervous system building the interface between neuronal tissue and the cerebrospinal fluid (CSF). MECs were previously shown to be involved in the clearance of waste products from the CSF and in maintaining the optic nerve microenvironment. In addition, MECs are involved in immunological processes in the brain by secretion of pro-inflammatory cytokines in response to various pathologically relevant stress conditions. RESULTS: In this study, we analysed the uptake of latex beads as well as bacteria by human MECs using flow cytometric analyses. We found that MECs are highly active phagocytes able of ingesting large amounts of latex beads, as well as Gram-positive and Gram negative bacteria. Phagocytic activity of MECs was sensitive to nocodazole and cytochalasin D treatment to a varying degree depending on particle composition. Interestingly, Gram-positive bacteria such as Staphylococcus aureus are more readily taken up compared with Gram-negative Escherichia coli. In addition, pre treatment of MECs with lipopolysaccharide (LPS) or phorbol-12-myristate-13 acetate (PMA) enhanced S. aureus uptake, whereas PMA but not LPS was effective in enhancing E. coli uptake. CONCLUSIONS: Thus, MECs are highly active facultative phagocytes likely important for the maintenance of CSF homeostasis and host defence in the central nervous system especially against Gram-positive bacteria. PMID- 23634772 TI - A frontier orbital study with ab initio molecular dynamics of the effects of solvation on chemical reactivity: solvent-induced orbital control in FeO activated hydroxylation reactions. AB - Solvation effects on chemical reactivity are often rationalized using electrostatic considerations: the reduced stabilization of the transition state results in higher reaction barriers and lower reactivity in solution. We demonstrate that the effect of solvation on the relative energies of the frontier orbitals is equally important and may even reverse the trend expected from purely electrostatic arguments. We consider the H abstraction reaction from methane by quintet [EDTAH(n).FeO]((n-2)+), (n = 0-4) complexes in the gas phase and in aqueous solution, which we examine using ab initio thermodynamic integration. The variation of the charge of the complex with the protonation of the EDTA ligand reveals that the free energy barrier in gas phase increases with the negative charge, varying from 16 kJ mol(-1) for [EDTAH4.FeO](2+) to 57 kJ mol(-1) for [EDTAHn.FeO](2-). In aqueous solution, the barrier for the +2 complex (38 kJ mol( 1)) is higher than in gas phase, as predicted by purely electrostatic arguments. For the negative complexes, however, the barrier is lower than in gas phase (e.g., 45 kJ mol(-1) for the -2 complex). We explain this increase in reactivity in terms of a stabilization of the virtual 3sigma* orbital of FeO(2+), which acts as the dominant electron acceptor in the H-atom transfer from CH4. This stabilization originates from the dielectric screening caused by the reorientation of the water dipoles in the first solvation shell of the charged solute, which stabilizes the acceptor orbital energy for the -2 complex sufficiently to outweigh the unfavorable electrostatic destabilization of the transition-state relative to the reactants in solution. PMID- 23634771 TI - Profilin-1 mutations are rare in patients with amyotrophic lateral sclerosis and frontotemporal dementia. AB - Mutations in profilin-1 (PFN1) have recently been identified in patients with amyotrophic lateral sclerosis (ALS). Because of the considerable overlap between ALS and the common subtype of frontotemporal dementia, which is characterized by transactive response DNA-binding protein 43 pathology (FTLD-TDP), we tested cohorts of ALS and FTLD-TDP patients for PFN1 mutations. DNA was obtained from 342 ALS patients and 141 FTLD-TDP patients at our outpatient clinic and brain bank for neurodegenerative diseases at the Mayo Clinic Florida, Jacksonville, USA. We screened these patients for mutations in coding regions of PFN1 by Sanger sequencing. Subsequently, we used TaqMan genotyping assays to investigate the identified variant in 1167 control subjects. From the results, one variant, p.E117G, was detected in one ALS patient, one FTLD-TDP patient, and two control subjects. The mutation frequency of patients versus control subjects was not significantly different (p-value = 0.36). Moreover, PFN1 and TDP-43 staining of autopsy material did not differ between patients with or without this variant. In conclusion, the p.E117G variant appears to represent a benign polymorphism. PFN1 mutations, in general, are rare in ALS and FTLD-TDP patients. PMID- 23634773 TI - Liver melanomacrophage centres as indicators of Atlantic bluefin tuna, Thunnus thynnus L. well-being. AB - Melanomacrophage centres (MMCs), located in different organs of non-mammalian vertebrates, play a role in the destruction, detoxification or recycling of endogenous and exogenous materials. Cytochrome P450 monoxygenase 1A (CYP1A) is involved in xenobiotics biotransformation, and its liver expression is considered as a biomarker for detecting exposure to environmental pollutants. Atlantic bluefin tuna (ABFT), Thunnus thynnus L., liver samples were collected from: wild animals caught in the eastern Atlantic; juveniles reared in the central Adriatic; juveniles reared in the northern Adriatic; adults reared in the western Mediterranean. The samples were processed for basic histology, histochemistry and for CYP1A immunodetection. An unexpected high density of MMCs, containing ferric iron and lipofuscin-ceroids, was detected in the juveniles sampled in the northern Adriatic Sea. These individuals showed also a strong anti-CYP1A immunopositivity in hepatocytes and in the epithelium of bile ducts. This study supports the utility of MMCs as biomarkers of fish 'health status' and gives concern for a potential contaminant accumulation in ABFT. PMID- 23634774 TI - Autosomal dominant hereditary ataxia in Sri Lanka. AB - BACKGROUND: Spinocerebellar ataxias (SCA) are a group of hereditary neurodegenerative disorders. Prevalence of SCA subtypes differ worldwide. Autosomal dominant ataxias are the commonest types of inherited ataxias seen in Sri Lanka. The aim of the study is to determine the genetic etiology of patients with autosomal dominant ataxia in Sri Lanka and to describe the clinical features of each genetic subtype. METHODS: Thirty four patients with autosomal dominant ataxia were recruited. For every patient the following was done: recording of clinical details and genotyping for SCA 1, 2, 3, 6, 7, 8, 12, and 17. RESULTS: Sixty one per cent of the subjects were identified as SCA1. One subject had SCA2, 12 remain unidentified. Mean age at onset was 34.8 +/- 10years for SCA1 and 32.7 +/- 9.8 for non SCA1. 76% of SCA1 patients and 50% of non SCA1 were using walking aids. Quantification of symptoms and signs were similar in the SCA1 and non SCA1 groups. Clinical depression was evidenced in 68.4% of SCA1 and 75% non SCA-1 patients. Mean CAG repeat length in SCA1 patients was 52.0 +/- 3.8, with greater anticipation seen with paternal inheritance. CONCLUSION: SCA1 was the predominant subtype and showed similar phenotype to previous reports. However, disease severity was higher and depression more prevalent in this population than previously described. PMID- 23634775 TI - The bacterial effector DspA/E is toxic in Arabidopsis thaliana and is required for multiplication and survival of fire blight pathogen. AB - The type III effector DspA/E is an essential pathogenicity factor of the phytopathogenic bacterium Erwinia amylovora. We showed that DspA/E was required for transient bacterial growth in nonhost Arabidopsis thaliana leaves, as an E. amylovora dspA/E mutant was unable to grow. We expressed DspA/E in A. thaliana transgenic plants under the control of an oestradiol-inducible promoter, and found that DspA/E expressed in planta restored the growth of a dspA/E mutant. DspA/E expression in these transgenic plants led to the modulation by at least two-fold of the expression of 384 genes, mostly induced (324 genes). Both induced and repressed genes contained high proportions of defence genes. DspA/E expression ultimately resulted in plant cell death without requiring a functional salicylic acid signalling pathway. Analysis of A. thaliana transgenic seedlings expressing a green fluorescent protein (GFP):DspA/E fusion indicated that the fusion protein could only be detected in a few cells per seedling, suggesting the degradation or absence of accumulation of DspA/E in plant cells. Consistently, we found that DspA/E repressed plant protein synthesis when injected by E. amylovora or when expressed in transgenic plants. Thus, we conclude that DspA/E is toxic to A. thaliana: it promotes modifications, among which the repression of protein synthesis could be determinant in the facilitation of necrosis and bacterial growth. PMID- 23634776 TI - Ascending excitatory neural pathways modulate slow phasic myogenic contractions in the isolated human colon. AB - BACKGROUND: In animal models, enteric reflex pathways have potent effects on motor activity; their roles have been much less extensively studied in human gut. The aim of this study was to determine if ascending excitatory interneuronal pathways can modulate spontaneous phasic contractions in isolated preparations of human colonic circular muscle. METHODS: Human colonic preparations were cut into T shapes, with vertical bar of the 'T' pharmacologically isolated. Electrical stimulation and the nicotinic agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), were applied to the isolated region and circular muscle contractile activity was measured from the cross-bar of the T, more than 10 mm orally from the region of stimulation. KEY RESULTS: The predominant form of spontaneous muscle activity consisted of tetrodotoxin-resistant, large amplitude, slow phasic contractions (SPCs), occurring at average intervals of 124 +/- 68 s. Addition of a high concentration of hexamethonium (1 mmol L(-1)) to the superfusing solution significantly increased the interval between SPCs to 278.1 +/- 138.3 s (P < 0.005). Focal electrical stimulation more than 10 mm aboral to the muscle recording site advanced the onset of the next SPC, and this effect persisted in hexamethonium. However, the effect of electrical stimulation was blocked by tetrodotoxin (TTX, 1 MUmol L(-1)). Application of the nicotinic agonist DMPP (1 mmol L(-1)) to the aboral chamber often stimulated a premature SPC (n = 4). CONCLUSIONS & INFERENCES: The major form of spontaneous contractility in preparations of human colonic circular muscle is SPCs, which are myogenic in origin. Activation of ascending excitatory neural pathways, which involve nicotinic receptors, can modulate the timing of SPCs and thus influence human colonic motility. PMID- 23634777 TI - Editorial comment to "Predictors of benign histology in clinical T1a renal cell carcinoma tumors undergoing partial nephrectomy". PMID- 23634779 TI - Osteochondral lesions in children with juvenile idiopathic arthritis. AB - BACKGROUND: Joint pain and swelling are typical symptoms in children with juvenile idiopathic arthritis (JIA) and these are often related to inflammation of the joint. Juvenile osteochondritis dissecans (JOCD), that is separation of a bone-cartilage segment from the articular surface, can manifest with similar symptoms. FINDINGS: We studied thirteen cases of osteochondritis dissecans lesions (OCD) in children with JIA. There were nine girls and four boys with a mean age of 6.5 (2-12) years at the time of diagnosis of JIA. Mean time between diagnosis of JIA and manifestation of OCD was 5.5 (1-11) years. Indications for MRI were the presence of pain or discomfort in the joint, despite otherwise effective treatment, with no evidence from ultrasound examination of any obvious signs of active inflammation. The most common location of osteochondral lesion was the knee, although the ankle joint was affected in one case. Five patients had lesions in both knees. Operative treatment was needed in eight cases (joints). CONCLUSIONS: Pain, and minor dysfunction of the joint are common complaints of children suffering from JIA. Earlier research has discounted the possibility of children who were not athletes presenting with this condition. However, this study demonstrates that these lesions also seem to be relatively common in patients with JIA. When there is no sign of inflammation, the possibility of OCD must therefore be considered in these children. PMID- 23634778 TI - Leptin, resistin and visfatin: the missing link between endocrine metabolic disorders and immunity. AB - Adipose tissue is still regarded as a principle site for lipid storage and mobilizing tissue with an important role in the control of energy homeostasis. Additionally, adipose tissue-secreted hormones such as leptin, visfatin, resistin, apelin, omentin, sex steroids, and various growth factors are now regarded as a functional part of the endocrine system. These hormones also play an important role in the immune system. Several in vitro and in vivo studies have suggested the complex role of adipocyte-derived hormones in immune system and inflammation. Adipokines mediate beneficial and detrimental effects in immunity and inflammation. Many of these adipocytokines have a physiological role in metabolism. The uncontrolled secretions of several adipocytokines were associated with the stimulation of inflammatory processes leading to metabolic disorders including obesity, atherosclerosis, insulin resistance and type 2 diabetes. Obesity leads to the dysfunction of adipocytes andcorrelated with the imbalance of adipokines levels. In obese and diabetic conditions, leptin deficiency inhibited the Jak/Stat3/PI3K and insulin pathways. In this review, ample evidence exists to support the recognition of the adipocyte's role in various tissues and pathologies. New integral insights may add dimensions to translate any potential agents into the future clinical armamentarium of chronic endocrine metabolic and inflammatory diseases. Functional balance of both adipocytes and immune cells is important to exert their effects on endocrine metabolic disorders; furthermore, adipose tissue should be renamed not only as a functional part of the endocrine system but also as a new part of the immune system. PMID- 23634780 TI - Transdermal delivery of diclofenac using water-in-oil microemulsion: formulation and mechanistic approach of drug skin permeation. AB - The objective of the present investigation was to enhance skin permeation of diclofenac using water-in-oil microemulsion and to elucidate its skin permeation mechanism. The w/o microemulsion formulations were selected based on constructed pseudoternary phase diagrams depending on water solubilization capacity and thermodynamic stability. These formulations were also subjected to physical characterization based on droplet size, viscosity, pH and conductivity. Permeation of diclofenac across rat skin using side-by-side permeation cells from selected w/o microemulsion formulations were evaluated and compared with control formulations. The selected w/o microemulsion formulations were thermodynamically stable, and incorporation of diclofenac sodium into microemulsion did not affect the phase behavior of system. All microemulsion formulations had very low viscosity (11-17 cps) and droplet size range of 30-160 nm. Microemulsion formulations exhibited statistically significant increase in diclofenac permeation compared to oily solution, aqueous solution and oil-Smix solution. Higher skin permeation of diclofenac was observed with low Smix concentration and smaller droplet size. Increase in diclofenac loading in aqueous phase decreased the partition of diclofenac. Diclofenac from the oil phase of microemulsion could directly partition into skin, while diclofenac from the aqueous droplets was carried through skin by carrier effect. PMID- 23634781 TI - Baseline factors predicting change from the initial DMARD treatment during the first 2 years of rheumatoid arthritis: experience in the ERAN inception cohort. AB - BACKGROUND: Outcomes in early Rheumatoid Arthritis (RA) may be improved by rapidly establishing a stable and effective disease modifying anti-rheumatic drug (DMARD) treatment regimen. We aimed to investigate whether baseline factors and initial treatment strategies are associated with changes to the first DMARD treatment, due to either Lack of Efficacy (LoE) or Adverse Drug Reaction (ADR) within 2 years of presentation. METHODS: Reasons for changes from initial DMARD therapy within 2 years of baseline, and associated factors, were examined using logistic regression in data from the Early RA Network (ERAN) inception cohort. RESULTS: Data were available for 766 participants. 410 (54%) changed their initial DMARD regime within 2 years, including 230 (56%) due to Lack of Efficacy (LoE) and 139 (34%) due to Adverse Drug Reaction (ADR). The first DMARD was recorded as methotrexate monotherapy in 336 (44%), sulphasalazine monotherapy in 273 (36%), or combined methotrexate/sulphasalazine/hydroxychlorquine in 52 (7%).Baseline predictors of changing DMARD (for all reasons) were HAQ-disability (aOR 1.44, 95% CI 1.12 - 1.86), poor mental health (aOR 1.44, 95% CI 1.16 - 1.78) and extra-articular disease (aOR 1.78, 95% CI 1.00 - 3.16). In this model, the triple combination therapy also predicted lower likelihood of DMARD change (aOR 0.30, 95% CI 0.12 - 0.79).Subgroup analyses showed that MTX monotherapy was associated with lower risk of change due to ADR. Combination therapy conferred lower risk of change due to LoE. Poor mental health was associated with change due to ADR, and extra-articular disease, HAQ-disability at baseline, and younger age predicted LoE. CONCLUSIONS: Our findings suggest that non-pharmacological interventions to improve disability and mental health, may reduce initial DMARD treatment failure. PMID- 23634782 TI - Determination of the optimal tubulin isotype target as a method for the development of individualized cancer chemotherapy. AB - BACKGROUND: As microtubules are essential for cell growth and division, its constituent protein beta-tubulin has been a popular target for various treatments, including cancer chemotherapy. There are several isotypes of human beta-tubulin and each type of cell expresses its characteristic distribution of these isotypes. Moreover, each tubulin-binding drug has its own distribution of binding affinities over the various isotypes, which further complicates identifying the optimal drug selection. An ideal drug would preferentially bind only the tubulin isotypes expressed abundantly by the cancer cells, but not those in the healthy cells. Unfortunately, as the distributions of the tubulin isotypes in cancer cells overlap with those of healthy cells, this ideal scenario is clearly not possible. We can, however, seek a drug that interferes significantly with the isotype distribution of the cancer cell, but has only minor interactions with those of the healthy cells. METHODS: We describe a quantitative methodology for identifying this optimal tubulin isotype profile for an ideal cancer drug, given the isotype distribution of a specific cancer type, as well as the isotype distributions in various healthy tissues, and the physiological importance of each such tissue. RESULTS: We report the optimal isotype profiles for different types of cancer with various routes of delivery. CONCLUSIONS: Our algorithm, which defines the best profile for each type of cancer (given the drug delivery route and some specified patient characteristics), will help to personalize the design of pharmaceuticals for individual patients. This paper is an attempt to explicitly consider the effects of the tubulin isotype distributions in both cancer and normal cell types, for rational chemotherapy design aimed at optimizing the drug's efficacy with minimal side effects. PMID- 23634784 TI - World society of emergency surgery study group initiative on Timing of Acute Care Surgery classification (TACS). AB - Timing of surgical intervention is critical for outcomes of patients diagnosed with surgical emergencies. Facing the challenge of multiple patients requiring emergency surgery, or of limited resource availability, the acute care surgeon must triage patients according to their disease process and physiological state. Emergency operations from all surgical disciplines should be scheduled by an agreed time frame that is based on accumulated data of outcomes related to time elapsed from diagnosis to surgery. Although literature exists regarding the optimal timing of various surgical interventions, implementation of protocols for triage of surgical emergencies is lacking. For institutions of a repetitive triage mechanism, further discussion on optimal timing of surgery in diverse surgical emergencies should be encouraged. Standardizing timing of interventions in surgical emergencies will promote clinical investigation as well as a commitment by administrative authorities to proper operating theater provision for acute care surgery. PMID- 23634783 TI - Sex-biased gene expression in the brown alga Fucus vesiculosus. AB - BACKGROUND: The fucoid brown algae (Heterokontophyta, Phaeophyceae) are increasingly the focus of ecological genetics, biodiversity, biogeography and speciation research. The molecular genetics underlying mating system variation, where repeated dioecious - hermaphrodite switches during evolution are recognized, and the molecular evolution of sex-related genes are key questions currently hampered by a lack of genomic information. We therefore undertook a comparative analysis of male and female reproductive tissue transcriptomes against a vegetative background during natural reproductive cycles in Fucus vesiculosus. RESULTS: Over 300 k reads were assembled and annotated against public protein databases including a brown alga. Compared with the vegetative tissue, photosynthetic and carbohydrate metabolism pathways were under-expressed, particularly in male tissue, while several pathways involved in genetic information processing and replication were over-expressed. Estimates of sex biased gene (SBG) expression were higher for male (14% of annotated orthologues) than female tissue (9%) relative to the vegetative background. Mean expression levels and variance were also greater in male- than female-biased genes. Major female-biased genes were carbohydrate-modifying enzymes with likely roles in zygote cell wall biogenesis and/or modification. Male-biased genes reflected distinct sperm development and function, and orthologues for signal perception (a phototropin), transduction (several kinases), and putatively flagella-localized proteins (including candidate gamete-recognition proteins) were uniquely expressed in males. Overall, the results suggest constraint on female-biased genes (possible pleiotropy), and less constrained male-biased genes, mostly associated with sperm-specific functions. CONCLUSIONS: Our results support the growing contention that males possess a large array of genes regulating male fitness, broadly supporting findings in evolutionarily distant heterogametic animal models. This work identifies an annotated set of F. vesiculosus gene products that potentially regulate sexual reproduction and may contribute to prezygotic isolation, one essential step towards developing tools for a functional understanding of species isolation and differentiation. PMID- 23634785 TI - Food insecurity and linear growth of adolescents in Jimma Zone, Southwest Ethiopia. AB - BACKGROUND: Although many studies showed that adolescent food insecurity is a pervasive phenomenon in Southwest Ethiopia, its effect on the linear growth of adolescents has not been documented so far. This study therefore aimed to longitudinally examine the association between food insecurity and linear growth among adolescents. METHODS: Data for this study were obtained from a longitudinal survey of adolescents conducted in Jimma Zone, which followed an initial sample of 2084 randomly selected adolescents aged 13-17 years. We used linear mixed effects model for 1431 adolescents who were interviewed in three survey rounds one year apart to compare the effect of food insecurity on linear growth of adolescents. RESULTS: Overall, 15.9% of the girls and 12.2% of the boys (P=0.018) were food insecure both at baseline and on the year 1 survey, while 5.5% of the girls and 4.4% of the boys (P=0.331) were food insecure in all the three rounds of the survey. In general, a significantly higher proportion of girls (40%) experienced food insecurity at least in one of the survey rounds compared with boys (36.6%) (P=0.045).The trend of food insecurity showed a very sharp increase over the follow period from the baseline 20.5% to 48.4% on the year 1 survey, which again came down to 27.1% during the year 2 survey.In the linear mixed effects model, after adjusting for other covariates, the mean height of food insecure girls was shorter by 0.87 cm (P<0.001) compared with food secure girls at baseline. However, during the follow up period on average, the heights of food insecure girls increased by 0.38 cm more per year compared with food secure girls (P<0.066). However, the mean height of food insecure boys was not significantly different from food secure boys both at baseline and over the follow up period. Over the follow-up period, adolescents who live in rural and semi-urban areas grew significantly more per year than those who live in the urban areas both for girls (P<0.01) and for boys (P<0.01). CONCLUSIONS: Food insecurity is negatively associated with the linear growth of adolescents, especially on girls. High rate of childhood stunting in Ethiopia compounded with lower height of food insecure adolescents compared with their food secure peers calls for the development of direct nutrition interventions targeting adolescents to promote catch-up growth and break the intergenerational cycle of malnutrition. PMID- 23634786 TI - Lanostane triterpenoids from the mushroom Naematoloma fasciculare. AB - In our continuing search for structurally interesting and bioactive metabolites from Korean wild mushrooms, bioassay-guided fractionation and a chemical investigation of the MeOH extracts of the fruiting bodies of the mushroom Naematoloma fasciculare resulted in the isolation of four new lanostane triterpenoids (1-4), together with 11 known compounds (5-15). The structures of 1 5 were determined by a combination of 1D and 2D NMR and HRMS. The absolute configuration of the 3-hydroxy-3-methylglutaryl group as a side chain in 1 and 2 was determined by the alkaline methanolysis method. The full NMR data assignment of the known compound fasciculol G (5) is reported for the first time. Compounds 1-15 were tested for their antiproliferative activities against four human cancer cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15) and evaluated for their inhibitory effects on nitric oxide production in a lipopolysaccharide-activated murine microglial cell line. PMID- 23634787 TI - Bioavailability of antioxidants applied to stratified human corneal epithelial cells. AB - PURPOSE: Oxidative damage to the corneal epithelium may be involved in dry eye disease. The bioavailability and efficacy of antioxidants in human corneal limbal epithelial (HCLE) cells were measured to determine whether antioxidants might be beneficial constituents of lubricant eye drops. METHODS: The activity of antioxidants was evaluated using a cellular antioxidant activity assay in which, cells were loaded with the reactive oxygen species (ROS)-sensitive fluorescent indicator, 2',7'-dichlorofluorescin diacetate (DCFH-DA), and an antioxidant compound. ROS were then generated intracellularly using 2,2'-azobis(2 amidinopropane) dihydrochloride (ABAP) or extracellularly using xanthine oxidase, and the ability of an antioxidant to inhibit ROS-generated fluorescence was measured. RESULTS: When ROS were generated by ABAP, EC50 values for quercetin, epigallocatechin gallate (EGCG), n-propyl gallate, and gallic acid were 2.98, 3.41, 6.30, and 50.7 MUM, respectively. When ROS were generated extracellularly by xanthine oxidase, EC50 values for quercetin, EGCG, n-propyl gallate, and gallic acid were 41.3, 56.5, 70.5, and 337.5 MUM. These values were reduced significantly when an antioxidant was present both in the medium with the xanthine oxidase and within the cells. CONCLUSIONS: The antioxidants were effective at quenching ROS in HCLE cells, indicating that they are bioavailable and might be effective in protecting the corneal epithelium from oxidative damage if included in a lubricant eye drop. PMID- 23634788 TI - Abstracts of the XXVI International Symposium on Technological Innovations in Laboratory Hematology. May 10-12, 2013. Toronto, Canada. PMID- 23634789 TI - Precession electron diffraction tomography for solving complex modulated structures: the case of Bi5Nb3O15. AB - The crystal structure of the 1D incommensurately modulated phase Bi5Nb3O15 [superspace group X2mb(0b0)000, a = 5.46781(7) A, b = 5.47381(8) A, c = 41.9005(5) A, and q = 0.17588(8)b*] is solved by electron diffraction using a tomography technique combined with precession of the electron beam. The (3 + 1)D structure is further validated by a refinement against powder X-ray diffraction (PXRD). A coherent picture of the true nature of this compound is obtained, conciliating experimental observations made by different groups using transmission electron microscopy and PXRD. Bi5Nb3O15 does not have a mixed-layer Aurivillius-type structure but does contain structural elements, [Bi2O2](2+) slabs, and perovskite-like blocks, characteristic of Aurivillius phases. The presence of aperiodic crystallographic shear planes (CSPs) along the modulated direction b leads to the formation of an original layered structure containing both continuous and discontinuous [Bi2O2](2+) and perovskite-like octahedral layers. Between CSPs, the stacking of these two structural elements exhibits an unprecedented nonuniform sequence referring to Aurivillius phases. PMID- 23634790 TI - Twin-free GaAs nanosheets by selective area growth: implications for defect-free nanostructures. AB - Highly perfect, twin-free GaAs nanosheets grown on (111)B surfaces by selective area growth (SAG) are demonstrated. In contrast to GaAs nanowires grown by (SAG) in which rotational twins and stacking faults are almost universally observed, twin formation is either suppressed or eliminated within properly oriented nanosheets are grown under a range of growth conditions. A morphology transition in the nanosheets due to twinning results in surface energy reduction, which may also explain the high twin-defect density that occurs within some III-V semiconductor nanostructures, such as GaAs nanowires. Calculations suggest that the surface energy is significantly reduced by the formation of {111}-plane bounded tetrahedra after the morphology transition of nanowire structures. By contrast, owing to the formation of two vertical {11[overline]0} planes which comprise the majority of the total surface energy of nanosheet structures, the energy reduction effect due to the morphology transition is not as dramatic as that for nanowire structures. Furthermore, the surface energy reduction effect is mitigated in longer nanosheets which, in turn, suppresses twinning. PMID- 23634791 TI - Rasagiline meta-analysis: a spotlight on clinical safety and adverse events when treating Parkinson's disease. AB - INTRODUCTION: Rasagiline (Azilect, AGN 1135) is a selective irreversible inhibitor of monoamine oxidase B (MAO-B). MAO-B regulates the brain concentrations of important neurotransmitters that are related to movement, emotion, and cognition. Oral rasagiline, as monotherapy or as adjunctive therapy to levodopa, was effective in the symptomatic treatment of adult patients with Parkinson's disease participating in double-blind, placebo-controlled, international studies. AREAS COVERED: This article reviews the reported adverse effects of rasagiline. A MEDLINE search was performed for all articles from 1990 to present, which reported any adverse effects from rasagiline or related references. We conducted an analysis of the adverse effects of rasagiline based on the reported clinical studies. Furthermore, we compared the incidence of adverse events in clinical trials for rasagiline and placebo. EXPERT OPINION: Among the most frequently reported adverse effects for rasagiline as monotherapy are headache, dizziness, and insomnia. Depression, dizziness, somnolence, and other sleep disorders are reported when used in combination therapy. Our analysis demonstrates that the most frequently reported adverse effects in trials did not occur more often with rasagiline than placebo. In conclusion, rasagiline is a well-tolerated MAO-B inhibitor that may help to achieve the desired level of clinical benefit in Parkinson's disease. PMID- 23634792 TI - Assessment of optic disc photographs for glaucoma by UK optometrists: the Moorfields Optic Disc Assessment Study (MODAS). AB - PURPOSE: To assess the ability of UK optometrists to accurately discriminate between stereoscopic photographs of healthy and glaucomatous optic discs. METHODS: An online survey, including questions relating to qualification, practice environment, and diagnostic methods was completed by 1256 optometrists. Based on their responses, 208 (17%) were selected to undertake an online disc assessment exercise. Optometrists evaluated the same disc images previously assessed by European ophthalmologists as part of the European Optic Disc Assessment Trial (EODAT); the task was to state if the disc appeared healthy or glaucomatous. There were 110 stereoscopic disc images, of which 40 were healthy, 48 glaucomatous, and six ocular hypertensive, with 16 duplicates images. Sensitivity, specificity and overall accuracy were calculated and compared between optometrist groups and with the EODAT ophthalmologists using permutation analysis. RESULTS: Median sensitivity was 0.92 (95% CI: 0.70, 1.00) and median specificity was 0.74 (95% CI: 0.62, 0.88). Median overall accuracy was 80% (95% CI: 67%, 88%). Agreement between optometrists was moderate (Fleiss' kappa: 0.57). Optometrists with higher qualifications did not have overall higher sensitivity than those without (p = 0.23), but had higher specificity (p = 0.001) and higher overall accuracy (p < 0.001). Optometrists displayed higher sensitivity but lower specificity than the EODAT ophthalmologists. CONCLUSION: UK optometrists displayed a high sensitivity and moderate specificity when assessing optic discs for the presence of glaucoma, in the context of this study. PMID- 23634793 TI - The impact of age and clinical factors in non-muscle-invasive bladder cancer treated with Bacillus Calmette Guerin therapy. AB - BACKGROUND: Bladder cancer is a disease of older persons, the incidence of which is expected to increase as the population ages. Prognostic factors for local recurrence for patients with non-muscle invasive bladder cancer have not been fully established. The aim of our study was to determine the influence of age on the outcomes of non muscle invasive bladder (NMIBC) cancer treated with intravesical Bacillus Calmette-Guerin (BCG) therapy. METHODS: We retrospectively reviewed the clinical and pathologic data of primary NMIBC from 112 patients who were treated with transurethral resection followed by BCG-immunotherapy. Time follow-up was 30 months. Clinicopathologic characteristics and response to BCG therapy were correlated with age using univariate and multivariate methods of analysis. RESULTS: Univariate analysis showed that age analyzed as a categorical variable was not associated with other clinicopathological characteristics. On the other hand, multivariate analysis showed that only multiplicity, stage and tumor size were independent significant prognosticators. CONCLUSIONS: The results of our study have shown that aging has no impact on the outcomes of high-risk NMIBC treated by BCG immunotherapy. PMID- 23634794 TI - Impact of smoking intensity on outcomes of patients with non muscle invasive bladder cancer treated by BCG immunotherapy. AB - BACKGROUND: Cigarette smoking is a well-known risk factor of bladder carcinogenesis. The clinical impact of smoking on bladder cancer recurrence and response to BCG immunotherapy remains unclear. We sought to investigate the effect of smoking intensity on bladder cancer response to BCG therapy, and the interactions between smoking and clinicopathological factors on bladder cancer recurrence. METHODS: Clinical information was obtained from 81 smokers patients (smokers at diagnosis) with NMIBC treated with transurethral resection of the bladder tumor followed by BCG immunotherapy. The distribution of smoking intensity on patient age (>=60 years or <60 years), gender, tumor grade, tumor stage, carcinoma in situ, multiplicity and tumor size was assessed. The effect of cigarette smoking on cancer recurrence was estimated using Cox proportional hazard models and Kaplan-Meier analysis. RESULTS: The results showed that smoking intensity was significantly associated with response to BCG immunotherapy (p = 0.010). Univariate Cox regression analysis of clinicopathologic characteristics showed that PT1 stage, tumor size more than 3 cm and smoking intensity significantly increased the risk of recurrence (respectively, p = 0.006; p = 0.008 and p = 0.012). These results were confirmed by Kaplan-Meier survival curves. In addition, multivariate analysis using Cox regression selected the model involving stage, tumor size and smoking intensity as the quasi-independent predictor of recurrence. CONCLUSION: These findings suggest that cigarette smoking is an independent predictor for patients with NMIBC. Although the current evidence supports a positive link between smoking intensity and the risk of recurrence on NMIBC treated by BCG immunotherapy, additional studies, are needed before definitive conclusions can be drawn. PMID- 23634795 TI - Blocking mtDNA replication upregulates the expression of stemness-related genes in prostate cancer cell lines. AB - Ethidium bromide (EtBr) is an intercalating agent, which binds tightly to mitochondrial DNA (mtDNA) during replication, and so blocks the function of mitochondria. EtBr inserts itself between the stacked bases in double-stranded DNA and specifically inhibits mtDNA transcription and replication by deleting RNA primers required for initiating mtDNA replication. In this study, the authors wanted to examine whether blocking mtDNA replication with EtBr could change the expression of stenmness genes and the expression of the immuneregulator B7-H3 in prostate cancer cell lines in vitro. Both PC-3 and DU145 prostate cancer cell lines were treated with 50 and 500 ng/mL of EtBr for 2 weeks. There was no difference in growth between EtBr-treated and control cells after 1 week. A slightly slower growth was observed for both cell lines during the second week of culture with EtBr compared to controls. After 2 weeks of culture with EtBr both cell lines showed increased expression of the stemness-related genes ABCG2, Oct3/4, Nanog1/Nanogp8, and CD44. Concomitantly, a dose-dependent increase of B7 H3 protein expression in both cell lines was identified and verified by both flow cytometry and immunocytochemistry. In conclusion, blocking mtDNA replication by EtBr induces increased expression of stemness genes, such as Oct3/4, Nanog, CD44, and ABCG2, in addition to the immune regulator B7-H3 in PC-3 and DU145 prostate cancer cell lines. The findings indicate that mitochondrial function may be associated with stemness of cancer cells and/or maintenance of a cancer stem cell phenotype. The finding of increased B7-H3 expression may be associated with the immunosuppression of cancer cells. PMID- 23634796 TI - Neutrophil-rich gastric carcinomas: light and electron microscopic study of 9 cases with particular reference to neutrophil apoptosis. AB - The authors report 9 cases of gastric carcinomas characterized by a prominent neutrophilic infiltration of the stroma. These tumors (8 of intestinal type, 1 of diffuse type) showed a pushing growth pattern. Metastatic involvement of regional lymph nodes was seen in 5 cases. The metastatic foci were associated with heavy neutrophilia as well. There was no histologic evidence of Helicobacter pylori infection, whereas various degrees of multifocal intestinal metaplasia were present in the background mucosa. Based on histologic and histochemical results, there were no apparent causes due to other infectious agents responsible for the neutrophil-rich gastric carcinomas. Some of intraepithelial and stromal neutrophils exhibited apoptotic changes, such as chromatin condensation and cell shrinkage, and were TUNEL-positive. Electron microscopy disclosed apoptotic neutrophils in cytoplasmic vacuoles of tumor cells, a finding suggestive of neutrophil-tumor cell phagocytosis (cannibalism). Different stages of neutrophil apoptosis were also shown by electron microscopy and the ultrastructural findings were compared to those described in experimental models, both in vivo and in vitro. PMID- 23634797 TI - Human sperm anatomy: different expression and localization of phosphatidylinositol 3-kinase in normal and varicocele human spermatozoa. AB - Abstract Recent reports support the possible role of PI3K in sperm capacitation and acrosome reaction, although studies regarding PI3K identity in human sperm, under certain disease states such as varicocele, are still lacking. The authors, therefore, examined the expression profile and ultrastructural localization of PI3K in human semen samples, comparing healthy donors and patients with varicocele. The results obtained performing western blotting assay showed decreased PI3K expression in varicocele with respect to the "healthy" sperm. Immunogold labeling revealed human sperm cellular compartments containing PI3K, evidencing it in the head at both the membrane and nucleus and the entire tail, from the middle to the end piece of normal sperm. In varicocele PI3K label was confined to the head, with a strong reduction of specific reaction in the neck, middle piece, and tail. In conclusion, the data suggest that PI3K may play a role in the maintenance of male factor infertility associated with varicocele, and it may be further exploited as an additional molecular marker for the diagnosis of male infertility disorders. PMID- 23634799 TI - Making sense of enthalpy of vaporization trends for ionic liquids: new experimental and simulation data show a simple linear relationship and help reconcile previous data. AB - Vaporization enthalpy of an ionic liquid (IL) is a key physical property for applications of ILs as thermofluids and also is useful in developing liquid state theories and validating intermolecular potential functions used in molecular modeling of these liquids. Compilation of the data for a homologous series of 1 alkyl-3-methylimidazolium bis(trifluoromethane-sulfonyl)imide ([C(n)mim][NTf2]) ILs has revealed an embarrassing disarray of literature results. New experimental data, based on the concurring results from quartz crystal microbalance, thermogravimetric analyses, and molecular dynamics simulation have revealed a clear linear dependence of IL vaporization enthalpies on the chain length of the alkyl group on the cation. Ambiguity of the procedure for extrapolation of vaporization enthalpies to the reference temperature 298 K was found to be a major source of the discrepancies among previous data sets. Two simple methods for temperature adjustment of vaporization enthalpies have been suggested. Resulting vaporization enthalpies obey group additivity, although the values of the additivity parameters for ILs are different from those for molecular compounds. PMID- 23634798 TI - Bioefficacy of long-lasting insecticidal nets against pyrethroid-resistant populations of Anopheles gambiae s.s. from different malaria transmission zones in Uganda. AB - BACKGROUND: There are major concerns over sustaining the efficacy of current malaria vector control interventions given the rapid spread of resistance, particularly to pyrethroids. This study assessed the bioefficacy of five WHO recommended long-lasting insecticidal nets (LLINs) against pyrethroid-resistant Anopheles gambiae field populations from Uganda. METHODS: Adult An. gambiae from Lira, Tororo, Wakiso and Kanungu districts were exposed to permethrin (0.75%) or deltamethrin (0.05%) in standard WHO susceptibility tests. Cone bioassays were used to measure the bioefficacy of four mono-treated LLINs (Olyset(r), Interceptor(r), Netprotect(r) and PermaNet(r) 2.0) and one combination LLIN (PermaNet(r) 3.0) against the four mosquito populations. Wireball assays were similarly conducted to determine knockdown rates. Species composition and kdr mutation frequency were determined for a sample of mosquitoes from each population. Chemical assays confirmed that test nets fell within target dose ranges. RESULTS: Anopheles gambiae s.s. predominated at all four sites (86-99% of Anopheles spp.) with moderate kdr L1014S allelic frequency (0.34-0.37). Confirmed or possible resistance to both permethrin and deltamethrin was identified for all four test populations. Reduced susceptibility to standard LLINs was observed for all four populations, with mortality rates as low as 45.8% even though the nets were unused. The combination LLIN PermaNet(r)3.0 showed the highest overall bioefficacy against all four An. gambiae s.l. populations (98.5-100% mortality). Wireball assays provided a more sensitive indicator of comparative bioefficacy, and PermaNet 3.0 was again associated with the highest bioefficacy against all four populations (76.5-91.7% mortality after 30 mins). CONCLUSIONS: The bioefficacy of mono-treated LLINs against pyrethroid-resistant field populations of An. gambiae varied by LLIN type and mosquito population, indicating that certain LLINs may be more suitable than others at particular sites. In contrast, the combination LLIN PermaNet 3.0 performed optimally against the four An. gambiae populations tested. The observed reduced susceptibility of malaria vectors to mono-treated LLINs is of particular concern, especially considering all nets were unused. With ongoing scale-up of insecticidal tools in the advent of increasing resistance, it is essential that those interventions with proven enhanced efficacy are given preference particularly in areas with high resistance. PMID- 23634801 TI - Construction of a chiral quaternary carbon center by catalytic asymmetric alkylation of 2-arylcyclohexanones under phase-transfer conditions. AB - In this paper, we present an asymmetric alkylation of modified 2 arylcyclohexanones that employs a novel chiral ammonium bromide as a phase transfer catalyst and an achiral auxiliary as a controller to improve the enantioselectivity to afford optically enriched products having a chiral quaternary carbon center. PMID- 23634800 TI - Clinical signs of barotrauma in golden perch, Macquaria ambigua (Richardson), and associated effects on post-release mortality and health. AB - This study assessed the effects of different retrieval depths (2, 10 or 20 m), surface intervals (none or 15 min) and release methods (untreated, vented or recompressed) on the incidence of external and internal clinical signs of barotrauma (ECSB and ICSB) and post-release mortality in golden perch, Macquaria ambigua (Richardson). Fish were assessed for ECSB before and after surface intervals and either monitored for mortality over 3 days in two deep cages or killed for internal examination. When all fish were left untreated, short-term mortality increased with retrieval depth from 0% and 4.2% among 2 and 10-m fish, respectively, to 19.2% among 20-m fish; while surface interval only affected the incidence of two ECSB (excess buoyancy and a prolapsed cloaca). Mortality was also greater among 20-m fish that were subjected to a 15-min surface interval and left untreated (22.2%) or vented (22.2%) than those that were recompressed (5.6%). Of the ECSB, only exophthalmia was associated with increased mortality, with half of the affected fish dying. However, many fish retrieved from 10 and 20 m also sustained numerous ICSB, including compressed gonads or vital organs and ruptured or collapsed, haemorrhaging swimbladders that remained deflated for up to 3 days after release. PMID- 23634803 TI - Endometriosis of the lung: report of a case and literature review. AB - This paper reports a case of endometriosis of the lung in a 29-year-old woman with long-term periodic catamenial hemoptysis. A chest computed tomography image obtained during menstruation revealed a radiographic opaque lesion in the lingular segment of the left superior lobe. During bronchoscopy, bleeding in the mucosa of the distal bronchus of the lingular segment of the left superior lobe was observed. Histopathology subsequent to an exploratory thoracotomy confirmed the diagnosis of endometriosis of the left lung. The 2-year follow-up after lingular lobectomy of the left superior lobe showed no recurrence or complications. PMID- 23634804 TI - Diagnosis, management and treatment of glucometabolic disorders emerging after kidney transplantation: a position statement from the Nordic Transplantation Societies. AB - After successful solid organ transplantation, new-onset diabetes (NODAT) is reported to develop in about 15-40% of the patients. The variation in incidence may partly depend on differences in the populations that have been studied and partly depend on the different definitions of NODAT that have been used. The diagnosis was often based on 'the use of insulin postoperatively', 'oral agents used', random glucose monitoring and a fasting glucose value between 7 and 13 mmol/l (126-234 mg/dl). Only few have used a 2-h glucose tolerance test performed before transplantation. There is a huge variation in the literature regarding risk factors for developing NODAT. They can be divided into factors related to glucose metabolism or to patient demographics and the latter into modifiable and nonmodifiable. Screening for risk factors should start early and be re-evaluated while being on the waitlist. Patients on the waiting list for renal transplantation and transplanted patients share many characteristics in having hyperglycaemia, disturbed insulin secretion and increased insulin resistance. We present guidelines for early risk factor assessment and a screening/treatment strategy for disturbed glucose metabolism, both before and after transplantation. The aim was to avoid the increased cardiovascular disease and mortality rates associated with NODAT. PMID- 23634802 TI - Rates of obstetric intervention during birth and selected maternal and perinatal outcomes for low risk women born in Australia compared to those born overseas. AB - BACKGROUND: There are mixed reports in the literature about obstetric intervention and maternal and neonatal outcomes for migrant women born in resource rich countries. The aim of this study was to compare the risk profile, rates of obstetric intervention and selected maternal and perinatal outcomes for low risk women born in Australia compared to those born overseas. METHOD: A population-based descriptive study was undertaken in NSW of all singleton births recorded in the NSW Midwives Data Collection between 2000-2008 (n=691,738). Risk profile, obstetric intervention rates and selected maternal and perinatal outcomes were examined. RESULTS: Women born in Australia were slightly younger (30 vs 31 years), less likely to be primiparous (41% vs 43%), three times more likely to smoke (18% vs 6%) and more likely to give birth in a private hospital (26% vs 18%) compared to women not born in Australia. Among the seven most common migrant groups to Australia, women born in Lebanon were the youngest, least likely to be primiparous and least likely to give birth in a private hospital. Hypertension was lowest amongst Vietnamese women (3%) and gestational diabetes highest amongst women born in China (14%). The highest caesarean section (31%), instrumental birth rates (16%) and episiotomy rates (32%) were seen in Indian women, along with the highest rates of babies <10th centile (22%) and <3rd centile (8%). Lebanese women had the highest rates of stillbirth (7.2/1000). Similar trends were found in the different migrant groups when only low risk women were included. CONCLUSION: The results suggest there are significant differences in risk profiles, obstetric intervention rates and maternal and neonatal outcomes between Australian-born and women born overseas and these differences are seen overall and in low risk populations. The finding that Indian women (the leading migrant group to Australia) have the lowest normal birth rate and high rates of low birth weight babies is concerning, and attention needs to be focused on why there are disparities in outcomes and on effective models of care that might improve outcomes for this population. PMID- 23634806 TI - First-principles study of spin-dependent transport through graphene/BNC/graphene structure. AB - : First-principles study on the electronic structure and transport property of the boron nitride sheet (BNC) structure, in which a triangular graphene flake surrounded by a hexagonal boron nitride sheet, is implemented. As the graphene flake becomes small and is more isolated by the boron nitride region, the magnetic ordering of the flake increases. When the BNC structure is connected to the graphene electrodes, the spin-polarized charge-density distribution appears only at the triangular graphene flake region, and the electronic structure of the graphene electrode is not spin polarized. First-principles transport calculation reveals that the transport property of the BNC structure is spin dependent. PMID- 23634807 TI - Pepino mosaic virus triple gene block protein 1 (TGBp1) interacts with and increases tomato catalase 1 activity to enhance virus accumulation. AB - Various plant factors are co-opted by virus elements (RNA, proteins) and have been shown to act in pathways affecting virus accumulation and plant defence. Here, an interaction between Pepino mosaic virus (PepMV) triple gene block protein 1 (TGBp1; p26) and tomato catalase 1 (CAT1), a crucial enzyme in the decomposition of toxic hydrogen peroxide (H2O2), was identified using the yeast two-hybrid assay, and confirmed via an in vitro pull-down assay and bimolecular fluorescent complementation (BiFC) in planta. Each protein was independently localized within loci in the cytoplasm and nuclei, sites at which their interaction had been visualized by BiFC. Following PepMV inoculation, CAT mRNA and protein levels in leaves were unaltered at 0, 3 and 6 days (locally) and 8 days (systemically) post-inoculation; however, leaf extracts from the last two time points contained increased CAT activity and lower H2O2 evels. Overexpression of PepMV p26 in vitro and in planta conferred the same effect, suggesting an additional involvement of TGBp1 in potexvirus pathogenesis. The accumulation of PepMV genomic and subgenomic RNAs and the expression of viral coat protein in noninoculated (systemic) leaves were reduced significantly in CAT-silenced plants. It is postulated that, during PepMV infection, a p26-CAT1 interaction increases H2O2 cavenging, thus acting as a negative regulator of plant defence mechanisms to promote PepMV infections. PMID- 23634808 TI - Identification of Plasmopara viticola genes potentially involved in pathogenesis on grapevine suggests new similarities between oomycetes and true fungi. AB - Plant diseases caused by fungi and oomycetes result in significant economic losses every year. Although phylogenetically distant, these organisms share many common features during infection. We identified genes in the oomycete Plasmopara viticola that are potentially involved in pathogenesis in grapevine by using fungal databases and degenerate primers. Fragments of P. viticola genes encoding NADH-ubiquinone oxidoreductase (PvNuo), laccase (PvLac), and invertase (PvInv) were obtained. PvNuo was overexpressed at 2 days postinoculation (dpi), during the development of the first hyphal structures and haustoria. PvLac was overexpressed at 5 dpi when genes related to pterostilbene biosynthesis were induced in grapevine. Transcript level for PvInv increased between 1 and 4 dpi before reaching a plateau. These results might suggest a finely tuned strategy of infection depending on nutrition and plant response. Phylogenetic analyses of PvNuo showed that P. viticola clustered with other oomycetes and was associated with brown algae and diatoms, forming a typical Straminipila clade. Based on the comparison of available sequences for laccases and invertases, the group formed by P. viticola and other oomycetes tended to be more closely related to Opisthokonta than to Straminipila. Convergent evolution or horizontal gene transfer could explain the presence of fungus-like genes in P. viticola. PMID- 23634805 TI - Choices choices: regulation of precursor differentiation during enteric nervous system development. AB - Background The enteric nervous system (ENS) is the largest subdivision of the peripheral nervous system and forms a complex circuit of neurons and glia that controls the function of the gastrointestinal (GI) tract. Within this circuit, there are multiple subtypes of neurons and glia. Appropriate differentiation of these various cell subtypes is vital for normal ENS and GI function. Studies of the pediatric disorder Hirschprung's Disease (HSCR) have provided a number of important insights into the mechanisms and molecules involved in ENS development; however, there are numerous other GI disorders that potentially may result from defects in development/differentiation of only a subset of ENS neurons or glia. Purpose Our understanding of the mechanisms and molecules involved in enteric nervous system differentiation is far from complete. Critically, it remains unclear at what point the fates of enteric neural crest cells (ENCCs) become committed to a specific subtype cell fate and how these cell fate choices are made. We will review our current understanding of ENS differentiation and highlight key questions that need to be addressed to gain a more complete understanding of this biological process. PMID- 23634809 TI - In vivo wear performance of highly cross-linked polyethylene vs. yttria stabilized zirconia and alumina stabilized zirconia at a mean seven-year follow up. AB - BACKGROUND: Zirconia was introduced as an alternative to alumina for use in the femoral head. The yttria stabilized zirconia material was improved by adding alumina. We evaluated highly cross-linked polyethylene wear performance of zirconia in total hip arthroplasty. The hypothesis was that alumina stabilized zirconia could decrease highly cross-linked polyethylene wear. METHODS: Highly cross-linked polyethylene wear was measured with a computerized method (PolyWare) in 91 hips. The steady-state wear rates were measured based on the radiographs from the first year postoperatively to the final follow-up and were compared between hips with yttria stabilized zirconia and alumina stabilized zirconia. RESULTS: The steady-state wear rate of highly cross-linked polyethylene against zirconia was 0.02 mm/year at a mean follow-up of 7 years. No significant difference was observed between groups with yttria stabilized zirconia and alumina stabilized zirconia. CONCLUSIONS: Addition of alumina to the zirconia material failed to show further reduction of highly cross-linked polyethylene wear and our hypothesis was not verified. PMID- 23634810 TI - Whole genome scanning and association mapping identified a significant association between growth and a SNP in the IFABP-a gene of the Asian seabass. AB - BACKGROUND: Aquaculture is the quickest growing sector in agriculture. However, QTL for important traits have been only identified in a few aquaculture species. We conducted QTL mapping for growth traits in an Asian seabass F(2) family with 359 individuals using 123 microsatellites and 22 SNPs, and performed association mapping in four populations with 881 individuals. RESULTS: Twelve and nine significant QTL, as well as 14 and 10 suggestive QTL were detected for growth traits at six and nine months post hatch, respectively. These QTL explained 0.9 12.0% of the phenotypic variance. For body weight, two QTL intervals at two stages were overlapped while the others were mapped onto different positions. The IFABP-a gene located in a significant QTL interval for growth on LG5 was cloned and characterized. A SNP in exon 3 of the gene was significantly associated with growth traits in different populations. CONCLUSIONS: The results of QTL mapping for growth traits suggest that growth at different stages was controlled by some common QTL and some different QTL. Positional candidate genes and association mapping suggest that the IFABP-a is a strong candidate gene for growth. Our data supply a basis for fine mapping QTL, marker-assisted selection and further detailed analysis of the functions of the IFABP-a gene in fish growth. PMID- 23634811 TI - Totally thoracoscopic surgery for the treatment of atrial septal defect without of the robotic Da Vinci surgical system. AB - BACKGROUND: More and more surgeons and patients focus on the minimally invasive surgical techniques in the 21st century. Totally thoracoscopic operation provides another minimal invasive surgical option for patients with ASD (atrial septal defect). In this study, we reported our experience of 61 patients with atrial septal defect who underwent totally thoracoscopic operation and discussed the feasibility and safety of the new technique. METHODS: From January 2010 to October 2012, 61 patients with atrial septal defect underwent totally thoracoscopic closure but not traditional median sternotomy surgery. We divided the 61 patients into two groups based on the operation sequence. The data of group A (the first 30 cases) and group B (the last 31 cases). The mean age of the patients was 35.1 +/- 12.8 years (range, 6.3 to 63.5 years), and mean weight was 52.7 +/- 11.9 kg (range, 30.5 to 80 kg). Mean size of the atrial septal defect was 16.8 +/- 11.3 mm (range, 13 to 39 mm) based on the description of the echocardiography. RESULTS: All patients underwent totally thoracoscopy successfully, 36 patients with pericardium patch and 25 patients were sutured directly. 7 patients underwent concomitant tricuspid valvuloplasty with Key technique. No death, reoperation or complete atrioventricular block occurred. The mean time of cardiopulmonary bypass was 68.5 +/- 19.1 min (range, 31.0 to 153.0 min), the mean time of aortic cross-clamp was 27.2 +/- 11.3 min (range, 0.0 to 80.0 min) and the mean time of operation was 149.8 +/- 35.7 min (range, 63.0 to 300.0 min). Postoperative mechanical ventilation averaged 4.9 +/- 2.5 hours (range, 3.5 to 12.6 hours), and the duration of intensive care unit stay 20.0 +/- 4.8 hours (range, 15.5 to 25 hours). The mean volume of blood drainage was 158 +/ 38 ml (range, 51 to 800 ml). No death, residual shunt, lung atelectasis or moderate tricuspid regurgitation was found at 3-month follow-up. CONCLUSION: The totally thoracoscopic operation is feasible and safe for patients with ASD, even with or without tricuspid regurgitation. This technique provides another minimal invasive surgical option for patients with atrial septal defect. PMID- 23634814 TI - Discussing goals of care for a delirious advanced cancer patient in the hospice setting. AB - In the United States, patient autonomy is generally considered the most important ethical principle; however, patients sometimes make decisions that are medically futile or in conflict with the principles of beneficence and nonmaleficence. Difficult issues are often compounded if the patient loses capacity and a surrogate must provide substituted judgments. Allowing autonomy free reign can sometimes be detrimental to patient care and contribute to family distress. Here, we describe the case of a terminally ill patient whose conflicting desires were to have "everything" done--including cardiopulmonary resuscitation--and to simultaneously avoid hospitalization and die peacefully at home. PMID- 23634815 TI - Revisiting the spectroscopy of the Bi3+ ion in oxide compounds. AB - A model is introduced to predict the energy of metal-to-metal charge-transfer transitions in oxide compounds containing Bi(3+) ions and d(0) or d(10) metals (M(n+)). The model takes into account the structural characteristics of the host lattices, the anion relaxation resulting from Bi(3+) doping, and the electronegativities and coordination numbers of the Bi(3+) and M(n+) ions in the compounds. It is shown, through a critical review of the archival literature, that this model provides new insights on the assignment of the luminescence spectra and the related interpretation of the spectroscopic behaviors. PMID- 23634812 TI - Platelet activation suppresses HIV-1 infection of T cells. AB - BACKGROUND: Platelets, anucleate cell fragments abundant in human blood, can capture HIV-1 and platelet counts have been associated with viral load and disease progression. However, the impact of platelets on HIV-1 infection of T cells is unclear. RESULTS: We found that platelets suppress HIV-1 spread in co cultured T cells in a concentration-dependent manner. Platelets containing granules inhibited HIV-1 spread in T cells more efficiently than degranulated platelets, indicating that the granule content might exert antiviral activity. Indeed, supernatants from activated and thus degranulated platelets suppressed HIV-1 infection. Infection was inhibited at the stage of host cell entry and inhibition was independent of the viral strain or coreceptor tropism. In contrast, blockade of HIV-2 and SIV entry was less efficient. The chemokine CXCL4, a major component of platelet granules, blocked HIV-1 entry and neutralization of CXCL4 in platelet supernatants largely abrogated their anti-HIV 1 activity. CONCLUSIONS: Release of CXCL4 by activated platelets inhibits HIV-1 infection of adjacent T cells at the stage of virus entry. The inhibitory activity of platelet-derived CXCL4 suggests a role of platelets in the defense against infection by HIV-1 and potentially other pathogens. PMID- 23634813 TI - Contribution of socioeconomic status to the risk of small for gestational age infants--a population-based study of 1,390,165 singleton live births in Finland. AB - BACKGROUND: Small for gestational age (SGA) infants are at increased risk of short- and long-term adverse outcomes. METHODS: Population-based case-control study using data derived from the Finnish Medical Birth Register for the years 1987-2010 (total population of singleton live births n = 1,390,165). The aim was to quantify the importance of risk factors for SGA and describe their contribution to socioeconomic status (SES) disparities in SGA by using logistic regression analysis. RESULTS: Of all the singleton live births (n = 1,390,165), 3.1% (n = 42,702) were classified as SGA (defined as below 2 standard deviations of the sex-specific population reference mean for gestational age). The risk of SGA was 11 - 24% higher in the lower SES groups compared to the highest SES group. Smoking alone made the largest contribution, explaining 41.7 - 50.9% of SES disparities in SGA. The risk of SGA was 2.3-fold and 7% higher among women who smoked or had quit smoking during the first trimester of pregnancy (adjusted odds ratio (aOR) 2.34, 95% CI 2.28-2.42 and aOR 1.07, 95% CI 1.00 - 1.15, respectively) compared with the non-smokers. CONCLUSIONS: SGA is substantially affected by SES. Smoking explained up to 50% of the difference in risk of SGA between high and low SES groups. Quitting smoking during the first trimester of pregnancy resulted in a 7% higher incidence of SGA comparable to that of non smoking women. Thus, interventional attempts to reduce smoking during pregnancy might help to decrease the socioeconomic gradient of SGA. PMID- 23634816 TI - New SNPs for population genetic analysis reveal possible cryptic speciation of eastern Australian sea mullet (Mugil cephalus). AB - Sustainable management of sea mullet (Mugil cephalus) fisheries needs to account for recent observations of regional-scale differentiation. Population genetic analysis is sought to assess the situation of this ecologically and economically important fish species in eastern Australian waters. Here, we report (i) new population genetic markers [single nucleotide polymorphisms (SNPs) and potential microsatellites], (ii) first estimates of spatial genetic differentiation and (iii) prospective power tests for designing more comprehensive studies. Six DNA samples from three sampling regions (North Queensland, South Queensland and central New South Wales) on the eastern coast of Australia were used to prepare restriction site associated DNA (RAD) tag libraries from genomic DNA digested with EcoRI and MseI. A pooled sample of regional RAD tag libraries was sequenced using the Roche GS-FLX Titanium platform. A total of 172,837 raw reads (17.4 Mbp) were retrieved, 95,500 of which were used to discover 1267 SNPs and 1417 microsatellites. A subset of 161 SNPs was validated based on 63 additional DNA samples genotyped using the Sequenom MassArray (iPLEX Gold chemistry). Altogether 92 SNPs (57%) were confirmed, with 40% of these marking fixed variants between northern and southern sampling regions. Our preliminary findings indicate a multispecies fishery stock of M. cephalus in eastern Australian waters, but suggest that strong genetic differentiation occurs north of major fishing grounds. Low potential differentiation within major fishing grounds (e.g. FST = 0.0025) can be resolved with a likely power >=67% by using standard sample sizes of 50 and validated subsets of available markers. PMID- 23634818 TI - The role of N-doped multiwall carbon nanotubes in achieving highly efficient polymer bulk heterojunction solar cells. AB - This paper reports an improved solar cell performance of 8.6% by incorporation of N-doped multiwall carbon nanotubes (N-MCNTs) into BHJ solar cells composed of PTB7 and PC71BM. It was demonstrated for the first time that incorporation of N MCNTs leads to not only increased nanocrystallite sizes but also smaller phase separated domain sizes of both PTB7 copolymers and PC71BM from X-ray scattering study. The results show that N-MCNTs could serve as both exciton dissociation centers and charge transfer channels. The enhanced charge dissociation probabilities and effective charge carrier lifetime in the active layer material offer evidence to support the conclusion that N-MCNTs facilitated charge separation and transport. PMID- 23634819 TI - Total thyroidectomy versus bilateral subtotal thyroidectomy in patients with Graves' diseases: a meta-analysis of randomized clinical trials. PMID- 23634817 TI - Synthetic anti-lipopolysaccharide peptides and hepatitis C virus infection. AB - INTRODUCTION: Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma. Although antiviral therapy has been markedly improved by the licensing of direct-acting antivirals, safety, resistance, high costs and difficult-to-treat patients remain important challenges. AREAS COVERED: This article focuses and comments on the recent development of synthetic anti lipopolysaccharide peptides (SALPs) which bind to highly sulfated glycosaminoglycan/heparan sulfate (HS) on cell surface. HS serves as a primary docking site for several viruses to their respective host cells before the viruses interact with their cell surface receptor(s). In vitro studies have shown that SALPs inhibit entry of HCV without cell toxicity. EXPERT OPINION: SALPs prevent viral infection in cell culture model systems. Treatment studies of established HCV infection in cell culture models as well as proof-of-concept and safety studies in animal models are needed to evaluate their potential for drug development. The mechanism of action of SALPs as entry inhibitors suggests a potential application for HCV-infected patients to prevent reinfection of the liver graft in liver transplantation. Potential limitations may include high doses to obtain an antiviral effect and a target which is widely expressed and has a key function in cell physiology. PMID- 23634820 TI - Regional variation in caesarean deliveries in Germany and its causes. AB - BACKGROUND: Determinants of regional variation in caesarean sections can contribute explanations for the observed overall increasing trend of caesarean sections. We assessed which mechanism explains the higher rate of caesarean sections in the former West than East Germany: a more liberal use of caesarean sections in the case of relative indications or more common caesarean sections without indications. METHODS: We used a health insurance database from all regions of Germany with approximately 14 million insured individuals (about 17% of the total population in Germany). We selected women who gave birth in the years 2004 to 2006 and identified indications for caesarean section on the basis of hospital diagnoses in 30 days around birth. We classified pregnancies into three groups: those with strong indications for caesarean section (based on classification of absolute indications recommended by the Unmet Obstetrics Need network), those with moderate indications (other indications increasing the probability of caesarean section) and those with no indications. We investigated the percentage of caesarean sections among all births, presence of strong or moderate indications in all pregnancies, the probability of caesarean sections in the presence of indications and the fraction of caesarean sections attributable to strong, moderate and no indications. RESULTS: In total, 294,841 births from 2004-2006 were included in the analysis. In the former West Germany, 30% births occurred by caesarean section, while in the former East Germany the caesarean section rate was 22%. Proportions of pregnancies with strong and moderate indications for caesarean section were similar in both regions. For strong indications the probability of caesarean section was similar in East and West Germany, but the probability of caesarean section among women with moderate indications was substantially higher in the former West Germany. Caesarean sections were also more common among women with no indications in the former West (8%) than in the former East (4-5%). The higher probability of caesarean section in the case of strong or moderate indications in the former West than in the East explained 87% of the difference between section rates in these two regions, while caesarean sections without indications contributed to only 13% of the difference observed. CONCLUSIONS: The observed difference between caesarean section rates in the former East and West Germany was most likely due to different medical practice in handling relative indications. PMID- 23634823 TI - Synthetic control of FePtM nanorods (M = Cu, Ni) to enhance the oxygen reduction reaction. AB - To further enhance the catalytic activity and durability of nanocatalysts for the oxygen reduction reaction (ORR), we synthesized a new class of 20 nm * 2 nm ternary alloy FePtM (M = Cu, Ni) nanorods (NRs) with controlled compositions. Supported on carbon support and treated with acetic acid as well as electrochemical etching, these FePtM NRs were converted into core/shell FePtM/Pt NRs. These core/shell NRs, especially FePtCu/Pt NRs, exhibited much improved ORR activity and durability. The Fe10Pt75Cu15 NRs showed a mass current densities of 1.034 A/mgPt at 512 mV vs Ag/AgCl and 0.222 A/mgPt at 557 mV vs Ag/AgCl, which are much higher than those for a commercial Pt catalyst (0.138 and 0.035 A/mgPt, respectively). Our controlled synthesis provides a general approach to core/shell NRs with enhanced catalysis for the ORR or other chemical reactions. PMID- 23634822 TI - Therapeutic vaccination using cationic liposome-adjuvanted HIV type 1 peptides representing HLA-supertype-restricted subdominant T cell epitopes: safety, immunogenicity, and feasibility in Guinea-Bissau. AB - We have designed a therapeutic HIV-1 vaccine concept based on peptides together with the adjuvant CAF01. Peptides represented 15 HLA-supertype-restricted subdominant and conserved CD8 T cell epitopes and three CD4 T-helper cell epitopes. In this phase I clinical trial, safety and immunogenicity were assessed in untreated HIV-1-infected individuals in Guinea-Bissau, West Africa. Twenty three HIV-1-infected individuals were randomized to receive placebo (n=5) or vaccine (n=18). Safety was appraised by clinical follow-up combined with monitoring of biochemistry, hematology, CD4 T cell counts, and HIV-1 viral loads. T cell immunogenicity was monitored longitudinally by interferon (IFN)-gamma ELISpot. New vaccine-specific T cell responses were induced in 6/14 vaccinees for whom ELISpot data were valid. CD4 T cell counts and viral loads were stable. The study shows that therapeutic immunization is feasible and safe in Guinea-Bissau and that it is possible to redirect T cell immunity with CAF01-adjuvanted HIV-1 peptide vaccine during untreated HIV-1 infection in some patients. However, relatively few preexisting and vaccine-induced HIV-1 T cell responses to CD8 T cell epitopes were detected against HIV-1 using IFN-gamma ELISpot in this chronically infected African population. PMID- 23634824 TI - A new cultivation-independent tool for fast and reliable detection of Mycobacterium marinum. AB - The Mycobacterium marinum group (MMG) is a class of mycobacteria that includes M. marinum, the cause of chronic systemic infections in fish. This species occasionally causes granulomatous skin lesions in humans. Other members of MMG are mycolactone-producing mycobacteria (MPM; M. ulcerans, M. shottsii and M. pseudoshottsii). The cultivation-independent approach presented in this study brings a fast and reliable alternative to classically used cultivation methods. The developed triplex erp/IS2404 qPCR assay is based on a primary species specific erp detection, which allows enumeration of MMG in analysed samples, and secondary IS2404 detection is suitable for the differentiation of M. marinum from MPM. The detection of M. marinum in clinical specimens and in artificially contaminated tissue samples has proven its applicability for diagnostic purposes. PMID- 23634821 TI - Regulation of epileptiform activity by two distinct subtypes of extrasynaptic GABAA receptors. AB - BACKGROUND: GABAergic deficit is one of the major mechanisms underlying epileptic seizures. Previous studies have mainly focused on alterations of synaptic GABAergic inhibition during epileptogenesis. Recent work suggested that tonic inhibition may also play a role in regulating epileptogenesis, but the underlying mechanism is not well understood. RESULTS: We employed molecular and pharmacological tools to investigate the role of tonic inhibition during epileptogenesis both in vitro and in vivo. We overexpressed two distinct subtypes of extrasynaptic GABAA receptors, alpha5beta3gamma2 and alpha6beta3delta receptors, in cultured hippocampal neurons. We demonstrated that overexpression of both alpha5beta3gamma2 and alpha6beta3delta receptors enhanced tonic inhibition and reduced epileptiform activity in vitro. We then showed that injection of THIP (5 MUM), a selective agonist for extrasynaptic GABAA receptors at low concentration, into rat brain also suppressed epileptiform burst activity and behavioral seizures in vivo. Mechanistically, we discovered that low concentration of THIP had no effect on GABAergic synaptic transmission and did not affect the basal level of action potentials, but significantly inhibited high frequency neuronal activity induced by epileptogenic agents. CONCLUSIONS: Our studies suggest that extrasynaptic GABAA receptors play an important role in controlling hyperexcitatory activity, such as that during epileptogenesis, but a less prominent role in modulating a low level of basal activity. We propose that tonic inhibition may play a greater role under pathological conditions than in physiological conditions in terms of modulating neural network activity. PMID- 23634825 TI - Regulatory role of ubiquitin in eukaryotic DNA translesion synthesis. AB - Although often associated with proteasome-mediated protein degradation, ubiquitin plays essential nondegradative roles in a myriad of cellular processes, including chromatin dynamics, membrane trafficking, innate immunity, and DNA damage response. The recent progress in understanding DNA translesion synthesis (TLS), an important branch of DNA damage response, has largely been stimulated by the finding that ubiquitination of an essential nuclear protein, proliferating cell nuclear antigen (PCNA), controls precisely how eukaryotic cells respond to DNA damage. Despite the remarkable activity of the TLS polymerases in synthesizing past the damaged nucleotides, they are intrinsically error-prone on the normal DNA template. Therefore, a stringent regulation of the TLS polymerases is essential for the faithful replication of the DNA genome. Here we review the structure and function of the Y-family TLS polymerases and their interactions with ubiquitin and monoubiquitinated PCNA (Ub-PCNA). Driven by the need for monoubiquitinated PCNA in a sufficient quantity and purity, researchers developed both chemical and enzymatic methods for PCNA monoubiquitination, which have propelled our understanding of the structure of Ub-PCNA by X-ray crystallography and small-angle X-ray scattering. Together with studies using a reconstituted polymerase switching assay, these investigations revealed a surprising conformational flexibility of ubiquitin as a modifier on PCNA. Although the molecular details of TLS in cells still need to be deciphered, two working models, polymerase switching and postreplicative gap filling, have been proposed and tested in both in vitro and cellular systems. Evidence for both models is discussed herein. Compared to PCNA monoubiquitination, polyubiquitination of PCNA in DNA damage response is much less well understood and will be the subject of a future investigation. Given the close connection of DNA damage response and anticancer therapy, an in-depth understanding of the eukaryotic translesion synthesis and its regulation by ubiquitin will likely provide new opportunities for therapeutic intervention. PMID- 23634827 TI - A comparison of the conformational distributions of the achiral symmetric liquid crystal dimer CB7CB in the achiral nematic and chiral twist-bend nematic phases. AB - The sets of residual dipolar couplings between carbon and hydrogen nuclei obtained from the proton-encoded (13)C 2D NMR experiment are used to investigate the conformational changes which occur when the achiral symmetric liquid crystal dimer CB7CB changes from the achiral nematic to the chiral twist-bend nematic phase. It is found that these changes are a consequence of the chirality of the twist-bend nematic phase, rather than being the driving force for the stability of this phase. PMID- 23634826 TI - Modeling Alzheimer's disease with non-transgenic rat models. AB - Alzheimer's disease (AD), for which there is no cure, is the most common form of dementia in the elderly. Despite tremendous efforts by the scientific community, the AD drug development pipeline remains extremely limited. Animal models of disease are a cornerstone of any drug development program and should be as relevant as possible to the disease, recapitulating the disease phenotype with high fidelity, to meaningfully contribute to the development of a successful therapeutic agent. Over the past two decades, transgenic models of AD based on the known genetic origins of familial AD have significantly contributed to our understanding of the molecular mechanisms involved in the onset and progression of the disease. These models were extensively used in AD drug development. The numerous reported failures of new treatments for AD in clinical trials indicate that the use of genetic models of AD may not represent the complete picture of AD in humans and that other types of animal models relevant to the sporadic form of the disease, which represents 95% of AD cases, should be developed. In this review, we will discuss the evolution of non-transgenic rat models of AD and how these models may open new avenues for drug development. PMID- 23634828 TI - Changes in the innervation of the mouse internal anal sphincter during aging. AB - BACKGROUND: The innervation of the mouse internal anal sphincter (IAS) has been little studied, and how it changes during aging has not previously been investigated. The aim of this study was therefore to characterize the distribution and density of subtypes of nerve fibers in the IAS and underlying mucosa in 3-, 12- to 13-, 18- and 24- to 25-month-old male C57BL/6 mice. METHODS: Nerve fibers were immunolabeled with antibodies against protein gene product 9.5 (PGP9.5), neuronal nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), and calretinin (CR). Immunoreactivity in nerve fibers in the circular muscle and mucosa was quantified using Image J software. KEY RESULTS: In young adult (3 month) mice, nNOS-immunoreactive (IR) nerve fibers were densely distributed in the circular muscle, but relatively few in the mucosa; VIP-IR nerve fibers were abundant in the circular muscle and common in the mucosa; SP-IR nerve fibers were common in circular muscle and mucosa; CGRP- and CR-IR nerve fibers were dense in mucosa and sparse in circular muscle. The density of PGP9.5 immunoreactivity (IRY) was not significantly reduced with age, but a significant reduction in nNOS IRY and SP-IRY with age was found in the IAS circular muscle. Neuronal nitric oxide synthase-, VIP-, and SP-IRY in the anal mucosa were significantly reduced with age. CGRP-IRY in both circular muscle and mucosa was increased in 18-month old animals. CONCLUSIONS & INFERENCES: The density of immunoreactivity of markers for some types of IAS nerve fibers decreases during aging, which may contribute to age-related ano-rectal dysfunction. PMID- 23634829 TI - Essentially exact ground-state calculations by superpositions of nonorthogonal Slater determinants. AB - An essentially exact ground-state calculation algorithm for few-electron systems based on superposition of nonorthogonal Slater determinants (SDs) is described, and its convergence properties to ground states are examined. A linear combination of SDs is adopted as many-electron wave functions, and all one electron wave functions are updated by employing linearly independent multiple correction vectors on the basis of the variational principle. The improvement of the convergence performance to the ground state given by the multi-direction search is shown through comparisons with the conventional steepest descent method. The accuracy and applicability of the proposed scheme are also demonstrated by calculations of the potential energy curves of few-electron molecular systems, compared with the conventional quantum chemistry calculation techniques. PMID- 23634830 TI - Increase of chronic low back pain prevalence in a medium-sized city of southern Brazil. AB - BACKGROUND: Chronic low back pain (CLBP) is a highly disabling morbidity with high social, economic and individual effects. Demographic, occupational and behavioral changes that took place in Brazil over the last decade are related with an increasing burden of chronic conditions. Despite these changes, comparison studies on CLBP prevalence and associated factors, over time are scarce in the literature in general, and unknown in Brazil. The present study compared the CLBP prevalence in a medium sized city in Brazil between the years 2002 and 2010 and examined factors associated with prevalence in 2010. METHODS: Two cross-sectional studies with similar methodology were conducted in a medium sized city in southern Brazil, in 2002 and 2010. 3182 individuals were interviewed in the first study and 2732 in the second one, all adults aged twenty years or more. Those who reported pain for seven weeks or more in the last three months in the lumbar region where considered cases of CLBP. RESULTS: The CLBP prevalence increased from 4.2% to 9.6% in 8 years. In most of the studied subgroups the CLBP prevalence has at least doubled and the increase was even larger among younger individuals with more years of education and higher economic status. CONCLUSIONS: Increase in CLBP prevalence is worrisome because it is a condition responsible for substantial social impact, besides being an important source of demand for health services. PMID- 23634832 TI - Genetic and environmental structure of individual differences in hand, foot, and ear preferences: a twin study. AB - Recent studies with large sample size have reported moderate heritability of hand preference. However, little is known about genetic and environmental factors for lateral preference. We examined the genetic and environmental factors for hand, foot, and ear preferences using a twin design study. A lateral preference questionnaire was administered to twin participants (N=956). Phenotypic correlation matrices of lateral preferences were computed for monozygotic and dizygotic twin pairs, and were subjected to Cholesky decomposition to compute additive genetic and unique environmental correlation matrices. Promax rotation factor analysis of each genetic and environmental correlation matrix yielded six genetic and four environmental factors. Factor-loading patterns for these factors indicated that hand and foot lateral activities were affected by different genetic factors. By contrast, each of the four environmental factors was mainly associated with hand, foot, or ear preference. These results suggest that the genetic structure for lateral preference may be more complex than the environmental structure. In particular, hand preference may be multidimensional in terms of genetic factors. PMID- 23634831 TI - Product feedback regulation implicated in translational control of the Trypanosoma brucei S-adenosylmethionine decarboxylase regulatory subunit prozyme. AB - Human African sleeping sickness (HAT) is caused by the parasitic protozoan Trypanosoma brucei. Polyamine biosynthesis is an important drug target in the treatment of HAT. Previously we showed that trypanosomatid S-adenosylmethionine decarboxylase (AdoMetDC), a key enzyme for biosynthesis of the polyamine spermidine, is activated by heterodimer formation with an inactive paralogue termed prozyme. Furthermore, prozyme protein levels were regulated in response to reduced AdoMetDC activity. Herein we show that T. brucei encodes three prozyme transcripts. The 3'UTRs of these transcripts were mapped and chloramphenicol acetyltransferase (CAT) reporter constructs were used to identify a 1.2 kb region that contained a 3'UTR prozyme regulatory element sufficient to upregulate CAT protein levels (but not RNA) upon AdoMetDC inhibition, supporting the hypothesis that prozyme expression is regulated translationally. To gain insight into trans acting factors, genetic rescue of AdoMetDC RNAi knock-down lines with human AdoMetDC was performed leading to rescue of the cell growth block, and restoration of prozyme protein to wild-type levels. Metabolite analysis showed that prozyme protein levels were inversely proportional to intracellular levels of decarboxylated AdoMet (dcAdoMet). These data suggest that prozyme translation may be regulated by dcAdoMet, a metabolite not previously identified to play a regulatory role. PMID- 23634834 TI - Extramedullary haematopoiesis presented as intrathoracic tumour in a patient with alpha-thalassaemia. AB - The authors report a case of extramedullary haematopoiesis (EMH) presenting as an intrathoracic tumour in a patient with alpha-thalassaemia. CT scan and MRI of the chest were obtained and followed by tumour excision. Compared to beta thalassaemia, only two cases of EMH in patients with alpha-thalassaemia have been described in the literature. A possible reason for this disparity is discussed. PMID- 23634836 TI - Characterization of the LOV1-mediated, victorin-induced, cell-death response with virus-induced gene silencing. AB - Victoria blight, caused by Cochliobolus victoriae, is a disease originally described on oat and recapitulated on Arabidopsis. C. victoriae pathogenesis depends upon production of the toxin victorin. In oat, victorin sensitivity is conferred by the Vb gene, which is genetically inseparable from the Pc2 resistance gene. Concurrently, in Arabidopsis, sensitivity is conferred by the LOCUS ORCHESTRATING VICTORIN EFFECTS1 (LOV1) gene. LOV1 encodes a nucleotide binding site leucine-rich repeat protein, a type of protein commonly associated with disease resistance, and LOV1 "guards" the defense thioredoxin, TRX-h5. Expression of LOV1 and TRX-h5 in Nicotiana benthamiana is sufficient to confer victorin sensitivity. Virus-induced gene silencing was used to characterize victorin-induced cell death in N. benthamiana. We determined that SGT1 is required for sensitivity and involved in LOV1 protein accumulation. We screened a normalized cDNA library and identified six genes that, when silenced, suppressed LOV1-mediated, victorin-induced cell death and cell death induced by expression of the closely related RPP8 resistance gene: a mitochondrial phosphate transporter, glycolate oxidase, glutamine synthetase, glyceraldehyde 3-phosphate dehydrogenase, and the P- and T-protein of the glycine decarboxylase complex. Silencing the latter four also inhibited cell death and disease resistance mediated by the PTO resistance gene. Together, these results provide evidence that the victorin response mediated by LOV1 is a defense response. PMID- 23634833 TI - Genetic analysis of the roles of agaA, agaI, and agaS genes in the N-acetyl-D galactosamine and D-galactosamine catabolic pathways in Escherichia coli strains O157:H7 and C. AB - BACKGROUND: The catabolic pathways of N-acetyl-D-galactosamine (Aga) and D galactosamine (Gam) in E. coli were proposed from bioinformatic analysis of the aga/gam regulon in E. coli K-12 and later from studies using E. coli C. Of the thirteen genes in this cluster, the roles of agaA, agaI, and agaS predicted to code for Aga-6-P-deacetylase, Gam-6-P deaminase/isomerase, and ketose-aldolase isomerase, respectively, have not been experimentally tested. Here we study their roles in Aga and Gam utilization in E. coli O157:H7 and in E. coli C. RESULTS: Knockout mutants in agaA, agaI, and agaS were constructed to test their roles in Aga and Gam utilization. Knockout mutants in the N-acetylglucosamine (GlcNAc) pathway genes nagA and nagB coding for GlcNAc-6-P deacetylase and glucosamine-6-P deaminase/isomerase, respectively, and double knockout mutants DeltaagaA DeltanagA and ?agaI ?nagB were also constructed to investigate if there is any interplay of these enzymes between the Aga/Gam and the GlcNAc pathways. It is shown that Aga utilization was unaffected in DeltaagaA mutants but DeltaagaA DeltanagA mutants were blocked in Aga and GlcNAc utilization. E. coli C DeltanagA could not grow on GlcNAc but could grow when the aga/gam regulon was constitutively expressed. Complementation of DeltaagaA DeltanagA mutants with either agaA or nagA resulted in growth on both Aga and GlcNAc. It was also found that DeltaagaI, DeltanagB, and ?agaI DeltanagB mutants were unaffected in utilization of Aga and Gam. Importantly, DeltaagaS mutants were blocked in Aga and Gam utilization. Expression analysis of relevant genes in these strains with different genetic backgrounds by real time RT-PCR supported these observations. CONCLUSIONS: Aga utilization was not affected in DeltaagaA mutants because nagA was expressed and substituted for agaA. Complementation of DeltaagaA DeltanagA mutants with either agaA or nagA also showed that both agaA and nagA can substitute for each other. The ?agaI, ?nagB, and ?agaI ?nagB mutants were not affected in Aga and Gam utilization indicating that neither agaI nor nagB is involved in the deamination and isomerization of Gam-6-P. We propose that agaS codes for Gam-6-P deaminase/isomerase in the Aga/Gam pathway. PMID- 23634838 TI - Rice yellow stunt rhabdovirus protein 6 suppresses systemic RNA silencing by blocking RDR6-mediated secondary siRNA synthesis. AB - The P6 protein of Rice yellow stunt rhabdovirus (RYSV) is a virion structural protein that can be phosphorylated in vitro. However its exact function remains elusive. We found that P6 enhanced the virulence of Potato virus X (PVX) in Nicotiana benthamiana and N. tabacum plants, suggesting that it might function as a suppressor of RNA silencing. We examined the mechanism of P6-mediated silencing suppression by transiently expressing P6 in both N. benthamiana leaves and rice protoplasts. Our results showed that P6 could repress the production of secondary siRNAs and inhibit systemic green fluorescent protein RNA silencing but did not interfere with local RNA silencing in N. benthamiana plants or in rice protoplasts. Intriguingly, P6 and RDR6 had overlapping subcellular localization and P6 bound both rice and Arabidopsis RDR6 in vivo. Furthermore, transgenic rice plants expressing P6 showed enhanced susceptibility to infection by Rice stripe virus. Hence, we propose that P6 is part of the RYSV's counter-defense machinery against the plant RNA silencing system and plays a role mainly in affecting RDR6 mediated secondary siRNA synthesis. Our work provides a new perspective on how a plant-infecting nucleorhabdovirus may counteract host RNA silencing-mediated antiviral defense. PMID- 23634837 TI - Guard cell purification and RNA isolation suitable for high-throughput transcriptional analysis of cell-type responses to biotic stresses. AB - Stomata, micro-pores on the leaf surface, are formed by a pair of guard cells. In addition to controlling water loss and gas exchange between the plant and the environment, these cells act as immunity gates to prevent pathogen invasion of the plant apoplast. Here, we report a brief procedure to obtain highly pure guard cell preparations using conditions that preserve the guard cell transcriptome as much as possible for a robust high-throughput RNA sequence analysis. The advantages of this procedure included i) substantial shortening of the time required for obtaining high yield of >97% pure guard cell protoplasts (GCP), ii) extraction of enough high quality RNA for direct sequencing, and iii) limited RNA decay during sample manipulation. Gene expression analysis by reverse transcription quantitative polymerase chain reaction revealed that wound-related genes were not induced during release of guard cells from leaves. To validate our approach, we performed a high-throughput deep-sequencing of guard cell transcriptome (RNA-seq). A total of 18,994 nuclear-encoded transcripts were detected, which expanded the transcriptome by 70%. The optimized GCP isolation and RNA extraction protocols are simple, reproducible, and fast, allowing the discovery of genes and regulatory networks inherent to the guard cells under various stresses. PMID- 23634839 TI - Expression of alpha-DIOXYGENASE 1 in tomato and Arabidopsis contributes to plant defenses against aphids. AB - Plant alpha-dioxygenases (alpha-DOX) are fatty acid-hydroperoxidases that contribute to the synthesis of oxylipins, a diverse group of compounds primarily generated through oxidation of linoleic (LA) and linolenic acid (LNA). Oxylipins are implicated in plant signaling against biotic and abiotic stresses. We report here that the potato aphid (Macrosiphum euphorbiae) induces Slalpha-DOX1 but not Slalpha-DOX2 expression in tomato (Solanum lycopersicum). Slalpha-DOX1 upregulation by aphids does not require either jasmonic acid (JA) or salicylic acid (SA) accumulation, since tomato mutants deficient in JA (spr2, acx1) or SA accumulation (NahG) still show Slalpha-DOX1 induction. Virus-induced gene silencing of Slalpha-DOX1 enhanced aphid population growth in wild-type (WT) plants, revealing that Slalpha-DOX1 contributes to basal resistance to aphids. Moreover, an even higher percent increase in aphid numbers occurred when Slalpha DOX1 was silenced in spr2, a mutant line characterized by elevated LA levels, decreased LNA, and enhanced aphid resistance as compared with WT. These results suggest that aphid reproduction is influenced by oxylipins synthesized from LA by Slalpha-DOX1. In agreement with our experiments in tomato, two independent alpha dox1 T-DNA insertion mutant lines in Arabidopsis thaliana also showed increased susceptibility to the green peach aphid (Myzus persicae), indicating that the role alpha-DOX is conserved in other plant-aphid interactions. PMID- 23634840 TI - The bacterial superoxide dismutase and glutathione reductase are crucial for endophytic colonization of rice roots by Gluconacetobacter diazotrophicus PAL5. AB - Gluconacetobacter diazotrophicus is an aerobic diazotrophic plant-growth promoting bacterium isolated from different gramineous plants. We showed that reactive oxygen species (ROS) were produced at early stages of rice root colonization, a typical plant defense response against pathogens. The transcription of the pathogen-related-10 gene of the jasmonic acid (JA) pathway but not of the PR-1 gene of the salicylic acid pathway was activated by the endophytic colonization of rice roots by G. diazotrophicus strain PAL5. Quantitative polymerase chain reaction analyses showed that, at early stages of colonization, the bacteria upregulated the transcript levels of ROS-detoxifying genes such as superoxide dismutase (SOD) and glutathione reductase (GR). To proof the role of ROS-scavenging enzymes in the colonization and interaction process, transposon insertion mutants of the SOD and GR genes of strain PAL5 were constructed. The SOD and GR mutants were unable to efficiently colonize the roots, indicated by the decrease of tightly root-associated bacterial cell counts and endophytic colonization and by fluorescence in situ hybridization analysis. Interestingly, the mutants did not induce the PR-10 of the JA-pathway, probably due to the inability of endophytic colonization. Thus, ROS-scavenging enzymes of G. diazotrophicus strain PAL5 play an important role in the endophytic colonization of rice plants. PMID- 23634841 TI - Medicago truncatula esn1 defines a genetic locus involved in nodule senescence and symbiotic nitrogen fixation. AB - Symbiotic interaction between Medicago truncatula and Sinorhizobium meliloti results in the formation on the host roots of new organs, nodules, in which biological nitrogen fixation takes place. In infected cells, rhizobia enclosed in a plant-derived membrane, the symbiosome membrane, differentiate to nitrogen fixing bacteroids. The symbiosome membrane serves as an interface for metabolite and signal exchanges between the host cells and endosymbionts. At some point during symbiosis, symbiosomes and symbiotic cells are disintegrated, resulting in nodule senescence. The regulatory mechanisms that underlie nodule senescence are not fully understood. Using a forward genetics approach, we have uncovered the early senescent nodule 1 (esn1) mutant from an M. truncatula fast neutron-induced mutant collection. Nodules on esn1 roots are spherically shaped, ineffective in nitrogen fixation, and senesce early. Atypical among fixation defective mutants isolated thus far, bacteroid differentiation and expression of nifH, Leghemoglobin, and DNF1 genes are not affected in esn1 nodules, supporting the idea that a process downstream of bacteroid differentiation and nitrogenase gene expression is affected in the esn1 mutant. Expression analysis shows that marker genes involved in senescence, macronutrient degradation, and remobilization are greatly upregulated during nodule development in the esn1 mutant, consistent with a role of ESN1 in nodule senescence and symbiotic nitrogen fixation. PMID- 23634842 TI - A simple millifluidic benchtop reactor system for the high-throughput synthesis and functionalization of gold nanoparticles with different sizes and shapes. AB - Despite the continuing interest in the applications of functionalized nanomaterials, the controlled and reproducible synthesis of many important functionalized nanoparticles (NPs) above the milligram scale continues to be a significant challenge. The synthesis of functionalized NPs in automated reactors provides a viable approach to circumvent some of the shortcomings of traditional nanomaterial batch syntheses, providing superior control over reagent addition, improved reproducibility, the opportunity to interface real-time product monitoring, and a viable high-throughput synthetic approach. Here, we demonstrate the construction and operation of a simple millifluidic reactor assembled entirely from commercially available components found in almost any chemical laboratory. This reactor facilitates the aqueous gram-scale synthesis of a variety of functionalized gold nanoparticles, including the synthesis of gold nanospheres with tightly controlled core diameters and gold nanorods with controlled aspect ratios between 1.5 and 4.0. The absolute dimensions (i.e., the transverse diameter) of gold nanorods synthesized within the reactor can also be tailored to produce different gold nanorod shapes, including "small" gold nanorods and gold nanocubes. In addition, we show that the reactor can interface with existing purification and monitoring techniques in order to enable the high throughput functionalization/purification of gold nanorods and real-time monitoring of gold nanoparticle products for quality control. We anticipate that this millifluidic reactor will provide the blueprint for a versatile and portable approach to the gram-scale synthesis of monodisperse, hydrophilically functionalized metal NPs that can be realized in almost any chemistry research laboratory. PMID- 23634844 TI - Reversible sliding in networks of nanowires. AB - This work demonstrates that metal nanowires in a percolating network can reversibly slide across one another. Reversible sliding allows networks of metal nanowires to maintain electrical contact while being stretched to strains greater than the fracture strain for individual nanowires. This phenomenon was demonstrated by using networks of nanowires as compliant electrodes for a dielectric elastomer actuator. Reversible nanowire sliding enabled actuation to a maximum area strain of 200% and repetitive cycling of the actuator to an area strain of 25% over 150 times. During actuation, the transmittance of the network increased 4.5 times, from 13% to 58%. Compared to carbon-based compliant electrodes, networks of metal nanowires can actuate across a broader range of optical transmittance. The widely tunable transmittance of nanowire-based actuators allows for their use as a light valve. PMID- 23634845 TI - SP-Designer: a user-friendly program for designing species-specific primer pairs from DNA sequence alignments. AB - SP-Designer is an open-source program providing a user-friendly tool for the design of specific PCR primer pairs from a DNA sequence alignment containing sequences from various taxa. SP-Designer selects PCR primer pairs for the amplification of DNA from a target species on the basis of several criteria: (i) primer specificity, as assessed by interspecific sequence polymorphism in the annealing regions, (ii) the biochemical characteristics of the primers and (iii) the intended PCR conditions. SP-Designer generates tables, detailing the primer pair and PCR characteristics, and a FASTA file locating the primer sequences in the original sequence alignment. SP-Designer is Windows-compatible and freely available from http://www2.sophia.inra.fr/urih/sophia_mart/sp_designer/info_sp_designer.php. PMID- 23634843 TI - Extranuclear ERalpha is associated with regression of T47D PKCalpha overexpressing, tamoxifen-resistant breast cancer. AB - BACKGROUND: Prior to the introduction of tamoxifen, high dose estradiol was used to treat breast cancer patients with similar efficacy as tamoxifen, albeit with some undesirable side effects. There is renewed interest to utilize estradiol to treat endocrine resistant breast cancers, especially since findings from several preclinical models and clinical trials indicate that estradiol may be a rational second-line therapy in patients exhibiting resistance to tamoxifen and/or aromatase inhibitors. We and others reported that breast cancer patients bearing protein kinase C alpha (PKCalpha)- expressing tumors exhibit endocrine resistance and tumor aggressiveness. Our T47D:A18/PKCalpha preclinical model is tamoxifen resistant, hormone-independent, yet is inhibited by 17beta-estradiol (E2) in vivo. We previously reported that E2-induced T47D:A18/PKCalpha tumor regression requires extranuclear ERalpha and interaction with the extracellular matrix. METHODS: T47D:A18/PKCalpha cells were grown in vitro using two-dimensional (2D) cell culture, three-dimensional (3D) Matrigel and in vivo by establishing xenografts in athymic mice. Immunofluoresence confocal microscopy and co localization were applied to determine estrogen receptor alpha (ERalpha) subcellular localization. Co-immunoprecipitation and western blot were used to examine interaction of ERalpha with caveolin-1. RESULTS: We report that although T47D:A18/PKCalpha cells are cross-resistant to raloxifene in cell culture and in Matrigel, raloxifene induces regression of tamoxifen-resistant tumors. ERalpha rapidly translocates to extranuclear sites during T47D:A18/PKCalpha tumor regression in response to both raloxifene and E2, whereas ERalpha is primarily localized in the nucleus in proliferating tumors. E2 treatment induced complete tumor regression whereas cessation of raloxifene treatment resulted in tumor regrowth accompanied by re-localization of ERalpha to the nucleus. T47D:A18/neo tumors that do not overexpress PKCalpha maintain ERalpha in the nucleus during tamoxifen-mediated regression. An association between ERalpha and caveolin-1 increases in tumors regressing in response to E2. CONCLUSIONS: Extranuclear ERalpha plays a role in the regression of PKCalpha-overexpressing tamoxifen resistant tumors. These studies underline the unique role of extranuclear ERalpha in E2- and raloxifene-induced tumor regression that may have implications for treatment of endocrine-resistant PKCalpha-expressing tumors encountered in the clinic. PMID- 23634846 TI - Redox-active behavior of the [{Ti(eta(5)-C5Me5)(MU-NH)}3(MU3-N)] metalloligand. AB - Treatment of [Cl3Y{(MU3-NH)3Ti3(eta(5)-C5Me5)3(MU3-N)}] with [K(C5Me5)] in toluene gives C10Me10 and the paramagnetic [K(MU-Cl)3Y{(MU3-NH)3Ti3(eta(5) C5Me5)3(MU3-N)}] (3) derivative. Crystallization of 3 in pyridine affords the potassium-free [Cl2(py)2Y{(MU3-NH)3Ti3(eta(5)-C5Me5)3(MU3-N)}] (4) complex. Whereas the reaction of 3 with 1 equiv of 18-crown-6 leads to the molecular complex [(18-crown-6)K(MU-Cl)3Y{(MU3-NH)3Ti3(eta(5)-C5Me5)3(MU3-N)}] (5), the analogous treatment of 3 with cryptand-222 affords the ion pair [K(crypt 222)][Cl3Y{(MU3-NH)3Ti3(eta(5)-C5Me5)3(MU3-N)}] (6). The X-ray crystal structures of 4, 5, and 6 have been determined. Density functional theory (DFT) calculations have elucidated the electronic structure of these species, which should be regarded as containing trivalent Y bonded to the {(MU3-NH)3Ti3(eta(5)-C5Me5)3(MU3 N)} metalloligand radical anion. PMID- 23634847 TI - Chemotactic activity of channel catfish, Ictalurus punctatus (Rafinesque), recombinant cyclophilin A. PMID- 23634848 TI - 5-hydroxymethylcytosine and its potential roles in development and cancer. AB - Only a few years ago it was demonstrated that mammalian DNA contains oxidized forms of 5-methylcytosine (5mC). The base 5-hydroxymethylcytosine (5hmC) is the most abundant of these oxidation products and is referred to as the sixth DNA base. 5hmC is produced from 5mC in an enzymatic pathway involving three 5mC oxidases, Ten-eleven translocation (TET)1, TET2, and TET3. The biological role of 5hmC is still unclear. Current models propose that 5hmC is an intermediate base in an active or passive DNA demethylation process that operates during important reprogramming phases of mammalian development. Tumors originating in various human tissues have strongly depleted levels of 5hmC. Apparently, 5hmC cannot be maintained in proliferating cells. Furthermore, mutations in the TET2 gene are commonly observed in human myeloid malignancies. Since TET proteins and many lysine demethylases require 2-oxoglutarate as a cofactor, aberrations in cofactor biochemical pathways, including mutations in isocitrate dehydrogenase (IDH), may affect levels of 5hmC and 5mC in certain types of tumors, either directly or indirectly. We discuss current data and models of the function of 5hmC in general, with special emphasis on its role in mechanisms of development and cancer. PMID- 23634850 TI - Distance dependence of intrahelix Ru(II)* to Os(II) polypyridyl excited-state energy transfer in oligoproline assemblies. AB - Energy transfer between the metal-to-ligand charge transfer (MLCT) excited states of [Pra [M(II)(bpy)2(4-Me-4'(-N(H)CO)bpy)](PF6)2 units ([Pra(M(II)bpy2(mbpy)](2+): M(II) = Ru(II) or Os(II), bpy = 2,2'-bipyridine, mbpy = 4'-methyl-2,2'-bipyridine-4-carboxamido, Pra = 4-M(II)-L-proline) linked covalently to oligoproline assemblies in room temperature acetonitrile occurs on the picosecond-nanosecond time scale and has been time-resolved by transient emission measurements. Three derivatized oligoprolines, [CH3-CO-Pro6 Pra[Os(II)(bpy)2(mbpy)](2+)-Pro2-Pra[Ru(II)(bpy)2(mbpy)](2+)-Pro2 Pra[Ru(II)(bpy)2(mbpy)](2+)-Pro6-Glu-NH2](6+) (ORR-2, Pro = L-proline and Glu = glutamic acid); [CH3-CO-Pro6-Pra[Os(II)(bpy)2(mbpy)](2+)-Pro3 Pra[Ru(II)(bpy)2(mbpy)](2+)-Pro3-Pra[Ru(II)(bpy)2(mbpy)](2+)-Pro6-Glu-NH2](6+) (ORR-3); and CH3-CO-Pro6-Pra[Os(II)(bpy)2(mbpy)](2+)-Pro5 Pra[Ru(II)(bpy)2(mbpy)](2+)-Pro5-Pra[Ru(II)(bpy)2(mbpy)](2+)Pro6-Glu2-NH2](6+) (ORR-5), were prepared by using solid-phase peptide synthesis. Given the helical nature of the resulting assemblies and the nature of the synthesis, composition, length, and loading pattern are precisely controlled in the assemblies. In acetonitrile, they adopt a proline I helical secondary structure, confirmed by circular dichroism, in which the appended chromophores are ordered in well defined orientations and internuclear separation distances although helix formation for ORR-2 is incomplete. Quantitative comparison of oligoproline ground state absorption and steady-state emission spectra to those for the constituents, [Boc-Pra[M(II)(bpy)2(mbpy)](2+)-OH](PF6)2 (Boc = N(alpha)-(1,1 dimethylethoxycarbonyl), shows that following Ru(II) light absorption, Ru(II)* undergoes facile energy transfer resulting in sensitization of Os(II). Sensitization efficiencies are 93% for ORR-2, 77% for ORR-3, and 73% for ORR-5. Picosecond-resolved emission measurements reveal complex, coupled dynamics that arise from excited-state decay and kinetically competitive -Ru(II)*-Ru(II)- -> Ru(II)-Ru(II)*- energy transfer migration/exchange and downhill -Ru(II)*-Os(II) > -Ru(II)-Os(II)* energy transfer. These processes were modeled simultaneously to extract rate constants for Ru(II)* -> Ru(II) energy-transfer migration, k(Ru* Ru), and Ru(II)* -> Os(II) energy transfer, k(Ru*-Os). For ORR-2, k(Ru*-Ru) = 2.9 * 10(7) s(-1) and k(Ru*-Os) = 3.4 * 10(8) s(-1). For ORR-3, k(Ru*-Ru) = 1.2 * 10(7) s(-1) and k(Ru*-Os) = 1.3 * 10(8) s(-1). For ORR-5, k(Ru*-Ru) = 3.6 * 10(6) s(-1) and k(Ru*-Os) = 5.8 * 10(7) s(-1), all in acetonitrile at 22 degrees C. The data were analyzed by assuming Dexter energy transfer with the Franck-Condon factors arising from intramolecular structural and medium changes evaluated by use of an emission spectral fitting procedure. Fits of the data to the Dexter mechanism were consistent with the predicted distance dependence of energy transfer. PMID- 23634851 TI - Modulation of carcinogen-metabolizing cytochromes P450 by phytochemicals in humans. AB - INTRODUCTION: Cytochrome P450 (CYP) families 1 - 3, besides oxidizing environmental and dietary chemicals, leading to their elimination, catalyze the bioactivation of exogenous as well as endogenous carcinogens. Phytochemicals, particularly those which are active food components, were shown to be able to affect specific CYP expression and/or activity in animal models and in human in vitro systems. Human intervention studies involving healthy volunteers were also performed. This review describes human CYP modulation by naturally occurring phytochemicals which can not only affect carcinogen metabolism in humans, but also change the drug response. AREAS COVERED: The authors present an overview of carcinogens metabolizing human CYP modulation in different model systems as well as studies on human dietary intervention. Furthermore, the authors provide examples of the phytochemicals that affect CYP expression and activity. EXPERT OPINION: CYP, which are involved in carcinogen activation, can metabolize a range of substrates and inducing CYP by one substrate may also increase the metabolism of another. The ultimate proof of the efficacy of CYP modulation strategy for chemoprevention may be provided by clinical trials involving risk populations, which are difficult to perform. The new human-like models are highly desired for the study of modulation of carcinogen-metabolizing CYP. PMID- 23634849 TI - Genetic variation in TLR or NFkappaB pathways and the risk of breast cancer: a case-control study. AB - BACKGROUND: Toll-like receptors (TLRs) and the transcription factor nuclear factor-kappaB (NFkappaB) are important in inflammation and cancer. METHODS: We examined the association between breast cancer risk and 233 tagging single nucleotide polymorphisms within 31 candidate genes involved in TLR or NFkappaB pathways. This population-based study in the Seattle area included 845 invasive breast cancer cases, diagnosed between 1997 and 1999, and 807 controls aged 65 79. RESULTS: Variant alleles in four genes were associated with breast cancer risk based on gene-level tests: MAP3K1, MMP9, TANK, and TLR9. These results were similar when the risk of breast cancer was examined within ductal and luminal subtypes. Subsequent exploratory pathway analyses using the GRASS algorithm found no associations for genes in TLR or NFkappaB pathways. Using publicly available CGEMS GWAS data to validate significant findings (N = 1,145 cases, N = 1,142 controls), rs889312 near MAP3K1 was confirmed to be associated with breast cancer risk (P = 0.04, OR 1.15, 95% CI 1.01-1.30). Further, two SNPs in TANK that were significant in our data, rs17705608 (P = 0.05) and rs7309 (P = 0.04), had similar risk estimates in the CGEMS data (rs17705608 OR 0.83, 95% CI 0.72-0.96; CGEMS OR 0.90, 95% CI 0.80-1.01 and rs7309 OR 0.83, 95% CI 0.73-0.95; CGEMS OR 0.91, 95% CI 0.81-1.02). CONCLUSIONS: Our findings suggest plausible associations between breast cancer risk and genes in TLR or NFkappaB pathways. Given the few suggestive associations in our data and the compelling biologic rationale for an association between genetic variation in these pathways and breast cancer risk, further studies are warranted that examine these effects. PMID- 23634852 TI - Process and impact as the Journal moves forward. PMID- 23634853 TI - Humanizing the mouse: in defense of murine models of critical illness. PMID- 23634854 TI - Chronic obstructive pulmonary disease genomics: yesterday, discovering population biomarkers; tomorrow, defining disease clusters. PMID- 23634856 TI - N95 respirators or surgical masks to protect healthcare workers against respiratory infections: are we there yet? PMID- 23634855 TI - Chronic cough in chronic obstructive pulmonary disease: time for listening? PMID- 23634857 TI - Metabolism, metabolome, and metabolomics in intensive care: is it time to move beyond monitoring of glucose and lactate? PMID- 23634858 TI - Severe respiratory syncytial virus bronchiolitis in underserved populations and the association with unhealthy diets during pregnancy. PMID- 23634859 TI - Update in cystic fibrosis 2012. PMID- 23634860 TI - Update in diffuse parenchymal lung disease 2012. PMID- 23634861 TI - An official American Thoracic Society clinical practice guideline: exercise induced bronchoconstriction. AB - BACKGROUND: Exercise-induced bronchoconstriction (EIB) describes acute airway narrowing that occurs as a result of exercise. EIB occurs in a substantial proportion of patients with asthma, but may also occur in individuals without known asthma. METHODS: To provide clinicians with practical guidance, a multidisciplinary panel of stakeholders was convened to review the pathogenesis of EIB and to develop evidence-based guidelines for the diagnosis and treatment of EIB. The evidence was appraised and recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: Recommendations for the treatment of EIB were developed. The quality of evidence supporting the recommendations was variable, ranging from low to high. A strong recommendation was made for using a short-acting beta(2)-agonist before exercise in all patients with EIB. For patients who continue to have symptoms of EIB despite the administration of a short-acting beta(2)-agonist before exercise, strong recommendations were made for a daily inhaled corticosteroid, a daily leukotriene receptor antagonist, or a mast cell stabilizing agent before exercise. CONCLUSIONS: The recommendations in this Guideline reflect the currently available evidence. New clinical research data will necessitate a revision and update in the future. PMID- 23634862 TI - Abnormal liver uptake of (99m)Tc-macroaggregated albumin in a patient with superior vena cava syndrome. PMID- 23634863 TI - Prognostic value of functional decline in middle-aged smokers. PMID- 23634864 TI - Reply: Prognostic value of functional decline in middle-aged smokers. PMID- 23634865 TI - A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis: a hidden subgroup? PMID- 23634866 TI - Reply: A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis: a hidden subgroup? PMID- 23634867 TI - Coughing up urine: urinoptysis? PMID- 23634869 TI - Exploiting high pressures to generate porosity, polymorphism, and lattice expansion in the nonporous molecular framework Zn(CN)2. AB - Systematic exploration of the molecular framework material Zn(CN)2 at high pressure has revealed several distinct series of transitions leading to five new phases: four crystalline and one amorphous. The structures of the new crystalline phases have been resolved through ab initio structural determination, combining charge flipping and direct space methods, based on synchrotron powder diffraction data. The specific transition activated under pressure depends principally on the pressure-transmitting fluid used. Without fluid or in large molecule fluids (e.g., isopropanol, ethanol, or fluorinert), the high-pressure behavior intrinsic to Zn(CN)2 is observed; the doubly interpenetrated diamondoid framework structure transforms to a distorted, orthorhombic polymorph, Zn(CN)2-II (Pbca) at ~1.50 1.58 GPa with asymmetric displacement of the bridging CN ligand and reorientation of the Zn(C/N)4 tetrahedra. In small molecule fluids (e.g., water, methanol, methanol-ethanol-water), the nonporous interpenetrated Zn(CN)2 framework can undergo reconstructive transitions to porous, non-interpenetrated polymorphs with different topologies: diamondoid (dia-Zn(CN)2, Fd3m, P(trans) ~ 1.2 GPa), londaleite (lon-Zn(CN)2, P6(3)/mmc, P(trans) ~ 0.9 GPa), and pyrite-like (pyr Zn(CN)2, Pa3, P(trans) ~ 1.8 GPa). Remarkably, these pressure-induced transitions are associated with near 2-fold volume expansions. While an increase in volume with pressure is counterintuitive, the resulting new phases contain large fluid filled pores, such that the combined solid + fluid volume is reduced and the inefficiencies in space filling by the interpenetrated parent phase are eliminated. That both dia-Zn(CN)2 and lon-Zn(CN)2 phases were retained upon release to ambient pressure demonstrates the potential for application of hydrostatic pressures to interpenetrated framework systems as a novel means to generate new porous materials. PMID- 23634868 TI - Bubble-like air opacities in the mediastinum. PMID- 23634872 TI - Interface properties of SiOxNy layer on Si prepared by atmospheric-pressure plasma oxidation-nitridation. AB - SiOxNy films with a low nitrogen concentration (< 4%) have been prepared on Si substrates at 400 degrees C by atmospheric-pressure plasma oxidation-nitridation process using O2 and N2 as gaseous precursors diluted in He. Interface properties of SiOxNy films have been investigated by analyzing high-frequency and quasistatic capacitance-voltage characteristics of metal-oxide-semiconductor capacitors. It is found that addition of N into the oxide increases both interface state density (Dit) and positive fixed charge density (Qf). After forming gas anneal, Dit decreases largely with decreasing N2/O2 flow ratio from 1 to 0.01 while the change of Qf is insignificant. These results suggest that low N2/O2 flow ratio is a key parameter to achieve a low Dit and relatively high Qf, which is effective for field effect passivation of n-type Si surfaces. PMID- 23634871 TI - Shoulder pain in primary care: diagnostic accuracy of clinical examination tests for non-traumatic acromioclavicular joint pain. AB - BACKGROUND: Despite numerous methodological flaws in previous study designs and the lack of validation in primary care populations, clinical tests for identifying acromioclavicular joint (ACJ) pain are widely utilised without concern for such issues. The aim of this study was to estimate the diagnostic accuracy of traditional ACJ tests and to compare their accuracy with other clinical examination features for identifying a predominant ACJ pain source in a primary care cohort. METHODS: Consecutive patients with shoulder pain were recruited prospectively from primary health care clinics. Following a standardised clinical examination and diagnostic injection into the subacromial bursa, all participants received a fluoroscopically guided diagnostic block of 1% lidocaine hydrochloride (XylocaineTM) into the ACJ. Diagnostic accuracy statistics including sensitivity, specificity, predictive values, positive and negative likelihood ratios (LR+ and LR-) were calculated for traditional ACJ tests (Active Compression/O'Brien's test, cross-body adduction, localised ACJ tenderness and Hawkins-Kennedy test), and for individual and combinations of clinical examination variables that were associated with a positive anaesthetic response (PAR) (P<=0.05) defined as 80% or more reduction in post-injection pain intensity during provocative clinical tests. RESULTS: Twenty two of 153 participants (14%) reported an 80% PAR. None of the traditional ACJ tests were associated with an 80% PAR (P<0.05) and combinations of traditional tests were not able to discriminate between a PAR and a negative anaesthetic response (AUC 0.507; 95% CI: 0.366, 0.647; P>0.05). Five clinical examination variables (repetitive mechanism of pain onset, no referred pain below the elbow, thickened or swollen ACJ, no symptom provocation during passive glenohumeral abduction and external rotation) were associated with an 80% PAR (P<0.05) and demonstrated an ability to accurately discriminate between an PAR and NAR (AUC 0.791; 95% CI 0.702, 0.880; P<0.001). Less than two positive clinical features resulted in 96% sensitivity (95% CI 0.78, 0.99) and a LR- 0.09 (95% CI 0.02, 0.41) and four positive clinical features resulted in 95% specificity (95% CI 0.90, 0.98) and a LR+ of 4.98 (95% CI 1.69, 13.84). CONCLUSIONS: In this cohort of primary care patients with predominantly subacute or chronic ACJ pain of non-traumatic onset, traditional ACJ tests were of limited diagnostic value. Combinations of other history and physical examination findings were able to more accurately identify injection-confirmed ACJ pain in this cohort. PMID- 23634870 TI - Morphological demonstration of a vagal inhibitory pathway to the lower esophageal sphincter via nitrergic neurons in the rat esophagus. AB - BACKGROUND: The involvement of vagal parasympathetic efferents in esophageal myenteric neurons in vagal inhibitory pathways to the lower esophageal sphincter (LES) is not clear. Thus, this study was performed to demonstrate morphologically the presence of vagal inhibitory pathways to the LES via esophageal neurons. METHODS: Fast Blue (FB) was injected into the LES of Wistar rats, and 3 days after injection, the animals were subjected to electrical stimulation of the vagus nerve. The esophagus was processed for immunohistochemistry for Fos that was an immediate-early gene as a marker of neuronal activity, nitric oxide synthase (NOS), vasoactive intestinal polypeptide (VIP) and choline acetyltransferase (ChAT). The immunoreactivities were then compared with the FB labeling in esophageal neurons. KEY RESULTS: Fast Blue-labeled neurons were observed within an esophageal area of 30 mm oral to the LES, with the highest frequency in the esophagus just above the LES. Most of the FB-labeled neurons were positive for NOS and VIP, but a few for ChAT. Following vagal-electrical stimulation, one fourth of the FB-labeled neurons presented nuclei expressing Fos and most of these Fos/FB neurons were NOS-positive. CONCLUSIONS & INFERENCES: A majority of the FB-labeled esophageal neurons appeared to be descending motor neurons innervating the LES. Moreover, the colocalization of VIP and NOS in most of the LES-projecting neurons suggests that VIP and NO released from these neurons induce LES relaxation, and the innervation of the vagal efferents to the LES-projecting esophageal neurons in the distal esophagus implies a vagal inhibitory pathway responsible for LES relaxation. PMID- 23634873 TI - Bacterial DNA polymerases participate in oligonucleotide recombination. AB - Synthetic single-strand oligonucleotides (oligos) with homology to genomic DNA have proved to be highly effective for constructing designed mutations in targeted genomes, a process referred to as recombineering. The cellular functions important for this type of homologous recombination have yet to be determined. Towards this end, we have identified Escherichia coli functions that process the recombining oligo and affect bacteriophage lambda Red-mediated oligo recombination. To determine the nature of oligo processing during recombination, each oligo contained multiple nucleotide changes: a single base change allowing recombinant selection, and silent changes serving as genetic markers to determine the extent of oligo processing during the recombination. Such oligos were often not incorporated into the host chromosome intact; many were partially degraded in the process of recombination. The position and number of these silent nucleotide changes within the oligo strongly affect both oligo processing and recombination frequency. Exonucleases, especially those associated with DNA Polymerases I and III, affect inheritance of the silent nucleotide changes in the oligos. We demonstrate for the first time that the major DNA polymerases (Pol I and Pol III) and DNA ligase are directly involved with oligo recombination. PMID- 23634874 TI - Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant. AB - BACKGROUND: We studied a family including two half-siblings, sharing the same mother, affected by slowly progressive, adult-onset neurological syndromes. In spite of the diversity of the clinical features, characterized by a mild movement disorder with cognitive impairment in the elder patient, and severe motor-neuron disease (MND) in her half-brother, the brain Magnetic Resonance Imaging (MRI) features were compatible with adult-onset Alexander's disease (AOAD), suggesting different expression of the same, genetically determined, condition. METHODS: Since mutations in the alpha isoform of glial fibrillary acidic protein, GFAP alpha, the only cause so far known of AOAD, were excluded, we applied exome Next Generation Sequencing (NGS) to identify gene variants, which were then functionally validated by molecular characterization of recombinant and patient derived cells. RESULTS: Exome-NGS revealed a mutation in a previously neglected GFAP isoform, GFAP-epsilon, which disrupts the GFAP-associated filamentous cytoskeletal meshwork of astrocytoma cells. To shed light on the different clinical features in the two patients, we sought for variants in other genes. The male patient had a mutation, absent in his half-sister, in X-linked histone deacetylase 6, a candidate MND susceptibility gene. CONCLUSIONS: Exome-NGS is an unbiased approach that not only helps identify new disease genes, but may also contribute to elucidate phenotypic expression. PMID- 23634875 TI - Macrophage environment turns otherwise MccJ25-resistant Salmonella into sensitive. AB - BACKGROUND: Microcin J25 (MccJ25) is a plasmid-encoded antibiotic peptide produced by Escherichia coli (E. coli). MccJ25 enters into the sensitive E. coli strains by the outer membrane receptor FhuA and the inner membrane proteins TonB, ExbB, ExbD and SbmA. The resistance of Salmonella enterica serovar Typhimurium (S. Typhimurium) to MccJ25 is attributed to the inability of its FhuA protein to incorporate the antibiotic into the cell. RESULTS: In this work we demonstrate that S. Typhimurium becomes notably susceptible to MccJ25 when replicating within macrophages. In order to determine the possible cause of this phenomenon, we studied the sensitivity of S. Typhimurium to MccJ25 at conditions resembling those of the internal macrophage environment, such as low pH, low magnesium and iron deprivation. We observed that the strain was only sensitive to the antibiotic at low pH, leading us to attribute the bacterial sensitization to this condition. A MccJ25-resistant E. coli strain in which fhuA is deleted was also inhibited by the antibiotic at low pH. Then, we could assume that the MccJ25 sensitivity change observed in both E. coli fhuA and S. Typhimurium is mediated by a MccJ25 uptake independent of the FhuA receptor. Moreover, low pH incubation also sensitized S. Typhimurium to the hydrophobic antibiotic novobiocin, which does not affect enteric bacteria viability because it is unable to penetrate the bacterial outer membrane. This observation supports our hypothesis about low pH producing a modification in the bacterial membrane permeability that allows an unspecific MccJ25 uptake. On the other hand, MccJ25 inhibited S. Typhimurium when cells were preincubated in acidic pH medium and then treated at neutral pH with the antibiotic. CONCLUSIONS: Our results suggest that acidic condition does not alter MccJ25 hydrophobicity but irreversibly modifies bacterial membrane permeability. This would allow an unspecific antibiotic uptake into the cell.From our data it is possible to infer that intracellular pathogenic strains, which are in vitro resistant to MccJ25, could become susceptible ones in vivo. Therefore, the MccJ25 action spectrum would be broader than what in vitro experiments indicate. PMID- 23634876 TI - Successful use of rituximab in platelet transfusion refractoriness in a multi transfused patient with myelodysplastic syndrome. AB - A 61-year-old man with newly diagnosed INT-1 risk myelodysplastic syndrome- refractory cytopenia with multilineage dysplasia (MDS-RCMD) was not responsive to treatment, such as androgen, thalidomide, granulocyte--colony stimulating factor (G-CSF) combined with erythropoietin (EPO), interleukin-11 (IL-11) and thrombopoietin (TPO), and became transfusion dependent. Due to repeated blood transfusions, he developed platelet transfusion refractoriness (PTR) to platelets from cross-matched donors as well as random donors. Anti-HLA class I antibodies were positive with enzyme-linked immunosorbent assay; however, HLA-compatible platelet products were unavailable. PTR was unresponsive to high-dose immunoglobulin and plasma exchange. The patient was then treated with rituximab 375 mg/m(2) on days 1 and 8, and 100 mg total dose on days 15 and 22. Already after the first dose of rituximab, the patient was able to received successful platelet transfusion from all donors. Therefore rituximab may be considered as a potential therapy for PTR. PMID- 23634877 TI - In vivo effect of statins on the expression of the HIV co-receptors CCR5 and CXCR4. AB - BACKGROUND: During the HIV-1 replication cycle, several molecules including chemokine receptors and cholesterol are crucial, and are therefore potential targets for therapeutic intervention. Indeed statins, compounds that inhibit cellular synthesis of cholesterol and have anti-inflammatory and immunomodulatory properties were shown to inhibit HIV-1 infection by R5 tropic strains but not by X4 strains in vitro, mainly by altering the chemokine receptor/ligands axes. Therefore, the objective of this study was to characterize in vivo, the capacity of statins to modulate in HIV seronegative and chronically HIV-1-infected adults the expression of CCR5 and CXCR4, of their ligands and the tropism of circulating HIV-1 strains. METHODS: Samples from asymptomatic HIV-1-infected adults enrolled in a clinical trial aimed at evaluating the antiretroviral activity of lovastatin were used to evaluate in vivo the modulation by lovastatin of CCR5, CXCR4, their ligands, and the shift in plasma viral tropism over one year of intervention. In addition, ten HIV negative adults received a daily oral dose of 40 mg of lovastatin or 20 mg of atorvastatin; seven other HIV negative individuals who received no treatment were followed as controls. The frequency and phenotype of immune cells were determined by flow-cytometry; mRNA levels of chemokine receptors and their ligands were determined by real-time PCR. Viral tropism was determined by PCR and sequencing, applying the clonal and clinical model of analyses. RESULTS: Our study shows that long-term administration of lovastatin in HIV-infected individuals does not induce a shift in viral tropism, or induce a significant modulation of CCR5 and CXCR4 on immune cells in HIV-infected patients. Similar results were found in HIV seronegative control subjects, treated with lovastatin or atorvastatin, but a significant increase in CCL3 and CCL4 transcription was observed in these individuals. CONCLUSIONS: These findings suggest that long-term administration of statins at therapeutic doses, does not significantly affect the expression of HIV-1 co-receptors or of their ligands. In addition it is important to point out that based on the results obtained, therapeutic administration of statins in HIV-infected patients with lipid disorders is safe in terms of selecting X4 strains. PMID- 23634878 TI - Dissociative chemisorption of methane on Pt(110)-(1*2): effects of lattice motion on reactions at step edges. AB - The dissociative chemisorption of methane on Pt(110)-(1*2) is examined, with a focus on how the reaction dynamics are modified by the motion of the lattice atoms. The barriers to dissociation are found to be lowest at the step edges. The relaxation of the lattice in the presence of the dissociating molecule is found to be far more complicated than on the smooth surfaces of Pt and Ni. The dissociative sticking probabilities are computed using a full-dimensional treatment based on the reaction path Hamiltonian that includes all 15 molecular degrees of freedom and the effects of lattice motion. The potential energy surface and all parameters in our model are computed from first principles. The effects of lattice motion are strong, but not significantly larger than for dissociation on smoother surfaces. Vibrational excitation of the molecule can significantly enhance reactivity, though this effect varies from mode to mode. Agreement with recent experiments with regard to the variation of reactivity with translational energy and substrate temperature is good. PMID- 23634880 TI - Biodegradation of iron oxide nanocubes: high-resolution in situ monitoring. AB - The long-term fate of nanomaterials in biological environment represents a critical matter, which determines environmental effects and potential risks for human health. Predicting these risks requires understanding of nanoparticle transformations, persistence, and degradation, some issues somehow ignored so far. Safe by design, inorganic nanostructures are being envisioned for therapy, yet fundamental principles of their processing in biological systems, change in physical properties, and in situ degradability have not been thoroughly assessed. Here we report the longitudinal visualization of iron oxide nanocube transformations inflicted by the intracellular-like environment. Structural degradation of individual nanocubes with two different surface coatings (amphiphilic polymer shell and polyethylene glycol ligand molecules) was monitored at the atomic scale with aberration-corrected high-resolution transmission electron microscopy. Our results suggest that the polymer coating controls surface reactivity and that availability and access of chelating agents to the crystal surface govern the degradation rate. This in situ study of single nanocube degradation was compared to intracellular transformations observed in mice over 14 days after intravenous injection, revealing the role of nanoparticle clustering, intracellular sorting within degradation compartments, and iron transfer and recycling into ferritin storage proteins. Our approach reduces the gap between in situ nanoscale observations in mimicking biological environments and in vivo real tracking of nanoparticle fate. PMID- 23634881 TI - Electrical bistability around room temperature in an unprecedented one dimensional coordination magnetic polymer. AB - The synthesis, crystal structure, and physical properties of an unprecedented one dimensional (1D) coordination polymer containing [Fe2(S2C6H2Cl2)4](2-) entities bridged by dicationic [K2(MU-H2O)2(THF)4](2+) units are described. The magnetic properties show that the title compound presents pairwise Fe-Fe antiferromagnetic interactions that can be well reproduced with a S = 1/2 dimer model with an exchange coupling, J = -23 cm(-1). The electrical conductivity measurements show that the title compound is a semiconductor with an activation energy of about 290 meV and two different transitions, both with large hysteresis of about 60 and 30 K at 260-320 K and 350-380 K, respectively. These two transitions are assumed to be due to slight structural changes in the cation-anion interactions. Differential Scanning Calorimetry confirms the presence of both transitions. This compound represents the first sample of a coordination polymer showing electrical bistability. PMID- 23634879 TI - The N-terminal region of two-pore channel 1 regulates trafficking and activation by NAADP. AB - TPCs (two-pore channels) are NAADP (nicotinic acid-adenine dinucleotide phosphate)-sensitive Ca2+-permeable ion channels expressed on acidic organelles. In the present study we show that deletion of the N-terminal region redirects TPC1 to the ER (endoplasmic reticulum). The introduction of fluorophores at the N terminus of TPC1 does not affect its subcellular location, but does reversibly abolish NAADP sensitivity. Our results reveal a dual role for the N-terminus in localization and function of TPC1. PMID- 23634882 TI - Functionalized nanoscale micelles improve drug delivery for cancer therapy in vitro and in vivo. AB - Poor penetration of therapeutic drugs into tumors is a major challenge in anticancer therapy, especially in solid tumors, leading to reduced therapeutic efficacy in vivo. In the study, we used a new tumor-penetrating peptide, CRGDK, to conjugate onto the surface of doxorubicin encapsulated nanoscale micelles. The CRGDK peptide triggered specific binding to neuropilin-1, leading to enhanced cellular uptake and cytotoxicity in vitro and highly accumulation and penetration in the tumors in vivo. PMID- 23634883 TI - Flaxseed oil and alpha-lipoic acid combination ameliorates hepatic oxidative stress and lipid accumulation in comparison to lard. AB - BACKGROUND: Intake of high-fat diet is associated with increased non-alcoholic fatty liver disease (NAFLD). Hepatic lipid accumulation and oxidative stress are key pathophysiological mechanisms in NAFLD. Both flaxseed oil (FO) and alpha lipoic acid (LA) exert potential benefit to NAFLD. The aim of this study was to determine the effect of the combination of FO and LA on hepatic lipid accumulation and oxidative stress in rats induced by high-fat diet. METHODS: LA was dissolved in flaxseed oil to a final concentration of 8 g/kg (FO + LA). The rodent diet contained 20% fat. One-fifth of the fat was soybean oil and the others were lard (control group), or 75% lard and 25% FO + LA (L-FO + LA group), or 50% lard and 50% FO + LA (M-FO + LA group), or FO + LA (H-FO + LA group). Male Sprague-Dawley rats were fed for 10 weeks and then killed for liver collection. RESULTS: Intake of high-fat lard caused a significant hepatic steatosis. Replacement with FO + LA was effective in reducing steatosis as well as total triglyceride and total cholesterol contents in liver. The combination of FO and LA also significantly elevated hepatic antioxidant defense capacities, as evaluated by the remarkable increase in the activities of SOD, CAT and GPx as well as the level of GSH, and the significant decline in lipid peroxidation. CONCLUSION: The combination of FO and LA may contribute to prevent fatty livers such as NAFLD by ameliorating hepatic lipid accumulation and oxidative stress. PMID- 23634884 TI - Factor Xa inhibitor attenuates leukocyte adhesion and thrombus formation in an experimental mouse model of the metabolic syndrome. AB - AIMS: In a model of acute inflammation, Factor Xa inhibitors have been reported not only to suppress the coagulation system but also to exert anti-inflammatory effects. However, this has not been experimentally demonstrated in a model of chronic inflammation. Recent studies demonstrated that vascular inflammation in the metabolic syndrome plays major roles in the development of thrombotic diseases. Therefore, we examined the anti-inflammatory effects of fondaparinux, a Factor Xa inhibitor, in a mouse model of the metabolic syndrome, looking at both leukocyte adhesion on the vascular endothelium and thrombus formation. METHODS: Following clamping of the mesenteric vein for 20 min in the KK-A(y) mouse, mice were administered by subcutaneous injection either low-dose or high-dose fondaparinux or placebo (n = 10 in each group. Microscopic observation of the intestinal microcirculation was carried out. In another series, blood samples were taken and measured for blood cell counts and organ damage markers (n = 6 in each). RESULTS: Both leukocyte adherence and thrombus formation were inhibited by treatment with fondaparinux. Red blood cell and white blood cell counts were maintained better in high-dose group. Levels of alanine aminotransferase (ALT) were significantly reduced in both low-dose and high-dose groups (P < 0.05 and 0.01, compared with control, respectively). CONCLUSIONS: Factor Xa inhibitor attenuates leukocyte adhesion and leukocyte-platelet conjugate formation in a mouse model of the metabolic syndrome. These effects appeared to be related to both inhibition of thrombus formation and reduction in markers of organ damage. PMID- 23634885 TI - The histone deacetylase inhibitor sodium valproate causes limited transcriptional change in mouse embryonic stem cells but selectively overrides Polycomb-mediated Hoxb silencing. AB - BACKGROUND: Histone deacetylase inhibitors (HDACi) cause histone hyperacetylation and H3K4 hypermethylation in various cell types. They find clinical application as anti-epileptics and chemotherapeutic agents, but the pathways through which they operate remain unclear. Surprisingly, changes in gene expression caused by HDACi are often limited in extent and can be positive or negative. Here we have explored the ability of the clinically important HDACi valproic acid (VPA) to alter histone modification and gene expression, both globally and at specific genes, in mouse embryonic stem (ES) cells. RESULTS: Microarray expression analysis of ES cells exposed to VPA (1 mM, 8 h), showed that only 2.4% of genes showed a significant, >1.5-fold transcriptional change. Of these, 33% were down regulated. There was no correlation between gene expression and VPA-induced changes in histone acetylation or H3K4 methylation at gene promoters, which were usually minimal. In contrast, all Hoxb genes showed increased levels of H3K9ac after exposure to VPA, but much less change in other modifications showing bulk increases. VPA-induced changes were lost within 24 h of inhibitor removal. VPA significantly increased the low transcription of Hoxb4 and Hoxb7, but not other Hoxb genes. Expression of Hoxb genes increased in ES cells lacking functional Polycomb silencing complexes PRC1 and PRC2. Surprisingly, VPA caused no further increase in Hoxb transcription in these cells, except for Hoxb1, whose expression increased several fold. Retinoic acid (RA) increased transcription of all Hoxb genes in differentiating ES cells within 24 h, but thereafter transcription remained the same, increased progressively or fell progressively in a locus specific manner. CONCLUSIONS: Hoxb genes in ES cells are unusual in being sensitive to VPA, with effects on both cluster-wide and locus-specific processes. VPA increases H3K9ac at all Hoxb loci but significantly overrides PRC-mediated silencing only at Hoxb4 and Hoxb7. Hoxb1 is the only Hoxb gene that is further up regulated by VPA in PRC-deficient cells. Our results demonstrate that VPA can exert both cluster-wide and locus-specific effects on Hoxb regulation. PMID- 23634886 TI - A generation of laparoscopic nephrectomy: stage-specific surgical and oncologic outcomes for laparoscopic nephrectomy in a single center. AB - PURPOSE: To determine the stage-specific operative, postoperative and oncologic outcomes, for patients undergoing a laparoscopic radical nephrectomy (LRN) for renal cell carcinoma (RCC) in a single center and assess changes over a generation of practice. PATIENTS AND METHODS: From December 1992 to July 2011, data were collected prospectively for 854 consecutive simple laparoscopic necphrectomies (LNs) and LRNs, 397 of which were LRNs for RCC. The first LRN was performed in December 1997. Stage-specific surgical and oncologic outcomes were assessed across the study period. Patients were then grouped into three equal consecutive cohorts. Case mix and surgical outcomes were compared to assess changes with departmental experience. RESULTS: There were 206, 71, 118, and 2 patients across stages pT1, pT2, pT3, and pT4, respectively. Median operative time was significantly shorter for pT1 tumors (125, 150 and 150 min for pT1-3, P<0.021), while median estimated blood loss (EBL) was greater for pT3 tumors (50, 50, 100 mL, for pT1-3, P<0.001). Median follow-up time was 31, 30, and 18 months, respectively, across pT1-pT3. There was a significant difference in 5-year overall survival (82.4%, 68.4%, 58.9%), cancer-specific survival (99.5%, 83.6%, 66.5%) and progression free survival (86.5%, 66.3%, 47.5%) across these stage specific subgroups. Over the three cohorts, there was an increase in LRN performed for locally advanced disease and cytoreduction. With greater surgical experience, there was improvement in median operative time and median EBL in localized disease over the three periods, but no significant changes for locally advanced disease. CONCLUSION: This is the largest reported series of LRN in the United Kingdom. Departmental experience has resulted in improved surgical outcomes for localized RCC, with expansion of practice in more complex advanced disease. Laparoscopic nephrectomy is both operatively and oncologically safe in T1 and T2 disease, and although technically more demanding, it is also safe in selected T3 disease. PMID- 23634887 TI - Human Papillomavirus-associated oropharyngeal cancer: an observational study of diagnosis, prevalence and prognosis in a UK population. AB - BACKGROUND: The incidence of Human Papillomavirus (HPV) associated oropharyngeal cancer (OPC) is increasing. HPV-associated OPC appear to have better prognosis than HPV-negative OPC. The aim of this study was to robustly determine the prevalence of HPV-positive OPC in an unselected UK population and correlate HPV positivity with clinical outcome. METHODS: HPV testing by GP5+/6+ PCR, In Situ Hybridisation (ISH) and p16 immunohistochemistry (IHC) was performed on 138 OPCs diagnosed in South Wales (UK) between 2001-06. Kaplan-Meier analysis was used to correlate HPV status with clinical outcome. RESULTS: Using a composite definition of HPV positivity (HPV DNA and p16 overexpression), HPV was detected in 46/83 (55%) samples where DNA quality was assured. Five year overall survival was 75.4% (95% CI: 65.2 to 85.5) in HPV-positives vs 25.3% (95% CI: 14.2 to 36.4) in HPV negatives, corresponding to a 78% reduction in death rate (HR 0.22, p < 0.001). HPV-positives had less locoregional recurrence but second HPV-positive Head and Neck primaries occurred. Poor quality DNA in fixed pathological specimens reduced both HPV prevalence estimates and the prognostic utility of DNA-based HPV testing methods. As a single marker, p16 was least affected by sample quality and correlated well with prognosis, although was not sufficient on its own for accurate HPV prevalence reporting. CONCLUSIONS: This study highlights the significant burden of OPC associated with HPV infection. HPV positive cases are clinically distinct from other OPC, and are associated with significantly better clinical outcomes. A composite definition of HPV positivity should be used for accurate prevalence reporting and up-front DNA quality assessment is recommended for any DNA-based HPV detection strategy. PMID- 23634888 TI - Computer simulation-molecular-thermodynamic framework to predict the micellization behavior of mixtures of surfactants: application to binary surfactant mixtures. AB - We present a computer simulation-molecular-thermodynamic (CSMT) framework to model the micellization behavior of mixtures of surfactants in which hydration information from all-atomistic simulations of surfactant mixed micelles and monomers in aqueous solution is incorporated into a well-established molecular thermodynamic framework for mixed surfactant micellization. In addition, we address the challenges associated with the practical implementation of the CSMT framework by formulating a simpler mixture CSMT model based on a composition weighted average approach involving single-component micelle simulations of the mixture constituents. We show that the simpler mixture CSMT model works well for all of the binary surfactant mixtures considered, except for those containing alkyl ethoxylate surfactants, and rationalize this finding molecularly. The mixture CSMT model is then utilized to predict mixture CMCs, and we find that the predicted CMCs compare very well with the experimental CMCs for various binary mixtures of linear surfactants. This paper lays the foundation for the mixture CSMT framework, which can be used to predict the micellization properties of mixtures of surfactants that possess a complex chemical architecture, and are therefore not amenable to traditional molecular-thermodynamic modeling. PMID- 23634891 TI - Long-chain terminal alcohols through catalytic CO hydrogenation. AB - We show that long-chain 1-alcohols can be produced with high selectivities using heterogeneous CO hydrogenation catalysis. This breakthrough is achieved through the targeted design of "CoCuMn" nanosized core-shell particles using co precipitation of metal salts into oxalate precursors and subsequent thermal decomposition. Using stoichiometric CO/H2 feeds, the selectivities to 1-alcohols or combined 1-alcohols/1-alkenes are usually higher than 60% and occasionally up to 95%. The Anderson-Schulz-Flory chain-lengthening probabilities for these products are higher than 0.6, but usually below 0.9 so as to optimize the C8-C14 slate as feedstock for plasticizers, lubricants, or detergents. PMID- 23634890 TI - The bile acid receptor, TGR5, regulates basal and cholinergic-induced secretory responses in rat colon. AB - Bile acids (BA) are becoming increasingly appreciated as enteric hormones that regulate many aspects of intestinal physiology. The BA receptor, TGR5, has been recently shown to be expressed on enteric nerves and enterochromaffin cells (ECs), where its activation regulates small intestinal and colonic motility. Here, we show that TGR5 is also expressed on colonic epithelial cells and that its activation decreases basal secretory tone and inhibits cholinergic-induced secretory responses. Our data demonstrate a new role for TGR5 in regulating colonic fluid and electrolyte transport and suggest that the receptor represents a good therapeutic target for intestinal transport disorders. PMID- 23634892 TI - Determinants of place of death: a population-based retrospective cohort study. AB - BACKGROUND: As Canada's population ages, the location of end of life care (whether at home, extended care facility or hospital) may change depending on the location of death. We carried out a study to identify determinants of the place of death. METHODS: Data on deaths in British Columbia between 2004 and 2008 were obtained from the Vital Statistics Agency. Place of death was categorized into home, extended care facility, hospital or other. Logistic regression analyses were used to estimate the effects of age, sex, marital status, residence, place of birth and cause of death on place of death using adjusted odds ratios and 95% confidence intervals (95% CI). RESULTS: Of the 153,111 deaths in the study, 16.5% occurred at home, 29.0% in extended care, 51.0% in hospital and 3.5% occurred elsewhere. Male deaths were less likely to occur in extended care as compared with female deaths (odds ratio 0.73, 95% CI 0.71-0.75). Age (odds ratio 3.31, 95% CI 3.19-3.45 for those for >=90 vs 70-79 years), marital status (odds ratio 1.42, 95% CI 1.38-1.47 widowed vs married), residence (odds ratio 0.80, 95% CI 0.76 0.83 rural vs Vancouver), place of birth (odds ratio 0.80, 95% CI 0.75-0.86 China vs Canada) and cause of death (odds ratio 3.91, 95% CI 3.69-4.13 dementia vs cancer) were also associated with death in extended care. CONCLUSIONS: Information on determinants of place of death can inform public health policy regarding care at the end of life and make resource allocation more efficient. PMID- 23634893 TI - Voltage distribution over capacitively coupled plasma electrode for atmospheric pressure plasma generation. AB - When capacitively coupled plasma (CCP) is used to generate large-area plasma, the standing wave effect becomes significant, which results in the hindering of the uniform plasma process such as in a plasma etcher or plasma chemical vapor deposition. In this study, the transmission line modeling method is applied to calculate the voltage distribution over atmospheric-pressure CCP electrodes with the size of 1 m * 0.2 m. The measured plasma impedance in our previous study was used in the present calculation. The results of the calculations clearly showed the effects of excitation frequency and the impedance of the plasma on the form of the voltage distribution caused by the standing wave effect. In the case of 150 MHz frequency, the standing wave effect causes a drastic change in the voltage distribution via plasma ignition; however, the change is small for 13.56 MHz. It was also clarified that the power application position is important for obtaining a uniform voltage distribution. PMID- 23634894 TI - Bacillus subtilis serine/threonine protein kinase YabT is involved in spore development via phosphorylation of a bacterial recombinase. AB - We characterized YabT, a serine/threonine kinase of the Hanks family, from Bacillus subtilis. YabT is a putative transmembrane kinase that lacks the canonical extracellular signal receptor domain. We demonstrate that YabT possesses a DNA-binding motif essential for its activation. In vivo YabT is expressed during sporulation and localizes to the asymmetric septum. Cells devoid of YabT sporulate more slowly and exhibit reduced resistance to DNA damage during sporulation. We established that YabT phosphorylates DNA-recombinase RecA at the residue serine 2. A non-phosphorylatable mutant of RecA exhibits the same phenotype as the DeltayabT mutant, and a phosphomimetic mutant of RecA complements DeltayabT, suggesting that YabT acts via RecA phosphorylation in vivo. During spore development, phosphorylation facilitates the formation of transient and mobile RecA foci that exhibit a scanning-like movement associated to the nucleoid in the mother cell. In some cells these foci persist at the end of spore development. We show that persistent RecA foci, which presumably coincide with irreparable lesions, are mutually exclusive with the completion of spore morphogenesis. Our results highlight similarities between the bacterial serine/threonine kinase YabT and eukaryal kinases C-Abl and Mec1, which are also activated by DNA, and phosphorylate proteins involved in DNA damage repair. PMID- 23634897 TI - Slow avoidance response to contaminated sediments elicits sublethal toxicity to benthic invertebrates. AB - Advanced analytical techniques have identified the heterogeneity of sediments in aquatic environments which may impact the exposure of benthic organisms to contaminants. Acute and chronic toxicity associated with short, intermittent exposure to four field-collected contaminated sediments were assessed for the epi benthic amphipod Melita plumulosa and the harpacticoid copepod Nitocra spinipes. Increasing the duration of exposure caused a decrease in survival of M. plumulosa and N. spinipes during 10-d bioassays. Increasing the frequency of exposure to a total exposure time >96-h resulted in a significant toxicity to M. plumulosa. Reproduction decreased for both species from exposure to contaminated sediment. For M. plumulosa, reproductive effects occurred for shorter exposures than the time taken to sense and avoid contaminant exposure. Thus, while avoidance behaviors may prevent acute lethality, slow responses may not prevent sublethal effects. Exposure of M. plumulosa to contaminated sediment appeared to cause a physiological change in females which reduced fecundity. This study indicates that sediment toxicity methods which utilize static continuous exposures may overestimate the toxicity that would occur at a field location. However, by preventing organisms from avoiding unfavorable sediments, these methods provide a precautionary assessment of possible effects, which is usually the aim of most assessments frameworks. PMID- 23634895 TI - Knockout of 5-lipoxygenase prevents dexamethasone-induced tau pathology in 3xTg mice. AB - Emerging evidence suggests that dysregulation stress hormones, such as glucocorticoids, in aged persons put them at a higher risk to develop Alzheimer's disease (AD). However, the mechanisms underlying such vulnerability remain to be unraveled. Pharmacologic inhibition of 5-lipoxygenase (5LO), an active player in AD pathogenesis whose protein level increases with aging in the human, has been shown to blunt glucocorticoid-mediated amyloid beta (Ab) formation in vitro. In this article, we investigated the role of this pathway in modulating the development of the corticosteroid-dependent AD-like phenotype in the triple transgenic mice (3xTg). Dexamethasone was administered for 1 week to 3xTg or 3xTg genetically deficient for 5LO (3xTg/5LO-/-) mice, and its effect on memory, amyloid-beta and tau levels, and metabolism assessed. At the end of the treatment, we observed that dexamethasone did not induce changes in behavior. Compared with controls, treated mice did not show significant alterations in brain soluble Abeta levels. While total tau protein levels were unmodified in all groups, we found that dexamethasone significantly increased tau phosphorylation at S396, as recognized by the antibody PHF-13, which was specifically associated with an increase in the GSK3beta activity. Additionally, dexamethasone-treated mice had a significant increase in the tau insoluble fraction and reduction in the postsynaptic protein PDS-95. By contrast, these modifications were blunted in the 3xTg/5LO-/- mice. Our findings highlight the functional role that 5LO plays in stress-induced AD tau pathology and support the hypothesis that pharmacologic inhibition of this enzyme could be a useful tool for individuals with this risk factor. PMID- 23634896 TI - NaMYC2 transcription factor regulates a subset of plant defense responses in Nicotiana attenuata. AB - BACKGROUND: To survive herbivore attack, plants have evolved potent mechanisms of mechanical or chemical defense that are either constitutively present or inducible after herbivore attack. Due to the costs of defense deployment, plants often regulate their biosynthesis using various transcription factors (TFs). MYC2 regulators belong to the bHLH family of transcription factors that are involved in many aspects of plant defense and development. In this study, we identified a novel MYC2 TF from N. attenuata and characterized its regulatory function using a combination of molecular, analytic and ecological methods. RESULTS: The transcript and targeted metabolite analyses demonstrated that NaMYC2 is mainly involved in the regulation of the biosynthesis of nicotine and phenolamides in N. attenuata. In addition, using broadly-targeted metabolite analysis, we identified a number of other metabolite features that were regulated by NaMYC2, which, after full annotation, are expected to broaden our understanding of plant defense regulation. Unlike previous reports, the biosynthesis of jasmonates and some JA /NaCOI1-dependent metabolites (e.g. HGL-DTGs) were not strongly regulated by NaMYC2, suggesting the involvement of other independent regulators. No significant differences were observed in the performance of M. sexta on MYC2 silenced plants, consistent with the well-known ability of this specialist insect to tolerate nicotine. CONCLUSION: By regulating the biosynthesis of nicotine, NaMYC2 is likely to enhance plant resistance against non-adapted herbivores and contribute to plant fitness; however, multiple JA/NaCOI1-dependent mechanisms (perhaps involving other MYCs) that regulate separate defense responses are likely to exist in N. attenuata. The considerable variation observed amongst different plant families in the responses regulated by jasmonate signaling highlights the sophistication with which plants craft highly specific and fine tuned responses against the herbivores that attack them. PMID- 23634898 TI - The effect and mechanisms of implementation intentions on prospective memory in individuals with and without schizotypal personality features. AB - Prospective memory (PM) refers to remembering to do something at a future time. Studies have shown that implementation intention can improve PM performance. The present study aimed to examine the effect and mechanism of implementation intention on PM in individuals prone for schizotypal personality disorder (SPD proneness) in a laboratory condition. A total of 51 participants with SPD proneness and 51 controls were administered a PM task. They were further randomly assigned to an implementation intention condition and a typical instruction condition. All participants completed the PM task with low and high cognitive load conditions. The results showed that implementation intention improved PM performances in both SPD prone and control groups, indicating that implementation intention was an effective strategy for improving PM performance. However, the mechanisms were different for the two groups. For controls, implementation intention did not affect their cognitive resources allocation strategy. Participants with SPD proneness allocated significantly more cognitive resources to the PM task in the implementation intention condition. PMID- 23634899 TI - Isotopic spectra of the hydroxyl radical. AB - Rotational spectra of OH and its isotopologues have been precisely measured using high efficiency terahertz (THz) sources. The measurements are compared with existing data and are useful for global modeling. For the first time, microwave measurements of the Lambda-doubling transitions of the (17)OH isotopologue are combined with THz data successfully. Precise rotational, fine-structure, and hyperfine structure parameters for the (17)OH isotopologue are reported. An isotopically independent Dunham model for all isotopologues of (2)Pi OH v < 3 is presented. PMID- 23634901 TI - Non-homogeneous combination of two porous genomes induces complex body shape trajectories in cyprinid hybrids. AB - INTRODUCTION: Hybridization is a common phenomenon in fish and is considered to be a major source of diversification. Deciphering the remoulding of genomic regions and phenotypes in zones where hybrid specimens occur is of particular interest to elucidate the emergence of evolutionary novelties. This approach is particularly challenging because the first step of hybridization seems to be the most important stage in the emergence of hybrid lineages. However, the signal can be significantly altered after only a few generations. RESULTS: We studied 41 microsatellites and partial cytochrome b gene sequences in 970 specimens belonging to two fish species (Chondrostoma nasus and Parachondrostoma toxostoma) in allopatric/parapatric zones, hybrids between them in a natural sympatric zone: the Ardeche basin. We showed that the genomic architecture in hybrids presented pattern heterogeneity of selection for the different loci. Indeed, the upstream part of the river (Rosieres and Labeaume) presented an overdominant fitness of heterozygotes (12.20%) corresponding to a genomic compatibility, and underselection was observed for 4.88%-7.32% of the loci tested indicating a genomic incompatibility. Moreover the upstream station (Rosieres) presented a positive selection of invasive C. nasus homozygotes (17.07% to 21.95%) indicating that hybridization may increase the fitness of admixed individuals.We showed that hybrid morphology (body shape based on 21 landmarks) correlated with genomic dilution indicating a species fingerprint. However, we demonstrated that the hybrid morphology was not a linear modification between the two parental species but a trade-off between several correlated traits. CONCLUSIONS: Hybrid specimens present a mosaic of genomic combination, showing regions with genomic compatibility and others with genomic incompatibility between the two species. Positive selection (invasive advantage ranging from 9.76% to 21.95% of the loci) was evidenced in the upstream part of the Ardeche indicating that environmental selection makes a substantial contribution. Although the presence of a dam is known to impose heterogeneous hybrid zones between these two species, we demonstrated in this study that a natural environment can also generate a hybrid zone with a large number (and diversity) of hybrids. The combination of the two genomes in the hybrids results in complex ontogenetic trajectories (with different morphological traits evolving at different rates) that correspond to novel developmental pathways. PMID- 23634900 TI - Neoplastic-like transformation effect of single-walled and multi-walled carbon nanotubes compared to asbestos on human lung small airway epithelial cells. AB - Accumulating evidence indicates that carbon nanotubes (CNTs) are biopersistent and can cause lung damage. With similar fibrous morphology and mode of exposure to asbestos, a known human carcinogen, growing concern has arisen for elevated risk of CNT-induced lung carcinogenesis; however, relatively little is known about the long-term carcinogenic effect of CNT. Neoplastic transformation is a key early event leading to carcinogenesis. We studied the ability of single- and multi-walled CNTs to induce neoplastic transformation of human lung epithelial cells compared to asbestos. Long-term (6-month) exposure of the cells to occupationally relevant concentrations of CNT in culture caused a neoplastic-like transformation phenotype as demonstrated by increased cell proliferation, anchorage-independent growth, invasion and angiogenesis. Whole-genome expression signature and protein expression analyses showed that single- and multi-walled CNTs shared similar signaling signatures which were distinct from asbestos. These results provide novel toxicogenomic information and suggest distinct particle associated mechanisms of neoplasia promotion induced by CNTs and asbestos. PMID- 23634902 TI - Mutant prevention concentration of orbifloxacin: comparison between Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus pseudintermedius of canine origin. AB - BACKGROUND: The mutant prevention concentration (MPC) is an important parameter to evaluate the likelihood of growth of fluoroquinolone-resistant mutants for antimicrobial-pathogen combinations. The MPCs of fluoroquinolones for different canine pathogens have not been compared. In this study, we compared for the first time orbifloxacin MPCs between susceptible strains of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus pseudintermedius of canine origin. METHODS: More than 1010 CFU/ml of 10 strains of each bacterial species were inoculated onto Muller-Hinton agar supplemented with different concentrations of orbifloxacin from 1* to 64* minimum inhibitory concentration (MIC) and the MPCs were recorded. MICs of original strains and of mutants arising after exposure to sub-MPC concentrations (one per original strain) were determined in the presence or absence of efflux pump inhibitors (EPIs). The effects of quinolone resistance determining region (QRDR) mutations were also examined. RESULTS: MPCs were significantly higher for P. aeruginosa (16-128 MUg/ml) than for E. coli (0.5-32 MUg/ml). MPCs for S. pseudintermedius varied between the low-susceptible (16-128 MUg/ml) and the high-susceptible strains (4-16 MUg/ml) and were the most broadly distributed among the three species. Regarding resistance mechanisms, only one QRDR mutation in gyrA was found in all of the 10 mutants of E. coli and in 4 of the 10 mutants of P. aeruginosa, whereas mutations in both grlA and gyrA were found in 3 mutants and one mutation in grlA was found in 2 mutants among the 10 mutants of S. pseudintermedius. In the presence of an EPI, the MICs of P. aeruginosa mutants decreased markedly, those of E. coli mutants decreased moderately, and those of S. pseudintermedius mutants were unaffected. CONCLUSIONS: MPCs of orbifloxacin vary between bacterial species of canine pathogens, possibly due to the diversity of the main fluoroquinolone resistance mechanism among these species. Therefore, the type of bacterial species should be taken into consideration when using fluoroquinolone drugs such as orbifloxacin in canines. PMID- 23634904 TI - Well-designed strategy to construct helical silver(I) coordination polymers from flexible unsymmetrical bis(pyridyl) ligands: syntheses, structures, and properties. AB - In this Article, self-assembly of AgX (X = NO3(-) and ClO4(-)) salts and four flexible unsymmetrical bis(pyridyl) ligands, namely, N-(pyridin-2 ylmethyl)pyridin-3-amine (L1), N-(pyridin-3-ylmethyl)pyridin-2-amine (L2), N (pyridin-4-ylmethyl)pyridin-2-amine (L3), and N-(pyridin-4-ylmethyl)pyridin-3 amine (L4), results in the formation of eight helical silver(I) coordination polymers, [Ag(L)(NO3)]n [L = L1 (1), L2 (2), L3 (3), L4 (4)] and [Ag(L)(ClO4)]n [L = L1 (5), L2 (6), L3 (7), L4 (8)], which have been characterized by elemental analysis, IR, TG, PL, and powder and single-crystal X-ray diffraction. The alternating one-dimensional (1-D) left- and right-handed helical chains are included in achiral complexes 1-3 and 5-8. By contrast, the ligand L4 only alternately bridges Ag(I) cation to form the 1-D right-handed helical chain in complex 4. The pitches of these helical chains locate in the range 5.694(5) 17.016(6) A. Meanwhile, the present four unsymmetrical bis(pyridyl) ligands in the eight complexes present diverse cis-trans and trans-trans conformation and facilitate the construction of helical structures. Moreover, the solid-state luminescent emission intensities of the perchlorate-containing complexes are stronger than those of nitrate-containing complexes at room temperature. PMID- 23634903 TI - Proteolytic cleavage and truncation of NDRG1 in human prostate cancer cells, but not normal prostate epithelial cells. AB - NDRG1 (N-myc downstream regulated gene-1) is a metastasis suppressor that is down regulated in prostate cancer. NDRG1 phosphorylation is associated with inhibition of metastasis and Western blots indicate two bands at ~41 and ~46 kDa. Previous investigations by others suggest the higher band is due to NDRG1 phosphorylation. However, the current study using a dephosphorylation assay and the Phos-tag (phosphate-binding tag) SDS/PAGE assay, demonstrated that the 46 kDa NDRG1 protein band was not due to phosphorylation. Further experiments showed that the NDRG1 protein bands were not affected upon glycosidase treatment, despite marked effects of these enzymes on the glycosylated protein, fetuin. Analysis using RT PCR (reverse transcriptase-PCR) demonstrated only a single amplicon, and thus, the two bands could not result from an alternatively spliced NDRG1 transcript. Western-blot analysis of prostate cancer cell lysates identified the 41 kDa band to be a truncated form of NDRG1, with MS confirming the full and truncated proteins to be NDRG1. Significantly, this truncated protein was not present in normal human PrECs (prostate epithelial cells). Western-blot analysis using anti NDRG1 raised to its N-terminal sequence failed to detect the truncated protein, suggesting that it lacked N-terminus amino acids (residues 1-49). Sequence analysis predicted a pseudotrypsin protease cleavage site between Cys49-Gly50. Such cleavage of NDRG1 in cancer cells may result in loss of NDRG1 tumour suppressive activity. PMID- 23634905 TI - Improving nanowire sensing capability by electrical field alignment of surface probing molecules. AB - We argue that the structure ordering of self-assembled probing molecular monolayers is essential for the reliability and sensitivity of nanowire-based field-effect sensors because it can promote the efficiency for molecular interactions as well as strengthen the molecular dipole field experienced by the nanowires. In the case of monolayers, we showed that structure ordering could be improved by means of electrical field alignment. This technique was then employed to align multilayer complexes for nanowire sensing applications. The sensitivity we achieved for detection of hybridization between 15-base single-strand DNA molecules is 0.1 fM and for alcohol sensors is 0.5 ppm. The reliability was confirmed by repeated tests on chips that contain multiple nanowire sensors. PMID- 23634907 TI - Validating whole slide imaging for diagnostic purposes in pathology: guideline from the College of American Pathologists Pathology and Laboratory Quality Center. AB - CONTEXT: There is increasing interest in using whole slide imaging (WSI) for diagnostic purposes (primary and/or consultation). An important consideration is whether WSI can safely replace conventional light microscopy as the method by which pathologists review histologic sections, cytology slides, and/or hematology slides to render diagnoses. Validation of WSI is crucial to ensure that diagnostic performance based on digitized slides is at least equivalent to that of glass slides and light microscopy. Currently, there are no standard guidelines regarding validation of WSI for diagnostic use. OBJECTIVE: To recommend validation requirements for WSI systems to be used for diagnostic purposes. DESIGN: The College of American Pathologists Pathology and Laboratory Quality Center convened a nonvendor panel from North America with expertise in digital pathology to develop these validation recommendations. A literature review was performed in which 767 international publications that met search term requirements were identified. Studies outside the scope of this effort and those related solely to technical elements, education, and image analysis were excluded. A total of 27 publications were graded and underwent data extraction for evidence evaluation. Recommendations were derived from the strength of evidence determined from 23 of these published studies, open comment feedback, and expert panel consensus. RESULTS: Twelve guideline statements were established to help pathology laboratories validate their own WSI systems intended for clinical use. Validation of the entire WSI system, involving pathologists trained to use the system, should be performed in a manner that emulates the laboratory's actual clinical environment. It is recommended that such a validation study include at least 60 routine cases per application, comparing intraobserver diagnostic concordance between digitized and glass slides viewed at least 2 weeks apart. It is important that the validation process confirm that all material present on a glass slide to be scanned is included in the digital image. CONCLUSIONS: Validation should demonstrate that the WSI system under review produces acceptable digital slides for diagnostic interpretation. The intention of validating WSI systems is to permit the clinical use of this technology in a manner that does not compromise patient care. PMID- 23634908 TI - Tracking in anatomic pathology. AB - Bar code-based tracking solutions, long present in clinical pathology laboratories, have recently made an appearance in anatomic pathology (AP) laboratories. Tracking of AP "assets" (specimens, blocks, slides) can enhance laboratory efficiency, promote patient safety, and improve patient care. Routing of excess clinical material into research laboratories and biorepositories are other avenues that can benefit from tracking of AP assets. Implementing tracking is not as simple as installing software and turning it on. Not all tracking solutions are alike. Careful analysis of laboratory workflow is needed before implementing tracking to assure that this solution will meet the needs of the laboratory. Such analysis will likely uncover practices that may need to be modified before a tracking system can be deployed. Costs that go beyond simply that of purchasing software will be incurred and need to be considered in the budgeting process. Finally, people, not technology, are the key to assuring quality. Tracking will require significant changes in workflow and an overall change in the culture of the laboratory. Preparation, training, buy-in, and accountability of the people involved are crucial to the success of this process. This article reviews the benefits, available technology, underlying principles, and implementation of tracking solutions for the AP and research laboratory. PMID- 23634906 TI - Oligofructose supplementation (10%) during pregnancy and lactation does not change the inflammatory effect of concurrent trans fatty acid ingestion on 21-day old offspring. AB - BACKGROUND: Previously, we demonstrated that trans fatty acid ingestion during pregnancy and lactation caused a pro-inflammatory effect on the newborn. The opposite effect was described for gestational prebiotic intake. In the present study, we examined whether supplementation of the diet of the dams with 10% of oligofructose with or without hydrogenated vegetable fat during pregnancy and lactation affected the pro-inflammatory status on the pups at age 21 days. METHODS: On the first day of pregnancy, rats were divided into four groups, each of which received one of four diets: a control diet (C group), a control diet supplemented with 10% oligofructose (CF group), a diet enriched with hydrogenated vegetable fat containing trans fatty acids (T group) or a diet enriched with hydrogenated vegetable fat containing trans fatty acids supplemented with 10% oligofructose (TF group). The pups were weighed at birth and at 7, 14 and 21 days of life and were euthanized on post-natal day 21. The serum glucose, insulin and adiponectin concentrations were analyzed. The IL-6, IL-10 and TNF-alpha contents of the retroperitoneal white adipose tissue, liver, soleus and extensor digital longus muscles were analyzed by ELISA. The results are presented as the means +/- standard error of the mean. Statistical significance was assessed using two-way ANOVA, followed by Tukey's test and considered significant at p < 0.05 RESULTS: The body weights of the 21-day old pups in the CF and TF groups were significant lower than those of the C (27% and 21%) and T (25% and 19%, respectively) groups. The serum levels of adiponectin in the CF, T and TF groups were lower than in the C group (41%; 34% and 31%, respectively). In the retroperitoneal adipose tissue, the IL-6 content was increased in TF group relative to the C and CF groups (74% for both), and the TNF-alpha content was higher in the T and TF groups than in the C group (62% and 98%, respectively). In the liver, the TNF-alpha (56% and 104%) and IL-10 (52% and 73%) contents were increased in the CF group relative to the C and TF groups. CONCLUSIONS: Supplementation of the diet of the dams with 10% of oligofructose during pregnancy and lactation, independent of supplementation with hydrogenated vegetable fat, adversely affected the development of the offspring and contributed to development of a pro-inflammatory status in the pups on postnatal day 21. PMID- 23634910 TI - Solvent-free methallylboration of ketones accelerated by tert-alcohols. AB - A solvent- and metal-free process has been developed for the direct methallylboration of ketones employing the stable B-methallylborinane 1, which was accelerated by tertiary alcohols. In the presence of 2.0 equiv of readily available tertiary alcohols such as tert-amyl alcohol, the methallylation products were prepared at room temperature in excellent yields. The salient features of the described process include simple operation, high efficiency, and mild reaction conditions. PMID- 23634909 TI - Reduced P300 amplitude during retrieval on a spatial working memory task in a community sample of adolescents who report psychotic symptoms. AB - BACKGROUND: Deficits in working memory are widely reported in schizophrenia and are considered a trait marker for the disorder. Event-related potentials (ERPs) and imaging data suggest that these differences in working memory performance may be due to aberrant functioning in the prefrontal and parietal cortices. Research suggests that many of the same risk factors for schizophrenia are shared with individuals from the general population who report psychotic symptoms. METHODS: Forty-two participants (age range 11-13 years) were divided into those who reported psychotic symptoms (N = 17) and those who reported no psychotic symptoms, i.e. the control group (N = 25). Behavioural differences in accuracy and reaction time were explored between the groups as well as electrophysiological correlates of working memory using a Spatial Working Memory Task, which was a variant of the Sternberg paradigm. Specifically, differences in the P300 component were explored across load level (low load and high load), location (positive probe i.e. in the same location as shown in the study stimulus and negative probe i.e. in a different location to the study stimulus) and between groups for the overall P300 timeframe. The effect of load was also explored at early and late timeframes of the P300 component (250-430 ms and 430 750 ms respectively). RESULTS: No between-group differences in the behavioural data were observed. Reduced amplitude of the P300 component was observed in the psychotic symptoms group relative to the control group at posterior electrode sites. Amplitude of the P300 component was reduced at high load for the late P300 timeframe at electrode sites Pz and POz. CONCLUSIONS: These results identify neural correlates of neurocognitive dysfunction associated with population level psychotic symptoms and provide insights into ERP abnormalities associated with the extended psychosis phenotype. PMID- 23634912 TI - Violent behaviour in a forensic psychiatric hospital in Finland: an analysis of violence incident reports. AB - The aim of this paper was to explore the frequency and provocation of physically violent incidents in a Finnish forensic psychiatric hospital. Three years (2007 2009) of violent incident reports were analysed retrospectively. The data were analysed by content analysis, and statistically by Poisson regression analysis. During the study period a total of 840 incidents of physical violence occurred. Six main categories were found to describe the provocation of violence where three of these categories seemed to be without a specified reason (61%), and three represented a reaction to something (36%). The risk for violent behaviour was highest for the civil patients (RR = 11.96; CI 95% 9.43-15.18; P < 0.001), compared to criminal patients (RR = 1). The civil patients represented 36.7% of the patients, and in 43.6% of the studied patient days, they caused 89.8% of the reported violence incidents. Patients undergoing a forensic mental examination did not frequently behave aggressively (RR = 1.97; CI 95% 0.91-4.28). These results can be used in the reorganization of health-care practices and the allocation of resources. PMID- 23634913 TI - Spontaneous intracerebral hemorrhage and the challenge of surgical decision making: a review. AB - Decision making for patients with spontaneous intracerebral hemorrhage (ICH) poses several challenges. Outcomes in this patient population are generally poor, prognostication is often uncertain, and treatment strategies offer limited benefits. Studies demonstrate variability in the type and intensity of treatment offered, which is attributed to clinical uncertainty and habits of training. Research has focused on new techniques and more stringent evidence-based selection criteria to improve outcomes and produce consensus around treatment strategies for patients with ICH. Such focus, however, offers little description of how ICH treatment decisions are made and how such decisions reflect patient preferences regarding medical care. A growing body of literature suggests that the process of decision making in ICH is laden with bias, value assumptions, and subjective impressions. Factors such as geography, cognitive biases, patient perceptions, and physician characteristics can all shape decision making and the selection of treatment. Such factors often serve as a barrier to providing patient-centered medical care. In this article, the authors review how surgical decision making for patients with ICH is shaped by these decisional factors and suggest future research pathways to study decision making in ICH. Such research efforts are important for establishing quality guidelines and pay-for-performance measures that reflect the preferences of individual patients and the contextual nature of medical decision making. PMID- 23634911 TI - The efficacy and safety of pharmacoinvasive therapy with prourokinase for acute ST-segment elevation myocardial infarction patients with expected long percutaneous coronary intervention-related delay. AB - OBJECTIVES: To elucidate the efficacy and safety of pharmacoinvasive therapy by using prourokinase (prouk) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Patients with STEMI often have long percutaneous coronary intervention (PCI)-related delays due to various reasons, which are associated with poor outcomes. METHODS: A randomized study which enrolled patients from four centers in China was conducted. Patients were randomly assigned to accept routine primary PCI or prouk-PCI. The primary end points were the angiographic parameters, including thrombolysis in myocardial infarction (TIMI) flow grade, TIMI frame count, and myocardial blush grade. Secondary endpoints were incidence of major adverse cardiac events (MACE, defined as death from all causes, reinfarction, revascularization, or rehospitalization due to new or worsening congestive heart failure) at 30 days and 1 year. RESULTS: One hundred and ninety-seven eligible patients were enrolled, of whom 100 were randomized to the prouk-PCI group. Significantly more patients in the prouk-PCI group than in the PCI group had an opened infarct-related artery on arrival in the catheterization laboratory (48% vs. 21%, P = 0.0002) and better TIMI frame count after PCI (33 +/- 6 vs. 40 +/- 10, P < 0.001). At 1-year follow-up, there was a trend that patients in the prouk-PCI group had less chances to have MACE (7.0% vs. 12.6%, P = 0.235) or be readmitted to hospital due to new or worsening congestive heart failure (1.0% vs. 4.1%, P = 0.209). CONCLUSION: A strategy of emergent PCI preceded by fibrinolysis with prouk results in a better myocardial perfusion in infarct-related artery compared with primary PCI alone in patients with STEMI and long PCI-related delay. PMID- 23634914 TI - Alpha-7 nicotinic acetylcholine receptor agonists in intracerebral hemorrhage: an evaluation of the current evidence for a novel therapeutic agent. AB - Intracerebral hemorrhage (ICH) is the most deadly and least treatable subtype of stroke, and at the present time there are no evidence-based therapeutic interventions for patients with this disease. Secondary injury mechanisms are known to cause substantial rates of morbidity and mortality following ICH, and the inflammatory cascade is a major contributor to this post-ICH secondary injury. The alpha-7 nicotinic acetylcholine receptor (alpha7-nAChR) agonists have a well-established antiinflammatory effect and have been shown to attenuate perihematomal edema volume and to improve functional outcome in experimental ICH. The authors evaluate the current evidence for the use of an alpha7-nAChR agonist as a novel therapeutic agent in patients with ICH. PMID- 23634915 TI - Hydrocephalus after arteriovenous malformation rupture. AB - OBJECT: The rates and risk factors for external ventricular drain (EVD) placement and long-term shunt dependence in patients with ruptured arteriovenous malformations (AVMs) have not been systematically studied. In this study the authors evaluated the rates of EVD placement and shunt dependence, and risk factors for them, in a cohort of patients with ruptured AVMs. METHODS: The records of 87 consecutive patients with ruptured AVMs were reviewed for patient demographics, hemorrhage pattern, AVM angioarchitectural features, and surgical treatment. Univariate and multivariate logistic regression analyses were performed to evaluate risk factors for EVD placement, permanent shunt dependence, and long-term outcome (as measured by the modified Rankin Scale). RESULTS: Thirty eight patients (44%) required EVD placement, and 16 (18%) required a permanent shunt. Statistically significant risk factors for EVD placement in the univariate analysis included initial Glasgow Coma Scale (GCS) score (p = 0.002), the presence of intraventricular hemorrhage (IVH; p < 0.001), AVM-associated aneurysms (p = 0.002), and early surgery (p = 0.01). Multivariate analysis revealed only AVM-associated aneurysms as statistically significant (p = 0.006). Risk factors for shunt placement included initial GCS score (p = 0.003), IVH (p = 0.01), deep supratentorial location (p = 0.034), and associated aneurysms (p = 0.03). Multivariate analysis revealed initial GCS score as a statistically significant risk factor (p = 0.041) as well as a strong trend for associated aneurysms (p = 0.06). Patient age, sex, associated subarachnoid hemorrhage, AVM grade, AVM size, and deep venous drainage were not associated with EVD placement or long-term shunt dependence. CONCLUSIONS: Hydrocephalus from AVM rupture was associated with initial GCS score, IVH, and AVM-associated aneurysms. Arteriovenous malformations with associated aneurysms thus not only have a greater risk of hemorrhage but also a greater risk of hemorrhage-associated morbidity as a result of hydrocephalus. PMID- 23634916 TI - Rates and determinants of ventriculostomy-related infections during a hospital transition to use of antibiotic-coated external ventricular drains. AB - OBJECT: The authors evaluated the rates of ventriculostomy-related infections (VRIs) after antibiotic-coated extraventricular drains (ac-EVDs) were introduced as the standard of care. METHODS: A retrospective chart review was conducted of adult patients admitted to NewYork-Presbyterian Hospital neurological intensive care unit in whom an EVD was placed between February 2007 and November 2009, excluding individuals receiving EVDs due to an infection of a primary device. Three time periods were defined depending on type of EVD in use: Period 1, conventional EVDs; Period 2, either ac-EVDs or conventional EVDs; and Period 3, ac-EVDs. Definite/probable VRIs that occurred during the 3 periods were evaluated and established as determinants of VRIs by using a Cox proportional hazards model. Prolonged systemic antibiotics were given for the duration of EVD placement in each of the 3 periods per institutional policy. RESULTS: Data from 141 individuals were evaluated; mean patient age was 53.8 +/- 17.2 years and 54% were female. There were 2 definite and 19 probable VRIs. The incidence of definite/probable VRI (per 1000 person-catheter days) decreased from Period 1 to 3 (24.5, 16.2, and 4.4 in Periods 1, 2, and 3, respectively; p < 0.0001). Patients with VRIs were more likely to be female than male (23.7% vs 3.1%, p < 0.003) and have had an EVD in place for a longer duration, although there was no significant difference among the 3 periods (7.9 +/- 6.7 [Period 1], 8.1 +/- 7.1 [Period 2], and 8.6 +/- 5.8 [Period 3] mean days; p = 0.87, ANOVA). Analysis of effect modification in a stepwise model showed that period, age, and age and female interaction were significant predictors of VRIs. The period was the strongest predictor of VRI (p = 0.0075). After adjustment for age and age and sex interaction, the survival rate was 53% at the end of Period 2 and 91% at the end of Period 3. CONCLUSIONS: Rates of VRIs have decreased with the addition of ac EVDs to the routine use of prolonged systemic antibiotics at the authors' institution. PMID- 23634917 TI - Magnetic resonance-guided focused ultrasound. PMID- 23634918 TI - Transcranial MR-guided focused ultrasound sonothrombolysis in the treatment of intracerebral hemorrhage. AB - Intracerebral hemorrhage remains a significant cause of morbidity and mortality. Current surgical therapies aim to use a minimally invasive approach to remove as much of the clot as possible without causing undue disruption to surrounding neural structures. Transcranial MR-guided focused ultrasound (MRgFUS) surgery is an emerging technology that permits a highly concentrated focal point of ultrasound energy to be deposited to a target deep within the brain without an incision or craniotomy. With appropriate ultrasound parameters it has been shown that MRgFUS can effectively liquefy large-volume blood clots through the human calvaria. In this review the authors discuss the rationale for using MRgFUS to noninvasively liquefy intracerebral hemorrhage (ICH), thereby permitting minimally invasive aspiration of the liquefied clot via a small drainage tube. The mechanism of action of MRgFUS sonothrombolysis; current investigational work with in vitro, in vivo, and cadaveric models of ICH; and the potential clinical application of this disruptive technology for the treatment of ICH are discussed. PMID- 23634919 TI - Intracranial hemorrhage from dural arteriovenous fistulas: clinical features and outcome. AB - OBJECT: In this paper the authors' goal was to review the clinical features and outcome of patients with intracranial dural arteriovenous fistulas (DAVFs) who presented with hemorrhage. METHODS: A retrospective study of 28 patients with DAVFs who presented with intracranial hemorrhage to 2 separate institutions was performed. The information reviewed included clinical presentation, location and size of hemorrhage, angiographic features, treatment, and clinical and radiologically documented outcomes. Clinical and radiological follow-up were available in 27 of 28 patients (mean follow-up 17 months). RESULTS: The vast majority of patients were male (86%), and the most common presenting symptom was sudden-onset headache. All DAVFs had cortical venous drainage, and about one third were associated with a venous varix. The most common location was tentorial (75%). Treatment ranged from endovascular (71%), surgical (43%), Gamma Knife surgery (4%), or a combination of modalities. The majority of fistulas (75%) were completely obliterated, and most patients experienced excellent clinical outcome (71%, modified Rankin Scale score of 0 or 1). There were no complications in this series. CONCLUSIONS: Case series, including the current one, suggest that the vast majority of patients who present with intracranial hemorrhage from a DAVF are male. The most common location for DAVFs presenting with hemorrhage is tentorial. Excellent outcomes are achieved with individualized treatment, which includes various therapeutic strategies alone or in combination. Despite the hemorrhagic presentation, almost two-thirds of patients experience a full recovery with no or minimal residual symptoms. PMID- 23634920 TI - Concussion. PMID- 23634921 TI - Modern intraoperative imaging modalities for the vascular neurosurgeon treating intracerebral hemorrhage. AB - This paper reviews the current intraoperative imaging tools that are available to assist neurosurgeons in the treatment of intracerebral hemorrhage (ICH). This review shares the authors' experience with each modality and discusses the advantages, potential limitations, and disadvantages of each. Surgery for ICH is directed at blood clot removal, reduction of intracranial pressure, and minimization of secondary damage associated with hematoma breakdown products. For effective occlusion and safe obliteration of vascular anomalies associated with ICH, vascular neurosurgeons today require a thorough understanding of the various intraoperative imaging modalities available for obtaining real-time information. Use of one or more of these modalities may improve the surgeon's confidence during the procedure, the patient's safety during surgery, and surgical outcome. The modern techniques discussed include 1) indocyanine green-based video angiography, which provides real-time information based on high-quality images showing the residual filling of vascular pathological entities and the patency of blood vessels of any size in the surgical field; and 2) intraoperative angiography, which remains the gold standard intraoperative diagnostic test in the surgical management of cerebral aneurysms and arteriovenous malformations. Hybrid procedures, providing multimodality image-guided surgeries and combining endovascular with microsurgical strategies within the same surgical session, have become feasible and safe. Microdoppler is a safe, noninvasive, and reliable technique for evaluation of hemodynamics of vessels in the surgical field, with the advantage of ease of use. Intraoperative MRI provides an effective navigation tool for cavernoma surgery, in addition to assessing the extent of resection during the procedure. Intraoperative CT scanning has the advantage of very high sensitivity to acute bleeding, thereby assisting in the confirmation of the extent of hematoma evacuation and the extent of vascular anomaly resection. Intraoperative ultrasound aids navigation and evacuation assessment during intracerebral hematoma evacuation surgeries. It supports the concept of minimally invasive surgery and has undergone extensive development in recent years, with the quality of ultrasound imaging having improved considerably. Image-guided therapy, combined with modern intraoperative imaging modalities, has changed the fundamentals of conventional vascular neurosurgery by presenting real-time visualization of both normal tissue and pathological entities. These imaging techniques are important adjuncts to the surgeon's standard surgical armamentarium. Familiarity with these imaging modalities may help the surgeon complete procedures with improved safety, efficiency, and clinical outcome. PMID- 23634922 TI - Retrospective comparison of craniotomy and decompressive craniectomy for surgical evacuation of nontraumatic, supratentorial intracerebral hemorrhage. AB - Surgical evacuation of nontraumatic, supratentorial intracerebral hemorrhage (SICH) is uncommonly performed, and outcomes are generally poor. On the basis of published experimental data and the authors' anecdotal observations, a retrospective chart review study was performed to test the hypothesis that large decompressive craniectomies (DCs), compared with craniotomies, would improve clinical outcomes after surgical evacuation of SICH. For patients with putaminal SICH, DC was associated with a statistically significant improvement in midline shift, compared with craniotomy. Decompressive craniectomies also resulted in a strong trend toward decreased likelihood of poor neurological outcome (modified Rankin Scale score > 3). For patients with lobar SICH, no associations were found between DC or craniotomy and clinical outcomes. For patients selected to undergo surgical evacuation of putaminal SICH, a DC in addition to surgical evacuation of the hematoma might improve outcome. PMID- 23634924 TI - Decompressive hemicraniectomy for spontaneous intracerebral hemorrhage. AB - Intracerebral hemorrhage (ICH) is devastating, with high mortality rates, but its optimum management has not been fully established. Decompressive hemicraniectomy is a surgical procedure used to relieve the malignant elevation of intracranial pressure. The application of decompressive hemicraniectomy in patients with hemispheric ICH has been much less common, although several studies have shown the usefulness of this procedure for large hemispheric ICH. In this review, the present knowledge of the safety and efficacy of this procedure are evaluated. The authors conclude that decompressive hemicraniectomy with hematoma evacuation for large ICH might be a safe and effective procedure in patients with severely disturbed consciousness and large hematoma volume. PMID- 23634923 TI - Decompressive hemicraniectomy without clot evacuation in dominant-sided intracerebral hemorrhage with ICP crisis. AB - OBJECT: Large intracerebral hemorrhage (ICH), compounded by perihematomal edema, can produce severe elevations of intracranial pressure (ICP). Decompressive hemicraniectomy (DHC) with or without clot evacuation has been considered a part of the armamentarium of treatment options for these patients. The authors sought to assess the preliminary utility of DHC without evacuation for ICH in patients with supratentorial, dominant-sided lesions. METHODS: From September 2009 to May 2012, patients with ICH who were admitted to the neurological ICU at Columbia University Medical Center were prospectively enrolled in that institution's ICH Outcomes Project (ICHOP). Five patients with spontaneous supratentorial dominant sided ICH underwent DHC without clot evacuation for recalcitrant elevated ICP. Data pertaining to the patients' characteristics and outcomes of treatment were prospectively collected. RESULTS: The patients' median age was 43 years (range 30 55 years) and the ICH etiology was hypertension in 4 of 5 patients, and systemic lupus erythematosus vasculitis in 1 patient. On admission, the median Glasgow Coma Scale (GCS) score was 7 (range 5-9). The median ICH volume was 53 cm(3) (range 28-79 cm(3)), and the median midline shift was 7.6 mm (range 3.0-11.3 mm). One day after surgery, the median decrease in midline shift was 2.7 mm (range 1.5 4.6 mm), and the median change in GCS score was +1 (range -3 to +5). At discharge, all patients were still alive, and the median GCS score was 10 (range 9-11), the median modified Rankin Scale (mRS) score was 5 (range 5-5), and the median NIHSS (National Institutes of Health Stroke Scale) score was 22 (range 17 27). Six months after hemorrhage, 1 patient had died, 2 were functionally dependent (mRS Score 4-5), and 2 were functionally independent (mRS Score 0-3). Outcomes for the patients treated with DHC were good compared with 1) outcomes for all patients with spontaneous supratentorial ICH admitted during the same period (n = 144) and 2) outcomes for matched patients (dominant ICH, GCS Score 5 9, ICH volume 28-79 cm(3), age < 60 years) whose cases were managed nonoperatively (n = 5). CONCLUSIONS: Decompressive hemicraniectomy without clot evacuation appears feasible in patients with large ICH and deserves further investigation, preferably in a randomized controlled setting. PMID- 23634925 TI - The role of anticoagulants, antiplatelet agents, and their reversal strategies in the management of intracerebral hemorrhage. AB - New anticoagulant and antiplatelet medications have been approved and are prescribed with increased frequency. Intracranial hemorrhage is associated with the use of these medications. Therefore, neurosurgeons need to be aware of these new medications, how they are different from their predecessors, and the strategies for the urgent reversal of their effects. Utilization of intraluminal stents by endovascular neurosurgeons has resulted in the need to have a thorough understanding of antiplatelet agents. Increased use of dabigatran, rivaroxaban, and apixaban as oral anticoagulants for the treatment of atrial fibrillation and acute deep venous thrombosis has increased despite the lack of known antidotes to these medications. PMID- 23634926 TI - Dabigatran, intracranial hemorrhage, and the neurosurgeon. AB - Dabigatran etexilate (Pradaxa) is a novel oral anticoagulant that has gained FDA approval for the prevention of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In randomized trials, the incidence of hemorrhagic events has been demonstrated to be lower in patients treated with dabigatran compared with the traditional anticoagulant warfarin. However, dabigatran does not have reliable laboratory tests to measure levels of anticoagulation and there is no pharmacological antidote. These drawbacks are challenging in the setting of intracerebral hemorrhage. In this article, the authors provide background information on dabigatran, review the existing anecdotal experiences with treating intracerebral hemorrhage related to dabigatran therapy, present a case study of intracranial hemorrhage in a patient being treated with dabigatran, and suggest clinical management strategies. The development of reversal agents is urgently needed given the growing number of patients treated with this medication. PMID- 23634927 TI - Space-occupying cerebellar infarction: complications, treatment, and outcome. AB - Space-occupying brain edema is a frequent and one of the most dreaded complications in ischemic cerebellar stroke. Because the tight posterior fossa provides little compensating space, any space-occupying lesion can lead to life threatening complications through brainstem compression or compression of the fourth ventricle and subsequent hydrocephalus, both of which may portend transtentorial/transforaminal herniation. Patients with large cerebellar infarcts should be treated and monitored very early on in an experienced stroke unit or (neuro)intensive care unit. The general treatment of ischemic cerebellar infarction does not differ from that of supratentorial ischemic strokes. Treatment strategies for space-occupying edema include pharmacological antiedema and intracranial pressure-lowering therapies, ventricular drainage by means of an extraventricular drain, and suboccipital decompressive surgery, with or without resection of necrotic tissue. Timely escalation of treatment is crucial and should be guided by clinical and neuroradiological rationales. Patients in a coma after hydrocephalus and/or local brainstem compression may also benefit from more aggressive surgical treatment, as long as the conditions are reversible. Contrary to the general belief that outcome in survivors of space-occupying cerebellar stroke is usually good, recent studies suggest that for many of these patients, the long-term outcome is not good. In particular, advanced age and additional brainstem infarction seem to be predictors for poor outcome. Further trials are necessary to investigate these findings systematically and provide better selection criteria to help guide decisions about surgical therapies, which should always be carried out in close cooperation among neurointensive care physicians, neurologists, and neurosurgeons. PMID- 23634928 TI - Emerging experimental therapies for intracerebral hemorrhage: targeting mechanisms of secondary brain injury. AB - Intracerebral hemorrhage (ICH) is associated with a higher degree of morbidity and mortality than other stroke subtypes. Despite this burden, currently approved treatments have demonstrated limited efficacy. To date, therapeutic strategies have principally targeted hematoma expansion and resultant mass effect. However, secondary mechanisms of brain injury are believed to be critical effectors of cell death and neurological outcome following ICH. This article reviews the pathophysiology of secondary brain injury relevant to ICH, examines pertinent experimental models, and highlights emerging therapeutic strategies. Treatment paradigms discussed include thrombin inhibitors, deferoxamine, minocycline, statins, granulocyte-colony stimulating factors, and therapeutic hypothermia. Despite promising experimental and preliminary human data, further studies are warranted prior to effective clinical translation. PMID- 23634929 TI - Intracerebral hemorrhage: a changing landscape. PMID- 23634931 TI - The estimation of visceral adipose tissue with a body composition monitor predicts the metabolic syndrome. AB - BACKGROUND: Central obesity has a higher risk of the metabolic syndrome (MetS) and cardiovascular diseases. It is estimated by measuring waist circumference (WC) and waist-to-hip ratio (WHR), which are operator-dependent. The present study aimed to validate a body composition monitor (BCM) as a tool for estimating visceral adipose tissue (VAT), as well as to assess its capacity to predict the MetS and its correlation with anthropometric parameters. METHODS: We measured WC, WHR and body mass index (BMI) in 60 recruited subjects. BCM estimated VAT (1-30 points). Body composition and resting energy expenditure (REE) were compared with bioelectrical impedance analysis (BIA) and indirect calorimetry, respectively. VAT was estimated by BCM (range 1-30 points), We evaluated the capability of VAT, WC, BMI and WHR to predict the MetS by ATP-III criteria. RESULTS: The mean (SD) age of subjects was 36.8 (12.9) years, 80% were female, and 47% had the MetS. Body composition and REE estimated by BCM had a significant correlation with BIA (r = 0.85-0.91, P< 0.001) and REE (r = 0.86, P < 0.001), respectively, even after adjusting by sex. VAT estimation by BCM was positively correlated with WC (r = 0.75, P< 0.001) and WHR (r = 0.61, P < 0.001). The area under the receiver operator characteristic curves to predict the MetS was 0.93 for VAT, 0.81 for WC, 0.76 for WHR and 0.74 for BMI. VAT >=10 points had a sensitivity of 100% and a specificity of 82% for predicting the MetS. CONCLUSIONS: VAT estimation by BCM efficiently predicts the MetS and correlates with anthropometric parameters of central obesity. Its routine use could facilitate cardiovascular risk estimation and follow-up in overweight and obese patients in ambulatory practice. PMID- 23634930 TI - Effects of Ginkgo biloba on chemically-induced mammary tumors in rats receiving tamoxifen. AB - BACKGROUND: Ginkgo biloba extract (GbE) is used extensively by breast cancer patients undergoing treatment with Tamoxifen (TAM). Thus, the present study investigated the effects of GbE in female Sprague-Dawley (SD) rats bearing chemically-induced mammary tumors and receiving TAM. METHODS: Animals bearing mammary tumors (>=1 cm in diameter) were divided into four groups: TAM [10 mg/kg, intragastrically (i.g.)], TAM plus GbE [50 and 100 mg/kg, intraperitoneally (i.p.)] or an untreated control group. After 4 weeks, the therapeutic efficacy of the different treatments was evaluated by measuring the tumor volume (cm(3)) and the proportions of each tumor that were alive, necrotic or degenerative (mm(2)). In addition, labeling indexes (LI%) were calculated for cell proliferation (PCNA LI%) and apoptosis (cleaved caspase-3 LI%), expression of estrogen receptor-alpha (ER-alpha) and p63 biomarkers. RESULTS: Overall, the tumor volume and the PCNA LI% within live tumor areas were reduced by 83% and 99%, respectively, in all TAM treated groups when compared to the untreated control group. GbE treatment (100 mg/kg) reduced the proportions of live (24.8%) and necrotic areas (2.9%) (p = 0.046 and p = 0.038, respectively) and significantly increased the proportion of degenerative areas (72.9%) (p = 0.004) in mammary tumors when compared to the group treated only with TAM. The expression of ER-alpha, p63 and cleaved caspase 3 in live tumor tissues was not modified by GbE treatment. CONCLUSIONS: Co treatment with 100 mg/kg GbE presented a slightly beneficial effect on the therapeutic efficacy of TAM in female SD rats bearing mammary tumors. PMID- 23634932 TI - Catalytic asymmetric reductive acyl cross-coupling: synthesis of enantioenriched acyclic alpha,alpha-disubstituted ketones. AB - The first enantioselective Ni-catalyzed reductive acyl cross-coupling has been developed. Treatment of acid chlorides and racemic secondary benzyl chlorides with a Ni(II)/bis(oxazoline) catalyst in the presence of Mn(0) as a stoichiometric reductant generates acyclic alpha,alpha-disubstituted ketones in good yields and high enantioselectivity without requiring stoichiometric chiral auxiliaries or pregeneration of organometallic reagents. The mild, base-free reaction conditions are tolerant of a variety of functional groups on both coupling partners. PMID- 23634933 TI - First-principles investigation on the segregation of Pd at LaFe1-xPdxO3-y surfaces. AB - First-principles calculations were performed to investigate the effect of Pd concentration and oxygen vacancies on the stability of Pd at LaFeO3 surfaces. We found a much stronger tendency of Pd to segregate by taking the aggregation of Pd at LaFe1-xPdxO3-y surfaces into consideration, resulting in a pair of Pd-Pd around a vacancy. Moreover, we predicted that one oxygen-vacancy-containing FeO2 terminated surfaces would be stable at high temperatures by comparing the stability of LaFe1-xPdxO3-y surfaces, which further supports our previous conclusion that a Pd-containing perovskite catalyst should be calcined at 1,073 K or higher temperatures in air to enhance the segregation of Pd in the vicinity of surfaces to rapidly transform the Pd catalyst from oxidized to reduced states on the perovskite support. PMID- 23634935 TI - microRNAs in cardiac development and regeneration. AB - Heart development involves the precise orchestration of gene expression during cardiac differentiation and morphogenesis by evolutionarily conserved regulatory networks. miRNAs (microRNAs) play important roles in the post-transcriptional regulation of gene expression, and recent studies have established critical functions for these tiny RNAs in almost every facet of cardiac development and disease. The realization that miRNAs are amenable to therapeutic manipulation has also generated considerable interest in the potential of miRNA-based drugs for the treatment of a number of human diseases, including cardiovascular disease. In the present review, I discuss well-established and emerging roles of miRNAs in cardiac development, their relevance to congenital heart disease and unresolved questions in the field for future investigation, as well as emerging therapeutic possibilities for cardiac regeneration. PMID- 23634934 TI - Molecular evidence for natural hybridization in the mangrove fern genus Acrostichum. AB - BACKGROUND: Natural hybridization is prevalent in ferns, and plays an important role in fern evolution and speciation. In the Indo West-Pacific region, the mangrove fern genus Acrostichum consists of two largely sympatric species, A. aureum and A. speciosum. Although there has been no report of interspecific hybridization before, we found some individuals morphologically intermediate between them in Guangdong and Hainan, China, for the first time, which were suspected to be hybrids. In this study, we aimed to test the hypothesis of natural hybridization between A. aureum and A. speciosum in Guangdong and Hainan using three low-copy nuclear genes. A chloroplast intergenic spacer was used to infer the hybridization direction once the hybrid status was confirmed. In addition, we examined spore shapes and germination for these taxa. RESULTS: Both A. aureum and A. speciosum showed a low level of polymorphism at all three nuclear genes; however, they were well separated at these loci. At both locations, each individual of the putative hybrid showed additivity in chromatograms at all sites where the two species showed fixed differences. Haplotype analysis at all three nuclear genes indicated that each individual of the putative hybrid possessed two haplotypes, matching with those of A. aureum and A. speciosum, respectively. Sequencing of the chloroplast trnV-trnM regions showed that A. aureum differed from A. speciosum by eleven nucleotide substitutions and three indels (insertions/deletions), and all sampled individuals of the putative hybrid had the identical sequences with A. speciosum. Compared with A. aureum and A. speciosum, the putative hybrid had much reduced spore germination rate. CONCLUSIONS: Sequence data of the three nuclear genes provide compelling evidence for natural hybridization between A. aureum and A. speciosum, and all the hybrid individuals are likely F1s. The hybridization is unidirectional and A. speciosum is the maternal parent of the hybrid based on the assumption of maternal inheritance of chloroplast DNA. Human disturbance on mangrove habitats may facilitate the establishment of hybrids of Acrostichum. PMID- 23634936 TI - The vascular smooth muscle cell: a therapeutic target in Type 2 diabetes? AB - The rising epidemic of T2DM (Type 2 diabetes mellitus) worldwide is of significant concern. The inherently silent nature of the disease in its early stages precludes early detection; hence cardiovascular disease is often established by the time diabetes is diagnosed. This increased cardiovascular risk leads to significant morbidity and mortality in these individuals. Progressive development of complications as a result of previous exposure to metabolic disturbances appears to leave a long-lasting impression on cells of the vasculature that is not easily reversed and is termed 'metabolic memory'. SMCs (smooth muscle cells) of blood vessel walls, through their inherent ability to switch between a contractile quiescent phenotype and an active secretory state, maintain vascular homoeostasis in health and development. This plasticity also confers SMCs with the essential capacity to adapt and remodel in pathological states. Emerging clinical and experimental studies propose that SMCs in diabetes may be functionally impaired and thus contribute to the increased incidence of macrovascular complications. Although this idea has general support, the underlying molecular mechanisms are currently unknown and hence are the subject of intense research. The aim of the present review is to explore and evaluate the current literature relating to the problem of vascular disease in T2DM and to discuss the critical role of SMCs in vascular remodelling. Possibilities for therapeutic strategies specifically at the level of T2DM SMCs, including recent novel advances in the areas of microRNAs and epigenetics, will be evaluated. Since restoring glucose control in diabetic patients has limited effect in ameliorating their cardiovascular risk, discovering alternative strategies that restrict or reverse disease progression is vital. Current research in this area will be discussed. PMID- 23634938 TI - Congenital infection with Anaplasma phagocytophilum in a calf in northern Germany. AB - Anaplasma phagocytophilum is a Gram-negative, obligate intracellular tick transmitted bacterium that replicates in neutrophils. It causes tick-borne fever (TBF) in sheep and cattle, but also elicits febrile disease in humans as well as in other domestic animals such as dogs, horses, and cats. Although increasingly recognized in Europe, the first laboratory-confirmed case of TBF in cattle from Germany has been published only recently. We here present the unusual case of an intrauterine transmission of A. phagocytophilum in a calf from northern Germany. To our knowledge, this is the first report of such an event occurring under field conditions in cattle. PMID- 23634939 TI - Application of a self-enhancing classification method to electromyography pattern recognition for multifunctional prosthesis control. AB - BACKGROUND: The nonstationary property of electromyography (EMG) signals usually makes the pattern recognition (PR) based methods ineffective after some time in practical application for multinational prosthesis. The conventional EMG PR, which is accomplished in two separate steps: training and testing, ignores the mismatch between training and testing conditions and often discards the useful information in testing dataset. METHOD: This paper presents a novel self enhancing approach to improve the classification performance of the electromyography (EMG) pattern recognition (PR). The proposed self-enhancing method incorporates the knowledge beyond the training condition to the classifiers from the testing data. The widely-used linear discriminant analysis (LDA) and quadratic discriminant analysis (QDA) are extended to self-enhancing LDA (SELDA) and self-enhancing QDA (SEQDA) by continuously updating their model parameters such as the class mean vectors, the class covariances and the pooled covariance. Autoregressive (AR) and Fourier-derived cepstral (FC) features are adopted. Experimental data in two different protocols are used to evaluate performance of the proposed methods in short-term and long-term application respectively. RESULTS: In protocol of short-term EMG, based on AR and FC, the recognition accuracy of SEQDA and SELDA is 2.2% and 1.6% higher than conventional that of QDA and LDA respectively. The mean results of SEQDA(C) and SEQDA (M) are improved by 2.2% and 0.75% for AR, and 1.99% and 1.1% for FC respectively when compared to QDA. The mean results of SELDA(C) and SELDA (M) are improved by 0.48% and 1.55% for AR, and 0.67% and 1.22% for FC when compared to LDA. In protocol of long-term EMG, the mean result of SEQDA is 3.15% better than that of QDA. CONCLUSION: The experimental results show that the self-enhancing classifiers significantly outperform the original versions using both AR and FC coefficient feature sets. The performance of SEQDA is superior to SELDA. In addition, preliminary study on long-term EMG data is conducted to verify the performance of SEQDA. PMID- 23634940 TI - Understanding self-aligned planar growth of InAs nanowires. AB - Semiconducting nanowires have attracted lots of attention because of their potential applications. Compared with free-standing nanowires, self-aligned planar nanowires grown epitaxially on the substrate have shown advantageous properties such as being twin defect free and ready for device fabrication, opening potentials for the large-scale device applications. Understanding of planar nanowire growth, which is essential for selective growth of planar vs free standing wires, is still limited. In this paper, we reported different growth behaviors for self-aligned planar and free-standing InAs nanowires under identical growth conditions. We present a new model based on a revised Gibbs Thomson equation for the planar nanowires. Using this model, we predicted and successfully confirmed through experiments that higher arsenic vapor partial pressure promoted free-standing InAs nanowire growth. A smaller critical diameter for planar nanowire growth was predicted and achieved experimentally. Successful control and understanding of planar and free-standing nanowire growth established in our work opens up the potential of large-scale integration of self-aligned nanowires for practical device applications. PMID- 23634937 TI - Investigation of mercury methylation pathways in biofilm versus planktonic cultures of Desulfovibrio desulfuricans. AB - Biofilms can methylate mercury (Hg) at higher rates than unattached bacteria and are increasingly recognized as important Hg methylation sites in the environment. Our previous study showed that methylation rates in biofilm cultures were up to 1 order of magnitude greater than those in planktonic cultures of a sulfate reducing bacterium. To probe whether the differential Hg methylation rates resulted from metabolic differences between these two cultures, Hg methylation assays following molybdate or chloroform inhibition (a specific inhibitor of the acetyl-CoA pathway) were conducted on biofilm and planktonic cultures of Desulfovibrio desulfuricans strains M8 and ND132. Molybdate was as effective in inhibiting Hg methylation as well as growth in both planktonic and biofilm cultures. The addition of chloroform only impacted Hg methylation in biofilm cultures, suggesting that different pathways are used for methylation in biofilm compared to planktonic cultures. To investigate this further, expression of the cooS gene, which encodes for carbon monoxide dehydrogenase, a key enzyme in the acetyl-CoA pathway, was compared in biofilm and planktonic cultures of ND132. Biofilm cultures showed up to 4 times higher expression of cooS than planktonic cultures. On the basis of these results, the acetyl-CoA pathway appears to play an important role in methylation in biofilm cultures of this organism, possibly by supplying the methyl group to Hg methylating enzymes; methylation in planktonic cultures appears to be independent of this pathway. This observation has important implications, particularly in developing reliable models to predict Hg methylation rates in different environments and perhaps eventually in being able to control this undesirable chemical transformation. PMID- 23634941 TI - Asymmetric transfer hydrogenation of ketones catalyzed by enantiopure osmium(II) pybox complexes. AB - The complexes trans-[OsCl2(L){(S,S)-(i)Pr-pybox}] ((S,S)-(i)Pr-pybox = 2,6-bis[4' (S)-isopropyloxazolin-2'-yl]pyridine, L = P(OMe)3 (1a), P(OEt)3 (2a), P(O(i)Pr)3 (3a), P(OPh)3 (4a), and cis-[OsCl2(L){(S,S)-(i)Pr-pybox}] (L = PPh3 (5a), P(i)Pr3 (6a), and PCy3 (7a)) have been synthesized from the complex trans-[OsCl2(eta(2) C2H4){(S,S)-(i)Pr-pybox}] via substitution of ethylene by phosphites and phosphines, respectively, under toluene reflux conditions. On the other hand, the synthesis of the complexes trans-[OsCl2(L){(R,R)-Ph-pybox}] (L = P(OMe)3 (1b) and cis-[OsCl2(L){(R,R)-Ph-pybox}] (L = PPh3 (5b), P(i)Pr3 (6b), and PCy3 (7b)) has been achieved from the complex trans-[OsCl2(eta(2)-C2H4){(R,R)-Ph-pybox}] ((R,R) Ph-pybox = 2,6-bis[4'-(R)-phenyloxazolin-2'-yl]pyridine under microwave irradiation. Complexes 1a-6a, 1b, 5b, and 6b have been assayed as catalysts for the asymmetric transfer hydrogenation (ATH) of ketones. Among the catalysts tested, the (i)Pr-pybox complexes trans-[OsCl2(L){(S,S)-(i)Pr-pybox}] (L = P(OMe)3 (1a), P(OEt)3 (2a), P(O(i)Pr)3 (3a), P(OPh)3 (4a)) have proven to be the most active catalysts for the reduction of a variety of aromatic ketones as nearly complete conversion and high enantioselectivity (up to 94%) are reached. PMID- 23634942 TI - Investigating the origins of nanostructural variations in differential ethnic hair types using X-ray scattering techniques. AB - OBJECTIVE: Human hair is a major determinant of visual ethnic differentiation. Although hair types are celebrated as part of our ethnic diversity, the approach to hair care has made the assumption that hair types are structurally and chemically similar. Although this is clearly not the case at the macroscopic level, the intervention of many hair treatments is at the nanoscopic and molecular levels. The purpose of the work presented here is to identify the main nanoscopic and molecular hierarchical differences across five different ethnic hair types from hair fibres taken exclusively from the scalp. These are Afro (subdivided into elastic 'rubber' and softer non-elastic 'soft'), Chinese, European and Mullato (mixed race). METHODS: Small angle X-Ray scattering (SAXS) is a technique capable of resolving nanostructural variations in complex materials. Individual hair fibres from different ethnic hair types were used to investigate structural features found in common and also specific to each type. Simultaneous wide angle X-Ray scattering (WAXS) was used to analyse the submolecular level structure of the fibrous keratin present. The data sets from both techniques were analysed with principal component analysis (PCA) to identify underlying variables. RESULTS: Principal component analysis of both SAXS and WAXS data was shown to discriminate the scattering signal between different hair types. The X-ray scattering results show a common underlying keratin intermediate filament (KIF) structure. However, distinct differences were observed in the preferential orientation and intensity signal from the lipid component of the hair. In addition, differences were observed in the intensity distribution of the very low-angle sample-dependent diffuse scatter surrounding the 'beamstop.' CONCLUSION: The results indicate that the fibrous keratin scaffold remains consistent between ethnic hair types. The hierarchies made by these may be modulated by variation in the content of keratin-associated proteins (KAPs) and lipids that alter the interfacial structures and lead to macroscopic differences in hair morphology. PMID- 23634943 TI - From iron pentacarbonyl to the iron ion by imaging photoelectron photoion coincidence. AB - The dissociation dynamics of internal energy selected iron pentacarbonyl cations, Fe(CO)5(+), have been investigated using the imaging photoelectron photoion coincidence (iPEPICO) spectrometer at the Swiss Light Source. The molecular ion loses all five carbonyl ligands in sequential dissociations in the 8.5-20 eV photon energy range. The Fe(CO)5(+) parent ion is metastable at the onset of the first dissociation reaction on the time scale of the experiment. The slightly asymmetric and broad daughter ion time-of-flight distributions indicate parent ion lifetimes in the microsecond range, and are used to obtain an experimental dissociation rate curve. Further carbonyl losses were found to be fast at threshold. The fractional parent and daughter ion abundances as a function of the photon energy, that is, breakdown diagram, as well as the dissociation rates for the first CO loss were modeled using the statistical Rice-Ramsperger-Kassel Marcus (RRKM) and statistical adiabatic channel model (SSACM) theories. The excess energy redistribution in the products was also taken into account in a statistical framework. The 0 K dissociative photoionization thresholds for the five carbonyl-loss channels were found to be 9.015 +/- 0.024 eV, 10.199 +/- 0.027 eV, 10.949 +/- 0.033 eV, 12.282 +/- 0.39 eV, and 13.821 +/- 0.045 eV for the processes leading to Fe(CO)4(+), Fe(CO)3(+), Fe(CO)2(+), Fe(CO)(+), and Fe(+), respectively. The iron cation thermochemistry is well-known, and these onsets connect the bare metal ion to the other fragment ions as well as to the gas phase neutral Fe(CO)5. PMID- 23634944 TI - Telomere-homologous G-rich oligonucleotides sensitize human ovarian cancer cells to TRAIL-induced growth inhibition and apoptosis. AB - G-rich T-oligos (GT-oligos; oligonucleotides with homology to telomeres) elicit a DNA damage response in cells and induce cytotoxic effects in certain tumor cell lines. We have previously shown that GT-oligo inhibits growth, arrests cell cycle, and induces apoptosis in ovarian, pancreatic, and prostate cancer cells. However, not all ovarian cancer cell lines are susceptible to GT-oligo exposure. GT-oligo was found to induce transcript expression of the tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors DR-4 and DR-5, which are generally silenced in ovarian cancer cells, rendering them insensitive to TRAIL. Exposure of TRAIL- and GT-oligo-resistant cell lines to GT-oligo rendered them sensitive to the cytotoxic effects of TRAIL, producing more than additive inhibition of growth. An intracellular inhibitor of the extrinsic apoptotic pathway, FLICE-like Inhibitory Protein-Short (FLIPs), was down-regulated and Jun kinase (JNK) was activated by exposure to GT-oligo. JNK inhibition partially reversed the growth inhibition caused by the combination of GT-oligo and TRAIL indicating partial involvement of the Jun kinase pathway in the resulting cytotoxic effect. Both capase-8 and caspases 3/7 were activated by exposure to GT oligo plus TRAIL, consistent with activation of the extrinsic apoptotic pathway. These results demonstrate a novel way of sensitizing resistant ovarian cancer cells to TRAIL-mediated cytotoxicity. PMID- 23634945 TI - Dose-dependent pharmacokinetic profiles of 2'-O-methyl phosphorothioate antisense oligonucleotidesin mdx mice. AB - Antisense-mediated exon skipping is a promising therapeutic approach for Duchenne muscular dystrophy. It aims to restore the dystrophin open reading frame by skipping exons with antisense oligonucleotides (AONs) to allow production of partly functional proteins. The approach is currently tested in phase 3 clinical trials, but dosing and maintenance regimens have not yet been well studied. This study compared pharmacokinetic and pharmacodynamic effects of different 2'-O methyl phosphorothioate RNA AON dosing and maintenance regimens in the preclinical mdx mouse model. When comparing different dosing regimens over a period of 8 weeks, higher levels of AON, exon skipping, and protein were observed in muscle after low daily doses compared with large weekly doses. Secondly, after receiving a high loading dose (1,250 mg/kg) in the first week, mice treated with maintenance injections twice weekly for 8 weeks showed higher preservation of therapeutic effects than mice receiving less or no maintenance injections. In both cases, the regimen resulting in the highest AON and exon skipping levels in muscle also resulted in high AON levels in liver and kidneys. These studies underline the importance of balancing optimal AON efficacy and tolerable levels in non-target organs, which may be fine-tuned by further optimization of AON treatment regimens. PMID- 23634946 TI - Hemoglobin is associated with periventricular but not deep white matter hyperintensities in lacunar ischemic stroke. PMID- 23634947 TI - Synthesis of alkaloids by Stevens rearrangement of nitrile-stabilized ammonium ylides: (+/-)-laudanosine, (+/-)-laudanidine, (+/-)-armepavine, (+/-)-7 methoxycryptopleurine, and (+/-)-xylopinine. AB - The Stevens rearrangement of nitrile-stabilized ammonium ylides in conjunction with the reductive removal of the nitrile function permits the facile construction of alpha-branched amines from alpha-aminonitriles. We employed this reaction sequence for the preparation of (+/-)-laudanosine, (+/-)-laudanidine and (+/-)-armepavine, (+/-)-7-methoxycryptopleurine, and (+/-)-xylopinine from two closely related and readily accessible bicyclic alpha-aminonitriles. The final products were obtained in high to almost quantitative yields (71-98%) from the quaternary ammonium salts obtained by N-alkylation of these starting materials. PMID- 23634948 TI - Roles of lipid metabolism in keloid development. AB - Keloids are common cutaneous pathological scars that are characterised by the histological accumulation of fibroblasts, collagen fibres, and clinically significant invasive growth. Although increasing lines of research on keloids have revealed genetic and environmental factors that contribute to their formation, the etiology of these scars remains unclear. Several studies have suggested the involvement of lipid metabolism, from a nutritional point of view. However, the role that lipid metabolism plays in the pathogenesis and progression of keloids has not previously been reviewed. The progress that has been made in understanding the roles of the pro- and anti-inflammatory lipid mediators in inflammation, and how they relate to the formation and progression of keloids, is also outlined. In particular, the possible relationships between mechanotransduction and lipid metabolites in keloids are explored. Mechanotransduction is the process by which physical forces are converted into biochemical signals that are then integrated into cellular responses. It is possible that lipid rafts and caveolae provide the location of lipid signaling and interactions between these signaling pathways and mechanotransduction. Moreover, interactions between lipid signaling pathway molecules and mechanotransduction molecules have been observed. A better understanding of the lipid profile changes and the functional roles lipid metabolism plays in keloids will help to identify target molecules for the development of novel interventions that can prevent, reduce, or even reverse pathological scar formation and/or progression. PMID- 23634949 TI - Historical facts of screening and diagnosing diabetes in pregnancy. AB - Diabetes is the most common metabolic disorder affecting pregnancy. Its prevalence seems to be growing in parallel with the epidemics of overweight and obesity. Recognizing and treating diabetes or any degree of glucose intolerance in pregnancy results in lowering maternal and fetal complications. These patients present higher risk for excessive weight gain, preeclampsia, cesarean sections, a high risk of developing type 2 diabetes and cardiovascular disease in the future. Infants born to these mothers are at higher risk for macrosomia and birth trauma, and after delivery, these infants have a higher risk of developing hypoglycemia, hypocalcemia, hyperbilirubinemia, respiratory distress syndrome, polycythemia and subsequent obesity and type 2 diabetes. Despite several international workshops and a lot of research there is still no unique approach to diagnose and treat diabetes in pregnancy. Who, when and how to screen and diagnose diabetes in pregnancy has been debated in the literature for so many decades and this debate seems to be endless. We present the evolution that screening and diagnosing diabetes in pregnancy has had over time. Besides many evidence of the benefits these procedures bring, health care providers still often prefer to use alternate criteria for this purpose. The myriad of maternal and fetal complications that could be avoided with an appropriate and simple screening procedure are ignored. Robust clinical trials such as the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study have shown how harmful can even slightly altered blood glucose levels be, but it has been found a resistance in the adoption of the new criteria proposed after this and other trials by many diabetes organizations. These organizations state that these new criteria would increase the incidence of diabetes in pregnancy, would imply in longer term follow-up of these patients and would pose an economic problem; they also state that alerting too many people in order to benefit a relatively few potential diabetics would arise psychologic ill effects. We think that health care providers should look for an uniformity in the screening and diagnosing diabetes in pregnancy based on evidence based medicine and not on specialists consensus. PMID- 23634950 TI - Predicting water consumption habits for seven arsenic-safe water options in Bangladesh. AB - BACKGROUND: In Bangladesh, 20 million people are at the risk of developing arsenicosis because of excessive arsenic intake. Despite increased awareness, many of the implemented arsenic-safe water options are not being sufficiently used by the population. This study investigated the role of social-cognitive factors in explaining the habitual use of arsenic-safe water options. METHODS: Eight hundred seventy-two randomly selected households in six arsenic-affected districts of rural Bangladesh, which had access to an arsenic-safe water option, were interviewed using structured face-to-face interviews in November 2009. Habitual use of arsenic-safe water options, severity, vulnerability, affective and instrumental attitudes, injunctive and descriptive norms, self-efficacy, and coping planning were measured. The data were analyzed using multiple linear regressions. RESULTS: Linear regression revealed that self-efficacy (B = 0.42, SE = .03, p < .001), the instrumental attitude towards the safe water option (B = 0.24, SE = .04, p < .001), the affective attitude towards contaminated tube wells (B = -0.04, SE = .02, p = .024), vulnerability (B = -0.20, SE = .02, p < .001), as well as injunctive (B = 0.08, SE = 0.04, p = .049) and descriptive norms (B = 0.34, SE = .03, p < .001) primarily explained the habitual use of arsenic-safe water options (R2 = 0.688). This model proved highly generalizable to all seven arsenic-safe water options investigated, even though habitual use of single options were predicted on the basis of parameters estimated without these options. CONCLUSIONS: This general model for the habitual use of arsenic-safe water options may prove useful to predict other water consumption habits. Behavior-change interventions are derived from the model to promote the habitual use of arsenic-safe water options. PMID- 23634951 TI - Prior extended daily access to cocaine elevates the reward threshold in a conditioned place preference test. AB - We have previously shown that extended-access subjects exhibit heightened motivation for cocaine in the runway model, as reflected by reduced number of retreats. This heightened motivation could reflect either an increase in cocaine induced reward or a decrease in cocaine-induced aversion. The current experiment was therefore devised to assess the cocaine-induced reward and aversion in extended-access rats using a place conditioning test. Rats trained to lever press for intravenous (IV) cocaine (0.25 mg/infusion) were provided 6-hour daily access to the drug over 10 days. Lever pressing in control subjects produced IV infusions of saline. Following drug self-administration, subjects underwent place conditioning for the immediate or delayed effects of cocaine (1.0 or 2.5 mg/kg, IV). In control subjects, the immediate effects of the low dose of cocaine produced conditioned places preferences (CPPs), while the delayed effects produced conditioned place aversions (CPAs). In contrast, the animals receiving low cocaine dose for 6 hours, exhibited place aversions but not preferences; an effect that was reversed when the dose of cocaine was increased. Additionally, in the 6-hour group, delayed conditioning was associated with a reduction in zif268 immunoreactivity in the medial prefrontal cortex and nucleus accumbens shell while immediate conditioning was associated with an increase in zif268-positive cells in the central nucleus of the amygdala. Collectively, these data suggest that extended daily access to cocaine produces a shift in the subject's perceived reward threshold that is paralleled by alterations in the activity of both the reward and stress pathways. PMID- 23634953 TI - Medical student self-reported confidence in obstetrics and gynaecology: development of a core clinical competencies document. AB - BACKGROUND: Clinical competencies in obstetrics and gynaecology have not been clearly defined for Australian medical students, the growing numbers of which may impact clinical teaching. Our aim was to administer and validate a competencies list, for self-evaluation by medical students of their confidence to manage common clinical tasks in obstetrics and gynaecology; to evaluate students' views on course changes that may result from increasing class sizes. METHODS: A draft list of competencies was peer-reviewed, and discussed at two student focus groups. The resultant list was administered as part of an 81 item online survey. RESULTS: Sixty-eight percent (N = 172) of those eligible completed the survey. Most respondents (75.8%) agreed or strongly agreed that they felt confident and well equipped to recognise and manage most common and important obstetric and gynaecological conditions. Confidence was greater for women, and for those who received a higher assessment grade. Free-text data highlight reasons for lack of clinical experience that may impact perceived confidence. CONCLUSIONS: The document listing competencies for medical students and educators is useful for discussions around a national curriculum in obstetrics and gynaecology in medical schools, including the best methods of delivery, particularly in the context of increasing student numbers. PMID- 23634952 TI - Paramagnetic nuclear magnetic resonance relaxation and molecular mechanics studies of the chloroperoxidase-indole complex: insights into the mechanism of chloroperoxidase-catalyzed regioselective oxidation of indole. AB - To unravel the mechanism of chloroperoxidase (CPO)-catalyzed regioselective oxidation of indole, we studied the structure of the CPO-indole complex using nuclear magnetic resonance (NMR) relaxation measurements and computational techniques. The dissociation constant (KD) of the CPO-indole complex was calculated to be approximately 21 mM. The distances (r) between protons of indole and the heme iron calculated via NMR relaxation measurements and molecular docking revealed that the pyrrole ring of indole is oriented toward the heme with its 2-H pointing directly at the heme iron. Both KD and r values are independent of pH in the range of 3.0-6.5. The stability and structure of the CPO-indole complex are also independent of the concentration of chloride or iodide ion. Molecular docking suggests the formation of a hydrogen bond between the NH group of indole and the carboxyl O of Glu 183 in the binding of indole to CPO. Simulated annealing of the CPO-indole complex using r values from NMR experiments as distance restraints reveals that the van der Waals interactions were much stronger than the Coulomb interactions in the binding of indole to CPO, indicating that the association of indole with CPO is primarily governed by hydrophobic rather than electrostatic interactions. This work provides the first experimental and theoretical evidence of the long-sought mechanism that leads to the "unexpected" regioselectivity of the CPO-catalyzed oxidation of indole. The structure of the CPO-indole complex will serve as a lighthouse in guiding the design of CPO mutants with tailor-made activities for biotechnological applications. PMID- 23634954 TI - Vibration-assisted upconversion of molecular luminescence induced by scanning tunneling microscopy. AB - : We investigate the effects of coupling between a molecular exciton, which consists of an electron and a hole in a molecule, and a surface plasmon (exciton plasmon coupling) on the electron transitions of the molecule using nonequilibrium Green's function method. Due to the exciton-plasmon coupling, excitation channels of the molecule arise in the energy range lower than the electronic excitation energy of the molecule. It is found that the electron transitions via these excitation channels give rise to the molecular luminescence and the vibrational excitations at the bias voltage lower than the electronic excitation energy of the molecule. Our results also indicate that the vibrational excitations assist the emission of photons, whose energy exceeds the product of the elementary charge and the bias voltage, (upconverted luminescence). PMID- 23634955 TI - Admission CTG, is there any evidence from which to draw conclusions? PMID- 23634956 TI - Catalytic enantioselective carbon insertion into the beta-vinyl C-H bond of cyclic enones. AB - Chiral oxazaborolidinium ion-catalyzed Csp(2)-H functionalization of enones using diazoacetate has been developed. Various beta-substituted cyclic enones were synthesized in high yield (up to 99%) with high to excellent enantioselectivity (up to 99% ee). The synthetic utility of this reaction was demonstrated by the formal synthesis of (+)-epijuvabione. PMID- 23634957 TI - Detection of specific HPV subtypes responsible for the pathogenesis of condylomata acuminata. AB - BACKGROUND: The low-risk human papillomavirus types 6 and 11 are responsible for approximately 90% of anogenital wart cases, with approximately 190,000 new and recurrent cases reported in the UK in 2010. The UK has recently selected the quadrivalent HPV vaccine, which conveys protection against both HPV6 and HPV 11, as part of its immunisation programme for 2012 and it is expected that this will reduce disease burden in the UK. The aims of the study were to evaluate current strategies used for the monitoring of HPV infection in genital warts and to assess the suitability of laser-capture microdissection (LCM) as a technique to improve the understanding of the natural history of HPV types associated with genital wart lesions. METHODS: DNA and RNA were extracted from whole wart, surface swabs and LCM sections from 23 patients. HPV types present were determined using the Linear Array HPV Genotyping Test (Roche), with HPV DNA viral load and mRNA expression investigated using qPCR and qRT-PCR, respectively. RESULTS: Results indicated that swabbing the surface of warts does not accurately reflect potential causative HPV types present within a wart lesion, multiple HPV types being present on the surface of the wart that are absent in the lower layers of tissue isolated by LCM. Although it was shown that HPV DNA viral load does not directly correlate with HPV mRNA load, the presence of both DNA and mRNA from a single HPV type suggested a causative role in lesion development in 8/12 (66.6%) of patients analysed, with dual infections seen in 4/12 (33.3%) cases. HPV 6 and HPV 11 were present in more than 90% of the lesions examined. CONCLUSIONS: Surface swabbing of warts does not necessarily reflect the causative HPV types. HPV type specific DNA and mRNA loads do not correlate. HPV 6 and 11 were likely to be causally involved in over 90% of the lesions. Dual infections were also found, and further studies are required to determine the biological and clinical nature of dual/multiple infections and to establish the relationship of multiple HPV types within a single lesion. PMID- 23634959 TI - CuH-ZSM-5 as hydrocarbon trap under cold start conditions. AB - Cold start tests are carried out to evaluate the performance of copper-exchanged zeolites as hydrocarbon traps under simulated gasoline car exhaust gases, paying special attention to the role of copper in the performance of these zeolites. It is concluded that the partial substitution of the protons in the parent H-ZSM-5 zeolite is highly beneficial for hydrocarbon trapping due to the formation of selective adsorption sites with specific affinity for the different exhaust components. However, it is also observed that uncontrolled exchanging process conditions could lead to the presence of CuO nanoparticles in the zeolite surface, which seem to block the pore structure of the zeolite, decreasing the hydrocarbon trap efficiency. Among all the zeolites studied, the results point out that a CuH-ZSM-5 with a partial substitution of extra-framework protons by copper cations and without any detectable surface CuO nanoparticles is the zeolite that showed the best performance under simulated cold start conditions due to both the high stability and the hydrocarbon retaining capacity of this sample during the consecutive cycles. PMID- 23634958 TI - Phylogeny and a structural model of plant MHX transporters. AB - BACKGROUND: The Arabidopsis thaliana MHX gene (AtMHX) encodes a Mg2+/H+ exchanger. Among non-plant proteins, AtMHX showed the highest similarity to mammalian Na+/Ca2+ exchanger (NCX) transporters, which are part of the Ca2+/cation (CaCA) exchanger superfamily. RESULTS: Sequences showing similarity to AtMHX were searched in the databases or sequenced from cDNA clones. Phylogenetic analysis showed that the MHX family is limited to plants, and constitutes a sixth family within the CaCA superfamily. Some plants include, besides a full MHX gene, partial MHX-related sequences. More than one full MHX gene was currently identified only in Oryza sativa and Mimulus guttatus, but an EST for more than one MHX was identified only in M. guttatus. MHX genes are not present in the currently available chlorophyte genomes. The prevalence of upstream ORFs in MHX genes is much higher than in most plant genes, and can limit their expression. A structural model of the MHXs, based on the resolved structure of NCX1, implies that the MHXs include nine transmembrane segments. The MHXs and NCXs share 32 conserved residues, including a GXG motif implicated in the formation of a tight-turn in a reentrant-loop. Three residues differ between all MHX and NCX proteins. Altered mobility under reducing and non-reducing conditions suggests the presence of an intramolecular disulfide-bond in AtMHX. CONCLUSIONS: The absence of MHX genes in non-plant genomes and in the currently available chlorophyte genomes, and the presence of an NCX in Chlamydomonas, are consistent with the suggestion that the MHXs evolved from the NCXs after the split of the chlorophyte and streptophyte lineages of the plant kingdom. The MHXs underwent functional diploidization in most plant species. De novo duplication of MHX occurred in O. sativa before the split between the Indica and Japonica subspecies, and was apparently followed by translocation of one MHX paralog from chromosome 2 to chromosome 11 in Japonica. The structural analysis presented and the identification of elements that differ between the MHXs and the NCXs, or between the MHXs of specific plant groups, can contribute to clarification of the structural basis of the function and ion selectivity of MHX transporters. PMID- 23634960 TI - Maillard reactions in hyperthermophilic archaea: implications for better understanding of non-enzymatic glycation in biology. AB - Maillard reactions are an unavoidable feature of life that appear to be damaging to cell and organisms. Consequently, all living systems must have ways to protect themselves against this process. As of 2012, several such defense mechanisms have been identified. They are all enzymatic and were found in mesophilic organisms. To date, no systematic study of Maillard reactions and the relevant defense mechanisms has been conducted in thermophiles (50 degrees C-80 degrees C) or hyperthermophiles (80 degrees C-120 degrees C). This is surprisingly because Maillard reactions become significantly faster and potent with increasing temperatures. This review examines this neglected issue in two well-defined sets of hyperthermophiles. My analysis suggests that hyperthermophiles cope with glycation stress by several mechanisms: * Absence of glycation-prone head groups (such as ethanoalamine) from hyperthermophilic phospholipids * Protection of reactive carbohydrates and labile metabolic intermediates by substrate channeling. * Conversion of excess reactive sugars such as glucose to non reactive compounds including trehalose, di-myo-inositol-phosphate and mannosylglycerate. * Detoxification of methylglyoxal and other ketoaldehydes by conversion to inert products through a variety of reductases and dehydrogenases. * Scavenging of the remaining carbonyls by nucleophilic amines, including a variety of novel polyamines. Disruption of the Maillard process at its early stages, rather than repair of damage caused by it at later stages, appears to be the preferred strategy in the organisms examined. The most unique among these mechanisms appears to be a polyamine-based scavenging system. Undertaking research of the Maillard process in hyperthermophiles is important in its own right and is also likely to provide new insights for the control of these reactions in humans, especially in diseases such as diabetes mellitus. PMID- 23634961 TI - A comparison of general practitioners prescribing of gluten-free foods for the treatment of coeliac disease with national prescribing guidelines. AB - BACKGROUND: Coeliac disease is an autoimmune disorder that is considered to affect approximately one in 100 people. In the UK, gluten-free (GF) foods can be prescribed by general practitioners (GPs) to treat this condition and there are national guidelines on the quantities of GF food an individual should receive on prescription. Information on actual prescribing behaviour by GPs, and how this compares with guideline recommendations, is scarce. The present study aimed to describe GPs prescribing practice of GF foods, within one locality in the UK, comparing this with national guidelines. METHODS: A retrospective evaluation of GP electronic medical records for all patients with a gluten-sensitive enteropathy diagnosis and/or those prescribed GF food between April 2010 and March 2011 was carried out in 16 GP practices in the west of Scotland, serving a total of 85 667 patients. RESULTS: Of 175 (0.18% of the total practice population) patients, 152 were identified with coeliac disease, eight with dermatitis herpetiformis and six with both conditions. A further nine patients received GF foods on prescriptions with no recorded diagnosis. There was a positive association between adherence to the prescribing guidelines and female sex (P < 0.0001) and (for those with a recorded diagnosis) increasing age (P = 0.001). There was no significant association between either socio-economic deprivation or co-morbidities and adherence to the prescribing guidelines. CONCLUSIONS: There was significant under prescribing of GF foods in those identified. Further research is required to establish whether these results are representative of wider practice in the UK. PMID- 23634962 TI - Structural and optical characterization of metal tungstates (MWO4; M=Ni, Ba, Bi) synthesized by a sucrose-templated method. AB - BACKGROUND: Metal tungstates have attracted much attention due to their interesting structural and photoluminescence properties. Depending on the size of the bivalent cation present, the metal tungstates will adopt structures with different phases. In this work, three different phases of metal tungstates MWO4 (M= Ba, Ni and Bi) were synthesized via the sucrose templated method. RESULTS: The powders of BaWO4 (tetragonal), NiWO4 (monoclinic) and Bi2WO6 (orthorhombic) formed after calcination temperatures of 750, 650 and 600 degrees C for 4 h respectively are found to be crystalline and exist in their pure phase. Based on Scherrer estimation, their crystallite size are of nanosized. BET results showed NiWO4 has the highest surface area. BaWO4 exhibited less Raman vibrations than the NiWO4 because of the increased lattice symmetry but Bi2WO6 showed almost the same Raman vibrations as BaWO4. From the UV-vis spectra, the band gap transition of the metal tungstates are of the order of BaWO4 > Bi2WO6 > NiWO4. Broad blue green emission peaks were detected in photoluminescence spectra and the results showed the great dependence on morphology, crystallinity and size of the metal tungstates. CONCLUSION: Three different phases of metal tungstates of BaWO4 (scheelite), NiWO4 (wolframite) and Bi2WO6 (perovskite layer) in their pure phase were successfully prepared by the simple and economical sucrose-templated method. The highest surface area is exhibited by NiWO4 while largest band gap is shown by BaWO4. These materials showed promising optical properties. PMID- 23634963 TI - Experimental and analytical performance evaluation of short circular hydrodynamic journal bearings used in rotary blood pumps. AB - Rotary blood pumps (RBPs) have demonstrated considerable promise while treating heart failure patients, such that they are being placed at an earlier stage of the disease. These devices may therefore be required to operate for prolonged durations which yields the need for RBPs exhibiting high durability, reliability, and blood compatibility. Noncontacting bearings, utilizing magnetic and/or hydrodynamic suspension techniques, appear to provide a suitable solution to these challenges. Hydrodynamic suspension has the advantage that it does not need feedback control systems. Among various hydrodynamic bearing types, the circular journal bearing has the particular benefit of easy manufacturing. This study presents methods to evaluate the performance of short (length to diameter ratio <1) circular hydrodynamic journal bearings (HJBs) for RBPs. Analytical calculations with specific boundary conditions are presented to predict the rotor's eccentricity under equilibrium states and thus the related performance parameters such as load capacity, power loss, and shear rates. These results and boundary conditions were confirmed experimentally in a specially designed test set-up. The bearing performance was found to correlate to analytical solutions using the full Sommerfeld boundary condition instead of the half Sommerfeld condition conventionally used for such applications. Geometrical and operational parameter variations showed that HJB designs with a short Sommerfeld Number SS >0.02 can provide sufficient fluid film thicknesses and low shear rates. The measurements were further used to evaluate the bearings' stability. The estimation of the stability threshold drawn in relation to a modified stability index and the equilibrium eccentricity of the rotor allows the prediction of stability for short circular HJB designs under full Sommerfeld condition. PMID- 23634964 TI - Random measurements of adiponectin and IL-6 may not be indicative of the 24-h profile in critically ill patients. AB - CONTEXT: The anti-inflammatory role of adiponectin has prompted interest in a potential role in acute inflammatory conditions associated with critical illness. It is unclear whether a random adiponectin measurement adequately reflects the 24 h profile in critically ill patients. OBJECTIVE: To assess the temporal profile of total and high molecular weight (HMW) adiponectin and interleukin-6 (IL-6) in 15 critically ill patients. DESIGN: A prospective, observational study. SETTING: Level II intensive care unit in a metropolitan hospital. PATIENTS OR OTHER PARTICIPANTS: Fifteen critically ill patients expected to stay in the ICU for longer than 48 h were eligible for enrolment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serial, hourly measurements of total and HMW adiponectin and IL-6. RESULTS: Over a 24-h period, total and HMW adiponectin display considerable within-patient variability (coefficient of variation 34% and 87% respectively) and show no trend over time. Averaging 2 or 3 continuous measures reduced within patient variability of both total and HMW adiponectin by up to 50% compared to one measure. There was a negative correlation between serum glucose and adiponectin (total P = 0.016, HMW P = 0.039). No relationship existed between adiponectin and IL-6 (total P = 0.62, HMW P = 0.35). CONCLUSIONS: Marked within patient, hourly variability in total and HMW adiponectin is evident in critically ill patients. A random measurement may not be reflective of the 24-h profile in these patients. A negative correlation exists between adiponectin and blood glucose levels and a positive correlation between adiponectin and oxygen saturation. No clear relationship exists between adiponectin and IL-6. PMID- 23634966 TI - cis-2,3-Disubstituted cyclopropane 1,1-diesters in [3 + 2] annulations with aldehydes: highly diastereoselective construction of densely substituted tetrahydrofurans. AB - A series of cis-2,3-disubstituted cyclopropane 1,1-diesters were examined in the AlCl3-promoted [3 + 2]-annulations with aldehydes. In this reaction, these cis cyclopropanes displayed reactivities starkly different from their trans counterparts in terms of the high chemical yields (up to 98%) and provided the desired annulation products with excellent diastereomeric purity. This protocol provides a facile and highly stereoselective way to construct synthetically useful pentasubstituted tetrahydrofurans not easily accessible using other methods. PMID- 23634965 TI - Targeting norepinephrine in mild cognitive impairment and Alzheimer's disease. AB - The Alzheimer's disease (AD) epidemic is a looming crisis, with an urgent need for new therapies to delay or prevent symptom onset and progression. There is growing awareness that clinical trials must target stage-appropriate pathophysiological mechanisms to effectively develop disease-modifying treatments. Advances in AD biomarker research have demonstrated changes in amyloid-beta (Abeta), brain metabolism and other pathophysiologies prior to the onset of memory loss, with some markers possibly changing one or two decades earlier. These findings suggest that amyloid-based therapies would optimally be targeted at the earliest clinically detectable stage (such as mild cognitive impairment (MCI)) or before. Postmortem data indicate that tau lesions in the locus coeruleus (LC), the primary source of subcortical norepinephrine (NE), may be the first identifiable pathology of AD, and recent data from basic research in animal models of AD indicate that loss of NE incites a neurotoxic proinflammatory condition, reduces Abeta clearance and negatively impacts cognition - recapitulating key aspects of AD. In addition, evidence linking NE deficiency to neuroinflammation in AD also exists. By promoting proinflammatory responses, suppressing anti-inflammatory responses and impairing Abeta degradation and clearance, LC degeneration and NE loss can be considered a triple threat to AD pathogenesis. Remarkably, restoration of NE reverses these effects and slows neurodegeneration in animal models, raising the possibility that treatments which increase NE transmission may have the potential to delay or reverse AD-related pathology. This review describes the evidence supporting a key role for noradrenergic-based therapies to slow or prevent progressive neurodegeneration in AD. Specifically, since MCI coincides with the onset of clinical symptoms and brain atrophy, and LC pathology is already present at this early stage of AD pathogenesis, MCI may offer a critical window of time to initiate novel noradrenergic-based therapies aimed at the secondary wave of events that lead to progressive neurodegeneration. Because of the widespread clinical use of drugs with a NE-based mechanism of action, there are immediate opportunities to repurpose existing medications. For example, NE transport inhibitors and NE precursor therapies that are used for treatment of neurologic and psychiatric disorders have shown promise in animal models of AD, and are now prime candidates for early-phase clinical trials in humans. PMID- 23634968 TI - A clock reaction based on molybdenum blue. AB - Clock reactions are rare kinetic phenomena, so far limited mostly to systems with ionic oxoacids and oxoanions in water. We report a new clock reaction in cyclohexanol that forms molybdenum blue from a noncharged, yellow molybdenum complex as precursor, in the presence of hydrogen peroxide. Interestingly, the concomitant color change is reversible, enabling multiple clock cycles to be executed consecutively. The kinetics of the clock reaction were experimentally characterized, and by adding insights from quantum chemical calculations, a plausible reaction mechanism was postulated. Key elementary reaction steps comprise sigmatropic rearrangements with five-membered or bicyclo[3.1.0] transition states. Importantly, numerical kinetic modeling demonstrated the mechanism's ability to reproduce the experimental findings. It also revealed that clock behavior is intimately connected to the sudden exhaustion of hydrogen peroxide. Due to the stoichiometric coproduction of ketone, the reaction bears potential for application in alcohol oxidation catalysis. PMID- 23634967 TI - Social motivation in individuals with isolated cleft lip and palate. AB - Social isolation is common among individuals with isolated cleft lip and palate (ICLP), but the available data on why this may be are mixed. We present a novel theory relating to reduced social motivation in ICLP, called the social abulia hypothesis. Based on this hypothesis, we predicted that reduced social motivation would lead to reduced responsiveness to negative social feedback, in terms of both explicit responses and noncontrolled, psychophysiological responses. Twenty males with ICLP and 20 normal comparison males between 13 and 25 years old participated in the study. Social motivation was examined by measuring participants' response to negative social feedback (social exclusion). Additionally, psychophysiological reactivity to positive and negative social stimuli was measured. In order to rule out other potential contributors to social isolation, we tested basic social perception, emotion recognition, and social anxiety. In line with the social abulia hypothesis, we show that negative social feedback had less of an effect on males with ICLP than on healthy male peers, which was evident in explicit responses and noncontrolled, psychophysiological responses to negative social feedback. Our results could not be attributed to problems in social perception, a lack of understanding facial expressions, or increased social anxiety, as groups did not differ on these constructs. This study suggests that current views on social isolation in ICLP may need to be reconsidered to include the possibility that isolation in this population may be the direct result of reduced social motivation. PMID- 23634969 TI - Advantages of using molecular coancestry in the removal of introgressed genetic material. AB - BACKGROUND: When introgression of undesired exogenous genetic material occurs in a population intended to remain pure, actions are necessary to recover the original background. It has been shown that genome-wide information can replace pedigree information for different objectives and is a valuable tool in the fields of genetic conservation and breeding. In this simulation study, molecular information provided by 50 000 SNP was used to minimise the molecular coancestry between individuals of an admixed population and the foreign individuals that originally introgressed a native population in order to remove the exogenous DNA. RESULTS: This management method, which detects the 'purest' individuals to be used as parents for the next generation, allowed recovery of the native genetic background to a great extent in all simulated scenarios. However, it also caused an increase in inbreeding larger than expected because of the lower number of individuals selected as parents and the higher coancestry between them. In scenarios involving several introgression events the method was more efficient than in those involving a single introgression event because part of the genetic information was mixed with the native genetic material for a shorter period. CONCLUSIONS: Genome-wide information can be used to identify the purest individuals via the minimisation of molecular coancestry between individuals of the admixed and exogenous populations. Removal of the undesired genetic material is more efficient with a molecular-based approach than with a pedigree-based approach. PMID- 23634970 TI - High magnetic field reveals the nature of excitons in a single GaAs/AlAs core/shell nanowire. AB - Magneto-photoluminescence measurements of individual zinc-blende GaAs/AlAs core/shell nanowires are reported. At low temperature, a strong emission line at 1.507 eV is observed under low power (nW) excitation. Measurements performed in high magnetic field allowed us to detect in this emission several lines associated with excitons bound to defect pairs. Such lines were observed before in epitaxial GaAs of very high quality, as reported by Kunzel and Ploog. This demonstrates that the optical quality of our GaAs/AlAs core/shell nanowires is comparable to the best GaAs layers grown by molecular beam epitaxy. Moreover, strong free exciton emission is observed even at room temperature. The bright optical emission of our nanowires in room temperature should open the way for numerous optoelectronic device applications. PMID- 23634971 TI - Now on display: a gallery of group II intron structures at different stages of catalysis. AB - Group II introns are mobile genetic elements that self-splice and retrotranspose into DNA and RNA. They are considered evolutionary ancestors of the spliceosome, the ribonucleoprotein complex essential for pre-mRNA processing in higher eukaryotes. Over a 20-year period, group II introns have been characterized first genetically, then biochemically, and finally by means of X-ray crystallography. To date, 17 crystal structures of a group II intron are available, representing five different stages of the splicing cycle. This review provides a framework for classifying and understanding these new structures in the context of the splicing cycle. Structural and functional implications for the spliceosome are also discussed. PMID- 23634973 TI - An empirical study of patient participation in guideline development: exploring the potential for articulating patient knowledge in evidence-based epistemic settings. AB - BACKGROUND: Patient participation on both the individual and the collective level attracts broad attention from policy makers and researchers. Participation is expected to make decision making more democratic and increase the quality of decisions, but empirical evidence for this remains wanting. OBJECTIVE: To study why problems arise in participation practice and to think critically about the consequence for future participation practices. We contribute to this discussion by looking at patient participation in guideline development. METHODS: Dutch guidelines (n = 62) were analysed using an extended version of the AGREE instrument. In addition, semi-structured interviews were conducted with actors involved in guideline development (n = 25). RESULTS: The guidelines analysed generally scored low on the item of patient participation. The interviews provided us with important information on why this is the case. Although some respondents point out the added value of participation, many report on difficulties in the participation practice. Patient experiences sit uncomfortably with the EBM structure of guideline development. Moreover, patients who develop epistemic credibility needed to participate in evidence-based guideline development lose credibility as representatives for 'true' patients. DISCUSSION AND CONCLUSIONS: We conclude that other options may increase the quality of care for patients by paying attention to their (individual) experiences. It will mean that patients are not present at every decision-making table in health care, which may produce a more elegant version of democratic patienthood; a version that neither produces tokenistic practices of direct participation nor that denies patients the chance to contribute to matters where this may be truly meaningful. PMID- 23634974 TI - Models and standards of proof in cross-disciplinary science: the case of arsenic DNA. PMID- 23634972 TI - Assessment of selection bias in a health survey of children and families - the IDEFICS Sweden-study. AB - BACKGROUND: A health survey was performed in 2007-2008 in the IDEFICS/Sweden study (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) in children aged 2-9 years. We hypothesized that families with disadvantageous socioeconomic and -demographic backgrounds and children with overweight and obesity were underrepresented. METHODS: In a cross sectional study, we compared Swedish IDEFICS participants (N=1,825) with referent children (N=1,825) using data from Statistics Sweden population registers. IDEFICS participants were matched for age and gender with a referent child living in the same municipality. Longitudinal weight and height data from birth to 8 years was collected for both populations (n=3,650) from the children's local health services. Outcome measures included the family's socioeconomic and demographic characteristics, maternal body mass index (BMI) and smoking habits before pregnancy, the children's BMI standard deviation score (SDS) at the age of inclusion in the IDEFICS study (BMISDS-index), and the children's BMI-categories during the age-span. Comparisons between groups were done and a multiple logistic regression analysis for the study of determinants of participation in the IDEFICS study was performed. RESULTS: Compared with IDEFICS participants, referent families were more likely to have lower education and income, foreign backgrounds, be single parents, and have mothers who smoked before pregnancy. Maternal BMI before pregnancy and child's BMISDS-index did not differ between groups. Comparing the longitudinal data-set, the prevalence of obesity was significantly different at age 8 years n= 45 (4.5%) versus n= 31 (2.9%) in the referent and IDEFICS populations, respectively. In the multivariable adjusted model, the strongest significant association with IDEFICS study participation was parental Swedish background (odds ratio (OR) = 1.91, 95% confidence interval (CI) (1.48-2.47) followed by parents having high education OR 1.80, 95% CI (1.02-3.16) and being married or co-habiting OR 1.75 95% CI (1.38-2.23). CONCLUSION: Families with single parenthood, foreign background, low education and income were underrepresented in the IDEFICS Sweden study. BMI at inclusion had no selection effect, but developing obesity was significantly greater among referents. PMID- 23634975 TI - Transthoracic echocardiography reference values in juvenile and adult 129/Sv mice. AB - BACKGROUND: In the recent years, the use of Doppler-echocardiography has become a standard non-invasive technique in the analysis of cardiac malformations in genetically modified mice. Therefore, normal values have to be established for the most commonly used inbred strains in whose genetic background those mutations are generated. Here we provide reference values for transthoracic echocardiography measurements in juvenile (3 weeks) and adult (8 weeks) 129/Sv mice. METHODS: Echocardiographic measurements were performed using B-mode, M-mode and Doppler-mode in 15 juvenile (3 weeks) and 15 adult (8 weeks) mice, during isoflurane anesthesia. M-mode measurements variability of left ventricle (LV) was determined. RESULTS: Several echocardiographic measurements significantly differ between juvenile and adult mice. Most of these measurements are related with cardiac dimensions. All B-mode measurements were different between juveniles and adults (higher in the adults), except for fractional area change (FAC). Ejection fraction (EF) and fractional shortening (FS), calculated from M-mode parameters, do not differ between juvenile and adult mice. Stroke volume (SV) and cardiac output (CO) were significantly different between juvenile and adult mice. SV was 31.93 +/- 8.67 MUl in juveniles vs 70.61 +/- 24.66 MUl in adults, rho < 0.001. CO was 12.06 +/- 4.05 ml/min in juveniles vs 29.71 +/- 10.13 ml/min in adults, rho < 0.001. No difference was found in mitral valve (MV) and tricuspid valve (TV) related parameters between juvenile and adult mice. It was demonstrated that variability of M-mode measurements of LV is minimal. CONCLUSIONS: This study suggests that differences in cardiac dimensions, as wells as in pulmonary and aorta outflow parameters, were found between juvenile and adult mice. However, mitral and tricuspid inflow parameters seem to be similar between 3 weeks and 8 weeks mice. The reference values established in this study would contribute as a basis to future studies in post-natal cardiovascular development and diagnosing cardiovascular disorders in genetically modified mouse mutant lines. PMID- 23634976 TI - A salt bridge in intracellular loop 2 is essential for folding of human p glycoprotein. AB - There is no high-resolution structure of the human P-glycoprotein (P-gp, ABCB1) drug pump. Homology models based on the crystal structures of mouse and Caenorhabditis elegans P-gps show extensive contacts between intracellular loop 2 (ICL2, in the first transmembrane domain) and the second nucleotide-binding domain. Human P-gp modeled on these P-gp structures yields different ICL2 structures. Only the model based on the C. elegans P-gp structure predicts the presence of a salt bridge. We show that the Glu256-Arg276 salt bridge was critical for P-gp folding. PMID- 23634977 TI - NH2+ implantations induced superior hemocompatibility of carbon nanotubes. AB - NH2+ implantation was performed on multiwalled carbon nanotubes (MWCNTs) prepared by chemical vapor deposition. The hemocompatibility of MWCNTs and NH2+-implanted MWCNTs was evaluated based on in vitro hemolysis, platelet adhesion, and kinetic clotting tests. Compared with MWCNTs, NH2+-implanted MWCNTs displayed more perfect platelets and red blood cells in morphology, lower platelet adhesion rate, lower hemolytic rate, and longer kinetic blood-clotting time. NH2+ implanted MWCNTs with higher fluency of 1 * 1016 ions/cm2 led to the best thromboresistance, hence desired hemocompatibility. Fourier transfer infrared and X-ray photoelectron spectroscopy analyses showed that NH2+ implantation caused the cleavage of some pendants and the formation of some new N-containing functional groups. These results were responsible for the enhanced hemocompatibility of NH2+-implanted MWCNTs. PMID- 23634978 TI - Effect of dissolved organic matter source and character on microbial Hg methylation in Hg-S-DOM solutions. AB - Dissolved organic matter (DOM) is a key component of fate and transport models for most metals, including mercury (Hg). Utilizing a suite of diverse DOM isolates, we demonstrated that DOM character, in addition to concentration, influences inorganic Hg (Hg(II)i) bioavailability to Hg-methylating bacteria. Using a model Hg-methylating bacterium, Desulfovibrio desulfuricans ND132, we evaluated Hg-DOM-sulfide bioavailability in washed-cell assays at environmentally relevant Hg/DOM ratios (~1-8 ng Hg/mg C) and sulfide concentrations (1-1000 MUM). All tested DOM isolates significantly enhanced Hg methylation above DOM-free controls (from ~2 to >20-fold for 20 mg C/L DOM solutions), but high molecular weight/highly aromatic DOM isolates and/or those with high sulfur content were particularly effective at enhancing Hg methylation. Because these experiments were conducted under conditions of predicted supersaturation with respect to metacinnabar (beta-HgS(s)), we attribute the DOM-dependent enhancement of Hg(II)i bioavailability to steric and specific chemical (e.g., DOM thiols) inhibition of beta-HgS(s) growth and aggregation by DOM. Experiments examining the role of DOM across a wide sulfide gradient revealed that DOM only enhances Hg methylation under fairly low sulfide conditions (?30 MUM), conditions that favor HgS nanoparticle/cluster formation relative to dissolved HgS species. PMID- 23634979 TI - Brain gamma-aminobutyric acid (GABA) abnormalities in bipolar disorder. AB - OBJECTIVES: Gamma-aminobutyric acid (GABA) abnormalities have been implicated in bipolar disorder. However, due to discrepant studies measuring postmortem, cerebrospinal fluid, plasma, and in vivo brain levels of GABA, the nature of these abnormalities is unclear. Using proton magnetic resonance spectroscopy, we investigated tissue levels of GABA in the anterior cingulate cortex and parieto occipital cortex of participants with bipolar disorder and healthy controls. METHODS: Fourteen stably medicated euthymic outpatients with bipolar disorder type I (mean age 32.6 years, eight male) and 14 healthy control participants (mean age 36.9 years, 10 male) completed a proton magnetic resonance spectroscopy scan at 4-Tesla after providing informed consent. We collected data from two 16.7 mL voxels using MEGAPRESS, and they were analyzed using LCModel. RESULTS: GABA/creatine ratios were elevated in bipolar disorder participants compared to healthy controls [F(1,21) = 4.4, p = 0.048] in the anterior cingulate cortex (25.1% elevation) and the parieto-occipital cortex (14.6% elevation). Bipolar disorder participants not taking GABA-modulating medications demonstrated greater GABA/creatine elevations than patients taking GABA-modulating medications. CONCLUSIONS: We found higher GABA/creatine levels in euthymic bipolar disorder outpatients compared to healthy controls, and the extent of this elevation may be affected by the use of GABA-modulating medications. Our findings suggest that elevated brain GABA levels in bipolar disorder may be associated with GABAergic dysfunction and that GABA-modulating medications reduce GABA levels in this condition. PMID- 23634980 TI - Activating mutations and senescence secretome: new insights into HER2 activation, drug sensitivity and metastatic progression. AB - HER2 amplification and overexpression is observed in approximately 20% of breast cancers and is strongly associated with poor prognosis and therapeutic responsiveness to HER2 targeted agents. A recent study by Bose and colleagues suggests that another subset of breast cancer patients without HER2 amplification but with activating HER2 mutation might also benefit from existing HER2-targeted agents and the authors functionally characterize these somatic mutations in experimental models. In a second study on HER2-driven breast cancer, Angelini and colleagues investigate how the constitutively active, truncated carboxy-terminal fragment of HER2, p95HER2, promotes metastatic progression through non cellautonomous secretion of factors from senescent cells. These new findings advance our understanding of HER2 biology in the context of HER2 activation as well as offer new insights into our understanding of drug sensitivity and metastatic progression. PMID- 23634982 TI - Cost-effectiveness of a coronary heart disease secondary prevention program in patients with myocardial infarction: results from a randomised controlled trial (ProActive Heart). AB - BACKGROUND: Participation in coronary heart disease (CHD) secondary prevention programs is low. Telephone-delivered CHD secondary prevention programs may overcome the treatment gap. The telephone-based health coaching ProActive Heart trial intervention has previously been shown to be effective for improving health related quality of life, physical activity, body mass index, diet, alcohol intake and anxiety. As a secondary aim, the current study evaluated the cost effectiveness of the ProActive Heart intervention compared to usual care. METHODS: 430 adult myocardial infarction patients were randomised to a six-month CHD secondary prevention 'health coaching' intervention or 'usual care' control group. Primary outcome variables were health-related quality of life (SF-36) and physical activity (Active Australia Survey). Data were collected at baseline, six months (post-intervention) and 12 months (six-months post-intervention completion) for longer term effects. Cost-effectiveness data [health utility (SF 6D) and health care utilisation] were collected using self-reported (general practitioner, specialist, other health professionals, health services, and medication) and claims data (hospitalisation rates). Intervention effects are presented as mean differences (95% CI), p-value. RESULTS: Improvements in health status (SF-6D) were observed in both groups, with no significant difference between the groups at six [0.012 (-0.016, 0.041), p = 0.372] or 12 months [0.011 (-0.028, 0.051) p = 0.738]. Patients in the health coaching group were significantly more likely to be admitted to hospital due to causes unrelated to cardiovascular disease (p = 0.042). The overall cost for the health coaching group was higher ($10,574 vs. $8,534, p = 0.021), mainly due to higher hospitalisation (both CHD and non-CHD) costs ($6,841 vs. $4,984, p = 0.036). The incremental cost-effectiveness ratio was $85,423 per QALY. CONCLUSIONS: There was no intervention effect measured using the SF-36/SF-6D and ProActive Heart resulted in significantly increased costs. The cost per QALY gained from ProActive Heart was high and above acceptable limits compared to usual care. PMID- 23634981 TI - Comparison of a loop-mediated isothermal amplification for orf virus with quantitative real-time PCR. AB - BACKGROUND: Orf virus (ORFV) causes orf (also known as contagious ecthyma or contagious papular dermatitis), a severe infectious skin disease in goats, sheep and other ruminants. Therefore, a rapid, highly specific and accurate method for the diagnosis of ORFV infections is essential to ensure that the appropriate treatments are administered and to reduce economic losses. METHODS: A loop mediated isothermal amplification (LAMP) assay based on the identification of the F1L gene was developed for the specific detection of ORFV infections. The sensitivity and specificity of the LAMP assay were evaluated, and the effectiveness of this method was compared with that of real-time PCR. RESULTS: The sensitivity of this assay was determined to be 10 copies of a standard plasmid. Furthermore, no cross-reactivity was found with either capripox virus or FMDV. The LAMP and real-time PCR assays were both able to detect intracutaneous- and cohabitation-infection samples, with a concordance of 97.83%. LAMP demonstrated a sensitivity of 89.13%. CONCLUSION: The LAMP assay is a highly efficient and practical method for detecting ORFV infection. This LAMP method shows great potential for monitoring the prevalence of orf, and it could prove to be a powerful supplemental tool for current diagnostic methods. PMID- 23634983 TI - A population-based cross-sectional study of health service deficits among U.S. adults with depressive symptoms. AB - BACKGROUND: Depression is a psychiatric condition that affects approximately one in five U.S. adults in their lifetime. No study that we know of has examined depressive symptoms and health service deficits in rural compared with non-rural populations. Four factors constitute the variable health service deficits: did not have health insurance, did not have a healthcare provider, deferred medical care because of cost and did not have a routine medical exam, all within the last 12 months. The aim of this study was to ascertain the prevalence of health service deficits in rural versus non-rural adults with depressive symptoms. Examining depressive symptoms by health service deficits is important because it allows us to approximate those with the condition who might not be receiving care for it. By analyzing national, population-based data, this study sought to fill in some important epidemiological gaps regarding depressive symptoms and health service deficits. METHODS: For this analysis the population of interest was U.S. adults identified as currently having depressive symptoms using the PHQ-8 criteria. Behavior Risk Factor Surveillance Survey 2006 data were used in this analysis. Health service deficits was the primary dependent variable. Multivariate logistic regression analysis was performed to examine health service deficits experienced by adults with depression controlling for socioeconomic status, race and ethnicity and geographic locale (rural or non-rural). RESULTS: Logistic regression analysis yielded that U.S. adults currently having depressive symptoms who were of low socioeconomic status, Hispanic ethnicity, or living in a rural locale were more likely to have at least one health service deficit. CONCLUSION: Analyzing data collected by a large surveillance system such as BRFSS, allows for an analysis incorporating an array of covariates not available from clinically-based data such as electronic health records. By identifying clinically depressed U.S. adults who also have at least one health service deficit, we were able to ascertain those most likely not receiving care for this debilitating condition. We believe community pharmacists are well suited to assist in connecting depressed, vulnerable populations with appropriate and needed care. This care would be best provided by an inter-professional team led by a primary care provider. PMID- 23634984 TI - The commercialization of regenerative medicine into a routine healthcare offering. Interview by Emily Culme-Seymour. PMID- 23634985 TI - Air- and water-stable gold-coated gadolinium metal nanocrystals. AB - Gold-coated gadolinium nanocrystals, with an average diameter of 3.20 +/- 0.35 nm, have been synthesized at ambient temperature by alkalide reduction. Whereas uncoated gadolinium nanoparticles react violently with air and water, the gold coated gadolinium nanocrystals reported here show no reaction even upon long-term exposure. This is the first example of air- and water-stable lanthanide metal nanocrystals, which may allow for the development of magnetic and biomedical applications of gadolinium and other lanthanide metal and alloy nanocrystals. PMID- 23634986 TI - Highly regioselective syntheses of substituted triphenylenes from 1,2,4 trisubstituted arenes via a co-catalyzed intermolecular alkyne cyclotrimerization. AB - Herein, we report the development of a new method for the syntheses of substituted triphenylenes from the corresponding 1,2,4-trisubstituted arenes, which were themselves generated in a highly regioselective manner according to an intermolecular alkyne cyclotrimerization reaction that was catalyzed by a novel Co-TMTU complex. This highly regioselective reaction for the formation of 1,2,4 trisubstituted arenes will be a valuable addition to the plethora of tools already available to synthetic chemists and encourage further mechanistic studies of this important alkyne trimerization process. PMID- 23634987 TI - Direct hospital costs of total laparoscopic hysterectomy compared with fast-track open hysterectomy at a tertiary hospital: a retrospective case-controlled study. AB - AIMS: To assess the direct intraoperative and postoperative costs in women undergoing total laparoscopic hysterectomy and fast-track open hysterectomy. METHODS: A retrospective review of the direct hospital-related costs in a matched cohort of women undergoing total laparoscopic hysterectomy (TLH) and fast-track open hysterectomy (FTOH) at a tertiary hospital. All costs were calculated, including the cost of advanced high-energy laparoscopic devices. The effect of the learning curve on cost in laparoscopic hysterectomy was also assessed, as was the hospital case-weighted cost, which was compared with the actual cost. RESULTS: Fifty women were included in each arm of the study. TLH had a higher intraoperative cost, but a lower postoperative cost than FTOH (AUD$3877 vs AUD$2776 P < 0.001, AUD$3965 vs AUD$6233 P < 0.001). The total cost of TLH was not different from FTOH (AUD$7842 vs AUD$9009 P = 0.068) and after a learning curve; TLH cost less than FTOH (AUD$6797 vs AUD$8647, P < 0.001). The use of high energy devices did not impact on the cost benefit of TLH, and hospital case weight-based funding correlated poorly with actual cost. CONCLUSION: Despite the use of fast-track recovery protocols, the cost of TLH is no different to FTOH and after a learning curve is cheaper than open hysterectomy. Judicious use of advanced energy devices does not impact on the cost, and hospital case-weight based funding model in our hospital is inaccurate when compared to directly calculated hospital costs. PMID- 23634988 TI - Formation of functional gap junctions in amniotic fluid-derived stem cells induced by transmembrane co-culture with neonatal rat cardiomyocytes. AB - Amniotic fluid-derived stem cells (AFSC) have been reported to differentiate into cardiomyocyte-like cells and form gap junctions when directly mixed and cultured with neonatal rat ventricular myocytes (NRVM). This study investigated whether or not culture of AFSC on the opposite side of a Transwell membrane from NRVM, allowing for contact and communication without confounding factors such as cell fusion, could direct cardiac differentiation and enhance gap junction formation. Results were compared to shared media (Transwell), conditioned media and monoculture media controls. After a 2-week culture period, AFSC did not express cardiac myosin heavy chain or troponin T in any co-culture group. Protein expression of cardiac calsequestrin 2 was up-regulated in direct transmembrane co cultures and media control cultures compared to the other experimental groups, but all groups were up-regulated compared with undifferentiated AFSC cultures. Gap junction communication, assessed with a scrape-loading dye transfer assay, was significantly increased in direct transmembrane co-cultures compared to all other conditions. Gap junction communication corresponded with increased connexin 43 gene expression and decreased phosphorylation of connexin 43. Our results suggest that direct transmembrane co-culture does not induce cardiomyocyte differentiation of AFSC, though calsequestrin expression is increased. However, direct transmembrane co-culture does enhance connexin-43-mediated gap junction communication between AFSC. PMID- 23634989 TI - Application of novel extraction technologies for bioactives from marine algae. AB - Marine algae are a rich source of bioactive compounds. This paper outlines the main bioactive compounds in marine algae and recent advances in novel technologies for extracting them. Novel extraction technologies reviewed include enzyme-assisted extraction, microwave-assisted extraction, ultrasound-assisted extraction, supercritical fluid extraction, and pressurized liquid extraction. These technologies are reviewed with respect to principles, benefits, and potential applications for marine algal bioactives. Advantages of novel technologies include higher yield, reduced treatment time, and lower cost compared to traditional solvent extraction techniques. Moreover, different combinations of novel techniques used for extraction and technologies suitable for thermolabile compounds are identified. The limitations of and challenges to employing these novel extraction technologies in industry are also highlighted. PMID- 23634991 TI - A numerical method to enhance the performance of a cam-type electric motor-driven left ventricular assist device. AB - Pulsatile left ventricular assist devices (LVADs) driven by electric motors have been widely accepted as a treatment of heart failure. Performance enhancement with computer assistance for this kind of LVAD has seldom been reported. In this article, a numerical method is proposed to assist the design of a cam-type pump. The method requires an integrated model of an LVAD system, consisting of a motor, a transmission mechanism, and a cardiovascular circulation. Performance indices, that is, outlet pressure, outlet flow, and pump efficiency, were used to select the best cam profile from six candidates. A prototype pump connected to a mock circulatory loop (MCL) was used to calibrate the friction coefficient of the cam groove and preliminarily evaluate modeling accuracy. In vitro experiments show that the mean outlet pressure and flow can be predicted with high accuracy by the model, and gross geometries of the measurements can also be reproduced. Simulation results demonstrate that as the total peripheral resistance (TPR) is fixed at 1.1 mm Hg.s/mL, the two-cycle 2/3-rise profile is the best. Compared with other profiles, the maximum increases of pressure and flow indices are 75 and 76%, respectively, and the maximum efficiency increase is over 51%. For different TPRs (0.5~1.5 mm Hg.s/mL) and operation intervals (0.1~0.4 s) in counterpulsation, the conclusion is also acceptable. PMID- 23634992 TI - Millimeter-wave spectroscopy of S2Cl2: a candidate molecule for measuring ortho para transition. AB - S2Cl2 is a candidate for the observation of ortho-para transition. To estimate the ortho-para mixing in a hyperfine-resolved rotational state, pure rotational transitions were measured by millimeter-wave (mm-wave) spectroscopy using two different experimental set-ups. The transitions from the term value around 20 K was measured with a supersonic jet and those around 200 K were measured with a dry ice cooled gas cell. Several hundred peaks were assigned for the naturally abundant S2(35)Cl2 and S2(35)Cl(37)Cl isotopic species and the rotational molecular parameters including the fourth-order and sixth-order centrifugal distortion constants were determined. The hyperfine structures were partly resolved in some Q-branch transitions, which were well described with the hyperfine constants determined by FTMW spectroscopy in the centimeter-wave region. With the new rotational constants determined in our study and the previous hyperfine constants, it will be possible to obtain a more reliable ortho para mixing ratio and to narrow down the possible candidate transitions in the mm wave region for the observation of ortho-para transition. PMID- 23634990 TI - New insights of P2X7 receptor signaling pathway in alveolar functions. AB - Purinergic P2X7 receptor (P2X7R), an ATP-gated cation channel, is unique among all other family members because of its ability to respond to various stimuli and to modulate pro-inflammatory signaling. The activation of P2X7R in immune cells is absolutely required for mature interleukin -1beta (IL-1beta) and IL-18 production and release. Lung alveoli are lined by the structural alveolar epithelial type I (AEC I) and alveolar epithelial type II cells (AEC II). AEC I plays important roles in alveolar barrier protection and fluid homeostasis whereas AEC II synthesizes and secrete surfactant and prevents alveoli from collapse. Earlier studies indicated that purinergic P2X7 receptors were specifically expressed in AEC I. However, their implication in alveolar functions has not been explored. This paper reviews two important signaling pathways of P2X7 receptors in surfactant homeostatsis and Acute Lung Injury (ALI). Thus, P2X7R resides at the critical nexus of alveolar pathophysiology. PMID- 23634993 TI - Zinc absorption in Brazilian subjects fed a healthy meal. AB - BACKGROUND: The high amounts of phytic acid present in diets from developing countries are considered as important inhibitors of zinc (Zn) absorption. The present study aimed to assess the fractional absorption of Zn from a meal containing common Brazilian foods using the stable isotope technique. METHODS: Twelve men, aged 19-42 years, were fed a healthy experimental diet comprising lettuce, tomato, French fries, steak with onions, rice, beans, papaya, orange, pineapple, and passion fruit juice. Each subject received one intravenous dose of enriched (70) Zn, and the lunch was extrinsically labelled with enriched (67) Zn. Urinary (67) Zn and (70) Zn enrichments were assessed by inductively coupled plasma mass spectrometry. RESULTS: The labelled meal phytate : Zn molar ratio was very divergent with respect to chemically determined and calculated data. Subjects presented a normal Zn nutritional status before and after the study. The mean Zn absorption from the labelled meal was 30% (range 11-47%). CONCLUSIONS: According to the World Health Organization parameters, the results denote a moderate/high Zn bioavailability in the evaluated meal, with a variability in the absorption percentage that is similar to other studies. The data show that a typical Brazilian meal, with an adequate energy amount and a balanced macronutrient distribution, presents a Zn bioavailability in accordance with the worldwide recommended standard. PMID- 23634994 TI - Adrenal insufficiency is prevalent in HbE/beta-thalassaemia paediatric patients irrespective of their clinical severity and transfusion requirement. AB - OBJECTIVES: Transfusion dependency is known to cause endocrinopathies in patients with thalassaemia such as adrenal insufficiency, because transfusion-related iron overload is injurious to endocrine organs. Children with HbE/beta-thalassaemia vary greatly in red cell transfusion requirement and some are transfusion dependent (TD), whereas others are nontransfusion dependent (NTD). Because iron overload is thought to be the primary cause of adrenal insufficiency, TD children with HbE/beta-thalassaemia are considered likely candidates for the development of adrenal insufficiency, while the adrenal function of NTD children is generally considered to be normal. As yet, the prevalence of adrenal insufficiency among children with NTD HbE/beta-thalassaemia is not known. The present study was performed to (i) assess the prevalence of adrenal insufficiency in children with both TD and NTD HbE/beta-thalassaemia and to evaluate whether there is any difference in the prevalence of adrenal insufficiency between both groups and (ii) determine the type of adrenal insufficiency (primary or secondary). METHODS: We investigated the prevalence of adrenal insufficiency among TD (n = 42) and NTD (n = 43) children with HbE/beta-thalassaemia by assessing morning serum cortisol levels, and we distinguished between primary and secondary adrenal insufficiency by assessing the cortisol responses following the 1- and 250-MUg ACTH stimulation tests. RESULTS: The prevalence of adrenal insufficiency among TD and NTD children with HbE/beta-thalassaemia was 50% and 53.5%, respectively. By using the 250-MUg ACTH stimulation test, at least 39% and 23.5% were diagnosed with adrenal gland hypofunction in TD and NTD children, respectively. CONCLUSION: This is the first study to show that adrenal insufficiency is common among all children with HbE/beta-thalassaemia, irrespective of their transfusion history or requirement. Our findings have important implications for the clinical management of these children. PMID- 23634995 TI - The beginning of the end of the beginning in cancer genomics. PMID- 23634997 TI - Neuropathogenic Escherichia coli K1 does not exhibit proteolytic activities to exert its pathogenicity. AB - BACKGROUND: Proteases are well-known virulence factors that promote survival, pathogenesis and immune evasion of many pathogens. Several lines of evidence suggest that the blood-brain barrier permeability is a prerequisite in microbial invasion of the central nervous system. Because proteases are frequently associated with vascular permeability by targeting junctional proteins, here it is hypothesized that neuropathogenic Escherichia coli K1 exhibit proteolytic activities to exert its pathogenicity. METHODS: Zymographic assays were performed using collagen and gelatin as substrates. The lysates of whole E. coli K1 strain E44, or E. coli K-12 strain HB101 were tested for proteolytic activities. The conditioned media were prepared by incubating bacteria in RPMI-1640 in the presence or absence of serum. The cell-free supernatants were collected and tested for proteases in zymography as mentioned above. Additionally, proteolytic degradation of host immune factors was determined by co-incubating conditioned media with albumin/immunoglobulins using protease assays. RESULTS: When collagen or gelatin were used as substrates in zymographic assays, neither whole bacteria nor conditioned media exhibited proteolytic activities. The conditioned media of neuropathogenic E. coli K1 strain E44, or E. coli K-12 strain HB101 did not affect degradation of albumin and immunoglobulins using protease assays. CONCLUSIONS: Neither zymographic assays nor protease assays detected proteolytic activities in either the whole bacteria or conditioned media of E. coli K1 strain E44 and E. coli K-12 strain HB101. These findings suggest that host cell monolayer disruptions and immune evasion strategies are likely independent of proteolytic activities of neuropathogenic E. coli K1. PMID- 23634999 TI - Developing high-transmittance heterojunction diodes based on NiO/TZO bilayer thin films. AB - In this study, radio frequency magnetron sputtering was used to deposit nickel oxide thin films (NiO, deposition power of 100 W) and titanium-doped zinc oxide thin films (TZO, varying deposition powers) on glass substrates to form p(NiO) n(TZO) heterojunction diodes with high transmittance. The structural, optical, and electrical properties of the TZO and NiO thin films and NiO/TZO heterojunction devices were investigated with scanning electron microscopy, X-ray diffraction (XRD) patterns, UV-visible spectroscopy, Hall effect analysis, and current-voltage (I-V) analysis. XRD analysis showed that only the (111) diffraction peak of NiO and the (002) and (004) diffraction peaks of TZO were observable in the NiO/TZO heterojunction devices, indicating that the TZO thin films showed a good c-axis orientation perpendicular to the glass substrates. When the sputtering deposition power for the TZO thin films was 100, 125, and 150 W, the I-V characteristics confirmed that a p-n junction characteristic was successfully formed in the NiO/TZO heterojunction devices. We show that the NiO/TZO heterojunction diode was dominated by the space-charge limited current theory. PMID- 23634998 TI - Evidence-informed recommendations for constructing and disseminating messages supplementing the new Canadian Physical Activity Guidelines. AB - BACKGROUND: Few validated guidelines exist for developing messages in health promotion practice. In clinical practice, the Appraisal of Guidelines, Research, and Evaluation II (AGREE II) Instrument is the international gold standard for guideline assessment, development, and reporting. In a case study format, this paper describes the application of the AGREE II principles to guide the development of health promotion guidelines for constructing messages to supplement the new Canadian Physical Activity Guidelines (CPAG) released in 2011. METHODS: The AGREE II items were modified to suit the objectives of developing messages that (1) clarify key components of the new CPAG and (2) motivate Canadians to meet the CPAG. The adapted AGREE II Instrument was used as a systematic guide for the recommendation development process. Over a two-day meeting, five workgroups (one for each CPAG - child, youth, adult, older adult - and one overarching group) of five to six experts (including behavior change, messaging, and exercise physiology researchers, key stakeholders, and end users) reviewed and discussed evidence for creating and targeting messages to supplement the new CPAG. Recommendations were summarized and reviewed by workgroup experts. The recommendations were pilot tested among end users and then finalized by the workgroup. RESULTS: The AGREE II was a useful tool in guiding the development of evidence-based specific recommendations for constructing and disseminating messages that supplement and increase awareness of the new CPAG (child, youth, adults, and older adults). The process also led to the development of sample messages and provision of a rationale alongside the recommendations. CONCLUSIONS: To our knowledge, these are the first set of evidence-informed recommendations for constructing and disseminating messages supplementing physical activity guidelines. This project also represents the first application of international standards for guideline development (i.e., AGREE II) to the creation of practical recommendations specifically aimed to inform health promotion and public health practice. The messaging recommendations have the potential to increase the public health impact of evidence-based guidelines. PMID- 23635000 TI - Synthesis, enantiomer separation, and absolute configuration of 2,6-oxygenated 9 azabicyclo[3.3.1]nonanes. AB - The synthesis of the enantiomerically pure N-Boc 9-azabicyclo[3.3.1]nonane-2,6 dione (4b), a potentially useful chiral building block, from N-Bn and N-Boc 9 azabicyclo[3.3.1]nonane-2,6-diols 2a and 2b was accomplished. The enantiomer resolution of diols 2a and 2b was achieved by crystallization of their diastereomeric esters or by kinetic resolution of the racemic diol 2a using lipase from Candida rugosa (CRL). Both enantiomers of N-Boc protected diol 2b were converted into the corresponding enantiomerically pure diones 4b, the absolute configuration of which was determined by comparison of the experimental and simulated circular dichroism (CD) spectra, obtained by ab initio time dependent density functional theory (TDDFT) calculations. The (-)-(1R,5R)/(+) (1S,5S) absolute configuration of 4b inferred from the TDDFT calculations was confirmed via analysis of the CD spectrum of endo,endo-dibenzoate (+)-7 derived from diol (+)-2b and application of the benzoate exciton chirality method. The assigned absolute configuration was further supported by the results of kinetic resolution of diol 2a using Candida rugosa lipase, which exhibited kinetic preference toward the (1R,2R,5R,6R)-enantiomer in agreement with the Kazlauskas' rule. PMID- 23635001 TI - Comparison of sugar content for ionic liquid pretreated Douglas-fir woodchips and forestry residues. AB - BACKGROUND: The development of affordable woody biomass feedstocks represents a significant opportunity in the development of cellulosic biofuels. Primary woodchips produced by forest mills are considered an ideal feedstock, but the prices they command on the market are currently too expensive for biorefineries. In comparison, forestry residues represent a potential low-cost input but are considered a more challenging feedstock for sugar production due to complexities in composition and potential contamination arising from soil that may be present. We compare the sugar yields, changes in composition in Douglas-fir woodchips and forestry residues after pretreatment using ionic liquids and enzymatic saccharification in order to determine if this approach can efficiently liberate fermentable sugars. RESULTS: These samples were either mechanically milled through a 2 mm mesh or pretreated as received with the ionic liquid (IL) 1-ethyl 3-methylimidazolium acetate [C2mim][OAc] at 120 degrees C and 160 degrees C. IL pretreatment of Douglas-fir woodchips and forestry residues resulted in approximately 71-92% glucose yields after enzymatic saccharification. X-ray diffraction (XRD) showed that the pretreated cellulose was less crystalline after IL pretreatment as compared to untreated control samples. Two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) revealed changes in lignin and hemicellulose structure and composition as a function of pretreatment. Mass balances of sugar and lignin streams for both the Douglas-fir woodchips and forestry residues throughout the pretreatment and enzymatic saccharification processes are presented. CONCLUSIONS: While the highest sugar yields were observed with the Douglas-fir woodchips, reasonably high sugar yields were obtained from forestry residues after ionic liquid pretreatment. Structural changes to lignin, cellulose and hemicellulose in the woodchips and forestry residues of Douglas-fir after [C2mim][OAc] pretreatment are analyzed by XRD and 2D-NMR, and indicate that significant changes occurred. Irrespective of the particle sizes used in this study, ionic liquid pretreatment successfully allowed high glucose yields after enzymatic saccharification. These results indicate that forestry residues may be a more viable feedstock than previously thought for the production of biofuels. PMID- 23634996 TI - Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. AB - BACKGROUND: Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS: We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. RESULTS: AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. CONCLUSIONS: We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.). PMID- 23635002 TI - Delaying the bath and in-hospital breastfeeding rates. AB - BACKGROUND AND OBJECTIVE: Until 2010, newborns at our institution were bathed in the nursery at approximately 2 hours of life. In May 2010, infant baths were delayed until at least 12 hours of life. Infants are now bathed in the hospital room with parents' participation and are placed skin-to-skin immediately after the bath. This study explored whether delaying the newborn's first bath correlates with increased in-hospital breastfeeding rates at our Baby-Friendly, urban safety-net hospital. SUBJECTS AND METHODS: We performed a retrospective chart review comparing in-hospital breastfeeding rates during the 6 months before and the 6 months after the bath was delayed. RESULTS: Of the infants, 702 met inclusion criteria. Before the bath was delayed, infants were bathed at an average of 2.4 hours of life. Afterward, infants were bathed at an average of 13.5 hours of life. In-hospital exclusive breastfeeding rates increased from 32.7% to 40.2% (p<0.05) after the bath was delayed. Multivariate logistic regression analysis showed that infants born after implementation of delayed bathing had odds of exclusive breastfeeding 39% greater than infants born prior to the intervention (adjusted odds ratio [AOR]=1.39; 95% confidence interval [CI] 1.02, 1.91) and 59% greater odds of near-exclusive breastfeeding (AOR=1.59; 95% CI 1.18, 2.15). The odds of breastfeeding initiation were 166% greater for infants born after the intervention than for infants born before the intervention (AOR=2.66; 95% CI 1.29, 5.46). CONCLUSIONS: In our cohort, a delayed newborn bath was associated with increased likelihood of breastfeeding initiation and with increased in-hospital breastfeeding rates. PMID- 23635003 TI - Acremolin from Acremonium strictum is N(2),3-etheno-2'-isopropyl-1-methylguanine, not a 1H-azirine. Synthesis and structural revision. AB - The first synthesis of the heterocyclic marine natural product, acremolin, is reported along with the revision of the structure from a 1H-azirine to a substituted N(2),3-ethenoguanine (5-methyl-7-isopropyl-4,5-dihydroimidazo[2,1 b]purine). Additional properties of acremolin are also described including its (1)H-(15)N-HMBC and fluorescence spectra. PMID- 23635004 TI - Adhesion molecules in subjects with COPD and healthy non-smokers: a cross sectional parallel group study. AB - BACKGROUND: The aim of the study was to investigate how the expression of adhesion molecules changes as neutrophils migrate from the circulation to the lung and if these changes differ between non-smoking subjects and smokers with and without COPD. METHODS: Non-smoking healthy subjects (n=22), smokers without (n=21) and with COPD (n=18) were included. Neutrophils from peripheral blood, sputum and bronchial biopsies were analysed for cell surface expression of adhesion molecules (CD11b, CD62L, CD162). Serum, sputum supernatant and BAL-fluid were analysed for soluble adhesion molecules (ICAM-1, -3, E-selectin, P-selectin, VCAM-1, PECAM-1). RESULTS: Expression of CD11b was increased on circulating neutrophils from smokers with COPD. It was also increased on sputum neutrophils in both smokers groups, but not in non-smokers, as compared to circulating neutrophils.Serum ICAM-1 was higher in the COPD group compared to the other two groups (p<0.05) and PECAM-1 was lower in smokers without COPD than in non-smoking controls and the COPD group (p<0.05). In BAL-fluid ICAM-1 was lower in the COPD group than in the other groups (p<0.05). CONCLUSIONS: Thus, our data strongly support the involvement of a systemic component in COPD and demonstrate that in smokers neutrophils are activated to a greater extent at the point of transition from the circulation into the lungs than in non-smokers. PMID- 23635005 TI - Antioxidative carbohydrate polymer from Enhydra fluctuans and its interaction with bovine serum albumin. AB - Enhydra fluctuans leaves are traditionally sold on Indian markets for various health benefits. However, no phytochemical study on its high molecular weight compound has so far been performed. Chemical, chromatographic, ESI-TOF-MS, and NMR analyses of the water extracted carbohydrate polymer (CP) of E. fluctuans leaves showed the presence of a 24 kDa arabinogalactan having a (1,3)-linked beta d-Galp main chain, substituted at O-6 by (1,6)-linked beta-d-Galp side chains. The latter residues were substituted at O-3 by (1,3)-, (1,5)-, and (1,3,5)-linked alpha-l-Araf chains, and nonreducing end-units of alpha-l-Araf and beta-d-Galp. This polymer contained esterified phenolic acids. Biochemical analysis revealed similarity in antioxidative potential between the identified carbohydrate polymer and known standard antioxidants. The highly branched side chains and the phenolic acid residues of the arabinogalactan might be the functional sites. Fluorimetric and ultraviolet spectrometric analyses showed that the studied carbohydrate polymer can form complex with bovine serum albumin having binding constant K = 2.42 * 10(6)/M and changes its microenvironment. Thus, traditional aqueous extraction method provides a carbohydrate polymer, which stimulates a fair biological response: this could represent an interesting approach in phytotherapeutic treatments. PMID- 23635007 TI - Heating temperature dependence of Cr(III) oxidation in the presence of alkali and alkaline earth salts and subsequent Cr(VI) leaching behavior. AB - In this paper, the temperature dependence of Cr(III) oxidation in high temperature processes and the subsequent Cr(VI) leaching was studied using synthetic mixtures. It was experimentally shown that in the presence of alkali and alkaline earth salts, oxidation of Cr(III) takes place, consistent with thermodynamic calculations. Heating of synthetic mixtures of Cr2O3 and Na, K, or Ca salts led to elevated leaching of Cr(VI); in the presence of Na, more than 80% of the initial Cr(III) amount was converted to Cr(VI) at 600-800 degrees C. Kinetic experiments allowed explanation of the increase in Cr(VI) leaching for increasing temperatures up to 600-800 degrees C. After reaching a maximum in Cr(VI) leaching at temperatures around 600-800 degrees C, the leaching decreased again, which could be explained by the formation of a glassy phase that prevents leaching of the formed Cr(VI). By way of illustration, Cr(VI) formation and leaching was evaluated for a case study, the fabrication of ceramic material from contaminated sludge. Based on the proposed reaction mechanisms, countermeasures to prevent Cr oxidation (addition of NH4H2PO4, heating under inert atmosphere) were proposed and successfully tested for synthetic mixtures and for the case study. PMID- 23635008 TI - Predicting hemoglobin levels in whole blood donors using transition models and mixed effects models. AB - BACKGROUND: To optimize the planning of blood donations but also to continue motivating the volunteers it is important to streamline the practical organization of the timing of donations. While donors are asked to return for donation after a suitable period, still a relevant proportion of blood donors is deferred from donation each year due to a too low hemoglobin level. Rejection of donation may demotivate the candidate donor and implies an inefficient planning of the donation process. Hence, it is important to predict the future hemoglobin level to improve the planning of donors' visits to the blood bank. METHODS: The development of the hemoglobin prediction rule is based on longitudinal (panel) data from blood donations collected by Sanquin (the only blood product collecting and supplying organization in the Netherlands). We explored and contrasted two popular statistical models, i.e. the transition (autoregressive) model and the mixed effects model as plausible models to account for the dependence among subsequent hemoglobin levels within a donor. RESULTS: The predictors of the future hemoglobin level are age, season, hemoglobin levels at the previous visits, and a binary variable indicating whether a donation was made at the previous visit. Based on cross-validation, the areas under the receiver operating characteristic curve (AUCs) for male donors are 0.83 and 0.81 for the transition model and the mixed effects model, respectively; for female donors we obtained AUC values of 0.73 and 0.72 for the transition model and the mixed effects model, respectively. CONCLUSION: We showed that the transition models and the mixed effects models provide a much better prediction compared to a multiple linear regression model. In general, the transition model provides a somewhat better prediction than the mixed effects model, especially at high visit numbers. In addition, the transition model offers a better trade-off between sensitivity and specificity when varying the cut-off values for eligibility in predicted values. Hence transition models make the prediction of hemoglobin level more precise and may lead to less deferral from donation in the future. PMID- 23635009 TI - The communication of a secondary care diagnosis of autoimmune hepatitis to primary care practitioners: a population-based study. AB - BACKGROUND: Autoimmune Hepatitis is a chronic liver disease which affects young people and can result in liver failure leading to death or transplantation yet there is a lack of information on the incidence and prevalence of this disease and its natural history in the UK. A means of obtaining this information is via the use of clinical databases formed of electronic primary care records. How reliably the diagnosis is coded in such records is however unknown. The aim of this study therefore was to assess the proportion of consultant hepatologist diagnoses of Autoimmune Hepatitis which were accurately recorded in General Practice computerised records. METHODS: Our study population were patients with Autoimmune Hepatitis diagnosed by consultant hepatologists in the Queens Medical Centre, Nottingham University Hospitals (UK) between 2004 and 2009. We wrote to the general practitioners of these patients to obtain the percentage of patients who had a valid READ code specific for Autoimmune Hepatitis. RESULTS: We examined the electronic records of 51 patients who had biopsy evidence and a possible diagnosis of Autoimmune Hepatitis. Forty two of these patients had a confirmed clinical diagnosis of Autoimmune Hepatitis by a consultant hepatologist: we contacted the General Practitioners of these patients obtaining a response rate of 90.5% (39/42 GPs). 37/39 of these GPs responded with coding information and 89% of these patients (33/37) used Read code J638.00 (Autoimmune Hepatitis) to record a diagnosis. CONCLUSIONS: The diagnosis of Autoimmune Hepatitis made by a Consultant Hepatologist is accurately communicated to and electronically recorded by primary care in the UK. As a large proportion of cases of Autoimmune Hepatitis are recorded in primary care, this minimises the risk of introducing selection bias and therefore selecting cases using these data will be a valid method of conducting population based studies on Autoimmune Hepatitis. PMID- 23635010 TI - Maternal response to high-risk obstetric telemedicine consults when perinatal prognosis is poor. AB - This is a qualitative descriptive study evaluating the maternal response after the woman has learned her pregnancy has a poor prognosis via telemedicine rather than in a traditional, face-to-face, consultation method. In general, telemedicine was positively viewed by the participants; however, the experience may be markedly improved by implementing several simple changes in the overall consultative process. PMID- 23635006 TI - The estrogen-regulated anterior gradient 2 (AGR2) protein in breast cancer: a potential drug target and biomarker. AB - Initially discovered as an estrogen-responsive gene in breast cancer cell lines, anterior gradient 2 (AGR2) is a developmentally regulated gene belonging to the protein disulfide isomerase (PDI) gene family. Developmentally, AGR2 is expressed in the mammary gland in an estrogen-dependent manner, and AGR2 knockout and overexpression mouse models indicate that the gene promotes lobuloalveolar development by stimulating cell proliferation. Although AGR2 overexpression alone seems insufficient for breast tumorigenesis in mice, several lines of investigations suggest that AGR2 promotes breast tumorigenesis. Overexpression of AGR2 in several breast cancer cell lines increases cell survival in clonogenic assays and cell proliferation, whereas AGR2 loss of function leads to decreased cell cycle progression and cell death. In addition, AGR2 was shown to promote metastasis of breast epithelial cells in an in vivo metastasis assay. As a PDI, AGR2 is thought to be involved in the unfolded protein response that alleviates endoplasmic reticulum stress. Since cancer has to overcome proteotoxic stress due to excess protein production, AGR2 may be one of many pro-survival factors recruited to assist in protein folding or degradation or both. When AGR2 is secreted, it plays a role in cellular adhesion and dissemination of metastatic tumor cells. In breast cancer, AGR2 expression is associated with estrogen receptor (ER)-positive tumors; its overexpression is a predictor of poor prognosis. The AGR2 gene is directly targeted by ER-alpha, which is preferentially bound in tumors with poor outcome. Whereas aromatase inhibitor therapy decreases AGR2 expression, tamoxifen acts as an agonist of AGR2 expression in ER-positive tumors, perhaps contributing to tamoxifen resistance. AGR2 is also overexpressed in a subset of ER-negative tumors. Furthermore, AGR2 expression is associated with the dissemination of metastatic breast cancer cells and can be used as a marker to identify circulating tumor cells and metastatic cells in sentinel lymph nodes. In conclusion, AGR2 is a promising drug target in breast cancer and may serve as a useful prognostic indicator as well as a marker of breast cancer metastasis. PMID- 23635011 TI - Synthesis and In vitro cytotoxic activity evaluation of (E)-16-(substituted benzylidene) derivatives of dehydroepiandrosterone. AB - BACKGROUND AND THE PURPOSE OF THE STUDY: Modified androsterone derivatives are class of steroidal compounds with potential anticancer properties. Various steroidal derivatives containing substitution at position 16 have shown diversified pharmacological activities. In the present study, a new series of cytotoxic 16-(substituted benzylidene) derivatives of dehydroepiandrosterone (DHEA) were synthesized and evaluated against three different cancer cell lines. METHODS: The cytotoxic 16-(substituted benzylidene) derivatives of DHEA were synthesized via aldol condensation of DHEA with corresponding benzaldehyde derivatives. The cytotoxic activity of synthesized derivatives was evaluated against three different cancer cells including KB, T47D and SK-N-MC cell lines by MTT reduction colorimetric assay. RESULTS: The results indicated that 16 (substituted benzylidene) derivatives of DHEA could be served as a potent anti cancer agent. The 3-cholro benzylidene derivatives of DHEA was the most potent synthesized derivative especially against KB and T47D cell lines (IC50 values were 0.6 and 1.7 MUM; respectively). CONCLUSION: The cytotoxic potential of novel benzylidene derivatives of DHEA is mainly attributed to the position and nature of the substituted group on the benzylidene pendant. PMID- 23635012 TI - Effect of dialysate sodium reduction on body water volume, blood pressure, and inflammatory markers in hemodialysis patients--a prospective randomized controlled study. AB - Accumulating evidence suggests an association between body volume overload and inflammation in chronic kidney diseases. The purpose of this study was to evaluate the effect of dialysate sodium concentration reduction on extracellular water volume, blood pressure (BP), and inflammatory state in hemodialysis (HD) patients. In this prospective controlled study, adult patients on HD for at least 90 days and those with C-reactive protein (CRP) levels >= 0.7 mg/dL were randomly allocated into two groups: group A, which included 29 patients treated with reduction of dialysate sodium concentration from 138 to 135 mEq/L; and group B, which included 23 HD patients not receiving dialysate sodium reduction (controls). Of these, 20 patients in group A and 18 in group B completed the protocol study. Inflammatory, biochemical, hematological, and nutritional markers were assessed at baseline and after 8 and 16 weeks. Baseline characteristics were not significantly different between the two groups. Group A showed a significant reduction in serum concentrations of tumor necrosis factor-alpha, and interleukin 6 over the study period, while the BP and extracellular water (ECW) did not change. In Group B, there were no changes in serum concentrations of inflammatory markers, BP, and ECW. Dialysate sodium reduction is associated with attenuation of the inflammatory state, without changes in the BP and ECW, suggesting inhibition of a salt-induced inflammatory response. PMID- 23635014 TI - Diagnosis of gastric glomus tumour by endoscopic ultrasound-guided fine needle aspiration cytology: a case report. PMID- 23635015 TI - Endohedral fullerenes. PMID- 23635013 TI - Lipopolysaccharide induces a fibrotic-like phenotype in endothelial cells. AB - Endothelial dysfunction is crucial in endotoxaemia-derived sepsis syndrome pathogenesis. It is well accepted that lipopolysaccharide (LPS) induces endothelial dysfunction through immune system activation. However, LPS can also directly generate actions in endothelial cells (ECs) in the absence of participation by immune cells. Although interactions between LPS and ECs evoke endothelial death, a significant portion of ECs are resistant to LPS challenge. However, the mechanism that confers endothelial resistance to LPS is not known. LPS-resistant ECs exhibit a fibroblast-like morphology, suggesting that these ECs enter a fibrotic programme in response to LPS. Thus, our aim was to investigate whether LPS is able to induce endothelial fibrosis in the absence of immune cells and explore the underlying mechanism. Using primary cultures of ECs and culturing intact blood vessels, we demonstrated that LPS is a crucial factor to induce endothelial fibrosis. We demonstrated that LPS was able and sufficient to promote endothelial fibrosis, in the absence of immune cells through an activin receptor like kinase 5 (ALK5) activity-dependent mechanism. LPS-challenged ECs showed an up-regulation of both fibroblast-specific protein expression and extracellular matrix proteins secretion, as well as a down-regulation of endothelial markers. These results demonstrate that LPS is a crucial factor in inducing endothelial fibrosis in the absence of immune cells through an ALK5-dependent mechanism. It is noteworthy that LPS-induced endothelial fibrosis perpetuates endothelial dysfunction as a maladaptive process rather than a survival mechanism for protection against LPS. These findings are useful in improving current treatment against endotoxaemia-derived sepsis syndrome and other inflammatory diseases. PMID- 23635016 TI - Determination of total sulfur in food samples by solid sampling high-resolution continuum source graphite furnace molecular absorption spectrometry. AB - The determination of sulfur in food samples via the rotational molecular absorption of carbon monosulfide (CS) was performed using a solid sampling high resolution continuum source electrothermal atomic absorption spectrophotometer (SS-HR-CS-ETAAS). In the presence of plenty of carbon in the graphite furnace as well as in food samples, CS was formed in the gas phase without the addition of any molecule forming element externally. The effects of the wavelength selected to detect CS, graphite furnace program, amount of sample, coating of the graphite tube and platform with Ir, and the use of a Pd modifier on the accuracy, precision, and sensitivity were investigated and optimized. Sulfur was determined in an iridium-coated graphite tube/platform at 258.056 nm by applying a pyrolysis temperature of 1000 degrees C and a molecule forming temperature of 2400 degrees C. The calibration curve prepared from Na2S was linear between 0.01 MUg (LOQ) and 10 MUg of S. The accuracy of the method was tested by analyzing certified reference spinach and milk powder samples by applying a linear calibration technique prepared from aqueous standard. The results were in good agreement with certified values. The limit of detection and characteristic mass of the method were 3.5 and 8.1 ng of S, respectively. By applying the optimized parameters, the concentrations of S in onion and garlic samples were determined. PMID- 23635017 TI - Increase in skin autofluorescence and release of heart-type fatty acid binding protein in plasma predicts mortality of hemodialysis patients. AB - Advanced glycation end-products (AGEs) are uremic toxins that accumulate progressively in hemodialysis (HD) patients. The aim of this study was to assess the 1-year increase in skin autofluorescence (DeltaAF), a measure of AGEs accumulation and plasma markers, as predictors of mortality in HD patients. One hundred sixty-nine HD patients were enrolled in this study. Skin autofluorescence was measured twice, 1 year apart using an AGE Reader (DiagnOptics Technologies BV, Groningen, The Netherlands). Besides routine blood chemistry, additional plasma markers including superoxide dismutase, myeloperoxydase, intercellular adhesion molecule 1 (ICAM-1), C-reactive protein (hs-CRP), heart-type fatty acid binding protein (H-FABP), and von Willebrand factor were measured at baseline. The mortality of HD patients was followed for 36 months. Skin autofluorescence values of the HD patients at the two time points were significantly higher (P < 0.001) than those of healthy subjects of the same age. Mean 1-year DeltaAF of HD patients was 0.16 +/- 0.06, which was around seven- to ninefold higher than 1 year DeltaAF in healthy subjects. Multivariate Cox regression showed that age, hypertension, 1-year DeltaAF, hs-CRP, ICAM-1, and H-FABP were independent predictors of overall mortality. Hypertension, 1-year DeltaAF, hs-CRP, and H-FABP were also independent predictors of cardiovascular mortality. One-year DeltaAF and plasma H-FABP, used separately and in combination, are strong predictors of overall and cardiovascular mortality in HD patients. PMID- 23635018 TI - A comparative study of psychopathology, symptom severity, and short-term outcome of postpartum and nonpostpartum mania. AB - OBJECTIVES: Most studies acknowledge that postpartum psychosis is a variant of bipolar disorder with certain unique clinical features. There have been several descriptions of similarities and differences between postpartum psychosis and postpartum mania to support this conclusion. However, not many studies have compared postpartum-onset and nonpostpartum-onset mania. This study compared short-term outcome, clinical features, and severity of symptoms between these two groups. METHODS: Two groups of women (n = 30 each) matching the study criteria were recruited from psychiatric inpatient units in India during the period from April 2007 to August 2008. They had been systematically assessed for psychiatric symptoms and symptom severity using the Comprehensive Psychopathology Rating Scale (CPRS), Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), and Global Assessment of Functioning Scale (GAF). To evaluate short-term outcome, all assessments were conducted within a week of admission and were repeated at six weeks. RESULTS: Women with postpartum-onset mania had higher scores on the HDRS, indicating more depressive symptoms. The score on the anxiety factor of the HDRS was also higher in the postpartum group. Based on CPRS ratings, perplexity, muscle tension, worrying, inner tension, lability of mood, lassitude, and disorientation were more common in the postpartum group, while typical manic symptoms were more common in the nonpostpartum group. Duration of hospital stay and short-term outcome were, however, similar in the two groups. CONCLUSIONS: Symptoms of depression and anxiety are more common and more severe in mania of postpartum onset and typical manic symptoms are fewer. However, six week outcomes appear similar to those of nonpostpartum mania. PMID- 23635019 TI - We fight like we train. PMID- 23635021 TI - Distributions of industry payments to Massachusetts physicians. PMID- 23635020 TI - Be prepared--the Boston Marathon and mass-casualty events. PMID- 23635023 TI - Monolithic barrier-all-around high electron mobility transistor with planar GaAs nanowire channel. AB - High-quality growth of planar GaAs nanowires (NWs) with widths as small as 35 nm is realized by comprehensively mapping the parameter space of group III flow, V/III ratio, and temperature as the size of the NWs scales down. Using a growth mode modulation scheme for the NW and thin film barrier layers, monolithically integrated AlGaAs barrier-all-around planar GaAs NW high electron mobility transistors (NW-HEMTs) are achieved. The peak extrinsic transconductance, drive current, and effective electron velocity are 550 MUS/MUm, 435 MUA/MUm, and ~2.9 * 10(7) cm/s, respectively, at 2 V supply voltage with a gate length of 120 nm. The excellent DC performance demonstrated here shows the potential of this bottom-up planar NW technology for low-power high-speed very-large-scale-integration (VLSI) circuits. PMID- 23635022 TI - Biglycan fragmentation in pathologies associated with extracellular matrix remodeling by matrix metalloproteinases. AB - BACKGROUND: The proteoglycan biglycan (BGN) is involved in collagen fibril assembly and its fragmentation is likely to be associated with collagen turnover during the pathogenesis of diseases which involve dysregulated extracellular matrix remodeling (ECMR), such as rheumatoid arthritis (RA) and liver fibrosis. The scope of the present study was to develop a novel enzyme-linked immunosorbent assay (ELISA) for the measurement of a MMP-9 and MMP-12-generated biglycan neo epitope and to test its biological validity in a rat model of RA and in two rat models of liver fibrosis, chosen as models of ECMR. RESULTS: Biglycan was cleaved in vitro by MMP-9 and -12 and the 344'YWEVQPATFR'353 peptide (BGM) was chosen as a potential neo-epitope. A technically sound competitive ELISA for the measurement of BGM was generated and the assay was validated in a bovine cartilage explant culture (BEX), in a collagen induced model of rheumatoid arthritis (CIA) and in two different rat models of liver fibrosis: the carbon tetrachloride (CCL4)-induced fibrosis model, and the bile duct ligation (BDL) model. Significant elevation in serum BGM was found in CIA rats compared to controls, in rats treated with CCL4 for 16 weeks and 20 weeks compared to the control groups as well as in all groups of rats subject to BDL compared with sham operated groups. Furthermore, there was a significant correlation of serum BGM levels with the extent of liver fibrosis determined by the Sirius red staining of liver sections in the CCL4 model. CONCLUSION: We demonstrated that the specific tissue remodeling product of MMPs-degraded biglycan, namely the neo-epitope BGM, is correlated with pathological ECMR. This assay represents both a novel marker of ECM turnover and a potential new tool to elucidate biglycan role during the pathological processes associated with ECMR. PMID- 23635024 TI - Persistent toxic burdens of halogenated phenolic compounds in humans and wildlife. AB - Halogenated phenolic compounds (HPCs) including hydroxylated polychlorobiphenyls (OH-PCBs) and hydroxylated polybromodiphenyl-ethers (OH-PBDEs) can be persistent organic pollutant (POP) metabolites or natural marine compounds. Structurally similar to thyroid hormones (THs), they are retained in blood, transported through selective barriers, and the cause of endocrine and neuronal POP effects. This study presents a meta-analysis of HPC burdens in human and wildlife tissues, including OH-PCBs, OH-PBDEs, Pentachlorophenol, and polybromophenols. HPC blood plasma levels were also compared to known in vitro and in vivo toxicological effect concentrations. Blood, highly perfused, and fetal tissues contained the highest levels of HPCs. Plasma concentrations of analyzed OH-PCBs/PBDEs ranged from 0.1 to 100 nM in humans and up to 240, 454, 800, and 7650 nM for birds, fish, cetaceans, and other mammals, respectively. These concentrations fully fall within the in vitro effect concentrations reported in literature for HPCs of 0.05 10000 nM. We strongly advise further study of HPC blood levels in the general population, children, and fetal tissue to establish background levels and the risk at sensitive development stages. As not all HPCs are, or can be, chemically analyzed, the application of additional bioanalysis might reveal an even greater toxicological relevance of HPCs. In addition, metabolic activation should always be included within in vitro hazard assessment of POPs. PMID- 23635025 TI - The highly pathogenic H7N3 avian influenza strain from July 2012 in Mexico acquired an extended cleavage site through recombination with host 28S rRNA. AB - BACKGROUND: A characteristic difference between highly and non-highly pathogenic avian influenza strains is the presence of an extended, often multibasic, cleavage motif insertion in the hemagglutinin protein. Such motif is found in H7N3 strains from chicken farm outbreaks in 2012 in Mexico. METHODS: Through phylogenetic, sequence and structural analysis, we try to shed light on the role, prevalence, likelihood of appearance and origin of the inserted cleavage motifs in these H7N3 avian influenza strains. RESULTS: The H7N3 avian influenza strain which caused outbreaks in chicken farms in June/July 2012 in Mexico has a new extended cleavage site which is the likely reason for its high pathogenicity in these birds. This cleavage site appears to have been naturally acquired and was not present in the closest low pathogenic precursors. Structural modeling shows that insertion of a productive cleavage site is quite flexible to accept insertions of different length and with sequences from different possible origins. Different from recent cleavage site insertions, the origin of the insert here is not from the viral genome but from host 28S ribosomal RNA (rRNA) instead. This is a novelty for a natural acquisition as a similar insertion has so far only been observed in a laboratory strain before. Given the abundance of viral and host RNA in infected cells, the acquisition of a pathogenicity-enhancing extended cleavage site through a similar route by other low-pathogenic avian strains in future does not seem unlikely. Important for surveillance of these H7N3 strains, the structural sites known to enhance mammalian airborne transmission are dominated by the characteristic avian residues and the risk of human to human transmission should currently be low but should be monitored for future changes accordingly. CONCLUSIONS: This highly pathogenic H7N3 avian influenza strain acquired a novel extended cleavage site which likely originated from recombination with 28S rRNA from the avian host. Notably, this new virus can infect humans but currently lacks critical host receptor adaptations that would facilitate human to human transmission. PMID- 23635026 TI - Total synthesis of (+/-)-delta-rubromycin. AB - Transition-metal-catalyzed spiroketalization cyclization has been performed successfully and has led to the first total synthesis of (+/-)-delta-rubromycin with a longest linear sequence of 18 steps from commercially available guaiacol in a 2.7% overall yield. PMID- 23635027 TI - Completeness and accuracy of crash outcome data in a cohort of cyclists: a validation study. AB - BACKGROUND: Bicycling, despite its health and other benefits, raises safety concerns for many people. However, reliable information on bicycle crash injury is scarce as current statistics rely on a single official database of limited quality. This paper evaluated the completeness and accuracy of crash data collected from multiple sources in a prospective cohort study involving cyclists. METHODS: The study recruited 2438 adult cyclists from New Zealand's largest mass cycling event in November 2006 and another 190 in 2008, and obtained data regarding bicycle crashes that were attended by medical personnel or the police and occurred between the date of recruitment and 30 June 2011, through linkage to insurance claims, hospital discharges, mortality records and police reports. The quality of the linked data was assessed by capture-recapture methods and by comparison with self-reported injury data collected in a follow-up survey. RESULTS: Of the 2590 cyclists who were resident in New Zealand at recruitment, 855 experienced 1336 crashes, of which 755 occurred on public roads and 120 involved a collision with a motor vehicle, during a median follow-up of 4.6 years. Log-linear models estimated that the linked data were 73.7% (95% CI: 68.0% 78.7%) complete with negligible differences between on- and off-road crashes. The data were 83.3% (95% CI: 78.9%-87.6%) complete for collisions. Agreement with the self-reported data was moderate (kappa: 0.55) and varied by personal factors, cycling exposure and confidence in recalling crash events. If self-reports were considered as the gold standard, the linked data had 63.1% sensitivity and 93.5% specificity for all crashes and 40.0% sensitivity and 99.9% specificity for collisions. CONCLUSIONS: Routinely collected databases substantially underestimate the frequency of bicycle crashes. Self-reported crash data are also incomplete and inconsistent. It is necessary to improve the quality of individual data sources as well as record linkage techniques so that all available data sources can be used reliably. PMID- 23635028 TI - The potential harm of oxygen therapy in medical emergencies. AB - In medical emergencies, supplemental oxygen is often administrated routinely. Most paramedics and physicians believe that high concentrations of oxygen are life-saving 1. Over the last century, however, a plethora of studies point to possible detrimental effects of hyperoxia induced by supplemental oxygen in a variety of medical emergencies. This viewpoint provides a historical overview and questions the safety of routine high-dose oxygen administration and is based on pathophysiology and (pre)clinical findings in various medical emergencies. PMID- 23635029 TI - Chloroquine cardiomyopathy - a review of the literature. AB - Chloroquine and hydroxychloroquine are still used for the prevention and treatment of malaria. Moreover, they are experiencing a renaissance in the long term therapy of connective tissue diseases (particularly in systemic lupus erythematosus). They induce a lysosomal dysfunction with an accumulation of pathologic metabolic products, which can be seen in ultrastructural histology as pathognomonic cytoplasmic inclusion bodies. Due to its lower toxicity, hydroxychloroquine is the form used predominantly today. Retinopathy as a toxic result of this medication is well known. Cardiac side effects are rarely reported, but in some cases can be severe and irreversible - two cases of organ transplantation have been described in the literature. They comprise conduction disturbances (bundle-branch block, atrioventricular block) and cardiomyopathy - often with hypertrophy, restrictive physiology and congestive heart failure. As the clinical features of cardiotoxicity are unspecific, the identification and follow-up of potentially affected patients is of utmost importance. Confirming the diagnosis of this toxic storage disease requires histological examination of the myocardium in conjunction with electron microscopy. The primary clinical parameters (diagnostic criteria for this cardiomyopathy, differential diagnostics, incidence, risk factors, prognosis) as well as the diagnostic procedures are discussed against the background of the available literature. PMID- 23635030 TI - Successful treatment of severe iron intoxication with gastrointestinal decontamination, deferoxamine, and hemodialysis. AB - Acute iron poisoning is a common and potentially serious problem in the pediatric population. Early recognition and treatment is crucial for a better outcome and to prevent morbidity and mortality. An 18-year-old female, who had accidental ingestion of 50 tablets of ferrous sulfate (100 mg of elemental iron per 335 mg tablet), 100 mg/kg of elemental iron, developed acute gastrointestinal and neurologic signs of toxicity and severe anion gap metabolic acidosis. The patient had received gastrointestinal decontamination, deferoxamine (DFO) infusion, and hemodialysis (HD) resulting in a decrease in serum iron concentration from 2150 to 160 mcg/dL at 24-h post-ingestion and improved mental status. Our cases demonstrate that HD may assist in decreasing serum iron concentration and improving clinical status in patients with massive overdose and life-threatening toxicity. PMID- 23635031 TI - Carbon dioxide clathrate hydrates: selective role of intermolecular interactions and action of the SDS catalyst. AB - The ability of a single sodium dodecyl sulfate (SDS) molecule to promote the formation of CO2 clathrate hydrates in water (as it does for methane) has been investigated at the microscopic level. For this purpose, the components of the related force field were carefully formulated and assembled following the procedure previously adopted for methane. The properties of the whole system (as well as those of its components) were analyzed by carrying out extended molecular dynamics calculations. Contrary to what happens for methane, the calculations singled out the propensity of CO2 (pure) water clusters to form clathrate hydrate like structures and the disappearance of such propensity when a single SDS molecule is added to the clusters. This feature was found to be due to the strong interaction of carbon dioxide with the additive that makes the SDS molecule lose its shape together with its ability to drive water molecules to form a suitable cage. PMID- 23635032 TI - Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn's disease. AB - BACKGROUND: Influence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn's disease (CD). METHODS: 85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD). RESULTS: Chronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213). CONCLUSIONS: These data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants. PMID- 23635034 TI - Abnormal lipid metabolism down-regulates adenosine triphosphate synthase beta subunit protein expression in corpus cavernosum smooth muscle in vitro and in vivo. AB - Metabolic syndrome is closely related to erectile dysfunction (ED), and hyperlipidaemia is considered a major risk factor for ED. Adenosine triphosphate (ATP) synthase is believed to play an important role in metabolic syndrome; it has been hypothesised that ATP synthase contributes to ED development. We have verified this hypothesis using primary cultured human corpus cavernosum smooth muscle (HCCSM) cells treated with excessive free fat acid (FFA) and a high-fat diet (HFD) mouse model. Our results showed that high fatty factors could cause lipid accumulation in HCCSM cells, which could result in abnormal lipid metabolism, such as high levels of triglycerides, cholesterol and glucose in the HFD mice. There was a remarkable down-regulation of ATP synthase and p-Akt after in vivo and in vitro excessive FFA treatments. These results indicated that abnormal lipid metabolism could induce ATP synthase down-regulation via the Akt phosphorylation pathway and that ATP synthase may be a target of lipotoxicity in corpus cavernosum smooth muscle cells. PMID- 23635033 TI - A SELDI mass spectrometry study of experimental autoimmune encephalomyelitis: sample preparation, reproducibility, and differential protein expression patterns. AB - BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is an autoimmune, inflammatory disease of the central nervous system that is widely used as a model of multiple sclerosis (MS). Mitochondrial dysfunction appears to play a role in the development of neuropathology in MS and may also play a role in disease pathology in EAE. Here, surface enhanced laser desorption ionization mass spectrometry (SELDI-MS) has been employed to obtain protein expression profiles from mitochondrially enriched fractions derived from EAE and control mouse brain. To gain insight into experimental variation, the reproducibility of sub-cellular fractionation, anion exchange fractionation as well as spot-to-spot and chip-to chip variation using pooled samples from brain tissue was examined. RESULTS: Variability of SELDI mass spectral peak intensities indicates a coefficient of variation (CV) of 15.6% and 17.6% between spots on a given chip and between different chips, respectively. Thinly slicing tissue prior to homogenization with a rotor homogenizer showed better reproducibility (CV = 17.0%) than homogenization of blocks of brain tissue with a Teflon(r) pestle (CV = 27.0%). Fractionation of proteins with anion exchange beads prior to SELDI-MS analysis gave overall CV values from 16.1% to 18.6%. SELDI mass spectra of mitochondrial fractions obtained from brain tissue from EAE mice and controls displayed 39 differentially expressed proteins (p<= 0.05) out of a total of 241 protein peaks observed in anion exchange fractions. Hierarchical clustering analysis showed that protein fractions from EAE animals with severe disability clearly segregated from controls. Several components of electron transport chain complexes (cytochrome c oxidase subunit 6b1, subunit 6C, and subunit 4; NADH dehydrogenase flavoprotein 3, alpha subcomplex subunit 2, Fe-S protein 4, and Fe-S protein 6; and ATP synthase subunit e) were identified as possible differentially expressed proteins. Myelin Basic Protein isoform 8 (MBP8) (14.2 kDa) levels were lower in EAE samples with advanced disease relative to controls, while an MBP fragment (12. 4kDa), likely due to calpain digestion, was increased in EAE relative to controls. The appearance of MBP in mitochondrially enriched fractions is due to tissue freezing and storage, as MBP was not found associated with mitochondria obtained from fresh tissue. CONCLUSIONS: SELDI mass spectrometry can be employed to explore the proteome of a complex tissue (brain) and obtain protein profiles of differentially expressed proteins from protein fractions. Appropriate homogenization protocols and protein fractionation using anion exchange beads can be employed to reduce sample complexity without introducing significant additional variation into the SELDI mass spectra beyond that inherent in the SELDI- MS method itself. SELDI-MS coupled with principal component analysis and hierarchical cluster analysis provides protein patterns that can clearly distinguish the disease state from controls. However, identification of individual differentially expressed proteins requires a separate purification of the proteins of interest by polyacrylamide electrophoresis prior to trypsin digestion and peptide mass fingerprint analysis, and unambiguous identification of differentially expressed proteins can be difficult if protein bands consist of several proteins with similar molecular weights. PMID- 23635035 TI - Efficient quantification of the health-relevant anthocyanin and phenolic acid profiles in commercial cultivars and breeding selections of blueberries ( Vaccinium spp.). AB - Anthocyanins and phenolic acids are major secondary metabolites in blueberry with important implications for human health maintenance. An improved protocol was developed for the accurate, efficient, and rapid comparative screening for large blueberry sample sets. Triplicates of six commercial cultivars and four breeding selections were analyzed using the new method. The compound recoveries ranged from 94.2 to 97.5 +/- 5.3% when samples were spiked with commercial standards prior to extraction. Eighteen anthocyanins and 4 phenolic acids were quantified in frozen and freeze-dried fruits. Large variations for individual and total anthocyanins, ranging from 201.4 to 402.8 mg/100 g, were assayed in frozen fruits. The total phenolic acid content ranged from 23.6 to 61.7 mg/100 g in frozen fruits. Across all genotypes, freeze-drying resulted in minor reductions in anthocyanin concentration (3.9%) compared to anthocyanins in frozen fruits. However, phenolic acids increased by an average of 1.9-fold (+/-0.3) in the freeze-dried fruit. Different genotypes frequently had comparable overall levels of total anthocyanins and phenolic acids, but differed dramatically in individual profiles of compounds. Three of the genotypes contained markedly higher concentrations of delphinidin 3-O-glucoside, cyanidin 3-O-glucoside, and malvidin 3-O-glucoside, which have previously been implicated as bioactive principles in this fruit. The implications of these findings for human health benefits are discussed. PMID- 23635037 TI - Revisiting the pre-hypertension debate: increasing evidence for treatment--or not? PMID- 23635038 TI - Blood screening for human immunodeficiency virus: a new algorithm to reduce the false-positive results. AB - OBJECTIVES: The objectives to this study were to evaluate the performance of an anti-human immunodeficiency virus (HIV) blood screening test and propose a new screening algorithm for blood banks routinely using nucleic acid amplification testing (NAT) to reduce false-positive results. BACKGROUND: Most anti-HIV enzyme linked immunosorbent assay (ELISA) results are false-positive because of the low prevalence of HIV infection and high sensitivity of the ELISAs. METHODS/MATERIALS: A total of 281 588 voluntary donations were collected and sera reactive on one or both anti-HIV ELISAs were confirmed by Western blot (WB) testing. All samples with nonreactive results for the two ELISAs underwent NAT. A confirmed HIV-1-positive result was defined by a reactive result on NAT or WB testing. Correlations between signal-to-cutoff ratios and the confirmed HIV-1 infection rate were analysed for each enzyme immunoassay and two-enzyme immunoassay combination. The positive predictive values (PPVs) of the current and proposed algorithms were calculated. RESULTS: Seventy-nine donations (13.9%) were positive on WB analysis and one donation negative for anti-HIV antibody was reactive on NAT and confirmed to be a window period donation on additional follow up testing. The PPV of the 567 donations reactive on one or two ELISAs was 13.9%. However, using the new screening algorithm, 457 donations underwent NAT immediately instead of WB testing. Only 110 donations were tested with WB and the PPV was 71.8%. CONCLUSION: Screening for HIV is sensitive, specific and time saving for donors with this algorithm, which is suitable for HIV screening in low prevalence settings. PMID- 23635036 TI - Plasma cell neoplasms in US solid organ transplant recipients. AB - Transplant recipients have elevated risk for plasma cell neoplasms (PCNs, comprising multiple myeloma and plasmacytoma), but little is known about risk factors in the transplant setting. Through linkage of the US solid organ transplant registry with 15 state/regional cancer registries, we identified 140 PCNs in 202 600 recipients (1987-2009). PCN risk was 1.8-fold increased relative to the general population (standardized incidence ratio [SIR] 1.80, 95%CI 1.51 2.12). Among cases, 102 were multiple myeloma (SIR 1.41) and 38 were plasmacytoma (SIR 7.06). PCN incidence increased with age, but due to the rarity of PCNs in younger people in the general population, SIRs were highest in younger transplant recipients (p = 0.03). PCN risk was especially high in recipients who were Epstein-Barr virus (EBV) seronegative at transplantation (SIR 3.93). EBV status was known for 18 tumors, of which 7 (39%) were EBV positive. Following liver transplantation, PCN risk was higher in recipients with cholestatic liver disease (SIR 2.78); five of these cases had primary biliary cirrhosis (PBC). A role for primary EBV infection after transplantation is supported by the increased PCN risk in young EBV seronegative recipients and the presence of EBV in tumors. PBC may be another risk factor, perhaps by causing chronic immune activation. PMID- 23635039 TI - Syntheses of (+)-complanadine A and lycodine derivatives by regioselective [2 + 2 + 2] cycloadditions. AB - The dimeric alkaloid complanadine A has shown promise in regenerative science, promoting neuronal growth by inducing the secretion of growth factors from glial cells. Through the use of tandem, cobalt-mediated [2 + 2 + 2] cycloaddition reactions, two synthetic routes have been developed with different sequences for the formation of the unsymmetric bipyridyl core. The regioselective formation of each of the pyridines was achieved based on the inherent selectivity of the molecules or by reversing the regioselectivity through the addition of Lewis bases. This strategy has been successfully employed to provide laboratory access to complanadine A as well as structurally related compounds possessing the lycodine core. PMID- 23635040 TI - Immediate post-partum initiation of intrauterine contraception and implants: a review of the safety and guidelines for use. AB - Women are particularly susceptible to unintended pregnancies in the first year after birth, with 10-44% of pregnancies being unintended. In many settings, post partum birth control is initiated at the six-week post-partum visit but most women are sexually active by this time, and ovulation can occur as early as day 28. There are many potential advantages of initiating intrauterine contraception (IUC) and implants use in the immediate post-partum period, including their high efficacy and reversibility which rivals sterilisation as well as ease of access to providers trained in their insertion. This review aims to describe the benefits and risks of use of IUC and implants in the immediate post-partum period. It discusses the maternal and infant health safety issues of early initiation of the progestogen containing methods and provides a critical review of existing international guidelines. Overall low rates of adverse effects such as pain, bleeding, infection and perforation, are documented to occur in all studies regardless of the timing or route of IUC insertion. Expulsion rates are significantly higher immediately after vaginal delivery compared to interval insertions, but are no higher after insertion at caesarean section. Post-partum implants appear to have the same side effects as interval insertions, and to date, no adverse impact on breast milk or infant growth has been demonstrated. Most international evidence-based guidelines support the initiation of IUC and progestogen containing contraceptive methods in the immediate post-partum period as they regard the advantages of provision at this time to outweigh the risks. PMID- 23635041 TI - Semiquantitative proteomic analysis of human hippocampal tissues from Alzheimer's disease and age-matched control brains. AB - BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia affecting people over 65 years of age. The hallmarks of AD are the extracellular deposits known as amyloid beta plaques and the intracellular neurofibrillary tangles, both of which are the principal players involved in synaptic loss and neuronal cell death. Tau protein and Abeta fragment 1-42 have been investigated so far in cerebrospinal fluid as a potential AD biomarkers. However, an urgent need to identify novel biomarkers which will capture disease in the early stages and with better specificity remains. High-throughput proteomic and pathway analysis of hippocampal tissue provides a valuable source of disease-related proteins and biomarker candidates, since it represents one of the earliest affected brain regions in AD. RESULTS: In this study 2954 proteins were identified (with at least 2 peptides for 1203 proteins) from both control and AD brain tissues. Overall, 204 proteins were exclusively detected in AD and 600 proteins in control samples. Comparing AD and control exclusive proteins with cerebrospinal fluid (CSF) literature-based proteome, 40 out of 204 AD related proteins and 106 out of 600 control related proteins were also present in CSF. As most of these proteins were extracellular/secretory origin, we consider them as a potential source of candidate biomarkers that need to be further studied and verified in CSF samples. CONCLUSIONS: Our semiquantitative proteomic analysis provides one of the largest human hippocampal proteome databases. The lists of AD and control related proteins represent a panel of proteins potentially involved in AD pathogenesis and could also serve as prospective AD diagnostic biomarkers. PMID- 23635042 TI - BioUSeR: a semantic-based tool for retrieving Life Science web resources driven by text-rich user requirements. AB - BACKGROUND: Open metadata registries are a fundamental tool for researchers in the Life Sciences trying to locate resources. While most current registries assume that resources are annotated with well-structured metadata, evidence shows that most of the resource annotations simply consists of informal free text. This reality must be taken into account in order to develop effective techniques for resource discovery in Life Sciences. RESULTS: BioUSeR is a semantic-based tool aimed at retrieving Life Sciences resources described in free text. The retrieval process is driven by the user requirements, which consist of a target task and a set of facets of interest, both expressed in free text. BioUSeR is able to effectively exploit the available textual descriptions to find relevant resources by using semantic-aware techniques. CONCLUSIONS: BioUSeR overcomes the limitations of the current registries thanks to: (i) rich specification of user information needs, (ii) use of semantics to manage textual descriptions, (iii) retrieval and ranking of resources based on user requirements. PMID- 23635043 TI - Multi-factorial drivers of ammonia oxidizer communities: evidence from a national soil survey. AB - The factors driving the abundance and community composition of soil microbial communities provide fundamental knowledge on the maintenance of biodiversity and the ecosystem services they underpin. Several studies have suggested that microbial communities are spatially organized, including functional groups and much of the observed variation is explained by geographical location or soil pH. Soil ammonia-oxidizing archaea (AOA) and bacteria (AOB) are excellent models for such study due to their functional, agronomic and environmental importance and their relative ease of characterization. To identify the dominant drivers of different ammonia oxidizers, we used samples (n = 713) from the National Soil Inventory of Scotland (NSIS). Our results indicate that 40-45% of the variance in community compositions can be explained by 71 environmental variables. Soil pH and substrate, which have been regarded as the two main drivers, only explained 13-16% of the total variance. We provide strong evidence of multi-factorial drivers (land use, soil type, climate and N deposition) of ammonia-oxidizing communities, all of which play a significant role in the creation of specific niches that are occupied by unique phylotypes. For example, one AOA phylotype was strongly linked to woodland/semi-natural grassland, rainfall and N deposition. Some soil typologies, namely regosols, have a novel AOA community composition indicating typology as one of the factors which defines this ecological niche. AOA abundance was high and strongly linked the rate of potential nitrification in the highly acidic soils supporting the argument that AOA are main ammonia oxidizers in acidic soils. However, for AOB, soil pH and substrate (ammonia) were the main drivers for abundance and community composition. These results highlight the importance of multiple drivers of microbial niche formation and their impact on microbial biogeography that have significant consequences for ecosystem functioning. PMID- 23635045 TI - Optical far-field method with subwavelength accuracy for the determination of nanostructure dimensions in large-area samples. AB - The physical, chemical, and biological properties of nanostructures depend strongly on their geometrical dimensions. Here we present a fast, noninvasive, simple-to-perform, purely optical method that is capable of characterizing nanostructure dimensions over large areas with an accuracy comparable to that of scanning electron microscopy. This far-field method is based on the analysis of unique fingerprints in experimentally measured reflectance spectra using full three-dimensional optical modeling. We demonstrate the strength of our method on large-area (millimeter-sized) arrays of vertical InP nanowires, for which we simultaneously determine the diameter and length as well as cross-sample morphological variations thereof. Explicitly, the diameter is determined with an accuracy better than 10 nm and the length with an accuracy better than 30 nm. The method is versatile and robust, and we believe that it will provide a powerful and standardized measurement technique for large-area nanostructure arrays suitable for both research and industrial applications. PMID- 23635046 TI - Cardiovascular risks with azithromycin and other antibacterial drugs. PMID- 23635047 TI - Discrimination at the doctor's office. PMID- 23635044 TI - Hospital laboratory reporting may be a barrier to detection of 'microsize' myocardial infarction in the US: an observational study. AB - BACKGROUND: International guidelines recommend that the decision threshold for troponin should be the 99th percentile of a normal population, or, if the laboratory assay is not sufficiently precise at this low level, the level at which the assay achieves a 10% or better coefficient of variation (CV). Our objectives were to examine US hospital laboratory troponin reports to determine whether either the 99th percentile or the 10% CV level were clearly indicated, and whether nonconcordance with these guidelines was a potential barrier to detecting clinically important microscopic or 'microsize' myocardial infarctions (MIs). To confirm past reports of the clinical importance of microsize MIs, we also contrasted in-hospital, 28-day and 1-year mortality among those with microsize and nonmicrosize MI. METHODS: In the REasons for Geographic And Racial Differences in Stroke national prospective cohort study (n=30,239), 1029 participants were hospitalized for acute coronary syndrome (ACS) between 2003 2009. For each case, we recorded all thresholds of abnormal troponin on the laboratory report and whether the 99th percentile or 10% CV value were clearly identified. All cases were expert adjudicated for presence of MI. Peak troponin values were used to classify MIs as microsize MI (< five times the lowest listed upper limit of normal) and nonmicrosize MI. RESULTS: Participants were hospitalized at 649 acute care US hospitals, only 2% of whose lab reports clearly identified the 99th percentile or the 10% CV level; 52% of reports indicated an indeterminate range, a practice that is no longer recommended. There were 183 microsize MIs and 353 nonmicrosize MIs. In-hospital mortality tended to be lower in the microsize than in the nonmicrosize MI group (1.1 vs. 3.6%, p = 0.09), but 28-day and 1-year mortality were similar (2.5% vs. 2.7% [p = 0.93] and 5.2% vs. 4.3% [p = 0.64], respectively). CONCLUSIONS: Current practices in many US hospitals created barriers to the clinical recognition of microsize MI, which was common and clinically important in our study. Improved hospital troponin reporting is warranted. PMID- 23635048 TI - Eastern equine encephalitis virus--old enemy, new threat. PMID- 23635050 TI - Use of azithromycin and death from cardiovascular causes. AB - BACKGROUND: Azithromycin use is associated with an increased risk of death from cardiovascular causes among patients at high baseline risk. Whether azithromycin confers a similar risk in the unselected general population is unknown. METHODS: We conducted a nationwide historical cohort study involving Danish adults (18 to 64 years of age), linking registry data on filled prescriptions, causes of death, and patient characteristics for the period from 1997 through 2010. We estimated rate ratios for death from cardiovascular causes, comparing 1,102,050 episodes of azithromycin use with no use of antibiotic agents (matched in a 1:1 ratio according to propensity score, for a total of 2,204,100 episodes) and comparing 1,102,419 episodes of azithromycin use with 7,364,292 episodes of penicillin V use (an antibiotic with similar indications; analysis was conducted with adjustment for propensity score). RESULTS: The risk of death from cardiovascular causes was significantly increased with current use of azithromycin (defined as a 5-day treatment episode), as compared with no use of antibiotics (rate ratio, 2.85; 95% confidence interval [CI], 1.13 to 7.24). The analysis relative to an antibiotic comparator included 17 deaths from cardiovascular causes during current azithromycin use (crude rate, 1.1 per 1000 person-years) and 146 during current penicillin V use (crude rate, 1.5 per 1000 person-years). With adjustment for propensity scores, current azithromycin use was not associated with an increased risk of cardiovascular death, as compared with penicillin V (rate ratio, 0.93; 95% CI, 0.56 to 1.55). The adjusted absolute risk difference for current use of azithromycin, as compared with penicillin V, was -1 cardiovascular death (95% CI, -9 to 11) per 1 million treatment episodes. CONCLUSIONS: Azithromycin use was not associated with an increased risk of death from cardiovascular causes in a general population of young and middle-aged adults. (Funded by the Danish Medical Research Council.). PMID- 23635052 TI - Injuries. PMID- 23635049 TI - Penicillin to prevent recurrent leg cellulitis. AB - BACKGROUND: Cellulitis of the leg is a common bacterial infection of the skin and underlying tissue. We compared prophylactic low-dose penicillin with placebo for the prevention of recurrent cellulitis. METHODS: We conducted a double-blind, randomized, controlled trial involving patients with two or more episodes of cellulitis of the leg who were recruited in 28 hospitals in the United Kingdom and Ireland. Randomization was performed according to a computer-generated code, and study medications (penicillin [250 mg twice a day] or placebo for 12 months) were dispensed by a central pharmacy. The primary outcome was the time to a first recurrence. Participants were followed for up to 3 years. Because the risk of recurrence was not constant over the 3-year period, the primary hypothesis was tested during prophylaxis only. RESULTS: A total of 274 patients were recruited. Baseline characteristics were similar in the two groups. The median time to a first recurrence of cellulitis was 626 days in the penicillin group and 532 days in the placebo group. During the prophylaxis phase, 30 of 136 participants in the penicillin group (22%) had a recurrence, as compared with 51 of 138 participants in the placebo group (37%) (hazard ratio, 0.55; 95% confidence interval [CI], 0.35 to 0.86; P=0.01), yielding a number needed to treat to prevent one recurrent cellulitis episode of 5 (95% CI, 4 to 9). During the no-intervention follow-up period, there was no difference between groups in the rate of a first recurrence (27% in both groups). Overall, participants in the penicillin group had fewer repeat episodes than those in the placebo group (119 vs. 164, P=0.02 for trend). There was no significant between-group difference in the number of participants with adverse events (37 in the penicillin group and 48 in the placebo group, P=0.50). CONCLUSIONS: In patients with recurrent cellulitis of the leg, penicillin was effective in preventing subsequent attacks during prophylaxis, but the protective effect diminished progressively once drug therapy was stopped. (Funded by Action Medical Research; PATCH I Controlled-Trials.com number, ISRCTN34716921.). PMID- 23635051 TI - The Oregon experiment--effects of Medicaid on clinical outcomes. AB - BACKGROUND: Despite the imminent expansion of Medicaid coverage for low-income adults, the effects of expanding coverage are unclear. The 2008 Medicaid expansion in Oregon based on lottery drawings from a waiting list provided an opportunity to evaluate these effects. METHODS: Approximately 2 years after the lottery, we obtained data from 6387 adults who were randomly selected to be able to apply for Medicaid coverage and 5842 adults who were not selected. Measures included blood-pressure, cholesterol, and glycated hemoglobin levels; screening for depression; medication inventories; and self-reported diagnoses, health status, health care utilization, and out-of-pocket spending for such services. We used the random assignment in the lottery to calculate the effect of Medicaid coverage. RESULTS: We found no significant effect of Medicaid coverage on the prevalence or diagnosis of hypertension or high cholesterol levels or on the use of medication for these conditions. Medicaid coverage significantly increased the probability of a diagnosis of diabetes and the use of diabetes medication, but we observed no significant effect on average glycated hemoglobin levels or on the percentage of participants with levels of 6.5% or higher. Medicaid coverage decreased the probability of a positive screening for depression (-9.15 percentage points; 95% confidence interval, -16.70 to -1.60; P=0.02), increased the use of many preventive services, and nearly eliminated catastrophic out-of pocket medical expenditures. CONCLUSIONS: This randomized, controlled study showed that Medicaid coverage generated no significant improvements in measured physical health outcomes in the first 2 years, but it did increase use of health care services, raise rates of diabetes detection and management, lower rates of depression, and reduce financial strain. PMID- 23635053 TI - Images in clinical medicine. Pain in the thumb related to disease in the lung. PMID- 23635054 TI - Clinical problem-solving. In the thick of it. PMID- 23635055 TI - Protecting finances and improving access to care with Medicaid. PMID- 23635056 TI - Kwashiorkor and the gut microbiota. PMID- 23635057 TI - Intracranial-pressure monitoring in traumatic brain injury. PMID- 23635058 TI - Intracranial-pressure monitoring in traumatic brain injury. PMID- 23635059 TI - Intracranial-pressure monitoring in traumatic brain injury. PMID- 23635060 TI - Intracranial-pressure monitoring in traumatic brain injury. PMID- 23635061 TI - Intracranial-pressure monitoring in traumatic brain injury. PMID- 23635062 TI - Intracranial-pressure monitoring in traumatic brain injury. PMID- 23635063 TI - Intracranial-pressure monitoring in traumatic brain injury. PMID- 23635064 TI - Smoking-related mortality in the United States. PMID- 23635065 TI - Smoking-related mortality in the United States. PMID- 23635066 TI - Smoking-related mortality in the United States. PMID- 23635067 TI - Smoking-related mortality in the United States. PMID- 23635068 TI - Proteotoxicity and cardiac dysfunction. PMID- 23635069 TI - Proteotoxicity and cardiac dysfunction. PMID- 23635070 TI - Proteotoxicity and cardiac dysfunction. PMID- 23635071 TI - Hepatocellular carcinoma after the Fontan procedure. PMID- 23635072 TI - Images in clinical medicine. Elephantiasis neuromatosa. PMID- 23635073 TI - Evaluation of suction detection during different pumping states in an implantable rotary blood pump. AB - In recent times, the problem of noninvasive suction detection for implantable rotary blood pumps has attracted substantial research interest. Here, we compare the performance of various suction indices for different types of suction and non suction events based on pump speed irregularity. A total of 171 different indices that consist of previously proposed as well as newly introduced suction indices are tested using regularized logistic regression. These indices can be classified as amplitude based (derived from the mean, maximum, and minimum values of a cycle), duration based (derived from the duration of a cycle), gradient based (derived from the first order as well as higher order differences) and frequency based (derived from the power spectral density). The non-suction event data consists of ventricular ejection with or without arrhythmia and intermittent and continuous non-opening of the aortic valve. The suction event data consists of partial ventricular collapse that occurs intermittently as well as continuously with or without arrhythmia. In addition, we also attempted to minimize the usage of multiple indices by applying the sequential forward floating selection method to find which combination of indices gives the best performance. In general, the amplitude-based and gradient-based indices performed quite well while the duration-based and frequency-based indices performed poorly. By having only two indices ([i] the maximum gradient change in positive slope; and [ii] the standard deviation of the maximum value in a cycle), we were able to achieve a sensitivity of 98.9% and a specificity of 99.7%. PMID- 23635074 TI - Wet adhesion of buckypaper produced from oxidized multiwalled carbon nanotubes on soft animal tissue. AB - Buckypaper (BP) is the general definition of a macroscopic assembly of entangled carbon nanotubes. In this paper, a new property of a BP film produced from oxidized multiwalled carbon nanotubes was investigated. In particular, BP shows to be able to promptly and strongly adhere to animal internal soft and wet tissues, as evaluated by peeling and shear tests. BP adhesion strength is higher than that recorded for a commercial prosthetic fabric (sealed to the tissue by fibrin glue) and comparable with that of other reported optimized nanopatterned surfaces. In order to give an interpretation of the observed behavior, the BP composition, morphology, porosity, water wettability, and mechanical properties were analyzed by AFM, X-ray photoelectron spectroscopy, wicking tests, contact angle, and stress-strain measurements. Although further investigations are needed to assess the biocompatibility and safety of the BP film used in this work, the obtained results pave the way for a possible future use of buckypaper as adhesive tape in abdominal prosthetic surgery. This would allow the substitution of conventional sealants or the reduction in the use of perforating fixation. PMID- 23635076 TI - Comment on Screening for PBT chemicals among the "existing" and "new" chemicals of the EU. PMID- 23635075 TI - Costs, outcomes and challenges for diabetes care in Spain. AB - BACKGROUND: Diabetes is becoming of increasing concern in Spain due to rising incidence and prevalence, although little information is known with regards to costs and outcomes. The information on cost of diabetes in Spain is fragmented and outdated. Our objective is to update diabetes costs, and to identify outcomes and quality of care of diabetes in Spain. METHODS: We performed systematic searches from secondary sources, including scientific literature and government data and reports. RESULTS: Diabetes Type II prevalence is estimated at 7.8%, and an additional 6% of the population is estimated to be undiagnosed. Four Spanish diabetes cost studies were analyzed to create a projection of direct costs in the NHS and productivity losses, estimating ?5.1 billion for direct costs along with ?1.5 billion for diabetes-related complications (2009) and labour productivity losses represented ?2.8 billion. Glycemic control (glycolysated hemoglobin) is considered acceptable in 59% of adult Type II cases, in addition to 85% with HDL cholesterol >=40mg/dl and 65% with blood pressure <140/90 mmHg, pointing to good intermediate outcomes. However, annual figures indicate that over half of the Type II diabetics are obese (BMI >30), 15% have diabetic retinopathy, 16% with microalbuminuria, and 15% with cardiovascular disease. CONCLUSIONS: The direct health care costs (8% of the total National Health System expenditure) and the loss of labour productivity are high. The importance of a multi-sectoral approach in prevention and improvements in management of diabetes are discussed, along with policy considerations to help modify the disease course. PMID- 23635077 TI - Palladium-catalyzed intramolecular direct arylation of 2-bromo-diaryl sulfoxides via C-H bond activation. AB - Efficient access to dibenzothiophene-S-oxides from differently substituted 2 bromo-diarylsulfinyl moieties using ligandless Pd(OAc)2 as the catalyst and KOAc as the base in dimethylacetamide at 130 degrees C is reported. Various dibenzothiophene-S-oxides were obtained in excellent yields. PMID- 23635078 TI - A metadata-aware application for remote scoring and exchange of tissue microarray images. AB - BACKGROUND: The use of tissue microarrays (TMA) and advances in digital scanning microscopy has enabled the collection of thousands of tissue images. There is a need for software tools to annotate, query and share this data amongst researchers in different physical locations. RESULTS: We have developed an open source web-based application for remote scoring of TMA images, which exploits the value of Microsoft Silverlight Deep Zoom to provide a intuitive interface for zooming and panning around digital images. We use and extend existing XML-based standards to ensure that the data collected can be archived and that our system is interoperable with other standards-compliant systems. CONCLUSION: The application has been used for multi-centre scoring of TMA slides composed of tissues from several Phase III breast cancer trials and ten different studies participating in the International Breast Cancer Association Consortium (BCAC). The system has enabled researchers to simultaneously score large collections of TMA and export the standardised data to integrate with pathological and clinical outcome data, thereby facilitating biomarker discovery. PMID- 23635080 TI - Effects of a rapid response system on quality of life: a prospective cohort study in surgical patients before and after implementing a rapid response system. AB - BACKGROUND: The aim of a rapid response system (RRS) is to improve the timely recognition and treatment of ward patients with deteriorating vital signs The system is based on a set of clinical criteria that are used to assess patient's vital signs on a general ward. Once a patient is evaluated as critical, a medical emergency team is activated to more thoroughly assess the patient's physical condition and to initiate treatment. The medical emergency team included a critical care physician and a critical care nurse. AIM: To assess the effect of an RRS on health-related quality of life (HRQOL). METHODS: Prospective cohort study in surgical patients before and after implementing an RRS. HRQOL was measured using the EuroQol-5 dimensions (EQ-5D) and the EQ visual analogue scale (VAS) at pre surgery and at 3 and 6 months following surgery. RESULTS: No statistical significant effects of RRS implementation on the EQ-5D index and EQ VAS were found. This was also true for the subpopulation of patients with an unplanned intensive care unit admission. Regarding the EQ-5D dimensions, deterioration in the 'mobility' and 'usual activities' dimensions in the post implementation group was significantly less compared to the pre-implementation group with a respective mean difference of 0.08 (p = 0.03) and 0.09 (p = 0.04) on a three-point scale at 6 months. Lower pre-surgery EQ-5D index and higher American Society of Anesthesiologists physical status (ASA-PS) scores were significantly associated with lower EQ-5D index scores at 3 and 6 months following surgery. CONCLUSIONS: Implementation of an RRS did not convincingly affect HRQOL following major surgery. We question if HRQOL is an adequate measure to assess the influence of an RRS. Pre-surgery HRQOL- and ASA-PS scores were strongly associated with HRQOL outcomes and may have abated the influence of the RRS implementation. PMID- 23635079 TI - Dihydroartemisinin suppresses ovalbumin-induced airway inflammation in a mouse allergic asthma model. AB - Asthma is a complex disease characterized by reversible airway obstruction, airway hyper-responsiveness (AHR) and chronic inflammation of the airways. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin isolated from the traditional Chinese herb Artemisia annua, has been shown to possess antimalarial and antitumor activities, but whether it can be used in asthma treatment has not been investigated. In this study, we attempted to determine whether DHA regulates inflammatory mediators in the ovalbumin (OVA)-induced mouse asthma model. BALB/c mice were sensitized and challenged by OVA to induce chronic airway inflammation. The intragastrical administration of DHA at 30 mg/kg significantly decreased the number of infiltrating inflammatory cells, T-helper type 2 (Th2) cytokines, OVA-specific immunoglobulin E (IgE) and AHR. Treatment with DHA also attenuated OVA-induced mRNA expression of Muc5ac and chitinase 3 like protein 4 (Ym2) in lung tissues. In addition, lung histopathological studies revealed that DHA inhibited inflammatory cell infiltration and mucus hypersecretion. Then signal transduction studies showed that DHA significantly inhibited extracellular signal-regulated protein kinase (ERK), p38 mitogen activated protein kinase phosphorylation. DHA also inhibited nuclear factor kappaB (NF-kappaB) activation via the inhibition of phosphorylation of IkappaBalpha. These findings provide new insight into the immunopharmacological role of DHA in terms of its effects in a mouse model of asthma. PMID- 23635081 TI - Parental bonding and personality characteristics of first episode intention to suicide or deliberate self-harm without a history of mental disorders. AB - BACKGROUND: There is substantial overlap between deliberate self-harm (DSH) and intention to suicide (ITS), although the psychopathologies and motivations behind these behaviors are distinctly different. The purpose of this study was to investigate (i) the pathway relationship among parental bonding, personality characteristics, and alexithymic traits, and (ii) the association of these features with ITS and DSH using structural equation modeling to determine the risks and protective factors for these behaviors. METHODS: Sixty-nine first-time DSH and 36 first-time ITS patients without medical or psychiatric illnesses, and 66 controls were recruited. The Parental Bonding Inventory (PBI), Eysenck Personality Questionnaire (EPQ), 20-item Toronto Alexithymia Scale (TAS-20), and the Chinese Health Questionnaire (CHQ) were filled out by the participants. RESULTS: Our structural equation models showed that parental bonding had the greatest influence on the development of DSH behavior in patients. On the other hand, participants who were younger, less extraverted, with a greater extent of the alexithymic trait of difficulty identifying feeling (DIF), and a worse mental health condition, were more likely to develop ITS behavior. Males were more likely than females to develop the alexithymic trait of DIF. CONCLUSIONS: Although there are many covariates that affect both ITS and DSH behaviors, these covariates may have different functions in the development of these behaviors, thus revealing the psychopathological difference between DSH and ITS. Policymakers should consider these differences and build intervention and prevention programs for gender- and age-specific high-risk groups to target the differences, with a focus on family counseling to treat DSH and a focus on attempting to increase emotional awareness to treat ITS. PMID- 23635083 TI - The STOP the Bleeding Campaign. AB - According to the World Health Organization, traumatic injuries worldwide are responsible for over 5 million deaths annually. Post-traumatic bleeding caused by traumatic injury-associated coagulopathy is the leading cause of potentially preventable death among trauma patients. Despite these facts, awareness of this problem is insufficient and treatment options are often unclear. The STOP the Bleeding Campaign therefore aims to increase awareness of the phenomenon of post traumatic coagulopathy and its appropriate management by publishing European guidelines for the management of the bleeding trauma patient, by promoting and monitoring the implementation of these guidelines and by preparing promotional and educational material, organising activities and developing health quality management tools. The campaign aims to reduce the number of patients who die within 24 hours after arrival in the hospital due to exsanguination by a minimum of 20% within the next 5 years. PMID- 23635082 TI - Long term evolution of patients treated in a TIA unit. AB - BACKGROUND: Transient ischemic attacks (TIA) entail a high risk of stroke recurrence, which depends on the etiology. New organizational models have been created, but there is not much information about the long-term evolution of patients managed according to these premises. Our aim is to refer the follow-up of patients attended according to our model of TIA Unit. METHODS: TIA Unit is located in the Emergency Department and staffed by vascular neurologists. Patients admitted during the Neurology night shift stayed in such Unit <48h with complete etiological study. Preventive treatment is instituted in patients discharged to a high resolution Neurology consult, in order to review in <2 weeks and subsequent follow-up. RESULTS: During a year 161 patients were attended, being admitted to the hospital 8.6%. A total of 1470 hospital days were avoided. Recurrence at 90 days was of 0.6%. Mean follow-up was 18.14 +/- 8.02 months (0 34), total recurrence 6.2% (70% cardioembolic strokes). There were no complications derived from treatment. Cardiological events were recorded in 10.6%, neoplastic in 5%, cognitive impairment in 11%. There were 3 deaths unrelated nor to the stroke or its treatment. CONCLUSIONS: This model allows an early diagnosis and treatment of TIA, preventing recurrences of stroke in a long term. It detects atherothrombotic strokes, most of them admitted to the hospital, and it shows a greater difficulty for detecting all cardioembolic strokes. TIA Unit appeared to be safe in using anticoagulation therapy, as the follow-up shows. It shows the same quality of management than hospital admission, with a significant saving in hospital stays. PMID- 23635084 TI - NH3 as a strong H-bond donor in singly- and doubly-bridged ammonia solvent clusters: 2-pyridone.(NH3)(n), n = 1-3. AB - Mass- and isomer-selected infrared spectra of 2-pyridone.(NH3)n clusters with n = 1-3 were measured in the NH and CH stretch fundamental region (2400-3700 cm(-1)) using infrared (IR) laser depletion spectroscopy combined with resonant two photon ionization UV laser detection. The IR depletion spectra reveal three different H-bonding topologies of these clusters: The n = 1 and 2 clusters form ammonia bridges stretching from the N-H to the C?O group of the cis-amide function of 2-pyridone (2PY), giving rise to intense and strongly red-shifted (2PY)NH and ammonia NH stretch bands. For n = 3, two isomers (3X and 3Y) are observed in the IR spectra: The spectrum of 3X is compatible with an ammonia bridge structure like n = 2, with the third NH3 accepting an H-bond from C(6)-H of 2PY. The IR spectrum of 3Y exhibits a broad IR band in the 2500-3000 cm(-1) range and is characteristic of a bifurcated double-bridged structure in which the first NH3 accepts an H-bond from the (2PY)NH and donates two H-bonds to the other two ammonias, both of which donate to the C?O group of 2PY. This double donor/double-bridge H-bonding pattern increases the acceptor strength of the first ammonia and dramatically lowers the (2PY)NH stretching frequency to ~2700 cm(-1). For all clusters the ammonia 2nu4 HNH bend overtones in the 3180-3320 cm( 1) region gain intensity by anharmonic coupling (Fermi resonance) to the hydrogen bonded ammonia NH stretches, which are red-shifted into the 3250-3350 cm(-1) region. The experimental results are supported by optimized structures, vibrational frequencies, and IR intensities calculated using density-functional theory with the B3LYP and PW91 functionals, as well as with the more recent functionals B97-D and M06-2X, which are designed to include long-range dispersive interactions. PMID- 23635085 TI - Interaction between graphene oxide and Pluronic F127 at the air-water interface. AB - Triblock copolymer Pluronic F127 (PF127) has previously been demonstrated to disperse graphene oxide (GO) in electrolyte solution and block the hydrophobic interaction between GO and l-tryptophan and l-tyrosine. However, the nature of this interaction between PF127 and GO remains to be characterized and elucidated. In the present study, we aimed to characterize and understand the interaction between GO and PF127 using a 2-dimensional Langmuir monolayer methodology at the air-water interface by surface pressure-area isotherm measurement, stability, adsorption, and atomic force microscopy (AFM) imaging. Based on the observation of surface pressure-area isotherms, adsorption, and stability of PF127 and PF127/GO mixture at the air-water interface, GO is suggested to change the conformation of PF127 at the air-water interface and also drag PF127 from the interface to the bulk subphase. Atomic force microscopy (AFM) image supports this assumption, as GO and PF127 can be observed by spreading the subphase solution outside the compressing barriers, as shown in the TOC graphic. PMID- 23635087 TI - Derivation and genetic modification of embryonic stem cells from disease-model inbred rat strains. AB - The lack of rat embryonic stem cells (ESCs) and approaches for manipulation of their genomes have restricted the ability to create new genetic models and to explore the function of a single gene in complex diseases in the laboratory rat. The recent breakthrough in isolating germline-competent ESCs from rat and subsequent demonstration of gene knockout has propelled the field forward, but such tools do not yet exist for many disease-model rat strains. Here we derive new ESCs from several commonly used rat models including the Dahl Salt Sensitive (SS), the sequenced Brown Norway (BN), and Fischer (F344) rat and establish the first germline-competent ESCs from a hypertension disease model strain, the Fawn Hooded Hypertensive (FHH) rat. Genetic manipulations including transgenesis mediated by lentivirus, routine homologous recombination, and homologous recombination mediated by zinc-finger nucleases (ZFNs) were performed effectively in FHH rat ESCs. Our results showed these rat ESC lines, isolated from inner cell masses using mechanical splitting, had germline competency; the Pparg gene locus and homologous genomic region to the mouse Rosa26 locus can be targeted effectively in these rat ESCs. Furthermore, our results also demonstrated that ZFNs increased the efficiency of proper homologous recombination in FHH rat ESCs using targeting vectors with short homology arms. These rat ESC lines and advancements in genetic manipulation pave the way to novel genetic approaches in this valuable biomedical model species and for exploration of complex disease in these strains. PMID- 23635086 TI - Laxative use and incident falls, fractures and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative. AB - BACKGROUND: Laxatives are among the most widely used over-the-counter medications in the United States but studies examining their potential hazardous side effects are sparse. Associations between laxative use and risk for fractures and change in bone mineral density [BMD] have not previously been investigated. METHODS: This prospective analysis included 161,808 postmenopausal women (8907 users and 151,497 nonusers of laxatives) enrolled in the WHI Observational Study and Clinical Trials. Women were recruited from October 1, 1993, to December 31, 1998, at 40 clinical centers in the United States and were eligible if they were 50 to 79 years old and were postmenopausal at the time of enrollment. Medication inventories were obtained during in-person interviews at baseline and at the 3 year follow-up visit on everyone. Data on self-reported falls (>=2), fractures (hip and total fractures) were used. BMD was determined at baseline and year 3 at 3 of the 40 clinical centers of the WHI. RESULTS: Age-adjusted rates of hip fractures and total fractures, but not for falls were similar between laxative users and non-users regardless of duration of laxative use. The multivariate adjusted hazard ratios for any laxative use were 1.06 (95% confidence interval [CI], 1.03-1.10) for falls, 1.02 (95% CI, 0.85-1.22) for hip fractures and 1.01 (95% CI, 0.96-1.07) for total fractures. The BMD levels did not statistically differ between laxative users and nonusers at any skeletal site after 3-years intake. CONCLUSION: These findings support a modest association between laxative use and increase in the risk of falls but not for fractures. Its use did not decrease bone mineral density levels in postmenopausal women. Maintaining physical functioning, and providing adequate treatment of comorbidities that predispose individuals for falls should be considered as first measures to avoid potential negative consequences associated with laxative use. PMID- 23635088 TI - Gallic acid-grafted-chitosan inhibits foodborne pathogens by a membrane damage mechanism. AB - In this study, antimicrobial activity of gallic acid-grafted-chitosans (gallic acid-g-chitosans) against five Gram-positive and five Gram-negative foodborne pathogens was evaluated. The minimum inhibitory concentrations (MICs) of gallic acid-g-chitosans ranged from 16 to 64 MUg/mL against Gram-positive bacteria and ranged from 128 to 512 MUg/mL against Gram-negative bacteria. These activities were higher than those of unmodified chitosan. The bactericidal activity of gallic acid-g-chitosan (I), which showed the highest antimicrobial activity, was evaluated by time-killing assay with multiples of MIC, and it was recognized to depend on its dose. The integrity of cell membrane, outer membrane (OM), inner membrane (IM) permeabilization experiments, and transmission electron microscopy (TEM) observation were conducted for elucidation of the detailed antimicrobial mode of action of gallic acid-g-chitosan. Results showed that treatment of gallic acid-g-chitosan (I) quickly increased the release of intracellular components for both Escherichia coli and Staphylococcus aureus. In addition, gallic acid-g chitosan (I) also rapidly increased the 1-N-phenylanphthylamine (NPN) uptake and the release of beta-galactosidase via increasing the permeability of OM and IM in E. coli. TEM observation demonstrated that gallic acid-g-chitosan (I) killed the bacteria via disrupting the cell membrane. PMID- 23635089 TI - Study of the protective effect of vitamin C on testicular tissue following experimental unilateral cryptorchidism in rats. AB - This study investigated the role of vitamin C as an antioxidant in protecting the testis against damage in experimental unilateral cryptorchidism. Forty-five male Wistar Albino rats were divided into three groups. The control group had intact rats, the cryptorchid group had unilateral cryptorchid rats and the treatment group had unilateral cryptorchid rats that it received vitamin C at a dose of 50 mg kg(-1) body weight intraperitoneal, once a day, during experimental period. Histopathological samples were obtained from five cases of 15 animals of each group at 15, 30 and 60 days after induction of cryptorchidism. The results showed histopathological parameters of the cryptorchid (left) testes in the cryptorchid group significantly decreased compared with the control group (P < 0.05), and treatment with vitamin C after 60 days significantly improved all parameters of these testes compared with the cryptorchid group (P < 0.05). In addition, the left testes on unilateral cryptorchid rats had noticeable adverse effects on the scrotal (right) testes (P < 0.05). Treatment with vitamin C after 60 days significantly improved all parameters of these testes compared with the cryptorchid group (P < 0.05). It can be concluded that treatment with vitamin C significantly improved histopathological parameters in scrotal testes on unilateral cryptorchid rats. PMID- 23635090 TI - Hox gene expression during postlarval development of the polychaete Alitta virens. AB - BACKGROUND: Hox genes are the family of transcription factors that play a key role in the patterning of the anterior-posterior axis of all bilaterian animals. These genes display clustered organization and colinear expression. Expression boundaries of individual Hox genes usually correspond with morphological boundaries of the body. Previously, we studied Hox gene expression during larval development of the polychaete Alitta virens (formerly Nereis virens) and discovered that Hox genes are expressed in nereid larva according to the spatial colinearity principle. Adult Alitta virens consist of multiple morphologically similar segments, which are formed sequentially in the growth zone. Since the worm grows for most of its life, postlarval segments constantly change their position along the anterior-posterior axis. RESULTS: We studied the expression dynamics of the Hox cluster during postlarval development of the nereid Alitta virens and found that 8 out of 11 Hox genes are transcribed as wide gene-specific gradients in the ventral nerve cord, ectoderm, and mesoderm. The expression domains constantly shift in accordance with the changing proportions of the growing worm, so expression domains of most Hox genes do not have stable anterior or/and posterior boundaries.In the course of our study, we revealed long antisense RNA (asRNA) for some Hox genes. Expression patterns of two of these genes were analyzed using whole-mount in-situ hybridization. This is the first discovery of antisense RNA for Hox genes in Lophotrochozoa. CONCLUSION: Hox gene expression in juvenile A. virens differs significantly from Hox gene expression patterns both in A. virens larva and in other Bilateria.We suppose that the postlarval function of the Hox genes in this polychaete is to establish and maintain positional coordinates in a constantly growing body, as opposed to creating morphological difference between segments. PMID- 23635091 TI - A four-way, double-blind, randomized, placebo controlled study to determine the efficacy and speed of azelastine nasal spray, versus loratadine, and cetirizine in adult subjects with allergen-induced seasonal allergic rhinitis. AB - BACKGROUND: Azelastine has been shown to be effective against seasonal allergic rhinitis (SAR). The Environmental Exposure Unit (EEU) is a validated model of experimental SAR. The objective of this double-blind, four-way crossover study was to evaluate the onset of action of azelastine nasal spray, versus the oral antihistamines loratadine 10 mg and cetirizine 10 mg in the relief of the symptoms of SAR. METHODS: 70 participants, aged 18-65, were randomized to receive azelastine nasal spray, cetirizine, loratadine, or placebo after controlled ragweed pollen exposure in the EEU. Symptoms were evaluated using the total nasal symptom score (TNSS). The primary efficacy parameter was the onset of action as measured by the change from baseline in TNSS. RESULTS: Azelastine displayed a statistically significant improvement in TNSS compared with placebo at all time points from 15 minutes through 6 hours post dose. Azelastine, cetirizine, and loratadine reduced TNSS compared to placebo with an onset of action of 15 (p < 0.001), 60 (p = 0.015), and 75 (p = 0.034) minutes, respectively. The overall assessment of efficacy was rated as good or very good by 46% of the participants for azelastine, 51% of the participants for cetirizine, and 30% of the participants for loratadine compared to 18% of the participants for placebo. CONCLUSIONS: Azelastine's onset of action for symptom relief was faster than that of cetirizine and loratadine. The overall participant satisfaction in treatment with azelastine is comparable to cetirizine and statistically superior to loratadine. These results suggest that azelastine may be preferential to oral antihistamines for the rapid relief of SAR symptoms. PMID- 23635092 TI - Caregiver forgiveness is associated with less burden and potentially harmful behaviors. AB - OBJECTIVES: This study investigated whether caregiver forgiveness of care recipient's (CR's) upsetting behaviors is associated with less burden and potentially harmful behaviors (PHB) by the caregiver. METHOD: Seventy-six family caregivers of persons with dementia were recruited by means of convenience sampling through two local dementia service centers in Hong Kong. Caregivers were asked to complete an anonymous questionnaire that assessed CR behavior problems and caregiver burden, PHB and forgiveness. RESULTS: Results showed that forgiveness partially mediated the associations between CR disruptive behaviors and caregiver burden, and between CR depression and caregiver burden. At the same time, burden partially mediated the relationship between forgiveness and PHB. CONCLUSION: The associations between certain behavioral problems and burden were mediated by caregiver forgiveness. Forgiveness also predicted harmful behaviors, both directly and indirectly through burden. Future research should investigate the basis of forgiveness in dementia caregivers and whether forgiveness may constitute another dimension in caregiver interventions. PMID- 23635094 TI - Partly conditional estimation of the effect of a time-dependent factor in the presence of dependent censoring. AB - We propose semiparametric methods for estimating the effect of a time-dependent covariate on treatment-free survival. The data structure of interest consists of a longitudinal sequence of measurements and a potentially censored survival time. The factor of interest is time-dependent. Treatment-free survival is of interest and is dependently censored by the receipt of treatment. Patients may be removed from consideration for treatment, temporarily or permanently. The proposed methods combine landmark analysis and partly conditional hazard regression. A set of calendar time cross-sections is specified, and survival time (from cross section date) is modeled through weighted Cox regression. The assumed model for death is marginal in the sense that time-varying covariates are taken as fixed at each landmark, with the mortality hazard function implicitly averaging across future covariate trajectories. Dependent censoring is overcome by a variant of inverse probability of censoring weighting (IPCW). The proposed estimators are shown to be consistent and asymptotically normal, with consistent covariance estimators provided. Simulation studies reveal that the proposed estimation procedures are appropriate for practical use. We apply the proposed methods to pre-transplant mortality among end-stage liver disease (ESLD) patients. PMID- 23635093 TI - Ex vivo-expanded cynomolgus macaque regulatory T cells are resistant to alemtuzumab-mediated cytotoxicity. AB - Alemtuzumab (Campath-1H) is a humanized monoclonal antibody (Ab) directed against CD52 that depletes lymphocytes and other leukocytes, mainly by complement dependent mechanisms. We investigated the influence of alemtuzumab (i) on ex vivo expanded cynomolgus monkey regulatory T cells (Treg) generated for prospective use in adoptive cell therapy and (ii) on naturally occurring Treg following alemtuzumab infusion. Treg were isolated from PBMC and lymph nodes and expanded for two rounds. CD52 expression, binding of alemtuzumab and both complement mediated killing and Ab-dependent cell-mediated cytotoxicity (ADCC) were compared between freshly isolated and expanded Treg and effector T cells. Monkeys undergoing allogeneic heart transplantation given alemtuzumab were monitored for Treg and serum alemtuzumab activity. Ex vivo-expanded Treg showed progressive downregulation of CD52 expression, absence of alemtuzumab binding, minimal change in complement inhibitory protein (CD46) expression and no complement-dependent killing or ADCC. Infusion of alemtuzumab caused potent depletion of all lymphocytes, but a transient increase in the incidence of circulating Treg. After infusion of alemtuzumab, monkey serum killed fresh PBMC, but not expanded Treg. Thus, expanded cynomolgus monkey Treg are resistant to alemtuzumab-mediated, complement-dependent cytotoxicity. Furthermore, our data suggest that these expanded monkey Treg can be infused into graft recipients given alemtuzumab without risk of complement-mediated killing. PMID- 23635095 TI - Synthesis of orthogonally protected (2S)-2-amino-adipic acid (alpha-AAA) and (2S,4R)-2-amino-4-hydroxyadipic acid (Ahad). AB - (2S,4R)-2-amino-4-hydroxyadipic acid (Ahad) building block 45 was synthesized in 11 steps and 6.5% overall yield from commercially available materials. Key steps in stereocontrol were an asymmetric conjugate addition employing a proline-based catalyst and a syn-selective intramolecular-conjugate addition of an oxygen nucleophile to an alpha,beta-unsaturated ester. To enable incorporation of alpha amino-adipic acid (alpha-AAA) and Ahad into peptides, a truly orthogonal protecting group scheme was developed, encompassing an allyloxycarbonyl (Alloc) carbamate for Nalpha, a tert-butyl ester for the delta-COOH, an acetol ester for the alpha-COOH, and a tert-butyldimethylsilyl ether for the gamma-hydroxy group of Ahad. PMID- 23635096 TI - Effects of co-administration of candesartan with pioglitazone on inflammatory parameters in hypertensive patients with type 2 diabetes mellitus: a preliminary report. AB - BACKGROUND: Angiotensin receptor blockers (ARBs) are reported to provide direct protection to many organs by controlling inflammation and decreasing oxidant stress. Pioglitazone, an anti-diabetic agent that improves insulin resistance, was also reported to decrease inflammation and protect against atherosclerosis. This study aimed to evaluate the utility of combination therapy with both medicines from the viewpoint of anti-inflammatory effects. METHODS: We administered candesartan (12 mg daily) and pioglitazone (15 mg daily) simultaneously for 6 months to hypertensive patients with type 2 diabetes mellitus (T2DM) and evaluated whether there were improvements in the serum inflammatory parameters of high-molecular-weight adiponectin (HMW-ADN), plasminogen activator inhibitor-1 (PAI-1), highly sensitive C-reactive protein (Hs-CRP), vascular cell adhesion molecule-1 (VCAM-1), and urinary-8 hydroxydeoxyguanosine (U-8-OHdG). We then analyzed the relationship between the degree of reductions in blood pressure and HbA1c values and improvements in inflammatory factors. Furthermore, we analyzed the relationship between pulse pressure and the degree of lowering of HbA1c and improvements in inflammatory factors. Finally, we examined predictive factors in patients who received benefits from the co-administration of candesartan with pioglitazone from the viewpoint of inflammatory factors. RESULTS: After 6 months of treatment, in all patients significant improvements from baseline values were observed in HMW-ADN and PAI-1 but not in VCAM-1, Hs-CRP, and U-8-OHdG. Changes in HbA1c were significantly correlated with changes in HMW-ADN and PAI-1 in all patients, but changes in blood pressure were not correlated with any of the parameters examined. Correlation and multilinear regression analyses were performed to determine which factors could best predict changes in HbA1c. Interestingly, we found a significant positive correlation of pulse pressure values at baseline with changes in HbA1c. CONCLUSIONS: Our data suggest that the pulse pressure value at baseline is a key predictive factor of changes in HbA1c. Co administration of candesartan with pioglitazone, which have anti-inflammatory (changes in HMW-ADN and PAI-1) effects and protective effects on organs, could be an effective therapeutic strategy for treating hypertensive patients with type 2 diabetes mellitus. TRIAL REGISTRATION: UMIN-CTR: UMIN000010142. PMID- 23635097 TI - 3D printed bionic ears. AB - The ability to three-dimensionally interweave biological tissue with functional electronics could enable the creation of bionic organs possessing enhanced functionalities over their human counterparts. Conventional electronic devices are inherently two-dimensional, preventing seamless multidimensional integration with synthetic biology, as the processes and materials are very different. Here, we present a novel strategy for overcoming these difficulties via additive manufacturing of biological cells with structural and nanoparticle derived electronic elements. As a proof of concept, we generated a bionic ear via 3D printing of a cell-seeded hydrogel matrix in the anatomic geometry of a human ear, along with an intertwined conducting polymer consisting of infused silver nanoparticles. This allowed for in vitro culturing of cartilage tissue around an inductive coil antenna in the ear, which subsequently enables readout of inductively-coupled signals from cochlea-shaped electrodes. The printed ear exhibits enhanced auditory sensing for radio frequency reception, and complementary left and right ears can listen to stereo audio music. Overall, our approach suggests a means to intricately merge biologic and nanoelectronic functionalities via 3D printing. PMID- 23635098 TI - The spiral groove bearing as a mechanism for enhancing the secondary flow in a centrifugal rotary blood pump. AB - The rapid evolution of rotary blood pump (RBP) technology in the last few decades was shaped by devices with increased durability, frequently employing magnetic or hydrodynamic suspension techniques. However, the potential for low flow in small gaps between the rotor and pump casing is still a problem for hemocompatibility. In this study, a spiral groove hydrodynamic bearing (SGB) is applied with two distinct objectives: first, as a mechanism to enhance the washout in the secondary flow path of a centrifugal RBP, lowering the exposure to high shear stresses and avoiding thrombus formation; and second, as a way to allow smaller gaps without compromising the washout, enhancing the overall pump efficiency. Computational fluid dynamics was applied and verified via bench-top experiments. An optimization of selected geometric parameters (groove angle, width and depth) focusing on the washout in the gap rather than generating suspension force was conducted. An optimized SGB geometry reduced the residence time of the cells in the gap from 31 to 27 ms, an improvement of 14% compared with the baseline geometry of 200 MUm without grooves. When optimizing for pump performance, a 15% smaller gap yielded a slightly better rate of fluid exchange compared with the baseline, followed by a 22% reduction in the volumetric loss from the primary pathway. Finally, an improved washout can be achieved in a pulsatile environment due to the SGB ability to pump inwardly, even in the absence of a pressure head. PMID- 23635101 TI - Communication: Calibration of a strong-correlation density functional on transition-metal atoms. AB - In recent work [A. D. Becke, J. Chem. Phys. 138, 074109 (2013)], a suite of density functionals for static, dynamical, and strong correlation was introduced. The strong-correlation part is intended to describe dissociating chemical systems using symmetry-restricted orbitals, and was calibrated on spin- and spatially symmetrized open-shell atoms of the first and second rows. This Communication extends the calibration of our functionals to transition-metal atoms by including all open-shell atoms through the third row. We find that the theory works well for transition-metal atoms also. The new concomitant parametrization will be applied to problems of chemical interest in upcoming work. PMID- 23635099 TI - Combined effects of 17-DMAG and TNF on cells through a mechanism related to the NF-kappaB pathway. AB - OBJECTIVE: The tumor necrosis factor (TNF) and the cellular NF-kappaB pathway protein IKKbeta play important roles in various cellular processes such as cell proliferation, survival, differentiation, and apoptosis. A heat shock protein 90 inhibitor, 17-DMAG, can induce apoptosis of some tumor cells. This study is to determine the combined effects of 17-DMAG and TNF on malignant cells and the related mechanisms. METHODS: We have determined effects of 17-DMAG, an Hsp90 inhibitor, and TNF treatments on the small cell lung cancer cell line (MS-1), the adenocarcinoma cell line (A549), the squamous-cell carcinoma cell line (LK-2), and the normal human bronchial epithelium cell line (NuLi-1) by using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrozolium bromide assay. To determine if 17 DMAG inhibit the expression of IKKbeta in the normal human NuLi-1 cells, and the malignant MS-1, A549, and LK-2 cells, immunoblotting assays and luciferase assays were performed. RESULTS: It was found that the combined treatments resulted in synergistic killing of malignant cells, which was confirmed by the apoptosis determination using a fluorescence microscopic assay following staining of the drug-treated cells with Hoescht 33258. The immunoblotting results indicated that the synergistic killing due to 17-DMAG and TNF treatments may be related to the decreases in IKKbeta levels in the presence of 17-DMAG. CONCLUSIONS: The results suggest that combination of 17-DMAG and TNF treatments might be useful for treating malignancies upon further study in the further. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2041198513886824. PMID- 23635100 TI - Software for selecting the most informative sets of genomic loci for multi-target microbial typing. AB - BACKGROUND: High-throughput sequencing can identify numerous potential genomic targets for microbial strain typing, but identification of the most informative combinations requires the use of computational screening tools. This paper describes novel software-- Automated Selection of Typing Target Subsets (AuSeTTS) -that allows intelligent selection of optimal targets for pathogen strain typing. The objective of this software is to maximise both discriminatory power, using Simpson's index of diversity (D), and concordance with existing typing methods, using the adjusted Wallace coefficient (AW). The program interrogates molecular typing results for panels of isolates, based on large target sets, and iteratively examines each target, one-by-one, to determine the most informative subset. RESULTS: AuSeTTS was evaluated using three target sets: 51 binary targets (13 toxin genes, 16 phage-related loci and 22 SCCmec elements), used for multilocus typing of 153 methicillin-resistant Staphylococcus aureus (MRSA) isolates; 17 MLVA loci in 502 Streptococcus pneumoniae isolates from the MLVA database (http://www.mlva.eu) and 12 MLST loci for 98 Cryptococcus spp. isolates.The maximum D for MRSA, 0.984, was achieved with a subset of 20 targets and a D value of 0.954 with 7 targets. Twelve targets predicted MLST with a maximum AW of 0.9994. All 17 S. pneumoniae MLVA targets were required to achieve maximum D of 0.997, but 4 targets reached D of 0.990. Twelve targets predicted pneumococcal serotype with a maximum AW of 0.899 and 9 predicted MLST with maximum AW of 0.963. Eight of the 12 MLST loci were sufficient to achieve the maximum D of 0.963 for Cryptococcus spp. CONCLUSIONS: Computerised analysis with AuSeTTS allows rapid selection of the most discriminatory targets for incorporation into typing schemes. Output of the program is presented in both tabular and graphical formats and the software is available for free download from http://www.cidmpublichealth.org/pages/ausetts.html. PMID- 23635102 TI - Communication: New approach for analysis of thermodiffusion coefficients in ternary mixtures. AB - A new approach is proposed to cross-check conflicting measured values of the thermodiffusion coefficients in ternary mixtures. The results of recent measurements performed in ternary mixture of hydrocarbons 1,2,3,4 tetrahydronaphthalene, isobutylbenzene, and dodecane by thermogravitational column [P. Blanco, M. M. Bou-Ali, J. K. Platten, D. A. de Mezquia, J. A. Madariaga, and C. Santamaria, J. Chem. Phys. 132, 114506 (2010)] and optical beam deflection [A. Koniger, H. Wunderlich, and W. Kohler, J. Chem. Phys. 132, 174506 (2010)] are critically analyzed. A way of matching them into a unique value is reported. The accuracy of the integrated value should significantly exceed that of the original results. Two diagnostics are required to determine thermodiffusion coefficients in ternary mixture, e.g., two different wavelengths or density and refractive index. It is shown that by attributing a reliability weight for each pair of diagnostics among the available techniques the best combination can be selected. The true values of thermodiffusion coefficients are extremely sensitive to the knowledge of precise values of mass diffusion coefficients and contrast factors. PMID- 23635103 TI - Communication: Induced photoemission from nonadiabatic dynamics assisted by dynamical Stark effect. AB - Through nonadiabatic interaction due to electron transfer as that in alkali halides, vibrational dynamics on the ionic potential energy surface (large dipole moment) is coupled to that on the covalent surface (small dipole moment). Thus, population transfer between the states should cause long-range electron jump between two remote sites, which thereby leads to a sudden change of the large molecular dipole moment. Therefore, by making repeated use of the dynamical Stark effect, one may expect emission of photons from it. We show with coupled quantum wavepacket dynamics calculation that such photoemission can indeed occur and can be controlled by an external field. The present photoemission can offer an alternative scheme to study femtosecond and subfemtosecond vibrational and electronic dynamics and may serve as a unique optical source. PMID- 23635104 TI - Communication: Virial coefficients and demixing in highly asymmetric binary additive hard-sphere mixtures. AB - The problem of demixing in a binary fluid mixture of highly asymmetric additive hard spheres is revisited. A comparison is presented between the results derived previously using truncated virial expansions for three finite size ratios with those that one obtains with the same approach in the extreme case in which one of the components consists of point particles. Since this latter system is known not to exhibit fluid-fluid segregation, the similarity observed for the behavior of the critical constants arising in the truncated series in all instances, while not being conclusive, may cast serious doubts as to the actual existence of a demixing fluid-fluid transition in disparate-sized binary additive hard-sphere mixtures. PMID- 23635105 TI - Excitation energies and Stokes shifts from a restricted open-shell Kohn-Sham approach. AB - Restricted open-shell Kohn-Sham (ROKS) theory provides a powerful computational tool for calculating singlet excited state energies and dynamics. However, the possibility of multiple solutions to the ROKS equations - with the associated difficulty of automatically selecting the physically meaningful solution - limits its usefulness for intensive applications such as long-time Born-Oppenheimer molecular dynamics. We present an implementation of ROKS for excited states which prescribes the physically correct solution from an overlap criterion and guarantees that this solution is stationary, allowing for straightforward evaluation of nuclear gradients. The method is used to benchmark ROKS for vertical excitation energies of small and large organic dyes and for the calculation of Stokes shifts. With common density functional approximations, ROKS vertical excitation energies, and Stokes shifts show similar accuracy to those from time-dependent density functional theory and Delta-self-consistent-field approaches. Advantages of the ROKS approach for excited state structure and molecular dynamics are discussed. PMID- 23635106 TI - Inverting pump-probe spectroscopy for state tomography of excitonic systems. AB - We propose a two-step protocol for inverting ultrafast spectroscopy experiments on a molecular aggregate to extract the time-evolution of the excited state density matrix. The first step is a deconvolution of the experimental signal to determine a pump-dependent response function. The second step inverts this response function to obtain the quantum state of the system, given a model for how the system evolves following the probe interaction. We demonstrate this inversion analytically and numerically for a dimer model system, and evaluate the feasibility of scaling it to larger molecular aggregates such as photosynthetic protein-pigment complexes. Our scheme provides a direct alternative to the approach of determining all Hamiltonian parameters and then simulating excited state dynamics. PMID- 23635107 TI - Analytic second derivatives of the energy in the fragment molecular orbital method. AB - We developed the analytic second derivatives of the energy for the fragment molecular orbital (FMO) method. First we derived the analytic expressions and then introduced some approximations related to the first and second order coupled perturbed Hartree-Fock equations. We developed a parallel program for the FMO Hessian with approximations in GAMESS and used it to calculate infrared (IR) spectra and Gibbs free energies and to locate the transition states in SN2 reactions. The accuracy of the Hessian is demonstrated in comparison to ab initio results for polypeptides and a water cluster. By using the two residues per fragment division, we achieved the accuracy of 3 cm(-1) in the reduced mean square deviation of vibrational frequencies from ab initio for all three polyalanine isomers, while the zero point energy had the error not exceeding 0.3 kcal/mol. The role of the secondary structure on IR spectra, zero point energies, and Gibbs free energies is discussed. PMID- 23635108 TI - A local superbasin kinetic Monte Carlo method. AB - We present a local superbasin kinetic Monte Carlo (LSKMC) method that efficiently treats multiple-time-scale problems in kinetic Monte Carlo (KMC). The method is designed to solve the small-barrier problem created by groups of recurrent free energy minima connected by low free-energy barriers and separated from the full phase space of the system by high barriers. We propose an algorithm to detect, on the fly, groups of recurrent free-energy minima connected by low free-energy barriers and to consolidate them into "superbasins," which we treat with rate equations and/or absorbing Markov chains. We discuss various issues involved with implementing LSKMC simulations that contain local superbasins and non-superbasin events concurrently. These issues include the time distribution of superbasin escapes and interactions between superbasin and non-superbasin states. The LSKMC method is exact, as it introduces no new approximations into conventional KMC simulations. We demonstrate various aspects of LSKMC in several examples, which indicate that significant increases in computational efficiency can be achieved using this method. PMID- 23635109 TI - A natural orbital analysis of the long range behavior of chemical bonding and van der Waals interaction in singlet H2: the issue of zero natural orbital occupation numbers. AB - This paper gives a natural orbital (NO) based analysis of the van der Waals interaction in (singlet) H2 at long distance. The van der Waals interaction, even if not leading to a distinct van der Waals well, affects the shape of the interaction potential in the van der Waals distance range of 5-9 bohrs and can be clearly distinguished from chemical bonding effects. In the NO basis the van der Waals interaction can be quantitatively covered with, apart from the ground state configurations (1sigma(g))(2) and (1sigma(u))(2), just the 4 configurations (2sigma(g))(2) and (2sigma(u))(2), and (1pi(u))(2) and (1pi(g))(2). The physics of the dispersion interaction requires and explains the peculiar relatively large positive CI coefficients of the doubly excited electron configurations (2sigma(u))(2) and (1pi(g))(2) (the occupancy amplitudes of the 2sigma(u) and 1pi(gx, y) NOs) in the distance range 5-9 bohrs, which have been observed before by Cioslowski and Pernal [Chem. Phys. Lett. 430, 188 (2006)]. We show that such positive occupancy amplitudes do not necessarily lead to the existence of zero occupation numbers at some H-H distances. PMID- 23635110 TI - Surface hopping modeling of two-dimensional spectra. AB - Recently, two-dimensional (2D) electronic spectroscopy has become an important tool to unravel the excited state properties of complex molecular assemblies, such as biological light harvesting systems. In this work, we propose a method for simulating 2D electronic spectra based on a surface hopping approach. This approach self-consistently describes the interaction between photoactive chromophores and the environment, which allows us to reproduce a spectrally observable dynamic Stokes shift. Through an application to a dimer, the method is shown to also account for correct thermal equilibration of quantum populations, something that is of great importance for processes in the electronic domain. The resulting 2D spectra are found to nicely agree with hierarchy of equations of motion calculations. Contrary to the latter, our method is unrestricted in describing the interaction between the chromophores and the environment, and we expect it to be applicable to a wide variety of molecular systems. PMID- 23635111 TI - An improved first-order mean spherical approximation theory for the square shoulder fluid. AB - The theory, which utilizes an exponential enhancement of the first-order mean spherical approximation (FMSA) for the radial distribution functions of the hard core plus square-well fluid, is adopted to study the properties of the simplest model of the core-softened fluids, i.e., the hard spheres with a square-shoulder interaction. The results for structure and thermodynamic properties are reported and compared against both the Monte Carlo simulation data as well as with those obtained within the conventional FMSA theory. We found that in the region of low densities and low temperatures, where the conventional FMSA theory fails, the exponential-based FMSA theory besides being qualitatively correct also provides with a notable quantitative improvement of the theoretical description. PMID- 23635112 TI - Electron correlation dynamics in atoms and molecules. AB - In this paper, we present quantum dynamical calculations on electron correlation dynamics in atoms and molecules using explicitly time-dependent ab initio configuration interaction theory. The goals are (i) to show that in which cases it is possible to switch off the electronic correlation by ultrashort laser pulses, and (ii) to understand the temporal evolution and the time scale on which it reappears. We characterize the appearance of correlation through electron electron scattering when starting from an uncorrelated state, and we identify pathways for the preparation of a Hartree-Fock state from the correlated, true ground state. Exemplary results for noble gases, alkaline earth elements, and selected molecules are provided. For Mg we show that the uncorrelated state can be prepared using a shaped ultrashort laser pulse. PMID- 23635113 TI - Linear response approximation to reference interaction site model self-consistent field explicitly including spatial electron density distribution. Free energy. AB - We proposed linear response approximation to reference interaction site model self-consistent field explicitly including spatial electron density distribution (RISM-SCF-SEDD). Because the electrostatic potential induced by solvent molecules is approximated by linear response to the density change of solute molecule, new algorithm becomes significantly simple compared to the original RISM-SCF-SEDD. The present method was applied to simple molecules and p-nitroaniline (PNA). The maximum relative error of the linear response approximation is less than 1.0% in the solvation free energies of the simple molecules. The present method also achieved a stable calculation of PNA. PMID- 23635114 TI - Equivalence of the Ehrenfest theorem and the fluid-rotor model for mixed quantum/classical theory of collisional energy transfer. AB - The theory of two seemingly different quantum/classical approaches to collisional energy transfer and ro-vibrational energy flow is reviewed: a heuristic fluid rotor method, introduced earlier to treat recombination reactions [M. Ivanov and D. Babikov, J. Chem. Phys. 134, 144107 (2011)], and a more rigorous method based on the Ehrenfest theorem. It is shown analytically that for the case of a diatomic molecule + quencher these two methods are entirely equivalent. Notably, they both make use of the average moment of inertia computed as inverse of average of inverse of the distributed moment of inertia. Despite this equivalence, each of the two formulations has its own advantages, and is interesting on its own. Numerical results presented here illustrate energy and momentum conservation in the mixed quantum/classical approach and open opportunities for computationally affordable treatment of collisional energy transfer. PMID- 23635115 TI - Stochastic evaluation of second-order Dyson self-energies. AB - A stochastic method is proposed that evaluates the second-order perturbation corrections to the Dyson self-energies of a molecule (i.e., quasiparticle energies or correlated ionization potentials and electron affinities) directly and not as small differences between two large, noisy quantities. With the aid of a Laplace transform, the usual sum-of-integral expressions of the second-order self-energy in many-body Green's function theory are rewritten into a sum of just four 13-dimensional integrals, 12-dimensional parts of which are evaluated by Monte Carlo integration. Efficient importance sampling is achieved with the Metropolis algorithm and a 12-dimensional weight function that is analytically integrable, is positive everywhere, and cancels all the singularities in the integrands exactly and analytically. The quasiparticle energies of small molecules have been reproduced within a few mEh of the correct values with 10(8) Monte Carlo steps. Linear-to-quadratic scaling of the size dependence of computational cost is demonstrated even for these small molecules. PMID- 23635116 TI - Automatic, optimized interface placement in forward flux sampling simulations. AB - Forward flux sampling (FFS) provides a convenient and efficient way to simulate rare events in equilibrium or non-equilibrium systems. FFS ratchets the system from an initial state to a final state via a series of interfaces in phase space. The efficiency of FFS depends sensitively on the positions of the interfaces. We present two alternative methods for placing interfaces automatically and adaptively in their optimal locations, on-the-fly as an FFS simulation progresses, without prior knowledge or user intervention. These methods allow the FFS simulation to advance efficiently through bottlenecks in phase space by placing more interfaces where the probability of advancement is lower. The methods are demonstrated both for a single-particle test problem and for the crystallization of Yukawa particles. By removing the need for manual interface placement, our methods both facilitate the setting up of FFS simulations and improve their performance, especially for rare events which involve complex trajectories through phase space, with many bottlenecks. PMID- 23635117 TI - Efficient Bayesian estimation of Markov model transition matrices with given stationary distribution. AB - Direct simulation of biomolecular dynamics in thermal equilibrium is challenging due to the metastable nature of conformation dynamics and the computational cost of molecular dynamics. Biased or enhanced sampling methods may improve the convergence of expectation values of equilibrium probabilities and expectation values of stationary quantities significantly. Unfortunately the convergence of dynamic observables such as correlation functions or timescales of conformational transitions relies on direct equilibrium simulations. Markov state models are well suited to describe both stationary properties and properties of slow dynamical processes of a molecular system, in terms of a transition matrix for a jump process on a suitable discretization of continuous conformation space. Here, we introduce statistical estimation methods that allow a priori knowledge of equilibrium probabilities to be incorporated into the estimation of dynamical observables. Both maximum likelihood methods and an improved Monte Carlo sampling method for reversible transition matrices with fixed stationary distribution are given. The sampling approach is applied to a toy example as well as to simulations of the MR121-GSGS-W peptide, and is demonstrated to converge much more rapidly than a previous approach of Noe [J. Chem. Phys. 128, 244103 (2008)]. PMID- 23635118 TI - A full implementation of the response iteration scheme for density functional calculations. AB - We describe the implementation of the response algorithm for solving the Kohn Sham equations and equations of similar structure that appear frequently in calculations of the structure of inhomogeneous many-body systems. The algorithm solves directly for the (spin) density. We have implemented the method for arbitrary geometries in a way that does not need the explicit calculation of unoccupied states. We apply the method to the two sample molecules C6H6 and C60, as well as to the metal clusters Mg30 and Na40. Starting from very rough guesses for the initial electron density, convergence is reached significantly faster than with previous update algorithms. PMID- 23635119 TI - Charge mobility in molecules: charge fluxes from second derivatives of the molecular dipole. AB - On the basis of the analytical model previously suggested by Dinur, we discuss here a method for the calculation of vibrational charge fluxes in planar molecules, obtained as numerical second derivatives of the molecular dipole moment. This model is consistent with the partitioning of the atomic polar tensors into atomic charge and charge fluxes according to the Equilibrium Charges Charge Fluxes model and it is directly related to experimentally measurable quantities such as IR intensities. On the basis of density functional theory calculations carried out for several small benchmark molecules, the complete set of charge fluxes is calculated for each molecule and compared with the approximated flux parameters previously derived and reported in the past literature. The degree of localization of charge fluxes is investigated and discussed; in addition, some approximations are analyzed in order to verify the applicability of the method to large and/or non-planar molecules, aimed at obtaining a description of the electron charge mobility in different molecular environments. PMID- 23635120 TI - Improvements to Kramers turnover theory. AB - The Kramers turnover problem, that is, obtaining a uniform expression for the rate of escape of a particle over a barrier for any value of the external friction was solved in the 1980s. Two formulations were given, one by Mel'nikov and Meshkov (MM) [V. I. Mel'nikov and S. V. Meshkov, J. Chem. Phys. 85, 1018 (1986)], which was based on a perturbation expansion for the motion of the particle in the presence of friction. The other, by Pollak, Grabert, and Hanggi (PGH) [E. Pollak, H. Grabert, and P. Hanggi, J. Chem. Phys. 91, 4073 (1989)], valid also for memory friction, was based on a perturbation expansion for the motion along the collective unstable normal mode of the particle. Both theories did not take into account the temperature dependence of the average energy loss to the bath. Increasing the bath temperature will reduce the average energy loss. In this paper, we analyse this effect, using a novel perturbation theory. We find that within the MM approach, the thermal energy gained from the bath diverges, the average energy gain becomes infinite implying an essential failure of the theory. Within the PGH approach increasing the bath temperature reduces the average energy loss but only by a finite small amount of the order of the inverse of the reduced barrier height. Then, this does not seriously affect the theory. Analysis and application for a cubic potential and Ohmic friction are presented. PMID- 23635121 TI - Line-mixing in absorption bands of linear molecules diluted in high-density rare gases: measurements and modeling for OCS-He. AB - Absorption coefficients in the bending nu2 and stretching 2nu3 bands of OCS perturbed by He at high pressures up to 300 atm have been measured and analyzed in the impact-approximation region by two theoretical models accounting for the line mixing. In the first approach, the frequency-independent relaxation operator is treated semi-classically [N. N. Filippov and M. V. Tonkov, J. Quant. Spectrosc. Radiat. Transf. 50, 111 (1993)] with adiabatic corrections. To characterize the strength of collisions and the line mixing efficiency a single parameter G is used and its value is estimated from the intermolecular interaction potential. The adiabaticity of collisions and the corresponding correction to the collisional cross sections amplitude are taken into account by two other parameters nu(corr) and sigma deduced from fitting to experimental line widths. In the second approach, the symmetrized non-Markovian relaxation operator of Energy-Corrected Sudden type developed for rototranslational Raman spectra of linear rotators [J. Buldyreva and L. Bonamy, Phys. Rev. A 60, 370 (1999)] and satisfying all the basic properties (in particular, the detailed balance relation and the double-sided sum rules) is adapted to absorption spectra for the first time. Its off-diagonal elements are determined via the common adiabaticity factor and the basic transition rates whose parameters are adjusted on experimental values of isolated line widths. Both models provide a very consistent description of OCS-He 2nu3 and nu2 band intensities up to the maximal experimentally studied pressure, with a slightly more realistic picturing of the inter-branch exchange by the second approach. PMID- 23635122 TI - Fast Shepard interpolation on graphics processing units: potential energy surfaces and dynamics for H + CH4 -> H2 + CH3. AB - A strategy for the fast evaluation of Shepard interpolated potential energy surfaces (PESs) utilizing graphics processing units (GPUs) is presented. Speed ups of several orders of magnitude are gained for the title reaction on the ZFWCZ PES [Y. Zhou, B. Fu, C. Wang, M. A. Collins, and D. H. Zhang, J. Chem. Phys. 134, 064323 (2011)]. Thermal rate constants are calculated employing the quantum transition state concept and the multi-layer multi-configurational time-dependent Hartree approach. Results for the ZFWCZ PES are compared to rate constants obtained for other ab initio PESs and problems are discussed. A revised PES is presented. Thermal rate constants obtained for the revised PES indicate that an accurate description of the anharmonicity around the transition state is crucial. PMID- 23635123 TI - Nonorthogonal orbital based N-body reduced density matrices and their applications to valence bond theory. I. Hamiltonian matrix elements between internally contracted excited valence bond wave functions. AB - In this series, the n-body reduced density matrix (n-RDM) approach for nonorthogonal orbitals and their applications to ab initio valence bond (VB) methods are presented. As the first paper of this series, Hamiltonian matrix elements between internally contracted VB wave functions are explicitly provided by means of nonorthogonal orbital based RDM approach. To this end, a more generalized Wick's theorem, called enhanced Wick's theorem, is presented both in arithmetical and in graphical forms, by which the deduction of expressions for the matrix elements between internally contracted VB wave functions is dramatically simplified, and the matrix elements are finally expressed in terms of tensor contractions of electronic integrals and n-RDMs of the reference VB self-consistent field wave function. A string-based algorithm is developed for the purpose of evaluating n-RDMs in an efficient way. Using the techniques presented in this paper, one is able to develop new methods and efficient algorithms for nonorthogonal orbital based many-electron theory much easier than by use of the first quantized formulism. PMID- 23635124 TI - Nonorthogonal orbital based N-body reduced density matrices and their applications to valence bond theory. II. An efficient algorithm for matrix elements and analytical energy gradients in VBSCF method. AB - In this paper, by applying the reduced density matrix (RDM) approach for nonorthogonal orbitals developed in the first paper of this series, efficient algorithms for matrix elements between VB structures and energy gradients in valence bond self-consistent field (VBSCF) method were presented. Both algorithms scale only as nm(4) for integral transformation and d(2)n(beta)(2) for VB matrix elements and 3-RDM evaluation, while the computational costs of other procedures are negligible, where n, m, d, and n(beta )are the numbers of variable occupied active orbitals, basis functions, determinants, and active beta electrons, respectively. Using tensor properties of the energy gradients with respect to the orbital coefficients presented in the first paper of this series, a partial orthogonal auxiliary orbital set was introduced to reduce the computational cost of VBSCF calculation in which orbitals are flexibly defined. Test calculations on the Diels-Alder reaction of butadiene and ethylene have shown that the novel algorithm is very efficient for VBSCF calculations. PMID- 23635125 TI - Dissipative time-dependent quantum transport theory. AB - A dissipative time-dependent quantum transport theory is developed to treat the transient current through molecular or nanoscopic devices in presence of electron phonon interaction. The dissipation via phonon is taken into account by introducing a self-energy for the electron-phonon coupling in addition to the self-energy caused by the electrodes. Based on this, a numerical method is proposed. For practical implementation, the lowest order expansion is employed for the weak electron-phonon coupling case and the wide-band limit approximation is adopted for device and electrodes coupling. The corresponding hierarchical equation of motion is derived, which leads to an efficient and accurate time dependent treatment of inelastic effect on transport for the weak electron-phonon interaction. The resulting method is applied to a one-level model system and a gold wire described by tight-binding model to demonstrate its validity and the importance of electron-phonon interaction for the quantum transport. As it is based on the effective single-electron model, the method can be readily extended to time-dependent density functional theory. PMID- 23635126 TI - Efficiently finding the minimum free energy path from steepest descent path. AB - Minimum Free Energy Path (MFEP) is very important in computational biology and chemistry. The barrier in the path is related to the reaction rate, and the start to-end difference gives the relative stability between reactant and product. All these information is significant to experiment and practical application. But finding MFEP is not an easy job. Lots of degrees of freedom make the computation very complicated and time consuming. In this paper, we use the Steepest Descent Path (SDP) to accelerate the sampling of MFEP. The SHAKE algorithm and the Lagrangian multipliers are used to control the optimization of both SDP and MFEP. These strategies are simple and effective. For the former, it is more interesting. Because as we known, SHAKE algorithm was designed to handle the constraints in molecular dynamics in the past, has never been used in geometry optimization. Final applications on ALA dipeptide and 10-ALA peptide show that this combined optimization method works well. Use the information in SDP, the initial path could reach the more optimal MFEP. So more accurate free energies could be obtained and the amount of computation time could be saved. PMID- 23635127 TI - An accurate expression for the rates of diffusion-influenced bimolecular reactions with long-range reactivity. AB - By using the recently developed method for solving the Fredholm integral equations of the second kind, we derive a very accurate expression for the steady state rate constant of diffusion-influenced bimolecular reactions involving long range reactivity. We consider the general case in which the reactants interact via an arbitrary central potential and hydrodynamic interaction. The rate expression becomes exact in the two opposite limits of small and large reactivity, and also performs very well in the intermediate regime. PMID- 23635128 TI - Uniform electron gases. I. Electrons on a ring. AB - We introduce a new paradigm for one-dimensional uniform electron gases (UEGs). In this model, n electrons are confined to a ring and interact via a bare Coulomb operator. We use Rayleigh-Schrodinger perturbation theory to show that, in the high-density regime, the ground-state reduced (i.e., per electron) energy can be expanded as epsilon(r(s),n)=epsilon0(n)r(s)(-2)+epsilon1(n)r(s)( 1)+epsilon2(n)+epsilon3(n)r(s+)? , where r(s) is the Seitz radius. We use strong coupling perturbation theory and show that, in the low-density regime, the reduced energy can be expanded as epsilon(r(s),n)=eta0(n)r(s)(-1)+eta1(n)r(s)( 3/2)+eta2(n)r(s)(-2)+? . We report explicit expressions for epsilon0(n), epsilon1(n), epsilon2(n), epsilon3(n), eta0(n), and eta1(n) and derive the thermodynamic (large-n) limits of each of these. Finally, we perform numerical studies of UEGs with n = 2, 3, [ellipsis (horizontal)], 10, using Hylleraas-type and quantum Monte Carlo methods, and combine these with the perturbative results to obtain a picture of the behavior of the new model over the full range of n and r(s) values. PMID- 23635129 TI - Steady state conductance in a double quantum dot array: the nonequilibrium equation-of-motion Green function approach. AB - We study steady state transport through a double quantum dot array using the equation-of-motion approach to the nonequilibrium Green functions formalism. This popular technique relies on uncontrolled approximations to obtain a closure for a hierarchy of equations; however, its accuracy is questioned. We focus on 4 different closures, 2 of which were previously proposed in the context of the single quantum dot system (Anderson impurity model) and were extended to the double quantum dot array, and develop 2 new closures. Results for the differential conductance are compared to those attained by a master equation approach known to be accurate for weak system-leads couplings and high temperatures. While all 4 closures provide an accurate description of the Coulomb blockade and other transport properties in the single quantum dot case, they differ in the case of the double quantum dot array, where only one of the developed closures provides satisfactory results. This is rationalized by comparing the poles of the Green functions to the exact many-particle energy differences for the isolate system. Our analysis provides means to extend the equation-of-motion technique to more elaborate models of large bridge systems with strong electronic interactions. PMID- 23635130 TI - Stochastic determination of effective Hamiltonian for the full configuration interaction solution of quasi-degenerate electronic states. AB - We propose a novel quantum Monte Carlo method in configuration space, which stochastically samples the contribution from a large secondary space to the effective Hamiltonian in the energy dependent partitioning of Lowdin. The method treats quasi-degenerate electronic states on a target energy with bond dissociations and electronic excitations avoiding significant amount of the negative sign problem. The performance is tested with small model systems of H4 and N2 at various configurations with quasi-degeneracy. PMID- 23635131 TI - DQ-DRENAR: a new NMR technique to measure site-resolved magnetic dipole-dipole interactions in multispin-1/2 systems: theory and validation on crystalline phosphates. AB - A new solid state NMR technique is described for measuring homonuclear dipole dipole interactions in multi-spin-1/2 systems under magic-angle spinning conditions. Re-coupling is accomplished in the form of an effective double quantum (DQ) Hamiltonian created by a symmetry-based POST-C7 sequence consisting of two excitation blocks, attenuating the signal (intensity S'). For comparison, a reference signal S0 with the dipolar re-coupling absent is generated by shifting the phase of the second block by 90 degrees relative to the first block. As in rotational echo double resonance, the homonuclear dipole-dipole coupling constant can then be extracted from a plot of the normalized difference signal (S0 - S')/S0 versus dipolar mixing time. The method is given the acronym DQ-DRENAR ("Double-Quantum-based Dipolar Re-coupling effects Nuclear Alignment Reduction"). The method is analyzed mathematically, and on the basis of detailed simulations, with respect to the order and the geometry of the spin system, the dipolar truncation phenomenon, and the influence of the chemical shift anisotropy on experimental curves. Within the range of (S0 - S')/S0 <=0.3-0.5 such DRENAR curves can be approximated by simple parabolae, yielding effective squared dipole dipole coupling constants summed over all the pairwise interactions present. The method has been successfully validated for (31)P-(31)P distance determinations of numerous crystalline model compounds representing a wide range of dipolar coupling strengths. PMID- 23635132 TI - Conformation-resolved UV spectra of Pb(II) complexes: a gas phase study of the sandwich structures [Pb(toluene)2]2+ and [Pb(benzene)2]2+. AB - Toxic heavy metals, such as Pb(2+), have become important targets for the development of efficient receptors that are capable of recognizing their presence as environmental and biological pollutants, and an important part of that receptor-metal characterization process is the provision of spectral evidence that identifies the presence of a metal ion. From results reported here on a combined experimental and theoretical study it is shown that, when complexed with aromatic ligands, Pb(2+) is capable of yielding structured UV spectra, which: (i) exhibit discrete electronic transitions that include significant contributions from the metal ion; (ii) are very sensitive to the electronic properties of coordinating ligands; and (iii) are sensitive to subtle changes in coordination geometry. Two aromatic sandwich complexes, [Pb(benzene)2](2+) and [Pb(toluene)2](2+) have been prepared in the gas phase and their UV action spectra recorded from ions held and cooled in an ion trap. Whilst [Pb(benzene)2](2+) exhibits a spectrum with very little detail, that recorded for [Pb(toluene)2](2+) reveals a rich structure in the wavelength range 220-280 nm. Theory in the form of density functional theory (DFT) shows that both types of complex take the form of hemidirected structures, and that [Pb(toluene)2](2+) can adopt three distinct conformers depending upon the relative positions of the two methyl groups. Further calculations, using adiabatic time-dependent DFT to assign electronic transitions, provide evidence of individual [Pb(toluene)2](2+) conformers having been resolved in the experimental spectrum. Of particular significance for the development of methods for identifying Pb(2+) as an environmental or biological pollutant, is the observation that there are distinct ligand-to-metal charge transfer transitions in the UV that are sensitive to both the geometry and the electronic characteristics of molecules that accommodate the metal ion. PMID- 23635133 TI - Spectroscopy of the double minimum 3 (3)PiOmega electronic state of 39K85Rb. AB - We report the observation and analysis of the 3 (3)PiOmega double-minimum electronic excited state of (39)K(85)Rb. The spin-orbit components (0(+), 0(-), 1, and 2) of this state are investigated based on potentials developed from the available ab initio potential curves. We have assigned the vibrational levels v' = 2-11 of the 3 (3)Pi1,2 potentials and v' = 2-12 of the 3(3)Pi0(+/-) potential. We compare our experimental observations of the 3 (3)PiOmega state with predictions based on theoretical potentials. The observations are based on resonance enhanced multiphoton ionization of ultracold KRb in vibrational levels v" = 14-25 of the a (3)Sigma(+) state. These a-state ultracold molecules are formed by photoassociation of ultracold (39)K and (85)Rb atoms to the 5(1) state of KRb followed by spontaneous emission to the a state. PMID- 23635134 TI - An all-electron density functional theory study of the structure and properties of the neutral and singly charged M12 and M13 clusters: M = Sc-Zn. AB - The electronic and geometrical structures of the M12 and M13 clusters where M = Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn along with their singly negatively and positively charged ions are studied using all-electron density functional theory within the generalized gradient approximation. The geometries corresponding to the lowest total energy states of singly and negatively charged ions of V13, Mn12, Co12, Ni13, Cu13, Zn12, and Zn13 are found to be different from the geometries of the corresponding neutral parents. The computed ionization energies of the neutrals, vertical electron detachment energies from the anions, and energies required to remove a single atom from the M13 and M13(+) clusters are in good agreement with experiment. The change in a total spin magnetic moment of the cation or anion with respect to a total spin magnetic moment of the corresponding neutral is consistent with the one-electron model in most cases, i.e., they differ by +/-1.0 MU(B). Exceptions are found only for Sc12(-), Ti12(+), Mn12(-), Mn12(+), Fe12(-), Fe13(+), and Co12(+). PMID- 23635135 TI - Core hole screening and decay rates of double core ionized first row hydrides. AB - Because of the high intensity, X-ray free electron lasers allow one to create and probe double core ionized states in molecules. The decay of these multiple core ionized states crucially determines the evolution of radiation damage in single molecule diffractive imaging experiments. Here we have studied the Auger decay in hydrides of first row elements after single and double core ionization by quantum mechanical ab initio calculations. In our approach the continuum wave function of the emitted Auger electron is expanded into spherical harmonics on a radial grid. The obtained decay rates of double K-shell vacancies were found to be systematically larger than those for the respective single K-shell vacancies, markedly exceeding the expected factor of two. This enhancement is attributed to the screening effects induced by the core hole. We propose a simple model, which is able to predict core hole decay rates in molecules with low Z elements based on the electron density in the vicinity of the core hole. PMID- 23635136 TI - Exact quantum scattering calculations of transport properties: CH2(X3B1, a1A1) helium. AB - Transport properties for collisions of methylene, in both its ground X(3)B1 and low-lying a(1)A1 electronic states, with helium have been computed using recently computed high-quality ab initio potential energy surfaces (PESs). Because of the difference in the orbital occupancy of the two electronic states, the anisotropies of the PESs are quite different. The CH2(a)-He PES is very anisotropic because of the strong interaction of the electrons on the helium atom with the unoccupied CH2 orbital perpendicular to the molecular plane, while the anisotropy of the CH2(X)-He PES is significantly less since this orbital is singly occupied in this case. To investigate the importance of the anisotropy on the transport properties, calculations were performed with the full potential and with the spherical average of the potential for both electronic states. Significant differences (over 20% for the a state at the highest temperatures considered) in the computed transport properties were found. PMID- 23635137 TI - High accuracy ab initio studies of electron-densities for the ground state of Be like atomic systems. AB - Benchmark results for electron densities in the ground states of Li(-), Be, C(2+), Ne(6+), and Ar(14+) have been generated from very accurate variational wave functions represented in terms of extensive basis sets of exponentially correlated Gaussian functions. For Ne(6+), and Ar(14+), the upper bounds to the energies improve over previous results known from the literature. For the remaining systems our bounds are from 0.1 to 1.1 MUhartree higher than the most accurate ones. We present in graphical and, partially, numerical form results both for the radial electron densities and for the difference radial density distributions (DRD) (defined with respect to the Hartree-Fock radial density) that highlight the impact of correlation effects on electron densities. Next, we have employed these DRD distributions in studies of the performance of several broadly used orbital-based quantum-chemical methods in accounting for correlation effects on the density. Our computed benchmark densities for Be have been also applied for testing the possibility of using the mathematically strict result concerning exact atomic electron densities, obtained by Ahlrichs et al. [Phys. Rev. A 23, 2106 (1981)], for the determination of the reliability range of computed densities in the long-range asymptotic region. The results obtained for Be are encouraging. PMID- 23635138 TI - High-resolution electron spectroscopy of lanthanide (Ce, Pr, and Nd) complexes of cyclooctatetraene: the role of 4f electrons. AB - Cerium, praseodymium, and neodymium complexes of 1,3,5,7-cyclooctatetraene (COT) complexes were produced in a laser-vaporization metal cluster source and studied by pulsed-field ionization zero electron kinetic energy spectroscopy and quantum chemical calculations. The computations included the second-order Moller-Plesset perturbation theory, the coupled cluster method with single, double, and perturbative triple excitations, and the state-average complete active space self consistent field method. The spectrum of each complex exhibits multiple band systems and is assigned to ionization of several low-energy electronic states of the neutral complex. This observation is different from previous studies of M(COT) (M = Sc, Y, La, and Gd), for which a single band system was observed. The presence of the multiple low-energy electronic states is caused by the splitting of the partially filled lanthanide 4f orbitals in the ligand field, and the number of the low-energy states increases rapidly with increasing number of the metal 4f electrons. On the other hand, the 4f electrons have a small effect on the geometries and vibrational frequencies of these lanthanide complexes. PMID- 23635139 TI - Prediction of 2D Rydberg energy levels of 6Li and 7Li based on very accurate quantum mechanical calculations performed with explicitly correlated Gaussian functions. AB - Very accurate variational nonrelativistic finite-nuclear-mass calculations employing all-electron explicitly correlated Gaussian basis functions are carried out for six Rydberg (2)D states (1s(2)nd, n = 6, [ellipsis (horizontal)], 11) of the (7)Li and (6)Li isotopes. The exponential parameters of the Gaussian functions are optimized using the variational method with the aid of the analytical energy gradient determined with respect to these parameters. The experimental results for the lower states (n = 3, ..., 6) and the calculated results for the higher states (n = 7, ..., 11) fitted with quantum-defect-like formulas are used to predict the energies of (2)D 1s(2)nd states for (7)Li and (6)Li with n up to 30. PMID- 23635140 TI - Electronic spectroscopy of the HCCN radical. AB - The A(3)A"-X(3)Sigma(-) electronic transition of the HCCN/DCCN radical was observed by laser-induced fluorescence spectroscopy. Rotationally resolved excitation spectra were observed for HCCN and DCCN, and effective molecular constants of the upper state were determined. The observed intensities of the rotational lines were anomalous, probably due to a level-dependent non-radiative decay process in the excited state. Fluorescence depletion spectroscopy was applied in order to observe non-fluorescent vibronic levels. A dispersed fluorescence spectrum was also observed to determine the vibrational level structure in the ground electronic state. The observed vibrational structures in the fluorescence depletion and dispersed fluorescence spectra were tentatively assigned based on the results of ab initio calculations. PMID- 23635141 TI - Ultracold collisions of O(1D) and H2: the effects of H2 vibrational excitation on the production of vibrationally and rotationally excited OH. AB - A quantum dynamics study of the O((1)D) + H2(v = 0 - 2, j = 0) system has been carried out using the potential energy surfaces of Dobbyn and Knowles [Mol. Phys. 91, 1107 (1997)]. A time-independent quantum mechanical method based on hyperspherical coordinates is adopted for the dynamics calculations. Energy dependent cross section, probability, and rate coefficients are computed for the elastic, inelastic, and reactive channels over collision energies ranging from the ultracold to thermal regimes and for total angular momentum quantum number J = 0. The effect of initial vibrational excitation of the H2 molecule on vibrational and rotational populations of the OH product is investigated as a function of the collision energy. Comparison of results for vibrational levels v = 0 - 2 of H2 demonstrates that the vibrational excitation of H2 and its non reactive relaxation pathway play a minor role in the overall collisional outcome of O((1)D) and H2. It is also found that while the state-resolved product vibrational distributions are sensitive to the initial collision energy and H2 vibrational level, the product rotational distribution depicts an inverted population that is largely insensitive to initial conditions. Rate coefficients evaluated using a J-shifting approximation show reasonable agreement with available theoretical and experimental results suggesting that the J-shifting approximation may be used to evaluate the rate coefficients for O((1)D) + H2 reaction. PMID- 23635142 TI - Global permutationally invariant potential energy surface for ozone forming reaction. AB - We constructed new global potential energy surface for O + O2 -> O3 reaction. It is based on high level electronic structure theory calculations and employs fitting by permutationally invariant polynomial functions. This method of surface construction takes full advantage of permutation symmetry of three O nuclei and allows reducing dramatically the number of ab initio data points needed for accurate surface representation. New potential energy surface offers dramatic improvement over older surface of ozone in terms of dissociation energy and behavior along the minimum energy path. It can be used to refine the existing theories of ozone formation. PMID- 23635143 TI - Is near-"spectroscopic accuracy" possible for heavy atoms and coupled cluster theory? An investigation of the first ionization potentials of the atoms Ga-Kr. AB - Recent developments in ab initio coupled cluster (CC) theory and correlation consistent basis sets have ushered in an era of unprecedented accuracy when studying the spectroscopy and thermodynamics of molecules containing main group elements. These same developments have recently seen application to heavier inorganic or transition metal-containing species. The present work benchmarks conventional single reference coupled cluster theory (up to full configuration interaction for valence electron correlation and coupled cluster with up to full pentuple excitations (CCSDTQP) for core-valence correlation) and explicitly correlated coupled cluster methods [CC with single, double, and perturbative triple substitutions (CCSD(T)-F12)] for the atomic ionization potentials of the six 4p elements (Ga-Kr), a property with experimental error bars no greater than a few cm(-1). When second-order spin orbit coupling effects are included, a composite methodology based on CCSD(T) calculations yielded a mean signed error of just -0.039 kcal mol(-1) and a mean unsigned error of 0.043 kcal mol(-1). Inclusion of post-CCSD(T) correlation corrections reduced both of these values to -0.008 kcal mol(-1) and 0.025 kcal mol(-1), respectively, with the latter corresponding to an average error of just 9 cm(-1). The maximum signed error in the latter scheme was just -0.043 kcal mol(-1) (15 cm(-1)). PMID- 23635144 TI - Cooperative effects in novel LiF/HF?LiF?XF (X = F, Cl, Br) clusters. AB - Highly stable trimeric clusters of general formula LiF/HF?LiF?XF (X = F, Cl, Br) are predicted computationally. These clusters involve a LiF?XF dyad, with both the positively charged Li and negatively charged F atom of LiF non-covalently bonded to the X atom of XF. A third molecule (LiF or HF) is complexed to this dyad via ionic-type F?Li and Li(H)?F interactions to form a substantially stronger cluster. PMID- 23635145 TI - Thermally induced solid-solid structural transition of copper nanoparticles through direct geometrical conversion. AB - Molecular dynamics simulations of small Cu nanoparticles using three different interatomic potentials at rising temperature indicate that small nanoparticles can undergo solid-solid structural transitions through a direct geometrical conversion route. The direct geometrical conversion can happen for cuboctahedral nanoparticles, which turn into an icosahedra shape: one diagonal of the square faces contracts, and the faces are folded along the diagonal to give rise to two equilateral triangles. The transition is a kinetic process that cannot be fully explained through an energetic point of view. It has low activation energy and fast reaction time in the simulations. The transition mechanism is via the transmission of shear waves initiated from the particle surface and does not involve dislocation activity. PMID- 23635146 TI - Valence photoelectron spectra of alkali bromides calculated within the propagator theory. AB - The valence ionization spectra covering the binding energy range 0-45 eV of alkali bromide XBr (X = Li, Na, K, Rb) vapors are studied within the framework of the propagator theory. Relativistic Algebraic Diagrammatic Construction calculations have been carried out in order to investigate photoionization processes and to describe molecular electronic structure. Theoretical results are compared with available experimental data. PMID- 23635147 TI - Improved molecular constants of the 000-000 band of the electronic transition A2Sigma+-X2Pi of N2O+ radical. AB - In this paper the 000-000 vibrational band of the electronic transition A(2)Sigma(+)-X(2)Pi of the N2O(+) radical is analyzed, through high resolution Fourier Transform spectroscopy. The N2O(+) radical was produced by Penning ionization of N2O by colliding with metastable atoms of He(2(3)S) in a vacuum chamber. The spectrum was recorded in a spectral range of 24,500-30,000 cm(-1) and obtained from 200 coadded interferograms recorded at an apodized resolution of 0.08 cm(-1). Through a recursive way, the wavenumbers of the correspondent rotational transitions were reduced into molecular constants. A total of 280 lines were adjusted to the model with a standard deviation of 0.006 cm(-1). PMID- 23635148 TI - Assignment of photoelectron spectra of halide-water clusters: contrasting patterns of delocalization in Dyson orbitals. AB - Ab initio electron propagator calculations in various self-energy approximations provide accurate assignments of peaks observed in the photoelectron spectra of complexes that comprise a fluoride or chloride anion and two or three water molecules. More than one minimum structure is found in all four cases. When the halide anion is Cl(-), the first three final states may be described as quasi degenerate (2)P chlorine atoms coordinated to water molecules. Higher final states consist of a chloride anion juxtaposed to a positive charge that is delocalized over the water molecules. For the clusters with fluoride anions, most of the final states correspond to Dyson orbitals that are delocalized over the F and O nuclei. A variety of F-O sigma and pi bonding and antibonding patterns are evident in the Dyson orbitals. The assignment of low-lying spectral peaks to halide p orbital vacancies or to delocalized solvent orbitals is more valid for the chloride clusters than for the fluoride clusters, where a delocalized picture arises from strong bonding interactions between F 2p and H2O 1b1 orbitals. PMID- 23635149 TI - UV photolysis of 4-iodo-, 4-bromo-, and 4-chlorophenol: competition between C-Y (Y = halogen) and O-H bond fission. AB - The wavelength dependences of C-Y and O-H bond fission following ultraviolet photoexcitation of 4-halophenols (4-YPhOH) have been investigated using a combination of velocity map imaging, H Rydberg atom photofragment translational spectroscopy, and high level spin-orbit resolved electronic structure calculations, revealing a systematic evolution in fragmentation behaviour across the series Y = I, Br, Cl (and F). All undergo O-H bond fission following excitation at wavelengths lambda ? 240 nm, on repulsive ((n/pi)sigma*) potential energy surfaces (PESs), yielding fast H atoms with mean kinetic energies ~11,000 cm(-1). For Y = I and Br, this process occurs in competition with prompt C-I and C-Br bond cleavage on another (n/pi)sigma* PES, but no Cl/Cl* products unambiguously attributable to one photon induced C-Cl bond fission are observed from 4-ClPhOH. Differences in fragmentation behaviour at longer excitation wavelengths are more marked. Prompt C-I bond fission is observed following excitation of 4-IPhOH at all lambda <= 330 nm; the wavelength dependent trends in I/I* product branching ratio, kinetic energy release, and recoil anisotropy suggest that (with regard to C-I bond fission) 4-IPhOH behaves like a mildly perturbed iodobenzene. Br atoms are observed when exciting 4-BrPhOH at long wavelengths also, but their velocity distributions suggest that dissociation occurs after internal conversion to the ground state. O-H bond fission, by tunnelling (as in phenol), is observed only in the cases of 4-FPhOH and, more weakly, 4-ClPhOH. These observed differences in behaviour can be understood given due recognition of (i) the differences in the vertical excitation energies of the C-Y centred (n/pi)sigma* potentials across the series Y = I < Br < Cl and the concomitant reduction in C-Y bond strength, cf. that of the rival O-H bond, and (ii) the much increased spin-orbit coupling in, particularly, 4-IPhOH. The present results provide (another) reminder of the risks inherent in extrapolating photochemical behaviour measured for one molecule at one wavelength to other (related) molecules and to other excitation energies. PMID- 23635150 TI - Performance of dispersion-corrected double hybrid density functional theory: a computational study of OCS-hydrocarbon van der Waals complexes. AB - The performance of double hybrid density functionals (DHDFs) has been assessed by studying the spectroscopic properties and potential energy curves of OCS-C2H4 (carbonyl sulfide-ethylene) and OCS-C4H6 (carbonyl sulfide-dimethylacetylene) van der Waals complexes. Both dispersion corrected and uncorrected DHDF theories have been applied to study the intermolecular interaction energies, stability, spectroscopic parameters, rigidity, and binding energies or depths of the potential well of the weakly bound complexes and also to explore the possibility of formation of three isomers of each complex. The correlation consistent valence triple zeta quality basis set is used to investigate the complexes. The calculated results provide insight into the computational methods applied to the weakly bound complexes. The double hybrid density functional B2PLYP and mPW2PLYP methods with dispersion corrections (B2PLYP-D2, B2PLYP-D3 and mPW2PLYP-D2, mPW2PLYP-D3) performed better over the B2PLYP and mPW2PLYP density functional methods without dispersion correction to deal with the weak dispersion interaction that prevails in these complexes. The results obtained by the dispersion-corrected density functional mPW2PLYP-D2 and mPW2PLYP-D3 methods agree very well with the earlier experimental values wherever available. The contributing components of the interaction energy have been analyzed by the symmetry-adapted perturbation theory (SAPT, here, SAPT0) to get insight into the interaction energy. PMID- 23635151 TI - A maximum-entropy approach to the adiabatic freezing of a supercooled liquid. AB - I employ the van der Waals theory of Baus and co-workers to analyze the fast, adiabatic decay of a supercooled liquid in a closed vessel with which the solidification process usually starts. By imposing a further constraint on either the system volume or pressure, I use the maximum-entropy method to quantify the fraction of liquid that is transformed into solid as a function of undercooling and of the amount of a foreign gas that could possibly be also present in the test tube. Upon looking at the implications of thermal and mechanical insulation for the energy cost of forming a solid droplet within the liquid, I identify one situation where the onset of solidification inevitably occurs near the wall in contact with the bath. PMID- 23635152 TI - Relation between occupation in the first coordination shells and Widom line in core-softened potentials. AB - Three core-softened families of potentials are checked for the presence of density and diffusion anomalies. These potentials exhibit a repulsive core with a softening region and at larger distances an attractive well. We found that the region in the pressure-temperature phase diagram in which the anomalies are present increases if the slope between the core-softened scale and the attractive part of the potential decreases. The anomalous region also increases if the range of the core-softened or of the attractive part of the potential decreases. We also show that the presence of the density anomaly is consistent with the non monotonic changes of the radial distribution function at each one of the two scales when temperature and density are varied. Then, using this anomalous behavior of the structure we show that the pressure and the temperature at which the radial distribution function of one of the two length scales equals the radial distribution function of the other length scales identify the Widom line. PMID- 23635153 TI - Structural, electronic, and linear optical properties of organic photovoltaic PBTTT-C14 crystal. AB - Poly(2,5-bis(3-tetradecylthiophen-2yl)thieno(3,2-b)thiophene) (PBTTT-C14) is an important electro-optical polymer, whose three-dimensional crystal structure is somewhat ambiguous and the fundamental electronic and linear optical properties are not well known. We carried out first-principles calculations to model the crystal structure and to study the effect of side-chains on the physical structure and electronic properties. Our calculations suggest that the patterns of side-chain has little direct effect on the valence band maximum and conduction band minimum but they do have impact on the bandgap through changing the pi-pi stacking distance. By examining the band structure and wave functions, we conclude that the fundamental bandgap of the PBTTT-C14 crystal is determined by the conduction band energy at the Q point. The calculations indicate that the bandgap of PBTTT-C14 crystal may be tunable by introducing different side-chains. The significant peak in the imaginary part of the dielectric function arises from transitions along the polymer backbone axis, as determined by the critical-point analysis and the large optical transition matrix elements in the direction of the backbone. PMID- 23635154 TI - Generalized Gibbs' approach in heterogeneous nucleation. AB - Heterogeneous nucleation (condensation and boiling) on planar solid surfaces is described taking into account changes of the state parameters of the critical clusters in dependence on supersaturation. The account of the variation of the state parameters of the cluster phase on nucleation is performed in the framework of the generalized Gibbs' approach. One-component van der Waals fluids are chosen as a model for the analysis of the basic qualitative characteristics of the process. The analysis is performed for both hydrophobic and hydrophilic surfaces and similarities and differences between condensation and boiling processes are discussed for the two different cases. It is shown that, in the generalized Gibbs' approach, contact angle and catalytic factor for heterogeneous nucleation become dependent on the degree of metastability (undercooling or superheating) of the fluid. For the case of formation of a droplet in supersaturated vapor on a hydrophobic surface and bubble formation in a liquid on a hydrophilic surface the solid surface has only a minor influence on nucleation. In the alternative cases of condensation of a droplet on a hydrophilic surface and of bubble formation in a liquid on a hydrophobic surface, nucleation is significantly enhanced by the solid. Effectively, the existence of the solid surface results in a significant shift of the spinodal to lower supersaturations as compared with homogeneous nucleation. Qualitatively the same behavior is observed now near the new (solid surface induced) limits of instability of the fluid as compared with the behavior near to the spinodal curve in the case of homogeneous nucleation. PMID- 23635155 TI - Predicting crystals of Janus colloids. AB - We present a numerical study on the phase diagram for a simple model of Janus colloids, including ordered and disordered structures. Using a range of techniques, we generate a set of crystal structures and investigate their relative stability field in the pressure-temperature and temperature-density planes by means of free-energy calculations and thermodynamic integration schemes. We find that despite the Janus colloids' simple architecture, they form stable crystal structures with complicated bond-topologies on an underlying face centered-cubic or hexagonal-close-packed lattice. In addition, we find a phase consisting of wrinkled bilayer sheets, competing with both the fluid and the crystal phases. We detect a metastable gas-liquid coexistence which displays a micellization-driven re-entrant behavior. PMID- 23635156 TI - Stability of phases of a square-well fluid within superposition approximation. AB - The analytic and numerical methods introduced previously to study the phase behavior of hard sphere fluids starting from the Yvon-Born-Green (YBG) equation under the Kirkwood superposition approximation (KSA) are adapted to the square well fluid. We are able to show conclusively that the YBG equation under the KSA closure when applied to the square-well fluid: (i) predicts the existence of an absolute stability limit corresponding to freezing where undamped oscillations appear in the long-distance behavior of correlations, (ii) in accordance with earlier studies reveals the existence of a liquid-vapor transition by the appearance of a "near-critical region" where monotonically decaying correlations acquire very long range, although the system never loses stability. PMID- 23635157 TI - Impurity modes in Frenkel exciton systems with dipolar interactions and cubic symmetry. AB - We introduce a continuum model for impurity modes of Frenkel excitons in fully occupied face-centered and body-centered cubic lattices with dipole-dipole interactions and parallel moments. In the absence of impurities, the model reproduces the small-k behavior found in numerical calculations of dipolar lattice sums. The exciton densities of states near the upper and lower band edges are calculated and compared with the corresponding results for a random array of dipoles. The Green function obtained with the continuum model, together with a spherical approximation to the Brillouin zone, is used to determine the conditions for the formation of a localized exciton mode associated with a shift in the transition energy of a single chromophore. The dependence of the local mode energy on the magnitude of the shift is ascertained. The formation of impurity bands at high concentrations of perturbed sites is investigated using the coherent potential approximation. The contribution of the impurity bands to the optical absorption is calculated in the coherent potential approximation. The locations of the optical absorption peaks of the dipolar system are shown to depend on the direction of propagation of the light relative to the dipolar axis, a property that is maintained in the presence of short-range interactions. PMID- 23635158 TI - Coherent neutron scattering and collective dynamics on mesoscale. AB - By combining, and modestly extending, a variety of theoretical concepts for the dynamics of liquids in the supercooled regime, we formulate a simple analytic model for the temperature and wavevector dependent collective density fluctuation relaxation time that is measurable using coherent dynamic neutron scattering. Comparison with experiments on the ionic glass-forming liquid Ca-K-NO3 in the lightly supercooled regime suggests the model captures the key physics in both the local cage and mesoscopic regimes, including the unusual wavevector dependence of the collective structural relaxation time. The model is consistent with the idea that the decoupling between diffusion and viscosity is reflected in a different temperature dependence of the collective relaxation time at intermediate wavevectors and near the main (cage) peak of the static structure factor. More generally, our analysis provides support for the ideas that decoupling information and growing dynamic length scales can be at least qualitatively deduced by analyzing the collective relaxation time as a function of temperature and wavevector, and that there is a strong link between dynamic heterogeneity phenomena at the single and many particle level. Though very simple, the model can be applied to other systems, such as molecular liquids. PMID- 23635159 TI - Surface adsorption in strontium chloride ammines. AB - An adsorbed state and its implications on the ab- and desorption kinetics of ammonia in strontium chloride ammine is identified using a combination of ammonia absorption measurements, thermogravimetric analysis, and density functional theory calculations. During thermogravimetric analysis, ammonia desorption originating from the adsorbed state is directly observed below the bulk desorption temperature, as confirmed by density functional theory calculations. The desorption enthalpy of the adsorbed state of strontium chloride octa-ammine is determined with both techniques to be around 37-39 kJ/mol. A simple kinetic model is proposed that accounts for the absorption of ammonia through the adsorbed state. PMID- 23635160 TI - Structure and functionality of bromine doped graphite. AB - First-principles calculations are used to study the enhanced in-plane conductivity observed experimentally in Br-doped graphite, and to study the effect of external stress on the structure and functionality of such systems. The model used in the numerical calculations is that of stage two doped graphite. The band structure near the Fermi surface of the doped systems with different bromine concentrations is compared to that of pure graphite, and the charge transfer between carbon and bromine atoms is analyzed to understand the conductivity change along different high symmetry directions. Our calculations show that, for large interlayer separation between doped graphite layers, bromine is stable in the molecular form (Br2). However, with increased compression (decreased layer layer separation) Br2 molecules tend to dissociate. While in both forms, bromine is an electron acceptor. The charge exchange between the graphite layers and Br atoms is higher than that with Br2 molecules. Electron transfer to the Br atoms increases the number of hole carriers in the graphite sheets, resulting in an increase of conductivity. PMID- 23635161 TI - From Kelvin problem to Kelvin carbons. AB - As children's toys, soap bubbles also underpin many important scientific questions. What is the most efficient structure for foam? - the "Kelvin problem," has been one of the most intriguing science and widely discussed over the past hundred years. Soap bubbles' frameworks have similar topology with sp(3)-bonded carbon or silicon allotropes, e.g., Weaire-Phelan foam and superconducting clathrate Na8Si46. By looking at the most efficient structure for foams, we construct a series of new carbon allotropes, named "Kelvin carbons." Unexpectedly, all 11 Kelvin carbons are structurally stable wide-bandgap semiconductors, and their densities and their intrinsic hardnesses are both about 81%-87% that of diamond. The seventh state of Kelvin carbons, K(VII), is a very low energy carbon structure after graphite, diamond, lonsdaleite, and type-II carbon clathrate. Kelvin carbons, which constitute a "bridge" between macro-foams and micro-carbons, together with recently proposed novel carbon phases can enrich the study of carbon allotropes. PMID- 23635162 TI - Density functional theory for crystal-liquid interfaces of Lennard-Jones fluid. AB - A density functional approach is presented to describe the crystal-liquid interfaces and crystal nucleations of Lennard-Jones fluid. Within the theoretical framework, the modified fundamental measure theory is applied to describe the free energy functional of hard sphere repulsion, and the weighted density method based on first order mean spherical approximation is used to describe the free energy contribution arising from the attractive interaction. The liquid-solid equilibria, density profiles within crystal cells and at liquid-solid interfaces, interfacial tensions, nucleation free energy barriers, and critical cluster sizes are calculated for face-centered-cubic and body-centered-cubic nucleus. Some results are in good agreement with available simulation data, indicating that the present model is quantitatively reliable in describing nucleation thermodynamics of Lennard-Jones fluid. PMID- 23635163 TI - Size-selective self-assembly of magnetic Mn nanoclusters on Si(111). AB - We show by first-principles calculations two types of magnetic magic Mn clusters on the Si(111)-(7 * 7) surface. The first is a small triangular Mn7 cluster stabilized by the solid-centered Mn-Si3 bonds on the top layer, and the second is a large hexagonal Mn13 cluster favored by the confining potential wells of the faulted half unit cells on the Si(111) surface. These two structural models are distinct from that of the planar group-III clusters on Si(111) and produce simulated scanning tunneling microscopy images in reasonable agreement with recent experimental observations. These results offer key insights for understanding the complex energetic landscape on the Si(111)-(7 * 7) surface, which is critical to precisely controlled growth of Mn nanocluster arrays with specific size, magnetic moment, and good uniformity. PMID- 23635164 TI - The atomic structures of carbon nitride sheets for cathode oxygen reduction catalysis. AB - Carbon nitride sheets are promising Pt replacement materials for cathode oxygen reduction catalysis. Using first principles calculations with a global optimization method, we search for the most stable structures of the monolayer carbon nitrides at various C:N ratios. The results show that the larger the ratio, the more energetically favorable the obtained structures, and the more preferably for the C, N atoms to assume sp(2) configurations. A volcano shape is revealed for the curve of the representative O2 adsorption energies on the sheets vs. the ratios. In the ratio range of 2.0-3.0, the sheets not only have lower formation energies than the stable graphitic-C3N4, but also can potentially catalyze the oxygen reduction as efficiently as Pt. PMID- 23635165 TI - Solvation of polymers as mutual association. I. General theory. AB - A Flory-Huggins (FH) type lattice theory of self-assembly is generalized to describe the equilibrium solvation of long polymer chains B by small solvent molecules A. Solvation is modeled as a thermally reversible mutual association between the polymer and a relatively low molar mass solvent. The FH Helmholtz free energy F is derived for a mixture composed of the A and B species and the various possible mutual association complexes AiB, and F is then used to generate expressions for basic thermodynamic properties of solvated polymer solutions, including the size distribution of the solvated clusters, the fraction of solvent molecules contained in solvated states (an order parameter for solvation), the specific heat (which exhibits a maximum at the solvation transition), the second and the third osmotic virial coefficients, and the boundaries for phase stability of the mixture. Special attention is devoted to the analysis of the "entropic" contribution chi(s) to the FH interaction parameter chi of polymer solutions, both with and without associative interactions. The entropic chi(s) parameter arises from correlations associated with polymer chain connectivity and disparities in molecular structure between the components of the mixture. Our analysis provides the first explanation of the longstanding enigma of why chi(s) for polymer solutions significantly exceeds chi(s) for binary polymer blends. Our calculations also reveal that chi(s) becomes temperature dependent when interactions are strong, in sharp contrast to models currently being used for fitting thermodynamic data of associating polymer-solvent mixtures, where chi(s) is simply assumed to be an adjustable constant based on experience with solutions of homopolymers in nonassociating solvents. PMID- 23635166 TI - Solvation of polymers as mutual association. II. Basic thermodynamic properties. AB - The theory of equilibrium solvation of polymers B by a relatively low molar mass solvent A, developed in the simplest form in Paper I, is used to explore some essential trends in basic thermodynamic properties of solvated polymer solutions, such as the equilibrium concentrations of solvated polymers AiB and free solvent molecules A, the mass distribution phi(AiB)(i) of solvated clusters, the extent of solvation of the polymer Phi(solv), the solvation transition lines T(solv)(phiB(o)), the specific heat C(V), the osmotic second virial coefficient B2, phase stability boundaries, and the critical temperatures associated with closed loop phase diagrams. We discuss the differences between the basic thermodynamic properties of solvated polymers and those derived previously for hierarchical mutual association processes involving the association of two different species A and B into AB complexes and the subsequent polymerization of these AB complexes into linear polymeric structures. The properties of solvated polymer solutions are also compared to those for solutions of polymers in a self associating solvent. Closed loop phase diagrams for solvated polymer solutions arise in the theory from the competition between the associative and van der Waals interactions, a behavior also typical for dispersed molecular and nanoparticle species that strongly associate with the host fluid. Our analysis of the temperature dependence of the second osmotic virial coefficient reveals that the theory must be generalized to describe the association of multiple solvent molecules with each chain monomer, and this complex extension of the present model will be developed in subsequent papers aimed at a quantitative rather than qualitative treatment of solvated polymer solutions. PMID- 23635167 TI - Condensation of circular DNA. AB - A simple model of a circularly closed double-stranded DNA in a poor solvent is considered as an example of a semi-flexible polymer with self-attraction. To find the ground states, the conformational energy is computed as a sum of the bending and torsional elastic components and the effective self-attraction energy. The model includes a relative orientation or sequence dependence of the effective attraction forces between different pieces of the polymer chain. Two series of conformations are analysed: a multicovered circle (a toroid) and a multifold two headed racquet. The results are presented as a diagram of state. It is suggested that the stability of particular conformations may be controlled by proper adjustment of the primary structure. Application of the model to other semi flexible polymers is considered. PMID- 23635168 TI - Computing the phase diagram of binary mixtures: a patchy particle case study. AB - We investigate the phase behaviour of 2D mixtures of bi-functional and three functional patchy particles and 3D mixtures of bi-functional and tetra-functional patchy particles by means of Monte Carlo simulations and Wertheim theory. We start by computing the critical points of the pure systems and then we investigate how the critical parameters change upon lowering the temperature. We extend the successive umbrella sampling method to mixtures to make it possible to extract information about the phase behaviour of the system at a fixed temperature for the whole range of densities and compositions of interest. PMID- 23635169 TI - Dynamics of exciton dissociation in donor-acceptor polymer heterojunctions. AB - Exciton dissociation in a donor-accepter polymer heterojunction has been simulated using a nonadiabatic molecular dynamics approach, which allows for the coupled evolution of the nuclear degrees of freedom and the electronic degrees of freedom described by multiconfigurational electronic wavefunctions. The simulations reveal important details of the charge separation process: the exciton in the donor polymer first dissociates into a "hot" charge transfer state, which is best described as a polaron pair. The polaron pair can be separated into free polaron charge carriers if a sufficiently strong external electric field is applied. We have also studied the effects of inter-chain interaction, temperature, and the external electric field strength. Increasing inter-chain interactions makes it easier for the exciton to dissociate into a polaron pair state, but more difficult for the polaron pair to dissociate into free charge carriers. Higher temperature and higher electric field strength both favor exciton dissociation as well as the formation of free charge carriers. PMID- 23635170 TI - The isotropic-to-nematic phase transition in hard helices: theory and simulation. AB - We investigate the isotropic-to-nematic phase transition in systems of hard helical particles, using Onsager theory and Monte Carlo computer simulations. Motivation of this work resides in the ubiquity of the helical shape motif in many natural and synthetic polymers, as well as in the well known importance that the details of size and shape have in determining the phase behaviour and properties of (soft) condensed matter systems. We discuss the differences with the corresponding spherocylinder phase diagram and find that the helix parameters affect the phase behaviour and the existence of the nematic phase. We find that for high helicity Onsager theory significantly departs from numerical simulations even when a modified form of the Parsons-Lee rescaling is included to account for the non-convexity of particles. PMID- 23635171 TI - Grafted polymers inside cylindrical tubes: chain stretching vs layer thickness. AB - We present a study of the detailed structure of grafted polymer chains and the layers they form inside cylindrical tubes, using the finitely extensible nonlinear elastic chain model and numerical self-consistent field theory. For very large tube radius, the chain stretching and layer thicknesses are the same as for polymers grafted to a planar surface. For decreasing radius, our calculations indicate that the layer almost always gets thinner, although there can be situations where it is very slightly thicker. However, we find that this thinning is not necessarily due to changes to the polymers: in fact, the root mean-squared layer thickness would decrease even if the polymers themselves are completely unchanged. Furthermore, we find that the polymer stretching can increase at the same time that the layer thickness decreases. These apparent paradoxes are resolved by analyzing and distinguishing between the volume fraction profiles and monomer number distributions in these systems, including how they change and why. We also find that, in a given system, parts of each polymer move towards the curved surface and parts away from it, and that these differences are key to understanding the behavior. PMID- 23635173 TI - On the estimation of cooperativity in ion channel kinetics: activation free energy and kinetic mechanism of Shaker K+ channel. AB - In this paper, we have explored generic criteria of cooperative behavior in ion channel kinetics treating it on the same footing with multistate receptor-ligand binding in a compact theoretical framework. We have shown that the characterization of cooperativity of ion channels in terms of the Hill coefficient violates the standard Hill criteria defined for allosteric cooperativity of ligand binding. To resolve the issue, an alternative measure of cooperativity is proposed here in terms of the cooperativity index that sets a unified criteria for both the systems. More importantly, for ion channel this index can be very useful to describe the cooperative kinetics as it can be readily determined from the experimentally measured ionic current combined with theoretical modelling. We have analyzed the correlation between the voltage value and slope of the voltage-activation curve at the half-activation point and consequently determined the standard free energy of activation of the ion channel using two well-established mechanisms of cooperativity, namely, Koshland-Nemethy Filmer (KNF) and Monod-Wyman-Changeux (MWC) models. Comparison of the theoretical results for both the models with appropriate experimental data of mutational perturbation of Shaker K(+) channel supports the experimental fact that the KNF model is more suitable to describe the cooperative behavior of this class of ion channels, whereas the performance of the MWC model is unsatisfactory. We have also estimated the mechanistic performance through standard free energy of channel activation for both the models and proposed a possible functional disadvantage in the MWC scheme. PMID- 23635172 TI - Functional understanding of solvent structure in GroEL cavity through dipole field analysis. AB - Solvent plays a ubiquitous role in all biophysical phenomena. Yet, just how the molecular nature of water impacts processes in biology remains an important question. While one can simulate the behavior of water near biomolecules such as proteins, it is challenging to gauge the potential structural role solvent plays in mediating both kinetic and equilibrium processes. Here, we propose an analysis scheme for understanding the nature of solvent structure at a local level. We first calculate coarse-grained dipole vector fields for an explicitly solvated system simulated through molecular dynamics. We then analyze correlations between these vector fields to characterize water structure under biologically relevant conditions. In applying our method to the interior of the wild type chaperonin complex GroEL+ES, along with nine additional mutant GroEL complexes, we find that dipole field correlations are strongly related to chaperonin function. PMID- 23635174 TI - Invited review article: Large ring lasers for rotation sensing. AB - Over the last two decades a series of large ring laser gyroscopes have been built having an unparalleled scale factor. These upscaled devices have improved the sensitivity and stability for rotation rate measurements by six orders of magnitude when compared to previous commercial developments. This progress has made possible entirely new applications of ring laser gyroscopes in the fields of geophysics, geodesy, and seismology. Ring lasers are currently the only viable measurement technology, which is directly referenced to the instantaneous rotation axis of the Earth. The sensor technology is rapidly developing. This is evidenced by the first experimentally viable proposals to make terrestrial tests of general relativistic effects such as the frame dragging of the rotating Earth. PMID- 23635175 TI - Interferometric measurement of angular motion. AB - This paper describes the design and realization of a homodyne polarization interferometer for measuring angular motion. The optical layout incorporates carefully designed cat's eye retroreflectors that maximize the measurable range of angular motion and facilitate initial alignment. The retroreflectors are optimized and numerically characterized in terms of defocus and spherical aberrations using Zemax software for optical design. The linearity of the measurement is then calculated in terms of the aberrations. The actual physical interferometer is realized as a compact device with optical components from stock and without relying on adjustable holders. Evaluation of its performance using a commercial autocollimator confirmed a reproducibility within 0.1%, a non linearity of less than 1 ppm with respect to the autocollimator, an upper limit to its sensitivity of about 5 * 10(-11) rad/Hz from audioband down to 100 mHz and an angular measurement range of more than +/-1 degrees . PMID- 23635177 TI - Comparison of modified driver circuit and capacitor-transfer circuit in longitudinally excited N2 laser. AB - We developed a modified driver circuit composed of a capacitance and a spark gap, called a direct-drive circuit, for a longitudinally excited gas laser. The direct drive circuit uses a large discharge impedance caused by a long discharge length of the longitudinal excitation scheme and eliminates the buffer capacitance used in the traditional capacitor-transfer circuit. We compared the direct-drive circuit and the capacitor-transfer circuit in a longitudinally excited N2 laser (wavelength: 337 nm). Producing high output energy with the capacitor-transfer circuit requires a large storage capacitance and a discharge tube with optimum dimensions (an inner diameter of 4 mm and a length of 10 cm in this work); in contrast, the direct-drive circuit requires a high breakdown voltage, achieved with a small storage capacitance and a large discharge tube. Additionally, for the same input energy of 792 mJ, the maximum output energy of the capacitor transfer circuit was 174.2 MUJ, and that of the direct-drive circuit was 344.7 MUJ. PMID- 23635176 TI - Integrated multichannel photon timing instrument with very short dead time and high throughput. AB - Precisely timed detection of single photons plays an important role in the field of quantum information processing and fluorescence sensing. The method of time correlated single photon counting is therefore constantly evolving and the associated instrumentation is being improved with new ideas and technologies. Simultaneous, time tagged readout of multiple detector channels is invaluable in many applications, spanning from fluorescence lifetime imaging in biology to the measurement of quantum optical correlations in basic research. Here we present a new integrated design, providing up to three independent input channels, a very short dead time, very high throughput, and a timing resolution of 25 ps at reasonable cost and small size. Apart from design features and test results of the instrument, we show an application in quantum optics, namely, the measurement of the photon statistics of a heralded single photon source based on cavity enhanced spontaneous parametric down-conversion. PMID- 23635178 TI - Counter-propagating dual-trap optical tweezers based on linear momentum conservation. AB - We present a dual-trap optical tweezers setup which directly measures forces using linear momentum conservation. The setup uses a counter-propagating geometry, which allows momentum measurement on each beam separately. The experimental advantages of this setup include low drift due to all-optical manipulation, and a robust calibration (independent of the features of the trapped object or buffer medium) due to the force measurement method. Although this design does not attain the high-resolution of some co-propagating setups, we show that it can be used to perform different single molecule measurements: fluctuation-based molecular stiffness characterization at different forces and hopping experiments on molecular hairpins. Remarkably, in our setup it is possible to manipulate very short tethers (such as molecular hairpins with short handles) down to the limit where beads are almost in contact. The setup is used to illustrate a novel method for measuring the stiffness of optical traps and tethers on the basis of equilibrium force fluctuations, i.e., without the need of measuring the force vs molecular extension curve. This method is of general interest for dual trap optical tweezers setups and can be extended to setups which do not directly measure forces. PMID- 23635179 TI - Experimental energy resolution of a paracentric hemispherical deflector analyzer for different entry positions and bias. AB - A specially designed hemispherical deflector analyzer (HDA) with 5-element input lens having a movable entry position R0 suitable for electron energy analysis in atomic collisions was constructed and tested. The energy resolution of the HDA was experimentally determined for three different entry positions R0 = 84, 100, 112 mm as a function of the nominal entry potential V(R0) under pre-retardation conditions. The resolution for the (conventional) entry at the mean radius R0 = 100 mm was found to be a factor of 1.6-2 times worse than the resolution for the two (paracentric) positions R0 = 84 and 112 mm at particular values of V(R0). These results provide the first experimental verification and a proof of principle of the utility of such a paracentric HDA, while demonstrating its advantages over the conventional HDA: greater dispersion with reduced angular aberrations resulting in better energy resolution without the use of any additional fringing field correction electrodes. Supporting simulations of the entire lens plus HDA spectrometer are also provided and mostly found to be within 20%-30% of experimental values. The paracentric HDA is expected to provide a lower cost and/or more compact alternative to the conventional HDA particularly useful in modern applications utilizing a position sensitive detector. PMID- 23635180 TI - Energy-scalable temporal cleaning device for femtosecond laser pulses based on cross-polarized wave generation. AB - We report on a compact energy-scalable device for generating high-fidelity femtosecond laser pulses based on spatial filtering through a hollow-core fiber followed by a nonlinear crystal for cross-polarized wave (XPW) generation. This versatile device is suited for temporal pulse cleaning over a wide range of input energies (from 0.1 to >10 mJ) and is successfully qualified on different ultrafast laser systems. Full characterization of the XPW output is presented. In particular, we demonstrate the generation of 1.6 mJ energy pulses starting from 11 mJ input pulse energy. The temporal contrast of the pulses is enhanced by more than 4 orders of magnitude. In addition, pulse shortening from 40 fs down to 15 fs Fourier-transform limit yields an overall peak-power transmission of up to 50%. This device not only serves as an integrated pulse contrast filter inside an ultrafast laser amplifier but also as a simple back-end solution for temporal post-compression of amplified pulses. PMID- 23635181 TI - Photoionization of optically trapped ultracold atoms with a high-power light emitting diode. AB - Photoionization of laser-cooled atoms using short pulses of a high-power light emitting diode (LED) is demonstrated. Light pulses as short as 30 ns have been realized with the simple LED driver circuit. We measure the ionization cross section of (85)Rb atoms in the first excited state, and show how this technique can be used for calibrating efficiencies of ion detector assemblies. PMID- 23635182 TI - Evanescent straight tapered-fiber coupling of ultra-high Q optomechanical micro resonators in a low-vibration helium-4 exchange-gas cryostat. AB - We developed an apparatus to couple a 50-MUm diameter whispering-gallery silica microtoroidal resonator in a helium-4 cryostat using a straight optical tapered fiber at 1550 nm wavelength. On a top-loading probe specifically adapted for increased mechanical stability, we use a specifically-developed "cryotaper" to optically probe the cavity, allowing thus to record the calibrated mechanical spectrum of the optomechanical system at low temperatures. We then demonstrate excellent thermalization of a 63-MHz mechanical mode of a toroidal resonator down to the cryostat's base temperature of 1.65 K, thereby proving the viability of the cryogenic refrigeration via heat conduction through static low-pressure exchange gas. In the context of optomechanics, we therefore provide a versatile and powerful tool with state-of-the-art performances in optical coupling efficiency, mechanical stability, and cryogenic cooling. PMID- 23635183 TI - Creation of quantum-degenerate gases of ytterbium in a compact 2D-/3D-magneto optical trap setup. AB - We report on the first experimental setup based on a 2D-/3D-magneto-optical trap (MOT) scheme to create both Bose-Einstein condensates and degenerate Fermi gases of several ytterbium isotopes. Our setup does not require a Zeeman slower and offers the flexibility to simultaneously produce ultracold samples of other atomic species. Furthermore, the extraordinary optical access favors future experiments in optical lattices. A 2D-MOT on the strong (1)S0 -> (1)P1 transition captures ytterbium directly from a dispenser of atoms and loads a 3D-MOT on the narrow (1)S0 -> (3)P1 intercombination transition. Subsequently, atoms are transferred to a crossed optical dipole trap and cooled evaporatively to quantum degeneracy. PMID- 23635184 TI - Measurements with magnetic field in the National Spherical Torus Experiment using the motional Stark effect with laser induced fluorescence diagnostic. AB - The motional Stark effect with laser-induced fluorescence diagnostic (MSE-LIF) has been installed and tested on the National Spherical Torus Experiment (NSTX) at the Princeton Plasma Physics Lab. The MSE-LIF diagnostic will be capable of measuring radially resolved profiles of magnetic field magnitude or pitch angle in NSTX plasmas. The system includes a diagnostic neutral hydrogen beam and a laser which excites the n = 2 to n = 3 transition. A viewing system has been implemented which will support up to 38 channels from the plasma edge to past the magnetic axis. First measurements of MSE-LIF signals in the presence of small applied magnetic fields in neutral gas are reported. PMID- 23635185 TI - Optical emission from a small scale model electric arc furnace in 250-600 nm region. AB - Optical emission spectroscopy has been for long proposed for monitoring and studying industrial steel making processes. Whereas the radiative decay of thermal excitations is always taking place in high temperatures needed in steel production, one of the most promising environment for such studies are electric arc furnaces, creating plasma in excited electronic states that relax with intense characteristic emission in the optical regime. Unfortunately, large industrial scale electric arc furnaces also present a challenging environment for optical emission studies and application of the method is not straightforward. To study the usability of optical emission spectroscopy in real electric arc furnaces, we have developed a laboratory scale DC electric arc furnace presented in this paper. With the setup, optical emission spectra of Fe, Cr, Cr2O3, Ni, SiO2, Al2O3, CaO, and MgO were recorded in the wavelength range 250-600 nm and the results were analyzed with the help of reference data. The work demonstrates that using characteristic optical emission, obtaining in situ chemical information from oscillating plasma of electric arc furnaces is indeed possible. In spite of complications, the method could possibly be applied to industrial scale steel making process in order to improve its efficiency. PMID- 23635186 TI - Modular cryostat for ion trapping with surface-electrode ion traps. AB - We present a simple cryostat purpose built for use with surface-electrode ion traps, designed around an affordable, large cooling power commercial pulse tube refrigerator. A modular vacuum enclosure with a single vacuum space facilitates interior access and enables rapid turnaround and flexibility for future modifications. Long rectangular windows provide nearly 360 degrees of optical access in the plane of the ion trap, while a circular bottom window near the trap enables NA 0.4 light collection without the need for in-vacuum optics. We evaluate the system's mechanical and thermal characteristics and we quantify ion trapping performance by trapping (40)Ca(+), finding small stray electric fields, long ion lifetimes, and low ion heating rates. PMID- 23635187 TI - Bandwidth-variable tunable optical filter unit for illumination and spectral imaging systems using thin-film optical band-pass filters. AB - An optical filter unit is demonstrated, which uses two successively arranged tunable thin-film optical band-pass filters and allows for simultaneous adjustment of the central wavelength in the spectral range 522-555 nm and of the spectral bandwidth in the range 3-16 nm with a wavelength switching time of 8 ms/nm. Different spectral filter combinations can cover the complete visible spectral range. The transmitted intensity was found to decrease only linearly with the spectral bandwidth for bandwidths >6 nm, allowing a high maximum transmission efficiency of >75%. The image of a fiber bundle was spectrally filtered and analyzed in terms of position-dependency of the transmitted bandwidth and central wavelength. PMID- 23635188 TI - Multipoint relative humidity measurement by polyvinyl alcohol-coated Fresnel reflection-based optical fiber sensors with an array-waveguide grating. AB - A simple multipoint humidity measurement by polyvinyl alcohol (PVA)-coated Fresnel reflection-based optical fiber sensors with an Array-Waveguide Grating (AWG) is proposed and demonstrated. Every channel end of the AWG is split as a vertical planar surface, and then is coated with a layer of a PVA whose refractive index is sensitive to moisture. The reflection intensity for each channel will change with its surrounding humidity, since the optical fiber interface's Fresnel reflection is affected strongly by the refractive index difference of the interface two sides. Multiplexing is achieved by the AWG with 16 channels, in which 15 channels can be used as sensing heads when they are coated with a layer of PVA and the left one is used as a reference channel. The experimental setup is simple and easy to handle. Experimental results show that the proposed Fresnel reflection-based optical fiber sensor for multipoint humidity measurement works well and the average sensitivity is 0.135 dB/% relative humidity (RH) within the measurement range of 30%-80% RH. PMID- 23635189 TI - A spectrometer on chemical vapour deposition-diamond basis for the measurement of the charge-state distribution of heavy ions in a laser-generated plasma. AB - This article reports on the development and the first applications of a new spectrometer which enables the precise and time-resolved measurement of both the energy loss and the charge-state distribution of ion beams with 10 < Z < 30 at energies of 4-8 MeV/u after their interaction with a laser-generated plasma. The spectrometer is based on five 20 * 7 mm(2) large and 20 MUm thick polycrystalline diamond samples produced via the Chemical Vapour Deposition (CVD) process and was designed with the help of ion-optical simulations. First experiments with the spectrometer were successfully carried out at GSI using (48)Ca ions at an energy of 4.8 MeV/u interacting with a carbon plasma generated by the laser irradiation of a thin foil target. Owing to the high rate capability and the short response time of the spectrometer, pulsed ion beams with 10(3)-10(4) ions per bunch at a bunch frequency of 108 MHz could be detected. The temporal evolution of the five main charge states of the calcium ion beams as well as the corresponding energy loss values could be measured simultaneously. Due to the outstanding properties of diamond as a particle detector, a beam energy resolution DeltaEE ~ 0.1% could be reached using the presented experimental method, while a precision of 10% in the energy loss and charge-state distribution data was obtained. PMID- 23635190 TI - Conceptual design of the tangentially viewing combined interferometer-polarimeter for ITER density measurements. AB - One of the systems planned for the measurement of electron density in ITER is a multi-channel tangentially viewing combined interferometer-polarimeter (TIP). This work discusses the current status of the design, including a preliminary optical table layout, calibration options, error sources, and performance projections based on a CO2/CO laser system. In the current design, two-color interferometry is carried out at 10.59 MUm and 5.42 MUm and a separate polarimetry measurement of the plasma induced Faraday effect, utilizing the rotating wave technique, is made at 10.59 MUm. The inclusion of polarimetry provides an independent measure of the electron density and can also be used to correct the conventional two-color interferometer for fringe skips at all densities, up to and beyond the Greenwald limit. The system features five chords with independent first mirrors to reduce risks associated with deposition, erosion, etc., and a common first wall hole to minimize penetration sizes. Simulations of performance for a projected ITER baseline discharge show the diagnostic will function as well as, or better than, comparable existing systems for feedback density control. Calculations also show that finite temperature effects will be significant in ITER even for moderate temperature plasmas and can lead to a significant underestimate of electron density. A secondary role TIP will fulfill is that of a density fluctuation diagnostic; using a toroidal Alfven eigenmode as an example, simulations show TIP will be extremely robust in this capacity and potentially able to resolve coherent mode fluctuations with perturbed densities as low as deltan/n ~ 10(-5). PMID- 23635191 TI - Non-invasive in situ plasma monitoring of reactive gases using the floating harmonic method for inductively coupled plasma etching application. AB - The floating harmonic method was developed for in situ plasma diagnostics of allowing real time measurement of electron temperature (Te) and ion flux (Jion) without contamination of the probe from surface modification by reactive species. In this study, this novel non-invasive diagnostic system was studied to characterize inductively coupled plasma of reactive gases monitoring Te and Jion for investigating the optimum plasma etching conditions and controlling of the real-time plasma surface reaction in the range of 200-900 W source power, 10-100 W bias power, and 3-15 mTorr chamber pressure, respectively. PMID- 23635192 TI - Electron-ion hybrid instability experiment upgrades to the Auburn Linear Experiment for Instability Studies. AB - The Auburn Linear EXperiment for Instability Studies (ALEXIS) is a laboratory plasma physics experiment used to study spatially inhomogeneous flows in a magnetized cylindrical plasma column that are driven by crossed electric (E) and magnetic (B) fields. ALEXIS was recently upgraded to include a small, secondary plasma source for a new dual source, interpenetrating plasma experiment. Using two plasma sources allows for highly localized electric fields to be made at the boundary of the two plasmas, inducing strong E * B velocity shear in the plasma, which can give rise to a regime of instabilities that have not previously been studied in ALEXIS. The dual plasma configuration makes it possible to have independent control over the velocity shear and the density gradient. This paper discusses the recent addition of the secondary plasma source to ALEXIS, as well as the plasma diagnostics used to measure electric fields and electron densities. PMID- 23635193 TI - Measurement of 2/1 intrinsic error field of Joint TEXT tokamak. AB - The amplitude and spatial phase of the intrinsic error field of Joint TEXT (J TEXT) tokamak were measured by scanning the spatial phase of an externally exerted resonant magnetic perturbation and fitting the mode locking thresholds. For a typical plasma with current of 180 kA, the amplitude of the 2/1 component of the error field at the plasma edge is measured to be 0.31 G, which is about 1.8 * 10(-5) relative to the base toroidal field. The measured spatial phase is about 317 degrees in the specified coordinate system (r, theta, phi) of J-TEXT tokamak. An analytical model based on the dynamics of rotating island is developed to verify the measured phase. PMID- 23635194 TI - Production of large volume, strongly magnetized laser-produced plasmas by use of pulsed external magnetic fields. AB - The production of strongly magnetized laser plasmas, of interest for laboratory astrophysics and inertial confinement fusion studies, is presented. This is achieved by coupling a 16 kV pulse-power system. This is achieved by coupling a 16 kV pulse-power system, which generates a magnetic field by means of a split coil, with the ELFIE laser facility at Ecole Polytechnique. In order to influence the plasma dynamics in a significant manner, the system can generate, repetitively and without debris, high amplitude magnetic fields (40 T) in a manner compatible with a high-energy laser environment. A description of the system and preliminary results demonstrating the possibility to magnetically collimate plasma jets are given. PMID- 23635195 TI - The magnetic recoil spectrometer for measurements of the absolute neutron spectrum at OMEGA and the NIF. AB - The neutron spectrum produced by deuterium-tritium (DT) inertial confinement fusion implosions contains a wealth of information about implosion performance including the DT yield, ion-temperature, and areal-density. The Magnetic Recoil Spectrometer (MRS) has been used at both the OMEGA laser facility and the National Ignition Facility (NIF) to measure the absolute neutron spectrum from 3 to 30 MeV at OMEGA and 3 to 36 MeV at the NIF. These measurements have been used to diagnose the performance of cryogenic target implosions to unprecedented accuracy. Interpretation of MRS data requires a detailed understanding of the MRS response and background. This paper describes ab initio characterization of the system involving Monte Carlo simulations of the MRS response in addition to the commission experiments for in situ calibration of the systems on OMEGA and the NIF. PMID- 23635196 TI - Applied magnetic field design for the field reversed configuration compression heating experiment. AB - Detailed calculations of the formation, guide, and mirror applied magnetic fields in the FRC compression-heating experiment (FRCHX) were conducted using a commercially available generalized finite element solver, COMSOL Multiphysics((r)). In FRCHX, an applied magnetic field forms, translates, and finally captures the FRC in the liner region sufficiently long to enable compression. Large single turn coils generate the fast magnetic fields necessary for FRC formation. Solenoidal coils produce the magnetic field for translation and capture of the FRC prior to liner implosion. Due to the limited FRC lifetime, liner implosion is initiated before the FRC is injected, and the magnetic flux that diffuses into the liner is compressed. Two-dimensional axisymmetric magnetohydrodynamic simulations using MACH2 were used to specify optimal magnetic field characteristics, and this paper describes the simulations conducted to design magnetic field coils and compression hardware for FRCHX. This paper presents the vacuum solution for the magnetic field. PMID- 23635198 TI - Scanning noise microscopy. AB - The paper describes a simple scheme enabling the real-time characterization of fluctuations, e.g., of the conductance in scanning tunneling microscopy. The technique can be used in parallel to other data acquisition, evaluating the rate, the amplitude, and the duty cycle of telegraphic noise in the tunneling current. This kind of scanning probe microscopy allows to evaluate the noise parameters as a function of the average tunneling current, the electron energy, and the lateral position. Images of the noise with Angstrom spatial resolution are acquired simultaneously to the topographic information providing a direct correlation between the structural information and the noise. The method can be applied to a large variety of systems to monitor dynamics on the nanoscale, e.g., the localization of tunneling current induced switching within a single molecule. Noise spectroscopy may reveal the involved molecular orbitals, even if they cannot be resolved in standard scanning tunneling spectroscopy. As an example we present experimental data of the organic molecule copper phthalocyanine on a Cu(111) surface [J. Schaffert, M. C. Cottin, A. Sonntag, H. Karacuban, C. A. Bobisch, N. Lorente, J.-P. Gauyacq, and R. Moller, Nature Mater. 12, 223-227 (2013)]. PMID- 23635197 TI - Tuning donut profile for spatial resolution in stimulated emission depletion microscopy. AB - In stimulated emission depletion (STED)-based or up-conversion depletion-based super-resolution optical microscopy, the donut-shaped depletion beam profile is of critical importance to its resolution. In this study, we investigate the transformation of the donut-shaped depletion beam focused by a high numerical aperture (NA) microscope objective, and model STED point spread function (PSF) as a function of donut beam profile. We show experimentally that the intensity profile of the dark kernel of the donut can be approximated as a parabolic function, whose slope is determined by the donut beam size before the objective back aperture, or the effective NA. Based on this, we derive the mathematical expression for continuous wave (CW) STED PSF as a function of focal plane donut and excitation beam profiles, as well as dye properties. We find that the effective NA and the residual intensity at the center are critical factors for STED imaging quality and the resolution. The effective NA is critical for STED resolution in that it not only determines the donut shape but also the area the depletion laser power is dispersed. An improperly expanded depletion beam will have negligible improvement in resolution. The polarization of the depletion beam also plays an important role as it affects the residual intensity in the center of the donut. Finally, we construct a CW STED microscope operating at 488 nm excitation and 592 nm depletion with a resolution of 70 nm. Our study provides detailed insight to the property of donut beam, and parameters that are important for the optimal performance of STED microscopes. This paper will provide a useful guide for the construction and future development of STED microscopes. PMID- 23635199 TI - Piezoresponse force microscopy at sub-room temperatures. AB - Piezoresponse force microscopy is demonstrated at temperatures between -80 degrees C and +120 degrees C using a commercial room temperature atomic force microscope upgraded with a home-built cooling/heating-stage. We applied temperature-ramp-synchronized piezoresponse force microscope (PFM) for tracing the temperature dependence of the formation of ferroelectric domains. The potential of our sub-room temperature PFM is demonstrated by investigating the formation and evolution of ferroelectric domains in RbHSO4 as a function of temperature and time, respectively. PMID- 23635200 TI - SODI-COLLOID: a combination of static and dynamic light scattering on board the International Space Station. AB - Microgravity research in space is a complex activity where the often scarce resources available for the launch, accommodation, and operation of instrumentation call for a careful experiment planning and instrument development. In this paper we describe a module of the Selectable Optical Diagnostic Instrument, that has been designed as a compact optical diagnostic instrument for colloidal physics experiments. The peculiarity of the instrument is the combination of a novel light scattering technique known as near field scattering and standard microscopy with a low-coherence laser light source. We describe its main design features, as well as measurement results on colloidal aggregation taken on the International Space Station. PMID- 23635201 TI - Separate-type scanner and wideband high-voltage amplifier for atomic-resolution and high-speed atomic force microscopy. AB - We have developed a liquid-environment atomic force microscope with a wideband and low-noise scanning system for atomic-scale imaging of dynamic processes at solid/liquid interfaces. The developed scanning system consists of a separate type scanner and a wideband high-voltage amplifier (HVA). By separating an XY sample scanner from a Z-tip scanner, we have enabled to use a relatively large sample without compromising the high resonance frequency. We compared various cantilever- and sample-holding mechanisms by experiments and finite element analyses for optimizing the balance between the usability and frequency response characteristics. We specifically designed the HVA to drive the developed scanners, which enabled to achieve the positioning accuracy of 5.7 and 0.53 pm in the XY and Z axes, respectively. Such an excellent noise performance allowed us to perform atomic-resolution imaging of mica and calcite in liquid. Furthermore, we demonstrate in situ and atomic-resolution imaging of the calcite crystal growth process in water. PMID- 23635202 TI - Electrokinetic microscopy: a technique for imaging three-dimensional surface topography and heterogeneity of surface material. AB - In the present study, we introduce the concept of an electrokinetic microscope (EKM), a non-contact type probe microscope that can simultaneously provide a test specimen's three-dimensional surface topography and heterogeneity of surface material. In the EKM, the flow impedance and the streaming potential are measured during the scanning process to reproduce the topography and the heterogeneity, respectively. The working principle of the EKM is experimentally demonstrated by measuring specimens whose surfaces consist of thin layers of various materials and topographical differences. Experimental results also show that the EKM can be used regardless of the electrical conductivity of test specimens. PMID- 23635203 TI - A new highly automated sputter equipment for in situ investigation of deposition processes with synchrotron radiation. AB - HASE (Highly Automated Sputter Equipment) is a new mobile setup developed to investigate deposition processes with synchrotron radiation. HASE is based on an ultra-high vacuum sputter deposition chamber equipped with an in-vacuum sample pick-and-place robot. This enables a fast and reliable sample change without breaking the vacuum conditions and helps to save valuable measurement time, which is required for experiments at synchrotron sources like PETRA III at DESY. An advantageous arrangement of several sputter guns, mounted on a rotative flange, gives the possibility to sputter under different deposition angles or to sputter different materials on the same substrate. The chamber is also equipped with a modular sample stage, which allows for the integration of different sample environments, such as a sample heating and cooling device. The design of HASE is unique in the flexibility. The combination of several different sputtering methods like standard deposition, glancing angle deposition, and high pressure sputter deposition combined with heating and cooling possibilities of the sample, the large exit windows, and the degree of automation facilitate many different grazing incidence X-ray scattering experiments, such as grazing incidence small and wide angle X-ray scattering, in one setup. In this paper we describe in detail the design and the performance of the new equipment and present the installation of the HASE apparatus at the Micro and Nano focus X-ray Scattering beamline (MiNaXS) at PETRA III. Furthermore, we describe the measurement options and present some selected results. The HASE setup has been successfully commissioned and is now available for users. PMID- 23635204 TI - Pulsed laser deposition with simultaneous in situ real-time monitoring of optical spectroscopic ellipsometry and reflection high-energy electron diffraction. AB - We present a pulsed laser deposition system that can monitor growth by simultaneously using in situ optical spectroscopic ellipsometry (SE) and reflection high-energy electron diffraction (RHEED). The RHEED precisely monitors the number of thin-film layers and surface structure during the deposition, and the SE measures the optical spectra of the samples simultaneously. The thin-film thickness information obtained from RHEED facilitates the SE modeling process, which allows extracting the in situ optical spectra, i.e., the dielectric functions of thin-films during growth. The in situ dielectric functions contain indispensable information about the electronic structure of thin-films. We demonstrate the performance of this system by growing LaMnO(3+delta) (LMO) thin films on SrTiO3 (001) substrates. By using in situ SE and RHEED simultaneously, we show that real-time thickness and dielectric functions of the LMO thin-films can be effectively extracted. The simultaneous monitoring of both optical SE and RHEED offers important clues to understand the growth mechanism of atomic-scale thin-films. PMID- 23635205 TI - An experimental apparatus for simultaneously measuring Seebeck coefficient and electrical resistivity from 100 K to 600 K. AB - In this paper, we report a fully automated experimental apparatus for measuring Seebeck coefficient and electrical resistivity of a sample simultaneously in a temperature range of 100-600 K. The Seebeck coefficient is measured using a quasi steady temperature differential method in which two ceramic heaters are employed to alternately heat the sample. The sample holder is designed to reduce temperature disturbance on its base during a measurement cycle. To demonstrate the accuracy and reliability of the experimental setup, we have performed tests on reference materials including constantan and platinum. PMID- 23635206 TI - A new magneto-elastic resonance based technique to determine magneto-mechanical parameters of amorphous ferromagnetic ribbons. AB - Measurement of the magneto-mechanical parameters characteristics of amorphous ribbons often requires complex or limited methods due to their very small thickness. In this paper, it is shown how one can establish and estimate the characteristics of a magnetostrictive resonator from the experimental frequency response free of any kind of mechanical measurement (stress or elongation). This technique which is completely developed with a ribbon exhibiting good resonator properties, is suitable to estimate the magneto-mechanical coupling coefficient k33 and the Young's modulus and also to establish the magnetostriction curves lambda(H) of amorphous ribbons. Results obtained from resonators made of 2605SC and 2826 from Metglas(TM) ribbons confirmed the validity of the present technique. However, measurements performed on a thin foil of nickel demonstrate that the present method cannot be extended to semi-soft magnetic materials. The technique which is proposed, has serious advantages upon others as it is non destructive, low cost and easy to develop compared to common ones. PMID- 23635207 TI - The source-sample stage of the new two-dimensional angular correlation of annihilation radiation spectrometer at Technische Universitat Munchen. AB - Angular correlation of annihilation radiation (ACAR) is a well established technique for the investigation of the electronic structure. A major limitation of ACAR studies is the available positron flux at a small spot on the sample. For this reason, the focus of this work is put on the discussion of a newly developed source-sample stage of the new 2D-ACAR spectrometer at Technische Universitat Munchen which uses an optimized static magnetic field configuration to guide the positrons onto the sample. The achieved spot diameter is d(FWHM) = 5.4 mm, with a high efficiency over the whole energy spectrum of the (22)Na positron source. The implications of the performance of the source-sample stage are discussed with regard to 2D-ACAR measurements of single crystalline alpha-quartz, which serves as a model system for the determination of the total resolution. A value of (1.53 * 1.64) mrad(2) FWHM was achieved at room temperature. PMID- 23635208 TI - Axial temperature gradient and stress measurements in the deformation-DIA cell using alumina pistons. AB - The deformation-DIA apparatus (D-DIA) coupled with synchrotron X-rays allows investigating materials elastic and plastic properties at high pressure. Most D DIA deformation cells use alumina pistons that can also be used for measurement of the differential stress in the compression column by in situ X-ray diffraction. Here, we quantify the axial temperature (T) gradient in the D-DIA deformation cell and better constrain stress measurements in its compression column by studying an alumina specimen compressed and deformed at pressure P in the range 3.9-5.5 GPa and nominal temperature To = 1673 K. The axial T gradient, obtained from alumina equation of state, is ~155 K/mm at the centre of the cell and does not vary significantly during deformation to 20% specimen strain. This T gradient, if not taken into account when measuring the experimental pressure in the alumina pistons, leads to significantly overestimating pressure. Unlike pressure, stress measurements in alumina are weakly sensitive to temperature. During deformation, the "true" differential stress in the compression column is evaluated at 596 +/- 20 MPa using an elastoplastic self-consistent model, while raw uncertainties on experimental differential stresses reach 84 MPa. A comparison between the simulated and experimental data allows to conclude that, although dislocation glide in the basal plane is the primary slip system at run condition, with an estimated critical resolved shear stress (CRSS) of 120 MPa, prism plane slips and pyramidal plane slips also contribute significantly to the aggregate homogenous deformation and texture development, with CRSS on the order of 280 MPa. PMID- 23635210 TI - An improved technique of expanding metal ring experiment under high explosive loading. AB - An experimental technique for metal expanding ring subjected to high explosive loading is conducted to significantly improve the loading stability compared with the traditional setup of two-end detonator initiation. Aspects of the circuit design, experimental arrangement, and initiation principle are illustrated in great detail. In terms of this experimental platform, we examine the velocity response of an individual ring, which demonstrates the experimental reproducibility. Moreover, fragmentation of multiple rings stacked on a metal driver is discussed. PMID- 23635209 TI - Analysis of rich inelastic electron tunneling spectra: case study of terthiophene on Au(111). AB - Even moderately small molecules like 2,2':5',2"-terthiophene exhibit quite rich vibrational spectra. Detection and assignment of vibronic transitions of such a single adsorbed molecule in inelastic electron tunneling spectroscopy (IETS) using scanning tunneling microscopy are notoriously hampered by noise and the low efficiency of inelastic channels of typically well below 1%. We demonstrate by a thorough statistical analysis that detection of almost all predicted transitions can be determined experimentally within the energy range 0-120 meV with an estimated detection limit for the efficiency of inelastic channels of ~0.15%. The maximum accuracy of our transition energies is 2 meV and thus smaller than the thermal broadening at 5 K. On short time scales up to some hours, that accuracy appears to be limited by tunneling current noise. The present analysis confirms earlier results which showed that IETS obeys propensity rules rather than selection rules as observed for optical transitions. Furthermore, the previous indications that anharmonic components in the interaction potentials are important for calculating properties of molecular vibrations were corroborated. PMID- 23635211 TI - Validation of velocity map imaging conditions over larger areas. AB - We have established through simulations and experiments the area over which Velocity Map Imaging (VMI) conditions prevail. We designed a VMI setup in which we can vary the ionization position perpendicular to the center axis of the time of-flight spectrometer. We show that weak extraction conditions are far superior over standard three-plate setups if the aim is to increase the ionization volume without distorting VMI conditions. This is important for a number of crossed molecular beam experiments that already utilize weak extraction conditions, but to a greater extent for surface studies where fragments are desorbed or scattered off a surface in all directions. Our results on the dissociation of NO2 at 226 nm show that ionization of the fragments can occur up to +/-5.5 mm away from the center axis of the time-of-flight spectrometer without affecting resolution or arrival position. PMID- 23635212 TI - A high-speed magnetic tweezer beyond 10,000 frames per second. AB - The magnetic tweezer is a single-molecule instrument that can apply a constant force to a biomolecule over a range of extensions, and is therefore an ideal tool to study biomolecules and their interactions. However, the video-based tracking inherent to most magnetic single-molecule instruments has traditionally limited the instrumental resolution to a few nanometers, above the length scale of single DNA base-pairs. Here we have introduced superluminescent diode illumination and high-speed camera detection to the magnetic tweezer, with graphics processing unit-accelerated particle tracking for high-speed analysis of video files. We have demonstrated the ability of the high-speed magnetic tweezer to resolve particle position to within 1 A at 100 Hz, and to measure the extension of a 1566 bp DNA with 1 nm precision at 100 Hz in the presence of thermal noise. PMID- 23635213 TI - A new approach to kinetics study of the anhydrite crystallization at 373 K using a diamond anvil cell with Raman spectroscopy. AB - A new approach to the kinetics study of anhydrite (CaSO4) crystallization has been performed in situ using a hydrothermal diamond anvil cell with Raman spectroscopy in the pressure range 896-1322 MPa and a constant temperature of 373 K. Transformed volume fraction X(t) was determined from Raman peak intensity of the sulfate ion in aqueous solution. The transformation-time plots display a sigmoidal shape with time, which indicates that the reaction rate is different at each stage of anhydrite crystallization. At 373 K, the rate constant k increases from 1.14 * 10(-4) s(-1) to 1.86 * 10(-3) s(-1), demonstrating a positive effect of pressure on the overall rate at isothermal condition. We first achieved the molar volume change (DeltaVm) equal to -1.82 * 10(-5) m(3)/mol in the course of anhydrite crystallization through Avrami kinetic theory, showing a process of reduction in volume at high pressure and high temperature. According to the exponent n derived from our experiments, a grain-boundary nucleation and diffusion-controlled growth kinetically dominates the crystallization of anhydrite. PMID- 23635214 TI - A waveguide-coupled thermally isolated radiometric source. AB - The design and validation of a dual polarization source for waveguide-coupled millimeter and sub-millimeter wave cryogenic sensors is presented. The thermal source is a waveguide mounted absorbing conical dielectric taper. The absorber is thermally isolated with a kinematic suspension that allows the guide to be heat sunk to the lowest bath temperature of the cryogenic system. This approach enables the thermal emission from the metallic waveguide walls to be subdominant to that from the source. The use of low thermal conductivity Kevlar threads for the kinematic mount effectively decouples the absorber from the sensor cold stage. Hence, the absorber can be heated to significantly higher temperatures than the sensor with negligible conductive loading. The kinematic suspension provides high mechanical repeatability and reliability with thermal cycling. A 33 50 GHz blackbody source demonstrates an emissivity of 0.999 over the full waveguide band where the dominant deviation from unity arises from the waveguide ohmic loss. The observed thermal time constant of the source is 40 s when the absorber temperature is 15 K. The specific heat of the lossy dielectric, MF-117, is well approximated by C(v)(T) = 0.12 T (2.06) mJ g(-1) K(-1) between 3.5 K and 15 K. PMID- 23635215 TI - Precise measurement of a magnetic field generated by the electromagnetic flux compression technique. AB - The precision of the values of a magnetic field generated by electromagnetic flux compression was investigated in ultra-high magnetic fields of up to 700 T. In an attempt to calibrate the magnetic field measured by pickup coils, precise Faraday rotation (FR) measurements were conducted on optical (quartz and crown) glasses. A discernible "turn-around" phenomenon was observed in the FR signal as well as the pickup coils before the end of a liner implosion. We found that the magnetic field measured by pickup coils should be corrected by taking into account the high-frequency response of the signal transmission line. Near the peak magnetic field, however, the pickup coils failed to provide reliable values, leaving the FR measurement as the only method to precisely measure extremely high magnetic fields. PMID- 23635216 TI - Apparatus for measuring the Seebeck coefficients of highly resistive organic semiconducting materials. AB - A Seebeck coefficient measurement apparatus for high resistance organic semiconductor materials has been designed and built. It can measure materials with resistance over 7 * 10(12) Omega. This is the highest material resistance value ever reported for Seebeck coefficient measurement. A cyclic temperature gradient generation technique and a corresponding algorithm are proposed to eliminate the negative effects of the long term drift of Seebeck voltage. Sources of errors in these measurements are discussed. PMID- 23635217 TI - A recursive least squares-based demodulator for electrical tomography. AB - In this paper, a recursive least squares (RLS)-based demodulator is proposed for Electrical Tomography (ET) that employs sinusoidal excitation. The new demodulator can output preliminary demodulation results on amplitude and phase of a sinusoidal signal by processing the first two sampling data, and the demodulation precision and signal-to-noise ratio can be further improved by involving more sampling data in a recursive way. Thus trade-off between the speed and precision in demodulation of electrical parameters can be flexibly made according to specific requirement of an ET system. The RLS-based demodulator is suitable to be implemented in a field programmable gate array (FPGA). Numerical simulation was carried out to prove its feasibility and optimize the relevant parameters for hardware implementation, e.g., the precision of the fixed-point parameters, sampling rate, and resolution of the analog to digital convertor. A FPGA-based capacitance measurement circuit for electrical capacitance tomography was constructed to implement and validate the RLS-based demodulator. Both simulation and experimental results demonstrate that the proposed demodulator is valid and capable of making trade-off between demodulation speed and precision and brings more flexibility to the hardware design of ET systems. PMID- 23635218 TI - Design and implementation of a 150 GHz single-channel millimeter wave interferometer on Joint TEXT tokamak. AB - A simple, single-channel millimeter-wave interferometer system has been designed, fabricated, and installed on the J-TEXT tokamak. For the plasma density anticipated on J-TEXT, a solid-state source operating at 150 GHz has been chosen to minimize errors due to both vibration along the beam path and refraction in the plasma. The new aspect of the interferometer design is to use a subharmonic mixer for detection with a frequency doubled 150 GHz source. It employs a single source which is bias-tuned and modulated with a sawtooth wave form up to 100 kHz in order to generate the intermediate frequency. The 12.5 GHz voltage-controlled oscillator is multiplied to 75 GHz before a final doubler raises it to 150 GHz. A portion of the 75 GHZ power is used for the local oscillator (LO) and is directly connected to the LO input of the subharmonic mixer. The phase is evaluated by a digital phase comparator using a software-based algorithm. Detection noise limits the minimum resolvable phase change with the interferometer to +/-0.05 fringe, which corresponds to an averaged electron density change along the chord of +/ 1.1 * 10(17) m(-2). The maximum measurable electron density is expected to be ~9 * 10(19) m(-3). A comparison of preliminary results from the millimeter wave interferometer with that from the far-infrared hydrogen cyanide laser (wavelength of 337 MUm) interferometer shows good agreement during the pulse flat-top period. The millimeter wave interferometer system will be used as a part of the density feedback control system in the future. PMID- 23635219 TI - Printed circuit board metal powder filters for low electron temperatures. AB - We report the characterisation of printed circuit boards (PCB) metal powder filters and their influence on the effective electron temperature which is as low as 22 mK for a quantum dot in a silicon MOSFET structure in a dilution refrigerator. We investigate the attenuation behaviour (10 MHz-20 GHz) of filter made of four metal powders with a grain size below 50 MUm. The room-temperature attenuation of a stainless steel powder filter is more than 80 dB at frequencies above 1.5 GHz. In all metal powder filters, the attenuation increases with temperature. Compared to classical powder filters, the design presented here is much less laborious to fabricate and specifically the copper powder PCB-filters deliver an equal or even better performance than their classical counterparts. PMID- 23635220 TI - A radio frequency/high voltage pulse generator for the operation of a planar multipole ion trap/time-of-flight mass spectrometer. AB - We present a radio frequency (RF)/high voltage pulse generator designed to provide suitable waveforms for the operation of a planar multipole ion trap/time of-flight mass spectrometer. Our generator supplies a RF signal to two pairs of trapping electrodes, allowing ions to be stored in between them. Subsequently, the RF is rapidly switched off and high voltage extraction pulses are applied to the trap electrodes in order to obtain a time-of-flight spectrum of the stored ions. The quenching of the RF and the extraction pulses are synchronized to the RF phase, ensuring well-defined ejection conditions. PMID- 23635221 TI - Simultaneous measurement of thermal conductivity and thermal contact resistance of individual carbon fibers using Raman spectroscopy. AB - In this paper, a new method employing Raman spectroscopy to determine thermal conductivity (TC) and thermal contact resistance (TCR) of an individual fiber was developed. Laser absorption is accounted for, but there is no need to be determined in this method. The local temperatures along the fiber longitudinal direction were determined by Raman shift. Two independent equations related to TC and TCR were established through measuring the temperature variation induced by changing electrical heating power at the center of the sample and the local temperature rise induced by a focused laser heating from Raman spectroscopy at two different positions on the sample, respectively. By solving the two equations, TC and TCR can then be obtained. This method has been validated by measuring two suspended carbon fibers. PMID- 23635222 TI - Heat-conduction error of temperature sensors in a fluid flow with nonuniform and unsteady temperature distribution. AB - In temperature measurement of non-isothermal fluid flows by a contact-type temperature sensor, heat conduction along the sensor body can cause significant measurement error which is called "heat-conduction error." The conventional formula for estimating the heat-conduction error was derived under the condition that the fluid temperature to be measured is uniform. Thus, if we apply the conventional formula to a thermal field with temperature gradient, the heat conduction error will be underestimated. In the present study, we have newly introduced a universal physical model of a temperature-measurement system to estimate accurately the heat-conduction error even if a temperature gradient exists in non-isothermal fluid flows. Accordingly, we have been able to successfully derive a widely applicable estimation and/or evaluation formula of the heat-conduction error. Then, we have verified experimentally the effectiveness of the proposed formula using the two non-isothermal fields-a wake flow formed behind a heated cylinder and a candle flame-whose fluid-dynamical characteristics should be quite different. As a result, it is confirmed that the proposed formula can represent accurately the experimental behaviors of the heat conduction error which cannot be explained appropriately by the existing formula. In addition, we have analyzed theoretically the effects of the heat-conduction error on the fluctuating temperature measurement of a non-isothermal unsteady fluid flow to derive the frequency response of the temperature sensor to be used. The analysis result shows that the heat-conduction error in temperature fluctuation measurement appears only in a low-frequency range. Therefore, if the power-spectrum distribution of temperature fluctuations to be measured is sufficiently away from the low-frequency range, the heat-conduction error has virtually no effect on the temperature-fluctuation measurements even by the temperature sensor accompanying the heat-conduction error in the mean-temperature measurements. PMID- 23635223 TI - Magnetic sensing via ultrasonic excitation. AB - We present ultrasonic techniques for magnetic measurements. Acoustically modulated magnetization is investigated with sensitive rf detection by narrowband loop antennas. Magnetization on the surface of ferromagnetic metals is temporally modulated with the rf frequency of the irradiated ultrasonic waves, and the near field components emitted from the focal point of the ultrasonic beam are detected. Based on the principle of the acoustically stimulated electromagnetic (ASEM) response, magnetic sensing and tomography are demonstrated by ultrasonic scanning. We show that ASEM imaging combines good acoustic resolution with magnetic contrast. The sensitivity of this method is estimated to be about 6 G/Hz(1/2) in our current setup. PMID- 23635224 TI - Formation of nanostructure and nano-hardness characterization on the meso-scale workpiece by a novel laser indirect shock forming method. AB - The meso-scale workpiece with greatly enhanced mechanical properties is potential to be widely used in the electronics productions and micro-electro mechanical systems. In this study, it demonstrates that the meso-scale cup-shape workpiece with good geometry can be obtained by a novel laser indirect shock forming method. After the forming process, the mechanical properties and microstructures of the formed workpiece were characterized. By transmission electron microscope observation, it was found that a mixed refined microstructure consisting of nano scale twins embedded in nano-sized grains was produced at the center of the formed sample. Formation of these nanograins could be mainly attributed to two mechanisms: twin-twin intersections and twin/matrix lamellae fragmentation. By nanoindentation tests, it reveals that the hardness of the sample has increased greatly after laser shock forming and the hardness increases with the laser energy. The elevated hardness originates from a considerable number of nano-scale twins and nanograins, which possess a pretty high strength due to the significant effects of grain boundary strengthening and twin boundary strengthening. PMID- 23635225 TI - High-resolution fiber optic temperature sensors using nonlinear spectral curve fitting technique. AB - A generic new data processing method is developed to accurately calculate the absolute optical path difference of a low-finesse Fabry-Perot cavity from its broadband interference fringes. The method combines Fast Fourier Transformation with nonlinear curve fitting of the entire spectrum. Modular functions of LabVIEW are employed for fast implementation of the data processing algorithm. The advantages of this technique are demonstrated through high performance fiber optic temperature sensors consisting of an infrared superluminescent diode and an infrared spectrometer. A high resolution of 0.01 degrees C is achieved over a large dynamic range from room temperature to 800 degrees C, limited only by the silica fiber used for the sensor. PMID- 23635226 TI - Metal foil gap switch and its electrical properties. AB - In order to reduce the volume of exploding initiator system, a metal foil spark gap switch was designed and fabricated using magnetron sputter deposition and standard microelectronic technology. The switch constitutes of two main electrodes and a trigger electrode, and stylus profiler was employed to ascertain dimension of the switch. We discussed the discharge characterization of the metal foil spark gap switch under nitrogen atmosphere and at pressure of 0.5 bars, 0.75 bars, 1.0 bar, 1.25 bars, 1.5 bars, and 1.75 bars, respectively. The relationship between self-breakdown voltage of the switch and pressure times distance corresponds to linearity. The switch had short delay time and low time jitter when the operating voltage was between 70% and 90% of its self-breakdown voltage. Compared with a commercial stereo spark gap switch, when it was fired by a conventional capacitive discharge unit, the firing circuit had lower inductance and higher resistance. PMID- 23635227 TI - A diffracted-beam monochromator for long linear detectors in X-ray diffractometers with Bragg-Brentano parafocusing geometry. AB - A new diffracted-beam monochromator has been developed for Bragg-Brentano X-ray diffractometers equipped with a linear detector. The monochromator consists of a cone-shaped graphite highly oriented pyrolytic graphite crystal oriented out of the equatorial plane such that the parafocusing geometry is preserved over the whole opening angle of the linear detector. In our standard setup a maximum wavelength discrimination of 3% is achieved with an overall efficiency of 20% and a small decrease in angular resolution of only 0.02 degrees 2theta. In principle, an energy resolution as low as 1.5% can be achieved. PMID- 23635228 TI - Elevated temperature, nano-mechanical testing in situ in the scanning electron microscope. AB - A general nano-mechanical test platform capable of performing variable temperature and variable strain rate testing in situ in the scanning electron microscope is described. A variety of test geometries are possible in combination with focused ion beam machining or other fabrication techniques: indentation, micro-compression, cantilever bending, and scratch testing. The system is intrinsically displacement-controlled, which allows it to function directly as a micro-scale thermomechanical test frame. Stable, elevated temperature indentation/micro-compression requires the indenter tip and the sample to be in thermal equilibrium to prevent thermal displacement drift due to thermal expansion. This is achieved through independent heating and temperature monitoring of both the indenter tip and sample. Furthermore, the apex temperature of the indenter tip is calibrated, which allows it to act as a referenced surface temperature probe during contact. A full description of the system is provided, and the effects of indenter geometry and of radiation on imaging conditions are discussed. The stabilization time and temperature distribution throughout the system as a function of temperature is characterized. The advantages of temperature monitoring and thermal calibration of the indenter tip are illustrated, which include the possibility of local thermal conductivity measurement. Finally, validation results using nanoindentation on fused silica and micro-compression of [100] silicon micro-pillars as a function of temperature up to 500 degrees C are presented, and procedures and considerations taken for these measurements are discussed. A brittle to ductile transition from fracture to splitting then plastic deformation is directly observed in the SEM for silicon as a function of temperature. PMID- 23635229 TI - Novel in situ device for investigating the tensile and fatigue behaviors of bulk materials. AB - For investigating the static tensile and dynamic fatigue behaviors of bulk materials, a miniaturized device with separate modular tensile and fatigue actuators was developed. The fatigue actuator presented good compatibility with the tensile actuator and mainly consisted of a special flexure hinge and piezoelectric stack. In situ fatigue tests under scanning electron microscope or metallographic microscope could be carried out due to the miniaturized dimensions of the device. A displacement correction method of tensile actuator based on load sensor compliance was investigated, and the feasibility of the method was verified by the comparison tests with a commercial tensile instrument. The application of testing the storage and loss modulus as a function of frequency was explained, and the temperature rises of both the piezoelectric stack and specimen were obtained as a function of frequency. Output characteristics of the fatigue actuator were also investigated. Additionally, the discharge performance of piezoelectric stack based on various initial voltages and fatigue tests on C11000 copper was carried out. This paper shows a modularized example that combines a servo motor with a piezoelectric actuator attached to the specimen grip to realize the in situ fatigue tests. PMID- 23635230 TI - Automated high precision secondary pH measurements. AB - A new setup for high precision, automated secondary pH measurements together with a reference measurement procedure has been developed and tested in interlaboratory comparisons using buffers pH 4.005, pH 7.000, and pH 10.012 at 25 degrees C and 37 degrees C. Using primary buffers as standards, a standard uncertainty in pH better than 0.005 can be reached. The central measuring device is a one piece, thermostatted cell of PFA (perfluoroalkoxy) with a built-in Hamilton((r)) Single PoreTM Glass electrode. Due to its flow-through principle this device allows pH measurements with low consumption of measurement solutions. The very hydrophobic and smooth PFA as construction material facilitates complete emptying of the cell. Furthermore, the tempering unit affords very precise temperature control and hence contributes to the low target uncertainty of the produced secondary buffer solutions. Use of a symmetric measurement sequence and the two point calibration was sufficient to reach high precision and accuracy. PMID- 23635231 TI - A novel instrument for quantitative nanoanalytics involving complementary X-ray methodologies. AB - A novel ultra-high vacuum instrument for X-ray reflectometry and spectrometry related techniques for nanoanalytics by means of synchrotron radiation has been constructed and commissioned. This versatile instrument was developed by the Physikalisch-Technische Bundesanstalt, Germany's national metrology institute, and includes a 9-axis manipulator that allows for an independent alignment of the samples with respect to all degrees of freedom. In addition, a rotational and translational movement of several photodiodes as well as a translational movement of an aperture system in and out of the beam is provided. Thus, the new instrument enables various analytical techniques based on energy dispersive X-ray detectors such as reference-free X-ray fluorescence analysis (XRF), total reflection XRF, grazing-incidence XRF in addition to optional X-ray reflectometry measurements or polarization-dependent X-ray absorption fine structure analyses. With this instrument samples having a size of up to 100 mm * 100 mm can be analyzed with respect to their mass deposition, elemental or spatial composition, or the species in order to probe surface contamination, layer composition and thickness, the depth profile of matrix elements or implants, the species of nanolayers, nanoparticles or buried interfaces as well as the molecular orientation of bonds. Selected applications of this advanced ultra-high vacuum instrument demonstrate both its flexibility and capability. PMID- 23635232 TI - Ultrafast ultrasonic imaging coupled to rheometry: principle and illustration. AB - We describe a technique coupling standard rheology and ultrasonic imaging with promising applications to characterization of soft materials under shear. Plane wave imaging using an ultrafast scanner allows to follow the local dynamics of fluids sheared between two concentric cylinders with frame rates as high as 10 000 images per second, while simultaneously monitoring the shear rate, shear stress, and viscosity as a function of time. The capacities of this "rheo ultrasound" instrument are illustrated on two examples: (i) the classical case of the Taylor-Couette instability in a simple viscous fluid and (ii) the unstable shear-banded flow of a non-Newtonian wormlike micellar solution. PMID- 23635233 TI - Revision of laser-induced damage threshold evaluation from damage probability data. AB - In this study, the applicability of commonly used Damage Frequency Method (DFM) is addressed in the context of Laser-Induced Damage Threshold (LIDT) testing with pulsed lasers. A simplified computer model representing the statistical interaction between laser irradiation and randomly distributed damage precursors is applied for Monte Carlo experiments. The reproducibility of LIDT predicted from DFM is examined under both idealized and realistic laser irradiation conditions by performing numerical 1-on-1 tests. A widely accepted linear fitting resulted in systematic errors when estimating LIDT and its error bars. For the same purpose, a Bayesian approach was proposed. A novel concept of parametric regression based on varying kernel and maximum likelihood fitting technique is introduced and studied. Such approach exhibited clear advantages over conventional linear fitting and led to more reproducible LIDT evaluation. Furthermore, LIDT error bars are obtained as a natural outcome of parametric fitting which exhibit realistic values. The proposed technique has been validated on two conventionally polished fused silica samples (355 nm, 5.7 ns). PMID- 23635234 TI - Flow bioreactor design for quantitative measurements over endothelial cells using micro-particle image velocimetry. AB - Mechanotransduction in endothelial cells (ECs) is a highly complex process through which cells respond to changes in hemodynamic loading by generating biochemical signals involving gene and protein expression. To study the effects of mechanical loading on ECs in a controlled fashion, different in vitro devices have been designed to simulate or replicate various aspects of these physiological phenomena. This paper describes the design, use, and validation of a flow chamber which allows for spatially and temporally resolved micro-particle image velocimetry measurements of endothelial surface topography and stresses over living ECs immersed in pulsatile flow. This flow chamber also allows the study of co-cultures (i.e., ECs and smooth muscle cells) and the effect of different substrates (i.e., coverslip and/or polyethylene terepthalate (PET) membrane) on cellular response. In this report, the results of steady and pulsatile flow on fixed endothelial cells seeded on PET membrane and coverslip, respectively, are presented. Surface topography of ECs is computed from multiple two-dimensional flow measurements. The distributions of shear stress and wall pressure on each individual cell are also determined and the importance of both types of stress in cell remodeling is highlighted. PMID- 23635235 TI - Note: Submicrometer-precision sample holder for accurate re-positioning of samples in scanning force microscopy. AB - In this work we describe two simple and compact submicrometer-precision sample holders that are easily integrated into a Scanning Force Microscopy (SFM) system. The designs are based on a traditional kinematic mounting or on self-adjustment of the sample holder and the upper piece of the piezoelectric scanner. With these sample holders the sample position is automatically recovered to within about 100 nm. The setup allows ex situ manipulation of the sample and SFM imaging of the same region without the aid of an optical microscope, positioning marks, and tedious re-allocation. PMID- 23635236 TI - Note: A high Mach number arc-driven shock tube for turbulence studies. AB - A high Mach arc-driven shock tube has been built at the Center for Plasma Science and Technology of Florida A&M University to study shock waves. A larger apparatus with higher voltage was built to study more stable shock waves and subsequent plasmas. Initial measurements of the apparatus conclude that the desired Mach numbers can be reached using only two-thirds the maximum possible energy that the circuit can provide. PMID- 23635237 TI - Note: Measuring breakdown characteristics during the hot re-ignition of high intensity discharge lamps using high frequency alternating current voltage. AB - To investigate the cold and hot re-ignition properties of High Intensity Discharge (HID) lamps in more detail an automated setup was designed in such a way that HID lamps of various sizes and under different background pressures can be tested. The HID lamps are ignited with a ramped sinusoidal voltage signal with frequencies between 60 and 220 kHz and with amplitude up to 7.5 kV. Some initial results of voltage and current measurements on a commercially available HID lamp during hot and cold re-ignition are presented. PMID- 23635238 TI - Note: Generation of Raman laser beams based on a sideband injection-locking technique using a fiber electro-optical modulator. AB - Two phase-coherent Raman laser beams with a frequency offset of 6.835 GHz were generated by sideband injection-locking technique. A master diode laser was phase modulated at 6.835 GHz by a fiber electro-optic modulator. A slave diode was injection-locked to the -1 sideband of the phase-modulated beam, and another diode was locked to the master laser carrier. This method produced stable and spatially separated Raman lasers with a large frequency shift range (>180 MHz). The relative linewidth of these two beams was ~1 Hz, and the unwanted carrier mode was suppressed down to -24 dB. Stimulated Raman transitions and Ramsey fringes were driven by Raman lasers in a cold atomic beam. PMID- 23635239 TI - Note: Improved sensitivity of magnetic measurements under high pressure in miniature ceramic anvil cell for a commercial SQUID magnetometer. AB - Two modifications have been made to a miniature ceramic anvil high pressure cell (mCAC) designed for magnetic measurements at pressures up to 12.6 GPa in a commercial superconducting quantum interference (SQUID) magnetometer [N. Tateiwa et al., Rev. Sci. Instrum. 82, 053906 (2011); ibid. 83, 053906 (2012)]. Replacing the Cu-Be piston in the former mCAC with a composite piston composed of the Cu-Be and ceramic cylinders reduces the background magnetization significantly smaller at low temperatures, enabling more precise magnetic measurements at low temperatures. A second modification to the mCAC is the utilization of a ceramic anvil with a hollow in the center of the culet surface. High pressures up to 5 GPa were generated with the "cupped ceramic anvil" with the culet size of 1.0 mm. PMID- 23635240 TI - Note: A variable temperature cell for spectroscopy of thin films. AB - We report the design and construction of a cell that enables precisely controlled measurement of UV/Vis spectra of thin films on transparent substrates at temperatures up to 800 K. The dimensions of the setup are accommodated by a standard Varian Cary 5E spectrophotometer allowing for widespread use in standard laboratory settings. The cell also fits in a Bio-Rad IR-spectrometer. The cell is constructed with an outer water cooled heat shield of aluminum and an inner sample holder with heating element, thermo-resistor and windows, made from nickel coated copper. The cell can operate both in air, and with an inert gas filling. We illustrate the utility of the cell by characterization of three commercially available near infrared absorbers that are commonly used for laser welding of plastics and are known to possess high thermal stability. PMID- 23635241 TI - Note: Solid state photon counters with sub-picosecond timing stability. AB - We are reporting on a design, construction, and performance of photon counting detector packages based on solid state sensors. These photon counting devices have been optimized for extremely high stability of their detection delay. The detectors have been designed for applications in fundamental metrology and optical time transfer. The single photon avalanche diode structure manufactured on silicon using the K14 technology is used as a sensor. The active area of the sensor is circular with a diameter of 100 or 200 MUm. The sensor is operated in an active quenching and gating mode. The photon detection efficiency exceeds 40% in a wavelength range spanning from 500 to 800 nm. The timing resolution is better than 20 ps rms. Its detection delay is stable within +/-600 fs over several days of operation, in a sense of time deviation the detection delay stability of 150 fs has been achieved. The temperature change of the detection delay is as low as 280 fs/K. This timing performance is preserved even under extremely high background photon fluxes exceeding 100 Mc/s. The detectors have been qualified for operation in space missions. PMID- 23635242 TI - Note: Portable total reflection X-ray fluorescence spectrometer with small vacuum chamber. AB - To improve the detection limits of a portable total reflection X-ray fluorescence (TXRF) spectrometer using white X-rays (i.e., both characteristic X-rays and continuum X-rays) from a 5 W X-ray tube, the measurement was performed in vacuum. The TXRF spectrum measured in vacuum was compared with that measured in air. The spectral background was significantly reduced when the scattering of the incident X-rays from air was reduced using a vacuum pump, leading to improvement in the detection limit. A detection limit of 8 pg was achieved for Cr when measuring in vacuum. PMID- 23635246 TI - Point/Counterpoint. Submillimeter accuracy in radiosurgery is not possible. PMID- 23635247 TI - An adaptive planning strategy for station parameter optimized radiation therapy (SPORT): Segmentally boosted VMAT. AB - PURPOSE: Conventional volumetric modulated arc therapy (VMAT) discretizes the angular space into equally spaced control points during planning and then optimizes the apertures and weights of the control points. The aperture at an angle in between two control points is obtained through interpolation. This approach tacitly ignores the differential need for intensity modulation of different angles. As such, multiple arcs are often required, which may oversample some angle(s) and undersample others. The purpose of this work is to develop a segmentally boosted VMAT scheme to eliminate the need for multiple arcs in VMAT treatment with improved dose distribution and/or delivery efficiency. METHODS: The essence of the new treatment scheme is how to identify the need of individual angles for intensity modulation and to provide the necessary beam intensity modulation for those beam angles that need it. We introduce a "demand metric" at each control point to decide which station or control points need intensity modulation. To boost the modulation at selected stations, additional segments are added in the vicinity of the selected stations. The added segments are then optimized together with the original set of station or control points as a whole. The authors apply the segmentally boosted planning technique to four previously treated clinical cases: two head and neck (HN) cases, one prostate case, and one liver case. The proposed planning technique is compared with conventional one-arc and two-arc VMAT. RESULTS: The proposed segmentally boosted VMAT technique achieves better critical structure sparing than one-arc VMAT with similar or better target coverage in all four clinical cases. The segmentally boosted VMAT also outperforms two-arc VMAT for the two complicated HN cases, yet with ~30% reduction in the machine monitor units (MUs) relative to two-arc VMAT, which leads to less leakage/scatter dose to the patient and can potentially translate into faster dose delivery. For the less challenging prostate and liver cases, similar critical structure sparing as the two-arc VMAT plans was obtained using the segmentally boosted VMAT. The benefit for the two simpler cases is the reduction of MUs and improvement of treatment delivery efficiency. CONCLUSIONS: Segmentally boosted VMAT achieves better dose conformality and/or reduced MUs through effective consideration of the need of individual beam angles for intensity modulation. Elimination of the need for multiple arcs in rotational arc therapy while improving the dose distribution should lead to improved workflow and treatment efficacy, thus may have significant implication to radiation oncology practice. PMID- 23635249 TI - On the feasibility of optical-CT imaging in media of different refractive index. AB - PURPOSE: Achieving accurate optical-CT 3D dosimetry without the use of viscous refractive index (RI) matching fluids would greatly increase convenience. METHODS: Software has been developed to simulate optical-CT 3D dosimetry for a range of scanning configurations including parallel-beam, point, and converging light sources. For each configuration the efficacy of three refractive media was investigated: air, water, a fluid closely matched to PRESAGE((r)), and perfect matching (RI = 1.00, 1.33, 1.49, and 1.501 respectively). Reconstructions were performed using both filtered backprojection (FBP) and algebraic reconstruction technique (ART). The efficacy of the three configurations and the two algorithms was evaluated by calculating the usable radius (i.e., the outermost radius where data were accurate to within 2%), and gamma (Gamma) analysis. This definition recognizes that for optical-CT imaging, errors are greatest near the edge of the dosimeter, where refraction can be most pronounced. Simulations were performed on three types of dose distribution: uniform, volumetric modulated arc therapy (VMAT), and brachytherapy (Cs-137). RESULTS: For a uniformly irradiated dosimeter the usable radius achieved with filtered backprojection was 68% for water matching and 31% for dry-scanning in air. Algebraic reconstruction gave usable radii of 99% for both water and air (dry-scanning), indicating greater recovery of useful data for the uniform distribution. FBP and ART performed equally well for a VMAT dose distribution where less dose is delivered near the edge of the dosimeter. In this case, the usable radius was 86% and 53% for scanning in water and air, respectively. For brachytherapy, the usable radius was 99% and 98% for scanning in water and air, respectively using FBP, and a major decrease was seen with ART. Point source geometry provided 1%-2% larger usable radii than parallel geometry. Converging geometry recovered less usable dosimetry data (up to 10% reduced usable radii) than point and parallel geometries. A further disadvantage of converging geometry was an increased requirement on detector size by up to 18 degrees . CONCLUSIONS: For applications where dose information is not required in the periphery of the dosimeter, some dry and low-viscous matching configurations may be feasible. For all three dose distributions (uniform, VMAT, brachytherapy) the point source geometry produced slightly more favorable results (an extra 1% 2% usable radii) than parallel and converging. When dosimetry is required on the periphery, best results were obtained using close refractive matching and ART. A concern for water or dry-scanning is the increase in required detector size, introducing potential cost penalties for manufacturing. PMID- 23635250 TI - Feasibility study on inverse four-dimensional dose reconstruction using the continuous dose-image of EPID. AB - PURPOSE: When an intensity-modulated radiation beam is delivered to a moving target, the interplay effect between dynamic beam delivery and the target motion due to miss-synchronization can cause unpredictable dose delivery. The portal dose image in electronic portal imaging device (EPID) represents radiation attenuated and scattered through target media. Thus, it may possess information about delivered radiation to the target. Using a continuous scan (cine) mode of EPID, which provides temporal dose images related to target and beam movements, the authors' goal is to perform four-dimensional (4D) dose reconstruction. METHODS: To evaluate this hypothesis, first, the authors have derived and subsequently validated a fast method of dose reconstruction based on virtual beamlet calculations of dose responses using a test intensity-modulated beam. This method was necessary for processing a large number of EPID images pertinent for four-dimensional reconstruction. Second, cine mode acquisition after summation over all images was validated through comparison with integration mode acquisition on EPID (IAS3 and aS1000) for the test beam. This was to confirm the agreement of the cine mode with the integrated mode, specifically for the test beam, which is an accepted mode of image acquisition for dosimetry with EPID. Third, in-phantom film and exit EPID dosimetry was performed on a moving platform using the same beam. Heterogeneous as well as homogeneous phantoms were used. The cine images were temporally sorted at 10% interval. The authors have performed dose reconstruction to the in-phantom plane from the sorted cine images using the above validated method of dose reconstruction. The reconstructed dose from each cine image was summed to compose a total reconstructed dose from the test beam delivery, and was compared with film measurements. RESULTS: The new method of dose reconstruction was validated showing greater than 95.3% pass rates of the gamma test with the criteria of dose difference of 3% and distance to agreement of 3 mm. The dose comparison of the reconstructed dose with the measured dose for the two phantoms showed pass rates higher than 96.4% given the same criteria. CONCLUSIONS: Feasibility of 4D dose reconstruction was successfully demonstrated in this study. The 4D dose reconstruction demonstrated in this study can be a promising dose validation method for radiation delivery on moving organs. PMID- 23635251 TI - GammaPod-a new device dedicated for stereotactic radiotherapy of breast cancer. AB - PURPOSE: This paper introduces a new external beam radiotherapy device named GammaPod that is dedicated for stereotactic radiotherapy of breast cancer. METHODS: The design goal of the GammaPod as a dedicated system for treating breast cancer is the ability to deliver ablative doses with sharp gradients under stereotactic image guidance. Stereotactic localization of the breast is achieved by a vacuum-assisted breast immobilization cup with built-in stereotactic frame. Highly focused radiation is achieved at the isocenter due to the cross-firing from 36 radiation arcs generated by rotating 36 individual Cobalt-60 beams. The dedicated treatment planning system optimizes an optimal path of the focal spot using an optimization algorithm borrowed from computational geometry such that the target can be covered by 90%-95% of the prescription dose and the doses to surrounding tissues are minimized. The treatment plan is intended to be delivered with continuous motion of the treatment couch. In this paper the authors described in detail the gamma radiation unit, stereotactic localization of the breast, and the treatment planning system of the GammaPod system. RESULTS: A prototype GammaPod system was installed at University of Maryland Medical Center and has gone through a thorough functional, geometric, and dosimetric testing. The mechanical and functional performances of the system all meet the functional specifications. CONCLUSIONS: An image-guided breast stereotactic radiotherapy device, named GammaPod, has been developed to deliver highly focused and localized doses to a target in the breast under stereotactic image guidance. It is envisioned that the GammaPod technology has the potential to significantly shorten radiation treatments and even eliminate surgery by ablating the tumor and sterilizing the tumor bed simultaneously. PMID- 23635252 TI - A two-dimensional matrix correction for off-axis portal dose prediction errors. AB - PURPOSE: This study presents a follow-up to a modified calibration procedure for portal dosimetry published by Bailey et al. ["An effective correction algorithm for off-axis portal dosimetry errors," Med. Phys. 36, 4089-4094 (2009)]. A commercial portal dose prediction system exhibits disagreement of up to 15% (calibrated units) between measured and predicted images as off-axis distance increases. The previous modified calibration procedure accounts for these off axis effects in most regions of the detecting surface, but is limited by the simplistic assumption of radial symmetry. METHODS: We find that a two-dimensional (2D) matrix correction, applied to each calibrated image, accounts for off-axis prediction errors in all regions of the detecting surface, including those still problematic after the radial correction is performed. The correction matrix is calculated by quantitative comparison of predicted and measured images that span the entire detecting surface. The correction matrix was verified for dose linearity, and its effectiveness was verified on a number of test fields. The 2D correction was employed to retrospectively examine 22 off-axis, asymmetric electronic-compensation breast fields, five intensity-modulated brain fields (moderate-high modulation) manipulated for far off-axis delivery, and 29 intensity-modulated clinical fields of varying complexity in the central portion of the detecting surface. RESULTS: Employing the matrix correction to the off axis test fields and clinical fields, predicted vs measured portal dose agreement improves by up to 15%, producing up to 10% better agreement than the radial correction in some areas of the detecting surface. Gamma evaluation analyses (3 mm, 3% global, 10% dose threshold) of predicted vs measured portal dose images demonstrate pass rate improvement of up to 75% with the matrix correction, producing pass rates that are up to 30% higher than those resulting from the radial correction technique alone. As in the 1D correction case, the 2D algorithm leaves the portal dosimetry process virtually unchanged in the central portion of the detector, and thus these correction algorithms are not needed for centrally located fields of moderate size (at least, in the case of 6 MV beam energy). CONCLUSION: The 2D correction improves the portal dosimetry results for those fields for which the 1D correction proves insufficient, especially in the inplane, off-axis regions of the detector. This 2D correction neglects the relatively smaller discrepancies that may be caused by backscatter from nonuniform machine components downstream from the detecting layer. PMID- 23635248 TI - Nuclear imaging of the breast: translating achievements in instrumentation into clinical use. AB - Approaches to imaging the breast with nuclear medicine and/or molecular imaging methods have been under investigation since the late 1980s when a technique called scintimammography was first introduced. This review charts the progress of nuclear imaging of the breast over the last 20 years, covering the development of newer techniques such as breast specific gamma imaging, molecular breast imaging, and positron emission mammography. Key issues critical to the adoption of these technologies in the clinical environment are discussed, including the current status of clinical studies, the efforts at reducing the radiation dose from procedures associated with these technologies, and the relevant radiopharmaceuticals that are available or under development. The necessary steps required to move these technologies from bench to bedside are also discussed. PMID- 23635253 TI - Optimization of normalized prescription isodose selection for stereotactic body radiation therapy: conventional vs robotic linac. AB - PURPOSE: Although modern technology has allowed for target dose escalation by minimizing normal tissue dose, the dose delivered to a tumor and surrounding tissues still depends largely on the inherent characteristics of the radiation delivery platform. This work aims to determine the optimal prescription isodose line that minimizes normal tissue irradiation for stereotactic body radiation therapy (SBRT) for a conventional linear accelerator and a robotic delivery platform. METHODS: Spherical targets with diameters of 10, 20, and 30 mm were constructed in the lungs and liver of a computer based digital torso phantom which simulates respiratory and cardiac motion. Normal tissue contours included normal lung, normal liver, and a concentric 10 mm shell of normal tissue extending from the spherical target surface. For linac planning, noncoplanar, nonopposing three dimensional (3D) conformal beams were designed, and variable prescription isodose lines were achieved by varying the MLC block margin. For CyberKnife planning, variable prescription isodose lines were achieved by inverse planning. True 4D dose calculations were used for the moving target and surrounding tissue based on each of ten phases of a 4D CT dataset. Doses of 60 Gy in three fractions were prescribed to cover 95% of the target tumor. Commonly used conformality, dosimetric, and radiobiological indices for lung and liver SBRT were used to compare different plans and determine the optimally prescribed isodose line for each treatment platform. RESULTS: For linac plans, the average optimal prescription isodose line based on all indices evaluated occurred between 59% and 69% for lung tumors and between 67% and 77% for liver tumors depending on the tumor size. CyberKnife plans had average optimal prescription isodose lines occurring between 40% and 48% for lung tumors and between 41% and 42% depending on the tumor size. However, prescription isodose lines under 50% are not advised to prevent large heterogeneous dose distributions within the target. CONCLUSIONS: The choice of prescription isodose line was shown to have a significant impact on parameters commonly used as constraints for lung and liver SBRT treatment planning for both linac-based and CyberKnife delivery platforms. By methodically choosing the prescription isodose line, normal tissue toxicities from SBRT may be reduced. PMID- 23635254 TI - Subject-centered free-response ROC (FROC) analysis. AB - PURPOSE: To develop an approach of estimating subject-centered free-response receiver operating characteristic (FROC) curve for providing patient-centered inferences regarding detection-localization characteristics of a diagnostic system. METHODS: The authors examine properties of the conventional, target centered, FROC curve and demonstrate that in scenarios where the diagnostic performance correlates with the total number of targets on a subject, it may lead to inadequate inferences from the perspective of possible benefits to a patient. Following solutions to patient-centered approaches in other applications, the authors define a subject-centered FROC curve and develop its formulation as a covariate-adjusted FROC curve. The authors also conduct a numerical study illustrating the relative properties of the conventional and subject-centered approach and provide an example. RESULTS: A simple-to-implement approach for estimating the subject-centered FROC curve and its overall index can be formulated as a type of stratified FROC analysis. The authors demonstrate that when diagnostic performance is associated with the number of targets, the diagnostic system with apparently superior target-centered characteristics (conventional approach) can be actually inferior from the subject-centered perspective. The authors show that under some clinically reasonable conditions the magnitude of disagreement in results could be substantial. An example from an actual observer performance study illustrates the natural setting where the developed approach would be relevant and lead to conclusions that are contradictory to those obtained from conventional analysis. CONCLUSIONS: The authors developed a subject-centered FROC curve and its overall index provides tools for inferences that may be relevant from a perspective of potential benefits to a patient. PMID- 23635255 TI - A source model for modulated electron radiation therapy using dynamic jaw movements. AB - PURPOSE: The development of fast and accurate source models (SMs) might be of crucial importance for the future clinical implementation of modulated electron radiation therapy (MERT). In this study, a SM is presented for reconstructing phase-space information of modulated electron beams using a few-leaf electron collimator (FLEC) and the photon jaws. METHODS: During a FLEC-based delivery, two collimation devices (jaws and FLEC) modulate the electron beam characteristics dynamically. The SM separates the beam into a primary and a scattered component. The primary component is derived by a fast Monte Carlo (MC) transport calculation in air using the EGSnrc/BEAMnrc code. The scattered beam is modeled analytically. The accelerator was decomposed into its individual leaf components and the scattered beam was characterized at various levels of the accelerator. Scattered particles are assigned an energy and position by sampling pre-calculated probability distributions. The direction is estimated by geometrical arguments. Particles were assumed to emerge from tunable virtual sources on the side of each collimator leaf. A leaf-hit algorithm was developed to dynamically reject particles that are incident on any collimating leaf. Electron transport in air between the two collimation levels was calculated based on a MC-modified version of the Fermi-Eyges scattering theory. Correlations between direction and position were observed and taken into account at the final collimation level. RESULTS: To validate the model, reconstructed phase-space data were compared with the full accelerator MC phase-space data. The model accurately reproduced the beam characteristics and preserved important correlations. Depth and profile dose distributions in water were derived for square, rectangular, and off-axis field sizes and for a range of clinical energies. Discrepancies in the dose distributions and dose output were within 3% in all cases. CONCLUSIONS: Fast and accurate SMs open the possibility for fast treatment planning in MERT, based on an inverse optimization MC treatment planning scheme. PMID- 23635256 TI - Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions. AB - PURPOSE: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. METHODS: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. RESULTS: IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. CONCLUSIONS: In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled. PMID- 23635257 TI - Dosimetric comparison of patient setup strategies in stereotactic body radiation therapy for lung cancer. AB - PURPOSE: In this work, the authors retrospectively compared the accumulated dose over the treatment course for stereotactic body radiation therapy (SBRT) of lung cancer for three patient setup strategies. METHODS: Ten patients who underwent lung SBRT were selected for this study. At each fraction, patients were immobilized using a vacuum cushion and were CT scanned. Treatment plans were performed on the simulation CT. The planning target volume (PTV) was created by adding a 5-mm uniform margin to the internal target volume derived from the 4DCT. All plans were normalized such that 99% of the PTV received 60 Gy. The plan parameters were copied onto the daily CT images for dose recalculation under three setup scenarios: skin marker, bony structure, and soft tissue based alignments. The accumulated dose was calculated by summing the dose at each fraction along the trajectory of a voxel over the treatment course through deformable image registration of each CT with the planning CT. The accumulated doses were analyzed for the comparison of setup accuracy. RESULTS: The tumor volume receiving 60 Gy was 91.7 +/- 17.9%, 74.1 +/- 39.1%, and 99.6 +/- 1.3% for setup using skin marks, bony structures, and soft tissue, respectively. The isodose line covering 100% of the GTV was 55.5 +/- 7.1, 42.1 +/- 16.0, and 64.3 +/- 7.1 Gy, respectively. The corresponding average biologically effective dose of the tumor was 237.3 +/- 29.4, 207.4 +/- 61.2, and 258.3 +/- 17.7 Gy, respectively. The differences in lung biologically effective dose, mean dose, and V20 between the setup scenarios were insignificant. CONCLUSIONS: The authors' results suggest that skin marks and bony structure are insufficient for aligning patients in lung SBRT. Soft tissue based alignment is needed to match the prescribed dose delivered to the tumors. PMID- 23635258 TI - Dosimetric impact of Acuros XB deterministic radiation transport algorithm for heterogeneous dose calculation in lung cancer. AB - PURPOSE: The novel deterministic radiation transport algorithm, Acuros XB (AXB), has shown great potential for accurate heterogeneous dose calculation. However, the clinical impact between AXB and other currently used algorithms still needs to be elucidated for translation between these algorithms. The purpose of this study was to investigate the impact of AXB for heterogeneous dose calculation in lung cancer for intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT). METHODS: The thorax phantom from the Radiological Physics Center (RPC) was used for this study. IMRT and VMAT plans were created for the phantom in the Eclipse 11.0 treatment planning system. Each plan was delivered to the phantom three times using a Varian Clinac iX linear accelerator to ensure reproducibility. Thermoluminescent dosimeters (TLDs) and Gafchromic EBT2 film were placed inside the phantom to measure delivered doses. The measurements were compared with dose calculations from AXB 11.0.21 and the anisotropic analytical algorithm (AAA) 11.0.21. Two dose reporting modes of AXB, dose-to-medium in medium (Dm,m) and dose-to-water in medium (Dw,m), were studied. Point doses, dose profiles, and gamma analysis were used to quantify the agreement between measurements and calculations from both AXB and AAA. The computation times for AAA and AXB were also evaluated. RESULTS: For the RPC lung phantom, AAA and AXB dose predictions were found in good agreement to TLD and film measurements for both IMRT and VMAT plans. TLD dose predictions were within 0.4%-4.4% to AXB doses (both Dm,m and Dw,m); and within 2.5%-6.4% to AAA doses, respectively. For the film comparisons, the gamma indexes (+/- 3%/3 mm criteria) were 94%, 97%, and 98% for AAA, AXB_Dm,m, and AXB_Dw,m, respectively. The differences between AXB and AAA in dose-volume histogram mean doses were within 2% in the planning target volume, lung, heart, and within 5% in the spinal cord. However, differences up to 8% between AXB and AAA were found at lung/soft tissue interface regions for individual IMRT fields. AAA was found to be 5-6 times faster than AXB for IMRT, while AXB was 4-5 times faster than AAA for VMAT plan. CONCLUSIONS: AXB is satisfactorily accurate for the dose calculation in lung cancer for both IMRT and VMAT plans. The differences between AXB and AAA are generally small except in heterogeneous interface regions. AXB Dw,m and Dm,m calculations are similar inside the soft tissue and lung regions. AXB can benefit lung VMAT plans by both improving accuracy and reducing computation time. PMID- 23635260 TI - Feasibility of a simple method of hybrid collimation for megavoltage grid therapy. AB - PURPOSE: Megavoltage grid therapy is currently delivered with step-and-shoot multisegment techniques or using a high attenuation block with divergent holes. However, the commercial availability of grid blocks is limited, their construction is difficult, and step-and-shoot techniques require longer treatment times and are not practical with some multileaf collimators. This work studies the feasibility of a hybrid collimation system for grid therapy that does not require multiple segments and can be easily implemented with widely available technical means. METHODS: The authors have developed a system to generate a grid of beamlets by the simultaneous use of two perpendicular sets of equally spaced leaves that project stripe patterns in orthogonal directions. One of them is generated with the multileaf collimator integrated in the accelerator and the other with an in-house made collimator constructed with a low melting point alloy commonly available at radiation oncology departments. The characteristics of the grid fields for 6 and 18 MV have been studied with a shielded diode, an unshielded diode, and radiochromic film. RESULTS: The grid obtained with the hybrid collimation is similar to some of the grids used clinically with respect to the beamlet size (about 1 cm) and the percentage of open beam (1/4 of the total field). The grid fields are less penetrating than the open fields of the same energy. Depending on the depth and the direction of the profiles (diagonal or along the principal axes), the measured valley-to-peak dose ratios range from 5% to 16% for 6 MV and from 9% to 20% for 18 MV. All the detectors yield similar results in the measurement of profiles and percent depth dose, but the shielded diode seems to overestimate the output factors. CONCLUSIONS: The combination of two stripe pattern collimators in orthogonal directions is a feasible method to obtain two-dimensional arrays of beamlets and has potential usefulness as an efficient way to deliver grid therapy. The implementation of this method is technically simpler than the construction of a conventional grid block. PMID- 23635259 TI - Effectiveness of robust optimization in intensity-modulated proton therapy planning for head and neck cancers. AB - PURPOSE: Intensity-modulated proton therapy (IMPT) is highly sensitive to uncertainties in beam range and patient setup. Conventionally, these uncertainties are dealt using geometrically expanded planning target volume (PTV). In this paper, the authors evaluated a robust optimization method that deals with the uncertainties directly during the spot weight optimization to ensure clinical target volume (CTV) coverage without using PTV. The authors compared the two methods for a population of head and neck (H&N) cancer patients. METHODS: Two sets of IMPT plans were generated for 14 H&N cases, one being PTV based conventionally optimized and the other CTV-based robustly optimized. For the PTV-based conventionally optimized plans, the uncertainties are accounted for by expanding CTV to PTV via margins and delivering the prescribed dose to PTV. For the CTV-based robustly optimized plans, spot weight optimization was guided to reduce the discrepancy in doses under extreme setup and range uncertainties directly, while delivering the prescribed dose to CTV rather than PTV. For each of these plans, the authors calculated dose distributions under various uncertainty settings. The root-mean-square dose (RMSD) for each voxel was computed and the area under the RMSD-volume histogram curves (AUC) was used to relatively compare plan robustness. Data derived from the dose volume histogram in the worst-case and nominal doses were used to evaluate the plan optimality. Then the plan evaluation metrics were averaged over the 14 cases and were compared with two-sided paired t tests. RESULTS: CTV-based robust optimization led to more robust (i.e., smaller AUCs) plans for both targets and organs. Under the worst-case scenario and the nominal scenario, CTV-based robustly optimized plans showed better target coverage (i.e., greater D95%), improved dose homogeneity (i.e., smaller D5% - D95%), and lower or equivalent dose to organs at risk. CONCLUSIONS: CTV-based robust optimization provided significantly more robust dose distributions to targets and organs than PTV-based conventional optimization in H&N using IMPT. Eliminating the use of PTV and planning directly based on CTV provided better or equivalent normal tissue sparing. PMID- 23635261 TI - Fusion of planning CT and cystoscopy images for bladder tumor delineation: a feasibility study. AB - PURPOSE: Bladder tumor delineation and localization during treatment are challenging problems in radiotherapy for bladder cancer. The purpose of this study is to investigate improvement of tumor delineation by the fusion of cystoscopy images with the planning CT-scan using lipiodol markers injected around the visible tumor during cystoscopy. METHODS: A registration method was developed for the fusion of cystoscopy images with a planning CT-scan and was tested on a phantom and retrospectively on the imaging data of four bladder cancer patients. For the patients, small deposits of lipiodol were injected at the visible margin of the tumor or previous transurethral resection site during cystoscopy. These deposits were clearly visible on the planning CT-scan and served as markers for both tumor delineation and image guidance of the radiotherapy treatment. Here, the markers were used for the registration of cystoscopy images with the planning CT-scan. The registration procedure works as follows: First, coarse registrations were made to orient the cystoscopy image correctly, using the center of gravity of the markers, the center of the CT bladder, and one of N markers as fiducial points in a point matching procedure. Starting from these N orientations, full registrations are performed taking lens deformation into account. Since a cystoscopy image is 2D, each pixel corresponds to a line-of-sight. The distances between the CT markers and the lines-of-sight of the cystoscopy markers were minimized. The final cost function (the root mean square distance between corresponding CT markers and lines-of-sight) was used to quantify the quality of the registration. The registration with the lowest final cost was considered to represent the correct orientation. The CT-based tumor delineation was finally backprojected onto the cystoscopy image. RESULTS: The fusion of cystoscopy images with a planning CT-scan succeeded for the phantom and three out of four patients. The fiducial registration error (FRE) for the phantom image registration based on five markers was 1.1 mm, while the target registration error was 1.2-1.7 mm. The FREs for the patient images were 0.1-3.6 mm. The registration procedure failed for one patient, since it was not possible to indicate unambiguously the corresponding lipiodol marker locations in the cystoscopy image and the planning CT-scan. The difference between the CT and cystoscopy defined tumor outlines clearly exceeded the registration accuracy. CONCLUSIONS: Registration of cystoscopy images and planning CT-scan is feasible and allows for improvement of tumor delineation. However, the lipiodol injection protocol needs to be improved to facilitate identification of markers on both cystoscopy images and planning CT-scans. PMID- 23635262 TI - A novel dose-based positioning method for CT image-guided proton therapy. AB - PURPOSE: Proton dose distributions can potentially be altered by anatomical changes in the beam path despite perfect target alignment using traditional image guidance methods. In this simulation study, the authors explored the use of dosimetric factors instead of only anatomy to set up patients for proton therapy using in-room volumetric computed tomographic (CT) images. METHODS: To simulate patient anatomy in a free-breathing treatment condition, weekly time-averaged four-dimensional CT data near the end of treatment for 15 lung cancer patients were used in this study for a dose-based isocenter shift method to correct dosimetric deviations without replanning. The isocenter shift was obtained using the traditional anatomy-based image guidance method as the starting position. Subsequent isocenter shifts were established based on dosimetric criteria using a fast dose approximation method. For each isocenter shift, doses were calculated every 2 mm up to +/- 8 mm in each direction. The optimal dose alignment was obtained by imposing a target coverage constraint that at least 99% of the target would receive at least 95% of the prescribed dose and by minimizing the mean dose to the ipsilateral lung. RESULTS: The authors found that 7 of 15 plans did not meet the target coverage constraint when using only the anatomy-based alignment. After the authors applied dose-based alignment, all met the target coverage constraint. For all but one case in which the target dose was met using both anatomy-based and dose-based alignment, the latter method was able to improve normal tissue sparing. CONCLUSIONS: The authors demonstrated that a dose-based adjustment to the isocenter can improve target coverage and/or reduce dose to nearby normal tissue. PMID- 23635263 TI - Image-guided method for TLD-based in vivo rectal dose verification with endorectal balloon in proton therapy for prostate cancer. AB - PURPOSE: To present a practical image-guided method to position an endorectal balloon that improves in vivo thermoluminiscent dosimeter (TLD) measurements of rectal doses in proton therapy for prostate cancer. METHODS: TLDs were combined with endorectal balloons to measure dose at the anterior rectal wall during daily proton treatment delivery. Radiopaque metallic markers were employed as surrogates for balloon position reproducibility in rotation and translation. The markers were utilized to guide the balloon orientation during daily treatment employing orthogonal x-ray image-guided patient positioning. TLDs were placed at the 12 o'clock position on the anterior balloon surface at the midprostatic plane. Markers were placed at the 3 and 9 o'clock positions on the balloon to align it with respect to the planned orientation. The balloon rotation along its stem axis, referred to as roll, causes TLD displacement along the anterior posterior direction. The magnitude of TLD displacement is revealed by the separation distance between markers at opposite sides of the balloon on sagittal x-ray images. RESULTS: A total of 81 in vivo TLD measurements were performed on six patients. Eighty-three percent of all measurements (65 TLD readings) were within +5% and -10% of the planning dose with a mean of -2.1% and a standard deviation of 3.5%. Examination of marker positions with in-room x-ray images of measured doses between -10% and -20% of the planned dose revealed a strong correlation between balloon roll and TLD displacement posteriorly from the planned position. The magnitude of the roll was confirmed by separations of 10-20 mm between the markers which could be corrected by manually adjusting the balloon position and verified by a repeat x-ray image prior to proton delivery. This approach could properly correct the balloon roll, resulting in TLD positioning within 2 mm along the anterior-posterior direction. CONCLUSIONS: Our results show that image-guided TLD-based in vivo dosimetry for rectal dose verification can be perfomed reliably and reproducibly for proton therapy in prostate cancer. PMID- 23635264 TI - Estimation of optimal margin for intrafraction movements during frameless brain radiosurgery. AB - PURPOSE: To examine the dosimetric effect of intrafraction movements occurred during image-guided frameless brain radiosurgery and to derive the optimal margin recipe to compensate the movement. METHODS: The patients' movements during image guided radiosurgeries were measured using skull-tracking method incorporated in the CyberKnife system. The dosimetric changes with the movements were computed using the six different dynamic-arc treatment plans based on the dose-grid analysis method. The authors extensively searched the proper relationship between the dose variations and the intrafraction geometric errors. The optimal margin for intrafraction movement was estimated via statistical analysis of the dosimetric changes with 262 actual patients' data. RESULTS: The overall geometric effect of intrafraction movements was approximated as 1.0 r+0.2sigma, where r and sigma are the average and standard deviation of the movements, respectively. The authors computed the required margins to compensate the movements with various confidence levels and with various estimated times for completing the treatments. The computed optimal margins were calculated as 2.1, 3.2, and 4.2 mm at 90% confidence level when the authors assumed the estimated treatment times of 10, 20, and 30 min, respectively. CONCLUSIONS: The authors provide a quantitative relationship for dosimetric change with the intrafraction movement and derived appropriate margin recipes to ensure the prescribed dose delivery to targeted area for frameless brain radiosurgery. PMID- 23635265 TI - Determination of transit dose profile for a (192)Ir HDR source. AB - PURPOSE: Several studies have reported methodologies to calculate and correct the transit dose component of the moving radiation source for high dose rate (HDR) brachytherapy planning systems. However, most of these works employ the average source speed, which varies significantly with the measurement technique used, and does not represent a realistic speed profile, therefore, providing an inaccurate dose determination. In this work, the authors quantified the transit dose component of a HDR unit based on the measurement of the instantaneous source speed to produce more accurate dose values. METHODS: The Nucletron microSelectron HDR Ir-192 source was characterized considering the Task Group 43 (TG-43U1) specifications. The transit dose component was considered through the calculation of the dose distribution using a Monte Carlo particle transport code, MCNP5, for each source position and correcting it by the source speed. The instantaneous source speed measurements were performed in a previous work using two optical fibers connected to a photomultiplier and an oscilloscope. Calculated doses were validated by comparing relative dose profiles with those obtained experimentally using radiochromic films. RESULTS: TG-43U1 source parameters were calculated to validate the Monte Carlo simulations. These agreed with the literature, with differences below 1% for the majority of the points. Calculated dose profiles without transit dose were also validated by comparison with ONCENTRA((r)) Brachy v. 3.3 dose values, yielding differences within 1.5%. Dose profiles obtained with MCNP5 corrected using the instantaneous source speed profile showed differences near dwell positions of up to 800% in comparison to values corrected using the average source speed, but they are in good agreement with the experimental data, showing a maximum discrepancy of approximately 3% of the maximum dose. Near a dwell position the transit dose is about 22% of the dwell dose delivered by the source dwelling 1 s and reached 104.0 cGy per irradiation in a hypothetical clinical case studied in this work. CONCLUSIONS: The present work demonstrated that the transit dose correction based on average source speed fails to accurately correct the dose, indicating that the correct speed profile should be considered. The impact on total dose due to the transit dose correction near the dwell positions is significant and should be considered more carefully in treatments with high dose rate, several catheters, multiple dwell positions, small dwell times, and several fractions. PMID- 23635266 TI - First demonstration of intrafractional tumor-tracked irradiation using 2D phantom MR images on a prototype linac-MR. AB - PURPOSE: To demonstrate intrafractional MR tumor tracking using a prototype linac MR by delivering radiation to a moving target undergoing simulated tumor motions. METHODS: A prototype linac-MR at the Cross Cancer Institute was used for intrafractional MR imaging and simultaneous beam delivery. A Varian 52-leaf MK-II multileaf collimator (MLC) was used for beam collimation. The authors used an inhouse built MR compatible motion phantom to simulate tumor motions during tracking with two different motion patterns (sine and modified cosine). Gafchromic film was inserted in the phantom to measure radiation exposure, and this film measurement was converted to dose (cGy) for further analysis. The authors demonstrated intrafractional tracking in various scenarios: [Scenario 0 (S0)] no phantom motion + no beam margin, (S1) no phantom motion + maximum beam margin, (S2) phantom motion + no beam margin, (S3) S2 + MLC tracking, and (S4) S3 + motion prediction. S0 emulates a perfect tumor tracking scenario, and its result was used as a "gold-standard" to evaluate tracking accuracy from other scenarios. The authors compared (1) time difference in phantom and MLC motion curves in S3 and S4, and (2) dose profiles (50% beam width, 80%-20% penumbra width) from scenarios S1-S4 to S0. RESULTS: In S4, no observable time difference exists between the phantom and MLC motion curves, indicating that MLC tracks phantom motion accurately. Comparing S4 to S0, 50% beam width reveals minimal differences of < 0.5 mm, while the increase in 80%-20% penumbra width is limited to 0.4 and 1.7 mm in the sine and modified cosine patterns, respectively. CONCLUSIONS: The authors report the first demonstration of intrafractional tumor tracking using 2D MR images. During 2 min of tracking, the authors delivered highly conformal dose to a moving target that simulates tumor motions. Compared to static target irradiation, the 50% beam width remains essentially the same (within 0.5 mm), with an increase in 80%-20% penumbra width of less than 1.7 mm in moving target irradiation. These results illustrate potential dosimetric advantages of intrafractional MR tumor tracking in treating mobile tumors as shown for the phantom case. PMID- 23635267 TI - Toward correcting drift in target position during radiotherapy via computer controlled couch adjustments on a programmable Linac. AB - PURPOSE: Real-time tracking of respiratory target motion during radiation therapy is technically challenging, owing to rapid and possibly irregular breathing variations. The authors report on a method to predict and correct respiration averaged drift in target position by means of couch adjustments on an accelerator equipped with such capability. METHODS: Dose delivery is broken up into a sequence of 10 s field segments, each followed by a couch adjustment based on analysis of breathing motion from an external monitor as a surrogate of internal target motion. Signal averaging over three respiratory cycles yields a baseline representing target drift. A Kalman filter predicts the baseline position 5 s in advance, for determination of the couch correction. The method's feasibility is tested with a motion phantom programmed according to previously recorded patient signals. Computed couch corrections are preprogrammed into a research mode of an accelerator capable of computer-controlled couch translations synchronized with the motion phantom. The method's performance is evaluated with five cases recorded during hypofractionated treatment and five from respiration-correlated CT simulation, using a root-mean-squared deviation (RMSD) of the baseline from the treatment planned position. RESULTS: RMSD is reduced in all 10 cases, from a mean of 4.9 mm (range 2.7-9.4 mm) before correction to 1.7 mm (range 0.7-2.3 mm) after correction. Treatment time is increased ~5% relative to that for no corrections. CONCLUSIONS: This work illustrates the potential for reduction in baseline respiratory drift with periodic adjustments in couch position during treatment. Future treatment machine capabilities will enable the use of "on-the fly" couch adjustments during treatment. PMID- 23635268 TI - Rapid emission angle selection for rotating-shield brachytherapy. AB - PURPOSE: The authors present a rapid emission angle selection (REAS) method that enables the efficient selection of the azimuthal shield angle for rotating shield brachytherapy (RSBT). The REAS method produces a Pareto curve from which a potential RSBT user can select a treatment plan that balances the tradeoff between delivery time and tumor dose conformity. METHODS: Two cervical cancer patients were considered as test cases for the REAS method. The RSBT source considered was a Xoft Axxent(TM) electronic brachytherapy source, partially shielded with 0.5 mm of tungsten, which traveled inside a tandem intrauterine applicator. Three anchor RSBT plans were generated for each case using dose volume optimization, with azimuthal shield emission angles of 90 degrees , 180 degrees , and 270 degrees . The REAS method converts the anchor plans to treatment plans for all possible emission angles by combining neighboring beamlets to form beamlets for larger emission angles. Treatment plans based on exhaustive dose-volume optimization (ERVO) and exhaustive surface optimization (ERSO) were also generated for both cases. Uniform dwell-time scaling was applied to all plans such that that high-risk clinical target volume D90 was maximized without violating the D2cc tolerances of the rectum, bladder, and sigmoid colon. RESULTS: By choosing three azimuthal emission angles out of 32 potential angles, the REAS method performs about 10 times faster than the ERVO method. By setting D90 to 85-100 Gy10, the delivery times used by REAS generated plans are 21.0% and 19.5% less than exhaustive surface optimized plans used by the two clinical cases. By setting the delivery time budget to 5-25 and 10-30 min/fx, respectively, for two the cases, the D90 contributions for REAS are improved by 5.8% and 5.1% compared to the ERSO plans. The ranges used in this comparison were selected in order to keep both D90 and the delivery time within acceptable limits. CONCLUSIONS: The REAS method enables efficient RSBT treatment planning and delivery and provides treatment plans with comparable quality to those generated by exhaustive replanning with dose-volume optimization. PMID- 23635269 TI - Lumen segmentation and stenosis quantification of atherosclerotic carotid arteries in CTA utilizing a centerline intensity prior. AB - PURPOSE: The degree of stenosis is an important biomarker in assessing the severity of cardiovascular disease. The purpose of our work is to develop and evaluate a semiautomatic method for carotid lumen segmentation and subsequent carotid artery stenosis quantification in CTA images. METHODS: The authors present a semiautomatic stenosis detection and quantification method following lumen segmentation. The lumen of the carotid arteries is segmented in three steps. First, centerlines of the internal and external carotid arteries are extracted with an iterative minimum cost path approach in which the costs are based on a measure of medialness and intensity similarity to lumen. Second, the lumen boundary is delineated using a level set procedure which is steered by gradient information, regional intensity information, and spatial information. Special effort is made in adding terms based on local centerline intensity prior so as to exclude all possible plaque tissues from the segmentation. Third, side branches in the segmented lumen are removed by applying a shape constraint to the envelope of the maximum inscribed spheres of the segmentation. From the segmented lumen, the authors detect and quantify the cross-sectional area-based and cross sectional diameter-based stenosis degrees according to the North American Symptomatic Carotid En-darterectomy Trial criterion. RESULTS: The method is trained and tested on a publicly available database from the cls2009 challenge. For the segmentation, the authors obtain a Dice similarity coefficient of 90.2% and a mean absolute surface distance of 0.34 mm. For the stenosis quantification, the authors obtain an average error of 15.7% for cross-sectional diameter-based stenosis and 19.2% for cross-sectional area-based stenosis quantification. CONCLUSIONS: With these results, the method ranks second in terms of carotid lumen segmentation accuracy, and first in terms of carotid artery stenosis quantification. PMID- 23635270 TI - Upgrade and benchmarking of a 4D treatment planning system for scanned ion beam therapy. AB - PURPOSE: Upgrade and benchmarking of a research 4D treatment planning system (4DTPS) suitable for realistic patient treatment planning and treatment simulations taking into account specific requirements for scanned ion beam therapy, i.e., modeling of dose heterogeneities due to interplay effects and range changes caused by patient motion and dynamic beam delivery. METHODS: The 4DTPS integrates data interfaces to 4D computed tomography (4DCT), deformable image registration and clinically used motion monitoring devices. The authors implemented a novel data model for 4D image segmentation using Boolean mask volume datasets and developed an algorithm propagating a manually contoured reference contour dataset to all 4DCT phases. They further included detailed treatment simulation and dose reconstruction functionality, based on the irregular patient motion and the temporal structure of the beam delivery. The treatment simulation functionality was validated against experimental data from irradiation of moving radiographic films in air, 3D moving ionization chambers in a water phantom, and moving cells in a biological phantom with a scanned carbon ion beam. The performance of the program was compared to results obtained with predecessor programs. RESULTS: The measured optical density distributions of the radiographic films were reproduced by the simulations to (-2 +/- 12)%. Compared to earlier versions of the 4DTPS, the mean agreement improved by 2%, standard deviations were reduced by 7%. The simulated dose to the moving ionization chambers in water showed an agreement with the measured dose of (-1 +/- 4)% for the typical beam configuration. The mean deviation of the simulated from the measured biologically effective dose determined via cell survival was (617 +/- 538) mGy relative biological effectiveness corresponding to (10 +/- 9)%. CONCLUSIONS: The authors developed a research 4DTPS suitable for realistic treatment planning on patient data and capable of simulating dose delivery to a moving patient geometry for scanned ion beams. The accuracy and reliability of treatment simulations improved considerably with respect to earlier versions of the 4DTPS. PMID- 23635271 TI - A method of measuring gold nanoparticle concentrations by X-ray fluorescence for biomedical applications. AB - PURPOSE: This paper reports a technique that enables the quantitative determination of the concentration of gold nanoparticles (GNPs) through the accurate detection of their fluorescence radiation in the diagnostic x-ray spectrum. METHODS: Experimentally, x-ray fluorescence spectra of 1.9 and 15 nm GNP solutions are measured using an x-ray spectrometer, individually and within chicken breast tissue samples. An optimal combination of excitation and emission filters is determined to segregate the fluorescence spectra at 66.99 and 68.80 keV from the background scattering. A roadmap method is developed that subtracts the scattered radiation (acquired before the insertion of GNP solutions) from the signal radiation acquired after the GNP solutions are inserted. RESULTS: The methods effectively minimize the background scattering in the spectrum measurements, showing linear relationships between GNP solutions from 0.1% to 10% weight concentration and from 0.1% to 1.0% weight concentration inside a chicken breast tissue sample. CONCLUSIONS: The investigation demonstrated the potential of imaging gold nanoparticles quantitatively in vivo for in-tissue studies, but future studies will be needed to investigate the ability to apply this method to clinical applications. PMID- 23635272 TI - Toward in vivo lung's tissue incompressibility characterization for tumor motion modeling in radiation therapy. AB - PURPOSE: A novel technique is proposed to characterize lung tissue incompressibility variation during respiration. Estimating lung tissue incompressibility parameter variations resulting from air content variation throughout respiration is critical for computer assisted tumor motion tracking. Continuous tumor motion is a major challenge in lung cancer radiotherapy, especially with external beam radiotherapy. If not accounted for, this motion may lead to areas of radiation overdosage for normal tissue. Given the unavailability of imaging modality that can be used effectively for real-time lung tumor tracking, computer assisted approach based on tissue deformation estimation can be a good alternative. This approach involves lung biomechanical model where its fidelity depends on input tissue properties. This investigation shows that considering variable tissue incompressibility parameter is very important for predicting tumor motion accurately, hence improving the lung radiotherapy outcome. METHODS: First, an in silico lung phantom study was conducted to demonstrate the importance of employing variable Poisson's ratio for tumor motion predication. After it was established that modeling this variability is critical for accurate tumor motion prediction, an optimization based technique was developed to estimate lung tissue Poisson's ratio as a function of respiration cycle time. In this technique, the Poisson's ratio and lung pressure value were varied systematically until optimal values were obtained, leading to maximum similarity between acquired and simulated 4D CT lung images. This technique was applied in an ex vivo porcine lung study where simulated images were constructed using the end exhale CT image and deformation fields obtained from the lung's FE modeling of each respiration time increment. To model the tissue, linear elastic and Marlow hyperelastic material models in conjunction with variable Poisson's ratio were used. RESULTS: The phantom study showed that the tumor motion trajectory and its final locations obtained from simulations with and without considering tissue incompressibility variation were very different. For example, tumor displacements in the z direction were -11.23 and -38.10 mm obtained with the Marlow hyperelastic material model in conjunction with constant and variable Poisson's ratio, respectively. By comparing the acquired 4D-CT image sequence of the porcine lung with their image sequence counterparts obtained from the hyperelastic model with constant and variable Poisson's ratio, it was shown that using variable tissue incompressibility reduced errors significantly in tumor motion prediction. CONCLUSIONS: This investigation demonstrates the importance of incompressibility variation estimation and utilization for accurate tumor tracking in computer assisted lung external beam radiation therapy. An optimization framework was developed to estimate a Poisson's ratio function in terms of respiration cycle time using experimental image data of the lung. Utilizing this function along with respiratory system FE modeling may lead to more effective tumor targeting, hence potentially improving the outcome of lung external beam radiation therapy techniques. This is particularly true for stereotactic body radiation therapy where only one or a few fraction treatments are applied, precluding the possibility of averaging out dosimetric deviations introduced by the respiratory motion. PMID- 23635275 TI - Photon counting spectral breast CT: effect of adaptive filtration on CT numbers, noise, and contrast to noise ratio. AB - PURPOSE: Photon counting spectral (PCS) computed tomography (CT) shows promise for breast imaging. An issue with current photon-counting detectors is low count rate capabilities, artifacts resulting from nonuniform count rate across the field of view, and suboptimal spectral information. These issues are addressed in part by using tissue-equivalent adaptive filtration of the x-ray beam. The purpose of the study was to investigate the effect of adaptive filtration on different aspects of PCS breast CT. METHODS: The theoretical formulation for the filter shape was derived for different filter materials and evaluated by simulation and an experimental prototype of the filter was fabricated from a tissue-like material (acrylic). The PCS CT images of a glandular breast phantom with adipose and iodine contrast elements were simulated at 40, 60, 90, and 120 kVp tube voltages, with and without adaptive filter. The CT numbers, CT noise, and contrast-to-noise ratio (CNR) were compared for spectral CT images acquired with and without adaptive filters. Similar comparison was made for material decomposed PCS CT images. RESULTS: The adaptive filter improved the uniformity of CT numbers, CT noise, and CNR in both ordinary and material decomposed PCS CT images. At the same tube output the average CT noise with adaptive filter, although uniform, was higher than the average noise without adaptive filter due to x-ray absorption by the filter. Increasing tube output, so that average skin exposure with the adaptive filter was same as without filter, made the noise with adaptive filter comparable to or lower than that without adaptive filter. Similar effects were observed when energy weighting was applied, and when material decompositions were performed using energy selective CT data. CONCLUSIONS: An adaptive filter decreases count rate requirements to the photon counting detectors which enables PCS breast CT based on commercially available detector technologies. Adaptive filter also improves image quality in PCS breast CT by decreasing beam hardening artifacts and by eliminating spatial nonuniformities of CT numbers, noise, and CNR. PMID- 23635273 TI - The feasibility of a regional CTDIvol to estimate organ dose from tube current modulated CT exams. AB - PURPOSE: In AAPM Task Group 204, the size-specific dose estimate (SSDE) was developed by providing size adjustment factors which are applied to the Computed Tomography (CT) standardized dose metric, CTDI(vol). However, that work focused on fixed tube current scans and did not specifically address tube current modulation (TCM) scans, which are currently the majority of clinical scans performed. The purpose of this study was to extend the SSDE concept to account for TCM by investigating the feasibility of using anatomic and organ specific regions of scanner output to improve accuracy of dose estimates. METHODS: Thirty nine adult abdomen/pelvis and 32 chest scans from clinically indicated CT exams acquired on a multidetector CT using TCM were obtained with Institutional Review Board approval for generating voxelized models. Along with image data, raw projection data were obtained to extract TCM functions for use in Monte Carlo simulations. Patient size was calculated using the effective diameter described in TG 204. In addition, the scanner-reported CTDI(vo)l (CTDI(vol),global) was obtained for each patient, which is based on the average tube current across the entire scan. For the abdomen/pelvis scans, liver, spleen, and kidneys were manually segmented from the patient datasets; for the chest scans, lungs and for female models only, glandular breast tissue were segmented. For each patient organ doses were estimated using Monte Carlo Methods. To investigate the utility of regional measures of scanner output, regional and organ anatomic boundaries were identified from image data and used to calculate regional and organ-specific average tube current values. From these regional and organ-specific averages, CTDI(vol) values, referred to as regional and organ-specific CTDI(vol), were calculated for each patient. Using an approach similar to TG 204, all CTDI(vol) values were used to normalize simulated organ doses; and the ability of each normalized dose to correlate with patient size was investigated. RESULTS: For all five organs, the correlations with patient size increased when organ doses were normalized by regional and organ-specific CTDI(vol) values. For example, when estimating dose to the liver, CTDI(vol),global yielded a R(2) value of 0.26, which improved to 0.77 and 0.86, when using the regional and organ-specific CTDI(vol) for abdomen and liver, respectively. For breast dose, the global CTDI(vol) yielded a R(2) value of 0.08, which improved to 0.58 and 0.83, when using the regional and organ-specific CTDI(vol) for chest and breasts, respectively. The R(2) values also increased once the thoracic models were separated for the analysis into females and males, indicating differences between genders in this region not explained by a simple measure of effective diameter. CONCLUSIONS: This work demonstrated the utility of regional and organ-specific CTDI(vol) as normalization factors when using TCM. It was demonstrated that CTDI(vol),global is not an effective normalization factor in TCM exams where attenuation (and therefore tube current) varies considerably throughout the scan, such as abdomen/pelvis and even thorax. These exams can be more accurately assessed for dose using regional CTDI(vol) descriptors that account for local variations in scanner output present when TCM is employed. PMID- 23635274 TI - Evaluating noise reduction techniques while considering anatomical noise in dual energy contrast-enhanced mammography. AB - PURPOSE: The authors describe modifications to previously developed cascaded systems analysis to include the anatomical noise in evaluation of dual-energy noise reduction techniques. Previous models have ignored the anatomical noise in theoretical analysis of noise reduction techniques. The inclusion of anatomical noise leads to more accurate estimation of potential noise reduction improvements and optimization. METHODS: The model is applied to dual-energy contrast-enhanced mammography. The effect of linear noise reduction filters on the anatomical noise is taken into account using cascaded systems analysis. The noise model is included in the ideal observer detectability for performance evaluation of the noise reduction techniques. RESULTS: Dual-energy image noise with and without including the effect of anatomical noise in noise reduction technique analysis is reported. The theoretical model is compared with clinical images from a previous dual-energy contrast enhanced mammography clinical study and good agreement is observed. The results suggest that the inclusion of anatomical noise in the evaluation and comparison of noise reduction techniques is highly warranted for more accurate analysis. CONCLUSIONS: This work establishes a useful extension to dual-energy cascaded systems analysis for maximizing image quality using noise reduction techniques. The extension includes the effect of linear image filtering, such as that used for noise reduction, on anatomical noise. The results suggest that the inclusion of anatomical noise in the evaluation of noise reduction techniques can lead to more accurate optimization, noise, and performance estimations. PMID- 23635276 TI - ALBIRA: a small animal PET/SPECT/CT imaging system. AB - PURPOSE: The authors have developed a trimodal PET/SPECT/CT scanner for small animal imaging. The gamma ray subsystems are based on monolithic crystals coupled to multianode photomultiplier tubes (MA-PMTs), while computed tomography (CT) comprises a commercially available microfocus x-ray tube and a CsI scintillator 2D pixelated flat panel x-ray detector. In this study the authors will report on the design and performance evaluation of the multimodal system. METHODS: X-ray transmission measurements are performed based on cone-beam geometry. Individual projections were acquired by rotating the x-ray tube and the 2D flat panel detector, thus making possible a transaxial field of view (FOV) of roughly 80 mm in diameter and an axial FOV of 65 mm for the CT system. The single photon emission computed tomography (SPECT) component has a dual head detector geometry mounted on a rotating gantry. The distance between the SPECT module detectors can be varied in order to optimize specific user requirements, including variable FOV. The positron emission tomography (PET) system is made up of eight compact modules forming an octagon with an axial FOV of 40 mm and a transaxial FOV of 80 mm in diameter. The main CT image quality parameters (spatial resolution and uniformity) have been determined. In the case of the SPECT, the tomographic spatial resolution and system sensitivity have been evaluated with a (99m)Tc solution using single-pinhole and multi-pinhole collimators. PET and SPECT images were reconstructed using three-dimensional (3D) maximum likelihood and ordered subset expectation maximization (MLEM and OSEM) algorithms developed by the authors, whereas the CT images were obtained using a 3D based FBP algorithm. RESULTS: CT spatial resolution was 85 MUm while a uniformity of 2.7% was obtained for a water filled phantom at 45 kV. The SPECT spatial resolution was better than 0.8 mm measured with a Derenzo-like phantom for a FOV of 20 mm using a 1-mm pinhole aperture collimator. The full width at half-maximum PET radial spatial resolution at the center of the field of view was 1.55 mm. The SPECT system sensitivity for a FOV of 20 mm and 15% energy window was 700 cps/MBq (7.8 * 10( 2)%) using a multi-pinhole equipped with five apertures 1 mm in diameter, whereas the PET absolute sensitivity was 2% for a 350-650 keV energy window and a 5 ns timing window. Several animal images are also presented. CONCLUSIONS: The new small animal PET/SPECT/CT proposed here exhibits high performance, producing high quality images suitable for studies with small animals. Monolithic design for PET and SPECT scintillator crystals reduces cost and complexity without significant performance degradation. PMID- 23635278 TI - Evaluation of over 100 scanner-years of computed tomography daily quality control data. AB - PURPOSE: The results of a long-term, comprehensive CT quality control (QC) program were analyzed to investigate differences in failure rates based on QC test, scanner utilization pattern, and number of channels, as well as explore issues regarding testing frequency. METHODS: CT QC data were collected over a 4 yr period for 26 CT scanners representing two different vendors and using three different QC programs culminating in over 100 scanner-years of QC data. QC tests analyzed included water tests [mean CT number, standard deviation, and uniformity], linearity tests [air, water, and acrylic], and artifact analysis [water phantom and large phantom]. The data were organized based on scanner use, number of channels, scanner modality, and QC test. Logistic regression model analysis with generalized estimating equation method was used to estimate failure rates for each group. RESULTS: A significant difference between failure rates with respect to QC test was found (p-value = 0.02). Large phantom artifacts, standard deviation of water, and water phantom artifacts had the three highest failure rates. No significant difference was found between failure rates organized by scanner use, scanner modality, or number of channels. CONCLUSIONS: Standard deviation of water is the most important quantitative value to collect as part of a daily QC program. Uniformity and linearity tests have relatively low failure rates and, therefore, may not require daily verification. While its failure rates were moderate, daily artifact analysis is suggested due to its potentially high impact on clinical image quality. Weekly or monthly large phantom artifact analysis is encouraged for those sites possessing an appropriate phantom. PMID- 23635277 TI - A simple approach to measure computed tomography (CT) modulation transfer function (MTF) and noise-power spectrum (NPS) using the American College of Radiology (ACR) accreditation phantom. AB - PURPOSE: To develop an easily-implemented technique with free publicly-available analysis software to measure the modulation transfer function (MTF) and noise power spectrum (NPS) of a clinical computed tomography (CT) system from images acquired using a widely-available and standardized American College of Radiology (ACR) CT accreditation phantom. METHODS: Images of the ACR phantom were acquired on a Siemens SOMATOM Definition Flash system using a standard adult head protocol: 120 kVp, 300 mAs, and reconstructed voxel size of 0.49 mm * 0.49 mm * 4.67 mm. The radial (axial) MTF was measured using an edge method where the boundary of the third module of the ACR phantom, originally designed to measure uniformity and noise, was used as a circular edge. The 3D NPS was measured using images from this same module and using a previously-described methodology that quantifies noise magnitude and 3D noise correlation. RESULTS: The axial MTF was radially symmetrical and had a value of 0.1 at 0.62 mm(-1). The 3D NPS shape was consistent with the filter-ramp function of filtered-backprojection reconstruction algorithms and previously reported values. The radial NPS peak value was ~115 HU(2)mm(3) at ~0.25 mm(-1) and dropped to 0 HU(2)mm(3) by 0.8 mm( 1). CONCLUSIONS: The authors have developed an easily-implementable technique to measure the axial MTF and 3D NPS of clinical CT systems using an ACR phantom. The widespread availability of the phantom along with the free software the authors have provided will enable many different institutions to immediately measure MTF and NPS values for comparison of protocols and systems. PMID- 23635279 TI - Respiration-based sorting of dynamic MRI to derive representative 4D-MRI for radiotherapy planning. AB - PURPOSE: Current pretreatment, 4D imaging techniques are suboptimal in that they sample breathing motion over a very limited "snap-shot" in time. To potentially address this, the authors have developed a longer-duration MRI and postprocessing technique to derive the average or most-probable state of mobile anatomy and meanwhile capture and convey the observed motion variability. METHODS: Sagittal and coronal multislice, 2D dynamic MRI was acquired in a sequential fashion over extended durations in two abdominal and four lung studies involving healthy volunteers. Two sequences, readily available on a commercial system, were employed. Respiratory interval-correlated, or 4D-MRI, volumes were retrospectively derived using a two-pass approach. In a first pass, a respiratory trace acquired simultaneous with imaging was processed and slice stacking was used to derive a set of MRI volumes, each representing an equal time or proportion of respiration. Herein, all raw 2D frames mapping to the given respiratory interval, per slice location, were averaged. In a second-pass, this prior reconstruction provided a set of template images and a similarity metric was employed to discern the subset of best-matching raw 2D frames for secondary averaging (per slice location and respiratory interval). Breathing variability (per respiratory interval and slice location) was depicted by computing both a maximum intensity projection as well as a pixelwise standard deviation image. RESULTS: These methods were successfully demonstrated in both the lung and abdomen for both applicable sequences, performing reconstructions with ten respiratory intervals. The first-pass (average) resulted in motion-induced blurring, especially for irregular breathing. The authors have demonstrated qualitatively that the second-pass result can mitigate this blurring. CONCLUSIONS: They have presented a novel methodology employing dMRI to derive representative 4D-MRI. This set of techniques are practical in that (1) they employ MRI sequences that are standard across commercial vendors; (2) the 2D imaging planes can be oriented onto an arbitrary axis (e.g., sagittal, coronal, axial[ellipsis (horizontal)]); (3) the image processing techniques are relatively simple. Systematically applying this and similar dMRI-based techniques in patients is a crucial next step to demonstrate efficacy beyond CT-only based practice. PMID- 23635280 TI - Anatomical noise in contrast-enhanced digital mammography. Part I. Single-energy imaging. AB - PURPOSE: The use of an intravenously injected iodinated contrast agent could help increase the sensitivity of digital mammography by adding information on tumor angiogenesis. Two approaches have been made for clinical implementation of contrast-enhanced digital mammography (CEDM), namely, single-energy (SE) and dual energy (DE) imaging. In each technique, pairs of mammograms are acquired, which are then subtracted with the intent to cancel the appearance of healthy breast tissue to permit sensitive detection and specific characterization of lesions. Patterns of contrast agent uptake in the healthy parenchyma, and uncanceled signal from background tissue create a "clutter" that can mask or mimic an enhancing lesion. This type of "anatomical noise" is often the limiting factor in lesion detection tasks, and thus, noise quantification may be useful for cascaded systems analysis of CEDM and for phantom development. In this work, the authors characterize the anatomical noise in CEDM clinical images and the authors evaluate the influence of the x-ray energy used for acquisition, the presence of iodine in the breast, and the timing of imaging postcontrast administration on anatomical noise. The results are presented in a two-part report, with SE CEDM described here, and DE CEDM in Part II. METHODS: A power law is used to model anatomical noise in CEDM images. The exponent, beta, which describes the anatomical structure, and the constant alpha, which represents the magnitude of the noise, are determined from Wiener spectra (WS) measurements on images. A total of 42 SE CEDM cases from two previous clinical pilot studies are assessed. The parameters alpha and beta are measured both from unprocessed images and from subtracted images. RESULTS: Consistent results were found between the two SE CEDM pilot studies, where a significant decrease in beta from a value of approximately 3.1 in the unprocessed images to between about 1.1 and 1.8 in the subtracted images was observed. Increasing the x-ray energy from that used in conventional DM to those of typical SE CEDM spectra with mean energies above 33 keV significantly decreased alpha by about a factor of 19, in agreement with theory. Compared to precontrast images, in the unprocessed postcontrast images at 30 s postinjection, alpha was larger by about 7.4 * 10(-7) mm(2) and beta was decreased by 0.2. While alpha did not vary significantly with the time after contrast administration, beta from the unprocessed image WS increased linearly, and beta from subtracted image WS increased with an initial quadratic relationship that plateaued by about 5 min postinjection. CONCLUSIONS: The presence of an iodinated contrast agent in the breast produced small, but significant changes in the power law parameters of unprocessed CEDM images compared to the precontrast images. Image subtraction in SE CEDM significantly reduced anatomical noise compared to conventional DM, with a reduction in both alpha and beta by about a factor of 2. The data presented here, and in Part II of this work, will be useful for modeling of CEDM backgrounds, for systems characterization and for lesion detectability experiments using models that account for anatomical noise. PMID- 23635281 TI - A real-time regional adaptive exposure method for saving dose-area product in x ray fluoroscopy. AB - PURPOSE: Reduction of radiation dose in x-ray imaging has been recognized as a high priority in the medical community. Here the authors show that a regional adaptive exposure method can reduce dose-area product (DAP) in x-ray fluoroscopy. The authors' method is particularly geared toward providing dose savings for the pediatric population. METHODS: The scanning beam digital x-ray system uses a large-area x-ray source with 8000 focal spots in combination with a small photon counting detector. An imaging frame is obtained by acquiring and reconstructing up to 8000 detector images, each viewing only a small portion of the patient. Regional adaptive exposure was implemented by varying the exposure of the detector images depending on the local opacity of the object. A family of phantoms ranging in size from infant to obese adult was imaged in anteroposterior view with and without adaptive exposure. The DAP delivered to each phantom was measured in each case, and noise performance was compared by generating noise arrays to represent regional noise in the images. These noise arrays were generated by dividing the image into regions of about 6 mm(2), calculating the relative noise in each region, and placing the relative noise value of each region in a one-dimensional array (noise array) sorted from highest to lowest. Dose-area product savings were calculated as the difference between the ratio of DAP with adaptive exposure to DAP without adaptive exposure. The authors modified this value by a correction factor that matches the noise arrays where relative noise is the highest to report a final dose-area product savings. RESULTS: The average dose-area product saving across the phantom family was (42 +/- 8)% with the highest dose-area product saving in the child-sized phantom (50%) and the lowest in the phantom mimicking an obese adult (23%). CONCLUSIONS: Phantom measurements indicate that a regional adaptive exposure method can produce large DAP savings without compromising the noise performance in the image regions with highest noise. PMID- 23635282 TI - A support vector machine classifier reduces interscanner variation in the HRCT classification of regional disease pattern in diffuse lung disease: comparison to a Bayesian classifier. AB - PURPOSE: To investigate the effect of using different computed tomography (CT) scanners on the accuracy of high-resolution CT (HRCT) images in classifying regional disease patterns in patients with diffuse lung disease, support vector machine (SVM) and Bayesian classifiers were applied to multicenter data. METHODS: Two experienced radiologists marked sets of 600 rectangular 20 * 20 pixel regions of interest (ROIs) on HRCT images obtained from two scanners (GE and Siemens), including 100 ROIs for each of local patterns of lungs-normal lung and five of regional pulmonary disease patterns (ground-glass opacity, reticular opacity, honeycombing, emphysema, and consolidation). Each ROI was assessed using 22 quantitative features belonging to one of the following descriptors: histogram, gradient, run-length, gray level co-occurrence matrix, low-attenuation area cluster, and top-hat transform. For automatic classification, a Bayesian classifier and a SVM classifier were compared under three different conditions. First, classification accuracies were estimated using data from each scanner. Next, data from the GE and Siemens scanners were used for training and testing, respectively, and vice versa. Finally, all ROI data were integrated regardless of the scanner type and were then trained and tested together. All experiments were performed based on forward feature selection and fivefold cross-validation with 20 repetitions. RESULTS: For each scanner, better classification accuracies were achieved with the SVM classifier than the Bayesian classifier (92% and 82%, respectively, for the GE scanner; and 92% and 86%, respectively, for the Siemens scanner). The classification accuracies were 82%/72% for training with GE data and testing with Siemens data, and 79%/72% for the reverse. The use of training and test data obtained from the HRCT images of different scanners lowered the classification accuracy compared to the use of HRCT images from the same scanner. For integrated ROI data obtained from both scanners, the classification accuracies with the SVM and Bayesian classifiers were 92% and 77%, respectively. The selected features resulting from the classification process differed by scanner, with more features included for the classification of the integrated HRCT data than for the classification of the HRCT data from each scanner. For the integrated data, consisting of HRCT images of both scanners, the classification accuracy based on the SVM was statistically similar to the accuracy of the data obtained from each scanner. However, the classification accuracy of the integrated data using the Bayesian classifier was significantly lower than the classification accuracy of the ROI data of each scanner. CONCLUSIONS: The use of an integrated dataset along with a SVM classifier rather than a Bayesian classifier has benefits in terms of the classification accuracy of HRCT images acquired with more than one scanner. This finding is of relevance in studies involving large number of images, as is the case in a multicenter trial with different scanners. PMID- 23635283 TI - A new segmentation framework based on sparse shape composition in liver surgery planning system. AB - PURPOSE: To improve the accuracy and the robustness of the segmentation in living donor liver transplantation (LDLT) surgery planning system, the authors present a new segmentation framework that addresses challenges induced by the complex shape variations of patients' livers with cancer. It is designed to achieve the accurate and robust segmentation of hepatic parenchyma, portal veins, hepatic veins, and tumors in the LDLT surgery planning system. METHODS: The segmentation framework proposed in this paper includes two important modules: (1) The robust shape prior modeling for liver, in which the sparse shape composition (SSC) model is employed to deal with the complex variations of liver shapes and obtain patient-specific liver shape priors. (2) The integration of the liver shape prior with a minimally supervised segmentation algorithm to achieve the accurate segmentation of hepatic parenchyma, portal veins, hepatic veins, and tumors simultaneously. The authors apply this segmentation framework to our previously developed LDLT surgery planning system to enhance its accuracy and robustness when dealing with complex cases of patients with liver cancer. RESULTS: Compared with the principal component analysis, the SSC model shows a great advantage in handling the complex variations of liver shapes. It also effectively excludes gross errors and outliers that appear in the input shape and preserves local details for specific patients. The proposed segmentation framework was evaluated on the clinical image data of liver cancer patients, and the average symmetric surface distance for hepatic parenchyma, portal veins, hepatic veins, and tumors was 1.07 +/- 0.76, 1.09 +/- 0.28, 0.92 +/- 0.35 and 1.13 +/- 0.37 mm, respectively. The Hausdorff distance for these four tissues was 7.68, 4.67, 4.09, and 5.36 mm, respectively. CONCLUSIONS: The proposed segmentation framework improves the robustness of the LDLT surgery planning system remarkably when dealing with complex clinical liver shapes. The SSC model is able to handle non Gaussian errors and preserve local detail information of the input liver shape. As a result, the proposed framework effectively addresses the problems caused by the complex shape variations of livers with cancer. Our framework not only obtains accurate segmentation results for healthy persons and common patients, but also shows high robustness when dealing with specific patients with large variations of liver shapes in complex clinical environments. PMID- 23635286 TI - Resolution enhancement of lung 4D-CT data using multiscale interphase iterative nonlocal means. AB - PURPOSE: Four-dimensional computer tomography (4D-CT) has been widely used in lung cancer radiotherapy due to its capability in providing important tumor motion information. However, the prolonged scanning duration required by 4D-CT causes considerable increase in radiation dose. To minimize the radiation-related health risk, radiation dose is often reduced at the expense of interslice spatial resolution. However, inadequate resolution in 4D-CT causes artifacts and increases uncertainty in tumor localization, which eventually results in extra damages of healthy tissues during radiotherapy. In this paper, the authors propose a novel postprocessing algorithm to enhance the resolution of lung 4D-CT data. METHODS: The authors' premise is that anatomical information missing in one phase can be recovered from the complementary information embedded in other phases. The authors employ a patch-based mechanism to propagate information across phases for the reconstruction of intermediate slices in the longitudinal direction, where resolution is normally the lowest. Specifically, the structurally matching and spatially nearby patches are combined for reconstruction of each patch. For greater sensitivity to anatomical details, the authors employ a quad-tree technique to adaptively partition the image for more fine-grained refinement. The authors further devise an iterative strategy for significant enhancement of anatomical details. RESULTS: The authors evaluated their algorithm using a publicly available lung data that consist of 10 4D-CT cases. The authors' algorithm gives very promising results with significantly enhanced image structures and much less artifacts. Quantitative analysis shows that the authors' algorithm increases peak signal-to-noise ratio by 3-4 dB and the structural similarity index by 3%-5% when compared with the standard interpolation-based algorithms. CONCLUSIONS: The authors have developed a new algorithm to improve the resolution of 4D-CT. It outperforms the conventional interpolation-based approaches by producing images with the markedly improved structural clarity and greatly reduced artifacts. PMID- 23635284 TI - A virtual trial framework for quantifying the detectability of masses in breast tomosynthesis projection data. AB - PURPOSE: Digital breast tomosynthesis (DBT) is a promising breast cancer screening tool that has already begun making inroads into clinical practice. However, there is ongoing debate over how to quantitatively evaluate and optimize these systems, because different definitions of image quality can lead to different optimal design strategies. Powerful and accurate tools are desired to extend our understanding of DBT system optimization and validate published design principles. METHODS: The authors developed a virtual trial framework for task specific DBT assessment that uses digital phantoms, open-source x-ray transport codes, and a projection-space, spatial-domain observer model for quantitative system evaluation. The authors considered evaluation of reconstruction algorithms as a separate problem and focused on the information content in the raw, unfiltered projection images. Specifically, the authors investigated the effects of scan angle and number of angular projections on detectability of a small (3 mm diameter) signal embedded in randomly-varying anatomical backgrounds. Detectability was measured by the area under the receiver-operating characteristic curve (AUC). Experiments were repeated for three test cases where the detectability-limiting factor was anatomical variability, quantum noise, or electronic noise. The authors also juxtaposed the virtual trial framework with other published studies to illustrate its advantages and disadvantages. RESULTS: The large number of variables in a virtual DBT study make it difficult to directly compare different authors' results, so each result must be interpreted within the context of the specific virtual trial framework. The following results apply to 25% density phantoms with 5.15 cm compressed thickness and 500 MUm(3) voxels (larger 500 MUm(2) detector pixels were used to avoid voxel-edge artifacts): 1. For raw, unfiltered projection images in the anatomical variability-limited regime, AUC appeared to remain constant or increase slightly with scan angle. 2. In the same regime, when the authors fixed the scan angle, AUC increased asymptotically with the number of projections. The threshold number of projections for asymptotic AUC performance depended on the scan angle. In the quantum- and electronic-noise dominant regimes, AUC behaviors as a function of scan angle and number of projections sometimes differed from the anatomy-limited regime. For example, with a fixed scan angle, AUC generally decreased with the number of projections in the electronic-noise dominant regime. These results are intended to demonstrate the capabilities of the virtual trial framework, not to be used as optimization rules for DBT. CONCLUSIONS: The authors have demonstrated a novel simulation framework and tools for evaluating DBT systems in an objective, task-specific manner. This framework facilitates further investigation of image quality tradeoffs in DBT. PMID- 23635287 TI - Isotropic three-dimensional MRI-Fricke-infused gel dosimetry. AB - PURPOSE: Fricke-infused gel has been shown to be a simple and attainable method for the conformal measurement of absorbed radiation dose. Nevertheless, its accuracy is seriously hindered by the irreversible ferric ion diffusion during magnetic resonance imaging, particularly when three-dimensional (3D) dose measurement in radiosurgery is considered. In this study, the authors developed a fast three-dimensional spin-echo based Fricke gel dosimetry technique to reduce the adverse effects of ferric ion diffusion and to obtain an accurate isotropic 3D dose measurement. METHODS: A skull shaped phantom containing Fricke-infused gel was irradiated using Leksell Gamma Knife. The rapid image-based dosimetry technique was applied with the use of a 3D fast spin-echo magnetic resonance imaging sequence. The authors mathematically derived and experimentally validated the correlations between dose-response characteristics and parameters of the 3D fast spin-echo MR imaging sequence. Absorbed dose profiles were assessed and compared to the calculated profiles given by the Gamma Knife treatment planning system. Coefficient of variance (CV%) and coefficient of determination (R(2)) were used to evaluate the precision of dose-response curve estimation. The agreement between the measured and the planned 3D dose distributions was quantified by gamma-index analysis of two acceptance criteria. RESULTS: Proper magnetic resonance imaging parameters were explored to render an accurate three dimensional absorbed dose mapping with a 1 mm(3) isotropic image resolution. The efficacy of the dose-response estimation was approved by an R(2) > 0.99 and an average CV% of 1.6%. Average gamma pass-rate between the experimentally measured and GammaPlan calculated dose distributions were 83.8% and 99.7% for 2%/2 and 3%/3 mm criteria, respectively. CONCLUSIONS: With the designed MR imaging sequence and parameters, total 3D MR acquisition time was confined to within 20 min postirradiation, during which time ferric ion diffusion effects were negligible, thus enabling an accurate 3D radiation dose measurement. PMID- 23635285 TI - Monte Carlo study of the effects of system geometry and antiscatter grids on cone beam CT scatter distributions. AB - PURPOSE: The proliferation of cone-beam CT (CBCT) has created interest in performance optimization, with x-ray scatter identified among the main limitations to image quality. CBCT often contends with elevated scatter, but the wide variety of imaging geometry in different CBCT configurations suggests that not all configurations are affected to the same extent. Graphics processing unit (GPU) accelerated Monte Carlo (MC) simulations are employed over a range of imaging geometries to elucidate the factors governing scatter characteristics, efficacy of antiscatter grids, guide system design, and augment development of scatter correction. METHODS: A MC x-ray simulator implemented on GPU was accelerated by inclusion of variance reduction techniques (interaction splitting, forced scattering, and forced detection) and extended to include x-ray spectra and analytical models of antiscatter grids and flat-panel detectors. The simulator was applied to small animal (SA), musculoskeletal (MSK) extremity, otolaryngology (Head), breast, interventional C-arm, and on-board (kilovoltage) linear accelerator (Linac) imaging, with an axis-to-detector distance (ADD) of 5, 12, 22, 32, 60, and 50 cm, respectively. Each configuration was modeled with and without an antiscatter grid and with (i) an elliptical cylinder varying 70-280 mm in major axis; and (ii) digital murine and anthropomorphic models. The effects of scatter were evaluated in terms of the angular distribution of scatter incident upon the detector, scatter-to-primary ratio (SPR), artifact magnitude, contrast, contrast-to-noise ratio (CNR), and visual assessment. RESULTS: Variance reduction yielded improvements in MC simulation efficiency ranging from ~17-fold (for SA CBCT) to ~35-fold (for Head and C-arm), with the most significant acceleration due to interaction splitting (~6 to ~10-fold increase in efficiency). The benefit of a more extended geometry was evident by virtue of a larger air gap-e.g., for a 16 cm diameter object, the SPR reduced from 1.5 for ADD = 12 cm (MSK geometry) to 1.1 for ADD = 22 cm (Head) and to 0.5 for ADD = 60 cm (C-arm). Grid efficiency was higher for configurations with shorter air gap due to a broader angular distribution of scattered photons-e.g., scatter rejection factor ~0.8 for MSK geometry versus ~0.65 for C-arm. Grids reduced cupping for all configurations but had limited improvement on scatter-induced streaks and resulted in a loss of CNR for the SA, Breast, and C-arm. Relative contribution of forward-directed scatter increased with a grid (e.g., Rayleigh scatter fraction increasing from ~0.15 without a grid to ~0.25 with a grid for the MSK configuration), resulting in scatter distributions with greater spatial variation (the form of which depended on grid orientation). CONCLUSIONS: A fast MC simulator combining GPU acceleration with variance reduction provided a systematic examination of a range of CBCT configurations in relation to scatter, highlighting the magnitude and spatial uniformity of individual scatter components, illustrating tradeoffs in CNR and artifacts and identifying the system geometries for which grids are more beneficial (e.g., MSK) from those in which an extended geometry is the better defense (e.g., C-arm head imaging). Compact geometries with an antiscatter grid challenge assumptions of slowly varying scatter distributions due to increased contribution of Rayleigh scatter. PMID- 23635288 TI - Numerical study of ultra-low field nuclear magnetic resonance relaxometry utilizing a single axis magnetometer for signal detection. AB - PURPOSE: This paper investigates optimal placement of a localized single-axis magnetometer for ultralow field (ULF) relaxometry in view of various sample shapes and sizes. METHODS: The authors used finite element method for the numerical analysis to determine the sample magnetic field environment and evaluate the optimal location of the single-axis magnetometer. RESULTS: Given the different samples, the authors analysed the magnetic field distribution around the sample and determined the optimal orientation and possible positions of the sensor to maximize signal strength, that is, the power of the free induction decay. The authors demonstrate that a glass vial with flat bottom and 10 ml volume is the best structure to achieve the highest signal out of samples studied. CONCLUSIONS: This paper demonstrates the importance of taking into account the combined effects of sensor configuration and sample parameters for signal generation prior to designing and constructing ULF systems with a single axis magnetometer. Through numerical simulations the authors were able to optimize structural parameters, such as sample shape and size, sensor orientation and location, to maximize the measured signal in ultralow field relaxometry. PMID- 23635289 TI - MTF behavior of compressed sensing MR spectroscopic imaging. AB - PURPOSE: To investigate the modulation transfer function (MTF) behavior of compressed sensing (CS) MR spectroscopic imaging (MRSI) with regard to CS reconstruction weights and the acquired peak signal-to-noise ratio (SNR); which may have an effect on MTF due to the nonlinear nature of the CS reconstruction process. METHODS: A specially designed phantom consisting of wedges arranged in a fan pattern was used to calculate the MTF of the MRSI scans. Arc profiles of the phantom yield a square wave with a spatial frequency inversely proportional to the radius of the profile. The MTF was derived by considering the amplitude ratio of the fundamental frequency between the ideal square wave and the reconstructed output. As compressed sensing relies on nonlinear reconstruction and a minimization algorithm that requires the definition of reconstruction weights, the behavior of the MTF with respect to the choice of reconstruction weights and peak SNR is not intuitive. As such, simulations were used to investigate the response of the MTF to CS reconstruction weights at varying peak SNRs. The resulting optimized reconstruction weight was used to reconstruct an experimental CS-MRSI scan of the phantom and compare the corresponding MTF to those of a fully sampled dataset, and a time-equivalent Nyquist-sampled low-resolution dataset. RESULTS: Simulations showed that MTFs of CS-MRSI datasets varied widely with different reconstruction weights. Moreover, the response of the MTF to peak SNR was not consistent across the range of reconstruction weights. An optimized reconstruction weight was derived from the simulations and used in reconstructing the experimental dataset. The MTF of the experimental CS-MRSI dataset showed improvement over the equivalent Nyquist sampled dataset at the resolution limit of 0.1 MTF, while it suffered from reduced response at low resolutions between 0.4 and 0.8 lp/cm. CONCLUSIONS: The authors have shown that in certain cases small variations in the reconstruction weights yield a measureable effect on the CS reconstructed images, particularly with regard to MTF. Furthermore, it was found that peak SNR affects CS-MRSI MTF especially at higher wavelet reconstruction weights. Accordingly, prior knowledge of the expected peak SNR is essential to optimize the CS reconstruction process. Their phantom-MTF technique provides a quantitative performance measure of MRSI sequences, through which they were able to quantify a loss of 32.4% in spatial resolution for CS-MRSI at 0.1 MTF compared to a loss of 48.6% for the time-equivalent Nyquist-sampled low resolution scans. They also showed that CS-MRSI suffered decreased low-resolution response as opposed to the equivalent low-resolution datasets. PMID- 23635291 TI - Improved realism of hybrid mouse models may not be sufficient to generate reference dosimetric data. AB - PURPOSE: Recent developments of hybrid realistic models, such as Moby (mouse) and Roby (rat) developed by Segars et al. ["Development of a 4-D digital mouse phantom for molecular imaging research," Mol. Imaging Biol. 6, 149-159 (2004)] have found several applications in preclinical experiments. Indeed, their improved realism and flexibility in terms of mass scaling represent an attractive option for absorbed dose calculations based on "representative" models. However, the range of radiations involved in small animal molecular imaging and radiotherapy is of the same order of magnitude as organs of interest dimensions. As a consequence, minor geometric variations between rodents may lead to major differences in absorbed dose calculations. This study aims at validating a voxel based model for use in absorbed dose estimates with two Monte Carlo codes and at assessing the dosimetric impact of Moby-based models definition. METHODS: The authors generated a 30 g-mouse phantom based on realistic hybrid model Moby (version 1). Dosimetric calculations (S-values, specific absorbed fraction) were performed with two Monte Carlo codes (MCNPX v2.7a and GATE v6.1) for (18)F, and a comparison with values published for Radiation Dose Assessment Resource realistic animal series was made. Several parameters such as material definition/densities, fine suborgan segmentation for airways (trachea, lungs, remaining body), bones (ribs, spine, skull, remaining bones), heart (blood pool and myocardium), and stomach (wall and gastrointestinal content) were further studied, as well as nuclear data and spatial sampling. RESULTS: Most organ masses matched the reference model (Moby v1) within +/- 6%, except lungs, thyroid, and bones for which differences could reach 29%. Comparison of S-values (especially self-S values) was consistent with mass differences observed between the two models. The reciprocity theorem for source/target pairs was satisfied within few percents for specific absorbed fractions (g(-1)). However, significant discrepancies, reaching 160%, were observed for mutual liver/stomach/spleen S-values and could not be directly related to mass variations. Nonetheless, differences between S-values calculated with MCNPX and GATE for our model remained in the order of a few percents, i.e., within statistical uncertainties. Besides, modifications of organ densities increased S-values up to a factor 50 for the lungs/thyroid pair when upper airway was properly segmented out of the body. Specific material composition and densities for several bone types led to a 10% decrease of S values from the bone source to several target organs. Moreover, relative differences up to 100% were observed for S(stomach wall<=spleen) when improving spatial-sampling by a factor 3. CONCLUSIONS: This study demonstrated that comparison between two "similar" realistic digital mouse whole-body phantoms generated from the same software still led to very different S-values, even when total body and organ mass scaling were performed. Moreover, parameters such as organ segmentation, tissue material/density, or spatial sampling should be defined and reported with great care to perform accurate small animal absorbed dose calculation based on "reference" models. PMID- 23635290 TI - Potential of in vivo MRI-based nonlinear finite-element analysis for the assessment of trabecular bone post-yield properties. AB - PURPOSE: Bone strength is the key factor impacting fracture risk. Assessment of bone strength from high-resolution (HR) images have largely relied on linear micro-finite element analysis (MUFEA) even though failure always occurs beyond the yield point, which is outside the linear regime. Nonlinear MUFEA may therefore be more informative in predicting failure behavior. However, existing nonlinear models applied to trabecular bone (TB) have largely been confined to micro-computed tomography (MUCT) and, more recently, HR peripheral quantitative computed tomography (HR-pQCT) images, and typically have ignored evaluation of the post-yield behavior. The primary purpose of this work was threefold: (1) to provide an improved algorithm and program to assess TB yield as well as post yield properties; (2) to explore the potential benefits of nonlinear MUFEA beyond its linear counterpart; and (3) to assess the feasibility and practicality of performing nonlinear analysis on desktop computers on the basis of micro-magnetic resonance (MUMR) images obtained in vivo in patients. METHODS: A method for nonlinear MUFE modeling of TB yield as well as post-yield behavior has been designed where material nonlinearity is captured by adjusting the tissue modulus iteratively according to the tissue-level effective strain obtained from linear analysis using a computationally optimized algorithm. The software allows for images at in vivo MUMRI resolution as input with retention of grayscale information. Associations between axial stiffness estimated from linear analysis and yield as well as post-yield parameters from nonlinear analysis were investigated from in vivo MUMR images of the distal tibia (N = 20; ages: 58-84) and radius (N = 20; ages: 50-75). RESULTS: All simulations were completed in 1 h or less for 61 strain levels using a desktop computer (dual quad-core Xeon 3.16 GHz CPUs equipped with 40 GB of RAM). Although yield stress and ultimate stress correlated strongly (R(2) > 0.95, p < 0.001) with axial stiffness, toughness correlated moderately at the distal tibia (R(2) = 0.81, p < 0.001) and only weakly at the distal radius (R(2) = 0.34, p = 0.007). Further, toughness was found to vary by up to 16% for bone of very similar axial stiffness (<2%). CONCLUSIONS: The work demonstrates the practicality of nonlinear MUFE simulations at in vivo MUMRI resolution, as well as its potential for providing additional information beyond that obtainable from linear analysis. The data suggest that a direct assessment of toughness may provide information not captured by stiffness. PMID- 23635292 TI - CT-perfusion versus [(15)O]H2O PET in lung tumors: effects of CT-perfusion methodology. AB - PURPOSE: Nowadays, PET and dynamic contrast enhanced CT or MRI are used to assess tumor blood perfusion. Although [(15)O]H2O PET is the gold standard, it is hardly available for routine clinical practice, due to the short half-life of (15)O. However, the lack of uniformity in scanning and analytic methods limits the use of CT perfusion (CTP) in clinical trials and practice. This study compares [(15)O]H2O PET with CT based perfusion in lung tumors and assesses the effects of various CTP postprocessing and analytical methods on the CTP results using [(15)O]H2O PET as the reference technique. METHODS: Various CTP analysis and image postprocessing methods were assessed. Furthermore, parametric images were obtained using the Slope method. Volumes of interests were defined using several different segmentation methods including Hounsfield unit based contouring thresholds, both with and without framewise application of dynamic contouring thresholds to exclude lung tissue or intravascular contrast. A head-to-head comparison of tumor perfusion obtained by CTP and [(15)O]H2O PET was performed using linear regressions, Bland-Altman plots, and an intraclass correlation coefficient (ICC). In addition, the different postprocessing methods were compared reciprocally. RESULTS: In six lung cancer patients, perfusion assessed using CTP studies combined with the Slope method correlated best with [(15)O]H2O PET (ICC = 0.88; R(2) = 0.89; Y = 0.80). The Mullani-Gould method showed best correlation with the Slope method (ICC >= 0.71; R(2) >= 0.80; Y = 0.71-1.35). These correlations were obtained using dynamic contouring thresholds and show the influence of CTP postprocessing methods. CONCLUSIONS: Tumor perfusion assessed by CTP in combination with dynamic contouring thresholds using the Slope method correlates well with [(15)O]H2O PET. This suggests that CTP can be used as a method to evaluate tumor perfusion in lung cancer. PMID- 23635293 TI - An ordered-subsets proximal preconditioned gradient algorithm for edge-preserving PET image reconstruction. AB - PURPOSE: In iterative positron emission tomography (PET) image reconstruction, the statistical variability of the PET data precorrected for random coincidences or acquired in sufficiently high count rates can be properly approximated by a Gaussian distribution, which can lead to a penalized weighted least-squares (PWLS) cost function. In this study, the authors propose a proximal preconditioned gradient algorithm accelerated with ordered subsets (PPG-OS) for the optimization of the PWLS cost function and develop a framework to incorporate boundary side information into edge-preserving total variation (TV) and Huber regularizations. METHODS: The PPG-OS algorithm is proposed to address two issues encountered in the optimization of PWLS function with edge-preserving regularizers. First, the second derivative of this function (Hessian matrix) is shift-variant and ill-conditioned due to the weighting matrix (which includes emission data, attenuation, and normalization correction factors) and the regularizer. As a result, the paraboloidal surrogate functions (used in the optimization transfer techniques) end up with high curvatures and gradient-based algorithms take smaller step-sizes toward the solution, leading to a slow convergence. In addition, preconditioners used to improve the condition number of the problem, and thus to speed up the convergence, would poorly act on the resulting ill-conditioned Hessian matrix. Second, the PWLS function with a nondifferentiable penalty such as TV is not amenable to optimization using gradient-based algorithms. To deal with these issues and also to enhance edge preservation of the TV and Huber regularizers by incorporating adaptively or anatomically derived boundary side information, the authors followed a proximal splitting method. Thereby, the optimization of the PWLS function is split into a gradient descent step (upgraded by preconditioning, step size optimization, and ordered subsets) and a proximal mapping associated with boundary weighted TV and Huber regularizers. The proximal mapping is then iteratively solved by dual formulation of the regularizers. RESULTS: The convergence performance of the proposed algorithm was studied with three different diagonal preconditioners and compared with the state-of-the-art separable paraboloidal surrogates accelerated with ordered-subsets (SPS-OS) algorithm. In simulation studies using a realistic numerical phantom, it was shown that the proposed algorithm depicts a considerably improved convergence rate over the SPS-OS algorithm. Furthermore, the results of bias-variance and signal-to-noise evaluations showed that the proposed algorithm with anatomical edge information depicts an improved performance over conventional regularization. Finally, the proposed PPG-OS algorithm is used for image reconstruction of a clinical study with adaptively derived boundary edge information, demonstrating the potential of the algorithm for fast and edge-preserving PET image reconstruction. CONCLUSIONS: The proposed PPG-OS algorithm shows an improved convergence rate with the ability of incorporating additional boundary information in regularized PET image reconstruction. PMID- 23635294 TI - Weighted cross-correlation based variational optical flow for gastric flow analysis in ultrasonic videos. AB - PURPOSE: Estimating the fluid motion in ultrasonic videos is a crucial step in the analysis of duodenogastric reflux. Severe image noise and illumination changes in the pyloric region (the region of interest) challenge the accurate estimation of gastric flow. In this paper, the authors propose an illumination robust optical flow method based on the weighted cross-correlation. METHODS: Cross-correlation was combined with the variational optical method framework as an illumination-robust local feature identifier. In consideration of accuracy near edges, they constructed visual similarity weights according to the characteristics of ultrasonic images. A processing procedure containing coarse-to fine step and refinement was designed to get the final results. They tested the proposed method on synthetic and real ultrasonic images and compared it with other three optical flow methods. For quantitative evaluation, two metrics of angular and amplitude error were used. RESULTS: The synthetic results demonstrate that the proposed method performs better on ultrasonic images, with angular error of 4.1 degrees and amplitude error of 3.3%. In qualitative comparison, the proposed method kept the motion field smooth in the homogeneous region while preserving edge information. When they used the results of the proposed method to judge the gastric flow direction, the automatic judgments agreed well with visual observation. CONCLUSIONS: The proposed method is a good tool for image velocimetry in ultrasonic images. It provides promising results to estimate the motion of gastric flow in ultrasonic videos. PMID- 23635295 TI - Acoustic dipole radiation based electrical impedance contrast imaging approach of magnetoacoustic tomography with magnetic induction. AB - PURPOSE: Different from the theory of acoustic monopole spherical radiation, the acoustic dipole radiation based theory introduces the radiation pattern of Lorentz force induced dipole sources to describe the principle of magnetoacoustic tomography with magnetic induction (MAT-MI). Although two-dimensional (2D) simulations have been studied for cylindrical phantom models, layer effects of the dipole sources within the entire object along the z direction still need to be investigated to evaluate the performance of MAT-MI for different geometric specifications. The purpose of this work is further verifying the validity and generality of acoustic dipole radiation based theory for MAT-MI with two new models in different shapes, dimensions, and conductivities. METHODS: Based on the theory of acoustic dipole radiation, the principles of MAT-MI were analyzed with derived analytic formulae. 2D and 3D numerical studies for two new models of aluminum foil and cooked egg were conducted to simulate acoustic pressures and corresponding waveforms, and 2D images of the scanned layers were reconstructed with the simplified back projection algorithm for the waveforms collected around the models. The spatial resolution for conductivity boundary differentiation was also analyzed with different foil thickness. For comparison, two experimental measurements were conducted for a cylindrical aluminum foil phantom and a shell peeled cooked egg. The collected waveforms and the reconstructed images of the scanned layers were achieved to verify the validation of the acoustic dipole radiation based theory for MAT-MI. RESULTS: Despite the difference between the 2D and 3D simulated pressures, good consistence of the collected waveforms proves that wave clusters are generated by the abrupt pressure changes with bipolar vibration phases, representing the opposite polarities of the conductivity changes along the measurement direction. The configuration of the scanned layer can be reconstructed in terms of shape and size, and the conductivity boundaries are displayed in stripes with different contrast and bipolar intensities. Layer effects are demonstrated to have little influence on the collected waveforms and the reconstructed images of the scanned layers for the two new models. The experimental results have good agreements with numerical simulations, and the reconstructed 2D images provide conductivity configurations in the scanned layers of the aluminum foil and the egg models. CONCLUSIONS: It can be concluded that the acoustic pressure of MAT-MI is produced by the divergence of the induced Lorentz force, and the collected waveforms comprise wave clusters with bipolar vibration phases and different amplitudes, providing the information of conductivity boundaries in the scanned layer. With the simplified back projection algorithm for diffraction sources, collected waveforms can be used to reconstruct 2D conductivity contrast image and the conductivity configuration in the scanned layer can be obtained in terms of shape and size in stripes with the spatial resolution of the acoustic wavelength. The favorable results further verify the validity and generality of the acoustic dipole radiation based theory and suggest the feasibility of MAT-MI as an effective electrical impedance contrast imaging approach for medical imaging. PMID- 23635296 TI - Three-dimensional segmentation of three-dimensional ultrasound carotid atherosclerosis using sparse field level sets. AB - PURPOSE: Three-dimensional ultrasound (3DUS) vessel wall volume (VWV) provides a 3D measurement of carotid artery wall remodeling and atherosclerotic plaque and is sensitive to temporal changes of carotid plaque burden. Unfortunately, although 3DUS VWV provides many advantages compared to measurements of arterial wall thickening or plaque alone, it is still not widely used in research or clinical practice because of the inordinate amount of time required to train observers and to generate 3DUS VWV measurements. In this regard, semiautomated methods for segmentation of the carotid media-adventitia boundary (MAB) and the lumen-intima boundary (LIB) would greatly improve the time to train observers and for them to generate 3DUS VWV measurements with high reproducibility. METHODS: The authors describe a 3D algorithm based on a modified sparse field level set method for segmenting the MAB and LIB of the common carotid artery (CCA) from 3DUS images. To the authors' knowledge, the proposed algorithm is the first direct 3D segmentation method, which has been validated for segmenting both the carotid MAB and the LIB from 3DUS images for the purpose of computing VWV. Initialization of the algorithm requires the observer to choose anchor points on each boundary on a set of transverse slices with a user-specified interslice distance (ISD), in which larger ISD requires fewer user interactions than smaller ISD. To address the challenges of the MAB and LIB segmentations from 3DUS images, the authors integrated regional- and boundary-based image statistics, expert initializations, and anatomically motivated boundary separation into the segmentation. The MAB is segmented by incorporating local region-based image information, image gradients, and the anchor points provided by the observer. Moreover, a local smoothness term is utilized to maintain the smooth surface of the MAB. The LIB is segmented by constraining its evolution using the already segmented surface of the MAB, in addition to the global region-based information and the anchor points. The algorithm-generated surfaces were sliced and evaluated with respect to manual segmentations on a slice-by-slice basis using 21 3DUS images. RESULTS: The authors used ISD of 1, 2, 3, 4, and 10 mm for algorithm initialization to generate segmentation results. The algorithm-generated accuracy and intraobserver variability results are comparable to the previous methods, but with fewer user interactions. For example, for the ISD of 3 mm, the algorithm yielded an average Dice coefficient of 94.4% +/- 2.2% and 90.6% +/- 5.0% for the MAB and LIB and the coefficient of variation of 6.8% for computing the VWV of the CCA, while requiring only 1.72 min (vs 8.3 min for manual segmentation) for a 3DUS image. CONCLUSIONS: The proposed 3D semiautomated segmentation algorithm yielded high-accuracy and high-repeatability, while reducing the expert interaction required for initializing the algorithm than the previous 2D methods. PMID- 23635297 TI - Automatic assessment of regional and global wall motion abnormalities in echocardiography images by nonlinear dimensionality reduction. AB - PURPOSE: Identification and assessment of left ventricular (LV) global and regional wall motion (RWM) abnormalities are essential for clinical evaluation of various cardiovascular diseases. Currently, this evaluation is performed visually which is highly dependent on the training and experience of echocardiographers and thus is prone to considerable interobserver and intraobserver variability. This paper presents a new automatic method, based on nonlinear dimensionality reduction (NLDR) for global wall motion evaluation and also detection and classification of RWM abnormalities of LV wall in a three-point scale as follows: (1) normokinesia, (2) hypokinesia, and (3) akinesia. METHODS: Isometric feature mapping (Isomap) is one of the most popular NLDR algorithms. In this paper, a modified version of Isomap algorithm, where image to image distance metric is computed using nonrigid registration, is applied on two-dimensional (2D) echocardiography images of one cycle of heart. By this approach, nonlinear information in these images is embedded in a 2D manifold and each image is characterized by a point on the constructed manifold. This new representation visualizes the relationship between these images based on LV volume changes. Then, a new global and regional quantitative index from the resultant manifold is proposed for global wall motion estimation and also classification of RWM of LV wall in a three-point scale. Obtained results by our method are quantitatively evaluated to those obtained visually by two experienced echocardiographers as the reference (gold standard) on 10 healthy volunteers and 14 patients. RESULTS: Linear regression analysis between the proposed global quantitative index and the global wall motion score index and also with LV ejection fraction obtained by reference experienced echocardiographers resulted in the correlation coefficients of 0.85 and 0.90, respectively. Comparison between the proposed automatic RWM scoring and the reference visual scoring resulted in an absolute agreement of 82% and a relative agreement of 97%. CONCLUSIONS: The proposed diagnostic method can be used as a useful tool as well as a reference visual assessment by experienced echocardiographers for global wall motion estimation and also classification of RWM abnormalities of LV wall in a three-point scale in clinical evaluations. PMID- 23635298 TI - An investigation of industrial molding compounds for use in 3D ultrasound, MRI, and CT imaging phantoms. AB - PURPOSE: This study investigated the ultrasound, MRI, and CT imaging characteristics of several industrial casting and molding compounds as a precursor to the future development of durable and anatomically correct flow phantoms. METHODS: A set of usability and performance criteria was established for a proposed phantom design capable of supporting liquid flow during imaging. A literature search was conducted to identify the materials and methods previously used in phantom fabrication. A database of human tissue and casting material properties was compiled to facilitate the selection of appropriate materials for testing. Several industrial casting materials were selected, procured, and used to fabricate test samples that were imaged with ultrasound, MRI, and CT. RESULTS: Five silicones and one polyurethane were selected for testing. Samples of all materials were successfully fabricated. All imaging modalities were able to discriminate between the materials tested. Ultrasound testing showed that three of the silicones could be imaged to a depth of at least 2.5 cm (1 in.). The RP 6400 polyurethane exhibited excellent contrast and edge detail for MRI phantoms and appears to be an excellent water reference for CT applications. The 10T and 27T silicones appear to be usable water references for MRI imaging. CONCLUSIONS: Based on study data and the stated selection criteria, the P-4 silicone provided sufficient material contrast to water and edge detail for use across all imaging modalities with the benefits of availability, low cost, dimensional stability, nontoxic, nonflammable, durable, cleanable, and optical clarity. The physical and imaging differences of the materials documented in this study may be useful for other applications. PMID- 23635301 TI - Response to comment on Screening for PBT chemicals among the "existing" and "new" chemicals of the EU. PMID- 23635302 TI - Disease-specific health-related quality of life (HRQL) instruments for food allergy: protocol for a systematic review. AB - BACKGROUND: The European Academy of Allergy and Clinical Immunology is in the process of developing its Guideline for Food Allergy and Anaphylaxis, and this systematic review is one of seven inter-linked evidence syntheses that are being undertaken in order to provide a state-of-the-art synopsis of the current evidence base in relation to epidemiology, prevention, diagnosis and clinical management, and impact on quality of life, which will be used to inform clinical recommendations. The aim of this systematic review will be to determine which validated instruments can be employed to enable assessment of the impact of, and investigations and interventions for, food allergy on health-related quality of life. METHODS: Seven bibliographic databases were searched from their inception to September 30, 2012 for disease-specific HRQL questionnaires that were specifically designed for use with patients/carers and any articles relating to the description, development and/or the validation of the above identified HRQLs. There were no language or geographic restrictions. We will assess the development of the instruments identified and their performance properties including: validity; generalizability; responsiveness; managing missing data; how variation in patient demography was managed; and cross-cultural and linguistic adaptation, using a previously reported quality assessment tool. DISCUSSION: Using appropriately developed and validated instruments is critical to the accurate evaluation of HRQL in people with food allergy. This review will systematically appraise the evidence on the subject and help to identify any gaps. PMID- 23635303 TI - Neighbourhood safety and area deprivation modify the associations between parkland and psychological distress in Sydney, Australia. AB - BACKGROUND: The aim of this study was to investigate how perceived neighbourhood safety and area deprivation influenced the relationship between parklands and mental health. METHODS: Information about psychological distress, perceptions of safety, demographic and socio-economic background at the individual level was extracted from New South Wales Population Health Survey. The proportion of a postcode that was parkland was used as a proxy measure for access to parklands and was calculated for each individual. Generalized Estimating Equations logistic regression analyses were performed to account for correlation between participants within postcodes, and with controls for socio-demographic characteristics and socio-economic status at the area level. RESULTS: In areas where the residents reported perceiving their neighbourhood to be "safe" and controlling for area levels of socio-economic deprivation, there were no statistically significant associations between the proportion of parkland and high or very high psychological distress. In the most disadvantaged neighbourhoods which were perceived as unsafe by residents, those with greater proportions of parkland, over 20%, there was greater psychological distress, this association was statistically significant (20-40% parkland: OR=2.27, 95% CI=1.45 3.55; >40% parkland: OR=2.53, 95% CI=1.53-4.19). CONCLUSION: Our study indicates that perceptions of neighbourhood safety and area deprivation were statistically significant effect modifiers of the association between parkland and psychological distress. PMID- 23635304 TI - The effect of feeding a low iron diet prior to and during gestation on fetal and maternal iron homeostasis in two strains of rat. AB - BACKGROUND: Iron deficiency anaemia during pregnancy is a global problem, with short and long term consequences for maternal and child health. Animal models have demonstrated that the developing fetus is vulnerable to maternal iron restriction, impacting on postnatal metabolic and blood pressure regulation. Whilst long-term outcomes are similar across different models, the commonality in mechanistic events across models is unknown. This study examined the impact of iron deficiency on maternal and fetal iron homeostasis in two strains of rat. METHODS: Wistar (n=20) and Rowett Hooded Lister (RHL, n=19) rats were fed a control or low iron diet for 4 weeks prior to and during pregnancy. Tissues were collected at day 21 of gestation for analysis of iron content and mRNA/protein expression of regulatory proteins and transporters. RESULTS: A reduction in maternal liver iron content in response to the low iron diet was associated with upregulation of transferrin receptor expression and a reduction in hepcidin expression in the liver of both strains, which would be expected to promote increased iron absorption across the gut and increased turnover of iron in the liver. Placental expression of transferrin and DMT1+IRE were also upregulated, indicating adaptive responses to ensure availability of iron to the fetus. There were considerable differences in hepatic maternal and fetal iron content between strains. The higher quantity of iron present in livers from Wistar rats was not explained by differences in expression of intestinal iron transporters, and may instead reflect greater materno-fetal transfer in RHL rats as indicated by increased expression of placental iron transporters in this strain. CONCLUSIONS: Our findings demonstrate substantial differences in iron homeostasis between two strains of rat during pregnancy, with variable impact of iron deficiency on the fetus. Whilst common developmental processes and pathways have been observed across different models of nutrient restriction during pregnancy, this study demonstrates differences in maternal adaptation which may impact on the trajectory of the programmed response. PMID- 23635306 TI - Molecular-level insight into unusual low pressure CO2 affinity in pillared metal organic frameworks. AB - Fundamental insight into how low pressure adsorption properties are affected by chemical functionalization is critical to the development of next-generation porous materials for postcombustion CO2 capture. In this work, we present a systematic approach to understanding low pressure CO2 affinity in isostructural metal-organic frameworks (MOFs) using molecular simulations and apply it to obtain quantitative, molecular-level insight into interesting experimental low pressure adsorption trends in a series of pillared MOFs. Our experimental results show that increasing the number of nonpolar functional groups on the benzene dicarboxylate (BDC) linker in the pillared DMOF-1 [Zn2(BDC)2(DABCO)] structure is an effective way to tune the CO2 Henry's coefficient in this isostructural series. These findings are contrary to the common scenario where polar functional groups induce the greatest increase in low pressure affinity through polarization of the CO2 molecule. Instead, MOFs in this isostructural series containing nitro, hydroxyl, fluorine, chlorine, and bromine functional groups result in little increase to the low pressure CO2 affinity. Strong agreement between simulated and experimental Henry's coefficient values is obtained from simulations on representative structures, and a powerful yet simple approach involving the analysis of the simulated heats of adsorption, adsorbate density distributions, and minimum energy 0 K binding sites is presented to elucidate the intermolecular interactions governing these interesting trends. Through a combined experimental and simulation approach, we demonstrate how subtle, structure-specific differences in CO2 affinity induced by functionalization can be understood at the molecular-level through classical simulations. This work also illustrates how structure-property relationships resulting from chemical functionalization can be very specific to the topology and electrostatic environment in the structure of interest. Given the excellent agreement between experiments and simulation, predicted CO2 selectivities over N2, CH4, and CO are also investigated to demonstrate that methyl groups also provide the greatest increase in CO2 selectivity relative to the other functional groups. These results indicate that methyl ligand functionalization may be a promising approach for creating both water stable and CO2 selective variations of other MOFs for various industrial applications. PMID- 23635305 TI - Genome-wide search for the genes accountable for the induced resistance to HIV-1 infection in activated CD4+ T cells: apparent transcriptional signatures, co expression networks and possible cellular processes. AB - BACKGROUND: Upon co-stimulation with CD3/CD28 antibodies, activated CD4 + T cells were found to lose their susceptibility to HIV-1 infection, exhibiting an induced resistant phenotype. This rather unexpected phenomenon has been repeatedly confirmed but the underlying cell and molecular mechanisms are still unknown. METHODS: We first replicated the reported system using the specified Dynal beads with PHA/IL-2-stimulated and un-stimulated cells as controls. Genome-wide expression and analysis were then performed by using Agilent whole genome microarrays and established bioinformatics tools. RESULTS: We showed that following CD3/CD28 co-stimulation, a homogeneous population emerged with uniform expression of activation markers CD25 and CD69 as well as a memory marker CD45RO at high levels. These cells differentially expressed 7,824 genes when compared with the controls on microarrays. Series-Cluster analysis identified 6 distinct expression profiles containing 1,345 genes as the representative signatures in the permissive and resistant cells. Of them, 245 (101 potentially permissive and 144 potentially resistant) were significant in gene ontology categories related to immune response, cell adhesion and metabolism. Co-expression networks analysis identified 137 "key regulatory" genes (84 potentially permissive and 53 potentially resistant), holding hub positions in the gene interactions. By mapping these genes on KEGG pathways, the predominance of actin cytoskeleton functions, proteasomes, and cell cycle arrest in induced resistance emerged. We also revealed an entire set of previously unreported novel genes for further mining and functional validation. CONCLUSIONS: This initial microarray study will stimulate renewed interest in exploring this system and open new avenues for research into HIV-1 susceptibility and its reversal in target cells, serving as a foundation for the development of novel therapeutic and clinical treatments. PMID- 23635307 TI - Simulating Ru L3-edge X-ray absorption spectroscopy with time-dependent density functional theory: model complexes and electron localization in mixed-valence metal dimers. AB - Ruthenium L3-edge X-ray absorption (XA) spectroscopy probes unoccupied 4d orbitals of the metal atom and is increasingly being used to investigate the local electronic structure in ground and excited electronic states of Ru complexes. The simultaneous development of computational tools for simulating Ru L3-edge spectra is crucial for interpreting the spectral features at a molecular level. This study demonstrates that time-dependent density functional theory (TDDFT) is a viable and predictive tool for simulating ruthenium L3-edge XA spectroscopy. We systematically investigate the effects of exchange correlation functional and implicit and explicit solvent interactions on a series of Ru(II) and Ru(III) complexes in their ground and electronic excited states. The TDDFT simulations reproduce all of the experimentally observed features in Ru L3-edge XA spectra within the experimental resolution (0.4 eV). Our simulations identify ligand-specific charge transfer features in complicated Ru L3-edge spectra of [Ru(CN)6](4-) and Ru(II) polypyridyl complexes illustrating the advantage of using TDDFT in complex systems. We conclude that the B3LYP functional most accurately predicts the transition energies of charge transfer features in these systems. We use our TDDFT approach to simulate experimental Ru L3-edge XA spectra of transition metal mixed-valence dimers of the form [(NC)5M(II)-CN Ru(III)(NH3)5](-) (where M = Fe or Ru) dissolved in water. Our study determines the spectral signatures of electron delocalization in Ru L3-edge XA spectra. We find that the inclusion of explicit solvent molecules is necessary for reproducing the spectral features and the experimentally determined valencies in these mixed-valence complexes. This study validates the use of TDDFT for simulating Ru 2p excitations using popular quantum chemistry codes and providing a powerful interpretive tool for equilibrium and ultrafast Ru L3-edge XA spectroscopy. PMID- 23635308 TI - Mini-BAL: not a small matter. PMID- 23635309 TI - Comparing effects of low- and high-volume moderate-intensity exercise on sexual function and testosterone in obese men. AB - INTRODUCTION: Obesity and inactivity are associated with erectile dysfunction and hypogonadism. AIM: To compare the effects of low volume (LV) and high volume (HV) of moderate-intensity exercise on sexual function, testosterone, lower urinary tract symptoms (LUTS), endothelial function, and quality of life (QoL) in obese men. MAIN OUTCOME MEASURES: Weight, waist circumference (WC), body composition, International Index of Erectile Function 5-item (IIEF-5), International Prostate Symptom Scale (IPSS) (for LUTS), and 36-item Short Form Survey version 2 Instrument (SF-36) (for QoL) scores, plasma testosterone, sex-hormone binding globulin, glucose, insulin and lipids, and endothelial function (by Reactive Hyperaemia Index [RHI] using finger plethysmography) were measured at baseline and 24 weeks. METHODS: Ninety abdominally obese (body mass index > 27.5 kg/m(2), WC > 90 cm), sedentary (exercise ~ 80 minutes/week) Asian men (mean age 43.6 years, range 30-60) were prescribed a diet to reduce daily intake by ~ 400 kcal below calculated requirement and randomized to perform moderate-intensity exercise of LV (<150 minutes/week) or HV (200-300 minutes/week) (n = 45 each) for 24 weeks. Seventy-five men (83.3%) completed the study. RESULTS: Weekly exercise volume was significantly greater in the HV (236 +/- 9 minutes) than the LV (105 +/- 9 minutes) group. The HV group had significantly greater increases in IIEF-5 score (2.6 +/- 0.5 points) and testosterone (2.06 +/- 0.46 nmol/L) and reductions in weight (-5.9 +/- 0.7 kg, -6.2%), WC (-4.9 +/- 0.8 cm, -4.9%), and fat mass ( 4.7 +/- 1.0 kg, -14.5%) than the LV group (-2.9 +/- 0.7 kg, -3.0%; -2.7 +/- 0.7 cm, -2.5%; -1.1 +/- 0.8 kg, -3.2%; 0.79 +/- 0.46 nmol/L; and 1.8 +/- 0.5 points). Improvements in IPSS and SF-36 scores, and RHI, were similar. CONCLUSIONS: Moderate-intensity HV aerobic exercise > 200 minutes/week produces greater improvements in sexual function, testosterone, weight, WC, and fat mass than smaller exercise volume. PMID- 23635310 TI - Primary care providers' self-efficacy and outcome expectations for childhood obesity counseling. AB - BACKGROUND: Primary care providers have a role in the prevention and management of childhood obesity. We explored the relationship of providers' self-efficacy, outcome expectations, and practice level support with childhood obesity counseling frequency. METHODS: Providers (n=123) completed a survey that assessed their self-efficacy, outcome expectations, and reported obesity counseling frequency. A practice level assessment tool was used to characterize the practices. We analyzed data using frequencies and proportional odds modeling. RESULTS: Providers were confident or very confident (78.5-93.5%) in their ability to counsel about healthy eating, physical activity, and weight and agreed or strongly agreed (64.2-86.2%) that their counseling would result in actual changes. Providers with higher outcome expectations were more likely [odds ratio (OR)=3.4] to report providing obesity counseling. Female providers were more likely to report counseling about obesity (OR=2.3) than males. Providers in practices with resources for healthy eating and physical activity reported higher levels of self-efficacy and counseling frequency. CONCLUSIONS: In our study, providers were confident in their ability to provide obesity counseling and expected changes from their efforts, suggesting that future studies should build on the high level of outcome expectations as well as self-efficacy. The gender difference found regarding obesity counseling may need further exploration. PMID- 23635311 TI - Nutritional quality of meals compared to snacks in child care. AB - BACKGROUND: Most young children are in child care. Previous studies suggest that children may receive insufficient vegetables, and foods and beverages with added sugars, fats, and sodium in these settings. None have compared the nutritional quality of meals to snacks. METHODS: Directors from 258 full-day child-care centers in two urban counties of southwestern Ohio were surveyed via telephone in the fall of 2009 about their nutrition practices, and asked to provide a current menu. Lunch and afternoon snack menus were categorized according to average weekly frequency for fruits, vegetables, lean meats, juice (100%), and sweet or salty foods served. Frequencies were compared by meal occasion (lunch vs. snack) using the Fisher exact test. RESULTS: Most (60%) directors reported serving 2% milk to children >=3 years; 31% served whole milk. Menu analysis demonstrated the composition of lunches differed from snacks (p<0.0001) in all food categories. A total of 87% centers rarely (<1 time per week) listed nonstarchy vegetables for snacks, but 67% of centers included them at lunch >=3 times per week. Juice (100%) was on snack menus >2 times per week in 37% centers, but in only 1 center as a regular component of lunch. Similarly, 87% centers listed sweet and salty foods at snack >=3 times per week, but rarely at lunch. CONCLUSIONS: Despite efforts to improve children's diets in child care, meals-and particularly snacks still lack whole fruits and nonstarchy vegetables and contain added sugars and fats. Snacks represent a missed opportunity to improve the nutritional quality of foods served in childcare. PMID- 23635312 TI - Slow and steady: readiness, pretreatment weekly strengthening activity, and pediatric weight management program completion. AB - BACKGROUND: Pediatric weight management programs have substantial attrition rates, which have led to recommendations to assess readiness prior to enrollment. Both pretreatment readiness scales and behaviors, such as exercise, have been theorized to predict subsequent program completion. The purpose of this study was to explore the role of self-reported pretreatment exercise in adolescents on completion of a pediatric weight management program and to explore the predictive ability of standard readiness scales. METHODS: A total of 146 obese (BMI>=95(th) percentile) pediatric (ages 11-18) participants joined a 6-month multidisciplinary weight management program between March, 2007, and July, 2010. Completers were compared retrospectively to noncompleters on demographic, readiness, and pretreatment exercise practices from clinic-developed intake questionnaires using univariate analyses. Regression analyses specified the degree to which these variables predicted program completion. RESULTS: The 6 month completion rate was 53%. There was no relationship between self-reported readiness and program completion. Self-reported pretreatment weekly strengthening activity (SA) was significantly associated with program completion, compared to those who performed SA either never [univariate odds ratio (OR) 3.18, 95% confidence interval (CI) 1.51-6.68, p=0.002; multivariate OR 2.43, 95% CI 1.06 5.58, p=0.036] or daily (univariate OR 4.90, 95% CI 1.74-13.77, p=0.002; multivariate OR 4.69, 95% CI 1.45-15.14, p=0.010). No relationship was found between other forms of exercise and program completion. CONCLUSIONS: Self reported pretreatment weekly SA, but not standard readiness scales, predicted pediatric weight management program completion. PMID- 23635314 TI - Fas-associated factor 1 plays a negative regulatory role in the antibacterial immunity of Locusta migratoria. AB - Insect immune responses are precisely regulated to maintain immune balance. In this study, the Fas-associated factor 1 (FAF1) gene of Locusta migratoria manilensis, a homologue of the caspar gene that functions as a specific negative regulator in the antibacterial immunity pathway, was cloned. Gene expression analysis showed that FAF1 was expressed throughout the developmental stages and in all tested tissues, but its transcription levels varied significantly. Thus, FAF1 appears to be tightly regulated and is probably involved in multiple physiological processes. In addition, the antimicrobial peptide gene prolixicin was cloned and characterized. After bacterial challenge, prolixicin was rapidly up-regulated, whereas FAF1 was markedly down-regulated. This result was consistent with the observation that prolixicin was hyperactivated when FAF1 was suppressed by RNA interference. Moreover, after bacterial infection, the survival rate of FAF1-knockdown locusts was much higher than that of the wild-type. Taken together, these findings strongly suggest that FAF1 shares a similar function as caspar in Drosophila and may be involved in the negative regulation of antibacterial immunity in locusts. PMID- 23635313 TI - Facile and efficient reprogramming of ciliary body epithelial cells into induced pluripotent stem cells. AB - Induced pluripotent stem (iPS) cells are attractive for cell replacement therapy, because they overcome ethical and immune rejection issues that are associated with embryonic stem cells. iPS cells have been derived from autonomous fibroblasts at low efficiency using multiple ectopic transcription factors. Recent evidence suggests that the epigenome of donor cell sources plays an important role in the reprogramming and differentiation characteristics of iPS cells. Thus, identification of somatic cell types that are easily accessible and are more amenable for cellular reprogramming is critical for regenerative medicine applications. Here, we identify ciliary body epithelial cells (CECs) as a new cell type for iPS cell generation that has higher reprogramming efficiency compared with fibroblasts. The ciliary body is composed of epithelial cells that are located in the anterior portion of the eye at the level of the lens and is readily surgically accessible. CECs also have a reduced reprogramming requirement, as we demonstrate that ectopic Sox2 and c-Myc are dispensable. Enhanced reprogramming efficiency may be due to increased basal levels of Sox2 in CECs. In addition, we are the first to report a cellular reprogramming haploinsufficiency observed when reprogramming with fewer factors (Oct4 and Klf4) in Sox2 hemizygous cells. Taken together, endogenous Sox2 levels are critical for the enhanced efficiency and reduced exogenous requirement that permit facile cellular reprogramming of CECs. PMID- 23635315 TI - Regional variation in care at the end of life: discontinuation of dialysis. AB - BACKGROUND: Regional variation in the intensity of end-of-life care contributes significantly to the overall cost of health care. The interpretation of patterns of regional variation hinges, in part, on appropriate adjustment for regional variation in demographic variables such as age, race, sex, and rural vs. urban residence. This study examined regional variation in discontinuation of dialysis prior to death in the US, after adjustment for key demographic variables. METHODS: In this retrospective cohort study of the 2009 United States Renal Data System (USRDS) database we examined discontinuation of dialysis prior to death among deceased adult patients with end-stage renal disease (ESRD) from the 50 states and the District of Columbia. The discontinuation of dialysis prior to death was ascertained from the Centers for Medicare & Medicaid Services form 2746 (ESRD Death Notification form). We used logistic regression to estimate the log odds of discontinuation of dialysis with ESRD network as independent variable adjusted for urban-rural status, demographic and treatment variables. RESULTS: The study cohort included 715,605 deceased ESRD patients; for 176,021 of whom (24.6%) dialysis was discontinued prior to death. Dialysis was discontinued at higher rates for women than for men (26.3% vs. 23.0%, p < 0.001) and for whites than for blacks (29.5% vs. 14.7%, p < 0.001). Significant regional variation in dialysis discontinuation prior to death was noted after adjustment for age, race and rural-urban status: rates of discontinuation in the Upper Midwest and Mountain regions were more than double the rates in Southern and Coastal regions. This pattern parallels the regional pattern of end-of-life health service utilization documented in the Dartmouth Atlas and other studies. CONCLUSIONS: Discontinuation of dialysis prior to death was common in the US between 1995 and 2009. The deaths of nearly one quarter of chronic dialysis patients followed a decision to discontinue dialysis. Significant regional variation in discontinuation rates exists after adjusting for age, race, sex, and rural-urban status. Further research and analysis is needed on the cultural and economic factors that affect regional variation in health services utilization, especially in regard to the use of expensive medical services near the end of life. PMID- 23635316 TI - Small breast epithelial mucin tumor tissue expression is associated with increased risk of recurrence and death in triple-negative breast cancer patients. AB - BACKGROUND: Small breast epithelial mucin (SBEM) has been implicated in tumor genesis and micrometastasis in breast cancer. Triple-negative breast cancer (TNBC) was characterized by high incidence in young women,early relapse and a very poor prognosis. The aim of this study was to evaluate the association of SBEM expression in tissues of TNBC with disease-free survival (DFS) and overall survival (OS). METHODS: SBEM protein expression was detected in 87 available formalin-fixed paraffin-embedded (FFPE) tissue specimens from TNBC patients by means of immunohistochemistry (IHC). We analyzed the correlation between the SBEM protein expression and DFS and OS during a 5 year follow-up period, respectively. And a SBEM cut-off value of prognosis was established associated with DFS and OS. SBEM was analyzed against other risk factors in multivariate analysis. RESULTS: SBEM 3+ score was cut-off value of prognosis and significantly correlated with DFS (p = 0.000) and OS (p = 0.001) in TNBC patients. There was a marked associations (p <0.05) between SBEM 3+ score and tumor size, grade, node status, TNM stage and Ki67. Multivariate analysis showed that patients with SBEM 3+ represented a higher risk of recurrence and mortality than those with a lower SBEM expression (HR = 3.370 with p = 0.008 for DFS and HR = 4.185 with p = 0.004 for OS). CONCLUSIONS: SBEM is an independent risk predictor and may offer utility as a prognostic marker in TNBC patients. PMID- 23635317 TI - Enantioselective bioaccumulation and degradation of sediment-associated metalaxyl enantiomers in Tubifex tubifex. AB - Knowledge about the enantioselective bioavailability of chiral pesticides in aquatic organisms facilitates more accurate interpretation of their environmental behaviors. In this study, the enantioselective bioaccumulation of metalaxyl enantiomers in Tubifex tubifex was detected in two uptake pathways. For the spike water treatment, a 16 day exposure experiment was employed and the enantiomer fractions (EFs) in tubifex tissue were maintained approximately at 0.47 during the experiment. For the spike sediment treatment, a 14 day bioaccumulation period indicated the concentrations of (-)-(R)-metalaxyl were higher than those of (+) (S)-metalaxyl. Therefore, the bioaccumulation of metalaxyl in worms was enantioselective for these treatments. With the presence of tubifex, higher concentrations of metalaxyl in overlying water and lower concentrations in sediment were detected than in worm-free treatments. This means that tubifex has positive functions in metalaxyl's diffusion from the sediment to overlying water and in the degradation of the sediment-associated metalaxyl. PMID- 23635318 TI - Emergence of large chiroptical responses by ligand exchange cross-linking of monolayer-protected gold clusters with chiral dithiol. AB - We here present a study of cross-linking chemistry of optically inactive monothiol-protected gold clusters by chiral bidentate dithiol with two stereogenic centers, (2R,3R)-1,4-dimercapto-2,3-butanediol (L-dithiothreitol; L DTT), and explore the impacts of the cross-linking on their chiroptical responses. The pristine protective ligand is racemic penicillamine (rac-Pen), and the products of the ligand exchange reactions include clusters containing both rac-Pen and L-DTT (partial exchange). Electrophoresis using polyacrylamide gel with a very low gel concentration (3%) can make the products separable into two components, each of which has the similar mean core diameter of 0.78 and 0.83 nm, so the difference in the relative mobility is mainly ascribed to the size of the cluster assembly. In addition, very large optical activity with the maximum anisotropy factors of about 1.0 * 10(-3) is found for the assemblies. In comparison with chiral 1,3-dithiol protection incapable of cross-linking between gold clusters, we propose that the observed optical activity is due to surface intrinsic handedness caused by a cyclic cross-linking with at least two L-DTT molecules. PMID- 23635319 TI - Piezotronic effect in solution-grown p-type ZnO nanowires and films. AB - Investigating the piezotronic effect in p-type piezoelectric semiconductor is critical for developing a complete piezotronic theory and designing/fabricating novel piezotronic applications with more complex functionality. Using a low temperature solution method, we were able to produce ultralong (up to 60 MUm in length) Sb doped p-type ZnO nanowires on both rigid and flexible substrates. For the p-type nanowire field effect transistor, the on/off ratio, threshold voltage, mobility, and carrier concentration of 0.2% Sb-doped sample are found to be 10(5), 2.1 V, 0.82 cm(2).V(-1).s(-1), and 2.6 * 10(17) cm(-3), respectively, and the corresponding values for 1% Sb doped samples are 10(4), 2.0 V, 1.24 cm(2).V( 1).s(-1), and 3.8 * 10(17) cm(-3). We further investigated the universality of piezotronic effect in the as-synthesized Sb-doped p-type ZnO NWs and reported for the first time strain-gated piezotronic transistors as well as piezopotential driven mechanical energy harvesting based on solution-grown p-type ZnO NWs. The results presented here broaden the scope of piezotronics and extend the framework for its potential applications in electronics, optoelectronics, smart MEMS/NEMS, and human-machine interfacing. PMID- 23635320 TI - Smart fluorescent proteins: innovation for barrier-free superresolution imaging in living cells. AB - During the past decade, several novel fluorescence microscopy techniques have emerged that achieve incredible spatial and temporal resolution beyond the diffraction limit. These microscopy techniques depend on altered optical setups, unique fluorescent probes, or post-imaging analysis. Many of these techniques also depend strictly on the use of unique fluorescent proteins (FPs) with special photoswitching properties. These photoswitchable FPs are capable of switching between two states in response to light. All localization precision and patterned illumination techniques-such as photo-activation localization microscopy, stochastic optical reconstruction microscopy, reversible saturable optically linear transitions, and saturated structured illumination microscopy-take advantage of these inherent switching properties to achieve superior spatial resolution. This review provides extensive analysis of the positive and negative aspects of photoswitchable FPs, highlighting their application in diffraction unlimited imaging and suggesting the most suitable fluorescent proteins for superresolution imaging. PMID- 23635321 TI - Ag-mediated charge transport during metal-assisted chemical etching of silicon nanowires. AB - The charge transport mechanism during metal-assisted chemical etching of Si nanowires with contiguous metal films has been investigated. The experiments give a better insight how the charges and reaction products can penetrate to the etching front. The formation of a layer of porous Si between the metal film and the bulk Si is a prerequisite for the etching process. The electronic holes (positive charges) necessary for the etching of porous Si are generated at the surface of the metal in contact with the oxidative agent. Because of the insulating character of the thin walls of the porous Si, the transport of the electronic holes through this layer is not possible. Instead, it is found that the transport of electronic holes proceeds primarily by means of the Ag/Ag(+) redox pair circulating in the electrolyte and diffusing through the etched pores in the Si. The charge transport occurs without the ionic contribution at the positions where the metal is in direct contact with the Si. Here, an electropolishing process takes place, leading to an extensive removal of the Si and sinking in of the film into the Si substrate. PMID- 23635323 TI - 2013 update on the worldwide standardization of the HbA1c measurement. PMID- 23635322 TI - Human astrocytes derived from glial restricted progenitors support regeneration of the injured spinal cord. AB - Cellular transplantation using neural stem cells and progenitors is a promising therapeutic strategy that has the potential to replace lost cells, modulate the injury environment, and create a permissive environment for the regeneration of injured host axons. Our research has focused on the use of human glial restricted progenitors (hGRP) and derived astrocytes. In the current study, we examined the morphological and phenotypic properties of hGRP prepared from the fetal central nervous system by clinically-approved protocols, compared with astrocytes derived from hGRP prepared by treatment with ciliary neurotrophic factor or bone morphogenetic protein 4. These differentiation protocols generated astrocytes that showed morphological differences and could be classified along an immature to mature spectrum, respectively. Despite these differences, the cells retained morphological and phenotypic plasticity upon a challenge with an alternate differentiation protocol. Importantly, when hGRP and derived astrocytes were transplanted acutely into a cervical dorsal column lesion, they survived and promoted regeneration of long ascending host sensory axons into the graft/lesion site, with no differences among the groups. Further, hGRP taken directly from frozen stocks behaved similarly and also supported regeneration of host axons into the lesion. Our results underscore the dynamic and permissive properties of human fetal astrocytes to promote axonal regeneration. They also suggest that a time-consuming process of pre-differentiation may not be necessary for therapeutic efficacy, and that the banking of large quantities of readily available hGRP can be an appropriate source of permissive cells for transplantation. PMID- 23635325 TI - Multiplexed electrochemical protein detection and translation to personalized cancer diagnostics. AB - Measuring diagnostic panels of multiple proteins promises a new, personalized approach to early detection and therapy of diseases like cancer. Levels of biomarker proteins in patient serum can provide a continually updated record of disease status. Research in electrochemical detection of proteins has produced exquisitely sensitive approaches. Most utilize ELISA-like sandwich immunoassays incorporating various aspects of nanotechnology. Several of these ultrasensitive methodologies have been extended to microfluidic multiplexed protein detection, but engineered solutions are needed to measure more proteins in a single device from a small patient sample such as a drop of blood or tissue lysate. To achieve clinical or point-of-care (POC) use, simplicity and low cost are essential. In multiplexed microfluidic immunoassays, required reagent additions and washing steps pose a significant problem calling for creative engineering. A grand challenge is to develop a general cancer screening device to accurately measure 50-100 proteins in a simple, cost-effective fashion. This will require creative solutions to simplified reagent addition and multiplexing. PMID- 23635324 TI - Immunity, atherosclerosis and cardiovascular disease. AB - Atherosclerosis, the major cause of cardiovascular disease (CVD), is a chronic inflammatory condition with immune competent cells in lesions producing mainly pro-inflammatory cytokines. Dead cells and oxidized forms of low density lipoproteins (oxLDL) are abundant. The major direct cause of CVD appears to be rupture of atherosclerotic plaques. oxLDL has proinflammatory and immune stimulatory properties, causes cell death at higher concentrations and contains inflammatory phospholipids with phosphorylcholine (PC) as an interesting epitope. Antibodies against PC (anti-PC) may be atheroprotective, one mechanism being anti inflammatory. Bacteria and virus have been discussed, but it has been difficult to find direct evidence, and antibiotic trials have not been successful. Heat shock proteins could be one major target for atherogenic immune reactions. More direct causes of plaque rupture include pro-inflammatory cytokines, chemokines, and lipid mediators. To prove that inflammation is a cause of atherosclerosis and CVD, clinical studies with anti-inflammatory and/or immune-modulatory treatment are needed. The potential causes of immune reactions and inflammation in atherosclerosis and how inflammation can be targeted therapeutically to provide novel treatments for CVD are reviewed. PMID- 23635326 TI - A new device for intraoperative renal blood flow measurement during open-heart surgery: an experimental study and the clinical pilot study. AB - Renal blood flow (RBF) may vary during cardiopulmonary bypass and low flow may cause insufficient blood supply of the kidney triggering renal failure postoperatively. Still, a valid intraoperative method of continuous RBF measurement is not available. A new catheter combining thermodilution and intravascular Doppler was developed, first calibrated in an in vitro model, and the catheter specific constant was determined. Then, application of the device was evaluated in a pilot study in an adult cardiovascular population. The data of the clinical pilot study revealed high correlation between the flow velocities detected by intravascular Doppler and the RBF measured by thermodilution (Pearson's correlation range: 0.78 to 0.97). In conclusion, the RBF can be measured excellently in real time using the new catheter, even under cardiopulmonary bypass. PMID- 23635327 TI - Construction of Escherichia coli strains with chromosomally integrated expression cassettes for the synthesis of 2'-fucosyllactose. AB - BACKGROUND: The trisaccharide 2'-fucosyllactose (2'-FL) is one of the most abundant oligosaccharides found in human milk. Due to its prebiotic and anti infective properties, 2'-FL is discussed as nutritional additive for infant formula. Besides chemical synthesis and extraction from human milk, 2'-FL can be produced enzymatically in vitro and in vivo. The most promising approach for a large-scale formation of 2'-FL is the whole cell biosynthesis in Escherichia coli by intracellular synthesis of GDP-L-fucose and subsequent fucosylation of lactose with an appropriate alpha1,2-fucosyltransferase. Even though whole cell approaches have been demonstrated for the synthesis of 2'-FL, further improvements of the engineered E. coli host are required to increase product yields. Furthermore, an antibiotic-free method of whole cell synthesis of 2'-FL is desirable to simplify product purification and to avoid traces of antibiotics in a product with nutritional purpose. RESULTS: Here we report the construction of the first selection marker-free E. coli strain that produces 2'-FL from lactose and glycerol. To construct this strain, recombinant genes of the de novo synthesis pathway for GDP-L-fucose as well as the gene for the H. pylori fucosyltransferase futC were integrated into the chromosome of E. coli JM109 by using the lambda-Red recombineering technique. Strains carrying additional copies of the futC gene and/or the gene fkp (from Bacteroides fragilis) for an additional salvage pathway for GDP-L-fucose production were used and shown to further improve production of 2'-FL in shake flask experiments. An increase of the intracellular GDP-L-fucose concentration by expression of fkp gene as well as an additional copy of the futC gene lead to an enhanced formation of 2'-FL. Using an improved production strain, feasibility of large scale 2'-FL production was demonstrated in an antibiotic-free fed-batch fermentation (13 l) with a final 2' FL concentration of 20.28 +/- 0.83 g l(-1) and a space-time-yield of 0.57 g l(-1) h(-1). CONCLUSIONS: By chromosomal integration of recombinant genes, altering the copy number of these genes and analysis of 2'-FL and intracellular GDP-L-fucose levels, we were able to construct and improve the first selection marker-free E. coli strain which is capable to produce 2'-FL without the use of expression plasmids. Analysis of intracellular GDP-L-fucose levels identified the de novo synthesis pathway of GDP-L-fucose as one bottleneck in 2'-FL production. In antibiotic-free fed-batch fermentation with an improved strain, scale-up of 2'-FL could be demonstrated. PMID- 23635328 TI - Investigations on the efficacy of routinely used phenotypic methods compared to genotypic approaches for the identification of staphylococcal species isolated from companion animals in Irish veterinary hospitals. AB - BACKGROUND: Identification of Staphylococci to species level in veterinary microbiology is important to inform therapeutic intervention and management. We report on the efficacy of three routinely used commercial phenotypic methods for staphylococcal species identification, namely API Staph 32 (bioMerieux), RapID (Remel) and Staph-Zym (Rosco Diagnostica) compared to genotyping as a reference method to identify 52 staphylococcal clinical isolates (23 coagulase positive; 29 coagulase negative) from companion animals in Irish veterinary hospitals. RESULTS: Genotyping of a 412 bp fragment of the staphylococcal tuf gene and coagulase testing were carried out on all 52 veterinary samples along with 7 reference strains. In addition, genotyping of the staphylococcal rpoB gene, as well as PCR-RFLP of the pta gene, were performed to definitively identify members of the Staphylococcus intermedius group (SIG). The API Staph 32 correctly identified all S. aureus isolates (11/11), 83% (10/12) of the SIG species, and 66% (19/29) of the coagulase negative species. RapID and Staph-Zym correctly identified 61% (14/23) and 0% (0/23) respectively of the coagulase-positives, and 10% (3/29) and 3% (1/29) respectively of the coagulase-negative species. CONCLUSIONS: Commercially available phenotypic species identification tests are inadequate for the correct identification of both coagulase negative and coagulase positive staphylococcal species from companion animals. Genotyping using the tuf gene sequence is superior to phenotyping for identification of staphylococcal species of animal origin. However, use of PCR-RFLP of pta gene or rpoB sequencing is recommended as a confirmatory method for discriminating between SIG isolates. PMID- 23635329 TI - Treatment of malignant effusion by oncolytic virotherapy in an experimental subcutaneous xenograft model of lung cancer. AB - BACKGROUND: Malignant pleural effusion (MPE) is associated with advanced stages of lung cancer and is mainly dependent on invasion of the pleura and expression of vascular endothelial growth factor (VEGF) by cancer cells. As MPE indicates an incurable disease with limited palliative treatment options and poor outcome, there is an urgent need for new and efficient treatment options. METHODS: In this study, we used subcutaneously generated PC14PE6 lung adenocarcinoma xenografts in athymic mice that developed subcutaneous malignant effusions (ME) which mimic pleural effusions of the orthotopic model. Using this approach monitoring of therapeutic intervention was facilitated by direct observation of subcutaneous ME formation without the need of sacrificing mice or special imaging equipment as in case of MPE. Further, we tested oncolytic virotherapy using Vaccinia virus as a novel treatment modality against ME in this subcutaneous PC14PE6 xenograft model of advanced lung adenocarcinoma. RESULTS: We demonstrated significant therapeutic efficacy of Vaccinia virus treatment of both advanced lung adenocarcinoma and tumor-associated ME. We attribute the efficacy to the virus-mediated reduction of tumor cell-derived VEGF levels in tumors, decreased invasion of tumor cells into the peritumoral tissue, and to viral infection of the blood vessel-invading tumor cells. Moreover, we showed that the use of oncolytic Vaccinia virus encoding for a single-chain antibody (scAb) against VEGF (GLAF-1) significantly enhanced mono therapy of oncolytic treatment. CONCLUSIONS: Here, we demonstrate for the first time that oncolytic virotherapy using tumor-specific Vaccinia virus represents a novel and promising treatment modality for therapy of ME associated with advanced lung cancer. PMID- 23635330 TI - Long-term cardiac changes in patients with systemic lupus erythematosus. AB - BACKGROUND: The aim of this study was evaluate the late-onset repercussions of heart alterations of patients with systemic lupus erythematosus (SLE) after a 13 year follow up. METHODS: A historical prospective study was carried out involving the analysis of data from the charts of patients with a confirmed diagnosis of lupus in follow up since 1998. The 13-year evolution was systematically reviewed and tabulated to facilitate the interpretation of the data. RESULTS: Forty-eight patient charts were analyzed. Mean patient age was 34.5 +/- 10.8 years at the time of diagnosis and 41.0 +/- 10.3 years at the time of the study (45 women and 3 men). Eight deaths occurred in the follow-up period (two due to heart problems). Among the alterations found on the complementary exams, 46.2% of cases demonstrated worsening at reevaluation and four patients required a heart catheterization. In these cases, coronary angioplasty was performed due to the severity of the obstructions and one case required a further catheterization, culminating in the need for surgical myocardial revascularization. CONCLUSION: The analysis demonstrated progressive heart impairment, with high rates of alterations on conventional complementary exams, including the need for angioplasty or revascularization surgery in four patients. These findings indicate the need for rigorous cardiac follow up in patients with systemic lupus erythematosus. PMID- 23635332 TI - Antiplatelet therapy: a double-edged sword in head injury? AB - Antiplatelet therapy for the treatment of cardiovascular diseases is common in the ageing population. Whether this therapy exacerbates brain injury after head trauma is an important, but unsettled, topic. In this issue of Critical Care, Fabbri and colleagues address the question of whether pre-injury intake of antiplatelet medication increases the risk profile of patients with posttraumatic intracranial lesions after head trauma. Antiplatelet medication, and in particular clopidogrel, increased the risk for haematoma progression, need for neurosurgical intervention and an unfavourable outcome. Clinicians should consider this increased risk profile in the treatment of respective patients. Since its introduction as an analgesic in 1897, aspirin has surprised the medical community more than once due to its versatile properties. Prevention of secondary brain damage through aspirin has been reported for ischaemic stroke and subarachnoid haemorrhage. In cases of acute traumatic haemorrhage after head injury, antiplatelet therapy's neuroprotective effects may be outweighed by the increased bleeding tendency. PMID- 23635331 TI - The effectiveness of text messages support for diabetes self-management: protocol of the TEXT4DSM study in the democratic Republic of Congo, Cambodia and the Philippines. AB - BACKGROUND: People with diabetes find it difficult to sustain adequate self management behaviour. Self-Management Support strategies, including the use of mobile technology, have shown potential benefit. This study evaluates the effectiveness of a mobile phone support intervention on top of an existing strategy in three countries, DR Congo, Cambodia and the Philippines to improve health outcomes, access to care and enablement of people with diabetes, with 480 people with diabetes in each country who are randomised to either standard support or to the intervention. DESIGN/METHODS: The study consists of three sub studies with a similar design in three countries to be independently implemented and analysed. The design is a two-arm Randomised Controlled Trial, in which a total of 480 adults with diabetes participating in an existing DSME programme will be randomly allocated to either usual care in the existing programme or to usual care plus a mobile phone self-management support intervention. Participants in both arms complete assessments at baseline, one year and two years after inclusion.Glycosylated haemoglobin blood pressure, height, weight, waist circumference will be measured. Individual interviews will be conducted to determine the patients' assessment of chronic illness care, degree of self enablement, and access to care before implementation of the intervention, at intermediate moments and at the end of the study.Analyses of quantitative data including assessment of differences in changes in outcomes between the intervention and usual care group will be done. A probability of <0.05 is considered statistically significant. Outcome indicators will be plotted over time. All data are analysed for confounding and interaction in multivariate regression analyses taking potential clustering effects into account.Differences in outcome measures will be analysed per country and realistic evaluation to assess processes and context factors that influence implementation in order to understand why it works, for whom, under which circumstances. A costing study will be performed. DISCUSSION: The intervention addresses the problem that the greater part of diabetes management takes place without external support and that many challenges, unforeseen problems and questions occur at moments in between scheduled contacts with the support system, by exploiting communication technology. TRIAL REGISTRATION: ISRCTN86247213. PMID- 23635333 TI - 74 MHz nonthermal emission from molecular clouds: evidence for a cosmic ray dominated region at the galactic center. AB - We present 74 MHz radio continuum observations of the Galactic center region. These measurements show nonthermal radio emission arising from molecular clouds that is unaffected by free-free absorption along the line of sight. We focus on one cloud, G0.13-0.13, representative of the population of molecular clouds that are spatially correlated with steep spectrum (alpha(327MHz)(74MHz) = 1.3 +/- 0.3) nonthermal emission from the Galactic center region. This cloud lies adjacent to the nonthermal radio filaments of the Arc near l 0.2 degrees and is a strong source of 74 MHz continuum, SiO (2-1), and Fe I Kalpha 6.4 keV line emission. This three-way correlation provides the most compelling evidence yet that relativistic electrons, here traced by 74 MHz emission, are physically associated with the G0.13-0.13 molecular cloud and that low-energy cosmic ray electrons are responsible for the Fe I Kalpha line emission. The high cosmic ray ionization rate 10(-1)3 s(-1) H(-1) is responsible for heating the molecular gas to high temperatures and allows the disturbed gas to maintain a high-velocity dispersion. Large velocity gradient (LVG) modeling of multitransition SiO observations of this cloud implies H2 densities 10(4-5) cm(-3) and high temperatures. The lower limit to the temperature of G0.13-0.13 is 100 K, whereas the upper limit is as high as 1000 K. Lastly, we used a time-dependent chemical model in which cosmic rays drive the chemistry of the gas to investigate for molecular line diagnostics of cosmic ray heating. When the cloud reaches chemical equilibrium, the abundance ratios of HCN/HNC and N2H+/HCO+ are consistent with measured values. In addition, significant abundance of SiO is predicted in the cosmic ray dominated region of the Galactic center. We discuss different possibilities to account for the origin of widespread SiO emission detected from Galactic center molecular clouds. PMID- 23635334 TI - The impact of extrinsic demographic factors on Cantonese speech acquisition. AB - This study modeled the associations between extrinsic demographic factors and children's speech acquisition in Hong Kong Cantonese. The speech of 937 Cantonese speaking children aged 2;4 to 6;7 in Hong Kong was assessed using a standardized speech test. Demographic information regarding household income, paternal education, maternal education, presence of siblings and having a domestic helper as the main caregiver was collected via parent questionnaires. After controlling for age and sex, higher maternal education and higher household income were significantly associated with better speech skills; however, these variables explained a negligible amount of variance. Paternal education, number of siblings and having a foreign domestic helper did not associate with a child's speech acquisition. Extrinsic factors only exerted minimal influence on children's speech acquisition. A large amount of unexplained variance in speech ability still warrants further research. PMID- 23635336 TI - Sentence comprehension in Swahili-English bilingual agrammatic speakers. AB - For this study, sentence comprehension was tested in Swahili-English bilingual agrammatic speakers. The sentences were controlled for four factors: (1) order of the arguments (base vs. derived); (2) embedding (declarative vs. relative sentences); (3) overt use of the relative pronoun "who"; (4) language (English and Swahili). Two theories were tested: the Trace Deletion Hypothesis (TDH; [Grodzinsky, Y. (1995). A restrictive theory of agrammatic comprehension. Brain and Language, 50, 27-51]) that assumes a representational deficit in agrammatic aphasia and the Derived Order Problem Hypothesis (DOP-H; Bastiaanse & Van Zonneveld, 2005), which is a processing account. Both theories have the same predictions for sentences in derived order. The difference is that the TDH predicts chance level performance for sentences in which the arguments are not in base order, whereas the DOP-H predicts poorer performance when processing demands increase. The results show that word order influences performance, in that sentences in which the arguments are in derived order are harder to comprehend than sentences in which the arguments are in base order. However, there is a significant interaction with the factor "embedding": sentences with an embedding are harder to comprehend than simple declaratives and this influence is larger in derived order sentences. There is no effect of language nor of the use of a relative pronoun. These results are correctly accounted for by the DOP-H. PMID- 23635335 TI - Speech perception and lexical effects in specific language impairment. AB - Using an identification task, we examined lexical effects on the perception of vowel duration as a cue to final consonant voicing in 12 children with specific language impairment (SLI) and 13 age-matched (6;6-9;6) peers with typical language development (TLD). Naturally recorded CV/t/sets [word-word (WW), nonword nonword (NN), word-nonword (WN) and nonword-word (NW)] were edited to create four 12-step continua. Both groups used duration as an identification cue but it was a weaker cue for children with SLI. For NN, WN and NW continua, children with SLI demonstrated certainty at shorter vowel durations than their TLD peers. Except for the WN continuum, children with SLI demonstrated category boundaries at shorter vowel durations. Both groups exhibited lexical effects, but they were stronger in the SLI group. Performance on the WW continuum indicated adequate perception of fine-grained duration differences. Strong lexical effects indicated reliance on familiar words in speech perception. PMID- 23635337 TI - The relationship of phonological skills to language skills in Spanish-English speaking bilingual children. AB - These two studies investigate the relationship between phonological production skills and performance in other domains of language in Spanish-English-speaking bilingual children. We examine the relationship between scores on a single-word phonology test and language measures selected from formal testing and narrative samples in Spanish and English. The first study explores the language and phonology scores of 186 children (mean age = 5 years, 9 months) who represent a range of language ability levels. Phonology scores in both languages were most strongly correlated with performance on the Spanish morphosyntax subtest of the bilingual English-Spanish assessment and grammaticality of utterances in English narratives. The second study focuses on 12 children with low or high phonology skills selected from those who participated in the first study. Children with higher phonological production accuracy in both languages produced grammatical structures of low-phonetic salience with greater accuracy than children with lower phonological skills. PMID- 23635340 TI - Ddx46 is required for multi-lineage differentiation of hematopoietic stem cells in zebrafish. AB - Balanced and precisely controlled processes between self-renewal and differentiation of hematopoietic stem cells (HSCs) into all blood lineages are critical for vertebrate definitive hematopoiesis. However, the molecular mechanisms underlying the maintenance and differentiation of HSCs have not been fully elucidated. Here, we show that zebrafish Ddx46, encoding a DEAD-box RNA helicase, is expressed in HSCs of the caudal hematopoietic tissue (CHT). The number of HSCs expressing the molecular markers cmyb or T-cell acute lymphocytic leukemia 1 (tal1) was markedly reduced in Ddx46 mutants. However, massive cell death of HSCs was not detected, and proliferation of HSCs was normal in the CHT of the mutants at 48 h postfertilization. We found that myelopoiesis occurred, but erythropoiesis and lymphopoiesis were suppressed, in Ddx46 mutants. Consistent with these results, the expression of spi1, encoding a regulator of myeloid development, was maintained, but the expression of gata1a, encoding a regulator of erythrocyte development, was downregulated in the mutants. Taken together, our results provide the first genetic evidence that zebrafish Ddx46 is required for the multilineage differentiation of HSCs during development, through the regulation of specific gene expressions. PMID- 23635341 TI - The acceptability, feasibility, and efficacy (phase I/II study) of the OVERcome (Olive Oil, Vaginal Exercise, and MoisturizeR) intervention to improve dyspareunia and alleviate sexual problems in women with breast cancer. AB - INTRODUCTION: Almost half of breast cancer survivors experience chronic sexual problems. Despite the negative effects of dyspareunia on physical and overall quality of life, sexual dysfunction remains underreported and undertreated in clinical practice. This is likely due to the paucity of evidence-based interventions to improve sexual functioning. AIM: The study aims to prospectively evaluate the acceptability, feasibility, and efficacy of a novel intervention (Olive Oil, Vaginal Exercise, and MoisturizeR [OVERcome]) to improve sexual problems following breast cancer treatment. MAIN OUTCOME MEASURES: Dyspareunia, sexual functioning, quality of life, distress, and pelvic floor muscles (PFMs) functioning were evaluated. METHODS: Twenty-five women with dyspareunia were instructed to perform pelvic floor muscle (PFM) relaxation exercises twice/day to prevent/manage PFM overactivity, apply a polycarbophil-based vaginal moisturizer three times/week to alleviate vaginal dryness, use olive oil as a lubricant during intercourse, and complete a weekly compliance diary. PFM relaxation training was administered by a physiotherapist at weeks 0 and 4, with follow-up at weeks 12 and 26. At each visit, women completed validated self-report questionnaires and the physiotherapist recorded objective measures of PFM functioning. RESULTS: OVERcome resulted in significant improvements in dyspareunia, sexual function, and quality of life over time (all P<0.001). PFM relaxation training was reported to be effective (P<=0.001). Maximum benefits were observed at week 12. Most women rated PFM relaxation exercises (92%), vaginal moisturizer (88%), and olive oil (73%) as helpful, indicating that the intervention was acceptable. Unexpectedly, six cases (11%) of vaginal stenosis were noted during initial screening. CONCLUSIONS: This novel intervention is acceptable to patients with demonstrated efficacy in improving dyspareunia and sexual function following breast cancer. Delivery of the OVERcome intervention appears feasible in a clinical setting, providing a potential treatment for this important clinical issue. The unexpected number of observed cases of stenosis further highlights the underreporting of sexual problems in this population, deserving further exploration. PMID- 23635342 TI - Hydroa vacciniforme-like lymphoma of an adult: a case report with review of the literature. AB - Hydroa vacciniforme-like lymphoma (HVL) is a rare type of Epstein-Barr virus (EBV)-positive lymphoma of cytotoxic T-cell or natural killer cell origin that mainly affect children, characterized by a vesicopapular skin eruption that clinically resemble hydroa vacciniforme (HV). In current study, we report an adult patient with the tumor. The patient presented similar morphologic, immunophenotypic and genotypic changes of the disease with that occurred in children, whereas clinically, he showed a prolonged clinical course without hepatosplenomegaly or generalized lymphadenopathy. Whether there are some differences in biologic behavior between children and adults still remains unknown and it is necessary to collect more data to observe and to investigate in the future. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7644172219178472. PMID- 23635344 TI - Usefulness of the fluid balance: a randomised controlled trial in neonates. AB - AIM: To assess the effects of fluid balance charts in neonates with moderate disease severity on duration of hospitalisation and medical interventions. METHODS: Randomised, controlled trial in a neonatal ward in a general teaching hospital in the Netherlands between June 2009 and March 2010. One hundred seventy neonates with moderate disease severity, requiring continuous monitoring of vital parameters (mean gestational age 36(+2) weeks (standard deviation 2(+5) days), mean birthweight 2782 g (standard deviation 749 g)) participated. In the control group (n = 86), attending physicians could access all fluid balance data, whilst these data were blacked out in the intervention group (n = 84). Primary outcome was length of hospital stay. Secondary outcomes were percentage weight loss, interventions based on the fluid status, unblinding of fluid balance data and incident reporting. RESULTS: Length of hospital stay did not differ significantly between the intervention and the control group (median 9 vs. 8 days, with ratio of geometric mean 1.25, 95% confidence interval 0.99 to 1.57; P = 0.06). We found no significant differences in secondary outcomes. CONCLUSIONS: Routinely keeping fluid balances in neonates with moderate disease severity does not affect duration of hospitalisation or medical treatment. PMID- 23635345 TI - Orientation-dependent electronic structures and charge transport mechanisms in ultrathin polymeric n-channel field-effect transistors. AB - We investigated the role of metal/organic semiconductor interface morphology on the charge transport mechanisms and energy level alignment of the n-channel semiconductor poly{[N,N'-bis(2-octyldodecyl)-naphthalene-1,4,5,8 bis(dicarboximide)-2,6-diyl]-alt-5,5'-(2,2'-bithiophene)} (P(NDI2ODT2)). Variable temperature study of well-ordered edge-on-oriented P(NDI2OD-T2) monolayer and multilayer field-effect transistors fabricated via Langmuir-Schafer (LS) method reveals a higher activation energy for the edge-on morphology when compared to that extracted for the face-on oriented P(NDI2OD-T2) spin-coated films, which showed a weaker temperature dependence. Near-ultraviolet inverse photoemission and low-energy electron transmission spectroscopies are utilized to study these microstructurally defined polymeric films. The cross correlations of these techniques with the device characterization reveals the role of the molecular orientation at the semiconductor/contact interface in shifting the charge injection barrier. Finally, we demonstrate that the injection barrier for electrons is higher for the LS/edge-on than in the spin-coated/face-on films. PMID- 23635343 TI - Development and validation of a questionnaire for analyzing real-life falls in long-term care captured on video. AB - BACKGROUND: Falls are the number one cause of injuries in older adults, and are particularly common in long-term care (LTC). Lack of objective evidence on the mechanisms of falls in this setting is a major barrier to prevention. Video capture of real-life falls can help to address this barrier, if valid tools are available for data analysis. To address this need, we developed a 24-item fall video analysis questionnaire (FVAQ) to probe key biomechanical, behavioural, situational, and environmental aspects of the initiation, descent, and impact stages of falls. We then tested the reliability of this tool using video footage of falls collected in LTC. METHODS: Over three years, we video-captured 221 falls experienced by 130 individuals in common areas (e.g., dining rooms, hallways, and lounges) of two LTC facilities. The FVAQ was developed through literature review and an iterative process to ensure our responses captured the most common behaviours observed in preliminary review of fall videos. Inter-rater reliability was assessed by comparing responses from two teams, each having three members, who reviewed 15 randomly-selected videos. Intra-rater reliability was measured by comparing responses from one team at baseline and 12 months later. RESULTS: In 17 of the 24 questions, the percentage of inter- and intra-rater agreement was over 80% and the Cohen's Kappa was greater than 0.60, reflecting good reliability. These included questions on the cause of imbalance, activity at the time of the fall, fall direction, stepping responses, and impact to specific body sites. Poorer agreement was observed for footwear, contribution of clutter, reach-to grasp responses, and perceived site of injury risk. CONCLUSIONS: Our results provide strong evidence of the reliability of the FVAQ for classifying biomechanical, behavioural, situational, and environmental aspects of falls captured on video in common areas in LTC. Application of this tool should reveal new and important strategies for the prevention and treatment of falls and fall related injuries in this setting. PMID- 23635346 TI - Probing the relationship between silicalite-1 defects and polyol adsorption properties. AB - The relationship between polyol adsorption affinity and silanol defect density was investigated through the development of vapor and aqueous adsorption isotherms on silicalite-1 materials which vary in structural and surface properties. Silicalite-1 crystals prepared through alkaline synthesis, alkaline synthesis with steaming post-treatment, and fluoride synthesis routes were confirmed as crystalline mordenite framework inverted (MFI) by SEM and XRD and were shown to contain ~8.5-0 silanol defects per unit cell by (29)Si MAS, (1)H MAS, and (1)H-(29)Si CPMAS NMR. A hysteresis in the Ar 87 K adsorption isotherm at 10(-3)P/P0 evolved with a decrease in silanol defects, and, through features in the XRD and (29)Si MAS NMR spectra, it is postulated that the hysteresis is the result of an orthorhombic-monoclinic symmetry shift with decreasing silanol defect density. Gravimetric and aqueous solution measurements reveal that propylene glycol adsorption at 333 K is promoted by silanol defects, with a maximum 20-fold increase observed for aqueous adsorption at ~10(-3) g/mL with an increase from ~0 to 8.5 silanols per unit cell. A comparison of vapor and aqueous propylene glycol adsorption isotherms on defect-free silicalite-1 at 333 K, both of which exhibit the Type-V character, indicates that water enhances adsorption by a factor of ~2 in the Henry's Law regime. Henry's constants for aqueous C2-C4 polyol adsorption (concentrations below 0.004 g/mL) at 298 K are shown to have a linear dependence on the silanol defect density, demonstrating that these molecules preferentially adsorb at silanol defects at dilute concentrations. This systematic study of polyol adsorption on silicalite-1 materials highlights the critical role of defects on adsorption of hydrophilic molecules and clearly details the effects of coadsorption of water, which can guide the selection of zeolites for separation of biomass-derived oxygenates. PMID- 23635347 TI - Introduction: fertility preservation, from cancer to benign disease to social reasons: the challenge of the present decade. AB - Predicting the likelihood of infertility following gonadotoxic treatments is extremely difficult. In the present issue, several hot topics in the field of fertility preservation are discussed. PMID- 23635348 TI - Ovarian stimulation in cancer patients. AB - The patients referred for fertility preservation owing to a malignant disease do not represent the typical population of subfertile patients treated in IVF units. Cancer may affect multiple tissues throughout the body and can result in a variety of complications during controlled ovarian stimulation. Determination of the controlled ovarian stimulation protocol and gonadotropin dose for oocyte/embryo cryopreservation requires an individualized assessment. This review highlights the new protocols that are emerging to reduce time constraints and emphasizes management considerations to decrease complications. PMID- 23635349 TI - Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation. AB - Aggressive chemotherapy/radiotherapy and bone marrow transplantation can cure >90% of girls and young women affected by disorders requiring such treatment. However, the ovaries are very sensitive to cytotoxic drugs, especially to alkylating agents. Several options are currently available to preserve fertility in cancer patients. The present review reports the results of 60 orthotopic reimplantations of cryopreserved ovarian tissue performed by three teams, as well as 24 live births reported in the literature to date. Restoration of ovarian activity occurred in almost all cases in the three series. Among the 60 patients, eleven conceived and six of those had already delivered twelve healthy babies. In the future, we are looking to: 1) improve freezing techniques; and 2) enhance the "vascular bed" before reimplantation to increase pregnancy rates. On the other hand, cryopreservation of ovarian tissue may be combined with removal, via puncture, of small antral follicles, making it possible to freeze both ovarian tissue and isolated immature oocytes. PMID- 23635351 TI - Predictors of increased body weight and waist circumference for middle-aged adults. AB - OBJECTIVE: To identify predictors of increased adiposity for different measures of adiposity. DESIGN: Prospective cohort study, the Melbourne Collaborative Cohort Study (MCCS), with data at baseline (1990-1994) and wave 2 (2003-2007). SETTING: Participants recruited from the community. SUBJECTS: Australian-born participants (n 5879) aged 40 to 69 years who were not current smokers and who were free from common chronic diseases at recruitment. At baseline and at wave 2, weight and waist circumference were measured; while demographic and lifestyle variables were obtained at baseline via structured interviews. RESULTS: Participants who reported any recreational physical activity at baseline had lower weight and smaller waist circumference at wave 2 than those who did not, particularly for younger participants and for vigorous physical activity. Walking for leisure was not associated, and greater physical activity at work was associated, with greater adiposity measures at wave 2. A diet low in carbohydrates and fibre, but high in fat and protein, predicted greater weight and waist circumference at wave 2. Participants were less likely to have elevated weight or waist circumference at wave 2 if they consumed low to moderate amounts of alcohol. CONCLUSIONS: Our findings indicate that promoting vigorous physical activity, encouraging a diet high in carbohydrate and fibre but low in fat and protein, and limiting alcohol intake could be promising approaches for preventing obesity in middle-aged adults. Similar interventions should successfully address the management of both weight and waist circumference, as they were predicted by similar factors. PMID- 23635350 TI - Ovarian follicle culture: advances and challenges for human and nonhuman primates. AB - The removal and cryostorage of ovarian cortical biopsies is now offered as a fertility preservation option for young women. The only available option to restore fertility using this tissue is by transplantation, which may not be possible for all patients. The full potential of this tissue to restore fertility could be achieved by the development of in vitro systems that support oocyte development from the most immature stages to maturation. The techniques of in vitro growth (IVG) combined with in vitro maturation (IVM) are being developed with human tissue, but comparing different systems has been difficult because of the scarcity of tissue so nonhuman primates are being used as model systems. There are many challenges to developing a complete culture system that would support human oocyte development, and this review outlines the approaches being taken by several groups using tissue from women and nonhuman primate models to support each of the stages of oocyte development. PMID- 23635352 TI - Melatonin, given at the time of reperfusion, prevents ventricular arrhythmias in isolated hearts from fructose-fed rats and spontaneously hypertensive rats. AB - Melatonin reduces reperfusion arrhythmias when administered before coronary occlusion, but in the clinical context of acute coronary syndromes, most of the therapies are administered at the time of reperfusion. Patients frequently have physiological modifications that can reduce the response to therapeutic interventions. This work determined whether acute melatonin administration starting at the moment of reperfusion protects against ventricular arrhythmias in Langendorff-perfused hearts isolated from fructose-fed rats (FFR), a dietary model of metabolic syndrome, and from spontaneous hypertensive rats (SHR). In both experimental models, we confirmed metabolic alterations, a reduction in myocardial total antioxidant capacity and an increase in arterial pressure and NADPH oxidase activity, and in FFR, we also found a decrease in eNOS activity. Melatonin (50 MUm) initiated at reperfusion after 15-min regional ischemia reduced the incidence of ventricular fibrillation from 83% to 33% for the WKY strain, from 92% to 25% in FFR, and from 100% to 33% in SHR (P = 0.0361, P = 0.0028, P = 0.0013, respectively, by Fisher's exact test, n = 12 each). Although, ventricular tachycardia incidence was high at the beginning of reperfusion, the severity of the arrhythmias progressively declined in melatonin-treated hearts. Melatonin induced a shortening of the action potential duration at the beginning of reperfusion and in the SHR group also a faster recovery of action potential amplitude. We conclude that melatonin protects against ventricular fibrillation when administered at reperfusion, and these effects are maintained in hearts from rats exposed to major cardiovascular risk factors. These results further support the ongoing translation to clinical trials of this agent. PMID- 23635353 TI - New insight into a microfluidic-based bipolar system for an electrochemiluminescence sensing platform. AB - In this work, a novel style of a microfluidic-based bipolar system with two direction driving electrodes and dual-channel configuration was described for the first time, which could reach 100% current efficiency in theory. More importantly, the background signal from the integrated driving electrodes was completely eliminated, when this unique design was used to construct an electrochemiluminescence (ECL) sensing platform. First, universal pH indicator was employed to study the mechanism and demonstrate that this new bipolar system possessed 100% current efficiency theoretically. Then, the Ru(bpy)32+/TPrA ECL system was introduced to construct the dual-channel bipolar ECL sensing platform, and the results of visual ECL experiments proved that the background signals from the driving electrodes were completely dispelled with our design. To illustrate the promising applications of this dual-channel device, TPrA, dopamine (DA), H2O2, and K3Fe(CN)6 were detected as model targets under different principles. PMID- 23635354 TI - Effects of donor-, pancreas-, and isolation-related variables on human islet isolation outcome: a systematic review. AB - Different factors have been reported to influence islet isolation outcome, but their importance varies between studies and are hampered by the small sample sizes in most studies. The purpose of this study was to perform a systematic review to assess the impact of donor-, pancreas-, and isolation-related variables on successful human islet isolation outcome. PubMed, Embase, and Web of Science were searched electronically in April 2009. All studies reporting on donor-, pancreas-, and isolation-related factors relating to prepurification and postpurification islet isolation yield and proportion of successful islet isolations were selected. Seventy-four retrospective studies had sufficient data and were included in the analyses. Higher pre- and postpurification islet yields and a higher proportion of successful islet isolations were obtained when pancreata were preserved with the two-layer method rather than University of Wisconsin solution in donors with shorter cold ischemia times (CITs) [1 h longer CIT resulted in an average decline of prepurification and postpurification yields and proportion of successful isolations of 59 islet equivalents (IEQs)/g, 54 IEQs/g, and 21%, respectively]. Higher prepurification yields and higher percentage of successful islet isolations were found in younger donors with higher body mass index. Lower yields were found in donation after brain death donors compared to donation after cardiac death donors. Higher postpurification yields were found for isolation with Serva collagenase. This review identified donor-, pancreas-, and isolation-related factors that influence islet isolation yield. Standardized reports of these factors in all future studies may improve the power and identify additional factors and thereby contribute to improving islet isolation yield. PMID- 23635355 TI - Video Q&A: what is ASIA? An interview with Yehuda Shoenfeld. AB - In this Q&A, we talk to Professor Yehuda Shoenfeld about Autoimmune Syndrome Induced by Adjuvants (ASIA) and discuss his recommendations regarding further research in the field. PMID- 23635356 TI - Use of a Tn5-based transposon system to create a cost-effective Zymomonas mobilis for ethanol production from lignocelluloses. AB - BACKGROUND: Current methods of ethanol production from lignocelluloses generate a mixture of sugars, primarily glucose and xylose; the fermentation cells are always exposed to stresses like high temperature and low nutritional conditions that affect their growth and productivity. Stress-tolerant strains capable of using both glucose and xylose to produce ethanol with high yield are highly desirable. RESULTS: A recombinant Zymomonas mobilis (Z. mobilis) designated as HYMX was constructed by integrating seven genes (Pfu-sHSP, yfdZ, metB, xylA, xylB, tktA and talB) into the genome of Z. mobilis CP4 (CP4) via Tn5 transposon in the present study. The small heat shock protein gene (Pfu-sHSP) from Pyrococcus furious (P. furious) was used to increase the heat-tolerance, the yfdZ and metB genes from E. coli were used to decrease the nutritional requirement. To overcome the bottleneck of CP4 being unable to use pentose, xylose catabolic genes (xylA, xylB, tktA and talB) from E. coli were integrated into CP4 also for construction of the xylose utilizing metabolic pathway. CONCLUSIONS: The genomic integration confers on Z. mobilis the ability to grow in medium containing xylose as the only carbon source, and to grow in simple chemical defined medium without addition of amino acid. The HYMX demonstrated not only the high tolerance to unfavorable stresses like high temperature and low nutrient, but also the capability of converting both glucose and xylose to ethanol with high yield at high temperature. What's more, these genetic characteristics were stable up to 100 generations on nonselective medium. Although significant improvements were achieved, yeast extract is needed for ethanol production. PMID- 23635357 TI - Palatal erosion and oronasal fistulation following covered nasopharyngeal stent placement in two dogs. AB - Treatment options for dogs with nasopharyngeal stenosis include fluoroscopic placement of metallic stents. Reported complications include entrapment of hair and food, obstruction and persistent nasal discharge. Two toy breed dogs were examined for persistent nasal discharge and halitosis at 4 and 20 months after placement of permanent metallic stents for acquired nasopharyngeal stenosis. Full thickness defects were found in the palate of both dogs, with extensive communication between the mouth and the nasal passages. Portions of the metal stent were observed within the lesion in both patients. Additional treatment was declined by the owner of one dog; the stent was removed through the fistula in the other dog. Palatal erosion with secondary oronasal fistulation is a potential complication of nasopharyngeal stent placement in dogs. PMID- 23635359 TI - Antioxidant relevance to human health. AB - Human ecology requires both oxygen and water with the generation from food of an immediate energy source, ATP, by oxidative phosphorylation. A continuing balance between oxidation and antioxidation is necessary for longer less-disabled lives, taking account of oxidative stresses and the critical roles of oxidants in defence against infection, tissue repair and signalling. Antioxidant capacity is derived both exogenously (from food, beverage and sunlight) and endogenously (from enzymatic and non-enzymatic pathways). A number of oxidant food factors service antioxidant metallo-enzymes. The capacity operates extra- or intracellularly. Uric acid is the major antioxidant in primate blood. Uric acid synthesis is increased by dietary fructose from fruit, sugary foods and drinks. This indirect antioxidant effect of fruit is separate from that attributable to its flavonoids. Alcohol also increases serum uric acid. Urate excess and retention is associated with disease. The high prevalence of hyperuricaemia in NE Asia presents a major public health dilemma in regard to putative benefits and risks. Foods with high antioxidant activity include berries, nuts and legumes, tomatoes and sweet potato leaves. Each of the antioxidants in these foods is pleiotropic being inter-alia anti-inflammatory, anti-angiogenic or anti neoplastic. Moreover, food matrices and patterns contribute to the safety of antioxidant consumption. There is no evidence to date that isolated antioxidants as food supplements improve health outcomes or survival; and some that indicate unacceptable risk. Their use as biomarkers of food cannot justify their isolated use. Nevertheless, a spectrum of dietary pluripotential antioxidants for tissues, metabolic and immune systems is advantageous. PMID- 23635358 TI - Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. AB - BACKGROUND: Neurodegenerative diseases such as Alzheimer's are associated with the aggregation of endogenous peptides and proteins that contribute to neuronal dysfunction and loss. The glymphatic system, a brain-wide perivascular pathway along which cerebrospinal fluid (CSF) and interstitial fluid (ISF) rapidly exchange, has recently been identified as a key contributor to the clearance of interstitial solutes from the brain, including amyloid beta. These findings suggest that measuring changes in glymphatic pathway function may be an important prognostic for evaluating neurodegenerative disease susceptibility or progression. However, no clinically acceptable approach to evaluate glymphatic pathway function in humans has yet been developed. METHODS: Time-sequenced ex vivo fluorescence imaging of coronal rat and mouse brain slices was performed at 30-180 min following intrathecal infusion of CSF tracer (Texas Red- dextran-3, MW 3 kD; FITC- dextran-500, MW 500 kD) into the cisterna magna or lumbar spine. Tracer influx into different brain regions (cortex, white matter, subcortical structures, and hippocampus) in rat was quantified to map the movement of CSF tracer following infusion along both routes, and to determine whether glymphatic pathway function could be evaluated after lumbar intrathecal infusion. RESULTS: Following lumbar intrathecal infusions, small molecular weight TR-d3 entered the brain along perivascular pathways and exchanged broadly with the brain ISF, consistent with the initial characterization of the glymphatic pathway in mice. Large molecular weight FITC-d500 remained confined to the perivascular spaces. Lumbar intrathecal infusions exhibited a reduced and delayed peak parenchymal fluorescence intensity compared to intracisternal infusions. CONCLUSION: Lumbar intrathecal contrast delivery is a clinically useful approach that could be used in conjunction with dynamic contrast enhanced MRI nuclear imaging to assess glymphatic pathway function in humans. PMID- 23635360 TI - Development and validity assessment of a diet quality index for Australians. AB - Existing Australian diet quality indices have assumed links to health outcomes but their validity for this has not been reported. We extend the features of existing indices for Australian adults by constructing a new diet quality index (Aussie-DQI) using the national dietary guidelines linked to the Australia National Health Priority Areas. Construct validity was assessed using 24 hour dietary recalls from the 1995 National Nutrition Survey (n=10,851 adults aged 19 years and older). Construct and criterion validity were assessed using food frequency questionnaire data from the Nambour Skin Cancer study (n=1355), a community-based longitudinal study with 16 year follow-up and cause-specific mortality outcomes. Generalised linear regression was used to assess associations between Aussie-DQI scores and socio-economic, demographic, health-behaviour characteristics, and food and nutrient intakes, while Cox proportional-hazards modeling was used to assess associations with cancer and allcause mortality. A high Aussie-DQI score was associated with being female, being older, non-smoking status, and BMI in the normal range in both study populations; and Aussie-DQI scores were inversely associated with cancer mortality among men in multivariable adjusted analyses (hazard ratio = 0.30, 95% CI: 0.11, 0.83; p for trends = 0.06). In conclusion, Aussie-DQI successfully discriminated diet quality and showed that men, younger adults, current smokers and those overweight/obese were less likely to consume foods that meet dietary recommendations; and that a high diet quality is associated with decreased risk of cancer mortality among men. This study adds further evidence to clarify the role of diet quality in decreasing mortality from chronic diseases. PMID- 23635361 TI - Development of an amino acid composition database and estimation of amino acid intake in Japanese adults. AB - Investigations of the association between an individual's habitual amino acid intake and several types of health outcome require a comprehensive amino acid composition database. The lack of a database of the amino acid content of foods routinely consumed makes estimating daily amino acid intake difficult. The aim of this study was to develop an amino acid database for use in epidemiological studies, and to estimate amino acid intake among a Japanese population. Data were obtained from published food composition data, and when published data were unavailable, calculated data were imputed using established criteria. Adequate data were available for 1100 food items. Using a purpose-developed amino acid composition table, we estimated amino acid intake among a Japanese population (121 women and 109 men aged 30 to 69 years) living in four areas in Japan using a 16-day diet record. All subjects met the estimated average requirements of the nine indispensable amino acids as reported by WHO/FAO/UNU. The major contributors to dietary amino acid intake were cereals, fish and shellfish, and meats, which accounted for approximately 60% of total intake. This database contains amino acid values of foods items frequently consumed in Japan, and represents a valuable tool for use in epidemiological studies. PMID- 23635362 TI - Can't we just let them eat? Defining and addressing under-use of the oral route in a post-surgical ward. AB - Early postoperative nutrition improves outcomes. However, postoperative fasting is a tradition that persists in some areas of surgical practice. This retrospective audit was performed to benchmark current nutrition support practices on a mixed specialty surgical ward in a large tertiary-referral teaching hospital. Thirty-eight consecutive patients, who were undergoing gynaecological or urological surgical procedures between November 2010 and May 2011, had data collected including demographics, nutritional status, details of surgery performed, postoperative complications, modes of nutrition support and time taken to progress to solid oral diet. Energy and protein provision and adequacy was estimated for the first week postoperatively. Sixteen patients commenced parenteral nutrition postoperatively without any trial of oral or enteral nutrition. Reasons for using parenteral nutrition included observed or expected gut dysmotility and lack of enteral access for feeding. These patients did demonstrate longer length of stay and higher rates of postoperative complications. Given the proportion of patients initiated immediately on parenteral nutrition and maintained on it alone, it can be argued that these patients are not able to demonstrate tolerance and receive the benefits of early enteral feeding predicted by studies within these patient groups. None of the patients met their energy and protein requirements in the first week postoperatively. Despite support in the literature, it can be challenging to implement early postoperative nutrition support after pelvic surgery. It may be necessary to employ a variety of strategies to change this aspect of practice and promote earlier introduction of an oral diet or the use of enteral nutrition. PMID- 23635363 TI - NutritionDay 2010 audit in Jinling hospital of China. AB - BACKGROUND: NutritionDay is an annual worldwide cross-sectional multicentre audit. This report aimed to describe the results of nutritionDay 2010 in Jinling hospital, providing a map of the prevalence of malnutrition and actual nutrition therapy practice in different units. The risk factors to malnutrition and length of hospital stay were also investigated. METHODS: The data was collected from 233 inpatients from Jinling hospital on Nov 4th, 2010, using standardized questionnaires. Malnutrition was objectively defined as BMI <20 or unintentional weight loss >5% in the past three months. Risk factors for malnutrition and the impact of multiple factors on length of hospital stay were analyzed. RESULTS: 233 inpatients participated in this audit (143 M: 90 F; mean+/-SD age 50.6+/-18.5 years). Of the patients, 42.5% were malnourished. Multivariable analysis revealed three risk factors for malnutrition: gender, food intake and length of hospital stay before audit. Longer length of hospital stay prevailed in patients aged >=65 years (p<0.001), and there was a positive and significant, but weak, correlation between length of hospital stay and age. CONCLUSIONS: The prevalence of malnutrition was high. Higher age may be the main contributor to longer length of hospital stay. This was the first study to obtain data from hospitalized patients' nutritional status in China during the nutritionDay audit and the valuable results could supply evidence for clinical nutrition support. PMID- 23635364 TI - Effects of egg and vitamin A supplementation on hemoglobin, retinol status and physical growth levels of primary and middle school students in Chongqing, China. AB - Lack of protein and vitamin A influences the growth of student in impoverished mountain areas. The aim of the study was to assess the effects of egg and vitamin A supplementation on hemoglobin, serum retinol and anthropometric indices of 10 18 years old students of a low socioeconomic status. A total number of 288 students from four boarding schools were randomly selected by using cluster sampling method in Chongqing, and they were assigned into supplement group and control group non-randomly. Students in supplement group received a single 200,000 international units vitamin A and 1 egg/day (including weekends) for 6 months. The control group did not receive any supplementation. We measured hemoglobin, serum retinol and height and weight at baseline and after supplementation. The supplementation increased the mean hemoglobin concentration by 7.13 g/L compared with 1.38 g/L in control group (p<0.001), the mean serum retinol concentration by 0.31 MUmol/L compared with 0.09 MUmol/L in the control group (p=0.005), the mean height-for-age z score by 0.05 compared with 0.03 in the control group (p=0.319), the mean weight-for-age z score by 0.05 compared with -0.12 in the control group (p<0.001). Our results revealed that egg and vitamin A supplementation is an effective, convenient, and practical method to improve the levels of hemoglobin, serum retinol and prevent the deterioration of growth in terms of weight for primary and middle school students from outlying poverty-stricken areas. Our intervention did not have a beneficial effect on linear growth. PMID- 23635365 TI - Effects of dietary traditional fermented soybean on reproductive hormones, lipids, and glucose among postmenopausal women in northern Thailand. AB - Isoflavone in soybean and its products have numerous beneficial health effects. A number of clinical studies have demonstrated that dietary soy isoflavone can relieve menopausal symptoms, lower risks of breast cancer, and lower cholesterol and glucose. Among the various effects of isoflavone, the role of cholesterol and glucose reduction seems to be well documented; however, other effects such as reproductive hormones were inconclusive and inconsistent. The main objective of the present study was to investigate the effects of six-month dietary traditional fermented soybean intake on BMI, reproductive hormones, lipids, and glucose among postmenopausal women. Subjects were women with their last menstrual period occurring at least 12 months prior to selection by interview and health screening from Baan Tham Village, Phayao Province, Thailand. A total of 60 women were divided into 2 groups: experimental group (n=31) and reference group (n=29). The experimental group was permitted to continue their usual diet, and supplemented with fermented soybean for 6 months. The fermented soybean provided approximately 60 mg of isoflavone per day. The remarkable findings were that dietary fermented soybean had favorable effects on progesterone and cholesterol, but had no effects on estradiol, glucose, and triglycerides. Although estradiol and glucose in the experimental group did not change, a decrease of estradiol and an increase of glucose were found in the reference group. Our results, therefore, suggest that fermented soybean may have beneficial effects on reproductive hormones and cholesterol, and they would be warrant further detail investigations. PMID- 23635366 TI - The application of a feeding protocol in older patients fed through percutaneous endoscopic gastrostomy tubes by the intermittent or bolus methods: a single center, retrospective chart review. AB - BACKGROUND: While previous studies have reported that feeding protocols improved clinical outcomes in critical care settings, the evidence supporting the application of feeding protocols in older patients has not yet been assessed. Here, we evaluated the effects of a feeding protocol in older patients fed through percutaneous endoscopic gastrostomy (PEG) tubes. METHODS: We conducted a retrospective chart review of 109 patients aged >=65 who underwent PEG placement between April 2010 and March 2012 at a single acute care hospital. The protocol group was administered enteral nutrition (EN) according to a feeding protocol, while the non-protocol group was administered EN at the attending physician's discretion. RESULTS: Length of hospital stay (LOS) overall and after EN initiation were significantly shorter in the protocol group than in the non protocol group. (LOS: p=0.001; LOS after EN initiation: p=0.026). During the second week after EN initiation, significantly fewer patients had percutaneous oxygen saturation (SpO2) <93% and required oxygen therapy in the protocol group (p=0.032 for both comparisons). Nutrition intakes via PEG in the protocol group were significantly greater from Days 6 to 13 for energy and from Days 6 to 11 for protein compared with the non-protocol group. CONCLUSION: The application of a feeding protocol after PEG placement in older patients was associated with shorter LOS, more efficient EN delivery, and lower incidence of low SpO2 than non protocol group. Larger prospective studies are required to determine whether a feeding protocol is useful in improving health outcomes in this population. PMID- 23635367 TI - Effectiveness of strategies for recruiting overweight and obese Generation Y women to a clinical weight management trial. AB - AIM: Limited research in young overweight and obese women indicates that they are difficult to recruit to weight management trials, with attrition higher and weight loss success lower than middle to older age participants. This study aimed to evaluate the effectiveness of different recruitment strategies for a clinical weight loss trial in overweight and obese Generation Y women. METHODS: Overweight and obese (BMI >=27.5 kg/m-2) women aged 18-25 years (n=70) were required for a 12 month clinical weight management trial including diet, exercise and behaviour modification. Contact with researchers and eventual recruitment are reported for the various strategies employed to engage participants. Data reported as % or mean+/-SE. RESULTS: Recruitment was challenging with only 50 of the total 70 participants recruited within the scheduled time frame (24 months). Just over one quarter (27%) of volunteers assessed were recruited. Flyers posted around local tertiary education campuses were the most successful method, yielding 36% of included participants. This was followed by advertisements on the local area health service intranet (26%) and in local and metropolitan newspapers (16%). CONCLUSIONS: Recruitment of overweight and obese Generation Y women for a clinical weight loss trial was difficult. Multiple strategies targeted at this age and gender group were required. Less rigorous selection criteria and reduced face-to-face intervention time may improve recruitment and retention rates into clinical trials for this age group. PMID- 23635368 TI - Plasma adiponectin concentrations are associated with dietary glycemic index in Malaysian patients with type 2 diabetes. AB - Adiponectin, an adipocyte-derived hormone has been implicated in the control of blood glucose and chronic inflammation in type 2 diabetes. However, limited studies have evaluated dietary factors on plasma adiponectin levels, especially among type 2 diabetic patients in Malaysia. The aim of this study was to investigate the influence of dietary glycemic index on plasma adiponectin concentrations in patients with type 2 diabetes. A cross-sectional study was conducted in 305 type 2 diabetic patients aged 19-75 years from the Penang General Hospital, Malaysia. Socio-demographic information was collected using a standard questionnaire while dietary details were determined by using a pre validated semi-quantitative food frequency questionnaire. Anthropometry measurement included weight, height, BMI and waist circumference. Plasma adiponectin concentrations were measured using a commercial ELISA kit. Data were analyzed using multiple linear regression. After multivariate adjustment, dietary glycemic index was inversely associated with plasma adiponectin concentrations (beta =-0.272, 95% CI -0.262, - 0.094; p<0.001). It was found that in individuals who consumed 1 unit of foods containing high dietary glycemic index that plasma adiponectin level reduced by 0.3 MUg/mL. Thirty two percent (31.9%) of the variation in adiponectin concentrations was explained by age, sex, race, smoking status, BMI, waist circumference, HDL-C, triglycerides, magnesium, fiber and dietary glycemic index according to the multiple linear regression model (R2=0.319). These results support the hypothesis that dietary glycemic index influences plasma adiponectin concentrations in patients with type 2 diabetes. Controlled clinical trials are required to confirm our findings and to elucidate the underlying mechanism. PMID- 23635369 TI - Attenuated associations between increasing BMI and unfavorable lipid profiles in Chinese Buddhist vegetarians. AB - Obesity is related to hyperlipidemia and risk of cardiovascular disease. Health benefits of vegetarian diets have well-documented in the Western countries where both obesity and hyperlipidemia were prevalent. We studied the association between BMI and various lipid/lipoprotein measures, as well as between BMI and predicted coronary heart disease probability in lean, low risk populations in Southern China. The study included 170 Buddhist monks (vegetarians) and 126 omnivore men. Interaction between BMI and vegetarian status was tested in the multivariable regression analysis adjusting for age, education, smoking, alcohol drinking, and physical activity. Compared with omnivores, vegetarians had significantly lower mean BMI, blood pressures, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, total cholesterol to high density lipoprotein ratio, triglycerides, apolipoprotein B and A-I, as well as lower predicted probability of coronary heart disease. Higher BMI was associated with unfavorable lipid/lipoprotein profile and predicted probability of coronary heart disease in both vegetarians and omnivores. However, the associations were significantly diminished in Buddhist vegetarians. CONCLUSIONS: Vegetarian diets not only lower BMI, but also attenuate the BMI-related increases of atherogenic lipid/ lipoprotein and the probability of coronary heart disease. PMID- 23635370 TI - Hair mineral analysis by X-ray fluorescence spectrometry: associations with body fat. AB - Hair mineral analysis using an X-ray fluorescence spectrometer as a method of estimating body fat percentage (BF%) was investigated. Body fat percentage of 24 healthy Japanese, aged 20-27 years, was measured using a hand-held impedance analyzer (BF%IMP). X-ray (Kalpha-ray) intensities of sulfur, chlorine, potassium, calcium, titanium, and iron (Fe) in hair were measured using an X-ray fluorescence spectrometer. Body fat percentage was also measured using a Hologic whole body dual energy X-ray absorptiometer (BF%DXA) in nine subjects selected from the above 24 subjects based on their BF%IMP. Correlations of the two BF%s with Fe-Kalpha were significant (BFIMP: r = 0.60 n = 24, p<0.01; BFDXA: r = 0.67 n = 9, p<0.05). The mean (+/-SD) biases (measured minus estimated using multiple regression equations by Fe-Kalpha) for BF%IMP and BF%DXA were 2.97 +/- 2.25% and 1.77 +/- 1.33%, respectively. The SEEs for the two equations for BF%IMP and for BF%DXA were less than 4%. These results suggest that Fe-Kalpha may be a predictor of body fat percentage. However, the subjects were few and only Japanese in their twenties, so that further investigation is needed for methodological generalization. PMID- 23635371 TI - Japanese mothers' breastfeeding knowledge and attitudes assessed by the Iowa Infant Feeding Attitudes Scale. AB - This study describes Japanese mothers' knowledge and attitudes towards breastfeeding using the Iowa Infant Feeding Attitudes Scale (IIFAS). A cross sectional survey of 1,612 mothers was conducted in Japan in 2007. The participants were recruited at the free health checks conducted for infants at 18 months of age. The survey was self-administered using the Japanese version of the IIFAS. Descriptive statistics were used to summarise sample characteristics and IIFAS score followed by multiple logistic regression to identify association between total IIFAS score and breastfeeding duration. While the IIFAS showed that the majority recognized some benefits of breastfeeding, their overall knowledge and attitudes towards breastfeeding were neutral and more positive towards the use of infant formula. It is important to provide accurate prenatal education that focuses on methods and long-term benefits of infant feeding to mothers, family and health professionals. PMID- 23635372 TI - Attitudes towards breastfeeding - the Iowa Infant Feeding Attitude Scale in Chinese mothers living in China and Australia. AB - This study aimed to translate and validate a Chinese (simplified) version of the Iowa Infant Feeding Attitude Scale (IIFAS) and compare the infant feeding attitudes of Chinese mothers living in Perth Australia and in Chengdu P.R. China. A survey was undertaken on 200 Chinese mothers living in Perth and 1620 mothers living in Chengdu. The simplified Chinese version of IIFAS had a moderate level of internal consistency with a Cronbach's alpha of 0.69 for mothers in Australia and 0.55 for mothers in China. The mean IIFAS scores in both country groups lay in the range of 'neutral breastfeeding attitudes'. Higher IIFAS scores were significantly associated with the likelihood of both breastfeeding initiation (OR: 3.85; CI: 2.49-5.96; p<0.001) and longer (>=8 months) breastfeeding duration (OR: 2.52; CI: 1.87-3.40; p<0.001). Chinese mothers in Perth (mean IIFAS score=60.0+/-6.3) tended to have more positive attitudes towards breastfeeding than mothers in Chengdu (mean IIFAS score=57.7+/-5.1, p<0.001), and had a longer duration of 'any breastfeeding' (10.0+/-6.2 months in Perth compared to 7.4+/-4.3 months in Chengdu, p<0.001). In conclusion, higher scores on the IIFAS in simplified Chinese are associated with breastfeeding initiation and duration in Chinese populations. PMID- 23635373 TI - Factors associated with exclusive breastfeeding in low birth weight infants at NICU discharge and the start of complementary feeding. AB - The aim of the present study was to clarify clinical factors in low birth weight infants and their mothers associated with exclusive breastfeeding at both neonatal intensive care unit (NICU) discharge and the start of complementary feeding. One hundred and fifteen low birth weight children and 98 mothers attending the follow-up clinic of two tertiary NICUs in Nara prefecture (Japan), between June and September, 2011, were enrolled. The relationship between the feeding categories at NICU discharge or the start of complementary feeding, and clinical factors of the mothers and low birth weight infants collected by either their charts or a face-to-face interview was analyzed. The prevalence of exclusive breastfeeding was 22.6% at NICU discharge, and 15.7% at the start of complementary feeding. In logistic analysis, exclusive breastfeeding at NICU discharge was associated with mother's younger age at delivery and an earlier start of oral nutrition. Among 26 exclusively breast-fed infants at NICU discharge, fifteen infants (57.7%) were still being exclusively breast-fed at the start of complementary feeding. In low birth weight infants, a shorter stay at NICU and an earlier start of oral nutrition were associated factors with exclusive breastfeeding at the start of complementary feeding. None of maternal factors were found to be associated with exclusive breastfeeding at the start of complementary feeding. Conclusively, starting of oral nutrition as early as possible is thought to be crucial for introducing exclusive breastfeeding in low birth weight infants both at NICU discharge and the start of complementary feeding. PMID- 23635374 TI - The fatty acid composition of colostrum in three geographic regions of China. AB - PURPOSE: To describe the fatty acid composition of human colostrum in three different regions of China. METHODS: Women were recruited from river/lake, coastal and inland regions of China during late pregnancy. Their diet frequency was assessed during the 34th week of pregnancy. Colostrum samples were collected between postpartum days 3 and 5. Thirty-one different fatty acids were separated and identified in colostrum. RESULTS: There were significant differences among the women in the three regions with respect to food and culinary oil consumption patterns. The mean+/-SD fat content (g/100 g) of colostrum from river/lake, coastal and inland regions was 2.17+/-1.26, 2.50+/-1.39 and 2.68+/-1.26, respectively (p=0.265, adjusted by pregnant women's age). The main saturated, monounsaturated, n-6 polyunsaturated and n-3 polyunsaturated fatty acids in colostrum were 16:0, 18:1n9, 18:2n6 and 18:3n3, respectively. Colostrum from river/lake region had the lowest composition of total SFA and of total n-6 PUFA and the highest composition of total MUFA and of total n-3 PUFA. The amount of DHA (22:6n3) in colostrum (mean+/-SD, % wt/wt) was 0.51+/-0.18, 0.52+/-0.20 and 0.35+/-0.13 in the river/lake, coastal and inland regions, respectively (p=0.0002, adjusted by pregnant women's age). Frequency of maternal marine fish intake during the late pregnancy was positively correlated with DHA in colostrum (r=0.203, p=0.040). CONCLUSIONS: The fatty acid composition of colostrum differs across geographical regions in China, which may be related to differences in maternal dietary pattern. PMID- 23635375 TI - The influence of primary caregivers on body size and self-body image of preschool children in Taiwan. AB - OBJECTIVE: The purpose of this study was to investigate preschool children's body size and image, and analyze the impact of the primary caregiver on a child's body size and awareness in Taiwan. METHODS: In a cross-sectional survey, 699 preschool children and their primary caregivers participated in this study. Our study used an anonymous self-administered questionnaire, which was divided into parts A and part B. Part A was a questionnaire for the primary caregivers, including their demographic and anthropometric information, and expectation for children's body size. Part B was a two part questionnaire for children, including the children's expectation on their own body size and their consciousness in terms of body size evaluation by parents and teachers. Data was analyzed by chi-square analysis. RESULTS: In our study, the majority of boys and girls have a normal body size (69.0% and 64.6%, respectively). There was a significant positive correlation (p<0.05) between children and primary caregivers' body size, and a negative correlation (p<0.05) between children body size and caregivers' education level. Furthermore, we found that caregiver's satisfaction and evaluation of the children's body size had significantly affected the children's satisfaction towards their body size. CONCLUSION: Influences by the primary caregiver is an important factor that affects a preschool child's body size and body image in Taiwan. Body size evaluation by caregivers will influence the child's satisfaction level. PMID- 23635376 TI - Vitamin D deficiency awareness among African migrant women residing in high-rise public housing in Melbourne, Australia: a qualitative study. AB - The aims of this study were: 1) to explore the individual perceptions, experience and understandings of vitamin D deficiency (VDD) amongst African migrant women residing in high-rise public housing, 2) to identify the most useful sources of information about VDD among this population, and 3) to document the barriers and enablers to addressing VDD. The Health Belief Model was used to guide the study. Convenience sampling was used with women living in particular high-rise public housing. Five focus group discussions were conducted (n=30). Thematic analysis was used to code and categorise the data to develop a deeper, conceptual understanding of the issue. We found that participants were aware of VDD and could identify the impacts that VDD had on their health. Barriers to addressing VDD included the women's: 1) living conditions in Australia, 2) risk of skin cancer, and 3) cultural roles in the family. The most positive strategy for preventing and addressing VDD was peer information sharing. This study has highlighted the significant need for health promotion strategies to combat VDD in this population. Future health promoting public health strategies for this population should encompass community based peer education programs. This study demonstrates the critical role of qualitative inquiry in gaining a deeper understanding of VDD in a particular migrant community. It is clear that this issue requires a coordinated solution that must involve the community themselves. Health care professionals must take into consideration the multiple barriers that exist to address VDD which is a significant public health issue. PMID- 23635377 TI - Dietary exposure to essential and potentially toxic elements for the population of Hanoi, Vietnam. AB - Knowledge of the dietary intake of essential and toxic elements in fast developing Southeast Asian countries such as Vietnam is limited. Iron and Zn deficiency in Asia is a well-known problem and is partly due to rice constituting a major part of the diet. Dietary habits are changing and there is a need to build more knowledge so authorities can give dietary recommendations. The aim of this study was to determine the total dietary intake of essential and potentially toxic elements and to assess the nutritional quality and food safety risks of the average Hanoi diet. Twenty-two foods or food groups were identified and 14 samples of each food group were collected from markets and/or supermarkets in the period 2007-2009. Water spinach, water dropwort, watercress, water mimosa and pond fish are typically produced in wastewater-fed systems. Therefore, these samples were collected both at markets and from wastewater-fed production systems. The results showed little or no risk of toxic elements from the Hanoi diet in general. Further, element contributions from wastewater-fed products were low and does not seem to constitute a problem with respect to potentially toxic elements. A comparison of the average Hanoi dietary intake of essential elements to required intakes shows that the Hanoi diet is sufficient in most elements. However, the diet may be insufficient in Ca, Cr, Fe, K and possibly Zn for which dietary diversification of biofortification might provide solutions. PMID- 23635379 TI - Estimation of usual intake and food sources of choline and betaine in New Zealand reproductive age women. AB - Recently, choline has been associated with neurodevelopment, cognitive function and neural tube defect incidence. However, data on usual intakes are limited, and estimates of dietary intakes of choline and its metabolite betaine, are not available for New Zealanders. The objective of the present study was to determine usual intake and food sources of choline and betaine in a group of New Zealand reproductive age women. Dietary intake data were collected from a sample of 125 women, aged 18-40 years, by means of a 3-day weighed food record, and usual choline and betaine intake distributions were determined. The mean (SD) daily intakes of choline and betaine were 316 (66) mg and 178 (66) mg, respectively. The total choline intake relative to energy intake and body weight was 0.18 mg/kcal and 5.1 mg/kg, respectively. Only 16% of participants met or exceeded the Adequate Intake (AI) for adult women of 425 mg of choline. The top five major food contributors of choline were eggs, red meat, milk, bread and chicken; and of betaine were bread, breakfast cereal, pasta, grains and root vegetables (carrots, parsnips, beetroot, swedes). Our findings contribute towards the recent emergence of published reports on the range of dietary choline and betaine intakes consumed by free-living populations. In our sample of New Zealand women, few participants were meeting or exceeding the AI level. Given recent epidemiological evidence suggesting health benefits of increased choline and betaine intakes, recommendations should be made to encourage the consumption of choline and betaine-rich foods. PMID- 23635378 TI - Dental caries is correlated with knowledge of comprehensive food education in Japanese university students. AB - In Japan, the "Food Education Basic Law" (The Basic Law on Shokuiku, food education) was enacted in 2005. The comprehensive food education programs, namely Shokuiku, aim to improve dietary practices to reduce lifestyle-related diseases. Dental caries is one of the diseases associated with inappropriate dietary habits. Thus, food education may influence the prevalence of dental caries. However, there are no data regarding the association between public based-food education and dental caries. The aim of the present study was to investigate the relationship between knowledge about comprehensive food education (Shokuiku) and dental caries experience in Japanese university students. A total of 2,184 students (1,240 men, 944 women), aged 18-20 years, were examined. They had attended the Shokuiku program while in junior/senior high school. The numbers of teeth present, and decayed, missing and filled teeth (DMFT) (dental caries experience) were recorded. Additional information was collected via a questionnaire regarding knowledge about food education, dietary habits and oral health behavior. Of the students, 315 men (20.7%) and 345 women (52.8%) reported that they know and can explain the meaning and content of the word "Shokuiku". After adjusting for potential confounding factors, subjects who did not have knowledge about Shokuiku had higher adjusted odds ratio (OR) for dental caries experience (DMFT >0) than those who had (adjusted OR, 1.23; 95% CI, 1.02-1.48; p<0.05). These observations revealed that having knowledge about comprehensive food education in university students correlates with low prevalence of dental caries. PMID- 23635380 TI - Mini-bronchoalveolar lavage fluid can be used for biomarker identification in patients with lung injury by employing 1H NMR spectroscopy. PMID- 23635381 TI - Genetic diversity of the Mycobacterium tuberculosis complex in San Luis Potosi, Mexico. AB - BACKGROUND: Although epidemiologic and socioeconomic criteria and biomedical risk factors indicate high-priority for tuberculosis (TB) control in Mexico, molecular epidemiology studies of the disease in the country are scarce. METHODS: Complete sociodemographic and clinical data were obtained from 248 of the 432 pulmonary TB (PTB) cases confirmed from 2006 to 2010 on the population under epidemiological surveillance in the state of San Luis Potosi, Mexico. From most PTB cases with complete data Mycobacterium tuberculosis complex (MTC) isolates were recovered and their spoligotypes, lineages and families, geographic distribution and drug resistance determined. RESULTS: Pulmonary tuberculosis incidence ranged from 2.4 to 33.4 (cases per 100,000 inhabitants) in the six state sanitary jurisdictions that were grouped in regions of low (jurisdictions I-II-III), intermediate (jurisdictions IV-V) and high incidence (jurisdiction VI) with 6.2, 17.3 and 33.4 rates, respectively. Most patients were poor, 50-years-median-age males and housewives. Among the 237 MTC spoligotyped isolates, 232 corresponded to M. tuberculosis (104 spoligotypes in 24 clusters) and five to M. bovis. The predominant Euro-American lineage was distributed all over the state, the East Asian lineage (Beijing family) in the capital city, the Indo-Oceanic (Manila family) in eastern localities, and M. bovis in rural localities. CONCLUSIONS: In San Luis Potosi TB affects mainly poor male adults and is caused by M. tuberculosis and to a minor extent by M. bovis. There is great genotypic diversity among M. tuberculosis strains, the Euro-American lineage being much more prevalent than the Indo-Oceanic and East-Asian lineages. The frequency of resistant strains is relatively low and not associated to any particular lineage. PMID- 23635382 TI - Designed synthesis of SiO2/TiO2 core/shell structure as light scattering material for highly efficient dye-sensitized solar cells. AB - SiO2/TiO2 core/shell nanoparticles (STCS-NPs) with diameters of 110, 240, and 530 nm were fabricated to investigate the influence of the size and refractive index of light-scattering particles on light-scattering properties. The optical properties of STCS-NPs were evaluated and compared with SiO2-NPs and TiO2-NPs. The structure of STCS-NPs, consisting of a low refractive index core and high refractive index shell, provides efficient light scattering. The optimized anode film with STCS-NPs had ca. 20% improved power conversion efficiency (PCE). PMID- 23635383 TI - Frozen shoulder: what can a physical therapist do for my painful and stiff shoulder? PMID- 23635384 TI - Dynamic electrostatic force microscopy technique for the study of electrical properties with improved spatial resolution. AB - The need to resolve the electrical properties of confined structures (CNTs, quantum dots, nanorods, etc) is becoming increasingly important in the field of electronic and optoelectronic devices. Here we propose an approach based on amplitude modulated electrostatic force microscopy to obtain measurements at small tip-sample distances, where highly nonlinear forces are present. We discuss how this improves the lateral resolution of the technique and allows probing of the electrical and surface properties. The complete force field at different tip biases is employed to derive the local work function difference. Then, by appropriately biasing the tip-sample system, short-range forces are reconstructed. The short-range component is then separated from the generic tip sample force in order to recover the pure electrostatic contribution. This data can be employed to derive the tip-sample capacitance curve and the sample dielectric constant. After presenting a theoretical model that justifies the need for probing the electrical properties of the sample in the vicinity of the surface, the methodology is presented in detail and verified experimentally. PMID- 23635385 TI - The role of bacterial biofilms in chronic infections. AB - Acute infections caused by pathogenic bacteria have been studied extensively for well over 100 years. These infections killed millions of people in previous centuries, but they have been combated effectively by the development of modern vaccines, antibiotics and infection control measures. Most research into bacterial pathogenesis has focused on acute infections, but these diseases have now been supplemented by a new category of chronic infections caused by bacteria growing in slime-enclosed aggregates known as biofilms. Biofilm infections, such as pneumonia in cystic fibrosis patients, chronic wounds, chronic otitis media and implant- and catheter-associated infections, affect millions of people in the developed world each year and many deaths occur as a consequence. In general, bacteria have two life forms during growth and proliferation. In one form, the bacteria exist as single, independent cells (planktonic) whereas in the other form, bacteria are organized into sessile aggregates. The latter form is commonly referred to as the biofilm growth phenotype. Acute infections are assumed to involve planktonic bacteria, which are generally treatable with antibiotics, although successful treatment depends on accurate and fast diagnosis. However, in cases where the bacteria succeed in forming a biofilm within the human host, the infection often turns out to be untreatable and will develop into a chronic state. The important hallmarks of chronic biofilm-based infections are extreme resistance to antibiotics and many other conventional antimicrobial agents, and an extreme capacity for evading the host defences. In this thesis, I will assemble the current knowledge on biofilms with an emphasis on chronic infections, guidelines for diagnosis and treatment of these infections, before relating this to my previous research into the area of biofilms. I will present evidence to support a view that the biofilm lifestyle dominates chronic bacterial infections, where bacterial aggregation is the default mode, and that subsequent biofilm development progresses by adaptation to nutritional and environmental conditions. I will make a series of correlations to highlight the most important aspects of biofilms from my perspective, and to determine what can be deduced from the past decades of biofilm research. I will try to bridge in vitro and in vivo research and propose methods for studying biofilms based on this knowledge. I will compare how bacterial biofilms exist in stable ecological habitats and opportunistically in unstable ecological habitats, such as infections. Bacteria have a similar lifestyle (the biofilm) in both habitats, but the fight for survival and supremacy is different. On the basis of this comparison, I will hypothesize how chronic biofilm infections are initiated and how bacteria live together in these infections. Finally, I will discuss different aspects of biofilm infection diagnosis. Hopefully, this survey of current knowledge and my proposed guidelines will provide the basis and inspiration for more research, improved diagnostics, and treatments for well-known biofilm infections and any that may be identified in the future. PMID- 23635386 TI - Effects of salt labelling and repeated in-home consumption on long-term liking of reduced-salt soups. AB - OBJECTIVE: The present study investigated the impact of salt labelling and repeated in-home consumption on liking of reduced-salt soups. DESIGN: Participants received a chicken noodle soup to be consumed twice weekly at home for 5 weeks. Three soups were included: (i) regular-salt soup as available on the market; (ii) 22 %-reduced-salt soup; and (iii) 32 %-reduced-salt soup. The soups were tasted blind or with the label: 'same great taste, less salt and more herbs'. In total, there were six experimental groups. All groups received the same soup over the whole period. Desire and liking were measured at each time of consumption. SETTING: In-home and central location test. SUBJECTS: French consumers (n 646). RESULTS: There was no significant difference in liking between the three soups when consumed at home, whereas the reduced-salt soups were less liked than the regular-salt soup in the central location test. Labelling did not boost liking scores, which is probably explained by the fact that all soups were similarly liked when eaten at home. CONCLUSIONS: The surprising results of the present study in France suggest that a salt reduction of up to 32 % in a chicken noodle soup did not affect long-term liking score as assessed by consumers at home. In addition, initial liking measured at the central location was not predictive of liking after repeated in-home consumption. How far we can go in reducing salt in other products without compromising product quality, and how this impacts consumers' choice behaviour and in turn table salt use at home, are still unanswered questions. PMID- 23635387 TI - Effect of timing of thrombectomy on survival of thrombosed arteriovenous hemodialysis grafts. AB - BACKGROUND: The use of an arteriovenous (AV) graft for hemodialysis is associated with a relatively high rate of thrombosis. Unfortunately, the urgent thrombectomy is not always readily available. Our aim was to investigate a possible association between the timing of thrombectomy and the patency rates of AV grafts. METHODS: A retrospective single-center study on patients who underwent thrombectomy of clotted AV grafts was conducted. According to the time of thrombectomy, all patients were divided into 4 groups. RESULTS: Primary graft patency at 6 months after thrombectomy was 28.3%, with no significant difference between the study groups (P = .161). Secondary graft patency at 6 months was significantly worse in the group that underwent thrombectomy between the third and fifth days than in the whole cohort: 15.4% versus 45.6% (P = .038). CONCLUSIONS: Timing of thrombectomy of a clotted AV graft may have a significant impact on the graft survival. PMID- 23635388 TI - Utility of the quantitative Ki-67 proliferation index and CD56 together in the cytologic diagnosis of small cell lung carcinoma and other lung neuroendocrine tumors. AB - BACKGROUND: Distinction of small cell lung carcinoma (SCLC) from non-small cell lung carcinoma (NSCLC) is critical because of the differences in prognosis and management. Patients with SCLC usually present with distant metastasis, and clinicians demand an accurate diagnosis in order to initiate appropriate therapy. Limited cytology material, occasionally with crush artifact, is not uncommon. Therefore, robust cytomorphologic features and a small immunostaining panel would be ideal to differentiate SCLC from NSCLC and other neuroendocrine neoplasms. We evaluated CD56 and the quantitative Ki-67 immunohistochemical panel in comparison to synaptophysin and chromogranin, along with cytomorphology to diagnose SCLC. DESIGN: Eighty-eight cases of SCLC were retrieved from the cytology archives of The Johns Hopkins Hospital. Forty neuroendocrine neoplasms were used as control cases. RESULTS: SCLCs included 33 lung cases and 55 metastatic lesions. The specimens were obtained by fine needle aspiration, thoracocentesis, bronchoalveolar lavage and abdominal paracentesis. CD56 was expressed in 98.9% of SCLCs, which is significantly more sensitive than synaptophysin and chromogranin. The Ki-67 labeling index was high (>70%) in all cases, which is a reliable marker to differentiate SCLC from other neuroendocrine neoplasms and NSCLC. CONCLUSION: CD56 and quantitative Ki-67 along with cytomorphology is a robust immunohistochemical panel to differentiate SCLC from other neuroendocrine neoplasms and NSCLC. PMID- 23635389 TI - Reference ranges of ductus arteriosus derived by cardio-spatiotemporal image correlation from 14 to 40 weeks of gestation. AB - OBJECTIVE: To construct reference ranges of fetal ductus arteriosus (DA) derived by volume datasets of cardio-spatiotemporal image correlation (cardio-STIC). METHODS: Cardio-STIC volume datasets were acquired from low-risk singleton pregnancies with a reliable gestational age from 14 to 40 weeks. In offline analysis with 4D View version 9, fetal DA was measured in the transverse ductal arch view with orthogonal control in the multiplanar view. The reference ranges of the DA and Z-score equation were constructed against gestational weeks and biparietal diameter (BPD) as independent variables. RESULTS: A total of satisfactory 606 volumes were analyzed. The reference ranges for predicting means and SDs of fetal DA were constructed based on the best-fit regression model. Mean DA (mm) was best predicted by linear model as a function of GA (weeks) and BPD (cm) as follows: Predicted DA diameter (cm) = -0.051 + 0.014 * GA (weeks) (r = 0.84) and Predicted DA diameter (cm) = -0.015 + 0.053 * BPD (cm) (r = 0.83). Models for Z-score calculation and centile charts for predicting fetal DA were also provided. CONCLUSION: Reference ranges of the fetal DA and Z-score model are provided. These may serve as a useful tool in the assessment of fetal DA, especially in fetal cardiac anomalies or in monitoring fetuses exposed to maternal indomethacin. PMID- 23635390 TI - Validity of dual MRI and F-FDG PET imaging in predicting vulnerable and inflamed carotid plaque. AB - BACKGROUND: Vulnerable and inflamed plaques in the carotid artery are at high risk of ischemic stroke, suggesting the importance of diagnostic modalities to detect them in patients with carotid stenosis with high sensitivity and specificity. Although many investigators have reported that magnetic resonance imaging (MRI) is a useful tool to predict the vulnerable components of carotid plaque, its validity is not established. On the other hand, (18)F fluorodeoxyglucose (FDG) positron emission tomography (PET) may be an alternative modality to directly identify the inflamed plaque in carotid artery stenosis. Therefore, this study aimed at evaluating the validity of MRI and FDG-PET to predict vulnerable and inflamed carotid plaque. METHODS: This prospective study totally included 25 patients who underwent carotid endarterectomy (CEA) for carotid artery stenosis at our institute between January 2009 and January 2012. Prior to CEA, FDG-PET, black-blood T1-weighted imaging (BB-T1WI), and 3 dimensional time-of-flight (TOF) imaging were performed. The specimens were stained with hematoxylin-eosin to assess the different plaque components (lipid, hemorrhage, calcification, and fibrous tissue). In addition, they were stained with primary antibodies against CD68 (activated macrophages) and matrix metalloproteinase (MMP)-9. RESULTS: High FDG uptake was detected in 13 (52.0%) of 25 patients. All of them had lipid-rich plaque. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) to identify the lipid-rich plaques were all 100% for FDG-PET. More importantly, all of the FDG-positive plaques had strong immunoreactivity against both CD68 and MMP-9. There was a significant correlation between the findings on FDG-PET and those on immunohistochemistry against CD68 and MMP-9 (p = 0.006 and 0.004, respectively). On the other hand, 16 (64.0%) of 25 patients had high signal intensity plaque on BB-T1WI. In 7 of these 16 patients, the lesions also showed high signal intensity on TOF imaging. All of them had a large intraplaque hemorrhage. The sensitivity, specificity, PPV, and NPV to identify a large intraplaque hemorrhage were 70, 100, 100, and 83%, respectively, for MRI. CONCLUSIONS: These findings suggest that FDG-PET and MRI are complementary to predict high-risk carotid plaque, such as lipid-rich or hemorrhagic plaque. FDG-PET can accurately predict the lipid rich and inflamed plaque. MRI is valuable to identify unstable plaque with a large intraplaque hemorrhage. The combination of these two modalities may play an important role in predicting carotid plaque at high risk of ischemic stroke. PMID- 23635391 TI - Aromatase variants modify risk for Alzheimer's disease in a multiethnic female cohort. AB - BACKGROUND/AIMS: Few studies of gene variants that affect estrogen activity investigate their association with risk for Alzheimer's disease (AD) in women of different ethnicities. We investigated the influence of CYP19 polymorphisms on risk for AD in a multiethnic cohort of women, with individual ethnicity assessed by genetic population ancestry informative markers (AIMs) as well as by self identified ethnicity. METHODS: Among 1,686 women participating in the Washington Heights Inwood Columbia Aging Project, association with risk for AD was assessed for 41 single nucleotide polymorphisms (SNPs) on the CYP19 gene using multivariable logistic regression, adjusting for age, presence of an APOE epsilon4 allele, years of education, and body mass index. RESULTS: Risk for AD was associated with 6 SNPs in women of predominantly Caucasian AIMs-defined ancestry. Of these, 2 were also associated with decreased risk of AD in women of admixed/Hispanic AIMs ancestry. Two separate SNPs were found to be protective in women of predominantly African AIMs-based ancestry. CONCLUSIONS: CYP19 polymorphisms affect risk for AD in women, and risk alleles vary by AIMs-defined ancestry. These effects are possibly due to linkage disequilibrium patterns or differences in the prevalence of comorbid risk factors mediating the SNP effect on risk for AD by group. PMID- 23635392 TI - Vascular endothelial cadherin expression in lung specimens of patients with sepsis-induced acute respiratory distress syndrome and endothelial cell cultures. AB - AIMS: Vascular endothelial (VE) cadherin is a cell adhesion molecule localized at endothelial cell (EC) junctions. As a major component of endothelial adherens junctions, its main function is the maintenance and regulation of EC integrity. In the acute respiratory distress syndrome (ARDS), increased vascular permeability is a major mechanism in pulmonary edema and lung dysfunction. In this study, VE-cadherin expression was investigated in ARDS lungs and control tissue as well as in an ARDS cell culture model. METHODS: Lung specimens of patients with ARDS due to Gram-negative sepsis (n = 20; control lung tissue: n = 41) and cell cultures of human pulmonary microvascular ECs and human umbilical vein ECs stimulated with LPS, TNF-alpha and IFN-gamma were stained with a VE cadherin antibody. Staining intensity was semiquantitatively evaluated by conventional light and immunofluorescence microscopy. RESULTS: VE-cadherin expression was statistically significantly reduced in the endothelium of all vessel types in ARDS lungs compared to control tissue. Cell cultures showing disrupted cellular borders confirmed these results. CONCLUSION: Reduced expression of VE-cadherin has to be considered as a major mechanism of increased vessel permeability in ARDS. The previously described vessel-type-specific expression pattern of VE-cadherin in the human lung is not influenced by ARDS. PMID- 23635394 TI - How to evaluate a graduate studentship, or choosing the right doctoral advisor. PMID- 23635393 TI - Preferred sources of health information in persons with multiple sclerosis: degree of trust and information sought. AB - BACKGROUND: Effective health communication is important for informed decision making, yet little is known about the range of information sources used by persons with multiple sclerosis (MS), the perceived trust in those information sources, or how this might vary according to patient characteristics. OBJECTIVE: We aimed to investigate the sources of health information used by persons with MS, their preferences for the source of health information, and levels of trust in those information sources. We also aimed to evaluate how these findings varied according to participant characteristics. METHODS: In 2011, participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry were asked about their sources of health information using selected questions adapted from the 2007 Health Information National Trends (HINTS) survey. RESULTS: Of 12,974 eligible participants, 66.18% (8586/12,974) completed the questionnaire. Mass media sources, rather than interpersonal information sources, were the first sources used by 83.22% (5953/7153) of participants for general health topics and by 68.31% (5026/7357) of participants for MS concerns. Specifically, the Internet was the first source of health information for general health issues (5332/7267, 73.40%) and MS (4369/7376, 59.23%). In a logistic regression model, younger age, less disability, and higher annual income were independently associated with increased odds of use of mass media rather than interpersonal sources of information first. The most trusted information source was a physician, with 97.94% (8318/8493) reporting that they trusted a physician some or a lot. Information sought included treatment for MS (4470/5663, 78.93%), general information about MS (3378/5405, 62.50%), paying for medical care (1096/4282, 25.59%), where to get medical care (787/4282, 18.38%), and supports for coping with MS (2775/5031, 55.16%). Nearly 40% (2998/7521) of participants had concerns about the quality of the information they gathered. CONCLUSIONS: Although physicians remain the most trusted source of health information for people with MS, the Internet is the first source of health information for most of them. This has important implications for the dissemination of health information. PMID- 23635396 TI - The effects of television and Internet food advertising on parents and children. AB - OBJECTIVE: The current study examined the impact of television and Internet food advertising on Australian parents and children. DESIGN: Parents and their children aged 8 to 14 years were exposed to a television advertisement, an Internet advertisement or a control picture for four commonly advertised energy dense, nutrient-poor foods. SETTING: Online web panel survey, Australia. SUBJECTS: Parents (n 1302) and their children aged 8 to 14 years (n 1302). RESULTS: After a single exposure to each advertisement, parent respondents in the two exposure conditions evaluated the products more favourably, had a greater desire to consume the products and thought the product could be consumed more frequently than those in the control condition. Similar trends were observed among children, although the differences were statistically significant only for the frequency of food consumption in the Internet advertisement condition and the evaluation of one product. CONCLUSIONS: The results have implications for assumptions of adults' immunity to advertising. This is of particular importance in efforts to address child obesity and the reliance on parents to mediate the effects of food advertising. PMID- 23635397 TI - Experience of mini-percutaneous nephrolithotomy in the treatment of large impacted proximal ureteral stones. AB - OBJECTIVES: To evaluate the efficacy and safety of mini- percutaneous nephrolithotomy (PCNL) in the treatment of large impacted proximal ureteral stones. METHODS: We retrospectively reviewed the outcomes of 163 patients who underwent mini-PCNL between January 2006 and August 2010. Mean age was 48.6 years and mean stone size was 18.4 mm. Hydronephrosis and/or hydroureterosis appeared in all patients. In the prone position, percutaneous access (16-Fr sheath) was established by placement of an access needle into the intended calyx under fluoroscopic guidance or combined with ultrasound guidance for complete obstruction by stones while the contrast agent cannot transit. Pneumatic or ultrasonic probes were used throughout ureterorenoscopy for lithotripsy. The ureteral stents and nephrostomy tube were placed at the end of the procedure. Mean drop in hemoglobin, operative time, success rate, hospital stay, and complications were assessed. RESULTS: Mini-PCNL operations were performed successfully in all patients. Mean operation time was 37 min. Mean postoperative hospital stay was 3.6 days. All cases were followed up for 6-20 months. No major complications like hemorrhage, perforation or organic injury were noted during the operation or postoperatively. The stone-free rate in all patients was 95.7%. Calculus had no recurrence during the follow-up period. Hydronephrosis and hydroureterosis disappeared or were relieved. CONCLUSIONS: Mini-PCNL is a safe and effective therapy for large impacted proximal ureteral stones. PMID- 23635398 TI - Association between genetic variants of the VEGFR-2 gene and the risk of developing endometriosis in Northern Chinese Women. AB - AIM: To investigate the association of tag single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor receptor 2 (VEGFR-2) gene with susceptibility to endometriosis. METHODS: This study comprised 571 patients with endometriosis and 580 women in the control group. Five tag SNPs in the VEGFR-2 gene were selected using a Haploview program, and those SNPs were genotyped by a method of polymerase chain reaction and ligase detection reaction. RESULTS: Statistical results show that there was a significant difference in the genotype and allele distribution of the 1192C/T polymorphism between the disease group and the control group (p = 0.041 and 0.017). The women carrying the T allele (C/T+T/T genotype) had a lower risk of developing endometriosis compared with the women with the C/C genotype (OR 0.75, 95% CI 0.57-0.99). There was no significant difference in the allele and genotype distribution of four other tag SNPs (1719T/A, +31C/T, IVS25-92A/G and IVS6+54C/T) between the disease group and the control group (all p > 0.05). CONCLUSIONS: Our results suggested that the 1192C/T polymorphisms on the VEGFR-2 gene might affect the risk of developing endometriosis in Northern Chinese women of Han ethnicity. PMID- 23635399 TI - The potential value of phosphohistone-h3 mitotic index determined by digital image analysis in the assessment of pancreatic endocrine tumors in fine-needle aspiration cytology specimens. AB - OBJECTIVE: According to the World Health Organization, pancreatic endocrine tumors are graded by assessment of the Ki67 proliferation index and/or mitotic count. The objective was to find comparable grading on the basis of the novel mitotic marker phosphohistone-H3 (PHH3). STUDY DESIGN: A computer-assisted system was used to assess 23 cell blocks stained with PHH3 and Ki67 antibodies. We investigated possible cut-points for PHH3 and computed percent agreement between the PHH3- and Ki67-based grading. RESULTS: The Spearman correlation between percent Ki67 positive and percent PHH3 positive was 0.76 (p = 0.001). A value of 0.3% for the lower cut-point ('cut-point 1', differentiating between grades 1 and 2) and values of about 1.8-1.9% for the higher cut-point ('cut-point 2', differentiating between grades 2 and 3) shows optimal agreement between PHH3 and Ki67 grading. The percentage of positive cells was much higher for Ki67 than for PHH3 (mean 10.6 vs. 3.0%). CONCLUSIONS: PHH3 has good correlation with Ki67, but the range of PHH3 positivity is much narrower than that of Ki67 (range 0-4% for PHH3 vs. 0-50% for Ki67). Therefore, to be as accurate, grading on the basis of PHH3 requires evaluation of a larger number of tumor cells for a precise determination of percent PHH3-positive nuclei. PMID- 23635401 TI - Transcription factor interactions mediate EGF-dependent COX-2 expression. AB - Cyclooxygenase-2 (COX-2) is linked to poor prognosis in patients with malignant gliomas. Amplification/overexpression of epidermal growth factor receptor (EGFR) is commonly seen in these tumors. EGFR signaling, through activation of the p38 MAPK/PKC-delta/Sp1 cascade, plays an essential role in the regulation of COX-2 expression in glioma cells. Here, we report that Src kinase contributes upstream to this signaling cascade. In addition, more detailed analysis revealed the involvement of FOXM1, a member of the forkhead box family of transcriptional activators, in EGF-dependent COX-2 induction. FOXM1 protein increased after stimulation with EGF, although its role in modulating COX-2 expression does not depend on this increase. While a conventional FOXM1 responsive element resides in a distal region (-2872/-2539 relative to the transcriptional start site) of the COX-2 promoter, this is not required for EGF-dependent induction of COX-2. Instead, FOXM1 forms a cooperative interaction with Sp1 at the Sp1-binding site ( 245/-240 relative to the start site) of the COX-2 promoter to mediate EGF-induced COX-2 expression. Definition of this novel interaction provides a clearer understanding of the mechanistic basis for EGF induction of COX-2. IMPLICATIONS: These data provide a guide for the evaluation of potential newer therapeutic targets that have relevance in this disease. PMID- 23635400 TI - Improvement of the methods for skin mechanical properties evaluation through correlation between different techniques and factor analysis. AB - BACKGROUND: In the past decades, many instruments have been developed to measure skin elasticity and firmness. The offer is extensive and is constantly increasing, becoming difficult to decide which equipment and mechanical property measurement are better to portrait the desired characteristics. The aim of this study was to compare and correlate parameters assessed with different probes, based on different methodologies, to understand which probe characterizes each skin elasticity property. METHODS: Measurements were performed in the abdomen region of 34 female volunteers, with three different probes: Cutometer((r)) SEM575, Reviscometer((r)) RVM600 and Frictiometer((r)) FR700. Statistical data analysis was performed by Factor Analysis on IBM SPSS Statistics 17.0. RESULTS: Frictiometer((r)) and Reviscometer((r)) measurements showed significant correlations with Cutometer's Uf, Ua, Ur and Ue parameters. Ue was strongly and significantly correlated to Uf and Ur. Ua was strongly and significantly correlated with Ur, Uf and Ue. Reviscometer((r)) measurements were similar along the same axis, and measurements performed in a specific direction are significantly correlated with age. CONCLUSION: A simpler and faster methodology for the complete assessment of elasticity and firmness of human skin is possible, in alternative to elaborate and time consuming methods, involving several equipments and parameters. The simpler methodology does not reduce the information obtained about the skin properties. PMID- 23635403 TI - Oatp1a4 and an L-thyroxine-sensitive transporter mediate the mouse blood-brain barrier transport of amyloid-beta peptide. AB - The influx of amyloid-beta peptide (Abeta) across the blood-brain barrier is partly mediated by the receptor for advanced glycation end products (RAGE). But other transporters, like Oatp (organic anion transporter polypeptide, SLC21) transporters, could also be involved. We used in situ brain perfusion to show that rosuvastatin and taurocholate, two established Oatp1a4 substrates, decreased (5-fold) the Clup of [3H]Abeta while L-thyroxine increased it (5.5-fold). We demonstrated an interaction between Abeta and Oatp1a4 by co-immunoprecipitation and western blotting experiments, supporting the hypothesis that the rosuvastatin and taurocholate-sensitive transporter was Oatp1a4. In conclusion, our results suggest that, in mice, the brain uptake of Abeta is partly mediated by Oatp1a4 and that L-thyroxine may play a crucial role in the inhibition of brain Abeta clearance. PMID- 23635404 TI - Several direct and calculated biomarkers from the amyloid-beta pool in blood are associated with an increased likelihood of suffering from mild cognitive impairment. AB - Validation of cost-effective, non-invasive methods to identify early (pre clinical) Alzheimer's disease (AD) is increasingly becoming a key research challenge. We have developed two ELISA sandwich colorimetric tests for the accurate detection of amyloid-beta (Abeta)1-40 and Abeta1-42: i) directly accessible (DA) in the plasma, ii) recovered from the plasma sample (RP) after diluting the plasma sample in a formulated buffer, and iii) associated with the remaining cellular pellet (CP). These tests were carried out on samples from healthy controls (n = 19) and individuals with mild cognitive impairment (MCI; n = 27) with amnestic-hippocampal syndrome to investigate whether this comprehensive approach may help to explain the association between blood Abeta levels and MCI. A logistic regression analysis detected seven direct or calculated markers (CP 40, DA 42, RP 42, DA/CP 40, DA/RP 42, DA/CP 42, and DA 42/40) with significant odds ratios (OR) after they were dichotomized with regard to the median of the pooled population. In particular, the likelihood [OR (95% CI)] of having MCI for patients with catCP 40, catDA/RP 42, catDA/CP 42, or catDA 42/40 below the corresponding population median ("positive test") was 11.48 (1.87 70.52), 22.09 (3.19-152.61), 11.48 (1.87-70.50), and 9.54 (1.77-51.38)-fold higher, respectively, than in those with a "negative test" after adjusting for the effect of the ApoE genotype. These results are congruent with the hypothesis that changes in blood Abeta levels may be associated with the initial stages of AD. Thus, these Abeta blood biomarkers might be useful tools for screening for those at increased risk of developing AD. PMID- 23635405 TI - Plasma fatty acid lipidomics in amnestic mild cognitive impairment and Alzheimer's disease. AB - Polyunsaturated fatty acids (PUFA) of the n-3 series have been linked to brain physiology and cognitive decline, but little is known about the other components of the complex fatty acids category. Here, we compared 30 molecular species pertaining to saturated, monounsaturated, polyunsaturated, and trans fatty acids, measured in plasma by gas chromatography, in 14 patients with a diagnosis of amnestic single domain mild cognitive impairment (aMCI), 30 patients with mild Alzheimer's disease (AD), and 30 healthy controls (HC). As no participants showed neuroimaging evidence of cerebrovascular disease, patients could be considered as purely neurodegenerative. We found differences in specific components of almost all fatty acid classes except n-3-polyunsaturated fatty acids. Compared with HC, aMCI and AD patients had higher levels of arachidic (C20:0), erucic (C22:1, n-9), and vaccenic acid (C18:1, n-9) and lower levels of cerotic (C26:0) and linoleic acid (C18:2, n-6). In particular, level of linoleic acid decreased and level of mead acid increased progressively from HC to aMCI to AD patients, and they were also inversely correlated in AD and aMCI patients. In conclusion, we found a previously unrecognized linoleic acid deficiency in the early phase of neurodegeneration that was strongly supported by an increased, compensatory mead acid level. These findings suggest the importance of creating new dietary manipulation strategies to counteract disease progression. PMID- 23635402 TI - Systems analysis of the NCI-60 cancer cell lines by alignment of protein pathway activation modules with "-OMIC" data fields and therapeutic response signatures. AB - The NCI-60 cell line set is likely the most molecularly profiled set of human tumor cell lines in the world. However, a critical missing component of previous analyses has been the inability to place the massive amounts of "-omic" data in the context of functional protein signaling networks, which often contain many of the drug targets for new targeted therapeutics. We used reverse-phase protein array (RPPA) analysis to measure the activation/phosphorylation state of 135 proteins, with a total analysis of nearly 200 key protein isoforms involved in cell proliferation, survival, migration, adhesion, etc., in all 60 cell lines. We aggregated the signaling data into biochemical modules of interconnected kinase substrates for 6 key cancer signaling pathways: AKT, mTOR, EGF receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), integrin, and apoptosis signaling. The net activation state of these protein network modules was correlated to available individual protein, phosphoprotein, mutational, metabolomic, miRNA, transcriptional, and drug sensitivity data. Pathway activation mapping identified reproducible and distinct signaling cohorts that transcended organ-type distinctions. Direct correlations with the protein network modules involved largely protein phosphorylation data but we also identified direct correlations of signaling networks with metabolites, miRNA, and DNA data. The integration of protein activation measurements into biochemically interconnected modules provided a novel means to align the functional protein architecture with multiple "-omic" data sets and therapeutic response correlations. This approach may provide a deeper understanding of how cellular biochemistry defines therapeutic response. Such "-omic" portraits could inform rational anticancer agent screenings and drive personalized therapeutic approaches. PMID- 23635406 TI - LDL phenotype in subjects with mild cognitive impairment and Alzheimer's disease. AB - BACKGROUND: Centenarians with normal cognitive function have a "longevity phenotype" characterized by large low-density lipoproteins (LDL) and high-density lipoproteins (HDL) and low incidence of metabolic syndrome, hypertension, and cognitive impairment. Alzheimer's disease (AD) is associated with a number of cardiovascular risk factors, but it is not known if they have or lack the "longevity phenotype". OBJECTIVE: The study was designed to determine LDL size and body fat content and distribution in subjects with mild cognitive impairment (MCI) and AD. RESULTS: Fifty-eight persons with MCI or AD (cases) and 42 control subjects of similar age had measurement of LDL size and lipoprotein lipids after a 12 h fast and analysis of body composition by dual x-ray absorptiometry. Cases had small LDL size more often than controls (73% versus 66%) associated with significantly higher triglycerides, lower HDL cholesterol, and higher triglyceride/HDL cholesterol ratio (p <= 0.02). Cases with large LDL had a better lipoprotein profile than those with small LDL. Cases and controls had similar percent body fat, fat index, and lean mass index. Forty-seven percent of cases and 39% of controls were obese. CONCLUSION: The prevalence of small LDL phenotype in MCI and AD cases contrasts with the "longevity phenotype" reported for centenarians with preserved cognitive function. The small LDL phenotype is an atherogenic lipoprotein profile found in metabolic syndrome, type 2 diabetes, and insulin resistance. It is now also reported in persons with MCI and AD. PMID- 23635408 TI - A combination of neuropsychological, neuroimaging, and cerebrospinal fluid markers predicts conversion from mild cognitive impairment to dementia. AB - BACKGROUND: Mild cognitive impairment (MCI) is a condition with increased risk for further cognitive decline. A considerable challenge lies in predicting which patients will eventually convert to dementia. OBJECTIVE: To study prediction of dementia in MCI using neuropsychological tests, commonly used cerebrospinal fluid (CSF) biomarkers, and hippocampal volume. METHODS: Twenty-one MCI patients converting to dementia, 21 stable MCI patients, and 26 controls were included in the study with a follow-up time of two years. The study participants underwent comprehensive examinations at inclusion: a neuropsychological assessment comprising 20 tests, MRI scanning with subsequent hippocampal volumetry, and CSF analyses of T-tau, P-tau, and Abeta42. RESULTS: Neuropsychological tests, hippocampal volume, and the CSF markers Abeta42, P-tau, and T-tau all predicted conversion from MCI to dementia. A combination of all classes of markers was the most successful at predicting dementia (AUC 0.96) with a memory test (RAVLT) as the best individual predictor (AUC 0.93). Similar findings are reported for the prediction of Alzheimer's disease. CONCLUSION: Neuropsychological tests were the best individual predictors of dementia. A combination of markers improved the predictive ability with the combination of neuropsychological tests, CSF, and hippocampal volume as the best predictors of dementia. PMID- 23635407 TI - Effects of emotionally-rated material on visual memory in Alzheimer's disease in relation to medial temporal atrophy. AB - Emotional material tends to be better retrieved in memory than neutral material. This emotional enhancement of memory may be related to the attentional effects of the amygdala's response to emotional stimuli. Because early neuropathological changes in Alzheimer's disease involve the amygdala and the hippocampus, it has been suggested that this effect is impaired in patients. However inconsistent results have been reported. The goal of our study was to evaluate the effects of emotion on picture recognition in patients affected by Alzheimer's disease, and to explore the link between this effect and the degree of amygdalar and hippocampal atrophy. Mild Alzheimer's disease patients (n = 15) and control participants (n = 20) performed an Old/New recognition task using pictures of negative, neutral, and positive emotional valence. Automated segmentation of their high-resolution T1 MRI scans was performed in order to obtain amygdalar and hippocampal volumes. Correlation analyses were then performed between volumetric data, memory, and the emotional effect on memory. An effect of emotion on memory was found for control participants (with positive items being better recognized than neutral and negative ones), with no correlation between this effect and medial temporal volumes, and a significant correlation between overall recognition scores and hippocampal volumes. Conversely, no emotional effect on memory was found across the group of patients; however, significant correlations were found between the loss of this effect and amygdalar and hippocampal volumes. These results tend to confirm a link between the loss of emotional effect on memory and neuropathological change in medial temporal structures during the course of Alzheimer's disease. PMID- 23635410 TI - Effectiveness and safety of memantine treatment for Alzheimer's disease. AB - BACKGROUND/OBJECTIVE: Memantine is approved as a treatment for moderate to severe Alzheimer's disease (AD). However, recent studies report that memantine is harmful for AD patients in several ways. This paper will systematically review all the available studies to provide an update regarding memantine as a treatment for AD. METHOD: Two authors queried nine databases containing literature published prior to September 15, 2012 and determined eligible studies based on the inclusion criteria. We used Review Manager to pool similar data. The Cochrane Handbook was used to assess the bias of the included studies. The chi-squared test, sensitivity analysis, Egger's test, and funnel plots were used to determine the heterogeneity and report bias, respectively. RESULT: We obtained 889 studies and determined that 12 of those studies met the inclusion criteria. The pooled analysis showed that memantine had significant benefits for AD patients in terms of cognition and the clinician's global impression. There were no significant benefits for AD patients in terms of mental state or activities of daily life. The results on brain volume and metabolism were controversial in two of the studies. Memantine did not significantly affect discontinuation caused by serious adverse events but did increase the risk for somnolence, weight gain, confusion, hypertension, nervous system disorders, and falling. CONCLUSION: Memantine is beneficial for AD patients with regards to cognition and clinician's global impression but increases the risk for somnolence, weight gain, confusion, hypertension, nervous system disorders, and falling. PMID- 23635409 TI - Alterations in the nuclear architecture produced by the overexpression of tau protein in neuroblastoma cells. AB - Abnormal intracellular aggregation of tau protein is a pathological condition leading to neuronal death in Alzheimer's disease. Fibrillar and nonfibrillar aggregates of tau protein alter the normal functioning of neurons by disturbing important cellular processes and distinct membranous organelles. However, tau caused alterations in the nuclear compartment are not totally established so far. In our study we evaluated whether tau protein and its Asp421-truncated variant produce alterations in the normal architecture of the nucleus when expressed in cultured neuroblastoma cells. After 48 hours of transfection, significant deformity of the nuclear compartment with extensive lobulations along the nuclear envelope was observed in SH-SY5Y cells expressing either full-length tau or Asp421-truncated tau. This aberrant formation did not involve either nuclear fragmentation or cell death. The lobulated nuclei were devoid of tau protein, which mostly remained in the cytoplasm in a nonfibrillar state. Degradation of nuclear Lamins was not observed in tau-expressing SH-SY5Y cells, and a cell-cycle analysis did not show aberrant chromosome accumulation. Thus multiple division defects leading to multinucleation were discarded. The lobulated nuclei in tau expressing SH-SY5Y cells seem to more resemble the multilobular phenotype of the nuclear envelope seen in Lamin-mutated cells from those pathological conditions leading to premature aging. Nevertheless, in our tau-expressing cells, the abnormal formation of cortical and perinuclear rings of tubulin generated by tau binding may be a more feasible mechanism of a nuclear-cytoskeleton generating force that causes the nuclear deformation. PMID- 23635411 TI - Methyl/allyl monolayer on silicon: efficient surface passivation for silicon conjugated polymer hybrid solar cell. AB - We demonstrate a hybrid Schottky junction solar cell based on methyl/allyl groups terminated silicon nanowire arrays (SiNWs) and poly(3,4 ethylenedioxythiophene)/poly(styrenesulfonate) with a power conversion efficiency (PCE) of 10.2%. The methyl/allyl organic monolayer on silicon can act as an excellent passivation layer for suppressing surface charge recombination, which is characterized by grazing angle attenuated total reflectance Fourier-transform infrared spectroscopy and X-ray photoelectron spectroscopy measurements. The transient and steady electric output characteristics measurements indicate that the density of trap states of SiNWs are dramatically suppressed by methyl/allyl surface modification. In addition, the device based on methyl/allyl passivated SiNWs exhibits improved stable electrical output over those based on either methyl or allyl passivated ones. The improved PCE and good stability of the device are ascribed to efficient functionalization of the SiNW surface. PMID- 23635412 TI - Adherence to cholinesterase inhibitors in Alzheimer's disease: a review. AB - BACKGROUND/AIMS: Treatment adherence is a major problem in numerous medical conditions, and is a particular challenge in patients with Alzheimer's disease (AD). METHODS: This non-systematic review summarises the current literature on factors that affect adherence to cholinesterase inhibitors, the mainstay of AD treatment. Articles listed on PubMed and published during the last 10 years were included. RESULTS: Intentional factors affecting adherence include patient, caregiver and prescriber beliefs about therapies and the disease itself. Unintentional factors include tolerability, physical limitations of the patient and caregiver burden. Interventions aiming to improve adherence include educational programmes and new drug delivery methods. CONCLUSION: Due to the high level of caregiver involvement in the care of patients with AD, strategies that address caregiver concerns may improve adherence. PMID- 23635414 TI - Renal dimensions at ultrasonography in healthy Ragdoll cats with normal kidney morphology: correlation with age, gender and bodyweight. AB - Fifty-six healthy Ragdoll cats underwent an ultrasonographical examination of the urinary tract to evaluate if gender, age, bodyweight and presence of a medullary rim sign had a significant influence on renal length and corticomedullary ratio (CM). Individual variation percentage was much more pronounced for renal length in comparison with CM ratio. Mean renal length measured 3.83 +/- 0.45 cm (range 2.98-5.09 cm), mean cortical thickness 0.73 +/- 0.15 cm (range 0.36-1.18 cm), mean medullary thickness 0.87 +/- 0.19 cm (range 0.46-1.39 cm) and mean CM ratio 0.88 +/- 0.29 (range 0.29-1.78). Renal length showed a significant positive correlation with bodyweight (P <0.0001), age (P = 0.0073) and male gender (P <0.0001). Therefore, these parameters have to be kept in mind when evaluating renal length on ultrasound. The CM ratio was solely influenced by the presence of a medullary rim sign (P <0.0001). Further research, however, is needed to investigate the usefulness of the CM ratio for the detection of kidney disease by ultrasonography. PMID- 23635413 TI - Prevalence of intestinal parasites in pet shop kittens in Japan. AB - The present study examined the prevalence of intestinal parasites in kittens from five pet shops in East Japan. Fresh faecal samples were collected from 555 kittens (aged 1-3 months) on a single occasion. The samples were tested for the presence of Giardia species coproantigen using a commercially available enzyme linked immunosorbent assay kit. Other intestinal parasites were identified microscopically using the formalin-ethyl acetate sedimentation technique. The overall prevalence of intestinal parasites was 27.2%; two genera of protozoa (Giardia species and Cystoisospora species) and one nematode (Toxocara cati) were detected. Faecal condition was not related to intestinal parasite infections. Significant differences among the pet shops were observed in the overall prevalence of intestinal parasites and the presence of Cystoisospora species infections. PMID- 23635415 TI - Nonfocal symptoms are more frequent in patients with vertebral artery than carotid artery stenosis. AB - INTRODUCTION: In patients with a transient ischemic attack (TIA) or ischemic stroke, the combination of focal and nonfocal symptoms has been associated with a higher risk of cardiovascular events. We hypothesized that nonfocal symptoms are more frequent in patients with symptomatic stenosis of a vertebral artery (VA) than of a carotid artery (CA). Therefore, we assessed the prevalence of nonfocal symptoms in patients with a recent TIA or nondisabling ischemic stroke and studied their relation with symptomatic CA or VA stenosis. METHODS: We administered a standardized questionnaire on the occurrence of focal and nonfocal symptoms during the qualifying TIA or nondisabling ischemic stroke and in the preceding 6 months. We included 50 consecutive patients with a recently symptomatic CA stenosis >=50%, 50 consecutive patients with a recently symptomatic VA stenosis >=50%, 25 consecutive patients with an anterior circulation event without an ipsilateral CA stenosis >=50%, and 25 consecutive patients with a posterior circulation event without a relevant VA stenosis >=50%. Relative risks for the presence of nonfocal symptoms in relation to the presence of a symptomatic stenosis were calculated with univariate and multivariate Poisson regression. Adjustments were made for age, sex, stroke as the qualifying event, and cardiovascular risk factors. A subgroup analysis was performed for patients in whom the vascular territory of the event was confirmed on imaging. RESULTS: During the qualifying ischemic event, focal symptoms were accompanied by nonfocal symptoms in 80 (53%) patients. Nonfocal symptoms occurred more frequently in patients with a VA stenosis (72%) than in patients with a CA stenosis [26%; adjusted relative risk (aRR), 2.9; 95% confidence interval (CI), 1.8-4.6]. A higher prevalence of nonfocal symptoms was found in patients with posterior circulation TIAs and strokes (73%) than in patients with anterior circulation TIAs and strokes (33%; aRR, 2.2; 95% CI, 1.6-3.1). During the preceding 6 months, 45% of patients with and 20% of patients without a symptomatic stenosis had had nonfocal symptoms (aRR, 2.4; 95% CI, 1.3-4.3). Subgroup analysis for the 89 (59%) patients with ischemia visible on imaging gave essentially the same results. CONCLUSIONS: More than half of the TIAs or nondisabling ischemic strokes were associated with nonfocal neurological symptoms. Nonfocal symptoms occurred more frequently in patients with a symptomatic VA stenosis than CA stenosis. PMID- 23635416 TI - Effects of pamidronate and calcitriol on the set point of the parathyroid gland in postmenopausal hemodialysis patients with secondary hyperparathyroidism. AB - BACKGROUND/AIMS: Secondary hyperparathyroidism may worsen after the administration of pamidronate in postmenopausal hemodialysis (HD) patients. The aim of this study was to evaluate the short-term effect of coadministration of calcitriol and pamidronate on dynamic parathyroid hormone (PTH) secretion. METHODS: Fifteen postmenopausal women undergoing regular HD with serum intact PTH levels of >200 pg/ml were enrolled. The PTH-ionized calcium (iCa) curve was evaluated by the response to hypo- and hypercalcemia induced with 1 and 4 mEq/l of dialysate calcium, respectively. Parameters were compared after pamidronate was administered and after coadministration of pamidronate and calcitriol. Changes in serum levels of maximal serum PTH (PTHmax), basal PTH (PTHbase) and minimal PTH (PTHmin) were evaluated. RESULTS: Pamidronate therapy resulted in a decrease in predialysis basal plasma iCa (p < 0.05) and an increase in PTHmax (p < 0.01), PTHbase (p < 0.01) and PTHmin (p < 0.01). The change in serum iCa and PTH was reversed after the coadministration of calcitriol and pamidronate. CONCLUSION: Our study demonstrated that pamidronate therapy is associated with a reduced plasma iCa and increased PTH secretion. These adverse effects may be reversed by calcitriol. These findings suggest that in considering pamidronate treatment in postmenopausal patients with osteoporosis receiving HD, it might be safer to add calcitriol to prevent the increased PTH secretion. PMID- 23635418 TI - The value of combining autofluorescence and optical coherence tomography in predicting the visual prognosis of sealed macular holes. AB - PURPOSE: To investigate the autofluorescence patterns of sealed macular holes and determine the correlations of the postoperative changes in spectral-domain optical coherence tomography and fundus autofluorescence (FAF) with the best corrected visual acuity (BCVA) of patients with sealed idiopathic macular holes. DESIGN: Retrospective consecutive observational case series. METHODS: Seventy seven eyes from 75 consecutive patients who had undergone successful vitrectomies for idiopathic macular holes by a single surgeon with postoperative follow-ups for over 1 year were included. FAF imaging studies were performed 1 month and 6 months post surgery, and optical coherence tomography (OCT) was performed at regular intervals after surgery. The main outcome measures were macular hole size, FAF patterns, retina outer segment from OCT, and BCVA before and after operation. RESULTS: The patients who had intact external limiting membranes (ELMs) at 1 month after surgery had better BCVAs than those without (P < .001), regardless of the photoreceptor inner segment/outer segment (IS/OS) condition. The FAF patterns were divided into 3 groups: homogenous hyperfluorescence, patchy hyperfluorescence, and normal hypofluorescence. No significant BCVA differences were noted (P = .28) among the 3 groups. However, significantly better BCVAs were noted in the patients who had both intact ELMs and normal hypofluorescence patterns (P = .011). CONCLUSIONS: In sealed macular holes, intact ELMs predicted good postoperative BCVA. In this subgroup, a hypofluorescence pattern on the FAF imaging predicted the best postoperative BCVA. PMID- 23635420 TI - No answer in the images: ultrasound, computed tomography, and magnetic resonance imaging suggested 3 possible diagnoses, none of which were accurate. PMID- 23635419 TI - Hints to the diagnosis of mixed acinar-endocrine carcinoma on pancreatic fine needle aspiration: avoiding a potential diagnostic pitfall. AB - BACKGROUND: Mixed acinar-endocrine carcinoma (MAEC) is a rare mixed tumor of the pancreas defined by both acinar and endocrine cell differentiation. CASE: We present 2 cases of MAEC initially diagnosed as pancreatic endocrine neoplasm on fine-needle aspiration. Both patients were male, aged 51 and 75 years, and presented with 16-mm and 6-mm pancreatic masses, respectively. Aspirates showed loose aggregates and dispersed single plasmacytoid cells with moderate nuclear size variation, slightly irregular nuclear contours, fine to coarsely granular chromatin, occasional prominent nucleoli, and scant to moderate finely granular cytoplasm. Rare mitotic figures and pyknotic forms were noted in one of the cases. Endocrine differentiation was confirmed by immunocytochemistry which led to an initial diagnosis of pancreatic endocrine neoplasm. Trypsin and lipase immunocytochemistry were later obtained, confirming a component of acinar cell differentiation. Findings were confirmed on surgical excision. CONCLUSION: Because of their potentially more aggressive clinical course and different therapeutic implications, MAECs are an important consideration in the differential diagnosis of pancreatic neoplasms. Certain cytomorphologic features and immunocytochemical markers of acinar cell differentiation may be helpful in raising the possibility of MAEC on cytology. PMID- 23635417 TI - Who participates in Web-assisted tobacco interventions? The QUIT-PRIMO and National Dental Practice-Based Research Network Hi-Quit studies. AB - INTRODUCTION: Smoking is the most preventable cause of death. Although effective, Web-assisted tobacco interventions are underutilized and recruitment is challenging. Understanding who participates in Web-assisted tobacco interventions may help in improving recruitment. OBJECTIVES: To understand characteristics of smokers participating in a Web-assisted tobacco intervention (Decide2Quit.org). METHODS: In addition to the typical Google advertisements, we expanded Decide2Quit.org recruitment to include referrals from medical and dental providers. We assessed how the expanded recruitment of smokers changed the users' characteristics, including comparison with a population-based sample of smokers from the national Behavioral Risk Factors Surveillance Survey (BRFSS). Using a negative binomial regression, we compared demographic and smoking characteristics by recruitment source, in particular readiness to quit and association with subsequent Decide2Quit.org use. RESULTS: The Decide2Quit.org cohort included 605 smokers; the 2010 BRFSS dataset included 69,992. Compared to BRFSS smokers, a higher proportion of Decide2Quit.org smokers were female (65.2% vs 45.7%, P=.001), over age 35 (80.8% vs 67.0%, P=.001), and had some college or were college graduates (65.7% vs 45.9%, P=.001). Demographic and smoking characteristics varied by recruitment; for example, a lower proportion of medical (22.1%) and dental-referred (18.9%) smokers had set a quit date or had already quit than Google smokers (40.1%, P<.001). Medical- and dental-referred smokers were less likely to use Decide2Quit.org functions; in adjusted analysis, Google smokers (predicted count 17.04, 95% CI 14.97-19.11) had higher predicted counts of Web page visits than medical-referred (predicted count 12.73, 95% CI 11.42 14.04) and dental-referred (predicted count 11.97, 95% CI 10.13-13.82) smokers, and were more likely to contact tobacco treatment specialists. CONCLUSIONS: Recruitment from clinical practices complimented Google recruitment attracting smokers less motivated to quit and less experienced with Web-assisted tobacco interventions. PMID- 23635422 TI - Involvement of the orexin system in adrenal sympathetic regulation. AB - Orexin (hypocretin) is a neuropeptide secreted from hypothalamic neurons that is known to be activated during motivated behaviors and active waking. Presently, our knowledge of orexin is mainly limited to the central nervous system, and the involvement of the orexin system in peripheral tissues has received little attention. In the present study, we analyzed the existence of the orexin system in the adrenal medulla, which is part of the sympathetic nervous system. Orexin and its receptors are expressed in the bovine adrenal medulla. Orexins stimulated intracellular calcium changes and epinephrine release from cultured bovine adrenal medullary cells. Applied orexin decreased expression of prepro-orexin, orexin receptor-1 and orexin receptor-2, suggesting negative feedback regulation in the adrenal gland. Our results indicate involvement of the orexin system in the sympathetic regulation of the adrenal medulla. PMID- 23635421 TI - Gestational weight gain and obesity: is 20 pounds too much? AB - OBJECTIVE: To compare maternal and neonatal outcomes in obese women according to weight change and obesity class. STUDY DESIGN: Cohort study from the Consortium on Safe Labor of 20,950 obese women with a singleton, term live birth from 2002 2008. Risk for adverse outcomes was calculated by multiple logistic regression analysis for weight change categories (weight loss [<0 kg], low [0-4.9 kg], normal [5.0-9.0 kg], high weight gain [>9.0 kg]) in each obesity class (I 30.0 34.9 kg/m(2), II 35.0-39.9 kg/m(2), and III >=40 kg/m(2)) and by predicted probabilities with weight change as a continuous variable. RESULTS: Weight loss was associated with decreased cesareans for class I women (nulliparas odds ratio [OR], 0.21; 95% confidence interval [CI], 0.11-0.42; multiparas OR, 0.61; 95% CI, 0.45-0.83) and increased small for gestational age infants (class I OR, 1.8; 95% CI, 1.3-2.5; class II OR, 2.2; 95% CI, 1.5-3.2; class III OR, 1.7; 95% CI, 1.1 2.6). High weight gain was associated with increased large for gestational age infants (class I OR, 2.4; 95% CI, 1.9-2.9; class II OR, 1.7; 95% CI, 1.3-2.1; class III OR, 1.6; 95% CI, 1.3-2.1). As weight change increased, the predicted probability for cesareans and large for gestational age infants increased. The predicted probability of low birthweight never exceeded 4% for all obesity classes, but small for gestational age infants increased with decreased weight change. The lowest average predicted probability of adverse outcomes (cesarean, postpartum hemorrhage, small for gestational age, large for gestational age, neonatal care unit admission) occurred when women (class I, II, III) lost weight. CONCLUSION: Optimal maternal and neonatal outcomes appear to occur when weight gain is less than current Institute of Medicine recommendations for obese women. Further study of long-term outcomes is needed with respect to gestational weight changes. PMID- 23635423 TI - Severe malnutrition among children under the age of 5 years admitted to a rural district hospital in southern Mozambique. AB - OBJECTIVE: To describe the burden, clinical characteristics and prognostic factors of severe malnutrition in children under the age of 5 years. DESIGN: Retrospective study of hospital-based data systematically collected from January 2001 to December 2010. SETTING: Rural Mozambican district hospital. SUBJECTS: All children aged <5 years admitted with severe malnutrition. RESULTS: During the 10 year long study surveillance, 274 813 children belonging to Manhica's Demographic Surveillance System were seen at out-patient clinics, almost half of whom (47 %) presented with some indication of malnutrition and 6% (17 188/274 813) with severe malnutrition. Of these, only 15% (2522/17 188) were eventually admitted. Case fatality rate of severe malnutrition was 7% (162/2274). Bacteraemia, hypoglycaemia, oral candidiasis, prostration, oedema, pallor and acute diarrhoea were independently associated with an increased risk of in-hospital mortality, while malaria parasitaemia and breast-feeding were independently associated with a lower risk of a poor outcome. Overall minimum communitybased incidence rate was 15 cases per 1000 child-years at risk and children aged 12-23 months had the highest incidence. CONCLUSIONS: Severe malnutrition among admitted children in this Mozambican setting was common but frequently went undetected, despite being associated with a high risk of death. Measures to improve its recognition by clinicians responsible for the first evaluation of patients at the out-patient level are urgently needed so as to improve their likelihood of survival. Together with this, the rapid management of complications such as hypoglycaemia and concomitant co-infections such as bacteraemia, acute diarrhoea, oral candidiasis and HIV/AIDS may contribute to reverse the intolerable toll that malnutrition poses in the health of children in rural African settings. PMID- 23635425 TI - Predictors of benign histology in clinical T1a renal cell carcinoma tumors undergoing partial nephrectomy. AB - The anatomical characteristics of renal tumors have been classified using several systems. An association between tumor anatomical characteristics and postoperative histological diagnosis can be expected. The present study aimed to assess the rate of and predictive factors for benign histological findings for renal tumors diagnosed as T1a by preoperative imaging. From January 2000 through December 2010, 149 patients underwent partial nephrectomy (either open or laparoscopic) for T1a renal cell carcinoma. The frequency of benign histological findings was evaluated. Logistic regression analysis estimated the relative importance of predictive factors. The overall frequency of benign lesions was 8.1%. Multivariate analysis identified three statistically significant predictive factors for benign lesions: age, sex and exophytic tumor property (P = 0.0356, 0.0183 and 0.0330, respectively). The present findings suggest that exophytic tumors on preoperative imaging are more likely to be benign at histology after partial nephrectomy. PMID- 23635427 TI - The second deletion mutation in exon 8 of EDA gene in an XLHED pedigree. AB - BACKGROUND: X-linked hypohidrotic ectodermal dysplasia (XLHED) is characterized by hypodontia, hypohidrosis, sparse hair and characteristic facial features and is caused by mutation in the ectodysplasin A (EDA) gene. OBJECTIVE: In this study we report on a large Chinese XLHED family and investigate the molecular genetics of the defect. METHODS: All individuals of the family were examined by clinical and radiographic examinations. The EDA gene was sequenced in the whole family and in 150 controls. RESULTS: Three male patients had classic XLHED phenotype. A novel one-nucleotide deletion mutation (c.855delG) in exon 8 which caused premature termination of the polypeptide at amino acid 307 was confirmed. The mutant lost parts of the TNF domain may prevent transmission of the intracellular downstream signal. This was the second deletion mutation in exon 8 that was reported in a Chinese individual. CONCLUSIONS: Our findings suggested deletion mutations in exon 8 might be specific to the Chinese population. PMID- 23635426 TI - Evidence for two karyotypic variants of the lesser horseshoe bat ( Rhinolophus hipposideros , Chiroptera, Mammalia) in Central Europe. AB - Three different diploid chromosome numbers (2n = 54, 56 and 58) have been reported in the lesser horseshoe bat, Rhinolophus hipposideros. Asia Minor and the Middle East are inhabited by R. hipposideros specimens with 58 chromosomes. In Europe, specimens with 56 chromosomes have been recorded from several localities in the Czech Republic, Slovakia, Italy and Greece. Up to now, specimens with 54 chromosomes have been reported only from Spain and possibly from Switzerland. With the record of 54 chromosomes in specimens from Germany presented here, the distributional area of this variant is expanded into Central Europe. According to the cytogenetic data presently available, we presume that the European R. hipposideros population is divided into a western form (from Spain to Germany) with a 2n = 54 karyotype and an eastern form (from the Czech Republic to Greece) with a 2n = 56 karyotype. This study presents banded karyotypes for the 2n = 54 and 2n = 56 variants for the first time. In addition, chromosomal arm homology to the vespertilionid bat species Myotis myotis revealed by chromosome painting is reported. Whether the variants could represent separate species is also discussed. PMID- 23635428 TI - Is poststroke depression a major depression? AB - BACKGROUND: Poststroke depression (PSD) is the most common neuropsychiatric consequence of stroke. A large number of studies have focused on the pathogenesis of PSD, but only a few aimed to characterize its psychopathology; these studies yielded results that are difficult to compare because of the different methods utilized. The current study aimed to characterize the symptom profile of PSD in an attempt to better understand the disease and allow a more accurate diagnosis. METHODS: The study sample comprised 64 patients divided into three groups: stroke patients without diagnosis of depression (n = 33), stroke patients diagnosed with PSD (PSD group, n = 14) and patients diagnosed with major depression (MD) but with no clinical comorbidity (MD group, n = 17). All patients were diagnosed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). The initial diagnostic interview was complemented by the Mini Mental State Examination (MMSE), the Rankin Scale, and four scales for the assessment of the intensity of symptoms of anxiety and depression: the Beck Depression Inventory (BDI), the Hospital Anxiety and Depression General Scale (HADS), the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM A). The Star Plot, a graphical method of data visualization, was used to analyze the results. The t test was used for independent samples (two-tailed analysis). RESULTS: As measured by the BDI, HAM-D and HAM-A scales and HADS depression subscale, the average total scores of symptoms for the sample of patients diagnosed with MD without clinical comorbidity was significantly higher than that of the PSD patients (p < 0.05). Similar results were obtained by plotting the BDI data on Star Plot. The PSD patients showed mild typical depressive symptoms such as less depressed mood, anhedonia, disinterest, guilt, negative thoughts, depreciation, suicidal ideation and anxiety, when evaluated by the HAM-A scale. Moreover, the somatic symptoms of depression did not lead to increased diagnosis of major depression in stroke patients. CONCLUSIONS: The results indicate that the PSD clinical picture comprised, in general, symptoms of mild/moderate intensity, especially those considered as pillars for the diagnosis of depression: depressed mood, loss of pleasure and lack of interest. Given the imprecision of boundaries that separate the clinical forms of depression from subclinical and nonpathological forms, or even from the concepts of demoralization and adjustment disorders, we situate PSD in a complex biopsychosocial context in which a better understanding of its psychopathological profile could provide diagnostic and therapeutic alternatives best suited to the difficult reality experienced by stroke patients. PMID- 23635424 TI - Protein-protein interaction networks: probing disease mechanisms using model systems. AB - Protein-protein interactions (PPIs) and multi-protein complexes perform central roles in the cellular systems of all living organisms. In humans, disruptions of the normal patterns of PPIs and protein complexes can be causative or indicative of a disease state. Recent developments in the biological applications of mass spectrometry (MS)-based proteomics have expanded the horizon for the application of systematic large-scale mapping of physical interactions to probe disease mechanisms. In this review, we examine the application of MS-based approaches for the experimental analysis of PPI networks and protein complexes, focusing on the different model systems (including human cells) used to study the molecular basis of common diseases such as cancer, cardiomyopathies, diabetes, microbial infections, and genetic and neurodegenerative disorders. PMID- 23635430 TI - Enhancement of in vitro and in vivo function of agarose-encapsulated porcine islets by changes in the islet microenvironment. AB - The transplantation of porcine islets of Langerhans to treat type 1 diabetes may provide a solution to the demand for insulin-producing cells. Porcine islets encapsulated in agarose-agarose macrobeads have been shown to function in nonimmunosuppressed xenogeneic models of both streptozotocin-induced and autoimmune type 1 diabetes. One advantage of agarose encapsulation is the ability to culture macrobeads for extended periods, permitting microbiological and functional assessment. Herein we describe optimization of the agarose matrix that results in improved islet function. Porcine islets (500 IEQs) from retired breeding sows were encapsulated in 1.5% SeaKem Gold (SG), 0.8% SG, or 0.8% Litex (Li) agarose, followed by an outer capsule of 5% SG agarose. Insulin production by the encapsulated islets exhibited an agarose-specific effect with 20% (0.8% SG) to 50% (0.8% Li) higher initial insulin production relative to 1.5% SG macrobeads. Insulin production was further increased by 40-50% from week 2 to week 12 in both agarose types at the 0.8% concentration, whereas islets encapsulated in 1.5% SG agarose increased insulin production by approximately 20%. Correspondingly, fewer macrobeads were required to restore normoglycemia in streptozotocin-induced diabetic female CD(SD) rats that received 0.8% Li (15 macrobeads) or 0.8% SG (17 macrobeads) as compared to 1.5% SG (19 macrobeads). Islet cell proliferation was also observed during the first 2 months postencapsulation, peaking at 4 weeks, where approximately 50% of islets contained proliferative cells, including beta-cells, regardless of agarose type. These results illustrate the importance of optimizing the microenvironment of encapsulated islets to improve islet performance and advance the potential of islet xenotransplantation for the treatment of type 1 diabetes. PMID- 23635429 TI - A direct comparison of the prevalence of advanced adenoma and cancer between surveillance and screening colonoscopies. AB - BACKGROUND/AIMS: Surveillance colonoscopy is recommended after polypectomy of adenoma and surgery for colorectal cancer. The purpose of this study was to assess the frequency of advanced adenoma and cancer in colonoscopies performed for surveillance compared to screening colonoscopies. METHODS: Analysis of relative frequencies of findings in colonoscopies performed for post-adenoma surveillance (post-ad), post-cancer surveillance (post-crc), screening, and follow-up of a positive fecal occult blood test (FOBT). Logistic regression was used to identify the risk for advanced adenoma (adenoma >=10 mm, containing high grade dysplasia, or villous histology) and cancer. RESULTS: 324,912 colonoscopies were included in the analysis: 81,877 post-ad, 26,896 post-crc, 178,305 screening, 37,834 positive FOBT. Advanced adenoma (cancer) was diagnosed in 8.0% (0.4%) of post-ad, 5.0% (1.0%) of post-crc, 7.4% (1.1%) of screening, and 11.7% (3.6%) of positive FOBT colonoscopies. Compared to screening, the odds ratios for finding advanced adenoma were 0.93 (95% CI 0.88-0.98) for post-ad, 0.96 (0.86 1.08) for post-crc, and 1.18 (1.09-1.28) for positive FOBT colonoscopies. The odds ratios for the diagnosis of cancer were 0.29 (0.24-0.36) for post-ad, 0.81 (0.61-1.07) for post-crc, and 2.77 (2.43-3.17) for positive FOBT. CONCLUSION: Colonoscopy for post-ad surveillance but not colonoscopy for post-crc surveillance is associated with a lower risk of diagnosis of advanced adenoma and cancer. PMID- 23635431 TI - A fast method to produce strong NFC films as a platform for barrier and functional materials. AB - In this study, we present a rapid method to prepare robust, solvent-resistant, nanofibrillated cellulose (NFC) films that can be further surface-modified for functionality. The oxygen, water vapor, and grease barrier properties of the films were measured, and in addition, mechanical properties in the dry and wet state and solvent resistance were evaluated. The pure unmodified NFC films were good barriers for oxygen gas and grease. At a relative humidity below 65%, oxygen permeability of the pure and unmodified NFC films was below 0.6 cm(3) MUm m(-2) d(-1) kPa(-1), and no grease penetrated the film. However, the largest advantage of these films was their resistance to various solvents, such as water, methanol, toluene, and dimethylacetamide. Although they absorbed a substantial amount of solvent, the films could still be handled after 24 h of solvent soaking. Hot pressing was introduced as a convenient method to not only increase the drying speed of the films but also enhance the robustness of the films. The wet strength of the films increased due to the pressing. Thus, they can be chemically or physically modified through adsorption or direct chemical reaction in both aqueous and organic solvents. Through these modifications, the properties of the film can be enhanced, introducing, for example, functionality, hydrophobicity, or bioactivity. Herein, a simple method using surface coating with wax to improve hydrophobicity and oxygen barrier properties at very high humidity is described. Through this modification, the oxygen permeability decreased further and was below 17 cm(3) MUm m(-2) d(-1) kPa(-1) even at 97.4% RH, and the water vapor transmission rate decreased from 600 to 40 g/m(2) day. The wax treatment did not deteriorate the dry strength of the film. Possible reasons for the unique properties are discussed. The developed robust NFC films can be used as a generic, environmentally sustainable platform for functional materials. PMID- 23635432 TI - Histotopographical characterization of the para-aortic lymph nodes in the area near the origin of the thoracic duct, and its relationship to nodal cancer metastasis. AB - Using 10 elderly cadavers without macroscopically evident tumors, we histologically examined 115 para-aortic lymph nodes located near the origin of the thoracic duct after preparation of en bloc specimens using a clearance method. The afferent and efferent sides of these nodes were usually not discriminated clearly because i) the superficial cortex (B-lymphocyte area) and deep cortex (T-lymphocyte area) were not clearly differentiated due to lack of a typical hilus, and both cortices were intermingled to form "nodular masses"; ii) each nodule with a lining of macrophages was surrounded by dilated intermediate and subcapsular sinuses; iii) the nodes were often surrounded by multiple tributaries of the thoracic duct. Moreover, the nodes sometimes involved these tributaries inside. Therefore, the nodal architecture seemed to accelerate intranodal shunt flow without filtration through the cortex. Valves of the lymphatic vessel tended to be restricted to an area immediately before drainage into the thoracic duct. Thus, lymph flow was likely to change along a network of tributaries around a node. These morphologies suggested very limited barrier function of the para-aortic node against cancer metastasis. However, we hypothesized that "better" or "worse" types of nodes are histologically identifiable when they are picked up surgically along with the surrounding tissues. PMID- 23635433 TI - Overexpression of beta-actin is closely associated with metastasis of gastric cancer. AB - BACKGROUND/AIMS: beta-actin is known to be involved in motility of cancer cells. However, the association between beta-actin expression and metastasis of gastric cancer remains unclear. METHODOLOGY: We enrolled 40 gastric cancer patients who underwent gastrectomy and evaluated the expression of beta-actin in gastric cancer tissues and the corresponding normal mucosa by the analysis of Western blotting. To further study the function of beta-actin in cancer cell migration, wound healing assay was performed in SGC7901 transfected with beta-actin siRNA. RESULTS: The level of beta-actin was significantly higher in gastric cancer tissues than in the corresponding normal mucosa. The correlation between beta actin expression and the local lymph node metastasis was statistically significant, which demonstrated that overexpression of beta-actin might contribute to the local lymph node metastasis of gastric cancer. Interference of beta-actin expression could inhibit migration of SGC7901 cells. CONCLUSIONS: beta actin, the most conservative and dynamic protein, is overexpressed in gastric cancer tissues and may play a crucial role in metastasis of gastric cancer. PMID- 23635434 TI - Liver resection for gastric cancer metastases. AB - BACKGROUND/AIMS: Surgical indications in patients with liver metastases from gastric cancer are debated. To analyze outcomes of surgery and the impact of neoadjuvant chemotherapy (NeoCTx). METHODOLOGY: Consecutive patients undergoing liver resection for gastric metastases between January 1997 and December 2008 were analyzed. RESULTS: Liver metastases were synchronous in 9 patients and multiple in 5. Eight patients received NeoCTx. NeoCTx and non-NeoCTx groups had similar characteristics. Mortality was nil, morbidity was 40%. After a mean follow-up of 42.5 months, 5-year survival rate was 33.2%. Presence of multiple metastases was a negative prognostic factor (p=0.029), while synchronous presentation and NeoCTx were not. Disease-free survival rates were significantly different by stratifying patients according to response to chemotherapy: at 5 years 32.4% in non-NeoCTx group, 0% in disease progression (PD) while on NeoCTx group and 60.0% in non-PD while on NeoCTx group (p=0.018). One-year recurrence rates were 40%, 100% and 0%, (p=0.020). CONCLUSIONS: Liver resection for gastric metastases achieves good long-term results, especially in solitary metastases. NeoCTx helps to select candidates for surgery and, in patients without PD, is associated with improved disease-free survival PMID- 23635435 TI - Concurrent chemoradiotherapy for squamous cell carcinoma of the rectum. AB - BACKGROUND/AIMS: Primary squamous cell carcinoma of the rectum is a rare malignancy. Early reports suggest that the standard treatment is surgery, but clinical outcomes of chemoradiotherapy are more satisfying than those of surgery in recent experience. Our aim was to ascertain the effectiveness of chemoradiotherapy for squamous cell carcinoma of the rectum. METHODOLOGY: Between May 2002 and April 2006, four patients with primary squamous cell carcinoma of the rectum underwent curative concurrent chemoradiotherapy. The clinical stage of the patients was T3N1M0 in one patient, T1N2M0 in two, and T2N0M0 in one. Radiotherapy was administered to the entire pelvis, followed by a boost to the primary tumor. The total dose ranged from 5040cGy to 6300cGy in 180cGy fractions. Curative chemotherapy was concurrently initiated on the first day of pelvic radiotherapy, and a capecitabine plus cisplatin or 5-fluorouracil plus cisplatin regimen was used. RESULTS: A complete clinical response was achieved in all four patients. One patient died of pneumonia 2 months after chemoradiotherapy without progression of the primary tumor. The remaining three patients have been alive with no evidence of disease for 52-99 months. CONCLUSIONS: The results suggest that chemoradiotherapy is an effective treatment option for squamous cell carcinoma of the rectum. PMID- 23635436 TI - Impact of C-reactive protein on prognosis of patients with colorectal carcinoma. AB - BACKGROUND/AIMS: The aim of this study was to investigate the impact of preoperative serum C-reactive protein (CRP) level as a prognostic indicator in patients with colorectal carcinoma (CRC). METHODOLOGY: We investigated the correlation between preoperative CRP level and clinicopathological factors including prognosis of 167 patients who underwent resection for CRC retrospectively. Clinicopathological variables were compared between patients with serum CRP levels >1mg/dL (29 patients; high-CRP group) and patients with serum CRP levels <1mg/dL (138 patients; low-CRP group). RESULTS: In high-CRP group, 9 patients were stage I+II and 20 patients ware stage III+IV. In low-CRP group, 93 patients were stage I+II and 45 patients were stage III+IV. There were significant differences in the clinical stage, tumor diameter, curativity, final stage between the two groups (p<0.01). The overall survival and recurrence-free survival rates in high-CRP group were lower compared with the rates in low-CRP group (p<0.05 and p=0.14). In addition, the overall survival rate in stage I+II patients with high-CRP was significantly lower than that in patients with low-CRP (p<0.05). Using multivariate analysis, the preoperative elevation of serum CRP level was an independent prognostic factor in patients with CRC (p<0.05). CONCLUSIONS: We found that the preoperative elevation of serum CRP to be an independent prognostic indicator of CRC. PMID- 23635437 TI - A prospective observational study of 468 patients undergoing D2 or D3 lymphadenectomy for gastric cancer. AB - BACKGROUND/AIMS: A single-center, prospective observational study was performed to evaluate outcomes in patients undergoing D2 or D3 lymphadenectomy for gastric cancer. METHODOLOGY: Lymphadenectomies were performed according to the classification published by the Japanese Gastric Cancer Association. RESULTS: Of 468 consecutive patients, 370 underwent D2 and 98 underwent D3 lymphadenectomy. Postoperative complications were significantly less common in the D2 group than in the D3 group (19.2% vs. 35.7%, p=0.001). Postoperative mortality in the two groups was similar, being 3.8% in the D2 group and 5.1% in the D3 group (p>0.05). Median postoperative survival times were also similar, in the D2 group being 37.8 months (95% CI: 23-52.5), and in the D3 group 30.2 months (95% CI: 13-47.3, p>0.05). CONCLUSIONS: In patients who underwent gastrectomy with curative intent, lymphadenectomy that was more extensive than D2 did not provide a survival benefit compared to D2 dissection. PMID- 23635438 TI - Two staged minimally invasive treatment for acute cholecystitis in high risk patients. AB - BACKGROUND/AIMS: The most optimal treatment for acute cholecystitis in high risk patients and severe acute cholecystitis remains still controversial. We review the outcomes of a two step treatment with percutaneous cholecystostomy and delayed laparoscopic cholecystectomy (DLC). METHODOLOGY: We collected data prospectively from January 2004 to April 2010 from 26 patients that underwent percutaneous transhepatic CT-guided cholecystostomy and DLC. RESULTS: Percutaneous transhepatic CT-guided cholecystostomy was achieved in all cases with no complications. There was just one catheter dislodgement. Most of patients, 92%, improved after drainage. There was one case of mortality. Laparoscopic cholecystectomy was achieved in 88% of patients with no mortality, and a low rate of morbidity (7.6%) and of conversion to open surgery. Pre operative percutaneous cholangiogram showed additional and useful information in 55.5% of patients. CONCLUSIONS: Two-step minimally invasive treatment combining percutaneous transhepatic CT-guided cholecystostomy and DLC is safe and feasible and report low morbi-mortality rates. PMID- 23635439 TI - The prevalence and risk factors of gallstones in Korean patients with liver cirrhosis. AB - BACKGROUND/AIMS: The aims of this study were to evaluate the frequency of gallstones and the related risk factors in patients with liver cirrhosis. METHODOLOGY: Patients (n=1,333) with liver cirrhosis who were diagnosed at Yeungnam University Hospital between January 2006 and December 2008 were analyzed retrospectively. Healthy people (n=16,922) who underwent an examination at the health promotion center were enrolled as a control group. We analyzed the clinical and laboratory findings between the cirrhotic patients with and without gallstones. RESULTS: Liver cirrhosis was an independent risk factor for gallstone formation (OR: 2.017; p=0.00). Diabetes and hypertriglyceridemia increased the risk for gallstones by 2.2-fold and 1.9-fold in cirrhotic patents, respectively. The severity of the liver cirrhosis according to the Child-Pugh class carried a significantly greater risk of gallstone formation. Multiple logistic regression analysis showed that diabetes, hypertriglyceridemia, and Child-Pugh class C were significantly related to the risk of gallstone formation in patients with liver cirrhosis. CONCLUSIONS: The prevalence of gallstones is significantly higher in patients with liver cirrhosis, and the related risk factors are diabetes, hypertriglyceridemia and severity of liver cirrhosis. PMID- 23635441 TI - A novel technique of percutaneous stone extraction in choledocholithiasis after cholecystostomy. AB - BACKGROUND/AIMS: To evaluate the technical feasibility and clinical efficacy of percutaneous common bile duct stone extraction via cystic duct after percutaneous cholecystostomy. METHODOLOGY: Twenty-five consecutive patients with choledocholithiasis underwent percutaneous stone extraction under conscious sedation. The stones were extracted through the 12-Fr sheath using Wittich nitinol stone basket under fluoroscopic guidance via cystic duct after percutaneous trnas-hepatic cholecystostomy. RESULTS: Common bile duct stones were successfully removed in 22 of the 25 patients (88%) by this new technique. The causes of failure in three patients were bile leakage, hematoma of the gallbladder and failure of cystic duct cannulation. Cystic duct injury during this procedure did not occur and there was no post-procedure mortality. The mean period of indwelling catheter was 8.7+/-4.6 days and the mean duration of hospitalization was 13.4+/-5.9 days. CONCLUSIONS: Percutaneous commmon bile duct stone extraction via the cystic duct through percutaneous cholecystostomy route is effective and feasible for treating choledocholithiasis. PMID- 23635440 TI - Prognostic accuracy of staging systems in patients with primary liver cancer undergoing transarterial chemoembolization. AB - BACKGROUND/AIMS: To compare the performance of the Child-Turcotte-Pugh (CTP), the Okuda, the Cancer of Liver Italian Program (CLIP), the Barcelona Clinic Liver Cancer (BCLC), the Chinese staging (CS), Chinese university prognostic index (CUPI), Japan integrated staging (JIS), the Tokyo and the French staging systems, in predicting the survival of patients with primary liver cancer (PLC) receiving transarterial chemoembolization (TACE). METHODOLOGY: The clinical data of patients undergoing TACE in our department were retrospectively analyzed and compared with the 9 staging systems based on survival after TACE. RESULTS: A cohort of 60 patients was involved. The survival curves showed that Okuda, BCLC, CS and JIS had better discriminatory ability. By the Cox regression model, Okuda, CS and JIS showed a stronger significance on prognosis. The staging systems with smaller value of -2Ln(L), Akaike Information criterion (AIC) and Schwarz-Bayesian criterion (SBC) were CS, JIS, CLIP and BCLC. An analysis involving 11 factors by Cox model indicated that ascites and vascular invasion were independent prognostic factors. CONCLUSIONS: JIS provides better prognostic stratification for a cohort of the patients with PLC receiving TACE. However, studies with larger samples are still required. PMID- 23635442 TI - Selective utilization of pre-operative endoscopic ultrasound to exclude choledocholithiasis prior to laparoscopic cholecystectomy: a retrospective study. AB - BACKGROUND/AIMS: The objective of this study was to define the clinical, biochemical and ultrasonographic criteria correlating with a likelihood of a positive preoperative endoscopic ultrasound (EUS) in patients presenting with acute gallstone-related pancreatobiliary disease. METHODOLOGY: All patients who underwent EUS prior to elective laparoscopic cholecystectomy were analyzed at the Gastroenterology Unit, Kaplan Medical Center, following acute admission with cholecystitis, cholelithiasis, cholangitis, acute pancreatitis and obstructive jaundice. RESULTS: One hundred and seventy four patients met the inclusion criteria. EUS showed choledocholithiasis in 37 (21.3%) with 35/37 undergoing a preoperative ERCP (24/35 cases - 64.9% positive yield). Twenty seven of the positive EUS studies (73%) were performed during the acute illness, with 50 of the 137 negative studies (36.4%) performed during the acute phase of the illness (p=0.0001). On multivariate analysis, a positive EUS was more commonly found during the acute phase of the illness [OR: 3.445; 95% CI: 1.48-8.008, p=0.004] or if there was transient jaundice [OR: 1.167; 95% CI: 1.002-1.36, p=0.047]. CONCLUSIONS: The timing of the examination influences the detection rate of CBD stones by EUS prior to surgery although it may be appropriate to more selectively use EUS in those patients with hyperbilirubinaemia and/or where the CBD is dilated. PMID- 23635443 TI - A prospective multi-institutional study assessing clinical outcome with the NiTi compression anastomosis ring (Biodynamix ColonRingTM) in elective colorectal anastomoses. AB - BACKGROUND/AIMS: This 3-institution study assessed the short-term clinical outcome and safety profile of the NiTi Biodynamix ColonRingTM compression anastomosis in elective colorectal resection. METHODOLOGY: A prospective, open label, non-randomized trial was conducted at 3 separate institutions between October 2008 to October 2009 in patients undergoing elective colorectal resection with the Biodynamix ColonRingTM compression anastomosis ring, assessing technical factors in its operative use, immediate and short-term clinical outcome parameters (length of hospital stay, time to first passage of flatus and stool and to oral intake) and peri-operative complications including anastomotic failure or stenosis and wound infection. RESULTS: Forty patients (22 females, mean age 65.9 years; range 36-83 years were included in the analysis with 14 cases being performed laparoscopically. The median duration of surgery was 120 minutes (range 60-456 minutes) with a mean anastomotic time of 14.8 minutes (range 1.75-50 minutes). The mean height of anastomosis from the anal verge was 18.2cm. The median time to passage of first flatus and first stool was 2.4 and 3.5 days, respectively with a mean hospital stay of 7.3 days. There was one postoperative death (unrelated to an anastomotic complication) with 2 anastomotic leaks (5%), 2 wound infections (5%) and no cases of early anastomotic stricture. CONCLUSIONS: The compression anastomosis ColonRingTM handles easily with an acceptable clinical outcome following both laparoscopic and open use. The incidence of anastomotic and wound complications is comparable to conventional stapled technology. PMID- 23635445 TI - Screening ultrasonography is useful for the diagnosis of gastric and colorectal cancer. AB - BACKGROUND/AIMS: To clarify the usefulness of screening ultrasonography (US) to diagnose gastric and colorectal cancer, patient records were analyzed retrospectively. METHODOLOGY: Ultrasonography was performed for patients with abdominal symptoms. They were then subjected to computed tomography (CT) when diagnosed with gastric cancer, colorectal cancer, or bowel obstruction. Patient records were analyzed retrospectively after final diagnosis of gastric cancer or colorectal cancer by endoscopy, surgery or necropsy. RESULTS: Twelve patients were diagnosed with colorectal cancer and six with gastric cancer. The detailed structure of colorectal cancer was visible as wall thickening with US, while cancer was often illustrated as a mass by CT. Loss of stratification was clear with US in 11 patients. US demonstrated wall thickening in 10 patients and a mass in 1 patient, while CT demonstrated wall thickening in 3 patients and a mass in 8 patients. The structure of colorectal cancer was more obvious when using US than when using CT. One patient demonstrated focal wall thickening with US, but this was not detected by CT. CONCLUSIONS: US is useful for diagnosis of gastric cancer and colorectal cancer. US produces more detailed findings in colorectal cancer than CT. PMID- 23635444 TI - Complete clinical response to neoadjuvant chemoradiation in rectal cancers: can surgery be avoided? AB - BACKGROUND/AIMS: Neoadjuvant chemoradiation for rectal cancers may result in complete clinical response (cCR) in some patients. The aim of this study was to analyze the long-term outcomes of such patients in a tertiary cancer center. METHODOLOGY: Patients with rectal cancer who had a cCR to neoadjuvant chemoradiation were divided into two groups: Group A (n=23) did not undergo surgery, and Group B (n=10) underwent elective surgery. The recurrence patterns and survival outcomes were compared between the two groups. RESULTS: After a median follow-up of 72 months (range 12-180), seven patients (30%) in Group A developed an isolated local recurrence. In Group B, after a median follow-up of 37 months (range 12-180) there were no local recurrences. The median disease-free and overall survival was 36 months (range 6-168) and 66 months (range 12-180) in Group A and 36 months (range 12-180) and 37 months (range 18-180) in Group B respectively. CONCLUSIONS: Our results suggest that surgery could be avoided in selected patients with rectal cancer who have a cCR to neoadjuvant chemoradiation. However, until the safety of a non-surgical approach is proven in a prospective randomized trial, it cannot be recommended outside a clinical protocol study. PMID- 23635446 TI - Technique appraisement of comparative proteomics and screening of differentiation related protein in gastric carcinoma. AB - BACKGROUND/AIMS: Different differentiations of cancer have resulted in its unique biological characteristics. We screen and appraise differentially expressed proteins in different differentiated gastric adenocarcinoma with comparative proteomics technology in order to find regulatory factors of tumor differentiation related and finally reach the purpose of tumor differentiation reversal. METHODOLOGY: With two-dimensional fluorescence difference gel electrophoresis (2-D DIGE) and liquid chromatography in conjunction with tandem mass spectrometry (LC-MS/MS), the differentially expressed proteins from 8 patients with different differentiated gastric adenocarcinoma were identified and some factors identified were verified with application of QPCR and Western blot techniques. RESULTS: Significant differences in 35 protein spots were found and 48 kinds of proteins were identified. Other than structural proteins and non specific protein, six possible proteins associated with tumor differentiation were determined - the serine protease inhibitor B1 (serine protease inhibitor, clade B, member 1, SERPINB1), calcium-phospholipid binding protein III (annexin A3), transcription factor Nm23-H1, adenine phosphoribosyl-transferase enzyme APRT (Adenine Phosphoribosyltransferase in APO and AMP), glutathione S-transferase P1 1 (GST-pi-1), antimicrobial peptides Dermcidin-lL. The identified SERPINB1, annexin A3, Nm23-H1 and APRT were verified, confirming the expression of these factors was in line with proteomics identification. CONCLUSIONS: Protein expression in different differentiated gastric adenocarcinoma was varied. PMID- 23635447 TI - Reconsideration of liver transplantation for portal hypertension due to hepatitis B cirrhosis: a single center experience. AB - BACKGROUND/AIMS: Some patients with portal hypertension due to hepatitis B cirrhosis who were suitable for periesophagogastric devascularization with splenectomy (PDS) also met the indications of liver transplantation (LT), the study compared the effect of PDS and LT, and of PDS followed by LT when required. METHODOLOGY: Patients with portal hypertension due to hepatitis B cirrhosis were analyzed. Patients were organized into PDS or LT groups, and PDS followed by LT. RESULTS: The PDS group suffered from lower incidence of severe postoperative complications (p=0.007) and perioperative death (p=0.015) than group LT. The 1-, 3- and 5-year survival rates of the PDS and LT groups were 99.3%, 98.1% and 89.0%, and 91.1%, 85.4% and 79.0%, respectively (p=0.04). There were no significant differences in severe postoperative complications (p=1.000) or perioperative mortality (p=1.000) between the PDS followed by LT and the LT groups, and their 1-, 3- and 5-year survival rates were 91.2%, 82.1% and 82.1%, and 91.1%, 85.4% and 79.0%, respectively (p=0.694). CONCLUSION: For patients with portal hypertension due to hepatitis B cirrhosis, when they satisfy the indications for both PDS and LT, we appeal to perform PDS as bridging therapy for final liver transplantation. PMID- 23635448 TI - Keeping donor hearts in completely beating status with normothermic blood perfusion for transplants. AB - BACKGROUND: Previously, we reported the preservation method of donor hearts in an empty beating status with mild hypothermic perfusion. To completely avoid cardiac arrest and myocardial ischemia, we performed the beating preservation technique from procurement of hearts to transplants and assessed its efficacy for long-term preservation and feasibility for heart transplantation. METHODS: Thirty-two swine donor hearts were preserved in beating status (group A, n = 8 pairs, perfused continuously with normothermic blood) or in static cold storage (group B, n = 8 pairs, stored in 4 degrees C histidine-tryptophan-ketoglutarate solutions) for 8 hours. Then the donor hearts were implanted either in beating or static status. During transplantation, the incidence of arrhythmia, duration of anastomosis and cardiopulmonary bypass, and dosage of inotropic drugs were recorded. Hemodynamics of left ventricle and serum level of creatine kinase-MB were measured during transplantation. Myocardial ultrastructure was observed. RESULTS: Compared with group B, in group A the anastomotic time was significantly longer, the cardiopulmonary bypass time was significantly shorter, the cardiac output was larger, and the incidence of arrhythmia, dosage of cardiovascular-active drugs, and serum level of creatine kinase-MB were lower. After declamping for 2 hours and 3.5 hours, the left ventricular hemodynamics of group A was significantly better than that of group B. The myocardial ultrastructure of group A was superior to that of group B. CONCLUSIONS: Preservation of donor hearts in beating status with continuous, normothermic, blood perfusion is an effective approach for long-term preservation and is appropriate for heart transplantation. PMID- 23635449 TI - Results with selective preoperative lumbar drain placement for thoracic endovascular aortic repair. AB - BACKGROUND: The optimal use of lumbar cerebrospinal fluid drainage for the prevention of spinal cord ischemia (SCI) with thoracic endovascular aortic repair (TEVAR) remains unclear. Here, we report our experience with selective preoperative lumbar drain placement with TEVAR. METHODS: Between May 2002 and January 12, 381 TEVAR procedures were performed at a single referral institution. Preoperative lumbar drains were placed selectively in patients considered high risk for SCI due to planned long-segment aortic coverage with a history of prior aortic intervention or planned hybrid Crawford extent I to III thoracoabdominal aortic aneurysm repair. RESULTS: Preoperative lumbar drains were placed in 81 patients (21%); of these, drain placement in 38 (47%) was for procedures involving long-segment descending thoracic aortic coverage in the setting of prior descending thoracic or infrarenal aortic repair, and in 43 (53%) was for hybrid thoracoabdominal aortic aneurysm repair. SCI occurred in 12 patients (14.8%) who received a preoperative lumbar drain, transient in 6 (7.4%) and permanent in 6 (7.4%), whereas SCI occurred in 13 patients (4.3%) who did not receive a preoperative lumbar drain, 12 transient (4.0%) and 1 permanent (0.3%). A lumbar drain complication occurred in 9 drain patients (11.1%), although none resulted in permanent disability. Age, postoperative hypotension, and the number of endografts implanted were independently associated with SCI. Preoperative lumbar drain placement was not associated with reduced SCI. CONCLUSIONS: Restricted use of preoperative lumbar drains for patients at high-risk of SCI undergoing TEVAR appears safe and leads to low rates of SCI in nondrained patients. However, the utility of preoperative lumbar drains in preventing SCI with TEVAR remains questionable and should be weighed against the risk of drain complications. PMID- 23635450 TI - Spindle epithelial tumor with thymus-like differentiation: a case report and review of literature. AB - Spindle epithelial tumor with thymus-like differentiation (SETTLE) is an extremely rare type of thyroid tumor with fewer than 35 reported cases available in the literature so far, most of them having been diagnosed histologically after resection. The tumor is believed to be derived from branchial-pouch or thymic remnants, occurring in young adults, predominantly in males, with a male:female ratio 1.8:1. CASE: A 14-year-old girl presented with a nodular mass in her right thyroid that had been present for 1 year. Ultrasonological study revealed a heterogeneous solid mass (2.5 * 1.5 * 1.5 cm) in the right lobe of the thyroid. Fine-needle aspiration (FNA) smears were highly cellular and comprised of predominantly dissociated uniform spindle cells with naked oval nuclei along with some aggregates and groups. Occasional islands of epithelial cells were also present. Cytologically, the spindle cells had bland nuclear chromatin, with very scanty mitotic figures. Upon examination of the FNA smears, a provisional diagnosis of SETTLE was suggested along with a request for an incisional biopsy to rule out another differential diagnosis of medullary carcinoma thyroid. On the resected tissue specimen, diagnosis was histologically confirmed to be SETTLE. Immunohistochemical study revealed a strong and diffuse positivity for high molecular-weight keratin and vimentin, and negativity for thyroglobulin, calcitonin, S-100 protein, desmin, chromogranin and synaptophysin. CONCLUSION: Cytologically, SETTLE can safely be considered, especially if spindle elements are observed along with the occasional group of epithelial cells in FNA smears from the thyroid of young adults. It can help in the preoperative recognition of lesions based on distinctive cytomorphological features and immunohistochemical characteristics, allowing a more sound therapeutic approach because these patients can present with delayed metastasis. PMID- 23635452 TI - Salvage bone marrow harvest in patients failing plerixafor-based stem cell mobilization attempt: feasibility and autologous transplantation outcomes. AB - Inadequate mobilization of peripheral blood progenitor cells (PBPC) is sometimes a limiting factor to proceed with an autologous hematopoietic cell transplantation (auto-HCT), in an otherwise eligible patient. In such situations, a bone marrow harvest (BMH) procedure may be considered to achieve the CD34+ target dose for an autograft. Plerixafor-based mobilization has recently been shown to improve PBPC collection yields. However, the feasibility and outcomes of BMH in patients failing plerixafor-based mobilization is not known. We report here, 6 patients who underwent BMH after PBPC mobilization failure with plerixafor. The median CD34+ yield with plerixafor mobilization and BMH were 1.15 x 10^6/Kg (range, 0.2-1.7 * 10^6/Kg) and 0.32 (range, 0.12-0.38 * 10^6/Kg), respectively. Three patients proceeded to an auto-HCT, with only 1 patient receiving CD34+ cell dose of at least 2 * 10^6/Kg. While neutrophil recovery was seen, platelet recovery and red cell transfusion independence were delayed. All 3 autografted patients experienced disease progression by day +100. These data suggest, limited incremental benefit of a salvage BMH after plerixafor mobilization failure, cautioning against routine use of this strategy. PMID- 23635451 TI - How accurately do nephrologists predict the need for dialysis within one year? AB - BACKGROUND/AIMS: Knowing when patients with chronic kidney disease will need dialysis can improve patient counselling and timing of vascular access. We aimed to assess the accuracy of clinician judgement in predicting the need for dialysis within 12 months. METHODS: We asked the nephrologists in a dedicated pre-dialysis clinic to predict the time until initiation of dialysis for patients. We compared predicted with actual time to dialysis and the accuracy of predictions made by different grades of clinician. Multivariate logistic regression compared clinical parameters that correlated with predicted and actual time to dialysis. RESULTS: One hundred and eighty-four patients were included. The sensitivity of clinician judgement as a predictor of dialysis within 12 months was 95% and the specificity was 62%. Consultants were correct in 71% of cases and trainees in 68% of cases. Estimated glomerular filtration rate (eGFR) was the only independent correlate of predicted time to dialysis [odds ratio (OR) = 1.6 per 1 ml/min/1.73 m(2) reduction, p < 0.001]. eGFR was also associated with actual time to dialysis (OR = 1.6 per 1 ml/min/1.73 m(2), p < 0.001) along with age (OR = 0.94 per year increase, p = 0.005) and itch (OR = 3.7, p = 0.048). CONCLUSION: Clinical judgement is sensitive but not specific in predicting the need for dialysis. Educating the clinicians may improve the specificity of judgement and improve the accuracy of prognostic information given to patients. PMID- 23635453 TI - Pilot study of prophylactic ex vivo costimulated donor leukocyte infusion after reduced-intensity conditioned allogeneic stem cell transplantation. AB - Donor leukocyte infusion (DLI) can induce potent graft-versus-leukemia (GVL) activity in patients with relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT). Unfortunately, except in patients with chronic-phase chronic myelogenous leukemia, responses to DLI have been disappointing. GVL induction is likely to be most effective in the setting of minimal residual disease. Prevention of relapse through the provision of prophylactic DLI to high-risk patients may improve the outcome of allogeneic HSCT. We previously reported that ex vivo costimulated T cell infusion of activated DLI (aDLI) as treatment for relapse is safe and has potent GVL effects. We hypothesized that prophylactic aDLI can be given safely and prevent relapse in high-risk patients after allogeneic HSCT. Eighteen patients with acute myeolgenous leukemia (n = 14), acute lymphoblastic leukemia (n = 3), or myelodysplastic syndrome (n = 1) underwent allogeneic HSCT after a reduced intensity conditioning (RIC) regimen with alemtuzumab, fludarabine, and busulfan. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate with a planned early and rapid taper of tacrolimus. Patients without GVHD, off immune suppression, and in remission received aDLI at a dose of 1 * 10(7) CD3(+) cells/kg (aDLI 1) at day +120, followed by a second infusion of 1 * 10(8) CD3 cells/kg (aDLI 2) at day +180. At a median follow-up of 58 months, 5 of the 18 patients (28%) were alive, and 4 patients were in remission. Eleven patients (65%) relapsed, at a median time of 191 days. Twelve of the 18 patients received at least one aDLI, and 6 of these 12 patients also received aDLI 2. Six patients did not receive any aDLI owing to early relapse (n = 2), protocol ineligibility (n = 1), or GVHD (n = 3). Only 2 of the 12 patients who received aDLI 1 developed GVHD. Two out of the 12 patients remain in remission at the time of this report. Disease recurrence was the cause of death in 10 of the 13 patients (77%) who died. Our data indicate that prophylactic ex vivo costimulated CD3/CD28 DLI is safe, feasible, and not associated with significant GVHD. Relapse remains the major cause of treatment failure after RIC HSCT even with rapid withdrawal of immune suppression and the use of prophylactic aDLI, and better strategies to prevent relapse are needed. PMID- 23635456 TI - [Evaluation of clinical results in patients undergoing laparoscopic nephroureterectomy]. AB - We evaluated the efficacy of laparoscopic radical nephroureterectomy (LNUx) by comparing the clinical results in 55 patients undergoing LNUx at the National Defense Medical College since 2001 with those in patients undergoing open radical nephroureterectomy (ONUx) there over the same period. LNUx was performed successfully in 54 of the patients, but one patient required conversion to ONUx. The mean operating time for LNUx was not significantly different from that for ONUx, and the mean estimated blood loss during LNUx was significantly lower than that during ONUx. Major complications occurring early in our laparoscopic series of cases were injury of the duodenum and bleeding from the inferior vena cava. Oncological outcomes were compared between LNUx (n=50) and ONUx (n=50) in patients with pathologically-confirmed urothelial carcinoma. The pT stage, histological grade, percentage of lymph node dissection and percentage of high grade hydronephrosis did not differ significantly between the two groups. Because the intravesical recurrence-free survival rates, extravesical recurrence-free survival rates, and disease specific survival rates were also similar in the two groups, we concluded that LNUx is an appropriate treatment for upper urinary tract urothelial carcinoma. PMID- 23635454 TI - [Analysis of multimodal treatment outcome in renal cell carcinoma patients with bone metastasis]. AB - We retrospectively reviewed the treatment outcome of 12 renal cell carcinoma (RCC) patients with bone metastasis who had undergone targeted therapy along with a regimen of multimodal treatment. We performed metastatectomy following nephrectomy on patients with resectable foci. Patients with unresectable bone metastasis underwent radiation therapy. With the exception of two patients, zoledronic acid was also administered. As a result, the overall survival rates of 83.3% at 1 year and 72.9% at 2 years in our study compared favorably with reported cases. Patients with complete resection of solitary bone metastasis with or without extrabone lesions had favorable outcomes. As differences in the response of the targeted therapy can be observed between bone and extrabone metastases, control of bone metastasis may be a key factor for the prognosis of metastatic RCC patients. PMID- 23635455 TI - [Effect of prophylactic intravesical instillation of pirarubicin to prevent recurrent bladder tumors following nephroureterectomy for upper urinary tract cancer]. AB - We retrospectively evaluated 23 patients who had been administered pirarubicin by intravesical instillation once weekly for 5 weeks, after undergoing surgery for upper urinary tract cancer between May 2003 and October 2008. We compared their clinical records with those of 19 patients with upper urinary tract cancer subjected to nephroureterectomy between 1998 and 2008, and who did not receive intravesical instillation of pirarubicin. This prophylactic therapy was well tolerated and contributed to reduce the rate of bladder recurrence. The non recurrence rate at 2 years was 87.0% in the instillation group and 68.4% in the non-instillation group (P=0.0025). The overall analysis of the study population did not reveal any statistically significant risk factors of bladder recurrence. PMID- 23635457 TI - [The prevalence of hypertension after adrenalectomy in patients with primary aldosteronism]. AB - The cure rate of hypertension after surgery for primary aldosteronism (PA) was assessed in a single institution. In the present study, we studied the risk factors on the cure rate of hypertension after surgery in patients with PA. Thirty-five patients who underwent surgery for PA between January 2004 and December 2009, with a follow-up time of 1 year or longer were studied. The mean age at surgery was 50.7 years old. The male to female ratio was 24 : 11. Factors confounding the cure rate of hypertension after surgery were analyzed using the univariate and the multivariate analysis. Nineteen (54%) of the 35 patients were completely cured after surgery. In most cases, a complete cure was seen within 1 month after surgery. At 1 year after surgery, the dose of medication for hypertension could be decreased in 11 (13%) of the 16 non cured patients. Although hypertension in patients with PA may be curable by surgery, the cure rate of hypertension after surgery has been reported to be from 16 to 67%. In the present study, age, gender, preoperative serum creatinine, the period of hypertension, the number of medications for hypertension, and family history for hypertension were significant in the univariate analysis for the cure rate of hypertension (persistent hypertension) after surgery. Multivariate analysis showed that the age of 55 years old or older was a significant predictor for non curable hypertension after surgery. Our result suggests that earlier surgery may contribute to a better outcome on the cure rate of postoperative hypertension in patients with PA. PMID- 23635458 TI - [A case of hand-assisted laparoscopic radical nephrectomy in a severely obese patient (body mass index : 62.6)]. AB - A 41-year-old Japanese man (177 cm, 196 kg, body mass index 62.6) was referred for treatment of a right renal mass 7 cm in diameter. Preoperative examination showed slight liver dysfunction and elevated hemoglobin A1c level (7. 2%). Cardiac and respiratory functions were within normal limits. Hand assisted laparoscopic radical nephrectomy with a transperitoneal approach was performed. The patient was laid on two parallel-shifted beds and intubation was performed in the lateral position. Insufflation time was 6.5 h, and estimated blood loss was 550 ml. Although the amount of bleeding was greater than usual, surgery was uneventful and no blood transfusion was required. On postoperative day 1, the patient resumed oral fluid intake and ambulation. An antithrombotic drug was administered subcutaneously as prophylaxis for deep vein thrombosis. The patient was discharged 9 days after surgery without any complications. Pathological diagnosis was renal cell carcinoma (clear cell carcinoma, pT3a). The surgical margin was negative. Despite the increasing prevalence of obesity, laparoscopic surgery in severely obese patients is uncommon in Japan and standard procedures have not been established. The transperitoneal approach is appropriate for such patients because it provides good orientation and surgical space. Hand-assisted laparoscopic surgery in obese patient has the advantage that the first incision for the hand port is long enough for safe laparotomy. Moreover, counter-traction by the hand is useful and the pulse of the renal artery can be perceived. However, extraction of the specimen from the hand port was more difficult than expected and an extra incision was required in this case. PMID- 23635459 TI - [Incomplete Reiter syndrome caused by BCG instillation : a case report]. AB - A 91-year-old man was treated for upper urinary carcinoma in situ via intravesical bacillus Calmette Guerin (BCG) therapy using a double-J catheter. After the fourth infusion, he experienced fever of >38 degrees C, multiple arthralgia, and back pain. One week after cessation of intravesical BCG immunotherapy and initiation of antibiotic treatment, he continued to complain of symptoms. Reiter's syndrome was diagnosed, and subsequently, an antitubercular agent, a nonsteroidal antiinflammatory drug and a corticosteroid were administered. His symptoms improved 17 days after onset. Reiter syndrome is an uncommon complication after intravesical BCG immunotherapy. Nevertheless, side effects may be severe and must be closely monitored. PMID- 23635460 TI - [A case of primary mucosa-associated lymphoid tissue-type lymphoma of the urinary bladder that progressed after antibiotic therapy]. AB - We report a case of primary mucosa-associated lymphoid tissue (MALT)-type lymphoma of the urinary bladder, which temporarily regressed after antibiotic therapy and progressed 1 year after the treatment. The patient was a 72-year-old female with a history of recurrent cystitis. She was referred to our hospital for microscopic hematuria. Urinalysis also showed microscopic pyuria and cystoscopy revealed an erythematous and edematous submucosal lesion in the right side wall of the bladder. She was diagnosed with acute cystitis and treated with antibiotics. Cystoscopy after 2 months was normal. However, she presented with macroscopic hematuria and fever 1 year after the treatment. Computed tomography (CT) scan showed a solitary mass measuring 25*40 mm above the right ureteric orifice and right hydronephrosis. Transurethral resection was performed, and the histopathological findings were consistent with MALT-type lymphoma. No evidence of lymphoma was found on positron emission tomography-CT scan and bone marrow biopsy, and she was diagnosed with primary MALT-type lymphoma of the bladder. She was successfully treated with a combination of rituximab and radiotherapy. Since MALT-type lymphoma of the bladder sometimes regresses temporarily after antibiotic therapy, it should be followed carefully. PMID- 23635461 TI - [A case of inverted urothelial carcinoma of bladder]. AB - We present a case of inverted urothelial carcinoma of the bladder. A 60-year-old male was referred to our hospital for bilateral ureteral stones. When transurethral ureterolithotripsy was performed to treat these stones, a tumor at the trigone of bladder was incidentally diagnosed. This tumor was pedunculated and its surface was not uniformly round. After the operation, this tumor was diagnosed as inverted urothelial carcinoma through the histopathologic examination. The patient was subsequently followed up for 6 months and there was no evidence of recurrence. Although this is a rare case, it is worth considering there is an urothelial carcinoma with inverted proliferation. PMID- 23635462 TI - [Paget's disease mimicking metastatic prostate cancer on bone scan image : a case report]. AB - A 61-year-old man was referred to our hospital complaining of elevated serum prostate-specific antigen (PSA) (5.1 ng/ml). Histopathologic diagnosis with trans rectal prostate biopsy specimen was adenocarcinoma, Gleason score 4+5 = 9. Bone scintigraphy revealed an abnormal uptake on left coxal bone. The patient was diagnosed with prostate cancer with bone metastasis. He received androgen deprivation therapy for two years. Serum PSA decreased to an undetected level. However, the abnormal activity of left coxal bone lesion was not changed on bone scintigraphy. Coxal bone biopsy was performed. The bone lesion was histopathologically diagnosed as Paget's disease of bone. PMID- 23635463 TI - [Four cases of penile fracture]. AB - Penile fracture is not common but is an emergency disease. We report 4 cases of penile fracture treated at the Department of Urology, Yokohama City University between 2005 and 2012. The age of the patients ranged between 26 and 67 years (mean age, 41.5 years). Of the patients in our series, 3 sustained injury during sexual intercourse, and 1 while rolling over in bed. All patients were treated surgically and cured without any functional disturbance after treatment. Reports before 2002 and 99 cases after 2002 were also reviewed. The number of patients between 40 and 60 years was increasing. Magnetic resonance imaging was useful to detect the site of penile fracture and immediate surgical treatment was important. PMID- 23635464 TI - Compact fluorescent lighting in Wisconsin: elevated atmospheric emission and landfill deposition post-EISA implementation. AB - The majority of states in the USA, including Wisconsin, have been affected by elevated air, soil and waterborne mercury levels. Health risks associated with mercury increase from the consumption of larger fish species, such as Walleye or Pike, which bio-accumulate mercury in muscle tissue. Federal legislation with the 2011 Mercury and Air Toxics Standards and the Wisconsin legislation on mercury, 2009 Wisconsin Act 44, continue to aim at lowering allowable levels of mercury emissions. Meanwhile, mercury-containing compact fluorescent lights (CFL) sales continue to grow as businesses and consumers move away from energy intensive incandescent light bulbs. An exchange in pollution media is occurring as airborne mercury emissions from coal-burning power plants, the largest anthropogenic source of mercury, are being reduced by lower energy demand and standards, while more universal solid waste containing mercury is generated each time a CFL is disposed. The treatment of CFLs as a 'universal waste' by the Environmental Protection Agency (EPA) led to the banning of non-household fluorescent bulbs from most municipal solid waste. Although the EPA encourages recycling of bulbs, industry currently recycles fluorescent lamps and CFLs at a rate of only 29%. Monitoring programs at the federal and state level have had only marginal success with industrial and business CFL recycling. The consumer recycling rate is even lower at only 2%. A projected increase in residential CFL use in Wisconsin owing to the ramifications of the Energy Independence and Security Act of 2007 will lead to elevated atmospheric mercury and landfill deposition in Wisconsin. PMID- 23635465 TI - Waste incineration in rotary kilns: a new simulation combustion tool to support design and technical change. AB - This article presents a tool based on a simplified model developed for the combustion processes in a rotary kiln incinerator (slightly inclined rotating primary combustion chamber). The model was developed with the aim of supporting the design phase of the incinerator combustion chamber and, at the same time, of investigating possible technical changes in existing plants in order to optimise the combustion process and the dimension of the rotary kiln (length, diameter) as a function of the characteristics of the fed waste. The tool has been applied and the obtained results compared with a real incineration plant operating on healthcare waste located in Rome (Italy). The mass and thermal balances were taken into account, together with kinetic parameters for the combustion of the specific waste stream. The mass balance considered only the major mass components (carbon, hydrogen, oxygen, nitrogen and sulphur). The measured external temperatures appear to be in good agreement with the simulated results. A sensitivity analysis of the plant under different operating conditions was carried out using different input flow rates and excess air ratios, and an assessment was made of the refractory and insulator properties of the kiln's behaviour. Some of the simulated results were used during the periodical maintenance to improve the refractory characteristics in order to reduce the fret and corrosion process. PMID- 23635466 TI - Toxicity evaluation of two dental composites: three-dimensional confocal laser scanning microscopy time-lapse imaging of cell behavior. AB - The purpose of this study was to investigate the in vitro biocompatibility of two dental composites (namely A and B) with similar chemical composition used for direct restoration using three-dimensional confocal laser scanning microscopy (CLSM) time-lapse imaging. Time-lapse imaging was performed on cultured human HGF 1 fibroblast-like cells after staining using Live/Dead(r). Image analysis showed a higher mortality rate in the presence of composite A than composite B. The viability rate decreased in a time-dependent manner during the 5 h of exposure. Morphological alterations were associated with toxic effects; cells were enlarged and more rounded in the presence of composite A as shown by F-actin and cell nuclei staining. Resazurin assay was used to confirm the active potential of composites in cell metabolism; results showed severe cytotoxic effects in the presence of both no light-curing composites after 24 h of direct contact. However, extracts of polymerized composites induced a moderate decrease in cell metabolism after the same incubation period. Composite B was significantly better tolerated than composite A at all investigated end points and all time points. The finding confirmed that the used CLSM method was sufficiently sensitive to differentiate the biocompatibility behavior of two composites based on similar methacrylate monomers. PMID- 23635468 TI - Corrigendum. AB - Kavanagh KF, Lou Z, Nicklas JC, Habibi MF, Murphy LT. Breastfeeding knowledge, attitudes, prior exposure, and intent among undergraduate students. J Hum Lact. 2012;28(4):556-564. (Original DOI: 10.1177/0890334412446798) On p 558 of the above article, the Cronbach's alpha for the knowledge scale was incorrectly reported to be 0.928, as it was generated from the unadjusted knowledge scale score prior to reverse-coding some of the responses. The Cronbach's alpha should have been reported as 0.352. All analyses were performed using the correct (adjusted) knowledge scale score, so all other portions of the article remain accurate. PMID- 23635467 TI - Robotic partial nephrectomy: current technique and outcomes. AB - Over the past decade, management of the T1 renal mass has focused on nephron sparing surgery. Robotic partial nephrectomy has played an increasing role in the technique of preserving renal function by decreasing warm ischemia time, as well as optimizing outcomes of hemorrhage and fistula. Robot-assisted partial nephrectomy is designed to provide a minimally-invasive nephron-sparing surgical option utilizing reconstructive capability, decreasing intracorporeal suturing time, technical feasibility and safety. Ultimately, its benefits are resulting in its dissemination across institutions. Articulated instrumentation and three dimensional vision facilitate resection, collecting system reconstruction and renorrhaphy, leading to decreased warm ischemia time while preserving oncological outcomes. The aim of the present review was to present our surgical sequence and technique, as well as review the current status of robot-assisted partial nephrectomy. PMID- 23635470 TI - Ectodermal dysplasia: thoughts and practical concepts concerning disease classification - the role of functional pathways in the molecular genetic diagnosis. PMID- 23635469 TI - Providing mother's own milk in the context of the NICU: a paradoxical experience. AB - BACKGROUND: Mothers of very preterm infants continue to face challenges related to providing their expressed breast milk in the neonatal intensive care unit (NICU). OBJECTIVE: This qualitative study sought to understand the experience of mothers of hospitalized very preterm infants related to their daily pumping routine during the NICU stay. METHODS: Fourteen women who were pumping breast milk for their hospitalized infants were interviewed. Sequential, semistructured, audiotaped individual interviews were conducted at 2 different time points: within 2 weeks following delivery when the mothers were pumping only, and 4 to 6 weeks once breastfeeding had been initiated. RESULTS: The central themes found were: becoming a "mother-interrupted" and negotiating a paradoxical experience of separation and connection. Unique to these findings were the paradoxical view of the pump as both a wedge and a link to their infants, the intense dislike the mothers had for the tasks required to provide their expressed breast milk, and diversionary tactics used during pumping sessions. CONCLUSION: The complexity of thoughts, actions, and behaviors revealed in the mothers' narrative accounts provides a guide to direct future breastfeeding interventions and management. PMID- 23635471 TI - Nonaccidental arterial cerebral air embolism: a ten-year stroke center experience. PMID- 23635472 TI - Linked 5S and 45S rDNA sites are highly conserved through the subfamily Aurantioideae (Rutaceae). AB - Sites of 5S and 45S rDNA are more commonly located on different chromosomes of most angiosperms. Previous investigations have shown that in the subfamily Aurantioideae these sites may appear closely linked (adjacent sites), as in Poncirustrifoliata, or completely isolated, as in some species of Citrus. In the present work, the distribution of rDNA sites was investigated in representatives of 9 genera of Aurantioideae by FISH and CMA banding, aiming to understand the evolution of adjacent sites in the subfamily. A total of 57 rDNA sites were observed, 40 of them being adjacent to each other. All adjacent sites displayed the 45S rDNA array more terminally located. Assuming that the linked 5S-45S rDNA arrangement was the ancestral condition in Aurantioideae, the isolated rDNA sites observed in Clausena excavata,Bergera koenigii, and Fortunella obovata, as well as the complete linkage loss in Citrus maxima and C. medica indicates that unlinked sites arose independently several times in the evolution of the group. The linkage loss may be due to independent dispersion of one or both rDNA sequence families followed by deletion of the corresponding array in the adjacent site. The possible mechanisms behind these events and their occurrence in other groups are discussed. PMID- 23635474 TI - Expression of apoptosis- and vitamin D pathway-related genes in hepatocellular carcinoma. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and therapeutic options are scarce. As they might represent future targets for cancer therapy, the expression of apoptosis-related genes in HCC is of particular interest. In this pilot study, we further examined apoptosis related genes in human HCC and also focused on vitamin D signaling as this might be a regulator of HCC cell apoptosis. METHODS: We employed tumor tissue and serum samples from 62 HCC patients as well as 62 healthy controls for these studies. Tissue and serum specimens were analyzed by quantitative RT-PCR, immunohistochemistry and ELISA. RESULTS: In HCC patients the apoptosis marker M30 was found to be elevated and several pro-apoptotic (TRAIL, FasL and FasR) as well as anti-apoptotic genes (Mcl-1 and Bcl-2) were simultaneously upregulated in tumor tissue and especially tumor-surrounding tissue as compared to healthy control livers. Moreover, vitamin D serum levels were decreased in HCC patients whereas vitamin D receptor mRNA expression was increased in tumor tissue and tumor-surrounding tissue as compared to healthy livers. CONCLUSIONS: In human HCC, M30 serum levels are elevated indicating an increased cell turnover. Modulation of the vitamin D pathway might be a supportive, pro-apoptotic HCC therapy. PMID- 23635476 TI - Early diagnosis and surgical treatment of acute superior mesenteric artery occlusion. AB - BACKGROUND/AIMS: To investigate the value of early diagnosis and the effect of surgical treatment of acute superior mesenteric artery occlusion. METHODOLOGY: Forty-eight patients underwent superior mesenteric artery embolectomy. The diagnosis was made by mesenteric angiography in 12 patients, by explorative laparotomy in 15 patients and by abdominal contrast-enhanced CT in 21 patients. The patients were divided into three groups according to the onset of symptoms and operation time. Patients in group I (n = 15) were operated on in the first 6 hours after onset of symptoms; Patients in group II (n = 19) were operated on between 6 and 12 hours after onset; and patients in group III (n = 14) underwent embolectomy after 12 hours. RESULTS: The macroscopic view of the intestine was normal in 24 patients (15 in group I and 9 in group II) 30 minutes after embolectomy and administration of urokinase. Segmental resection was necessary in 8 patients in group II. Extended resection was necessary in 2 patients in group II and 14 patients in group III, and all of the patients died during the early postoperative period. CONCLUSIONS: Early diagnosis and prompt surgical treatment can reduce the incident of bowel necrosis and mortality rate of patients with superior mesenteric artery occlusion. PMID- 23635475 TI - MUC1 and HER2 might be associated with invasive phenotype of intraductal papillary mucinous neoplasm. AB - BACKGROUND/AIMS: The purpose of this study was to clarify the biomarkers which distinguish invasive Intraductal papillary mucinous neoplasms (IPMNs) from noninvasive IPMNs. METHODOLOGY: In tumor specimens from sixty patients with IPMNs (42 noninvasive IPMNs and 18 invasive IPMNs) who underwent surgical resection at our institute, we analyzed the correlation between the immunohistochemical expression level of MUC1, MUC2, MUC4, MUC5AC, p53, VEGFR2, HER2, and HER3. RESULTS: The 5-year survival rate was 100% in noninvasive IPMNs, while that of invasive IPMNs was only 36.5%. MUC1, MUC4, HER2 and HER3 were significantly associated with invasive IPMNs in univariate analysis. Multivariate analysis revealed that MUC1 and HER2 were significantly associated with invasive IPMNs. The 5-year survival of IPMN patients with either MUC1-positive and/or HER2 positive (54.5%) is significantly poorer than that of IPMN patients with MUC1 negative and HER2 negative (100%). CONCLUSIONS: MUC1 and HER2 might be closely associated with invasive phenotype of IPMNs. PMID- 23635477 TI - Apple peels--a versatile biomass for water purification? AB - The presence of anions such as chromate, arsenate, and arsenite in drinking water is a major health concern in many parts of the world due to their high toxicity. Removal of such anions from water using low cost biomass is an efficient and affordable treatment process. Owing to the easy availability and biodegradability, we chose to use apple peel as a substrate for our investigations. Zirconium cations were immobilized onto the apple peel surface and used for the extraction of anions. Zirconium loaded apple peels were used to extract anions such as phosphate, arsenate, arsenite, and chromate ions from aqueous solutions. The presence of Zr cations on the apple peel surface was characterized using XPS. The modified adsorbent was characterized using SEM, EDS, and FT-IR. Zr treated apple peels showed efficient adsorption toward AsO2(-) (15.64 mg/g), AsO4(3-) (15.68 mg/g), Cr2O7(2-) (25.28 mg/g), and PO4(3-) (20.35 mg/g) anions. The adsorption and desorption studies revealed the adsorption mechanism involves electrostatic interactions. Anion removal efficiency was estimated by batch adsorption studies. Adsorption kinetic parameters for all anions at different concentrations were described using pseudo-first-order and pseudo-second-order rate equations. Langumir and Freundlich isotherms were used to validate our adsorption data. Arsenate and chromate anions were strongly adsorbed at the pH range from 2 to 6, while arsenite was extracted efficiently between pH 9 and 10. Overall, the Zr immobilized apple peel is an efficient adsorbent for common anionic pollutants. PMID- 23635479 TI - Removal of boron species by layered double hydroxides: a review. AB - Boron, which is an essential element for plants, is toxic to humans and animals at high concentrations. Layered double hydroxides (LDHs) and thermally activated LDHs have shown good uptake of a range of boron species in laboratory scale experiments when compared to current available methods, which are for the most part ineffective or prohibitively expensive. LDHs were able to remove anions from water by anion exchange, the reformation (or memory) effect and direct precipitation. The main mechanism of boron uptake appeared to be anion exchange, which was confirmed by powder X-ray diffraction (XRD) measurements. Solution pH appeared to have little effect on boron sorption while thermal activation did not always significantly improve boron uptake. In addition, perpetration of numerous LDHs with varying boron anions in the interlayer region by direct co precipitation and anion exchange have been reported by a number of groups. The composition and orientation of the interlayer boron ions could be identified with reasonable certainty by applying a number of characterisation techniques including: powder XRD, nuclear magnetic resonance spectroscopy (NMR), X-ray photoelectron spectroscopy (XPS) and infrared (IR) spectroscopy. There is still considerable scope for future research on the application of LDHs for the removal of boron contaminants. PMID- 23635478 TI - EpCAM Induction Functionally Links to the Wnt-Enhanced Cell Proliferation in Human Keratinocytes. AB - Accelerating proliferation of primary keratinocytes benefits skin autografts for severely burned patients. Wnt signal, a conserved pathway controlling cell cycle and morphogenesis in embryo, also involves in cell proliferation and tumorigenesis in adult tissues. Here the effects of Wnt signal on the growth of human interfollicular keratinocytes were investigated. We demonstrated that recombinant Wnt3a significantly promoted the growth of primary keratinocytes at a low cell density. A well-characterized GSK-3b inhibitor, BIO, activated the Wnt signals and also enhanced the colony formation of keratinocytes dose dependently. Gene expression profile of the BIO-treated keratinocytes revealed the linkage of BIO with cell mitosis and indicated that epithelial cell adhesion molecule (EpCAM), a Wnt target gene, was significantly upregulated. Compared to the sorted EpCAM- keratinocytes, the EpCAM+ cells showed a higher proliferation rate and efficacy of colony formation. Inhibiting the EpCAM expression by shRNA attenuated the proliferation effect of BIO and the growth advantage of the EpCAM+ keratinocytes. These evidences emphasize the positive roles of canonical Wnt and EpCAM on the regulation of cell growth and self-renewal of human keratinocytes. PMID- 23635480 TI - Warthin tumor with signet-ring cell features as a pitfall in salivary gland cytopathology. AB - BACKGROUND: Warthin tumor (WT) is a common parotid lesion reliably diagnosed by fine-needle aspiration (FNA). Worrisome metaplastic changes may occur in WT. Their interpretation as mucoepidermoid carcinoma represents a diagnostic pitfall. Moreover, WT and mucoepidermoid carcinoma may coexist, making this distinction difficult. So it is worthwhile to report unusual WT features. We describe a WT with signet-ring cells (SRCs). CASE: A 61-year-old male presenting with a 3.6-cm right parotid gland mass underwent FNA with rapid on-site evaluation. DiffQuik stained smears showed groups of oncocytic cells with abundant granular cytoplasm in a background rich with debris, foamy macrophages and lymphoid cells. SRCs were observed on Papanicolaou-stained smears prepared from a second pass. A WT with SRC features was diagnosed. Histology revealed a WT with post-FNA infarctual changes. CONCLUSION: To avoid false-positive diagnoses, the cytopathologist should be aware that SRC features may occur in WT. The concomitant presence of oncocytes and SRCs is useful to correctly diagnose this unusual WT variant. PMID- 23635482 TI - Three years of Stem Cell Research & Therapy. PMID- 23635483 TI - In situ study of live specimens in an environmental scanning electron microscope. AB - In this paper we introduce new methodology for the observation of living biological samples in an environmental scanning electron microscope (ESEM). The methodology is based on an unconventional initiation procedure for ESEM chamber pumping, free from purge-flood cycles, and on the ability to control thermodynamic processes close to the sample. The gradual and gentle change of the working environment from air to water vapor enables the study of not only living samples in dynamic in situ experiments and their manifestation of life (sample walking) but also its experimentally stimulated physiological reactions. Moreover, Monte Carlo simulations of primary electron beam energy losses in a water layer on the sample surface were studied; consequently, the influence of the water thickness on radiation, temperature, or chemical damage of the sample was considered. PMID- 23635481 TI - Association of functional kallikrein-1 promoter polymorphisms and acute kidney injury: a case-control and longitudinal cohort study. AB - BACKGROUND: Kallikrein-1 (KLK1) is a highly conserved serine protease that is expressed in the kidney and involved in blood pressure regulation. The activity of this enzyme is diminished in acute kidney injury (AKI). METHODS: We first evaluated the potential role of functional multiallelic KLK1 promoter gene polymorphisms in a case-control study of 481 subjects (214 hospitalized patients with AKI of mixed causes and 267 healthy subjects). The complex, multiallelic G/C rich repeat region of the proximal KLK1 promoter was determined by direct Sanger/capillary resequencing. RESULTS: 16 alleles were identified in a complex, polymorphic G/C-rich region of the KLK1 proximal promoter; 5 of these alleles (F, G, H, I, and K) were associated with development of AKI. Alleles I and G were classified as risk-alleles (unadjusted OR 1.86; 95% CI 1.23, 2.81; p = 0.003), whereas alleles F, H, and K were classified as protective-alleles (unadjusted OR 0.32; 95% CI 0.22, 0.46; p < 0.001) according to their directional association with development of AKI. After adjustment for sex, race, preexisting chronic kidney disease and APACHE II score, the KLK1 risk-allele (I or G) carrier state was associated with the composite of >=2-fold increase in serum creatinine, oliguria, or dialysis requirement (adjusted OR 2.71; 95% CI 1.14, 6.44; p = 0.02). The KLK1 risk-allele carrier state was also marginally associated with the composite of >=2-fold increase in serum creatinine, oliguria, dialysis requirement, or in-hospital death (adjusted OR 2.33; 95% CI 0.98, 5.52; p = 0.06). CONCLUSIONS: KLK1 promoter polymorphisms are associated with development of AKI and adverse outcomes. Further studies are needed to validate these findings. PMID- 23635484 TI - Relationship between diastolic function and coronary artery calcification in hypertensive patients. AB - BACKGROUND: Impaired diastolic function and increased left ventricular mass are common findings in hypertensive patients and may occur early in the natural history of essential hypertension. In this study, we aimed to investigate the relationship between diastolic function parameters and coronary artery calcification (CAC) in hypertensive patients. METHODS: The study was carried out on 128 asymptomatic hypertensive patients (58 women and 70 men). Diastolic function was evaluated by the mean ratio of peak of early (E) and peak of late (A) mitral inflow (E/A ratio), deceleration time, and isovolumic relaxation time. Patients were classified into two groups on the basis of the presence of CAC and were also divided into two groups on the basis of the presence of left ventricular hypertrophy. RESULTS: The mean E/A ratio, deceleration time, and isovolumic relaxation time of CAC+ patients were 0.87+/-0.34, 143.93+/-29.11, and 87.86+/-16.34 ms, respectively, and 0.92+/-0.31, 140.80+/-27.90, 86.40+/-13.96 ms in CAC- patients, respectively. Diastolic function was not found to be related to the presence of CAC. The mean left ventricular mass index (LVMI) was determined to be 115.60+/-18.16 g/m in CAC+ patients and 104.93+/-29.54 g/m in CAC- patients, and the correlation between the presence of CAC and LVMI was statistically significant (P=0.019). A multivariate analysis showed that the E/A ratio was inversely related to age, blood pressure, pulse pressure, and LVMI (P<0.001) in CAC+ patients. In stepwise regression analysis, LVMI was the strongest determinant for the E/A ratio in CAC+ hypertensive patients (R=0.26, P<0.001). CONCLUSION: Our results identify that diastolic functions are not affected by the presence of CAC in hypertensive patients; however, left ventricular diastolic function is impaired in the presence of left ventricular hypertrophy. PMID- 23635486 TI - The validity of blood pressure kiosk validation studies: a systematic review. AB - OBJECTIVE: Public-use blood pressure (BP) kiosks are commonly used, and yet their accuracy has been questioned on the basis of the results of the published validation studies. However, the adherence of these studies to established validation standards has not been studied. We carried out a systematic review of the published peer-reviewed literature on the validity of public-use BP kiosks to assess their adherence to validation standards. METHODS: With medical librarian assistance, the literature was searched systematically for studies claiming to validate kiosks up to June 2012. Studies were limited to English articles that studied adult patients and were excluded if they were carried out solely on pregnant women. Two authors independently compared the study methods with those recommended in the Association for the Advancement of Medical Instrumentation, British Hypertension Society and the European Society of Hypertension International Protocol validation standards. RESULTS: Nine studies were identified, of which only one came close to adhering to selected validation standard criteria, and found the device to be accurate. One study found device accuracy with poor adherence to standards, whereas the remaining seven found device inaccuracy with poor adherence to standards, therefore potentially reporting false conclusions. CONCLUSION: The majority of the reviewed studies validating public-use BP kiosks did not adhere to existing validation standards and therefore may have reported false conclusions. The one study that came close to following the validation standards found the device tested to be accurate. Readers must critically appraise the quality of validation studies published on these devices before interpreting their accuracy, and future studies should better adhere to existing validation standards to reduce the risk of reporting potentially false conclusions. PMID- 23635485 TI - Simple determination of the systolic-diastolic pressure relationship from blood pressure readings taken at different arm heights. AB - OBJECTIVES: The slope of the linear relationship between systolic blood pressure (SBP) and diastolic blood pressure (DBP) determined from 24-h ambulatory measurements incorporates clinical and prognostic information and is believed to reflect arterial properties. We evaluated the feasibility of determining a similar relationship using the gravity-induced brachial blood pressure (BP) variation in response to vertical cuff displacement with reference to the heart. METHODS: Nine consecutive BP readings were taken in the sitting position with arm postures stabilized by a mechanical support and with the cuff positioned at four different measured heights. The SBP-on-DBP slope (dS/dD) was estimated on the basis of the SBP and DBP variability ratio and expressed in terms of SD. The test was applied to 30 unselected volunteers (52% men, age 48+/-14). RESULTS: A mean cuff elevation of 32 cm was associated with a BP reduction of 21/19 mmHg (P<0.00001) without changes in the heart rate. The SBP-DBP correlation was 0.94+/ 0.03 and the dS/dD was 1.10+/-0.03, with a determination error of 13+/-4% (mean+/ SE). Our results were similar to those of a previous study (n=37) having the same protocol, but in which the arm was self-supported. A case report that included 20 dS/dD determinations over 5 consecutive days and nights without height measurements demonstrated the repeatability of dS/dD, with a mean test duration of 13 min. CONCLUSION: The present study provides a novel, simple, and rapid method of attaining vascular-related information and its variation over time from BP measurements, with good accuracy that is applicable to both office and home. However, comparability with the ambulatory method, prognostic significance, and outcome variation over time remain to be evaluated. PMID- 23635487 TI - EMT impairs breast carcinoma cell susceptibility to CTL-mediated lysis through autophagy induction. AB - Epithelial to mesenchymal transition (EMT) has become one of the most exciting fields in cancer biology. While its role in cancer cell invasion, metastasis and drug resistance is well established, the molecular basis of EMT-induced immune escape remains unknown. We recently reported that EMT coordinately regulates target cell recognition and sensitivity to specific lysis. In addition to the well-characterized role for EMT in tumor phenotypic change including a tumor initiating cell phenotype, we provided evidence indicating that EMT-induced tumor cell resistance to cytotoxic T-lymphocytes (CTLs) also correlates with autophagy induction. Silencing of BECN1 in target cells that have gone through the EMT restored CTL susceptibility to CTL-induced lysis. Although EMT may represent a critical target for the development of novel immunotherapy approaches, a more detailed understanding of the inter-relationship between EMT and autophagy and their reciprocal regulation will be a key determinant in the rational approach to future tumor immunotherapy design. PMID- 23635488 TI - Narrowband ultraviolet B interferes with gene expression in the peripheral blood T cells of patients with psoriasis. AB - BACKGROUND: Psoriasis pathogenesis and development are closely related to abnormal T cell activity. Narrowband ultraviolet B (NB-UVB) treatment markedly improves skin lesions in psoriasis. OBJECTIVES: To investigate differential gene expression in psoriasis and to understand the possible mechanisms of NB-UVB therapy for psoriasis. METHODS: The mRNA expression profiles and differentially expressed genes from peripheral blood T cells of psoriatic patients before and after NB-UVB treatment were examined using RNA sequencing and validated by real time reverse-transcription polymerase chain reaction. RESULTS: A total of 129 genes were differentially expressed in the peripheral blood T cells of psoriatic patients: 83 genes were downregulated and 46 were upregulated in psoriatic patients compared to those of healthy subjects. These genes were enriched in intracellular membrane-bound organelles, membrane-bound organelles and the nucleus, and are involved in the cell cycle, apoptosis, inflammation and other processes. These changes are reversed in psoriatic patients with good clinical outcomes following NB-UVB treatment. CONCLUSION: NB-UVB treatment has beneficial effects on local psoriatic lesions, possibly due to its effect on peripheral blood T cell gene expression. PMID- 23635489 TI - A case of late-onset leukoencephalopathy, calcifications, and cysts presenting with intracerebral hemorrhage resembling a neoplasm. PMID- 23635490 TI - Fabrication and in vitro evaluation of stable collagen/hyaluronic acid biomimetic multilayer on titanium coatings. AB - Layer-by-layer (LBL) self-assembly technique has been proved to be a highly effective method to immobilize the main components of the extracellular matrix such as collagen and hyaluronic acid on titanium-based implants and form a polyelectrolyte multilayer (PEM) film by electrostatic interaction. However, the formed PEM film is unstable in the physiological environment and affects the long time effectiveness of PEM film. In this study, a modified LBL technology has been developed to fabricate a stable collagen/hyaluronic acid (Col/HA) PEM film on titanium coating (TC) by introducing covalent immobilization. Scanning electron microscopy, diffuse reflectance Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy were used to characterize the PEM film. Results of Sirius red staining demonstrated that the chemical stability of PEM film was greatly improved by covalent cross-linking. Cell culture assays further illustrated that the functions of human mesenchymal stem cells, such as attachment, spreading, proliferation and differentiation, were obviously enhanced by the covalently immobilized Col/HA PEM on TCs compared with the absorbed Col/HA PEM. The improved stability and biological properties of the Col/HA PEM covalently immobilized TC may be beneficial to the early osseointegration of the implants. PMID- 23635491 TI - Microtopography of the eye surface of the crab Carcinus maenas: an atomic force microscope study suggesting a possible antifouling potential. AB - Marine biofouling causes problems for technologies based on the sea, including ships, power plants and marine sensors. Several antifouling techniques have been applied to marine sensors, but most of these methodologies are environmentally unfriendly or ineffective. Bioinspiration, seeking guidance from natural solutions, is a promising approach to antifouling. Here, the eye of the green crab Carcinus maenas was regarded as a marine sensor model and its surface characterized by means of atomic force microscopy. Engineered surface micro- and nanotopography is a new mechanism found to limit biofouling, promising an effective solution with much reduced environmental impact. Besides giving a new insight into the morphology of C. maenas eye and its characterization, our study indicates that the eye surface probably has antifouling/fouling-release potential. Furthermore, the topographical features of the surface may influence the wettability properties of the structure and its interaction with organic molecules. Results indicate that the eye surface micro- and nanotopography may lead to bioinspired solutions to antifouling protection. PMID- 23635492 TI - Stochastic transitions in a bistable reaction system on the membrane. AB - Transitions between steady states of a multi-stable stochastic system in the perfectly mixed chemical reactor are possible only because of stochastic switching. In realistic cellular conditions, where diffusion is limited, transitions between steady states can also follow from the propagation of travelling waves. Here, we study the interplay between the two modes of transition for a prototype bistable system of kinase-phosphatase interactions on the plasma membrane. Within microscopic kinetic Monte Carlo simulations on the hexagonal lattice, we observed that for finite diffusion the behaviour of the spatially extended system differs qualitatively from the behaviour of the same system in the well-mixed regime. Even when a small isolated subcompartment remains mostly inactive, the chemical travelling wave may propagate, leading to the activation of a larger compartment. The activating wave can be induced after a small subdomain is activated as a result of a stochastic fluctuation. Such a spontaneous onset of activity is radically more probable in subdomains characterized by slower diffusion. Our results show that a local immobilization of substrates can lead to the global activation of membrane proteins by the mechanism that involves stochastic fluctuations followed by the propagation of a semi-deterministic travelling wave. PMID- 23635494 TI - Snakes mimic earthworms: propulsion using rectilinear travelling waves. AB - In rectilinear locomotion, snakes propel themselves using unidirectional travelling waves of muscular contraction, in a style similar to earthworms. In this combined experimental and theoretical study, we film rectilinear locomotion of three species of snakes, including red-tailed boa constrictors, Dumeril's boas and Gaboon vipers. The kinematics of a snake's extension-contraction travelling wave are characterized by wave frequency, amplitude and speed. We find wave frequency increases with increasing body size, an opposite trend than that for legged animals. We predict body speed with 73-97% accuracy using a mathematical model of a one-dimensional n-linked crawler that uses friction as the dominant propulsive force. We apply our model to show snakes have optimal wave frequencies: higher values increase Froude number causing the snake to slip; smaller values decrease thrust and so body speed. Other choices of kinematic variables, such as wave amplitude, are suboptimal and appear to be limited by anatomical constraints. Our model also shows that local body lifting increases a snake's speed by 31 per cent, demonstrating that rectilinear locomotion benefits from vertical motion similar to walking. PMID- 23635495 TI - How does tooth cusp radius of curvature affect brittle food item processing? AB - Tooth cusp sharpness, measured by radius of curvature (RoC), has been predicted to play a significant role in brittle/hard food item fracture. Here, we set out to test three existing hypotheses about this relationship: namely, the Blunt and Strong Cusp hypotheses, which predict that dull cusps will be most efficient at brittle food item fracture, and the Pointed Cusp hypothesis, which predicts that sharp cusps will be most efficient at brittle food item fracture using a four cusp bunodont molar. We also put forth and test the newly constructed Complex Cusp hypothesis, which predicts that a mixture of dull and sharp cusps will be most efficient at brittle food item fracture. We tested the four hypotheses using finite-element models of four cusped, bunodont molars. When testing the three existing hypotheses, we assumed all cusps had the same level of sharpness (RoC), and gained partial support for the Blunt Cusp hypotheses. We found no support for the Pointed Cusp or Strong Cusp hypotheses. We used the Taguchi sampling method to test the Complex Cusps hypothesis with a morphospace created by independently varying the radii of curvature of the four cusps in the buccolingual and mesiodistal directions. The optimal occlusal morphology for fracturing brittle food items consists of a combination of sharp and dull cusps, which creates high stress concentrations in the food item while stabilizing the food item and keeping the stress concentrations in the enamel low. This model performed better than the Blunt Cusp hypothesis, suggesting a role for optimality in the evolution of cusp form. PMID- 23635496 TI - Predictive ethoinformatics reveals the complex migratory behaviour of a pelagic seabird, the Manx Shearwater. AB - Understanding the behaviour of animals in the wild is fundamental to conservation efforts. Advances in bio-logging technologies have offered insights into the behaviour of animals during foraging, migration and social interaction. However, broader application of these systems has been limited by device mass, cost and longevity. Here, we use information from multiple logger types to predict individual behaviour in a highly pelagic, migratory seabird, the Manx Shearwater (Puffinus puffinus). Using behavioural states resolved from GPS tracking of foraging during the breeding season, we demonstrate that individual behaviours can be accurately predicted during multi-year migrations from low cost, lightweight, salt-water immersion devices. This reveals a complex pattern of migratory stopovers: some involving high proportions of foraging, and others of rest behaviour. We use this technique to examine three consecutive years of global migrations, revealing the prominence of foraging behaviour during migration and the importance of highly productive waters during migratory stopover. PMID- 23635497 TI - Gastrointestinal lymphoma: recent advances in diagnosis and treatment. AB - The recent trends in the diagnosis and management of gastrointestinal lymphoma are reviewed. Primary gastrointestinal lymphoma accounts for 30-40% of all extranodal lymphomas, while it comprises only 1-8% of all gastrointestinal malignancies. The most common histological type is mucosa-associated lymphoid tissue lymphoma, followed by diffuse large B-cell lymphoma. Recently, the incidence of intestinal follicular lymphoma has been increasing. Balloon-assisted endoscopy and capsule endoscopy are essential tools for the assessment of small bowel lymphomas. Treatment modalities for gastrointestinal lymphomas include 'watch and wait' strategy, antibiotics (e.g., Helicobacter pylori eradication), radiotherapy, chemotherapy, surgical resection, immunotherapy (e.g. rituximab), and combinations of these. Optimal therapeutic strategies should be determined based on the involved site, histological type, and clinical stage. It should be noted that accurate pretreatment diagnosis of the disease is most important. PMID- 23635500 TI - [Prevalence of gestational diabetes in high-risk pregnancies: screened using an oral glucose tolerance test]. AB - OBJECTIVE: To determine the prevalence of gestational diabetes mellitus in high risk pregnancies during the second or third trimester diagnosed by screening with the 75-gram oral glucose tolerance test (75 g-OGTT) and, to determine the prevalence of the need for insulin therapy after an initial dietary intervention. DESIGN: Prospective cohort study. METHODS: Pregnant women at high-risk for gestational diabetes mellitus were challenged with the 75 g-OGTT in the second or third trimester, ideally between the 24th and the 28th week of pregnancy. The diagnosis of gestational diabetes mellitus was established when the fasting plasma glucose was >= 7.0 mmol/l or when the plasma glucose was >= 7.8 mmol/l two hours after the oral ingestion of 75 g glucose. The women with gestational diabetes were initially treated with a dietary regime. Insulin treatment was added if the hyperglycaemia persisted. RESULTS: A total of 471 pregnant women were included. Of these women, 75.8% underwent the 75 g-OGTT between the 24th and 28th week of pregnancy; 24.2% underwent the test between the 28th and 35th week. The diagnosis of gestational diabetes mellitus was established in 24.2% of the pregnant women. Dietary intervention was successful in normalising the blood glucose levels in 77.2% of the cases. The remaining 22.8% needed the additional insulin treatment. CONCLUSION: We ascertained that the prevalence of gestational diabetes mellitus in high-risk pregnancies was high. In most cases, the gestational diabetes mellitus could be managed by diet. A multidisciplinary approach involving obstetricians, gynaecologists, dieticians and internists is needed to ensure a timely diagnosis and adequate treatment during pregnancy. PMID- 23635501 TI - [Imputation of missing data]. AB - In medical research missing data are sometimes inevitable. Different missingness mechanisms can be distinguished: (a) missing completely at random; (b) missing by design; (c) missing at random, and (d) missing not at random. If participants with missing data are excluded from statistical analyses, this can lead to biased study results and loss of statistical power. Imputation methods can be applied to estimate missing values; multiple imputation gives a good idea of the inaccuracy of the reconstructed measurements. The most common imputation methods assume that missing data are missing at random. Multiple imputation contributes greatly to the efficiency and reliability of estimates because maximum use is made of the data collected. Imputation is not meant to obviate low-quality data. PMID- 23635493 TI - Mesenchymal stem cell mechanobiology and emerging experimental platforms. AB - Experimental control over progenitor cell lineage specification can be achieved by modulating properties of the cell's microenvironment. These include physical properties of the cell adhesion substrate, such as rigidity, topography and deformation owing to dynamic mechanical forces. Multipotent mesenchymal stem cells (MSCs) generate contractile forces to sense and remodel their extracellular microenvironments and thereby obtain information that directs broad aspects of MSC function, including lineage specification. Various physical factors are important regulators of MSC function, but improved understanding of MSC mechanobiology requires novel experimental platforms. Engineers are bridging this gap by developing tools to control mechanical factors with improved precision and throughput, thereby enabling biological investigation of mechanics-driven MSC function. In this review, we introduce MSC mechanobiology and review emerging cell culture platforms that enable new insights into mechanobiological control of MSCs. Our main goals are to provide engineers and microtechnology developers with an up-to-date description of MSC mechanobiology that is relevant to the design of experimental platforms and to introduce biologists to these emerging platforms. PMID- 23635498 TI - High-resolution SNP microarray investigation of copy number variations on chromosome 18 in a control cohort. AB - Copy number variations (CNVs) as described in the healthy population are purported to contribute significantly to genetic heterogeneity. Recent studies have described CNVs using lymphoblastoid cell lines or by application of specifically developed algorithms to interrogate previously described data. However, the full extent of CNVs remains unclear. Using high-density SNP array, we have undertaken a comprehensive investigation of chromosome 18 for CNV discovery and characterisation of distribution and association with chromosome architecture. We identified 399 CNVs, of which loss represents 98%, 58% are less than 2.5 kb in size and 71% are intergenic. Intronic deletions account for the majority of copy number changes with gene involvement. Furthermore, one-third of CNVs do not have putative breakpoints within repetitive sequences. We conclude that replicative processes, mediated either by repetitive elements or microhomology, account for the majority of CNVs in the healthy population. Genomic instability involving the formation of a non-B structure is demonstrated in one region. PMID- 23635502 TI - [Familial Mediterranean fever: not to be missed]. AB - Familial Mediterranean fever (FMF) is common among Turkish and Moroccan migrants. We describe three patients with FMF. A 3-year-old girl with recurrent fever and abdominal pain who was diagnosed early with FMF and treated effectively with colchicine. An adolescent girl who required interleukin (IL)-1 blockade to achieve disease remission. And a 37-year-old woman in whom the attacks of FMF had not been recognised, but who developed end-stage kidney failure due to AA amyloidosis. Mutations in the MEFV gene underlie the disease in most but not all patients. Therefore, FMF remains a clinical diagnosis. FMF patients suffer recurrent bouts of inflammation, often with fever, serositis or arthritis. The major complication is AA amyloidosis. The inflammatory process is mediated by IL 1beta. When started early, colchicine prophylaxis can prevent amyloidosis. When colchicine fails, IL-1 blockade has shown promising results. Timely diagnosis and treatment can make the difference between near normal health and end-stage kidney failure. PMID- 23635503 TI - [Cultural diversity in diet and obesity]. AB - In the Netherlands, excess body weight and obesity occur more commonly in certain ethnic minority groups. Diet plays an undeniable role in the development of obesity. Insight into the roles of diet and eating behaviour in the development of obesity among ethnic minorities is, however, limited. The migration histories, socio-economic statuses and socio-cultural environments of ethnic minorities are important determinants for eating patterns. It is important to take these determinants into account when treating overweight patients who are ethnic minorities. PMID- 23635504 TI - [A woman with an umbilical swelling]. AB - A 78-year-old woman presented with a 9-month history of an ulcerative umbilical swelling, which had recently started to produce feces. An abdominal CT-scan showed a tumour in the transverse colon, infiltrating the abdominal wall and skin, but without signs of distant metastases. Histopathological examination of a biopsy specimen revealed a slime-producing adenocarcinoma. Due to a myocardial infarction, the patient died two days prior to surgery. No permission to conduct an autopsy was granted. PMID- 23635505 TI - [Summary of the NHG practice guideline 'Lower urinary tract symptoms in men']. AB - In general practice, lower urinary tract symptoms (LUTS) in men are usually not attributable to specific disorders. Prostate cancer is rarely the cause of LUTS. Education, counselling, and non-pharmaceutical advice form the basis for treatment of LUTS. Only when these measures do not relieve the patient's symptoms sufficiently, drug therapy could be considered. Alpha-blockers are the drugs of first choice and are also recommended when transurethral catheterization is needed for acute urinary retention. The effect of medication on LUTS is limited and largely based on placebo effect. The effectiveness of prostate cancer screening is a subject of debate; therefore patients asking for a PSA test should be informed about the benefits and harms of measuring PSA before having a test. A PSA value > 4 ng/ml, or abnormal results on digital rectal examination should prompt further diagnostic evaluation. PMID- 23635507 TI - Sentinel lymph node and skip metastases in gastric cancer: a prospective study. AB - BACKGROUND/AIMS: The aim of the present study was to investigate localization and distribution of sentinel lymph node (SLN) in gastric cancer and influenced factors of skip metastasis. METHODOLOGY: Eighty-nine cases with solitary or single station metastatic lymph nodes (LNs) among 779 gastric cancer patients were included in this study. D2 or D2+ lymph node dissection with total or distal gastrectomy had been performed. The location of SLNs and characteristics were analyzed retrospectively. RESULTS: Seventy-one patients (79.8%) had SLNs at the first level of the regional LN group and 18 cases (20.2%) had skip metastases SLNs. NO.7 (44.4%) and NO.8a (27.8%) were the most common sites of skip metastases. Multivariate analysis identified the differentiated degree of tumor as the only significant influenced factor of skip metastases (p=0.031). The number of metastatic SLNS was significantly greater in advanced gastric cancer patients (2.4 +/- 1.4) than early gastric cancer patients (1.5 +/- 0.9) (pT4 vs. pT1, p=0.002; pT4 vs. pT2, p=0.014; pT3 vs. pT1, p=0.018). CONCLUSIONS: The differentiated degree of gastric cancer is the most important influenced factor of skip metastases and NO.7 and NO.8a are the most important N2 LN stations that should be observed when lymphadenectomy is performed. PMID- 23635508 TI - Survival advantage of radiofrequency ablation for hepatocellular carcinoma: comparison with ethanol injection. AB - BACKGROUND/AIMS: The aims of this study were to compare long-term prognosis of patients with hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI). METHODOLOGY: Two hundred and thirteen patients with HCC were initially treated with PEI or RFA at Saga University Hospital between 1990 and 2004. The present study included 190 patients: 98 treated with PEI from 1990 to 1999, and 92 with RFA from 2000 to 2004. The association of treatment method with survival prognosis was evaluated by multivariate analysis. RESULTS: There were no significant differences in gender, etiology, and tumor stage between the two groups. Five-year survival rate in the PEI group was 40% and 51% in the RFA group. According to tumor stage, there were no differences in 5-year survival rate between the two groups for tumor stage I and III. For stage II patients, RFA had better survival than PEI (48% vs. 28%, p = 0.03). Multivariate analysis indicated that RFA was more effective for long-term survival than PEI in patients with tumor stage II (p = 0.04). CONCLUSIONS: Compared to PEI, RFA improved survival in patients with stage II HCC, indicating a therapeutic advantage of RFA. PMID- 23635509 TI - Combination therapy of low-dose of PegIFNa-2a and ribavirin for patients with HCV infected decompensated cirrhosis. AB - BACKGROUND/AIMS: This study aims to evaluate the efficacy and tolerability of low dose PEGylated interferon (PEG-IFN) a-2a combined with standard of care ribavirin (RBV). The therapy was administered to patients with chronic hepatitis C virus (HCV) with decompensated cirrhosis who underwent splenectomy or partial splenic artery embolization. METHODOLOGY: A total of 106 patients with decompensated liver cirrhosis with chronic HCV infection were subjected to splenectomy (n = 89) or partial spleen artery embolization (n = 17) without the possibility of starting or continuing PEG-IFN and RBV because of neutropenia and/or thrombocytopenia. Antiviral treatment was started when the neutrocyte and platelet counts were increased and without severe surgical complications. A sustained virological response was obtained in 38 genotype 1 patients (59.3%) and 14 non-genotype 1 patients (56%) who underwent splenectomy and 6 genotype 1 patients (46.15%) and 3 non-genotype 1 patients (75%) who underwent partial splenic embolization. In the splenectomy group, the non-response rate of the genotype 1 patients was 28.13%, whereas that for non-genotype 1 patients was 24%. RESULTS: In the PSE group, the non-response rate among genotype 1 patients was 23.08%. All patients in the non-genotype 1 group obtained virological responses. The side effect was neutropenia. No patient died while on therapy. CONCLUSIONS: Both splenectomy and partial spleen artery embolization could be beneficial for low-dose PEG-IFNa-2a plus RBV antiviral therapy for early decompensated liver cirrhosis patients with chronic HCV infection and would not influence antiviral efficacy. However, patients should undergo complete follow-up. PMID- 23635510 TI - Expression of the transmembrane lysosomal protein SCARB2/Limp-2 in renin secretory granules controls renin release. AB - BACKGROUND/AIMS: Renin processing and storage is believed to occur in lysosome like structures in the afferent arteriole. SCARB2/Limp-2 is a transmembrane lysosomal protein responsible for the intracellular trafficking of beta glucocerebrosidase. This study aimed to confirm the expression of SCARB2/Limp-2 in renin secretory granules, and explore its role in renin processing and secretion. METHODS: Co-localisation studies of (pro)renin with lysosomal membrane proteins, SCARB2/Limp-2, LAMP-1 and LAMP-2, were performed in mouse and human kidney sections. Intrarenal expression and secretion of (pro)renin in wild-type (WT) and Limp-2(-/-) mice were compared with and without stimulation. RESULTS: SCARB2/Limp-2, LAMP-1 and LAMP-2 co-localised with (pro)- renin in mouse and human kidney. Plasma renin concentration was increased in Limp-2(-/-) mice when compared to WT littermates. No change in (pro)renin expression, however, was observed in Limp-2(-/-) mouse kidney cortex by immunofluorescence microscopy, Western blotting, quantitative RT-PCR or the ultrastructural appearance of renin secretory granules. Acute stimulation of renin release by isoprenaline or hydralazine was similar in WT and Limp-2(-/-) mice. Following chronic salt restriction, however, immunofluorescence microscopy showed less (pro)renin expressed in Limp-2(-/-) compared with WT mouse kidneys, and there was significantly less prorenin but not renin by Western blotting in Limp-2(-/-) mouse kidney cortex, despite no difference in circulating renin levels. CONCLUSION: Renin secretory granules possess integral lysosomal proteins, confirming that they are indeed modified lysosomes. Limp-2 deficiency leads to a minor increase in circulating renin. Limp-2, however, is not required for acute or chronic stimulation of renin release. PMID- 23635511 TI - Melatonin Pretreatment Improves the Survival and Function of Transplanted Mesenchymal Stem Cells after Focal Cerebral Ischemia. AB - Mesenchymal stem cell (MSC) transplantation has been shown to be beneficial in treating cerebral ischemia. However, such benefit is limited by the low survival of transplanted MSCs in an ischemic microenvironment. Previous studies showed that melatonin pretreatment can increase MSC survival in the ischemic kidney. However, whether it will improve MSC survival in cerebral ischemia is unknown. Our study examined the effect of melatonin pretreatment on MSCs under ischemia related conditions in vitro and after transplantation into ischemic rat brain. Results showed that melatonin pretreatment greatly increased survival of MSCs in vitro and reduced their apoptosis after transplantation into ischemic brain. Melatonin-treated MSCs (MT-MSCs) further reduced brain infarction and improved neurobehavioral outcomes. Angiogenesis, neurogenesis, and the expression of vascular endothelial growth factor (VEGF) were greatly increased in the MT-MSC treated rats. Melatonin treatment increased the level of p-ERK1/2 in MSCs, which can be blocked by the melatonin receptor antagonist luzindole. ERK phosphorylation inhibitor U0126 completely reversed the protective effects of melatonin, suggesting that melatonin improves MSC survival and function through activating the ERK1/2 signaling pathway. Thus, stem cells pretreated by melatonin may represent a feasible approach for improving the beneficial effects of stem cell therapy for cerebral ischemia. PMID- 23635512 TI - NOX2 protects against prolonged inflammation, lung injury, and mortality following systemic insults. AB - The systemic inflammatory response syndrome (SIRS) is a clinical condition occurring in intensive care unit patients as a consequence of both infectious and noninfectious insults. The mechanisms underlying resolution of SIRS are not well characterized. NOX2 (NADPH oxidase 2)-derived reactive oxygen species are critical for killing of certain pathogens by polymorphonuclear leukocytes (PMN). Patients with chronic granulomatous disease who lack functional NOX2 are not only prone to serious infections, they also exhibit chronic inflammatory conditions, suggesting a local anti-inflammatory role for NOX2. We hypothesized that NOX2 is required for the resolution of sterile systemic inflammation. Using a murine model of sterile generalized inflammation, we observed dramatically increased mortality of gp91(phox-/y) (NOX2-deficient) as compared to wild-type (WT) mice. Both genotypes developed robust SIRS with hypothermia, hypotension, and leukopenia; however, WT mice recovered within 48 h whereas NOX2-deficient mice did not. Although both groups displayed rapid peritoneal PMN recruitment, the recruited NOX2-deficient PMN demonstrated an enhanced inflammatory phenotype. Moreover, NOX2-deficient mice exhibited a hemorrhagic inflammatory response in the lungs with rapid and persistent recruitment of neutrophils to the alveolar space, whereas WT mice had minimal lung pathology. Several proinflammatory cytokines remained elevated in NOX2-deficient mice. The persistent inflammatory environment observed in NOX2-deficient mice resulted from continued peritoneal chemokine secretion and not delayed apoptosis of PMN. These data suggest a requirement for NOX2 in the resolution of systemic inflammation. PMID- 23635514 TI - Pesticide spraying may spread norovirus. PMID- 23635513 TI - In vitro culture of tumour-derived hepatocytes in decellularised whole-liver biological scaffolds. AB - BACKGROUND: To explore the feasibility of preparing transplantable recellularised liver grafts by preparing a decellularised whole-liver scaffold, decellularisation and recellularisation of a liver scaffold using a chemical detergent were performed on the liver cancer cell lines HepG2 and C3A. MATERIALS AND METHODS: D-Hanks' solution containing sodium EDTA, gradient sodium dodecyl sulphate (SDS, 1/0.5/0.1%) and Triton X-100 were infused via the portal vein to prepare the decellularised scaffold. HepG2 and C3A cells were seeded onto the scaffold, and a circulation perfusion culture was carried out. The efficiency of the engraftment and the function of the cells in the scaffold were evaluated. RESULTS: The decellularisation method used completely removed the intrahepatic cellular components while only components with low immunogenicity were retained, such as collagen and fibronectin. Meanwhile, the vascular structure was completely retained, which provided a structural basis for circulation bypass. The engraftment efficiencies of the HepG2 and C3A cells were 86 +/- 5 and 88 +/- 5%, respectively, and were not significantly different between the two groups (p > 0.05, n = 10). The cells grew well on the scaffold, and the albumin synthesis and urea secretion functions were superior to those obtained after a traditional two-dimensional culture. CONCLUSIONS: The preparation of a liver scaffold using a chemical detergent technique has good reproducibility, and the scaffold is suitable for the growth of liver tumour cell lines. PMID- 23635516 TI - Molecular and phenotypic characterization of ring chromosome 22 in two unrelated patients. AB - We report on the cytogenetic and molecular characterization of a constitutional de novo ring chromosome 22 (r(22)) in 2 unrelated patients with emphasis on different hypotheses proposed to explain the phenotypic variability characterizing this genomic disorder. In both patients, molecular investigations using FISH and array-CGH techniques revealed a 22q terminal deletion involving the 22q13.33 critical region. The size of the deletion was estimated to at least 1.35 Mb in the first proband and to only 300 kb in the second. They both exhibited the major features of r(22) syndrome, but the first patient was more profoundly affected. He had a more severe phenotype, further complicated by behavioral anomalies, autistic-like features with abnormal EEG pattern and brain MRI profile. Haploinsufficiency of the SHANK3 gene, lying in the minimal critical region, is nowadays considered as responsible for most neurobehavioral anomalies. Nevertheless, phenotypic severity and occurrence of additional features in the first patient suggest a potential involvement of one or more specific gene(s) located proximally to SHANK3 (as PLXNB2, PANX2, ALG12 or MLC1), acting either independently of it or by regulating or promoting its expression and thus disrupting its function when deleted. PMID- 23635517 TI - Determinants of fibroblast growth factor-23 and parathyroid hormone variability in dialysis patients. AB - BACKGROUND/AIMS: Treatment strategies for abnormal mineral metabolism in chronic kidney disease are largely based on achieving target ranges of biomarkers that vary considerably over time, yet determinants of their variability are poorly defined. METHODS: Observational study including 162 patients of three dialysis cohorts (peritoneal dialysis, n = 78; hemodialysis, n = 49; hemodiafiltration, n = 35). Clinical and biochemical determinants of parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) variability were analyzed in the peritoneal dialysis cohort. All cohorts were used for comparison of PTH and FGF23 intra subject variability (intra-class correlation), and their intra-subject variability in different modes of dialysis was explored. RESULTS: High PTH variability was independently associated with lower 25-hydroxyvitamin D concentration and factors of lipid and glucose metabolism, whereas high FGF23 variability was mainly associated with lower baseline serum phosphorous. These results were consistent in multivariate and sensitivity analyses. The intra subject variability of FGF23 was lower than for PTH irrespective of dialysis mode. CONCLUSIONS: Baseline vitamin D status and serum phosphorous are independent determinants of the longitudinal variation in PTH and FGF23, respectively. The clinical utility of FGF23 measurement remains unknown, yet it appears favorable based on its greater temporal stability than PTH in dialysis patients. PMID- 23635518 TI - Prevalence, serotypes and resistance patterns of Salmonella in Danish pig production. AB - The objective of this paper is to analyse in further detail the Danish results of the EFSA baseline studies in slaughter pigs and breeding herds, and compare them with the results obtained in (1) the pre-implementation study that was carried out to establish the initial prevalence values in fattening herds as part of the Danish Salmonella control programme, and (2) the study performed four years later in breeding and finishing herds to obtain information about the prevalence in breeding farms and the status of the finishers after the first years of the National Salmonella Control Programme. In the slaughter pigs Salmonella was detected in a 7.4% of 1218 ileocaecal lymph nodes and on 3.2% of 438 carcasses examined. Among the breeding herds examined by floor faecal or swab samples 122 of 298 (40.9%) were positive in at least one of the ten samples collected. The most prevalent serotypes were Salmonella Typhimurium in finishers and Salmonella Derby in breeding herds while the most prevalent phage types of the S. Typhimurium isolates were DT 12 and DT 120. The antimicrobial resistance analysis yielded a 35.2% of the isolates from the slaughter pigs resistant to one or more antimicrobials while 19.3% were resistant to four or more antimicrobials. A significantly higher percentage of resistance to antimicrobials was found in the S. Typhimurium isolates (chi(2)=4.72, p=0.029), where 42.9% presented resistance to one or more compounds. In breeding herds, just S. Typhimurium and S. 4,5],12:i: - isolates were tested. As many as 56.8% of the S. Typhimurium-like strains positive breeding farms had resistant strains, while 27% had multidrug resistant strains. The distribution of the isolates in regions showed that S. Derby is at present the predominant serotype in breeding farms from most of the regions of the country. PMID- 23635519 TI - Effects of catechin polyphenols and preparations from the plant-parasitic nematode Heterodera glycines on protease activity and behaviour in three nematode species. AB - Protease activities in preparations from the plant-parasitic nematodes Heterodera glycines and Meloidogyne incognita and the free-living nematode Panagrellus redivivus were inhibited by exposure to a series of eight catechin polyphenol analogues, (+)-catechin, (-)-epicatechin (EC), (-)-gallocatechin (GC), (-) epigallocatechin (EGC), (-)-catechin gallate (CG), (-)-gallocatechin gallate (GCG), (-)-epicatechin gallate (ECG) and (-)-epigallocatechin gallate (EGCG) (1 mm each), and by a preparation from H. glycines cysts. General protease activity detected with the FRET-peptide substrate QXL520-KSAYMRF-K(5-FAM)a and proteasome chymotrypsin-like (CTL) activity detected with succinyl-LLVY-AMC were each inhibited significantly more (P < 0.05) by the gallated form of the polyphenol than by the corresponding non-gallated form. Species differences in response to inhibition across all analogues were revealed with the CTL substrate, but CG was a consistently potent inhibitor across all three species and with each substrate. A heat-stable component (CE) from H. glycines cysts inhibited M. incognita CTL activity by 92.07 +/- 0.68%, significantly less (P < 0.05) in H. glycines (52.86 +/- 2.77%), and by only 17.24 +/- 0.55% (P < 0.05) in P. redivivus preparations. CTL activity was, however, inhibited more than 60% in all preparations by the proteasome-specific inhibitor MG-132. Hatching of M. incognita infective juveniles exposed to 1 mm CG, ECG, GCG or EGCG was reduced by 83.88 +/- 4.26%, 69.98 +/- 9.14%, 94.93 +/- 1.71% and 87.93 +/- 2.89%, respectively, while hatching of H. glycines was reduced less than 25% by each analogue. CE had no effect on nematode hatch, but did cause a 60% reduction in mobility of H. glycines infective juveniles exposed overnight to CE in vitro, which was more (P < 0.05) than the reduction of M. incognita infective juvenile mobility (20%). PMID- 23635520 TI - Adrenal function in preterm infants undergoing patent ductus arteriosus ligation. AB - BACKGROUND: Targeted milrinone treatment for low left ventricular output (LVO) reduces the incidence of acute cardiorespiratory instability following ligation of patent ductus arteriosus (PDA) in preterm infants. Despite this, some infants continue to experience postoperative deterioration. Adrenal insufficiency related to prematurity has been postulated as a possible mechanism. OBJECTIVES: To describe adrenal function in premature infants undergoing PDA ligation and to investigate its association with pre- and postoperative clinical and echocardiography-derived indices of disease severity. METHODS: A retrospective cohort study was conducted over a 2-year period on infants who underwent PDA ligation and had preoperative adrenocorticotropic hormone (ACTH) stimulation. All infants were screened by echocardiography for low LVO at 1 h after surgery and treated with intravenous milrinone if LVO <200 ml/kg/min. The primary outcome evaluated was low LVO at 1 h after surgery. Secondary outcomes included hypotension and oxygenation and ventilation failure occurring within 24 h. RESULTS: A total of 35 infants at a median gestation of 25.4 (24.5-26.4) weeks and weight at birth of 700 (600-810) g were included. Baseline median cortisol measured preoperatively was 202 (137-403) nmol/l. Following the ACTH stimulation test, 3 infants had cortisol <=500 nmol/l while 15 had <=750 nmol/l. There was no association seen between any cortisol value and low LVO postoperatively. Post ACTH cortisol <=750 nmol/l was significantly associated with hypotension (p = 0.03) and oxygenation (p = 0.04) and ventilation (p = 0.008) failure. Receiver operator characteristic curve showed a high predictive value of post-ACTH cortisol for all clinical outcomes. CONCLUSIONS: Post-ACTH cortisol (<=750 nmol/l) may be associated with clinical indices of postoperative cardiorespiratory instability. Relative adrenal insufficiency may play a role in the etiology of post-PDA ligation hemodynamic and respiratory instability. PMID- 23635523 TI - Social outcomes in pediatric traumatic brain injury: perspectives from social neuroscience and developmental psychology. PMID- 23635521 TI - Conserved roles of ems/Emx and otd/Otx genes in olfactory and visual system development in Drosophila and mouse. AB - The regional specialization of brain function has been well documented in the mouse and fruitfly. The expression of regulatory factors in specific regions of the brain during development suggests that they function to establish or maintain this specialization. Here, we focus on two such factors-the Drosophila cephalic gap genes empty spiracles (ems) and orthodenticle (otd), and their vertebrate homologues Emx1/2 and Otx1/2-and review novel insight into their multiple crucial roles in the formation of complex sensory systems. While the early requirement of these genes in specification of the neuroectoderm has been discussed previously, here we consider more recent studies that elucidate the later functions of these genes in sensory system formation in vertebrates and invertebrates. These new studies show that the ems and Emx genes in both flies and mice are essential for the development of the peripheral and central neurons of their respective olfactory systems. Moreover, they demonstrate that the otd and Otx genes in both flies and mice are essential for the development of the peripheral and central neurons of their respective visual systems. Based on these recent experimental findings, we discuss the possibility that the olfactory and visual systems of flies and mice share a common evolutionary origin, in that the conserved visual and olfactory circuit elements derive from conserved domains of otd/Otx and ems/Emx action in the urbilaterian ancestor. PMID- 23635526 TI - Mycobacterium tuberculosis- induced neutrophil extracellular traps activate human macrophages. AB - Neutrophils activated by Mycobacterium tuberculosis (Mtb) form neutrophil extracellular traps (NETs), containing DNA and several biologically active cytosolic and granular proteins. These NETs may assist in the innate immune defense against different pathogens. We investigated whether the NET-forming neutrophils mediate an activating signal to macrophages during the early multicellular inflammatory reaction and granuloma formation. Mtb-induced NETs were found to be reactive oxygen species dependent and phagocytosis dependent. A neutrophil elastase inhibitor also delayed NET formation. However, NET formation occurred independently of Mtb-induced apoptosis. We observed close interactions between macrophages and Mtb-activated neutrophils, where macrophages bound and phagocytosed NETs. Significant secretion of the cytokines interleukin (IL)-6, tumor necrosis factor-alpha, IL-1beta and IL-10 were detected from macrophages cocultured with NETs from Mtb-activated but not phorbol myristate acetate activated neutrophils. NETs binding heat shock protein 72 (Hsp72) or recombinant Hsp72 were able to trigger cytokine release from macrophages. Only Mtb-induced NETs contained Hsp72, suggesting that these NETs can transfer this danger signal to adjacent macrophages. We propose that Hsp72 sequestered in NETs plays an important role in the interaction between neutrophils and macrophages during the early innate immune phase of an Mtb infection. The immunomodulatory role of NETs and proteins derived from them may influence not only chronic inflammation during tuberculosis but also immune regulation and autoimmunity. PMID- 23635527 TI - Cisplatin plus capecitabine as first-line chemotherapy for recurrent or metastatic head and neck squamous cell cancer: experience outside of a trial setting. AB - PURPOSE: Cisplatin/5-fluorouracil (5-FU) is an accepted palliative chemotherapy treatment for head and neck squamous cell carcinoma, improving quality of life but not overall survival. Capecitabine in place of 5-FU removes the morbidity of an infusional regime with potential benefit in patient well-being. This study looks at outcomes for cisplatin plus capecitabine (PX) outside of a trial setting. METHODS: Consecutive patients receiving this treatment in a single centre were retrospectively analysed. Cisplatin (mean dose 75 mg/m2) was given on day 1 of a 3-week cycle and capecitabine (mean dose 808 mg/m2 twice daily) on days 1-14, for up to 6 cycles. RESULTS: Sixty-five patients (median age 58.6 years) received a median of 4 cycles of chemotherapy. The overall response rate was 30.7%, with a median overall survival of 7.3 months. Treatment was well tolerated with a 10.7% grade 3 and a 1.5% grade 4 neutropenia rate, with no other grade 4 toxicities. One patient died of neutropenic sepsis whilst on treatment. Twenty-seven percent of patients stopped treatment early due to chemotherapy related side effects. CONCLUSION: PX is well tolerated outside the trial setting with outcomes similar to historical published literature. Ease of administration and benefit to patient convenience make it an attractive alternative to standard palliative treatment. PMID- 23635528 TI - Asthma exacerbations: predisposing factors and prediction rules. AB - PURPOSE OF REVIEW: Asthma is a multifaceted disease that is associated with decreased lung function, multiple symptoms, varying levels of asthma control, and risk of acute exacerbations. The ability to predict the risk of developing acute exacerbations may improve the management of asthmatics and facilitate identification of these patients for interventional studies. RECENT FINDINGS: Factors that are associated with different manifestations of asthma differ. Biomarkers that are correlated with airways hyper-responsiveness do not necessarily correlate with risk of future exacerbations. Genetic factors that segregate with exacerbation risk are beginning to emerge. Outcome measures that demonstrate predictive validity have been developed and may facilitate patient management and provide novel clinically meaningful endpoints in clinical trials. SUMMARY: This review will emphasize underlying factors associated with asthma exacerbations and clinical prediction rules that correlate with the risk of developing severe exacerbations of asthma. PMID- 23635529 TI - Dual-color high-resolution fiber-FISH analysis on lethal white syndrome carriers in sheep. AB - Molecular defects occurring in the endothelin receptor type-B (EDNRB) gene are known to be associated with pigmentary anomalies and intestinal aganglionosis in humans, rodents and horses. We carried out a cytogenetic investigation in 2 ewes heterozygous for the deletion of the EDNRB gene and in 2 more females as control. The RBA-banding showed that all 4 ewes were karyologically normal. EDNRB gene specific probes were produced by PCR and cloning. The application of the R banding and propidium iodide-staining fluorescent in situ hybridization allowed mapping the gene to OAR 10q22 and confirmed the heterozygous status of the ewes investigated for the EDNRB gene deletion. For the fine estimation of the gene length in sheep and for the correct sizing of the chromosomal gap, a dual-color FISH was applied to high-resolution DNA fibers in combination with digital imaging microscopy. The comparison of the DNA fiber barcodes indicated a chromosomal deletion larger than the EDNRB gene itself. The length of the gene, not known for sheep until now, was estimated to be ~21 kb, whereas the microchromosomal deletion was ~100 kb. EDNRB is located in a chromosomal region previously shown to be a fragile site. The applied method allowed locating the potential breakpoints, thus permitting further interesting prospective investigations also in the field of the fragile sites in sheep. PMID- 23635530 TI - Gut bacteria and melamine toxicity. PMID- 23635522 TI - Evolutionary cell biology of chromosome segregation: insights from trypanosomes. AB - Faithful transmission of genetic material is essential for the survival of all organisms. Eukaryotic chromosome segregation is driven by the kinetochore that assembles onto centromeric DNA to capture spindle microtubules and govern the movement of chromosomes. Its molecular mechanism has been actively studied in conventional model eukaryotes, such as yeasts, worms, flies and human. However, these organisms are closely related in the evolutionary time scale and it therefore remains unclear whether all eukaryotes use a similar mechanism. The evolutionary origins of the segregation apparatus also remain enigmatic. To gain insights into these questions, it is critical to perform comparative studies. Here, we review our current understanding of the mitotic mechanism in Trypanosoma brucei, an experimentally tractable kinetoplastid parasite that branched early in eukaryotic history. No canonical kinetochore component has been identified, and the design principle of kinetochores might be fundamentally different in kinetoplastids. Furthermore, these organisms do not appear to possess a functional spindle checkpoint that monitors kinetochore-microtubule attachments. With these unique features and the long evolutionary distance from other eukaryotes, understanding the mechanism of chromosome segregation in T. brucei should reveal fundamental requirements for the eukaryotic segregation machinery, and may also provide hints about the origin and evolution of the segregation apparatus. PMID- 23635532 TI - Surgical and endoscopic treatment of pain in chronic pancreatitis: a multidisciplinary update. AB - Chronic pancreatitis is an inflammatory disease of the pancreas with abdominal pain as the most prominent symptom. Adequate treatment of patients with chronic pancreatitis remains a major challenge, mainly because of the lack of evidence based treatment protocols. The primary goal of treatment is to achieve long-term pain relief, control of the complications associated with the disease, and to restore the quality of life. Currently, a conservative step-up approach is often used for the treatment of pain; progression to severe and intractable pain is considered necessary before invasive treatment is considered. Recent studies, however, suggest that surgical intervention should not be considered only as last resort treatment, since it can mitigate disease progression, achieve excellent pain control, and preserve pancreatic function. In this review, we present a state-of-the art overview of endoscopic and surgical treatment options for patients with painful chronic pancreatitis, and elaborate on the timing of surgery. PMID- 23635533 TI - Comment on "QSPR modeling of bioconcentration factor of nonionic compounds using Gaussian processes and theoretical descriptors derived from electrostatic potentials on molecular surface [Peng et al. Chemosphere 83 (2011) 1045-1052]". PMID- 23635534 TI - Toxicity of the ionophore antibiotic lasalocid to soil-dwelling invertebrates: avoidance tests in comparison to classic sublethal tests. AB - Lasalocid is a veterinary ionophore antibiotic used for prevention and treatment of coccidiosis in poultry. It enters the environment with the use of contaminated manure on agricultural land. Despite its extensive use, the effects of lasalocid on non-target soil organisms are poorly explored. We used classical subleathal ecotoxicity tests to assess the effects of lasalocid on earthworms (Eisenia andrei) and isopods (Porcellio scaber) and compared the results with tests using avoidance behaviour as the endpoint. The results showed that avoidance is a much more sensitive endpoint. For earthworms, EC50 for avoidance (12.3 mg kg(-1) dry soil) was more than five times lower than EC50 for reproduction (69.6 mg kg(-1) dry soil). In isopods the sensitivity of the behavioural response test was even higher. While the highest lasalocid concentration 202 mg kg(-1) had no significant effects on isopod growth or survival, already the lowest used concentration in the behavioural assay (4.51 mg kg(-1)) caused significant impact on isopod behaviour. Using the avoidance test results for calculating the predicted no-effect concentration (PNEC) of lasalocid to soil invertebrates, the value is close to the predicted environmental concentration (PEC). This indicates that the use of lasalocid-contaminated manure could potentially impair the habitat function of agricultural soils. PMID- 23635536 TI - WHO's response to article on doctors and the alcohol industry. PMID- 23635539 TI - Training and ignorance in the new NHS. PMID- 23635537 TI - Global alcohol producers group's reply to WHO. PMID- 23635535 TI - Kinetics and isotherm of fibronectin adsorption to three-dimensional porous chitosan scaffolds explored by 125I-radiolabelling. AB - In this study, (125)I-radiolabelling was explored to follow the kinetics and isotherm of fibronectin (FN) adsorption to porous polymeric scaffolds, as well as to assess the elution and exchangeability of pre-adsorbed FN following incubation in serum-containing culture medium. Chitosan (CH) porous scaffolds with two different degrees of acetylation (DA 4% and 15%) were incubated in FN solutions with concentrations ranging from 5 to 50 ug/mL. The kinetic and isotherm of FN adsorption to CH were successfully followed using (125)I-FN as a tracer molecule. While on DA 4% the levels of adsorbed FN increased linearly with FN solution concentration, on DA 15% a saturation plateau was attained, and FN adsorbed amounts were significantly lower. These findings were supported by immunofluorescent studies that revealed, for the same FN solution concentration, higher levels of exposed cell-binding domains on DA 4% as compared with DA 15%. Following incubation in serum containing medium, DA 4% also revealed higher ability to exchange pre-adsorbed FN by new FN molecules from serum than DA 15%. In accordance, when assessing the efficacy of passively adsorbed FN to promote endothelial cell (EC) adhesion to CH, ECs were found to adhere at higher levels to DA 4% as compared with DA 15%, 5 ug/mL of FN being already efficient in promoting cell adhesion and cytoskeletal organization on CH with DA 4%. Taken together the results show that protein radiolabelling can be used as an effective tool to study protein adsorption to porous polymeric scaffolds, both from single and complex protein solutions. PMID- 23635540 TI - Do patient reported outcome measures do more harm than good? PMID- 23635538 TI - The meaning of "partnership working" to the alcohol industry. PMID- 23635541 TI - Time to reconsider guidelines on clarithromycin in chronic rhinosinusitis? PMID- 23635542 TI - Portfolio of pap. PMID- 23635543 TI - Private Eye weighs in against tobacco industry's attack on plain packaging. PMID- 23635544 TI - Measles in the UK: a test of public health competency in a crisis. PMID- 23635545 TI - Understanding patterns in maternity care in the NHS and getting it right. PMID- 23635546 TI - The private clinics that advertise unlicensed measles jabs. PMID- 23635547 TI - Computed tomography and magnetic resonance imaging findings for primary middle ear carcinoma. AB - OBJECTIVE: This study aimed to investigate the computed tomography and magnetic resonance imaging findings of primary middle-ear carcinoma. METHODS: In this retrospective study of 13 patients with primary middle-ear carcinoma, we collected pre- and post-contrast magnetic resonance images for all 13 cases, high resolution computed tomography scans for 11 cases, and conventional computed tomography scans with contrast for 2 cases. RESULTS: Soft-tissue masses were mainly located in the tympanum, tympanic sinus and deep within the external auditory canal, and involved the jugular fossa (9 of 13 patients), middle cranial fossa (5/13), parotid gland (2/13) and temporomandibular joint fossa (1/13). An irregular, 'moth-eaten' bone destruction pattern was seen on high-resolution computed tomography images, most commonly in the eustachian tube (9/13), jugular foramen (9/13) and facial nerve canal (7/13). On non-contrast magnetic resonances images, masses were isointense or slightly hypointense on T1-weighted images, and isointense or slightly hyperintense on T2-weighted images. On post-contrast images, lesions were moderately and homogeneously enhanced in seven cases and inhomogeneously enhanced in six. CONCLUSION: High-resolution computed tomography precisely detects regions of bone destruction, whereas MRI can better assess soft tissue tumour margins, intracranial extension and vessel patency. Eustachian tube erosion is an important characteristic of primary middle-ear carcinoma. PMID- 23635548 TI - Tonsillar CD4+CD25+ regulatory T cells from IgA nephropathy patients have decreased immunosuppressive activity in experimental IgA nephropathy rats. AB - BACKGROUND/AIM: CD4+CD25+ regulatory T (Treg) cells are of critical importance for maintenance of tolerance. We showed that the number of CD4+CD25+ Treg cells was significantly lower in tonsils of patients with IgA nephropathy (IgAN); however, the function of tonsillar CD4+CD25+ Treg cells in IgAN has not been reported. The aim of this study was to investigate the effect of tonsillar CD4+CD25+ Treg cells of IgAN patients on experimental IgAN in rats. METHODS: Tonsillar CD4+CD25+ Treg cells were isolated by magnetic beads. A total of 2 * 10(6) CD4+CD25+ Treg cells were transferred into rats that were previously orally immunized over a period of 14 weeks and subsequently received an injection of BSA into the tail vein on 3 consecutive days. Urine protein and erythrocytes were measured. Glomerular injury was assessed by histopathology. Plasminogen activator inhibitor type 1 (PAI-1), interleukin (IL)-6 and transforming growth factor (TGF) beta1 in mesangial cells of rats were examined by reverse transcription PCR. Serum IgA and C3 and supernatants of IL-2, IL-4 and IL-6 in splenic cells were analysed by ELISA. Transferred tonsillar CD4+CD25+ Treg cells were tracked by reverse transcription PCR and flow cytometry. RESULTS: IgA deposition in the mesangial region and the glomerular planar area and the number of cells, levels of serum IgA and supernatant IL-2, IL-4 and IL-6 in splenic cells and PAI-1, IL-6 and TGF-beta1 expression in renal mesangial cells of rats that received CD4+CD25+ Treg cells from IgAN patients were significantly higher than in rats that received CD4+CD25+ Treg cells from the control group, although they were dramatically lower compared with rats treated without CD4+CD25+ Treg cells. Transferred tonsillar CD4+CD25+ Treg cells migrated predominantly to secondary lymphoid organs but not to the kidneys. CONCLUSION: Dysfunction of tonsillar CD4+CD25+ Treg cells may be an important cause of IgAN progression. PMID- 23635549 TI - Perioperative care of adolescents. AB - PURPOSE OF REVIEW: To describe adolescent development within the context of perioperative anesthetic management. RECENT FINDINGS: Most adolescent deaths are as a result of unintentional injury. Motor vehicle accidents are the most common cause, with homicide the second most common cause of intentional injury. Suicide is also a significant cause of adolescent death. The thinning of gray matter following preadolescence overtakes synaptogenesis, resulting in a more efficient, adult-like brain. Although adolescent substance use has declined over the last 30 years, cigarette smoking, alcohol and illicit drug use, sexual activity, and violent behavior remain significant concerns in perioperative care. The tremendous increase in physical working capacity and maximum oxygen consumption during adolescence commonly results in the pursuit of muscularity, substance use and abuse, dieting regimens, and muscle dysmorphia. Childhood obesity has risen by more than 50% in the last 10 years. Anorexics die at a rate of 10-20% from complications of starvation or from suicide. Up to 8% of adolescents are diagnosed with major depressive disorder. Poorly controlled perioperative pain is still common. Many adolescents have decision-making capacity and therefore assent to surgery becomes an important perioperative consideration. SUMMARY: Adolescents are a very healthy population subject to unintentional and intentional injury. Emotional and judgmental maturation is a cofactor in these injuries, better appreciated through improved understanding of developmental neurobiology. In addition, increases in muscle mass, requirements for nutrition and rest, maladaptive behavior, and health choices are important for optimal perioperative care. PMID- 23635551 TI - Remifentanil-induced tolerance, withdrawal or hyperalgesia in infants: a randomized controlled trial. RAPIP trial: remifentanil-based analgesia and sedation of paediatric intensive care patients. AB - BACKGROUND: Short-acting opioids like remifentanil are suspected of an increased risk for tolerance, withdrawal and opioid-induced hyperalgesia (OIH). These potential adverse effects have never been investigated in neonates. OBJECTIVES: To compare remifentanil and fentanyl concerning the incidence of tolerance, withdrawal and OIH. METHODS: 23 mechanically ventilated infants received up to 96 h either a remifentanil- or fentanyl-based analgesia and sedation regimen with low-dose midazolam. We compared the required opioid doses and the number of opioid dose adjustments. Following extubation, withdrawal symptoms were assessed by a modification of the Finnegan score. OIH was evaluated by the CHIPPS scale and by testing the threshold of the flexion withdrawal reflex with calibrated von Frey filaments. RESULTS: Remifentanil had to be increased by 24% and fentanyl by 47% to keep the infants adequately sedated during mechanical ventilation. Following extubation, infants revealed no pronounced opioid withdrawal and low average Finnegan scores in both groups. Only 1 infant of the fentanyl group and 1 infant of the remifentanil group required methadone for treatment of withdrawal symptoms. Infants also revealed no signs of OIH and low CHIPPS scores in both groups. The median threshold of the flexion withdrawal reflex was 4.5 g (IQR = 2.3) in the fentanyl group and 2.7 g (IQR = 3.3) in the remifentanil group (p = 0.312), which is within the physiologic range of healthy infants. CONCLUSIONS: Remifentanil does not seem to be associated with an increased risk for tolerance, withdrawal or OIH. PMID- 23635550 TI - Two novel GATA6 mutations cause childhood-onset diabetes mellitus, pancreas malformation and congenital heart disease. AB - BACKGROUND: GATA6 mutations are the most frequent cause of pancreatic agenesis and diabetes in human sporadic cases. In families, dominantly inherited mutations show a variable phenotype also in terms of endocrine and exocrine pancreatic disease. We report two novel GATA6 mutations in an independent cohort of 8 children with pancreas aplasia or hypoplasia and diabetes. METHODS: We sequenced GATA6 in 8 children with diabetes and inborn pancreas abnormalities, i.e. hypoplasia or aplasia in which other known candidate genes causing monogenic diabetes and pancreatic defects had been excluded. RESULTS: We found two novel heterozygous GATA6 mutations (c.951_954dup and c.754_904del) in 2 patients with sporadic pancreas hypoplasia, diabetes and severe cardiac defects (common truncus arteriosus and tetralogy of Fallot), but not in the remaining 6 patients. GATA6 mutations in carriers exhibited hypoplastic pancreas with absent head in 1 patient and with increased echogenicity and decreasing exocrine function in the other patient. Additionally, hepatobiliary malformations and brain atrophy were found in 1 patient. CONCLUSION: Our 2 cases with novel GATA6 mutations add more phenotype characteristics of GATA6 haploinsufficiency. In agreement with an increasing number of published cases, the wide phenotypic spectrum of GATA6 diabetes syndrome should draw the attention of both pediatric endocrinologists and geneticists. PMID- 23635552 TI - A phase I trial of sunitinib and rapamycin in patients with advanced non-small cell lung cancer. AB - BACKGROUND: Sunitinib is an oral multitargeted tyrosine kinase inhibitor, with single-agent activity in non-small cell lung cancer (NSCLC). Resistance to tyrosine kinase inhibitor therapy is mediated by the mammalian target of rapamycin (mTOR) pathway, and may be reversed by using mTOR inhibitors. METHODS: We performed a phase I study evaluating the combination of sunitinib and rapamycin in patients with advanced NSCLC. RESULTS: Nineteen patients were enrolled in the study. The dose-limiting toxicities included infection, pneumonia, diarrhea/dehydration and treatment delay due to thrombocytopenia in 1 patient each. Sunitinib 25 mg orally daily and rapamycin 2 mg orally daily with 4 weeks on and 2 weeks off therapy were determined to be the maximum tolerated dose. No objective responses were noted, and 6 patients had stable disease as a best response. CONCLUSION: The combination of sunitinib and rapamycin is well tolerated and warrants further investigation in the phase II setting. PMID- 23635553 TI - Assessment of the macula in keratoconus: an optical coherence tomography and multifocal electroretinography study. AB - PURPOSE: The purpose of our study was to assess the macular thickness and the electrophysiological changes in keratoconic patients without any systemic or ocular disorders. METHODS: 64 eyes of 32 keratoconus patients as well as 60 eyes of 30 controls participated in the study. All participants underwent a complete ophthalmological examination, including best-corrected visual acuity (BCVA) assessment, color vision testing, fundus examination, intraocular pressure measurement, central foveal thickness (CFT) measurement by optical coherence tomography (OCT) scan, and multifocal-electroretinogram (mf-ERG) recording. CFT, retinal response density (RRD) and P1 latency were measured. RESULTS: There was no statistically significant difference between the two groups concerning CFT and P1 latency in mf-ERG. The RRD in mf-ERG differed significantly between keratoconus patients and controls. Of note, BCVA was positively associated with RRD in keratoconus patients. CONCLUSION: In some cases of keratoconus, a macular dysfunction not visible ophthalmoscopically may coexist and the low visual acuity could be due not only to the corneal abnormality, but also to the photoreceptor dysfunction. As a result, the preoperative electrophysiological study of patients with keratoconus is crucial to avoid a needless corneal transplantation. PMID- 23635554 TI - Exposure to TDCPP appears widespread. PMID- 23635555 TI - The relationship between eight GWAS-identified single-nucleotide polymorphisms and primary breast cancer outcomes. AB - BACKGROUND: Several single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome-wide association studies (GWAS). We investigated whether eight risk SNPs identified in GWAS were associated with breast cancer disease-free survival (DFS) and overall survival (OS) rates. PATIENTS AND METHODS: A cohort of 739 white women with early-stage breast cancer was genotyped for eight GWAS-identified SNPs (rs2981582, rs1219648 [FGFR2], rs3803662, rs12443621, rs8051542 [TOX3], rs999737 [RAD51L1], rs6504950 [17q23], and rs4973768 [3p24]). Relationships between SNPs and breast cancer outcomes were evaluated using Cox proportional hazard regression models. The cumulative effects of SNPs on breast cancer outcomes were assessed by computing the number of at risk genotypes. RESULTS: At a median follow-up of 121 months (range: 188-231 months) for survivors, 237 deaths (32%) and 186 breast cancer events (25%) were identified among the 739 patients. After adjusting for age, clinical stage, and treatment, rs12443621 (16q12; p = .03) and rs6504950 (17q23; p = .008) were prognostic for OS but not DFS. A higher risk for death was also found in the multivariable analysis of patients harboring three or four at-risk genotypes of the GWAS SNPs compared to patients carrying two or less at-risk genotypes (hazard ratio: 1.60, 95% confidence interval: 1.23-2.24; p = .0008). CONCLUSION: The study results suggest that previously identified breast cancer risk susceptibility loci, rs12443621 (16q12) and rs6504950 (17q23), may influence breast cancer prognosis or comorbid conditions associated with overall survival. The precise molecular mechanisms through which these risk SNPs, as well as others that were not included in the analysis, influence clinical outcomes remain to be determined. PMID- 23635557 TI - Treatment of older patients with head and neck cancer: a review. AB - The incidence of head and neck cancer (HNC) in the elderly is increasing. The treatment of HNC often includes multimodality therapy that can be quite morbid. Older patients (herein, defined as >=65 years) with HNC often have significant comorbidity and impaired functional status that may hinder their ability to receive and tolerate combined modality therapy. They have often been excluded from clinical trials that have defined standards of care. Therefore, tailoring cancer therapy for older patients with HNC can be quite challenging. In this paper, we performed a comprehensive literature review to better understand and discuss issues related to therapeutic recommendations that are particular to patients 65 years and older. Evidence suggests that older patients have similar survival outcomes compared with their younger peers; however, they may experience worse toxicity, especially with treatment intensification. Similarly, older patients may require more supportive care throughout the treatment process. Future studies incorporating geriatric tools for predictive and interventional purposes will potentially allow for improved patient selection and tolerance to intensive treatment. PMID- 23635556 TI - Role of postoperative vitamin D and/or calcium routine supplementation in preventing hypocalcemia after thyroidectomy: a systematic review and meta analysis. AB - BACKGROUND: Transient hypocalcemia is a frequent complication after total thyroidectomy. Routine postoperative administration of vitamin D and calcium can reduce the incidence of symptomatic postoperative hypocalcemia. We performed a systematic review to assess the effectiveness of this intervention. The primary aim was to evaluate the efficacy of routine postoperative oral calcium and vitamin D supplementation in preventing symptomatic post-thyroidectomy hypocalcemia. The second aim was to draw clear guidelines regarding prophylactic calcium and/or vitamin D therapy for patients after thyroidectomy. METHODS: We identified randomized controlled trials comparing the administration of vitamin D or its metabolites to calcium or no treatment in adult patients after thyroidectomy. The search was performed in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Google Scholar, and Web of Knowledge databases. Patients with a history of previous neck surgery, calcium supplementation, or renal impairment were excluded. RESULTS: Nine studies with 2,285 patients were included: 22 in the vitamin D group, 580 in the calcium group, 792 in the vitamin D and calcium group, and 891 in the no intervention group, with symptomatic hypocalcemia incidences of 4.6%, 14%, 14%, and 20.5%, respectively. Subcomparisons demonstrated that the incidences of postoperative hypocalcemia were 10.1% versus 18.8% for calcium versus no intervention and 6.8% versus 25.9% for vitamin D and calcium versus no intervention. The studies showed a significant range of variability in patients' characteristics. CONCLUSIONS: A significant decrease in postoperative hypocalcemia was identified in patients who received routine supplementation of oral calcium or vitamin D. The incidence decreased even more with the combined administration of both supplements. Based on this analysis, we recommend oral calcium for all patients following thyroidectomy, with the addition of vitamin D for high-risk individuals. PMID- 23635558 TI - Real-world effectiveness of systemic agents approved for advanced non-small cell lung cancer: a SEER-Medicare analysis. AB - OBJECTIVES: Disparity exists between patients with lung cancer enrolled in clinical trials and patients treated in the community setting. This study assessed the real-world effectiveness of cytotoxic agents that became available for the treatment of non-small cell lung cancer (NSCLC) in the last 2 decades. METHODS: We employed the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database for patients diagnosed with stage IIIB/IV NSCLC between 1988 and 2005 to assess the effectiveness of newly approved agents. Effectiveness of specific agents was assessed at time periods immediately following the approval of the agent for NSCLC: baseline, 1988-1994; platinum, 1995-1999; docetaxel, 1999-2003; pemetrexed and bevacizumab, 2004-2005. Significant associations between specific drug treatment and survival improvement were determined using the Kaplan-Meier method, Cox proportional hazard model, and propensity score analyses. Significant differences were established by log-rank test. RESULTS: This analysis employed data from 143,548 patients by sex (58% male, 42% female), cancer stage (35% stage IIIB, 65% stage IV), and age (12% 20 64 years, 22% 65-69 years, 45% 70-79 years, 22% 80 years and older). There was temporal improvement in survival for patients treated with newly approved chemotherapy (1-year survival rates: 32.41% in 1988-1994, 32.95% in 1995-1998, 37.40% in 1999-2003, and 39.55% in 2004-2005). Patients treated with a newly approved drug during the relevant treatment era had a significant reduction in the risk of death when compared with patients treated with chemotherapy other than the newly approved agent (hazard ratios [95% confidence interval] were 0.76 [0.71-0.81] for platinum, 0.73 [0.70-0.75] for docetaxel, 0.40 [0.37-0.44] for pemetrexed, and 0.33 [0.27-0.40] for bevacizumab; p < .001). Propensity score adjustment did not significantly alter these results. CONCLUSIONS: Currently approved drugs for the treatment of advanced NSCLC are associated with improved survival in the U.S. Medicare patient population. Our findings support the effectiveness of these agents in the real-world oncology practice. PMID- 23635561 TI - Small bowel gastrointestinal stromal tumors presenting with small bowel obstruction. PMID- 23635562 TI - Modified duodenum-preserving pancreatic head resection and nutrition management: our experience for chronic pancreatitis. PMID- 23635559 TI - Prospective head and neck cancer research: a four-decade bibliometric perspective. AB - BACKGROUND: It is unknown whether changes in study sponsorship have affected the proportion of prospective research on surgery, radiotherapy, and pharmacotherapy for head and neck squamous cell carcinoma (HNSCC) being published over time. PATIENTS AND METHODS: We examined prospective studies from PubMed, Ovid MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1980, 1985, 1990, 1995, 2000, 2005, and 2010. Chi-squared tests were used to identify significant associations between sponsorship and authorship, treatments within study protocols, and presentation of results, whereas time-based trends were analyzed using the Cochran-Armitage test. RESULTS: Among 309 articles, industry (70, 22.7%) and the U.S. government (65, 21%) were the most common sponsors. There was a significant increase in the proportion of industry-sponsored research (p for trend = .013) and a decline in U.S. government-sponsored research (p for trend = .001) over time. The inclusion of surgery in treatment protocols declined over the past four decades (p for trend = .003). Protocols incorporating pharmacotherapy were more likely to have industry support than those without pharmacotherapy (p = .001), whereas protocols with radiotherapy (p = .003) or surgery (p = .002) were less likely to have industry support. CONCLUSION: Industry is the predominant sponsor of prospective HNSCC research, with an emphasis on pharmacotherapy. PMID- 23635563 TI - Video endoscope removal from the right main bronchus using a flexible esophagogastroduodenoscope. PMID- 23635560 TI - Weekly paclitaxel/carboplatin/trastuzumab therapy improves pathologic complete remission in aggressive HER2-positive breast cancers, especially in luminal-B subtype, compared with a once-every-3-weeks schedule. AB - BACKGROUND: The efficacy and tolerability of two different schedules of paclitaxel, carboplatin, and trastuzumab (PCarH) for HER2-positive, locally aggressive (stage IIB-IIIC) breast cancers were evaluated in this phase II trial. METHODS: Patients were randomly assigned to receive either weekly (12 doses over 16 weeks) or once-every-3-weeks (4 doses over 12 weeks) treatment. The primary endpoint was pathologic complete remission (pCR) in the breast and axilla. To detect an assumed 35% pCR absolute difference between the two schedules, a minimum of 26 assessable patients in each group was required (two-sided alpha = 0.05, beta = 0.2). RESULTS: A total of 56 patients were enrolled (weekly group, n = 29; every-3-weeks group, n = 27). In the intent-to-treat analysis, pCR in the breast/axilla were found in 31 patients (55%; 95% confidence interval [CI]: 41% 69%). Compared with the every-3-weeks schedule, the weekly administration achieved higher pCR (41% vs. 69%; p = .03). After adjustment for clinical and pathological factors, the weekly administration was more effective than the every 3-weeks schedule, with hazard ratio of 0.3 (95% CI: 0.1-0.9; p = .03). Interestingly, weekly administration resulted in high pCR rates in both luminal-B (HER2-positive) and ERBB2+ tumors (67% vs. 71%; p = .78), whereas luminal-B (HER2 positive) tumors benefited less from the every-3-weeks schedule compared with the ERBB2+ tumors (21% vs. 62%, p = .03). These results remain after multivariate adjustment, showing weekly administration was more effective in the luminal-B (HER2-positive) subgroup (p = .02) but not in the ERBB2+ subgroup (p = .50). CONCLUSION: A more frequent administration might improve the possibility of eradicating invasive cancer in the breast and axilla, especially in the luminal-B (HER2-positive) subtype. Further studies to validate our findings are warranted. PMID- 23635564 TI - Iatrogenic rectal perforations from phosphate enemas: a retrospective series over 1 year of activity in a university hospital. PMID- 23635565 TI - Surgery for giant gastrointestimal stromal tumor in the elderly. PMID- 23635566 TI - Traumatic abdominal wall hernia from a handlebar injury. PMID- 23635567 TI - Hepatic metastasis of a carotid body paraganglioma 5 years after resection of the primary tumor. PMID- 23635568 TI - Symptomatic suture granuloma of the cecum after silk suture appendectomy. PMID- 23635569 TI - Long-term survival of a patient with neuroendocrine carcinoma of the ampulla of vater with lymph node micrometastasis. PMID- 23635570 TI - Congenitally absent inferior vena cava. PMID- 23635571 TI - Increased severe all-terrain vehicle accidents at a rural tennessee trauma center despite safety legislation. PMID- 23635572 TI - The clinicopathologic and prognostic analysis of adenosquamous and squamous cell carcinoma of the stomach. PMID- 23635573 TI - Air force breast cancer detection and treatment trends. PMID- 23635574 TI - Liposarcoma of the spermatic cord: an unexpected finding of inguinal hernia repair. PMID- 23635575 TI - Florid papillomatosis of the nipple. PMID- 23635576 TI - Horace G. Smithy, M.D.: troubled heart, innovative mind, unwavering spirit. PMID- 23635577 TI - Horace G. Smithy, M.D.: troubled heart, innovative mind, unwavering spirit. PMID- 23635578 TI - Chevalier Jackson, M.D. (1865-1958): Il ne se repose jamais. PMID- 23635580 TI - Risk Factors for Falls among Hospitalized Trauma Patients. AB - Inpatient falls lead to an injury in 30 per cent of cases and serious injury in 5 per cent. Increasing staffing and implementing fall prevention programs can be expensive and require a significant use of resources. We hypothesized that trauma patients have unique risk factors to sustain a fall while hospitalized. This is a retrospective cohort study from 2005 to 2010 of all trauma patients admitted to an urban Level I trauma center. Patients who fell while hospitalized were compared with patients who did not fall to identify risk factors for sustaining an inpatient fall. There were 16,540 trauma patients admitted during the study period and 128 (0.8%) fell while hospitalized. Independent risk factors for a trauma patient to fall while hospitalized included older age (odds ratio [OR], 1.02 [1.01 to 1.03], P < 0.001), male gender (OR, 1.6 [1.0 to 2.4], P = 0.03), blunt mechanism (OR, 5.1 [1.6 to 16.3], P = 0.006), Glasgow Coma Score at admission (OR, 0.59 [0.35 to 0.97], P = 0.04), intensive care unit admission (OR, 2.3 [1.4 to 3.7], P = 0.001), and need for mechanical ventilation (OR, 2.2 [1.2 to 3.9], P = 0.01). Trauma patients who fell while hospitalized sustained an injury in 17 per cent of cases and a serious injury in 5 per cent. Inpatient falls in hospitalized trauma patients are uncommon. Risk factors include older age, male gender, blunt mechanism, lower Glasgow Coma Score, and the need for intensive care unit admission or mechanical ventilation. Trauma patients with these risk factors may require higher staffing ratios and should be enrolled in a formal fall prevention program. PMID- 23635579 TI - Gastric electrical stimulation for abdominal pain in patients with symptoms of gastroparesis. AB - Abdominal pain physiology may be better understood studying electrophysiology, histology, and symptom scores in patients with the symptoms of gastroparesis (Gp) treated with gastric electrical stimulation (GES). Ninety-five Gp patients' symptoms were recorded at baseline and during temporary and permanent GES. Gastric-emptying times and cutaneous, mucosal, and serosal electrogastrograms were obtained. S100-stained, full-thickness gastric biopsies were compared with autopsy controls. Sixty-eight patients reported severe pain at baseline. Severe pain patients' mean pain scores decreased with temporary GES from 3.62 to 1.29 (P < 0.001) and nonsevere pain from 1.26 to 0.67 (P = 0.01). With permanent GES, severe mean pain scores fell to 2.30 (P < 0.001); nonsevere pain changed to 1.60 (P = 0.221). Mean follow-up was 275 days. Mean cutaneous, mucosal, and serosal frequencies and frequency-to-amplitude ratios were markedly higher than literature controls. For patients with Gp overall and subdivided by etiology and severity of pain, S-100 neuronal fibers were significantly reduced in both muscularis propria layers. GES improved severe pain associated with symptoms of Gp. This severe pain is associated with abnormal electrogastrographic activity and loss of S100 neuronal fibers in the stomach's inner and outer muscularis propria and, therefore, could be the result of gastric neuropathy. PMID- 23635581 TI - Retropancreatic retroperitoneal tumors: a 30-year experience with 38 cases. AB - Retropancreatic retroperitoneal tumors (RRTs) are seldom encountered in clinical practice. The lack of characteristics on clinical presentation and imaging make preoperative diagnosis difficult and surgical management remains a challenge. This retrospective report surveys the presenting diagnosis and surgical management of 38 patients with RRTs presenting at our center between August 1981 and May 2012. Six patients were misdiagnosed on the basis of computerized tomography and one each by magnetic resonance imaging and magnetic resonance cholangiopancreatography. Tumors were localized posterior to the pancreatic head and uncinate process (n = 18); posterior to the neck and body of the pancreas (n = 9); or posterior to the body and tail of the pancreas (n = 11). Thirty-three patients underwent surgical resections. Operative approaches were chosen on the basis of tumor size and localization. The tumors were mostly commonly originating from neurogenic tissue (n = 16). There were 25 benign neoplasms (65.8%), 10 malignant tumors (26.3%), and three undefined tumors. The morbidity of postsurgical complications was 21 per cent (eight of 38). The number of patients who underwent follow-up was 21, and the mean follow-up time was 35 months (range, 2 to 90 months). Three patients died during follow-up. The morbility of local recurrence was 10.5 per cent (four of 38). Definitive diagnosis of RRTs is made at laparotomy. Complete resection remains the fundamental objective of disease management. Different operative approaches should be used according to tumor localization and size. PMID- 23635582 TI - Single-institution outcome experience using AlloDerm(r) as temporary coverage or definitive reconstruction for cutaneous and soft tissue malignancy defects. AB - Definitive reconstruction after excision of cutaneous and soft tissue malignancies is sometimes limited as a result of lack of native tissue coverage options, patient comorbidities, or pending permanent margin analysis. Acellular dermis (AlloDerm(r)) reconstruction offers an excellent coverage alternative in these situations. We describe our experience using AlloDerm for coverage of skin and soft tissue defects. An Institutional Review Board approved review of patients undergoing skin/soft tissue coverage with AlloDerm from 2006 to 2012 was performed. Clinicopathologic variables, early postoperative findings, and subjective final cosmetic outcome were analyzed. Sixty-seven patients underwent AlloDerm reconstruction. Melanoma (67%) was the most frequent diagnosis. The median defect size was 42 cm(2) (range, 2 to 340 cm(2)), involving predominantly the lower extremity (45%) or head and neck (32%). AlloDerm was intended for use as a temporary dressing in 64 per cent (43 of 67) and permanent coverage in 24 (36%). Ten patients required reexcision for positive margins. Twenty-five (37%) underwent split-thickness skin graft or flap coverage after AlloDerm placement. Radiation was administered to 16 patients (24%) after AlloDerm reconstruction within a median of 53 days after surgery (range, 18 to 118 days). At first postoperative examination (median, 11 days after surgery), 85 per cent had evidence of healthy AlloDerm incorporation. Cellulitis was the most frequent complication (13%), all resolving with oral antibiotics. AlloDerm reconstruction after skin and soft tissue resection offers a suitable coverage alternative and may serve as a bridge to permanent reconstruction or as a permanent biologic dressing of complex surgical defects. In situations in which adjuvant radiation is needed, AlloDerm can be used without major complications. PMID- 23635583 TI - What is the role of nodal ratio as a prognostic factor for gastric cancer nowadays? Comparison with new TNM staging system and analysis according to the number of resected nodes. AB - Nodal ratio (NR) has been demonstrated to be an important prognostic factor in patients with gastric cancer. The aim of this study is to evaluate the prognostic role of nodal ratio comparing it with the new TNM (2010) classification. One hundred forty-two patients were submitted to potentially curative gastrectomy for cancer. Patients with low performance status underwent D1.5 lymphadenectomy, whereas the other patients underwent D2-D2.5 lymphadenectomy. Nodal staging was classified according to 2010 International Union Against Cancer/American Joint Committee on Cancer classification. Kaplan-Meier method was used to evaluate survival, stratified for nodal classes and nodal status. Total gastrectomy was performed in 39 per cent of cases and distal gastrectomy in 61 per cent. Mean number of resected nodes was 25.5. Whereas N status was strictly related to the number of resected nodes, the NR was independent from the extension of the lymphadenectomy. Overall five-year survival was 81 per cent for N0 patients, 72 per cent for N1, and 26 and 23 per cent for N2 and N3, respectively. Patients with NR0 had 81 per cent five-year survival, whereas NR1 67 per cent, NR2 51 per cent, and NR3 22 per cent. NR seems to be a simple method to predict the prognosis of patients with gastric cancer; unlike N status, it is independent from the number of resected nodes, and therefore it is particularly useful in case of inadequate lymphadenectomy. PMID- 23635585 TI - Short-term results of laparoscopic versus open liver resection for liver metastasis from colorectal cancer: a comparative study. AB - Laparoscopic liver resection is currently performed in an increasing number of institutions as a minimally invasive treatment. However, no randomized controlled trials have compared laparoscopic and open liver resections. Twenty-three laparoscopic and 24 open liver resections for colorectal cancer liver metastases (CRCLM) were performed, and these data for both were retrospectively compared in the short-term results. The estimated blood loss was 99 +/- 207 mL in the laparoscopic group and 397 +/- 381 mL in the open group (P = 0.0018); blood loss was significantly higher in the open group. There were no differences in the surgical procedure, blood loss, transfusion rate, pathological margins, postoperative complications, 30-day mortality, duration of intravenous drip, or hospital stay. On postoperative courses, the values of total bilirubin, white blood cell count, and C-reactive protein were significantly lower in the laparoscopic group. The data of the present series suggest the lesser invasiveness and safety of laparoscopic liver resection even for patients with CRCLM, and they showed that postoperative laboratory tests were better after laparoscopy than after the traditional open approach with better short-term results. Tumor diameter less than 5 cm appears to be the appropriate indication for laparoscopic liver resection for CRCLM. PMID- 23635584 TI - Assessment of psychiatric symptoms at a level I trauma center surgery follow-up clinic: a preliminary report. AB - At Level I trauma centers, psychiatric consultation is readily available to inpatient surgical services. This study sought to characterize the psychiatric symptoms present in the surgical follow-up clinic. Patients aged 18 years and older were assessed over one month for symptoms of posttraumatic stress disorder (PTSD) with the Short PTSD Rating Interview (SPRINT), depression with the Patient Health Questionnaire (PHQ-9), alcohol abuse with the Alcohol Use Disorder Identification Test (AUDIT), and the presence of violence using the MacArthur Community Violence Instrument (MCVIa [victimization] MCVIb [perpetration]). Twenty-five individuals participated. Using the SPRINT, 13 (52.0%) met the cutoff for PTSD. For PHQ-9 depression, 11 (44%) were in the moderate to severe range. For AUDIT, five (20.0%) likely had an alcohol problem. Using the MCVI, 15 (60.0%) reported victimization and 12 (48.0%) reported perpetration. Elevated levels of psychiatric symptoms were found in the trauma surgery follow-up clinic. Psychiatric care embedded in this setting may be warranted. PMID- 23635586 TI - Risk factors associated with venous thromboembolism in isolated blunt chest trauma. AB - Isolated chest trauma is not historically considered to be a major risk factor for venous thromboembolism (VTE). After blunt chest trauma, VTE may be underappreciated because pain, immobility, and inadequate prophylaxis as a result of hemorrhage risk may all increase the risk of VTE. This investigation determines the predictors and rate of VTE after isolated blunt chest trauma. A review of patients admitted to a Level I trauma center with chest trauma between 2007 and 2009 was performed. Demographics, injuries, VTE occurrence, prophylaxis, comorbidities, Injury Severity Score, intensive care unit/hospital length of stay, chest tube, and mechanical ventilation use were recorded. VTE rate was compared between those with isolated chest injury and those with chest injury plus extrathoracic injury. Predictors of VTE were determined with regression analysis. Three hundred seventy patients had isolated chest trauma. The incidence of VTE was 5.4 per cent (n = 20). The VTE rate in those with chest injury plus extrathoracic injury was not significantly different, 4.8 per cent (n = 56 of 1140, P = 0.58). Independent risk factors for VTE after isolated chest trauma were aortic injury (P < 0.01, odds ratio [OR], 47.7), mechanical ventilation (P < 0.01; OR, 6.8), more than seven rib fractures (P < 0.01; OR, 6.1), hemothorax (P < 0.05; OR, 3.9), hypercoagulable state (P < 0.05; OR, 6.3), and age older than 65 years (P < 0.05; OR, 1.03). Patients with the risk factors mentioned are at risk for VTE despite only having thoracic injury and might benefit from more aggressive surveillance and prophylaxis. PMID- 23635587 TI - The impact of perioperative glutamine-supplemented parenteral nutrition on outcomes of patients undergoing abdominal surgery: a meta-analysis of randomized clinical trials. AB - The objective of this study was to evaluate the impact of perioperative glutamine supplemented parenteral nutrition (GLN-PN) on clinical outcomes in patients undergoing abdominal surgery. MEDLINE, EMBASE, and the Cochrane Controlled Clinical Trials Register were searched to retrieve the eligible studies. Eligible studies were randomized controlled trials (RCTs) that compared the effect of GLN PN and standard PN on clinical outcomes in patients undergoing abdominal surgery. Clinical outcomes of interest were postoperative mortality, length of hospital stay, morbidity of infectious complication, and cumulative nitrogen balance. Statistical analysis was conducted by RevMan 5.0 software from the Cochrane Collaboration. Sixteen RCTs with 773 patients were included in this meta analysis. The results showed a significant decrease in the infectious complication rates of patients undergoing abdominal surgery receiving GLN-PN (risk ratio [RR], 0.48; 95% confidence interval [CI], 0.32 to 0.72; P = 0.0004). The overall effect indicated glutamine significantly reduced the length of hospital stay in the form of alanyl-glutamine (weighted mean difference [WMD], 3.17; 95% CI, -5.51 to -0.82; P = 0.008) and in the form of glycyl-glutamine (WMD, -3.40; 95% CI, -5.82 to -0.97; P = 0.006). A positive effect in improving postoperative cumulative nitrogen balance was observed between groups (WMD, 7.40; 95% CI, 3.16 to 11.63; P = 0.0006), but no mortality (RR, 1.52; 95% CI, 0.21 to 11.9; P = 0.68). Perioperative GLN-PN is effective and safe to shorten the length of hospital stay, reduce the morbidity of postoperative infectious complications, and improve nitrogen balance in patients undergoing abdominal surgery. PMID- 23635588 TI - Coronary stents and subsequent surgery: reported provider attitudes and practice patterns. AB - Management of antiplatelet therapy in patients with cardiac stents who need subsequent surgery is complex. Current guidelines recommend delaying elective surgery or, if surgery is emergent, proceeding without aspirin cessation. This study assessed provider knowledge, attitudes, and practices for patients with cardiac stents needing subsequent surgery. A national survey was administered to Veterans Administration surgeons, anesthesiologists, and cardiologists. Questions examined guideline awareness and agreement, perceptions of bleeding risk and stent thrombosis, practice patterns for antiplatelet therapy management, and experience with perioperative stent thrombosis. Chi-square tests and generalized estimating equations were used to examine differences in reported practices. Among 295 respondents, guideline awareness (92%) and agreement (93%) were high but higher among cardiologists and anesthesiologists than surgeons. Guideline agreement and personal experience with stent thrombosis were also associated with reported practice patterns. In adjusted models for early surgeries, cardiologists and anesthesiologists were more likely to report continuation of dual therapy as compared with surgeons regardless of stent type (drug-eluting P = 0.03; bare metal P < 0.01). Despite successful guideline adoption, significant variations in practice patterns by provider type were found. Understanding reasons behind the variation and outcomes of various antiplatelet management strategies are important steps in optimizing care of patients with coronary stents undergoing noncardiac surgery. PMID- 23635589 TI - Percutaneous cholecystostomy is a definitive treatment for acute cholecystitis in elderly high-risk patients. AB - Percutaneous cholecystostomy (PC) is an alternative treatment for acute cholecystitis (AC) in elderly patients with high surgical risk and has lower morbidity and mortality than emergency cholecystectomy. There is controversy about whether cholecystectomy should be performed after PC in elderly high-risk patients. Medical records of patients with AC admitted to the Department of Surgery, Jinling Hospital, Nanjing University School of Medicine, China, between January 2004 and July 2009 were reviewed retrospectively. The elderly high-risk patients with AC who underwent PC were selected for further study. The safety, efficacy, and long-term outcome of PC without cholecystectomy were evaluated in these patients. The symptoms of AC resolved in 98.6 per cent of patients; drainage-related morbidity and mortality rates were 4.1 and 1.4 per cent, respectively. No patient underwent cholecystectomy after PC. The recurrence rate of cholecystitis was 4.1 per cent. The one-year survival rate was 82.2 per cent, and the three-year survival rate was 39.7 per cent. No death was related to cholecystitis, but one patient died of septic shock on the second day after PC. Considering limited survival and a low recurrence rate of cholecystitis in elderly high-risk patients with AC, we propose that PC is a definitive treatment and cholecystectomy is not necessary after resolution of AC symptoms. PMID- 23635590 TI - Predicting early cancer-related deaths after curative esophagectomy for esophageal cancer. AB - Esophagectomy is the primary treatment for esophageal cancers, but a few patients still suffer from early recurrence and die within one year after surgery. The aim of this study was to identify preoperative predictive risk factors for early cancer-related deaths after curative esophagectomy for esophageal squamous cell carcinoma. The records of 200 consecutive patients with esophageal cancer who underwent esophagectomy between 1990 and 2009 were retrospectively reviewed. The preoperative clinical characteristics of the remaining 32 patients who died of cancer within one year were compared with those of 168 patients who survived for more than one year postsurgery. The most frequent cause of death was lymph node recurrence followed by local recurrence and lung metastases. A tumor size 60 mm or greater and lymph node metastases in two fields on preoperative imaging were identified as prognostic factors on multivariate analysis. The one-year survival rate and median survival time of patients with both these risk factors were 40 per cent and 12 months, respectively. Aggressive additional treatment may be needed if both a tumor size 60 mm or greater and lymph node metastases in two fields are found during diagnostic imaging before esophagectomy for esophageal squamous cell carcinoma. PMID- 23635591 TI - Synchronous portal-superior mesenteric vein or adjacent organ resection for solid pseudopapillary neoplasms of the pancreas: a single-institution experience. AB - Solid pseudopapillary neoplasms of the pancreas (SPN) have been reported increasingly; however, series focusing on portal-superior mesenteric vein (PV/SMV) or adjacent organ resection are limited in the literature. The aim of this study was to present our experience in treating patients with SPN who underwent this extensive resection. Ten eligible patients were retrospectively reviewed and analyzed. Eight females and two males with a median age of 23 years (range, 11 to 58 years) and a median tumor diameter of 12 cm (range, 4 to 20 cm) were observed. All patients had imaging signs of vascular and/or adjacent organ involvement. Resection with curative intent was performed in all patients; eight underwent synchronous PV/SMV resection and two underwent synchronous left nephrectomy. Malignant SPN was confirmed in seven patients. Postoperative mortality was nil and morbidity occurred in five patients. At a median follow-up of 67.5 months (range, 12 to 110 months), nine patients were alive with no evidence of disease and one died of liver metastases. In conclusion, malignant SPN are low-grade tumors with good prognosis. More aggressive attitude should be adopted when PV/SMV or adjacent organ involvement is indicated on preoperative imaging. En bloc synchronous PV/SMV or adjacent organ resection should be applied, when necessary, to achieve complete resection. PMID- 23635592 TI - Understanding the reasons and significance of low oxygen saturation in the early postoperative period after laparoscopic Roux-en-Y gastric bypass. PMID- 23635593 TI - You like t-ma-tos and I like t-ma-tos: a systematic review on the pronunciation of 'centimeter'. PMID- 23635594 TI - Comparative analysis of gender differences in outcomes after biliopancreatic diversion with duodenal switch: revisiting male gender as a predictor for adverse outcomes in bariatric surgery. PMID- 23635596 TI - Don't touch the sides: a fun and novel system for using Operation((r)) for practicing open and robotic surgical skills. PMID- 23635595 TI - Characteristics and prognoses of small obstructing colorectal cancers: the combination of gross findings has value in predicting recurrence after curative therapy. PMID- 23635597 TI - Full-time orthopedic traumatologists enhance value and increase pelvic fracture caseloads at a rural Level I trauma center. PMID- 23635598 TI - Esophagopericardial fistula: a delayed complication after esophageal stenting. PMID- 23635600 TI - Risk factors for conversion during laparoscopic cholecystectomy: retrospective analysis of ten years' experience at a single tertiary referral centre. AB - BACKGROUND/PURPOSE: Laparoscopic cholecystectomy (LC) is the standard treatment for symptomatic benign gallbladder disease. The identification of factors that reliably predict the need to convert LC to open cholecystectomy (OC) would help with patient education and counseling. METHODS: Between January 2000 and December 2009, 4,698 patients underwent cholecystectomy. LC was attempted in 4,434 patients (94.4%) and OC from the start was performed in 264 patients (5.6%). The causes for conversion were evaluated. The change in conversion rate between 2000 and 2004 and between 2005 and 2009 was analyzed. Factors predictive of conversion were identified by univariate and multivariate analysis. RESULTS: Conversion to OC from an initial LC approach was required in 234 patients (5.3%). The main cause for conversion was dense adhesions (54.7%). Independent risk factors in multivariate analysis were male gender (p < 0.001), increased age (p < 0.001), a history of previous upper abdominal surgery (p < 0.001), a WBC count >9 * 10(3)/MUl, and urgently indicated cholecystectomy (p <0.001). The conversion rate decreased significantly from 6.7 to 3.6% over the two time intervals (p < 0.001). CONCLUSIONS: Those at highest risk for conversion are elderly male patients with prior abdominal surgery who present emergently with laboratory evidence of biliary inflammation. PMID- 23635599 TI - Effects of spatial-memory decay and dual-task interference on perturbation-evoked reach-to-grasp reactions in the absence of online visual feedback. AB - Recent findings suggest that rapid perturbation-evoked reach-to-grasp balance recovery reactions can be (and often are) guided by visuospatial information stored in working memory. To further our understanding, the present study examined the influence of memory-decay and concurrent cognitive-task performance on the speed, accuracy and effectiveness of these reactions by using liquid crystal goggles to initiate occlusion of vision at various "recall-delay" times prior to perturbation-onset, in ten healthy young-adults. A small handhold was moved unpredictably to one of four locations 2s prior to vision-occlusion; reactions to recover balance by grasping the handhold were evoked by unpredictable antero-posterior platform-translation perturbations. Recall-delay time (0s/2s/5s/10s) was randomized, and subjects performed a spatial- or non spatial-memory task during the delay-time in a subset of trials. Consistent with studies of volitional reach-to-grasp, recall-delay led to some reduction in endpoint accuracy; however, unlike those studies, the present results showed no evidence that recall-delay led to slowing of the arm movement. Both spatial and non-spatial cognitive tasks had similar effects (slowing of movement initiation and execution), suggesting these effects were related to generic attentional demands rather than competition for specific resources related to spatial working memory. Further work is needed to determine effects of age-related impairments in visuospatial memory and attentional capacity. PMID- 23635602 TI - Transplantation of human fetal tissue for neurodegenerative diseases: validation of a new protocol for microbiological analysis and bacterial decontamination. AB - Restorative cell therapy concepts in neurodegenerative diseases are aimed at replacing lost neurons. Despite advances in research on pluripotent stem cells, fetal tissue from routine elective abortions is still regarded as the only safe cell source. Progenitor cells isolated from distinct first-trimester fetal CNS regions have already been used in clinical trials and will be used again in a new multicenter trial funded by the European Union (TRANSEURO). Bacterial contamination of human fetal tissue poses a potential risk of causing infections in the brain of the recipient. Thus, effective methods of microbial decontamination and validation of these methods are required prior to approval of a neurorestorative cell therapy trial. We have developed a protocol consisting of subsequent washing steps at different stages of tissue processing. Efficacy of microbial decontamination was assessed on rat embryonic tissue incubated with high concentrations of defined microbe solutions including representative bacterial and fungal species. Experimental microbial contamination was reduced by several log ranks. Subsequently, we have analyzed the spectrum of microbial contamination and the effect of subsequent washing steps on aborted human fetal tissue; 47.7% of the samples taken during human fetal tissue processing were positive for a microbial contamination, but after washing, no sample exhibited bacterial growth. Our data suggest that human fetal tissue for neural repair can carry microbes of various species, highlighting the need for decontamination procedures. The decontamination protocol described in this report has been shown to be effective as no microbes could be detected at the end of the procedure. PMID- 23635603 TI - Validity and reliability of the PDCB: a tool for the assessment of caregiver burden in Parkinson's disease. AB - BACKGROUND: Existing instruments for caregiver burden assessment are not specific or sensitive to various aspects of caring for patients with Parkinson's disease. A better understanding of burden may enhance patient care and improve health of both patient and caregiver. The goal of this study was to evaluate the validity of the Parkinson's Disease Caregiver Burden (PDCB) questionnaire, a novel instrument designed to appraise more accurately the burden experienced by caregivers in the setting of Parkinson's disease. METHODS: Common sources of distress for caregivers were taken from discussions with Parkinson's disease patients, caregivers, and clinicians, and used as the foundation of the PDCB questionnaire items. Fifty patients and their respective caregivers were recruited from three specialist movement disorder clinics. Caregiver burden in the sample was gauged with the PDCB scale and the Caregiver Burden Inventory (CBI). Item sensitivity and questionnaire validity were assessed. RESULTS: In this pilot analysis, the PDCB questionnaire was found to be feasible and reliable. Strong correlations were found between the PDCB questionnaire and the CBI. The PDCB questionnaire contained more relevant items for this population compared with the CBI. CONCLUSION: Strong initial feasibility, reliability, validity, and sensitivity for the PDCB questionnaire were demonstrated. With further evaluation and development, the PDCB questionnaire may prove to be a valuable supplementary tool to the existing CBI or a standalone instrument for use in the setting of Parkinson's disease. PMID- 23635601 TI - Implementation and management of a biomedical observation dictionary in a large healthcare information system. AB - OBJECTIVE: This study shows the evolution of a biomedical observation dictionary within the Assistance Publique Hopitaux Paris (AP-HP), the largest European university hospital group. The different steps are detailed as follows: the dictionary creation, the mapping to logical observation identifier names and codes (LOINC), the integration into a multiterminological management platform and, finally, the implementation in the health information system. METHODS: AP-HP decided to create a biomedical observation dictionary named AnaBio, to map it to LOINC and to maintain the mapping. A management platform based on methods used for knowledge engineering has been put in place. It aims at integrating AnaBio within the health information system and improving both the quality and stability of the dictionary. RESULTS: This new management platform is now active in AP-HP. The AnaBio dictionary is shared by 120 laboratories and currently includes 50 000 codes. The mapping implementation to LOINC reaches 40% of the AnaBio entries and uses 26% of LOINC records. The results of our work validate the choice made to develop a local dictionary aligned with LOINC. DISCUSSION AND CONCLUSIONS: This work constitutes a first step towards a wider use of the platform. The next step will support the entire biomedical production chain, from the clinician prescription, through laboratory tests tracking in the laboratory information system to the communication of results and the use for decision support and biomedical research. In addition, the increase in the mapping implementation to LOINC ensures the interoperability allowing communication with other international health institutions. PMID- 23635606 TI - Time to say goodbye to minocycline? PMID- 23635605 TI - RNA pentaloop structures as effective targets of regulators belonging to the RsmA/CsrA protein family. AB - In the Gac/Rsm signal transduction pathway of Pseudomonas fluorescens CHA0, the dimeric RNA-binding proteins RsmA and RsmE, which belong to the vast bacterial RsmA/CsrA family, effectively repress translation of target mRNAs containing a typical recognition sequence near the translation start site. Three small RNAs (RsmX, RsmY, RsmZ) with clustered recognition sequences can sequester RsmA and RsmE and thereby relieve translational repression. According to a previously established structural model, the RsmE protein makes optimal contacts with an RNA sequence 5'- (A)/(U)CANGGANG(U)/(A)-3', in which the central ribonucleotides form a hexaloop. Here, we questioned the relevance of the hexaloop structure in target RNAs. We found that two predicted pentaloop structures, AGGGA (in pltA mRNA encoding a pyoluteorin biosynthetic enzyme) and AAGGA (in mutated pltA mRNA), allowed effective interaction with the RsmE protein in vivo. By contrast, ACGGA and AUGGA were poor targets. Isothermal titration calorimetry measurements confirmed the strong binding of RsmE to the AGGGA pentaloop structure in an RNA oligomer. Modeling studies highlighted the crucial role of the second ribonucleotide in the loop structure. In conclusion, a refined structural model of RsmE-RNA interaction accommodates certain pentaloop RNAs among the preferred hexaloop RNAs. PMID- 23635604 TI - Mineralocorticoid receptor blockade reduced oxidative stress in renal transplant recipients: a double-blind, randomized pilot study. AB - BACKGROUND: Previous experimental studies from our laboratory have demonstrated that aldosterone plays a central role in renal ischemic processes. This study was designed to evaluate the effect of mineralocorticoid receptor blockade in renal transplant recipients from living donors. METHODS: 20 adult kidney transplant recipients from living donors were included in a double-blind, randomized, placebo-controlled clinical pilot study that compared spironolactone and placebo. Placebo or spironolactone (25 mg) was administered 1 day before and 3 days posttransplantation. Renal function and urinary kidney injury molecule-1, interleukin-18, and heat shock protein 72 as well as urinary hydrogen peroxide (H2O2) levels were quantified. RESULTS: No significant differences were seen between the groups studied regarding age, gender, indication for kidney transplantation, residual renal function, renal replacement therapy, or warm and cold ischemia periods. In contrast, spironolactone administration significantly reduced the oxidative stress assessed by the urinary H2O2 excretion, in spite of no differences in renal function or reduction in tubular injury biomarkers. CONCLUSIONS: The findings of this exploratory study strongly suggest that aldosterone promotes oxidative stress and that the administration of spironolactone reduces the production of urinary H2O2 as a result of lesser formation of surrogate reactive oxygen species secondary to the ischemia reperfusion phenomenon. PMID- 23635608 TI - Anaesthetic considerations for endoscopic retrograde cholangio-pancreatography procedures. AB - PURPOSE OF REVIEW: The purpose of this review is to evaluate the current literature on the use of general anaesthesia and propofol deep sedation for patients undergoing endoscopic retrograde cholangio-pancreatography (ERCP) procedures. Propofol is primarily an anaesthetic agent, but its use in a sedative capacity has resulted in the extensive off-label administration of this drug by gastroenterologists and other nonanaesthesia personnel. This has created controversy and enabled the gastroenterology community to gather evidence and campaign for US Food and Drug Administration approval to administer propofol to patients undergoing ERCP and other endoscopic procedures. RECENT FINDINGS: General anaesthesia appears to be a well tolerated technique for patients undergoing ERCP procedures, although there is a scarcity of publications in this field. The available evidence from prospective and retrospective cohort studies suggests a low incidence of serious outcomes (from sedation-related incidents) in patients undergoing ERCP procedures under propofol deep sedation. However, data from the American Society of Anesthesiologists closed claims analysis report suggests that endoscopy procedures performed under monitored anaesthetic care using propofol as a sedative agent can result in serious patient harm. SUMMARY: Deep sedation with propofol, administered by anaesthesia personnel, can be used as an alternative to general anaesthesia for a select group of patients undergoing ERCP procedures. Further research is necessary to clarify the nature and parameters of deep sedation. PMID- 23635609 TI - Influenza vaccine: a safe bet for mother and baby. PMID- 23635610 TI - Intraperitoneal carbon dioxide after laparoscopy: are two interventions better than one? PMID- 23635607 TI - A hypnic hypothesis of Alzheimer's disease. AB - BACKGROUND: Understanding the pathophysiology of Alzheimer's disease (AD) is of fundamental importance for improved diagnosis, monitoring and ultimately, treatment. OBJECTIVE: A role for the sleep-wake cycle in the pathogenesis of AD has been proposed, but remains to be worked out in detail. METHODS: Here we draw together several lines of previous work to outline a 'hypnic hypothesis' of AD. RESULTS: We propose that altered function of brainstem neurotransmitter pathways associated with sleep, promotes regionally specific disintegration of a cortico subcortical 'default mode' brain network that is selectively vulnerable in AD. CONCLUSION: The formation of a dynamic toxic state within this vulnerable network linked to sleep-wake disruption, would in turn lead to failure of synaptic repair, increased transmission of pathogenic misfolded proteins and a self amplifying neurodegenerative process. We consider the evidence for this hypnic hypothesis and the implications that follow on from it. PMID- 23635611 TI - Quality measurement: what it means for obstetricians and gynecologists. PMID- 23635612 TI - Safety of the pandemic H1N1 influenza vaccine among pregnant U.S. military women and their newborns. AB - OBJECTIVES: To assess adverse pregnancy outcomes among active-duty U.S. military women who received pandemic H1N1 vaccine during pregnancy as well as adverse health outcomes among the newborns resulting from these pregnancies. METHODS: The primary study population was a retrospective cohort of active-duty U.S. military women vaccinated during pregnancy with either the pandemic H1N1 vaccine between October 2009 and June 2010 or with seasonal influenza vaccine between October 2008 and June 2009. Rates of pregnancy loss, preeclampsia or eclampsia, and preterm labor were compared between pandemic H1N1 vaccine-exposed (n=10,376) and seasonal influenza vaccine-exposed pregnancies (n=7,560). A secondary study population consisted of newborns resulting from these pregnancies. Rates of preterm birth, birth defects, fetal growth problems, and the male-to-female sex ratio were compared between newborns exposed to pandemic H1N1 vaccine and newborns exposed to seasonal influenza vaccine in utero. RESULTS: No significant differences were observed in rates of pregnancy loss (6.4% compared with 6.5%), preeclampsia or eclampsia (5.8% compared with 5.2%), or preterm labor (6.5% compared with 6.2%) between pandemic H1N1 vaccine-exposed and seasonal influenza vaccine-exposed pregnancies. Furthermore, no significant differences were observed in rates of preterm birth (6.2% compared with 6.3%), birth defects (2.1% compared with 2.0%), fetal growth problems (2.6% compared with 2.4%), or the male to-female sex ratio (1.05 compared with 1.07) between newborns exposed in utero to pandemic H1N1 vaccine compared with seasonal influenza vaccine. Rates of all outcomes were lower or similar to overall general population rates. This study had at least 80% power to detect hazard ratios of 1.18-1.21 or odds ratios of 1.10-1.36, depending on outcome prevalence. CONCLUSION: No adverse pregnancy or newborn health outcomes associated with pandemic H1N1 vaccination during pregnancy were noted among our cohort. These findings should be used to encourage increased vaccine coverage among pregnant women. PMID- 23635613 TI - Maternal safety of trivalent inactivated influenza vaccine in pregnant women. AB - OBJECTIVE: To estimate the risks for medically attended events occurring within 42 days of receiving trivalent inactivated influenza vaccine and to evaluate specific risks of first-trimester vaccination. METHODS: This retrospective observational cohort study compared rates of medically attended adverse events in trivalent inactivated influenza-vaccinated and unvaccinated pregnant women in the Vaccine Safety Datalink. Using a Poisson distribution and log link, we calculated maternal adjusted incident rate ratios for composite safety outcomes for the full cohort and the subset vaccinated during the first trimester. RESULTS: The cohort included 75,906 vaccinated (28.4% in the first trimester) and 147,992 unvaccinated women matched by age, site, and pregnancy start date. In the first 3 days after vaccination, trivalent inactivated influenza vaccine was not associated with increased risk of specified medically attended events, including allergic reactions, cellulitis, and seizures (full cohort adjusted incident rate ratio 1.12, 95% confidence interval [CI] 0.81-1.55; P=.48; first-trimester adjusted incident rate ratio .97, 95% CI 0.53-1.78; P=.93). In the first 42 days, no incident cases of Guillain-Barre syndrome, optic neuritis, transverse myelitis, or Bells palsy were identified. Trivalent inactivated influenza vaccine was not associated with thrombocytopenia (full cohort adjusted incident rate ratio 0.90, 95% CI 0.68--1.19; P=.45; first-trimester adjusted incident rate ratio 0.56, 95% CI 0.22-1.39; P=.21) or an acute neurologic event (full cohort adjusted incident rate ratio 0.92, 95% CI 0.54-1.6; P=.75; first-trimester adjusted incident rate ratio 1.05, 95% CI 0.46-2.38; P=.91). CONCLUSIONS: Receipt of trivalent inactivated influenza vaccine during pregnancy was not associated with increased risk of adverse events in the 42 days after vaccination, supporting its safety for the mother. PMID- 23635614 TI - Prevention of postlaparoscopic shoulder and upper abdominal pain: a randomized controlled trial. AB - OBJECTIVES: To estimate the effectiveness of combined intervention with the pulmonary recruitment maneuver and intraperitoneal normal saline infusion to reduce postlaparoscopic shoulder and upper abdominal pain. METHODS: Patients were randomly assigned to undergo the combined intervention (n=50) or to a control group (n=50). Postlaparoscopic shoulder pain and upper abdominal pain were evaluated at 12, 24, and 48 hours postoperatively. RESULTS: At 12, 24, and 48 hours, the incidence of laparoscopic-induced shoulder pain was lower in the intervention group (54%, 46%, and 30%, respectively) than in the control group (72%, 70%, and 50%, respectively; P=.008, P=.001, and P=.004, respectively). The number needed to treat for benefit to reduce shoulder pain incidence was six (95% confidence interval [CI], 4-21) at 12 hours, five (95% CI, 3-10) at 24 hours, and five (95% CI, 4-15) at 48 hours. The incidence of laparoscopic-induced upper abdominal pain also was lower in the intervention group (78%, 72%, and 58%, respectively) than in the control group (92%, 90%, and 70%, respectively) at 12, 24, and 48 hours postoperatively (P=.006, P=.001, and P=.077, respectively). The number needed to treat for benefit to reduce upper abdominal pain incidence was eight (95% CI, 5-24) at 12 hours and six (95% CI, 4-14) at 24 hours. CONCLUSIONS: Combined intervention with the pulmonary recruitment maneuver and intraperitoneal normal saline infusion is easy to implement in daily clinical practice to significantly reduce postlaparoscopic shoulder and upper abdominal pain. PMID- 23635615 TI - Ambulation of hospitalized gynecologic surgical patients: a randomized controlled trial. AB - OBJECTIVE: To estimate whether specific ambulation goals affect the adequacy or perceived barriers to ambulation in hospitalized surgical patients after major gynecologic surgery. METHODS: One hundred forty-six surgical inpatients were randomized to specific ambulation goals or routine care. We assessed the number of pedometer-recorded steps in the 24 hours preceding discharge as well as patient-identified barriers to ambulation. Groups were compared using the Mann Whitney U test. RESULTS: Of the 129 participants with outcome data, 12% were discharged without any pedometer-recorded steps. We did not detect an effect of specific ambulation goals by group (routine care: 87 compared with ambulation goals: 80, P=.7). The three main barriers to ambulation from a patient perspective were indwelling catheters (38.5%), intravenous poles (28%), and pain (12.5%) The median number of postoperative steps was higher after minimally invasive surgery (143) compared with laparotomy (27) (P=.035). CONCLUSION: Approximately 12% of gynecologic surgical patients do not walk while hospitalized despite formal encouragement to ambulate. Ambulation is easily quantified and may improve with attention to modifiable barriers, potentially improving postoperative recovery. PMID- 23635616 TI - Surgical and patient outcomes using mechanical bowel preparation before laparoscopic gynecologic surgery: a randomized controlled trial. AB - OBJECTIVE: Mechanical bowel preparation is a common practice before laparoscopic gynecologic surgery. This study aims to evaluate its capacity to improve surgical view and bowel handling in the deep pelvis. METHODS: A single-blinded, randomized, controlled trial was undertaken with laparoscopic gynecologic surgical patients assigned to one of the following three groups: fasting only; minimal residue diet for 2 days; or minimal residue diet for 2 days plus mechanical bowel preparation with oral sodium picosulphate. Outcomes included intraoperative surgical view and bowel handling, preoperative patient symptomatology, hematologic and biochemical characteristics, and bowel function. RESULTS: Three hundred eight participants were randomized. The intraoperative surgical view and bowel handling was minimally but statistically better in the minimal residue plus mechanical bowel preparation group compared with the other groups with less than a 1-point difference on a 10-point visual analog scale (P<.01 and P<.04, respectively). Women were assessed at baseline and on the day of surgery for the difference in visual analog scale score in the fasting only, minimal residue diet, and minimal residue diet with mechanical bowel preparation groups for headache (2.2 compared with 10.5 compared with 21; P<.01), thirst (14.7 compared with 24.7 compared with 30.9; P<.01), weakness (-0.2 compared with 16.6 compared with 25; P<.01), tiredness (-4.5 compared with 8.1 compared with 15.4; P<.01), anxiety (12.5 compared with 10.1 compared with 10.3; P=.66), and discomfort (-8.2 compared with 8.7 compared with 6.6; P<.01), respectively. Hematologic parameters were not different among the groups, and there was no significant difference in bowel function between the groups. CONCLUSION: Minimal residue diet plus mechanical bowel preparation provides statistical improvement in surgical view and bowel handling, but the benefit is likely of little clinical significance given overall blinded ratings from surgeons. Given the significant symptoms and discomfort caused for patients undertaking minimal residue diet with or without mechanical bowel preparation, fasting only without any preoperative diet or bowel preparation is a preferable alternative for laparoscopic gynecologic surgery involving the posterior pelvic compartment. PMID- 23635617 TI - Postoperative pain and recovery after conventional laparoscopy compared with robotically assisted laparoscopy. AB - OBJECTIVE: To compare postoperative pain after conventional laparoscopic and robotically assisted laparoscopic surgery in gynecology. METHODS: This is a prospective nonrandomized analysis of patients undergoing conventional laparoscopy or robotically assisted laparoscopy in a university-affiliated hospital between March 2011 and March 2012. Postoperative pain was measured using the Numeric Rating Scale and the narcotic use converted to morphine sulfate equivalents. The primary outcome was the Numeric Rating Scale pain score obtained on the first postoperative day. RESULTS: One hundred ten patients were enrolled; 91 were included in the statistical analysis. Both groups were similar with regard to race, history of abdominopelvic surgeries, psychiatric history, and substance abuse. Patients undergoing robotically assisted laparoscopy were 6 years older and had a body mass index 6 points higher. Median length of hospital stay for conventional laparoscopy and robotically assisted laparoscopy was 2 days and 3 days, respectively (P<.001); median to being off narcotics was 4 days and 4.5 days, respectively (P=.336); and median return to normal activities was 13 days and 21 days, respectively (P=.021). There were no significant differences in mean Numeric Rating Scale pain scores over time (P=.499) or mean narcotic requirements (P=.393) between groups. CONCLUSION: Robotically assisted laparoscopy is equivalent to conventional laparoscopy in terms of subjective and objective measures of postoperative pain. PMID- 23635618 TI - Vaginal prolapse recurrence after uterosacral ligament suspension in normal weight compared with overweight and obese women. AB - OBJECTIVE: To compare recurrent prolapse after vaginal uterosacral ligament suspension in normal-weight compared with overweight or obese women. METHODS: We performed a retrospective cohort study of the risk of recurrent prolapse after uterosacral ligament suspension in normal-weight compared with overweight or obese women at our institution from December 1, 1996, through June 30, 2011. Women with fewer than 6 months of follow-up and those with a prior vault suspension were excluded. Our primary outcome was a composite measure defined as anterior, posterior, or apical prolapse recurrence extending beyond the hymen or repeat treatment for prolapse with surgery or a pessary in women undergoing uterosacral ligament suspension and other vaginal repairs. RESULTS: We included 219 participants (81 [37%] normal-weight and 138 [63%] overweight or obese women). There was no difference in median follow-up (14 months; interquartile range 8.5-26.5 months] in the normal-weight compared with 13 months [interquartile range 9.0-29.0 months] in the overweight or obese women, P=.98). Prolapse recurred in 22.2% (n=18) of the normal-weight group and 26.1% (n=36) of the overweight or obese group (P=.52). Surgery for recurrent prolapse was performed in 16.0% (n=13) of the normal-weight women and in 14.5% (n=20) of the overweight or obese women (P=.76). The most common site of recurrence was the anterior compartment (17.4% [n=38]) compared with the apical compartment (8.7% [n=19]) or posterior compartment (6.8% [n=15]) with no significant difference between cohorts. CONCLUSIONS: After uterosacral ligament suspension, overweight or obese women have similar prolapse recurrence compared with normal-weight women. Anterior prolapse is the most common site of recurrence after uterosacral ligament suspension. PMID- 23635620 TI - Effectiveness of intrapartum antibiotic prophylaxis for prevention of early-onset group B streptococcal disease. AB - OBJECTIVE: To estimate the effectiveness against early-onset group B streptococcal (GBS) disease of intrapartum antibiotic prophylaxis among term and preterm deliveries, deliveries with fewer than 4 hours of antibiotics, and deliveries receiving clindamycin regimens. METHODS: We performed a secondary analysis of the Birthnet cohort, a survey of 7,691 births to residents of the Active Bacterial Core surveillance system from 2003 to 2004. We used propensity score matching on covariates associated with prophylaxis and early-onset GBS disease to evaluate the effectiveness (1-risk ratio) of specific intrapartum antibiotic prophylaxis regimens against the disease end point. RESULTS: The effectiveness of 4 or more hours of prophylaxis with penicillin or ampicillin was high among term (91%, 95% confidence interval [CI] +63% to +98%) and preterm (86%, 95% CI +38% to +97%) neonates. Effectiveness was significantly lower for clindamycin (22%, 95% CI -53% to +60%). The effectiveness of 2 or fewer to fewer than 4 hours of prophylaxis with penicillin or ampicillin before delivery (47%, 95% CI -16% to +76%) and the effectiveness of prophylaxis with penicillin or ampicillin fewer than 2 hours before delivery (38%, 95% CI -17% to +67%) were both lower than the effectiveness of prophylaxis durations at 4 or more hours. CONCLUSION: Beta-lactam prophylaxis given 4 or more hours before delivery is highly effective for prevention of early-onset GBS disease. Prophylaxis of shorter durations or with clindamycin is less effective, reinforcing the need for health care providers to adhere to prevention recommendations, particularly for preterm deliveries, penicillin-allergic women, and neonates exposed to fewer than 4 hours of prophylaxis. PMID- 23635619 TI - Timing of delivery and adverse outcomes in term singleton repeat cesarean deliveries. AB - OBJECTIVE: To compare the maternal and neonatal risks of elective repeat cesarean delivery compared with pregnancy continuation at different gestational ages, starting from 37 weeks. METHODS: We analyzed the composite maternal and neonatal outcomes of repeat cesarean deliveries studied prospectively over 4 years at 19 U.S. centers. Maternal outcome was a composite of pulmonary edema, cesarean hysterectomy, pelvic abscess, thromboembolism, pneumonia, transfusion, or death. Composite neonatal outcome consisted of respiratory distress, transient tachypnea, necrotizing enterocolitis, sepsis, ventilation, seizure, hypoxic ischemic encephalopathy, neonatal intensive care unit admission, 5-minute Apgar of 3 or lower, or death. Outcomes after elective repeat cesarean delivery without labor at each specific gestational age were compared with outcomes for all who were delivered later as a result of labor onset, specific obstetric indications, or both. RESULTS: Twenty-three thousand seven hundred ninety-four repeat cesarean deliveries were included. Elective delivery at 37 weeks of gestation had significantly higher risks of adverse maternal outcome (odds ratio [OR] 1.56, 95% confidence interval [CI] 1.06-2.31), whereas elective delivery at 39 weeks of gestation was associated with better maternal outcome when compared with pregnancy continuation (OR 0.51, 95% CI 0.36-0.72). Elective repeat cesarean deliveries at 37 and 38 weeks of gestation had significantly higher risks of adverse neonatal outcome (37 weeks OR 2.02, 95% CI 1.73-2.36; 38 weeks OR 1.39 95% CI 1.24-1.56), whereas delivery at 39 and 40 weeks of gestation presented better neonatal outcome as opposed to pregnancy continuation (39 weeks OR 0.79, 95% CI 0.68-0.92; 40 weeks OR 0.57, 95% CI 0.43-0.75). CONCLUSION: In women with prior cesarean delivery, 39 weeks of gestation is the optimal time for repeat cesarean delivery for both mother and neonate. PMID- 23635622 TI - Contraceptive failures in overweight and obese combined hormonal contraceptive users. AB - OBJECTIVE: To estimate weather contraceptive failure rates among combined oral contraceptive pill (OCP), patch, and vaginal ring users was associated with increasing body mass index (BMI). METHODS: Females enrolled in a large contraceptive study offering the reversible method of their choice at no cost were followed-up for 2-3 years. We compared the failure rates (pregnancy) among users of the OCP, transdermal patch, and contraceptive vaginal ring stratified by BMI. RESULTS: Among the 7,486 participants available for this analysis, 1,523 chose OCPs, patch, or ring at enrollment. Of the 334 unintended pregnancies, 128 were found to be a result of OCP, patch, or ring failure. Three-year failure rates were not different across BMI categories (BMI less than 25 8.44%, 95% confidence interval [CI] 6.1-11.5; BMI 25-30 11.03%, 95% CI 7.5-16.0; BMI more than 30 8.92%, 95% confidence interval 7.6-11.5). Increasing parity (hazard ratio [HR] 3.06, CI 1.31-7.18) and history of a previous unintended pregnancy (HR 2.82, CI 1.63-4.87), but not BMI, were significant risk factors for unintended pregnancy. CONCLUSION: Overweight and obese females do not appear to be at increased risk for contraceptive failure when using the OCP, patch, or vaginal ring. PMID- 23635621 TI - Effect of validated skills simulation on operating room performance in obstetrics and gynecology residents: a randomized controlled trial. AB - OBJECTIVES: To estimate whether training on previously validated laparoscopic skill stations translates into improved technical performance in the operating room. METHODS: We performed a multicenter, randomized, controlled trial evaluating the performance of a laparoscopic bilateral midsegment salpingectomy. Residents were randomized to either traditional teaching (no simulation) or faculty-directed sessions in a simulation laboratory. A sample size of at least 44 lower-level residents (postgraduate year [PGY] 1 or 2) and 66 upper-level (PGY 3 or 4) were necessary to demonstrate a 50% improvement in performance assuming an alpha error of 0.05 and beta error of 0.20 for each group independently. The primary outcomes were the final total normalized simulation score and the operating room performance score. Paired t test and Wilcoxon rank-sum tests were used to evaluate the differences within and between cohorts. Our final model involved a multiple linear regression analysis for the main effects of a priori- specified variables. RESULTS: We enrolled 116 residents from eight centers across the United States. There was no statistically significant difference in baseline simulation or operative performances. Although both groups demonstrated improvement with time, the trained group improved significantly higher normalized simulation scores (378 +/- 54 compared with 264 +/- 86; P<.01) and higher levels of competence on the simulated tasks (96.2% compared with 61.1%; P<.01). The simulation group also had higher objective structured assessment of technical skills scores in the operating room (27.5 compared with 30.0; P=.03). CONCLUSION: We found that proficiency-based simulation offers additional benefit to traditional education for all levels of residents. The use of easily accessible, low-fidelity tasks should be incorporated into formal laparoscopic training. PMID- 23635623 TI - Use of depot medroxyprogesterone acetate contraception and incidence of bone fracture. AB - OBJECTIVE: Depot medroxyprogesterone acetate (DMPA) reversibly reduces bone mineral density. To estimate the extent to which DMPA might increase fracture risk, we undertook a retrospective cohort study of fractures in DMPA users and users of non-DMPA contraceptives, using the General Practice Research Database. METHODS: Eligible women were aged younger than 50 years at the qualifying first contraceptive prescription. The DMPA users were classified by DMPA exposure (cumulative and time of last dose) based on prescription records. All incident fractures were included; fracture incidence and risk factors before starting contraceptive use (DMPA or other) also were estimated. RESULTS: We identified 11,822 fractures in 312,395 women during 1,722,356 person-years of follow-up. Before contraceptive use started, DMPA users had higher fracture risk than nonusers (incidence rate ratio 1.28, 95% confidence interval [CI] 1.07-1.53). After DMPA started, crude fracture incidence was 9.1 per 1,000 person-years for DMPA users and 7.3 for nonusers (crude incidence rate ratio 1.23, 95% CI 1.16 1.30). Fracture risk in DMPA users did not increase after starting DMPA (incidence rate ratio after or before 1.08, 95% CI 0.92-1.26). There was little confounding by age or other factors that could be measured. Fracture incidence was 9.4 per 1,000 person-years in low-exposure DMPA users, and 7.8 per 1,000 in high-exposure DMPA users. The DMPA users had higher fracture risk than nonusers at the start of contraceptive use, with no discernible induction period. CONCLUSION: Although DMPA users experienced more fractures than nonusers, this association may be the result of confounding by a pre-existing higher risk for fractures in women who chose DMPA for contraception. PMID- 23635624 TI - Prevalence and associated factors of female sexual dysfunction in women with endometriosis. AB - OBJECTIVE: The issue of female sexual function is often overlooked in women with endometriosis, especially in mainland China. The objectives of this study were to estimate the prevalence and associated factors of female sexual dysfunction in endometriosis in China. METHODS: This cross-sectional study was conducted at a referral university hospital in Beijing, Peoples Republic of China from July 2011 to April 2012. Women were recruited among inpatients scheduled for laparoscopic surgery based on signs and symptoms suggestive of endometriosis. Before laparoscopy, a semi-structured questionnaire was used to collect demographic data and disease characteristics. The simplified Chinese version of the Female Sexual Function Index was used to assess sexual function. RESULTS: A total of 111 consecutive women with histologically confirmed endometriosis were enrolled in this study. The prevalence of female sexual dysfunction was 73% for those with endometriosis. Univariable analysis identified three potential predictors of female sexual dysfunction: pelvic pain intensity; deep infiltrating endometriosis status; and revised American Society for Reproductive Medicine stages. Multivariable analysis showed that moderate-to-severe pelvic pain (adjusted odds ratio [OR] 3.4, 95% confidence interval [CI] 1.3-8.8) and revised American Society for Reproductive Medicine stage III or IV (adjusted OR 4.4, 95% CI 1.3 15.5) were associated with increased risk of having female sexual dysfunction. CONCLUSION: Female sexual dysfunction is common in women with endometriosis, especially for those with severe pelvic pain and advanced stages of endometriosis. PMID- 23635625 TI - Medical abortion follow-up with serum human chorionic gonadotropin compared with ultrasonography: a randomized controlled trial. AB - OBJECTIVE: To estimate whether follow-up with serum human chorionic gonadotropin (hCG) results in fewer unplanned visits and interventions than follow-up with ultrasonography. METHODS: Women were randomized to either in-clinic serum hCG or ultrasound follow-up after medical abortion. The primary outcome, unplanned interventions and visits, was measured as a composite binary outcome including: additional clinic or emergency room visits, repeat dosing of misoprostol, and surgical evacuation of the uterus. Surveys were administered at initial follow-up and again 1 month after abortion to inquire about unscheduled visits, interventions, and patient satisfaction. Medical records were reviewed for evidence of additional interventions and visits. RESULTS: A total of 376 patients was randomized. Most participants were white (56%), single (83%), nulliparous (63%), and had completed high school (96%). Average participant age was 26+/-6 years and average gestational age was 46+/-6 days. Within 2 weeks of abortion, there was no significant difference in the rate of unplanned interventions and visits between arms, 8.2% (13/159) in the serum hCG arm compared with 6.6% (10/151) in the ultrasound arm (relative risk 1.23, 95% confidence interval [CI] 0.56-2.73, P=.60). By 4 weeks postabortion, 4.4% (6/135) in the ultrasound arm and 1.4% (2/142) in the hCG arm had undergone surgical evacuation (relative risk 0.32, 95% CI 0.07-1.54, P=.16). The majority in both the serum hCG (88%) and ultrasound (95%) arms was satisfied with their assigned follow-up method. CONCLUSION: Medical abortion follow-up with serum hCG does not reduce the rate of unplanned interventions and visits compared with ultrasonography. Overall, the number of unplanned interventions is low and both methods of follow-up are acceptable to women. PMID- 23635626 TI - Antiemetics added to phenylephrine infusion during cesarean delivery: a randomized controlled trial. AB - OBJECTIVE: To estimate whether the addition of metoclopramide or its combination with ondansetron to a prophylactic phenylephrine infusion provides improved intraoperative nausea and vomiting prophylaxis compared with phenylephrine infusion alone. METHODS: Women scheduled for elective cesarean delivery were randomized to one of three groups: placebo (placebo plus placebo); metoclopramide (metoclopramide 10 mg plus placebo); or combination (metoclopramide 10 mg plus ondansetron 4 mg). The first study drug was administered before spinal placement and the second was administered after cord clamping. Spinal anesthesia was standardized. The primary outcome was intraoperative nausea and vomiting. RESULTS: Three-hundred patients completed the study in two centers. Intraoperative nausea and vomiting occurred in 49%, 31%, and 23% of patients in the placebo, metoclopramide, and combination groups, respectively (P<.001). There was a significant difference between the two centers in exteriorization of the uterus (93% compared with 39%; P<.001) and intraoperative nausea and vomiting rates (47% compared with 20%; P<.001). In a multivariable model adjusting for center, exteriorization of the uterus, age, and hypotension, intraoperative nausea and vomiting were significantly lower in the metoclopramide and combination groups compared with placebo (odds ratio [OR] 2.34, 95% confidence interval [CI] 1.24--4.42; P=.001 and OR 4.06, 95% CI 2.06--7.97; P<.001, respectively). Postoperative nausea and vomiting were reduced with the combination compared with placebo at 2 hours (39% compared with 20%; P<.017), but not at 2-6 hours or at 6-24 hours. CONCLUSION: Metoclopramide with ondansetron reduced intraoperative nausea and vomiting and early postoperative nausea and vomiting compared with placebo. Metoclopramide alone also decreased intraoperative but not postoperative nausea and vomiting. Surgical factors contributed to a significant difference in intraoperative nausea and vomiting between the two centers. PMID- 23635627 TI - Validity of the colposcopic criteria inner border sign, ridge sign, and rag sign for detection of high-grade cervical intraepithelial neoplasia. AB - OBJECTIVE: To evaluate the association of three pathognomonic criteria, inner border, ridge sign, and rag sign with high-grade cervical intraepithelial neoplasia (CIN) using video exoscopy. METHODS: Retrospective evaluation of video recordings of 335 patients, referred for diagnostic colposcopy, who underwent cervical biopsies, and, if indicated loop excisions, was performed. The most severe histologic diagnosis was recorded. Sensitivity, specificity, positive, negative predictive value, and likelihood ratios for high-grade CIN were calculated. RESULTS: In 285 patients (85%), a single colposcopy directed biopsy was taken; 50 patients (15%) underwent two biopsies. One hundred sixty-two patients (48%) underwent subsequent magnification-guided loop excision. Sensitivity, specificity, positive predictive value, and negative predictive value of the inner border to detect high-grade CIN were 20%, 99%, 97.9%, and 34.8%, respectively. The positive likelihood ratio (LR+) was 20.3 and the negative likelihood ratio (LR-) was 0.81. Sensitivity, specificity, positive predictive value, and negative predictive value of the ridge sign to detect high grade CIN were 52.5%, 96.4%, 96.8%, and 46.6%, respectively. The LR+ ratio was 13.2 and the LR- ratio was 0.49. Sensitivity, specificity, positive predictive value, and negative predictive value of the rag sign to detect high-grade CIN were 38.4%, 96%, 95.7%, and 40.2%, respectively. The LR+ ratio was 9.7 and the LR ratio was 0.6. Only the ridge sign showed a correlation with young age. Presence of any two signs significantly increased the LR of the presence of high-grade CIN. CONCLUSION: The inner border, ridge sign, and the newly defined rag sign are objective, effective colposcopic signs and are significantly associated with high grade CIN. PMID- 23635629 TI - Musculoskeletal causes of chronic pelvic pain: what a gynecologist should know. AB - Ten percent of all gynecologic consultations are for chronic pelvic pain, and 20% of patients require a laparoscopy. Chronic pelvic pain affects 15% of all women annually in the United States, with medical costs and loss of productivity estimated at $2.8 billion and $15 billion per year, respectively. Chronic pelvic pain in women may have multifactorial etiology, but 22% have pain associated with musculoskeletal causes. Unfortunately, pelvic musculoskeletal dysfunction is not routinely evaluated as a cause of pelvic pain by gynecologists. A pelvic musculoskeletal examination is simple to perform, is not time-consuming, and is one of the most important components to investigate in all chronic pelvic pain patients. This article describes common musculoskeletal causes of chronic pelvic pain and explains how to perform a simple musculoskeletal examination that can be easily incorporated into the gynecologist physical examination. PMID- 23635628 TI - Nonsurgical management of heavy menstrual bleeding: a systematic review. AB - OBJECTIVE: To compare the effectiveness of nonsurgical abnormal uterine bleeding treatments for bleeding control, quality of life (QOL), pain, sexual health, patient satisfaction, additional treatments needed, and adverse events. DATA SOURCES: MEDLINE, Cochrane databases, and Clinicaltrials.gov were searched from inception to May 2012. We included randomized controlled trials of nonsurgical treatments for abnormal uterine bleeding presumed secondary to endometrial dysfunction and abnormal uterine bleeding presumed secondary to ovulatory dysfunction. Interventions included the levonorgestrel intrauterine system, combined oral contraceptive pills (OCPs), progestins, nonsteroidal anti inflammatory drugs (NSAIDs), and antifibrinolytics. Gonadotropin-releasing hormone agonists, danazol, and placebo were allowed as comparators. METHODS OF STUDY SELECTION: Two reviewers independently screened 5,848 citations and extracted eligible trials. Studies were assessed for quality and strength of evidence. TABULATION, INTEGRATION, AND RESULTS: Twenty-six articles met inclusion criteria. For reduction of menstrual bleeding in women with abnormal uterine bleeding presumed secondary to endometrial dysfunction, the levonorgestrel intrauterine system (71-95% reduction), combined OCPs (35-69% reduction), extended cycle oral progestins (87% reduction), tranexamic acid (26-54% reduction), and NSAIDs (10-52% reduction) were all effective treatments. The levonorgestrel intrauterine system, combined OCPs, and antifibrinolytics were all superior to luteal-phase progestins (20% increase in bleeding to 67% reduction). The levonorgestrel intrauterine system was superior to combined OCPs and NSAIDs. Antifibrinolytics were superior to NSAIDs for menstrual bleeding reduction. Data were limited on other important outcomes such as QOL for women with abnormal uterine bleeding presumed secondary to endometrial dysfunction and for all outcomes for women with abnormal uterine bleeding presumed secondary to ovulatory dysfunction. CONCLUSION: For the reduction in mean blood loss in women with heavy menstrual bleeding presumed secondary to abnormal uterine bleeding presumed secondary to endometrial dysfunction, we recommend the use of the levonorgestrel intrauterine system over OCPs, luteal-phase progestins, and NSAIDs. For other outcomes (QOL, pain, sexual health, patient satisfaction, additional treatments needed, and adverse events) and for treatment of abnormal uterine bleeding presumed secondary to ovulatory dysfunction, we were unable to make recommendations based on the limited available data. PMID- 23635630 TI - Score zero: making stillbirths count. PMID- 23635631 TI - Complications of hysterectomy. AB - Hysterectomy is the most common gynecologic procedure performed in the United States, with more than 600,000 procedures performed each year. Complications of hysterectomy vary based on route of surgery and surgical technique. The objective of this article is to review risk factors associated with specific types of complications associated with benign hysterectomy, methods to prevent and recognize complications, and appropriate management of complications. The most common complications of hysterectomy can be categorized as infectious, venous thromboembolic, genitourinary (GU) and gastrointestinal (GI) tract injury, bleeding, nerve injury, and vaginal cuff dehiscence. Infectious complications after hysterectomy are most common, ranging from 10.5% for abdominal hysterectomy to 13.0% for vaginal hysterectomy and 9.0% for laparoscopic hysterectomy. Venous thromboembolism is less common, ranging from a clinical diagnosis rate of 1% to events detected by more sensitive laboratory methods of up to 12%. Injury to the GU tract is estimated to occur at a rate of 1-2% for all major gynecologic surgeries, with 75% of these injuries occurring during hysterectomy. Injury to the GI tract after hysterectomy is less common, with a range of 0.1-1%. Bleeding complications after hysterectomy also are rare, with a median range of estimated blood loss of 238-660.5 mL for abdominal hysterectomy, 156-568 mL for laparoscopic hysterectomy, and 215-287 mL for vaginal hysterectomy, with transfusion only being more likely after laparoscopic compared to vaginal hysterectomy (odds ratio 2.07, confidence interval 1.12-3.81). Neuropathy after hysterectomy is a rare but significant event, with a rate of 0.2-2% after major pelvic surgery. Vaginal cuff dehiscence is estimated at a rate of 0.39%, and it is more common after total laparoscopic hysterectomy (1.35%) compared with laparoscopic-assisted vaginal hysterectomy (0.28%), total abdominal hysterectomy (0.15%), and total vaginal hysterectomy (0.08%). With an emphasis on optimizing surgical technique, recognition of surgical complications, and timely management, we aim to minimize risk for women undergoing hysterectomy. PMID- 23635632 TI - Febrile illness in pregnancy: disseminated herpes simplex virus. PMID- 23635633 TI - What is new in preeclampsia?: best articles from the past year. AB - This month, the focus is on preeclampsia and specifically emphasizes three areas: prediction, clinical management, and long-term sequelae. The current reviews serve to highlight the increasing importance of this disease across the health care continuum. The complete reference for each article reviewed can be found in on this page, along with direct links to the abstracts. PMID- 23635634 TI - Enoxaparin treatment for vulvodynia: a randomized controlled trial. PMID- 23635635 TI - Enoxaparin treatment for vulvodynia: a randomized controlled trial. In reply. PMID- 23635636 TI - Severe brachial plexus palsy in women without shoulder dystocia. PMID- 23635637 TI - Severe brachial plexus palsy in women without shoulder dystocia. PMID- 23635638 TI - Severe brachial plexus palsy in women without shoulder dystocia. In reply. PMID- 23635639 TI - Preventing the first cesarean delivery: summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal Fetal Medicine, and American College of Obstetricians and Gynecologists workshop. PMID- 23635640 TI - Preventing the first cesarean delivery: summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal Fetal Medicine, and American College of Obstetricians and Gynecologists workshop. In reply. PMID- 23635641 TI - Advocacy and the importance of supporting patients beyond the examination room. PMID- 23635642 TI - Advocacy and the importance of supporting patients beyond the examination room. In reply. PMID- 23635647 TI - Committee opinion no. 555: hospital disaster preparedness for obstetricians and facilities providing maternity care. AB - Numerous occurrences in the past decade have brought the issue of disaster preparedness, and specifically hospital preparedness, to the national forefront. Much of the work in this area has focused on large hospital system preparedness for various disaster scenarios. Many unique features of the obstetric population warrant additional consideration in order to optimize the care received by expectant mothers and their fetuses or newborns in the face of future natural or biologic disasters. PMID- 23635648 TI - Seeing double: the low carb diet. PMID- 23635649 TI - Isoflurane preconditioning increases survival of rat skin random-pattern flaps by induction of HIF-1alpha expression. AB - BACKGROUND: Survival of random-pattern skin flaps is important for the success of plastic and reconstructive surgeries. This study investigates isoflurane-induced protection against ischemia of skin flap and the underlying molecular mechanism in this process. METHODS: Human umbilical vein endothelial cells (HUVECs) and human skin fibroblast cells were exposed to isoflurane for 4 h. Expression of hypoxia inducible factor-1alpha (HIF-1alpha), heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) were analyzed up to 24 h post isoflurane exposure using qRT-PCR and western blot, or ELISA analyses. PI3K inhibitors--LY 294002 and wortmannin, mTOR inhibitor--rapamycin, and GSK3beta inhibitor--SB 216763 were used respectively to assess the effects of isoflurane treatment and HIF-1alpha expression. Furthermore, 40 rats were randomly divided into 5 groups (control, isoflurane, scrambled siRNA plus isoflurane, HIF-1alpha siRNA plus isoflurane, and DMOG) and subjected to random-pattern skin flaps operation. Rats were prepared for evaluation of flap survival and full-feld laser perfusion imager (FLPI) (at 7 day) and microvessel density evaluation (at 10 day). RESULTS: Isoflurane exposure induced expression of HIF-1alpha protein, HO-1 and VEGF mRNA and proteins in a time-dependent manner. Both LY 294002 and wortmannin inhibited phospho-Akt, phospho-mTOR, phospho-GSK 3beta and HIF-1alpha expression after isoflurane exposure. Both wortmannin and rapamycin inhibited isoflurane-induced phospho-4E-BP1 (Ser 65) and phospho-P70(s6k) (Thr 389) and HIF 1alpha expression. SB 216763 pre-treatment could further enhance isoflurane induced expression of phospho-GSK 3beta (Ser 9) and HIF-1alpha protein compared to the isoflurane-alone cells. In animal experiments, isoflurane alone, scrambled siRNA plus isoflurane, or DMOG groups had significantly upregulated vascularity and increased survival of the skin flaps compared to the controls. However, HIF 1alpha knockdown abrogated the protective effect of isoflurane preconditioning in rats. CONCLUSIONS: Isoflurane preconditioning improves survival of skin flaps by up the regulation of HIF-1alpha expression via Akt-mTOR and Akt-GSK 3beta signaling pathways. PMID- 23635650 TI - Study of primary IGF-1 deficiency in Egyptian children with idiopathic short stature. AB - BACKGROUND/AIMS: Primary insulin-like growth factor-1 (IGF-1) deficiency (IGFD) is defined by low levels of IGF-1 without growth hormone (GH) deficiency and absence of secondary causes. The aim of this study was to evaluate IGF-1 in Egyptian children with idiopathic short stature (ISS) and describe patients with IGFD. METHODS: This cross-sectional study included 50 children with ISS following up at the Diabetes Endocrine and Metabolism Pediatric Unit at Cairo University Pediatric Hospital. Children were included based on the following criteria: (1) short stature with current height standard deviation score (SDS) <=-2.5; (2) age between 2 and 9 years in boys and 2 and 8 years in girls, and (3) prepubertal status. Exclusion criteria were: (1) identified cause of short stature and (2) pubertal children. IGF-1-deficient children were defined as children without GH deficiency and with IGF-1 levels below the 2.5th percentile. RESULTS: Among 50 children with ISS, 14 (28%) patients had low IGF-1 levels, consistent with the diagnosis of primary IGFD. When compared with non-IGFD children, IGFD children had lower birth weight SDS (-1.8 vs. -0.7 SDS, p < 0.0001) and lower height SDS ( 4.2 vs. -3.1 SDS, p < 0.05) and more delayed bone age (2.6 vs. 1.6 years, p = 0.001). CONCLUSION: Primary IGF-1 deficiency is found in 28% of children with ISS. PMID- 23635651 TI - Overlapping functions of ABC transporters in topotecan disposition as determined in gene knockout mouse models. AB - It is established that efflux transporters of the ATP-binding cassette (ABC) superfamily can affect the pharmacokinetics of drugs through mechanisms pertaining to drug absorption, elimination, and distribution. To characterize the role of multiple transporters in topotecan's pharmacokinetics, total (lactone+carboxylate) and lactone forms were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS) in plasma, bile, urine, and feces following intravenous administration at doses of 1 and 4 mg/kg to eight mouse strains: C57BL/6 [wild-type (WT)], Abcb1(-/-), Abcc2(-/-), Abcc4(-/-), Abcg2(-/-), Abcc2;Abcb1(-/-), Abcc2;Abcg2(-/-), and Abcc4;Abcg2(-/-). Compared with WT mice and at both dose levels, the plasma areas under the curve for topotecan lactone were not significantly different in the Abcc2(-/-), Abcc4(-/-), and Abcb1(-/-) strains, whereas significant differences were found in Abcg2(-/-), Abcc2;Abcb1(-/-) (only at the high dose), Abcc4;Abcg2(-/-), and Abcc2;Abcg2(-/-) mice and ranged from 2.1- to 3.3-fold higher. Consistent with these changes, the fecal and biliary excretion of topotecan was reduced, whereas renal elimination was elevated in Abcg2(-/-)-based strains. Similarly, the Abcc2;Abcb1(-/-) strain also had elevated renal elimination and reduced fecal excretion of topotecan lactone. This was more pronounced at the 4 mg/kg dose level, suggesting possible saturation of Abcg2. The Abcc4 transporter was found not to be a major determinant of topotecan pharmacokinetics. It is concluded that Abcg2 has the most significant effect on topotecan elimination, whereas both Abcb1 and Abcc2 have overlapping functions with Abcg2. As such it is relevant to examine how polymorphisms in these transporters influence topotecan activity in patients and whether coadministration of transport modulators could positively affect efficacy without increasing toxicity. PMID- 23635652 TI - Triptolide induces the expression of miR-142-3p: a negative regulator of heat shock protein 70 and pancreatic cancer cell proliferation. AB - Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest malignancies, is resistant to current chemotherapies. We previously showed that triptolide inhibits PDAC cell growth in vitro and blocks metastatic spread in vivo. Triptolide downregulates HSP70, a molecular chaperone upregulated in several tumor types. This study investigates the mechanism by which triptolide inhibits HSP70. Because microRNAs (miRNA) are becoming increasingly recognized as negative regulators of gene expression, we tested whether triptolide regulates HSP70 via miRNAs. Here, we show that triptolide as well as quercetin, but not gemcitabine, upregulated miR-142-3p in PDAC cells (MIA PaCa-2, Capan-1, and S2-013). Ectopic expression of miR-142-3p inhibited cell proliferation, measured by electric cell substrate impedance sensing, and decreased HSP70 expression, measured by real time PCR and immunoblotting, compared with controls. We showed that miR-142-3p directly binds to the 3'UTR of HSP70, and that this interaction is important as HSP70 overexpression rescued miR-142-3p-induced cell death. We found that miR-142 3p regulates HSP70 independently of heat shock factor 1. Furthermore, Minnelide, a water-soluble prodrug of triptolide, induced the expression of miR-142-3p in vivo. This is the first description of an miRNA-mediated mechanism of HSP70 regulation in cancer, making miR-142-3p an attractive target for PDAC therapeutic intervention. PMID- 23635654 TI - The efficacy of CHK1 inhibitors is not altered by hypoxia, but is enhanced after reoxygenation. AB - Inhibitors of CHK1 are in clinical trials for cancer treatment in combination with DNA-damaging agents. Importantly, it was previously suggested that hypoxic cancer cells may be particularly sensitive to CHK1 inhibition. However, this suggestion was based on studies in severe, toxic levels of hypoxia (anoxia). The influence of less severe hypoxia on the efficacy of CHK1 inhibitors, administered either as single agents or in combination with other treatments, remains to be investigated. Here, we have assayed the effects of the CHK1 inhibitors, AZD7762 and UCN-01, during various hypoxic conditions and after reoxygenation in the absence and presence of ionizing radiation. Treatment with CHK1 inhibitors during acute or prolonged hypoxia (< 0.03%, 0.2%, and 1% O2; 3 h or 20-24 h) gave similar effects on cell survival as treatment with these inhibitors during normoxia. CHK1 inhibitors combined with ionizing radiation showed similar radiosensitization in hypoxic and normoxic cells. However, when the inhibitors were administered after reoxygenation following prolonged hypoxia (< 0.03% and 0.2%; 20-24 h), we observed decreased cell survival and stronger induction of the DNA damage marker, gammaH2AX, in S-phase cells. This was accompanied by enhanced phosphorylation of the single-stranded DNA-binding replication protein A. These results suggest that the cytotoxic effects of CHK1 inhibitors are enhanced after reoxygenation following prolonged hypoxia, most likely due to the increased replication-associated DNA damage. Combining CHK1 inhibitors with other treatments that cause increased reoxygenation, such as fractionated radiotherapy, might therefore be beneficial. PMID- 23635653 TI - Impact of tumor vascularity on responsiveness to antiangiogenesis in a prostate cancer stem cell-derived tumor model. AB - Drugs that target the tumor vasculature and inhibit angiogenesis are widely used for cancer treatment. Individual tumors show large differences in vascularity, but it is uncertain how these differences affect responsiveness to antiangiogenesis. We investigated this question using two closely related prostate cancer models that differ markedly in tumor vascularity: PC3, which has very low vascularity, and the PC3-derived cancer stem-like cell holoclone PC3/2G7, which forms tumors with high microvessel density, high tumor blood flow, and low hypoxia compared with parental PC3 tumors. Three angiogenesis inhibitors (axitinib, sorafenib, and DC101) all induced significantly greater decreases in tumor blood flow and microvessel density in PC3/2G7 tumors compared with PC3 tumors, as well as significantly greater decreases in tumor cell proliferation and cell viability and a greater increase in apoptosis. The increased sensitivity of PC3/2G7 tumors to antiangiogenesis indicates they are less tolerant of low vascularity and suggests they become addicted to their oxygen- and nutrient-rich environment. PC3/2G7 tumors showed strong upregulation of the proangiogenic factors chemokine ligand 2 (CCL2) and VEGFA compared with PC3 tumors, which may contribute to their increased vascularity, and they have significantly lower endothelial cell pericyte coverage, which may contribute to their greater sensitivity to antiangiogenesis. Interestingly, high levels of VEGF receptor-2 were expressed on PC3 but not PC3/2G7 tumor cells, which may contribute to the growth static response of PC3 tumors to VEGF-targeted antiangiogenesis. Finally, prolonged antiangiogenic treatment led to resumption of PC3/2G7 tumor growth and neovascularization, indicating these cancer stem-like cell-derived tumors can adapt and escape from antiangiogenesis. PMID- 23635656 TI - ATXN2 CAG repeat expansions increase the risk for Chinese patients with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unclear etiology. Recently, intermediate CAG repeat expansions in ATXN2, the gene responsible for spinocerebellar ataxia type 2 (SCA2), have been identified as a possible genetic risk factor for ALS. In this study, we analyzed the ATXN2 CAG repeat length in Chinese patients with ALS to evaluate the relationship between the genotype and phenotype. We studied 1,067 patients with ALS and 506 controls from mainland China (excluding Tibet). We collected clinical data and analyzed fluorescent PCR products to assess ATXN2 CAG repeat length in all of the samples. We observed that intermediate CAG repeat expansions in ATXN2 (CAG repeat length >30) were associated with ALS (p = 0.004). There was no significant difference in clinical characteristics between the groups with and without intermediate CAG repeat expansions in ATXN2. Our data indicate that, for ALS patients from mainland China, intermediate CAG repeat expansions in ATXN2 increase the risk of ALS but have no effect on disease phenotype. PMID- 23635655 TI - New paradigms in microtubule-mediated endocrine signaling in prostate cancer. AB - Metastatic prostate cancer has limited therapeutic options and has remained a major clinical challenge. Historically, prostate cancer has been widely recognized as a chemotherapy-resistant disease. However, clinical studies with anti-microtubule agents over the past decade have shown important efficacy in improving survival in patients with advanced disease. The favorable outcomes with microtubule-targeted agents have thus rekindled interest in such therapies for the clinical management of prostate cancer. Microtubules are dynamic polymers of tubulin molecules that play diverse roles within the cell. The dynamic property of microtubules is responsible for forming the bipolar mitotic apparatus, the mitotic spindle, that functions to precisely segregate the chromosomes during cell division. Thus, owing to the pivotal role that they play in the orchestration of mitotic events, microtubules provide excellent targets for anti cancer therapy. Recent evidence also suggests that microtubules play a crucial role in the regulation of endocrine signaling pathways. Interestingly, microtubule-targeted agents such as taxanes not only inhibit cell division but also impair endocrine receptor signaling in prostate cancer. Herein, we provide an overview of the current status of microtubule-targeted therapies that are used in the treatment of prostate cancer and discuss novel mechanisms by which such therapies modulate endocrine signaling in prostate cancer. We also address the emerging roles of microtubule regulatory proteins in prostate carcinogenesis that could serve as attractive targets for prostate cancer therapy and might also serve as predictive biomarkers to identify patients who may benefit from endocrine and/or chemotherapy. This may have important implications in designing mechanism-based and targeted-therapeutic strategies for prostate cancer. PMID- 23635657 TI - Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS. AB - The nuclear protein fused in sarcoma (FUS) is found in cytoplasmic inclusions in a subset of patients with the neurodegenerative disorder frontotemporal lobar degeneration (FTLD-FUS). FUS contains a methylated arginine-glycine-glycine domain that is required for transport into the nucleus. Recent findings have shown that this domain is hypomethylated in patients with FTLD-FUS. To determine whether the cause of hypomethylation is the result of mutations in protein N arginine methyltransferases (PRMTs), we selected 3 candidate genes (PRMT1, PRMT3, and PRMT8) and performed complete sequencing analysis and real-time polymerase chain reaction mRNA expression analysis in 20 FTLD-FUS cases. No mutations or statistically significant changes in expression were observed in our patient samples, suggesting that defects in PRMTs are not the cause of FTLD-FUS. PMID- 23635658 TI - RIT2 variant is not associated with Parkinson's disease in a Taiwanese population. AB - Recent genome-wide association studies of Parkinson's disease (PD) have identified the rs12456492 variant of the novel susceptibility loci, RIT2, as being associated with disease risk in a large white population. Studies among Asians are scarce. We genotyped RIT2 rs12456492 variant in a total of 1000 participants, comprising 500 patients with PD and 500 control subjects in a Taiwanese population. The frequency of GA/AA genotype was slightly higher in PD patients compared with controls, but was without statistical significance (odds ratio = 1.03, 95% confidence interval = 0.73-1.46, p = 0.86). We failed to replicate the RIT2 rs12456492 variant as a genetic risk factor for PD in our population. PMID- 23635659 TI - Mutation analysis and immunopathological studies of PFN1 in familial and sporadic amyotrophic lateral sclerosis. AB - Mutations in PFN1, a gene encoding the actin monomer-binding protein profilin 1, were recently reported in 1% to 2% of familial amyotrophic lateral sclerosis (ALS) patients. In vitro functional studies suggested that PFN1 mutations lead to ubiquitin-positive inclusions and impairment of cytoskeletal pathways. In the present study, mutation analysis of PFN1 was performed in an Australian cohort of 110 ALS families and 715 sporadic ALS patients. No PFN1 mutations were identified in familial ALS patients. Two rare non-synonymous variants (E117D and E117G) were found in sporadic ALS patients at similar incidences to that reported in public SNP databases. Immunostaining of PFN1 in sporadic ALS and familial ALS patients, including those with mutations in SOD1, FUS, UBQLN2 and C9ORF72, found no PFN1 positive inclusions in spinal motor neurons. Our data suggest that PFN1 mutations and pathology are not common in an Australian ALS cohort of predominantly European ancestry. PMID- 23635661 TI - Preparing for the unexpected: violence in the home care environment, one agency's story. AB - Home care and hospice agencies, bound by regulations, prepare for emergencies and disasters by creating policies and protocols for management of emergency situations, perhaps conducting table top or other types of drills, and discussing hazards likely to impact home care. Is this preparation merely an exercise to meet a requirement, or is it life-saving preparation? For one home care agency, the emergency exercise saved the day as the scenario enacted in the drill was actually lived out a few weeks after the exercise-a scenario the agency leaders hoped they would never face. This account explores how the agency prepared to meet the emergent situation and details lessons learned in the aftermath. PMID- 23635662 TI - Effects of losartan and pentoxifylline on renal dimethylarginine dimethylaminohydrolase-1 expression in proteinuric nephropathy. AB - BACKGROUND/AIMS: Circulatory asymmetric dimethylarginine (ADMA) is correlated with proteinuria and endothelial dysfunction in patients with proteinuric renal diseases. However, it is not known whether proteinuria itself affects expression of dimethylarginine dimethylaminohydrolase (DDAH), a degrading enzyme of ADMA, in kidney. The aim of this study is to evaluate the direct effects of losartan and/or pentoxifylline on expression of renal DDAH-1 and its relation to oxidative stress in the setting of albuminuria. METHODS: Using NRK52E cells, DDAH-1 mRNA and protein were determined after exposure to albumin with losartan and/or pentoxifylline. Reactive oxygen species (ROS), PKC activity, and NOX-4 mRNA were also measured. In addition, the effect of losartan and/or pentoxifylline on renal expression of DDAH-1 and serum ADMA were evaluated in a rat model of proteinuric nephropathy. RESULTS: Exposure to albumin resulted in increased release of N acetyl-beta-D-glucosaminidase along with an increase of TNF-alpha, 8-hydroxy-2' deoxyguanosine, and angiotensin II in NRK52E cells. Losartan and pentoxifylline reversed albumin-induced decrease of DDAH-1 mRNA and protein expression and DDAH 1 activity. The effects of losartan and pentoxifylline on DDAH-1 mRNA were associated with reduction of ROS. In addition, treatment with losartan and pentoxifylline resulted in an attenuated change of renal DDAH-1 protein expression and serum ADMA levels in vivo. CONCLUSION: DDAH-1 was positively regulated by losartan and pentoxifylline with its antioxidative effect in albumin exposed renal proximal tubular cells. Combined treatment with losartan and pentoxifylline has a direct beneficial effect on expression of renal DDAH-1, and, thus, at least in part, modulates the circulatory levels of ADMA in proteinuric nephropathy. PMID- 23635663 TI - Detection of mild cognitive impairment and early stage dementia with an audio recorded cognitive scale. AB - BACKGROUND: Physicians often miss diagnosis of mild cognitive impairment (MCI) or early dementia and screening measures can be insensitive to very mild impairments. Other cognitive assessments may take too much time or be frustrating to seniors. This study examined the ability of an audio-recorded scale, developed in Australia, to detect MCI or mild Alzheimer's disease (AD) and compared cognitive domain-specific performance on the audio-recorded scale to in-person battery and common cognitive screens. METHOD: Seventy-six patients from the Mount Sinai Alzheimer's Disease Research Center were recruited. Patients were aged 75 years or older, with clinical diagnosis of AD or MCI (n = 51) or normal control (n = 25). Participants underwent in-person neuropsychological testing followed by testing with the audio-recorded cognitive screen (ARCS). RESULTS: ARCS provided better discrimination between normal and impaired elderly individuals than either the Mini-Mental State Examination or the clock drawing test. The in-person battery and ARCS analogous variables were significantly correlated, most in the 0.4 to 0.7 range, including verbal memory, executive function/attention, naming, and verbal fluency. The area under the curve generated from the receiver operating characteristic curves indicated high and equivalent discrimination for ARCS and the in-person battery (0.972 vs. 0.988; p = 0.23). CONCLUSION: The ARCS demonstrated better discrimination between normal controls and those with mild deficits than typical screening measures. Performance on cognitive domains within the ARCS was well correlated with the in-person battery. Completion of the ARCS was accomplished despite mild difficulty hearing the instructions even in very elderly participants, indicating that it may be a useful measure in primary care settings. PMID- 23635664 TI - Attentional bias for alcohol-related stimuli among belief based and non-belief based non-drinkers. AB - BACKGROUND/AIMS: Research has provided evidence for an association between attentional biases for substance-related stimuli and the development and maintenance of a variety of addictive behaviours. Attempts at reducing attentional bias amongst harmful and dependent drinkers have provided evidence to suggest that reduced attentional bias in heavy drinkers would lead to necessary reductions in alcohol intake. We tested one aspect of this assumption by measuring attentional bias amongst non-drinkers who, if the link between attentional bias and actual drug use is causal, should demonstrate no attentional bias for alcohol-related stimuli. METHODS: An alcohol Stroop task was administered to belief-based abstainers, non-belief based abstainers and light social drinkers to measure attentional biases for alcohol-related words compared to neutral words. RESULTS: Belief-based abstainers demonstrated significant attentional bias for alcohol-related stimuli, whilst non-belief based abstainers and light social drinkers did not. CONCLUSION: Attentional biases towards alcohol related stimuli are not specific to harmful and problem drinkers, which has implications for interventions based on attentional bias change. PMID- 23635666 TI - Ovaries, estrogen, and longevity. PMID- 23635665 TI - Three-year visual outcome and injection frequency of intravitreal ranibizumab therapy for neovascular age-related macular degeneration. AB - BACKGROUND: To assess the 3-year visual outcome and injection frequency for patients on ranibizumab for neovascular age-related macular degeneration (NV AMD). METHODS: Retrospective case-note review of 174 treatment-naive eyes of 156 patients with NV-AMD with 3-year follow-up was done at specific time points closest to 12, 24 and 36 months. RESULTS: The median baseline visual acuity (VA) of 50 Early Treatment Diabetic Retinopathy Study letters (mean 48.2 +/- 16.9) improved significantly to 55 (mean 51.2 +/- 18.7) by the end of 12 months (p = 0.04). At 24 months, the median letter score remained unchanged at 55 (mean 50.4 +/- 20.8; p = 0.14 as compared to baseline) and at 36 months, the median VA was 54 letters (mean 49.1 +/- 21.7; p = 0.34 compared to baseline). The mean numbers of injections were 4.8 +/- 2.2 at 1 year, 7.8 +/- 4.2 at 2 years (2.9 in the second year) and 10.2 +/- 6.2 at the end of the third year (2.4 in the third year). CONCLUSION: Our study demonstrates the efficacy of a variable dosing regimen of ranibizumab for the treatment of NV-AMD. The mean gain in VA is inversely proportional to the baseline VA and did not correlate with the number of injections. PMID- 23635667 TI - New guidelines: it's complicated. PMID- 23635668 TI - Medicare and Medicaid quality programs. PMID- 23635669 TI - Long-term mortality associated with oophorectomy compared with ovarian conservation in the nurses' health study. AB - OBJECTIVE: To report long-term mortality after oophorectomy or ovarian conservation at the time of hysterectomy in subgroups of women based on age at the time of surgery, use of estrogen therapy, presence of risk factors for coronary heart disease, and length of follow-up. METHODS: This was a prospective cohort study of 30,117 Nurses' Health Study participants undergoing hysterectomy for benign disease. Multivariable adjusted hazard ratios for death from coronary heart disease, stroke, breast cancer, epithelial ovarian cancer, lung cancer, colorectal cancer, total cancer, and all causes were determined comparing bilateral oophorectomy (n=16,914) with ovarian conservation (n=13,203). RESULTS: Over 28 years of follow-up, 16.8% of women with hysterectomy and bilateral oophorectomy died from all causes compared with 13.3% of women who had ovarian conservation (hazard ratio 1.13, 95% confidence interval 1.06-1.21). Oophorectomy was associated with a lower risk of death from ovarian cancer (four women with oophorectomy compared with 44 women with ovarian conservation) and, before age 47.5 years, a lower risk of death from breast cancer. However, at no age was oophorectomy associated with a lower risk of other cause-specific or all-cause mortality. For women younger than 50 years at the time of hysterectomy, bilateral oophorectomy was associated with significantly increased mortality in women who had never used estrogen therapy but not in past and current users: assuming a 35 year lifespan after oophorectomy: number needed to harm for all-cause death=8, coronary heart disease death=33, and lung cancer death=50. CONCLUSIONS: Bilateral oophorectomy is associated with increased mortality in women aged younger than 50 years who never used estrogen therapy and at no age is oophorectomy associated with increased survival. LEVEL OF EVIDENCE: I. PMID- 23635671 TI - Maternal and pregnancy-related factors associated with developmental delay in moderately preterm-born children. AB - OBJECTIVE: To estimate the association between pre-existing maternal and pregnancy-related factors and developmental delay in early childhood in moderately preterm-born children. METHODS: We measured development with the Ages and Stages Questionnaire at age 43-49 months in 834 moderately preterm-born (between 32 0/7 and 35 6/7 weeks of gestation) children born in 2002-2003. We obtained data on preexisting maternal, maternal pregnancy-related, fetal, and delivery-related factors. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) and attributable risks for developmental delay adjusted for sociodemographic and lifestyle variables. RESULTS: Attributable risk for developmental delay for small-for-gestational-age (SGA, as a proxy for intrauterine growth restriction [IUGR]) was 14.2% (SGA 21.9%, no SGA 7.7%, P<.05, adjusted OR 2.75, CI 1.25-6.08), for preexisting maternal obesity 10.5% (obesity 18.0%, no obesity 7.5%, P<.01, adjusted OR 2.73, CI 1.35-5.52), for multiple pregnancy 4.2% (multiple 12.0%, singleton 7.8%, P<.05, adjusted OR 1.86, CI 1.02 3.42), and for male sex 9.3% (male 13.0%, female 3.8%, P<.001, adjusted OR 4.20, CI 2.09-8.46). No other preexisting or pregnancy-related maternal factors or any delivery-related factors were associated with increased risk of developmental delay. CONCLUSIONS: Of all preexisting maternal and pregnancy-related factors studied, SGA, maternal prepregnancy obesity, being one of a multiple, and male sex were associated with the risk of developmental delay in early childhood after moderately preterm birth. Reinforced focus on prevention of IUGR, preconception lifestyle interventions aiming at weight reduction in fertile women, and reinforced efforts to reduce rates of multiple pregnancies in assisted reproduction may all contribute toward more favorable developmental outcomes in moderately preterm-born children. LEVEL OF EVIDENCE: II. PMID- 23635670 TI - Variation in ovarian conservation in women undergoing hysterectomy for benign indications. AB - OBJECTIVE: Emerging data suggest that oophorectomy at the time of hysterectomy for benign indications may increase long-term morbidity and mortality. We performed a population-based analysis to estimate the rates of oophorectomy in women undergoing hysterectomy for benign indications. METHODS: The Perspective database was used to estimate the rate of ovarian preservation in women aged 40 64 years who underwent hysterectomy for benign indications. Hierarchical mixed effects regression models were developed to estimate the influence of patient, procedural, physician, and hospital characteristics on ovarian conservation. Between-hospital variation in ovarian preservation also was estimated. RESULTS: Among 752,045 women, 348,972 (46.4%) underwent bilateral oophorectomy, whereas 403,073 (53.6%) had ovarian conservation. Stratified by age, the rate of ovarian conservation was 74.3% for those younger than 40 years of age; 62.7% for those 40 44 years of age; 40.8% for those 45-49 years of age; 25.2% for those 50-54 years of age; 25.5% for those 55-59 years of age; and 31.0% for those 60-64 years of age. Younger age and more recent year of surgery had the strongest association with ovarian conservation. The observed patient, procedural, physician, and hospital characteristics accounted for only 46% of the total variation in the rate of ovarian conservation; 54% of the variability remained unexplained, suggesting a large amount of intrinsic between-hospital variation in the decision to perform oophorectomy. CONCLUSION: The rate of ovarian conservation is increasing, particularly among women younger than 50 years old. Although demographic and clinical factors influence the decision to perform oophorectomy, there appears to be substantial between-hospital variation in performance of oophorectomy that remains unexplained by measurable patient, physician, or hospital characteristics. LEVEL OF EVIDENCE: II. PMID- 23635672 TI - Improving influenza vaccination rates in pregnancy through text messaging: a randomized controlled trial. AB - OBJECTIVE: To estimate whether text messages sent to ambulatory pregnant women could improve influenza vaccine uptake. METHODS: Obstetric patients at less than 28 weeks of gestation were enrolled in a randomized controlled trial from an academic center's outpatient clinic during two consecutive influenza seasons (2010-2011 and 2011-2012). Potential participants were excluded if they had already received that season's influenza vaccine. Participants were randomized to receive 12 weekly text messages encouraging general pregnancy health (General) or general pregnancy health plus influenza vaccination (Flu). Study participants completed preintervention and postintervention surveys about preventive health beliefs. Influenza vaccine receipt was assessed using prenatal record review. The study was powered to detect a 55% increase in the vaccination rate in the intervention group. RESULTS: Two hundred sixteen women were enrolled, 204 of whom were available for intention-to-treat analysis (n=100 General, n=104 Flu). Participants were primarily African American (66%) with low educational attainment (90% equivalent to or less than high school education) and predominantly with either public or no insurance (88%). The overall influenza vaccination rate among participants was 32% with no difference between participants in the General (31% [n=31]) compared with Flu (33% [n=34]) groups (difference 1.7%, 95% confidence interval -11.1 to 14.5%). CONCLUSION: Text messaging prompts were not effective at increasing influenza vaccination rates among a low-income, urban, ambulatory obstetric population. Ongoing efforts are needed to improve vaccine uptake among pregnant women unsure about or unwilling to receive influenza vaccination. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01248520. LEVEL OF EVIDENCE: : I. PMID- 23635674 TI - Influence of food intake on the predictive value of the gestational diabetes mellitus screening test. AB - OBJECTIVE: To investigate the influence of prior food ingestion on the predictive value of a screening test for gestational diabetes mellitus. METHODS: This prospective, nonrandomized study enrolled 1,387 pregnant women who underwent the 50-g glucose challenge test. Gestational diabetes mellitus was diagnosed according to the National Diabetes Data Group criteria. A nutritional survey of dietary information before the glucose challenge test was conducted. The patients were stratified into three groups based on the time of last food ingestion (fasting interval): 1 hour or less, 1-2 hours, and more than 2 hours. The more than 2-hours fasting interval group was defined as the "fasting" group, and the combined 1 hour or less and 1-2 hours fasting interval groups were defined as the "fed" group. We calculated the positivity rate and the positive predictive value to detect the predictive value. RESULTS: Among women who fasted 1 hour or less, 1 2 hours, and more than 2 hours before a glucose challenge test, 2.5%, 3.1%, and 6.9% were diagnosed with gestational diabetes mellitus, respectively. The positive predictive value of the glucose challenge test was greater in the fasting group than in the fed group (27.1% compared with 13.7%, P=.003). A multinomial logistic analysis showed that gestational diabetes mellitus was more prevalent in the fasting group than in the fed group (adjusted odds ratio 2.86, 95% confidence interval 1.65-4.95). CONCLUSION: Our findings suggest that food intake influences the predictive value of the gestational diabetes screening test. LEVEL OF EVIDENCE: II. PMID- 23635673 TI - Predictors of seasonal influenza vaccination during pregnancy. AB - OBJECTIVE: Although pregnant women are a high-priority group for influenza vaccination, vaccination rates in this population remain below recommended levels. This prospective cohort study followed a group of pregnant women during the 2010-2011 influenza season to determine possible predictors of vaccination. METHODS: Participants were 552 pregnant women who had not already received the influenza vaccine at the time of enrollment. Women completed a survey assessing knowledge, attitudes, and beliefs about vaccination (based on the Health Belief Model) by telephone and were then followed to determine vaccination status by the end of the 2010-2011 influenza season. RESULTS: Forty-six percent (n=252) of the women were vaccinated, and 54% (n=300) remained unvaccinated after enrollment in the study. Few baseline characteristics, with the exception of study site, month of enrollment, and maternal ethnicity, were predictive of vaccination status. Even after adjusting for significant baseline characteristics, we found that at least one item from each domain of the Health Beliefs Model was predictive of subsequent vaccination. Specifically, women who perceived they were susceptible to influenza, that they were at risk of getting seriously ill from influenza, that they would regret not getting vaccinated, and who trusted recommended guidelines about influenza vaccination during pregnancy were more likely to get vaccinated. Women who were concerned about vaccine side effects were less likely to get vaccinated. CONCLUSION: Trust in recommendations, perceived susceptibility to and seriousness of influenza, perceived regret about not getting vaccinated, and vaccine safety concerns predict vaccination in pregnant women. LEVEL OF EVIDENCE: II. PMID- 23635675 TI - Potential effects of updated pap test screening guidelines and adenocarcinoma in situ of the cervix. AB - OBJECTIVE: To review cases of adenocarcinoma in situ (AIS) at our institution to examine how updated guidelines affect the timing of diagnosis. METHODS: We identified patients with AIS diagnosed between 1998 and 2010 using the International Classification of Diseases, 9 Revision, Clinical Modification, code 233.1. Diagnosis was confirmed by pathology review. We abstracted demographic data, dysplasia history, and modalities utilized for diagnosis and treatment. RESULTS: We identified 242 patients who met selection criteria. Two hundred eight (86%) had Pap test abnormalities at presentation. One hundred thirty-seven out of 208 (66%) patients with abnormal Pap test results had a squamous, rather than glandular, abnormality. The mean time from abnormal Pap test to diagnosis of AIS was 29 months in patients older than 30 years and was 21 months in patients 30 years or younger. In patients younger than 21 years, 16 out of 17 had abnormal screening Pap test results showing squamous lesions. Their subsequent treatment for squamous dysplasia ultimately led to the diagnosis of AIS. CONCLUSION: : Updated screening guidelines may prevent the expeditious diagnosis of AIS in females younger than 21 years and those aged 21-29 years, many of whom had normal Pap test results within 3 years of diagnosis. LEVEL OF EVIDENCE: II. PMID- 23635676 TI - Primary surgical management with tailored adjuvant radiation for stage IB2 cervical cancer. AB - OBJECTIVE: To examine the outcome for patients with stage IB2 cervical cancer treated primarily with radical hysterectomy, and to determine the need for adjuvant therapy, the sites of recurrence, and the morbidity of the treatment. METHODS: We reviewed our experience with 93 patients with stage IB2 cervical cancer treated with primary surgery at the Royal Hospital for Women in Sydney from 1988 to 2008. All patients underwent radical hysterectomy and pelvic lymphadenectomy. If bulky positive nodes were encountered, they were resected without complete lymphadenectomy. Postoperative radiation was tailored to the histologic findings. RESULTS: The mean age of the patients was 46 years, and 70% had squamous cell carcinomas. Tumor invaded into the outer third of the cervical stroma in 73 cases (78.5%), occult parametrial extension occurred in 15 cases (16.1%), and vascular space invasion occurred in 65 cases (69.9%). Positive pelvic nodes were present in 42 patients (45.2%) and bulky positive para-aortic nodes were present in 5 patients (5.4%). Some type of postoperative adjuvant (chemoradiation) radiation was given to 74 patients (79.6%). With a median follow up of 96 months, the overall 5-year survival was 80.7%, being 85% for patients with negative nodes and 75% for those with positive nodes (hazard ratio 2.63, 95% confidence interval 1--5.6; P=.045). The major long-term surgical morbidity was lymphedema, which occurred in eight patients (8.6%). Serious long-term radiation morbidity (Radiation Therapy Oncology Group grade 3) occurred in three patients (3.2%). CONCLUSIONS: Primary radical hysterectomy with tailored postoperative adjuvant radiation for patients with stage IB2 cervical cancer provides good survival with acceptably low morbidity. LEVEL OF EVIDENCE: III. PMID- 23635677 TI - Intravaginal practices and risk of bacterial vaginosis and candidiasis infection among a cohort of women in the United States. AB - OBJECTIVE: To measure intravaginal practices among women of differing ages, ethnicities, and human immunodeficiency virus status and the association between intravaginal practices and bacterial vaginosis and candidiasis infection. METHODS: Between 2008 and 2010, we recruited and followed sexually active women aged 18-65 years living in Los Angeles. At the enrollment and month 12 visit, participants completed a self-administered, computer-assisted questionnaire covering demographics, sexual behaviors, vaginal symptoms, and intravaginal practices over the past month. At each visit, bacterial vaginosis and candidiasis infection were diagnosed by Nugent criteria and DNA probe, respectively. RESULTS: We enrolled 141 women. Two thirds (66%) reported an intravaginal practice over the past month; 49% reported insertion of an intravaginal product (other than tampons) and 45% reported intravaginal washing. The most commonly reported practices included insertion of commercial sexual lubricants (70%), petroleum jelly (17%), and oils (13%). In univariable analysis, intravaginal use of oils was associated with Candida species colonization (44.4% compared with 5%, P<.01). In multivariable analysis, women reporting intravaginal use of petroleum jelly over the past month were 2.2 times more likely to test positive for bacterial vaginosis (adjusted relative risk 2.2, 95% confidence interval 1.3-3.9). CONCLUSION: Intravaginal insertion of over-the-counter products is common among women in the United States and is associated with increased risk of bacterial vaginosis. The context, motivations for, and effects of intravaginal products and practices on vaginal health are of concern and warrant further study. LEVEL OF EVIDENCE: III. PMID- 23635678 TI - Risk profiles and outcomes of total laparoscopic hysterectomy compared with laparoscopically assisted vaginal hysterectomy. AB - OBJECTIVE: With the increasing rates of minimally invasive hysterectomy procedures serving as impetus, the aim of this study was to analyze the 30-day risk profiles associated with total laparoscopic hysterectomy and laparoscopically assisted vaginal hysterectomy (LAVH). METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent a total laparoscopic hysterectomy or LAVH operation between 2006 and 2010. Patient demographics and 30-day complication rates were calculated. Multivariable regression analyses were used to study the effect of hysterectomy approach on outcomes. RESULTS: A total of 6,190 patients underwent laparoscopic hysterectomy, with 66.3% receiving LAVH and 33.7% receiving a total laparoscopic hysterectomy. The patient cohorts were well matched. Although total laparoscopic hysterectomy procedures were significantly longer than LAVH operations (2.66 hours compared with 2.20 hours; P<.001), there was no difference in overall morbidity or reoperation rates between the LAVH and total laparoscopic hysterectomy populations (7.05% compared with 6.3% for overall morbidity; 1.3% compared with 1.7% for reoperation). Regression analyses revealed that surgical approach was not a significant predictor of overall postoperative morbidity or reoperation in minimally invasive hysterectomy patients. Additionally, obesity did not demonstrate a significant association with morbidity or reoperation rates; however, operative time was found to be a significant predictor of reoperation (odds ratio 1.23, 95% confidence interval 1.07-1.42). CONCLUSION: Laparoscopic hysterectomy is well-tolerated with total laparoscopic hysterectomy and LAVH, yielding comparable rates of postoperative morbidity and reoperation. On average, LAVH procedures were 28 minutes faster than total laparoscopic hysterectomy. Additionally, increasing body mass index was not associated with higher rates of morbidity. LEVEL OF EVIDENCE: II. PMID- 23635679 TI - Consequences of a primary elective cesarean delivery across the reproductive life. AB - OBJECTIVE: To estimate cumulative risks of morbidity associated with the choice of elective cesarean delivery for a first delivery. METHODS: A decision analytic model was designed to compare major adverse outcomes across a woman's reproductive life associated with the choice of elective cesarean delivery compared with a trial of labor at a first delivery. Maternal outcomes assessed included maternal transfusion, hysterectomy, thromboembolism, operative injury, and death. Neonatal outcomes assessed included cerebral palsy and permanent brachial plexus palsy in the offspring. RESULTS: Choosing an initial cesarean delivery resulted in a 0.3% increased risk of a major adverse maternal outcome in the first pregnancy. In each subsequent pregnancy, the difference in composite maternal morbidity increased such that by the fourth pregnancy, the cumulative risk of a major adverse maternal outcome was nearly 10% in the elective primary cesarean delivery group, three times higher than women who initially underwent a trial of labor. Although the choice of an initial cesarean delivery resulted in 2.4 and 0.41 fewer cases of cerebral palsy and brachial plexus palsy, respectively, per 10,000 women in the first pregnancy, by a fourth pregnancy, the risk of a adverse neonatal outcome was higher among offspring of women who had chosen the initial elective cesarean delivery (0.368% compared with 0.363%). CONCLUSION: Maternal morbidity associated with the choice of primary elective cesarean delivery increases in each subsequent pregnancy and is greater in magnitude than that associated with the choice of a trial of labor. These increased risks are not offset by a substantive reduction in the risk of neonatal morbidity. PMID- 23635680 TI - Impaired ultrasonographic cervical assessment after voiding: a randomized controlled trial. AB - OBJECTIVE: To estimate whether the timing of bladder emptying affects focal myometrial contraction development and image adequacy. METHODS: Women at 14 0/7 32 0/7 weeks of gestation undergoing a transvaginal ultrasound examination from January 1, 2012, to September 1, 2012, were eligible for this blinded randomized controlled trial. Participants were randomly assigned to undergo transvaginal imaging immediately after urination (within 5 minutes) or to defer the imaging by at least 15 minutes. The primary outcome was focal myometrial contraction development as determined by two independent blinded reviews of the images. Secondary outcomes included image adequacy and the diagnosis of placenta previa. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using repeated-measures log binomial regression. RESULTS: Two hundred twenty-one women provided 335 randomized encounters for analysis. Women in the deferred scan group were 30% less likely to experience a focal myometrial contraction (28.1% compared with 40.5%, RR 0.70, 95% CI 0.52-0.93) and 41% less likely to have inadequate images (18.6% compared with 31.5%, RR 0.59, 95% CI 0.40-0.86). The two groups were equally likely to be diagnosed with placenta previa (P=.13). However, participants in the deferred scan group were 76% less likely to have images demonstrating a placenta previa and focal myometrial contraction (3.0% compared with 12.5%, RR 0.24, 95% CI 0.09-0.62) than participants in the immediate scan group. Eight women would need to defer imaging for 15 minutes from bladder voiding to prevent one focal myometrial contraction of the lower uterine segment or inadequate imaging. CONCLUSIONS: A brief interval (at least 15 minutes) between voiding and transvaginal cervical evaluation is associated with decreased risk for focal myometrial contractions and improved imaging. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01513395. LEVEL OF EVIDENCE: I. PMID- 23635682 TI - Peripartum bacteremia in the era of group B streptococcus prophylaxis. AB - OBJECTIVE: To define the microbial epidemiology and clinical risk factors associated with peripartum bacteremia in the era of group B streptococcus prophylaxis. METHODS: We identified all cases of maternal bacteremia occurring during the peripartum time period (defined as from 7 days before delivery until 30 days after delivery) in a large maternity center from 2000 to 2008. Chart review was performed to determine the clinical factors associated with bacteremia. RESULTS: During the study period, blood cultures were obtained from 1,295 febrile peripartum women (1.6% of all parturients); 172 of 1,295 febrile peripartum women (13.3%) had bacteremia (2.2 cases per 1,000 deliveries) with 194 microbial isolates and 1 yeast. The most frequent bacterial isolates were Escherichia coli (35.9%), enterococci (23.6%), and anaerobic species (9.2%); group B streptococcus was isolated in only eight cases (4.1%). Clinical diagnoses among infected women included endometritis (56%), chorioamnionitis (21%), and urosepsis (8%). Among women with endometritis, 77% underwent cesarean delivery (compared with vaginal delivery; relative risk [RR] 10.85, 95% confidence interval [CI] 6.75-17.45) and 39% delivered at less than 37 weeks of gestation (compared with 37 weeks or more; RR 3.21, 95% CI 2.42-4.25). Severe maternal complications of bacteremia were noted; six women required intensive care unit admission, five women had development of ileus, and one death occurred because of urosepsis. CONCLUSION: In the era of group B streptococcus prophylaxis, E coli and enterococci are the most frequent bacteria isolated in peripartum bacteremia. Group B streptococcus accounted for only 4% of cases. LEVEL OF EVIDENCE: III. PMID- 23635681 TI - Change in mononuclear leukocyte responsiveness in midpregnancy and subsequent preterm birth. AB - OBJECTIVE: To estimate the associations of change in immune response with preterm delivery, omega-3 supplementation, and fish diet. METHODS: This was an ancillary study to a randomized trial of omega-3 fatty acid supplementation for the prevention of recurrent preterm birth. In vitro maternal peripheral blood mononuclear leukocyte production of the anti-inflammatory cytokine, interleukin 10, and the proinflammatory cytokine, tumor necrosis factor-alpha, in response to stimulation with lipopolysaccharide, was measured at 16-22 weeks of gestation (baseline) and again at 25-28 weeks of gestation (follow-up) among women with prior spontaneous preterm birth. Changes in concentrations from baseline to follow-up ([INCREMENT]) were compared separately among groups defined by gestational age category at delivery, fish diet history, and omega-3 compared with placebo treatment assignment with Kruskal-Wallis tests. RESULTS: Interleukin 10 [INCREMENT] differed by gestational age category among 292 women with paired assays. Concentrations increased less in women delivering between 35 and 36 6/7 weeks of gestation (48.9 pg/mL) compared with women delivering at term (159.3 pg/mL) and decreased by 65.2 pg/mL in women delivering before 35 weeks of gestation (P=.01). Tumor necrosis factor-alpha Delta also differed by gestational age category among 319 women, but the pattern was inconsistent. Those delivering between 35 and 36 6/7 weeks of gestation exhibited decreased concentrations of tumor necrosis factor-alpha at follow-up compared with baseline (-356.0 pg/mL); concentrations increased among women delivering before 35 weeks of gestation and those delivering at term, 132.1 and 86.9 pg/mL (P=.03). Interleukin-10 Delta and tumor necrosis factor-alpha Delta were unaffected by either omega-3 supplementation or fish diet. CONCLUSION: Recurrent preterm birth was associated with decreased peripheral blood mononuclear leukocyte production of interleukin 10 in response to a stimulus during the second trimester. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00135902. LEVEL OF EVIDENCE: II. PMID- 23635683 TI - Single-incision laparoscopy in gynecologic surgery: a systematic review and meta analysis. AB - OBJECTIVE: To evaluate surgical outcomes for gynecologic surgery performed by single-incision laparoscopy compared with conventional multi-incision laparoscopy. DATA SOURCES: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and clinicaltrials.gov through August 2012. We also screened reference lists of retrieved articles and manually searched abstracts from conference proceedings. METHODS OF STUDY SELECTION: We included randomized control trials (RCTs) and high-quality observational studies that compared outcomes for single-incision laparoscopy and conventional laparoscopy for gynecologic surgery in patients. Included studies met predefined quality criteria and reported, at minimum, on complications, conversions, and operative time. TABULATION, INTEGRATION, RESULTS: Six RCTs and 15 observational studies met inclusion criteria, with a total of 2,085 patients (899 single-incision laparoscopies and 1,186 conventional laparoscopies). In the pooled analysis, there was no significant difference in the risk of total complications between single-incision laparoscopy and conventional laparoscopy groups (relative risk 1.01, 95% confidence interval [CI] 0.72-1.40; P=.97, random effects model). The meta-analysis was powered to detect a 5% difference in complications (power=0.8, alpha=0.05). Mean operative time for adnexal surgery performed by single-incision laparoscopy was 6.97 minutes longer than conventional laparoscopy (95% CI 0.16 13.77; P=.045; I=47.2; random effects based on three RCTs). There was no significant difference in mean operative time for hysterectomy procedures performed by single-incision laparoscopy (8.29 minutes, 95% CI -5.85 to 22.43; P=.251; I=83.6; random effects based on three RCTs). Clinical outcomes of postoperative pain, change in hemoglobin, length of hospital stay, and scar cosmesis could not be pooled because of paucity of data and lack of uniform reporting. CONCLUSION: There was no difference in the risk of complications between single-incision laparoscopy and conventional laparoscopy approaches in gynecologic surgery. Studies with imprecise effect sizes suggest that single incision laparoscopy may have longer operative time for adnexal surgery, but not for hysterectomy. Effects on other surgical outcomes remain uncertain. PMID- 23635685 TI - Noninvasive prenatal testing for fetal aneuploidy: clinical assessment and a plea for restraint. AB - The recent introduction of clinical tests to detect fetal aneuploidy by analysis of cell-free DNA in maternal plasma represents a tremendous advance in prenatal diagnosis and the culmination of many years of effort by researchers in the field. The development of noninvasive prenatal testing for clinical application by commercial industry has allowed much faster introduction into clinical care, yet also presents some challenges regarding education of patients and health care providers struggling to keep up with developments in this rapidly evolving area. It is important that health care providers recognize that the test is not diagnostic; rather, it represents a highly sensitive and specific screening test that should be expected to result in some false-positive and false-negative diagnoses. Although currently being integrated in some settings as a primary screening test for women at high risk of fetal aneuploidy, from a population perspective, a better option for noninvasive prenatal testing may be as a second tier test for those patients who screen positive by conventional aneuploidy screening. How noninvasive prenatal testing will ultimately fit with the current prenatal testing algorithms remains to be determined. True cost-utility analyses will be needed to determine the actual clinical efficacy of this approach in the general prenatal population. PMID- 23635684 TI - 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. AB - A group of 47 experts representing 23 professional societies, national and international health organizations, and federal agencies met in Bethesda, MD, September 14-15, 2012, to revise the 2006 American Society for Colposcopy and Cervical Pathology Consensus Guidelines. The group's goal was to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) following adoption of cervical cancer screening guidelines incorporating longer screening intervals and co-testing. In addition to literature review, data from almost 1.4 million women in the Kaiser Permanente Northern California Medical Care Plan provided evidence on risk after abnormal tests. Where data were available, guidelines prescribed similar management for women with similar risks for CIN 3, AIS, and cancer. Most prior guidelines were reaffirmed. Examples of updates include: Human papillomavirus-negative atypical squamous cells of undetermined significance results are followed with co-testing at 3 years before return to routine screening and are not sufficient for exiting women from screening at age 65 years; women aged 21-24 years need less invasive management, especially for minor abnormalities; postcolposcopy management strategies incorporate co-testing; endocervical sampling reported as CIN 1 should be managed as CIN 1; unsatisfactory cytology should be repeated in most circumstances, even when HPV results from co-testing are known, while most cases of negative cytology with absent or insufficient endocervical cells or transformation zone component can be managed without intensive follow-up. PMID- 23635686 TI - Obstetricians and their role in cord blood banking: promoting a public model. AB - Umbilical cord blood, the blood remaining in the umbilical cord at birth, can be collected at birth and be a source of stem cells for a patient in need of a bone marrow transplant. Obstetricians and other health care practitioners are recognized as a patient's primary source for medical information affecting the mother and her neonate and frequently are asked to provide education and guidance regarding options of private and public cord blood banking. As the use of cord blood continues to grow in medicine and research uncovers more potential for cord blood, cord blood banking has become an important resource. The Stem Cell Therapeutic and Research Act has provided funding to expand public banking initiatives in the United States and to create a more ethnically diverse inventory of units. Private storage is not advocated unless there is an identified need in the family such that banked cord blood would offer a benefit. A recent report outlined the challenges of increasing participation and inventory, particularly among minority groups. Obstetricians and other health care practitioners should have a primary role in efforts to increase awareness of umbilical cord blood donation and be involved in initiatives to expand current public banking activities. PMID- 23635688 TI - Is breast always best?: a personal reflection on the challenges of breastfeeding. PMID- 23635687 TI - Surgical management of leiomyomas for fertility or uterine preservation. AB - Leiomyomas are the most common pelvic tumors in women. These tumors are not always symptomatic but can cause abnormal uterine bleeding and anemia, pelvic pressure and pain, urinary frequency, and adverse reproductive outcomes-symptoms that can diminish the quality of life of women. Myomectomy is the primary treatment modality for women with symptomatic leiomyomas who are of reproductive age and desire future fertility. Myomectomy can significantly improve symptoms and quality of life and, in some clinical situations, improve reproductive outcomes. There are robust surgical outcome data supporting the use of a minimally invasive approach such as laparoscopy and hysteroscopy over laparotomy. Perioperative outcomes and return to normal activity are significantly better with a minimally invasive approach. Reproductive outcomes are not adversely affected. Detailed preoperative imaging is required for minimally invasive procedures to be successful. There are several evidence-based techniques that can be used to reduce blood loss during surgery. The role of robotic technology in enhancing surgical outcomes has not been clearly defined. PMID- 23635689 TI - What is new in gynecologic oncology?: thought-provoking articles from the past year. AB - This month, we focus on current research in gynecologic oncology. Dr. Modesitt discusses five recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 23635690 TI - Preventing unintended pregnancies by providing no-cost contraception. PMID- 23635691 TI - In reply. PMID- 23635692 TI - Perinatal outcomes associated with obstructive sleep apnea in obese pregnant women. PMID- 23635693 TI - In reply. PMID- 23635694 TI - Incidence of venous thromboembolism after minimally invasive surgery in patients with newly diagnosed endometrial cancer. PMID- 23635695 TI - In reply. PMID- 23635697 TI - In reply. PMID- 23635696 TI - Hospital discharge on the first compared with the second day after a planned cesarean delivery: a randomized controlled trial. PMID- 23635698 TI - Preventing the first cesarean delivery: summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal Fetal Medicine, and American College of Obstetricians and Gynecologists Workshop. PMID- 23635699 TI - In reply. PMID- 23635700 TI - Peripartum cardiomyopathy: population-based birth prevalence and 7-year mortality. PMID- 23635701 TI - In reply. PMID- 23635705 TI - ACOG committee opinion no. 556: Postmenopausal estrogen therapy: route of administration and risk of venous thromboembolism. AB - The development of menopausal symptoms and related disorders, which lead women to seek prescriptions for postmenopausal estrogen therapy and hormone therapy, is a common reason for a patient to visit her gynecologist, but these therapies are associated with an increased risk of venous thromboembolism. The relative risk seems to be even greater if the treated population has preexisting risk factors for venous thromboembolism, such as obesity, immobilization, and fracture. Recent studies suggest that orally administered estrogen may exert a prothrombotic effect, whereas transdermally administered estrogen has little or no effect in elevating prothrombotic substances and may have beneficial effects on proinflammatory markers. When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy. As part of the shared decision-making process, the gynecologist should weigh the risks against the benefits when prescribing combination estrogen plus progestin hormone therapy or estrogen therapy and counsel the patient accordingly. PMID- 23635706 TI - ACOG committee opinion no. 557: Management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. AB - Initial evaluation of the patient with acute abnormal uterine bleeding should include a prompt assessment for signs of hypovolemia and potential hemodynamic instability. After initial assessment and stabilization, the etiologies of acute abnormal uterine bleeding should be classified using the PALM-COEIN system. Medical management should be the initial treatment for most patients, if clinically appropriate. Options include intravenous conjugated equine estrogen, multi-dose regimens of combined oral contraceptives or oral progestins, and tranexamic acid. Decisions should be based on the patient's medical history and contraindications to therapies. Surgical management should be considered for patients who are not clinically stable, are not suitable for medical management, or have failed to respond appropriately to medical management. The choice of surgical management should be based on the patient's underlying medical conditions, underlying pathology, and desire for future fertility. Once the acute bleeding episode has been controlled, transitioning the patient to long-term maintenance therapy is recommended. PMID- 23635708 TI - ACOG committee opinion no. 559: Cesarean delivery on maternal request. AB - Cesarean delivery on maternal request is defined as a primary prelabor cesarean delivery on maternal request in the absence of any maternal or fetal indications. Potential risks of cesarean delivery on maternal request include a longer maternal hospital stay, an increased risk of respiratory problems for the infant, and greater complications in subsequent pregnancies, including uterine rupture, placental implantation problems, and the need for hysterectomy. Potential short term benefits of planned cesarean delivery compared with a planned vaginal delivery (including women who give birth vaginally and those who require cesarean delivery in labor) include a decreased risk of hemorrhage and transfusion, fewer surgical complications, and a decrease in urinary incontinence during the first year after delivery. Given the balance of risks and benefits, the Committee on Obstetric Practice believes that in the absence of maternal or fetal indications for cesarean delivery, a plan for vaginal delivery is safe and appropriate and should be recommended to patients. In cases in which cesarean delivery on maternal request is planned, delivery should not be performed before a gestational age of 39 weeks. Cesarean delivery on maternal request should not be motivated by the unavailability of effective pain management. Cesarean delivery on maternal request particularly is not recommended for women desiring several children, given that the risks of placenta previa, placenta accreta, and gravid hysterectomy increase with each cesarean delivery. PMID- 23635707 TI - ACOG committee opinion no. 558: Integrating immunizations into practice. AB - Given demonstrated vaccine efficacy, safety, and the large potential for prevention of many infectious diseases among adults, newborns, and pregnant women, obstetrician-gynecologists should embrace immunizations as an integral part of their women's health care practice. To provide direct examples, evidence based recommendations for three commonly administered immunizations by practicing obstetrician-gynecologists are discussed: 1) human papillomavirus vaccine, 2) influenza vaccine, and 3) tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine. PMID- 23635709 TI - ACOG committee opinion no. 560: Medically indicated late-preterm and early-term deliveries. AB - The neonatal risks of late preterm (34 0/7-36 6/7 weeks of gestation) and early term (37 0/7-38 6/7 weeks of gestation) births are well established. However, there are a number of maternal, fetal, and placental complications in which either a late-preterm or early-term delivery is warranted. The timing of delivery in such cases must balance the maternal and newborn risks of late-preterm and early-term delivery with the risks of further continuation of pregnancy. Decisions regarding timing of delivery must be individualized. Amniocentesis for the determination of fetal lung maturity in well-dated pregnancies generally should not be used to guide the timing of delivery. PMID- 23635710 TI - ACOG committee opinion no. 561: Nonmedically indicated early-term deliveries. AB - For certain medical conditions, available data and expert opinion support optimal timing of delivery in the late-preterm or early-term period for improved neonatal and infant outcomes. However, for nonmedically indicated early-term deliveries such an improvement has not been demonstrated. Morbidity and mortality rates are greater among neonates and infants delivered during the early-term period compared with those delivered between 39 weeks and 40 weeks of gestation. Nevertheless, the rate of nonmedically indicated early-term deliveries continues to increase in the United States. Implementation of a policy to decrease the rate of nonmedically indicated deliveries before 39 weeks of gestation has been found to both decrease the number of these deliveries and improve neonatal outcomes; however, more research is necessary to further characterize pregnancies at risk for in utero morbidity or mortality. Also of concern is that at least one state Medicaid agency has stopped reimbursement for nonindicated deliveries before 39 weeks of gestation. Avoidance of nonindicated delivery before 39 weeks of gestation should not be accompanied by an increase in expectant management of patients with indications for delivery before 39 weeks of gestation. Management decisions, therefore, should balance the risks of pregnancy prolongation with the neonatal and infant risks associated with early-term delivery. PMID- 23635711 TI - Anakinra and tocilizumab enhance survival and function of human islets during culture: implications for clinical islet transplantation. AB - Pretreatment culture before islet transplantation represents a window of opportunity to ameliorate the proinflammatory profile expressed by human beta cells in duress. Anakinra (IL-1 receptor antagonist) and tocilizumab (monoclonal IL-6 receptor antibody) are two known anti-inflammatory agents successfully used in the treatment of inflammatory states like rheumatoid arthritis. Both compounds have also been shown to reduce blood glucose and glycosylated hemoglobin in diabetic patients. We therefore sought to evaluate the impact of anakinra and tocilizumab on human beta-cells. The islets were precultured with or without anakinra or tocilizumab and then transplanted in a marginal mass model using human islets in immunodeficient mice. Islet viability was evaluated in an in vitro model. The pretreatment culture led to a significantly improved engraftment in treated islets compared to the vehicle. Anakinra and tocilizumab are not toxic to human islets and significantly reduce markers of inflammation and cell death. These results strongly support a pretreatment culture with anakinra and tocilizumab prior to human islet transplantation. PMID- 23635712 TI - Approaches to querying bacterial genomes with transposon-insertion sequencing. AB - In this review, we discuss transposon-insertion sequencing, variously known in the literature as TraDIS, Tn-seq, INSeq, and HITS. By monitoring a large library of single transposon-insertion mutants with high-throughput sequencing, these methods can rapidly identify genomic regions that contribute to organismal fitness under any condition assayable in the laboratory with exquisite resolution. We discuss the various protocols that have been developed and methods for analysis. We provide an overview of studies that have examined the reproducibility and accuracy of these methods, as well as studies showing the advantages offered by the high resolution and dynamic range of high-throughput sequencing over previous methods. We review a number of applications in the literature, from predicting genes essential for in vitro growth to directly assaying requirements for survival under infective conditions in vivo. We also highlight recent progress in assaying non-coding regions of the genome in addition to known coding sequences, including the combining of RNA-seq with high throughput transposon mutagenesis. PMID- 23635713 TI - Time-dependent effects of systemic lipopolysaccharide injection on regulators of antioxidant defence Nrf2 and PGC-1alpha in the neonatal rat brain. AB - BACKGROUND/AIMS: Both excitotoxicity and neuroinflammation are associated with oxidative stress. One transcription factor, nuclear factor E2-related factor 2 (Nrf2), and one transcription cofactor, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), increase the endogenous antioxidant defence and can thus modulate neuronal cell death. Here, we investigated the temporal effects (after 24 and 72 h) of systemic (i.p.) administration of lipopolysaccharide (LPS) on the cerebral Nrf2 and PGC-1alpha systems. METHODS AND RESULTS: Seven-day-old rat pups were injected with LPS (0.3 mg/kg). After 24 h, the protein levels of gamma-glutamylcysteine ligase modulatory subunit, gamma-glutamylcysteine ligase catalytic subunit, Nrf2, PGC 1alpha and manganese superoxide dismutase (MnSOD) were increased in parallel with decreased levels of Keap1. These effects were correlated with an increased level of phosphorylated Akt and elevated acetylation of histone 4. In contrast, 72 h following LPS, a decrease in the components of the Nrf2 system in parallel with an increase in Keap1 was observed. The down-regulation after 72 h correlated with phosphorylation of p38 mitogen-activated protein kinase, while there were no changes in PGC-1alpha and MnSOD protein levels or the acetylation/methylation pattern of histones. CONCLUSION: Systemic LPS in neonatal rats induced time dependent changes in brain Nrf2 and PGC-1alpha that correlated well with the protective effect observed after 24 h (pre-conditioning) and the deleterious effects observed after 72 h (sensitizing) of systemic LPS reported earlier. Collectively, the results point towards Nrf2 and PGC-1alpha as a possible mechanism behind these effects. PMID- 23635714 TI - The association of prevalent kidney stone disease with mortality in US adults: the National Health and Nutrition Examination Survey III, 1988-1994. AB - BACKGROUND: Kidney stone disease is associated with hypertension, diabetes, metabolic syndrome, kidney function decline, and increased cardiovascular (CV) events. However, its association with all-cause and CV mortality is unclear. METHODS: We used the Third National Health and Nutrition Examination Survey, a large US population-based study with mortality data through 2006 determined via linkage to the National Death Index to examine kidney stone disease in relation to all-cause and CV mortality risks. RESULTS: Among 14,879 men and women over 18 years of age who were eligible for analysis, 683 participants reported a history of kidney stones. There was a total of 3,590 all-cause and 1,608 CV deaths during a median follow-up of 14.9 years. Stone formers had a significantly higher risk for all-cause mortality [hazard ratio (HR): 1.95, 95% CI: 1.64-2.33, p < 0.0001) and CV mortality (HR: 2.05, 95% CI: 1.60-2.62, p < 0.0001) in unadjusted analyses. However, after multivariate adjustment for age, gender, race, and poverty, stone formers no longer had increased risk for all-cause mortality (HR: 1.08, 95% CI: 0.93-1.26, p = 0.3) and CV mortality (HR: 1.07, 95% CI: 0.84-1.36, p = 0.6). Results remain unchanged after further adjustment for other clinical variables including history of hypertension, diabetes, and CV disease. CONCLUSION: The increased risk of all-cause and CV mortality in kidney stone formers is likely a reflection of unique demographics and associated comorbidities. There is no independent association of prevalent kidney stone disease with all-cause and CV mortality. PMID- 23635715 TI - Practical strategies for enhancing adherence to treatment regimen in inflammatory bowel disease. AB - Promoting adherence to treatment among pediatric and adult patients with inflammatory bowel disease (IBD) is a critical yet challenging task for health care providers. Several existing interventions to enhance adherence among individuals with IBD offer useful information about practical strategies to enhance adherence. The current review article has 3 goals. First, the review provides a context for understanding treatment regimen adherence in IBD by reviewing key definitional, measurement, and conceptual challenges in this area. Next, published studies focused on interventions to enhance adherence in IBD are briefly summarized, followed by a synthesis of practical adherence promotion strategies for use in IBD by health care providers. Strategies are distinguished by the level of evidence supporting their utility as well as by age group. Finally, recommendations for future research to facilitate the development and implementation of practical, evidence-based strategies for adherence promotion in IBD are provided. Findings from the literature review suggest that strategies including education, regimen simplification, and use of reminder systems and organizational strategies (e.g., pill boxes) are likely to be best suited for addressing accidental nonadherence. In contrast, addressing motivational issues, teaching problem-solving skills, and addressing problematic patterns of family functioning are more likely to benefit individuals displaying intentional nonadherence. PMID- 23635717 TI - The long road to recovery: environmental health impacts of Hurricane Sandy. PMID- 23635716 TI - Cytokine-induced chromatin modifications of the type I collagen alpha 2 gene during intestinal endothelial-to-mesenchymal transition. AB - BACKGROUND: Fibrosis of the intestine is currently an irreversible complication of inflammatory bowel disease; yet, little is understood of the underlying pathogenesis and antifibrotic strategies remain elusive. To develop effective therapies, knowledge of the mechanism of transcription and excessive deposition of type I collagen, a hallmark of fibrosis, is needed. We have shown previously that endothelial-to-mesenchymal transition (EndoMT) contributes to the pool of intestinal fibrotic cells and that a cytokine cocktail (interleukin 1-beta, tumor necrosis factor alpha, and transforming growth factor beta) induces collagen I alpha 2 (COL1A2) mRNA and protein. METHODS: Chromatin immunoprecipitation assays on pure cultures of human intestinal mucosal endothelial cells undergoing EndoMT were performed with antibodies to specific histone modifications and RNA polymerase II. Reverse transcriptase-PCR was used to quantify the levels of Col1A2 and endothelial-specific von Willebrand factor (vWF) mRNA. RESULTS: We showed that cytokines induce selective chromatin modifications (histone 4 hyperacetylation, and hypermethylation of histone 3) and phosphorylated RNA polymerase II at the COL1A2 promoter. Hypoacetylated and hypomethylated histone 3 was detected on the repressed vWF gene. Prolonged exposure to cytokines (16 days) retained hyperacetylation of select lysines in H4 on the COL1A2 promoter. Removal of cytokines after 16 days and continued culture for 10 days showed persistent hyperacetylation at lysine 16 in histone H4. CONCLUSIONS: This is the first study to show that COL1A2 gene expression is associated with cytokine-induced, temporally ordered, and persistent chromatin modifications and suggests that these are important determinants of gene expression in EndoMT and intestinal fibrosis. PMID- 23635718 TI - Different long-term response to growth hormone therapy in small- versus appropriate-for-gestational-age children with growth hormone deficiency. AB - BACKGROUND/AIMS: The role of birth weight on growth hormone (GH) therapy response in GH-deficient (GHD) children has not been fully elucidated. Therefore, we examined the growth of 23 small-for-gestational-age GHD children (SGA-GHD, 11 females and 12 males), 26 appropriate-for-gestational-age GHD children (AGA-GHD, 11 females and 15 males) during the first 5 years of GH therapy and that of 22 non-GH-treated SGA children (12 females and 10 males). METHODS: We collected height and height velocity measurements yearly. RESULTS: In AGA-GHD children, height was always greater than in the SGA groups and significantly increased from the fourth year of treatment. Height velocity was higher (SGA-GHD: 1.72 +/- 0.30 standard deviation score, SDS, AGA-GHD: 2.67 +/- 0.21 SDS; p = 0.039) in AGA-GHD children during the first year of treatment. The AGA-GHD group showed the highest percentage (52.4%) of subjects surpassing mid-parental height and the greatest height gain after 5 years of follow-up. CONCLUSION: Our results show that birth size is an important factor affecting the response to GH therapy in GHD children during the first 5 years of treatment. The paediatric endocrinologist should be aware of this factor when planning the management of GHD children born SGA. PMID- 23635719 TI - In our hands: responding to the IOM report on workforce needs for older adults with mental health and substance use disorders. PMID- 23635720 TI - Reports of patients and relatives from the CogniCIS study about cognition in clinically isolated syndrome: what are our patients telling us? AB - OBJECTIVE: To assess the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) in patients with clinically isolated syndrome (CIS). METHODS: 130 European CIS patients and 60 relatives completed the MSNQ. RESULTS: The mean (SD) MSNQ score for CIS patients was 15.5 (10.8) and for their informants 11.3 (9.6). Neither the CIS patient nor relative MSNQ report scores correlated with any of the cognitive test scores in the Brief Repeatable Battery of Neuropsychological Tests, but they were significantly related to psychosocial scales including depression. CONCLUSIONS: In CIS, patient and relative MSNQ scores are influenced by psychosocial variables rather than actual objective cognitive status. Formal cognitive test assessment is recommended for CIS patients. PMID- 23635721 TI - RNA-based blood genomics as an investigative tool and prospective biomarker for ischemic stroke. AB - Stroke is a leading cause of death and disability, and considerable effort is being expended to investigation of its pathological mechanisms, as well as the identification of clinically relevant biomarkers that could assist in diagnosis. RNA-based analysis of gene expression in blood represents a new field of study addressing both paradigms. A number of recent animal and human studies using microarray technology demonstrate rapidly-induced, measurable changes in gene expression in response to ischemic trauma, and distinct expression 'profiles' specific to the injury subtype. The incorporation of newer technologies for a more detailed transcriptome analysis holds great promise for further improving our knowledge of stroke at the molecular level, and potentially enhancing standards of diagnosis. PMID- 23635722 TI - Current world literature. Fertility. PMID- 23635724 TI - Electronic fetal monitoring: the debate goes on...and on...and on. PMID- 23635726 TI - Translating guidelines and public policy into optimal health care for women: carrots and sticks. PMID- 23635725 TI - The intrauterine device: a good thing revisited. PMID- 23635727 TI - Electronic fetal monitoring in the United States: temporal trends and adverse perinatal outcomes. AB - OBJECTIVE: To examine trends in electronic fetal monitoring (EFM) use and quantify the extent to which such trends are associated with changes in rates of primary cesarean delivery and neonatal morbidity and mortality. METHODS: We carried out a retrospective study of more than 55 million nonanomalous singleton live births (24-44 weeks of gestation) delivered in the United States between 1990 and 2004. Changes in the risks of neonatal mortality, cesarean delivery, and operative vaginal delivery for fetal distress, 5-minute Apgar score lower than 4, and neonatal seizures (at 34 weeks of gestation or after) were examined in relation to changes in EFM use. RESULTS: Electronic fetal monitoring use increased from 73.4% in 1990 to 85.7% in 2004, a relative increase of 17% (95% confidence interval 16-18%). This increase was associated with an additional 5% and 2% decline in early and late neonatal deaths, respectively, at 24-33 weeks of gestation as well as a 4-7% additional decline in the 5-minute Apgar score lower than 4 at 24-33, 34-36, and 37-44 weeks of gestation. Increasing EFM use was associated with a 2-4% incremental increased rate of both cesarean delivery and operative vaginal delivery for fetal distress at 24-33, 34-36, and 37-44 weeks of gestation. Increasing EFM was not associated with any temporal changes in the rate of neonatal seizures. CONCLUSIONS: The temporal increase in EFM use in the United States appears to be modestly associated with the recent declines in neonatal mortality, especially at preterm gestations. LEVEL OF EVIDENCE: II. PMID- 23635729 TI - Prophylactic use of levonorgestrel-releasing intrauterine system in women with breast cancer treated with tamoxifen: a randomized controlled trial. AB - OBJECTIVE: To estimate the rate of endometrial pathology with the prophylactic use of levonorgestrel-releasing intrauterine system in women with breast cancer treated with tamoxifen. METHODS: This was a randomized contro-lled trial of 129 Chinese women who attended a university hospital in Hong Kong and required adjuvant tamoxifen for breast cancer after the completion of postoperative radiotherapy and chemotherapy. Women were randomized to treatment (prophylactic levonorgestrel-releasing intrauterine system insertion before the commencement of tamoxifen) or control group. The uterine cavity was examined by hysteroscopy and endometrial sampling before the commencement of tamoxifen and at 12, 24, 45, and 60 months afterward. Any endometrial polyps or submucosal fibroids were resected through hysteroscopy at each assessment and specimens were sent for histologic confirmation. RESULTS: A total of 94 women completed 5-year follow-up. There was no significant difference in the occurrence of submucosal fibroids (1 [1.8%] compared with 2 [3.4%]) and endometrial hyperplasia (both 0) in the treatment and control groups, respectively. Levonorgestrel-releasing intrauterine system significantly reduced de novo endometrial polyps (hazard ratio 0.19, 95% confidence interval 0.07-0.48) over the course of 5 years on an intention-to treat basis. There was no statistically significant increase in breast cancer recurrence rate (10 [17.2%] compared with 6 [10.0%]) or cancer-related deaths (6 [10.3%] compared with 5 [8.3%]) in the treatment group, but the study was underpowered in this regard. CONCLUSIONS: Prophylactic levonorgestrel-releasing intrauterine system prevents de novo endometrial polyps in women using tamoxifen. However, its role in the prevention of endometrial hyperplasia and adenocarcinoma as well as its effect on risk of breast cancer recurrence remain uncertain. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry, http://www.chictr.org/en/, ChiCTR-TRC-09000625. LEVEL OF EVIDENCE: I. PMID- 23635728 TI - Management of initial bleeding or spotting after levonorgestrel-releasing intrauterine system placement: a randomized controlled trial. AB - OBJECTIVE: To assess the efficacy of tranexamic acid or mefenamic acid in the management of the initial "nuisance" bleeding or spotting in the period immediately after placement of the levonorgestrel-releasing intrauterine system. METHODS: Women were randomized after levonorgestrel-releasing intrauterine system placement to oral tranexamic acid (500 mg), mefenamic acid (500 mg), or placebo three times daily during bleeding or spotting episodes over a 90-day treatment period. Treatment was initiated from onset of a bleeding or spotting episode and continued until the first day after bleeding or spotting stopped and restarted with a new bleeding or spotting episode. The primary efficacy variable was reduction in the number of bleeding or spotting days. Tranexamic acid and mefenamic acid were compared with placebo using a one-sided Wilcoxon rank-sum test. Bonferroni-Holm adjustment was used to account for multiple testing. RESULTS: A total of 204 women were screened; 187 were randomized to tranexamic acid (n=63), mefenamic acid (n=63), or placebo (n=61). The median number of bleeding or spotting days experienced during treatment was 25, 29, and 33 days in the three groups, respectively. The median number of bleeding or spotting days was reduced by 6 days (95% confidence interval [CI] -14.0 to 1.0, P=.049) with tranexamic acid and by 3 days (95% CI -11.0 to 5.0, P=.229) with mefenamic acid compared with placebo. The relative risk of bleeding or spotting compared with placebo with tranexamic acid and mefenamic acid was 0.82 (95% CI 0.65-1.03) and 0.89 (95% CI 0.71-1.11), respectively. Most women (85% or more) were satisfied with the levonorgestrel-releasing intrauterine system across the groups. CONCLUSIONS: Tranexamic acid and mefenamic acid during the first 90 days after levonorgestrel-releasing intrauterine system placement do not alleviate "nuisance" bleeding or spotting. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01295294. LEVEL OF EVIDENCE: I. PMID- 23635730 TI - Complications and continuation of intrauterine device use among commercially insured teenagers. AB - OBJECTIVE: Many U.S. health care providers remain reluctant to prescribe intrauterine devices (IUDs) to teenagers as a result of concerns about serious complications. This study examined whether 15-19-year-old IUD users were more likely to experience complications, failure, or early discontinuation than adult users aged 20-24 years and 25-44 years and whether there were differences in these outcomes between users of levonorgestrel-releasing intrauterine systems and copper IUDs. METHODS: A retrospective cohort study was conducted using health insurance claims obtained from a private insurance company of 90,489 women who had an IUD inserted between 2002 and 2009. Logistic regression models were used to estimate the odds of experiencing complications, method failure, or early discontinuation within 12 months of insertion by age group and type of IUD inserted. RESULTS: Serious complications, including ectopic pregnancy and pelvic inflammatory disease, occurred in less than 1% of patients regardless of age or IUD type. Women aged 15-19 years were more likely than those aged 25-44 years to have a claim for dysmenorrhea (odds ratio [OR] 1.4, confidence interval [CI] 1.1 1.6), amenorrhea (OR 1.3, CI 1.1-1.5), or normal pregnancy (OR 1.4, CI 1.1-1.8). Overall, early discontinuation did not differ between teenagers and women aged 25 44 years (13% compared with 11%, P>.05). However, use of the levonorgestrel releasing intrauterine system was associated with fewer complications and less early discontinuation than the copper IUD in all age groups. CONCLUSIONS: The IUD is as appropriate for teenagers to use as it is for older women, with serious complications occurring infrequently in all groups. The levonorgestrel-releasing intrauterine system may be a better choice than the copper IUD as a result of lower odds of complications, discontinuation, and failure. LEVEL OF EVIDENCE: II. PMID- 23635731 TI - Breast effects of bazedoxifene-conjugated estrogens: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effects of bazedoxifene-conjugated estrogens on mammographic breast density and other breast parameters in nonhysterectomized postmenopausal women enrolled in a randomized, double-blind, placebo-controlled, and active-controlled phase 3 study. METHODS: The 1-year Selective estrogens, Menopause, And Response to Therapy-5 trial estimated the efficacy and safety of bazedoxifene-conjugated estrogens in 1,843 postmenopausal women seeking vasomotor symptom treatment. A substudy enrolled 940 women with technically acceptable digital mammograms at screening and at 1 year. Treatments included bazedoxifene 20 mg and conjugated estrogens 0.45 or 0.625 mg, placebo, bazedoxifene 20 mg, and conjugated estrogens (0.45 mg) and medroxyprogesterone acetate (1.5 mg). Mammograms were centrally read by a single radiologist blinded to treatment and time sequence; percent breast density was determined using validated software. Noninferiority was based on a predefined margin of 1.5% for comparison of adjusted mean differences in breast density at 12 months. RESULTS: Bazedoxifene 20 mg and conjugated estrogens 0.45 and 0.625 mg demonstrated noninferiority to placebo in breast density. Mammographic breast density decreased from baseline with bazedoxifene 20 mg and conjugated estrogens 0.45 and 0.625 mg and placebo (mean -0.38% and standard error [SE] 0.22%, mean -0.44% and SE 0.22%, mean -0.32% and SE 0.23%, respectively). Conjugated estrogens-medroxyprogesterone acetate significantly increased breast density from baseline (mean 1.60%, SE 0.35%; P<.001) compared with placebo. Both bazedoxifene-conjugated estrogens doses showed rates of breast tenderness similar to placebo and significantly (P<.001) lower than conjugated estrogens-medroxyprogesterone acetate. No differences in incidence of breast-related adverse events were identified. CONCLUSION: Bazedoxifene 20 mg and conjugated estrogens 0.45 and 0.625 mg did not increase mammographic breast density or breast tenderness over the course of 1 year with a favorable breast-related safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00808132. LEVEL OF EVIDENCE: I. PMID- 23635733 TI - Risk of childhood obesity in the toddler offspring of mothers with gestational diabetes. AB - OBJECTIVE: To estimate whether children aged 2-4 years of mothers with gestational diabetes are at increased risk for childhood obesity. Secondary objectives included examining the associations between maternal body mass index (BMI), gestational weight gain, large-for-gestational-age (LGA) newborns, and race or ethnicity with childhood obesity. METHODS: Retrospective cohort study of women with and without gestational diabetes mellitus (GDM), and their term offspring, who delivered at a single institution between 2004 and 2007. RESULTS: We identified 255 woman and toddler pairs with GDM and 1,838 woman and toddler pairs without GDM. Mean BMI percentiles of toddlers of women with and without GDM did not differ (mean 51.8 percentile compared with 55.3 percentile; P=.12). Adjusted logistic regression models demonstrated increased risk of toddler obesity with higher prepregnancy BMI compared with normal-weight mothers (adjusted odds ratio [OR] 2.56, 95% confidence interval [CI] 1.92-3.42). Additionally, LGA increased the odds of toddler overweight and obesity (adjusted OR 1.8, 95% CI 1.4-2.3). CONCLUSION: Childhood obesity was not associated with GDM but was associated with higher prepregnancy maternal BMI and LGA. LEVEL OF EVIDENCE: II. PMID- 23635734 TI - Factors associated with urgent cesarean delivery in women with type 1 diabetes mellitus. AB - OBJECTIVE: Type 1 diabetes mellitus (DM) is associated with a threefold to fivefold increased risk for stillbirth during pregnancy. The objective of the present study was to identify factors associated with prelabor urgent cesarean delivery for fetal compromise in women with type 1 DM. METHODS: We performed a nested case-control study within a prospective cohort of single pregnancies in women with type 1 DM managed with standardized protocols regarding treatment of diabetes and prenatal care. Twice-weekly home antenatal surveillance including nonstress test was initiated at 32 weeks of gestation and continued until planned delivery at 38-39 weeks of gestation. We identified factors associated with urgent cesarean delivery for an abnormal nonstress test. The calculated total sample size was 416 pregnancies. Independent factors and adjusted odds ratio (OR) were identified by logistic regression. RESULTS: Among 479 pregnancies, the rate of urgent cesarean delivery for an abnormal nonstress test was 4%. A hemoglobin A1C (Hb A1C) level at delivery of 6.4% or higher occurred in 34% of the pregnancies and was independently associated with urgent cesarean delivery (2% compared with 8%, P=.003, OR 4.16, 95% confidence interval 1.40-12.32). In the multivariable analysis, lack of preconception care and occurrence of gestational hypertension or preeclampsia were not associated with urgent cesarean delivery. The rate of stillbirth was 2 per 1,000. CONCLUSION: In women with type 1 DM, an Hb A1C level at delivery of 6.4% or higher was associated with prelabor urgent cesarean delivery. This suggests that tight glycemic control throughout pregnancy might reduce the risk of late fetal compromise. LEVEL OF EVIDENCE: III. PMID- 23635735 TI - Expectant management compared with elective delivery at 37 weeks for gastroschisis. AB - OBJECTIVE: To estimate obstetric and neonatal outcomes after induction of labor at 37 weeks of gestation compared with expectant management in pregnancies complicated by fetal gastroschisis. METHODS: The management of 296 pregnancies involving fetal gastroschisis (1980-2011) was reviewed from a single perinatal center. Ultrasound surveillance and nonstress testing were performed every 2 weeks from 30 weeks of gestation, weekly from 34 weeks of gestation, and twice weekly after 35 weeks of gestation until delivery. Labor was induced if fetal well-being testing was abnormal and, since 1994, labor was routinely induced at 37 weeks of gestation. RESULTS: Of 153 pregnancies reaching 37 weeks of gestation, labor was induced in 77 (26%) and 76 (25.7%) were allowed to labor spontaneously. There were no significant differences in mean maternal age (22 years in both), parity (56% compared with 66% nulliparous), presence of other fetal anomalies (12% compared with 9%), cesarean delivery rate (20% in both), 5 minute Apgar score less than 7 (10% compared with 12%), meconium at birth (36% compared with 49%), or respiratory distress syndrome (16% compared with 7%) between the induced and expectantly managed groups. However, neonatal sepsis (25% compared with 42%; P=.02) and a composite outcome of neonatal death and bowel damage (necrosis, atresia, perforation, adhesion; 8% compared with 21%; P=.02) were more common in expectantly managed pregnancies. Moreover, time to oral feeds (-3.4 days), time on total parenteral nutrition (-6.2 days), and hospital stay ( 6.7 days) were reduced when labor was induced. CONCLUSION: In fetuses with gastroschisis, induction of labor at 37 weeks of gestation was associated with reduced risks of sepsis, bowel damage, and neonatal death compared with pregnancies managed expectantly beyond 37 weeks of gestation. LEVEL OF EVIDENCE: II. PMID- 23635732 TI - Pregnancy outcomes with weight gain above or below the 2009 Institute of Medicine guidelines. AB - OBJECTIVE: To evaluate pregnancy outcomes according to 2009 Institute of Medicine (IOM) gestational weight gain guidelines. METHODS: This study is a secondary analysis of a preeclampsia prevention trial among nulliparas carrying singletons. Odds ratios and 95% confidence intervals (adjusted for maternal age, race, smoking, and treatment group) were calculated based on total weight gain below or above the IOM guidelines stratified by prepregnancy body mass index (BMI). The referent group was weight gain within the guidelines. RESULTS: Of 8,293 pregnancies, 9.5% had weight gain below, 17.5% within, and 73% above IOM guidelines. With excess weight gain, all BMI categories had an increased risk of hypertensive disorders; normal weight and overweight women also had increased risk of cesarean delivery and neonatal birth weight at or above the 90 centile but a decreased risk of weight below the 10 centile. There were no consistent associations with insufficient weight gain and adverse outcomes. CONCLUSION: Excess weight gain was prevalent and associated with an increased risk of hypertensive disorders, cesarean delivery, and large-for-gestational-age neonates. PMID- 23635736 TI - Value of urodynamics before stress urinary incontinence surgery: a randomized controlled trial. AB - OBJECTIVE: To estimate whether a strategy of immediate surgery was noninferior to a strategy based on discordant urodynamic findings followed by individually tailored therapy in women with stress urinary incontinence (SUI). METHODS: A multicenter diagnostic cohort study with an embedded noninferiority randomized controlled trial was conducted in six academic and 24 nonacademic Dutch hospitals. Women with predominant SUI eligible for surgical treatment based on clinical assessment were included between January 2009 and November 2010. All patients underwent urodynamics. In patients in whom urodynamics were discordant with clinical assessment, participants were randomly allocated to receive either immediate surgery or individually tailored therapy based on urodynamics. The primary outcome was clinical improvement assessed by the Urogenital Distress Inventory 12 months after baseline. Analysis was by intention to treat; a difference in mean improvement of 5 points or less was considered noninferior. RESULTS: Five hundred seventy-eight women with SUI were studied, of whom 268 (46%) had discordant findings. One hundred twenty-six patients gave informed consent for randomization and were allocated to receive immediate surgery (n=64) or individually tailored therapy (n=62). The mean improvement measured with the Urogenital Distress Inventory after 1 year was 44 points (+/-24) in the group receiving immediate surgery and 39 (+/-25) points in the group receiving individually tailored treatment. The difference in mean improvement was 5 points in favor of the group receiving immediate surgery (95% confidence interval infinity to 5). There were no differences with respect to cure or complication rate. CONCLUSION: In women with uncomplicated SUI, an immediate midurethral sling operation is not inferior to individually tailored treatment based on urodynamic findings. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00814749. LEVEL OF EVIDENCE: I. PMID- 23635738 TI - Levator ani deficiency and pelvic organ prolapse severity. AB - OBJECTIVE: To estimate whether levator ani deficiency severity is a predictor of clinically significant pelvic organ prolapse (POP) and to determine whether there is a levator ani deficiency threshold above which POP occurs. METHODS: Two hundred twenty three-dimensional ultrasound scans performed on urogynecologic clinic patients were reviewed, and each levator ani muscle subdivision was individually scored (0=no defect, 1=50% or less defect, 2=more than 50% defect, 3=total absence of the muscle) on each side. A levator ani deficiency score was calculated and categorized as mild (score 0-6), moderate (score 7-12), and severe (score more than 13). Clinically significant prolapse was defined as stage 2 or higher. RESULTS: The mean age was 56.50 (standard deviation +/-15.58) and median parity was 2 (range 0-6). A mild positive correlation was demonstrated between levator ani deficiency category and prolapse stage (rs=0.44; P<.001). Score distribution significantly differed by prolapse stage (P<.001). No patients with stage 3 prolapse had a levator ani score less than 6, and no patients with stage 4 prolapse had a levator ani score less than 9. In patients with prolapse, those with moderate levator ani deficiency had 3.2 times the odds of POP compared with patients with a minimal defect; those with severe levator ani deficiency had 6.4 times the odds of prolapse than those with minimal deficiency. CONCLUSIONS: Levator ani deficiency severity is associated with clinically significant prolapse. LEVEL OF EVIDENCE: II. PMID- 23635739 TI - A multistate quality improvement program to decrease elective deliveries before 39 weeks of gestation. AB - OBJECTIVE: Nonmedically indicated (elective) deliveries before 39 weeks of gestation result in unnecessary neonatal morbidity. We sought to determine whether implementation of a process improvement program will decrease the rate of elective scheduled singleton early-term deliveries (37 0/7-38 6/7 weeks of gestation) in a group of diverse community and academic hospitals. METHODS: Policies and procedures for scheduling inductions and cesarean deliveries were implemented and patient and health care provider education was provided. Outcomes for scheduled singleton deliveries at 34 weeks of gestation or higher were submitted through a web-based data entry system. The rate of scheduled singleton elective early-term deliveries as well as the rates of early-term medically indicated and unscheduled deliveries, neonatal intensive care unit admissions, and singleton term fetal mortality rate were evaluated. RESULTS: A total of 29,030 scheduled singletons at 34 weeks of gestation or higher were delivered in 26 participating hospitals between January 2011 and December 2011. Elective scheduled early-term deliveries decreased from 27.8% in the first month to 4.8% in the 12th month (P<.001); rates of elective scheduled singleton early-term inductions (72%, P=.029) and cesarean deliveries (84%; P<.001) decreased significantly. There was no change in medically indicated or unscheduled early term deliveries. Neonatal intensive care unit admissions among scheduled early term singletons decreased nonsignificantly from 1.5% to 1.2% (P=.24). There was no increase in the term fetal mortality rate. CONCLUSION: A rapid-cycle process improvement program substantially decreased elective scheduled early-term deliveries to less than 5% in a group of diverse hospitals across multiple states. LEVEL OF EVIDENCE: III. PMID- 23635740 TI - Maternal and neonatal outcomes of successful Kielland's rotational forceps delivery. AB - OBJECTIVE: To estimate the rates of early neonatal and maternal complications in a consecutive series of successful Kielland's rotational forceps deliveries. METHODS: This was a retrospective cohort study of consecutive cases of successful rotational forceps deliveries performed in singleton pregnancies at 36 weeks of gestation or more in a tertiary referral center in Scotland, UK, from 2001 to 2008 (n=873). We also compared outcomes associated with successful rotational forceps deliveries in 2008 (n=150) with those of nonrotational forceps delivery (n=873), ventouse delivery (n=159), spontaneous vertex delivery (n=3,494), and emergency cesarean delivery (n=947). RESULTS: There was one stillbirth associated with a rotational forceps delivery. This was diagnosed before application of forceps. After rotational forceps deliveries, 58 of 872 (6.7%) of live-born neonates were admitted to the neonatal unit. Twenty-seven of 872 (3.1%) neonates had one or more complications that could be attributable to traumatic delivery and seven neonates (0.8%) had a diagnosis of neonatal encephalopathy. When compared with alternative methods of delivery over a single year, neonatal admission rates after delivery by rotational forceps deliveries (5 of 150 [3.3%]) were not significantly different from spontaneous vertex delivery (128 of 3,494 [3.7%; P=1.00]) or ventouse delivery (6 of 159 [3.8%; P=1.00]) and lower than emergency cesarean delivery (106 of 947 [11.2%; P=.002). Postpartum hemorrhage rates after rotational forceps deliveries (8 of 150 [5.3%; P=.008]) were lower than those associated with emergency cesarean delivery (142 of 947 [15.0%; P=.008]). CONCLUSION: Rates of short-term neonatal and maternal complications after successful rotational forceps deliveries are low. LEVEL OF EVIDENCE: II. PMID- 23635741 TI - Cardiovascular disease risk factors in women with a history of early-onset preeclampsia. AB - OBJECTIVE: To assess the prevalence of established cardiovascular disease risk factors and to estimate 10-year absolute risk of cardiovascular disease after early-onset preeclampsia. METHODS: We assessed major cardiovascular disease risk factors in 243 primiparous women with a history of early-onset preeclampsia (delivery at less than 34 weeks of gestation) at least 6 months after delivery; 374 healthy nonpregnant women of similar age served as a reference group. RESULTS: After adjustment for age, we observed significantly higher means for body mass index, blood pressure, total and low-density lipoprotein cholesterol, triglycerides, glucose, and lower mean high-density lipoprotein cholesterol (all P<.01) in women with previous early-onset preeclampsia compared with the reference group. Prevalence of the metabolic syndrome was 15.2% compared with 4.3% (P<.001), two or more major cardiovascular disease risk factors were present in 51.0% compared with 26.5%, and three or more risk factors were present in 18.9% compared with 6.4%, respectively. Mean estimated 10-year cardiovascular disease risks by the Framingham Risk Score were 1.08% (95% confidence interval 1.04-1.12) and 1.01% (95% CI 1.00-1.01; P<.001) for the difference. CONCLUSION: Women with a history of early-onset preeclampsia have a high prevalence of several major cardiovascular disease risk factors. Although the estimated 10-year cardiovascular disease risk is low (less than 5%) after delivery, cardiovascular disease risk is expected to increase rapidly with increasing age. LEVEL OF EVIDENCE: II. PMID- 23635737 TI - Patient satisfaction after midurethral sling surgery for stress urinary incontinence. AB - OBJECTIVE: To identify factors that may contribute to patient satisfaction with outcome in women who received retropubic and transobturator midurethral slings. METHODS: Satisfaction was assessed 12 months postsurgery as a planned analysis in 597 participants from a multicenter randomized trial comparing retropubic with transobturator midurethral slings using the Incontinence Surgery Satisfaction Questionnaire. Significantly related variables associated with satisfaction in univariable analyses were entered into multivariable logistic regression models to test their independent association with satisfaction. RESULTS: One year after surgery, 264 (88.6%) in the retropubic group and 263 (88.0%) in the transobturator group completed satisfaction questionnaires. Both treatment groups demonstrated a high level of satisfaction with respect to urine leakage (retropubic 85.9% compared with transobturator 90.0%; P=.52), urgency to urinate, frequency of urination, capability of physical activity, social activity, ability to engage in sexual activity, and from an emotional standpoint. Baseline characteristics associated with reduced satisfaction were higher Medical, Epidemiologic, and Social Aspects of Aging Questionnaire urgency subscale scores, detrusor overactivity, and diabetes mellitus. The severity of both objective (frequency of incontinence episodes, pad test weight) and subjective (Incontinence Impact Questionnaire and Urogenital Distress Inventory score) measures of incontinence at baseline and the patients' perceptions of preoperative severity of incontinence and expectations of achieving postoperative cure or improvement were not statistically different between satisfied and unsatisfied patients. In the final multivariable model, satisfaction was associated with overall treatment success (odds ratio [OR] 2.57, 95% confidence interval [CI] 1.29-5.13], greater reduction in Urogenital Distress Inventory (OR 0.97, 95% CI 0.96-0.98) and Incontinence Impact Questionnaire scores (OR 0.99, 95% CI 0.98-0.99), and fewer complications (OR 0.55, 95% CI 0.30-0.99). CONCLUSION: The high level of satisfaction seen after midurethral sling procedures is associated with greater objective and patient-perceived improvement of stress incontinence and fewer complications. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00325039. LEVEL OF EVIDENCE: II. PMID- 23635742 TI - A prediction score for maternal mortality in Senegal and Mali. AB - OBJECTIVE: To develop and validate a maternal mortality score to identify patients at risk of in-hospital death in developing countries. METHODS: We performed a prospective observational study in 46 referral hospitals in Senegal and Mali, starting October 1, 2007. Derivation of a maternal mortality score was performed, using generalized estimating equation, on patients included during the first 6 months of the study (301 deaths out of 43,624 deliveries) and validated on patients included during the next 6 months (345 deaths out of 46,328 deliveries). RESULTS: Nine criteria were independently associated with maternal death: severe anemia in pregnancy, malaria diagnosed during pregnancy, parity greater than 4, fewer than three antenatal visits, referral from another health facility, antepartum or postpartum hemorrhage, preeclampsia or eclampsia, uterine rupture, and genital infection or sepsis. The maternal mortality score, ranging from 0 to 100, occupies an area under the receiver operating characteristics curve of 0.89 (95% confidence interval [CI] 0.87-0.91). The low-risk group for maternal mortality, based on a score less than 10, has a negative predictive value of 99.9% (95% CI 99.8-99.9) and a negative likelihood ratio of 0.18, ruling out maternal mortality with a probability of 0.13% (95% CI 0.09-0.17). Sensitivity of the score to identify patients at risk of in-hospital death was 85.0% (95% CI 80.5-88.8). Validation of the score yielded a sensitivity of 87.8% (95% CI 83.9-91.1), a negative predictive value of 99.9% (95% CI 99.8-99.9), and a probability of maternal death of 0.12% (95% CI 0.08-0.17) in the low-risk group. CONCLUSION: : The maternal mortality score could help health care professionals to identify patients at risk of maternal mortality who need careful management. LEVEL OF EVIDENCE: III. PMID- 23635744 TI - Loop electrosurgical excision procedure and the risk for preterm delivery. AB - OBJECTIVE: To estimate whether the severity of cervical intraepithelial neoplasia (CIN) and the loop electrosurgical excision procedure (LEEP) increase the risk for preterm delivery, and to evaluate the role of repeat LEEP and time interval since LEEP. METHODS: This was a retrospective register-based study from Finland from 1997 to 2009. We linked Hospital Discharge Register and Finnish Medical Birth Register data. Case group women consisted of 20,011 women who underwent LEEP during the study period and their subsequent singleton deliveries in 1998 2009. Control population included women from the Medical Birth Register with no LEEP (n=430,975). The main outcome measure was preterm delivery before 37 weeks of gestation. RESULTS: The risk for preterm delivery increased after LEEP. Women with previous LEEP had 547 (7.2%) preterm deliveries, whereas the control population had 30,151 (4.6%) preterm deliveries (odds ratio [OR] 1.61, confidence interval [CI] 1.47-1.75, number needed to harm 38.5). The overall preterm delivery rate in the study period was 4.6% for singleton deliveries. Repeat LEEP was associated with an almost threefold risk for preterm delivery (OR 2.80, CI 2.28-3.44). The severity of CIN did not increase the risk for preterm delivery. However, with LEEP for carcinoma in situ or microinvasive cancer, the risk for preterm delivery was higher (OR 2.55, CI 1.68-3.87). The increased risk also was associated with non-CIN lesions (OR 2.04, CI 1.46-2.87). Similarly, the risk was increased after diagnostic LEEP (OR 1.39, 95% CI 1.16-1.67). Time interval since LEEP was not associated with preterm delivery. Adjusting for maternal age, parity, socioeconomic or marital status, urbanism, and previous preterm deliveries did not change the results. CONCLUSION: The risk for preterm delivery was increased after LEEP regardless of the histopathologic diagnosis. The risk was highest after repeat LEEP, which should be avoided, especially among women of reproductive age. LEVEL OF EVIDENCE: II. PMID- 23635743 TI - Massively parallel sequencing of maternal plasma DNA in 113 cases of fetal nuchal cystic hygroma. AB - OBJECTIVE: To estimate the accuracy and potential clinical effect of using massively parallel sequencing of maternal plasma DNA to detect fetal aneuploidy in a cohort of pregnant women carrying fetuses with nuchal cystic hygroma. METHODS: The MatErnal BLood IS Source to Accurately diagnose fetal aneuploidy (MELISSA) study database was queried to identify eligible patients carrying fetuses with cystic hygroma (n=113) based on clinical ultrasonographic examination reports near enrollment. Archived plasma samples were newly sequenced and normalized chromosome values were determined. Aneuploidy classifications for chromosomes 21, 18, 13, and X were made using the massively parallel sequencing data by laboratory personnel blinded to fetal karyotype and compared for analysis. RESULTS: : Sixty-nine of 113 (61%) patients had fetuses with abnormal karyotypes, including trisomy 21 (n=30), monosomy X (n=21), trisomy 18 (n=10), trisomy 13 (n=4), and other (n=4). There were 44 euploid cases; none was called positive for aneuploidy. The massively parallel sequencing detection rates were as follows: T21: 30 of 30, T18: 10 of 10, T13: three of four, and monosomy X: 20 of 21, including two complex mosaic cases. Overall, using massively parallel sequencing results of the four studied chromosomes, 107 of 113 (95%, 95% confidence interval [CI] 88.8-98.0) cases were accurately called by massively parallel sequencing, including 63 of 65 (97%, 95% CI 89.3-99.6) of cases of whole chromosome aneuploidy. CONCLUSION: : Massively parallel sequencing provides an accurate way of detecting the most prevalent aneuploidies associated with cystic hygroma. Massively parallel sequencing could advance prenatal care by providing alternative point-of-care noninvasive testing for pregnant women who either decline or do not have access to an invasive procedure. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01122524. LEVEL OF EVIDENCE: II. PMID- 23635746 TI - Outpatient procedure for the treatment and relief of symptomatic uterine myomas. AB - OBJECTIVE: To estimate the safety and efficacy of laparoscopic ultrasound-guided radiofrequency volumetric thermal ablation of uterine myomas in symptomatic women. METHODS: A cohort of 135 premenopausal symptomatic women with uterine myomas, uteri 14 weeks of gestation-sized or less with no single myoma exceeding 7 cm, and objectively confirmed heavy menstrual bleeding participated in this prospective, international trial of outpatient laparoscopic ultrasound-guided radiofrequency volumetric thermal ablation. Bleeding outcomes were measured by alkaline hematin analysis at baseline and again at 3, 6, and 12 months posttreatment. Validated quality-of-life and patient satisfaction scales and objective measurements of uterine and myoma volume were conducted at 3, 6, and 12 months. RESULTS: The mean baseline menstrual blood loss of women in the full analysis set (n=127) was 272.7+/-82.3 mL. At 3-, 6-, and 12-month follow-ups, mean alkaline hematin and associated menstrual blood loss decreased from baseline levels by 31.8%, 40.7%, and 38.3%, respectively (P<.001, paired t test). Symptom severity decreased from a baseline mean transformed score of 61.1 to 26.6 at 12 months postprocedure (P<.001, paired t test). Health-related quality of life improved from a mean transformed score of 37.3 at baseline to 79.5 at 12 months (P<.001, paired t test). At 12 months postprocedure, total mean myoma volume decreased from baseline by 45.1% (measured by magnetic resonance imaging). There was one serious adverse event (one of 135 [0.7%]) requiring readmission 5 weeks postprocedure and one surgical reintervention for persistent bleeding. Ninety four percent of the women reported satisfaction with the treatment. CONCLUSION: Radiofrequency volumetric thermal ablation of myomas is well tolerated and results in rapid recovery, high patient satisfaction, improved quality of life, and effective symptom relief. CLINICAL TRIAL REGISTRATION: : ClinicalTrials.gov, www.clinicaltrials.gov, NCT00874029. LEVEL OF EVIDENCE: II. PMID- 23635745 TI - Risk of oophorectomy after hysterectomy. AB - OBJECTIVE: To compare the risk of subsequent oophorectomy among women who underwent hysterectomy for benign indications and those who did not. METHODS: Using Rochester Epidemiology Project resources, we compared the risk of oophorectomy through December 31, 2008, among 4,931 women in Olmsted County, Minnesota, who underwent ovary-sparing hysterectomy for benign indications (case group) between 1965 and 2002, with 4,931 age-matched women who did not undergo hysterectomy (referent group). The cumulative incidence of subsequent oophorectomy was estimated by the Kaplan-Meier method, and comparisons were evaluated by Cox proportional hazard models using age as the time scale to allow for complete age adjustment. RESULTS: The median follow-up times for case group and referent group participants were 19.6 and 19.4 years, respectively. At 10, 20, and 30 years after hysterectomy, the respective cumulative incidences of subsequent oophorectomy were 3.5%, 6.2%, and 9.2% among case group participants and 1.9%, 4.8%, and 7.3% among referent group participants. The overall risk of subsequent oophorectomy among case group participants was significantly higher than among referent group participants (hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.02-1.42; P=.03). Furthermore, among case group participants, the risk of subsequent oophorectomy was significantly higher (HR 2.15, 95% CI 1.51 3.07; P<.001) in women who had both ovaries preserved compared with those who initially had one ovary preserved. CONCLUSION: The incidence of oophorectomy after hysterectomy is only 9.2% at 30-year follow-up and is only 1.9 percentage points higher than the incidence of oophorectomy in referent women with intact reproductive organs. LEVEL OF EVIDENCE: II. PMID- 23635748 TI - Pitfalls of research linking the intrauterine device to pelvic inflammatory disease. AB - Correctly diagnosing pelvic inflammatory disease (PID) using noninvasive clinical criteria remains challenging. Current guidelines for initiating treatment, based on minimal criteria (sensitive but not specific), are justified for public health purposes but inadequate and misleading for scientific purposes. Previous research on the link between the intrauterine device (IUD) and PID was controversial and subject to many limitations. Even today, these limitations still exist and include uncertainty of the PID diagnosis, unfair contraceptive comparisons, selection and diagnostic bias, and confounding. For example, IUD users are on heightened alert for PID relative to users of other methods. In addition, IUD users with pelvic pain may be more likely to seek physician consultation and consequently receive a PID diagnosis (true-positive or false-positive). Confounding factors such as higher coital frequency, multiple sexual partners, and low condom use may explain any finding that shows a higher PID rate among IUD users compared with other contraceptive users. Good evidence on how or whether the IUD changes the etiology of PID is lacking. In the past 10 years, use of the intrauterine device in the United States has increased markedly. Thus today, researchers may now have sufficient population-level exposure (IUD use) and disease (PID) to search for a connection and repeat past mistakes. Any new findings using observational research should be interpreted with caution. More rigorous research designs may not be pragmatic or feasible. PMID- 23635747 TI - Severity of urinary incontinence and effect on quality of life in women by incontinence type. AB - OBJECTIVE: To estimate how symptom severity, extent of bother, and quality of life differ across urinary incontinence (UI) subtypes. METHODS: We evaluated prevalent UI cases from the Nurses' Health Studies, including women aged 41-83 years. Women with UI (leaking more than once per month) were subclassified according to reported symptoms such as stress UI (SUI, leakage with activity), urge UI (UUI, leakage with urgency), or mixed UI (SUI and UI co-occurring equally). The UI severity was assessed in 102,418 women based on the Sandvik severity index. In a subset of older women with weekly UI, we asked about bother (n=1,697) and quality of life (Incontinence Impact Questionnaire; n=1,748). The UI severity, bother, and quality of life were compared across subtypes using polytomous logistic regression, adjusting for other characteristics. RESULTS: The distributions of UI subtypes were 51% SUI, 27% UUI, and 22% mixed UI. Approximately half had slight UI, 26% had moderate UI, and 23% had severe UI. Severe UI was more common in women reporting mixed UI (37%) than UUI (27%) or SUI symptoms (15%) (P<.001). More women with severe mixed (21%; P=.02) and UUI symptoms (13%; P=.1) reported being "greatly" bothered by their UI compared with SUI (10%). Women with severe mixed (mean 18.0; P<.001) and UUI symptoms (mean 13.4; P=.004) had higher mean incontinence effect scores compared with SUI (mean 9.8). CONCLUSION: Women reporting mixed UI symptoms describe more severe and bothersome incontinence, with higher effect on quality of life. LEVEL OF EVIDENCE: II. PMID- 23635749 TI - Noor. PMID- 23635750 TI - What is new in endometriosis? Best articles from the past year. PMID- 23635752 TI - Association of atypical decelerations with acidemia. PMID- 23635751 TI - Spontaneous reports of seizure in association with leuprolide (lupron depot), goserelin (zoladex implant), and naferelin (synarel nasal spray). PMID- 23635753 TI - Incontinence outcomes in women undergoing primary and repeat midurethral sling procedures. PMID- 23635754 TI - In reply. PMID- 23635755 TI - The learning curve of robotic hysterectomy. PMID- 23635757 TI - Effect of maternal body mass index on serum magnesium levels given for seizure prophylaxis. PMID- 23635756 TI - In reply. PMID- 23635758 TI - In reply. PMID- 23635759 TI - Unintended pregnancy among active-duty women in the United States military, 2008 and "do ask, do provide" contraception for women in the U.S. Military. PMID- 23635760 TI - In reply. PMID- 23635765 TI - ACOG Practice bulletin no. 134: fetal growth restriction. AB - Fetal growth restriction, also known as intrauterine growth restriction, is a common complication of pregnancy that has been associated with a variety of adverse perinatal outcomes. There is a lack of consensus regarding terminology, etiology, and diagnostic criteria for fetal growth restriction, with uncertainty surrounding the optimal management and timing of delivery for the growth restricted fetus. An additional challenge is the difficulty in differentiating between the fetus that is constitutionally small and fulfilling its growth potential and the small fetus that is not fulfilling its growth potential because of an underlying pathologic condition. The purpose of this document is to review the topic of fetal growth restriction with a focus on terminology, etiology, diagnostic and surveillance tools, and guidance for management and timing of delivery. PMID- 23635761 TI - In reply. PMID- 23635766 TI - Committee opinion: no. 562: mullerian agenesis: diagnosis, management, and treatment. AB - Mullerian agenesis occurs in 1 out of every 4,000-10,000 females. The most common presentation of mullerian agenesis is congenital absence of the vagina, uterus, or both, which also is referred to as mullerian aplasia, Mayer-Rokitansky-Kuster Hauser syndrome, or vaginal agenesis. Satisfactory vaginal creation usually can be managed nonsurgically with successive vaginal dilation; however, there are a variety of surgical options for creation of a neovagina. Regardless of the treatment option selected, patients should be thoroughly counseled and prepared psychologically before the initiation of any treatment. Evaluation for associated congenital renal anomalies or other anomalies is also important. Although exact gynecologic screening recommendations are evolving, all women with a neovagina should undergo routine gynecologic care; however, vaginal cytologic screening is not indicated. PMID- 23635767 TI - Committee opinion: no. 563: ethical issues in pandemic influenza planning concerning pregnant women. AB - Pregnant women traditionally have been assigned priority in the allocation of prevention and treatment resources during outbreaks of influenza because of their increased risk of morbidity and mortality. The Committee on Ethics of the American College of Obstetricians and Gynecologists explores ethical justifications for assigning priority for prevention and treatment resources to pregnant women during an influenza pandemic, makes recommendations to incorporate ethical issues in pandemic influenza planning concerning pregnant women, and calls for pandemic preparedness efforts to include clinical research specifically designed to address safety and efficacy of treatment interventions or prevention strategies used by pregnant women. PMID- 23635768 TI - Committee opinion no.564: ethical issues with vaccination for the obstetrician gynecologist. AB - Because of the growing importance of infectious disease prevention in the individual patient and the larger community, it is vital that Fellows of the American College of Obstetricians and Gynecologists be prepared to navigate the practical and ethical challenges that come with vaccination. Health care professionals have an ethical obligation to keep their patients' best interests in mind by following evidence-based guidelines to encourage patients to be vaccinated and to be vaccinated themselves. College Fellows should counsel their patients about vaccination in an evidence-based manner that allows patients to make an informed decision about the use of these agents in their health care. The Centers for Disease Control and Prevention reports that no evi-dence exists of risk to the fetus from vaccinating pregnant women with noninfectious virus or bacterial vaccines or toxoids. Mandatory vaccination of health care professionals may be an ethically justified strategy in cases in which the harm to patients and the general population is believed to outweigh the autonomy of individual physicians. PMID- 23635771 TI - Resilience of the immune system in healthy young students to 30-hour sleep deprivation with psychological stress. AB - OBJECTIVE: Young adults often encounter sleep deprivation and stressful events. Both have been separately reported to modulate immunity, and occasionally they occur simultaneously. We assessed the combined effects of these conditions on immune competence in healthy students. METHODS: Twenty-three participants (mean age 24 years; SD 1.86; 14 females) were exposed to 30 h of sleep deprivation during which they conducted physiological, social and cognitive tasks. The control group consisted of 18 participants (mean age 23.67 years; SD 1.46; 11 females). All participants underwent cognitive and psychological evaluations at 10:00 AM, followed by blood and saliva collection, 3 days before sleep deprivation induction and on the morning following it. Immune/endocrine measures included blood counts of lymphocytes, granulocytes, monocytes and natural killer (NK) cells; levels of several cell surface markers; NK cytotoxicity; plasma levels of interleukin (IL)-6, IL-10, dehydroepiandrosterone and neuropeptide Y, and plasma and salivary cortisol levels. RESULTS: Although the experimental protocol significantly elevated state anxiety and psychological dissociation levels, no effects were evident in any of the immunological/endocrine indices. In contrast, expected sex differences in immune measures were found, including significantly higher NK cytotoxicity and monocyte counts in males, validating the integrity of the measurements. CONCLUSIONS: The findings suggest resilience of the immune system to a combined sleep deprivation and stressful exposure in young adults, while previous studies reported immune perturbations following either of these conditions separately. These apparent contradictions might reflect differences in the study design or in the methodology used for immunological assessments, including the time of sample collection, the combination of sleep deprivation with stress and our in vivo assessment of cytokine levels. PMID- 23635770 TI - Pentatricopeptide repeats: modular blocks for building RNA-binding proteins. AB - Pentatricopeptide repeat (PPR) proteins control diverse aspects of RNA metabolism across the eukaryotic domain. Recent computational and structural studies have provided new insights into how they recognize RNA, and show that the recognition is sequence-specific and modular. The modular code for RNA-binding by PPR proteins holds great promise for the engineering of new tools to target RNA and identifying RNAs bound by natural PPR proteins. PMID- 23635772 TI - Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta. AB - The remodeling of maternal uterine spiral arteries (SAs) is an essential process for ensuring low-resistance, high-capacitance blood flow to the growing fetus. Failure of SAs to remodel is causally associated with preeclampsia, a common and life-threatening complication of pregnancy that is harmful to both mother and fetus. Here, using both loss-of-function and gain-of-function genetic mouse models, we show that expression of the pregnancy-related peptide adrenomedullin (AM) by fetal trophoblast cells is necessary and sufficient to promote appropriate recruitment and activation of maternal uterine NK (uNK) cells to the placenta and ultimately facilitate remodeling of maternal SAs. Placentas that lacked either AM or its receptor exhibited reduced fetal vessel branching in the labyrinth, failed SA remodeling and reendothelialization, and markedly reduced numbers of maternal uNK cells. In contrast, overexpression of AM caused a reversal of these phenotypes with a concomitant increase in uNK cell content in vivo. Moreover, AM dose-dependently stimulated the secretion of numerous chemokines, cytokines, and MMPs from uNK cells, which in turn induced VSMC apoptosis. These data identify an essential function for fetal-derived factors in the maternal vascular adaptation to pregnancy and underscore the importance of exploring AM as a biomarker and therapeutic agent for preeclampsia. PMID- 23635773 TI - HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas. AB - High-risk types of human papilloma virus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). Strikingly, patients with HPV positive OPSCC are highly curable with ionizing radiation and have better survival compared with HPV-negative patients, but the underlying molecular mechanisms remain poorly understood. We applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. HPV-related alterations were confirmed for the majority of candidate gene promoters by mass spectrometric, quantitative methylation analysis. There was a significant inverse correlation between promoter hypermethylation of ALDH1A2, OSR2, GATA4, GRIA4, and IRX4 and transcript levels. Interestingly, Kaplan-Meier analysis revealed that a combined promoter methylation pattern of low methylation levels in ALDH1A2 and OSR2 promoters and high methylation levels in GATA4, GRIA4, and IRX4 promoters was significantly correlated with improved survival in 3 independent patient cohorts. ALDH1A2 protein levels, determined by immunohistochemistry on tissue microarrays, confirmed the association with clinical outcome. In summary, our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs. PMID- 23635774 TI - Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth. AB - Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo- and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumor-initiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs. PMID- 23635775 TI - Plasmacytoid dendritic cells promote rotavirus-induced human and murine B cell responses. AB - B cell-dependent immunity to rotavirus, an important intestinal pathogen, plays a significant role in viral clearance and protects against reinfection. Human in vitro and murine in vivo models of rotavirus infection were used to delineate the role of primary plasmacytoid DCs (pDCs) in initiating B cell responses. Human pDCs were necessary and sufficient for B cell activation induced by rotavirus. Type I IFN recognition by B cells was essential for rotavirus-mediated B cell activation in vitro and murine pDCs and IFN-alpha/beta-mediated B cell activation after in vivo intestinal rotavirus infection. Furthermore, rotavirus-specific serum and mucosal antibody responses were defective in mice lacking functional pDCs at the time of infection. These data demonstrate that optimal B cell activation and virus-specific antibody secretion following mucosal infection were a direct result of pDC-derived type I IFN. Importantly, viral shedding significantly increased in pDC-deficient mice, suggesting that pDC-dependent antibody production influences viral clearance. Thus, mucosal pDCs critically influence the course of rotavirus infection through rotavirus recognition and subsequent IFN production and display powerful adjuvant properties to initiate and enhance humoral immunity. PMID- 23635776 TI - RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. AB - The PI3K signaling pathway regulates diverse cellular processes, including proliferation, survival, and metabolism, and is aberrantly activated in human cancer. As such, numerous compounds targeting the PI3K pathway are currently being clinically evaluated for the treatment of cancer, and several have shown some early indications of efficacy in breast cancer. However, resistance against these agents, both de novo and acquired, may ultimately limit the efficacy of these compounds. Here, we have taken a systematic functional approach to uncovering potential mechanisms of resistance to PI3K inhibitors and have identified several genes whose expression promotes survival under conditions of PI3K/mammalian target of rapamycin (PI3K/mTOR) blockade, including the ribosomal S6 kinases RPS6KA2 (RSK3) and RPS6KA6 (RSK4). We demonstrate that overexpression of RSK3 or RSK4 supports proliferation upon PI3K inhibition both in vitro and in vivo, in part through the attenuation of the apoptotic response and upregulation of protein translation. Notably, the addition of MEK- or RSK-specific inhibitors can overcome these resistance phenotypes, both in breast cancer cell lines and patient-derived xenograft models with elevated levels of RSK activity. These observations provide a strong rationale for the combined use of RSK and PI3K pathway inhibitors to elicit favorable responses in breast cancer patients with activated RSK. PMID- 23635780 TI - A conversation with Bruce Spiegelman. Interviewed by Ushma Neill. PMID- 23635777 TI - Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. AB - Primary effusion lymphoma (PEL) is a rare form of aggressive B cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Current chemotherapy approaches result in dismal outcomes, and there is an urgent need for new PEL therapies. Previously, we established, in a direct xenograft model of PEL-bearing immune-compromised mice, that treatment with the proteasome inhibitor, bortezomib (Btz), increased survival relative to that after treatment with doxorubicin. Herein, we demonstrate that the combination of Btz with the histone deacetylase (HDAC) inhibitor suberoylanilidehydroxamic acid (SAHA, also known as vorinostat) potently reactivates KSHV lytic replication and induces PEL cell death, resulting in significantly prolonged survival of PEL-bearing mice. Importantly, Btz blocked KSHV late lytic gene expression, terminally inhibiting the full lytic cascade and production of infectious virus in vivo. Btz treatment led to caspase activation and induced DNA damage, as evidenced by the accumulation of phosphorylated gammaH2AX and p53. The addition of SAHA to Btz treatment was synergistic, as SAHA induced early acetylation of p53 and reduced interaction with its negative regulator MDM2, augmenting the effects of Btz. The eradication of KSHV-infected PEL cells without increased viremia in mice provides a strong rationale for using the proteasome/HDAC inhibitor combination therapy in PEL. PMID- 23635779 TI - Lung tumor NF-kappaB signaling promotes T cell-mediated immune surveillance. AB - NF-kappaB is constitutively activated in many cancer types and is a potential key mediator of tumor-associated inflammation, tumor growth, and metastasis. We investigated the role of cancer cell NF-kappaB activity in T cell-mediated antitumor responses. In tumors rendered immunogenic by model antigen expression or following administration of antitumor vaccines, we found that high NF-kappaB activity leads to tumor rejection and/or growth suppression in mice. Using a global RNA expression microarray, we demonstrated that NF-kappaB enhanced expression of several T cell chemokines, including Ccl2, and decreased CCL2 expression was associated with enhanced tumor growth in a mouse lung cancer model. To investigate NF-kappaB function in human lung tumors, we identified a gene expression signature in human lung adenocarcinoma cell lines that was associated with NF-kappaB activity level. In patient tumor samples, overall lung tumor NF-kappaB activity was strongly associated with T cell infiltration but not with cancer cell proliferation. These results therefore indicate that NF-kappaB activity mediates immune surveillance and promotes antitumor T cell responses in both murine and human lung cancer. PMID- 23635778 TI - PD1-based DNA vaccine amplifies HIV-1 GAG-specific CD8+ T cells in mice. AB - Viral vector-based vaccines that induce protective CD8+ T cell immunity can prevent or control pathogenic SIV infections, but issues of preexisting immunity and safety have impeded their implementation in HIV-1. Here, we report the development of what we believe to be a novel antigen-targeting DNA vaccine strategy that exploits the binding of programmed death-1 (PD1) to its ligands expressed on dendritic cells (DCs) by fusing soluble PD1 with HIV-1 GAG p24 antigen. As compared with non-DC-targeting vaccines, intramuscular immunization via electroporation (EP) of the fusion DNA in mice elicited consistently high frequencies of GAG-specific, broadly reactive, polyfunctional, long-lived, and cytotoxic CD8+ T cells and robust anti-GAG antibody titers. Vaccination conferred remarkable protection against mucosal challenge with vaccinia GAG viruses. Soluble PD1-based vaccination potentiated CD8+ T cell responses by enhancing antigen binding and uptake in DCs and activation in the draining lymph node. It also increased IL-12-producing DCs and engaged antigen cross-presentation when compared with anti-DEC205 antibody-mediated DC targeting. The high frequency of durable and protective GAG-specific CD8+ T cell immunity induced by soluble PD1 based vaccination suggests that PD1-based DNA vaccines could potentially be used against HIV-1 and other pathogens. PMID- 23635782 TI - Underlying potential: cellular and molecular determinants of adult liver repair. AB - The liver has a unique and extraordinary capacity for regeneration, even in adult organisms. This regenerative potential has traditionally been attributed to the replicative capabilities of mature hepatocytes and cholangiocytes, though emerging evidence suggests that other resident liver cell types such as progenitors, liver sinusoidal endothelial cells, and hepatic stellate cells respond to liver injury and contribute to repair. These other cells types are also associated with liver scarring, dysfunction, and carcinogenesis, which suggests that appropriate regulation of these cells is a major determinant of response to liver injury. The Reviews in this series explore possible contributions of liver progenitor cells, liver sinusoidal endothelial cells, and hepatic stellate cells to liver homeostasis and repair and highlight how these processes can go awry in chronic liver injury, fibrosis, and liver cancer. PMID- 23635781 TI - Thinking laterally about neurodegenerative proteinopathies. AB - Many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and frontotemporal dementia, are proteinopathies that are associated with the aggregation and accumulation of misfolded proteins. While remarkable progress has been made in understanding the triggers of these conditions, several challenges have hampered the translation of preclinical therapies targeting pathways downstream of the initiating proteinopathies. Clinical trials in symptomatic patients using therapies directed toward initiating trigger events have met with little success, prompting concerns that such therapeutics may be of limited efficacy when used in advanced stages of the disease rather than as prophylactics. Herein, we discuss gaps in our understanding of the pathological processes downstream of the trigger and potential strategies to identify common features of the downstream degenerative cascade in multiple CNS proteinopathies, which could potentially lead to the development of common therapeutic targets for multiple disorders. PMID- 23635783 TI - Liver sinusoidal endothelial cells and liver regeneration. AB - Liver sinusoidal endothelial cells (LSECs) have long been noted to contribute to liver regeneration after liver injury. In normal liver, the major cellular source of HGF is the hepatic stellate cell, but after liver injury, HGF expression has been thought to increase markedly in proliferating LSECs. However, emerging data suggest that even after injury, LSEC expression of HGF does not increase greatly. In contrast, bone marrow progenitor cells of LSECs (BM SPCs), which are rich in HGF, are recruited to the liver after injury. This Review examines liver regeneration from the perspective that BM SPCs that have been recruited to the liver, rather than mature LSECs, drive liver regeneration. PMID- 23635784 TI - Differentiation of progenitors in the liver: a matter of local choice. AB - The liver is a complex organ that requires multiple rounds of cell fate decision for development and homeostasis throughout the lifetime. During the earliest phases of organogenesis, the liver acquires a separate lineage from the pancreas and the intestine, and subsequently, the liver bud must appropriately differentiate to form metabolic hepatocytes and cholangiocytes for proper hepatic physiology. In addition, throughout life, the liver is bombarded with chemical and pathological insults, which require the activation and correct differentiation of adult progenitor cells. This Review seeks to provide an overview of the complex signaling relationships that allow these tightly regulated processes to occur. PMID- 23635785 TI - Hepatic stem cell niches. AB - Stem cell niches are special microenvironments that maintain stem cells and control their behavior to ensure tissue homeostasis and regeneration throughout life. The liver has a high regenerative capacity that involves stem/progenitor cells when the proliferation of hepatocytes is impaired. In recent years progress has been made in the identification of potential hepatic stem cell niches. There is evidence that hepatic progenitor cells can originate from niches in the canals of Hering; in addition, the space of Disse may also serve as a stem cell niche during fetal hematopoiesis and constitute a niche for stellate cells in adults. PMID- 23635786 TI - Sox9 and programming of liver and pancreatic progenitors. AB - Recent advances in developmental biology have greatly expanded our understanding of progenitor cell programming and the fundamental roles that Sox9 plays in liver and pancreas organogenesis. In the last 2 years, several studies have dissected the behavior of the Sox9+ duct cells in adult organs, but conflicting results have left unanswered the long-standing question of whether physiologically functioning progenitors exist in adult liver and pancreas. On the other hand, increasing evidence suggests that duct cells function as progenitors in the tissue restoration process after injury, during which embryonic programs are sometimes reactivated. This article discusses the role of Sox9 in programming liver and pancreatic progenitors as well as controversies in the field. PMID- 23635787 TI - Evolving therapies for liver fibrosis. AB - Fibrosis is an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. With protracted damage, fibrosis can progress toward excessive scarring and organ failure, as in liver cirrhosis. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development, with enormous potential but also high risks. Preclinical research has yielded numerous targets for antifibrotic agents, some of which have entered early-phase clinical studies, but progress has been hampered due to the relative lack of sensitive and specific biomarkers to measure fibrosis progression or reversal. Here we focus on antifibrotic approaches for liver that address specific cell types and functional units that orchestrate fibrotic wound healing responses and have a sound preclinical database or antifibrotic activity in early clinical trials. We also touch upon relevant clinical study endpoints, optimal study design, and developments in fibrosis imaging and biomarkers. PMID- 23635788 TI - Hepatic stellate cells in liver development, regeneration, and cancer. AB - Hepatic stellate cells are liver-specific mesenchymal cells that play vital roles in liver physiology and fibrogenesis. They are located in the space of Disse and maintain close interactions with sinusoidal endothelial cells and hepatic epithelial cells. It is becoming increasingly clear that hepatic stellate cells have a profound impact on the differentiation, proliferation, and morphogenesis of other hepatic cell types during liver development and regeneration. In this Review, we summarize and evaluate the recent advances in our understanding of the formation and characteristics of hepatic stellate cells, as well as their function in liver development, regeneration, and cancer. We also discuss how improved knowledge of these processes offers new perspectives for the treatment of patients with liver diseases. PMID- 23635790 TI - Steroids and osteoporosis: the quest for mechanisms. AB - Advances made during the last 35 years have improved our understanding of the mechanisms of steroid hormone action on bone and how physiologic, pathologic, or iatrogenic changes in hormone levels can lead to increased fracture risk. Estrogens, androgens, and glucocorticoids alter the cellular composition of bone by regulating the supply and lifespan of osteoclasts and osteoblasts. Additionally, they influence the survival of osteocytes, long-lived cells that are entombed within the mineralized matrix and mediate the homeostatic adaptation of bone to mechanical forces. Altered redox balance is a proximal underlying mechanism of some of these effects, and sex steroid deficiency or glucocorticoid excess contributes to the aging of the skeleton. PMID- 23635794 TI - First report on path analysis for cardiometabolic components in a nationally representative sample of pediatric population in the Middle East and North Africa (MENA): the CASPIAN-III Study. AB - BACKGROUND/AIMS: This study aimed to test a potential model of the relationship between various cardiometabolic risk factors including obesity, unhealthy diet, low physical activity, dyslipidemia, and high blood pressure in a large population-based sample of children and adolescents. METHODS: In this nationwide study, a representative sample of 5,528 students aged 10-18 years was selected by multistage random cluster sampling from 27 provinces of Iran. Demographic, anthropometric, biological, and biochemical factors were determined. Structural equation modeling (path analysis) was applied to evaluate the causal relationship between these variables. RESULTS: The mean age of study participants was 14.7 +/- 2.41 years and the mean body mass index (BMI) was 19.4 +/- 4.1. Higher socioeconomic status was directly associated with unhealthy diet, low physical activity and BMI in both sexes. Age had a positive direct effect on low physical activity in both sexes. BMI showed the greatest direct effect on total cholesterol, triglyceride, low-density lipoprotein cholesterol, and mean arterial pressure in comparison with the direct effects of unhealthy diet and low physical activity. BMI was associated negatively with high-density lipoprotein cholesterol in both groups. CONCLUSIONS: No previous study has used path analysis for determining the interactions examined in this study among a nationally representative sample of children in the Middle East and North Africa (MENA). The results of this study underline the imperative need for the weight loss and lifestyle change from childhood as the first-line preventive strategy for metabolic syndrome and noncommunicable diseases. PMID- 23635795 TI - Revisiting the management of fatigue in multiple sclerosis in the context of rehabilitation: a narrative review of current evidence. AB - Fatigue is one of the most frequently reported symptoms of multiple sclerosis, interfering with functioning and resulting in activity limitations and participation restrictions. Therefore, it is important to manage fatigue in a rehabilitation context considering not only disability associated with impaired functioning but also all the problems relevant to environmental and personal factors as defined in the International Classification of Functioning, Disability and Health (ICF). In addition to pharmacological treatment, there are many rehabilitation interventions with evidence of effectiveness in reducing fatigue and thereby facilitating improvement, particularly in body functions and structures and activities and participation components of the ICF. However, more research is required to provide evidence for effective treatment strategies in overcoming fatigue and related problems, especially in the components of contextual factors of the ICF. PMID- 23635789 TI - Cancer stem cells in the development of liver cancer. AB - Liver cancer is an aggressive disease with a poor outcome. Several hepatic stem/progenitor markers are useful for isolating a subset of liver cells with stem cell features, known as cancer stem cells (CSCs). These cells are responsible for tumor relapse, metastasis, and chemoresistance. Liver CSCs dictate a hierarchical organization that is shared in both organogenesis and tumorigenesis. An increased understanding of the molecular signaling events that regulate cellular hierarchy and stemness, and success in defining key CSC specific genes, have opened up new avenues to accelerate the development of novel diagnostic and treatment strategies. This Review highlights recent advances in understanding the pathogenesis of liver CSCs and discusses unanswered questions about the concept of liver CSCs. PMID- 23635796 TI - Phylogenetic lineages of tuberculosis isolates in New Zealand and their association with patient demographics. AB - SETTING: In New Zealand, the lineage genotypes of Mycobacterium tuberculosis clinical isolates and their role in the epidemiology of tuberculosis (TB) are currently unknown. OBJECTIVE: 1) To measure the relative frequency of each phylogenetic lineage of the M. tuberculosis complex in New Zealand, and 2) to examine its relationship with patient demographics and multidrug-resistant TB (MDR-TB). METHODS: All non-duplicate M. tuberculosis complex isolates recovered in 2010 and 2011 underwent large sequence polymorphism and/or single nucleotide polymorphism analyses. Mycobacterial interspersed repetitive units (MIRU) profiling was also performed for cluster identification. RESULTS: New Zealand isolates were dominated by lineage 4 (Euro-American: 37.8%, 95%CI 33.6-42.2), followed by lineage 1 (Indo-Oceanic: 22.6%, 95%CI 19.1-26.5), lineage 2 (East Asian: 19.5%, 95%CI 16.2-23.3) and lineage 3 (East-African Indian, which included Central Asian: 17.7%, 95%CI 14.5-21.3). Lineage 2 accounted for 58.1% of MDR-TB cases from 2002 to 2011. Among immigrants, the predominant lineages corresponded to high prevalence lineages in the country of origin. In New Zealand-born individuals, Maori and NZ Europeans share the same predominant lineage, lineage 4, with a higher proportion of non-unique MIRU types observed in Maori cases. Lineage 3 was more prevalent in Maori than in NZ Europeans. CONCLUSION: In New Zealand, M. tuberculosis complex phylogenetic lineage is associated with TB epidemiology in terms of ethnicity, country of origin and MDR-TB. PMID- 23635797 TI - Understanding the growth hormone therapy adherence paradigm: a systematic review. AB - INTRODUCTION: Growth hormone (GH) therapy is used to treat a variety of growth disorders in childhood/adolescence. Its efficacy is thought to be dependent on patients' adherence to their treatment regimen. METHODS: PubMed was searched using the keywords 'growth hormone', 'child'[Mesh], 'adolescent'[Mesh], and 'patient compliance'[Mesh]. RESULTS: Most studies of adherence to paediatric GH therapy have used either issued/encashed GH prescriptions or questionnaires. Estimates of prevalence of non-adherence vary from 5-82%, depending on the methods and definitions used. Different studies have variously demonstrated an association (or lack thereof) between adherence and age, socioeconomic status, treatment duration, injection device used and injection-giver. A number of interventions have been proposed to improve adherence, including offering a choice of injection device, but none are supported by trials. Poor adherence is associated with reduced height velocity and likely increased economic costs; evidence for other effects is circumstantial. CONCLUSION: Adherence to paediatric GH therapy is suboptimal, which may partially explain why the mean final height attained is below that of the general population. Analysis of the causes of non adherence is complicated by conflicting evidence from different studies. Multifactorial interventions are most likely to be successful in improving adherence. We make recommendations for further research. PMID- 23635798 TI - Environmental exposures in the context of child care. PMID- 23635799 TI - Increasing microbleeds in CADASIL. PMID- 23635800 TI - State-of-the-art in the management of locally advanced and metastatic gallbladder cancer. AB - PURPOSE OF REVIEW: Gallbladder carcinoma (GBC), classified as a biliary tract cancer (BTC) along with intrahepatic and extrahepatic cholangiocarcinomas, is a rare disease in Western countries, but a highly prevalent disease in Chile, other countries in Latin America, India and Japan. It commonly presents at an advanced stage, and has limited therapeutic options. Cisplatin/gemcitabine has emerged as the first-line standard of care for patients with advanced BTCs, but the prognosis remains poor. Development of molecularly targeted therapies in advanced BTC remains challenging. RECENT FINDINGS: Comprehension of the molecular events in gallbladder carcinogenesis may provide a novel targeted therapeutic approach, and early stage clinical trials with targeted therapies appear promising, although the relationship between subsets of patients with positive responses to therapy and tumor genetics requires further exploration. Recent developments in targeted therapeutics, directed against several key signalling pathways in BTC, including epidermal growth factor receptor, angiogenesis, and the mitogen activated protein kinase pathway will be discussed, in addition to the potential application of prognostic factors and markers. SUMMARY: The future therapeutic spectrum for BTC and GBC will likely encompass novel combinations of targeted therapies with cytostatics in scientifically and molecularly directed schedules, thus permitting fewer mechanisms of escape for tumor cells. PMID- 23635801 TI - Diagnosis, prognosis, and management of leiomyosarcoma: recognition of anatomic variants. AB - PURPOSE OF REVIEW: The purpose of this review is to present the most recent advances in the diagnosis of the more common leiomyosarcoma (LMS) anatomic variants, potentially useful prognostic markers that have recently been identified and the systemic approaches currently used or under evaluation to improve the outcome of patients with this disease. RECENT FINDINGS: Over the last few years emphasis has been placed on incorporating effective imaging tools and using pathological biomarkers in the diagnostic workup of LMS. Moreover, efforts are being made to identify meaningful prognostic and predictive parameters that will aid the development of effective novel therapeutics. The number of systemic therapies available to treat LMS has increased over the last decade, but the selection of systemic therapy is not based on the anatomic origin of LMS. SUMMARY: Currently, the only curative option in LMS is surgery and despite progress in systemic therapy the outcome of patients with advanced/metastatic disease remains poor. Better understanding of the underlying biology of the LMS variants, improved diagnostics and more effective, less toxic therapeutic agents are required. PMID- 23635802 TI - Light and shadows of dietary protein restriction in elderly with chronic kidney disease. AB - Approximately 45% of the elderly population suffers from chronic kidney disease (CKD). The onset and the course of CKD can be ameliorated to a significant degree by several interventions, such as lowering blood pressure and serum lipid levels and achieving optimal glucose control in diabetes. In elderly patients with more advanced CKD, additional treatment may be needed. In these patients, a low protein diet (LPD) regimen may delay the need for dialysis therapy. However, in the elderly, feasibility and compliance to LPD could be difficult and its effects are uncertain. In this contribution, we discuss the usefulness and the barriers of LPD regimen in the elderly. PMID- 23635805 TI - Plasma amyloid-beta levels in drug-resistant bipolar depressed patients receiving electroconvulsive therapy. AB - AIMS: Alterations of plasma amyloid-beta (Abeta) peptides have been related to a high risk for cognitive impairment and dementia. The present study aimed to measure plasma Abeta peptides (Abeta40, Abeta42) and the Abeta40/Abeta42 ratio in a sample of drug-resistant bipolar depressed patients, as well as to explore the possible correlation between biological parameters and clinical changes along an electroconvulsive therapy (ECT) course. METHODS: Abeta40 and Abeta42 were measured by means of an ELISA assay in 25 drug-resistant bipolar depressed patients before (T0) and 1 week after (T1) the end of ECT. The patients were clinically evaluated by means of the Hamilton Rating Scale for Depression, 21 item (HRSD-21), the Mini-Mental State Examination, and the Clinical Global Impressions-Severity of Illness Scale. RESULTS: Plasma Abeta levels and the Abeta40/Abeta42 ratio were similar at T0 and T1. The Abeta40/Abeta42 ratio correlated positively with the HRSD total score at both T0 and T1. At T0, a negative correlation was found between the Abeta40/Abeta42 ratio and the improvement of depressive and cognitive symptoms. Moreover, remitters (n = 9; HRSD <=10) showed a significantly lower Abeta40/Abeta42 ratio at T0 than nonremitters. CONCLUSION: The present data suggest that a low Abeta40/Abeta42 ratio might characterize a subgroup of depressed patients who respond to ECT, while higher values of this parameter seem to be typical of more severe cases of patients with cognitive impairment. PMID- 23635804 TI - SCN5A promoter haplotype affects the therapeutic range for serum flecainide concentration in Asian patients. AB - OBJECTIVE: An increased slowing of cardiac conduction induced by sodium channel blockers is remarkably observed in carriers of an Asian-specific promoter haplotype [haplotype B (HapB)] of the cardiac sodium channel gene (SCN5A). We investigated the effect of HapB on the therapeutic range for serum flecainide concentration in Asian patients. PATIENTS AND METHODS: We examined the serum concentration and antiarrhythmic efficacy of flecainide, together with the SCN5A promoter haplotype, in 146 patients with supraventricular tachyarrhythmias. Trough serum flecainide concentrations were determined by HPLC. The antiarrhythmic efficacy of flecainide was assessed for at least 2 months through examination of symptomatology, ECG, and Holter monitoring. RESULTS: The serum flecainide concentration did not differ between the wild-type HapA homozygotes and HapB carriers under treatment with the usual dose. A genetic difference in the antiarrhythmic efficacy of flecainide was observed between the HapA homozygotes and HapB carriers at serum flecainide concentrations less than 300 ng/ml (42.9 vs. 68.8%; P=0.022). PR prolongation and QRS widening were observed more commonly among the HapB carriers with serum flecainide concentrations of at least 300 ng/ml than in the HapA homozygotes (PR, 210 +/- 25 vs. 195 +/- 25 ms; P=0.036; and QRS, 112 +/- 10 vs. 105 +/- 9 ms; P=0.030). CONCLUSION: These findings suggest that the therapeutic range for serum flecainide concentration is lower in HapB carriers than in HapA homozygotes. PMID- 23635803 TI - ANKK1 and DRD2 pharmacogenetics of disulfiram treatment for cocaine abuse. AB - OBJECTIVE: Disulfiram is a potential cocaine addiction pharmacotherapy. Since dopamine deficiency has been found with cocaine addiction, our objective was to examine whether functional variants in the ankyrin repeat and kinase domain containing 1 (ANKK1) and/or the dopamine receptor D2 (DRD2) genes interact with response to treatment with disulfiram. MATERIALS AND METHODS: Cocaine and opioid codependent (DSM-IV) patients were stabilized on methadone and subsequently randomized into treatment groups - disulfiram (250 mg/day, N=31) or placebo (N=37). They were genotyped for ANKK1 (rs1800497) and DRD2 (rs2283265) polymorphisms, and the data were evaluated for an association between a cocaine free state, as assessed by cocaine-free urine samples, and disulfiram treatment. Data were analyzed using repeated measures analysis of variance corrected for population structure. RESULTS: Patients with CT or TT ANKK1 genotypes dropped from 80 to 52% cocaine-positive urines on disulfiram (N=13; P<=0.0001), whereas those on placebo (N=20) showed no treatment effect. Patients carrying the CC ANKK1 genotype showed no effect on treatment with disulfiram (N=18) or placebo (N=17). The GT/TT DRD2 genotype group showed a significant decrease in the number of cocaine-positive urine samples on disulfiram (N=9; 67-48%; P <= 0.0001), whereas the GG DRD2 genotype group showed only a marginal decrease (N=23; 84-63%; P=0.04). Genotype pattern analysis revealed that individuals carrying at least one minor allele in either gene responded better to disulfiram treatment (N=13; P <= 0.0001) compared with individuals carrying only the major alleles (N=17). CONCLUSION: A patient's genotype for ANKK1, DRD2, or both, may be used to identify individuals for whom disulfiram may be an effective pharmacotherapy for cocaine dependence. PMID- 23635807 TI - A novel MYO6 splice site mutation causes autosomal dominant sensorineural hearing loss type DFNA22 with a favourable outcome after cochlear implantation. AB - Mutations in MYO6 encoding an atypical myosin motor protein important for inner ear hair cell function have been associated with autosomal recessive (DFNB37) and autosomal dominant (DFNA22) types of hearing loss in a few families worldwide. After genome-wide linkage analysis, we identified a novel MYO6 mutation at the splice acceptor site of exon 7 (c.554-1G>A) in an extended German family with autosomal dominant postlingual non-syndromic hearing impairment. Analysis of blood-derived cDNA revealed different aberrantly spliced mRNAs caused by the mutation, which are predicted to severely interfere with protein function. Two of the family members underwent cochlear implantation at ages 53 and 65. Here, we present detailed clinical data of this family which suggest a favourable outcome of cochlear implantation in hearing-impaired individuals with a MYO6 mutation. PMID- 23635806 TI - Human pentatricopeptide proteins: only a few and what do they do? AB - Pentatricopeptide repeat (PPR) proteins constitute a large family of RNA-binding proteins that contain a canonical 35 residue repeat motif. Originally identified in Arabidopsis thaliana, family members are found in protists, fungi, and metazoan but are by far most abundant in plant organelles. Seven examples have been identified in human mitochondria and roles have been tentatively ascribed to each. In this review, we briefly outline each of these PPR proteins and discuss the role each is believed to play in facilitating mitochondrial gene expression. PMID- 23635808 TI - Using a single screening question for depressive symptoms in patients with acute coronary syndrome. AB - BACKGROUND: Despite the prevalence of depressive symptoms and increased risk for future cardiovascular events, depressive symptoms frequently go underrecognized in patients hospitalized for acute coronary syndrome (ACS). Identifying an effective approach to depressive symptom screening is imperative in this population. OBJECTIVE: The purpose of this cross-sectional study was to explore the agreement between Beck Depression Inventory-II (BDI-II) scores and a single screening question for depressive symptoms in 1122 patients hospitalized for ACS. METHODS: Independent-samples t tests and chi tests were used to compare the groups with BDI-II scores of 14 or higher and lower than 14. Three separate agreement analyses were conducted using categorized BDI-II scores (>=14, >=20, and >=29). Agreement of the BDI-II categories with the responses to the single screening question was assessed with the simple kappa statistic. Sensitivity and specificity were calculated using the BDI-II categories as the criterion standards for depressive symptom screening. RESULTS: The agreement analysis revealed a moderate level of agreement (kappa coefficient = 0.42) between the BDI II scores of 14 or higher and the single screening question. Of the participants who reported a BDI-II score of 14 or higher, 61.65% answered yes to the single screening question (sensitivity, 0.62). For those who had BDI-II scores of lower than 14, a total of 82% responded no to the single screening question (specificity, 0.82). When using higher BDI-II scores to define depressive symptoms (>=20 and >=29), the level of agreement decreased, whereas sensitivity increased to 0.76 and 0.90, with a trade-off in specificity (0.79 and 0.74, respectively). CONCLUSIONS: These results suggest that the single screening question for depressive symptoms correctly identifies depressive symptoms 62% of the time but inappropriately identifies depressive symptoms 18% of the time in patients hospitalized for ACS. This suggests that the single screening question for depressive symptoms may be used with caution to initially screen patients with ACS, who can then undergo a more thorough assessment for clinical depression. PMID- 23635809 TI - Cost-effectiveness of nurse practitioner/community health worker care to reduce cardiovascular health disparities. AB - BACKGROUND: Although evidence-based guidelines on the management of cardiovascular disease (CVD) and type 2 diabetes have been widely published, implementation of recommended therapies is suboptimal. OBJECTIVE: The aim of this study was to evaluate the cost-effectiveness of a comprehensive program of CVD risk reduction delivered by nurse practitioner/community health worker (NP/CHW) teams versus enhanced usual care to improve lipids, blood pressure (BP), and hemoglobin (Hb) A1c levels in patients in urban community health centers. METHODS: A total of 525 patients with documented CVD, type 2 diabetes, hypercholesterolemia, or hypertension and levels of low-density lipoprotein cholesterol, BP, or Hb A1c that exceeded goals established by national guidelines were randomized to NP/CHW (n = 261) or enhanced usual care (n = 264) groups. Cost effectiveness ratios were calculated, determining costs per percent and unit change in the primary outcomes. RESULTS: The mean incremental total cost per patient (NP/CHW and physician) was only $627 (confidence interval, 248-1015). The cost-effectiveness of the 1-year intervention was $157 for every 1% drop in systolic BP and $190 for every 1% drop in diastolic BP, $149 per 1% drop in Hb A1c, and $40 per 1% drop in low-density lipoprotein cholesterol. CONCLUSIONS: The findings suggest that management by an NP/CHW team is a cost-effective approach for community health centers to consider in improving the care of patients with existing CVD or at high risk for the development of CVD. PMID- 23635810 TI - Evaluation of a pro-active strategy for managing tuberculosis-HIV co-infection in a UK tertiary care setting. AB - Management of tuberculosis (TB)-HIV co-infection is complicated by interactions between the diseases and their therapies. We developed and evaluated a strategy to (i) treat co-infected patients in a single co-infection clinic, (ii) maximize use of first-line drugs, (iii) delay antiretroviral therapy (ART) until two months post-TB treatment except in severe immunosuppression, (iv) commence efavirenz at 600 mg daily with therapeutic drug monitoring (TDM) and (v) target treatment completion. We conducted a prospective cohort review over 5.5 years in a UK tertiary referral center where 56 HIV-positive patients treated for TB were followed-up for a median 30 months. Main outcome measures were treatment completion, adverse events, immune reconstitution inflammatory syndrome, immunological and virological parameters, and TDM for efavirenz. Treatment completion rates were 88% (49/56); four patients were lost to local follow-up and three (5.4%) died during treatment; no deaths were TB-related. Adverse events were common (55%), but caused no treatment interruptions. Standard doses (600 mg daily) of efavirenz with rifampicin achieved or exceeded therapeutic levels in 25/28 (89%). This study supports combined management for TB-HIV co-infected patients. Delaying ART to two months post-TB treatment did not seem to result in poor clinical outcomes in this well-resourced context. Although efavirenz 600 mg daily usually achieved satisfactory levels, TDM is recommended. PMID- 23635812 TI - Reverse influence modeling: estimating source-by-source health benefits of reduced emissions. PMID- 23635811 TI - Effect of hydroxocobalamin on surface oximetry in nonexposed humans. AB - INTRODUCTION: The newer cyanide antidote, hydroxocobalamin, due to its pigmentation, has been found to cause interferences in some laboratory assays. Co oximetry may also be affected by hydroxocobalamin, leading to false elevations in hemoglobin concentration, methemoglobin, carboxyhemoglobin, and false decreases in oxyhemoglobin. The Masimo Radical-7 is a medical device that performs noninvasive oximetry and estimates hemoglobin (Hb) concentration and percent carboxyhemoglobin (COHb), methemoglobin (MetHb), and oxyhemoglobin saturation (O2Hb). STUDY OBJECTIVES: The study sought to determine the effect of hydroxocobalamin on noninvasive measurement of hemoglobin indices using the Masimo Radical-7 monitor. METHODS: Seven asymptomatic volunteers who were unexposed to cyanide had baseline heart rate (HR), blood pressure (BP), and oximeter measurements recorded followed by an infusion of five grams of hydroxocobalamin over 15 minutes. The above parameters were subsequently recorded at: 5, 10, 15, 30 and 60 minutes post infusion. Data were analyzed by calculating the area under the curve (AUC) for each variable and comparing the results to expected values by paired t tests. Expected AUC values were calculated by extrapolating baseline values across the entire time period. RESULTS: The mean differences from baseline values with 95% confidence intervals and t tests of mean difference were: SBP: 11 mm Hg (95% CI, 0-22; P = .051); HR: -9 (95% CI, -15 to -3; P = .01); Hb: -0.1 (95% CI, -0.7 to 0.4; P = .57); O2Hb: 0 g/dL (95% CI, 1 to 1; P = .41); COHb: -1 (95% CI, -3 to 1; P = .25); MetHb: -0.2 (95% CI, -0.3 to 0; P = .03). DISCUSSION: After infusion of hydroxocobalamin there was a significant elevation of systolic blood pressure and decrease in heart rate. There were no significant differences in Hb, O2Hb, and COHb. Although percent methemoglobin concentrations were statistically lower, the authors feel this difference is of trivial clinical significance. CONCLUSION: The administration of hydroxocobalamin does not significantly impact noninvasive oximetry. PMID- 23635813 TI - Intra-amniotic delivery of amniotic-derived neural stem cells in a syngeneic model of spina bifida. AB - OBJECTIVE: Neural stem cells (NSCs) may promote spinal cord repair in fetuses with experimental spina bifida. We sought to determine the fate of amniotic derived NSCs (aNSCs) after simple intra-amniotic injection in a syngeneic model of spina bifida. METHODS: Fetal neural tube defects were induced on 20 pregnant Lewis dams by prenatal administration of retinoic acid. Ten dams served as amniotic fluid donors for epigenetic isolation of aNSCs, which were expanded and labeled with 5-bromo-2'-deoxyuridine. The remaining 10 dams received intra amniotic injections of the processed aNSCs, blindly in all their fetuses (n = 37) on gestational day 17 (term = E21-22). Fetuses with spina bifida underwent screening for the presence of donor aNSCs in the spinal cord at term. RESULTS: Donor cells were identified in 93.3% of the animals with spina bifida, selectively populating the neural placode, typically in clusters, retaining an undifferentiated morphology, and predominantly on exposed neural surfaces, though some were detected deeper in neighboring neural tissue. CONCLUSIONS: The amniotic cavity can serve as a route of administration of NSCs in experimental spina bifida. Simple intra-amniotic delivery of NSCs may be a practical adjuvant to regenerative strategies for the treatment of spina bifida. PMID- 23635814 TI - Wake-up stroke: incidence, risk factors and outcome of acute stroke during sleep in a Japanese population. Takashima Stroke Registry 1988-2003. AB - Characterization of the time of stroke onset has been plagued by the problem of determining the time of the onset of events that are detected when the patient awakens. Our aim was to evaluate the characteristics, risk factors and acute fatality associated with wake-up stroke. Data was obtained from Takashima Stroke Registry covering approximately 55,000 residents in central Japan. During the period 1988-2003, information about the situation at stroke onset was available for 897 cerebral infarction (CI) and 335 intracerebral hemorrhage (ICH) events. Differences in characteristics and outcome between stroke during sleep and stroke while awake were explored. Among CI and ICH cases, 9.7 and 11.9% suffered from stroke during sleep, respectively. Hypertension and experiencing a severe event were associated with stroke during sleep among CI. Smoking and experiencing a severe event were associated with stroke during sleep and a drinking history reduced the chance of stroke during sleep among ICH. Acute fatality risks did not differ between stroke during sleep and stroke while awake among both CI and ICH cases. About 1 in 10 stroke patients had an onset of stroke during sleep. Hypertensive, smoker and clinically more severely affected patients had a higher prevalence of stroke during sleep. There were no differences between the 2 groups with respect to acute-case fatality. PMID- 23635815 TI - Transtubal spread of endometrial carcinoma: correlation of intra-luminal tumour cells with tumour grade, peritoneal fluid cytology, and extra-uterine metastasis. AB - AIMS: To assess the significance of intra-luminal tumour cells (ILTC) within the fallopian tubes of patients with endometrial carcinoma, with emphasis on high grade histological subtypes. METHODS: Complete histological examination of fallopian tube tissue was performed in 36 low grade endometrioid adenocarcinomas and in a consecutive series of 226 high grade endometrial malignancies including 92 serous carcinomas, 64 grade 3 endometrioid carcinomas, 26 carcinosarcomas, 25 undifferentiated/dedifferentiated carcinomas, and 19 clear cell carcinomas. The presence of ILTC was correlated with peritoneal fluid cytology, histologically confirmed peritoneal tumour spread, and lymph node metastases. RESULTS: ILTC were identified in 26% and 3% of high and low grade carcinomas, respectively. The presence of ILTC correlated strongly with positive peritoneal fluid cytology and with peritoneal metastasis in high grade tumours (both p < 0.001), and there was also a correlation with lymph node metastasis (p = 0.049). ILTC were more common in serous and undifferentiated carcinomas (>30%) but the differences between the high grade tumour subtypes were not statistically significant. CONCLUSIONS: These findings suggest that ILTC associated with high grade endometrial cancers have the capacity to implant and invade the peritoneal cavity. Positive cytology in such cases may be more significant than in low grade tumours. Complete tubal examination may provide additional prognostic information in high grade endometrial carcinoma. PMID- 23635816 TI - Mutation status of the mediator complex subunit 12 (MED12) in uterine leiomyomas and concurrent/metachronous multifocal peritoneal smooth muscle nodules (leiomyomatosis peritonealis disseminata). AB - AIMS: The pathogenesis and classification of multicentric smooth muscle tumours with benign appearance and concurrent/metachronous uterine and peritoneal involvement is controversial and may on occasion be diagnostically challenging. Leiomyomatosis peritonealis disseminata (LPD) is a rare condition affecting women of reproductive age, characterised by the occurrence of multiple small peritoneal smooth muscle nodules with bland histology. METHODS: We investigated a total of 12 uterine and seven concurrent/metachronous peritoneal smooth muscle nodules with benign appearance from two females for mutations in the mediator complex subunit 12 (MED12), which has recently been identified as the most frequent genetic aberration in uterine leiomyomas. RESULTS: The first case harboured different MED12 mutations in the peritoneal nodules. Mutational status of peritoneal nodules was discordant with that of the uterine leiomyomas. The second case displayed the same MED12 mutation in all five peritoneal nodules, but this mutation was not detected in her current uterine leiomyomas. CONCLUSIONS: Our results suggest that smooth muscle neoplasms with benign appearance of the primary and secondary mullerian system share a similar genetic background of MED12 mutation in combination with oestrogen dependency. Analysis of MED12 mutation status might be a valuable adjunct tool for the future classification of these sometimes diagnostically challenging multicentric tumours. PMID- 23635817 TI - Immunohistochemical staining for p16 is a useful adjunctive test in the diagnosis of Bowen's disease. AB - AIMS: The aim of this study was to document the pattern of immunohistochemical staining seen with p16 (INK4a) in actinic keratosis, Bowen's disease and seborrhoeic keratosis. METHODS: We gathered 20 examples each of actinic keratosis, Bowen's disease and seborrheic keratosis. The cases were stained for p16 using standard immunohistochemical techniques, and the staining patterns were categorised into one of five different patterns. RESULTS: All cases of Bowen's disease as defined in our practice showed strong positive staining in all abnormal cells, and 95% of these cases showed a distinctive pattern of sparing in a layer of palisaded basal cells. None of the actinic keratoses or seborrheic keratoses, as defined by our morphological criteria, showed this distinctive pattern. CONCLUSIONS: Bowen's disease, as we define the term, shows a distinctive, repeatable pattern of staining with p16, characterised by moderate to strong staining of all abnormal cells with sparing of a layer of basal cells. This pattern is not seen in actinic keratoses or in seborrheic keratoses. Thus immunohistochemistry for p16 is a useful adjunctive test in the differential diagnosis of these lesions. PMID- 23635818 TI - Pituitary metastasis of an unknown neuroendocrine breast carcinoma mimicking a pituitary adenoma. PMID- 23635819 TI - Immunohistochemical staining for factor XIIIa does not distinguish thromboembolus from clot. PMID- 23635820 TI - Primary hepatic inflammatory malignant fibrous histiocytoma: report of a rare entity and diagnostic pitfall mimicking a liver abscess. PMID- 23635821 TI - Laboratory testing for the new oral anticoagulants: a review of current practice. PMID- 23635822 TI - An atypical presentation of persistent polyclonal B-lymphocytosis with symptomatic splenomegaly and response to rituximab. PMID- 23635823 TI - Immunohistochemistry in nodular fasciitis of the head and neck. PMID- 23635824 TI - Delayed diagnosis of vaginal leiomyoma following misrepresentative core biopsy. PMID- 23635825 TI - Re-excision perineural invasion in basal cell carcinoma. PMID- 23635826 TI - A novel oncocytoid papillary renal cell carcinoma, type 2, with aberrant cytogenetic abnormalities: oncocytic papillary renal cell carcinoma? PMID- 23635827 TI - Differentiating patterns of oligoclonal banding in the cerebrospinal fluid and the diagnosis of multiple sclerosis. PMID- 23635828 TI - Effect of HbE heterozygosity on the measurement of HbA1c. AB - AIM: Measurement of HbA1c provides an excellent measure of glycaemic control for diabetic patients. However, haemoglobin (Hb) variants are known to interfere with HbA1c analysis. In our laboratory HbA1c measurement is performed by Variant II turbo 2.0. The aim of this study is to investigate the influence of HbE trait on HbA1c analysis. METHODS: Haemoglobin variants were identified by HbA1c analysis in 93 of 3522 samples sent to our laboratory in a period of 1 month. Haemoglobin analysis identified HbE trait in 81 of 93 samples. To determine the influence of HbE trait on HbA1c analysis by Variant II Tubo 2.0, boronate affinity high performance liquid chromatography (HPLC) method (Primus PDQ) was used as the comparison method. Two stage linear regression analysis, Bland Altman plot and Deming regression analysis were performed to analyse whether the presence of HbE trait produced a statistically significant difference in the results. The total allowable error for HbA1c by the Royal Australasian College of Pathologists (RCPA) external quality assurance is 5%. Hence clinically significant difference is more than 5% at the medical decision level of 6% and 9%. RESULTS: Statistically and clinically significant higher results were observed in Variant II Turbo 2.0 due to the presence of HbE trait. A positive bias of ~10% was observed at the medical decision levels. CONCLUSION: Laboratories should be cautious when evaluating HbA1c results in the presence of haemoglobin variants. PMID- 23635829 TI - Synthesis and biological evaluation of 68Ga labeled bis-DOTA-3,3'-(benzylidene) bis-(1H-indole-2-carbohydrazide) as a PET tracer for in vivo visualization of necrosis. AB - The aim of the present study was to develop a (68)Ga labeled bis-DOTA derivative of benzylidene-bis-indole and compare the in vivo stability and biodistribution with that of the previously reported bis-DTPA derivate for in vivo imaging of necrosis using PET. Uptake of the tracer was evaluated in a mouse model of Fas mediated hepatic apoptosis in correlation with histochemical stainings. The novel (68)Ga labeled tracer showed an improved in vivo stability and could therefore be used for selective non-invasive imaging of necrotic cell death using PET. PMID- 23635830 TI - Serotonergic genes (5-HTT and HTR1A) and separation life events: gene-by environment interaction for panic disorder. AB - BACKGROUND: The polymorphisms of serotonergic genes (5-HTTLPR and HTR1A rs6295) and separation life events have been studied to find an association with panic disorder, respectively. However, there are no studies that have yet evaluated the interaction effect between serotonergic genes and separation life events for panic disorder. METHODS: For this study, 194 panic disorder patients and 172 healthy controls were included for genotyping and environmental factor analysis. Separation life events were assessed using the Stressful Life Events Scale and clinical interviews. To evaluate the potential endophenotypes of panic disorder, the Anxiety Sensitivity Index-revised (ASI-R), harm avoidance in the Temperament and Character Inventory (HA), and neuroticism in the Eysenck Personality Questionnaire (neuroticism) scales were administered. RESULTS: For 5-HTTLPR and HTR1A rs6295, there was no significant main effect of each genotype on panic disorder alone. However, the number of separation life events and their interaction with 5-HTTLPR showed a statistically significant effect on panic disorder. In addition, the interaction between 5-HTTLPR and the number of separation life events significantly affected the HA for potential endophenotypes. CONCLUSION: This study could suggest the effect of the interaction between 5-HTTLPR and separation life events on panic disorder and its potential endophenotype. PMID- 23635831 TI - The value of HIV screening in the United States in the era of effective treatment. PMID- 23635832 TI - Toward a science of research prioritization? The use of value of information by multidisciplinary stakeholder groups. PMID- 23635835 TI - Affordability, accountability, and accessibility in health care reform: implications for cardiovascular and pulmonary rehabilitation. AB - Because health care costs in the United States have been growing disproportionately compared to inflation for many years, without a clear connection to improved quality or increased access to care, employers and payers have begun to test new models of health care delivery and payment. These models are linked to the concepts of affordability, accountability, and accessibility and incorporate the premise that there must be shared responsibility for improving meaningful patient outcomes, with attention to the coordination of team based and patient-centered care, and value for services purchased. This article explores emerging health care delivery and payment models, including expanded access to care related to the Affordable Care Act of 2010, patient-centered medical homes and neighborhoods, accountable and coordinated care organizations, and value-based purchasing and insurance design, with an emphasis on implications for cardiovascular and pulmonary rehabilitation programs and the American Association of Cardiovascular and Pulmonary Rehabilitation. PMID- 23635834 TI - Current status of spirituality in cardiac rehabilitation programs: a review of literature. AB - PURPOSE: Strong spiritual experiences in life are a protective, positive, prognostic factor in cardiovascular diseases. However, spirituality is often neglected in cardiac rehabilitation (CR) programs. The purpose of this article was to review studies that investigated spirituality in CR programs. METHODS: The electronic databases PubMed, CINHAL, PsycINFO, and Cochrane Library of Systematic Reviews were searched for studies that measured spirituality in a CR population. The search included studies with and without spiritual interventions in CR settings. RESULTS: Five quantitative studies and 1 qualitative study that enrolled a total of 1636 patients in phase 2 CR programs were reviewed. The spiritual interventions found were relaxation responses and spiritual classes. Two studies showed preliminary evidence that supports the further exploration of spiritual interventions in CR programs. CONCLUSIONS: Evidence supporting the use of spiritual interventions for medical and psychological outcomes in CR programs is very limited because of a lack of controlled clinical trials. However, the descriptive and observational studies provide some empirical support to further explore spiritual interventions in CR programs, with the goal of enhancing the psychosocial and emotional status of CR participants. Further rigorous research design and procedures are needed to establish the contribution of spirituality in CR programs for cardiac patients. PMID- 23635833 TI - Value-of-information analysis within a stakeholder-driven research prioritization process in a US setting: an application in cancer genomics. AB - OBJECTIVE: The objective of this study was to evaluate the feasibility and outcomes of incorporating value-of-information (VOI) analysis into a stakeholder driven research prioritization process in a US-based setting. METHODS: . Within a program to prioritize comparative effectiveness research areas in cancer genomics, over a period of 7 months, we developed decision-analytic models and calculated upper-bound VOI estimates for 3 previously selected genomic tests. Thirteen stakeholders representing patient advocates, payers, test developers, regulators, policy makers, and community-based oncologists ranked the tests before and after receiving VOI results. The stakeholders were surveyed about the usefulness and impact of the VOI findings. RESULTS: The estimated upper-bound VOI ranged from $33 million to $2.8 billion for the 3 research areas. Seven stakeholders indicated the results modified their rankings, 9 stated VOI data were useful, and all indicated they would support its use in future prioritization processes. Some stakeholders indicated expected value of sampled information might be the preferred choice when evaluating specific STUDY DESIGN: Limitations. Our study was limited by the size and the potential for selection bias in the composition of the external stakeholder group, lack of a randomized design to assess effect of VOI data on rankings, and the use of expected value of perfect information v. expected value of sample information methods. CONCLUSIONS: Value of information analyses may have a meaningful role in research topic prioritization for comparative effectiveness research in the United States, particularly when large differences in VOI across topic areas are identified. Additional research is needed to facilitate the use of more complex value of information analyses in this setting. PMID- 23635836 TI - Barriers to cardiac rehabilitation use in Canada versus Brazil. AB - PURPOSE: Despite its well-established benefits, cardiac rehabilitation (CR) is greatly underutilized globally. Barriers to its utilization have been identified in high-income countries. Given the growing epidemic of noncommunicable diseases in low- to middle-income countries, the identification of barriers to use of these low-cost interventions is warranted. The aim of this study was to describe and compare barriers to CR use in Brazilian and Canadian cardiac outpatients. METHODS: Two cardiac samples consisting of 237 Brazilian (recruited from 2 CR centers in southern Brazil) and 1434 Canadian (recruited from 11 community and academic hospitals in Ontario) outpatients were compared cross-sectionally. Barriers were assessed by using the Cardiac Rehabilitation Barriers Scale, psychometrically validated in English and Portuguese. Mann-Whitney U tests were used to compare barriers between samples. RESULTS: Overall, 139 (58.6%) Brazilian and 779 (54.3%) Canadian respondents were enrolled in CR. The mean total barriers score for Brazilian respondents was 1.71 +/- 0.63, and 2.37 +/- 1.0 (P < .01) for the Canadians. For 17 of 21 barriers, Canadians reported significantly greater barriers than Brazilians (P < .02). As their greatest barriers, Canadians rated already exercising at home or in the community and personal travel, while Brazilians identified distance to and cost of the CR program. CONCLUSION: Despite the significantly lower availability of CR in Brazil and the universal health care system in Canada, cardiac outpatients in Canada perceived significantly greater CR barriers. Arguably, however, these barriers were more modifiable. PMID- 23635838 TI - Treatment frequency and efficiency in hemodiafiltration. AB - BACKGROUND: One of the main objectives of dialysis is uremic retention product elimination. Efficiency of dialysis modalities varies both regarding the range of solutes removed and the extent of such removal. We analyzed plasma (or blood) concentrations of marker solutes in intermittent treatment schedules using hemodiafiltration (HDF). METHODS: Elimination and rebound of uremic solutes were measured in 10 patients (77 +/- 12 kg, 66.5 +/- 9.2 years) treated with postdilution HDF in one 4-hour treatment and in two 2-hour treatments on consecutive days (Polyflux 2.1 m(2), QB 451 +/- 53 ml/min, QD 598 +/- 13 ml/min). Blood urea, creatinine, phosphate, beta2-microglobulin, complement factor D and advanced glycation end products were analyzed before, during and after HDF for 24 48 h. RESULTS: Applying two 2-hour HDF treatments on consecutive days resulted in significantly lower plasma (or blood) levels of urea, creatinine, phosphate, beta2-microglobulin, and advanced glycation end products after 48 h than using one 4-hour session. CONCLUSIONS: Increased treatment frequency could further optimize blood purification in HDF therapy. PMID- 23635839 TI - Citations of scientific results and conflicts of interest: the case of mammography screening. AB - INTRODUCTION: In 2001, a Cochrane review of mammography screening questioned whether screening reduces breast cancer mortality, and a more comprehensive review in Lancet, also in 2001, reported considerable overdiagnosis and overtreatment. This led to a heated debate and a recent review of the evidence by UK experts intended to be independent. OBJECTIVE: To explore if general medical and specialty journals differed in accepting the results and methods of three Cochrane reviews on mammography screening. METHODS: We identified articles citing the Lancet review from 2001 or updated versions of the Cochrane review (last search 20 April 2012). We explored which results were quoted, whether the methods and results were accepted (explicit agreement or quoted without caveats), differences between general and specialty journals, and change over time. RESULTS: We included 171 articles. The results for overdiagnosis were not quoted in 87% (148/171) of included articles and the results for breast cancer mortality were not quoted in 53% (91/171) of articles. 11% (7/63) of articles in general medical journals accepted the results for overdiagnosis compared with 3% (3/108) in specialty journals (p=0.05). 14% (9/63) of articles in general medical journals accepted the methods of the review compared with 1% (1/108) in specialty journals (p=0.001). Specialty journals were more likely to explicitly reject the estimated effect on breast cancer mortality 26% (28/108), compared with 8% (5/63) in general medical journals, p=0.02. CONCLUSIONS: Articles in specialty journals were more likely to explicitly reject results from the Cochrane reviews, and less likely to accept the results and methods, than articles in general medical journals. Several specialty journals are published by interest groups and some authors have vested interests in mammography screening. PMID- 23635840 TI - Childbirth and subsequent development of pelvic organ prolapse. PMID- 23635841 TI - The levonorgestrel intrauterine system: effective non-surgical treatment for heavy menstrual bleeding. PMID- 23635842 TI - Renin-angiotensin system blockers increase risk of angio-oedema. PMID- 23635843 TI - Maternal folic acid supplements associated with reduced autism risk in the child. PMID- 23635844 TI - Ursodeoxycholic acid for intrahepatic cholestasis of pregnancy: good for the mother, not bad for the baby. PMID- 23635845 TI - Acupuncture is superior to sham for painful conditions. PMID- 23635847 TI - Pathways for processing noise: heart health and the sounds of everyday life. PMID- 23635849 TI - CD4+CD25+ regulatory T cells attenuate lipopolysaccharide-induced systemic inflammatory responses and promotes survival in murine Escherichia coli infection. AB - It is well established that CD4CD25 regulatory T cells (Tregs) downregulate inflammatory immune responses and help to maintain immune homeostasis. Recent reports have shown that ligation of germline encoded pattern recognition receptors such as Toll-like receptors can stimulate Tregs and therefore implicate Tregs in the pathophysiology of sepsis and other inflammatory diseases. In this report, we show that injection of lipopolysaccharide (LPS) leads to expansion of CD4CD25FoxP3 Tregs, suggesting that these cells may play an important role in immune regulation in LPS-induced acute inflammation. Indeed, genetic or immunological inhibition of Treg function using mice lacking functional Tregs (CD25 KO mice) or anti-CD25 monoclonal antibody (anti-CD25 mAb), respectively, led to acute death in an otherwise nonlethal LPS challenge. This was accompanied by exaggerated production of proinflammatory cytokines. Strikingly, adoptive transfer of CD4CD25 Tregs to CD25 KO mice before LPS challenge rescues mice from death. Unlike LPS, depletion of Tregs followed by concanavalin A (Con A) challenge does not result in mortality, suggesting that Treg depletion does not globally influence all models of acute inflammation. We authenticate our findings by showing that depletion of Tregs leads to mortality in a nonlethal Escherichia coli challenge accompanied by elevated serum levels of proinflammatory cytokines. Collectively, our results indicate that in addition to regulation of LPS-induced acute inflammation, Tregs help to improve bacterial clearance and promote survival in an acute model of bacterial infection. PMID- 23635848 TI - Role of RhoA in regulating the pump function of isolated lymphatics from hemorrhagic shock rats. AB - The aim of this present study was to examine changes in RhoA protein levels and the role in RhoA in lymphatic contractility and reactivity after hemorrhagic shock. Levels of RhoA and phospho-RhoA in lymphatic tissue isolated from hemorrhagic shock rats were measured, and the contractility and reactivity to substance P of lymphatics isolated from control rats and rats subjected to shock 0.5 and 2 h were determined with an isolated lymphatic perfusion system at a transmural pressure of 3 cmH2O. At the same time, lymphatics isolated from rats subjected to shock 0.5 and 2 h were incubated with agonists and antagonists of RhoA/Rho kinase signaling. Contractile frequency, end-diastolic and end-systolic diameter, and passive diameter were recorded and used to calculate lymphatic tonic index, contractile amplitude, and fractional pump flow. After stimulation with a gradient of substance P, the differences between the preadministration and postadministration values of contractile frequency, contractile amplitude, tonic index, and fractional pump flow were calculated to further assess lymphatic reactivity. RhoA protein levels were significantly increased at 0.5 h after shock but decreased at 2 and 3 h after shock; p-Rho levels were initially increased after shock and subsequently decreased. The contractility and reactivity of 0.5-h shocked lymphatics were significantly reduced by the RhoA antagonist C3 transferase and the Rho kinase antagonist Y-27632. The RhoA agonist U-46619 increased the contractility and reactivity of 2-h-shocked lymphatics, whereas Y 27632 suppressed the effect of U-46619. Okadaic acid, an inhibitor of myosin light-chain phosphatase, had no effect on the contractility of 2-h-shocked lymphatics, but improved lymphatic reactivity. These results suggest that RhoA is involved in the modulation of lymphatic pump function during hemorrhagic shock and that its effects may be mediated by Rho kinase and MLCP. PMID- 23635846 TI - Cognitive behaviour therapy for psychotic symptoms: a randomized controlled effectiveness trial. AB - BACKGROUND: Cognitive behavioural therapy for psychosis (CBTp) is currently a recommended form of psychosocial treatment for persons suffering from persistent psychotic symptoms. It has been argued that effect sizes from efficacy studies cannot be generalized to real clinical settings. AIMS: Our aim was to evaluate whether the positive results from randomized controlled trials conducted by experts could be replicated in clinical setting with a heterogeneous sample of patients with psychotic disorder. METHOD: Patients referred to the study were either randomized to CBTp+TAU (the treatment group) or to a waiting-list group, only receiving TAU. The patients were assessed on different outcome measures such as the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), and the Psychotic Symptom Rating Scales (PSYRATS), at pretreatment, at posttreatment (6 months), and at 12 months follow-up. In total, 45 patients participated in the study. RESULTS: The results showed that 20 sessions of CBTp performed significantly better than the waiting list controls with respect to the global score on the BPRS, the delusional scale on the PSYRATS, and the GAF symptom score at posttreatment. At 12 months follow-up only the GAF symptom score remained significantly changed for the total sample. CONCLUSIONS: The study revealed that CBTp delivered by non-experts in routine clinical settings can produce improvements in positive psychotic symptoms, and also that some of these improvements can be maintained at one year follow-up. PMID- 23635850 TI - Post resusicitation fluid boluses in severe sepsis or septic shock: prevalence and efficacy (price study). AB - INTRODUCTION: Administration of fluid boluses (FBs) beyond initial resuscitation in patients with severe sepsis is common and may contribute to positive fluid balance. Little is known regarding the efficacy and risk profile of this strategy. OBJECTIVE: To estimate the prevalence and efficacy of FBs after initial resuscitation in septic patients. METHODS: In a prospective study, patients with severe sepsis/septic shock were recruited after initial resuscitation and followed up for 3 days. Number, types, and volumes of FBs; resuscitation goals; and their perceived success rates were recorded. Data are presented as median (interquartile range). RESULTS: Over a 1-year period, 50 patients were recruited, 47 (94%) of them received FBs, with a total of 184 FBs (3 [2-5] per patient) administered over 72 h. On day 1, 2 (1-3) FBs, totaling 750 mL (500-1,720 mL), were administered, which comprised 52.4% (22.1%-124.2%) of the fluid balance. Low blood pressure (mean arterial pressure [MAP]) (76.0%) and increased vasopressor requirement (60.3%) were the two most common indications for FBs. Low filling pressure (70.9%) and clinical signs (79.4%) were perceived as the most successful indications. One hour after these FBs, there was a small increase in MAP (P < 0.01) and central venous pressure (P < 0.01); however, there was also concomitant increase in noradrenaline administered. There was a significant decrease in PaO2/FIO2 ratio, hemoglobin, and temperature, whereas urine output remained unchanged. Factors (Exp[b] [SE], P) (R = 0.296) that affected the increase in MAP were baseline MAP (-0.49 [0.057], P < 0.001) and amount of these FBs (-0.05 [0.01], P = 0.001). Cumulative fluid balance had a weak correlation with delta sequential organ failure assessment score (r = 0.32, P = 0.001) and lung injury score (r = 0.13, P = 0.02) and negative correlation with PaO2/FIO2 ratio (r = 0.28, P = 0.001). CONCLUSION: Postresuscitation FBs are common in septic patients, meet limited success, and may be harmful. PMID- 23635851 TI - Improvements in the hemodynamic stability of combat casualties during en route care. AB - Three Forward Aeromedical Evacuation platforms operate in Southern Afghanistan: UK Medical Emergency Response Team (MERT), US Air Force Expeditionary Rescue Squadron (PEDRO), and US Army Medical Evacuation Squadrons (DUSTOFF), each with a different clinical capability. Recent evidence suggests that retrieval by a platform with a greater clinical capability (MERT) is associated with improved mortality in critical patients when compared with platforms with less clinical capability (PEDRO and DUSTOFF). It is unclear whether this is due to en route resuscitation or the dispatch procedure. The aim of this study was to compare prehospital Shock Index (SI = heart rate / systolic blood pressure) with admission values as a measure of resuscitation, across these platforms. Patients were identified from the Department of Defense Trauma Registry, who were evacuated between June 2009 and June 2011 in Southern Afghanistan. Data on platform type, physiology, and injury severity was extracted. Overall, 865 patients were identified: 478 MERT, 291 PEDRO, and 96 DUSTOFF patients and groups were compared across three injury severity scoring (ISS) bins: 1 to 9, 10 to 25, and 26 or greater. An improvement in the admission SI was observed across all platforms in the lowest ISS bin. Within the middle bin, both the MERT and PEDRO groups saw improved SI on admission, but not the DUSTOFF group. This trend was continued only in the MERT group for the highest ISS bin (1.39 +/- 0.62 vs. 1.09 +/- 0.42; P = 0.001), whereas a deterioration was identified in the PEDRO group (0.88 +/- 0.37 vs. 1.02 +/- 0.43; P = 0.440). The use of a Forward Aeromedical Evacuation platform with a greater clinical capability is associated with an improved hemodynamic status in critical casualties. The ideal prehospital triage should endeavor to match patient need with clinical capability. PMID- 23635852 TI - Bilateral microkeratome-assisted anterior lamellar contralateral corneal autograft: a case report. AB - PURPOSE: To present a case in which bilateral microkeratome-assisted contralateral anterior lamellar corneal autografting was used in the treatment of a patient with a stromal scar in one eye and dense amblyopia in the fellow eye. METHODS: Case report based on chart review. RESULTS: Anterior lamellar flaps were created in both eyes with a microkeratome. Six weeks later, central trephination through both flaps was performed, and the resulting corneal discs were switched. Visual acuity improved to 20/30 in the nonamblyopic eye 1 year after the surgery. CONCLUSIONS: Microkeratome-assisted contralateral lamellar autokeratoplasty can be useful in the treatment of an anterior stromal scar when the fellow eye has a clear cornea and poor vision limited by untreatable noncorneal pathology. PMID- 23635853 TI - Corneal manifestations and in vivo confocal microscopy of Gaucher disease. AB - PURPOSE: To report corneal abnormalities and confocal microscopy findings in a patient with a variant of Gaucher disease (GD). METHODS: Case report with slit lamp photography, confocal microscopy, and molecular analysis of the glucocerebrosidase gene. RESULTS: Ophthalmic evaluation in a 57-year-old white patient demonstrated corneal opacities scattered throughout the cornea. Confocal microscopy revealed a completely distorted stromal architecture. The anterior part showed keratocytes with an abnormal morphology intermingled with minute white dots. In the posterior part, normal keratocytes were virtually absent and replaced by hyperreflective rod-like structures. Analysis of the glucocerebrosidase gene disclosed a heterozygous F216Y/L444P mutation. The patient's old records revealed that these corneal abnormalities were already present at the age of 16 years, almost 15 years before the diagnosis of GD was made. His 2 siblings known with the same disorder and mutations also showed abnormal visual acuity and increased central corneal thickness. The confocal microscopy demonstrated some subclinical abnormalities, but otherwise normal corneas. CONCLUSIONS: Our patient had an unusual mutation responsible for his GD. Although corneal opacities are virtually unknown in GD, except in the D409H homozygous cardiovascular subtype, this patient had marked corneal stromal abnormalities. PMID- 23635855 TI - Long-term outcomes of penetrating keratoplasty and Descemet stripping endothelial keratoplasty for Fuchs endothelial dystrophy: fellow eye comparison. AB - PURPOSE: To compare the visual outcomes and complications after Descemet stripping endothelial keratoplasty (DSEK) and penetrating keratoplasty (PK) in the same set of patients. METHODS: Fifteen patients underwent PK in 1 eye and DSEK in the fellow eye for Fuchs endothelial dystrophy at the Wills Eye Institute from 1993 to 2011. RESULTS: Mean postoperative best-corrected visual acuity in the PK and DSEK groups (0.39 +/- 0.39 and 0.23 +/- 0.12 logarithm of the minimum angle of resolution, respectively) was statistically significantly better than mean preoperative best-corrected visual acuity (0.83 +/- 0.36 and 0.76 +/- 0.34 logarithm of the minimum angle of resolution, respectively) (P < 0.025 and P < 0.001, respectively). Mean manifest refraction cylinder was higher in the PK eyes than in the DSEK eyes at 1 year [3.58 +/- 1.82 and 1.23 +/- 1.63 diopter (D), respectively] and at 2 years of follow-up (3.57 +/- 1.81 and 1.05 +/- 1.18 D, respectively) (P < 0.001) but was not statistically different at the last visit (3.18 +/- 2.67 and 1.5 +/- 1.66 D, respectively) (P = 0.052). Mean postoperative follow-up was 101.9 +/- 39.5 and 29.9 +/- 19.9 months after PK and DSEK, respectively. Most common complications after PK were high astigmatism in 15 eyes, monocular diplopia in 7 eyes, posterior capsule opacity in 6 eyes, and secondary glaucoma and graft rejection episodes in 5 eyes each. After DSEK, secondary glaucoma in 3 eyes and graft rejection in 2 eyes were the most common complications. CONCLUSIONS: Final visual outcomes were not statistically different between the 2 procedures, but DSEK had early visual stabilization and PK had a more complicated course, with more astigmatism, rejections, suture related infections, and graft failures. PMID- 23635854 TI - In vivo confocal microscopic findings in posterior polymorphous corneal dystrophy. AB - PURPOSE: To describe the corneal findings in posterior polymorphous corneal dystrophy (PPCD) as imaged with laser scanning in vivo confocal microscopy (IVCM). METHODS: IVCM images of 7 subjects with PPCD who had typical slit-lamp biomicroscopic findings of endothelial vesicular, band, and/or placoid lesions were evaluated. RESULTS: Five women and 2 men aged 7 to 64 years were included in this study. Laser scanning IVCM (Heidelberg Retina Tomograph II, Rostock Cornea Module) revealed hyporeflective, round, vesicular lesions with diameters ranging between 20 and 200 um in 3 subjects, combined vesicular and curvilinear hyperreflective band-like lesions in 3 subjects, and combined vesicular and placoid hyperreflective lesions in 1 subject at the level of Descemet membrane (DM), endothelial cell layer, and posterior stroma adjacent to DM. One subject had coassociated epithelial basement membrane dystrophy. Additional findings included posterior stromal keratocytes with elongated spindle-like nucleus, giant and nucleated endothelial cells, endothelial deposits, and guttae-like dark spots. The mean endothelial cell density was 1485.7 +/- 486.3 cells per square millimeter (range, 990-2365 cells/mm). The mean central corneal thickness was 585.3 +/- 37.17 MUm (range, 534-643 MUm). CONCLUSIONS: Laser scanning IVCM is able to highlight the characteristic microstructural alterations at the level of endothelium and DM in the setting of PPCD and may have diagnostic utility in equivocal cases with borderline biomicroscopic findings. The possible association of PPCD with epithelial basement membrane dystrophy warrants further investigation. PMID- 23635856 TI - Direct surgical repair of corneal perforation in pellucid marginal degeneration: a case series. AB - PURPOSE: To report a novel technique for repairing corneal perforations in 5 eyes of 3 patients with pellucid marginal degeneration (PMD). Four cases were successfully repaired with corneal sutures and 1 case required a penetrating keratoplasty. METHODS: Retrospective case series of corneal perforation repairs in the setting of PMD. RESULTS: Four perforations were managed successfully with primary closure resulting in acceptable best spectacle-corrected visual acuity and stable corneal topography. One corneal perforation required a penetrating keratoplasty after unsuccessful suture repair. CONCLUSIONS: Primary repair of corneal perforations in cases of PMD can be achieved with corneal suturing alone. This technique may achieve a satisfactory visual and topographic outcome with minimal complications. PMID- 23635857 TI - Descemet membrane endothelial keratoplasty: learning curve of a single surgeon. AB - PURPOSE: To evaluate the learning curve of standardized "no-touch" Descemet membrane endothelial keratoplasty (DMEK) of a single surgeon in a clinic without an in-house eye bank facility. METHODS: For 25 eyes of 22 patients, Descemet graft preparation and DMEK surgery were performed according to the protocols of the Netherlands Institute for Innovative Ocular Surgery with minor modifications. Best spectacle-corrected visual acuity, subjective refraction, Scheimpflug tomography, and endothelial cell density of the donor tissue were documented before and at 1, 3, and 6 months after the surgery; intraoperative and postoperative complications were recorded. RESULTS: No donor tissue was lost owing to preparation failure of the Descemet graft allowing all surgeries to be completed as planned. At 6 months after the surgery, 83% of eyes reached >= 20/40 (>= 0.5), 48% >= 20/28 (>= 0.8), and 30% (7/23) >= 20/20 (>= 1.0) (n = 23). The mean change in both spherical equivalent and refractive cylinder in the same interval was minimal (0.03 diopter). Mean donor endothelial cell density decreased from 2444 cells per square millimeter (+/- 198 cells/mm2) before the surgery to 1331 cells per square millimeter (+/- 491 cells/mm2) at 6 months after the surgery. Partial graft detachment requiring rebubbling occurred in 9 cases (36%). One eye developed primary graft failure. CONCLUSIONS: This case series shows that DMEK by a beginning surgeon can achieve good results without preparing the graft in an eye bank. Use of backup tissue can be avoided by strictly adhering to the Netherlands Institute for Innovative Ocular Surgery techniques and by harvesting the graft the day before surgery to avoid last-minute cancellation. PMID- 23635859 TI - Reply: To PMID 22790186. PMID- 23635858 TI - Effect of donor preparation-to-use times on Descemet membrane endothelial keratoplasty outcomes. AB - PURPOSE: To report the effect of varying donor preparation-to-use times on outcomes of Descemet membrane endothelial keratoplasty (DMEK). METHODS: Prospective interventional series. DMEK donor tissues prepared at a single center on the day of surgery (group 0), 1 day before the surgery (group 1), or 2 days before the surgery (group 2) were transplanted into 361 eyes for Fuchs dystrophy, pseudophakic bullous keratopathy, or graft failure, with or without combined cataract surgery. When prepared ahead, the donor tissue was stored in refrigerated corneal storage solution until use. Primary outcome measures were air reinjection rate, primary failure rate, and endothelial cell loss. RESULTS: Donor and recipient characteristics did not differ significantly between the groups. In groups 0, 1, and 2, the rate of failure to clear was 1.5%, 1.9%, and 2.8%, respectively (P = 0.78), and the rebubbling rate was 15%, 13%, and 14%, respectively, in the grafts that cleared successfully (P = 0.92). Median endothelial cell loss at 3 months was 28%, 29%, and 29%, respectively (P = 0.56). CONCLUSIONS: Having DMEK donor tissue prepared in advance can be logistically advantageous. Tissue preparation in advance with storage for 1 or 2 days in corneal storage solution at 4 degrees C was not associated with any significant difference in the primary failure rate, air reinjection rate, or endothelial cell loss compared with the same-day preparation. The maximum allowable preparation-to use time and the effects, if any, of different storage media or transportation from off-site locations have yet to be determined for precut DMEK tissue. PMID- 23635860 TI - Effects of diquafosol sodium eye drops on tear film stability in short BUT type of dry eye. AB - PURPOSE: To investigate the effects of diquafosol sodium (DQS) eye drops, a purinergic P2Y2 receptor agonist, on tear film stability in patients with unstable tear film (UTF). METHODS: Two prospective studies were conducted. One was an exploratory nonrandomized trial on 39 eyes with dry eye symptoms and short tear film break-up time (BUT), but without epithelial damage. Changes in symptoms, BUT, Schirmer value, and ocular surface fluorescein staining (FS) scores were studied for 3 months. The other was a randomized clinical trial of DQS and artificial tears (AT) in 17 eyes with short BUT. Eyes with decreased Schirmer values (<= 5 mm) were excluded. Changes in symptoms, BUT, FS scores, and tear film stability using continuous corneal topographic analysis were studied for 4 weeks. RESULTS: In the exploratory study, while Schirmer values were not significantly increased, significant improvements in symptoms and BUT were noted at both 1 and 3 months. In the randomized clinical trial, significant improvements in symptoms were noted in the DQS group, but not in the AT group, at 2 weeks. BUT was significantly prolonged in the DQS group at 4 weeks but not in the AT group. No significant changes were noted in FS scores or tear film stability. CONCLUSIONS: DQS improved subjective symptoms and prolonged BUT in eyes with UTF not associated with low tear secretion and ocular surface epithelial damage. Because many patients who have UTF are refractory to conventional treatments, DQS may offer benefits in the treatment of dry eyes. PMID- 23635862 TI - Bell's palsy and hereditary neuropathy with liability to pressure palsy (HNPP): is there a common genetic background? PMID- 23635861 TI - Emergence of methicillin-resistant Staphylococcus aureus in the Maternity Hospital, Kuwait. AB - OBJECTIVE: To establish the relatedness of methicillin-resistant Staphylococcus aureus (MRSA) isolates in the Maternity Hospital, Kuwait. MATERIALS AND METHODS: A total of 22 MRSA were isolated from 20 neonates and 1 mother in the Special Care Unit, Maternity Hospital, Kuwait. They were characterized using antibiogram, pulsed-field gel electrophoresis (PFGE), SCCmec typing, spa typing and multi locus sequence typing (MLST), and were screened for genes encoding Panton Valentine leukocidin (PVL) and capsular polysaccharide types 5 and 8. RESULTS: The isolates were resistant to cadmium acetate (n = 22 or 100%), trimethoprim (n = 13 or 59.1%), gentamicin (n = 7 or 31.8%), ciprofloxacin (n = 5 or 22.7%), erythromycin and clindamycin (n = 2 or 9.1%), tetracycline (n = 2 or 9.1%) and fusidic acid (n = 2 or 9.1%). Eight isolates contained genes for PVL while 15 and 6 carried genes for types 5 and 8 capsular polysaccharide, respectively. Molecular typing distinguished 12 clones. Ten of these clones consisted of 20 isolates belonging to ST60-SCCmec-IV-t3935 (5 isolates), ST6-SCCmec-IV-t6269 (4 isolates), ST194-SCCmec-IV-t6892 (3 isolates), ST1-SCCmec-V-t2962 (2 isolates) and 1 isolate each of ST77-SCCmec-IV-t339, ST935-SCCmec-V-t1084, ST1317-SCCmec-V t1548, ST9-SCCmec-V-t5801, ST627-SCCmec-IV-t1340 and ST2148-SCCmec-IV-t2810. CONCLUSION: The study demonstrated the emergence of MRSA including novel ST60 and ST194 clones at the Maternity Hospital in Kuwait. PMID- 23635863 TI - Is there a negative interpretation bias in depressed patients? An affective startle modulation study. AB - BACKGROUND/AIMS: Scientists proposed that patients with depression favour negative interpretations when appraising ambiguity. As self-report measures seem prone to response bias, implicit measures of emotional valence should be additionally used. METHODS: A total of 16 patients with depression and 19 controls underwent an acoustic imagery task comprising neutral and negative words, as well as ambiguous words that could be understood either way. Affective startle modulation and direct interrogation were used to assess implicit and explicit emotional valence, respectively. We expected a negative bias for ambiguous words in the patient group, resulting in augmented startle magnitudes and preference for negative interpretations of the ambiguous words in the interrogation. RESULTS: Surprisingly, both groups preferred neutral interpretations and showed augmented startle magnitudes to ambiguous words. Furthermore, both groups displayed an emotional startle potentiation for negative words. CONCLUSION: In summary, our results do not confirm a negative interpretation bias or a blunted emotional response in patients with major depression. The mismatch between self-report and affective startle reaction to ambiguous targets might reflect defensive mobilization or attention effects. PMID- 23635864 TI - Lexical priming in Alzheimer's disease and aphasia. AB - Lexical priming was examined in patients with Alzheimer's disease and in aphasic patients. Control participants were divided into young and elderly [cf. Arroyo Anllo et al.: Eur J Cogn Psychol 2004;16:535-553]. For lexical priming, a word stem completion task was used. Normal elderly participants had lexical priming scores that were significantly lower than those of young individuals. Analysis of covariance with age and educational level as covariates showed that the control participants, aphasic and Alzheimer patients did not differ significantly on the lexical priming task. Our results suggest that performance in the lexical priming task diminishes with physiological aging, but is not significantly affected by mild or moderate Alzheimer's disease or by fluent or non-fluent aphasia. PMID- 23635865 TI - Gene invasion in distant eukaryotic lineages: discovery of mutually exclusive genetic elements reveals marine biodiversity. AB - Inteins are rare, translated genetic parasites mainly found in bacteria and archaea, while spliceosomal introns are distinctly eukaryotic features abundant in most nuclear genomes. Using targeted metagenomics, we discovered an intein in an Atlantic population of the photosynthetic eukaryote, Bathycoccus, harbored by the essential spliceosomal protein PRP8 (processing factor 8 protein). Although previously thought exclusive to fungi, we also identified PRP8 inteins in parasitic (Capsaspora) and predatory (Salpingoeca) protists. Most new PRP8 inteins were at novel insertion sites that, surprisingly, were not in the most conserved regions of the gene. Evolutionarily, Dikarya fungal inteins at PRP8 insertion site a appeared more related to the Bathycoccus intein at a unique insertion site, than to other fungal and opisthokont inteins. Strikingly, independent analyses of Pacific and Atlantic samples revealed an intron at the same codon as the Bathycoccus PRP8 intein. The two elements are mutually exclusive and neither was found in cultured Bathycoccus or other picoprasinophyte genomes. Thus, wild Bathycoccus contain one of few non-fungal eukaryotic inteins known and a rare polymorphic intron. Our data indicate at least two Bathycoccus ecotypes exist, associated respectively with oceanic or mesotrophic environments. We hypothesize that intein propagation is facilitated by marine viruses; and, while intron gain is still poorly understood, presence of a spliceosomal intron where a locus lacks an intein raises the possibility of new, intein-primed mechanisms for intron gain. The discovery of nucleus-encoded inteins and associated sequence polymorphisms in uncultivated marine eukaryotes highlights their diversity and reveals potential sexual boundaries between populations indistinguishable by common marker genes. PMID- 23635866 TI - Can we detect oceanic biodiversity hotspots from space? AB - Understanding the variability of marine biodiversity is a central issue in microbiology. Current observational programs are based on in situ studies, but their implementation at the global scale is particularly challenging, owing to the ocean extent, its temporal variability and the heterogeneity of the data sources on which compilations are built. Here, we explore the possibility of identifying phytoplanktonic biodiversity hotspots from satellite. We define a Shannon entropy index based on patchiness in ocean color bio-optical anomalies. This index provides a high resolution (1 degree) global coverage. It shows a relation to temperature and mid-latitude maxima in accordance with those previously evidenced in microbiological biodiversity model and observational studies. Regional maxima are in remarkable agreement with several known biodiversity hotspots for plankton organisms and even for higher levels of the marine trophic chain, as well as with some in situ planktonic biodiversity estimates (from Atlantic Meridional Transect cruise). These results encourage to explore marine biodiversity with a coordinated effort of the molecular, ecological and remote sensing communities. PMID- 23635868 TI - Telepathology in cytopathology: challenges and opportunities. AB - OBJECTIVE: Telepathology in cytopathology is becoming more commonly utilized, and newer technologic infrastructures afford the laboratory a variety of options. The options and design of a telepathology system are driven by the clinical needs. This is primarily focused on providing rapid on-site evaluation service for fine needle aspiration. STUDY DESIGN: The clinical requirements and needs of a system are described. Available tools to design and implement a telepathology system are covered, including methods of image capture, network connectivity and remote viewing options. RESULTS: The primary telepathology method currently used and described involves the delivery via a network connection of a live video image to a remote site which is passively viewed by an internet web-based browser. By utilizing live video information and a voice connection to the on-site location, the remote viewer can collect clinical information and direct their view of the slides. CONCLUSIONS: Telepathology systems for use in cytopathology can be designed and implemented with commercially available infrastructure. It is necessary for the laboratory to validate the designed system and adhere to the required regulatory requirements. Telepathology for cytopathology can be reliably utilized by adapting existing technology, and newer advances hold great promise for further applications in the cytopathology laboratory. PMID- 23635867 TI - Global morphological analysis of marine viruses shows minimal regional variation and dominance of non-tailed viruses. AB - Viruses influence oceanic ecosystems by causing mortality of microorganisms, altering nutrient and organic matter flux via lysis and auxiliary metabolic gene expression and changing the trajectory of microbial evolution through horizontal gene transfer. Limited host range and differing genetic potential of individual virus types mean that investigations into the types of viruses that exist in the ocean and their spatial distribution throughout the world's oceans are critical to understanding the global impacts of marine viruses. Here we evaluate viral morphological characteristics (morphotype, capsid diameter and tail length) using a quantitative transmission electron microscopy (qTEM) method across six of the world's oceans and seas sampled through the Tara Oceans Expedition. Extensive experimental validation of the qTEM method shows that neither sample preservation nor preparation significantly alters natural viral morphological characteristics. The global sampling analysis demonstrated that morphological characteristics did not vary consistently with depth (surface versus deep chlorophyll maximum waters) or oceanic region. Instead, temperature, salinity and oxygen concentration, but not chlorophyll a concentration, were more explanatory in evaluating differences in viral assemblage morphological characteristics. Surprisingly, given that the majority of cultivated bacterial viruses are tailed, non-tailed viruses appear to numerically dominate the upper oceans as they comprised 51-92% of the viral particles observed. Together, these results document global marine viral morphological characteristics, show that their minimal variability is more explained by environmental conditions than geography and suggest that non-tailed viruses might represent the most ecologically important targets for future research. PMID- 23635869 TI - Kava in the treatment of generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. AB - Kava (Piper methysticum) is a plant-based medicine, which has been previously shown to reduce anxiety. To date, however, no placebo-controlled trial assessing kava in the treatment of generalized anxiety disorder (GAD) has been completed. A total of 75 participants with GAD and no comorbid mood disorder were enrolled in a 6-week double-blind trial of an aqueous extract of kava (120/240 mg of kavalactones per day depending on response) versus placebo. gamma-Aminobutyric acid (GABA) and noradrenaline transporter polymorphisms were also analyzed as potential pharmacogenetic markers of response. Reduction in anxiety was measured using the Hamilton Anxiety Rating Scale (HAMA) as the primary outcome. Intention to-treat analysis was performed on 58 participants who met inclusion criteria after an initial 1 week placebo run-in phase. Results revealed a significant reduction in anxiety for the kava group compared with the placebo group with a moderate effect size (P = 0.046, Cohen d = 0.62). Among participants with moderate to severe Diagnostic and Statistical Manual of Mental Disorders diagnosed GAD, this effect was larger (P = 0.02; d = 0.82). At conclusion of the controlled phase, 26% of the kava group were classified as remitted (HAMA <= 7) compared with 6% of the placebo group (P = 0.04). Within the kava group, GABA transporter polymorphisms rs2601126 (P = 0.021) and rs2697153 (P = 0.046) were associated with HAMA reduction. Kava was well tolerated, and aside from more headaches reported in the kava group (P = 0.05), no other significant differences between groups occurred for any other adverse effects, nor for liver function tests. Standardized kava may be a moderately effective short-term option for the treatment of GAD. Furthermore, specific GABA transporter polymorphisms appear to potentially modify anxiolytic response to kava. PMID- 23635872 TI - Pain: Feeling the heat (and cold). PMID- 23635873 TI - Neuroendocrinology: Hypothalamic self-tuning to stress. PMID- 23635874 TI - Amphipaths differentially modulate membrane surface deformation in rat peritoneal mast cells during exocytosis. AB - BACKGROUND/AIMS: Salicylate and chlorpromazine exert differential effects on the chemokine release from mast cells. Since these drugs are amphiphilic and preferentially partitioned into the lipid bilayers of the plasma membranes, they would induce some morphological changes in mast cells and thus affect the process of exocytosis. METHODS: Employing the standard patch-clamp whole-cell recording technique, we examined the effects of salicylate and chlorpromazine on the membrane capacitance (Cm) during exocytosis in rat peritoneal mast cells. Using confocal imaging of a water-soluble fluorescent dye, lucifer yellow, we also examined their effects on plasma membrane deformation of the cells. RESULTS: Salicylate dramatically accelerated the GTP-gamma-S-induced increase in the Cm immediately after its application, whereas chlorpromazine significantly suppressed the increase. Treatment with salicylate increased the trapping of the dye on the cell surface, while treatment with chlorpromazine completely washed it out, indicating that both drugs induced membrane surface deformation in mast cells. CONCLUSION: This study demonstrated for the first time that membrane amphipaths, such as salicylate and chlorpromazine, may oppositely modulate the process of exocytosis in mast cells, as detected by the changes in the Cm. The plasma membrane deformation induced by the drugs was thought to be responsible for their differential effects. PMID- 23635870 TI - The contextual brain: implications for fear conditioning, extinction and psychopathology. AB - Contexts surround and imbue meaning to events; they are essential for recollecting the past, interpreting the present and anticipating the future. Indeed, the brain's capacity to contextualize information permits enormous cognitive and behavioural flexibility. Studies of Pavlovian fear conditioning and extinction in rodents and humans suggest that a neural circuit including the hippocampus, amygdala and medial prefrontal cortex is involved in the learning and memory processes that enable context-dependent behaviour. Dysfunction in this network may be involved in several forms of psychopathology, including post traumatic stress disorder, schizophrenia and substance abuse disorders. PMID- 23635875 TI - New details on organophosphate flame retardants: exposure in men appears stable over time. PMID- 23635876 TI - Glomerular mRNA expression of prothrombotic and antithrombotic factors in renal transplants with thrombotic microangiopathy. AB - BACKGROUND: Thrombotic microangiopathy (TMA) in renal transplants (rTx-TMA) is a serious complication and is usually either recurrent TMA (RecTMA) due to humoral rejection (HR-TMA) or due to calcineurin inhibitor toxicity (CNI-TMA). Although the triggers are known, our knowledge about the thrombogenic transcriptome changes in the microvessels is rudimentary. METHODS: We examined the expression of several prothrombotic and antithrombotic genes in 25 biopsies with rTx-TMA (6 RecTMA, 9 HR-TMA, and 10 CNI-TMA) and 8 controls. RNA from microdissected glomeruli of paraffin-embedded tissue was isolated and mRNA transcripts were quantified with real-time polymerase chain reaction after preamplification. Results were correlated with clinicopathologic parameters. RESULTS: Glomerular mRNA expression of KLF2, KLF4, and tPA was lower and that of PAI-1 was higher in rTx-TMA than in the controls. Glomerular mRNA expression of KLF2 and KLF4 correlated with that of tPA and inversely with that of PAI-1 in rTx-TMA. The mRNA expression of complement regulators CD46 and CD59 were higher in rTx-TMA than in the controls. Only in HR-TMA were glomerular ADAMTS13 and CD55 down-regulated. CONCLUSIONS: The glomerular capillary bed seems to contribute to all subtypes of rTx-TMA by down-regulation of the endothelial transcription factors KLF2 and KLF4, indicating dedifferentiation with subsequent up-regulation of PAI-1 and down-regulation of tPA, resulting in inhibition of local fibrinolysis. Decreased glomerular expression of ADAMTS13 and CD55 could be an additional pathway toward microthrombosis exclusively in HR-TMA. PMID- 23635877 TI - Popliteal venous aneurysms and iliac vein compression: a possible association. AB - Popliteal venous aneurysms have always been linked to death from pulmonary embolism. Incidental finding of an asymptomatic popliteal venous aneurysm during duplex scan performed for patients with chronic venous disease is increasingly diagnosed but the relation between popliteal venous aneurysms and chronic venous disease remains unknown. We report the incidental finding of three asymptomatic popliteal venous aneurysms associated with iliac vein compression in patients with chronic venous disease who had undergone computed tomography venography with direct pedal contrast injection. An association between popliteal venous aneurysms and iliac vein compression is postulated. PMID- 23635871 TI - Sleep and the single neuron: the role of global slow oscillations in individual cell rest. AB - Sleep is universal in animals, but its specific functions remain elusive. We propose that sleep's primary function is to allow individual neurons to perform prophylactic cellular maintenance. Just as muscle cells must rest after strenuous exercise to prevent long-term damage, brain cells must rest after intense synaptic activity. We suggest that periods of reduced synaptic input ('off periods' or 'down states') are necessary for such maintenance. This in turn requires a state of globally synchronized neuronal activity, reduced sensory input and behavioural immobility - the well-known manifestations of sleep. PMID- 23635878 TI - Management of neuropathic pain in children with cancer. AB - PURPOSE OF REVIEW: Many children with cancer suffer from neuropathic pain. However, there are no published pediatric randomized controlled trials (RCTs), nor agreed upon pediatric treatment recommendations. Pediatric neuropathic pain in patients with malignancies is often underassessed and undertreated with ineffective therapies. RECENT FINDINGS: This article describes main themes in the literature and commonly used treatment strategies. SUMMARY: A combination of integrative, rehabilitative, and supportive therapies with pharmacotherapy, including first line medications such as NSAIDs, opioids, low-dose tricyclics, and gabapentinoids, appear to be successful treatment strategies. There is a dearth of evidence regarding the management of neuropathic pain in children with cancer; studies, especially RCTs, are desperately needed. PMID- 23635879 TI - Models of palliative care delivery in the United States. AB - PURPOSE OF REVIEW: To summarize the current United States healthcare system and describe current models of palliative care delivery. RECENT FINDINGS: Palliative care services in the USA have been heavily influenced by the public-private fee for-service reimbursement system. Hospice provides care for 46% of adults at the end-of-life under the Medicare hospice benefit. Palliative care teams in hospitals have rapidly expanded to provide care for seriously ill patients irrespective of prognosis. To date, over two-thirds of all hospitals and over 85% of mid to large size hospitals report a palliative care team. With the passage of the Patient Protection and Affordable Care Act of 2010, healthcare reform provides an opportunity for new models of care. SUMMARY: Palliative care services are well established within hospitals and hospice. Future work is needed to develop quality metrics, create care models that provide services in the community, and increase the palliative care workforce. PMID- 23635880 TI - Palliative care in Japan: a review focusing on care delivery system. AB - PURPOSE OF REVIEW: Providing palliative care in Japan is one of the most important health issues. Understanding palliative care delivery systems of other countries is useful when developing and modifying palliative care systems worldwide. This review summarizes the current status of palliative care in Japan, focusing on the structure and process development. RECENT FINDINGS: Palliative care units and hospital palliative care consultation teams are the two main specialized palliative care services in Japan. The number of palliative care units is 215 (involved in 8.4% of all cancer deaths), and there are approximately 500 hospital palliative care teams. Conversely, specialized home care services are one of the most undeveloped areas in Japan. However, the government has been trying to develop more efficient home care services through modifying laws, healthcare systems, and multiple educational and cooperative projects. The numbers of palliative care specialists are increasing across all disciplines: cancer pain nurses (1365), palliative care nurses (1100), palliative care physicians (646), and palliative care pharmacists (238). Postgraduate education for physicians is performed via the special nationwide efforts of the Palliative care Emphasis program on symptom management and Assessment for Continuous medical Education (PEACE) project - a 2-day program adopting a trainer-trainee strategy. Over 30,000 physicians have participated in the PEACE program. A total of 1298 and 544 physicians have completed a trainer course for palliative medicine and psycho-oncology, respectively. Multiple structure and process evaluation, bereaved family surveys in palliative care units, and patient and family evaluation in the regional palliative care program indicate many improvements. SUMMARY: Palliative care in Japan has progressed rapidly, and the Cancer Control Act has played a very important role in developing palliative medicine. Challenges include developing a structure for palliative care in the community or regional palliative care programs, establishing a method to measure and improve the quality of palliative care at a national level, developing evidence-based medicine and policy making, and palliative care for the noncancerous population. PMID- 23635881 TI - Models of delivering palliative and end-of-life care in India. AB - PURPOSE OF REVIEW: India is home to one-fifth of the global population. This review aims to explore the structures, functions and relevance of palliative care services in India. Although palliative care has been initiated in India almost 3 decades ago, development of services has been patchy and inadequate. Some of the regions are well covered, but most are not. The Indian palliative care scene, with its diversity in approach and delivery of services, can offer valuable lessons to service development in low-income and middle-income countries. RECENT FINDINGS: The number of people dying each year in India is more than 9.8 million. The number of people in need of palliative care will be around six million if we assume that 60% of all those who die would benefit from palliative care. Less than 2% of the needy have access to palliative care in India. The available services are very unevenly distributed with the state of Kerala with 3% of the country's population having more than 90% of the palliative care services in the country. SUMMARY: The state of palliative care in India is discussed with particular attention to the successful Kerala Model in palliative care. Lessons learned from the experiment in Kerala are listed. PMID- 23635882 TI - The relation between social anxiety and audience perception: examining Clark and Wells' (1995) model among adolescents. AB - BACKGROUND: Clark and Wells' cognitive model of social anxiety proposes that socially anxious individuals have negative expectations of performance prior to a social event, focus their attention predominantly on themselves and on their negative self-evaluations during an event, and use this negative self-processing to infer that other people are judging them harshly. AIMS: The present study tested these propositions. METHOD: The study used a community sample of 161 adolescents aged 14-18 years. The participants gave a speech in front of a pre recorded audience acting neutrally, and participants were aware that the projected audience was pre-recorded. RESULTS: As expected, participants with higher levels of social anxiety had more negative performance expectations, higher self-focused attention, and more negative perceptions of the audience. Negative performance expectations and self-focused attention were found to mediate the relationship between social anxiety and audience perception. CONCLUSIONS: The findings support Clark and Wells' cognitive model of social anxiety, which poses that socially anxious individuals have distorted perceptions of the responses of other people because their perceptions are coloured by their negative thoughts and feelings. PMID- 23635883 TI - Cross Sectional: bilateral parent-child interactions in school-age children's tooth-brushing behaviors. AB - PURPOSE: The purpose of this study was to examine bilateral dynamics between parents and children in influencing children's tooth-brushing behaviors. METHODS: In-depth conversational interviews-a specific qualitative method-were conducted with 38 parents in urban Xiamen, China and Singapore to learn insights into parental strategies for encouraging tooth-brushing habits in 6- to 9-year-old children. The interviews also examined the range of responses from children toward these parental strategies. RESULTS: Children usually do not comply with these tooth-brushing instructions from parents without a process of negotiation. Children's responses ranged from active resistant to compliant. Parents in Xiamen tended to use softer strategies and were more prone to be emotionally and behaviorally influenced by children's effort to thwart these strategies. Conversely, Singapore parents tended to demonstrate greater tenacity in negotiating with children. CONCLUSIONS: The process of developing children's tooth-brushing habits is not a unilateral from-parent-to-children process. Instead, it should be conceptualized as an ongoing interaction with bilateral power of influence from both parties. PMID- 23635885 TI - What has been happening with your journals? PMID- 23635884 TI - Randomized controlled trial: a randomized controlled clinical trial comparing a remineralizing paste with an antibacterial gel to prevent early childhood caries. AB - PURPOSE: The purpose of this study was to compare twice daily tooth-brushing using 0.304 percent fluoride toothpaste alone with: (1) twice daily tooth brushing plus once daily 10% casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) paste; and (2) twice daily tooth-brushing plus once daily 0.12% chlorhexidine gel (CHX) for reducing early childhood caries (ECC) and mutans streptococci (MS) colonization. METHODS: Subjects (n=622) recruited at birth were randomized to receive either CPP-ACP or CHX or no product (study control [SC]). All children were examined at 6, 12, and 18 months old in their homes, and at 24 months old in a community dental clinic. RESULTS: At 24 months old, the caries incidence was 1% (2/163) in CPP-ACP, 2% (4/180) in CHX, and 2% (3/188) in SC groups. In children who were previously MS colonized at 12 and 18 months old, 0% (0/11) and 5% (3/63), respectively, of the CPP-ACP group remained MS-positive versus 22% (2/9) and 72% (18/25) in CHX and 16% (4/25) and 50% (7/14) in SC groups (P<.001). CONCLUSIONS: There is insufficient evidence to justify the daily use of casein phosphopeptide-amorphous calcium phosphate or chlorhexidine gel to control early childhood caries. PMID- 23635886 TI - Observational: prospective study of indirect pulp treatment in primary molars using resin-modified glass ionomer and 2% chlorhexidine gluconate: a 12-month Follow-up. AB - PURPOSE: This study's purpose was to determine the efficacy of indirect pulp treatment (IPT) in primary molars when using 2% chlorhexidine gluconate disinfecting solution and resin-modified glass ionomer (RMGI) liner after 12 months. METHODS: Three- to 10-year-old subjects with deep carious lesions who met selection criteria participated. Infected dentin was removed using a caries detector, and residual affected dentin was left on the pulpal floor to prevent pulp exposure. A 2% chlorhexidine gluconate solution and a RMGI liner were placed. Teeth were restored with composite or full-coverage (stainless steel crown [SSC]) restorations. Follow-up evaluations at 3, 6, and 12 months included clinical, radiographic, and photographic assessments. RESULTS: A total of 60 teeth were treated. Treatment was successful in 50/50 (100%), 41/42 (~98%), and 31/32 (~97%) teeth at the 3-, 6-, and 12-month follow-up visits, respectively. Failures included one at 6 months in a primary second molar with a composite restoration and another at 12 months in a primary first molar with a SSC. CONCLUSIONS: Indirect pulp treatment is effective in primary teeth, although appropriate case selection and an adequate marginal seal are essential for a successful outcome. Further prospective studies are needed to expand the body of evidence that clinicians use to justify decisions on clinical care. PMID- 23635888 TI - Cross sectional: use of coolant for high-speed tooth preparation: a survey of pediatric dentist members of the American Academy of Pediatric Dentistry. AB - PURPOSE: To report the findings of a survey to determine the educational experiences, opinions and clinical practices relative to the use of coolant during cavity preparation of pediatric dentist members of the American Academy of Pediatric Dentistry (AAPD) and to determine whether teaching policies influenced the type of coolant used in private practice. METHODS: Four thousand fifty surveys were emailed to AAPD members and included questions regarding demographics and predoctoral, graduate, and current practice policies for the use of dry cutting. RESULTS: Returned survey numbered 1730 for a response rate of 43%. Fifteen percent were taught the concept of dry cutting in their predoctoral programs and 34% in their specialty, programs. Sixty percent never or rarely prepare teeth without water coolant. Slightly more than 40% prepared teeth with air coolant alone. Patient behavior (25%) and sedation (21%) were reported as determining factors for cutting dry. Thirty-one percent of private practice clinicians and 34% of part time academics use dry cutting, while only 15% of full time academicians use the technique (P<0.0001). CONCLUSIONS: Respondents tend to use the technique they were taught during their residency. Use of dry cutting was more likely to be utilized during sedations or general anesthesia to avoid airway compromise. PMID- 23635889 TI - Load distribution in fixed space maintainers: a strain-gauge analysis. AB - PURPOSE: The purpose of this study was to compare the biomechanics of space maintainers supported by primary and permanent teeth. METHODS: Photoelastic models of permanent and primary teeth with a single missing tooth space were cast, and band-and-loop, direct-bonded, and fiber-reinforced space maintainers were fabricated. Linear strain-gauges were bonded next to the teeth and in the middle of the missing tooth space. Strain gauge signals were quantified during 50 N and 100 N static axial load applications on the molar, maintainer, and anterior support at 10 KHz using a data acquisition device and associated computer software. RESULTS: Regardless of the tooth being restored, strains around the molar teeth and the maintainer region were comparable between the groups under molar and maintainer loading (P>.05). Under 100 N loading on the anterior support, the highest strains were observed in the direct-bonded group (P<.01). Direct-bonded design led to higher strains than the band-and-loop design under 100 N maintainer loading, whereas the strain output of other designs were comparable. CONCLUSION: Load distribution of band-and-loop, direct-bonded, and fiber-reinforced space maintainers seem comparable, although direct-bonded maintainers could lead to higher strain concentrations in the buccal side due to bending moments. PMID- 23635887 TI - Formulation and characterization of antibacterial fluoride-releasing sealants. AB - PURPOSE: The purpose of this study was to formulate and characterize experimental antibacterial fluoride-releasing sealants and compare them with commercial sealants for fluoride release, recharge, adhesion, and microleakage. METHODS: Two experimental sealants (Exp-1, Exp-2) containing a synthesized antibacterial fluoride-releasing monomer and fluoride-releasing filler were formulated. Exp-2 also contained NovaMin nanoparticles. Commercial sealants Clinpro (CL) FluroShield (FS), and SeLECT Defense (E34) were also included. Fluoride release from disk samples in deionized water was measured daily using an ion-selective electrode for 14 days, and after recharging with Neutra-Foam (2.0% sodium fluoride), fluoride was measured for 5 days. Microtensile bonding strengths (MTBS) to enamel were tested after 24-hour storage in water at 37 degrees C or thermocycling 5-55 degrees C for 1,000 cycles. A microleakage test was conducted on extracted teeth using a dye-penetration method. The data were analyzed using analysis of variance with the Tukey's honestly significant difference test and Kruskal-Wallis test. RESULTS: Exp-1 and Exp-2 had significantly higher fluoride release and recharge capabilities than CL and FL (P<.05). All tested sealants had similar MTBS before and after thermocycling. Exp-2 and Exp-1 had significantly lower microleakage scores (P<.05) than other groups. CONCLUSION: The experimental sealants had higher fluoride release and recharge capabilities and similar or better retention than commercial sealants. PMID- 23635890 TI - Randomized controlled trial: lip piercing: the impact of material on microbiological findings. AB - PURPOSE: The purpose of this study was to investigate whether there are microbiological differences in bacterial samples collected from labial piercings made of different materials. METHODS: Sterile piercings of 4 materials were randomly allocated to 80 pierced subjects. After 2 weeks, microbiologic samples were collected and processed by checkerboard DNA-DNA hybridization methods. Wilcoxon signed ranks and Mann-Whitney tests were used for statistical analysis (adjustment for multiple comparisons). RESULTS: There were no statistically significant differences between material groups in relation to baseline data. In samples from stainless steel piercings, the total microbial load was significantly higher than the other materials (P<.05). Ten (mainly periopathogenic) species were found at significantly higher levels (P<.001) on steel than on polypropylene and/or polytetrafluoroethylene piercings. CONCLUSIONS: Labial piercings made of stainless steel could promote the development of a pathogenic biofilm. PMID- 23635892 TI - A performance measurement plan for pediatric dentists: using accuracy of caries diagnosis from intraoral radiographs. AB - PURPOSE: The purpose of this study was to develop a metric for measuring (1) an individual pediatric dentist's performance against peer performance and (2) aggregate group performance, using accuracy of caries diagnosis. METHODS: A total of 3,985 tooth surfaces (from 174 patients) on intraoral bitewing radiographs were assessed by 9 precalibrated attending pediatric dentists at Children's Hospital Boston over a 3-year period. Each surface was reviewed by 3 pediatric dentists (the operating dentist and 2 peer reviewers) using a score card. An accurate diagnosis was defined as agreement between the operating dentist and at least 1 peer reviewer as to the presence or absence of caries. RESULTS: Average percentage diagnostic accuracy within the group over the course of the project was approximately 95% (95% confidence interval=94.0-95.4). Individual dentist scores ranged from approximately 89% to 96%. Group average rose steadily over time, from approximately 93% in 2008 to 97% by 2010. Unacceptable diagnosis (~5% of surfaces assessed) did not directly translate into unfavorable treatment (~4% of surfaces with unacceptable diagnosis). CONCLUSIONS: Interexaminer reliability as a proxy for accuracy of caries diagnoses from bitewing radiographs is a viable metric for improving and assessing the quality of care provided by pediatric dentists. PMID- 23635891 TI - Effects of ultraviolet irradiation on the bond strength of a composite resin adhered to stainless steel crowns. AB - PURPOSE: A technique whereby the practitioner could improve the esthetic appearance of anterior stainless steel crowns (SSC) could provide a cost effective alternative to more expensive commercially available preveneered SSCs, which may not be uniformly available. The purpose of this study was to evaluate the effects of ultraviolet (UV) irradiation of the metal crown surface on the shear bond strength of composite resin adhered to stainless steel crowns. METHODS: Seventy extracted anterior bovine teeth randomly divided into 2 groups (n=35/group), were restored with primary maxillary left central incisor SSCs. Surface roughening with a green stone was performed on the labial surfaces, and the crowns of the experimental group were exposed to UV irradiation for 80 minutes. All samples were treated with metal-composite adhesive, followed by composite opaquer. Standardized composite blocks were bonded on the treated surfaces, and the shear bond strength was tested at 1 mm/minute. The values were recorded in MPa and statistically analyzed. RESULTS: The mean value of shear bond strength was significantly higher for the experimental group (19.7 +/- 4.3 MPa) than the control group (16.3 +/- 4.5 MPa). CONCLUSION: Ultraviolet irradiation of primary tooth stainless steel crowns significantly increased the shear bond strength of composite resin adhered to the facial surface. PMID- 23635893 TI - Cross sectional: perception of children from public and private schools regarding the esthetic impact of different types of face masks. AB - PURPOSE: The purpose was to evaluate the esthetic perception among children from public and private schools regarding the use of different types of face masks. METHODS: Six different types of orthopedic face masks made from images of the same patient were evaluated. Initially, the images were standardized with the help of Adobe Photoshop software. The variable considered was type of mask: (A) Delaire with facebow; (B) Petit; (C) Delaire; (D)Turley; (E) Hickham; and (F) Sky Hook. The images were printed on photographic paper and incorporated into a specific personalized questionnaire that was distributed to 7- to 10-year-olds attending public and private schools (n=120). The data obtained were compared via chi-square, Fisher's exact tests, Mann-Whitney and Spearman's tests. RESULTS: The proportion of participants who chose image A as the best was significantly higher (P<.05) compared to the other masks. Images B and F were chosen as the worst, without a significant difference between them (P>.05). The mean scores between groups were not significantly correlated between private vs public schoolchildren (r=0.32) and between boys and girls (r=0.41). CONCLUSIONS: Delaire face mask with facebow was chosen as the most attractive, and the Petit and Sky Hook face masks were voted the least attractive. PMID- 23635894 TI - Using elements of hypnosis prior to or during pediatric dental treatment. AB - Most dental practitioners are familiar with pediatric patients expressing dental fear or anxiety. Occasionally, the dentist may encounter a situation where all behavioral techniques fail, while, for some reason, premedication or general anesthesia are contraindicated or rejected by the patient or his/her parents and a different approach is required. Hypnosis may solve the problem in some cases. The purpose of this study was to review the literature about techniques that use elements of hypnosis and hypnotic techniques prior to or during pediatric dental treatment. There is a limited amount of literature regarding the use of hypnosis and hypnotic elements in pediatric dentistry. Induction techniques, reframing, distraction, imagery suggestions, and hypnosis are identified, although mostly anecdotally, while there are very few structured controlled studies. Nevertheless, the advantages of using hypnotic elements and hypnosis in pediatric dentistry are evident. PMID- 23635895 TI - Diagnosis and conservative treatment of dens invaginatus type III using cone beam computed tomography: two case reports. AB - Dens invaginatus is a dental anomaly that may give rise to many complex anatomical forms. The complexity of the internal anatomy creates clinical challenges directly related to debridement, disinfection, and the subsequent sealing of the canal system. Additionally, conventional periapical radiographs provide limited information regarding the anatomical configuration. The use of cone beam computed tomography allows for 3-dimensional diagnosis and treatment planning, with the subsequent development of conservative approaches with predictable outcomes. The purpose of this paper was to present 2 cases of dens invaginatus type III, both diagnosed and treatment planned using cone beam computed tomography technology and approached conservatively to treat the necrotic spaces while maintaining the pulp's vitality. PMID- 23635896 TI - Systematic review: change in the quality of life of children and adolescents younger than 14 years old after oral health interventions: a systematic review. AB - PURPOSE: The purpose of this study was to perform a systematic review that evaluated changes in the quality of life (QoL) of children and adolescents younger than 14 years old after oral health interventions. METHODS: The search strategy was based on OVID, PubMed, VHL, Cochrane, and Google Scholar databases and was completed by a manual cross-reference search. The keywords used for the search were "child" and "oral health" and "quality of life"; for Google Scholar, "before and after treatment" were also used. Articles that met the inclusion criteria were classified considering methodological quality and risk of bias. RESULTS: A total of 1,044 articles were initially retrieved; after excluding duplicate abstracts, 13 articles remained from the electronic search, and the manual search of their references detected 14 new articles. The exclusion criteria eliminated 16 of these 27 articles, leaving 11 for quality assessment. Of these, 2 were classified as high, 7 as moderate, and 2 as low methodological quality, and the majority of them had moderate risk of bias. Thus, our final selection was reduced to 9 articles for final analysis. CONCLUSION: The level of evidence was moderate and detected changes in the impact on the quality of life of children and adolescents younger than 14 years old after interventions related to oral health. PMID- 23635897 TI - Retrospective record review: reinforced zinc oxide-eugenol pulpotomy: a retrospective study. AB - PURPOSE: The purpose of this retrospective study was to evaluate pulpotomies completed without the use of a fixative, preservative, or astringent agent prior to placement of a reinforced zinc oxide-eugenol (ZOE) sub-base in the pulp chamber and subsequent restoration. METHODS: Clinical and radiographic data were collected from a private pediatric dental office in Toronto, Ontario, Canada. The pulpotomy technique used involved: amputation of coronal pulp; radicular hemostasis via pressure with dry cotton pellet; placement of ZOE into the pulp chamber; and restoration with stainless steel crown or amalgam. RESULTS: One hundred-ninety primary molars in 116 children (follow-up=6-94 months; mean=35.8 months) met the inclusion criteria. The radiographic, clinical, and overall success rates were approximately 95%, 97%, and 94%, respectively. The most frequently observed pathologic pulpal response was furcation radiolucency (N=7, ~4%). The patient's age at time of pulpotomy, restoration type, tooth type, arch, and location of treatment (in-office vs general anesthesia) were not statistically significant factors influencing the success of the reinforced ZOE pulpotomy technique. CONCLUSION: The success rates indicate that the reinforced zinc oxide-eugenol pulpotomy technique may be an acceptable treatment modality for primary molars requiring vital pulp therapy. PMID- 23635898 TI - Randomized controlled trial: parental compliance with instructions to remain silent in the dental operatory. AB - PURPOSE: The purposes of this study were to: (1) determine compliance in requesting parents to remain silent (noncommunicative) when accompanying their child into the dental operatory for restorative care; and (2) determine if any difference in parental compliance existed when combined written and verbal instructions were given to a parent vs written instructions only. METHODS: Thirty nine parents of 4- to 9-year-olds presenting for restorative care met eligibility criteria for the study. Parents were randomly assigned to a written instructions only group or a group that received combined written and verbal instructions. RESULTS: Thirty-two of 39 parents (82%) followed instructions to remain silent. There was no statistical difference in parental compliance to remain silent comparing written instructions (78%) to combined written and verbal instructions (86%). CONCLUSION: Parents may be expected to comply with instructions to remain silent in the operatory when given either written or combined written and verbal instructions. PMID- 23635899 TI - Observational study: discomfort following dental procedures for children. AB - PURPOSE: The purpose of this study was to measure the incidence of pain and analgesic use following restorative and surgical procedures and preventive fissure sealants in children and adolescents. METHODS: One hundred and thirty 2- to 18-year-olds were selected from the Louisiana State University School of Dentistry pediatric dental clinic and appointed for restorative and surgical procedures and preventive fissure sealants. Each child's discomfort was evaluated immediately after the procedure using a Wong-Baker FACES Pain Rating Scale. Parents were contacted by phone within 48 hours following the procedure for a verbal survey to assess discomfort and analgesic use. RESULTS: Thirty-three percent of the children reported discomfort, and 31% were given over-the-counter analgesics by their parents. Compared to all other subjects, patients who had received a primary stainless steel crown were significantly more likely to report discomfort (P<.001). The extraction of primary teeth did not result in a significant increase in reported pain. CONCLUSIONS: Postoperative discomfort is significantly associated with stainless steel crown treatment of primary teeth. PMID- 23635901 TI - Cross sectional: normal maximal incisal opening and associations with physical variables in children. AB - PURPOSE: The purpose of this investigation was to establish a normal range of maximal incisal opening (MIO) in children, and the correlation between MIO with age, height, weight, gender, race, and molar relationship. METHODS: Calibrated examiners used the TheraBite Range of Motion (ROM) scale to obtain two MIO readings from 500 enrolled subjects, accounting for overbite or open bite. The subject's height, weight, molar relationship, age, gender, and race were recorded. Subjects were stratified according to age, and mean MIO +/- standard deviation for each age group was determined. RESULTS: Mean MIO was positively correlated with age (P<.001), height (P<.001), weight (P<.001), and race (P<.001). However, height became insignificant in the multivariable regression model. On average, MIO of African-Americans was 3.66 mm larger than Whites (P<.001), and MIO of Hispanics/Latinos was 2.52mm greater than Whites (P<.001). There was no statistically significant association with left or right molar relationships (P=.07, P=.26 respectively) or gender (P=.58). CONCLUSIONS: TheraBite ROM scale is a practical tool to clinically measure MIO. MIO mimics somatic growth, peaking at age 12-13 years for females and 14-15 years for males. African-Americans and Hispanics/Latinos have a greater mean MIO than Whites. The established norms will be useful in diagnosis and treatment. PMID- 23635900 TI - Case series: management of immature permanent teeth with pulpal necrosis: a case series. AB - The management of immature permanent teeth with necrotic pulps has changed in recent years from apexification techniques to regenerative endodontic procedures, which enable apexogenesis with physiologic maturation of the roots. This regenerative technique lies squarely in the endodontist's scope of practice, but children presenting with necrotic immature incisors may pose behavior management problems that endodontists are untrained and unwilling to handle. Treatment of these immature permanent teeth provides an excellent opportunity for collaboration and shared patient management between pediatric dentists and endodontists that can yield optimal clinical outcomes. The purpose of this paper was to report a series of 32 regenerative endodontic cases in 28 children treated at the Nationwide Children's Hospital, Columbus, Ohio. The report describes procedural and patient management issues and the need for a collaborative relationship between pediatric dentists and endodontists in tackling these challenging cases. PMID- 23635903 TI - Neurocardiogenic syncope of child dental patient: a case review. AB - Neurocardiogenic syncope is a condition that frequently occurs in children. The purpose of this case report was to describe the clinical manifestations of a 7 year old child with neurocardiogenic syncope and the remedial management of loss of consciousness during dental treatment. PMID- 23635902 TI - Case series: conditions inhibiting eruption of permanent first molars. AB - PURPOSE: The purpose of this study was to evaluate the radiological and histopathological findings of 11 patients with unerupted first molars to verify the factors obstructing spontaneous eruption. METHODS: The patients' clinical, radiological, and histopathological data were evaluated retrospectively to determine histopathological diagnosis, radiographic findings, methods of surgical management, and postoperative course. RESULTS: This study involved 4 male and 7 female patients (mean age=9.5 years old). Nine cases involved the mandible. The patients' histopathological diagnoses included 3 odontogenic tumors, 2 odontogenic cysts, and 6 hyperplastic dental follicles. Radiographically, 10 cases showed characterless enlargement of the follicular space, while only 1 displayed radiopaque bodies. One patient with a tumor underwent enucleation, and 1 with a cyst underwent cystectomy and tooth extraction. The others underwent wide excision or partial excision of the surrounding tissue at the top of the impacted tooth. Tumor relapse was observed in 3 cases. CONCLUSION: Surgeons should perform aggressive treatment for patients with unerupted teeth because spontaneous eruption is rare in cases involving non-neoplastic lesions such as hyperplastic dental follicles. PMID- 23635904 TI - Benzofuran-, benzothiophene-, indazole- and benzisoxazole-quinones: excellent substrates for NAD(P)H:quinone oxidoreductase 1. AB - A series of heterocyclic quinones based on benzofuran, benzothiophene, indazole and benzisoxazole has been synthesized, and evaluated for their ability to function as substrates for recombinant human NAD(P)H:quinone oxidoreductase (NQO1), a two-electron reductase upregulated in tumor cells. Overall, the quinones are excellent substrates for NQO1, approaching the reduction rates observed for menadione. PMID- 23635905 TI - Aspirin resistance in patients with hemodynamic cerebral ischemia undergoing extracranial-intracranial bypass surgery. AB - BACKGROUND: Aspirin (acetylsalicylic acid, ASA) is the treatment of choice for prevention of vascular events in symptomatic steno-occlusive cerebrovascular disease (CVD). Cerebral revascularization using standard extracranial intracranial (EC-IC) bypass surgery may be used to revert hemodynamic compromise. Aspirin is prescribed as standard medication in order to avoid bypass failure. Accumulating evidence of an increased risk of major adverse clinical events led to this study, in which we aimed to assess the prevalence of aspirin resistance and prothrombotic disorders among patients scheduled for EC-IC bypass surgery, and the effectiveness of aspirin dose escalation. METHODS: We prospectively screened patients with circumscribed high-grade stenosis or occlusion of brain supplying vessels fulfilling the hemodynamic criteria for EC-IC bypass surgery for aspirin resistance using a platelet function analyzer (PFA-100(r)) test. We also determined their smoking habits and screened for prothrombotic disorders and comorbidities. The patients were divided into 2 major groups: group A had atherosclerotic steno-occlusive CVD and group B consisted of patients with nonatherosclerotic steno-occlusive CVD (moyamoya disease) and a subgroup of pediatric moyamoya patients (pediatric subgroup). Bypass patency was documented via digital subtraction angiography. Standard initial ASA dose applied was 100 mg/day. In cases of aspirin resistance, doses were increased and the PFA-100 test was repeated. RESULTS: A total of 56 patients were included over a time period of 6 months. In group A (n = 25), we found a ratio of 40% of patients with primary resistance to aspirin 100 mg/day. In contrast, in group B (n = 25), only 20% of the patients were resistant to aspirin 100 mg/day; in the pediatric population (n = 6), there was no primary aspirin resistance. After a dose escalation to 300 mg/day, the ratio of aspirin resistance was reduced to 20% in group A and to 0% in group B. Altogether 5 patients with atherosclerotic steno-occlusive CVD remained aspirin-resistant despite the dose escalation; 2 of them suffered an early bypass failure. Smoking habits and diabetes mellitus were positively correlated with aspirin resistance. Moreover, 25% of all patients had laboratory signs of a prothrombotic disorder, but this had no influence on aspirin response or bypass patency. CONCLUSIONS: Aspirin resistance is common in the population of patients with hemodynamic cerebral ischemia scheduled for cerebral revascularization. It may have an adverse impact on the outcome of surgery. Screening and treatment via dose escalation of aspirin is a straightforward and sensible routine for patients undergoing EC-IC bypass surgery. PMID- 23635906 TI - Prediction of treatment response and the effect of independent component neurofeedback in obsessive-compulsive disorder: a randomized, sham-controlled, double-blind study. AB - AIMS: The goal of this study was to assess the effect of independent component neurofeedback (NFB) on EEG and clinical symptoms in patients with obsessive compulsive disorder (OCD). Subsequently, we explored predictors of treatment response and EEG correlates of clinical symptoms. METHODS: In a randomized, double-blind, parallel design, 20 inpatients with OCD underwent 25 sessions of NFB or sham feedback (SFB). NFB aimed at reducing EEG activity in an independent component previously reported abnormal in this diagnosis. Resting-state EEG recorded before and after the treatment was analyzed to assess its posttreatment changes, relationships with clinical symptoms and treatment response. RESULTS: Overall, clinical improvement in OCD patients was not accompanied by EEG change as assessed by standardized low-resolution electromagnetic tomography and normative independent component analysis. Pre- to posttreatment comparison of the trained component and frequency did not yield significant results; however, in the NFB group, the nominal values at the downtrained frequency were lower after treatment. The NFB group showed significantly higher percentage reduction of compulsions compared to the SFB group (p = 0.015). Pretreatment higher amount of delta (1-6 Hz) and low alpha oscillations as well as a lower amount of high beta activity predicted a worse treatment outcome. Source localization of these delta and high beta oscillations corresponded with previous EEG resting-state findings in OCD patients compared to healthy controls. CONCLUSION: Independent component NFB in OCD proved useful in percentage improvement of compulsions. Based on our correlation analyses, we hypothesize that we targeted a network related to treatment resistance. PMID- 23635907 TI - Multimodal CT: favorable outcome factors in acute middle cerebral artery stroke with large artery occlusion. AB - BACKGROUND: We investigated which parameters of multimodal computed tomography (CT) or their combinations might be useful as additional imaging predictors for favorable outcomes in acute stroke patients with large artery occlusion. METHODS: The parameters of multimodal CT, including non-enhanced CT, CT angiography, perfusion CT parameters, CT angiography source image (CTA-SI), and collateral flow, were analyzed in 66 consecutive patients with acute middle cerebral artery stroke with large artery occlusion. For favorable outcomes at the 3-month follow up, odds ratios of multimodal CT parameters with an optimum predictive cut-off Alberta Stroke Program Early CT Score (ASPECTS) were assessed. RESULTS: Cerebral blood volume (CBV) ASPECTS >=6, CTA-SI ASPECTS >=7, and good collateral flow were associated with a favorable outcome. The combination of those parameters had better predictive validity compared to a single parameter only: CBV (p = 0.039), CTA-SI (p = 0.038), and collateral flow (p < 0.001). CONCLUSION: Among the various parameters of multimodal CT, CBV ASPECTS >=6, CTA-SI ASPECTS >=7, and good collateral flow might be the most reliable predictors for favorable outcomes in acute stroke patients with large artery occlusion. Moreover, considering these parameters simultaneously might improve the predictive validity of multimodal CT for functional outcome. PMID- 23635909 TI - Unemployment in multiple sclerosis (MS): utility of the MS Functional Composite and cognitive testing. AB - Unemployment is a significant concern among individuals with multiple sclerosis (MS). Determinations regarding ability to work are highly dependent on measurement tools used by neurologists and allied professionals. However, little is known of the usefulness of these tools when determining issues pertaining to employment status. The purpose of the present investigation was to examine the utility of the Multiple Sclerosis Functional Composite (MSFC) and a brief cognitive test battery when examining employment status in MS. Seventy-seven individuals with MS completed the MSFC and a brief cognitive test battery. On the MSFC, unemployed individuals demonstrated worse upper extremity functioning. There was no difference on the Paced Auditory Serial Addition Task (PASAT), the sole cognitive measure of the MSFC. On cognitive testing, unemployed individuals performed worse on measures of memory, information processing speed, and executive functioning. Through logistic regression analysis, the Symbol Digit Modalities Test (SDMT) was found to be the sole predictor of employment status among the significant disease, MSFC and cognitive variables. Consistent with previous findings, logistic regression found the SDMT to be a significant predictor of employment status. Given the lack of significant group differences on the PASAT, continued consideration of replacing the PASAT with the SDMT in the MSFC appears warranted. PMID- 23635908 TI - Prevalence and factors associated with the use of illicit substances among male university students in Kuwait. AB - OBJECTIVES: To estimate the prevalence of illicit use of substances and identify the factors associated with illicit drug use among male students in the state-run Kuwait University and private universities in Kuwait. SUBJECTS AND METHODS: The study was a cross-sectional survey with a sample of 1,587 male students from both private universities (n = 869) and the public (n = 718) Kuwait University in Kuwait. A self-administered questionnaire was used to collect data. Overall lifetime prevalence of substance use was computed with 95% confidence interval. Logistic regression was used to identify the factors influencing substance use, which was adjusted for potential confounders. RESULTS: The total lifetime prevalence of illicit drug use was 14.4% and the most frequently used illicit substance was marijuana (11%). The substance use in general varied significantly (p <= 0.001) between private (18%) and public (10%) universities. Multivariate logistic regression model revealed that drug use was positively associated with age, poor academic performance, high family income, being an only child, divorced parents, and graduation from a private high school. CONCLUSION: Drug use among male university students in Kuwait was high and requires attention and appropriate intervention. The factors identified with drug use in this study could be utilized to develop appropriate public health policies and preventive measures that may improve the health status of the student population. PMID- 23635911 TI - Liquid-based fine needle aspiration biopsy of papillary thyroid carcinoma: logistic regression analysis with conventional and new cytomorphologic features. AB - OBJECTIVE: The morphological interpretation of liquid-based preparation (LBP) remains a diagnostic challenge due to altered cytomorphology with technical reason. Only a few published accounts of the cytopathological features needed for diagnosis of papillary thyroid carcinoma (PTC) on an LBP exist. We utilized the SurePath LBP system to evaluate conventional and newly recognized cytomorphologic features on histologically confirmed PTC to identify their potent diagnostic significance compared to benign follicular neoplasm (BFN). STUDY DESIGN: One hundred and three cases of PTC and 84 BFNs were collected using preoperative fine needle aspiration biopsies. We evaluated and compared 16 cytomorphologic findings in PTC and BFN using an LBP. RESULTS: Among the conventional criteria, papillary structures, fewer background colloids and macrophages, hobnail patterns (54.4% in PTC vs. 10.7% in BFN; p < 0.001) and swirling architecture (14.6% in PTC vs. 0% in BFN; p < 0.001; positive predictive value 100.0%) were significant diagnostic findings for PTC compared to BFN. The hobnail pattern was shown as a newly recognized strong diagnostic parameter for PTC (odds ratio 50.157, p < 0.001). CONCLUSION: The identified distinctive cytological criteria may be helpful in cases where conventional criteria for PTC are insufficient. Furthermore, application of these findings, along with classical criteria, may enhance the diagnostic accuracy of PTC by fine needle aspiration biopsy. PMID- 23635910 TI - Employment status in multiple sclerosis: impact of disease-specific and non disease-specific factors. AB - BACKGROUND: Multiple sclerosis (MS) is associated with high rates of early retirement (ER). OBJECTIVES: A German cohort of MS patients and healthy control subjects (HCs) were compared cross-sectionally to investigate disease- and non disease-specific factors that are associated with employment status (ES) in MS and to identify predictors of ES in MS. METHODS: A total of 39 ER MS patients, 48 employed MS patients, and 37 HCs completed a brief neuropsychological battery and questionnaires related to depressive symptoms, fatigue, health-related quality of life (HrQoL) and health locus of control (HLC). Neurological disability was assessed by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC). RESULTS: ER compared with employed MS patients scored significantly higher in neurological disability, depressive symptoms and fatigue and significantly lower in cognitive functioning and HrQoL. Further, both groups differed with regard to age, education, disease course and duration but not in HLC. Neurological disability, age and fatigue were identified as significant predictors of ES in MS. CONCLUSIONS: ES in MS was associated with demographic aspects, neurological and cognitive status, depressive symptoms, fatigue and HrQoL but was not associated with HLC. Findings confirm neurological disability, age and fatigue as independent predictors of ES in MS. PMID- 23635913 TI - Pit latrines and groundwater contamination: negative impacts of a popular sanitation method. PMID- 23635912 TI - Human bone marrow stromal cells can differentiate to a retinal pigment epithelial phenotype when co-cultured with pig retinal pigment epithelium using a transwell system. AB - BACKGROUND: There is an increasing interest in generating retinal pigment epithelial (RPE) cells from stem cells for therapy against degenerative eye diseases. Human bone marrow stromal cells (hBMSCs) can be induced to express retinal neuron-specific markers when co-cultured with retinal neurons, however, whether hBMSCs can differentiate into RPE-like cells in a co-culture system has not been clarified. METHODS: The induction of hBMSCs into RPE-like cells was performed by combining hBMSCs and pig RPE cells in a transwell system. The biomarkers of hBMSCs-derived RPE cells were determined by quantitative RT-PCR and immunofluorescence. The function of induced cells was assayed by ELISA for secretion of neurotrophic factors. RESULTS: Intracellular pigment granules and many RPE markers existed in hBMSCs-derived RPE cells after co-culturing with pig RPE cells for 14 days. Typical RPE functions, such as phagocytosis of photoreceptor outer segments and secretion of the trophic factors, brain-derived neurotrophic factor (BDNF) and glia-derived neurotrophic factor (GDNF), were observed in these induced cells. CONCLUSION: hBMSCs can be induced toward functional RPE cells simply by transwell-based co-culture with RPE cells. PMID- 23635914 TI - Lorazepam does not improve the quality of recovery in day-case surgery patients: a randomised placebo-controlled clinical trial. AB - BACKGROUND: In day-case surgery, the effects of the anxiolytic lorazepam as premedication on the quality of postoperative recovery are unknown. OBJECTIVE: To evaluate whether lorazepam as a premedication beneficially affects quality of recovery (primary outcome) and psychological manifestations (secondary outcome) after day-case surgery. DESIGN: A randomised, double-blind, placebo-controlled clinical trial. SETTING: Single tertiary centre. PATIENTS: INCLUSION CRITERIA: day-case surgery; age at least 18 years. EXCLUSION CRITERIA: insufficient knowledge of the Dutch language; intellectual disability; ophthalmology surgery; extracorporeal shock wave lithotripsy; endoscopy; botulinum toxin A treatment; abortion; chronic pain treatment; preceding use of psychopharmaceuticals; contraindication to lorazepam. INTERVENTION: Lorazepam (1 to 1.5 mg) intravenously vs. NaCl 0.9% as a premedication prior to surgery. MAIN OUTCOME MEASURE: Quality of Recovery-40 (QoR-40) score. SECONDARY OUTCOMES: State-Trait Anxiety Inventory (STAI-State/Trait); State-Trait Anger Scale (STAS-State/Trait); Multidimensional Fatigue Inventory (MFI); Hospital Anxiety and Depression Scale (HADS). Timing of evaluation: T0: preoperatively (all scales); T1: before discharge (STAI-State/Trait); T2: first postoperative working day (QoR-40); T3: 7th day after surgery (all scales). Robust regression analysis was applied. Statistical analyses were adjusted for the corresponding baseline value and sex. RESULTS: Four hundred patients were randomised; 398 patients were analysed. Postoperative mean QoR-40 scores were similar in both groups at T2 (174.5 vs. 176.4, P = 0.34) and T3 (172.8 vs.176.3, P = 0.38). Postoperative mean STAI State/Trait scores decreased less in the group with lorazepam at T1 (32.3 vs. 29.3, P < 0.0001; 32.7 vs. 30.8, P = 0.0002). STAI-Trait and HADS-Anxiety decreased less in the group with lorazepam at T3 (31.1 vs. 30.0; P = 0.03, 3.3 vs. 2.5, P = 0.003). STAS-State increased in the group with lorazepam at T3 (10.8 vs. 10.3, P = 0.04). CONCLUSION: In day-case surgery, lorazepam as a premedication did not improve quality of recovery. Furthermore, this premedication may delay the decrease in postoperative anxiety and aggression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01441843. PMID- 23635915 TI - Key environmental impacts of global genetically modified (GM) crop use 1996-2011. AB - Given the increasing awareness and appreciation of issues such as global warming and the impact of mankind's activities such as agriculture on the global environment, this paper updates previous assessments of the environmental impact of an important and relatively new technology, crop biotechnology has had on global agriculture. It focuses on the environmental impacts associated with changes in pesticide use and greenhouse gas emissions arising from the use of GM crops. The adoption of the technology has reduced pesticide spraying by 474 million kg (-8.9%) and, as a result, decreased the environmental impact associated with herbicide and insecticide use on these crops [as measured by the indicator the Environmental Impact Quotient (EIQ)] by 18.1%. The technology has also facilitated a significant reduction in the release of greenhouse gas emissions from this cropping area, which, in 2011, was equivalent to removing 10.22 million cars from the roads. PMID- 23635916 TI - A NICE example? Variation in provision of bariatric surgery in England. PMID- 23635917 TI - Keeping hand hygiene high on the patient safety agenda. PMID- 23635918 TI - New blood test can detect genes that drive cancer and help to determine best treatment. PMID- 23635919 TI - Isolated bilateral middle cerebellar peduncle infarcts. AB - Our objective is to report an interesting case of a patient with known severe vertebrobasilar disease who presented with isolated bilateral middle cerebellar peduncle (MCP) infarction. Isolated infarction of the MCP is uncommon, occurring in roughly 0.12% of acute strokes. Isolated bilateral MCP infarction is extremely rare and has been described in only a few cases in the literature. The MCP is a watershed zone between the anterior inferior cerebellar artery and the superior cerebellar artery and its occurrence suggests hypoperfusion. PMID- 23635920 TI - Thrombolysis for acute ischemic stroke: do patients treated out of hours have a worse outcome? AB - INTRODUCTION: Previous studies on the impact of nonworking hours (NWH) have produced conflicting results. We aimed to compare the time to treatment with thrombolysis between NWH and working hours (WH) at an Australian comprehensive stroke center. MATERIALS AND METHODS: All acute ischemic stroke patients treated with intravenous alteplase (IV-alteplase) from January 2003 to December 2011 at the Royal Melbourne Hospital were included. Data collected included demographics, serial time points (including onset, presentation to emergency department, neuroimaging, and thrombolysis), and clinical outcomes (modified Rankin Scale [mRS] and death) at 3 months. NWH were defined as weekdays 5 PM-8 AM, weekends, and public holidays. Comparisons were made in the door-to-computed tomography (CT) time, the door-to-needle time, mRS, and mortality within 3 months between the NWH group and WH group. RESULTS: We recruited 388 consecutive patients who received IV-alteplase, 226 patients were in NWH and 162 patients in WH. The median age was 71 years (Interquartile range [IQR] = 60-79), 54.1% of patients were male, and the median National Institutes of Health Stroke Scale score was 13 (IQR = 8-18). No significant differences were observed at baseline between the NWH and WH groups except for prior stroke. There was a 15-minute increase in the median door-to-needle time (80 minutes in the NWH group versus 64.5 minutes in the WH group, 95% confidence interval [CI]: 6.36-23.64, P = .001). No significant differences were noted in the median door-to-CT time (95% CI: -1.16 to 9.16, P = .128) and clinical outcomes at 3 months (P > .05). Both the door-to-CT time and the door-to-needle time became shorter over the period of the study (P < .001). CONCLUSIONS: Our study showed that the "NWH effect" increased the door-to-needle time. The patients treated out of hours did not have a worse outcome. PMID- 23635922 TI - Outcomes of thrombolytic treatment for acute ischemic stroke in dialysis dependent patients in the United States. AB - OBJECTIVE: To determine the outcomes of dialysis-dependent renal failure patients who had ischemic stroke and were treated with intravenous (IV) thrombolytics in the United States. METHODS: We analyzed the data from Nationwide Inpatient Sample (2002-2009) for all thrombolytic-treated patients presenting with acute ischemic stroke with or without dialysis dependence. Patients were identified using the International Classification of Disease, Ninth Revision, Clinical Modification codes. Baseline characteristics, in-hospital complications including secondary intracerebral hemorrhage (ICH), sepsis, pneumonia, pulmonary embolism, deep venous thrombosis, urinary tract infections, and discharge outcomes (mortality, minimal disability, and moderate-to-severe disability) were compared between the groups. RESULTS: Of the 82,142 patients with ischemic stroke who receive thrombolytic treatment, 1072 (1.3%) was dialysis dependent. The ICH rates did not differ significantly between patients with ischemic stroke with or without dialysis who received thrombolytics (5.2% versus 6.1%). The in-hospital mortality rate was higher in dialysis-dependent patients treated with thrombolytics (22% versus 11%, P<=.0001). After adjusting for age, sex, and comorbidities, dialysis dependence was associated with higher rates of in-hospital mortality in patients treated with thrombolytics (odds ratio, 1.92; 95% confidence interval, 1.33-2.78, P=.0005). CONCLUSIONS: The 2-fold higher odds of in-hospital mortality associated with administration of IV thrombolytics in dialysis-dependent patients who present with acute ischemic stroke warrant a careful assessment of risk-benefit ratio in this population. PMID- 23635921 TI - Pituitary ischemic apoplexy in a young woman using oral contraceptives: a case report. AB - Estrogen is suggested to be one of the plausible risk factors for pituitary hemorrhagic apoplexy through pituitary hyperemia. We experienced a 33-year-old woman with pituitary ischemic apoplexy of a nonfunctional macroadenoma under oral contraceptive use. Our case indicates that hypercoagulable state, but not hyperemia, associated with estrogen may promote pituitary ischemic apoplexy. PMID- 23635923 TI - High-resolution magnetic resonance imaging of symptomatic middle cerebral artery dissection. AB - Dissection of the middle cerebral artery (MCA) is less frequent compared with dissection of vessels in the vertebrobasilar system or dissection of the carotid artery. High-resolution cross-sectional magnetic resonance imaging (HRMRI) has emerged as a potential technique for atherosclerotic plaque imaging in MCA. We enrolled 3 patients with MCA dissection on whom HRMRI was performed for evaluation of MCA stenosis. Two patients had an embolic infarction in the MCA territory and focal dissection. One patient had a massive infarction in the MCA territory and long-segment dissection of the MCA. On HRMRI, our objectives had an intimal flap with patency of the lumen and 1 had extensive hemorrhaging in the false lumen. PMID- 23635925 TI - Visual system involvement in CADASIL. AB - BACKGROUND AND OBJECTIVE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriolar small-vessel disease caused by Notch3 mutations. A detailed definition of the neuro-ophthalmologic spectrum of CADASIL might provide new insights in the pathophysiology of small-vessel diseases. Therefore, this study aims to precisely delineate the features and the prevalence of the visual system impairment in CADASIL. METHODS: A cohort of 34 genetically confirmed CADASIL patients was enrolled in an observational cross-sectional study. Subjects underwent a complete neuro-ophthalmological evaluation. Clinical features and common cardiovascular risk factors were also considered. Data were compared with those already reported in previous studies. RESULTS: Both afferent and efferent visual structures were commonly impaired in CADASIL patients. Retinal microvascular changes such as arteriolar narrowing and arteriovenous nicking, described in most patients and detected also in asymptomatic carriers, reflect the typical hemodynamic changes of CADASIL. However, less frequent findings, like early macular and lens changes, would indicate a possible further role played by susceptibility to premature aging and degeneration. Cotton wool spots and vessel occlusions were not common. Finally, eye movement abnormalities suggest that the brainstem is particularly vulnerable to damage in CADASIL. CONCLUSIONS: Although no specific or prominent neuro-ophthalmologic finding can be considered as hallmark of the disease, afferent and efferent visual system abnormalities could be accounted as complementary markers to study cerebral small-vessel diseases. PMID- 23635926 TI - Publish (high-quality evidence for clinical practice) or (patients may) perish. PMID- 23635924 TI - Associations of durations of antiplatelet use and vascular risk factors with the presence of cerebral microbleeds. AB - The association of the presence of cerebral microbleeds with antiplatelet use remains controversial. Long durations of antiplatelet use and vascular risk factors may have a greater impact on the development of cerebral microbleeds than short durations. The aim of this study was to determine whether the durations of antiplatelet use and vascular risk factors were associated with the presence of cerebral microbleeds in patients with ischemic cerebrovascular disease, who are frequently treated with antiplatelet agents. Two hundred twenty outpatients with ischemic cerebrovascular lesions (eg, cerebral infarcts and/or white matter lesions) detected by magnetic resonance imaging were examined. Patients with a history of cerebral hemorrhage were excluded. Cerebral microbleeds were observed in 71 (32.3%) patients. Deep or infratentorial microbleeds and strictly lobar microbleeds were observed in 53 (24.1%) patients and 18 (8.2%) patients, respectively. Aspirin use (odds ratio, 2.14; 95% confidence interval [CI], 1.02 4.73; P = .04) and a long duration (>=10 years) of aspirin use (odds ratio, 3.75; 95% CI, 1.31-10.86; P = .01) were significantly associated with deep or infratentorial microbleeds in the crude analysis, but this became nonsignificant after adjustment for hypertension and other confounding factors. The prevalence of antiplatelet use was significantly higher in the patients with hypertension than in those without hypertension (72.5% versus 49.1%, P = .002). Hypertension (odds ratio, 2.50; 95% CI, 1.11-6.41; P = .04) was significantly associated with the development of deep or infratentorial microbleeds even after adjustment for confounding factors and the association increased with the duration of hypertension. In conclusion, we found a significant association between aspirin use and deep or infratentorial microbleeds, but this association may reflect the presence of hypertension as a confounding factor. PMID- 23635928 TI - Role responsibilities in mechanical ventilation and weaning in pediatric intensive care units: a national survey. AB - BACKGROUND: Organizational processes affect the duration of mechanical ventilation in adult and pediatric intensive care units, but surprisingly little is known about role responsibilities for mechanical ventilation and weaning and related contextual factors that may influence timely liberation from mechanical ventilation. OBJECTIVE: To determine the professional group and seniority of clinicians responsible for key decisions regarding ventilation and weaning; use of ventilation protocols and automated closed loop systems; and provision of education on mechanical ventilation. METHODS: Mailed survey to nurse managers of pediatric intensive care units in the United Kingdom. RESULTS: Response rate was 61%. In most units, nurse managers reported that physicians and nurses usually collaborated in making decisions about initializing (63%) and adjusting (94%) ventilator settings and for determining weaning readiness (88%), weaning method (59%), extubation readiness (82%), and weaning failure (100%). Protocols for mechanical ventilation were available in 35% of units, some specific to weaning (18%) and others for noninvasive ventilation (35%). Automated closed loop systems were used in 18% of units. Competency training was required before nurses could adjust ventilator settings in 35% of responding units; in the remaining units, settings were adjusted by nurses who had no specific competency training. CONCLUSIONS: Key decisions were mainly collaborative, but nurses were limited in their ability to adjust ventilator settings independently. This limitation may be due to a lack of standardized competency programs and the infrequent use of non physician-led weaning protocols and automated systems. These findings indicate some ways of improving processes to avoid delays in ventilator weaning. PMID- 23635929 TI - Rapid response teams: qualitative analysis of their effectiveness. AB - BACKGROUND: Multidisciplinary rapid response teams focus on patients' emergent needs and manage critical situations to prevent avoidable deaths. Although research has focused primarily on outcomes, studies of the actual team effectiveness within the teams from multiple perspectives have been limited. OBJECTIVE: To describe effectiveness of rapid response teams in a large teaching hospital in California that had been using such teams for 5 years. METHODS: The grounded-theory method was used to discover if substantive theory might emerge from interview and/or observational data. Purposeful sampling was used to conduct in-person semistructured interviews with 17 key informants. Convenience sampling was used for the 9 observed events that involved a rapid response team. Analysis involved use of a concept or indicator model to generate empirical results from the data. Data were coded, compared, and contrasted, and, when appropriate, relationships between concepts were formed. Results Dimensions of effective team performance included the concepts of organizational culture, team structure, expertise, communication, and teamwork. CONCLUSIONS: Professionals involved reported that rapid response teams functioned well in managing patients at risk or in crisis; however, unique challenges were identified. Teams were loosely coupled because of the inconsistency of team members from day to day. Team members had little opportunity to develop relationships or team skills. The need for team training may be greater than that among teams that work together regularly under less time pressure to perform. Communication between team members and managing a crisis were critical aspects of an effective response team. PMID- 23635930 TI - Implications of the new international sepsis guidelines for nursing care. AB - Sepsis is a serious worldwide health care condition that is associated with high mortality rates, despite improvements in the ability to manage infection. New guidelines for the management of sepsis were recently released that advocate for implementation of care based on evidence-based practice for both adult and pediatric patients. Critical care nurses are directly involved in the assessment of patients at risk for developing sepsis and in the treatment of patients with sepsis and can, therefore, affect outcomes for critically ill patients. Nurses' knowledge of the recommendations in the new guidelines can help to ensure that patients with sepsis receive therapies that are based on the latest scientific evidence. This article presents an overview of new evidence-based recommendations for the treatment of adult patients with sepsis, highlighting the role of critical care nurses. PMID- 23635931 TI - Admission to the intensive care unit and well-being in patients with advanced chronic illness. AB - PURPOSE: To describe the association of intensive care with trajectories of functional, emotional, social, and physical well-being in patients with 3 common advanced illnesses. METHODS: Cross-sectional cohort study of 42 patients admitted to the intensive care unit selected from 210 patients with stage IV breast, prostate, or colon cancer or stage IIIb or IV lung cancer; New York Heart Association class III or IV congestive heart failure; and chronic obstructive pulmonary disease with hypercapnea (Pco2 > 46 mm Hg). Scores on subscales of the Functional Assessment of Chronic Illness Therapy-General survey were measured monthly for 6 months before and after admission to the intensive care unit and were analyzed by using the unit admission date as a point of discontinuous change to illustrate trajectories before and after the admission. RESULTS: Overall, trajectories of well-being declined sharply after admission to the intensive care unit. Declines in physical, functional, and emotional well-being were statistically significant. During the 6 months after admission, physical, functional, and emotional well-being scores trended back up to baseline while social well-being scores continued to decline. CONCLUSIONS: Well-being trajectories declined sharply after admission to the intensive care unit, with recovery in the subsequent 6 months, and may be characterized by common patterns. These results help to better describe intensive care as a marker for advancing illness in patients with advanced chronic illness. PMID- 23635932 TI - Effect of collaborative care on cost variation in an intensive care unit. AB - BACKGROUND: Improving the cost-effectiveness of health care requires an understanding of the genesis of health care costs and in particular the sources of cost variation. Little is known about how multiple physicians, caring collaboratively for patients, contribute to costs. OBJECTIVE: To explore the effect of collaborative care by physicians on variation in discretionary costs in an intensive care unit (ICU) by determining the contributions of the attending intensivists and ICU fellows. METHODS: Prospective, observational study using a multivariable model of median discretionary costs for the first day in the ICU, adjusting for confounding variables. Analysis included 3514 patients who spent more than 2 hours in the ICU on the initial day. Impact of the physicians was assessed via variables representing the specific intensivist and ICU fellow responsible on the first ICU day and allowing for interaction terms. RESULTS: On the initial day, patients spent a median of 10.6 hours (interquartile range, 6.3 16.5) in the ICU, with median discretionary costs of $1343 (interquartile range, $788-2208). There was large variation in adjusted costs attributable to both the intensivists ($359; 95% CI, $244-$474) and the fellows ($756; 95% CI, $550-$965). The interaction terms were not significant (P = .12-.79). CONCLUSIONS: In an ICU care model with intensivists and subspecialty fellows, both types of physicians contributed significantly to the observed variation in discretionary costs. However, even in the presence of a hierarchical arrangement of clinical responsibilities, the influences on costs of the 2 types of physicians were independent. PMID- 23635933 TI - End-tidal carbon dioxide as a measure of stress response to clustered nursing interventions in neurologic patients. AB - BACKGROUND: Guidelines recommend rest periods between nursing interventions for patients with a neurologic diagnosis but do not specify a safe number of interventions. OBJECTIVES: To examine the physiological stress response to clustered nursing interventions in neurologic patients receiving mechanical ventilation. METHODS: Prospective, comparative, descriptive design to examine effects of clustered interventions (>=6 interventions in a single nursing interaction) versus nonclustered interventions on patients' stress. Stress response was defined as a 10% change in end-tidal carbon dioxide from before the interaction to (1) 5 and 10 minutes after the start of the interaction, (2) at the end of the interaction, and (3) 15 minutes after the interaction. RESULTS: The mean percent change in end-tidal carbon dioxide at 5 minutes differed significantly between patients with clustered interventions and patients with nonclustered interventions (6.7% vs -0.2%; P = .001). Patients with clustered interventions were significantly more likely than patients with low clustering to exhibit a stress response at 5 minutes (24.3% vs 0%; P = .01). CONCLUSIONS: Neurologic patients receiving mechanical ventilation who experienced 6 or more clustered nursing interventions showed a higher mean change in end-tidal carbon dioxide than did patients who received fewer than 6 clustered interventions. These findings suggest that providing fewer interventions during 1 nursing interaction may minimize induced stress in neurologic patients receiving mechanical ventilation. PMID- 23635935 TI - Pain assessment in nonverbal patients. PMID- 23635934 TI - Behavioral pain assessment tool for critically ill adults unable to self-report pain. AB - BACKGROUND: Critically ill adults often cannot self-report pain. OBJECTIVE: To determine the effect of the Critical-Care Pain Observation Tool on frequency of documentation of pain assessment and administration of analgesics and sedatives in critically ill patients unable to self-report pain. METHODS: Data on patients in 2 intensive care units of a university-affiliated hospital were collected before and after implementation of the tool. Patients were prospectively screened for eligibility; data were extracted retrospectively. RESULTS: Data were recorded for a maximum of 72 hours before and after implementation of the tool in the cardiovascular intensive care unit (130 patients before and 132 after) and in the medical/surgical/trauma unit (59 patients before and 52 after). Proportion of pain assessment intervals with pain assessment documented increased from 15% to 64% (P < .001) in the cardiovascular unit and from 22% to 80% (P < .001) in the other unit. Median total dose of opioid analgesics decreased from 5 mg to 4 mg in the cardiovascular unit (P = .02) and increased from 27 mg to 75 mg (P = .002) in the other unit. Median total dose of benzodiazepines decreased from 12 mg to 2 mg (P < .001) in the cardiovascular unit and remained unchanged in the other unit. Increased documentation of pain assessment was associated with increased age in the cardiovascular unit and with decreased maximum scores on the Sequential Organ Failure Assessment in the other unit. CONCLUSION: Implementation of the tool increased frequency of pain assessment and appeared to influence administration of analgesics in both units. PMID- 23635937 TI - Is dying in an ICU a sign of poor quality end-of-life care? PMID- 23635936 TI - Clinical decision support system and incidence of delirium in cognitively impaired older adults transferred to intensive care. AB - BACKGROUND: Elderly patients with cognitive impairment are at increased risk of developing delirium, especially in the intensive care unit. OBJECTIVE: To evaluate the efficacy of a computer-based clinical decision support system that recommends consulting a geriatrician and discontinuing use of urinary catheters, physical restraints, and unnecessary anticholinergic drugs in reducing the incidence of delirium. METHODS: Data for a subgroup of patients enrolled in a large clinical trial who were transferred to the intensive care units of a tertiary-care, urban public hospital in Indianapolis were analyzed. Data were collected on frequency of orders for consultation with a geriatrician; discontinuation of urinary catheterization, physical restraints, or anticholinergic drugs; and the incidence of delirium. RESULTS: The sample consisted of 60 adults with cognitive impairment. Mean age was 74.6 years; 45% were African American, and 52% were women. No differences were detected between the intervention and the control groups in orders for consultation with a geriatrician (33% vs 40%; P = .79) or for discontinuation of urinary catheters (72% vs 76%; P = .99), physical restraints (12% vs 0%; P=.47), or anticholinergic drugs (67% vs 36%; P=.37). The 2 groups did not differ in the incidence of delirium (27% vs 29%; P = .85). CONCLUSION: Use of a computer-based clinical decision support system may not be effective in changing prescribing patterns or in decreasing the incidence of delirium. PMID- 23635938 TI - Emergency evaluation of 12-lead ECGs. PMID- 23635939 TI - Acute generalized exanthematous pustulosis with multiple organ dysfunction syndrome. AB - Acute generalized exanthematous pustulosis is a rare condition characterized by sterile pustules on erythematous and edematous tissue. Mostly drug induced, this condition can also be caused by other factors. Cases due to vancomycin are rare. A 67-year-old woman with cellulitis of the left lower extremity was admitted with marked bilateral lymphedema of the lower extremities and diffuse erythema of the left lower extremity from foot to knee. She was given clindamycin and then vancomycin. On day 5, her condition worsened, with erythema involving the entire back. Although treatment with clindamycin and vancomycin was discontinued, acute generalized exanthematous pustulosis developed. After successful treatment of other complications, the skin condition improved. Because vancomycin is frequently used, clinicians should be aware of the possibility of acute generalized exanthematous pustulosis. Because the pustulosis decreases after withdrawal of the causative drug, being able to diagnose and differentiate the abnormality from other conditions is prudent. PMID- 23635940 TI - Surveillance of device-associated infection rates and mortality in 3 Greek intensive care units. AB - BACKGROUND: Several studies suggest that device-associated, health care associated infections (DA-HAIs) affect the quality of care in intensive care units, increasing patients' morbidity and mortality and the costs of patient care. OBJECTIVES: To assess the DA-HAIs rates, microbiological profile, antimicrobial resistance, and crude excess mortality in 3 intensive care units in Athens, Greece. METHODS: A prospective cohort, active DA-HAI surveillance study was conducted in 3 Greek intensive care units from July 2009 to June 2010. The rates of mechanical ventilator-associated pneumonia (VAP), central catheter associated bloodstream infection (CLABSI), and catheter-associated urinary tract infection (CAUTI) were calculated along with microbiological profile, antimicrobial resistance, and crude excess mortality. RESULTS: During 6004 days in intensive care, 152 of 294 patients acquired 205 DA-HAIs, an overall rate of 51.7% of patients or 34.1 DA-HAIs per 1000 days (95% CI, 29.3-38.6). The VAP rate was 20 (95% CI, 16.3-23.7) per 1000 ventilator-days, the CLABSI rate was 11.8 (95% CI: 9.2-14.8) per 1000 catheter-days, and the CAUTI rate was 4.2 (95% CI, 2.5-5.9) per 1000 catheter-days. The most frequently isolated pathogen was Acinetobacter baumannii among patients with CLABSI (37.8%) and Candida species among patients with CAUTI (66.7%). Excess mortality was 20.3% for VAP and CLABSI and 32.2% for carbapenem-resistant A baumannii CLABSI. CONCLUSION: High rates of DA-HAIs, device utilization, and antimicrobial resistance emphasize the need for antimicrobial stewardship, the establishment of an active surveillance program of DA-HAIs, and the implementation of evidence-based preventive strategies. PMID- 23635942 TI - Unusual carotid stenosis detected by F-18 FDG PET/CT. PMID- 23635943 TI - Control of myeloid cell trafficking in resolution. AB - Following tissue injury or microbial invasion, neutrophils are robustly recruited to inflammatory loci, which is a hallmark of the host inflammatory response. This event initiates a series of processes required to activate resolution, including recruitment of monocytes, clearance of microbes, cellular debris and apoptotic neutrophils, the egress of phagocytes and, ultimately, regain of tissue homeostasis. Substantial evidence now signifies that resolution of inflammation is a highly coordinated, active process dictated by the spatial-temporal generation of proresolving mediators that act on specific receptors to modulate cell and tissue reactivity. This review will focus on the mediators, targets and pathways initiated to orchestrate resolution. Importantly, disruption of the key processes involved in inflammatory resolution could result in delayed restoration of tissue homeostasis, leading to fibrosis and/or persistent inflammation. PMID- 23635944 TI - A pilot study of anterior cingulate cortex neurochemistry in adolescents with generalized anxiety disorder. AB - BACKGROUND/AIMS: This study used proton magnetic resonance spectroscopy (1H MRS) to evaluate the neurochemistry of the anterior cingulate cortex (ACC) in adolescents with generalized anxiety disorder (GAD). METHODS: Adolescents with GAD (n = 10) and healthy subjects (n = 10) underwent a 1H MRS scan at 4 T. Glutamate (Glu), N-acetyl aspartate, creatine (Cr) and myo-inositol concentrations were measured in the ACC and were compared between untreated adolescents with GAD and age- and sex-matched healthy subjects. RESULTS: Glu/Cr ratios in the ACC correlated with the severity of both generalized anxiety symptoms on the Pediatric Anxiety Rating Scale and with total anxiety symptom severity as measured by the Hamilton Anxiety Rating Scale, but did not differ between adolescents with GAD and healthy subjects. In addition, no differences in N-acetyl aspartate, Cr, or myo-inositol were detected between groups. CONCLUSION: These findings suggest that Glu/Cr in untreated adolescents with GAD may relate to the severity of anxiety symptoms and raise the possibility that dysregulation of Glu within the ACC may be linked to the pathophysiology of pediatric GAD. PMID- 23635945 TI - Leukoaraiosis on MRI in patients with minimally symptomatic obstructive sleep apnoea. AB - BACKGROUND: Obstructive sleep apnoea (OSA) is associated with hypertension, nocturnal blood pressure (BP) surges, and increased risk of stroke. It may therefore also be associated with a higher risk of developing leukoaraiosis. Only few data about the prevalence of leukoaraiosis in patients with OSA, and any association between degrees of severity of either condition, exist. METHODS: We studied patients who were part of a clinical trial (MOSAIC) in minimally symptomatic OSA. All patients had brain MRI (T2, FLAIR) at baseline. A single observer assessed the images for the presence and severity of leukoaraiosis (ARWMC-score). We related the extent of leukoaraiosis to the severity of OSA (measured by oxygen desaturation index [ODI]) and the presence of other vascular risk factors. RESULTS: 183 patients (156 men, 85.2%; mean age +/- SD = 57.7 +/- 7.4 years; median oxygen desaturation index = 9.6, interquartile range = 4.6 16.0) took part in the study. Although 135 (74%) patients had some leukoaraiosis, this was generally mild. We confirmed the well-known risk factor associations between leukoaraiosis, increasing age (p < 0.0001) and hypertension (p = 0.003), but we did not find any association between OSA and leukoaraiosis (p = 0.33), despite both conditions being associated with increasing current BP and a history of hypertension. CONCLUSION: Our data confirm the well-known association between leukoaraiosis, age and increasing BP. However, we found no association between OSA and leukoaraiosis despite some shared risk factor associations. Our findings suggest that OSA is not a strong independent risk factor for leukoaraiosis. Confounding by hypertension may explain any apparent association in previously reported studies of patients with severer OSA. PMID- 23635946 TI - Assessing diets of 3-year-old children: evaluation of an FFQ. AB - OBJECTIVE: To evaluate the use of an administered eighty-item FFQ to assess nutrient intake and diet quality in 3-year-old children. DESIGN: Frequency of consumption and portion size of the foods listed on the FFQ during the 3 months preceding the interview were reported by the child's main caregiver; after the interview a 2 d prospective food diary (FD) was completed on behalf of the child. Nutrient intakes from the FFQ and FD were estimated using UK food composition data. Diet quality was assessed from the FFQ and FD according to the child's scores for a principal component analysis-defined dietary pattern ('prudent' pattern), characterised by high consumption of fruit, vegetables, water and wholemeal cereals. SETTING: Southampton, UK. SUBJECTS: Children (n 892) aged 3 years in the Southampton Women's Survey. RESULTS: Intakes of all nutrients assessed by the FFQ were higher than FD estimates, but there was reasonable agreement in terms of ranking of children (range of Spearman rank correlations for energy-adjusted nutrient intakes, r s = 0.41 to 0.59). Prudent diet scores estimated from the FFQ and FD were highly correlated (r = 0.72). Some family and child characteristics appeared to influence the ability of the FFQ to rank children, most notably the number of child's meals eaten away from home. CONCLUSIONS: The FFQ provides useful information to allow ranking of children at this age with respect to nutrient intake and quality of diet, but may overestimate absolute intakes. Dietary studies of young children need to consider family and child characteristics that may impact on reporting error associated with an FFQ. PMID- 23635948 TI - A nonsynonymous variant of IL1A is associated with endometriosis in Japanese population. AB - Our previous genome-wide association study has demonstrated that single nucleotide polymorphisms (SNPs) located in intronic and downstream regions of IL1A (interleukin 1alpha) were associated with the risk of endometriosis. These SNPs on the genome-wide association study platform could be only surrogates for the true causal variant. Thus, we resequenced all the exons of IL1A in 377 patients with endometriosis and 457 healthy controls. We detected seven rare variants (minor allele frequency <0.01) and four common variants. All the rare variants were not associated with endometriosis. The four common variants (rs17561, rs1304037, rs2856836 and rs3783553) in IL1A were significantly associated with endometriosis (P=0.0024, 0.0024, 0.0014 and 0.0061, respectively). All the four SNPs were within a linkage disequilibrium block. Among them, only rs17561 was nonsynonymous (p.A114S), which has been reported to be associated with susceptibility to ovarian cancer. Taken together, we examined association between rs17561 and endometriosis in an independent validation data set (524 patients and 533 healthy controls) replicating significant association (P=4.0 * 10(-5); odds ratio (OR), 1.91; 95% confidence interval (CI), 1.41-2.61). Meta-analysis by combining results from the two stages strengthened the evidence of association (P=2.5 * 10(-7); OR, 1.90; 95% CI, 1.49-2.43). Our findings demonstrated that the nonsynonymous variant of IL1A might confer genetic susceptibility to endometriosis in Japanese population. PMID- 23635947 TI - Pharmacogenomics of severe cutaneous adverse reactions and drug-induced liver injury. AB - Rare but severe adverse drug reactions (ADRs) are an important issue in drug development and in the proper usage of drugs during the post-approval phase. The ability to predict patient susceptibility to severe ADRs would prevent drug administration to high-risk patients. This would save lives and ensure the quality of life for these patients, but occurrence of idiosyncratic severe ADRs had been very difficult to predict for a long time. However, in this decade, genetic markers have been found for several ADRs, especially for severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). In this review, we summarize recent progress in identifying genetic markers for SCARS and DILI, and discuss issues that remain unresolved. As for SCARs, associations of HLA B*15:02 or HLA-A*31:01 and HLA-B*58:01 have been revealed for carbamazepine- and allopurinol-related Stevens-Johnson syndrome and toxic epidermal neclolysis, respectively. HLA-B*57:01 is strongly associated with abacavir-induced hypersensitivity syndrome. Several HLA alleles also demonstrate drug-specific associations with DILI, such as HLA-A*33:03 for ticlopidine, HLA-B*57:01 for flucloxacillin and HLA-DQA1*02:01 for lapatinib. Efforts should be continued to find other genetic markers to achieve high predictability for ADRs, with the goal being development of genetic tests for use in clinical settings. PMID- 23635949 TI - Epithelial-mesenchymal transition-related microRNA-200s regulate molecular targets and pathways in renal cell carcinoma. AB - Our recent studies of microRNA (miRNA) expression signatures demonstrated that the epithelial-mesenchymal transition (EMT)-related microRNA-200 family (miR 200s: miR-200a/b/c, miR-141 and miR-429) were significantly downregulated in renal cell carcinoma (RCC) and putative tumor-suppressive miRNAs in RCC. In this study, our aim was to investigate the functional significance of the miR-200s in cancer cells and to identify novel miR-200s-regulated molecular targets and pathways in RCC. Expression levels of all the miR-200s members were significantly downregulated in human RCC tissues compared with normal renal tissues. Restoration of mature miR-200s in RCC cell line resulted in significant inhibition of cell proliferation and migration, suggesting that miR-200s function as tumor suppressors in RCC. Furthermore, we utilized gene expression analysis and in silico database analysis to identify miR-200s-regulated molecular targets and pathways in RCC. The miR-200s was categorized into two groups, according to their seed sequences, miR-200b/c/429 and miR-200a/141. Our data demonstrated that the 'Focal adhesion' and 'ErbB signaling' pathways were significantly regulated by miR-200b/c/429 and miR-200a/141, respectively. The identification of novel tumor-suppressive miR-200s-regulated molecular targets and pathways has provided new insights into RCC oncogenesis and metastasis. PMID- 23635950 TI - Serbian high-risk families: extensive results on BRCA mutation spectra and frequency. AB - Mutations in BRCA genes elevate risk for breast and ovarian cancer. These mutations are population specific. As there are no data on BRCA mutation screening on larger number of probands in Serbia to date, aim of this study was to determine types and frequencies of BRCA mutations in individuals from high risk families from Serbia, as well as to determine which BRCA mutations may be considered as founder for Serbian population. We analyzed 94 probands and detected 9 frameshift mutations in 12 individuals, 1 benign BRCA2 nonsense mutation and numerous missense and synonymous mutations in both genes. Frequency of frameshift mutations is 12.77%. In addition to two novel mutations detected in our population we reported previously, we detected another novel mutation- c.7283delT in BRCA2 exon 14. None of the detected deleterious mutations may be considered as founder mutations for Serbian population, as each of them was found in no more than two high-risk families. This mutation diversity is most probably due to high migration rate in history of this part of Europe. Interpretation of genetic testing results with missense mutations of unknown clinical importance is very challenging and should be approached with caution, using all available data sources for results' interpretation. PMID- 23635951 TI - Association studies of TNFSF4, TNFAIP3 and FAM167A-BLK polymorphisms with primary Sjogren's syndrome in Han Chinese. AB - Single-nucleotide polymorphisms (SNPs) in the TNFSF4, TNFAIP3 and FAM167A-BLK genes have been associated with several autoimmune diseases. Associations of TNFSF4 and FAM167A-BLK with primary Sjogren's syndrome (pSS) have also been described in a Caucasian population. However, it remains unknown whether polymorphisms of TNFSF4, TNFAIP3 and FAM167A-BLK are associated with pSS in Han Chinese. This study aimed to determine whether SNPs in TNFSF4, TNFAIP3 or FAM167A BLK genetically predispose a Chinese Han population to pSS. Ten SNPs in the TNFSF4 region (rs1234315, rs2205960, rs844648 and rs704840), the TNFAIP3 gene (rs5029939 and rs2230926) and the FAM167A-BLK region (rs7812879, rs2254546, rs2618479 and rs2248932) were genotyped in a cohort of 555 pSS patients and 597 healthy controls, by using the Sequenom MassArray system. Weak associations were observed when the SNPs in TNFSF4 (rs2205960, rs844648 and rs704840) and FAM167A BLK (rs7812879, rs2254546 and rs2618479) were directly analyzed or analyzed under dominant model between pSS and controls (all P<0.05). However, when Bonferroni correction was applied to the multiple comparisons, all of the associations vanished, except for rs7812879 (Pa=0.045). The frequencies of alleles, genotypes and haplotypes of TNFAIP3 SNPs and rs2248932 of FAM167A-BLK were not significantly different between the pSS patients and controls. No epistatic interactions were found to exist between the SNPs examined. Unlike the SNPs in TNFAIP3 and TNFSF4, rs7812879 in FAM167A-BLK imparts susceptibility to pSS in a Han Chinese population. The differential genetic risk profiles from other autoimmune diseases may indicate differential molecular mechanisms underlying pSS pathogenesis in this group. PMID- 23635952 TI - Follow-up nationwide survey on predictive genetic testing for late-onset hereditary neurological diseases in Japan. AB - A follow-up nationwide survey on predictive genetic testing for late-onset neurological diseases in Japan was conducted. A questionnaire was sent to 89 institutional members of the Japan's National Liaison Council for Clinical Sections of Medical Genetics, and was returned by 60 (67.4%). A total of 301 clients with an interest in predictive testing were accumulated from April 2006 to March 2011. The greatest interest was shown for spinocerebellar degeneration (SCD, n=110), followed by myotonic dystrophy type 1 (DM1, n=69), Huntington's disease (HD, n=52) and familial amyloid polyneuropathy (FAP, n=35). The ratios of clients who actually underwent predictive testing were: SCD, 21.8%; DM1, 39.1%; HD, 26.9%; and FAP, 74.3%, indicating that predictive testing was conducted very cautiously for untreatable neurological diseases in Japan. Clinical geneticists were predominantly involved in genetic counseling, whereas the participation of non-medical doctor (non-MD) staff, including nurses, clinical psychologists and genetic counselors, was not common. Lack of non-MD counseling staff was one of the most serious issues in conducting predictive testing, which has not been improved since the previous survey performed in 2006. Institutional arrangements, such as revision of medical insurance system regarding genetic testing and counseling, might be necessary to resolve this issue. PMID- 23635954 TI - Serous cystadenoma of the pancreas with endoscopic ultrasound fine needle aspiration biopsy and surgical correlation. AB - OBJECTIVES: Endoscopic ultrasound (EUS) fine needle aspiration (FNA) biopsies are commonly used to diagnose tumors of the pancreas. Serous cystadenoma (SCA) is a benign neoplasm that is uncommon and accounts for 1-2% of all pancreatic neoplasms. STUDY DESIGN: Surgically excised SCAs with preoperative EUS FNA biopsy over a 10-year span were identified. Clinical data were collected, and cytomorphologic features reviewed retrospectively and correlated with surgical excision data. Original cytopathologic diagnoses and retrospectively reviewed cytomorphology features were recorded. RESULTS: Seventeen patients were identified. Original EUS FNA interpretation included 1 'unsatisfactory', 9 'negative for malignancy' and 7 'atypical' or greater; however, all cases were categorized as benign/negative or nondiagnostic on retrospective review. The cases were hypocellular and possessed variable (rare to few-moderate) groups of bland cuboidal epithelial cells embedded in granular debris. Mucosal sampling was present (7/17) and cell blocks were acellular (5/17). CONCLUSION: This is a large series of pancreas SCAs subjected exclusively to EUS FNA biopsy where all cases had surgical excision confirmation. The 17 cases had hypocellular aspirate smears with the majority showing few bland epithelial cells; however, this can limit definitive diagnosis based on the cytomorphologic evaluation alone. The aspirate smear pattern of EUS FNA of SCAs of the pancreas supports a benign/negative or nondiagnostic categorization. PMID- 23635953 TI - Pharmacogenomics of endocrine therapy in breast cancer. AB - The most important modality of treatment in the two-thirds of patients with an estrogen receptor (ER)-positive early breast cancer is endocrine therapy. In postmenopausal women, options include the selective ER modulators (SERMs), tamoxifen and raloxifene, and the 'third-generation' aromatase inhibitors (AIs), anastrozole, exemestane and letrozole. Under the auspices of the National Institutes of Health Global Alliance for Pharmacogenomics, Japan, the Mayo Clinic Pharmacogenomics Research Network Center and the RIKEN Center for Genomic Medicine have worked collaboratively to perform genome-wide association studies (GWAS) in women treated with both SERMs and AIs. On the basis of the results of the GWAS, scientists at the Mayo Clinic have proceeded with functional genomic laboratory studies. As will be seen in this review, this has led to new knowledge relating to endocrine biology that has provided a clear focus for further research to move toward truly personalized medicine for women with breast cancer. PMID- 23635955 TI - In infants born extremely preterm, aspirin or NSAID use during pregnancy are associated with increased risk of quadriparetic cerebral palsy. PMID- 23635956 TI - Even with regular use of an observational scale to assess pain among nursing home residents with dementia, pain-relieving interventions are not frequently used. PMID- 23635957 TI - Around half of nurses and midwives report workplace aggression in the past month: 36% report violence from patients or visitors and 32% report bullying by colleagues. PMID- 23635958 TI - Administration of isoflurane-controlled dyskinetic movements caused by anti-NMDAR encephalitis. PMID- 23635959 TI - Metabolite changes in radiologically isolated syndrome: more pathology than meets the eye? PMID- 23635960 TI - Similarities between familial and sporadic autopsy-proven progressive supranuclear palsy. AB - Progressive supranuclear palsy (PSP) is a relatively common neurodegenerative tauopathy clinically characterized by parkinsonism, axial rigidity, and supranuclear gaze palsy. Pathologic findings of PSP are neuronal loss, gliosis, and neurofibrillary tangles in basal ganglia, diencephalon, and brainstem; there is increasing recognition of clinicopathologic variants of PSP.(1.) PMID- 23635961 TI - Association of brain pathology with the progression of frailty in older adults. AB - OBJECTIVE: We tested the hypothesis that brain pathology is associated with the rate of progression of physical frailty in older adults. METHODS: A total of 791 older adults participating in the Religious Orders Study and Memory and Aging Project had annual clinical evaluations from which a previously established composite measure of physical frailty was derived and brain autopsy after death. A uniform neuropathologic examination included the assessment of macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, Alzheimer disease and Lewy body pathology, and nigral neuronal loss. RESULTS: Mean follow-up before death was 6.4 years and age at death was 88.5 years. More than 95% of cases had evidence of one or more brain pathologies. In a linear mixed-effect model controlling for age, sex, and education, frailty increased at approximately 0.12 unit/year (estimate 0.117, SE 0.035, p < 0.001). The rate of progression of frailty was accelerated with increasing age (estimate 0.002, SE 0.001, p = 0.012). In separate models, the presence of macroinfarcts, Alzheimer disease and Lewy body pathology, and nigral neuronal loss was associated with a more rapid progression of frailty (all p values <=0.010). When these 4 brain pathologies were considered together in a single model, Alzheimer disease pathology, macroinfarcts, and nigral neuronal loss showed independent associations with the rate of progression of frailty and accounted for more than 8% of the variance unexplained by demographic variables alone. CONCLUSION: The accumulation of common brain pathologies contributes to progressive physical frailty in old age. PMID- 23635962 TI - Brain metabolic changes suggestive of axonal damage in radiologically isolated syndrome. AB - BACKGROUND: The MRI incidental finding in asymptomatic subjects of brain white matter (WM) changes meeting the Barkhof criteria for the diagnosis of multiple sclerosis (MS) has been recently characterized as the radiologically isolated syndrome (RIS). This entity needs to be more specifically defined to allow risk stratification of these subjects. We used brain proton magnetic resonance spectroscopic imaging (1H-MRSI) to assess metabolic changes in an RIS population. METHODS: Twenty-three RIS subjects who were classified according to the Okuda Criteria underwent 1H-MRSI examination with a central brain (CB) volume of interest (VOI) to measure levels of N-acetylaspartate (NAA) and choline (Cho) normalized to creatine (Cr) in the whole CB-VOI, in lesional/perilesional and normal-appearing WM regions, and in the cortical gray matter (CGM). The 1H-MRSI data were compared with those of 20 demographically matched healthy controls (HC). RESULTS: NAA/Cr levels were significantly lower in RIS than in HC in all regions (p < 0.005 for all). No differences in Cho/Cr levels were found in either brain region. A single-subject analysis showed that NAA/Cr levels were at least 2 SDs below the HC mean in the 44% of RIS in the normal-appearing WM and in the 61% of RIS in the CGM. CONCLUSION: Decreased brain NAA/Cr levels in a group of RIS subjects indicates that brain metabolic abnormalities suggestive of axonal damage can be significant even at this early disease stage. This information could be useful for stratifying RIS individuals with a high risk of progression to MS. PMID- 23635963 TI - Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. AB - OBJECTIVES: Myoclonic epilepsy with ragged-red fibers (MERRF) is a rare mitochondrial syndrome, mostly caused by the 8344A>G mitochondrial DNA mutation. Most of the previous studies have been based on single case/family reports or series with few patients. The primary aim of this study was the characterization of a large cohort of patients with the 8344A>G mutation. The secondary aim was revision of the previously published data. METHODS: Retrospective, database-based study (Nation-wide Italian Collaborative Network of Mitochondrial Diseases) and systematic revision. RESULTS: Forty-two patients carrying the mutation were identified. The great majority did not have full-blown MERRF syndrome. Myoclonus was present in 1 of 5 patients, whereas myopathic signs and symptoms, generalized seizures, hearing loss, eyelid ptosis, and multiple lipomatosis represented the most common clinical features. Some asymptomatic mutation carriers have also been observed. Myoclonus was more strictly associated with ataxia than generalized seizures in adult 8344A>G subjects. Considering all of the 321 patients so far available, including our dataset and previously published cases, at the mean age of approximately 35 years, the clinical picture was characterized by the following signs/symptoms, in descending order: myoclonus, muscle weakness, ataxia (35%-45% of patients); generalized seizures, hearing loss (25%-34.9%); cognitive impairment, multiple lipomatosis, neuropathy, exercise intolerance (15%-24.9%); and increased creatine kinase levels, ptosis/ophthalmoparesis, optic atrophy, cardiomyopathy, muscle wasting, respiratory impairment, diabetes, muscle pain, tremor, migraine (5%-14.9%). CONCLUSIONS: Our results showed higher clinical heterogeneity than commonly thought. Moreover, MERRF could be better defined as a myoclonic ataxia rather than a myoclonic epilepsy. PMID- 23635964 TI - Cervical artery dissection: trauma and other potential mechanical trigger events. AB - OBJECTIVE: To examine the import of prior cervical trauma (PCT) in patients with cervical artery dissection (CeAD). METHODS: In this observational study, the presence of and the type of PCT were systematically ascertained in CeAD patients using 2 different populations for comparisons: 1) age- and sex-matched patients with ischemic stroke attributable to a cause other than CeAD (non-CeAD-IS), and 2) healthy subjects participating in the Cervical Artery Dissection and Ischemic Stroke Patients Study. The presence of PCT within 1 month was assessed using a standardized questionnaire. Crude odds ratios (ORs) with 95% confidence intervals (CIs) and ORs adjusted for age, sex, and center were calculated. RESULTS: We analyzed 1,897 participants (n = 966 with CeAD, n = 651 with non-CeAD-IS, n = 280 healthy subjects). CeAD patients had PCT in 40.5% (38.2%-44.5%) of cases, with 88% (344 of 392) classified as mild. PCT was more common in CeAD patients than in non-CeAD-IS patients (ORcrude 5.6 [95% CI 4.20-7.37], p < 0.001; ORadjusted 7.6 [95% CI 5.60-10.20], p < 0.001) or healthy subjects (ORcrude 2.8 [95% CI 2.03 3.68], p < 0.001; ORadjusted 3.7 [95% CI 2.40-5.56], p < 0.001). CeAD patients with PCT were younger and presented more often with neck pain and less often with stroke than CeAD patients without PCT. PCT was not associated with functional 3 month outcome after adjustment for age, sex, and stroke severity. CONCLUSION: PCT seems to be an important environmental determinant of CeAD, but was not an independent outcome predictor. Because of the characteristics of most PCTs, the term mechanical trigger event rather than trauma may be more appropriate. PMID- 23635965 TI - Motor neuron involvement in multisystem proteinopathy: implications for ALS. AB - OBJECTIVE: To explore the putative connection between inclusion body myopathy, Paget disease, frontotemporal dementia (IBMPFD) and motor neuron disease (MND). METHODS: Clinical, genetic, and EMG characterization of 17 patients from 8 IBMPFD families. RESULTS: Limb weakness was the most common clinical manifestation (present in 15 patients, median onset age 38 years, range 25-52), with unequivocal evidence of upper motor neuron dysfunction in 3. EMG, abnormal in all 17, was purely neurogenic in 4, purely myopathic in 6, and mixed neurogenic/myopathic in 7. Cognitive/behavioral impairment was detected in at least 8. Mutations in VCP (R155H, R159G, R155C) were identified in 6 families, and in hnRNPA2B1 (D290V) in another family. The genetic cause in the eighth family has not yet been identified. CONCLUSION: Mutations in at least 4 genes may cause IBMPFD, and its phenotypic spectrum extends beyond IBM, Paget disease, and frontotemporal dementia (FTD). Weakness, the most common and disabling manifestation, may be caused by muscle disease or MND. The acronym IBMPFD is, therefore, insufficient to describe disorders due to VCP mutations or other recently identified IBMPFD-associated genes. Instead, we favor the descriptor multisystem proteinopathy (MSP), which encompasses both the extended clinical phenotype and the previously described prominent pathologic feature of protein aggregation in affected tissues. The nomenclature MSP1, MSP2, and MSP3 may be used for VCP-, HNRNPA2B1-, and HNRNPA1-associated disease, respectively. Genetic defects in MSP implicate a range of biological mechanisms including RNA processing and protein homeostasis, both with potential relevance to the pathobiology of more common MNDs such as amyotrophic lateral sclerosis (ALS) and providing an additional link between ALS and FTD. PMID- 23635966 TI - Multifocal VZV vasculopathy with temporal artery infection mimics giant cell arteritis. AB - OBJECTIVE: To address the incidence of varicella-zoster virus (VZV) infection in patients with biopsy-negative giant cell arteritis (GCA), we examined archived biopsy-negative temporal arteries from subjects with clinically suspected GCA for the presence of VZV antigen. METHODS: Formalin-fixed, paraffin-embedded temporal arteries that were pathologically negative for GCA and normal temporal arteries were analyzed immunohistochemically for VZV and herpes simplex virus-1 (HSV-1) antigen. RESULTS: Five (21%) of 24 temporal arteries from patients who were clinically suspect but biopsy negative for GCA revealed VZV but not HSV-1 by immunohistochemical analysis. Thirteen normal temporal arteries did not contain VZV or HSV-1 antigen. All 5 subjects whose temporal arteries contained VZV antigen presented with clinical and laboratory features of GCA and early visual disturbances. CONCLUSION: Multifocal VZV vasculopathy can present with the full spectrum of clinical features and laboratory abnormalities characteristically seen in GCA. PMID- 23635968 TI - Root canal length determination by different methods in primary teeth: an in vivo study. AB - PURPOSE: To evaluate and compare the accuracy of root canal lengths (RCLs) in primary teeth using different clinical methods. METHODS: RCLs of 70 extracted human primary single-rooted teeth were estimated in vivo by a calibrated investigator using the electronic apex locator (EAL) method, radiovisiography (RVG), conventional radiography (X-ray), and tactile sensation method (TSM). The teeth were categorized into Group 1 (G1; teeth without physiological root resorption [PRR]); Group 2 (G2; teeth with one-fourth apical PRR); and Group 3 (G3; teeth with one-fourth to three-fourths lingual PRR). RCLs determined by various in vivo methods were compared with the ex vivo actual root canal length method (ARCL), as determined by stereo-microscope. Data obtained were compared using analysis of variance, Newman-Keuls test, and Student's test. RESULTS: In Groups 1 and 2, the mean RCL determined by EAL was closest to that of the gold standard ARCL, followed by RVG, X-ray, and TSM. In G3, the mean RCL determined by EAL was closest to ARCL, followed by TSM, RVG, and X-ray. CONCLUSION: A fifth generation electronic apex locator was found to be useful in accurately determining root canal lengths of primary teeth with or without physiological root resorption. PMID- 23635967 TI - Interrater reliability of the new criteria for behavioral variant frontotemporal dementia. AB - OBJECTIVE: To evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD). METHODS: Twenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by kappa statistics for multiple raters with categorical ratings. RESULTS: The mean kappa value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD ("almost perfect agreement"). Interrater reliability for 4 of the 6 core features had "substantial" agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; kappa = 0.61-0.80), whereas 2 had "moderate" agreement (apathy/inertia, neuropsychological; kappa = 0.41-0.6). Clinician years of experience did not significantly influence rater accuracy. CONCLUSIONS: The FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important. PMID- 23635969 TI - Design and preliminary validation of the verbal skill scale in the dental setting: an anxiety scale for children. AB - PURPOSE: The purpose of this study was to design and examine the validity of a scale that uses the verbal performance of children as an indicator of dental anxiety. METHODS: A total of 128 healthy 4- to 6-year-olds were included. The first sessions consisted of a dental examination; in the second session, identical dental treatment was provided to all subjects. In each session, a short communication was done for verbal assessment. During treatment, Frankl and clinical anxiety rating scales were utilized to assess the child's anxiety. Construct validity was assessed using Spearman's correlation coefficient; a factor analysis, concurrent validity, and inter-rater reliability were determined by kappa agreement statistics. Chi-square and Fisher's exact tests were used to assess the difference between sexes. RESULTS: The agreement between the raters was high and significant (k=0.71, P<.001). Intraclass correlation coefficient of 50 same children (28 boys and 22 girls) across a 2-week period showed a strong correlation (correlation=0.8, P<.001). Spearman's correlation coefficient revealed a high and significant correlation between the measures (P<.001). The kappa values ranged from 0.58 to 0.67, suggesting moderate to good agreement between measures. CONCLUSIONS: The verbal skill scale is a reliable and valid measure of assessing child dental anxiety in a clinical context. PMID- 23635970 TI - Advocacy practices among U. S. pediatric dentists. AB - PURPOSE: Advocacy is the primary mission of the American Academy of Pediatric Dentistry (AAPD), but members' participation in advocacy is not well known. The purpose of this study was to examine advocacy by AAPD members and their attitudes toward various advocacy-related activities. METHODS: An Internet-based questionnaire, e-mailed to 4,328 AAPD members via Survey Monkey, consisted of 19 questions on: demography; advocacy training; attitudes toward advocacy; and past, recent, and current advocacy practices. RESULTS: A total of 1,046 respondents provided a 25% response rate. Ninety percent supported advocacy as a role for pediatric dentists. Two-thirds felt prepared for advocacy, but only 22% had training in residency. Participation in clinical advocacy was the most common activity, but most respondents reported local oral health promotion and promotion of oral health with other professionals. Approximately half or fewer reported participation in political action or lobbying. Pediatric dentists out of training longer were more likely to participate in advocacy as were male pediatric dentists. CONCLUSIONS: American Academy of Pediatric Dentistry members support the advocacy role of pediatric dentists and participate in a wide range of advocacy activities. PMID- 23635972 TI - Effects of different combinations of fused primary teeth on eruption of the permanent successors. AB - PURPOSE: The fusion of primary teeth may be associated with the absence of 1 of the 2 permanent successors. Moreover, even if both successors erupt, developmental disturbances such as microdontia or delayed tooth formation may occur. The purpose of this study was to elucidate the effects of different combinations of fused primary teeth on the eruption of permanent successors. METHODS: One hundred ninety-seven children with 247 fused primary teeth were examined. Combinations of primary teeth involved in the fusion were identified, and the effects of these different combinations on the presence, morphology, and eruption of the permanent successors were determined. RESULTS: Three types of fusion in the primary teeth were identified: (1) between the maxillary central and lateral incisors (UCI/LI); (2) between the mandibular central and lateral incisors (LCI/LI); and (3) between the mandibular lateral incisor and canine (LLI/C). The results revealed an absence of the successional lateral incisor in 65% of UCI/LI cases and 74% of LLI/C cases, whereas only 16% of LCI/LI cases resulted in a missing successor. CONCLUSIONS: Fused primary teeth are highly correlated with the absence of permanent teeth, and the prevalence depends on the combination of fused primary teeth. PMID- 23635971 TI - Treatment of periodontitis as a manifestation of neutropenia with or without systemic antibiotics: a systematic review. AB - The purposes of this paper were to systematically review the clinical presentations and management of periodontitis patients with neutropenia and present a patient with severe autoimmune neutropenia. Twenty-four case reports describing a total of 33 patients were identified. The reported signs and symptoms occurred in either a generalized or localized pattern. Improvements in periodontal condition were observed in 86% of patients who were administered adjuvant systemic antibiotics compared to 47% of patients who were not given supplemental therapy. Granulocyte-colony stimulating factor was administered to 67% of the neutropenic patients, and both improvement and progression of the hematological condition were monitored. Scaling and root planing, in combination with systemic antibiotics to supplement therapy for the underlying disease, have been successful in most cases. PMID- 23635973 TI - Oral literacy demand of preventive dental visits in a pediatric medical office: a pilot study. AB - PURPOSE: The purpose of this study was to examine the oral literacy demands placed on parents of young children during preventive dental visits in a pediatric medical office. METHODS: Transcripts of audio recordings for 15 pediatric medical visits were analyzed to assess the oral literacy demand of the visit, as measured by use of terminology, language complexity, and structural characteristics of the dialogue. Parent-completed surveys were used to determine recall of dental concepts discussed during the visit. Pearson's correlation coefficients were calculated to identify relationships among these measures and parental recall of the visit. RESULTS: Visits were interactive and used limited jargon and uncomplicated language. Oral literacy demand measures were associated with each other. Parental recall of the visit was associated with measures of high oral literacy demand. CONCLUSIONS: Assessing measures of oral literacy demand is a novel method for examining provider communication used during preventive dental visits in a pediatric medical office. Providers displayed low oral literacy demand when communicating with parents. Parental recall of dental concepts, however, was associated unexpectedly with higher oral literacy demand. Further research should examine a larger sample size and the effect of measures of oral literacy demand among low- and high-literacy patients. PMID- 23635974 TI - Oral changes stemming from hemangioma of the tongue. AB - Hemangiomas are among the most common tumors found in children and are characterized by an excess of blood vessels. They most often affect the area of the head and neck, occur with greater frequency among women and Caucasians, and can be found in the oral cavity-especially on the lips, tongue, or mucosa. Clinically, hemangiomas present as asymptomatic red or blue-colored lesions that grow rapidly and are capable of spontaneous regression. When they are found on the tongue, they can result in clinical problems as well as recurrent trauma due to biting of the tongue and tooth-brushing, resulting in bleeding, obstruction of the upper airways, and difficulty with chewing, deglutition, and speaking. The purpose of this article was to present a case study of a 4-year-old child with a diagnosis of hemangioma of the tongue, emphasizing the oral changes found as a result of this lesion, as well as the dental treatment used to minimize these changes. PMID- 23635975 TI - Epidemiology of traumatic dental injuries. AB - The oral region comprises 1% of the total body area, yet it accounts for 5% of all bodily injuries. In preschool children, oral injuries make up as much as 17% of all bodily injuries. The incidence of traumatic dental injuries is 1%-3%, and the prevalence is steady at 20%-30%. The annual cost of treatment is US $2-$5 million per 1 million inhabitants. Etiologic factors vary between countries and with age groups. Important public health implications such as how to best organize emergency dental care and how to prevent dental injuries, decrease cost, and increase lay knowledge are important factors needed to change epidemiologic data toward more favorable figures in the future. PMID- 23635976 TI - Dental trauma guidelines. AB - Guidelines have been developed for management of numerous medical and dental conditions. If carefully developed and based on best available evidence, they serve a very useful purpose in giving information in dealing with health problems to health care providers as well as patients. The history of trauma guidelines is quite limited, but the American Association of Endodontists has been involved since the 1980s. In recent years, the International Association of Dental Traumatology has developed guidelines for management of traumatic dental injuries, with input from specialists in all relevant disciplines of dentistry. These guidelines, first developed and published in 2001 and updated twice since then, have been accepted as reliable recommendations for the urgent care of traumatic dental injuries; the most recent trauma guidelines were completed by the International Association of Dental Traumatology and published in 2012. The application of these guidelines is to provide both patients and practitioners with the best available information about management of such injuries. As with most guidelines, there are limitations that are primarily related to the level of evidence available, which is low. However, they are useful and, when followed, can lead to better outcomes than when no guidelines are used. PMID- 23635978 TI - Pulp and periradicular testing. AB - Pulp and periradicular testing is crucial to the initial trauma evaluation and to subsequent monitoring of the traumatized teeth and supporting structures. An accurate diagnosis serves as the basis for therapeutic intervention and helps to ensure that destruction of the dental structures will be minimized and function will be regained. The purpose of this review is to present the current best evidence for accurate diagnostic testing of the pulp and periapex of traumatized teeth. Five databases were searched for literature pertaining to pulpal testing and trauma. Widely recognized textbooks were also consulted. Currently used pulp vitality testing is constrained by its subjective character and by the fact that it is a measure of neuronal status and not true pulpal viability. Tests that measure tissue perfusion more accurately reflect pulpal vitality, but they are not available commercially. This review discusses the specificity, sensitivity, and accuracy of commonly used tests, with emphasis on the applicability of certain tests to specific patient presentations in trauma. Factors that influence test selection are discussed, and specific recommendations are made on the basis of best evidence. Although differences exist between the various studies as to the accuracy of commonly used pulpal and periradicular tests, most of these have acceptable predictive value. Pulpal and periradicular tests in the trauma patient should be used in conjunction with clinical and radiographic observations to arrive at a diagnosis and treatment plan. PMID- 23635977 TI - Rapid physical assessment of the injured child. AB - Traumatic injuries that involve the dentition and maxillofacial region may occur as isolated events in pediatric patients but are often associated with multisystem injuries and traumatic brain injuries. The primary trauma survey serves to identify and treat life-threatening injuries. The secondary trauma survey is a complete examination of the patient after the stabilization of physiological parameters. Frequent neurologic and physical assessments of the injured child are crucial to preventing deterioration. The role of the dental professional is to identify and refer for medical evaluation patients who present with concerning neurologic signs and symptoms after traumatic injuries to the maxillofacial region. PMID- 23635979 TI - Contemporary management of horizontal root fractures to the permanent dentition: diagnosis--radiologic assessment to include cone-beam computed tomography. AB - Historically, obtaining several periapical radiographs has been recommended to diagnose horizontal root fractures. Assessing the 3-dimensional orientation of a fracture is correlated to treatment and outcome. However, conventional radiography yields only limited information for accurate diagnosis. Cone-beam computed tomography (CBCT) is a relatively new and useful technology, which provides an auxiliary imaging modality to supplement conventional radiography for evaluating horizontal root fractures. Despite the increasing application of this technology as well as a growing body of evidence supporting its value in diagnosing horizontal root fractures, there are no specific guidelines for its use. This article aimed to provide such preliminary guidelines for cases of suspected horizontal root fracture as a result of trauma. From a database search it was concluded that CBCT is most useful in cases in which conventional radiography yields inconclusive results or shows a fracture in the middle third of a root. In such cases CBCT may rule out false negatives, ie, a suspected root fracture not visualized with conventional radiography. For a root fracture in the middle third, CBCT may rule out or confirm an oblique course of fracture involving the cervical third in the labiolingual dimension. Although there are considerable advantages when CBCT is included in the assessment of horizontal root fracture and its possible sequelae, more experimental and clinical studies are warranted to determine the exact impact on outcomes. PMID- 23635980 TI - Treatment options: apexogenesis and apexification. AB - This article will describe requirements for case selection and review the procedures for apexogenesis and apexification in immature permanent teeth. Nonclinical and clinical data will be presented to support the recommendations, and outcomes will be presented from clinical studies. The dental pulp is an ectomesenchymally derived connective tissue with certain unique properties such as being encased in hard tissues, which limits its collateral circulation. The pulp provides a matrix for binding of its cells and provides support allowing communication between the cells. In addition to immune cells, the dental pulp contains odontoblasts, which are specialized cells capable of producing dentin. In the absence of a vital pulp, dentin deposition is arrested. When an immature tooth is affected by caries or trauma, the pulp requires proper management according to the degree of inflammation and its vitality. Maintenance of pulp vitality will allow continued root development along the entire root length. If the pulp is irreversibly inflamed or necrotic, root-end closure procedures are required when the apex has not fully formed. PMID- 23635981 TI - Treatment options: biological basis of regenerative endodontic procedures. AB - Dental trauma occurs frequently in children and often can lead to pulpal necrosis. The occurrence of pulpal necrosis in the permanent but immature tooth represents a challenging clinical situation because the thin and often short roots increase the risk of subsequent fracture. Current approaches for treating the traumatized immature tooth with pulpal necrosis do not reliably achieve the desired clinical outcomes, consisting of healing of apical periodontitis, promotion of continued root development, and restoration of the functional competence of pulpal tissue. An optimal approach for treating the immature permanent tooth with a necrotic pulp would be to regenerate functional pulpal tissue. This review summarizes the current literature supporting a biological rationale for considering regenerative endodontic treatment procedures in treating the immature permanent tooth with pulp necrosis. PMID- 23635982 TI - Considerations for regeneration procedures. AB - When pulp tissue becomes necrotic in immature teeth, the prognosis of the teeth is compromised. Disinfection of the root(s) presents several challenges including difficulties in cleaning and shaping large canals with open apices, obturation of canals with open apices, and potential root fractures caused by thin and/or weakened root walls. Regenerative endodontic procedures may increase the prognosis of the compromised immature tooth by re-establishment of a functional pulp tissue that fosters continued root development and immune competency. This article reviews the literature related to and discuss considerations for regenerative endodontic procedures and how these procedures may increase the prognosis for immature teeth with necrotic pulp tissue. PMID- 23635983 TI - Root fortification. AB - An incompletely formed tooth is left with thin dentin walls and experiences a higher incidence of cervical root fracture that reduces the long-term overall prognosis of the tooth. Faced with these situations, clinicians have attempted to use various restorative methods to reinforce the remaining root. Various techniques have been reported, and the scientific evidence for each has been reviewed. The biomechanical considerations of reinforcing a weakened root are also reviewed, and the most current information about failure analysis, fracture characteristics of natural dentin, and in vitro test configurations used have been considered. In light of these additional considerations, some recommendations for future understanding of this complex problem have been proposed. PMID- 23635984 TI - Outcomes. AB - Outcomes encompass multiple factors, not just success and failure. They include other considerations such as being workable and profitable to the dentist and safe and acceptable to the patient. The more biological outcomes are most frequently measured. These measurements are on a scale from least to most predictable outcomes of treatment by the dentist, as shown on the evidence pyramid. Impact trauma is an example of a general scarcity of high-level evidence with treatment because of the nature and individuality of the injuries and the difficulty (or impossibility) of designing controlled clinical trials in humans. Much of the evidence is cohort (retrospective or observational studies), case reports, animal studies, and "expert" opinion. Thus, guidelines are largely based on lower levels of evidence. Nonetheless, the current guidelines provide the clinician with the best evidence that is available. The best opportunity for randomized controlled trials is in prevention. Specifically, mouthguard design and usage can be subjected to higher levels of controlled research. Revitalization and regeneration are relatively new procedures. To date, there is a lack of high levels of evidence to be able to substantiate whether these are clinically feasible to become a routine in practice. PMID- 23635985 TI - Ridge preservation/decoronation. AB - Dentoalveolar ankylosis of a tooth is a serious complication in growing individuals. The ankylosed root is continuously resorbed and replaced by bone, and an infraposition of the damaged tooth will develop. The normal alveolar development will be disrupted in this way, and prosthetic treatment will be compromised. Therefore, an ankylosed tooth should be removed before future orthodontic and/or prosthetic therapy is jeopardized. This article will present a method, decoronation, to remove an ankylosed tooth in such a way that the alveolar ridge is preserved and give guidelines for the timing to intervene. The decoronation method is described, and a possible explanation for the favorable outcome is discussed. Different aids to decide the time for intervention are presented. The alveolar ridge was maintained in buccal/palatinal direction, and the bone level increased after decoronation in patients treated before or during pubertal growth periods. The bone level also increased in those treated after this period but not at the same rate, and in a few patients it was unchanged. The clinical finding that decoronation can maintain or reestablish normal alveolar conditions is important for successful implant insertion later. PMID- 23635986 TI - Management of child patient behavior: quality of care, fear and anxiety, and the child patient. AB - Behavior management is a key component when providing dental care to children who have suffered traumatic dental injuries. This article reviews the current status of behavior management including basic communication techniques and advanced techniques used by pediatric dentists. Emphasis is given to oral and inhalation sedation when treating children at initial visits status post dental injury. Little is known about the use of pharmacologic agents in managing young but behaviorally challenging patients who have suffered dental trauma. Future care involving sedation and specialized endodontic procedures of these young patients through collaborative efforts between endodontists and pediatric dentists seems promising and should be pursued. PMID- 23635987 TI - Orthodontic procedures after trauma. AB - This review considers oral trauma and its relationship to orthodontics with respect to prevention and primary, secondary, and tertiary care. The level of evidence is not high in regard to this topic, but recommendable approaches to trauma at each stage are discussed on the basis of available literature and published guidelines. Simplified biomechanics are presented to aid treatment. PMID- 23635989 TI - AAPD and AAE symposium overview: Contemporary management of traumatic injuries to the permanent dentition. PMID- 23635988 TI - Evidence-based review of prevention of dental injuries. AB - Despite efforts in reducing the number of dental traumas, most current studies indicate that the incidence of dental trauma remains unchanged and is at a relatively high level for children and young adults. When reviewing the literature on prevention, it is clear that until now the main focus has been on making and promoting mouthguards. The majority of the published studies on mouthguards have focused on materials used and how those behave and protect in vitro. The few epidemiologic studies that have been published on the possible protectiveness of the mouthguards in vivo are mostly of low level of evidence, and even those studies do not all agree on how much they actually protect the dentition. To compound the problem is the fact that the proportional ratio of dental trauma in organized sports is low compared with injuries that occur during children's play or leisure activities. It could be argued that the best strategic measure for preventing dental and oral injuries is education on both how to avoid them and what to do if an injury occurs. The demand of evidence-based dentistry and medicine calls for large prospective studies with randomized intervention to investigate the actual protection of mouthguards and faceguards. In addition, more emphasis should be placed on which is the best and most constructive way to educate youngsters and teenagers on how to avoid traumatic injuries to their teeth by using contemporary means like the Internet and apps. PMID- 23635991 TI - Synergetic and antagonist muscle strength and activity in women with knee osteoarthritis. AB - BACKGROUND AND PURPOSE: People with knee osteoarthritis (OA) display limitations in daily activities and a lower quality of life. The purpose of this study was to investigate the differences in strength balance and activation during maximum strength efforts between women with knee OA and asymptomatic women. METHODS: Twelve women with knee OA (age 60.33 +/- 6.66 years) and 11 controls (age 56.54 +/- 5.46 years) performed maximum isokinetic eccentric and concentric knee extension and flexion tests at 60 degrees /s, 120 degrees /s, and 150 degrees /s. Surface electromyography (EMG) was recorded from the biceps femoris (BF), vastus lateralis (VL), and vastus medialis (VM). Hamstrings-to-quadriceps moment ratios (H/Q), the synergetic (VL/VM), and co-contraction (BF/[VM + VL]) EMG ratios were calculated. RESULTS: Analysis-of-variance designs showed that women experiencing knee OA had significantly higher H/Q moment ratios and VM/VL EMG ratios than controls (P < 0.05). The co-contraction index was significantly lower in the OA group only during knee flexion (P < 0.05). CONCLUSIONS: Women with knee OA showed a higher H/Q moment ratios probably because of the need for better joint stability or a lower quadriceps capacity. This deficiency was accompanied by a higher VM activation, which probably serves to stabilize the patella upon maximum contraction as well as a higher activation of antagonist muscles. PMID- 23635990 TI - Aging does not affect radial viscoelastic behavior of the left ventricle. AB - OBJECTIVES: This study investigates the effect of aging on the radial viscoelastic behavior of the left ventricle (LV) based on a previously validated model that uses myocardial tissue phase mapping (TPM) of cine phase-contrast MRI. METHODS: Previous studies suggest that aging remarkably influences regional myocardial motion, mostly myocardial velocities in both radial and long-axis directions. However, the effect of aging on cardiac viscoelasticity, which exhibits time-dependent strain, has not been elucidated yet. In this study, myocardial velocity and displacement mapping of the LV was performed using TPM in 39 healthy subjects divided into three age groups. The viscoelasticity parameters were obtained for each segment of the LV and compared among the studied groups. RESULTS: The analyses showed that myocardial elasticity ranged from approximately 20 to -20 dyne/cm2 during a cardiac cycle, and the myocardial viscous-damping component ranged from -1 to 1 dyne * s/cm2. Overall, no statistically significant difference was observed in the viscoelasticity components among the subjects in the different age groups (p > 0.05). CONCLUSION: Myocardial viscoelastic behavior of the LV in radial direction was found to be considerably similar in pattern and magnitude among the studied subjects of different age groups with no statistically significant difference, despite the fact that the regional myocardial velocities change due to aging. PMID- 23635993 TI - The JPC-SE position statement on asbestos: a long-overdue appeal by epidemiologists to ban asbestos worldwide and end related global environmental injustice. PMID- 23635994 TI - Preoperative testing in non-cardiac surgery patients: a survey amongst European anaesthesiologists. PMID- 23635995 TI - An unnoticed retained cannula fragment in the radial artery: Should ultrasound investigation be included in guidelines? PMID- 23635996 TI - Effects of magnesium sulphate on the pharmacodynamics of rocuronium in patients aged 60 years and older: A randomised trial. AB - BACKGROUND: There is little information on the interaction between magnesium sulphate (MgSO4) and rocuronium in elderly patients. With a growing number of older patients who need surgical procedures, it is increasingly important to study this age group. OBJECTIVE: To evaluate the effects of MgSO4 administration on the pharmacodynamics of rocuronium in patients aged 60 years or older. DESIGN: A randomised controlled trial. SETTING: A tertiary care hospital. PATIENTS: Sixty four patients, aged 60 years or older, American Society of Anesthesiologists (ASA) physical status classes I to III, scheduled for elective oncological head and neck surgery. Exclusion criteria were severe renal insufficiency (calculated creatinine clearance <30 ml min(-1)), preoperatorive serum magnesium concentration of more than 1.25 mmol l(-1) and patients receiving drugs known to affect neuromuscular function. INTERVENTIONS: Patients were randomly allocated to one of two groups: in the magnesium group, patients received MgSO4 30 mg kg(-1) intravenously, for 10 min, and then a continuous intravenous infusion at a rate of 1 g h(-1). The control group received the same volume of physiological saline. Neuromuscular function was evaluated continuously in both groups. MAIN OUTCOME MEASURES: Total recovery time was the primary outcome. Onset time, clinical duration, recovery index and recovery time were considered as secondary endpoints. Values are given as mean [SD]. RESULTS: Total recovery time from neuromuscular block (NMB) was 113 [36] min in the magnesium group and 101 [39] min in the control group. Clinical duration was 69 [23] min in the magnesium group and 59 [28] min in the control group. Recovery index was 19 [36] min in the magnesium group and 17 [6] min in the control group. Recovery time was 44 [22] min in the magnesium group and 42 [18] min in the control group. There were no statistically significant differences between the groups in any of the recovery indices. In the magnesium group, the mean onset time was 144 [58] s, significantly shorter than the onset time in the group that received physiological saline, which was 187 [90] s (P = 0.03). Group variances were compared using an F test: onset time varied significantly less in the magnesium group (P = 0.02). CONCLUSION: In oncology patients of 60 or more years of age, preadministration of MgSO4, with the doses used in this study, significantly reduced the onset time of NMB induced by rocuronium. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01804205. PMID- 23635997 TI - Efficacy of endotoxin adsorption therapy (polymyxin B hemoperfusion) for methicillin-resistant Staphylococcus aureus toxic shock syndrome: a case report about five patients. AB - BACKGROUND: Toxic shock syndrome (TSS), which can be life-threatening, is clinically and pathologically characterized by the presence of high fever, skin rash, desquamation, hypotension, and multiple organ failure caused by an enterotoxin produced by Staphylococcus aureus. In this study, we evaluated the effects of endotoxin adsorption therapy (polymyxin B [PMX] hemoperfusion) in critical patients with methicillin-resistant Staphylococcus aureus TSS (MRSA-TSS) who showed no improvement with the conventional therapy. METHODS: Five MRSA-TSS patients (men/women: 3/2; median age: 39 years) who showed no improvement with the conventional therapy underwent PMX hemoperfusion in addition to the conventional therapy. The primary outcomes were change in the systolic arterial pressure (SAP) and requirement of a vasopressor after PMX hemoperfusion, and the secondary outcomes were change in laboratory data and sequential organ failure assessment (SOFA) scores 24 h after the therapy. RESULTS: The median duration of PMX hemoperfusion was 9 h (range, 4-20 h). SAP significantly increased (from 89 to 125 mmHg, P<0.05) and the requirement of a vasopressor significantly decreased (from 10 to 2, P<0.05) after PMX hemoperfusion. Furthermore, the patients' white blood cell count decreased (from 17640 to 10090 /uL, P<0.05), and SOFA scores decreased (from 13 to 9, P<0.05) after PMX hemoperfusion. All patients recovered and were discharged from the ICU. CONCLUSION: Our results showed that PMX hemoperfusion significantly improved the hemodynamics and severity in patients with life-threatening MRSA-TSS. PMID- 23635998 TI - Hemodynamic changes associated with spinal and general anesthesia for hip fracture surgery in severe ASA III elderly population: a pilot trial. AB - BACKGROUND: Patients affected by hip fracture (HF) have high risk of perioperative complications. Despite regional anesthesia is widely used, hypotension is common and increases the risk of myocardial ischemia. The aim of this work was to study hemodynamic changes following spinal (SA) and general (GA) anesthesia in this selected population of patients. METHODS: Twenty patients over 70 years, ASA III, scheduled for HF repair were randomized to receive SA or general anesthesia GA. Hemodynamic responses to SA and GA were analyzed trough LiDCOTMplus monitor (LiDCO Ltd., Cambridge, UK). RESULTS: SA provided a more stable hemodynamic profile. SA group received less interventions to keep mean arterial pressure (MAP) within limits. GA group had intraoperative cardiac index (CI), stroke volume index (SVI) and MAP significantly lower than baseline. Despite both groups experienced hypotension after the induction, MAP reduction in SA group was primarily due to systemic vascular resistance index (SVRI) decline, whereas hypotension in GA group was primarily due to a reduction in SVI and CI. The coefficient of variation (CV) was significantly higher in GA group for CI, SVI, MAP and heart rate (HR) within one hour analysis comparing to SA group. SA group had an higher CV for SVRI. CONCLUSION: SA in the elderly population with hip fracture provides a more stable hemodynamic profile requiring less intervention to keep MAP close to baseline value. Hypotension was common in SA and GA after induction and within intraoperative period. A larger randomized clinical study should be performed to confirm these preliminary data. PMID- 23636000 TI - Perioperative management of Wilson disease for therapeutic abortion: a report. PMID- 23635999 TI - Effect of angiotensin converting enzyme gene I/D polymorphism and its expression on clinical outcome in acute respiratory distress syndrome. AB - BACKGROUND: The role of the D allele of the angiotensin-converting enzyme (ACE) gene I/D polymorphism in the clinical outcomes of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) remains controversial. Our aim was to assess simultaneously the effect of the ACE I/D polymorphisms as well as the serum and BALF ACE levels on prognosis of patients with ARDS. METHODS: Sixty nine mechanically ventilated patients with ALI/ARDS were recruited. ACE activity levels both in serum and BALF were assessed by chemical methods. Patients were genotyped for ACE I/D polymorphisms. Time-to-event analysis evaluated the variables associated with the 28-day and 90-day mortality. Finally, we performed a meta-analysis of studies examining the association between ACE I/D polymorphisms and mortality of ALI/ARDS patients. RESULTS: In the multivariable model, age, lung compliance, serum lactate and serum ACE levels were significantly associated with both 28- and 90-day mortality. No significant correlation was found between serum and BALF ACE levels (Spearman's rho=0.054; P=0.66). Serum ACE concentrations were significantly higher (P=0.046) in patients with D/D genotype versus the two other groups combined (I/D and I/I genotypes). The meta-analysis of 6 studies (including ours) provided evidence that D allele is significantly associated with increased mortality in ALI/ARDS patients, yielding a per-allele odds ratio of 1.76 (95% CI: 1.19, 2.59). CONCLUSION: Serum ACE levels appear to be affected by the I/D polymorphism and are correlated with prognosis in patients with ALI/ARDS indicating that further investigation of the clinical significance of the ACE in ARDS might be of value. PMID- 23636001 TI - Increased carotid intima-media thickness and plasma homocysteine levels predict cardiovascular and all-cause death: a population-based cohort study. AB - BACKGROUND: There is still debate over the utility of carotid intima-media thickness (C-IMT) or carotid plaque in predicting future cardiovascular events and death. Additionally, the importance of plasma homocysteine levels was raised as a predictor of cardiovascular events and death. METHODS: 1,391 subjects were recruited from the Ansan Geriatric cohort. We used B-mode carotid ultrasonography to assess C-IMT and plaque, measuring average maximal IMT and average mean IMT through 6-8 measurements of far-wall IMT in both common carotid arteries. We evaluated the presence of plaque in carotid segments. Multivariable Cox regression analysis was used to predict both cardiovascular and all-cause mortality. RESULTS: During a mean follow-up of 62.4 +/- 12.4 months, 71 subjects (5.12%) died and 23 (1.66%) died of cardiovascular causes. Multivariable Cox regression analysis found the predictors of cardiovascular mortality to be average maximal IMT (HR = 3.709; 95% CI: 1.202-11.446) and plasma homocysteine (HR = 1.057; 95% CI: 1.012-1.103). All-cause mortality was independently associated with C-IMT (average maximal and average mean IMT) and plasma homocysteine. CONCLUSIONS: C-IMT and plasma homocysteine levels were found to predict cardiovascular and all-cause mortality independently of the presence of carotid plaque and other cardiovascular risk factors. PMID- 23636002 TI - Risk of metabolic bone disease is increased both during and after weaning off parenteral nutrition in pediatric intestinal failure. AB - AIM: To assess bone health in pediatric intestinal failure (IF). METHODS: A population-based cohort of 41 IF patients (age 9.9 years) underwent evaluation of bone mineral density (BMD), bone biochemistry, nutritional status and growth. Eleven patients remained on parenteral nutrition (PN) after 69 months. Thirty had weaned off PN 9.0 years earlier (mean), i.e. after 30 months on PN. RESULTS: The majority of patients had lumbar spine or femoral BMD Z-score <=-1.0 (70%), vitamin D deficiency (serum 25-hydroxyvitamin-D, S-25-OHD, <50 nmol/l, 41%) or secondary hyperparathyroidism (plasma parathyroid hormone >47 ng/l, 44%), equally during and after weaning off PN. Hyperparathyroidism was absent when S-25-OHD was >80 nmol/l. Until puberty, height (-1.4 to -0.8, age 1-12) and weight Z-scores ( 1.3 to -0.5, age 1-16) were below the normal mean (p < 0.05). Small bowel length associated with S-25-OHD levels (r = 0.489, p = 0.013). In a multivariate model, time after weaning off PN (beta = -0.597, p = 0.001), duration of PN (beta = 0.466, p = 0.006) and calcium intake (beta = -0.331, p = 0.035) predicted decreased lumbar spine BMD. CONCLUSIONS: In pediatric IF, vitamin D insufficiency, secondary hyperparathyroidism and decreased BMD are common. BMD, vitamin D, calcium and nutritional status should be closely monitored during and after weaning off PN to ensure sufficient vitamin D and mineral substitution for normal growth and bone mass attainment. PMID- 23636004 TI - Executive functions of sedentary elderly may benefit from walking: a systematic review and meta-analysis. AB - OBJECTIVE: The goal of the present meta-analysis was to address studies that examined the relationship between walking as one of the most prevalent types of leisure-time activity and executive function being a higher-order cognitive function essential for independent functioning. METHODS: The following data sources were used: English-language publications in PubMed, EMBASE, PsycINFO, Cinahl, and Cochrane; the last search took place in January 2012. From these data sources, only randomized controlled trials including older people with (N = 3) and without (N = 5) cognitive impairment were selected. RESULTS: Walking has been shown to improve set-shifting and inhibition in sedentary older persons without cognitive impairment (d = 0.36; 95% confidence interval: 0.16-0.55; z = 3.56; p <0.0001). In older persons with cognitive impairment, walking did not show improvements in executive functioning (d = 0.14; 95% confidence interval: -0.36 0.64; z = 0.35; p = 0.56). CONCLUSION: This finding is clinically relevant because participation in a walking program may prevent or postpone a (further) decline in executive function in those who are sedentary. PMID- 23636003 TI - Are apathy and depression independently associated with longitudinal trajectories of cortical atrophy in mild cognitive impairment? AB - OBJECTIVES: To examine whether depression and apathy are independently associated with longitudinal trajectories of cortical atrophy in the entorhinal cortex compared with frontal subregions previously implicated in late-life mood disturbance. METHODS: Data from 334 participants classified as having mild cognitive impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed by using multilevel models for change adjusted for age, global cognitive status, and total intracranial volume at enrollment. Participants in ADNI were recruited from >50 clinical research sites in the United States and Canada. Depression and apathy were identified by informants using the Neuropsychiatric Inventory Questionnaire. Serial magnetic resonance imaging was performed on 1.5-Tesla scanners according to the standardized ADNI-1 protocol on an average of 5 occasions over an average of 30.5 months. Regional cortical thickness values were derived from longitudinal data processing in FreeSurfer version 4.4. RESULTS: Depression was associated with reduced cortical thickness in the entorhinal cortex at baseline and accelerated atrophy in the anterior cingulate cortex. Similar relationships between depression and the orbitofrontal cortex and between apathy and the anterior cingulate cortex were not significant. CONCLUSIONS: In mild cognitive impairment, depression signs are a better marker of longitudinal cortical atrophy than apathy. Results are consistent with hypotheses that depression is an early sign of a more aggressive neurodegenerative process or that depression lowers brain reserve capacity, allowing for more rapid progression of Alzheimer disease neuropathology. PMID- 23636005 TI - The Aurora kinases inhibitor VE-465 is a novel treatment for glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is one of the most common and aggressive types of primary brain tumor. After complete surgical resection combined with radiation and chemotherapy, approximately 10% of patients survive for more than 5 years. Therefore, a novel therapy for GBM is needed. Aurora-A (AURKA) plays important roles in cell cycle regulation, such as centrosome maturation, chromatic separation, bipolar spindle assembly, and mitotic entry. To investigate the effects of AURKA inhibition, three GBM cell lines, including GBM 8401, GBM 8901, and U87-MG cells, were treated with the AURKA inhibitor VE-465. Sensitivities to VE-465, as indicated by 50% inhibitory concentration values for GBM 8401, GBM 8901, and U87-MG cells, were 6, 25, and 19 nM, respectively. Additionally, colony formation of GBM 8401 and GBM 8901 cells was decreased after treatment with the VE-465. VE-465 treatment increased polyploidy and p53 protein expression, and inhibited cell growth in a caspase-independent manner. Taken together, these results suggest that the inhibition of AURKA by a small-molecule inhibitor may have potential to serve as a novel therapeutic approach for GBM. PMID- 23636006 TI - Risk of hypertension in cancer patients treated with sorafenib: an updated systematic review and meta-analysis. AB - Sorafenib, a multi-kinase inhibitor, has been reported to be associated with hypertension (HTN). However, the risk of severe HTN with sorafenib treatment has not been well described. We performed an up-to-date meta-analysis of high-grade HTN in cancer patients treated with sorafenib. Medline databases and the American Society of Clinical Oncology online database of meeting abstracts were searched up to August 2012 for relevant clinical trials. Eligible studies included phase II and III trials of sorafenib in patients with any type of cancer describing events of HTN according to the Common Terminology Criteria for Adverse Events. The summary incidence, relative risk (RR), and 95% confidence intervals (CIs) were calculated. The incidence of sorafenib-associated high-grade (grade 3-4) HTN was 6.0% (95% CI 4.7-7.3) in a total of 4722 patients from 55 trials of sorafenib as a single agent. Sorafenib-treated patients (4878 subjects from 13 randomized trials) had a significantly higher risk of high-grade HTN (RR 3.20 (95% CI 2.19 4.68)). Subgroup analysis revealed a significantly higher RR of high-grade HTN in patients receiving sorafenib as a single agent compared with patients receiving concomitant chemotherapy or immunotherapy (P=0.0076). The incidence of high-grade HTN associated with sorafenib was significantly higher in patients with renal cell carcinoma (RCC) than those with non-RCC cancer (P<0.0001) as well as patients treated with sorafenib for a longer duration than those treated for a shorter duration (P=0.003). The use of sorafenib is associated with a significantly higher risk of high-grade HTN compared with control. PMID- 23636007 TI - Percutaneous transluminal angioplasty for peripheral artery disease confers cardiorenal protection. AB - The effects of percutaneous transluminal angioplasty (PTA) on hemodynamic parameters are not established. We tested the hypothesis that PTA would achieve reductions in hemodynamic and target organ damage (TOD) measures in patients with peripheral artery disease (PAD). We enrolled 56 consecutive PAD patients who were scheduled to undergo elective PTA procedures. Brachial blood pressure (BP), central BP, left ventricular mass index (LVMI) and urinary microalbumin excretion ratio (UACR) were assessed at baseline and follow-up. The ankle-brachial index in the diseased leg significantly improved after the PTA (P<0.001). Compared with the pretreatment levels, brachial and central BPs, the carotid augmentation index (AI) and central augmentation pressure (AP) were significantly reduced after the PTA, as were LVMI and UACR. The change in AI in the PTA group was significantly associated with the extent of change in LVMI (P=0.002) and marginally associated with the change in UACR (P=0.07), independently of other covariates. In conclusion, in patients with PAD, significant reductions in carotid AI were observed by PTA treatment; these changes may be attributable to improvements in measures of cardiac and renal target organ damage. PMID- 23636008 TI - Resistant hypertension: a practical clinical approach. AB - Resistant hypertension (RH) is defined as an uncontrolled office blood pressure (BP) despite the use of at least three antihypertensive drugs. With an increasing prevalence, RH implies in a very high cardiovascular risk and needs a careful clinical approach, aiming to control BP and to reduce its morbidity and mortality. The initial diagnostic approach involves drug adherence checking and the evaluation of antihypertensive scheme, emphasizing the use of diuretics and adequate combination and dosages of the two other drugs, which preferentially reduces cardiovascular risk and promotes prevention/regression of target organ damages. Because of an exaggerated white-coat effect, ambulatory BP monitoring (ABPM) at baseline is mandatory to classify patients into true RH (uncontrolled ambulatory BPs) and white-coat RH (controlled ambulatory BPs), and define initial therapeutic approach. Ideally, the objective is ambulatory BP control, so the treatment follow-up shall be based on ABPM measurements. The treatment involves lifestyle changes and use of adequate combinations of antihypertensive agents from different classes. In this way, patients with true RH need to intensify antihypertensive treatment by adding aldosterone antagonists as the fourth drug and also changing antihypertensive treatment to bedtime. Otherwise, in patients with controlled ambulatory BP, the therapeutic scheme should be maintained and ABPM or home BP monitoring repeated serially. Despite pharmacological interventions, ambulatory BP control in RH patients remains challenging and new interventional procedures have been recently proposed, as renal denervation and baroreflex activation therapy. Currently, these procedures shall be reserved to true RH patients in whom other alternatives have failed. PMID- 23636009 TI - Interpreting treatment-induced blood pressure reductions measured by ambulatory blood pressure monitoring. AB - It is well known that 24-h ambulatory blood pressure monitoring (ABPM) provides a more accurate picture of a patient's blood pressure (BP) compared with clinic BP measurement. Twenty-four-hour ABPM better predicts hypertension-related risks such as end-organ damage including left ventricular hypertrophy, cardiovascular (CV) events and mortality. Threshold BP values for hypertension based on 24-h ABPM results have been established, including daytime and night-time averages. Nevertheless, the relationship between 24-h ABPM and clinic BP measurement in patients on antihypertensive therapy, and in particular how each may change in response to antihypertensive therapy, is less clear. This review will provide an overview of current knowledge on the relation between clinic BP and ambulatory BP reductions in clinical trials on antihypertensive therapies. Reduction in CV risk and its correlation with the magnitude of reduction in both clinic and ambulatory BP are explored. The most striking result is that reduction in clinic BP and ambulatory BP do not correspond in a 1:1 fashion, that is, smaller changes in 24 h ABPM correspond to significantly larger changes in clinic BP. PMID- 23636010 TI - Plasma renin and cardiovascular risk: what is the evidence for an association? AB - Renin is a key component of the renin-angiotensin system (RAS), which plays an important role in the maintenance of blood pressure and electrolyte-volume homeostasis. RAS also plays a role in cardiovascular (CV) disease as a result of effects on inflammation and oxidative stress. There is growing evidence that plasma renin activity may be a marker of CV risk in hypertensive patients. This increase in CV risk likely reflects activation of the RAS as a whole. Patients undergoing treatment for hypertension experience a reactive increase in renin, especially if treated with diuretics, vasodilators or agents that block the RAS. There is not sufficient evidence, however, that this reactive increase in renin is intrinsically harmful for hypertensive patients in whom adequate levels of RAS blockade have been achieved. Indeed, in such patients, additional RAS blockade may not be beneficial and may even increase the risk of adverse events. Plasma renin may be an important prognostic indicator in untreated patients, and one that can be used to help in the choice of antihypertensive treatment. Currently, however, the link between plasma renin and CV risk in treated patients is inconsistent between different populations and in various clinical conditions, calling for further investigation. PMID- 23636011 TI - Bariatric surgery complications leading to small bowel transplant: a report of 4 cases. AB - Obesity is a major chronic disease affecting the U.S. population. Bariatric surgery has consistently shown greater weight loss and improved outcomes compared with conservative therapy. However, complications after bariatric surgery can be catastrophic, resulting in short bowel syndrome with a potential risk of intestinal failure, ultimately resulting in the need for a small bowel transplant. A total of 6 patients became dependent on home parenteral nutrition (HPN) after undergoing bariatric surgery at an outside facility. Four of the 6 patients required evaluation for small bowel transplant; 2 of the 6 patients were successfully managed with parenteral nutrition and did not require further small bowel transplant evaluation. Catheter-related bloodstream infection, a serious complication of HPN, occurred in 3 patients despite extensive patient education on catheter care and use of ethanol lock. Two patients underwent successful small bowel transplantation, 1 died before transplant could be performed, and 1 was listed for a multivisceral transplantation. Surgical procedures to treat morbid obesity are common and growing in popularity but are not without risk of serious complications, including intestinal failure and HPN dependency. Despite methods to prevent complications, failure of HPN may lead to the need for transplant evaluation. In selected cases, the best therapeutic treatment may be a small bowel transplant to resolve irreversible, post-bariatric surgery intestinal failure. PMID- 23636012 TI - Intestinal microbial diversity and perioperative complications. AB - BACKGROUND AND AIMS: Enteral nutrient deprivation via parenteral nutrition (PN) in a mouse model leads to a local mucosal inflammatory response. This proinflammatory response leads to a loss of epithelial barrier function and atrophy of the intestine. Although the underlying mechanisms are unknown, a potential contributing factor is the impact PN has on the intestinal microbiome. We recently identified a shift in the intestinal microbial community in mice given PN; however, it is unknown whether such changes occur in humans. We hypothesized that similar microbial changes occur in humans during periods of enteral nutrient deprivation. METHODS: A series of small bowel specimens were obtained from pediatric and adult patients undergoing small intestinal resection. Mucosally associated bacteria were harvested and analyzed using 454 pyrosequencing techniques. Statistical analysis of microbial diversity and differences in microbial characteristics were assessed between enterally fed and enterally deprived portions of the intestine. Occurrence of postoperative infectious and anastomotic complications was also examined. RESULTS: Pyrosequencing demonstrated a wide variability in microbial diversity within all groups. Principal coordinate analysis demonstrated only a partial stratification of microbial communities between fed and enterally deprived groups. Interestingly, a tight correlation was identified in patients who had a low level of enteric microbial diversity and those who developed postoperative enteric derived infections or intestinal anastomotic disruption. CONCLUSIONS: Loss of enteral nutrients and systemic antibiotic therapy in humans is associated with a significant loss of microbial biodiversity within the small bowel mucosa. These changes were associated with a number of enteric-derived intestinal infections and intestinal anastomotic disruptions. PMID- 23636014 TI - Hypertension-related target organ damage: is it a continuum? PMID- 23636015 TI - Protein intake in type 1 diabetes: putting controversies into perspectives. PMID- 23636013 TI - Cytomorphological factors and BRAF mutation predicting risk of lymph node metastasis in preoperative liquid-based fine needle aspirations of papillary thyroid carcinoma. AB - OBJECTIVE: Preoperative fine needle aspiration biopsy (FNAB) has become the initial diagnostic method for papillary thyroid carcinoma (PTC). Identification of cytomorphologic factors predicting lymph node metastasis (LNM) is clinically important for determining the appropriate treatment regimen due to the high rate of lymph node involvement in PTC at the time of diagnosis. Hobnail features (HF) have previously been described as potential histomorphologic features in the histological examination of PTC. This study evaluated the value of HF as a predictor of LNM. STUDY DESIGN: Histologically confirmed FNABs (n = 111) of papillary thyroid microcarcinoma prepared by the liquid-based method were enrolled. Along with other cytomorphologic parameters, HF were evaluated for their value in predicting LNM. RESULTS: Although HF were closely correlated with cytoplasmic vacuoles of tumor cells and background macrophages (p < 0.05), which were considered diagnostic indicators of PTC with cystic changes, HF were only found to be significantly correlated with LNM (p = 0.008). The BRAF(V660E) mutation was not associated with LNM. All combinations including HF were revealed as stronger predictors of LNM (odds ratios: 2.254-2.524, p < 0.05). CONCLUSIONS: HF, a distinctive cytomorphologic feature, may be used as a factor predicting LNM in preoperative FNAB of PTC. PMID- 23636016 TI - Renal angioplasty for treatment of hypertensive patients with fibromuscular dysplasia. No country for old men. PMID- 23636017 TI - Blood pressure control in the hypertensive population. Is the trend favourable? PMID- 23636018 TI - Positive association between testosterone, blood pressure, and hypertension in women: longitudinal findings from the Study of Health in Pomerania. AB - BACKGROUND: The association between sex hormones and blood pressure (BP) in women has been investigated mostly in cross-sectional studies yielding inconsistent results. METHODS: Data from 1428 women from the population-based Study of Health in Pomerania were used. Associations of total testosterone, androstenedione, sex hormone-binding globulin (SHBG), and free testosterone concentrations with BP and hypertension were analyzed in multivariable cross-sectional and longitudinal regression models in the full sample and stratified by menopausal status. RESULTS: A positive association between total testosterone and BP was revealed in the full sample [SBP: beta per standard deviation (SD) increase: 3.22; pulse pressure (PP): beta per SD increase: 2.30] and among postmenopausal women (DBP: beta per SD increase: 3.33; SBP: beta per SD increase: 7.11; PP: beta per SD increase: 3.77). Longitudinal analyses also showed a positive association between baseline total testosterone and follow-up BP. Furthermore, low total testosterone concentrations were associated with a decreased risk of prevalent hypertension in all women [relative risk (RR) quartile 1 (Q1) vs. Q4, 0.79; 95% confidence interval, CI 0.67-0.94]. Low SHBG was associated with prevalent hypertension in postmenopausal women (RR 1.27; 95% CI 1.06-1.53) and with incident hypertension in the full sample (RR 1.73; 95% CI 1.10-2.75). CONCLUSION: The present population-based study is the first to show a consistent positive association between total testosterone and BP in both, cross-sectional and longitudinal analyses, suggesting high total testosterone as a risk marker of increased BP, as well as prevalent hypertension in women. PMID- 23636019 TI - The difficult art of detecting left ventricular hypertrophy in obesity: not all ECG criteria are created equal. PMID- 23636020 TI - Letter on 'sodium-dependent modulation of systemic and urinary renalase expression and activity in the rat remnant kidney'. PMID- 23636021 TI - Reply: To PMID 23314744. PMID- 23636023 TI - Impact of the diagnostic process on the accuracy of source identification and time to antibiotics in septic emergency department patients. AB - OBJECTIVE: Timely administration of effective antibiotics is important in sepsis management. Source-targeted antibiotics are believed to be most effective, but source identification could cause time delays. OBJECTIVES: First, to describe the accuracy/time delays of a diagnostic work-up and the association with time to antibiotics in septic emergency department (ED) patients. Second, to assess the fraction in which source-targeted antibiotics could have been administered solely on the basis of patient history and physical examination. METHODS: Secondary analysis of the prospective observational study on septic ED patients was carried out. The time to test result availability was associated with time to antibiotics. The accuracy of the suspected source of infection in the ED was assessed. For patients with pneumosepsis, urosepsis, and abdominal sepsis, combinations of signs and symptoms were assessed to achieve a maximal positive predictive value for the sepsis source, identifying a subset of patients in whom source-targeted antibiotics could be administered without waiting for diagnostic test results. RESULTS: The time to antibiotics increased by 18 (95% confidence interval: 12-24) min/h delay in test result availability (n=323). In 38-79% of patients, antibiotics were administered after additional tests, whereas the ED diagnosis was correct in 68-85% of patients. The maximal positive predictive value of signs and symptoms was 0.87 for patients with pneumosepsis and urosepsis and 0.75 for those with abdominal sepsis. Use of signs and symptoms would have led to correct ED diagnosis in 33% of patients. CONCLUSION: Diagnostic tests are associated with delayed administration of antibiotics to septic ED patients while increasing the diagnostic accuracy to only 68-85%. In one-third of septic ED patients, the choice of antibiotics could have been accurately determined solely on the basis of patient history and physical examination. PMID- 23636024 TI - Suicide among adults aged 35-64 years--United States, 1999-2010. PMID- 23636026 TI - State-specific prevalence of walking among adults with arthritis--United States, 2011. PMID- 23636025 TI - Adult participation in aerobic and muscle-strengthening physical activities- United States, 2011. PMID- 23636027 TI - Progress toward eradication of polio--worldwide, January 2011-March 2013. PMID- 23636028 TI - [Brain without a mind?--poor rich Europe!]. PMID- 23636029 TI - Role of reflexology and antiepileptic drugs in managing intractable epilepsy--a randomized controlled trial. AB - BACKGROUND: This report is based on the results of a randomized parallel controlled trial conducted to determine the efficacy of reflexology therapy in managing intractable epilepsy. METHODS: Subjects who failed epilepsy surgery or were not candidates for epilepsy surgery or were non-responders of antiepileptic drugs (AEDs) took part in this study. The trial was completed by 77 subjects randomly assigned to 2 arms: control (AEDs) and reflexology (AEDs + reflexology therapy). The hypothesis was that hand reflexology therapy could produce results similar to those of vagus nerve stimulation, and foot reflexology therapy could maintain homeostasis in the functional status of individual body parts. Reflexology therapy was applied by family members. The follow-up period was 1.5 years. Quality of life in epilepsy patients was assessed with the QOLIE-31 instrument. RESULTS: In the reflexology group, the median baseline seizure frequency decreased from 9.5 (range 2-120) to 2 (range 0-110) with statistical significance (p < 0.001). In the control arm, the decrease was less than 25% with a baseline value of 16 (range 2-150). The pretherapy QOLIE-31 scores in the control group and the reflexology group were 41.05 +/- 7 and 43.6 +/- 8, respectively. Posttherapy data were 49.07 +/- 6 and 65.4 +/- 9, respectively (p < 0.002). The reflexology method allowed detection of knee pain in 85% of the reflexology group patients (p < 0.001), and 85.3% of patients derived 81% relief from it (p < 0.001). 4 reflexology group patients reported nausea/vomiting (n = 1), change in voice (n = 2), and hoarseness (n = 1). CONCLUSION: Reflexology therapy together with AEDs may help reducing seizure frequency and improving quality of life in individuals with epilepsy. PMID- 23636030 TI - [Modalities of acupuncture treatments in assisted reproductive technology--a comparison of treatment practice in Swiss, German, and Austrian fertility centers with findings from randomized controlled trials]. AB - BACKGROUND: One in 5 couples is affected by infertility. To increase the effectiveness of assisted reproductive technology (ART) adjuvant acupuncture treatments are frequently administered. However, little is known about acupuncture treatment modalities employed in fertility centers. The aim of our study was to assess modalities of acupuncture treatments in fertility centers and compare them with investigated acupuncture treatments in randomized controlled trials (RCTs) related to ART. METHODS: Referring to fertility centers listed on the websites of the Swiss, German, and Austrian national fertility associations, 180 centers were invited to participate in an online survey assessing the provision of acupuncture in ART. Survey results were compared with data from 17 RCTs. RESULTS: Acupuncture was offered by 33 (38.4%) of all responding fertility centers (n = 86; responder rate = 47.8%). In 39.4% the selection of acupuncture points is standardized or semi-standardized (24.2%) and in 27.3% based on individual TCM-diagnosis. Body acupuncture using needle stimulation was mentioned most frequently (84.8%). Some clinics reported additional use of auricular acupuncture (24.2%) and moxibustion (21.2%). Treatment providers were mainly physician-acupuncturists (84.8%). Compared to the RCTs, we found strong differences in point selection, mode of stimulation, and professional background of treatment providers. CONCLUSIONS: Less than 40% of all fertility centres in Switzerland, Germany, and Austria offering acupuncture employ standardized acupuncture treatment protocols. To increase external validity of acupuncture research in ART, and to investigate clinical effectiveness of this adjuvant intervention, semi-standardized and individualized point selection should be considered, and treatment provision by non-acupuncturists should be omitted in future trials. PMID- 23636031 TI - Analysis of the contents of German magazines for tumor patients. AB - BACKGROUND: Cancer patients have high information needs. Besides direct discussion with the physician, media provide important access to information. In the age of the internet, print media are still being used by many patients. In Germany, several magazines for cancer patients are distributed at no cost to cancer institutions for display. The aim of our study was to assess the content of these magazines. METHODS: In a first step, a search of the literature concerning patient information needs and evaluation of patient information was done. This search revealed important criteria for evaluation. 2 instruments are recognized internationally as appropriate in evaluating and certifying patient information: HONcode and DISCERN. As we did not find an instrument for the evaluation of patient magazines, we combined the central items from both instruments. With this new instrument, we assessed the 2010 issues of all 5 magazines . RESULTS: The Krebsmagazin offers a vast range of different topics in cancer and thus aims at general patient education, irrespective of the level of knowledge. Befund Krebs offers a wider variety of topics in each issue. Understanding the articles requires basic knowledge. The same applies to Leben? Leben! which specifically addresses the topic of breast cancer. All 3 journals provide information in line with evidence-based medicine. K Journal - Mensch & Krebs provides information on conventional as well as alternative treatments, the latter not being evidence-based. Several issues contained both advertisements and articles by providers of alternative therapies. Signal only deals with alternative medicine in cancer care and does not provide scientifically proven data. CONCLUSION: As our analysis shows, content and evidence vary greatly in the magazines currently distributed in Germany. Physicians should familiarize themselves with the characteristics of the different journals before recommending them. PMID- 23636032 TI - Stress management and mind-body medicine: a randomized controlled longitudinal evaluation of students' health and effects of a behavioral group intervention at a middle-size German university (SM-MESH). AB - BACKGROUND: Student life can be stressful. Hence, we started a regular mind-body medical stress management program in 2006. By today, more than 500 students took part and evaluations showed significant results, especially with regard to a reduction of stress warning signals. For further analysis, we now decided to run a randomized controlled longitudinal trial. METHODS: Participating students at Coburg University were randomized into an intervention (n = 24) or a waitlist control group (n = 19). The intervention group completed 3 sets (pre/post/follow up) and the control group 2 sets (pre/post) of self-administered questionnaires. The questionnaires included: SF-12 Health Survey, Perceived Stress Scale (PSS), Sense of Coherence (SOC-L9), Visual Analogue Scale (VAS) concerning stress, and the Stress Warning Signs (SWS) scale. Randomly selected participants of the intervention group were also queried in qualitative interviews. The intervention consisted of an 8 week stress management group program (mind-body medical stress reduction - MBMSR). Follow-up measures were taken after 6 months. RESULTS: Virtually, no drop-out occurred. Our study showed significant effects in the intervention group concerning SF-12 Mental Component Scale (p = 0.05), SF-12 Physical Component Scale (p = 0.001), VAS (in general, p = 0.001) and SWS (emotional reactions, p <0.001), underlined by qualitative results, which showed a higher quality of life. CONCLUSIONS: The effectiveness of an MBMSR program in a group of supposedly healthy students could be demonstrated. Findings suggest that stress management might be given importance at universities that care for the performance, the quality of life, and stress-health status of their students, acknowledging and accounting for the challenging circumstances of university life, as well as the specific needs of the modern student population. PMID- 23636033 TI - Successful therapy of vulvodynia with local anesthetics: a case report. AB - BACKGROUND: Vulvodynia often occurs with unexplained vulvar pain and hyperesthesia, sexual dysfunction, and psychological disability, lacking an organic or microbiological substrate. CASE REPORT: A 25-year-old woman with generalized, unprovoked vulvodynia for 12 years was treated repeatedly with procaine 1% for 14 sessions after she had previously had numerous unsatisfying multidisciplinary treatments. We observed a decrease in pain scores on the visual analogue scale (VAS) from initially 8-9 to presently 0-2. Injection sites were: Head's zones and trigger points of the lower abdomen, regional hypogastric ganglia, bilateral maxillary sinus, and scars of the lower jaw. No major adverse events were observed. Injections to remote sites improved symptoms more strongly than local or regional therapy. After a 3-year follow-up the patient is free of symptoms. CONCLUSION: Therapy with local anesthetics (TLA, neural therapy) can be a useful additional therapy in complicated cases of vulvodynia. Further studies on the underlying mechanism of injections into remote foci (interference field, stoerfeld) and the effectiveness of TLA in chronic pain syndromes should be performed. PMID- 23636035 TI - Italy and the Dialogue on Human Health between Traditional Chinese Medicine Culture and Western Medicine. PMID- 23636034 TI - Ayurvedic management of ulcerative colitis--a non-randomized observational clinical study. PMID- 23636037 TI - Differential expression of circulating microRNAs in diabetic and healthy lean cats. AB - MicroRNAs (miRNAs) regulate gene expression and play a role in the pathogenesis of human type 2 diabetes mellitus. This study investigated whether miRNA expression profiles differ between healthy and diabetic cats. Total RNA was extracted from sera of healthy lean cats, newly diagnosed diabetic cats and cats in diabetic remission. Microarrays representing 1079 mouse miRNA targets were used to measure miRNA expression in serum samples from eight healthy lean and seven newly diagnosed diabetic cats; 227 distinct miRNAs could be detected. Nineteen miRNAs were differentially expressed in newly diagnosed diabetic cats compared to healthy lean cats, with a false discovery rate of 10%. Hierarchical cluster analysis of these 19 miRNAs grouped healthy lean and newly diagnosed diabetic cats into separate clusters. After correction for multiple testing, only miR-122 and miR-193b reached statistical significance (P<0.05), with a false discovery rate of 1%. Specific quantitative real-time PCR assays for three target miRNAs (miR-122, miR-193b and miR-483(*)) were applied to four samples from each of the three groups. miR-122 expression was >40-fold higher in newly diagnosed diabetic cats compared to healthy lean cats and cats in diabetic remission, whereas miR-193b showed >14-fold higher expression. MiR-483(*) was expressed sixfold higher in newly diagnosed diabetic cats compared to both other groups. PMID- 23636036 TI - Perennial is more effective than preseasonal subcutaneous immunotherapy in the treatment of seasonal allergic rhinoconjunctivitis. AB - BACKGROUND: Two different regimens of subcutaneous immunotherapy (IT), perennial or preseasonal, may be used in the treatment of seasonal allergy. The aim of this study was to compare the efficacy and safety of perennial IT (PIT) and preseasonal IT (PSIT) in patients suffering from seasonal rhinoconjunctivitis. METHODS: The study was planned as a randomized, double-blind, comparative study on the efficacy and safety of PIT and PSIT. The study group comprised 120 patients allergic to grass and rye pollen. After the observational season they were randomized to receive PIT or PSIT for 3 years. The effect of IT was assessed based on symptom severity and medication use recorded in diaries. RESULTS: Ninety nine patients completed the study. No difference was seen between the groups regarding combined symptom medication score (SMS) in the first season of IT. During the second season, the difference between PIT and PSIT regarding combined SMS was 27.9% (p = 0.063) and reached 42.7% (p = 0.012) in favor of PIT in the third season. Both treatments had a similar safety profile. CONCLUSION: PIT was more effective than PSIT in the treatment of rhinoconjunctivitis in patients allergic to grass and rye pollens. PMID- 23636038 TI - AANP and ACNP merger: what does this mean for advanced practice registered nurses? PMID- 23636039 TI - Tribute to Judith C. Kelleher: (August 5, 1923-January 24, 2013). PMID- 23636040 TI - Managing dental pain in the emergency department: dental disparities with practice implications. AB - This column critiques the findings from a retrospective medical record review, "Doctor, my tooth hurts, the costs of incomplete dental care in the emergency room," by . The study was designed to examine characteristics of patients presenting to emergency departments (EDs) with dental related problems and their associated costs of care. The study also looked at the frequency of dental related return visits speculated to represent ineffective ED treatment of underlying dental problems. We discuss the findings from this study in the context of growing concern about dental health disparities within the United States, including implications for advanced practice nurse management of dental related problems in the ED. PMID- 23636041 TI - A 30-year-old industrial worker with upper back pain. AB - This column presents the case of a 30-year-old man seeking care for upper back pain at a freestanding emergency center. His occupation involved carrying 50-lb buckets of chemicals up ladders to the rooftops of industrial buildings. Back pain is a common complaint in emergency departments and most often musculoskeletal in nature. In this case, the back pain was not musculoskeletal but resulted from bilateral pulmonary emboli. The patient did not know that he had Factor V Leiden disorder. This column emphasizes the importance of ruling out serious life-threatening conditions in patients who present with common complaints and no traditional red flag symptoms. PMID- 23636042 TI - Rabies prophylaxis in the emergency department. AB - The rabies virus is transmitted through exposure to infected saliva during either a bite or direct contact with mucosal tissues. Infection with this virus results in a progressive encephalitis, ultimately leading to coma, end-organ damage, and death. Because rabies-associated mortality is strikingly high, preventing viral transmission associated with an exposure is paramount. Fortunately, 2 available options exist for this purpose and include the rabies vaccine and the associated immunoglobulin. Patients presenting for consideration of rabies postexposure prophylaxis constitute a frequent complaint seen in the emergency department (ED) in most geographical areas. Management of these patients should be guided by an accurate and thorough discussion of the circumstances surrounding their exposure to attain maximum pharmacological benefit and avoid viral transmission. This article provides an overview of the practice recommendations surrounding rabies virus prophylaxis and their associated pharmacological characteristics in the ED. PMID- 23636044 TI - Emergency management of pancreatic injury in a 5-year-old. AB - Pediatric pancreatic injuries are less common than many other intra-abdominal organ traumatic injuries; failure to identify pancreatic injury during the emergency phase will result in delayed diagnosis, delayed treatment, and potentially poor health outcomes. Injured children may present to nontrauma center/nonpediatric hospitals or urgent care settings where practitioners may not be experienced in diagnosing and treating pediatric pancreatic injuries. This case study explores the medical course of a child with persistent abdominal pain after a fall from a horse. He was evaluated in a nonpediatric trauma center and was discharged home, continued with symptoms, presented to a different community emergency department, and then transferred to the emergency department at a Level 1 pediatric trauma center. Educating health care providers about pediatric pancreatic injuries in emergency or urgent care settings will help improve quality of care for injured children who are not initially evaluated in a pediatric specific hospital or trauma center. PMID- 23636045 TI - The art of remediation in professional emergency nursing practice. AB - One of the most difficult arenas in the emergency environment for the new and seasoned clinical nurse specialist is the clinical remediation of professional nursing staff. It is easy to say that each person must be treated the same, but the foundation of each practice issue and problem is unique. Identifying and utilizing a standardized process with which concerns are addressed on the basis of theoretical models, expert nursing knowledge, and standards of practice are the keys to success. PMID- 23636046 TI - The Emergency Department Sickle Cell Assessment of Needs and Strengths (ED SCANS): reliability and validity. AB - Emergency department (ED) management of adults with sickle cell disease (SCD) is complex and frustrating. The Emergency Department Sickle Cell Assessment of Needs and Strengths (ED-SCANS) is a research-based decision support and quality improvement (QI) tool to guide management of individual patients with SCD and can also be used to guide the development of ED protocols and other QI initiatives for this population. The study evaluated ED-SCANS' inter-rater reliability, face and utility validity among clinicians, and construct validity of anxiety, depression, and psychiatric or social service needs among patients. ED nurses and physicians found the ED-SCANS to be useful, relevant, and easy to use. Nurse practitioners can use the ED-SCANS to assess and manage individual patients. Clinical nurse specialists can use the ED-SCANS as a framework to guide departmental QI efforts. PMID- 23636047 TI - What is the evidence to guide best practice for the management of older people with cognitive impairment presenting to emergency departments? A systematic review. AB - The aim of this study was to conduct a systematic literature review of research based studies to identify practices designed to meet the specific care needs of older cognitively impaired patients in emergency departments (ED). A systematic literature review of studies was completed using PRIMSA methodology. The search criteria included articles from both emergency and acute care settings. A total of 944 articles were screened, and a total of 43 articles were identified as eligible. The review found a number of intervention studies to improve quality of care for older persons with cognitive impairment carried out or commenced in emergency settings, including interventions to improve cognitive impairment recognition (n = 9) and clinical approaches to reduce falls (n = 1) and both delirium incidence and prevalence (n = 2). Relevant studies carried out in acute care settings regarding cognitive impairment recognition (n = 4) and primary and secondary prevention of delirium (n = 18) and intervention studies that reduced the prescription of deliriogenic drugs (n = 1), reduced behavioral symptoms and discomfort (n = 7), and improved nutritional intake (n = 1) in hospitalized older persons with dementia were also identified. There is limited research available that reports interventions that improve the quality of care of older ED patients with cognitive impairment. Although this review found evidence obtained from the acute care setting, additional research is needed to identify whether these interventions are beneficial in fast-paced emergency settings. PMID- 23636048 TI - Interprofessional program to provide emergency sheltering to abused elders. AB - Abuse of senior citizens should be paradoxical in a civilized society; however, the U.S. Government Accountability Office reports that 14.1% of noninstitutionalized older adults experienced some type of abuse within the previous year. This is suspected to be an underestimation of the number of abuses reported. In a society where the older population is predicted to increase significantly, it is likely that the number of cases for abused elders will increase proportionately. Through the success of advocacy groups to raise awareness of child and domestic partner abuse, funding has been channeled to shelter these abuse victims. The same cannot be said for elders who are abused. Providing shelter in a safe, secure, medically appropriate environment, free from violence, for an older adult is essential. This article describes a community's collaborative health planning process to respond to elder abuse and develop a program to shelter elders experiencing abuse or suspected abuse. PMID- 23636049 TI - Survival and integration of developing and progenitor-derived retinal ganglion cells following transplantation. AB - There is considerable interest in transplanting stem cells or progenitors into the injured nervous system and enhancing their differentiation into mature, integrated, functional neurons. Little is known, however, about what intrinsic or extrinsic signals control the integration of differentiated neurons, either during development or in the adult. Here we ask whether purified, postmitotic, differentiated retinal ganglion cells (RGCs) directly isolated from rat retina or derived from in vitro-differentiated retinal progenitor cells can survive, migrate, extend neurites, and form morphologic synapses in a host retina, in vivo and ex vivo. We found that acutely purified primary and in vitro-differentiated RGCs survive transplantation and migrate into deeper retinal layers, including into their normal environment, the ganglion cell layer (GCL). Transplanted RGCs from a wide range of developmental ages, but not from adults, were capable of extending lengthy neurites in the normal and injured adult rat retina ex vivo and to a lesser degree after transplantation in vivo. We have also demonstrated that RGCs may be differentiated and purified from retinal precursor cultures and that they share many of the same cell biological properties as primary RGCs. We have established that progenitor-derived RGCs have similar capacity for integration as developing primary RGCs but appear to form a lower number of presynaptic punctae. This work provides insight for further understanding of the integration of developing RGCs into their normal environment and following injury. PMID- 23636050 TI - Association between urinary prostaglandin E2 metabolite and breast cancer risk: a prospective, case-cohort study of postmenopausal women. AB - Overweight or obese women are at increased risk of developing and dying from breast cancer. Obesity-driven inflammation may stimulate prostaglandin E2 (PGE2) mediated aromatase activation and estrogen biosynthesis in breast tissues. We hypothesized that increased production of PGE2 would contribute to elevated breast cancer risk in postmenopausal women. We carried out a case-cohort study with 307 incident breast cancer cases and 300 subcohort members from the Sister Study cohort. HRs and 95% confidence intervals (CI) were estimated for the association between urinary levels of a major PGE2 metabolite (PGE-M) and breast cancer risk using Prentice's pseudo-likelihood approach. Several lifestyle factors were associated with urinary levels of PGE-M: smoking, high-saturated fat diet, and obesity increased urinary PGE-M, and use of nonsteroidal antiinflammatory drugs (NSAID) decreased urinary PGE-M. Although there was no association between urinary PGE-M and postmenopausal breast cancer risk in the overall analysis or among regular users of NSAIDs, there was a positive association among postmenopausal women who did not regularly use NSAIDs with HRs of 2.1 [95% confidence interval (CI): 1.0-4.3]; 2.0 (95% CI: 1.0-3.9); and 2.2 (95% CI: 1.1-4.3) for the second, third, and highest quartiles of PGE-M. Our findings suggest a link between systemic PGE2 formation and postmenopausal breast cancer, and a possible modification of the association by lifestyle and pharmacologic interventions. If confirmed in larger studies, these results may have useful implications for the development of preventive strategies. PMID- 23636051 TI - Urinary PGE-M: a promising cancer biomarker. AB - Cancer prevention, early diagnosis, and targeted therapies are the keys to success in better cancer control and treatment. A big challenge remains to identify biomarkers for predicting who may have higher cancer risk and are able to respond to certain chemopreventive agents as well as for assessing a patient's response during treatment. Although a large body of evidence indicates that chronic inflammation is a risk factor for cancer, it is unclear whether inflammatory biomarkers can be used to predict cancer risk, progression, and death. Considering the importance of the proinflammatory COX-2-derived prostaglandin E2 (PGE2) in inflammation and cancer, Morris and colleagues found that urinary PGE-M is positively associated with obesity, smoking, and lung metastases in patients with breast cancer (4). Along the same lines, Kim and colleagues showed a potential association between urinary PGE-M and breast cancer risk in postmenopausal women (beginning on page 511). In agreement with previous reports, their findings indicate that urinary PGE-M may serve as a promising biomarker for prognosticating cancer risk and disease progression. PMID- 23636053 TI - Igs expressed by chronic lymphocytic leukemia B cells show limited binding-site structure variability. AB - Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated. PMID- 23636052 TI - Loss of TLR2 worsens spontaneous colitis in MDR1A deficiency through commensally induced pyroptosis. AB - Variants of the multidrug resistance gene (MDR1/ABCB1) have been associated with increased susceptibility to severe ulcerative colitis (UC). In this study, we investigated the role of TLR/IL-1R signaling pathways including the common adaptor MyD88 in the pathogenesis of chronic colonic inflammation in MDR1A deficiency. Double- or triple-null mice lacking TLR2, MD-2, MyD88, and MDR1A were generated in the FVB/N background. Deletion of TLR2 in MDR1A deficiency resulted in fulminant pancolitis with early expansion of CD11b(+) myeloid cells and rapid shift toward TH1-dominant immune responses in the lamina propria. Colitis exacerbation in TLR2/MDR1A double-knockout mice required the unaltered commensal microbiota and the LPS coreceptor MD-2. Blockade of IL-1beta activity by treatment with IL-1R antagonist (IL-1Ra; Anakinra) inhibited colitis acceleration in TLR2/MDR1A double deficiency; intestinal CD11b(+)Ly6C(+)-derived IL-1beta production and inflammation entirely depended on MyD88. TLR2/MDR1A double knockout CD11b(+) myeloid cells expressed MD-2/TLR4 and hyperresponded to nonpathogenic Escherichia coli or LPS with reactive oxygen species production and caspase-1 activation, leading to excessive cell death and release of proinflammatory IL-1beta, consistent with pyroptosis. Inhibition of reactive oxygen species-mediated lysosome degradation suppressed LPS hyperresponsiveness. Finally, active UC in patients carrying the TLR2-R753Q and MDR1-C3435T polymorphisms was associated with increased nuclear expression of caspase-1 protein and cell death in areas of acute inflammation, compared with active UC patients without these variants. In conclusion, we show that the combined defect of two UC susceptibility genes, MDR1A and TLR2, sets the stage for spontaneous and uncontrolled colitis progression through MD-2 and IL-1R signaling via MyD88, and we identify commensally induced pyroptosis as a potential innate immune effector in severe UC pathogenesis. PMID- 23636054 TI - Mast cell-deficient Kit(W-sh) "Sash" mutant mice display aberrant myelopoiesis leading to the accumulation of splenocytes that act as myeloid-derived suppressor cells. AB - Mast cell-deficient Kit(W-sh) "sash" mice are widely used to investigate mast cell functions. However, mutations of c-Kit also affect additional cells of hematopoietic and nonimmune origin. In this study, we demonstrate that Kit(W-sh) causes aberrant extramedullary myelopoiesis characterized by the expansion of immature lineage-negative cells, common myeloid progenitors, and granulocyte/macrophage progenitors in the spleen. A consistent feature shared by these cell types is the reduced expression of c-Kit. Populations expressing intermediate and high levels of Ly6G, a component of the myeloid differentiation Ag Gr-1, are also highly expanded in the spleen of sash mice. These cells are able to suppress T cell responses in vitro and phenotypically and functionally resemble myeloid-derived suppressor cells (MDSC). MDSC typically accumulate in tumor-bearing hosts and are able to dampen immune responses. Consequently, transfer of MDSC from naive sash mice into line 1 alveolar cell carcinoma tumor bearing wild-type littermates leads to enhanced tumor progression. However, although it can also be observed in sash mice, accelerated growth of transplanted line 1 alveolar cell carcinoma tumors is a mast cell-independent phenomenon. Thus, the Kit(W-sh) mutation broadly affects key steps in myelopoiesis that may have an impact on mast cell research. PMID- 23636055 TI - Altered immunity and dendritic cell activity in the periphery of mice after long term engraftment with bone marrow from ultraviolet-irradiated mice. AB - Alterations to dendritic cell (DC) progenitors in the bone marrow (BM) may contribute to long-lasting systemic immunosuppression (>28 d) following exposure of the skin of mice to erythemal UV radiation (UVR). DCs differentiated in vitro from the BM of mice 3 d after UVR (8 kJ/m(2)) have a reduced capacity to initiate immunity (both skin and airways) when adoptively transferred into naive mice. Studies in IL-10(-/-) mice suggested that UV-induced IL-10 was not significantly involved. To investigate the immune capabilities of peripheral tissue DCs generated in vivo from the BM of UV-irradiated mice, chimeric mice were established. Sixteen weeks after reconstitution, contact hypersensitivity responses were significantly reduced in mice reconstituted with BM from UV irradiated mice (UV-chimeric). When the dorsal skin of UV-chimeric mice was challenged with innate inflammatory agents, the hypertrophy induced in the draining lymph nodes was minimal and significantly less than that measured in control-chimeric mice challenged with the same inflammatory agent. When DCs were differentiated from the BM of UV-chimeric mice using FLT3 ligand or GM-CSF + IL 4, the cells maintained a reduced priming ability. The diminished responses in UV chimeric mice were not due to different numerical or proportional reconstitution of BM or the hematopoietic cells in blood, lymph nodes, and skin. Erythemal UVR may imprint a long-lasting epigenetic effect on DC progenitors in the BM and alter the function of their terminally differentiated progeny. PMID- 23636057 TI - TRPC6 regulates CXCR2-mediated chemotaxis of murine neutrophils. AB - Unraveling the mechanisms involved in chemotactic navigation of immune cells is of particular interest for the development of new immunoregulatory therapies. It is generally agreed upon that members of the classical transient receptor potential channel family (TRPC) are involved in chemotaxis. However, the regulatory role of TRPC channels in chemoattractant receptor-mediated signaling has not yet been clarified in detail. In this study, we demonstrate that the TRPC6 channels play a pronounced role in CXCR2-mediated intermediary chemotaxis, whereas N-formyl-methionine-leucine-phenylalanine receptor-mediated end-target chemotaxis is TRPC6 independent. The knockout of TRPC6 channels in murine neutrophils led to a strongly impaired intermediary chemotaxis after CXCR2 activation which is not further reinforced by CXCR2, PI3K, or p38 MAPK inhibition. Furthermore, CXCR2-mediated Ca(2+) influx but not Ca(2+) store release was attenuated in TRPC6(-/-) neutrophils. We demonstrate that the TRPC6 deficiency affected phosphorylation of AKT and MAPK downstream of CXCR2 receptor activation and led to altered remodeling of actin. The relevance of this TRPC6 depending defect in neutrophil chemotaxis is underscored by our in vivo findings. A nonseptic peritoneal inflammation revealed an attenuated recruitment of neutrophils in the peritoneal cavity of TRPC6(-/-) mice. In summary, this paper defines a specific role of TRPC6 channels in CXCR2-induced intermediary chemotaxis. In particular, TRPC6-mediated supply of calcium appears to be critical for activation of downstream signaling components. PMID- 23636056 TI - T cell-specific notch inhibition blocks graft-versus-host disease by inducing a hyporesponsive program in alloreactive CD4+ and CD8+ T cells. AB - Graft-versus-host disease (GVHD) induced by donor-derived T cells remains the major limitation of allogeneic bone marrow transplantation (allo-BMT). We previously reported that the pan-Notch inhibitor dominant-negative form of Mastermind-like 1 (DNMAML) markedly decreased the severity and mortality of acute GVHD mediated by CD4(+) T cells in mice. To elucidate the mechanisms of Notch action in GVHD and its role in CD8(+) T cells, we studied the effects of Notch inhibition in alloreactive CD4(+) and CD8(+) T cells using mouse models of allo BMT. DNMAML blocked GVHD induced by either CD4(+) or CD8(+) T cells. Both CD4(+) and CD8(+) Notch-deprived T cells had preserved expansion in lymphoid organs of recipients, but profoundly decreased IFN-gamma production despite normal T-bet and enhanced Eomesodermin expression. Alloreactive DNMAML T cells exhibited decreased Ras/MAPK and NF-kappaB activity upon ex vivo restimulation through the TCR. In addition, alloreactive T cells primed in the absence of Notch signaling had increased expression of several negative regulators of T cell activation, including Dgka, Cblb, and Pdcd1. DNMAML expression had modest effects on in vivo proliferation but preserved overall alloreactive T cell expansion while enhancing accumulation of pre-existing natural regulatory T cells. Overall, DNMAML T cells acquired a hyporesponsive phenotype that blocked cytokine production but maintained their expansion in irradiated allo-BMT recipients, as well as their in vivo and ex vivo cytotoxic potential. Our results reveal parallel roles for Notch signaling in alloreactive CD4(+) and CD8(+) T cells that differ from past reports of Notch action and highlight the therapeutic potential of Notch inhibition in GVHD. PMID- 23636058 TI - Blockade of programmed death-1 in young (New Zealand Black x New Zealand White)F1 mice promotes the suppressive capacity of CD4+ regulatory T cells protecting from lupus-like disease. AB - Programmed death-1 (PD-1) usually acts as a negative signal for T cell activation, and its expression on CD8(+)Foxp3(+) T cells is required for their suppressive capacity. In this study, we show that PD-1 signaling is required for the maintenance of functional regulatory CD4(+)CD25(+)Foxp3(+) regulatory T cells (CD4(+) T(reg)) that can control autoimmunity in (New Zealand Black * New Zealand White)F1 lupus mice. PD-1 signaling induced resistance to apoptosis and prolonged the survival of CD4(+) T(reg). In vivo, the blockade of PD-1 with a neutralizing Ab reduced PD-1 expression on CD4(+) T(reg) (PD1(lo)CD4(+) T(reg)). PD1(lo)CD4(+) T(reg) had an increased ability to promote B cell apoptosis and to suppress CD4(+) Th as compared with CD4(+) T(reg) with elevated PD-1 expression (PD1(hi)CD4(+) T(reg)). When PD-1 expression on CD4(+) T(reg) was blocked in vitro, PD1(lo)CD4(+) T(reg) suppressed B cell production of IgG and anti-dsDNA Ab. Finally, in vitro studies showed that the suppressive capacity of CD4(+) T(reg) depended on PD-1 expression and that a fine-tuning of the expression of this molecule directly affected cell survival and immune suppression. These results indicate that PD-1 expression has multiple effects on different immune cells that directly contribute to a modulation of autoimmune responses. PMID- 23636059 TI - Hierarchy of CD4 T cell epitopes of the ANRS Lipo5 synthetic vaccine relies on the frequencies of pre-existing peptide-specific T cells in healthy donors. AB - The Agence National de Recherche sur le SIDA et les hepatitis Lipo5 vaccine is composed by five long fragments of HIV proteins and was recently shown to induce in seronegative volunteers a CD4 T cell response largely dominated by the G2 fragment. To understand this response profile, we submitted the five HIV fragments to HLA-DR-binding assays and evaluated the frequency of naive Lipo5 specific CD4 T lymphocytes in the blood of 22 healthy individuals. We enumerated the Lipo5-specific T cell lines induced in vitro by weekly rounds of specific stimulation. Four peptides and hence not only G2 exhibited a broad specificity for HLA-DR molecules. In contrast, most of the T cell lines specific for Lipo5 reacted with G2, revealing a G2-specific T cell repertoire superior to 2 cells per million, whereas it is close to 0.4 for the other peptides. We also found good cross-reactivity of all the peptides with clade B and C variants and that G2 and P1 are able to recruit T cells that recognize HIV-infected cells. We therefore mainly observed very good concordance between the frequency to individual Lipo5 peptides among vaccinees in a large-scale vaccine trial and the distribution of peptide specificity of the in vitro induced T cell lines. These findings underline the role of the size of the epitope-specific naive repertoire in shaping the CD4 T cell response after vaccination and highlight the value of evaluating the naive repertoire to predict vaccine immunogenicity. PMID- 23636060 TI - Different GATA factors dictate CCR3 transcription in allergic inflammatory cells in a cell type-specific manner. AB - The chemokine receptor CCR3 is expressed in prominent allergic inflammatory cells, including eosinophils, mast cells, and Th2 cells. We previously identified a functional GATA element within exon 1 of the CCR3 gene that is responsible for GATA-1-mediated CCR3 transcription. Because allergic inflammatory cells exhibit distinct expression patterns of different GATA factors, we investigated whether different GATA factors dictate CCR3 transcription in a cell type-specific manner. GATA-2 was expressed in EoL-1 eosinophilic cells, GATA-1 and GATA-2 were expressed in HMC-1 mast cells, and GATA-3 was preferentially expressed in Jurkat cells. Unlike a wild-type CCR3 reporter, reporters lacking the functional GATA element were not active in any of the three cell types, implying the involvement of different GATA factors in CCR3 transcription. RNA interference assays showed that small interfering RNAs specific for different GATA factors reduced CCR3 reporter activity in a cell type-specific fashion. Consistent with these findings, chromatin immunoprecipitation and EMSA analyses demonstrated cell type specific binding of GATA factors to the functional GATA site. More importantly, specific inhibition of the CCR3 reporter activity by different GATA small interfering RNAs was well preserved in respective cell types differentiated from cord blood; in particular, GATA-3 was entirely responsible for reporter activity in Th2 cells and replaced the role predominantly played by GATA-1 and GATA-2. These results highlight a mechanistic role of GATA factors in which cell type specific expression is the primary determinant of transcription of the CCR3 gene in major allergic inflammatory cells. PMID- 23636062 TI - SWAP-70 restricts spontaneous maturation of dendritic cells. AB - Spontaneous maturation observed in dendritic cell (DC) cultures has been linked to their capacity to induce immune responses. Despite several recent studies, the mechanisms and signals triggering spontaneous maturation of DCs are largely unknown. We found that the absence of SWAP-70 causes spontaneous maturation of spleen- and bone marrow-derived DCs and, in vivo, of spleen-resident CD11c(+)CD11b(+)CD8alpha(-) DCs. Activation markers, cross-presentation of exogenous Ags, and activation of CD8(+) T cells are much increased in Swap-70(-/ ) DCs. Spontaneous maturation of Swap-70(-/-) DCs depends on cell-cell contact and does not involve beta-catenin signaling. SWAP-70 is known to regulate integrin activity. Signaling through the integrin CD11b (alphaM) subunit increases spontaneous maturation of wild-type (wt), but not of Swap-70(-/-) DCs. Signaling through the CD18 (beta2) subunit decreases spontaneous maturation of wt and Swap-70(-/-) DCs. Constitutive activation of RhoA in Swap-70(-/-) DCs was determined as a key mechanism causing the increased spontaneous maturation. Inhibition of RhoA early, but not late, in the activation process reduces spontaneous maturation in Swap-70(-/-) DCs to wt levels. Inhibition of RhoA activation during CD11b integrin activation had a significant effect only in Swap 70(-/-) but not in wt DCs. Together, our data suggest that integrin-mediated spontaneous maturation of wt DCs does not depend on active RhoA, whereas the increase in spontaneous maturation of Swap-70(-/-) DCs is supported by integrin CD11b and by hyperactive RhoA. Thus, SWAP-70 deficiency reveals two pathways that contribute to spontaneous maturation of DCs. PMID- 23636064 TI - Blocking potassium channels (Kv1.3): a new treatment option for alopecia areata? PMID- 23636065 TI - Modulating autophagy improves cardiac function in a rat model of early-stage dilated cardiomyopathy. AB - OBJECTIVES: Previous studies reported that autophagy is activated in human dilated cardiomyopathy (DCM). It is still unknown whether modulating autophagy can improve cardiac function of the failing heart. METHODS: We immunized rats with porcine cardiac myosin to set up a model of DCM. Rapamycin, a kind of mTOR inhibitor upregulating autophagy, was given to rats weeks after the immunization at low (1 mg/kg . day i.p.), intermediate (2 mg/kg . day i.p.) and high dose (4 mg/kg . day i.p.) for 2 weeks. RESULTS: Compared to the control group (ejection fraction, EF = 81.3 +/- 3.8%), the average EF decreased in both the DCM group (EF = 56.1 +/- 3.3%) and the high-dose rapamycin group (EF = 55.9 +/- 3.6%), but recovered in the low-/intermediate-dose rapamycin groups (EF = 64.9 +/- 4.6/69.4 +/- 4.4%). Phosphorylation of p70s6k and 4E-BP1 decreased and the expression of LC3BI/II increased in all rapamycin groups. Autophagic vacuoles were easily found in these groups. However, body weight was significantly reduced in the rapamycin groups. Furthermore, mortality was increased in the high-dose rapamycin group. CONCLUSIONS: Rapamycin could improve cardiac function of early-stage DCM, but the effect of rapamycin turned out to be biphasic and the effective range appeared narrow. PMID- 23636067 TI - Evidence to guide nursing interventions for critically ill neurologically impaired patients with ICP monitoring. PMID- 23636066 TI - Transitions. PMID- 23636063 TI - Immunocytochemical detection of raf kinase inhibitor protein and human papillomavirus profiling of normal and abnormal cervical ThinPrep samples. AB - OBJECTIVES: This study investigates the potential value of Raf kinase inhibitor protein (RKIP) as a marker of normal squamous cells in ThinPrep slides. RKIP was evaluated for its ability to distinguish between normal and abnormal cervical samples in the context of human papillomavirus (HPV) infections. STUDY DESIGN: A total of 316 ThinPrep samples were taken from women with normal and abnormal cervices. ThinPrep slides were Papanicolaou stained and reported. Residual samples were used for RKIP immunostaining and HPV PCR-based sequencing. RESULTS: RKIP expression was seen in both nuclei and cytoplasm in 83.7% of samples. RKIP expression was highest (84.6%) in samples with a diagnosis of high-grade squamous intraepithelial lesion (HSIL) or worse; expression was lower in low-grade squamous intraepithelial lesions (73%) and was lowest in samples with normal cytology (p = 0.0023). A total of 74% of HPV-infected ThinPrep samples were immunopositive, and 67% of samples that did not harbor HPV were also immunopositive (p = 0.414). Sensitivity and specificity of RKIP were 84.6 and 34.6%, respectively, for the detection of samples with HSIL or worse. CONCLUSIONS: This study showed that RKIP expression may be of some value as a marker for abnormal cervical cells. Combined RKIP expression and HPV testing could improve the identification of samples with abnormal cytology. PMID- 23636061 TI - Age-associated increase of low-avidity cytomegalovirus-specific CD8+ T cells that re-express CD45RA. AB - The mechanisms regulating memory CD8(+) T cell function and homeostasis during aging are unclear. CD8(+) effector memory T cells that re-express CD45RA increase considerably in older humans and both aging and persistent CMV infection are independent factors in this process. We used MHC class I tetrameric complexes that were mutated in the CD8 binding domain to identify CMV-specific CD8(+) T cells with high Ag-binding avidity. In individuals who were HLA-A*0201, CD8(+) T cells that expressed CD45RA and were specific for the pp65 protein (NLVPMVATV epitope) had lower avidity than those that expressed CD45RO and demonstrated decreased cytokine secretion and cytolytic potential after specific activation. Furthermore, low avidity NLVPMVATV-specific CD8(+) T cells were significantly increased in older individuals. The stimulation of blood leukocytes with CMV lysate induced high levels of IFN-alpha that in turn induced IL-15 production. Moreover, the addition of IL-15 to CD45RA(-)CD45RO(+) CMV-specific CD8(+) T cells induced CD45RA expression while Ag activated cells remained CD45RO(+). This raises the possibility that non-specific cytokine-driven accumulation of CMV specific CD8(+)CD45RA(+) T cells with lower Ag-binding avidity may exacerbate the effects of viral reactivation on skewing the T cell repertoire in CMV-infected individuals during aging. PMID- 23636068 TI - To provoke or not provoke: ethical considerations in the epilepsy monitoring unit. AB - Epilepsy is the second most common neurological disorder after migraines and headaches, with an economic burden of 15.5 billion dollars annually. Most patients with epilepsy can be controlled with antiepileptic drugs. Those who remain uncontrolled are considered refractory and are often admitted to an epilepsy monitoring unit for definitive diagnosis. Nonepileptic seizures are a common differential diagnosis in persons with refractory seizures. It is helpful for providers to witness the patients' seizures to make a definitive diagnosis for seizure classification. Frequently, unstandardized practice-provocation techniques are employed in an epilepsy monitoring unit setting. The purpose of these techniques is to elicit a seizure. A debate is occurring on whether the use of provocation techniques is ethical and necessary. This article will review the literature related to the current evidence and moral opinions swirling around this topic. It is important for the neuroscience nurse to be familiar with both sides of the seizure provocation debate as he or she will be on the front lines of shaping future policy and practice to come. PMID- 23636069 TI - Dysphagia screening and intensified oral hygiene reduce pneumonia after stroke. AB - OBJECTIVES: Dysphagia occurs in approximately 51%-78% of patients with acute stroke. The incidence of pneumonia caused by aspiration in dysphagic patients increases both mortality and the need for hospitalization. The aim of this study was to investigate whether the incidence of aspiration pneumonia could be reduced in such patients by an early screening for dysphagia and intensified oral hygiene. MATERIAL AND METHODS: In this controlled trial, 146 hospitalized acute stroke patients with moderate or severe dysphagia were included in three groups: an intervention group (n = 58), one internal control group (n = 58, retrospectively selected from same clinic), and one external control group (n = 30) from a comparable stroke unit in a neighboring hospital. The intervention consisted of early screening with a clinical method of dysphagia screening, the Gugging Swallowing Screen, and intensified oral hygiene. RESULTS: The incidence of x-ray verified pneumonia was 4 of 58 (7%) in the intervention group compared with 16 of 58 (28%) in the internal control group (p < .01) and with 8 of 30 (27%) in the external control group (p < .05). CONCLUSIONS: Early and systematic dysphagia screening by the Gugging Swallowing Screen method and intensified oral hygiene reduced the incidence of x-ray verified pneumonia. PMID- 23636070 TI - Nursing roles and functions in the inpatient neurorehabilitation of stroke patients: a literature review. AB - Stroke is a major cause of morbidity and mortality in the world. In the United States, it was estimated that approximately 750,000 patients had a stroke annually. Denmark, with a population of 5.5 million, had about 12,500 cases of hospitalizations from stroke in 2009. Despite the patient's obvious need for complex nursing care and a common recognition of the nurse's central role in rehabilitation after a stroke, a description of their specific contributions appeared sparse. Therefore, a literature review was conducted using the matrix method. The purpose was to explore the nursing roles and functions identified in empirical research and to discern any possible evolution in the nursing roles and functions during a span of years. The rehabilitation literature related to inpatient rehabilitation after stroke during the period from 1997 to 2010 was reviewed. The total number of identified citations was 1,529. After screening for relevancy, 134 eligible articles remained. Of these, 30 articles were extracted into a table and formed the basis for the conclusion. We found that four nursing roles and functions described in 1997 still accommodated central aspects of the current nursing practice but also emerging changes reflecting a development in the nurses' responsibilities and contributions in conducting rehabilitation after a stroke. These changes seemed mainly to be shaped instigated by changes in the (1) patient role, (2) increasing interdisciplinary teamwork, and (3) focus on rehabilitation efforts conducted in the patient's environment. PMID- 23636071 TI - What brain tumor patients and their families have taught me. AB - The purpose of this article is to identify the experience of the patient with a World Health Organization grade III/IV and IV/IV brain tumor, and that of their family, to best understand how to treat them. It is the cumulative input of hundreds of patients and family members seen over a 20-year career of specialization at two teaching hospitals. No patient who has been diagnosed with a brain tumor, whether low grade, high grade, or benign, escapes totally unharmed because tumor existence, surgical removal, and/or toxicity of treatment combine to cause varying degrees of brain injury. Additional considerations are the variables of tumor location within the brain, the age of the patient, their premorbid intellectual capacity, and their fear and anxiety, for full understanding of the impact and the complexity of the tumor and treatment on the individual patient. The mental health provider's mandate in caring for this population is threefold: first, provide hope in what patients feel is a hopeless situation; second, serve as witness to their experience and acknowledge and validate the changes and loses that occur; and third, create empowerment in what seems a helpless situation. For the purposes of this article, further reference to brain tumors will be World Health Organization grade III/IV and IV/IV. PMID- 23636073 TI - The impact of a patient support program for multiple sclerosis on patient satisfaction and subjective health status. AB - BACKGROUND: Leading multiple sclerosis (MS) therapies have patient support programs (PSPs) aimed at improving patients' lives. There is limited knowledge about what drives patient satisfaction with PSPs and little evidence about its impact on patient-reported health status or health-related quality of life. OBJECTIVE: The aims of this study were to evaluate patient needs and the PSP's role in meeting those needs; understand the drivers of PSP satisfaction and loyalty; and assess whether a MS PSP provides quantifiable, incremental benefit to patients, as measured by patient-reported health status, health state utility, and/or health-related quality of life. METHODS: An Internet survey was conducted among 1,123 adult German MS patients currently enrolled in Bayer's German BETAPLUS PSP. Health status, health state utility, and health-related quality of life were measured using the EQ-5D Visual Analog Scale, the EQ-5D Index, and Short Form-12 Health Survey, respectively. RESULTS: MS patient needs vary by disease severity, duration of disease, and gender. Patients with greater self reported needs and lower health status, health state utility, and health-related quality of life value and use the PSP more than other patients. Drivers of PSP satisfaction include use of patient hotline, nurse telephone calls, and mail education. Patients estimate that their health status would be 15 points lower if the PSP ceased to exist (translating to 0.15 on the time trade-off utility scale). This impact is significant, as it is nearly two times the minimally important difference. CONCLUSIONS: MS patients place inherent value on PSPs. From a patient's viewpoint, PSPs provide real incremental benefit in patient-reported health status at all stages of MS. PMID- 23636074 TI - A presentation of latent tropical sprue in a Canadian hospital. AB - Tropical sprue (TS) is a chronic diarrheal disease of unknown etiology characterized by malabsorption and small bowel mucosal abnormalities. TS affects residents of, and visitors to, endemic tropical regions. Rarely the disease may remain latent for several years, and to date, few cases of latent TS have been reported in Europe or North America. However, in our increasingly multicultural communities and in a 'global village' where travel is common, clinicians must maintain a high index of suspicion for TS in patients presenting with diarrhea and malabsorption who have traveled to endemic regions. TS may mimic common diarrheal diseases that are seen in developed nations, including celiac disease, Crohn's disease, bacterial overgrowth, and other infectious etiologies. Accordingly, once these more common etiologies have been ruled out, TS must be considered in patients presenting with diarrhea after travel to endemic regions. We present a unique Canadian case of latent TS, with a brief review of the diagnostic approach and treatment. PMID- 23636075 TI - Outpatient treatment for acute uncomplicated diverticulitis. AB - BACKGROUND: Traditionally, treatment of acute diverticulitis has mostly been based on inpatient care. The question arises whether these patients can be treated on an outpatient basis as the admissions for diverticular disease have been shown to be increasing every year. We studied whether outpatient treatment of acute uncomplicated diverticulitis is feasible and safe, and which patients could benefit from outpatient care. MATERIALS AND METHODS: A retrospective cohort study was carried out in two teaching hospitals using hospital registry codes for diverticulitis. All patients diagnosed with acute uncomplicated diverticulitis between January 2004 and January 2012, confirmed by imaging or colonoscopy, were included. Exclusion criteria were patients with recurrent diverticulitis, complicated diverticulitis (Hinchey stages 2, 3, and 4), and right-sided diverticulitis. Inpatient care was compared with outpatient care. Primary outcome was admission for outpatient care and the complication rate in both groups. Multivariate analysis was carried out to identify potential factors for inpatient care. RESULTS: Of 627 patients with diverticulitis, a total of 312 consecutive patients were identified with primary uncomplicated diverticulitis of the sigmoid colon; 194 patients had been treated as inpatients and 118 patients primarily as outpatients. In this last group, 91.5% had been treated successfully without diverticulitis-related complications or the need for hospital admission during a mean follow-up period of 48 months. CONCLUSION: Despite inherent patient selection in a retrospective cohort, ambulatory treatment of patients presenting with uncomplicated acute diverticulitis seems feasible and safe. In mildly ill and younger patients, hospital admission can be avoided. PMID- 23636076 TI - Label-free imaging of mammalian cell nucleoli by Raman microspectroscopy. AB - The nucleolus is a prominent subnuclear structure whose major function is the transcription and assembly of ribosome subunits. The size of the nucleolus varies with the cell cycle, proliferation rate and stress. Changes in nucleolar size, number, chemical composition, and shape can be used to characterize malignant cells. We used spontaneous Raman microscopy as a label-free technique to examine nucleolar spatial and chemical features. Raman images of the 1003 cm(-1) phenylalanine band revealed large, well-defined subnuclear protein structures in MFC-7 breast cancer cells. The 783 cm(-1) images showed that nucleic acids were similarly distributed, but varied more in intensity, forming observable high intensity regions. High subnuclear RNA concentrations were observed within some of these regions as shown by 809 cm(-1) Raman band images. Principal component analyses of sub-images and library spectra validated the subnuclear presence of RNA. They also revealed that an actin-like protein covaried with DNA within the nucleolus, a combination that accounted for 64% or more of the spectral variance. Embryonic stem cells are another rapidly proliferating cell type, but their nucleoli were not as large or well defined. Estimating the size of the larger MCF 7 nucleolus was used to show the utility of Raman microscopy for morphometric analyses. It was concluded that imaging based on Raman microscopy provides a promising new method for the study of nucleolar function and organization, in the evaluation of drug and experimental effects on the nucleolus, and in clinical diagnostics and prognostics. PMID- 23636078 TI - The effectiveness of the liquid-based preparation method in cerebrospinal fluid cytology. AB - OBJECTIVES: Since malignant cells were first detected in the cerebrospinal fluid (CSF), numerous methods have been used for CSF examination. The cytocentrifugation and liquid-based cytology (LBC) methods are two of these. We aimed to investigate whether the results from the LBC method were different from the results of the cytological diagnosis of the CSF materials that were prepared using the cytocentrifugation method. MATERIALS AND METHODS: A retrospective analysis was conducted using the pathological records of 3,491 (cytocentrifugation on 1,306 and LBC on 2,185) cytological specimens of CSF which were diagnosed over a 4-year period between January 2007 and December 2011. The Fisher exact test was used to compare the results of the LBC and cytocentrifugation methods. RESULTS: While there was a noticeable decrease in nondiagnostic diagnosis and a slight decrease in suspicious diagnosis, there was an increase in malignant and benign diagnosis with the LBC method in comparison to the centrifugation method. Statistically, the decrease in nondiagnostic diagnosis was considered significant (p < 0.0001). DISCUSSION: The LBC method seems like a better option than the cytocentrifugation method, because of many preparatory, screening and diagnostic advantages, especially in pathology departments where materials come from far away and large volumes are examined. PMID- 23636080 TI - The authors respond. PMID- 23636079 TI - Discontinuation of anticoagulation therapy in patients who have experienced an acute intramuscular bleed and are also at risk for a stroke. PMID- 23636081 TI - RE: botulinum toxin type A injection into the gastrocnemius muscle for spastic equinus in adults with stroke. PMID- 23636083 TI - A patient-centered care ethics analysis model for rehabilitation. AB - There exists a paucity of ethics resources tailored to rehabilitation. To help fill this ethics resource gap, the authors developed an ethics analysis model specifically for use in rehabilitation care. The Patient-Centered Care Ethics Analysis Model for Rehabilitation is a process model to guide careful moral reasoning for particularly complex or challenging matters in rehabilitation. The Patient-Centered Care Ethics Analysis Model for Rehabilitation was developed over several iterations, with feedback at different stages from rehabilitation professionals and bioethics experts. Development of the model was explicitly informed by the theoretical grounding of patient-centered care and the context of rehabilitation, including the International Classification of Functioning, Disability and Health. Being patient centered, the model encourages (1) shared control of consultations, decisions about interventions, and management of the health problems with the patient and (2) understanding the patient as a whole person who has individual preferences situated within social contexts. Although the major process headings of the Patient-Centered Care Ethics Analysis Model for Rehabilitation resemble typical ethical decision-making and problem-solving models, the probes under those headings direct attention to considerations relevant to rehabilitation care. The Patient-Centered Care Ethics Analysis Model for Rehabilitation is a suitable tool for rehabilitation professionals to use (in real time, for retrospective review, and for training purposes) to help arrive at ethical outcomes. PMID- 23636082 TI - Relationship between obesity and plantar pressure distribution in youths with Down syndrome. AB - OBJECTIVE: This study aimed to characterize the effect of obesity on foot-ground contact in young individuals affected by Down syndrome (DS) during quiet upright stance. DESIGN: This is a cross-sectional study on 118 individuals with Down syndrome, 59 with obesity aged 3-18 yrs and 59 with normal weight, age- and sex matched forming the control group. Both groups were evaluated while standing on a pressure-sensitive mat. Foot-ground contact was characterized using contact area and mean pressure calculated for the rearfoot, the midfoot, and the forefoot. RESULTS: The results show that obesity significantly influences the foot-ground interaction, with some differences related to sex. In particular, the females with obesity exhibited larger contact areas and higher plantar pressures (in the forefoot and the midfoot) with respect to the control group, whereas in the males with obesity, only the plantar pressures were found higher than those of the controls. Flatfoot is the prevalent arch type for both groups, but its incidence seems to be unrelated to obesity. CONCLUSIONS: The modifications introduced by obesity in foot-ground contact pressure and area may represent a factor capable of aggravating existing negative podiatric issues associated with Down syndrome. Thus, planning periodical monitoring of foot-ground contact during childhood and adolescence is recommended to avoid possible problems related to adverse effects of repeated excessive mechanical stresses on the plantar region. PMID- 23636084 TI - Use of rimabotulinum toxin for focal hypertonicity management in children with cerebral palsy with nonresponse to onabotulinum toxin. AB - OBJECTIVE: The aim of this study was to review the effect of rimabotulinum toxin (BoNT-B) for focal hypertonicity management in children with cerebral palsy and secondary nonresponse to onabotulinum toxin treated at the authors' tertiary care academic medical center. DESIGN: A retrospective review of the medical treatment of children was conducted at the authors' institution (March 16, 2001, to August 2, 2002) using the key words botulinum toxin B and Myobloc (Solstice Neurosciences Inc, South San Francisco, CA). Demographic information was analyzed using descriptive statistics (number [percentage] and mean [range]). The Pearson chi test was used to evaluate differences in incidence of adverse events. RESULTS: Eighty-two children had BoNT-B injections (116 treatments). Overall, 26.8% (19/71) of the children or their parents/guardians reported no or minimal response to the injections, with 89.5% (17/19) of these children having secondary nonresponse to onabotulinum toxin. Adverse events were frequent but did not require hospitalization of any patient. No significant differences were found in incidence of adverse events related to BoNT-B dosing, medical fragility, or Gross Motor Function Classification System level. CONCLUSIONS: More than one-fourth of the children receiving BoNT-B injections had nonresponse, with most having previous nonresponse to onabotulinum toxin. Adverse events related to BoNT-B injections were frequent and unpredictable but not severe. PMID- 23636085 TI - Effects of whole-body vibration on muscle architecture, muscle strength, and balance in stroke patients: a randomized controlled trial. AB - OBJECTIVE: The aim of the present study was to analyze the effects of whole-body vibration on lower limb muscle architecture, muscle strength, and balance in stroke patients during a period of 3 mos. DESIGN: The inclusion criteria were having had ischemic or hemorrhagic stroke at least 6 mos before the study and a National Institutes of Health Stroke Scale score of greater than 1 and less than 20. The patients were randomly divided into two groups: an experimental group (n = 11, six men and five women; age, 62.4 +/- 10.7 yrs; height, 1.64 +/- 0.07 m; mass, 69.4 +/- 12.9 kg) and a sham group (n = 9, five men and four women; age, 64.4 +/- 7.6 yrs; height, 1.62 +/- 0.07 m; mass, 75.0 +/- 15.8 kg). The experimental group received a whole-body vibration treatment, with an increase in frequency, sets, and time per set during 17 sessions. The sham group performed the same exercises as that of the experimental group but was not exposed to vibration. Outcome variables included the muscle architecture (the rectus femoris, the vastus lateralis, and the medial gastrocnemius), the maximal isometric voluntary contraction of the knee extensors, and the Berg Balance Scale. RESULTS: There were no significant differences between the groups on the primary outcomes of lower limb muscle architecture, muscle strength, and balance. CONCLUSIONS: It seems that whole-body vibration exercise does not augment the increase in neuromuscular performance and lower limb muscle architecture induced by isometric exercise alone in stroke patients. PMID- 23636086 TI - Is kyphosis related to mobility, balance, and disability? AB - OBJECTIVE: The aim of this study was to determine the association of increased kyphosis with declines in mobility, balance, and disability among community living older adults. DESIGN: The 18-mo follow-up visit data from 2006 to 2009 for 620 participants from the population-based Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly Boston Study of older adults was used. Cross-sectional multivariable regression analyses were performed to assess the relationship between kyphosis (measured using the kyphosis index) and measures of mobility performance (Short Physical Performance Battery), balance (Berg Balance Scale score), and disability (self-reported difficulty walking a quarter of a mile or climbing a flight of stairs). The authors then evaluated the men and the women separately. Adjustment variables included demographic factors (age, sex, race, and education), body mass index, self-rated health, comorbidities (heart disease, diabetes, stroke, and depressive symptoms), back pain, knee pain, and falls self-efficacy. RESULTS: After full adjustment, greater kyphosis index was associated with lower Short Physical Performance Battery scores (adjusted beta = 0.08, P = 0.01) but not with lower Berg Balance Scale (adjusted beta = -0.09, P = 0.23) or self-reported disability (adjusted beta = 1.00; 95% confidence interval, 0.93-1.06) scores. In sex-specific analyses, kyphosis index was associated with only the Short Physical Performance Battery in the women. CONCLUSIONS: Greater kyphosis is associated with poorer mobility performance but not with poorer balance or self-reported disability. This association with the Short Physical Performance Battery was observed only among the women. Mechanisms by which increased kyphosis influences physical performance should be explored prospectively. PMID- 23636087 TI - Ultrasound-guided vs. fluoroscopy-guided caudal epidural steroid injection for the treatment of unilateral lower lumbar radicular pain: a prospective, randomized, single-blind clinical study. AB - OBJECTIVE: The aim of this study was to compare the short-term effects and advantages of ultrasound-guided caudal epidural steroid injections with fluoroscopy-guided epidural steroid injections for unilateral radicular pain in the lower lumbar spine. DESIGN: A total of 120 patients with unilateral radicular pain were enrolled and randomly assigned to either the fluoroscopy or the ultrasound group. Complication frequencies during the procedures, treatment effects, functional improvement, and adverse events were compared after the procedures. RESULTS: The verbal numerical rating scale and the Oswestry Disability Index improved 2 and 12 wks after the injections in both groups. Statistical differences were not observed in the verbal numerical rating scale, the Oswestry Disability Index, or the effectiveness of the procedure between the groups. Two cases of intravascular injections were observed in the fluoroscopy group, without the prevalence of complication between the groups. CONCLUSIONS: The ultrasound approach with color Doppler mode may avoid intravascular injection induced complications. The results showed similar improvements in short-term pain relief, function, and patient satisfaction with both ultrasound and fluoroscopic guidance. PMID- 23636090 TI - Integrating physical sciences perspectives in cancer research. AB - Cancer research integrated a physical sciences perspective through team science, which fostered communication, trust, joint publication, and open access to data. PMID- 23636088 TI - Comparison of ultrasound-guided intra-articular injections by long axis in plane approach on three different sites of the knee. AB - OBJECTIVE: The objective of this study was to examine the accuracy of ultrasound guided intra-articular (IA) injections on three different sites of the knee using midmedial, midlateral, and superolateral portals. DESIGN: Ultrasound-guided IA injection and a radiographic evaluation were performed on 120 knees with osteoarthritis. Five milliliters of a mixed material consisting of 1% lidocaine (1 ml), 20 mg of triamcinolone (1 ml), and nonionic contrast (3 ml) was injected into the IA space of the knee through three different portals. After each injection, a radiographic evaluation was performed to determine whether the injected material had reached the IA space or infiltrated into the soft tissue. RESULTS: Of 40 injections administered through the midmedial portal, 38 were confirmed as having been placed in the IA space on the first attempt (95% accuracy rate). Thirty-nine of 40 injections administered through the midlateral portal were IA on the first attempt (98.5% accuracy rate), as were 40 of 40 injections administered through a superolateral portal (100% accuracy rate). No significant differences (P > 0.05) were observed in the accuracy rate obtained with placement through the midmedial, midlateral, and superolateral portals. CONCLUSIONS: All three ultrasound-guided IA injections may be used to access the knee joint, with a high rate of accuracy. PMID- 23636091 TI - Probing the brain of comorbidity. PMID- 23636093 TI - Addressing safety liabilities of TfR bispecific antibodies that cross the blood brain barrier. AB - Bispecific antibodies using the transferrin receptor (TfR) have shown promise for boosting antibody uptake in brain. Nevertheless, there are limited data on the therapeutic properties including safety liabilities that will enable successful development of TfR-based therapeutics. We evaluate TfR/BACE1 bispecific antibody variants in mouse and show that reducing TfR binding affinity improves not only brain uptake but also peripheral exposure and the safety profile of these antibodies. We identify and seek to address liabilities of targeting TfR with antibodies, namely, acute clinical signs and decreased circulating reticulocytes observed after dosing. By eliminating Fc effector function, we ameliorated the acute clinical signs and partially rescued a reduction in reticulocytes. Furthermore, we show that complement mediates a residual decrease in reticulocytes observed after Fc effector function is eliminated. These data raise important safety concerns and potential mitigation strategies for the development of TfR-based therapies that are designed to cross the blood-brain barrier. PMID- 23636095 TI - Tip enhanced Raman spectroscopy (TERS) as a probe for the buckling distortion in silicene. AB - Silicene, the all-Si analogue of graphene, is symmetrically buckled in each of the six-membered units and this buckling is periodically translated across the surface. Raman spectra of silicene clusters were calculated using first principles DFT methods to explore the intrinsic buckling in silicene. The presence of metal clusters as a tip over the silicene units affects the intensity of the buckling modes which can be enhanced by increasing the number of atoms in the clusters. The favourable sites of chemisorption of metal clusters over the silicene surface are studied along with the resulting red shift in buckling frequency and chemical enhancement in the Raman intensity. PMID- 23636092 TI - Casein kinase idelta mutations in familial migraine and advanced sleep phase. AB - Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Idelta (CKIdelta), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIdelta, where they caused reduced enzyme activity. Mice engineered to carry the CKIdelta-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIdelta-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIdelta-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIdelta activity can contribute to the pathogenesis of migraine. PMID- 23636096 TI - What's in a name? Using movement system diagnoses versus pathoanatomic diagnoses. PMID- 23636098 TI - A randomized trial of platelet transfusions over 30 vs 120 minutes: is there an effect on post-transfusion platelet counts? AB - OBJECTIVE: To determine whether platelet infusion time affects platelet counts in thrombocytopenic newborns. STUDY DESIGN: This was a prospective randomized control study of 43 platelet transfusions given to newborns. Transfusions were randomized to run over either 30 min or 2 h. Platelet counts taken 30 min and 6 h after transfusion were compared using parametric, nonparametric, Pearson's correlation and logistic regression. RESULT: Changes in platelet counts 30 min and 6 h after transfusion were not different between the groups. Weak but significant negative correlations existed between postmenstrual age and change in platelet count at 30 min (r=-0.33, P=0.04) and 6 h (r=-0.37, P=0.018) after transfusion. There were no differences between the mean blood pressures before and after transfusion in either group. CONCLUSION: Transfusion duration does not affect post-transfusion platelet counts in newborns. Babies of lower postmenstrual age (PMA) may have better responses to platelet transfusions. Finally, platelet transfusions over both durations are well tolerated in neonates. PMID- 23636097 TI - Microfluidic cell sorter for use in developing red fluorescent proteins with improved photostability. AB - This paper presents a novel microfluidic cytometer for mammalian cells that rapidly measures the irreversible photobleaching of red fluorescent proteins expressed within each cell and achieves high purity (>99%) selection of individual cells based on these measurements. The selection is achieved by using sub-millisecond timed control of a piezo-tilt mirror to steer a focused 1064-nm laser spot for optical gradient force switching following analysis of the fluorescence signals from passage of the cell through a series of 532-nm laser beams. In transit through each beam, the fluorescent proteins within the cell undergo conversion to dark states, but the microfluidic chip enables the cell to pass sufficiently slowly that recovery from reversible dark states occurs between beams, thereby enabling irreversible photobleaching to be quantified separately from the reversible dark-state conversion. The microfluidic platform achieves sorting of samples down to sub-millilitre volumes with minimal loss, wherein collected cells remain alive and can subsequently proliferate. The instrument provides a unique first tool for rapid selection of individual mammalian cells on the merits of photostability and is likely to form the basis of subsequent lab-on a-chip platforms that combine photobleaching with other spectroscopic measurements for on-going research to develop advanced red fluorescent proteins by screening of genetic libraries. PMID- 23636094 TI - Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice. AB - Aortic aneurysms are life-threatening and often associated with defects in connective tissues and mutations in smooth muscle cell (SMC) contractile proteins. Despite recent advances in understanding altered signaling in aneurysms of Marfan syndrome, the underlying mechanisms and options for pharmacological treatment for other forms of aneurysms are still under investigation. We previously showed in mice that deficiency in the fibulin-4 gene in vascular SMCs (Fbln4(SMKO)) leads to loss of the SMC contractile phenotype, hyperproliferation, and ascending aortic aneurysms. We report that abnormal up-regulation of angiotensin-converting enzyme (ACE) in SMCs and subsequent activation of angiotensin II (AngII) signaling are involved in the onset of aortic aneurysms in Fbln4(SMKO) mice. In this model, aneurysm formation was completely prevented by inhibition of the AngII pathway with losartan or captopril within a narrow therapeutic window during the first month of life, even though the altered mechanical properties of blood vessel walls were not reversed by the pharmacological treatment. The therapeutic effects of losartan in Fbln4(SMKO) mice do not require the AngII receptor type 2 (Agtr2) but likely require both type 1a (Agtr1a) and 1b (Agtr1b) receptors. The results indicate that fibulin-4 is a vascular matrix component required for regulation of local angiotensin signaling and development and maintenance of the SMC phenotype. PMID- 23636099 TI - Electrical activity of the diaphragm (Edi) values and Edi catheter placement in non-ventilated preterm neonates. AB - OBJECTIVE: The electrical activity of the diaphragm (Edi) reflects neural respiratory drive. Edi peak correlates with inspiratory drive and Edi minimum (Edi min) correlates with the tonic activity of the diaphragm. Edi data in non ventilated preterm neonates have not been determined.The primary aim of this study was to determine Edi values in non-ventilated preterm neonates throughout postnatal maturation and with various types of noninvasive respiratory support. The secondary aim was to evaluate the success or complications of placement of the Edi catheter in premature neonates. STUDY DESIGN: This was a prospective observational study of non-ventilated neonates <33 weeks gestation. Data were collected weekly using an Edi catheter placed in neonates on highflow nasal cannula (HFNC), nasal cannula (NC) or room air (RA). Clinical stability was determined by measuring heart rate (HR), respiratory rate (RR) and oxygen saturation (Sats). Success and adverse events of Edi catheter placement was monitored. Statistics were obtained by analysis of variance, P<0.05 was considered significant. RESULT: Seventeen neonates were enrolled at 26 to 33 weeks postmenstrual age and studied from 1 to 10 weeks in duration. Overall Edi peak was 10.8+/-3.7 mcV (range 3.7 to 18.7) and Edi min was 2.8+/-1.1 mcV (range 0.8 to 7.6). There was no difference in Edi peak and min over postmenstrual ages within or between neonates, and no difference between those neonates on HFNC, NC or RA. HR, RR and Sats were not different over postmenstrual age or between any groups. The Edi catheter was placed successfully in 100% of these neonates. There were no adverse events noted. CONCLUSION: In clinically stable neonates, the inspiratory drive (Edi peak) and tonic activity (Edi min) do not change with postnatal maturation or with the level of noninvasive respiratory support. The Edi catheter can be placed successfully in these premature neonates. These Edi data have the potential to guide ventilatory management of premature neonates. PMID- 23636100 TI - Intestinal location of necrotizing enterocolitis among infants with congenital heart disease. AB - OBJECTIVE: To determine whether differences exist in the location of necrotizing enterocolitis (NEC) in infants with congenital heart disease (CHD) versus those without CHD. STUDY DESIGN: Retrospective cohort study utilizing 11 years of patient data. Inclusion criterion was surgical exploration for NEC. Presence or absence of CHD was determined. Surgical and/or pathology reports were reviewed to identify the location of NEC. Data were analyzed by t-tests and chi(2) analyses. RESULT: One hundred and sixty-seven patients met the inclusion criteria. CHD infants had a higher percentage of mortality. There was no difference in the location of NEC between non-CHD and CHD patients, with the predominant location being the small intestine in both. In addition, there was no difference in the location of NEC between preterm non-CHD patients and full-term CHD patients with the small intestine again being the primary site. CONCLUSION: Despite differences in gestational age between non-CHD and CHD patients, the location of NEC in these infants did not differ. PMID- 23636102 TI - Effective photocatalysis of functional nanocomposites based on carbon and TiO2 nanoparticles. AB - A unique nanocomposite C-TiO2 was prepared by the growth of TiO2 on carbon nanoparticles using a simple hydrothermal procedure. Transmission electron microscopic (TEM) measurements showed that the nanocomposites exhibited an average core diameter of approximately 5 nm with a rather well-defined lattice space (0.4 nm) that was somewhat larger than that (0.38 nm) of the (100) crystalline planes of anatase TiO2. This lattice expansion was accounted for by the formation of surface defect dipoles of the nanosized TiO2 particles. X-ray photoelectron spectroscopic (XPS) measurements suggested that partial charge transfer occurred from carbon nanoparticles to TiO2 by the interfacial Ti-O-C linkages, which led to effective diminishment of the C-TiO2 photoluminescence as compared to that of pure TiO2 or carbon nanoparticles, suggesting intimate electronic interactions between the carbon and TiO2 components in the nanocomposites. Such unique characteristics were then exploited for the effective photocatalytic degradation of organic pollutants, as exemplified by methylene blue, by C-TiO2 under UV photoirradiation. Experimental measurements showed that the photocatalytic activity of C-TiO2 nanocomposites was about twice that of TiO2 alone, whereas little activity was observed with carbon nanoparticles. This was attributed to the electron-accepting sites on the carbon nanoparticles that facilitated interfacial charge separation. PMID- 23636101 TI - Increased survival despite failure of transplanted human hepatocyte implantation into liver parenchyma of nude mice with repeated lethal Jo2-induced liver deficiency. AB - We recently found that rat hepatocyte transplantation was efficient (liver repopulation: 2.4%) in a sublethal nude mouse model (less than 33% mortality) of repeated liver injury generated using Jo2, a mouse-specific anti-Fas antibody, at sublethal dose of 250 ug/kg for 3 weeks. Genomic analysis of the livers revealed cell cycle blockade and an antiproliferative status of circadian genes, suggesting a selective advantage. By contrast, in the present study, freshly isolated human hepatocyte transplantation performed in the same mouse model resulted in implantation of less than 6,000 cells per liver (about 0.006% repopulation) in all animals. Genomic analysis of nude mouse livers revealed a lack of P21 upregulation, while a signature of stimulation of liver regeneration was observed, including upregulation of early response genes and upregulation of circadian genes. When we translated this sublethal model to a lethal model (65% mortality) by increasing the Jo2 repeated doses to 375 ug/kg, human hepatocyte engraftment was still very low; however, animal mortality was corrected by transplantation (only 20% mortality). Genomic findings in livers from the mice of the lethal Jo2 transplanted group were similar to those of the sublethal Jo2 transplanted group, that is, no selective advantage genomic signature and signature of mouse liver regeneration. In conclusion, transplanted human hepatocytes acted as if they modified nude mouse liver responses to Jo2 by stimulating liver regeneration, leading to an increased survival rate. PMID- 23636103 TI - What's in a setting?: Influence of organizational culture on provider adherence to clinical guidelines for treating tobacco use. AB - BACKGROUND: Organizational culture is an important but underinvestigated feature of the work environment that can impact provider behavior, including adherence to clinical practice guidelines. There is substantial evidence that physician assistance to smokers can produce significant reductions in tobacco use. However, this evidence has not been well translated into practice, as only a small proportion of smokers receive recommended treatment during medical visits. PURPOSE: This study examines organizational culture as a contextual feature of primary care clinics and its impact on adherence to evidence-based guidelines for treating tobacco use. METHODOLOGY: Cross-sectional survey data were collected from 500 primary care providers in 60 community clinics located in New York City. Relationships between provider adherence to "5A" clinical guidelines, as recommended by the U.S. Public Health Service, and both provider and organizational covariates were described. We used hierarchical linear modeling to examine the associations between clinic culture and provider treatment patterns. FINDINGS: Providers in clinics with stronger "group/clan," "hierarchical," and "rational" culture types, as compared with a "developmental" culture, reported greater adherence to 5A guidelines (p < .05). System-level structures and care processes were positively associated (p < .01), whereas number of ongoing quality initiatives was negatively associated with 5A delivery (p < .05). Provider familiarity with guidelines (p < .01), confidence with cessation counseling (p < .05), and perceived effectiveness in helping smokers quit were associated with more frequent 5A intervention (p < .01). PRACTICE IMPLICATIONS: Findings suggest that organizational culture can influence provider adherence to cessation treatment guidelines, even when controlling for other factors known to affect practice patterns. Specifically, cultures that emphasize human resources and performance standards are conducive to integrating 5A guidelines into routine practice. Understanding the role of organizational culture enables healthcare managers and practitioners to be strategic when implementing, and also sustaining, use of evidence-based guidelines. PMID- 23636104 TI - Congenital mydriasis associated with megacystis microcolon intestinal hypoperistalsis syndrome. AB - We report a case of congenital mydriasis in a neonate with megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS). Pilocarpine testing and gastrointestinal pathology in our patient suggest that the mydriasis is due to an underlying smooth muscle myopathy of the iris sphincter muscle. These findings may have important implications regarding the pathogenesis of MMIHS. PMID- 23636105 TI - A resting state functional magnetic resonance imaging study of patients with benign essential blepharospasm. AB - BACKGROUND: Benign essential blepharospasm (BEB) is a neurologic disorder characterized by an adult-onset focal dystonia that causes involuntary blinking and eyelid spasms. The pathophysiology of BEB patients remains unclear. This study investigated intrinsic low-frequency fluctuation in BEB patients during resting state functional magnetic resonance imaging (fMRI). METHODS: The study included 9 patients with BEB (mean age, 61.7 years; range, 52-66 years), in whom the average duration of symptoms was 2.7 +/- 1.8 years, and another 9 subjects from an age- and sex-matched control group. Resting state fMRI was performed in both the patients with BEB and the normal controls. Voxel-based analysis was used to characterize the alteration of amplitude of low-frequency fluctuation (ALFF) in both patients with BEB and the normal controls. RESULTS: The whole brain analysis indicated that in comparison with the normal control group, there was a significantly increased ALFF in the left putamen, pallidum, insular lobe, and medial prefrontal cortex and a significantly decreased ALFF in the bilateral somatosensory regions, thalami, cerebellum, and medial and posterior cingulate cortex. CONCLUSION: The present study suggests that both an abnormal default mode network and corticostriatopallidothalamic loop may play a role in the pathophysiology of BEB. PMID- 23636107 TI - A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT. AB - PURPOSE: To delineate the molecular basis for a novel autosomal recessive syndrome, characterised by distinct facial features, intellectual disability, hypotonia and seizures, in combination with abnormal skeletal, endocrine, and ophthalmologic findings. METHODS: We examined four patients from a consanguineous kindred with a strikingly similar phenotype, by using whole exome sequencing (WES). Functional validation of the initial results were performed by flow cytometry determining surface expression of glycosylphosphatidylinositol (GPI) and GPI anchored proteins and, in addition, by in vivo assays on zebrafish embryos. RESULTS: The results from WES identified a homozygous mutation, c.547A>C (p.Thr183Pro), in PIGT; Sanger sequencing of additional family members confirmed segregation with the disease. PIGT encodes phosphatidylinositol-glycan biosynthesis class T (PIG-T) protein, which is a subunit of the transamidase complex that catalyses the attachment of proteins to GPI. By flow cytometry, we found that granulocytes from the patients had reduced levels of the GPI anchored protein CD16b, supporting pathogenicity of the mutation. Further functional in vivo validation via morpholino mediated knockdown of the PIGT ortholog in zebrafish (pigt) showed that, unlike human wild-type PIGT mRNA, the p.Thr183Pro encoding mRNA failed to rescue gastrulation defects induced by the suppression of pigt. CONCLUSIONS: We identified mutations in PIGT as the cause of a novel autosomal recessive intellectual disability syndrome. Our results demonstrate a new pathogenic mechanism in the GPI anchor pathway and expand the clinical spectrum of disorders belonging to the group of GPI anchor deficiencies. PMID- 23636108 TI - An identity crisis: the need for core competencies in undergraduate medical education. AB - A medical student perspective on the role of core competencies in undergraduate medical education in light of medical education reform associated with recent Flexner II. PMID- 23636109 TI - Chronic eczematous eruptions in the aging: further support for an association with exposure to calcium channel blockers. AB - IMPORTANCE: Dermatologists frequently encounter patients of advanced age presenting with chronic eczematous eruptions of uncertain etiology. When a drug induced cutaneous eruption is suspected, identifying the responsible drug(s) is a complex clinical challenge. OBJECTIVE: To determine whether certain drug classes, and in particular calcium channel blockers, are associated with chronic eczematous eruptions in the aging (CEEA) in the United States. DESIGN: Retrospective case-control study. SETTING: Ambulatory patients from the Department of Dermatology, University of Utah School of Medicine, Salt Lake City. PATIENTS: The cases consisted of 94 patients 50 years and older presenting with otherwise unexplainable symmetrical eczematous eruptions of at least 2 months' duration between January 1, 2005, and December 31, 2011. Inclusion criteria also included histopathologic changes of spongiotic and/or interface dermatitis and clinical suspicion for a drug-induced cutaneous eruption. The controls consisted of 132 age-, sex-, and race-matched patients presenting with benign dermatologic conditions. A subgroup analysis on cases whose skin biopsy specimens showed a pattern of inflammation that is conventionally thought to be associated with eczematous drug eruptions (ie, eczematous and interface dermatitis) was also performed. MAIN OUTCOMES AND MEASURES: Specific drug classes associated with otherwise unexplainable CEEA. RESULTS: A statistically significant difference in drug class use between cases and controls for calcium channel blockers and thiazides was noted. For calcium channel blockers and thiazides, the matched odds ratios were 4.21 (95% CI, 1.77-9.97; P = .001) and 2.07 (95% CI, 1.08-3.96; P = .03) respectively. The histopathological pattern subgroup analysis failed to show any statistically significant associations. CONCLUSIONS: The findings of this study further support an association of calcium channel blockers, as well as thiazides, with CEEA in the United States. PMID- 23636110 TI - Direct analysis in real time mass spectrometry (DART-MS) of "bath salt" cathinone drug mixtures. AB - Rapid and versatile direct analysis in real time mass spectrometry (DART-MS) methods were developed for detection and characterization of synthetic cathinone designer drugs, also known as "bath salts". The speed and efficiency associated with DART-MS testing of such highly unpredictable samples demonstrate the technique as an attractive alternative to conventional GC-MS and LC-MS methods. A series of isobaric and closely related synthetic cathinones, alone and in mixtures, were differentiated using high mass accuracy and in-source collision induced dissociation (CID). Crime laboratories have observed a dramatic rise in the use of these substances, which has caused sample testing backlogs, particularly since the myriad of structurally related compounds are challenging to efficiently differentiate. This challenge is compounded by the perpetual emergence of new structural variants as soon as older generation derivatives become scheduled. Because of the numerous chemical substances that fall into these categories, along with the varying composition and complexity of mixtures of these drugs, DART-MS CID has the potential to dramatically streamline sample analysis, minimize the number of sample preparation steps, and enable rapid characterization of emerging structural analogs. PMID- 23636111 TI - The importance of early operative treatment in open fractures of the fingers. AB - INTRODUCTION: Current guidelines suggest early surgical treatment of open fractures. This rule in open hand fractures is not well supported and may be practically difficult to observe. Furthermore, desirable washout can be obtained in the emergency department (ED). The purpose of this study was to determine the importance of early surgery in our institution. METHODS: Seventy patients with open fractures of the hand were retrospectively reviewed for demographics, fracture characteristics, and complications. Statistical analysis included univariate analysis, Fisher exact test, and Akaike information criterion. RESULTS: Intravenous antibiotics were administered early in 53 (75.7%) patients. Mean (SD) time to surgery was 2.3 (134.9) hours. The infection rate was 11.4%. No significant relationship was found between fracture type, finger involved, hand dominance, comorbidities, and infection. Antibiotic administration was significantly related to infection (P = 0.007), whereas time to surgery was not (P = 0.33). Age was weakly related to infection (P = 0.08). DISCUSSION: Administration of intravenous antibiotics in the ED was the most significant factor in preventing infection, whereas the time to operation was not significant. Because a thorough washout and debridement can be performed on open hand fractures in the ED due to the ability to provide adequate anesthesia, the actual time to surgery may possibly be delayed without increasing the risk of infection. Future prospective studies may allow for better guidelines for the treatment of open hand fractures. PMID- 23636112 TI - Paracrine mechanism of angiogenesis in adipose-derived stem cell transplantation. AB - INTRODUCTION: Adipose-derived stem cells (ASCs) have shown potential for cell based therapy in the field of plastic surgery. However, the fate of ASCs after transplantation and the mechanism(s) of their biologic capabilities remain unclear. METHODS: We isolated and cultured ASCs from transgenic mice that express both luciferase and green fluorescent protein and injected the cells into the inguinal fat pads of wild-type mice. We tested 4 experimental groups, namely, ischemic fat pads with/without ASCs and control fat pads with/without ASCs. RESULTS: Transplanted ASCs were tracked with bioluminescence imaging. The luminescence gradually decreased over 28 days, indicating cell death after transplantation. More ASCs were retained in ischemic fat pads on day 7 compared to control fat pads. On day 14, adipose tissue vascular density was higher in the ASC transplantation groups compared to those without ASCs. On day 28, there was decreased atrophy of adipose tissue in ASC-treated ischemic fat pads. Transplanted ASCs were detected as nonproliferating green fluorescent protein positive cells, whereas native endothelial cells adjacent to the transplanted ASCs were proliferative. Protein analysis demonstrated higher expression of hepatocyte growth factor and vascular endothelial growth factor in the ASC transplantation groups, suggesting a paracrine mechanism, which was confirmed by in vitro experiments with conditioned media from ASCs. CONCLUSIONS: Transplanted ASCs are preferentially retained in ischemic adipose tissue, although most of the cells eventually undergo cell death. They exert an angiogenic effect on adipose tissue mainly through a paracrine mechanism. Increased understanding of these effects will help develop ASCs as a tool for cell-based therapy. PMID- 23636113 TI - The effect of centrifugation condition on mature adipocytes and adipose stem cell viability. AB - Different researchers have recommended different lipoaspirate centrifugation speeds and times, probably due to the limits in fat cell viability assays. We assessed fat cell viability using a fluorescein diacetate and propidium iodide (FDA-PI) stain and 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5 carboxanilide (XTT) assay after harvesting syringe liposuction and spun with different centrifugation speeds to determine the optimal conditions. Lipoaspirates, harvested from 13 donors, were transferred into a centrifuge tube and spun at 1000, 3000, and 4000 rpm for 3 minutes. Mature adipocytes and adipose stem cells were isolated and tested with a direct counting of FDA-PI-stained cells under fluorescence microscope and XTT assay. We incubated adipocytes and adipose stem cells for 1 day and 3 days, and we compared both of them with fresh samples to evaluate the influence of culturing condition on fat cell viability. Centrifugation speeds from 1000 rpm to 4000 rpm for 3 minutes showed no change in the percentage of adipocytes and adipose stem cell viability not only in the fresh samples but also in the cultured samples (1 day and 3 days). Centrifugation speeds under 4000 rpm do not change the percentage of fat cell viability. To differentiate viable cells from dying or dead mature adipocytes and oil accurately, combinations of viability tests are essential. PMID- 23636115 TI - Urethra reconstruction with a prelaminated pedicled anterolateral thigh flap: a case report. AB - We present a case report of urethral reconstruction with a pedicled anterolateral thigh flap prelaminated with bladder mucosa in sex reassignment. The successful outcome may make this technique worthy to be considered in the secondary reconstruction of urethra in difficult cases. To the best of the authors' knowledge, no similar case has been previously described. PMID- 23636116 TI - Mandibular marginal contouring in oriental aesthetic surgery: refined surgical concept and operative procedure. AB - OBJECTIVES: In aesthetic mandibular contouring surgery, which is often conducted in Asians, the operative procedure is thought to deliver a more aesthetic mandibular shape by means of contouring conducted as a whole from the ramus to the symphysis. The authors describe the refined concept and operative procedures of mandibular marginal contouring. METHODS: For the 7-year period from 2004 to 2011, mandibular marginal contouring has been used in 57 consecutive series of Japanese subjects. Patient ages ranged from 18 to 33 years, and the subjects included 15 men and 42 women. The surgery was carried out by cutting off the protruding deformed mandibular margin from the ramus to the symphysis. In 53 of 57 cases, the focus was on angle contouring. Concomitant genioplasty by horizontal osteotomy of the chin was conducted in 42 of 57 cases (recession, advancement, shortening, elongation, and correction of the shift variously). In 22 materials exhibiting bulk around the mandibular, the ramus to the body was excised sagittally and thinned. In all the patients, mandibular marginal contouring from the ramus to the symphysis was completed. Partial masseter muscle resection was conducted in 11 of 57 cases. RESULTS: Mandibular contouring effectively achieved a highly satisfactory result in all cases. The upper portion of the peripheral branch of the trunk of the mental nerve was dissected by an electric scalpel in 1 case but sutured immediately using an 8-0 nylon stitch. Transient palsy of the mental nerve was noticed in a few cases but subsided in 1 to 2 months. No particular complications were encountered. No secondary revision was required in this series. CONCLUSIONS: In mandibular angle plasty, mandibular marginal contouring from the ramus to the symphysis should be carried out by cutting off the angle keeping in mind the entire mandibular shape. This concept and the procedure can deliver greater patient satisfaction. PMID- 23636114 TI - Comparison of outcomes using AlloDerm versus FlexHD for implant-based breast reconstruction. AB - BACKGROUND: Prosthetic reconstruction using human acellular dermis (ADM) is a common practice in breast reconstruction. AlloDerm and FlexHD are two different forms of ADM, each with unique characteristics. No studies have directly compared the postoperative complications of these 2 products. METHODS: The outcomes of 547 consecutive implant-based breast reconstructions were reviewed. RESULTS: Reconstruction was performed in 382 consecutive women (547 total breasts), employing mostly immediate reconstruction (81%). Mean follow-up was 6.4 months. Among immediate reconstructions, 165 used AlloDerm and 97 used FlexHD. Complications were similar by univariate analysis. In multivariate analysis, smoking and higher initial implant fill were risk factors for delayed healing. The use of FlexHD, single-stage reconstruction, and smoking were independent risk factors for implant loss. CONCLUSIONS: There is no significant difference in the complication rates between AlloDerm and FlexHD in immediate breast reconstruction. Multivariate analysis suggests that FlexHD may be a risk factor for implant loss. PMID- 23636119 TI - Preoperative imaging of perforator flaps in reconstructive surgery: a systematic review of the evidence for current techniques: reply. PMID- 23636118 TI - Autologous transplantation of adipose-derived stem cells enhances skin graft survival and wound healing in diabetic rats. AB - BACKGROUND: Diabetes can lead to impaired wound healing and skin grafts used surgically for diabetic wounds are often complicated with necrosis, although different therapies have been proposed. Adipose-derived stem cells (ASCs) participate in tissue repair processes and may have a role during impaired wound healing. In this study, autologous transplantation of ASCs was used to determine if it increases angiogenesis and skin graft survival and enhances wound healing in diabetic rats. METHODS: Adipose-derived stem cells were successfully isolated and cultured. A full-thickness skin graft model was used to determine the effects of locally administered ASCs in 10 rats rendered diabetic (group 1), whereas 10 others served as controls (group 2). Histological examination of skin grafts followed after 1 week. Additionally, immunohistochemical staining intensity of vascular endothelial growth factor (VEGF) and transforming growth factor beta3 (TGF-beta3) was assessed in all grafts. RESULTS: The gross and histological results showed significantly increased survival, angiogenesis, and epithelialization. Mean area of graft necrosis was significantly less in group 1 than in group 2 (7.49% vs 39.67%, P < 0.001). Statistically significant increase of capillary density, collagen intensity, VEGF, and TGF-beta3 expression was noted in group 1 compared with group 2. CONCLUSIONS: These findings suggest that autologous ASC transplantation can enhance skin graft survival in diabetic rats through differentiation, vasculogenesis, and secretion of growth factors such as VEGF and TGF-beta3. This might represent a novel therapeutic approach in skin graft surgery for diabetic wounds. PMID- 23636120 TI - Medial epicanthoplasty without a vertical scar. AB - BACKGROUND: The epicanthal fold (Mongolian fold) in Asians reduces the aesthetic results of eyelid surgery, and thus, medial epicanthoplasty is commonly performed in combination with a double fold operation or blepharoptosis correction. Epicanthoplasty is one of the most popular cosmetic operations conducted in Asia, but scarring is a common problem. METHODS: From December of 2006 to July of 2011, we treated 60 cases using our epicanthoplasty method, which was designed to reduce scarring. A double fold operation and blepharoptosis correction was performed along with epicanthoplasty in 54 cases and an epicanthoplasty without a double fold operation in the remaining 6 cases. Follow-up periods ranged from 6 months to 4 years and 10 months. Previously, we used an elliptical excision epicanthoplasty method, which was simple and practical. However, the elliptical excision method leaves a vertical scar on the nasal side of the upper and lower eyelids. To avoid this scar, we placed an additional incision parallel with the ciliary margin of the lower and/or upper eyelids. The results of epicanthoplasty were evaluated by asking the patients and the surgeon involved to allocate visual analog scale scores. RESULTS: With the exception of 1 case of hypertrophic scarring and 4 cases of undercorrection, patients were satisfied with their results. Mean patient and surgeon visual analog scale scores were 4.6 and 4.2, respectively. The advantages of the described procedure are its simplicity and the minimal scarring caused in the epicanthal area. CONCLUSIONS: This method could become an effective means of removing the Asian epicanthal fold and minimizing vertical scars. PMID- 23636122 TI - Control of protein and energy intake - brain mechanisms. AB - The protein content of the diet has long been investigated for its influence on food behavior. High-protein diets promote satiety and reduce calorie intake, whereas results for low-protein diets are more contradictory and less established. Protein sensing might take place in the oral cavity or in the post oral gastrointestinal tract, where specific receptors have been found. Protein signaling to the brain may act through the vagal nerve and involve gastric hormones, such as cholecystokinin and peptide YY. Other pathways are post absorptive signaling and the direct influence of brain levels of amino acids. High-protein diet enhances the activity of brain satiety centers, mainly the nucleus of the solitary tract and arcuate nucleus, although the activity of brain reward centers might also be modified. A better understanding of the role of both homeostatic and hedonic systems is needed to fully describe the influence of protein on food intake. PMID- 23636123 TI - Urinary cytopathology in primary bladder amyloidosis. AB - BACKGROUND: Amyloidosis results from the accumulation of unique extracellular proteins which are not able to be degraded via the usual mechanism of lysosomal proteolysis. Isolated collections of amyloid within the bladder are extremely uncommon, and a cytopathologic description in voided urine has not been described to date. METHODS: A retrospective review was performed at a tertiary-care hospital, and 3 patients with isolated bladder amyloidosis and corresponding voided urine specimens were identified. The following clinical data were collected for each case: age, gender, treatment and follow-up information. RESULTS: The patient age range was 76-84 years, with 2 males and 1 female. Amyloidosis was never clinically suspected. In 1 patient, a urinary amyloid manifested, which was thought to represent extraneous debris at the time of original diagnosis. Two patients never manifested signs of systemic amyloidosis or multiple myeloma, and the third was found to have a monoclonal gammopathy. CONCLUSIONS: Our results show the difficulty of diagnosing urinary amyloid in the absence of clinical suspicion. Further, the presence of urinary amyloid is unlikely in patients with bladder amyloidosis as the cohesive nature of the protein makes spontaneous shedding uncommon. Testing for systemic amyloidosis is warranted and if the disease is localized, a favorable outcome can be expected. PMID- 23636124 TI - Single-layered V2O5 a promising cathode material for rechargeable Li and Mg ion batteries: an ab initio study. AB - Using first principles calculations based on density functional theory, the adsorption and diffusion properties of Li and Mg atoms on single-layered and bulk V2O5 are investigated. The simulation results show that the diffusion barrier of Li on the single-layered V2O5 is decreased compared with that of the bulk V2O5, which indicates that the Li mobility can be significantly enhanced on the single layered V2O5. The increased binding energies of Li to single-layered V2O5 make them more attractive for promising cathode materials. Although the diffusion barrier of Mg on the single-layered V2O5 does not decrease, the binding energies of Mg to single-layered V2O5 is increased compared with that of bulk V2O5, thus the single-layered V2O5 is an attractive cathode material for rechargeable ion batteries. PMID- 23636125 TI - Shoulder pain and mobility deficits: adhesive capsulitis. PMID- 23636126 TI - EYA1 phosphatase function is essential to drive breast cancer cell proliferation through cyclin D1. AB - The Drosophila Eyes Absent Homologue 1 (EYA1) is a component of the retinal determination gene network and serves as an H2AX phosphatase. The cyclin D1 gene encodes the regulatory subunits of a holoenzyme that phosphorylates and inactivates the pRb protein. Herein, comparison with normal breast showed that EYA1 is overexpressed with cyclin D1 in luminal B breast cancer subtype. EYA1 enhanced breast tumor growth in mice in vivo, requiring the phosphatase domain. EYA1 enhanced cellular proliferation, inhibited apoptosis, and induced contact independent growth and cyclin D1 abundance. The induction of cellular proliferation and cyclin D1 abundance, but not apoptosis, was dependent upon the EYA1 phosphatase domain. The EYA1-mediated transcriptional induction of cyclin D1 occurred via the AP-1-binding site at -953 and required the EYA1 phosphatase function. The AP-1 mutation did not affect SIX1-dependent activation of cyclin D1. EYA1 was recruited in the context of local chromatin to the cyclin D1 AP-1 site. The EYA1 phosphatase function determined the recruitment of CBP, RNA polymerase II, and acetylation of H3K9 at the cyclin D1 gene AP-1 site regulatory region in the context of local chromatin. The EYA1 phosphatase regulates cell cycle control via transcriptional complex formation at the cyclin D1 promoter. PMID- 23636128 TI - Cost of and access to surgical care: how much, and how far? PMID- 23636127 TI - miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. AB - miRNAs (miR) have been shown to modulate critical gene transcripts involved in tumorigenesis, but their role in tumor-mediated immunosuppression is largely unknown. On the basis of miRNA gene expression in gliomas using tissue microarrays, in situ hybridization, and molecular modeling, miR-124 was identified as a lead candidate for modulating STAT3 signaling, a key pathway mediating immunosuppression in the tumor microenvironment. miR-124 is absent in all grades and pathologic types of gliomas. Upon upregulating miR-124 in glioma cancer stem cells (gCSC), the STAT3 pathway was inhibited, and miR-124 reversed gCSC-mediated immunosuppression of T-cell proliferation and induction of forkhead box P3 (Foxp3)(+) regulatory T cells (Treg). Treatment of T cells from immunosuppressed glioblastoma patients with miR-124 induced marked effector response including upregulation of interleukin (IL)-2, IFN-gamma, and TNF-alpha. Both systemic administration of miR-124 or adoptive miR-124-transfected T-cell transfers exerted potent anti-glioma therapeutic effects in clonotypic and genetically engineered murine models of glioblastoma and enhanced effector responses in the local tumor microenvironment. These therapeutic effects were ablated in both CD4(+)- and CD8(+)-depleted mice and nude mouse systems, indicating that the therapeutic effect of miR-124 depends on the presence of a T cell-mediated antitumor immune response. Our findings highlight the potential application of miR-124 as a novel immunotherapeutic agent for neoplasms and serve as a model for identifying miRNAs that can be exploited as immunotherapeutics. PMID- 23636130 TI - Worldwide need for a comprehensive database of stability data for pharmaceuticals stored in uncontrolled environments. AB - Developing a database to compile all known, relevant information on the stability of pharmaceuticals in tropical environments would vastly increase access to this information, improving safety and reducing cost. Many studies have examined the stability of pharmaceuticals stored under conditions that exceed manufacturer specifications, but this information is published across so many journals and Websites that it can be virtually inaccessible to clinics or suppliers needing to make pharmaceutical inventory management decisions. We have made progress toward the completion of a database of this nature, but resources and abilities of international public health organizations will be needed to bring the database fully to fruition. PMID- 23636131 TI - The difficult diagnosis of cartilaginous tibial eminence fractures in young children. AB - PURPOSE: Anterior tibial eminence fracture is the main mode of ACL failure in patients with open physes. In young children, purely cartilaginous avulsions of the tibial ACL insertion are possible. The aim of this study was to focus on patients referred for misdiagnosed cartilaginous tibial eminence fractures. METHODS: Ten young patients with cartilaginous tibial eminence fractures were identified in the hospital database. Six of them were misdiagnosed and included in this retrospective case series. Clinical data at the time of injury, radiographs and MRI were analysed in order to evaluate the causes which could have led to inappropriate management. RESULTS: The patients' median age at the time of injury was 7 years (5-8.5). The main cause of injury was a low-energy domestic accident (n = 4). Radiographs at the time of injury were normal (n = 4) or showed a very thin ossification (n = 2). The traditional MRI findings of ACL injuries were all negative. On T2 sequences, an epiphyseal fluid signal allowed for a retrospective diagnosis. Cartilaginous tibial eminence fractures were regularly prolonged posteriorly giving a 'double-PCL sign' in 4 of the 6 patients. On a median of 6 months (2.5-48) after the injury, patients were referred for repeat giving ways (n = 5) and/or limitation of extension or hyperextension (n = 4). Symptoms were related to non-union, ossification and secondary enlargement of the avulsed fragment. CONCLUSIONS: Post-traumatic knee joint effusions in children aged 9 or younger, even occurring after a low energy trauma and with normal radiographs, should suggest a cartilaginous tibial eminence fracture. Systematic MRI examinations should be mandatory in these patients in whom the avulsed fragment may appear as a double-PCL sign. During follow-up, new radiographs are recommended. A better knowledge of this rare entity should allow us to avoid misdiagnosis and to perform an early refixation of the avulsed fragment. PMID- 23636132 TI - Meta-analysis in asymmetric catalysis. Influence of chelate geometry on the roles of PN chelating ligands. AB - All X-ray structures of PN ligands forming 6-ring metal complex chelates have been retrieved from the CDS database, and those lacking chelate chirality filtered out. Many of the remainder fit naturally into four main families (PPFA, FcPhox, Phox and Quinap), which have been widely applied to asymmetric catalysis in diverse ways. It is known through experimental observation that certain of these ligand structures are more effective for specific classes of reaction but there has been little by way of explanation for their divergent behaviour. In this paper we examine the wide variation of conformations within individual families of PN complexes in the solid state, establish common features, and make cross-correlations with their effectiveness in specific catalytic asymmetric reactions. The extent of rigidity in the chelate varies widely and yet flexible complexes may be extremely effective in asymmetric catalysis. These observations emphasise the importance of induced fit between reactants and catalyst and militate against over-reliance on rigid lock-and-key models. PMID- 23636129 TI - Topographically-patterned porous membranes in a microfluidic device as an in vitro model of renal reabsorptive barriers. AB - Models of reabsorptive barriers require both a means to provide realistic physiologic cues to and quantify transport across a layer of cells forming the barrier. Here we have topographically-patterned porous membranes with several user-defined pattern types. To demonstrate the utility of the patterned membranes, we selected one type of pattern and applied it to a membrane to serve as a cell culture support in a microfluidic model of a renal reabsorptive barrier. The topographic cues in the model resemble physiological cues found in vivo while the porous structure allows quantification of transport across the cell layer. Sub-micron surface topography generated via hot-embossing onto a track-etched polycarbonate membrane, fully replicated topographical features and preserved porous architecture. Pore size and shape were analyzed with SEM and image analysis to determine the effect of hot embossing on pore morphology. The membrane was assembled into a bilayer microfluidic device and a human kidney proximal tubule epithelial cell line (HK-2) and primary renal proximal tubule epithelial cells (RPTEC) were cultured to confluency on the membrane. Immunofluorescent staining of both cell types revealed protein expression indicative of the formation of a reabsorptive barrier responsive to mechanical stimulation: ZO-1 (tight junction), paxillin (focal adhesions) and acetylated alpha-tubulin (primary cilia). HK-2 and RPTEC aligned in the direction of ridge/groove topography of the membrane in the device, evidence that the device has mechanical control over cell response. This topographically-patterned porous membrane provides an in vitro platform on which to model reabsorptive barriers with meaningful applications for understanding biological transport phenomenon, underlying disease mechanisms, and drug toxicity. PMID- 23636135 TI - Coralline algal barium as indicator for 20th century northwestern North Atlantic surface ocean freshwater variability. AB - During the past decades climate and freshwater dynamics in the northwestern North Atlantic have undergone major changes. Large-scale freshening episodes, related to polar freshwater pulses, have had a strong influence on ocean variability in this climatically important region. However, little is known about variability before 1950, mainly due to the lack of long-term high-resolution marine proxy archives. Here we present the first multidecadal-length records of annually resolved Ba/Ca variations from Northwest Atlantic coralline algae. We observe positive relationships between algal Ba/Ca ratios from two Newfoundland sites and salinity observations back to 1950. Both records capture episodical multi-year freshening events during the 20th century. Variability in algal Ba/Ca is sensitive to freshwater-induced changes in upper ocean stratification, which affect the transport of cold, Ba-enriched deep waters onto the shelf (highly stratified equals less Ba/Ca). Algal Ba/Ca ratios therefore may serve as a new resource for reconstructing past surface ocean freshwater changes. PMID- 23636134 TI - Tuberous breast: revised classification and a new hypothesis for its development. AB - The tuberous breast classification proposed by Grolleau does not account for a minor form of the deformity characterized by isolated nipple-areola protrusion with a normal breast base. We have observed this minor form in six patients with normal breast shape and in ten patients with hypertrophic breasts. We propose an anatomical and physiological hypothesis for the development of the mammary gland. The breast is subjected to hormonal influences as early as the prepubertal period. These influences result in thrusting forces with both horizontal (estrogen) and vertical (progesterone) vectors, unfortunately not always balanced and harmonious. Close observation of the anomaly in our patients substantiated the basic anatomical defect, namely, the structural congenital dermal weakness of the nipple-areola complex (NAC) already described in all forms of tuberous breast deformity. This weakness explains the morphologic anomaly and confirms that all types of tuberous breast deformity constitute a spectrum of a single entity. It indicates also that the classification of tuberous breasts should include, in addition to the three types (types I-III) already described, a fourth type (type 0) to describe isolated simple areola protrusion, either permanent or intermittent, that is associated with a normal mammary base. The revised classification of tuberous breasts and the proposed hypothesis of breast development allow better assessment of all possible variants of breast morphologic anomalies. In the six cases of isolated herniated NAC, the deformity was corrected through a perinipple approach (not circumareolar), with adequate stable correction of the deformity and minimal scarring. PMID- 23636137 TI - Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factor-alpha antagonists. AB - With the discovery of the central pathogenic role of tumor necrosis factor (TNF) alpha in many immunoinflammatory diseases, specific inhibition of this pleiotropic cytokine has revolutionized the treatment of patients with several non-infectious inflammatory disorders. As a result, genetically engineered anti TNF-alpha antibody constructs now constitute one of the heaviest medicinal expenditures in many countries. All currently used TNF antagonists may dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favorably, and safety can be severely impaired by immunogenicity, i.e., the ability of a drug to induce anti drug antibodies (ADA). Assessment of ADA is therefore an important component of the evaluation of drug safety in both pre-clinical and clinical studies and in the process of developing less immunogenic and safer biopharmaceuticals. Therapeutics diagnostics, also called theranostics, i.e., monitoring functional drug levels and neutralizing ADA in the circulation, is central to more effective use of biopharmaceuticals. Hence, testing-based strategies rather than empirical dose-escalation may provide more cost-effective use of TNF antagonists as this allows therapies tailored according to individual requirements rather than the current universal approach to diagnosis. The objective of the present review is to discuss the reasons for recommending theranostics to implement an individualized use of TNF antagonists and to highlight some of the methodological obstacles that have obscured cost-effective ways of using these therapies. PMID- 23636136 TI - Reviews of wellness and physical activity web sites for persons with neurological disability. PMID- 23636138 TI - Mitochondria, prostate cancer, and biopsy sampling error. AB - Mitochondria and their associated genome are emerging as sophisticated indicators of prostate cancer biology. Alterations in the mitochondrial genome (mtgenome) have been implicated in cell proliferation, metastatic behavior, androgen independence, as a signal for apoptosis, and as a predictor of biochemical recurrence. Somatic mutation patterns in complete mtgenomes are associated with prostate specific antigen levels (PSA) in prostate cancer patients and a large scale mtgenome deletion (3.4 kb) is consistent with a prostate "cancerization" field effect. This review will focus on the biological characteristics of mitochondria and their direct clinical application to prostate cancer. Mitochondrial science is currently influencing clinical prostate cancer diagnostics and the rapid progress in this area indicates future, break-through contributions in the general field of oncology. PMID- 23636139 TI - Advances and challenges in the treatment of glioblastoma: a clinician's perspective. AB - Glioblastoma (GBM) is the most deadly form of human cancer. Most patients diagnosed with this WHO grade IV malignant glioma survive about 12 months. Despite international efforts, treatment of GBM remains one of the most challenging tasks in clinical oncology. While new molecular pathways active in the biology and invasiveness of glioma are being constantly discovered, translation of basic science achievements into clinical practice is rather slow. Advances in surgical approaches, radiotherapy, and chemotherapy are contributing to incremental improvements in survival of the patients with GBM and improved quality of life. Yet much more significant strides need to be made before we can witness positive outcomes, similar to those seen in certain other cancers that can now be treated successfully. This review will discuss standard of care approach to GBM therapy in a newly diagnosed and recurrent setting. It will summarize the recent developments in management of this disease as well as future directions, keeping a practicing clinician in mind. PMID- 23636141 TI - Asthma phenotypes and endotypes: an evolving paradigm for classification. AB - Asthma is a common chronic disease characterized by intermittent chest symptoms, variable airways obstruction, and bronchial hyperresponsiveness. Research performed over the past one to two decades has sought to better understand the heterogeneous clinical nature of asthma. Whereas older attempts at phenotyping asthma emphasized the duality of allergic vs. non-allergic asthma, more recent non-biased analyses have attempted to cluster patients by a multitude of possible features, including age of onset, atopy, severity of airways obstruction, and requirement for medication. Examples of these phenotypes include early-onset mild allergic asthma, later-onset asthma associated with obesity, and severe non atopic asthma with frequent exacerbations. The elucidation of asthma phenotypes has been further refined by including information regarding pathophysiologic mechanisms present in different groups. These groups, called endotypes, include examples such as aspirin-exacerbated respiratory disease and allergic bronchopulmonary mycosis. A growing understanding of these mechanistically distinct groups, along with the identification of relevant cellular or molecular biomarkers, is already showing promise as a way of predicting clinical response to various asthma therapies. As the number of targeted treatments for asthma continues to grow, physicians will have the opportunity to practice an individualized approach to diagnosis and treatment, which will hopefully improve asthma outcomes and quality of life for these patients. PMID- 23636140 TI - Adherence to targeted oral anticancer medications. AB - The use of targeted oral anticancer medications (OAMs) is becoming increasingly prevalent in cancer care. Approximately 25-30% of the oncology drug pipeline involves oral agents and there are now over 50 OAMs approved by the Food and Drug Administration. This change represents a major shift in management of patients with cancer from directly observed, intermittent intravenous therapy to self administered, oral chronic therapy. The increased prevalence of OAMs raises the issue of adherence in oncology, including understanding the challenges of adherence to OAMs. This review focuses on studies of adherence for patients taking molecularly targeted OAMs for breast cancer, chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GIST), non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). We then discuss barriers to adherence and studies performed to date testing interventions for improving adherence. Finally, we discuss future areas of investigation needed to define and improve adherence to OAMs in targeted therapy for cancer. PMID- 23636142 TI - Therapeutic strategies for the treatment of multiple myeloma. AB - The outcome of patients with myeloma has improved significantly in the past decade with the incorporation of the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor, bortezomib. Considering nearly all patients relapse, myeloma remains an active area of investigation. There are several promising classes of agents including next generation immunomodulatory agents, proteasome inhibitors, antibody and antitumor immunotherapy approaches that are being evaluated. This article provides an overview on the therapeutic strategies in the treatment of multiple myeloma. PMID- 23636144 TI - Wide area coverage Raman spectroscopy for reliable quantitative analysis and its applications. AB - This review summarizes recent studies to improve sample representation in Raman measurement by covering a large area of a sample in spectral collection. Three different schemes have been mainly investigated to fulfill the goal: (1) averaging of Raman spectra collected at many different locations on a sample, (2) rotation of a sample during spectral collection and (3) simultaneous wide area illumination (WAI) for spectral collection. The use of a wide area illumination scheme, simultaneously illuminating a laser over a large area for spectral acquisition without any further assistance such as sample rotation, has increased in diverse fields. Applications employing the WAI scheme in pharmaceutical, polymer/chemical/petrochemical and other areas are described in this review. PMID- 23636143 TI - Personalized cancer treatment and the myth of KRAS wild-type colon tumors. AB - The impact of KRAS mutations on the efficacy of therapies that target the epidermal growth factor receptor (EGFR) is a major, ongoing area of oncology research, aimed at identifying the best possible treatments for individual colon cancer patients. Because patients with KRAS mutant colorectal tumors rarely respond to anti-EGFR monoclonal antibodies, testing is required to confirm the patient's tumor is KRAS wild-type before utilizing these therapies. Despite being studied for more than 30 years, new information continues to develop regarding KRAS and its role in colon carcinogenesis. This information must be integrated into the development of effective colon cancer treatment strategies. This review will summarize recent evidence that most, if not all, colon tumors encompass at least a subpopulation of KRAS mutant cells, meaning tumors characterized as KRAS wild-type are in most cases tumors with relatively low KRAS mutant tumor cell content. Recent studies support the hypothesis that relapse in advanced colorectal patients treated with EGFR-targeted monoclonal antibody therapy involves the outgrowth of previously undetected KRAS mutant tumor cell populations. Studies investigating the effects of oxidative stress on Ras signaling suggest that the frequent presence of minor KRAS mutant tumor cell populations may be a consequence of hypoxic conditions within tumors, which produce a negative selection against KRAS mutant cells in polyclonal tumors. Thus, the literature and current practices for characterizing tumor KRAS mutation don't accurately reflect the nature of colon tumor KRAS mutation, even though an accurate understanding is critical for identifying the best strategies for intervention. PMID- 23636145 TI - Can breast nipple fluid collected with automated aspiration and preserved in based-liquid solution improve the cytological samples? AB - OBJECTIVE: Samples from breast nipples collected with the automated HALOTM Mamo Cito Test were studied in order to evaluate the cellularity for the diagnosis of breast cancer. STUDY DESIGN: One hundred and fifty-nine asymptomatic women were prospectively examined. Women younger than 18 years, pregnant or lactating women, and women with a history of breast cancer, with previous radio- or chemotherapy and with nipple piercing were excluded from the study. Nipple samples from both breasts were collected. RESULTS: In 107 (34.96%) of the 306 samples of nipple discharge analyzed by optical microscopy, adequate cellularity was observed after the HALO procedure. Cytological findings, previously categorized according to the National Health Service Breast Screening Program (NHSBSP), were grouped as unsatisfactory, benign, suspected for malignancy, and malignant. Of the cellular breast samples, 97.19% (104/107) were classified as benign, and 2.81% (3/107) were classified as suspicious for malignancy. In 199 cases there were samples without cells (65.03%). Most of the cells observed were easily recognized as well preserved and adequately stained macrophages. None of the women reported discomfort with the nipple aspiration procedure. CONCLUSIONS: The results discussed here encouraged us to use samples collected automatically in routine procedures. PMID- 23636146 TI - Alteration in radiological subtype of spinal lipoma: case report. AB - We experienced a rare case of lipomyelomeningocele diagnosed at birth by magnetic resonance imaging which transformed the radiological appearance after 2 months into the transitional-type spinal lipoma with rapid increase in size of lipoma. Intraoperative findings revealed the presence of the dural sac extended dorsally outside the vertebral canal, which was characteristic of lipomyelomeningocele. Although there have been several reports showing that the size of spinal lipoma changed during development, there have been no reports which demonstrated alteration of radiological subtype with rapid increase of lipoma. Herein, we describe the first case of lumbosacral lipoma which changed radiological subtype from lipomyelomeningocele into transitional-type spinal lipoma. PMID- 23636147 TI - Kluver-Bucy syndrome after unilateral frontotemporal resection in a child with tuberous sclerosis. AB - Kluver-Bucy syndrome (KBS) is a behavioral phenotype that appears most often after bilateral temporal damage. The main features of KBS are compulsion to examine objects orally, increased sexual activity, placidity, hypermetamorphosis (irresistible impulse to notice and react to everything within sight), visual agnosia, and problems with memory. It is more rarely reported in children than in adults. We present a case of KBS in a 2-year-old boy with tuberous sclerosis complex (TSC) after left frontotemporal resection for refractory epilepsy. This is the first KBS after unilateral temporal resection in a child, although it has already been reported in two adult cases. It also is the first case reported in a TSC patient. PMID- 23636148 TI - Venolymphatic malformation of the proximal gastrocnemius muscle in a girl. AB - The patient was an 8-year-old girl who was referred to a physical therapist by her pediatrician for a chief complaint of worsening proximal right calf pain and progressive right-sided toe walking for the past 6 weeks. Due to concern that the patient's symptoms were nonmusculoskeletal in nature, the physical therapist discussed the history and physical examination findings with the patient's pediatrician and an orthopaedic surgeon. Subsequent magnetic resonance imaging and percutaneous biopsy led to a diagnosis of a low-flow venolymphatic malformation of the proximal gastrocnemius muscle. PMID- 23636149 TI - The art, science, and practice of pharmacy compounding. PMID- 23636151 TI - Impact of wellness coaching and monitoring services provided in a community pharmacy. AB - OBJECTIVE: To assess the clinical and patient-centered outcomes of health coaching provided in the workplace by community pharmacists. DESIGN: Prospective interventional cohort study. SETTING: 11 independent community pharmacy chain locations in northwest and central Missouri, from January 2010 to January 2011. PARTICIPANTS: 81 benefit-eligible patients and 23 community pharmacy coaches employed by the self-insured pharmacy chain. INTERVENTION: Patients were stratified into monitoring groups according to baseline screening values for cholesterol, blood pressure, fasting blood glucose (FBG), body mass index (BMI), and waist circumference. Patients selected their pharmacist coach. Follow-up appointments occurred monthly to quarterly. Appointments consisted of education, goal setting, and monitoring through evaluation of treatment goals and physical assessment. MAIN OUTCOME MEASURES: Change from baseline in mean total cholesterol, serum triglycerides, high-density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, systolic blood pressure (SBP), diastolic blood pressure (DBP), FBG, weight, BMI, waist circumference, health-related quality of life (HRQoL), and patient satisfaction. RESULTS: Patients' total cholesterol, LDL cholesterol, HDL cholesterol, DBP, and FBG were reduced significantly. Mean changes in triglycerides, SBP, weight, BMI, and waist circumference were not statistically significant. The 36-Item Short-Form Health Survey version 2.0 showed improvements in both the Physical and Mental Component Summaries but did not reach statistical significance. More than 90% of patients were satisfied with the service and the care they received. CONCLUSION: Wellness coaching by a pharmacist provided in a community pharmacy can result in significant improvements in cardiovascular risk factors, with a trend toward improved HRQoL. In addition, patients were satisfied with the wellness program from the start of the project. PMID- 23636152 TI - Development, implementation, and evaluation of a pharmacist-conducted screening program for depression. AB - OBJECTIVE: To develop, implement, and evaluate a depression screening program performed by pharmacists in the community setting; to determine the ability of this screening to identify and refer patients with symptoms of depression; and to determine whether physician referral results in initiation or modification of treatment. DESIGN: Prospective study. SETTING: 32 locations of a large grocery chain pharmacy in the Cincinnati and Dayton, OH, area from February 8, 2010, to March 30, 2011. PATIENTS: 3,726 patients 18 years or older. INTERVENTION: Patients were screened for depression using the Patient Health Questionnaire (PHQ). Patients who screened positive on the two-item PHQ (PHQ-2) then were given the nine-item PHQ (PHQ-9). Patients who screened positive on the PHQ-9 were referred to their physician. Pharmacists followed up with these patients to determine the action that was taken following the screening. MAIN OUTCOME MEASURES: Number of patients with a positive PHQ-9, number of patients referred to their physician, and number of patients for whom treatment was initiated or modified as a result of screening. RESULTS: 3,726 patients were screened for depression by pharmacists during the study period. A total of 67 (1.8%) patients screened positive on the PHQ-2. Of the patients who completed the PHQ-9, approximately 25% met the criteria for consideration of diagnosis and were referred to their physician. Five patients presented with suicidal thoughts and were referred for urgent treatment. Approximately 60% of patients with a positive PHQ-9 had initiated or modified treatment at the time of follow-up. CONCLUSION: A screening program for depression was successfully developed and implemented in the community pharmacy setting. Using the PHQ, pharmacists were able to quickly identify undiagnosed patients with symptoms of depression. The majority of patients with a positive screening had initiated or modified treatment at the time of follow-up. PMID- 23636153 TI - Intervention based on social cognitive theory: evaluating adolescents' knowledge of OTC pain medications. AB - OBJECTIVE: To evaluate the effect of a social cognitive theory (SCT)-based intervention on the constructs of situational perception, behavioral capabilities, outcome expectations, outcome expectancies, and self-efficacy concerning over-the-counter (OTC) pain medications among an adolescent population. DESIGN: Pre-posttest control group design. SETTING: Rural high school in the southeastern United States, between February and March 2011. PARTICIPANTS: 203 high school students recruited from 10 classrooms. INTERVENTION: Classrooms were randomly assigned to an SCT-based education intervention group or the control group. Pre- and posttest data were collected from each group 2 weeks before and 2 weeks after the intervention was delivered. MAIN OUTCOME MEASURES: Change in the five selected constructs of SCT. RESULTS: Compared with the control group, significant improvements at posttest were observed in the intervention group for outcome expectations of OTC pain medications ( P <= 0.05) and behavioral capabilities ( P <= 0.05). CONCLUSION: The results suggest that lessons based on SCT to improve the outcome expectations that an adolescent population places on the consumption of OTC pain medications may assist in developing the knowledge and skills needed to consume these products properly. PMID- 23636154 TI - Assessing patients' information needs regarding drug-drug interactions. AB - OBJECTIVE: To assess patients' information needs regarding drug-drug interactions (DDIs) to inform patient DDI education resources. DESIGN: Cross-sectional study. SETTING: Online (United States in May 2011). PARTICIPANTS: Registered users of an online medication monitoring service (MediGuard). INTERVENTION: Online questionnaire. MAIN OUTCOME MEASURE: Participants' information needs regarding DDIs and perceived importance of questions related to detecting and preventing harm from DDIs. RESULTS: Characteristics of the 100 surveyed participants were as follows: 57% women, 88% white, 96% non-Hispanic, 71% retired, mean (+/-SD) age 65.2 +/- 9.7 years (range 35-86). The number of prescription medications ranged from 2 to 22 (median 7) and the number of over-the-counter (OTC) medications from 1 to 10 (4). The most common concerns cited by participants were identification of interacting medications, seriousness of DDIs, interactions with OTC medications, interactions with foods, exacerbating comorbidities, short- and long term adverse effects, signs and frequency of DDIs, and how to minimize adverse effects. Statistically significant differences based on gender, number of prescriptions, and number of OTC medications were observed in rankings of the importance of some DDI questions ( P < 0.05). CONCLUSION: Patient-centered DDI education programs should consider addressing the seriousness of DDIs, the effect of DDIs on comorbidities, and interactions with OTC medications and foods and determining methods for identifying, minimizing, and managing DDIs. PMID- 23636155 TI - Effect of pharmacist intervention on herpes zoster vaccination in community pharmacies. AB - OBJECTIVE: To evaluate the effectiveness of community pharmacy-based interventions in increasing vaccination rates for the herpes zoster vaccine. DESIGN: Prospective intervention study with a pre-post design. SETTING: Three independent community pharmacies in Tennessee, from December 2007 to June 2008. PATIENTS: Patients whose pharmacy profiles indicated that they were eligible for the vaccine and patients presenting to receive the vaccine at study sites. INTERVENTION: Pharmacists promoted the herpes zoster vaccine through a press release published in local newspapers, a flyer accompanying each prescription dispensed at participating pharmacies, and a personalized letter mailed to patients whose pharmacy profiles indicated that they were eligible for the vaccine. MAIN OUTCOME MEASURES: Comparison of vaccination rates for the herpes zoster vaccine during the control and intervention periods and patients' indication for their sources of education and influence in receiving the vaccine. RESULTS: Vaccination rates increased from 0.37% (n = 59 of 16,121) during the control period to 1.20% (n = 193 of 16,062) during the intervention period ( P < 0.0001). Cochran-Armitage trend analyses, including the months before and after the interventions, confirmed a significantly higher vaccination rate during the intervention month than other months analyzed. More patients indicated that they were educated about the herpes zoster vaccine by one of the pharmacist-driven interventions than by a physician, family/friend, or other source during the intervention period ( P < 0.0001 for all comparisons). Also, more patients were influenced to receive the vaccination as a result of one of the pharmacist-driven interventions than influenced by a physician ( P = 0.0260) or other source ( P < 0.0001). No difference in the effectiveness of patient influence was found when the pharmacy interventions were compared with family/friends ( P = 0.1025). CONCLUSION: Three pharmacist-driven interventions were effective in increasing vaccination rates for the herpes zoster vaccine. PMID- 23636156 TI - Comparison of equations for dosing of medications requiring renal adjustment. AB - OBJECTIVE: To compare the Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) equations for renal dosing of medications in primary care patients. METHODS: Patients with stages 3, 4, or 5 chronic kidney disease who had been prescribed one of the renally cleared study medications during a 16-month time period were identified. The appropriate dose of patients' study medications, based on their most recent creatinine clearance (CrCl) and estimated glomerular filtration rate (eGFR), was determined. The primary outcome was the rate in which the CG and MDRD equations provided the same dosing recommendation. RESULTS: The rate at which the CG ideal body weight and MDRD equations recommended the same dose was 59.6% (P = 0.001). The rate at which the CG actual body weight and MDRD equations recommended the same dose was 71.1% ( P = 0.001). CONCLUSION: A significant difference exists in the doses derived from the CG and MDRD equations in the primary care setting. CG should continue to be used for renal dosing until further recommendations are available. PMID- 23636157 TI - Self-sealing capacity of vial stoppers after multiple needle punctures. AB - OBJECTIVE: To evaluate the self-sealing capacity of vial stoppers in two common radiopharmaceuticals after more than 10 needle punctures. METHODS: Assessment of self-sealing capacity was performed according to the self-sealing capacity test described in United States Pharmacopeial Convention (USP) General Chapter <381>. Groups of 10 vials of technetium (Tc)-99m sulfur colloid and Tc-99m tetrofosmin were tested for maintenance of self-sealing capacity following 10 punctures with 22-, 20-, and 18-gauge needles. Each vial was sequentially retested after additional sets of 10 punctures until failure of self-sealing capacity or until a total of 100 punctures, whichever came first. RESULTS: The median number of needle punctures with maintenance of self-sealing ability before failure for 22-, 20-, and 18-gauge needles was >100 (range all >100), >100 (all >100), and 60 (30 90), respectively, for sulfur colloid and >100 (all >100), >100 (50 to >100), and 50 (20-70), respectively, for tetrofosmin. Incidentally, coring particles were observed frequently in vials after many punctures with 18-gauge needles, but infrequently with 20-gauge and rarely with 22-gauge needles. CONCLUSION: Vial stoppers in two radiopharmaceutical products demonstrated robust self-sealing capacity, substantially exceeding the USP standard of 10 punctures with a 21 gauge needle. Coring particles were frequently observed after many punctures when using larger-bore needles but rarely when using smaller-bore needles. Under conditions commonly used, failure of self-sealing capacity and generation of coring particles are not anticipated to be problems encountered when puncturing vial stoppers of these two products substantially more than 10 times. PMID- 23636158 TI - Pilot testing of checklists to discern adverse drug reactions and adverse drug events. AB - OBJECTIVES: To estimate the prevalence of patient-reported adverse drug events (ADEs)/adverse drug reactions (ADRs) in the community pharmacy setting and determine the prevalence relative to pharmacist judgment. DATA SOURCES: The 2009 version of the Pharmacy Times top 200 drugs was used to identify the prescription medications most commonly used within the ambulatory population during 2008. All ADEs/ADRs for each medication were obtained by combining the ADEs/ADRs listed in Drug Facts and Comparisons, Lexi-Comp, and Micromedex. METHODS: Checklists for each pharmacologic class within the top 200 medications (n = 51) were developed, with questions about the five most common ADEs/ADRs in each class. Ten community pharmacies administered the checklists. Patients requesting a prescription refill for a medication listed in the top 200 were asked to complete a class-specific checklist to determine ADEs/ADRs experienced in the previous 4 weeks. Upon completion, pharmacists engaged in routine counseling procedures, including a discussion of patient-reported ADEs/ADRs. Pharmacists indicated if they believed, based on their clinical judgment, whether the ADE/ADR reported was related to the medication. RESULTS: 2,057 checklists were completed, with a total of 10,285 potential ADEs/ADRs. Patients reported 2,185 ADEs/ADRs (21.24%), with 755 (7.3%) definitively confirmed by the pharmacist as being related to their medication. CONCLUSION: Use of these checklists resulted in the identification of previously unrecognized ADEs/ADRs in the community setting. Routine use of these short, patient-completed checklists may assist pharmacists in earlier identification of ADEs/ADRs, which can have a positive impact on patient safety across settings. PMID- 23636159 TI - Advocating zoster vaccination in a community pharmacy through use of personal selling. AB - OBJECTIVE: To evaluate whether the use of personal selling, in combination with other promotional techniques, could improve patient commitment to receive the targeted intervention of herpes zoster vaccine (Zostavax-Merck). SETTING: Two locally owned grocery store chain pharmacies in the Kansas City, MO, metropolitan area (Price Chopper Pharmacy 11 [PC11] and Price Chopper Pharmacy 36 [PC36]). PRACTICE DESCRIPTION: Price Chopper Pharmacy employs pharmacists who are able to administer vaccinations to patients within the dispensing workflow. PRACTICE INNOVATION: Passive signage promoting zoster vaccine was placed at both PC11 and PC36. Personal selling by pharmacy staff to targeted patients was implemented at PC36, where patients were encouraged to receive zoster vaccine at prescription pick up and/or by personalized letter. MAIN OUTCOME MEASURES: Primary measures included comparison of the number committing to receive zoster vaccine at either pharmacy, comparison of patient perceptions regarding each pharmacy's promotion of zoster vaccine, and pharmacy staff time spent identifying targeted patients and performing personal selling activities. RESULTS: 90 of 745 targeted patients (12.1%) at PC36 made commitments to receive zoster vaccine compared with 9 of 614 (1.5%) at PC11 (P < 0.001). The barrier of "Dr. hasn't told me I need it" was reduced for PC36 patients (P < 0.05). Patients receiving vaccination had a more favorable attitude toward receiving zoster vaccine than unvaccinated patients (P < 0.01). Among unvaccinated patients, those at PC36 had a more favorable attitude toward receiving zoster vaccine after interacting with a pharmacist (P < 0.05). CONCLUSION: Personal selling increased patient commitment to receiving a targeted intervention significantly. By using personal selling, pharmacists resolved barriers to immunization. PMID- 23636160 TI - Postdischarge pharmacist medication reconciliation: impact on readmission rates and financial savings. AB - OBJECTIVE: To assess the impact of ambulatory clinical pharmacist medication therapy assessment and reconciliation for patients postdischarge in terms of hospital readmission rates, financial savings, and medication discrepancies. SETTING: Group Health Cooperative (Group Health) in Washington State, from September 2009 through February 2010. PRACTICE DESCRIPTION: Group Health is a nonprofit integrated group practice and health plan, operating 25 primary care medical centers and 5 specialty centers. Group Health's practice design is a patient-centered medical home model. PRACTICE INNOVATION: All patients identified as high risk for readmission were followed by Group Health care management. Patients in care management who received a phone call from a pharmacist 3 to 7 days postdischarge for medication therapy assessment and reconciliation were identified as the medication review group (n = 243). Patients who did not receive clinical pharmacist intervention were included in the comparison group (n = 251). MAIN OUTCOME MEASURES: Readmission rates, financial savings, and medication discrepancies. RESULTS: Patients who received medication therapy assessment and reconciliation had decreased readmission rates at 7, 14, and 30 days postdischarge, with statistical significance at 7 and 14 days. Medication review versus comparison readmission rates were as follows: 7 days: 0.8% vs. 4% ( P = 0.01); 14 days: 5% vs. 9% ( P = 0.04); and 30 days: 12% vs. 14% ( P = 0.29). Financial savings for Group Health per 100 patients who received medication reconciliation was an estimated $35,000, translating to more than $1,500,000 in savings annually. Of patients, 80% had at least one medication discrepancy upon discharge. CONCLUSION: Most literature on medication reconciliation evaluates inpatient processes, whereas data on medication reconciliation postdischarge are limited. Our data support the hypothesis that medication assessment and reconciliation by pharmacists 3 to 7 days postdischarge can decrease readmissions and provide cost savings. PMID- 23636163 TI - Vaccine administration: preventing serious shoulder injuries. PMID- 23636164 TI - Aclidinium bromide, tofacitinib citrate, and teriflunomide. PMID- 23636165 TI - Science Snippets. Pharmacy surveillance and low-literacy pharmacist intervention. PMID- 23636166 TI - Class-wide REMS for extended-release and long-acting opioids: potential impact on pharmacies. AB - OBJECTIVES: To provide an update on the recently approved class-wide risk evaluation and mitigation strategy (REMS) for extended-release (ER) and long acting (LA) opioids and to discuss the potential impact on pharmacy practice. DATA SOURCES: In mid-2011, the Food and Drug Administration notified drug manufacturers that a single, class-wide REMS would be required for ER and LA opioids. This regulation was the result of a multiyear process that incorporated input from government, drug manufacturers, medical associations, and other stakeholders. SUMMARY: The goal of the class-wide REMS for ER/LA opioids is to reduce addiction, unintentional overdose, and death resulting from inappropriate prescribing, misuse, and abuse. To accomplish these goals, this REMS focuses on physician education on safe and appropriate prescribing and patient counseling on the risks of opioids. Although voluntary, a movement to require physician education to obtain or renew Drug Enforcement Administration licensing is occurring. Pharmacists are not included in the class-wide REMS per se. Pharmacists play an important role in overall risk reduction and are critical to the success of the class-wide REMS. CONCLUSION: Although the changing requirements for prescribing ER/LA opioids will not have a direct effect on pharmacist workflow, the pharmacist-patient interaction remains critical for overall risk reduction with this class of medication. PMID- 23636167 TI - Photofragmentation at 263 nm of small peptides containing tyrosine: the role of the charge transfer on CO. AB - The photofragmentation pathways at 263 nm of several small peptides containing tyrosine as the UV chromophore have been characterized using a multi-coincidence technique. A detailed study of the fragmentation dynamics of protonated Glycine Tyrosine (GYH(+)), Tyrosine-Glycine (YGH(+)), Glycine-Tyrosine-Glycine (GYGH(+)), Alanine-Tyrosine (AYH(+)) and Tyrosine-Alanine (YAH(+)) is presented in this paper. Fragmentations occurring or initiated in an excited state are distinguished from those occurring after internal conversion to the ground electronic state by their rapid fragmentation times and binary nature. For the studied systems, it is shown that fragmentations occurring after internal conversion to the ground state are the dominant processes compared to fragmentations occurring in the excited state. The low abundances associated with the observed UV photospecific channels, i.e. Calpha-Cbeta bond breakage in YGH(+) and YAH(+) and direct z-type bond breakage in GYGH(+), respectively, can be rationalized upon consideration of charge transfer states accessible after absorption of one UV photon. Indeed, excited state calculations performed at the RI-CC2 level of theory indicate that charge transfer on the active CO group is a prerequisite for photospecific bond ruptures. The fragmentation mechanisms and the localization of the charge on the side chain after fragmentation are discussed in terms of ionization energies of the fragments. PMID- 23636168 TI - Information content and scalability in signal transduction network reconstruction formats. AB - One of the first steps towards holistic understanding of cellular networks is the integration of the available information in a human and machine readable format. This network reconstruction process is well established for metabolic networks, and numerous genome wide metabolic reconstructions are already available. Extending these strategies to signalling networks has proven difficult, primarily due to the combinatorial nature of regulatory modifications. The combinatorial nature of possible protein-protein interactions and post translational modifications affects both network size and the correspondence between the reconstructed network and the underlying empirical data. Here, we discuss different approaches to reconstruction of signal transduction networks. We divide the current approaches into topological, specific state based and reaction contingency based, and discuss their different information content and scalability. The discussion focusses on graphical formats but the points are in general applicable also to mathematical models and databases. While the formats have complementary strengths especially for small networks, reaction-contingency based formats have a number of advantages in the light of global network reconstruction. In particular, they minimise the need for assumptions, maximise the congruence with empirical data, and scale efficiently with network size. PMID- 23636169 TI - Simvastatin reduces venous stenosis formation in a murine hemodialysis vascular access model. AB - Venous neointimal hyperplasia (VNH) is responsible for hemodialysis vascular access malfunction. Here we tested whether VNH formation occurs, in part, due to vascular endothelial growth factor-A (VEGF-A) and matrix metalloproteinase (MMP) 9 gene expression causing adventitial fibroblast transdifferentiation to myofibroblasts (alpha-SMA-positive cells). These cells have increased proliferative and migratory capacity leading to VNH formation. Simvastatin was used to decrease VEGF-A and MMP-9 gene expression in our murine arteriovenous fistula model created by connecting the right carotid artery to the ipsilateral jugular vein. Compared to fistulae of vehicle-treated mice, the fistulae of simvastatin-treated mice had the expected decrease in VEGF-A and MMP-9 but also showed a significant reduction in MMP-2 expression with a significant decrease in VNH and a significant increase in the mean lumen vessel area. There was an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, and decreases in alpha-SMA density, cell proliferation, and HIF-1alpha and hypoxyprobe staining. This latter result prompted us to determine the effect of simvastatin on fibroblasts subjected to hypoxia in vitro. Simvastatin-treated fibroblasts had a significant decrease in myofibroblast production along with decreased cellular proliferation, migration, and MMP-9 activity but increased caspase 3 activity suggesting increased apoptosis. Thus, simvastatin results in a significant reduction in VNH, with increase in mean lumen vessel area by decreasing VEGF-A/MMP-9 pathway activity. PMID- 23636171 TI - Raising awareness of acute kidney injury: a global perspective of a silent killer. AB - Worldwide, acute kidney injury (AKI) is associated with poor patient outcomes. Over the last few years, collaborative efforts, enabled by a common definition of AKI, have provided a description of the epidemiology, natural history, and outcomes of this disease and improved our understanding of the pathophysiology. There is increased recognition that AKI is encountered in multiple settings and in all age groups, and that its course and outcomes are influenced by the severity and duration of the event. The effect of AKI on an individual patient and the resulting societal burden that ensues from the long-term effects of the disease, including development of chronic kidney disease (CKD) and end-stage renal disease (ESRD), is attracting increasing scrutiny. There is evidence of marked variation in the management of AKI, which is, to a large extent, due to a lack of awareness and an absence of standards for prevention, early recognition, and intervention. These emerging data point to an urgent need for a global effort to highlight that AKI is preventable, its course is modifiable, and its treatment can improve outcomes. In this article, we provide a framework of reference and propose specific strategies to raise awareness of AKI globally, with the goal to ultimately improve outcomes from this devastating disease. PMID- 23636170 TI - Numerous protein-bound solutes are cleared by the kidney with high efficiency. AB - The kidney clears numerous solutes from the plasma; however, retention of these solutes causes uremic illness when the kidneys fail. We know remarkably little about which retained solutes are toxic and this limits our ability to improve dialysis therapies. To explore this, we employed untargeted mass spectrometry to identify solutes that are efficiently cleared by the kidney. High-resolution mass spectrometry detected 1808 features in the urine and plasma ultrafiltrate of 5 individuals with normal renal function. The estimated clearance rates of 1082 peaks were greater than the creatinine clearance indicating tubular secretion. Further analysis identified 90 features representing solutes with estimated clearance rates greater than the renal plasma flow. Quantitative mass spectrometry with stable isotope dilution confirmed that efficient clearance of these solutes is made possible by the combination of binding to plasma proteins and tubular secretion. Tandem mass spectrometry established the chemical identity of 13 solutes including hippuric acid, indoxyl sulfate, and p-cresol sulfate. These 13 efficiently cleared solutes were found to accumulate in the plasma of hemodialysis patients, with free levels rising to more than 20-fold normal for all but two of them. Thus, further analysis of solutes efficiently cleared by secretion in the native kidney may provide a potential route to the identification of uremic toxins. PMID- 23636172 TI - Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway. AB - In chronic kidney disease (CKD), uremic solutes accumulate in blood and tissues. These compounds probably contribute to the marked increase in cardiovascular risk during the progression of CKD. The uremic solutes indoxyl sulfate and indole-3 acetic acid (IAA) are particularly deleterious for endothelial cells. Here we performed microarray and comparative PCR analyses to identify genes in endothelial cells targeted by these two uremic solutes. We found an increase in endothelial expression of tissue factor in response to indoxyl sulfate and IAA and upregulation of eight genes regulated by the transcription factor aryl hydrocarbon receptor (AHR). The suggestion by microarray analysis of an involvement of AHR in tissue factor production was confirmed by siRNA inhibition and the indirect AHR inhibitor geldanamycin. These observations were extended to peripheral blood mononuclear cells. Tissue factor expression and activity were also increased by AHR agonist dioxin. Finally, we measured circulating tissue factor concentration and activity in healthy control subjects and in patients with CKD (stages 3-5d), and found that each was elevated in patients with CKD. Circulating tissue factor levels were positively correlated with plasma indoxyl sulfate and IAA. Thus, indolic uremic solutes increase tissue factor production in endothelial and peripheral blood mononuclear cells by AHR activation, evoking a 'dioxin-like' effect. This newly described mechanism of uremic solute toxicity may help understand the high cardiovascular risk of CKD patients. PMID- 23636174 TI - SLC26 Cl-/HCO3- exchangers in the kidney: roles in health and disease. AB - Solute-linked carrier 26 (SLC26) isoforms constitute a conserved family of anion transporters with 10 distinct members. Except for SLC26A5 (prestin), all can operate as multifunctional anion exchangers, with three members (SLC26A7, SLC26A9, and SLC26A11) also capable of functioning as chloride channels. Several SLC26 isoforms can specifically mediate Cl(-)/HCO(3)(-) exchange. These include SLC26A3, A4, A6, A7, A9, and A11, which are expressed in the kidney except for SLC26A3 (DRA), which is predominantly expressed in the intestine. SLC26 Cl( )/HCO(3)(-) exchanger isoforms display unique nephron segment distribution patterns with distinct subcellular localization in the kidney tubules. Together with studies in pathophysiologic states and the examination of genetically engineered mouse models, the evolving picture points to important roles for the SLC26 family in health and disease states. This review summarizes recent advances in the characterization of the SLC26 Cl(-)/HCO(3)(-) exchangers in the kidney with emphasis on their essential role in diverse physiological processes, including chloride homeostasis, oxalate excretion and kidney stone formation, vascular volume and blood pressure regulation, and acid-base balance. PMID- 23636175 TI - Discrete functions of M2a and M2c macrophage subsets determine their relative efficacy in treating chronic kidney disease. AB - Two types of alternatively activated macrophages, M(2a) induced by IL-4/IL-13 and M(2c) by IL-10/TGF-beta, exhibit anti-inflammatory functions in vitro and protect against renal injury in vivo. Since their relative therapeutic efficacy is unclear, we compared the effects of these two macrophage subsets in murine adriamycin nephrosis. Both subsets significantly reduced renal inflammation and renal injury; however, M(2c) macrophages more effectively reduced glomerulosclerosis, tubular atrophy, interstitial expansion, and proteinuria than M(2a) macrophages. The M(2c) macrophages were also more effective than M(2a) in reduction of macrophage and CD4(+) T-cell infiltration in kidney. Moreover, nephrotic mice treated with M(2c) had a greater reduction in renal fibrosis than those treated with M(2a). M(2c) but not M(2a) macrophages induced regulatory T cells (Tregs) from CD4(+)CD25(-) T cells in vitro, and increased Treg numbers in local draining lymph nodes of nephrotic mice. To determine whether the greater protection with M(2c) was due to their capability to induce Tregs, the Tregs were depleted by PC61 antibody in nephrotic mice treated with M(2a) or M(2c). Treg depletion diminished the superior effects of M(2c) compared to M(2a) in protection against renal injury, inflammatory infiltrates, and renal fibrosis. Thus, M(2c) are more potent than M(2a) macrophages in protecting against renal injury due to their ability to induce Tregs. PMID- 23636173 TI - The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection. AB - Although the role of the erythropoietin (EPO) receptor (EpoR) in erythropoiesis has been known for decades, its role in nonhematopoietic tissues is still not well defined. Klotho has been shown and EPo has been suggested to protect against acute ischemia-reperfusion injury in the kidney. Here we found in rat kidney and in a rat renal tubular epithelial cell line (NRK cells) EpoR transcript and antigen, and EpoR activity signified as EPo-induced phosphorylation of Jak2, ErK, Akt, and Stat5 indicating the presence of functional EpoR. Transgenic overexpression of Klotho or addition of exogenous recombinant Klotho increased kidney EpoR protein and transcript. In NRK cells, Klotho increased EpoR protein, enhanced EPo-triggered phosphorylation of Jak2 and Stat5, the nuclear translocation of phospho-Stat5, and protected NRK cells from hydrogen peroxide cytotoxicity. Knockdown of endogenous EpoR rendered NRK cells more vulnerable, and overexpression of EpoR more resistant to peroxide-induced cytotoxicity, indicating that EpoR mitigates oxidative damage. Knockdown of EpoR by siRNA abolished Epo-induced Jak2, and Stat5 phosphorylation, and blunted the protective effect of Klotho against peroxide-induced cytotoxicity. Thus in the kidney, EpoR and its activity are downstream effectors of Klotho enabling it to function as a cytoprotective protein against oxidative injury. PMID- 23636177 TI - Incidence of antibodies to protamine sulfate/heparin complexes incardiac surgery patients and impact on platelet activation and clinical outcome. AB - A new ELISA (Zymutest HIA(r)), based on incubation of diluted plasma with protamine/heparin (PRT/H) complexes without and with platelet factor 4 (PF4) provided by a platelet lysate, was used to detect heparin-dependent antibodies in a cohort of 232 cardiac surgery (CS) patients and in 47 patients with heparin induced thrombocytopenia (HIT). Significant binding of IgG/A/M to PRT/H complexes was demonstrated in 59 CS patients (25.4%), with similar absorbances whether platelet lysate was added to the plasma or not, and significant reactivity to PF4/H in 29 of them. Antibodies to PRT or heparin alone were present in 15 and two of these patients, respectively. Importantly, antibodies to PRT/H were detected in only three of the 47 HIT patients, who had also undergone recent CS. The Zymutest HIA(r) was positive in another 41 CS patients (17%), but only or mainly when their plasma was tested with platelet lysate, with significant levels of antibodies to PF4/H in 40 of them without detectable reactivity to PRT or heparin alone. Slight antibody binding to PRT/H complexes was also measured in six of these 41 patients. Therefore, a total of 35 CS patients exhibited dual antibody reactivity towards PRT/H and PF4/H complexes. Serotonin release assay performed with PRT alone was positive in 17 CS patients with antibodies to PRT/H, but all had normal platelet count evolution without thrombosis postoperatively. In conclusion, antibodies to PRT/H are frequently present in CS patients postoperatively (25.4%), and can activate platelets in vitro, but their clinical impact remains questionable. PMID- 23636176 TI - Changes in dialysis treatment modalities during institution of flat rate reimbursement and quality assurance programs. AB - Dialysis procedure rates in Germany were changed in 2002 from per-session to weekly flat rate payments, and quality assurance was introduced in 2009 with defined treatment targets for spKt/V, dialysis frequency, treatment time, and hemoglobin. In order to understand trends in treatment parameters before and after the introduction of these changes, we analyzed data from 407 to 618 prevalent patients each year (hemodialysis over 90 days) in 14-21 centers in cross-sections of the Dialysis Outcomes and Practice Patterns Study (phases 1-4, 1998-2011). Descriptive statistics were used to report differences over time in the four quality assurance parameters along with erythropoietin-stimulating agent (ESA) and intravenous iron doses. Time trends were analyzed using linear mixed models adjusted for patient demographics and comorbidities. The proportion of patients with short treatment times (less than 4 h) and low spKt/V (below 1.2) improved throughout the study and was lowest after implementation of quality assurance. Hemoglobin levels have increased since 1998 and remained consistent since 2005, with only 8-10% of patients below 10 g/dl. About 90% of patients were prescribed ESAs, with the dose declining since peaking in 2006. Intravenous iron use was highest in 2011. Hence, trends to improve quality metrics for hemodialysis have been established in Germany even after introduction of flat rate reimbursement. Thus, analysis of facility practice patterns is needed to maintain quality of care in a cost-containment environment. PMID- 23636179 TI - Arthrogryposis, renal dysfunction, and cholestasis syndrome caused by VIPAR mutation. PMID- 23636178 TI - Duplicated STM-like KNOX I genes act in floral meristem activity in Eschscholzia californica (Papaveraceae). AB - In angiosperms, the shoot apical meristem is at the origin of leaves and stems and is eventually transformed into the floral meristem. Class I knotted-like homeobox (KNOX I) genes are known as crucial regulators of shoot meristem formation and maintenance. KNOX I genes maintain the undifferentiated state of the apical meristem and are locally downregulated upon leaf initiation. In Arabidopsis, KNOX I genes, especially SHOOTMERISTEMLESS (STM), have been shown to regulate flower development and the formation of carpels. We investigated the role of STM-like genes in the reproductive development of Eschscholzia californica, to learn more about the evolution of KNOX I gene function in basal eudicots. We identified two orthologs of STM in Eschscholzia, EcSTM1 and EcSTM2, which are predominantly expressed in floral tissues. In contrast, a KNAT1/BP-like and a KNAT2/6-like KNOX I gene are mainly expressed in vegetative organs. Virus induced gene silencing (VIGS) was used to knockdown gene expression, revealing that both EcSTM genes are required for the formation of reproductive organs. Silencing of EcSTM1 resulted in the loss of the gynoecium and a reduced number of stamens. EcSTM2-VIGS flowers had reduced and defective gynoecia and a stronger reduction in the number of stamen than observed in EcSTM1-VIGS. Co-silencing of both genes led to more pronounced phenotypes. In addition, silencing of EcSTM2 alone or together with EcSTM1 resulted in altered patterns of internodal elongation and sometimes in other floral defects. Our data suggest that some aspects of STM function present in Arabidopsis evolved already before the basal eudicots diverged from core eudicots. PMID- 23636180 TI - Underground hibernation in a primate. AB - Hibernation in mammals is a remarkable state of heterothermy wherein metabolic rates are reduced, core body temperatures reach ambient levels, and key physiological functions are suspended. Typically, hibernation is observed in cold adapted mammals, though it has also been documented in tropical species and even primates, such as the dwarf lemurs of Madagascar. Western fat-tailed dwarf lemurs are known to hibernate for seven months per year inside tree holes. Here, we report for the first time the observation that eastern dwarf lemurs also hibernate, though in self-made underground hibernacula. Hence, we show evidence that a clawless primate is able to bury itself below ground. Our findings that dwarf lemurs can hibernate underground in tropical forests draw unforeseen parallels to mammalian temperate hibernation. We expect that this work will illuminate fundamental information about the influence of temperature, resource limitation and use of insulated hibernacula on the evolution of hibernation. PMID- 23636181 TI - Comminuted fractures of the femoral neck and scaphoid. AB - The patient was a 48-year-old man serving in a deployed combat setting, who was referred to a physical therapist for evaluation of progressively worsening left hip and left wrist pain. Due to concern for hip and wrist fractures, the physical therapist ordered radiographs of the left hip and left wrist. The radiographs revealed comminuted fractures of the midneck to distal neck of the left femur and left scaphoid. PMID- 23636182 TI - The use of erythromycin and colistin-loaded cement in total knee arthroplasty does not reduce the incidence of infection: a prospective randomized study in 3000 knees. AB - BACKGROUND: The use of antibiotic-loaded cement is believed to prevent infection in primary total knee arthroplasty, but there is a lack of randomized studies to support this concept. The aim of this study was to evaluate the use of an antibiotic-loaded cement to reduce the infection rate in primary total knee arthroplasty. METHODS: This is a prospective randomized study with 2948 cemented total knee arthroplasties, in which bone cement without antibiotic was used in 1465 knees (the control group) and a bone cement loaded with erythromycin and colistin was used in 1483 knees (the study group). All patients received the same systemic prophylactic antibiotics. The patients were followed for a minimum of twelve months. The rate of infection was analyzed according to the criteria of the Centers for Disease Control and Prevention. RESULTS: The rate of deep infection (1.4% in the control group and 1.35% in the study group; p = 0.96) and the rate of superficial infection (1.2% and 1.8%, respectively; p = 0.53) were similar in both groups. The factors related to a higher rate of deep infection in a multivariate analysis were male sex and an operating time of >125 minutes. CONCLUSIONS: The use of erythromycin and colistin-loaded bone cement in total knee arthroplasty did not lead to a decrease in the rate of infection when systemic prophylactic antibiotics were used, a finding that suggests that the use of antibiotic-loaded bone cement would not be indicated in the general population. Further research is needed to assess whether its use is recommended for patients with a higher risk of infection. PMID- 23636183 TI - Risk factors associated with deep surgical site infections after primary total knee arthroplasty: an analysis of 56,216 knees. AB - BACKGROUND: Deep surgical site infection following total knee arthroplasty is a devastating complication. Patient and surgical risk factors for this complication have not been thoroughly examined. The purpose of this study was to evaluate risk factors associated with deep surgical site infection following total knee arthroplasty in a large U.S. integrated health-care system. METHODS: A retrospective review of a prospectively followed cohort of primary total knee arthroplasties recorded in a total joint replacement registry from 2001 to 2009 was conducted. Records were screened for deep surgical site infection with use of a validated algorithm, and the results were adjudicated by chart review. Patient factors, surgical factors, and surgeon and hospital characteristics were identified with use of the total joint replacement registry. Cox regression models were used to assess risk factors associated with deep surgical site infection. RESULTS: A total of 56,216 total knee arthroplasties were identified; 63.0% were done in women, the average age of the patients was 67.4 years (standard deviation [SD] = 9.6), and the average body mass index (BMI) was 32 kg/m2 (SD = 6). The incidence of deep surgical site infection was 0.72% (404/56,216). In a fully adjusted model, patient factors associated with deep surgical site infection included a BMI of >=35 (hazard ratio [HR] = 1.47), diabetes mellitus (HR = 1.28), male sex (HR = 1.89), an American Society of Anesthesiologists (ASA) score of >=3 (HR = 1.65), a diagnosis of osteonecrosis (HR = 3.65), and a diagnosis of posttraumatic arthritis (HR = 3.23). Hispanic race was protective (HR = 0.69). Protective surgical factors included use of antibiotic irrigation (HR = 0.67), a bilateral procedure (HR = 0.51), and a lower annual hospital volume (HR = 0.33). Surgical risk factors included quadriceps release exposure (HR = 4.76) and the use of antibiotic-laden cement (HR = 1.53). In a subanalysis, operative time was a risk factor, with a 9% increased risk per fifteen-minute increment. CONCLUSIONS: Use of a comprehensive infection surveillance system, combined with a total joint replacement registry, identified patient and surgical factors associated with infection following total knee arthroplasty in a large sample. High-risk patients should be counseled, and modifiable clinical conditions should be optimized. Use of antibiotic irrigation should be encouraged, but antibiotic-laden cement may not be useful. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 23636184 TI - Human growth hormone may be detrimental when used to accelerate recovery from acute tendon-bone interface injuries. AB - BACKGROUND: There have been few scientific studies that have examined usage of human growth hormone to accelerate recovery from injury. The hypothesis of this study was that human growth hormone would accelerate tendon-to-bone healing compared with control animals treated with placebo in a rat model of acute rotator cuff injury repair. METHODS: Seventy-two rats underwent repair of acute rotator cuff injuries and were randomized into the following postoperative dosing regimens: placebo, and human growth hormone at 0.1, 1, 2, 5, and 10 mg/kg/day, administered subcutaneously once per day for fourteen days (Protocol 1). An additional twenty-four rats were randomized to receive either (1) placebo or (2) human growth hormone at 5 mg/kg, administered subcutaneously twice per day for seven days preoperatively and twenty-eight days postoperatively (Protocol 2). All rats were killed twenty-eight days postoperatively. Mechanical testing was performed. Ultimate stress, ultimate force, stiffness, energy to failure, and ultimate distension were determined. RESULTS: For Protocol 1, analysis of variance testing showed no significant difference between the groups with regard to ultimate stress, ultimate force, stiffness, energy to failure, or ultimate distension. In Protocol 2, ultimate force to failure was significantly worse in the human growth hormone group compared with the placebo group (21.1 +/- 5.85 versus 26.3 +/- 5.47 N; p = 0.035). Failure was more likely to occur through the bone than the tendon-bone interface in the human growth hormone group compared with the placebo group (p = 0.001). No significant difference was found for ultimate stress, ultimate force, stiffness, energy to failure, or ultimate distension between the groups in Protocol 2. CONCLUSIONS: In this rat model of acute tendon-bone injury repair, daily subcutaneous postoperative human growth hormone treatment for fourteen days failed to demonstrate a significant difference in any biomechanical parameter compared with placebo. Furthermore, subcutaneous administration of 5 mg/kg of human growth hormone twice daily from seven days preoperatively until twenty-eight days postoperatively demonstrated lower loads to ultimate failure and a higher risk of bone fracture failure compared with placebo. PMID- 23636185 TI - Methylprednisolone injections for the treatment of Morton neuroma: a patient blinded randomized trial. AB - BACKGROUND: Morton neuroma is a common cause of neuralgia affecting the web spaces of the toes. Corticosteroid injections are commonly administered as a first-line therapy, but the evidence for their effectiveness is weak. Our primary research aim was to determine whether corticosteroid injection is an effective treatment for Morton neuroma compared with an anesthetic injection as a placebo control. METHODS: We performed a pragmatic, patient-blinded randomized trial set within hospital orthopaedic outpatient clinics in Edinburgh, United Kingdom. One hundred and thirty-one participants with Morton neuroma (mean age, fifty-three years; 111 [85%] female) were randomized to receive either corticosteroid and anesthetic (1 mL methylprednisolone [40 mg] and 1 mL 2% lignocaine) or anesthetic alone (2 mL 1% lignocaine). An ultrasonographic image was obtained before treatment, and injections were performed with the needle placed under ultrasonographic guidance. The primary outcome was the difference in patient global assessment of foot health between the two groups at three months after injection. This was measured with use of a 100-unit visual analog scale (VAS) anchored by "best imaginable health state" and "worst imaginable health state." RESULTS: Compared with the control group, global assessment of foot health in the corticosteroid group was significantly better at three months (mean difference, 14.1 scale points [95% confidence interval, 5.5 to 22.8 points]; p = 0.002). The difference between the groups was also significant at one month. Significant and nonsignificant improvements associated with the corticosteroid injection were observed for measures of pain, function, and patient global assessment of general health at one and three months after injection. The size of the neuroma as determined by ultrasonography did not significantly influence the treatment effect. CONCLUSIONS: Corticosteroid injections for Morton neuroma can be of symptomatic benefit for at least three months. PMID- 23636186 TI - Surgical site infection following spinal instrumentation for scoliosis: a multicenter analysis of rates, risk factors, and pathogens. AB - BACKGROUND: Surgical site infection following correction of pediatric scoliosis is well described. However, we are aware of no recent multicenter study describing the rates of surgical site infection, and associated pathogens, among patients with different etiologies for scoliosis. METHODS: A multicenter, retrospective review of surgical site infections among pediatric patients undergoing spinal instrumentation to correct scoliosis was performed at three children's hospitals in the United States. Study subjects included all patients undergoing posterior spinal instrumentation from January 2006 to December 2008. Surgical site infections were defined according to the Centers for Disease Control and Prevention's National Healthcare Safety Network case definition, with infections occurring within one year after surgery. RESULTS: Following the analysis of 1347 procedures performed in 946 patients, surgical site infection rates varied among procedures performed in patients with different scoliosis etiologies. Procedures performed in patients with neuromuscular scoliosis had the highest surgical site infection rates (9.2%), followed by those performed in patients with syndromic scoliosis (8.8%), those performed in patients with other scoliosis (8.4%), those performed in patients with congenital scoliosis (3.9%), and those performed in patients with idiopathic scoliosis (2.6%). Surgical site infection rates varied among procedures in patients undergoing primary spinal arthrodesis based on etiology, ranging from 1.2% (95% confidence interval, 0.1% to 1.3%) in patients with idiopathic scoliosis to 13.1% (95% confidence interval, 8.4% to 17.8%) in patients with neuromuscular scoliosis. Surgical site infection rates following primary and revision procedures were similar among patients with different etiologies. In distraction-based growing constructs, rates were significantly lower for lengthening procedures than for revision procedures (p = 0.012). Multivariate analysis demonstrated that non-idiopathic scoliosis and extension of instrumentation to the pelvis were risk factors for surgical site infections. The three most common pathogens were Staphylococcus aureus (25.0% [95% confidence interval, 17.8% to 32.2%]), coagulase-negative staphylococci (17.1% [95% confidence interval, 10.9% to 23.3%]), and Pseudomonas aeruginosa (10.7% [95% confidence interval, 5.6% to 15.8%]). Overall, 46.5% (95% confidence interval, 35.5% to 57.5%) of surgical site infections contained at least one gram negative organism; 97.0% (95% confidence interval, 90.8% to 100.0%) of these infections were in patients with non-idiopathic scoliosis. CONCLUSIONS: Surgical site infection rates were significantly higher following procedures in patients with non-idiopathic scoliosis (p < 0.001). Lengthening procedures had the lowest rate of surgical site infection among patients with early onset scoliosis who had undergone instrumentation with growing constructs. Gram-negative pathogens were common and were most common following procedures in patients with non-idiopathic scoliosis. These findings suggest a role for targeted perioperative antibiotic prophylaxis to prevent surgical site infection following pediatric scoliosis instrumentation procedures. PMID- 23636187 TI - Elevated postoperative blood glucose and preoperative hemoglobin A1C are associated with increased wound complications following total joint arthroplasty. AB - BACKGROUND: Diabetes is an established risk factor for complications following total joint arthroplasty. However, the correlation between postoperative blood glucose and preoperative hemoglobin A1C levels with complications following total joint arthroplasty is not well described. METHODS: All patients undergoing elective primary total joint arthroplasty at our institution from 2004 through 2011 with both postoperative blood glucose and preoperative hemoglobin A1C levels were identified in a retrospective review. From among 1702 patients, those with wound complications within thirty days after the index arthroplasty were identified. A control group matched for exact age, sex, procedure, tourniquet use, surgical approach, and use of antibiotic cement was also created. Thirty patients met the study group inclusion criteria. The mean patient age was seventy two years (range, fifty-three to eighty-nine years); the majority (53%) of patients were female. RESULTS: The odds ratio for developing a wound complication was 3.75 (95% confidence interval, 1.25 to 11.22; p = 0.02) in patients with a mean postoperative glucose of >200 mg/dL, 3.0 (95% confidence interval, 0.97 to 9.30; p = 0.08) in patients with a maximum postoperative blood glucose of >260 mg/dL, and 9.0 (95% confidence interval, 1.14 to 71.20; p = 0.03) in patients with a preoperative hemoglobin A1C value of >6.7%. CONCLUSIONS: Patients with a mean postoperative blood glucose of >200 mg/dL or a preoperative hemoglobin A1C level of >6.7% are at increased risk for wound complications following elective primary total joint arthroplasty. These results show that poor preoperative and postoperative glucose control is independently associated with wound complications. PMID- 23636188 TI - Periprosthetic fractures in total ankle replacement: classification system and treatment algorithm. AB - BACKGROUND: Despite progress in implant design and surgical technique, the reported number of periprosthetic ankle fractures following total ankle joint replacement continues to increase. A treatment-oriented classification of these fractures has not yet been reported. The purpose of this study was to evaluate the prevalence, cause, and location of periprosthetic fractures and the stability of the associated prosthetic components after total ankle replacement and to develop a method of classification. METHODS: Data regarding 503 total ankle replacements with a mean follow-up of 14.7 months were reviewed. The prevalence, location, and possible cause of the fractures as well as prosthesis stability were analyzed and a systematic method of classification based on these factors was developed. RESULTS: Twenty-one patients (4.2%) with a periprosthetic fracture were identified. The fracture was intraoperative (Type 1) in eleven patients (2.2%) and postoperative in the remaining ten (2.0%). Two of the latter fractures were traumatic (Type 2) and eight were stress fractures (Type 3). Two-thirds (fourteen) of the twenty-one fractures occurred in the medial malleolus. CONCLUSIONS: The prevalence of periprosthetic fractures following primary total ankle replacement was relatively low. We propose a classification system for these fractures that is based on more than 500 cases. We believe that this classification can facilitate therapeutic decision-making, as it allows for differential analysis of the cause and guides the choice among operative and nonoperative treatment options. PMID- 23636189 TI - Contralateral C7 nerve transfer with direct coaptation to restore lower trunk function after traumatic brachial plexus avulsion. AB - BACKGROUND: Contralateral C7 nerve transfer to the median nerve has been used in an attempt to restore finger flexion in patients with total brachial plexus avulsion injury. However, the results have not been satisfactory mainly because of the requirement to use a long bridging nerve graft, which causes an extended nerve regeneration process and irreversible muscle atrophy. A new procedure involving contralateral C7 nerve transfer via a modified prespinal route and direct coaptation with the injured lower trunk is presented here. METHODS: Contralateral C7 nerve transfer via the modified prespinal route and direct coaptation with the injured lower trunk was performed in seventy-five patients with total brachial plexus avulsion injury. Thirty-five required humeral shortening osteotomy (3 to 4.5 cm) in order to accomplish the direct coaptation. The contralateral C7 nerve was also transferred to the musculocutaneous nerve through the bridging medial antebrachial cutaneous nerve arising from the lower trunk in forty-seven of the seventy-five patients. Recovery of finger, wrist, and elbow flexion was evaluated with use of the modified British Medical Research Council muscle grading system. RESULTS: The mean follow-up period (and standard deviation) was 57 +/- 6 months (range, forty-eight to seventy-eight months). Motor function with a grade of M3+ or greater was attained in 60% of the patients for elbow flexion, 64% of the patients for finger flexion, 53% of the patients for thumb flexion, and 72% of the patients for wrist flexion. CONCLUSIONS: Contralateral C7 nerve transfer via a modified prespinal route and direct coaptation with the injured lower trunk decreases the distance for nerve regeneration in patients with total brachial plexus avulsion injury. There was satisfactory recovery of finger flexion and wrist flexion in this series. In addition, contralateral C7 nerve transfer was successfully used to repair two different target nerves: the lower trunk and the musculocutaneous nerve. PMID- 23636190 TI - Ten percent of patients with adolescent idiopathic scoliosis have variations in the number of thoracic or lumbar vertebrae. AB - BACKGROUND: Surveys have demonstrated that wrong-site surgery of the spine is performed by up to 50% of spine surgeons over the course of a career. Inaccurate identification of appropriate vertebral levels is a common reason for wrong-site spine surgery. The present study examined the prevalence of variations in the number of vertebrae in patients with adolescent idiopathic scoliosis. METHODS: A retrospective review of radiographs and reports of 364 consecutive patients undergoing operative treatment for adolescent idiopathic scoliosis at a single center was performed. The study included eighty-eight male patients (24%) and 276 female patients (76%) with a mean age of fourteen years (range, ten to twenty years). Radiographs were reviewed to assess the number of thoracic and lumbar vertebrae and the presence of a lumbosacral transitional vertebra. RESULTS: Ten percent of the patients (thirty-eight) had an atypical number of vertebrae in the thoracic and/or lumbar spine. Twenty-one patients (5.8%) had an atypical number of thoracic vertebrae, with fourteen having eleven thoracic vertebrae and seven patients having thirteen. Twenty-four patients (6.6%) had an atypical number of lumbar vertebrae, with four having four lumbar vertebrae and twenty patients having six. A lumbosacral transitional vertebra was present in 6.3% (twenty three) of the patients. Multilevel vertebral anomalies were present in 1.9% of the patients (seven of 364). A variation in the number of vertebrae had been identified in 0.5% (two) of the reports by the radiologist. CONCLUSIONS: Variations in the number of thoracic or lumbar vertebrae were found in 10% of patients with adolescent idiopathic scoliosis but had been identified in only 0.5% of the radiology reports. PMID- 23636191 TI - Effects of vertebral column distraction on transcranial electrical stimulation motor evoked potential and histology of the spinal cord in a porcine model. AB - BACKGROUND: Spinal cord injury can occur following surgical procedures for correction of scoliosis and kyphosis, as these procedures produce lengthening of the vertebral column. The objective of this study was to cause spinal cord injury by vertebral column distraction and evaluate the histological changes in the spinal cord in relationship to the pattern of recovery from the spinal cord injury. METHODS: Global osteotomy of all three spinal columns was performed on the ninth thoracic vertebra of sixteen pigs. The osteotomized vertebra was distracted until transcranial electrical stimulation-motor evoked potential (TES MEP) signals disappeared or decreased by >80% compared with the baseline amplitude; this was defined as spinal cord injury. The distraction distance at which spinal cord injury occurred was measured, the distraction was released, and the TES-MEP recovery pattern was observed. A wake-up test was performed, two days of observations were made, and histological changes were evaluated in relationship to the recovery pattern. RESULTS: Spinal cord injury developed at a distraction distance of 20.2 +/- 4.7 mm, equivalent to 3.6% of the thoracolumbar spinal length, and the distraction distance was correlated with the thoracolumbar spinal length (r = 0.632, p = 0.009). No animals exhibited complete recovery according to TES-MEP testing, eleven exhibited incomplete recovery, and five exhibited no recovery. During the two days of observation, all eleven animals with incomplete recovery showed positive responses to sensory and motor tests, whereas none of the five animals with no recovery had positive responses. On histological evaluation, three animals that exhibited no recovery all showed complete severance of nerve fibers (axotomy), whereas six animals that exhibited incomplete recovery all showed partial white-matter injury. CONCLUSIONS: Parallel distraction of approximately 3.6% of the thoracolumbar length after global osteotomy resulted in spinal cord injury and histological evidence of spinal cord damage. The pattern of recovery from the spinal cord injury after release of the distraction was consistent with the degree of axonal damage. Axotomy was observed in animals that exhibited no recovery on TES-MEP, and only hemorrhagic changes in the white matter were observed in animals that exhibited incomplete recovery. PMID- 23636192 TI - Incidence of knee sepsis after ACL reconstruction at one institution: the impact of a clinical pathway. AB - BACKGROUND: After experiencing an unusually high incidence of knee sepsis after anterior cruciate ligament (ACL) reconstruction, we sought to (1) describe how we resolved this problem through temporary discontinuation of the procedure, formation of a multidisciplinary ACL Task Force, systematic investigation of clinical data and institutional care practices, and development and implementation of an evidence-based ACL Clinical Pathway (the Pathway); and (2) report our findings and results. METHODS: From 1999 through 2008, thirty-seven cases of knee sepsis after ACL reconstruction were recorded at our institution. In 2008 (yearly incidence, 4.4%), ACL reconstructions were temporarily suspended and a Task Force was assembled to (1) identify infection risk factors or epidemiological links among cases, (2) inspect environment and processes for possible infection sources, and (3) update existing perioperative practices according to current evidence-based guidelines to reduce surgical site infection risk. These actions led to the development of the Pathway for patients and providers. The rates of knee sepsis before and after the Pathway was implemented were compared. RESULTS: There was no consistent risk factor or epidemiologic link among the cases of knee sepsis other than the time and place of the ACL reconstruction. Process review identified shortfalls in decontamination and sterilization of some surgical equipment. Perioperative care practices review revealed wide interprovider variation. Pathway implementation reduced the rate of knee sepsis after ACL reconstruction from 1.96% (twenty-four cases after 1226 ACL reconstructions performed from 2002 to 2008) to 0% (zero cases after 500 ACL reconstructions performed from 2008 to 2011); the difference was significant (p = 0.003). CONCLUSIONS: When a Task Force investigation suggested that knee sepsis after ACL reconstruction was a multifactorial problem, we implemented and standardized evidence-based perioperative care practices via the institution-wide Pathway, which significantly improved the quality and consistency of care for patients undergoing ACL reconstruction, as well evidenced by the elimination of knee sepsis. PMID- 23636193 TI - The musculoskeletal effects of cigarette smoking. AB - ? Cigarette smoking decreases bone mineral density and increases the risk of sustaining a fracture or tendon injury, with partial reversibility of these risks with long-term cessation of smoking. ? Cigarette smoking increases the risk for perioperative complications, nonunion and delayed union of fractures, infection, and soft-tissue and wound-healing complications. ? Brief preoperative cessation of smoking may mitigate these perioperative risks. ? Informed-consent discussions should include notification of the higher risk of perioperative complications with cigarette smoking and the benefits of temporary cessation of smoking. PMID- 23636194 TI - Common peroneal nerve palsy following total hip arthroplasty: prognostic factors for recovery. AB - BACKGROUND: Common peroneal nerve palsy, although rare, is a serious complication of total hip arthroplasty. Although several publications have dealt with the risk factors for peroneal nerve palsy, there is little literature regarding the time it takes for the nerve to recover and the factors that influence its recovery. The purpose of this study was to elucidate the clinical course of this injury and identify prognostic factors for recovery. METHODS: From January 2000 to December 2007, 7969 primary and 1601 revision total hip arthroplasties were performed at our institution. Common peroneal nerve palsy developed following thirty-one (0.32%) of these procedures. Thirty of these patients were evaluated by a neurologist at the time of diagnosis and at regular intervals thereafter. Univariate and multivariate regression analyses were performed to identify risk factors and prognostic factors for recovery. RESULTS: On average, patients who developed common peroneal nerve palsy were significantly younger (fifty-six years) than those who did not develop palsy (sixty-three years, p < 0.05). Higher body mass index (BMI) was a negative prognostic factor for recovery from palsy (p < 0.05). The palsy was incomplete in twenty-five of the thirty patients, and fourteen of these recovered fully at a mean of 10.3 months (range, 1.0 to 50.0 months). Three of the five patients with complete nerve palsy recovered fully at a mean of 14.5 months (range, 8.0 to 21.0 months). CONCLUSIONS: Only one-half of the patients in the study who developed common peroneal nerve palsy following total hip arthroplasty recovered fully. The mean time to recovery was approximately one year for partial peroneal palsy and one and one-half years for complete palsy. Obesity adversely influenced the nerve recovery. PMID- 23636195 TI - Reconstruction of bone defects after osteomyelitis with nonvascularized fibular graft: a retrospective study in twenty-six children. AB - BACKGROUND: Persistent infection, soft-tissue fibrosis, and damage to periosteum compound the treatment of children with a bone defect following osteomyelitis. We report on a series of twenty-six patients treated with nonvascularized fibular graft and intramedullary fixation. METHODS: The series included eleven boys and fifteen girls (mean age, 6.8 years; range, three to twelve years) with gap nonunion after osteomyelitis. Initial treatment involved thorough debridement and sequestrectomy. When the infection was quiescent as indicated by inflammatory parameters, nonvascular fibular grafting with intramedullary Kirschner wire fixation (with or without additional external fixation) was performed. The time to union was noted, and a subgroup analysis was performed to correlate the size of the bone defect with the time to union. RESULTS: The mean duration of follow up was 3.02 +/- 0.74 years (range, 1.3 to 4.2 years), and the mean time to union was 38.76 +/- 12.02 weeks (range, fifteen to sixty weeks). There was a weak positive correlation between the time to union and the preoperative bone defect size (Pearson correlation coefficient, 0.699). The mean time to union was 31.7 +/ 11.5 weeks for a defect of <4 cm, 36.6 +/- 9 weeks for a defect of 4 to 6 cm, and 51 +/- 6.7 weeks for a defect of >6 cm. Delayed union was seen at one end of the fibular graft in four (15%) of the patients and was treated with plate fixation. One patient had recurrence of infection. Limb-length discrepancy (range, 2 to 5 cm) was seen in all patients in whom the lower limb was involved and was treated with a shoe lift. CONCLUSIONS: This series illustrates the potential benefits of staged sequestrectomy and nonvascular fibular grafting for the treatment of gap nonunion following osteomyelitis in children. The procedure is simple, does not require specialized training or equipment, and has a low complication rate. PMID- 23636196 TI - Effect of initial postoperative visit radiographs on treatment plans. AB - BACKGROUND: It is a common practice among orthopaedic surgeons to make radiographs at the first outpatient postoperative visit after surgical repair of acute fractures. There is not much literature that investigates the benefits and necessity of such a practice. We hypothesized that the practice of routine postoperative radiographs is unnecessary and increases cost to the patients and the health-care system, increases radiation exposure, and provides no change in patient management. METHODS: A retrospective review of patients sustaining acute fractures requiring operative fixation was done with the goal of determining how often a radiograph made at the first postoperative visit in the surgeon's office resulted in a change in patient management. RESULTS: Fifteen (7.5%) of 200 fractures in 171 patients had a clinical indication for a radiograph because of an abnormal physical examination finding or history of additional trauma. Three (1.5%) of these fractures had a deviation from standard postoperative care; this deviation was a change in postoperative care on the basis of the patient history and physical examination rather than radiographs. One fracture (0.5%) had a radiographic change from the immediate postoperative radiograph to the clinic radiograph, yet did not have a change in treatment. The estimated average radiation exposure per radiograph was 0.164 mSv, and the average charge to the patient per radiograph was $335.13. CONCLUSIONS: The majority of radiographs made at the first postoperative visit in the surgeon's office after acute fracture fixation did not result in a change in patient management and added substantial cost to the health-care system. PMID- 23636197 TI - EOS imaging of the human pelvis: reliability, validity, and controlled comparison with radiography. AB - BACKGROUND: The EOS technique represents a unique imaging modality combining low radiation exposure with high image quality. As its applications for pelvic imaging may increase with time, we performed a pilot study to evaluate the validity and reliability of this technique for the assessment of gross pelvic and acetabular morphology. METHODS: Consecutive conventional and EOS radiographs of a human cadaveric pelvis were made in 5 degrees intervals of sagittal tilt and axial rotation (range, -15 degrees to 15 degrees for each). Six measurements were made on each image: (1) the vertical distance between the sacrococcygeal joint and the upper border of the pubic symphysis, (2) the horizontal distance between the midpoints of these structures, (3) the distance between the anterior superior iliac spines, (4) the distance between the facets of S1, (5) the Sharp angle, and (6) the Tonnis angle. Coxa profunda and crossover signs were also evaluated. The findings of the two imaging techniques were correlated with each other and with true linear measurements made on the cadaveric pelvis. All measurements were performed by two independent observers, and one observer repeated all measurements to assess reproducibility. Both observers were blinded to the true linear measurements made on the pelvis. RESULTS: There was a strong correlation between the results of the conventional and EOS radiography (Pearson correlation coefficient, 0.644 to 0.998), and both modalities had high intraobserver and interobserver reproducibility (intraclass correlation coefficient, 0.795 to 1.000). Intraobserver and interobserver agreement on the presence of coxa profunda were both 100%. Intraobserver agreement (96.2%) and interobserver agreement (92.3%) on the presence of the crossover sign were marginally lower. Linear measurements differed significantly between the two modalities because of distortion caused by magnification effects in the conventional radiographic imaging (p < 0.05). CONCLUSIONS: The EOS imaging technique proved reliable for the assessment of gross pelvic and acetabular morphology, and it may be an alternative to current radiography for primary imaging in the pediatric population and potentially in adults as well. This study did not evaluate the ability of EOS imaging to detect subtle radiographic anatomic abnormalities. PMID- 23636198 TI - Mentorship in orthopaedic surgery-road map to success for the mentor and the mentee: AOA critical issues. PMID- 23636200 TI - The ethical and practical challenges of patient noncompliance in orthopaedic surgery. AB - A fifty-five-year old man attends a trauma follow-up clinic six weeks after undergoing primary repair of a zone-II finger flexor tendon laceration. The patient has a history of substance abuse and has been noncompliant with postoperative treatment. He has not attended any postoperative outpatient or physiotherapy appointments, he removed his splint immediately on discharge, and he admits to moving the finger freely without restrictions, against advice. On examination it is evident that the patient has sustained a rupture of the tendon repair. Does the history of noncompliance with initial treatment affect decisions regarding the further management of this patient? The term compliance relates to the degree of constancy and accuracy with which an individual patient follows a prescribed treatment. Patient noncompliance is a common problem across all specialties and presents a major obstacle to safe, effective, and efficient health-care delivery. In this article, we discuss the risk factors for noncompliance, the difficult ethical and medico-legal dilemmas posed by this issue, and mechanisms for potential solutions to this common problem. PMID- 23636199 TI - A comparison of orthopaedic resident performance on surgical fixation of an ulnar fracture using virtual reality and synthetic models. AB - BACKGROUND: Surgical trainees develop surgical skills using various techniques, with simulators providing a safe learning environment. Fracture fixation is the most common procedure in orthopaedic surgery, and residents may benefit from simulated fracture fixation. The performance of residents on a virtual simulator that allows them to practice the surgical fixation of fractures by providing a sense of touch (haptics) has not yet been compared with their performance using other methods of practicing fracture fixation, such as a Sawbones simulator model. The purpose of this study was to assess whether residents performed similarly on a newly developed virtual simulator compared with a Sawbones simulator fracture fixation model. METHODS: A stratified, randomized controlled study involving twenty-two orthopaedic surgery residents was performed. The residents were randomized to first perform surgical fixation of the ulna on either the virtual or the Sawbones simulator, after which they performed the same procedure on the other simulator. Their performance was evaluated by examiners experienced in fracture fixation who completed a task-specific checklist, global rating scale (GRS) form, and time-to-completion record for each participant on each simulator. RESULTS: Both simulators distinguished between differing experience levels, demonstrating construct validity; for the Sawbones simulator, the Cohen d value (effect size) was >0.90, and for the virtual simulator, d was >1.10 (p < 0.05 for both). The participants achieved significantly better scores on the virtual simulator compared with the Sawbones simulator (p < 0.05) for all measures except time to completion. The GRS scores showed a high level of internal consistency (Cronbach alpha, >0.80). However, Pearson product-moment correlation analysis showed no significant correlations between the results on the two simulators; therefore, concurrent validity was not achieved. CONCLUSIONS: The newly developed virtual ulnar surgical fixation simulator, which incorporates haptics, shows promise for helping surgical trainees learn and practice basic skills, but it did not attain the same standards as the current standard Sawbones simulator. The procedural measures used to assess resident performance demonstrated good reliability and validity, and both the Sawbones and the virtual simulator showed evidence of construct validity. PMID- 23636201 TI - What is the role of antibiotic-containing cement in total knee arthroplasty? PMID- 23636202 TI - Human growth hormone may not have biomechanical benefits, but is it detrimental? PMID- 23636203 TI - Steroid injection for Morton neuroma - data-based justification. PMID- 23636204 TI - Ecosystem service restoration after 10 years of rewetting peatlands in NE Germany. AB - The restoration of ecosystem services, i.e., production, regulation, and information, is a global challenge, which the federal state of Mecklenburg Vorpommern in NE Germany addressed in 2000 by rewetting over 20,000 ha of degraded peatlands within the Mire Restoration Program. We evaluated ecosystem services in 23 rewetted sites by assessing the following mire parameters within a ten year period: (a) dominant vegetation at the ecosystem level, (b) peat formation potential at the landscape level, and (c) aboveground biomass and nutrient levels. Seven to 10 years after rewetting, the wetlands formed a mosaic of vegetation types with the highest potential for peat formation and several dominant, peat-forming species accumulated high levels of aboveground biomass and nutrients (C, N, P). Common reed (Phragmites australis) accumulated the most biomass (up to 24 t dry matter/ha), and N+P during the growing season. A future management option is to annually harvest aquatic and wetland plants to reduce nutrient levels in restored mire ecosystems. PMID- 23636205 TI - Technical and institutional innovation in agroforestry for protected areas management in the Brazilian Amazon: opportunities and limitations. AB - Tropical forest countries are struggling with the partially conflicting policy objectives of socioeconomic development, forest conservation, and safeguarding the livelihoods of local forest-dependent people. We worked with communities in the lower Tapajos region of the central Brazilian Amazon for over 10 years to understand their traditional and present land use practices, the constraints, and decision making processes imposed by their biophysical, socioeconomic, and political environment, and to facilitate development trajectories to improve the livelihoods of forest communities while conserving the forest on the farms and in the larger landscape. The work focused on riverine communities initially in the Tapajos National Forest and then in the Tapajos-Arapiuns Extractive Reserve. These communities have a century-old tradition of planting rubber agroforests which despite their abandonment during the 1990s still widely characterize the vegetation of the river banks, especially in the two protected areas where they are safe from the recent expansion of mechanized rice and soybean agriculture. The project evolved from the capacity-building of communities in techniques to increase the productivity of the rubber agroforests without breaking their low input and low-risk logic, to the establishment of a community enterprise that allowed reserve inhabitants to reforest their own land with tree species of their choice and sell reforestation (not carbon) credits to local timber companies while retaining the ownership of the trees. By making land use practices economically more viable and ecologically more appropriate for protected areas, the project shows ways to strengthen the system of extractive and sustainable development reserves that protects millions of hectares of Amazon forest with the consent of the communities that inhabit them. PMID- 23636206 TI - Auditory research at the Walter Reed National Military Medical Center. PMID- 23636207 TI - Introduction: auditory models of suprathreshold distortion in persons with impaired hearing. PMID- 23636208 TI - Understanding excessive SNR loss in hearing-impaired listeners. AB - BACKGROUND: Traditional audiometric measures, such as pure-tone thresholds or unaided word-recognition in quiet, appear to be of marginal use in predicting speech understanding by hearing-impaired (HI) individuals in background noise with or without amplification. Suprathreshold measures of auditory function (tolerance of noise, temporal and frequency resolution) appear to contribute more to success with amplification and may describe more effectively the distortion component of hearing. However, these measures are not typically measured clinically. When combined with measures of audibility, suprathreshold measures of auditory distortion may provide a much more complete understanding of speech deficits in noise by HI individuals. PURPOSE: The primary goal of this study was to investigate the relationship among measures of speech recognition in noise, frequency selectivity, temporal acuity, modulation masking release, and informational masking in adult and elderly patients with sensorineural hearing loss to determine whether peripheral distortion for suprathreshold sounds contributes to the varied outcomes experienced by patients with sensorineural hearing loss listening to speech in noise. RESEARCH DESIGN: A correlational study. STUDY SAMPLE: Twenty-seven patients with sensorineural hearing loss and four adults with normal hearing were enrolled in the study. DATA COLLECTION AND ANALYSIS: The data were collected in a sound attenuated test booth. For speech testing, subjects' verbal responses were scored by the experimenter and entered into a custom computer program. For frequency selectivity and temporal acuity measures, subject responses were recorded via a touch screen. Simple correlation, step-wise multiple linear regression analyses and a repeated analysis of variance were performed. RESULTS: Results showed that the signal-to-noise ratio (SNR) loss could only be partially predicted by a listener's thresholds or audibility measures such as the Speech Intelligibility Index (SII). Correlations between SII and SNR loss were higher using the Hearing-in-Noise Test (HINT) than the Quick Speech-in-Noise test (QSIN) with the SII accounting for 71% of the variance in SNR loss for the HINT but only 49% for the QSIN. However, listener age and the addition of suprathreshold measures improved the prediction of SNR loss using the QSIN, accounting for nearly 71% of the variance. CONCLUSIONS: Two standard clinical speech-in-noise tests, QSIN and HINT, were used in this study to obtain a measure of SNR loss. When administered clinically, the QSIN appears to be less redundant with hearing thresholds than the HINT and is a better indicator of a patient's suprathreshold deficit and its impact on understanding speech in noise. Additional factors related to aging, spectral resolution, and, to a lesser extent, temporal resolution improved the ability to predict SNR loss measured with the QSIN. For the HINT, a listener's audibility and age were the only two significant factors. For both QSIN and HINT, roughly 25-30% of the variance in individual differences in SNR loss (i.e., the dB difference in SNR between an individual HI listener and a control group of NH listeners at a specified performance level, usually 50% word or sentence recognition) remained unexplained, suggesting the need for additional measures of suprathreshold acuity (e.g., sensitivity to temporal fine structure) or cognitive function (e.g., memory and attention) to further improve the ability to understand individual variability in SNR loss. PMID- 23636209 TI - Suprathreshold auditory processing and speech perception in noise: hearing impaired and normal-hearing listeners. AB - BACKGROUND: It is widely believed that suprathreshold distortions in auditory processing contribute to the speech recognition deficits experienced by hearing impaired (HI) listeners in noise. Damage to outer hair cells and attendant reductions in peripheral compression and frequency selectivity may contribute to these deficits. In addition, reduced access to temporal fine structure (TFS) information in the speech waveform may play a role. PURPOSE: To examine how measures of peripheral compression, frequency selectivity, and TFS sensitivity relate to speech recognition performance by HI listeners. To determine whether distortions in processing reflected by these psychoacoustic measures are more closely associated with speech deficits in steady-state or modulated noise. RESEARCH DESIGN: Normal-hearing (NH) and HI listeners were tested on tasks examining frequency selectivity (notched-noise task), peripheral compression (temporal masking curve task), and sensitivity to TFS information (frequency modulation [FM] detection task) in the presence of random amplitude modulation. Performance was tested at 500, 1000, 2000, and 4000 Hz at several presentation levels. The same listeners were tested on sentence recognition in steady-state and modulated noise at several signal-to-noise ratios. STUDY SAMPLE: Ten NH and 18 HI listeners were tested. NH listeners ranged in age from 36 to 80 yr (M = 57.6). For HI listeners, ages ranged from 58 to 87 yr (M = 71.8). RESULTS: Scores on the FM detection task at 1 and 2 kHz were significantly correlated with speech scores in both noise conditions. Frequency selectivity and compression measures were not as clearly associated with speech performance. Speech Intelligibility Index (SII) analyses indicated only small differences in speech audibility across subjects for each signal-to-noise ratio (SNR) condition that would predict differences in speech scores no greater than 10% at a given SNR. Actual speech scores varied by as much as 80% across subjects. CONCLUSIONS: The results suggest that distorted processing of audible speech cues was a primary factor accounting for differences in speech scores across subjects and that reduced ability to use TFS cues may be an important component of this distortion. The influence of TFS cues on speech scores was comparable in steady-state and modulated noise. Speech recognition was not related to audibility, represented by the SII, once high frequency sensitivity differences across subjects (beginning at 5 kHz) were removed statistically. This might indicate that high-frequency hearing loss is associated with distortions in processing in lower-frequency regions. PMID- 23636210 TI - Spectrotemporal modulation sensitivity as a predictor of speech intelligibility for hearing-impaired listeners. AB - BACKGROUND: A model that can accurately predict speech intelligibility for a given hearing-impaired (HI) listener would be an important tool for hearing-aid fitting or hearing-aid algorithm development. Existing speech-intelligibility models do not incorporate variability in suprathreshold deficits that are not well predicted by classical audiometric measures. One possible approach to the incorporation of such deficits is to base intelligibility predictions on sensitivity to simultaneously spectrally and temporally modulated signals. PURPOSE: The likelihood of success of this approach was evaluated by comparing estimates of spectrotemporal modulation (STM) sensitivity to speech intelligibility and to psychoacoustic estimates of frequency selectivity and temporal fine-structure (TFS) sensitivity across a group of HI listeners. RESEARCH DESIGN: The minimum modulation depth required to detect STM applied to an 86 dB SPL four-octave noise carrier was measured for combinations of temporal modulation rate (4, 12, or 32 Hz) and spectral modulation density (0.5, 1, 2, or 4 cycles/octave). STM sensitivity estimates for individual HI listeners were compared to estimates of frequency selectivity (measured using the notched-noise method at 500, 1000, 2000, and 4000 Hz), TFS processing ability (2 Hz frequency modulation detection thresholds for 500, 1000, 2000, and 4000 Hz carriers) and sentence intelligibility in noise (at a 0 dB signal-to-noise ratio) that were measured for the same listeners in a separate study. STUDY SAMPLE: Eight normal hearing (NH) listeners and 12 listeners with a diagnosis of bilateral sensorineural hearing loss participated. DATA COLLECTION AND ANALYSIS: STM sensitivity was compared between NH and HI listener groups using a repeated measures analysis of variance. A stepwise regression analysis compared STM sensitivity for individual HI listeners to audiometric thresholds, age, and measures of frequency selectivity and TFS processing ability. A second stepwise regression analysis compared speech intelligibility to STM sensitivity and the audiogram-based Speech Intelligibility Index. RESULTS: STM detection thresholds were elevated for the HI listeners, but only for low rates and high densities. STM sensitivity for individual HI listeners was well predicted by a combination of estimates of frequency selectivity at 4000 Hz and TFS sensitivity at 500 Hz but was unrelated to audiometric thresholds. STM sensitivity accounted for an additional 40% of the variance in speech intelligibility beyond the 40% accounted for by the audibility-based Speech Intelligibility Index. CONCLUSIONS: Impaired STM sensitivity likely results from a combination of a reduced ability to resolve spectral peaks and a reduced ability to use TFS information to follow spectral peak movements. Combining STM sensitivity estimates with audiometric threshold measures for individual HI listeners provided a more accurate prediction of speech intelligibility than audiometric measures alone. These results suggest a significant likelihood of success for an STM-based model of speech intelligibility for HI listeners. PMID- 23636211 TI - Auditory models of suprathreshold distortion and speech intelligibility in persons with impaired hearing. AB - BACKGROUND: Hearing-impaired (HI) individuals with similar ages and audiograms often demonstrate substantial differences in speech-reception performance in noise. Traditional models of speech intelligibility focus primarily on average performance for a given audiogram, failing to account for differences between listeners with similar audiograms. Improved prediction accuracy might be achieved by simulating differences in the distortion that speech may undergo when processed through an impaired ear. Although some attempts to model particular suprathreshold distortions can explain general speech-reception deficits not accounted for by audibility limitations, little has been done to model suprathreshold distortion and predict speech-reception performance for individual HI listeners. Auditory-processing models incorporating individualized measures of auditory distortion, along with audiometric thresholds, could provide a more complete understanding of speech-reception deficits by HI individuals. A computational model capable of predicting individual differences in speech recognition performance would be a valuable tool in the development and evaluation of hearing-aid signal-processing algorithms for enhancing speech intelligibility. PURPOSE: This study investigated whether biologically inspired models simulating peripheral auditory processing for individual HI listeners produce more accurate predictions of speech-recognition performance than audiogram-based models. RESEARCH DESIGN: Psychophysical data on spectral and temporal acuity were incorporated into individualized auditory-processing models consisting of three stages: a peripheral stage, customized to reflect individual audiograms and spectral and temporal acuity; a cortical stage, which extracts spectral and temporal modulations relevant to speech; and an evaluation stage, which predicts speech-recognition performance by comparing the modulation content of clean and noisy speech. To investigate the impact of different aspects of peripheral processing on speech predictions, individualized details (absolute thresholds, frequency selectivity, spectrotemporal modulation [STM] sensitivity, compression) were incorporated progressively, culminating in a model simulating level-dependent spectral resolution and dynamic-range compression. STUDY SAMPLE: Psychophysical and speech-reception data from 11 HI and six normal-hearing listeners were used to develop the models. DATA COLLECTION AND ANALYSIS: Eleven individualized HI models were constructed and validated against psychophysical measures of threshold, frequency resolution, compression, and STM sensitivity. Speech-intelligibility predictions were compared with measured performance in stationary speech-shaped noise at signal-to-noise ratios (SNRs) of -6, -3, 0, and 3 dB. Prediction accuracy for the individualized HI models was compared to the traditional audibility-based Speech Intelligibility Index (SII). RESULTS: Models incorporating individualized measures of STM sensitivity yielded significantly more accurate within-SNR predictions than the SII. Additional individualized characteristics (frequency selectivity, compression) improved the predictions only marginally. A nonlinear model including individualized level-dependent cochlear-filter bandwidths, dynamic-range compression, and STM sensitivity predicted performance more accurately than the SII but was no more accurate than a simpler linear model. Predictions of speech-recognition performance simultaneously across SNRs and individuals were also significantly better for some of the auditory-processing models than for the SII. CONCLUSIONS: A computational model simulating individualized suprathreshold auditory-processing abilities produced more accurate speech-intelligibility predictions than the audibility-based SII. Most of this advantage was realized by a linear model incorporating audiometric and STM-sensitivity information. Although more consistent with known physiological aspects of auditory processing, modeling level-dependent changes in frequency selectivity and gain did not result in more accurate predictions of speech-reception performance. PMID- 23636212 TI - Conclusion: predicting speech intelligibility by individual hearing-impaired listeners: the path forward. PMID- 23636214 TI - From the mouth of Apollo. PMID- 23636215 TI - Appraisal of the LIFT and BIOLIFT procedure: initial experience and short-term outcomes of 33 consecutive patients. AB - PURPOSE: A new sphincter-saving technique known as the LIFT (ligation of intersphincteric tract) procedure has gained growing interest. Use of a bioprosthetic device has also been suggested to augment the LIFT procedure (BIOLIFT). This study evaluates outcomes of patients undergoing LIFT and BIOLIFT for repair of complex anal fistulae. METHODS: This study is a single-surgeon, single-centre retrospective review of a prospectively collected database. Study was conducted at Royal Prince Alfred Hospital Department of Colorectal Surgery, Sydney, Australia, from May 2009 to April 2012. Thirty-three patients were evaluated. Twenty-nine LIFTs and five BIOLIFT procedures were evaluated. Primary success is defined as successful healing from initial procedure while secondary success is successful healing after management of failure or recurrence. RESULTS: In a cohort of predominantly female (67 %) and 94 % transsphincteric fistulae, primary success was 63 %. At a median follow-up of 20 weeks (6-81 weeks), there were 11 failures and one recurrence. The median time to failure/recurrence was 3 weeks (1-25 weeks). Six patients had a subsequent fistulotomy and three patients had a BIOLIFT for non-successful outcomes. The median follow-up for those with failures/recurrences is 60 weeks (range 20-76 weeks) and secondary success was 88 %. Post-operative anal manometry studies showed a 9 % reduction of resting and 11 % reduction of squeeze pressures but this was not statistically significant. There was also no post-operative incontinence. Anterior fistulas were noted do significantly worse (47%) compared with non-anteriorly located fistulas (84 %; p = 0.03). CONCLUSIONS: LIFT and BIOLIFT procedures can be performed safely and effectively in a technically demanding study cohort of predominantly females with complex fistulas. Anterior fistulas have a higher risk of failure but present early and are amendable to repeat procedures. In particular, fistulotomies are useful in downstaged tracts and performing BIOLIFTs is an alternative in the management of LIFT failures and recurrences. PMID- 23636216 TI - Targeting heat shock transcription factor 1 for novel hyperthermia therapy (review). AB - Hyperthermia (HT) has shown promising antitumor effects against various types of malignant tumors, and its pleiotropic effects support its combined use with radiotherapy and/or chemotherapy. However, HT is rendered less effective by the acquisition of thermoresistance in tumors, which arises through the elevation of heat shock proteins (HSPs) or other tumor responses. In mammals, the induction of HSPs is principally regulated at the transcriptional level by the activation of heat shock transcription factor 1 (HSF1). This transactivator has been shown to be abundantly expressed in a wide variety of tumors in humans. In addition, HSF1 participates in the initiation, proliferation and maintenance of tumors. Of note, HSF1 silencing has been shown to prevent the progression of tumors and to enhance their sensitivity to HT. Here, we review the physiological and pathological roles of HSF1 in cancer cells, and discuss its potential as a therapeutic target for HT therapy. PMID- 23636217 TI - Comparison of two trocar-guided trans-vaginal mesh systems for repair of pelvic organ prolapse: a retrospective cohort study. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to compare failure and complication rates in patients who underwent a trocar-guided vaginal mesh repair with either a non-absorbable or a partially absorbable mesh. METHODS: Retrospective analysis of prospectively collected data from consecutive women undergoing either non-absorbable or partially absorbable mesh for symptomatic stage 2 prolapse or higher were evaluated at 12 months. Outcome measures included objective and subjective failure rates, patient's satisfaction, complications and perioperative outcomes. RESULTS: Five hundred and sixty-nine women (347 with non absorbable mesh, 222 with partially absorbable mesh) were included. Failure rates were similar in the two groups; the re-operation rate in the untreated compartments was higher in the non-absorbable mesh group compared with the partially absorbable mesh group (5% vs 1%). Mesh exposure rate in the non absorbable mesh group was 12% and in the partially absorbable mesh group it was 5%. Other complication and patient satisfaction rates were similar. CONCLUSIONS: Non-absorbable and partially absorbable mesh demonstrated similar outcome rates at 12 months. The risk of reoperation was lower for partially absorbable mesh. The mesh exposure rate was significantly lower for the partially absorbable mesh group compared with the non-absorbable mesh group. PMID- 23636218 TI - Urea in aqueous solution studied by quantum mechanical charge field-molecular dynamics (QMCF-MD). AB - This work presents a quantum mechanical charge field-molecular dynamics (QMCF-MD) simulation of urea in dilute aqueous solution. Detailed data for structure and dynamics are provided and compared to previous works of other groups. Radial and angular distributions are employed, as well as higher degree spatial investigations, two-dimensional particle mapping, volume maps and the previously proposed SLICE formalism. Information on dynamical properties are presented in the form of hydrogen bond correlation functions and mean lifetime analysis based on weighted Voronoi decomposition. Dihedral and tilt/theta angle distributions substantiate the previous findings of other groups, that urea is far from being planar within aqueous solution. In addition to the analysis of the complete hydration shell, several specific regions of hydration have been identified, for which individual analysis has been performed in terms of hydrogen bond lifetime correlation functions and re-orientational times. A decomposition study based on Laguerre tessellation further investigates the structure and dynamics of the individual hydration layers. It is found that urea does not show properties found in the case of typical structure breaking agents, such as Rb(+) or Cs(+), which is in accordance with spectroscopic data of Rezus and Bakker. PMID- 23636219 TI - Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. AB - Rivaroxaban is an oral, direct factor Xa inhibitor for the management of thromboembolic disorders. Despite its short half-life, the ability to reverse rivaroxaban anticoagulation could be beneficial in life-threatening emergencies. The potential of prothrombin complex concentrate (PCC; Beriplex(r)), activated PCC (aPCC; FEIBA(r)) or recombinant activated factor VII (rFVIIa; NovoSeven(r)) to reverse rivaroxaban in rats and baboons was investigated. Anaesthetised rats pre-treated with intravenous rivaroxaban (2 mg/kg) received intravenous rFVIIa (100/400 MUg/kg), PCC (25/50 U/kg) or aPCC (50/100 U/kg) after initiation of bleeding. Clotting times and bleeding times (BTs) were recorded. Rivaroxaban was administered as an intravenous 0.6 mg/kg bolus followed by continuous 0.6 mg/kg/hour infusion in baboons. Animals received intravenous aPCC 50 U/kg (2 U/kg/minute) or rFVIIa 210 MUg/kg. BT and clotting parameters were measured. In rats pretreated with high-dose rivaroxaban, PCC 50 U/kg, aPCC 100 U/kg and rFVIIa 400 MUg/kg significantly reduced BT vs rivaroxaban alone (5.4 +/- 1.4-fold to 1.5 +/- 0.4-fold [p<0.05]; 3.0 +/- 0.4-fold to 1.4 +/- 0.1-fold [p<0.001]; and 3.5 +/ 0.7-fold to 1.7 +/- 0.2-fold [p<0.01] vs baseline, respectively). In baboons pre infused with rivaroxaban and then given aPCC, BT increased by 2.0 +/- 0.2-fold and aPCC returned BT to baseline for the duration of its infusion. rFVIIa reduced BT from 2.5 +/- 0.3-fold over baseline to 1.7 +/- 0.3-fold over baseline. Prolongation of prothrombin time was reduced by PCC, aPCC and rFVIIa in both species. Rivaroxaban reduced thrombin-antithrombin levels; application of PCC and aPCC, but not rFVIIa, increased these levels. In conclusion, PCC, aPCC or rFVIIa have the potential to reverse the anticoagulant and anti-haemostatic effects of rivaroxaban. PMID- 23636222 TI - Causes and costs of a decade of litigations following emergency appendicectomies in England. PMID- 23636220 TI - Enrichment of vitamin D response elements in RA-associated loci supports a role for vitamin D in the pathogenesis of RA. AB - The aim of this study was to explore the role of vitamin D in rheumatoid arthritis (RA) pathogenesis by investigating the enrichment of vitamin D response elements (VDREs) in confirmed RA susceptibility loci and testing variants associated with vitamin D levels for association with RA. Bioinformatically, VDRE genomic positions were overlaid with non-HLA (human leukocyte antigen)-confirmed RA susceptibility regions. The number of VDREs at RA loci was compared to a randomly selected set of genomic loci to calculate an average relative risk (RR). Single-nucleotide polymorphisms (SNPs) in the DHCR7/NADSYN1 (nicotinamide adenine dinucleotide synthase 1) and CYP2R1 loci, previously associated with circulating vitamin D levels, were tested in UK RA cases (n=3870) and controls (n=8430). Significant enrichment of VDREs was seen at RA loci (P=9.23 * 10(-8)) when regions were defined either by gene (RR 5.50) or position (RR 5.86). SNPs in the DHCR7/NADSYN1 locus showed evidence of positive association with RA, rs4944076 (P=0.008, odds ratio (OR) 1.14, 95% confidence interval (CI) 1.03-1.24). The significant enrichment of VDREs at RA-associated loci and the modest association of variants in loci-controlling levels of circulating vitamin D supports the hypothesis that vitamin D has a role in the development of RA. PMID- 23636223 TI - Medullo-ponto-cerebellar white matter degeneration altered brain network organization and cortical morphology in multiple system atrophy. AB - The cerebellum involves diverse functions from motor coordination to higher cognitive functions. Impairment of the cerebellum can cause ataxia and cerebellar cognitive affective syndrome. Multiple system atrophy of the cerebellar type (MSA C) is a neurodegenerative disorder with atrophy of medullo-ponto-cerebellar (MPC) white matter (WM). To understand the role of the cerebellum from the perspective of the local structure to the global function in the presence of MPC WM degeneration, we acquired T1-weighted and diffusion tensor images for 17 patients with MSA-C and 19 normal controls. We concurrently used the measures of local morphology, including MPC WM volume and inner surface area, and properties of global network organization based on graph theory for the MSA-C and control groups. The results showed that MPC WM degeneration caused the destruction of cerebello-ponto-cerebral loops, resulting in reduced communication efficiency between regions in the whole-brain network. In addition, the sulcal area of the inner cortical surface in the cerebellum decreased linearly with the MPC WM volume, and the inferoposterior lobe exhibited a steeper atrophy rate than that of vermis regions. We concluded that the integrity of MPC WM is critical in sustaining the local morphology and the global functions of the whole-brain fiber network. PMID- 23636221 TI - Relation of HLA class I and II supertypes with spontaneous clearance of hepatitis C virus. AB - Human leukocyte antigen (HLA) genotype has been associated with the probability of spontaneous clearance of hepatitis C virus (HCV). However, no prior studies have examined whether this relationship may be further characterized by grouping HLA alleles according to their supertypes, defined by their binding capacities. There is debate regarding the most appropriate method to define supertypes. Therefore, previously reported HLA supertypes (46 class I and 25 class II) were assessed for their relation with HCV clearance in a population of 758 HCV seropositive women. Two HLA class II supertypes were significant in multivariable models that included: (i) supertypes with significant or borderline associations with HCV clearance after adjustment for multiple tests, and (ii) individual HLA alleles not part of these supertypes, but associated with HCV clearance in our prior study in this population. Specifically, supertype DRB3 (prevalence ratio (PR)=0.4; P=0.004) was associated with HCV persistence, whereas DR8 (PR=1.8; P=0.01) was associated with HCV clearance. Two individual alleles (B*57:01 and C*01:02) associated with HCV clearance in our prior study became nonsignificant in analysis that included supertypes, whereas B*57:03 (PR=1.9; P=0.008) and DRB1*07:01 (PR=1.7; P=0.005) retained their significance. These data provide epidemiologic support for the significance of HLA supertypes in relation to HCV clearance. PMID- 23636225 TI - Delayed union in internal fixation of pediatric both-bone forearm fractures. AB - The aim of this study was to retrospectively determine the risk factors for delayed union in 117 consecutive pediatric both-bone forearm fractures treated with internal fixation. Eight patients (7%, 8/117) had delayed unions, all were boys treated with intramedullary fixation for a fracture in the middle-third of the bone; and in seven patients, the ulna was the site of the delayed union. Older age, double-bone fixation, increased initial fracture displacement, and opening a closed ulna fracture were associated with longer time to union (P<0.05). Identification of risk factors will aid in the selection and duration of internal fixation and duration of immobilization. PMID- 23636224 TI - Gray matter density in relation to different facets of verbal creativity. AB - Neuroscience studies on creativity have revealed highly variegated findings that often seem to be inconsistent. As recently argued in Fink and Benedek (Neurosci Biobehav Rev, 2012), this might be primarily due to the broad diversity in defining and measuring creativity as well as to the diversity of experimental procedures and methodologies used in this field of research. In specifically focusing on one measure of brain activation and on the well-established process of creative ideation (i.e., divergent thinking), EEG studies revealed a quite consistent and replicable pattern of right-lateralized brain activity over posterior parietal and occipital sites. In this study, we related regional gray matter density (as assessed by means of voxel-based morphometry) to different facets of psychometrically determined verbal creativity in a sample of 71 participants. Results revealed that verbal creativity was significantly and positively associated with gray matter density in clusters involving the right cuneus and the right precuneus. Enhanced gray matter density in these regions may be indicative of vivid imaginative abilities in more creative individuals. These findings complement existing functional studies on creative ideation which are, taken as a whole, among the most consistent findings in this field. PMID- 23636226 TI - Retrospective radiographic evaluation of treatment results of developmental dysplasia of the hip in walking-age children. AB - We evaluated treatment results of 22 children (32 hips) with idiopathic hip dislocation after walking age in two Dutch academic hospitals. The Tonnis classification was used preoperatively. Outcome was measured using the Severin and Kalamchi classification. The mean age at treatment was 24 months and the mean follow-up was 6.8 years. In 24 hips (73%), a perfect outcome was found (Kalamchi score<=1 and Severin score of 1). A fair or a poor outcome according to Severin (>=3) was found in five hips (15%). Treatment of a hip dislocation beyond 18 months of age usually results in adequate hip development with limited avascular necrosis. LEVEL OF EVIDENCE: Level III. PMID- 23636227 TI - Persistent angina: highly prevalent and associated with long-term anxiety, depression, low physical functioning, and quality of life in stable angina pectoris. AB - AIMS: To evaluate persistent angina in stable angina pectoris with no obstructive coronary artery disease (CAD) compared to obstructive CAD and its relation to long-term anxiety, depression, quality of life (QOL), and physical functioning. METHODS AND RESULTS: We invited 357 patients (men = 191; women = 166; response rate 83 %) with no prior cardiovascular disease who had a first-time coronary angiography (CAG) in 2008-2009 due to suspected stable angina to participate in a questionnaire survey in 2011 with the Seattle Angina Questionnaire and the Hospital Anxiety and Depression Scale as key elements. Long-term persistent angina (i.e., symptoms at least once a month) was present in 64 % of patients with diffuse non-obstructive CAD (1-49 % stenosis), 49 % of patients with normal coronary arteries (0 % stenosis), and 41 % of patients with obstructive CAD (>= 50 % stenosis) (P = 0.01). Depression and anxiety were more common in patients with persistent angina: 24 versus 7 % (P < 0.001) reported HADS-Depression-scores >7 and 42 versus 21 % (P < 0.001) reported HADS-Anxiety-scores >7. In multivariate regression models, persistent angina was associated with depression (OR 4.3, 95 % confidence interval (CI) 1.9-9.6, P < 0.001), anxiety (OR 2.9, 95 % CI 1.6-5.1, P < 0.001), the severity of persistent angina with impaired physical functioning (P < 0.001), and QOL (P < 0.001); whereas outcomes were not related to age, gender, or degree of CAD. CONCLUSIONS: The study indicates higher prevalence of persistent angina in patients with diffuse non-obstructive CAD or normal coronary arteries than in patients with obstructive CAD. Persistent angina symptoms were associated with long-term anxiety, depression, impaired physical functioning, and QOL irrespective of the degree of CAD. Contrary to common perception, excluding obstructive CAD in stable angina does not ensure a favorable disease course, and further risk stratification and treatment strategies are warranted. PMID- 23636228 TI - Long-term follow-up of ETV6-RUNX1 ALL reveals that NCI risk, rather than secondary genetic abnormalities, is the key risk factor. PMID- 23636230 TI - Interventions to improve osteoporosis medication adherence and persistence: a systematic review and literature appraisal by the ISPOR Medication Adherence & Persistence Special Interest Group. AB - This study aims to systematically review, critically appraise and identify from the published literature, the most effective interventions to improve medication adherence in osteoporosis. A literature search using Medline, EMBASE, Cochrane library, and Cumulative Index to Nursing and Allied Health Literature was undertaken to identify prospective studies published between January 1, 1999 and June 30, 2012. We included studies on adult users of osteoporosis medications that tested a patient adherence intervention (e.g., patient education, intensified patient care, different dosing regimens) and reported quantitative results of adherence. The Delphi list was modified to assess the quality of studies. Of 113 articles identified, 20 studies fulfilled the inclusion criteria. The most frequent intervention was education (n = 11) followed by monitoring/supervision (n = 4), drug regimens (n = 2), drug regimens and patient support (n = 1), pharmacist intervention (n = 1), and electronic prescription (n = 1). Although patient education improved medication adherence in four studies, two large-scale randomized studies reported no benefits. Simplification of dosing regimens (with and without patient support program) was found to have a significant clinical impact on medication adherence and persistence. Monitoring/supervision showed no impact on medication persistence while electronic prescription and pharmacist intervention increased medication adherence or persistence. In conclusion, this review found that simplification of dosing regimens, decision aids, electronic prescription, or patient education may help to improve adherence or persistence to osteoporosis medications. We identified wide variation of quality of studies in the osteoporosis area. The efficacy of patient education was variable across studies, while monitoring/supervision does not seem an effective way to enhance medication adherence or persistence. PMID- 23636231 TI - Chrysin overcomes TRAIL resistance of cancer cells through Mcl-1 downregulation by inhibiting STAT3 phosphorylation. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills various types of cancer cells without harming normal cells, but TRAIL resistance has been frequently observed in cancer cells. Propolis (bee glue) is a material collected from various plants by honeybees and is a rich source of bioactive compounds, including the natural flavonoid chrysin, which possesses multiple anticancer effects. We investigated the mechanism underlying the TRAIL sensitization effect of chrysin, which is a major constituent of Thai propolis, in human lung and cervical cancer cell lines. Propolis extract and chrysin sensitizes A549 and HeLa human cancer cell lines to TRAIL-induced apoptosis. The TRAIL sensitization effect of chrysin is not mediated by inhibition of TRAIL induced NF-kappaB activation or by glutathione depletion. Immunoblot analysis using a panel of anti-apoptotic proteins revealed that chrysin selectively decreases the levels of Mcl-1 protein, by downregulating Mcl-1 gene expression as determined by qRT-PCR. The contribution of Mcl-1 in TRAIL resistance was confirmed by si-Mcl-1 knockdown. Among signaling pathways that regulate Mcl-1 gene expression, only constitutive STAT3 phosphorylation was suppressed by chrysin. The proposed action of chrysin in TRAIL sensitization by inhibiting STAT3 and downregulating Mcl-1 was supported by using a STAT3-specific inhibitor, cucurbitacin-I, which decreased Mcl-1 levels and enhanced TRAIL-induced cell death, similar to that observed with chrysin treatment. In conclusion, we show the potential of chrysin in overcoming TRAIL resistance of cancer cells and elucidate its mechanism of action. PMID- 23636232 TI - Influence of PNA containing 8-aza-7-deazaadenine on structure stability and binding affinity of PNA.DNA duplex: insights from thermodynamics, counter ion, hydration and molecular dynamics analysis. AB - This paper describes the synthesis of a novel 8-aza-7-deazapurin-2,6-diamine (DPP)-containing peptide nucleic acid (PNA) monomer and Boc protecting group based oligomerization of PNA, replacing adenine (A) with DPP monomers in the PNA strand. The PNA oligomers were synthesized against the biologically relevant SV40 promoter region (2494-AATTTTTTTTATTTA-2508) of pEGFP-N3 plasmid. The DPP-PNA.DNA duplex showed enhanced stability as compared to normal duplex (A-PNA.DNA). The electronic distribution of DPP monomer suggested that DPP had better electron donor properties over 2,6-diamino purine. UV melting and thermodynamic analysis revealed that the PNA oligomer containing a diaminopyrazolo(3,4-d)pyrimidine moiety (DPP) stabilized the PNA.DNA hybrids compared to A-PNA.DNA. DPP-PNA.DNA duplex showed higher water activity (Deltanw = 38.5) in comparison to A-PNA.DNA duplex (Deltanw = 14.5). The 50 ns molecular dynamics simulations of PNA.DNA duplex containing DPP or unmodified nucleobase-A showed average H-bond distances in the DPP-dT base pair of 2.90 A (OH-N bond) and 2.91 A (NH-N bond), which were comparably shorter than in the A-dT base pair, in which the average distances were 3.18 A (OH-N bond) and 2.97 A (NH-N bond), and there was one additional H bond in the DPP-dT base pair of around 2.98 A (O2H-N2 bond), supporting the higher stability of DPP-PNA.DNA. The analysis of molecular dynamics simulation data showed that the system binding free energy increased at a rate of approximately -4.5 kcal mol(-1) per DPP base of the PNA.DNA duplex. In summary, increased thermal stability, stronger hydrogen bonding and more stable conformation in the DPP-PNA.DNA duplex make it a better candidate as antisense/antigene therapeutic agents. PMID- 23636233 TI - Enantio- and diastereoselective palladium catalysed arylative and vinylative allene carbocyclisation cascades. AB - The enantioselective synthesis of heavily decorated spirolactams has been accomplished via an arylative or vinylative allene carbocyclisation cascade. Mediated by silver phosphate, a range of allene-linked pro-nucleophiles and aryl or vinyl iodides were reacted in the presence of catalytic Pd(OAc)2 and chiral bis(oxazoline) ligands to afford the spirolactam products in good yields and high enantio- and diastereoselectivities. PMID- 23636235 TI - Weight change at 1 mo of antiretroviral therapy and its association with subsequent mortality, morbidity, and CD4 T cell reconstitution in a Tanzanian HIV infected adult cohort. AB - BACKGROUND: The development of low-cost point-of-care technologies to improve HIV treatment is a major focus of current research in resource-limited settings. OBJECTIVE: We assessed associations of body mass index (BMI; in kg/m(2)) at antiretroviral therapy (ART) initiation and weight change after 1 mo of treatment with mortality, morbidity, and CD4 T cell reconstitution. DESIGN: A prospective cohort of 3389 Tanzanian adults initiating ART enrolled in a multivitamin trial was followed at monthly clinic visits (median: 19.7 mo). Proportional hazard models were used to analyze mortality and morbidity associations, whereas generalized estimating equations were used for CD4 T cell counts. RESULTS: The median weight change at 1 mo of ART was +2.0% (IQR: -0.4% to +4.6%). The association of weight loss at 1 mo with subsequent mortality varied significantly by baseline BMI (P = 0.011). Participants with >=2.5% weight loss had 6.43 times (95% CI: 3.78, 10.93 times) the hazard of mortality compared with that of participants with weight gains >=2.5%, if their baseline BMI was <18.5 but only 2.73 times (95% CI: 1.49, 5.00 times) the hazard of mortality if their baseline BMI was >=18.5 and <25.0. Weight loss at 1 mo was also associated with incident pneumonia (P = 0.002), oral thrush (P = 0.007), and pulmonary tuberculosis (P < 0.001) but not change in CD4 T cell counts (P > 0.05). CONCLUSIONS: Weight loss as early as 1 mo after ART initiation can identify adults at high risk of adverse outcomes. Studies identifying reasons for and managing early weight loss are needed to improve HIV treatment, with particular urgency for malnourished adults initiating ART. The parent trial was registered at clinicaltrials.gov as NCT00383669. PMID- 23636236 TI - Efficacy of zinc given as an adjunct in the treatment of severe and very severe pneumonia in hospitalized children 2-24 mo of age: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Pneumonia is a leading cause of death; in India, an estimated 370,000 children die of pneumonia each year. Zinc has multiple influences on the immune response to infections. Zinc supplementation has been shown to prevent diarrhea and pneumonia in children. However, zinc's therapeutic effect on respiratory infections is less clear. OBJECTIVE: We evaluated the role of zinc as an adjunct to antibiotics in the treatment of children hospitalized for severe or very severe pneumonia. DESIGN: In this randomized, double-blind, placebo-controlled trial, we enrolled 550 children aged 2-24 mo with severe or very severe pneumonia. Within each hospital and pneumonia-severity stratum, children were randomly assigned to receive zinc (20 mg elemental zinc/d) or a placebo in addition to antibiotics and supportive care. RESULTS: The time to recovery from severe or very severe pneumonia was similar in both groups (HR: 0.98; 95% CI: 0.82, 1.17). In the stratified analysis, zinc was shown to be efficacious in reducing the time to recovery in children with very severe pneumonia (HR: 1.52; 95% CI: 1.03, 2.23); however, the effect was no longer statistically significant after adjustment for differences in severely underweight children in the 2 groups. CONCLUSIONS: This study showed no overall benefit of the addition of zinc to antibiotics in reducing the time to recovery from pneumonia but showed a possible benefit of zinc supplementation in a subgroup of children with very severe pneumonia. Additional research is needed in specific subgroups such as children with very severe pneumonia. This trial was registered at http://www.controlled-trials.com as ISRCTN48954234. PMID- 23636234 TI - Management of protein-energy wasting in non-dialysis-dependent chronic kidney disease: reconciling low protein intake with nutritional therapy. AB - Protein-energy wasting (PEW), characterized by a decline in body protein mass and energy reserves, including muscle and fat wasting and visceral protein pool contraction, is an underappreciated condition in early to moderate stages of chronic kidney disease (CKD) and a strong predictor of adverse outcomes. The prevalence of PEW in early to moderate CKD is >=20-25% and increases as CKD progresses, in part because of activation of proinflammatory cytokines combined with superimposed hypercatabolic states and declines in appetite. This anorexia leads to inadequate protein and energy intake, which may be reinforced by prescribed dietary restrictions and inadequate monitoring of the patient's nutritional status. Worsening uremia also renders CKD patients vulnerable to potentially deleterious effects of uncontrolled diets, including higher phosphorus and potassium burden. Uremic metabolites, some of which are anorexigenic and many of which are products of protein metabolism, can exert harmful effects, ranging from oxidative stress to endothelial dysfunction, nitric oxide disarrays, renal interstitial fibrosis, sarcopenia, and worsening proteinuria and kidney function. Given such complex pathways, nutritional interventions in CKD, when applied in concert with nonnutritional therapeutic approaches, encompass an array of strategies (such as dietary restrictions and supplementations) aimed at optimizing both patients' biochemical variables and their clinical outcomes. The applicability of many nutritional interventions and their effects on outcomes in patients with CKD with PEW has not been well studied. This article reviews the definitions and pathophysiology of PEW in patients with non-dialysis-dependent CKD, examines the current indications for various dietary modification strategies in patients with CKD (eg, manufactured protein-based supplements, amino acids and their keto acid or hydroxyacid analogues), discusses the rationale behind their potential use in patients with PEW, and highlights areas in need of further research. PMID- 23636238 TI - The obesity paradox in the US population. AB - BACKGROUND: Recently a number of studies have found a lower risk of dying for obese individuals than for normal-weight individuals. The explanation for these paradoxical findings has not yet been identified. OBJECTIVE: The objective was to assess whether this paradoxical pattern exists in the US population and whether it can be explained by reverse causation. DESIGN: Survival analyses were used to calculate the RR of all-cause mortality for obesity by using data from 35,673 participants in NHANES I (1971-1975), NHANES II (1976-1980), and NHANES III (1988 1994), which reported 7087 deaths during 3 different 15-y follow-up periods. RESULTS: With normal weight as a referent, a lower relative mortality risk of obesity was found only in NHANES III and only among men with a wide variety of preexisting serious illnesses. For this subgroup, the relative mortality risks in NHANES I, II, and III were 2.22 (95% CI: 1.45, 3.40), 0.89 (95% CI: 0.70, 1.15), and 0.65 (95% CI: 0.47, 0.91), respectively. Whereas the mortality rate among seriously ill normal-weight men did not change significantly between NHANES I and III, it did decrease significantly among seriously ill obese men, suggesting that reverse causation was not responsible for the lower relative mortality risk among seriously ill obese men in NHANES III. CONCLUSIONS: Only obese NHANES male participants with a wide variety of serious illnesses experienced lower mortality risk than their normal-weight counterparts and only in NHANES III. Reverse causation seems unlikely to have played a role. These conclusions require confirmation. PMID- 23636239 TI - Diet spanning infancy and toddlerhood is associated with child blood pressure at age 7.5 y. AB - BACKGROUND: Diet in the first 2 y of life may be a pivotal period regarding effects on future blood pressure (BP). However, data on early-life diet and BP in childhood are sparse. OBJECTIVE: We prospectively assessed associations between types of diet spanning infancy and toddlerhood (ie, transition diets across the complementary feeding period) and BP at age 7.5 y. DESIGN: In a birth cohort study (Avon Longitudinal Study of Parents and Children; United Kingdom), a total of 1229 children had complete dietary intake data at 6, 15, and 24 mo; BP data at 7.5 y of age; and all 18 covariables. RESULTS: Of the 2 transition diets that were extracted by using principal components analysis, the less-healthy diet was associated with an increase in systolic BP of 0.62 mm Hg (95% CI: 0.00, 1.24 mm Hg) and an increase in diastolic BP of 0.55 mm Hg (95% CI: 0.10, 1.00 mm Hg) for every one-unit (SD) increase in the less-healthy-diet score after adjustment for 15 potential confounders, including maternal characteristics and sociodemographic factors, birth variables, and breastfeeding duration. In contrast with systolic BP, the positive association between the less-healthy transition-diet score and diastolic BP persisted after additional adjustment for child body-size factors [height, body mass index (BMI), and waist circumference] at 7.5 y. CONCLUSIONS: A less-healthy transition diet by age 2 y was associated with higher BP at 7.5 y. The BMI-related reduction in effect size reinforces the importance of BMI on the diet-BP relation. PMID- 23636237 TI - Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. AB - BACKGROUND: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants. OBJECTIVE: The objective of the study was to identify common genetic variants that are associated with macronutrient intake. DESIGN: We performed 2 stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 * 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data. RESULTS: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (beta +/- SE: 0.25 +/- 0.04%; P = 1.68 * 10(-8)) and lower fat (beta +/- SE: -0.21 +/- 0.04%; P = 1.57 * 10( 9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (beta +/- SE: 0.10 +/- 0.02%; P = 9.96 * 10(-10)), independent of BMI (after adjustment for BMI, beta +/- SE: 0.08 +/- 0.02%; P = 3.15 * 10(-7)). CONCLUSION: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis). PMID- 23636240 TI - FADS genotype and diet are important determinants of DHA status: a cross sectional study in Danish infants. AB - BACKGROUND: Infant docosahexaenoic acid (DHA) status is supported by the DHA content of breast milk and thus can decrease once complementary feeding begins. Furthermore, it is unclear to what extent endogenous DHA synthesis contributes to status. OBJECTIVE: We investigated several determinants, including FADS genotypes on DHA status at 9 mo and 3 y. DESIGN: This was a cross-sectional study with Danish infants from 2 prospective studies [Essentielle Fedtsyrer i OvergangskosteN (EFiON) and the Smaborns Kost Og Trivsel (SKOT) cohort] in which we measured red blood cell (RBC) DHA status at 9 mo (n = 409) and 3 y (n = 176) and genotyped 4 FADS tag single nucleotide polymorphisms (SNPs): rs3834458, rs1535, rs174575, and rs174448 (n = 401). Information about breastfeeding was obtained by using questionnaires, and fish intake was assessed by using 7-d precoded food diaries. RESULTS: FADS genotype, breastfeeding, and fish intake explained 25% of the variation in infant RBC DHA status [mean +/- SD: 6.6 +/- 1.9% of fatty acids (FA%)]. Breastfeeding explained most of the variation (~20%), and still being breastfed at 9 mo was associated with a 0.7 FA% higher DHA compared with no longer being breastfed (P < 0.001). The FADS SNPs rs1535 and rs3834458 were highly correlated (r = 0.98). Homozygous carriers of the minor allele of rs1535 had a DHA increase of 1.8 FA% (P = 0.001) relative to those with the wild-type allele, whereas minor allele carriers of rs174448 and rs174575 had a decrease of 1.1 FA% (P = 0.005) and 2.0 FA% (P = 0.001), respectively. Each 10 g increment in fish intake was associated with an increased DHA status of 0.3 FA%. At 3 y, fish intake was the only significant determinant of DHA status (0.2 FA%/10 g). CONCLUSION: Breastfeeding, FADS genotype, and fish intake are important determinants of DHA status in late infancy. The EFiON study was registered at clinicaltrials.gov as NCT 00631046. PMID- 23636241 TI - Minced beef is more rapidly digested and absorbed than beef steak, resulting in greater postprandial protein retention in older men. AB - BACKGROUND: Older individuals generally experience a reduced food-chewing efficiency. As a consequence, food texture may represent an important factor that modulates dietary protein digestion and absorption kinetics and the subsequent postprandial protein balance. OBJECTIVE: We assessed the effect of meat texture on the dietary protein digestion rate, amino acid availability, and subsequent postprandial protein balance in vivo in older men. DESIGN: Ten older men (mean +/ SEM age: 74 +/- 2 y) were randomly assigned to a crossover experiment that involved 2 treatments in which they consumed 135 g of specifically produced intrinsically L-[1-(13)C]phenylalanine-labeled beef, which was provided as beef steak or minced beef. Meat consumption was combined with continuous intravenous L [ring-(2)H5]phenylalanine and L-[ring-(2)H2]tyrosine infusion to assess beef protein digestion and absorption kinetics as well as whole-body protein balance and skeletal muscle protein synthesis rates. RESULTS: Meat protein-derived phenylalanine appeared more rapidly in the circulation after minced beef than after beef steak consumption (P < 0.05). Also, its availability in the circulation during the 6-h postprandial period was greater after minced beef than after beef steak consumption (61 +/- 3% compared with 49 +/- 3%, respectively; P < 0.01). The whole-body protein balance was more positive after minced beef than after beef steak consumption (29 +/- 2 compared with 19 +/- 3 MUmol phenylalanine/kg, respectively; P < 0.01). Skeletal muscle protein synthesis rates did not differ between treatments when assessed over a 6-h postprandial period. CONCLUSIONS: Minced beef is more rapidly digested and absorbed than beef steak, which results in increased amino acid availability and greater postprandial protein retention. However, this does not result in greater postprandial muscle protein synthesis rates. This trial was registered at clinicaltrials.gov as NCT01145131. PMID- 23636242 TI - Homocysteine, folate, vitamin B-12, and 10-y incidence of age-related macular degeneration. AB - BACKGROUND: Epidemiologic evidence of a relation between serum total homocysteine (tHcy), vitamin B-12, and folate and age-related macular degeneration (AMD) is inconsistent and unresolved. OBJECTIVE: In this cohort study, we aimed to investigate associations between intakes and serum concentrations of folate and vitamin B-12 or serum tHcy and 10-y AMD incidence. DESIGN: Serum folate, vitamin B-12, and tHcy were determined from blood samples drawn in 1997-1999 from cohort members aged >=55 y. AMD was assessed in 1760 survivors from retinal photographs taken in 2002-2004 and 2007-2009. Total intakes of folate and vitamin B-12 were assessed by using a food-frequency questionnaire. RESULTS: After adjustment for age, sex, current smoking, white blood cell count, and fish consumption, each 1 SD increase in serum tHcy was associated with increased risk of incident early and any AMD [ORs (95% CIs): 1.33 (1.09, 1.63) and 1.33 (1.11, 1.60), respectively]. Participants with a serum vitamin B-12 deficiency (<185 pmol/L) had higher risk of incident early and late AMD [ORs (95% CIs): 1.58 (1.06, 2.36) and 2.56 (1.38, 4.73), respectively]. Folate deficiency (<11 nmol/L) was associated with 75% and 89% increased risk of incident early and any AMD, respectively, 10 y later. Participants who reported supplementary vitamin B-12 intake had 47% reduced risk of incident any AMD (OR: 0.53; 95% CI: 0.33, 0.85). CONCLUSION: Elevated serum tHcy and folate and vitamin B-12 deficiencies predicted increased risk of incident AMD, which suggests a potential role for vitamin B-12 and folate in reducing AMD risk. PMID- 23636243 TI - Compromised shear-dependent cleavage of type 2N von Willebrand factor variants by ADAMTS13 in the presence of factor VIII. PMID- 23636244 TI - Inhibition of neointimal hyperplasia in a rabbit vein graft model following non viral transfection with human iNOS cDNA. AB - Vein graft failure caused by neointimal hyperplasia (IH) after coronary artery bypass grafting with saphenous veins is a major clinical problem. The lack of safe and efficient vectors for vascular gene transfer has significantly hindered progress in this field. We have developed a Receptor-Targeted Nanocomplex (RTN) vector system for this purpose and assessed its therapeutic efficacy in a rabbit vein graft model of bypass grafting. Adventitial delivery of beta-Galactosidase showed widespread transfection throughout the vein wall on day 7, estimated at about 10% of cells in the adventitia and media. Vein grafts were then transfected with a plasmid encoding inducible nitric oxide synthase (iNOS) and engrafted into the carotid artery. Fluorescent immunohistochemistry analysis of samples from rabbits killed at 7 days after surgery showed that mostly endothelial cells and macrophages were transfected. Morphometric analysis of vein graft samples from the 28-day groups showed approximately a 50% reduction of neointimal thickness and 64% reduction of neointimal area in the iNOS-treated group compared with the surgery control groups. This study demonstrates efficacy of iNOS gene delivery by the RTN formulation in reducing IH in the rabbit model of vein graft disease. PMID- 23636245 TI - Specificity redirection by CAR with human VEGFR-1 affinity endows T lymphocytes with tumor-killing ability and anti-angiogenic potency. AB - Immunotherapy that is based on adoptive transfer of T lymphocytes, which are genetically modified to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens, has been demonstrated to be an efficient cancer therapy. Vascular endothelial growth factor receptor-1 (VEGFR-1), a vital molecule involved in tumor growth and angiogenesis, has not been targeted by CAR modified T lymphocytes. In this study, we generated CAR-modified T lymphocytes with human VEGFR-1 specificity (V-1 CAR) by electroporation. V-1 CAR-modified T lymphocytes were demonstrated to elicit lytic cytotoxicity to target cells in a VEGFR-1-dependent manner. The adoptive transfer of V-1 CAR T lymphocytes delayed tumor growth and formation and inhibited pulmonary metastasis in xenograft models and such efficacies were enhanced by cotransfer of T lymphocytes that expressed interleukin-15 (IL-15). Moreover, V-1 CAR-modified T lymphocytes lysed primary endothelial cells and impaired tube formation, in vitro. These data demonstrated the antitumor and anti-angiogenesis ability of V-1 CAR-modified T lymphocytes. Our study provides the rationale for the clinical translation of CAR-modified T lymphocytes with VEGFR-1 specificity. PMID- 23636246 TI - Use of high-frequency jet ventilation for percutaneous tumor ablation. AB - PURPOSE: To report feasibility and potential benefits of high-frequency jet ventilation (HFJV) in tumor ablations techniques in liver, kidney, and lung lesions. METHODS: This prospective study included 51 patients (14 women, mean age 66 years) bearing 66 tumors (56 hepatic, 5 pulmonary, 5 renal tumors) with a median size of 16 +/- 8.7 mm, referred for tumor ablation in an intention-to treat fashion before preoperative anesthesiology visit. Cancellation and complications of HFJV were prospectively recorded. Anesthesia and procedure duration, as well as mean CO2 capnea, were recorded. When computed tomography guidance was used, 3D spacial coordinates of an anatomical target <2 mm in diameter on 8 slabs of 4 slices of 3.75-mm slice thickness were registered. RESULTS: HFJV was used in 41 of 51 patients. Of the ten patients who were not candidate for HFJV, two patients had contraindication to HFJV (severe COPD), three had lesions invisible under HFJV requiring deep inspiration apnea for tumor targeting, and five patients could not have HFJV because of unavailability of a trained anesthetic team. No specific complication or hypercapnia related to HFJV were observed despite a mean anesthetic duration of 2 h and ventilation performed in procubitus (n = 4) or lateral decubitus (n = 6). Measured internal target movement was 0.3 mm in x- and y-axis and below the slice thickness of 3.75 mm in the z-axis in 11 patients. CONCLUSIONS: HFJV is feasible in 80 % of patients allowing for near immobility of internal organs during liver, kidney, and lung tumor ablation. PMID- 23636247 TI - The changing face of vascular interventional radiology: the future role of pharmacotherapies and molecular imaging. AB - Interventional radiology has had to evolve constantly because there is the ever present competition and threat from other specialties within medicine, surgery, and research. The development of new technologies, techniques, and therapies is vital to broaden the horizon of interventional radiology and to ensure its continued success in the future. In part, this change will be due to improved chronic disease prevention altering what we treat and in whom. The most important of these strategies are the therapeutic use of statins, Beta-blockers, angiotensin-converting enzyme inhibitors, and substances that interfere with mast cell degeneration. Molecular imaging and therapeutic strategies will move away from conventional techniques and nano and microparticle molecular technology, tissue factor imaging, gene therapy, endothelial progenitor cells, and photodynamic therapy will become an important part of interventional radiology of the future. This review looks at these new and exciting technologies. PMID- 23636248 TI - Endovascular treatment of a symptomatic thoracoabdominal aortic aneurysm by chimney and periscope techniques for total visceral and renal artery revascularization. AB - Conventional endovascular therapy of thoracoabdominal aortic aneurysm with involving visceral and renal arteries is limited by the absence of a landing zone for the aortic endograft. Solutions have been proposed to overcome the problem of no landing zone; however, most of them are not feasible in urgent and high-risk patients. We describe a case that was successfully treated by total endovascular technique with a two-by-two chimney-and-periscope approach in a patient with acute symptomatic type IV thoracoabdominal aortic aneurysm with supra-anastomotic aneurysm formation involving the renal and visceral arteries and a pseduaneurismatic sac localized in the left ileopsoas muscle. PMID- 23636249 TI - Transjugular endovascular recanalization of splenic vein in patients with regional portal hypertension complicated by gastrointestinal bleeding. AB - PURPOSE: Regional portal hypertension (RPH) is an uncommon clinical syndrome resulting from splenic vein stenosis/occlusion, which may cause gastrointestinal (GI) bleeding from the esophagogastric varices. The present study evaluated the safety and efficacy of transjugular endovascular recanalization of splenic vein in patients with GI bleeding secondary to RPH. METHODS: From December 2008 to May 2011, 11 patients who were diagnosed with RPH complicated by GI bleeding and had undergone transjugular endovascular recanalization of splenic vein were reviewed retrospectively. Contrast-enhanced computed tomography revealed splenic vein stenosis in six cases and splenic vein occlusion in five. Etiology of RPH was chronic pancreatitis (n = 7), acute pancreatitis with pancreatic pseudocyst (n = 2), pancreatic injury (n = 1), and isolated pancreatic tuberculosis (n = 1). RESULTS: Technical success was achieved in 8 of 11 patients via the transjugular approach, including six patients with splenic vein stenosis and two patients with splenic vein occlusion. Two patients underwent splenic vein venoplasty only, whereas four patients underwent bare stents deployment and two covered stents. Splenic vein pressure gradient (SPG) was reduced from 21.5 +/- 7.3 to 2.9 +/- 1.4 mmHg after the procedure (P < 0.01). For the remaining three patients who had technical failures, splenic artery embolization and subsequent splenectomy was performed. During a median follow-up time of 17.5 (range, 3-34) months, no recurrence of GI bleeding was observed. CONCLUSIONS: Transjugular endovascular recanalization of splenic vein is a safe and effective therapeutic option in patients with RPH complicated by GI bleeding and is not associated with an increased risk of procedure-related complications. PMID- 23636250 TI - Iodine-125 seeds strand for treatment of tumor thrombus in inferior vena cava: an experimental study in a rabbit model. AB - OBJECTIVE: The purpose of this study was to establish an animal model of implanted inferior vena cava tumor thrombus (IVCTT) and to evaluate the effect of linear iodine-125 seeds strand in treating implanted IVCTT. METHODS: Tumor cell line VX2 was inoculated subcutaneously into New Zealand rabbit to develop the parent tumor. The tumor strip was inoculated into inferior vena cava (IVC) to establish the IVCTT model. The IVCTT was confirmed by multidetector computed tomography (MDCT) after 2 weeks. Twelve rabbits with IVCTT were randomly divided into two groups. Treatment group (group T; n = 6) underwent Iodine-125 seeds brachytherapy, and the control group (group C; n = 6) underwent blank seeds strand. The blood laboratory examination (including blood routine examination, hepatic and renal function), body weight, survival time, and IVCTT volume by MDCT were monitored. All rabbits were dissected postmortem, and the therapeutic effects were evaluated on the basis of histopathology. The proliferating cell nuclear antigen index (PI) and apoptosis index (AI) of IVCTT were compared between two groups. T test, Wilcoxon rank test, and Kaplan-Meier survival curve analysis were used. RESULTS: The success rate of establishing IVCTT was 100 %. The body weight loss and cachexia of rabbits in group C appeared earlier than in group T. Body weight in the third week, the mean survival time, PI, AI in groups T and C were 2.23 +/- 0.12 kg, 57.83 +/- 8.68 days, (16.73 +/- 5.18 %), (29.47 +/ 7.18 %), and 2.03 +/- 0.13 kg, 43.67 +/- 5.28 days, (63.01 +/- 2.01 %), (6.02 +/ 2.93 %), respectively. There were statistically significant differences between group T and group C (P < 0.05). The IVCTT volume of group T was remarkably smaller than that of group C. CONCLUSIONS: Injecting and suspensory fixing VX2 tumor strip into IVC is a reliable method to establish IVCTT animal model. The linear Iodine-125 seeds strand brachytherapy was a safe and effective method for treating IVCTT in rabbit model. PMID- 23636251 TI - A novel technique for inferior vena cava filter extraction. AB - Inferior vena cava (IVC) filters are used to protect against pulmonary embolism in high-risk patients. Whilst the insertion of retrievable IVC filters is gaining popularity, a proportion of such devices cannot be removed using standard techniques. We describe a novel approach for IVC filter removal that involves snaring the filter superiorly along with the use of flexible forceps or laser devices to dissect the filter struts from the caval wall. This technique has used to successfully treat three patients without complications in whom standard techniques failed. PMID- 23636252 TI - Pulmonary aspergilloma in a cavity formed after percutaneous radiofrequency ablation. AB - We report two cases of pulmonary aspergilloma (PA) in a cavity formed after percutaneous radiofrequency ablation (PRFA), a rare complication that has only been described once in the literature. The first patient was a 59-year-old white woman treated for a secondary lung nodule of an advanced hepatocellular carcinoma. One month after PRFA, a consolidation of a cavity was noticed with an "air crescent sign," and aspergilloma serology was highly positive. A bisegmentectomy was performed due to the proximity of the lesion to mediastinal vessels and the absence of significant regression after antifungal treatment. Histological examination confirmed the diagnosis of PA. The second patient was a 61-year-old white man followed-up for a non-small-cell lung cancer. A cavitation with thick margins in the ablation zone was noticed 6 months after PRFA. A biopsy was performed, and aspergilloma was diagnosed. Medical treatment with itraconazole was administered for 13 months, and there was significant regression. PMID- 23636253 TI - Dickkopf-1 (DKK1) phosphatase and tensin homolog on chromosome 10 (PTEN) crosstalk via microRNA interference in the diabetic heart. AB - Competitive endogenous RNAs (ceRNAs) regulate mRNA transcripts containing common microRNA (miRNA) recognition elements (MREs) through sequestration of shared miRNAs. Interactions of ceRNA have been demonstrated in cancerous cells. However, a paucity of information is available relative to the interactions of ceRNAs interaction in diabetes mellitus and the myocardium. The purpose of this study is to assess the potential role of DKK1 and PTEN in ceRNA regulation utilizing their common miRNAs in diabetic cardiomyocytes. The interactions' regulation between PTEN and DKK1 were determined in two diabetic models in vivo (streptozotocin induced type-1 DM mice and db/db mice) and in vitro (human cardiomyocytes cells exposed to hyperglycemia). The levels of DKK1 and PTEN (mRNA and protein) were upregulated in parallel in all three diabetic models. DKK1 modulates PTEN protein levels in a miRNA and 3'UTR-dependent manner. RNAi-mediated DKK1 gene silencing resulted in a decreased PTEN expression and vice versa. The effect was blocked when Dicer was inhibited. Silencing either PTEN or DKK1 resulted in an increase of the availabilities of shared miRNAs. The silencing of either PTEN or DKKI resulted in a suppression end of the luciferase-PTEN 3'UTR activity. However, the over expression of DKK1 3'UTR or PTEN 3'UTR resulted in an increase in the activity. The attenuation of DKK1 increased AKT phosphorylation, improved glucose uptake and decreased apoptosis in HCMs exposed to hyperglycemia. The effects were blocked by PI3K inhibition. DKK1 and PTEN transcripts are co-upregulated in DM and hyperglycemia. DKK1 and PTEN serve as ceRNA, affecting the expression of each other via competition for miRNAs binding. PMID- 23636255 TI - Treadmill exercise elevates striatal dopamine D2 receptor binding potential in patients with early Parkinson's disease. AB - We have previously demonstrated changes in dopaminergic neurotransmission after intensive exercise in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease (PD), including an increase in the dopamine D2 receptor (DA-D2R), using noninvasive PET imaging with the radioligand [18F]fallypride. The purpose of this feasibility and translational study was to examine whether intensive exercise leads to similar alterations in DA-D2R expression using PET imaging with [18F]fallypride in individuals with early-stage PD. In this pilot study, four patients with early-stage PD were randomized to receive intensive exercise (treadmill training sessions three times/week for 8 weeks) or no exercise. Two healthy age-matched individuals participated in treadmill training. Alterations in the DA-D2R binding potential (BP) as a marker for receptor expression were determined using PET imaging with [18F]fallypride. Turning performance in the patients with PD as a measure of postural control and the Unified Parkinson's Disease Rating Scale scores pre-exercise and postexercise were determined. Our data showed an exercise-induced increase in [18F]fallypride BP as well as improved postural control in patients with PD who exercised. Changes in DA-D2R BP were not observed in patients with PD who did not exercise. These results suggest that exercise can lead to neuroplasticity in dopaminergic signaling and contribute to improved function that may be task specific (postural control) in early-stage PD. PMID- 23636254 TI - Herpes simplex virus 1 DNA polymerase processivity factor UL42 inhibits TNF-alpha induced NF-kappaB activation by interacting with p65/RelA and p50/NF-kappaB1. AB - Herpes simplex virus 1 (HSV-1) is the archetypal member of the alphaherpesvirus with a large genome encoding over 80 viral proteins, many of which are involved in virus-host interactions and show immune modulatory capabilities. In this study, we demonstrated that the HSV-1 UL42 protein, a DNA polymerase processivity factor, was a novel antagonism of the canonical NF-kappaB signaling pathway. UL42 was shown to significantly suppress TNF-alpha mediated NF-kappaB activation. Co immunoprecipitation experiment revealed that UL42 bound to the NF-kappaB subunits p65 and p50. Fluorescence microscopy demonstrated that UL42 abolished nuclear translocation of p65 and p50 upon TNF-alpha-stimulation. But the inhibiting capacity of UL42 2R/2A (R279A, R280A) and UL42 3R/3A (R113A, R279A and R280A) mutants were less than wild type UL42. Also UL42 bound to the Rel homology domain of the NF-kappaB subunit p65 and p50. Notably, the N-terminal of UL42 was sufficient to interact with p65 and p50 and abolished NF-kappaB reporter gene activity. Thus, it was first time we demonstrated that HSV-1 UL42 appeared to prevent NF-kappaB-dependent gene expression by retaining p65 and p50 in the cytoplasm, and UL42-dependent transcriptional activation were inherently coupled to promote HSV-1 lytic replication, which also may contribute to immune evasion and pathogenesis of HSV-1. PMID- 23636257 TI - Physiology and redundancy. PMID- 23636256 TI - Antidepressive effect of paroxetine in a rat model: upregulating expression of serotonin and norepinephrine transporter. AB - Paroxetine is a selective serotonin reuptake inhibitor used for the treatment of depression; this study investigated its other mechanisms by studying the expression and therefore involvement of norepinephrine transporter (NET) and serotonin transporter (5-HTT). Male Sprague-Dawley rats were divided into a vehicle-treated control group (VC), a paroxetine-treated control group (PC), a vehicle-treated model group (VM), and a paroxetine-treated model group (PM). The depression model was established by chronic unpredicted stress. Paroxetine (1.8 mg/kg once daily) was administered to rats (PM and PC groups) by an intragastric gavage, and the same dosage of vehicle was administered to rats in the VM and VC groups. Rat behaviors, superoxide dismutase and catalase activities, malondialdehyde level in the serum, and expression of 5-HTT in the hippocampus and NET in the pons were determined, respectively. Compared with VM rats, the PM rats showed significant relief of depression-like behaviors, decrease in the malondialdehyde level, increase in superoxide dismutase and catalase activities, and increase in 5-HTT and NET expression. The results may suggest that the antidepressive effect of paroxetine is at least partly related to reversing oxidative stress imbalance and elevating the expression of 5-HTT and NET. PMID- 23636258 TI - Physiology's impact: discovering life. PMID- 23636259 TI - Exploring how cells communicate. PMID- 23636260 TI - Hairy sensation. AB - The hairs of the skin not only function to prevent heat loss but also have important sensory functions. Recent work has now established that each hair of the skin is innervated by one or more of three types of mechanoreceptor ending. Each of these three mechanoreceptor types possesses distinct molecular features and detects distinctive information about skin touch, which is relayed to specific brain locations in a somatotopic fashion. PMID- 23636261 TI - Nogo-A represses anatomical and synaptic plasticity in the central nervous system. AB - Nogo-A was initially discovered as a myelin-associated growth inhibitory protein limiting axonal regeneration after central nervous system (CNS) injury. This review summarizes current knowledge on how myelin and neuronal Nogo-A and its receptors exert physiological functions ranging from the regulation of growth suppression to synaptic plasticity in the developing and adult intact CNS. PMID- 23636262 TI - Membrane-tethered ligands: tools for cell-autonomous pharmacological manipulation of biological circuits. AB - Detection of secreted signaling molecules by cognate cell surface receptors is a major intercellular communication pathway in cellular circuits that control biological processes. Understanding the biological significance of these connections would allow us to understand how cellular circuits operate as a whole. Membrane-tethered ligands are recombinant transgenes with structural modules that allow them to act on cell-surface receptors and ion channel subtypes with pharmacological specificity in a cell-autonomous manner. Membrane-tethered ligands have been successful in the specific manipulation of ion channels as well as G-protein-coupled receptors, and, in combination with cell-specific promoters, such manipulations have been restricted to genetically defined subpopulations within cellular circuits in vivo to induce specific phenotypes controlled by those circuits. These studies establish the membrane-tethering approach as a generally applicable method for dissecting neural and physiological circuits. PMID- 23636264 TI - Gap junction remodeling in skin repair following wounding and disease. AB - In the present review, we provide an overview of connexin expression during skin development and remodeling in wound healing, and reflect on how loss- or gain-of function connexin mutations may change cellular phenotypes and lead to diseases of the skin. We also consider the therapeutic value of targeting connexins in wound healing. PMID- 23636263 TI - Transduction of voltage and Ca2+ signals by Slo1 BK channels. AB - Large-conductance Ca2+ -and voltage-gated K+ channels are activated by an increase in intracellular Ca2+ concentration and/or depolarization. The channel activation mechanism is well described by an allosteric model encompassing the gate, voltage sensors, and Ca2+ sensors, and the model is an excellent framework to understand the influences of auxiliary beta and gamma subunits and regulatory factors such as Mg2+. Recent advances permit elucidation of structural correlates of the biophysical mechanism. PMID- 23636267 TI - Relationship between urinary bisphenol A levels and prediabetes among subjects free of diabetes. AB - Bisphenol A (BPA) is a high volume production chemical used in the manufacture of polycarbonate plastics and epoxy resins. Recent experimental studies have suggested that BPA affects glucose metabolism through diverse mechanisms including insulin resistance, pancreatic beta-cell dysfunction, adipogenesis, inflammation and oxidative stress. Prediabetes is a stage earlier in the hyperglycemia continuum associated with increased future risk of developing diabetes. Therefore, we examined the association between BPA exposure and prediabetes among subjects free of diabetes. We examined the association between urinary BPA levels and prediabetes in 3,516 subjects from the National Health and Nutritional Examination Survey 2003-2008. Urinary BPA levels were examined in tertiles. Prediabetes was defined as fasting glucose concentration 100-125 mg/dL or 2-h glucose concentration of 140-199 mg/dL or an A1C value of 5.7-6.4 %. Overall, we observed a positive association between higher levels of urinary BPA and prediabetes, independent of potential confounders including body mass index, alcohol intake, blood pressure and serum cholesterol levels. Compared to tertile 1 (referent), the multivariate-adjusted odds ratio (95 % confidence interval) of prediabetes associated with tertile 3 of BPA was 1.34 (1.03-1.73), p-trend = 0.02. In subgroup analysis, this association was stronger among women and obese subjects. Higher urinary BPA levels are found to be associated with prediabetes independent of traditional diabetes risk factors. Future prospective studies are needed to confirm or disprove this finding. PMID- 23636268 TI - Expression of tissue inhibitor of metalloprotease 3 is reduced in ischemic but not neuropathic ulcers from patients with type 2 diabetes mellitus. AB - Diabetic foot ulceration remains one of the most common and most serious consequences of diabetes. Persistently high levels of matrix metalloproteases (MMPs) contribute to wound chronicity. Our aim was to assess the concentrations of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in neuropathic and ischemic diabetic foot ulcers by analyzing biopsy samples. In this study, biopsies were taken from 35 diabetic foot ulcers of type 2 diabetes mellitus patients and distinguished in neuropathic (n = 14) or ischemic (n = 21). Zymography assay was utilized for the analysis of MMP-2 and MMP-9 activity. TACE activity was evaluated by a specific fluorimetric assay. mRNA levels of MMPs as well as TIMPs were detected using quantitative real-time polymerase chain reaction. The activity of MMP9 and A Disintegrin and A MetalloProtease Domain 17/TNF-Alpha Converting Enzyme (ADAM17/TACE) was significantly increased in ischemic compared to neuropathic biopsies. No differences were detected between both groups for the mRNA levels of MMPs as well as of ADAMs. However, TIMP3 mRNA expression was decreased in ischemic samples. The combination of increased activity of MMP9 and ADAM17/TACE with decreased concentrations of TIMP-3 mRNA expression in ischemic diabetic foot ulcers compared to neuropathic samples suggests that the increased proteolytic environment may represent a causative factor in the ulcer progression. New treatment strategies for healing diabetic foot ulcers could be directed toward increasing levels of TIMP3. PMID- 23636265 TI - cAMP and mitochondria. AB - Phosphorylation of mitochondrial proteins has emerged as a major regulatory mechanism for metabolic adaptation. cAMP signaling and PKA phosphorylation of mitochondrial proteins have just started to be investigated, and the presence of cAMP-generating enzymes and PKA inside mitochondria is still controversial. Here, we discuss the role of cAMP in regulating mitochondrial bioenergetics through protein phosphorylation and the evidence for soluble adenylyl cyclase as the source of cAMP inside mitochondria. PMID- 23636269 TI - Individual differences in pain sensitivity vary as a function of precuneus reactivity. AB - Although humans differ widely in how sensitive they are to painful stimuli, the neural correlates underlying such variability remains poorly understood. A better understanding of this is important given that baseline pain sensitivity scores relate closely to the risk of developing refractory, chronic pain. To address this, we used a matched perception paradigm which allowed us to control for individual variations in subjective experience. By measuring subjective pain, nociceptive flexion reflexes, and, somatosensory evoked brain potentials (with source localization analysis), we were able to map the brain's sequential response to pain while also investigating its relationship to pain sensitivity (i.e. change in the stimulation strength necessary to experience pain) and spinal cord activity. We found that pain sensitivity in healthy adults was closely tied to pain-evoked responses in the contralateral precuneus. Importantly, the precuneus did not contribute to the actual representation of pain in the brain, suggesting that pain sensitivity and pain representation depend on separate neuronal sub-systems. PMID- 23636270 TI - Rapeseed oil-rich diet alters hepatic mitochondrial membrane lipid composition and disrupts bioenergetics. AB - Diet is directly related with physiological alterations occurring at a cell and subcellular level. However, the role of diet manipulation on mitochondrial physiology is still largely unexplored. Aiming at correlating diet with alterations of mitochondrial membrane composition and bioenergetics, Wistar-Han male rats were fed for 11, 22 and 33 days with a rapeseed oil-based diet and mitochondrial bioenergetics, and membrane composition were compared at each time point with a standard diet group. Considerable differences were noticed in mitochondrial membrane lipid composition, namely in terms of fatty acyl chains and relative proportions of phospholipid classes, the modified diet inducing a decrease in the saturated to unsaturated molar ratio and an increase in the phosphatidylcholine to phosphatidylethanolamine molar ratio. Mass spectrometry lipid analysis showed significant differences in the major species of cardiolipin, with an apparent increased incorporation of oleic acid as a result of exposure to the modified diet. Rats fed the modified diet during 22 days showed decreased hepatic mitochondrial state 3 respiration and were more susceptible to Ca(2+)-induced transition pore opening. Rapeseed oil-enriched diet also appeared to promote a decrease in hydroperoxide production by the respiratory chain, although a simultaneous decrease in vitamin E content was detected. In conclusion, our data indicate that the rapeseed oil diet causes negative alterations on hepatic mitochondrial bioenergetics, which may result from membrane remodeling. Such alterations may have an impact not only on energy supply to the cell, but also on drug-induced hepatic mitochondrial liabilities. PMID- 23636271 TI - Sphere-forming cell subsets with cancer stem cell properties in human musculoskeletal sarcomas. AB - Musculoskeletal sarcomas are aggressive malignancies often characterized by an adverse prognosis despite the use of intense multiagent chemotherapy or molecular targeted therapy in combination to surgery and radiotherapy. Stem-like cells identified within solid tumors have been recently implicated in drug resistance, metastasis and local relapse. Here, we report the identification of putative cancer stem cells (CSCs) in sarcomas using a sphere culture system. These sarcospheres, able to grow in anchorage-independent and serum-starved conditions, express the pluripotent embryonic stem cell marker genes OCT3/4, Nanog and SOX2. Expression levels of these genes were greater in sarcospheres than in the parental tumor cultures. Importantly, the isolated tumor spheres transplanted into mice were tumorigenic and capable of recapitulating the human disease. Finally, we demonstrated that low (1%) O2 conditions, reproducing those found within the tumor microenvironment, significantly increase the number and the size of sarcospheres. The sphere formation assay is, therefore, a valuable method for the isolation of putative CSCs from human sarcomas and its efficiency is improved by controlling oxygen availability. This method provides a reliable preclinical model that can be used for future studies aimed at investigating crucial aspects of sarcoma biology, such as resistance to treatments and relapse. PMID- 23636272 TI - Human cathelicidin peptide LL37 binds telomeric G-quadruplex. AB - Stabilization of G-quadruplex inhibits the activity of the enzyme telomerase in cancer cells. We found LL37, a host defense human cathelicidin antimicrobial peptide, to be a potent binder of G-quadruplex structures. PMID- 23636273 TI - J- vs. H-type assembly: pentamethine cyanine (Cy5) as a near-IR chiroptical reporter. AB - The DNA-enabled dimerization of pentamethine cyanine (Cy5) dyes was studied by optical methods. The value of cyanine as a chiroptical reporter using a monomer to-dimer switch is demonstrated. The specific shape of the CD signal and its high intensity are a result of J-type assembly. PMID- 23636274 TI - Sympathetic skin response in patients with primary premature ejaculation. AB - To evaluate the possible role of the autonomic (sympathetic) nervous system function among the patients with primary premature ejaculation (PPE) and determine whether there is an etiological basis for this condition. We performed sympathetic skin response located in the penis (PSSR) in 52 patients with PPE and 46 normally potent men. The latencies and amplitudes of PSSR were measured. The PSSR waveforms were classified into P type and N type according to the waveform characteristics. The waveform distribution in the PPE patients was not statistically different from that in the control group (P=0.609). Mean latency of the PSSR was significantly shorter in the patients than that in the normally potent men (P<0.001). Mean amplitude of the PSSR was significantly greater in patients than that in the normal men (P<0.001). Patients with PPE have hyperactivity of the sympathetic nervous system, which may be another factor involved in the pathological mechanisms of PPE, and the PSSR is an objective test to evaluate patients with PPE. PMID- 23636275 TI - Establishing the content validity of the confidence in performing sexual intercourse and difficulty in performing sexual intercourse questionnaires. AB - The aim of this qualitative analysis was to establish the content validity of two new patient-reported outcome (PRO) measures, Confidence in Performing Sexual Intercourse Questionnaire (CPSIQ) and Difficulty in Performing Sexual Intercourse Questionnaire (DPSIQ). Six separate qualitative studies (interviews/focus groups) were conducted from December 2009 to August 2010 by a single moderator and included 227 men with erectile dysfunction (ED; mean age: 54 years, 58% Caucasian). In the first three studies, concepts about ED and its treatment that were important and relevant to men with ED were identified. They included: getting and controlling erection; erection hardness; maintaining erection for desired duration; achieving and controlling ejaculation; satisfying partner; changing sexual positions; and frequency and spontaneity of sexual intercourse. In the subsequent two studies, concepts were confirmed and transformed into CPSIQ and DPSIQ items. The last study entailed a cognitive interview of the CPSIQ and DPSIQ to ensure that respondents' interpretation of the PRO items were consistent with their intended meaning and that both recall periods and response sets were acceptable. After psychometric testing, the CPSIQ and DPSIQ could serve as complementary tools to existing PROs used in ED clinical trials. PMID- 23636276 TI - Limited effect of testosterone treatment for erectile dysfunction caused by high estrogen levels in rats. AB - Some studies suggest that high-estrogen levels lead to erectile dysfunction (ED); high-estrogen levels are known to decrease testosterone levels. However, no study has examined whether testosterone replacement can improve the ED induced by high estrogen levels. We investigated the effects of testosterone on ED caused by high estrogen levels in rats. Rats were distributed in the following groups: (1) control (vehicle for 2 weeks), (2) the estrogen-treated group (ES; estradiol (3 MUg kg(-1) day(-1)) for 2 weeks), and (3) the estrogen- and testosterone-treated group (ES+TE; estradiol (3 MUg kg(-1) day(-1)) and testosterone (3 mg kg(-1) day( 1)) for 2 weeks). We measured smooth muscle function via isometric tension and erectile function by measuring the intracavernosal pressure on cavernous nerve stimulation. In the ES group, the contraction of the corpus cavernosum smooth muscle increased in response to noradrenalin, and its relaxation decreased in response to the nitric oxide donor, sodium nitroprusside. Further, the erectile function was significantly decreased. In the ES+TE group, neither smooth muscle function nor erectile function was significantly improved. In conclusion, a high estrogen milieu affected erectile function in rats, and testosterone treatment did not improve the ED caused by high-estrogen levels. PMID- 23636277 TI - Elevated plasma factor VIII enhances venous thrombus formation in rabbits: contribution of factor XI, von Willebrand factor and tissue factor. AB - Elevated plasma levels of factor VIII (FVIII) are associated with increased risk of deep venous thrombosis. The aim of this study is to elucidate how elevated FVIII levels affect venous thrombus formation and propagation in vivo. We examined rabbit plasma FVIII activity, plasma thrombin generation, whole blood coagulation, platelet aggregation and venous wall thrombogenicity before and one hour after an intravenous infusion of recombinant human FVIII (rFVIII). Venous thrombus induced by the endothelial denudation of rabbit jugular veins was histologically assessed. Thrombus propagation was evaluated as indocyanine green fluorescence intensity. Argatroban, a thrombin inhibitor, and neutralised antibodies for tissue factor (TF), factor XI (FXI), and von Willebrand factor (VWF) were infused before or after thrombus induction to investigate their effects on venous thrombus formation or propagation. Recombinant FVIII (100 IU/kg) increased rabbit plasma FVIII activity two-fold and significantly enhanced whole blood coagulation and total plasma thrombin generation, but did not affect initial thrombin generation time, platelet aggregation and venous wall thrombogenicity. The rFVIII infusion also increased the size of venous thrombus 1 hour after thrombus induction. Argatroban and the antibodies for TF, FXI or VWF inhibited such enhanced thrombus formation and all except TF suppressed thrombus propagation. In conclusion, elevated plasma FVIII levels enhance venous thrombus formation and propagation. Excess thrombin generation by FXI and VWF-mediated FVIII recruitment appear to contribute to the growth of FVIII-driven venous thrombus. PMID- 23636280 TI - Early fetal development of the human vertebral artery especially at and above the occipitovertebral junction. AB - Little is known about the chronological changes that occur in the topographical anatomy of the fetal vertebral artery (VA), especially at and above the occipitovertebral junction. We histologically examined paraffin-embedded horizontal, sagittal and frontal sections of the heads of 25 human embryos and fetuses of crown-rump length 20-110 mm, corresponding to 6-15 weeks of gestation. At 6 weeks, the VA ran anterosuperiorly through a large intracranial subdural space filled with loose mesenchymal tissue. This intracranial course was distant from the brain stem, suggesting that the developing brain did not "guide" the VA. Before 8-9 weeks, the VA appeared to take an almost straight upward course at the occipitovertebral junction. Later, however, the atlanto-occipital joint growing along the mediolateral axis caused the VA to curve at the junction area. In specimens before 10 weeks, the terminal of the VA, or the origin of the basilar artery, was on the anterior side of the inferior olive and near the jugular foramen. The fetal posterior inferior cerebellar artery originated at the same caudal site distant from the primitive cerebellum. Later, the terminal or origin moved rostrally to the level of the pons. These findings indicate that the basic branching pattern of the VA-basilar artery is independent of the developing brain, whereas the arterial courses are secondarily "corrected" by the growing brain and atlanto-occipital joint. PMID- 23636281 TI - Analysis of EphA5 receptor in the developing rat brain: an in vivo study in congenital hypothyroidism model. AB - The EphA5 receptor has recently been known to play an important role in the initiation of the early phase of synaptogenesis, during which irreparable harm would be done to the developing brain in the absence of sufficient thyroid hormone (TH). In the present article, we aimed to analyze the characteristics of EphA5 receptor expression in the brain of congenital hypothyroid rats. The results showed that the levels of the EphA5 receptor were downregulated by TH deficiency in the developing rat brain with remarkable spatial and temporal characteristics. In the hypothyroid rats, the mRNA and protein levels of EphA5 receptor decreased significantly in the hippocampus (27.92-53.26%), cerebral cortex (12.52-47.16%), and cerebellum (8.72-31.69%) compared with those in the normal rats from postnatal day 0 (P0) to P21 (p < 0.01). The expression of EphA5 receptor was highest and declined most as much as 53% in the hippocampus with TH deficiency. At P7, the EphA5 receptor decreased most prominently during all the observed time point. CONCLUSION: The EphA5 receptor plays actively in the brain development in congenital hypothyroid rats. Our study highlights the high expression of EphA5 receptor protein in hippocampus and dramatic changes at P7 in condition of TH deficiency, which may provide important basis for further investigations in manipulating congenital hypothyroidism. PMID- 23636282 TI - Jugular vein phlebectasia in paediatric patients with vocal fold nodules. AB - Jugular vein phlebectasia (JVP) may often be overlooked in clinical practice and the management for JVP include surgery and a conservative approach. We have studied the relationship between JVP and vocal fold nodules in paediatric patients as well as the effects of treatment. Twenty-three cases of paediatric vocal fold nodules with JVP were studied. All patients received voice therapy. After 6 months of treatment, hoarseness, neck appearance (subjective evaluation) and the degree of dilation of the jugular vein detected by Doppler ultrasonography were analysed. The follow-up period was 6 to 84 months. The hoarseness disappeared or lessened noticeably after treatment for 1-4 months. The neck masses also lessened (pre vs. post: 2.58 +/- 0.40 vs. 1.60 +/- 0.19) after treatment for 1-4 months. The visual analogue score of the post-treatment symptoms decreased significantly compared with pre-treatment (p <0.05). The degree of dilation of the post-treatment jugular vein also decreased significantly (p <0.05). CONCLUSION: Paediatric vocal fold nodules may be related to JVP. Voice changes may also be observed in cases of paediatric JVP. Voice therapy may offer another conservative treatment option for JVP accompanied by vocal fold nodules, and it may offer better results than simple observation of JVP. PMID- 23636284 TI - Lipschutz ulcer in a 17-month-old girl: a rare manifestation of Epstein-Barr primoinfection. AB - Lipschutz ulcer is an uncommon entity that is clinically characterised by a flu like syndrome accompanied by an acute painful necrotic vulvar ulcer. It typically occurs in young women with no sexual contact history, and it is very rare among children. The aetiology is unknown, although recently several reports have related Epstein-Barr virus primary infection with this entity. We report a 17 month-old girl with fever and an acute genital ulcer. All the complementary tests for the most frequent causes of vulvar ulcers yielded negative results, whereas viral serology and polymerase chain reaction technique confirmed the presence of an acute Epstein-Barr virus infection. When main causes of genital ulcer have been excluded, and there is no history of sexual contact, Lipschutz ulcer should be included in the differential diagnosis. Detection of Epstein-Barr virus genome by polymerase chain reaction can lead to an earlier diagnosis. PMID- 23636283 TI - Risk factors for high blood pressure in low income children aged 3-4 years. AB - This study aimed to evaluate the effect of dietary sodium intake on blood pressure among low income children aged 3-4 years. Data were collected during a randomized trial conducted in Sao Leopoldo, Brazil, with 500 mother-child pairs recruited from the maternity ward of a local hospital. Breastfeeding data were obtained during the children's first year of life. At 3 to 4 years of age, children's anthropometric, dietary, and blood pressure assessments were obtained. Sodium intake was estimated from two multiple-pass 24-h dietary recalls. Systolic blood pressure > 90th percentile for age, sex, and height was classified as high systolic blood pressure, according to the population-based percentiles provided by the Task Force on Hypertension Control in Children and Adolescents. Blood pressure data were obtained from 331 children at 3 to 4 years. The mean value of systolic blood pressure was 91.31 mmHg (SD = 8.30 mmHg) and 5.2% (n = 17) presented high systolic blood pressure. The results of the multivariable analyses showed that children who consumed more than 1,200 mg of sodium/day and with waist to-height ratio higher than 0.5 presented, respectively, 3.32 (95%CI 0.98-11.22) and 8.81 (95%CI 2.13-36.31) greater risk of having high systolic blood pressure. Exclusive breastfeeding, child overweight and change in body mass index z score during the first year of life were not associated with the outcome. CONCLUSIONS: The results of this study suggest that at preschool age sodium intake and high waist-to-height ratio are risk factors for high systolic blood pressure. PMID- 23636285 TI - Association between body mass index, skinfold thickness and blood pressure in 12 year-old children. AB - The present study examined the association between body mass index (BMI) and skinfold thickness (SFT) with blood pressure (BP) in 12-year-old children in Shandong, China. A total of 920 (464 boys and 456 girls) 12-year-old students participated in this study. All subjects were divided into four groups (BMI < 25th, 25th <= BMI < 50th, 50th <= BMI < 75th, and BMI >= 75th) according to the percentile of BMI and into four groups (SFT < 25th, 25th <= SFT < 50th, 50th <= SFT < 75th, and SFT >= 75th) according to the percentile of SFT, respectively. Comparisons of BP among different groups were made by one-way ANOVA. High BP status was defined as systolic blood pressure (SBP) >= 95th and/or diastolic blood pressure (DBP) >= 95th percentile for age and gender. BMI and SFT were all significantly (P < 0.001) and positively related to SBP and DBP in both boys and girls. The prevalence of high BP in each group is rising with the percentiles of BMI and SFT in both boys and girls. CONCLUSION: There is a strong positive relationship between BMI, SFT, and BP in 12-year-old children; the present findings emphasize the importance of preventing excess BMI and SFT in order to prevent future-related problems such as hypertension in children and adolescents. PMID- 23636286 TI - Long-term body composition and metabolic changes in HIV-infected children switched from stavudine to tenofovir and from protease inhibitors to efavirenz. AB - This is an 8-year cohort study of 24 HIV-infected patients aged 5-17 years to assess body composition and metabolic changes after switching from lamivudine + stavudine (d4T) + protease inhibitors (PI) to lamivudine + tenofovir (TDF) + efavirenz (EFV). Body composition (dual-energy X-ray absorptiometry) and cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, glucose and insulin were measured annually. Linear mixed models and generalized linear mixed models were used to evaluate time changes of the outcome of interest. Body mass index increased linearly by 0.3 kg/m(2)/year (p < 0.001); waist circumference increased non-linearly from 68 to 74 cm (p = 0.004 for the linear term and p = 0.04 for the quadratic term). Percent body fat, percent trunk fat and percent bone mineral content increased linearly by 0.6%/year (p = 0.005), 1.2%/year (p < 0.001) and 0.02%/year (p = 0.04), respectively. Percent arm fat remained stable (p = 0.5), and percent leg fat decreased linearly by 1.2%/year (p < 0.001). The probability of low HDL was 0.2% at baseline and remained stable during the study. The probability of high triglycerides was 3% at baseline and increased linearly to become 11% at the 8th year of follow-up (p = ns). The probability of high glucose was 1% for the whole study duration. CONCLUSIONS: patients, after switching from d4T to TDF and from PI to EFV, show most of the changes in anthropometry and body composition associated with normal growth and no frankly pathological change in metabolic parameters. PMID- 23636290 TI - Splicing: hear and now! PMID- 23636291 TI - Targeting tumors using nanoparticle platforms: a phase I study of a systemically administered gene therapy system. PMID- 23636292 TI - A patient with severely reduced LV function and electrical storm saved by wearable cardioverter-defibrillator: a case report. AB - The wearable cardioverter-defibrillator (WCD) is indicated in patients who are considered to be at temporarily high risk for sudden cardiac death (SCD), when an implantable defibrillator is not yet clearly indicated. We report the case of a 41-year-old patient with a newly diagnosed severely reduced left ventricular (LV) function for suspected myocarditis and repeated nonsustained ventricular tachycardia (VT). This patient was supplied with a WCD who came back to the hospital 4 weeks after discharge with an electrical storm and adequate discharge of the WCD. After application of amiodarone, no further arrhythmias were detected during intrahospital course. For further risk stratification, we performed a magnetic field imaging (MFI), that was reported to be useful in risk assessment of SCD in patients with ischemic cardiomyopathy. This measurement showed a normal result, but we decided to give an implantable cardioverter-defibrillator (ICD) to the patient. During a follow-up of 1 year, no further arrhythmias occurred. With this case, we report the efficacy of a WCD, which is a novel tool in patients at temporarily high risk of SCD and we report a novel method of risk stratification in patients with a high risk of SCD. PMID- 23636293 TI - Diagnostic performance of 18F-FDG PET/CT in patients with fever of unknown origin: a meta-analysis. AB - PURPOSE: The aim of this study was to systematically review and perform a meta analysis of published data on the diagnostic value of F-fluorodeoxyglucose (F FDG) PET/CT in the diagnosis of patients with fever of unknown origin (FUO). MATERIALS AND METHODS: A comprehensive computer literature search of studies published through 31 March 2012 on the use of F-FDG PET/CT in patients with FUO was performed in PubMed/MEDLINE, Embase, and Scopus databases. The pooled sensitivity of F-FDG PET/CT in patients with FUO on a per-patient-based analysis was calculated. The area under the receiver-operating characteristic curve was calculated to measure the accuracy of F-FDG PET/CT in the diagnosis of patients with FUO. RESULTS: Fifteen studies comprising 595 patients with FUO were included in this meta-analysis. The pooled sensitivity of F-FDG PET/CT in detecting the cause of FUO was 85% (95% confidence interval 81-88%) on a per-patient-based analysis. The area under the receiver-operating characteristic curve was 0.88. CONCLUSION: F-FDG PET/CT demonstrated high sensitivity for the diagnosis of patients with FUO. F-FDG PET/CT is an accurate technique in this setting, but the possibility of false-positive results should be kept in mind. This meta-analysis demonstrated the value of F-FDG PET/CT in the diagnosis of patients with FUO. PMID- 23636294 TI - Impact of 18F-FDG-PET/CT on treatment strategy in colorectal cancer lung metastasis before lung radiofrequency ablation. AB - OBJECTIVE: The aim of the study was to evaluate prospectively the clinical impact of 2-(F)-fluoro-2-deoxy-D-glucose (F-FDG) PET/computed tomography (CT) on the pretreatment assessment of patients with colorectal lung metastasis before radiofrequency (RF) ablation. METHODS: The institutional review board approved this prospective study. The eligibility criteria for lung RF ablation were the presence of five or fewer colorectal lung metastases with a maximum tumor size of 3 cm and absence of extrapulmonary lesions. Lung RF ablation candidates who underwent pretreatment PET/CT studies were included. The incidence of detection of unexpected recurrent lesions on PET/CT was evaluated, along with its impact on subsequent treatments. Factors linked with the incidence of unexpected recurrent lesions were evaluated using univariate and multivariate analyses. RESULTS: Between October 2008 and June 2011, 60 patients were enrolled. Among the unexpected abnormal F-FDG accumulations found in 13 patients (21.7%), presence of extrapulmonary lesions was proved in 12 patients (20.0%, 12/60), prompting treatment strategy changes. One false-positive case was found (1.7%, 1/60). The sensitivity, specificity, and accuracy in detecting unexpected lesions by PET/CT were, respectively, 100, 97.9, and 98.3%. Elevation of the serum carcinoembryonic antigen level (>6.0 ng/ml) was the only significant factor linked with unexpected lesions in both univariate (P=0.02) and multivariate analyses (P=0.02). CONCLUSION: A PET/CT study should be performed in patients with colorectal lung metastasis before selecting them for lung RF ablation, especially when the carcinoembryonic antigen level is elevated. PMID- 23636295 TI - Positive action is required to achieve the 2020.30 goal of gender equality in Japanese medical societies. PMID- 23636296 TI - Evaluation of different types of enamel conditioning before application of a fissure sealant. AB - The aim of the study was to compare fissure sealant quality after mechanical conditioning of erbium-doped yttrium aluminium garnet (Er:YAG) laser or air abrasion prior to chemical conditioning of phosphoric acid etching or of a self etch adhesive. Twenty-five permanent molars were initially divided into three groups: control group (n = 5), phosphoric acid etching; test group 1 (n = 10), air abrasion; and test group 2, (n = 10) Er:YAG laser. After mechanical conditioning, the test group teeth were sectioned buccolingually and the occlusal surface of one half tooth (equal to one sample) was acid etched, while a self etch adhesive was applied on the other half. The fissure system of each sample was sealed, thermo-cycled and immersed in 5% methylene dye for 24 h. Each sample was sectioned buccolingually, and one slice was analysed microscopically. Using specialized software microleakage, unfilled margin, sealant failure and unfilled area proportions were calculated. A nonparametric ANOVA model was applied to compare the Er:YAG treatment with that of air abrasion and the self-etch adhesive with phosphoric acid (alpha = 0.05). Test groups were compared to the control group using Wilcoxon rank sum tests (alpha = 0.05). The control group displayed significantly lower microleakage but higher unfilled area proportions than the Er:YAG laser + self-etch adhesive group and displayed significantly higher unfilled margin and unfilled area proportions than the air-abrasion + self-etch adhesive group. There was no statistically significant difference in the quality of sealants applied in fissures treated with either Er:YAG laser or air abrasion prior to phosphoric acid etching, nor in the quality of sealants applied in fissures treated with either self-etch adhesive or phosphoric acid following Er:YAG or air-abrasion treatment. PMID- 23636297 TI - Mechanical properties of thin films of laser-welded titanium and their associated welding defects. AB - The aim of this study was to evaluate the mechanical properties of thin films of laser-welded cast titanium using an interference strain/displacement gauge (ISDG) and to analyze factors that affect laser welding. Dog-bone-shaped small specimens of cast titanium were prepared by wire cutting after they were laser-welded. The specimens were divided into three groups according to the gap distance of the laser weld; the control was non-welded titanium. Small specimens without cast defects detected by X-ray screening were measured by a tensile test machine using ISDG, and stress-strain curves were drawn. Finally, the fracture texture was analyzed. The ultimate tensile strengths (UTSs) of specimens with a gap distance of 0.00, 0.25, and 0.50 mm were 492.16 +/- 33.19, 488.09 +/- 43.18, and 558.45 +/ 10.80 MPa, respectively. There were no significant differences in UTS between the test groups and the control group (p > 0.05). However, the plastic deformation and the percent elongation increased as the gap distance increased. Incomplete penetration defects appeared in groups that had small gap distances, which may have affected the properties of the laser-welded titanium. However, the welding material was still pure titanium. These results suggest that an appropriate gap distance should be maintained to improve the application of dental laser welding. PMID- 23636298 TI - Comments on: "efficacy of low-level laser therapy in the management of orthodontic pain: a systematic review and meta-analysis". PMID- 23636299 TI - Effects of laser irradiation at different wavelengths (660, 810, 980, and 1,064 nm) on mucositis in an animal model of wound healing. AB - The aim of the present study was to compare the effectiveness of four different laser wavelengths (660, 810, 980, and 1,064 nm) used for low-level laser therapy (LLLT) on the healing of mucositis in an animal model of wound healing by investigating the expression of platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-beta), and blood-derived fibroblast growth factor (bFGF). Thirty-five male Wistar albino rats with a weight of 250-300 g body mass and 5 months old were used in the study. All animals were intraperitoneally injected with 100 mg/kg of 5-fluorouracil (5-FU) on the first day and 65 mg/kg of 5-FU on the third day. The tip of an 18-gauge needle was used in order to develop a superficial scratching on the left cheek pouch mucosa by dragging twice in a linear movement on third and fifth days. After ulcerative mucositis were clinically detected on the animals' left cheek pouch mucosa, the laser therapy was started. Four different laser wavelengths (660 nm, HELBO, Bredent; 810 nm, Fotona XD, Fotona; 980 nm, ARC Fox; and 1,064 nm, Fidelis Plus 3, Fotona) used for LLLT at ED 8 J/cm(2) daily from the first to the fourth days. Oval excisional biopsy was taken from the site of the wound, and the expression of PDGF, TGF-beta, and bFGF was evaluated. The obtained data were analyzed by one2-way ANOVA, and then Tukey HSD tests were used for pairwise comparisons among groups (alpha = 0.05). The one-way ANOVA test indicated that expression values of the growth factors, PDGF and bFGF, were significantly affected by irradiation of different wavelengths of lasers (p < 0.001). However, expression value of the TGF beta was not affected by irradiation of different wavelengths of lasers (p > 0.05). The highest PDGF expression was detected in neodymium-doped yttrium aluminum garnet (Nd:YAG) laser group (p < 0.05), and there were no statistically significant differences among the other groups (p > 0.05). The highest bFGF expression was detected in 980-nm diode and Nd:YAG laser groups (p < 0.05), and there were no statistically significant differences among the other groups (p > 0.05). These findings suggest that low-level Nd:YAG and 980-nm diode laser therapy accelerate the wound healing process by changing the expression of PDGF and bFGF genes responsible for the stimulation of the cell proliferation and fibroblast growth. PMID- 23636300 TI - First in vivo head-to-head comparison of high-definition versus standard definition stent imaging with 64-slice computed tomography. AB - The aim of this study was to compare image quality characteristics from 64-slice high definition (HDCT) versus 64-slice standard definition CT (SDCT) for coronary stent imaging. In twenty-five stents of 14 patients, undergoing contrast-enhanced CCTA both on 64-slice SDCT (LightSpeedVCT, GE Healthcare) and HDCT (Discovery HD750, GE Healthcare), radiation dose, contrast, noise and stent characteristics were assessed. Two blinded observers graded stent image quality (score 1 = no, 2 = mild, 3 = moderate, and 4 = severe artefacts). All scans were reconstructed with increasing contributions of adaptive statistical iterative reconstruction (ASIR) blending (0, 20, 40, 60, 80 and 100 %). Image quality was significantly superior in HDCT versus SDCT (score 1.7 +/- 0.5 vs. 2.7 +/- 0.7; p < 0.05). Image noise was significantly higher in HDCT compared to SDCT irrespective of ASIR contributions (p < 0.05). Addition of 40 % ASIR or more reduced image noise significantly in both HDCT and SDCT. In HDCT in-stent luminal attenuation was significantly lower and mean measured in-stent luminal diameter was significantly larger (1.2 +/- 0.4 mm vs. 0.8 +/- 0.4 mm; p < 0.05) compared to SDCT. Radiation dose from HDCT was comparable to SDCT (1.8 +/- 0.7 mSv vs. 1.7 +/- 0.7 mSv; p = ns). Use of HDCT for coronary stent imaging reduces partial volume artefacts from stents yielding improved image quality versus SDCT at a comparable radiation dose. PMID- 23636301 TI - Coronary computed tomography angiography-adapted Leaman score as a tool to noninvasively quantify total coronary atherosclerotic burden. AB - To describe a coronary computed tomography angiography (CCTA)-adapted Leaman score (CT-LeSc) as a tool to quantify total coronary atherosclerotic burden with information regarding localization, type of plaque and degree of stenosis and to identify clinical predictors of a high coronary atherosclerotic burden as assessed by the CT-LeSc. Single center prospective registry including a total of 772 consecutive patients undergoing CCTA (Dual-source CT) from April 2011 to March 2012. For the purpose of this study, 581 stable patients referred for suspected coronary artery disease (CAD) without previous myocardial infarction or revascularization procedures were included. Pre-test CAD probability was determined using both the Diamond-Forrester extended CAD consortium method (DF CAD consortium model) and the Morise score. Cardiovascular risk was assessed with the HeartScore. The cut-off for the 3rd tercile (CT-LeSc >=8.3) was used to define a population with a high coronary atherosclerotic burden. The median CT LeSc in this population (n = 581, 8,136 coronary segments evaluated; mean age 57.6 +/- 11.1; 55.8 % males; 14.6 % with diabetes) was 2.2 (IQR 0-6.8). In patients with CAD (n = 341), the median CT-LeSc was 5.8 (IQR 3.2-9.6). Among patients with nonobstructive CAD, most were classified in the lowest terciles (T1, 43.0 %; T2, 36.1 %), but 20.9 % were in the highest tercile (T3). The majority of the patients with obstructive CAD were classified in T3 (78.2 %), but 21.8 % had a CT-LeSc in lower terciles (T1 or T2). The independent predictors of a high CT-LeSc were: Male sex (OR 1.73; 95 % CI 1.04-2.90) diabetes (OR 2.91; 95 % CI 1.61-5.23), hypertension (OR 2.54; 95 % CI 1.40-4.63), Morise score >= 16 (OR 1.97; 95 % CI 1.06-3.67) and HeartScore >= 5 (OR 2.42; 95 % CI 1.41-4.14). We described a cardiac CT adapted Leaman score as a tool to quantify total (obstructive and nonobstructive) coronary atherosclerotic burden, reflecting the comprehensive information about localization, degree of stenosis and type of plaque provided by CCTA. Male sex, hypertension, diabetes, a HeartScore >=5 % and a Morise score >= 16 were associated with a high coronary atherosclerotic burden, as assessed by the CT-LeSc. About one fifth of the patients with nonobstructive CAD had a CT-LeSc in the highest tercile, and this could potentially lead to a reclassification of the risk profile of this subset of patients identified by CCTA, once the prognostic value of the CT-LeSc is validated. PMID- 23636302 TI - Cigarette craving and withdrawal symptoms during temporary abstinence and the effect of nicotine gum. AB - RATIONALE: It is widely believed that nicotine withdrawal symptoms appear within a few hours of stopping smoking, but few data exist documenting their emergence in naturalistic settings. In several countries, nicotine replacement products are licensed for relief of withdrawal symptoms during temporary abstinence, but again, there are no data supporting this from naturalistic settings. OBJECTIVES: To examine the emergence of cigarette craving and withdrawal symptoms during temporary abstinence in a naturalistic setting while using either nicotine or placebo gum. METHODS: Double-blind, randomised, placebo-controlled study in which 132 dependent smokers abstained for 6 h with the assistance of either nicotine (2 mg, n = 42 or 4 mg, n = 24) or placebo (n = 66) gum while travelling on a non smoking train. Outcome measures were ratings of craving and mood withdrawal symptoms prior to treatment and at regular intervals during abstinence. RESULTS: In a multivariate analysis of all symptoms, there was no interaction between treatment and time [F(21,110) = 1.28, p = 0.20, eta2(p)= 0.20] nor an effect of treatment [F(7,124) = 0.45, p = 0.87, eta2(p)= 0.03]. There was an effect of time [F(21,110) = 11.59, p < 0.001, eta2(p)= 0.69) and univariate analyses revealed that the majority of symptoms increased linearly throughout the period of abstinence with detectable onsets typically between the first 60 and 180 min of abstinence. CONCLUSIONS: Smokers who temporarily abstain in naturalistic settings experience craving and withdrawal symptoms that emerge linearly over the first 6 h of abstinence. Changes in craving and several mood withdrawal symptoms can be detected within the first 3 h. Nicotine gum may not have an acute effect on the development of these symptoms. PMID- 23636304 TI - Delay discounting of food and remifentanil in rhesus monkeys. AB - RATIONALE: Drug abuse can be conceptualized as choice between drug and nondrug reinforcers in which drug choice is excessive; factors impacting drug taking can be examined using procedures in which subjects choose between drug and an alternative reinforcer. OBJECTIVE: This experiment examined the effects of delayed reinforcement on choice between food and the mu-opioid receptor agonist remifentanil. METHODS: Rhesus monkeys responded under a concurrent fixed-ratio 5, fixed-ratio 5 schedule in which responding on one lever delivered one food pellet and responding on another lever delivered an i.v. infusion. RESULTS: With no delay, monkeys responded predominantly for food rather than saline or small doses of remifentanil; as the dose of remifentanil increased (0.1-1.0 MUg/kg/infusion), monkeys responded more for drug. Delaying delivery (30-240 s) of 0.32 and not 1.0 MUg/kg/infusion of remifentanil (food delivered immediately) decreased responding for drug and increased responding for food, resulting in a rightward shift in the remifentanil dose-effect curve. Delaying delivery of food (60-240 s) when doses of remifentanil smaller than 0.32 MUg/kg/infusion (but not saline) were available decreased responding for food and increased responding for drug, resulting in a leftward shift in the remifentanil dose-effect curve. CONCLUSION: These results provide evidence that delaying the delivery of a mu-opioid receptor agonist reduces its potency as a positive reinforcer; more importantly, delaying the delivery of an alternative nondrug reinforcer (e.g., food) enhances the reinforcing potency of the agonist. Thus, understanding the factors that control substance abuse requires examination of contingencies for both drug and nondrug reinforcers. PMID- 23636305 TI - Transmembrane receptor CXCR7 increases the risk of extrahepatic metastasis of relatively well-differentiated hepatocellular carcinoma through upregulation of osteopontin. AB - Recurrence and metastasis are the main obstacles to improving the survival of patients with post-resective hepato-cellular carcinoma (HCC). Our previous study suggests a critical role of CXCR7 in the metastasis of HCC. In the present study, the effect of CXCR7 as a risk factor for metastasis of HCC was evaluated. Immunohistochemical assay was performed on tissue microarrays based on HCC with extrahepatic metastases after hepatectomy. Two categories based on staining scores were used to evaluate the risk effect of CXCR7, respectively. The effect of CXCR7 on osteopontin (OPN) was explored by RNA interference. Based on the results, in both categories, highly expressed CXCR7 was a dependent risk factor for extrahepatic metastasis because of the potential association with relatively good cell differentiation. Stratification analyses indicated that CXCR7 was a strong independent risk factor (OR, 3.40; 95% CI, 1.07-18.84; P=0.038 in category 1 and OR, 6.40; 95% CI, 1.64-24.92; P=0.007 in category 2, respectively) in patients with Edmondson grade 1/2. Furthermore, CXCR7 correlated well and positively with expression of OPN (P=0.019 and P<0.001 in two categories, respectively) in HCC cases with Edmondson grade 1/2. Immunocytochemistry and RT PCR demonstrated downregulation of OPN in a highly metastatic HCC cell line following knockdown of CXCR7. Taken together, these findings suggest that high expression of CXCR7 increases the risk of metastasis in post-resective HCC patients with relatively good differentiated tumors, potentially through upregulation of OPN. This group of patients may acquire a survival benefit from early detection and treatment of recurrence and metastasis. PMID- 23636303 TI - Involvement of serotonin 5-HT3 receptors in the modulation of noradrenergic transmission by serotonin reuptake inhibitors: a microdialysis study in rat brain. AB - RATIONALE: Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance serotonergic neurotransmission, are able to modulate other brain systems involved in depression. OBJECTIVES: This study evaluates the neurochemical effect of the SSRI citalopram on brain noradrenergic activity and the serotonin receptor involved in this effect. METHODS: Dual-probe microdialysis in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely awake rats. RESULTS: Systemic citalopram (10 mg/kg, i.p.) increased noradrenaline (NA) in the LC (E max = 141 +/- 13%) and simultaneously decreased NA in the PFC (Emax = -46 +/- 7%). In the local presence into the LC of the alpha2-adrenoceptor antagonist RS79948 (1 MUM), systemic citalopram increased NA in the LC (Emax = 157 +/- 25%) and PFC (Emax = 175 +/- 24%). Local citalopram (0.1-100 MUM) into the LC induced NA increase in the LC (Emax = 210 +/- 25%) and decrease in the PFC (Emax = -38 +/- 9%). Local LC citalopram effect was abolished by LC presence of the 5-HT3 receptor antagonist MDL72222 (1 MUM) but not the 5-HT1/2 receptor antagonist methiothepin (1 MUM). Systemic citalopram in the LC presence of MDL72222 did not modify NA in the LC but increased NA in the PFC (Emax = 158 +/- 26%). Local citalopram into the PFC enhanced NA (Emax = 376 +/- 18%) in the area, which was prevented by MDL72222. CONCLUSIONS: The SSRI citalopram modulates central noradrenergic neurotransmission by activation, through endogenous serotonin, of 5-HT3 receptors expressed in the somatodendritic (LC) and terminal (PFC) areas, which subsequently promote an enhancement of local NA. Therefore, 5 HT3 receptors and somatodendritic alpha2-adrenoceptors in the LC play an important role in the global effect of SSRIs. PMID- 23636306 TI - Platelets and neurovascular inflammation. AB - Platelets participate in haemostasis and in thrombus formation in health and disease. Moreover, they contribute to inflammation and cooperate with immune cells in a magnitude of inflammatory/immune responses. Although the inflammatory response has been recognised to be critical in neuronal diseases such as Alzheimer's disease or multiple sclerosis and its mouse counterpart, experimental autoimmune encephalomyelitis, the participation of platelets in these diseases is poorly investigated so far. Emerging studies, however, point to an interesting crosstalk between platelets and neuroinflammation. For instance, when the integrity of the blood brain barrier is compromised, platelets may be relevant for endothelial inflammation, as well as recruitment and activation of inflammatory cells, thereby potentially contributing to central nervous tissue pathogenesis. This review summarises recent insights in the role of platelets for neurovascular inflammation and addresses potential underlying mechanisms, by which platelets may affect the pathophysiology of neurovascular diseases. PMID- 23636308 TI - Repellent activity of eugenol on larvae of Rhipicephalus microplus and Dermacentor nitens (Acari: Ixodidae). AB - The repellent activity of eugenol was evaluated on Rhipicephalus microplus and Dermacentor nitens larvae in a bioassay based on the vertical migration of these tick larvae during the host-seek phase. Solutions were used at concentrations of 10, 20, 30, 40, and 50 MUl/ml and a control only with the solvent ethanol 50 GL. The larvae's reaction of climbing the rods of filter paper was observed each hour for 12 h and once more at 24 h. The repellence was calculated as a percentage through visual estimation, from the tendency of the larvae to climb the rods when the top part was impregnated with the eugenol solutions. For R. microplus larvae, the four highest concentrations produced repellence levels were greater than 80 % for up to 9 h. The repellence rates after 10 h for the concentration of 10 MUl/ml was lower than 2 % (p > 0.05); and after 24 h, the values observed for the concentrations of 40 and 50 MUl/ml were 77 and 80 % (p < 0.05). For the D. nitens larvae, the repellence was greater than 80 % for up to 5 h at the concentrations of 40 and 50 MUl/ml; and after 9 h, the repellence fell for all treated groups were significantly different than the control were found only at the three highest concentrations. Therefore, eugenol has repellent activity on the larval stage of these two tick species, with the R. microplus larvae being more sensitive. PMID- 23636307 TI - Comparative analysis of midgut bacterial communities of Aedes aegypti mosquito strains varying in vector competence to dengue virus. AB - Differences in midgut bacterial communities of Aedes aegypti, the primary mosquito vector of dengue viruses (DENV), might influence the susceptibility of these mosquitoes to infection by DENV. As a first step toward addressing this hypothesis, comparative analysis of bacterial communities from midguts of mosquito strains with differential genetic susceptibility to DENV was performed. 16S rRNA gene libraries and real-time PCR approaches were used to characterize midgut bacterial community composition and abundance in three Aedes aegypti strains: MOYO, MOYO-R, and MOYO-S. Although Pseudomonas spp.-related clones were predominant across all libraries, some interesting and potentially significant differences were found in midgut bacterial communities among the three strains. Pedobacter sp.- and Janthinobacterium sp.-related phylotypes were identified only in the MOYO-R strain libraries, while Bacillus sp. was detected only in the MOYO S strain. Rahnella sp. was found in MOYO-R and MOYO strains libraries but was absent in MOYO-S libraries. Both 16S rRNA gene library and real-time PCR approaches confirmed the presence of Pedobacter sp. only in the MOYO-R strain. Further, real-time PCR-based quantification of 16S rRNA gene copies showed bacterial abundance in midguts of the MOYO-R strain mosquitoes to be at least 10 100-folds higher than in the MOYO-S and MOYO strain mosquitoes. Our study identified some putative bacteria with characteristic physiological properties that could affect the infectivity of dengue virus. This analysis represents the first report of comparisons of midgut bacterial communities with respect to refractoriness and susceptibility of Aedes aegypti mosquitoes to DENV and will guide future efforts to address the potential interactive role of midgut bacteria of Aedes aegypti mosquitoes in determining vectorial capacity for DENV. PMID- 23636309 TI - Detection of Anaplasma marginale in Hyalomma asiaticum ticks by PCR assay. AB - A polymerase chain reaction (PCR) assay was performed in this study to amplify the major surface protein 5 (msp5) gene from the genomic DNA of Anaplasma marginale in Hyalomma asiaticum ticks by species-specific primers. Sequence analysis showed that the msp5 gene was 643 bases long and that the PCR products from the samples had an identical sequence (JX507127). Moreover, the BLAST showed that the sequence was identical to the msp5 sequences of A. marginale and most closely related to the A. marginale msp5 gene (AB704328) and the Liangdang strain of the A. marginale msp5 gene (EF546443) with similarity of 99 % (differing only by two bases). An epidemiological survey was performed in several dairy farms: a total of 68 ticks were collected from 49 cattle. As a result, 14 of the 49 (28.57 %) blood smears stained with Wright-Giemsa and 22 of the 68 (32.35 %) ticks examined by PCR assay exhibited A. marginale infection. The results of the PCR assay were mostly consistent with the results of the microscopic examination. A number of results were negative in blood smear but positive in PCR, which is important for the early diagnosis of anaplasmosis. PMID- 23636311 TI - Reliability and validity of a treatment fidelity assessment for motivational interviewing targeting sexual risk behaviors in people living with HIV/AIDS. AB - This study psychometrically evaluates the Motivational Interviewing Treatment Integrity Code (MITI) to assess fidelity to motivational interviewing to reduce sexual risk behaviors in people living with HIV/AIDS. 74 sessions from a pilot randomized controlled trial of motivational interviewing to reduce sexual risk behaviors in people living with HIV were coded with the MITI. Participants reported sexual behavior at baseline, 3-month, and 6-months. Regarding reliability, excellent inter-rater reliability was achieved for measures of behavior frequency across the 12 sessions coded by both coders; global scales demonstrated poor intraclass correlations, but adequate percent agreement. Regarding validity, principle components analyses indicated that a two-factor model accounted for an adequate amount of variance in the data. These factors were associated with decreases in sexual risk behaviors after treatment. The MITI is a reliable and valid measurement of treatment fidelity for motivational interviewing targeting sexual risk behaviors in people living with HIV/AIDS. PMID- 23636312 TI - The kinetics and apoptotic profile of circulating endothelial cells in autologous hematopoietic stem cell transplantation in patients with lymphoproliferative disorders. AB - In neoplastic disorders, endothelial cells take part in tumor progression and also influence the recovery of hematopoiesis after high-dose chemotherapy. Measurements of circulating endothelial cells (CEC), their subsets and kinetics were taken in patients with lymphoid malignancies (37 multiple myeloma, ten lymphoma) during autologous hematopoietic stem cell transplantation (HSCT). CEC were evaluated by four-color flow cytometry at different time points. Additionally levels of angiopoietins 1 and 2 were evaluated by ELISA assay. The baseline number of CECs and their subsets in patients were higher than in the control group. The median CEC number dropped significantly after transplantation (from 9.5/MUL to 6.2/MUL, p < 0.001). Apoptosis of CECs 24 h after chemotherapy was enhanced in comparison to baseline values (median apoptotic CEC number 4.15/MUL vs 3.1/MUL; p < 0,001). The time for neutrophil engraftment was shorter for patients with a low apoptotic CEC count at baseline as compared to those with a high apoptotic CEC count (median time to engraftment 13 vs. 16 days respectively, p = 0.04). We observed an adverse correlation of progenitor CEC numbers measured 1 h after transplantation with the time to neutrophil engraftment (r = -0.49, p = 0.008). We also found a negative correlation between the number of CECs originating from microvessels measured 1 h after transplantation, and the time to neutrophil engraftment (r = -0.39, p = 0.04). Baseline angiopoietins 1 and 2 concentration did not influence the post transplant regeneration time. CEC numbers significantly change during autologous HSCT. Our results suggest that progenitor CECs and CECs derived from microvessels both take part in successful engraftment. PMID- 23636313 TI - Activation of the PI3K/AKT/mTOR pathway in diffuse large B cell lymphoma: clinical significance and inhibitory effect of rituximab. AB - Diffuse large B cell lymphoma (DLBCL) represents the most common subtype of non Hodgkin lymphoma and accounts for approximately 30% of newly diagnosed lymphoid neoplasms in Western countries, and 40-50% in China. A better understanding of the biology of DLBCL is needed for the development of potential therapeutic agents that target specific intracellular pathways. In this study, expression of the important components of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway and their clinical significance were investigated in 73 DLBCL cases. The effect of rituximab alone or combined with the PI3K/AKT/mTOR pathway inhibitor rapamycin was further evaluated in the DLBCL cell lines. A total of 73 patients were identified, including 45 men and 28 women aged 18 to 78 years (median age 50 years). Of these patients, p-AKT was positive in 40 cases (54.8%), p-p70S6K in 34 cases (46.6%), and p-4E-BP1 in 33 cases (45.2%). Activation of the PI3K/AKT/mTOR pathway was related to poor disease outcome in DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) but not in those treated with rituximab-CHOP. Rituximab combined with rapamycin synergically downregulated the PI3K/AKT/mTOR signaling pathway. Western blot analysis revealed a baseline activation status of the PI3K/AKT/mTOR pathway in DLBCL cell lines, with high levels of p-AKT, p-mTOR, in addition to downstream molecules p-p70S6K and p-4E-BP1. The results indicate that the PI3K/AKT/mTOR pathway is a potentially important signaling route and an unfavorable prognostic factor for DLBCL. Patients with PI3K/AKT/mTOR activation experience a more rapidly deteriorating clinical course with poor treatment response and decreased survival time. Addition of rituximab could downregulate PI3K/AKT/mTOR activation, reversing its negative effect on chemotherapy-treated patients. In addition, our results indicate that the combination of rituximab and inhibition of the activated PI3K/AKT/mTOR pathway could be a promising target for DLBCL therapeutic intervention in the future. PMID- 23636314 TI - Burkitt lymphomas failing dose-adjusted R-EPOCH (DA-R-EPOCH). PMID- 23636317 TI - Traumatic and degenerative cartilage lesions: arthroscopic differentiation using near-infrared spectroscopy (NIRS). AB - INTRODUCTION: Cartilage lesions or defects are the most common finding during knee arthroscopy. During arthroscopy, it is often difficult to differentiate between degenerative and traumatic cartilage lesions. The study aimed to determine the impact of near-infrared spectroscopy (NIRS) on the distinction between traumatic and degenerative cartilage lesions in the medial femoral condyle (MFC). It was hypothesized that NIRS as able to distinguish between traumatic and degenerative cartilage lesions. MATERIALS AND METHODS: Arthroscopic evaluation was performed in six patients who had undergone anterior cruciate ligament (ACL) reconstruction and in six patients who had undergone high tibial osteotomy (HTO). In both groups, a grade III cartilage lesion was present within the MFC. NIRS evaluation was performed with a special probe (arthrospec-one, Arthrospec GmbH, Jena, Germany). NIRS measurements produced semi-quantitative values ranging from 0 (heavily degenerated cartilage) to 100 (completely intact cartilage). RESULTS: The mean near-infrared-light absorption within the traumatic lesions in the MFC of the ACL group was 71.5 (range 61-80). In the HTO patients, this value was significantly (p < 0.001) lower at 31.7 (range 31-33). The margin of the MFC outside the lesion in the ACL group had the same adsorption as the lesion (p = 0.549). CONCLUSION: After an injury, cartilage has a normal or nearly normal absorbance on near-infrared-light. Thus, it is possible to distinguish intraoperatively between traumatic and degenerative lesions. In addition, our results demonstrate that evaluating cartilage with NIRS is a dependable method for improving the diagnosis of significant chondral lesions. PMID- 23636318 TI - An anatomic study on the placement of the second sacral screw and its clinical applications. AB - BACKGROUND: The fixation of lumbosacral and sacral pelvis can be performed on the ilium and the Second Sacrum Vertebrae (S2). Although several studies on the anatomical and biomechanical features of S2 screw fixation have been published, little clinical application has been reported, especially combination of anatomical investigation and clinical study. This study was performed to design and optimize the method of pedicle screw placement for S2. MATERIALS AND METHODS: Fifteen adult dry sacrum specimens were prepared and truncated from the S1-S2 and S2-S3 vertebral fusion remnants, and the morphology of the S2 vertebral body was observed from this section. The intersection of the horizontal line through the lowest point of the inferior edge of the first posterior sacral foramen and the lateral sacral crest was the entry point (Point X). The screws were inserted anterolaterally or anteromedially at Point X in 10 cadavers, with all of the screws penetrating the sacrum. Finally, the S2 sacral screw fixation technique was applied to a total of 13 patients with lumbosacral lesions, and the clinical outcome was evaluated at a minimum follow-up of 1 year. RESULTS: Two S2 sacral screw placement methods were developed, i.e., the anterolateral and anteromedial insertions. Seven patients had complete preoperative, postoperative, and follow up data. In all cases, the bilateral S2 screws were placed in good position and the fixation was firm. There was no surgical wound infection or internal fixation loosening. All the patients achieved partial bone graft healing, which was verified by computed tomography. CONCLUSIONS: The intersection of the horizontal line through the lowest point of the inferior edge of the first posterior sacral foramen and the lateral sacral crest can be used as the entry point for S2 sacral screw fixation. The S2 pedicle screw fixation shows good clinical effectiveness and safety for stable reconstruction of lumbosacral lesions. PMID- 23636319 TI - Intraoperative panoramic image using alignment grid, is it accurate? AB - BACKGROUND: Minimally invasive orthopedic trauma surgery relies heavily on intraoperative fluoroscopic images to evaluate the quality of fracture reduction and fixation. However, fluoroscopic images have a narrow field of view and often cannot visualize the entire long bone axis. OBJECTIVES: To compare the coronal femoral alignment between conventional X-rays to that achieved with a new method of acquiring a panoramic intraoperative image. MATERIALS AND METHODS: Twenty-four cadaveric femurs with simple diaphyseal fractures were fixed with an angulated broad DCP to create coronal plane malalignment. An intraoperative alignment grid was used to help stitch different fluoroscopic images together to produce a panoramic image. A conventional X-ray of the entire femur was then performed. The coronal plane angulation in the panoramic images was then compared to the conventional X-rays using a Wilcoxon signed rank test. RESULTS: The mean angle measured from the panoramic view was 173.9 degrees (range 169.3 degrees -178.0 degrees ) with median of 173.2 degrees . The mean angle measured from the conventional X-ray was 173.4 degrees (range 167.7 degrees -178.7 degrees ) with a median angle of 173.5 degrees . There was no significant difference between both methods of measurement (P = 0.48). CONCLUSION: Panoramic images produced by stitching fluoroscopic images together with help of an alignment grid demonstrated the same accuracy at evaluating the coronal plane alignment of femur fractures as conventional X-rays. PMID- 23636321 TI - Physiology: Inflammation links ageing to the brain. PMID- 23636320 TI - The TLR4 antagonist Eritoran protects mice from lethal influenza infection. AB - There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection. Previous studies reported that acute lung injury caused by chemical or microbial insults is secondary to the generation of host-derived, oxidized phospholipid that potently stimulates Toll-like receptor 4 (TLR4)-dependent inflammation. Subsequently, we reported that Tlr4(-/-) mice are highly refractory to influenza-induced lethality, and proposed that therapeutic antagonism of TLR4 signalling would protect against influenza-induced acute lung injury. Here we report that therapeutic administration of Eritoran (also known as E5564)-a potent, well tolerated, synthetic TLR4 antagonist-blocks influenza-induced lethality in mice, as well as lung pathology, clinical symptoms, cytokine and oxidized phospholipid expression, and decreases viral titres. CD14 and TLR2 are also required for Eritoran-mediated protection, and CD14 directly binds Eritoran and inhibits ligand binding to MD2. Thus, Eritoran blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections. PMID- 23636322 TI - Structural biology: Security measures of a master regulator. PMID- 23636323 TI - Evolution: stuck between the teeth. PMID- 23636324 TI - Structure of the human smoothened receptor bound to an antitumour agent. AB - The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It is classified as a class frizzled (class F) G protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 A resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops. PMID- 23636325 TI - Adaptive dynamics under development-based genotype-phenotype maps. AB - It is not known whether natural selection can encounter any given phenotype that can be produced by genetic variation. There has been a long-lasting debate about the processes that limit adaptation and, consequently, about how well adapted phenotypes are. Here we examine how development may affect adaptation, by decomposing the genotype-fitness map-the association between each genotype and its fitness-into two: one mapping genotype to phenotype by means of a computational model of organ development, and one mapping phenotype to fitness. In the map of phenotype and fitness, the fitness of each individual is based on the similarity between realized morphology and optimal morphology. We use three different simulations to map phenotype to fitness, and these differ in the way in which similarity is calculated: similarity is calculated for each trait (in terms of each cell position individually), for a large or a small number of phenotypic landmarks (the 'many-traits' and 'few-traits' phenotype-fitness maps), and by measuring the overall surface roughness of morphology (the 'roughness' phenotype fitness map). Evolution is simulated by applying the genotype-phenotype map and one phenotype-fitness map to each individual in the population, as well as random mutation and drift. We show that the complexity of the genotype-phenotype map prevents substantial adaptation in some of the phenotype-fitness maps: sustained adaptation is only possible using 'roughness' or 'few-traits' phenotype-fitness maps. The results contribute developmental understanding to the long-standing question of which aspects of phenotype can be effectively optimized by natural selection. PMID- 23636326 TI - mTOR kinase structure, mechanism and regulation. AB - The mammalian target of rapamycin (mTOR), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to nutrients and growth factors and is frequently deregulated in cancer. Here we report co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 (mLST8) with an ATP transition state mimic and with ATP-site inhibitors. The structures reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. The active site is highly recessed owing to the FKBP12-rapamycin-binding (FRB) domain and an inhibitory helix protruding from the catalytic cleft. mTOR-activating mutations map to the structural framework that holds these elements in place, indicating that the kinase is controlled by restricted access. In vitro biochemistry shows that the FRB domain acts as a gatekeeper, with its rapamycin-binding site interacting with substrates to grant them access to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. The structures also reveal active site residues and conformational changes that underlie inhibitor potency and specificity. PMID- 23636328 TI - Formation of a topological non-Fermi liquid in MnSi. AB - Fermi liquid theory provides a remarkably powerful framework for the description of the conduction electrons in metals and their ordering phenomena, such as superconductivity, ferromagnetism, and spin- and charge-density-wave order. A different class of ordering phenomena of great interest concerns spin configurations that are topologically protected, that is, their topology can be destroyed only by forcing the average magnetization locally to zero. Examples of such configurations are hedgehogs (points at which all spins are either pointing inwards or outwards) and vortices. A central question concerns the nature of the metallic state in the presence of such topologically distinct spin textures. Here we report a high-pressure study of the metallic state at the border of the skyrmion lattice in MnSi, which represents a new form of magnetic order composed of topologically non-trivial vortices. When long-range magnetic order is suppressed under pressure, the key characteristic of the skyrmion lattice--that is, the topological Hall signal due to the emergent magnetic flux associated with the topological winding--is unaffected in sign or magnitude and becomes an important characteristic of the metallic state. The regime of the topological Hall signal in temperature, pressure and magnetic field coincides thereby with the exceptionally extended regime of a pronounced non-Fermi-liquid resistivity. The observation of this topological Hall signal in the regime of the NFL resistivity suggests empirically that spin correlations with non-trivial topological character may drive a breakdown of Fermi liquid theory in pure metals. PMID- 23636329 TI - EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2. AB - MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at the post-transcriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in the regulation of cellular response to a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumour. However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumour cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here we show that epidermal growth factor receptor (EGFR), which is the product of a well characterized oncogene in human cancers, suppresses the maturation of specific tumour-suppressor-like miRNAs in response to hypoxic stress through phosphorylation of argonaute 2 (AGO2) at Tyr 393. The association between EGFR and AGO2 is enhanced by hypoxia, leading to elevated AGO2-Y393 phosphorylation, which in turn reduces the binding of Dicer to AGO2 and inhibits miRNA processing from precursor miRNAs to mature miRNAs. We also identify a long-loop structure in precursor miRNAs as a critical regulatory element in phospho-Y393-AGO2-mediated miRNA maturation. Furthermore, AGO2-Y393 phosphorylation mediates EGFR-enhanced cell survival and invasiveness under hypoxia, and correlates with poorer overall survival in breast cancer patients. Our study reveals a previously unrecognized function of EGFR in miRNA maturation and demonstrates how EGFR is likely to function as a regulator of AGO2 through novel post-translational modification. These findings suggest that modulation of miRNA biogenesis is important for stress response in tumour cells and has potential clinical implications. PMID- 23636330 TI - Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH. AB - Ageing is a result of gradual and overall functional deteriorations across the body; however, it is unknown whether an individual tissue primarily works to mediate the ageing progress and control lifespan. Here we show that the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by IkappaB kinase-beta (IKK-beta), nuclear factor kappaB (NF-kappaB) and related microglia neuron immune crosstalk. Several interventional models were developed showing that ageing retardation and lifespan extension are achieved in mice by preventing ageing-related hypothalamic or brain IKK-beta and NF-kappaB activation. Mechanistic studies further revealed that IKK-beta and NF-kappaB inhibit gonadotropin-releasing hormone (GnRH) to mediate ageing-related hypothalamic GnRH decline, and GnRH treatment amends ageing-impaired neurogenesis and decelerates ageing. In conclusion, the hypothalamus has a programmatic role in ageing development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating ageing-related health problems. PMID- 23636332 TI - Polymerase IV occupancy at RNA-directed DNA methylation sites requires SHH1. AB - DNA methylation is an epigenetic modification that has critical roles in gene silencing, development and genome integrity. In Arabidopsis, DNA methylation is established by DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) and targeted by 24 nucleotide small interfering RNAs (siRNAs) through a pathway termed RNA-directed DNA methylation (RdDM). This pathway requires two plant-specific RNA polymerases: Pol-IV, which functions to initiate siRNA biogenesis, and Pol-V, which functions to generate scaffold transcripts that recruit downstream RdDM factors. To understand the mechanisms controlling Pol-IV targeting we investigated the function of SAWADEE HOMEODOMAIN HOMOLOG 1 (SHH1), a Pol-IV-interacting protein. Here we show that SHH1 acts upstream in the RdDM pathway to enable siRNA production from a large subset of the most active RdDM targets, and that SHH1 is required for Pol-IV occupancy at these same loci. We also show that the SHH1 SAWADEE domain is a novel chromatin-binding module that adopts a unique tandem Tudor-like fold and functions as a dual lysine reader, probing for both unmethylated K4 and methylated K9 modifications on the histone 3 (H3) tail. Finally, we show that key residues within both lysine-binding pockets of SHH1 are required in vivo to maintain siRNA and DNA methylation levels as well as Pol-IV occupancy at RdDM targets, demonstrating a central role for methylated H3K9 binding in SHH1 function and providing the first insights into the mechanism of Pol-IV targeting. Given the parallels between methylation systems in plants and mammals, a further understanding of this early targeting step may aid our ability to control the expression of endogenous and newly introduced genes, which has broad implications for agriculture and gene therapy. PMID- 23636333 TI - Corticostriatal neurons in auditory cortex drive decisions during auditory discrimination. AB - The neural pathways by which information about the acoustic world reaches the auditory cortex are well characterized, but how auditory representations are transformed into motor commands is not known. Here we use a perceptual decision making task in rats to study this transformation. We demonstrate the role of corticostriatal projection neurons in auditory decisions by manipulating the activity of these neurons in rats performing an auditory frequency-discrimination task. Targeted channelrhodopsin-2 (ChR2)-mediated stimulation of corticostriatal neurons during the task biased decisions in the direction predicted by the frequency tuning of the stimulated neurons, whereas archaerhodopsin-3 (Arch) mediated inactivation biased decisions in the opposite direction. Striatal projections are widespread in cortex and may provide a general mechanism for the control of motor decisions by sensory cortex. PMID- 23636334 TI - Time-motion analysis of emergency radiologists and emergency physicians at an urban academic medical center. AB - Our objective was to characterize the tasks of emergency radiologists and emergency physicians and quantify the proportion of time spent on these tasks to assess their roles in patient evaluation. Our study involved emergency radiologists and emergency physicians at an urban academic level I trauma medical center. Participants were observed for continuous 2-h periods during which all of their activities were timed and categorized into the following tasks: patient history, patient physical findings, assessment/plan, procedures, technical/administration, paperwork, and personal time. We performed multivariate analyses to compare the proportion of time spent on task categories between specialties. Twenty physicians (10 emergency medicine and 10 radiology) were observed for a total of 146,802 s (2,446.7 min). Radiologists spent a significantly larger combined proportion of time on determining physical findings and paperwork than emergency physicians (61.9 vs. 28.3 %, p<0.0001). Emergency physicians spent a significantly larger proportion of time than radiologists on determining patient history (17.5 vs. 2.5 %, p=0.0008) and assessment/plan (42.3 vs. 19.3 %, p<0.0001). Both specialties devoted minimal time toward personal tasks. Radiologists play a major role in the diagnostic evaluation of a subset of acute patients, spending significantly more of their time determining physical findings than their emergency physician counterparts. PMID- 23636335 TI - The role of stereotactic radiosurgery for multiple brain metastases in stable systemic disease: a review of the literature. AB - BACKGROUND: Cancer patients with brain metastases display a median survival of only 1 to 2 months if left untreated. Although whole-brain radiation therapy (WBRT) has lengthened median patient survival, the long-term neurotoxic effects of WBRT have become a deterrent to its use in the context of stable systemic disease. Therefore, it is important to identify patients who might benefit from stereotactic radiosurgery (SRS) in order to delay or avoid WBRT. Here we present a review of the literature to elucidate the role of SRS in patients with multiple brain metastases. METHODS: MEDLINE search for English-language articles from 1998 to 2012 describing survival or neurocognitive functioning of patients with multiple brain metastases treated with SRS, WBRT, or a combination. RESULTS: SRS monotherapy yields an equivalent survival with low risk of long-term neurotoxicity, but higher rate of recurrence, compared to WBRT or combined radiotherapy. Patients with <=4 brain metastases or KPS >= 80 are expected to survive significantly longer than the onset time of prominent WBRT-induced neurocognitive decline. CONCLUSIONS: SRS, administered alone or adjuvant to surgical resection of symptomatic metastases, is preferred for patients with <=4 brain metastases or KPS >= 80 to delay or avoid WBRT. WBRT can then be employed in the event of recurrence. WBRT with or without resection is preferred for patients with >=5 brain metastases and KPS < 80, due to these patients' shorter survival and increased recurrence risk. SRS boost treatments can then be used in the event of poor tumor response or progression. PMID- 23636336 TI - Association between sympathetic response, neurogenic cardiomyopathy, and venous thromboembolization in patients with primary subarachnoid hemorrhage. AB - INTRODUCTION: Sympathetic activation promotes hemostasis, and subarachnoid hemorrhage (SAH) is associated with pronounced sympathetic activation. This investigation will assess whether catecholaminergic activity relates to venous thrombotic events in patients with acute SAH. METHODS: Observational study of consecutive SAH grade 3-5 patients requiring ventriculostomy insertion who did not undergo open surgical treatment of cerebral aneurysm. Cerebrospinal fluid (CSF) samples were obtained within 48 h of hemorrhage for assay of catecholamines, which were related to occurrence of deep venous thrombosis (DVT) and pulmonary embolization (PE). RESULTS: Of the 92 subjects, mean age was 57 years, 76% were female, and 57% Caucasian; 11% experienced lower extremity (LE) DVT, 12% developed upper extremity (UE) or LE DVT, and 23% developed any DVT/PE. Mean time to occurrence of UE/LE DVT was 7.8 days (+/-5.9 days), and mean time to development of PE was 8.8 days (+/-5.4 days). In hazards analysis models, independent predictors of LE DVT included neurogenic cardiomyopathy (NC) [HR 4.97 (95%CI 1.32-18.7)], norepinephrine/3,4-dihydroxyphenylglycol ratio (NE/DHPG) [3.81 (2.04-7.14)], NE [5.91 (2.14-16.3)], and dopamine (DA) [2.27 (1.38-3.72)]. Predictors of UE/LE DVT included NC [5.78 (1.70-19.7)], cerebral infarction [4.01 (1.18-13.7)], NE [3.58 (1.40-9.19)], NE/DHPG [3.38 (1.80-6.33)] and DA [2.01 (1.20-3.35)]. Predictors of DVT/PE included Hunt-Hess grade (H/H) [3.02 (1.19 7.66)], NE [2.56 (1.23-5.37)] and 3,4-dihydroxyphenylalanine (DOPA) [3.49 (1.01 12.0)]. CONCLUSIONS: In severe SAH, central sympathetic activity and clinical manifestations of (nor)adrenergic activity relate to the development of venous thromboemboli. Catecholamine activation may promote hemostasis, or may represent a biomarker for venous thromboses. PMID- 23636337 TI - Study the effects of zonisamide on fine structure of rabbit basilar artery and hippocampus in rabbit subarachnoid hemorrhage model. AB - BACKGROUND: In this study, we investigated the effect of a novel antiepileptic drug, zonisamide (ZNS), on the basilar artery and hippocampus in a rabbit subarachnoid hemorrhage (SAH) model. METHODS: Three groups of New Zealand white rabbits were used: a sham (non-SAH) group, an SAH + saline group, and SAH + drug treatment group that received ZNS. In the treatment group, the subjects were given ZNS for 3 days after the SAH. Hippocampal sections were evaluated for neural tissue degeneration. Basilar artery lumen areas and arterial wall thickness were also measured in all groups. RESULTS: The mean luminal area of the SAH + ZNS was significantly greater than the SAH + saline group. In addition, the arterial wall thickness of SAH + ZNS group was significantly thinner than the SAH + saline group. The neuronal degeneration scores of the hippocampal CA1 regions in the SAH + ZNS group were significantly lower than the SAH + saline treatment animals. CONCLUSIONS: These results indicate that ZNS has a vasodilatatory effect on the basilar artery and a neuronal protective effect in the CA1 region of the hippocampus in a rabbit SAH model. PMID- 23636338 TI - Transfacet screw fixation of the subaxial cervical spine--how I do it? AB - BACKGROUND: Transfacet screw fixation is a biomechanically effective way of fusing the subaxial cervical spine. The technique used by this author is described. METHODS: With the patient in prone position, a conventional posterior exposure of the cervical spine is done. The entry point used by this author is 2 mm above the middle of the lateral mass without any lateral angulation. Under fluoroscopic guidance the facet is drilled until all the four cortical surfaces are purchased. Then the depth is measured to assess the length of the screw required. This is followed by tapping and screw insertion both of which are done under fluoroscopic control. All screws are placed prior to laminectomy to decompress the cervical cord. CONCLUSIONS: This is a simple, inexpensive and biomechanically effective way of stabilizing the subaxial cervical spine. PMID- 23636339 TI - Pial arteriovenous fistula with giant venous varix and dilation of vein of Galen, treated with surgical clipping. PMID- 23636341 TI - Use progress in psychometrics to advance nursing science: revisiting factor analysis. PMID- 23636343 TI - Psychometric evaluation of the family-centered care scale for pediatric acute care nursing. AB - BACKGROUND: Caring for families is fundamental to pediatric nursing. However, existing measures do not capture parents' experiences with family-centered nursing care. OBJECTIVE: The aim of this study was to describe the development and initial psychometric testing of the Family-Centered Care Scale, a seven-item instrument designed to measure a parent's experience of nursing care that embodies core principles of family-centered care. METHODS: In Phase 1, 18 items describing what nurses do to engage parents of hospitalized children were derived from the literature describing mutuality. After establishing face validity, pretesting, and revision for clarity, the scale was administered to a convenience sample of 91 parents of hospitalized patients. In Phase 2, two items on parents' perceptions of being well-cared-for were added. The 20-item scale was administered to 564 parents of children recruited from all inpatient units in a children's hospital. In Phase 3, the scale was shortened to seven items and retested for validity among 454 additional parents. RESULTS: Internal consistency reliability was high across all versions and testing phases. Confirmatory factor analysis with data from a subsequent sample supported the final factor structure, regardless of patient type and race. There was a linear association between the scale consistency scores and overall quality of care ratings, supporting predictive validity of the scale. DISCUSSION: The Family-Centered Care Scale showed initial evidence of reliability and validity among parents with hospitalized children. PMID- 23636342 TI - Using the Rasch measurement model in psychometric analysis of the Family Effectiveness Measure. AB - BACKGROUND: Valid assessment of family functioning can play a vital role in optimizing client outcomes. Because family functioning is influenced by family structure, socioeconomic context, and culture, existing measures of family functioning-primarily developed with nuclear, middle-class European American families-may not be valid assessments of families in diverse populations. The Family Effectiveness Measure was developed to address this limitation. OBJECTIVES: The aim of this study was to test the Family Effectiveness Measure with data from a primarily low-income African American convenience sample using the Rasch measurement model. METHODS: A sample of 607 adult women completed the measure. Rasch analysis was used to assess unidimensionality, response category functioning, item fit, person reliability, differential item functioning by race and parental status, and item hierarchy. Criterion-related validity was tested using correlations with five other variables related to family functioning. RESULTS: The Family Effectiveness Measure measures two separate constructs: The Effective Family Functioning construct was a psychometrically sound measure of the target construct that was more efficient because of the deletion of 22 items. The Ineffective Family Functioning construct consisted of 16 of those deleted items but was not as strong psychometrically. Items in both constructs evidenced no differential item functioning by race. Criterion-related validity was supported for both. DISCUSSION: In contrast to the prevailing conceptualization that family functioning is a single construct, assessed by positively and negatively worded items, use of the Rasch analysis suggested the existence of two constructs. Whereas the Effective Family Functioning scale is a strong and efficient measure of family functioning, the Ineffective Family Functioning scale will require additional item development and psychometric testing. PMID- 23636344 TI - Reading the Bible for guidance, comfort, and strength during stressful life events. AB - BACKGROUND: The use of religious practices to promote mental health among African Americans is well documented. African Americans are more likely to report strong religious affiliations and to use religion over prescribed medications for mental health problems. However, few studies have explored how African Americans use religious practices in response to stressful life events. OBJECTIVE: The aim of this study is to examine how African American women and men find comfort in using scripture passages from The Bible. METHODS: Fifty-four African American adults residing in the Southeastern United States participated in a qualitative descriptive study using open-ended semistructured interviews. Participants were asked to describe their use of scripture passages from The Bible and the personal meanings associated with these scriptures in the context of a family death or life-threatening illness. RESULTS: These participants used scripture passages categorized as God as Protector, God as Beneficent, Praise and Thanksgiving, God as Healer, Memory of Forefathers, Prayers to God, and Life after Death. Few gender differences were noted. However, women were more likely to use scripture passages of God as Protector and Life after Death, whereas men were more likely to use God as Beneficent and God as Healer. DISCUSSION: The religious practice of reading scripture passages from The Bible is a mental health-promoting strategy used during stressful life events. The findings of this study have practical uses for nurses and can be used to inform acceptable and sensitive approaches in addressing mental health issues and spiritual care needs in African American patients. PMID- 23636345 TI - Underestimation of adolescent obesity. AB - BACKGROUND: Previous studies assessing the validity of adolescent self-reported height and weight for estimating obesity prevalence have not accounted for, potential bias due to nonresponse in self-reports. OBJECTIVES: The aim of this study was to assess the implications of selective nonresponse in self-reports of height and weight for estimates of adolescent obesity. METHODS: The authors analyzed 613 adolescents ages 12-17 years from the 2006-2008 Los Angeles Family and Neighborhood Survey, a longitudinal study of Los Angeles County households with an oversample of poor neighborhoods. Obesity prevalence estimates were compared based on (a) self-report, (b) measured height and weight for those who did report, and (c) measured height and weight for those who did report. RESULTS: Among younger teens, measured obesity prevalence was higher for those who did not report height and weight compared with those who did (40% vs. 30%). Consequently, obesity prevalence based on self-reported height and weight underestimated measured prevalence by 12 percentage points (when accounting for nonresponse) versus 9 percentage points (when nonresponse was not accounted for). Results were robust to the choice of difference child growth references. DISCUSSION: Adolescent obesity surveillance and prevention efforts must take into account selective nonresponse for self-reported height and weight, particularly for younger teens. Results should be replicated in a nationally representative sample. PMID- 23636346 TI - Evaluation of time-varying and cumulative effects in nursing in a longitudinal study. AB - BACKGROUND: Traditional statistics in longitudinal data analysis are likely to be insufficient in nursing studies, in which the time varying characteristics of explanatory variables and cumulative effects require additional consideration. OBJECTIVES: The aims of this study were to introduce alternative longitudinal approaches for incorporating time-varying variables and cumulative effects, to discuss their strengths, and to highlight key issues that nursing researchers should recognize before and while undertaking such analyses. RESULTS: The three alternative models provide differing analytical outcomes based on the research focus. The baseline tracking model was used to estimate the stability effect of an intervention program, detecting risk factors early. The temporal sequence of potential cause and effect was incorporated further in the time-dependent model. The cumulative model was used to explore whether cumulative intervention effects existed. CONCLUSION: Nurse researchers should incorporate alternative methods into the longitudinal data analysis tools they commonly use when facing explanatory variables with time variations or cumulative effects on the variable being measured. PMID- 23636347 TI - Tumor type-specific and skin region-selective metastasis of human cancers: another example of the "seed and soil" hypothesis. AB - Metastasis of human cancer is an organ-selective process that is determined by anatomical and biological factors as well as by specific microenvironmental properties. Dissemination of visceral malignancies to the skin is rather rare and usually occurs in a later stage of the disease. Using statistical approaches, both positive (renal and lung cancers) and negative (pancreatic and liver cancers) organ preferences can be identified in a variety of cancers. While certain cancer types are characterized by random distribution for skin metastasis (liver cancer), a number of cancers demonstrate a colonization preference to the region of origin: lung cancer to the supradiaphragmatic (mostly chest) and colorectal cancers to the infradiaphragmatic (abdominal) skin regions. In certain cases, however, skin metastasis develops more frequently at specific distant locations, as evidenced by the dissemination of renal cancer at the head and neck region. These findings are clinically relevant and useful especially in patients where skin metastasis is the first indication of a malignancy. Nevertheless, it is a strong argument for the predominant role of microenvironmental factors in cancer dissemination. On the other hand, skin metastases of visceral cancers provide a unique model to analyze the pathomechanisms determining organ selectivity, including the organ-specific vascularization, the dermatome-specific innervation, or immunological and developmental factors. PMID- 23636348 TI - The pre-metastatic niche: finding common ground. AB - It is rapidly becoming evident that the formation of tumor-promoting pre metastatic niches in secondary organs adds a previously unrecognized degree of complexity to the challenge of curing metastatic disease. Primary tumor cells orchestrate pre-metastatic niche formation through secretion of a variety of cytokines and growth factors that promote mobilization and recruitment of bone marrow-derived cells to future metastatic sites. Hypoxia within the primary tumor, and secretion of specific microvesicles termed exosomes, are emerging as important processes and vehicles for tumor-derived factors to modulate pre metastatic sites. It has also come to light that reduced immune surveillance is a novel mechanism through which primary tumors create favorable niches in secondary organs. This review provides an overview of our current understanding of underlying mechanisms of pre-metastatic niche formation and highlights the common links as well as discrepancies between independent studies. Furthermore, the possible clinical implications, links to metastatic persistence and dormancy, and novel approaches for treatment of metastatic disease through reversal of pre metastatic niche formation are identified and explored. PMID- 23636351 TI - Simultaneous measurement of ATP release and LTA does not potentiate platelet aggregation to epinephrine. PMID- 23636349 TI - Chronic adverse events and quality of life after radiochemotherapy in anal cancer patients. A single institution experience and review of the literature. AB - PURPOSE: To report on chronic adverse events (CAE) and quality of life (QOL) after radiochemotherapy (RCT) in patients with anal cancer (AC). PATIENTS AND METHODS: Of 83 patients who had received RCT at our department between 1988 and 2011, 51 accepted the invitation to participate in this QOL study. CAE were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 and QOL was assessed with the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) questionnaire. RESULTS: CAE could be evaluated in 49 patients. There was a tendency toward a higher rate of grade 3 CAE in female patients, i.e. 18 out of 37 (49 %) vs. 2 out of 12 (17 %) male patients (p = 0.089). The most common grade 3 CAE were dyspareunia and vaginal symptoms (itching, burning and dryness) in 35 and 22 % of female patients, respectively, followed by stool incontinence in 13 % of all patients (6 out of 49). Both FACT-C and CAE information were available for 42 patients, allowing evaluation of the impact of CAE on QOL. The median total FACT-C score was 110 (40-132) out of a possible maximum of 136. The absence of grade 3 CAE (115 vs. 94, p = 0.001); an interval of >= 67 months after the end of the treatment (111 vs. 107, p = 0.010), no stool incontinence vs. grade 3 stool incontinence (111 vs. 74, p = 0.009), higher education (114 vs. 107, p = 0.013) and no dyspareunia vs. grade 3 dyspareunia (116 vs. 93, p = 0.012) were significantly associated with a higher median FACT-C score. CONCLUSION: The majority of AC patients treated with RCT have acceptable overall QOL scores, which are comparable to those of the normal population. Patients with grade 3 CAE particularly dyspareunia and fecal incontinence-have a poorer QOL compared to patients without CAE. In order to improve long-term QOL, future strategies might aim at a reduction in dose to the genitalia and more intensive patient support measures. PMID- 23636352 TI - Serum methylglyoxal level and its association with oxidative stress and disease severity in patients with psoriasis. AB - Psoriasis vulgaris (PV), a chronic inflammatory skin disease, is a condition of increased oxidative stress (OxS). However, interest related to oxidative and carbonyl stress damages to proteins, such as the formation of advanced glycation end products (AGEs) and their precursor molecule methylglyoxal (MG) has been modest. The objective of this study was to compare the systemic levels of OxS markers in patients with PV and healthy controls (Co) and to investigate their correlation with the serum level of MG. Total peroxide concentration (TPX) and total antioxidant capacity (TAC) were estimated by means of spectrophotometry. The TPX and TAC ratio was regarded as OxS index (OSI). MG level was determined using ELISA. Compared to Co, patients with PV had significantly increased blood levels of TPX (P < 0.0001), OSI (P < 0.0001), and MG (P = 0.01), and lower TAC levels (P < 0.0001). Increase in body mass index (BMI) appeared to contribute to this imbalance as TAC levels decreased with increasing BMI (r = -0.252, P < 0.01). Increased TPX concentration was associated with higher serum level of MG (r = 0.610, P = 0.004), the latter being positively correlated with psoriasis area and severity index (r = 0.577, P = 0.008). In performed multivariate regression analysis, TPX, TAC, and OSI were all significant predictors of MG level. Our study gave further proof of increased systemic psoriasis-related OxS. MG serum level, reflecting simultaneously OxS as well as carbonyl stress status, could be used as a marker of disease activity in clinical trials while looking for new systemic therapies for psoriasis. PMID- 23636353 TI - Synthesis and photoluminescent properties of lanthanides acetoacetanilide complexes. AB - This work reports on the photoluminescent properties of three new lanthanide complexes with acetoacetanilide (aaa), a beta-diketonate ligand. The complexes have the general molecular formulae [RE(aaa)3(H2O)], they are soluble in organic solvents such as ethanol and chloroform and insoluble in water. The energy of the triplet state was determined at about 4,700 cm(-1) higher than the (5)D4 emitting level of the Tb(III) ion, leading to an absolute quantum yield of 22% for the [Tb(aaa)3(H2O)] complex. The photoluminescent properties were studied and the luminescence parameters of the [Eu(aaa)3(H2O)] complex were experimentally determined. The photostabilities of the complexes under continuous UV irradiation were measured and the data indicate low stability of the [Tb(aaa)3(H2O)] complex when the system is excited at the band attributed to energy transfer from the ligand to terbium(III) ion. However, its photostability is significantly improved under inert atmosphere. PMID- 23636356 TI - Australian science needs more female fellows. PMID- 23636354 TI - Organelle DNA accumulation in the recently evolved papaya sex chromosomes. AB - Sex chromosomes are a pair of specialized chromosomes containing a sex determination region that is suppressed for recombination. Without recombination, Y chromosomes are thought to accumulate repetitive DNA sequences which contribute to their degeneration. A pair of primitive sex chromosomes controls sex type in papaya with male and hermaphrodite determined by the slightly different male specific region of the Y (MSY) and hermaphrodite-specific region of Y(h) (HSY) chromosomes, respectively. Here, we show that the papaya HSY and MSY in the absence of recombination have accumulated nearly 12 times the amount of chloroplast-derived DNA than the corresponding region of the X chromosome and 4 times the papaya genome-wide average. Furthermore, a chloroplast genome fragment containing the rsp15 gene has been amplified 23 times in the HSY, evidence of retrotransposon-mediated duplication. Surprisingly, mitochondria-derived sequences are less abundant in the X and HSY compared to the whole genome. Shared organelle integrations are sparse between X and HSY, with only 11 % of chloroplast and 12 % of mitochondria fragments conserved, respectively, suggesting that the accelerated accumulation of organelle DNA occurred after the HSY was suppressed for recombination. Most of the organelle-derived sequences have divergence times of <7 MYA, reinforcing this notion. The accumulated chloroplast DNA is evidence of the slow degeneration of the HSY. PMID- 23636369 TI - Global carbon dioxide levels near worrisome milestone. PMID- 23636370 TI - Flu papers spark row over credit for data. PMID- 23636371 TI - Disputed results a fresh blow for social psychology. PMID- 23636372 TI - Transgenic salmon nears approval. PMID- 23636373 TI - Targeted drugs to tackle hepatitis C. PMID- 23636376 TI - Plant biotechnology: Tarnished promise. PMID- 23636375 TI - Clinician to head Wellcome Trust. PMID- 23636377 TI - GM crops: A story in numbers. PMID- 23636378 TI - Case studies: A hard look at GM crops. PMID- 23636379 TI - Transgenics: A new breed. PMID- 23636386 TI - Biotechnology: Thirty years of transgenic plants. PMID- 23636380 TI - Biotechnology: Africa and Asia need a rational debate on GM crops. PMID- 23636381 TI - Chinese agriculture: An experiment for the world. PMID- 23636387 TI - Research integrity: Journals should be clear on misconduct. PMID- 23636388 TI - Science and economy: Don't judge research on economics alone. PMID- 23636389 TI - Cladistics: The high cost of overspecialization. PMID- 23636390 TI - Journals: Open-access boom in developing nations. PMID- 23636391 TI - Earth science: Small differences in sameness. PMID- 23636392 TI - Solid-state physics: Single spins in silicon see the light. PMID- 23636394 TI - Biochemistry: Oxidation controls the DUB step. PMID- 23636393 TI - Optical devices: Seeing the world through an insect's eyes. PMID- 23636396 TI - Globally networked risks and how to respond. AB - Today's strongly connected, global networks have produced highly interdependent systems that we do not understand and cannot control well. These systems are vulnerable to failure at all scales, posing serious threats to society, even when external shocks are absent. As the complexity and interaction strengths in our networked world increase, man-made systems can become unstable, creating uncontrollable situations even when decision-makers are well-skilled, have all data and technology at their disposal, and do their best. To make these systems manageable, a fundamental redesign is needed. A 'Global Systems Science' might create the required knowledge and paradigm shift in thinking. PMID- 23636397 TI - Using membrane transporters to improve crops for sustainable food production. AB - With the global population predicted to grow by at least 25 per cent by 2050, the need for sustainable production of nutritious foods is critical for human and environmental health. Recent advances show that specialized plant membrane transporters can be used to enhance yields of staple crops, increase nutrient content and increase resistance to key stresses, including salinity, pathogens and aluminium toxicity, which in turn could expand available arable land. PMID- 23636399 TI - Structures of the human and Drosophila 80S ribosome. AB - Protein synthesis in all cells is carried out by macromolecular machines called ribosomes. Although the structures of prokaryotic, yeast and protist ribosomes have been determined, the more complex molecular architecture of metazoan 80S ribosomes has so far remained elusive. Here we present structures of Drosophila melanogaster and Homo sapiens 80S ribosomes in complex with the translation factor eEF2, E-site transfer RNA and Stm1-like proteins, based on high-resolution cryo-electron-microscopy density maps. These structures not only illustrate the co-evolution of metazoan-specific ribosomal RNA with ribosomal proteins but also reveal the presence of two additional structural layers in metazoan ribosomes, a well-ordered inner layer covered by a flexible RNA outer layer. The human and Drosophila ribosome structures will provide the basis for more detailed structural, biochemical and genetic experiments. PMID- 23636400 TI - Optical addressing of an individual erbium ion in silicon. AB - The detection of electron spins associated with single defects in solids is a critical operation for a range of quantum information and measurement applications under development. So far, it has been accomplished for only two defect centres in crystalline solids: phosphorus dopants in silicon, for which electrical read-out based on a single-electron transistor is used, and nitrogen vacancy centres in diamond, for which optical read-out is used. A spin read-out fidelity of about 90 per cent has been demonstrated with both electrical read-out and optical read-out; however, the thermal limitations of the former and the poor photon collection efficiency of the latter make it difficult to achieve the higher fidelities required for quantum information applications. Here we demonstrate a hybrid approach in which optical excitation is used to change the charge state (conditional on its spin state) of an erbium defect centre in a silicon-based single-electron transistor, and this change is then detected electrically. The high spectral resolution of the optical frequency-addressing step overcomes the thermal broadening limitation of the previous electrical read out scheme, and the charge-sensing step avoids the difficulties of efficient photon collection. This approach could lead to new architectures for quantum information processing devices and could drastically increase the range of defect centres that can be exploited. Furthermore, the efficient electrical detection of the optical excitation of single sites in silicon represents a significant step towards developing interconnects between optical-based quantum computing and silicon technologies. PMID- 23636401 TI - Digital cameras with designs inspired by the arthropod eye. AB - In arthropods, evolution has created a remarkably sophisticated class of imaging systems, with a wide-angle field of view, low aberrations, high acuity to motion and an infinite depth of field. A challenge in building digital cameras with the hemispherical, compound apposition layouts of arthropod eyes is that essential design requirements cannot be met with existing planar sensor technologies or conventional optics. Here we present materials, mechanics and integration schemes that afford scalable pathways to working, arthropod-inspired cameras with nearly full hemispherical shapes (about 160 degrees). Their surfaces are densely populated by imaging elements (artificial ommatidia), which are comparable in number (180) to those of the eyes of fire ants (Solenopsis fugax) and bark beetles (Hylastes nigrinus). The devices combine elastomeric compound optical elements with deformable arrays of thin silicon photodetectors into integrated sheets that can be elastically transformed from the planar geometries in which they are fabricated to hemispherical shapes for integration into apposition cameras. Our imaging results and quantitative ray-tracing-based simulations illustrate key features of operation. These general strategies seem to be applicable to other compound eye devices, such as those inspired by moths and lacewings (refracting superposition eyes), lobster and shrimp (reflecting superposition eyes), and houseflies (neural superposition eyes). PMID- 23636403 TI - The necessity of strengthening the cooperation between tissue banks and organ transplant organizations at national, regional, and international levels. AB - The donation of tissues and organs increases significantly when tissue banks and organ transplant organizations work together in the procurement of organs and tissues at donor sources (hospitals, coroners system, organ procurement agencies, and funeral homes, among others). To achieve this important goal, national competent health authorities should considered the establishment of a mechanism that promote the widest possible cooperation between tissue banks and organ transplant organizations with hospitals, research medical institutions, universities, and other medical institutions and facilities. One of the issues that can facilitate this cooperation is the establishment of a coding and traceability system that could identify all tissues and organs used in transplant activities carried out in any country. The promotion of national, regional, and international cooperation between tissue banks and organ transplant organizations would enable the sharing of relevant information that could be important for medical practice and scientific studies carried out by many countries, particularly for those countries with a weak health care system. PMID- 23636404 TI - Nyamiviridae: proposal for a new family in the order Mononegavirales. AB - Nyamanini virus (NYMV) and Midway virus (MIDWV) are unclassified tick-borne agents that infect land birds and seabirds, respectively. The recent molecular characterization of both viruses confirmed their already known close serological relationship and revealed them to be nonsegmented, single- and negative-stranded RNA viruses that are clearly related to, but quite distinct from, members of the order Mononegavirales (bornaviruses, filoviruses, paramyxoviruses, and rhabdoviruses). A third agent, soybean cyst nematode virus 1 (SbCNV-1, previously named soybean cyst nematode nyavirus), was recently found to be an additional member of this new virus group. Here, we review the current knowledge about all three viruses and propose classifying them as members of a new mononegaviral family, Nyamiviridae. PMID- 23636405 TI - Development of human papillomavirus chimaeric L1/L2 candidate vaccines. AB - Recombinant human papillomavirus (HPV) virus-like particle (VLP) vaccines based on the L1 capsid protein have been shown to be efficient prophylactic vaccines, albeit type-specific. As a first step to investigate the feasibility of extending protection against non-vaccine types, HPV-16 L1 chimaeras were generated. The region downstream of L1 amino acid (aa) 413 was replaced with selected cross neutralising epitopes (aa 108-120; 56-81 and 17-36) derived from the HPV-16 L2 protein, generating proteins designated SAF, L2.56 and L2.17, respectively. The chimaera L1BPV containing BPV-1 L2 peptide aa 1-88 was similarly constructed. The chimaeras were evaluated for expression in insect cells; their ability to form particles was studied by electron microscopy, and their immunogenicity was evaluated in mice. SAF, L2.56 and L2.17 proteins were expressed to high concentrations in insect cells and elicited HPV-16 pseudovirus-neutralising anti L1 antibodies. L2.56 and L2.17 also elicited anti-L2 antibodies. L1BPV was a poor vaccine candidate due to low levels of expression with concomitant lack of immunogenicity. All chimaeras assembled into tertiary structures. The results indicate that chimaeric L1 vaccines incorporating cross-neutralising L2 peptides could be promising second-generation prophylactic HPV vaccine candidates. PMID- 23636407 TI - Patterned recognition of amines and ammonium ions by a stimuli-responsive foldamer-based hexameric oligophenol host. AB - A stimuli-responsive hexameric oligophenol host undergoes amine-induced co operative folding from a more fluorescent, more linear structure into less fluorescent, more curved or helically folded states, enabling easy identification and classification of the bound amine guests. PMID- 23636406 TI - Culicoides sonorensis (Diptera: Ceratopogonidae) is not a competent vector of Cache Valley virus (family Bunyaviridae, genus Orthobunyavirus). AB - We investigated the susceptibility of Culicoides sonorensis to Cache Valley virus (CVV) (family Bunyaviridae, genus Orthobunyavirus) infection and the potential that it could be a vector or site of virus reassortment. CVV is native to the New World and causes disease in livestock. Infected blood meals were fed to both a competent vector, Anopheles quadrimaculatus, and Culicoides sonorensis. All Anopheles mosquitoes were infected as expected, but only 21 % of the C. sonorensis insects were susceptible to infection. These appeared to present a midgut barrier, because virus persisted but did not disseminate. This means Culicoides sonorensis is not likely to be a vector of CVV but could be involved in viral reassortment. Schmallenberg virus (SBV) (family Bunyaviridae, genus Orthobunyavirus) was recently discovered in Europe and probably is a novel virus resulting from a reassortment of two orthobunyaviruses, and an ongoing epizootic in cattle and small ruminants has caused significant economic damage. PMID- 23636408 TI - Characterization of smallholder pig production system: productive and reproductive performances of local and crossbred pigs in Sikkim Himalayan region. AB - The present study was conducted to know the smallholder pig production system in tribal areas of Sikkim State, India. Two hundred tribal farmers were selected randomly from the North and East District of the state. Information on socio economic characteristics of farmers (gender, occupation, educational status, and farming experience), management practices, disease prevalence, and economics in pig production was collected. The study recorded the mean land holding as 1.2 +/- 0.8 ha, and the number of pigs per farm was 5.0 +/- 0.28. Pigs were mainly kept as a source of income, and 70 % of farmers reared crossbreed pigs. Ninety percent (90 %) of respondents practiced the intensive system of management whereby kitchen wastes along with cooked mixture comprising maize bhusa, mustard oil cake, pseudostem of banana, tuber, stem, and plant leaves were used to feed their animals. About 40.5 % of farmers procured their breeding stock from government farms that had good records and utilized veterinary services like timely vaccination and deworming. The diseases prevalent in the study area were swine fever, diarrhea, helminthoses, sarcoptic mange, pneumonia, etc. The litter sizes at birth (local, 4.3 +/- 0.45; crossbreed, 7.2 +/- 0.33), at weaning (local, 2.79 +/- 0.24; crossbreed, 6.1 +/- 0.21), and age at first farrowing (local, 365.39 +/ 7.96 days; crossbreed, 337.24 +/- 8.79 days) were recorded. Production costs of meat extracted from local and crossbred pigs were 1.08 $/kg and 0.86 $/kg, respectively. PMID- 23636410 TI - "Successful" coiling of a giant ophthalmic aneurysm resulting in blindness: case report and critical review. PMID- 23636409 TI - Intraventricular fibrinolysis for severe aneurysmal intraventricular hemorrhage: a randomized controlled trial and meta-analysis. AB - The aim of this study was to assess the safety and efficacy of intraventricular fibrinolysis (IVF) for aneurysmal subarachnoid hemorrhage (aSAH) with severe intraventricular hemorrhage (IVH). In this randomized controlled trial, between 2005 and 2009, patients with aSAH and severe IVH were randomly assigned into two groups: one treated with external ventricular drainage (EVD) combined with intraventricular recombinant tissue plasminogen activator (rt-PA) and the second with EVD alone. The primary end-point was mortality rate within the first 30 days. We performed meta-analysis including all published articles that compared IVF + EVD to EVD alone in patients with aSAH IVH. Eleven patients were included in the rt-PA group, eight in the control group. At 30 days, mortality rate was lower in the rt-PA group (45.5 vs. 62.5%), but results were not statistically significant (p = 0.65). Clearance of third and fourth ventricles was obtained previously in the rt-PA group (4.25 days) compared to the control group (10.67 days) (p = 0.001). There was no statistically significant difference concerning the occurrence of complications. The meta-analysis showed a better survival rate with IVF without raised statistical significance (odds ratio = 0.32 [95% confidence interval, 0.10-1.03]). This study shows that IVF is as safe as EVD alone for aSAH with severe IVH. It accelerates blood clot resolution in the ventricular system. Mortality rate could be improved by IVF but without significant results. Because of the severity and rarity of this pathology, a multicenter study is required. CLINICAL TRIAL REGISTRATION INFORMATION: www.clinicaltrials.gov (NCT00823485). PMID- 23636411 TI - [Botulinum toxin: the misguided path]. AB - Botulinum toxin is widely used and has become a popular mass phenomenon in aesthetic medicine. Considerable scientific data concerning the biopsychosocial impact of botulinum toxin use have become available. The bidirectional interaction of mimic and emotion, described as the facial feedback hypothesis, is particularly influenced, as is mimicry. Furthermore, botulinum toxin can cause dysfunction of face harmony including false laughing or the "frozen face". As a result, complex psychosocial disturbances can occur and may affect social interaction and cause flattening of affect. Thus one must ask whether in the future botulinum toxin will continue to be employed in aesthetic dermatology or perhaps be regarded as a misguided path. PMID- 23636413 TI - Magnetic responsive polymer composite materials. AB - Magnetic responsive materials are the topic of intense research due to their potential breakthrough applications in the biomedical, coatings, microfluidics and microelectronics fields. By merging magnetic and polymer materials one can obtain composites with exceptional magnetic responsive features. Magnetic actuation provides unique capabilities as it can be spatially and temporally controlled, and can additionally be operated externally to the system, providing a non-invasive approach to remote control. We identified three classes of magnetic responsive composite materials, according to their activation mode and intended applications, which can be defined by the following aspects. (A) Their ability to be deformed (stretching, bending, rotation) upon exposure to a magnetic field. (B) The possibility of remotely dragging them to a targeted area, called magnetic guidance, which is particularly interesting for biomedical applications, including cell and biomolecule guidance and separation. (C) The opportunity to use magnetic induction for thermoresponsive polymer materials actuation, which has shown promising results for controlled drug release and shape memory devices. For each category, essential design parameters that allow fine-tuning of the properties of these magnetic responsive composites are presented using key examples. PMID- 23636412 TI - Prediction of dystocia-related cesarean section risk in uncomplicated Taiwanese nulliparas at term. AB - PURPOSE: We aimed to assess risk factors for dystocia-related cesarean section (CS) in uncomplicated Taiwanese nulliparas at term METHODS: We reviewed 1,272 deliveries by 1 obstetrician in a Taiwanese hospital between February 2004 and December 2011. These parturients were nulliparas with singleton pregnancies >= 37 weeks gestation who had liveborn cephalic deliveries. The CS group consisted of parturients with dystocia-related CS for the following indications: prolonged latent phase, failure to progress, or arrest of descent. Eight confounding variables [maternal age, height, weight, body mass index (BMI) in labor, gestational age, infant birth weight, gender, and cervical dilatation] were obtained from the medical records. Multivariate logistic regression analysis was used to determine the association between each variable and route of delivery. A predictive formula for CS probability was generated using a logistic regression model. RESULTS: Overall 15.0 % of nulliparas in our population underwent CS. Logistic regression analysis revealed a significant association between maternal BMI and CS (adjusted OR 1.112; 95 % CI 1.065-1.161; P < 0.001). The association between maternal age and CS was also statistically significant (adjusted OR 1.074, 95 % CI 1.033-1.116, P = 0.001). Maternal height, weight in labor, gestational age, infant birth weight, gender, and cervical dilatation were not significantly associated with the route of delivery. A predictive formula for CS probability was developed based on a combination of maternal BMI and age. CONCLUSIONS: Our results show that maternal age and BMI in labor are significantly associated with dystocia-related CS in uncomplicated Taiwanese nulliparas at term. We develop a practical formula to predict the probability for CS. Using this formula, obstetricians can estimate the risk of CS according to maternal age and BMI in labor. PMID- 23636414 TI - Endothelial CSN5 impairs NF-kappaB activation and monocyte adhesion to endothelial cells and is highly expressed in human atherosclerotic lesions. AB - The COP9 signalosome (CSN), a multifunctional protein complex involved in the regulation of cullin-RING-E3 ubiquitin ligases (CRLs), has emerged as a regulator of NF-kappaB signalling. As NF-kappaB drives the expression of pro-inflammatory and pro-atherosclerotic genes, we probed the yet unknown role of the CSN, in particular CSN5, on NF-kappaB-mediated atherogenic responses in endothelial cells. Co-immunoprecipitation in human umbilical vein endothelial cells (HUVECs) revealed the presence of a super-complex between IKK and CSN, which dissociates upon TNF-alpha stimulation. Furthermore, CSN5 silencing enhanced TNF-alpha induced IkappaB-alpha degradation and NF-kappaB activity in luciferase reporter assays. This was paralleled by an increased NF-kappaB-driven upregulation of atherogenic chemokines and adhesion molecules, as measured by qPCR and flow cytometry, and translated into an enhanced arrest of THP-1 monocytes on TNF-alpha stimulated, CSN5-depleted HUVECs. Reverse effects on NF-kappaB activity and THP-1 arrest were seen upon CSN5 overexpression. Finally, double-immunostaining confirmed the expression of CSN subunits in the endothelium of human atherosclerotic lesions, and revealed an increased expression of CSN5 which correlated with atheroprogression. In conclusion, endothelial CSN5 attenuates NF kappaB-dependent pro-inflammatory gene expression and monocyte arrest on stimulated endothelial cells in vitro, suggesting that CSN5 might serve as a negative regulator of atherogenesis. PMID- 23636416 TI - Home unintentional non-fatal injury among children under 5 years of age in a rural area, El Minia Governorate, Egypt. AB - Injury is the leading cause of morbidity and mortality in children aged 1-14 years, with home injuries a particular problem in the preschool-age group. The focus of this study was to determine the frequency, and the outcome of unintentional non-fatal injuries among children under 5 years of age in the household, and to describe the related risk factors through a community-based survey. A cross-sectional community based study was conducted on a random sample of 1,255 rural Egyptian children under 5 years of age. Data were collected by a questionnaire which included; socio-demographic data, history, type, and the outcome of unintentional home injuries in the previous year. Of 1,255 children, 55.9 % were males and 44.1 % were females, and their mean age was 28.6 +/- 11.8 months. The frequency of unintentional non-fatal home-related injuries was 20.6 %. Injury rates were the highest among children during the third year of life, those of less educated parents, those whom mothers are of young age, and those with low household socioeconomic standard. Homes of injured children were not significantly different from the homes of non-injured children. Burns were the most common injuries among all the study groups (38 %) followed by falls (35.3 %). 'Handicaps' were more strongly associated with falls and burns (6.6 and 4.1 % respectively). Unintentional injuries are common among children under 5 years of age in rural Egypt. Therefore, measures should be taken to prevent children from the most frequently recorded home injuries such as burns and falls. PMID- 23636398 TI - Integrated genomic characterization of endometrial carcinoma. AB - We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ~25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours. PMID- 23636417 TI - Synthesis of (E)-nitroolefins via decarboxylative nitration using t-butylnitrite (t-BuONO) and TEMPO. AB - Nitroolefins are usually synthesized using the Henry reaction. Here we report an alternative metal-free decarboxylative nitration protocol for the preparation of the nitroolefins from alpha,beta-unsaturated carboxylic acids using t butylnitrite (t-BuONO) and TEMPO. alpha,beta-Unsaturated carboxylic acids bearing beta-aromatic and beta-heteroaromatic substituents gave (E)-nitroolefins exclusively under mild conditions. A radical based pathway has been proposed for this decarboxylative nitration reaction. PMID- 23636415 TI - Do patients choose community health services (CHS) for first treatment in China? Results from a community health survey in urban areas. AB - In recent years, the government has paid more attention to the development of community health service (CHS) in urban areas in China. Therefore, determining if it plays important roles and establishing methods to evaluate the effects of CHS are critical emphases in research. This study measured the effects of CHS through the choices of patients and their evaluation of CHS, and aimed to contribute to the development of primary health services. Face-to-face interviews were performed using the questionnaire with a random sample of 865 patients in CHS institutions from five provinces in China. Pearson's Chi square tests and binary logistic regression were used to analyze influencing factors that are associated with the patients' choices and evaluations. A total of 62.2 % of the patients would choose CHS for their first treatment. Patient choice was mainly affected by the following: (1) social demographic factors of the patients, namely, age, educational level, medical insurance, and survey areas; (2) evaluation of CHS by the patients: convenience, reasonable charges, and attitude of the doctors. In addition, the patients showed more satisfaction with convenience, waiting time, and communication with doctors, and less satisfaction with the medical charges, drug costs, and medical equipment of CHS. Through the results, we suggest that the government should provide more regard to the convenience, reasonable charges, and the attitude of the doctors as important factors to attract the patients to CHS. The government should also exert efforts to reduce the medical charges (especially the drug costs) for CHS. PMID- 23636418 TI - Breast cancer tissue slices as a model for evaluation of response to rapamycin. AB - Rapamycin is a selective inhibitor of the mammalian target of rapamycin (mTOR), a regulator kinase that integrates growth factors signaling via the phosphoinositide-3-kinase pathway and that has emerged as a novel therapeutic modality in breast cancer (BC). We propose a pre-clinical "ex-vivo" personalized organotypic culture of BC that preserves the microenvironment to evaluate rapamycin-mediated gene expression changes. Freshly excised ductal invasive BC slices, 400 MUm thick (n=30), were cultured in the presence or absence (control) of rapamycin (20 nM) for 24 h. Some slices were formalin-fixed for immunohistochemical determinations and some were processed for microarray analysis. Control slices in culture retained their tissue morphology and tissue viability (detected by BrdU uptake). The percentage of proliferating cells (assessed by Ki67) did not change up to 24 h of treatment. Immunohistochemical evaluation of p-AKT, p-mTOR, p-4EBP1 and p-S6K1 indicated that AKT/mTOR pathway activation was maintained during cultivation. For microarray analysis, slices were divided into two groups, according to the presence/absence of epidermal growth factor receptor-type 2 and analyzed separately. Limited overlap was seen among differentially expressed genes after treatment (P<0.01) in both groups suggesting different responses to rapamycin between these BC subtypes. Ontology analysis indicated that genes involved in biosynthetic processes were commonly reduced by rapamycin. Our network analysis suggested that concerted expression of these genes might distinguish controls from treated slices. Thus, breast carcinoma slices constitute a suitable physiological tool to evaluate the short term effects of rapamycin on the gene profile of individual BC samples. PMID- 23636420 TI - Expression of synaptogyrin-1 in T1R2-expressing type II taste cells and type III taste cells of rat circumvallate taste buds. AB - Synaptogyrins are conserved components of the exocytic apparatus and function as regulators of Ca(2+)-dependent exocytosis. The synaptogyrin family comprises three isoforms: two neuronal (synaptogyrin-1 and -3) and one ubiquitous (synaptogyrin-2) form. Although the expression patterns of the exocytic proteins synaptotagmin-1, SNAP-25, synaptobrevin-2 and synaptophysin have been elucidated in taste buds, the function and expression pattern of synaptogyrin-1 in rat gustatory tissues have not been determined. Therefore, we examined the expression patterns of synaptogyrin-1 and several cell-specific markers of type II and III cells in rat gustatory tissues. Reverse transcription/polymerase chain reaction assays and immunoblot analysis revealed the expression of synaptogyrin-1 mRNA and its protein in circumvallate papillae. In fungiform, foliate and circumvallate papillae, the antibody against synaptogyrin-1 immunolabeled a subset of taste bud cells and intra- and subgemmal nerve processes. Double-labeling experiments revealed the expression of synaptogyrin-1 in most taste cells immunoreactive for aromatic L-amino acid decarboxylase and the neural cell adhesion molecule. A subset of synaptogyrin-1-immunoreactive taste cells also expressed phospholipase Cbeta2, gustducin, or sweet taste receptor (T1R2). In addition, most synaptogyrin 1-immunoreactive taste cells expressed synaptobrevin-2. These results suggest that synaptogyrin-1 plays a regulatory role in transmission at the synapses of type III cells and is involved in exocytic function with synaptobrevin-2 in a subset of type II cells in rat taste buds. PMID- 23636419 TI - Reduced RANKL expression impedes osteoclast activation and tooth eruption in alendronate-treated rats. AB - The creation of the eruption pathway requires the resorption of the occlusal alveolar bone by osteoclasts and signaling events between bone and dental follicle are necessary. The aim of the present study has been to evaluate the effect of alendronate on osteoclastogenesis and the expression of the regulator proteins of osteoclast activation, namely RANK, RANKL and OPG, in the bone that covers the first molar germ. Newborn Wistar rats were treated daily with 2.5 mg/kg alendronate for 4, 8, 14, 21 and 28 days, whereas controls received sterile saline solution. At the time points cited, maxillae were fixed, decalcified and processed for light and electron microscopic analysis. TRAP histochemistry was performed on semi-serial sections and the osteoclasts in the occlusal half of the bony crypt surface were counted. TUNEL analysis was carried out on paraffin sections. The occlusal bone that covers the upper first molar was removed in additional 4- and 8-day-old alendronate-treated and control rats in which the expression of RANK, RANKL and OPG was analyzed by SDS-polyacrylamide gel electrophoresis and Western blotting. TRAP-positive osteoclasts were more numerous in the alendronate group at all time points, despite their unactivated phenotype and the presence of apoptotic cells. RANKL expression in the alendronate specimens was inhibited at all time points, unlike in controls. Our findings indicate that the expression of RANKL in the occlusal portion of the bony crypt is unrelated to osteoclast recruitment and differentiation but is crucial to their activation during the creation of the eruption pathway. PMID- 23636422 TI - FOXO flips the longevity SWItch. AB - FOXO transcription factors promote longevity from worms to mammals, but the mechanisms by which FOXO extends lifespan have remained elusive. In the nematode Caenorhabditis elegans, FOXO is now shown to recruit the nucleosome remodelling complex SWI/SNF to its target genes, which is essential for FOXO to elicit stress resistance and longevity. PMID- 23636423 TI - A nexus for receptor recycling. AB - Sorting nexin proteins (SNXs) and the cargo-selective retromer complex play key roles in receptor recycling from endosomes to the cell surface. A global proteomics analysis reveals a collection of cell surface proteins that rely on SNX27 and the retromer complex for their cell surface localization at steady state. PMID- 23636429 TI - Synthesis of uniformly dispersed anatase nanoparticles inside mesoporous silica thin films via controlled breakup and crystallization of amorphous TiO2 deposited using atomic layer deposition. AB - Amorphous titanium dioxide was introduced into the pores of mesoporous silica thin films with 75% porosity and 12 nm average pore diameter via Atomic Layer Deposition (ALD) using alternating pulses of tetrakis(dimethylamino)titanium and water. Calcination provoked fragmentation of the deposited amorphous TiO2 phase and its crystallization into anatase nanoparticles inside the nanoporous film. The narrow particle size distribution of 4 +/- 2 nm and the uniform dispersion of the particles over the mesoporous silica support were uniquely revealed using electron tomography. These anatase nanoparticle bearing films showed photocatalytic activity in methylene blue degradation. This new synthesis procedure of the anatase nanophase in mesoporous silica films using ALD is a convenient fabrication method of photocatalytic coatings amenable to application on very small as well as very large surfaces. PMID- 23636430 TI - Risk factors for cognitive dysfunction in CKD and hypertensive subjects. AB - PURPOSE: Cognitive dysfunction (CO/DY) in chronic kidney disease (CKD) patients has long been recognized. Hypertension is also associated with CO/DY. The study describes associated factors with CO/DY in CKD patients compared to hypertensive subjects. METHODS: Ninety-six hypertensive subjects without CKD, 19 patients with CKD stages I-II, 33 with CKD III, 42 with CKD stage IV, 33 on hemodialysis (HD) and 33 on peritoneal dialysis (PD) were included in our study. Cognitive impairment measured by MMSE, clock-drawing test and IADL was considered as primary outcome. RESULTS: In all groups tested, age was significantly associated with CO/DY by almost all cognitive function tests. Among CKD patients, CKD stage and DM were significantly associated with CO/DY by all three cognitive function tests. PTH levels were also associated with CO/DY by MMSE and clock-drawing tests. In hypertensives, pulse pressure (PP) was associated with CO/DY by clock drawing and IADL tests, while those receiving CCBs as monotherapy were less likely to have CO/DY by IADL test. For dialysis patients, DM was significantly related to CO/DY by MMSE and clock-drawing tests. In the same group of patients Hb <11 g/dl was significantly correlated with CO/DY by MMSE, dialysis modality and Kt/V >1.2 by IADL test. PD patients were less likely to present with CO/DY by clock-drawing test. CONCLUSIONS: In every CKD stage, the risk of CO/DY increased significantly. Low Hb levels (Hb <11 g/dl) and increased serum PTH levels were associated with CO/DY while DM plays also a significant role in cognitive function deterioration. Among hypertensive subjects, those with PP <=60 mmHg or receiving CCBs showed a better executive function. PMID- 23636431 TI - Arenarol isolated from a marine sponge abrogates endothelin-1-stimulated melanogenesis by interrupting MEK phosphorylation in normal human melanocytes. AB - Using B16 melanoma cells for screening, we found that a marine sponge extract has a potent anti-pigmenting effect and identified arenarol as its major active compound. In normal human melanocytes (NHMs), arenarol significantly abrogated the endothelin 1 (EDN1) stimulated expression of tyrosinase, tyrosinase-related protein 1 and dopachrome tautomerase at the transcriptional, translational and enzymatic activity (only for tyrosinase) levels. That effect was accompanied by the attenuation of the increased expression level of microphthalmia-associated transcription factor (MITF) protein at the transcriptional and translational levels. Analysis of EDN1 signaling demonstrated that arenarol significantly suppressed the EDN1-induced phosphorylation of MEK, ERK, MITF and CREB but not of Raf-1s. In contrast, the forskolin-induced phosphorylation of CREB was not down regulated by arenarol. As for the mode of action of the suppressed phosphorylation of MEK, Raf-1 activity was not directly inhibited by arenarol in vitro and pretreatment with the protein phosphatase inhibitor okadaic acid did not affect the down-regulated phosphorylation of MEK that was induced by arenarol in NHMs. The sum of these findings suggests that arenarol abrogates the EDN1 stimulated expression of melanocyte-specific proteins by interrupting MEK phosphorylation in an as yet unknown Raf-1 inactivation mechanism. PMID- 23636432 TI - Survival and ultrastructural features of peach palm (Bactris gasipaes, Kunth) somatic embryos submitted to cryopreservation through vitrification. AB - Bactris gasipaes (Arecaceae), also known as peach palm, was domesticated by Amazonian Indians and is cultivated for its fruit and heart-of-palm, a vegetable grown in the tree's inner core. Currently, the conservation of this species relies on in situ conditions and field gene banks. Complementary conservation strategies, such as those based on in vitro techniques, are indicated in such cases. To establish an appropriate cryopreservation protocol, this study aimed to evaluate the ultrastructural features of B. gasipaes embryogenic cultures submitted to vitrification and subsequent cryogenic temperatures. Accordingly, somatic embryo clusters were submitted to Plant Vitrification Solution 3 (PVS3). In general, cells submitted to PVS3 had viable cell characteristics associated with apparently many mitochondria, prominent nucleus, and preserved cell walls. Cells not incubated in PVS3 did not survive after the cryogenic process in liquid nitrogen. The best incubation time for the vitrification technique was 240 min, resulting in a survival rate of 37 %. In these cases, several features were indicative of quite active cell metabolism, including intact nuclei and preserved cell walls, an apparently many of mitochondria and lipid bodies, and the presence of many starch granules and condensed chromatin. Moreover, ultrastructure analysis revealed that overall cellular structures had been preserved after cryogenic treatment, thus validating the use of vitrification in conjunction with cryopreservation of peach palm elite genotypes, as well as wild genotypes, which carry a rich pool of genes that must be conserved. PMID- 23636433 TI - Inactivation of Ca2+-induced ciliary reversal by high-salt extraction in the cilia of Paramecium. AB - Intracellular Ca(2+) induces ciliary reversal and backward swimming in Paramecium. However, it is not known how the Ca(2+) signal controls the motor machinery to induce ciliary reversal. We found that demembranated cilia on the ciliated cortical sheets from Paramecium caudatum lost the ability to undergo ciliary reversal after brief extraction with a solution containing 0.5 M KCl. KNO(3), which is similar to KCl with respect to chaotropic effect; it had the same effect as that of KCl on ciliary response. Cyclic AMP antagonizes Ca(2+) induced ciliary reversal. Limited trypsin digestion prevents endogenous A-kinase and cAMP-dependent phosphorylation of an outer arm dynein light chain and induces ciliary reversal. However, the trypsin digestion prior to the high-salt extraction did not affect the inhibition of Ca(2+)-induced ciliary reversal caused by the high-salt extraction. Furthermore, during the course of the high salt extraction, some axonemal proteins were extracted from ciliary axonemes, suggesting that they may be responsible for Ca(2+)-induced ciliary reversal. PMID- 23636434 TI - Lifetime costs for peritoneal dialysis and hemodialysis in patients in Taiwan. AB - BACKGROUND: This study compared the lifetime costs for peritoneal dialysis (PD) and hemodialysis (HD) patients in Taiwan. METHODS: Using the National Health Insurance (NHI) database of all end-stage renal disease patients on maintenance dialysis registered from July 1997 to December 2005, we matched eligible PD patients with eligible HD patients on age, sex, and diabetes status. The matched patients were followed until 31 December 2006. Patients were excluded if they were less than 18 years of age, had been diagnosed with cancer before dialysis, or had been dialyzed at centers or clinics other than hospitals. Outcomes including life expectancy, total lifetime costs, and costs per life-year paid by the NHI-were estimated and compared. RESULTS: The 3136 pairs of matched PD and HD patients had a mean age of 53.2 +/- 15.4 years. The total lifetime cost for PD patients (US$139 360 +/- US$8 336) was significantly lower than that for HD patients (US$185 235 +/- US$9 623, p < 0.001). Except for patients with diabetes (who had a short life expectancy), the total lifetime cost was significantly lower for PD patients than for HD patients regardless of sex and age (p < 0.01). CONCLUSION: In Taiwan, the total lifetime costs paid by the NHI were lower for PD than for HD patients. PMID- 23636435 TI - Pre-treatment of dairy and breast milk with sevelamer hydrochloride and sevelamer carbonate to reduce phosphate. AB - INTRODUCTION: Young children and infants with chronic kidney disease are at increased risk of hyperphosphatemia because of high intake of dairy products. Hyperphosphatemia leads to metastatic calcifications and an increased risk of cardiovascular complications. Sevelamer is an effective phosphate binder, but for children it has important practical disadvantages: it clogs enteral feeding tubes and can cause gastrointestinal complaints. Pre-treatment of dairy products to reduce their phosphate content might solve those problems. METHODS: Sevelamer hydrochloride and sevelamer carbonate were suspended in various dairy products (cow's milk, breast milk, baby formula, and tube-feeding formula). Each product was tested with varying concentrations of sevelamer. After suspension, each sample was stored for 10 minutes, allowing the sevelamer to precipitate. The supernatant was decanted and analyzed for pH and for phosphate, calcium, magnesium, potassium, sodium, and chloride content. RESULTS: We observed a significant decrease in the phosphate content of all tested products. With sevelamer hydrochloride, the phosphate reduction was 48% - 91% in the various products, and with sevelamer carbonate, it was 22% - 87%. The highest effectiveness was found in breast milk. A pH increase was found in all products. With sevelamer hydrochloride, a significant increase in chloride occurred. Notably, a significant decrease in calcium content (-75%) was observed in treated breast milk. CONCLUSIONS: Pretreatment of a variety of dairy products with either sevelamer hydrochloride or sevelamer carbonate effectively reduced their phosphate content and might avoid troublesome ingestion of sevelamer in children. The change in pH with sevelamer hydrochloride was remarkable, reflecting buffering mechanisms. The reduction in the calcium content of breast milk is a potential concern and should be carefully considered and monitored during clinical use of sevelamer. PMID- 23636436 TI - Hyponatremia in peritoneal dialysis: epidemiology in a single center and correlation with clinical and biochemical parameters. AB - BACKGROUND: Hyponatremia in peritoneal dialysis (PD) patients has previously been associated with water overload and weight gain, or with malnutrition and intracellular potassium depletion. Although there is a sizable literature about transmembrane sodium and water removal in PD, there are few reports about the incidence and characteristics of hyponatremia in the clinical setting. AIM: We evaluated the incidence and factors associated with hyponatremia in PD patients in a single PD unit. METHODS: We retrospectively evaluated the records of all patients (n = 198) who were treated with PD in the Home PD Unit of the University Health Network at Toronto General Hospital during 2010. We identified 166 patients who had a minimum follow-up of 60 days during 2010 and at least 2 consecutive sodium measurements at least a month apart. We examined baseline differences between patients who developed hyponatremia and those who did not, and clinical and biochemical factors that correlated with mean sodium values. In the 24 patients who developed hyponatremia, we examined paired differences between the normonatremic and hyponatremic periods. Finally, we investigated any possible correlations of change in serum sodium with clinical and biochemical characteristics before and during the hyponatremic period. RESULTS: The incidence of hyponatremia was 14.5%. In multivariate analysis, serum sodium correlated significantly and independently with residual renal function (RRF: r = 0.463, p = 0.0001) and negatively with the daily volume of instilled icodextrin (r = -0.476, p = 0.0001). Residual renal function was significantly lower in patients with hyponatremia than in those with normal serum sodium (1.97 +/- 2.3 mL/min vs 4.31 +/- 5.01 mL/min, p = 0.033). The mean paired difference in body weight was -1.113 kg and the median difference was -0.55 kg (range: -8.5 kg to +4.2 kg). Impressively, hyponatremia was not associated with an increase in body weight in most patients who developed this complication (13 of 16 for whom comparative weights were known). Moreover, the mean paired change in serum sodium (DeltaNa) from normonatremia to hyponatremia was, contrary to our expectations, significantly correlated with a decrease in body weight (r = 0.584, p = 0.017). The DeltaNa was also significantly correlated with serum potassium (r = 0.526, p = 0.008), the greatest drop in serum sodium being associated with lower serum potassium in the hyponatremic period, as predicted. CONCLUSIONS: Hyponatremia is seen more often than expected in a clinical setting. Serum sodium is strongly correlated with RRF, hyponatremia being associated with lower RRF. In patients who experienced hyponatremia, the fall in serum sodium was associated with a decrease, not an increase, in body weight and was correlated with serum potassium, suggesting that sodium and potassium depletion-and, by inference, malnutrition-may be important contributors in the clinical setting. PMID- 23636437 TI - 1H-MR spectroscopy of adult-onset autosomal dominant leukodystrophy with autonomic symptoms. AB - INTRODUCTION: Adult-onset ADLD with autonomic symptoms is a rare disease with a clinical course somewhat similar to chronic progressive MS but with different imaging findings consisting of extensive white matter changes in the cerebrum and cerebellar peduncles. Patients usually present in the fourth to sixth decade with autonomic symptoms, manifesting later symptoms from the pyramidal tracts and ataxia. Here, we present magnetic resonance spectroscopy (MRS) findings in this disease. METHODS: Fourteen subjects, from two non-related families, with genetic linkage to the disease were studied with magnetic resonance imaging and single voxel MRS. Clinically, they ranged from asymptomatic to wheelchair-using. Their results were compared to those of age- and sex-matched healthy controls. RESULTS: One MRS was excluded due to suboptimal quality. The remaining 13 subjects manifested characteristic evidence of pathology on MRI, 11 of them exhibited extensive changes. The metabolite concentrations of total Cr, total Cho, and total NAA measured in millimolars, using internal water as a reference, were significantly lower in these 11 subjects compared to controls, and we found linear correlations between all these metabolite levels. When total Cr was used as a reference, we found no difference between subjects and controls. No lactate was detected. CONCLUSION: The decreased metabolite concentrations measured using internal water as a reference are most likely due to increased water content in the tissues, diluting all metabolites to a similar degree. This is also in agreement with the high signal intensity exhibited in the white matter on T2 weighted MR images and with the reported histopathological findings of vacuolated myelin. PMID- 23636439 TI - [Award for best continuing medical education article: Springer CME award Der Internist presented for the ninth time]. PMID- 23636438 TI - [Inflammatory aortic diseases]. AB - Inflammatory diseases of the aorta fall under the umbrella term "aortitis" and encompass a broad spectrum of autoimmune and infectious disorders. Giant cell arteritis and Takayasu arteritis represent the most common causative primary large vessel vasculitides. Isolated aortitis is a further important entity, whilst IgG4-associated systemic disease today represents yet another disease entity belonging to this group. Clinical presentation is highly variable, ranging from asymptomatic incidental findings to acute aortic syndrome due to rupture. Diagnostic imaging techniques form the cornerstone of the diagnostic workup. These techniques should also be used in screening for diseases with frequent aortic involvement. The treatment approach depends on the underlying disease and on the extent of aortic damage secondary to vascular inflammation. Against this background, differentiation between autoimmune and infectious aortitis is therefore necessary due to the contrasting treatment strategies. The present article is intended to provide the internist with an overview of this heterogeneous disease entity. PMID- 23636440 TI - [Atrial fibrillation: current recommendations for diagnosis and treatment]. AB - Atrial fibrillation (AF) is by far the most common arrhythmia. It occurs more often with increasing age. Patients with AF almost always require oral anticoagulants and a rate-control treatment. In addition, other cardiovascular diseases must also be carefully treated in order to reduce the risks of cardiovascular complications from AF. Most patients profit from rate-control treatment with drugs that slow the conduction of the electrical impulse through the AV node. The aim is a resting heart rate of 100-110/min. If patients suffer from AF whilst on optimal rate control therapy, rhythm-control treatment with antiarrhythmic drugs, cardioversion or catheter ablation is indicated. The choice of the rhythm-control therapy should be made based on safety considerations. Whether achieving sinus rhythm beyond improvement of symptoms improves the prognosis of AF is tested in ongoing trials. PMID- 23636444 TI - Treatment of sigmoid volvulus: a single-center experience of 952 patients over 46.5 years. AB - BACKGROUND: Sigmoid volvulus describes the wrapping of the sigmoid colon around itself and its mesentery, causing an intestinal obstruction. The aim of this study was to assess the outcomes of 952 patients treated for sigmoid volvulus over a period of 46.5 years. METHODS: Clinical records were reviewed retrospectively. RESULTS: Nonsurgical detorsion was performed in 686 patients with 77.1 % success, 2.5 % morbidity, 0.7 % mortality, and 4.5 % early recurrence rates; emergency surgical procedures were performed in 447 patients with 35.3 % morbidity, 16.1 % mortality, 0.7 % early recurrence, and 7.4 % late recurrence rates, while elective surgical treatment was performed in 104 patients with 12.5 % morbidity, no mortality, and no recurrence. CONCLUSIONS: The principal strategy in the treatment for sigmoid volvulus is early nonsurgical detorsion followed by elective surgery in uncomplicated patients, while emergency surgical treatment is performed for patients with bowel gangrene, perforation, or peritonitis, other difficulties with diagnosis, unsuccessful nonsurgical detorsion, and early recurrence. PMID- 23636446 TI - A glucocorticoid education group meeting: an effective strategy for improving self-management to prevent adrenal crisis. AB - OBJECTIVE: To assess self-management in patients receiving glucocorticoid replacement therapy for primary or secondary adrenal failure before and 6 months after a glucocorticoid education group meeting. METHODS: All patients with primary or secondary adrenal insufficiency, treated at the Department of Medicine, Division of Endocrinology, were invited by their endocrinologist to participate in a 3-h glucocorticoid education group meeting, consisting of a lecture about the disease and glucocorticoid doses adjustments in case of stress, followed by an instruction on how to inject hydrocortisone i.m. Finally, all participants could practise the i.m. injection and discuss their experience with (imminent) adrenal crises with other patients and the health care providers. Two weeks before the meeting and 6 months after the meeting, patients were asked to fill out a questionnaire about how they would act in six different conditions (e.g. febrile illness or vomiting). RESULTS: Of the 405 patients who were invited, 246 patients (61%) participated. At baseline the response by the participants on the questionnaire was 100% (n=246) and at follow-up 74% (n=183). At follow-up, significantly more participants (P<=0.005) gave the correct answers to how to act in different situations (e.g. self-administration of a glucocorticoid injection and phone contact in case of vomiting/diarrhoea without fever). Moreover, the use of self-management tools, such as having a 'medicine passport (travel document with information about disease and medication) (P=0.007) or SOS medallion (P=0.0007)', increased. CONCLUSION: A glucocorticoid education group meeting for patients with adrenal failure seems helpful to improve self-management and proper use of stress-related glucocorticoid dose adjustment. PMID- 23636445 TI - Gestational diabetes mellitus among Norwegian women with polycystic ovary syndrome: prevalence and risk factors according to the WHO and the modified IADPSG criteria. AB - OBJECTIVE: The consequences of the recently proposed International Association of Diabetes in Pregnancy Study Group (IADPSG) criteria for gestational diabetes mellitus (GDM) in women with polycystic ovary syndrome (PCOS) are not known. We compared the prevalence rates and risk factors for GDM in PCOS women according to both the WHO and the modified IADPSG criteria. DESIGN: Post hoc analyses from a randomized, multicenter study were used. METHODS: Fasting and 2-h plasma glucose levels were measured using a 75 g oral glucose tolerance test. GDM was diagnosed according to both the WHO and the modified IADPSG criteria. RESULTS: The prevalence rates of GDM according to the WHO and the modified IADPSG criteria were 9.2 and 15.0% at week 12, 18.7 and 18.7% at week 19, and 25.6 and 24.2% at week 32. Shorter stature and increased insulin levels were correlated with WHO GDM, but not with modified IADPSG-GDM at weeks 12 and 19. Less weight gain in pregnancy predicted GDM according to both sets of criteria. GDM diagnosis was correlated with less maternal weight loss the first year post-partum. CONCLUSIONS: No difference was found in the prevalence of GDM between the two sets of criteria used. Less weight gain in pregnancy was associated with GDM, independent of the diagnostic criteria used. Reduced weight loss the first year post-partum in women with GDM raises the question of whether GDM diagnosis per se or the fact that these women lose less weight after pregnancy predicts later diabetes mellitus. PMID- 23636447 TI - Individual multi-locus heterozygosity is associated with lower morning plasma cortisol concentrations. AB - OBJECTIVE: Stress is implicated as a risk factor for numerous illnesses in humans, putatively in part mediated by biological responses to stress, such as elevated cortisol concentrations. The theory of genetic homoeostasis suggests that individual heterozygosity facilitates compensation for environmental stresses. We hypothesized that heterozygosity ameliorates the biological response to a given level of perceived stress, reflected in lower plasma cortisol concentrations. DESIGN: We examined the role of heterozygosity in the association between perceived psychological stress and morning cortisol concentrations in 854 individuals from the isolated island of Vis, Croatia. METHODS: Cortisol concentrations were measured in morning plasma samples. A total of 1184 autosomal microsatellite markers were genotyped and individual multi-locus heterozygosity (MLH) was calculated as the proportion of heterozygous markers. The General Health Questionnaire with 30 items (GHQ-30) was used to assess the degree of psychological distress. RESULTS: MEAN MLH WAS 34.850.45% (RANGE: 31.97-36.22%). Psychological distress (GHQ Likert score >31) was more prevalent in women (37 vs 18% in men, P<0.0001), in less educated people (beta=-0.35 per year in school, P<0.001) and in lower socio-economic classes (beta=-3.59, P<0.0001). Cortisol concentrations were positively associated with psychological distress (beta=2.20, P=0.01). In a regression model adjusted for age, BMI, education and GHQ-30 score, MLH was independently and inversely associated with morning plasma cortisol concentrations (P=0.005). CONCLUSION: More heterozygous individuals, as measured by microsatellite markers, had lower morning plasma cortisol concentrations for a given level of perceived psychological stress. This may be important, as higher cortisol concentrations may increase the allostatic load and be associated with a higher risk of stress-related illness. PMID- 23636448 TI - Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors. AB - PURPOSE: The metabolism of pazopanib is primarily mediated by CYP3A4. The solubility of pazopanib is pH-dependent, and an elevated gastric pH may decrease its bioavailability. This study evaluated the effect of a potent CYP3A4 inhibitor, ketoconazole, and the proton pump inhibitor esomeprazole on the pharmacokinetics and safety of pazopanib and its metabolites. METHODS: In Arm A, patients received pazopanib 400 mg alone once daily for 7 days followed by pazopanib 400 mg plus ketoconazole 400 mg once daily for 5 days. In Arm B, patients received pazopanib 800 mg once daily for 7 days, followed by pazopanib 800 mg plus esomeprazole 40 mg once daily for 5 days, and then pazopanib alone on the last day. RESULTS: Arm A enrolled 21 patients. In the presence of ketoconazole, mean area under the plasma concentration-time curve 24 h post-dose (AUC(0-24)) and mean maximum observed concentration (C max) of pazopanib increased by 66 and 45 %, respectively; mean AUC(0-24) and C max for pazopanib metabolites were lower or remained unchanged. Arm B enrolled 13 patients. In the presence of esomeprazole, mean pazopanib AUC(0-24) and C max decreased by 40 and 42 %, respectively; mean values of those parameters for metabolites of pazopanib also decreased. CONCLUSIONS: Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered. PMID- 23636449 TI - Prophylaxis of catheter-related deep vein thrombosis in cancer patients with low dose warfarin, low molecular weight heparin, or control: a randomized, controlled, phase III study. AB - PURPOSE: Whether an anticoagulant prophylaxis is needed for patients with cancer with a central venous catheter is a highly controversial subject. We designed a study to compare different prophylactic strategies over 3 months of treatment. METHODS: We performed a phase III prospective, open-label randomized trial. After the insertion of a central venous access device, consecutive patients with planned chemotherapy for cancer were randomized to no anticoagulant prophylaxis, low molecular weight heparin [low molecular weight heparin (LMWH); with isocoagulation doses], or warfarin 1 mg/day. Treatments were given over the first 3 months. Doppler ultrasound and venographies were performed on days 1 and 90, respectively, or sooner in case of clinical presumption of thrombosis. RESULTS: A total of 420 patients were randomized, and 407 were evaluable. Forty-two catheter related deep vein thrombosis (DVT) occurred (10.3 %), 20 in those with no anticoagulation, 8 in those receiving warfarin, and 14 in those receiving LMWH. Nine additional non-related catheter deep vein thrombosis (CDVT) occurred. Anticoagulation significantly reduced the incidence of catheter-related DVT (p = 0.035) and catheter non-related DVT (p = 0.007), with no difference between warfarin and LMWH. Safety was good (3.4 % of attributable events) but compliance with randomized prophylaxis was lower than expected. CONCLUSIONS: Prophylaxis showed a benefit regarding catheter-related and non-catheter-related DVT with no increase in serious side effects. PMID- 23636450 TI - MSH3 expression does not influence the sensitivity of colon cancer HCT116 cell line to oxaliplatin and poly(ADP-ribose) polymerase (PARP) inhibitor as monotherapy or in combination. AB - PURPOSE: Defective expression of the mismatch repair protein MSH3 is frequently detected in colon cancer, and down-regulation of its expression was found to decrease sensitivity to platinum compounds or poly(ADP-ribose) polymerase inhibitors (PARPi) monotherapy. We have investigated whether MSH3 transfection in MSH3-deficient colon cancer cells confers resistance to oxaliplatin or PARPi and whether their combination restores chemosensitivity. METHODS: MSH3-deficient/MLH1 proficient colon cancer HCT116(MLH1) cells were transfected with the MSH3 cDNA cloned into the pcDNA3.1(-) vector. MSH3/MLH1-deficient HCT116, carrying MLH1 and MSH3 mutations on chromosome 3 and 5, respectively, and HCT116 in which wild-type MLH1 (HCT116+3), MSH3 (HCT116+5) or both genes (HCT116+3+5) were introduced by chromosome transfer were also tested. Sensitivity to oxaliplatin and to PARPi was evaluated by analysis of clonogenic survival, cell proliferation, apoptosis and cell cycle. RESULTS: MSH3 transfection in HCT116 cells did not confer resistance to oxaliplatin or PARPi monotherapy. MSH3-proficient HCT116+5 or HCT116+3+5 cells, which were more resistant to oxaliplatin and PARPi in comparison with their MSH3-deficient counterparts, expressed higher levels of the nucleotide excision repair ERCC1 and XPF proteins, involved in the resistance to platinum compounds, and lower PARP-1 levels. In all cases, PARPi increased sensitivity to oxaliplatin. CONCLUSIONS: Restoring of MSH3 expression by cDNA transfection, rather than by chromosome transfer, did not affect colon cancer sensitivity to oxaliplatin or PARPi monotherapy; PARP-1 levels seemed to be more crucial for the outcome of PARPi monotherapy. PMID- 23636452 TI - Sulfide ions as modulators of metal-thiolate cluster size in a plant metallothionein. AB - Metallothioneins are small cysteine-rich proteins coordinating various transition metal ions preferably with the electron configuration d(10). They are ubiquitously present in all phyla, and next to phytochelatins they represent a successful molecular concept for high-capacity metal ion binding. Recent studies showed the incorporation of sulfide ions into the metal-thiolate cluster of metallothionein 2 from the plant Cicer arietinum (cicMT2) increasing the cadmium binding capacity and stability of the cluster. In the present work, the sulfide induced structural changes accompanying the cluster formation and the sulfide modulated increase in cluster size are analyzed in detail with a variety of analytical and spectroscopic techniques. Evaluation of the mechanism of sulfide containing Cd(II)-thiolate cluster formation in cicMT2 reveals a strong dependence on the sequence of metal and sulfide additions for successful sulfide incorporation. To probe the general ability of metallothioneins to form sulfide containing larger metal-thiolate clusters, analogous experiments were performed with a mammalian metallothionein. The observation that the cadmium binding ability of rabbit liver MT2A was only slightly increased led to the development of a hypothesis in which the long cysteine-free linker regions present in certain plant metallothioneins may contribute to the accommodation of the respective larger cluster assemblies. PMID- 23636451 TI - A phase II study of gemcitabine and oxaliplatin in advanced transitional cell carcinoma of the bladder. AB - Cisplatin-based chemotherapy is recommended for use as first-line treatment for patients with advanced transitional cell carcinoma of the bladder. Unfortunately, 30-50 % of patients are ineligible for cisplatin due to renal insufficiency. Oxaliplatin is a less nephrotoxic platin which can be used for patients with impaired renal function. We carried out a phase II study of gemcitabine (1,200 mg/m2) in combination with oxaliplatin (100 mg/m2) given on days 1 and 14 every 28 days (GEMOX) in predominantly cisplatin-'unfit' stage IV transitional cell bladder cancer patients to determine whether this combination exhibited a clinical activity profile similar to cisplatin plus gemcitabine. Eighteen patients with a median GFR of 49 ml/min were enrolled. GEMOX treatment led to a 36 % response rate in assessable patients. Median progression-free survival was 4.9 months, with a median overall survival (OS) of 10.4 months and a one-year survival rate of 44.4 %. GEMOX in bladder cancer patients exhibited a tolerable side effects profile, with thrombocytopenia as the most frequent grade 3/4 toxicity. These findings suggest that GEMOX is an active combination in advanced bladder cancer patients with reduced renal function. PMID- 23636453 TI - Skeletal muscle interleukin-6 regulation in hyperthermia. AB - We previously reported that IL-6 production is acutely elevated in skeletal muscles exposed to >=41 degrees C, but the regulatory pathways are poorly understood. The present study characterizes the heat-induced transcriptional control of IL-6 in C2C12 muscle fibers. Hyperthermia exposure (42 degrees C for 1 h) induced transcription from an IL-6 promoter-luciferase reporter plasmid. Heat shock factor-1 (HSF-1), a principal mediator of the heat shock response, was then tested for its role in IL-6 regulation. Overexpression of a constitutively active HSF-1 construct increased basal (37 degrees C) promoter activity, whereas overexpression of a dominant negative HSF-1 reduced IL-6 promoter activity during basal and hyperthermia conditions. Since hyperthermia also induces stress activated protein kinase (SAPK) signaling, we tested whether mutation of a transcription site downstream of SAPK, (i.e., activator protein-1, AP-1) influences IL-6 transcription in hyperthermia. The mutation had no effect on baseline reporter activity but completely inhibited heat-induced activity. We then tested whether pharmacologically induced states of protein stress, characteristic of cellular responses to hyperthermia and known to induce SAPKs and HSF-1, would induce IL-6 production in the absence of heat. The proteasome was inhibited with MG-132 in one set of experiments, and the unfolded protein response was stimulated with dithiothreitol, thapsigargin, tunicamycin, or castanospermine in other experiments. All treatments stimulated IL-6 protein secretion in the absence of hyperthermia. These studies demonstrate that IL-6 regulation in hyperthermia is directly controlled by HSF-1 and AP-1 signaling and that the IL-6 response in C2C12 myotubes is sensitive to categories of protein stress that reflect accumulation of damaged or unfolded proteins. PMID- 23636455 TI - DIDS and the Janus-faced Na+-K+-activated ATPase. Focus on "DIDS inhibits Na-K ATPase activity in porcine nonpigmented ciliary epithelial cells by a Src family kinase-dependent mechanism". PMID- 23636454 TI - RACK1 interacts with filamin-A to regulate plasma membrane levels of the cystic fibrosis transmembrane conductance regulator. AB - Mutations in cystic fibrosis transmembrane regulator (CFTR), a chloride channel in the apical membranes of secretory epithelial cells, underlie the fatal genetic disorder cystic fibrosis. Certain CFTR mutations, including the common mutation DeltaF508-CFTR, result in greatly decreased levels of active CFTR at the apical membrane. Direct interactions between CFTR and the cytoskeletal adaptors filamin A (FlnA) and Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) stabilize the expression and localization of CFTR at the plasma membrane. The scaffold protein receptor for activated C kinase 1 (RACK1) also stabilizes CFTR surface expression; however, RACK1 does not interact directly with CFTR and its mechanism of action is unknown. In the present study, we report that RACK1 interacts directly with FlnA in vitro and in a Calu-3 airway epithelial cell line. We mapped the interaction between RACK1 and FlnA to the WD4 and WD6 repeats of RACK1 and to a segment of the large rod domain of FlnA, consisting of immunoglobulin like repeats 8-15. Disruption of the RACK1-FlnA interaction causes a reduction in CFTR surface levels. Our results suggest that a novel RACK1-FlnA interaction is an important regulator of CFTR surface localization. PMID- 23636458 TI - Functional morphology underlies performance differences among invasive and non invasive ruderal Rubus species. AB - The ability of some introduced plant species to outperform native species under altered resource conditions makes them highly productive in ecosystems with surplus resources. However, ruderal native species are also productive when resources are available. The differences in abundance among invasive and non invasive ruderal plants may be related to differences in ability to maintain access to or store resources for continual use. For a group of ruderal species in the Pacific Northwest of North America (invasive Rubus armeniacus; non-invasive R. ursinus, R. parviflorus, R. spectabilis, and Rosa nutkana), we sought to determine whether differences in functional morphological traits, especially metrics of water access and storage, were consistent with differences in water conductance and growth rate. We also investigated the changes in these traits in response to abundant vs. limited water availability. Rubus armeniacus had among the largest root systems and cane cross-sectional areas, the lowest cane tissue densities, and the most plastic ratios of leaf area to plant mass and of xylem area to leaf area, often sharing its rank with R. ursinus or Rosa nutkana. These three species had the highest water conductance and relative growth rates, though Rubus armeniacus grew the most rapidly when water was not limited. Our results suggest that water access and storage abilities vary with morphology among the ruderal species investigated, and that these abilities, in combination, are greatest in the invasive. In turn, functional morphological traits allow R. armeniacus to maintain rapid gas exchange rates during the dry summers in its invaded range, conferring on it high productivity. PMID- 23636456 TI - Missense mutation T485S alters NBCe1-A electrogenicity causing proximal renal tubular acidosis. AB - Mutations in SLC4A4, the gene encoding the electrogenic Na(+)-HCO3(-) cotransporter NBCe1, cause severe proximal renal tubular acidosis (pRTA), growth retardation, decreased IQ, and eye and teeth abnormalities. Among the known NBCe1 mutations, the disease-causing mechanism of the T485S (NBCe1-A numbering) mutation is intriguing because the substituted amino acid, serine, is structurally and chemically similar to threonine. In this study, we performed intracellular pH and whole cell patch-clamp measurements to investigate the base transport and electrogenic properties of NBCe1-A-T485S in mammalian HEK 293 cells. Our results demonstrated that Ser substitution of Thr485 decreased base transport by ~50%, and importantly, converted NBCe1-A from an electrogenic to an electroneutral transporter. Aqueous accessibility analysis using sulfhydryl reactive reagents indicated that Thr485 likely resides in an NBCe1-A ion interaction site. This critical location is also supported by the finding that G486R (a pRTA causing mutation) alters the position of Thr485 in NBCe1-A thereby impairing its transport function. By using NO3(-) as a surrogate ion for CO3(2-), our result indicated that NBCe1-A mediates electrogenic Na(+)-CO3(2-) cotransport when functioning with a 1:2 charge transport stoichiometry. In contrast, electroneutral NBCe1-T485S is unable to transport NO3(-), compatible with the hypothesis that it mediates Na(+)-HCO3(-) cotransport. In patients, NBCe1-A-T485S is predicted to transport Na(+)-HCO3(-) in the reverse direction from blood into proximal tubule cells thereby impairing transepithelial HCO3(-) absorption, possibly representing a new pathogenic mechanism for generating human pRTA. PMID- 23636457 TI - NLRP3 deletion protects from hyperoxia-induced acute lung injury. AB - Inspiration of a high concentration of oxygen, a therapy for acute lung injury (ALI), could unexpectedly lead to reactive oxygen species (ROS) production and hyperoxia-induced acute lung injury (HALI). Nucleotide-binding domain and leucine rich repeat PYD-containing protein 3 (NLRP3) senses the ROS, triggering inflammasome activation and interleukin-1beta (IL-1beta) production and secretion. However, the role of NLRP3 inflammasome in HALI is unclear. The main aim of this study is to determine the effect of NLRP3 gene deletion on inflammatory response and lung epithelial cell death. Wild-type (WT) and NLRP3(-/ ) mice were exposed to 100% O2 for 48-72 h. Bronchoalveolar lavage fluid and lung tissues were examined for proinflammatory cytokine production and lung inflammation. Hyperoxia-induced lung pathological score was suppressed in NLRP3( /-) mice compared with WT mice. Hyperoxia-induced recruitment of inflammatory cells and elevation of IL-1beta, TNFalpha, macrophage inflammatory protein-2, and monocyte chemoattractant protein-1 were attenuated in NLRP3(-/-) mice. NLRP3 deletion decreased lung epithelial cell death and caspase-3 levels and a suppressed NF-kappaB levels compared with WT controls. Taken together, this research demonstrates for the first time that NLRP3-deficient mice have suppressed inflammatory response and blunted lung epithelial cell apoptosis to HALI. PMID- 23636459 TI - Sex-biased parasitism is not universal: evidence from rodent-flea associations from three biomes. AB - The distribution of parasites among individual hosts is characterised by high variability that is believed to be a result of variations in host traits. To find general patterns of host traits affecting parasite abundance, we studied flea infestation of nine rodent species from three different biomes (temperate zone of central Europe, desert of Middle East and tropics of East Africa). We tested for independent and interactive effects of host sex and body mass on the number of fleas harboured by an individual host while accounting for spatial clustering of host and parasite sampling and temporal variation. We found no consistent patterns of the effect of host sex and body mass on flea abundance either among species within a biome or among biomes. We found evidence for sex-biased flea infestation in just five host species (Apodemus agrarius, Myodes glareolus, Microtus arvalis, Gerbillus andersoni, Mastomys natalensis). In six rodent species, we found an effect of body mass on flea abundance (all species mentioned above and Meriones crassus). This effect was positive in five species and negative in one species (Microtus arvalis). In M. glareolus, G. andersoni, M. natalensis, and M. arvalis, the relationship between body mass and flea abundance was mediated by host sex. This was manifested in steeper change in flea abundance with increasing body mass in male than female individuals (M. glareolus, G. andersoni, M. natalensis), whereas the opposite pattern was found in M. arvalis. Our findings suggest that sex and body mass are common determinants of parasite infestation in mammalian hosts, but neither of them follows universal rules. This implies that the effect of host individual characteristics on mechanisms responsible for flea acquisition may be manifested differently in different host species. PMID- 23636460 TI - Predator faunas past and present: quantifying the influence of waterborne cues in divergent ecotypes of the isopod Asellus aquaticus. AB - Waterborne chemical cues are an important source of information for many aquatic organisms, in particular when assessing the current risk of predation. The ability to use chemical cues to detect and respond to potential predators before an actual encounter can improve prey chances of survival. We investigated predator recognition and the impact of chemical cues on predator avoidance in the freshwater isopod Asellus aquaticus. This isopod has recently colonised a novel habitat and diverged into two distinct ecotypes, which encounter different predator communities. Using laboratory-based choice experiments, we have quantified behavioural responses to chemical cues from predators typical of the two predator communities (larval dragonflies in the ancestral habitat, perch in the newly colonised habitat) in wild-caught and lab-reared Asellus of the two ecotypes. Individuals with prior experience of predators showed strong predator avoidance to cues from both predator types. Both ecotypes showed similar antipredator responses, but sexes differed in terms of threat-sensitive responses with males avoiding areas containing predator cues to a larger extent than females. Overall, chemical cues from fish elicited stronger predator avoidance than cues from larval dragonflies. Our results indicate that in these isopods, prior exposure to predators is needed to develop antipredator behaviour based on waterborne cues. Furthermore, the results emphasise the need to analyse predator avoidance in relation to waterborne cues in a sex-specific context, because of potential differences between males and females in terms of vulnerability and life history strategies. PMID- 23636461 TI - Home range size variation in a recovering wolf population: evaluating the effect of environmental, demographic, and social factors. AB - Home range size in mammals is a key ecological trait and an important parameter in conservation planning, and has been shown to be influenced by ecological, demographic and social factors in animal populations. Information on space requirements is especially important for carnivore species which range over very large areas and often come into direct conflict with human interest. We used long term telemetry-location data from a recovering wolf population in Scandinavia to investigate variation in home range size in relation to environmental and social characteristics of the different packs. Wolves showed considerable variation in home range size, which ranged from 259 to 1,676 km(2). Although wolf density increased fourfold during the study period, we found no evidence that intraspecific competition influenced range size. Local variation in moose density, which was the main prey for most packs, did not influence wolf home range size. Home ranges increased with latitude and elevation and decreased with increased roe deer density. Although prey biomass alone did not influence range size, our data suggest that there is a correlation between habitat characteristics, choice of prey species and possible hunting success, which currently combine to shape home range size in Scandinavian wolves. PMID- 23636463 TI - Coagulation potential of immobilised factor VIII in flow-dependent fibrin generation on platelet surfaces. AB - Coagulation factor VIII (FVIII) plays an essential role in haemostasis. To date, physiologic activity of FVIII circulating in the bloodstream (S-FVIII) is evaluated by classic coagulation assays. However, the functional relevance of FVIII (-von Willebrand factor complex) immobilised on thrombogenic surfaces (I FVIII) remains unclear. We used an in vitro perfusion chamber system to evaluate the function of I-FVIII in the process of mural thrombus formation under whole blood flow conditions. In perfusion of either control or synthetic haemophilic blood, the intra-thrombus fibrin generation on platelet surfaces significantly increased as a function of I-FVIII, independent of S-FVIII, under high shear rate conditions. This I-FVIII effect was unvarying regardless of anti-FVIII inhibitor levels in synthetic haemophilic blood. Thus, our results illustrate coagulation potentials of immobilised clotting factors, distinct from those in the bloodstream, under physiologic flow conditions and may give a clue for novel therapeutic approaches for haemophilic patients with anti-FVIII inhibitors. PMID- 23636462 TI - Extended leaf senescence promotes carbon gain and nutrient resorption: importance of maintaining winter photosynthesis in subtropical forests. AB - The relative advantages of being deciduous or evergreen in subtropical forests and the relationship between leaf phenology and nutrient resorption efficiency are not well understood. The most successful deciduous species (Lyonia ovalifolia) in an evergreen-dominated subtropical montane cloud forest in southwest (SW) China maintains red senescing leaves throughout much of the winter. The aim of this study was to investigate whether red senescing leaves of this species were able to assimilate carbon in winter, to infer the importance of maintaining a positive winter carbon balance in subtropical forests, and to test whether an extended leaf life span is associated with enhanced nutrient resorption and yearly carbon gain. The red senescing leaves of L. ovalifolia assimilated considerable carbon during part of the winter, resulting in a higher yearly carbon gain than co-occurring deciduous species. Its leaf N and P resorption efficiency was higher than for co-occurring non-anthocyanic deciduous species that dropped leaves in autumn, supporting the hypothesis that anthocyanin accumulation and/or extended leaf senescence help in nutrient resorption. Substantial winter carbon gain and efficient nutrient resorption may partially explain the success of L. ovalifolia versus that of the other deciduous species in this subtropical forest. The importance of maintaining a positive carbon balance for ecological success in this forest also provides indirect evidence for the dominance of evergreen species in the subtropical forests of SW China. PMID- 23636464 TI - Examining patient race and area predictors of inpatient admission for schizophrenia among hospital users in California. AB - According to international research African-Caribbean and Black African populations have increased risk of hospitalization for schizophrenia, compared to Whites. Less is known about admission risk for other racial-ethnic groups. This study investigated racial-ethnic differences in hospital admission for schizophrenia in California. It also investigated the influence of area social factors (racial-ethnic neighborhood composition, and per capita income) and health service factors (presence of primary care clinics). The study sample included individuals admitted to a California hospital during 1990-2005 with a primary appendicitis related diagnosis, and without a prior or concurrent indication of schizophrenia. The adjusted logistic model examined how patient racial-ethnicity (White, Black, Hispanic, Other), other personal, area social characteristics and presence of primary care clinics influenced hospital admissions for schizophrenia. Black individuals were almost twice as likely as Whites to be admitted while Hispanics and Other race individuals were less to be admitted. In addition, male sex, having more comorbidities and living in areas with greater proportions of non-Whites increased risk. The increased risk for Blacks compared to Whites was consistent with the existing literature. However, this is among the first studies to report that Hispanics had a reduced risk of admission for schizophrenia, compared to Whites. Future studies may want to include a broader range of health services to better understand patterns of care use among individuals with schizophrenia. PMID- 23636465 TI - Type 2 diabetes is associated with vertebral fractures in a sample of clinic- and hospital-based Latinos. AB - Latinos are the fastest growing ethnic population in the United States and type 2 diabetes is a major health burden in this population, but little effort has been made to study the prevalence of diabetic vertebral fragility in Latinos. We performed a cross-sectional study to determine vertebral fracture prevalence in a hospital-based population of South Texas residents (N = 296). We defined fractures in X-rays as a >20% reduction in vertebral body height. Numerous variables were recorded, including age, body mass index, indicators of diabetes management and others. 71% of the sample (N = 296) was Latino. The prevalence of vertebral fracture was increased in diabetic subjects relative to non-diabetic subjects (diabetic 27.9%, non-diabetic 13.8%) and, regardless of sex and diabetics status, decreased in Latinos relative to non-Latinos (Latino 16.7%, non Latino 26.4%). These data suggest that vertebral fractures may be a growing concern for diabetic Latinos as well as diabetics of any racial/ethnic background. PMID- 23636467 TI - The unusual effect of AgNO3 on the growth of Au nanostructures and their catalytic performance. AB - Au nanostructures attract much attention due to their potential applications in many fields. The controlled synthesis is critical to their properties modulation and applications. AgNO3-assisted synthesis is a widely used method for controllably preparing Au nanostructures in aqueous system. Herein, the effect of AgNO3 on the growth of Au nanostructures in polyol is studied. We observe an unusual effect that AgNO3 can induce the formation of pentatwinned Au nanostructures (nanorods and decahedra) and block the growth of Au nanorods. More interestingly, this blocking effect can be tuned through controlling the amount of AgNO3. A moderate amount of AgNO3 facilitates the formation of Au nanorods. A large amount of AgNO3 completely blocks the growth of nanorods and favors the formation of high quality decahedra (decahedra can be considered as nanorods with 0 nm longitudinal length). Besides, this blocking effect also allows preparation of different high-index-faceted Au nanobipyramids. These prepared Au nanostructures further serve as starting templates to fabricate other heterostructured Au/Ag nanomaterials, such as Ag-Au-Ag segmental nanorods, Au@Ag core-shelled nanostructures. The prepared nanostructures exhibit size- and structure-dependent catalytic performance in the reduction of p-nitrophenol to p aminophenol by sodium borohydride. PMID- 23636466 TI - Prefrontal/amygdalar system determines stress coping behavior through 5-HT/GABA connection. AB - Coping is defined as the behavioral and physiological effort made to master stressful situations. The ability to cope with stress leads either to healthy or to pathogenic outcomes. The medial prefrontal cortex (mpFC) and amygdala are acknowledged as having a major role in stress-related behaviors, and mpFC has a critical role in the regulation of amygdala-mediated arousal in response to emotionally salient stimuli. Prefrontal cortical serotonin (5-hydroxytryptamine (5-HT)) is involved in corticolimbic circuitry, and GABA has a major role in amygdala functioning. Here, using mice, it was assessed whether amygdalar GABA regulation by prefrontal 5-HT is involved in processing stressful experiences and in determining coping outcomes. First (experiment 1), bilateral selective 5-HT depletion in mpFC of mice reduced GABA release induced by stress in basolateral amygdala (BLA) and passive coping in the Forced Swimming Test (FST) (experiment 2). Moreover, prefrontal-amygdala disconnection procedure that combined a selective unilateral 5-HT depletion of mpFC and infusion of an inhibitor of GABA synthesis into the contralateral BLA, thereby to disrupt prefrontal-amygdalar serial connectivity bilaterally, showed that disconnection selectively decreases immobility in the FST. These results point to prefrontal/amygdala connectivity mediated by 5-HT and GABA transmission as a critical neural mechanism in stress induced behavior. PMID- 23636468 TI - Complete nucleotide sequence of a begomovirus associated with satellites molecules infecting a new host Tagetes patula in India. AB - In the year 2012 leaf curl disease was observed on Marigold (Tagetes patula) in Lakshmangrh, Sikar province of India. Affected plants were severely stunted with apical leaf curl and crinkled leaves, symptoms typical of begomovirus infection. This is the first report of complete nucleotide sequence of a begomovirus associated with satellites molecules infecting a new host Tagetes patula in India. PMID- 23636469 TI - Suppression of native defense mechanisms, SIRT1 and PPARgamma, by dietary glycoxidants precedes disease in adult humans; relevance to lifestyle-engendered chronic diseases. AB - SIRT1 and PPARgamma, host defenses regulating inflammation and metabolic functions, are suppressed under chronic high oxidant stress and inflammation (OS/Infl) conditions. In diabetes, dietary advanced glycation end products (dAGEs) cause OS/Infl and suppress SIRT1. Herein, we ask whether dAGEs also suppress host defense in adults without diabetes. The relationships between dAGEs and basal SIRT1 mRNA, PPARgamma protein levels in mononuclear cells (MNC) and circulating inflammatory/metabolic markers were examined in 67 healthy adults aged >60 years and in 18 subjects, before and after random assignment to either a standard diet (regular >15 AGE Eq/day) or an isocaloric AGE-restricted diet (<10 AGE Eq/day) for 4 months. Also, the interactions of AGEs and anti-AGE receptor-1 (AGER1) with SIRT1 and PPARgamma were assessed in wild type (WT) and AGER1 transduced (AGER1(+)) MNC-like THP-1 cells. We found that dAGE, but not caloric intake, correlated negatively with MNC SIRT1 mRNA levels and positively with circulating AGEs (sAGEs), OS/infl, MNC TNFalpha and RAGE. Basal MNC PPARgamma protein was also lower in consumers of regular vs. AGE-restricted diet. AGE restriction restored MNC SIRT1 and PPARgamma, and significantly decreased sAGEs, 8-isoprostanes, VCAM-1, MNC TNFalpha and RAGE. Model AGEs suppressed SIRT1 protein and activity, and PPARgamma protein in WT, but not in AGER1(+) cells in vitro. In conclusion, chronic consumption of high-AGE diets depletes defenses such as SIRT1 and PPARgamma, independent of calories, predisposing to OS/Infl and chronic metabolic disease. Restricted entry of oral AGEs may offer a disease prevention alternative for healthy adults. PMID- 23636472 TI - Influence of flow rate variation on the development of Escherichia coli biofilms. AB - This work investigates the effect of flow rate variation on mass transfer and on the development of Escherichia coli biofilms on a flow cell reactor under turbulent flow conditions. Computational fluid dynamics (CFD) was used to assess the applicability of this reactor for the simulation of industrial and biomedical biofilms and the numerical results were validated by streak photography. Two flow rates of 374 and 242 L h(-1) (corresponding to Reynolds numbers of 6,720 and 4,350) were tested and wall shear stresses between 0.183 and 0.511 Pa were predicted in the flow cell reactor. External mass transfer coefficients of 1.38 * 10(-5) and 9.64 * 10(-6) m s(-1) were obtained for the higher and lower flow rates, respectively. Biofilm formation was favored at the lowest flow rate because shear stress effects were more important than mass transfer limitations. This flow cell reactor generates wall shear stresses that are similar to those found in some industrial and biomedical settings, thus it is likely that the results obtained on this work can be used in the development of biofilm control strategies in both scenarios. PMID- 23636473 TI - A kinetic study on bacterial sulfate reduction. AB - The activity of anaerobic sulfate reduction was studied using sulfate-reducing bacteria isolated from the water produced from a Brazilian oil reservoir. The effects of the initial sulfate concentration on the anaerobic sulfate reduction and sulfide generation kinetics were investigated. The redox potential, the biomass solution content, and the sulfate and the sulfide solution content were measured. The results indicate that the sulfate conversion and the sulfide generation are both first-order processes for the initial sulfate concentration of 823, 1,282, and 1,790 mg/L. The results for the kinetic constants for the sulfate conversion indicate an inhibition with the enhancement of the initial sulfate solution content. The kinetic constants for the sulfide generation indicate that this reaction is almost independent of the initial sulfate solution content due to the presence of at least two in-series processes that are faster than the microbial conversion of the sulfate. The kinetic test using the water from an onshore oil field, with an initial sulfide content of 228 mg/L and sulfate content of 947 mg/L, shows a sulfate conversion of 50 % in 528 h. The kinetic modeling for the net content of sulfate and sulfide indicates that the sulfate conversion is slower for this water than for the deionized water tests; however, the sulfide formation has almost the same conversion velocity. The reactions are first order in both cases. PMID- 23636471 TI - Mathematical model of the role of degradation on matrix development in hydrogel scaffold. AB - Despite tremendous advances in the field of tissue engineering, a number of obstacles are still hindering its successful translation to the clinic. One of these challenges has been to design cell-laden scaffolds that can provide an appropriate environment for cells to successfully synthesize new tissue while providing a mechanical support that can resist physiological loads at the early stage of in situ implementation. A solution to this problem has been to balance tissue growth and scaffold degradation by creating new hydrogel systems that possess both hydrolytic and enzymatic degradation behaviors. Very little is known, however, about the complex behavior of these systems, emphasizing the need for a rigorous mathematical approach that can eventually assist and guide experimental advances. This paper introduces a mathematical and numerical formulation based on mixture theory, to describe the degradation, swelling, and transport of extracellular matrix (ECM) molecules released by cartilage cells (chondrocytes) within a hydrogel scaffold. The model particularly investigates the relative roles of hydrolytic and enzymatic degradations on ECM diffusion and their impacts on two important outcomes: the extent of ECM transport (and deposition) and the evolution of the scaffold's mechanical integrity. Numerical results based on finite element show that if properly tuned, enzymatic degradation differs from hydrolytic degradation in that it can create a degradation front that is key to maintaining scaffold stiffness while allowing ECM deposition. These results therefore suggest a hydrogel design that could enable successful in situ cartilage tissue engineering. PMID- 23636474 TI - Photo-patternable electroluminescence based on one-way photoisomerization reaction of tetraoxidized triangle terarylenes. AB - Oxidized triangle terarylenes with asymmetric side-aryl units are synthesized, which show photo-induced turn-on yellow luminescence based on photochemical intramolecular ring-cyclization reaction in the solid state. A direct photo patterning process for organic electroluminescent devices is successfully demonstrated with selective light irradiation through an appropriate mask pattern. PMID- 23636476 TI - Postpartum depression symptoms associated with Val158Met COMT polymorphism. PMID- 23636475 TI - Evolution of the ABPA subunit of androgen-binding protein expressed in the submaxillary glands in New and Old World rodent taxa. AB - The salivary androgen-binding proteins (ABPs) are members of the secretoglobin gene family present in mammals. Each ABP is a heterodimer assembled as an ABPA subunit encoded by an Abpa gene and linked by disulfide bridges to an ABPBG subunit encoded by an Abpbg gene. The ABP dimers are secreted into the saliva of mice and then transferred to the pelage after grooming and subsequently to the environment allowing an animal to mark territory with a biochemical signal. The putative role of the mouse salivary ABPs is that of pheromones mediating mate selection resulting in assortative mating in the Mus musculus species complex. We focused on comparing patterns of molecular evolution between the Abpa genes expressed in the submaxillary glands of species of New World and Old World muroids. We found that in both sets of rodents the Abpa genes expressed in the submaxillary glands appear to be evolving under a similar evolutionary regime, with relatively high nonsynonymous substitution rates, suggesting that ABP might play a similar biological role in both systems. Thus, ABP could be involved with mate recognition and species isolation in New World as well as Old World muroids. PMID- 23636477 TI - Parenteral anticoagulants in heart disease: current status and perspectives (Section II). Position paper of the ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease. AB - Anticoagulants are a mainstay of cardiovascular therapy, and parenteral anticoagulants have widespread use in cardiology, especially in acute situations. Parenteral anticoagulants include unfractionated heparin, low-molecular-weight heparins, the synthetic pentasaccharides fondaparinux, idraparinux and idrabiotaparinux, and parenteral direct thrombin inhibitors. The several shortcomings of unfractionated heparin and of low-molecular-weight heparins have prompted the development of the other newer agents. Here we review the mechanisms of action, pharmacological properties and side effects of parenteral anticoagulants used in the management of coronary heart disease treated with or without percutaneous coronary interventions, cardioversion for atrial fibrillation, and prosthetic heart valves and valve repair. Using an evidence based approach, we describe the results of completed clinical trials, highlight ongoing research with currently available agents, and recommend therapeutic options for specific heart diseases. PMID- 23636478 TI - Transient pseudothrombocytopenia associated with immune heparin-induced thrombocytopenia complicated by pulmonary embolism. PMID- 23636479 TI - Hazard of CO2 laser-induced airway fire in laryngeal surgery: experimental data of contributing factors. AB - In carbon dioxide (CO2) laser surgery of the larynx, the potentially dangerous combination of laser-induced heat in an oxygen-enriched atmosphere typically occurs when jet ventilation is used or due to an insufficiently blocked endotracheal tube. Until now, no limitations for safe oxygen concentrations or laser intervals have been established. The aim of this study was to investigate and quantify the factors that may contribute to an airway fire in laryngeal laser surgery. Fat, muscle and cartilage were irradiated with a CO2 laser at 2, 4, 6 and 8 W in five different oxygen concentrations with and without smoke exhaustion. The time to ignition was recorded for each different experimental setup. Fat burnt fastest, followed by cartilage and muscle. The elevation of laser energy or oxygen concentration reduced the time to inflammation of any tissue. The elevation of oxygen by 10 % increases the risk of inflammation more than the elevation of laser power by 2 W. Under smoke exhaustion, inflammation and burning occurred delayed or were even inhibited at lower oxygen concentrations. Lasing in more than 50 % oxygen is comparatively dangerous and can cause airway fire in less than 5 s, especially when laser energies of more than 5 W are applied. In equal or lower than 50 % oxygen, an irradiation interval of 5 s can be considered a comparatively safe time limit to prevent inflammation in laryngeal laser surgery. Smoke exhaustion should always be applied. PMID- 23636480 TI - Ex vivo water exchange performance and short-term clinical feasibility assessment of newly developed heat and moisture exchangers for pulmonary rehabilitation after total laryngectomy. AB - Laryngectomized patients suffer from respiratory complaints due to insufficient warming and humidification of inspired air in the upper respiratory tract. Improvement of pulmonary humidification with significant reduction of pulmonary complaints is achieved by the application of a heat and moisture exchanger (HME) over the tracheostoma. The aim of this study was to determine whether the new Provox HMEs (XM-HME and XF-HME) have a better water exchange performance than their predecessors (R-HME and L-HME, respectively; Atos Medical, Horby, Sweden). The other aim was to assess the short-term clinical feasibility of these HMEs. The XM-HME and XF-HME were weighed at the end of inspiration and at the end of expiration at different breathing volumes produced by a healthy volunteer. The associations between weight changes, breathing volume and absolute humidity were determined using both linear and non-linear mixed effects models. Study-specific questionnaires and tally sheets were used in the clinical feasibility study. The weight change of the XM-HME is 3.6 mg, this is significantly higher than that of the R-HME (2.0 mg). The weight change of the XF-HME (2.0 mg) was not significantly higher than that of the L-HME (1.8 mg). The absolute humidity values of both XM- and XF-HME were significantly higher than that of their predecessors. The clinical feasibility study did not reveal any practical problems over the course of 3 weeks. The XM-HME has a significantly better water exchange performance than its predecessor (R-HME). Both newly designed HMEs did succeed in the clinical feasibility study. PMID- 23636482 TI - Do shade-grown coffee plantations pose a disease risk for wild birds? AB - Shade-grown coffee plantations are often promoted as a conservation strategy for wild birds. However, these agro-ecosystems are actively managed for food production, which may alter bird behaviors or interactions that could change bird health, compared to natural forest. To examine whether there is a difference between the health parameters of wild birds inhabiting shade-grown coffee plantations and natural forest, we evaluated birds in Costa Rica for (1) their general body condition, (2) antibodies to pathogens, (paramyxovirus and Mycoplasma spp.), and (3) the prevalence and diversity of endo-, ecto-, and hemoparasites. We measured exposure to Mycoplasma spp. and paramyxovirus because these are pathogens that could have been introduced with domestic poultry, one mechanism by which these landscapes could be detrimental to wild birds. We captured 1,561 birds representing 75 species. Although seasonal factors influenced body condition, we did not find bird general body condition to be different. A total of 556 birds of 31 species were tested for antibodies against paramyxovirus-1. Of these, five birds tested positive, four of which were from shade coffee. Out of 461 other tests for pathogens (for antibodies and nucleotide detection), none were positive. Pterolichus obtusus, the feather mite of chickens, was found on 15 birds representing two species and all were from shade coffee plantations. Larvated eggs of Syngamus trachea, a nematode typically associated with chickens, were found in four birds captured in shade coffee and one captured in forest. For hemoparasites, a total of 1,121 blood smears from 68 bird species were examined, and only one species showed a higher prevalence of infection in shade coffee. Our results indicate that shade-coffee plantations do not pose a significant health risk to forest birds, but at least two groups of pathogens may deserve further attention: Haemoproteus spp. and the diversity and identity of endoparasites. PMID- 23636487 TI - Abstracts of the American Conference on Pharmacometrics 2013. May 12-15, 2013. Fort Lauderdale, Florida, USA. PMID- 23636488 TI - Coordination and extraction of mercury(II) with an ionic liquid-based thione extractant. AB - A neutral thione extractant, 1,3-diethylimidazole-2-thione (C2C2ImT), was prepared from an ionic liquid (IL), 1,3-diethylimidazolium acetate, and used within a hydrophobic ionic liquid, 1-ethyl-3-methylimidazolium bis(trifluoromethane)sulfonamide ([C2mim][NTf2]), to extract Hg(II) from aqueous solutions of HgCl2 or Hg(OAc)2. Investigations of the extraction mechanism, spectroscopic analyses of the extracted species, and crystallographic studies of the interactions of C2C2ImT with Hg(II) are reported, including the first structurally characterized Hg-NTf2 coordination compound, Hg(C2C2ImT)2(NTf2)2. Coordination complexes of the thione ligand with Hg(II) show variability in coordination numbers and geometries with stoichiometry, suggesting that the extraction mechanism is dependent on the speciation of mercury in aqueous solution. HgCl2 can form neutral, extractable complexes with the thione in aqueous solution. Hg(OAc)2 dissociates on dissolution in water and Hg(II) is extracted through a cation exchange mechanism involving [Hg(C2C2ImT)2](2+) ions. The precipitation of neutral mercury complexes from the IL following the extraction of excess mercury suggests a simple and unusual way to recycle the IL. PMID- 23636484 TI - Increase in antimicrobial resistance in bacteria isolated from stranded marine mammals of the Northwest Atlantic. AB - Studies on marine mammals can inform our understanding of the environmental health of the ocean. To evaluate the potential for changes in antimicrobial resistance, we analyzed a database spanning 2004-2010 that consisted of bacterial isolate identity and antimicrobial sensitivity for stranded pinnipeds in the Northwest Atlantic. Samples (n = 170) from treated animals yielded 310 bacterial isolates representing 24 taxa. We evaluated changes in antimicrobial class resistance from 2004 to 2010 for eight taxa. Escherichia coli displayed a significant increase in resistance to several antimicrobial classes. Other taxa displayed significant increases in resistance to aminoglycosides, and/or fluoroquinolones. In addition, we observed a significant increase in multiple antimicrobial resistance in cultures from untreated animals. These results demonstrate an increase in resistance among common bacterial pathogens of marine mammals over a time span of 6 years. PMID- 23636489 TI - Dual-tracer PET using generalized factor analysis of dynamic sequences. AB - PURPOSE: With single-photon emission computed tomography, simultaneous imaging of two physiological processes relies on discrimination of the energy of the emitted gamma rays, whereas the application of dual-tracer imaging to positron emission tomography (PET) imaging has been limited by the characteristic 511-keV emissions. PROCEDURES: To address this limitation, we developed a novel approach based on generalized factor analysis of dynamic sequences (GFADS) that exploits spatio-temporal differences between radiotracers and applied it to near simultaneous imaging of 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) (brain metabolism) and (11)C-raclopride (D2) with simulated human data and experimental rhesus monkey data. We show theoretically and verify by simulation and measurement that GFADS can separate FDG and raclopride measurements that are made nearly simultaneously. RESULTS: The theoretical development shows that GFADS can decompose the studies at several levels: (1) It decomposes the FDG and raclopride study so that they can be analyzed as though they were obtained separately. (2) If additional physiologic/anatomic constraints can be imposed, further decomposition is possible. (3) For the example of raclopride, specific and nonspecific binding can be determined on a pixel-by-pixel basis. We found good agreement between the estimated GFADS factors and the simulated ground truth time activity curves (TACs), and between the GFADS factor images and the corresponding ground truth activity distributions with errors less than 7.3 +/- 1.3 %. Biases in estimation of specific D2 binding and relative metabolism activity were within 5.9 +/- 3.6 % compared to the ground truth values. We also evaluated our approach in simultaneous dual-isotope brain PET studies in a rhesus monkey and obtained accuracy of better than 6 % in a mid-striatal volume, for striatal activity estimation. CONCLUSIONS: Dynamic image sequences acquired following near simultaneous injection of two PET radiopharmaceuticals can be separated into components based on the differences in the kinetics, provided their kinetic behaviors are distinct. PMID- 23636490 TI - Comparison of (18)F-labeled CXCR4 antagonist peptides for PET imaging of CXCR4 expression. AB - PURPOSE: CXCR4 is overexpressed on tumor cells from many types of human cancers. A high level of CXCR4 expression often correlates with poor prognosis, chemotherapy resistance, and metastasis. The development of CXCR4-specific radiotracers for positron emission tomography (PET) imaging will allow in vivo evaluation of receptor expression level for diagnosis or therapeutic evaluation. PROCEDURES: Two new (18)F-labeled radiotracers based on an Ac-TC14012 peptide, [(18)F]FP-Ac-TC14012 and [(18)F]FB-Ac-TC14012, were synthesized and characterized. The affinities of the 2-fluoropropionate (FP)-conjugated or 4 fluorobenzoate (FB)-conjugated peptides to CXCR4-transfected Chinese hamster ovarian (CHO) cells were evaluated in a competitive binding assay with [(125)I]CXCL12 radioligand. The cell uptake and retention of [(18)F]FP-labeled and [(18)F]FB-labeled peptides were measured. The tumor targetability and pharmacokinetics of these two tracers were also evaluated by microPET imaging and biodistribution studies. RESULTS: The labeled peptides retained high binding affinity to CXCR4 and showed much higher uptake in CXCR4-positive CHO cells than in CXCR4-negative cells in vitro. The smaller and more hydrophilic [(18)F]FP prosthetic group resulted in higher affinity and lower nonspecific cell uptake compared to the [(18)F]FB-labeled peptide. Both radiotracers showed much higher accumulation in CXCR4-positive than CXCR4-negative tumor xenografts in mice and allowed clear visualization of CXCR4 expression by PET. Among the two, [(18)F]FP Ac-TC14012 showed higher tumor uptake and better tumor-to-background contrast. Unlike their N-terminal 4-F-benzoate analogs, these two tracers had minimal blood retention, likely due to reduced red blood cell binding. Metabolic organs, such as the liver and kidney, also showed high uptake. When blocked with low-dose cold peptide (10 MUg), the tumor uptake was significantly increased, most likely due to the increased concentration in blood circulation, as evidenced by decreased liver uptake. CONCLUSION: These results demonstrate that the [(18)F]FP-labeled Ac TC14012 peptide with high tumor uptake, low nonspecific binding, and good tumor to-background contrast promises [(18)F]FP-Ac-TC14012 as a PET tracer for in vivo PET imaging of CXCR4 expression. PMID- 23636492 TI - Vertical distribution of ammonia-oxidizing archaea and bacteria in sediments of a eutrophic lake. AB - In order to characterize the vertical variation of abundance and community composition of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) in sediments of a eutrophic lake, Lake Taihu, molecular techniques including real-time PCR, clone library, and sequencing were carried out in this study. Abundances of archaeal amoA gene (ranged from 2.34 * 10(6) to 4.43 * 10(7) copies [g dry sediment](-1)) were higher than those of bacterial amoA gene (ranged from 5.02 * 10(4) to 6.91 * 10(6) copies [g dry sediment](-1)) for all samples and both of them exhibited negative correlations with the increased depths. Diversities of archaeal and bacterial amoA gene increased with the elevated depths. There were no significant variations of AOB community structures derived from different sediment depths, whereas obvious differences were observed for the AOA community compositions. The information acquired in this study would be useful to elucidate the roles of AOA and AOB in the nitrogen cycling of freshwater ecosystems. PMID- 23636493 TI - The effect of growth temperature on the pathogenicity of Campylobacter. AB - Control of Campylobacter in the food chain requires a better understanding of the behaviour of the bacteria in relevant environments. Campylobacter species are largely non-pathogenic in poultry, the body temperature of which is 42 degrees C. However, the bacteria are highly pathogenic in humans whose body temperature is 37 degrees C. The aim of this study was to examine if switching from commensal to pathogenic behaviour was related to temperature. We examined the growth, motility and invasion of T84 cells by three species of Campylobacter: C. jejuni 81116, C. jejuni M1, C. coli 1669, C. coli RM2228 and C. fetus fetus NC10842 grown at 37 and 42 degrees C. Our results suggest that C. jejuni isolates grow similarly at both temperatures but some are more motile at 42 degrees C and some are more invasive at 37 degrees C, which may account for its rapid spread in poultry flocks and for infection in humans, respectively. C. coli, which are infrequent causes of Campylobacter infections in humans, is less able to grow and move at 37 degrees C compared to 42 degrees C but was significantly more invasive at the lower temperature. C. fetus fetus, which is infrequently found in poultry, is less able to grow and invade at 42 degrees C. PMID- 23636494 TI - Use of pyrosequencing to characterize the microbiota in the ileum of goats fed with increasing proportion of dietary grain. AB - This study evaluated the effects of an increasing proportion of dietary grain on changes in bacterial populations in the goat ileum. Nine ruminally fistulated, castrated male goats were assigned to three diets in a completely randomized design. Goats were fed three different dietary treatments containing different proportions of corn grain (0, 25, and 50 %). The pH of the ileal contents and rumen fluid (P = 0.015) linearly decreased (P < 0.001), and the acetate, propionate, butyrate, and total volatile fatty acid in ileal contents increased (P < 0.05) with increases in dietary corn, and similar results were also observed in rumen fluid. The barcoded DNA pyrosequencing method was used to reveal 8 phyla, 70 genera, and 1,693 16S operational taxonomic units (OTUs). At the genus level, the proportions of Acetitomaculum, Enterococcus, Atopobium, unclassified Coriobacteriaceae, and unclassified Planctomycetaceae were linearly decreased (P < 0.05) with increases in corn grain. At the species level, high grain feeding linearly decreased the percentage of OTU8686 (unclassified Bacteria) (P = 0.004). To the best of our knowledge, this is the first study using barcoded DNA pyrosequencing method to survey the ileal microbiome of goats and the results suggest that increasing levels of dietary corn change the composition of the ileal bacterial community. These findings provide previously unknown information about the ileal microbiota of goats and a new understanding of the ileal microbial ecology, which may be useful in modulating the gut microbiome. PMID- 23636495 TI - Composition of heterotrophic flagellates in coastal waters of different trophic status. AB - Heterotrophic flagellates (HFs) are important members of the aquatic microbial food web. However, information on their spatial patterns in relation to eutrophication is limited. Here, we examined the composition and spatial distributions of HFs (<3 MUm) in subtropical coastal waters of different trophic status by re-analyzing two previously published small subunit rDNA pyrosequence datasets using information from the newly launched Protist Ribosomal Reference database (PR(2)). Whereas the contributions of different major clades composing the Marine Stramenopiles (MASTs), picobiliphytes and Chrysophyceae were found relatively comparable between the stations, contrasting compositions of the Marine Alveolates (MALV) groups I and II were observed. The high and relatively stable contribution of MAST-1, -3 and -7 among the MASTs in both stations suggest their importance as bacterial grazers in coastal waters, irrespective of trophic status. By contrast, the dominance of clades 3, 5 and 14 of MALV II in the eutrophic station implies their importance in regulating the dinoflagellate population at the site. Our study provides insights into the ecological importance of different HF groups in eutrophic coastal ecosystems. PMID- 23636497 TI - Protein metabolism: Quality control at the ribosome. PMID- 23636496 TI - Yeast diversity isolated from grape musts during spontaneous fermentation from a Brazilian winery. AB - Saccharomyces and non-Saccharomyces yeast species from a winery located in Brazil were identified by ribosomal gene-sequencing analysis. A total of 130 yeast strains were isolated from grape surfaces and musts during alcoholic fermentation from Isabel, Bordeaux, and Cabernet Sauvignon varieties. Samples were submitted to PCR-RFLP analysis and genomic sequencing. Thirteen species were identified: Candida quercitrusa, Candida stellata, Cryptococcus flavescens, Cryptococcus laurentii, Hanseniaspora uvarum, Issatchenkia occidentalis, Issatchenkia orientalis, Issatchenkia terricola, Pichia kluyveri, Pichia guilliermondii, Pichia sp., Saccharomyces cerevisiae, and Sporidiobolus pararoseus. A sequential substitution of species during the different stages of fermentation, with a dominance of non-Saccharomyces yeasts at the beginning, and a successive replacement of species by S. cerevisiae strains at the final steps were observed. This is the first report about the yeast distribution present throughout the alcoholic fermentation in a Brazilian winery, providing supportive information for future studies on their contribution to wine quality. PMID- 23636498 TI - Signalling change: signal transduction through the decades. AB - The past few years have marked significant anniversaries in signal transduction, including the identification of classic growth factors and morphogens, the notion of protein modification through phosphorylation and the characterization of protein interaction domains. Here, six researchers reflect on the context in which these discoveries were made, and how our concept of cell signalling has evolved during the past three decades. PMID- 23636499 TI - Variations in the physicochemical characteristics of the Buffalo River in the Eastern Cape Province of South Africa. AB - The physicochemical characteristics of the Buffalo River in the Eastern Cape Province of South Africa were evaluated using standard methods. The assessment was carried out with total of 72 water samples collected from six sites over a 12 month period, from August 2010 to July 2011. Water temperature ranged from 11 to 28 degrees C, while pH varied from 6.6 to 10.7 and turbidity from 1.7 to 133 NTU. Electrical conductivity, total dissolved solids (TDS) and salinity showed drastic variations (42.3-46,693 MUS/cm, 20.3-23,350 mg/l and 0.02-33.8 PSU, respectively) and the significantly (P < 0.05) higher mean values of these parameters recorded at Parkside reflect the influence of seawater at the Buffalo River estuary. The concentrations of other parameters ranged as follows: chloride (3.7-168 mg/l), DO (6.9-11.1), BOD (0.6-9.4), COD (3.7-45.9), nitrite-nitrogen (0.02-0.21), nitrate-nitrogen (1-4.47) and orthophosphate (0.01-1.72). There was a significant positive correlation between water temperature and DO (r = 0.200; P < 0.01). Significant (P < 0.01) positive correlations also existed between TDS and salinity (r = 0.921), COD and each of salinity (r = 0.398), TDS (r = 0.375) and chloride (r = 0.330), nitrate and phosphate (r = 0.323) and BOD and turbidity (r = 0.290). Significant (p < 0.01) inverse relationships existed between DO and each of phosphate (r = -0.295) and nitrate (r = -0.168). We conclude that the Buffalo River water quality deteriorated in the plains, compared with the upper reaches. Urgent measures are needed to safeguard the river in view of the potential health concerns as many households rely solely on the untreated river water. PMID- 23636500 TI - Characterization of the monthly variation in (1 -> 3)-beta-D-glucan concentrations in university laboratories. AB - We characterize the monthly variation in (1 -> 3)-beta-D-glucan concentration measured over the course of 1 year, and we evaluate the characteristics of size selection using a two-stage cyclone sampler. The (1 -> 3)-beta-D-glucan concentrations were measured in four bio-related laboratories. A total of 156 samples were collected using a new two-stage cyclone sampler. Analysis of (1 -> 3)-beta-D-glucan was performed using the kinetic Limulus amebocyte lysate assay. The study showed that airborne (1 -> 3)-beta-D-glucan concentrations were significantly higher in laboratory D (mean +/- SD 1,105 +/- 1,893 pg/m(3)) and in the spring (5,458 pg/m(3)). The highest concentration of (1 -> 3)-beta-D-glucan occurred in the spring, particularly in May. PMID- 23636501 TI - Distribution and sources of organochlorine pesticides in sediments of the Xiangjiang River, south-central China. AB - The Xiangjiang River (XR), the second largest tributary of the Yangtze River, is mainly located in Hunan province in south-central China. Nineteen surface sediment samples (the top 3-cm layer) collected from XR were analyzed to determine the concentrations, distribution, sources, and ecological risk of organochlorine pesticides (OCPs). The concentrations of OCPs were 3.0-29.8 ng/g (dry weight) with a mean of 12.6 +/- 7.7 ng/g. The widely detected compounds included HCHs, DDTs, HCB, and dieldrin. Overall, the dominant OCPs in the sediments were mainly composed of residual and degradation products, e.g., beta HCH with a mean of 42.2% in HCHs and p,p'-DDE with a mean of 43.5% in DDTs, implying that OCPs in the sediments had suffered from long-term aging without fresh inputs in XR. However, there was a high proportion of p,p'-DDT to DDTs in three sites, suggesting that there was use of technical DDT from their surrounding areas at present. The ratios of alpha-HCH/gamma-HCH and p,p'-DDD + p,p'-DDE/DDTs increase from the upper reaches to the lower reaches of XR, suggesting sediments enriched with alpha-HCH and metabolites DDD and DDE during sediment transport process and could be attributed to the transformation of gamma HCH to alpha-HCH and DDT to DDE or DDD. The assessment of the ecological risk indicates that the OCPs in the sediments of XR have a moderate adverse biological effect on organisms. PMID- 23636502 TI - Process parameters for decolorization and biodegradation of orange II (Acid Orange 7) in dye-simulated minimal salt medium and subsequent textile effluent treatment by Bacillus cereus (MTCC 9777) RMLAU1. AB - In this study, Bacillus cereus isolate from tannery effluent was employed for orange II dye decolorization in simulated minimal salt broth and textile effluent. Most of the physicochemical parameters of textile effluent were above the permissible limits. The strain was highly tolerant to dye up to 500 mg l(-1). Increasing dye concentration exerted inhibitory effect on the bacterial growth and decolorization. The maximum decolorization of initial 100 mg dye l(-1) was achieved at optimum pH 8.0 and 33 degrees C under static culture conditions during 96-h incubation. Supplementation with optimized glucose (0.4%, w/v) and ammonium sulfate (0.1%, w/v) with 3.0% B. cereus inoculum further enhanced dye decolorization to highest 68.5% within 96-h incubation. A direct correlation was evident between bacterial growth and dye decolorization. Under above optimized conditions, 24.3% decolorization of unsterilized real textile effluent by native microflora was achieved. The effluent decolorization enhanced substantially to 37.1% with B. cereus augmentation and to 40.5% when supplemented with glucose and ammonium sulfate without augmentation. The maximum decolorization of 52.5% occurred when textile effluent was supplemented with optimized exogenous carbon and nitrogen sources along with B. cereus augmentation. Gas chromatography-mass spectrometry identified sulfanilic acid as orange II degradation product. Fourier transform infra red spectroscopy of metabolic products indicated the presence of amino and hydroxyl functional groups. This strain may be suitably employed for in situ decolorization of textile industrial effluent under broad environmental conditions. PMID- 23636503 TI - Humus characteristics and seasonal changes of soil arthropod communities in a natural sessile oak (Quercus petraea L.) stand and adjacent Austrian pine (Pinus nigra Arnold) plantation. AB - In order to assess the effects of conversion of natural stands into plantations, soil invertebrate micro- and macroarthropod communities were evaluated for their abundance and richness in a sessile oak (SO; Quercus petraea L.) stand and adjacent Austrian pine (AP; Pinus nigra Arnold) plantation. Sites were sampled four times a year in 3-month intervals from May 2009 to February 2010. Humus characteristics such as total mass; carbon, lignin, and cellulose contents; and C/N ratio were significantly different between SO and AP. Statistically significant differences were detected on soil pH, carbon and nitrogen contents, and electrical conductivity between the two sites. The number of microarthropods was higher in AP than in the SO site. The annual mean abundance values of microarthropods in a square meter were 67,763 in AP and 50,542 in SO, and the annual mean abundance values of macroarthropods were 921 m(-2) in AP and 427 m( 2) in SO. Among the soil microarthropods, Acari and Collembola were the dominant groups. Shannon's diversity index was more affected by evenness than species number despite the species diversity (H') of soil arthropods being generally higher in the SO stand. The abundance of microarthropods showed clear seasonal trends depending upon the humidity of the soil. PMID- 23636504 TI - Nanofibrous patterns by direct electrospinning of nanofibers onto topographically structured non-conductive substrates. AB - Patterning of electrospun nanofibers has recently attracted much attention for its usefulness in a wide range of applications. This paper reports on the generation of spatially defined nanofibrous patterns by direct deposition of electrospun nanofibers onto a variety of insulating substrates. It was found that topographical features of different non-conducting substrates could be readily replicated by the electrospun nanofibers of interest. To elucidate the underlying mechanism of nanofiber patterning, we have systematically studied the effects of surface topography of non-conducting substrates (in particular protrusions) on the nanofiber deposition and assembly. Results from experiments and electric field simulation indicated that under a strong electric field the insulating substrates can be polarized, which could consequently affect the distribution of the original electric field. For particular non-conductive substrates with small mesh sizes or sufficient thickness, surface topography of the dielectric substrate may play a key role in determining the deposition and the arrangement of electrospun fibers. In addition, parameters that could influence the fineness of nanofibrous patterns have also been investigated. This contribution is believed to warrant further scientific understanding of the patterning mechanism of electrospun nanofibers, and to allow for design of specific and complex non conductive substrate collectors for easy generation of patterned nanofibrous architectures, applicable in a variety of areas such as tissue engineering scaffolds and optoelectronic displays. PMID- 23636505 TI - Improvement of the boron neutron capture therapy (BNCT) by the previous administration of the histone deacetylase inhibitor sodium butyrate for the treatment of thyroid carcinoma. AB - We have shown that boron neutron capture therapy (BNCT) could be an alternative for the treatment of poorly differentiated thyroid carcinoma (PDTC). Histone deacetylase inhibitors (HDACI) like sodium butyrate (NaB) cause hyperacetylation of histone proteins and show capacity to increase the gamma irradiation effect. The purpose of these studies was to investigate the use of the NaB as a radiosensitizer of the BNCT for PDTC. Follicular thyroid carcinoma cells (WRO) and rat thyroid epithelial cells (FRTL-5) were incubated with 1 mM NaB and then treated with boronophenylalanine 10BPA (10 MUg 10B ml-1) + neutrons, or with 2, 4 bis (alpha,beta-dihydroxyethyl)-deutero-porphyrin IX 10BOPP (10 MUg 10B ml-1) + neutrons, or with a neutron beam alone. The cells were irradiated in the thermal column facility of the RA-3 reactor (flux = (1.0 +/- 0.1) * 1010 n cm-2 s-1). Cell survival decreased as a function of the physical absorbed dose in both cell lines. Moreover, the addition of NaB decreased cell survival (p < 0.05) in WRO cells incubated with both boron compounds. NaB increased the percentage of necrotic and apoptotic cells in both BNCT groups (p < 0.05). An accumulation of cells in G2/M phase at 24 h was observed for all the irradiated groups and the addition of NaB increased this percentage. Biodistribution studies of BPA (350 mg kg-1 body weight) 24 h after NaB injection were performed. The in vivo studies showed that NaB treatment increases the amount of boron in the tumor at 2-h post BPA injection (p < 0.01). We conclude that NaB could be used as a radiosensitizer for the treatment of thyroid carcinoma by BNCT. PMID- 23636506 TI - A secular increase in BMD in Chinese women. AB - Population-based studies have revealed a decline in the incidence of age-adjusted hip fractures in southern Chinese women during the past decade. To determine whether there was a secular change in population characteristics that accounted for this decline, we compared the bone mineral density (BMD) and lifestyle habits of two cohorts of women who were more than 50 years of age and who were recruited from 1995 to 2000 and 2005 to 2010. The BMD levels in the 2005-2010 cohort were significantly higher at the spine and hip and ranged from 3.6 to 17.8% among the different age groups. Additionally, a significantly lower prevalence of subjects with osteoporosis and osteopenia was observed. Longer reproductive years, higher levels of physical activity, higher estradiol and 25(OH) vitamin D levels, and lower alkaline phosphatase levels were found in the 2005-2010 cohort. After adjusting for bone-determining factors, significant differences were detected in the BMD levels at the lumbar spine, femoral neck, and total hip (4.17, 9.02, and 9.34%, respectively) in women >50 years of age but not in women <=50 years of age. The secular increase in BMD and healthier lifestyles most likely led to the decline in the incidence of age-adjusted fractures. PMID- 23636507 TI - Cannabinoid receptor 1 inhibition improves cardiac function and remodelling after myocardial infarction and in experimental metabolic syndrome. AB - The cannabinoid receptors, CB1 and CB2, are expressed in the heart, but their role under pathological conditions remains controversial. This study examined the effect of CB1 receptor blockade on cardiovascular functions after experimental MI and in experimental metabolic syndrome. MI was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with the CB1 receptor antagonist rimonabant (10 mg/kg i.p. daily) started 7 days before or 6 h after MI and continued for 6 weeks. Haemodynamic parameters were measured via echocardiography and intracardiac Samba catheter. CB1 blockade improved systolic and diastolic heart function, decreased cardiac collagen and hydroxyproline content and down-regulated TGF-beta1. Additionally, rimonabant decreased arterial stiffness, normalised QRS complex duration and reduced brain natriuretic peptide levels in serum. In primary cardiac fibroblasts, rimonabant decreased MMP-9 activity and TGF-beta1 expression. Furthermore, rimonabant improved depressed systolic function of spontaneously hypertensive obese rats and reduced weight gain. Blocking of CB1 receptor with rimonabant improves cardiac functions in the early and late stages after MI, decreases arterial stiffness and reduces cardiac remodelling. Rimonabant also has cardioprotective actions in rats characterised by the metabolic syndrome. Inhibition of proteolysis and TGF-beta1 expression and reduced collagen content by rimonabant may attenuate destruction of the extracellular matrix and decrease fibrosis after MI. PMID- 23636508 TI - The enzymatic activity of the VEGFR2 receptor for the biosynthesis of dinucleoside polyphosphates. AB - The group of dinucleoside polyphosphates encompasses a large number of molecules consisting of two nucleosides which are connected by a phosphate chain of variable length. While the receptors activated by dinucleoside polyphosphates as well as their degradation have been studied in detail, its biosynthesis has not been elucidated so far. Since endothelial cells released the dinucleoside polyphosphate uridine adenosine tetraphosphate (Up4A), we tested cytosolic proteins of human endothelial cells obtained from dermal vessels elicited for enzymatic activity. When incubated with ADP and UDP, these cells showed increasing concentrations of Up4A. The underlying enzyme was isolated by chromatography and the mass spectrometric analysis revealed that the enzymatic activity was caused by the vascular endothelial growth factor receptor 2 (VEGFR2). Since VEGFR2 but neither VEGFR1 nor VEGFR3 were capable to synthesise dinucleoside polyphosphates, Tyr-1175 of VEGFR2 is most likely essential for the enzymatic activity of interest. Further, VEGFR2-containing cells like HepG2, THP 1 and RAW264.7 were capable of synthesising dinucleoside polyphosphates. VEGFR2 transfected HEK 293T/17 but not native HEK 293T/17 cells synthesised dinucleoside polyphosphates in vivo too. The simultaneous biosynthesis of dinucleoside polyphosphates could amplify the response to VEGF, since dinucleoside polyphosphates induce cellular growth via P2Y purinergic receptors. Thus the biosynthesis of dinucleoside polyphosphates by VEGFR2 may enhance the proliferative response to VEGF. Given that VEGFR2 is primarily expressed in endothelial cells, the biosynthesis of dinucleoside polyphosphates is mainly located in the vascular system. Since the vasculature is also the main site of action of dinucleoside polyphosphates, activating vascular purinoceptors, blood vessels appear as an autocrine system with respect to dinucleoside polyphosphates. We conclude that VEGFR2 receptor is capable of synthesising dinucleoside polyphosphates. These mediators may modulate the effects of VEGFR2 due to their proliferative effects. PMID- 23636509 TI - Protective role for netrin-1 during diabetic nephropathy. AB - Recent studies implicate neuronal guidance molecules in the orchestration of inflammatory events. For example, previous studies demonstrate a functional role for netrin-1 in attenuating acute kidney injury. Here, we hypothesized a kidney protective role for netrin-1 during chronic kidney disease, such as occurs during diabetic nephropathy. To study the role of netrin-1 during diabetic nephropathy, we induced diabetes in mice at the age of 8 weeks by streptocotozin (STZ) treatment. Sixteen weeks after STZ treatment, we examined the kidneys. Initial studies in wild-type mice demonstrated robust induction of renal, urinary, and plasma netrin-1 protein levels during diabetic nephropathy. Subsequent genetic studies in mice with partial netrin-1 deficiency (Ntrn1(+/-) mice) revealed a more severe degree of diabetic nephropathy, including more severe loss of kidney function (albuminuria, glomerular filtration rate, histology). We subsequently performed pharmacologic studies with recombinant netrin-1 treatment given continuously via osmotic pump. Indeed, netrin-1 treatment was associated with attenuated albuminuria and improved histologic scores for diabetic nephropathy compared to controls. Consistent with previous studies implicating purinergic signaling in netrin-1-elicited tissue protection, mice deficient in the Adora2b adenosine receptor were not protected. Taken together, these studies demonstrate a functional role for endogenous netrin-1 in attenuating diabetic kidney disease. PMID- 23636510 TI - MicroRNA in immunity and autoimmunity. AB - MicroRNAs (miRNAs) are about 20-22 nucleotide conserved non-coding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3' untranslated region of specific messenger RNAs (mRNAs) for degradation or translational repression. During the last two decades, miRNAs have emerged as critical regulators of a range of biological processes including immune cell lineage commitment, differentiation, maturation, and immune signaling pathways. The endoribonucleases such as Dicer, which is required for miRNA biogenesis, has also been shown to play an important role in inflammatory response and autoimmunity. Thus, dysregulated miRNA expression patterns have been documented in a broad range of human diseases including inflammatory and autoimmune diseases. In this review, we will discuss recent advances in miRNAs mediated regulation of inflammatory responses and autoimmune pathogenesis. Specifically, we will discuss how miRNAs regulate autoimmunity through affecting the development, differentiation, and function of various cell types such as innate immune cells, adaptive immune cells and local resident cells. The identification of distinct miRNA expression patterns, and a comprehensive understanding of the roles of those dysregulated miRNAs in inflammatory autoimmune pathogenesis offers inspirations of not only potential molecular diagnostic markers but also novel therapeutic strategies for treating inflammatory autoimmune diseases. PMID- 23636513 TI - Should an involved but functioning recurrent laryngeal nerve be shaved or resected in a locally advanced papillary thyroid carcinoma? AB - BACKGROUND: The issue of whether an involved but functioning recurrent laryngeal nerve (RLN) should be shaved or resected in locally advanced papillary thyroid carcinoma (PTC) remains controversial. Our study aimed to compare the early and late outcomes between those who underwent shaving and those who underwent resection and also to identify independent prognostic factors in this subset of patients. METHODS: Of the 77 patients with 1 RLN involved by PTC, 39 (50.6%) underwent RLN preservation (group I) while 38 (49.4%) underwent RLN resection (group II). Early and late vocal cord function (as assessed by flexible laryngoscopy) and disease status were compared between the 2 groups. A multivariate Cox proportional hazards model was carried out to identify independent factors. RESULTS: Baseline characteristics were comparable between the 2 groups. Although temporary vocal cord palsy rate was similar between the 2 groups (p=0.532), 5 patients in group II (13.2%) suffered temporary bilateral vocal cord palsies with 1 requiring a tracheostomy lasting for 1 month. After a median follow-up of 113.8 months, 1 patient from each group developed new onset vocal cord palsy. Presence of distant metastases (hazard ratio [HR]=5.892, 95% CI=1.971-17.604, p=0.001) and incomplete surgical resection in non-RLN concomitant sites (HR=2.491, 95% CI=1.181-5.476, p=0.024) were the 2 independent predictors for a poor cancer-specific survival. CONCLUSIONS: Our data suggested that shaving could preserve the normal functionality in most of the involved RLNs (>90%) in the short to medium term. In the presence of distant metastases or incomplete resection in other non-RLN concomitant sites, the argument for shaving over resection appears even stronger. PMID- 23636511 TI - NF-kappaB in colorectal cancer. AB - Colorectal cancer (CRC) is a leading cause of morbidity and mortality worldwide, responsible for more than half a million deaths annually. CRC is a multistep process that entails the accumulation of genetic/epigenetic aberrations, which lead to the simultaneous failure of protective mechanisms and the activation of tumorigenic pathways. In most cases of CRC a deregulation of the Wnt-signaling pathway is required. The transcription factor nuclear factor kappaB (NF-kappaB) has been recognized as a key player in the initiation and propagation of CRC. Under physiological conditions, NF-kappaB orchestrates the inflammatory process and participates in the modulation of various steps of cell cycle and survival. It is normally kept in an inactive state in the cytoplasm by binding to a group of inhibitory proteins. Upon receipt of a signal, its inhibitor is phosphorylated and proteolytically degraded and NF-kappaB is actively translocated to the nucleus, where it facilitates target-gene transcription. Recent experimental data reveal the important role of NF-kappaB in tumor cells as well as in the surrounding "cancerous" and reactive microenvironment. Various tumor cell-derived and contextual cues feed constantly this vicious circuitry sustaining inflammation and promoting proliferation, angiogenesis, invasion and eventually metastasis. Therefore NF-kappaB along with its upstream and downstream network presents a rational target for therapeutic interventions. Numerous small molecules, inhibitory peptides, antisense RNAs, natural compounds, as well as gene therapy strategies interfere with multiple steps of the NF-kappaBeta signaling cascade. The design of NF-kappaBeta-targeted treatment may aid the efforts towards the pursuit of more efficient therapeutic measures devoid of severe systemic side-effects. PMID- 23636514 TI - Financial comparison of laparoscopic versus open hepatic resection using deviation-based cost modeling. AB - BACKGROUND: There is a growing body of evidence suggesting the equivalence and in some cases superiority of laparoscopic liver resection versus open resection. Fewer data exist regarding the financial impact of laparoscopic liver resection. METHODS: Retrospective review of 98 consecutive patients at a single institution from 2007 through 2011 undergoing first time hepatic resection was performed. Laparoscopic and open cases were compared primarily on OR and hospital charges. Deviation-based cost modeling and weighted average mean cost for the two procedures were used to determine both financial and clinical efficacy on the basis of differences in length of stay, complications, and charges. RESULTS: There were 57 laparoscopic and 41 open cases included in the study. Right hepatectomy was the most common procedure performed in both the laparoscopic (n=23, 40.4%) and open (n=22, 53.7%) groups. Patients in the laparoscopic group were significantly more likely to have an "on course" postoperative hospitalization (73.7 vs. 26.8%; p<0.001), which translated into a WAMC of $58,401 for the laparoscopic cases and $69,728 for the open cases. In the subset of patients undergoing right hepatectomy, patients in the laparoscopic group remained more likely to have an on course hospitalization (61.2 vs. 31.8%; p=0.025). WAMC for the laparoscopic right hepatectomy group, however, was higher than the open group ($69,544 vs. $68,266). CONCLUSIONS: The cost-effectiveness of laparoscopic hepatectomy appears to vary with the complexity of the procedure. Overall, laparoscopy offers a cost advantage; however, with more complex procedures such as right hepatectomy, higher up-front operating room charges offset the financial benefits of less complicated hospitalization. PMID- 23636515 TI - The financial burden of reexcising incompletely excised soft tissue sarcomas: a cost analysis. AB - BACKGROUND: Although survival outcomes have been evaluated between those undergoing a planned primary excision and those undergoing a reexcision following an unplanned resection, the financial implications associated with a reexcision have yet to be elucidated. METHODS: A query for financial data (professional, technical, indirect charges) for soft tissue sarcoma excisions from 2005 to 2008 was performed. A total of 304 patients (200 primary excisions and 104 reexcisions) were identified. Wilcoxon rank sum tests and chi2 or Fisher's exact tests were used to compare differences in demographics and tumor characteristics. Multivariable linear regression analyses were performed with bootstrapping techniques. RESULTS: The average professional charge for a primary excision was $9,694 and $12,896 for a reexcision (p<.001). After adjusting for tumor size, American Society of Anesthesiologists status, grade, and site, patients undergoing reexcision saw an increase of $3,699 in professional charges more than those with a primary excision (p<.001). Although every 1-cm increase in size of the tumor results in an increase of $148 for a primary excision (p=.006), size was not an independent factor in affecting reexcision charges. The grade of the tumor was positively associated with professional charges of both groups such that higher-grade tumors resulted in higher charges compared to lower-grade tumors (p<.05). CONCLUSIONS: Reexcision of an incompletely excised sarcoma results in significantly higher professional charges when compared to a single, planned complete excision. Additionally, when the cost of the primary unplanned surgery is considered, the financial burden nearly doubles. PMID- 23636512 TI - The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease. AB - Metabolites of the kynurenine pathway (KP), which arise from the degradation of tryptophan, have been studied in detail for over a century and garnered the interest of the neuroscience community in the late 1970s and early 1980s with work uncovering the neuromodulatory potential of this pathway. Much research in the following decades has found that perturbations in the levels of KP metabolites likely contribute to the pathogenesis of several neurodegenerative diseases. More recently, it has become apparent that targeting KP enzymes, in particular kynurenine 3-monooxygenase (KMO), may hold substantial therapeutic potential for these disorders. Here we provide an overview of the KP, the neuroactive properties of KP metabolites and their role in neurodegeneration. We also discuss KMO as a therapeutic target for these disorders, and our recent resolution of the crystallographic structure of KMO, which will permit the development of new and improved KMO inhibitors which may ultimately expedite clinical application of these compounds. PMID- 23636516 TI - Solubilization and identification of hen eggshell membrane proteins during different times of chicken embryo development using the proteomic approach. AB - A fertilized chicken egg is a unit of life. During hatching, transport of nutrients, including calcium, have been reported from the egg components to the developing embryo. Calcium is mobilized from the eggshell with the involvement of Ca(2+)-binding proteins. In addition, other unknown proteins may also play some important roles during embryo developing process. Therefore identification and prediction of biological functions of eggshell membrane (ESM) proteins during chick embryo development was conducted by proteome analysis. Comparison of different lysis solutions indicated that the highest ability to extract ESM proteins could be obtained with 1 % sodium dodecyl sulfate in 5 mM Tris-HCl buffer pH 8.8 containing 0.1 % 2-mercaptoethanol. In this study fertilized Cornish chicken eggs were incubated at 37 degrees C in humidified incubators for up to 21 days. At selected times (days 1, 9, 15 and 21), samples were taken and the ESMs were carefully separated by hand, washed with distilled water, and air dried at room temperature. The ESM proteins were then solubilized and analyzed by proteome analysis. Sodium dodecyl sulfate polyacrylamide gel electrophoresis combined with high performance liquid chromatography and mass spectrometry revealed 62 proteins in the ESM; only keratin is known ESM protein, 8 of which are egg white proteins and related while 53 others have not previously been reported. Some differences in the types of proteins and their molecular functions were noted in ESM at different incubation times. One protein which was present only at days 15 and 21 of egg incubation was identified as a calcium binding protein i.e. EGF like repeats and discoidin I like domain 3 (EDIL3 homologous protein). PMID- 23636517 TI - Understanding thermostability factors of Aspergillus niger PhyA phytase: a molecular dynamics study. AB - Molecular dynamics simulation was used to study the dynamic differences between native Aspergillus niger PhyA phytase and a mutant with 20 % greater thermostability. Atomic root mean square deviation, radius of gyration, and number of hydrogen bonds and salt bridges are examined to determine thermostability factors. The results suggest that, among secondary structure elements, loops have the most impact on the thermal stability of A. niger phytase. In addition, the location rather than the number of hydrogen bonds is found to have an important contribution to thermostability. The results also show that salt bridges may have stabilizing or destabilizing effect on the enzyme and influence its thermostability accordingly. PMID- 23636518 TI - Laparoscopic repair of a lumbar hernia: report of a case and extensive review of the literature. AB - Lumbar hernias are a protrusion of intra-abdominal contents through a weakness or rupture in the posterior abdominal wall. They are considered to be a rare entity with approximately 300 cases reported in the literature since it was first described by Barbette in 1672. Petit described the inferior lumbar triangle in 1783 and Grynfeltt described the superior lumbar triangle in 1866; both are anatomical boundaries where 95% of lumbar hernias occur, whereas the other 5% are considered to be diffuse. Twenty percent of lumbar hernias are congenital and the other 80% are acquired; the acquired lumbar hernias can be further classified into either primary (spontaneous) or secondary. The typical presentation of lumbar hernias is a patient with a protruding semispherical bulge in the back with a slow growth. However, they may present with an incarcerated or strangulated bowel, so it is recommended that all lumbar hernias must be repaired as soon as they are diagnosed. The "gold standard" for diagnosing a lumbar hernia is a CT scan, because it is able to delineate muscular and fascial layers, detect a defect in one or more of these layers, evaluate the presence of herniated contents, differentiate muscle atrophy from a real hernia, and serve as a useful tool in the differential diagnosis, such as tumors. Recent studies have demonstrated the advantages of a laparoscopic repair instead of the classic open approach as the ideal treatment option for lumbar hernias. We report a case of a spontaneous lumbar hernia initially diagnosed as a lipoma and corrected with the open approach, but after relapsing 2 years later it was corrected using a laparoscopic approach. It is followed by an extensive review of lumbar hernias literature regarding history, anatomy, and surgical techniques. PMID- 23636520 TI - Comment on "prospective randomized clinical trial comparing laparoscopic cholecystectomy and hybrid natural orifice transluminal endoscopic surgery (NOTES) (NCT00835250)" (doi:10.1007/s00464-012-2359-4). PMID- 23636519 TI - Total laparoscopic esophageal bypass using a colonic conduit for corrosive induced esophageal stricture. AB - BACKGROUND: The colon and the stomach are the most commonly used conduits for esophageal replacement in patients with esophageal strictures resulting from corrosive ingestion. The replacement surgeries have traditionally been performed by an open approach. While laparoscopic replacement surgery using a stomach conduit has been previously reported, a total laparoscopic bypass using a colonic conduit has not been previously described. We herein describe the surgical technique and results of laparoscopic esophageal bypass using a colonic conduit. METHODS: Patients with corrosive stricture involving the esophagus with the proximal level at the hypopharynx, or those with concomitant gastric scarring, were selected. The surgery was performed with the patient in a supine position using five abdominal ports and a hockey stick/transverse skin crease neck incision. The main steps include colonic mobilization and assessment of the adequacy of the marginal vascular arcade, creation of a retrosternal tunnel, preparation of the colonic conduit, neck dissection, delivery of the colonic conduit into the neck and cervical pharyngo/esophagocolic anastomosis, and intra abdominal cologastric and ileocolic anastomosis. RESULTS: During the study period, 39 patients with corrosive stricture of the esophagus were managed surgically at our center with either gastric or colonic bypass. Of these, 22 patients underwent an open procedure (12 retrosternal colonic bypasses and 10 retrosternal gastric bypasses) and 17 patients underwent a laparoscopic procedure (13 retrosternal gastric bypasses and 4 retrosternal colonic bypasses). Patients with stricture at the hypopharynx (n = 2) or those in whom the stomach was contracted (n = 2) were considered for a laparoscopic esophagocoloplasty. The average duration of surgery of these latter four patients was 370 (380, 320, 360, and 420) min and the mean estimated blood loss was 100 mL. All patients could be ambulated on the first postoperative day and were allowed oral liquids by the 7th postoperative day. Compared with patients who underwent an open colonic bypass, there was significantly less need for analgesics. At a median follow-up of 5 (range 3-6) months, all patients are euphagic to solid diet and have excellent cosmetic results. CONCLUSION: Laparoscopic colonic bypass is an achievable, safe, and effective procedure for the management of corrosive strictures of the esophagus. PMID- 23636521 TI - Gas-related symptoms after antireflux surgery. AB - BACKGROUND: Gas-related symptoms such as bloating, flatulence, and impaired ability to belch are frequent after antireflux surgery, but it is not known how these symptoms affect patient satisfaction with the procedure or what determines the severity of these complaints. We aimed to assess the impact of gas-related symptoms on patient-perceived success of surgery and to determine whether the severity of gas-related complaints after antireflux surgery is associated with objectively measured abnormalities. METHODS: Fifty-two patients were studied at a median of 27 months after antireflux surgery. The influence of gas-related symptoms on their quality of life and satisfaction with surgical outcome was assessed. The rates of air swallows and gastric and supragastric belches before and after surgery were assessed using impedance measurements. RESULTS: Bloating and flatulence were associated with a decreased quality of life and less satisfaction with surgical outcome. Notably, 9 % of the patients would not opt for surgery again due to gas-related symptoms. Antireflux surgery decreased the total number of gastric belches but did not affect the number of air swallows. The severity of gas-related symptoms was not associated with an increased number of preoperative air swallows and/or belches or a larger postoperative decrease in the number of gastric belches. CONCLUSION: Gas-related symptoms are associated with less satisfaction with surgical outcome. The severity of gas-related symptoms is not determined by the number of preoperative air swallows or a more severe impairment of the ability to belch after surgery. Preoperative predictors of postoperative gas-related symptoms therefore could not be identified. PMID- 23636523 TI - TransAnal Minimally Invasive Surgery (TAMIS) with SILSTM port versus Transanal Endoscopic Microsurgery (TEM): a comparative experimental study. AB - BACKGROUND: TransAnal Minimally Invasive Surgery (TAMIS) has been proposed as an alternative to Transanal Endoscopic Microsurgery (TEM) for resection of benign polyps and early cancers of rectum. Since clinical application has begun in the absence of any experimental validation, we assessed its feasibility and efficacy ex vivo in a pilot study. METHODS: In a dedicated trainer box for transanal procedures, 10 surgeons with no experience in transanal surgery were asked to perform a dissection/suture task using both TAMIS and TEM in randomly allocated order. Surgeons were asked to dissect two identically drawn lesions of ~3 cm in larger diameter. Precision of dissection was assessed using a quantitative photographic method, while the time needed for dissection and suturing was considered a measure of quantitative evaluation. Each participant expressed a subjective opinion regarding difficulty with dissection, difficulty with suturing, vision quality, and conflict between instruments on a scale from 1 to 5. RESULTS: No difference was observed between the two techniques regarding the accuracy of dissection as the margin was interrupted along 4.1 % of the circumference in the TEM group compared with 2.48 % in the SILS group (P = 0.271). Dissection and suturing were significantly quicker in the TEM group [04:30 vs. 06:35 min (P = 0.049) and 14:34 versus 19:18 min (P = 0.003)]. In three cases in the SILS group, completing the suture was not considered possible, and the procedures were terminated by TEM. Subjective evaluation revealed a better appreciation of TEM in all proposed comparisons: dissection (2.6 vs. 3.5, P = 0.004), suturing difficulty (3.1 vs. 4.6, P < 0.001), quality of vision (2.3 vs. 2.8, P = 0.18), and instrument conflicts (3.1 vs. 4.0, P = 0.054). CONCLUSIONS: In the ex vivo setting, both techniques were comparable for achieving a good dissection, although TAMIS failed to prove effective in suturing the rectal wall. Moreover, TEM was significantly quicker despite the small groups and was better appreciated by the surgeons. PMID- 23636522 TI - Grading of complications and risk factor evaluation in laparoscopic colorectal surgery. AB - BACKGROUND: A grading system for postoperative complications is important for quality control and comparison among investigations. The objective of the current study was to evaluate complications associated with laparoscopic colorectal surgery according to a standardized grading system, and to examine risk factors associated with different complication grades. METHODS: Data of all patients who underwent elective laparoscopic colorectal surgery at two medical centers between September 2003 and January 2011 were collected prospectively. Complications were graded retrospectively into five categories based on a previously proposed grading system for colorectal operations. Age, gender, BMI, Charlson comorbidity score, indication for surgery, pathology site, conversion rate, learning curve, operative times, previous abdominal surgery, concurrent surgical procedures performed, and length of hospital stay were evaluated as risk factors and outcome measures for complications. RESULTS: A total of 501 patients were included in the study. Of them, 30.5 % suffered at least one complication and 6.5 % more than one. Complications that were mainly medical or surgical site infections requiring minor intervention (grades 1 and 2) occurred in 22.9 % of patients. Surgical complications requiring invasive interference (grades 3 and 4) occurred in 7.4 % of patients and mortality (grade 5) occurred in 0.2 % (1 patient). Length of hospital stay was directly related to complication grade. Average hospital stay was 6.8 +/- 3.5, 10.5 +/- 5.1, and 20.2 +/- 12.3 days for patients with no complications, grade 1-2 complications, and grade 3-4 complications, respectively (p < 0.01). Minor complications (grades 1-2) were associated with conversion (p < 0.01), high Charlson score (p = 0.004), and additional surgical procedures (p = 0.04). Major complications (grades 3-4) were associated solely with conversion (p < 0.01) and rectal pathology (p < 0.01). CONCLUSION: This study demonstrates the use of a uniform grading system for complications in laparoscopic colorectal surgery. Conversion was found to be associated with all grades of complications. PMID- 23636524 TI - Reply to: doi:10.1007/s00464-013-2958-8: Re: Prospective randomized clinical trial comparing laparoscopic cholecystectomy and hybrid natural orifice transluminal endoscopic surgery (NOTES) (NCT00835250) : do we know the correct sample size? PMID- 23636525 TI - Comparison of a gasless unilateral axillo-breast and axillary approach in robotic thyroidectomy. AB - BACKGROUND: New approaches to robotic thyroidectomy help to prevent neck scarring and improve surgical ergonomics. The purpose of this study was to compare the efficacy and advantages of a gasless unilateral axillary (GUA) approach and an axillo-breast (GUAB) approach in robotic thyroidectomy. METHODS: We retrospectively reviewed the data of 131 patients who underwent robotic thyroidectomy with or without central neck dissection using a GUAB (90 cases) or GUA (41 cases) approach between September 2009 and December 2011. We excluded patients who underwent simultaneous lateral neck dissection and cases within the learning curve. We compared patient and tumor characteristics, surgical outcomes, perioperative complications, and cosmetic satisfaction between the two approaches. RESULTS: Robotic thyroidectomy was successful in all patients. There were no differences in terms of patient and tumor characteristics, extent of thyroidectomy and central neck dissection, operative time, and postoperative complications between the two approaches. Cosmetic satisfaction was excellent in both groups. There was no difference in satisfaction with the cosmetic result in the neck area, but the GUA patients expressed higher satisfaction with the appearance of the breast. CONCLUSIONS: The surgical outcomes of GUA and GUAB approaches are similar in robotic thyroidectomy. Both are safe, effective, and yield cosmetically excellent results when performed by an experienced robotic thyroid surgeon. However, a GUA approach is associated with superior cosmetic satisfaction with the appearance of the breast. PMID- 23636526 TI - Retraction note: Management of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy. PMID- 23636527 TI - Retraction note: Prevention of postoperative nausea and vomiting with a small dose of propofol alone and combined with dexamethasone in patients undergoing laparoscopic cholecystectomy: a prospective, randomized, double-blind study. PMID- 23636528 TI - Can all through-the-scope endoscopic clipping devices be rotated? Yes, they can. PMID- 23636529 TI - Not all through-the-scope endoscopic clipping devices are born equal: some can be rotated while others cannot. PMID- 23636530 TI - Endoscopic ultrasound (EUS)-guided fiducial placement allows localization of small neuroendocrine tumors during parenchymal-sparing pancreatic surgery. AB - BACKGROUND: Parenchymal-sparing pancreatic surgery is ideal for lesions such as small pancreatic neuroendocrine tumors (PanNET). However, precise localization of these small tumors at surgery can be difficult. The placement of fiducials under endoscopic ultrasound (EUS) guidance (EUS-F) has been used to direct stereotactic radiation therapy for pancreatic adenocarcinoma. This report describes two cases in which placement of fiducials was used to guide surgical resection. This study aimed to assess the feasibility, safety, and efficacy of using EUS-F for intraoperative localization of small PanNETs. METHODS: A retrospective study analyzed two consecutive patients with small PanNETs who underwent EUS-F followed by enucleation in a tertiary-care referral hospital. The following features were examined: technical success and complication rates of EUS-F, visibility of the fiducial at the time of surgery, and fiducial migration. RESULTS: In the study, EUS-F was performed for two female patients with a 7-mm and a 9-mm PanNET respectively in the uncinate process and neck of the pancreas. In both patients, EUS-F was feasible with two Visicoil fiducials (Core Oncology, Santa Barbara, CA, USA) placed either within or adjacent to the tumors using a 22-gauge Cook Echotip needle. At surgery, the fiducials were clearly visible on intraoperative ultrasound, and both the tumor and the fiducials were successfully enucleated in both cases. No complications were associated with EUS-F, and no evidence of pancreatitis was shown either clinically or on surgical pathology. This investigation had the limitations of a small single-center study. CONCLUSIONS: For patients undergoing enucleation, EUS-F is technically feasible and safe and aids intraoperative localization of small PanNETs. PMID- 23636533 TI - Structures and magnetic properties of copper(II) and manganese(II) polymers derived from pseudohalides and a flexible zwitterionic dicarboxylate ligand. AB - The flexible zwitterionic dicarboxylate ligand 1,4-bis(4-carboxylato-1 pyridinium)butane (bcpb) assumes different conformations to collaborate with pseudohalides in various coordination modes to produce coordination polymers in which distinct anionic motifs with mixed carboxylate and pseudohalide bridges are interlinked by the cationic butylenebis(pyridinium) tethers. The Cu(II) compound, [Cu2(bcpb)(N3)4]n.nH2O (1), is a 1D coordination polymer based on the defective dicubane-like [Cu4(MU3-1,1,1-N3)2(MU-1,1-N3)2(MU-1,1-OCO)2] cluster. With Mn(II), four distinct 3D coordination polymers, [Mn4(bcpb)4(N3)(H2O)4]n(ClO4)7n.nCH3OH.3nH2O (2), [Mn2.5(bcpb)(N3)5(H2O)2]n (3), [Mn2(bcpb)(N3)4]n.nH2O (4), and [Mn2(bcpb)(NCO)4]n.nH2O (5), were characterized. 2 is the first Mn(II) compound with the rare MU4-1,1,3,3 azide bridge and exhibits an unusual 3D framework based on the [Mn4(MU4-1,1,3,3-N3)(MU-1,3-OCO)6] cluster. In 3, the unique undulated honeycomb-like [Mn2(MU-1,3-N3)3]n layers are interlinked into a 3D framework by disordered [Mn(MU-1,1-N3)4(MU-1,3-OCO)2] and [(O(aqua)-H)2...OCO]2 moieties, and the bcpb ligands serve as additional interlayer linkers to lead to the rare self-catenated 6(6) net. 4 and 5 show 3 fold interpenetrated 3D frameworks based on the chains with (MU-1,1-N3)2(MU-1,3 OCO) and (MU-N,N-NCO)2(MU-1,3-OCO) bridges, respectively. Magnetic studies indicated that 1 shows competing ferromagnetic and antiferromagnetic interactions. Compounds 2-5 all show antiferromagnetic coupling between Mn(ii) ions, while 3 shows 3D ordering. Analyses of magneto-structural data suggest a general trend that the antiferromagnetic interaction through (MU-1,1-N3)2(MU-1,3 OCO) or (MU-N,N-NCO)2(MU-1,3-OCO) increases with a decrease of the Mn...Mn distance. PMID- 23636532 TI - Prevalence and risk factors for adenomas in the ileal pouch and the afferent loop after restorative proctocolectomy for patients with familial adenomatous polyposis. AB - BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become the treatment of choice in familial adenomatous polyposis (FAP) to prevent the risk of colorectal cancer. However, it currently is recognized that adenomas may develop in the ileal pouch. The risk of adenoma occurring in the afferent ileal loop above the pouch is less clearly identified. This study aimed to evaluate the difference in prevalence of adenomas between the ileal pouch and the afferent ileum after IPAA in FAP. METHODS: The study analyzed 442 endoscopies performed between 2003 and 2008 for 139 FAP patients. The patients had undergone an IPAA in 118 cases, an ileorectal anastomosis in 13 cases, or an ileostomy in 8 cases. RESULTS: Among the 118 IPAA patients, 57 (48.3 %) had pouch adenomas a median of 15 years after surgery. The risk factors for pouch adenomas were delay since pouch construction [odds ratio (OR), 1.11; p = 0.016] and presence of advanced duodenal adenomas (OR, 4.35; p = 0.011). Seven patients had pouch adenomas with high-grade dysplasia. Only nine patients had afferent ileal loop adenomas (6.5 %). The only significant risk factor for ileal adenomas was the presence of pouch adenomas (OR, 2.16; p = 0.007). CONCLUSION: After restorative proctocolectomy in FAP, adenoma recurrence is frequent in the pouch, with a higher risk for patients with advanced duodenal adenomas and an increasing risk over time, whereas adenomas are rarely found in the afferent ileal loop. This finding may help to propose redo ileal pouch anal anastomosis if required. PMID- 23636534 TI - Salt metathesis in three dimensional metal-organic frameworks (MOFs) with unprecedented hydrolytic regenerability. AB - Eight Zn-based porous (1.2 nm) homochiral MOFs (ValZnX, AlaZnX, X = Cl(-), Br(-), HCO2(-) and CH3CO2(-)) were synthesized which possess extremely rare zeolitic (unh) topology. These MOFs show an unprecedented hydrolytic regenerability. Salt metathesis reaction performed on these 3D MOFs in water resulted in 2D coordination polymers (CPs). PMID- 23636536 TI - Craniosynostosis: imaging review and primer on computed tomography. AB - Craniosynostosis is encountered in the pediatric population in isolated or syndromic forms. The resulting deformity depends on the number and type of sutures involved and, in multi-sutural synostosis, the order of suture fusion. Primary craniosynostosis needs to be differentiated from the secondary variety and positional or deformational mimics. Syndromic craniosynostoses are associated with other craniofacial deformities. Evaluation with 3-D CT plays an important role in accurate diagnosis and management; however, implementation of appropriate CT techniques is essential to limit the radiation burden in these children. In this article, the authors briefly review the classification, embryopathogenesis and epidemiology and describe in detail the radiologic appearance and differential diagnoses of craniosynostosis. PMID- 23636537 TI - Comparison of radiation dose estimates, image noise, and scan duration in pediatric body imaging for volumetric and helical modes on 320-detector CT and helical mode on 64-detector CT. AB - BACKGROUND: Advanced multidetector CT systems facilitate volumetric image acquisition, which offers theoretic dose savings over helical acquisition with shorter scan times. OBJECTIVE: Compare effective dose (ED), scan duration and image noise using 320- and 64-detector CT scanners in various acquisition modes for clinical chest, abdomen and pelvis protocols. MATERIALS AND METHODS: ED and scan durations were determined for 64-detector helical, 160-detector helical and volume modes under chest, abdomen and pelvis protocols on 320-detector CT with adaptive collimation and 64-detector helical mode on 64-detector CT without adaptive collimation in a phantom representing a 5-year-old child. Noise was measured as standard deviation of Hounsfield units. RESULTS: Compared to 64 detector helical CT, all acquisition modes on 320-detector CT resulted in lower ED and scan durations. Dose savings were greater for chest (27-46%) than abdomen/pelvis (18-28%) and chest/abdomen/pelvis imaging (8-14%). Noise was similar across scanning modes, although some protocols on 320-detector CT produced slightly higher noise. CONCLUSION: Dose savings can be achieved for chest, abdomen/pelvis and chest/abdomen/pelvis examinations on 320-detector CT compared to helical acquisition on 64-detector CT, with shorter scan durations. Although noise differences between some modes reached statistical significance, this is of doubtful diagnostic significance and will be studied further in a clinical setting. PMID- 23636538 TI - Optic nerve tortuosity in children with neurofibromatosis type 1. AB - BACKGROUND: Optic nerve tortuosity is often reported in children with neurofibromatosis type 1 (NF1). OBJECTIVE: To employ quantitative and subjective criteria to assess optic nerve tortuosity in individuals with NF1. MATERIALS AND METHODS: A retrospective study over a period of 8 years was performed on children with NF1, with and without optic pathway glioma, compared with children without NF1. A tortuosity index was computed for the optic nerve in each child using a high-resolution 3-D T1-weighted magnetization-prepared rapid gradient-echo sequence, which was averaged and compared across groups. RESULTS: The tortuosity index for subjects with NF1, regardless of an optic pathway glioma, was greater than those without NF1. There was no difference in the tortuosity index between NF1 subjects with optic pathway glioma and NF1 subjects without optic pathway glioma. There was also no correlation between subjective measures of tortuosity and the quantitative scoring (tortuosity index) or between the degree of tortuosity and subject age or gender. CONCLUSION: Individuals with NF1 have increased optic nerve tortuosity relative to unaffected individuals. Quantitative tortuosity index is a superior measure to subjective assessment in the evaluation of optic nerve tortuosity in children with NF1. PMID- 23636539 TI - Subclavian vein aneurysm secondary to a benign vessel wall hamartoma. AB - Venous aneurysms are rare clinical entities, particularly in children, and their presentation and natural history often depend on the anatomical location and underlying etiology. We present a single case of a 12-year-old girl who presented with a palpable right supraclavicular mass. Imaging evaluation with CT, conventional venography, MRI and sonography revealed a large fusiform subclavian vein aneurysm with an unusual, mass-like fibrofatty component incorporated into the vessel wall. The girl ultimately required complete resection of the right subclavian vein with placement of a synthetic interposition graft. This case provides a radiology/pathology correlation of an entity that has not previously been described as well as an example of the utility of multiple imaging modalities to aid diagnosis and preoperative planning. PMID- 23636540 TI - Relative distribution of pertinent findings on portable neonatal abdominal radiographs: can we shield the gonads? AB - BACKGROUND: Shielding of the gonads is a dose-saving strategy in pediatric radiography and its use is the law in New York and the majority of other states. However, routine use of gonadal shields is controversial because of concerns that important diagnostic information can be obscured. OBJECTIVE: The purpose of this study was to assess the frequency and spatial distribution of key findings on portable neonatal abdominal radiographs. MATERIALS AND METHODS: We reviewed the 2,544 portable neonatal intensive care unit anteroposterior abdominal radiographs performed in 2010 at a university medical center, of which 962 were inadequately shielded. These 962 radiographs were reviewed by pairs of pediatric radiologists for the presence of findings in different regions, including bowel abnormalities, pneumatosis, free air, inguinal hernias, osseous abnormalities, and catheter/tube tips. RESULTS: The fewest pertinent findings were present below the level of the sacrosciatic notches (n = 181, 18.8%). Of the 853 abnormalities below the level of the iliac crests in our cohort, six were isolated to these regions, whereas others had concomitant abnormalities more superiorly. Of 35 radiographs with pneumatosis or suspected pneumatosis in the pelvis, 33 had pneumatosis in more superior regions. Suspected free air was never isolated to the pelvis. Osseous abnormalities were only present in the pelvis below the sacrosciatic notch, and 37.5% of lower extremity catheters terminated below the level of the sacrosciatic notches. CONCLUSION: Pertinent findings on neonatal intensive care unit abdominal radiographs are rarely isolated to the pelvic regions. PMID- 23636541 TI - Radiologic protection in pediatric radiology: ICRP recommendations. PMID- 23636542 TI - Baseline determinants of global diet quality in older men and women from the NuAge cohort. AB - Judicious food choices are of prime importance during aging. OBJECTIVES: This study was conducted to identify individual and collective attributes determining global diet quality (DQ). METHODOLOGY: Participants were 1,793 adults (52% women) from the NuAge study on nutrition and successful aging. Subjects aged 67 to 84 years in relatively good health were recruited from the Quebec Medicare Database. Sociodemographic, affective, and cognitive data, health conditions, perceived physical health and functional status, dietary habits and dietary attributes and community resources were obtained using questionnaires. Body weight and height were measured and body mass index (BMI) was calculated. Three non-consecutive 24 hour diet recalls were collected at recruitment. DQ, assessed using the Canadian Healthy Eating Index (C-HEI, /100), was computed on the mean intakes from the diet recalls. Analyses were stratified by gender. Variables significantly related to DQ in bivariate analyses (p<.05) were entered into backward stepwise multiple regression analyses. RESULTS: Among men, the final model showed higher education (beta=0.23, p=.01), diet knowledge (beta=0.96, p<.0001), number of daily meals (beta=1.91, p=.02) and perceived physical health (beta=0.06, p=.01) to be positive determinants of DQ, whereas alcohol consumption (beta=-2.25, p=.05), wearing dentures (beta=-2.31, p=.01) and eating regularly in restaurants (beta= 1.65, p=.03) were negative determinants of DQ (adjusted R2 = 13.7%). Among women, higher education (beta=0.29, p=.002), diet knowledge (beta=0.54, p=.002), number of daily meals (beta=3.61, p<.0001), and hunger (beta=0.61, p<.0001) were positive determinants of global DQ; greater BMI (beta=-0.16, p=.03) and chewing problems (beta=-0.48, p=.03) were negative determinants of DQ (adjusted R2 = 7.8%). DISCUSSION: These results point to several key factors influencing global DQ in older adults and also show gender-based differences. More research must be done to better understand how these factors change with aging and exert their impact on diet, particularly since variance in DQ was largely unexplained. As diet knowledge was an independent predictor for both genders, targeted, sustainable interventions are needed to ensure good diet quality as people age. PMID- 23636543 TI - Micronutrients-incorporated calcium phosphate particles with protective effect on osteoporotic bone tissue. AB - BACKGROUND: Supplementation of individual micronutrient is inadequate for maintaining bone function because single micronutrient can not contribute significantly a positive remodeling balance. OBJECTIVE: We developed the highly integrated, stably dietary multi-micronutrients with good bioavailability and low adverse effect on the improvement of bone consolidation in osteoporosis. METHODS: The trace element-codoped calcium phosphate (teCaP) particles were prepared in the modified body fluid and carefully evaluated. Rats, aged 3 months, were ovariectomized and when 6 month intervened with the conditioned, low, moderate, and high teCaP diets. RESULTS: The teCaP particles showed highly dissolvable in stomach juice-mimicing acidic solutions. Three months after intervention, the body weight increase showed remarkable differences among the low teCaP diet (~52 g), moderate teCaP diet (~34 g) and high teCaP diet (~23 g) group. In particular, the intake of moderate teCaP greatly improved the retention of trace elements in femural bone for better protection against the skeletal weakening, and resulted in a significant increase of bone mineral density (104.06%) in comparison with the conventional high calcium plus vitamin D3 diet (Control group). CONCLUSIONS: These investigations improve our understanding of micronutrient retention on bone consolidation in osteoporotic bone tissue, and also provide new mild wet-chemical approach to prepare potent nutritionally effective edible complements to synergistically relieve bone degeneration and prevent osteoporosis. PMID- 23636544 TI - Validation of the interRAI Cognitive Performance Scale against independent clinical diagnosis and the Mini-Mental State Examination in older hospitalized patients. AB - OBJECTIVE: To compare the diagnostic accuracy of the interRAI Acute Care (AC) Cognitive Performance Scale (CPS2) and the Mini-Mental State Examination (MMSE), against independent clinical diagnosis for detecting dementia in older hospitalized patients. DESIGN, SETTING, AND PARTICIPANTS: The study was part of a prospective observational cohort study of patients aged >=70 years admitted to four acute hospitals in Queensland, Australia, between 2008 and 2010. Recruitment was consecutive and patients expected to remain in hospital for >=48 hours were eligible to participate. Data for 462 patients were available for this study. MEASUREMENTS: Trained research nurses completed comprehensive geriatric assessments and administered the interRAI AC and MMSE to patients. Two physicians independently reviewed patients' medical records and assessments to establish the diagnosis of dementia. Indicators of diagnostic accuracy included sensitivity, specificity, predictive values, likelihood ratios and areas under receiver (AUC) operating characteristic curves. RESULTS: 85 patients (18.4%) were considered to have dementia according to independent clinical diagnosis. The sensitivity of the CPS2 [0.68 (95%CI: 0.58-0.77)] was not statistically different to the MMSE [0.75 (0.64-0.83)] in predicting physician diagnosed dementia. The AUCs for the 2 instruments were also not statistically different: CPS2 AUC = 0.83 (95%CI: 0.78 0.89) and MMSE AUC = 0.87 (95%CI: 0.83-0.91), while the CPS2 demonstrated higher specificity [0.92 95%CI: 0.89-0.95)] than the MMSE [0.82 (0.77-0.85)]. Agreement between the CPS2 and clinical diagnosis was substantial (87.4%; kappa=0.61). CONCLUSION: The CPS2 appears to be a reliable screening tool for assessing cognitive impairment in acutely unwell older hospitalized patients. These findings add to the growing body of evidence supporting the utility of the interRAI AC, within which the CPS2 is embedded. The interRAI AC offers the advantage of being able to accurately screen for both dementia and delirium without the need to use additional assessments, thus increasing assessment efficiency. PMID- 23636545 TI - Mediterranean diet and depressive symptoms among older adults over time. AB - OBJECTIVE: To examine whether adherence to a Mediterranean-based dietary pattern is predictive of depressive symptoms among older adults. DESIGN: Generalized estimating equation models were used to test the association between a Mediterranean-based dietary pattern and depressive symptoms over time. Models were adjusted for age, sex, race, education, income, widowhood, antidepressant use, total calorie intake, body mass index, smoking, alcohol consumption, number of self-reported medical conditions, cognitive function, and physical disability. SETTING: Chicago, Illinois. PARTICIPANTS: Community-dwelling participants (n=3502) of the Chicago Health and Aging Project aged 65+ years (59% African American) who had no evidence of depression at the baseline. MEASUREMENTS: Adherence to a Mediterranean-based dietary pattern was assessed by the MedDietScore. Dietary evaluation was performed with a food frequency questionnaire at baseline and related to incident depression as measured by the presence of four or more depressive symptoms from the 10-item version of the Center for Epidemiologic Studies Depression scale. RESULTS: Over an average follow-up of 7.2 years, greater adherence to a Mediterranean-based diet was associated with a reduced number of newly occurring depressive symptoms (parameter estimate = -0.002, standard error = 0.001; p = 0.04). The annual rate of developing depressive symptoms was 98.6% lower among persons in the highest tertile of a Mediterranean-based dietary pattern compared with persons in the lowest tertile group. CONCLUSION: Our results support the hypothesis that adherence to a diet comprised of vegetables, fruits, whole grains, fish, and legumes may protect against the development of depressive symptoms in older age. PMID- 23636546 TI - Serum 25-hydroxyvitamin D levels and the risk of depression: a systematic review and meta-analysis. AB - OBJECTIVE: No quantitative systematic review or meta-analysis of population-based epidemiological studies has been conducted to assess the association between serum 25-hydroxyvitamin D (25(OH)D) levels and the risk of depression. This study aimed to summarize the current evidence from cross-sectional and prospective cohort studies that have evaluated the association between 25(OH)D levels and the risk of depression. METHODS: Relevant studies were identified by systematically searching the PubMed, EMBASE, Web of Science, and PsycINFO databases through April 2012. Cross-sectional and cohort studies that reported adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association of interest were included. The reported risk estimates for 25(OH)D categories were recalculated, employing a comprehensive trend estimation from summarized dose-response data. A pooled OR was calculated separately for cross-sectional and cohort studies using random-effects models. RESULTS: In the meta-analysis, 25(OH)D levels were significantly inversely associated with depression in 5 of 11 case-control studies and 2 of 5 cohort studies. The pooled estimate of the adjusted OR of depression in 11 cross-sectional studies (n = 43,137) was 0.96 (95% CI = 0.94 0.99, I2 = 63%) for a 10 ng/ml increase in 25(OH)D levels. The 5 included cohort studies comprised 12,648 participants, primarily elderly individuals, whose serum 25(OH)D levels were measured, and 2,663 experienced depression events during follow-up. The pooled adjusted OR of depression was 0.92 (95% CI = 0.87-0.98, I2 = 50%) for a 10 ng/ml increase in 25(OH)D levels. CONCLUSIONS: Our results indicate an inverse association between serum 25(OH)D levels and the risk of depression. Further studies are warranted to establish whether this association is causal. PMID- 23636547 TI - Low vitamin and carotenoid levels are related to cerebral white matter lesions. AB - OBJECTIVES: PURPOSE: To determine the effects of vitamins and carotenoids on brain white matter lesions (WMLs), we examined the associations between WMLs with vitamin and carotenoid levels in Japanese middle-aged and elderly subjects. SUBJECTS AND METHODS: Four-hundred and sixty-nine healthy participants (male = 317; female = 152) that underwent medical examinations were examined. Deep white matter lesions (DWLs) were detected via magnetic resonance imaging (MRI) in 39 subjects. We evaluated the effects of vitamin and carotenoid levels on DWLs via logistic regression analysis. RESULTS: Lower gamma-tocopherol levels were significantly associated with DWLs in all subjects. While lower gamma-tocopherol and vitamin C levels were significantly associated with DWLs in males, lower delta-tocopherol levels were associated with DWLs in females. The associations between DWLs and lower gamma- and delta-tocopherol and vitamin C levels were independent of age, hypertension, or smoking. However, the associations between DWLs and lower alfa-tocopherol were not significant following adjustments for smoking. CONCLUSION: Lower carotenoid and vitamin levels were independently associated with cerebral DWLs in Japanese subjects. PMID- 23636548 TI - Effect of long-term treatment with galantamine on weight of patients with Alzheimer's dementia. AB - OBJECTIVES: There is discussion about the effect of cholinesterase inhibitors (CERs) on weight of patients with Alzheimer's disease (AD). Given the adverse outcomes of weight loss in AD patients, it is important to establish the effect of CERs on weight. This study aimed tot assess the long-term effect of galantamine on weight of AD patients. DESIGN, SETTING AND PARTICIPANTS: This longitudinal study was performed at a large memory clinic in the North of the Netherlands. During the period 2002 to 2010, 303 community-dwelling AD patients, aged 65 years or older who started using a cholinesterase inhibitor (CER), were included. MEASUREMENTS: Socio-demographic characteristics and data on comorbidity, number of medications, type and dosage of CER, use of care, cognitive function, behaviour and nutritional status (weight, Body Mass Index (BMI)) were recorded at the time the diagnosis AD was made and at subsequent outpatient clinic visits. The Generalized Estimating Equations (GEE) model was used to determine the effect of galantamine of 16 mg and 24 mg on weight. The effect of galantamine in a dose of 16 and 24 mg was investigated because the other groups (rivastigmine, galantamine 8 mg) were too small to determine the effect on weight by GEE analysis. Donepezil is not available in the Netherlands. RESULTS: The median follow-up time between the moment patients started using a CER (T0) and the 1st visit was 6 months (n=300); between T0 and the 2nd visit 13 months (n=212); between T0 and the 3rd visit 25 months (n=117) and between T0 and the 4th visit 37 months (n=58). Galantamine 16 mg and 24 mg, corrected for age, gender, social status, informal care, professional care, comorbidity, number of medications, cognition, behaviour and appetite, had no effect on weight (p > 0.05). Male patients had a higher average weight compared to female patients (p=0.000, B=8.333). Patients without an informal caregiver (p=0.01, B=-3.697) or partner (p=0.042, B=-3.197) had a lower average weight compared to patients with an informal caregiver or partner. CONCLUSION: Weight loss in AD patients should not be attributed to long-term treatment with galantamine. This is in accordance with the French guideline. If AD patients are losing weight, other causes, including insufficient care, should be investigated. PMID- 23636550 TI - Impact of an oncogeriatric consulting team on therapeutic decision-making. AB - Increased life expectancy and cancer incidence imply the need to develop a specialized care policy for elderly patients with cancer. We created an oncogeriatric consulting team (OGCT) in Toulouse University Hospital to carry out comprehensive gerontological assessment at the bedside of hospitalized patients. We analyze the impact on the final cancer treatment decision of this mobile geriatric assessment. We carried out a descriptive, retrospective real-life analysis of a patient cohort over a two-year period. The OGCT assessed 124 patients, of whom the majority were women (54.8%), median age 81 years, living at home (95.2%) and with family caregivers (86.5%). Nearly all were frail (96.7% according to the classification of Balducci and colleagues) and 3.2% were vulnerable. The team's decisions were analyzed for patients who had not yet been treated (n=107). After analysis, the team's proposal was in line with the initial cancer treatment plan in 68.2% of cases (n=73). In cases where there was a disagreement, the final decision was in line with the mobile team's proposal in 17.75% of 107 patients (n=19). The decision of the team was followed more often when their assessment proposed strictly palliative treatment. The decision to give elderly patients specific cancer treatment seems in our experience rather to be a matter for the oncologists, and is not very susceptible to modification by geriatric opinion. On the other hand, the geriatrician appears to be more credible and his/her opinion more likely to be followed when the patient is considered too frail and less aggressive, or even exclusively palliative, treatment is proposed. PMID- 23636549 TI - Adherence to a physical activity intervention among older adults in a post transitional middle income country: a quantitative and qualitative analysis. AB - OBJECTIVES: The effectiveness of community level interventions depends to a great extent on adherence. Currently, information on factors related to adherence in older adults from developing countries is scarce. Our aim was to identify factors associated to adherence to a physical activity intervention in older adults from a post-transitional middle income country. DESIGN, SETTING AND PARTICIPANTS: Using a combination of quantitative and qualitative methods we studied 996 older Chilean subjects (65-67.9 years at baseline) with low to medium socioeconomic status from 10 health centers randomized to receive a physical activity intervention as part of the CENEX cluster trial (ISRCTN48153354). MEASUREMENTS: Using a multilevel regression model, the relationship between adherence (defined a priori as attendance at a minimum of 24 physical activity classes spread over at least 12 months) and individual, intervention-related and contextual factors was evaluated. We also conducted 40 semi-structured interviews with older adults (n=36) and instructors (n=4). Transcripts of the interviews were analyzed using content analysis to identify barriers and facilitators to adherence. RESULTS: Adherence to physical activity intervention was 42.6% (CI 95% 39.5 to 45.6). Depression, diabetes mellitus, percentage of impoverished households and rate of arrests for violent crimes in the neighborhood predicted less adherence (p<0.05) while being retired, participation in physical activity prior to the intervention, and green areas per habitant were positively associated with adherence (p<0.05). The qualitative interviews identified three primary barriers to adherence: current health problems, lack of time due to commitments for caring for family members, and being employed, and two primary facilitators to adherence: the health benefits attributed to the intervention and the opportunity the classes provided for social interaction with others. CONCLUSION: In order to enhance effectiveness of community exercise interventions, strategies to improve participation should be targeted to older adults from deprived areas and those with psychological and medical conditions. PMID- 23636551 TI - Moderate alcohol consumption predicts long-term mortality in elderly subjects with chronic heart failure. AB - OBJECTIVE: Moderate alcohol consumption is related to a reduction of mortality. However, this phenomenon is not well established in the elderly, especially in the presence of chronic heart failure (CHF). The aim of the study was to verify the effect of moderate alcohol consumption on 12-year mortality in elderly community-dwelling with and without CHF. SETTINGS: community-dwelling from 5 regions of Italy. PARTICIPANTS: A cohort of 1332 subjects aged 65 and older. MEASUREMENT: Mortality after 12-year follow-up in elderly subjects (>=65 years old) with and without CHF was studied. Moderate alcohol consumption was considered <=250 ml/day (drinkers). RESULTS: In the absence of CHF (n=947), mortality was 42.2% in drinkers vs. 53.7% in non-drinker elderly subjects (p=0.021). In contrast, in the presence of CHF (n=117), mortality was 86.5% in drinkers vs. 69.7% in non-drinker elderly subjects (p=0.004). Accordingly, Cox regression analysis shows that a moderate alcohol consumption is protective of mortality in the absence (HR=0.79; CI 95% 0.66-0.95; p<0.01) but it is predictive of mortality in the presence of CHF (HR=1.29; CI 95% 1.05-1.97; p<0.05). CONCLUSIONS: Our data demonstrates that moderate alcohol consumption is associated with an increased long-term mortality risk in the elderly in the presence of CHF. PMID- 23636553 TI - sTNFr1 and it's contributory role in the evolution and progression of different psychiatric disorders. PMID- 23636552 TI - Sustainability of a physical activity and nutrition program for seniors. AB - OBJECTIVE: This prospective cohort study aimed to determine the impact of a low cost, home-based physical activity and nutrition program for older adults at 6 months follow-up. DESIGN: A follow-up survey was conducted 6 months after program completion via computer-assisted telephone interviewing. The International Physical Activity Questionnaire and the Fat and Fibre Barometer were used to measure physical activity levels and dietary behaviours, respectively. Self reported height, weight, waist and hip circumferences were obtained. Changes over three time points of data collection (baseline, post-program, follow-up) and differences between the intervention and control groups were assessed. The use of program materials was also evaluated. SETTING: Community and home-based. PARTICIPANTS: Insufficiently active 60 to 70 year olds (n = 176, intervention and n = 198, control) residing in suburbs within the Perth metropolitan area. RESULTS: A sustained improvement was observed for the intervention group in terms of fat avoidance behaviours (p interaction = .007). Significant improvements were found for strength exercises, fibre intake, body mass index and waist-to-hip ratio at either post-program or follow-up, however the overall effect was not significant. At post-program, the intervention group increased time spent participating in moderate activity by 50 minutes (p > .05), which was followed by a significant decline at follow-up (p < .05). Among intervention group participants, males and females differed with respect to strength exercises and moderate physical activity. CONCLUSION: This low-cost physical activity and nutrition intervention resulted in a sustained improvement in fat avoidance behaviours and overall short-term gains in physical activity. Future studies for older adults are recommended to investigate gender-specific behavioural barriers as well as booster interventions which focus on physical activity. PMID- 23636554 TI - Modern-day hipsters. PMID- 23636555 TI - Biomechanical evaluation of the TightRope versus traditional docking ulnar collateral ligament reconstruction technique: kinematic and failure testing. AB - BACKGROUND: Numerous variations of ulnar collateral ligament (UCL) reconstruction have been described since the original technique by Jobe et al. Purpose/ HYPOTHESIS: To biomechanically compare the new TightRope technique and the traditional ulnar bone tunnels as used in the docking technique. The hypothesis was that the TightRope technique would exhibit improved kinematics and comparable failure properties. STUDY DESIGN: Controlled laboratory study. METHODS: Seven matched pairs of cadaveric arms (mean age, 44.71 years) were tested in both the native state and reconstructed state. Kinematics were assessed at 15 degrees to 90 degrees of flexion by applying a 1.5-N.m valgus torque and measuring the resultant angular displacement. Failure testing was performed by loading to failure at 4.5 deg/s in 70 degrees of flexion. Sides of a matched pair were randomized to the TightRope (TR) and docking (DO) techniques after testing the native state. RESULTS: There was no significant difference in kinematic results between the native state and reconstructed state in either the TR or DO group at 15 degrees to 75 degrees of flexion. At 90 degrees , the TR group had significantly higher angular displacement (2.23 degrees +/- 1.0 degrees ) compared with the native state (1.31 degrees +/- 0.7 degrees ) (P = .020). The TR-reconstructed specimens had significantly lower initial stiffness (49.34 +/- 19.3 N.m/rad vs 82.47 +/- 36.0 N.m/rad, respectively; P = .007) and total stiffness (53.81 +/- 27.8 N.m/rad vs 101.06 +/- 34.4 N.m/rad, respectively; P < .001) than did the paired native specimens. In addition, the TR-reconstructed specimens had significantly lower torsional torque at 5 degrees of valgus rotation (mean, 4.61 +/- 2.2 N.m vs 7.62 +/- 3.7 N.m, respectively; P = .010), at 15 degrees of valgus rotation (12.24 +/- 4.4 N.m vs 20.65 +/- 6.8 N.m, respectively; P = .002), and at ultimate failure (19.18 +/- 7.5 N.m vs 25.42 +/- 7.1 N.m, respectively; P = .025) than did the paired native specimens. There was no significant difference in torsional torque between the TR and DO groups at 5 degrees of valgus rotation (4.61 +/- 2.2 N.m vs 4.09 +/- 1.7 N.m, respectively; P = .644), at 15 degrees of valgus rotation (12.24 +/- 4.4 N.m vs 17.94 +/- 7.23 N.m, respectively; P = .178), or at failure (19.18 +/- 7.5 N.m vs 23.19 +/- 10.6 N.m, respectively; P = .444). The DO group exhibited significantly higher angular displacement at failure than did the native state (28.12 degrees +/- 8.5 degrees vs 18.04 degrees +/- 4.8 degrees , respectively; P = .009), but there was no difference at 3 N.m of loading. There was no significant difference in angular displacement either at 3 N.m or at failure between the native state and reconstructed state in the TR group. CONCLUSION: Both the TR and DO techniques restored native joint kinematics from 15 degrees to 75 degrees of flexion under low loading conditions. While the TR technique exhibited inferior failure torque compared with the native state, the DO technique did not differ from the native state. No differences were found between the TR and DO groups when compared directly. The DO technique restored valgus stability under high loading to a greater extent than did the TR technique but also failed at higher angular displacement. CLINICAL RELEVANCE: Strong postoperative UCL reconstruction fixation is important to restore ulnotrochlear joint stability. Our study demonstrates that the new TR technique has comparable kinematic and failure properties to the traditional DO technique. PMID- 23636556 TI - Causality in biology has to answer 2 main questions--which and how: letter to the editor. PMID- 23636557 TI - Hyaluronic acid and platelet-rich plasma, intra-articular infiltration in the treatment of gonarthrosis: letter to the editor. PMID- 23636558 TI - Analyzing chondrocyte viability: letter to the editor. PMID- 23636563 TI - Bicuspid aortic valve and lusory artery: an unusual association. PMID- 23636560 TI - Optic disc and retinal nerve fiber layer parameters as indicators of neurodegenerative brain changes in patients with obstructive sleep apnea syndrome. AB - PURPOSE: Retina is a unique part of the central nervous system (CNS) for visualizing the processes of axonal and neuronal degeneration. Optical coherence tomography (OCT) allows direct visualization and measurement of retinal nerve fiber layer (RNFL) thickness, macular volume, and optic disc (OD) parameters. One of the disorders associated with atrophy in different brain regions is obstructive sleep apnea syndrome (OSAS). In the present study, we aimed to determine OD and RNFL changes measured by OCT for investigating the progress of neurodegeneration development in OSAS, excluding all the other conditions that can directly affect RNFL thickness and optic nerve parameters. METHODS: Both eyes of 101 patients with OSAS and 20 controls were investigated by OCT. Full-night polysomnography (PSG) and ophthalmologic examination including automated visual field (VF) examination and OCT were performed in all of the patients. RESULTS: According to the OSAS grading, patients were grouped as mild (n=15), moderate (n=27), and severe (n=59). We found significant decrease in RNFL thickness only in the patients with severe OSAS compared with the other groups and decreased macular ganglion cell thickness in the severe OSAS group compared with the control group. VF parameters were significantly worsened in all the OSAS subgroups compared to the control group. We found different data such as normal or increased optic nerve parameters as result of subtle OD edema, which may mask possible peripapillar axonal loss. CONCLUSIONS: We think that evaluation of neurodegeneration in OSAS is not always possible by examining OD and RNFL because there are difficulties due to the confounding issues of cerebral atrophy and OD edema. PMID- 23636562 TI - Competitive exclusion in a two-species chemotaxis model. AB - We consider a mathematical model for the spatio-temporal evolution of two biological species in a competitive situation. Besides diffusing, both species move toward higher concentrations of a chemical substance which is produced by themselves. The resulting system consists of two parabolic equations with Lotka Volterra-type kinetic terms and chemotactic cross-diffusion, along with an elliptic equation describing the behavior of the chemical. We study the question in how far the phenomenon of competitive exclusion occurs in such a context. We identify parameter regimes for which indeed one of the species dies out asymptotically, whereas the other reaches its carrying capacity in the large time limit. PMID- 23636564 TI - Anti-thrombotic treatment in patients with a long-term indication for anticoagulant therapy undergoing coronary stenting. PMID- 23636561 TI - Central sleep apnea and complex sleep apnea in patients with epilepsy. AB - PURPOSE: We sought to examine the prevalence of central sleep apnea (CSA) and complex sleep apnea (CompSA) in patients with epilepsy and to examine their clinical profile, with respect to epilepsy type, etiology, medication use, and EEG abnormalities. METHODS: We undertook a retrospective analysis of 719 consecutive patients with epilepsy who underwent polysomnography (PSG) at our institution between 2004 and 2011. Of the 458 patients with complete data, we excluded 42 patients with congestive heart failure or left ventricular ejection fraction <40 %. Comparison of clinical and PSG variables between the three groups were conducted with Fisher exact test and analysis of variance. RESULTS: Out of 416 patients tested, 315 (75 %) had obstructive sleep apnea (OSA), 16 (3.7 %) had CSA, 33 (7.9 %) had CompSA. There were more males in the CSA and CompSA groups than in the OSA group (81.2, 81.8, and 59.6 %, respectively, p=0.04). Focal seizures were more prevalent in patients with CSA than in patients OSA or CompSA (62.5, 265, and 21.1 %, respectively, p=0.02). CONCLUSION: About 11 % of epilepsy patients have sleep-breathing disorders with central apneas, which is not higher than that in a general population. These data should be expanded with future research investigating the role of interictal, ictal, and postictal central apneas in epileptogenesis and epilepsy. PMID- 23636565 TI - The audit-intervention-reaudit cycle can improve diagnostic standards for chronic obstructive pulmonary disease (COPD). PMID- 23636566 TI - Synthesis of aluminum oxide supported fluorescent gold nanodots for the detection of silver ions. AB - Photoluminescent gold nanodots (Au NDs) on aluminum oxide nanoparticles (Al2O3 NPs) with the emission wavelengths ranging from 510 to 630 nm are unveiled. Orange Al2O3 NP@AuNDs show high selectivity and sensitivity towards Ag(+) ions by metallophilic Ag(+)-Au(+) interactions and induced fluorescence quenching of Au NDs. PMID- 23636568 TI - Validity and reliability of dental age estimation of teeth root translucency based on digital luminance determination. AB - In forensic anthropological casework, estimating age-at-death is key to profiling unknown skeletal remains. The aim of this study was to examine the reliability of a new, simple, fast, and inexpensive digital odontological method for age-at death estimation. The method is based on the original Lamendin method, which is a widely used technique in the repertoire of odontological aging methods in forensic anthropology. We examined 129 single root teeth employing a digital camera and imaging software for the measurement of the luminance of the teeth's translucent root zone. Variability in luminance detection was evaluated using statistical technical error of measurement analysis. The method revealed stable values largely unrelated to observer experience, whereas requisite formulas proved to be camera-specific and should therefore be generated for an individual recording setting based on samples of known chronological age. Multiple regression analysis showed a highly significant influence of the coefficients of the variables "arithmetic mean" and "standard deviation" of luminance for the regression formula. For the use of this primer multivariate equation for age-at death estimation in casework, a standard error of the estimate of 6.51 years was calculated. Step-by-step reduction of the number of embedded variables to linear regression analysis employing the best contributor "arithmetic mean" of luminance yielded a regression equation with a standard error of 6.72 years (p < 0.001). The results of this study not only support the premise of root translucency as an age-related phenomenon, but also demonstrate that translucency reflects a number of other influencing factors in addition to age. This new digital measuring technique of the zone of dental root luminance can broaden the array of methods available for estimating chronological age, and furthermore facilitate measurement and age classification due to its low dependence on observer experience. PMID- 23636570 TI - Comment on Jigami et al.: Effects of weekly and fortnightly therapeutic exercise on physical function and health-related quality of life in individuals with hip osteoarthritis. PMID- 23636569 TI - Driving under the influence of synthetic cannabinoids ("Spice"): a case series. AB - Recreational use of synthetic cannabinoid receptor agonists-so-called "Spice" products-became very popular during the last few years. Several reports on clinical symptoms and poisonings were published. Unfortunately, most of these reports do not contain any analytical data on synthetic cannabinoids in body fluids, and no or only a limited number of cases were reported concerning driving under the influence (DUI) of this kind of drugs. In this article, several cases of DUI of synthetic cannabinoids (AM-2201, JWH-018, JWH-019, JWH-122, JWH-210, JWH-307, MAM-2201 (JWH-122 5-fluoropentyl derivative), and UR-144) are presented, focusing on analytical results and signs of impairment documented by the police or the physicians who had taken the blood sample from the suspects. Consumption of synthetic cannabinoids can lead to impairment similar to typical performance deficits caused by cannabis use which are not compatible with safe driving. These deficits include centrally sedating effects and impairment of fine motor skills necessary for keeping the vehicle on track. Police as well as forensic toxicologists and other groups should become familiar with the effects of synthetic cannabinoid use, and be aware of the fact that drug users may shift to these "legal" alternatives due to their nondetectability by commonly used drug screening tests based on antibodies. Sophisticated screening procedures covering the complete range of available compounds or their metabolites have to be developed for both blood/serum and urine testing. PMID- 23636571 TI - Reply to letter to the editor by Nishii. PMID- 23636572 TI - Effect of Achilles tenotomy on congenital clubfoot-associated calf-muscle atrophy: an ultrasonographic study. AB - BACKGROUND: The Ponseti method for treating congenital clubfoot requires Achilles tenotomy to be performed toward the end of serial casting. However, it remains unclear if Achilles tenotomy has a negative effect on clubfoot-associated calf muscle atrophy. We therefore investigated this issue by ultrasonographic examination. MATERIALS AND METHODS: We studied 36 patients with congenital clubfoot who were treated with the Ponseti method and underwent Achilles tenotomy. Only unilateral cases were evaluated to enable comparison of the severity of atrophy and its changes over time between affected and unaffected sides. Tenotomy was performed at a mean age of 10.2 weeks after birth (range 8-16 weeks). The transverse and anteroposterior diameters of the calf muscles on the unaffected and affected sides were measured ultrasonographically by two examiners. The mean observation period was 27 months (range 24-34 months). Measurements were performed within 6 months after tenotomy, between 7 and 17 months after tenotomy, and at the final assessment. Differences between the diameters of the affected and unaffected sides at each time point, and changes in the diameters over time were determined. The data were analyzed by use of one-way ANOVA and repeated-measures ANOVA. RESULTS: Tendon healing and gliding were achieved in all cases. There were significant differences between the diameters of the unaffected and affected sides at all measurement points (transverse p < 0.005, anteroposterior p < 0.01). The diameters of calf muscles on both sides increased significantly over time (p < 0.0001). The patterns of change in diameter were similar on both sides. CONCLUSION: The transverse and anteroposterior diameters of the calf muscles differed significantly between the affected and unaffected sides after Achilles tenotomy, but there were no significant differences in changes over time. These results suggest that Achilles tenotomy had no negative short-term effects on calf-muscle atrophy associated with clubfoot. PMID- 23636573 TI - Tip to apex distance in femoral intertrochanteric fractures: a systematic review. AB - BACKGROUND: Hip fractures are associated with high morbidity, mortality, and cost. Implants used for hip fracture fixation can fail for many reasons including lag screw cut-out. Tip-apex distance (TAD) is indicative of the position and depth of a screw in the femoral head and has been shown to be associated with cut out failure. We conducted a systematic review of the published literature to quantify the association between TAD and cut-out failure for patients undergoing hip fracture fixation surgery. METHODS: We performed a search of the Medline, Embase, and Cochrane databases. We performed abstract and full text reviews independently and in duplicate. We used a random effects model to combine, in duplicate, the incidence of cut-out for patients who had TAD <25 mm and TAD >25 mm. We also combined mean TAD values for patients who had cut-out failure and those who did not. RESULTS: Seventeen studies were eligible for this review, four of which were included in combined analysis of dichotomous outcomes and seven in combined analysis of continuous outcomes. Patients with TAD >25 mm had a significantly greater risk of cut-out than patients with TAD <25 mm (RR = 12.71). Patients who experienced implant cut-out had significantly higher TAD scores than those who did not (mean difference = 6.54 mm). CONCLUSION: Tip-apex distance is an important concept in relation to cut-out failure of hip fracture fixation surgery. Surgeons should understand and apply the concept of TAD to improve outcomes for their patients. PMID- 23636574 TI - [Narcissistic personality disorder]. AB - Narcissism is a multifaceted term which encompasses traits of normal personality as well as a specific personality disorder. While much research has been concerned with narcissism as a trait there are only few empirical studies available on narcissistic personality disorder (NPS). The current diagnostic of NPS according to DSM-IV-TR focuses on grandiose type narcissism whereas vulnerable narcissism, which has been described by clinicians and researchers has not yet been recognised. Psychotherapy of narcissistic patients through different psychotherapeutic schools focuses mainly on processes in the therapeutic relationship, the analysis and change of grandiose and vulnerable schemas, emotion regulation techniques and correction of narcissistic behavior in favor of prosocial interactions. PMID- 23636575 TI - Mechanics of the mitral annulus in chronic ischemic cardiomyopathy. AB - Approximately one third of all patients undergoing open-heart surgery for repair of ischemic mitral regurgitation present with residual and recurrent mitral valve leakage upon follow up. A fundamental quantitative understanding of mitral valve remodeling following myocardial infarction may hold the key to improved medical devices and better treatment outcomes. Here we quantify mitral annular strains and curvature in nine sheep 5 +/- 1 weeks after controlled inferior myocardial infarction of the left ventricle. We complement our marker-based mechanical analysis of the remodeling mitral valve by common clinical measures of annular geometry before and after the infarct. After 5 +/- 1 weeks, the mitral annulus dilated in septal-lateral direction by 15.2% (p = 0.003) and in commissure commissure direction by 14.2% (p < 0.001). The septal annulus dilated by 10.4% (p = 0.013) and the lateral annulus dilated by 18.4% (p < 0.001). Remarkably, in animals with large degree of mitral regurgitation and annular remodeling, the annulus dilated asymmetrically with larger distortions toward the lateral posterior segment. Strain analysis revealed average tensile strains of 25% over most of the annulus with exception for the lateral-posterior segment, where tensile strains were 50% and higher. Annular dilation and peak strains were closely correlated to the degree of mitral regurgitation. A complementary relative curvature analysis revealed a homogenous curvature decrease associated with significant annular circularization. All curvature profiles displayed distinct points of peak curvature disturbing the overall homogenous pattern. These hinge points may be the mechanistic origin for the asymmetric annular deformation following inferior myocardial infarction. In the future, this new insight into the mechanism of asymmetric annular dilation may support improved device designs and possibly aid surgeons in reconstructing healthy annular geometry during mitral valve repair. PMID- 23636576 TI - Noninvasive technique for monitoring drug transport through the murine cochlea using micro-computed tomography. AB - Local delivery of drugs to the inner ear has the potential to treat inner ear disorders including permanent hearing loss or deafness. Current mathematical models describing the pharmacokinetics of drug delivery to the inner ear have been based on large rodent studies with invasive measurements of concentration at few locations within the cochlea. Hence, estimates of clearance and diffusion parameters are based on fitting measured data with limited spatial resolution to a model. To overcome these limitations, we developed a noninvasive imaging technique to monitor and characterize drug delivery inside the mouse cochlea using micro-computed tomography (MUCT). To increase the measurement accuracy, we performed a subject-atlas image registration to exploit the information readily available in the atlas image of the mouse cochlea and pass segmentation or labeling information from the atlas to our MUCT scans. The approach presented here has the potential to quantify concentrations at any point along fluid-filled scalae of the inner ear. This may permit determination of spatially dependent diffusion and clearance parameters for enhanced models. PMID- 23636577 TI - Hypophosphatemic rickets due to perturbations in renal tubular function. AB - The common denominator for all types of rickets is hypophosphatemia, leading to inadequate supply of the mineral to the growing bone. Hypophosphatemia can result from insufficient uptake of the mineral from the gut or its disproportionate losses in the kidney, the latter being caused by either tubular abnormalities per se or the effect on the tubule of circulating factors like fibroblast growth factor-23 and parathyroid hormone (PTH). High serum levels of the latter result in most cases from abnormalities in vitamin D metabolism which lead to decreased calcium absorption in the gut and hypocalcemia, triggering PTH secretion. Rickets is a disorder of the growth plate and hence pediatric by definition. However, it is important to recognize that the effect of hypophosphatemia on other parts of the skeleton results in osteomalacia in both children and adults. This review addresses the etiology, pathophysiologic mechanisms, clinical manifestations and treatment of entities associated with hypophosphatemic rickets due to perturbations in renal tubular function. PMID- 23636578 TI - Does the ureteric jet Doppler waveform have a role in detecting vesicoureteric reflux? AB - Data reported in this issue of Pediatric Nephrology suggest that the ureteric jet Doppler waveform can predict the occurrence of vesicoureteric reflux (VUR). Many different methods are currently used to detect VUR, including traditional X-ray micturating cystourethrogram, indirect and direct nuclear imaging and contrast enhanced ultrasonography. These methods are invasive, do have some radiation burden and are also quite uncomfortable to paediatric patients. This relatively new non-invasive method is therefore of interest, but its efficacy needs to be confirmed in further studies and, in particular, in babies and infants before it can possibly be considered as a good method to provide clinical information on VUR. Once such studies have been performed, this method may also prove to be a useful approach to obtain modern knowledge on the occurrence of VUR in healthy children. PMID- 23636579 TI - Renal tubular dysgenesis. AB - Renal tubular dysgenesis (RTD) is a severe foetal disorder characterised by the absence or poor development of proximal tubules, early onset and persistent anuria (leading to oligohydramnios and the Potter sequence) and ossification defects of the skull. In most cases, early death occurs from pulmonary hypoplasia, anuria and refractory arterial hypotension. RTD may be acquired during foetal development or inherited as an autosomal recessive disease. Inherited RTD is genetically heterogeneous and linked to mutations in the genes encoding the major components of the renin-angiotensin system (RAS): angiotensinogen, renin, angiotensin-converting enzyme or angiotensin II receptor type 1. Mutations result in either the absence of production or lack of efficacy of angiotensin II. Secondary RTD has been observed in various situations, particularly in the donor twin of severe twin-to-twin transfusion syndrome, in foetuses affected with congenital haemochromatosis or in foetuses exposed to RAS blockers. All cases result in renal hypoperfusion. These examples illustrate the importance of a functional RAS in the maintenance of blood pressure and renal blood flow for humans during foetal life. The diagnosis of RTD in an anuric foetus with normal renal sonography results is important for the management of the foetus or neonate. Depending on the genetic or secondary cause of the disease, such findings can lead to genetic counselling or the prevention of recurrence in subsequent pregnancies. PMID- 23636580 TI - Psychoecological model of alcohol use in Mexican American adolescents. AB - In this study, we proposed and tested a structural model based on Bronfenbrenner's ecological systems theory in order to further understand alcohol use among Hispanic adolescents, who are at greater risk of alcohol use than adolescents of other racial/ethnic groups. Family cohesion, school connectedness, and peer influence were conceptualized as three primary process factors, while psychological distress was used as a mediating factor and Mexican culture orientation as a cultural factor. The sample comprised 444 Mexican American adolescents (aged 16-20) living along the U.S./Mexico border. The proposed model explained 33 % of the variance in alcohol use. Most of the hypothesized relationships in the proposed model were supported: (a) low family cohesion had significant indirect effects mediated through psychological distress, poor school connectedness, and negative peer influence; (b) poor school connectedness had significant indirect effects mediated through psychological distress and negative peer influence; (c) psychological distress had a significant direct effect as well as a significant indirect effect mediated through negative peer influence; and (d) negative peer influence had the strongest direct effect. However, contrary to the hypothesis, Mexican culture orientation was not a protective factor, but rather had a significant positive relationship with negative peer influence. Lastly, it was found that gender, school status, Anglo cultural orientation, and severity of alcohol use did not have any moderating effects. Based on the collective findings, suggestions for primary prevention programs designed to reduce underage drinking among Mexican American youth were given. PMID- 23636581 TI - Ion pumps as biological targets for decavanadate. AB - The putative applications of poly-, oligo- and mono-oxometalates in biochemistry, biology, pharmacology and medicine are rapidly attracting interest. In particular, these compounds may act as potent ion pump inhibitors and have the potential to play a role in the treatment of e.g. ulcers, cancer and ischemic heart disease. However, the mechanism of action is not completely understood in most cases, and even remains largely unknown in other cases. In the present review we discuss the most recent insights into the interaction between mono- and polyoxometalate ions with ion pumps, with particular focus on the interaction of decavanadate with Ca(2+)-ATPase. We also compare the proposed mode of action with those of established ion pump inhibitors which are currently in therapeutic use. Of the 18 classes of compounds which are known to act as ion pump inhibitors, the complete mechanism of inhibition is only known for a handful. It has, however, been established that most ion pump inhibitors bind mainly to the E2 ion pump conformation within the membrane domain from the extracellular side and block the cation release. Polyoxometalates such as decavanadate, in contrast, interact with Ca(2+)-ATPase near the nucleotide binding site domain or at a pocket involving several cytoplasmic domains, and therefore need to cross through the membrane bilayer. In contrast to monomeric vanadate, which only binds to the E2 conformation, decavanadate binds to all protein conformations, i.e. E1, E1P, E2 and E2P. Moreover, the specific interaction of decavanadate with sarcoplasmic reticulum Ca(2+)-ATPase has been shown to be non-competitive with respect to ATP and induces protein cysteine oxidation with concomitant vanadium reduction which might explain the high inhibitory capacity of V10 (IC50 = 15 MUM) which is quite similar to the majority of the established therapeutic drugs. PMID- 23636582 TI - Ectomycorrhizas naturally established in Nothofagus nervosa seedlings under different cultivation practices in a forest nursery. AB - Mycorrhizas are mutualistic associations between soil fungi and plant roots which usually improve water and nutrient uptake, influencing plant fitness. Nothofagus nervosa (Rauli) is an ecologically and economically important species of South American temperate forests. Since this native tree species yields valuable timber, it was overexploited and its natural distribution area was critically reduced, so it is currently included in domestication and conservation programs. Among the factors that should be considered in these programs are the ectomycorrhizas (EcM), which would be important for the successful establishment and survival of outplanted seedlings. The aim of this work was to analyze the abundance and diversity of EcM in N. nervosa nursery-cultivated seedlings assessed by morphotyping, fungal isolation, and DNA sequencing. Arbuscular mycorrhiza (AM) occurrence was also studied. A 2-year trial was conducted following the cultivation conditions used for domestication programs. Seedlings were cultivated under two different cultivation practices (greenhouse and nursery soil) without artificial inoculation of mycorrhizal fungi. Seedlings' roots were examined at different times. It was observed that they developed EcM between 6 and 12 months after germination and AMs were not detected in any plant. The most abundant ectomycorrhizal fungi present in seedlings' roots were Tomentella ellisii (Basidiomycota) and an unidentified fungus named Ascomicetous EcM sp. 1. Abundance and diversity of EcM varied between the two cultivation techniques analyzed in this study, since seedlings that continued growing in the greenhouse had higher colonization values, but those transplanted to the nursery soil were colonized by a higher diversity of fungal taxa. PMID- 23636583 TI - Light and phosphate competition between Cylindrospermopsis raciborskii and Microcystis aeruginosa is strain dependent. AB - The hypothesis that outcomes of phosphorus and light competition between Cylindrospermopsis raciborskii and Microcystis aeruginosa are strain dependent was tested experimentally. Critical requirements of phosphorus (P*) and of light (I*) of two strains of each species were determined through monoculture experiments, which indicated a trade-off between species and also between Microcystis strains. Competition experiments between species were performed using the weakest predicted competitors (with the highest values of P* and of I*) and with the strongest predicted competitors (with the lowest values of P* and of I*). Under light limitation, competition between the weakest competitors led C. raciborskii to dominate. Between the strongest competitors, the opposite was observed, M. aeruginosa displaced C. raciborskii, but both strains co-existed in equilibrium. Under phosphate limitation, competition between the weakest competitors led C. raciborskii to exclude M. aeruginosa, and between the strongest competitors, the opposite was observed, M. aeruginosa displaced C. raciborskii, but the system did not reach an equilibrium and both strains were washed out. Hence, outcomes of the competition depended on the pair of competing strains and not only on species or on type of limitation. We concluded that existence of different trade-offs among strains and between species underlie our results showing that C. raciborskii can either dominate or be displaced by M. aeruginosa when exposed to different conditions of light or phosphate limitation. PMID- 23636584 TI - A tuneable array of unique steady-state microfluidic gradients. AB - We report an on-chip gradient generator that has been designed, modelled, fabricated, and characterized to facilitate temporal tuning of several unique gradients in parallel for multiple applications. This design allows for steady state programming of the intensities across multiple orders of magnitude while producing exponential, linear, and logarithmic gradient profiles. The magnitude of the gradients is controlled through regulating the ratio of the two on-chip flow inlets without the need for valves or other active mixers. On-chip binding of biotin by a fluorescent streptavidin complex creates a diffusive barrier that regulates access to the gradient inlets, providing a second orthogonal mechanism for regulating the microgradient intensities. The device is also characterized using an on-chip enzymatic reaction to produce an array of tuneable product concentrations within the various microchannels. PMID- 23636587 TI - Abstracts of the 97th Annual Meeting of the German Society of Pathology. May 23 26, 2013. Heidelberg. Germany. PMID- 23636585 TI - Asthma and the immune response to MMR vaccine viruses in Somali immigrant children: a cross-sectional retrospective cohort study. AB - BACKGROUND: According to the 'hygiene hypothesis', an increase in microbial exposure in childhood leads to a T-helper cell 1 (Th1) predominant immune response and protection against asthma and atopic conditions. AIMS: To assess the prevalence of asthma and other atopic conditions in Somali immigrants and to determine the humoral immune response to the measles, mumps, and rubella (MMR) vaccine viruses in Somali immigrants with asthma. METHODS: A retrospective cohort study was conducted in Olmsted County, Minnesota. Study subjects were Somali immigrants who were born and lived in Africa during childhood and immigrated to the USA. The subjects had participated in a previous MMR vaccine study. Asthma was ascertained using predetermined asthma criteria after a thorough medical record review. An atopic condition was determined from physician-diagnosed ICD codes. Virus-specific IgG levels in response to the MMR vaccine viruses were determined using an enzyme immunoassay. RESULTS: Of the 62 eligible subjects, 33 (53%) were female and 29 (47%) were male; 10 (16%) had asthma and 22 (35%) had other atopic conditions. There was no difference in the rubella (p=0.150) and measles (p=0.715) virus-specific IgG levels between the subjects with and without asthma. Mumps virus-specific IgG antibody levels were lower in those with asthma than in those without asthma (mean+/-SE 2.08+/-0.28 vs. 3.06+/-0.14, p=0.005). CONCLUSIONS: Our study results may not support the hygiene hypothesis. In addition, the previously reported abnormal T-cell development in Caucasian children with atopy can be considered even in Somali immigrants. PMID- 23636588 TI - Note: steps taken to optimise probe specificity and signal intensity prior to field validation of the MIDTAL (Microarray for the Detection of Toxic Algae). AB - A microarray for the detection of toxic algal species was developed in the European Union 7th Framework project MIDTAL. We initially tested all available fluorescence in situ hybridisation probes for toxic algae, which are normally designed to a length of 18 nt, and found that in most cases the signal was rather weak or all probes designed from the second half of the molecule were inaccessible in a microarray format because of secondary structure of the ribosomal RNA molecule We modified the length of the probes, the fragmentation of the rRNA, the stringency of the washing buffers and the length of the spacer molecules linking the probes to the glass surface of the microarray. Because of the secondary structure of the rRNA molecule, regions of the molecule can be difficult to access by the probes. Each of these modifications has improved probe accessibility and probe specificity to reduce false positives. PMID- 23636589 TI - Effects of multigenerational exposures of D. magna to environmentally relevant concentrations of pentachlorophenol. AB - The re-emergence of schistosomiasis has given rise to ubiquitous concentrations of the primary control agent pentachlorophenol (PCP) in the environment, especially in the surface waters of China. In this study, the effects of environmentally relevant concentrations of PCP, namely, 0.0002, 0.002, 0.02, 0.2, and 2 MUmol/L on survival, age at first reproduction, fecundity, length of mothers, and number of molts of Daphnia magna were studied over three generations. The survival of D. magna exposed to 2 MUmol/L was significantly affected in the three generations. Toxic effects were enhanced in later generations. Age at first reproduction of F1 and F2 D. magna was significantly slower than that of the controls. The total number of offspring per female exposed to concentrations of 0.002 MUmol/L or greater was less (23.5 to 67.6, 9.4 to 73.7, and 3.6 to 83.7%) than that of the controls in the F0, F1, and F2 generations, respectively. The body length of mothers significantly decreased (4.7 to 6.8, 9.6 to 15.1, and 13.3 to 23.2%) after exposure to 0.002 MUmol/L or greater than those of unexposed individuals in the F0, F1, and F2 generations, respectively. Dose-response relationships between concentrations of PCP and length and number of molts of D. magna were observed in the F0 to F2 generations. PCP concentrations on the surface waters of China caused adverse effects to D. magna, which increased over successive generations. Significant effects were observed in the third generation. The multigenerational studies were more sensitive than the single-generation experiments. Thus, multigenerational exposure may be more predictive of chronic exposure under field conditions. PMID- 23636590 TI - Adsorptive removal and photocatalytic decomposition of sulfamethazine in secondary effluent using TiO2-zeolite composites. AB - We investigated the adsorption and decomposition of sulfamethazine (SMT), which is used as a synthetic antibacterial agent and discharged into environmental water, using high-silica Y-type zeolite (HSZ-385), titanium dioxide (TiO2), and TiO2-zeolite composites. By using ultrapure water and secondary effluent as solvents, we prepared SMT solutions (10 MUg/L and 10 mg/L) and used them for adsorption and photocatalytic decomposition experiments. When HSZ-385 was used as an adsorbent, rapid adsorption of SMT in the secondary effluent was confirmed, and the adsorption reached equilibrium within 10 min. The photocatalytic decomposition rate using TiO2 in the secondary effluent was lower than that in ultrapure water, and we clarified the inhibitory effect of ions and organic matter contained in the secondary effluent on the reaction. We synthesized TiO2 zeolite composites and applied them to the removal of SMT. During the treatment of 10 MUg/L SMT in the secondary effluent using the composites, 76% and more than 99% of the SMT were decomposed within 2 and 4 h by photocatalysis. The SMT was selectively adsorbed onto high-silica Y-type zeolite in the composites. Resultantly, the inhibitory effect of the coexisting materials was reduced, and the composites could remove SMT more effectively compared with TiO2 alone in the secondary effluent. PMID- 23636591 TI - Accounting for both local aquatic community composition and bioavailability in setting site-specific quality standards for zinc. AB - Recent years have seen considerable improvement in water quality standards (QS) for metals by taking account of the effect of local water chemistry conditions on their bioavailability. We describe preliminary efforts to further refine water quality standards, by taking account of the composition of the local ecological community (the ultimate protection objective) in addition to bioavailability. Relevance of QS to the local ecological community is critical as it is important to minimise instances where quality classification using QS does not reconcile with a quality classification based on an assessment of the composition of the local ecology (e.g. using benthic macroinvertebrate quality assessment metrics such as River InVertebrate Prediction and Classification System (RIVPACS)), particularly where ecology is assessed to be at good or better status, whilst chemical quality is determined to be failing relevant standards. The alternative approach outlined here describes a method to derive a site-specific species sensitivity distribution (SSD) based on the ecological community which is expected to be present at the site in the absence of anthropogenic pressures (reference conditions). The method combines a conventional laboratory ecotoxicity dataset normalised for bioavailability with field measurements of the response of benthic macroinvertebrate abundance to chemical exposure. Site-specific QSref are then derived from the 5%ile of this SSD. Using this method, site QSref have been derived for zinc in an area impacted by historic mining activities. Application of QSref can result in greater agreement between chemical and ecological metrics of environmental quality compared with the use of either conventional (QScon) or bioavailability-based QS (QSbio). In addition to zinc, the approach is likely to be applicable to other metals and possibly other types of chemical stressors (e.g. pesticides). However, the methodology for deriving site-specific targets requires additional development and validation before they can be robustly applied during surface water classification. PMID- 23636592 TI - New perspectives on the passive treatment of ferruginous circumneutral mine waters in the UK. AB - This paper examines major physico-chemical processes during the passive treatment of ferruginous circumneutral drainage from abandoned coal mines in the UK. Data collected over several years of studies on mine water treatment systems shed new light on the relative importance of hydraulics, settling velocity, Fe(II) oxidation rates and cascade aeration, which, in turn, informs the design of future systems. This paper demonstrates that (1) the complex settling behaviour of Fe(III) precipitates may be described by a first-order volumetric process and that settling rate is different for different mine waters; (2) the hydraulic efficiency (ratio of time to peak tracer concentration to nominal residence time) of the settling ponds studied was widely variable at low flow rates in comparison to constructed wetlands; (3) aeration cascades contribute dissolved oxygen and lead to a rise in pH due to CO2 degassing, which are very important in reducing the required time for iron oxidation and removal; (4) for at least 10 of the 30 sites examined, modelling of the rates of Fe(II) oxidation and particulate settling reveals that removal of iron is primarily dependent on settling rate; and (5) that substantial increases in pH can be brought about by forced aeration of mine water over several hours. Findings of this study apply to the majority of coal mine water treatment sites in the UK and may have broader application to other ferruginous waters with circumneutral pH or after treatment to increase pH. PMID- 23636593 TI - Polychlorinated biphenyls (PCBs) in Africa: a review of environmental levels. AB - Several studies have shown an increase in PCB sources in Africa due to leakage and wrongly disposed transformers, continuing import of e-waste from countries of the North, shipwreck, and biomass burning. Techniques used in the recycling of waste such as melting and open burning to recover precious metals make PCBs contained in waste and other semivolatile organic substances prone to volatilization, which has resulted in an increase of PCB levels in air, blood, breast milk, and fish in several regions of Africa. Consequences for workers performing these activities without adequate measures of protection could result in adverse human health effects. Recent biodegradation studies in Africa have revealed the existence of exotic bacterial strains exhibiting unique and unusual PCB metabolic capability in terms of array of congeners that can serve as carbon source and diversity of congeners attacked, marking considerable progress in the development of effective bioremediation strategies for PCB-contaminated matrices such as sediments and soils in tropical regions. Action must be taken to find and deal with the major African sources of these pollutants. The precise sources of the PCB plume should be pinned down and used to complete the pollutant inventories of African countries. These nations must then be helped to safely dispose of the potentially dangerous chemicals. PMID- 23636594 TI - Accumulation, transformation, and release of inorganic arsenic by the freshwater cyanobacterium Microcystis aeruginosa. AB - Arsenic (As) as a major hazardous metalloid was affected by phytoplankton in many aquatic environments. The toxic dominant algae Microcystis aeruginosa was exposed to different concentrations of inorganic arsenic (arsenate or arsenite) for 15 days in BG11 culture media. Arsenic accumulation, toxicity, and speciation in M. aeruginos as well as the changes of As species in media were examined. M. aeruginosa has a general well tolerance to arsenate and a definite sensitivity to arsenite. Additionally, arsenate actively elevated As methylation by the algae but arsenite definitely inhibited it. Interestingly, the uptake of arsenite was more pronounced than that of arsenate, and it was correlated to the toxicity. Arsenate was the predominant species in both cells and their growth media after 15 days of exposure to arsenate or arsenite. However, the amount of the methylated As species in cells was limited and insignificantly affected by the external As concentrations. Upon uptake of the inorganic arsenic, significant quantities of arsenate as well as small amounts of arsenite, DMA, and MMA were produced by the algae and, in turn, released back into the growth media. Bio oxidation was the first and primary process and methylation was the minor process for arsenite exposures, while bioreduction and the subsequent methylation were the primary metabolisms for arsenate exposures. Arsenic bioaccumulation and transformation by M. aeruginosa in aquatic environment should be paid more attention during a period of eutrophication. PMID- 23636595 TI - Hydroxylated polychlorinated biphenyls in the environment: sources, fate, and toxicities. AB - Hydroxylated polychlorinated biphenyls (OH-PCBs) are produced in the environment by the oxidation of PCBs through a variety of mechanisms, including metabolic transformation in living organisms and abiotic reactions with hydroxyl radicals. As a consequence, OH-PCBs have been detected in a wide range of environmental samples, including animal tissues, water, and sediments. OH-PCBs have recently raised serious environmental concerns because they exert a variety of toxic effects at lower doses than the parent PCBs and they are disruptors of the endocrine system. Although evidence about the widespread dispersion of OH-PCBs in various compartments of the ecosystem has accumulated, little is currently known about their biodegradation and behavior in the environment. OH-PCBs are, today, increasingly considered as a new class of environmental contaminants that possess specific chemical, physical, and biological properties not shared with the parent PCBs. This article reviews recent findings regarding the sources, fate, and toxicities of OH-PCBs in the environment. PMID- 23636597 TI - Evaluation of the groundwater quality feasibility zones for irrigational purposes through GIS in Omalur Taluk, Salem District, South India. AB - The present work is employed in Omalur Taluk (study area 538.10 km(2)), Salem District, Tamil Nadu, India. Eighty-nine groundwater samples were collected during pre-monsoon (May) 2011 and were analyzed for major cations and anions. The irrigational parameters like; EC, Kelley's ratio, sodium absorption ratio (SAR) values, Mg(2+) hazards, HCO3 (-) and residual sodium carbonate (RSC) have been worked out to know the suitability of the groundwater for irrigational purpose. Wilcox diagram indicates that out of 89 samples, 39 samples belong to good permissible category and Doneen diagram revealed that 98.88 % of the groundwater samples fall in Class I. The plotting of SAR values in USSL diagram indicates that all the samples have low SAR value. Out of 89 samples, 44 samples were in C3 S1 field. This implies that no alkali hazard is anticipated to the crops. In 44 locations (49.44 %), samples fall within C3-S1 category. This category is suitable for irrigation purpose. However, the concentration of bicarbonate was in significant amount showing 82 % of sites under "increasing problem" and the 4 % sites under "Severe Problem" zones. Finally, the above-said results are taken into a Geographic Information System (GIS) platform. To understand the spatial distribution of unsuitable zones, ArcGIS was employed. The present work reveals that groundwater in the Omalur Taluk is of good quality and is suitable for all uses including interbrain water transfer in the region. PMID- 23636596 TI - Seasonal variations in cholinesterase activity, nerve conduction velocity and lung function among sprayers exposed to mixture of pesticides. AB - Pesticide spraying operation is associated with the increased risk of adverse health effects among sprayers who do not follow safe farm work practices. A study was conducted among pesticide sprayers in North India to evaluate the clinical and subclinical variations in their vital health parameters before and after the pesticide spraying season. Blood cholinesterase levels, pulmonary function test, nerve conduction velocity and self-reported symptoms were studied among 18 eligible and consenting male sprayers. Mean acetylcholinesterase activity was reduced by 55 % in the post-exposure assessment (P<0.001) as compared to pre exposure levels. Mean forced expiratory volume in 1 s was 20 % lower in the post exposure assessment as compared to the pre-exposure level (P<0.05). No significant change was observed in the motor and sensory nerve conduction velocity in the median nerve of sprayers before and after the spraying activity. Also, no significant variation was observed with respect to self-reported symptoms except weakness in arms and legs (P<0.05). The significant decline in lung function and acetylcholinesterase level after pesticide exposure reflects the strongly negative effect of exposure to pesticides during spraying activity. More longitudinal studies among pesticide sprayers must be undertaken to further substantiate the cause-effect relationship between pesticide exposure and its subclinical effects. There is a strong necessity to minimise the exposure through the use of personal protective equipment in pesticide sprayers. PMID- 23636600 TI - Exploration of the medical periodic table: towards new targets. AB - Metallodrugs offer potential for unique mechanisms of drug action based on the choice of the metal, its oxidation state, the types and number of coordinated ligands and the coordination geometry. We discuss recent progress in identifying new target sites and elucidating the mechanisms of action of anti-cancer, anti bacterial, anti-viral, anti-parasitic, anti-inflammatory, and anti neurodegenerative agents, as well as in the design of metal-based diagnostic agents. Progress in identifying and defining target sites has been accelerated recently by advances in proteomics, genomics and metal speciation analysis. Examples of metal compounds and chelating agents (enzyme inhibitors) currently in clinical use, clinical trials or preclinical development are highlighted. PMID- 23636599 TI - Neutral poly- and perfluoroalkyl substances in air and seawater of the North Sea. AB - Concentrations of neutral poly- and perfluoroalkyl substances (PFASs), such as fluorotelomer alcohols (FTOHs), perfluoroalkane sulfonamides (FASAs), perfluoroalkane sufonamidoethanols (FASEs), and fluorotelomer acrylates (FTACs), have been simultaneously determined in surface seawater and the atmosphere of the North Sea. Seawater and air samples were taken aboard the German research vessel Heincke on the cruise 303 from 15 to 24 May 2009. The concentrations of FTOHs, FASAs, FASEs, and FTACs in the dissolved phase were 2.6-74, <0.1-19, <0.1-63, and <1.0-9.0 pg L(-1), respectively. The highest concentrations were determined in the estuary of the Weser and Elbe rivers and a decreasing concentration profile appeared with increasing distance from the coast toward the central part of the North Sea. Gaseous FTOHs, FASAs, FASEs, and FTACs were in the range of 36-126, 3.1-26, 3.7-19, and 0.8-5.6 pg m(-3), which were consistent with the concentrations determined in 2007 in the North Sea, and approximately five times lower than those reported for an urban area of Northern Germany. These results suggested continuous continental emissions of neutral PFASs followed by transport toward the marine environment. Air-seawater gas exchanges of neutral PFASs were estimated using fugacity ratios and the two-film resistance model based upon paired air-seawater concentrations and estimated Henry's law constant values. Volatilization dominated for all neutral PFASs in the North Sea. The air-seawater gas exchange fluxes were in the range of 2.5*10(3)-3.6*10(5) pg m(-2) for FTOHs, 1.8*10(2)-1.0*10(5) pg m(-2) for FASAs, 1.1*10(2)-3.0*10(5) pg m(-2) for FASEs and 6.3*10(2)-2.0*10(4) pg m(-2) for FTACs, respectively. These results suggest that the air-seawater gas exchange is an important process that intervenes in the transport and fate for neutral PFASs in the marine environment. PMID- 23636601 TI - Sudden onset proptosis: a rare presentation of sinusitis. PMID- 23636598 TI - Environmental factors and unhealthy lifestyle influence oxidative stress in humans--an overview. AB - Oxygen is the most essential molecule for life; since it is a strong oxidizing agent, it can aggravate the damage within the cell by a series of oxidative events including the generation of free radicals. Antioxidative agents are the only defense mechanism to neutralize these free radicals. Free radicals are not only generated internally in our body system but also trough external sources like environmental pollution, toxic metals, cigarette smoke, pesticides, etc., which add damage to our body system. Inhaling these toxic chemicals in the environment has become unavoidable in modern civilization. Antioxidants of plant origin with free radical scavenging properties could have great importance as therapeutic agents in several diseases caused by environmental pollution. This review summarizes the generation of reactive oxygen species and damage to cells by exposure to external factors, unhealthy lifestyle, and role of herbal plants in scavenging these reactive oxygen species. PMID- 23636602 TI - When PE is 'in transit'. PMID- 23636603 TI - Barriers and facilitators to CPR knowledge transfer in an older population most likely to witness cardiac arrest: a theory-informed interview approach. AB - BACKGROUND: We sought to identify perceived barriers and facilitators to cardiopulmonary resuscitation (CPR) training and performing CPR among people above the age of 55 years. METHODS: We conducted semistructured qualitative interviews with a purposive sample of independent-living individuals aged 55 years and older from urban and rural settings. We developed an interview guide based on the constructs of the Theory of Planned Behaviour, which elicits salient attitudes, social influences and control beliefs potentially influencing CPR training and performance. Interviews were recorded, transcribed verbatim and analysed until achieving data saturation. Two independent reviewers performed inductive analyses to identify emerging themes, and ranked them by way of consensus. RESULTS: Demographics for the 24 interviewees: mean age 71.4 years, women 58.3%, urban location 75.0%, single dwelling 58.3%, CPR training 79.2% and prior CPR on real victim 8.3%. Facilitators of CPR training included: (1) classes in a convenient location; (2) more advertisements; and (3) having a spouse. Barriers to taking CPR training included: (1) perception of physical limitations; (2) time commitment; and (3) cost. Facilitators of providing CPR included: (1) 9 1-1 CPR instructions; (2) reminders/pocket cards; and (3) frequent but brief updates. Barriers to providing CPR included: (1) physical limitations; (2) lack of confidence; and (3) ambivalence of duty to act in a large group. CONCLUSIONS: We identified key facilitators and barriers for CPR training and performance in a purposive sample of individuals aged 55 years and older. PMID- 23636604 TI - Ambulance handovers: can a dedicated ED nurse solve the delay in ambulance turnaround times? AB - With ever increasing concern over ambulance handover delays this paper looks at the impact of dedicated A&E nurses for ambulance handovers and the effect it can have on ambulance waiting times. It demonstrates that although such roles can bring about reduced waiting times, it also suggests that using this as a sole method to achieve these targets would require unacceptably low staff utilisation. PMID- 23636605 TI - New long chain bases in lipophosphonoglycan of Acanthamoeba castellanii. AB - The polymer called lipophosphonoglycan (LPG) was isolated from Acanthamoeba castellanii membranes after exhaustive delipidation and butanol extraction. A novel extremely long phytosphingosine was revealed in glycoinositolphosphosphingolipid (GIPSL). All data obtained by gas-liquid chromatography coupled with MS analyses of products liberated during acid methanolysis and products of sodium metaperiodate and permanganate-periodate oxidations showed an unusual pattern of long chain bases (LCB) with branched bases (anteiso-C24, anteiso-C25, anteiso-C26, iso-C26, anteiso-C27, and anteiso C28) and normal ones (C24, C25, C26, C27). The phytosphingosines with hexa-, hepta-, and octacosanoic chains have not been detected in Acanthamoeba cells up to now. Also, the isomer configuration of long chain bases in LPG of A. castellanii was not defined in earlier reports. In the GC-MS chromatograms, the component forming a peak corresponding to anteiso-C25 phytosphingosine was the most abundant and constituted more than 50 % of all LCB. PMID- 23636606 TI - Inhibition of hepatocellular carcinoma growth and angiogenesis by dual silencing of NET-1 and VEGF. AB - Simultaneous silencing of multiple up-regulated genes is an attractive and viable strategy to treat many incurable diseases including cancer. Herein we used dual gene targeted siRNA (DGT siRNA) conjugate composed of NET-1 and VEGF siRNA sequences in the same backbone could inhibit growth and angiogenesis HCC. DGT siRNA showed a further down regulation on VEGF mRNA and protein levels compared with NET-1 siRNA or VEGF siRNA, but not on NET-1 expression. It also exhibited greater suppression on proliferation and trigger of apoptosis in HepG2 cells than NET-1 siRNA or VEGF siRNA; this could be explained by the significant down regulation of cyclin D1 and Bcl-2. A lower level of ANG2 mRNA and protein was detected in HUVEC cultured with supernatant of HepG2 cells treated with DGT siRNA than that of VEGF siRNA or NET-1 siRNA, resulting in much more inhibited angiogenesis of HUVEC. Tumor growth was inhibited and microvessel density dropped in the xenograft tumor models compared to the untreated controls. NET-1 and VEGF silencing play a key role in inhibiting hepatocellular cell proliferation, promoting apoptosis, and reducing angiogenesis. Simultaneous silencing of NET-1 and VEGF using DGT siRNA construct may provide an advantageous alternative in development of therapeutics for Hepatocellular carcinoma. PMID- 23636607 TI - Chitosan-functionalized silk fibroin 3D scaffold for keratocyte culture. AB - The goal of this study was to evaluate the potential suitability of an artificial membrane composed of silk fibroin (SF) functionalized by different ratios of chitosan (CS) as a substrate for the stroma of the cornea. Keratocytes were cultured on translucent membranes made of SF and CS with different ratios. The biophysical properties of the silk fibroin and chitosan (SF/CS) membrane were examined. The SF/CS showed tensile strengths that increased as the CS concentration increased, but the physical and mechanical properties of chitosan functionalized silk fibroin scaffolds weakened significantly compared with those of native corneas. The resulting cell scaffolds were evaluated using western blot in addition to light and electron microscopy. The cell attachment and proliferation on the scaffold were similar to those on a plastic plate. Keratocytes cultured in serum on SF/CS exhibited stellate morphology along with a marked increase in the expression of keratocan compared with identical cultures on tissue culture plastics. The biocompatibility was tested by transplanting the acellular membrane into rabbit corneal stromal pockets. There was no inflammatory complication detected at any time point on the macroscopic level. Taken together, these results indicate that SF/CS holds promise as a substrate for corneal reconstruction. PMID- 23636609 TI - A high efficiency microfluidic-based photocatalytic microreactor using electrospun nanofibrous TiO2 as a photocatalyst. AB - We present a novel microfluidic-based photocatalytic microreactor by using electrospun nanofibrous TiO2 as a photocatalyst for the first time. The microreactor exhibits not only a simple fabrication process, but also much higher photocatalytic activity than that achieved by a TiO2 film microreactor. PMID- 23636608 TI - The influence of high glucose on the Cip/Kip family expression profiles in HRECs. AB - Neovascularization is the main characteristic of the proliferative stage of diabetic retinopathy. It has been proven that cell cycle regulation is involved in angiogenesis. The cell cycle regulators, Cip/Kip protein family, belong to the cyclin-dependent kinase inhibitors, are versatile proteins, and except for their function in cell cycle regulation, they also participate in transcription, apoptosis and migration. The expression profiles of the Cip/Kip family in human retina microvascular endothelial cells (HRECs) under normal or high glucose conditions has not been described before. This study was undertaken to determine the expression profiles of the Cip/Kip family proteins, e.g., proteins which are influenced by high glucose and in what manner. Western blot and immunofluorescence analyses were used to investigate the protein expression profiles. Only p21(cip1) and p27(kip1) were detected in HRECs, and they were located in the nucleus. P21(cip1) protein abundance was higher than p27(kip1) in HRECs. Incubation of HRECs in medium containing 30 mM D-glucose for 48 h resulted in downregulation of p21(cip1) protein expression, but had no influence on p27(kip1) protein levels or p21(cip1) mRNA abundance. These results were accompanied by cell cycle G1 phase exit and a lower cell survival rate. Our data show for the first time that high glucose changes the Cip/Kip family expression profiles in HRECs, which may be the foundation for the investigation of the role of the Cip/Kip family in the pathogenesis of diabetic retinopathy. PMID- 23636610 TI - Marginal adaptation of ceramic and composite inlays in minimally invasive mod cavities. AB - OBJECTIVES: This study aims to evaluate the effect of a minimally invasive mesial occlusal-distal (mod) preparation on the marginal adaptation of ceramic and composite inlays with the aim of saving sound dental substance. MATERIALS AND METHODS: Class II mod cavities were prepared in 50 extracted human molars and randomly allocated to five groups (n = 10). In all groups, the mesial-proximal box margins were located in the dentin, 1 mm below the cementoenamel junction (CEJ), while the distal box margins were 1 mm above the CEJ. In groups A and B, conventional standard preparations with a divergent angle of alpha = 6 degrees were prepared. In groups C, D, and E, minimally invasive standard preparations with a convergent angle of alpha = 10 degrees were prepared. In groups A and D, composite inlays and, in groups B and C, ceramic inlays were fabricated (chairside economical restoration of esthetic ceramics (CEREC)) and adhesively inserted. In group E, a direct composite filling using the incremental technique was placed. Replicas were taken before and after thermomechanical loading (1,200,000 cycles, 50/5 degrees C, max. load 49 N). Marginal integrity (tooth luting composite, luting composite-inlay) was evaluated by scanning electron microscopy (* 200). The percentage of continuous margins in the different locations was compared between and within groups before and after cycling, using ANOVA and Scheffe post hoc test. RESULTS: After the thermomechanical loading, no significant differences were observed between the different groups with respect to the interface of luting composite-inlay. At the interface of tooth-luting composite for preparations involving the dentin, groups A and B behaved significantly better compared to the control group E, which in turn were not different to groups C and D. CONCLUSION: Composite and ceramic inlays inserted in minimally invasive prepared mod cavities result in margins not different from those of inlays placed in conventional mod preparations. Direct composite filling margins, however, were inferior to those attained by conventional indirect restorations. CLINICAL RELEVANCE: Minimally invasive preparations for mod inlays with undercuts show marginal adaptation equal to that of conventional inlay preparation design. PMID- 23636611 TI - Human white adipose tissue vasculature contains endothelial colony-forming cells with robust in vivo vasculogenic potential. AB - Blood-derived endothelial colony-forming cells (ECFCs) have robust vasculogenic potential that can be exploited to bioengineer long-lasting human vascular networks in vivo. However, circulating ECFCs are exceedingly rare in adult peripheral blood. Because the mechanism by which ECFCs are mobilized into circulation is currently unknown, the reliability of peripheral blood as a clinical source of ECFCs remains a concern. Thus, there is a need to find alternative sources of autologous ECFCs. Here we aimed to determine whether ECFCs reside in the vasculature of human white adipose tissue (WAT) and to evaluate if WAT-derived ECFCs have equal clinical potential to blood-derived ECFCs. We isolated the complete endothelial cell (EC) population from intact biopsies of normal human subcutaneous WAT by enzymatic digestion and selection of CD31(+) cells. Subsequently, we extensively compared WAT-derived EC phenotype and functionality to bonafide ECFCs derived from both umbilical cord blood and adult peripheral blood. We demonstrated that human WAT is indeed a dependable source of ECFCs with indistinguishable properties to adult peripheral blood ECFCs, including hierarchical clonogenic ability, large expansion potential, stable endothelial phenotype, and robust in vivo blood vessel-forming capacity. Considering the unreliability and low rate of occurrence of ECFCs in adult blood and that biopsies of WAT can be obtained with minimal intervention in an ambulatory setting, our results indicate WAT as a more practical alternative to obtain large amounts of readily available autologous ECFCs for future vascular cell therapies. PMID- 23636612 TI - Cloning and characterization of chromosomal markers in alfalfa (Medicago sativa L.). AB - Eleven tandemly repetitive sequences were identified from a Cot-1 library by FISH and sequence analysis of alfalfa (Medicago sativa). Five repetitive sequences (MsCR-1, MsCR-2, MsCR-3, MsCR-4, and MsCR-5) were centromeric or pericentromeric, of which three were satellite DNAs and two were minisatellite DNAs. Monomers of 144, 148, and 168 bp were identified in MsCR-1, MsCR-2, and MsCR-3, respectively, while 15 and 39 bp monomers were identified in MsCR-4 and MsCR-5, respectively. Three repetitive sequences were characterized as subtelomeric; one repetitive sequence, MsTR-1, had a 184 bp monomer, and two repetitive sequences had fragments of 204 and 327 bp. Sequence analysis revealed homology (70-80 %) between MsTR-1 and a highly repeated sequence (C300) isolated from M. ssp. caerulea. Three identified repetitive sequences produced hybridization signals at multiple sites in a few of the chromosomes; one repetitive sequence was identified as the E180 satellite DNA previously isolated from M. sativa, while the other 163 and 227 bp fragments had distinct sequences. Physical mapping of the repetitive sequences with double-target FISH revealed different patterns. Thus, nine novel tandemly repetitive sequences that can be adopted as distinct chromosome markers in alfalfa were identified in this study. Furthermore, the chromosome distribution of each sequence was well described. Though significant chromosome variations were detected within and between cultivars, a molecular karyotype of alfalfa was suggested with the chromosome markers we identified. Therefore, these novel chromosome markers will still be a powerful tool for genome composition analysis, phylogenetic studies, and breeding applications. PMID- 23636613 TI - A case of loxoscelism in southern France. PMID- 23636615 TI - Topographic diagnosis of internuclear ophthalmoparesis: evidence from a lesion behavior mapping study. PMID- 23636616 TI - Nutritional supplements and plasma antioxidants in childhood asthma. AB - OBJECTIVE: This study investigated the relationship of plasma antioxidants to airway inflammation and systemic oxidative stress in children suffering from atopic asthma with consideration of the intake of nutritional supplements. SUBJECTS AND RESEARCH METHODS: A total of 35 asthmatic children (AG) and 21 healthy controls (CG) participated in this study. Plasma levels of vitamins A and E, beta-carotene, coenzyme Q10 and malondialdehyde (MDA) were analyzed with high performance liquid chromatography (HPLC); the total antioxidant capacity (TAC) was measured photometrically, and selenium was determined by atomic absorption spectroscopy (AAS). The volume of fractionated exhaled nitric oxide (FeNO) was measured with the NIOX nitric oxide monitoring system. RESULTS: The plasma antioxidants vitamins A and E, selenium, and coenzyme Q10 but not beta-carotene were significantly (p < 0.05) lower in asthmatics than in controls. Further, asthmatic children had significantly reduced plasma concentrations of TAC (p < 0.01), significantly enhanced levels of MDA (p < 0.001), and exhaled a significantly (p < 0.001) higher mean volume of FENO than healthy children. Regular intake of supplements had a significant positive influence on plasma vitamin E (p < 0.01), selenium (p < 0.01), TAC (p < 0.05), MDA (p < 0.01), and FENO (p < 0.01) in asthmatics but not in controls. Additionally, significant negative associations of vitamin E and MDA (AG: p < 0.01; CG: p < 0.05), and vitamin E and FENO (AG: p < 0.05; CG: p > 0.05) were identified. CONCLUSION: These results indicate that nutritional supplements beneficially modulate plasma antioxidants and thus might have a positive influence on systemic redox balance and subsequently, pulmonary inflammation in asthmatic children. PMID- 23636617 TI - Involvement of dopamine D2 receptors activation in ischemic post-conditioning induced cardioprotection through promoting PKC-epsilon particulate translocation in isolated rat hearts. AB - Dopamine D2 receptors (DR2) are important regulators in many organs, including cardiac system. Protein kinase C (PKC) activation and translocation is associated with cardioprotection against ischemic post-conditioning (PC); however, the regulatory role of DR2 during this process has been unknown. This study hypothesized that the prevention of cardiomyocyte damage by DR2 activation is associated with PKC translocation to the cell membrane. In the present study, we found that the ischemia/reperfusion (I/R) increased the expressions of DR2 mRNA and protein, which were further enhanced by PC. Bromocriptine (DR2 agonist) up regulated the PC-induced DR2 expressions, and Haloperidol (DR2 antagonist) reversed the increase of DR2 expressions by Bromocriptine. PC reduced I/R-induced cardiomyocytes damage, apoptosis and myocardial infarct size, and improved cardiac function. Compared with PC, Bromocriptine further enhanced the cardioprotective roles of PC, but Haloperidol canceled the protection effect of Bromocriptine. PC up-regulated PKC-epsilon translocation in the particulate fraction, which was further strengthened by Bromocriptine but canceled by Haloperidol. In the cytosolic fraction, the changes of the PKC-epsilon translocation were opposite to the particulate fraction. These findings suggest that DR2 activation provides cardioprotection via promoting PC-induced translocation of PKC-epsilon. PMID- 23636619 TI - A pilot study examining trainee treatment session fidelity when Parent-Child Interaction Therapy (PCIT) is implemented in community settings. AB - Research supports the impact of empirically based treatments, such as Parent Child Interaction Therapy (PCIT), on producing positive treatment outcomes for clients. However, achieving outcomes in community settings that are similar to those found in research settings can be challenging, and little research has been conducted on how to best train community providers to implement PCIT with fidelity. This study assessed trainee implementation fidelity to the PCIT protocol in community settings. Session fidelity was reviewed for trainees using pre-established session integrity checklists and post hoc video review of key sessions. Analyses revealed that trainees maintained strong overall session fidelity, although fidelity percentages varied by session type and treatment phase. Results also highlight those session content items that are frequently left out by trainees during implementation. Implications of these findings, limitations, and future directions for research and PCIT workshops and consultation are discussed. PMID- 23636618 TI - Effects of acute and chronic administration of fenproporex on DNA damage parameters in young and adult rats. AB - Obesity is a chronic and multifactorial disease, whose prevalence is increasing in many countries. Pharmaceutical strategies for the treatment of obesity include drugs that regulate food intake, thermogenesis, fat absorption, and fat metabolism. Fenproporex is the second most commonly consumed amphetamine-based anorectic worldwide; this drug is rapidly converted in vivo into amphetamine, which is associated with neurotoxicity. In this context, the present study evaluated DNA damage parameters in the peripheral blood of young and adult rats submitted to an acute administration and chronic administration of fenproporex. In the acute administration, both young and adult rats received a single injection of fenproporex (6.25, 12.5 or 25 mg/kg i.p.) or vehicle. In the chronic administration, both young and adult rats received one daily injection of fenproporex (6.25, 12.5, or 25 mg/kg i.p.) or Tween for 14 days. 2 h after the last injection, the rats were killed by decapitation and their peripheral blood removed for evaluation of DNA damage parameters by alkaline comet assay. Our study showed that acute administration of fenproporex in young and adult rats presented higher levels of damage index and frequency in the DNA. However, chronic administration of fenproporex in young and adult rats did not alter the levels of DNA damage in both parameters of comet assay. The present findings showed that acute administration of fenproporex promoted damage in DNA, in both young and adult rats. Our results are consistent with other reports which showed that other amphetamine-derived drugs also caused DNA damage. We suggest that the activation of an efficient DNA repair mechanism may occur after chronic exposition to fenproporex. Our results are consistent with other reports that showed some amphetamine-derived drugs also caused DNA damage. PMID- 23636620 TI - Factor structure of the Mental Health Statistics Improvement Program (MHSIP) Family and Youth satisfaction surveys. AB - Two studies of the Mental Health Statics Improvement Project (MHSIP) Family and Youth consumer satisfaction surveys factor structure and psychometrics were conducted. In study 1, the 2002-2006 Youth Services Survey for Families (N = 6,007) was administered to parents of children receiving services, and in study 2, the 2002-2004 Youth Services Survey (N = 1,718) was administered to children age 12-18 receiving services. Factor analyses across both studies found five factors that strongly supported the hypothesized scale domains of outcomes, satisfaction, cultural sensitivity, participation, and access. Scales based on these factors had good reliability with an average coefficient alpha of 0.85. The average convergent validity correlation between scale scores from the parent and child surveys was r = 0.62. Overall, the results supported the structure, reliability, and validity of the surveys. PMID- 23636621 TI - Distribution of HLA-DRbeta1 alleles among well-characterized rheumatoid arthritis patients from Western India. AB - An association between human leukocyte antigen-DRbeta1*04 and rheumatoid arthritis (RA) has been known for more than 25 years. It has been observed in many different populations, and it accounts for approximately one-third of the genetic component of RA susceptibility. Our aim was to study the distribution of HLA-DRbeta1 alleles in well-characterized RA patients from Western India. Polymerase chain reaction-based sequence-specific oligonucleotide probing (PCR SSOP) technique was used to identify HLA-DRbeta1 alleles among 80 clinically well defined patients and 90 normal controls from same ethnicity. A significant increase in the frequency of DRbeta1*04 was observed among RA patients (PF% 30 vs. 7.7, OR 4.959, p value 0.00018), whereas DRbeta1*03 and *14 were significantly decreased among patients when compared with controls (DRbeta1*03, PF% 8.75 vs. 26.6, OR 0.2637, p value 0.00253; DRbeta1*14, PF% 17.5 vs. 30.0, OR 0.4949, p value 0.05722). Our results suggest that DRbeta1*04 was strongly associated with well-characterized RA patients from Western India, whereas DRbeta1*03 and *14 may be protective alleles for RA. The identification of susceptible allele in patients with RA may help physician to make early decisions regarding initiation of early intensive therapy with disease modifying anti rheumatic drugs and biological agents to decrease disability in RA patients. PMID- 23636623 TI - Immediate functional and cosmetic open rhinoplasty following acute nasal fractures: our experience with Asian noses. AB - BACKGROUND: Closed reduction and splinting are generally recommended in the acute management of nasal fractures. Although open reduction is recommended for more severe nasal fractures, immediate functional and cosmetic open rhinoplasty following nasal fractures has not been described for Asian noses. OBJECTIVES: The authors document their experiences with combining open reduction of acute nasal fractures with simultaneous cosmetic correction of preexisting aesthetic concerns in an Asian population. METHODS: Twenty-five Asian patients underwent primary functional and cosmetic open rhinoplasty immediately following acute nasal fracture. Grafts consisted of autologous material, including septum, concha, rib, and deep temporal fascia. Prior to opening the nose, anatomical reduction of the bony vault fractures was performed. Spreader grafts were used to stabilize the fractured or dislocated dorsal septum as well as to straighten the nose. Aesthetic refinement of the nose included lengthening, refining the tip, and increasing tip projection and was performed according to the patients' aesthetic desires. Patient satisfaction was subjectively reported on a 1 to 10 scale. RESULTS: Mean follow-up was 17 months (range, 10-24 months). Twenty-three patients rated the results of their procedures as 7 or higher. Functionally, all patients were breathing as well or better postoperatively compared with their preinjury functional state. One patient (4%) underwent a secondary filler procedure for a slight dorsal irregularity. CONCLUSIONS: Immediate cosmetic and functional open rhinoplasty is safe, predictable, and effective in Asian patients. LEVEL OF EVIDENCE: 4. PMID- 23636622 TI - Twenty years of measurement of polycyclic aromatic hydrocarbons (PAHs) in UK ambient air by nationwide air quality networks. AB - The impact of human activities on the health of the population and of the wider environment has prompted action to monitor the presence of toxic compounds in the atmosphere. Toxic organic micropollutants (TOMPs) are some of the most insidious and persistent of these pollutants. Since 1991 the United Kingdom has operated nationwide air quality networks to assess the presence of TOMPs, including polycyclic aromatic hydrocarbons (PAHs), in ambient air. The data produced in 2010 marked 20 years of nationwide PAH monitoring. This paper marks this milestone by providing a novel and critical review of the data produced since nationwide monitoring began up to the end of 2011 (the latest year for which published data is available), discussing how the networks performing this monitoring has evolved, and elucidating trends in the concentrations of the PAHs measured. The current challenges in the area and a forward look to the future of air quality monitoring for PAHs are also discussed briefly. PMID- 23636624 TI - Capsular contracture rate in a low-risk population after primary augmentation mammaplasty. AB - BACKGROUND: The safety of augmentation mammaplasty has increased dramatically in the past 20 years. Capsular contracture (CC) is the most commonly reported complication of augmentation mammaplasty. OBJECTIVES: The authors report the incidence of CC in a low-risk patient population after primary augmentation. METHODS: The authors retrospectively reviewed the charts of 856 consecutive patients who underwent primary augmentation mammaplasty between 1999 and 2009. This series did not include patients who underwent breast augmentation-mastopexy, secondary augmentation, revision, and/or reconstruction. Data points included demographics, functional and aesthetic outcomes, complications, and revision rate/type. RESULTS: The overall incidence of CC in 856 patients was 2.8%. Average follow-up time was 14.9 months. Antibiotic irrigation decreased CC rates from 3.9% to 0.4% (P = .004). Tobacco users had higher rates of contracture than nonsmokers (5.5% vs 1.9%; P = .036). Saline implants had a higher CC rate than silicone gel (4.3% vs 1.3%; P = .032). Using multivariate logistic regression, CC was 7.89 times more likely in saline implants than in silicone gel (P = .027, 95% confidence interval, 1.26-49.00). CONCLUSIONS: Based on our findings, it is apparent that the early CC rate in primary augmentation can be less than 1%. To avoid CC, we advocate an inframmamary approach, submuscular implant placement, and antibiotic irrigation of the breast pocket. LEVEL OF EVIDENCE: 3. PMID- 23636625 TI - Tuberous breast correction by fat grafting. AB - INTRODUCTION: Tuberous breast is a rare malformation that has negative physical and psychological impacts during puberty. A range of surgical techniques has been used to correct breast shape and volume in this context, including a combination of skin plasty and mammary gland remodeling, as well as prostheses and locoregional flaps. The authors have used fat grafting as a complementary technique to correct tuberous breasts since 1998. OBJECTIVES: The authors discuss application of their lipomodeling technique for correction of tuberous breast deformity. METHODS: The charts of tuberous breast patients treated consecutively over an 11-year period (n = 31) solely with fat grafting (ie, without using an implant) were retrospectively reviewed. Each breast deformation was graded according to the Grolleau classification. The number of sessions and the mean transfer of fat volume by lipomodeling session were recorded. Patient and surgeon satisfaction were evaluated. RESULTS: Of the 31 patients in this series, 18 had bilateral formations and 13 had unilateral malformations. The mean patient age was 23 years, and the mean body mass index was 21.9. A single session (mean transfer volume, 158 mL; range, 90-253 mL) was required in 14 (45%) cases. A second session (mean transfer volume, 226 mL; range, 100-316 mL) was necessary in the remaining 55% of cases. Mean follow-up period after the last fat transfer session was 6.5 years (range, 1.5-11 years). Patients were very satisfied in 94% of cases (n = 29) and satisfied in 6% (n = 2). The surgical team rated 94% of cases as being successful or very successful. No complications were observed. One patient developed hypertrophy of the treated breast following weight gain and thus required breast reduction. Imaging performed preoperatively and 1 year postoperatively did not reveal any anomalies other than oil cysts. CONCLUSION: Fat grafting is a reliable technique that produces excellent results and high levels of patient satisfaction for the treatment of tuberous breast. The aesthetic outcome is natural, implant free, and long lasting. LEVEL OF EVIDENCE: 4. PMID- 23636626 TI - Commentary on: clinical trial outcomes of high- and extra high-profile breast implants. PMID- 23636627 TI - Editor's Note on: clinical trial outcomes of high- and extra high-profile breast implants. PMID- 23636628 TI - Dynamic definition mini-lipoabdominoplasty combining multilayer liposculpture, fat grafting, and muscular plication. AB - BACKGROUND: There is a select group of women for whom mini-abdominoplasty techniques combined with 3-dimensional liposculpture and fat grafting can effectively correct postpartum deformities. OBJECTIVE: The authors describe a multilayer and 360-degree approach, dynamic definition mini-abdominoplasty (DDM), to create athletic definition and contour and to restore a feminine appearance postpartum. METHODS: A total of 181 consecutive women ages 20 to 56 years underwent DDM between January 2005 and May 2012. Patients who were a minimum of 6 months postpartum and in good health, with a body mass index below 30, were considered for inclusion in the study. Fat grafting was performed in select cases in the buttocks, deltoids, and/or calves. A satisfaction index (SI) was estimated based on patient survey responses. RESULTS: An overall SI of 91.5% was achieved. No major complications were reported. Twenty-nine minor complications included postoperative anemia, seroma, and infection in the surgical wound. In most patients, the postpartum abdomen was restored to an aesthetic and even athletic appearance. Athletic definition to the rectus, arms, trunk, thighs, and buttocks was also achieved. No burns or flap necrosis were reported. CONCLUSIONS: Dynamic definition mini-abdominoplasty is safe and reproducible. It serves as a viable alternative to a full abdominoplasty in selected cases and for women who wish to restore an athletic and feminine appearance after childbirth. LEVEL OF EVIDENCE: 4. PMID- 23636629 TI - Complications of injectable fillers, part I. AB - Dermal filling has rapidly become one of the most common procedures performed by clinicians worldwide. The vast majority of treatments are successful and patient satisfaction is high. However, complications, both mild and severe, have been reported and result from injection of many different types of dermal fillers. In this Continuing Medical Education review article, the author describes common technical errors, the signs and symptoms of both common and rare complications, and management of sequelae in clear, easily adaptable treatment algorithms. PMID- 23636631 TI - Plastic surgery's identity crisis. PMID- 23636630 TI - Patient preferences in print advertisement marketing for plastic surgery. AB - BACKGROUND: Plastic surgeons are competing for their share of a growing but still limited market, thus making advertising an important component in a successful plastic surgery practice. OBJECTIVE: The authors evaluate the variables, characteristics, and presentation features that make print advertisements most effectively pique the interest of individuals selecting a plastic surgeon. METHODS: An online survey was administered to 404 individuals with active interest in plastic surgery from 10 major metropolitan areas. Participants were presented with 5 different advertisements from plastic surgeons throughout the country and were asked a series of both closed- and open-ended questions to assess verity, quality, and marketability of each advertisement. Reponses to open ended questions were analyzed using the Wordle program (www.wordle.net). RESULTS: The most frequent themes identified for all 5 ads were "Being beautiful is possible" (41%), "I could be beautiful" (24%), "Some people need surgery to be beautiful" (16%), and "Being beautiful is important" (14%). Advertisement 1 featuring 3 women and no pre- or posttreatment photography, no physician photography, and a listing of the 3 physicians' credentials but not a list of the services provided-received the highest overall preference rating. CONCLUSIONS: Factors including emotions felt while reading, unique qualities of the advertisement, list of procedures performed, use of models versus actual patients, and pictures of the plastic surgeons were found to contribute to the respondents' overall perception of advertisements used to market a plastic surgery practice. PMID- 23636632 TI - Stromal enriched lipograft for rhinoplasty refinement. PMID- 23636633 TI - Betadine and breast implants: an update. PMID- 23636634 TI - Modified Konno procedure: surgical management of tunnel-like left ventricular outflow tract stenosis. AB - Left ventricular outflow tract stenosis represents 1-2 % of all congenital anomalies. In particular, tunnel-like left ventricular stenosis which is one type of fixed left ventricular outflow stenosis requires aggressive surgery to reduce the left ventricular outflow gradient. The purpose of the modified Konno procedure is to release fixed left ventricular outflow tract stenosis while preserving the native aortic valve and its function. Although the clinical results of the modified Konno procedure are acceptable, it is necessary to precisely understand this procedure and the anatomy of the left ventricular outflow tract in order to avoid complications. PMID- 23636635 TI - Parietal pleural hematoma: plausible aortic dissection in an octogenarian on multiple antiplatelets, coumadin and oral steroids. AB - An 84-year-old male on oral steroids, coumadin and multiple antiplatelets for stented superficial femoral artery presented to our hospital with chest oppression. His CT scan showed cardiac tamponade with periaortic hematoma. At first, sealed rupture of aortic dissection with thrombosed false lumen was suspected. However, delayed enhancement view revealed extravasation of contrast agent, which appeared to drain into the pericardium or pericardial space. Emergency thoracotomy revealed normal aorta with several small spurting vessels of pulmonary side of the pericardium. To the best of our knowledge, this is the first reported case in the literature of a parietal pleural hematoma without known cause such as malignancy or hematologic disorders. PMID- 23636636 TI - Highly ordered monolayer/bilayer TiO2 hollow sphere films with widely tunable visible-light reflection and absorption bands. AB - Monolayer and bilayer TiO2 hollow hemisphere/sphere (THH/THS) films consisting of highly ordered hexagonal-patterned THHs/THSs with thin shells of ~10 nm and different diameters of ~170 and ~470 nm have been prepared by templating of two dimensional polystyrene sphere (PS) assembly films coupled with TiO2 sputtering/wet coating approaches. Owing to their precisely adjustable structural parameters, such as THH/THS shape and diameter as well as film layer thickness, the prepared THH/THS films exhibit widely tunable visible-light reflection and absorption bands, i.e. from 380 to 850 nm for reflection and 390 to 520 nm for absorption, respectively. The mechanism of the novel optical behaviors of the THH/THS films has been discussed in depth, combined with some calculations according to Bragg's law. In addition, photocatalytic experiments of RhB degradation employing the THH/THS films as recyclable catalysts have been conducted. The THH/THS films with controlled structures and precisely tunable optical properties are attractive for a wide range of applications, such as recyclable catalysts for photocatalysis, efficient oxide electrodes or scattering layers for solar cells, gas-permeable electrode materials for high-performance sensors and so on. PMID- 23636637 TI - Plasma levels of interleukin 18, interleukin 10, and matrix metalloproteinase-9 and -137G/C polymorphism of interleukin 18 are associated with incidence of in stent restenosis after percutaneous coronary intervention. AB - This study aims to investigate the relationship between the levels of IL-18, IL 10, and MMP-9 and -137G/C polymorphism of interleukin 18 with the risk of in stent restenosis (ISR). The study population consisted of 68 patients with ISR, 173 in non-ISR group, treated with drug-eluting stent and evaluated by coronary angiography post-procedure and at follow-up, and also 109 without angiographic evidence of coronary artery disease (CAD) which formed a reference control group (non-CAD group). The sequential plasma IL-18, IL-10, and MMP-9 levels were assessed at admission, 24 h, and 2 weeks after percutaneous coronary intervention. The -137G/C polymorphism of IL-18 was genotyped by the ligase detection reaction-polymerase chain reaction. Plasma IL-18 and MMP-9 increased significantly from admission, peaking after 24 h and fall after 2 weeks. Compared with the non-ISR group, the ISR group had higher levels of IL-18 and MMP-9, but IL-10 level was the opposite. The -137GG genotype of IL-18 was significantly higher than of the CG and CC genotypes. A significant higher frequency of -137G allele or GG genotype of IL-18 was observed in patients with ISR group compared with the non-ISR group. There is correlation between the changes of IL-18, IL-10, MMP-9, and ISR. IL-18 promoter -137G/C polymorphism influences IL-18 levels and the susceptibility to ISR, suggesting that IL-18-mediated pathways are causally involved in the process of ISR. PMID- 23636638 TI - Quorum sensing signal molecules produced by Pseudomonas aeruginosa cause inflammation and escape host factors in murine model of urinary tract infection. AB - Quorum sensing (QS) is well established for its role in pathogenesis of various infections of Pseudomonas aeruginosa. However, its role in local tissue damage during urinary tract infection (UTI) is not yet fully established. To have insight in this, the present study was planned. UTI was established in mice using standard strain PAO1 and its isogenic QS mutant JP2. One group was challenged only with QS signals. Damage was assessed in terms of histopathology and pathology markers, malondialdehyde (MDA) and reactive nitrogen intermediates (RNI). Effect on pathogen motility, uroepithelial adhesion, and host serum sensitivity was also ascertained. PAO1-infected mice showed severe inflammation and tissue destruction, while mice infected with JP2 showed no significant destruction. JP2 was also unable to mount any tissue pathology markers, MDA and RNI, whereas PAO1 showed significantly higher levels of these two. Presence of only QS signals also showed considerable renal pathology. Strain JP2 also showed less motility, reduced uroepithelial cell adhesion, and increased serum sensitivity. Result highlights that QS signals induce local tissue pathology along with interference of host protective mechanisms during UTI. PMID- 23636639 TI - Islet encapsulation: advances and obstacles. AB - It has been known for decades that encapsulation can protect transplanted islets from immune destruction in rodents, but it has proved difficult to extend this success to large animals and humans. A new study in this issue by Jacobs Tulleneers-Thevissen et al (doi: 10.1007/s00125-013-2906-0 ) advances the field by showing that human islets contained in alginate capsules can function very well, not only in the peritoneal cavity of mice, but also in a human with type 1 diabetes. Many obstacles must still be overcome, but this technology has the potential to safely protect transplanted beta cells from autoimmunity and allorejection. PMID- 23636640 TI - Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet induced obesity mouse model. AB - AIMS/HYPOTHESIS: Studies have shown that dipeptidyl peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD) induced-obesity model in mice of advanced age (10 months old). METHODS: After 1 month of HFD alone, the mice were given the DPP4 inhibitor vildagliptin for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated. RESULTS: Beta cell function and glucose tolerance were significantly improved by vildagliptin with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3 positive T cells, which were completely prevented by vildagliptin treatment. Chronic vildagliptin treatment also improved survival rates for HFD-fed mice. CONCLUSIONS/INTERPRETATION: In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic DPP4 inhibition. The improved survival rates for obese mice chronically treated with vildagliptin suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy. PMID- 23636641 TI - [(B3O3H3)(n)M]+ (n = 1, 2;M = Cu, Ag, Au): a new class of metal-cation complexes. AB - A density functional theory (DFT) investigation into the structures and bonding characteristics of [(B3O3H3)nM](+)(n = 1, 2;M = Cu, Ag, Au) complexes was performed. DFT calculations and natural bond orbital (NBO) analyses indicate that the IotaB metal complexes of boroxine exhibit intriguing bonding characteristics, different from the typical cation-pi interactions between IotaB metal-cations and benzene. The complexes of [B3O3H3M](+) and [(B3O3H3)2 M](+) (M = Cu, Ag, and Au) favor the conformation of perfectly planar structures with the C2v and D2h symmetry along one of the threefold molecular axes of boroxine, respectively. Detailed natural resonance theory (NRT) and canonical molecular orbitals (CMOs) analyses show that interaction between the metal cation and the boroxine in [B3O3H3M](+) (M = Cu, Ag, and Au) is mainly ionic, while the IotaB metal-cations< pi donation effect is responsible for the binding site. In these complexes, boroxine serves as terminals eta(1)-B3O3H3 with one O atom of the B3O3 ring. The infra-red (IR) spectra of [B3O3H3M](+) were simulated to facilitate their future experimental characterization. The complexes all give two IR active modes at about 1,300 and 2,700 cm(-1), which are inactive in pure boroxine. Simultaneously, the B-H stretching modes of the complexes are red-shifted due to the interaction between the metal-cation and boroxine. To explore the possibility of the structural pattern developed in this work forming mesoporous materials, complexes [(B3O3H3M)6](6+) (M = Cu, Ag, and Au) were also studied, which appear to be unique and particular interesting: they are all true minima with D6h symmetries and pore sizes ranging from 12.04 A to 13.65 A. PMID- 23636642 TI - A Gaussian-3 theoretical study of the alkylthio radicals and their anions: structures, thermochemistry, and electron affinities. AB - The optimized geometries, electron affinities, and dissociation energies of the alkylthio radicals have been determined with the higher level of the Gaussian 3(G3) theory. The geometries are fully optimized and discussed. The reliable adiabatic electron affinities with ZPVE correction have been predicted to be 1.860 eV for the methylthio radical, 1.960 eV for the ethylthio radical, 1.980 and 2.074 eV for the two isomers (n-C3H7S and i-C3H7S) of the propylthio radical, 1.991, 2.133 and 2.013 eV for the three isomers (n-C4H9S, t-C4H9S, and i-C4H9S) of the butylthio radical, and 1.999, 2.147, 2.164, and 2.059 eV for the four isomers (n-C5H11S, b-C5H11S, c-C5H11S, and d-C5H11S) of the pentylthio radical, respectively. These corrected EAad values for the alkylthio radicals are in good agreement with available experiments, and the average absolute error of the G3 method is 0.041 eV. The dissociation energies of S atom from neutral CnH2n+1S (n = 1-5) and S(-) from corresponding anions CnH2n+1S(-) species have also been estimated respectively to examine their relative stabilities. PMID- 23636643 TI - What counts as validity evidence? Examples and prevalence in a systematic review of simulation-based assessment. AB - Ongoing transformations in health professions education underscore the need for valid and reliable assessment. The current standard for assessment validation requires evidence from five sources: content, response process, internal structure, relations with other variables, and consequences. However, researchers remain uncertain regarding the types of data that contribute to each evidence source. We sought to enumerate the validity evidence sources and supporting data elements for assessments using technology-enhanced simulation. We conducted a systematic literature search including MEDLINE, ERIC, and Scopus through May 2011. We included original research that evaluated the validity of simulation based assessment scores using two or more evidence sources. Working in duplicate, we abstracted information on the prevalence of each evidence source and the underlying data elements. Among 217 eligible studies only six (3 %) referenced the five-source framework, and 51 (24 %) made no reference to any validity framework. The most common evidence sources and data elements were: relations with other variables (94 % of studies; reported most often as variation in simulator scores across training levels), internal structure (76 %; supported by reliability data or item analysis), and content (63 %; reported as expert panels or modification of existing instruments). Evidence of response process and consequences were each present in <10 % of studies. We conclude that relations with training level appear to be overrepresented in this field, while evidence of consequences and response process are infrequently reported. Validation science will be improved as educators use established frameworks to collect and interpret evidence from the full spectrum of possible sources and elements. PMID- 23636644 TI - Outer photoreceptor layer thickness mapping in normal eyes and eyes with various macular diseases using spectral domain optical coherence tomography: a pilot study. AB - BACKGROUND: To obtain a de novo map of outer photoreceptor layer (OPRL) thickness using a semiautomatic segmentation method for commercial spectral-domain optical coherence tomography (SD-OCT) and analyze the features of the resulting OPRL map in normal eyes and eyes with various inactive macular diseases. METHODS: Forty normal eyes and 50 eyes with various inactive macular diseases such as resolved central serous chorioretinopathy (20 eyes), surgically-repaired macular hole (10 eyes), epiretinal membrane (10 eyes), and reattached rhegmatogenous retinal detachment (10 eyes) were screened. All subjects underwent a 12 radial scan protocol in SD-OCT. The segmentation lines defining the OPRL were modified using built-in software. The diseased eyes were subdivided into two groups (good vision, or intermediate to poor vision) based on a visual acuity better or worse than 20/40. The map of the OPRL thickness was obtained automatically by the embedded software and was presented as the Early Treatment Diabetic Retinopathy Study (ETDRS) style. RESULTS: The mean OPRL thickness in normal eyes in all subfields was 40.37 +/- 4.35 MUm. The central subfield area showed the greatest mean OPRL thickness in normal eyes. The mean OPRL thickness of diseased eyes with good vision in the central subfield was greater than that of eyes with intermediate to poor vision. The OPRL thickness map showed various patterns according to the type of macular diseases. CONCLUSIONS: We suggest that our semiautomated segmentation method using a 12 radial scan protocol is simple, fast, and suitable for producing a reliable OPRL map with ETDRS. This quantitative data could be useful in clinical practice or research of various macular diseases. PMID- 23636645 TI - Efficacy and tolerability of two scalp cooling systems for the prevention of alopecia associated with docetaxel treatment. AB - PURPOSE: Chemotherapy-induced alopecia is very distressing for a patient and may have an impact on treatment decisions. On docetaxel-based therapy, alopecia occurs in a substantial proportion of patients. We aimed to investigate whether two different methods of scalp cooling can prevent hair loss. METHODS: In this open-label, prospective, nonrandomized trial, patients with solid tumors receiving docetaxel in a palliative setting were allocated according to patients' preference to short-term cooling (over 45 min postinfusion) with a Paxman PSC-2 machine (PAX), with cold cap (CC), or no cooling. The combined endpoint was alopecia World Health Organisation (WHO) III or IV or the necessity to wear a wig. Study identifier is Clinicaltrials.gov NCT01008774. RESULTS: Two hundred thirty-eight patients were included in the trial (128 patients PAX, 71 CC, and 39 no cooling). Number of cycles (median 4) and median docetaxel doses were similar across groups (55-60 mg/day on weekly therapy, 135-140 mg/day on 3-weekly therapy). Alopecia occurred with PAX, CC, and no cooling under 3-weekly docetaxel in 23, 27, and 74% and under weekly docetaxel in 7, 8, and 17%, respectively. Overall, cooling (PAX and CC combined) reduced risk of alopecia by 78% (hazard ratio 0.22; 95% confidence interval 0.12 to 0.41). CC and PAX prophylaxis led to the same degree of prevention of alopecia. Adverse events (AE) were reported in 5% (most frequently, sensation of cold), and 30 patients (13%) discontinued cooling measures after cycle 1. CONCLUSIONS: In this first comparison published to date, both PAX and CC offer efficacious protection against hair loss, in particular when docetaxel is administered in a 3-weekly interval. PMID- 23636646 TI - Psychosocial service use: a qualitative exploration from the perspective of rural Australian cancer patients. AB - PURPOSE: This study aims to identify key issues associated with the provision of psychosocial care from the perspective of rural Australian cancer patients and determine culturally appropriate methods that may reduce barriers to service use. METHOD: Seventeen purposively sampled adult South Australians who lived outside metropolitan Adelaide, had a diagnosis of cancer and various demographic and medical histories participated in semi-structured, face-to-face interviews. Participants also completed a demographic questionnaire. Qualitative data were analysed using thematic analysis. RESULTS: Five key themes were identified: (1) psychosocial support is highly valued by those who have accessed it, (2) having access to both lay and professional psychosocial support is vitally important, (3) accessing psychosocial services is made difficult by several barriers (lack of information about services, initial beliefs they are unnecessary, feeling overwhelmed and concerns about stigma and dual relationships), (4) medical staff located in metropolitan treatment centres are not sufficiently aware of the unique needs of rural patients and (5) patients require better access to psychosocial services post-treatment. Methods through which rural patients believe access to psychosocial services could be improved include: (1) providing more rural-specific information on psychosocial care, (2) improving communication between health care providers and referral to psychosocial services and (3) making psychosocial services a standard part of care. CONCLUSIONS: Rural cancer patients want their unique needs to be recognised and to be treated differently to their urban counterparts. There is a need for more targeted and rurally relevant information for rural cancer patients, both to inform them of, and change their attitudes towards, psychosocial services. Other practical recommendations are also discussed. PMID- 23636647 TI - A survey of Canadian cancer patients' perspectives on the characteristics and treatment of breakthrough pain. AB - OBJECTIVE: Breakthrough pain is defined as a transient exacerbation of pain that occurs spontaneously or in response to a trigger despite stable and controlled background pain. The purpose of this study was to explore Canadian patients' awareness of and experience with breakthrough pain in cancer (BTPc). METHODS: Four Canadian cancer centers participated in a non-interventional survey recruiting cancer patients who experienced breakthrough pain. These patients were asked about their pain, its impact on functioning, current management and interest in new treatments of BTPc. RESULTS: Ninety-four Canadian cancer patients participated in this study, with 96% stating that cancer pain impacted their daily living with over half unable to go to work or shopping. Fifty percent of patients said that an episode of BTPc lasted greater than 60 minutes, with the pain score being on average 7.8/10, impacting normal work (7.2/10) and general activity (7.1/10). Only 35% of patients were very satisfied with the speed of relief of their medications. Those who did not take their breakthrough pain medication for every episode stated that was because the pain was not always severe (37%), or they were afraid of becoming tolerant (23%) or addicted (12%). Patients stated that the most important features of a new treatment for BTPc were the ability to relieve pain completely (47%), and quickly (43%). Patients expressed willingness to try transmucosal products (80%) or nasal products (59%). CONCLUSION: Breakthrough cancer pain in Canadian cancer patients greatly impacts their daily lives. There is room for improvement in the management of BTPc, and the majority of patients would be willing to try new treatments. PMID- 23636650 TI - Comparative study of SOS2 and a novel PMP3-1 gene expression in two sunflower (Helianthus annuus L.) lines differing in salt tolerance. AB - Gene expression pattern of two important regulatory proteins, salt overly sensitive 2 (SOS2) and plasma membrane protein 3-1 (PMP3-1), involved in ion homeostasis, was analyzed in two salinity-contrasting sunflower (Helianthus annuus L.) lines, Hysun-38 (salt tolerant) and S-278 (moderately salt tolerant). The pattern was studied at selected time intervals (24 h) under 150 mM NaCl treatment. Using reverse transcription PCR, SOS2 gene fragment was obtained from young leaf and root tissues of opposing lines while that for PMP3-1 was obtained only from young root tissues. Both tolerant and moderately tolerant lines showed a gradual increase in SOS2 expression in sunflower root tissues. Leaf tissues showed the gradually increasing pattern of SOS2 expression in tolerant plants as compared to that for moderately tolerant ones that showed a relatively lower level of expression for this gene. We found the highest level of PMP 3-1 expression in the roots of tolerant sunflower line at 6 and 12 h postsalinity treatment. The moderately tolerant line showed higher expression of PMP3-1 at 12 and 24 h after salt treatment. Overall, the expression of genes for both the regulator proteins varied significantly in the two sunflower lines differing in salinity tolerance. PMID- 23636649 TI - Effects of a 12-week home-based exercise program on the level of physical activity, insulin, and cytokines in colorectal cancer survivors: a pilot study. AB - PURPOSE: The purposes of this study are to examine (1) the feasibility and efficacy of two different home-based exercise protocols on the level of physical activity (PA), and (2) the effect of increased PA via home-based exercise program on biomarkers of colorectal cancer. METHODS: Seventeen patients (age 55.18 +/- 13.3 years) with stage II-III colorectal cancer completed the 12-week home-based exercise program. Subjects were randomized into either casually intervened home based exercise group (CIHE) or intensely intervened home-based exercise group (IIHE). The primary outcome was the level of PA. Furthermore, insulin, homeostasis model assessment of insulin resistance, insulin-like growth factor axis, and adipocytokines were measured. RESULTS: Both CIHE and IIHE program significantly increased the level of PA at 12 weeks compared to its level at baseline (CIHE, 10.00 +/- 8.49 vs. 46.07 +/- 45.59; IIHE, 12.08 +/- 11.04 vs. 35.42 +/- 27.42 MET hours per week). Since there was no difference in PA change between groups (p = 0.511), the data was combined in analyzing the effects of increased PA on biomarkers. Increase in PA significantly reduced insulin (6.66 +/ 4.58 vs. 4.86 +/- 3.48 MUU/ml, p = 0.006), HOMA-IR (1.66 +/- 1.23 vs. 1.25 +/- 1.04, p = 0.017), and tumor necrosis alpha-alpha (TNF-alpha 4.85 +/- 7.88 vs. 2.95 +/- 5.38 pg/ml, p = 0.004), and significantly increased IGF-1 (135.39 +/- 60.15 vs. 159.53 ng/ml, p = 0.007), IGF binding protein (IGFBP)-3 (2.67 +/- 1.48 vs. 3.48 +/- 1.00 ng/ml, p = 0.013), and adiponectin (6.73 +/- 3.07 vs. 7.54 +/- 3.96 MUg/ml, p = 0.015). CONCLUSION: CIHE program was as effective as IIHE program in increasing the level of PA, and the increase in PA resulted in significant change in HOMA-IR, IGF-1 axis, TNF-alpha, and adiponectin levels in stage II-III colorectal cancer survivors. PMID- 23636651 TI - Fluorescent dye conjugates of rabbit arylsulfatase A as a biological tracer for protein endocytosis. AB - Fluorescent dye conjugates of arylsulfatase A (ASA) from rabbit liver were prepared at pH 9.0 in 0.1 M sodium bicarbonate buffer. The modification of amino or sulphadryl groups by dichlorotriazinylamino-fluorescein or Lucifer yellow fluorescent dyes did not alter the characteristic features of the enzyme molecule such as enzyme activity, dimerization of the protein molecule at pH 4.5 and anomalous kinetics of the native enzyme. The fluorescence intensity of the Lucifer yellow enzyme conjugates were quenched when the pH of the protein solution was changed from pH 7.5 to 4.5. Therefore, the Lucifer yellow enzyme conjugate can be used to study the kinetics of pH-dependent association and dissociation of the ASA. Availability of such fluorescent dyes conjugates of ASA or other lysosomal enzyme may be used as a biological tracer to study the receptor dependent endocytosis of enzyme molecules. PMID- 23636648 TI - Risk of oral and gastrointestinal mucosal injury among patients receiving selected targeted agents: a meta-analysis. AB - PURPOSE: The purpose of this study was to estimate the risk and severity of oral and gastrointestinal mucosal toxicities associated with selected targeted agents. METHODS: We searched the English-language literature in February 2011 for reports of randomized clinical trials comparing a FDA-approved targeted agent to a standard of care regimens. Long-term follow-up and secondary reports of trials were excluded, leaving 85 studies for analysis. Using meta-analytic methods, we calculated the relative risks of oral and gastrointestinal toxicities, adjusting for sample size using the inverse variance technique. For each targeted agent and each side effect, we calculated the number needed to harm, the number of patients that, if treated with the more toxic regimen, would produce one additional episode of the toxicity. RESULTS: Oral mucositis was significantly more frequent among patients treated with bevacizumab, erlotinib, sorafenib, or sunitinib, although this difference was confined to low-grade mucositis. The clinical significance of these findings is unclear given its low incidence and mild severity. In contrast, diarrhea was significantly more frequent with most of the targeted agents studied, with adjusted relative risks between 1.5 and 4.5. An additional patient with diarrhea will be observed for every three to five patients treated with these targeted agents, compared with conventional regimens. CONCLUSIONS: Oral mucosal toxicities occasionally complicate treatment with these targeted agents, but the clinical significance of this finding is not clear. Diarrhea is a hallmark of treatment with these targeted agents; this side effect should be carefully ascertained to permit early intervention and control. PMID- 23636652 TI - In vitro evaluation of Zn-norfloxacin complex as a potent cytotoxic and antibacterial agent, proposed model for DNA binding. AB - A tetrahedral Zn(II) complex with the second generation fluoroquinolone, norfloxacin, was prepared and characterized (NOR-Zn complex, NZC). The antibacterial efficiency of the NZC was tested on two Gram-positive and four Gram negative bacteria by minimum inhibitory concentration method. The cytotoxic potential of NZC on MDA (human breast adenocarcinoma), Caco-2 (human colon adenocarcinoma), and Hela (human cervix carcinoma) cell lines was studied. The DNA interaction property of the NZC has been investigated using UV-vis, fluorescence, Fourier transform infrared, as well as cyclic voltammetry methods. Intrinsic binding constant (K(b)), thermodynamic, and other spectroscopic and voltammetric data indicate that the NZC has more affinity for DNA than for norfloxacin and interacted with DNA via two modes: electrostatic and outside hydrogen binding. The proposed DNA binding mode supports the large enhancement in the cytotoxicity and antibacterial activity of NZC. PMID- 23636653 TI - Microbial transformation of curcumin to its derivatives with a novel Pichia kudriavzevii ZJPH0802 strain. AB - Curcumin, a polyphenolic compound, has shown a wide range of pharmacological activities and has been widely used as a food additive. However, the clinical use of curcumin is limited to some extent because of its poor water solubility and low bioavailability. To overcome these problems, many approaches have been attempted and structural modification of curcumin by microbial transformation has been proven to be an alternative. In this study, we isolated a novel yeast strain Pichia kudriavzevii ZJPH0802 from a soil sample, which is capable of converting curcumin to its derivatives. The transformed products by this strain were evaluated by HPLC, (+) electrospray ionization (ESI)-MS(n), and (1)H nuclear magnetic resonance methods. Compared with controls, two new peaks of the transformed broth appeared at retention times of 26 min (I) and 62 min (II) by HPLC analysis. The two transformed products were then further identified by (+) ESI-MS(n). The spectrum showed that compound I had an accurate [M+H+NH3](+) ion at m/z 392, [M+H](+) ion at m/z 375, [M+H-H2O](+) ion at m/z 357, and (+) ESI MS(3) spectrum showed that ion at m/z 357 could further form fragment ions at m/z 339, 177, and 163; compound II had an accurate [M+H](+) ion at m/z 373, [M+H H2O](+) ion at m/z 355, and (+) ESI-MS(3) spectrum showed that ion at m/z 355 could further form fragment ions at m/z 219, 179, 177, 163, and 137. These two transformed products thereby were confirmed as hexahydrocurcumin (I) and tetrahydrocurcumin (II). PMID- 23636654 TI - Whole-body MRI in the assessment of disease activity in juvenile dermatomyositis. AB - OBJECTIVE: To compare whole-body MRI (WB-MRI) with clinical examination in the assessment of disease activity in juvenile dermatomyositis (JDM). METHODS: WB-MR images were obtained from 41 JDM patients and 41 controls using a 1.5 T MRI scanner and short tau inversion recovery sequences. 18 patients had follow-up WB MRI. Muscle, subcutaneous tissue and myofascial signal abnormalities were scored in 36 muscular groups and on proximal and distal extremities. WB-MRI and clinical assessments were performed concurrently and results compared. Validation procedures included analysis of feasibility, reliability, construct validity, discriminative ability and responsiveness. RESULTS: WB-MRI revealed distal legs (26/41 patients) and forearm (19/41 patients) muscle inflammation undetected during clinical examination and allowed an accurate assessment of subcutaneous (23/41 patients) and myofascial involvement (13/41 patients). 27 patients showed a patchy distribution of muscle inflammation while in seven the abnormal hyperintense areas tended to be homogeneously distributed. The inter-reader agreement for muscular, subcutaneous and myofascial WB-MRI scores was excellent. Correlations between WB-MRI muscle score and disease activity measures were excellent (Manual Muscle Test: rs=-0.84, Childhood Myositis Assessment Scale: rs= 0.81). WB-MRI score was higher in JDM active patients when compared with the control group (pB<0.0001) and the inactive patients (pB=0.004), and showed an excellent responsiveness (standardised response mean=1.65). Follow-up WB-MRI showed resolution of inflammation in nine patients whereas clinical criteria for remission were satisfied in five. CONCLUSIONS: WB-MRI provides additional information to clinical evaluation and represents a promising tool to estimate total inflammatory burden, tailor treatment and monitor its efficacy. PMID- 23636656 TI - Diffusion tensor imaging (DTI) and its clinical correlates in drug naive Wilson's disease. AB - The purpose is to evaluate white matter (WM) abnormalities in Wilson's disease (WD) using the technique of diffusion tensor imaging (DTI). The prospective case control study comprised of 15 drug-naive patients with WD and 15 controls. The phenotype of subjects was evaluated. The DTI/conventional MRI was acquired (3T MRI): Fractional anisotropy (FA) and mean diffusivity (MD) values were extracted from regions of interest placed in pons, midbrain, bilateral frontal and occipital cerebral white matter, bilateral internal capsules (IC), middle cerebellar peduncles (MCP) and corpus callosum (CC). Six patients showed lobar WM signal changes on T(2)-Weighted (T2W)/Fluid attenuation inversion recovery (FLAIR) images while remaining had normal appearing WM. MD was significantly increased in the lobar WM, bilateral IC and midbrain of WD patients. FA was decreased in the frontal and occipital WM, bilateral IC, midbrain and pons. Normal-appearing white matter on FLAIR images showed significantly increased MD and decreased FA values in both frontal and occipital lobar WM and IC compared with those in controls. Correlation of clinical scores and DTI metrics revealed positive correlation between neurological symptom score (NSS) and MD of anterior limb of right internal capsule, Chu stage and MD of frontal and occipital WM. Negative correlation was observed between the Modified Schwab and England Activities of Daily Living (MSEADL) score and MD of bilateral frontal and occipital WM and IC. This is the probably the first study to reveal widespread alterations in WM by DTI metrics in drug naive WD. DTI analysis revealed lobar WM abnormalities which is less frequently noted on conventional MRI and suggests widespread WM abnormalities in WD. It may be valuable in assessing the true extent of involvement and therefore the severity of the illness. PMID- 23636655 TI - The fibrin-derived citrullinated peptide beta60-74Cit60,72,74 bears the major ACPA epitope recognised by the rheumatoid arthritis-specific anticitrullinated fibrinogen autoantibodies and anti-CCP2 antibodies. AB - OBJECTIVES: To evaluate the proportions of rheumatoid arthritis (RA) sera containing anticitrullinated proteins autoantibodies (ACPA) reactive to alpha36 50Cit38,42 and/or beta60-74Cit60,72,74, two peptides identified as bearing the immunodominant epitopes of their major target, citrullinated fibrin. To analyse the relationships of anti-alpha36-50Cit38,42 and anti-beta60-74Cit60,72,74 autoantibodies with autoantibodies reactive to the complete citrullinated human fibrinogen molecule (AhFibA) and with anti-CCP2 antibodies. METHODS: 617 sera from 181 patients with established RA and 436 with non-RA rheumatic diseases were tested by ELISA for AhFibA, anti-CCP2, anti-alpha36-50Cit38,42, anti-beta60 74Cit60,72,74 autoantibodies, and by nephelometry for rheumatoid factor (RF). Diagnostic indexes, correlations and concordances between tests were analysed. Crossreactivity of anti-alpha36-50Cit38,42 and anti-beta60-74Cit60,72,74 autoantibodies was assessed in competition experiments. RESULTS: At a diagnostic specificity of 95%, the diagnostic sensitivity of AhFibA (83%) was significantly higher than that of all other tests. The diagnostic sensitivity of anti-beta60 74Cit60,72,74 (71%) was significantly higher than that of anti-alpha36-50Cit38,42 autoantibodies (51%) but similar to that of anti-CCP2 (74%). Titres of RF, anti alpha36-50Cit38,42 and anti-beta60-74Cit60,72,74 autoantibodies were weakly correlated with each other, whereas titres of anti-beta60-74Cit60,72,74 were strongly correlated with those of AhFibA (r=0.633) and anti-CCP2 (r=0.634). Anti alpha36-50Cit38,42 and anti-beta60-74Cit60,72,74 mainly corresponded to two non crossreactive subfamilies of ACPA. More than 90% of AhFibA-positive or anti-CCP2 positive sera recognised the alpha36-50Cit38,42 and/or the beta60-74Cit60,72,74 peptide. CONCLUSIONS: Autoantibodies reactive to alpha36-50Cit38,42 and beta60 74Cit60,72,74 form two distinct, non-overlapping subfamilies of ACPA that, together, cover practically all the ACPA reactivity to citrullinated fibrinogen and to CCP2 antigens. In established RA, anti-beta60-74Cit60,72,74 autoantibodies show diagnostic indexes similar to those of anti-CCP2. PMID- 23636657 TI - L-Carnitine for the treatment of a calcium channel blocker and metformin poisoning. AB - INTRODUCTION: The object of the current communication is to discuss the theory and the evidence for the use of L-carnitine in calcium channel blocker and metformin poisonings. CASE REPORT: A 68-year-old male known for hypertension and type II diabetes was admitted to the critical care unit of a community hospital following an overdose of amlodipine and metformin. The patient was intubated, ventilated, and hemodynamically supported with vasopressors. Despite calcium, glucagon, high-dose insulin (HDI), and lipid emulsion for calcium channel blocker and bicarbonate for metabolic acidosis, the patient remained hemodynamically unstable. The patient was considered too unstable to initiate continuous renal replacement therapy; and without access to extracorporeal life support, the administration of L-carnitine was administered as a last resort. One hour after L carnitine, the norepinephrine requirements started to decrease, the patient began to improve and was subsequently extubated successfully without apparent sequelae in less than 4 days. DISCUSSION: L-Carnitine combined with HDI may have helped with the calcium channel blocker (CCB) poisoning by decreasing insulin resistance, promoting intracellular glucose transport, facilitating the metabolism of free fatty acids, and increasing calcium channel sensitivity. It may have also stimulated oxidative utilization of glucose instead of converting pyruvate into lactate and contributed to decrease lactate production with metformin poisoning. PMID- 23636658 TI - Sodium acetate as a replacement for sodium bicarbonate in medical toxicology: a review. AB - Sodium bicarbonate is central to the treatment of many poisonings. When it was placed on the FDA drug shortage list in 2012, alternative treatment strategies to specific poisonings were considered. Many hospital pharmacies, poison centers, and medical toxicologists proposed sodium acetate as an adequate alternative, despite a paucity of data to support its use in medical toxicology. The intention of this review is to educate the clinician on the use of sodium acetate and to advise them on the potential adverse events when given in excess. We conducted a literature search focused on the pharmacology of sodium acetate, its use as a buffer in pathologic acidemia and dialysis baths, and potential adverse events associated with excess sodium acetate infusion. It appears safe to replace sodium bicarbonate infusion with sodium acetate on an equimolar basis. The metabolism of acetate, however, is more complex than bicarbonate. Future prospective studies will be needed to confirm the efficacy of sodium acetate in the treatment of the poisoned patient. PMID- 23636659 TI - Severe anion gap acidosis associated with intravenous sodium thiosulfate administration. AB - INTRODUCTION: Severe anion gap (AG) acidosis associated with intravenous sodium thiosulfate (STS) administration has not been previously described in nondialysis chronic kidney disease (CKD) patients. CASE REPORT: We present a CKD patient with a baseline creatinine 1.8 mg/dL (eGFR 28 ml/min/1.73 m2) who developed sustained and life-threatening AG acidosis associated with intravenous STS treatment for calciphylaxis. DISCUSSION: Although marketed as a safe drug, STS can cause life threatening acidosis as illustrated in this case. STS-induced AG acidosis should be considered in the differential diagnosis of severe acidosis in patients receiving STS. Dosage adjustment and close follow-up of patients' acid-base status after STS initiation is necessary. PMID- 23636661 TI - Cost of illness in colorectal cancer: an international review. AB - OBJECTIVES: Given the current-and increasing-pressure to limit expenditure on health care provision in many countries, a better understanding of the cost burden of colorectal cancer is needed. Cost-of-illness studies and reviews thereof can be a useful tool for analysing and critically evaluating the cost related development of colorectal cancer, and they highlight important cost drivers. METHODS: A systematic review was conducted from 2002 to 2012 to identify cost-of-illness studies related to colorectal cancer, searching the Medline, PubMed, Science Direct, Cochrane Library and the York CRD databases. RESULTS: Among the 10 studies (from France, the US, Ireland and Taiwan) included in the review, 6 studies reported prevalence-based estimates and 4 studies focussed on incidence-based data. In the studies included in the review, long-term costs for colorectal cancer of up to $50,175 per patient (2008 values) were estimated. Most of the studies in the review showed that the initial and terminal phases of colorectal cancer care are the most expensive, with continuing treatment being the least costly phase. One study also highlighted that stage I CRC disease was the least costly and stage III the most costly of all 4 stages, due to the high cost impact of biological agents. CONCLUSIONS: This review has highlighted a trend for rising costs associated with CRC, which is linked to the increasing use of targeted biological therapies. COI studies in colorectal cancer can identify specific components and areas of care that are especially costly, thereby focussing attention on more cost-effective approaches, which is especially relevant to the increased use of biological agents in the field of personalised medicine. COI studies are an important tool for further health economic evaluations of personalised medicine. PMID- 23636662 TI - How much should the NHS pay for a QALY? PMID- 23636660 TI - Temperature dependence of Congo red binding to amyloid beta12-28. AB - Because Congo red (CR) can bind to critical intermediate structural forms of amyloid beta (Abeta), it has been suggested as a potential therapeutic agent against neurodegenerative disorders such as Alzheimer's disease. In this study, the interaction of CR with Abeta(12-28) was investigated by use of isothermal titration calorimetry (ITC). Studies conducted between 15 and 35 degrees C show that binding of CR to Abeta(12-28) was strongly dependent on temperature, with a decrease in CR-Abeta(12-28) complexation as temperature increases, presumably because of conformational changes within Abeta(12-28) at the highest temperatures, that conceal the CR binding sites. In fact, no CR binding was observed at 35 degrees C. The binding of CR to Abeta(12-28) was associated with favorable changes in both enthalpy and entropy that resulted in binding constants (K) of between 10(5) and 10(6) M (-1). An early (and more intense) entropy-driven CR disaggregation phase (K ~10(7)-10(8) M (-1)) was observed before the onset of CR-Abeta(12-28) complexation. Only CR disaggregation was observed at 35 degrees C. These results may provide further insights into the ability of CR to inhibit Abeta toxicity in neurodegenerative diseases. PMID- 23636664 TI - Identification of MV-generated ROS responsive EST clones in floral buds of Litchi chinensis Sonn. AB - KEY MESSAGE: A suppression subtractive hybridization library was constructed using inflorescence primordia of 'Nuomici' litchi to identify EST clones responsive to MV-generated ROS. 93 ESTs could be aligned as unique gene sequences in the inflorescence primordia of litchi. Litchi is an evergreen woody tree widely cultivated in subtropical and tropical regions. However, defective flowering is a pending problem of litchi production. Our previous study indicated that reactive oxygen species (ROS) induced by methyl viologen dichloride hydrate (MV) promotes flowering in litchi. In the present study, a suppression subtractive hybridization (SSH) library was constructed using inflorescence primordia of 'Nuomici' with the aim to find out ROS responsive clones during floral differentiation. 1856 Expressed sequence tag (EST) clones were randomly selected. Clones carrying single exogenous fragments were screened by reverse northern analysis to identify those responsive to MV-generated ROS. A total of 783 differentially expressed EST clones were identified as MV responsive cDNA and were subjected to sequencing. Among them, 26 clones were represented more than three times. 783 clones were aligned to 93 unique gene sequences. The unique genes were classified into 9 categories. 16 % of them were involved in transport facilitation, 11 % in transcription regulation, 4 % in stress response, 9 % in carbohydrate metabolism, 1 % in secondary metabolism, 14 % in intracellular signaling, and 25 % in other metabolism, while 9 % were genes with unknown functions and 11 % were genes with no match in the database. PMID- 23636663 TI - Cloning and functional analysis of the flowering gene GmSOC1-like, a putative SUPPRESSOR OF OVEREXPRESSION CO1/AGAMOUS-LIKE 20 (SOC1/AGL20) ortholog in soybean. AB - KEY MESSAGE: The major insight in this manuscript is that we identified a new flowering regulator, GmSOC1-like, which may participate in the initiation and maintenance of flowering in soybean. Flowering is pivotal for the reproductive behavior of plants, and it is regulated by complex and coordinated genetic networks that are fine-tuned by endogenous cues and environmental signals. To better understand the molecular basis of flowering regulation in soybean, we isolated GmSOC1 and GmSOC1-like, two putative soybean orthologs for the Arabidopsis SUPPRESSOR OF OVEREXPRESSION OF CO1/AGAMOUS-LIKE 20 (SOC1/AGL20). The expression pattern of GmSOC1-like was analyzed by qRT-PCR in Zigongdongdou, a photoperiod-sensitive soybean cultivar. GmSOC1-like was widely expressed at different levels in most organs of the soybean, with the highest expression in the shoot apex during the early stage of floral transition. In addition, its expression showed a circadian rhythm pattern, with the highest expression at midnight under short-day (SD) condition. Intriguingly, GmSOC1-like was induced 4 days earlier than GmSOC1 during flowering transition in SD, suggesting that GmSOC1 and GmSOC1-like expression might be differentially regulated. However, under long-day (LD) condition, the expression of GmSOC1 and GmSOC1-like decreased gradually in the shoot apex of Zigongdongdou, which is in accordance with the fact that Zigongdongdou maintains vegetative growth in LD. In addition, overexpression of GmSOC1-like stimulated the flowering of Lotus corniculatus cv. supperroot plants. In conclusion, the results of this study indicate that GmSOC1 like may act as a flowering inducer in soybean. PMID- 23636665 TI - IFN-beta therapy modulates B-cell and monocyte crosstalk via TLR7 in multiple sclerosis patients. AB - The implication of B lymphocytes in the immunopathology of multiple sclerosis (MS) is increasingly recognized. Here we investigated the response of B cells to IFN-beta, a first-line therapy for relapsing-remitting MS patients, upon stimulation with TLR. IFN-beta restored the frequency of TLR7-induced IgM and IgG secreting cells in MS patients to the levels found in healthy donors, showing a specific deficiency in the TLR7 pathway. However, no difference was observed in the TLR9 response. Furthermore, in MS-derived PBMCs, TLR7-mediated production of IL-6 and the ex vivo expression of B-cell-activating factor of the TNF family, two crucial cytokines for B-cell differentiation and survival, were induced by IFN-beta. Depletion of monocytes, which are key producers of both IL-6 and B-cell activating factor of the TNF family, showed that TLR7-mediated B-cell differentiation into Ig-secreting cells is strongly dependent on the cross-talk between B cells and monocytes. Accordingly, impaired expression of TLR7 mRNA was observed in PBMCs and monocytes isolated from MS-affected individuals as compared with those from healthy donors, which was rescued by IFN-beta therapy. Collectively, our data unveil a novel TLR7-regulated mechanism in in vivo IFN beta-stimulated whole leukocytes that could be exploited to define new TLR7-based strategies for the treatment of MS. PMID- 23636666 TI - Chronic unilateral eruption of painful, erythematous papules and nodules. Piloleiomyoma. PMID- 23636667 TI - Prognostic value of telomere attrition in patients with aplastic anemia. AB - The decision to pursue hematopoietic stem cell transplantation or immunosuppression as first therapy in severe aplastic anemia is currently based on age and availability of a histocompatible donor. The ability to predict hematologic response, relapse and clonal evolution could improve treatment allocation. In the past 15 years, telomeres have been implicated in clinical diseases such as aplastic anemia, pulmonary fibrosis, cirrhosis and cancer development. The clinical relevance of varying telomere lengths (TL) and/or mutations in genes of the telomerase complex (TERC, TERT) is evolving in aplastic anemia. A large retrospective analysis suggests that baseline TL associate with late events of hematologic relapse and clonal evolution in aplastic anemia patients treated initially with anti-thymocyte globulin-based therapy. Further laboratory experiments propose possible mechanistic insight into genomic instability of bone marrow cells derived from patients with critically short telomeres and/or mutation in telomerase genes. The possibility of modulating telomere attrition rate with sex hormones could positively affect clonal evolution rates in humans. This review will summarize studies in marrow failure that explore the association between telomeres and aplastic anemia outcomes. PMID- 23636668 TI - Clinical signs and symptoms associated with increased risk for thrombosis in patients with paroxysmal nocturnal hemoglobinuria from a Korean Registry. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by chronic, complement mediated hemolysis, frequently leading to debilitating clinical symptoms and life threatening complications such as thromboembolism (TE). A retrospective analysis was performed on 301 patients from the South Korean National PNH Registry to describe disease burden and identify TE-associated risk factors. TE was identified in 18 % of patients and was associated with increased risk for mortality [odds ratio (OR), 6.85; P < 0.001]. A multivariate analysis showed that PNH patients with elevated hemolysis [lactate dehydrogenase (LDH) levels >=1.5 times the upper limit of normal (ULN)] at diagnosis were at significantly higher risk for TE than patients with LDH <1.5 * ULN (OR 7.0; P = 0.013). The combination of LDH >=1.5 * ULN with the clinical symptoms of abdominal pain, chest pain, dyspnea, or hemoglobinuria was associated with a greater increased risk for TE than elevated hemolysis or clinical symptoms alone. Continuous monitoring of these risk factors is critical for identifying PNH patients at risk for morbidities and mortality and allowing early intervention. PMID- 23636670 TI - A dynamic model to assess tradeoffs in power production and riverine ecosystem protection. AB - Major strategic planning decisions loom as society aims to balance energy security, economic development and environmental protection. To achieve such balance, decisions involving the so-called water-energy nexus must necessarily embrace a regional multi-power plant perspective. We present here the Thermoelectric Power & Thermal Pollution Model (TP2M), a simulation model that simultaneously quantifies thermal pollution of rivers and estimates efficiency losses in electricity generation as a result of fluctuating intake temperatures and river flows typically encountered across the temperate zone. We demonstrate the model's theoretical framework by carrying out sensitivity tests based on energy, physical and environmental settings. We simulate a series of five thermoelectric plants aligned along a hypothetical river, where we find that warm ambient temperatures, acting both as a physical constraint and as a trigger for regulatory limits on plant operations directly reduce electricity generation. As expected, environmental regulation aimed at reducing thermal loads at a single plant reduces power production at that plant, but ironically can improve the net electricity output from multiple plants when they are optimally co-managed. On the technology management side, high efficiency can be achieved through the use of natural gas combined cycle plants, which can raise the overall efficiency of the aging population of plants, including that of coal. Tradeoff analysis clearly shows the benefit of attaining such high efficiencies, in terms of both limiting thermal loads that preserve ecosystem services and increasing electricity production that benefits economic development. PMID- 23636671 TI - Gram-scale fractionation of nanodiamonds by density gradient ultracentrifugation. AB - Size is a defining characteristic of nanoparticles; it influences their optical and electronic properties as well as their interactions with molecules and macromolecules. Producing nanoparticles with narrow size distributions remains one of the main challenges to their utilization. At this time, the number of practical approaches to optimize the size distribution of nanoparticles in many interesting materials systems, including diamond nanocrystals, remains limited. Diamond nanocrystals synthesized by detonation protocols - so-called detonation nanodiamonds (DNDs) - are promising systems for drug delivery, photonics, and composites. DNDs are composed of primary particles with diameters mainly <10 nm and their aggregates (ca. 10-500 nm). Here, we introduce a large-scale approach to rate-zonal density gradient ultracentrifugation to obtain monodispersed fractions of nanoparticles in high yields. We use this method to fractionate a highly concentrated and stable aqueous solution of DNDs and to investigate the size distribution of various fractions by dynamic light scattering, analytical ultracentrifugation, transmission electron microscopy and powder X-ray diffraction. This fractionation method enabled us to separate gram-scale amounts of DNDs into several size ranges within a relatively short period of time. In addition, the high product yields obtained for each fraction allowed us to apply the fractionation method iteratively to a particular size range of particles and to collect various fractions of highly monodispersed primary particles. Our method paves the way for in-depth studies of the physical and optical properties, growth, and aggregation mechanism of DNDs. Applications requiring DNDs with specific particle or aggregate sizes are now within reach. PMID- 23636669 TI - Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists. AB - Knowledge in the field of inherited thrombocytopenias (ITs) has considerably improved over the recent years. In the last 5 years, nine new genes whose mutations are responsible for thrombocytopenia have been identified, and this also led to the recognition of several novel nosographic entities, such as thrombocytopenias deriving from mutations in CYCS, TUBB1, FLNA, ITGA2B/ITGB3, ANKRD26 and ACTN1. The identification of novel molecular alterations causing thrombocytopenia together with improvement of methodologies to study megakaryopoiesis led to considerable advances in understanding pathophysiology of ITs, thus providing the background for proposing new treatments. Thrombopoietin receptor agonists (TPO-RAs) represent an appealing therapeutic hypothesis for ITs and have been tested in a limited number of patients. In this review, we provide an updated description of pathogenetic mechanisms of thrombocytopenia in the different forms of ITs and recapitulate the current management of these disorders. Moreover, we report the available clinical and preclinical data about the role of TPO-RAs in ITs and discuss the rationale for the use of these molecules in view of pathogenesis of the different forms of thrombocytopenia of genetic origin. PMID- 23636673 TI - Ahmed glaucoma valve surgery for necrotizing scleritis with secondary glaucoma. AB - To report the challenges in management in a case of scleritis with extensive staphylomas with secondary glaucoma. A 35-year-old one eyed female, a known case of scleromalacia perforans, presented with raised intraocular pressure on maximum medical treatment. She underwent successful Ahmed glaucoma valve surgery with exposure of the implant following a repeat episode of necrotizing scleritis after 3 months. Management of eyes with scleritis and secondary glaucoma can be challenging with unexpected complications and postoperative course. PMID- 23636674 TI - Microcantilever sensors. AB - Microfabricated cantilevers have been used in atomic force microscopy for the topography imagingof non-conductive surfaces for more than 20 years. Cantilever beams without tips have proved theirapplicability in recent years as miniaturized, ultrasensitive, and fast-responding sensors for applicationsin chemistry, physics, biochemistry, and medicine. Microcantilever sensors respond by bending dueto the absorption of molecules. A shift in resonance frequency also occurs. They can be operatedin different environments such as gaseous environment, liquids, or vacuum. In gas, microcantileversensors can be operated as an artificial nose, whereby the bending pattern of a microfabricatedarray of eight polymer-coated silicon cantilevers is characteristic of the different vapors from solvents,flavors, and beverages. When operated in a liquid, microcantilever sensors are able to detectbiochemical reactions. Each cantilever is functionalized with a specific biochemical probe receptor,sensitive for detection of the corresponding target molecule. Applications lie in the fields of label-and amplification-free detection of DNA hybridization, the detection of proteins as well as antigen-antibodyreactions, and the detection of larger entities, such as bacteria and fungi. PMID- 23636672 TI - Irritable bowel syndrome in the UK military after deployment to Iraq: what are the risk factors? AB - PURPOSE: Diarrhoea and vomiting (D & V) was common in military personnel during deployment to the initial phases of the Iraq war. D & V is an established risk factor for irritable bowel syndrome (IBS). This study examined the prevalence of IBS in a military sample with a history of deployment to Iraq and the association between D & V and common mental disorder (CMD) with IBS. METHODS: The study used data from a two-phase cohort study of military/personnel. The sample was restricted to individuals who had been deployed to Iraq before phase 1 of the study and who had completed the self-report D & V question. A measure of probable IBS was derived at both phases of the study based on self-reported symptoms in the previous month. CMD was assessed by the General Health Questionnaire (GHQ 12). RESULTS: Fifty-nine percent of the sample reported a D & V event and 6.6 % met the criteria for probable IBS at phase 1. Reporting D & V, thinking one might be killed on deployment, poor physical health and CMD were associated with probable IBS at phase 1. CMD at phase 1 was strongly associated with chronic symptoms of IBS. CONCLUSIONS: There was a high prevalence of D & V during deployment to the early stages of the Iraq war, yet the prevalence of probable IBS on return from deployment was relatively low. D & V was strongly associated with IBS after deployment, and CMD was a risk factor for chronic symptoms of IBS. PMID- 23636675 TI - Functionalization of probe tips and supports for single-molecule recognition force microscopy. AB - The measuring tip of a force microscope can be converted into a monomolecular sensorif one or few "ligand" molecules are attached to the apex of the tip while maintainingligand function. Functionalized tips are used to study fine details of receptor-ligand interactionby force spectroscopy or to map cognate "receptor" molecules on the sample surface. Thereceptor (or target) molecules can be present on the surface of a biological specimen; alternatively,soluble target molecules must be immobilized on ultraflat supports. This review describes the methodsof tip functionalization, as well as target molecule immobilization. Silicon nitride tips, siliconchips, and mica have usually been functionalized in three steps: (1) aminofunctionalization,(2) crosslinker attachment, and (3) ligand/receptor coupling, whereby numerous crosslinkersare available to couple widely different ligand molecules. Gold-covered tips and/or supports haveusually been coated with a self-assembled monolayer, on top of which the ligand/receptor moleculehas been coupled either directly or via a crosslinker molecule. Apart from these general strategies,many simplified methods have been used for tip and/or support functionalization, even single-stepmethods such as adsorption or chemisorption being very efficient under suitable circumstances. Allmethods are described with the same explicitness and critical parameters are discussed. In conclusion,this review should help to find suitable methods for specific problems of tip and support functionalization. PMID- 23636676 TI - Molecular workbench for imaging and manipulation of single macromolecules and their complexes with the scanning force microscope. AB - The structure and properties of single macromolecules are key to understanding function in biologicalmolecular systems, as well as to developing artificial functional systems. In order to systematicallyinvestigate and control the conformations of single macromolecules and their complexes a "molecularworkbench" has been developed. It consists of an atomically flat, inert solid substrate suchas the basal plane of highly oriented pyrolytic graphite (HOPG), coated with a layer of moleculessuch as alkanes or alkyl chains containing amphiphiles that control the interaction between the substrateand adsorbed macromolecules. A scanning force microscope (SFM) operated in tapping or contactmode is used to both image and manipulate the macromolecules to correlate their structure with mechanicalproperties, and to assemble macromolecular systems that would not form spontaneously. PMID- 23636677 TI - Friction and Surface Dynamics of Polymers on the Nanoscale by AFM. AB - In this article the measurement and understanding of friction forces and surface dynamics ofpolymers on the one hand and the importance of molecular relaxation processes and viscoelasticityin polymers for advanced micro- and nanoscale applications on the other hand are discussed. Particularattention is paid to the nanoscale (surface) analysis by scanned probe microscopic approaches, includingatomic force microscopy (AFM), as a means to assess molecular relaxation processes that operateat a given temperature. Established AFM approaches, including lateral force and force modulationmicroscopy, are introduced and more recently developed techniques, such as torsional resonant modes,are briefly sketched. On the basis of the discussion of the techniques to measure friction and toprobe surface dynamics of polymers on the nanoscale, illustrative examples are reviewed. The examplesdiscussed address in particular the determination of values of the glass transition temperature (T g) and the difference of T gassessed in the bulk vs. at the free surface of polymers. Confinement and thin film effects on T g, but also on sub-T gtransitions and chain dynamics, are treated in detail. Finally, the mapping of multiphase systemsand anisotropic friction receive attention. PMID- 23636679 TI - Two-dimensional nanotemplates as surface cues for the controlled assembly of organic molecules. AB - Controlled two-dimensional assembly of organic molecules can be successfully realized by meansof surface nanotemplates that provide surface cues for assembly upon adsorption. Examples of suchtemplates are nanostructured surfaces and organic porous networks. In this review, we discuss theformation and use of such templates for controlled molecular assembly. The formation of the organicporous network is typically based on non-covalent interactions, e.g., hydrogen bonds, dipole-dipoleinteractions, metal-organic coordination bonds together with substrate-mediated molecular interactions.The pores of the network can act as hosts for specific organic molecules. The chemical structureof the molecular building blocks of the porous network has a primary effect on the shape, size,and chemical reactivity of the cavities. Long-range mesoscale reconstructions can also be employedas surface nanotemplates based on the selective adsorption of atomic or molecular species at specificsurface sites. Scanning tunneling microscopy is the key tool to study the formation of the nanotemplatesas well as the effect of the template in the growth of the ordered organic structures. The reportedstudies contribute to build the rationale in the design and fabrication of two-dimensional organicnetworks. The topic covered in this review represents an important challenge in nanotechnology sincethese findings might have a wide range of applications, e.g., in electronics, sensing, and bio-recognition. PMID- 23636678 TI - Exploring electronic transport in molecular junctions by conducting atomic force microscopy. AB - Measuring the electronic transport properties of single molecules and molecular nanostructuresis an interesting and challenging new frontier from both a fundamental as well as technologicalperspective. Conducting atomic force microscopy (C-AFM) represents an attractive line of approachgiven its ability to position a sharp electrical probe with nanometer-scale precision and a controllednano-Newton-range force. Moreover, the combination of AFM imaging and C AFM electrical characterizationenables investigation of the relationship between structure and function in molecular architectures.The aim of the present review is twofold: (1) to introduce the C-AFM method, alongside a discussionof experimental practices, capabilities and limitations, and (2) to provide an overview of the applicationof C-AFM to different types of molecular systems. These include alkane-based and oligomer-based self-assembledmonolayers, molecular crystals, conducting polymer films, molecular wires (e.g. carbon nanotubes),and electrically active biomolecules. We will also discuss C-AFM approaches that allow single moleculemeasurements as well as other recent developments. PMID- 23636680 TI - STM, STS and Bias-Dependent Imaging on Organic Monolayers at the Solid-Liquid Interface. AB - This chapter deals with various aspects of scanning tunneling spectroscopy (STS) and in particularit reviews STS investigations on organic films. Though this chapter addresses in particular thosesystems which have been probed under ambient conditions and at the solid-liquid interface, a significantpart deals with studies under UHV conditions. Some key principles of STS are highlighted and variousmolecular systems are reviewed, ranging from prototypical dyes or conjugated systems such as phthalocyanines,over conjugated polymers and multi component covalent and non-covalent systems. PMID- 23636681 TI - Personal or relational? Examining sexual health in the context of HIV serodiscordant same-sex male couples. AB - Couples' ability to adopt a "we" orientation has been associated with optimal health outcomes. This study examined how personal and relational motivations are uniquely associated with unprotected anal intercourse (UAI), protected anal intercourse (PAI), and the absence of sexual activity within HIV-serodiscordant same-sex male couples. HIV-positive men and their HIV-negative partners (N = 116 couples, 232 men) completed questionnaires and HIV-positive men had blood drawn for viral load. Results of a multinomial logistic regression illustrated that sexual satisfaction was positively associated with PAI among HIV-negative partners and negatively associated with PAI among HIV-positive partners. Endorsing a "we" orientation was positively associated with PAI among HIV positive partners. Findings suggest that HIV-positive partners who espouse a "we" orientation may be willing to forgo their personal interests to protect their HIV negative partners from HIV transmission. Couples-based interventions are warranted to help strengthen relationship dynamics to enhance the sexual health of serodiscordant couples. PMID- 23636682 TI - A solution-phase parallel synthesis of alkylated guanidines from thioisocyanates and amines. AB - An efficient solution-phase parallel synthesis of alkylated guanidines from commercial thioisocyanates and amines is described. In the first step, a thioisocyanate reacts with one equivalent of ammonia or a primary or secondary amine to give a thiourea intermediate. The latter is S-alkylated with n-dodecyl bromide resulting in the corresponding thiouronium bromide. Finally, the reaction of the thiouronium salt with a second equivalent of ammonia or a primary amine yields an alkylated guanidine. All three synthetic steps are easily combined in a one-pot high-yielding procedure with a simple work-up. Ca. 250 guanidine derivatives with high structural and functional diversity were synthesized by the developed method. 35 representatives reported in this study were fully characterized. PMID- 23636683 TI - Exploring the dreams of hospice workers. AB - Nine adults who worked at least 1 year with patients at US hospice centers completed an in-person audiotaped dream session focusing on a dream about a patient. Data were analyzed using consensual qualitative research. Patients were generally manifestly present in participants' dreams, and dreams were typically realistic (i.e., not bizarre). In the dream, the dreamer typically interacted with the patient as a caretaker but was also typically frustrated by an inability to help as fully as desired. Dreams gave dreamers insight into the stress of hospice work, their own fears of death, and inter-/intrapersonal interactions beyond hospice work. Dreamers generally sought to take better care of themselves and find balance in their lives after the dream session. Implications for research and practice are discussed. PMID- 23636685 TI - PT-ACRAMTU, a platinum-acridine anticancer agent, lengthens and aggregates, but does not stiffen or soften DNA. AB - We used atomic force microscopy (AFM) to study the dose-dependent change in conformational and mechanical properties of DNA treated with PT-ACRAMTU ([PtCl(en)(ACRAMTU-S)](NO3)2, (en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9 ylamino)ethyl]-1,3-dimethylthiourea. PT-ACRAMTU is the parent drug of a family of non-classical platinum-based agents that show potent activity in non-small cell lung cancer in vitro and in vivo. Its acridine moiety intercalates between DNA bases, while the platinum group forms mono-adducts with DNA bases. AFM images show that PT-ACRAMTU causes some DNA looping and aggregation at drug-to-base pair ratio (r b) of 0.1 and higher. Very significant lengthening of the DNA was observed with increasing doses of PT-ACRAMTU, and reached saturation at an r b of 0.15. At r b of 0.1, lengthening was 0.6 nm per drug molecule, which is more than one fully stretched base pair stack can accommodate, indicating that ACRAMTU also disturbs the stacking of neighboring base pair stacks. Analysis of the AFM images based on the worm-like chain (WLC) model showed that PT-ACRAMTU did not change the flexibility of (non-aggregated) DNA, despite the extreme lengthening. The persistence length of untreated DNA and DNA treated with PT-ACRAMTU was in the range of 49-65 nm. Potential consequences of the perturbations caused by this agent for the recognition and processing of the DNA adducts it forms are discussed. PMID- 23636684 TI - Noninvasive monitoring of small intestinal oxygen in a rat model of chronic mesenteric ischemia. AB - We noninvasively monitored the partial pressure of oxygen (pO2) in rat's small intestine using a model of chronic mesenteric ischemia by electron paramagnetic resonance oximetry over a 7-day period. The particulate probe lithium octa-n butoxynaphthalocyanine (LiNc-BuO) was embedded into the oxygen permeable material polydimethyl siloxane by cast-molding and polymerization (Oxy-Chip). A one-time surgical procedure was performed to place the Oxy-Chip on the outer wall of the small intestine (SI). The superior mesenteric artery (SMA) was banded to ~30% of blood flow for experimental rats. Noninvasive measurement of pO2 was performed at the baseline for control rats or immediate post-banding and on days 1, 3, and 7. The SI pO2 for control rats remained stable over the 7-day period. The pO2 on day 7 was 54.5 +/- 0.9 mmHg (mean +/- SE). SMA-banded rats were significantly different from controls with a noted reduction in pO2 post banding with a progressive decline to a final pO2 of 20.9 +/- 4.5 mmHg (mean +/- SE; p = 0.02). All SMA-banded rats developed adhesions around the Oxy-Chip, yet remained asymptomatic. The hypoxia marker HypoxyprobeTM was used to validate the low tissue pO2. Brown cytoplasmic staining was consistent with hypoxia. Mild brown staining was noted predominantly on the villus tips in control animals. SMA banded rats had an extended region of hypoxic involvement in the villus with a higher intensity of cytoplasmic staining. Deep brown stainings of the enteric nervous system neurons and connective tissue both within layers and in the mesentery were noted. SMA-banded rats with lower pO2 values had a higher intensity of staining. Thus, monitoring SI pO2 using the probe Oxy-Chip provides a valid measure of tissue oxygenation. Tracking pO2 in conditions that produce chronic mesenteric ischemia will contribute to our understanding of intestinal tissue oxygenation and how changes impact symptom evolution and the trajectory of chronic disease. PMID- 23636687 TI - TNFR-1 on tumor cells contributes to the sensitivity of fibrosarcoma to chemotherapy. AB - Impaired tumor necrosis factor receptor-1 (TNFR-1) signaling has been found in some malignant tumors with poor prognosis. However, the exact role of TNFR-1 signaling in fibrosarcoma remains unclear. Here, we explored the question by comparing the growth of TNFR-1 deficient (Tnfr1 (-)) and TNFR-1 competent (Tnfr1 (+)) fibrosarcoma FB61 cells (FB61-m and FB61-R1) in mice. TNFR-1 expression on fibrosarcoma cells delayed their growth in vivo but not in vitro. Moreover, reduced FB61-R1 tumor growth was also obtained in TNFR-1 knockout mice. The mechanism relies mainly on the TNFR-1-mediated downregulation of vascular endothelial growth factor (VEGF) production by tumor cells. Importantly, treatment of FB61-m tumors with melphalan resulted in a short delay of tumor growth, followed by a quick remission. However, when FB61-R1 tumors were treated with melphalan, tumor growth was similarly delayed at first and then completely rejected. Our results reveal evidence for TNFR-1 on tumor cells as a prerequisite in chemotherapy for fibrosarcoma, and provide novel insight into the therapeutic approach against some types of tumors using TNFR-1 angonist. PMID- 23636686 TI - EZH2, an epigenetic driver of prostate cancer. AB - The histone methyltransferase EZH2 has been in the limelight of the field of cancer epigenetics for a decade now since it was first discovered to exhibit an elevated expression in metastatic prostate cancer. It persists to attract much scientific attention due to its important role in the process of cancer development and its potential of being an effective therapeutic target. Thus here we review the dysregulation of EZH2 in prostate cancer, its function, upstream regulators, downstream effectors, and current status of EZH2-targeting approaches. This review therefore provides a comprehensive overview of EZH2 in the context of prostate cancer. PMID- 23636689 TI - Heat shock cognate 71 (HSC71) regulates cellular antiviral response by impairing formation of VISA aggregates. AB - In response to viral infection, RIG-I-like RNA helicases detect viral RNA and signal through the mitochondrial adapter protein VISA. VISA activation leads to rapid activation of transcription factors IRF3 and NF-kappaB, which collaborate to induce transcription of type I interferon (IFN) genes and cellular antiviral response. It has been demonstrated that VISA is activated by forming prion-like aggregates. However, how this process is regulated remains unknown. Here we show that overexpression of HSC71 resulted in potent inhibition of virus-triggered transcription of IFNB1 gene and cellular antiviral response. Consistently, knockdown of HSC71 had opposite effects. HSC71 interacted with VISA, and negatively regulated virus-triggered VISA aggregation. These findings suggest that HSC71 functions as a check against VISA-mediated antiviral response. PMID- 23636688 TI - Distinct evolution process among type I interferon in mammals. AB - Interferon (IFN) is thought to play an important role in the vertebrate immune system, but systemic knowledge of IFN evolution has yet to be elucidated. To evaluate the phylogenic distribution and evolutionary history of type I IFNs, 13genomes were searched using BLASTn program, and a phylogenetic tree of vertebrate type I IFNs was constructed. In the present study, an IFNdelta-like gene in the human genome was identified, refuting the concept that humans have no IFNdelta genes, and other mammalian IFN genes were also identified. In the phylogenetic tree, the mammalian IFNbeta, IFNE, and IFNkappa formed a clade separate from the other mammalian type I IFNs, while piscine and avian IFNs formed distinct clades. Based on this phylogenetic analysis and the various characteristics of type I IFNs, the evolutionary history of type I IFNs was further evaluated. Our data indicate that an ancestral IFNalpha-like gene forms a core from which new IFNs divided during vertebrate evolution. In addition, the data suggest how the other type I IFNs evolved from IFNalpha and shaped the complex type I IFN system. The promoters of type I IFNs were conserved among different mammals, as well as their genic regions. However, the intergenic regions of type I IFN clusters were not conserved among different mammals, demonstrating a high selection pressure upon type I IFNs during their evolution. PMID- 23636690 TI - Heterologous expression and characterization of bacterial 2-C-methyl-D-erythritol 4-phosphate pathway in Saccharomyces cerevisiae. AB - Transfer of a biosynthetic pathway between evolutionary distant organisms can create a metabolic shunt capable of bypassing the native regulation of the host organism, hereby improving the production of secondary metabolite precursor molecules for important natural products. Here, we report the engineering of Escherichia coli genes encoding the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway into the genome of Saccharomyces cerevisiae and the characterization of intermediate metabolites synthesized by the MEP pathway in yeast. Our UPLC-MS analysis of the MEP pathway metabolites from engineered yeast showed that the pathway is active until the synthesis of 2-C-methyl-D-erythritol-2,4 cyclodiphosphate, but appears to lack functionality of the last two steps of the MEP pathway, catalyzed by the [4Fe-4S] iron sulfur cluster proteins encoded by ispG and ispH. In order to functionalize the last two steps of the MEP pathway, we co-expressed the genes for the E. coli iron sulfur cluster (ISC) assembly machinery. By deleting ERG13, thereby incapacitating the mevalonate pathway, in conjunction with labeling experiments with U-13C6 glucose and growth experiments, we found that the ISC assembly machinery was unable to functionalize ispG and ispH. However, we have found that leuC and leuD, encoding the heterodimeric iron sulfur cluster protein, isopropylmalate isomerase, can complement the S. cerevisiae leu1 auxotrophy. To our knowledge, this is the first time a bacterial iron-sulfur cluster protein has been functionally expressed in the cytosol of S. cerevisiae under aerobic conditions and shows that S. cerevisiae has the capability to functionally express at least some bacterial iron-sulfur cluster proteins in its cytosol. PMID- 23636691 TI - Expression of genes involved in rhamnolipid synthesis in Pseudomonas aeruginosa PAO1 in a bioreactor cultivation. AB - There is a growing demand for economic bioprocesses based on sustainable resources rather than petrochemical-derived substances. Particular attention has been paid to rhamnolipids--surface-active glycolipids--that are naturally produced by Pseudomonas aeruginosa. Rhamnolipids have gained increased attention over the past years due to their versatile chemical and biological properties as well as numerous biotechnological applications. However, rhamnolipid synthesis is tightly governed by a complex growth-dependent regulatory network. Quantitative comprehension of the molecular and metabolic mechanisms during bioprocesses is key to manipulating and improving rhamnolipid production capacities in P. aeruginosa. In this study, P. aeruginosa PAO1 was grown under nitrogen limitation with sunflower oil as carbon and nitrate as nitrogen source in a batch fermentation process. Gene expression was monitored using quantitative PCR over the entire time course. Until late deceleration phase, an increase in relative gene expression of the las, rhl, and pqs quorum-sensing regulons was observed. Thereafter, expression of the rhamnolipid synthesis genes, rhlA and rhlC, as well as the las regulon was downregulated. RhlR was shown to remain upregulated at the late phase of the fermentation process. PMID- 23636692 TI - The effect of corrosion inhibitors on microbial communities associated with corrosion in a model flow cell system. AB - A model flow cell system was designed to investigate pitting corrosion in pipelines associated with microbial communities. A microbial inoculum producing copious amounts of H2S was enriched from an oil pipeline biofilm sample. Reservoirs containing a nutrient solution and the microbial inoculum were pumped continuously through six flow cells containing mild steel corrosion coupons. Two cells received corrosion inhibitor "A", two received corrosion inhibitor "B", and two ("untreated") received no additional chemicals. Coupons were removed after 1 month and analyzed for corrosion profiles and biofilm microbial communities. Coupons from replicate cells showed a high degree of similarity in pitting parameters and in microbial community profiles, as determined by 16S rRNA gene sequence libraries but differed with treatment regimen, suggesting that the corrosion inhibitors differentially affected microbial species. Viable microbial biomass values were more than 10-fold higher for coupons from flow cells treated with corrosion inhibitors than for coupons from untreated flow cells. The total number of pits >10 mils diameter and maximum pitting rate were significantly correlated with each other and the total number of pits with the estimated abundance of sequences classified as Desulfomicrobium. The maximum pitting rate was significantly correlated with the sum of the estimated abundance of Desulfomicrobium plus Clostridiales, and with the sum of the estimated abundance of Desulfomicrobium plus Betaproteobacteria. The lack of significant correlation with the estimated abundance of Deltaproteobacteria suggests not all Deltaproteobacteria species contribute equally to microbiologically influenced corrosion (MIC) and that it is not sufficient to target one bacterial group when monitoring for MIC. PMID- 23636693 TI - Substrate-limited co-culture for efficient production of propionic acid from flour hydrolysate. AB - Propionic acid is presently mainly produced by chemical synthesis. For many applications, especially in feed and food industries, a fermentative production of propionic acid from cheap and renewable resources is of large interest. In this work, we investigated the use of a co-culture to convert household flour to propionic acid. Batch and fed-batch fermentations of hydrolyzed flour and a process of simultaneous saccharification and fermentation were examined and compared. Fed-batch culture with substrate limitation was found to be the most efficient process, reaching a propionic acid concentration of 30 g/L and a productivity of 0.33 g/L*h. This is the highest productivity so far achieved with free cells on media containing flour hydrolysate or glucose as carbon source. Batch culture and culture with controlled saccharification and fermentation delivered significantly lower propionic acid production (17-20 g/L) due to inhibition by the intermediate product lactate. It is concluded that co-culture fermentation of flour hydrolysate can be considered as an appealing bioprocess for the production of propionic acid. PMID- 23636694 TI - Characterization of novel mutants with an altered gibberellin spectrum in comparison to different wild-type strains of Fusarium fujikuroi. AB - The rice pathogen Fusarium fujikuroi is known for producing a wide range of secondary metabolites such as pigments, mycotoxins, and a group of phytohormones, the gibberellic acids (GAs). Bioactive forms of these diterpenes are responsible for hyperelongation of rice stems, yellowish chlorotic leaves, and reduced grain formation during the bakanae disease leading to severely decreased crop yields. GAs are also successfully applied in agriculture and horticulture as plant growth regulators to enhance crop yields, fruit size, and to induce earlier flowering. In this study, six F. fujikuroi wild-type and mutant strains differing in GA yields and the spectrum of produced GAs were cultivated in high-quality lab fermenters for optimal temperature and pH control and compared regarding their growth, GA production, and GA gene expression levels. Comparative analysis of the six strains revealed that strain 6314/DeltaDES/DeltaPPT1, holding mutations in two GA biosynthetic genes and an additional deletion of the 4' phosphopantetheinyl transferase gene PPT1, exhibits the highest total GA amount. Expression studies of two GA biosynthesis genes, CPS/KS and DES, showed a constantly high expression level for both genes under production conditions (nitrogen limitation) in all strains. By cultivating these genetically engineered mutant strains, we were able to produce not only mixtures of different bioactive GAs (GA3, GA4, and GA7) but also pure GA4 or GA7. In addition, we show that the GA yields are not only determined by different production rates, but also by different decomposition rates of the end products GA3, GA4, and GA7 explaining the varying GA levels of genetically almost identical mutant strains. PMID- 23636695 TI - Phenazine-1-carboxylic acid production in a chromosomally non-scar triple-deleted mutant Pseudomonas aeruginosa using statistical experimental designs to optimize yield. AB - We constructed a non-scar triple-deleted mutant Pseudomonas aeruginosa to improve phenazine-1-carboxylic acid (PCA) yield and then optimized the culture conditions for PCA production. Using a non-scar deletion strategy, the 5'-untranslated region of the phz1 gene cluster and two genes, phzM and phzS, were knocked out of the P. aeruginosa strain M18 genome. The potential ability for high-yield PCA production in this triple-deleted mutant M18MSU1 was successfully realized by using statistical experimental designs. A 2(5-1) fractional factorial design was used to show that the three culture components of soybean meal, corn steep liquor and ethanol had the most significant effect on PCA production. Using a central composite design, the concentration of the three components was optimized. The maximum PCA production was predicted to be 4,725.1 mg/L. With the optimal medium containing soybean meal 74.25 g/L, corn steep liquor 13.01 g/L and ethanol 21.84 ml/L, a PCA production of 4,771.2 mg/L was obtained in the validation experiments, which was nearly twofold of that before optimization and tenfold of that in the wild-type strain. This non-scar triple-deleted mutant M18MSU1 may be a suitable strain for industrial production of this biologically synthesized fungicide due to its high PCA production, presumed safety, thermal adaptability and cost-effectiveness. PMID- 23636696 TI - Influence of training on markers of platelet activation in response to a bout of heavy resistance exercise. AB - Recent connections between platelet activity and cardiovascular disease have raised questions of whether platelet function varies in exercising individuals. Resistance training has been linked to a possible reduction in hyper aggregability of platelets, especially following acute strenuous exercise. The present investigation was designed to explore the effects of an acute resistance exercise test on the primary hemostatic system in both resistance-trained (RT) and untrained (UT) individuals. Ten RT (five men and five women; age, 26.0 +/- 4.5 years; height, 175.12 +/- 8.54 cm; weight, 79.56 +/- 13.56 kg) and ten UT (five men and five women; age, 26.4 +/- 6.2 years; height, 170.31 +/- 7.45 cm; weight 67.88 +/- 16.90 kg) individuals performed an Acute Exhaustive Resistance Exercise Test (AERET; six sets of ten repetitions of squats at 80 % of the 1 Repetition Maximum (RM)). Blood samples were obtained before, immediately after, and at 15, 60, and 120 min following the AERET. Blood samples were analyzed for platelet count, von Willebrand factor antigen (vWF:Ag), beta-thromboglobulin (beta-TG), and platelet factor 4 (PF4). B-TG showed significant differences (p < 0.05) between RT and UT at +15 and +60 min. Both groups showed a main effect for time in platelet count, vWF, and beta-TG following the AERET, whereas PF4 remained unchanged. All blood variables returned to baseline 120 min after exercise. Compared with UT, RT demonstrated reduced platelet activation in response to an acute bout of heavy resistance exercise. Reduced platelet activation may be attributed to training status, as shown by a reduction in plasma concentrations of B-TG in the RT group. PMID- 23636697 TI - Blood pressure regulation III: what happens when one system must serve two masters: temperature and pressure regulation? AB - When prolonged intense exercise is performed at high ambient temperatures, cardiac output must meet dual demands for increased blood flow to contracting muscle and to the skin. The literature has commonly painted this scenario as a fierce competition, wherein one circulation preserves perfusion at the expense of the other, with the regulated maintenance of blood pressure as the ultimate goal. This review redefines this scenario as commensalism, an integrated balance of regulatory control where one circulation benefits with little functional effect on the other. In young, healthy subjects, arterial pressure rarely falls to any great extent during either extreme passive heating or prolonged dynamic exercise in the heat, nor does body temperature rise disproportionately due to a compromised skin blood flow. Rather, it often takes the superimposition of additional stressors--e.g., dehydration or simulated hemorrhage--upon heat stress to substantially impact blood pressure regulation. PMID- 23636698 TI - Variable resistance training promotes greater fatigue resistance but not hypertrophy versus constant resistance training. AB - Loading using variable resistance devices, where the external resistance changes in line with the force:angle relationship, has been shown to cause greater acute neuromuscular fatigue and larger serum hormone responses. This may indicate a greater potential for adaptation during long-term training. Twelve (constant resistance group) and 11 (variable resistance group) men completed 20 weeks of resistance training with 10 men as non-training controls. Training-induced adaptations were assessed by bilateral leg press one repetition maximum, a repetition to failure test using 75 % 1RM, lower limb lean mass and vastus lateralis cross-sectional area. Only the variable resistance training group improved the total number of repetitions (41 +/- 46 %) and volume load (52 +/- 37 %) during the repetition to failure test (P < 0.05). Similar improvements in maximum strength and hypertrophy of the lower limbs were observed in both training groups. Also, constant and variable resistance 5 * 10RM leg press loadings were performed before and after training in a crossover design. Acute loading-induced responses were assessed by concentric and isometric force, serum hormone concentrations and phosphorylation of intramuscular signalling proteins (0-30 min post-loading). Greater acute decreases in force (P < 0.05-0.01), and greater increases in serum testosterone and cortisol concentration (P < 0.05) and ERK 1/2 phosphorylation (P < 0.05) were observed following variable resistance loadings before and after training. Greater training-induced improvements in fatigue resistance occurred in the variable resistance training group, which may be due to greater acute fatigue and physiological responses during variable versus constant resistance loadings. PMID- 23636700 TI - Long-term outcome for two heifers with a granulosa-theca cell tumour. PMID- 23636699 TI - No evidence for cumulative effects in a Dnmt3b hypomorph across multiple generations. AB - Observations of inherited phenotypes that cannot be explained solely through genetic inheritance are increasing. Evidence points to transmission of non-DNA molecules in the gamete as mediators of the phenotypes. However, in most cases it is unclear what the molecules are, with DNA methylation, chromatin proteins, and small RNAs being the most prominent candidates. From a screen to generate novel mouse mutants of genes involved in epigenetic reprogramming, we produced a DNA methyltransferase 3b allele that is missing exon 13. Mice that are homozygous for the mutant allele have smaller stature and reduced viability, with particularly high levels of female post-natal death. Reduced DNA methylation was also detected at telocentric repeats and the X-linked Hprt gene. However, none of the abnormal phenotypes or DNA methylation changes worsened with multiple generations of homozygous mutant inbreeding. This suggests that in our model the abnormalities are reset each generation and the processes of transgenerational epigenetic reprogramming are effective in preventing their inheritance. PMID- 23636701 TI - Identification of a new reovirus causing substantial losses in broiler production in France, despite routine vaccination of breeders. AB - Numerous cases of tenosynovitis appeared in France causing high morbidity in free range and standard broilers. The main clinical findings were lameness, stunting and non-uniform bodyweights. Although the natural mortality was low, the economic losses due to birds that had to be removed from the flock prematurely, downgrading of carcases and lower average weights at slaughter were substantial. Postmortem examinations, bacteriological, virological and serological examination confirmed the aetiology of avian orthoreovirus (ARV)-induced tenosynovitis. The isolated ARVs were analysed serologically and genetically. Sequencing of sigmaC RT-PCR products and phylogenetic analysis revealed a new type of ARV. The virus was not neutralised in serum neutralisation test using monovalent sera from vaccinated chickens. Together with the flock data, epidemiology of these recent reovirus outbreaks in France was reconstructed. It is concluded that these reovirus isolates differ serologically and genetically from the well described reovirus isolates used in commercial vaccines which were not capable of preventing the disease. The outbreaks resulted in substantial losses in broilers from vaccinated breeders. PMID- 23636702 TI - Echinococcus multilocularis introduction and establishment in wildlife via imported beavers. PMID- 23636704 TI - Cardiovascular determinants involved in pacing under heat stress. PMID- 23636706 TI - A microfluidic impedance flow cytometer for identification of differentiation state of stem cells. AB - This paper presents a microfluidic electrical impedance flow cytometer (FC) for identifying the differentiation state of single stem cells. This device is comprised of a novel dual micropore design, which not only enhances the processing throughput, but also allows the associated electrodes to be used as a reference for one another. A signal processing algorithm, based on the support vector machine (SVM) theory, and a data classification method were developed to automate the identification of sample types and cell differentiation state based on measured impedance values. The device itself was fabricated using a combination of standard and soft lithography techniques to generate a PDMS-gold electrode construct. Experimental testing with non-biological particles and mouse embryonic carcinoma cells (P19, undifferentiated and differentiated) was carried out using a range of excitation frequencies. The effects of the frequency and the interrogation parameters on sample identification performance were investigated. It was found that the real and imaginary part of the detected impedance signal were adequate for distinguishing the undifferentiated P19 cells from non biological polystyrene beads at all tested frequencies. A higher frequency and an opacity index were required to resolve the undifferentiated and differentiated P19 cells by capturing capacitive changes in electrophysiological properties arising from differentiation. The experimental results demonstrated salient accuracy of the device and algorithm, and established its feasibility for non invasive, label-free identification of the differentiation state of the stem cells. PMID- 23636703 TI - The role of heat shock proteins in inflammatory injury induced by cold stress in chicken hearts. AB - The aim of this study was to investigate the effects of cold stress on the expression levels of heat shock proteins (Hsps90, 70, 60, 40, and 27) and inflammatory factors (iNOS, COX-2, NF-kappaB, TNF-alpha, and PTGEs) and oxidative indexes in hearts of chickens. Two hundred forty 15-day-old male chickens were randomly divided into 12 groups and kept at the temperature of 12 +/- 1 degrees C for acute and chronic cold stress. There were one control group and five treatment groups for acute cold stress, three control groups, and three treatment groups for chronic cold stress. After cold stress, malondialdehyde level increased in chicken heart; the activity of superoxide dismutase and glutathione peroxidase in the heart first increased and then decreased. The inflammatory factors mRNA levels were increased in cold stress groups relative to control groups. The histopathological analysis showed that heart tissues were seriously injured in the cold stress group. Additionally, the mRNA levels of Hsps (70, 60, 40, and 27) increased significantly (P < 0.05) in the cold stress groups relative to the corresponding control group. Meanwhile, the mRNA level and protein expression of Hsp90 decreased significantly (P < 0.05) in the stress group, and showed a gradually decreasing tendency. These results suggested that the levels of inflammatory factors and Hsps expression levels in heart tissues can be influenced by cold stress. Hsps commonly played an important role in the protection of the heart after cold stress. PMID- 23636707 TI - Ultrasensitive single-nucleotide polymorphism detection using target-recycled ligation, strand displacement and enzymatic amplification. AB - We report herein the development of a highly sensitive and selective approach for label-free DNA detection by combining target-recycled ligation (TRL), magnetic nanoparticle assisted target capture/separation, and efficient enzymatic amplification. We show that our approach can detect as little as 30 amol (600 fM in 50 MUL) of unlabelled single-stranded DNA targets and offer an exquisitely high discrimination ratio (up to >380 fold with background correction) between a perfect-match cancer mutant and its single-base mismatch (wild-type) DNA target. Furthermore, it can quantitate the rare cancer mutant (KRAS codon 12) in a large excess of coexisting wild-type DNAs down to 0.75%. This sensor appears to be well suited for sensitive SNP detection and a wide range of DNA mutation based diagnostic applications. PMID- 23636708 TI - Pulmonary leiomyosarcoma mimicking glomus tumor at first biopsy and surgically treated with isolated left main bronchus resection: rare clinical documentation. AB - Soft tissue tumors originating within the endobronchial tree are extremely rare and most of them correspond to lipomas or leiomyomas. We here report a rare clinical presentation of leiomyosarcoma mimicking glomus tumor at initial biopsy arising from the left main bronchial trunk leading to left lower lobe atelectasis. Primary leiomyosarcoma of the lung is an unusual malignancy. Among this entity, the endobronchial form is very rare and the preoperative diagnosis is extremely difficult. We documented two different presentations and outcomes of primary endobronchial leiomyosarcoma of the lung. In this clinical presentation, histological study and immunohistochemical stain of the surgical resection provided the final diagnosis. Through the following we present the diagnostic and therapeutic difficulties encountered with endobronchial leiomyosarcoma. PMID- 23636709 TI - Cnesterodon decemmaculatus juveniles as test organisms in toxicity assessment: cadmium case. AB - The poeciliid Cnesterodon decemmaculatus is one of the native species of southern South America recently recommended for use as a test species in biomonitoring. Therefore, it is important to characterize its responses to stress conditions caused by pollution. The aim of this work was to determine the toxicity of the reference toxicant cadmium (Cd) and to evaluate the lethality response of juveniles of C. decemmaculatus exposed to an environmental sample with a high degree of pollution (Lujan River, Buenos Aires, Argentina). The LC50 values at 24 and 96 h were 6.00 and 2.27 mg Cd/L, respectively. The uptake of Cd was significantly greater in the first 24 h in relation to the total time of exposure in the bioassay. The toxicity of the water was in agreement with the level of contamination. A Cd contaminant pulse exerted an important additive effect on the toxicity of the environmental sample. The results provide information regarding the sensitivity of a native species to be used as a test organism in environmental monitoring. PMID- 23636711 TI - Illustrating the multiple facets and levels of fidelity of implementation to a teacher classroom management intervention. AB - Many school-based interventions to promote student mental health rely on teachers as implementers. Thus, understanding the interplay between the multiple domains of fidelity to the intervention and intervention support systems such as coaching and teacher implementation of new skills is an important aspect of implementation science. This study describes a systematic process for assessing multiple domains of fidelity. Data from a larger efficacy trial of the Incredible Years Teacher Classroom Management (IY TCM) program are utilized. Data on fidelity to the IY TCM workshop training sessions and onsite weekly coaching indicate that workshop leaders and the IY TCM coach implemented the training and coaching model with adequate adherence. Further, workshop leaders' ratings of engagement were associated with teacher implementation of specific praise, following training on this content. Lastly, the IY TCM coach differentiation of teacher exposure to coaching was evaluated and found to be associated with teacher implementation of classroom management practices and student disruptive behavior. PMID- 23636710 TI - A prospective assessment of reports of drinking to self-medicate mood symptoms with the incidence and persistence of alcohol dependence. AB - IMPORTANCE: Mood disorders and alcohol dependence frequently co-occur. Etiologic theories concerning the comorbidity often focus on drinking to self-medicate or cope with affective symptoms. However, there have been few, if any, prospective studies in population-based samples of alcohol self-medication of mood symptoms with the occurrence of alcohol dependence. Furthermore, it is not known whether these associations are affected by treatment or symptom severity. OBJECTIVE: To evaluate the hypothesis that alcohol self-medication of mood symptoms increases the probability of subsequent onset and the persistence or chronicity of alcohol dependence. DESIGN: Prospective study using face-to-face interviews-the National Epidemiologic Survey on Alcohol and Related Conditions. SETTING: Nationally representative survey of the US population. PARTICIPANTS: Drinkers at risk for alcohol dependence among the 43 093 adults surveyed in 2001 and 2002 (wave 1); 34 653 of whom were reinterviewed in 2004 and 2005 (wave 2). MAIN OUTCOMES AND MEASURES: Association of alcohol self-medication of mood symptoms with incident and persistent DSM-IV alcohol dependence using logistic regression and the propensity score method of inverse probability of treatment weighting. RESULTS: The report of alcohol self-medication of mood symptoms was associated with an increased odds of incident alcohol dependence at follow-up (adjusted odds ratio [AOR], 3.10; 95% CI, 1.55-6.19; P = .002) and persistence of dependence (AOR, 3.45; 95% CI, 2.35-5.08; P < .001). The population-attributable fraction was 11.9% (95% CI, 6.7%-16.9%) for incident dependence and 30.6% (95% CI, 24.8% 36.0%) for persistent dependence. Stratified analyses were conducted by age, sex, race/ethnicity, mood symptom severity, and treatment history for mood symptoms. CONCLUSIONS AND RELEVANCE: Drinking to alleviate mood symptoms is associated with the development of alcohol dependence and its persistence once dependence develops. These associations occur among individuals with subthreshold mood symptoms, with DSM-IV affective disorders, and for those who have received treatment. Drinking to self-medicate mood symptoms may be a potential target for prevention and early intervention efforts aimed at reducing the occurrence of alcohol dependence. PMID- 23636712 TI - Determining engagement in services for high-need individuals with serious mental illness. AB - This study examined whether Medicaid claims and other administrative data could identify high-need individuals with serious mental illness in need of outreach in a large urban setting. A claims-based notification algorithm identified individuals belonging to high-need cohorts who may not be receiving needed services. Reviewers contacted providers who previously served the individuals to confirm whether they were in need of outreach. Over 10,000 individuals set a notification flag over 12-months. Disengagement was confirmed in 55 % of completed reviews, but outreach was initiated for only 30 %. Disengagement and outreach status varied by high-need cohort. PMID- 23636713 TI - Adenoid cystic carcinoma of the skull base mimicking temporomandibular disorder. AB - BACKGROUND: Temporomandibular disorder (TMD) involves problems of the temporomandibular joint and its adjacent muscular system. Because TMD prevalence is high among Western populations, complaints in these regions are generally attributed to TMD. However, in rare cases, TMD symptoms are mimicked by malignant tumors of the head. CASE REPORT: Upon first presentation, an 18-year-old female complained about typical symptoms of TMD. After an initial splint therapy and physiotherapy, painful symptoms increased significantly. Twelve weeks after initial diagnosis, further diagnostic imaging revealed a tumor formation at the skull base with infiltration of the infratemporal fossa. Histological evaluation confirmed the diagnosis of adenoid cystic carcinoma. Two years after resection of the tumor, lung metastases were detected with no option of curative treatment. CONCLUSION: TMD symptoms, which are refractory to treatment or exhibit significant worsening during therapy, should be regarded as warning signals and as an indication that early further diagnostic imaging is warranted. PMID- 23636714 TI - Reliability generalization for Childhood Autism Rating Scale. AB - The Childhood Autism Rating Scale (CARS) is a popular behavior-observation instrument that was developed more than 34 years ago and has since been adopted in a wide variety of contexts for assessing the presence and severity of autism symptomatology in both children and adolescents. This investigation of the reliability of CARS scores involves meta-analysis and meta-regression of empirical data from reports of original research that made use of CARS between 1980 and 2012. Findings of good internal consistency (.896, 95 % CI .877-.913) and good interrater reliability (.796, 95 % CI .736-.844) support use of CARS at least in early-phase, exploratory research. Evidence of heterogeneity among literature data indicates that reliability is a property of CARS scores and is not intrinsic to the instrument itself. As the first of its kind pertaining to autism, this investigation provides guidance for reviews of other instruments' ratings. PMID- 23636716 TI - Residual rotational error of X-ray volume imaging system and its dosimetric effect in spinal tumor radiation therapy. AB - This study was designed to investigate the residual rotational error (RRE) of an X-ray volume imaging (XVI) system and evaluate the dosimetric impact of this error on spinal tumor radiation therapy. Various rotational displacements (set rotations) were applied to an anthropomorphic phantom placed on a HexaPod evo RT CouchTop (HexaPod couch). To detect these set rotations, a series of cone-beam computed tomography (CBCT) scans of the phantom were acquired and registered to the planning CT in the XVI system. The RRE of the XVI system was evaluated by comparing the difference between the set rotations and the registration results from the XVI. The error-introduced plans (by applying the RRE to the copies of the reference plan) were generated in the treatment planning system. The dose distribution was compared between the reference plan and the error-introduced plans to assess the dosimetric impact of RRE. The root-mean-square (RMS) of RREs were 0.31 degrees , 0.35 degrees , and 0.25 degrees in the X (pitch), Y (roll), and Z (yaw) direction, respectively. For the reference plan versus the error introduced plans, the PTV volumes receiving the prescribed dose (V 100) were 95.1 % versus 94.8-95.7 %; the conformity indices of the PTV were 1.17 versus 1.16 1.19; the minimum dose to 1 cc of volume (D1 cc) of spinal cord were 43.73 Gy versus 43.71-43.89 Gy; the left kidney volumes receiving 15 Gy (V 15) were 29.7 % versus 29.2-30.7 %; and the V 15 values of the right kidney were 26.1 % versus 24.6-27.5 %. Relative to the reference plan, the dose difference of error introduced plans exceeded 3 % in kidney V 15. In conclusion, the XVI system can accurately detect the rotational displacement. However, large dose deviations were introduced by RREs when organs at risk were away from the iso-center even for small RREs. PMID- 23636717 TI - Dry eye modifies the thermal and menthol responses in rat corneal primary afferent cool cells. AB - Dry eye syndrome is a painful condition caused by inadequate or altered tear film on the ocular surface. Primary afferent cool cells innervating the cornea regulate the ocular fluid status by increasing reflex tearing in response to evaporative cooling and hyperosmicity. It has been proposed that activation of corneal cool cells via a transient receptor potential melastatin 8 (TRPM8) channel agonist may represent a potential therapeutic intervention to treat dry eye. This study examined the effect of dry eye on the response properties of corneal cool cells and the ability of the TRPM8 agonist menthol to modify these properties. A unilateral dry eye condition was created in rats by removing the left lacrimal gland. Lacrimal gland removal reduced tears in the dry eye to 35% compared with the contralateral eye and increased the number of spontaneous blinks in the dry eye by over 300%. Extracellular single-unit recordings were performed 8-10 wk following surgery in the trigeminal ganglion of dry eye animals and age-matched controls. Responses of corneal cool cells to cooling were examined after the application of menthol (10 MUM-1.0 mM) to the ocular surface. The peak frequency of discharge to cooling was higher and the cooling threshold was warmer in dry eye animals compared with controls. The dry condition also altered the neuronal sensitivity to menthol, causing desensitization to cold evoked responses at concentrations that produced facilitation in control animals. The menthol-induced desensitization of corneal cool cells would likely result in reduced tearing, a deleterious effect in individuals with dry eye. PMID- 23636715 TI - Functional neuroimaging of social and nonsocial cognitive control in autism. AB - This study investigated cognitive control of social and nonsocial information in autism using functional magnetic resonance imaging. Individuals with autism spectrum disorders (ASDs) and a neurotypical control group completed an oddball target detection task where target stimuli were either faces or nonsocial objects previously shown to be related to circumscribed interests in autism. The ASD group demonstrated relatively increased activation to social targets in right insular cortex and in left superior frontal gyrus and relatively decreased activation to nonsocial targets related to circumscribed interests in multiple frontostriatal brain regions. Findings suggest that frontostriatal recruitment during cognitive control in ASD is contingent on stimulus type, with increased activation for social stimuli and decreased activation for nonsocial stimuli related to circumscribed interests. PMID- 23636719 TI - Fixational saccades reflect volitional action preparation. AB - Human volitional actions are preceded by preparatory processes, a critical mental process of cognitive control for future behavior. Volitional action preparation is regulated by large-scale neural circuits including the cerebral cortex and the basal ganglia. Because volitional action preparation is a covert process, the network dynamics of such neural circuits have been examined by neuroimaging and recording event-related potentials. Here, we examined whether such covert processes can be measured by the overt responses of fixational saccades (including microsaccades), the largest miniature eye movements that occur during eye fixation. We analyzed fixational saccades while adult humans maintained fixation on a central visual stimulus as they prepared to generate a volitional saccade in response to peripheral stimulus appearance. We used the antisaccade paradigm, in which subjects generate a saccade toward the opposite direction of a peripheral stimulus. Appropriate antisaccade performance requires the following two aspects of volitional control: 1) facilitation of saccades away from the stimulus and 2) suppression of inappropriate saccades toward the stimulus. We found that fixational saccades that occurred before stimulus appearance reflected the dual preparatory states of saccade facilitation and suppression and correlated with behavioral outcome (i.e., whether subjects succeeded or failed to cancel inappropriate saccades toward the stimulus). Moreover, fixational saccades explained a large proportion of individual differences in behavioral performance (poor/excellent) across subjects. These results suggest that fixational saccades predict the outcome of future volitional actions and may be used as a potential biomarker to detect people with difficulties in volitional action preparation. PMID- 23636720 TI - Effects of caudate microstimulation on spontaneous and purposive saccades. AB - Electrical stimulation has been delivered to the basal ganglia (BG) to treat intractable symptoms of a variety of clinical disorders. However, it is still unknown how such treatments improve behavioral symptoms. A difficulty of this problem is that artificial signals created by electrical stimulation interact with intrinsic signals before influencing behavior, thereby making it important to understand how such interactions between artificial and intrinsic signals occur. We addressed this issue by analyzing the effects of electrical stimulation under the following two behavioral conditions that induce different states of intrinsic signals: 1) subjects behave spontaneously without task demands; and 2) subjects perform a behavioral paradigm purposefully. We analyzed saccadic eye movements in monkeys while delivering microstimulation to the head and body of the caudate nucleus, a major input stage of the oculomotor BG. When monkeys generated spontaneous saccades, caudate microstimulation biased saccade vector endpoints toward the contralateral direction of stimulation sites. However, when caudate microstimulation was delivered during a purposive prosaccade (look toward a visual stimulus) or an antisaccade (look away from a stimulus) paradigm, it created overall ipsilateral biases by suppressing contralateral saccades more strongly than ipsilateral saccades. These results suggest that the impact of BG electrical stimulation changes dynamically depending on the state of intrinsic signals that vary under a variety of behavioral demands in everyday life. PMID- 23636718 TI - Long-term potentiation of synaptic transmission in the adult mouse insular cortex: multielectrode array recordings. AB - The insular cortex (IC) is widely believed to be an important forebrain structure involved in cognitive and sensory processes such as memory and pain. However, little work has been performed at the cellular level to investigate the synaptic basis of IC-related brain functions. To bridge the gap, the present study was designed to characterize the basic synaptic mechanisms for insular long-term potentiation (LTP). Using a 64-channel recording system, we found that an enduring form of late-phase LTP (L-LTP) could be reliably recorded for at least 3 h in different layers of IC slices after theta burst stimulation. The induction of insular LTP is protein synthesis dependent and requires activation of both GluN2A and GluN2B subunits of the NMDA receptor, L-type voltage-gated calcium channels, and metabotropic glutamate receptor 1. The paired-pulse facilitation ratio was unaffected by insular L-LTP induction, and expression of insular L-LTP required the recruitment of postsynaptic calcium-permeable AMPA receptors. Our results provide the first in vitro report of long-term multichannel recordings of L-LTP in the IC in adult mice and suggest its potential important roles in insula related memory and chronic pain. PMID- 23636721 TI - Cyclophosphamide-induced cystitis reduces ASIC channel but enhances TRPV1 receptor function in rat bladder sensory neurons. AB - Using patch-clamp techniques, we studied the plasticity of acid-sensing ion channels (ASIC) and transient receptor potential V1 (TRPV1) channel function in dorsal root ganglia (DRG) neurons retrogradely labeled from the bladder. Saline (control) or cyclophosphamide (CYP) was given intraperitoneally on days 1, 3, and 5. On day 6, lumbosacral (LS, L6-S2) or thoracolumbar (TL, T13-L2) DRG were removed and dissociated. Bladders and bladder DRG neurons from CYP-treated rats showed signs of inflammation (greater myeloperoxidase activity; lower intramuscular wall pH) and increased size (whole cell capacitance), respectively, compared with controls. Most bladder neurons (>90%) responded to protons and capsaicin. Protons produced multiphasic currents with distinct kinetics, whereas capsaicin always triggered a sustained response. The TRPV1 receptor antagonist A 425619 abolished capsaicin-triggered currents and raised the threshold of heat activated currents. Prolonged exposure to an acidic environment (pH range: 7.2 to 6.6) inhibited proton-evoked currents, potentiated the capsaicin-evoked current, and reduced the threshold of heat-activated currents in LS and TL bladder neurons. CYP treatment reduced density but not kinetics of all current components triggered by pH 5. In contrast, CYP-treatment was associated with an increased current density in response to capsaicin in LS and TL bladder neurons. Correspondingly, heat triggered current at a significantly lower temperature in bladder neurons from CYP-treated rats compared with controls. These results reveal that cystitis differentially affects TRPV1- and ASIC-mediated currents in both bladder sensory pathways. Acidification of the bladder wall during inflammation may contribute to changes in nociceptive transmission mediated through the TRPV1 receptor, suggesting a role for TRPV1 in hypersensitivity associated with cystitis. PMID- 23636723 TI - Sucking and swallowing rates after palatal anesthesia: an electromyographic study in infant pigs. AB - Infant mammalian feeding consists of rhythmic suck cycles and reflexive pharyngeal swallows. Although we know how oropharyngeal sensation influences the initiation and frequency of suck and swallow cycles, the role of palatal sensation is unknown. We implanted EMG electrodes into the mylohyoid muscle, a muscle active during suckling, and the thyrohyoid muscle, a muscle active during swallowing, in eight infant pigs. Pigs were then bottle-fed while lateral videofluoroscopy was simultaneously recorded from the electrodes. Two treatments were administered prior to feeding and compared with control feedings: 1) palatal anesthesia (0.5% bupivacaine hydrochloride), and 2) palatal saline. Using the timing of mylohyoid muscle and thyrohyoid muscle activity, we tested for differences between treatment and control feedings for swallowing frequency and suck cycle duration. Following palatal anesthesia, four pigs could not suck and exhibited excessive jaw movement. We categorized the four pigs that could suck after palatal anesthesia as group A, and those who could not as group B. Group A had no significant change in suck cycle duration and a higher swallowing frequency after palatal saline (P = 0.021). Group B had significantly longer suck cycles after palatal anesthesia (P < 0.001) and a slower swallowing frequency (P < 0.001). Swallowing frequency may be a way to predict group membership, since it was different in control feedings between groups (P < 0.001). The qualitative and bimodal group response to palatal anesthesia may reflect a developmental difference. This study demonstrates that palatal sensation is involved in the initiation and frequency of suck and swallow cycles in infant feeding. PMID- 23636725 TI - Synaptic inhibition and excitation estimated via the time constant of membrane potential fluctuations. AB - When recording the membrane potential, V, of a neuron it is desirable to be able to extract the synaptic input. Critically, the synaptic input is stochastic and nonreproducible so one is therefore often restricted to single-trial data. Here, we introduce means of estimating the inhibition and excitation and their confidence limits from single sweep trials. The estimates are based on the mean membrane potential, V, and the membrane time constant, tau. The time constant provides the total conductance (G = capacitance/tau) and is extracted from the autocorrelation of V. The synaptic conductances can then be inferred from V when approximating the neuron as a single compartment. We further employ a stochastic model to establish limits of confidence. The method is verified on models and experimental data, where the synaptic input is manipulated pharmacologically or estimated by an alternative method. The method gives best results if the synaptic input is large compared with other conductances, the intrinsic conductances have little or no time dependence or are comparably small, the ligand-gated kinetics is faster than the membrane time constant, and the majority of synaptic contacts are electrotonically close to soma (recording site). Although our data are in current clamp, the method also works in V-clamp recordings, with some minor adaptations. All custom made procedures are provided in Matlab. PMID- 23636722 TI - Inhibitory inputs tune the light response properties of dopaminergic amacrine cells in mouse retina. AB - Dopamine (DA) is a neuromodulator that in the retina adjusts the circuitry for visual processing in dim and bright light conditions. It is synthesized and released from retinal interneurons called dopaminergic amacrine cells (DACs), whose basic physiology is not yet been fully characterized. To investigate their cellular and input properties as well as light responses, DACs were targeted for whole cell recording in isolated retina using two-photon fluorescence microscopy in a mouse line where the dopamine receptor 2 promoter drives green fluorescent protein (GFP) expression. Differences in membrane properties gave rise to cell-to cell variation in the pattern of resting spontaneous spike activity ranging from silent to rhythmic to periodic burst discharge. All recorded DACs were light sensitive and generated responses that varied with intensity. The threshold response to light onset was a hyperpolarizing potential change initiated by rod photoreceptors that was blocked by strychnine, indicating a glycinergic amacrine input onto DACs at light onset. With increasing light intensity, the ON response acquired an excitatory component that grew to dominate the response to the strongest stimuli. Responses to bright light (photopic) stimuli also included an inhibitory OFF response mediated by GABAergic amacrine cells driven by the cone OFF pathway. DACs expressed GABA (GABA(A)alpha1 and GABA(A)alpha3) and glycine (alpha2) receptor clusters on soma, axon, and dendrites consistent with the light response being shaped by dual inhibitory inputs that may serve to tune spike discharge for optimal DA release. PMID- 23636724 TI - Proportional spike-timing precision and firing reliability underlie efficient temporal processing of periodicity and envelope shape cues. AB - Temporal sound cues are essential for sound recognition, pitch, rhythm, and timbre perception, yet how auditory neurons encode such cues is subject of ongoing debate. Rate coding theories propose that temporal sound features are represented by rate tuned modulation filters. However, overwhelming evidence also suggests that precise spike timing is an essential attribute of the neural code. Here we demonstrate that single neurons in the auditory midbrain employ a proportional code in which spike-timing precision and firing reliability covary with the sound envelope cues to provide an efficient representation of the stimulus. Spike-timing precision varied systematically with the timescale and shape of the sound envelope and yet was largely independent of the sound modulation frequency, a prominent cue for pitch. In contrast, spike-count reliability was strongly affected by the modulation frequency. Spike-timing precision extends from sub-millisecond for brief transient sounds up to tens of milliseconds for sounds with slow-varying envelope. Information theoretic analysis further confirms that spike-timing precision depends strongly on the sound envelope shape, while firing reliability was strongly affected by the sound modulation frequency. Both the information efficiency and total information were limited by the firing reliability and spike-timing precision in a manner that reflected the sound structure. This result supports a temporal coding strategy in the auditory midbrain where proportional changes in spike-timing precision and firing reliability can efficiently signal shape and periodicity temporal cues. PMID- 23636726 TI - Simultaneous characterizations of reflex and nonreflex dynamic and static changes in spastic hemiparesis. AB - This study characterizes tonic and phasic stretch reflex and stiffness and viscosity changes associated with spastic hemiparesis. Perturbations were applied to the ankle of 27 hemiparetic and 36 healthy subjects under relaxed or active contracting conditions. A nonlinear delay differential equation model characterized phasic and tonic stretch reflex gains, elastic stiffness, and viscous damping. Tendon reflex was characterized with reflex gain and threshold. Reflexively, tonic reflex gain was increased in spastic ankles at rest (P < 0.038) and was not regulated with muscle contraction, indicating impaired tonic stretch reflex. Phasic-reflex gain in spastic plantar flexors was higher and increased faster with plantar flexor contraction (P < 0.012) than controls (P < 0.023) and higher in dorsi-flexors at lower torques (P < 0.038), primarily because of its increase at rest (P = 0.045), indicating exaggerated phasic stretch reflex especially in more spastic plantar flexors, which showed higher phasic stretch reflex gain than dorsi-flexors (P < 0.032). Spasticity was associated with increased tendon reflex gain (P = 0.002) and decreased threshold (P < 0.001). Mechanically, stiffness in spastic ankles was higher than that in controls across plantar flexion/dorsi-flexion torque levels (P < 0.032), and the more spastic plantar flexors were stiffer than dorsi-flexors at comparable torques (P < 0.031). Increased stiffness in spastic ankles was mainly due to passive stiffness increase (P < 0.001), indicating increased connective tissues/shortened fascicles. Viscous damping in spastic ankles was increased across the plantar flexion torque levels and at lower dorsi-flexion torques, reflecting increased passive viscous damping (P = 0.033). The more spastic plantar flexors showed higher viscous damping than dorsi-flexors at comparable torque levels (P < 0.047). Simultaneous characterizations of reflex and nonreflex changes in spastic hemiparesis may help to evaluate and treat them more effectively. PMID- 23636727 TI - Which neurons survive the glutamate storm? PMID- 23636728 TI - Bilateral tremor responses to unilateral loading and fatiguing muscle contractions. AB - Although physiological tremor has been extensively studied within a single limb, tremor relationships between limbs are not well understood. Early investigations proposed that tremor in each limb is driven by CNS oscillators operating in parallel. However, recent evidence suggests that tremor in both limbs arises from shared neural inputs and is more likely to be observed under perturbed conditions. In the present study, postural tremor about the elbow joint and elbow flexor EMG activity were examined on both sides of the body in response to unilateral loading and fatiguing muscle contractions. Applying loads of 0.5, 1.0, 1.5, and 3.0 kg to a single limb increased tremor and muscle activity in the loaded limb but did not affect the unloaded limb, indicating that manipulating the inertial characteristics of a limb does not evoke bilateral tremor responses. In contrast, maximal-effort unilateral isometric contractions resulted in increased tremor and muscle activity in both the active limb and the nonactive limb without any changes in between-limb tremor or muscle coupling. When unilateral contractions were repeated intermittently, to the extent that maximum torque generation about the elbow joint declined by 50%, different tremor profiles were observed in each limb. Specifically, unilateral fatigue altered coupling between limbs and generated a bilateral response such that tremor and brachioradialis EMG decreased for the fatigued limb and increased in the contralateral nonfatigued limb. Our results demonstrate that activity in the nonactive limb may be due to a "spillover" effect rather than directly coupled neural output to both arms and that between-limb coupling for tremor and muscle activity is only altered under considerably perturbed conditions, such as fatigue inducing contractions. PMID- 23636729 TI - Method for stationarity-segmentation of spike train data with application to the Pearson cross-correlation. AB - Correlations among neurons are supposed to play an important role in computation and information coding in the nervous system. Empirically, functional interactions between neurons are most commonly assessed by cross-correlation functions. Recent studies have suggested that pairwise correlations may indeed be sufficient to capture most of the information present in neural interactions. Many applications of correlation functions, however, implicitly tend to assume that the underlying processes are stationary. This assumption will usually fail for real neurons recorded in vivo since their activity during behavioral tasks is heavily influenced by stimulus-, movement-, or cognition-related processes as well as by more general processes like slow oscillations or changes in state of alertness. To address the problem of nonstationarity, we introduce a method for assessing stationarity empirically and then "slicing" spike trains into stationary segments according to the statistical definition of weak-sense stationarity. We examine pairwise Pearson cross-correlations (PCCs) under both stationary and nonstationary conditions and identify another source of covariance that can be differentiated from the covariance of the spike times and emerges as a consequence of residual nonstationarities after the slicing process: the covariance of the firing rates defined on each segment. Based on this, a correction of the PCC is introduced that accounts for the effect of segmentation. We probe these methods both on simulated data sets and on in vivo recordings from the prefrontal cortex of behaving rats. Rather than for removing nonstationarities, the present method may also be used for detecting significant events in spike trains. PMID- 23636730 TI - Challenges in the therapy of chromoblastomycosis. AB - Chromoblastomycosis (CBM) is an implantation mycosis mainly occurring in tropical and subtropical zones worldwide. If not diagnosed at early stages, patients with CBM require long-term therapy with systemic antifungals flanked by various physical treatment regimens. As in other neglected endemic mycoses, comparative clinical trials have not been performed for this disease; nowadays, therapy is mainly based on a few open trials and on expert opinions. Itraconazole, either as monotherapy or associated with other drugs, or with physical methods, is widely used. Recently, photodynamic therapy has been employed successfully in combination with antifungals in patients presenting with CBM. In the present paper, the most used therapeutic options against CBM are reviewed as well as the several factors that may have impact on the patient's outcome. PMID- 23636731 TI - MRI features most often associated with surgically proven tears of the spring ligament complex. AB - OBJECTIVES: The authors aim to present the common MRI appearances of surgically proven spring ligament tears as minimal radiological literature exists regarding injury to this increasingly important structure. MATERIALS AND METHODS: Our retrospective review identified a treatment group comprising 13 cases of surgically proven spring ligament injury and a 96-patient comparison group. All patients underwent standard musculoskeletal MRI sequences of the foot and ankle. Images were reviewed by a registrar-grade orthopedic surgeon and a consultant musculoskeletal radiologist for abnormalities of the spring ligament complex. RESULTS: MRI findings in relation to surgically proven injury of the superior medial portion of the spring ligament included proximal thickening >5 mm in 92 % and distal thinning <2 mm in 85 % of proven injures to the spring ligament complex. Common abnormalities of the medio-plantar portion comprised ligament thickening >7 mm in 31 % and intra-substance signal heterogenicity demonstrated in 38 % of cases. CONCLUSIONS: The complex orientation of the medio-plantar ligament makes its evaluation unreliable due to the difficulty obtaining diagnostic quality imaging and our inability to correlate MRI findings in this portion of the ligament with surgically proven injury. However, MRI abnormalities of the superior-medial ligament are consistent, reproducible, and correlate with surgical pathology. As our incomplete understanding of the flexible flatfoot deformity evolves, our ability to recognize injury to the spring ligament may encourage novel surgical treatments looking to incorporate its repair or reconstruction into deformity correction. PMID- 23636732 TI - Rapid osteolysis of the femoral neck: consequence of an insufficiency fracture of the hip? AB - PURPOSE: To describe the imaging and clinical features of rapid osteolysis of the femoral neck in an attempt to better understand this uncommon pathology. MATERIALS AND METHODS: We retrospectively reviewed the files of 11 patients (six women and five men) aged 53-78 years diagnosed with rapid osteolysis of the femoral neck. Available imaging studies included radiographs, CT, MRI, and bone scintigraphy. Histopathological evaluations were available for seven cases. RESULTS: All patients presented with complaints of hip pain, six of whom had acute symptoms, while the rest had progressive symptoms and impairment. All but one case were found to have bone deposition in adjacent hip muscles. CT confirmed bone deposition in adjacent tissues and true osteolysis of the femoral neck with relative sparing of the articular surfaces. Bone scintigraphy and MRI were useful to exclude underlying neoplastic disease. CONCLUSIONS: Rapid osteolysis of the femoral neck tends to occur in patients with underlying comorbidities leading to bone fragility and may actually represent a peculiar form of spontaneous insufficiency fracture. Recognition of its imaging features and clinical risk factors may help distinguish this process from other more concerning disorders such as infection or neoplasm. PMID- 23636733 TI - Alternative drugs of abuse. AB - The incidence of drug abuse with alternative agents is increasing. The term "alternative drugs of abuse" is a catch-all term for abused chemicals that do not fit into one of the classic categories of drugs of abuse. The most common age group abusing these agents range from 17 to 25 years old and are often associated with group settings. Due to their diverse pharmacological nature, legislative efforts to classify these chemicals as a schedule I drug have lagged behind the development of new alternative agents. The potential reason for abuse of these agents is their hallucinogenic, dissociative, stimulant, anti-muscarinic, or sedative properties. Some of these drugs are easily obtainable such as Datura stramonium (Jimson Weed) or Lophophora williamsii (Peyote) because they are natural plants indigenous to certain regions. The diverse pharmacology and clinical effects of these agents are so broad that they do not produce a universal constellation of signs and symptoms. Detailed physical exams are essential for identifying clues leading one to suspect an alternative drug of abuse. Testing for the presence of these agents is often limited, and even when available, the results do not return in a timely fashion. Intoxications from these agents pose unique challenges for health care providers. Physician knowledge of the physiological effects of these alternative agents and the local patterns of drug of abuse are important for the accurate diagnosis and optimal care of poisoned patients. This review summarizes the current knowledge of alternative drugs of abuse and highlights their clinical presentations. PMID- 23636734 TI - The effects of opioids on the lung. AB - The term opioid refers to a broad class of medications that are used most frequently for their analgesic effects. Along with this effect, they also produce euphoria, and it is for this reason that they have been used illicitly, as well as medicinally, for thousands of years. While the most well-known complications of opioid use and misuse include respiratory and central nervous system depression, there are many other toxicities that have been associated with these drugs. Many complications can occur with multiple different opioids, such as non cardiogenic pulmonary edema, while many of the complications are unique to the opioid used as well as the route of administration. This review focuses on the pulmonary complications associated with opioid use and abuse, but opioids can affect nearly every organ system. Their effects on the pulmonary system can be direct, such as causing granulomatous change, but they can also work indirectly. For example, opioids cause respiratory depression by decreasing sensitivity of peripheral chemoreceptors to carbon dioxide and decreasing activity in the central respiratory centers. Opioids have also been reported to affect the immune system, and place users at increased risk for many different infectious complications. Patients can have a wide array of signs and symptoms, sometimes making it difficult to recognize opioids as a cause for a patient's clinical picture. Due to the sedative effects of opioids, patients are also often not able to provide a reliable history. Knowledge of the possible toxicities of opioids can help prepare a physician to recognize the many complications associated with opioid use. PMID- 23636736 TI - Chromatin-associated proteins HP1 and Mod(mdg4) modify Y-linked regulatory variation in the drosophila testis. AB - Chromatin remodeling is crucial for gene regulation. Remodeling is often mediated through chemical modifications of the DNA template, DNA-associated proteins, and RNA-mediated processes. Y-linked regulatory variation (YRV) refers to the quantitative effects that polymorphic tracts of Y-linked chromatin exert on gene expression of X-linked and autosomal genes. Here we show that naturally occurring polymorphisms in the Drosophila melanogaster Y chromosome contribute disproportionally to gene expression variation in the testis. The variation is dependent on wild-type expression levels of mod(mdg4) as well as Su(var)205; the latter gene codes for heterochromatin protein 1 (HP1) in Drosophila. Testis specific YRV is abolished in genotypes with heterozygous loss-of-function mutations for mod(mdg4) and Su(var)205 but not in similar experiments with JIL-1. Furthermore, the Y chromosome differentially regulates several ubiquitously expressed genes. The results highlight the requirement for wild-type dosage of Su(var)205 and mod(mdg4) in enabling naturally occurring Y-linked regulatory variation in the testis. The phenotypes that emerge in the context of wild-type levels of the HP1 and Mod(mdg4) proteins might be part of an adaptive response to the environment. PMID- 23636737 TI - Dissecting high-dimensional phenotypes with bayesian sparse factor analysis of genetic covariance matrices. AB - Quantitative genetic studies that model complex, multivariate phenotypes are important for both evolutionary prediction and artificial selection. For example, changes in gene expression can provide insight into developmental and physiological mechanisms that link genotype and phenotype. However, classical analytical techniques are poorly suited to quantitative genetic studies of gene expression where the number of traits assayed per individual can reach many thousand. Here, we derive a Bayesian genetic sparse factor model for estimating the genetic covariance matrix (G-matrix) of high-dimensional traits, such as gene expression, in a mixed-effects model. The key idea of our model is that we need consider only G-matrices that are biologically plausible. An organism's entire phenotype is the result of processes that are modular and have limited complexity. This implies that the G-matrix will be highly structured. In particular, we assume that a limited number of intermediate traits (or factors, e.g., variations in development or physiology) control the variation in the high dimensional phenotype, and that each of these intermediate traits is sparse - affecting only a few observed traits. The advantages of this approach are twofold. First, sparse factors are interpretable and provide biological insight into mechanisms underlying the genetic architecture. Second, enforcing sparsity helps prevent sampling errors from swamping out the true signal in high dimensional data. We demonstrate the advantages of our model on simulated data and in an analysis of a published Drosophila melanogaster gene expression data set. PMID- 23636735 TI - Exclusive enteral nutrition induces early clinical, mucosal and transmural remission in paediatric Crohn's disease. AB - BACKGROUND AND AIMS: Exclusive enteral nutrition (EEN) induces clinical and mucosal healing (MH) in Crohn's disease (CD), with MH the best determinant of future outcome. We investigated efficacy of EEN for inducing early clinical, biochemical, mucosal and transmural remission of CD and related early endoscopic response to outcomes at 1 year. METHODS: In a prospective, open label study 34 children (mean 13.1 years; 21 males) with new diagnosis CD were offered EEN, 26 completed a minimum 6 weeks EEN and underwent paired clinical, biochemical and endoscopic assessment at start and completion using PCDAI, BMI, CRP and Simple Endoscopic Score for CD (SES-CD). A subset, 16/26, had paired MR enterography scored. Early good endoscopic response (complete MH, or near complete, SES-CD 0 3) was related to outcome at 1 year. RESULTS: EEN improved mean PCDAI (37.88 7.01, p < 0.001; BMI Z scores (-1.54 to -0.54, p < 0.01); weight Z score (-0.79 to -0.08, p < 0.03); CRP (44.86-5.5, p < 0.001); endoscopy (SES-CD 14.28-3.88, p < 0.001) and MRE (5.14-2.79, p = 0.01). Of 26 children, 22 (84 %) achieved clinical remission; 20 (76 %) biochemical remission. Fifteen (58 %) had early good endoscopic response (11 complete, 4 near complete MH) and 3/14 (21 %) had complete transmural remission of ileal CD (MRE-CD: 0-1). Early good endoscopic response was associated with reduced endoscopic confirmed relapse (53 vs. 100 %, p = 0.02), anti-TNF use (33 vs. 88 %, p = 0.01) and hospitalisation (40 vs. 88 %) at 1 year. CONCLUSIONS: EEN is effective for inducing early clinical, biochemical, mucosal and transmural remission. Early endoscopic remission improves outcomes at 1 year. PMID- 23636738 TI - Rare variant association testing under low-coverage sequencing. AB - Deep sequencing technologies enable the study of the effects of rare variants in disease risk. While methods have been developed to increase statistical power for detection of such effects, detecting subtle associations requires studies with hundreds or thousands of individuals, which is prohibitively costly. Recently, low-coverage sequencing has been shown to effectively reduce the cost of genome wide association studies, using current sequencing technologies. However, current methods for disease association testing on rare variants cannot be applied directly to low-coverage sequencing data, as they require individual genotype data, which may not be called correctly due to low-coverage and inherent sequencing errors. In this article, we propose two novel methods for detecting association of rare variants with disease risk, using low coverage, error-prone sequencing. We show by simulation that our methods outperform previous methods under both low- and high-coverage sequencing and under different disease architectures. We use real data and simulation studies to demonstrate that to maximize the power to detect associations for a fixed budget, it is desirable to include more samples while lowering coverage and to perform an analysis using our suggested methods. PMID- 23636739 TI - Priors in whole-genome regression: the bayesian alphabet returns. AB - Whole-genome enabled prediction of complex traits has received enormous attention in animal and plant breeding and is making inroads into human and even Drosophila genetics. The term "Bayesian alphabet" denotes a growing number of letters of the alphabet used to denote various Bayesian linear regressions that differ in the priors adopted, while sharing the same sampling model. We explore the role of the prior distribution in whole-genome regression models for dissecting complex traits in what is now a standard situation with genomic data where the number of unknown parameters (p) typically exceeds sample size (n). Members of the alphabet aim to confront this overparameterization in various manners, but it is shown here that the prior is always influential, unless n ? p. This happens because parameters are not likelihood identified, so Bayesian learning is imperfect. Since inferences are not devoid of the influence of the prior, claims about genetic architecture from these methods should be taken with caution. However, all such procedures may deliver reasonable predictions of complex traits, provided that some parameters ("tuning knobs") are assessed via a properly conducted cross-validation. It is concluded that members of the alphabet have a room in whole-genome prediction of phenotypes, but have somewhat doubtful inferential value, at least when sample size is such that n ? p. PMID- 23636740 TI - Statistical methods for analyzing Drosophila germline mutation rates. AB - Most studies of mutation rates implicitly assume that they remain constant throughout development of the germline. However, researchers recently used a novel statistical framework to reveal that mutation rates differ dramatically during sperm development in Drosophila melanogaster. Here a general framework is described for the inference of germline mutation patterns, generated from either mutation screening experiments or DNA sequence polymorphism data, that enables analysis of more than two mutations per family. The inference is made more rigorous and flexible by providing a better approximation of the probabilities of patterns of mutations and an improved coalescent algorithm within a single host with realistic assumptions. The properties of the inference framework, both the estimation and the hypothesis testing, were investigated by simulation. The refined inference framework is shown to provide (1) nearly unbiased maximum likelihood estimates of mutation rates and (2) robust hypothesis testing using the standard asymptotic distribution of the likelihood-ratio tests. It is readily applicable to data sets in which multiple mutations in the same family are common. PMID- 23636741 TI - The aurora B kinase promotes inner and outer kinetochore interactions in budding yeast. AB - The kinetochore is the macromolecular protein complex that mediates chromosome segregation. The Dsn1 component is crucial for kinetochore assembly and is phosphorylated by the Aurora B kinase. We found that Aurora B phosphorylation of Dsn1 promotes the interaction between outer and inner kinetochore proteins in budding yeast. PMID- 23636742 TI - Ultrasonography in prostate cancer: current roles and potential applications in radiorecurrent disease. AB - The use of ultrasound technology for prostate cancer imaging has evolved over many years. In order to fully appreciate today's application of prostate ultrasound in the primary diagnostic setting as well as for radiorecurrent prostate cancer, it is helpful to understand the progression of this technology from its inception. This review begins with a brief history of the development of ultrasonography for the prostate. This is followed by a summary of the data evaluating ultrasound in the primary diagnosis of prostate cancer. Its application in the post-treatment setting is then addressed. Finally, several emerging technologies are discussed, including contrast-enhanced ultrasound, elastography and HistoScanning. These new modalities may hold promise for identifying incompletely ablated prostate tissue following radiation therapy or other ablative techniques. PMID- 23636744 TI - A comparison and verification of computational methods to determine the permeability of vertebral trabecular bone. AB - Fluid flow in the intertrabecular spaces of vertebral bone has been implicated in a number of physiological phenomena. Despite the potential clinical significance of the flow of various fluids through the intertrabecular cavities, the intrinsic permeability of trabecular bone is not fully characterized or understood. Furthermore, very little is known about the interdependence of permeability and morphological parameters. The main purpose of this study is to characterize computational methods to determine intrinsic bone permeability from three dimensional computed tomography (CT) image stacks that were, depending on the underlying algorithm of each model, acquired at a spatial resolution ranging from the order of 500 MUm (macroscale) up to 10 MUm (microscale). A Finite Element formulation of the steady-state Stokes flow and an in house developed pore network modeling approach compute permeability on the microscopic length scale. To approximate the geometry of the trabecular bone network, a cellular model is used to map morphological information into intrinsic permeability by means of a log-linear regression equation. If the image resolution is too low for the quantification of the trabecular bone architecture, permeability is directly derived by fitting a simplified version of the log-linear regression equation to the CT Hounsfield values. Depending on the resolution of the raw image data and the chosen model, permeability value correlations are 0.31 <= R(2) <= 0.90 compared to the Finite Element method, that is referred to as the baseline for any comparisons in this study. Furthermore, we found no significant dependence of the intrinsic permeability on the trabecular thickness parameter. PMID- 23636746 TI - Pairwise diversity ranking of polychotomous features for ensemble physiological signal classifiers. AB - It is well known that fusion classifiers for physiological signal classification with diverse components (classifiers or data sets) outperform those with less diverse components. Determining component diversity, therefore, is of the utmost importance in the design of fusion classifiers that are often employed in clinical diagnostic and numerous other pattern recognition problems. In this article, a new pairwise diversity-based ranking strategy is introduced to select a subset of ensemble components, which when combined will be more diverse than any other component subset of the same size. The strategy is unified in the sense that the components can be classifiers or data sets. Moreover, the classifiers and data sets can be polychotomous. Classifier-fusion and data-fusion systems are formulated based on the diversity-based selection strategy, and the application of the two fusion strategies are demonstrated through the classification of multichannel event-related potentials. It is observed that for both classifier and data fusion, the classification accuracy tends to increase/decrease when the diversity of the component ensemble increases/decreases. For the four sets of 14 channel event-related potentials considered, it is shown that data fusion outperforms classifier fusion. Furthermore, it is demonstrated that the combination of data components that yield the best performance, in a relative sense, can be determined through the diversity-based selection strategy. PMID- 23636747 TI - Computed tomography carotid wall plaque characterization using a combination of discrete wavelet transform and texture features: A pilot study. AB - In 30% of stroke victims, the cause of stroke has been found to be the stenosis caused by plaques in the carotid artery. Early detection of plaque and subsequent classification of the same into symptomatic and asymptomatic can help the clinicians to choose only those patients who are at a higher risk of stroke for risky surgeries and stenosis treatments. Therefore, in this work, we have proposed a non-invasive computer-aided diagnostic technique to classify the detected plaque into the two classes. Computed tomography (CT) images of the carotid artery images were used to extract Local Binary Pattern (LBP) features and wavelet energy features. Significant features were then used to train and test several supervised learning algorithm based classifiers. The Support Vector Machine (SVM) classifier with various kernel configurations was evaluated using LBP and wavelet features. The SVM classifier presented the highest accuracy of 88%, sensitivity of 90.2%, and specificity of 86.5% for radial basis function (RBF) kernel function. The CT images of the carotid artery provide unique 3D images of the artery and plaque that could be used for calculating percentage of stenosis. Our proposed technique enables automatic classification of plaque into asymptomatic and symptomatic with high accuracy, and hence, it can be used for deciding the course of treatment. We have also proposed a single-valued integrated index (Atheromatic Index) using the significant features which can provide a more objective and faster prediction of the class. PMID- 23636745 TI - A comparison of estimation methods for computational fluid dynamics outflow boundary conditions using patient-specific carotid artery. AB - Computational fluid dynamics simulations can provide important hemodynamic insights for investigating the effectiveness of carotid artery stenting, but its accuracy is dependent on the boundary conditions such as the outflow pressure, which is difficult to obtain by measurements. Many computational fluid dynamics simulations assume that the outflow pressure is constant (P = 0), but this method is likely to produce different results compared to clinical measurements. We have developed an alternative estimation method called the minimum energy loss method based on the concept of energy loss minimization at flow bifurcation. This new method has been tested on computational fluid dynamics simulation of two patients treated with carotid artery stenting, and its flow ratio at internal carotid artery and wall shear stress distribution was compared with the constant zero outlet pressure method. Three different procedure stages (prestent, poststent, and follow-up) were analyzed. The internal carotid artery flow ratio using the minimum energy loss method generally matched well with ultrasound measurements, but the internal carotid artery flow ratio based on zero outlet pressure method showed a large difference. Wall shear stress distributions varied between methods in response to the change in internal carotid artery flow rate. This study demonstrates the importance of accurate outlet boundary condition for assessing the long-term efficacy of carotid artery stenting and the risk of restenosis in treated patients. PMID- 23636749 TI - Decision support system for breast cancer detection using mammograms. AB - Mammograms are by far one of the most preferred methods of screening for breast cancer. Early detection of breast cancer can improve survival rates to a greater extent. Although the analysis and diagnosis of breast cancer are done by experienced radiologists, there is always the possibility of human error. Interobserver and intraobserver errors occur frequently in the analysis of medical images, given the high variability between every patient. Also, the sensitivity of mammographic screening varies with image quality and expertise of the radiologist. So, there is no golden standard for the screening process. To offset this variability and to standardize the diagnostic procedures, efforts are being made to develop automated techniques for diagnosis and grading of breast cancer images. This article presents a classification pipeline to improve the accuracy of differentiation between normal, benign, and malignant mammograms. Several features based on higher-order spectra, local binary pattern, Laws' texture energy, and discrete wavelet transform were extracted from mammograms. Feature selection techniques based on sequential forward, backward, plus-l takeaway-r, individual, and branch-and-bound selections using the Mahalanobis distance criterion were used to rank the features and find classification accuracies for combination of several features based on the ranking. Six classifiers were used, namely, decision tree classifier, fisher classifier, linear discriminant classifier, nearest mean classifier, Parzen classifier, and support vector machine classifier. We evaluated our proposed methodology with 300 mammograms obtained from the Digital Database for Screening Mammography and 300 mammograms from the Singapore Anti-Tuberculosis Association CommHealth database. Sensitivity, specificity, and accuracy values were used to compare the performances of the classifiers. Our results show that the decision tree classifier demonstrated an excellent performance compared to other classifiers with classification accuracy, sensitivity, and specificity of 91% for the Digital Database for Screening Mammography database and 96.8% for the Singapore Anti Tuberculosis Association CommHealth database. PMID- 23636748 TI - A meta-model analysis of a finite element simulation for defining poroelastic properties of intervertebral discs. AB - Finite element analysis is an effective tool to evaluate the material properties of living tissue. For an interactive optimization procedure, the finite element analysis usually needs many simulations to reach a reasonable solution. The meta model analysis of finite element simulation can be used to reduce the computation of a structure with complex geometry or a material with composite constitutive equations. The intervertebral disc is a complex, heterogeneous, and hydrated porous structure. A poroelastic finite element model can be used to observe the fluid transferring, pressure deviation, and other properties within the disc. Defining reasonable poroelastic material properties of the anulus fibrosus and nucleus pulposus is critical for the quality of the simulation. We developed a material property updating protocol, which is basically a fitting algorithm consisted of finite element simulations and a quadratic response surface regression. This protocol was used to find the material properties, such as the hydraulic permeability, elastic modulus, and Poisson's ratio, of intact and degenerated porcine discs. The results showed that the in vitro disc experimental deformations were well fitted with limited finite element simulations and a quadratic response surface regression. The comparison of material properties of intact and degenerated discs showed that the hydraulic permeability significantly decreased but Poisson's ratio significantly increased for the degenerated discs. This study shows that the developed protocol is efficient and effective in defining material properties of a complex structure such as the intervertebral disc. PMID- 23636751 TI - The generation of loads in excess of the osteogenic threshold by physical movement. AB - This study investigates the use of physical movement to cause joint and bone loads that stimulate bone growth in order to reduce the adverse effects of osteoporosis. It has been established that stresses in bones in excess of the osteogenic threshold will stimulate bone growth; however, protocols for the generation of these stresses had not been established. Two trial movements were examined in the study: the plie and a movement requiring the subject to move a leg sequentially to 45 degrees displaced positions - the star excursion balance test. Using inverse dynamics and an optimisation approach, the loads in the muscles crossing the hip and knee joints and the corresponding joint contact forces were calculated. It was found that the osteogenic threshold was exceeded in both these trials identifying them as suitable exercises in the maintenance of bone health. In the order of increasing bone load at the hip, and hence increasing bone growth stimulation, are the following demi plie, star excursion balance test with maximum reach criterion, grande plie and star excursion balance test with maximum speed criterion. In the order of increasing bone load at the knee are demi plie, grande plie, star excursion balance test with maximum reach criterion and star excursion balance test with maximum speed criterion. However, due to the high loads encountered, these exercises are not recommended for subjects with advanced osteoporosis although the boundary between therapeutic bone loading leading to increase in bone mineral density and loads capable of causing fracture is unclear. PMID- 23636750 TI - Investigation of the biomechanical behaviour of hindfoot ligaments. AB - The aim of this work is to provide a computational tool for the mechanical characterization of the hindfoot ligaments. The investigation is performed by a coupled numerical and experimental approach. For this purpose, a numerical model that represents the complex structural configuration of the hindfoot and the typical features of the mechanical behaviour of the ligament tissue is developed. The geometrical analysis of the anatomical site is performed starting from the processing of computed tomography and magnetic resonance images. Accounting for morphometric measurements, the virtual solid model provides an averaged configuration of the hindfoot structure. In order to specify the mechanical behaviour of the ligament tissue, a fibre-reinforced visco-hyperelastic model is adopted. The formulation accounts for the anisotropic configuration, geometric non-linearity, non-linear elasticity and time-dependent phenomena. Numerical analyses are performed to evaluate the biological tissues and structure mechanics with regard to physiological boundary conditions, accounting for dorsiflexion and plantarflexion movements. In order to evaluate the reliability of the numerical model developed, the experimental data are compared with the numerical results. The numerical results are in agreement with the range of values obtained by experimental test confirming the accuracy of the procedure adopted. PMID- 23636752 TI - In vitro tests of substitute lubricants for wear testing orthopaedic biomaterials. AB - Bovine serum is the lubricant recommended by several international standards for the wear testing of orthopaedic biomaterials; however, there are issues over its use due to batch variation, degradation, cost and safety. For these reasons, alternative lubricants were investigated. A 50-station Super-CTPOD (circularly translating pin-on-disc) wear test rig was used, which applied multidirectional motion to ultra-high-molecular-weight polyethylene test pins rubbing against cobalt chromium discs. Thirteen possible alternative lubricants were tested. The use of soy protein as a lubricant gave statistically higher wear, while soya oil, olive oil, Channel Island milk, whole milk, whey, wheatgerm oil, 11 mg/mL egg white, albumin/globulin mix and albumin/globulin/chondroitin sulphate mix all gave statistically lower wear than bovine serum. The lubricants giving the closest wear results to bovine serum were 20 and 40 mg/mL egg white solutions. A light absorbance assay found that these egg white solutions suffered from a high degradation rate that increased with increasing protein content. While egg white solutions offer the best alternative lubricant to bovine serum due to the wear volumes produced, cost-effectiveness and safety of handling, protein degradation will still occur, leading to the need for regular lubricant replacement. Of the lubricants tested in this study, none were found to be superior to bovine serum. PMID- 23636754 TI - Total hip arthroplasty by using a cementless ultrashort stem: a subject-specific finite element analysis for a young patient clinical case. AB - In this article, a subject-specific finite element analysis has been developed to study a clinical case of a surgically misaligned hip prosthesis with an ultrashort stem. It was set out to study the strain energy density pattern, comparing the results obtained with computed tomography images. The authors developed two other numerical models: the first one analyzes the stress and strain distributions in the healthy femur (without prosthesis) and the second one analyzes the same boneimplant biomechanical system of the clinical case but assuming the prosthesis in the proper position. The misaligned prosthesis produced an overload at the proximal posterior plane of the femur, as confirmed by computed tomography images, which detect the formation of new bone. The numerical model of the correctly positioned prosthesis demonstrated that the bone is not overloaded and that the position of neutral axis does not significantly shift from the physiological condition. PMID- 23636753 TI - New wearable walking-type continuous passive motion device for postsurgery walking rehabilitation. AB - While total knee arthroplasty is useful for treating osteoarthritis of the knee, the success of this treatment depends on effective rehabilitation. The goal of this study was to develop an assistive device for post-total knee arthroplasty patients for walking rehabilitation and for shortening the hospitalization period. We developed a brace electronic assist system termed the knee assistive instrument for walking rehabilitation (KAI-R) to illustrate the need for training during postoperative rehabilitation. Sixteen osteoarthritis patients (1 male and 15 females; average age 68.9 years) who underwent total knee arthroplasty were analyzed before operation and 2-4 weeks after operation, and 25 healthy individuals (14 males and 11 females; average age 26.2 years) formed the control group. Based on the pre- and postoperative data on peak knee flexion angle, foot height, and walking velocity, we developed the KAI-R, which consists of an assistive mechanism for the knee joint, a hip joint support system, and a foot pressure sensor system and is driven by a CPU board that generates the walking pattern. We then tested the walking gait in seven healthy volunteers with and without KAI-R assistance. KAI-R increased the peak flexion angle of the knee and foot height in all seven volunteers; their range of motion of the knee joint was increased. However, KAI-R also decreased the walking velocity of subjects, which was explained by reaction delay and slightly compromised physical balance, which was caused by wearing the KAI-R. KAI-R is useful for gait improvement. In future studies, KAI-R will be investigated in a clinical trial for its ability for walking rehabilitation in post-total knee arthroplasty patients. PMID- 23636755 TI - A low-cost solution for the restoration of femoral head centre during total hip arthroplasty. AB - Restoration of joint centre during total hip arthroplasty is critical. While computer-aided navigation can improve accuracy during total hip arthroplasty, its expense makes it inaccessible to the majority of surgeons. This article evaluates the use, in the laboratory, of a calliper with a simple computer application to measure changes in femoral head centres during total hip arthroplasty. The computer application was designed using Microsoft Excel and used calliper measurements taken pre- and post-femoral head resection to predict the change in head centre in terms of offset and vertical height between the femoral head and newly inserted prosthesis. Its accuracy was assessed using a coordinate measuring machine to compare changes in preoperative and post-operative head centre when simulating stem insertion on 10 sawbone femurs. A femoral stem with a modular neck was used, which meant nine possible head centre configurations were available for each femur, giving 90 results. The results show that using this technique during a simulated total hip arthroplasty, it was possible to restore femoral head centre to within 6 mm for offset (mean 1.67 +/- 1.16 mm) and vertical height (mean 2.14 +/- 1.51 mm). It is intended that this low-cost technique be extended to inform the surgeon of a best-fit solution in terms of neck length and neck type for a specific prosthesis. PMID- 23636756 TI - Evaluation of a new approach for modelling the screw-bone interface in a locking plate fixation: a corroboration study. AB - Computational modelling of the screw-bone interface in fracture fixation constructs is challenging. While incorporating screw threads would be a more realistic representation of the physics, this approach can be computationally expensive. Several studies have instead suppressed the threads and modelled the screw shaft with fixed conditions assumed at the screw-bone interface. This study assessed the sensitivity of the computational results to modelling approaches at the screw-bone interface. A new approach for modelling this interface was proposed, and it was tested on two locking screw designs in a diaphyseal bridge plating configuration. Computational models of locked plating and far cortical locking constructs were generated and compared to in vitro models described in prior literature to corroborate the outcomes. The new approach led to closer agreement between the computational and the experimental stiffness data, while the fixed approach led to overestimation of the stiffness predictions. Using the new approach, the pattern of load distribution and the magnitude of the axial forces, experienced by each screw, were compared between the locked plating and far cortical locking constructs. The computational models suggested that under more severe loading conditions, far cortical locking screws might be under higher risk of screw pull-out than the locking screws. The proposed approach for modelling the screw-bone interface can be applied to any fixation involved application of screws. PMID- 23636757 TI - In vitro investigation of friction at the interface between bone and a surgical instrument. AB - This study investigated the friction between surgical instruments and bone to aid improvements to instrument design. The bases of orthopaedic surgical instruments are usually made of metal, especially stainless steel. Silicone elastomer was chosen as an alternate biocompatible material, which would be compliant on the bone surface when used as the base of an instrument. The coefficient of static friction was calculated at the bone/material interface in the presence of a synthetic solution that had a comparable viscosity to that of blood, to assess the friction provided by each base material. Three types of silicone elastomers with different hardnesses (Shore A hardness 23, 50 and 77) and three distinct stainless steel surfaces (obtained by spark erosion, sand blasting and surface grinding) were used to assess the friction provided by the materials on slippery bone. The bone specimens were taken from the flattest region of the femoral shaft of a bovine femur; the outer surfaces of the specimens were kept intact. In general, the stainless steel surfaces exhibited higher values of coefficient of static friction, compared to the silicone elastomer samples. The stainless steel surface finished by spark erosion (surface roughness Ra = 8.9 +/- 1.6 um) had the highest coefficient value of 0.74 +/- 0.04. The coefficient values for the silicone elastomer sample with the highest hardness (Dow Corning Silastic Q7 4780, Shore A hardness 77) was not significantly different to values provided by the stainless steel surface finished by sand blasting (surface roughness Ra = 2.2 +/- 0.1 um) or surface grinding (surface roughness Ra = 0.1 +/- 0.0 um). Based on the results of this study, it is concluded that silicone could be a potentially useful material for the design of bases of orthopaedic instruments that interface with bone. PMID- 23636759 TI - Numerical simulations of the occupant head response in an infantry vehicle under blunt impact and blast loading conditions. AB - This article presents the results of a finite element simulation on the occupant head response in an infantry vehicle under two separated loading conditions: (1) blunt impact and (2) blast loading conditions. A Hybrid-III dummy body integrated with a previously validated human head model was used as the surrogate. The biomechanical response of the head was studied in terms of head acceleration due to the impact by a projectile on the vehicle and intracranial pressure caused by blast wave. A series of parametric studies were conducted on the numerical model to analyze the effect of some key parameters, such as seat configuration, impact velocity, and boundary conditions. The simulation results indicate that a properly designed seat and internal surface of the infantry vehicle can play a vital role in reducing the risk of head injury in the current scenarios. Comparison of the kinematic responses under the blunt impact and blast loading conditions reveals that under the current loading conditions, the acceleration pulse in the blast scenario has much higher peak values and frequency than blunt impact case, which may reflect different head response characteristics. PMID- 23636758 TI - Towards a realistic in vitro experience of epidural Tuohy needle insertion. AB - The amount of pressure exerted on the syringe and the depth of needle insertion are the two key factors for successfully carrying out epidural procedure. The force feedback from the syringe plunger is helpful in judging the loss of pressure, and the depth of the needle insertion is crucial in identifying when the needle is precisely placed in the epidural space. This article presents the development of two novel wireless devices to measure these parameters to precisely guide the needle placement in the epidural space. These techniques can be directly used on patients or implemented in a simulator for improving the safety of procedure. A pilot trial has been conducted to collect depth and pressure data with the devices on a porcine cadaver. These measurements are then combined to accurately configure a haptic device for creating a realistic in vitro experience of epidural needle insertion. PMID- 23636760 TI - Knee abduction angular impulses during prolonged running with wedged insoles. AB - Wedged insoles may produce immediate effects on knee abduction angular impulses during running; however, it is currently not known whether these knee abduction angular impulse magnitudes are maintained throughout a run when fatigue sets in. If changes occur, this could affect the clinical utility of wedged insoles in treating conditions such as patellofemoral pain. Thus, the purpose of this study was to determine whether knee abduction angular impulses are altered during a prolonged run with wedged insoles. It was hypothesized that knee abduction angular impulses would be reduced following a prolonged run with wedged insoles. Nine healthy runners participated. Runners were randomly assigned to either a 6 mm medial wedge condition or a 6-mm lateral wedge condition and then ran continuously overground for 30 min. Knee abduction angular impulses were quantified at 0 and 30 min using a gait analysis procedure. After 2 days, participants returned to perform the same test but with the other wedge type. Two way repeated-measures analysis of variance was used to evaluate main effects of wedge condition and time and interactions between wedge condition and time (alpha = 0.05). Paired t-tests were used for post hoc analysis (alpha = 0.01). No interaction effects (p = 0.958) were found, and knee abduction angular impulses were not significantly different over time (p = 0.384). Lateral wedge conditions produced lesser knee abduction angular impulses than medial conditions at 0 min (difference of 2.79 N m s, p = 0.006) and at 30 min (difference of 2.76 N m s, p < 0.001). It is concluded that significant knee abduction angular impulse changes within wedge conditions do not occur during a 30-min run. Additionally, knee abduction angular impulse differences between wedge conditions are maintained during a 30-min run. PMID- 23636761 TI - Diagnosis of Hashimoto's thyroiditis in ultrasound using tissue characterization and pixel classification. AB - Hashimoto's thyroiditis is the most common type of inflammation of the thyroid gland, and accurate diagnosis of Hashimoto's thyroiditis would be helpful to better manage the disease process and predict thyroid failure. Most of the published computer-based techniques that use ultrasound thyroid images for Hashimoto's thyroiditis diagnosis are limited by lack of procedure standardization because individual investigators use various initial ultrasound settings. This article presents a computer-aided diagnostic technique that uses grayscale features and classifiers to provide a more objective and reproducible classification of normal and Hashimoto's thyroiditis-affected cases. In this paradigm, we extracted grayscale features based on entropy, Gabor wavelet, moments, image texture, and higher order spectra from the 100 normal and 100 Hashimoto's thyroiditis-affected ultrasound thyroid images. Significant features were selected using t-test. The resulting feature vectors were used to build the following three classifiers using tenfold stratified cross validation technique: support vector machine, k-nearest neighbor, and radial basis probabilistic neural network. Our results show that a combination of 12 features coupled with support vector machine classifier with the polynomial kernel of order 1 and linear kernel gives the highest accuracy of 80%, sensitivity of 76%, specificity of 84%, and positive predictive value of 83.3% for the detection of Hashimoto's thyroiditis. The proposed computer-aided diagnostic system uses novel features that have not yet been explored for Hashimoto's thyroiditis diagnosis. Even though the accuracy is only 80%, the presented preliminary results are encouraging to warrant analysis of more such powerful features on larger databases. PMID- 23636762 TI - Individual motion patterns during gait and sit-to-stand contribute to edge loading risk in metal-on-metal hip resurfacing. AB - The occurrence of pseudotumours (soft tissue masses relating to the hip joint) following metal-on-metal hip resurfacing arthroplasty has been associated with higher than normal bearing wear and high serum metal ion levels although both these findings do not necessarily coexist. The purpose of this study was to examine patient activity patterns and their influence on acetabular component edge loading in a group of subjects with known serum metal ion levels. Fifteen subjects with metal-on-metal hip resurfacing arthroplasty (eight males and seven females) were recruited for motion analysis followed by computed tomography scans. They were divided into three groups based on their serum metal ion levels and the orientation of their acetabular component: well-positioned acetabular component with low metal ions, mal-positioned acetabular component with low metal ions and mal-positioned acetabular component with high ions. A combination of motion analysis, subject-specific modelling (AnyBody Modeling System, Aalborg, Denmark) and computed tomography measurements was used to calculate dynamically the contact patch-to-rim distance for each subject during gait and sit-to-stand. The contact-pitch-to-rim distance for the high ion group was significantly lower (p<0.001) than for the two low ion groups (well-positioned and mal-positioned) during the stance phase of gait (0%-60%) and loading phase of sit-to-stand (20% 80%). The results of this study, in particular, the significant difference between the two mal-positioned groups, suggest that wear of metal-on-metal hip resurfacing arthroplasty is not only affected by acetabular cup orientation but also influenced by individual patient activity patterns. PMID- 23636763 TI - Analysis of forces in conventional and ultrasonically assisted plane cutting of cortical bone. AB - Bone cutting is a well accepted but technically demanding surgical procedure in orthopaedics. A level of tool penetration force during cutting of bones has been the prime concern to surgeons, since it can produce unnecessary mechanical damage to surrounding tissues. Research in this area has been undertaken for many decades to find ways to minimise the cutting force. Cutting of bone with ultrasonic tools is a relatively new technique replacing conventional procedures in neuro-, dental and orthopaedic surgeries, due to its precision and safety. In this article, the level of forces produced during a chisel-like tool penetration in a fresh cortical bone is studied. The obtained force data are analysed for both conventional cutting and ultrasonically assisted cutting. Through a series of experiments, it was demonstrated that the depth of cut and parameters of ultrasonic oscillations affected the level of cutting force, the former being the main factor in both types of cutting. It was found that the tool penetration force was decreased with an increase in the ultrasonic frequency or amplitude and was not affected by the cutting speed. The rise in bone temperature was measured and was found to be insensitive to the level of cutting speed within the range used in this study. PMID- 23636764 TI - Evaluation of cast creep occurring during simulated clubfoot correction. AB - The Ponseti method is a widely accepted and highly successful conservative treatment of pediatric clubfoot involving weekly manipulations and cast applications. Qualitative assessments have indicated the potential success of the technique with cast materials other than standard plaster of Paris. However, guidelines for clubfoot correction based on the mechanical response of these materials have yet to be investigated. The current study sought to characterize and compare the ability of three standard cast materials to maintain the Ponseti corrected foot position by evaluating cast creep response. A dynamic cast testing device, built to model clubfoot correction, was wrapped in plaster of Paris, semi rigid fiberglass, and rigid fiberglass. Three-dimensional motion responses to two joint stiffnesses were recorded. Rotational creep displacement and linearity of the limb-cast composite were analyzed. Minimal change in position over time was found for all materials. Among cast materials, the rotational creep displacement was significantly different (p < 0.0001). The most creep displacement occurred in the plaster of Paris (2.0 degrees ), then the semi-rigid fiberglass (1.0 degrees ), and then the rigid fiberglass (0.4 degrees ). Torque magnitude did not affect creep displacement response. Analysis of normalized rotation showed quasi-linear viscoelastic behavior. This study provided a mechanical evaluation of cast material performance as used for clubfoot correction. Creep displacement dependence on cast material and insensitivity to torque were discovered. This information may provide a quantitative and mechanical basis for future innovations for clubfoot care. PMID- 23636765 TI - Bilateral asymmetry in microarchitecture of trabecular bone in male C57BL/6 mouse tibia: implication for experimental sample size estimations. AB - This study aimed to determine whether there is bilateral asymmetry between the left and right tibiae in the microarchitectural characteristics of the trabecular bone and estimate a moderate sample size for detections of such bilateral differences. The left and right tibiae of 20 C57BL/6 mice (12 weeks old) were scanned by micro-computed tomography, and the structural parameters of the trabecular bone were measured. There were significant differences in the structural parameters between the left and right tibiae (p<0.05); specifically, the microarchitecture was greater in quantity and quality in the left tibia than in the right tibia. Moreover, the percent of bilateral differences between the left and right tibiae ranged from 2.26% to 22.52%. For most of the structural parameters except for trabecular bone thickness (Tb.Th) and trabecular bone separation (Tb.Sp), the 20 mice involved in this study were enough to detect differences. These results show that the directional left-right asymmetry in the microarchitecture of the trabecular bone may exist despite the samples being from an inbred strain. Furthermore, we estimated a sample size for detections of such differences between the left and right tibiae. PMID- 23636766 TI - A biomechanical study of the Birmingham mid head resection arthroplasty: effect of stem size on femoral neck fracture. AB - The Birmingham mid head resection (BMHR) arthroplasty can be used as an alternative to conventional stemmed total hip arthroplasty in young patients unsuitable for hip resurfacing. This study investigated the effect of stem size on femoral neck fracture in the BMHR. Sawbones composite femurs were randomly allocated to one of the following groups: (1) unprepared femur with no prosthesis, (2) femur prepared with a Birmingham hip resurfacing (BHR) prosthesis, (3) femur prepared with a BMHR stem size 1 (BMHR-1) and (4) femur prepared with a BMHR stem size 3 (BMHR-3). Each femur was subjected to a compressive force using a materials testing machine until fracture of the femoral neck occurred. The highest force at fracture was in the unprepared femurs with a mean (+/-standard deviation) force at failure of 5.9 +/- 0.2 kN. The mean force at failure for the femurs fitted with a prosthesis was 2.6 +/- 0.4, 3.0 +/- 0.4 and 3.5 +/- 0.5 kN for the BHR, BMHR-1 and BMHR-3, respectively. Statistical analysis showed that the failure force for the unprepared femur was significantly (p<0.05) greater than that of the BHR, BMHR-1 and BMHR-3. There was a significant difference (p<0.05) between the force at failure for the BMHR-1 and BMHR-3, indicating that these two stem sizes have an effect on fracture force. PMID- 23636767 TI - The use of muscle dynamometer for correction of muscle imbalances in the area of deep stabilising spine system. AB - Dorsal pain caused by spine dysfunctions belongs to most frequent chronic illnesses. The muscles of the deep stabilising spine system work as a single functional unit where a dysfunction of only one muscle causes dysfunction of the whole system. Non-invasive, objective and statistically measurable evaluation of the condition of deep stabilising spine system has been made possible by the construction of muscular dynamometer. The aim of our work has been the assessment of deep stabilising spine system by diaphragm test and muscular dynamometer measurements. Based on an initial examination, a 6-week intervention programme was established including instructions on physiological body posture and correct basic body stabilisation for the given exercises and muscle strengthening. Consecutive measurements are then compared with the initial ones. It was presumed that a smaller number of the tested subjects would be able to correctly activate the deep stabilising spine system muscles before the intervention programme when compared to those after the intervention programme. A positive change of 87% has been found. It is clear that if a person actively approaches the programme, then positive adaptation changes on the deep stabilising spine system are seen only after 6 weeks. With the muscular dynamometer, activation of deep stabilising spine system can be objectively measured. Changes between the initial condition of a subject and the difference after some exercise or rehabilitation are especially noticeable. Also, the effect of given therapy or correct performance of the exercise can be followed and observed. PMID- 23636768 TI - Experimental and computer simulation validation of ultrasound phase interference created by lateral inhomogeneity of transit time in replica bone: marrow composite models. AB - The measurement of broadband ultrasound attenuation in cancellous bone for the assessment of osteoporosis follows a parabolic-type dependence with bone volume fraction, having minima values corresponding to both entire bone and entire marrow. Langton has recently proposed that the primary attenuation mechanism is phase interference due to variations in propagation transit time through the test sample as detected over the phase-sensitive surface of the receive ultrasound transducer. This fundamentally simple concept assumes that the propagation may be considered as an array of parallel 'sonic rays'. The transit time of each ray is defined by the proportion of bone and marrow propagated, being a minimum (t(min)) solely through bone and a maximum (t(max)) solely through marrow, from which a transit time spectrum, may be defined describing the proportion of sonic rays having a particular transit time. The aim of this study was to test the hypothesis that there is a dependence of phase interference upon the lateral inhomogeneity of transit time by comparing experimental measurements and computer simulation predictions of ultrasound propagation through a range of relatively simplistic solid:liquid models. From qualitative and quantitative comparison of the experimental and computer simulation results, there is an extremely high degree of agreement of 94.2%-99.0% between the two approaches. This combined experimental and computer simulation study has successfully demonstrated that lateral inhomogeneity of transit time has significant potential for phase interference to occur if a phase-sensitive receive ultrasound transducer is implemented as in most commercial ultrasound bone analysis devices. PMID- 23636769 TI - Manufacturing lot affects polyethylene tibial insert volume, thickness, and surface geometry. AB - To perform wear measurements on retrieved joint replacement implants, a reference geometry of the implant's original state is required. Since implants are rarely individually scanned before implantation, a different, new implant of the same kind and size is frequently used. However, due to manufacturing variability, errors may be introduced into these measurements, as the dimensions between the retrieved and reference components may not be exactly the same. The hypothesis of this study was that new polyethylene tibial inserts from different manufacturing lots would demonstrate greater variability than those from the same lot. In total, 12 new tibial inserts of the same model and size were obtained, 5 from the same lot and the remainder from different lots. The geometry of each tibial insert was obtained using microcomputed tomography. Measurements of tibial insert volume, thickness, and three-dimensional surface deviations were obtained and compared between tibial inserts from the same and different manufacturing lots. Greater variability was found for the tibial inserts from different manufacturing lots for all types of measurements, including a fourfold difference in volume variability (p < 0.001) and a maximum of 0.21 mm difference in thickness (p < 0.001). Investigators should be aware of this potential confounding error and take steps to minimize it, such as by averaging together the geometries of multiple new components from different manufacturing lots for use as the reference geometry. PMID- 23636771 TI - Transgenic rescue of defective Cd36 enhances myocardial adenylyl cyclase signaling in spontaneously hypertensive rats. AB - Dysfunction or abnormalities in the regulation of fatty acid translocase Cd36, a multifunctional membrane protein participating in uptake of long-chain fatty acids, has been linked to the development of heart diseases both in animals and humans. We have previously shown that the Cd36 transgenic spontaneously hypertensive rat (SHR-Cd36), with a wild type Cd36, has higher susceptibility to ischemic ventricular arrhythmias when compared to spontaneously hypertensive rat (SHR) carrying a mutant Cd36 gene, which may have been related to increased beta adrenergic responsiveness of these animals (Neckar et al., 2012 Physiol. Genomics 44:173-182). The present study aimed to determine whether the insertion of the wild type Cd36 into SHR would affect the function of myocardial G protein regulated adenylyl cyclase (AC) signaling. beta-Adrenergic receptors (beta-ARs) were characterized by radioligand-binding experiments and the expression of selected G protein subunits, AC, and protein kinase A (PKA) was determined by RT PCR and Western blot analyses. There was no significant difference in the amount of trimeric G proteins, but the number of beta-ARs was higher (by about 35 %) in myocardial preparations from SHR-Cd36 as compared to SHR. Besides that, transgenic rats expressed increased amount (by about 20 %) of the dominant myocardial isoforms AC5/6 and contained higher levels of both nonphosphorylated (by 11 %) and phosphorylated (by 45 %) PKA. Differently stimulated AC activity in SHR-Cd36 significantly exceeded (by about 18-30 %) the enzyme activity in SHR. Changes at the molecular level were reflected by higher contractile responses to stimulation by the adrenergic agonist dobutamine. In summary, it can be concluded that the increased susceptibility to ischemic arrhythmias of SHR-Cd36 is attributable to upregulation of some components of the beta-AR signaling pathway, which leads to enhanced sensitization of AC and increased cardiac adrenergic responsiveness. PMID- 23636770 TI - Tissue-specific expression and in vivo regulation of zebrafish orthologues of mammalian genes related to symptomatic hypomagnesemia. AB - Introduction of zebrafish as a model for human diseases with symptomatic hypomagnesemia urges to identify the regulatory transport genes involved in zebrafish Mg(2+) physiology. In humans, mutations related to hypomagnesemia are located in the genes TRPM6 and CNNM2, encoding for a Mg(2+) channel and transporter, respectively; EGF (epidermal growth factor); SLC12A3, which encodes for the Na(+)-Cl(-) co-transporter NCC; KCNA1 and KCNJ10, encoding for the K(+) channels Kv1.1 and Kir4.1, respectively; and FXYD2, which encodes for the gamma subunit of the Na(+),K(+)-ATPase. Orthologues of these genes were found in the zebrafish genome. For cnnm2, kcna1 and kcnj10, two conserved paralogues were retrieved. Except for fxyd2, kcna1b and kcnj10 duplicates, transcripts of orthologues were detected in ionoregulatory organs such as the gills, kidney and gut. Gene expression analyses in zebrafish acclimated to a Mg(2+)-deficient (0 mM Mg(2+)) or a Mg(2+)-enriched (2 mM Mg(2+)) water showed that branchial trpm6, gut cnnm2b and renal slc12a3 responded to ambient Mg(2+). When changing the Mg(2+) composition of the diet (the main source for Mg(2+) in fish) to a Mg(2+) deficient (0.01 % (w/w) Mg) or a Mg(2+)-enriched diet (0.7 % (w/w) Mg), mRNA expression of branchial trpm6, gut trpm6 and cnnm2 duplicates, and renal trpm6, egf, cnnm2a and slc12a3 was the highest in fish fed the Mg(2+)-deficient diet. The gene regulation patterns were in line with compensatory mechanisms to cope with Mg(2+)-deficiency or surplus. Our findings suggest that trpm6, egf, cnnm2 paralogues and slc12a3 are involved in the in vivo regulation of Mg(2+) transport in ionoregulatory organs of the zebrafish model. PMID- 23636772 TI - Smooth muscle cell mineralocorticoid receptors: role in vascular function and contribution to cardiovascular disease. AB - The mineralocorticoid receptor (MR), a member of the steroid receptor family, regulates blood pressure by mediating the effects of the hormone aldosterone on renal sodium handling. In recent years, it has become clear that MR is expressed in vascular smooth muscle cells (SMCs), and interest has grown in understanding the direct role of SMC MR in regulating vascular function. This interest stems from multiple clinical studies where MR inhibitor treatment reduced the incidence of cardiovascular events and mortality. This review summarizes the most recent advances in our understanding of SMC MR in regulating normal vascular function and in promoting vascular disease. Many new studies suggest a role for SMC MR activation in stimulating vascular contraction and contributing to vessel inflammation, fibrosis, and remodeling. These detrimental vascular effects of MR activation appear to be independent of changes in blood pressure and are synergistic with the presence of endothelial dysfunction or damage. Thus, in humans with underlying cardiovascular disease or cardiovascular risk factors, SMC MR activation may promote hypertension, atherosclerosis, and vascular aging. Further exploration of the molecular mechanisms for the effects of SMC MR activation has the potential to identify novel therapeutic targets to prevent or treat common cardiovascular disorders. PMID- 23636775 TI - PI3K-dependent actions of insulin and IGF-I on seminiferous tubules from immature rats. AB - There is clear evidence that insulin and insulin-like growth factor I (IGF-I) are crucial for the normal metabolism and development of Sertoli cells. However, the mechanisms of insulin regulatory signaling remain unknown in these cells, especially during the immature period. The aim of this study was to investigate the electrophysiological effects of insulin and the effects of insulin and IGF-I on calcium uptake, amino acid, and glucose transport in whole seminiferous tubules from 12-day-old rats, as well as the involvement of PI3K/Akt signaling pathway in these effects. Insulin produces a depolarizing effect on the membrane potential of Sertoli cells in seminiferous tubules within 180 s. This effect was nullified by verapamil, an L-type voltage-dependent calcium channel blocker, therefore demonstrating a calcium-dependent depolarizing effect. Both insulin and IGF-I stimulate calcium uptake, amino acid, and glucose transport in whole testes from 12-day-old rats. These stimulatory effects of insulin and IGF-I on calcium uptake and amino acid and glucose transport on testicular tissue were nullified by wortmannin, which demonstrates the involvement of the PI3K/Akt signaling pathway in these hormonal effects. PMID- 23636774 TI - Changing world of neutrophils. AB - Neutrophilic granulocytes are no longer regarded as cells involved only in the last phase of the immune response with one single-although vitally important task: engulfing and killing of microorganisms marked by immunoglobulin or complement fragments. In recent years, it was shown that neutrophils are actively involved in initiation and organization of the adaptive immune response by releasing various cytokines, interacting with all major types of immune cells, regulating their own lifespan, and participating in the anaphylactic reaction and in several classically nonimmune functions such as hemostasis, atherogenesis, and even insulin resistance. The antibacterial effect is no longer restricted to killing and destruction of microorganisms sequestered in the phagosomal space. Bacteriostasis also occurs at certain locations of the extracellular space, by formation of neutrophil extracellular traps (NETs) that were shown in the last 2 years to have a significant role in the prevention of dissemination of microorganisms. Extracellular vesicles represent a recently discovered form of intercellular communication carried out both by lipids, proteins, and nucleic acids. In this review, we also summarize the role of neutrophil-derived extracellular vesicles in modifying the function of other cell types as well as their direct antibacterial effect that differs significantly from mechanisms applied either by neutrophils or by the NETs. PMID- 23636773 TI - New insights into the mechanisms of itch: are pain and itch controlled by distinct mechanisms? AB - Itch and pain are closely related but distinct sensations. They share largely overlapping mediators and receptors, and itch-responding neurons are also sensitive to pain stimuli. Itch-mediating primary sensory neurons are equipped with distinct receptors and ion channels for itch transduction, including Mas related G protein-coupled receptors (Mrgprs), protease-activated receptors, histamine receptors, bile acid receptor, toll-like receptors, and transient receptor potential subfamily V1/A1 (TRPV1/A1). Recent progress has indicated the existence of an itch-specific neuronal circuitry. The MrgprA3-expressing primary sensory neurons exclusively innervate the epidermis of skin, and their central axons connect with gastrin-releasing peptide receptor (GRPR)-expressing neurons in the superficial spinal cord. Notably, ablation of MrgprA3-expressing primary sensory neurons or GRPR-expressing spinal cord neurons results in selective reduction in itch but not pain. Chronic itch results from dysfunction of the immune and nervous system and can manifest as neural plasticity despite the fact that chronic itch is often treated by dermatologists. While differences between acute pain and acute itch are striking, chronic itch and chronic pain share many similar mechanisms, including peripheral sensitization (increased responses of primary sensory neurons to itch and pain mediators), central sensitization (hyperactivity of spinal projection neurons and excitatory interneurons), loss of inhibitory control in the spinal cord, and neuro-immune and neuro-glial interactions. Notably, painful stimuli can elicit itch in some chronic conditions (e.g., atopic dermatitis), and some drugs for treating chronic pain are also effective in chronic itch. Thus, itch and pain have more similarities in pathological and chronic conditions. PMID- 23636776 TI - Fast evaluation of 69 basal cell carcinomas with ex vivo fluorescence confocal microscopy: criteria description, histopathological correlation, and interobserver agreement. AB - IMPORTANCE: Fluorescence confocal microscopy (FCM) represents a first step toward a rapid "bedside pathology" in the Mohs surgery setting and in other fields of general pathology. OBJECTIVE: To describe and validate FCM criteria for the main basal cell carcinoma (BCC) subtypes and to demonstrate the overall agreement with classic pathologic analysis of hematoxylin-eosin-stained samples. DESIGN A total of 69 BCCs from 66 patients were prospectively imaged using ex vivo FCM. Confocal mosaics were evaluated in real time and compared with classic pathologic analysis. SETTING: Department of Dermatology, Hospital Clinic of Barcelona, Barcelona, Spain, between November 2010 and July 2011. PARTICIPANTS: Patients with BCC attending the Mohs Surgery Unit. MAIN OUTCOMES AND MEASURES: Presence or absence of BCC and histological subtype (superficial, nodular, and infiltrating) in the confocal mosaics. Eight criteria for BCC were described, evaluated, and validated. RESULTS: Although there were minor differences among BCC subtypes, the most BCC-defining criteria were peripheral palisading, clefting, nuclear pleomorphism, and presence of stroma. These criteria were validated with independent observers (kappa values >0.7 [corrected] for most criteria). CONCLUSIONS AND RELEVANCE: We herein propose, describe, and validate FCM criteria for BCC diagnosis. Fluorescence confocal microscopy is an attractive alternative to histopathologic analysis of frozen sections during Mohs surgery because large areas of freshly excised tissue can be assessed in real time without the need for tissue processing while minimizing labor and costs. PMID- 23636777 TI - Description of Pseudomonas jessenii subsp. pseudoputida subsp. nov., amended description of Pseudomonas jessenii and description of Pseudomonas jessenii subsp. jessenii subsp. nov. AB - Fluorescent Pseudomonas putida CCM 3656 (ATCC 11250) was analysed according to the methods of polyphasic approach which were based on sequence analyses involving the rpoB and rrs genes, manual ribotyping using endonuclease HindIII, DNA base composition determination and DNA-DNA hybridization. The results obtained by these genotyping methods showed that the strain CCM 3656 is distant from P. putida taxon, which was supported with phenotype characterization represented by whole-cell protein profile analysis, matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry profiling and extended biotyping. The DNA-DNA hybridization experiments performed between the strain CCM 3656 and the closest relatives revealed 77 % similarity with Pseudomonas jessenii. However, the outcomes of sequencing, ribotyping and phenotype characterization allow distinguishing the studied strain from P. jessenii. On the basis of the obtained taxonomic data, we suggest reclassifying strain CCM 3656 to a novel subspecies of P. jessenii and propose naming P. jessenii subsp. pseudoputida subsp. nov. with CCM 3656(T) as type strain. Furthermore, we present an amended description of P. jessenii and proposal of P. jessenii subsp. jessenii subsp. nov. PMID- 23636778 TI - Commercial multiplex technologies for the microbiological diagnosis of sepsis. AB - In patients with suspected sepsis, rapid and accurate diagnosis of the causative infectious agent is critical. Although clinicians often use empiric antimicrobial therapy until the blood cultures are available to potentially adjust treatment, this approach is often not optimum for patient care. Recently, several commercial molecular multiplex technologies have shown promise for fast and comprehensive diagnosis of microorganisms and their antimicrobial resistance signatures. While one class of multiplex technologies is directed at improving the speed and diagnostic information obtained from positive blood cultures, the other identifies the causative microorganisms directly from clinical blood samples. This review provides an overview of these molecular technologies and describes their performance capabilities compared to standard blood cultures and in some cases to each other. We discuss the current clinical impact, limitations, and likely futures advances these multiplex technologies may have in guiding the management of patients with sepsis. PMID- 23636782 TI - [Ettore Majorana's legacy: An historical analysis]. AB - Since his mysterious disappearance in 1938, there have been many biographical accounts of Ettore Majorana's short life. Yet, his scientific work and his influence on the development of physics are often left in the background. The thrust of this article is precisely to shed light on them. In fact, some of Majorana's articles were only understood after World War II. Notably, this was the case of his last article. Written in 1937, it represents the best long lasting contribution of Ettore Majorana to particle physics. He envisages, thanks to a new formalism, that neutrinos could be identical to their own antiparticles. The answer to this question posed by Majorana more than half a century ago may be found thanks to several experiments now carried out. It could give a lightning on the nature of dark matter and an explanation to the dominance of matter over antimatter in our universe. PMID- 23636781 TI - [Not Available]. PMID- 23636780 TI - Tumours and tissues: similar homeostatic systems? AB - The currently prevalent somatic mutation theory of carcinogenesis and metastases explicitly assumes that cancer is a cellular disease, i.e. a disease of the control of cell proliferation and/or cell differentiation. Accordingly, explanations should always be sought for at a gene and/or gene product level, regardless of the level of organization at which the phenomenon is observed. Such a reductionist approach characterized the century-old effort to find cancer cell singularities, absent in normal cells, without apparent success, however. More recently alternative views have been put forward, assuming that cancer is a tissue-based disease involving disturbed interactions within the tissue architecture. In this review, selected reports on normal tissue homeostasis and bone marrow contribution to both tumour cells and tumour stroma are reviewed. Regarding normal tissues, the existence of a complex homeostatic system actually involving the whole organism emerges. Regarding tumours, remarkable similarities with normal tissue activities are apparent, providing some evidence that tumours share many biological features and processes with normal tissues. The review supports the concept that cancer is a tissue-based disease and that its pathological nature may result from unbalanced/untimely activation of otherwise normal physiological processes. PMID- 23636779 TI - Nanosilver suppresses growth and induces oxidative damage to DNA in Caenorhabditis elegans. AB - Studies on the effects of nanomaterial exposure in mammals are limited, and new methods for rapid risk assessment of nanomaterials are urgently required. The utility of Caenorhabditis elegans cultured in axenic liquid media was evaluated as an alternative in vivo model for the purpose of screening nanomaterials for toxic effects. Spherical silver nanoparticles of 10 nm diameter (10nmAg) were used as a test material, and ionic silver from silver acetate as a positive control. Silver uptake and localization, larval growth, morphology and DNA damage were utilized as endpoints for toxicity evaluation. Confocal reflection analysis indicated that 10nmAg localized to the lumen and tissues of the digestive tract of C. elegans. 10nmAg at 10 ug ml(-1) reduced the growth of C. elegans larvae, and induced oxidative damage to DNA as measured by 8-OH guanine levels. Consistent with previously published studies using mammalian models, ionic silver suppressed growth in C. elegans larvae to a greater extent than 10nmAg. Our data suggest that medium-throughput growth screening and DNA damage analysis along with morphology assessments in C. elegans could together provide powerful tools for rapid toxicity screening of nanomaterials. PMID- 23636784 TI - [Ettore Majorana and philosophy : Between elective affinities and philosophical reflections]. AB - This article seeks to "take on" Ettore Majorana by establishing his "philosophical profile." Doing so, one not only finds that the question of "fiction" was central to his work, but one also discovers the important superationalist - and European - dimension of his elective affinities with Giovanni Gentile Junior. Indeed their work was part of a constructive and inductive mathematism (Gaston Bachelard, later Robert Blanche) that was in opposition to classical geometricism (Emile Meyerson), and spiritualist Pythagoreanism (Arthur Eddington). PMID- 23636783 TI - [Ettore Majoran's transversal epistemology]. AB - " Il valore delle leggi statistiche nella fisica e nelle scienze sociali " is Ettore Majorana's only work on science. It offers a critique of classical determinism, establishing an analogy between the laws of quantum mechanics and social science and arguing that both are intrinsically linked to probability. This article first studies this argument from the standpoing of metaphysics, physics, and sociology, and then assesses the significance of this transversal epistemology. PMID- 23636785 TI - [A bibliometrical analysis of Majorana's scientific legacy]. AB - This article analyzes the reception of Ettore Majorana's articles by tracing all the references made to them since the beginning of the 1930s. This methodology allows me to show that Ettore Majorana's 1937 piece on spin-1/2 particles was largely rediscovered during the 1960s, but also to identify the people who actively promoted Majorana's work, which has loomed larger in scientific debates since the 1970s. Analyzing co-citations, this article shows the conceptual network in which Majorana's work fits. PMID- 23636787 TI - [Not Available]. PMID- 23636786 TI - [Scientism. On the history of a difficult concept]. AB - Today "scientism" is a pejorative concept in every language. But isn't that just a projection made in order to exploit the fear of "science"? The article develops the argument that scientism is a historical current which can be analyzed in a concrete way. It shows that the word goes back to the 19(th) century and got its negative emphasis when "scientific" spiritism on the one hand and Catholicism on the other were struggling against the "exaggerated" claims of natural science. PMID- 23636788 TI - Direct effect of dsRNA mimetics on cancer cells induces endogenous IFN-beta production capable of improving dendritic cell function. AB - Viral double-stranded RNA (dsRNA) mimetics have been explored in cancer immunotherapy to promote antitumoral immune response. Polyinosine-polycytidylic acid (poly I:C) and polyadenylic-polyuridylic acid (poly A:U) are synthetic analogs of viral dsRNA and strong inducers of type I interferon (IFN). We describe here a novel effect of dsRNA analogs on cancer cells: besides their potential to induce cancer cell apoptosis through an IFN-beta autocrine loop, dsRNA-elicited IFN-beta production improves dendritic cell (DC) functionality. Human A549 lung and DU145 prostate carcinoma cells significantly responded to poly I:C stimulation, producing IFN-beta at levels that were capable of activating STAT1 and enhancing CXCL10, CD40, and CD86 expression on human monocyte-derived DCs. IFN-beta produced by poly I:C-activated human cancer cells increased the capacity of monocyte-derived DCs to stimulate IFN-gamma production in an allogeneic stimulatory culture in vitro. When melanoma murine B16 cells were stimulated in vitro with poly A:U and then inoculated into TLR3(-/-) mice, smaller tumors were elicited. This tumor growth inhibition was abrogated in IFNAR1(-/-) mice. Thus, dsRNA compounds are effective adjuvants not only because they activate DCs and promote strong adaptive immunity, but also because they can directly act on cancer cells to induce endogenous IFN-beta production and contribute to the antitumoral response. PMID- 23636790 TI - [Spastic foot deformities in children: surgical management]. AB - Although the neurological defects associated with cerebral palsy are not progressive, secondary musculoskeletal disorders due to growth and gravity are variable. In the clinical analysis of spastic foot deformities different mechanisms that produce a variety of deformities have to be analyzed. The goals of surgical treatment are correction of the deformity, reestablishment of stability of the foot and preservation of functionally important ranges of motion and muscle strength. The most common spastic foot deformities are equinus, planovalgus, equinovarus and calcaneus. For treatment soft tissue surgery, such as muscle lengthening and transfer together with bone surgery, such as osteotomy or arthrodesis are used and combinations of these methods are often required. Subsequently postoperative plasters are necessary followed by dynamic orthotic management. PMID- 23636789 TI - Brain imaging biomarkers to predict relapse in alcohol addiction. PMID- 23636791 TI - Pre-conceptional exposure to rituximab: comment on the article by Ojeda-Uribe et al. PMID- 23636793 TI - The uveitis and its relationship with disease activity and quality of life in Moroccan children with juvenile idiopathic arthritis. AB - The aim of our study is to investigate ocular involvement in juvenile idiopathic arthritis (JIA) and its relationship with disease activity and quality of life in Moroccan patients who suffer from JIA. This is a cross-sectional study conducted between January and June 2012 which includes patients with juvenile idiopathic arthritis (n = 30). All patients have undergone clinical and paraclinical assessment of JIA and a complete eye examination. Functional impairment is assessed by the Childhood Health Assessment Questionnaire while visual function is studied by the Effect of Youngsters' Eyesight in Quality of Life instrument (EYE-Q). Quality of life is assessed using the Pediatric Quality of Life Inventory Version 4.0 (PedsQL 4.0). Four patients (13.33 %) have uveitis with a confidence interval between 3.4 and 30.7. Involvement is bilateral in three children (75 %). One patient (25 %) has elevated intraocular pressure with loss of the right eye due to glaucoma. There is a strong but not significant relationship between uveitis and the number of awakenings (r = 0.71, p = 0.69) and morning stiffness (r = 3.05, p = 0, 21). This relationship is moderate with erythrocyte sedimentation rate (r = 0.48, p = 0.78) and C-reactive protein (r = 0.25, p = 0.88). A strong but not significant association is found between the overall quality of life assessed by the PedsQL 4.0 and visual function assessed by EYE-Q in the uveitis group (r = -0.64, p = 0.55). This study suggests that uveitis associated with JIA can present serious complications and could have a direct relationship with the activity of the JIA as well as with the quality of life of the patient. PMID- 23636792 TI - Validation of clinical examination versus magnetic resonance imaging and arthroscopy for the detection of rotator cuff lesions. AB - Limited evidence exists regarding the validity of clinical examination for the detection of shoulder pathology. We therefore wished to establish the sensitivity, specificity, positive predictive value and negative predictive value of clinical tests and magnetic resonance imaging (MRI) in the diagnosis of rotator cuff disorders against findings at arthroscopy. Using recognised tests for specific shoulder lesions, 117 patients with shoulder symptoms awaiting surgery were examined in a standard manner. The diagnoses were categorised and compared with abnormalities found on MRI and at surgery. Results were cross tabulated to determine the above parameters. Ninety-four patients formed the study group with a mean age of 51 years. The median duration of symptoms was 45 weeks. For clinical examination, sensitivity and specificity to detect a tear or rupture of supraspinatus were 30 % (16/54) and 38 % (15/40) and, for the detection of any pathology, were 94 % (67/71) and 22 % (5/23), respectively, compared with arthroscopy. Correspondingly, the sensitivity of MRI compared with arthroscopy to detect a tear or rupture of supraspinatus was 90 % (28/31) with a specificity of 70 % (46/53), whereas for the detection of any abnormality, the sensitivity was 92 % (65/71) with a specificity of 48 % (11/23). The sensitivity of detecting any rotator cuff abnormality is high when examination and MRI is compared with arthroscopy with the specificity being greater with MRI than examination. In patients with shoulder symptoms severe enough to consider surgery, clinical assessment followed by specific imaging may help define the pathology in order to direct appropriate management. PMID- 23636794 TI - Effects of 15 consecutive cryotherapy sessions on the clinical output of fibromyalgic patients. AB - Fibromyalgia is a chronic widespread pain disorder in which, the neurogenic origin of the pain, featured by allodynia and hyperalgesia, results from an imbalance in the levels of neurotransmitters and consequently of the peripheral pro- and anti-inflammatory mediators. Whole body cryotherapy is a peculiar physical therapy known to relieve pain and inflammatory symptoms characteristics of rheumatic diseases, through the regulation of the cytokine expression. The aim of this study was to qualitatively evaluate the effects of cryotherapy on the clinical output of fibromyalgic patients. A total of 100 fibromyalgic patients (age range 17-70 years) were observed; 50 subjects were addressed to cryotherapy, while the second group (n = 50) did not underwent to the cryotherapic treatment. All subjects kept the prescribed pharmacological therapy during the study (analgesic and antioxidants). The referred health status pre- and post observation was evaluated with the following scales: Visual Analogue Scale, Short Form-36, Global Health Status and Fatigue Severity Scale. Fibromyalgic patients treated with cryotherapy reported a more pronounced improvement of the quality of life, in comparison with the non-cryo treated fibromyalgic subjects, as indicated by the scores of the qualitative indexes and sub-indexes, that are widely recognized tools to assess the overall health status and the effect of the treatments. We speculate that this improvement is due to the known direct effect of cryotherapy on the balance between pro- and anti-inflammatory mediators having a recognized role in the modulation of pain. PMID- 23636795 TI - Cheminformatics aspects of high throughput screening: from robots to models: symposium summary. AB - The "Cheminformatics aspects of high throughput screening (HTS): from robots to models" symposium was part of the computers in chemistry technical program at the American Chemical Society National Meeting in Denver, Colorado during the fall of 2011. This symposium brought together researchers from high throughput screening centers and molecular modelers from academia and industry to discuss the integration of currently available high throughput screening data and assays with computational analysis. The topics discussed at this symposium covered the data infrastructure at various academic, hospital, and National Institutes of Health funded high throughput screening centers, the cheminformatics and molecular modeling methods used in real world examples to guide screening and hit-finding, and how academic and non-profit organizations can benefit from current high throughput screening cheminformatics resources. Specifically, this article also covers the remarks and discussions in the open panel discussion of the symposium and summarizes the following talks on "Accurate Kinase virtual screening: biochemical, cellular and selectivity", "Selective, privileged and promiscuous chemical patterns in high-throughput screening" and "Visualizing and exploring relationships among HTS hits using network graphs". PMID- 23636796 TI - Association between FAS-1377 G/A polymorphism and susceptibility to gastric cancer: evidence from a meta-analysis. AB - Previous studies published to evaluate the association between FAS-1377 G/A polymorphism and susceptibility to gastric cancer provided inconclusive outcomes. To derive a more precise estimation on this association, a meta-analysis of published case-control studies was performed. Eligible studies up to November 13, 2012 were identified from PubMed, Wanfang Medicine database, and Web of Science. Nine studies with a total of 2,086 cases and 2,701 controls were finally included into this meta-analysis. Overall, there was an obvious association between FAS 1377 G/A polymorphism and susceptibility to gastric cancer (for AA versus GG: odds ratio (OR) = 1.38; 95 % confidence interval (CI) 1.00-1.91, P = 0.05; for AA versus GA/GG: OR = 1.28; 95 %CI 1.07-1.53, P = 0.006). After excluding studies with low quality, there was no between-study heterogeneity, and there was still an obvious association between FAS-1377 G/A polymorphism and susceptibility to gastric cancer (for AA versus GG: OR = 1.25; 95 %CI 1.02-1.52, P = 0.03; for AA versus GA/GG: OR = 1.27; 95 %CI 1.05-1.53, P = 0.01). Subgroup analyses by ethnicity showed that the association above was still obvious in Asians, but the association was still unclear in Caucasians owing to the limited sample. In summary, this meta-analysis suggests that the FAS-1377 G/A polymorphism is associated with susceptibility to gastric cancer, especially in Asians. More studies from Caucasians are needed to provide further evidence for the possible association in Caucasians. PMID- 23636797 TI - CYP2E1 T7632A and 9-bp insertion polymorphisms and colorectal cancer risk: a meta analysis based on 4,592 cases and 5,918 controls. AB - Previous studies suggest that genetic factors play important roles in the development of colorectal cancer. CYP2E1 T7632A and 9-bp insertion polymorphisms may influence the risk of colorectal cancer, but published results are conflicting. We therefore conducted a meta-analysis comprising 9 case-control studies with 4,592 cases and 5,918 controls. Odds ratios (ORs) with 95 % confidence interval (95 % CI) were used to assess the strength of the associations of CYP2E1 T7632A and 9-bp insertion polymorphisms with colorectal cancer. For CYP2E1 T7632A polymorphism, meta-analysis showed that there was no significant association between the CYP2E1 T7632A polymorphism and colorectal cancer risk under all contrast models (A vs. T: OR = 1.06, 95 % CI 0.88-1.29, P = 0.528; AA vs. TT: OR = 0.85, 95 % CI 0.61-1.19, P = 0.351; AA/TA vs. TT: OR = 1.08, 95 % CI 0.87-1.34, P = 0.484; and AA vs. TT/TA: OR = 0.87, 95 % CI 0.62 1.21, P = 0.395). For CYP2E1 96-bp insertion polymorphism, meta-analysis showed that there was a significant association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk under the allele contrast model and the dominant contrast model (for the allele contrast model: OR = 1.20, 95 % CI 1.06 1.36, P = 0.005; for the dominant contrast model: OR = 1.25, 95 % CI 1.07-1.45, P = 0.005). Subgroup analysis by race suggested that there was an obvious association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk in Asians under the codominant contrast model. In conclusion, our meta analysis demonstrates that there is a significant association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk, and CYP2E1 9-bp insertion polymorphism is a risk factor for developing colorectal cancer. PMID- 23636798 TI - The difference in clinic-pathological features between signet ring cell carcinoma and gastric mucinous adenocarcinoma. AB - We investigated the clinical and pathological features as well as the prognosis of signet ring cell carcinoma (SRC) and gastric mucinous carcinoma (GMC) to lay a foundation for the management of these two diseases. Two thousand four hundred thirty gastric cancer patients, including 288 SRCs and 80 GMCs who had received a gastrectomy between 1997 and 2007, were retrospectively evaluated. There were significant differences in tumor location, distant metastasis status, lymph node dissection, depth of invasion, Borrmann type, pTNM stage, and pathological lymph node status between SRCs and GMC (P = 0.001, 0.003, 0.01, 0.0002, 0.0013, 0.0001, and 0.265, respectively). After prognostic analysis, the cases with GMC received a relatively low 5-year specific survival rate compared to SRC (58.68 % vs. 66.25 %; P = 0.064). After Cox regression analysis, gender, age, lymph node metastatic ratio, pTNM stage, curative operation, and distant metastasis were identified as the independent prognostic factors in SRC. On the other hand, pTNM stage and distant metastasis were identified as the independent prognostic factors in GMC. In conclusion, the clinical and pathological features as well as prognosis of GMC and gastric SRC differed. Therefore, the treatment of the two diseases should be individualized. PMID- 23636799 TI - XRCC1 polymorphisms increase bladder cancer risk in Asians: a meta-analysis. AB - X-ray cross complementing group 1 (XRCC1) polymorphisms and bladder cancer risk has been investigated for years, but the result in Asian population is till inconclusive. Thus, we performed this meta-analysis to determine the association of XRCC1 Arg194Trp, Arg280His, and Arg399Gln polymorphisms with bladder cancer risk in the Asian population. PubMed, EMBASE, and China National Knowledge Infrastructure were searched up to January 2013 to identify eligible studies. The association strength was measured with odd ratios (ORs) and 95 % confidence intervals (95 % CIs). A total of nine eligible studies, including 1,931 bladder cancer patients and 2,192 controls, were identified. Significant increased risk of bladder cancer was observed for Arg194Trp polymorphism (allele comparison OR = 1.20, 95 % CI: 1.06-1.36, P heterogeneity = 0.11; dominant model OR = 1.20, 95 % CI: 1.02-1.41, P heterogeneity = 0.37) and Arg280His polymorphism (heterozygote comparison OR = 1.87, 95 % CI: 1.21-2.90, P heterogeneity = 0.01; dominant model OR = 1.75, 95 % CI: 1.05-2.90, P heterogeneity = 0.01); however, Arg399Gln was not associated with susceptibility to bladder cancer. No evidence of publication bias was detected. Our meta-analysis results suggest that XRCC1 Arg194Trp and Arg280His polymorphisms are associated with significantly increased risk of bladder cancer in Asians. PMID- 23636800 TI - Prognostication of OCT4 isoform expression in prostate cancer. AB - Cancer stem cells (CSCs) refer to a subset of tumor cells that self-renew and affect tumor heterogeneity. This model has attracted considerable interest in recent years due to its implications in the prognosis and clinical management of cancer because CSCs mediate the occurrence, growth, and recurrence of tumors. OCT4 is central to embryonic stem cell self-renewal and differentiation into specific lineages and encodes two chief isoforms that are generated by alternative splicing--OCT4A and OCT4B. Their function in prostate cancer (PCa) is unknown. The prognostic function of OCT4 isoforms in PCa samples was examined by immunohistochemistry (IHC) and sensitivity and specificity of the antibodies used were evaluated by molecular biology techniques. Biochemical and pathological data and specimens from 193 patients with PCa were evaluated retrospectively. IHC, western blot, immunofluorescence, and automated image analysis were also performed. IHC was performed on a tissue microarray, and western blot and immunofluorescence were performed using the PCa cell line DU-145. IHC expression of OCT4 isoforms correlated with biochemical and pathological parameters, particularly biochemical recurrence-free survival (BCRFS). Patients with higher levels of OCT4B had lower Gleason scores and decreased likelihood of experiencing biochemical recurrence (BR). OCT4A(+) OCT4B(-) patients had the shortest BCRFS, and positivity for OCT4B expression was an independent prognostic factor for BCRFS in the multivariate analysis. We conclude that the expression of OCT4B is a strong marker of good prognosis, and its presence is associated with a decreased likelihood of BR. Thus, OCT4B might represent a powerful clinical prognostic biomarker for PCa patients. PMID- 23636801 TI - The expression of glutamine-metabolism-related proteins in breast phyllodes tumors. AB - The aim of this study was to investigate the expression of glutamine-metabolism related proteins according to the histologic grade of phyllodes tumors (PTs) and to assess its clinical implication. We generated tissue microarrays of 224 PTs and performed immunohistochemical staining and western blot analysis of glutamine metabolism-related molecules, including GLS1, GDH, and ASCT2. The associations between immunohistochemical results and clinicopathologic parameters were evaluated. The expression of GLS1 (p < 0.001), GDH (p < 0.001), and ASCT2 (p = 0.005) in stromal components significantly increased with worsening PT histological grade. GDH expression in epithelial components significantly increased in high-grade PT (p = 0.026). In western blot, stromal expression of GLS1, GDH, and ASCT2 increased as histologic grade increased. By univariate analysis, stromal GLS1 expression (p = 0.022) and stromal GDH expression (p = 0.009) were independent predictors of shorter DFS. Stromal GLS1 expression (p < 0.001) and stromal GDH expression (p < 0.001) were independent predictors of shorter OS. This study demonstrated that the stromal expression of the glutamine metabolism-related proteins GLS1, GDH, ASCT2 increases with worsening histological PT grade. PMID- 23636802 TI - Standardized added metabolic activity (SAM) IN 18F-FDG PET assessment of treatment response in colorectal liver metastases. AB - PURPOSE: Standardized added metabolic activity (SAM) is a PET parameter for assessing the total metabolic load of malignant processes, avoiding partial volume effects and lesion segmentation. The potential role of this parameter in the assessment of response to chemotherapy and bevacizumab was tested in patients with metastatic colorectal cancer with potentially resectable liver metastases (mCRC). METHODS: (18)F-FDG PET/CT was performed in 18 mCRC patients with liver metastases before treatment and after five cycles of FOLFOX/FOLFIRI and bevacizumab. Of the 18 patients, 16 subsequently underwent resection of liver metastases. Baseline and follow-up SUVmax, and SAM as well as reduction in SUVmax (?SUVmax) and SAM (?SAM) of all liver metastases were correlated with morphological response, and progression-free and overall survival (PFS and OS). RESULTS: A significant reduction in metabolic activity of the liver metastases was seen after chemotherapy with a median ?SUVmax of 25.3% and ?SAM of 94.5% (p = 0.033 and 0.003). Median baseline SUVmax and SAM values were significantly different between morphological responders and nonresponders (3.8 vs. 7.2, p = 0.021; and 34 vs. 211, p = 0.002, respectively), but neither baseline PET parameters nor morphological response was correlated with PFS or OS. Follow-up SUVmax and SAM as well as ?SAM were found to be prognostic factors. The median PFS and OS in the patient group with a high follow-up SUVmax were 10.4 months and 32 months, compared to a median PFS of 14.7 months and a median OS which had not been reached in the group with a low follow-up SUVmax (p = 0.01 and 0.003, respectively). The patient group with a high follow-up SAM and a low ?SAM had a median PFS and OS of 9.4 months and 32 months, whereas the other group had a median PFS of 14.7 months and a median OS which had not been reached (p = 0.002 for both PFS and OS). CONCLUSION: (18)F-FDG PET imaging is a useful tool to assess treatment response and predict clinical outcome in patients with mCRC who undergo chemotherapy before liver metastasectomy. Follow-up SUVmax, follow-up SAM and ?SAM were found to be significant prognostic factors for PFS and OS. PMID- 23636803 TI - Transfer kinetics of perfluorooctane sulfonate from water and sediment to a marine benthic fish, the marbled flounder (Pseudopleuronectes yokohamae). AB - The authors investigated the kinetics of transfer of perfluorooctane sulfonate (PFOS) from water, suspended sediment, and bottom sediment to a marine benthic fish, the marbled flounder (Pseudopleuronectes yokohamae). Fish were exposed in 3 treatments to PFOS in combinations of these exposure media for 28 d and then depurated for 84 d. A major part (37-66%) of PFOS in the fish was in the carcass (i.e., whole body minus muscle and internal organs). Three first-order-kinetic models that differed in exposure media, that is, 1) sum of dissolved and particulate phases and sediment; 2) dissolved phase, particulate phase, and sediment; and 3) dissolved phase only, were fitted to the data assuming common rate constants among the treatments. The uptake efficiency of dissolved PFOS at the respiratory surfaces was estimated to be 3.2% that of oxygen, and the half life of PFOS in the whole body to be 29 d to 31 d. The better fit of models 1 and 2 and the values of the estimated uptake rate constants suggested that the PFOS in suspended and bottom sediments, in addition to that dissolved in water, contributed to the observed body burden of the fish. Based on an evaluation of several possible contributing factors to the uptake of PFOS from suspended and bottom sediments, the authors propose that further investigation is necessary regarding the mechanisms responsible for the uptake. PMID- 23636804 TI - Cooperation of histone deacetylase inhibitors SAHA and valproic acid in promoting sodium/iodide symporter expression and function in rat Leydig testicular carcinoma cells. AB - The presence of the sodium/iodide symporter (NIS) is the prerequisite for the use of the radioiodine in the treatment of thyroid cancer. Thus, stimulators of NIS expression and function are currently investigated in cellular models of various human malignancies, also including extrathyroid cancers. In this study, we analyzed the effects of the histone deacetylase inhibitors (HDACi), suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA), on NIS expression and function in rat Leydig testicular carcinoma cells (LC540). LC540 cells were exposed to SAHA 3 MUM and VPA 3 mM (alone and in combination), and cell viability evaluated by MTT assay and cell counting, NIS mRNA and protein levels by using, respectively, real-time RT-PCR and western blotting. NIS function was evaluated by iodide uptake assay. We found that both HDACi were able to stimulate the transcription of NIS gene, but not its protein expression, while the association of SAHA and VPA increased both NIS transcript and protein levels, resulting in significant sixfold enhancement of radioiodine uptake capacity of LC540 cells. These data demonstrate the presence of an epigenetic control of NIS expression in Leydig tumor cells, suggesting the possibility to use the combination of these two HDACi for a radioiodine-based treatment of these malignancies. PMID- 23636805 TI - Special issue dedicated to Elisabeth Bock. PMID- 23636806 TI - Shikonin protects dopaminergic cell line PC12 against 6-hydroxydopamine-mediated neurotoxicity via both glutathione-dependent and independent pathways and by inhibiting apoptosis. AB - We have investigated the mechanism of shikonin function on protection of dopaminergic neurons against 6-OHDA-induced neurotoxicity. Treatment of rat pheochromocytoma cell line PC12 by serial dilutions of shikonin determined 10 MUM of the compound as its optimum concentration for protection saving nearly 70 % of the cells against toxicity. Reverse transcription-PCR analysis of shikonin treated cells showed threefold increase in mRNA levels of glutathione peroxidase 1 (GPX-1) as a representative component of the intracellular anti-oxidant defense system. To elucidate shikonin-GPX1 relationships and maximize protection, we transduced PC12 cells using recombinant lentivirus vectors that harbored GPX-1 coding sequence. This change upregulated GPX-1 expression, increased peroxidase activity and made neuronal cells resistant to 6-OHDA-mediated toxicity. More importantly, addition of shikonin to GPX1-overexpressing PC12 cells augmented GPX 1 protein content by eightfold leading to fivefold increase of enzymatic activity, 91 % cell survival against neurotoxicity and concomitant increases in intracellular glutathione (GSH) levels. Depletion of intracellular GSH rendered all cell groups highly susceptible to toxicity; however, shikonin was capable of partially saving them. Subsequently, GSH-independent superoxide dismutase mRNA was found upregulated by shikonin. As signs of apoptosis inhibition, the compound upregulated Bcl-2, downregulated Bax, and prevented cell nuclei from undergoing morphological changes typical of apoptosis. Also, a co-staining method demonstrated GPX-1 overexpression significantly increases the percent of live cells that is maximized by shikonin treatment. Our data indicate that shikonin as an antioxidant compound protects dopaminergic neurons against 6-OHDA toxicity and enhances their survival via both glutathione-dependent and direct anti-apoptotic pathways. PMID- 23636807 TI - Mycorrhizal status of Cyperaceae from New Caledonian ultramafic soils: effects of phosphorus availability on arbuscular mycorrhizal colonization of Costularia comosa under field conditions. AB - Plants from the Cyperaceae family (sedges), usually considered as non mycorrhizal, constitute almost exclusively the herbaceous stratum of the ultramafic maquis in New Caledonia. These plants are pioneers and are important for the ecological restoration of mined areas. Costularia comosa, one of the most common sedges in this environment, was grown under field conditions on ultramafic soil, fertilized or not with phosphate and/or nitrogen. Results showed that the addition of phosphate to the soil induced a clear increase in mycorrhizal colonization of C. comosa and an increase in arbuscule abundance, reflecting the establishment of a functional mycorrhizal symbiosis. Significant positive correlations were found among mycorrhizal parameters and plant or soil phosphorus concentrations. Nitrogen fertilization did not affect mycorrhizal colonization of C. comosa. The improvement in mycorrhizal colonization by phosphate fertilization did not influence significantly nickel concentrations in the roots and shoots of plants. This study demonstrated that phosphate fertilization of ultramafic soil improved mycorrhizal colonization of C. comosa, with formation of a functional symbiosis under field conditions. PMID- 23636808 TI - Echolocation in Blainville's beaked whales (Mesoplodon densirostris). AB - Here we use sound and movement recording tags to study how deep-diving Blainville's beaked whales (Mesoplodon densirostris) use echolocation to forage in their natural mesopelagic habitat. These whales ensonify thousands of organisms per dive but select only about 25 prey for capture. They negotiate their cluttered environment by radiating sound in a narrow 20 degrees field of view which they sample with 1.5-3 clicks per metre travelled requiring only some 60 clicks to locate, select and approach each prey. Sampling rates do not appear to be defined by the range to individual targets, but rather by the movement of the predator. Whales sample faster when they encounter patches of prey allowing them to search new water volumes while turning rapidly to stay within a patch. This implies that the Griffin search-approach-capture model of biosonar foraging must be expanded to account for sampling behaviours adapted to the overall prey distribution. Beaked whales can classify prey at more than 15 m range adopting stereotyped motor patterns when approaching some prey. This long detection range relative to swimming speed facilitates a deliberate mode of sensory-motor operation in which prey and capture tactics can be selected to optimize energy returns during long breath-hold dives. PMID- 23636809 TI - A novel role for FOXO3 in human labor: increased expression in laboring myometrium, and regulation of proinflammatory and prolabor mediators in pregnant human myometrial cells. AB - Preterm birth is the leading factor causing neonatal mortality and morbidity. Inflammation plays a central role in stimulating uterine contractility, which is responsible for approximately one-third of all preterm births. Recent studies have shown that the transcription factor Forkhead box O3 (FOXO3) regulates inflammation in nongestational tissues such as adipocytes and hepatocytes. Thus, in this study, we sought to determine the effect of 1) human term labor on myometrial FOXO3 expression and 2) FOXO3 inhibition and FOXO3 overexpression on proinflammatory and prolabor mediators in human myometrial cells. Higher FOXO3 gene and protein expression were detected in myometrium obtained from women in labor when compared to samples taken from nonlaboring women. Myometrial cells were isolated from pregnant human myometrium, and FOXO3 silencing was achieved using siRNA and overexpression using a cDNA clone. We found that the loss of FOXO3 in myometrial cells was associated with a significant decrease in IL1B induced IL6 and IL8 expression and production, cyclooxygenase ([COX]-2, official symbol PTGS2) expression and subsequent prostaglandin (PGE2 and PGF2alpha) release, and matrix metalloproteinase 9 (MMP9) and mRNA expression and activity. Conversely, FOXO3 overexpression increased cytokine expression and secretion, prostaglandin production, and MMP9 expression in myometrial cells treated with IL1B. In summary, we have identified FOXO3 as an upstream mediator of inflammation in human myometrium. Thus, FOXO3 may present an alternative therapeutic target for preventing preterm birth and its associated morbidity and mortality. PMID- 23636810 TI - Characterization, localization, and stage-dependent gene expression of gonadotropin receptors in chub mackerel (Scomber japonicus) ovarian follicles. AB - The pituitary gonadotropins (GtHs), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are key regulators of gametogenesis in teleosts. However, little is known about the physiological mechanisms by which GtHs regulate asynchronous oocyte development in multiple-spawning marine fishes. We cloned cDNAs encoding GtH receptors (FSHR and LHR) from chub mackerel (Scomber japonicus). FSH and LH were purified by anion-exchange chromatography, gel filtration, and concanavalinA-agarose. When expressed in mammalian cells, FSHR and LHR responded strongly to their own ligands. By separating LH into two subunits by the use of reverse-phase chromatography, we found that the beta subunit is responsible for signal transduction and the alpha-subunit may be important for holding hormone-receptor complex. In situ hybridization showed that only fshr was expressed in prefollicle and granulosa cells in oocytes at the perinucleolus and cortical alveolus stages, suggesting that FSH is involved in the primary and early secondary growth of oocytes. In ovarian follicles during vitellogenesis, both fshr and lhr were expressed in granulosa and thecal cells, and lhr was strongly expressed during germinal vesicle migration (GVM). Real-time PCR analysis of stage-dependent fshr and lhr expression showed that fshr expression was high in ovarian follicles throughout vitellogenesis and decreased during GVM, whereas lhr expression was low in early vitellogenesis, but increased markedly in the late phase of vitellogenesis, remaining high during GVM. These findings suggest that switching of the expression of FSHR to LHR controls the effects of FSH and/or LH on vitellogenesis and final oocyte maturation via steroid production in granulosa and thecal cells. PMID- 23636811 TI - Minimal concentrations of retinoic acid induce stimulation by retinoic acid 8 and promote entry into meiosis in isolated pregonadal and gonadal mouse primordial germ cells. AB - In the present study, we demonstrate that minimal concentrations (<= 1 nM) of retinoic acid (RA), equivalent to the quantity contaminating serum-containing culture medium, are sufficient to promote meiotic entry and progression through meiotic prophase I (MPI) stages in isolated 12.5-days postcoitum (dpc) XX and XY mouse primordial germ cells (PGCs) in culture. Similarly, we found that the same low RA concentration up-regulated or induced stimulation by retinoic acid 8 (Stra8) in such cells, both at mRNA and protein level. In preleptotene/leptotene germ cells, STRA8 was localized in nuclear dots that disappeared at later MPI stages. In addition to Stra8, other meiotic genes such as Dmc1 and Rec8 appeared stimulated by RA directly in PGCs with similar concentration-dependent trends. Finally, we found that RA induced Stra8, Sycp3, Dmc1, and Rec8 transcripts, promoting meiotic entry in culture also in pregonadal 10.5-dpc PGCs of both sexes. When cultured isolated from somatic cells, such PGCs, however, were unable to progress through MPI stages, while after entering meiosis, they progressed through MPI when cultured within aorta/gonad/mesonephros tissues. We conclude that besides RA, germ cell intrinsic factors and other exogenous signals from the surrounding somatic cells are probably necessary for meiotic entry and progression in mouse PGCs. PMID- 23636812 TI - New insights into the mechanisms of ram sperm protection by seminal plasma proteins. AB - To provide new insights into the mechanisms through which seminal plasma proteins (SPP) are able to protect spermatozoa, we tested the hypothesis that apoptosis can contribute to the negative effect of refrigeration on ram spermatozoa, and that SPP prevent this damage. Having proved the presence of key constituents of apoptosis-related pathways in ram sperm protein extracts, we carried out a comparative analysis of the effects of the addition of SPP before refrigeration (15 degrees C, 30 min) and induced-apoptosis with betulinic acid or fibroblast associated receptor ligand, assessing sperm quality parameters and apoptotic markers. The protective effect of SPP on plasma membrane integrity and potential, motility and mitochondrial inner membrane potential, and surface (cardiolipin content) was evidenced in refrigerated and induced-apoptosis samples. The addition of SPP resulted in lower values of phosphatidylserine externalization, DNA damage, and caspase activity. Therefore, apoptosis in fresh or refrigerated ram spermatozoa can occur due to activation of both the extrinsic and the intrinsic mediated pathway, and SPP might interfere with both pathways. The addition of SPP also resulted in higher proportions of viable, noncapacitated sperm and fertilizing ability (ZBA rate). This report demonstrates that SPP support survival of ram spermatozoa acting not only at the plasma membrane but also by inhibition of capacitation, and proposes the possibility that SPP might interfere with the extrinsic and the intrinsic apoptotic pathways. This opens new, interesting perspectives for the study of cellular regulatory mechanisms in spermatozoa that could be crucial for the improvement of ram semen preservation protocols. PMID- 23636813 TI - Analysis of maternal and fetal cardiovascular systems during hyperglycemic pregnancy in the nonobese diabetic mouse. AB - Preconception or gestationally induced diabetes increases morbidities and elevates long-term cardiovascular disease risks in women and their children. Spontaneously hyperglycemic (d)-NOD/ShiLtJ female mice, a type 1 diabetes model, develop bradycardia and hypotension after midpregnancy compared with normoglycemic, age- and gestational day (GD)-matched control (c-NOD) females. We hypothesized that onset of the placental circulation at GD 9-10 and rapid fetal growth from GD 14 correlate with aberrant hemodynamic outcomes in d-NOD females. To develop further gestational time-course correlations between maternal cardiac and renal parameters, high-frequency ultrasonography was applied to d- and c-NOD mice (virgin and at GD 8-16). Cardiac output and left ventricular (LV) mass increased in c-NOD but not in d-NOD mice. Ultrasound and postmortem histopathology showed overall greater LV dilation in d-NOD than in c-NOD mice at mid to late gestation. These changes suggest blunted remodeling and altered functional adaptation of d-NOD hearts. Umbilical cord ultrasounds revealed lower fetal heart rates from GD 12 and lower umbilical flow velocities at GD 14 and GD 16 in d-NOD versus c-NOD pregnancies. From GD 14 to GD 16, d-NOD fetal losses exceeded c-NOD fetal losses. Similar aberrant responses in pregnancies of women with diabetes may elevate postpartum maternal and child cardiovascular risk, particularly if mothers lack adequate prenatal care or have poor glycemic control during gestation. PMID- 23636815 TI - A dyadic analysis of the influence of trauma exposure and posttraumatic stress disorder severity on intimate partner aggression. AB - This study used structural equation modeling to evaluate a mediation model of the relationship between trauma exposure, posttraumatic stress disorder (PTSD) symptoms, and perpetration of intimate partner physical and psychological aggression in trauma-exposed veterans and their cohabitating spouses (n = 286 couples; 88% male veteran and female spouse, 80.8% White, non-Hispanic). Dyadic data analyses were used to simultaneously evaluate actor and partner effects using the actor-partner interdependence model (Kashy & Kenny, 2000). The primary hypothesis was that PTSD would mediate the association between trauma exposure and intimate partner physical and psychological aggression with these effects evident both within and across members of a couple (i.e., actor and partner effects). The best-fitting model included (a) equivalent actor and partner direct effects of trauma on veterans' acts of psychological aggression (beta = .17 to .20, p = .001), and (b) equivalent actor and partner indirect effects via PTSD on veterans' acts of physical aggression (beta = .08 to .10, p < .001). There were no direct or indirect effects predicting the spouses' aggression. Results suggest it is important to consider the trauma histories and possible presence of PTSD in both partners as this may be a point of intervention when treating distressed couples. PMID- 23636814 TI - Gender differences in patterns of second premolar agenesis observed in 4,756 individuals. AB - AIM: To elucidate intra- and inter-maxillary patterns of second premolar agenesis in the mandible and maxilla-including unilateral and/or bilateral occurrence and gender differences. STUDY DESIGN: The study comprised panoramic radiographs from 4,756 children with and without orthodontic treatment needs. METHODS: All radiographs were screened twice. 251 individuals had agenesis of one or more mandibular and/or maxillary second premolars; 37 had agenesis of both mandibular and maxillary second premolars. STATISTICS: Gender differences were analysed using chi2 and Fisher's exact test. RESULTS: 193 individuals had agenesis of one or both mandibular second premolars, while 95 had agenesis of one or both maxillary second premolars. In females, agenesis of left and right second premolars was significantly associated in both the mandible and in maxilla (p < 0.0001). In males, this association was only significant in the maxilla (p < 0.0001). Bilateral agenesis occurred almost twice as frequently in females. Unilateral agenesis in the maxilla occurred almost twice as frequently in females. The probability of finding second premolar agenesis in the maxilla was significantly greater in females than in males (p = 0.03). A significant association was seen between agenesis of tooth 25 and 35 in females and males combined (p = 0.03) and in males alone (p = 0.01). No significance was found between agenesis of tooth 15 and 45 in either females or males. CONCLUSIONS: The study confirms some previous findings of second premolar agenesis and presents new observations on gender differences, especially concerning associations in agenesis occurrence within and between the jaws. PMID- 23636817 TI - Electrospun chitosan microspheres for complete encapsulation of anionic proteins: controlling particle size and encapsulation efficiency. AB - Electrospinning was employed to fabricate chitosan microspheres by a single-step encapsulation of proteins without organic solvents. Chitosan in acetic acid was electrospun toward a grounded sodium carbonate solution at various electric potential and feeding rates. Electrospun microspheres became insoluble and solidified in the sodium carbonate solution by neutralization of chitosan acetate. When the freeze-dried microspheres were examined by scanning electron microscopy, the small particle size was obtained at higher voltages. This is explained by the chitosan droplet size at the electrospinning needle was clearly controllable by the electric potential. The recovery yield of chitosan microspheres was dependent on the concentration of chitosan solution due to the viscosity is the major factor affecting formation of chitosan droplet during curling of the electrospinning jets. For protein encapsulation, fluorescently labeled bovine serum albumin (BSA) was codissolved with chitosan in the solution and electrospun. At higher concentration of sodium carbonate solution and longer solidification time in the solution, the encapsulation efficiency of the protein was confirmed to be significantly high. The high encapsulation efficiency was achievable by instant solidification of microspheres and electrostatic interactions between chitosan and BSA. Release profiles of BSA from the microspheres showed that the protein release was faster in acidic solution due to dissolution of chitosan. Reversed-phase chromatography of the released fractions confirmed that exposure of BSA to acidic solution during the electrospinning did not result in structural changes of the encapsulated protein. PMID- 23636819 TI - Dynamics analysis of a multi-strain cholera model with an imperfect vaccine. AB - A new two-strain model, for assessing the impact of basic control measures, treatment and dose-structured mass vaccination on cholera transmission dynamics in a population, is designed. The model has a globally-asymptotically stable disease-free equilibrium whenever its associated reproduction number is less than unity. The model has a unique, and locally-asymptotically stable, endemic equilibrium when the threshold quantity exceeds unity and another condition holds. Numerical simulations of the model show that, with the expected 50% minimum efficacy of the first vaccine dose, vaccinating 55% of the susceptible population with the first vaccine dose will be sufficient to effectively control the spread of cholera in the community. Such effective control can also be achieved if 50% of the first vaccine dose recipients take the second dose. It is shown that a control strategy that emphasizes the use of antibiotic treatment is more effective than one that emphasizes the use of basic (non-pharmaceutical) anti-cholera control measures only. Numerical simulations show that, while the universal strategy (involving all three control measures) gives the best outcome in minimizing cholera burden in the community, the combined basic anti-cholera control measures and treatment strategy also has very effective community-wide impact. PMID- 23636816 TI - Preparation and evaluation of solid dispersions of a new antitumor compound based on early-stage preparation discovery concept. AB - Ensuring sufficient drug solubility is a crucial problem in pharmaceutical related research. For water-insoluble drugs, various formulation approaches are employed to enhance the solubility and bioavailability of lead compounds. The goal of this study was to enhance the dissolution and absorption of a new antitumor lead compound, T-OA. Early-stage preparation discovery concept was employed in this study. Based on this concept, a solid dispersion system was chosen as the method of improving drug solubility and bioavailability. Solid dispersions of T-OA in polyvinylpyrrolidone (PVP) K30 were prepared by the solvent evaporation method. Dissolution testing determined that the ideal drug-to PVP ratio was 1:5. X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry were employed to confirm the formation of solid dispersions. Scanning electron microscopy demonstrated that T-OA was converted into an amorphous form. Both in vitro dissolution testing and the in vivo studies demonstrated that the solubility and bioavailability of T-OA were significantly improved when formulated in a solid dispersion with PVP. The dissolution rate of the T-OA/PVP solid dispersion was greatly enhanced relative to the pure drug, and the relative bioavailability of T-OA solid dispersions was found to be 392.0%, which is 4-fold higher than the pure drug. PMID- 23636818 TI - Batch-to-batch quality consistency evaluation of botanical drug products using multivariate statistical analysis of the chromatographic fingerprint. AB - Botanical drug products have batch-to-batch quality variability due to botanical raw materials and the current manufacturing process. The rational evaluation and control of product quality consistency are essential to ensure the efficacy and safety. Chromatographic fingerprinting is an important and widely used tool to characterize the chemical composition of botanical drug products. Multivariate statistical analysis has showed its efficacy and applicability in the quality evaluation of many kinds of industrial products. In this paper, the combined use of multivariate statistical analysis and chromatographic fingerprinting is presented here to evaluate batch-to-batch quality consistency of botanical drug products. A typical botanical drug product in China, Shenmai injection, was selected as the example to demonstrate the feasibility of this approach. The high performance liquid chromatographic fingerprint data of historical batches were collected from a traditional Chinese medicine manufacturing factory. Characteristic peaks were weighted by their variability among production batches. A principal component analysis model was established after outliers were modified or removed. Multivariate (Hotelling T(2) and DModX) control charts were finally successfully applied to evaluate the quality consistency. The results suggest useful applications for a combination of multivariate statistical analysis with chromatographic fingerprinting in batch-to-batch quality consistency evaluation for the manufacture of botanical drug products. PMID- 23636820 TI - Immunotherapy safety: what have we learned from surveillance surveys? AB - Subcutaneous allergen immunotherapy (SCIT) is beneficial for the treatment of allergic rhinitis, asthma, and in preventing stinging insect anaphylaxis, but is not without risks. Four retrospective surveillance surveys and one on-going national prospective study have attempted to characterize the incidence and risk factors for fatal and non-fatal SCIT reactions. These studies have contributed significantly to currently recommended SCIT safety guidelines. Recent surveillance studies indicate stable SR rates, and a possible decline in the incidence of fatal reactions since the implementation of evidence-based safety guidelines. This review will provide a detailed summary of the evidence from surveillance studies for risk factors associated with SCIT reactions, including: uncontrolled asthma, prior systemic reactions, dosing during peak pollen seasons, epinephrine being delayed or not given, dosing or administration errors, inadequate waiting times, reactions occurring more than 30 min after injections, injections given in medically unsupervised settings, concomitant beta-blocker and angiotensin-converting enzyme inhibitor (ACEi) use, and accelerated build-up regimens. PMID- 23636821 TI - Reliable and sensitive determination of dutasteride in human plasma by liquid chromatography-tandem mass spectrometry. AB - An accurate and precise method was developed and validated using LC-MS/MS to quantify dutasteride in human plasma. The analyte and dutasteride-13C6 as internal standard (IS) were extracted from 300 MUL plasma volume using methyl tert-butyl ether-n-hexane (80:20, v/v). Chromatographic analysis was performed on a Gemini C18 (150 * 4.6 mm, 5 um) column using acetonitrile-5 mm ammonium formate, pH adjusted to 4.0 with formic acid (85:15, v/v) as the mobile phase. Tandem mass spectrometry in positive ionization mode was used to quantify dutasteride by multiple reaction monitoring. The entire data processing was done using Watson LIMS(TM) software, which provided excellent data integrity and high throughput with improved operational efficiency. The calibration curve was linear in the range of 0.1-25 ng/mL, with intra-and inter-batch values for accuracy and precision (coefficient of variation) ranging from 95.8 to 104.0 and from 0.7 to 5.3%, respectively. The mean overall recovery across quality controls was >=95% for the analyte and IS, while the interference of matrix expressed as IS normalized matrix factors ranged from 1.01 to 1.02. The method was successfully applied to support a bioequivalence study of 0.5 mg dutasteride capsules in 24 healthy subjects. Assay reproducibility was demonstrated by reanalysis of 103 incurred samples. PMID- 23636822 TI - Non-structural protein P6 encoded by rice black-streaked dwarf virus is recruited to viral inclusion bodies by binding to the viroplasm matrix protein P9-1. AB - Like other members of the family Reoviridae, rice black-streaked dwarf virus (RBSDV, genus Fijivirus) is thought to replicate and assemble within cytoplasmic viral inclusion bodies, commonly called viroplasms. RBSDV P9-1 is the key protein for the formation of viroplasms, but little is known about the other proteins of the viroplasm or the molecular interactions amongst its components. RBSDV non structural proteins were screened for their association with P9-1 using a co immunoprecipitation assay. Only P6 was found to directly interact with P9-1, an interaction that was confirmed by bimolecular fluorescence complementation assay in Spodoptera frugiperda (Sf9) cells. Immunoelectron microscopy showed that P6 and P9-1 co-localized in electron-dense inclusion bodies, indicating that P6 is a constituent of the viroplasm. In addition, non-structural protein P5 also localized to viroplasms and interacted with P6. In Sf9 cells, P6 was diffusely distributed throughout the cytoplasm when expressed alone, but localized to inclusions when co-expressed with P9-1, suggesting that P6 is recruited to viral inclusion bodies by binding to P9-1. P5 localized to the inclusions formed by P9 1 when co-expressed with P6 but did not when P6 was absent, suggesting that P5 is recruited to viroplasms by binding to P6. This study provides a model by which viral non-structural proteins are recruited to RBSDV viroplasms. PMID- 23636824 TI - Insight into structural diversity of influenza virus haemagglutinin. AB - Influenza virus infects host cells through membrane fusion, a process mediated by the low pH-induced conformational change of the viral surface glycoprotein haemagglutinin (HA). We determined the structures and biochemical properties of the HA proteins from A/Korea/01/2009 (KR01), a 2009 pandemic strain, and A/Thailand/CU44/2006 (CU44), a seasonal strain. The crystal structure of KR01 HA revealed a V-shaped head-to-head arrangement, which is not seen in other HA proteins including CU44 HA. We isolated a broadly neutralizing H1-specific monoclonal antibody GC0757. The KR01 HA-Fab0757 complex structure also exhibited a head-to-head arrangement of HA. Both native and Fab complex structures reveal a different spatial orientation of HA1 relative to HA2, indicating that HA is flexible and dynamic at neutral pH. Further, the KR01 HA exhibited significantly lower protein stability and increased susceptibility to proteolytic cleavage compared with other HAs. Our structures provide important insights into the conformational flexibility of HA. PMID- 23636823 TI - Multiple effects of dendritic cell depletion on murine norovirus infection. AB - Dendritic cells (DCs) are permissive to murine norovirus (MNV) infection in vitro and in vivo. However, their roles during infection in vivo are not well defined. To determine the role of DCs during infection, conventional DCs were depleted from CD11c-DTR mice and infected with a persistent MNV strain. Viral titres in the intestine and secondary lymphoid organs were determined at early time points during infection, and anti-MNV antibody responses were analysed later during infection. Depletion of conventional DCs resulted in increased viral loads in intestinal tissues, impaired generation of antibody responses, and a failure of MNV to efficiently infect lymphoid tissues. These data suggest that DCs play multiple roles in MNV pathogenesis, in both innate immunity and the efficient generation of adaptive immune responses against MNV, as well as by promoting the dissemination of MNV to secondary lymphoid tissues. This is the first study to probe the roles of DCs in controlling and/or facilitating a norovirus infection in vivo and provides the basis for further studies aimed at defining mechanisms by which DCs control MNV replication and promote viral dissemination. PMID- 23636825 TI - Positive selection of self-antigen-specific CD8+ T cells by hematopoietic cells. AB - In contrast to thymic epithelial cells, which induce the positive selection of conventional CD8(+) T cells, hematopoietic cells (HCs) select innate CD8(+) T cells whose Ag specificity is not fully understood. Here we show that CD8(+) T cells expressing an H-Y Ag-specific Tg TCR were able to develop in mice in which only HCs expressed MHC class I, when HCs also expressed the H-Y Ag. These HC selected self-specific CD8(+) T cells resemble innate CD8(+) T cells in WT mice in terms of the expression of memory markers and effector functions, but are phenotypically distinct from the thymus-independent CD8(+) T-cell population. The peripheral maintenance of H-Y-specific CD8(+) T cells required presentation of the self-Ag and IL-15 on HCs. HC-selected CD8(+) T cells in mice lacking the Tg TCR also showed these features. Furthermore, by using MHC class I tetramers with a male Ag peptide, we found that self-Ag-specific CD8(+) T cells in TCR non-Tg mice could develop via HC-induced positive selection, supporting results obtained from H-Y TCR Tg mice. These findings indicate the presence of self-specific CD8(+) T cells that are positively selected by HCs in the peripheral T-cell repertoire. PMID- 23636827 TI - Acute harm: unplanned extubations and cardiopulmonary resuscitation in children and neonates. PMID- 23636826 TI - Clinical impact of arterial ammonia levels in ICU patients with different liver diseases. AB - PURPOSE: Increased arterial ammonia levels are associated with high mortality in patients with acute liver failure (ALF). Data on the prognostic impact of arterial ammonia is lacking in hypoxic hepatitis (HH) and scarce in critically ill patients with cirrhosis. METHODS: The patient cohort comprised 72 patients with HH, 43 patients with ALF, 100 patients with liver cirrhosis and 45 patients without evidence for liver disease. Arterial ammonia concentrations were assessed on a daily basis in all patients and the results were compared among these four patient groups and between 28-day survivors and 28-day non-survivors overall and in each group. RESULTS: Overall 28-day mortality rates in patients with HH, ALF and cirrhosis and in the control group were 54, 30, 49 and 27 %, respectively. Peak arterial ammonia levels differed significantly between transplant-free 28 day survivors and non-survivors in the HH and ALF groups (p < 0.01 for both). Multivariate regression identified peak arterial ammonia concentrations as an independent predictor of 28-day mortality or liver transplantation in patients with HH and ALF, respectively (p < 0.01). There was no association between mortality and arterial ammonia in patients with liver cirrhosis and in the control group. Admission arterial ammonia levels were independently linked to hepatic encephalopathy grades 3/4 in patients with HH (p < 0.01), ALF (p < 0.05) and cirrhosis (p < 0.05), respectively. CONCLUSIONS: Elevated arterial ammonia levels indicate a poor prognosis in acute liver injury and are associated with advanced HE in HH, ALF and cirrhosis. Arterial ammonia levels provide additional information in the risk assessment of critically ill patients with liver disease. PMID- 23636829 TI - Discrepancy between guidelines and practice of tracheal suctioning in mechanically ventilated patients: a French multicenter observational study. PMID- 23636828 TI - Periprocedural cessation of nutrition in the intensive care unit: opportunities for improvement. AB - PURPOSE: Delivery of enteral nutrition (EN) to ICU patients is commonly interrupted for diagnostic and therapeutic procedures. We investigated this practice in a cohort of trauma and surgical ICU patients. METHODS: This was a retrospective single-center study conducted in a 15-bed trauma ICU of a university-affiliated teaching hospital. Descriptive statistics were used. RESULTS: Of 69 patients assessed, 41 had 121 planned procedures over a mean ICU length of stay of 18.7 days (SD 9.6 days). EN was stopped prior to 108 (89 %, 95 % CI 82-94 %) of these 121 procedures, and 102 of these cessation episodes were related to the planned procedure. EN was stopped in 37 patients for a mean cumulative duration of 30.8 h (SD 22.7 h) per patient, which represented 7.9 % (SD 6.9 %) of the mean total time spent in the ICU leading to a mean energy and protein deficit of 7.2 % (SD 8.5 %) and 7.7 % (SD 9.6 %), respectively. Of the 121 planned procedures, 27 (22 %, 95 % CI 16-31 %) were postponed beyond the scheduled day. For 32 (31 %, 95 % CI 23-41 %) of the 102 EN cessation episodes, EN was stopped without a documented order and 23 (23 %, 95 % CI 16-32 %) episodes were not deemed necessary based on the institution's guidelines. CONCLUSION: In this ICU cohort, EN cessation for planned procedures was frequent and led to a nutritional deficit due to long periods without EN being delivered. Postponement of procedures and clinically unnecessary EN cessation were important factors that prevented delivery of planned nutrition. EN cessation practice should be a focus for improving EN delivery in ICU patients. PMID- 23636830 TI - Sex hormones and skeletal muscle weakness. AB - Human ageing is accompanied with deterioration in endocrine functions the most notable and well characterized of which being the decrease in the production of sex hormones. Current research literature suggests that low sex hormone concentration may be among the key mechanism for sarcopenia and muscle weakness. Within the European large scale MYOAGE project, the role of sex hormones, estrogens and testosterone, in causing the aging-related loss of muscle mass and function was further investigated. Hormone replacement therapy (HRT) in women is shown to diminish age-associated muscle loss, loss in fast muscle function (power), and accumulation of fat in skeletal muscle. Further HRT raises the protein synthesis rate in skeletal muscle after resistance training, and has an anabolic effect upon connective tissue in both skeletal muscle and tendon, which influences matrix structure and mechanical properties. HRT influences gene expression in e.g. cytoskeletal and cell-matrix proteins, has a stimulating effect upon IGF-I, and a role in IL-6 and adipokine regulation. Despite low circulating steroid-hormone level, postmenopausal women have a high local concentration of steroidogenic enzymes in skeletal muscle. PMID- 23636831 TI - Life satisfaction of older Chinese adults living in rural communities. AB - Guided by the socio-environmental theoretical framework, this study examined factors associated with life satisfaction experienced by older Chinese adults living in rural communities. The data used in this study were extracted from the Sample Survey on Aged Population in Urban/Rural China conducted by the China Research Center on Aging in 2000. This study included 10,084 rural older adults in mainland China. In this study 60.2 % of rural older adults were satisfied with their lives. Results from a multinomial logistic regression analysis showed that life satisfaction reported by rural older Chinese adults was significantly related to education, financial resources, self-rated health, financial support from children, satisfaction with children's support, house sitting for their children, visiting neighbors, and being invited to dinner by neighbors. Research and policy implications of these findings are also discussed. PMID- 23636832 TI - Aging and caregiving in the Republic of Palau. AB - Aging has been an important population trend of the twentieth century, with most elderly people living in developing countries. Little has been published on the healthcare needs of elderly in the Pacific Islands. The Pacific Islands Geriatric Education Center, at the University of Hawaii, has a mission to promote training in geriatric education in the Pacific Islands to improve healthcare to the elderly. The aim of this project was to develop and test a family caregiver training program for Palau and was achieved in two phases: (1) assessing needs by interviewing key informants and surveying elders and (2) evaluating the caregiver training program that was designed based on findings from the assessment. The Ecological Systems Theory provided the theoretical framework for this study. The needs assessment identified training and education of family caregivers as a top priority, with the Palauan culture of family caring for seniors presently threatened by caregiver burnout. Nearly all of the long-term care in Palau is provided by families, and elders have high prevalence of geriatric syndromes. A family caregiver train-the-trainer workshop was subsequently conducted in February 2011. Forty-four trainers, including 12 from other Pacific Islands, attended the workshop. To assess changes in knowledge and confidence to teach, we compared scores on pre- and post-questionnaires using paired t tests. The train the-trainer workshop resulted in significantly improved self-assessed competence and confidence to teach in all geriatric syndromes, including dealing with difficult behaviors, gait and transfer training, caregiver stress relief, and resources for caregivers (p < 0.0001). This successful intervention identified geriatric care needs in Palau and successfully trained family caregivers to meet these needs, and may be used as a model for similar interventions in other Pacific Islands. PMID- 23636836 TI - Reply to the comment on Kritsaneephaiboon et al.: Minimally invasive plate osteosynthesis of distal tibial fracture using a posterolateral approach: a cadaveric study and preliminary report. PMID- 23636833 TI - Patterns of caregiving of Cuban, other Hispanic, Caribbean Black, and White elders in South Florida. AB - Caregivers in Miami, Florida (185 Cubans, 108 other Hispanics, 229 non-Hispanic Whites, and 73 Caribbean Blacks) were described and compared along demographic and health variables, cultural attitudes, and caregiving behaviors. Participants were recruited at random through Home Health Services (61 %) and convenience sampling in the community (39 %), and interviewed at their home. Standardized instruments and measures constructed for this study were pretested. Multivariate analyses showed that the ethnic groups differed in age, education, income, and number of persons giving care, while caregiver health and patient functioning were similar. Controlling for demographics, differences in cultural variables were small. The sense of obligation, emotional attachment, openness about who should give care, spirituality, use of family help or community services were comparable in all groups. Commitment to caregiving was high, driven mainly by patient needs. Cubans had the greatest family stability, and worked the hardest, with the lowest sense of burden. Caribbean Black caregivers lived in bigger families, were youngest, and their patients had the lowest cognitive status. Burden was felt most by White caregivers who were older than the others. Professionals need to understand complex belief systems and behavior patterns to assist caregivers in mobilizing appropriate resources. PMID- 23636834 TI - Abdominal wall defect repair with biological prosthesis in transplanted patients: single center retrospective analysis and review of the literature. AB - The risk of fascial dehiscence, wound infection and incisional hernias in organ recipients is higher. Retrospective analysis of our departments database, checking the last 12 years (2000-2012), and of the literature (1966-2012) were conducted. In our database we found seven patients: five liver (71.4 %), one kidney (14.3 %), one multivisceral (14.3 %); five males (71.4 %), two females (28.6 %). Five (71.4 %) were operated in urgency setting and two in ordinary setting (28.6 %). The mean/median number of laparotomies before the incisional hernia is of 2.1/1 (range 1-5). In five patients swine intestinal submucosa (71.4 %) have been used and in two porcine dermal collagen (28.6 %). The mean/median age was 48.3/52 years (range 18-61). The mean/median body mass index was 26.7/27 (range 19-34). The mean/median for follow-up after intervention was 40.1/33 months (range 50-21). Recurrence rate was 14.3 %. Complication rate was 28.6 %. Adding the present report, the literature reports 70 cases. 20 % of prosthesis have been implanted inlay, 25.7 % underlay, in 5.7 % intraperitoneal and in 48.6 % were not specified. The mean age ranges from 0.7 to 48.3 years. Kidney, liver, pancreas, bowel and multivisceral transplant are reported. Porcine dermal collagen has been implanted in 24.3 %, human dermal collagen in 51.4 % and swine intestinal submucosa in 24.3 %. The immunosuppression regimens comprehend variable associations of tacrolimus, steroids, mycophenolate mofetil, sirolimus, thymoglobulin, azathioprine/basiliximab and daclizumab. The mean follow-up is 16.2 months. The mean complication rate is 9.4 %. Biological prosthesis seems to be useful and safe in abdominal wall repair surgery in transplanted patients. PMID- 23636837 TI - Distribution and visualisation of chlorhexidine within the skin using ToF-SIMS: a potential platform for the design of more efficacious skin antiseptic formulations. AB - PURPOSE: In order to increase the efficacy of a topically applied antimicrobial compound the permeation profile, localisation and mechanism of action within the skin must first be investigated. METHODS: Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used to visualise the distribution of a conventional antimicrobial compound, chlorhexidine digluconate, within porcine skin without the need for laborious preparation, radio-labels or fluorescent tags. RESULTS: High mass resolution and high spatial resolution mass spectra and chemical images were achieved when analysing chlorhexidine digluconate treated cryo-sectioned porcine skin sections by ToF-SIMS. The distribution of chlorhexidine digluconate was mapped throughout the skin sections and our studies indicate that the compound appears to be localised within the stratum corneum. In parallel, tape strips taken from chlorhexidine digluconate treated porcine skin were analysed by ToF-SIMS to support the distribution profile obtained from the skin sections. CONCLUSIONS: ToF-SIMS can act as a powerful complementary technique to map the distribution of topically applied compounds within the skin. PMID- 23636838 TI - Chemical drug stability in lipids, modified lipids, and polyethylene oxide containing formulations. AB - To critique the stability complications seen in formulating poorly water-soluble, problematic drugs in lipids, modified lipids, and polyethylene oxide solvents and surfactants in hard and soft gelatin capsules as well as some parenterals, a literature search was performed and personal experiences, and those of colleagues, collated. The literature is replete with examples of molecules undergoing rapid oxidative degradation in the presence of polyethylene oxide based solvents and surfactants as well as in the presence of unsaturated lipids. More recently appreciated is instability caused by the reaction of amine and amide drugs, with formaldehyde, formic acid found in many of these solvents as impurities and other degradation byproducts of the solvents themselves. One would expect acylation and transacylation reactions to be more common than reported but the literature has some good examples. An added complexity is occasionally seen with the use of hard and soft gelatin capsules with these solvents. The chemical stability of drugs in liquid and semi-solid formulations in the presence of lipids, modified lipids, and polyoxyethylene oxide-based solvents and surfactants can be complex, further exacerbated by the use of gelatin capsules, and can lead to a plethora of degradation pathways often not seen when the same drugs are formulated in solid dosage forms. PMID- 23636839 TI - In vitro digestion of the self-emulsifying lipid excipient Labrasol((r)) by gastrointestinal lipases and influence of its colloidal structure on lipolysis rate. AB - PURPOSE: Labrasol((r)) is a self-emulsifying excipient used to improve the oral bioavailability of poorly water-soluble drugs. It is a mixture of acylglycerols and PEG esters, these compounds being substrates for digestive lipases. The characterization of Labrasol((r)) gastrointestinal lipolysis is essential for understanding its mode of action. METHODS: Labrasol((r)) lipolysis was investigated using either individual enzymes (gastric lipase, pancreatic lipase related protein 2, pancreatic carboxyl ester hydrolase) or a combination of enzymes under in vitro conditions mimicking first the gastric phase of lipolysis and second the duodenal one. Specific methods for quantifying lipolysis products were established in order to determine which compounds in Labrasol((r)) were preferentially hydrolyzed. RESULTS: Gastric lipase showed a preference for di- and triacylglycerols and the main acylglycerols remaining after gastric lipolysis were monoacylglycerols. PEG-8 diesters were also hydrolyzed to a large extent by gastric lipase. Most of the compounds initially present in Labrasol((r)) were found to be totally hydrolyzed after the duodenal phase of lipolysis. The rate of Labrasol((r)) hydrolysis by individual lipases was found to vary significantly with the dilution of the excipient in water and the resulting colloidal structures (translucent dispersion; opaque emulsion; transparent microemulsion), each lipase displaying a distinct pattern depending on the particle size. CONCLUSIONS: The lipases with distinct substrate specificities used in this study were found to be sensitive probes of phase transitions occurring upon Labrasol((r)) dilution. In addition to their use for developing in vitro digestion models, these enzymes are interesting tools for the characterization of self-emulsifying lipid-based formulations. PMID- 23636840 TI - Brushed block copolymer micelles with pH-sensitive pendant groups for controlled drug delivery. AB - PURPOSE: To investigate the effects of small aliphatic pendent groups conjugated through an acid-sensitive linker to the core of brushed block copolymer micelles on particle properties. METHODS: The brushed block copolymers were synthesized by conjugating five types of 2-alkanone (2-butanone, 2-hexanone, 2-octanone, 2 decanone, and 2-dodecanone) through an acid-labile hydrazone linker to poly(ethylene glycol)-poly(aspartate hydrazide) block copolymers. RESULTS: Only block copolymers with 2-hexanone and 2-octanone (PEG-HEX and PEG-OCT) formed micelles with a clinically relevant size (< 50 nm in diameter), low critical micelle concentration (CMC, < 20 MUM), and drug entrapment yields (approximately 5 wt.%). Both micelles degraded in aqueous solutions in a pH-dependent manner, while the degradation was accelerated in an acidic condition (pH 5.0) in comparison to pH 7.4. Despite these similar properties, PEG-OCT micelles controlled the entrapment and pH-dependent release of a hydrophobic drug most efficiently, without altering particle size, shape, and stability. The molecular weight of PEG (12 kDa vs 5 kDa) induced no change in pH-controlled drug release rates of PEG-OCT micelles. CONCLUSION: Acid-labile small aliphatic pendant groups are useful to control the entrapment and release of a hydrophobic drug physically entrapped in the core of brushed block copolymer micelles. PMID- 23636841 TI - Clinically relevant modeling of urodynamics function: the VBN model. AB - BACKGROUND: For the past two decades, a mathematical model of micturition was built step by step. Fundamental studies, presentations of the model and several applications to various male and female lower urinary tract dysfunctions have been published. We expect now that other teams will be interested in using it. In order to do so, a VBN pack (software in Linux and tutorial) is freely available. AIMS: The purpose of this review is to describe the model and to show its practical usefulness. MATERIALS AND METHODS: After a short description of the basis of the model and of how to use it, some published applications were summed up. The main application of the VBN model is to obtain a coherent modelling for a given patient from a set of several recordings (free uroflows and pressure-flow study) obtained either during the same session or in follow up. RESULTS: This experience gradually led us to study what information could be extracted from a free uroflow. In addition, the model is valuable to quickly compute the effect of some additional condition; thus, it can predict the effect of an experimental artefact (urethral catheter, penile cuff). CONCLUSION: Because the process of fitting model computations and real recordings is a powerful way to detect unexpected phenomena, the use of the VBN model provides a method to improve the knowledge of misunderstood dysfunctions of the lower urinary tract. PMID- 23636842 TI - Disrupted ventromedial prefrontal function, alcohol craving, and subsequent relapse risk. AB - IMPORTANCE: Alcohol dependence is a chronic relapsing illness; stress, alcohol related cues, and neutral-relaxing states significantly influence craving and relapse risk. However, neural mechanisms underlying the association between these states and alcohol craving and relapse risk remain unclear. OBJECTIVES: To identify neural correlates associated with alcohol craving and relapse outcomes in 45 treatment-engaged, 4- to 8-week abstinent alcohol-dependent (AD) patients, and to compare brain responses of 30 demographically matched AD patients and 30 healthy control subjects during stress, alcohol, and neutral-relaxing cues. DESIGN: Functional magnetic resonance imaging study while participants were engaging in brief individualized script-driven imagery trials of stress, alcohol cues, and neutral-relaxing scenarios, and a prospective clinical outcome design to assess alcohol relapse 90 days postdischarge from inpatient treatment in the AD group. SETTINGS: Inpatient treatment setting in a community mental health center and hospital-based research unit. PATIENTS: Forty-five recovering AD patients in inpatient treatment for examining relapse, and 30 healthy control subjects demographically matched to 30 AD patients (subgroup of the relapse sample) for group comparisons. INTERVENTION: Twelve-step recovery-based addiction treatment for the patient group. MAIN OUTCOMES AND MEASURES: Brain response, alcohol craving, and relapse outcome measures (time to relapse and relapse severity). RESULTS: Increased ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) activation during neutral-relaxing trials was correlated with high alcohol cue-induced and stress-induced craving in early recovering AD patients (x = 6, y = 43, z = -6; P < .01, whole-brain corrected). This vmPFC/ACC hyperactivity significantly predicted subsequent alcohol relapse, with a hazards ratio greater than 8 for increased relapse risk. Additionally, vmPFC/ACC hyperactivation during neutral trials and reduced activity during stress trials were each predictive of greater days of alcohol used after relapse (P < .01, whole-brain corrected). In contrast, matched control subjects showed the reverse pattern of vmPFC/ACC responses to stress, alcohol cues, and relaxed trials (F = 6.42; P < .01, whole-brain corrected). CONCLUSIONS AND RELEVANCE: Findings indicate that disrupted vmPFC/ACC function plays a role in jeopardizing recovery from alcoholism and may serve as a neural marker to identify those at risk for alcohol relapse. PMID- 23636843 TI - Analysis of a beta-TCP bone graft extender explanted during revision surgery after 28 months in vivo. AB - PURPOSE: Analysis of a beta-tricalcium phosphate (beta-TCP) bone graft soaked with bone marrow aspirate explanted during revision surgery after 28 months. METHODS: A 41-year-old female patient undergoing scoliosis correction Th4-L5 in 2007 was revised due to screw loosening in 2008. During revision surgery, a beta TCP bone graft (chronOS((r)) chips) soaked with bone marrow aspirate was applied. Due to implant failure, the patient was revised again 2011. The bone graft was removed and taken to the laboratory for histological analysis. The biomaterial samples were stained with DAPI and analyzed under a fluorescence microscope. Five biomaterial chips were maintained in tissue culture to evaluate outgrowing cells. The remaining samples were embedded in paraffin, sectioned into 7 MUm sections and stained with Hemalaun/eosin. RESULTS: The morphology and rigidity of the beta TCP bone graft were comparable to the original. The pores were not filled with tissue and could be clearly identified. Only single vital cells were detected on the graft. The outgrowth culture yielded only erythrocytes-no cells of the osteoblastic lineage cells could be harvested. Histological analysis demonstrated a failure of resorption and the absence of new bone formation. CONCLUSION: Histological analysis of bone grafts is rare after implantation in humans due to ethical and clinical limitations of sample harvest. In this study, implantation of a beta-TCP bone graft did not result in bone formation after 28 months in vivo. PMID- 23636844 TI - Sleep disturbance as part of the neurofibromatosis type 1 phenotype in adults. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant condition with a wide array of neurological complications, including cognitive dysfunction, tumors, malformations, neuropathy, neurovascular disease, and epilepsy. Many of these complications may impact on sleep quality and cause sleep disturbance. Previously sleep disturbance in NF1 has been specifically addressed solely in children. We performed a prospective study of sleep quality in 114 consecutive out-patients with NF1 attending our national neurofibromatosis service. The Epworth sleepiness scale (ESS) and the Pittsburgh sleep quality index (PSQI) were administered, and information was obtained from patient records on drugs potentially impacting on sleep, complications directly affecting sleep and employment status. The mean ESS was 6.8, and 21% had an abnormally high ESS of 10 or more. The mean global PSQI score was 8.4 (norm mean 2.67), with abnormally high scores in all sleep domains. Thirty-nine patients had a bed partner and 54% reported features suggestive of periodic limb movements of sleep, 43% had features suggestive of obstructive sleep apnoea, and 10.8% experienced confusion on waking. There was no evidence of phase shift. The ESS did not correlate with the PSQI, but unemployment status was associated with worse global PSQI score and multiple domain sub-scales of sleep quality in the PSQI. We conclude that sleep disturbance and poor sleep quality are significantly more frequent in the adult NF1 patient population. It is likely to be multi-factorial, related to pain, anxiety, depression, cognitive issues, and organic sleep pathology. We recommend careful assessment of patients to determine underlying triggers and possible treatment strategies. PMID- 23636846 TI - Development of a new in-vial standard gas system for calibrating solid-phase microextraction in high-throughput and on-site applications. AB - In this work, an innovative, reproducible, and reusable standard generator vial is presented. The standard generator vial consists of vacuum-pump oil doped with McReynolds probes (benzene, 2-pentanone, pyridine, nitropropane, 1-pentanol, and n-octane) mixed with a polystyrene-divinylbenzene resin without functional groups. The evaluation of this vial was fully automated on a multifiber exchanger system and the extraction/desorption cycle, together with the programmed GC-qMS analysis, did not exceed 13 min. The results showed that after 160 extraction/injections cycles of the vial the relative SDs were smaller than 4% for all the standards. A randomized block design was used to evaluate the inter and intravial repeatability, and at 95% level of confidence nonstatistical differences among vials were found. Because of its compacted granular appearance this vial is easy to transport, and it is an ideal calibration standard for bench and field instruments and devices. PMID- 23636845 TI - Development of a swine model of left bundle branch block for experimental studies of cardiac resynchronization therapy. AB - Animal models that mimic human electrical and mechanical dyssynchrony often associated with chronic heart failure would provide an essential tool to investigate factors influencing response to cardiac resynchronization therapy. A standardized closed-chest porcine model of left bundle branch block (LBBB) was developed using 16 pigs. Radiofrequency applications were performed to induce LBBB, which was confirmed by QRS widening, a surface electrocardiogram pattern concordant with LBBB, and a prolonged activation time from endocardial. Echocardiography confirmed abnormal motion of the septum, which was not present at the baseline echocardiogram. High susceptibility of pigs to ventricular fibrillation during the endocardial ablation was overcome by applying high-rate pacing during radiofrequency applications. This is the first study to devise a closed-chest porcine model of LBBB that closely reproduces abnormalities found in patients with electrical and mechanical cardiac dyssynchrony, and provides a useful tool to investigate the basic mechanisms underlying cardiac resynchronization therapy benefits in heart failure. PMID- 23636851 TI - Economic inequality in presenting near vision acuity in a middle-aged population: a Blinder-Oaxaca decomposition. AB - PURPOSE: To investigate economic inequality and its determinants in near vision, in a middle-aged population. METHODS: In this population-based study, the presenting near vision in the better eye was investigated as the main outcome. If this vision revealed a value >=1.6 M, the participant was considered to have presenting near vision impairment (PNVI). The effect of variables studied on PNVI was investigated using logistic regression. Economic inequality in PNVI was investigated using the Oaxaca-Blinder decomposition method. RESULTS: PNVI in the better eye was observed in 18.2% (95% CI 16.8 to 19.6) of participants. The prevalence of PNVI in the high and low economic groups was 11.7% (95% CI 10.3 to 13.0) and 28.5% (95% CI 26.0 to 31.0), respectively. Age and education were observed as the main factors in the explained portion of this gap and were in favour of the high economic group. Gender and eye care utilisation were factors affecting the unexplained portion of this gap and were in favour of the low economic group. CONCLUSIONS: Economic inequality plays a significant role in PNVI, while age and education are among the main factors affecting this gap. The effect caused by any change in these two factors was found to have a greater effect on women with low economic status. PMID- 23636852 TI - Endothelium and regulatory inflammatory mechanisms during organ rejection. AB - Endothelial integrity is mandatory for physiologic organ function; however, endothelium dysfunction can be caused by systemic inflammation, occurring during sepsis or organ rejection after transplantation. This article will address our current understanding of endothelial involvement in organ transplantation and rejection. Overall, more detailed studies focusing on the endothelial modulation after organ transplantation would be necessary to investigate the role of endothelium activation during organ rejection. PMID- 23636849 TI - Somatic alterations contributing to metastasis of a castration-resistant prostate cancer. AB - Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease, and molecular markers that differentiate indolent from aggressive subtypes are needed. We sequenced the exomes of five metastatic tumors and healthy kidney tissue from an index case with mCRPC to identify lesions associated with disease progression and metastasis. An Ashkenazi Jewish (AJ) germline founder mutation, del185AG in BRCA1, was observed and AJ ancestry was confirmed. Sixty-two somatic variants altered proteins in tumors, including cancer-associated genes, TMPRSS2 ERG, PBRM1, and TET2. The majority (n = 53) of somatic variants were present in all metastases and only a subset (n = 31) was observed in the primary tumor. Integrating tumor next-generation sequencing and DNA copy number showed somatic loss of BRCA1 and TMPRSS2-ERG. We sequenced 19 genes with deleterious mutations in the index case in additional mCRPC samples and detected a frameshift, two somatic missense alterations, tumor loss of heterozygosity, and combinations of germline missense SNPs in TET2. In summary, genetic analysis of metastases from an index case permitted us to infer a chronology for the clonal spread of disease based on sequential accrual of somatic lesions. The role of TET2 in mCRPC deserves additional analysis and may define a subset of metastatic disease. PMID- 23636853 TI - Glomerular filtration rate is associated with burden of coronary atherosclerosis in patients with acute coronary syndrome. AB - We aimed to elucidate the relationship between mild to moderate renal impairements and burden of atherosclerosis in patients with acute coronary syndrome (ACS). A total of 380 patients with ACS were included in the study. Gensini and SYNTAX scores were also calculated. Kidney function was classified based on estimated glomerular filtration rate (eGFR) into stage 1: eGFR >90, stage 2: 60 to 89, and stage 3: 30 to 60 mL/min per 1.73 m(2). Gensini and SYNTAX scores were higher in stages 2 and 3 than in stage 1. Also, the number of diseased vessels, number of critical lesions (>50 and 70%), left main disease, and number of total occlusion vessels were higher in stages 2 and 3 than in stage 1. Multivariate linear regression analysis demonstrated that a decreased eGFR was an independent risk factor for SYNTAX and Gensini scores together with age and male gender. PMID- 23636854 TI - Aortic arterial stiffness is a moderate predictor of cardiovascular disease in patients with psoriasis vulgaris. AB - Psoriasis is associated with an increased risk of atherosclerosis. Endothelial dysfunction is the critical early step in the process of atherogenesis, and it is commonly investigated by measuring arterial stiffness. We aimed to investigate the relationship between arterial stiffness and high-sensitivity C-reactive protein (hsCRP) in patients with psoriasis. A total of 32 patients with psoriasis and 35 patients with other skin diseases were included in the study. The hsCRP levels and arterial stiffness measurements were compared. Arterial stiffness was significantly different between the 2 groups (P = .01). Arterial stiffness was not associated with the duration of the disease or the disease activity (P = .34 and .64, respectively). In patients with psoriasis, arterial stiffness correlated positively with age, sex, body mass index, diastolic blood pressure, and hsCRP level (P < .05). These findings provide further evidence of a link between inflammation, premature atherosclerosis, and psoriasis. PMID- 23636855 TI - A new parameter predicting chronic total occlusion of coronary arteries: platelet distribution width. AB - Platelet distribution width (PDW) measures the variability in platelet size and is a marker of platelet activation. We investigated whether PDW is associated with the extent of coronary artery disease (CAD) and coronary total occlusions (CTOs). We studied 162 patients: 108 had a coronary lesion with a diameter stenosis of >=50%, the CAD(+) group, and 54 patients had normal coronary anatomy, the CAD(-) group. The CAD(+) group was subdivided into CAD(+) CTO(+) and CAD(+) CTO(-) groups. Among patients with CAD, the CTO(+) group had a significantly greater PDW (%) than the CTO(-) group (16.9 +/- 2.8, 15.4 +/- 3.0, and 15.4 +/- 1.9, respectively; P = .008). In a receiver-operating characteristic analysis, a PDW cut point of 15.7% was identified in patients with CTO(+) (area under curve = 0.64, 95% confidence interval 0.54-0.75). A PDW value of more than 15.7% demonstrated a sensitivity of 64% and a specificity of 66%. The PDW is a simple platelet index that may predict the presence of CTO. PMID- 23636856 TI - New obesity indices and adipokines in normotensive patients and patients with hypertension: comparative pilot analysis. AB - We compared the obesity parameters and selected adipokines-leptin, adiponectin, and resistin-in obese patients with hypertension and normotensive patients. A total of 67 nondiabetic obese outpatients were divided into 2 groups: A hypertensive and B-normotensive. Serum levels of leptin, adiponectin, resistin, and insulin were measured. Weight, height, waist circumference, and hip circumference were measured to calculate waist-to-hip ratio (WHR), weight-to height ratio, visceral adiposity index, and body adiposity index (BAI). Among patients with hypertension, significant positive correlations were observed between leptin and body mass index and BAI (r = .31 and r = .63, respectively). In normotensive patients, leptin positively correlated with BAI (r = .73, P < .01) and negatively with WHR (r = -.55, P < .0001); adiponectin negatively correlated with WHR (r = .38, P < .01) and BAI (r = .52; P < .0001), and resistin negatively correlated with WHR (r = -.36, P < .05). In conclusion, visceral obesity and leptin are associated with hypertension in obese patients. PMID- 23636857 TI - Conditions that may affect serum bilirubin levels should be kept in mind in patients with ST-segment elevation myocardial infarction. PMID- 23636858 TI - MALDI-FTICR MS imaging as a powerful tool to identify Paenibacillus antibiotics involved in the inhibition of plant pathogens. AB - Nowadays, microorganisms are more and more often used as biocontrol agents for crop protection against diseases. Among them, bacteria of Bacillus and Paenibacillus genders are already used as commercial biocontrol agents. Their mode of action is supposed to be related to their production of antibiotics, such as cyclic lipopeptides, which exhibit great antimicrobial activities. We chose to work with a Paenibacillus polymyxa strain (Pp56) very resistant to various microorganisms. The bacteria were grown simultaneously with Fusarium oxysporum and we applied matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance (MALDI-FTICR) mass spectrometry to identify the antibiotics compounds present in the fungus growth inhibition area. We, therefore, identified fusaricidins A, B, and C and numerous members of the LI-F antibiotics family. MALDI-FTICR mass spectrometry imaging was then used to follow the diffusion of lipopeptides involved in the inhibitory activity over time. We analyzed the molecular content of the inhibitory area at different Pp56 and Fusarium incubation durations and concluded that some lipopeptides such as fusaricidin B and a mixture of LI-F05b/06b/08a were mainly involved in the defense mechanism of Pp56. Our study confirms that MALDI imaging may be a powerful tool to quickly determine which molecular species is involved in an antagonism with another microorganism, avoiding time-consuming steps of extraction, purification, and activity tests, which are still commonly used in microbiology. PMID- 23636861 TI - Anti-aging effect of Blakeslea trispora powder on adult mice. AB - Blakeslea trispora powder that contains 1.9 % lycopene was tested for its anti aging effect on adult mice. 48 adult mice were administered with the powder at 0, 267, 534, 1,068 mg lycopene kg(-1) body daily for 30 days. The body weight, hematology, clinical chemical and antioxidant activities in major organs of adult mice were measured. The powder had no effect on the body weight, hematology, clinical chemical parameters of adult mice but improved the antioxidant activities in major organs of adult mice. Increased activities of superoxide dismutase, catalase and glutathione peroxidase and a decreased amount of malondialdehyde in liver, brain, kidney and skin of adult mice when a high-dose of the B. trispora powder was administered, suggests that it has the ability to enhance the antioxidation system and improve the anti-aging abilities of adult mice. PMID- 23636859 TI - Decoding split and pool combinatorial libraries with electron-transfer dissociation tandem mass spectrometry. AB - Screening of bead-based split and pool combinatorial chemistry libraries is a powerful approach to aid the discovery of new chemical compounds able to interact with, and modulate the activities of, protein targets of interest. Split and pool synthesis provides for large and well diversified chemical libraries, in this case comprised of oligomers generated from a well-defined starting set. At the end of the synthesis, each bead in the library displays many copies of a unique oligomer sequence. Because the sequence of the oligomer is not known at the time of screening, methods for decoding of the sequence of each screening "hit" are essential. Here we describe an electron-transfer dissociation (ETD) based tandem mass spectrometry approach for the decoding of mass-encoded split and pool libraries. We demonstrate that the newly described "chiral oligomers of pentenoic amides (COPAs)" yield non-sequence-specific product ions upon collisional activated dissociation; however, complete sequence information can be obtained with ETD. To aid in the decoding of libraries from MS and MS/MS data, we have incorporated (79)Br/(81)Br isotope "tags" to differentiate N- and C-terminal product ions. In addition, we have created "Hit-Find," a software program that allows users to generate libraries in silico. The user can then search all possible members of the chemical library for those that fall within a user defined mass error. PMID- 23636862 TI - Usefulness of ultraslim endoscopy with flexible spectral imaging color enhancement for detection of gastric neoplasm: a preliminary study. AB - PURPOSE: Transnasal endoscopy with ultraslim endoscope has rapidly spread in Japan. Ultraslim endoscopy provides less resolution than that of conventional endoscopy and may lead to missed screening of early gastric carcinoma. We evaluated the efficacy of ultraslim endoscopy with flexible spectral imaging color enhancement (FICE) for the diagnosis of early gastric carcinoma. METHODS: This study included 20 consecutive patients in whom 22 gastric neoplasms were resected by endoscopic submucosal dissection (ESD) between April 2011 and January 2012 in Yamaguchi University Hospital. Prior to ESD, marking dots were made during observation with ultraslim endoscopy with FICE. We evaluated en bloc resection rate and tumor visibility with the FICE system. RESULTS: All tumors were resected with sufficient lateral margin. Only one case had tumor cells in the vertical margin. En bloc resection rate was 95.5 % (21/22 lesions). Ultraslim endoscopy with FICE more clearly visualized tumor margin than did conventional endoscopy. Especially, the effect was remarkable in discolored lesions (100.0 %, 3/3 lesions). CONCLUSIONS: Ultraslim endoscopy with FICE improved visibility of gastric neoplasms. PMID- 23636863 TI - Primary multifocal malignant melanoma of the esophagus. PMID- 23636865 TI - Overexpression of a GmGBP1 ortholog of soybean enhances the responses to flowering, stem elongation and heat tolerance in transgenic tobaccos. AB - Soybean is a typical short-day crop, and its photoperiodic and gibberellin (GA) responses for the control of flowering are critical to seed yield. The GmGBP1 mRNA abundance in leaves was dramatically increased in short-days (SDs) compared to that in long-days in which it was consistently low at all time points from 0 to 6 days (days after transfer to SDs). GmGBP1 was highly expressed in leaves and exhibited a circadian rhythm in SDs. Ectopic overexpression of GmGBP1 in tobaccos caused photoperiod-insensitive early flowering by increasing NtCO mRNA levels. GmGBP1 mRNA abundance was also increased by GAs. Transgenic GmGBP1 overexpressing (-ox) tobacco plants exhibited increased GA signaling-related phenotypes including flowering and plant height promotion. Furthermore, the hypocotyl elongation, early-flowering and longer internode phenotypes were largely accelerated by GA3 application in the GmGBP1-ox tobacco seedlings. Being consistent, overexpression of GmGBP1 resulted in significantly enhanced GA signaling (evidenced suppressed expression of NtGA20ox) both with and without GA treatments. GmGBP1 was a positive regulator of both photoperiod and GA-mediated flowering responses. In addition, GmGBP1-ox tobaccos were hypersensitive to ABA, salt and osmotic stresses during seed germination. Heat-inducible GmGBP1 also enhanced thermotolerance in transgenic GmGBP1-ox tobaccos during seed germination and growth. GmGBP1 protein was localized in the nucleus. Analyses of a series of 5'-deletions of the GmGBP1 promoter suggested that several cis-acting elements, including P-BOX, TCA-motif and three HSE elements necessary to induce gene expression by GA, salicic acid and heat stress, were specifically localized in the GmGBP1 promoter region. PMID- 23636867 TI - EZH2, a unique marker of malignancy in effusion cytology. AB - Distinguishing reactive mesothelial cells from metastatic disease, typically adenocarcinoma, in effusion cytology can be challenging at times. We currently use a panel of immunocytochemical markers for select cases including MOC-31 and BerEp4, but difficulties still exist. Enhancer of zeste homologue 2 (EZH2) plays important roles in epigenetic silencing and cell cycle regulation and is upregulated in a wide variety of malignancies. Thus, we hypothesized that EZH2 immunocytochemistry, which to our knowledge has not yet been reported on cytology material, might serve as a unique marker of malignancy in morphologically equivocal effusion specimens by highlighting aberrant protein expression in malignant cells. A total of 96 (48 benign and 48 malignant) effusion cases were selected retrospectively from our department archives. All malignant cases were metastatic adenocarcinomas except for three high grade neuroendocrine carcinomas (two lungs and one ovary), one cervical squamous cell carcinoma, and one epithelioid endometrial stromal sarcoma. The 48 benign cases were all negative for EZH2, and 43 of 48 malignant effusions were positive. As a solitary marker, EZH2 exhibited a sensitivity of 90% and a specificity of 100% (P < 0.0001). EZH2 functioned as a unique and accurate marker of malignancy in this series of effusions. Relative to published data, EZH2 demonstrated a sensitivity comparable to MOC-31 and superior to BerEp4, and a specificity superior to both of these commonly used immunostains. Thus, EZH2 is likely to be of great value as an adjunct to morphology in diagnosing malignancy in effusion specimens. PMID- 23636868 TI - Retinazone inhibits certain blood-borne human viruses including Ebola virus Zaire. AB - BACKGROUND: Human HBV and HIV integrate their retro-transcribed DNA proviruses into the human host genome. Existing antiretroviral drug regimens fail to directly target these intrachromosomal xenogenomes, leading to persistence of viral genetic information. Retinazone (RTZ) constitutes a novel vitamin A-derived (retinoid) thiosemicarbazone derivative with broad-spectrum antiviral activity versus HIV, HCV, varicella-zoster virus and cytomegalovirus. METHODS: The in vitro inhibitory action of RTZ on HIV-1 strain LAI, human HBV strain ayw, HCV-1b strain Con1, enhanced green fluorescent protein-expressing Ebola virus Zaire 1976 strain Mayinga, wild-type Ebola virus Zaire 1976 strain Mayinga, human herpesvirus 6B and Kaposi's sarcoma-associated herpesvirus replication was investigated. The binding of RTZ to human glucocorticoid receptor was determined. RESULTS: RTZ inhibits blood-borne human HBV multiplication in vitro by covalent inactivation of intragenic and intraexonic viral glucocorticoid response elements, and, in close analogy, RTZ suppresses HIV-1 multiplication in vitro. RTZ disrupts the multiplication of blood-borne human HCV and Ebola Zaire virus at nanomolar concentrations in vitro. RTZ has the capacity to bind to human glucocorticoid receptor, to selectively and covalently bind to intraexonic viral glucocorticoid response elements, and thereby to inactivate human genome integrated proviral DNA of human HBV and HIV. CONCLUSIONS: RTZ represents the first reported antiviral agent capable of eradicating HIV and HBV proviruses from their human host. Furthermore, RTZ represents a potent and efficacious small molecule in vitro inhibitor of Ebola virus Zaire 1976 strain Mayinga replication. PMID- 23636866 TI - Urethral dilatation: Is there any benefit over cystoscopy and distension? A randomized trial in women with overactive bladder symptoms. AB - AIM: To evaluate the effect of urethral dilatation (UD) on urgency symptoms in women with overactive bladder (OAB) and voiding dysfunction. METHODS: Women with OAB symptoms and a maximum flow rate of less than 15 ml/sec on a volume voided of 200 ml were eligible for entry to the trial. Fifty women with OAB symptoms and a maximum flow rate of less than 15 ml/sec on a volume voided of over 200 ml were randomized to undergo UD plus cystoscopy or cystoscopy alone. All subjects underwent filling and voiding cystometry pre-operatively and at 6 weeks' post operatively. Subjective outcomes were assessed using the Urgency Perception Scale (UPS) and King's Health Questionnaire at baseline, 6 weeks and 6 months. The primary outcome measure was cure of urgency, defined using the UPS. RESULTS: Urgency was cured in 10/22 (45%) patients in the UD group and 5/28 (18%) in the non-UD group at 6 weeks (Odds ratio 3.8, 95% confidence interval 1.1-13.8, P = 0.03). Cystometric flow data were available for all patients pre- and post-UD. UD was associated with a significant increase in the flow rate centile from 1.66 to 8.54 (P = 0.01). At 6 months there was no benefit from UD with 4/22 in the UD group cured of urgency and 4/28 in the non-UD group cured (Odds ratio 1.3, 95% confidence interval 0.3-6.1, P = 0.50). CONCLUSION: UD confers a significant short-term benefit in cure of urgency over cystoscopy alone, but there is no significant benefit in symptom relief in the long term. PMID- 23636864 TI - Anti-inflammatory strategies for plaque stabilization after acute coronary syndromes. AB - Despite dramatic advances in standard of care, the risk of recurrent myocardial infarction early after an acute coronary syndrome (ACS) remains high. This period of elevated risk after a cardiovascular event is associated with an acute inflammatory response. While post-ACS inflammation correlates with the risk for recurrent events and is likely to play a causal role in this period, the precise pathophysiologic mechanisms have been unclear. Recent studies have proposed that the cardiac event itself activates the sympathetic nervous system to directly mobilize hematopoietic stem cells to differentiate into inflammatory monocytes, acutely infiltrate plaque, and lead to recurrent plaque rupture. Here, we summarize the existing and emerging evidence implicating post-ACS activation of systemic inflammation in the progression of atherosclerosis, and identify possible targets for therapeutic intervention. We highlight experimental therapies and ongoing clinical studies that will validate these targets. PMID- 23636869 TI - Conduction recovery in patients with recurrent atrial fibrillation after pulmonary vein isolation using multi-electrode duty cycled radiofrequency ablation. AB - INTRODUCTION: The pulmonary vein ablation catheter (PVAC) is designed for pulmonary vein isolation (PVI). Electrical reconnection of pulmonary veins is believed to result in AF recurrence. The purpose of this study was to establish the location and extent of PV reconnection after PVI with the PVAC catheter. METHODS AND RESULTS: Eighty-two patients (79 % male, age 60 +/- 9 years) that underwent a redo procedure for recurrent AF after PVAC ablation were assessed for prevalence and location of reconnection. The number of reconnected PV's was 0, 1, 2, 3, or 4 in 2 (2.4 %), 14 (17 %), 23 (28 %), 28 (34 %), and 15 (18 %) patients, respectively. Reconnection of left superior, left inferior, left common, right superior, and right inferior PV's was found in 66, 63, 83, 57, and 67 %, respectively (p = 0.48). In the left PV's, reconnection was located significantly more anterior than posterior; LSPV anterior 32/70 vs posterior 13/70 (p < 0.01), LIPV anterior 26/70 vs posterior 9/70 (p < 0.01). In the right PV's reconnection was distributed equally in all quadrants. Different modes of RF delivery during PVAC ablation (bipolar/unipolar 2:1 [n = 35] vs. 4:1 [n = 47]) yielded comparable rates of PV reconnection. During follow-up (median 296 days) no AF/AT was documented in 57 patients (70 %). CONCLUSION: Almost all patients (98 %) with AF after PVAC ablation show reconnection of at least one PV. All PV's are equally likely to show reconnection. In the left PV's, reconnection was found more often anteriorly than posteriorly. During pulmonary vein isolation with the PVAC catheter, prevalent sites of reconnection deserve close attention to increase success. PMID- 23636870 TI - First experience with a novel robotic remote catheter system: AmigoTM mapping trial. AB - INTRODUCTION: AmigoTM (Catheter Robotics, Inc., Mount Olive, NJ) remote catheter system (RCS) was designed to provide a simple and relatively inexpensive system for remote catheter manipulation. The purpose of this study was to evaluate the performance and safety of Amigo in mapping the right side of the heart. METHODS AND RESULTS: This non-randomized, prospective clinical trial was conducted at 13 sites (NCT: #01139814). Using the controller, a mapping catheter was moved to eight pre-specified locations in a specific sequence: right ventricular apex, mid right ventricular septum, right ventricular outflow tract, His-bundle position, coronary sinus ostium, high right atrium, lateral tricuspid annulus, and low lateral right atrium. The pre-specified efficacy endpoint was to achieve 80 % successful navigation to all locations. Time to each location, location accuracy, and quality of contact were confirmed by imaging and specific criteria for electrograms and pacing thresholds. In 181 patients, a total of 1,396 of 1,448 (96 %) locations were successfully mapped with all protocol criteria met (one sided p value < 0.0001). The median time to move the catheter to a new location was 24 s. The Amigo-related major complication rate was 0 % which was significantly less than the predefined endpoint of 4 % (one-sided p = 0.003). CONCLUSION: We found the Amigo RCS to be safe and effective for positioning a mapping catheter at sites within the right atrium and ventricle. PMID- 23636872 TI - Rapid onset of efficacy of rasagiline in early Parkinson's disease. AB - Rasagiline is a monoamine oxidase type-B inhibitor used as monotherapy or in addition to levodopa in the treatment of Parkinson's disease (PD). This naturalistic single-blind study was aimed at evaluating the rapidity of onset effect of rasagiline on motor symptoms in a cohort of early relatively elderly PD patients. 102 outpatients (55 males, median age 71 years) have been selected: 26 were PD therapy-naive and 76 received rasagiline as add-on therapy. The third section of the Unified Parkinson's Disease Rating Scale (UPDRSIII) and the Hoehn Yahr (HY) scale were assessed at baseline and after 1 and 4 weeks thereafter. The mean UPDRS III total score (-6.7 at week 1 and -8.9 at week 4) and single items, as well as mean HY score (-0.40 at week 1 and -0.67 at week 4), significantly decreased from baseline (p < 0.001). Improvements were significant in both therapy-naive and add-on therapy patients: the mean decreases from baseline to week 4 in UPDRSIII and HY score were -8.8 and -0.46, and -9.0 and -0.74, respectively, in the two subgroups. The mean decrease from baseline in UPDRSIII and HY score did not significantly differ in patients aged > or <=71 years. Rasagiline had a rapid therapeutic effect from the first week of therapy, which further improved at 4 weeks. The rapid onset of action and the absence of a dose titration are important issues in the management of the PD patient. PMID- 23636876 TI - Lucian Freud's reflection (self-portrait). PMID- 23636874 TI - Nasopalpebral lipoma-coloboma syndrome: clinical, radiological, and histopathological description of a novel sporadic case. AB - Nasopalpebral lipoma-coloboma syndrome is an extremely uncommon autosomal dominant condition characterized by congenital upper eyelid and nasopalpebral lipomas, colobomata of upper and lower eyelids, telecanthus, and maxillary hypoplasia. A few familial and sporadic cases of this malformation syndrome have been previously reported. Here, the clinical, radiological, and histopathological features of a sporadic Mexican patient with the nasopalpebral lipoma-coloboma syndrome are described. To our knowledge, this is the first time that craniofacial 3D computed tomography imaging was used for a detailed assessment of the facial lipoma. PMID- 23636878 TI - Cognitive therapy in patients with schizophrenia. PMID- 23636879 TI - Cognitive therapy in patients with schizophrenia-reply. PMID- 23636880 TI - Methylphenidate vs atomoxetine: personalized medicine in attention- deficit/hyperactivity disorder. PMID- 23636881 TI - Cadmium exposure and liver disease among US adults. AB - BACKGROUND: Effects of chronic cadmium exposure on liver disease and liver related mortality are unknown. We evaluated the association of creatinine corrected urinary cadmium levels with hepatic necroinflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver-related mortality, and liver cancer mortality in the US general population. METHODS: We analyzed the relationship of individuals in the top quartile for urinary cadmium measured in 12,732 adults who participated in the Third National Health and Nutrition Examination Survey in 1988-1994 (NHANES III), and hepatic necroinflammation, NAFLD, and NASH. Associations between cadmium, liver-related mortality, and liver cancer mortality were evaluated in the NHANES III mortality follow-up study. RESULTS: The cutoffs for highest quartile of urinary cadmium per gram of urinary creatinine were 0.65 and 0.83 MUg/g for men and women, respectively (P < 0.001). After multivariate adjustment for other factors including smoking, the odds ratios [95 % confidence intervals (CI)] for hepatic necroinflammation, NAFLD, and NASH associated with being in the top quartile of cadmium levels by gender, were 2.21 (95 % CI, 1.64-3.00), 1.30 (95 % CI, 1.01 1.68) and 1.95 (95 % CI, 1.11-3.41) for men and 1.26 (95 % CI, 1.01-1.57), 1.11 (95 % CI, 0.88-1.41) and 1.34 (95 % CI, 0.72-2.50) for women, respectively. The hazard ratios for liver-related mortality and liver cancer mortality for both genders were 3.42 (95 % CI, 1.12-10.47) and 1.25 (95 % CI, 0.37-4.27). CONCLUSIONS: Environmental cadmium exposure was associated with hepatic necroinflammation, NAFLD, and NASH in men, and hepatic necroinflammation in women. Individuals in the top quartile of creatinine-corrected urinary cadmium had over a threefold increased risk of liver disease mortality but not in liver cancer related mortality. PMID- 23636882 TI - Improved long-term survival after esophagectomy for esophageal cancer: influence of epidemiologic shift and neoadjuvant therapy. AB - BACKGROUND: The study was done to determine long-term outcomes of surgically treated esophageal cancer and to identify trends in epidemiology, oncological therapy, and oncological prognosis over the last two decades. METHODS: Overall survival in 304 patients undergoing esophagectomy was analyzed. Fifty-three percent had squamous cell carcinoma and 46 % had adenocarcinoma (AC). A total of 161 patients received neoadjuvant chemoradiation, 38 received neoadjuvant chemotherapy, and 105 were treated with surgery alone. RESULTS: Median survival (MS) increased significantly from 18.0 months (1988-1994) to 26.6 months (1995 2001) and to 59.3 months (2002-2011; p < 0.001). The proportion of AC (22 vs 35 vs 65 %; p < 0.001) and the proportion of patients treated with neoadjuvant therapy (neoT; 15.9 vs 85.3 vs 77.8 %; p < 0.001) increased during the treatment period. After neoT, a beneficial outcome with a MS of 45.6 vs. 20.4 months (p = 0.003) was found. Lymph node ratio [LNR; relative risk (RR), 5.4; p < 0.001], response to neoT (RR, 1.6; p < 0.004), and histological subtype (RR, 1.7; p < 0.003) were identified as independent parameters of survival. CONCLUSION: Since 1988, the outcome of surgically resected esophageal cancer strongly improved. Besides tumorbiological factors like histological type and LNR, the outcome is also affected by the increasing use of neoT towards favorable survival rates. PMID- 23636884 TI - Smart transportation between three phases through a stimulus-responsive functionally cooperating device. AB - A "smart", functionally cooperating device consisting of a platinum strip and steel bead inside a nickel foam cube with a temperature-responsive polymer coating shows a diving-surfacing cycle when the water temperature first falls below and then rises above the lower critical solution temperature (LCST) of the polymer, which marks the change from superhydrophobicity to superhydrophilicity. Furthermore, the smart device allows a cycled directional delivery of lipophilic molecules between three phases. PMID- 23636883 TI - Pancreatic arteriovenous malformation. AB - BACKGROUND: Pancreatic arteriovenous malformation is very rare, but may cause significant clinical symptoms such as catastrophic bleeding. Herein, we discuss the clinical presentation and management of patients pancreatic arteriovenous malformations. METHODS: The data pool for the analysis was collected from pancreatic arteriovenous malformation cases encountered by our institution and sporadic case reports in the English literature. RESULTS: A total of 89 cases of pancreatic arteriovenous malformation were collected for this study, including 59 cases of arteriovenous malformation in the pancreatic head (62.3 %) and 30 in the pancreatic body-tail (33.7 %). The most commonly associated complications for overall cases of pancreatic arteriovenous malformation were bleeding (50.6 %), pancreatitis (16.9 %), portal hypertension (6.7 %), and pseudocyst (3.4 %). The most common presenting symptom of pancreatic arteriovenous malformation was gastrointestinal bleeding (47.2 %), followed by epigastric pain (46.1 %). Surgery (43.8 %) was the most common treatment for pancreatic arteriovenous malformation cases, followed by transarterial embolization (11.2 %), a combination of surgery and transarterial embolization (10.1 %), and radiotherapy (2.2 %). No intervention was done for 29.2 % of the cases of pancreatic arteriovenous malformation. CONCLUSIONS: Pancreatic arteriovenous malformation occurs most commonly in the pancreatic head; gastrointestinal bleeding is the main symptom. Surgical resection or transarterial embolization appears to be indicated in patients with symptomatic pancreatic arteriovenous malformation. PMID- 23636885 TI - Anti-inflammatory activities of crocetin derivatives from processed Gardenia jasminoides. AB - This study was designed to investigate changes of anti-oxidant and anti-nitric oxide (NO) production activities of Gardenia jasminoides (Gj) by roast processing, and anti-inflammatory activities of crocetin derivatives isolated from Gj. In order to evaluate anti-oxidant and anti-inflammatory activities, DPPH radical scavenging activities and inhibitory activities against lipopolysaccharide (LPS)-induced NO production were determined. Then we isolated crocin (1), gentiobiosyl glucosyl crocetin (3), and mono-gentiobiosyl crocetin (4) from the fruit of Gj, and crocetin (2) from the processed fruit of Gj (PGj) by column chromatography. Their structures were based on spectroscopic methods including IR, MS, and NMR (1D and 2D). Then we assayed contents of crocetin derivatives by HPLC analysis. These crocetin derivatives were evaluated the inhibitory activities on NO production in LPS-stimulated macrophage RAW 264.7 cells and expressions of protein and m-RNA of iNOS and COX-2 by western blot analysis and RT-PCR experiment. The DPPH radical scavenging activities were increased and NO productions in LPS-stimulated RAW 264.7 cells were decreased dose-dependently by processing. Crocin contents were decreased and crocetin contents were increased by processing in HPLC analysis. Compounds 1, 2, 3 and 4 reduced NO production in a dose-dependent manner with IC50 values of 58.9 MUM (1), 29.9 MUM (2), 31.1 MUM (3), and 37.6 MUM (4) respectively. Crocetin (2) showed the most potent anti-inflammatory activity (IC50 = 29.9 MUM), and compound 3 and 4 were firstly measured for inhibitory activities on NO production. Their correlation between structure and activity was not clear but the activity of aglycone type showed the most potent activity. They also suppressed the protein and m-RNA expressions of iNOS and COX-2 in LPS-activated macrophage. These results suggest that anti-oxidant and anti-NO production activities of Gj were increased by processing, and increased anti-inflammatory activities of Gj by processing were due to the increase of crocetin, the aglycone that has greater activity than crocin. PMID- 23636888 TI - [Simple measures for the prevention of nosocomial infections]. PMID- 23636886 TI - Statistical optimization of a multivariate fermentation process for enhancing antibiotic activity of Streptomyces sp. CS392. AB - Antibiotic activity against various gram positive bacteria including Staphylococcus aureus and Enterococcus was ascertained from a soil-isolated microbial strain Streptomyces sp. CS392. The antibiotic activity of the strain was maximized by using a dual-stage, multivariate statistical optimization framework based on the response surface methodology considering a lab-scale fermentation process. Multiple nutrient constituents of the fermentation broth were jointly optimized in the first stage, while the fermentation culture conditions were optimized in the subsequent stage. Based on the empirical models derived from the dual-stage statistical optimization framework, 39.79 % of cumulative enhancement in the antibiotic activity was obtained (analytically) at the concurrent optimal settings (Optimal nutrient composition for the first stage of optimization: 29.82 glucose, 7.6 peptone, 4.678 MgCl2 and 0.5005 g/l casamino acid; and optimal fermentation condition for the second stage of optimization: incubation period 47.55 h; incubation temperature 29.15 degrees C; and pH 8.36). The analytically depicted enhancement in the antibiotic activity was validated experimentally. PMID- 23636889 TI - [Trauma with involvement of the posterior segment of the eye--part 2]. PMID- 23636887 TI - PhenoTips: patient phenotyping software for clinical and research use. AB - We have developed PhenoTips: open source software for collecting and analyzing phenotypic information for patients with genetic disorders. Our software combines an easy-to-use interface, compatible with any device that runs a Web browser, with a standardized database back end. The PhenoTips' user interface closely mirrors clinician workflows so as to facilitate the recording of observations made during the patient encounter. Collected data include demographics, medical history, family history, physical and laboratory measurements, physical findings, and additional notes. Phenotypic information is represented using the Human Phenotype Ontology; however, the complexity of the ontology is hidden behind a user interface, which combines simple selection of common phenotypes with error tolerant, predictive search of the entire ontology. PhenoTips supports accurate diagnosis by analyzing the entered data, then suggesting additional clinical investigations and providing Online Mendelian Inheritance in Man (OMIM) links to likely disorders. By collecting, classifying, and analyzing phenotypic information during the patient encounter, PhenoTips allows for streamlining of clinic workflow, efficient data entry, improved diagnosis, standardization of collected patient phenotypes, and sharing of anonymized patient phenotype data for the study of rare disorders. Our source code and a demo version of PhenoTips are available at http://phenotips.org. PMID- 23636890 TI - [Trauma with involvement of the posterior segment of the eye--part 1]. PMID- 23636891 TI - Expressions of tumor necrosis factor alpha and microRNA-155 in immature rat model of status epilepticus and children with mesial temporal lobe epilepsy. AB - Recently, the role of inflammation has attracted great attention in the pathogenesis of mesial temporal lobe epilepsy (MTLE), and microRNAs start to emerge as promising new players in MTLE pathogenesis. In this study, we investigated the dynamic expression patterns of tumor necrosis factor alpha (TNF alpha) and microRNA-155 (miR-155) in the hippocampi of an immature rat model of status epilepticus (SE) and children with MTLE. The expressions of TNF-alpha and miR-155 were significantly upregulated in the seizure-related acute and chronic stages of MTLE in the immature rat model and also in children with MTLE. Modulation of TNF-alpha expression, either by stimulation using myeloid-related protein (MRP8) or lipopolysaccharide or inhibition using lenalidomide on astrocytes, leads to similar dynamic changes in miR-155 expression. Our study is the first to focus on the dynamic expression pattern of miR-155 in the immature rat of SE lithium-pilocarpine model and children with MTLE and to detect their relationship at the astrocyte level. TNF-alpha and miR-155, having similar expression patterns in the three stages of MTLE development, and their relationship at the astrocyte level may suggest a direct interactive relationship during MTLE development. Therefore, modulation of the TNF-alpha/miR-155 axis may be a novel therapeutic target for the treatment of MTLE. PMID- 23636892 TI - In vivo expression of the Arf6 Guanine-nucleotide exchange factor cytohesin-1 in mice exhibits enhanced myelin thickness in nerves. AB - The myelin sheath consists of a unique multiple layer structure that acts as an insulator between neuronal axons to enhance the propagation of the action potential. In neuropathies such as demyelinating or dismyelinating diseases, chronic demyelination and defective remyelination occur repeatedly, leading to more severe neuropathy. As yet, little is known about the possibility of drug target-specific medicine for such diseases. In the developing peripheral nervous system (PNS), myelin sheaths form as Schwann cells wrap individual axons. It is thought that the development of a drug promoting myelination by Schwann cells would provide effective therapy against peripheral nerve disorders: to test such treatment, genetically modified mice overexpressing the drug target molecules are needed. We previously identified an Arf6 activator, the guanine-nucleotide exchange factor cytohesin-1, as the signaling molecule controlling myelination of peripheral axons by Schwann cells; yet, the important issue of whether cytohesin 1 itself promotes myelin thickness in vivo has remained unclear. Herein, we show that, in mouse PNS nerves, Schwann cell-specific expression of wild-type cytohesin-1 exhibits enhanced myelin thickness. Downstream activation of Arf6 is also seen in these transgenic mice, revealing the involvement of the cytohesin-1 and Arf6 signaling unit in promoting myelination. These results suggest that cytohesin-1 may be a candidate for the basis of a therapy for peripheral neuropathies through its enhancement of myelin thickness. PMID- 23636893 TI - Neuroprotective effect of leukemia inhibitory factor on antimycin A-induced oxidative injury in differentiated PC12 cells. AB - As a neurotrophic cytokine, leukemia inhibitory factor (LIF) has neuroendocrine effects and exerts neuroprotective effects on various neuron injuries both in vitro and in vivo. The aim of the present study was to investigate whether LIF can protect PC12 cells from antimycin A (AMA)-induced oxidative stress. LIF (0.5 and 1 ng/ml) increased PC12 cell viability and significantly attenuated AMA induced cell death as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Results from Hoechst 33342 staining and flow cytometry assay showed that AMA induced apoptosis significantly in PC12 cells, while pretreatment with LIF (0.5 and 1 ng/ml) can attenuate this injury. The presence of LIF partly prevented AMA-induced elevated reactive oxygen species level and decreased superoxide dismutase level, which indicated the antioxidative effects of LIF on the neuron oxidative injury. In conclusion, LIF might protect PC12 cells from the injury induced by AMA through the downregulation of oxidative stress, which may provide basic information of using LIF as a potential targeted therapy for oxidative injury in neurons. PMID- 23636895 TI - The role of pelvic and perineal striated muscles in urethral function during micturition in female rabbits. AB - AIM: To evaluate the role of pelvic and perineal striated muscles on urethral function during micturition. METHODS: Pubococcygeus, or both bulbospongiosus and ischiocavernosus muscles were electrically stimulated during the voiding phase of micturition, and bladder and urethral pressure were simultaneously recorded in urethane anesthetized female rabbits. Bladder and urethral function were assessed measuring urodynamic and urethral pressure variables obtained before and during the stimulation of muscles. Two-tail paired t-tests were carried out in order to determine significant differences (P < 0.05) between groups. RESULTS: Electric stimulation of the pubococcygeus during voiding decreased voiding efficiency and voided volume, whereas residual volume, the duration of voiding, the interval between bladder contraction and urethral resistance increased. Simultaneously, there was an increase in maximum urethral pressure, as well as an increase in the pressure to return to baseline and in the pressure required to close the urethra. Electrical stimulation of bulbospongiosus and ischiocavernosus muscles increased voiding efficiency, voiding duration, and the maximal pressure in bladder. Meanwhile, the maximal urethral pressure, the time related to the rise of urethral pressure, and the urethral pressure required to close the urethra decreased. CONCLUSIONS: The stimulation of pelvic and perineal muscles have opposing roles in urethral function during micturition. Pubococcygeus muscles facilitate urethral closure, while they inhibit bladder contraction. In contrast, bulbospongiosus and ischiocavernosus muscles prevent urethral contraction while they promote bladder contraction. PMID- 23636894 TI - Web-enabled feedback control over energy balance promotes an increase in physical activity and a reduction of body weight and disease risk in overweight sedentary adults. AB - This study aims to investigate whether a Web-based tool will facilitate the adoption of feedback control over calorie balance in overweight individuals, thereby promoting an increase of physical activity and a reduction of body weight and cardiovascular risk factors. This is a prospective exercise intervention study, commencing with a minimum weekly 3 * 20-min requirement of high-intensity interval training and requirement for Web-based self-monitoring and self reporting of exercise and body weight. Subjects of this study include 83 overweight, sedentary, otherwise healthy adults aged 26-68 years. Anthropometric parameters, body fat, peak oxygen consumption, self-reported physical activity, frequency of use of the Web-based tool are among the characters measured in this study. This 24-week intervention substantially increased time spent for exercise (mean and median of 135 and 170 min/week, respectively) among the 72 % of participants who had adopted cognitive feedback control vs. no increase in the remaining participants of nonadopters. Adopters witnessed significantly improved peak oxygen consumption of >1 metabolic equivalent vs. no improvement among nonadopters. Adopters also reduced body mass index, body weight, and body fat by 1.6 kg/m(2), 4.8 kg, and 3.6 kg, respectively vs. 0.4 kg/m(2), 1.4 kg, and 1.1 kg in the control group. The increase in physical activity came at virtually no intervention effort of the investigators. This study demonstrates for the first time that adoption of cognitive feedback control over energy balance is possible with the help of a simple Web-based tool and that overweight adopters self regulate exercise volume to significantly reduce body weight and improve biomarkers of fitness and cardiovascular risk. PMID- 23636896 TI - Utilization and outcomes of inpatient surgical care at critical access hospitals in the United States. AB - IMPORTANCE: There is a growing interest in the quality and cost of care provided at Critical Access Hospitals (CAHs), a predominant source of care for many rural populations in the United States. OBJECTIVE: To evaluate utilization, outcomes, and costs of inpatient surgery performed at CAHs. DESIGN, SETTING, AND PATIENTS: A retrospective cohort study of patients undergoing inpatient surgery from 2005 through 2009 at CAHs or non-CAHs was performed using data from the Nationwide Inpatient Sample and American Hospital Association. EXPOSURE: The CAH status of the admitting hospital. MAIN OUTCOMES AND MEASURES: In-hospital mortality, prolonged length of stay, and total hospital costs. RESULTS: Among the 1283 CAHs and 3612 non-CAHs reporting to the American Hospital Association, 34.8% and 36.4%, respectively, had at least 1 year of data in the Nationwide Inpatient Sample. General surgical, gynecologic, and orthopedic procedures composed 95.8% of inpatient cases at CAHs vs 77.3% at non-CAHs (P < .001). For 8 common procedures examined (appendectomy, cholecystectomy, colorectal cancer resection, cesarean delivery, hysterectomy, knee replacement, hip replacement, and hip fracture repair), mortality was equivalent between CAHs and non-CAHs (P > .05 for all), with the exception that Medicare beneficiaries undergoing hip fracture repair in CAHs had a higher risk of in-hospital death (adjusted odds ratio = 1.37; 95% CI, 1.01-1.87). However, despite shorter hospital stays (P <= .001 for 4 procedures), costs at CAHs were 9.9% to 30.1% higher (P < .001 for all 8 procedures). CONCLUSIONS AND RELEVANCE: In-hospital mortality for common low-risk procedures is indistinguishable between CAHs and non-CAHs. Although our findings suggest the potential for cost savings, changes in payment policy for CAHs could diminish access to essential surgical care for rural populations. PMID- 23636898 TI - Cytologic findings and differential diagnoses of primary thyroid MALT lymphoma with striking plasma cell differentiation and amyloid deposition. AB - We report two cases of thyroid mucosa-associated lymphoid tissue (MALT) lymphoma with associated amyloid protein deposition. While other primary thyroid neoplasms sush as medullary carcinoma and plasmacytoma with associated amyloid protein are known to occur and have been previously described by fine-needle aspiration cytology (FNAC), to our knowledge, the current cases are the first of thyroid MALT lymphoma with amyloid deposition to be detailed in the cytopathology literature. Case 1 was a 73-year-old female with chronic thyroiditis. FNAC suspected MALT lymphoma. The amyloid material was not noticed, nevertheless it existed. Case 2 was a 71-year-old female with a nodule of the thyroid. Malignant lymphoma and medullary carcinoma were suspected by FNAC. The possibility of medullary carcinoma was excluded by a measurement of serum calcitonin and carcinoembryonic antigen. After follow-up for two years, the nodule was diagnosed as MALT lymphoma associated with plasma cell differentiation and amyloidosis by the fourth FNAC. When we encounter small round cell tumors associated with amyloid in thyroid FNAC, we should consider not only medullary carcinoma but also MALT lymphoma. PMID- 23636899 TI - Small molecule inhibitors of West Nile virus. AB - West Nile virus (WNV) is a human pathogen which is rapidly expanding worldwide. It is a member of the Flavivirus genus and it is transmitted by mosquitos between its avian hosts and occasionally in mammalian hosts. In humans the infection is often asymptomatic, however, the most severe cases result in encephalitis or meningitis. Approximately 10% of cases of neuroinvasive disease are fatal. To date there is no effective human vaccine or effective antiviral therapy available to treat WNV infections. For this reason, research in this field is rapidly growing. In this article we will review the latest efforts in the design and development of novel WNV inhibitors from a medicinal chemistry point of view, highlighting challenges and opportunities for the researchers working in this field. PMID- 23636897 TI - Molecular identification of bacterial DNA in the chorioretinal scars of chronic granulomatous disease. AB - PURPOSE: Chronic granulomatous disease (CGD) is an inherited disorder characterized by defects in phagocyte-derived nicotinamide adenine dinucleotide phosphate oxidase. It is typically diagnosed in childhood and leads to severe, recurrent bacterial or fungal infections. Chorioretinal lesions are the most common ocular manifestation. We sought to determine whether there are infectious agents in CGD-associated chorioretinopathy. METHODS: Medical records and ocular histopathology from CGD cases from January 1983 to January 2012 at the National Institutes of Health were retrospectively reviewed. Chorioretinal cells from normal and lesional tissues of the same eye were microdissected. Primers for Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia sp., and a panbacterial 16S ribosomal DNA were used for polymerase chain reaction. RESULTS: Seventeen CGD patients had ocular tissues (16 autopsied cases and 1 chorioretinal biopsy) examined. Of these 17, 8 demonstrated CGD associated chorioretinal lesions in at least one eye on histopathology. Of these 8, 7 showed amplification of 16S ribosomal DNA within the lesion; of these 7, two also amplified S. epidermidis and one P. aeruginosa. One had no bacterial DNA amplified. Importantly, no microbial DNA was amplified from the normal, non lesional ocular tissues of these 8 cases. Furthermore, only 1 of the 9 eyes without chorioretinopathy had amplified Burkholderia DNA, that patient had a history of Burkholderia infection. CONCLUSIONS: We detected bacterial DNA in 7 of 8 (88%) cases with CGD-associated chorioretinopathy and only in 1 normal ocular tissue of 17 CGD cases. Bacterial infection may play a role in the pathogenesis of CGD-associated chorioretinal lesions. PMID- 23636900 TI - Adolescents with anxiety and depression: is social recovery relevant? AB - Social recovery has become a prominent aspect of mental health service design and delivery in the past decade. Much of the literature on social recovery is derived from first-person accounts or primary research with adult service users experiencing severe mental illness. There is a lack of both theoretical and empirical work that could inform consideration of how the concept of social recovery might apply to adolescents experiencing common (non-psychotic) mental health problems such as anxiety and depression. The current study was conducted to understand the process of experiencing anxiety and depression in young people. Semi-structured interviews were conducted with nine adolescents with anxiety and depression (seven girls and two boys aged 14-16 years) and 12 mothers who were recruited from a specialist Child and Adolescent Mental Health Service in the South of England. Thematic analysis indicated that young people do experience a process of 'recovery'; the processes participants described have some congruence with the earlier stages of adult recovery models involving biographical disruption and the development of new meanings, in this case of anxiety or depression, and changes in sense of identity. The accounts diverge with regard to later stages of adult models involving the development of hope and responsibility. The findings suggest that services should attend to social isolation and emphasise support for positive aspirations for future selves whilst also attending to young people's and parents' expectations about change. Methodological challenges face enquiry about 'recovery' given its connotations with cure in everyday language. KEY PRACTITIONER MESSAGE: Theoretical and empirical work on social recovery in young people and families is lacking. Using interviews, this study sought to understand the relevance of social recovery for adolescents with anxiety and depression and their mothers. Findings suggest some congruence with the earlier stages of adult recovery models involving meaning and identity. Findings diverge with regard to later stages of adult recovery models involving hope and responsibility. Social recovery in mental health services for young people needs significant empirical attention and critical debate. PMID- 23636901 TI - Efficient light harvesting with micropatterned 3D pyramidal photoanodes in dye sensitized solar cells. AB - 3D TiO2 photoanodes in dye-sensitized solar cells (DSCs) are fabricated by the soft lithographic technique for efficient light trapping. An extended strategy to the construction of randomized pyramid structure is developed by the conventional wet-etching of a silicon wafer for low-cost fabrication. Moreover, the futher enhancement of light absorption resulting in photocurrent increase is achieved by combining the 3D photoanode with a conventional scattering layer. PMID- 23636902 TI - Paternal inheritance of classic X-linked bilateral periventricular nodular heterotopia. AB - Periventricular nodular heterotopia (PNH) is a developmental disorder of the central nervous system, characterized by heterotopic nodules of gray matter resulting from disturbed neuronal migration. The most common form of bilateral PNH is X-linked dominant inherited, caused by mutations in the Filamin A gene (FLNA) and associated with a wide variety of other clinical findings including congenital heart disease. The typical patient with FLNA-associated PNH is female and presents with difficult to treat seizures. In contrast, hemizygous FLNA loss of function mutations in males are reported to be perinatally lethal. In X-linked dominant traits like FLNA-associated PNH the causal mutation is commonly inherited from the mother. Here, we present an exceptional family with paternal transmission of classic bilateral FLNA-associated PNH from a mildly affected father with somatic and germline mosaicism for a c.5686G>A FLNA splice mutation to both daughters with strikingly variable clinical manifestation and PNH extent in cerebral MR imaging. Our observations emphasize the importance to consider in genetic counseling and risk assessment the rare genetic constellation of paternal transmission for families with X-linked dominant inherited FLNA-associated PNH. PMID- 23636905 TI - A case of delivery of healthy infant in breast cancer patient incidentally treated with goserelin acetate and tamoxifen during pregnancy. AB - In September 2000, a 32-year-old woman presented to our hospital with a right breast mass. In September 2000, she underwent pectoral muscle-preserving mastectomy for the treatment of right breast cancer. Pathologyy results revealed a mucinous carcinoma 27 * 20 * 18 mm in size accompanied by an extensive intraductal component. The tumor was staged as T2 N1M0 stage IIB and found to be estrogen receptor-positive, and 6 cycles of postoperative adjuvant chemotherapy consisting of 5-fluorouracil, epirubicin, and cyclophosphamide were carried out. Goserelin acetate plus tamoxifen was prescribed from April 2001 to March 2005. Since the patient received tamoxifen from April 2005 and eumenorrhea started in June 2006, goserelin acetate plus tamoxifen was started in August 2006. The patient was determined to be 25 weeks pregnant by abdominal ultrasonography in February 2007. This meant that she had been taking goserelin acetate plus tamoxifen for 6 months without realizing she was pregnant. She gave birth to a girl by cesarean section in May 2007. No abnormalities, including anomaly of the genitalia, were seen, and the subsequent growth of the infant was also satisfactory. We here report this case and a brief review of the literature. PMID- 23636904 TI - Proteogenomics for environmental microbiology. AB - Proteogenomics sensu stricto refers to the use of proteomic data to refine the annotation of genomes from model organisms. Because of the limitations of automatic annotation pipelines, a relatively high number of errors occur during the structural annotation of genes coding for proteins. Whether putative orphan sequences or short genes encoding low-molecular-weight proteins really exist is still frequently a mystery. Whether start codons are well defined is also an open debate. These problems are exacerbated for genomes of microorganisms belonging to poorly documented genera, as related sequences are not always available for homology-guided annotation. The functional annotation of a significant proportion of genes is also another well-known issue when annotating environmental microorganisms. High-throughput shotgun proteomics has recently greatly evolved, allowing the exploration of the proteome from any microorganism at an unprecedented depth. The structural and functional annotation process may be usefully complemented with experimental data. Indeed, proteogenomic mapping has been successfully performed for a wide variety of organisms. Specific approaches devoted to systematically establishing the N-termini of a large set of proteins are being developed. N-terminomics is giving rise to datasets of experimentally proven translational start codons as well as validated peptide signals for secreted proteins. By extension, combining genomic and proteomic data is becoming routine in many research projects. The proteomic analysis of organisms with unfinished genome sequences, the so-called composite proteomics, and the search for microbial biomarkers by bottom-up and top-down combined approaches are some examples of proteogenomic-flavored studies. They illustrate the advent of a new era of environmental microbiology where proteomics and genomics are intimately integrated to answer key biological questions. PMID- 23636903 TI - When does nutrition impact respiratory function? AB - Nutrition therapy is an essential aspect of patient care and an important determinant of outcomes in the ICU. Nutrition can impact respiratory function in a myriad of ways. Under- and overfeeding are two well-established ways by which nutrition impinges on respiratory function. Route of feeding, method of feeding, and carbohydrate composition of the diet are also other key factors regarding nutrition that influence outcomes in ICU patients. Recent studies are now elucidating the role of immune therapy in patients with acute respiratory distress syndrome. In the ICU, nutrition dogmas, such as the necessity of checking gastric residual volumes or utilizing full-calorie enteric feeds, as opposed to trophic feeds, are constantly being challenged by innovative clinical studies. Basic research brings the prospect of testing new approaches for ICU patients, such as the use of antioxidants to prevent diaphragm weakness in these patients. In this review article, we evaluate the recent observational and randomized control trials to critically appraise the evidence regarding nutrition in the ICU. PMID- 23636906 TI - Correlation between catechin content and NF-kappaB inhibition by infusions of green and black tea. AB - This study investigates whether infusions of green and black tea inhibit the NF kappaB driven transcription in human epithelial gastric AGS cells. Water extracts were prepared from different brands of green and black tea available on the Italian market. Teas with or without caffeine were studied. An industrially prepared freeze-dried water extract of green tea was also tested. Catechin and caffeine contents were measured by HPLC analysis. The decrease in phenol and catechin content three months after the expiry date was also investigated. The NF kappaB driven transcription and the free radical scavenger activity were inhibited, and this effect was related to catechin levels. The potency of epigallocatechin 3-gallate in inhibiting NF-kappaB driven transcription is so great that tea extracts low in epigallocatechin 3-gallate are still highly active. In one decaffeinated sample of green tea, the phenol and catechin content was very low, probably as a consequence of caffeine removal. The decrease in catechin levels after 3 months did not reduce the inhibition of NF-kappaB driven transcription by tea infusions. This is the first paper reporting the inhibitory effect of NF-kappaB of commercial green and black infusions at the gastric level, evaluating their stability as well. PMID- 23636907 TI - Single-nucleotide polymorphism-array improves detection rate of genomic alterations in core-binding factor leukemia. AB - Acute myeloid leukemia (AML) is a group of clonal diseases, resulting from two classes of mutation. Investigation for additional abnormalities associated with a well-recognized subtype, core-binding factor AML (CBF-AML) can provide further understanding and discrimination to this special group of leukemia. In order to better define genetic alterations in CBF-AML and identify possible cooperating lesions, a single-nucleotide polymorphism-array (SNP-array) analysis was performed, combined to KIT mutation screening, in a set of cases. Validation of SNP-array results was done by array comparative genomic hybridization and FISH. Fifteen cases were analyzed. Three cases had microscopic lesions better delineated by arrays. One case had +22 not identified by arrays. Submicroscopic abnormalities were mostly non-recurrent between samples. Of relevance, four regions were more frequently affected: 4q28, 9p11, 16q22.1, and 16q23. One case had an uncovered unbalanced inv(16) due to submicroscopic deletion of 5'MYH11 and 3'CBFB. Telomeric and large copy number neutral loss of heterozygosity (CNN-LOH) regions (>25 Mb), likely representing uniparental disomy, were detected in four out of fifteen cases. Only three cases had mutation on KIT gene, enhancing the role of abnormalities by SNP-array as presumptive cooperating alterations. Molecular karyotyping can add valuable information to metaphase karyotype analysis, emerging as an important tool to uncover and characterize microscopic, submicroscopic genomic alterations, and CNN-LOH events in the search for cooperating lesions. PMID- 23636909 TI - Conversion of local anesthesia-guided deep brain stimulation of the subthalamic nucleus to general anesthesia. AB - BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN) is a widely applied procedure in the treatment of patients with advanced Parkinson disease and is generally performed under local anesthesia. Here we report our experience with the conversion to general anesthesia in two patients with advanced Parkinson disease because of fear reactions intraoperatively. CASE DESCRIPTION: Patients received general anesthesia with propofol and were implanted with electrodes at the level of STN guided by multiple-microelectrode electrophysiological recordings after obtaining informed consent. During the recordings the propofol levels were reduced. Postoperative clinical assessments showed marked improvements of motor disability with significant reductions of dopaminergic medication. CONCLUSION: Our case observations document the possibility of fear reactions intraoperatively and show the possibility of conversion to general anesthesia with a successful outcome. PMID- 23636908 TI - Demographic and clinico-pathological characteristics in patients with invasive breast cancer receiving metformin. AB - There was a contradictory data with metformin use on breast cancer risk, but there is growing evidence that the use of metformin in diabetic patients was associated with lower risks of breast cancer mortality and incidence. The effect of metformin on clinical and pathological properties of breast cancer was not known exactly, and we aimed to investigate the demographic and clinico pathological characteristics of patients with metformin users at the time of breast cancer diagnosis. Patients with breast cancer diagnosed from 2000 to 2012 in our clinic were retrospectively analyzed. Patient's demographics, including survival data and tumor characteristics were obtained from medical charts. Breast cancer patients who were taking metformin at the time of breast cancer diagnosis were enrolled as metformin users (n = 148), where the patients matched with the same age who were not taking metformin were included as a control group (n = 636). A total of 784 patients were included in this study. Median age of both metformin users and nonusers was 57 (23-87). There were no significant differences in baseline tumor size (P = 0.60), tumor stage (P = 0.76), and node positivity (P = 0.13) between the two groups. Metformin user patients compared to nonusers had significantly lower incidence of histological grade III tumor (P = 0.03). A similar significant trend for lower incidence of triple negative (P = 0.01) and higher incidence ER positivity (P = 0.008) and PR positivity (P = 0.01) was also seen in metformin users. In survival analysis, the estimated median disease-free survival was 118 months in metformin users, whereas 69 months in nonusers (P = 0.09). Median overall survival (OS) could not be obtained due to low events. In patients with metformin users, OS rate was 98.4, 97.1, and 93.8 %, and in nonusers was 99.6, 94.4, and 90.5 %, the first, third, and fifth years, respectively. The use of metformin at the time of breast cancer diagnosis was associated with better clinico-pathological properties and nonsignificantly improved disease-free survival in breast cancer patients. PMID- 23636911 TI - A preliminary study of using active vision guided robotic arm for bone drilling in a developing country. AB - BACKGROUND: The study assesses the capability and accuracy of a robotic arm to perform burr holes. MATERIAL AND METHODS: The robotic systems are instructed to recognize targets on artificial skull models placed in different positions and to make burr holes. RESULTS: The accuracy ranged from 0.1 to 1.0 mm. CONCLUSION: Robotic arms are capable to perform basic surgical tasks. However, further improvement needs to be done to refine its accuracy and capability. PMID- 23636910 TI - Neuronavigation-assisted endoscopic unilateral cyst fenestration for treatment of symptomatic septum pellucidum cysts. AB - BACKGROUND: Traditional surgical treatments for this rare disease include open surgical procedures and ventriculoperitoneal shunting. In 1995, endoscopic fenestration was first applied to treatment of cysts of the septum pellucidum (CSP). However, cyst fenestration generally takes a bilateral approach by making two burr holes leading to two fenestrations in the lateral walls of the cyst. Some disadvantages are related to bilateral fenestration. So far, there is no consensus on the surgical indications, the endoscopic approaches, and techniques for CSPs. Based on our experience with 14 cases of symptomatic CSP treated with neuronavigation-assisted endoscopic unilateral cyst fenestration via a single burr hole, we discuss the operative indications and the utility of endoscope assisted techniques in combination with neuronavigation. METHODS: 14 patients underwent endoscopic CSP fenestration via a right frontal approach using a rigid endoscope and neuronavigation. Neuronavigation helped locating optimal skin incision, puncture point, optimal operation trajectory, and real-time operation monitoring. Postoperatively, a follow-up study on the 14 patients was performed. RESULTS: The follow-up period ranged from 6 months to 2 years. Postoperatively, the mass effect of the cysts and the self-reported symptoms disappeared immediately. In 7 patients with papilledema, the optic fundus examinations showed that papilledema improved. The computerized tomography (CT) or magnetic resonance imaging (MRI) scans showed significant decrease in the cyst size and no recurrence during the follow-up. In 2 patients with accompanying hydrocephalus, the hydrocephalus disappeared. CONCLUSION: The results after uni- and bilateral CSP fenestration show no significant difference. Avoiding damage of contralateral tissue, the surgical trauma in unilateral fenestration is less than in bilateral fenestration. Furthermore, the unilateral approach shortens the operation time. We believe that unilateral cyst fenestration is a better therapeutic option in symptomatic CSP. PMID- 23636912 TI - Liver toxicity with clozapine. PMID- 23636913 TI - The role of inflammatory cytokines on the aetiopathogenesis of depression. AB - OBJECTIVE: The primary focus of this review is to provide an overview of the role of inflammation in the development of depression. The article will describe how inflammatory cytokines contribute to depression via action on three major pathways in the brain: the neuroendocrine; neurotransmitter depletion; and neuroprogression pathways. METHODS: An online literature search was carried out in July 2012. Original articles and reviews were selected if they discussed the role of inflammation on the development of depression. RESULTS: There is a large body of current research on the role of inflammatory cytokines on the development of depression. Cytokines have been found to interact with different pathways in the brain, and may contribute to the development of depression. Cytokines cause hypercortisolaemia by dysregulation of the hypothalamic-pituitary-adrenal axis directly by activating it and indirectly by modifying glucocorticoid receptor sensitivity to cortisol leading to cortisol hypersecretion. Cytokines deplete central synaptic serotonin levels by reducing its synthesis and increasing its reuptake. They may also deplete neurotrophic factors which are believed to play a neuroprotective role against depression. Cytokines activate cellular cascades that cause excitotoxicity and apoptosis and inhibit neurogenesis in the hippocampus. CONCLUSION: There is a growing body of correlative studies that suggest inflammatory cytokines may be a central factor that can affect multiple neuronal pathways and have an additive effect on the development of depression. However, the fact that not all people with inflammatory conditions suffer from depression suggests that depression is not purely a result of elevated inflammatory cytokines. Depression may be a result of a complex pathology that remains an area of growing interest and importance. PMID- 23636914 TI - Shifting the paradigm for promoting appropriate antibiotic use. PMID- 23636915 TI - Hemorrhagic shock due to spontaneous pectoral hematoma associated with anticoagulation therapy. PMID- 23636916 TI - Migraine prophylaxis: which drugs work and which ones don't. PMID- 23636917 TI - An anatomical explanation for "urodynamic features and artefacts": re: Hogan S, Gammie A, Abrams P. Urodynamic features and artefacts. Neurourol Urodyn 2012; 31:1104-17. PMID- 23636918 TI - A review of uncommon swelling provides useful reminders. PMID- 23636920 TI - A young woman with enlarged lymph nodes. PMID- 23636919 TI - Not all joint pain is arthritis. PMID- 23636921 TI - Hyperpigmented patches on the neck, shoulder, and back. PMID- 23636922 TI - Recognizing and managing hereditary angioedema. AB - Hereditary angioedema is a rare but life-threatening disease characterized by recurring attacks of swelling of any part of the body, without hives. Prompt recognition is critical so that treatment can be started to minimize morbidity and the risk of death. Drugs have recently become available to prevent and treat acute attacks. PMID- 23636923 TI - Preserving fertility in female cancer patients: a snapshot of the options. AB - With the odds of surviving cancer improving, many young women facing chemotherapy or radiotherapy may first wish to take steps to ensure that they will still be able to bear children afterward. The options depend on the type of disease, the treatment required, the age of the patient, whether she has a long-term partner, and whether cancer treatment can be delayed. This paper is an overview of current and experimental strategies for preserving fertility in female cancer patients. PMID- 23636924 TI - Aspirin: its risks, benefits, and optimal use in preventing cardiovascular events. AB - Aspirin has a well-established role in preventing adverse events in patients with known cardiovascular disease. However, its benefit in patients without a history of cardiovascular disease is not as clear, particularly in people with diabetes, in women, and in the elderly. Recent studies have provided insight into the risks of aspirin use, particularly bleeding, compared with its benefits in these subgroups. PMID- 23636925 TI - Treatment of posttraumatic stress disorder reduces suicidal ideation. AB - BACKGROUND: Suicide is a significant public health problem. Although various studies have found evidence of posttraumatic stress disorder (PTSD) as a risk factor for suicidal behaviors, no study has examined whether or not PTSD treatment decreases suicidal thoughts. This study aims to fill this gap in the literature by examining changes in suicidal ideation over the course of a randomized clinical trial, which compared two widely used treatments for PTSD cognitive processing therapy (CPT) and prolonged exposure (PE). METHODS: Data from 163 trial participants over five time points (pre- and posttreatment, 3 and 9 months posttreatment, and 5-10 years posttreatment) were examined using multilevel growth curve analyses to determine if reductions in PTSD symptoms during treatment were associated with reductions in suicidal ideation. Major depression diagnosis and hopelessness were controlled. RESULTS: Suicidal ideation decreased sharply during treatment with continued, but more subtle decreases, during the follow-up period. These decreases were associated with decreases in PTSD symptoms over the course of treatment. These associations were not accounted for by depression diagnoses at the start of the study or changes in hopelessness over the course of treatment. CONCLUSIONS: Two widely used, effective treatments for PTSD reduce suicidal ideation. CPT exhibited a larger influence on suicidal ideation than PE, although the magnitude of the difference was small in size. Inclusion of PTSD screening and treatment could enhance suicide prevention efforts. PMID- 23636926 TI - Diagnostic screening identifies a wide range of mutations involving the SHOX gene, including a common 47.5 kb deletion 160 kb downstream with a variable phenotypic effect. AB - Leri-Weill dyschondrosteosis (LWD) results from heterozygous mutations of the SHOX gene, with homozygosity or compound heterozygosity resulting in the more severe form, Langer mesomelic dysplasia (LMD). These mutations typically take the form of whole or partial gene deletions, point mutations within the coding sequence, or large (>100 kb) 3' deletions of downstream regulatory elements. We have analyzed the coding sequence of the SHOX gene and its downstream regulatory regions in a cohort of 377 individuals referred with symptoms of LWD, LMD or short stature. A causative mutation was identified in 68% of the probands with LWD or LMD (91/134). In addition, a 47.5 kb deletion was found 160 kb downstream of the SHOX gene in 17 of the 377 patients (12% of the LWD referrals, 4.5% of all referrals). In 14 of these 17 patients, this was the only potentially causative abnormality detected (13 had symptoms consistent with LWD and one had short stature only), but the other three 47.5 kb deletions were found in patients with an additional causative SHOX mutation (with symptoms of LWD rather than LMD). Parental samples were available on 14/17 of these families, and analysis of these showed a more variable phenotype ranging from apparently unaffected to LWD. Breakpoint sequence analysis has shown that the 47.5 kb deletion is identical in all 17 patients, most likely due to an ancient founder mutation rather than recurrence. This deletion was not seen in 471 normal controls (P<0.0001), providing further evidence for a phenotypic effect, albeit one with variable penetration. PMID- 23636928 TI - Realizing ultrahigh modulus and high strength of macroscopic graphene oxide papers through crosslinking of mussel-inspired polymers. AB - Covalently crosslinked graphene oxide papers (GOPs) with enhanced mechanical properties are prepared by a strategy involving crosslinking by means of intercalated polymers. The strength and modulus of the crosslinked GOPs increase by 115% and 550%, respectively, compared to the pristine GOPs. These results broaden the potential applications of graphene, and the crosslinking strategy will open the door to the assembly of other nanometer-scale materials. PMID- 23636927 TI - Quantitative optimization of solid freeform deposition of aqueous hydrogels. AB - Many soft tissues exhibit complex anatomical geometry that is challenging to replicate for regenerative medicine applications. Solid freeform fabrication (SFF) has emerged as an attractive approach for creating 3D tissues, but a detailed understanding of how specific fabrication parameters affect accuracy and viability has not been established to date. In this study, we evaluate the effects of printing parameters of the Fab@Home 3D printing system on accuracy using alginate, photocrosslinkable polyethylene-glycol diacrylate (PEG-DA) and gelatin as commonly used model hydrogel materials. Print accuracy and resolution along the length, width and height were determined based on quantitative image analysis. The effects of extrusion parameters on cell viability were assessed using porcine aortic valve interstitial cells (PAVIC) as a model cell type. We observed that pressure, pathheight and pathspace all significantly affected print accuracy and resolution. Printing conditions did not affect PAVIC viability within the ranges applied. We predicted that optimal pressure, pathheight and pathspace values would be increased linearly with increasing nozzle diameter, and we confirmed that the predicted values generate accurate 3D geometries while poorly chosen parameters yield inaccurate, unpredictable geometries. This systematic optimization strategy therefore improves the accuracy of 3D printing platforms for biofabrication and tissue engineering applications. PMID- 23636929 TI - The value of expert review in prospective trials of automated assisted screening devices. AB - Previous prospective studies of automated assisted gynecologic screening devices have used a panel of experts for truth determination. We sought to determine the value of this practice. The relative sensitivity of the devices compared with manual screening was calculated using an expert panel for truth determination and compared using likelihood ratios to the relative sensitivity assuming all abnormal cases were truly abnormal. These results show that expert panel review has no significant effect on relative sensitivity at the threshold of ASCUS+ but may have an effect at HSIL+. Trials without expert consensus review may be compared to those with expert consensus review at the threshold of ASCUS+ but may not be reliable at the threshold of HSIL+ without additional confirmatory data. PMID- 23636930 TI - The diagnosis and treatment of attention deficit hyperactivity disorder in patients with epilepsy. AB - Attention deficit/hyperactivity disorder (AD/HD) can cause significant impairment in psychosocial and scholastic achievement. AD/HD should be appropriately managed even if patients have comorbid epilepsy. The diagnosis and treatment of AD/HD in patients with epilepsy presents several challenges. Differentiating independent problems in attention from frequent epileptic seizures is the first step in evaluating these individuals. Once this is accomplished the formal independent diagnosis of AD/HD can be pursued. Data from non-epileptic AD/HD populations should be applied with caution to patients with epilepsy. Once attention deficit disorder has been diagnosed formally, choices in treatment can create other problems as some pharmacological treatments for AD/HD pose a risk of exacerbating seizures. This article serves as a review for the diagnosis and treatment of AD/HD spectrum disorders in patients with epilepsy. PMID- 23636931 TI - Fourth cranial nerve palsy and Brown syndrome: two interrelated congenital cranial dysinnervation disorders? AB - Based on neuroimaging data showing absence of the trochlear nerve, congenital superior oblique palsy is now classified as a congenital cranial dysinnervation disorder. A similar absence of the abducens nerve is accompanied by misinnervation to the lateral rectus muscle from a branch of oculomotor nerve in the Duane retraction syndrome. This similarity raises the question of whether some cases of Brown syndrome could arise from a similar synkinesis between the inferior and superior oblique muscles in the setting of congenital superior oblique palsy. This hypothesis has gained support from the confluence of evidence from a number of independent studies. Using Duane syndrome as a model, we critically review the accumulating evidence that some cases of Brown syndrome are ultimately attributable to dysgenesis of the trochlear nerve. PMID- 23636932 TI - Understanding our best: eudaimonia's growing influence in psychology. PMID- 23636933 TI - Mechanistic and functional aspects of the interaction of AR-23 with mammalian cell membrane and improvement of branched polyethylenimine-mediated gene transfection. AB - BACKGROUND: Previous studies have suggested that reducing the positive charge of melittin could increase endosomal release activity and improve branched polyethylenimine (BPEI)-mediated transfection. AR-23 is a melittin-related peptide from Rana tagoi, which shows 81% sequence identity with melittin but has less positively-charged residues than melittin. The present study aimed to investigate the mechanistic and functional aspects of the interaction of AR-23 with mammalian cells and thus improve BPEI-mediated gene transfection. METHODS: AR23 and two AR-23 analogs (AR-20 without positively-charged residues and AR-26 with the same positively-charged residues as melittin) were analyzed. Circular dichroism (CD) spectrometry was used to analyze the secondary structures of the peptides. Peptide-induced depolarization of cell membrane, the membrane-lytic activity of the peptides, and their potency with respect to enhancing the cellular uptake of calcein were evaluated. The physicochemical characters of complexes were measured and the effect of the peptides on BPEI-mediated transfection was determined. RESULTS: The CD spectra results indicated that a positive charge in AR-23 played a crucial role in maintaining the alpha-helical conformation, whereas an extra positive charge could not increase alpha-helical formation. AR-23 displayed a similar depolarization ability to melittin. However, AR-23 showed a lower membrane lytic activity under physiological conditions and a higher lytic activity at endosomal pH than melittin and AR-26, which possess more positive charges. Compared to melittin and AR-26, AR-23, with a higher endosomal escaping activity, resulted in a higher enhancement of BPEI-mediated gene transfection, as well as the maintainance of a lower cytotoxicity. CONCLUSIONS: We suggest that AR-23 may be considered as a potential enhancer for improving the transfection efficiency of cationic polymers. PMID- 23636934 TI - Reprogrammed peripheral blood mononuclear cells are able to survive longer in irradiated female mice. AB - Induced multipotent stem (iMS) cells are originated from somatic cells and become multipotent by genetic and/or epigenetic modifications. Previous studies have shown that the fish oocytes extracts (FOE) can induce skin fibroblast cells into iMS cells. In this study, we aim to determine whether FOE can similarly induce mouse peripheral blood mononuclear cells (PBMCs) into the iMS state and if so, whether they can survive longer when they are transplanted into the irradiation female mice. PBMCs of GFP-transgenic male mice were cultured and transiently reprogrammed by FOE. They were deemed reaching the iMS state after detection of expression of stem cell markers. The iMS-like PBMCs were transplanted into female C57BL mice by tail vein injection. The spleen wet weights as well as numbers of colonies of the recipient mice were examined. The results showed the spleen wet weights and numbers of spleen colonies of FOE-induced group were all significantly higher than those of the non-induced group and negative control group. On day 90 after transplantation, FISH analysis detected the presence of Y chromosome in the induced group, but not of the other groups. The current findings demonstrate that FOE-induced PBMCs are able to survive longer in irradiated female mice. PMID- 23636935 TI - Piezotronic effect in flexible thin-film based devices. AB - Flexible piezotronic devices based on RF-sputtered piezoelectric semiconductor thin films have been investigated for the first time. The dominating role of the piezotronic effect over the geometrical and piezoresistive effect in the as fabricated devices has been confirmed and the modulation effect of the piezopotential on charge carrier transport under different strains is subsequently studied. Moreover, it is also demonstrated that the UV sensing capability of the as-fabricated thin film based piezotronic device can be tuned by the piezopotential, showing significantly enhanced sensitivity and improved reset time under tensile strain. PMID- 23636937 TI - The perfect soft mode: giant phonon instability in a ferroelectric. AB - Previous studies of unstable ('soft') optical modes in ferroelectrics have reported minimum frequencies of 1 cm(-1) (30 GHz) for underdamped phonons. In this work we fabricate a cylindrical coaxial specimen and rectangular plate waveguide specimens of tris-sarcosine calcium chloride (TSCC) and follow its soft mode several orders of magnitude lower to 1 GHz. Below 30 GHz the relaxation time is probably characteristic of domain wall motion; the new theory of Pakhomov et al (2013 Ferroelectrics at press) predicts 0.5 THz far from TC and a (T - T(C))/T(C) dependence, in agreement with our experimental values. This discovery has implications for GHz electronics such as phased array radar or other voltage tunable low-loss components. The mean-field frequency description of the soft mode response f(T) is supported via precision calorimetry on TSCC with and without Br-doping. The ferroelectric-antiferroelectric phase transition, previously suggested from high-pressure data, is confirmed at 45 K at 1 atm. PMID- 23636938 TI - Re: Petros, P. An anatomical explanation for "urodynamic features and artifacts". Neurourol Urodyn 2014; 33:153-4. PMID- 23636936 TI - Differential response in downstream processing of CHO cells grown under mild hypothermic conditions. AB - The manufacture of complex therapeutic proteins using mammalian cells is well established, with several strategies developed to improve productivity. The application of sustained mild hypothermic conditions during culture has been associated with increases in product titer and improved product quality. However, despite associated cell physiological effects, very few studies have investigated the impact on downstream processing (DSP). Characterization of cells grown under mild hypothermic conditions demonstrated that the stationary phase was prolonged by delaying the onset of apoptosis. This enabled cells to maintain viability for extended periods and increase volumetric productivity from 0.74 to 1.02 g L(-1) . However, host cell proteins, measured by ELISA, increased by ~50%, attributed to the extended time course and higher peak and harvest cell densities. The individual components making up this impurity, as determined by SELDI-TOF MS and 2D-PAGE, were shown to be largely comparable. Under mild hypothermic conditions, cells were less shear sensitive than those maintained at 37 degrees C, enhancing the preliminary primary recovery step. Adaptive changes in membrane fluidity were further investigated by adopting a pronounced temperature shift immediately prior to primary recovery and the improvement observed suggests that such a strategy may be implementable when shear sensitivity is of concern. Early and late apoptotic cells were particularly susceptible to shear, at either temperature, even under the lowest shear rate investigated. These findings demonstrate the importance of considering the impact of cell culture strategies and cell physiology on DSP, by implementing a range of experimental methods for process characterization. PMID- 23636939 TI - Splice variants DNMT3B4 and DNMT3B7 overexpression inhibit cell proliferation in 293A cell line. AB - DNA methyltransferase 3B (DNMT3B) is critical in abnormal DNA methylation patterns in cancer cells. Nearly 40 alternatively spliced variants of DNMT3B have been reported. DNMT3B4 and DNMT3B7 are two kinds of splice variants of DNMT3B lacking the conserved methyltransferase motif. In this study, the effect of inactivation of DNMT3B variants, DNMT3B4 and DNMT3B7, on cell proliferation was assessed. pCMV-DNMT3B4 and pCMV-DNMT3B7 recombinant plasmids were developed and stably transfected into 293A cells. 293A cells transfected with plasmid pCMV DNMT3B4 or pCMV-2B were then treated with G418 to the stable cell lines. After that, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method was used for testing the proliferation level, and flow cytometry was used to test cell cycle distribution of the cell line. The expression of p21 was detected by real-time PCR and Western blot. The methylation status of p21 promoter was detected by methylation-specific PCR (MS-PCR). It was found that DNMT3B4 and DNMT3B7 overexpression could inhibit cell proliferation and increase the expression of p21. Cell cycle analysis demonstrated that inactivation of DNMT3B variants overexpression inhibited cell cycle progression. Inactivation of DNMT3B variants overexpression facilitated p21 expression to delay 293A cell proliferation. These findings indicate that inactivation of DNMT3B variants might play an important role in cell proliferation correlating with the change of p21. PMID- 23636940 TI - Isolation of multilineage progenitors from mouse brain. AB - Stem cells are unique cell populations with the ability to undergo self-renewal and differentiation. These cells have been identified in a wide range of tissues and possess varied differentiation potentials. Tissue-specific stem cells have typically been thought to have limited differentiation capabilities. We show here that fibroblast-like cells isolated from mouse brain possess cross-germ layer differentiation abilities. These cells were found to express typical mesenchymal stem cell markers (CD44, CD29, and CD105) and were able to be passaged more than 50 times. When treated under defined conditions, the brain-derived cells were able to generate many different cell types including adipocytes, osteocytes, astrocytes, neurons, and even hepatocyte-like cells. The hepatocyte-like cells not only expressed liver cell-specific markers, but also exhibited the capacity for glycogen storage and low-density lipoprotein uptake. These results demonstrate the existence of cells in the brain with three-germ-layer differentiation potential. PMID- 23636941 TI - Severe Cenani-Lenz syndrome caused by loss of LRP4 function. AB - Limb patterning and growth are complex embryonic processes in which the elaborately orchestrated interplay of diverse endocrine and paracrine factors is crucial to limb integrity. LRP4 is a lipoprotein receptor known for its regulatory effects on LRP5- and LRP6-mediated Wnt signaling, a pathway that plays a pivotal role in limb development. Recessive mutations in LRP4 have been shown to cause Cenani-Lenz syndrome, which is characterized by severe limb malformations, an unusual face, and renal abnormalities. We report on a child with severe Cenani-Lenz syndrome caused by a novel homozygous nonsense mutation in LRP4. The severity of the phenotype in a patient with absent residual LRP4 function may point to a genotype-phenotype correlation. PMID- 23636942 TI - Quantitative proteomic analysis reveals concurrent RNA-protein interactions and identifies new RNA-binding proteins in Saccharomyces cerevisiae. AB - A growing body of evidence supports the existence of an extensive network of RNA binding proteins (RBPs) whose combinatorial binding affects the post transcriptional fate of every mRNA in the cell-yet we still do not have a complete understanding of which proteins bind to mRNA, which of these bind concurrently, and when and where in the cell they bind. We describe here a method to identify the proteins that bind to RNA concurrently with an RBP of interest, using quantitative mass spectrometry combined with RNase treatment of affinity purified RNA-protein complexes. We applied this method to the known RBPs Pab1, Nab2, and Puf3. Our method significantly enriched for known RBPs and is a clear improvement upon previous approaches in yeast. Our data reveal that some reported protein-protein interactions may instead reflect simultaneous binding to shared RNA targets. We also discovered more than 100 candidate RBPs, and we independently confirmed that 77% (23/30) bind directly to RNA. The previously recognized functions of the confirmed novel RBPs were remarkably diverse, and we mapped the RNA-binding region of one of these proteins, the transcriptional coactivator Mbf1, to a region distinct from its DNA-binding domain. Our results also provided new insights into the roles of Nab2 and Puf3 in post transcriptional regulation by identifying other RBPs that bind simultaneously to the same mRNAs. While existing methods can identify sets of RBPs that interact with common RNA targets, our approach can determine which of those interactions are concurrent-a crucial distinction for understanding post-transcriptional regulation. PMID- 23636943 TI - Enhancer transcripts mark active estrogen receptor binding sites. AB - We have integrated and analyzed a large number of data sets from a variety of genomic assays using a novel computational pipeline to provide a global view of estrogen receptor 1 (ESR1; a.k.a. ERalpha) enhancers in MCF-7 human breast cancer cells. Using this approach, we have defined a class of primary transcripts (eRNAs) that are transcribed uni- or bidirectionally from estrogen receptor binding sites (ERBSs) with an average transcription unit length of ~3-5 kb. The majority are up-regulated by short treatments with estradiol (i.e., 10, 25, or 40 min) with kinetics that precede or match the induction of the target genes. The production of eRNAs at ERBSs is strongly correlated with the enrichment of a number of genomic features that are associated with enhancers (e.g., H3K4me1, H3K27ac, EP300/CREBBP, RNA polymerase II, open chromatin architecture), as well as enhancer looping to target gene promoters. In the absence of eRNA production, strong enrichment of these features is not observed, even though ESR1 binding is evident. We find that flavopiridol, a CDK9 inhibitor that blocks transcription elongation, inhibits eRNA production but does not affect other molecular indicators of enhancer activity, suggesting that eRNA production occurs after the assembly of active enhancers. Finally, we show that an enhancer transcription "signature" based on GRO-seq data can be used for de novo enhancer prediction across cell types. Together, our studies shed new light on the activity of ESR1 at its enhancer sites and provide new insights about enhancer function. PMID- 23636944 TI - Mapping functional transcription factor networks from gene expression data. AB - A critical step in understanding how a genome functions is determining which transcription factors (TFs) regulate each gene. Accordingly, extensive effort has been devoted to mapping TF networks. In Saccharomyces cerevisiae, protein-DNA interactions have been identified for most TFs by ChIP-chip, and expression profiling has been done on strains deleted for most TFs. These studies revealed that there is little overlap between the genes whose promoters are bound by a TF and those whose expression changes when the TF is deleted, leaving us without a definitive TF network for any eukaryote and without an efficient method for mapping functional TF networks. This paper describes NetProphet, a novel algorithm that improves the efficiency of network mapping from gene expression data. NetProphet exploits a fundamental observation about the nature of TF networks: The response to disrupting or overexpressing a TF is strongest on its direct targets and dissipates rapidly as it propagates through the network. Using S. cerevisiae data, we show that NetProphet can predict thousands of direct, functional regulatory interactions, using only gene expression data. The targets that NetProphet predicts for a TF are at least as likely to have sites matching the TF's binding specificity as the targets implicated by ChIP. Unlike most ChIP targets, the NetProphet targets also show evidence of functional regulation. This suggests a surprising conclusion: The best way to begin mapping direct, functional TF-promoter interactions may not be by measuring binding. We also show that NetProphet yields new insights into the functions of several yeast TFs, including a well-studied TF, Cbf1, and a completely unstudied TF, Eds1. PMID- 23636945 TI - The transcription start site landscape of C. elegans. AB - More than half of Caenorhabditis elegans pre-mRNAs lose their original 5' ends in a process termed "trans-splicing" in which the RNA extending from the transcription start site (TSS) to the site of trans-splicing of the primary transcript, termed the "outron," is replaced with a 22-nt spliced leader. This complicates the mapping of TSSs, leading to a lack of available TSS mapping data for these genes. We used growth at low temperature and nuclear isolation to enrich for transcripts still containing outrons, applying a modified SAGE capture procedure and high-throughput sequencing to characterize 5' termini in this transcript population. We report from this data both a landscape of 5'-end utilization for C. elegans and a representative collection of TSSs for 7351 trans spliced genes. TSS distributions for individual genes were often dispersed, with a greater average number of TSSs for trans-spliced genes, suggesting that trans splicing may remove selective pressure for a single TSS. Upstream of newly defined TSSs, we observed well-known motifs (including TATAA-box and SP1) as well as novel motifs. Several of these motifs showed association with tissue-specific expression and/or conservation among six worm species. Comparing TSS features between trans-spliced and non-trans-spliced genes, we found stronger signals among outron TSSs for preferentially positioning of flanking nucleosomes and for downstream Pol II enrichment. Our data provide an enabling resource for both experimental and theoretical analysis of gene structure and function in C. elegans. PMID- 23636948 TI - Exogenous object-centered attention. AB - The present paper shows that the exogenous spatial cueing effect moves along with a rotating object. We exogenously cued one side of a horizontal bar with an abrupt onset.After cueing, this bar rotated to a vertical position. We found an object-centered cueing effect. In a second experiment, we cued one arm of a rotating cross and showed that retinotopic(eye-centered) and object-centered cueing effects are equally strong. Our results indicate that retinotopic and object centered reference frames are simultaneously present and accessible. Consistent with neurophysiology, we argue that there are two dissociable attentional systems: one for visual object processing and one for spatial processing [corrected]. PMID- 23636946 TI - Social insect genomes exhibit dramatic evolution in gene composition and regulation while preserving regulatory features linked to sociality. AB - Genomes of eusocial insects code for dramatic examples of phenotypic plasticity and social organization. We compared the genomes of seven ants, the honeybee, and various solitary insects to examine whether eusocial lineages share distinct features of genomic organization. Each ant lineage contains ~4000 novel genes, but only 64 of these genes are conserved among all seven ants. Many gene families have been expanded in ants, notably those involved in chemical communication (e.g., desaturases and odorant receptors). Alignment of the ant genomes revealed reduced purifying selection compared with Drosophila without significantly reduced synteny. Correspondingly, ant genomes exhibit dramatic divergence of noncoding regulatory elements; however, extant conserved regions are enriched for novel noncoding RNAs and transcription factor-binding sites. Comparison of orthologous gene promoters between eusocial and solitary species revealed significant regulatory evolution in both cis (e.g., Creb) and trans (e.g., fork head) for nearly 2000 genes, many of which exhibit phenotypic plasticity. Our results emphasize that genomic changes can occur remarkably fast in ants, because two recently diverged leaf-cutter ant species exhibit faster accumulation of species-specific genes and greater divergence in regulatory elements compared with other ants or Drosophila. Thus, while the "socio-genomes" of ants and the honeybee are broadly characterized by a pervasive pattern of divergence in gene composition and regulation, they preserve lineage-specific regulatory features linked to eusociality. We propose that changes in gene regulation played a key role in the origins of insect eusociality, whereas changes in gene composition were more relevant for lineage-specific eusocial adaptations. PMID- 23636947 TI - A broadly applicable high-throughput screening strategy identifies new regulators of Dlg4 (Psd-95) alternative splicing. AB - Most mammalian genes produce multiple mRNA isoforms derived from alternative pre mRNA splicing, with each alternative exon controlled by a complex network of regulatory factors. The identification of these regulators can be laborious and is usually carried out one factor at a time. We have developed a broadly applicable high-throughput screening method that simultaneously identifies multiple positive and negative regulators of a particular exon. Two minigene reporters were constructed: One produces green fluorescent protein (GFP) from the mRNA including an exon, and red fluorescent protein (RFP) from the mRNA lacking the exon; the other switches these fluorescent products of exon inclusion and exclusion. Combining results from these two reporters eliminates many false positives and greatly enriches for true splicing regulators. After extensive optimization of this method, we performed a gain-of-function screen of 15,779 cDNA clones and identified 40 genes affecting exon 18 of Discs large homolog 4 (Dlg4; also known as post-synaptic density protein 95 [Psd-95]). We confirmed that 28 of the 34 recoverable clones alter reporter splicing in RT-PCR assays. Remarkably, 18 of the identified genes encode splicing factors or RNA binding proteins, including PTBP1, a previously identified regulator of this exon. Loss of-function experiments examining endogenous Dlg4 transcripts validated the effects of five of eight genes tested in independent cell lines, and two genes were further confirmed to regulate Dlg4 splicing in primary neurons. These results identify multiple new regulators of Dlg4 splicing, and validate an approach to isolating splicing regulators for almost any cassette exon from libraries of cDNAs, shRNAs, or small molecules. PMID- 23636949 TI - Contextual cueing under working memory load: selective interference of visuospatial load with expression of learning. AB - In a series of experiments, we investigated the dependence of contextual cueing on working memory resources. A visual search task with 50 % repeated displays was run in order to elicit the implicit learning of contextual cues. The search task was combined with a concurrent visual working memory task either during an initial learning phase or a later test phase. The visual working memory load was either spatial or nonspatial. Articulatory suppression was used to prevent verbalization. We found that nonspatial working memory load had no effect, independent of presentation in the learning or test phase. In contrast, visuospatial load diminished search facilitation in the test phase, but not during learning. We concluded that visuospatial working memory resources are needed for the expression of previously learned spatial contexts, whereas the learning of contextual cues does not depend on visuospatial working memory. PMID- 23636950 TI - Tissue engineering for articular cartilage repair--the state of the art. AB - Articular cartilage exhibits little capacity for intrinsic repair, and thus even minor injuries or lesions may lead to progressive damage and osteoarthritic joint degeneration, resulting in significant pain and disability. While there have been numerous attempts to develop tissue-engineered grafts or patches to repair focal chondral and osteochondral defects, there remain significant challenges in the clinical application of cell-based therapies for cartilage repair. This paper reviews the current state of cartilage tissue engineering with respect to different cell sources and their potential genetic modification, biomaterial scaffolds and growth factors, as well as preclinical testing in various animal models. This is not intended as a systematic review, rather an opinion of where the field is moving in light of current literature. While significant advances have been made in recent years, the complexity of this problem suggests that a multidisciplinary approach - combining a clinical perspective with expertise in cell biology, biomechanics, biomaterials science and high-throughput analysis will likely be necessary to address the challenge of developing functional cartilage replacements. With this approach we are more likely to realise the clinical goal of treating both focal defects and even large-scale osteoarthritic degenerative changes in the joint. PMID- 23636951 TI - Mechanism of parathyroid hormone-mediated suppression of calcification markers in human intervertebral disc cells. AB - In degenerative intervertebral discs (IVD), type X collagen (COL X) expression (associated with hypertrophic differentiation) and calcification has been demonstrated. Suppression of COL X expression and calcification during disc degeneration can be therapeutic. In the present study we investigated the potential of human parathyroid hormone 1-34 (PTH) in suppressing indicators of calcification potential (alkaline phosphatase (ALP), Ca(2+), inorganic phosphate (Pi)), and COL X expression. Further, we sought to elucidate the mechanism of PTH action in annulus fibrosus (AF) and nucleus pulposus (NP) cells from human lumbar IVDs with moderate to advanced degeneration. Mitogen activated protein kinase (MAPK) signalling and alterations in the markers of calcification potential were analysed. PTH increased type II collagen (COL II) expression in AF (~200 %) and NP cells (~163 %) and decreased COL X levels both in AF and NP cells (~75 %). These changes in the expression of collagens were preceded by MAPK phosphorylation, which was increased in both AF and NP cells by PTH after 30 min. MAPK signalling inhibitor U0126 and protein kinase-A inhibitor H-89 DCH attenuated PTH stimulated COL II expression in both cell types. PTH decreased ALP activity and increased Ca(2+) release only in NP cells. The present study demonstrates that PTH can potentially retard IVD degeneration by stimulating matrix synthesis and suppressing markers of calcification potential in degenerated disc cells via both MAPK and PKA signalling pathways. Inhibition of further mineral deposition may therefore be a viable therapeutic option for improving the status of degenerating discs. PMID- 23636952 TI - Orthopedic navigation technology and biomechanical evaluation for total hip replacement. PMID- 23636954 TI - Development and evaluation of an image-free computer-assisted impingement detection technique for total hip arthroplasty. AB - Periprosthetic or bony impingement in total hip arthroplasty (THA) has been correlated to dislocation, increased wear, reduced postoperative functionality with pain and/or decreased range of motion (ROM). We sought to study the accuracy and assess the reliability of measuring bony and periprosthetic impingement on a virtual bone model prior to the implantation of the acetabular cup with the help of image-free navigation technology in an experimental cadaver study. Impingement free ROM measurements were recorded during minimally invasive, computer-assisted THA on 14 hips of 7 cadaveric donors. Preoperatively and postoperatively the donors were scanned using computed tomography (CT). Impingement-free ROM on three dimensional CT-based models was then compared with corresponding, intraoperative navigation models. Bony/periprosthetic impingement can be detected with a mean accuracy limit of below 5 degrees for motion angles, which should be reached after THA for activities of daily living with the help of image-free navigation technology. PMID- 23636953 TI - Nanoscale study of cartilage surfaces using atomic force microscopy. AB - Articulating cartilage wear plays an important role in cartilage degeneration and osteoarthritis (OA) progression. This study investigated the changes of mechanical properties and surface roughness of sheep cartilages with wear progression at a nanometre scale. Young sheep's rear legs were subjected to a series of wear tests to generate worn cartilage samples to simulate the OA progression. Atomic force microscopy (AFM) was used to determine the effective indentation modulus and to measure the surface morphology of moist cartilage surfaces. The study has found that the mean effective indentation modulus values of worn cartilages were lower than that of healthy cartilage as the control sample. A medium-to-strong correlation between the effective indentation modulus values and the OA grades has been found. The relation between surface topography and effective indentation modulus values of the cartilage surfaces with OA progression was weakly correlated. The method established in this study can be implemented to investigate the effective indentation modulus values of clinical osteoarthritic cartilages and to assist in the understanding and assessment of OA. PMID- 23636955 TI - Clinical experience with computer navigation in revision total hip arthroplasty. AB - The biomechanically and anatomically correct placement of hip prostheses components is the main challenge in revision hip arthroplasty. The orientation of the cup and stem with the restoration of leg length, offset and hip centre is hampered by the defect situations frequently present. In primary hip arthroplasty, it has been demonstrated that the components can be accurately positioned using computer-navigated procedures. However, such procedures could also be of considerable benefit in revision hip arthroplasty. Systems that not only detect anatomical landmarks using pointers but also use image data for referencing may provide a possible solution for the defect situation. Literature about navigation in revision arthroplasty is very rare. This article comprises general considerations on this subject and presents our experience and possible clinical applications. PMID- 23636957 TI - Measuring functional outcome after total hip replacement with subject-specific hip joint loading. AB - Total hip replacement is an often-performed orthopedic surgical procedure; the amount of procedures undertaken will increase since our life expectancy is growing. In order to optimize function, hip biomechanics should be restored to as near normal as possible. The goal of this pilot study was to determine whether or not it is feasible to compute the vectorial hip reaction force pathways on the head of the prosthesis and the force angles relative to the cup of the prosthesis that occur during gait in total hip replacement patients, serving as an objective measurement of the functional outcome following hip replacement. A three dimensional gait analysis, measuring ground reaction forces and kinematics, was performed. The data retrieved from the gait analysis was used as the input for the musculoskeletal model to compute vectorial joint reaction forces for data processing. To evaluate the position and orientation of the joint reaction forces, the force path, as well as the force angles for the operated and non operated joint, has been calculated during the stance phase of the specific leg. The force path for subject 2 on the non-operated side is only located in the posterior-lateral quarter, as is the force path for subject 1. In contrast to this subject, the force path for subject 2 at the operated hip joint can be found only within the anterior quarter of the head of the implant, where it is nearly equally distributed in the medio-lateral half of the prosthesis head. The force inclination angles on the cup of subject 1, with respect to the plane of the socket face, indicates that the force vector is mainly positioned in the same quadrant when compared with subject 2 (in a cup-fixed coordinate system). The force-anteversion angle behaves similarly to the force-inclination angle, even when the effects are not as pronounced. The proposed methods in this article are aiming to define two functional outcomes of total hip replacement that are related to wear and rim loading. It is accepted that wear is not only a function of time, but a function of use. Owing to the methods listed in this article, we are able to determine a) the applied force and b) the sliding distance (force pathway) in a subject-specific manner. The computed hip-reaction force angles and the distance to the rim cup are a measurement for cup or rim loading, and occurs in the so-called safe-zones. This method may well give us insight into the biomechanical situation during gait, after receiving total hip replacement, that we need to fully understand the mechanisms acting on a hip joint and to prove a possible increase of functional outcome after receiving total hip replacement. PMID- 23636956 TI - A probabilistic modelling scheme for analysis of long-term failure of cemented femoral joint replacements. AB - Reliable prediction of long-term medical device performance using computer simulation requires consideration of variability in surgical procedure, as well as patient-specific factors. However, even deterministic simulation of long-term failure processes for such devices is time and resource consuming so that including variability can lead to excessive time to achieve useful predictions. This study investigates the use of an accelerated probabilistic framework for predicting the likely performance envelope of a device and applies it to femoral prosthesis loosening in cemented hip arthroplasty. A creep and fatigue damage failure model for bone cement, in conjunction with an interfacial fatigue model for the implant-cement interface, was used to simulate loosening of a prosthesis within a cement mantle. A deterministic set of trial simulations was used to account for variability of a set of surgical and patient factors, and a response surface method was used to perform and accelerate a Monte Carlo simulation to achieve an estimate of the likely range of prosthesis loosening. The proposed framework was used to conceptually investigate the influence of prosthesis selection and surgical placement on prosthesis migration. Results demonstrate that the response surface method is capable of dramatically reducing the time to achieve convergence in mean and variance of predicted response variables. A critical requirement for realistic predictions is the size and quality of the initial training dataset used to generate the response surface and further work is required to determine the recommendations for a minimum number of initial trials. Results of this conceptual application predicted that loosening was sensitive to the implant size and femoral width. Furthermore, different rankings of implant performance were predicted when only individual simulations (e.g. an average condition) were used to rank implants, compared with when stochastic simulations were used. In conclusion, the proposed framework provides a viable approach to predicting realistic ranges of loosening behaviour for orthopaedic implants in reduced timeframes compared with conventional Monte Carlo simulations. PMID- 23636958 TI - The role of biomechanics and engineering in total hip replacement. Why surgeons need technical help. AB - Implanting the acetabular cup of hard-on-hard bearings, like metal-on-metal or ceramic-on-ceramic, requires considerable surgeon skill to avoid the complications associated with edge loading. Successful cup positioning instruments have been designed in the past by pioneering surgeons, like Peter Ring and Michael Freeman, and these are re-visited in this article. An advantage of these instruments is that they could position the acetabular cup without defining a reference pelvic plane. Computer-assisted cup orientation is able to reduce outliers in cup orientation, but the technology has not been widely adopted. There may be an opportunity to improve the uptake of computer-assisted surgery by incorporating some of the concepts from historically successful manual instruments. PMID- 23636959 TI - Application and evaluation of biomechanical models and scores for the planning of total hip arthroplasty. AB - Intimate knowledge of the biomechanics of a given individual hip joint provides a potential advantage during the planning of total hip arthroplasty, and would thus have a positive influence over the outcome of such an intervention. In current clinical practise, the surgical planning is based solely on the status of the individual hip and its radiographic appearance. However, additional information could be gathered from the radiography to be used as input data for biomechanical models aimed at calculating the resultant force FR within the hip joint. An investigation of the biomechanical models by Pauwels, Debrunner and Iglic was performed, where the magnitude of FR calculated by the models showed a favourable comparison to the in-vivo data from instrumented prostheses by Bergmann. The Blumentritt model returned abnormally high results. The computational results showed large variations for FR orientation, which tends to depend more on the model used than on patient-specific parameters. Furthermore, a discrepancy was found between the data gathered from instrumented prostheses and the Standing Human Model within the 'AnyBody Modeling SystemTM' software by AnyBody Tech. Additionally, the variations in inter-rater and intra-rater errors made while localizing radiographic landmarks were analysed with respect to their influence on Babisch-Layher-Blumentritt (BLB)-scoring using the Blumentritt hip model. PMID- 23636960 TI - Contact surface motion paths associated with leg length inequality following unilateral total hip replacement. AB - In the past, there has been little research into leg length inequality (LLI) and its effect on hip arthroplasty bearing longevity. This investigation aimed to determine the effects of post-operative LLI on hip motions during gait and to postulate the subsequent influence on the wear of the artificial hip joint replacement. Motion data from a clinical gait analysis were processed with an in house computational model to plot graphs showing the movement of loci of 20 points on the femoral head during one gait cycle for two cohorts: 19 LLI patients and 38 normal healthy patients. Loci paths were quantified by calculating the aspect ratio (AR) of the path shape. It was found that on average, LLI patients had a reduction in flexion/extension and abduction/adduction. Furthermore, the AR of LLI patients was found to be 8% smaller than the normal group. The shorter, more multidirectional, motion paths in LLI patients would suggest the potential for greater wear in a polyethylene bearing compared to an asymptomatic, non-LLI patient. The results have potential implications towards preclinical wear testing of joint replacements. PMID- 23636961 TI - Highly ordered MnO2 nanopillars for enhanced supercapacitor performance. AB - This report demonstrates a simple, but efficient method to print highly ordered nanopillars without the use of sacrificial templates or any expensive equipment. The printed polymer structure is used as a scaffold to deposit electrode material (manganese dioxide) for making supercapacitors. The simplicity of the fabrication method together with superior power density and energy density make this supercapacitor electrode very attractive for the next-generation energy storage systems. PMID- 23636963 TI - Ferromagnetic planar Josephson junction with transparent interfaces: a phi junction proposal. AB - We calculate the current-phase relation of a planar Josephson junction with a ferromagnetic weak link located on top of a thin normal metal film. Following experimental observations we assume transparent superconductor-ferromagnet interfaces. This provides the best interlayer coupling and a low suppression of the superconducting correlations penetrating from the superconducting electrodes into the ferromagnetic layer. We show that this Josephson junction is a promising candidate for experimental phi junction realization. PMID- 23636962 TI - Use of the mitochondria toxicity assay for quantifying the viable cell density of microencapsulated jurkat cells. AB - The mitochondria toxicity assay (MTT assay) is an established method for monitoring cell viability based on mitochondrial activity. Here the MTT assay is proposed for the in situ quantification of the living cell density of microencapsulated Jurkat cells. Three systems were used to encapsulate the cells, namely a membrane consisting of an interpenetrating polyelectrolyte network of sodium cellulose sulphate/poly(diallyldimethylammonium chloride) (NaCS/PDADMAC), a calcium alginate hydrogel covered with poly(L-lysine) (Ca-alg-PLL), and a novel calcium alginate-poly(ethylene glycol) hybrid material (Ca-alg-PEG). MTT results were correlated to data obtained by the trypan blue exclusion assay after release of the cells from the NaCS/PDADMAC and Ca-alg-PLL capsules, while a resazurin based assay was used for comparison in case of the Ca-alg-PEG material. Analysis by MTT assay allows quick and reliable determination of viable cell densities of encapsulated cells independent of the capsule material. The assay is highly reproducible with inter-assay relative standard deviations below 10%. PMID- 23636965 TI - Contained left ventricular free wall rupture: evaluation by ERNA & echocardiography. PMID- 23636964 TI - Quantitative assessment of cardiac mechanical synchrony using equilibrium radionuclide angiography. AB - BACKGROUND: Data on normal parameters of cardiac mechanical synchrony is limited, variable and obtained from small cohorts till date. In most studies, software used for such assessment has not been mentioned. The aim of study is to establish normal values of mechanical synchrony with equilibrium radionuclide angiography (ERNA) in a larger population using commercially available software. METHODS: We retrospectively analysed ERNA studies of 108 patients having low pretest likelihood of coronary artery disease, no known history of cardiac disease, normal electrocardiogram and whose ERNA studies were considered normal by experienced observers. In addition, ten patients diagnosed with dilated cardiomyopathy (DCM) and having LVEF <= 40% underwent ERNA. Fourier first harmonic analysis of phase images was used to quantify synchrony parameters using commercially available software (XT-ERNA). Intraventricular synchrony for each ventricle was measured as the standard deviation of the LV and RV mean phase angles (SD LVmPA and SD RVmPA, respectively). Interventricular synchrony was measured as LV-RVmPA. Absolute interventricular delay was calculated as absolute difference between LV and RVmPA (without considering +/- sign). All variables were expressed in milliseconds (ms) and degree ( degrees ). Intra-observer and inter-observer variabilities were assessed. Cut-off values for parameters were calculated from the normal database, and validated against patient group. RESULTS: On phase analysis, LVmPA was observed to be 343 +/- 48.5 milliseconds (174.7 degrees +/- 18.5 degrees ), SD LVmPA was 16.3 +/- 5.4 milliseconds (8.2 degrees +/- 2.5 degrees ), RVmPA was 339 +/- 50.4 milliseconds (171.8 degrees +/- 18.5 degrees ) and SD RVmPA was 37.3 +/- 15.7 milliseconds (18.7 degrees +/- 7.2 degrees ). LV-RVmPA was observed to be 3.9 +/- 21.7 milliseconds (2.9 degrees +/- 9.6 degrees ) and absolute interventricular delay was 16.3 +/- 14.8 milliseconds (7.9 degrees +/- 6.1 degrees ). The cut-off values for the presence of dyssynchrony were estimated as SD LVmPA > 27.1 milliseconds (>13.2 degrees ), SD RVmPA > 68.7 milliseconds (>33.1 degrees ) and LV-RVmPA > 47.3 milliseconds (>22.1 degrees ). There was no statistically significant intra-observer or inter observer variability. Using these cut offs, 9 patients with DCM showed the presence of left intraventricular dyssynchrony, 5 had right intraventricular dyssynchrony and 2 had interventricular dyssynchrony. CONCLUSIONS: ERNA phase analysis offers an objective and reproducible tool to quantify cardiac mechanical synchrony using commercially available software and can be used in routine clinical practice to assess mechanical dyssynchrony. PMID- 23636966 TI - Significance of I-123 metaiodobenzylguanidine (123I-MIBG) lung activity in subjects with heart failure in comparison to healthy control subjects. AB - BACKGROUND: Little is known concerning the significance of lung activity of the sympathetic neuronal imaging agent (123)I-MIBG in heart failure patients and healthy subjects. METHODS: (123)I-MIBG activity was assessed in lung, heart, and mediastinum regions of interest on early and late planar images in 951 heart failure patients and 94 controls. Cox regression analyses were performed to identify factors associated with outcome events during a median 17 month follow up. RESULTS: Heart failure subjects with pulmonary disease had significantly reduced late lung-to-mediastinum (L/M) ratios compared to heart failure subjects without pulmonary disease. Late L/M ratio was greater in heart failure subjects without outcome events than either subjects with events or healthy controls. L/M ratio was an independent predictor of all-cause mortality. Subjects with combined favorable prognosis L/M ratio >= 1.7 and heart-to-mediastinum ratio (H/M) >= 1.6 had a significantly lower 2-year mortality (2.0%) than subjects with unfavorable L/M ratio < 1.7 and H/M ratio < 1.6 (17.7% 2-year mortality, P < .0008). CONCLUSIONS: Increased (123)I-MIBG lung activity in heart failure subjects, compared to controls, is associated with a relatively low risk of adverse events, including all-cause mortality. L/M ratio may, therefore, be useful to provide incremental prognostic information on (123)I-MIBG imaging. PMID- 23636967 TI - Decrease in the frequency of stress-induced ischemia over the past two decades. PMID- 23636968 TI - Whole body assessment by 18F-FDG PET in a patient with infective endocarditis. PMID- 23636969 TI - Novel application of 18F-sodium fluoride an old tracer to a clinically neglected condition. PMID- 23636970 TI - Detection of silent myocardial ischemia: is it clinically relevant? PMID- 23636973 TI - Editorial: how multiplexed tools and approaches speed up the progress of metabolic engineering. AB - Systems metabolic engineering is becoming a widely-evoked paradigm for industrial strain design and optimization. Specifically, systems wide experimental and computational analyses of cells and their environments enable guide metabolic engineers to quickly parse the genome and creating desirable overproduction phenotypes. PMID- 23636971 TI - Early metabolic crisis-related brain atrophy and cognition in traumatic brain injury. AB - Traumatic brain injury often results in acute metabolic crisis. We recently demonstrated that this is associated with chronic brain atrophy, which is most prominent in the frontal and temporal lobes. Interestingly, the neuropsychological profile of traumatic brain injury is often characterized as 'frontal-temporal' in nature, suggesting a possible link between acute metabolic crisis-related brain atrophy and neurocognitive impairment in this population. While focal lesions and diffuse axonal injury have a well-established role in the neuropsychological deficits observed following traumatic brain injury, no studies to date have examined the possible contribution of acute metabolic crisis-related atrophy in the neuropsychological sequelae of traumatic brain injury. In the current study we employed positron emission tomography, magnetic resonance imaging, and neuropsychological assessments to ascertain the relationship between acute metabolic crisis-related brain atrophy and neurocognitive outcome in a sample of 14 right-handed traumatic brain injury survivors. We found that acute metabolic crisis-related atrophy in the frontal and temporal lobes was associated with poorer attention, executive functioning, and psychomotor abilities at 12 months post-injury. Furthermore, participants with gross frontal and/or temporal lobe atrophy exhibited numerous clinically significant neuropsychological deficits in contrast to participants with other patterns of brain atrophy. Our findings suggest that interventions that reduce acute metabolic crisis may lead to improved functional outcomes for traumatic brain injury survivors. PMID- 23636978 TI - A modified technique of end-to-end pancreaticojejunostomy with transpancreatic interlocking mattress sutures. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) represents the most important cause of morbidity after pancreaticoduodenectomy (PD) and contributes to prolonged hospitalization and increased mortality rates. This study presents a new technique, which involves end-to-end pancreaticojejunostomy with transpancreatic interlocking mattress sutures, and evaluates its safety and reliability. METHODS: From January 2011 to May 2012, 79 patients with periampullary malignancies underwent PD by using this modified technique, and the morbidity and mortality rates were calculated. RESULTS: In this study, all cases recovered well from PD. Four transpancreatic interlocking mattress sutures were performed in 79 patients. The median duration of surgery was 3.9 hr (range 3.1 6.8), and the median time to perform pancreaticojejunostomy was 15.3 min (range 9 24). Overall, morbidity occurred in 16 patients (22.3%), and the causes included upper gastrointestinal bleeding (n = 2), biliary fistula (n = 1), pulmonary infection (n = 1), delayed gastric emptying (n = 1), abdominal abscess (n = 1, caused by PF), wound infection (n = 3), arrhythmia or myocardial infarction (n = 3), urinary tract infection (n = 2), and POPF (n = 2, 2.53%). One patient had grade A POPF, one had grade B POPF, and none of them had grade C POPF. No death occurred during surgery. CONCLUSION: The end-to-end pancreaticojejunostomy with transpancreatic interlocking mattress sutures is a simple, rapid, safe, and reliable technique with low POPF rate and low delayed massive hemorrhage rate. PMID- 23636979 TI - Re: Gammie, A. re: an anatomical explanation for "urodynamic features and artifacts". Neurourol Urodyn 2014; 33:155. PMID- 23636980 TI - Monoamniotic monochorionic twins discordant for noncompaction cardiomyopathy. AB - Occasionally "identical twins" are phenotypically different, raising the question of zygosity and the issue of genetic versus environmental influences during development. We recently noted monochorionic-monoamniotic twins, one of which had an isolated cardiac abnormality, noncompaction cardiomyopathy, a condition characterized by cardiac ventricular hypertrabeculation. We examined the prenatal course and subsequent pathologic correlation since ventricular morphogenesis may depend on early muscular contraction and blood flow. The monochorionic monoamniotic female twin pair was initially identified since one fetus presented with increased nuchal translucency. Complete heart block was later identified in the fetus with nuchal translucency who did not survive after delivery. In contrast, the unaffected twin had normal cardiac studies both prenatally and postnatally. Pathologic analysis of the affected twin demonstrated noncompaction of the left ventricle with dysplasia of the aortic and pulmonary valves. Dissection of the cardiac conduction system disclosed atrioventricular bundle fibrosis. Maternal lupus studies, amniocentesis with karyotype, and studies for 22q11.2 were normal. To test for zygosity, we performed multiple STR marker analysis and found that all markers were shared even using nonblood tissues from the affected twin. These studies demonstrate that monozygotic twins that are monochorionic monoamniotic can be discordant for cardiac noncompaction. The results suggest further investigation into the potential roles of pathologic fibrosis, contractility, and blood flow in cardiac ventricle development. PMID- 23636981 TI - Interferon-beta therapy in multiple sclerosis: the short-term and long-term effects on the patients' individual gene expression in peripheral blood. AB - Therapy with interferon-beta (IFN-beta) is a mainstay in the management of relapsing-remitting multiple sclerosis (MS), with proven long-term effectiveness and safety. Much has been learned about the molecular mechanisms of action of IFN beta in the past years. Previous studies described more than a hundred genes to be modulated in expression in blood cells in response to the therapy. However, for many of these genes, the precise temporal expression pattern and the therapeutic relevance are unclear. We used Affymetrix microarrays to investigate in more detail the gene expression changes in peripheral blood mononuclear cells from MS patients receiving subcutaneous IFN-beta-1a. The blood samples were obtained longitudinally at five different time points up to 2 years after the start of therapy, and the patients were clinically followed up for 5 years. We examined the functions of the genes that were upregulated or downregulated at the transcript level after short-term or long-term treatment. Moreover, we analyzed their mutual interactions and their regulation by transcription factors. Compared to pretreatment levels, 96 genes were identified as highly differentially expressed, many of them already after the first IFN-beta injection. The interactions between these genes form a large network with multiple feedback loops, indicating the complex crosstalk between innate and adaptive immune responses during therapy. We discuss the genes and biological processes that might be important to reduce disease activity by attenuating the proliferation of autoreactive immune cells and their migration into the central nervous system. In summary, we present novel insights that extend the current knowledge on the early and late pharmacodynamic effects of IFN-beta therapy and describe gene expression differences between the individual patients that reflect clinical heterogeneity. PMID- 23636982 TI - Functional brain activation to emotional and nonemotional faces in healthy children: evidence for developmentally undifferentiated amygdala function during the school-age period. AB - The amygdala is a key region in emotion processing. In particular, fMRI studies have demonstrated that the amygdala is active during the viewing of emotional faces. Previous research has consistently found greater amygdala responses to fearful than to neutral faces in adults, convergent with a focus in the animal literature on the amygdala's role in fear processing. Studies have shown that the amygdala also responds differentially to other facial emotion types in adults. Yet the literature regarding when this differential amygdala responsivity develops is limited and mixed. Thus, the goal of the present study was to examine amygdala responses to emotional and neutral faces in a relatively large sample of healthy school-age children (N = 52). Although the amygdala was active in response to emotional and neutral faces, the results did not support the hypothesis that the amygdala responds differentially to emotional faces in 7- to 12-year-old children. Nonetheless, amygdala activity was correlated with the severity of subclinical depression symptoms and with emotional regulation skills. Additionally, sex differences were observed in frontal, temporal, and visual regions, as well as effects of pubertal development in visual regions. These findings suggest important differences in amygdala reactivity in childhood. PMID- 23636983 TI - Tracking the implicit self using event-related potentials. AB - Negative biases in implicit self-evaluation are thought to be detrimental to subjective well-being and have been linked to various psychological disorders, including depression. An understanding of the neural processes underlying implicit self-evaluation in healthy subjects could provide a basis for the investigation of negative biases in depressed patients, the development of differential psychotherapeutic interventions, and the estimation of relapse risk in remitted patients. We thus studied the brain processes linked to implicit self evaluation in 25 healthy subjects using event-related potential (ERP) recording during a self-relevant Implicit Association Test (sIAT). Consistent with a positive implicit self-evaluation in healthy subjects, they responded significantly faster to the congruent (self-positive mapping) than to the incongruent sIAT condition (self-negative mapping). Our main finding was a topographical ERP difference in a time window between 600 and 700 ms, whereas no significant differences between congruent and incongruent conditions were observed in earlier time windows. This suggests that biases in implicit self evaluation are reflected only indirectly, in the additional recruitment of control processes needed to override the positive implicit self-evaluation of healthy subjects in the incongruent sIAT condition. Brain activations linked to these control processes can thus serve as an indirect measure for estimating biases in implicit self-evaluation. The sIAT paradigm, combined with ERP, could therefore permit the tracking of the neural processes underlying implicit self evaluation in depressed patients during psychotherapy. PMID- 23636984 TI - Recent advances in neuroimaging biomarkers in geriatric psychiatry. AB - Neuroimaging, both structural and functional, serve as useful adjuncts to clinical assessment, and can provide objective, reliable means of assessing disease presence and process in the aging population. In the following review we briefly explain current imaging methodologies. Then, we analyze recent developments in developing neuroimaging biomarkers for two highly prevalent disorders in the elderly population- Alzheimer's disease (AD) and late-life depression (LLD). In AD, efforts are focused on early diagnosis through in vivo visualization of disease pathophysiology. In LLD, recent imaging evidence supports the role of white matter ischemic changes in the pathogenesis of depression in the elderly, the "vascular hypothesis." Finally, we discuss potential roles for neuroimaging biomarkers in geriatric psychiatry in the future. PMID- 23636986 TI - Pornography, sex crime, and paraphilia. AB - The current paper reviews research findings concerning the association of pornography with sexual violence and paraphilic interests. Little clarity concerning the causal impact of pornography on sexual aggression or child oriented sexual behavior has been achieved in the scientific literature. Laboratory experimentation demonstrates that violent pornography may contribute to antiwoman aggression, but the artificiality and constraints of the experimental setting severely limit generalization of these findings to real world situations, and observational studies in natural settings consistently find no association or an inverse association of pornography with sexual aggression. In addition, although pedophiles often use child pornography, the causal impact of child pornography on child sexual offending is not conclusive. The current analysis considers the confluence of predisposing factors and pornography use as issues requiring clinical judgment in the reduction of sexual aggression and management of paraphilic interest in children. PMID- 23636990 TI - Surface spectral function of momentum-dependent pairing potentials in a topological insulator: application to CuxBi2Se3. AB - We propose three possible momentum-dependent pairing potentials as candidates for topological superconductors (for example CuxBi2Se3), and calculate the surface spectral function and surface density of states with these pairing potentials. We find that the first two can give the same spectral functions as the fully gapped and node-contacted pairing potentials given by Fu and Berg (2010 Phys. Rev. Lett. 105 097001), and that the third one can obtain a topological non-trivial case in which there exists a flat Andreev bound state and which preserves the threefold rotation symmetry. We hope our proposals and results will be assessed by future experiment. PMID- 23636987 TI - Comorbid sleep disorders in neuropsychiatric disorders across the life cycle. AB - The association between psychopathology and poor sleep has long been recognized. The current review focuses on the association between the most prevalent sleep disorders (insomnia, sleep-related breathing disorders and restless legs syndrome) and four major psychiatric disorders: alcohol dependence, schizophrenia, depression and anxiety disorders. Decreased total sleep time and increased sleep onset latency as measured by polysomnography as well an increase of the prevalence of insomnia has been reported in all of these psychiatric disorders. Furthermore, sleep disturbance is a risk factor for their development. Cognitive-behavioral therapy for insomnia has been shown to have a positive impact on both sleep and symptoms of depression and anxiety. Whether adequate treatment of sleep disorders can prevent the incidence of psychiatric disorders, remains to be investigated. PMID- 23636989 TI - Buckling-induced reversible symmetry breaking and amplification of chirality using supported cellular structures. AB - Buckling-induced reversible symmetry breaking and amplification of chirality using macro- and microscale supported cellular structures is described. Guided by extensive theoretical analysis, cellular structures are rationally designed, in which buckling induces a reversible switching between achiral and chiral configurations. Additionally, it is demonstrated that the proposed mechanism can be generalized over a wide range of length scales, geometries, materials, and stimuli. PMID- 23636988 TI - Geriatric psychiatry review: differential diagnosis and treatment of the 3 D's - delirium, dementia, and depression. AB - The three D's of Geriatric Psychiatry-delirium, dementia, and depression represent some of the most common and challenging diagnoses for older adults. Delirium is often difficult to diagnose and treatment is sometimes controversial with the use of antipsychotic medications, but it is common in a variety of patient care settings and remains an independent risk factor for morbidity and mortality in older adults. Dementia may affect a significant number of older adults and is associated with delirium, depression, frailty, and failure to thrive. Treatment of dementia is challenging and while medication interventions are common, environmental and problem solving therapies may have some of the greatest benefits. Finally, depression increases with age and is more likely to present with somatic complaints or insomnia and is more likely to be reported to a primary care physician than any other healthcare provider by older adults. Depression carries an increased risk for suicide in older adults and proven therapies should be initiated immediately. These three syndromes have great overlap, can exist simultaneously in the same patient, and often confer increased risk for each other. The primary care provider will undoubtedly benefit from a solid foundation in the identification, classification, and treatment of these common problems of older adulthood. PMID- 23636985 TI - Systematic review reveals heterogeneity in the use of the Scale to Assess Unawareness of Mental Disorder (SUMD). AB - The Scale to Assess Unawareness of Mental Disorder (SUMD) is one of the most widely used instruments to measure insight into mental disorders. The aim of this study was to review all studies using the SUMD in the last 20 years. We performed an electronic search of MEDLINE using PubMed to identify all relevant studies published from 1993 to 2012. The following data were extracted from each article: characteristics of the SUMD (version, rating scale, scoring, and item/dimension used), methodological aspects (country, language, subject inclusion criteria, and sample size), and statistical methods to analyse insight. Of the 133 articles screened, 100 studies were included in the review. Fifty-two studies were published over the past five years. The SUMD was rarely used in its entirety, and the use of selected items or subscales was heterogeneous across studies. The studies also varied in terms of response modalities and in the use of 3- or 5 point Likert scales. The calculation of insight scores was highly variable and included the following: treating items as categorical or continuous variables, separate analysis of individual items, items expressed in terms of the sum total or the mean scores, and a range of score values used to define insight. This paper provides a systematic review of studies using the SUMD and reveals important differences in the versions used, the methods of calculation, and the interpretation of scores across studies. The use of a modified SUMD may compromise the psychometric properties of the scale, lead to erroneous conclusions, and prevents comparison of results across studies. Our review underlines the need for the standardised use of the SUMD. PMID- 23636992 TI - The authors respond: a multisite study of long-term remission and relapse of type 2 diabetes mellitus following gastric bypass. PMID- 23636991 TI - Letter to the editor: a multisite study of long-term remission and relapse of type 2 diabetes mellitus following gastric bypass. PMID- 23636993 TI - Rejecting the demise of vertical-banded gastroplasty: a long-term single institute experience. AB - Surgical interventions have proven to be more effective than other measures in the treatment of morbid obesity. The short-term outcomes of the various surgical interventions have been well documented in the literature, with fewer reports on long-term outcomes. The reported long-term outcome of the vertical-banded gastroplasty (VBG) is conflicting. The aim of the present study was to evaluate our long-term experience with VBG. A retrospective review of a prospectively maintained database was conducted. Records of patients who underwent VBG five or more years ago were retrieved. An analysis of the long-term weight changes and reported complications was conducted. The study included 150 patients: 43 males (29%) and 107 females (71%). Their mean age was 30 years old (12-53), and the mean body mass index (BMI) was 47 +/- 8.4 kg/m2. Patients were followed up for an average of 8 years (5-11). More than 60 % of patients had good long-term weight loss (EWL > 50%). A significant negative correlation was found between the excess weight loss percent (EWL%) and the pre-operative BMI (p < 0.05). The differences in EWL% between males and females were not significant (p = 0.061). Nevertheless, the change in EWL% over time for both males and females was significant (p = 0.004). Revision surgery was required in seven patients (4.7%). Five patients had conversion of VBG to gastric bypass (3.3%), while two patients (1.3%) had reversal of the procedure. Late complications included mesh erosion in three cases, staple line dehiscence in two patients, and stomal stenosis in six patients. VBG could be a long-term effective intervention for the treatment of morbid obesity. Good selection is the cornerstone for long-term success. Late complication rate is acceptable after VBG. VBG is a specifically useful tool under stringent financial circumstances. PMID- 23636995 TI - Bariatric surgery for the treatment of severely obese patients in South Korea--is it cost effective? AB - BACKGROUND: In South Korea, the number of severely obese patients has increased. An economic study comparing bariatric surgery with nonsurgical interventions has not been published for Asia. OBJECTIVES: This study was conducted to evaluate the cost effectiveness of bariatric surgery as compared to nonsurgical interventions for severe obese Korean people. METHODS: We used the Markov model to compare the lifetime expected costs and quality-adjusted life years (QALYs) between bariatric surgery and nonsurgical interventions from Korean Healthcare system perspectives. Our target cohort consisted of severe obese people defined as having a body mass index of 30-<40 kg/m(2) in South Korea. The starting age of the cohort was 30 years old, and the cycle length was 1 year. Nonsurgical interventions included a physician visit, exercise, diet, and pharmacotherapy. A discount of 5 % was applied in cost and QALY. The incremental cost-effectiveness ratio (ICER) of bariatric surgery compared to nonsurgery interventions was calculated. RESULTS: The cost-utility analysis study indicated that bariatric surgery had US$1,522 incremental costs and 0.86 incremental QALYs as compared to nonsurgical interventions. Through the base case analysis, ICER was US$1,771/QALY. The sensitivity analyses were performed using a variety of assumptions, and the robustness of the study results was also demonstrated. CONCLUSION: The study indicated that bariatric surgery was a cost-effective alternative to nonsurgical interventions over a lifetime, providing substantial lifetime benefits for severely obese Korean people. PMID- 23636994 TI - Bariatric surgery patients exhibit improved memory function 12 months postoperatively. AB - BACKGROUND: Previous work from our group demonstrated improved memory function in bariatric surgery patients at 12 weeks postoperatively relative to controls. However, no study has examined longer-term changes in cognitive functioning following bariatric surgery. METHODS: A total of 137 individuals (95 bariatric surgery patients and 42 obese controls) were followed prospectively to determine whether postsurgery cognitive improvements persist. Potential mechanisms of change were also examined. Bariatric surgery participants completed self-report measurements and a computerized cognitive test battery prior to surgery and at 12 week and 12-month follow-up; obese controls completed measures at equivalent time points. RESULTS: Bariatric surgery patients exhibited cognitive deficits relative to well-established standardized normative data prior to surgery, and obese controls demonstrated similar deficits. Analyses of longitudinal change indicated an interactive effect on memory indices, with bariatric surgery patients demonstrating better performance postoperatively than obese controls. CONCLUSIONS: While memory performance was improved 12 months postbariatric surgery, the mechanisms underlying these improvements were unclear and did not appear attributable to obvious postsurgical changes, such as reductions in body mass index or comorbid medical conditions. Future studies employing neuroimaging, metabolic biomarkers, and more precise physiological measurements are needed to determine the mechanisms underlying memory improvements following bariatric surgery. PMID- 23636996 TI - Impact of laparoscopic sleeve gastrectomy on upper gastrointestinal symptoms. AB - BACKGROUND: Altered gastric anatomy following laparoscopic sleeve gastrectomy (LSG) is likely to induce upper gastrointestinal (GI) symptoms. Published studies, however, have focused mainly on gastroesophageal reflux disease (GERD). This study aims to evaluate LSG's impact on the prevalence of upper GI symptoms and to assess the effects of time from surgery, weight loss, and proton pump inhibitor (PPI) therapy. METHODS: The validated Rome III Criteria symptom questionnaire for upper GI symptoms, including quality of life items, has been self-administered to 97 patients who underwent LSG. Symptoms were analyzed either separately or altogether to classify patients in GERD or dyspepsia, subdivided in epigastric pain (EPS) and post-prandial distress (PDS) syndromes. RESULTS: Before LSG, 52.7% of the patients were asymptomatic, 27.0% had GERD, and 8.1% had dyspepsia (2.7% EPS, 5.4% PDS). After a median follow-up of 13 months, 91.9% of the patients complained of upper GI symptoms, the most prevalent being PDS (59.4 %). GERD prevalence did not differ before and after LSG. The only symptom strongly related to LSG was dysphagia (OR 4.7, 95% CI 1.3-20.4, p = 0.015), which was present in 19.7% of the patients and mainly associated with PDS rather than GERD. GI symptoms, however, did not have a great impact on quality of life. Time from surgery, weight loss after surgery, as well as concomitant PPI, did not influence the symptoms. CONCLUSIONS: After a median follow-up of 13 months, PDS like dyspepsia, rather than GERD, was the main complaint, both poorly responding to PPI therapy. A longer follow-up will be necessary to evaluate their future persistency. PMID- 23636997 TI - Pre-operative weight loss does not predict weight loss following laparoscopic adjustable gastric banding. AB - BACKGROUND: This study aimed to test the hypothesis that the amount of weight lost on a mandatory 2-week pre-operative very-low-calorie diet (VLCD) would predict the longer-term outcomes of laparoscopic adjustable gastric banding (LAGB). METHODS: All patients treated with a primary LAGB from 21 October 2008 until 30 June 2010, who were prescribed a 2-week pre-operative VLCD, have been included in the study. Patient age, weight, BMI and excess weight (defined as weight above a BMI of 25) were extracted on the day of first visit, day of surgery and at the post-operative visits at 3, 12 and 24 months. From these data, percent excess weight loss (EWL) was calculated and compared at all time points. RESULTS: The weight loss achieved on a mandatory 2-week pre-operative diet did not predict weight outcomes at 2 years (r = -0.008; p = 0.931). Using multivariate analysis, the best predictor of 24-month percent EWL was percent EWL at 3 months post operation (sr(2) = 0.34; p = 0.003). CONCLUSIONS: Results from a pre-operative diet should not be used to predict the ultimate outcome of bariatric surgery. The weight loss at 3 months following LAGB was a strong predictor of longer-term outcomes. There may be potential for improving longer term results with LAGB by better supporting patients who are not achieving good weight loss at this early time point. PMID- 23636998 TI - Duodenal-jejunal bypass improves glucose metabolism and adipokine expression independently of weight loss in a diabetic rat model. AB - BACKGROUND: There is accumulating evidence that adipokines lead to a proinflammatory state, which plays crucial roles in insulin resistance and development of type 2 diabetes mellitus (T2DM). Previous studies demonstrated that weight loss after bariatric surgery is accompanied by a suppression of the proinflammatory state. However, the effect of bariatric surgery on adipokine expression beyond weight loss is still elusive. The aim of this study was to investigate the effect of duodenal-jejunal bypass (DJB) on glucose homeostasis and adipokine expression independently of weight loss. METHODS: A T2DM rat model was developed by a high-fat diet and low dose of streptozotocin. Twenty-one diabetic rats and 10 age-matched SD rats were randomly assigned to the DJB group, sham-DJB (S-DJB) group, and control group. For 12 weeks after surgery, their body weight, food intake, glucose homeostasis, lipid parameters, serum adipokine levels, and adipokine gene expression in the mesocolon adipose tissue were measured. RESULTS: Compared to the S-DJB group, DJB induced significant and sustained glycemic control with improved insulin sensitivity and glucose tolerance independently of weight loss. DJB improved the lipid metabolism by decreasing fasting free fatty acids and triglycerides. Serum leptin and IL-6 significantly decreased 12 weeks after DJB, whereas adiponectin increased and TNF alpha remained unchanged. The mRNA expression levels of leptin, TNF-alpha, and IL 6 decreased, whereas adiponectin increased in the mesocolon adipose tissue. CONCLUSION: DJB reduced the proinflammatory adipokines and increased the anti inflammatory adipokines independently of weight loss, which may contribute to the improvement of insulin sensitivity. PMID- 23636999 TI - Moderate physical activity as predictor of weight loss after bariatric surgery. AB - BACKGROUND: The prevalence of obesity is 33% and is expected to reach 50% based on current US trends. Bariatric surgery is effective in producing long-term weight loss, yet it requires adherence to the recommended diet and physical activity. This study assessed whether the short-form International Physical Activity Questionnaire (IPAQ-SF) data at 1 year postbariatric surgery would correlate with success (defined as more than 50% excess weight loss (EWL)) after surgery. METHODS: The IPAQ-SF questionnaire provided assessment of subjects' activity level over the last 7 days, in four separate activity domains: vigorous, moderate, walking, and sitting. RESULTS: Questionnaires were completed and collected at the 1-year postbariatric surgery group visit. Then, 118 subjects who completed the IPAQ-SF were subdivided based on loss of greater than or less than 50% of their excess weight, which in turn was based on ideal body weight. In subjects with >=50% EWL (n = 49), we noted 67.1 +/- 8.8% EWL versus 33.2 +/- 9.4% in those with <50% EWL (n = 69) (p < 0.001). The >=50% EWL group performed 420 (216-960) min of total activity per week versus 300 (172-718) min for the <50% group. The >=50% EWL group engaged in 120 (8-180) min of vigorous activity, 150 (28-330) min of moderate activity, and 233 (109-512) min of walking versus 40 (0 255), 68 (0-204), and 188 (83-341) min, respectively, for the <50% EWL group. CONCLUSIONS: Physical activity does correlate with success after bariatric surgery, as measured by excess weight loss (>=50% EWL). PMID- 23637000 TI - Bringing proteomics into the clinic: the need for the field to finally take itself seriously. AB - Proteomics has fast become a standard tool in the life sciences, with increasingly sophisticated approaches and instruments delivering ever growing numbers of identified and quantified proteins. Yet despite the enormous technological progress, and the triumphant papers published on whole-cell proteomes being collected and analyzed, proteomics has so far failed to enter the clinic for routine applications. This is a peculiar contradiction, and one that warrants some closer study. I here argue that for proteomics to make a difference in the clinic, it needs to stop shirking responsibility, and to mature into an analytical, transparent, and reproducible discipline that also invests in the consolidation of its technology rather than only focusing on the next big leap forward. A key enabling factor in this maturation process is quality control and quality assurance, with bioinformatics, in its least noticeable but most influential form, as a key underlying technology. PMID- 23637001 TI - Magnetic susceptibility induced white matter MR signal frequency shifts- experimental comparison between Lorentzian sphere and generalized Lorentzian approaches. AB - PURPOSE: The nature of the remarkable phase contrast in high-field gradient echo MRI studies of human brain is a subject of intense debates. The generalized Lorentzian approach (He and Yablonskiy, Proc Natl Acad Sci USA 2009;106:13558 13563) provides an explanation for the anisotropy of phase contrast, the near absence of phase contrast between white matter and cerebrospinal fluid, and changes of phase contrast in multiple sclerosis. In this study, we experimentally validate the generalized Lorentzian approach. THEORY AND METHODS: The Generalized Lorentzian Approach suggests that the local contribution to frequency shifts in white matter does not depend on the average tissue magnetic susceptibility (as suggested by Lorentzian sphere approximation), but on the distribution and symmetry of magnetic susceptibility inclusions at the cellular level. We use ex vivo rat optic nerve as a model system of highly organized cellular structure containing longitudinally arranged myelin and neurofilaments. The nerve's cylindrical shape allowed accurate measurement of its magnetic susceptibility and local frequency shifts. RESULTS: We found that the volume magnetic susceptibility difference between nerve and water is -0.116 ppm, and the magnetic susceptibilities of longitudinal components are -0.043 ppm in fresh nerve, and 0.020 ppm in fixed nerve. CONCLUSION: The frequency shift observed in the optic nerve as a representative of white matter is consistent with generalized Lorentzian approach but inconsistent with Lorentzian sphere approximation. PMID- 23637002 TI - A simple, flexible, and effective covariate-adaptive treatment allocation procedure. AB - We present a method for allocating treatment when subjects arrive in sequence. Based on the theory of propensity scores more commonly used in observational studies, the method balances both discrete and continuous covariates without assuming a model for the outcome. Although we allow for a number of possible specifications, we explore some specific instances in depth. The proposed method is compared with previously suggested sequential randomization and allocation procedures with relationships to some well-known methods highlighted. Through simulations, the deterministic version is shown to achieve both covariate balance and near optimum efficiency with minimal assumptions. We also investigate the properties of selected randomized versions with respect to both optimality and selection bias. We conclude with an application to a pilot study on weight loss. The proposed method is shown to be robust to the number of covariates balanced and the marginal and joint distributions of those covariates. PMID- 23637003 TI - Prothrombotic states in migraine. AB - The increased risk of cardiovascular and cerebrovascular events in patients with migraine remains unexplained. Prothrombotic states are thought to contribute to this increased risk. The present study aimed to compare the prevalence of prothrombotic states in patients with migraine and headache-free controls. We conducted a case-control study to screen for prothrombotic states protein C, protein S (PS), antithrombin III, factor V Leiden, lupus anticoagulant, anticardiolipin, and anti-beta2-glycoprotein 1 antibodies in 101 consecutive patients with migraine and 148 controls. An underlying prothrombotic state was encountered in 11.8% of the patients with migraine, PS deficiency being the most common (4.0%). There was no significant difference in the prevalence of prothrombotic states in patients with migraine compared to controls. Traditional prothrombotic states do not seem to have a higher prevalence in patients with migraine compared to controls. PMID- 23637004 TI - Venous thromboembolism in patients with prior stroke. AB - Patients with prior stroke are susceptible to venous thromboembolism (VTE). We studied patients with stroke in the Worcester VTE study of 2488 consecutive patients hospitalized with VTE. In all, 288 (11.6%) had a clinical history of stroke and 2200 (88.4%) did not. Patients with stroke were more likely to die inhospital (9.2% vs 4%) and within 30 days of VTE diagnosis (16.7% vs 6.9%) compared with patients without stroke (all P < .001). Recent immobilization (adjusted odds ratio [OR] 2.15; 95% confidence interval [CI] 1.15-4.09) and inferior vena cava (IVC) filter insertion (adjusted OR 2.1; 95% CI 1.15-3.83) were associated with a doubling of inhospital death. Recent immobilization (adjusted OR 1.84; 95% CI 1.19-2.83) and IVC filter insertion (adjusted OR 1.94; 95% CI 1.2-3.14) were associated with an increased risk of death within 30 days of VTE. In conclusion, patients with VTE and prior stroke were more than twice as likely to die while hospitalized and within 30 days of VTE diagnosis. PMID- 23637005 TI - Recombinant human thrombopoietin alleviates infection-associated thrombocytopenia: a retrospective study in senile patients. AB - OBJECTIVE: To examine the efficacy and adverse events of recombinant human thrombopoietin (rhTPO) in the treatment of infection-associated thrombocytopenia in senile patients. METHODS: The current study is a retrospective analysis of the patients receiving rhTPO for infection-associated thrombocytopenia in our hospital. RESULTS: Forty-nine cases were included in the analysis as rhTPO group. The absolute platelet count after treatment, increase in platelet count, and the overall response rate were considerably higher in the rhTPO group than that in the control group. Improvement in bleeding score was higher in the rhTPO treatment group than that in the control group (2.1 +/- 5.4 vs 0.4 +/- 1.7). Bleeding event was stopped in 68.2% of the patients after rhTPO treatment and in 35% of the patients in the control group (P = .032). A stratified analysis indicated that the therapeutic efficacy is much better in patients without organ failure. CONCLUSION: Recombinant human TPO is effective in alleviating infection associated thrombocytopenia and hemorrhage in senile patients, particularly if given prior to the emergence of organ failure. PMID- 23637006 TI - Oculoauriculofrontonasal syndrome: case series revealing new bony nasal anomalies in an old syndrome. AB - Frontonasal Dysplasia (FND) and Oculo-auriculo-vertebral spectrum (OAVS) are two well-recognized clinical entities. With features of both FND and OAVS, the term oculoauriculofrontonasal syndrome (OAFNS) was coined in 1981. The OAFNS phenotype combines elements of abnormal morphogenesis of the frontonasal and maxillary process (derived from forebrain neural crest) with abnormal development of the first and second branchial arches (derived from hindbrain neural crest). We present a case series of 33 children with OAFNS ascertained from a comprehensive review of the literature and report an additional retrospective series of eight patients displaying features consistent with OAFNS. Notably, in a subset of our cases, we have observed abnormalities in nasal ossification and bony structures of the maxilla that have not previously described in OAFNS and are not seen in either FND or OAVS. We present the phenotype and novel naso-maxillary findings and explore potential etiologic and developmental pathways for OAFNS. We highlight the differences in phenotypic characteristics of OAFNS compared to OAVS and FND. These observations support the classification of OAFNS as a discrete syndrome. Further phenotypic refinements of OAFNS are needed to understand pathogenesis of this syndrome and the newly described nasal malformation may help identify the etiology. PMID- 23637007 TI - Surgery for metastasis to the pancreas: is it safe and effective? AB - BACKGROUND: Pancreatic metastases are rare and only sparse data exists on treatment options. After recent advances in pancreatic surgery, metastasectomies have become promising treatment alternatives. METHODS: Twenty-six patients underwent pancreatic metastasectomy between 1991 and 2010 at our institution. Data was evaluated retrospectively. RESULTS: Renal cell carcinoma was the most common origin of pancreatic metastases (n = 16; 62%). Other primaries include gall bladder carcinoma, leiomyosarcoma, colon cancer (all n = 2), and others. The median time interval between primary tumor and pancreatic resection was 5.3 years [0-24]. Eleven pancreatic head resections (42%), fourteen distal pancreatectomies (54%), and one total pancreatectomy were performed (4%). The estimated 3- and 5 year survival rates were 73.2% and 52.3%, respectively. The estimated median overall survival was 63 months (CI: 37.8-88.1 months). There' was no perioperative death. The complication rate and relaparotomy rate was 31% and 19%, respectively. Patients suffering from synchronous metastases at the time of pancreatic surgery had a statistically significant shorter median overall survival time (11 months vs. 64 months). CONCLUSIONS: Despite the operative risk involved, we believe that pancreatic resection should be considered in selected patients with good performance status, stable disease and isolated pancreatic metastases. PMID- 23637008 TI - Randomness and multilevel interactions in biology. AB - The dynamic instability of living systems and the "superposition" of different forms of randomness are viewed, in this paper, as components of the contingently changing, or even increasing, organization of life through ontogenesis or evolution. To this purpose, we first survey how classical and quantum physics define randomness differently. We then discuss why this requires, in our view, an enriched understanding of the effects of their concurrent presence in biological systems' dynamics. Biological randomness is then presented not only as an essential component of the heterogeneous determination and intrinsic unpredictability proper to life phenomena, due to the nesting of, and interaction between many levels of organization, but also as a key component of its structural stability. We will note as well that increasing organization, while increasing "order", induces growing disorder, not only by energy dispersal effects, but also by increasing variability and differentiation. Finally, we discuss the cooperation between diverse components in biological networks; this cooperation implies the presence of constraints due to the particular nature of bio-entanglement and bio-resonance, two notions to be reviewed and defined in the paper. PMID- 23637010 TI - When the voluntary mind meets the irresistible event: stimulus-response correspondence effects on task selection during voluntary task switching. AB - In the present study, we investigated how task selection is biased by inherent stimulus characteristics in the voluntary task-switching paradigm. We used digits as the task stimuli, since they may automatically induce spatially horizontal representations of numbers. Specifically, we examined whether an irrelevant spatial representation of a number coincides with its associated response codes and whether such a stimulus-response (S-R) correspondence effect biases task selection for a digit. Participants were randomly assigned to one of two different action code layout conditions: Two numerical tasks were arranged as inner/outer in the horizontal layout condition or as upper/down in the vertical layout condition. Participants in the horizontal layout condition were more likely to choose a task when the task's action code and the digit's spatial representation corresponded, as compared with when they did not. On the other hand, no selection bias was observed in the vertical layout condition, since there was no overlapping spatial representation between the stimulus and response. The present study extends previous findings by considering the influence of the stimulus-driven effect on task selection with regard to the S-R correspondence effect. PMID- 23637009 TI - Vaccination and inflammatory arthritis: overview of current vaccines and recommended uses in rheumatology. AB - Patients with autoimmune inflammatory rheumatic diseases are prone to infectious complications during the course of their disease. The underlying disease with an impaired immune system and additional different immunosuppressive medication render patients more susceptible to infections, some of which are potentially preventable with vaccination. Since it is not clear how strongly the underlying and medication-induced immunosuppression interferes with vaccination, a lot of questions remain about its indications, efficacy and safety . Due to these unresolved questions, in 2011, EULAR published general guidelines about vaccination in patients with autoimmune rheumatic diseases. These guidelines provide a basis for patient care and are also the basis of the following review article. With more available and earlier used immunosuppressive medications, a lot of questions still remain about optimal use of vaccines, the role of different medication combinations on efficacy and safety of vaccinations especially of the actual prevention of disease, the role of age, gender, disease activity and duration, and optimal revaccination schedules in this patient group. Actual studies elute the role of different medication combinations on efficacy and safety mainly addressing influenza and pneumococcal vaccination. In addition, interesting new data on basic immunological processes during TNF-alpha-blockade open up questions for further research. PMID- 23637011 TI - Individual differences in fixation duration distributions in reading. AB - The present study investigated the relationship between the location and skew of an individual reader's fixation duration distribution. The ex-Gaussian distribution was fit to eye fixation data from 153 subjects in five experiments, four previously presented and one new. The tau parameter was entirely uncorrelated with the MU and sigma parameters; by contrast, there was a modest positive correlation between these parameters for lexical decision and speeded pronunciation response times. The conclusion that, for fixation durations, the degree of skew is uncorrelated with the location of the distribution's central tendency was also confirmed nonparametrically, by examining vincentile plots for subgroups of subjects. Finally, the stability of distributional parameters for a given subject was demonstrated to be relatively high. Taken together with previous findings of selective influence on the MU parameter of the fixation duration distribution, the present results suggest that in reading, the location and the skew of the fixation duration distribution may reflect functionally distinct processes. The authors speculate that the skew parameter may specifically reflect the frequency of processing disruption. PMID- 23637013 TI - Optical characterization of InAs quantum wells and dots grown radially on wurtzite InP nanowires. AB - Correlated micro-photoluminescence (MUPL) and cathodoluminescence (CL) measurements are reported for single core-shell InP-InAs wurtzite nanowires grown using metal-organic vapor phase epitaxy. Samples covering a radial InAs shell thickness of 1-12 ML were investigated. The effective masses for the wurtzite material were determined from the transition energy dependence of the InAs shell thickness, using a model based on linear deformation potential theory. InP cores with segments of mixed zincblende and wurtzite, on which quantum dots nucleated selectively, were also investigated. Narrow peaks were observed by MUPL and the spatial origin of the emission was identified with CL imaging. PMID- 23637012 TI - Lamellar hydrogels with high toughness and ternary tunable photonic stop-band. AB - A lamellar hydrogel with high toughness, exhibiting ternary stimuli-responsive structural color changes has been synthesized. The gel consists of alternating hard layers of a polymeric surfactant (PDGI) and soft layers of interpenetrating networks of poly(acrylamide)-poly(acrylic acid). Reversible, wide range switching of the stop-band position was achieved using different external stimuli of temperature, pH, and stress/strain. PMID- 23637015 TI - Revisiting the 2011 FDA decision on laparoscopic adjustable gastric banding. PMID- 23637014 TI - The Babinski-2 sign in hemifacial spasm. AB - BACKGROUND: Hemifacial spasm is a common movement disorder. Differential diagnosis relies on clinical examination and is often difficult. The Babinski-2 sign is an underrecognized physical sign specifically found in patients with hemifacial spasm, although its prevalence and usefulness are a matter of debate. METHODS: We examined 35 patients with hemifacial spasm prospectively for the presence of the Babinski-2 sign. We evaluated its correlation with severity of hemifacial spasm, concomitant facial nerve paralysis, and response to botulinum toxin. Twelve patients with blepharospasm served as the control population. RESULTS: The data for the Babinski-2 sign demonstrated high prevalence (86%), high specificity (100%), and high interrater reliability (92%). CONCLUSIONS: Increased awareness of the Babinski-2 sign may aid diagnosis and potentially prompt earlier initiation of appropriate treatment. (c) 2013 Movement Disorder Society. PMID- 23637017 TI - Testing and estimation of proportion (or risk) ratio under the matched-pair design with multiple binary endpoints. AB - The proportion ratio (PR) of responses between an experimental treatment and a control treatment is one of the most commonly used indices to measure the relative treatment effect in a randomized clinical trial. We develop asymptotic and permutation-based procedures for testing equality of treatment effects as well as derive confidence intervals of PRs for multivariate binary matched-pair data under a mixed-effects exponential risk model. To evaluate and compare the performance of these test procedures and interval estimators, we employ Monte Carlo simulation. When the number of matched pairs is large, we find that all test procedures presented here can perform well with respect to Type I error. When the number of matched pairs is small, the permutation-based test procedures developed in this paper is of use. Furthermore, using test procedures (or interval estimators) based on a weighted linear average estimator of treatment effects can improve power (or gain precision) when the treatment effects on all response variables of interest are known to fall in the same direction. Finally, we apply the data taken from a crossover clinical trial that monitored several adverse events of an antidepressive drug to illustrate the practical use of test procedures and interval estimators considered here. PMID- 23637016 TI - De novo 19p13.2 microdeletion encompassing the insulin receptor and resistin genes in a patient with obesity and learning disability. AB - Genetic studies have provided novel insights of appetite regulation and pathophysiology of obesity. The adipose tissue is an active endocrine organ secreting several hormones contributing to insulin resistance and the development of the comorbidities of obesity, such as type 2 diabetes and cardiovascular disease. Herein, we report on a patient with severe obesity and mild learning disability with a 750 kb de novo deletion of chromosome 19. The deletion encompasses several genes, including resistin and the first part of the insulin receptor, genes that are relevant for obesity. This novel deletion may therefore represent a region for obesity research. Plasma analyses and gene expression demonstrated that the deletion resulted in haploinsufficiency for resistin and insulin receptor in the patient compared to controls. We then studied the biochemical and adipocytokine profile in these subjects. We observed no differences in glucose and lipid parameters between the patient and the controls. Thus, haploinsufficiency of insulin receptor and resistin does not appear to influence glucose and lipid metabolism. However, the patient had considerably higher values of adiponectin and TNFalpha than controls. In conclusion, we identified a 19p13.2 microdeletion encompassing the insulin receptor and resistin genes resulting in haploinsufficiency in an obese, but otherwise healthy patient. No firm conclusions could be drawn regarding the potential effect of the microdeletion on adipokine profile. PMID- 23637018 TI - In response to the comments by Fernandes et al. PMID- 23637019 TI - Inhibition of CK2 binding to BMPRIa induces C2C12 differentiation into osteoblasts and adipocytes. AB - BMP2 is a growth factor that regulates the cell fate of mesenchymal stem cells into osteoblast and adipocytes. However, the detailed signaling pathways and mechanism are unknown. We previously reported a new interaction of Casein kinase II (CK2) with the BMP receptor type-Ia (BMPRIa) and demonstrated using mimetic peptides CK2.1, CK2.2 and CK2.3 that the release of CK2 from BMPRIa activates Smad signaling and osteogenesis. Previously, we showed that mutation of these CK2 sites on BMPRIa (MCK2.1 (476S-A), MCK2.2 (324S-A) and MCK2.3 (214S-A)) induced osteogenesis. However, one mutant MCK2.1 induced osteogenesis similar to overexpression of wild type BMPRIa, suggesting that the effect of this mutant on mineralization was due to overexpression. In this paper we investigated the signaling pathways involved in the CK2-BMPRIa mediated osteogenesis and identified a new signaling pathway activating adipogenesis dependent on the BMPRIa and CK2 association. Further the mechanism for adipogenesis and osteogenesis is specific to the CK2 interaction site on BMPRIa. In detail our data show that overexpression of MCK2.2 induced osteogenesis was dependent on Caveolin-1 (Cav1) and the activation of the Smad and mTor pathways, while overexpression of MCK2.3 induced osteogenesis was independent of Caveolin-1 without activation of Smad pathway. However, MCK2.3 induced osteogenesis via the MEK pathway. The adipogenesis induced by the overexpression of MCK2.2 in C2C12 cells was dependent on the p38 and ERK pathways as well as Caveolin-1. These data suggest that signaling through BMPRIa used two different signaling pathways to induce osteogenesis dependent on CK2. Additionally the data supports a signaling pathway initiated in caveolae and one outside of caveolae to induce mineralization. Moreover, they reveal the signaling pathway of BMPRIa mediated adipogenesis. PMID- 23637020 TI - Conduction disorders after transcatheter aortic valve implantation: a focused review. AB - OPINION STATEMENT: Transcatheter aortic valve implantation (TAVI) is a less invasive approach to aortic valve replacement than traditional open chest surgery. It has been very successful in elderly and sick patients who might have otherwise been turned down for surgery. However, many patients who have the procedure develop conduction disease, including new LBBB or complete heart block, and may need permanent pacing or ongoing follow-up to monitor for worsening conduction problems. Here we discuss the risk for conduction disease with TAVI, identifying which patients may need a pacemaker or long-term rhythm follow-up, and methods to decrease the risk of worsening conduction. PMID- 23637021 TI - Analysis of methods to determine the latency of online movement adjustments. AB - When studying online movement adjustments, one of the interesting parameters is their latency. We set out to compare three different methods of determining the latency: the threshold, confidence interval, and extrapolation methods. We simulated sets of movements with different movement times and amplitudes of movement adjustments, all with the same known latency. We applied the three different methods in order to determine when the position, velocity, and acceleration of the adjusted movements started to deviate from the values for unperturbed movements. We did so both for averaged data and for the data of individual trials. We evaluated the methods on the basis of their accuracy and precision, and according to whether the latency was influenced by the intensity of the movement adjustment. The extrapolation method applied to average acceleration data gave the most reliable estimates of latency, according to these criteria. PMID- 23637023 TI - Controlled fabrication and photonic structure of cholesteric liquid crystalline shells. AB - Omnidirectional laser action in W/O/W emulsion with CLC shells is demonstrated. The emulsion, in which the helical axis of the CLC phase is normal to the surface, is successfully fabricated by using a microfluidic device. The whole emulsion system with dispersed core-shell droplets with a CLC shell can serve as a flexible omnidirectional resonator for dye lasers. PMID- 23637022 TI - Why do we do as we do? Factors influencing clinical reasoning and decision-making among physiotherapists in an acute setting. AB - INTRODUCTION: Despite the current movement for health-care to become more informed by evidence, knowledge on effective implementation of evidence-based practice is scarce. To improve research application among physiotherapists, the process of implementation and clinical reasoning needs to be scrutinized. The aim of this study was to identify various experiences of factors that influence the physiotherapist's clinical reasoning in specialist care. METHODS DESIGN: A phenomenographic approach was chosen. SUBJECTS: Eleven physiotherapists at two acute care hospitals in nn. PROCEDURE: Data was obtained by observations and interviews. Phenomenographic data analysis identified various experiences of clinical decision-making. ETHICAL CONSIDERATIONS: The Ethical Review Board of the nn approved the study. RESULTS: The observations and the interviews enabled identification of various experiences that influenced clinical decision-making. The physiotherapists' clinical reasoning was perceived to be constrained by contextual factors. The physiotherapists collected current information on the patient by using written and verbal information exchange and used this to generate an inner picture of the patient. By creating hypotheses that were accepted or rejected, they made decisions in advance of their interventions. The decisions were influenced by the individual characteristics of the physiotherapist, his/her knowledge and patient perceptions. CONCLUSIONS: Clinical reasoning is a complex and constantly evolving process. Contextual factors such as economy and politics are not easily changed, but factors such as the patient and the physiotherapist as a person are more tangible. PMID- 23637024 TI - Highly ordered Pb(Zr0.52 Ti0.48)O3 piezoelectric nanorod arrays. AB - One-dimensional (1D) piezoelectric nanostructures have attracted significant attention for a broad range of applications including optoelectronics, thermoelectrics, electrochemical and electromechanical converters. We demonstrate the synthesis of 1D nanostructures based upon Pb(Zr0.52Ti0.48)O3 (PZT) on conductive substrates via sol-gel template synthesis. The vertically aligned PZT nanostructures with heights around one micron were synthesized by vacuum infiltration of sol-gel precursors into highly ordered cylindrical pores of anodized aluminum oxide templates. The 1D nanostructures were developed on large scale platinized silicon wafers and exhibited dense rod-like structure with a uniform diameter of 90 nm and an aspect ratio of 10. Scanning probe microscopy conducted on individual nanorods demonstrated good electromechanical properties with a high piezoelectric magnitude of 41 pm V(-1). We believe that this study opens the possibility of developing high performance nanoscale piezoelectric sensors and transducers. PMID- 23637026 TI - Feasibility study of semi-selective protein precipitation with salt-tolerant copolymers for industrial purification of therapeutic antibodies. AB - We present a feasibility study for an antibody capturing process from clarified cell culture fluid using semi-selective protein precipitation with salt-tolerant copolymers. Protein precipitation is mediated by hydrophobic and electrostatic interactions with the copolymer that can be customized for the respective target. Precipitation yield with different copolymers at ionic strength of 2-22.5 mS cm-1 and pH 5.0-pH 5.7 was evaluated using pure monoclonal antibody solutions. Optimized parameters were used to elucidate yield and purity of various antibodies precipitated at physiological conditions from cell culture fluid of CHO, NS0, and SP2/0 cell culture fluid. Precipitated protein was easily redissolved in small volume, enabling concentrating monoclonal antibodies (mAb) more than 40-fold and up to 100-fold, while residual polymer was removed to >98% using cationic polymer attached to silica flakes. mAb recovery of >90% and host cell protein clearance of >80% were achieved, not requiring any pre-dilution of cell culture fluid. Precipitation showed no impact on mAb binding affinity when compared to non-precipitated mAb. The obtained yield and purity were lower compared to a protein A based purification and loss of mAb was factor 1.5-3.0 higher. Yet, for high titer mAb purification processes being implemented in the future, precipitation is an attractive option due to its ease of scalability and cost-effectiveness. PMID- 23637025 TI - Clinical correlations of mutations affecting six components of the SWI/SNF complex: detailed description of 21 patients and a review of the literature. AB - Mutations in the components of the SWItch/sucrose nonfermentable (SWI/SNF)-like chromatin remodeling complex have recently been reported to cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and ARID1B-related intellectual disability (ID) syndrome. We detail here the genotype-phenotype correlations for 85 previously published and one additional patient with mutations in the SWI/SNF complex: four with SMARCB1 mutations, seven with SMARCA4 mutations, 37 with SMARCA2 mutations, one with an SMARCE1 mutation, three with ARID1A mutations, and 33 with ARID1B mutations. The mutations were associated with syndromic ID and speech impairment (severe/profound in SMARCB1, SMARCE1, and ARID1A mutations; variable in SMARCA4, SMARCA2, and ARID1B mutations), which was frequently accompanied by agenesis or hypoplasia of the corpus callosum. SMARCB1 mutations caused "classical" CSS with typical facial "coarseness" and significant digital/nail hypoplasia. SMARCA4 mutations caused CSS without typical facial coarseness and with significant digital/nail hypoplasia. SMARCA2 mutations caused NCBRS, typically with short stature, sparse hair, a thin vermillion of the upper lip, an everted lower lip and prominent finger joints. A SMARCE1 mutation caused CSS without typical facial coarseness and with significant digital/nail hypoplasia. ARID1A mutations caused the most severe CSS with severe physical complications. ARID1B mutations caused CSS without typical facial coarseness and with mild digital/nail hypoplasia, or caused syndromic ID. Because of the common underlying mechanism and overlapping clinical features, we propose that these conditions be referred to collectively as "SWI/SNF-related ID syndromes". PMID- 23637027 TI - Autologous hematopoietic stem cell transplantation as a treatment option for aggressive multiple sclerosis. AB - OPINION STATEMENT: Despite the development of several injectable or oral treatments for relapsing-remitting multiple sclerosis (RRMS), it remains difficult to treat patients with aggressive disease, and many of these continue to develop severe disability. During the last two decades autologous hematopoietic stem cell transplantation (aHSCT) has been explored with the goal to eliminate an aberrant immune system and then re-install a healthy and tolerant one from hematopoietic precursor cells that had been harvested from the patient prior to chemotherapy. Clinical studies have shown that aHSCT is able to completely halt disease activity in the majority of patients with aggressive RRMS. Research on the mechanisms of action supports that aHSCT indeed leads to renewal of a healthy immune system. Below we will summarize important aspects of aHSCT and mention the currently best-examined regimen. PMID- 23637028 TI - Zolpidem improves tardive dyskinesia and akathisia. PMID- 23637029 TI - LAP-BAND for lower BMI: 2-year results from the multicenter pivotal study. AB - OBJECTIVE: The goal of this study was to examine the safety and effectiveness of the LAP-BAND System for patients with 30-39.9 BMI and associated comorbidities. DESIGN AND METHODS: In this prospective, multicenter, interventional cohort study, subjects with a BMI between 30 and 39.9 who had failed prior weight loss attempts were recruited from 7 surgical centers. The primary effectiveness endpoint required that >40% of subjects achieve >=30% excess weight loss (EWL) at 1 year. Secondary endpoints included assessment of comorbidities and quality-of life. RESULTS: Of 149 subjects, 90.6% were female, with mean BMI of 35.3 kg/m2 . At 1 year, 84.6% of subjects achieved >=30% EWL (P < 0.0001), with 65.0% mean EWL; 66.4% of subjects were no longer obese (BMI < 30). Baseline comorbidities improved at 1 year for 64.4% with dyslipidemia, 59.6% with hypertension, and 85.7% with diabetes. Quality-of-life (IWQOL-Lite) also improved (P < 0.0001). The Year 1 results were maintained or improved at 2 years. Regression analysis indicates that each additional 10% weight loss at Year 2 was associated with an increase in IWQOL-Lite by 7.1 points and a decrease in triglycerides by 13.7 mg/dL, fasting glucose by 3.5 mg/dL, and systolic blood pressure by 3.3 mmHg. Most adverse events were mild to moderate and resolved without sequelae within 1 month. Five subjects (3.4%) had explantations. CONCLUSION: LAGB is safe and effective for people with 30-39.9 BMI, with weight loss and comorbidity improvement through at least 2 years. PMID- 23637030 TI - Electrical muscle stimulation after immediate nerve repair reduces muscle atrophy without affecting reinnervation. AB - INTRODUCTION: Electrical stimulation of denervated muscle has been shown to minimize atrophy and fibrosis and increase force in animal and human models. However, electrical stimulation after nerve repair is controversial due to questions of efficacy. METHODS: Using a rat model, we investigated the efficacy of short-term electrical muscle stimulation for increasing reinnervation and preventing muscle atrophy. After tibial nerve transection and immediate repair with the fibular nerve, 1 month of electrical stimulation was applied 5 days/week for 1 hour to the gastrocnemius muscle via implanted electrodes. RESULTS: After 2 months of further recovery without stimulation, muscle weights, twitch forces, and type I fiber areas were significantly greater in stimulated animals than in repaired controls without stimulation. Motor unit size and numbers were not different between the 2 groups. CONCLUSIONS: Short-term electrical muscle stimulation after nerve repair significantly reduces muscle atrophy and does not affect motor reinnervation. PMID- 23637031 TI - Factors that influence the selection of sterile glove brand: a randomized controlled trial evaluating the performance and cost of gloves. AB - PURPOSE: To determine whether glove use modifies tactile and psychomotor performance of health care providers when compared with no glove use and to evaluate factors that influence the selection of sterile glove brand. METHODS: Forty-two anesthesia providers (nine anesthesiologists, seven nurse anesthetists, 20 residents, six student nurse anesthetists) enrolled in and completed this cross-over randomized trial from May 2010 until August 2011. Participants underwent standardized psychomotor testing while wearing five different types of protective gloves. Assessments of psychomotor performance included tactile, fine motor/dexterity, and hand-eye coordination tests. Subjective ratings of glove comfort and performance were reported at the completion of each glove trial. The manufacturer's suggested retail price was collected for each glove tested. RESULTS: There were statistically significant differences in touch sensitivity for all nerve distributions, with all glove types resulting in less sensitivity than a bare hand. When compared with the non-sterile glove, only the thickest glove tested (Ansell Perry Orthopaedic) was found to have less touch sensitivity. Fine motor dexterity testing revealed no statistically significant differences in time to completion amongst glove types or bare handed performance. In hand-eye coordination testing across treatment conditions, the thickest glove tested (Ansell Perry((r)) Orthopaedic) was the only glove to show a statistically significant difference from a bare hand. There were statistically significant differences in glove comfort ratings across glove types, with latex-free, powder free (Cardinal Esteem((r))), and latex powder-free (Molnlycke-Biogel((r))) rated highest; however, there were no statistically significant differences in subjective performance ratings across glove types. CONCLUSIONS: Given the observed similarities in touch sensitivity and psychomotor performance associated with five different glove types, our results suggest that subjective provider preferences, such as glove comfort, should be balanced against material costs. PMID- 23637032 TI - Starches for fluid therapy: is it time for a re-appraisal, or has the horse left the barn? PMID- 23637033 TI - The catheter-over-needle assembly facilitates delivery of a second local anesthetic bolus to prolong supraclavicular brachial plexus block without time consuming catheterization steps: a randomized controlled study. AB - BACKGROUND: Single-shot delivery of a supraclavicular brachial plexus block is effective for providing outpatient surgical anesthesia; however, patients generally must use oral analgesics to control pain shortly after discharge from the hospital. Catheterized delivery of supraclavicular blocks can be challenging to perform. We aimed to show that administering a second postoperative bolus of local anesthetic through a catheter placed by a catheter-over-needle assembly not only avoids time-consuming steps but also provides an extended analgesic effect compared with the traditional single-shot approach. METHODS: Patients were randomized into two groups: one group received a single-shot supraclavicular block with 25-30 mL of local anesthetic (1.5% lidocaine and 0.125% bupivacaine mixture), while the other group received a supraclavicular block via a catheter over-needle assembly with the same volume and concentration of local anesthetic as for the single-shot block, which was followed by a second bolus of analgesic solution (0.2 % ropivacaine 20 mL) administered postoperatively through the catheter before its removal. The duration between the initial bolus and onset of pain was measured as well as the duration of pain relief from the last bolus. RESULTS: Thirty patients were enrolled and randomized into the single-shot supraclavicular block group (n = 15) and the catheter-over-needle group (n = 15). One patient withdrew from the study, and five patients were lost to follow-up. We observed no significant difference between the two groups in time to perform the blocks. The mean (standard deviation [SD]) times were 3.1 (1.9) min and 4.4 (2.7) min for the top-up group and single-shot group, respectively (single-shot took 1.3 min longer than the catheter-over-needle group; 95% confidence interval [CI]: -0.65 to 3.25; P = 0.17). The mean (SD) duration of analgesia, measured from the beginning of the local anesthetic bolus to the onset of pain requiring rescue analgesia was 617.5 (288) min in the catheter-over-needle group and 377.2 (161.3) min in the single-shot control group (difference = 240.3 min; 95% CI: 46.8 to 433.8; P = 0.03). CONCLUSIONS: Using the catheter-over-needle assembly for supraclavicular brachial plexus block facilitated effective delivery of a supplementary bolus of local anesthetic without extending the time to perform the block or increasing the number of steps. It also prolonged analgesia significantly compared with the single-shot approach. This trial was registered at: ClinicalTrials.gov, ID: NCT01522066. PMID- 23637034 TI - Retraction note to: Diltiazem-lidocaine combination for the attenuation of cardiovascular responses to tracheal intubation in hypertensive patients. PMID- 23637035 TI - Retraction note to: Calcium channel blockers attenuate cardiovascular responses to tracheal extubation in hypertensive patients. PMID- 23637036 TI - Retraction note to: Prophylactic antiemetic therapy with granisetron-droperidol combination in patients undergoing laparoscopic cholecystectomy. PMID- 23637038 TI - Pontine compression caused by "surgiceloma" after trigeminal decompression: case report and literature review. PMID- 23637037 TI - Sickle cell disease related mortality in the United States (1999-2009). AB - BACKGROUND: Little is known about the national outcome of children and adults with sickle cell disease (SCD) given contemporary care. PROCEDURE: We investigated the number of deaths, standardized crude and age-adjusted mortality rates, and causes of death among individuals with SCD across the United States during 1999-2009 according to death certificates by using a publicly available website (http://wonder.cdc.gov/). Data were compared to mortality during 1979 1998. RESULTS: When compared to 1979-1998, mortality significantly decreased by 61% in infants <1 year of age, by 67% in children aged 1-4 years, and by 22-35% in children aged 5-19 years. After 19 years of age, mortality rates increased from 0.6 in the 15-19 year group to 1.4/100,000 in the 20-24 year group, corresponding to the transition period from pediatric to adult medical care, and this increase was similar during 1979-1998. Although the age groups with the highest mortality were 35-44 years for males and 45-54 years for females, there was a tendency for longer survival because there were more deaths among those individuals 55-74 years of age compared to previous years. For all individuals, the causes of deaths were cardiac disease (31.6%), respiratory (28.1%), renal (16.4%), infectious (14.4%), neurologic (11.9%), and gastrointestinal and hepatobiliary (9.2%) in nature. Cancer was the cause of death in <1%. CONCLUSION: Mortality during childhood has decreased significantly. However, the transition period from pediatric to adult care is critical. Risk-reduction, monitoring, and early treatment intervention of cardiovascular disease in adults is warranted. PMID- 23637039 TI - Increased serum microRNA-155 level associated with nonresponsiveness to hepatitis B vaccine. AB - We compared the serum levels of microRNA-155 (miR-155) between subjects with normal response to hepatitis B vaccine and nonresponders. Results showed that serum expression of miR-155 was significantly higher in nonresponders than in responders (6.40 versus 2.55; Z = 2.125, P = 0.034), suggesting that overexpression of miR-155 is correlated with nonresponsiveness to hepatitis B vaccine. PMID- 23637040 TI - Toll-like receptor 4 agonistic antibody promotes innate immunity against severe pneumonia induced by coinfection with influenza virus and Streptococcus pneumoniae. AB - Coinfection with bacteria is a major cause of mortality during influenza epidemics. Recently, Toll-like receptor (TLR) agonists were shown to have immunomodulatory functions. In the present study, we investigated the effectiveness and mechanisms of the new TLR4 agonistic monoclonal antibody UT12 against secondary pneumococcal pneumonia induced by coinfection with influenza virus in a mouse model. Mice were intranasally inoculated with Streptococcus pneumoniae 2 days after influenza virus inoculation. UT12 was intraperitoneally administered 2 h before each inoculation. Survival rates were significantly increased and body weight loss was significantly decreased by UT12 administration. Additionally, the production of inflammatory mediators was significantly suppressed by the administration of UT12. In a histopathological study, pneumonia in UT12-treated mice was very mild compared to that in control mice. UT12 increased antimicrobial defense through the acceleration of macrophage recruitment into the lower respiratory tract induced by c-Jun N-terminal kinase (JNK) and nuclear factor kappaB (NF-kappaB) pathway-dependent monocyte chemoattractant protein 1 (MCP-1) production. Collectively, these findings indicate that UT12 promoted pulmonary innate immunity and may reduce the severity of severe pneumonia induced by coinfection with influenza virus and S. pneumoniae. This immunomodulatory effect of UT12 improves the prognosis of secondary pneumococcal pneumonia and makes UT12 an attractive candidate for treating severe infectious diseases. PMID- 23637042 TI - Nonfebrile seizures after mumps, measles, rubella, and varicella-zoster virus combination vaccination with detection of measles virus RNA in serum, throat, and urine. AB - We report the case of a child presenting with nonfebrile seizures 6 and 13 days after the first vaccination with a measles, mumps, rubella, and varicella (MMRV) combination vaccine. Measles virus RNA was detected in the patient's serum, throat, and urine. Genotyping revealed the Schwarz vaccine virus strain. PMID- 23637043 TI - TRPV1 ablation aggravates inflammatory responses and organ damage during endotoxic shock. AB - To test the hypothesis that ablation of transient receptor potential vanilloid type 1 (TRPV1) channels leads to exacerbated inflammatory responses and organ damage during endotoxic shock, lipopolysaccharide (LPS; 5 million endotoxin units/kg of body weight) was injected intraperitoneally (i.p.) into wild-type (WT) and TRPV1-null mutant (TRPV1(-/-)) mice. Mean arterial pressure and heart rate, determined by radiotelemetry, were severely depressed after LPS injection into WT and TRPV1(-/-) mice, with no distinction between the two strains. At 24 h after LPS injection, renal glomerular hypercellularity and hepatocellular injury were observed in both strains, accompanying further elevated serum levels of creatinine and alanine aminotransferase in TRPV1(-/-) mice compared to those in WT mice. At 6 or 24 h after LPS injection, neutrophil recruitment into kidneys and livers, serum cytokine (tumor necrosis factor alpha [TNF-alpha], interleukin 1beta [IL-1beta], IL-6) and renal chemokine (KC, macrophage inflammatory protein 2 [MIP-2]) levels, and renal VCAM-1 and ICAM-1 expression were greater in TRPV1( /-) mice than WT mice. In addition, increased plasma calcitonin gene-related peptide (CGRP) levels observed in WT mice 6 h after LPS injection were absent in TRPV1(-/-) mice. Thus, TRPV1 ablation aggravates inflammatory responses, including neutrophil infiltration, proinflammatory cytokine production, and adhesion molecule expression, leading to intensified organ damage during endotoxic shock in the absence of worsened circulatory failure. The data indicate that TRPV1 activation may attenuate endotoxin-induced organ damage, possibly via its anti-inflammatory action rather than alteration of hemodynamics. PMID- 23637041 TI - Distribution of Streptococcus pneumoniae serotypes that cause parapneumonic empyema in Turkey. AB - Streptococcus pneumoniae is the most common etiological cause of complicated pneumonia, including empyema. In this study, we investigated the serotypes of S. pneumoniae that cause empyema in children. One hundred fifty-six children who were diagnosed with pneumonia complicated with empyema in 13 hospitals in seven geographic regions of Turkey between 2010 and 2012 were included in this study. Pleural fluid samples were collected by thoracentesis and tested for 14 serotypes/serogroups using a Bio-Plex multiplex antigen detection assay. The serotypes of S. pneumoniae were specified in 33 of 156 samples. The mean age +/- the standard deviation of the 33 patients was 6.17 +/- 3.54 years (range, 0.6 to 15 years). All of the children were unvaccinated according to the vaccination reports. Eighteen of the children were male, and 15 were female. The serotypes of the non-7-valent pneumococcal conjugated vaccine (non-PCV-7), serotype 1, serotype 5, and serotype 3, were detected in eight (14.5%), seven (12.7%), and five (9.1%) of the samples, respectively. Serotypes 1 and 5 were codetected in two samples. The remaining non-PCV-7 serotypes were 8 (n = 3), 18 (n = 1), 19A (n = 1), and 7F/A (n = 1). PCV-7 serotypes 6B, 9V, 14, 19F, and 23F were detected in nine (16.3%) of the samples. The potential serotype coverages of PCV-7, PCV-10, and PCV-13 were 16.3%, 45.4%, and 60%, respectively. Pediatric parapneumonic empyema continues to be an important health problem despite the introduction of conjugated pneumococcal vaccines. Active surveillance studies are needed to monitor the change in S. pneumoniae serotypes that cause empyema in order to have a better selection of pneumococcal vaccines. PMID- 23637044 TI - Characterization of the native form of anthrax lethal factor for use in the toxin neutralization assay. AB - The cell-based anthrax toxin neutralization assay (TNA) is used to determine functional antibody titers of sera from animals and humans immunized with anthrax vaccines. The anthrax lethal toxin is a critical reagent of the TNA composed of protective antigen (PA) and lethal factor (LF), which are neutralization targets of serum antibodies. Cytotoxic potency of recombinant LF (rLF) lots can vary substantially, causing a challenge in producing a renewable supply of this reagent for validated TNAs. To address this issue, we characterized a more potent rLF variant (rLF-A) with the exact native LF amino acid sequence that lacks the additional N-terminal histidine and methionine residues present on the commonly used form of rLF (rLF-HMA) as a consequence of the expression vector. rLF-A can be used at 4 to 6 ng/ml (in contrast to 40 ng/ml rLF-HMA) with 50 ng/ml recombinant PA (rPA) to achieve 95 to 99% cytotoxicity. In the presence of 50 ng/ml rPA, both rLF-A and rLF-HMA allowed for similar potencies (50% effective dilution) among immune sera in the TNA. rPA, but not rLF, was the dominant factor in determining potency of serum samples containing anti-PA antibodies only or an excess of anti-PA relative to anti-rLF antibodies. Such anti-PA content is reflected in immune sera derived from most anthrax vaccines in development. These results support that 7- to 10-fold less rLF-A can be used in place of rLF-HMA without changing TNA serum dilution curve parameters, thus extending the use of a single rLF lot and a consistent, renewable supply. PMID- 23637046 TI - Charge density dependent mobility of organic hole-transporters and mesoporous TiO2 determined by transient mobility spectroscopy: implications to dye sensitized and organic solar cells. AB - Transient mobility spectroscopy (TMS) is presented as a new tool to probe the charge carrier mobility of commonly employed organic and inorganic semiconductors over the relevant range of charge densities. The charge density dependence of the mobility of semiconductors used in hybrid and organic photovoltaics gives new insights into charge transport phenomena in solid state dye sensitized solar cells. PMID- 23637047 TI - Selective area growth of III-V nanowires and their heterostructures on silicon in a nanotube template: towards monolithic integration of nano-devices. AB - We demonstrate a catalyst-free growth technique to directly integrate III-V semiconducting nanowires on silicon using selective area epitaxy within a nanotube template. The nanotube template is selectively filled by homo- as well as heteroepitaxial growth of nanowires with the morphology entirely defined by the template geometry. To demonstrate the method single-crystalline InAs wires on Si as well as InAs-InSb axial heterostructure nanowires are grown within the template. The achieved heterointerface is very sharp and confined within 5-6 atomic planes which constitutes a primary advantage of this technique. Compared to metal-catalyzed or self-catalyzed nanowire growth processes, the nanotube template approach does not suffer from the often observed intermixing of (hetero ) interfaces and non-intentional core-shell formation. The sequential deposition of different material layers within a nanotube template can therefore serve as a general monolithic integration path for III-V based electronic and optoelectronic devices on silicon. PMID- 23637048 TI - Modulation of metabolic syndrome-related inflammation by cocoa. AB - Cocoa (Theobroma cacao L., Sterculiaceae) is a widely consumed food ingredient. Although typically found in high-fat, high-sugar foods such as chocolate, cocoa is rich in polyphenols, methylxanthines, and monounsaturated fatty acids. There is increasing evidence that moderate consumption of cocoa and cocoa-containing foods may have beneficial effects on the health including vasodilatory, antioxidant, and anti-inflammatory effects. Polyphenols in cocoa, including monomeric flavanols, as well as polymeric proanthocyanidins, may play a role in these observed beneficial effects. Chronic inflammation represents a potential mechanistic link between obesity and its related pathologies: insulin resistance, dyslipidemia, and hypertension, which comprise the metabolic syndrome. In the present review, we discuss the available data regarding the modulation of metabolic syndrome-related inflammation by cocoa and cocoa-derived compounds. We emphasize studies using laboratory animals or human subjects since such studies often represent the strongest available evidence for biological effects. In vitro studies are included to provide some mechanistic context, but are critically interpreted. Although the available data seem to support the anti-inflammatory effects of cocoa, further studies are needed with regard to the dose-response relationship as well as the underlying mechanisms of action. We hope this review will stimulate further research on cocoa and its anti-inflammatory activities. PMID- 23637049 TI - In situ study of electric field-induced magnetization in multiferroic BiFeO(3) nanowires. AB - In this work, we have studied electric field-induced magnetization effect of multiferroic BiFeO3 (BFO) nanowires in situ using magnetic force microscopy (MFM). Changes in magnetic domain contrast have been observed in the MFM phase images under applied electric potential, which indicate local magnetoelectric (ME) coupling in the nanowires. The values of saturation and magnetization at different applied electric fields were evaluated. These results suggest that one dimensional multiferroic BFO nanowires are potential candidates for realizing multiferroic devices at nanoscale with unique functionalities. PMID- 23637045 TI - An MDCK cell culture-derived formalin-inactivated influenza virus whole-virion vaccine from an influenza virus library confers cross-protective immunity by intranasal administration in mice. AB - It is currently impossible to predict the next pandemic influenza virus strain. We have thus established a library of influenza viruses of all hemagglutinin and neuraminidase subtypes and their genes. In this article, we examine the applicability of a rapid production model for the preparation of vaccines against emerging pandemic influenza viruses. This procedure utilizes the influenza virus library, cell culture-based vaccine production, and intranasal administration to induce a cross-protective immune response. First, an influenza virus reassortant from the library, A/duck/Hokkaido/Vac-3/2007 (H5N1), was passaged 22 times (P22) in Madin-Darby canine kidney (MDCK) cells. The P22 virus had a titer of >2 *10(8) PFU/ml, which was 40 times that of the original strain, with 4 point mutations, which altered amino acids in the deduced protein sequences encoded by the PB2 and PA genes. We then produced a formalin-inactivated whole-virion vaccine from the MDCK cell-cultured A/duck/Hokkaido/Vac-3/2007 (H5N1) P22 virus. Intranasal immunization of mice with this vaccine protected them against challenges with lethal influenza viruses of homologous and heterologous subtypes. We further demonstrated that intranasal immunization with the vaccine induced cross-reactive neutralizing antibody responses against the homotypic H5N1 influenza virus and its antigenic variants and cross-reactive cell-mediated immune responses to the homologous virus, its variants within a subtype, and even an influenza virus of a different subtype. These results indicate that a rapid model for emergency vaccine production may be effective for producing the next generation of pandemic influenza virus vaccines. PMID- 23637050 TI - Prospective associations between benzodiazepine use and later life satisfaction, somatic pain and psychological health among the elderly. AB - OBJECTIVE: This study aimed to investigate prospective associations between benzodiazepine use and later life satisfaction, sleep difficulties, perceived general health, anxiety symptoms and somatic pain among the elderly. METHODS: A 13-year prospective cohort study was conducted in a Norwegian population-based sample of 15 830 elderly individuals. Baseline control measures of the investigated psychological constructs and a wide range of demographic and health relevant covariates were obtained from the Nord-Trondelag Health Study (HUNT 2, 1995-1997). Follow-up data were obtained from the third wave (HUNT 3, 2006-2008) of the same epidemiological study. The Norwegian Prescription Database (2004 2008) was used to link pharmacy prescription records of benzodiazepines for each case to the HUNT 2 and HUNT 3 materials. RESULTS: Use of benzodiazepines was associated with less life satisfaction and more sleep difficulties at follow-up. These tendencies increased by more frequent patterns of use. Benzodiazepine use had relatively weak relations to perceived general health, but intermittent and chronic use was related to higher anxiety symptoms at follow-up. Such patterns were also modestly related to somatic pain at follow-up. DISCUSSION AND CONCLUSION: Benzodiazepines should be dispensed at a high-threshold policy among the elderly. By developing clear-cut discontinuation plans, clinicians could avoid chronic use and focus on psychosocial treatment for psychological disorders. PMID- 23637051 TI - The palatability and tolerability of deferasirox taken with different beverages or foods. AB - BACKGROUND: Deferasirox is a once-daily, oral iron chelator that was developed out of a need for a long-acting, conveniently-administered chelator for patients with transfusional hemosiderosis. The approved mode of administration requires taking deferasirox on an empty stomach with water, apple juice, or orange juice to limit variation in bioavailability. This required administration schedule might not be palatable for patients. Additionally, approximately one-quarter of patients experience mild to moderate gastrointestinal (GI) symptoms, which may pose additional challenges, particularly in the younger and older age ranges. We present a trial to assess the palatability and safety of various administration modes of deferasirox in pediatric and adult patients. PROCEDURES: Participants rated palatability in a 4-week run-in phase, where deferasirox was administered per label. Subsequently, patients rated several administration modes during a 3 month assessment phase. RESULTS: Palatability was more favorable during the assessment phase, with 47% of patient ratings for palatability being favorable while only 38% were favorable during the run-in phase. The most highly rated choice was deferasirox taken with a soft food at breakfast. In addition, there was an indication of improved GI tolerability during the assessment phase (symptoms were reported in 37% of patients during run-in and 32% during the assessment phase; rates of diarrhea decreased significantly). Although trough PK values increased, no major new toxicities were observed. CONCLUSIONS: These data indicate that different administration options may improve palatability and GI tolerability, which could have a positive impact on treatment adherence. (ClinicalTrials.gov number, NCT00845871) PMID- 23637052 TI - Neuropathy-inducing effects of eribulin mesylate versus paclitaxel in mice with preexisting neuropathy. AB - Eribulin mesylate (E7389, INN:eribulin mesilate Halaven((r))) is a non-taxane microtubule dynamics inhibitor currently in clinical use for advanced breast cancer. Other microtubule-targeting agents for breast cancer, including paclitaxel and ixabepilone, display a common treatment dose-limiting toxicity of peripheral neuropathy (PN). In an earlier study, we found eribulin mesylate had a lower propensity to induce PN in mice than either paclitaxel or ixabepilone. In the current study, we compared additional PN induced by paclitaxel versus eribulin mesylate when administered to mice with preexisting paclitaxel-induced PN. Initially, paclitaxel at 0.75 * its maximum tolerated dose (MTD; 22.5 mg/kg) was given on a Q2Dx3 regimen for 2 weeks. The second chemotherapy was 0.5 MTD eribulin mesylate (0.875 mg/kg) or paclitaxel (15 mg/kg) on a similar regimen, starting 2 weeks after the first. Initial paclitaxel treatment produced significant decreases in caudal nerve conduction velocity (NCV; averaging 19.5 +/ 1 and 22.2 +/- 1.3 %, p < 0.001) and amplitude (averaging 53.2 +/- 2.6 and 72.4 +/- 2.1 %, p < 0.001) versus vehicle when measured 24 h or 2 weeks after dosing cessation, respectively. Additional 0.5 MTD paclitaxel further reduced caudal NCV and amplitude relative to immediately before initiation of the second regimen (by 11 +/- 2.1 and 59.2 +/- 5 %, p < 0.01, respectively). In contrast, 0.5 MTD eribulin mesylate caused no further decrease in caudal NCV. In conclusion, unlike additional paclitaxel treatment, eribulin mesylate administered to mice with preexisting paclitaxel-induced PN had limited additional deleterious effects at 6 weeks. These preclinical data suggest that eribulin mesylate may have reduced tendency to exacerbate preexisting paclitaxel-induced PN in clinical settings. PMID- 23637053 TI - Induction of neuronal mitophagy in acute spinal cord injury in rats. AB - Autophagy and up-regulation of autophagy-associated proteins microtubule associated protein 1 light chain 3 (LC3) and Beclin-1 have been shown to occur in spinal cord injury (SCI). Bcl-2/E1B-19 K-interacting protein 3 (BNIP3) and Nip like protein X (NIX, also known as BNIP3L) are mitochondrial BH3-only proteins that are implicated in mitophagy. In this study, we show that mitophagy is activated in the injured neurons, and hypoxia-inducible proteins BNIP3, NIX, and p53 are upregulated after SCI. Numerous autophagosomes containing damaged mitochondria (mitophagosomes) were found in the injured neurons 24 h after SCI in rats by transmission electron microscopy; mitophagy, therefore, had occurred. Hypoxia-inducible proteins BNIP3, NIX, and p53 were upregulated in spinal cord neurons in both a rat model of SCI and cultured primary spinal neurons exposed to hypoxia. BNIP3 and NIX were transcriptionally regulated mainly by hypoxia inducible factor-1alpha as well as p53 in cultured spinal cord neurons. This study provides direct morphological and biochemical evidence for mitophagy in the damaged neural tissue after SCI. PMID- 23637054 TI - Quantifying benefit-risk preferences for medical interventions: an overview of a growing empirical literature. AB - Decisions regarding the development, regulation, sale, and utilization of pharmaceutical and medical interventions require an evaluation of the balance between benefits and risks. Such evaluations are subject to two fundamental challenges-measuring the clinical effectiveness and harms associated with the treatment, and determining the relative importance of these different types of outcomes. In some ways, determining the willingness to accept treatment-related risks in exchange for treatment benefits is the greater challenge because it involves the individual subjective judgments of many decision makers, and these decision makers may draw different conclusions about the optimal balance between benefits and risks. In response to increasing demand for benefit-risk evaluations, researchers have applied a variety of existing welfare-theoretic preference methods for quantifying the tradeoffs decision makers are willing to accept among expected clinical benefits and risks. The methods used to elicit benefit-risk preferences have evolved from different theoretical backgrounds. To provide some structure to the literature that accommodates the range of approaches, we begin by describing a welfare-theoretic conceptual framework underlying the measurement of benefit-risk preferences in pharmaceutical and medical treatment decisions. We then review the major benefit-risk preference elicitation methods in the empirical literature and provide a brief overview of the studies using each of these methods. The benefit-risk preference methods described in this overview fall into two broad categories: direct-elicitation methods and conjoint analysis. Rating scales (6 studies), threshold techniques (9 studies), and standard gamble (2 studies) are examples of direct elicitation methods. Conjoint analysis studies are categorized by the question format used in the study, including ranking (1 study), graded pairs (1 study), and discrete choice (21 studies). The number of studies reviewed here demonstrates that this body of research already is substantial, and it appears that the number of benefit-risk preference studies in the literature will continue to increase. In addition, benefit-risk preference-elicitation methods have been applied to a variety of healthcare decisions and medical interventions, including pharmaceuticals, medical devices, surgical and medical procedures, and diagnostics, as well as resource-allocation decisions such as facility placement. While preference-elicitation approaches may differ across studies, all of the studies described in this review can be used to provide quantitative measures of the tradeoffs patients and other decision makers are willing to make between benefits and risks of medical interventions. Eliciting and quantifying the preferences of decision makers allows for a formal, evidence-based consideration of decision-makers' values that currently is lacking in regulatory decision making. Future research in this area should focus on two primary issues developing best-practice standards for preference-elicitation studies and developing methods for combining stated preferences and clinical data in a manner that is both understandable and useful to regulatory agencies. PMID- 23637056 TI - Why do hip arthroscopy procedures fail? AB - BACKGROUND: Despite the successes of hip arthroscopy, clinical failures do occur, and identifying risk factors for failure may facilitate refinement of surgical indications and treatment. Knowledge regarding the reasons for treatment failures may also improve surgical decision making. QUESTIONS/PURPOSES: We (1) characterized patients whose symptoms recurred after hip arthroscopy necessitating a revision hip preservation procedure or hip arthroplasty, (2) determined the etiologies of failure, (3) and reported the profile of revision surgical procedures. METHODS: In a prospective database of 1724 consecutive hip surgeries, we identified 58 patients (60 hips) with a history of failed hip arthroscopy. Thirty-seven patients (38 hips) underwent revision hip preservation and 21 (22) hip arthroplasty. Thirty-nine (67%) were female. Demographics, etiology of failure, and type of revision surgery were analyzed. RESULTS: Patients treated with revision hip preservation were younger, had a lower BMI, and lower Tonnis osteoarthritis grade at the time of revision surgery compared to patients treated with hip arthroplasty. Common etiologies of failure were residual femoroacetabular impingement (68%) and acetabular dysplasia (24%) in patients treated with revision hip preservation and advanced osteoarthritis in patients treated with hip arthroplasty. The revision preservation procedures included arthroscopy in 16 (42%), arthroscopy with limited open capsulorraphy in two (5.3%), periacetabular osteotomy in nine (24%), and surgical dislocation in 12 (32%). CONCLUSIONS: Residual or unaddressed structural deformity of the hip and underlying osteoarthritis are commonly associated with failure after hip arthroscopy. Thorough patient evaluation with detailed characterization of structural hip anatomy and articular cartilage integrity are critical to the selection of proper surgical intervention and successful patient outcome. PMID- 23637055 TI - Squinting through layers of fog: assessing the cost effectiveness of treatments for multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic neurological disorder, which can lead to a wide range of disabling symptoms. The condition has a significant negative impact on health-related quality of life, and the economic cost of the disease is substantial. Decision-making regarding treatments for MS, and particularly disease-modifying interventions, has been hampered by limitations in the data and evaluative framework for assessing their cost effectiveness. Whilst attention has been drawn to these weaknesses, the scope and extent of the challenges in this area have not been fully set out to date. AIMS: The aims of this review were to identify all published economic evaluations of MS treatments in order to provide a statement on the scope and characteristics of the cost effectiveness literature in the area of MS and to provide a basis on which to suggest practical recommendations for future research to aid decision-making. METHOD: A systematic search was undertaken to identify economic evaluations of treatments for people with MS published in English up to December 2011. Included studies were reviewed to provide a comprehensive description of the characteristics of the currently applied framework for cost effectiveness in MS, with the following key methodological components considered: methods for estimating disease progression, the impact of treatment and health outcomes and costs associated with MS. RESULTS: Thirty-seven papers were identified. Most studies (n = 32) were model-based evaluations of disease-modifying drugs. All models used disability stages defined by the Expanded Disability Status Scale (EDSS) to characterise disease progression, and the impact of treatment was based on data from clinical trials and epidemiological cohorts. Outcomes were primarily based on quality-adjusted life-years (n = 22) and/or related to relapse (n = 14). Estimates for health state utility values (HSUVs), costs and the impact of treatment on the course of MS varied considerably between studies, depending on the data sources used and the methods used to incorporate data into models. The scope of the studies was narrow, with a sparsity of economic evaluations of symptomatic and/or non-pharmacological interventions; exclusion of direct non medical, indirect and informal care costs from analyses; and a narrow view of the potential impact of treatment, concentrating on disability, according to the EDSS, and relapses. In addition, there were issues concerning how to capture losses in HSUVs due to relapses in a way that reflects their salience to people with MS, the wide variation in costs and outcomes from different sources and from potentially unrepresentative samples and modelling disease progression from natural history data from over 30 years ago. CONCLUSION: There are many complexities for those designing and reporting cost-effectiveness studies of treatments for MS. Analysts, and ultimately decision makers, face multiple data and methodological challenges. Policy makers, technology developers, clinicians, patients and researchers need to acknowledge and address these challenges and to consider recommendations that will improve the current scenario. There is a need for further research that can constructively inform decision-making regarding the funding of treatments for MS. PMID- 23637057 TI - Editor's spotlight/Take 5: A review of current fixation usage and registry outcomes in total hip arthroplasty: the uncemented paradox [DOI 10.1007/s11999 013-2941-7]. Interview by Seth S. Leopold. PMID- 23637058 TI - Letter to the editor: Intramedullary nails result in more reoperations than sliding hip screws in two-part intertrochanteric fractures. PMID- 23637059 TI - High prevalence of adverse reactions to metal debris in small-headed ASRTM hips. AB - BACKGROUND: There has been increasing concern of metal-on-metal (MOM) hip replacements regarding adverse reactions to metal debris. Information regarding prevalence and risk factors for these adverse reactions is scarce. QUESTIONS/PURPOSES: The primary purposes of our study were to determine (1) the prevalence of adverse reactions to metal debris among patients who received small headed (< 50 mm) Articular Surface Replacement (ASRTM) prostheses in hip resurfacing procedures or the ASRTM XL prostheses during THAs at our institution, and (2) the risk factors for adverse reactions to metal debris and if they are different in hip resurfacing replacements compared with THAs? METHODS: Small headed ASRTM prostheses were used in 482 operations (424 patients) at our institution. After the recall of ASRTM prostheses, we established a systematic screening program to find patients with adverse reactions to metal debris. At a mean of 4.9 years (range, 0.2-8.1 years) postoperatively, 379 patients (435 hips) attended a screening program, which consisted of clinical evaluation, whole blood cobalt and chromium measurements, and cross-sectional imaging. RESULTS: At followup, 162 hips (34%) have been revised. The majority (85%) were revised owing to causes related to adverse reactions to metal debris. The 7-year survivorship was 51% for the ASRTM hip replacement cohort and 38% for the ASRTM XL THA cohort, respectively. Reduced cup coverage was an independent risk factor for adverse reactions to metal debris in both cohorts. High preoperative ROM, use of the Corail((r)) stem, and female gender were associated with an increased risk of adverse reactions to metal debris only in patients undergoing THA. CONCLUSIONS: Adverse reactions to metal debris are common with small-headed ASRTM prostheses. Risk factors for these adverse reactions differ between hip resurfacing procedures and THAs. Our results suggest a more complicated failure mechanism in THAs than in hip resurfacing procedures. PMID- 23637060 TI - Application of high throughput pretreatment and co-hydrolysis system to thermochemical pretreatment. Part 2: Dilute alkali. AB - High throughput pretreatment (HTPH) and enzymatic hydrolysis systems are now vital for screening large numbers of biomass samples to investigate biomass recalcitrance over various pretreatment and enzymatic hydrolysis conditions. Although hydrothermal pretreatment is currently being employed in most high throughput applications, thermochemical pretreatment at low and high pH conditions can offer additional insights to better understand the roles of hemicellulose and lignin, respectively, in defining biomass recalcitrance. Thus, after successfully applying the HTPH approach to dilute acid pretreatment [Gao et al. (2012) Biotechnol. Bioeng. 110(3): 754-762], extension to dilute alkali pretreatment was also achieved using a similar single-step neutralization and buffering concept. In the latter approach, poplar and switchgrass were pretreated with 1 wt% sodium hydroxide at 120 degrees C for different reaction times. Following pretreatment, an H2Cit-/HCit2- buffer with a pH of 4.5 was used to condition the pretreatment slurry to a pH range of 4.69-4.89, followed by enzymatic hydrolysis for 72 h of the entire mixture. Sugar yields showed different trends for poplar and switchgrass with increases in pretreatment times, demonstrating the method provided a clearly discernible screening tool at alkali conditions. This method was then applied to selected Populus tremuloides samples to follow ring-by-ring sugar release patterns. Observed variations were compared to results from hydrothermal pretreatments, providing new insights in understanding the influence of biomass structural differences on recalcitrance. PMID- 23637061 TI - Glioblastoma metastasis to parotid gland and neck lymph nodes: fine-needle aspiration cytology with histopathologic correlation. AB - Glioblastoma (GBM) is one of the most highly aggressive neoplasms of the central nervous system. Extra-cranial metastases in GBM are rare. Here we present the case of a 26-year-old man with extra-cranial metastasis of a frontal lobe GBM to the parotid gland, cervical lymph nodes, and bones, with initial diagnosis made by fine needle aspiration cytology (FNAC) of the parotid gland. FNAC is a reliable technique in the study of primary and secondary parotid gland neoplasms, allowing a presumptive diagnosis in difficult cases. We correlate the cytologic, histopathologic, and immunohistochemical findings in this case and discuss previous literature reports. PMID- 23637062 TI - High electro-catalytic activities of glucose oxidase embedded one-dimensional ZnO nanostructures. AB - One-dimensional ZnO nanorods and nanowires are separately synthesized on Zn substrate by simple hydrothermal processes at low temperatures. Electro-catalytic responses of glucose oxidase/ZnO/Zn electrodes using these two synthesized nanostructures of ZnO are reported and compared with others available in literature. It is apparent the Michaelis-Menten constant, [Formula: see text], for the present ZnO nanowire, having a greater aspect ratio, is found to be the lowest when compared with others. This sensor shows lower oxidation peak potential with a long detection range of 6.6 MUM-380 mM and the highest sensitivity of ~35.1 MUA cm(-2) mM(-1), among the reported values in the literature. Enzyme catalytic efficiency and turnover numbers are also found to be remarkably high. PMID- 23637063 TI - Upgraded silicon nanowires by metal-assisted etching of metallurgical silicon: a new route to nanostructured solar-grade silicon. AB - Through metal-assisted chemical etching (MaCE), superior purification of dirty Si is observed, from 99.74 to 99.9884% for metallurgical Si and from 99.999772 to 99.999899% for upgraded metallurgical Si. In addition, large area of silicon nanowires (SiNW) are fabricated. The purification effect induces a ~35% increase in photocurrent for SiNW based photoelectrochemical cell. PMID- 23637066 TI - Gastric antral lipoma presenting as gastric outlet obstruction. PMID- 23637065 TI - Metabolomic fingerprint in patients at high risk of cardiovascular disease by cocoa intervention. AB - SCOPE: Metabolomics approach is focused on identifying all metabolites present in a biological sample (metabolome). Consumption of cocoa products has been related to health benefits including positive effect on cardiovascular health. METHODS AND RESULTS: Twenty volunteers were included in this randomized, crossover, and controlled clinical trial. After a 2-wk washout period, subjects received 40 g/day of cocoa powder with 500 mL skimmed milk (cocoa with skimmed milk intervention) or 500 mL/day of skimmed milk (skimmed milk intervention) for 4-wk. Urine (24 h) samples were collected at baseline and after each intervention and were analyzed by HPLC-hybrid quadrupole TOF in negative and positive ionization modes followed by multivariate analysis. This analysis revealed a marked separation between the cocoa with skimmed milk intervention and skimmed milk intervention and baseline periods. Thirty-nine compounds linked with cocoa intake, including alkaloid metabolites, polyphenol host and gut microbial metabolites (hydroxyphenylvalerolactones and hydroxyphenylvaleric acids), diketopiperazines and N-phenylpropenoyl-l-amino acids were identified. In the case of endogenous metabolites, putative identifications suggested that metabolites linked with carnitine metabolism and sulfation of tyrosine were decreased by the consumption of cocoa. CONCLUSION: LC-MS metabolomics strategy allows the defining of a complex metabolic profile derived from cocoa phytochemicals. Likewise, the identification of endogenous markers could lead to new hypotheses to unravel the relationship between cocoa intake and cardiovascular diseases. PMID- 23637067 TI - Killian-Jamieson diverticulum. PMID- 23637068 TI - The effects of pore size in bilayered poly(lactide-co-glycolide) scaffolds on restoring osteochondral defects in rabbits. AB - Bilayered porous scaffolds have recently attracted interest because of their considerable promise for repairing osteochondral defects. However, determination of optimal pore size in bilayered porous scaffolds remains an important issue. This study investigated the in vivo effects of pore size in bilayered scaffolds using a rabbit model of osteochondral defects. We fabricated five types of integrated bilayered poly(lactide-co-glycolide) (PLGA) scaffolds with different pore sizes in the chondral and osseous layers (50-100 um, 100-200 um, 200-300 um, and 300-450 um). A subset of bilayered scaffolds seeded with or without allogenic bone marrow mesenchymal stem cells (BMSCs) was implanted in rabbit osteochondral defects. All of the cell/scaffold composite constructs supported the simultaneous regeneration of articular cartilage and subchondral bone, but the best results were observed in cell-seeded PLGA scaffolds with 100-200 um pores in the chondral layer and 300-450 um pores in the osseous layer. Our study supports the concept that the effects of pore size on osteochondral repair should be taken into consideration during scaffold design for tissue engineering. PMID- 23637064 TI - Identification of novel variants in colorectal cancer families by high-throughput exome sequencing. AB - BACKGROUND: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants. METHODS: We completed exome sequencing on 40 affected cases from 16 multicase pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single-nucleotide variants (SNV) predicted to be benign. RESULTS: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or noncoding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively. CONCLUSIONS: Whole exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in CRC susceptibility. IMPACT: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk. PMID- 23637069 TI - Providing activity for people with dementia in care homes: a cluster randomised controlled trial. AB - BACKGROUND: Activity levels remain low in care homes, but activity engagement can enhance residents' quality of life. AIM: This study aimed to assess an occupational therapy programme designed to enable care home staff to increase activity provision. METHOD: A cluster randomised controlled trial with blinded assessment of outcome was conducted. A total of 210 residents with dementia in 16 care homes were recruited. Intervention homes received the programme, and control homes were provided usual care. Primary outcome is quality of life; secondary measures are dependency, challenging behaviour, depression, anxiety, severity of dementia and number and type of medication. RESULTS: Quality of life decreased overall with statistically significant change in staff ratings (p < 0.001). At follow-up, staff-rated quality of life was slightly lower in the intervention group (mean difference in staff ratings = -1.91, 95% CI -3.39 to -0.43, p = 0.01). There were no significant differences between the two groups for self rated quality of life or secondary outcomes. CONCLUSION: The results may be related to the following: wide variability in how the intervention was implemented, such as low staff attendance at the education and coaching sessions, and patchy provision of additional activities to residents; or the residents' severity of dementia or the choice of outcome measures. Future studies need to pay more attention to process measures such as implementation and fidelity strategies, and outcome measures that better capture the focus of the intervention such as level of engagement and activity. PMID- 23637070 TI - glyXalign: high-throughput migration time alignment preprocessing of electrophoretic data retrieved via multiplexed capillary gel electrophoresis with laser-induced fluorescence detection-based glycoprofiling. AB - Glycomics has become a rapidly emerging field and monitoring of protein glycosylation is needed to ensure quality and consistency during production processes of biologicals such as therapeutic antibodies or vaccines. Glycoanalysis via multiplexed CGE with LIF detection (xCGE-LIF) represents a powerful technique featuring high resolution, high sensitivity as well as high throughput performance. However, sample data retrieved from this method exhibit challenges for downstream computational analysis due to intersample migration time shifts as well as stretching and compression of electropherograms. Here, we present glyXalign, a freely available and easy-to-use software package to automatically correct for distortions in xCGE-LIF based glycan data. We demonstrate its ability to outperform conventional algorithms such as dynamic time warping and correlation optimized warping in terms of processing time and alignment accuracy for high-resolution datasets. Built upon a set of rapid algorithms, the tool includes an intuitive graphical user interface and allows full control over all parameters. Additionally, it visualizes the alignment process and enables the user to readjust misaligned results. Software and documentation are available at http://www.glyxera.com. PMID- 23637072 TI - Sources of uncertainty and their association with medical decision making: exploring mechanisms in Fanconi anemia. AB - BACKGROUND: Effects of different sources of medical uncertainty on people's health-related cognitions, emotions, and decision making have yet to be systematically examined. PURPOSE: The aim of this study is to examine how uncertainties arising from different sources are associated with decision making regarding stem cell transplantation in Fanconi anemia, a rare, inherited bone marrow failure syndrome that typically presents during childhood. METHODS: Data were collected through a cross-sectional survey of 178 parents of 126 Fanconi anemia patients. RESULTS: Two distinct sources of uncertainty were associated with decision outcomes: probability was associated with a lower likelihood of choosing stem cell transplantation, and ambiguity due to conflicting expert opinions was associated with greater decision-making difficulty. Concern about transplantation may mediate these associations. CONCLUSIONS: Different sources of uncertainty have different effects on Fanconi anemia treatment decisions, which may be mediated by parents' emotional reactions. Further research is needed to elucidate these effects and help Fanconi anemia families cope with uncertainty. PMID- 23637073 TI - Are simultaneously delivered health behavior change interventions the way of the future?: a comment on King et al. PMID- 23637074 TI - High-performance vertical organic transistors. AB - Vertical organic thin-film transistors (VOTFTs) are promising devices to overcome the transconductance and cut-off frequency restrictions of horizontal organic thin-film transistors. The basic physical mechanisms of VOTFT operation, however, are not well understood and VOTFTs often require complex patterning techniques using self-assembly processes which impedes a future large-area production. In this contribution, high-performance vertical organic transistors comprising pentacene for p-type operation and C60 for n-type operation are presented. The static current-voltage behavior as well as the fundamental scaling laws of such transistors are studied, disclosing a remarkable transistor operation with a behavior limited by injection of charge carriers. The transistors are manufactured by photolithography, in contrast to other VOTFT concepts using self assembled source electrodes. Fluorinated photoresist and solvent compounds allow for photolithographical patterning directly and strongly onto the organic materials, simplifying the fabrication protocol and making VOTFTs a prospective candidate for future high-performance applications of organic transistors. PMID- 23637075 TI - Fluorescent sensors. PMID- 23637071 TI - Safety of human papillomavirus vaccines: a review. AB - Vaccination to prevent human papillomavirus (HPV)-related infection leading to cancer, particularly cervical cancer, is a major public health breakthrough. There are currently two licensed HPV vaccines, both of which contain recombinant virus-like particles of HPV types 16 and 18 (which account for approximately 70 % of cervical cancer). One vaccine also protects against HPV types 6 and 11, which cause genital warts. The safety profile of both vaccines was assessed extensively in randomised controlled clinical trials conducted prior to licensure and has been further elucidated following licensure from surveillance and specific studies in large populations. This review aims to examine current evidence regarding the safety of HPV vaccines. In summary, both vaccines are associated with relatively high rates of injection site reactions, particularly pain, but this is usually of short duration and resolves spontaneously. Systemic reactions have generally been mild and self-limited. Post vaccination syncope has occurred, but can be avoided with appropriate care. Serious vaccine-attributable adverse events, such as anaphylaxis, are rare, and although not recommended for use in pregnancy, abnormal pregnancy outcomes following inadvertent administration do not appear to be associated with vaccination. HPV vaccines are used in a three dose schedule predominantly in adolescent females: as such case reports linking vaccination with a range of new onset chronic conditions, including autoimmune diseases, have been made. However, well-conducted population-based studies show no association between HPV vaccine and a range of such conditions. Whilst this reassuring safety profile affirms the positive risk benefit of vaccination, as HPV vaccine use expands into more diverse populations, including males, ongoing safety assessment using well-conducted studies is appropriate. PMID- 23637078 TI - Local electrical conduction in polycrystalline La-doped BiFeO3 thin films. AB - Local electrical conduction behaviors of polycrystalline La-doped BiFeO3 thin films have been investigated by combining conductive atomic force microscopy and piezoelectric force microscopy. Nanoscale current measurements were performed as a function of bias voltage for different crystal grains. Completely distinct conducting processes and resistive switching effects were observed in the grain boundary and grain interior. We have revealed that local electric conduction in a grain is dominated by both the grain boundary and ferroelectric domain, and is closely related to the applied electric field and the as-grown state of the grain. At lower voltages the electrical conduction is dominated by the grain boundary and is associated with the redistribution of oxygen vacancies in the grain boundary under external electric fields. At higher voltages both the grain boundary and ferroelectric domain are responsible for the electrical conduction of grains, and the electrical conduction gradually extends from the grain boundary into the grain interior due to the extension of the ferroelectric domain towards the grain interior. We have also demonstrated that the conduction dominated by the grain boundary exhibits a much small switching voltage, while the conduction of the ferroelectric domain causes a much high switching voltage in the grain interior. PMID- 23637077 TI - Ultrasensitive detection of proteins on Western blots with semiconducting polymer dots. AB - Ultrasensitive fluorescence imaging of proteins on western blots using a bright, compact, and orange-emitting semiconducting polymer dot (CN-PPV) is demonstrated. A detection limit at the single-picogram level in dot blots is achieved; with conventional western blotting, 50 pg of transferrin and trypsin inhibitor after sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transfer onto a polyvinylidene fluoride membrane are detected. This method does not require any additional equipment or time compared with the conventional procedure with traditional fluorescent probes. PMID- 23637079 TI - The fetal frontomaxillary facial angle in normal and trisomy 21 ultrasounds at 11 13(+6) weeks of gestation: findings among the ethnic Chinese compared with Caucasian. AB - OBJECTIVE: The aim of this research was to compare the fetal frontomaxillary facial (FMF) angle between normal and trisomy 21 fetuses at 11(+0) -13(+6) weeks gestation in a Chinese population. METHODS: A prospective observational study was performed that included 640 euploid and 45 trisomy 21 singleton pregnancies undergoing first trimester ultrasound screening between 11 and 13(+6) weeks of gestation. The FMF angle was measured in the midsagittal plane using the standard technique. RESULTS: The fetal mean FMF angle decreased with the increasing crown rump length (CRL) from 88.6 degrees at a CRL of 45 mm to 78.5 degrees at a CRL of 84 mm (FMF angle = 100.212 - 0.258 * CRL, R(2) = 0.222, p < 0.001). The overall mean FMF angle in the euploid population was 82.9 degrees +/- 4.1 degrees and in trisomy 21 cases, 92.3 degrees +/- 5.2 degrees . CONCLUSIONS: Fetal FMF angle is affected by gestational age in a Chinese population, although it remains a significant predictor of fetal trisomy 21. PMID- 23637080 TI - The prevalence and associated demographic factors of dementia from a cross sectional community survey in Kingston, Jamaica. AB - OBJECTIVES: Using a cross-sectional community survey, the authors aimed to estimate the prevalence of dementia among a sample of older Jamaicans and to identify associated demographic factors. METHODS: From February to July 2010, persons of age >=60 years were randomly selected from two communities in Kingston, Jamaica and screened with the Mini Mental Status Examination (MMSE). All MMSE-positive participants and an equal number of matched MMSE-negative participants underwent definitive diagnostic evaluation for dementia using the Clinical and Diagnostic Assessment Procedure for Dementia. Subsequently derived MMSE sensitivity and specificity measures from the subsample were used to estimate the overall prevalence of dementia (primary outcome). Chi square, Fisher's Exact, Exact, Spearman's correlation and t-tests were used to explore associations of dementia with age, gender, educational level and socioeconomic status. Statistical significance was taken as p < 0.05. RESULTS: Two hundred participants were recruited. Age-standardized prevalence rates of dementia were 5.07% (standardized to the Jamaican population) and 5.32% (standardized to the West Europe population). Dementia was more prevalent among older persons (Spearman's rho = 0.31; p < 0.001); no other significant associations were found. CONCLUSIONS: Dementia prevalence found in this study is lower than figures from previous Caribbean reports. The older persons are disproportionately affected. PMID- 23637081 TI - Highly stable and dispersive silver nanoparticle-graphene composites by a simple and low-energy-consuming approach and their antimicrobial activity. AB - A simple and low-energy-consuming approach to synthesize highly stable and dispersive silver nanoparticle-graphene (AgNP-GE) nanocomposites has been developed, in which the stability and dispersivity of the composites are varied greatly with the pH value and temperature of the reaction. The results demonstrate that the optimal reaction conditions are pH 11 at room temperature for 70 min. As-synthesized composites display excellent antimicrobial activity, and can completely inhibit the growth of Escherichia coli cells at a concentration of 20 mg L(-1) (20 ppm). After treatment with 10 ppm AgNP-GE composites, the cells are killed completely within 3 h. The unique structure imparts such good antimicrobial properties to the composites. Firstly, the sheetlike AgNP-GE tends to be adsorbed and accumulated onto the surface of cells, which can change the permeability and enhance the antimicrobial activity. Secondly, Ag(+) released from AgNPs can act on the cells effectively and fully, thereby resulting in cell death. PMID- 23637082 TI - Development of new atom transfer radical polymerization system by iron (III) metal salts without using any external initiator and reducing agent. AB - Atom transfer radical polymerization (ATRP) catalyzed by high oxidation state metal salts of FeX3 is developed for the first time in the absence of both external initiator and reducing agent. Methyl methacrylate (MMA) and styrene are polymerized successfully using FeX3 /Phosphorous ligands with well-controlled molecular weight distributions (=1.5). The molecular weight of the polymers increases with monomer consumption with the progress of time and the polymerization behaviors show a decent ATRP trend. Activators and initiators are suggested to generate in situ by the addition reaction of MMA and one equivalent of FeX3 . The PMMA synthesized from without-initiator system is characterized by (1) H, (13) C and DEPT (distortionless enhancement by polarization transfer nuclear magnetic resonance) nuclear magnetic resonance spectroscopy. Chain extension and copolymerization experiments prove the livingness of the obtained polymer. PMID- 23637083 TI - The interactive effect of an emerging infectious disease and an emerging contaminant on Woodhouse's toad (Anaxyrus woodhousii) tadpoles. AB - Two factors that influence amphibian population declines are infectious diseases and exposure to anthropogenic contaminants. The authors examined an emerging fungal pathogen, Batrachochytrium dendrobatidis (Bd), and its interaction with an emerging contaminant, the antimicrobial triclosan. They first conducted a 2 * 2 * 4 factorial study to examine the interactive impacts of dragonfly predator cues, Bd, and triclosan (0 ug/L, 10 ug/L, 100 ug/L, and 1000 ug/L) on Woodhouse's toad (Anaxyrus woodhousii) tadpoles. The authors measured the lethal and sublethal impacts of these stressors on tadpoles over 4 wk. All tadpoles in the 100-ug/L and 1000-ug/L concentrations of triclosan died within 24 h of exposure, but tadpoles in the low concentration (10 ug/L) survived. Tadpoles exposed to only Bd (no triclosan) exhibited a low survival rate (67.5%), whereas those exposed to both 10 ug/L triclosan and Bd exhibited a high survival rate (91.1%), implying that triclosan inhibits effects of Bd on tadpoles. Batrachochytrium dendrobatidis and predator cue exposure individually increased the developmental rate of the surviving tadpoles, but this effect was absent when these factors were combined with triclosan. In a follow-up study, the authors found Bd growth in culture was significantly inhibited at the 10-ug/L concentration of triclosan and completely inhibited at 100 ug/L. These findings suggest that interactions among multiple stressors can be complex and require examination in conjunction with one another to evaluate actual impacts to aquatic fauna. PMID- 23637085 TI - Abuse victimization in childhood or adolescence and risk of food addiction in adult women. AB - OBJECTIVE: Child abuse appears to increase obesity risk in adulthood, but the mechanisms are unclear. This study examined the association between child abuse victimization and food addiction, a measure of stress-related overeating, in 57,321 adult participants in the Nurses' Health Study II (NHSII). DESIGN AND METHODS: The NHSII ascertained physical and sexual child abuse histories in 2001 and current food addiction in 2009. Food addiction was defined as >=3 clinically significant symptoms on a modified version of the Yale Food Addiction Scale. Confounder-adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were estimated using modified Poisson regression. RESULTS: Over 8% of the sample reported severe physical abuse in childhood, while 5.3% reported severe sexual abuse. Eight percent met the criteria for food addiction. Women with food addiction were 6 U of BMI heavier than women without food addiction. Severe physical and severe sexual abuse were associated with roughly 90% increases in food addiction risk (physical abuse RR = 1.92; 95% CI: 1.76, 2.09; sexual abuse RR = 1.87; 95% CI: 1.69, 2.05). The RR for combined severe physical abuse and sexual abuse was 2.40 (95% CI: 2.16, 2.67). CONCLUSIONS: A history of child abuse is strongly associated with food addiction in this population. PMID- 23637086 TI - Nanoparticle transport in epithelial cells: pathway switching through bioconjugation. AB - The understanding and control of nanoparticle transport into and through cellular compartments is central to biomedical applications of nanotechnology. Here, it is shown that the transport pathway of 50 nm polystyrene nanoparticles decorated with vitamin B12 in epithelial cells is different compared to both soluble B12 ligand and unmodified nanoparticles, and this is not attributable to B12 recognition alone. Importantly, the study indicates that vitamin B12 -conjugated nanoparticles circumnavigate the lysosomal compartment, the destination of soluble vitamin B12 ligand. Whereas cellular trafficking of soluble B12 is confirmed to occur via the clathrin-mediated pathway, transport of B12 conjugated nanoparticles appears to predominantly take place by a route that is perturbed by caveolae-specific inhibitors. This data suggests that, following its conjugation to nanoparticles, in addition to dramatically increasing the cellular uptake of nanoparticles, the normal cell trafficking of B12 is switched to an alternative pathway, omitting the lysosomal stage: a result with important implications for oral delivery of nanoparticulate diagnostics and therapeutics. PMID- 23637084 TI - Xq25 duplications encompassing GRIA3 and STAG2 genes in two families convey recognizable X-linked intellectual disability with distinctive facial appearance. AB - We report here on two patients with Xq25 duplication encompassing GRIA3 gene, encoding glutamate receptor, ionotropic, AMPA subunit 3. The first case of Xq25 duplication was identified using genome-wide array comparative genomic hybridization (array-CGH) in a 24-year-old patient with syndromic intellectual disability. Based on similar facial features, we clinically suspected a second case of Xq25 duplication in a 4-year-old boy with intellectual disabilty. This duplication was confirmed by multiplex ligation-dependent probe amplification (MLPA) of the GRIA3 gene, as well as by fluorescence in situ hybridization (FISH) and further refined by array-CGH. We suggest that Xq25 duplication is responsible for a novel clinically recognizable X-linked intellectual disability. Finally, the review of so far published Xq25 duplications support, in addition to the role of GRIA3 gene, a potential contribution of the duplication of STAG2 (Stromal Antigen 2) gene coding for the subunit SA1 of the cohesin complex in the clinical phenotype. PMID- 23637088 TI - Gene expression responses for detecting sublethal effects of xenobiotics and whole effluents on a Xenopus laevis embryo assay. AB - In the present study, the authors investigated the effects of bisphenol A, chlorpyrifos, methylparaben, and 2 effluent samples from wastewater treatment plants located in the province of Madrid, Spain, on the messenger RNA expression of specific genes involved in early development (ESR1, pax6, bmp4, and myf5) and a gene involved in the general stress response (hsp70) during Xenopus laevis embryo development. Gene expression was analyzed after 4 h, 24 h, and 96 h of exposure by semiquantitative reverse-transcriptase-polymerase chain reaction. Concentration ranges of the compounds and dilutions for the samples were selected to cause morphological alterations in embryos after 96 h of exposure. Transcript levels of ESR1, pax6, and hsp70 were differentially altered at early developmental stages with patterns specific to the contaminant and the exposure time. However, further studies are needed to establish transcript levels of specific genes as biomarkers of sublethal effects in an environmental risk assessment framework. Besides, studies including more generic responses, such as genes encoding antioxidant enzymes, together with genes related to embryonic development have to be developed to look for a battery of mechanistic endpoints for the evaluation of chemical exposure at the molecular level in a first-tier assessment. PMID- 23637090 TI - Preparation of MoS2-coated three-dimensional graphene networks for high performance anode material in lithium-ion batteries. AB - A novel composite, MoS2 -coated three-dimensional graphene network (3DGN), referred to as MoS2 /3DGN, is synthesized by a facile CVD method. The 3DGN, composed of interconnected graphene sheets, not only serves as template for the deposition of MoS2 , but also provides good electrical contact between the current collector and deposited MoS2 . As a proof of concept, the MoS2 /3DGN composite, used as an anode material for lithium-ion batteries, shows excellent electrochemical performance, which exhibits reversible capacities of 877 and 665 mAh g(-1) during the 50(th) cycle at current densities of 100 and 500 mA g(-1) , respectively, indicating its good cycling performance. Furthermore, the MoS2 /3DGN composite also shows excellent high-current-density performance, e.g., depicts a 10(th) -cycle capacity of 466 mAh g(-1) at a high current density of 4 A g(-1). PMID- 23637089 TI - Arthropathy, osteolysis, keloids, relapsing conjunctival pannus and gingival overgrowth: a variant of polyfibromatosis? AB - Polyfibromatosis is a rare fibrosing condition characterized by fibromatosis in different body areas and by keloid formation, and which can be associated with arthropathy and osteolysis. Familial occurrence has been described, but the cause remains unknown. Here, we describe a patient with characteristics of polyfibromatosis with arthropathy who had in addition severe conjunctival fibrosis, distinctive face, gingival overgrowth, and pigmented keloids. We discuss the resemblances and differences with polyfibromatosis and descriptions of other, similar patients. We conclude that at present it remains uncertain whether the patient has a variant of polyfibromatosis or a separate entity. PMID- 23637092 TI - Questions concerning the potential impact of glyphosate-based herbicides on amphibians. AB - Use of glyphosate-based herbicides is increasing worldwide. The authors review the available data related to potential impacts of these herbicides on amphibians and conduct a qualitative meta-analysis. Because little is known about environmental concentrations of glyphosate in amphibian habitats and virtually nothing is known about environmental concentrations of the substances added to the herbicide formulations that mainly contribute to adverse effects, glyphosate levels can only be seen as approximations for contamination with glyphosate-based herbicides. The impact on amphibians depends on the herbicide formulation, with different sensitivity of taxa and life stages. Effects on development of larvae apparently are the most sensitive endpoints to study. As with other contaminants, costressors mainly increase adverse effects. If and how glyphosate-based herbicides and other pesticides contribute to amphibian decline is not answerable yet due to missing data on how natural populations are affected. Amphibian risk assessment can only be conducted case-specifically, with consideration of the particular herbicide formulation. The authors recommend better monitoring of both amphibian populations and contamination of habitats with glyphosate-based herbicides, not just glyphosate, and suggest including amphibians in standardized test batteries to study at least dermal administration. PMID- 23637087 TI - Developmental maturation of innate immune cell function correlates with susceptibility to central nervous system autoimmunity. AB - MS is an inflammatory CNS disorder, which typically occurs in early adulthood and rarely in children. Here we tested whether functional maturation of innate immune cells may determine susceptibility to CNS autoimmune disease in EAE. Two-week-old mice were resistant to active EAE, which causes fulminant paralysis in adult mice; this resistance was associated with an impaired development of Th1 and Th17 cells. Resistant, young mice had higher frequencies of myeloid-derived suppressor cells and plasma-cytoid DCs. Furthermore, myeloid APCs and B cells from young mice expressed lower levels of MHC class II and CD40, produced decreased amounts of proinflammatory cytokines, and released enhanced levels of anti-inflammatory IL-10. When used as APCs, splenocytes from 2-week-old mice failed to differentiate naive T cells into Th1 and Th17 cells irrespective of the T-cell donor's age, and promoted development of Treg cells and Th2 cells instead. Adoptive transfer of adult APCs restored the ability of 2-week-old mice to generate encephalitogenic T cells and develop EAE. Collectively, these findings indicate that the innate immune compartment functionally matures during development, which may be a prerequisite for development of T-cell-mediated CNS autoimmune disease. PMID- 23637091 TI - Validity of diagnostic codes and prevalence of psoriasis and psoriatic arthritis in a managed care population, 1996-2009. AB - BACKGROUND: Few population-based studies have reported the prevalence of psoriatic disease. OBJECTIVE: We validated computerized diagnoses to estimate the prevalence of psoriasis and psoriatic arthritis. METHOD: We identified adults with >=1 ICD-9 diagnosis codes of 696.0 (psoriatic arthritis) or 696.1 (psoriasis) in clinical encounter data during 1996-2009 and used chart review to confirm the diagnoses in random samples of patients. We then used the best performing case-finding algorithms to estimate the point prevalence of psoriasis and psoriatic arthritis. RESULTS: The number of persons with a diagnosis for psoriasis (ICD-9 code 696.1) was 87 827. Chart review of a random sample of 101 cases with at least one dermatologist-rendered psoriasis code revealed a positive predictive value (PPV) of 90% (95% CI, 83-95) with sensitivity of 88% (95% CI, 80 93). Psoriatic arthritis (code 696.0) was recorded for 5187 patients, with the best performing algorithm requiring >=2 diagnoses recorded by a rheumatologist or >=1 diagnosis recorded by a rheumatologist together with >=1 psoriasis diagnoses recorded by a dermatologist; the PPV was 80% (95% CI, 70-88) with sensitivity 73% (95% CI, 63-82). Among KPNC adults, the point prevalence of psoriasis, with or without psoriatic arthritis, was 939 (95% CI, 765-1142) per 100 000, and the overall prevalence of psoriatic arthritis, with or without psoriasis, was 68 (95% CI, 54-84) per 100 000. CONCLUSION: Within an integrated health care delivery system, the use of computerized diagnoses rendered by relevant disease specialists is a valid method for identifying individuals with psoriatic disease. PMID- 23637093 TI - Effectiveness of hybridized nano- and microstructure biodegradable, biocompatible, collagen-based, three-dimensional bioimplants in repair of a large tendon-defect model in rabbits. AB - This study was designed to investigate the effectiveness of hybridized, three dimensional (3D) collagen implants in repair of experimentally-induced tendon defects in rabbits. Seventy-five mature New Zealand albino rabbits were divided into treated (n = 50) and control (n = 20) groups. The left Achilles tendon was completely transected and 2 cm excised. In treated animals defects were filled with hybridized collagen implants and repaired with sutures. In control rabbits tendon defects were sutured similarly but the gap was left untreated. Changes in injured and normal contralateral tendons were assessed weekly by ultrasonography. Among the treated animals, small pilot groups were euthanized at 5, 10, 15, 20, 30, 40 (n = 5 at each time interval) and the remainder (n = 20) at 60 days post injury. All control animals were euthanized at 60 days. Tendon lesions of all animals were examined morphologically and histologically immediately after death. Those of the experimental groups (n = 20 for each) were examined for gross pathological, histopathological and ultrastructural changes together with dry matter content at 60 days post-injury, as were the normal, contralateral tendons of both groups. In comparison with healing lesions of control animals, the treated tendons showed greater numbers of mature tenoblasts and tenocytes, minimal peritendinous adhesions and oedema, together with greater echogenicity, homogeneity and fibril alignment. Fewer chronic inflammatory cells were present in treated than control tendons. Hybridized collagen implants acted as scaffolds for tenoblasts and longitudinally-orientated newly-formed collagen fibrils, which encouraged tendon repair with homogeneous, well-organized highly aligned scar tissue that was histologically and ultrastructurally more mature than in untreated controls. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 23637094 TI - Prenatal control of nondeletional alpha-thalassemia: first experience in mainland China. AB - OBJECTIVE: To demonstrate the performance of nondeletional alpha-thalassemia prevention at a mainland Chinese hospital. METHODS: A prenatal control program for nondeletional hemoglobin H (Hb H) disease was conducted from January 2010 to June 2012. All couples were screened for alpha-thalassemia trait, and for couples in whom one partner was tested positive for alpha(0) -thalassemia, the other was subjected to screening for Hb Constant Spring and Hb Quong Sze mutations. Prenatal diagnoses were offered in pregnancies of couples at-risk for nondeletional Hb H disease. RESULTS: Of the 30,152 couples screened, 18 (0.06%) were diagnosed as at risk for nondeletional Hb H disease. There were other 13 at risk couples who were referred to prenatal diagnosis because they had previously an affected child. Of the 31 cases with prenatal invasive tests, 11 (35.5%) had diagnosis by chorionic villous sampling, and 20 (64.5%) had amniocentesis. Totally, 12 fetuses were diagnosed with nondeletional Hb H disease, and all of the affected pregnancies were terminated. CONCLUSION: Implementation of a prevention and control program accompanying with a referral system for prenatal diagnosis is technically feasible in southern China, and a number of nondeletional Hb H disease have been prevented during the past 3 years of operation. PMID- 23637095 TI - Direct growth of polyaniline chains from N-doped sites of carbon nanotubes. AB - Polymer grafting from graphitic carbon materials has been pursued for several decades. Unfortunately, currently available methods mostly rely on the harsh chemical treatment of graphitic carbons which causes severe degradation of chemical structure and material properties. A straightforward growth of polyaniline chain from the nitrogen (N)-doped sites of carbon nanotubes (CNTs) is presented. N-doping sites along the CNT wall nucleate the polymerization of aniline, which generates seamless hybrids consisting of polyaniline directly grafted onto the CNT walls. The resultant materials exhibit excellent synergistic electrochemical performance, and can be employed for charge collectors of supercapacitors. This approach introduces an efficient route to hybrid systems consisting of conducting polymers directly grafted from graphitic dopant sites. PMID- 23637097 TI - Exploring the effect of erythropoietin on mortality using USRDS data. AB - PURPOSE: Erythropoietin (EPO) improves measures of quality of life and reduces transfusions. Clinical trials have reported higher mortality associated with higher hemoglobin targets in varied clinical settings, making difficult the selection of erythropoiesis stimulation strategies in end-stage kidney disease. Observational studies distinguishing an effect of EPO from underlying conditions are challenging, but promise insights relevant to real-world settings. METHODS: Using data from the United States Renal Data System, we performed a retrospective cohort study of hemodialysis patients treated between 2000 and 2004. 409 364 Medicare insured patients receiving hemodialysis therapy as of January 2000 or who began dialysis after January 2000 and survived >6 months were studied. We examined the association of EPO dose in any given month with death over subsequent follow-up. RESULTS: Within each hematocrit group (<30%, 30%-< 33%, 33% < 36%, 36%-< 39% and >39%), the hazard ratios comparing the 80th percentile to the median EPO dose were 0.88 (95% CI: [0.87-0.90]), 0.94 ([0.93-0.94]), 0.98 ([0.98-0.99]), 1.06 ([1.05-1.06]) and 1.08 ([1.07-1.09]), respectively. Within the highest hematocrit group, the association of a high EPO dose with elevated mortality was attenuated over time. Among patients with malignancy or indications of EPO resistance, the association of higher EPO dose with lower mortality was attenuated when hematocrit was low, while its association with higher mortality was stronger when hematocrit was high. CONCLUSIONS: These analyses demonstrate a complex relationship between EPO dosing and mortality, suggesting a possible beneficial effect among severely anemic hemodialysis patients, but possible harm when administered to individuals with higher hematocrit levels. PMID- 23637096 TI - 109 kb deletion of chromosome 4p16.3 in a patient with mild phenotype of Wolf Hirschhorn syndrome. AB - Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome associated with growth retardation, developmental disabilities, epileptic seizures, and distinct facial features resulting from a deletion of the short arm of chromosome 4. The Wolf-Hirschhorn Syndrome Critical Region WHSCR2 includes the LETM1 gene and 5' end of the WHSC1 gene. A haploinsufficiency of WHSC1 is thought to be responsible for a number of WHS characteristics. We report on a 2-year-old male with severe growth retardation, microcephaly and a characteristic facial appearance. He had no internal anomalies and his developmental milestones were mildly delayed. An array-CGH analysis revealed loss of genomic copy numbers in the region 4p16.3, which included FGFR3, LETM1, and WHSC1. The size of the deletion was only 109 kb. The deletion included the important genes in WHSCR2. We suspect that haploinsufficiency of WHSC1 is the most probable cause of the growth deficiency, microcephaly, and characteristic facial features in WHS. PMID- 23637098 TI - Microbial community structure and functioning along metal pollution gradients. AB - Toxic effects of heavy metals on soil microorganisms have been confirmed in a number of laboratory studies. However, most real-field studies do not allow for strong general conclusions due to a range of problems, such as pseudoreplication and confounding factors, which are almost impossible to control for with the most commonly used polluted versus unpolluted or random sampling designs. Effects of metal contamination on soil microbial community traits were measured along 2 pollution gradients in southern Poland. Employing an experimental regression design, using 2 separate gradients, the authors aimed to control for effects of soil properties and beta-diversity of microbial communities. General microbial activity was measured as soil basal respiration rate and substrate-induced respiration, while microbial functional and structural diversity were analyzed with community-level physiological profiles and phospholipid fatty acid patterns, respectively. Metal concentrations were normalized to their toxicity and integrated in a toxicity index (TI). Microbial activity (basal and substrate induced respiration) decreased in both gradients with increasing TI. Community level physiological profiles for fungi correlated positively with TI, but no impact of TI on the community-level physiological profiles of bacteria was observed. The phospholipid fatty acids a:15 and i:17 were positively correlated with TI, whereas 16:1omega9 and 18:2omega9 were negatively correlated with TI. The use of 2 gradients (Olkusz and Miasteczko Slaskie) allowed the authors to reveal a clear effect of pollution on general microbial structure and activities, even though they were not able to control completely for all confounding factors. Soil pH, organic matter content, and nutrient level appeared to be at least as important as TI in determining microbial community structure and activities. PMID- 23637099 TI - Comparison of total energy expenditure between school and summer months. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Childhood obesity has increased 3 to 4 fold. Some children gain excess weight in summer. WHAT THIS STUDY ADDS: Total energy expenditure increases almost linearly with fat-free mass. A lower total energy expenditure was not detected in summer. OBJECTIVE: Recent data report that the youth experience greater weight gain during summer than during school months. We tested the hypothesis that a difference in total energy expenditure (TEE) between school and summer months exists and may contribute to summer weight gain. SUBJECTS AND METHODS: A secondary analysis was performed on cross-sectional TEE data from school-age, sedentary African-American and Caucasian youth based in or near the District of Columbia who were at-risk for adult obesity because they had body mass index (BMI) >= 85th percentile or had overweight parents. TEE was estimated from 18-O and deuterium measurements during 1-week intervals using urine samples collected after ingestion of doubly labelled water. Differences in summer- and school-time TEE were assessed using analysis of covariance. The data were adjusted for fat-free mass (FFM) as determined by deuterium dilution to adjust for the effect of body size on TEE. RESULTS: Data were collected from 162 youth (average age 10 +/- 2 years, BMI 28 +/- 8 kg m(-2) and BMI z-score 1.96 + 0.96). Of these, 96 youth had TEE measured during the school year (September June); 66 different youths had TEE measured during summer months (June-August). After adjustment for FFM, average summertime TEE was 2450 +/- 270 kcal d(-1) and average school-time TEE was 2510 +/- 350 kcal d(-1) (P = 0.26). CONCLUSION: No difference in TEE was detected between the school year and the summer months. These data suggest that seasonal differences in youth weight gain are not necessarily due to differences in energy expenditures. PMID- 23637100 TI - Top-down HPLC-ESI-MS characterization of rat gliadoralin A, a new member of the family of rat submandibular gland glutamine-rich proteins and potential substrate of transglutaminase. AB - During HPLC-ESI-MS/MS analysis of rat submandibular saliva secreted under isoprenaline stimulation, a protein with an experimental [M+H](1+) = 10,544.24 m/z was detected (17.5 +/- 0.7 min). The MS/MS fragmentation pattern, manually investigated, allowed establishing an internal sequence in agreement with a DNA derived sequence of an unknown rat protein coded D3Z9M3 (Swiss-Prot). To match the experimental MS/MS fragmentation pattern and protein mass with theoretical data, the removal from the N terminus of the signal peptide and from the C terminus of three amino acid (a.a.) residues (Arg-Ala-Val) and the cyclization of the N-terminal glutamine in pyroglutamic had to be supposed, resulting in a mature protein of 90 a.a. HPLC-ESI-MS/MS of the trypsin digest ensured 100% sequence coverage. For the high glutamine content (34/90 = 37.8%) we propose to name this protein rat gliadoralin A 1-90. Low amounts of five different isoforms were sporadically detected, which did not significantly change their relative amounts after stimulation. Gliadoralin A is substrate for transglutaminase-2, having Lys 60 and different Gln residues as major determinants for enzyme recognition. In silico investigation of superior structures evidenced that a small part of the protein adopts an alpha-helical fold, whereas large segments are unfolded, suggesting an unordered conformation. PMID- 23637101 TI - Liquid-based cytology using CytoRich Red/Tripath is diagnostically equivalent to conventional smears for bronchial washings and brushings and reduces the cost. AB - A split sample study was performed on 109 bronchial brushings and washings and evaluated from conventional slides (CS) and CytoRich Red/Tripath preparations (CRR/Tripath). Unassessable bronchial washings were significantly more frequent in CS (5 vs. 0), but as all brushings were assessable with both methods, no overall diagnostic advantage was found. CS and CRR/Tripath gave discordant diagnoses in one case with a final benign diagnosis and in six cases with final malignant diagnoses. In the benign case, atypia was assessed in CS. In the malignant cases, suspected malignancy was found in one CRR/Tripath and one CS, atypia vs. benign assessment was also balanced, with three atypias in CRR/Tripath and two in CS. The better preserved cells in CRR/Tripath facilitated correct diagnosis in some cases, but might also lead to false positive diagnoses. In small cell carcinomas diagnostic hints such as smearing and moulding were less pronounced in CRR/Tripath but this did not affect the diagnostic accuracy. Overall, the diagnostic performance with CRR/Tripath was at least as good as with conventional slides, although statistically no difference could be seen. The number of slides and screening time, and thereby cost was significantly reduced with CRR/Tripath, thus the liquid-based method is preferred for bronchial washings and brushings. PMID- 23637102 TI - Cytomorphologic overlap of differentiated thyroid carcinoma and lung adenocarcinoma and diagnostic value of TTF-1 and TGB on cytologic material. AB - Thyroid carcinomas and lung adenocarcinoma share cytomorphological features yet have different prognoses. Thyroid Transcription Factor-1 (TTF-1) is an immunohistochemical (IHC) marker used to confirm pulmonary and thyroid carcinoma, while Thyroglobulin (TGB) is expressed by thyroid carcinoma. The cytopathology archive of The Johns Hopkins Hospital was searched for cases of lung adenocarcinoma versus thyroid carcinoma with TTF-1 and TGB IHC. Forty-four cases of lung adenocarcinoma (25) and thyroid carcinoma (19) were retrieved. One was metastatic lung adenocarcinoma to the thyroid and three were metastatic papillary thyroid carcinoma (PTC) to the lung. The initial interpretation of two cases from bony lesions was metastatic lung adenocarcinoma. In light of additional clinical information and TGB immunostain, the diagnoses of these two cases changed to metastatic thyroid carcinoma. TTF-1 and TGB is a small immunostain panel that can differentiate lung adenocarcinoma from thyroid carcinoma and prevent misdiagnosis and its consequences. PMID- 23637103 TI - Giant cell tumor of bone presenting in the lumbar spine of a 35-year-old female: cytodiagnosis and other diagnostic considerations. AB - Fine-needle aspiration (FNA) is commonly used in the evaluation of both primary and metastatic bone lesions. Giant cell tumor (GCT) of bone is one of the primary bone neoplasms that can be diagnosed with good success on FNA as its cytologic features are relatively reproducible. However, this entity classically involves the ends (or epiphyses) of the longs bones making an FNA diagnosis of a GCT of bone in other anatomic locations is challenging and requires the consideration of a differential diagnosis. By invoking clinico-radiographical correlation and maximizing our specimen, we were able to diagnose a GCT of bone involving the L1 vertebral body in a 35-year-old female. PMID- 23637104 TI - The future of academic psychiatry may be social. AB - The past 30 years have produced no discoveries leading to major changes in psychiatric practice. The rules regulating research and a dominant neurobiological paradigm may both have stifled creativity. Embracing a social paradigm could generate real progress and, simultaneously, make the profession more attractive. PMID- 23637105 TI - Fetal antipsychotic exposure in a changing landscape: seeing the future. AB - Pregnant women and their fetuses are increasingly likely to be exposed to antipsychotics. However, safety data remain limited. This editorial suggests that, in future, well-designed observational pharmaco-epidemiology is our best chance of illuminating risk for exposed populations and of informing decision making for women and clinicians. PMID- 23637106 TI - Attempted suicide v. non-suicidal self-injury: behaviour, syndrome or diagnosis? AB - Nomenclature used to describe acts of self-harm without fatal consequences varies considerably. The term 'non-suicidal self-injury' (NSSI) offers an opportunity to clarify study in this field, dichotomising the presence or absence of suicidal intent. This may improve consistency in reporting suicide and self-injurious behaviour with implications for management and prognosis. PMID- 23637107 TI - Non-suicidal self-injury v. attempted suicide: new diagnosis or false dichotomy? AB - Non-suicidal self-injury (NSSI) is a term that is becoming popular especially in North America and it has been proposed as a new diagnosis in DSM-5. In this paper we consider what self-harm research can tell us about the concept of NSSI and examine the potential pitfalls of introducing NSSI into clinical practice. PMID- 23637109 TI - Influence of problematic child-teacher relationships on future psychiatric disorder: population survey with 3-year follow-up. AB - BACKGROUND: Teacher-pupil relationships have been found to mediate behavioural, social and psychological outcomes for children at different ages according to teacher and child report, but most studies have been small. AIMS: To explore later psychiatric disorder among children with problematic teacher-pupil relationships. METHOD: Secondary analysis of a population-based cross-sectional survey of children aged 5-16 with a 3-year follow-up. RESULTS: Of the 3799 primary-school pupils assessed, 2.5% of parents reported problematic teacher pupil relationships; for secondary-school pupils (n = 3817) this rose to 6.6%. Among secondary-school pupils, even when children with psychiatric disorder at baseline were excluded and we adjusted for baseline psychopathology score, problematic teacher-pupil relationships were statistically significantly related to higher levels of psychiatric disorder at 3-year follow-up (odds ratio (OR) = 1.93, 95% CI 1.07-3.51 for any psychiatric disorder, OR = 3.00, 95% CI 1.37-6.58 for conduct disorder). Results for primary-school pupils were similar but non significant at this level of adjustment. CONCLUSIONS: This study underlines the need to support teachers and schools to develop positive relationships with their pupils. PMID- 23637108 TI - Late-life depression and risk of vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies. AB - BACKGROUND: Late-life depression may increase the risk of incident dementia, in particular of Alzheimer's disease and vascular dementia. AIMS: To conduct a systematic review and meta-analysis to evaluate the risk of incident all-cause dementia, Alzheimer's disease and vascular dementia in individuals with late-life depression in population-based prospective studies. METHOD: A total of 23 studies were included in the meta-analysis. We used the generic inverse variance method with a random-effects model to calculate the pooled risk of dementia, Alzheimer's disease and vascular dementia in older adults with late-life depression. RESULTS: Late-life depression was associated with a significant risk of all-cause dementia (1.85, 95% CI 1.67-2.04, P<0.001), Alzheimer's disease (1.65, 95% CI 1.42-1.92, P<0.001) and vascular dementia (2.52, 95% CI 1.77-3.59, P<0.001). Subgroup analysis, based on five studies, showed that the risk of vascular dementia was significantly higher than for Alzheimer's disease (P = 0.03). CONCLUSIONS: Late life depression is associated with an increased risk for all-cause dementia, vascular dementia and Alzheimer's disease. The present results suggest that it will be valuable to design clinical trials to investigate the effect of late-life depression prevention on risk of dementia, in particular vascular dementia and Alzheimer's disease. PMID- 23637110 TI - Joint crisis plans for people with borderline personality disorder: feasibility and outcomes in a randomised controlled trial. AB - BACKGROUND: People with borderline personality disorder frequently experience crises. To date, no randomised controlled trials (RCTs) of crisis interventions for this population have been published. AIMS: To examine the feasibility of recruiting and retaining adults with borderline personality disorder to a pilot RCT investigating the potential efficacy and cost-effectiveness of using a joint crisis plan. METHOD: An RCT of joint crisis plans for community-dwelling adults with borderline personality disorder (trial registration: ISRCTN12440268). The primary outcome measure was the occurrence of self-harming behaviour over the 6 month period following randomisation. Secondary outcomes included depression, anxiety, engagement and satisfaction with services, quality of life, well-being and cost-effectiveness. RESULTS: In total, 88 adults out of the 133 referred were eligible and were randomised to receive a joint crisis plan in addition to treatment as usual (TAU; n = 46) or TAU alone (n = 42). This represented approximately 75% of our target sample size and follow-up data were collected on 73 (83.0%) participants. Intention-to-treat analysis revealed no significant differences in the proportion of participants who reported self-harming (odds ratio (OR) = 1.9, 95% CI 0.53-6.5, P = 0.33) or the frequency of self-harming behaviour (rate ratio (RR) = 0.74, 95% CI 0.34-1.63, P = 0.46) between the two groups at follow-up. No significant differences were observed between the two groups on any of the secondary outcome measures or costs. CONCLUSIONS: It is feasible to recruit and retain people with borderline personality disorder to a trial of joint crisis plans and the intervention appears to have high face validity with this population. However, we found no evidence of clinical efficacy in this feasibility study. PMID- 23637111 TI - IAPT is probably not cost-effective. PMID- 23637112 TI - Drop out from treatment in the World Mental Health Survey initiative. PMID- 23637113 TI - Psychological therapies in anorexia nervosa: on the wrong track? PMID- 23637114 TI - Spirituality is not bad for our mental health. PMID- 23637116 TI - A systematic video analysis of National Hockey League (NHL) concussions, part II: how concussions occur in the NHL. AB - BACKGROUND: Concussions in sports are a growing cause of concern, as these injuries can have debilitating short-term effects and little is known about the potential long-term consequences. This work aims to describe how concussions occur in the National Hockey League. METHODS: Case series of medically diagnosed concussions for regular season games over a 3.5-year period during the 2006-2010 seasons. Digital video records were coded and analysed using a standardised protocol. RESULTS: 88% (n=174/197) of concussions involved player-to-opponent contact. 16 diagnosed concussions were a result of fighting. Of the 158 concussions that involved player-to-opponent body contact, the most common mechanisms were direct contact to the head initiated by the shoulder 42% of the time (n=66/158), by the elbow 15% (n=24/158) and by gloves in 5% of cases (n=8/158). When the results of anatomical location are combined with initial contact, almost half of these events (n=74/158) were classified as direct contact to the lateral aspect of the head. CONCLUSIONS: The predominant mechanism of concussion was consistently characterised by player-to-opponent contact, typically directed to the head by the shoulder, elbow or gloves. Also, several important characteristics were apparent: (1) contact was often to the lateral aspect of the head; (2) the player who suffered a concussion was often not in possession of the puck and (3) no penalty was called on the play. PMID- 23637115 TI - Genetic biomarkers and exercise-related injuries: current clinical applications? PMID- 23637117 TI - US pediatric injuries involving amusement rides, 1990-2010. AB - This study investigates pediatric injuries involving amusement rides treated in US emergency departments by retrospectively analyzing data from the National Electronic Injury Surveillance System. From 1990 to 2010, an estimated 92 885 children <=17 years sought treatment in US hospital emergency departments for injuries involving amusement rides, yielding an annual average of 4423 injuries. The average annual injury rate was 6.24 injuries per 100 000 US children, and the mean patient age was 8.73 years. The head and neck was the most commonly injured body region (28.0%), and the most common type of injury was a soft tissue injury (29.4%). Falling in, on, off, or against the ride was the most frequent mechanism of injury (31.7%). Only 1.5% of injuries resulted in hospitalization. An improved national system for monitoring injuries involving amusement rides is needed. There are opportunities to improve the safety of amusement rides for children, especially to prevent injuries from falls. PMID- 23637119 TI - beta-Adrenergic blockade in cardiovascular disease. AB - The development and subsequent clinical application of the beta-adrenergic receptor blocking drugs represent one of the major advances in human pharmacotherapeutics. No other class of synthetic drugs has demonstrated such widespread therapeutic utility for the treatment and prevention of so many cardiovascular diseases. In addition, these drugs have proven to be molecular probes that have contributed to our understanding of the disease, and on the molecular level, both the structure and function of the 7 transmembrane G protein receptors that mediate the actions of many different hormones, neurotransmitters, and drugs. The evolution of beta-blocker drug development has led to refinements in their pharmacodynamic actions that include agents with relative beta1 selectivity, partial agonist activity, concomitant alpha-adrenergic blockers activity, and direct vasodilator activity. In addition, long-acting and ultra short-acting formulations of beta-blockers have also demonstrated a remarkable record of clinical safety in patients of all ages. PMID- 23637118 TI - Challenges in caring for the neonate who acquires methicillin-resistant Staphylococcus aureus via vertical transmission. PMID- 23637120 TI - EDNRB and DCC salivary rinse hypermethylation has a similar performance as expert clinical examination in discrimination of oral cancer/dysplasia versus benign lesions. AB - PURPOSE: Promoter hypermethylation has been recently proposed as a means for head and neck squamous cell carcinoma (HNSCC) detection in salivary rinses. In a prospective study of a high-risk population, we showed that endothelin receptor type B (EDNRB) promoter methylation in salivary rinses is a useful biomarker for oral cancer and premalignancy. EXPERIMENTAL DESIGN: Using that cohort, we evaluated EDNRB methylation status and 8 additional genes. Clinical risk assessment by expert clinicians was conducted and compared with biomarker performance in the prediction of premalignant and malignant disease. Methylation status of 9 genes was analyzed in salivary rinses of 191 patients by quantitative methylation-specific PCR. RESULTS: HOXA9, EDNRB, and deleted in colorectal cancer (DCC) methylation were associated (P = 0.012; P < 0.0001; P = 0.0005) with premalignant or malignant disease. On multivariable modeling, histological diagnosis was only independently associated with EDNRB (P = 0.0003) or DCC (P = 0.004) methylation. A subset of patients received clinical risk classification (CRC) by expert clinicians based on lesion examination. CRC, DCC, and EDNRB were associated with diagnosis of dysplasia/cancer on univariate (P = 0.008; P = 0.026; P = 0.046) and multivariate analysis (P = 0.012; P = 0.037; P = 0.047). CRC identified dysplasia/cancer with 56% of sensitivity and 66% of specificity with a similar area under curve [AUC; 0.61, 95% confidence interval (CI) = 0.60 0.81] when compared to EDNRB and DCC combined AUC (0.60, 95% CI = 0.51-0.69), sensitivity of 46% and specificity of 72%. A combination of EDNRB, DCC, and CRC was optimal AUC (0.67, 95% CI = 0.58-0.76). CONCLUSIONS: EDNRB and/or DCC methylation in salivary rinses compares well to examination by an expert clinician in CRC of oral lesions. These salivary biomarkers may be particularly useful in oral premalignancy and malignancy screening in clinical care settings in which expert clinicians are not available. PMID- 23637121 TI - Targeting the CD20 and CXCR4 pathways in non-hodgkin lymphoma with rituximab and high-affinity CXCR4 antagonist BKT140. AB - PURPOSE: Chemokine axis CXCR4/CXCL12 is critically involved in the survival and trafficking of normal and malignant B lymphocytes. Here, we investigated the effect of high-affinity CXCR4 antagonist BKT140 on lymphoma cell growth and rituximab-induced cytotoxicity in vitro and in vivo. EXPERIMENTAL DESIGN: In vitro efficacy of BKT140 alone or in combination with rituximab was determined in non-Hodgkin lymphoma (NHL) cell lines and primary samples from bone marrow aspirates of patients with NHL. In vivo efficacy was evaluated in xenograft models of localized and disseminated NHL with bone marrow involvement. RESULTS: Antagonizing CXCR4 with BKT140 resulted in significant inhibition of CD20+ lymphoma cell growth and in the induction of cell death, respectively. Combination of BKT140 with rituximab significantly enhanced the apoptosis against the lymphoma cells in a dose-dependent manner. Moreover, rituximab induced CXCR4 expression in lymphoma cell lines and primary lymphoma cells, suggesting the possible interaction between CD20 and CXCR4 pathways in NHL. Primary bone marrow stromal cells (BMSC) further increased CXCR4 expression and protected NHL cells from rituximab-induced apoptosis, whereas BKT140 abrogated this protective effect. Furthermore, BKT140 showed efficient antilymphoma activity in vivo in the xenograft model of disseminated NHL with bone marrow involvement. BKT140 treatment inhibited the local tumor progression and significantly reduced the number of NHL cells in the bone marrow. Combined treatment of BKT140 with rituximab further decreased the number of viable lymphoma cells in the bone marrow, achieving 93% reduction. CONCLUSIONS: These findings suggest the possible role of CXCR4 in NHL progression and response to rituximab and provide the scientific basis for the development of novel CXCR4-targeted therapies for refractory NHL. PMID- 23637122 TI - Noninvasive detection of HER2 amplification with plasma DNA digital PCR. AB - PURPOSE: Digital PCR is a highly accurate method of determining DNA concentration. We adapted digital PCR to determine the presence of oncogenic amplification through noninvasive analysis of circulating free plasma DNA and exemplify this approach by developing a plasma DNA digital PCR assay for HER2 copy number. EXPERIMENTAL DESIGN: The reference gene for copy number assessment was assessed experimentally and bioinformatically. Chromosome 17 pericentromeric probes were shown to be suboptimal, and EFTUD2 at chromosome position 17q21.31 was selected for analysis. Digital PCR assay parameters were determined on plasma samples from a development cohort of 65 patients and assessed in an independent validation cohort of plasma samples from 58 patients with metastatic breast cancer. The sequential probability ratio test was used to assign the plasma DNA digital PCR test as being HER2-positive or -negative in the validation cohort. RESULTS: In the development cohort, the HER2:EFTUD2 plasma DNA copy number ratio had a receiver operator area under the curve (AUC) = 0.92 [95% confidence interval (CI), 0.86-0.99, P = 0.0003]. In the independent validation cohort, 64% (7 of 11) of patients with HER2-amplified cancers were classified as plasma digital PCR HER2-positive and 94% (44 of 47) of patients with HER2-nonamplified cancers were classified as digital PCR HER2-negative, with a positive and negative predictive value of 70% and 92%, respectively. CONCLUSION: Analysis of plasma DNA with digital PCR has the potential to screen for the acquisition of HER2 amplification in metastatic breast cancer. This approach could potentially be adapted to the analysis of any locus amplified in cancer. PMID- 23637124 TI - Using genome-wide association analysis to characterize environmental sensitivity of milk traits in dairy cattle. AB - Genotype-by-environment interaction (GxE) has been widely reported in dairy cattle. One way to analyze GxE is to apply reaction norm models. The first derivative of a reaction norm is the environmental sensitivity (ES). In the present study we conducted a large-scale, genome-wide association analysis to identify single-nucleotide polymorphisms (SNPs) that affect general production (GP) and ES of milk traits in the German Holstein population. Sire estimates for GP and for ES were calculated from approximately 13 million daughter records by the use of linear reaction norm models. The daughters were offspring from 2297 sires. Sires were genotyped for 54k SNPs. The environment was defined as the average milk energy yield performance of the herds at the time during which the daughter observations were recorded. The sire estimates were used as observations in a genome-wide association analysis, using 1797 sires. Significant SNPs were confirmed in an independent validation set (500 sires of the same population). To separate GxE scaling and other GxE effects, the observations were log-transformed in some analyses. Results from the reaction norm model revealed GxE effects. Numerous significant SNPs were validated for both GP and ES. Many SNPs that affect GP also affect ES. We showed that ES of milk traits is a typical quantitative trait, genetically controlled by many genes with small effects and few genes with larger effect. A log-transformation of the observation resulted in a reduced number of validated SNPs for ES, pointing to genes that not only caused scaling GxE effects. The results will have implications for breeding for robustness in dairy cattle. PMID- 23637123 TI - Genome-wide patterns of codon bias are shaped by natural selection in the purple sea urchin, Strongylocentrotus purpuratus. AB - Codon usage bias has been documented in a wide diversity of species, but the relative contributions of mutational bias and various forms of natural selection remain unclear. Here, we describe for the first time genome-wide patterns of codon bias at 4623 genes in the purple sea urchin, Strongylocentrotus purpuratus. Preferred codons were identified at 18 amino acids that exclusively used G or C at third positions, which contrasted with the strong AT bias of the genome (overall GC content is 36.9%). The GC content of third positions and coding regions exhibited significant correlations with the magnitude of codon bias. In contrast, the GC content of introns and flanking regions was indistinguishable from the genome-wide background, which suggested a limited contribution of mutational bias to synonymous codon usage. Five distinct clusters of genes were identified that had significantly different synonymous codon usage patterns. A significant correlation was observed between codon bias and mRNA expression supporting translational selection, but this relationship was driven by only one highly biased cluster that represented only 8.6% of all genes. In all five clusters preferred codons were evolutionarily conserved to a similar degree despite differences in their synonymous codon usage distributions and magnitude of codon bias. The third positions of preferred codons in two codon usage groups also paired significantly more often in stems than in loops of mRNA secondary structure predictions, which suggested that codon bias might also affect mRNA stability. Our results suggest that mutational bias has played a minor role in determining codon bias in S. purpuratus and that preferred codon usage may be heterogeneous across different genes and subject to different forms of natural selection. PMID- 23637125 TI - Dynamic imaging reveals promiscuous crosspresentation of blood-borne antigens to naive CD8+ T cells in the bone marrow. AB - The bone marrow (BM) hosts memory lymphocytes and supports secondary immune responses against blood-borne antigens, but it is unsettled whether primary responses occur there and which cells present the antigen. We used 2-photon microscopy in the BM of live mice to study these questions. Naive CD8(+) T cells crawled rapidly at steady state but arrested immediately upon sensing antigenic peptides. Following infusion of soluble protein, various cell types were imaged ingesting the antigen, while antigen-specific T cells decelerated, clustered, upregulated CD69, and were observed dividing in situ to yield effector cells. Unlike in the spleen, T-cell responses persisted when BM-resident dendritic cells (DCs) were ablated but failed when all phagocytic cells were depleted. Potential antigen-presenting cells included monocytes and macrophages but not B cells. Collectively, our results suggest that the BM supports crosspresentation of blood borne antigens similar to the spleen; uniquely, alongside DCs, other myeloid cells participate in crosspresentation. PMID- 23637126 TI - Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types. AB - Dipeptidylpeptidase (DPP) 4 has the potential to truncate proteins with a penultimate alanine, proline, or other selective amino acids at the N-terminus. DPP4 truncation of certain chemokines, colony-stimulating factors, and interleukins have recently been linked to regulation of hematopoietic stem/progenitor cells, more mature blood cells, and other cell types. We believe that the potential role of DPP4 in modification of many regulatory proteins, and their subsequent effects on numerous stem/progenitor and other cell-type functions has not been adequately appreciated. This review addresses the potential implications of the modifying effects of DPP4 on a large number of cytokines and other growth-regulating factors with either proven or putative DPP4 truncation sites on hematopoietic cells, and subsequent effects of DPP4-truncated proteins on multiple aspects of steady-state and stressed hematopoiesis, including stem/progenitor cell, and more mature cell, function. PMID- 23637127 TI - Splenectomy and the incidence of venous thromboembolism and sepsis in patients with immune thrombocytopenia. AB - Patients with immune thrombocytopenia (ITP) who relapse after an initial trial of corticosteroid treatment present a therapeutic challenge. Current guidelines recommend consideration of splenectomy, despite the known risks associated with surgery and the postsplenectomy state. To better define these risks, we identified a cohort of 9976 patients with ITP, 1762 of whom underwent splenectomy. The cumulative incidence of abdominal venous thromboembolism (AbVTE) was 1.6% compared with 1% in patients who did not undergo splenectomy; venous thromboembolism (VTE) (deep venous thrombosis and pulmonary embolus) after splenectomy was 4.3% compared with 1.7% in patients who did not undergo splenectomy. There was increased risk of AbVTE early (<90 days; hazard ratio [HR] 5.4 [confidence interval (CI), 2.3-12.5]), but not late (>=90 days; HR 1.5 [CI, 0.9-2.6]) after splenectomy. There was increased risk of VTE both early (HR 5.2 [CI, 3.2-8.5]) and late (HR 2.7 [CI, 1.9-3.8]) after splenectomy. The cumulative incidence of sepsis was 11.1% among the ITP patients who underwent splenectomy and 10.1% among the patients who did not. Splenectomy was associated with a higher adjusted risk of sepsis, both early (HR 3.3 [CI, 2.4-4.6]) and late (HR 1.6 or 3.1, depending on comorbidities). We conclude that ITP patients post splenectomy are at increased risk for AbVTE, VTE, and sepsis. PMID- 23637128 TI - Influence of KIR gene copy number on natural killer cell education. AB - Natural killer (NK) cells are functionally tuned by education via killer cell immunoglobulin receptors (KIRs) interacting with HLA class I molecules. We examined the effect of KIR gene copy number variation on the education of human NK cells. The frequency of NK cells expressing a given KIR correlated with the copy number of that gene. However, coexpression of multiple copies from a single locus, or duplicated loci, was infrequent, which is in line with independent transcriptional regulation of each allele or copy. Intriguingly, coexpression of 2 KIR alleles, resulting in higher surface expression, did not lead to enhanced functional responses in vitro or to selective advantages during in vivo responses to cytomegalovirus infection, suggesting that receptor density does not influence NK education at the single cell level. However, individuals with multiple KIR gene copies had higher frequencies of responding cells, consistent with heightened overall responsiveness. PMID- 23637130 TI - The impact of HLA unidirectional mismatches on the outcome of myeloablative hematopoietic stem cell transplantation with unrelated donors. AB - The impact of HLA homozygosity at mismatched (MM) loci on the outcome of 2687 myeloablative unrelated donor hematopoietic cell transplantations performed for malignant disease was evaluated among 4 groups: 7/8 bidirectional MM transplants (donor and recipient heterozygous MM, n = 1393), 7/8 host-versus-graft (HVG) vector MM (recipient homozygous, n = 112), 7/8 graft-versus-host (GVH) vector MM (donor homozygous, n = 119), and 8/8 matches (n = 1063). Multivariate analyses found 7/8 GVH (P = .001) and bidirectional MM groups (P < .0001) had significantly worse transplant-related mortality and overall and disease-free survival than the 8/8 match group, a difference not observed with the 7/8 HVG MM group (P > .01). The 3 7/8 groups differed only for grades III-IV acute GVH disease (GVHD), where HVG MM had less GVHD than the 7/8 bidirectional MM (hazard ratio [HR] 0.52, P = .0016) and GVH MM (HR 0.43, P = .0009) groups but not the 8/8 group (HR 0.83, P = .39). There were no differences between the 7/8 groups for relapse, chronic GVHD, neutrophil engraftment, or graft failure. GVH MM have the same risk as 7/8 bidirectional MM. 7/8 HVG MM confer a reduced risk of acute GVHD without an increased risk of disease relapse or graft failure compared with a 7/8 bidirectional MM. PMID- 23637129 TI - Defective K-Ras oncoproteins overcome impaired effector activation to initiate leukemia in vivo. AB - Reversing the aberrant biochemical output of oncogenic Ras proteins is one of the great challenges in cancer therapeutics; however, it is uncertain which Ras effectors are required for tumor initiation and maintenance. To address this question, we expressed oncogenic K-Ras(D12) proteins with "second site" amino acid substitutions that impair PI3 kinase/Akt or Raf/MEK/ERK activation in bone marrow cells and transplanted them into recipient mice. In spite of attenuated signaling properties, defective K-Ras oncoproteins initiated aggressive clonal T lineage acute lymphoblastic leukemia (T-ALL). Murine T-ALLs expressing second site mutant proteins restored full oncogenic Ras activity through diverse mechanisms, which included acquiring novel somatic third site Kras(D12) mutations and silencing PTEN. T-ALL cell lines lacking PTEN had elevated levels of phosphorylated Akt, a gene expression pattern similar to human early T-cell precursor ALL, and were resistant to the potent and selective MEK inhibitor PD0325901. Our data, which demonstrate strong selective pressure to overcome the defective activation of PI3 kinase/Akt and Raf/MEK/ERK, implicate both Ras effector pathways as drivers of aberrant growth in T-ALL and further suggest that leukemia cells will deploy multiple mechanisms to develop resistance to targeted inhibitors in vivo. PMID- 23637131 TI - Association between molecular lesions and specific B-cell receptor subsets in chronic lymphocytic leukemia. AB - Genetic lesions and B-cell receptor (BCR) signaling are both oncogenic drivers in chronic lymphocytic leukemia (CLL). However, scant data are available on preferential associations between specific genetic alterations and stereotyped BCR subsets. By analyzing 1419 cases, 2 CLL subsets (2 and 8) harboring stereotyped BCR are enriched in specific molecular alterations influencing disease course. SF3B1 mutations are the genetic hallmark of IGHV3-21-CLL belonging to subset 2 (52%) but are evenly represented in nonstereotyped IGHV3-21 CLL. Trisomy 12 (87%) and NOTCH1 mutations (62%) characterize IGHV4-39-CLL belonging to subset 8 but occur with the expected frequency in IGHV4-39-CLL with heterogeneous BCR. Clinically, co-occurrence of SF3B1 mutations and subset 2 BCR configuration prompts disease progression in IGHV3-21-CLL, whereas cooperation between NOTCH1 mutations, +12, and subset 8 BCR configuration invariably primes CLL transformation into Richter syndrome. These findings provide a proof of concept that specific stereotyped BCR may promote or select molecular lesions influencing outcome. PMID- 23637132 TI - Breast cancer detection and survival among women with cosmetic breast implants: systematic review and meta-analysis of observational studies. AB - OBJECTIVES: To evaluate whether the stage distribution among women diagnosed as having breast cancer differs between those who have received breast implants for cosmetic purposes and those with no implants and to evaluate whether cosmetic breast augmentation before the detection of breast cancer is a predictor of post diagnosis survival. DESIGN: Systematic review of observational studies with two meta-analyses. DATA SOURCES: Systematic search of the literature published before September 2012 conducted in Medline, Embase, Global health, CINAHL, IPAB, and PsycINFO. STUDY SELECTION: Eligible publications were those that included women diagnosed as having breast cancer and who had had augmentation mammaplasty for cosmetic purposes. RESULTS: The overall odds ratio of the first meta-analysis based on 12 studies was 1.26 (95% confidence interval 0.99 to 1.60; P=0.058; I(2)=35.6%) for a non-localized stage of breast cancer at diagnosis comparing women with implants who had breast cancer and women without implants who had breast cancer. The second meta-analysis, based on five studies, evaluated the relation between cosmetic breast implantation and survival. This meta-analysis showed reduced survival after breast cancer among women who had implants compared with those who did not (overall hazard ratio for breast cancer specific mortality 1.38, 95% confidence interval 1.08 to 1.75). CONCLUSIONS: The research published to date suggests that cosmetic breast augmentation adversely affects the survival of women who are subsequently diagnosed as having breast cancer. These findings should be interpreted with caution, as some studies included in the meta-analysis on survival did not adjust for potential confounders. Further investigations are warranted regarding diagnosis and prognosis of breast cancer among women with breast implants. PMID- 23637134 TI - The influence of acute resistance exercise on cyclooxygenase-1 and -2 activity and protein levels in human skeletal muscle. AB - This study evaluated the activity and content of cyclooxygenase (COX)-1 and -2 in response to acute resistance exercise (RE) in human skeletal muscle. Previous work suggests that COX-1, but not COX-2, is the primary COX isoform elevated with resistance exercise in human skeletal muscle. COX activity, however, has not been assessed after resistance exercise in humans. It was hypothesized that RE would increase COX-1 but not COX-2 activity. Muscle biopsies were taken from the vastus lateralis of nine young men (25 +/- 1 yr) at baseline (preexercise), 4, and 24 h after a single bout of knee extensor RE (three sets of 10 repetitions at 70% of maximum). Tissue lysate was assayed for COX-1 and COX-2 activity. COX-1 and COX-2 protein levels were measured via Western blot analysis. COX-1 activity increased at 4 h (P < 0.05) compared with preexercise, but returned to baseline at 24 h (PRE: 60 +/- 10, 4 h: 106 +/- 22, 24 h: 72 +/- 8 nmol PGH2.g total protein( 1).min(-1)). COX-2 activity was elevated at 4 and 24 h after RE (P < 0.05, PRE: 51 +/- 7, 4 h: 100 +/- 19, 24 h: 98 +/- 14 nmol PGH2.g total protein(-1).min( 1)). The protein level of COX-1 was not altered (P > 0.05) with acute RE. In contrast, COX-2 protein levels were nearly 3-fold greater (P > 0.05) at 4 h and 5 fold greater (P = 0.06) at 24 h, compared with preexercise. In conclusion, COX-1 activity increases transiently with exercise independent of COX-1 protein levels. In contrast, both COX-2 activity and protein levels were elevated with exercise, and this elevation persisted to at least 24 h after RE. PMID- 23637135 TI - Association of Rev-erbalpha in adipose tissues with Type 2 diabetes mellitus amelioration after gastric bypass surgery in Goto-Kakizaki rats. AB - We estimated the key molecules related to Type 2 diabetes mellitus (T2DM) in adipose, liver, and muscle tissues, from nonobese diabetic Goto-Kakizaki (GK) rats and their Wistar controls, by computationally analyzing the expression profiles in open source data. With the aid of information from previous reports, Rev-erbalpha in adipose tissue emerged as one of the most plausible candidates. Here, in animal models, including GK rats surgically treated to ameliorate T2DM, we examined the association of Rev-erbalpha in adipose tissue with T2DM progression. After analyses of the Rev-erbalpha mRNA expression in the adipose tissue of our animal models, we compared the Rev-erbalpha protein expression levels in the adipose, liver, and muscle tissues of GK and Wistar controls at the ages of 1 mo (M), 3M, and 6M. The Rev-erbalpha protein levels in adipose tissue showed a distinctive pattern, with the negative correlation of an increasing trend in GK rats, and a decreasing trend in Wistar rats during aging, from those in liver and muscle tissues. Moreover, dysregulation of the circadian Rev erbalpha expression in the adipose tissue of 6-mo-old GK rats was also observed. In particular, we ameliorated T2DM in GK rats by gastric bypass surgery, and revealed that T2DM amelioration in diabetic GK rats was associated with improved circadian Rev-erbalpha expression, in a comparison between the surgically treated and untreated GK rats. The roles of Rev-erbalpha in adipose tissue were further investigated by observations of Rev-erbalpha-related molecules, with reference to previous reports. PMID- 23637136 TI - Role of collecting duct renin in blood pressure regulation. AB - Numerous studies indicate that renin is synthesized and secreted by the collecting duct (CD). CD-derived renin may act directly on intercalated and/or principal cells through direct interaction with prorenin receptors and/or through cleavage of proximal tubule-derived angiotensinogen to ultimately produce angiotensin II and activate AT1 receptors. Preliminary studies suggest that the net effect of CD renin would be to increase distal nephron salt reabsorption and increase blood pressure. CD renin production is markedly increased in diabetes and angiotensin II-induced hypertension, suggesting that this system may exert pathophysiological effects. In this brief review, we summarize the current literature on synthesis and regulation of CD renin and consider potential mechanisms by which it regulates blood pressure. PMID- 23637133 TI - Spinal cord GABA receptors modulate the exercise pressor reflex in decerebrate rats. AB - Neurotransmitters and neuromodulators released by contraction-activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR). Whether gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter within the mammalian central nervous system, is involved in the modulation of the EPR at the level of dorsal horn remains to be determined. We performed local microinjection of either the GABA(A) antagonist bicuculline or the GABA(B) antagonist CGP 52432 into the ipisilateral L4/L5 dorsal horns to investigate the effect of GABA receptor blockade on the pressor response to either static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots, passive stretch, or hindlimb arterial injection of capsaicin (0.1 MUg/0.2 ml) in decerebrate rats. Microinjection of either bicuculline (1 mM, 100 nl) or CGP 52432 (10 mM, 100 nl) into the L4/5 dorsal horns significantly increased the pressor and cardioaccelerator responses to all stimuli. Microinjection of either bicuculline or CGP 52432 into the L5 dorsal horn significantly increased the pressor and cardioaccelerator responses to direct microinjection of l-glutatmate (10 mM, 100 nl) into this spinal segment. The disinhibitory effect of both GABA receptor antagonists on the EPR was abolished by microinjection of the broad-spectrum glutamate receptor antagonist kynurenate (10 mM/100 nl). These data suggest that 1) GABA exerts a tonic inhibition of the EPR at the level of dorsal horn; and 2) that an interaction between glutamatergic and GABAergic inputs exist at the level of dorsal horn, contributing to spinal control of the EPR. PMID- 23637137 TI - Adenosine A(2A) receptors regulate the activity of sleep regulatory GABAergic neurons in the preoptic hypothalamus. AB - The median preoptic nucleus (MnPN) and the ventrolateral preoptic area (VLPO) are two hypothalamic regions that have been implicated in sleep regulation, and both nuclei contain sleep-active GABAergic neurons. Adenosine is an endogenous sleep regulatory substance, which promotes sleep via A1 and A2A receptors (A2AR). Infusion of A2AR agonist into the lateral ventricle or into the subarachnoid space underlying the rostral basal forebrain (SS-rBF), has been previously shown to increase sleep. We examined the effects of an A2AR agonist, CGS-21680, administered into the lateral ventricle and the SS-rBF on sleep and c-Fos protein immunoreactivity (Fos-IR) in GABAergic neurons in the MnPN and VLPO. Intracerebroventricular administration of CGS-21680 during the second half of lights-on phase increased sleep and increased the number of MnPN and VLPO GABAergic neurons expressing Fos-IR. Similar effects were found with CGS-21680 microinjection into the SS-rBF. The induction of Fos-IR in preoptic GABAergic neurons was not secondary to drug-induced sleep, since CGS-21680 delivered to the SS-rBF significantly increased Fos-IR in MnPN and VLPO neurons in animals that were not permitted to sleep. Intracerebroventricular infusion of ZM-241385, an A2AR antagonist, during the last 2 h of a 3-h period of sleep deprivation caused suppression of subsequent recovery sleep and reduced Fos-IR in MnPN and VLPO GABAergic neurons. Our findings support a hypothesis that A2AR-mediated activation of MnPN and VLPO GABAergic neurons contributes to adenosinergic regulation of sleep. PMID- 23637140 TI - Encouraging outcomes for Sweden's extremely preterm babies. PMID- 23637139 TI - Reduced heart rate variability during sleep in long-duration spaceflight. AB - Limited data are available to describe the regulation of heart rate (HR) during sleep in spaceflight. Sleep provides a stable supine baseline during preflight Earth recordings for comparison of heart rate variability (HRV) over a wide range of frequencies using both linear, complexity, and fractal indicators. The current study investigated the effect of long-duration spaceflight on HR and HRV during sleep in seven astronauts aboard the International Space Station up to 6 mo. Measurements included electrocardiographic waveforms from Holter monitors and simultaneous movement records from accelerometers before, during, and after the flights. HR was unchanged inflight and elevated postflight [59.6 +/- 8.9 beats per minute (bpm) compared with preflight 53.3 +/- 7.3 bpm; P < 0.01]. Compared with preflight data, HRV indicators from both time domain and power spectral analysis methods were diminished inflight from ultralow to high frequencies and partially recovered to preflight levels after landing. During inflight and at postflight, complexity and fractal properties of HR were not different from preflight properties. Slow fluctuations (<0.04 Hz) in HR presented moderate correlations with movements during sleep, partially accounting for the reduction in HRV. In summary, substantial reduction in HRV was observed with linear, but not with complexity and fractal, methods of analysis. These results suggest that periodic elements that influence regulation of HR through reflex mechanisms are altered during sleep in spaceflight but that underlying system complexity and fractal dynamics were not altered. PMID- 23637142 TI - Swimming improves fitness in children with asthma. PMID- 23637138 TI - Endothelium-dependent relaxations in the aorta from K(2p)6.1 knockout mice. AB - K2P6.1 or TWIK-2, a two-pore domain K channel, is an important regulator of cardiovascular function. K2P6.1 is highly expressed in vascular smooth muscle and endothelium. Mice (8-12 wk) lacking functional K2P6.1 (K2P6.1(-/-)) are hypertensive and have enhanced vascular contractility. It is not known whether the lack of functional K2P6.1 in endothelium has a role in the vascular dysfunction in K2P6.1(-/-) mice. We tested the hypothesis: K2P6.1(-/-) mice have impaired endothelium-dependent relaxations. K2P6.1(-/-) mice were ~35 mmHg more hypertensive than WT mice at both 8-12 wk (young adult) and 20-24 wk (mature mice, P < 0.01; n = 8-10). Endothelium-dependent relaxations of the thoracic aorta were evaluated by isometric myography after contraction with phenylephrine (10(-6) M). Maximal ACh-dependent relaxations were increased from 65 +/- 1% to 73 +/- 1% in the aorta from young adult (P < 0.01; n = 6) and from 45 +/- 1% to 74 +/- 1% in the aorta from mature (P < 0.001; n = 5) K2P6.1(-/-) mice compared with K2P6.1(+/+) littermates. However, in the aorta from young adult and mature K2P6.1(+/+) mice, 10(-5) M indomethacin, a cyclooxygenase inhibitor, increased maximal ACh relaxations to knockout levels. Enhanced relaxation was also seen with ATP, a P2Y purinergic agonist, and A23187, a nonreceptor-based agonist in mature K2P6.1(-/-) mice. Mature adult aorta from K2P6.1(-/-) showed an attenuated ACh-mediated contraction in the presence of nitro-l-arginine methyl ester (l NAME) and without precontraction of 0.97 mN vs. 7.5 mN in K2P6.1(-/-) and K2P6.1(+/+) (P < 0.001; n = 5). In summary, K2P6.1(-/-) mice, which are hypertensive, have enhanced endothelium-dependent relaxations in the aorta due to the suppression of an indomethacin-sensitive constrictor component. PMID- 23637143 TI - Moving forward: from curses to blessings. PMID- 23637144 TI - Foot and ankle update. PMID- 23637146 TI - The adult paralytic foot. AB - The adult paralytic foot is a common clinical entity. It has numerous neurologic, systemic, and traumatic causes that result in muscle imbalance and foot deformity. A thorough physical examination and diagnostic work-up, as well as an understanding of the relevant functional anatomy, are essential to proper management. Treatment goals include the establishment of a plantigrade foot, elimination of deforming forces, and, when possible, restoration of active motor control. PMID- 23637147 TI - Transabdominal gunshot wounds of the hip and pelvis. AB - Transabdominal gunshot wounds (GSWs) of the hip and pelvis are those that traverse the gastrointestinal system before entering the pelvis and/or hip. These injuries may be contaminated by bowel contents. Some require urgent surgical intervention; others can be managed nonsurgically. A primary survey with attention to hemodynamic status is of utmost priority. After obtaining hemodynamic stability and addressing abdominal injuries, careful attention must be paid to evaluating hip joint involvement and injuries to the genitourinary and vascular systems. The available literature shows that transabdominal GSW with intra-articular contamination should be urgently debrided and irrigated; extra articular transabdominal GSW with stable fracture patterns may be managed with observation and empiric antibiotics. Extent of soft-tissue injury dictates the need for wound debridement. Bullets lodged in intra-articular locations should be removed, but retained bullets in other anatomic locations do not necessarily warrant removal. PMID- 23637145 TI - Pronator syndrome and anterior interosseous nerve syndrome. AB - Dysfunction of the median nerve at the elbow or proximal forearm can characterize two distinct clinical entities: pronator syndrome (PS) or anterior interosseous nerve (AIN) syndrome. PS is characterized by vague volar forearm pain, with median nerve paresthesias and minimal motor findings. AIN syndrome is a pure motor palsy of any or all of the muscles innervated by that nerve: the flexor pollicis longus, the flexor digitorum profundus of the index and middle fingers, and the pronator quadratus. The sites of anatomic compression are essentially the same for both disorders. Typically, the findings of electrodiagnostic studies are normal in patients with PS and abnormal in those with AIN syndrome. PS is a controversial diagnosis and is typically treated nonsurgically. AIN syndrome is increasingly thought to be neuritis and it often resolves spontaneously following prolonged observation. Surgical indications for nerve decompression include persistent symptoms for >6 months in patients with PS or for a minimum of 12 months with no signs of motor improvement in those with AIN syndrome. PMID- 23637148 TI - Synthetic playing surfaces and athlete health. AB - Synthetic playing surfaces have evolved considerably since their introduction in the 1960s. Today, third-generation turf is routinely installed in professional, collegiate, and community settings. Proponents of artificial surfaces tout their versatility and durability in a variety of climates. However, the health and injury ramifications have yet to be clearly defined. Musculoskeletal injury is largely affected by the shoe-playing surface interface. However, conclusive statements cannot be made regarding the risk of certain shoe-playing surface combinations because of the variety of additional factors, such as weather conditions, shoe wear, and field wear. Historically, clinical studies have indicated that higher injury rates occur on artificial turf than on natural surfaces. This conclusion is backed by robust biomechanical data that suggest that torque and strain may be greater on artificial surfaces than on natural grass. Recent data on professional athletes suggest that elite athletes may sustain injuries at increased rates on the newer surfaces. However, these surfaces remain attractive to athletes and administrators alike because of their durability, relative ease of maintenance, and multiuse potential. PMID- 23637150 TI - Wrong-site Spine Surgery. AB - Wrong-site spine surgery is an adverse event that has potentially devastating consequences for the patient as well as the surgeon. Despite substantial efforts to prevent wrong-site spine surgery, this complication continues to occur and has the potential for serious medical, personal, and legal repercussions. Although systems-based prevention methods are effective in identifying the proper patient, procedure, and region of the spinal column, they cannot be relied on to establish the correct vertebral level during the operation. The surgeon must design and implement a patient-specific protocol to ensure that the appropriate operation is performed on the correct side and level or levels of the spinal column. PMID- 23637151 TI - Biventricular pacing for adults with AV block and heart failure. PMID- 23637153 TI - Emerging epidemiology of H7N9 avian flu. PMID- 23637152 TI - Lessons in social competence help schoolchildren resist smoking. PMID- 23637149 TI - Cartilage regeneration. AB - Cartilage damaged by trauma has a limited capacity to regenerate. Current methods of managing small chondral defects include palliative treatment with arthroscopic debridement and lavage, reparative treatment with marrow-stimulation techniques (eg, microfracture), and restorative treatment, including osteochondral grafting and autologous chondrocyte implantation. Larger defects are managed with osteochondral allograft or total joint arthroplasty. However, the future of managing cartilage defects lies in providing biologic solutions through cartilage regeneration. Laboratory and clinical studies have examined the management of larger lesions using tissue-engineered cartilage. Regenerated cartilage can be derived from various cell types, including chondrocytes, pluripotent stem cells, and mesenchymal stem cells. Common scaffolding materials include proteins, carbohydrates, synthetic materials, and composite polymers. Scaffolds may be woven, spun into nanofibers, or configured as hydrogels. Chondrogenesis may be enhanced with the application of chondroinductive growth factors. Bioreactors are being developed to enhance nutrient delivery and provide mechanical stimulation to tissue-engineered cartilage ex vivo. The multidisciplinary approaches currently being developed to produce cartilage promise to bring to fruition the desire for cartilage regeneration in clinical use. PMID- 23637154 TI - Slightly higher risk of another cancer after a first non-melanoma skin cancer. PMID- 23637155 TI - Modeling emotion and learning of norms in social interactions. PMID- 23637156 TI - Hypothalamic neurotensin projections promote reward by enhancing glutamate transmission in the VTA. AB - The lateral hypothalamus (LH) sends a dense glutamatergic and peptidergic projection to dopamine neurons in the ventral tegmental area (VTA), a cell group known to promote reinforcement and aspects of reward. The role of the LH to VTA projection in reward-seeking behavior can be informed by using optogenetic techniques to dissociate the actions of LH neurons from those of other descending forebrain inputs to the VTA. In the present study, we identify the effect of neurotensin (NT), one of the most abundant peptides in the LH to VTA projection, on excitatory synaptic transmission in the VTA and reward-seeking behavior. Mice displayed robust intracranial self-stimulation of LH to VTA fibers, an operant behavior mediated by NT 1 receptors (Nts1) and NMDA receptors. Whole-cell patch clamp recordings of VTA dopamine neurons demonstrated that NT (10 nm) potentiated NMDA-mediated EPSCs via Nts1. Results suggest that NT release from the LH into the VTA activates Nts1, thereby potentiating NMDA-mediated EPSCs and promoting reward. The striking behavioral and electrophysiological effects of NT and glutamate highlight the LH to VTA pathway as an important component of reward. PMID- 23637157 TI - Glutamatergic signaling from the parabrachial nucleus plays a critical role in hypercapnic arousal. AB - The mechanisms of arousal from apneas during sleep in patients suffering from obstructive sleep apnea are not well understood. However, we know that respiratory chemosensory pathways converge on the parabrachial nucleus (PB), which sends glutamatergic projections to a variety of forebrain structures critical to arousal, including the basal forebrain, lateral hypothalamus, midline thalamus, and cerebral cortex. We tested the role of glutamatergic signaling in this pathway by developing an animal model for repetitive CO2 arousals (RCAs) and investigating the effect of deleting the gene for the vesicular glutamate transporter 2 (Vglut2) from neurons in the PB. We used mice with lox P sequences flanking exon2 of the Vglut2 gene, in which adeno-associated viral vectors containing genes encoding Cre recombinase and green fluorescent protein were microinjected into the PB to permanently and selectively disrupt Vglut2 expression while labeling the affected neurons. We recorded sleep in these mice and then investigated the arousals during RCA. Vglut2 deletions that included the external lateral and lateral crescent subdivisions of the lateral PB more than doubled the latency to arousal and resulted in failure to arouse by 30 s in >30% of trials. By contrast, deletions that involved the medial PB subdivision had minimal effects on arousal during hypercapnia but instead increased non-rapid eye movement (NREM) sleep by ~43% during the dark period, and increased delta power in the EEG during NREM sleep by ~50%. Our results suggest that glutamatergic neurons in the lateral PB are necessary for arousals from sleep in response to CO2, while medial PB glutamatergic neurons play an important role in promoting spontaneous waking. PMID- 23637159 TI - Maternal immune activation during gestation interacts with Disc1 point mutation to exacerbate schizophrenia-related behaviors in mice. AB - Schizophrenia is thought to result from interactions between susceptible genotypes and environmental risk factors. DISC1 is an important gene for schizophrenia and mood disorders based on both human and animal studies. In the present study we sought to investigate interactions between two distinct point mutations in the mouse Disc1 gene (L100P and Q31L) and maternal immune activation (MIA) during pregnancy with polyinosinic:polycytidylic acid (polyI:C). PolyI:C given at 5 mg/kg impaired cognitive and social behavior in both wild-type (WT) and Disc1-Q31L(+/-) offspring, and reduced prepulse inhibition at 16 but not 8 weeks of age. Disc1-L100P(+/-) mutants were more sensitive to MIA than WT or Disc1-Q31L(+/-) mice. Interleukin-6 (IL-6) is a critical cytokine for mediating the behavioral and transcriptional effects of polyI:C. We found a more pronounced increase of IL-6 in response to polyI:C in fetal brain in Disc1-L100P(+/-) mice compared with WT or Disc1-Q31L(+/-) mice. Coadministration of an anti-IL-6 antibody with polyI:C reversed schizophrenia-related behavioral phenotypes in Disc1-L100P(+/-) mice. In summary, we found specific interactions between discrete genetic (Disc1-L100P(+/-)) and environmental factors (MIA) that exacerbate schizophrenia-related phenotypes. IL-6 may be important in the pathophysiology of this interaction. PMID- 23637158 TI - Dendritic translocation establishes the winner in cerebellar climbing fiber synapse elimination. AB - In many regions of the developing mammalian nervous system, functional synaptic circuitry is formed by competitive elimination of early formed redundant synapses. However, how winning synapses emerge through competition remains unclear in the brain largely because of the technical difficulty of directly observing this dynamic cellular process in vivo. Here, we developed a method of two-photon multicolor vital imaging to observe competitive elimination of supernumerary climbing fibers (CFs) in the cerebellum of live mouse pups. At birth, each Purkinje cell (PC) in the cerebellar cortex is innervated by multiple CFs; an activity-dependent regression of supernumerary CFs ultimately yields a single innervation for most PCs by postnatal day 21. As supernumerary CFs are pruned, the terminal field of CFs translocates from the soma to the dendrites of PCs. In vivo time-lapse imaging of CF elimination revealed that (1) CF terminals were highly motile on the soma, but their motility was significantly reduced on dendrites; (2) only one CF could translocate to the dendrites whereas their competitors were restricted to perisomatic regions; and (3) the CF that began dendritic translocation became the winner. Moreover, selective photo-ablation of the winning CF (that undergoes dendritic translocation) reversed the fate of its losing competitor. These results indicate that dendritic translocation is a key cellular event that determines the winner during CF elimination. We propose that CF terminals are selectively stabilized on dendrites, providing irreversible competitive vigor to the first CF to form dendritic synapses. PMID- 23637162 TI - Feature-specific information processing precedes concerted activation in human visual cortex. AB - Current knowledge about the precise timing of visual input to the cortex relies largely on spike timings in monkeys and evoked-response latencies in humans. However, quantifying the activation onset does not unambiguously describe the timing of stimulus-feature-specific information processing. Here, we investigated the information content of the early human visual cortical activity by decoding low-level visual features from single-trial magnetoencephalographic (MEG) responses. MEG was measured from nine healthy subjects as they viewed annular sinusoidal gratings (spanning the visual field from 2 to 10 degrees for a duration of 1 s), characterized by spatial frequency (0.33 cycles/degree or 1.33 cycles/degree) and orientation (45 degrees or 135 degrees ); gratings were either static or rotated clockwise or anticlockwise from 0 to 180 degrees . Time resolved classifiers using a 20 ms moving window exceeded chance level at 51 ms (the later edge of the window) for spatial frequency, 65 ms for orientation, and 98 ms for rotation direction. Decoding accuracies of spatial frequency and orientation peaked at 70 and 90 ms, respectively, coinciding with the peaks of the onset evoked responses. Within-subject time-insensitive pattern classifiers decoded spatial frequency and orientation simultaneously (mean accuracy 64%, chance 25%) and rotation direction (mean 82%, chance 50%). Classifiers trained on data from other subjects decoded the spatial frequency (73%), but not the orientation, nor the rotation direction. Our results indicate that unaveraged brain responses contain decodable information about low-level visual features already at the time of the earliest cortical evoked responses, and that representations of spatial frequency are highly robust across individuals. PMID- 23637161 TI - Refractoriness enhances temporal coding by auditory nerve fibers. AB - A universal property of spiking neurons is refractoriness, a transient decrease in discharge probability immediately following an action potential (spike). The refractory period lasts only one to a few milliseconds, but has the potential to affect temporal coding of acoustic stimuli by auditory neurons, which are capable of submillisecond spike-time precision. Here this possibility was investigated systematically by recording spike times from chicken auditory nerve fibers in vivo while stimulating with repeated pure tones at characteristic frequency. Refractory periods were tightly distributed, with a mean of 1.58 ms. A statistical model was developed to recapitulate each fiber's responses and then used to predict the effect of removing the refractory period on a cell-by-cell basis for two largely independent facets of temporal coding: faithful entrainment of interspike intervals to the stimulus frequency and precise synchronization of spike times to the stimulus phase. The ratio of the refractory period to the stimulus period predicted the impact of refractoriness on entrainment and synchronization. For ratios less than ~0.9, refractoriness enhanced entrainment and this enhancement was often accompanied by an increase in spike-time precision. At higher ratios, little or no change in entrainment or synchronization was observed. Given the tight distribution of refractory periods, the ability of refractoriness to improve temporal coding is restricted to neurons responding to low-frequency stimuli. Enhanced encoding of low frequencies likely affects sound localization and pitch perception in the auditory system, as well as perception in nonauditory sensory modalities, because all spiking neurons exhibit refractoriness. PMID- 23637160 TI - Fractalkine signaling in microglia contributes to ectopic orofacial pain following trapezius muscle inflammation. AB - Fractalkine (FKN) signaling is involved in mechanical allodynia in the facial skin following trapezius muscle inflammation. Complete Freund's adjuvant (CFA) injection into the trapezius muscle produced mechanical allodynia in the ipsilateral facial skin that was not associated with facial skin inflammation and resulted in FKN but not FKN receptor (CX3CR1) expression, and microglial activation was enhanced in trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). Intra-cisterna magna anti-CX3CR1 or anti interleukin (IL)-1beta neutralizing antibody administration decreased the enhanced excitability of Vc and C1-C2 neurons in CFA-injected rats, whereas intra cisterna magna FKN administration induced microglial activation and mechanical allodynia in the facial skin. IL-1beta expression and p38 mitogen-activated protein kinase phosphorylation were enhanced in activated microglia after CFA injection. The excitability of neurons whose receptive fields was located in the facial skin was significantly enhanced in CFA-injected rats, and the number of cells expressing phosphorylated extracellular signal-regulated kinase (pERK) following noxious mechanical stimulation of the facial skin was significantly increased in Vc and C1-C2. We also observed mechanical allodynia of the trapezius muscle as well as microglial activation and increased pERK expression in C2-C6 after noxious stimulation of the trapezius muscle in facial skin-inflamed rats. These findings suggest that FKN expression was enhanced in Vc and C1-C2 or C2-C6 following trapezius muscle or facial skin inflammation, microglia are activated via FKN signaling, IL-1beta is released from the activated microglia, and the excitability of neurons in Vc and C1-C2 or C2-C6 is enhanced, resulting in the ectopic mechanical allodynia. PMID- 23637163 TI - Decay of motor memories in the absence of error. AB - When motor commands are accompanied by an unexpected outcome, the resulting error induces changes in subsequent commands. However, when errors are artificially eliminated, changes in motor commands are not sustained but show decay. Why does the adaptation-induced change in motor output decay in the absence of error? A prominent idea is that decay reflects the stability of the memory. We show results that challenge this idea and instead suggest that motor output decays because the brain actively disengages a component of the memory. Humans adapted their reaching movements to a perturbation and were then introduced to a long period of trials in which errors were absent (error-clamp). We found that, in some subjects, motor output did not decay at the onset of the error-clamp block but a few trials later. We manipulated the kinematics of movements in the error clamp block and found that, as movements became more similar to subjects' natural movements in the perturbation block, the lag to decay onset became longer and eventually reached hundreds of trials. Furthermore, when there was decay in the motor output, the endpoint of decay was not zero but a fraction of the motor memory that was last acquired. Therefore, adaptation to a perturbation installed two distinct kinds of memories: (1) one that was disengaged when the brain detected a change in the task and (2) one that persisted despite it. Motor memories showed little decay in the absence of error if the brain was prevented from detecting a change in task conditions. PMID- 23637164 TI - p62/SQSTM1 differentially removes the toxic mutant androgen receptor via autophagy and inclusion formation in a spinal and bulbar muscular atrophy mouse model. AB - Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders that are caused by the expansion of trinucleotide CAG repeats in the causative genes. Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease that is caused by the expansion of a polyQ tract within the androgen receptor (AR). p62 is a ubiquitin- and light-chain 3-binding protein that is known to regulate the degradation of targeted proteins via autophagy and inclusion formation. In this study, we examined the effects of p62 depletion and overexpression on cultured cells and in a transgenic mouse model that overexpressed the mutant AR. Here, we demonstrate that depletion of p62 significantly exacerbated motor phenotypes and the neuropathological outcome, whereas overexpression of p62 protected against mutant AR toxicity in SBMA mice. Depletion of p62 significantly increased the levels of monomeric mutant AR and mutant AR protein complexes in an SBMA mouse model via the impairment of autophagic degradation. In addition, p62 overexpression improved SBMA mouse phenotypes by inducing cytoprotective inclusion formation. Our results demonstrate that p62 provides two different therapeutic targets in SBMA pathogenesis: (1) autophagy-dependent degradation and (2) benevolent inclusion formation of the mutant AR. PMID- 23637166 TI - Primary hippocampal neurons, which lack four crucial extracellular matrix molecules, display abnormalities of synaptic structure and function and severe deficits in perineuronal net formation. AB - The extracellular matrix (ECM) of the brain plays crucial roles during the development, maturation, and regeneration of the CNS. In a subpopulation of neurons, the ECM condenses to superstructures called perineuronal nets (PNNs) that surround synapses. Camillo Golgi described PNNs a century ago, yet their biological functions remain elusive. Here, we studied a mouse mutant that lacks four ECM components highly enriched in the developing brain: the glycoproteins tenascin-C and tenascin-R and the chondroitin sulfate proteoglycans brevican and neurocan. Primary embryonic hippocampal neurons and astrocytes were cultivated using a cell insert system that allows for co-culture of distinct cell populations in the absence of direct membrane contacts. The wild-type and knock out cells were combined in the four possible permutations. Using this approach, neurons cultivated in the presence of mutant astrocytes displayed a transient increase of synapses after 2 weeks. However, after a period of 3 weeks or longer, synapse formation and stabilization were compromised when either neuron or astrocyte cell populations or both were of mutant origin. The development of PNN structures was observed, but their size was substantially reduced on knock-out neurons. The synaptic activity of both wild-type and knock-out neurons was monitored using whole-cell patch clamping. The salient observation was a reduced frequency of IPSCs and EPSCs, whereas the amplitudes were not modified. Remarkably, the knock-out neuron phenotypes could not be rescued by wild-type astrocytes. We conclude that the elimination of four ECM genes compromises neuronal function. PMID- 23637165 TI - Targeted deletion of the mouse alpha2 nicotinic acetylcholine receptor subunit gene (Chrna2) potentiates nicotine-modulated behaviors. AB - Baseline and nicotine-modulated behaviors were assessed in mice harboring a null mutant allele of the nicotinic acetylcholine receptor (nAChR) subunit gene alpha2 (Chrna2). Homozygous Chrna2(-/-) mice are viable, show expected sex and Mendelian genotype ratios, and exhibit no gross neuroanatomical abnormalities. A broad range of behavioral tests designed to assess genotype-dependent effects on anxiety (elevated plus maze and light/dark box), motor coordination (narrow bean traverse and gait), and locomotor activity revealed no significant differences between mutant mice and age-matched wild-type littermates. Furthermore, a panel of tests measuring traits, such as body position, spontaneous activity, respiration, tremors, body tone, and startle response, revealed normal responses for Chrna2-null mutant mice. However, Chrna2(-/-) mice do exhibit a mild motor or coordination phenotype (a decreased latency to fall during the accelerating rotarod test) and possess an increased sensitivity to nicotine-induced analgesia in the hotplate assay. Relative to wild-type, Chrna2(-/-) mice show potentiated nicotine self-administration and withdrawal behaviors and exhibit a sex-dependent enhancement of nicotine-facilitated cued, but not trace or contextual, fear conditioning. Overall, our results suggest that loss of the mouse nAChR alpha2 subunit has very limited effects on baseline behavior but does lead to the potentiation of several nicotine-modulated behaviors. PMID- 23637167 TI - Phox2b-expressing retrotrapezoid neurons are intrinsically responsive to H+ and CO2. AB - Central respiratory chemoreceptors sense changes in CO2/H(+) and initiate the adjustments to ventilation required to preserve brain and tissue pH. The cellular nature of the sensors (neurons and/or glia) and their CNS location are not conclusively established but the glutamatergic, Phox2b-expressing neurons located in the retrotrapezoid nucleus (RTN) are strong candidates. However, a direct demonstration that RTN neurons are intrinsically sensitive to CO2/H(+), required for designation as a chemosensor, has been lacking. To address this, we tested the pH sensitivity of RTN neurons that were acutely dissociated from two lines of Phox2b-GFP BAC transgenic mice. All GFP-labeled cells assayed by reverse transcriptase-PCR (n = 40) were Phox2b+, VGlut2+, TH-, and ChAT-, the neurochemical phenotype previously defined for chemosensitive RTN neurons in vivo. We found that most dissociated RTN neurons from both lines of mice were CO2/H(+)-sensitive (~79%), with discharge increasing during acidification and decreasing during alkalization. The pH-sensitive cells could be grouped into two populations characterized by similar pH sensitivity but different basal firing rates, as previously observed in recordings from GFP-labeled RTN neurons in slice preparations. In conclusion, these data indicate that RTN neurons are inherently pH-sensitive, as expected for a respiratory chemoreceptor. PMID- 23637168 TI - Presynaptic NMDA receptor mechanisms for enhancing spontaneous neurotransmitter release. AB - NMDA receptors (NMDARs) are required for experience-driven plasticity during formative periods of brain development and are critical for neurotransmission throughout postnatal life. Most NMDAR functions have been ascribed to postsynaptic sites of action, but there is now an appreciation that presynaptic NMDARs (preNMDARs) can modulate neurotransmitter release in many brain regions, including the neocortex. Despite these advances, the cellular mechanisms by which preNMDARs can affect neurotransmitter release are largely unknown. Here we interrogated preNMDAR functions pharmacologically to determine how these receptors promote spontaneous neurotransmitter release in mouse primary visual cortex. Our results provide three new insights into the mechanisms by which preNMDARs can function. First, preNMDARs can enhance spontaneous neurotransmitter release tonically with minimal extracellular Ca(2+) or with major sources of intracellular Ca(2+) blocked. Second, lowering extracellular Na(+) levels reduces the contribution of preNMDARs to spontaneous transmitter release significantly. Third, preNMDAR enhance transmitter release in part through protein kinase C signaling. These data demonstrate that preNMDARs can act through novel pathways to promote neurotransmitter release in the absence of action potentials. PMID- 23637170 TI - Bovine spongiform encephalopathy induces misfolding of alleged prion-resistant species cellular prion protein without altering its pathobiological features. AB - Bovine spongiform encephalopathy (BSE) prions were responsible for an unforeseen epizootic in cattle which had a vast social, economic, and public health impact. This was primarily because BSE prions were found to be transmissible to humans. Other species were also susceptible to BSE either by natural infection (e.g., felids, caprids) or in experimental settings (e.g., sheep, mice). However, certain species closely related to humans, such as canids and leporids, were apparently resistant to BSE. In vitro prion amplification techniques (saPMCA) were used to successfully misfold the cellular prion protein (PrP(c)) of these allegedly resistant species into a BSE-type prion protein. The biochemical and biological properties of the new prions generated in vitro after seeding rabbit and dog brain homogenates with classical BSE were studied. Pathobiological features of the resultant prion strains were determined after their inoculation into transgenic mice expressing bovine and human PrP(C). Strain characteristics of the in vitro-adapted rabbit and dog BSE agent remained invariable with respect to the original cattle BSE prion, suggesting that the naturally low susceptibility of rabbits and dogs to prion infections should not alter their zoonotic potential if these animals became infected with BSE. This study provides a sound basis for risk assessment regarding prion diseases in purportedly resistant species. PMID- 23637169 TI - Physical exercise prevents stress-induced activation of granule neurons and enhances local inhibitory mechanisms in the dentate gyrus. AB - Physical exercise is known to reduce anxiety. The ventral hippocampus has been linked to anxiety regulation but the effects of running on this subregion of the hippocampus have been incompletely explored. Here, we investigated the effects of cold water stress on the hippocampus of sedentary and runner mice and found that while stress increases expression of the protein products of the immediate early genes c-fos and arc in new and mature granule neurons in sedentary mice, it has no such effect in runners. We further showed that running enhances local inhibitory mechanisms in the hippocampus, including increases in stress-induced activation of hippocampal interneurons, expression of vesicular GABA transporter (vGAT), and extracellular GABA release during cold water swim stress. Finally, blocking GABAA receptors in the ventral hippocampus, but not the dorsal hippocampus, with the antagonist bicuculline, reverses the anxiolytic effect of running. Together, these results suggest that running improves anxiety regulation by engaging local inhibitory mechanisms in the ventral hippocampus. PMID- 23637171 TI - Reciprocal Homosynaptic and heterosynaptic long-term plasticity of corticogeniculate projection neurons in layer VI of the mouse visual cortex. AB - Most neurons in layer VI of the visual cortex project to the dorsal lateral geniculate nucleus (dLGN). These corticogeniculate projection neurons (CG cells) receive top-down synaptic inputs from upper layers (ULs) and bottom-up inputs from the underlying white matter (WM). Use-dependent plasticity of these synapses in layer VI of the cortex has received less attention than in other layers. In the present study, we used a retrograde tracer injected into dLGN to identify CG cells, and, by analyzing EPSPs evoked by electrical stimulation of the UL or WM site, examined whether these synapses show long-term synaptic plasticity. Theta burst stimulation induced long-term potentiation (LTP) of activated synapses (hom LTP) and long-term depression (LTD) of nonactivated synapses (het-LTD) in either pathway. The paired-pulse stimulation protocol and the analysis of coefficient variation of EPSPs suggested postsynaptic induction of these changes except UL induced het-LTD, which may be presynaptic in origin. Intracellular injection of a Ca(2+)-chelator suggested an involvement of postsynaptic Ca(2+) rise in all types of long-term plasticity. Pharmacological analysis indicated that NMDA receptors and type-5 metabotropic glutamate receptors are involved in WM-induced and UL induced plasticity, respectively. Analysis with inhibitors and/or in transgenic mice suggested an involvement of cannabinoid type 1 receptors and calcineurin in UL-induced and WM-induced het-LTD, respectively. These results suggest that hom LTP and het-LTD may play a role in switching the top-down or bottom-up regulation of CG cell function and/or in maintaining stability of synaptic transmission efficacy through different molecular mechanisms. PMID- 23637172 TI - Inactivation of mTORC1 in the developing brain causes microcephaly and affects gliogenesis. AB - The mammalian target of rapamycin (mTOR) regulates cell growth in response to various intracellular and extracellular signals. It assembles into two multiprotein complexes: the rapamycin-sensitive mTOR complex 1 (mTORC1) and the rapamycin-insensitive mTORC2. In this study, we inactivated mTORC1 in mice by deleting the gene encoding raptor in the progenitors of the developing CNS. Mice are born but never feed and die within a few hours. The brains deficient for raptor show a microcephaly starting at E17.5 that is the consequence of a reduced cell number and cell size. Changes in cell cycle length during late cortical development and increased cell death both contribute to the reduction in cell number. Neurospheres derived from raptor-deficient brains are smaller, and differentiation of neural progenitors into glia but not into neurons is inhibited. The differentiation defect is paralleled by decreased Stat3 signaling, which is a target of mTORC1 and has been implicated in gliogenesis. Together, our results show that postnatal survival, overall brain growth, and specific aspects of brain development critically depend on mTORC1 function. PMID- 23637173 TI - The Cav3-Kv4 complex acts as a calcium sensor to maintain inhibitory charge transfer during extracellular calcium fluctuations. AB - Synaptic transmission and neuronal excitability depend on the concentration of extracellular calcium ([Ca](o)), yet repetitive synaptic input is known to decrease [Ca](o) in numerous brain regions. In the cerebellar molecular layer, synaptic input reduces [Ca](o) by up to 0.4 mm in the vicinity of stellate cell interneurons and Purkinje cell dendrites. The mechanisms used to maintain network excitability and Purkinje cell output in the face of this rapid change in calcium gradient have remained an enigma. Here we use single and dual patch recordings in an in vitro slice preparation of Sprague Dawley rats to investigate the effects of physiological decreases in [Ca](o) on the excitability of cerebellar stellate cells and their inhibitory regulation of Purkinje cells. We find that a Ca(v)3 K(v)4 ion channel complex expressed in stellate cells acts as a calcium sensor that responds to a decrease in [Ca]o by dynamically adjusting stellate cell output to maintain inhibitory charge transfer to Purkinje cells. The Ca(v)3-K(v)4 complex thus enables an adaptive regulation of inhibitory input to Purkinje cells during fluctuations in [Ca](o), providing a homeostatic control mechanism to regulate Purkinje cell excitability during repetitive afferent activity. PMID- 23637174 TI - Hypofunction of glutamatergic neurotransmission in the periaqueductal gray contributes to nerve-injury-induced neuropathic pain. AB - Neuropathic pain, a chronic pain due to neuronal lesion, remains unaltered even after the injury-induced spinal afferent discharges have declined, suggesting an involvement of supraspinal dysfunction. The midbrain ventrolateral periaqueductal gray (vlPAG) is known to be a crucial supraspinal region for initiating descending pain inhibition, but its role in neuropathic pain remains unclear. Therefore, here we examined neuroplastic changes in the vlPAG of midbrain slices isolated from neuropathic rats induced by L5/L6 spinal nerve ligation (SNL) via electrophysiological and neurochemical approaches. Significant mechanical hypersensitivity was induced in rats 2 d after SNL and lasted for >14 d. Compared with the sham-operated group, vlPAG slices from neuropathic rats 3 and 10 days after SNL displayed smaller EPSCs with prolonged latency, less frequent and smaller miniature EPSCs, higher paired-pulse ratio of EPSCs, smaller AMPAR mediated EPSCs, smaller AMPA currents, greater NMDAR-mediated EPSCs, greater NMDA currents, lower AMPAR-mediated/NMDAR-mediated ratios, and upregulation of the NR1 and NR2B subunits, but not the NR2A, GluR1, or GluR2 subunits, of glutamate receptors. There were no significant differences between day 3 and day 10 neuropathic groups. These results suggest that SNL leads to hypoglutamatergic neurotransmission in the vlPAG resulting from both presynaptic and postsynaptic mechanisms. Upregulation of NMDARs might contribute to hypofunction of AMPARs via subcellular redistribution. Long-term hypoglutamatergic function in the vlPAG may lead to persistent reduction of descending pain inhibition, resulting in chronic neuropathic pain. PMID- 23637175 TI - Revisiting the functional specialization of left inferior frontal gyrus in phonological and semantic fluency: the crucial role of task demands and individual ability. AB - Despite a large body of research, extant findings on the functional role of left inferior frontal gyrus (LIFG) in phonological and semantic fluency are still controversial. Based on cross-study comparisons, a recent meta-analysis of neuroimaging results suggests that posterior-dorsal (Brodmann area, BA, 44) and anterior-ventral parts (BA 45) of LIFG contribute differentially to processes of phonologically and semantically cued word retrieval, respectively. In contrast, a subsequent functional magnetic resonance imaging experiment failed to validate the proposed dissociation using a within-subjects design. In particular, no evidence for a specific role of BA 45 in semantic fluency was found. Here, we resolve this apparent controversy by showing that the conflicting findings can be accounted for when considering the influence of task demands and individual ability on resulting functional magnetic resonance imaging activation patterns. By comparing phonological versus semantic fluency, higher activation was robustly observed in BA 44. For the opposite comparison, higher activation was found in dorsal BA 45; however, this was more pronounced in posterior-dorsal parts of BA 45 for low-performing subjects and was only apparent in anterior-dorsal parts of BA 45 under high demands on controlled semantic retrieval. Our results thus disclose important determinants for detecting a functional segregation of LIFG in verbal fluency that also have implications for the controversial findings in previous lesion studies. Moreover, the present parcellation of dorsal BA 45 corresponds well with anatomical evidence suggesting a subdivision into an anterior (45A) and posterior part (45B) and may therefore represent evidence for its functional significance in humans. PMID- 23637177 TI - Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling. AB - Proteolytic shedding of cell surface proteins generates paracrine signals involved in numerous signaling pathways. Neuregulin 1 (NRG1) type III is involved in myelination of the peripheral nervous system, for which it requires proteolytic activation by proteases of the ADAM family and BACE1. These proteases are major therapeutic targets for the prevention of Alzheimer's disease because they are also involved in the proteolytic generation of the neurotoxic amyloid beta-peptide. Identification and functional investigation of their physiological substrates is therefore of greatest importance in preventing unwanted side effects. Here we investigated proteolytic processing of NRG1 type III and demonstrate that the ectodomain can be cleaved by three different sheddases, namely ADAM10, ADAM17, and BACE1. Surprisingly, we not only found cleavage by ADAM10, ADAM17, and BACE1 C-terminal to the epidermal growth factor (EGF)-like domain, which is believed to play a pivotal role in signaling, but also additional cleavage sites for ADAM17 and BACE1 N-terminal to that domain. Proteolytic processing at N- and C-terminal sites of the EGF-like domain results in the secretion of this domain from NRG1 type III. The soluble EGF-like domain is functionally active and stimulates ErbB3 signaling in tissue culture assays. Moreover, the soluble EGF-like domain is capable of rescuing hypomyelination in a zebrafish mutant lacking BACE1. Our data suggest that NRG1 type III-dependent myelination is not only controlled by membrane-retained NRG1 type III, but also in a paracrine manner via proteolytic liberation of the EGF-like domain. PMID- 23637176 TI - Neural representations of contextual guidance in visual search of real-world scenes. AB - Exploiting scene context and object-object co-occurrence is critical in guiding eye movements and facilitating visual search, yet the mediating neural mechanisms are unknown. We used functional magnetic resonance imaging while observers searched for target objects in scenes and used multivariate pattern analyses (MVPA) to show that the lateral occipital complex (LOC) can predict the coarse spatial location of observers' expectations about the likely location of 213 different targets absent from the scenes. In addition, we found weaker but significant representations of context location in an area related to the orienting of attention (intraparietal sulcus, IPS) as well as a region related to scene processing (retrosplenial cortex, RSC). Importantly, the degree of agreement among 100 independent raters about the likely location to contain a target object in a scene correlated with LOC's ability to predict the contextual location while weaker but significant effects were found in IPS, RSC, the human motion area, and early visual areas (V1, V3v). When contextual information was made irrelevant to observers' behavioral task, the MVPA analysis of LOC and the other areas' activity ceased to predict the location of context. Thus, our findings suggest that the likely locations of targets in scenes are represented in various visual areas with LOC playing a key role in contextual guidance during visual search of objects in real scenes. PMID- 23637178 TI - Postural reorganization induced by torso cutaneous covibration. AB - Cutaneous information from joints has been attributed proprioceptive properties similar to those of muscle spindles. This study aimed to assess whether vibration induced changes in torso cutaneous information contribute to whole-body postural reorganization in humans. Ten healthy young adults stood in normal and Romberg stances with six vibrating actuators positioned on the torso in contact with the skin over the left and right external oblique, internal oblique, and erector spinae muscle locations at the L4/L5 vertebrae level. Vibrations around the torso were randomly applied at two locations simultaneously (covibration) or at all locations simultaneously. Kinematic analysis of the body segments indicated that covibration applied to the skin over the internal oblique muscles induced shifts of both the head and torso in the anterior direction (torso flexion) while the hips shifted in the posterior direction (ankle plantar flexion). Conversely, covibration applied to the skin over the erector spinae muscle locations produced opposite effects. However, covibration applied to the skin over the left internal oblique and left erector spinae, the right internal oblique and right erector spinae, or at all locations simultaneously did not induce any significant postural changes. In addition, the center of pressure position as measured by the force plate was unaffected by all covibration conditions tested. These results were independent of stance and suggest an integrated and coordinated reorganization of posture in response to vibration-induced changes in cutaneous information. In addition, combinations of vibrotactile stimuli over multiple locations exhibit directional summation properties in contrast to the individual responses we observed in our previous work. PMID- 23637179 TI - Glucocorticoid signaling in myeloid cells worsens acute CNS injury and inflammation. AB - Glucocorticoid stress hormones (GCs) are well known for being anti-inflammatory, but some reports suggest that GCs can also augment aspects of inflammation during acute brain injury. Because the GC receptor (GR) is ubiquitously expressed throughout the brain, it is difficult to know which cell types might mediate these unusual "proinflammatory" GC actions. We examined this with cell type specific deletion or overexpression of GR in mice experiencing seizure or ischemia. Counter to their classical anti-inflammatory actions, GR signaling in myeloid cells increased Iba-1 and CD68 staining as well as nuclear p65 levels in the injured tissue. GCs also reduced levels of occludin, claudin 5, and caveolin 1, proteins central to blood-brain-barrier integrity; these effects required GR in endothelial cells. Finally, GCs compromised neuron survival, an effect mediated by GR in myeloid and endothelial cells to a greater extent than by neuronal GR. PMID- 23637180 TI - eGFP expression under UCHL1 promoter genetically labels corticospinal motor neurons and a subpopulation of degeneration-resistant spinal motor neurons in an ALS mouse model. AB - Understanding mechanisms that lead to selective motor neuron degeneration requires visualization and cellular identification of vulnerable neurons. Here we report generation and characterization of UCHL1-eGFP and hSOD1(G93A)-UeGFP mice, novel reporter lines for cortical and spinal motor neurons. Corticospinal motor neurons (CSMN) and a subset of spinal motor neurons (SMN) are genetically labeled in UCHL1-eGFP mice, which express eGFP under the UCHL1 promoter. eGFP expression is stable and continues through P800 in vivo. Retrograde labeling, molecular marker expression, electrophysiological analysis, and cortical circuit mapping confirmed CSMN identity of eGFP(+) neurons in the motor cortex. Anatomy, molecular marker expression, and electrophysiological analysis revealed that the eGFP expression is restricted to a subset of small-size SMN that are slow-twitch alpha and gamma motor neurons. Crossbreeding of UCHL1-eGFP and hSOD1(G93A) lines generated hSOD1(G93A)-UeGFP mice, which displayed the disease phenotype observed in a hSOD1(G93A) mouse model of ALS. eGFP(+) SMN showed resistance to degeneration in hSOD1(G93A)-UeGFP mice, and their slow-twitch alpha and gamma motor neuron identity was confirmed. In contrast, eGFP(+) neurons in the motor cortex of hSOD1(G93A)-UeGFP mice recapitulated previously reported progressive CSMN loss and apical dendrite degeneration. Our findings using these two novel reporter lines revealed accumulation of autophagosomes along the apical dendrites of vulnerable CSMN at P60, early symptomatic stage, suggesting autophagy as a potential intrinsic mechanism for CSMN apical dendrite degeneration. PMID- 23637182 TI - Entrainment of the intrinsic dynamics of single isolated neurons by natural-like input. AB - Neuronal dynamics is intrinsically unstable, producing activity fluctuations that are essentially scale free. Here we study single cortical neurons of newborn rats in vitro, and show that while these scale-free fluctuations are independent of temporal input statistics, they can be entrained by input variation. Joint input output statistics and spike train reproducibility in synaptically isolated cortical neurons were measured in response to various input regimes over extended timescales (many minutes). Response entrainment was found to be maximal when the input itself possesses natural-like, scale-free statistics. We conclude that preference for natural stimuli, often observed at the system level, exists already at the elementary, single neuron level. PMID- 23637181 TI - Altered calcium metabolism in aging CA1 hippocampal pyramidal neurons. AB - Altered neuronal calcium homeostasis is widely hypothesized to underlie cognitive deficits in normal aging subjects, but the mechanisms that underlie this change are unknown, possibly due to a paucity of direct measurements from aging neurons. Using CCD and two-photon calcium imaging techniques on CA1 pyramidal neurons from young and aged rats, we show that calcium influx across the plasma membrane increases with aging, and that this change is countered by increased intracellular calcium buffering. The additional buffer in aging neurons balances the increased calcium influx following a small number (<3) action potentials, but is overwhelmed during sustained or theta-like activity which leads to a greater rise in intracellular calcium concentration in aging than that in young neurons. Our results demonstrate that calcium overload occurs regularly in aging CA1 pyramidal neurons under physiological conditions. This overload may be a critical factor in age-related decline in hippocampus-dependent cognitive function. PMID- 23637183 TI - Oscillatory beta activity mediates neuroplastic effects of motor cortex stimulation in humans. AB - Continuous theta burst stimulation (cTBS) is a repetitive transcranial magnetic stimulation protocol that can inhibit human motor cortex (M1) excitability and impair movement for <= 1 h. While offering valuable insights into brain function and potential therapeutic benefits, these neuroplastic effects are highly variable between individuals. The source of this variability, and the electrophysiological mechanisms underlying the inhibitory after-effects, are largely unknown. In this regard, oscillatory activity at beta frequency (15-35 Hz) is of particular interest as it is elevated in motor disorders such as Parkinson's disease and modulated during the generation of movements. Here, we used a source-level magnetoencephalography approach to investigate the hypothesis that the presence of neuroplastic effects following cTBS is associated with concurrent changes in oscillatory M1 beta activity. M1 cortices were localized with a synthetic aperture magnetometry beamforming analysis of visually cued index finger movements. Virtual electrode analysis was used to reconstruct the spontaneous and movement-related oscillatory activity in bilateral M1 cortices, before and from 10 to 45 min after cTBS. We demonstrate that 40 s of cTBS applied over left M1 reduced corticospinal excitability in the right index finger of 8/16 participants. In these responder participants only, cTBS increased the power of the spontaneous beta oscillations in stimulated M1 and delayed reaction times in the contralateral index finger. No further changes were observed in the latency or power of movement-related beta oscillations. These data provide insights into the electrophysiological mechanisms underlying cTBS-mediated impairment of motor function and demonstrate the association between spontaneous oscillatory beta activity in M1 and the inhibition of motor function. PMID- 23637186 TI - CD82 blocks cMet activation and overcomes hepatocyte growth factor effects on oligodendrocyte precursor differentiation. AB - Mechanisms that regulate oligodendrocyte (OL) precursor migration and differentiation are important in normal development and in demyelinating/remyelinating conditions. We previously found that the tetraspanin CD82 is far more highly expressed in O4(+) OL precursors of the adult rat brain than those of the neonatal brain. CD82 has been physically linked to cMet, the hepatocyte growth factor (HGF) receptor, in tumor cells, and this interaction decreases downstream signaling. We show here that CD82 inhibits the HGF activation of cMet in neonatal and adult rat OL precursors. CD82 expression is sufficient to allow precursor differentiation into mature OLs even in the presence of HGF. In contrast, CD82 downregulation in adult O4(+)/CD82(+) cells inhibits their differentiation, decreases their accumulation of myelin proteins, and causes a reversion to less mature stages. CD82 expression in neonatal O4(+)/CD82(-) cells also blocks Rac1 activation, suggesting a possible regulatory effect on cytoskeletal organization and mobility. Thus, CD82 is a negative regulator of HGF/cMet during OL development and overcomes HGF inhibitory regulation of OL precursor maturation. PMID- 23637185 TI - Phosducin-like protein 1 is essential for G-protein assembly and signaling in retinal rod photoreceptors. AB - G-protein beta subunits perform essential neuronal functions as part of G-protein betagamma and Gbeta5-regulators of G-protein signaling (RGS) complexes. Both Gbetagamma and Gbeta5-RGS are obligate dimers that are thought to require the assistance of the cytosolic chaperonin CCT and a cochaperone, phosducin-like protein 1 (PhLP1) for dimer formation. To test this hypothesis in vivo, we deleted the Phlp1 gene in mouse (Mus musculus) retinal rod photoreceptor cells and measured the effects on G-protein biogenesis and visual signal transduction. In the PhLP1-depleted rods, Gbetagamma dimer formation was decreased 50-fold, resulting in a >10-fold decrease in light sensitivity. Moreover, a 20-fold reduction in Gbeta5 and RGS9-1 expression was also observed, causing a 15-fold delay in the shutoff of light responses. These findings conclusively demonstrate in vivo that PhLP1 is required for the folding and assembly of both Gbetagamma and Gbeta5-RGS9. PMID- 23637184 TI - Increased cell-intrinsic excitability induces synaptic changes in new neurons in the adult dentate gyrus that require Npas4. AB - Electrical activity regulates the manner in which neurons mature and form connections to each other. However, it remains unclear whether increased single cell activity is sufficient to alter the development of synaptic connectivity of that neuron or whether a global increase in circuit activity is necessary. To address this question, we genetically increased neuronal excitability of in vivo individual adult-born neurons in the mouse dentate gyrus via expression of a voltage-gated bacterial sodium channel. We observed that increasing the excitability of new neurons in an otherwise unperturbed circuit leads to changes in both their input and axonal synapses. Furthermore, the activity-dependent transcription factor Npas4 is necessary for the changes in the input synapses of these neurons, but it is not involved in changes to their axonal synapses. Our results reveal that an increase in cell-intrinsic activity during maturation is sufficient to alter the synaptic connectivity of a neuron with the hippocampal circuit and that Npas4 is required for activity-dependent changes in input synapses. PMID- 23637187 TI - Differential GABAB-receptor-mediated effects in perisomatic- and dendrite targeting parvalbumin interneurons. AB - Inhibitory parvalbumin-containing interneurons (PVIs) control neuronal discharge and support the generation of theta- and gamma-frequency oscillations in cortical networks. Fast GABAergic input onto PVIs is crucial for their synchronization and oscillatory entrainment, but the role of metabotropic GABA(B) receptors (GABA(B)Rs) in mediating slow presynaptic and postsynaptic inhibition remains unknown. In this study, we have combined high-resolution immunoelectron microscopy, whole-cell patch-clamp recording, and computational modeling to investigate the subcellular distribution and effects of GABA(B)Rs and their postsynaptic effector Kir3 channels in rat hippocampal PVIs. Pre-embedding immunogold labeling revealed that the receptors and channels localize at high levels to the extrasynaptic membrane of parvalbumin-immunoreactive dendrites. Immunoreactivity for GABA(B)Rs was also present at lower levels on PVI axon terminals. Whole-cell recordings further showed that synaptically released GABA in response to extracellular stimulation evokes large GABA(B)R-mediated slow IPSCs in perisomatic-targeting (PT) PVIs, but only small or no currents in dendrite-targeting (DT) PVIs. In contrast, paired recordings demonstrated that GABA(B)R activation results in presynaptic inhibition at the output synapses of both PT and DT PVIs, but more strongly in the latter. Finally, computational analysis indicated that GABA(B) IPSCs can phasically modulate the discharge of PT interneurons at theta frequencies. In summary, our results show that GABA(B)Rs differentially mediate slow presynaptic and postsynaptic inhibition in PVIs and can contribute to the dynamic modulation of their activity during oscillations. Furthermore, these data provide evidence for a compartment-specific molecular divergence of hippocampal PVI subtypes, suggesting that activation of GABA(B)Rs may shift the balance between perisomatic and dendritic inhibition. PMID- 23637189 TI - Connexin47 protein phosphorylation and stability in oligodendrocytes depend on expression of Connexin43 protein in astrocytes. AB - Panglial networks are essential for normal physiology in the CNS, and the function of distinct connexins participating in these networks is not well understood. We generated Connexin32 (Cx32)-deficient mice with additional deletion of astrocytic Cx43 to explore the role of both connexins in panglial networks. Cx43/Cx32 double knock-out (dKO) mice revealed strong microglial activation in corpus callosum and cingulum along with severe astrogliosis and scar formation. In addition, most of the fine myelinated fibers projecting from the corpus callosum into the cortex were lost. Myelin loss was caused by a strong decrease of oligodendrocytes in the cingulum of Cx43/Cx32dKO mice. Immunoblot analyses using newly generated specific Cx47 antibodies revealed that oligodendrocytic Cx47 is phosphorylated in vivo depending on astrocytic Cx43 expression. In Cx43-deficient mice, Cx47 protein levels were strongly decreased, whereas Cx47 mRNA levels were not altered. Using Cx43G138R/Cx30KO mice, we show that Cx47 expression depends on the presence of astrocytic Cx43 protein and that its gap junctional channel function is not necessary for Cx47 stabilization. In consequence, Cx43/Cx32dKO mice additionally lack Cx47 expression and therefore cannot form oligodendrocytic gap junctions, which explains the phenotypic similarities to Cx32/Cx47dKO mice. Our findings provide strong evidence that phosphorylation and stability of oligodendrocytic Cx47 proteins is dependent on astrocytic Cx43 expression. These results further unravel the complexity of panglial networks and show that results of previous studies using astrocytic Cx43 deficient mice have to be reconsidered. PMID- 23637188 TI - Heterotrimeric G protein subunit Ggamma13 is critical to olfaction. AB - The activation of G-protein-coupled olfactory receptors on the olfactory sensory neurons (OSNs) triggers a signaling cascade, which is mediated by a heterotrimeric G-protein consisting of alpha, beta, and gamma subunits. Although its alpha subunit, Galphaolf, has been identified and well characterized, the identities of its beta and gamma subunits and their function in olfactory signal transduction, however, have not been well established yet. We, and others, have found the expression of Ggamma13 in the olfactory epithelium, particularly in the cilia of the OSNs. In this study, we generated a conditional gene knock-out mouse line to specifically nullify Ggamma13 expression in the olfactory marker protein expressing OSNs. Immunohistochemical and Western blot results showed that Ggamma13 subunit was indeed eliminated in the mutant mice's olfactory epithelium. Intriguingly, Galphaolf, beta1 subunits, Ric-8B and CEP290 proteins, were also absent in the epithelium whereas the presence of the effector enzyme adenylyl cyclase III remained largely unaltered. Electro-olfactogram studies showed that the mutant animals had greatly reduced responses to a battery of odorants including three presumable pheromones. Behavioral tests indicated that the mutant mice had a remarkably reduced ability to perform an odor-guided search task although their motivation and agility seemed normal. Our results indicate that Galphaolf exclusively forms a functional heterotrimeric G-protein with Gbeta1 and Ggamma13 in OSNs, mediating olfactory signal transduction. The identification of the olfactory G-protein's betagamma moiety has provided a novel approach to understanding the feedback regulation of olfactory signal transduction pathways as well as the control of subcellular structures of OSNs. PMID- 23637190 TI - Critical role of increased PTEN nuclear translocation in excitotoxic and ischemic neuronal injuries. AB - Stroke is the leading cause of disability in developed countries. However, no treatment is available beyond 3 h post-ictus. Here, we report that nuclear translocation of PTEN (phosphatase and tensin homolog deleted on chromosome TEN) is a delayed step causatively leading to excitotoxic (in vitro) and ischemic (in vivo) neuronal injuries. We found that excitotoxic stimulation of N-methyl-d aspartate (NMDA) resulted in PTEN nuclear translocation in cultured neurons, a process requiring mono-ubiquitination at the lysine 13 residue (K13), as the translocation was prevented by mutation of K13 or a short interfering peptide (Tat-K13) that flanks the K13 residue. More importantly, using a rat model of focal ischemia, we demonstrated that systemic application of Tat-K13, even 6 h after stroke, not only reduced ischemia-induced PTEN nuclear translocation, but also strongly protected against ischemic brain damage. Our study suggests that inhibition of PTEN nuclear translocation may represent a novel after stroke therapy. PMID- 23637192 TI - Foxa1 and foxa2 are required for the maintenance of dopaminergic properties in ventral midbrain neurons at late embryonic stages. AB - The maintained expression of transcription factors throughout the development of mesodiencephalic dopaminergic (mDA) neurons suggests multiple roles at various stages in development. Two members of the forkhead/winged helix transcription factor family, Foxa1 and Foxa2, have been recently shown to have an important influence in the early development of mDA neurons. Here we present data demonstrating that these genes are also involved in the later maintenance of the mDA system. We conditionally removed both genes in postmitotic mDA neurons using the dopamine transporter-cre mouse. Deletion of both Foxa1 and Foxa2 resulted in a significant reduction in the number of tyrosine hydroxylase (TH)-positive mDA neurons. The decrease was predominantly observed in the substantia nigra region of the mDA system, which led to a loss of TH+ fibers innervating the striatum. Further analysis demonstrated that the reduction in the number of TH+ cells in the mutant mice was not due to apoptosis or cell-fate change. Using reporter mouse lines, we found that the mDA neurons were still present in the ventral midbrain, but that they had lost much of their dopaminergic phenotype. The majority of these neurons remained in the ventral mesencephalon until at least 18 months of age. Chromatin immunoprecipitation suggested that the loss of the mDA phenotype is due to a reduction in the binding of the nuclear orphan receptor, Nurr-1 to the promoter region of TH. These results extend previous findings and demonstrate a later role for Foxa genes in regulating the maintenance of dopaminergic phenotype in mDA neurons. PMID- 23637191 TI - A role for an Hsp70 nucleotide exchange factor in the regulation of synaptic vesicle endocytosis. AB - Neurotransmission requires a continuously available pool of synaptic vesicles (SVs) that can fuse with the plasma membrane and release their neurotransmitter contents upon stimulation. After fusion, SV membranes and membrane proteins are retrieved from the presynaptic plasma membrane by clathrin-mediated endocytosis. After the internalization of a clathrin-coated vesicle, the vesicle must uncoat to replenish the pool of SVs. Clathrin-coated vesicle uncoating requires ATP and is mediated by the ubiquitous molecular chaperone Hsc70. In vitro, depolymerized clathrin forms a stable complex with Hsc70*ADP. This complex can be dissociated by nucleotide exchange factors (NEFs) that release ADP from Hsc70, allowing ATP to bind and induce disruption of the clathrin:Hsc70 association. Whether NEFs generally play similar roles in vesicle trafficking in vivo and whether they play such roles in SV endocytosis in particular is unknown. To address this question, we used information from recent structural and mechanistic studies of Hsp70:NEF and Hsp70:co-chaperone interactions to design a NEF inhibitor. Using acute perturbations at giant reticulospinal synapses of the sea lamprey (Petromyzon marinus), we found that this NEF inhibitor inhibited SV endocytosis. When this inhibitor was mutated so that it could no longer bind and inhibit Hsp110 (a NEF that we find to be highly abundant in brain cytosol), its ability to inhibit SV endocytosis was eliminated. These observations indicate that the action of a NEF, most likely Hsp110, is normally required during SV trafficking to release clathrin from Hsc70 and make it available for additional rounds of endocytosis. PMID- 23637193 TI - Potentiation of inhibitory synaptic transmission by extracellular ATP in rat suprachiasmatic nuclei. AB - The hypothalamic suprachiasmatic nuclei (SCN), the circadian master clock in mammals, releases ATP in a rhythm, but the role of extracellular ATP in the SCN is still unknown. In this study, we examined the expression and function of ATP gated P2X receptors (P2XRs) in the SCN neurons of slices isolated from the brain of 16- to 20-day-old rats. Quantitative RT-PCR showed that the SCN contains mRNA for P2X 1-7 receptors and several G-protein-coupled P2Y receptors. Among the P2XR subunits, the P2X2 > P2X7 > P2X4 mRNAs were the most abundant. Whole-cell patch clamp recordings from SCN neurons revealed that extracellular ATP application increased the frequency of spontaneous GABAergic IPSCs without changes in their amplitudes. The effect of ATP appears to be mediated by presynaptic P2X2Rs because ATPgammaS and 2MeS-ATP mimics, while the P2XR antagonist PPADS blocks, the observed enhancement of the frequency of GABA currents. There were significant differences between two SCN regions in that the effect of ATP was higher in the ventrolateral subdivision, which is densely innervated from outside the SCN. Little evidence was found for the presence of P2XR channels in somata of SCN neurons as P2X2R immunoreactivity colocalized with synapsin and ATP-induced current was observed in only 7% of cells. In fura-2 AM-loaded slices, BzATP as well as ADP stimulated intracellular Ca(2+) increase, indicating that the SCN cells express functional P2X7 and P2Y receptors. Our data suggest that ATP activates presynaptic P2X2Rs to regulate inhibitory synaptic transmission within the SCN and that this effect varies between regions. PMID- 23637194 TI - Dopamine differentially modulates the excitability of striatal neurons of the direct and indirect pathways in lamprey. AB - The functions of the basal ganglia are critically dependent on dopamine. In mammals, dopamine differentially modulates the excitability of the direct and indirect striatal projection neurons, and these populations selectively express dopamine D1 and D2 receptors, respectively. Although the detailed organization of the basal ganglia is conserved throughout the vertebrate phylum, it was unknown whether the differential dopamine modulation of the direct and indirect pathways is present in non-mammalian species. We aim here to determine whether the receptor expression and opposing dopaminergic modulation of the direct and indirect pathways is present in one of the phylogenetically oldest vertebrates, the river lamprey. Using in situ hybridization and patch-clamp recordings, we show that D1 receptors are almost exclusively expressed in the striatal neurons projecting directly to the homolog of the substantia nigra pars reticulata. In addition, the majority of striatal neurons projecting to the homolog of the globus pallidus interna/globus pallidus externa express D1 or D2 receptors. As in mammals, application of dopamine receptor agonists differentially modulates the excitability of these neurons, increasing the excitability of the D1-expressing neurons and decreasing the excitability of D2-expressing neurons. Our results suggest that the segregated expression of the D1 and D2 receptors in the direct and indirect striatal projection neurons has been conserved across the vertebrate phylum. Because dopamine receptor agonists differentially modulate these pathways, increasing the excitability of the direct pathway and decreasing the excitability of the indirect pathway, this organization may be conserved as a mechanism that biases the networks toward action selection. PMID- 23637195 TI - Independent control of presynaptic inhibition by reticulospinal and sensory inputs at rest and during rhythmic activities in the cat. AB - To be functionally relevant during movement, the transmission from primary afferents must be efficiently controlled by presynaptic inhibition. Sensory feedback, central pattern generators, and supraspinal structures can all evoke presynaptic inhibition, but we do not understand how these inputs interact during movement. Here, we investigated the convergence of inputs from the reticular formation and sensory afferents on presynaptic inhibitory pathways and their modulation at rest and during two fictive motor tasks (locomotion and scratch) in decerebrate cats. The amplitude of primary afferent depolarization (PAD), an estimate of presynaptic inhibition, was recorded in individual afferents with intra-axonal recordings and in a mix of afferents in lumbar dorsal rootlets (dorsal root potential [DRP]) with bipolar electrodes. There was no spatial facilitation between inputs from reticulospinal and sensory afferents with DRPs or PADs, indicating an absence of convergence. However, spatial facilitation could be observed by combining two sensory inputs, indicating that convergence was possible. Task-dependent changes in the amplitude of responses were similar for reticulospinal and sensory inputs, increasing during fictive locomotion and decreasing during fictive scratch. During fictive locomotion, DRP and PAD amplitudes evoked by reticulospinal inputs were increased during the flexion phase, whereas sensory-evoked DRPs and PADs showed maximal amplitude in either flexion or extension phases. During fictive scratch, the amplitudes of DRPs and PADs evoked by both sources were maximal in flexion. The absence of spatial facilitation and different phase-dependent modulation patterns during fictive locomotion are consistent with independent presynaptic inhibitory pathways for reticulospinal and sensory inputs. PMID- 23637196 TI - cAMP-mediated stabilization of fusion pores in cultured rat pituitary lactotrophs. AB - Regulated exocytosis mediates the release of hormones and transmitters. The last step of this process is represented by the merger between the vesicle and the plasma membranes, and the formation of a fusion pore. Once formed, the initially stable and narrow fusion pore may reversibly widen (transient exocytosis) or fully open (full-fusion exocytosis). Exocytosis is typically triggered by an elevation in cytosolic calcium activity. However, other second messengers, such as cAMP, have been reported to modulate secretion. The way in which cAMP influences the transitions between different fusion pore states remains unclear. Here, hormone release studies show that prolactin release from isolated rat lactotrophs stimulated by forskolin, an activator of adenylyl cyclases, and by membrane-permeable cAMP analog (dbcAMP), exhibit a biphasic concentration dependency. Although at lower concentrations (2-10 MUm forskolin and 2.5-5 mm dbcAMP) these agents stimulate prolactin release, an inhibition is measured at higher concentrations (50 MUm forskolin and 10-15 mm dbcAMP). By using high resolution capacitance (Cm) measurements, we recorded discrete increases in Cm, which represent elementary exocytic events. An elevation of cAMP leaves the frequency of full-fusion events unchanged while increasing the frequency of transient events. These exhibited a wider fusion pore as measured by increased fusion pore conductance and a prolonged fusion pore dwell time. The probability of observing rhythmic reopening of transient fusion pores was elevated by dbcAMP. In conclusion, cAMP-mediated stabilization of wide fusion pores prevents vesicles from proceeding to the full-fusion stage of exocytosis, which hinders vesicle content discharge at high cAMP concentrations. PMID- 23637199 TI - Three doses of HPV vaccine still recommended, for now. PMID- 23637197 TI - Ventral hippocampal neurons are shaped by experience to represent behaviorally relevant contexts. AB - Memories can be recalled at different levels of resolution, from a detailed rendition of specific events within a single experience to a broad generalization across multiple related experiences. Here we provide evidence that neural representations reflecting the specificity or generality of memories are differentially represented along the dorsoventral axis of the CA3 area of the rat hippocampus. In dorsal CA3, neurons rapidly associate the identity of events with specific locations whereas, in more ventrally located CA3 regions, neurons gradually accumulate information across extended training to form representations that generalize across related events within a spatial context and distinguish events across contexts. PMID- 23637198 TI - Autophagy promotes oligodendrocyte survival and function following dysmyelination in a long-lived myelin mutant. AB - The Long-Evans shaker (les) rat has a mutation in myelin basic protein that results in severe CNS dysmyelination and subsequent demyelination during development. During this time, les oligodendrocytes accumulate cytoplasmic vesicles, including lysosomes and membrane-bound organelles. However, the mechanism and functional relevance behind these oligodendrocyte abnormalities in les have not been investigated. Using high-magnification electron microscopy, we identified the accumulations in les oligodendrocytes as early and late autophagosomes. Additionally, immunohistochemistry and Western blots showed an increase in autophagy markers in les. However, autophagy did not precede the death of les oligodendrocytes. Instead, upregulating autophagy promoted membrane extensions in les oligodendrocytes in vitro. Furthermore, upregulating autophagy in les rats via intermittent fasting increased the proportion of myelinated axons as well as myelin sheath thickness in les and control rats. Overall, this study provides insight into the abnormalities described in les as well as identifying a novel mechanism that promotes the survival and function of oligodendrocytes. PMID- 23637200 TI - V/Q SPECT interpretation for pulmonary embolism diagnosis: which criteria to use? AB - Ventilation-perfusion (V/Q) SPECT has been reported to improve the diagnostic performance of V/Q imaging for the diagnosis of pulmonary embolism (PE). However, only sparse data based on an objective reference test are available, and the criteria used for interpretation have varied widely. Therefore, the aim of our study was to assess the performance of V/Q SPECT using various criteria for interpretation, in comparison with a validated independent diagnostic strategy. METHODS: The SPECT study included patients for whom V/Q SPECT data were compared with the results of an independent and validated diagnostic algorithm for PE. V/Q SPECT scans were performed after intravenous injection of (99m)Tc-macroaggregated albumin and simultaneous ventilation with (81m)Kr gas. Interpretation was performed independently by 2 nuclear medicine physicians who were not aware of the clinical history, diagnostic strategy conclusion, or patient's outcome. Sensitivity, specificity, and likelihood ratios were evaluated for various combinations of mismatched defect numbers and sizes (segmental or subsegmental). Generation of receiver-operating-characteristic curves was based on the number of mismatch defects and the number of subsegmental mismatch defects or equivalent. RESULTS: Of the 249 patients who were analyzed, the diagnosis of PE was confirmed in 49 and ruled out in 200 according to the previously validated independent strategy. Of all the tested criteria, the best performance was achieved using a diagnostic cutoff of at least 1 segmental or 2 subsegmental mismatches, with sensitivity and specificity of 0.92 (95% confidence interval, 0.84-1) and 0.91 (95% confidence interval, 0.87-0.95), respectively. With a negative V/Q SPECT result, the posttest probability of PE was 0.010, 0.037, and 0.119 for a low, intermediate, and high clinical probability. With a positive V/Q SPECT result, the posttest probability of PE was 0.531, 0.814, and 0.939 for a low, intermediate, and high probability. CONCLUSION: For V/Q SPECT interpretation, a diagnostic cutoff of 1 segmental or 2 subsegmental mismatches seems best for confirming or excluding acute PE. PMID- 23637201 TI - Striatal dopamine transporter binding does not correlate with clinical severity in dementia with Lewy bodies. AB - Patients who have dementia with Lewy bodies (DLB) show both clinical and histopathologic overlap with Alzheimer disease patients and Parkinson disease patients. In this study, we correlated the core features of DLB (dementia, parkinsonism, hallucinations, and fluctuations) with striatal dopamine transporter (DAT) availability as assessed with SPECT and (123)I-N-(3-iodoprop-2E enyl)-2-beta-carbomethoxy-3beta-(4-methylphenyl) nortropane ((123)I-PE2I) in patients with newly diagnosed DLB. METHODS: Two hundred eighty-eight patients were consecutively included in the study as they were referred for diagnostic SPECT scanning of DAT with (123)I-PE2I. Of those patients, 51 had, on the basis of clinical guideline criteria, a probable-DLB diagnosis at follow-up 16 +/- 11.6 mo later. Before or on the day of the SPECT scan, DLB patients had a routine neurologic examination including Hoehn and Yahr grading and were cognitively evaluated with the Mini Mental State Examination. RESULTS: There was no correlation between Mini Mental State Examination, Hoehn and Yahr score, fluctuations or hallucinations, and striatal DAT availability as measured with (123)I-PE2I and SPECT. CONCLUSION: In patients with newly diagnosed DLB, symptoms are not associated with a reduction in striatal DAT despite its firm involvement in DLB pathology. PMID- 23637203 TI - Functional interaction of COMMD3 and COMMD9 with the epithelial sodium channel. AB - The epithelial sodium channel (ENaC) plays an important role in controlling Na+ homeostasis, extracellular fluid volume, and blood pressure. Copper metabolism Murr1 domain-containing protein 1 (COMMD1) interacts with ENaC and downregulates ENaC. COMMD1 belongs to the COMMD family consisting of COMMD1-10, and all COMMD family members share a C-terminal COMM domain. Here, we report that COMMD2-10 also interacts with ENaC, and COMMD3 and COMMD9 were selected for further study. Amiloride-sensitive current in mammalian epithelia expressing ENaC was significantly reduced by COMMD3 or COMMD9, and ENaC expression at the cell surface was significantly decreased in the presence of COMMD3 or COMMD9. COMMD3 and COMMD9 retained their ability to reduce current when COMMD1 was knocked down. COMMD3 and COMMD9 were widely expressed in kidney and were colocalized with ENaC in renal collecting duct cells. These data suggest that COMMD3 and COMMD9 may be endogenous regulators of ENaC to regulate Na+ transport through altering ENaC cell surface expression. PMID- 23637202 TI - Cortical distal nephron Cl(-) transport in volume homeostasis and blood pressure regulation. AB - Renal intercalated cells mediate the secretion or absorption of Cl(-) and OH( )/H(+) equivalents in the connecting segment (CNT) and cortical collecting duct (CCD). In so doing, they regulate acid-base balance, vascular volume, and blood pressure. Cl(-) absorption is either electrogenic and amiloride-sensitive or electroneutral and thiazide-sensitive. However, which Cl(-) transporter(s) are targeted by these diuretics is debated. While epithelial Na(+) channel (ENaC) does not transport Cl(-), it modulates Cl(-) transport probably by generating a lumen-negative voltage, which drives Cl(-) flux across tight junctions. In addition, recent evidence indicates that ENaC inhibition increases electrogenic Cl(-) secretion via a type A intercalated cells. During ENaC blockade, Cl(-) is taken up across the basolateral membrane through the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) and then secreted across the apical membrane through a conductive pathway (a Cl(-) channel or an electrogenic exchanger). The mechanism of this apical Cl(-) secretion is unresolved. In contrast, thiazide diuretics inhibit electroneutral Cl(-) absorption mediated by a Na(+)-dependent Cl(-)/HCO3( ) exchanger. The relative contribution of the thiazide and the amiloride sensitive components of Cl(-) absorption varies between studies and probably depends on the treatment model employed. Cl(-) absorption increases markedly with angiotensin and aldosterone administration, largely by upregulating the Na(+) independent Cl(-)/HCO3(-) exchanger pendrin. In the absence of pendrin [Slc26a4(( /-)) or pendrin null mice], aldosterone-stimulated Cl(-) absorption is significantly reduced, which attenuates the pressor response to this steroid hormone. Pendrin also modulates aldosterone-induced changes in ENaC abundance and function through a kidney-specific mechanism that does not involve changes in the concentration of a circulating hormone. Instead, pendrin changes ENaC abundance and function, at least in part, by altering luminal HCO3(-). This review summarizes mechanisms of Cl(-) transport in CNT and CCD and how these transporters contribute to the regulation of extracellular volume and blood pressure. PMID- 23637205 TI - Impaired EphA4 signaling leads to congenital hydronephrosis, renal injury, and hypertension. AB - Experimental hydronephrosis induced by partial ureteral obstruction at 3 wk of age causes hypertension and renal impairment in adult rats and mice. Signaling by Ephrin receptors (Eph) and their ligands (ephrins) importantly regulates embryonic development. Genetically modified mice, where the cytoplasmic domain of the EphA4 receptor has been substituted by enhanced green fluorescent protein (EphA4gf/gf), develop spontaneous hydronephrosis and provide a model for further studies of the disorder. The present study aimed to determine if animals with congenital hydronephrosis develop hypertension and renal injuries, similar to that of experimental hydronephrosis. Ultrasound and Doppler techniques were used to visualize renal impairment in the adult mice. Telemetric blood pressure measurements were performed in EphA4gf/gf mice and littermate controls (EphA4+/+) during normal (0.7% NaCl)- and high (4% NaCl)-sodium conditions. Renal excretion, renal plasma flow, and glomerular filtration were studied, and histology and morphology of the kidneys and ureters were performed. EphA4gf/gf mice developed variable degrees of hydronephrosis that correlated with their blood pressure level. In contrast to EphA4+/+, the EphA4gf/gf mice displayed salt-sensitive hypertension, reduced urine concentrating ability, reduced renal plasma flow, and lower glomerular filtration rate. Kidneys from EphA4gf/gf mice showed increased renal injuries, as evidenced by fibrosis, inflammation, and glomerular and tubular changes. In conclusion, congenital hydronephrosis causes hypertension and renal damage, similar to that observed in experimentally induced hydronephrosis. This study further reinforces the supposed causal link between hydronephrosis and later development of hypertension in humans. PMID- 23637204 TI - Epidermal growth factors in the kidney and relationship to hypertension. AB - Members of the epidermal growth factor (EGF)-family bind to ErbB (EGFR)-family receptors that play an important role in the regulation of various fundamental cell processes in many organs including the kidney. In this field, most of the research efforts are focused on the role of EGF-ErbB axis in cancer biology. However, many studies indicate that abnormal ErbB-mediated signaling pathways are critical in the development of renal and cardiovascular pathologies. The kidney is a major site of the EGF-family ligands synthesis, and it has been shown to express all four members of the ErbB receptor family. The study of kidney disease regulation by ErbB receptor ligands has expanded considerably in recent years. In vitro and in vivo studies have provided direct evidence of the role of ErbB signaling in the kidney. Recent advances in the understanding of how the proteins in the EGF-family regulate sodium transport and development of hypertension are specifically discussed here. Collectively, these results suggest that EGF-ErbB signaling pathways could be major determinants in the progress of renal lesions, including its effects on the regulation of sodium reabsorption in collecting ducts. PMID- 23637208 TI - Progression of microalbuminuria in SHR is associated with lower expression of critical components of the apical endocytic machinery in the renal proximal tubule. AB - Cumulative epidemiological evidence indicates that the presence of microalbuminuria predicts a higher frequency of cardiovascular events, peripheral disease, and mortality in essential hypertension. Microalbuminuria may arise from increased glomerular permeability and/or reduced proximal tubular reabsorption of albumin by receptor-mediated endocytosis. This study aimed to evaluate the temporal pattern of urinary protein excretion and to test the hypothesis that progression of microalbuminuria is associated with decreased protein expression of critical components of the endocytic apparatus in the renal proximal tubule of spontaneously hypertensive rats (SHR). We found that urinary albumin excretion increased progressively with blood pressure in SHR from 6 to 21 wk of age. In addition, SDS-PAGE analysis of urinary proteins showed that microalbuminuric SHR virtually excreted proteins of the size of albumin or smaller (<70 kDa), typical of tubular proteinuria. Moreover, the protein abundance of the endocytic receptors megalin and cubilin as well as of the chloride channel ClC-5 progressively decreased in the renal cortex of SHR from 6 to 21 wk of age. Expression of the vacuolar H+-ATPase B2 subunit was also reduced in the renal cortex of 21-wk-old compared with both 6- and 14-wk-old SHR. Collectively, our study suggests that enhanced urinary protein excretion, especially of albumin, may be due, at least in part, to lower expression of key components of the apical endocytic apparatus in the renal proximal tubule. Finally, one may speculate that dysfunction of the apical endocytic pathway in the renal proximal tubule may contribute to the development of microalbuminuria in essential hypertension. PMID- 23637207 TI - Role of the endogenous opioid system in modulation of urinary bladder activity by spinal nerve stimulation. AB - The role of the endogenous opioid system in modulation of urinary bladder activity by spinal nerve (SN) stimulation was studied in anesthetized female rats, using the rat model of isovolumetric bladder contraction. SN stimulation at a fixed frequency of 10 Hz attenuated bladder contraction frequency; the magnitude of the inhibition was directly proportional to the current intensity. Neither the kappa-opioid antagonist nor-binaltorphimine (2 mg/kg iv) nor the delta-opioid antagonist naltrindole (5 mg/kg iv) attenuated the bladder inhibitory response to SN stimulation. In contrast, the MU-opioid receptor antagonist naloxone (NLX; 0.03 mg/kg iv) blocked the inhibitory responses evoked by SN stimulation at therapeutic current intensities at <=1 * motor threshold current (Tmot). An action at spinal and supraspinal centers was further confirmed by the ability of intrathecal or intracerebroventricular administration of NLX methiodide to attenuate the bladder inhibitory effects of 1 * Tmot SN stimulation. The magnitude of SN-mediated neuromodulation using therapeutically relevant stimulation intensity (Tmot) is equivalent to 0.16 mg/kg of systemically administered morphine, which produces 50% inhibition of bladder contraction frequency. These results suggest that the inhibitory effects of lower intensity SN stimulation may be mediated through the release of endogenous MU-opioid peptides. Additionally, these data suggest that neuromodulation may offer a mode of treating the symptoms of overactive bladder with efficacy equal to the opioid drugs but without their liability for abuse and dependence. PMID- 23637209 TI - Wear of surface-engineered metal-on-metal bearings for hip prostheses under adverse conditions with the head loading on the rim of the cup. AB - Clinical studies have found high wear rates, elevated ion levels and high revision rates of large-diameter metal-on-metal surface replacement bearings in some patients, which have been associated with edge loading of the head on the rim of the cup. We have simulated increased wear and ion levels in metal-on-metal bearings in vitro by introducing variations in translational and rotational positioning of the components, which reproduces stripe wear on the femoral head, cup rim wear and clinically relevant large as well as small wear particles. There is interest in technologies such as surface engineering, which might reduce metal wear and the release of wear particles and ions. Reduced wear with surface engineered surface replacements compared to metal-on-metal controls has been reported under standard walking conditions with correctly aligned and concentric components. In this in vitro study, the wear of chromium nitride surface engineered metal-on-metal bearings under conditions of microseparation associated with translational and rotational malpositioning of the components was investigated and the results were compared with a previously reported study of metal-on-metal bearings under the same conditions. Simulations were conducted using our unique hip simulation microseparation methodologies, which reproduce accelerated wear in metal-on-metal bearings and have previously been clinically validated with ceramic-on-ceramic bearings. Four of the six surface-engineered bearings had evidence of head contact on the rim of the cup, which produced stripe wear on the femoral head. Four of the six surface-engineered bearings (two without stripe and two with stripe wear) had lower wear than the previously reported high wearing metal-on-metal bearings. At 2 million cycles, two of the surface-engineered bearings had substantially increased wear rates, four times higher than the high wear rates previously reported for metal-on-metal bearings under the same conditions. There was wear through and cohesive failure of the thick atomic emission physical vapour deposition (AEPVD) chromium nitride (CrN) coating. At this point, the study was stopped to investigate the failure mode. This study highlights the need to pre-clinically investigate the tribology of new bearings under a wide set of clinical conditions as demonstrated by our stratified approach for enhanced reliability (SAFER) simulation methods. In adopting this SAFER approach to pre-clinical simulation testing of new bearings, it is important to communicate the failures as well as successes of technologies arising from the research, in order that the wider community can benefit from the analysis of the pre-clinical failure modes. PMID- 23637210 TI - Design and fabrication of a sleep apnea device using computer-aided design/additive manufacture technologies. AB - The aim of this study was to analyze the latest innovations in additive manufacture techniques and uniquely apply them to dentistry, to build a sleep apnea device requiring rotating hinges. Laser scanning was used to capture the three-dimensional topography of an upper and lower dental cast. The data sets were imported into an appropriate computer-aided design software environment, which was used to design a sleep apnea device. This design was then exported as a stereolithography file and transferred for three-dimensional printing by an additive manufacture machine. The results not only revealed that the novel computer-based technique presented provides new design opportunities but also highlighted limitations that must be addressed before the techniques can become clinically viable. PMID- 23637206 TI - Pathogenic and protective role of macrophages in kidney disease. AB - Macrophages (MPhi) are located throughout kidney tissue, where they play important roles in homeostasis, surveillance, tolerance, and cytoprotection. MPhi are highly heterogeneous cells and exhibit distinct phenotypic and functional characteristics depending on their microenvironment and the disease type and stage. Recent studies have identified a dual role for MPhi in several murine models of kidney disease. In this review, we discuss the pathogenic and protective roles of the various MPhi subsets in experimental and human kidney diseases and summarize current progress toward the therapeutic use of MPhi in kidney diseases. PMID- 23637211 TI - Wear in metal-on-metal total disc arthroplasty. AB - The wear of a model metal-on-metal ball-and-socket total disc arthroplasty was measured in a simulator. The ball had a radius of 10 mm, and there was a radial clearance between ball and socket of 0.015 mm. The model was subjected to simultaneous flexion-extension, lateral bending, axial rotation (frequency: 1 Hz) and compression (frequency: 2 Hz, maximum load: 2 kN). Throughout the tests, the models were immersed in calf serum diluted to a concentration of 15 g protein per litre, at a controlled temperature of 37 degrees C. Tests were performed on three models. At regular intervals (0, 0.5, 1, 2, 3, 4 and 5 million cycles), mass and surface roughness were determined; mass measurements were converted into the volume lost as a result of wear. All measurements were repeated six times. Wear occurred in two stages. In the first stage (duration about 1 million cycles), there was a linear wear rate of 2.01 +/- 0.04 mm(3) per million cycles; in the second stage, there was a linear wear rate of 0.76 +/- 0.02 mm(3) per million cycles. Surface roughness increased linearly in the first million cycles and then continued to increase linearly but more slowly. PMID- 23637213 TI - Real-time controller for foot-drop correction by using surface electromyography sensor. AB - Foot drop is a disease caused mainly by muscle paralysis, which incapacitates the nerves generating the impulses that control feet in a heel strike. The incapacity may stem from lesions that affect the brain, the spinal cord, or peripheral nerves. The foot becomes dorsiflexed, affecting normal walking. A design and analysis of a controller for such legs is the subject of this article. Surface electromyography electrodes are connected to the skin surface of the human muscle and work on the mechanics of human muscle contraction. The design uses real surface electromyography signals for estimation of the joint angles. Various speed flexions and extensions of the leg were analyzed. The two phases of the design began with surface electromyography of real human leg electromyography signal, which was subsequently filtered, amplified, and normalized to the maximum amplitude. Parameters extracted from the surface electromyography signal were then used to train an artificial neural network for prediction of the joint angle. The artificial neural network design included various-speed identification of the electromyography signal and estimation of the angles of the knee and ankle joints by a recognition process that depended on the parameters of the real surface electromyography signal measured through real movements. The second phase used artificial neural network estimation of the control signal, for calculation of the electromyography signal to be stimulated for the leg muscle to move the ankle joint. Satisfactory simulation (MATLAB/Simulink version 2012a) and implementation results verified the design feasibility. PMID- 23637212 TI - A novel distributed model of the heart under normal and congestive heart failure conditions. AB - Conventional models of cardiovascular system frequently lack required detail and focus primarily on the overall relationship between pressure, flow and volume. This study proposes a localized and regional model of the cardiovascular system. It utilizes noninvasive blood flow and pressure seed data and temporal cardiac muscle regional activity to predict the operation of the heart under normal and congestive heart failure conditions. The analysis considers specific regions of the heart, namely, base, mid and apex of left ventricle. The proposed method of parameter estimation for hydraulic electric analogy model is recursive least squares algorithm. Based on simulation results and comparison to clinical data, effect of congestive heart failure in the heart is quantified. Accumulated results for simulated ejection fraction percentage of the apex, mid and base regions of the left ventricle in congestive heart failure condition were 39 +/- 6, 36 +/- 9 and 38 +/- 8, respectively. These results are shown to satisfactorily match those found through clinical measurements. The proposed analytical method can in effect be utilized as a preclinical and predictive tool for high-risk heart patients and candidates for heart transplant, assistive device and total artificial heart. PMID- 23637214 TI - Volume rendering of three-dimensional fluoroscopic images for percutaneous scaphoid fixation: an in vitro study. AB - Percutaneous fixation of scaphoid fractures offers potential advantages to cast treatment but can be difficult to perform with conventional two-dimensional imaging. This study aimed to evaluate the use of a novel navigation technique using volume-rendered images derived from intraoperative cone-beam computed tomography imaging, without the need for typical patient-based registration. Randomized in vitro trials in which a guidewire was inserted into a scaphoid model were conducted to compare volumetric navigation to conventional fluoroscopic C-arm (n = 24). Central wire placement, surface breach, procedure time, drilling attempts, and radiation exposure were compared between groups. Compared to conventional percutaneous insertion, navigation achieved equal or significantly better placement of the guidewire with fewer drilling attempts and less radiation exposure. On average, navigation took 74 s longer to perform than the conventional method, which was statistically significant but clinically irrelevant. This evaluation suggests that the technology is promising and may have many clinical benefits including improved fixation placement, fewer complications, and less radiation exposure. The intraoperative workflow is more efficient and eliminates the need for preoperative computed tomography, image segmentation, and patient-based registration typical of traditional navigated procedures. PMID- 23637215 TI - Optical coherence tomography: a potential tool to predict premature rupture of fetal membranes. AB - A fundamental question addressed in this study was the feasibility of preterm birth prediction based on a noncontact investigation of fetal membranes in situ. Although the phenomena of preterm birth and the premature rupture of the fetal membrane are well known, currently, there are no diagnostic tools for their prediction. The aim of this study was to assess whether optical coherence tomography could be used for clinical investigations of high-risk pregnancies. The thickness of fetal membranes was measured in parallel by optical coherence tomography and histological techniques for the following types of birth: normal births, preterm births without premature ruptures and births at full term with premature rupture of membrane. Our study revealed that the membrane thickness correlates with the birth type. Normal births membranes were statistically significantly thicker than those belonging to the other two groups. Thus, in spite of almost equal duration of gestation of the normal births and the births at full term with premature rupture, the corresponding membrane thicknesses differed. This difference is possibly related to previously reported water accumulation in the membranes. The optical coherence tomography results were encouraging, suggesting that this technology could be used in future to predict and distinguish between different kinds of births. PMID- 23637217 TI - Mathematical representation of the normal proximal human femur: application in planning of cam hip surgery. AB - Precise modelling of the proximal femur can be used for detecting and planning corrective surgery for subjects with deformed femurs using robotic technology or navigation systems. In this study, the proximal femoral geometry has been modelled mathematically. It is hypothesised that it is possible to fit a quadratic surface or combinations of them onto different bone surfaces with a relatively good fit. Forty-six computed tomography datasets of normal proximal femora were segmented. A least-squares fitting algorithm was used to fit a quadratic surface on the femoral head and neck such that the sum of distances between a set of points on the femoral neck and the quadratic surface was minimised. Furthermore, the position of the head-neck articular margin was also measured. The femoral neck was found to be represented as a good fit to a hyperboloid with an average root mean-squared error of 1.0 +/- 0.13 mm while the shape of the femoral articular margin was a reproducible sinusoidal wave form with two peaks. The mathematical description in this study can be used for planning corrective surgery for subjects with cam-type femoroacetabular impingement. PMID- 23637216 TI - Computational aspects in mechanical modeling of the articular cartilage tissue. AB - This review focuses on the modeling of articular cartilage (at the tissue level), chondrocyte mechanobiology (at the cell level) and a combination of both in a multiscale computation scheme. The primary objective is to evaluate the advantages and disadvantages of conventional models implemented to study the mechanics of the articular cartilage tissue and chondrocytes. From monophasic material models as the simplest form to more complicated multiscale theories, these approaches have been frequently used to model articular cartilage and have contributed significantly to modeling joint mechanics, addressing and resolving numerous issues regarding cartilage mechanics and function. It should be noted that attentiveness is important when using different modeling approaches, as the choice of the model limits the applications available. In this review, we discuss the conventional models applicable to some of the mechanical aspects of articular cartilage such as lubrication, swelling pressure and chondrocyte mechanics and address some of the issues associated with the current modeling approaches. We then suggest future pathways for a more realistic modeling strategy as applied for the simulation of the mechanics of the cartilage tissue using multiscale and parallelized finite element method. PMID- 23637219 TI - Relationship between patellar tendon shortening and in vitro kinematics in the ovine stifle joint. AB - Post-operative patellar tendon shortening induces a distal positioning of the patella in the femoral trochlear groove, which has been associated with pain and impeded mobility. An idealized in vitro model was used to examine the effects of shortening on patellar kinematics. The PT length was progressively reduced by up to 5 mm (1-mm instalments) using a device secured onto the tendon in n = 9 ovine stifles. In vitro 6 degrees-of-freedom motion data for the patellofemoral and tibiofemoral joints under conditions of passively induced flexion-extension was acquired electromagnetically. Patellar motion was analysed as a function of both tibial and patellar flexion angles relative to the femoral co-ordinate frame. Linear regression with contrasts was used to compare kinematic changes for each shortening level, with significance set at P<0.01. A mean maximum percentage length reduction of 8.2% was achieved. Patellar flexion was linearly correlated with tibial flexion angle in the intact joint, and this correlation persisted after tendon shortening (R = 0.977, P < 0.01). Patellar kinematics expressed as a function of tibial flexion angle were significantly altered by a mean length decrease of 8.2%, while flexion and proximo-distal shift patterns were significantly affected at lesser shortening levels of 3.1% and 4.7%, respectively. Patellar kinematics expressed as a function of patellar flexion angle remained unchanged. These results suggest that patellar motion within the trochlear groove in the ovine stifle joint follows a repeatable three-dimensional path and that patellar tendon shortening advances the position of the patella along this path, without significantly altering it. PMID- 23637218 TI - An innovative shape equation to quantify the morphological characteristics of parasitized red blood cells by Plasmodium falciparum and Plasmodium vivax. AB - The morphology of red blood cells is affected significantly during maturation of malaria parasites, Plasmodium falciparum and Plasmodium vivax. A novel shape equation is presented that defines shape of parasitized red blood cells by P. falciparum (Pf-red blood cells) and P. vivax (Pv-red blood cells) at four stages of infection. The Giemsa-stained thin blood films are prepared using blood samples collected from healthy donors, patients having P. falciparum and P. vivax malaria. The diameter and thickness of healthy red blood cells plus Pf-red blood cells and Pv-red blood cells at each stage of infection are measured from their optical images using Olysia and Scanning Probe Image Processor softwares, respectively. Using diameters and thicknesses of parasitized red blood cells, a shape equation is fitted and relative two-dimensional shapes are plotted using MATHEMATICA. The shape of Pf-red blood cell drastically changes at ring stage as its thickness increases by 82%, while Pv-red blood cell remains biconcave (30% increase in thickness). By trophozoite and subsequent schizont stage, the Pf-red blood cell entirely loses its biconcave shape and becomes near spherical (diameter and thickness of ~8 um). The Pv-red blood cell remains biconcave throughout the parasite development even though its volume increases. These results could have practical use for faster diagnosis, prediction, and treatment of human malaria and sickle-cell diseases. PMID- 23637220 TI - Trabecular architecture analysis in femur radiographic images using fractals. AB - Trabecular bone is a highly complex anisotropic material that exhibits varying magnitudes of strength in compression and tension. Analysis of the trabecular architectural alteration that manifest as loss of trabecular plates and connection has been shown to yield better estimation of bone strength. In this work, an attempt has been made toward the development of an automated system for investigation of trabecular femur bone architecture using fractal analysis. Conventional radiographic femur bone images recorded using standard protocols are used in this study. The compressive and tensile regions in the images are delineated using preprocessing procedures. The delineated images are analyzed using Higuchi's fractal method to quantify pattern heterogeneity and anisotropy of trabecular bone structure. The results show that the extracted fractal features are distinct for compressive and tensile regions of normal and abnormal human femur bone. As the strength of the bone depends on architectural variation in addition to bone mass, this study seems to be clinically useful. PMID- 23637221 TI - Specimen-specific tibial kinematics model for in vitro gait simulations. AB - Until now, the methods used to set up in vitro gait simulations were not specimen specific, inflicting several problems when dealing with specimens of considerably different dimensions and requiring arbitrary parameter tuning of the control variables. We constructed a model that accounts for the geometric dimensions of the specimen and is able to predict the tibial kinematics during the stance phase. The model predicts tibial kinematics of in vivo subjects with very good accuracy. Furthermore, if used in in vitro gait simulation studies, it is able to recreate physiological vertical ground reaction forces. By using this methodology, in vitro studies can be performed by taking the specimen variability into account, avoiding pitfalls with specimens of different dimensions. PMID- 23637222 TI - Patient-specific finite element modeling of bones. AB - Finite element modeling is an engineering tool for structural analysis that has been used for many years to assess the relationship between load transfer and bone morphology and to optimize the design and fixation of orthopedic implants. Due to recent developments in finite element model generation, for example, improved computed tomography imaging quality, improved segmentation algorithms, and faster computers, the accuracy of finite element modeling has increased vastly and finite element models simulating the anatomy and properties of an individual patient can be constructed. Such so-called patient-specific finite element models are potentially valuable tools for orthopedic surgeons in fracture risk assessment or pre- and intraoperative planning of implant placement. The aim of this article is to provide a critical overview of current themes in patient specific finite element modeling of bones. In addition, the state-of-the-art in patient-specific modeling of bones is compared with the requirements for a clinically applicable patient-specific finite element method, and judgment is passed on the feasibility of application of patient-specific finite element modeling as a part of clinical orthopedic routine. It is concluded that further development in certain aspects of patient-specific finite element modeling are needed before finite element modeling can be used as a routine clinical tool. PMID- 23637225 TI - Evidence-based recommendations for the diagnosis and treatment of pediatric acne. AB - INTRODUCTION: Acne vulgaris is one of the most common skin conditions in children and adolescents. The presentation, differential diagnosis, and association of acne with systemic pathology differs by age of presentation. Current acknowledged guidelines for the diagnosis and management of pediatric acne are lacking, and there are variations in management across the spectrum of primary and specialty care. The American Acne and Rosacea Society convened a panel of pediatric dermatologists, pediatricians, and dermatologists with expertise in acne to develop recommendations for the management of pediatric acne and evidence-based treatment algorithms. METHODS: Ten major topic areas in the diagnosis and treatment of pediatric acne were identified. A thorough literature search was performed and articles identified, reviewed, and assessed for evidence grading. Each topic area was assigned to 2 expert reviewers who developed and presented summaries and recommendations for critique and editing. Furthermore, the Strength of Recommendation Taxonomy, including ratings for the strength of recommendation for a body of evidence, was used throughout for the consensus recommendations for the evaluation and management of pediatric acne. Practical evidence-based treatment algorithms also were developed. RESULTS: Recommendations were put forth regarding the classification, diagnosis, evaluation, and management of pediatric acne, based on age and pubertal status. Treatment considerations include the use of over-the-counter products, topical benzoyl peroxide, topical retinoids, topical antibiotics, oral antibiotics, hormonal therapy, and isotretinoin. Simplified treatment algorithms and recommendations are presented in detail for adolescent, preadolescent, infantile, and neonatal acne. Other considerations, including psychosocial effects of acne, adherence to treatment regimens, and the role of diet and acne, also are discussed. CONCLUSIONS: These expert recommendations by the American Acne and Rosacea Society as reviewed and endorsed by the American Academy of Pediatrics constitute the first detailed, evidence based clinical guidelines for the management of pediatric acne including issues of special concern when treating pediatric patients. PMID- 23637226 TI - A blood-brain barrier (BBB) disrupter is also a potent alpha-synuclein (alpha syn) aggregation inhibitor: a novel dual mechanism of mannitol for the treatment of Parkinson disease (PD). AB - The development of disease-modifying therapy for Parkinson disease has been a main drug development challenge, including the need to deliver the therapeutic agents to the brain. Here, we examined the ability of mannitol to interfere with the aggregation process of alpha-synuclein in vitro and in vivo in addition to its blood-brain barrier-disrupting properties. Using in vitro studies, we demonstrated the effect of mannitol on alpha-synuclein aggregation. Although low concentration of mannitol inhibited the formation of fibrils, high concentration significantly decreased the formation of tetramers and high molecular weight oligomers and shifted the secondary structure of alpha-synuclein from alpha helical to a different structure, suggesting alternative potential pathways for aggregation. When administered to a Parkinson Drosophila model, mannitol dramatically corrected its behavioral defects and reduced the amount of alpha synuclein aggregates in the brains of treated flies. In the mThy1-human alpha synuclein transgenic mouse model, a decrease in alpha-synuclein accumulation was detected in several brain regions following treatment, suggesting that mannitol promotes alpha-synuclein clearance in the cell bodies. It appears that mannitol has a general neuroprotective effect in the transgenic treated mice, which includes the dopaminergic system. We therefore suggest mannitol as a basis for a dual mechanism therapeutic agent for the treatment of Parkinson disease. PMID- 23637227 TI - Sphingosine-1-phosphate phosphatase 1 regulates keratinocyte differentiation and epidermal homeostasis. AB - Sphingosine 1-phosphate (S1P) is a bioactive lipid whose levels are tightly regulated by its synthesis and degradation. Intracellularly, S1P is dephosphorylated by the actions of two S1P-specific phosphatases, sphingosine-1 phosphate phosphatases 1 and 2. To identify the physiological functions of S1P phosphatase 1, we have studied mice with its gene, Sgpp1, deleted. Sgpp1(-/-) mice appeared normal at birth, but during the 1st week of life they exhibited stunted growth and suffered desquamation, with most dying before weaning. Both Sgpp1(-/-) pups and surviving adults exhibited multiple epidermal abnormalities. Interestingly, the epidermal permeability barrier developed normally during embryogenesis in Sgpp1(-/-) mice. Keratinocytes isolated from the skin of Sgpp1( /-) pups had increased intracellular S1P levels and displayed a gene expression profile that indicated overexpression of genes associated with keratinocyte differentiation. The results reveal S1P metabolism as a regulator of keratinocyte differentiation and epidermal homeostasis. PMID- 23637228 TI - Sumoylation of the basic helix-loop-helix transcription factor sharp-1 regulates recruitment of the histone methyltransferase G9a and function in myogenesis. AB - Sumoylation is an important post-translational modification that alters the activity of many transcription factors. However, the mechanisms that link sumoylation to alterations in chromatin structure, which culminate in tissue specific gene expression, are not fully understood. In this study, we demonstrate that SUMO modification of the transcription factor Sharp-1 is required for its full transcriptional repression activity and function as an inhibitor of skeletal muscle differentiation. Sharp-1 is modified by sumoylation at two conserved lysine residues 240 and 255. Mutation of these SUMO acceptor sites in Sharp-1 does not impact its subcellular localization but attenuates its ability to act as a transcriptional repressor and inhibit myogenic differentiation. Consistently, co-expression of the SUMO protease SENP1 with wild type Sharp-1 abrogates Sharp-1 dependent inhibition of myogenesis. Interestingly, sumoylation acts as a signal for recruitment of the co-repressor G9a. Thus, enrichment of G9a, and histone H3 lysine 9 dimethylation (H3K9me2), a signature of G9a activity, is dramatically reduced at muscle promoters in cells expressing sumoylation-defective Sharp-1. Our findings demonstrate how sumoylation of Sharp-1 exerts an impact on chromatin structure and transcriptional repression of muscle gene expression through recruitment of G9a. PMID- 23637229 TI - Regulation of Rad17 protein turnover unveils an impact of Rad17-APC cascade in breast carcinogenesis and treatment. AB - Aberrant regulation of DNA damage checkpoint function leads to genome instability that in turn can predispose cellular tissues to become cancerous. Previous works from us and others demonstrated the role of Rad17 in either activation or termination of DNA damage checkpoint function. In the current study, we have revealed the unexpected accumulation of Rad17 in various types of breast cancer cell lines as well as human breast cancer tissues. We observed that Rad17 protein turnover rate in breast epithelial cells is much faster than in breast cancer cells, where the turnover of Rad17 is regulated by the Cdh1/APC pathway. We further observed that Rad17-mediated checkpoint function is modulated by proteolysis. Stabilization of Rad17 disrupts cellular response to chemotherapeutic drug-induced DNA damage and enhances cellular transformation. In addition, manipulation of Rad17 by RNA interference or stabilization of Rad17 significantly sensitize breast cancer cell to various chemotherapeutic drugs. Our present results indicate the manipulation of Rad17 proteolysis could be a valuable approach to sensitize breast cancer cell to the chemotherapeutic treatment despite of the critical role in governing DNA damage response and cellular recovery from genotoxic stress. PMID- 23637232 TI - Injectable treatments for noninsertional achilles tendinosis: a systematic review. AB - BACKGROUND: Although there has been a recent increase in interest regarding injectable therapy for noninsertional Achilles tendinosis, there are currently no clear treatment guidelines for managing patients with this condition. The objective of this study was (1) to conduct a systematic review of clinical outcomes following injectable therapy of noninsertional Achilles tendinosis, (2) to identify patient-specific factors that are prognostic of treatment outcomes, (3) to provide treatment recommendations based on the best available literature, and (4) to identify knowledge deficits that require further investigation. METHODS: We searched MEDLINE (1948 to March week 1 2012) and EMBASE (1980 to 2012 week 9) for clinical studies evaluating the efficacy of injectable therapies for noninsertional Achilles tendinosis. Specifically, we included randomized controlled trials and cohort studies with a comparative control group. Data abstraction was performed by 2 independent reviewers. The Oxford Level of Evidence Guidelines and GRADE recommendations were used to rate the quality of evidence and to make treatment recommendations. RESULTS: Nine studies fit the inclusion criteria for our review, constituting 312 Achilles tendons at final follow-up. The interventions of interest included platelet-rich plasma (n = 54), autologous blood injection (n = 40), sclerosing agents (n = 72), protease inhibitors (n = 26), hemodialysate (n = 60), corticosteroids (n = 52), and prolotherapy (n = 20). Only 1 study met the criteria for a high-quality randomized controlled trial. All of the studies were designated as having a low quality of evidence. While some studies showed statistically significant effects of the treatment modalities, often studies revealed that certain injectables were no better than a placebo. CONCLUSIONS: The literature surrounding injectable treatments for noninsertional Achilles tendinosis has variable results with conflicting methodologies and inconclusive evidence concerning indications for treatment and the mechanism of their effects on chronically degenerated tendons. Prospective, randomized studies are necessary in the future to guide Achilles tendinosis treatment recommendations using injectable therapies. LEVEL OF EVIDENCE: Level II, systematic review. PMID- 23637230 TI - Modular organization of alpha-toxins from scorpion venom mirrors domain structure of their targets, sodium channels. AB - To gain success in the evolutionary "arms race," venomous animals such as scorpions produce diverse neurotoxins selected to hit targets in the nervous system of prey. Scorpion alpha-toxins affect insect and/or mammalian voltage gated sodium channels (Na(v)s) and thereby modify the excitability of muscle and nerve cells. Although more than 100 alpha-toxins are known and a number of them have been studied into detail, the molecular mechanism of their interaction with Na(v)s is still poorly understood. Here, we employ extensive molecular dynamics simulations and spatial mapping of hydrophobic/hydrophilic properties distributed over the molecular surface of alpha-toxins. It is revealed that despite the small size and relatively rigid structure, these toxins possess modular organization from structural, functional, and evolutionary perspectives. The more conserved and rigid "core module" is supplemented with the "specificity module" (SM) that is comparatively flexible and variable and determines the taxon (mammal versus insect) specificity of alpha-toxin activity. We further show that SMs in mammal toxins are more flexible and hydrophilic than in insect toxins. Concomitant sequence-based analysis of the extracellular loops of Na(v)s suggests that alpha toxins recognize the channels using both modules. We propose that the core module binds to the voltage-sensing domain IV, whereas the more versatile SM interacts with the pore domain in repeat I of Na(v)s. These findings corroborate and expand the hypothesis on different functional epitopes of toxins that has been reported previously. In effect, we propose that the modular structure in toxins evolved to match the domain architecture of Na(v)s. PMID- 23637233 TI - Hallux valgus in males--part 2: radiographic assessment of surgical treatment. AB - BACKGROUND: In an early report on this patient cohort, we concluded that a hallux valgus deformity in males is frequently hereditary in nature. An increase in the distal metatarsal articular angle (DMAA) was observed to be the major defining characteristic of hallux valgus in males. In this follow-up study, our goal was to evaluate the effectiveness of surgical treatment for this cohort of male patients. METHODS: Data from 50 feet of male patients with hallux valgus who were surgically treated by the same surgeon between 1985 and 2005 were retrospectively analyzed. The technique was algorithmically chosen according to the severity and complexity of the deformity. Thus, 10 chevron osteotomies, 9 biplanar chevron osteotomies, 12 Mitchell osteotomies, 9 scarf osteotomies, and 10 basilar first metatarsal osteotomies were performed. The average follow-up was 10 years (range, 2-20). RESULTS: After analyzing the angular radiological parameters, sesamoid subluxation, and the articular congruency, most procedures proved to have achieved adequate correction of the angular deformities. When examining each of the procedures separately, 4 of the 5 procedures had similar corrective capacities; the scarf osteotomy however had decidedly inferior results. The improvement in the postoperative American Orthopaedic Foot and Ankle Society (AOFAS) score demonstrated the clinical and functional improvement. CONCLUSIONS: The algorithm was based mainly upon the presence of increased DMAA and increased severity of angular deformities. We conclude that hallux valgus deformities in males were adequately corrected with the selected techniques. Greater difficulty or resistance to surgical treatment could not be detected when we contrasted our results to females. The scarf osteotomy proved to have an inferior corrective capacity compared to the other techniques used in this series. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 23637231 TI - LKB1 represses focal adhesion kinase (FAK) signaling via a FAK-LKB1 complex to regulate FAK site maturation and directional persistence. AB - Liver kinase beta1 (LKB1, also known as STK11) is a serine/threonine kinase that has multiple cellular functions including the regulation of cell polarity and motility. Murine proteomic studies show that LKB1 loss causes aberrant adhesion signaling; however, the mechanistic underpinnings of this relationship are unknown. We show that cells stably depleted of LKB1 or its co-activator STRADalpha have increased phosphorylation of focal adhesion kinase (FAK) at Tyr(397)/Tyr(861) and enhanced adhesion to fibronectin. LKB1 associates in a complex with FAK and LKB1 accumulation at the cellular leading edge is mutually excluded from regions of activated Tyr(397)-FAK. LKB1-compromised cells lack directional persistence compared with wild-type cells, but this is restored through subsequent pharmacological FAK inhibition or depletion, showing that cell directionality is mediated through LKB1-FAK signaling. Live cell confocal imaging reveals that LKB1-compromised cells lack normal FAK site maturation and turnover, suggesting that defects in adhesion and directional persistence are caused by aberrant adhesion dynamics. Furthermore, re-expression of full-length wild-type or the LKB1 N-terminal domain repressed FAK activity, whereas the kinase domain or C-terminal domain alone did not, indicating that FAK suppression is potentially regulated through the LKB1 N-terminal domain. Based upon these results, we conclude that LKB1 serves as a FAK repressor to stabilize focal adhesion sites, and when LKB1 function is compromised, aberrant FAK signaling ensues, resulting in rapid FAK site maturation and poor directional persistence. PMID- 23637234 TI - Single-stage flexor tendon transfer for the treatment of severe concomitant peroneus longus and brevis tendon tears. AB - BACKGROUND: Although peroneal tendon injuries are a common cause of lateral ankle pain, there is a paucity of literature specifically addressing the treatment of severe concomitant peroneus longus and brevis tears. The purpose of this study was to evaluate patient outcomes following a single-stage flexor tendon transfer for the treatment of severe concomitant tears of both peroneal tendons. METHODS: Eight patients were treated with a single-stage flexor tendon transfer for severe concomitant peroneus longus and brevis tears over a 15-year period. Mean age at the time of surgery was 54 years (range, 41-67 years), including 4 male and 4 female patients. Tendon transfer of either the flexor hallucis longus (FHL) or flexor digitorum longus (FDL) was performed when both peroneal tendons were found intraoperatively to have severe nonreconstructable tears. Mean follow-up time from surgery was 58 months (range, 12-91 months). Preoperative and postoperative AOFAS hindfoot and visual analog pain scores were prospectively collected, and patient charts were reviewed for complications. A postoperative outcome questionnaire was administered during latest follow-up to assess return to activities, satisfaction, and self-rated patient outcome. RESULTS: Mean pre- and postoperative AOFAS hindfoot scores increased from 64 (range, 54-77) to 86 (range, 69-100), whereas mean score for pain on a visual analog scale decreased from 4.2 (range, 0.5-6) to 0.7 (range, 0-3). One surgical complication occurred following FDL transfer in a patient who developed a transient peroneal nerve palsy, and 1 patient underwent a subsequent calcaneal osteotomy. Seven of 8 patients reported a return to preoperative activity levels, and no patient required bracing for activities of daily living. All patients reported satisfaction with surgical results, and 7 rated their outcomes as good or excellent. CONCLUSION: Single-stage flexor tendon transfer is an effective surgical option for the treatment of severe concomitant peroneus longus and brevis tendon tears. LEVEL OF EVIDENCE: Level IV, case series. PMID- 23637235 TI - Clinical outcomes and static and dynamic assessment of foot posture after lateral column lengthening procedure. AB - BACKGROUND: Lateral column lengthening (LCL) has been shown to radiographically restore the medial longitudinal arch. However, the impact of LCL on foot function during gait has not been reported using validated clinical outcomes and gait analysis. METHODS: Thirteen patients with a stage II flatfoot who had undergone unilateral LCL surgery and 13 matched control subjects completed self-reported pain and functional scales as well as a clinical examination. A custom force transducer was used to establish the maximum passive range of motion of first metatarsal dorsiflexion at 40 N of force. Foot kinematic data were collected during gait using 3-dimensional motion analysis techniques. RESULTS: Radiographic correction of the flatfoot was achieved in all cases. Despite this, most patients continued to report pain and dysfunction postoperatively. Participants post LCL demonstrated similar passive and active movement of the medial column when we compared the operated and the nonoperated sides. However, participants post LCL demonstrated significantly greater first metatarsal passive range of motion and first metatarsal dorsiflexion during gait than did controls (P < .01 for all pairwise comparisons). CONCLUSION: Patients undergoing LCL for correction of stage II adult-acquired flatfoot deformity experience mixed outcomes and similar foot kinematics as the uninvolved limb despite radiographic correction of deformity. These patients maintain a low arch posture similar to their uninvolved limb. The consequence is that first metatarsal movement operates at the end range of dorsiflexion and patients do not obtain full hindfoot inversion at push-off. Longitudinal data are necessary to make a more valid comparison of the effects of surgical correction measured using radiographs and dynamic foot posture during gait. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 23637236 TI - Prospective study of the treatment of adult primary hallux valgus with scarf osteotomy and soft tissue realignment. AB - BACKGROUND: The scarf osteotomy has been a widely practiced bunion operation, but relatively limited prospective data on its outcomes have been reported. The purpose of this investigation was to prospectively evaluate the clinical and radiographic results of treatment of adult primary hallux valgus using the scarf osteotomy of the first metatarsal with soft tissue realignment. METHODS: Hallux valgus corrections were performed on 51 patients (53 feet), who were followed for at least 1 year with an average follow-up of 24 months. Mean age at the time of surgery was 59 years, and subjects included 3 male and 48 female patients. Prospective clinical data collected included the American Orthopaedic Foot & Ankle Society (AOFAS) hallux-interphalangeal scale score, the SF-36 scores, and the visual analogue scale (VAS) for pain. Data were collected preoperatively and postoperatively. Prospective radiologic data were also collected including hallux valgus angle (HVA), first-second intermetatarsal angle (IMA), and medial sesamoid position (MSP). Clinical data were collected on complications and reoperations. RESULTS: Mean AOFAS hallux-interphalangeal score increased from 52 preoperatively to 88 postoperatively. Mean preoperative and last follow-up SF-36 physical component summary increased from 46 preoperatively to 52 postoperatively, whereas mean VAS pain scores decreased from 5.8 preoperatively to 1.1 postoperatively. All the changes in clinical outcomes were statistically significant, except the Mental Component Summary of the SF-36. Mean preoperative HVA decreased from 29 degrees preoperatively to 10.7 degrees in the initial postoperative period and was maintained at last follow-up at 10.6 degrees. The mean preoperative IMA decreased from 13.6 degrees preoperatively to 5.6 degrees in the initial postoperative period and regressed mildly at last follow-up to 7.8 degrees. The mean preoperative MSP grade of 2.3 decreased to 0.5 in the initial postoperative period and regressed mildly to 0.9 at last follow-up. All radiographic changes were statistically significant. The overall complication rate was 15% (8/53), attributable to 4 feet with symptomatic hardware, 2 feet with hallux varus, and 2 feet with progression of first MTP arthritis. Reoperations were performed in 4 feet (8%) for removal of symptomatic hardware. CONCLUSION: Scarf osteotomy was a reliable technique for correction of moderate to severe hallux valgus and had low rates of complication or recurrence. LEVEL OF EVIDENCE: Level IV, case series. PMID- 23637237 TI - Prognostic classification of fifth metatarsal stress fracture using plantar gap. AB - BACKGROUND: There have been diverse results even in same Torg type of fifth metatarsal stress fractures. METHODS: Eighty-six cases with a fifth metatarsal stress fracture that were treated with modified tension band wiring from January 2003 to May 2009 were evaluated retrospectively. Each case was classified according to Torg's classification and a new classification. Using the new proposed classification, cases were subdivided into complete fracture and incomplete fracture. The cases of incomplete fracture were subdivided based on presence or absence of plantar gap more than 1 mm. After surgery, bone union was determined by CT. Statistical analysis of the Torg classification and time for bone union as well as the proposed new classification and time for bone union was performed. RESULTS: There was a significant difference in the time for bone union among the three Torg types (P = 0.004). The mean time for bone union in group A (complete fracture, n = 32) was 67.5 +/- 28.8, and it was 103.2 +/- 47.7 for group B (incomplete fracture, n = 54). There was a significant difference in time for bone union between them (P < 0.001). The mean time for bone union in group B1 (incomplete fracture, plantar gap less than 1 mm, n = 16) was 73.9 +/- 26.7, and it was 115.5 +/- 45.4 for group B2 (incomplete fracture, plantar gap 1 mm or more, n = 38). There was a significant difference in time for bone union between them (P < 0.001). CONCLUSION: The results of this study suggest that the classification incorporating the plantar gap might be used for classification of fifth metatarsal stress fractures. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 23637238 TI - Role of preoperative computed tomography scans in operative planning for malleolar ankle fractures. AB - BACKGROUND: There remains no consensus regarding the role of computed tomography (CT) scans in preoperative planning for malleolar ankle fractures. The aim of this study was to determine the role of preoperative CT scans on operative planning in these fractures. METHODS: A retrospective analysis was performed on 100 consecutive patients treated at our institution for malleolar ankle fractures (AO type 44) with both preoperative radiographs and CT scans. Six study participants reviewed available radiographs and formulated an operative (or nonoperative) plan including positioning, operative approach, and fixation. Participants then analyzed CT scans of the same fractures, deciding whether (and how) they would alter operative strategy. Characteristics of fractures and radiographs were correlated with changes in operative strategy. RESULTS: Operative strategy was notably changed in 24% of cases after CT review, with strong intraclass correlation (0.733). Common changes included alterations in medial malleolar (21%) or posterior malleolar (15%) fixation and fixation of an occult anterolateral plafond fracture (9%). Notable predictors of changes in operative strategy included trimalleolar over unimalleolar fractures (29% vs 10% rate of change), preoperative dislocation over no dislocation (31% vs 20%), the presence of only radiographs with overlying plaster versus fractures with at least 1 set of radiographs without plaster (25% vs 14%), and suprasyndesmotic versus trans- and infra-syndesmotic fractures (40% vs 20% and 4%, respectively). CONCLUSIONS: CT scans may be useful adjuncts in preoperative planning for malleolar ankle fractures, most notably in fracture dislocations, cases in which all available radiographs are obscured by plaster, trimalleolar fractures, and suprasyndesmotic fractures. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 23637239 TI - Influence of approach and implant on reduction accuracy and stability in lisfranc fracture-dislocation at the tarsometatarsal joint. AB - BACKGROUND: Besides early diagnosis, an anatomical and stable reduction is paramount for obtaining a favorable outcome. The current study looked at the influence that the type of approach for tarsometatarsal injuries has on the accuracy of the reduction and the effect that the type of fixation has on stability. METHODS: Consecutive patients treated surgically for an acute Lisfranc injury were included. All radiographs were reassessed for accuracy and secondary displacement following either a closed or an open approach and in terms of the type of fixation (Kirschner wires alone or a combination of screws and plates and Kirschner wires). A total of 28 patients were included. Six patients were treated with closed reduction and percutaneous fixation and 22 with open reduction internal fixation. Sixteen patients were treated with Kirschner wires only (6 closed, 10 open), 7 with screws with or without Kirschner wires, and 5 with medial plating with or without Kirschner wires. RESULTS: In the closed reduction group, 2 of 6 (33%) reductions were considered acceptable versus 19 of 22 (86%) in the open group (P = .021). All 6 secondary displacements occurred in the Kirschner wire fixation group (37.5%) versus none in the rigid fixation group (P = .024). CONCLUSION: The results demonstrate that open reduction and internal fixation with screws or plate resulted in better reduction and better maintenance of reduction in both low- and high-energy Lisfranc injuries. These results should be further evaluated in light of functional outcome. LEVEL OF EVIDENCE: Level III, retrospective comparative case series. PMID- 23637240 TI - Pyoderma gangrenosum following foot and ankle surgery: a case report. PMID- 23637241 TI - Intraoperative O-arm computed tomography evaluation of syndesmotic reduction: case report. PMID- 23637242 TI - Myxoma of a lesser toe distal phalynx: case report and technique tip. PMID- 23637243 TI - Appropriateness of surgery. PMID- 23637244 TI - Posterior pilon fractures. PMID- 23637245 TI - Foot & ankle international. PMID- 23637247 TI - Marked biological variance in endocrine and biochemical markers in childhood: establishment of pediatric reference intervals using healthy community children from the CALIPER cohort. AB - BACKGROUND: Reference intervals are indispensable in evaluating laboratory test results; however, appropriately partitioned pediatric reference values are not readily available. The Canadian Laboratory Initiative for Pediatric Reference Intervals (CALIPER) program is aimed at establishing the influence of age, sex, ethnicity, and body mass index on biochemical markers and developing a comprehensive database of pediatric reference intervals using an a posteriori approach. METHODS: A total of 1482 samples were collected from ethnically diverse healthy children ages 2 days to 18 years and analyzed on the Abbott ARCHITECT i2000. Following the CLSI C28-A3 guidelines, age- and sex-specific partitioning was determined for each analyte. Nonparametric and robust methods were used to establish the 2.5th and 97.5th percentiles for the reference intervals as well as the 90% CIs. RESULTS: New pediatric reference intervals were generated for 14 biomarkers, including alpha-fetoprotein, cobalamin (vitamin B12), folate, homocysteine, ferritin, cortisol, troponin I, 25(OH)-vitamin D [25(OH)D], intact parathyroid hormone (iPTH), thyroid-stimulating hormone, total thyroxine (TT4), total triiodothyronine (TT3), free thyroxine (FT4), and free triiodothyronine. The influence of ethnicity on reference values was also examined, and statistically significant differences were found between ethnic groups for FT4, TT3, TT4, cobalamin, ferritin, iPTH, and 25(OH)D. CONCLUSIONS: This study establishes comprehensive pediatric reference intervals for several common endocrine and immunochemical biomarkers obtained in a large cohort of healthy children. The new database will be of global benefit, ensuring appropriate interpretation of pediatric disease biomarkers, but will need further validation for specific immunoassay platforms and in local populations as recommended by the CLSI. PMID- 23637249 TI - Type 1 diabetes mellitus. PMID- 23637248 TI - Complex biological pattern of fertility hormones in children and adolescents: a study of healthy children from the CALIPER cohort and establishment of pediatric reference intervals. AB - BACKGROUND: Pediatric endocrinopathies are commonly diagnosed and monitored by measuring hormones of the hypothalamic-pituitary-gonadal axis. Because growth and development can markedly influence normal circulating concentrations of fertility hormones, accurate reference intervals established on the basis of a healthy, nonhospitalized pediatric population and that reflect age-, gender-, and pubertal stage-specific changes are essential for test result interpretation. METHODS: Healthy children and adolescents (n = 1234) were recruited from a multiethnic population as part of the CALIPER study. After written informed parental consent was obtained, participants filled out a questionnaire including demographic and pubertal development information (assessed by self-reported Tanner stage) and provided a blood sample. We measured 7 fertility hormones including estradiol, testosterone (second generation), progesterone, sex hormone-binding globulin, prolactin, follicle-stimulating hormone, and luteinizing hormone by use of the Abbott Architect i2000 analyzer. We then used these data to calculate age-, gender-, and Tanner stage-specific reference intervals according to Clinical Laboratory Standards Institute C28-A3 guidelines. RESULTS: We observed a complex pattern of change in each analyte concentration from the neonatal period to adolescence. Consequently, many age and sex partitions were required to cover the changes in most fertility hormones over this period. An exception to this was prolactin, for which no sex partition and only 3 age partitions were necessary. CONCLUSIONS: This comprehensive database of pediatric reference intervals for fertility hormones will be of global benefit and should lead to improved diagnosis of pediatric endocrinopathies. The new database will need to be validated in local populations and for other immunoassay platforms as recommended by the Clinical Laboratory Standards Institute. PMID- 23637250 TI - Lymphadenopathy. PMID- 23637251 TI - Gonococcal infections. PMID- 23637253 TI - Infant with growth failure, body asymmetry, and dysmorphic features. PMID- 23637252 TI - Index of suspicion. Case 1: Fever, dysuria, and abdominal pain and distension in a 3-year-old girl. Case 2: Behavioral changes and staring spells in a healthy 8 year-old boy. Case 3: Intermittent headaches, calf pain, and fatigue in a 6-year old boy. PMID- 23637255 TI - "Glomeruloid" follicular thyroid adenoma. PMID- 23637254 TI - Toward personalized medicine of lung cancer: response to nontargeted therapy in invasive pulmonary adenocarcinoma as a function of tumor cell differentiation. AB - We evaluated clinical parameters, histomorphology, and thyroid transcription factor 1 (TTF-1) immunoreactivity in 40 epidermal growth factor receptor (EGFR) mutation- and anaplastic lymphoma kinase (ALK) rearrangement-negative invasive pulmonary adenocarcinomas. Tumors were histomorphologically quantitated by a pulmonary pathologist and TTF-1 immunohistochemistry applied. EGFR mutation and ALK rearrangement status was determined with polymerase chain reaction/DNA sequencing and fluorescence in situ hybridization, respectively. Treatment response was related to type of treatment (P < .005) and clinical stage (P = .001). EGFR mutation- and ALK rearrangement-negative pulmonary adenocarcinomas containing papillary/micropapillary histology showed greater morphologic heterogeneity (P < .001), greater TTF-1 immunoreactivity (P = .004), and were more common in treatment responders (P < .05). These findings support that patients with pulmonary adenocarcinomas that are subject to nontargeted therapies may respond to treatment as a function of tumor cell differentiation with TTF-1 as a potential biomarker of this response. PMID- 23637257 TI - Carcinoma of the thyroid with Ewing/PNET family tumor elements: a tumor of unknown histogenesis. PMID- 23637256 TI - Carcinoma of the thyroid with ewing family tumor elements and favorable prognosis: report of a second case. AB - The rare reports of primary, nonneuroendocrine small cell carcinomas of the thyroid have not provided enough evidence to support the recognition of these tumors as an entity or to understand their etiopathogenesis. We report the second case of a primary, nonneuroendocrine small cell carcinoma of the thyroid displaying diffuse expression of cytokeratins, CD99, and p63, in the absence of vimentin expression, in a 24-year-old male who is alive without any signs of disease 13 years after total thyroidectomy and radioactive iodine. The tumor disclosed the EWSR1-FLI1 rearrangement, and we propose to designate it as a carcinoma of the thyroid with Ewing family tumor elements. PMID- 23637258 TI - Shortening of an anatomical stem, how short is short enough? An in vitro study of load transfer and primary stability. AB - An anatomical stem should be short enough to avoid distal locking and distal load transfer but long enough to ensure adequate primary stability of the stem. In this in vitro study, the cortical strains in the femur and the primary stability of the stem were measured after insertion of Anatomic Benoist Girard-I anatomical stems with gradually reduced stem length in six human cadaver femurs in order to find the optimal stem length. A shortening of 40-50 mm, corresponding to a stem extending 30-40 mm below the lesser trochanter, did not affect stem stability but nearly normalized the load distribution in the lower metaphysis and upper diaphysis. The large strain shielding observed in the calcar region was not influenced by shortening of the stem. PMID- 23637259 TI - Bone remodelling around uncemented metallic and ceramic acetabular components. AB - Stress shielding-induced bone resorption around cementless acetabular components has been indicated as a potential failure mechanism that may threaten long-term fixation. Using a bone remodelling algorithm in combination with three dimensional finite element models of intact and implanted pelvises and musculoskeletal loading during normal walking, the objectives of the study were to investigate the deviations in load transfer due to implantation and bone adaptation around cementless metallic and ceramic acetabular components. Variations in implant-bone interfacial condition affected strain shielding and bone remodelling; strain shielding was higher for the bonded condition as compared to the debonded condition. For bonded interfacial condition, severe bone resorption, 20%-50% bone density reduction, was observed within the acetabulum. Considering debonded implant-bone interface, bone density increase of 50%-60% was observed around the supero-posterior part of acetabulum, whereas bone density reductions were low (2%-15%) in other locations. The implant-bone interface appeared less likely to fail, post-operatively and after bone remodelling. Moreover, the implant-bone micromotion was found to be low, less than 100 um. Strain shielding and bone remodelling were almost similar for the metallic and ceramic components. Based on the results of this study, the ceramic acetabular component appeared to be a viable alternative to metal. PMID- 23637260 TI - Distal stem features improve the torsional resistance of long-stem cemented revision hip stems: an in vitro biomechanical study. AB - When proximal bone stock is compromised at revision hip arthroplasty, distal fixation is often relied upon for stability of the femoral component. In such circumstances, torsional forces can result in debonding and loosening. This study compared the torsional behaviour of a cemented, polished and featureless (plain) stem with cemented, polished stems featuring fins or flutes. The finned stem construct was found to be significantly stiffer than the fluted stem. The maximum torque of the finned and fluted stems was significantly higher than the plain stem, with no difference between the finned and fluted stems. Distal stem features may provide a more reliable and greater resistance to torque in polished, cemented revision hip stems. Finned stem features may also increase the stiffness of the construct. PMID- 23637261 TI - Titanium implant with nanostructured zirconia surface promotes maturation of peri implant bone in osseointegration. AB - The goal of the experiment outlined in this article is to improve upon noncemented methods of arthroplasty for clinical application in elderly patients. This was done by determining whether titanium implants with a novel nanostructured zirconia surface, which was created by ion beam-assisted deposition, would prevent impaired osseointegration of intramedullary implants in 1-year-old rats receiving a protein-deficient diet. Specifically, we asked whether the implant with the nanostructured zirconia surface would increase expression of markers of bone maturation within the remodeling of peri-implant woven bone. The control implants, which were made of commercially pure titanium, had a polished surface ex vivo but are known to acquire a microstructured titania surface in vivo. Ten 1-year-old rats received experimental implant (group A) and 10 had control (group B) implants. Ten 3-month-old rats received normal protein diet and the control implant (group C). Animals were euthanized 8 weeks after implantation, and transverse sections of femur-implant samples were used for histology, micro-computed tomography and immunohistochemical evaluations. In group B, the expression of alpha2beta1 and alpha5beta1 integrins, which are known to mediate osteoblast adhesion, glycosaminoglycans, heparan sulfate and chondroitin sulfate, was less than half of that in group C. Important to this study, the zirconia surface used in group A prevented these deficiencies. Therefore, these results indicate that nanostructured zirconia surface created on clinical implants by ion beam-assisted deposition may prevent impaired osseointegration in elderly patients by promoting quicker maturation of peri implant woven bone. PMID- 23637262 TI - Effect of simplifications of bone and components inclination on the elastohydrodynamic lubrication modeling of metal-on-metal hip resurfacing prosthesis. AB - It is important to study the lubrication mechanism of metal-on-metal hip resurfacing prosthesis in order to understand its overall tribological performance, thereby minimize the wear particles. Previous elastohydrodynamic lubrication studies of metal-on-metal hip resurfacing prosthesis neglected the effects of the orientations of the cup and head. Simplified pelvic and femoral bone models were also adopted for the previous studies. These simplifications may lead to unrealistic predictions. For the first time, an elastohydrodynamic lubrication model was developed and solved for a full metal-on-metal hip resurfacing arthroplasty. The effects of the orientations of components and the realistic bones on the lubrication performance of metal-on-metal hip resurfacing prosthesis were investigated by comparing the full model with simplified models. It was found that the orientation of the head played a very important role in the prediction of pressure distributions and film profiles of the metal-on-metal hip resurfacing prosthesis. The inclination of the hemispherical cup up to 45 degrees had no appreciable effect on the lubrication performance of the metal-on-metal hip resurfacing prosthesis. Moreover, the combined effect of material properties and structures of bones was negligible. Future studies should focus on higher inclination angles, smaller coverage angle and microseparation related to the occurrences of edge loading. PMID- 23637263 TI - Wear of 36-mm BIOLOX(R) delta ceramic-on-ceramic bearing in total hip replacements under edge loading conditions. AB - Ceramic-on-ceramic bearings have become of great interest due to the substantial improvements in the manufacturing techniques and material properties and due to polyethylene wear debris-induced osteolysis and the issues with metal wear debris and ion release by metal-on-metal bearings. Edge loading conditions due to translational malpositioning (microseparation conditions) have been shown to replicate clinically relevant wear mechanisms and increase the wear of ceramic-on ceramic bearings; thus, it was necessary to test new bearing materials and designs under these adverse conditions. The aim of this study was to assess the effect of increasing head size on the wear of BIOLOX((r)) delta ceramic-on ceramic bearings under edge loading conditions due to rotational (steep cup inclination angle) and translational (microseparation) malpositioning. In this study, six 36-mm ceramic-on-ceramic bearings (BIOLOX delta, CeramTec, Germany) were tested under standard and edge loading conditions using the Leeds II hip simulator and compared to the 28-mm bearings tested and published previously under identical conditions. The mean wear rate under standard gait conditions was below 0.1 mm(3)/million cycles for both the 28-mm and the 36-mm ceramic-on ceramic bearings, and increasing the inclination angle did not affect the wear rates. The introduction of microseparation to the gait cycle increased the wear rate of ceramic-on-ceramic bearing and resulted in stripe wear on the femoral heads. Under microseparation conditions, the wear rate of size 36-mm bearings (0.22 mm(3)/million cycles) was significantly higher (p = 0.004) than that for size 28-mm bearings (0.13 mm(3)/million cycles). This was due to the larger contact area for the larger bearings and deprived lubrication under edge loading conditions. The wear rate of BIOLOX delta ceramic-on-ceramic bearings under microseparation conditions was still very low (<0.25 mm(3)/million cycles) compared to earlier generation ceramic-on-ceramic bearings (BIOLOX forte, 1.84 mm(3)/million cycles) and other bearing materials such as metal-on-metal bearings (2-8 mm(3)/million cycles). PMID- 23637264 TI - Effect of centers of rotation on spinal loads and muscle forces in total disk replacement of lumbar spine. AB - The placement of artificial disks can alter the center of rotation and kinematic pattern; therefore, forces in the spine during the motion will be affected as a result. The relationship between the location of joint center of artificial disks and forces in the spinal components is not investigated. A musculoskeletal model of the spine was developed, and three location cases of center of rotation were investigated varying 5 mm anteriorly and posteriorly from the default center. Resultant joint forces, ligament forces, facet forces, and muscle forces for each case were predicted during sagittal motion. No considerable difference was observed for joint force (maximum 14%). Anterior shift of center of rotation induced the most ligament forces (200 N) and facet forces (130 N) among the three cases. Posterior and anterior shifts of centers of rotation from the default location caused considerable changes in muscle forces, respectively: 108% and 70% of increase in multifidi muscle and 157% and 187% of increase in short segmental muscle. This study showed that the centers of rotation due to the design and the surgical placement of artificial disk can affect the kinetic results in the spine. PMID- 23637265 TI - Using additive manufacturing in accuracy evaluation of reconstructions from computed tomography. AB - Bone models derived from patient imaging and fabricated using additive manufacturing technology have many potential uses including surgical planning, training, and research. This study evaluated the accuracy of bone surface reconstruction of two diarthrodial joints, the hip and shoulder, from computed tomography. Image segmentation of the tomographic series was used to develop a three-dimensional virtual model, which was fabricated using fused deposition modelling. Laser scanning was used to compare cadaver bones, printed models, and intermediate segmentations. The overall bone reconstruction process had a reproducibility of 0.3 +/- 0.4 mm. Production of the model had an accuracy of 0.1 +/- 0.1 mm, while the segmentation had an accuracy of 0.3 +/- 0.4 mm, indicating that segmentation accuracy was the key factor in reconstruction. Generally, the shape of the articular surfaces was reproduced accurately, with poorer accuracy near the periphery of the articular surfaces, particularly in regions with periosteum covering and where osteophytes were apparent. PMID- 23637267 TI - Simulation of active skeletal muscle tissue with a transversely isotropic viscohyperelastic continuum material model. AB - Human body models with biofidelic kinematics in vehicle pre-crash and crash simulations require a constitutive model of muscle tissue with both passive and active properties. Therefore, a transversely isotropic viscohyperelastic continuum material model with element-local fiber definition and activation capability is suggested for use with explicit finite element codes. Simulations of experiments with New Zealand rabbit's tibialis anterior muscle at three different strain rates were performed. Three different active force-length relations were used, where a robust performance of the material model was observed. The results were compared with the experimental data and the simulation results from a previous study, where the muscle tissue was modeled with a combination of discrete and continuum elements. The proposed material model compared favorably, and integrating the active properties of the muscle into a continuum material model opens for applications with complex muscle geometries. PMID- 23637268 TI - An integrated approach towards future ballistic neck protection materials selection. AB - Ballistic protection for the neck has historically taken the form of collars attached to the ballistic vest (removable or fixed), but other approaches, including the development of prototypes incorporating ballistic material into the collar of an under body armour shirt, are now being investigated. Current neck collars incorporate the same ballistic protective fabrics as the soft armour of the remaining vest, reflecting how ballistic protective performance alone has historically been perceived as the most important property for neck protection. However, the neck has fundamental differences from the thorax in terms of anatomical vulnerability, flexibility and equipment integration, necessitating a separate solution from the thorax in terms of optimal materials selection. An integrated approach towards the selection of the most appropriate combination of materials to be used for each of the two potential designs of future neck protection has been developed. This approach requires evaluation of the properties of each potential material in addition to ballistic performance alone, including flexibility, mass, wear resistance and thermal burden. The aim of this article is to provide readers with an overview of this integrated approach towards ballistic materials selection and an update of its current progress in the development of future ballistic neck protection. PMID- 23637266 TI - Rotator cuff repair: a biomechanical ex vivo ovine study. AB - The purpose of this study was to assess load to failure of sutures, suturing techniques, and suture anchors used in rotator cuff surgery in order to explore their weaknesses. Ten types of sutures (absorbable and nonabsorbable), four types of suturing techniques, and eight types of suture anchors (bioabsorbable and metallic) were tested. Material Testing Machine and attached load cell were used to test the biomaterials in ex vivo ovine tissues. The results show that the mean load to failure and stiffness were higher in nonabsorbable sutures. Massive cuff tear and modified Mason-Allen suturing techniques had higher failure strength and stiffness when compared to simple and mattress techniques, but there was no substantial difference between them. Metallic suture anchors had higher failure strength when compared to bioabsorbable ones. Often either in metallic or in bioabsorbable anchors, the eyelet fails first. The failure sequence in ovine tissues is found to be in the following order: simple and mattress suturing techniques, nonabsorbable sutures, massive cuff tear and modified Mason-Allen suturing techniques, bioabsorbable anchors, and metallic anchors. Thus, it is concluded that metallic anchors mounted with modern nonabsorbable sutures will fail last. If we use simple and mattress techniques, the tendon-suture level will fail first, but it will improve substantially using more sophisticated suturing techniques (massive cuff tear or modified Mason-Allen). PMID- 23637269 TI - Does microcalcification increase the risk of rupture? AB - Rupture of atherosclerotic plaque, which is related to maximal stress conditions in the plaque among others, is a major cause of mortality. More careful examination of stress distributions in atherosclerotic plaques reports that it could be due to local stress behaviors at critical sites caused by cap thinning, inflammation, macroscopic heterogeneity, and recently, the presence of microcalcifications. However, the role of microcalcifications is not yet fully understood, and most finite element models of blood vessels with atheroma plaque ignore the heterogeneity of the plaque constituents at the microscale. The goal of this work is to investigate the effect of microcalcifications on the stress field of an atheroma plaque vessel section. This is achieved by performing a parametric finite element study, assuming a plane strain hypothesis, of a coronary artery section with eccentric atheroma plaque and one microcalcification incorporated. The geometrical parameters used to define and design the idealized coronary plaque anatomy and the microcalcification were the fibrous cap thickness and the microcalcification ratio, angle and eccentricity. We could conclude that microcalcifications should be considered in the modeling of this kind of problems since they cause a significant alteration of the vulnerable risk by increasing the maximum maximal principal stress up to 32%, although this increase of stress is not uniform (12% on average). The obtained results show that the fibrous cap thickness, the microcalcification ratio and the microcalcification eccentricity, in combination with the microcalcification angle, appear to be the key morphological parameters that play a determinant role in the maximal principal stress and accordingly in the rupture risk of the plaque. PMID- 23637270 TI - Comparative wear tests of ultra-high molecular weight polyethylene and cross linked polyethylene. AB - Wear particle-induced osteolysis is a major concern in hip implant failure. Therefore, recent research work has focussed on wear-resistant materials, one of the most important of which is cross-linked polyethylene. In view of this, the objective of this study was to compare the in vitro wear performance of cross linked polyethylene to traditional ultra-high molecular weight polyethylene. In order to mimic appropriate in vivo conditions, a novel high-capacity wear tester called a circularly translating pin-on-disc was used. The results of this in vitro study demonstrated that the wear rate for cross-linked polyethylene was about 80% lower than that of conventional ultra-high molecular weight polyethylene. This difference closely matches in vivo results reported in the literature for total hip replacements that use the two biopolymers. The in vitro results were also verified against ASTM F732-00 (standard test method for wear testing of polymeric materials for use in total joint prostheses). The 50-station circularly translating pin-on-disc proved to be a reliable device for in vitro wear studies of orthopaedic biopolymers. PMID- 23637271 TI - Measurement of the uniaxial mechanical properties of rat brains infected by Plasmodium berghei ANKA. AB - Degenerative and demyelinating diseases are known to alter the mechanical properties of brain tissue. While few studies have characterized these biomechanical changes, it is clear that accurate characterization of the mechanical properties of diseased brain tissue could be a substantial asset to neuronavigation and surgery simulation through haptic devices. In this study, samples of brain tissue from rats infected with Plasmodium berghei ANKA, an African murine malaria parasite, are evaluated using a uniaxial tensile test machine. Infected brains having different levels of parasitemia are mounted on the testing machine and extended until failure of the tissue. The stress-strain curve of each sample is obtained and compared to healthy rat brain tissue. Young's modulus of each sample is extracted from the Hookean part of the stress strain diagram. Young's modulus of rats' brain shows considerable difference among the samples having various levels of parasitemia compared with the controls. For instance, the brains with 0% (control), 1.5%, and 9% parasitemia showed a Young's modulus of 46.15, 54.54, and 266.67 kPa, respectively. This suggests sequestration of the stiffened and less deformable parasitized red blood cells in the brain microvasculature. PMID- 23637272 TI - Long-term effects of monocular deprivation revealed with binocular rivalry gratings modulated in luminance and in color. AB - During development, within a specific temporal window called the critical period, the mammalian visual cortex is highly plastic and literally shaped by visual experience; to what extent this extraordinary plasticity is retained in the adult brain is still a debated issue. We tested the residual plastic potential of the adult visual cortex for both achromatic and chromatic vision by measuring binocular rivalry in adult humans following 150 minutes of monocular patching. Paradoxically, monocular deprivation resulted in lengthening of the mean phase duration of both luminance-modulated and equiluminant stimuli for the deprived eye and complementary shortening of nondeprived phase durations, suggesting an initial homeostatic compensation for the lack of information following monocular deprivation. When equiluminant gratings were tested, the effect was measurable for at least 180 minutes after reexposure to binocular vision, compared with 90 minutes for achromatic gratings. Our results suggest that chromatic vision shows a high degree of plasticity, retaining the effect for a duration (180 minutes) longer than that of the deprivation period (150 minutes) and twice as long as that found with achromatic gratings. The results are in line with evidence showing a higher vulnerability of the P pathway to the effects of visual deprivation during development and a slower development of chromatic vision in humans. PMID- 23637273 TI - Labor market trends among registered nurses: 2008-2011. AB - This study uses recent data from the Bureau of Labor Statistics (BLS) and Registered Nurses (RNs) licensing exam to examine the recession's effect on the RN labor market. It then reports results of a survey of 518 hospital nursing officers conducted in 2008 and 2010 matched with institutional data from the American Hospital Association (AHA). These unique data show how the recession led hospitals to slow hiring despite accelerating attrition of retirement-age nurses; shift away from H1-B, agency, and, overtime work; and reduce training, and other benefits for new hires. More broadly, results show how nurse-staffing practices adapt to market conditions. Results also suggest reduced hospital support for nursing education may strain the supply of managerial and specialty nurses as baby-boom nurses retire. PMID- 23637274 TI - Prognostic value of serum paraoxonase and arylesterase activity in patients with sepsis. AB - OBJECTIVE: To determine whether serum paraoxonase (PON) and arylesterase (ARE) activity might predict sepsis mortality. METHODS: Patients with sepsis and healthy control subjects were enrolled in this retrospective study. Serum PON and ARE activity levels were measured. Patients were stratified according to 30-day mortality rates. RESULTS: Serum PON and ARE activity levels were significantly lower in patients with sepsis (n = 61) than in healthy controls (n = 32), and were significantly lower in nonsurviving patients (n = 22) than in surviving patients (n = 39). Low PON and ARE activity levels were significantly correlated with poor overall survival in patients with sepsis. CONCLUSIONS: Decreased serum PON and ARE activity is related to poor prognosis in patients with sepsis. Measuring the activity of PON and ARE may represent a new method for evaluating the prognosis of sepsis. In addition, both PON and ARE are potential molecular treatment targets for sepsis. PMID- 23637276 TI - Efficacy of shellac, a natural product, for the prevention of wet gangrene. AB - OBJECTIVE: To determine the effects of applying a natural polymer solution (shellac) to dry gangrene, and thereby prevent infection and progression to wet gangrene, in diabetic patients. METHODS: This randomized, controlled, pilot study included patients with type 2 diabetes mellitus who had unreconstructable peripheral vascular disease and were awaiting autoamputation. Eligible patients were contraindicated for surgery, had a limited life expectancy and/or had refused surgical amputations. All patients received the best possible medical treatment and were randomized to receive either topical shellac or antiseptic application of 10% povidone-iodine (PVP-I) solution to gangrenous areas. RESULTS: A total of 26 diabetic patients were eligible for inclusion, of whom 23 completed the study: 13 were treated with shellac and 10 with PVP-I. The amputation rate was higher in the conventional treatment group versus the shellac group (60.0% versus 46.2%, respectively), although this difference was not statistically significant. CONCLUSIONS: Shellac is a natural solution that may be used to embalm gangrenous tissue in selected diabetic patients. More studies are needed to assess the long-term outcomes of this technique. PMID- 23637275 TI - Value of D-dimer and protein S for diagnosis of portal vein thrombosis in patients with liver cirrhosis. AB - OBJECTIVE: To investigate the value of D-dimer and protein S plasma concentrations for diagnosis of portal vein thrombosis (PVT) in patients with liver cirrhosis. METHODS: D-dimer and protein S were quantified, PVT was diagnosed by dynamic enhanced computed tomography and liver function was classified using the Child-Pugh system. Receiver operating curve analysis was performed. RESULTS: D-dimer increased, and protein S decreased, with decreasing liver function in the total study population (n = 188). D-dimer concentrations were significantly higher and protein S concentrations were significantly lower in patients with (n = 51) than those without PVT (n = 137). D-dimer had high specificity and negative predictive value (NPV) in Child-Pugh class A or B patients (cut-off values>0.56 mg/l and >1.18 mg/l, respectively). In class C patients>0.77 mg/l D-dimer had high sensitivity and NPV. Protein S had high sensitivity but low specificity in class A or B patients (cut-off values < 17.4 mg/l and <19.2 mg/l, respectively). CONCLUSION: Plasma D-dimer and protein S are potential biomarkers for PVT diagnosis in patients with cirrhosis. PVT can be excluded when D-dimer is low and protein S is elevated. PMID- 23637277 TI - Generational changes in materialism and work centrality, 1976-2007: associations with temporal changes in societal insecurity and materialistic role modeling. AB - We examined whether culture-level indices of threat, instability, and materialistic modeling were linked to the materialistic values of American 12th graders between 1976 and 2007 (N = 355,296). Youth materialism (such as the importance of money and of owning expensive material items) increased over the generations, peaking in the late 1980s to early 1990s with Generation X and then staying at historically high levels for Millennials (GenMe). Societal instability and disconnection (e.g., unemployment, divorce) and social modeling (e.g., advertising spending) had both contemporaneous and lagged associations with higher levels of materialism, with advertising most influential during adolescence and instability during childhood. Societal-level living standards during childhood predicted materialism 10 years later. When materialistic values increased, work centrality steadily declined, suggesting a growing discrepancy between the desire for material rewards and the willingness to do the work usually required to earn them. PMID- 23637278 TI - Twenty-year route of prevalence of risk factors, treatment patterns, complications, and mortality rate of acute myocardial infarction in Iran. AB - OBJECTIVES: Coronary artery diseases are regarded as the main cause of mortality in most countries. The present study aims at evaluating variations and studying its complications in Iranian patients within past 20 years. METHODS: This cross sectional analytical-descriptive study retrospectively evaluated the files of 600 patients with acute myocardial infarction during a 20-year period. Basic data and laboratory information, chemotherapies and intervention treatments of patients were registered in special forms and compared regarding the mentioned time intervals. RESULTS: There were 440 (73.3%) male and 160 (26.7%) female patients and mean age of the patients was 60.03 +/- 11.61 years. Mean duration of hospitalization (p < 0.001) and prevalence of smoking (p < 0.001) had significantly decreased in the past two decades. There was no meaningful difference when considering mortality rate (p = 0.533) and cardiac insufficiency (p = 0.403). CONCLUSION: The results indicate prominent improvement in the management process of patients suffering from acute myocardial infarction within the past 20 years. PMID- 23637279 TI - A heat and moisture mask attenuates cardiovascular stress during cold air exposure. AB - BACKGROUND: Exposure to cold has been shown to cause cardiovascular stress and increased morbidity and mortality. Inhalation of cold, dry air can increase blood pressure and induce myocardial ischemia, particularly in people with preexisting hypertensive cardiovascular disease. Face masks that can warm and humidify inhaled cold air may reduce these cold air pressor effects. METHOD: We compared blood pressure measurements using a heat and moisture exchange mask (HME), a placebo mask (PL), and no mask (NM) in 53 patients with hypertension exposed to a cold chamber environment at -5 degrees C for 1 h. Blood pressure and heart rate were recorded at baseline, and at 15 min intervals from 0 to 60 min of chamber exposure. All patients were taking antihypertensive medications with drug and dosage determined by their own physicians. Data were analyzed by a one-way analysis of variance test with repeated measures, and significant interactions were analyzed by Fisher's least significant differences tests. A post hoc subgroup analysis for the effect of age was performed using Wilcoxon matched-pair rank tests. RESULTS: Wearing the HME resulted in significantly lower systolic and mean arterial blood pressures than the PL and NM conditions. Diastolic blood pressures were significantly lower for the HME than the NM, but not the PL condition. CONCLUSION: Subgroup analyses suggested that the effect of the HME in mitigating systolic blood pressure increase from inhalation of cold air was significantly greater for patients aged 60 years or over than for those under 60 years. PMID- 23637280 TI - Death receptor-ligand systems in cancer, cell death, and inflammation. AB - The discovery of tumor necrosis factor (TNF) marked the beginning of one of the most fascinating journeys in modern biomedical research. For the moment, this journey has culminated in the development of drugs that inhibit TNF. TNF blockers have revolutionized the treatment of many chronic inflammatory diseases. Yet, the journey seems far from over. TNF is the founding member of a family of cytokines with crucial functions in cell death, inflammation, and cancer. Some of these factors, most prominently TNF, CD95L, and TRAIL, can induce cell death. The receptors that mediate this signal are therefore referred to as death receptors, even though they also activate other signals. Here I will take you on a journey into the discovery and study of death receptor-ligand systems and how this inspired new concepts in cancer therapy and our current understanding of the interplay between cell death and inflammation. PMID- 23637281 TI - The role of MuSK in synapse formation and neuromuscular disease. AB - Muscle-specific kinase (MuSK) is essential for each step in neuromuscular synapse formation. Before innervation, MuSK initiates postsynaptic differentiation, priming the muscle for synapse formation. Approaching motor axons recognize the primed, or prepatterned, region of muscle, causing motor axons to stop growing and differentiate into specialized nerve terminals. MuSK controls presynaptic differentiation by causing the clustering of Lrp4, which functions as a direct retrograde signal for presynaptic differentiation. Developing synapses are stabilized by neuronal Agrin, which is released by motor nerve terminals and binds to Lrp4, a member of the low-density lipoprotein receptor family, stimulating further association between Lrp4 and MuSK and increasing MuSK kinase activity. In addition, MuSK phosphorylation is stimulated by an inside-out ligand, docking protein-7 (Dok-7), which is recruited to tyrosine-phosphorylated MuSK and increases MuSK kinase activity. Mutations in MuSK and in genes that function in the MuSK signaling pathway, including Dok-7, cause congenital myasthenia, and autoantibodies to MuSK, Lrp4, and acetylcholine receptors are responsible for myasthenia gravis. PMID- 23637282 TI - The mitochondrial nucleoid: integrating mitochondrial DNA into cellular homeostasis. AB - The packaging of mitochondrial DNA (mtDNA) into DNA-protein assemblies called nucleoids provides an efficient segregating unit of mtDNA, coordinating mtDNA's involvement in cellular metabolism. From the early discovery of mtDNA as "extranuclear" genetic material, its organization into nucleoids and integration into both the mitochondrial organellar network and the cell at large via a variety of signal transduction pathways, mtDNA is a crucial component of the cell's homeostatic network. The mitochondrial nucleoid is composed of a set of DNA-binding core proteins involved in mtDNA maintenance and transcription, and a range of peripheral factors, which are components of signaling pathways controlling mitochondrial biogenesis, metabolism, apoptosis, and retrograde mitochondria-to-nucleus signaling. The molecular interactions of nucleoid components with the organellar network and cellular signaling pathways provide exciting clues to the dynamic integration of mtDNA into cellular metabolic homeostasis. PMID- 23637283 TI - The maintenance of mitochondrial DNA integrity--critical analysis and update. AB - DNA molecules in mitochondria, just like those in the nucleus of eukaryotic cells, are constantly damaged by noxious agents. Eukaryotic cells have developed efficient mechanisms to deal with this assault. The process of DNA repair in mitochondria, initially believed nonexistent, has now evolved into a mature area of research. In recent years, it has become increasingly appreciated that mitochondria possess many of the same DNA repair pathways that the nucleus does. Moreover, a unique pathway that is enabled by high redundancy of the mitochondrial DNA and allows for the disposal of damaged DNA molecules operates in this organelle. In this review, we attempt to present a unified view of our current understanding of the process of DNA repair in mitochondria with an emphasis on issues that appear controversial. PMID- 23637287 TI - The role of the endoplasmic reticulum in peroxisome biogenesis. AB - Peroxisomes are essential cellular organelles involved in lipid metabolism. Patients affected by severe peroxisome biogenesis disorders rarely survive their first year. Genetic screens in several model organisms have identified more than 30 PEX genes that are required for the formation of functional peroxisomes. Despite significant work on the PEX genes, the biogenic origin of peroxisomes remains controversial. For at least two decades, the prevailing model postulated that peroxisomes propagate by growth and fission of preexisting peroxisomes. In this review, we focus on the recent evidence supporting a new, semiautonomous model of peroxisomal biogenesis. According to this model, peroxisomal membrane proteins (PMPs) traffic from the endoplasmic reticulum (ER) to the peroxisome by a vesicular budding, targeting, and fusion process while peroxisomal matrix proteins are imported into the organelle by an autonomous, posttranslational mechanism. We highlight the contradictory conclusions reached to answer the question of how PMPs are inserted into the ER. We then review what we know and what still remains to be elucidated about the mechanism of PMP exit from the ER and the contribution of preperoxisomal vesicles to mature peroxisomes. Finally, we discuss discrepancies in our understanding of de novo peroxisome biogenesis in wild-type cells. We anticipate that resolving these key issues will lead to a more complete picture of peroxisome biogenesis. PMID- 23637285 TI - Rescuing stalled or damaged replication forks. AB - In recent years, an increasing number of studies have shown that prokaryotes and eukaryotes are armed with sophisticated mechanisms to restart stalled or collapsed replication forks. Although these processes are better understood in bacteria, major breakthroughs have also been made to explain how fork restart mechanisms operate in eukaryotic cells. In particular, repriming on the leading strand and fork regression are now established as critical for the maintenance and recovery of stalled forks in both systems. Despite the lack of conservation between the factors involved, these mechanisms are strikingly similar in eukaryotes and prokaryotes. However, they differ in that fork restart occurs in the context of chromatin in eukaryotes and is controlled by multiple regulatory pathways. PMID- 23637286 TI - Protein folding in the endoplasmic reticulum. AB - In this article, we will cover the folding of proteins in the lumen of the endoplasmic reticulum (ER), including the role of three types of covalent modifications: signal peptide removal, N-linked glycosylation, and disulfide bond formation, as well as the function and importance of resident ER folding factors. These folding factors consist of classical chaperones and their cochaperones, the carbohydrate-binding chaperones, and the folding catalysts of the PDI and proline cis-trans isomerase families. We will conclude with the perspective of the folding protein: a comparison of characteristics and folding and exit rates for proteins that travel through the ER as clients of the ER machinery. PMID- 23637284 TI - Repair of double-strand breaks by end joining. AB - Nonhomologous end joining (NHEJ) refers to a set of genome maintenance pathways in which two DNA double-strand break (DSB) ends are (re)joined by apposition, processing, and ligation without the use of extended homology to guide repair. Canonical NHEJ (c-NHEJ) is a well-defined pathway with clear roles in protecting the integrity of chromosomes when DSBs arise. Recent advances have revealed much about the identity, structure, and function of c-NHEJ proteins, but many questions exist regarding their concerted action in the context of chromatin. Alternative NHEJ (alt-NHEJ) refers to more recently described mechanism(s) that repair DSBs in less-efficient backup reactions. There is great interest in defining alt-NHEJ more precisely, including its regulation relative to c-NHEJ, in light of evidence that alt-NHEJ can execute chromosome rearrangements. Progress toward these goals is reviewed. PMID- 23637289 TI - Polyclonal outbreak of KPC-3-producing Enterobacter cloacae at a single hospital in Montreal, Quebec, Canada. AB - From September 2010 to December 2011, 26 KPC-3-producing Enterobacter cloacae isolates were identified from 16 patients at a single hospital. Analyses revealed the blaKPC gene to be localized on multiple plasmids in a diverse nonclonal E. cloacae genetic background. These findings highlight the potential complexity of a KPC outbreak at a single hospital. PMID- 23637290 TI - Chemical decontamination with N-acetyl-L-cysteine-sodium hydroxide improves recovery of viable Mycobacterium avium subsp. paratuberculosis organisms from cultured milk. AB - Mycobacterium avium subsp. paratuberculosis is shed into the milk and feces of cows with advanced Johne's disease, allowing the transmission of M. avium subsp. paratuberculosis between animals. The objective of this study was to formulate an optimized protocol for the isolation of M. avium subsp. paratuberculosis in milk. The parameters investigated included chemical decontamination with N-acetyl-l cysteine-sodium hydroxide (NALC-NaOH), alone and in combination with antibiotics (vancomycin, amphotericin B, and nalidixic acid), and the efficacy of solid (Herrold's egg yolk medium [HEY]) and liquid (Bactec 12B and para-JEM) culture media. For each experiment, raw milk samples from a known noninfected cow were inoculated with 10(2) to 10(8) CFU/ml of live M. avium subsp. paratuberculosis organisms. The results indicate that an increased length of exposure to NALC-NaOH from 5 to 30 min and an increased concentration of NaOH from 0.5 to 2.0% did not affect the viability of M. avium subsp. paratuberculosis. Additional treatment of milk samples with the antibiotics following NALC-NaOH treatment decreased the recovery of viable M. avium subsp. paratuberculosis cells more than treatment with NALC-NaOH alone. The Bactec 12B medium was the superior medium of the three evaluated for the isolation of M. avium subsp. paratuberculosis from milk, as it achieved the lowest threshold of detection. The optimal conditions for NALC-NaOH decontamination were determined to be exposure to 1.50% NaOH for 15 min followed by culture in Bactec 12B medium. This study demonstrates that chemical decontamination with NALC-NaOH resulted in a greater recovery of viable M. avium subsp. paratuberculosis cells from milk than from samples treated with hexadecylpyridinium chloride (HPC). Therefore, it is important to optimize milk decontamination protocols to ensure that low concentrations of M. avium subsp. paratuberculosis can be detected. PMID- 23637288 TI - Endocytosis of receptor tyrosine kinases. AB - Endocytosis is the major regulator of signaling from receptor tyrosine kinases (RTKs). The canonical model of RTK endocytosis involves rapid internalization of an RTK activated by ligand binding at the cell surface and subsequent sorting of internalized ligand-RTK complexes to lysosomes for degradation. Activation of the intrinsic tyrosine kinase activity of RTKs results in autophosphorylation, which is mechanistically coupled to the recruitment of adaptor proteins and conjugation of ubiquitin to RTKs. Ubiquitination serves to mediate interactions of RTKs with sorting machineries both at the cell surface and on endosomes. The pathways and kinetics of RTK endocytic trafficking, molecular mechanisms underlying sorting processes, and examples of deviations from the standard trafficking itinerary in the RTK family are discussed in this work. PMID- 23637291 TI - First report of Nocardia asiatica olecranon bursitis in an immunocompetent traveler returning to Austria. AB - Nocardia spp. are rarely isolated in extrapulmonary clinical specimens. We describe the first case of olecranon bursitis caused by Nocardia asiatica. The patient, a traveler returning from Thailand, was successfully treated with linezolid. PMID- 23637292 TI - Comparison of a real-time PCR method with serology and blood smear analysis for diagnosis of human anaplasmosis: importance of infection time course for optimal test utilization. AB - Anaplasmosis and ehrlichiosis are emerging tick-borne diseases with clinically similar presentations caused by closely related pathogens. Currently, laboratories rely predominantly on blood smear analysis (for the detection of intracellular morulae) and on serologic tests, both of which have recognized limitations, for diagnostic purposes. We compared the performance of a published real-time PCR assay that incorporates melt curve analysis to differentiate Anaplasma and Ehrlichia species with blood smear and serologic methods in an upper Midwest population. Overall, 38.5% of the specimens selected for evaluation had one or more tests that were positive for anaplasmosis. The PCR positivity for all specimens was maximal (21.2%; 29/137) during the early acute phase of illness (0 to 4 days since illness onset) and significantly less frequent (11.5%; 20/174) during later phases (>4 days since illness onset). All positive specimens were Anaplasma phagocytophilum; no Ehrlichia species were identified. The real-time PCR detected 100% of infections that were detected by blood smear analysis (14/14) and broadened the detection window from a maximum of 14 days for smear positivity to 30 days for PCR. Additional infections were detected by real-time PCR in 12.9% (11/85) of smear-negative patients. There was poor agreement between the real-time PCR assay and serologic test results: 19.8% (19/96) and 13.7% (29/212) of seropositive and -negative patients, respectively, were PCR positive. Seropositivity increased with increasing days of illness, demonstrating that serologic detection methods are best utilized during presumed convalescence. Our results indicate that the optimal performance and utilization of laboratory tests for the diagnosis of anaplasmosis require knowledge regarding time of symptom onset or days of illness. PMID- 23637294 TI - Bovine papillomavirus type 13 DNA in equine sarcoids. AB - Equine sarcoids are locally aggressive fibroblastic neoplasms considered to be the most common skin tumors of horses worldwide. Bovine papillomavirus types 1 and 2 have typically been associated with sarcoids in equids. Investigations aiming to identify papillomavirus strains, aside from bovine papillomaviruses 1 and 2, which might be associated with sarcoid lesions, have been lacking. The aim of this article is to report the identification of a third bovine papillomavirus type, bovine papillomavirus 13, associated with equine sarcoids. Six sarcoid lesions were collected from diverse anatomical sites on two horses from southern Brazil. To detect a broad spectrum of papillomavirus strains, eight degenerate primer pairs designed to detect conserved regions on the L1 and E1 genes were tested on the DNA samples. Direct sequencing was then performed on the obtained amplicons, and sequence identities were compared with sequences from all bovine papillomavirus types. The FAP59/FAP64, MY09/MY11, and AR-E1F2/AR-E1R4 sequences generated from the sarcoids were shown to present 99 to 100% identity with bovine papillomavirus 13, a new bovine papillomavirus type previously described in cattle. The results from this study suggest that there is a need to identify bovine papillomavirus type 13 and other papillomavirus strains that might be associated with sarcoids in diverse geographical areas; such investigations might establish the frequency of occurrence of this viral type in these common tumors of equids. PMID- 23637293 TI - Multiple-locus variable-number tandem-repeat analysis in genotyping Yersinia enterocolitica strains from human and porcine origins. AB - Sporadic and epidemiologically linked Yersinia enterocolitica strains (n = 379) isolated from fecal samples from human patients, tonsil or fecal samples from pigs collected at slaughterhouses, and pork samples collected at meat stores were genotyped using multiple-locus variable-number tandem-repeat analysis (MLVA) with six loci, i.e., V2A, V4, V5, V6, V7, and V9. In total, 312 different MLVA types were found. Similar types were detected (i) in fecal samples collected from human patients over 2 to 3 consecutive years, (ii) in samples from humans and pigs, and (iii) in samples from pigs that originated from the same farms. Among porcine strains, we found farm-specific MLVA profiles. Variations in the numbers of tandem repeats from one to four for variable-number tandem-repeat (VNTR) loci V2A, V5, V6, and V7 were observed within a farm. MLVA was applicable for serotypes O:3, O:5,27, and O:9 and appeared to be a highly discriminating tool for distinguishing sporadic and outbreak-related strains. With long-term use, interpretation of the results became more challenging due to variations in more discriminating loci, as was observed for strains originating from pig farms. Additionally, we encountered unexpectedly short V2A VNTR fragments and sequenced them. According to the sequencing results, updated guidelines for interpreting V2A VNTR results were prepared. PMID- 23637296 TI - Time profile of viral DNA in aqueous humor samples of patients treated for varicella-zoster virus acute retinal necrosis by use of quantitative real-time PCR. AB - The objective of this study was to evaluate the kinetics of varicella-zoster virus (VZV) loads using quantitative PCR (qPCR) in patients treated for acute retinal necrosis (ARN). Six patients (52 +/- 13 years old) with ARN syndrome were consecutively studied. Aqueous humor (AH) was sampled from both eyes of all patients for qPCR evaluation. The patients were treated with intravenous acyclovir and intravitreal injections of antiviral drugs. The mean follow-up time was 17.6 +/- 16.4 months. Main outcome measures were the numbers of viral genome copies in the AH, assessed using real-time qPCR with hydrolysis probe technology with a threshold of detection of 200 copies/ml. Two main portions of the viral load curves were observed for each patient: a plateau phase (27.8 +/- 24.9 days) and a decrease in the number of viral genome copies. The mean baseline viral load was 3.4 * 10(7) +/- 4.45 * 10(7) copies/ml (6 * 10(6) to 1.2 * 10(8) copies/ml). The viral load decreased according to a logarithmic model, with a 50% reduction obtained in 3 +/- 0.7 days. There was a significant viral load (>102 copies/ml) at 50 days after the onset of treatment, despite antiviral drugs. qPCR use demonstrated reproducible VZV DNA kinetics with a two-phase evolution: a plateau followed by a logarithmic decrease. These data suggest that high-dosage antiviral therapy administered for the conventional 10-day duration is insufficient for most patients. This series of patients responded with a similar decrease in viral load once treatment was initiated, and the data from these patients may be used to predict the responses of future patients. PMID- 23637295 TI - Human cryptosporidiosis diagnosed in Western Australia: a mixed infection with Cryptosporidium meleagridis, the Cryptosporidium mink genotype, and an unknown Cryptosporidium species. AB - This report describes a case of cryptosporidiosis from an immunocompetent patient from Perth, Western Australia, suffering from diarrhea and a spectrum of other symptoms. Molecular identification revealed that this patient was infected with three Cryptosporidium species-Cryptosporidium meleagridis, the Cryptosporidium mink genotype, and an unknown Cryptosporidium species. PMID- 23637298 TI - Development of an internally controlled real-time reverse transcriptase PCR assay for pan-dengue virus detection and comparison of four molecular dengue virus detection assays. AB - A number of diagnostic tests are available for dengue virus (DENV) detection, including a variety of nucleic acid amplification tests (NAATs). However, reports describing a direct comparison of different NAATs have been limited. In this study, we report the design of an internally controlled real-time reverse transcriptase PCR (rRT-PCR) that detects all four DENV serotypes but does not distinguish between them (the pan-DENV assay). Two hundred clinical samples were then tested using four different DENV RT-PCR assays: the pan-DENV assay, a commercially produced, internally controlled DENV rRT-PCR (the Altona assay), a widely used heminested RT-PCR, and a serotype-specific multiplex rRT-PCR assay. The pan-DENV assay had a linear range extending from 1.0 to 7.0 log10 cDNA equivalents/MUl and a lower limit of 95% detection ranging from 1.7 to 7.6 cDNA equivalents/MUl, depending on the serotype. When measured against a composite reference standard, the pan-DENV assay proved to be more clinically sensitive than either the Altona or heminested assays, with a sensitivity of 98.0% compared to 72.3% and 78.8%, respectively (P <= 0.0001 for both comparisons). The pan-DENV assay detected DENV in significantly more samples collected on or after day 5 of illness and in a subgroup of patients with detectable anti-DENV IgM at presentation. No significant difference in sensitivity was observed between the pan-DENV assay and the multiplex rRT-PCR, despite the presence of an internal control in the former. The detection of DENV RNA late in the course of clinical illness should serve to lengthen the period during which a confirmed molecular diagnosis of DENV infection can be provided. PMID- 23637299 TI - Brachyspira species and gastroenteritis in humans. AB - Brachyspira species have been implicated as a potential cause of gastroenteritis in humans; this is, however, controversial. In 733 gastroenteritis cases and 464 controls, we found 29 samples positive for Brachyspira species (2.3% of cases and 2.6% of controls; P = 0.77). Brachyspira species were not associated with gastroenteritis in humans. PMID- 23637297 TI - Clinical validation of the Abbott RealTime High Risk HPV assay according to the guidelines for human papillomavirus DNA test requirements for cervical screening. AB - This study showed that the Abbott RealTime High Risk HPV assay fulfilled cross sectional clinical equivalence and reproducibility criteria of international consensus guidelines, which indicates that this assay can be considered clinically validated for cervical cancer screening purposes. PMID- 23637303 TI - Epidemiological and clinical complexity of amoxicillin-clavulanate-resistant Escherichia coli. AB - Two hundred twelve patients with colonization/infection due to amoxicillin clavulanate (AMC)-resistant Escherichia coli were studied. OXA-1- and inhibitor resistant TEM (IRT)-producing strains were associated with urinary tract infections, while OXA-1 producers and chromosomal AmpC hyperproducers were associated with bacteremic infections. AMC resistance in E. coli is a complex phenomenon with heterogeneous clinical implications. PMID- 23637301 TI - Identification of rare pathogenic bacteria in a clinical microbiology laboratory: impact of matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - During the past 5 years, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (MS) has become a powerful tool for routine identification in many clinical laboratories. We analyzed our 11-year experience in routine identification of clinical isolates (40 months using MALDI-TOF MS and 91 months using conventional phenotypic identification [CPI]). Among the 286,842 clonal isolates, 284,899 isolates of 459 species were identified. The remaining 1,951 isolates were misidentified and required confirmation using a second phenotypic identification for 670 isolates and using a molecular technique for 1,273 isolates of 339 species. MALDI-TOF MS annually identified 112 species, i.e., 36 species/10,000 isolates, compared to 44 species, i.e., 19 species/10,000 isolates, for CPI. Only 50 isolates required second phenotypic identifications during the MALDI-TOF MS period (i.e., 4.5 reidentifications/10,000 isolates) compared with 620 isolates during the CPI period (i.e., 35.2/10,000 isolates). We identified 128 bacterial species rarely reported as human pathogens, including 48 using phenotypic techniques (22 using CPI and 37 using MALDI-TOF MS). Another 75 rare species were identified using molecular methods. MALDI-TOF MS reduced the time required for identification by 55-fold and 169-fold and the cost by 5-fold and 96-fold compared with CPI and gene sequencing, respectively. MALDI-TOF MS was a powerful tool not only for routine bacterial identification but also for identification of rare bacterial species implicated in human infectious diseases. The ability to rapidly identify bacterial species rarely described as pathogens in specific clinical specimens will help us to study the clinical burden resulting from the emergence of these species as human pathogens, and MALDI-TOF MS may be considered an alternative to molecular methods in clinical laboratories. PMID- 23637302 TI - Emergence of a new norovirus GII.4 variant and changes in the historical biennial pattern of norovirus outbreak activity in Alberta, Canada, from 2008 to 2013. AB - The public health impact of the emergence of new norovirus (NoV) strains is uncertain. A biennial pattern of alternating quiescent and epidemic levels of NoV outbreak activity associated with the emergence of new GII.4 variants was observed in Alberta, Canada, between July 2000 and June 2008. In this study, NoV genogroup I (GI) and GII strains isolated from 710 outbreak specimens in Alberta between July 2008 and January 2013 were characterized to update historical data. The seasonality and annual variation in NoV outbreak burden were analyzed over a 10-year period (July 2002 to June 2012). We found that GII.4-2006b had persisted as the predominant variant over three observation periods (July 2006 to June 2009) during which the biennial NoV outbreak pattern continued. The emergence of GII.4-2010 (winter 2009) was not associated with increased outbreak activity, and outbreak activity between July 2009 and June 2012 when GII.4-2010 predominated (67.5 to 97.7%) did not follow a biennial pattern. GII.4-2012 first emerged in Alberta in September 2011 and became predominant in observation period July 2012 to June 2013. NoV GI, relatively rare in past years, had a higher activity level (37.3%) as represented by GI.6 and GI.7 in the winter of 2012 to 2013. A higher proportion of GI outbreaks occurred in non-health care facility settings compared to GII. Our study suggests that factors other than new variants emergence contribute to the levels of NoV outbreak activity in Alberta. PMID- 23637304 TI - Impact of income inequality on life expectancy in a highly unequal developing country: the case of Brazil. AB - BACKGROUND: Few studies have analysed the effects of income inequality on health in developing countries, particularly during economic growth, reduction of social disparities and reinforcement of the welfare and healthcare system. We evaluated the association between income inequality and life expectancy in Brazil, including the effect of social and health interventions, in the period 2000-2009. METHODS: A panel dataset was created for the 27 Brazilian states over the referred time period. Multivariable linear regressions were performed using fixed effects estimation with heteroscedasticity and serial correlation robust SEs. Models were fitted for life expectancy as a dependent variable, using the Gini index or a percentile income dispersion ratio as the main independent variable, and for demographic, socioeconomic and healthcare-related determinants as covariates. RESULTS: The Gini index, as the other measure of income inequality, was negatively associated with life expectancy (p<0.05), even after adjustment for all the socioeconomic and health-related covariates. The Family Health Program, the main primary healthcare (PHC) programme of the country, was positively associated with life expectancy (p<0.05). CONCLUSIONS: In recent years, effective social policies have enabled Brazil to partially reduce absolute poverty and income inequality, contributing-together with PHC-to decreasing death rates in the population. Reducing income inequality may represent an important step towards improving health and increasing life expectancy, particularly in developing countries where inequalities are high. PMID- 23637300 TI - Development and evaluation of a next-generation digital PCR diagnostic assay for ocular Chlamydia trachomatis infections. AB - Droplet digital PCR (ddPCR) is an emulsion PCR process that performs absolute quantitation of nucleic acids. We developed a ddPCR assay for Chlamydia trachomatis infections and found it to be accurate and precise. Using PCR mixtures containing plasmids engineered to include the PCR target sequences, we were able to quantify with a dynamic range between 0.07 and 3,160 targets/MUl (r(2) = 0.9927) with >95% confidence. Using 1,509 clinical conjunctival swab samples from a population in which trachoma is endemic in Guinea Bissau, we evaluated the specificity and sensitivity of the quantitative ddPCR assay in diagnosing ocular C. trachomatis infections by comparing the performances of ddPCR and the Roche Amplicor CT/NG test. We defined ddPCR tests as positive when we had >=95% confidence in a nonzero estimate of target load. The sensitivity of ddPCR against Amplicor was 73.3% (95% confidence interval [CI], 67.9 to 78.7%), and specificity was 99.1% (95% CI, 98.6 to 99.6%). Negative and positive predictive values were 94.6% (95% CI, 93.4 to 95.8%) and 94.5% (95% CI, 91.3 to 97.7%), respectively. Based on Amplicor CT/NG testing, the estimated population prevalence of C. trachomatis ocular infection was ~17.5%. Receiver-operator curve analysis was used to select critical cutoff values for use in clinical settings in which a balance between higher sensitivity and specificity is required. We concluded that ddPCR is an effective diagnostic technology suitable for both research and clinical use in diagnosing ocular C. trachomatis infections. PMID- 23637305 TI - Investigation of neurotoxic and immunotoxic effects of some plant growth regulators at subacute and subchronic applications on rats. AB - The present study was aimed to investigate the effects of subacute and subchronic treatment of some plant growth regulators (PGRs), such as abscisic acid (ABA) and gibberellic acid (GA3), on neurological and immunological biomarkers in various tissues of rats. The activities of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) were selected as biomarkers for neurotoxic biomarkers. Adenosine deaminase (ADA) and myeloperoxidase (MPO) were measured as indicators for immunotoxic investigation purpose. Wistar albino rats were orally administered with 25 and 50 ppm of PGRs ad libitum for 25-50 days continuously with drinking water. The treatment of PGRs caused different effects on the activities of enzymes. Results showed that the administrations of ABA and GA3 increased AChE and BChE activities in some tissues of rats treated with both the dosages and periods of ABA and GA3. With regard to the immunotoxic effects, ADA activity fluctuated, while MPO activity increased after subacute and subchronic exposure of treated rat tissues to both dosages when compared with the controls. The observations presented led us to conclude that the administrations of PGRs at subacute and subchronic exposure increased AChE, BChE, and MPO activities, while fluctuating the ADA activity in various tissues of rats. This may reflect the potential role of these parameters as useful biomarkers for toxicity of PGRs. PMID- 23637306 TI - Renal and hepatotoxic alterations in adult mice on inhalation of specific mixture of organic solvents. AB - This study was aimed at investigating alterations in renal and hepatic toxicity induced by exposing to a combination of three solvents, namely, benzene, toluene and xylene in adult mice. The mice were divided into three groups (control, low dose-treated (450 ppm) and high-dose (675 ppm) groups) using randomization methods. The treated groups were exposed to vapours of a mixture of benzene, toluene and xylene at doses of 450 and 675 ppm, for 6 h day(-1) for a short-term of 7-day exposure period. The study revealed that the solvent exposure resulted in an increase in the weight of liver and kidney as compared to the control. Biochemical analyses indicated a significant decline in the activities of superoxide dismutase and catalase in both the treated groups, with concomitant increase in lipid peroxidation. Liver aminotransferases (alanine aminotransferase and aspartate aminotransferase) were elevated with significant alterations in the levels of protein, creatinine and cholesterol in these tissues upon solvent exposure. Correlated with these changes, serum thyroid hormones T3 and T4 were also significantly altered. This study, therefore, demonstrates that inhalation of vapours from the solvent mixture resulted in significant dose-dependent biochemical and functional changes in the vital tissues (liver and kidney) studied. The study has specific relevance since humans are increasingly being exposed to such solvents due to increased industrial use in such combinations. PMID- 23637307 TI - The cystic fibrosis of exocrine pancreas. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) protein is highly expressed in the pancreatic duct epithelia and permits anions and water to enter the ductal lumen. This results in an increased volume of alkaline fluid allowing the highly concentrated proteins secreted by the acinar cells to remain in a soluble state. This work will expound on the pathophysiology and pathology caused by the malfunctioning CFTR protein with special reference to ion transport and acid-base abnormalities both in humans and animal models. We will also discuss the relationship between cystic fibrosis (CF) and pancreatitis, and outline present and potential therapeutic approaches in CF treatment relevant to the pancreas. PMID- 23637310 TI - Cocaine-evoked synaptic plasticity of excitatory transmission in the ventral tegmental area. AB - Cocaine leads to a strong euphoria, which is at the origin of its recreational use. Past the acute effects, the drug leaves traces in the brain that persist long after it has been cleared from the body. These traces eventually shape behavior such that drug use may become compulsive and addiction develops. Here we discuss cocaine-evoked synaptic plasticity of glutamatergic transmission onto dopamine (DA) neurons of the ventral tegmental area (VTA) as one of the earliest traces after a first injection of cocaine. We review the literature that has examined the induction requirements as well as the expression mechanism of this form of plasticity and ask the question about its functional significance. PMID- 23637309 TI - The molecular basis of beta-thalassemia. AB - The beta-thalassemias are characterized by a quantitative deficiency of beta globin chains underlaid by a striking heterogeneity of molecular defects. Although most of the molecular lesions involve the structural beta gene directly, some down-regulate the gene through distal cis effects, and rare trans-acting mutations have also been identified. Most beta-thalassemias are inherited in a Mendelian recessive fashion but there is a subgroup of beta-thalassemia alleles that behave as dominant negatives. Unraveling the molecular basis of beta thalassemia has provided a paradigm for understanding of much of human genetics. PMID- 23637311 TI - Vaccines, reverse vaccinology, and bacterial pathogenesis. AB - Advances in genomics and innovative strategies such as reverse vaccinology have changed the concepts and approaches to vaccine candidate selection and design. Genome mining and blind selection of novel antigens provide a novel route to investigate the mechanisms that underpin pathogenesis. The resulting lists of novel candidates are revealing new aspects of pathogenesis of target organisms, which in turn drives the rational design of optimal vaccine antigens. Here we use the discovery, characterization, and exploitation of fHbp, a vaccine candidate and key virulence factor of meningococcus, as an illustrative case in point. Applying genomic approaches to study both the pathogen and host will ultimately increase our fundamental understanding of pathogen biology, mechanisms responsible for the development of protective immunity, and guide next-generation vaccine design. PMID- 23637313 TI - Domestic violence against single, never-married women in the Occupied Palestinian Territory. AB - This study examines the association between decision-making power, with other background variables, and domestic violence against single, never-married women in the Occupied Palestinian Territory (OPT). Secondary analysis using data from a 2006 Palestinian Central Bureau of Statistics domestic violence survey revealed that decision-making power and age were significant predictors of physical and psychological abuse. Relation to household head, refugee status, education, employment, and locality were not significant; region was only significant for psychological abuse. Further studies are needed to understand what factors allow single, never-married women to exercise decision-making power in the household and its association with domestic violence. PMID- 23637312 TI - Mesenchymal stromal cells in transplantation rejection and tolerance. AB - Mesenchymal stromal cells (MSCs) have recently emerged as promising candidates for cell-based immunotherapy in solid organ transplantation (SOT). In addition to immune modulation, MSCs possess proreparative properties and preclinical studies indicate that MSCs have the capacity to prolong graft survival and in some cases induce tolerance. Currently, the application of MSCs in SOT is being evaluated in phase I/II clinical trials. Whereas the mechanisms of action used by MSC immunomodulation have been somewhat elucidated in vitro, the data from preclinical transplant models have been unclear. Furthermore, the optimal timing, dose, and route of administration remain to be elucidated. Importantly, MSCs have the ability to sense their environment, which may influence their function. In this article, we discuss the impact of the local microenvironment on MSCs and the mechanisms of MSC immunomodulation in the setting of SOT. PMID- 23637315 TI - Exploring rape myths, gendered norms, group processing, and the social context of rape among college women: a qualitative analysis. AB - The purpose of this research is to explore the negotiation strategies of college women as they interpret ambiguous rape scenarios. In focus groups, 1st- and 4th year college women were presented with a series of three vignettes depicting incidents that meet the legal criteria for rape yet are ambiguous due to the presence of cultural rape myths, contexts involving alcohol consumption, varying degrees of consent, and a known perpetrator. These contexts are critical in understanding how college women define rape. Key findings indicated many of these college women utilized rape myths and norms within their peer groups to interpret rape scenarios. PMID- 23637314 TI - Predicting shelter residence in women experiencing recent intimate partner violence. AB - This study sought to determine factors associated with shelter residence in women with recent histories of intimate partner violence (IPV). The sample included 113 women, approximately half of whom resided in a shelter over the past year. Participating women provided demographic information and completed standardized measures of IPV, trauma, and depression. Ethnicity, income, housing stability, and mental health, but not violence exposure, differentiated the shelter and community groups. Trauma symptoms, housing instability, and ethnicity best predicted shelter residence. Future research should focus on determining what types of services and interventions will best address the unique needs of each population. PMID- 23637308 TI - Chlamydial intracellular survival strategies. AB - Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen and the causative agent of blinding trachoma. Although Chlamydia is protected from humoral immune responses by residing within remodeled intracellular vacuoles, it still must contend with multilayered intracellular innate immune defenses deployed by its host while scavenging for nutrients. Here we provide an overview of Chlamydia biology and highlight recent findings detailing how this vacuole-bound pathogen manipulates host-cellular functions to invade host cells and maintain a replicative niche. PMID- 23637316 TI - Survival and causes of death in an unselected and complete cohort of Norwegian patients with systemic sclerosis. AB - OBJECTIVE: To determine survival and causes of death in an unselected and complete cohort of Norwegian patients with systemic sclerosis (SSc) compared to the background population. METHODS: Multiple methods were used to identify every patient with SSc living in southeast Norway, with a denominator population of 2,707,012, between 1999 and 2009. All patients who met either the American College of Rheumatology criteria or the Medsger and LeRoy criteria for SSc were included. Every patient was matched for sex and age with 15 healthy controls drawn from the national population registry. Vital status at January 1, 2010, was provided for patients and controls by the national population registry. Causes of death were obtained from death certificates and by chart review. RESULTS: Forty three (14%) of 312 patients with SSc died during the study period. The standardized mortality rate (SMR) was estimated to be 2.03 for the entire cohort and 5.33 for the subgroup with diffuse cutaneous (dc) SSc. The 5- and 10-year survival rates were 91% and 70%, respectively, for dcSSc and 98% and 93% for limited cutaneous (lc) SSc. Causes of death were related to SSc in 24/43 (56%) patients, mostly cardiopulmonary diseases (n = 13), including pulmonary hypertension (n = 8). Factors associated with fatal outcome included male sex, dcSSc, pulmonary hypertension, and interstitial lung disease. CONCLUSION: Compared to the Norwegian background population, our cohort of 312 unselected patients with SSc had decreased survival. The survival rates observed were, however, better than those previously reported from SSc referral centers. PMID- 23637317 TI - Classification and diagnostic investigation in inflammatory myopathies: a study of 99 patients. AB - OBJECTIVE: Insights into the pathogenesis of inflammatory myopathies have led to new diagnostic methods. The aims of our study were (1) to evaluate the consequences of using the classification of Amato/European Neuromuscular Centre Workshop (ENMC) compared to that of Bohan and Peter; and (2) to evaluate any diagnostic benefit in using an extended pathological investigation. METHODS: From a consecutive retrospective database, we evaluated 99 patients for classification. Patients with inclusion body myositis (IBM) were classified according to Griggs, et al. In addition to routine stainings and immunohistochemistry, a multilevel serial sectioning procedure was performed on paraffin-embedded material, to identify scarce pathological findings. RESULTS: Classification according to Bohan and Peter could be performed for 83 of the 99 patients, whereas only 60 patients met the Amato/ENMC criteria, the latter resulting in the following diagnostic groups: IBM (n = 18), nonspecific myositis (n = 14), polymyositis (n = 12), dermatomyositis (n = 10), dermatomyositis sine dermatitis (n = 5), and immune-mediated necrotizing myopathy (n = 1). Most of the Amato/ENMC diagnostic groups harbored patients from several of the Bohan and Peter groups, which included a substantial group lacking proximal muscle weakness. The serial sectioning procedure was essential for classification of 9 patients (15%), and led to a more specific diagnosis for 13 patients (22%) according to Amato/ENMC. CONCLUSION: The classification of Amato/ENMC was more restrictive, forming groups based on clinical criteria and specified myopathological findings, which clearly differed from the groups of the Bohan and Peter classification. An extended pathological investigation increased the diagnostic yield of a muscle biopsy and highlights the quantity and specificity of certain pathological findings. PMID- 23637318 TI - Serum interleukin 6 before and after therapy with tocilizumab is a principal biomarker in patients with rheumatoid arthritis. AB - OBJECTIVE: Biologic treatments including the humanized anti-interleukin 6 (anti IL-6) receptor antibody tocilizumab (TCZ) provide therapeutic options for patients with rheumatoid arthritis (RA). We investigated useful biomarkers to predict the responsiveness to TCZ by measurement of serum proinflammatory cytokine concentrations. METHODS: Serum samples were collected from 61 patients with RA before biologic treatment and at 4 weeks after initial administration of either TCZ (n = 32) or infliximab (IFX; n = 29) and from 13 healthy serum donor controls. Disease Activity Score of 28 joints (DAS28) was determined at baseline and after treatment. RESULTS: Although IL-1beta, IL-2, IL-6, IL-17A, IL-17F, interferon-alpha, and tumor necrosis factor-alpha (TNF-alpha) were all increased in sera from patients with RA compared with controls, only the IL-6 level was significantly correlated with DAS28 before treatment. The IL-6 level before treatment was positively correlated with DAS28 after TCZ treatment, and was significantly lower in TCZ-responsive patients (as judged by a post-treatment DAS28 < 3.2) than in TCZ-resistant patients (post-treatment DAS28 >= 3.2). DAS28 after TCZ was significantly lower than after administration of IFX in patients with low pretreatment IL-6 (< 51.5 pg/ml, the mean baseline value of IL-6 in all RA patients), but not in those with high pretreatment IL-6. These results indicate that low serum IL-6 is associated with a favorable response to TCZ. CONCLUSION: Although both TNF-alpha and IL-6 are major targets of therapeutic intervention in RA, baseline serum IL-6 but not baseline TNF-alpha level is a potential biomarker reflecting disease activity. Measurement of serum IL-6 in RA before treatment may be useful to estimate residual disease activity after TCZ treatment and to predict responsiveness to TCZ treatment. PMID- 23637319 TI - Identifying phenotypes of knee osteoarthritis by separate quantitative radiographic features may improve patient selection for more targeted treatment. AB - OBJECTIVE: Expression of osteoarthritis (OA) varies significantly between individuals, and over time, suggesting the existence of different phenotypes, possibly with specific etiology and targets for treatment. Our objective was to identify phenotypes of progression of radiographic knee OA using separate quantitative features. METHODS: Separate radiographic features of OA were measured by Knee Images Digital Analysis (KIDA) in individuals with early knee OA (the CHECK cohort: Cohort Hip & Cohort Knee), at baseline and at 2-year and 5 year followup. Hierarchical clustering was performed to identify phenotypes of radiographic knee OA progression. The phenotypes identified were compared for changes in joint space width (JSW), varus angle, osteophyte area, eminence height, bone density, for Kellgren-Lawrence (K-L) grade, and for clinical characteristics. Logistic regression analysis evaluated whether baseline radiographic features and demographic/clinical characteristics were associated with each of the specific phenotypes. RESULTS: The 5 clusters identified were interpreted as "Severe" or "No," "Early" or "Late" progression of the radiographic features, or specific involvement of "Bone density." Medial JSW, varus angle, osteophyte area, eminence height, and bone density at baseline were associated with the Severe and Bone density phenotypes. Lesser eminence height and bone density were associated with Early and Late progression. Larger varus angle and smaller osteophyte area were associated with No progression. CONCLUSION: Five phenotypes of radiographic progression of early knee OA were identified using separate quantitative features, which were associated with baseline radiographic features. Such phenotypes might require specific treatment and represent relevant subgroups for clinical trials. PMID- 23637321 TI - Childhood-onset eosinophilic granulomatosis with polyangiitis (formerly Churg Strauss syndrome): a contemporary single-center cohort. AB - OBJECTIVE: To date only 38 cases of childhood-onset eosinophilic granulomatosis with polyangiitis (cEGPA; formerly Churg-Strauss syndrome) have been reported. Additional patients with cEGPA could enhance the understanding of this rare and life-threatening condition. Our objectives were (1) to determine the frequency of specific organ system involvement; (2) to examine initial therapeutic regimen; and (3) to document disease and therapy-related morbidity in a contemporary cohort of patients with cEGPA. METHODS: Retrospective review of patients evaluated at the Cleveland Clinic between 2003 and 2011 who met either American College of Rheumatology or Lanham criteria for EGPA and whose age was < 18 years at symptom onset. RESULTS: Nine patients (8 female; 7 white) were identified. Median age at onset of rhinitis/asthma symptom was 13 years and median age at diagnosis of cEGPA was 15 years. All patients demonstrated eosinophilia, upper airway disease (allergic rhinitis, chronic sinusitis, and/or nasal polyps), and pulmonary involvement. Other frequently involved organ systems included musculoskeletal (67%), gastrointestinal (67%), cutaneous (67%), neurologic (56%), and cardiac (44%). Antineutrophil cytoplasmic antibody (ANCA) serologies were negative in all patients. The medications used most frequently for initial therapy included oral (44%) or intravenous corticosteroids (56%) and azathioprine (67%). Disease or therapeutic complications occurred in half of the cohort and included heart failure, stroke, and sequela from longterm, high-dose steroids. CONCLUSION: Eosinophilia, in combination with upper airway, pulmonary, musculoskeletal, neurologic, and cardiac manifestations, is frequently observed in cEGPA. ANCA titers are often negative. Steroids are the mainstay of initial therapy but steroid-related side effects occur regularly. PMID- 23637320 TI - Metaanalysis of the association of smoking and PTPN22 R620W genotype on autoantibody status and radiological erosions in rheumatoid arthritis. AB - OBJECTIVE: To investigate the interrelationships among smoking, protein tyrosine phosphatase non-receptor 22 (PTPN22) R620W (rs2476601) genotype, and anticitrullinated peptide antibody (ACPA) status; and among smoking, PTPN22 R620W genotype, and presence of bone erosions overall and separately by ACPA status in patients with rheumatoid arthritis (RA). METHODS: Six studies totaling 2680 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating ACPA status and up to 8 studies totaling 3172 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating presence of erosive damage. RESULTS: Evidence was found for an increase in the odds of ACPA positivity for ever smoking (OR 1.56, 95% CI 1.28-1.90, p = 8.5 * 10(-6)), carriage of at least 1 of the PTPN22 risk alleles (OR 1.50, 95% CI 1.13-2.00, p = 5.5 * 10(-3)) and both ever smoking and carriage of at least 1 of the PTPN22 risk alleles (OR 2.22, 95% CI 1.69-2.91, p = 8.3 * 10(-9)). There was no evidence of an association between presence of erosive damage and smoking status or carriage of PTPN22 risk alleles when analyzed overall or separately by ACPA status. CONCLUSION: This metaanalysis indicates that both smoking and the PTPN22 risk allele are associated with the risk of ACPA positivity. There was insufficient evidence to establish a relationship in either direction between PTPN22 and smoking with erosive damage, despite evidence that ACPA positivity is associated with erosive damage. PMID- 23637322 TI - Soluble biomarkers associated with response to treatment with tumor necrosis factor inhibitors in psoriatic arthritis. AB - OBJECTIVE: To identify soluble biomarkers associated with response to therapy with tumor necrosis factor inhibitors (TNFi) in patients with psoriatic arthritis (PsA). METHODS: The study was conducted at a PsA clinic where patients are assessed every 6 months, and serum samples are collected and stored once a year at the time of clinical assessment. Forty patients with active PsA who gave serum samples prior to treatment with TNFi and after at least 3 months of therapy were identified. Patients were classified as TNFi responders if tender joint count was < 3, swollen joint count was 0, and Psoriasis Area and Severity Index score was < 4 at the time the second sample was collected. The following biomarkers were tested by ELISA: TNF superfamily 14, matrix metalloprotease-3 (MMP-3), receptor activator of nuclear factor kappa-B ligand, osteoprotegerin, cartilage oligomeric matrix protein (COMP), CPII, C2C and C1-2C, CS-846, and highly sensitive C reactive protein. Paired t tests and logistic regression was used for statistical analyses. RESULTS: After a mean treatment duration of 11 months with TNFi (etanercept 28 patients, adalimumab 6, golimumab 4, infliximab 2), 29 patients were classified as TNFi responders. Baseline level of MMP-3 was independently associated with responder status (OR 1.067 for each 1-unit increase, p = 0.045). A reduction in MMP-3 levels with therapy increased the odds of achieving response (OR 1.213 for each 1-unit change, p = 0.030), whereas a reduction in COMP decreased the odds (OR 0.587, for each 100-unit increase, p = 0.039). None of the other biomarkers was associated with response. CONCLUSION: Baseline as well as reduction in serum MMP-3 and increase in serum COMP are independently associated with response to TNFi therapy in patients with PsA. PMID- 23637323 TI - Interaction of HLA-DRB1*09:01 and *04:05 with smoking suggests distinctive mechanisms of rheumatoid arthritis susceptibility beyond the shared epitope. AB - OBJECTIVE: Although HLA-DRB1 shared epitope (SE) alleles and HLA-DRB1*09:01 have repeatedly been shown to be associated with susceptibility to rheumatoid arthritis (RA), the effect of each allele on levels of anticyclic citrullinated peptide autoantibodies (anti-CCP) and interaction with cigarette smoking in RA remains to be fully defined. We investigated whether HLA-DRB1 risk alleles influence anti-CCP levels and whether each allele interacts with smoking in anti CCP-positive or -negative RA. METHODS: All patients with RA (n = 1924) and controls (n = 1119) were Korean. The HLA-DRB1 4-digit genotyping was performed by standard PCR-sequencing based typing method. OR and biologic interactions as departures from additivity or multiplicity were analyzed by logistic regression. RESULTS: SE alleles were significantly associated with increased anti-CCP levels. Conversely, HLA-DRB1*09:01 was associated with reduced levels, in both SE positive and SE-negative patients. Each of SE alleles interacted significantly with smoking, whereas HLA-DRB1*09:01 did not. Interactions between the 2 most significant risk alleles, HLA-DRB1*04:05 and HLA-DRB1*09:01, (attributable proportion = 0.68, 95% CI 0.46-0.89, multiplicity p = 0.012) significantly increased RA susceptibility regardless of anti-CCP and smoking status. Smoking increased the risk for RA by significant interaction with the heterozygote HLA DRB1*04:05/*09:01. CONCLUSION: HLA-DRB1*09:01 differs from SE alleles with regard to anti-CCP levels and interaction with smoking, suggesting a distinct mechanism of HLA-DRB1*09:01 in the pathogenesis of RA that may bypass anti-CCP formation. Also, a significant increase of the HLA-DRB1*04:05/ *09:01 heterozygote in RA susceptibility may be attributable to the synergistic contribution of 2 different pathways in which 2 alleles participate independently. PMID- 23637324 TI - Decreased pain threshold in juvenile idiopathic arthritis: a cross-sectional study. AB - OBJECTIVE: To examine the pain threshold in children with juvenile idiopathic arthritis (JIA) compared with healthy children by using a digital pressure algometer. METHODS: Fifty-eight children with JIA born between 1995 and 2000 and 91 age-related healthy children participated in the study. We used a digital pressure algometer to measure the pain threshold on 17 symmetric, anatomically predefined joint-related or bone-related areas. All children were asked to rate their current pain on a Faces Pain Scale, and parents of children with JIA were asked to complete a parental revised version of the Child Health Assessment Questionnaire (CHAQ-R). Clinical data were registered on children with JIA. RESULTS: The pain threshold was significantly lower among children with JIA (total mean PT = 1.33 +/- 0.69 kg/cm(2)) when compared with the healthy control group (total mean PT = 1.77 +/- 0.67 kg/cm(2)). The same pattern was found in all areas measured, including negative control areas that are normally unaffected in JIA (p = 0.0001 to 0.005). Overall, the pain threshold was 34% lower in females than in males in both groups (p < 0.0001). We found no correlation between pain threshold and age, current pain experience, disease duration, or disease activity. CONCLUSION: Children with JIA had a substantially lower pain threshold even in areas usually unaffected by arthritis. Our findings suggest that JIA alters the pain perception and causes decreased pain threshold. PMID- 23637327 TI - High-density lipoprotein profiling changes in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: a cohort study. AB - OBJECTIVE: We investigated changes in high-density lipoprotein (HDL) profiling in patients with rheumatoid arthritis who started treatment by taking tumor necrosis factor (TNF) inhibitors. The patients were stratified for European League Against Rheumatism (EULAR) response. METHODS: A group of 100 patients naive for TNF inhibitors at baseline were randomly selected from 204 adalimumab-treated and 203 etanercept-treated patients on the basis of their EULAR response. HDL profiling was measured using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. RESULTS: In EULAR good responders, mass charged markers representing serum amyloid A (SAA-1 and -2) decreased significantly after 4 months' therapy. There were no significant differences in HDL profiling in EULAR nonresponders. CONCLUSION: Effective suppression of inflammation with TNF inhibitors results in favorable changes in HDL composition. PMID- 23637326 TI - Use of lipid-lowering agents in rheumatoid arthritis: a population-based cohort study. AB - OBJECTIVE: Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease and mortality. Lipid-lowering therapy is reportedly underused in patients with RA. Longitudinal cohort studies comparing use of lipid lowering medications in patients with RA versus the general population are lacking. METHODS: Cardiovascular risk factors, lipid measures, and use of lipid lowering agents were assessed in a population-based inception cohort of patients with RA and a cohort of non-RA subjects followed from January 1, 1988, to December 31, 2008. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII) guidelines were assessed at the time of each lipid measure throughout followup. Time from meeting guidelines to initiation of lipid lowering agents was assessed using Kaplan-Meier methods. RESULTS: The study population included 412 RA and 438 non-RA patients with >= 1 lipid measure during followup and no prior use of lipid-lowering agents. Rates of lipid testing were lower among patients with RA compared to non-RA subjects. Among patients who met NCEP ATPIII criteria for lipid-lowering therapy (n = 106 RA; n = 120 non-RA), only 27% of RA and 26% of non-RA subjects initiated lipid-lowering agents within 2 years of meeting the guidelines for initiation. CONCLUSION: There was substantial undertreatment in both the RA and the non-RA cohorts who met NCEP ATPIII criteria for initiation of lipid-lowering agents. Patients with RA did not have as frequent lipid testing as individuals in the general population. PMID- 23637325 TI - Variable association of reactive intermediate genes with systemic lupus erythematosus in populations with different African ancestry. AB - OBJECTIVE: Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate-related genes biological candidates for disease susceptibility. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry. METHODS: A total of 244 single-nucleotide polymorphisms (SNP) from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls). Single-marker, haplotype, and 2-locus interaction tests were computed for these populations. RESULTS: The glutathione reductase gene GSR (rs2253409; p = 0.0014, OR 1.26, 95% CI 1.09-1.44) was the most significant single SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575; p = 0.0065, OR 2.10, 95% CI 1.23-3.59) and NO synthase gene NOS1 (rs561712; p = 0.0072, OR 0.62, 95% CI 0.44-0.88) were most strongly associated with SLE. When both populations were analyzed together, GSR remained the most significant effect (rs2253409; p = 0.00072, OR 1.26, 95% CI 1.10-1.44). Haplotype and 2-locus interaction analyses also uncovered different loci in each population. CONCLUSION: These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups. PMID- 23637328 TI - Clinical course, prognosis, and causes of death in mixed connective tissue disease. AB - OBJECTIVE: To study the survival rate and prognostic indicators of mixed connective tissue disease (MCTD) in a Hungarian population. METHODS: Two hundred eighty patients with MCTD diagnosed between 1979 and 2011 were followed prospectively. Clinical features, autoantibodies, and mortality data were assessed. Prognostic factors for survival were investigated and survival was calculated from the time of the diagnosis by Kaplan-Meier method. RESULTS: A total of 22 of 280 patients died: the causes of death were pulmonary arterial hypertension (PAH) in 9 patients, thrombotic thrombocytopenic purpura in 3, infections in 3, and cardiovascular events in 7. The 5, 10, and 15-year survival rates after the diagnosis was established were 98%, 96%, and 88%, respectively. The deceased patients were younger at the diagnosis of MCTD compared to patients who survived (35.5 +/- 10.4 vs 41.8 +/- 10.7 yrs; p < 0.03), while there was no difference in the duration of the disease (p = 0.835). Our cohort study showed that the presence of cardiovascular events (p < 0.0001), esophageal hypomotility (p = 0.04), serositis (p < 0.001), secondary antiphospholipid syndrome (p = 0.039), and malignancy (p < 0.001) was significantly higher in the deceased patients with MCTD. The presence of anticardiolipin (p = 0.019), anti-beta2 glycoprotein I (p = 0.002), and antiendothelial cell antibodies (p = 0.002) increased the risk of mortality. CONCLUSION: Overall, PAH remained the leading cause of death in patients with MCTD. The prevalence of cardiovascular morbidity and mortality, malignancy, and thrombotic events increased during the disease course of MCTD. The presence of antiphospholipid antibodies raised the risk of mortality. PMID- 23637329 TI - Kirrel3 is required for the coalescence of vomeronasal sensory neuron axons into glomeruli and for male-male aggression. AB - The accessory olfactory system controls social and sexual interactions in mice that are crucial for survival. Vomeronasal sensory neurons (VSNs) form synapses with dendrites of second order neurons in glomeruli of the accessory olfactory bulb (AOB). Axons of VSNs expressing the same vomeronasal receptor coalesce into multiple glomeruli within spatially conserved regions of the AOB. Here we examine the role of the Kirrel family of transmembrane proteins in the coalescence of VSN axons within the AOB. We find that Kirrel2 and Kirrel3 are differentially expressed in subpopulations of VSNs and that their expression is regulated by activity. Although Kirrel3 expression is not required for early axonal guidance events, such as fasciculation of the vomeronasal tract and segregation of apical and basal VSN axons in the AOB, it is necessary for proper coalescence of axons into glomeruli. Ablation of Kirrel3 expression results in disorganization of the glomerular layer of the posterior AOB and formation of fewer, larger glomeruli. Furthermore, Kirrel3(-/-) mice display a loss of male-male aggression in a resident-intruder assay. Taken together, our results indicate that differential expression of Kirrels on vomeronasal axons generates a molecular code that dictates their proper coalescence into glomeruli within the AOB. PMID- 23637332 TI - A versatile platform for creating a comprehensive UAS-ORFeome library in Drosophila. AB - Overexpression screens are used to explore gene functions in Drosophila, but this strategy suffers from the lack of comprehensive and systematic fly strain collections and efficient methods for generating such collections. Here, we present a strategy that could be used efficiently to generate large numbers of transgenic Drosophila strains, and a collection of 1149 UAS-ORF fly lines that were created with the site-specific PhiC31 integrase method. For this collection, we used a set of 655 genes that were cloned as two variants, either as an open reading frame (ORF) with a native stop codon or with a C-terminal 3xHA tag. To streamline the procedure for transgenic fly generation, we demonstrate the utility of injecting pools of plasmids into embryos, each plasmid containing a randomised sequence (barcode) that serves as a unique identifier for plasmids and, subsequently, fly strains. We also developed a swapping technique that facilitates the rapid exchange of promoters and epitope tags in vivo, expanding the versatility of the ORF collection. The work described here serves as the basis of a systematic library of Gal4/UAS-regulated transgenes. PMID- 23637330 TI - ASCL1 reprograms mouse Muller glia into neurogenic retinal progenitors. AB - Non-mammalian vertebrates have a robust ability to regenerate injured retinal neurons from Muller glia (MG) that activate the gene encoding the proneural factor Achaete-scute homolog 1 (Ascl1; also known as Mash1 in mammals) and de differentiate into progenitor cells. By contrast, mammalian MG have a limited regenerative response and fail to upregulate Ascl1 after injury. To test whether ASCL1 could restore neurogenic potential to mammalian MG, we overexpressed ASCL1 in dissociated mouse MG cultures and intact retinal explants. ASCL1-infected MG upregulated retinal progenitor-specific genes and downregulated glial genes. Furthermore, ASCL1 remodeled the chromatin at its targets from a repressive to an active configuration. MG-derived progenitors differentiated into cells that exhibited neuronal morphologies, expressed retinal subtype-specific neuronal markers and displayed neuron-like physiological responses. These results indicate that a single transcription factor, ASCL1, can induce a neurogenic state in mature MG. PMID- 23637331 TI - The homeobox gene Gsx2 controls the timing of oligodendroglial fate specification in mouse lateral ganglionic eminence progenitors. AB - The homeobox gene Gsx2 has previously been shown to be required for the specification of distinct neuronal subtypes derived from lateral ganglionic eminence (LGE) progenitors at specific embryonic time points. However, its role in the subsequent generation of oligodendrocytes from these progenitors remains unclear. We have utilized conditional gain-of-function and loss-of-function approaches in order to elucidate the role of Gsx2 in the switch between neurogenesis and oligodendrogenesis within the embryonic ventral telencephalon. In the absence of Gsx2 expression, an increase in oligodendrocyte precursor cells (OPCs) with a concomitant decrease in neurogenesis is observed in the subventricular zone of the LGE at mid-stages of embryogenesis (i.e. E12.5-15.5), which subsequently leads to an increased number of Gsx2-derived OPCs within the adjacent mantle regions of the cortex before birth at E18.5. Moreover, using Olig2(cre) to conditionally inactivate Gsx2 throughout the ventral telencephalon with the exception of the dorsal (d)LGE, we found that the increase in cortical OPCs in Gsx2 germline mutants are derived from dLGE progenitors. We also show that Ascl1 is required for the expansion of these dLGE-derived OPCs in the cortex of Gsx2 mutants. Complementing these results, gain-of-function experiments in which Gsx2 was expressed throughout most of the late-stage embryonic telencephalon (i.e. E15.5-18.5) result in a significant decrease in the number of cortical OPCs. These results support the notion that high levels of Gsx2 suppress OPC specification in dLGE progenitors and that its downregulation is required for the transition from neurogenesis to oligodendrogenesis. PMID- 23637333 TI - VEGFA-dependent and -independent pathways synergise to drive Scl expression and initiate programming of the blood stem cell lineage in Xenopus. AB - The first haematopoietic stem cells share a common origin with the dorsal aorta and derive from putative adult haemangioblasts in the dorsal lateral plate (DLP) mesoderm. Here we show that the transcription factor (TF) stem cell leukaemia (Scl/Tal1) is crucial for development of these adult haemangioblasts in Xenopus and establish the regulatory cascade controlling its expression. We show that VEGFA produced in the somites is required to initiate adult haemangioblast programming in the adjacent DLP by establishing endogenous VEGFA signalling. This response depends on expression of the VEGF receptor Flk1, driven by Fli1 and Gata2. Scl activation requires synergy between this VEGFA-controlled pathway and a VEGFA-independent pathway controlled by Fli1, Gata2 and Etv2/Etsrp/ER71, which also drives expression of the Scl partner Lmo2. Thus, the two ETS factors Fli1 and Etv6, which drives the VEGFA expression in both somites and the DLP, sit at the top of the adult haemangioblast gene regulatory network (GRN). Furthermore, Gata2 is initially activated by Fli1 but later maintained by another ETS factor, Etv2. We also establish that Flk1 and Etv2 act independently in the two pathways to Scl activation. Thus, detailed temporal, epistatic measurements of key TFs and VEGFA plus its receptor have enabled us to build a Xenopus adult haemangioblast GRN. PMID- 23637335 TI - Elastogenesis at the onset of human cardiac valve development. AB - Semilunar valve leaflets have a well-described trilaminar histoarchitecture, with a sophisticated elastic fiber network. It was previously proposed that elastin containing fibers play a subordinate role in early human cardiac valve development; however, this assumption was based on data obtained from mouse models and human second and third trimester tissues. Here, we systematically analyzed tissues from human fetal first (4-12 weeks) and second (13-18 weeks) trimester, adolescent (14-19 years) and adult (50-55 years) hearts to monitor the temporal and spatial distribution of elastic fibers, focusing on semilunar valves. Global expression analyses revealed that the transcription of genes essential for elastic fiber formation starts early within the first trimester. These data were confirmed by quantitative PCR and immunohistochemistry employing antibodies that recognize fibronectin, fibrillin 1, 2 and 3, EMILIN1 and fibulin 4 and 5, which were all expressed at the onset of cardiac cushion formation (~week 4 of development). Tropoelastin/elastin protein expression was first detectable in leaflets of 7-week hearts. We revealed that immature elastic fibers are organized in early human cardiovascular development and that mature elastin containing fibers first evolve in semilunar valves when blood pressure and heartbeat accelerate. Our findings provide a conceptual framework with the potential to offer novel insights into human cardiac valve development and disease. PMID- 23637336 TI - The Pygo2-H3K4me2/3 interaction is dispensable for mouse development and Wnt signaling-dependent transcription. AB - Pygopus has been discovered as a fundamental Wnt signaling component in Drosophila. The mouse genome encodes two Pygopus homologs, Pygo1 and Pygo2. They serve as context-dependent beta-catenin coactivators, with Pygo2 playing the more important role. All Pygo proteins share a highly conserved plant homology domain (PHD) that allows them to bind di- and trimethylated lysine 4 of histone H3 (H3K4me2/3). Despite the structural conservation of this domain, the relevance of histone binding for the role of Pygo2 as a Wnt signaling component and as a reader of chromatin modifications remains speculative. Here we generate a knock in mouse line, homozygous for a Pygo2 mutant defective in chromatin binding. We show that even in the absence of the potentially redundant Pygo1, Pygo2 does not require the H3K4me2/3 binding activity to sustain its function during mouse development. Indeed, during tissue homeostasis, Wnt/beta-catenin-dependent transcription is largely unaffected. However, the Pygo2-chromatin interaction is relevant in testes, where, importantly, Pygo2 binds in vivo to the chromatin in a PHD-dependent manner. Its presence on regulatory regions does not affect the transcription of nearby genes; rather, it is important for the recruitment of the histone acetyltransferase Gcn5 to chromatin, consistent with a testis-specific and Wnt-unrelated role for Pygo2 as a chromatin remodeler. PMID- 23637334 TI - Tcf21 regulates the specification and maturation of proepicardial cells. AB - The epicardium is a mesothelial cell layer essential for vertebrate heart development and pertinent for cardiac repair post-injury in the adult. The epicardium initially forms from a dynamic precursor structure, the proepicardial organ, from which cells migrate onto the heart surface. During the initial stage of epicardial development crucial epicardial-derived cell lineages are thought to be determined. Here, we define an essential requirement for transcription factor Tcf21 during early stages of epicardial development in Xenopus, and show that depletion of Tcf21 results in a disruption in proepicardial cell specification and failure to form a mature epithelial epicardium. Using a mass spectrometry based approach we defined Tcf21 interactions and established its association with proteins that function as transcriptional co-repressors. Furthermore, using an in vivo systems-based approach, we identified a panel of previously unreported proepicardial precursor genes that are persistently expressed in the epicardial layer upon Tcf21 depletion, thereby confirming a primary role for Tcf21 in the correct determination of the proepicardial lineage. Collectively, these studies lead us to propose that Tcf21 functions as a transcriptional repressor to regulate proepicardial cell specification and the correct formation of a mature epithelial epicardium. PMID- 23637337 TI - Lef1 regulates Dusp6 to influence neuromast formation and spacing in the zebrafish posterior lateral line primordium. AB - The posterior lateral line primordium (PLLp) migrates caudally and periodically deposits neuromasts. Coupled, but mutually inhibitory, Wnt-FGF signaling systems regulate proto-neuromast formation in the PLLp: FGF ligands expressed in response to Wnt signaling activate FGF receptors and initiate proto-neuromast formation. FGF receptor signaling, in turn, inhibits Wnt signaling. However, mechanisms that determine periodic neuromast formation and deposition in the PLLp remain poorly understood. Previous studies showed that neuromasts are deposited closer together and the PLLp terminates prematurely in lef1-deficient zebrafish embryos. It was suggested that this results from reduced proliferation in the leading domain of the PLLp and/or premature incorporation of progenitors into proto-neuromasts. We found that rspo3 knockdown reduces proliferation in a manner similar to that seen in lef1 morphants. However, it does not cause closer neuromast deposition or premature termination of the PLLp, suggesting that such changes in lef1-deficient embryos are not linked to changes in proliferation. Instead, we suggest that they are related to the role of Lef1 in regulating the balance of Wnt and FGF functions in the PLLp. Lef1 determines expression of the FGF signaling inhibitor Dusp6 in leading cells and regulates incorporation of cells into neuromasts; reduction of Dusp6 in leading cells in lef1-deficient embryos allows new proto neuromasts to form closer to the leading edge. This is associated with progressively slower PLLp migration, reduced spacing between deposited neuromasts and premature termination of the PLLp system. PMID- 23637338 TI - miR-200 and miR-96 families repress neural induction from human embryonic stem cells. AB - The role of miRNAs in neuroectoderm specification is largely unknown. We screened miRNA profiles that are differentially changed when human embryonic stem cells (hESCs) were differentiated to neuroectodermal precursors (NEP), but not to epidermal (EPI) cells and found that two miRNA families, miR-200 and miR-96, were uniquely downregulated in the NEP cells. We confirmed zinc-finger E-box-binding homeobox (ZEB) transcription factors as a target of the miR-200 family members and identified paired box 6 (PAX6) transcription factor as the new target of miR 96 family members via gain- and loss-of-function analyses. Given the essential roles of ZEBs and PAX6 in neural induction, we propose a model by which miR-200 and miR-96 families coordinate to regulate neural induction. PMID- 23637339 TI - Responses of Nannochloropsis oceanica IMET1 to Long-Term Nitrogen Starvation and Recovery. AB - The Nannochloropsis genus contains oleaginous microalgae that have served as model systems for developing renewable biodiesel. Recent genomic and transcriptomic studies on Nannochloropsis species have provided insights into the regulation of lipid production in response to nitrogen stress. Previous studies have focused on the responses of Nannochloropsis species to short-term nitrogen stress, but the effect of long-term nitrogen deprivation remains largely unknown. In this study, physiological and proteomic approaches were combined to understand the mechanisms by which Nannochloropsis oceanica IMET1 is able to endure long term nitrate deprivation and its ability to recover homeostasis when nitrogen is amended. Changes of the proteome during chronic nitrogen starvation espoused the physiological changes observed, and there was a general trend toward recycling nitrogen and storage of lipids. This was evidenced by a global down-regulation of protein expression, a retained expression of proteins involved in glycolysis and the synthesis of fatty acids, as well as an up-regulation of enzymes used in nitrogen scavenging and protein turnover. Also, lipid accumulation and autophagy of plastids may play a key role in maintaining cell vitality. Following the addition of nitrogen, there were proteomic changes and metabolic changes observed within 24 h, which resulted in a return of the culture to steady state within 4 d. These results demonstrate the ability of N. oceanica IMET1 to recover from long periods of nitrate deprivation without apparent detriment to the culture and provide proteomic markers for genetic modification. PMID- 23637340 TI - IL-15 in tumor microenvironment causes rejection of large established tumors by T cells in a noncognate T cell receptor-dependent manner. AB - A major challenge of cancer immunotherapy is the persistence and outgrowth of subpopulations that lose expression of the target antigen. IL-15 is a potent cytokine that can promote organ-specific autoimmunity when up-regulated on tissue cells. Here we report that T cells eradicated 2-wk-old solid tumors that expressed IL-15, eliminating antigen-negative cells. In contrast, control tumors that lacked IL-15 expression consistently relapsed. Interestingly, even tumors lacking expression of cognate antigen were rejected when expressing IL-15, indicating that rejection after adoptive T-cell transfer was independent of cognate antigen expression. Nevertheless, the T-cell receptor of the transferred T cells influenced the outcome, consistent with the notion that T-cell receptor activation and effector status determine whether IL-15 can confer lymphokine killer activity-like properties to T cells. The effect was limited to the microenvironment of tumors expressing IL-15; there were no noticeable effects on contralateral tumors lacking IL-15. Taken together, these results indicate that expression of IL-15 in the tumor microenvironment may prevent the escape of antigen loss variants and subsequent tumor recurrence by enabling T cells to eliminate cancer cells lacking cognate antigen expression in a locally restricted manner. PMID- 23637342 TI - Global view of the evolution and diversity of metazoan neuropeptide signaling. AB - Neuropeptides are signaling molecules that commonly act via G protein-coupled receptors (GPCRs) and are generated in neurons by proneuropeptide (pNP) cleavage. Present in both cnidarians and bilaterians, neuropeptides represent an ancient and widespread mode of neuronal communication. Due to the inherent difficulties of analyzing highly diverse and repetitive pNPs, the relationships among different families are often elusive. Using similarity-based clustering and sensitive similarity searches, I obtained a global view of metazoan pNP diversity and evolution. Clustering revealed a large and diffuse network of sequences connected by significant sequence similarity encompassing one-quarter of all families. pNPs belonging to this cluster were also identified in the early branching neuronless animal Trichoplax adhaerens. Clustering of neuropeptide GPCRs identified several orthology groups and allowed the reconstruction of the phyletic distribution of receptor families. GPCR phyletic distribution closely paralleled that of pNPs, indicating extensive conservation and long-term coevolution of receptor-ligand pairs. Receptor orthology and intermediate sequences also revealed the homology of pNPs so far considered unrelated, including allatotropin and orexin. These findings, together with the identification of deuterostome achatin and luqin and protostome opioid pNPs, extended the neuropeptide complement of the urbilaterian. Several pNPs were also identified from the hemichordate Saccoglossus kowalevskii and the cephalochordate Branchiostoma floridae, elucidating pNP evolution in deuterostomes. Receptor ligand conservation also allowed ligand predictions for many uncharacterized GPCRs from nonmodel species. The reconstruction of the neuropeptide-signaling repertoire at deep nodes of the animal phylogeny allowed the formulation of a testable scenario of the evolution of animal neuroendocrine systems. PMID- 23637344 TI - Rational integration of noisy evidence and prior semantic expectations in sentence interpretation. AB - Sentence processing theories typically assume that the input to our language processing mechanisms is an error-free sequence of words. However, this assumption is an oversimplification because noise is present in typical language use (for instance, due to a noisy environment, producer errors, or perceiver errors). A complete theory of human sentence comprehension therefore needs to explain how humans understand language given imperfect input. Indeed, like many cognitive systems, language processing mechanisms may even be "well designed"--in this case for the task of recovering intended meaning from noisy utterances. In particular, comprehension mechanisms may be sensitive to the types of information that an idealized statistical comprehender would be sensitive to. Here, we evaluate four predictions about such a rational (Bayesian) noisy-channel language comprehender in a sentence comprehension task: (i) semantic cues should pull sentence interpretation towards plausible meanings, especially if the wording of the more plausible meaning is close to the observed utterance in terms of the number of edits; (ii) this process should asymmetrically treat insertions and deletions due to the Bayesian "size principle"; such nonliteral interpretation of sentences should (iii) increase with the perceived noise rate of the communicative situation and (iv) decrease if semantically anomalous meanings are more likely to be communicated. These predictions are borne out, strongly suggesting that human language relies on rational statistical inference over a noisy channel. PMID- 23637341 TI - Diversity, host switching and evolution of Plasmodium vivax infecting African great apes. AB - Plasmodium vivax is considered to be absent from Central and West Africa because of the protective effect of Duffy negativity. However, there are reports of persons returning from these areas infected with this parasite and observations suggesting the existence of transmission. Among the possible explanations for this apparent paradox, the existence of a zoonotic reservoir has been proposed. May great apes be this reservoir? We analyze the mitochondrial and nuclear genetic diversity of P. vivax parasites isolated from great apes in Africa and compare it to parasites isolated from travelers returning from these regions of Africa, as well as to human isolates distributed all over the world. We show that the P. vivax sequences from parasites of great apes form a clade genetically distinct from the parasites circulating in humans. We show that this clade's parasites can be infectious to humans by describing the case of a traveler returning from the Central African Republic infected with one of them. The relationship between this P. vivax clade in great apes and the human isolates is discussed. PMID- 23637343 TI - DTF1 is a core component of RNA-directed DNA methylation and may assist in the recruitment of Pol IV. AB - DNA methylation is an important epigenetic mark in many eukaryotic organisms. De novo DNA methylation in plants can be achieved by the RNA-directed DNA methylation (RdDM) pathway, where the plant-specific DNA-dependent RNA polymerase IV (Pol IV) transcribes target sequences to initiate 24-nt siRNA production and action. The putative DNA binding protein DTF1/SHH1 of Arabidopsis has been shown to associate with Pol IV and is required for 24-nt siRNA accumulation and transcriptional silencing at several RdDM target loci. However, the extent and mechanism of DTF1 function in RdDM is unclear. We show here that DTF1 is necessary for the accumulation of the majority of Pol IV-dependent 24-nt siRNAs. It is also required for a large proportion of Pol IV-dependent de novo DNA methylation. Interestingly, there is a group of RdDM target loci where 24-nt siRNA accumulation but not DNA methylation is dependent on DTF1. DTF1 interacts directly with the chromatin remodeling protein CLASSY 1 (CLSY1), and both DTF1 and CLSY1 are associated in vivo with Pol IV but not Pol V, which functions downstream in the RdDM effector complex. DTF1 and DTF2 (a DTF1-like protein) contain a SAWADEE domain, which was found to bind specifically to histone H3 containing H3K9 methylation. Taken together, our results show that DTF1 is a core component of the RdDM pathway, and suggest that DTF1 interacts with CLSY1 to assist in the recruitment of Pol IV to RdDM target loci where H3K9 methylation may be an important feature. Our results also suggest the involvement of DTF1 in an important negative feedback mechanism for DNA methylation at some RdDM target loci. PMID- 23637345 TI - Peptide library-based evaluation of T-cell receptor breadth detects defects in global and regulatory activation in human immunologic diseases. AB - The ability of T-cells to respond to foreign antigens and to appropriately regulate this response is crucial for maintaining immune homeostasis. Using combinatorial peptide libraries, we functionally measured broad T-cell reactivity and observed impaired reactivity in established models of T-cell receptor repertoire restriction and in previously unrecognized disease contexts. By concurrently analyzing T-regulatory and T-effector cells, we show strong functional correlation between these subsets in healthy individuals and, strikingly, that alterations of this balance are associated with T helper type 2 (Th2)-mediated disease in a lymphopenic setting. Finally, we demonstrate that peptide-based priming of polyclonal naive cells with relatively low concentrations skews toward Th2 differentiation. These findings provide unique insight into the pathophysiology and functional consequences of abnormal T-cell repertoires and into differentiation of human naive T-cells. PMID- 23637346 TI - Vanishing lung syndrome mimicking pneumothorax. PMID- 23637347 TI - The atrial natriuretic peptide genetic variant rs5068 is associated with a favorable cardiometabolic phenotype in a Mediterranean population. AB - OBJECTIVE: We hypothesized that the minor allele of the atrial natriuretic peptide (ANP) genetic variant rs5068 is associated with a favorable cardiometabolic phenotype in a general Mediterranean population. RESEARCH DESIGN AND METHODS: We genotyped a random sample of the residents of Ventimiglia di Sicilia, Sicily, for rs5068. RESULTS: Genotype frequencies of rs5068 are AA, 93.5%; AG, 6.4%; and GG, 0.1%. All subsequent analyses are AA versus AG+GG. After adjusting for age and sex, the minor G allele is associated with lower BMI (estimate [SE]: -1.7 kg/m(2) [0.8], P = 0.04). In the AG+GG group, males with HDL cholesterol levels <40 mg/dL are less frequent (P = 0.05) and obesity tends to be less prevalent (P = 0.07). Importantly, the G allele is associated with a lower prevalence of metabolic syndrome (P = 0.02). After adjusting for BMI, the above associations were attenuated. Independently of age, sex, and BMI, the minor allele is also associated with lower systolic blood pressure (-6.0 mmHg [2.5], P = 0.02) and lower prevalence of hypertension (odds ratio 0.41 [95% CI 0.20-0.83], P = 0.01). CONCLUSIONS: The association between the minor allele of rs5068 and a favorable cardiometabolic phenotype that we previously reported in a U.S. population is now replicated in a Mediterranean population in which the G allele of rs5068 is associated with lower blood pressure, BMI, and prevalence of hypertension and metabolic syndrome. These findings may lead to a diagnostic strategy to assess cardiometabolic risk and lay the foundation for the future development of an ANP or ANP-like therapy for metabolic syndrome. PMID- 23637348 TI - Development and validation of a predicting model of all-cause mortality in patients with type 2 diabetes. AB - OBJECTIVE: To develop and validate a parsimonious model for predicting short-term all-cause mortality in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Two cohorts of patients with T2DM were investigated. The Gargano Mortality Study (GMS, n = 679 patients) was the training set and the Foggia Mortality Study (FMS, n = 936 patients) represented the validation sample. GMS and FMS cohorts were prospectively followed up for 7.40 +/- 2.15 and 4.51 +/- 1.69 years, respectively, and all-cause mortality was registered. A new forward variable selection within a multivariate Cox regression was implemented. Starting from the empty model, each step selected the predictor that, once included into the multivariate Cox model, yielded the maximum continuous net reclassification improvement (cNRI). The selection procedure stopped when no further statistically significant cNRI increase was detected. RESULTS: Nine variables (age, BMI, diastolic blood pressure, LDL cholesterol, triglycerides, HDL cholesterol, urine albumin-to-creatinine ratio, and antihypertensive and insulin therapy) were included in the final predictive model with a C statistic of 0.88 (95% CI 0.82 0.94) in the GMS and 0.82 (0.76-0.87) in the FMS. Finally, we used a recursive partition and amalgamation algorithm to identify patients at intermediate and high mortality risk (hazard ratio 7.0 and 24.4, respectively, as compared with those at low risk). A web-based risk calculator was also developed. CONCLUSIONS: We developed and validated a parsimonious all-cause mortality equation in T2DM, providing also a user-friendly web-based risk calculator. Our model may help prioritize the use of available resources for targeting aggressive preventive and treatment strategies in a subset of very high-risk individuals. PMID- 23637349 TI - Awareness, treatment, and control of LDL cholesterol are lower among U.S. adults with undiagnosed diabetes versus diagnosed diabetes. AB - OBJECTIVE: Diabetes is often undiagnosed, resulting in incorrect risk stratification for lipid-lowering therapy. We conducted a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) 2005 2010 to determine the prevalence, awareness, treatment, and control of elevated LDL cholesterol (LDL-C) among U.S. adults with undiagnosed diabetes. RESEARCH DESIGN AND METHODS: Fasting NHANES participants 20 years of age or older who had 10-year Framingham coronary heart disease (CHD) risk scores <20% and were free of CHD or other CHD risk equivalents (n = 5,528) were categorized as having normal glucose, impaired fasting glucose, undiagnosed diabetes, or diagnosed diabetes. High LDL-C was defined by the 2004 Adult Treatment Panel (ATP) III guidelines. RESULTS: The prevalence of diagnosed and of undiagnosed diabetes was 8 and 4%, respectively. Mean LDL-C was 102 +/- 2 mg/dL among those with diagnosed diabetes and 117 +/- 3 mg/dL for those with undiagnosed diabetes (P < 0.001). The prevalence of high LDL-C was similar among individuals with undiagnosed (81%) and diagnosed (77%) diabetes. Among individuals with undiagnosed diabetes and high LDL-C, 38% were aware, 27% were treated, and 16% met the ATP III LDL-C goal for diabetes. In contrast, among individuals with diagnosed diabetes and high LDL-C, 70% were aware, 61% were treated, and 36% met the ATP III goal. Subjects with undiagnosed diabetes remained less likely to have controlled LDL-C after multivariable adjustment (prevalence ratio, 0.42; 95% CI, 0.23-0.80). CONCLUSIONS: Improved screening for diabetes and reducing the prevalence of undiagnosed diabetes may identify individuals requiring more intensive LDL-C reduction. PMID- 23637350 TI - Cardiovascular complications and mortality after diabetes diagnosis for South Asian and Chinese patients: a population-based cohort study. AB - OBJECTIVE: Many non-European ethnic groups have an increased risk for diabetes; however, the published literature demonstrates considerable uncertainty about the rates of diabetes complications among minority populations. The objective of this study was to determine the risks of cardiovascular complications and of mortality after diabetes diagnosis for South Asian and Chinese patients, compared with European patients. RESEARCH DESIGN AND METHODS: A population-based cohort study identified all 491,243 adults with newly diagnosed diabetes in Ontario, Canada, between April 2002 and March 2009. Subjects were followed until March 2011 for the first occurrence of any cardiovascular complication of diabetes (coronary artery disease, stroke, or lower-extremity amputation) and for all-cause mortality. Median follow-up was 4.7 years. RESULTS: The crude incidence of cardiovascular complications after diabetes diagnosis was 17.9 per 1,000 patient years among European patients, 12.0 among South Asian patients, and 7.7 among Chinese patients. After adjusting for baseline characteristics, the cause specific hazard ratios (HRs) for cardiovascular complications relative to European patients were 0.95 (95% CI 0.90-1.00; P = 0.056) and 0.50 (0.46-0.53; P < 0.001) for South Asian and Chinese patients, respectively. Mortality was lower for both minority groups (adjusted HR for South Asian patients 0.56 [95% CI 0.52 0.60]; P < 0.001; for Chinese patients 0.58 [0.55-0.62]; P < 0.001). CONCLUSIONS: Chinese patients were at substantially lower risk than European patients for cardiovascular complications after diabetes diagnosis, whereas South Asian patients were at comparable risk. Mortality after diabetes diagnosis was markedly lower for both minority populations. PMID- 23637351 TI - The expression of inflammatory genes is upregulated in peripheral blood of patients with type 1 diabetes. AB - OBJECTIVE: Our previous gene expression microarray studies identified a number of genes differentially expressed in patients with type 1 diabetes (T1D) and islet autoantibody-positive subjects. This study was designed to validate these gene expression changes in T1D patients and to identify gene expression changes in diabetes complications. RESEARCH DESIGH AND METHODS: We performed high-throughput real-time RT-PCR to validate gene expression changes in peripheral blood mononuclear cells (PBMCs) from a large sample set of 928 T1D patients and 922 control subjects. RESULTS: Of the 18 genes analyzed here, eight genes (S100A8, S100A9, MNDA, SELL, TGFB1, PSMB3, CD74, and IL12A) had higher expression and three genes (GNLY, PSMA4, and SMAD7) had lower expression in T1D patients compared with control subjects, indicating that genes involved in inflammation, immune regulation, and antigen processing and presentation are significantly altered in PBMCs from T1D patients. Furthermore, one adhesion molecule (SELL) and three inflammatory genes mainly expressed by myeloid cells (S100A8, S100A9, and MNDA) were significantly higher in T1D patients with complications (odds ratio [OR] 1.3-2.6, adjusted P value = 0.005-10(-8)), especially those patients with neuropathy (OR 4.8-7.9, adjusted P value <0.005). CONCLUSIONS: These findings suggest that inflammatory mediators secreted mainly by myeloid cells are implicated in T1D and its complications. PMID- 23637352 TI - Metabolically healthy obesity and risk of mortality: does the definition of metabolic health matter? AB - OBJECTIVE: To assess the association of a "metabolically healthy obese" phenotype with mortality using five definitions of metabolic health. RESEARCH DESIGN AND METHODS: Adults (n = 5,269; 71.7% men) aged 39-62 years in 1991 through 1993 provided data on BMI and metabolic health, defined using data from the Adult Treatment Panel-III (ATP-III); criteria from two studies; and the Matsuda and homeostasis model assessment (HOMA) indices. Cross-classification of BMI categories and metabolic status (healthy/unhealthy) created six groups. Cox proportional hazards regression models were used to analyze associations with all cause and cardiovascular disease (CVD) mortality during a median follow-up of 17.7 years. RESULTS: A total of 638 individuals (12.1% of the cohort) were obese, of whom 9-41% were metabolically healthy, depending on the definition. Regardless of the definition, compared with metabolically healthy, normal-weight individuals, both the metabolically healthy obese (hazard ratios [HRs] ranged from 1.81 [95% CI 1.16-2.84] for ATP-III to 2.30 [1.13-4.70] for the Matsuda index) and the metabolically abnormal obese (HRs ranged from 1.57 [1.08-2.28] for the Matsuda index to 2.05 [1.44-2.92] for criteria defined in a separate study) had an increased risk of mortality. The only exception was the lack of excess risk using the HOMA criterion for the metabolically healthy obese (1.08; 0.67 1.74). Among the obese, the risk of mortality did not vary as a function of metabolic health apart from when using the HOMA criterion (1.93; 1.15-3.22). Similar results were obtained for cardiovascular mortality. CONCLUSIONS: For most definitions of metabolic health, both metabolically healthy and unhealthy obese patients carry an elevated risk of mortality. PMID- 23637353 TI - Diabetes prevention and treatment strategies: are we doing enough? AB - OBJECTIVE: Effective interventions to prevent, delay, or remit diabetes are currently available. However, their impact on the prevalence of diabetes at the population level is unknown. This study aimed to estimate the impact of a range of diabetes interventions on the population prevalence of diabetes for Australian adults between 2010 and 2025. RESEARCH DESIGN AND METHODS: We used the Australian Diabetes Projection Model to estimate the impact of a population-wide strategy, high-risk prevention, surgical diabetes treatment, and a combination strategy on the future population prevalence of diabetes and to estimate the number of diabetes cases that could be potentially prevented in the year 2025. RESULTS: We estimate that a population-wide strategy would reduce the number of diabetes cases by 60,000-85,000 in 2025 from an estimated 2 million cases under the status quo scenario. A high-risk prevention strategy would result in 106,000 to 150,000 fewer cases of diabetes in 2025, and surgically induced weight loss would result in 3,000-6,000 fewer cases. No single intervention, or combination of interventions, reversed the increasing trend in diabetes prevalence over the next 15 years. CONCLUSIONS: To reverse upward trends in diabetes prevalence in future years, it is essential that current approaches to diabetes prevention and treatment are optimized and implemented and that alternative approaches to reduce the prevalence of diabetes at a population level are developed. PMID- 23637354 TI - Secular changes in the age-specific prevalence of diabetes among U.S. adults: 1988-2010. AB - OBJECTIVE: To examine the age-specific changes of prevalence of diabetes among U.S. adults during the past 2 decades. RESEARCH DESIGN AND METHODS: This study included 22,586 adults sampled in three periods of the National Health and Nutrition Examination Survey (1988-1994, 1999-2004, and 2005-2010). Diabetes was defined as having self-reported diagnosed diabetes or having a fasting plasma glucose level >= 126 mg/dL or HbA1c >= 6.5% (48 mmol/mol). RESULTS: The number of adults with diabetes increased by 75% from 1988-1994 to 2005-2010. After adjusting for sex, race/ethnicity, and education level, the prevalence of diabetes increased over the two decades across all age-groups. Younger adults (20 34 years of age) had the lowest absolute increase in diabetes prevalence of 1.0%, followed by middle-aged adults (35-64) at 2.7% and older adults (>= 65) at 10.0% (all P < 0.001). Comparing 2005-2010 with 1988-1994, the adjusted prevalence ratios (PRs) by age-group were 2.3, 1.3, and 1.5 for younger, middle-aged, and older adults, respectively (all P < 0.05). After additional adjustment for body mass index (BMI), waist-to-height ratio (WHtR), or waist circumference (WC), the adjusted PR remained statistically significant only for adults >= 65 years of age. CONCLUSIONS: During the past two decades, the prevalence of diabetes increased across all age-groups, but adults >= 65 years of age experienced the largest increase in absolute change. Obesity, as measured by BMI, WHtR, or WC, was strongly associated with the increase in diabetes prevalence, especially in adults <65. PMID- 23637356 TI - Work stress, sense of coherence, and risk of type 2 diabetes in a prospective study of middle-aged Swedish men and women. AB - OBJECTIVE: To investigate the prospective influence of work stress on type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: This population-based cohort included 3,205 women and 2,227 men, aged 35-56 years, with baseline normal glucose tolerance measured with oral glucose tolerance test. At follow-up 8-10 years later, T2D was diagnosed in 60 women and 111 men. Work stress factors evaluated by questionnaire (i.e., demands, decision latitude, job strain, shift work, overtime work, and also sense of coherence) were studied in association with T2D. Odds ratios (ORs) and 95% CIs adjusted for age, education, BMI, physical activity, smoking, family history of diabetes, and psychological distress were calculated. RESULTS: In women, low decision latitude was associated with T2D on its own (OR 2.4 [95% CI 1.1-5.2]) and combined with high demands: job strain (OR 4.2 [2.0-8.7]), adjusted for all available potential confounders. Also, shift work increased the risk of T2D in women (OR 2.2 [1.0-4.7]) when adjusted for age, education, and psychological distress, although this risk was diluted after multifactor adjustment (OR 1.9 [0.8-4.4]). In men, high work demands and high strain decreased the risk of T2D (OR 0.5 [0.3-0.9]) for both measures, as did an active job (high demands and high decision latitude, OR 0.4 [0.2-0.9]). CONCLUSIONS: Work stress and shift work may contribute to the development of T2D in women. In men, the risk was decreased by high work demands, high strain, and an active job. PMID- 23637355 TI - Obesity and the food environment: income and ethnicity differences among people with diabetes: the Diabetes Study of Northern California (DISTANCE). AB - OBJECTIVE: It is unknown whether any association between neighborhood food environment and obesity varies according to individual income and/or race/ethnicity. The objectives of this study were to test whether there was an association between food environments and obesity among adults with diabetes and whether this relationship differed according to individual income or race/ethnicity. RESEARCH DESIGN AND METHODS: Subjects (n = 16,057) were participants in the Diabetes Study of Northern California survey. Kernel density estimation was used to create a food environment score for each individual's residence address that reflected the mix of healthful and unhealthful food vendors nearby. Logistic regression models estimated the association between the modeled food environment and obesity, controlling for confounders, and testing for interactions between food environment and race/ethnicity and income. RESULTS: The authors found that more healthful food environments were associated with lower obesity in the highest income groups (incomes 301-600% and >600% of U.S. poverty line) among whites, Latinos, and Asians. The association was negative, but smaller and not statistically significant, among high-income blacks. On the contrary, a more healthful food environment was associated with higher obesity among participants in the lowest-income group (<100% poverty threshold), which was statistically significant for black participants in this income category. CONCLUSIONS: These findings suggest that the availability of healthful food environments may have different health implications when financial resources are severely constrained. PMID- 23637357 TI - Chronotype is independently associated with glycemic control in type 2 diabetes. AB - OBJECTIVE: To examine whether chronotype and daily caloric distribution are associated with glycemic control in patients with type 2 diabetes independently of sleep disturbances. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes had a structured interview and completed questionnaires to collect information on diabetes history and habitual sleep duration, quality, and timing. Shift workers were excluded. A recently validated construct derived from mid-sleep time on weekends was used as an indicator of chronotype. One-day food recall was used to compute the temporal distribution of caloric intake. Hierarchical linear regression analyses controlling for demographic and sleep variables were computed to determine whether chronotype was associated with HbA1c values and whether this association was mediated by a higher proportion of caloric intake at dinner. RESULTS: We analyzed 194 completed questionnaires. Multiple regression analyses adjusting for age, sex, race, BMI, insulin use, depressed mood, diabetes complications, and perceived sleep debt found that chronotype was significantly associated with glycemic control (P = 0.001). This association was partially mediated by a greater percentage of total daily calories consumed at dinner. CONCLUSIONS: Later chronotype and larger dinner were associated with poorer glycemic control in patients with type 2 diabetes independently of sleep disturbances. These results suggest that chronotype may be predictive of disease outcomes and lend further support to the role of the circadian system in metabolic regulation. PMID- 23637358 TI - Introduction of aequorin into zebrafish embryos for recording Ca(2+) signaling during the first 48 h of development. AB - Ca(2+) signals, whether transient pulses, propagating waves, or long-duration, steady gradients, are generally considered to play an important role in the pattern-forming events that occur during vertebrate development. One vertebrate that has long been a favorite of embryologists because of its ex utero development and the optical clarity of its embryos is the zebrafish, Danio rerio. Using the bioluminescent Ca(2+) reporter aequorin, distinct Ca(2+) signals have been reported for at least the first 48 h of zebrafish development, with signals becoming progressively more complex as the embryo develops. Here we provide a general introduction to aequorin and its use in monitoring Ca(2+) signals and discuss methods for introducing aequorin into zebrafish embryos. PMID- 23637359 TI - Estimating length in biological structures. AB - Length estimates of particular features of biological tissues can be useful in evaluating function. Such estimates have been notoriously difficult to obtain because of the requirement for an isotropic interaction between the area probes and the linear features of cells and tissues, which are most likely not isotropically oriented. For complex embedded structures, such as subdivisions of the brain, the turning of the tissue before sectioning that is needed to ensure an isotropic interaction has made it difficult to delineate many regions of interest and limited the number of unbiased stereological studies of length. The recent development of a virtual isotropic spherical probe, the spaceball, makes it relatively easy for the isotropic interaction between probe and structure to be realized. This article describes the use of the spaceball probe to estimate length, and gives an example of estimating total capillary length in CA1 stratum radiatum of the human hippocampus. PMID- 23637360 TI - Microinjecting holo-aequorin into dechorionated and intact zebrafish embryos. AB - The injection of holo-aequorin into embryos at the one-cell stage, along with the use of a simple photomultiplier tube or luminescence imaging system, allows transient localized elevations of free cytosolic Ca(2+) to be recorded and observed during the first 24 h of zebrafish development. The technique for loading dechorionated or intact one-cell stage zebrafish embryos with holo aequorin is described here. PMID- 23637361 TI - Reconstitution of holo-aequorin with apoaequorin mRNA and coelenterazine in zebrafish embryos. AB - When holo-aequorin is injected into zebrafish embryos at the one-cell stage, it is normally depleted by ~24 h post-fertilization (hpf). In order to acquire Ca(2+) signaling information from embryos older than 24 hpf, we have developed a protocol to express apoaequorin transiently in embryos, after which we reconstitute active holo-aequorin in vivo by introducing the cofactor coelenterazine into the developing embryo. This protocol describes the preparation of apoaequorin mRNA, followed by microinjection into embryos and incubation with coelenterazine to reconstitute holo-aequorin. PMID- 23637362 TI - Tips for preparing mRNA-Seq libraries from poly(A)+ mRNA for Illumina transcriptome high-throughput sequencing. AB - Many investigators who do high-throughput sequencing of mRNA (mRNA-Seq) use kits for library preparation purchased from Illumina. Recognizing that these kits are continually being updated and improved, we provide here some background information, tips, and troubleshooting advice for the kits available at the time of this writing. PMID- 23637363 TI - Purification of rat and mouse astrocytes by immunopanning. AB - We describe the use of immunopanning to purify rodent astrocytes. Immunopanning of astrocytes permits the prospective isolation of astrocytes from the rodent brain. Prospective isolation refers to the direct selection of cells without multiple steps that extend over a few days, thereby permitting the selection of a representative proportion of the astrocytes from the cortex. Because immunopanning is a very gentle process, the cells are viable at the end of the preparation and can be cultured in a serum-free medium containing heparin-binding EGF-like growth factor (HBEGF), the critical survival factor of astrocytes in vitro, for at least 2 wk. This protocol was initially established and verified with rats, but modifications for the purification of mouse cells are also described here. PMID- 23637365 TI - Fluorescence molecular tomography of brain tumors in mice. AB - Fluorescence molecular tomography of tissues is a method that three-dimensionally resolves fluorescence biodistribution in vivo, with applications in small-animal research and pre-clinical diagnostics. There are many alternative imaging geometries in optical tomographic experimental systems, but in general, all imaging setups consist of four subsystems: illumination, animal mount, imaging, and automation and data acquisition (i.e., electronics and computer). Here we refer to charge-coupled device (CCD)-based systems that work in trans illumination (i.e., illumination and detection occur on opposite sides of the subject), while a mouse or other small animal is rotated through 360 degrees to allow photon acquisition from multiple projections. We present a procedure to tomographically reconstruct the biodistribution of fluorescence in small animals. The imaging system and equipment are described, the step-by-step image acquisition and preliminary image-processing methods are presented, and the tomographic reconstruction procedure is outlined. Finally, the method is showcased by imaging the fluorescence activity of a brain tumor of a glioblastoma mouse model. PMID- 23637366 TI - Digital micromirror devices: principles and applications in imaging. AB - A digital micromirror device (DMD) is an array of individually switchable mirrors that can be used in many advanced optical systems as a rapid spatial light modulator. With a DMD, several implementations of confocal microscopy, hyperspectral imaging, and fluorescence lifetime imaging can be realized. The DMD can also be used as a real-time optical processor for applications such as the programmable array microscope and compressive sensing. Advantages and disadvantages of the DMD for these applications as well as methods to overcome some of the limitations will be discussed in this article. Practical considerations when designing with the DMD and sample optical layouts of a completely DMD-based imaging system and one in which acousto-optic deflectors (AODs) are used in the illumination pathway are also provided. PMID- 23637364 TI - Quantitative imaging of morphogen gradients in Drosophila imaginal discs. AB - Cells at different positions in a developing tissue receive different concentrations of signaling molecules, called morphogens, and this influences their cell fate. Morphogen concentration gradients have been proposed to control patterning as well as growth in many developing tissues. Some outstanding questions about tissue patterning by morphogen gradients are the following: What are the mechanisms that regulate gradient formation and shape? Is the positional information encoded in the gradient sufficiently precise to determine the positions of target gene domain boundaries? What are the temporal dynamics of gradients and how do they relate to patterning and growth? These questions are inherently quantitative in nature and addressing them requires measuring morphogen concentrations in cells, levels of downstream signaling activity, and kinetics of morphogen transport. Here we first present methods for quantifying morphogen gradient shape in which the measurements can be calibrated to reflect actual morphogen concentrations. We then discuss using fluorescence recovery after photobleaching to study the kinetics of morphogen transport at the tissue level. Finally, we present particle tracking as a method to study morphogen intracellular trafficking. PMID- 23637368 TI - DNase I footprinting. AB - DNase I footprinting has found a wide following for both identifying and characterizing DNA-protein interactions, particularly because of its simplicity. The concept is that a partial digestion by DNase I of a uniquely (32)P-end labeled fragment will generate a ladder of fragments, whose mobilities on a denaturing acrylamide gel and whose positions in a subsequent autoradiograph will represent the distance from the end label to the points of cleavage. Bound protein prevents binding of DNase I in and around its binding site and thus generates a "footprint" in the cleavage ladder. The distance from the end label to the edges of the footprint represents the position of the protein-binding site on the DNA fragment. The position of the binding site can be determined by electrophoresing a DNA sequencing ladder alongside the footprint. DNase I cannot bind directly adjacent to a DNA-bound protein because of steric hindrance. Hence, the footprint gives a broad indication of the binding site, generally 8-10 base pairs (bp) larger than the site itself. PMID- 23637367 TI - Imaging sodium in axons and dendrites. AB - This protocol describes a one-photon method to detect the time course and the spatial distribution of intracellular sodium ion concentrations [Na(+)](i), which result from action potentials and synaptic activity in different regions of neurons in brain slices. The one-photon technique has been applied to several different cell types and can likely be applied to other neurons in brain slices, particularly those that are relatively flat. Imaging of [Na(+)](i) changes is much less common than imaging of [Ca(2+)](i) changes, in part because typical signals are much smaller and more difficult to detect. However, with careful experiments, accurate and interesting results can be obtained. In this protocol, a cell is loaded with an indicator that responds to Na(+), the cell is stimulated, and the spatial and temporal characteristics of the fluorescence changes are recorded with an appropriate detector or camera. PMID- 23637369 TI - Preparation of (32)P-end-labeled DNA fragments for performing DNA-binding experiments. AB - The generation of a uniquely (32)P-end-labeled DNA fragment is essential for DNA binding experiments such as DNase I footprinting and ethylation interference. We describe here a protocol for end-labeling a restriction fragment. For a plasmid DNA bearing a region containing the binding site of interest, cleaving with a single restriction endonuclease generates a 5' overhang containing a phosphate. This is generally necessary for both common forms of fragment end-labeling: phosphorylation with polynucleotide kinase and "filling in the end" with DNA polymerases (e.g., Klenow fragment). For the phosphorylation reaction, as described here, the phosphate is removed with calf intestinal phosphatase or bacterial alkaline phosphatase, and the resulting free 5'-OH is phosphorylated with polynucleotide kinase and [gamma-(32)P]ATP. This generates a plasmid labeled at each end with gamma-(32)P. The molar amount of plasmid DNA must be below the amount of ATP added to the reaction and the ATP must be of sufficiently high specific activity to generate a fragment labeled to the extent necessary for many DNA-binding experiments. To generate a uniquely end-labeled DNA fragment, the labeled plasmid is heat-treated to inactivate any remaining kinase and recleaved with a second endonuclease, releasing a short DNA fragment and a longer vector fragment. The DNA fragment is purified from the labeled vector on a 5%-8% native polyacrylamide gel. The preparation and labeling of DNA restriction fragments typically takes 1-2 d. PMID- 23637370 TI - Measuring vascular permeability in mice. AB - Noninvasive techniques have been developed for the assessment of vascular parameters, including vascular permeability, in normal and diseased tissues of mice. In this protocol, mice are injected with an appropriate fluorescent tracer. The effective average vascular permeability (P) of a region of vessels is measured by single-photon microscopy. Additionally, the vascular permeability of individual vessel segments within ~600 um of a tumor/window interface is measured by multiphoton laser-scanning microscopy (MPLSM). PMID- 23637371 TI - Inducing RNAi in Drosophila cells by transfection with dsRNA. AB - In Drosophila cells, RNA interference (RNAi) can be triggered by synthetic long double-stranded RNAs (dsRNAs). For many Drosophila cell lines and cell types, passive dsRNA uptake is inefficient. More complete silencing responses can often be obtained in Drosophila S2 cells using transfection, perhaps because higher levels of intracellular dsRNA are achieved. In this protocol, S2 cells are transfected with dsRNA using QIAGEN's Effectene reagent, which has proven to be reliable for many investigators. A plasmid DNA can also be included in the transfection mix to provide additional functionality. The plasmid DNA can encode, for example, a reporter of the activity of a pathway or specific transcription factor, or a marker that allows visualization of some cellular behavior or structure. It is also useful to include a plasmid that encodes a fluorescent protein simply to monitor transfection efficiency. PMID- 23637372 TI - Fragmentation of whole-transcriptome RNA using E. coli RNase III. AB - High-throughput sequencing (HTS) methods can provide short sequence reads for many millions of individual molecules in a sample, allowing the use of sequencing to measure the abundance of RNA molecules. To quantify the amount of a particular sequence in a sample of large RNAs (e.g., mRNAs), it is important to fragment the RNA into short pieces that can be ligated to oligonucleotides that allow polymerase chain reaction (PCR) amplification and sequencing. The most desired end structure of RNA for such ligation steps is a 5' phosphate and a 3' OH. Thus, enzymes that leave these groups after cleavage are of particular utility, avoiding the need to dephosphorylate the 3' end with phosphatases or phosphorylate the 5' end with kinase before proceeding. One such enzyme, RNase III, is widely available. Although it primarily cuts duplex RNA, this specificity is salt- and concentration-dependent, and many RNAs that lack strong extended duplexes are nonetheless susceptible to cleavage at many spots. RNA fragmentation by RNase III does not seem to grossly affect the distribution of RNA sequencing reads. Thus, it has become a standard method for creating nominally representative pools of transcriptome sequences with 5' phosphates and 3' OH for library construction. Three steps in preparing fragmented transcriptome RNA for sequencing library construction are described here: (1) fragmenting the RNA with RNase III to the extent that ~60-100-nucleotide fragments are created, (2) purifying the RNA from the RNase III reaction, and (3) analyzing the digestion products for their suitability in library production. PMID- 23637373 TI - Can large simple trials help us understand when and how to use generic drugs for uncommon diseases? PMID- 23637374 TI - Quality guidelines for systemic lupus erythematosus: slow but steady progress. PMID- 23637375 TI - C'mon, CAM. PMID- 23637376 TI - The role of complementary and alternative medicine (CAM) in rheumatology--it's time for integrative medicine. PMID- 23637377 TI - Five-year data from the REFLEX study: a different interpretation. PMID- 23637378 TI - Systemic lupus erythematosus disease activity index 2000 responder index-50 website. PMID- 23637379 TI - Cutaneous manifestations and comorbidities in 60 cases of Takayasu arteritis. PMID- 23637380 TI - Rapid interaction between CTLA4-Ig (abatacept) and synovial macrophages from patients with rheumatoid arthritis. PMID- 23637382 TI - Higher-dose Anakinra is effective in a case of medically refractory macrophage activation syndrome. PMID- 23637381 TI - Decreased expression of nicotinamide phosphoribosyltransferase in patients with juvenile idiopathic arthritis receiving methotrexate. PMID- 23637383 TI - Severe vocal cord dysfunction: an unusual complication of juvenile dermatomyositis. PMID- 23637384 TI - Microvascular angina: an underappreciated cause of SLE chest pain. PMID- 23637386 TI - Medicare mandate for claims-based functional data collection: an opportunity to advance care, or a regulatory burden? PMID- 23637388 TI - On "psychometric properties of the outpatient physical therapy improvement in movement assessment log..." Riddle DL, Stratford PW, Carter TL, et al. Phys Ther. 2013;93:672-680. PMID- 23637387 TI - In tribute: Dr. Jacquelin Perry. PMID- 23637389 TI - Stranded dolphin stomach contents represent the free-ranging population's diet. AB - Diet is a fundamental aspect of animal ecology. Cetacean prey species are generally identified by examining stomach contents of stranded individuals. Critical uncertainty in these studies is whether samples from stranded animals are representative of the diet of free-ranging animals. Over two summers, we collected faecal and gastric samples from healthy free-ranging individuals of an extensively studied bottlenose dolphin population. These samples were analysed by molecular prey detection and these data compared with stomach contents data derived from stranded dolphins from the same population collected over 22 years. There was a remarkable consistency in the prey species composition and relative amounts between the two datasets. The conclusions of past stomach contents studies regarding dolphin habitat associations, prey selection and proposed foraging mechanisms are supported by molecular data from live animals and the combined dataset. This is the first explicit test of the validity of stomach contents analysis for accurate population-scale diet determination of an inshore cetacean. PMID- 23637390 TI - Odour cues influence predation risk at artificial bat roosts in urban bushland. AB - Odours that accumulate from roosting can attract predators and increase predation risk. Consequently, selection should favour strategies that allow prey to evade detection by predators, including changing roosts. Insectivorous bats that roost in tree hollows regularly switch roosts and roost in different sized groups, strategies that would alter the accumulation of roost odours and are hypothesized to reduce predation risk. We experimentally manipulated the amount and refresh rate of roosting odour cues at 90 artificial bat roosts in Sydney, Australia, to test the hypothesis that odours increase predator visitation. Predators visited roosts with bat faeces significantly more often than untreated control roosts. Roosts with small amounts of faeces mimicking sites used by solitary bats had the greatest rate of visitation. This suggests that bats roosting alone, rather than in groups, have a greater likelihood of disturbance or predation. Roost switching probably decreases the predictability of finding occupied roosts; however, we show that all roosts (those currently or recently occupied) were visited by predators, suggesting generalist urban predators readily investigate potential roosts. This is the first demonstration that bat odours are attractive to predators that use olfactory cues, showing that bats are at risk of predation in visually cryptic roosts. PMID- 23637391 TI - The behavioural and genetic mating system of the sand tiger shark, Carcharias taurus, an intrauterine cannibal. AB - Sand tiger sharks (Carcharias taurus) have an unusual mode of reproduction, whereby the first embryos in each of the paired uteri to reach a certain size ('hatchlings') consume all of their smaller siblings during gestation ('embryonic cannibalism' or EC). If females commonly mate with multiple males ('behavioural polyandry') then litters could initially have multiple sires. It is possible, however, that EC could exclude of all but one of these sires from producing offspring thus influencing the species genetic mating system ('genetic monogamy'). Here, we use microsatellite DNA profiling of mothers and their litters (n = 15, from two to nine embryos per litter) to quantify the frequency of behavioural and genetic polyandry in this system. We conservatively estimate that nine of the females we examined (60%) were behaviourally polyandrous. The genetic mating system was characterized by assessing sibling relationships between hatchlings and revealed only 40 per cent genetic polyandry (i.e. hatchlings were full siblings in 60% of litters). The discrepancy stemmed from three females that were initially fertilized by multiple males but only produced hatchlings with one of them. This reveals that males can be excluded even after fertilizing ova and that some instances of genetic monogamy in this population arise from the reduction in litter size by EC. More research is needed on how cryptic post-copulatory and post-zygotic processes contribute to determining paternity and bridging the behavioural and genetic mating systems of viviparous species. PMID- 23637392 TI - Queen control of a key life-history event in a eusocial insect. AB - In eusocial insects, inclusive fitness theory predicts potential queen-worker conflict over the timing of events in colony life history. Whether queens or workers control the timing of these events is poorly understood. In the bumble bee Bombus terrestris, queens exhibit a 'switch point' in which they switch from laying diploid eggs yielding females (workers and new queens) to laying haploid eggs yielding males. By rearing foundress queens whose worker offspring were removed as pupae and sexing their eggs using microsatellite genotyping, we found that queens kept in the complete absence of adult workers still exhibit a switch point. Moreover, the timing of their switch points relative to the start of egg laying did not differ significantly from that of queens allowed to produce normal colonies. The finding that bumble-bee queens can express the switch point in the absence of workers experimentally demonstrates queen control of a key life history event in eusocial insects. In addition, we found no evidence that workers affect the timing of the switch point either directly or indirectly via providing cues to queens, suggesting that workers do not fully express their interests in queen-worker conflicts over colony life history. PMID- 23637393 TI - Stick tight: suction adhesion on irregular surfaces in the northern clingfish. AB - The northern clingfish, Gobiesox maeandricus, is able to adhere to slippery, fouled and irregular surfaces in the marine intertidal environment. We have found that the fish can adhere equally well to surfaces with a broad range of surface roughness, from the finest sandpaper (R(a) = 15 um) to textures suitable for removing finish from flooring (R(a) = 269 um). The fishes outperform man-made suction cups, which only adhere to the smoothest surfaces. The adhesive forces of clingfish correspond to pressures 0.2-0.5 atm below ambient and are 80-230 times the body weight of the fish. The tenacity appears related to hierarchically structured microvilli around the edges of the adhesive disc that are similar in size and aspect ratio to the setae found on the feet of geckoes, spiders and insects. This points to a possible biomimetic solution to the problem of reversibly adhering to irregular, submerged surfaces. PMID- 23637394 TI - Intranasal administration of antibody-bound respiratory syncytial virus particles efficiently primes virus-specific immune responses in mice. AB - Infants are protected from a severe respiratory syncytial virus (RSV) infection in the first months of life by maternal antibodies or by prophylactically administered neutralizing antibodies. Efforts are under way to produce RSV specific antibodies with increased neutralizing capacity compared to the currently licensed palivizumab. While clearly beneficial during primary infections, preexisting antibodies might affect the onset of adaptive immune responses and the ability to resist subsequent RSV infections. Therefore, we addressed the question of how virus neutralizing antibodies influence the priming of subsequent adaptive immune responses. To test a possible role of the neonatal Fc receptor (FcRn) in this process, we compared the responses in C57BL/6 wild type (WT) and FcRn(-/-) mice. We observed substantial virus-specific T-cell priming and B-cell responses in mice primed with RSV IgG immune complexes resulting in predominantly Th1-type CD4(+) T-cell and IgG2c antibody responses upon live-virus challenge. RSV-specific CD8(+) T cells were primed as well. Activation of these adaptive immune responses was independent of FcRn. Thus, neutralizing antibodies that localize to the airways and prevent infection related routes of antigen processing can still facilitate antigen presentation of neutralized virus particles and initiate adaptive immune responses against RSV. PMID- 23637395 TI - Annexin A2 and S100A10 regulate human papillomavirus type 16 entry and intracellular trafficking in human keratinocytes. AB - Human papillomaviruses (HPVs) cause benign and malignant tumors of the mucosal and cutaneous epithelium. The initial events regulating HPV infection impact the establishment of viral persistence, which is requisite for malignant progression of HPV-infected lesions. However, the precise mechanisms involved in HPV entry into host cells, including the cellular factors regulating virus uptake, are not clearly defined. We show that HPV16 exposure to human keratinocytes initiates epidermal growth factor receptor (EGFR)-dependent Src protein kinase activation that results in phosphorylation and extracellular translocation of annexin A2 (AnxA2). HPV16 particles interact with AnxA2 in association with S100A10 as a heterotetramer at the cell surface in a Ca(2+)-dependent manner, and the interaction appears to involve heparan-sulfonated proteoglycans. We show multiple lines of evidence that this interaction promotes virus uptake into host cells. An antibody to AnxA2 prevents HPV16 internalization, whereas an antibody to S100A10 blocks infection at a late endosomal/lysosomal site. These results suggest that AnxA2 and S100A10 have separate roles during HPV16 binding, entry, and trafficking. Our data additionally imply that AnxA2 and S100A10 may be involved in regulating the intracellular trafficking of virus particles prior to nuclear delivery of the viral genome. PMID- 23637396 TI - Influence of mismatch of Env sequences on vaccine protection by live attenuated simian immunodeficiency virus. AB - Vaccine/challenge experiments that utilize live attenuated strains of simian immunodeficiency virus (SIV) in monkeys may be useful for elucidating what is needed from a vaccine in order to achieve protective immunity. Derivatives of SIVmac239 and SIVmac239Deltanef were constructed in which env sequences were replaced with those of the heterologous strain E543; these were then used in vaccine/challenge experiments. When challenge occurred at 22 weeks, 10 of 12 monkeys exhibited apparent sterilizing immunity despite a mismatch of Env sequences, compared to 12 of 12 monkeys with apparent sterilizing immunity when challenge virus was matched in its Env sequence. However, when challenge occurred at 6 weeks, 6 of 6 SIV239Deltanef-immunized monkeys became superinfected by challenge virus mismatched in its Env sequence (SIV239/EnvE543). These results contrast markedly not only with the results of the week 22 challenge but also with the sterilizing immunity observed in 5 of 5 SIV239Deltanef-immunized rhesus monkeys challenged at 5 weeks with SIV239, i.e., with no mismatch of Env sequences. We conclude from these studies that a mismatch of Env sequences in the challenge virus can have a dramatic effect on the extent of apparent sterilizing immunity when challenge occurs relatively early, 5 to 6 weeks after the nef deleted SIV administration. However, by 22 weeks, mismatch of Env sequences has little or no influence on the degree of protection against challenge virus. Our findings suggest that anti-Env immune responses are a key component of the protective immunity elicited by live attenuated, nef-deleted SIV. PMID- 23637398 TI - Genetic requirement for hemagglutinin glycosylation and its implications for influenza A H1N1 virus evolution. AB - Influenza A virus has evolved and thrived in human populations. Since the 1918 influenza A pandemic, human H1N1 viruses had acquired additional N-linked glycosylation (NLG) sites within the globular head region of hemagglutinin (HA) until the NLG-free HA head pattern of the 1918 H1N1 virus was renewed with the swine-derived 2009 pandemic H1N1 virus. Moreover, the HA of the 2009 H1N1 virus appeared to be antigenically related to that of the 1918 H1N1 virus. Hence, it is possible that descendants of the 2009 H1N1 virus might recapitulate the acquisition of HA head glycosylation sites through their evolutionary drift as a means to evade preexisting immunity. We evaluate here the evolution signature of glycosylations found in the globular head region of H1 HA in order to determine their impact in the virulence and transmission of H1N1 viruses. We identified a polymorphism at HA residue 147 associated with the acquisition of glycosylation at residues 144 and 172. By in vitro and in vivo analyses using mutant viruses, we also found that the polymorphism at HA residue 147 compensated for the loss of replication, virulence, and transmissibility associated with the presence of the N-linked glycans. Our findings suggest that the polymorphism in H1 HA at position 147 modulates viral fitness by buffering the constraints caused by N-linked glycans and provide insights into the evolution dynamics of influenza viruses with implications in vaccine immunogenicity. PMID- 23637400 TI - Cellular chaperonin CCTgamma contributes to rabies virus replication during infection. AB - Rabies, as the oldest known infectious disease, remains a serious threat to public health worldwide. The eukaryotic cytosolic chaperonin TRiC/CCT complex facilitates the folding of proteins through ATP hydrolysis. Here, we investigated the expression, cellular localization, and function of neuronal CCTgamma during neurotropic rabies virus (RABV) infection using mouse N2a cells as a model. Following RABV infection, 24 altered proteins were identified by using two dimensional electrophoresis and mass spectrometry, including 20 upregulated proteins and 4 downregulated proteins. In mouse N2a cells infected with RABV or cotransfected with RABV genes encoding nucleoprotein (N) and phosphoprotein (P), confocal microscopy demonstrated that upregulated cellular CCTgamma was colocalized with viral proteins N and P, which formed a hollow cricoid inclusion within the region around the nucleus. These inclusions, which correspond to Negri bodies (NBs), did not form in mouse N2a cells only expressing the viral protein N or P. Knockdown of CCTgamma by lentivirus-mediated RNA interference led to significant inhibition of RABV replication. These results demonstrate that the complex consisting of viral proteins N and P recruits CCTgamma to NBs and identify the chaperonin CCTgamma as a host factor that facilitates intracellular RABV replication. This work illustrates how viruses can utilize cellular chaperonins and compartmentalization for their own benefit. PMID- 23637397 TI - Response of hepatitis C virus to long-term passage in the presence of alpha interferon: multiple mutations and a common phenotype. AB - Cell culture-produced hepatitis C virus (HCV) has been subjected to up to 100 serial passages in human hepatoma cells in the absence or presence of different doses of alpha interferon (IFN-alpha). Virus survival, genetic changes, fitness levels, and phenotypic traits have been examined. While high initial IFN-alpha doses (increasing from 1 to 4 IU/ml) did not allow HCV survival beyond passage 40, a gradual exposure (from 0.25 to 10 IU/ml) allowed the virus to survive for at least 100 passages. The virus passaged in the presence of IFN-alpha acquired IFN-alpha resistance as evidenced by enhanced progeny production and viral protein expression in an IFN-alpha environment. A partial IFN-alpha resistance was also noted in populations passaged in the absence of IFN-alpha. All lineages acquired adaptative mutations, and multiple, nonsynonymous mutations scattered throughout the genome were present in IFN-alpha-selected populations. Comparison of consensus sequences indicates a dominance of synonymous versus nonsynonymous substitutions. IFN-alpha-resistant populations displayed decreased sensitivity to a combination of IFN-alpha and ribavirin. A phenotypic trait common to all assayed viral populations is the ability to increase shutoff host cell protein synthesis, accentuated in infections with IFN-alpha-selected populations carried out in the presence of IFN-alpha. The trait was associated with enhanced phosphorylation of protein kinase R (PKR) and eIF2alpha, although other contributing factors are likely. The results suggest that multiple, independent mutational pathways can confer IFN-alpha resistance to HCV and might explain why no unified picture has been obtained regarding IFN-alpha resistance in vivo. PMID- 23637399 TI - Structural and functional characterization of the mumps virus phosphoprotein. AB - The phosphoprotein (P) is virally encoded by the Rhabdoviridae and Paramyxoviridae in the order Mononegavirales. P is a self-associated oligomer and forms complexes with the large viral polymerase protein (L), the nucleocapsid protein (N), and the assembled nucleocapsid. P from different viruses has shown structural diversities even though their essential functions are the same. We systematically mapped the domains in mumps virus (MuV) P and investigated their interactions with nucleocapsid-like particles (NLPs). Similar to other P proteins, MuV P contains N-terminal, central, and C-terminal domains with flexible linkers between neighboring domains. By pulldown assays, we discovered that in addition to the previously proposed nucleocapsid binding domain (residues 343 to 391), the N-terminal region of MuV P (residues 1 to 194) could also bind NLPs. Further analysis of binding kinetics was conducted using surface plasmon resonance. This is the first observation that both the N- and C-terminal regions of a negative-strand RNA virus P are involved in binding the nucleocapsid. In addition, we defined the oligomerization domain (POD) of MuV P as residues 213 to 277 and determined its crystal structure. The tetrameric MuV POD is formed by one pair of long parallel alpha-helices with another pair in opposite orientation. Unlike the parallel orientation of each alpha-helix in the tetramer of Sendai virus POD, this represents a novel orientation of a POD where both the N- and the C-terminal domains are at either end of the tetramer. This is consistent with the observation that both the N- and the C-terminal domains are involved in binding the nucleocapsid. PMID- 23637401 TI - The interaction of the cellular export adaptor protein Aly/REF with ICP27 contributes to the efficiency of herpes simplex virus 1 mRNA export. AB - Herpes simplex virus 1 (HSV-1) protein ICP27 enables viral mRNA export by accessing the cellular mRNA export receptor TAP/NXF, which guides mRNA through the nuclear pore complex. ICP27 binds viral mRNAs and interacts with TAP/NXF, providing a link to the cellular mRNA export pathway. ICP27 also interacts with the mRNA export adaptor protein Aly/REF, which binds cellular mRNAs and also interacts with TAP/NXF. Studies using small interfering RNA (siRNA) knockdown indicated that Aly/REF is not required for cellular mRNA export, and similar knockdown studies during HSV-1 infection led us to conclude that Aly/REF may be dispensable for viral RNA export. Recently, the structural basis of the interaction of ICP27 with Aly/REF was elucidated at atomic resolution, and it was shown that three ICP27 residues, W105, R107, and L108, interface with the RNA recognition motif (RRM) domain of Aly/REF. Here, to determine the role the interaction of ICP27 and Aly/REF plays during infection, these residues were mutated to alanine, and a recombinant virus, WRL-A, was constructed. Virus production was reduced about 10-fold during WRL-A infection, and export of ICP27 protein and most viral mRNAs was less efficient. We conclude that interaction of ICP27 with Aly/REF contributes to efficient viral mRNA export. PMID- 23637402 TI - Clustering and mobility of HIV-1 Env at viral assembly sites predict its propensity to induce cell-cell fusion. AB - HIV-1 Env mediates virus attachment to and fusion with target cell membranes, and yet, while Env is still situated at the plasma membrane of the producer cell and before its incorporation into newly formed particles, Env already interacts with the viral receptor CD4 on target cells, thus enabling the formation of transient cell contacts that facilitate the transmission of viral particles. During this first encounter with the receptor, Env must not induce membrane fusion, as this would prevent the producer cell and the target cell from separating upon virus transmission, but how Env's fusion activity is controlled remains unclear. To gain a better understanding of the Env regulation that precedes viral transmission, we examined the nanoscale organization of Env at the surface of producer cells. Utilizing superresolution microscopy (stochastic optical reconstruction microscopy [STORM]) and fluorescence recovery after photobleaching (FRAP), we quantitatively assessed the clustering and dynamics of Env upon its arrival at the plasma membrane. We found that Gag assembly induced the aggregation of small Env clusters into larger domains and that these domains were completely immobile. Truncation of the cytoplasmic tail (CT) of Env abrogated Gag's ability to induce Env clustering and restored Env mobility at assembly sites, both of which correlated with increased Env-induced fusion of infected and uninfected cells. Hence, while Env trapping by Gag secures Env incorporation into viral particles, Env clustering and its sequestration at assembly sites likely also leads to the repression of its fusion function, and thus, by preventing the formation of syncytia, Gag helps to secure efficient transfer of viral particles to target cells. PMID- 23637403 TI - Antiviral activity of trappin-2 and elafin in vitro and in vivo against genital herpes. AB - Serine protease inhibitor elafin (E) and its precursor, trappin-2 (Tr), have been associated with mucosal resistance to HIV-1 infection. We recently showed that Tr/E are among principal anti-HIV-1 molecules in cervicovaginal lavage (CVL) fluid, that E is ~130 times more potent than Tr against HIV-1, and that Tr/E inhibited HIV-1 attachment and transcytosis across human genital epithelial cells (ECs). Since herpes simplex virus 2 (HSV-2) is a major sexually transmitted infection and risk factor for HIV-1 infection and transmission, we assessed Tr/E contribution to defense against HSV-2. Our in vitro studies demonstrated that pretreatment of endometrial (HEC-1A) and endocervical (End1/E6E7) ECs with human Tr-expressing adenovirus (Ad/Tr) or recombinant Tr/E proteins before or after HSV 2 infection resulted in significantly reduced virus titers compared to those of controls. Interestingly, E was ~7 times more potent against HSV-2 infection than Tr. Conversely, knockdown of endogenous Tr/E by small interfering RNA (siRNA) significantly increased HSV-2 replication in genital ECs. Recombinant Tr and E reduced viral attachment to genital ECs by acting indirectly on cells. Further, lower viral replication was associated with reduced secretion of proinflammatory interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) and decreased NF kappaB nuclear translocation. Additionally, protected Ad/Tr-treated ECs demonstrated enhanced interferon regulatory factor 3 (IRF3) nuclear translocation and increased antiviral IFN-beta in response to HSV-2. Lastly, in vivo studies of intravaginal HSV-2 infection in Tr-transgenic mice (Etg) showed that despite similar virus replication in the genital tract, Etg mice had reduced viral load and TNF-alpha in the central nervous system compared to controls. Collectively, this is the first experimental evidence highlighting anti-HSV-2 activity of Tr/E in female genital mucosa. PMID- 23637404 TI - Structures of the procapsid and mature virion of enterovirus 71 strain 1095. AB - Enterovirus 71 (EV71) is an important emerging human pathogen with a global distribution and presents a disease pattern resembling poliomyelitis with seasonal epidemics that include cases of severe neurological complications, such as acute flaccid paralysis. EV71 is a member of the Picornaviridae family, which consists of icosahedral, nonenveloped, single-stranded RNA viruses. Here we report structures derived from X-ray crystallography and cryoelectron microscopy (cryo-EM) for the 1095 strain of EV71, including a putative precursor in virus assembly, the procapsid, and the mature virus capsid. The cryo-EM map of the procapsid provides new structural information on portions of the capsid proteins VP0 and VP1 that are disordered in the higher-resolution crystal structures. Our structures solved from virus particles in solution are largely in agreement with those from prior X-ray crystallographic studies; however, we observe small but significant structural differences for the 1095 procapsid compared to a structure solved in a previous study (X. Wang, W. Peng, J. Ren, Z. Hu, J. Xu, Z. Lou, X. Li, W. Yin, X. Shen, C. Porta, T. S. Walter, G. Evans, D. Axford, R. Owen, D. J. Rowlands, J. Wang, D. I. Stuart, E. E. Fry, and Z. Rao, Nat. Struct. Mol. Biol. 19:424-429, 2012) for a different strain of EV71. For both EV71 strains, the procapsid is significantly larger in diameter than the mature capsid, unlike in any other picornavirus. Nonetheless, our results demonstrate that picornavirus capsid expansion is possible without RNA encapsidation and that picornavirus assembly may involve an inward radial collapse of the procapsid to yield the native virion. PMID- 23637405 TI - Structural changes in dengue virus when exposed to a temperature of 37 degrees C. AB - Previous binding studies of antibodies that recognized a partially or fully hidden epitope suggest that insect cell-derived dengue virus undergoes structural changes at an elevated temperature. This was confirmed by our cryo-electron microscopy images of dengue virus incubated at 37 degrees C, where viruses change their surface from smooth to rough. Here we present the cryo-electron microscopy structures of dengue virus at 37 degrees C. Image analysis showed four classes of particles. The three-dimensional (3D) map of one of these classes, representing half of the imaged virus population, shows that the E protein shell has expanded and there is a hole at the 3-fold vertices. Fitting E protein structures into the map suggests that all of the interdimeric and some intradimeric E protein interactions are weakened. The accessibility of some previously found cryptic epitopes on this class of particles is discussed. PMID- 23637406 TI - Identification of cis-acting nucleotides and a structural feature in West Nile virus 3'-terminus RNA that facilitate viral minus strand RNA synthesis. AB - The 3'-terminal nucleotides (nt) of West Nile virus (WNV) genomic RNA form a penultimate 16-nt small stem-loop (SSL) and an 80-nt terminal stem-loop (SL). These RNA structures are conserved in divergent flavivirus genomes. A previous in vitro study using truncated WNV 3' RNA structures predicted a putative tertiary interaction between the 5' side of the 3'-terminal SL and the loop of the SSL. Although substitution or deletion of the 3' G (nt 87) within the SSL loop, which forms the only G-C pair in the predicted tertiary interaction, in a WNV infectious clone was lethal, a finding consistent with the involvement in a functionally relevant pseudoknot interaction, extensive mutagenesis of nucleotides in the terminal SL did not identify a cis-acting pairing partner for this SSL 3' G. However, both the sequence and the structural context of two adjacent base pairs flanked by symmetrical internal loops in the 3'-terminal SL were shown to be required for efficient viral RNA replication. Nuclear magnetic resonance analysis confirmed the predicted SSL and SL structures but not the tertiary interaction. The SSL was previously reported to contain one of three eEF1A binding sites, and G87 in the SSL loop was shown to be involved in eEF1A binding. The nucleotides at the bottom part of the 3'-terminal SL switch between 3' RNA-RNA and 3'-5' RNA-RNA interactions. The data suggest that interaction of the 3' SL RNA with eEF1A at three sites and a unique metastable structural feature may participate in regulating structural changes in the 3'-terminal SL. PMID- 23637407 TI - Hypervariable domain of nonstructural protein nsP3 of Venezuelan equine encephalitis virus determines cell-specific mode of virus replication. AB - Venezuelan equine encephalitis virus (VEEV) is one of the most pathogenic members of the Alphavirus genus in the Togaviridae family. This genus is divided into the Old World and New World alphaviruses, which demonstrate profound differences in pathogenesis, replication, and virus-host interactions. VEEV is a representative member of the New World alphaviruses. The biology of this virus is still insufficiently understood, particularly the function of its nonstructural proteins in RNA replication and modification of the intracellular environment. One of these nonstructural proteins, nsP3, contains a hypervariable domain (HVD), which demonstrates very low overall similarity between different alphaviruses, suggesting the possibility of its function in virus adaptation to different hosts and vectors. The results of our study demonstrate the following. (i) Phosphorylation of the VEEV nsP3-specific HVD does not play a critical role in virus replication in cells of vertebrate origin but is important for virus replication in mosquito cells. (ii) The VEEV HVD is not required for viral RNA replication in the highly permissive BHK-21 cell line. In fact, it can be either completely deleted or replaced by a heterologous protein sequence. These variants require only one or two additional adaptive mutations in nsP3 and/or nsP2 proteins to achieve an efficiently replicating phenotype. (iii) However, the carboxy-terminal repeat in the VEEV HVD is indispensable for VEEV replication in the cell lines other than BHK-21 and plays a critical role in formation of VEEV specific cytoplasmic protein complexes. Natural VEEV variants retain at least one of the repeated elements in their nsP3 HVDs. PMID- 23637409 TI - Host IQGAP1 and Ebola virus VP40 interactions facilitate virus-like particle egress. AB - We have identified host IQGAP1 as an interacting partner for Ebola virus (EBOV) VP40, and its expression is required for EBOV VP40 virus-like particle (VLP) budding. IQGAP1 is involved in actin cytoskeletal remodeling during cell migration and formation of filopodia. The physical interaction and the functional requirement for IQGAP1 in EBOV VP40 VLP egress link virus budding to the cytoskeletal remodeling machinery. Consequently, this interaction represents a novel target for development of therapeutics to block budding and transmission of filoviruses. PMID- 23637408 TI - The adenovirus L4-22K protein has distinct functions in the posttranscriptional regulation of gene expression and encapsidation of the viral genome. AB - The adenovirus L4-22K protein is multifunctional and critical for different aspects of viral infection. Packaging of the viral genome into an empty capsid absolutely requires the L4-22K protein to bind to packaging sequences in cooperation with other viral proteins. Additionally, the L4-22K protein is important for the temporal switch from the early to late phase of infection by regulating both early and late gene expression. To better understand the molecular mechanisms of these key functions of the L4-22K protein, we focused our studies on the role of conserved pairs of cysteine and histidine residues in the C-terminal region of L4-22K. We found that mutation of the cysteine residues affected the production of infectious progeny virus but did not interfere with the ability of the L4-22K protein to regulate viral gene expression. These results demonstrate that these two functions of L4-22K may be uncoupled. Mutation of the histidine residues resulted in a mutant with a similar phenotype as a virus deficient in the L4-22K protein, where both viral genome packaging and viral gene expression patterns were disrupted. Interestingly, both mutant L4-22K proteins bound to adenovirus packaging sequences, indicating that the paired cysteine and histidine residues do not function as a zinc finger DNA binding motif. Our results reveal that the L4-22K protein controls viral gene expression at the posttranscriptional level and regulates the accumulation of the L4-33K protein, another critical viral regulator, at the level of alternative pre-mRNA splicing. PMID- 23637410 TI - The cellular interactome of the coronavirus infectious bronchitis virus nucleocapsid protein and functional implications for virus biology. AB - The coronavirus nucleocapsid (N) protein plays a multifunctional role in the virus life cycle, from regulation of replication and transcription and genome packaging to modulation of host cell processes. These functions are likely to be facilitated by interactions with host cell proteins. The potential interactome of the infectious bronchitis virus (IBV) N protein was mapped using stable isotope labeling with amino acids in cell culture (SILAC) coupled to a green fluorescent protein-nanotrap pulldown methodology and liquid chromatography-tandem mass spectrometry. The addition of the SILAC label allowed discrimination of proteins that were likely to specifically bind to the N protein over background binding. Overall, 142 cellular proteins were selected as potentially binding to the N protein, many as part of larger possible complexes. These included ribosomal proteins, nucleolar proteins, translation initiation factors, helicases, and hnRNPs. The association of selected cellular proteins with IBV N protein was confirmed by immunoblotting, cosedimentation, and confocal microscopy. Further, the localization of selected proteins in IBV-infected cells as well as their activity during virus infection was assessed by small interfering RNA-mediated depletion, demonstrating the functional importance of cellular proteins in the biology of IBV. This interactome not only confirms previous observations made with other coronavirus and IBV N proteins with both overexpressed proteins and infectious virus but also provides novel data that can be exploited to understand the interaction between the virus and the host cell. PMID- 23637411 TI - Induction of an antiviral state and attenuated coxsackievirus replication in type III interferon-treated primary human pancreatic islets. AB - Type III interferons (IFNs), also called lambda interferons (IFN-lambda), comprise three isoforms, IFN-lambda1 (interleukin-29 [IL-29]), IFN-lambda2 (IL 28A), and IFN-lambda3 (IL-28B). Only limited information is available on their expression and biological functions in humans. Type I and type II IFNs protect human pancreatic islets against coxsackievirus infection, and this is important since such viruses have been proposed to play a role in the development of human type 1 diabetes. Here we investigated whether type III IFN is expressed during infection of human islet cells with coxsackievirus and if type III IFN regulates permissiveness to such infections. We show that human islets respond to a coxsackievirus serotype B3 (CVB3) infection by inducing the expression of type III IFNs. We also demonstrate that islet endocrine cells from nondiabetic individuals express the type III IFN receptor subunits IFN-lambdaR1 and IL-10R2. Pancreatic alpha cells express both receptor subunits, while pancreatic beta cells express only IL-10R2. Type III IFN stimulation elicited a biological response in human islets as indicated by the upregulated expression of antiviral genes as well as pattern recognition receptors. We also show that type III IFN significantly reduces CVB3 replication. Our studies reveal that type III IFNs are expressed during CVB3 infection and that the expression of the type III IFN receptor by the human pancreatic islet allows this group of IFNs to regulate the islets' permissiveness to infection. Our novel observations suggest that type III IFNs may regulate viral replication and thereby contribute to reduced tissue damage and promote islet cell survival during coxsackievirus infection. PMID- 23637414 TI - Functional similarity between E6 proteins of cutaneous human papillomaviruses and the adenovirus E1A tumor-restraining module. AB - The adenovirus E1A C-terminal region restrains oncogenic transformation through interaction with three distinct cellular protein complexes that include the DYRK1A/1B/HAN11 complex. The E6 proteins of beta-human papillomaviruses (beta HPVs) also interact with the DYRK1/HAN11 complex. A variant of HPV5 E6 frequently found in epidermodysplasia verruciformis skin lesions interacted less efficiently with DYRK1A/HAN11. The E6 variant and E7 of HPV5 efficiently coimmortalized primary epithelial cells, suggesting that naturally arising variants may contribute potential oncogenic activities of beta-HPV E6 proteins. PMID- 23637412 TI - Antigenic characterization of H3N2 influenza A viruses from Ohio agricultural fairs. AB - The demonstrated link between the emergence of H3N2 variant (H3N2v) influenza A viruses (IAVs) and swine exposure at agricultural fairs has raised concerns about the human health risk posed by IAV-infected swine. Understanding the antigenic profiles of IAVs circulating in pigs at agricultural fairs is critical to developing effective prevention and control strategies. Here, 68 H3N2 IAV isolates recovered from pigs at Ohio fairs (2009 to 2011) were antigenically characterized. These isolates were compared with other H3 IAVs recovered from commercial swine, wild birds, and canines, along with human seasonal and variant H3N2 IAVs. Antigenic cartography demonstrated that H3N2 IAV isolates from Ohio fairs could be divided into two antigenic groups: (i) the 2009 fair isolates and (ii) the 2010 and 2011 fair isolates. These same two antigenic clusters have also been observed in commercial swine populations in recent years. Human H3N2v isolates from 2010 and 2011 are antigenically clustered with swine-origin IAVs from the same time period. The isolates recovered from pigs at fairs did not cross-react with ferret antisera produced against the human seasonal H3N2 IAVs circulating during the past decade, raising the question of the degree of immunity that the human population has to swine-origin H3N2 IAVs. Our results demonstrate that H3N2 IAVs infecting pigs at fairs and H3N2v isolates were antigenically similar to the IAVs circulating in commercial swine, demonstrating that exhibition swine can function as a bridge between commercial swine and the human population. PMID- 23637413 TI - CK2 phosphorylation inactivates DNA binding by the papillomavirus E1 and E2 proteins. AB - Papillomaviruses have complex life cycles that are understood only superficially. Although it is well established that the viral E1 and E2 proteins play key roles in controlling viral transcription and DNA replication, how these factors are regulated is not well understood. Here, we demonstrate that phosphorylation by the protein kinase CK2 controls the biochemical activities of the bovine papillomavirus E1 and E2 proteins by modifying their DNA binding activity. Phosphorylation at multiple sites in the N-terminal domain in E1 results in the loss of sequence-specific DNA binding activity, a feature that is also conserved in human papillomavirus (HPV) E1 proteins. The bovine papillomavirus (BPV) E2 protein, when phosphorylated by CK2 on two specific sites in the hinge, also loses its site-specific DNA binding activity. Mutation of these sites in E2 results in greatly increased levels of latent viral DNA replication, indicating that CK2 phosphorylation of E2 is a negative regulator of viral DNA replication during latent viral replication. In contrast, mutation of the N-terminal phosphorylation sites in E1 has no effect on latent viral DNA replication. We propose that the phosphorylation of the N terminus of E1 plays a role only in vegetative viral DNA replication, and consistent with such a role, caspase 3 cleavage of E1, which has been shown to be necessary for vegetative viral DNA replication, restores the DNA binding activity to phosphorylated E1. PMID- 23637416 TI - Immature and mature dengue serotype 1 virus structures provide insight into the maturation process. AB - Dengue virus is a major human pathogen that has four serotypes (DENV1 to -4). Here we report the cryoelectron microscopy (cryo-EM) structures of immature and mature DENV1 at 6- and 4.5-A resolution, respectively. The subnanometer resolution maps allow accurate placement of all of the surface proteins. Although the immature and mature viruses showed vastly different surface protein organizations, the envelope protein transmembrane (E-TM) regions remain in similar positions. The pivotal role of the E-TM regions leads to the identification of the start and end positions of all surface proteins during maturation. PMID- 23637415 TI - Cross-inhibition of chikungunya virus fusion and infection by alphavirus E1 domain III proteins. AB - Alphaviruses are small enveloped RNA viruses that include important emerging human pathogens, such as chikungunya virus (CHIKV). These viruses infect cells via a low-pH-triggered membrane fusion reaction, making this step a potential target for antiviral therapies. The E1 fusion protein inserts into the target membrane, trimerizes, and refolds to a hairpin-like conformation in which the combination of E1 domain III (DIII) and the stem region (DIII-stem) pack against a core trimer composed of E1 domains I and II (DI/II). Addition of exogenous DIII proteins from Semliki Forest virus (SFV) has been shown to inhibit E1 hairpin formation and SFV fusion and infection. Here we produced and characterized DIII and DI/II proteins from CHIKV and SFV. Unlike SFV DIII, both core trimer binding and fusion inhibition by CHIKV DIII required the stem region. CHIKV DIII-stem and SFV DIII-stem showed efficient cross-inhibition of SFV, Sindbis virus, and CHIKV infections. We developed a fluorescence anisotropy-based assay for the binding of SFV DIII-stem to the core trimer and used it to demonstrate the relatively high affinity of this interaction (Kd [dissociation constant], ~85 nM) and the importance of the stem region. Together, our results support the conserved nature of the key contacts of DIII-stem in the alphavirus E1 homotrimer and describe a sensitive and quantitative in vitro assay for this step in fusion protein refolding. PMID- 23637417 TI - Interleukin-21 is a critical cytokine for the generation of virus-specific long lived plasma cells. AB - Long-lived plasma cells that reside in the bone marrow constitutively produce antibody in the absence of antigen and are the cellular basis of durable humoral immunity. The generation of these long-lived plasma cells depends upon a series of highly orchestrated interactions between antigen-specific CD4 T cells and B cells and the formation of germinal centers (GCs). In this study, we have examined the role of the cytokine interleukin-21 (IL-21) in regulating humoral immunity during acute viral infections. Using IL-21 receptor-deficient (IL-21R(-/ )) mice, we found that virus-specific CD4 T cells were generated after infection with lymphocytic choriomeningitis virus (LCMV) and that these CD4 T cells differentiated into T follicular helper (TFH)-like cells in the absence of IL-21 signaling. There was also no defect in the formation of GCs, although after day 15 these GCs disappeared faster in IL-21R(-/-) mice than in wild-type mice. Isotype switching and the initial LCMV-specific IgG response were normal in IL 21R(-/-) mice. However, these mice exhibited a profound defect in generating long lived plasma cells and in sustaining antibody levels over time. Similar results were seen after infection of IL-21R(-/-) mice with vesicular stomatitis virus and influenza virus. Using chimeric mice containing wild-type or IL-21R(-/-) CD4 T cells and B cells, we showed that both B and CD4 T cells need IL-21 signaling for generating long-term humoral immunity. Taken together, our results highlight the importance of IL-21 in humoral immunity to viruses. PMID- 23637419 TI - Prime/boost immunization with DNA and adenoviral vectors protects from hepatitis D virus (HDV) infection after simultaneous infection with HDV and woodchuck hepatitis virus. AB - Hepatitis D virus (HDV) superinfection of hepatitis B virus (HBV) carriers causes severe liver disease and a high rate of chronicity. Therefore, a vaccine protecting HBV carriers from HDV superinfection is needed. To protect from HDV infection an induction of virus-specific T cells is required, as antibodies to the two proteins of HDV, p24 and p27, do not neutralize the HBV-derived envelope of HDV. In mice, HDV-specific CD8(+) and CD4(+) T cell responses were induced by a DNA vaccine expressing HDV p27. In subsequent experiments, seven naive woodchucks were immunized with a DNA prime and adenoviral boost regimen prior to simultaneous woodchuck hepatitis virus (WHV) and HDV infection. Five of seven HDV immunized woodchucks were protected against HDV infection, while acute self limiting WHV infection occurred as expected. The two animals with the breakthrough had a shorter HDV viremia than the unvaccinated controls. The DNA prime and adenoviral vector boost vaccination protected woodchucks against HDV infection in the setting of simultaneous infection with WHV and HDV. In future experiments, the efficacy of this protocol to protect from HDV infection in the setting of HDV superinfection will need to be proven. PMID- 23637418 TI - Virus-specific effects of TRIM5alpha(rh) RING domain functions on restriction of retroviruses. AB - The tripartite motif protein TRIM5alpha restricts particular retrovirus infections by binding to the incoming capsid and inhibiting the early stage of virus infection. The TRIM5alpha RING domain exhibits E3 ubiquitin ligase activity and assists the higher-order association of TRIM5alpha dimers, which promotes capsid binding. We characterized a panel of RING domain mutants of the rhesus monkey TRIM5alpha (TRIM5alpha(rh)) protein. The RING domain function that significantly contributed to retroviral restriction depended upon the restricted virus. The E3 ubiquitin ligase activity of the RING domain contributes to the potency of HIV-1 restriction. Nonetheless, TRIM5alpha(rh) mutants without detectable E3 ubiquitin ligase activity still blocked reverse transcription and inhibited HIV-1 infection at a moderate level. When TRIM5alpha(rh) capsid binding was weakened by substitution with a less efficient B30.2/SPRY domain, the promotion of higher-order association by the RING domain was more important to HIV-1 restriction than its E3 ubiquitin ligase activity. For the restriction of N tropic murine leukemia virus (N-MLV) and equine infectious anemia virus (EIAV) infection, promotion of higher-order association represented the major contribution of the RING domain. Thus, both identity of the target virus and the B30.2/SPRY domain-mediated affinity for the viral capsid determine the relative contribution of the two known RING domain functions to TRIM5alpha restriction of retrovirus infection. PMID- 23637422 TI - Abortion, infanticide and allowing babies to die, 40 years on. PMID- 23637420 TI - Human cytomegalovirus-induced NKG2C(hi) CD57(hi) natural killer cells are effectors dependent on humoral antiviral immunity. AB - Recent studies indicate that expansion of NKG2C-positive natural killer (NK) cells is associated with human cytomegalovirus (HCMV); however, their activity in response to HCMV-infected cells remains unclear. We show that NKG2C(hi) CD57(hi) NK cells gated on CD3(neg) CD56(dim) cells can be phenotypically identified as HCMV-induced NK cells that can be activated by HCMV-infected cells. Using HCMV infected autologous macrophages as targets, we were able to show that these NKG2C(hi) CD57(hi) NK cells are highly responsive to HCMV-infected macrophages only in the presence of HCMV-specific antibodies, whereas they are functionally poor effectors of natural cytotoxicity. We further demonstrate that NKG2C(hi) CD57(hi) NK cells are intrinsically responsive to signaling through CD16 cross linking. Our findings show that the activity of pathogen-induced innate immune cells can be enhanced by adaptive humoral immunity. Understanding the activity of NKG2C(hi) CD57(hi) NK cells against HCMV-infected cells will be of relevance for the further development of adoptive immunotherapy. PMID- 23637421 TI - Metabolomics reveals that tumor xenografts induce liver dysfunction. AB - Metabolomics, based on ultraperformance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry, was used to explore metabolic signatures of tumor growth in mice. Urine samples were collected from control mice and mice injected with squamous cell carcinoma (SCCVII) tumor cells. When tumors reached ~2 cm, all mice were killed and blood and liver samples collected. The urine metabolites hexanoylglycine, nicotinamide 1-oxide, and 11beta,20alpha-dihydroxy-3-oxopregn-4-en-21-oic acid were elevated in tumor bearing mice, as was asymmetric dimethylarginine, a biomarker for oxidative stress. Interestingly, SCCVII tumor growth resulted in hepatomegaly, reduced albumin/globulin ratios, and elevated serum triglycerides, suggesting liver dysfunction. Alterations in liver metabolites between SCCVII-tumor-bearing and control mice confirmed the presence of liver injury. Hepatic mRNA analysis indicated that inflammatory cytokines, tumor necrosis factor alpha, and transforming growth factor beta were enhanced in SCCVII-tumor-bearing mice, and the expression of cytochromes P450 was decreased in tumor-bearing mice. Further, genes involved in fatty acid oxidation were decreased, suggesting impaired fatty acid oxidation in SCCVII-tumor-bearing mice. Additionally, activated phospholipid metabolism and a disrupted tricarboxylic acid cycle were observed in SCCVII-tumor bearing mice. These data suggest that tumor growth imposes a global inflammatory response that results in liver dysfunction and underscore the use of metabolomics to temporally examine these changes and potentially use metabolite changes to monitor tumor treatment response. PMID- 23637423 TI - Discussing infanticide. PMID- 23637424 TI - Clarifications on the moral status of newborns and the normative implications. AB - In this paper we clarify some issues related to our previous article 'After-birth abortion: why should the baby live?'. PMID- 23637425 TI - Philosophy, critical thinking and 'after-birth abortion: why should the baby live?'. PMID- 23637426 TI - Infanticide and moral consistency. AB - The aim of this essay is to show that there are no easy options for those who are disturbed by the suggestion that infanticide may on occasion be morally permissible. The belief that infanticide is always wrong is doubtfully compatible with a range of widely shared moral beliefs that underlie various commonly accepted practices. Any set of beliefs about the morality of abortion, infanticide and the killing of animals that is internally consistent and even minimally credible will therefore unavoidably contain some beliefs that are counterintuitive. PMID- 23637427 TI - Capacity, harm and experience in the life of persons as equals. AB - This paper identifies and contests the thesis it takes to be the central premise of Giubilini and Minerva, 'Why should the baby live?', namely that rights, subjecthood and personhood have as a necessary condition that the undergoing of a harm be experienced. That thesis entails the repugnant or absurd conclusion that we do not have the right not to be killed in our sleep. The conclusion can be avoided by adding some premise or qualification about actual capacities for experience of harm, but nothing in the Giubilini and Minerva article shows that such capacities do not exist, as actual and not merely potential, in the newly born human infant (and indeed in the unborn human child/foetus). The present paper reviews an earlier philosophical attempt to deploy an awareness criterion of personhood, and proposes objections to some other aspects of the article under consideration. PMID- 23637428 TI - The common premise for uncommon conclusions. AB - Recent controversy over philosophical advocacy of infanticide (or the comically styled euphemism 'postnatal abortion') reveals a surprisingly common premise uniting many of the opponents and supporters of the practice. This is the belief that the moral status of the early fetus or embryo with respect to a right to life is identical to that of a newly born or even very young baby. From this premise, infanticidists and strong anti-abortionists draw opposite conclusions, the former that the healthy newly born have no inherent right to life and the latter that minute embryos and the very early fetus have the same right to life as young babies. (Indeed strong anti-abortionists tend to regard this right to life as identical to that possessed by adult humans.) This paper argues that these opposed conclusions are both deeply implausible and that the implausibility resides in the common premise. The argument requires some attention to the structure of the philosophical case underpinning the supposed vice of speciesism that has been given intellectual currency by many philosophers, most notably Peter Singer, and also to the reasoning behind the strong anti-abortionist adoption of the common premise. PMID- 23637429 TI - Infanticide, moral status and moral reasons: the importance of context. AB - Giubilini and Minerva ask why birth should be a critical dividing line between acceptable and unacceptable reasons for terminating existence. Their argument is that birth does not change moral status in the sense that is relevant: the ability to be harmed by interruption of one's aims. Rather than question the plausibility of their position or the argument they give, we ask instead about the importance to scholarship or policy of publishing the article: does it to any extent make a novel or needed addition to the literature? Giubilini and Minerva's argument is remarkably similar to one advanced by Michael Tooley in 'Abortion and Infanticide,' almost 40 years ago. There have been immense changes in the intervening 40 years: in the ability to diagnose conditions early in pregnancy, in genetics and in the availability of in vitro fertilization; in understanding of the capabilities of persons with disabilities; in law; in economic support and access to healthcare for pregnant women and their children; in social customs and arrangements; and even in philosophy, with developments in feminist thought, bioethics and cognitive science. Some of these changes have been for the better, but others, such as the unravelling of social safety nets, have arguably been for the worse. Any or all of these changes might give rise to moral reasons for the relevance of birth that were not available 40 years ago. These changes might also be relevant to the identification of cases, if any, in which 'after-birth abortion' might be considered. If context is relevant to the applicability of moral reasons-as for theorists of justice in the non-idealised world it surely should be-it is questionable whether a view of the birth-line that ignores contextualising change can be adequate. PMID- 23637430 TI - The Groningen Protocol for newborn euthanasia; which way did the slippery slope tilt? AB - In The Netherlands, neonatal euthanasia has become a legal option and the Groningen Protocol contains an approach to identify situations in which neonatal euthanasia might be appropriate. In the 5 years following the publication of the protocol, neither the prediction that this would be the first step on a slippery slope, nor the prediction of complete transparency and legal control became true. Instead, we experienced a transformation of the healthcare system after antenatal screening policy became a part of antenatal care. This resulted in increased terminations of pregnancy and less euthanasia. PMID- 23637431 TI - Concern for our vulnerable prenatal and neonatal children: a brief reply to Giubilini and Minerva. AB - This is a response to Giubilini and Minerva arguing that, on the basis of the similar moral status of the fetus and infant, infanticide is justifiable for many of the same reasons that justify abortion. It argues that, although the authors are correct in claiming the logical connection between abortion and infanticide, they are mistaken in their moral anthropology and so misunderstand which way the reasoning should cut. It concludes with an exhortation-especially to fellow pro lifers-to have a different kind of discourse on these matters. PMID- 23637432 TI - Infanticide and madness. PMID- 23637434 TI - Response to: is the pro-choice position for infanticide 'madness'? PMID- 23637433 TI - Is the pro-choice position for infanticide 'madness'? PMID- 23637435 TI - In defence of academic freedom: bioethics journals under siege. AB - This article analyses, from a bioethics journal editor's perspective, the threats to academic freedom and freedom of expression that academic bioethicists and academic bioethics journals are subjected to by political activists applying pressure from outside of the academy. I defend bioethicists' academic freedom to reach and defend conclusions many find offensive and 'wrong'. However, I also support the view that academics arguing controversial matters such as, for instance, the moral legitimacy of infanticide should take clear responsibility for the views they defend and should not try to hide behind analytical philosophers' rationales such as wanting to test an argument for the sake of testing an argument. This article proposes that bioethics journals establish higher-quality requirements and more stringent mechanisms of peer review than usual for iconoclastic articles. PMID- 23637436 TI - Life in the cloud and freedom of speech. AB - This paper is primarily about the personal and public responsibilities of ethics and of ethicists in speaking, writing and commenting publicly about issues of ethical, political and social significance. The paper argues that any such interventions are 'willy-nilly', actually or potentially, in the public domain in ways that make any self-conscious decision about intended publics or audiences problematic. In it is argued that a famous, and hitherto useful, distinction relating to the ethical limitations on freedom of speech which we owe to John Stuart Mill may, because of the emergence of 'the cloud' have become redundant or inoperable. PMID- 23637437 TI - Should policy ethics come in two colours: green or white? AB - When writing about policy, do you think in green or white? If not, I recommend that you do. I suggest that writers and journal editors should explicitly label every policy ethics paper either 'green' or 'white'. A green paper is an unconstrained exploration of a policy question. The controversial 'After-birth abortion' paper is an example. Had it been labelled as 'green', readers could have understood what Giubilini and Minerva explained later: that it was a discussion of philosophical ideas, and not a policy proposal advocating infanticide. A serious policy proposal should be labelled by writer(s) and editor(s) as 'white'. Its purpose should be to influence policy. In order to influence policy, I suggest three essential, and two desirable, characteristics of any white paper. Most importantly, a white paper should be set in the context in which the policy is to be made and applied. PMID- 23637438 TI - The fragility of freedom of speech. AB - Freedom of speech is a fundamental liberty that imposes a stringent duty of tolerance. Tolerance is limited by direct incitements to violence. False notions and bad laws on speech have obscured our view of this freedom. Hence, perhaps, the self-righteous intolerance, incitements and threats in response to Giubilini and Minerva. Those who disagree have the right to argue back but their attempts to shut us up are morally wrong. PMID- 23637439 TI - The Italian reaction to the Giubilini and Minerva paper. AB - From 28 February to the end of March 2012, the Italian media reacted fiercely to the Giubilini and Minerva paper published in the Journal of Medical Ethics a few days earlier. The first article viewed the proposal as analogous to 'barbaric invasions', but in a first stage of the debate it could be seen as a case of the usual controversy between Catholics and secularists. Then emotive reactions prevailed and a flood of papers expressed strong opposition to 'infanticide'. The authors were even deemed insane; the fact that both are Italian certainly increased interest in the subject as well as surprise at their proposal, which some reckoned to be an insult to their 'national identity'. Even freedom of academic research and discussion was put in question, and defenders of free debate were accused of being supporters of the theory of infanticide. PMID- 23637441 TI - Public distress as a moral consideration in after-birth abortion. PMID- 23637443 TI - Moral uncertainty and the moral status of early human life. PMID- 23637442 TI - Some comments on the paper 'after-birth abortion: why should the baby live?'. PMID- 23637445 TI - The performativity of personhood. PMID- 23637444 TI - 'After-birth abortion' and arguments from potential. PMID- 23637446 TI - The moral significance of being born. AB - This paper is a response to Giubilini and Minerva's defence of infanticide. I argue that any account of moral worth or moral rights that depends on the intrinsic properties of individuals alone is committed to agreeing with Giubilini and Minerva that birth cannot by itself make a moral difference to the moral worth of the infant. However, I argue that moral worth need not depend on intrinsic properties alone. It might also depend on relational and social properties. I claim that the in principle availability of neonates to participate in scaffolded interactions with carers might plausibly be seen as contributing to their moral worth. PMID- 23637447 TI - Yes, the baby should live: a pro-choice response to Giubilini and Minerva. AB - In their paper 'After-birth abortion: why should the baby live?' Alberto Giubilini and Francesca Minerva argue that because there are no significant differences between a fetus and a neonate, in that neither possess sufficiently robust mental traits to qualify as persons, a neonate may be justifiably killed for any reason that also justifies abortion. To further emphasise their view that a newly born infant is more on a par with a fetus rather than a more developed baby, Giubilini and Minerva elect to call this 'after-birth abortion' rather than infanticide. In this paper, I argue that their thesis is incorrect, and that the moral permissibility of abortion does not entail the moral permissibility of 'after-birth' abortion. PMID- 23637448 TI - Infanticide: a reply to Giubilini and Minerva. AB - Alberto Giubilini and Francesco Minerva's recent infanticide proposal is predicated on their personism and actualism. According to these related ideas, human beings achieve their moral status in virtue of the degree to which they are capable of laying value upon their lives or exhibiting certain qualities or being desirable to third-party family members. This article challenges these criteria, suggesting that these and related ideas are rely on arbitrary and discriminatory notions of human moral status. Our propensity to sleep, fall unconscious, pass out and so on, demonstrates that we often exhibit our status as 'potential persons' who are not in the condition of attributing any value to their own existence. Our abilities, age and desirability can and do fluctuate. The equal dignity principle, distinguished in turn from both the excesses of vitalism and consequentialism, is analysed and defended in the context of human rights logic and law. The normalisation of non- and involuntary euthanasia, via such emerging practices as the self-styled Groningen Protocol, is considered. Substituted consent to the euthanasia of babies and others is scrutinised and the implications of institutionalising non-voluntary euthanasia in the context of financial, research and political interests are considered. The impact on the medical and legal professions, carers, families and societies, as well as public attitudes more generally, is discussed. It is suggested that eroding the value of human life carries with it significant destructive long-term implications. To elevate some, often short-term, implications while ignoring others demonstrates the irrational nature of the effort to institutionalise euthanasia. PMID- 23637449 TI - Potentials and burdens: a reply to Giubilini and Minerva. AB - This article responds to Giubilini and Minerva's article 'After birth abortion: why should the baby live?' published in the Journal of Medical Ethics. They argue for the permissibility of 'after-birth abortion', based on two conjoined considerations: (1) the fetus or newborn, though a 'potential person', is not an actual person, because it is not mature enough to appreciate its own interests, and (2) because we allow parents to terminate the life of a fetus when it is diagnosed with a deformity or fatal illness because of the burden it will place on the child, parent, family or society we should also allow parents to do the same to their newborn, since it is no more a person than the fetus. The author critiques this case by pointing out (a) the metaphysical ambiguity of potential personhood and (b) why the appeal to burdens is irrelevant or unnecessary. PMID- 23637450 TI - The moral status of babies. AB - In their controversial paper 'After-birth abortion', Alberto Giubilini and Francesca Minerva argue that there is no rational basis for allowing abortion but prohibiting infanticide ('after-birth abortion'). We ought in all consistency either to allow both or prohibit both. This paper rejects their claim, arguing that much-neglected considerations in philosophical discussions of this issue are capable of explaining why we currently permit abortion in some circumstances, while prohibiting infanticide. PMID- 23637451 TI - Abortion, infanticide and moral context. AB - In 'After-birth abortion: why should the baby live?', Giubilini and Minerva argue that infanticide should be permitted for the same reasons as abortion. In particular, they argue that infanticide should be permitted even for reasons that do not primarily serve the interests (or would-be best interests) of the newborn. They claim that abortion is permissible for reasons that do not primarily serve the interests (or would-be interests) of the fetus because fetuses lack a right to life. They argue that newborns also lack a right to life, and they conclude that therefore, the same reasons that justify abortion can justify infanticide. This conclusion does not follow. The lack of a right to life is not decisive. Furthermore, the justificatory power of a given reason is a function of moral context. Generalisations about reasons across dissimilar moral contexts are invalid. However, a similar conclusion does follow-that fetus-killing and newborn killing are morally identical in identical moral contexts-but this conclusion is trivial, since fetuses and newborns are never in identical moral contexts. PMID- 23637452 TI - Of course the baby should live: against 'after-birth abortion'. AB - In a recent paper, Giubilini and Minerva argue for the moral permissibility of what they call 'after-birth abortion', or infanticide. Here I suggest that they actually employ a confusion of two distinct arguments: one relying on the purportedly identical moral status of a fetus and a newborn, and the second giving an independent argument for the denial of moral personhood to infants (independent of whatever one might say about fetuses). After distinguishing these arguments, I suggest that neither one is capable of supporting Giubilini and Minerva's conclusion. The first argument is at best neutral between permitting infanticide and prohibiting abortion, and may in fact more strongly support the latter. The second argument, I suggest, contains an ambiguity in its key premise, and can be shown to fail on either resolution of that ambiguity. Hence, I conclude that Giubilini and Minerva have not demonstrated the permissibility of infanticide, or even great moral similarity between abortion and infanticide. PMID- 23637453 TI - Personhood, harm and interest: a reply to Alberto Giubilini and Francesca Minerva. AB - In the article 'After-birth abortion: why should the baby live?' arguments are made in favour of the moral permissibility of intentionally killing newborn infants, under particular conditions. Here we argue that their arguments are based on an indefensible view of personhood, and we question the logic of harm and interest that informs their arguments. Furthermore, we argue that the conclusions here are so contrary to ordinary moral intuitions that the argument and conclusions based upon it-including those which defend more mainstream methods of abortion-should be treated with immediate suspicion. PMID- 23637455 TI - Limitations on personhood arguments for abortion and 'after-birth abortion'. AB - Two notable limitations exist on the use of personhood arguments in establishing moral status. Firstly, although the attribution of personhood may give us sufficient reason to grant something moral status, it is not a necessary condition. Secondly, even if a person is that which has the 'highest' moral status, this does not mean that any interests of a person are justifiable grounds to kill something that has a 'lower' moral status. Additional justification is needed to overcome a basic wrongness associated with killing something possessing moral status. There are clear arguments already available in this regard in the case of a foetus that are not available in the case of a newborn infant. Hence, there is scope to consistently hold that abortion may be permissible but that after-birth abortion may not be permissible. PMID- 23637454 TI - After-birth and before-birth personhood: why the baby should live. AB - The basic human experience of the atrocities in the first half of the 20th century has significantly strengthened the recognition of human dignity and human rights for all born people at the political level. Therefore, the Charter of the United Nations in 1945 and its Universal Declaration of Human Rights of 1948, Article 1 affirms: 'All human beings are born free and equal in dignity and rights'. This article provides an ethical justification of why we in this political consensus should not waver, and why we should grant the right to life to all born human infants. Moreover, there is an ethical justification to granting the right to life even to unborn human beings, who already bear a human face. PMID- 23637456 TI - Killing fetuses and killing newborns. AB - The argument for the moral permissibility of killing newborns is a challenge to liberal positions on abortion because it can be considered a reductio of their defence of abortion. Here I defend the liberal stance on abortion by arguing that the argument for the moral permissibility of killing newborns on ground of the social, psychological and economic burden on the parents recently put forward by Giubilini and Minerva is not valid; this is because they fail to show that newborns cannot be harmed and because there are morally relevant differences between fetuses and newborns. PMID- 23637457 TI - After-birth abortion: the intuition argument. AB - The argument advanced by Giubilini and Minerva is an important one, but it suffers from some shortcomings. I briefly criticise their reasoning and method and argue that after birth abortion should be limited largely to infants with disabilities. My argument is based not on solid scientific evidence or cold rational reasoning but on intuition, something that has long been discounted as irrelevant in biomedical discourse. I end with a recommendation to all of us: in order to make a change, one should not only choose one's battles, but also one's weapon and mode of attack. PMID- 23637458 TI - Why should the baby live? Human right to life and the precautionary principle. AB - This paper discusses the issue of 'post-birth abortion' from an applied perspective. Three hypothetical situations where a newborn considered as a 'potential person' is at risk of being killed are proposed to highlight the potential controversial outcomes of post-birth abortion. The internal consistency of the argument proposed by Giubilini and Minerva to morally justify newborn killing is contested as well. Finally, an alternative moral strategy based on the precautionary principle and excluding any distinction between potential and actual persons is proposed as rational. PMID- 23637460 TI - Characterization of Salmonella enterica serovar Typhimurium aconitase A. AB - Aconitases (Acn) are iron-sulfur proteins that catalyse the reversible isomerization of citrate and isocitrate via the intermediate cis-aconitate in the Krebs cycle. Some Acn proteins are bi-functional and under conditions of iron starvation and oxidative stress lose their iron-sulfur clusters and become post transcriptional regulators by binding specific mRNA targets. Many bacterial species possess two genetically distinct aconitase proteins, AcnA and AcnB. Current understanding of the regulation and functions of AcnA and AcnB in dual Acn bacteria is based on a model developed in Escherichia coli. Thus, AcnB is the major Krebs cycle enzyme expressed during exponential growth, whereas AcnA is a more stable, stationary phase and stress-induced enzyme, and both E. coli Acns are bi-functional. Here a second dual Acn bacterium, Salmonella enterica serovar Typhimurium (S. Typhimurium), has been analysed. Phenotypic traits of S. Typhimurium acn mutants were consistent with AcnB acting as the major Acn protein. Promoter fusion experiments indicated that acnB transcription was ~10 fold greater than that of acnA and that acnA expression was regulated by the cyclic-AMP receptor protein (CRP, glucose starvation), the fumarate nitrate reduction regulator (FNR, oxygen starvation), the ferric uptake regulator (Fur, iron starvation) and the superoxide response protein (SoxR, oxidative stress). In contrast to E. coli, S. Typhimurium acnA was not induced in the stationary phase. Furthermore, acnA expression was enhanced in an acnB mutant, presumably to partially compensate for the lack of AcnB activity. Isolated S. Typhimurium AcnA protein had kinetic and mRNA-binding properties similar to those described for E. coli AcnA. Thus, the work reported here provides a second example of the regulation and function of AcnA and AcnB proteins in a dual Acn bacterium. PMID- 23637459 TI - Multiple alcohol dehydrogenases but no functional acetaldehyde dehydrogenase causing excessive acetaldehyde production from ethanol by oral streptococci. AB - Ethanol consumption and poor oral hygiene are risk factors for oral and oesophageal cancers. Although oral streptococci have been found to produce excessive acetaldehyde from ethanol, little is known about the mechanism by which this carcinogen is produced. By screening 52 strains of diverse oral streptococcal species, we identified Streptococcus gordonii V2016 that produced the most acetaldehyde from ethanol. We then constructed gene deletion mutants in this strain and analysed them for alcohol and acetaldehyde dehydrogenases by zymograms. The results showed that S. gordonii V2016 expressed three primary alcohol dehydrogenases, AdhA, AdhB and AdhE, which all oxidize ethanol to acetaldehyde, but their preferred substrates were 1-propanol, 1-butanol and ethanol, respectively. Two additional dehydrogenases, S-AdhA and TdhA, were identified with specificities to the secondary alcohol 2-propanol and threonine, respectively, but not to ethanol. S. gordonii V2016 did not show a detectable acetaldehyde dehydrogenase even though its adhE gene encodes a putative bifunctional acetaldehyde/alcohol dehydrogenase. Mutants with adhE deletion showed greater tolerance to ethanol in comparison with the wild-type and mutant with adhA or adhB deletion, indicating that AdhE is the major alcohol dehydrogenase in S. gordonii. Analysis of 19 additional strains of S. gordonii, S. mitis, S. oralis, S. salivarius and S. sanguinis showed expressions of up to three alcohol dehydrogenases, but none showed detectable acetaldehyde dehydrogenase, except one strain that showed a novel ALDH. Therefore, expression of multiple alcohol dehydrogenases but no functional acetaldehyde dehydrogenase may contribute to excessive production of acetaldehyde from ethanol by certain oral streptococci. PMID- 23637461 TI - Dual-color superresolution microscopy reveals nanoscale organization of mechanosensory podosomes. AB - Podosomes are multimolecular mechanosensory assemblies that coordinate mesenchymal migration of tissue-resident dendritic cells. They have a protrusive actin core and an adhesive ring of integrins and adaptor proteins, such as talin and vinculin. We recently demonstrated that core actin oscillations correlate with intensity fluctuations of vinculin but not talin, suggesting different molecular rearrangements for these components. Detailed information on the mutual localization of core and ring components at the nanoscale is lacking. By dual color direct stochastic optical reconstruction microscopy, we for the first time determined the nanoscale organization of individual podosomes and their spatial arrangement within large clusters formed at the cell-substrate interface. Superresolution imaging of three ring components with respect to actin revealed that the cores are interconnected and linked to the ventral membrane by radiating actin filaments. In core-free areas, alphaMbeta2 integrin and talin islets are homogeneously distributed, whereas vinculin preferentially localizes proximal to the core and along the radiating actin filaments. Podosome clusters appear as self-organized contact areas, where mechanical cues might be efficiently transduced and redistributed. Our findings call for a reevaluation of the current "core-ring" model and provide a novel structural framework for further understanding the collective behavior of podosome clusters. PMID- 23637462 TI - Multiple motifs regulate apical sorting of p75 via a mechanism that involves dimerization and higher-order oligomerization. AB - The sorting signals that direct proteins to the apical surface of polarized epithelial cells are complex and can include posttranslational modifications, such as N- and O-linked glycosylation. Efficient apical sorting of the neurotrophin receptor p75 is dependent on its O-glycosylated membrane proximal stalk, but how this domain mediates targeting is unknown. Protein oligomerization or clustering has been suggested as a common step in the segregation of all apical proteins. Like many apical proteins, p75 forms dimers, and we hypothesized that formation of higher-order clusters mediated by p75 dimerization and interactions of the stalk facilitate its apical sorting. Using fluorescence fluctuation techniques (photon-counting histogram and number and brightness analyses) to study p75 oligomerization status in vivo, we found that wild-type p75-green fluorescent protein forms clusters in the trans-Golgi network (TGN) but not at the plasma membrane. Disruption of either the dimerization motif or the stalk domain impaired both clustering and polarized delivery. Manipulation of O glycan processing or depletion of multiple galectins expressed in Madin-Darby canine kidney cells had no effect on p75 sorting, suggesting that the stalk domain functions as a structural prop to position other determinants in the lumenal domain of p75 for oligomerization. Additionally, a p75 mutant with intact dimerization and stalk motifs but with a dominant basolateral sorting determinant (Delta250 mutant) did not form oligomers, consistent with a requirement for clustering in apical sorting. Artificially enhancing dimerization restored clustering to the Delta250 mutant but was insufficient to reroute this mutant to the apical surface. Together these studies demonstrate that clustering in the TGN is required for normal biosynthetic apical sorting of p75 but is not by itself sufficient to reroute a protein to the apical surface in the presence of a strong basolateral sorting determinant. Our studies shed new light on the hierarchy of polarized sorting signals and on the mechanisms by which newly synthesized proteins are segregated in the TGN for eventual apical delivery. PMID- 23637463 TI - Inhibition of nuclear factor-erythroid 2-related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence. AB - Reactive oxygen species (ROS) can induce premature cellular senescence, which is believed to contribute to aging and age-related diseases. The nuclear erythroid 2 p45-related factor-2 (Nrf2) is a transcription factor that mediates cytoprotective responses against stress. We demonstrate that caveolin-1 is a direct binding partner of Nrf2, as shown by the binding of the scaffolding domain of caveolin-1 (amino acids 82-101) to the caveolin-binding domain of Nrf2 (amino acids 281-289). Biochemical studies show that Nrf2 is concentrated into caveolar membranes in human and mouse fibroblasts, where it colocalizes with caveolin-1, under resting conditions. After oxidative stress, caveolin-1 limits the movement of Nrf2 from caveolar membranes to the nucleus. In contrast, Nrf2 is constitutively localized to the nucleus before and after oxidative stress in caveolin-1-null mouse embryonic fibroblasts (MEFs), which do not express caveolin 1. Functional studies demonstrate that caveolin-1 acts as an endogenous inhibitor of Nrf2, as shown by the enhanced up-regulation of NQO1, an Nrf2 target gene, in caveolin-1-null MEFs and the activation or inhibition of a luciferase construct carrying an antioxidant responsive element (ARE) after down-regulation of caveolin-1 by small interfering RNA or overexpression of caveolin-1, respectively. Expression of a mutant form of Nrf2 that cannot bind to caveolin-1 (Phi->A-Nrf2) hyperactivates ARE and inhibits oxidative stress-induced activation of the p53/p21(Waf1/Cip1) pathway and induction of premature senescence in fibroblasts. Finally, we show that overexpression of caveolin-1 in colon cancer cells inhibits oxidant-induced activation of Nrf2-dependent signaling, promotes premature senescence, and inhibits their transformed phenotype. Thus, by inhibiting Nrf2-mediated signaling, caveolin-1 links free radicals to the activation of the p53/senescence pathway. PMID- 23637464 TI - Deacylation on the matrix side of the mitochondrial inner membrane regulates cardiolipin remodeling. AB - The mitochondrial-specific lipid cardiolipin (CL) is required for numerous processes therein. After its synthesis on the matrix-facing leaflet of the inner membrane (IM), CL undergoes acyl chain remodeling to achieve its final form. In yeast, this process is completed by the transacylase tafazzin, which associates with intermembrane space (IMS)-facing membrane leaflets. Mutations in TAZ1 result in the X-linked cardiomyopathy Barth syndrome. Amazingly, despite this clear pathophysiological association, the physiological importance of CL remodeling is unresolved. In this paper, we show that the lipase initiating CL remodeling, Cld1p, is associated with the matrix-facing leaflet of the mitochondrial IM. Thus monolysocardiolipin generated by Cld1p must be transported to IMS-facing membrane leaflets to gain access to tafazzin, identifying a previously unknown step required for CL remodeling. Additionally, we show that Cld1p is the major site of regulation in CL remodeling; and that, like CL biosynthesis, CL remodeling is augmented in growth conditions requiring mitochondrially produced energy. However, unlike CL biosynthesis, dissipation of the mitochondrial membrane potential stimulates CL remodeling, identifying a novel feedback mechanism linking CL remodeling to oxidative phosphorylation capacity. PMID- 23637465 TI - Ubiquitin conjugation triggers misfolded protein sequestration into quality control foci when Hsp70 chaperone levels are limiting. AB - Ubiquitin accumulation in amyloid plaques is a pathological marker observed in the vast majority of neurodegenerative diseases, yet ubiquitin function in these inclusions is controversial. It has been suggested that ubiquitylated proteins are directed to inclusion bodies under stress conditions, when both chaperone mediated refolding and proteasomal degradation are compromised or overwhelmed. Alternatively, ubiquitin and chaperones may be recruited to preformed inclusions to promote their elimination. We address this issue using a yeast model system, based on expression of several mildly misfolded degradation substrates in cells with altered chaperone content. We find that the heat shock protein 70 (Hsp70) chaperone pair Ssa1/Ssa2 and the Hsp40 cochaperone Sis1 are essential for degradation. Substrate ubiquitylation is strictly dependent on Sis1, whereas Ssa1 and Ssa2 are dispensable. Remarkably, in Ssa1/Ssa2-depleted cells, ubiquitylated substrates are sequestered into detergent-insoluble, Hsp42-positive inclusion bodies. Unexpectedly, sequestration is abolished by preventing substrate ubiquitylation. We conclude that Hsp40 is required for the targeting of misfolded proteins to the ubiquitylation machinery, whereas the decision to degrade or sequester ubiquitylated proteins is mediated by the Hsp70s. Accordingly, diminished Hsp70 levels, as observed in aging or certain pathological conditions, might be sufficient to trigger ubiquitin-dependent sequestration of partially misfolded proteins into inclusion bodies. PMID- 23637467 TI - A MEASURE-THEORETIC COMPUTATIONAL METHOD FOR INVERSE SENSITIVITY PROBLEMS I: METHOD AND ANALYSIS. AB - We consider the inverse sensitivity analysis problem of quantifying the uncertainty of inputs to a deterministic map given specified uncertainty in a linear functional of the output of the map. This is a version of the model calibration or parameter estimation problem for a deterministic map. We assume that the uncertainty in the quantity of interest is represented by a random variable with a given distribution, and we use the law of total probability to express the inverse problem for the corresponding probability measure on the input space. Assuming that the map from the input space to the quantity of interest is smooth, we solve the generally ill-posed inverse problem by using the implicit function theorem to derive a method for approximating the set-valued inverse that provides an approximate quotient space representation of the input space. We then derive an efficient computational approach to compute a measure theoretic approximation of the probability measure on the input space imparted by the approximate set-valued inverse that solves the inverse problem. PMID- 23637466 TI - Phosphorylation of centromeric histone H3 variant regulates chromosome segregation in Saccharomyces cerevisiae. AB - The centromeric histone H3 variant (CenH3) is essential for chromosome segregation in eukaryotes. We identify posttranslational modifications of Saccharomyces cerevisiae CenH3, Cse4. Functional characterization of cse4 phosphorylation mutants shows growth and chromosome segregation defects when combined with kinetochore mutants okp1 and ame1. Using a phosphoserine-specific antibody, we show that the association of phosphorylated Cse4 with centromeres increases in response to defective microtubule attachment or reduced cohesion. We determine that evolutionarily conserved Ipl1/Aurora B contributes to phosphorylation of Cse4, as levels of phosphorylated Cse4 are reduced at centromeres in ipl1 strains in vivo, and in vitro assays show phosphorylation of Cse4 by Ipl1. Consistent with these results, we observe that a phosphomimetic cse4-4SD mutant suppresses the temperature-sensitive growth of ipl1-2 and Ipl1 substrate mutants dam1 spc34 and ndc80, which are defective for chromosome biorientation. Furthermore, cell biology approaches using a green fluorescent protein-labeled chromosome show that cse4-4SD suppresses chromosome segregation defects in dam1 spc34 strains. On the basis of these results, we propose that phosphorylation of Cse4 destabilizes defective kinetochores to promote biorientation and ensure faithful chromosome segregation. Taken together, our results provide a detailed analysis, in vivo and in vitro, of Cse4 phosphorylation and its role in promoting faithful chromosome segregation. PMID- 23637468 TI - Measurement of Women's Empowerment in Rural Bangladesh. AB - Women's empowerment is a dynamic process that has been quantified, measured and described in a variety of ways. We measure empowerment in a sample of 3500 rural women in 128 villages of Bangladesh with five indicators. A conceptual framework is presented, together with descriptive data on the indicators. Linear regressions to examine effects of covariates show that a woman's exposure to television is a significant predictor of three of the five indicators. A woman's years of schooling is significantly associated with one of two self-esteem indicators and with freedom of mobility. Household wealth has a significant and positive association with a woman's resource control but a significant negative association with her total decision-making score. PMID- 23637469 TI - Pd(II)-Catalyzed Cross-Coupling of C(sp2 )-H Bonds and Alkyl-, Aryl- and Vinyl Boron Reagents via Pd(II)/Pd(0) Catalysis. AB - Pd(II)-catalyzed cross-coupling of ortho-C-H bonds in benzoic acid and phenylacetic acid amides with alkyl-, aryl- and vinyl-boron reagents have been achieved via Pd(II)/Pd(0) catalysis, demonstrating the unprecedented versatility of C-H activation reactions. PMID- 23637470 TI - Rethinking Familiarity: Remember/Know Judgments in Free Recall. AB - Although frequently used with recognition, a few studies have used the Remember/Know procedure with free recall. In each case, participants gave Know judgments to a significant number of recalled items (items that were presumably not remembered on the basis of familiarity). What do these Know judgments mean? We investigated this issue using a source memory/free-recall procedure. For each word that was recalled, participants were asked to (a) make a confidence rating on a 5-point scale, (b) make a Remember/Know judgment, and (c) recollect a source detail. The large majority of both Remember judgments and Know judgments were made with high confidence and high accuracy, but source memory was nevertheless higher for Remember judgments than for Know judgments. These source memory results correspond to what is found using recognition, and they raise the possibility that Know judgments in free recall identify the cue-dependent retrieval of item-only information from an episodic memory search set. In agreement with this idea, we also found that the temporal dynamics of free recall were similar for high-confidence Remember and high-confidence Know judgments (as if both judgments reflected retrieval from the same search set). If Know judgments in free recall do in fact reflect the episodic retrieval of item-only information, it seems reasonable to suppose that the same might be true of high confidence Know judgments in recognition. If so, then a longstanding debate about the role of the hippocampus in recollection and familiarity may have a natural resolution. PMID- 23637472 TI - Editor's Note. PMID- 23637471 TI - Childhood Violence Exposure: Cumulative and Specific Effects on Adult Mental Health. AB - Childhood exposure to violence and victimization is a significant public health problem, with potentially long-lasting, deleterious effects on adult mental health. Using a longitudinal study design, 123 young adults-identified in adolescence as at-risk for high school dropout-were examined for the effects of multi-domain childhood victimization on emotional distress and suicide risk, net of adolescent risk and protective factors, including family dysfunction. The hypothesis that higher levels of cumulative childhood victimization would be significantly associated with mental health maladjustment in young adulthood was confirmed by the analysis. However, the victimization predictors of adult emotional distress were different than the predictors of adult suicide risk. These findings indicate the need for prevention and intervention approaches that include thorough assessment, and focus on the childhood and adolescent problem areas that are most consequential for long-term psychological well-being. PMID- 23637473 TI - Evolution of HIV-1 in India. AB - Nearly 25 years after the discovery of the human immunodeficiency virus type 1 (HIV-1) effective control of the AIDS pandemic remains elusive. At the root of this challenge is the evolution of this virus to elude immune control. Error prone nature of replication and retro-transcription is the hallmark of this virus. This fidelity of replication in HIV-1 is due to the absence of proof reading/repair and post-replicative error correction mechanisms that normally operate during replication of DNA viruses. Advances in sequencing technology and expanded disease surveillance have allowed researchers to characterize the variation in HIV-1 around the world and within individual patient overtime. Although HIV-1 has been classified into distinct subtypes, the classification does not reflect dynamic genetic evolution of HIV-1 through which new strains are constantly emerging. The resultant viral diversity has implications for differential rates of disease progression in different geographical areas, differential responses to antiretroviral therapy (including the development of resistance), and vaccine development. In this review evolution of HIV-1 in India is discussed. PMID- 23637474 TI - Reemergence of Chikungunya virus in Indian Subcontinent. AB - Chikungunya virus (CHIKV), a reemerging arboviral disease of public health concern is characterized by a triad of fever, rash and arthralgia. It was responsible for a number of epidemics in Asia and Africa. The severity of the current epidemic can be judged by the fact that an estimated 1.38 million people in India and one-third of the La Reunion population (by April 2006) were affected by CHIKV. Aedes aegypti and Aedes albopictus are the major mosquitoes transmitting CHIKV in Asia. Various neurological complications and CHIKV associated deaths were encountered during the current outbreak (2005-2010). The aggressive nature of the recent CHIKV epidemic was attributed to the mutations in the viral genome in addition to their adaptation and spread to vectors like Aedes albopictus. Proper diet, adequate rest and symptomatic treatment using non salicylate analgesics and Non-steroidal anti inflammatory drugs (NSAIDS) helped the patients in recovering from CHIKV infections. In the absence of an effective vaccine, rapid implementation of mosquito control measures and establishment of a system for continuous surveillance of the disease seems to be the only possible solution to prevent any such outbreak in the near future. PMID- 23637476 TI - Canine parvovirus: current perspective. AB - Canine parvovirus 2 (CPV-2) has been considered to be an important pathogen of domestic and wild canids and has spread worldwide since its emergence in 1978. It has been reported from Asia, Australia, New Zealand, the Americas and Europe. Two distinct parvoviruses are now known to infect dogs-the pathogenic CPV-2 and CPV-1 or the minute virus of canine (MVC). CPV-2, the causative agent of acute hemorrhagic enteritis and myocarditis in dogs, is one of the most important pathogenic viruses with high morbidity (100%) and frequent mortality up to 10% in adult dogs and 91% in pups. The disease condition has been complicated further due to emergence of a number of variants namely CPV-2a, CPV-2b and CPV-2c over the years and involvement of domestic and wild canines. There are a number of different serological and molecular tests available for prompt, specific and accurate diagnosis of the disease. Further, both live attenuated and inactivated vaccines are available to control the disease in animals. Besides, new generation vaccines namely recombinant vaccine, peptide vaccine and DNA vaccine are in different stages of development and offer hope for better management of the disease in canines. However, new generation vaccines have not been issued license to be used in the field condition. Again, the presence of maternal antibodies often interferes with the active immunization with live attenuated vaccine and there always exists a window of susceptibility in spite of following proper immunization regimen. Lastly, judicious use of the vaccines in pet dogs, stray dogs and wild canids keeping in mind the new variants of the CPV-2 along with the proper sanitation and disinfection practices must be implemented for the successful control the disease. PMID- 23637475 TI - Advances in Small Isometric Multicomponent ssDNA Viruses Infecting Plants. AB - Multicomponent ssDNA plant viruses were discovered during 1990s. They are associated with bunchy top, yellowing and dwarfing diseases of several economic plants under family Musaceae, Leguminosae and Zingiberaceae. In the current plant virus taxonomy, these viruses are classified under the family Nanoviridae containing two genera, Nanovirus and Babuvirus. The family Nanoviridae was created with five members in 2005 and by 2010, it has expanded with four additional members. The viruses are distributed in the tropical and subtropical regions of Asia, Australia, Europe and Africa. The viruses are not sap or seed transmissible and are naturally transmitted by aphid vector in a persistent manner. The genome is consisted of several circular ssDNAs of about 1 kb each. Up to 12 DNA components have been isolated from the diseased plant. The major viral proteins encoded by these components are replication initiator protein (Rep), coat protein, cell-cycle link protein, movement protein and a nuclear shuttle protein. Each ssDNA contains a single gene and a noncoding region with a stable stem and loop structure. Several Rep encoding components have been reported from each virus, only one of them designated as master Rep has ability to control replication of the other genomic components. Infectivity of the genomic DNAs was demonstrated only for two nanoviruses, Faba bean necrotic yellows virus and Faba bean necrotic stunt virus (FBNSV). A group of eight ssDNA components of FBNSV were necessary for producing disease and biologically active progeny viruses. So far, infectivity of genomic components of Babuvirus has not been demonstrated. PMID- 23637477 TI - Diagnosis of Novel Pandemic Influenza Virus 2009 H1N1 in Hospitalized Patients. AB - A real-time RT-PCR assay was standardized and evaluated for the detection of the recent pandemic 2009 H1N1 strain that circulated around the world causing colossal loss of human life. We amplified the conserved regions of the hemagglutinin (HA) gene of 438 clinical specimens using real-time RT-PCR assay for rapid identification of pandemic influenza virus. The real-time RT-PCR was optimized and the primers and probes were tested against a panel of known negative and positive controls. RNA isolated from the HeLa cell line served as quality control. The conventional RT-PCR which is an established method of influenza virus diagnosis was compared to real-time RT-PCR. Of 438 clinical specimens tested, 212 specimens were found positive for influenza A virus (SD 46.669) in which 139 specimens were diagnosed positive for the pandemic 2009 H1N1 while 73 were the seasonal influenza viruses. We report that the real-time RT-PCR assay offers both, a high sensitivity and specificity when compared with the traditional identification method. The real-time RT-PCR assay allows rapid identification of the pandemic swine 2009-H1N1 at very low viral loads that are negative by the traditional RT-PCR. This optimized assay can be a very useful tool to assist both epidemiologists and the clinicians. PMID- 23637478 TI - Detection of influenza virus induced ultrastructural changes and DNA damage. AB - The influenza virus generally causes damage to epithelial cells of respiratory tract and infection of cells with this virus often results in cell death with apoptotic characteristics. Reports are available implicating influenza virus as a causative agent of chromosomal aberrations in cells and culture. The objective of this study was to analyze the process of cell death caused by influenza virus (A/Udorn/317/72, H3N2) infection in cultured HeLa cells by electron microscopy and comet assay. The apoptotic study was performed using light microscopy electron microscopy and comet assay to observe the changes in cell morphology and DNA fragmentation. HeLa cells, infected with influenza virus were harvested at various time periods to observe the ultrastructural changes. This infection gave rise to nuclear fragmentation and chromatin condensation accompanied by chromosomal DNA fragmentation into oligonucleosomes. The pattern of comet assay revealed that the apoptosis occurred due to fragmentation of the DNA of the cells which reached the maximum level at 36 h post infection. Ultrastructural study showed extensive chromatin condensation and nuclear fragmentation which are the characteristic features of apoptosis. PMID- 23637479 TI - Chlorotic curly stunt: a severe begomovirus disease of bottle gourd in northern India. AB - Bottle gourd (Lagenaria siceraria) an important vegetable crop in India was observed to be affected by a chlorotic curly stunt disease (CCSD) during 2003 2006 in the vegetable growing areas of Delhi and adjoining state of Haryana. The affected plants are severely stunted and bear very small chlorotic and mildly curled leaves. Incidence of the disease varied from 4.7 to 36%. The disease could be easily transmitted by whitefly, Bemisia tabaci but not by sap. The causal virus was found to be a Begomovirus on the basis of whitefly transmission and sequence identity of putative coat protein (CP) and replication initiator protein (Rep) genes. The virus was transmitted to Cucumis sativus, Luffa acutangula, L. cylndrica, Lycopersicon esculentum, Nicotiana tabacum and Praecitrullus fistulosus but not to Citrullus lunatus, Cucumis melo, Cucurbita moschata and Vigna unguiculata. The N-terminal 60 amino acids of CP of the virus had 100% sequence identity with all the isolates of Tomato leaf curl New Delhi virus (ToLCNDV) and two isolates of Squash leaf curl China virus (SLCCV). The full length amino acid sequence of the CP and Rep genes had 100% similarity with ToLCNDV-Svr and -Luffa isolates. The phylogenetic analysis showed that the virus associated with CCSD of bottle gourd belongs to ToLCNDV cluster of the begomoviruses. This is the first record of emergence of a Begomovirus associated severe disease in bottle gourd in India. PMID- 23637480 TI - Simultaneous Detection of Mixed Infection of Onion yellow dwarf virus and an Allexivirus in RT-PCR for Ensuring Virus Free Onion Bulbs. AB - Reduced seed production in onion is associated with Onion yellow dwarf virus (OYDV), a filamentous Potyvirus. Onion is also infected with other filamentous virus particles suspected to be Allexivirus. RT-PCR was used to detect mixed infection of both the viruses in leaves and bulbs. A duplex RT-PCR was developed, which simultaneously detected the presence of these two viruses in winter (Rabi) onion bulb. In summer (Kharif) onion bulbs only Allexivirus was detected. The absence of OYDV in summer crop is discussed. The sequencing of RT-PCR amplified products confirmed the identity of OYDV and Allexivirus, the latter showing closer identity to Garlic virus C (GVC)/Garlic mite-borne mosaic virus. This makes the first detection of an Allexivirus in onion crop in India. The duplex RT PCR to detect these viruses (OYDV and Allexivirus) would be an improvement for indexing of viruses in onion bulbs for seed production. PMID- 23637481 TI - Characterization and expression of e2 glycoprotein of classical Swine Fever virus in a eukaryotic expression system. AB - Classical swine fever (CSF) is an economically important Office International des Epizooties (OIE) list A disease of swine characterized by high fever and multiple haemmorhages. The E2 glycoprotein of CSFV is immunogenic and induces neutralizing antibodies against CSFV. In the present study, complete coding region of the E2 gene from Indian virulent field isolate (Mathura) was amplified by reverse transcription-polymerase chain reaction (RT-PCR) and subsequently cloned into a mammalian expression vector; pcDNA3.1(+) at BamHI and XbaI site. The recombinant plasmid; pcDNA.E2.CSFV. was confirmed by restriction enzyme digestion. The pcDNA.E2.CSFV. transfected Vero cell expressed E2 protein which was confirmed by western blotting, immunoperoxidase and indirect immunofluorescent tests. Additionally, flow cytometry analysis also confirmed that 15% of transfected Vero cells expressed the E2 glycoprotein compared to mock or vector alone transfected cells. Further study is under way to evaluate recombinant pcDNA.E2.CSFV. Mathura clone as DNA vaccine against CSFV. PMID- 23637482 TI - Molecular Characterization of Classical swine fever virus Involved in the Outbreak in Mizoram. AB - Classical swine fever is the most insidious and devastating disease of pigs and wild boars. The virus is closely related to the other members of the genus Pestivirus. The outbreak recorded in Mizoram, India was strategically important as the state shares porous international boundary with East Asian countries. Both immunodiagnostic and molecular techniques were used to confirm the involvement of Classical swine fever virus (CSFV) in this outbreak. Sandwich ELISA and direct FAT could detect CSFV in the tissue samples. RT-nPCR specifically amplified E2 and 5'NTR product of 271 bp. Phylogenetic analysis showed, that the Mizoram isolate (MZ4/69) was very close to the Chinese strain Shimen-HVRI (93.0%) rather than other Indian isolate (CSF-30-03). Present study provides a valuable sequence based molecular data on Indian isolate of CSFV and will be useful in investigation on transmission of such disease from neighbour countries. PMID- 23637483 TI - Engineering Resistance Against Mungbean yellow mosaic India virus Using Antisense RNA. AB - Yellow mosaic disease of cultivated legumes in South-East Asia, is caused by Mungbean yellow mosaic India virus (MYMIV) and Mungbean yellow mosaic virus (MYMV) belonging to the genus Begomovirus of the family Geminiviridae. Efforts to engineer resistance against the genus Begomovirus are focused mainly on silencing of complementary-sense virus genes involved in virus replication. Here we have targeted a complementary-sense gene (ACI) encoding Replication initiation Protein (Rep) to develop resistance against soybean isolate of Mungbean yellow mosaic India virus-[India:New Delhi:Soybean 2:1999], a bipartite begomovirus prevalent throughout the Indian subcontinent. We show that the legume host plants co agroinoculated with infectious constructs of soybean isolate of Mungbean yellow mosaic India virus [India:New Delhi:Soybean 2:1999] along with this antisense Rep gene construct show resistance to the virus. PMID- 23637485 TI - Vaccines for Pandemic Influenza A H1N1 (2009): Where Do We Stand? PMID- 23637486 TI - Can plant virus infect human being? PMID- 23637484 TI - Molecular Typing of Canine parvovirus Occurring in Pondicherry by Multiplex PCR and PCR-RFLP. AB - The present study was aimed at molecular typing of Canine parvovirus (CPV) occurring in Pondicherry using PCR based assays. CPV-2a and CPV-2b types were detected by PCR in 68 (53.12%) out of 128 faecal samples/rectal swabs. All the 68 samples found positive by PCR assay were subjected to multiplex PCR assay with CPV-2ab and CPV-2b primer pairs. Sixty-seven (98.52%) samples were characterized as CPV-2b type and one sample (1.47%) was categorized as CPV-2a type. Sixty clinical samples found negative by CPV-2ab primers were subjected to another PCR assay with CPV-555 primer pair for detecting CPV-2c. Though three samples (5%) responded to this PCR, subsequent RFLP of these PCR products with MboII did not show any cleavage indicating the absence of CPV-2c in Pondicherry. It was inferred that CPV-2b was the most prevalent CPV type in Pondicherry. It was further concluded that the CPV-2 variants (CPV-2a, CPV-2b and CPV-2c) currently circulating in the field worldwide could be diagnosed by employing multiplex PCR and PCR-RFLP assays. PMID- 23637487 TI - Protection of Penaeus monodon from Infection of White spot syndrome virus by DNA Construct Expressing Long Hairpin-RNA Against ICP11 Gene. AB - A plasmid construct (pICP11-LH) was designed to constitutively express long hairpin RNA (lhRNA) against icp11 gene, which is reportedly the most highly expressed gene of White spot syndrome virus (WSSV) and likely to have an important role in viral pathogenesis. The construct was used singly and in combination with other similar constructs designed against vp28 and vp19. A total of 6 treatments, T1 (pICP11-LH; 35 MUg), T2 (pVP28-LH; 35 MUg), T3 (pVP28-LH and pVP19-LH; 17.5 MUg each), T4 (pVP28-LH and pVP19-LH; 25 MUg:10 MUg), T5 (pICP11 LH, pVP28-LH and pVP19-LH; 11.5 MUg each) and T6 (pGFP-LH; 35 MUg) were injected intramuscularly into 20 g Penaeus monodon specimens. The shrimp were challenged with WSSV 24 hpi and protection efficacy was measured in terms of survival and viral load 15 days after challenge. Appropriate negative and positive controls were used. T2 and T3 offered highest protection (75%) followed by T1 (67%) and T4 and T5 groups (58%), while T6 showed 25% protection. In all the target specific treatments, the viral load as estimated by single tube WSSV kit was kept in check (10-100 copies), whereas in the unimmunized challenged controls it progressed to severe infection (>10(5) copies). In spite of over 3 times higher expression of ICP11 compared to VP28, its knockdown by pICP11-LH did not offer any protective advantage over pVP28-LH, either singly or in combination. Moreover, none of the combinations bettered the protection efficacy of pVP28-LH administered alone. To investigate concerns about deleterious effect of plasmid persistence and constitutive expression on shrimp growth, a lab-scale 1 month growth study was conducted with 4 treatments T2, T3, T4 and T6, where no difference in specific growth rate was observed compared to controls. PMID- 23637488 TI - A Geminivirus-Satellite Complex is Associated with Leaf Deformity of Mentha (Mint) Plants in Punjab. AB - A widespread leaf deformity disease of mentha (mint), accompanied by whiteflies, the vectors of begomoviruses, was observed in Punjab in the last few years. The presence of begomovirus was indicated by DNA dot-blot analysis using the conserved coat protein and replication-associated protein genes of another begomovirus, Sri Lankan cassava mosaic virus (SLCMV). A DNA fragment (2.0 kb), representing a partial genomic DNA of a begomovirus, amplified from the symptomatic mentha leaves was used to design end-primers and further amplify an additional 0.9 kb fragment, representing the remaining portion of the resident viral DNA. The two sequences, assembled together (2.7 kb), showed that they represented the complete sequence of an isolate of Tomato leaf curl Karnataka virus (ToLCKV) DNA. Using universal betasatellite primers, a 1.4 kb fragment was amplified from the same sample. This cloned DNA fragment showed complete sequence identity with the previously reported Cotton leaf curl Multan betasatellite (CLCuMB). Majority of the symptomatic mentha leaf samples, collected from four districts of Punjab, showed cross-hybridization in DNA dot-blot using cloned SLCMV and CLCuMB DNA, indicating the presence of one or more begomoviruses related to SLCMV and the betasatellite, CLCuMB. The begomovirus and betasatellite could be mechanically transmitted to Nicotiana benthamiana. Whitefly transmission of the resident begomovirus could also be demonstrated on mentha. The evidence indicates the association of ToLCKV and CLCuMB, a hitherto new combination of a begomovirus and a betasatellite associated with a leaf deformity disease in mentha in Punjab. PMID- 23637489 TI - Molecular Characterization of Geographically Different Banana bunchy top virus Isolates in India. AB - Banana bunchy top disease (BBTD) caused by Banana bunchy top virus (BBTV) is one of the most devastating diseases of banana and poses a serious threat for cultivars like Hill Banana (Syn: Virupakshi) and Grand Naine in India. In this study, we have cloned and sequenced the complete genome comprised of six DNA components of BBTV infecting Hill Banana grown in lower Pulney hills, Tamil Nadu State, India. The complete genome sequence of this hill banana isolate showed high degree of similarity with the corresponding sequences of BBTV isolates originating from Lucknow, Uttar Pradesh State, India, and from Fiji, Egypt, Pakistan, and Australia. In addition, sixteen coat protein (CP) and thirteen replicase genes (Rep) sequences of BBTV isolates collected from different banana growing states of India were cloned and sequenced. The replicase sequences of 13 isolates showed high degree of similarity with that of South Pacific group of BBTV isolates. However, the CP gene of BBTV isolates from Shervroy and Kodaikanal hills of Tamil Nadu showed higher amino acid sequence variability compared to other isolates. Another hill banana isolate from Meghalaya state had 23 nucleotide substitutions in the CP gene but the amino acid sequence was conserved. This is the first report of the characterization of a complete genome of BBTV occurring in the high altitudes of India. Our study revealed that the Indian BBTV isolates with distinct geographical origins belongs to the South Pacific group, except Shervroy and Kodaikanal hill isolates which neither belong to the South Pacific nor the Asian group. PMID- 23637490 TI - New Experimental Hosts of Tobacco streak virus and Absence of True Seed Transmission in Leguminous Hosts. AB - Of 70 plant species tested, 50 species were susceptible to Tobacco streak virus (TSV) on sap inoculation. Both localized (necrotic and chlorotic spots) and systemic (necrotic spots, axillary shoot proliferation, stunting, total necrosis and wilt) symptoms are observed by majority of plant species. Eleven new experimental hosts were identified viz., Amaranthus blitum var. oleracea (Chaulai sag), Celosia cristata (Cocks comb), Beta vulgaris var. bengalensis (Palak/Indian spinach), Calendula officinalis (Pot marigold), Chrysanthemum indicum, Cosmos sulphurens (Yellow cosmos), Citrullus lunatus (Watermelon), Lagenaria siceraria (Bottle gourd), Coriandrum sativum (Coriander), Hibiscus subderiffa var. subderiffa (Roselle) and Portulaca oleraceae (Little hogweed). Detected groundnut seed infection with TSV for the first time by Direct antigen coated immunosorbent assay (DAC-ELISA) using whole seed. The seed infection ranged from 18.9 to 28.9% among the seeds collected from naturally infected and sap inoculated groundnut varieties (JL 24, TMV 2, Prasuna, Kadiri 6, Kadiri 9, Anantha and Kadiri 7 Bold) belonging to spanish and virginia types. Further, TSV was detected both in pod shell and seed testa and none of the samples showed the presence of TSV either in cotyledon or embryo. Grow-out and bio-assay tests proved the absence of seed transmission in groundnut and other legume crops. Hence, TSV isolate was not a true seed transmission case under Indian conditions in legumes. PMID- 23637491 TI - Molecular Characterization of Tomato leaf curl Palampur virus and Pepper leaf curl betasatellite Naturally Infecting Pumpkin (Cucurbita moschata) in India. AB - Pumpkin cultivation in India is affected by severe incidence of a yellow vein mosaic disease. Tomato leaf curl New Delhi virus and Squash leaf curl China virus are known to be associated with this disease in India. We were able to identify a third begomovirus-Tomato leaf curl Palampur virus (ToLCPMV), from pumpkin showing typical symptoms of the disease at Varanasi based on the sequence of complete DNA A genome of the virus. The complete DNA-A sequence of the virus shared more than 99% sequence identity with other ToLCPMV isolates available in the GenBank and clustered with them in the phylogenetic analysis. This betasatellite amplified from the same infected sample has been identified as Pepper leaf curl betasatellite (PepLCB) which also infects chilli in India. There was 92% sequence identity between the two isolates. This is the first report of natural infection of ToLCPMV on pumpkin and association of PepLCB with yellow vein mosaic disease of pumpkin in India. PMID- 23637492 TI - Molecular Characterization and Phylogeny of a Phytoplasma Associated with Phyllody Disease of toria (Brassica rapa L. subsp. dichotoma (Roxb.)) in India. AB - Samples from toria plants (Brassica rapa L. subsp. dichotoma (Roxb.)) exhibiting phyllody, virescence, witches broom, extensive malformation of floral parts, formation of bladder like siliquae and flower sterility were collected from four different locations in India. Sequencing and phylogenetic analysis of the 16S rRNA, a part of 23S rRNA, partial sec A genes, rp gene and 16S-23S intergenic spacer region indicated that the phytoplasmas associated with toria phyllody (TP) symptoms were identical and belonged to 16SrIX phytoplasma Pigeon pea witches' broom (PPWB) group. The iPhyClassifier generated virtual RFLP pattern of 1.25 kb 16S rDNA sequences indicated that TP phytoplasma belongs to 16SrIX-C phytoplasma subgroup. Complete 23S rRNA gene of TP phytoplasma had 2,787 nucleotides and is the first sequence of 16SrIX phytoplasma group. Restriction digestion of 16S rDNA and 23S rDNA PCR products has also shown that TP phytoplasmas from all the four locations in India were identical. Toria is a previously unreported host for a phytoplasma in16SrIX-C subgroup. PMID- 23637493 TI - Prevalence of Citrus tristeza virus in Mandarin of Sikkim Himalayan Region. AB - The assessment of Citrus tristeza virus incidence in mandarin of Sikkim, involving sampling techniques, was estimated by DAS-ELISA. Mandarin orchards had high CTV incidence (46.32%), however, differential prevalence with regard to age of plant and location was observed. The CTV prevalence was relatively high in older orchards (51.01%) than that of younger ones (40.80%). Under all the plant age groups, south district had the highest CTV incidence (52.50%) and east district had the lowest (37.71%). The spatial distribution of CTV in plants indicates high concentration in twig followed by leaf tissue, however, stem had relatively less concentration. High aphid infestation was observed in all mandarin growing groves with the maximum in south district and minimum in east district. Taxoptera citricida was the predominating aphid species followed by T. aurantii, however, Aphis spp population was significantly less. Aphid infestation and CTV prevalence were positively and significantly correlated. PMID- 23637494 TI - Detection of Rotavirus Infection in Bovine Calves by RNA-PAGE and RT-PCR. AB - A total of 128 diarrhoeic faecal samples were collected from cattle and buffalo calves from Pantnagar and Dehradun during winter months. Of the 110 cattle calves screened by RNA-PAGE, rotavirus was detected in 13 samples (11.81%) while no sample from buffalo calves was found positive. All samples were found to have long electropherotype and two distinct electropherotypes having segment variation were observed. The overall prevalence of rotavirus was 10.15% (13/128). RT-PCR targeting group specific VP6 gene confirmed Group A rotavirus in 10 out of 13 samples, while three samples remained un-groupable. PMID- 23637495 TI - Survey and RT-PCR Based Detection of Cardamom mosaic virus Affecting Small Cardamom in India. AB - Mosaic or marble or katte disease caused by Cardamom mosaic virus (CdMV) is an important production constraint in all cardamom growing regions of the world. In the present study, 84 cardamom plantations in 44 locations of Karnataka and Kerala were surveyed. The incidence of the disease ranged from 0 to 85%. The incidence was highest in Madikeri (Karnataka) while no incidence was recorded in Peermade (Kerala). In general, incidence and severity of the disease was higher in cardamom plantations of Karnataka. A procedure for total RNA isolation from cardamom and detection of CdMV through reverse transcription-polymerase chain reaction (RT-PCR) using primers targeting the conserved region of coat protein was standardized and subsequently validated by testing more than 50 field cardamom samples originating from Karnataka and Kerala states. The method can be used for indexing the planting material and identifying resistant lines/cultivars before either they are further multiplied in large scale or incorporated in breeding. PMID- 23637496 TI - Clinical profile, genotype and management updates of hepatitis B virus. AB - Hepatitis B virus (HBV) is a well known agent of acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Around 400 million people worldwide carrier of HBV of which more than 250 million reside in Asia, and 1-2 million people have died from it. It has a partially double-stranded DNA, having 3.2-kb genome size and replicate via reverse transcription of RNA intermediate. In the natural history or during the antiviral therapy of chronic HBV infection, seroconversion from HBeAg to anti-HBeAg is usually accompanied by a decrease in viral replication and remission of liver disease. Based on genomic sequence data HBV is classified into eight genotypes A-H and four major serotypes ayw, ayr, adw and adr on the basis of complete genome and S gene sequence analysis. Genotypes and serotypes are useful tools in understanding the epidemiology of HBV infection. HBV genotypes have distinct geographical distributions. The HBV variants appear during HBeAg seroconversion and they bring mutations in the precore region (PC) that prevent HBeAg synthesis. Another common HBeAg variant is the basal core promoter mutant (BCP) characterized by point mutation in the promoter of both HBeAg mRNA and core protein mRNA. The most frequent core promoter mutation is the double A1762T and G1764A nucleotide exchange, which results in a substantial decrease in HBeAg expression but enhanced viral genome replication. The approved antiviral drugs such as Interferon, lamivudine, adefovir dipivoxil, entecavir and telbivudine for purpose of treating chronic HBV infection is to prevent or stop the progression of liver injury by suppressing viral replication or eliminating infection. Sustained losses of viral markers of active viral replication (HBeAg and HBV DNA) are the standard end point of the therapies. PMID- 23637498 TI - Distribution of hepatitis B virus genotypes and its association with severity of liver disease in patients with chronic hepatitis B in uttar pradesh, India. AB - The present study was designed to investigate the distribution of genotypes and its association with severity of liver disease in patients with Chronic Hepatitis B (CHB) in Uttar Pradesh, India. One hundred five HBsAg positive patients were selected for the study. The DNA was extracted by using pure viral DNA extraction kit. The genotype of Hepatitis B virus (HBV) was identified by using polymerase chain reaction- based restriction fragment length polymorphism (PCR-RFLP) method, by using AvaII and DpnII restriction enzyme to see the different patterns of cleavage that would occur at this specific site. Among 105 HBsAg positive chronic liver disease patients 58 patients were positive for HBeAg and 47 samples were HBeAg negative. Genotyping was done successfully in 91 samples. Genotype A was identified in 22% and genotype D in 78% CHB patients. Genotype A showed elevated liver enzymes much more than genotype D. The Child Pugh classification of 20 patients with genotype A was class A (n = 2), B (n = 9), C (n = 9) and of genotype D was class A (n = 13), B (n = 50) and C (n = 8). In conclusion our results showed that Genotype D was the commonest genotype in Uttar Pradesh, whereas genotype A had significantly more elevated ALT/AST levels than genotype D. (P < 0.05). Child Pugh Grade B was significantly more in patients with genotype D, whereas Child Pugh Grade C was more in genotype A. PMID- 23637499 TI - Isolation and characterization of baculoviruses from three major lepidopteran pests in the semi-arid tropics of India. AB - Baculoviruses were isolated from three major lepidopteran pests, Helicoverpa armigera, Spodoptera litura and Amsacta albistriga in the semi-arid tropics during natural epizootic conditions at ICRISAT fields, Patancheru, Andhra Pradesh, India. Biological, morphological and biochemical analysis identified these isolates as Nucleopolyhedroviruses (NPVs). Scanning electron microscopy of the occlusion bodies (OBs) purified from diseased larvae revealed polyhedral particles of size approximately 0.5-2.5 MUm [Helicoverpa armigera Nucleopolyhedrovirus (HearNPV)], 0.9-2.92 MUm [Spodoptera litura Nucleopolyhedrovirus (SpltNPV)] and 1.0-2.0 MUm [Amsacta albistriga Nucleopolyhedrovirus (AmalNPV)] in diameter. Transmission electron microscopy of thin sections of OBs of the three isolates revealed up to 5-8 multiple bacilliform shaped particles packaged within a single viral envelope. The dimensions of these particles were 277.7 * 41.6 nm for HearNPV, 285.7 * 34.2 nm for SpltNPV and 228.5 * 22.8 nm for AmalNPV. Each of HearNPV and AmalNPV contained up to 6 nucleocapsids and SpltNPV contained up to 7 nucleocapsids per envelope. The estimated molecular weights of the purified OB (polyhedrin) protein of the three NPVs were 31.29-31.67 kDa. Virus yield (OBs/larva) was 5.18 +/- 0.45 * 10(9) for HearNPV, 5.73 +/- 0.17 * 10(9) for SpltNPV and 7.90 +/- 0.54 * 10(9) for AmalNPV. The LC50 values of various NPVs against 2nd and 3rd instar larvae indicated 2.30 * 10(4) and 1.5 * 10(5) OBs/ml for HearNPV, 3.5 * 10(4) and 2.4 * 10(5) OBs/ml for SpltNPV and 5.6 * 10(4) and 3.96 * 10(5) OBs/ml for AmalNPV. The lethal time required to cause 50% mortality (LT50) for these three species were also defined. This study has shown that the NPVs infecting three major lepidopteran pests in India are multiple NPVs, and they have good potential to use as biocontrol agents against these important pests. PMID- 23637500 TI - Analysis of 3'-Terminal Region of Bean common mosaic virus Strains Infecting Common Bean in India. AB - Four strains (NL-1, NL-1n, NL-7 and NL-7n) of Bean common mosaic virus (BCMV) prevalent on common bean (Phaseolus vulgaris) in Himachal Pradesh, a north western Himalayan state of India were compared at the 3' terminal region of the viral genome to elucidate variation and relationship among these strains. 3' terminal region comprising of partial nuclear inclusion b (NIb) (171-233 bp), complete coat protein (CP) (860 bp) and 3' untranslated region (UTR) (208-244 bp) shared 96-98% nucleotide and 96-99% amino acids identity among various strains of BCMV. Multiple alignment as well as cluster dendrograms of the 3' terminal region placed the test isolates in BCMV species of genus Potyvirus. Phylogenetic analysis of complete CP as well as 3' UTR also showed Indian strains to be distinct strains. Sequence homology, multiple alignment and evolutionary divergence of 3' terminal region could not differentiate the pathogenic strain groups, thereby establishing least role of this region in strain characterization of the virus. Comparisons of CP and 3' UTR region of BCMV strains and other members of genus Potyvirus clearly indicated the little utility of 3' terminal region in distinction of virus strains. Implications of coat protein region in viral strain distinction are also discussed. PMID- 23637497 TI - Rotavirus infection: a perspective on epidemiology, genomic diversity and vaccine strategies. AB - For centuries, acute diarrhea has been a major cause of death in young children worldwide, and until 1973, before rotavirus was discovered; no infectious agents could be identified in about 80% of patients admitted to hospital with severe dehydrating diarrhea. Rotaviruses have now been shown to cause 40-50% of severe acute diarrhea in young children worldwide in both developing and developed countries. More than 600,000 young children die and approximately 2.4 million hospitalize annually from rotavirus disease, especially in South-East Asia and sub-Saharan Africa. Two safe and effective vaccines are now licensed in 100 countries but used in 17 countries. Rotarix (GSK) vaccine is derived from single attenuated human rotavirus G1P[8], representative of the most common serotype identified worldwide. RotaTeq (Merck) is a pentavalent mixture of naturally attenuated bovine/human rotavirus reassortants representing G1, G2, G3, G4, and P[8] serotypes. Though these vaccines have already dramatically decreased the morbidity associated with rotavirus in countries where they are widely used, the third generation of vaccines, based on inactivated viruses or recombinant virus like particle are already in pipeline. Continuous surveillance and the genetic and antigenic analysis of the various strains of rotavirus circulating worldwide will aid significantly in assessing the effectiveness of these vaccines and monitor emergence of new strains. Introduction of rotavirus vaccines in national vaccine policy along with other childhood vaccines may result in significant reduction in mortality in children in poor socioeconomic countries. PMID- 23637501 TI - Diversity of Apple mosaic virus Isolates in India Based on Coat Protein and Movement Protein Genes. AB - Apple mosaic virus (ApMV), an Ilarvirus is one of the most common pathogens of apple worldwide. During field surveys in commercial plantations of Himachal Pradesh and Jammu & Kashmir, observations of bright chlorotic mosaic like symptoms on apple trees indicated probable infection by the virus, which was later detected by double antibody sandwich-enzyme linked immunosorbent assay (DAS ELISA). An incidence of 24 and 28% (based on ELISA) was obtained as 6/25 and 15/53 samples from HP and J&K were positive, respectively. An amplification of approximately 700 and 850 bp was obtained for coat and movement protein genes (CP and MP), respectively. The CP was 223 amino acids in length and showed 87-99% identity when compared to 21 ApMV isolates. Whereas, MP (286 amino acids) showed 91-95% identity with other isolates. However, the gene sequences were quite conserved among Indian isolates and grouped together phylogenetically. CP of the Indian isolates showed maximum identity of 95% with Korean isolate (AY 125977) in apple and in other host these showed a maximum identity of 98% to Czech Republic pear isolate. MP showed maximum identity with Chinese isolate i.e., 95%. The diversity study will also help in analyzing variability among the isolates and also to formulate diagnostic and resistance strategies. PMID- 23637502 TI - Self Replicating Gene Vaccine Carrying P1-2A Gene of FMDV Serotype O and its Effects on the Immune Responses of Cattle. AB - DNA vaccines are considered as alternatives to live attenuated ones for those diseases like foot-and-mouth disease (FMD) where the production and application of live vaccines have been found unsuccessful. However, stability of DNA and the quantity of antigen expressed are the major limitation with naked DNA vaccines. To address these issues self replicating gene vaccine construct was made for foot and-mouth disease virus (FMDV) type 'O' and studied. The vector for vaccine construct, designated as pSinCMVVac carried CMV promoter and Poly(A) signal sequences at 5' and 3' end of Sindbis replicase gene respectively. Gene for structural protein precursor (P1-2A) of FMDV serotype 'O' was inserted into pSinCMVVac under subgenomic promoter. 5'UTR (untranslated region) of FMDV was introduced upstream of P1-2A to enhance the level of expression of cloned gene. Functionality of the vaccine construct was confirmed in vitro and in vivo. The self-replicating gene vaccine construct was tested in cattle in comparison with naked DNA vaccine carrying P1-2A and 3CD (pUP3CD). Humoral immune response by ELISA and SNT and cellular response by lymphoproliferation assay using MTT were studied. The default approach of using self replicating gene vaccine in high dose and multiple injection in cattle as followed in our studies might result in immunosuppression as this was observed in our subsequent experiments in guinea pigs. Hence based on dose response studies, vaccine strategy needs to be decided. However, the approach of using Sindbis polymerase gene and UTR in FMDV vaccine is the first report and shows future scope of developing such vaccines. PMID- 23637503 TI - Detection and Identification of Dasheen mosaic virus Infecting Colocasia esculenta in India. AB - Reverse transcription polymerase chain reaction of the infected leaf samples of Colocasia esculenta plants showing severe whitish feathery symptoms were carried out using Potyvirus group specific primers, resulting in an amplicon of 327 bp, encoding the core region of the coat protein gene. Sequencing and BLAST analysis showed that the virus is distinct, closely related to Dasheen mosaic virus (DsMV). Sequence analysis revealed 86 and 96% identity at the nucleotide and amino acid level respectively with the DsMV isolate SY1(accession Number AJ628756). This is the first molecular level characterisation of the DsMV infecting C. esculenta in India. PMID- 23637504 TI - Sequence Comparison and Phylogeny of Nucleotide Sequence of Coat Protein and Nucleic Acid Binding Protein of a Distinct Isolate of Shallot virus X from India. AB - Shallot virus X (ShVX), a type species in the genus Allexivirus of the family Alfaflexiviridae has been associated with shallot plants in India and other shallot growing countries like Russia, Germany, Netherland, and New Zealand. Coat protein (CP) and nucleic acid binding protein (NB) region of the virus was obtained by reverse transcriptase polymerase chain reaction from scales leaves of shallot bulbs. The partial cDNA contained two open reading frames encoding proteins of molecular weights of 28.66 and 14.18 kDa belonging to Flexi_CP super family and viral NB super-family, respectively. The percent identity and phylogenetic analysis of amino acid sequences of CP and NB region of the virus associated with shallot indicated that it was a distinct isolate of ShVX. PMID- 23637505 TI - Isolation and Phylogenetic Analysis of H1N1 Swine Influenza Virus from Sick Pigs in Southern China. AB - Two swine influenza (SI) H1N1 virus was isolated from a pig during a severe outbreak of respiratory disease in south China. The two H1N1 influenza viruses were classical SI virus. A/swine/Guangdong/L6/09 is classical SI virus of recent years, which is of the main SI virus in China. Howere, A/swine/Guangdong/L3/09 was closet to A/swine/Iowa/1931, which was the first isolated SI virus and had demonstrated significant pathogenicity in animal models. The results of phylogenetic analysis of A/swine/Guangdong/L3/09 showed a close relationship with the 1918 pandemic virus. The results suggested that the previous SI virus appeared again. Whether, it brought a new pandemic to pigs deserves more attention. PMID- 23637506 TI - Characterization of 132 bp Repeats BamH1-H Region in Pathogenic Marek's Disease Virus of Poultry in Gujarat, India, Using PCR and Sequencing. AB - A total of 34 clinical samples and four Marek's disease virus (MDV) vaccines were tested using primer BamH1/BamH2 in layer birds of poultry. Out of 34 samples tested for detection of MDV, 32 samples produced approximately 434 bp product. All the three HVT vaccines as well as SB-1 (MDV-2) vaccine failed to produce the expected amplicons, there by proving negative for the targeted 132 bp repeats of MDV genome by the primers BamH1/BamH2. Resultant PCR products of the field samples were purified and sequenced and resulted in 378 bp long sequences. PCR was found very satisfactory in detecting the presence of MDV either in feather follicle or in tissue samples. Sequencing study has proved beyond doubt that the two representative samples contained two 132 bp repeats indicating the virulent nature of the field virus. PMID- 23637507 TI - High Prevalence of Hepatitis C virus Among Injection Drug Users in Zhenjiang, Jiangsu, China. AB - The constant increase in the number of drug users and rapidly spread of Hepatitis C virus (HCV) and Human immunodeficiency virus (HIV) among drug users result in a serious public health problem in China. To investigate HCV prevalence among drug users in Zhenjiang city, Jiangsu, China, 207 drug users from Zhenjiang were enrolled in this study during 2009 and the prevalence of HCV, HIV and syphilis infection were detected. HCV prevalence among injection drug users (IDUs) was 81.6%, significantly higher than that (22.9%) among oral drug users (P < 0.001), suggesting a strong association of HCV infection with injection drug use (IDU). Most drug users were more than 25 years old (89.2%), single (60.5%, including single and divorced/widowed), and had a history of drug abuse over 6 years (92.9%). HCV prevalence among drug users with middle (72.6%) or high (83.8%) school diplomas was significantly higher than that among those with lower (46.9%) education level (P = 0.007). HCV prevalence among IDUs did not obviously change along with the increase in duration of drug use and in frequency of injection per day, suggesting less association of HCV infection with both variables. These results suggest that most Chinese addicts might start drug use after their middle/high school education. To reduce drug use and to prevent HIV and HCV transmission via IDU, large-scale drug prevention educations should be urgently conducted in all China's middle and high schools. PMID- 23637508 TI - Association of Human bocavirus with Respiratory Infections in Outpatients and in Patients Attended at a Reference Hospital. AB - The role of Human bocavirus (HBoV) in human infectious disease is unclear due to the frequent detection of this virus in association with other respiratory viruses with a recognized pathogenic role in acute respiratory infection. We have analyzed the impact of HBoV in outpatients and in patients requiring hospitalisation or emergency attention for acute respiratory infections. Respiratory viruses were investigated by real-time PCR, direct antigen detection and/or viral culture by shell-vial assay. Nasopharyngeal aspirates, BAL and/or sputum samples from patients attended at a reference hospital, and nasal/throat swabs from outpatients were used. Respiratory viruses were detected in 660 samples (47%). HBoV detection rate was 12.6%, only preceded by respiratory syncytial virus (25%). Co-detections were observed in 12.9% of samples, and HBoV was present in 81% of them. Similar detection rates of HBoV were obtained in individuals with positive and negative results for other respiratory viruses (12.5% and 12.7%, respectively). The crossing point value was taken as a measure of HBoV viral load. Higher HBoV loads were observed in children, and in patients from the hospital. HBoV viral load was not associated with symptoms of upper respiratory tract infection or lower respiratory tract disease. Although HBoV is frequently detected in respiratory specimens, there is a poor association between HBoV-positive specimens and clinical parameters. A clinical impact of HBoV in respiratory infection probably occurs in few cases. PMID- 23637509 TI - CD4(+) T Cell Response to Lamivudine, Stavudine and Nevirapine in Human Immunodeficiency Virus Infected Antiretroviral-Naive Men in Nigeria. AB - Increase of (>=) 50 CD4(+) T cells/MUl in post-commencement of highly active antiretroviral therapy (HAART) is acceptable as indicator of therapeutic success (TS). We therefore hypothesized that median change in CD4 count of the TS and therapeutic failure (TF) groups were comparable after 3 months; and that no associations existed between HAART outcome and adherence to therapy. One hundred Human immunodeficiency virus (HIV) infected antiretroviral (ARV) naive men on lamivudine + stavudine + nevirapine at Federal Medical Centre (FMC), Lokoja, Kogi State, Nigeria were studied. Data of the men were obtained with interviewer administered questionnaire forms. Their ethylene diamine tetra acetic acid (EDTA) treated whole blood samples were analysed with Partec CyFlow((r)) Counter for pre HAART and follow-up CD4 counts. Adherence to the ARV regimen was recorded for each patient as self-reported. We used Mann-Whitney U test, Kruskal-Wallis, Wilcoxon's matched pair and CHI(2) statistical tests for analyses. Overall adherence rate was 95.0%. Though the median follow-up CD4 count was higher (P = 0.001) than the pre-HAART value; only 85% of the men attained TS (increase of >=50 cells/MUl) at follow-up. Median change in CD4 count (+104.0 cells/MUl; n = 85) of the TS was higher (P = 0.001) than that (-8.0 cells/MUl; n = 15) of TF group; the two groups were however, comparable in age (P = 0.17) and body weight (P = 0.96). Only adherence and pre-HAART CD4 counts were associated (P = 0.001) with HAART outcome; while only age apparently influenced (P = 0.01) adherence rate. Eighty-five percent of the men benefited from the HAART. The success was apparently due to adherence and less than or (<=) 200 pre-HAART CD4 counts; while age >=40 years appearently reduced adherence level. PMID- 23637510 TI - Evidence for Occurrence of Human group B rotavirus in Central India Based on Characterization of NSP2 Gene. AB - Human group B rotavirus (HuGBR) was first described as the causative agent of severe gastroenteritis, affecting millions of people in China during 1982-1983. In spite of serological evidences for the presence of HuGBR in many countries of the world, the virus has only been detected from China, Bangladesh and some parts of India. The present study describes a HuGBR (designated as MP-1 isolate) which was confirmed in an adult patient suffering from gastroenteritis in 2008 in Madhya Pradesh, central India. The RNA electrophoresis in polyacrylamide gel (RNA PAGE) and NSP2 gene based RT-PCR assays and later sequencing was used to confirm the isolate. The nucleotide and deduced amino acid sequences of this HuGBR (MP-1) isolate were analyzed and their relationship with corresponding gene of other Indian, Bangladeshi and Chinese HuGBR and animal group B rotaviruses (AnGBR) was determined. The isolate showed a typical RNA banding pattern of 4:2:2:3 in RNA PAGE which was indicative of group B rotaviruses (GBR). The sequence comparison of MP-1 isolate with NSP2 gene revealed that MP-1 isolate had 98.6 and 97.7% nucleotide sequence homology and 93.8% amino acid similarity with Bang373 and CAL 1 strains, respectively. The nucleotide and amino acid sequence similarity of MP 1 isolate with one of the Chinese ADRV (WH-1) strain was 92.8 and 92.5%, respectively. While sequence homology with another Chinese strain ADRV (J19) was considerably lower (45.6 and 48.3%, respectively). The percent identity with AnGBRs (porcine and murine) was also lower at nucleotide and amino acid level (66 to 80%). The phylogenetic analysis suggested that MP-1 isolate is closer to Bangladeshi (Bang373) as compared to Indian strain (CAL-1). Our findings indicated that MP-1 isolate might have originated from a common ancestral HuGBR virus but distinct from AnGBR lineage. Occurrence of GBR in other parts of India warrants further epidemiological and molecular studies to develop effective control strategies for GBR infection in adults as well as children. PMID- 23637511 TI - Presence of Virus like Particles in Human Pathogenic Fungi: Chrysosporium sps and Candida albicans. AB - Out of eight isolates of different human pathogenic fungi, four were found to be infected with virus like particles (VLP): Chrysosporium pseudomerdarium, C. xerophillum, C. keratinophillum and Candida albicans through electron microscopy. Frozen mycelium without abrasive was seemingly better disruption method for VLP extraction in Chrysosporium extracts but in Candida albicans disruption with abrasive revealed the presence of considerable amount of VLP. The growth of five isolates of Chrysosporium species associated with VLP was significantly affected by different media tested. Absorption spectra revealed the nucleo protein nature of VLP in C. albicans. Virus like particles in Chrysosporium species reported for the first time and in C. albicans, it is reported for the first time in India. PMID- 23637512 TI - Intermolecular Interactions of Chrysanthemum virus B Coat Protein: Implications for Capsid Assembly. AB - Chrysanthemum virus B coat protein constitutes the viral capsid which, besides other functions, encapsulates and protects the viral nucleic acid. We have demonstrated homotypic interaction of the coat protein subunits, essentially important for dimer formation, which is the first step during capsid assembly in vivo and in vitro. Interaction capacity of full length and truncated protein has been investigated and important regions have been identified through protein protein interaction in yeast and by co-immunoprecipitation assays. Complete coat protein was found to interact strongly with similar subunits. Constructs with 102 amino acids from the N-terminal and 64 amino acids from C-terminal were found to be inconsequential for dimer formation as they did not show any interaction with similar subunits or with full length protein when analysed for beta-galactosidase or histidine prototrophy. Results suggest that the region of 98-184 amino acids from the middle plays an important role in the process, probably without the involvement of N- and C- terminals. PMID- 23637513 TI - Biological and Molecular Characterization of Two Distinct Tomato Strains of Cucumber mosaic virus Based on Complete RNA-3 Genome and Subgroup Specific Diagnosis. AB - Cucumber mosaic virus (CMV) is one of the most important viral pathogen infecting several plant species in India. Five isolates of CMV obtained from cucumber, muskmelon, tobacco and tomato from distinct geographical locations in India were analysed based on host-reactions and genome sequence. The majority of the isolates were very similar and only two isolates, Tfr-In and Tss-In showed distinct symptoms in tomato and high sequence diversity (77.8%) in coat protein (CP) gene. Tfr-In was isolated from tomato fruit showing grey patches in Aurangabad and Tss-In from tomato plant showing shoe-string symptoms in New Delhi. The RNA-3 genomes of Tfr-In (2,214 nt; JF279606), shared only 70.3% nucleotide sequence identity with Tss-In (2,178 nt; JF279605. The complete RNA-3 genome of Tss-In and Tfr-In were compared with that of 65 CMV isolates reported from various plants of the world, which formed four distinct subclades-IA, -IB, IC and -II. The Tfr-In isolate clustered with the CMV subgroup-IB and Tss-In with the subgroup-II. The comparison of the RNA-3 sequence of both the isolates revealed maximum heterogeneity in the intergenic region (IR). Reverse transcriptase polymerase chain reaction (RT-PCR) based detection of CMV subgroup I and -II was developed designing primers from flanking IR region. The specificity of the RT-PCR detection was confirmed using Tfr-In and Tss-In representing subgroup-I and -II and validated with field samples of tomato, cucurbits and chilli. This is the first report of complete RNA-3 of subgroup-IB CMV causing grey patches in tomato fruit and subgroup-II CMV causing shoe-string symptoms in tomato in India. The present and previous studies together showed that tomato in India was affected by multiple strains of CMV. PMID- 23637514 TI - Identification of Beet necrotic yellow vein virus in Lakes District: A Major Beet Growing Area in Turkey. AB - This study was conducted to determine the prevalence of Beet necrotic yellow vein virus (BNYVV) causal agent of rhizomania, in sugar beet cultivation areas in the Lakes District of Turkey, in 2006-2007. During surveys BNYVV suspected leaf, root, and soil samples were collected. Total of 203 soil samples were collected from different locations in the region. Sugar beet cultivar Kasandra plants were grown in these soil samples using bait plant techniques. In order to detect the structures of the vector protozoa Polymyxa betae Keskin in the root tissue of the bait plants, roots were stained with lactofuchsin and examined for the fungal cystosori under a light microscope. Presence of BNYVV was investigated using Double antibody sandwich enzyme linked immunosorbent assay (DAS-ELISA). ELISA test results showed that 85 samples were infected with BNYVV (41.87%). ELISA positive samples for BNYVV were used in the mechanical inoculation studies. Test plants produced typical BNYVV symptoms. Fifty ELISA negative samples when tested by reverse transcription polymerase chain reaction (RT-PCR), BNYVV could be detected in 50% of these samples. The present study provides evidence for occurrence of BNYVV in a major beet growing area in Turkey based on biological, serological and molecular detection of the virus. RT-PCR method was found more suitable and sensitive than DAS-ELISA for the detection of BNYVV. PMID- 23637515 TI - Analysis of the Fusion Protein Cleavage Site of Newcastle disease virus Isolates from India Reveals Preliminary Evidence for the Existence of II, VI and VII Genotypes. AB - Newcastle disease virus (NDV) has been a threat to poultry industry in most of the developing countries with a wide variety of avian species being susceptible, coupled with the presence of mobile wild bird reservoirs contributing not only to the vast genomic diversity of this virus but also to the diagnostic failures. NDV of multiple genotypes (I-XI) is known to be prevalent and reported worldwide. However, there is a paucity of information on the circulating genotypes of NDV in India. This study utilized the fusion protein cleavage site (FPCS) sequence to determine the different genotypes of NDV circulating in India. Our results indicate that majority of NDV isolates from southern states of India namely, Tamil Nadu, Kerala and Karnataka were found to belong to genotype II. However, some of the strains from Tamil Nadu and most from Uttar Pradesh belong to genotype groups VI and VII. Interestingly, three isolates recovered from Tamil Nadu grouped with genotype IV viruses (namely Herts/33) which had not been hitherto reported to GenBank since 1989. This preliminary information points to the existence of multiple genotypes and also the need for efficacy studies with vaccines incorporating multiple genotypes in controlling virulent NDV (vNDV) outbreaks in India. PMID- 23637516 TI - Rabies in South Indian Cows: An evidence of Sri Lankan Rabies virus Variant Infection Based on the Analysis of Partial Nucleoprotein Gene. AB - Rabies is a highly fatal non-suppurative encephalomyelitis, caused by the Rabies virus. Dogs are the major reservoir of rabies in India and are the source of infection to other domestic animals. In this report, laboratory investigation and molecular characterization of isolates from two cows with paralytic rabies is described. Necropsy brain samples from the two cows were tested for the presence of rabies antigen using a fluorescent antibody test and the results were confirmed using RT-PCR. Rabies virus was successfully isolated from both the brain samples in a murine neuroblastoma cell line. The phylogenetic analysis of partial nucleoprotein gene sequences of these isolates showed them to be of a variant of Rabies virus which is closely related to the Sri Lankan Rabies virus lineage as previously reported. In addition, partial nucleoprotein genes of 19 more Rabies virus isolates from southern India were sequenced and of these 11 isolates were found to be closely related to the Sri Lankan lineage. The deduced amino acid sequences of the partial nucleoprotein of the Indian isolates were 96 99% identical to the Sri Lankan isolates. This investigation re-confirms the previous speculations that the Sri Lankan variant of the virus may still be actively transmitted by animals in India. PMID- 23637517 TI - Comparative analysis of routine laboratory diagnostic tests for rabies. AB - Present study was undertaken to compare various routine laboratory diagnostic tests for rabies detection. Seller's staining, mouse inoculation test (MIT), Dot ELISA, Agar gel precipitation test (AGPT) and counter immunoelectrophoresis test (CIET) were the main basic tests performed in the laboratory for the rabies diagnosis. Out of 200 brain specimens, Negri bodies were observed in 52 brain samples by Seller's staining. Rabies virus was isolated in 56 samples by intra cerebral inoculation in newborn Swiss-albino mice. Dot-ELISA and AGPT could detect rabies antigen in 55 and 57 samples respectively. Comparative analysis revealed that the CIET is the most sensitive and rapid test among performed diagnostic tests. PMID- 23637518 TI - Changes in the Cytokine and Toll-Like Receptor Gene Expression Following Infection of Indigenous and Commercial Chickens With Infectious bursal disease virus. AB - A comparative study of cytokine and toll-like receptor (TLR) mRNA expression in 3 weeks old indigenous and commercial chickens infected with a very virulent strain of Infectious bursal disease virus (IBDV) was performed using a custom-made microarray chip. In uninfected indigenous chickens, the basal levels of interleukin (IL) 15 were lower and IL 16 was higher than their commercial counterparts. In the IBDV infected indigenous chickens, only IL16 gene expression was down regulated, while TLR3 expression was up regulated significantly. In the IBDV infected commercial chickens IL15, IL16 and TLR3 were down regulated. But, IL1-beta, IL2, IL8, IL12, IL17, interferon (IFN)-alpha and beta were significantly increased compared with the control. In IBDV infected indigenous chickens, IL15, IFN-gamma, beta-defensin and TLR3 were up regulated compared to virus-infected commercial chickens. The results suggested that up regulation of TLR3, a ligand for double-stranded (ds) RNA probably could account for the possible clinical resistance in these birds. There was a 5.2 fold difference by quantitative real-time RT-PCR between indigenous and commercial chickens in TLR3 mRNA expression. Therefore, TLR3, a receptor for dsRNA could be a putative molecule that could play a role in differential innate and adaptive immune responses to IBDV in commercial and indigenous chickens. PMID- 23637519 TI - Recent Changes Leading to Subsequent Changes: Extensions of Multivariate Latent Difference Score Models. AB - Latent difference score models (e.g., McArdle & Hamagami, 2001) are extended to include effects from prior changes to subsequent changes. This extension of latent difference scores allows for testing hypotheses where recent changes, as opposed to recent levels, are a primary predictor of subsequent changes. These models are applied to bivariate longitudinal data collected as part of the Baltimore Longitudinal Study of Aging on memory performance, measured by the California Verbal Learning Test, and lateral ventricle size, measured by structural MRIs. Results indicate that recent increases in the lateral ventricle size were a leading indicator of subsequent declines in memory performance from age 60 to 90. PMID- 23637520 TI - Correlation between baseline echographic features of endophthalmitis, microbiological isolates, and visual outcomes. AB - BACKGROUND: The purpose of this study was to examine the baseline echographic features in culture-positive and culture-negative endophthalmitis and to correlate these echographic features with final visual outcomes. METHODS: We identified a retrospective noncomparative case series of patients with a clinical diagnosis of endophthalmitis and a baseline echographic examination between 1996 and 2010 at a single institution. Graded echographic features studied included: dense, moderate, and mild vitreous opacities; marked, moderate, and mild vitreous membranes; retinal detachment; and choroidal detachment. These were compared between culture-negative, coagulase-negative staphylococci, and other culture positive cases of endophthalmitis, and were correlated with final visual outcomes. RESULTS: Of 149 patients reviewed, 60 were culture-negative, 26 grew coagulase-negative staphylococci, and 60 grew other culture-positive species. Three had multiple culture isolates. The presence of dense, moderate, and mild vitreous opacities, marked, moderate, and mild vitreous membranes, retinal detachment, and choroidal detachment was not significantly different between the three groups (P = 0.86, P = 0.56, P = 0.34, P = 0.45, respectively). The presence of advanced echographic features of dense vitreous opacities, marked vitreous membranes, retinal detachment, and choroidal detachment was correlated with poorer visual acuity outcomes (P = 0.005, P = 0.0001, P < 0.0001, and P < 0.0001, respectively). CONCLUSION: No correlation could be made between echographic features and the organism. The presence of advanced echographic features, such as dense vitreous opacities, marked vitreous membranes, retinal detachment, and choroidal detachment, was correlated with worse visual outcomes. PMID- 23637523 TI - Comparison of long-term clinical outcome between patients with chronic versus acute type B aortic dissection treated by implantation of a stent graft: a single center report. AB - BACKGROUND: Stent grafting for treatment of type B aortic dissection has been extensively used. However, the difference in the long-term clinical outcome between patients with chronic versus acute type B aortic dissection remains unknown. This study aimed to analyze the difference in long-term clinical outcome after endovascular repair for patients with chronic (>=2 weeks) versus acute (<2 weeks) type B aortic dissection. METHODS: Between May 2000 and June 2011, a total of 174 patients with type B aortic dissection (56 chronic, 118 acute) treated by endovascular repair were studied prospectively. Follow-up three-dimensional computed tomography scanning and aortoangiography were scheduled at 3-6 months after the index procedure. Propensity score matching was used to compare the difference in the endpoint between the two groups. RESULTS: The procedure-related event rate was 18.6% in the acute group and 5.4% in the chronic group (P = 0.021), but this difference became nonsignificant after propensity score matching. At the end of follow-up (mean 2.49 years), overall and aorta-related mortality was 11.0% and 7.6%, respectively, in the acute group, and was not significantly different from that in the chronic group (3.6% and 3.6%, P = 0.148 and P = 0.506, respectively). Both false and true lumina showed significant remodeling over time, with >93% complete false-lumen thrombosis. Untreated tear and type I endoleak were predictors of clinical events during follow-up. CONCLUSION: Comparable long-term clinical results were achieved in patients with chronic or acute type B aortic dissection after implantation of a stent graft. PMID- 23637522 TI - Pharmacology and clinical potential of guanylyl cyclase C agonists in the treatment of ulcerative colitis. AB - Agonists of the transmembrane intestinal receptor guanylyl cyclase C (GCC) have recently attracted interest as promising human therapeutics. Peptide ligands that can specifically induce GCC signaling in the intestine include endogenous hormones guanylin and uroguanylin, diarrheagenic bacterial enterotoxins (ST), and synthetic drugs linaclotide, plecanatide, and SP-333. These agonists bind to GCC at intestinal epithelial surfaces and activate the receptor's intracellular catalytic domain, an event initiating discrete biological responses upon conversion of guanosine-5'-triphosphate to cyclic guanosine monophosphate. A principal action of GCC agonists in the colon is the promotion of mucosal homeostasis and its dependent barrier function. Herein, GCC agonists are being developed as new medications to treat inflammatory bowel diseases, pathological conditions characterized by mucosal barrier hyperpermeability, abnormal immune reactions, and chronic local inflammation. This review will present important concepts underlying the pharmacology and therapeutic utility of GCC agonists for patients with ulcerative colitis, one of the most prevalent inflammatory bowel disease disorders. PMID- 23637524 TI - Can progressive resistance training twice a week improve mobility, muscle strength, and quality of life in very elderly nursing-home residents with impaired mobility? A pilot study. AB - PURPOSE: To determine the effects of progressive resistance training on mobility, muscle strength, and quality of life in nursing-home residents with impaired mobility. METHODS: Nursing-home residents aged 77 years and older with impaired mobility were recruited in Berlin, Germany. The eight-week exercise program consisted of progressive resistance training twice a week. Mobility (primary outcome) was assessed with the Elderly Mobility Scale (zero = worst, 20 = best) at baseline and after 8 weeks. Muscle strength (secondary outcome) was determined by the eight-repetition maximum. The Short Form-36 Health Survey was used to assess quality of life. RESULTS: Of the 15 participants (mean age 84 years, range 77-97 years), ten completed the 8-week program. Mobility (Elderly Mobility Scale mean +/- standard deviation pre 14.1 +/- 3.2 and post 17.5 +/- 3.6; P = 0.005) as well as muscle strength of upper and lower limbs improved (from 62% at chest press up to 108% at leg extension machine), whereas most quality of life subscales did not show considerable change. CONCLUSION: Resistance training twice a week over 2 months seemed to considerably improve mobility and muscle strength in persons aged 77-97 years with impaired mobility. PMID- 23637525 TI - Six-month leuprorelin acetate depot formulations in advanced prostate cancer: a clinical evaluation. AB - For nearly three decades, gonadotropin-releasing hormone (GnRH) agonists, particularly leuprorelin acetate (LA), have served as an important part of the treatment armamentarium for prostate cancer. The introduction of LA depot formulations provided a significant improvement in the acceptance of this therapy; however, their indicated treatment duration of 1 to 4 months was still not long enough to satisfy all medical needs. For this reason some manufacturers developed new injectable formulations that provide testosterone suppression for 6 months. This review article assesses key publications in order to compare these long-acting, commercially available, LA depot formulations and their clinical performance. The literature search identified 14 publications; by excluding reviews, duplications, and non-English articles, only three original papers describing clinical trial remained for review: two focused on microsphere-based LA formulations with either a 30 mg or 45 mg dose and one focused on a gel-based leuprorelin acetate with a 45 mg dose. All products were tested in individual clinical trials and have demonstrated their efficacy and safety. PMID- 23637527 TI - Diagnosis of COPD and clinical course in patients with unrecognized airflow limitation. AB - Chronic obstructive pulmonary disease (COPD) is frequently under-recognized and underdiagnosed. To determine the natural history of recognized and unrecognized COPD, we studied the rate of diagnosis, health care utilization, and mortality in patients with airflow limitation (AFL). Three hundred forty-seven outpatients at the Cincinnati Veterans Administration Medical Center performed spirometry and completed a respiratory questionnaire. Patients were followed for a minimum of 30 months and medical records were reviewed for COPD diagnosis, mortality, respiratory-related health care utilization, comorbidities, and respiratory medications. Three hundred twenty-five of 347 (94%) patients performed technically adequate spirometry and completed questionnaires. When AFL was defined by fixed ratio (FR, forced expiratory volume in 1 second [FEV(1)]/forced vital capacity [FVC] < 0.7), patients with AFL and a diagnosis of COPD had a higher annual mortality rate (7.1% +/- 2% versus 2.4% +/- 0.8%, P = 0.01), more hospitalizations per year (0.2 +/- 0.06 versus 0.04 +/- 0.01, P < 0.001 mean +/- standard error of the mean), increased respiratory symptoms (12.0 +/- 0.9 versus 7.2 +/- 0.6, P < 0.0001), and higher Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage compared with undiagnosed patients. Ninety-two of 137 patients with AFL (67%) had unrecognized AFL; 16 (17%) of the 92 were subsequently diagnosed. When AFL was defined by the lower limit of normal (LLN, FEV(1)/FVC < LLN), 67 of 103 patients (65%) had unrecognized AFL; 12 (18%) of the 67 were subsequently diagnosed. Patients with AFL defined by FR who were subsequently diagnosed had more emergency department visits per year (0.33 +/- 0.11 versus 0.11 +/- 0.05, P = 0.009), increased respiratory symptoms (10.2 +/- 1.6 versus 6.5 +/- 0.7, P < 0.05), and higher GOLD stage, but similar mortality and hospitalizations compared with the persistently undiagnosed patients. The annual rate of documented COPD diagnosis was 7% for both FR and LLN definitions. Patients with AFL and a diagnosis of COPD have more severe disease, higher health care utilization, and mortality than undiagnosed patients. The annual rate of COPD diagnosis is 7% among individuals with unrecognized AFL. Worse AFL, increased respiratory symptoms, and ED visits are associated with a subsequent COPD diagnosis in individuals with unrecognized AFL. PMID- 23637528 TI - Photodynamic therapy of a 2-methoxyestradiol tumor-targeting drug delivery system mediated by Asn-Gly-Arg in breast cancer. AB - Fullerene (C60) has shown great potential in drug delivery. In this study we exploited modified fullerene (diadduct malonic acid-fullerene-Asn-Gly-Arg peptide [DMA-C60-NGR]) as an antitumor drug carrier in order to build a new tumor targeting drug delivery system. We also investigated the synergistic enhancement of cancer therapy using photodynamic therapy (PDT) induced by DMA-C60-NGR and 2 methoxyestradiol (2ME). Cytotoxicity tests indicated that DMA-C60-NGR had no obvious toxicity, while our drug delivery system (DMA-C60-2ME-NGR) had a high inhibition effect on MCF-7 cells compared to free 2ME. The tumor-targeting drug delivery system could efficiently cross cell membranes, and illumination induced the generation of intracellular reactive oxygen species and DNA damage. Furthermore, DMA-C60-2ME-NGR with irradiation had the highest inhibition effect on MCF-7 cells compared to the other groups. DMA-C60-NGR combined with 2ME showed a good synergistic photosensitization effect for inhibiting the growth of MCF-7 cells, demonstrating that DMA-C60-2ME-NGR may be promising for high treatment efficacy with minimal side effects in future therapy. PMID- 23637529 TI - Complexes containing cationic and anionic pH-sensitive liposomes: comparative study of factors influencing plasmid DNA gene delivery to tumors. AB - pH-sensitive liposomes represent an effective gene vector in cancer therapy. However, their use is greatly hampered by their relatively low transfection efficiency. To improve the transfection efficiency of pH-sensitive liposomes, we prepared complexes containing 3beta-[N-(N',N'-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol) and dioleoylphosphatidyl ethanolamine (DOPE) liposomes and pH-sensitive liposomes composed of cholesteryl hemisuccinate (CHEMS) and DOPE, and evaluated the influence of various factors on plasmid DNA (pDNA) transfection efficiency. All DC-Chol/DOPE liposome/pDNA and pH-sensitive liposome complexes showed similarly potent pH sensitivity. In the presence of serum-containing medium, two optimized complexes of DC-Chol/DOPE liposomes/pDNA and pH-sensitive PEGylated liposomes showed high transfection efficiency of 22.94% and 20.07%, respectively. Notably, DC-Chol/DOPE (2:3) liposomes/pH-sensitive PEGylated (1%) liposome complexes with a charge ratio of 1:1 (m/m [+/-]) showed enhanced accumulation in tumors in vivo. Our results show the influence of various factors on pDNA transfection efficiency in complexes of DC-Chol/DOPE liposomes and pH sensitive PEGylated liposomes. Understanding of such mechanisms will lead to better design of complexes of DC-Chol/DOPE liposomes and pH-sensitive liposomes for gene therapy. PMID- 23637530 TI - Effects of nanoencapsulation and PEGylation on biodistribution of indocyanine green in healthy mice: quantitative fluorescence imaging and analysis of organs. AB - Near-infrared nanoconstructs present a potentially effective platform for site specific and deep tissue optical imaging and phototherapy. We have engineered a polymeric nanocapsule composed of polyallylamine hydrochloride (PAH) chains cross linked with sodium phosphate and doped with indocyanine green (ICG) toward such endeavors. The ICG-doped nanocapsules were coated covalently with polyethylene glycol (5000 daltons) through reductive amination. We administrated the constructs by tail vein injection to healthy mice. To characterize the biodistribution of the constructs, we performed in vivo quantitative fluorescence imaging and subsequently analyzed the various extracted organs. Our results suggest that encapsulation of ICG in these PEGylated constructs is an effective approach to prolong the circulation time of ICG and delay its hepatic accumulation. Increased bioavailability of ICG, due to encapsulation, offers the potential of extending the clinical applications of ICG, which are currently limited due to rapid elimination of ICG from the vasculature. Our results also indicate that PAH and ICG-doped nanocapsules (ICG-NCs) are not cytotoxic at the levels used in this study. PMID- 23637531 TI - Potential and problems in ultrasound-responsive drug delivery systems. AB - Ultrasound is an important local stimulus for triggering drug release at the target tissue. Ultrasound-responsive drug delivery systems (URDDS) have become an important research focus in targeted therapy. URDDS include many different formulations, such as microbubbles, nanobubbles, nanodroplets, liposomes, emulsions, and micelles. Drugs that can be loaded into URDDS include small molecules, biomacromolecules, and inorganic substances. Fields of clinical application include anticancer therapy, treatment of ischemic myocardium, induction of an immune response, cartilage tissue engineering, transdermal drug delivery, treatment of Huntington's disease, thrombolysis, and disruption of the blood-brain barrier. This review focuses on recent advances in URDDS, and discusses their formulations, clinical application, and problems, as well as a perspective on their potential use in the future. PMID- 23637532 TI - Physiologic load-bearing characteristics of autografts, allografts, and polymer based scaffolds in a critical sized segmental defect of long bone: an experimental study. AB - BACKGROUND: To address the challenge of treating critical sized intercalary defects, we hypothesized that under physiologic cyclic loading, autografts, allografts, and scaffolds loaded with and without human mesenchymal stem cells (hMSCs) would have different biomechanical characteristics. METHODS: Using a rat femoral defect model, 46 rats were assigned to four groups, ie, autograft (n = 12), allograft (n = 10), scaffold (n = 13), and scaffold with hMSCs (n = 11). The scaffold groups used a 5 mm segment of scaffold composed of 80% poly-epsilon caprolactone and 20% hydroxyapatite. Rats were sacrificed 4 months postoperatively, and the repairs were assessed radiographically and biomechanically. RESULTS: Autograft and allograft groups exhibited the most bridging callus, while the scaffold/hMSCs group had more callus than the scaffold repairs. Although signs of radiographic healing did not accurately reflect restoration of mechanical properties, addition of hMSCs on the scaffold enhanced bone formation. The scaffold alone group had significantly lower elastic and viscous stiffness and higher phase angles than other repairs and the contralateral controls. Addition of hMSCs increased the elastic and viscous stiffness of the repair, while decreasing the phase angle. CONCLUSION: Further comparative analysis is needed to optimize clinical use of scaffolds and hMSCs for critical sized defect repairs. However, our results suggest that addition of hMSCs to scaffolds enhances mechanical simulation of native host bone. PMID- 23637533 TI - Bismuth oxide aqueous colloidal nanoparticles inhibit Candida albicans growth and biofilm formation. AB - Multiresistance among microorganisms to common antimicrobials has become one of the most significant concerns in modern medicine. Nanomaterials are a new alternative to successfully treat the multiresistant microorganisms. Nanostructured materials are used in many fields, including biological sciences and medicine. Recently, it was demonstrated that the bactericidal activity of zero-valent bismuth colloidal nanoparticles inhibited the growth of Streptococcus mutans; however the antimycotic potential of bismuth nanostructured derivatives has not yet been studied. The main objective of this investigation was to analyze the fungicidal activity of bismuth oxide nanoparticles against Candida albicans, and their antibiofilm capabilities. Our results showed that aqueous colloidal bismuth oxide nanoparticles displayed antimicrobial activity against C. albicans growth (reducing colony size by 85%) and a complete inhibition of biofilm formation. These results are better than those obtained with chlorhexidine, nystatin, and terbinafine, the most effective oral antiseptic and commercial antifungal agents. In this work, we also compared the antimycotic activities of bulk bismuth oxide and bismuth nitrate, the precursor metallic salt. These results suggest that bismuth oxide colloidal nanoparticles could be a very interesting candidate as a fungicidal agent to be incorporated into an oral antiseptic. Additionally, we determined the minimum inhibitory concentration for the synthesized aqueous colloidal Bi2O3 nanoparticles. PMID- 23637534 TI - Blended E-health module on return to work embedded in collaborative occupational health care for common mental disorders: design of a cluster randomized controlled trial. AB - BACKGROUND: Common mental disorders (CMD) have a major impact on both society and individual workers, so return to work (RTW) is an important issue. In The Netherlands, the occupational physician plays a central role in the guidance of sick-listed workers with respect to RTW. Evidence-based guidelines are available, but seem not to be effective in improving RTW in people with CMD. An intervention supporting the occupational physician in guidance of sick-listed workers combined with specific guidance regarding RTW is needed. A blended E-health module embedded in collaborative occupational health care is now available, and comprises a decision aid supporting the occupational physician and an E-health module, Return@Work, to support sick-listed workers in the RTW process. The cost effectiveness of this intervention will be evaluated in this study and compared with that of care as usual. METHODS: This study is a two-armed cluster randomized controlled trial, with randomization done at the level of occupational physicians. Two hundred workers with CMD on sickness absence for 4-26 weeks will be included in the study. Workers whose occupational physician is allocated to the intervention group will receive the collaborative occupational health care intervention. Occupational physicians allocated to the care as usual group will give conventional sickness guidance. Follow-up assessments will be done at 3, 6, 9, and 12 months after baseline. The primary outcome is duration until RTW. The secondary outcome is severity of symptoms of CMD. An economic evaluation will be performed as part of this trial. CONCLUSION: It is hypothesized that collaborative occupational health care intervention will be more (cost)-effective than care as usual. This intervention is innovative in its combination of a decision aid by email sent to the occupational physician and an E-health module aimed at RTW for the sick-listed worker. PMID- 23637535 TI - Role of oral teriflunomide in the management of multiple sclerosis. AB - The landscape of the treatment of relapsing-remitting multiple sclerosis is changing fast. Several oral treatments have shown benefit and generate much interest because of the convenience of their administration. Two oral compounds, fingolimod and teriflunomide, have been approved in relapsing-remitting multiple sclerosis, while others have completed Phase III trials and are awaiting review for registration. Teriflunomide is a pyrimidine synthesis inhibitor with selective immunomodulatory and immunosuppressive properties that have shown consistent efficacy in clinical trials, and a good safety profile. This paper provides an overview of the mechanisms of action and efficacy and safety results from clinical trials with this drug. The role of teriflunomide in the treatment of relapsing-remitting multiple sclerosis is discussed. PMID- 23637536 TI - New developments in the management of overactive bladder: focus on mirabegron and onabotulinumtoxinA. AB - In the last few years, much new information has been generated on the pathophysiology, possible therapeutic targets, and pharmacologic treatment of overactive bladder (OAB). Antimuscarinic drugs are still first-line pharmacologic treatment for OAB and often have good initial response rates, but adverse effects and decreasing efficacy cause long-term compliance problems, prompting a search for new therapeutic alternatives. Mirabegron and onabotulinumtoxinA, two drugs with different mechanisms of action, and with adverse effect profiles different from those of antimuscarinics, were recently approved for treatment of OAB. However, their place in the treatment of this disorder has not yet been established. In this short review, the mechanisms of action, clinical efficacy, and safety profiles of these drugs are discussed and compared with those of the current gold standard, antimuscarinic agents. PMID- 23637537 TI - Vitamin D reduces falls and hip fractures in vascular Parkinsonism but not in Parkinson's disease. AB - PURPOSE: Vitamin D supplementation is suggested to reduce the risk of falls in older institutionalized or ambulatory individuals by 20%. The present study was undertaken to address the reduced risk, by vitamin D supplementation, of falls and hip fractures in patients with vascular Parkinsonism (VP) and Parkinson's disease (PD). PATIENTS AND METHODS: In the open-label-study, 94 elderly patients with VP and 92 age-matched patients with PD were followed for 2 years. All patients received 1200 IU ergocalciferol daily. The number of falls per person and incidence of hip fractures were compared between the two groups. RESULTS: At baseline, serum 25-hydroxyvitamin D (25-OHD) levels were in the deficient range (<25 nmol/L) in all patients, and vitamin D treatment enhanced serum 25-OHD and 1,25-dihydroxyvitamin D levels in both groups. Improved muscle strength of lower extremities was observed in both groups. There was significant difference between the two groups in the number of falls per subject during the 2 years (1.9 +/- 0.5 in the PD group and 0.8 +/- 0.4 in the VP group, P < 0.001). Hip fractures occurred in seven of 88 in the PD group and one in 90 of the VP group during the 2-year study period (P = 0.035). CONCLUSION: It is suggested that vitamin D decreases falls and hip fractures in VP by increasing muscle strength but not in PD. PMID- 23637540 TI - Interprofessional practice in primary care: development of a tailored process model. AB - PURPOSE: This study investigated the improvement of interprofessional practice in primary care by performing the first three steps of the implementation model described by Grol et al. This article describes the targets for improvement in a setting for children with complex care needs (step 1), the identification of barriers and facilitators influencing interprofessional practice (step 2), and the development of a tailored interprofessional process model (step 3). METHODS: In step 2, thirteen qualitative semistructured interviews were held with several stakeholders, including parents of children, an occupational therapist, a speech and language therapist, a physical therapist, the manager of the team, two general practitioners, a psychologist, and a primary school teacher. The data were analyzed using directed content analysis and using the domains of the Chronic Care Model as a framework. In step 3, a project group was formed to develop helpful strategies, including the development of an interprofessional process through process mapping. RESULTS: In step 2, it was found that the most important barriers to implementing interprofessional practice related to the lack of structure in the care process. A process model for interprofessional primary care was developed for the target group. CONCLUSION: The lack of a shared view of what is involved in the process of interprofessional practice was the most important barrier to its successful implementation. It is suggested that the tailored process developed, supported with the appropriate tools, may provide both professional staff and their clients, in this setting but also in other areas of primary care, with insight to the care process and a clear representation of "who should do what, when, and how." PMID- 23637539 TI - Safety and efficacy of vernakalant for acute cardioversion of atrial fibrillation: an update. AB - Intravenous vernakalant has recently been approved in Europe as an atrial selective antiarrhythmic drug for the conversion of recent-onset atrial fibrillation (AF). It inhibits atrial-selective K(+) currents (I(K,ACh) and I(Kur)) and causes rate-dependent atrial-predominant Na(+) channel block, with only a small inhibitory effect on the rapid delayed rectifier K(+) current (I(Kr)) in the ventricle. Due to its atrial-selective properties, vernakalant prolongs the effective refractory period of the atria with minimal effects on the ventricles, being associated with a low proarrhythmic risk for torsades de pointes arrhythmias. Five pivotal clinical trials consistently demonstrated that vernakalant rapidly terminates AF with stable maintenance of sinus rhythm for up to 24 hours. A head-to-head comparative trial showed that the 90-minute conversion rate of vernakalant was substantially higher than that of amiodarone. Initially, a longer-acting oral formulation of vernakalant was shown to be effective and safe in preventing AF recurrence after cardioversion in a Phase IIb study. However, the clinical studies testing oral vernakalant for maintenance of sinus rhythm after AF cardioversion were prematurely halted for undisclosed reasons. This review article provides an update on the safety and efficacy of intravenous vernakalant for the rapid cardioversion of AF. PMID- 23637541 TI - Faculty intent to engage in interprofessional education. AB - BACKGROUND: This descriptive correlational and comparative study explored health care faculty (HCF) attitudes toward interprofessional education (IPE) and interprofessional health-care teams, HCF perceptions of subjective norms, the influence of subjective norms on HCF intent to engage in IPE, and HCF intent to engage in IPE. In addition, differences among seven disciplines of HCF were explored. METHODS: Nursing, medicine, pharmacy, physical therapy, occupational therapy, physician assistants, and social work faculty were identified. Stratified random sampling was used to ensure that the population surveyed was representative of the target population. The total sample for this study included 439 HCF from the seven identified health-care professions in the US. Data collection included measures of attitudes toward IPE and attitudes toward interprofessional health-care teams. Subjective norms were measured using two 7 point rating scales. Intent to engage in IPE was measured using a 10-point rating scale. RESULTS: There were no significant differences among HCF groups regarding attitudes toward IPE or interprofessional health-care teams. Administrative faculty reported greater intent to engage in IPE than teaching faculty. HCF who were currently in or had previously engaged in IPE reported greater intent to engage in or continue to engage, and had higher attitude and subjective norm scores than faculty without IPE experience. The combination of perceived pressure from school administrators and attitudes toward IPE was the best predictor of intent to engage in IPE. CONCLUSION: IPE has the potential to influence patient quality of care and lead to better working relationships between health-care providers. HCF are more likely to engage in IPE when they believe their school's administrators think they should engage in IPE and when they have positive attitudes toward IPE. PMID- 23637538 TI - Avoiding hypoglycemia: a key to success for glucose-lowering therapy in type 2 diabetes. AB - Type 2 diabetes carries a risk for hypoglycemia, particularly in patients on an intensive glucose control plan as a glucose-lowering strategy, where hypoglycemia may be a limitation for the therapy and also a factor underlying clinical inertia. Glucose-lowering medications that increase circulating insulin in a glucose-independent manner, such as insulin and sulfonylurea therapy, are the most common cause of hypoglycemia. However, other factors such as a delayed or missed meal, physical exercise, or drug or alcohol consumption may also contribute. Specific risk factors for development of hypoglycemia are old age, long duration of diabetes, some concomitant medication, renal dysfunction, hypoglycemia unawareness, and cognitive dysfunction. Hypoglycemia is associated with acute short-term symptoms related to either counterregulation, such as tachycardia and sweating, or to neuroglycopenia, such as irritability, confusion, and in severe cases stupor, coma, and even death. However, there are also long term consequences of hypoglycemia such as reduced working capacity, weight gain, loss of self-confidence with reduced quality of life, and increased risk for cardiovascular diseases. For both the patients, the health care system, and the society at large, hypoglycemia carries a high cost. Strategies to mitigate the risk of hypoglycemia include awareness of the condition; education of patients, relatives, and health care providers; and selecting appropriate glucose-lowering medication that also judges the risk for hypoglycemia to prevent this complication. This article summarizes the current knowledge of hypoglycemia and its consequences with a special emphasis on its consequences for the choice of glucose-lowering therapy. PMID- 23637542 TI - Immunomodulatory effects of the botanical compound LCS101: implications for cancer treatment. AB - OBJECTIVE: To examine the effects of LSC101, a botanical compound, on adaptive and innate immunity. MATERIALS AND METHODS: LCS101 preparations were tested for batch-to-batch consistency using high-performance liquid chromatography. T-cell activation was quantified in murine spleen cells using 3H-thymidine incorporation, and cytokine production analyzed with enzyme-linked immunosorbent assay. Natural killer cell activity was tested on human blood cells using flow cytometry, and cytotoxicity measured by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and apoptosis using a FACSCalibur. Effects on interferon-gamma production in fluorouracil/doxorubicin-treated mice were tested with enzyme-linked immunosorbent assay. RESULTS: High-performance liquid chromatography analysis demonstrated batch-to-batch consistency. T-cell proliferation was increased, and a dose-dependent activation of natural killer cells and macrophage tumor necrosis factor-alpha secretion were observed with LCS101 treatment. Interferon-gamma levels, reduced following fluorouracil treatment, were corrected in treated animals. No toxicity or compromised treatment outcomes were associated with LCS101 exposure. CONCLUSIONS: LCS101 demonstrated significant effects on a number of immune processes. Further research is needed in order to understand the molecular immunomodulatory pathways affected by this compound, as well as clinical implications for treatment. PMID- 23637543 TI - Candidate cancer-targeting agents identified by expression-profiling arrays. AB - BACKGROUND: One particularly promising component of personalized medicine in cancer treatment is targeted therapy, which aims to maximize therapeutic efficacy while minimizing toxicity. However, the number of approved targeted agents remains limited. Expression microarray data for different types of cancer are resources to identify genes that were upregulated. The genes are candidate targets for cancer-targeting agents for future anticancer research and targeted treatments. METHODS AND FINDINGS: The gene expression profiles of 48 types of cancer from 2,141 microarrays reported in the Gene Expression Omnibus were analyzed. These data were organized into 78 experimental groups, on which we performed comprehensive analyses using two-tailed Student's t-tests with significance set at P < 0.01 to identify genes that were upregulated compared with normal cells in each cancer type. The resulting list of significantly upregulated genes was cross-referenced with three categories of protein inhibitor targets, categorized by inhibitor type ('Targets of US Food and Drug Administration (FDA)-approved anticancer drugs', 'Targets of FDA-approved nonantineoplastic drugs', or 'Targets of non-FDA-approved chemical agents'). Of the 78 experimental groups studied, 57 (73%) represent cancers that are currently treated with FDA-approved targeted treatment agents. However, the target genes for the indicated therapies are upregulated in only 33 of these groups (57%). Nevertheless, the mRNA expression of the genes targeted by FDA-approved treatment agents is increased in every experimental group, including all of the cancers without FDA-approved targeted treatments. Moreover, many targets of protein inhibitors that have been approved by the FDA as therapies for nonneoplastic diseases, such as 3-hydroxy-3-methylglutaryl-CoA reductase and cyclooxygenase-2 and the targets of many non-FDA-approved chemical agents, such as cyclin dependent kinase 1 and DNA-dependent protein kinase, are also overexpressed in many types of cancer. CONCLUSION: This research demonstrates a clinical correlation between bioinformatics data and currently approved treatments and suggests novel uses for known protein inhibitors in future antineoplastic research and targeted therapies. PMID- 23637544 TI - Comparison of health care resource utilization and costs among patients with GERD on once-daily or twice-daily proton pump inhibitor therapy. AB - BACKGROUND: The purpose of this study was to assess differences in health care resource utilization and costs associated with once-daily and twice-daily proton pump inhibitor (PPI) therapy. Most patients with gastroesophageal reflux disease (GERD) achieve symptom control on once-daily PPI therapy, but approximately 20% 30% require twice-daily dosing. METHODS: Patients were >=18 years of age with at least one medical claim for GERD and at least two PPI claims from HealthCore's Integrated Research Database (HIRD(SM)) during 2004-2009. Patients were continuously eligible for 12 months before and after the index date (date of first PPI claim). Based on PPI dosing throughout the post-index period (quantity of medication dispensed/number of days supply), patients were classified as once daily (dose <= 1.5 pills per day) or twice-daily (>=1.5) PPI users. RESULTS: The study cohort included 248,386 patients with GERD (mean age 52.8 +/- 13.93 years, 56% females) of whom 90% were once-daily and 10% were twice-daily PPI users. The Deyo-Charlson Comorbidity Index for once-daily and twice-daily PPI users was 0.70 +/- 1.37 and 0.89 +/- 1.54, respectively (P < 0.05). More once-daily patients had claims for Barrett's esophagus (5% versus 2%, P < 0.0001) than twice-daily patients. Post-index, higher proportions of twice-daily patients had at least one GERD-related inpatient visit (7% versus 5%), outpatient visit (60% versus 49%), and office visit (48% versus 38%) versus once-daily patients (P < 0.0001). Mean total GERD-related health care costs were $2065 +/- $6636 versus $3749 +/- $11,081 for once-daily and twice-daily PPI users, respectively (P < 0.0001). CONCLUSION: Patients receiving twice-daily PPI therapy were likely to have more comorbid conditions and greater health care utilization and overall costs compared with patients using once-daily PPI therapy. PMID- 23637545 TI - Health-resource use and costs associated with fibromyalgia in France, Germany, and the United States. AB - BACKGROUND: Fibromyalgia (FM) is a chronic disorder characterized by widespread, persistent pain. Prospective and retrospective studies have demonstrated substantial health-care costs associated with FM in a number of countries. This study evaluated and compared health-resource use (HRU) and associated costs related to FM in routine clinical practice across the US, France, and Germany. METHODS: Two separate, cross-sectional, observational studies of subjects with FM were conducted: one in the US and one in France and Germany. HRU related to prescription medication, physician office visits, diagnostic tests, and hospitalizations was abstracted from chart review; patient out-of-pocket costs and lost productivity were collected via subject self-report. Costs were assigned to HRU based on standard algorithms. Direct and indirect costs were evaluated and compared by simple linear regression. RESULTS: A total of 442 subjects (203 US, 70 France, 169 Germany) with FM were analyzed. The mean (standard deviation) age in the US, France, and Germany was 47.9 (10.9), 51.2 (9.5), and 49.2 (9.8), respectively (P = 0.085). Most subjects were female (95% US, 83% France, 80% Germany) (P < 0.001). Adjusted annual direct costs per subject for FM were significantly higher in the US ($7087) than in France ($481, P < 0.001) or Germany ($2417, P < 0.001). Adjusted mean annual indirect costs per subject for FM were lower in the US ($6431) than in France ($8718) or Germany ($10,001), but represented a significant proportion of total costs in all countries. CONCLUSION: The significant HRU and costs associated with FM in the US, France, and Germany documented in this study highlight the substantial global economic burden of FM. Indirect costs represented a significant proportion of the total costs, particularly in Europe. Comparisons between the three countries show differences in HRU, with significantly higher direct costs in the US compared with France and Germany. PMID- 23637547 TI - A possible role of IL-1RN gene polymorphism in the outcome of gastrointestinal diseases associated with H. pylori infection. AB - OBJECTIVE: To verify whether the variable number of tandem repeat (VNTR) polymorphism in the IL-1RN gene that encodes the interleukin (IL)-1 receptor antagonist (IL-1Ra) plays a role in the outcome of gastrointestinal diseases associated with Helicobacter pylori (H. pylori) infection. METHODS: Patients with normal endoscopy (n = 71), inflammation of the upper gastrointestinal tract only (n = 196), gastric ulcer (n = 28), duodenal ulcer (n = 76), and gastric cancer (n = 19) were studied. H. pylori infection was diagnosed by the urease test, histological examination, and polymerase chain reaction. The IL-1 receptor antagonist gene (IL-1RN intron 2 VNTR) was analyzed by polymerase chain reaction. Gastritis was scored according to the updated Sydney system of classification. RESULTS: H. pylori infection was an independent risk factor for mild (odds ratio [OR] = 5.53 [95% confidence interval [CI] = 2.63-11.64; P < 0.05]), moderate (OR = 83.93 [95% CI = 29.7-237.18; P < 0.05]) and marked (OR = 47.47 [95% CI = 5.39 418.05; P < 0.05]) gastritis. The carriage of IL-1RN*2/*2 had a significant protective effect of H. pylori infection (OR = 0.31 [95% CI = 0.17-0.57; P < 0.05]). H. pylori infection was identified as an independent risk of inflammation, duodenal ulcer, and gastric ulcer. The carriage of IL-1RN*2/*2 was an independent risk factor for gastric cancer (OR = 5.81 [95% CI = 1.06-31.98; P < 0.05]); nonetheless, the carriage of allele 2 (IL-1RN*2/*2 plus IL-1RN*L/*2) had an independent protective effect on duodenal ulcer (OR = 0.45 [95% CI = 0.22 0.91; P < 0.05]). CONCLUSIONS: Allele 2 of the VNTR IL-1RN polymorphism had a protective effect against duodenal ulcer and H. pylori infection; however, it increased the risk of gastric cancer. PMID- 23637548 TI - Intermittent saline flushes or continuous saline infusion: what works better when heparin-free dialysis is recommended? AB - INTRODUCTION: Coagulation-free dialysis, also commonly known as "heparin-free" dialysis, can be a challenging procedure as it increases the risk of clotting the dialysis circuit. Utilizing a better saline flushing technique can lead to improved patient outcomes as well as huge financial benefits to the health institution. The purpose of this study was to compare the effectiveness of continuous saline infusion (CSI) and intermittent saline flushing (ISF) in preventing clotting of the dialysis extracorporeal circuit (ECC). METHODS: Fifty heparin-free treatments were randomized into two treatment arms, namely CSI and ISF. Predialysis full blood count and coagulation studies were performed for all patients. During ISF, 100 mL saline was infused via the arterial line every 30 minutes while occluding the blood inlet line. Normal saline was infused into the ECC at a rate of 200 mL/hour throughout the duration of dialysis under CSI. The ECC was inspected for clotting and graded accordingly post-dialysis. RESULTS: Seventy-six percent of the CSI treatments were completed without losing the ECC while 52% of the ISF treatments were also successful. Patients who were treated with CSI were less likely to have clotted ECCs (odds ratio 3.4, 95% CI, 1.04 to 11.2; P = 0.04). No significant differences existed between the two groups' hematological factors that could influence clotting, such as hemoglobin and platelets. CONCLUSION: This study demonstrates that, when heparin-free dialysis is indicated, CSI might be a better method of preventing the ECC from clotting. There is a greater chance of realizing long-term benefits to patients and the health service with the CSI method since there is a likelihood of a reduction in the use of erythropoietin-stimulating agents and blood transfusions with the CSI method. PMID- 23637546 TI - Management of keloids and hypertrophic scars: current and emerging options. AB - In the context of growing aesthetic awareness, a rising number of patients feel disappointed with their scars and are frequently seeking help for functional and aesthetic improvement. However, excessive scarring following surgery or trauma remains difficult to improve despite a plethora of advocated treatment strategies as frequently observed in daily clinical routine. It is thus still preferable to prevent scarring by minimizing risk factors as much as possible. Hence, it remains crucial for the physician to be aware of basic knowledge of healing mechanisms and skin anatomy, as well as an appreciation of suture material and wound closure techniques to minimize the risk of postoperative scarring. Next to existing, well known prophylactic and therapeutic strategies for the improvement of excessive scarring, this article discusses emerging techniques such as intralesional cryotherapy, intralesional 5-fluorouracil, interferon, and bleomycin. Some of them have been successfully tested in well-designed trials and already have extended or may extend the current spectrum of excessive scar treatment in the near future. Innovative options such as imiquimod 5% cream, photodynamic therapy, or botulinum toxin A may also be of certain importance; however, the data currently available is too contradictory for definite recommendations. PMID- 23637550 TI - Reduced performance difference between sexes in master mountain and city marathon running. AB - BACKGROUND: The performance in master marathoners has been investigated in flat city marathons but not in mountain marathons. This study examined changes in the sex differences in performance across time in female and male master runners competing in a mountain marathon compared to a flat city marathon. METHODS: The association between age and performance of finishers in the Jungfrau Marathon, Switzerland, with 1830 meter changes in altitude and a flat city marathon (Lausanne Marathon), Switzerland, were analyzed from 2000 to 2011. RESULTS: In both events, athletes in the 35-44 years age group showed the highest number of finishers. In the mountain marathon, the number of female master runners aged > 35 years increased in contrast to female finishers aged < 35 years, while the number of male finishers was unchanged in all age groups. In the city marathon, the number of female finishers was unchanged while the number of male finishers in the age groups for 25-34-year-olds and 35-44-year-olds decreased. In female marathoners, performance improved in athletes aged 35-44 and 55-64 years in the city marathon. Male marathoners improved race time in age group 45-54 years in both the city marathon and the mountain marathon. Female master runners reduced the sex difference in performance in the 45-54-year age group in both competitions and in the 35-44-year age group in the mountain marathon. The sex difference in performance decreased in the 35-44-year age group from 19.1% +/- 4.7% to 16.6% +/- 1.9% in the mountain marathon (r(2) = 0.39, P = 0.03). In age groups 45-54 years, the sex difference decreased from 23.4% +/- 1.9% to 15.9% +/- 6.1% in the mountain marathon (r(2) = 0.39, P < 0.01) and from 34.7% +/- 4.6% to 11.8% +/- 6.2% in the city marathon (r(2) = 0.39, P < 0.01). CONCLUSION: These findings suggest that female master runners aged 35-54 years reduced sex differences in their performance in both mountain and city marathon running. PMID- 23637551 TI - RANTES and fibroblast growth factor 2 in jawbone cavitations: triggers for systemic disease? AB - BACKGROUND: Jawbone cavitations (JC) are hollow dead spaces in jawbones with dying or dead bone marrow. These areas are defined as fatty degenerative osteonecrosis of the jawbone or neuralgia-inducing cavitational osteonecrosis and may produce facial pain. These afflictions have been linked to the immune system and chronic illnesses. Surgical debridement of JC is reported to lead to an improvement in immunological complaints, such as rheumatic, allergic, and other inflammatory diseases (ID). Little is known about the underlying cause/effect relationship. OBJECTIVES: JC bone samples were analyzed to assess the expression and quantification of immune modulators that can play a role in the pathogenesis of IDs. The study supports a potential mechanism where JC is a mediating link in IDs. MATERIALS AND METHODS: Samples of fatty softened bone taken from JCs were extracted from 31 patients. The specimens were analyzed by bead-based multiplex technology and tested for seven immune messengers. RESULTS: Regulated upon activation, normal T-cell expressed, and secreted (RANTES) and fibroblast growth factor (FGF)-2 were found at high levels in the JCs tested. Other cytokines could not be detected at excessive levels. DISCUSSION: The study confirms that JC is able to produce inflammatory messengers, primarily RANTES, and, secondarily, FGF 2. Both are implicated in many serious illnesses. The excessive levels of RANTES/FGF-2 in JC patients with amyotrophic lateral sclerosis, multiple sclerosis, rheumatoid arthritis, and breast cancer are compared to levels published in medical journals. Levels detected in JCs are higher than in the serum and cerebrospinal fluid of amyotrophic lateral sclerosis and multiple sclerosis patients and four-fold higher than in breast cancer tissue. CONCLUSION: This study suggests that JC might serve as a fundamental cause of IDs, through RANTES/FGF-2 production. Thus, JC and implicated immune messengers represent an integrative aspect of IDs and serve as a possible cause. Removing JCs may be a key to reversing IDs. There is a need to raise awareness about JC throughout medicine and dentistry. PMID- 23637549 TI - Genetic polymorphisms and associated susceptibility to asthma. AB - As complex common diseases, asthma and allergic diseases are caused by the interaction of multiple genetic variants with a variety of environmental factors. Candidate-gene studies have examined the involvement of a very large list of genes in asthma and allergy, demonstrating a role for more than 100 loci. These studies have elucidated several themes in the biology and pathogenesis of these diseases. A small number of genes have been associated with asthma or allergy through traditional linkage analyses. The publication of the first asthma-focused genome-wide association (GWA) study in 2007 has been followed by nearly 30 reports of GWA studies targeting asthma, allergy, or associated phenotypes and quantitative traits. GWA studies have confirmed several candidate genes and have identified new, unsuspected, and occasionally uncharacterized genes as asthma susceptibility loci. Issues of results replication persist, complicating interpretation and making conclusions difficult to draw, and much of the heritability of these diseases remains undiscovered. In the coming years studies of complex diseases like asthma and allergy will probably involve the use of high throughput next-generation sequencing, which will bring a tremendous influx of new information as well as new problems in dealing with vast datasets. PMID- 23637554 TI - The effect of transdermal opioid use on breakthrough opioid and sedative prescribing for rural patients with chronic pain in Northwest Tasmania: a longitudinal study. AB - PURPOSE: The aim of the study reported here was to determine the frequency of prescribing of immediate-release (IR) opioids, and benzodiazepines, with both oral sustained-release (SR) and transdermal (TD) opioid maintenance treatment, in a rural population with chronic noncancer pain (CNCP). SUBJECTS AND METHODS: A longitudinal study measuring IR opioid and benzodiazepine dispensed prescriptions (scripts) by route of maintenance opioid administration over time (monthly for 1 year). Subjects were opioid-treated CNCP patients from Northwest Tasmania. The outcome measures of mean monthly scripts were analyzed using generalized estimating equations with robust standard errors. RESULTS: Details of 12,191 dispensed scripts were obtained from 140 subjects over 12 months. Mean monthly IR scripts with oral SR opioid maintenance were 0.21 (95% confidence interval [CI] 0.10; 0.32). With TD opioid maintenance, this was nonsignificantly lower (P = 0.06) at 0.04 (95% CI 0.00; 0.15). Mean monthly benzodiazepine scripts with oral SR opioids were 0.47 (95% CI 0.32; 0.62), and unchanged (P = 0.84) for TD opioids at 0.45 (95% CI 0.28; 0.62). CONCLUSION: There was a nonsignificant trend toward reduced prescribing of IR opioids with TD opioid-maintained, compared with oral SR opioid-maintained, CNCP rural patients. Benzodiazepine prescribing was similar for both groups. The rationale for use and the provision of breakthrough opioid analgesia for CNCP patients are complex, both for patients and their prescribers, while the regular use of benzodiazepines compounds the sedation from the subjects' maintenance opioid. The prolonged analgesic affect of TD opioids may benefit rural and remote CNCP populations and reduce the risk of diversion associated with oral opioids. PMID- 23637553 TI - The potential impact of various diagnostic strategies in cases of chronic pain syndromes associated with lumbar spine degeneration. AB - PURPOSE: To study the possible effects of various diagnostic strategies and the relative contribution of various structures in order to determine the optimal diagnostic strategy in treating patients with noncompressive pain syndromes. STUDY DESIGN: Prospective, nonrandomized cohort study of 83 consecutive patients with noncompressive pain syndromes resistant to repeated courses of conservative treatment. The follow-up period was 18 months. RESULTS: Nucleoplasty was effective in cases of discogenic pain; the consequences related to false positive results of the discography were significant. The most specific criterion was 80% pain relief after facet joint blocks, whereas 50% pain relief and any subjective pain relief were not associated with a significant increase in the success rate. A considerable rate of false negative results was associated with 80% pain relief, whereas 50% pain relief after facet joint blocks showed the optimal ratio of sensitivity and specificity. Facet joint pain was detected in 50.6% of cases (95% confidence interval 44.1%-66.3%), discogenic pain in 16.9% cases (95% confidence interval 9.5%-26.7%), and sacroiliac joint pain in 7.2% cases (95% confidence interval 2.7%-15%). It was impossible to differentiate the main source of pain in 25.3% of cases. CONCLUSION: It is rational to adjust the diagnostic algorithm to the probability of detecting a particular pain source and, in doing so, reduce the number of invasive diagnostic measures to evaluate a pain source. False positive results of diagnostic measures can negatively affect the overall efficacy of a particular technology; therefore, all reasons for the failure should be studied in order to reach an unbiased conclusion. In choosing diagnostic criteria, not only should the success rate of a particular technology be taken into consideration but also the rate of false negative results. Acceptable diagnostic criteria should be based on a rational balance of sensitivity and specificity. PMID- 23637555 TI - Latent class analysis of comorbidity patterns among women with generalized and localized vulvodynia: preliminary findings. AB - BACKGROUND: The pattern and extent of clustering of comorbid pain conditions with vulvodynia is largely unknown. However, elucidating such patterns may improve our understanding of the underlying mechanisms involved in these common causes of chronic pain. We sought to describe the pattern of comorbid pain clustering in a population-based sample of women with diagnosed vulvodynia. METHODS: A total of 1457 women with diagnosed vulvodynia self-reported their type of vulvar pain as localized, generalized, or both. Respondents were also surveyed about the presence of comorbid pain conditions, including temporomandibular joint and muscle disorders, interstitial cystitis, fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, endometriosis, and chronic headache. Age-adjusted latent class analysis modeled extant patterns of comorbidity by vulvar pain type, and a multigroup model was used to test for the equality of comorbidity patterns using a comparison of prevalence. A two-class model (no/single comorbidity versus multiple comorbidities) had the best fit in individual and multigroup models. RESULTS: For the no/single comorbidity class, the posterior probability prevalence of item endorsement ranged from 0.9% to 24.4%, indicating a low probability of presence. Conversely, the multiple comorbidity class showed that at least two comorbid conditions were likely to be endorsed by at least 50% of women in that class, and irritable bowel syndrome and fibromyalgia were the most common comorbidities regardless of type of vulvar pain. Prevalence of the multiple comorbidity class differed by type of vulvar pain: both (37.6% prevalence, referent), generalized (21.6% prevalence, adjusted odds ratio 0.41, 95% confidence interval 0.27-0.61), or localized (12.5% prevalence, adjusted odds ratio 0.31, 95% confidence interval 0.21-0.47). CONCLUSION: This novel work provides insight into potential shared mechanisms of vulvodynia by describing that a prominent comorbidity pattern involves having both irritable bowel syndrome and fibromyalgia. In addition, the prevalence of a multiple comorbidity class pattern increases with increasing severity of vulvar pain. PMID- 23637552 TI - Review of evidence for immune evasion and persistent infection in Lyme disease. AB - Is chronic illness in patients with Lyme disease caused by persistent infection? Three decades of basic and clinical research have yet to produce a definitive answer to this question. This review describes known and suspected mechanisms by which spirochetes of the Borrelia genus evade host immune defenses and survive antibiotic challenge. Accumulating evidence indicates that Lyme disease spirochetes are adapted to persist in immune competent hosts, and that they are able to remain infective despite aggressive antibiotic challenge. Advancing understanding of the survival mechanisms of the Lyme disease spirochete carry noteworthy implications for ongoing research and clinical practice. PMID- 23637558 TI - Association of physical inactivity with circulatory disease events and hospital treatment costs. AB - PURPOSE: Epidemiological studies of chronic disorders need to consider more responsive outcomes, particularly those that manifest themselves across a defined population over a shorter time period, to improve our ability to detect the causes of and intervene in the global epidemics of today. We explore the use of hospital episode statistics as a candidate for this role and estimate the strength of the association of circulatory disease-related events with physical inactivity, considered here as an undesirable health behavior. SETTINGS PATIENTS AND METHODS: The primary research was set in a mid-sized city in central England. Aggregation was at output area level (comprising ~300 residents); 51 of which were included. A random sample of 761 adults was selected to obtain estimates of the mean level of physical activity within each area. Circulatory disease hospital events were recorded and aggregated by output area over a 2-year period. Hierarchical linear modeling was used to establish the strength of the association between area-level physical activity and circulatory disease events. Sex, age, and reporting quarter were included as additional individual-level explanatory variables. RESULTS: Areas reporting greater activity were less likely (event rate ratio = 0.855; 95% confidence interval [CI]: 0.78-0.94) to have a circulatory disease event, as were females (0.593; 95% CI: 0.47-0.75). Areas with older residents (1.578; 95% CI: 1.5-1.66) and later reporting quarters (1.095; 95% CI: 1.04-1.15) were more likely to report circulatory disease events. CONCLUSION: This study supports the use of hospital episode statistics as an outcome measure in the epidemiology of circulatory disease and reaffirms the potential importance of physical inactivity in the disease process. PMID- 23637556 TI - Efficacy and tolerability of a single-pill combination of telmisartan 80 mg and hydrochlorothiazide 25 mg according to age, gender, race, hypertension severity, and previous antihypertensive use: planned analyses of a randomized trial. AB - BACKGROUND: The purpose of this work was to describe the efficacy and safety of a telmisartan 80 mg + hydrochlorothiazide 25 mg (T80/H25) single-pill combination therapy in patients with moderate-severe hypertension (mean seated trough cuff systolic blood pressure [BP] >= 160 mmHg and diastolic BP >= 100 mmHg) in specific patient subpopulations. METHODS: This was a planned analysis of a double blind, multicenter, parallel-group trial that demonstrated the superiority of a single-pill combination of T80/H25 versus T80 monotherapy in terms of systolic BP change from baseline to week 7. Subpopulations included older (aged >= 65 years) versus younger, gender, race, hypertension severity, and prior antihypertensive therapy. Endpoints were change from baseline in mean seated trough cuff systolic and diastolic BP, proportion of patients achieving their BP goal (systolic/diastolic BP < 140/90 mmHg), and proportion of patients attaining systolic BP reductions of >30 mmHg and >40 mmHg. RESULTS: Across all subgroups, the T80/H25 single-pill combination provided consistently greater systolic and diastolic BP reductions than T80 and more patients had systolic BP reductions of >30 mmHg. In the T80 and T80/H25 groups, BP control was achieved in 34.1% and 48.8% of men, 35.5% and 62.7% of women, 34.5% and 56.6% of Asians, 22.6% and 38.6% of blacks, 36.7% and 57.8% of whites, 36.9% and 57.5% of patients < 65 years, 29.3% and 49.3% >=65 years, 44.2% and 66.2% of those with grade 2 hypertension, 20.4% and 39.4% of those with grade 3 hypertension, 38.9% and 53.2% of previously untreated patients, 38.1% and 62.5% of patients previously treated with one antihypertensive, and 29.7% and 48.9% of patients previously treated with two or more antihypertensive agents respectively. Treatment was generally well tolerated across the patient subgroups. CONCLUSION: The T80/H25 single-pill combination provides consistent BP reductions and higher goal attainment rates versus T80 across a range of hypertensive patient subgroups, which are likely to have a positive impact on patients' cardiovascular risk. PMID- 23637557 TI - Current Perspectives on rosuvastatin. AB - Rosuvastatin is one of the most potent statins available for reducing circulating low-density lipoprotein cholesterol (LDL-C) levels, which enables more high-risk patients to achieve their lipid goals. Its favorable balance of effects on atherogenic and protective lipoproteins and its pleiotropic effects, including anti-inflammatory and antioxidant effects and improvement in endothelial dysfunction, are associated with slowing of progression of atherosclerosis within the artery wall and have been translated into clinical benefits for cardiovascular outcomes. This review provides an update on the safety and the efficacy of rosuvastatin in recent large clinical trials. It appears that rosuvastatin has a beneficial effect on the progression of atherosclerosis across the clinical dosage range of 2.5-40 mg. It reduced cardiovascular events in relatively low-risk subjects with elevated high-sensitivity C-reactive protein and normal low-density lipoprotein cholesterol. As with other statins, rosuvastatin did not show overall benefit in terms of survival in patients with heart failure, but certain clinical or biochemical markers reflecting underlying disease characteristics may help to identify subgroups of patients that benefit from statin therapy. In patients with end-stage renal disease undergoing chronic hemodialysis, rosuvastatin had no effect on reducing cardiovascular events. Although there is a slightly increased risk of incident diabetes with this class of agents, the absolute benefits of statin therapy on cardiovascular events overweigh the risk in patients with moderate or high cardiovascular risk or with documented cardiovascular disease. As with other statins, rosuvastatin is an appropriate therapy in addition to antihypertensive treatment to reduce cardiovascular risk in hypertensive patients. PMID- 23637559 TI - Pharmacovigilance as a tool for safety and monitoring: a review of general issues and the specific challenges with end-stage renal failure patients. AB - Pharmacovigilance is instrumental in helping to ensure patient safety for both newly released drugs and those that are well established in the market. However, while pharmacovigilance procedures are strictly regulated in the clinical trial setting, post-marketing adverse event reporting is not well implemented or enforced. As such, the underreporting of adverse events, in relation to drugs that are on the market, is estimated to be in the region of 90%. The identification of drug safety issues in patients with complex diseases and extensive comorbidities is therefore particularly challenging. Dialysis patients those with end-stage renal disease and often other comorbidities such as diabetes, hypertension, and cardiovascular disease - are a population with significant treatment challenges. Patients receive dialysis using complex medical devices (eg, a peritoneal dialysis home cycler) and also receive a range of pharmaceutical agents as part of dialysis itself (eg, peritoneal dialysis solutions). Many of the pharmaceutical agents used to treat these patients have been developed in populations without these complications and, therefore, an extensive knowledge of potential problems and contraindications in the dialysis population is lacking. It is important that the nephrology community understands the concept of pharmacovigilance - the pharmacologic science relating to the detection, assessment, understanding, and prevention of adverse effects, particularly long-term and short-term side effects, of medicines. Health care professionals (HCPs) and providers, pharmaceutical companies, global regulatory agencies, and the patients themselves all play unique and critical roles in this process. This review defines the science of pharmacovigilance and the process of adverse event reporting, highlights the new directions that pharmacovigilance has taken, and provides insight for HCPs managing dialysis patients into the important role that they play in helping to shape the understanding of a drug's safety profile in order to continually enhance patient safety. PMID- 23637561 TI - Sexual behaviors among men who have sex with men: a quantitative cross sectional study in Kathmandu Valley, Nepal. AB - Unprotected sexual transmission is the cause of approximately 70%-80% of human immunodeficiency virus (HIV) infections worldwide. Prevalence of HIV infection in 2011 was more than ten fold higher (3.8%) among men who have sex with men (MSM) than in the general population (0.33%) in Nepal. This study aimed to explore sexual behaviors, and social and demographic characteristics of MSM in Kathmandu Valley, Nepal. A quantitative cross sectional study was conducted among 113 MSM. MSM is a hidden population in Nepalese society, therefore, it was difficult to construct a sample frame for this research so, respondent driven sampling was used which gives unbiased estimates of population parameters and has the potential to reach MSM, who are not easily accessible. A structured interview was used to obtain the information. The majority of respondents were above 20 years old (mean = 27.9 years, SD = 7.4 years). Most respondents were receptive, 43.4% identified themselves as Meti. Forty six percent of respondents were married. The majority had sex with males which was predominantly anal. MSM had an average number of 74 sex partners (last three months). Nearly 95% had used a condom, and 92% had used lubricant during their last sex act. Thirty eight percent perceived themselves as at risk of HIV. The majority knew of a place for confidential HIV testing in Kathmandu. This study highlights the importance of partner tracing during HIV counseling and testing, the importance of drop-in centers to increase access to condoms, and supports the need to increase comprehensive health services and peer led participatory behavioral change communication activities to this population in the national HIV response. PMID- 23637560 TI - Non-small cell lung cancer therapy: safety and efficacy in the elderly. AB - BACKGROUND: Our objective was to evaluate and review the current literature on the treatment of non-small cell lung cancer (NSCLC) in the elderly. METHODS: We selected recent peer-reviewed articles addressing ageing, cancer treatment in the elderly, and lung cancer treatment in the elderly. We defined elderly as over the age of 70. RESULTS: The population is ageing dramatically throughout most of the world. Given that situation, clinicians are seeing and being asked to treat more elderly patients that have NSCLC. Elderly patients are less likely to participate or be allowed to participate in prospective or retrospective studies of treatments for NSCLC. Elderly patients are also less likely to be staged appropriately for their advanced tumors, and are less likely to be referred for surgery or adjuvant therapy after surgery. When treatment is tailored to patient comorbidities but not to age, the data support survival and outcomes comparable to those of younger patients. CONCLUSIONS: Data are limited on the treatment of elderly patients with NSCLC. No data exist to support limiting recommendations for treatment based on age alone. Treatments should be determined on an individual basis. PMID- 23637562 TI - Meaning-making of female genital cutting: children's perception and acquired knowledge of the ritual. AB - How do girls who have undergone female genital cutting understand the ritual? This study provides an analysis of the learning process and knowledge acquired in their meaning-making process. Eighteen participants were interviewed in qualitative indepth interviews. Women in Norway, mostly with Somali or Gambian backgrounds, were asked about their experiences of circumcision. Two different strategies were used to prepare girls for circumcision, ie, one involving giving some information and the other keeping the ritual a secret. Findings indicate that these two approaches affected the girls' meaning-making differently, but both strategies seemed to lead to the same educational outcome. The learning process is carefully monitored and regulated but is brought to a halt, stopping short of critical reflexive thinking. The knowledge tends to be deeply internalized, embodied, and morally embraced. The meaning-making process is discussed by analyzing the use of metaphors and narratives. Given that the educational outcome is characterized by limited knowledge without critical reflection, behavior change programs to end female genital cutting should identify and implement educational stimuli that are likely to promote critical reflexive thinking. PMID- 23637563 TI - Circulating nucleic acids in plasma and serum: applications in diagnostic techniques for noninvasive prenatal diagnosis. AB - The analysis of fetal nucleic acids in maternal blood 13 years ago has led to the initiation of noninvasive methods for the early determination of fetal gender, rhesus D status, and a number of aneuploid disorders and hemoglobinopathies. Subsequently, a comparatively large quantity of fetal DNA and RNA has been demonstrated in amniotic fluid as well as small amounts in premature infant saliva. The DNA and RNA in amniotic fluid has permitted an analysis of core transcriptomes, whilst the DNA and RNA in saliva allows the early detection and treatment monitoring of fetal developmental problems. These aspects are discussed together with the methodology and limits of analysis for noninvasive prenatal diagnosis in predictive, preventive, and personalized medicine. PMID- 23637564 TI - Post-steroid management of chronic vulvar itching with a topical formula containing natural anti-itching and anti-inflammatory actives. AB - AIM: To determine whether use of a topical, nonsteroidal, anti-inflammatory, and anti-itching formula was able to preserve the absence of symptoms, mainly itching and burning, induced by an earlier and relatively short treatment with topical steroids in women diagnosed with vulvar dermatitis or lichen simplex. METHODS: Ninety-six subjects (36 with contact dermatitis, 29 with allergic dermatitis, 31 with lichen simplex) were enrolled in the study. All participants were first treated with topical mometasone furoate (MF) 0.1%. When the symptoms disappeared, they were treated either with Zantogin((r)), a multicomponent topical formula containing anti-inflammatory and anti-itching natural actives, or a control cream for 60 days. RESULTS: The study demonstrated that, in about 85% of the participants treated with Zantogin((r)), symptoms disappeared completely, and only 15% had to resort to MF as needed, with an average use of about three applications per subject (in total). In the placebo group, approximately 90% of participants had to resort to MF as needed, with an average use per person of more than 16 applications in 60 days. CONCLUSION: Our study demonstrates that, following use of a topical steroid, symptoms such as burning and itching can be validly controlled with subsequent and longer therapy with a herbal topical formula, Zantogin((r)), which is able to properly counteract itching and inflammation, prevent symptom relapse, and avoid the typical side effects associated with prolonged use of topical steroids. PMID- 23637565 TI - Nutrition in pregnancy: the argument for including a source of choline. AB - Women, during pregnancy and lactation, should eat foods that contain adequate amounts of choline. A mother delivers large amounts of choline across the placenta to the fetus, and after birth she delivers large amounts of choline in milk to the infant; this greatly increases the demand on the choline stores of the mother. Adequate intake of dietary choline may be important for optimal fetal outcome (birth defects, brain development) and for maternal liver and placental function. Diets in many low income countries and in approximately one-fourth of women in high income countries, like the United States, may be too low in choline content. Prenatal vitamin supplements do not contain an adequate source of choline. For women who do not eat foods containing milk, meat, eggs, or other choline-rich foods, a diet supplement should be considered. PMID- 23637567 TI - Multi-functionality of fluorescent nanocrystals in glass ceramics. AB - Thermal processing of as-made fluorozirconate glasses, which were additionally doped with rare-earth and chlorine ions, results in the formation of fluorescent nanocrystals therein. For medical applications, the glasses were doped with divalent europium ions as the fluorescent rare-earth ion, while trivalent neodymium was used to develop up-conversion systems. The samples were annealed up to 290 degrees C to initiate the growth of hexagonal or orthorhombic phase BaCl2 nanocrystals therein. Upon annealing some of the rare-earth ions were incorporated into the BaCl2 nanocrystals leading to enhanced fluorescence properties. The particle diameters were in the range of a few nanometers to several tens of nanometers. PMID- 23637566 TI - Effect of famotidine on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. AB - BACKGROUND: Apixaban is an oral, selective, direct factor Xa inhibitor approved for thromboprophylaxis after orthopedic surgery and stroke prevention in patients with atrial fibrillation, and under development for treatment of venous thromboembolism. This study investigated the effect of a gastric acid suppressant, famotidine (a histamine H2-receptor antagonist), on the pharmacokinetics of apixaban in healthy subjects. METHODS: This two-period, two treatment crossover study randomized 18 healthy subjects to receive a single oral dose of apixaban 10 mg with and without a single oral dose of famotidine 40 mg administered 3 hours before dosing with apixaban. Plasma apixaban concentrations were measured up to 60 hours post-dose and pharmacokinetic parameters were calculated. RESULTS: Famotidine did not affect maximum apixaban plasma concentration (Cmax) or area under the plasma concentration-time curve from zero to infinite time (AUCinfinity). Point estimates for ratios of geometric means with and without famotidine were close to unity for Cmax (0.978) and AUCinfinity (1.007), and 90% confidence intervals were entirely contained within the 80%-125% no-effect interval. Administration of apixaban alone and with famotidine was well tolerated. CONCLUSION: Famotidine does not affect the pharmacokinetics of apixaban, consistent with the physicochemical properties of apixaban (lack of an ionizable group and pH-independent solubility). Apixaban pharmacokinetics would not be affected by an increase in gastrointestinal pH due to underlying conditions (eg, achlorhydria), or by gastrointestinal pH-mediated effects of other histamine H2-receptor antagonists, antacids, or proton pump inhibitors. Given that famotidine is also an inhibitor of the human organic cation transporter (hOCT), these results indicate that apixaban pharmacokinetics are not influenced by hOCT uptake transporter inhibitors. Overall, these results support that apixaban can be administered without regard to coadministration of gastric acid modifiers. PMID- 23637568 TI - Robust estimation for homoscedastic regression in the secondary analysis of case control data. AB - Primary analysis of case-control studies focuses on the relationship between disease D and a set of covariates of interest (Y, X). A secondary application of the case-control study, which is often invoked in modern genetic epidemiologic association studies, is to investigate the interrelationship between the covariates themselves. The task is complicated owing to the case-control sampling, where the regression of Y on X is different from what it is in the population. Previous work has assumed a parametric distribution for Y given X and derived semiparametric efficient estimation and inference without any distributional assumptions about X. We take up the issue of estimation of a regression function when Y given X follows a homoscedastic regression model, but otherwise the distribution of Y is unspecified. The semiparametric efficient approaches can be used to construct semiparametric efficient estimates, but they suffer from a lack of robustness to the assumed model for Y given X. We take an entirely different approach. We show how to estimate the regression parameters consistently even if the assumed model for Y given X is incorrect, and thus the estimates are model robust. For this we make the assumption that the disease rate is known or well estimated. The assumption can be dropped when the disease is rare, which is typically so for most case-control studies, and the estimation algorithm simplifies. Simulations and empirical examples are used to illustrate the approach. PMID- 23637569 TI - The expanding genomic landscape of autism: discovering the 'forest' beyond the 'trees' AB - Autism spectrum disorders are neurodevelopmental disorders characterized by significant deficits in reciprocal social interactions, impaired communication and restricted, repetitive behaviors. As autism spectrum disorders are among the most heritable of neuropsychiatric disorders, much of autism research has focused on the search for genetic variants in protein-coding genes (i.e., the 'trees'). However, no single gene can account for more than 1% of the cases of autism spectrum disorders. Yet, genome-wide association studies have often identified statistically significant associations of genetic variations in regions of DNA that do not code for proteins (i.e., intergenic regions). There is increasing evidence that such noncoding regions are actively transcribed and may participate in the regulation of genes, including genes on different chromosomes. This article summarizes evidence that suggests that the research spotlight needs to be expanded to encompass far-reaching gene-regulatory mechanisms that include a variety of epigenetic modifications, as well as noncoding RNA (i.e., the 'forest'). Given that noncoding RNA represents over 90% of the transcripts in most cells, we may be observing just the 'tip of the iceberg' or the 'edge of the forest' in the genomic landscape of autism. PMID- 23637570 TI - Ligands for pheromone-sensing neurons are not conformationally activated odorant binding proteins. AB - Pheromones form an essential chemical language of intraspecific communication in many animals. How olfactory systems recognize pheromonal signals with both sensitivity and specificity is not well understood. An important in vivo paradigm for this process is the detection mechanism of the sex pheromone (Z)-11 octadecenyl acetate (cis-vaccenyl acetate [cVA]) in Drosophila melanogaster. cVA evoked neuronal activation requires a secreted odorant binding protein, LUSH, the CD36-related transmembrane protein SNMP, and the odorant receptor OR67d. Crystallographic analysis has revealed that cVA-bound LUSH is conformationally distinct from apo (unliganded) LUSH. Recombinantly expressed mutant versions of LUSH predicted to enhance or diminish these structural changes produce corresponding alterations in spontaneous and/or cVA-evoked activity when infused into olfactory sensilla, leading to a model in which the ligand for pheromone receptors is not free cVA, but LUSH that is "conformationally activated" upon cVA binding. Here we present evidence that contradicts this model. First, we demonstrate that the same LUSH mutants expressed transgenically affect neither basal nor pheromone-evoked activity. Second, we compare the structures of apo LUSH, cVA/LUSH, and complexes of LUSH with non-pheromonal ligands and find no conformational property of cVA/LUSH that can explain its proposed unique activated state. Finally, we show that high concentrations of cVA can induce neuronal activity in the absence of LUSH, but not SNMP or OR67d. Our findings are not consistent with the model that the cVA/LUSH complex acts as the pheromone ligand, and suggest that pheromone molecules alone directly activate neuronal receptors. PMID- 23637572 TI - Flower petals take shape. PMID- 23637571 TI - feedback between population and evolutionary dynamics determines the fate of social microbial populations. AB - The evolutionary spread of cheater strategies can destabilize populations engaging in social cooperative behaviors, thus demonstrating that evolutionary changes can have profound implications for population dynamics. At the same time, the relative fitness of cooperative traits often depends upon population density, thus leading to the potential for bi-directional coupling between population density and the evolution of a cooperative trait. Despite the potential importance of these eco-evolutionary feedback loops in social species, they have not yet been demonstrated experimentally and their ecological implications are poorly understood. Here, we demonstrate the presence of a strong feedback loop between population dynamics and the evolutionary dynamics of a social microbial gene, SUC2, in laboratory yeast populations whose cooperative growth is mediated by the SUC2 gene. We directly visualize eco-evolutionary trajectories of hundreds of populations over 50-100 generations, allowing us to characterize the phase space describing the interplay of evolution and ecology in this system. Small populations collapse despite continual evolution towards increased cooperative allele frequencies; large populations with a sufficient number of cooperators "spiral" to a stable state of coexistence between cooperator and cheater strategies. The presence of cheaters does not significantly affect the equilibrium population density, but it does reduce the resilience of the population as well as its ability to adapt to a rapidly deteriorating environment. Our results demonstrate the potential ecological importance of coupling between evolutionary dynamics and the population dynamics of cooperatively growing organisms, particularly in microbes. Our study suggests that this interaction may need to be considered in order to explain intraspecific variability in cooperative behaviors, and also that this feedback between evolution and ecology can critically affect the demographic fate of those species that rely on cooperation for their survival. PMID- 23637573 TI - Cooperation and the fate of microbial societies. AB - Microorganisms have been cooperating with each other for billions of years: by sharing resources, communicating with each other, and joining together to form biofilms and other large structures. These cooperative behaviors benefit the colony as a whole; however, they may be costly to the individuals performing them. This raises the question of how such cooperation can arise from natural selection. Mathematical modeling is one important avenue for exploring this question. Evolutionary experiments are another, providing us with an opportunity to see evolutionary dynamics in action and allowing us to test predictions arising from mathematical models. A new study in this issue of PLOS Biology investigates the evolution of a cooperative resource-sharing behavior in yeast. Examining the competition between cooperating and "cheating" strains of yeast, the authors find that, depending on the initial mix of strains, this yeast society either evolves toward a stable coexistence or collapses for lack of cooperation. Using a simple mathematical model, they show how these dynamics arise from eco-evolutionary feedback, where changes in the frequencies of strains are coupled with changes in population size. This study and others illustrate the combined power of modeling and experiment to elucidate the origins of cooperation and other fundamental questions in evolutionary biology. PMID- 23637574 TI - Directional transport is mediated by a Dynein-dependent step in an RNA localization pathway. AB - Cytoplasmic RNA localization is a key biological strategy for establishing polarity in a variety of organisms and cell types. However, the mechanisms that control directionality during asymmetric RNA transport are not yet clear. To gain insight into this crucial process, we have analyzed the molecular machinery directing polarized transport of RNA to the vegetal cortex in Xenopus oocytes. Using a novel approach to measure directionality of mRNA transport in live oocytes, we observe discrete domains of unidirectional and bidirectional transport that are required for vegetal RNA transport. While kinesin-1 appears to promote bidirectional transport along a microtubule array with mixed polarity, dynein acts first to direct unidirectional transport of RNA towards the vegetal cortex. Thus, vegetal RNA transport occurs through a multistep pathway with a dynein-dependent directional cue. This provides a new framework for understanding the mechanistic basis of cell and developmental polarity. PMID- 23637575 TI - COMPASS: navigating the rules of scientific engagement. PMID- 23637577 TI - Air pollution and atherosclerosis: new evidence to support air quality policies. PMID- 23637576 TI - Fine particulate air pollution and the progression of carotid intima-medial thickness: a prospective cohort study from the multi-ethnic study of atherosclerosis and air pollution. AB - BACKGROUND: Fine particulate matter (PM2.5) has been linked to cardiovascular disease, possibly via accelerated atherosclerosis. We examined associations between the progression of the intima-medial thickness (IMT) of the common carotid artery, as an indicator of atherosclerosis, and long-term PM2.5 concentrations in participants from the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS AND RESULTS: MESA, a prospective cohort study, enrolled 6,814 participants at the baseline exam (2000-2002), with 5,660 (83%) of those participants completing two ultrasound examinations between 2000 and 2005 (mean follow-up: 2.5 years). PM2.5 was estimated over the year preceding baseline and between ultrasounds using a spatio-temporal model. Cross-sectional and longitudinal associations were examined using mixed models adjusted for confounders including age, sex, race/ethnicity, smoking, and socio-economic indicators. Among 5,362 participants (5% of participants had missing data) with a mean annual progression of 14 um/y, 2.5 ug/m(3) higher levels of residential PM2.5 during the follow-up period were associated with 5.0 um/y (95% CI 2.6 to 7.4 um/y) greater IMT progressions among persons in the same metropolitan area. Although significant associations were not found with IMT progression without adjustment for metropolitan area (0.4 um/y [95% CI -0.4 to 1.2 um/y] per 2.5 ug/m(3)), all of the six areas showed positive associations. Greater reductions in PM2.5 over follow-up for a fixed baseline PM2.5 were also associated with slowed IMT progression (-2.8 um/y [95% CI -1.6 to -3.9 um/y] per 1 ug/m(3) reduction). Study limitations include the use of a surrogate measure of atherosclerosis, some loss to follow-up, and the lack of estimates for air pollution concentrations prior to 1999. CONCLUSIONS: This early analysis from MESA suggests that higher long-term PM2.5 concentrations are associated with increased IMT progression and that greater reductions in PM2.5 are related to slower IMT progression. These findings, even over a relatively short follow-up period, add to the limited literature on air pollution and the progression of atherosclerotic processes in humans. If confirmed by future analyses of the full 10 years of follow-up in this cohort, these findings will help to explain associations between long-term PM2.5 concentrations and clinical cardiovascular events. PMID- 23637578 TI - Grand challenges in global mental health: integration in research, policy, and practice. PMID- 23637580 TI - Excess long-term mortality following non-variceal upper gastrointestinal bleeding: a population-based cohort study. AB - BACKGROUND: It is unclear whether an upper gastrointestinal bleed is an isolated gastrointestinal event or an indicator of a deterioration in a patient's overall health status. Therefore, we investigated the excess causes of death in individuals after a non-variceal bleed compared with deaths in a matched sample of the general population. METHODS AND FINDINGS: Linked longitudinal data from the English Hospital Episodes Statistics (HES) data, General Practice Research Database (GPRD), and Office of National Statistics death register were used to define a cohort of non-variceal bleeds between 1997 and 2010. Controls were matched at the start of the study by age, sex, practice, and year. The excess risk of each cause of death in the 5 years subsequent to a bleed was then calculated whilst adjusting for competing risks using cumulative incidence functions. 16,355 patients with a non-variceal upper gastrointestinal bleed were matched to 81,523 controls. The total 5-year risk of death due to gastrointestinal causes (malignant or non-malignant) ranged from 3.6% (<= 50 years, 95% CI 3.0%-4.3%) to 15.2% (>= 80 years, 14.2%-16.3%), representing an excess over controls of between 3.6% (3.0%-4.2%) and 13.4% (12.4%-14.5%), respectively. In contrast the total 5-year risk of death due to non gastrointestinal causes ranged from 4.1% (<= 50 years, 3.4%-4.8%) to 46.6% (>= 80 years, 45.2%-48.1%), representing an excess over controls of between 3.8% (3.1% 4.5%) and 19.0% (17.5%-20.6%), respectively. The main limitation of this study was potential misclassification of the exposure and outcome; however, we sought to minimise this by using information derived across multiple linked datasets. CONCLUSIONS: Deaths from all causes were increased following an upper gastrointestinal bleed compared to matched controls, and over half the excess risk of death was due to seemingly unrelated co-morbidity. A non-variceal bleed may therefore warrant a careful assessment of co-morbid illness seemingly unrelated to the bleed. PMID- 23637581 TI - Focusing the spotlight on lack of access to health information. PMID- 23637579 TI - Cinacalcet in patients with chronic kidney disease: a cumulative meta-analysis of randomized controlled trials. AB - BACKGROUND: Calcimimetic agents lower serum parathyroid hormone levels in people with chronic kidney disease (CKD), but treatment effects on patient-relevant outcomes are uncertain. We conducted a systematic review and meta-analysis to summarize the benefits and harms of calcimimetic therapy in adults with CKD and used cumulative meta-analysis to identify how evidence for calcimimetic treatment has developed in this clinical setting. METHODS AND FINDINGS: Cochrane and Embase databases (through February 7, 2013) were electronically searched to identify randomized trials evaluating effects of calcimimetic therapy on mortality and adverse events in adults with CKD. Two independent reviewers identified trials, extracted data, and assessed risk of bias. Eighteen trials comprising 7,446 participants compared cinacalcet plus conventional therapy with placebo or no treatment plus conventional therapy in adults with CKD. In moderate- to high quality evidence (based on Grading of Recommendations Assessment, Development, and Evaluation criteria) in adults with CKD stage 5D (dialysis), cinacalcet had little or no effect on all-cause mortality (relative risk, 0.97 [95% confidence interval, 0.89-1.05]), had imprecise effect on cardiovascular mortality (0.67 [0.16-2.87]), and prevented parathyroidectomy (0.49 [0.40-0.59]) and hypercalcemia (0.23 [0.05-0.97]), but increased hypocalcemia (6.98 [5.10-9.53]), nausea (2.02 [1.45-2.81]), and vomiting (1.97 [1.73-2.24]). Data for clinical outcomes were sparse in adults with CKD stages 3-5. On average, treating 1,000 people with CKD stage 5D for 1 y had no effect on survival and prevented about three patients from experiencing parathyroidectomy, whilst 60 experienced hypocalcemia and 150 experienced nausea. Analyses were limited by insufficient data in CKD stages 3-5 and kidney transplant recipients. CONCLUSIONS: Cinacalcet reduces the need for parathyroidectomy in patients with CKD stage 5D, but does not appear to improve all-cause or cardiovascular mortality. Additional trials in CKD stage 5D are unlikely to change our confidence in the treatment effects of cinacalcet in this population. PMID- 23637582 TI - Lifespan differences in hematopoietic stem cells are due to imperfect repair and unstable mean-reversion. AB - The life-long supply of blood cells depends on the long-term function of hematopoietic stem cells (HSCs). HSCs are functionally defined by their multi potency and self-renewal capacity. Because of their self-renewal capacity, HSCs were thought to have indefinite lifespans. However, there is increasing evidence that genetically identical HSCs differ in lifespan and that the lifespan of a HSC is predetermined and HSC-intrinsic. Lifespan is here defined as the time a HSC gives rise to all mature blood cells. This raises the intriguing question: what controls the lifespan of HSCs within the same animal, exposed to the same environment? We present here a new model based on reliability theory to account for the diversity of lifespans of HSCs. Using clonal repopulation experiments and computational-mathematical modeling, we tested how small-scale, molecular level, failures are dissipated at the HSC population level. We found that the best fit of the experimental data is provided by a model, where the repopulation failure kinetics of each HSC are largely anti-persistent, or mean-reverting, processes. Thus, failure rates repeatedly increase during population-wide division events and are counteracted and decreased by repair processes. In the long-run, a crossover from anti-persistent to persistent behavior occurs. The cross-over is due to a slow increase in the mean failure rate of self-renewal and leads to rapid clonal extinction. This suggests that the repair capacity of HSCs is self limiting. Furthermore, we show that the lifespan of each HSC depends on the amplitudes and frequencies of fluctuations in the failure rate kinetics. Shorter and longer lived HSCs differ significantly in their pre-programmed ability to dissipate perturbations. A likely interpretation of these findings is that the lifespan of HSCs is determined by preprogrammed differences in repair capacity. PMID- 23637583 TI - Cleavage entropy as quantitative measure of protease specificity. AB - A purely information theory-guided approach to quantitatively characterize protease specificity is established. We calculate an entropy value for each protease subpocket based on sequences of cleaved substrates extracted from the MEROPS database. We compare our results with known subpocket specificity profiles for individual proteases and protease groups (e.g. serine proteases, metallo proteases) and reflect them quantitatively. Summation of subpocket-wise cleavage entropy contributions yields a measure for overall protease substrate specificity. This total cleavage entropy allows ranking of different proteases with respect to their specificity, separating unspecific digestive enzymes showing high total cleavage entropy from specific proteases involved in signaling cascades. The development of a quantitative cleavage entropy score allows an unbiased comparison of subpocket-wise and overall protease specificity. Thus, it enables assessment of relative importance of physicochemical and structural descriptors in protease recognition. We present an exemplary application of cleavage entropy in tracing substrate specificity in protease evolution. This highlights the wide range of substrate promiscuity within homologue proteases and hence the heavy impact of a limited number of mutations on individual substrate specificity. PMID- 23637585 TI - Biomarker discovery by sparse canonical correlation analysis of complex clinical phenotypes of tuberculosis and malaria. AB - Biomarker discovery aims to find small subsets of relevant variables in 'omics data that correlate with the clinical syndromes of interest. Despite the fact that clinical phenotypes are usually characterized by a complex set of clinical parameters, current computational approaches assume univariate targets, e.g. diagnostic classes, against which associations are sought for. We propose an approach based on asymmetrical sparse canonical correlation analysis (SCCA) that finds multivariate correlations between the 'omics measurements and the complex clinical phenotypes. We correlated plasma proteomics data to multivariate overlapping complex clinical phenotypes from tuberculosis and malaria datasets. We discovered relevant 'omic biomarkers that have a high correlation to profiles of clinical measurements and are remarkably sparse, containing 1.5-3% of all 'omic variables. We show that using clinical view projections we obtain remarkable improvements in diagnostic class prediction, up to 11% in tuberculosis and up to 5% in malaria. Our approach finds proteomic-biomarkers that correlate with complex combinations of clinical-biomarkers. Using the clinical-biomarkers improves the accuracy of diagnostic class prediction while not requiring the measurement plasma proteomic profiles of each subject. Our approach makes it feasible to use omics' data to build accurate diagnostic algorithms that can be deployed to community health centres lacking the expensive 'omics measurement capabilities. PMID- 23637584 TI - Phosphorylation of the retinoic acid receptor alpha induces a mechanical allosteric regulation and changes in internal dynamics. AB - Nuclear receptor proteins constitute a superfamily of proteins that function as ligand dependent transcription factors. They are implicated in the transcriptional cascades underlying many physiological phenomena, such as embryogenesis, cell growth and differentiation, and apoptosis, making them one of the major signal transduction paradigms in metazoans. Regulation of these receptors occurs through the binding of hormones, and in the case of the retinoic acid receptor (RAR), through the binding of retinoic acid (RA). In addition to this canonical scenario of RAR activity, recent discoveries have shown that RAR regulation also occurs as a result of phosphorylation. In fact, RA induces non genomic effects, such as the activation of kinase signaling pathways, resulting in the phosphorylation of several targets including RARs themselves. In the case of RARalpha, phosphorylation of Ser369 located in loop L9-10 of the ligand binding domain leads to an increase in the affinity for the protein cyclin H, which is part of the Cdk-activating kinase complex of the general transcription factor TFIIH. The cyclin H binding site in RARalpha is situated more than 40 A from the phosphorylated serine. Using molecular dynamics simulations of the unphosphorylated and phosphorylated forms of the receptor RARalpha, we analyzed the structural implications of receptor phosphorylation, which led to the identification of a structural mechanism for the allosteric coupling between the two remote sites of interest. The results show that phosphorylation leads to a reorganization of a local salt bridge network, which induces changes in helix extension and orientation that affects the cyclin H binding site. This results in changes in conformation and flexibility of the latter. The high conservation of the residues implicated in this signal transduction suggests a mechanism that could be applied to other nuclear receptor proteins. PMID- 23637586 TI - Malaria's missing number: calculating the human component of R0 by a within-host mechanistic model of Plasmodium falciparum infection and transmission. AB - Human infection by malarial parasites of the genus Plasmodium begins with the bite of an infected Anopheles mosquito. Current estimates place malaria mortality at over 650,000 individuals each year, mostly in African children. Efforts to reduce disease burden can benefit from the development of mathematical models of disease transmission. To date, however, comprehensive modeling of the parameters defining human infectivity to mosquitoes has remained elusive. Here, we describe a mechanistic within-host model of Plasmodium falciparum infection in humans and pathogen transmission to the mosquito vector. Our model incorporates the entire parasite lifecycle, including the intra-erythrocytic asexual forms responsible for disease, the onset of symptoms, the development and maturation of intra erythrocytic gametocytes that are transmissible to Anopheles mosquitoes, and human-to-mosquito infectivity. These model components were parameterized from malaria therapy data and other studies to simulate individual infections, and the ensemble of outputs was found to reproduce the full range of patient responses to infection. Using this model, we assessed human infectivity over the course of untreated infections and examined the effects in relation to transmission intensity, expressed by the basic reproduction number R0 (defined as the number of secondary cases produced by a single typical infection in a completely susceptible population). Our studies predict that net human-to-mosquito infectivity from a single non-immune individual is on average equal to 32 fully infectious days. This estimate of mean infectivity is equivalent to calculating the human component of malarial R0 . We also predict that mean daily infectivity exceeds five percent for approximately 138 days. The mechanistic framework described herein, made available as stand-alone software, will enable investigators to conduct detailed studies into theories of malaria control, including the effects of drug treatment and drug resistance on transmission. PMID- 23637587 TI - Semi-automated 3D leaf reconstruction and analysis of trichome patterning from light microscopic images. AB - Trichomes are leaf hairs that are formed by single cells on the leaf surface. They are known to be involved in pathogen resistance. Their patterning is considered to emerge from a field of initially equivalent cells through the action of a gene regulatory network involving trichome fate promoting and inhibiting factors. For a quantitative analysis of single and double mutants or the phenotypic variation of patterns in different ecotypes, it is imperative to statistically evaluate the pattern reliably on a large number of leaves. Here we present a method that enables the analysis of trichome patterns at early developmental leaf stages and the automatic analysis of various spatial parameters. We focus on the most challenging young leaf stages that require the analysis in three dimensions, as the leaves are typically not flat. Our software TrichEratops reconstructs 3D surface models from 2D stacks of conventional light microscope pictures. It allows the GUI-based annotation of different stages of trichome development, which can be analyzed with respect to their spatial distribution to capture trichome patterning events. We show that 3D modeling removes biases of simpler 2D models and that novel trichome patterning features increase the sensitivity for inter-accession comparisons. PMID- 23637588 TI - Learning multisensory integration and coordinate transformation via density estimation. AB - Sensory processing in the brain includes three key operations: multisensory integration-the task of combining cues into a single estimate of a common underlying stimulus; coordinate transformations-the change of reference frame for a stimulus (e.g., retinotopic to body-centered) effected through knowledge about an intervening variable (e.g., gaze position); and the incorporation of prior information. Statistically optimal sensory processing requires that each of these operations maintains the correct posterior distribution over the stimulus. Elements of this optimality have been demonstrated in many behavioral contexts in humans and other animals, suggesting that the neural computations are indeed optimal. That the relationships between sensory modalities are complex and plastic further suggests that these computations are learned-but how? We provide a principled answer, by treating the acquisition of these mappings as a case of density estimation, a well-studied problem in machine learning and statistics, in which the distribution of observed data is modeled in terms of a set of fixed parameters and a set of latent variables. In our case, the observed data are unisensory-population activities, the fixed parameters are synaptic connections, and the latent variables are multisensory-population activities. In particular, we train a restricted Boltzmann machine with the biologically plausible contrastive-divergence rule to learn a range of neural computations not previously demonstrated under a single approach: optimal integration; encoding of priors; hierarchical integration of cues; learning when not to integrate; and coordinate transformation. The model makes testable predictions about the nature of multisensory representations. PMID- 23637589 TI - The evolution of collective restraint: policing and obedience among non conjugative plasmids. AB - The repression of competition by mechanisms of policing is now recognized as a major force in the maintenance of cooperation. General models on the evolution of policing have focused on the interplay between individual competitiveness and mutual policing, demonstrating a positive relationship between within-group diversity and levels of policing. We expand this perspective by investigating what is possibly the simplest example of reproductive policing: copy number control (CNC) among non-conjugative plasmids, a class of extra-chromosomal vertically transmitted molecular symbionts of bacteria. Through the formulation and analysis of a multi-scale dynamical model, we show that the establishment of stable reproductive restraint among plasmids requires the co-evolution of two fundamental plasmid traits: policing, through the production of plasmid-coded trans-acting replication inhibitors, and obedience, expressed as the binding affinity of plasmid-specific targets to those inhibitors. We explain the intrinsic replication instabilities that arise in the absence of policing and we show how these instabilities are resolved by the evolution of copy number control. Increasing levels of policing and obedience lead to improvements in group performance due to tighter control of local population size (plasmid copy number), delivering benefits both to plasmids, by reducing the risk of segregational loss and to the plasmid-host partnership, by increasing the rate of cell reproduction, and therefore plasmid vertical transmission. PMID- 23637590 TI - Human germline antibody gene segments encode polyspecific antibodies. AB - Structural flexibility in germline gene-encoded antibodies allows promiscuous binding to diverse antigens. The binding affinity and specificity for a particular epitope typically increase as antibody genes acquire somatic mutations in antigen-stimulated B cells. In this work, we investigated whether germline gene-encoded antibodies are optimal for polyspecificity by determining the basis for recognition of diverse antigens by antibodies encoded by three VH gene segments. Panels of somatically mutated antibodies encoded by a common VH gene, but each binding to a different antigen, were computationally redesigned to predict antibodies that could engage multiple antigens at once. The Rosetta multi state design process predicted antibody sequences for the entire heavy chain variable region, including framework, CDR1, and CDR2 mutations. The predicted sequences matched the germline gene sequences to a remarkable degree, revealing by computational design the residues that are predicted to enable polyspecificity, i.e., binding of many unrelated antigens with a common sequence. The process thereby reverses antibody maturation in silico. In contrast, when designing antibodies to bind a single antigen, a sequence similar to that of the mature antibody sequence was returned, mimicking natural antibody maturation in silico. We demonstrated that the Rosetta computational design algorithm captures important aspects of antibody/antigen recognition. While the hypervariable region CDR3 often mediates much of the specificity of mature antibodies, we identified key positions in the VH gene encoding CDR1, CDR2, and the immunoglobulin framework that are critical contributors for polyspecificity in germline antibodies. Computational design of antibodies capable of binding multiple antigens may allow the rational design of antibodies that retain polyspecificity for diverse epitope binding. PMID- 23637592 TI - OncomiR addiction is generated by a miR-155 feedback loop in Theileria transformed leukocytes. AB - The intracellular parasite Theileria is the only eukaryote known to transform its mammalian host cells. We investigated the host mechanisms involved in parasite induced transformation phenotypes. Tumour progression is a multistep process, yet 'oncogene addiction' implies that cancer cell growth and survival can be impaired by inactivating a single gene, offering a rationale for targeted molecular therapies. Furthermore, feedback loops often act as key regulatory hubs in tumorigenesis. We searched for microRNAs involved in addiction to regulatory loops in leukocytes infected with Theileria parasites. We show that Theileria transformation involves induction of the host bovine oncomiR miR-155, via the c Jun transcription factor and AP-1 activity. We identified a novel miR-155 target, DET1, an evolutionarily-conserved factor involved in c-Jun ubiquitination. We show that miR-155 expression led to repression of DET1 protein, causing stabilization of c-Jun and driving the promoter activity of the BIC transcript containing miR-155. This positive feedback loop is critical to maintain the growth and survival of Theileria-infected leukocytes; transformation is reversed by inhibiting AP-1 activity or miR-155 expression. This is the first demonstration that Theileria parasites induce the expression of host non-coding RNAs and highlights the importance of a novel feedback loop in maintaining the proliferative phenotypes induced upon parasite infection. Hence, parasite infection drives epigenetic rewiring of the regulatory circuitry of host leukocytes, placing miR-155 at the crossroads between infection, regulatory circuits and transformation. PMID- 23637593 TI - Immune regulation during helminth infections. PMID- 23637594 TI - Salmonella uses energy taxis to benefit from intestinal inflammation. AB - Chemotaxis enhances the fitness of Salmonella enterica serotype Typhimurium (S. Typhimurium) during colitis. However, the chemotaxis receptors conferring this fitness advantage and their cognate signals generated during inflammation remain unknown. Here we identify respiratory electron acceptors that are generated in the intestinal lumen as by-products of the host inflammatory response as in vivo signals for methyl-accepting chemotaxis proteins (MCPs). Three MCPs, including Trg, Tsr and Aer, enhanced the fitness of S. Typhimurium in a mouse colitis model. Aer mediated chemotaxis towards electron acceptors (energy taxis) in vitro and required tetrathionate respiration to confer a fitness advantage in vivo. Tsr mediated energy taxis towards nitrate but not towards tetrathionate in vitro and required nitrate respiration to confer a fitness advantage in vivo. These data suggest that the energy taxis receptors Tsr and Aer respond to distinct in vivo signals to confer a fitness advantage upon S. Typhimurium during inflammation by enabling this facultative anaerobic pathogen to seek out favorable spatial niches containing host-derived electron acceptors that boost its luminal growth. PMID- 23637596 TI - Defining the conformational features of anchorless, poorly neuroinvasive prions. AB - Infectious prions cause diverse clinical signs and form an extraordinary range of structures, from amorphous aggregates to fibrils. How the conformation of a prion dictates the disease phenotype remains unclear. Mice expressing GPI-anchorless or GPI-anchored prion protein exposed to the same infectious prion develop fibrillar or nonfibrillar aggregates, respectively, and show a striking divergence in the disease pathogenesis. To better understand how a prion's physical properties govern the pathogenesis, infectious anchorless prions were passaged in mice expressing anchorless prion protein and the resulting prions were biochemically characterized. Serial passage of anchorless prions led to a significant decrease in the incubation period to terminal disease and altered the biochemical properties, consistent with a transmission barrier effect. After an intraperitoneal exposure, anchorless prions were only weakly neuroinvasive, as prion plaques rarely occurred in the brain yet were abundant in extracerebral sites such as heart and adipose tissue. Anchorless prions consistently showed very high stability in chaotropes or when heated in SDS, and were highly resistant to enzyme digestion. Consistent with the results in mice, anchorless prions from a human patient were also highly stable in chaotropes. These findings reveal that anchorless prions consist of fibrillar and highly stable conformers. The additional finding from our group and others that both anchorless and anchored prion fibrils are poorly neuroinvasive strengthens the hypothesis that a fibrillar prion structure impedes efficient CNS invasion. PMID- 23637595 TI - Puf mediates translation repression of transmission-blocking vaccine candidates in malaria parasites. AB - Translational control of gene expression plays an essential role in development. In malaria parasites, translational regulation is critical during the development of specialized transition stages between the vertebrate host and mosquito vector. Here we show that a Pumilio/FBF (Puf) family RNA-binding protein, PfPuf2, is required for the translation repression of a number of transcripts in gametocytes including two genes encoding the transmission-blocking vaccine candidates Pfs25 and Pfs28. Whereas studies to date support a paradigm of Puf-mediated translation regulation through 3' untranslated regions (UTRs) of target mRNAs, this study, for the first time, identifies a functional Puf-binding element (PBE) in the 5'UTR of pfs25. We provide both in vitro and in vivo evidence to demonstrate that PfPuf2 binds to the PBEs in pfs25 and pfs28 to mediate translation repression. This finding provides a renewed view of Pufs as versatile translation regulators and sheds light on their functions in the development of lower branches of eukaryotes. PMID- 23637597 TI - A mechanistic paradigm for broad-spectrum antivirals that target virus-cell fusion. AB - LJ001 is a lipophilic thiazolidine derivative that inhibits the entry of numerous enveloped viruses at non-cytotoxic concentrations (IC50 <= 0.5 uM), and was posited to exploit the physiological difference between static viral membranes and biogenic cellular membranes. We now report on the molecular mechanism that results in LJ001's specific inhibition of virus-cell fusion. The antiviral activity of LJ001 was light-dependent, required the presence of molecular oxygen, and was reversed by singlet oxygen ((1)O2) quenchers, qualifying LJ001 as a type II photosensitizer. Unsaturated phospholipids were the main target modified by LJ001-generated (1)O2. Hydroxylated fatty acid species were detected in model and viral membranes treated with LJ001, but not its inactive molecular analog, LJ025. (1)O2-mediated allylic hydroxylation of unsaturated phospholipids leads to a trans-isomerization of the double bond and concurrent formation of a hydroxyl group in the middle of the hydrophobic lipid bilayer. LJ001-induced (1)O2 mediated lipid oxidation negatively impacts on the biophysical properties of viral membranes (membrane curvature and fluidity) critical for productive virus cell membrane fusion. LJ001 did not mediate any apparent damage on biogenic cellular membranes, likely due to multiple endogenous cytoprotection mechanisms against phospholipid hydroperoxides. Based on our understanding of LJ001's mechanism of action, we designed a new class of membrane-intercalating photosensitizers to overcome LJ001's limitations for use as an in vivo antiviral agent. Structure activity relationship (SAR) studies led to a novel class of compounds (oxazolidine-2,4-dithiones) with (1) 100-fold improved in vitro potency (IC50<10 nM), (2) red-shifted absorption spectra (for better tissue penetration), (3) increased quantum yield (efficiency of (1)O2 generation), and (4) 10-100-fold improved bioavailability. Candidate compounds in our new series moderately but significantly (p<=0.01) delayed the time to death in a murine lethal challenge model of Rift Valley Fever Virus (RVFV). The viral membrane may be a viable target for broad-spectrum antivirals that target virus-cell fusion. PMID- 23637598 TI - Genetic control of conventional and pheromone-stimulated biofilm formation in Candida albicans. AB - Candida albicans can stochastically switch between two phenotypes, white and opaque. Opaque cells are the sexually competent form of C. albicans and therefore undergo efficient polarized growth and mating in the presence of pheromone. In contrast, white cells cannot mate, but are induced - under a specialized set of conditions - to form biofilms in response to pheromone. In this work, we compare the genetic regulation of such "pheromone-stimulated" biofilms with that of "conventional" C. albicans biofilms. In particular, we examined a network of six transcriptional regulators (Bcr1, Brg1, Efg1, Tec1, Ndt80, and Rob1) that mediate conventional biofilm formation for their potential roles in pheromone-stimulated biofilm formation. We show that four of the six transcription factors (Bcr1, Brg1, Rob1, and Tec1) promote formation of both conventional and pheromone stimulated biofilms, indicating they play general roles in cell cohesion and biofilm development. In addition, we identify the master transcriptional regulator of pheromone-stimulated biofilms as C. albicans Cph1, ortholog of Saccharomyces cerevisiae Ste12. Cph1 regulates mating in C. albicans opaque cells, and here we show that Cph1 is also essential for pheromone-stimulated biofilm formation in white cells. In contrast, Cph1 is dispensable for the formation of conventional biofilms. The regulation of pheromone- stimulated biofilm formation was further investigated by transcriptional profiling and genetic analyses. These studies identified 196 genes that are induced by pheromone signaling during biofilm formation. One of these genes, HGC1, is shown to be required for both conventional and pheromone-stimulated biofilm formation. Taken together, these observations compare and contrast the regulation of conventional and pheromone-stimulated biofilm formation in C. albicans, and demonstrate that Cph1 is required for the latter, but not the former. PMID- 23637599 TI - IgG subclass and heavy chain domains contribute to binding and protection by mAbs to the poly gamma-D-glutamic acid capsular antigen of Bacillus anthracis. AB - Bacterial capsules are common targets for antibody-mediated immunity. The capsule of Bacillus anthracis is unusual among capsules because it is composed of a polymer of poly-gamma-d-glutamic acid (gammadPGA). We previously generated murine IgG3 monoclonal antibodies (mAbs) to gammadPGA that were protective in a murine model of pulmonary anthrax. IgG3 antibodies are characteristic of the murine response to polysaccharide antigens. The goal of the present study was to produce subclass switch variants of the gammadPGA mAbs (IgG3 -> IgG1 -> IgG2b -> IgG2a) and assess the contribution of subclass to antibody affinity and protection. Subclass switch antibodies had identical variable regions but differed in their heavy chains. The results showed that a switch from the protective IgG3 to IgG1, IgG2b or IgG2a was accompanied by i) a loss of protective activity ii) a change in mAb binding to the capsular matrix, and iii) a loss of affinity. These results identify a role for the heavy chain constant region in mAb binding. Hybrid mAbs were constructed in which the CH1, CH2 or CH3 heavy chain constant domains from a non-protective, low binding IgG2b mAb were swapped into the protective IgG3 mAb. The IgG3 mAb that contained the CH1 domain from IgG2b showed no loss of affinity or protection. In contrast, swapping the CH2 or CH3 domains from IgG2b into IgG3 produced a reduction in affinity and a loss of protection. These studies identify a role for the constant region of IgG heavy chains in affinity and protection against an encapsulated bacterial pathogen. PMID- 23637600 TI - Microbes bind complement inhibitor factor H via a common site. AB - To cause infections microbes need to evade host defense systems, one of these being the evolutionarily old and important arm of innate immunity, the alternative pathway of complement. It can attack all kinds of targets and is tightly controlled in plasma and on host cells by plasma complement regulator factor H (FH). FH binds simultaneously to host cell surface structures such as heparin or glycosaminoglycans via domain 20 and to the main complement opsonin C3b via domain 19. Many pathogenic microbes protect themselves from complement by recruiting host FH. We analyzed how and why different microbes bind FH via domains 19-20 (FH19-20). We used a selection of FH19-20 point mutants to reveal the binding sites of several microbial proteins and whole microbes (Haemophilus influenzae, Bordetella pertussis, Pseudomonas aeruginosa, Streptococcus pneumonia, Candida albicans, Borrelia burgdorferi, and Borrelia hermsii). We show that all studied microbes use the same binding region located on one side of domain 20. Binding of FH to the microbial proteins was inhibited with heparin showing that the common microbial binding site overlaps with the heparin site needed for efficient binding of FH to host cells. Surprisingly, the microbial proteins enhanced binding of FH19-20 to C3b and down-regulation of complement activation. We show that this is caused by formation of a tripartite complex between the microbial protein, FH, and C3b. In this study we reveal that seven microbes representing different phyla utilize a common binding site on the domain 20 of FH for complement evasion. Binding via this site not only mimics the glycosaminoglycans of the host cells, but also enhances function of FH on the microbial surfaces via the novel mechanism of tripartite complex formation. This is a unique example of convergent evolution resulting in enhanced immune evasion of important pathogens via utilization of a "superevasion site." PMID- 23637601 TI - Accelerated in vivo proliferation of memory phenotype CD4+ T-cells in human HIV-1 infection irrespective of viral chemokine co-receptor tropism. AB - CD4(+) T-cell loss is the hallmark of HIV-1 infection. CD4 counts fall more rapidly in advanced disease when CCR5-tropic viral strains tend to be replaced by X4-tropic viruses. We hypothesized: (i) that the early dominance of CCR5-tropic viruses results from faster turnover rates of CCR5(+) cells, and (ii) that X4 tropic strains exert greater pathogenicity by preferentially increasing turnover rates within the CXCR4(+) compartment. To test these hypotheses we measured in vivo turnover rates of CD4(+) T-cell subpopulations sorted by chemokine receptor expression, using in vivo deuterium-glucose labeling. Deuterium enrichment was modeled to derive in vivo proliferation (p) and disappearance (d*) rates which were related to viral tropism data. 13 healthy controls and 13 treatment-naive HIV-1-infected subjects (CD4 143-569 cells/ul) participated. CCR5-expression defined a CD4(+) subpopulation of predominantly CD45R0(+) memory cells with accelerated in vivo proliferation (p = 2.50 vs 1.60%/d, CCR5(+) vs CCR5(-); healthy controls; P<0.01). Conversely, CXCR4 expression defined CD4(+) T-cells (predominantly CD45RA(+) naive cells) with low turnover rates. The dominant effect of HIV infection was accelerated turnover of CCR5(+)CD45R0(+)CD4(+) memory T-cells (p = 5.16 vs 2.50%/d, HIV vs controls; P<0.05), naive cells being relatively unaffected. Similar patterns were observed whether the dominant circulating HIV-1 strain was R5-tropic (n = 9) or X4-tropic (n = 4). Although numbers were small, X4-tropic viruses did not appear to specifically drive turnover of CXCR4-expressing cells (p = 0.54 vs 0.72 vs 0.44%/d in control, R5 tropic, and X4-tropic groups respectively). Our data are most consistent with models in which CD4(+) T-cell loss is primarily driven by non-specific immune activation. PMID- 23637602 TI - Development of a highly protective combination monoclonal antibody therapy against Chikungunya virus. AB - Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK 263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar(-/-) ) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans. PMID- 23637603 TI - Mutations in FLS2 Ser-938 dissect signaling activation in FLS2-mediated Arabidopsis immunity. AB - Flagellin-sensing 2 (FLS2) is a leucine-rich repeat/transmembrane domain/protein kinase (LRR-RLK) that is the plant receptor for bacterial flagellin or the flagellin-derived flg22 peptide. Previous work has shown that after flg22 binding, FLS2 releases BIK1 kinase and homologs and associates with BAK1 kinase, and that FLS2 kinase activity is critical for FLS2 function. However, the detailed mechanisms for activation of FLS2 signaling remain unclear. The present study initially identified multiple FLS2 in vitro phosphorylation sites and found that Serine-938 is important for FLS2 function in vivo. FLS2-mediated immune responses are abolished in transgenic plants expressing FLS2(S938A), while the acidic phosphomimic mutants FLS2(S938D) and FLS2(S938E) conferred responses similar to wild-type FLS2. FLS2-BAK1 association and FLS2-BIK1 disassociation after flg22 exposure still occur with FLS2(S938A), demonstrating that flg22 induced BIK1 release and BAK1 binding are not sufficient for FLS2 activity, and that Ser-938 controls other aspects of FLS2 activity. Purified BIK1 still phosphorylated purified FLS2(S938A) and FLS2(S938D) mutant kinase domains in vitro. Phosphorylation of BIK1 and homologs after flg22 exposure was disrupted in transgenic Arabidopsis thaliana plants expressing FLS2(S938A) or FLS2(D997A) (a kinase catalytic site mutant), but was normally induced in FLS2(S938D) plants. BIK1 association with FLS2 required a kinase-active FLS2, but FLS2-BAK1 association did not. Hence FLS2-BIK1 dissociation and FLS2-BAK1 association are not sufficient for FLS2-mediated defense activation, but the proposed FLS2 phosphorylation site Ser-938 and FLS2 kinase activity are needed both for overall defense activation and for appropriate flg22-stimulated phosphorylation of BIK1 and homologs. PMID- 23637604 TI - Differential adaptation of Candida albicans in vivo modulates immune recognition by dectin-1. AB - The beta-glucan receptor Dectin-1 is a member of the C-type lectin family and functions as an innate pattern recognition receptor in antifungal immunity. In both mouse and man, Dectin-1 has been found to play an essential role in controlling infections with Candida albicans, a normally commensal fungus in man which can cause superficial mucocutaneous infections as well as life-threatening invasive diseases. Here, using in vivo models of infection, we show that the requirement for Dectin-1 in the control of systemic Candida albicans infections is fungal strain-specific; a phenotype that only becomes apparent during infection and cannot be recapitulated in vitro. Transcript analysis revealed that this differential requirement for Dectin-1 is due to variable adaptation of C. albicans strains in vivo, and that this results in substantial differences in the composition and nature of their cell walls. In particular, we established that differences in the levels of cell-wall chitin influence the role of Dectin-1, and that these effects can be modulated by antifungal drug treatment. Our results therefore provide substantial new insights into the interaction between C. albicans and the immune system and have significant implications for our understanding of susceptibility and treatment of human infections with this pathogen. PMID- 23637605 TI - Hepatitis C virus pathogen associated molecular pattern (PAMP) triggers production of lambda-interferons by human plasmacytoid dendritic cells. AB - Plasmacytoid Dendritic Cells (pDCs) represent a key immune cell in the defense against viruses. Through pattern recognition receptors (PRRs), these cells detect viral pathogen associated molecular patterns (PAMPs) and initiate an Interferon (IFN) response. pDCs produce the antiviral IFNs including the well-studied Type I and the more recently described Type III. Recent genome wide association studies (GWAS) have implicated Type III IFNs in HCV clearance. We examined the IFN response induced in a pDC cell line and ex vivo human pDCs by a region of the HCV genome referred to as the HCV PAMP. This RNA has been shown previously to be immunogenic in hepatocytes, whereas the conserved X-region RNA is not. We show that in response to the HCV PAMP, pDC-GEN2.2 cells upregulate and secrete Type III (in addition to Type I) IFNs and upregulate PRR genes and proteins. We also demonstrate that the recognition of this RNA is dependent on RIG-I-like Receptors (RLRs) and Toll-like Receptors (TLRs), challenging the dogma that RLRs are dispensable in pDCs. The IFNs produced by these cells in response to the HCV PAMP also control HCV replication in vitro. These data are recapitulated in ex vivo pDCs isolated from healthy donors. Together, our data shows that pDCs respond robustly to HCV RNA to make Type III Interferons that control viral replication. This may represent a novel therapeutic strategy for the treatment of HCV. PMID- 23637606 TI - A single amino acid substitution in the group 1 Trypanosoma brucei gambiense haptoglobin-hemoglobin receptor abolishes TLF-1 binding. AB - Critical to human innate immunity against African trypanosomes is a minor subclass of human high-density lipoproteins, termed Trypanosome Lytic Factor-1 (TLF-1). This primate-specific molecule binds to a haptoglobin-hemoglobin receptor (HpHbR) on the surface of susceptible trypanosomes, initiating a lytic pathway. Group 1 Trypanosoma brucei gambiense causes human African Trypanosomiasis (HAT), escaping TLF-1 killing due to reduced uptake. Previously, we found that group 1 T. b. gambiense HpHbR (TbgHpHbR) mRNA levels were greatly reduced and the gene contained substitutions within the open reading frame. Here we show that a single, highly conserved amino acid in the TbgHpHbR ablates high affinity TLF-1 binding and subsequent endocytosis, thus evading TLF-1 killing. In addition, we show that over-expression of TbgHpHbR failed to rescue TLF-1 susceptibility. These findings suggest that the single substitution present in the TbgHpHbR directly contributes to the reduced uptake and resistance to TLF-1 seen in these important human pathogens. PMID- 23637607 TI - Trypanosome infection establishment in the tsetse fly gut is influenced by microbiome-regulated host immune barriers. AB - Tsetse flies (Glossina spp.) vector pathogenic African trypanosomes, which cause sleeping sickness in humans and nagana in domesticated animals. Additionally, tsetse harbors 3 maternally transmitted endosymbiotic bacteria that modulate their host's physiology. Tsetse is highly resistant to infection with trypanosomes, and this phenotype depends on multiple physiological factors at the time of challenge. These factors include host age, density of maternally-derived trypanolytic effector molecules present in the gut, and symbiont status during development. In this study, we investigated the molecular mechanisms that result in tsetse's resistance to trypanosomes. We found that following parasite challenge, young susceptible tsetse present a highly attenuated immune response. In contrast, mature refractory flies express higher levels of genes associated with humoral (attacin and pgrp-lb) and epithelial (inducible nitric oxide synthase and dual oxidase) immunity. Additionally, we discovered that tsetse must harbor its endogenous microbiome during intrauterine larval development in order to present a parasite refractory phenotype during adulthood. Interestingly, mature aposymbiotic flies (Gmm(Apo)) present a strong immune response earlier in the infection process than do WT flies that harbor symbiotic bacteria throughout their entire lifecycle. However, this early response fails to confer significant resistance to trypanosomes. Gmm(Apo) adults present a structurally compromised peritrophic matrix (PM), which lines the fly midgut and serves as a physical barrier that separates luminal contents from immune responsive epithelial cells. We propose that the early immune response we observe in Gmm(Apo) flies following parasite challenge results from the premature exposure of gut epithelia to parasite-derived immunogens in the absence of a robust PM. Thus, tsetse's PM appears to regulate the timing of host immune induction following parasite challenge. Our results document a novel finding, which is the existence of a positive correlation between tsetse's larval microbiome and the integrity of the emerging adult PM gut immune barrier. PMID- 23637609 TI - The serine phosphatase SerB of Porphyromonas gingivalis suppresses IL-8 production by dephosphorylation of NF-kappaB RelA/p65. AB - Porphyromonas gingivalis is a major pathogen in severe and chronic manifestations of periodontal disease, which is one of the most common infections of humans. A central feature of P. gingivalis pathogenicity is dysregulation of innate immunity at the gingival epithelial interface, including suppression of IL-8 production by epithelial cells. NF-kappaB is a transcriptional regulator that controls important aspects of innate immune responses, and NF-kappaB RelA/p65 homodimers regulate transcription of IL8. Phosphorylation of the NF-kappaB p65 subunit protein on the serine 536 residue affects nuclear translocation and transcription of target genes. Here we show that SerB, a haloacid dehalogenase (HAD) family serine phosphatase secreted by P. gingivalis, is produced intracellularly and can specifically dephosphorylate S536 of p65 in gingival epithelial cells. A P. gingivalis mutant lacking SerB was impaired in dephosphorylation of p65 S536, and ectopically expressed SerB bound to p65 and co localized with p65 in the cytoplasm. Ectopic expression of SerB also resulted in dephosphorylation of p65 with reduced nuclear translocation in TNF-alpha stimulated epithelial cells. In contrast, the p105/50 subunit of NF-kappaB was unaffected by SerB. Co-expression of a constitutively active p65 mutant (S536D) relieved inhibition of nuclear translocation. Both the activity of the IL8 promoter and production of IL-8 were diminished by SerB. Deletion and truncation mutants of SerB lacking the HAD-family enzyme motifs of SerB were unable to dephosphorylate p65, inhibit nuclear translocation or abrogate IL8 transcription. Specific dephosphorylation of NF-kappaB p65 S536 by SerB, and consequent inhibition of nuclear translocation, provides the molecular basis for a bacterial strategy to manipulate host inflammatory pathways and repress innate immunity at mucosal surfaces. PMID- 23637608 TI - Factor H binds to the hypervariable region of many Streptococcus pyogenes M proteins but does not promote phagocytosis resistance or acute virulence. AB - Many pathogens express a surface protein that binds the human complement regulator factor H (FH), as first described for Streptococcus pyogenes and the antiphagocytic M6 protein. It is commonly assumed that FH recruited to an M protein enhances virulence by protecting the bacteria against complement deposition and phagocytosis, but the role of FH-binding in S. pyogenes pathogenesis has remained unclear and controversial. Here, we studied seven purified M proteins for ability to bind FH and found that FH binds to the M5, M6 and M18 proteins but not the M1, M3, M4 and M22 proteins. Extensive immunochemical analysis indicated that FH binds solely to the hypervariable region (HVR) of an M protein, suggesting that selection has favored the ability of certain HVRs to bind FH. These FH-binding HVRs could be studied as isolated polypeptides that retain ability to bind FH, implying that an FH-binding HVR represents a distinct ligand-binding domain. The isolated HVRs specifically interacted with FH among all human serum proteins, interacted with the same region in FH and showed species specificity, but exhibited little or no antigenic cross-reactivity. Although these findings suggested that FH recruited to an M protein promotes virulence, studies in transgenic mice did not demonstrate a role for bound FH during acute infection. Moreover, phagocytosis tests indicated that ability to bind FH is neither sufficient nor necessary for S. pyogenes to resist killing in whole human blood. While these data shed new light on the HVR of M proteins, they suggest that FH-binding may affect S. pyogenes virulence by mechanisms not assessed in currently used model systems. PMID- 23637611 TI - TIP48/Reptin and H2A.Z requirement for initiating chromatin remodeling in estrogen-activated transcription. AB - Histone variants, including histone H2A.Z, are incorporated into specific genomic sites and participate in transcription regulation. The role of H2A.Z at these sites remains poorly characterized. Our study investigates changes in the chromatin environment at the Cyclin D1 gene (CCND1) during transcriptional initiation in response to estradiol in estrogen receptor positive mammary tumour cells. We show that H2A.Z is present at the transcription start-site and downstream enhancer sequences of CCND1 when the gene is poorly transcribed. Stimulation of CCND1 expression required release of H2A.Z concomitantly from both these DNA elements. The AAA+ family members TIP48/reptin and the histone variant H2A.Z are required to remodel the chromatin environment at CCND1 as a prerequisite for binding of the estrogen receptor (ERalpha) in the presence of hormone. TIP48 promotes acetylation and exchange of H2A.Z, which triggers a dissociation of the CCND1 3' enhancer from the promoter, thereby releasing a repressive intragenic loop. This release then enables the estrogen receptor to bind to the CCND1 promoter. Our findings provide new insight into the priming of chromatin required for transcription factor access to their target sequence. Dynamic release of gene loops could be a rapid means to remodel chromatin and to stimulate transcription in response to hormones. PMID- 23637612 TI - ATP-dependent chromatin remodeling by Cockayne syndrome protein B and NAP1-like histone chaperones is required for efficient transcription-coupled DNA repair. AB - The Cockayne syndrome complementation group B (CSB) protein is essential for transcription-coupled DNA repair, and mutations in CSB are associated with Cockayne syndrome--a devastating disease with complex clinical features, including the appearance of premature aging, sun sensitivity, and numerous neurological and developmental defects. CSB belongs to the SWI2/SNF2 ATP dependent chromatin remodeler family, but the extent to which CSB remodels chromatin and whether this activity is utilized in DNA repair is unknown. Here, we show that CSB repositions nucleosomes in an ATP-dependent manner in vitro and that this activity is greatly enhanced by the NAP1-like histone chaperones, which we identify as new CSB-binding partners. By mapping functional domains and analyzing CSB derivatives, we demonstrate that chromatin remodeling by the combined activities of CSB and the NAP1-like chaperones is required for efficient transcription-coupled DNA repair. Moreover, we show that chromatin remodeling and repair protein recruitment mediated by CSB are separable activities. The collaboration that we observed between CSB and the NAP1-like histone chaperones adds a new dimension to our understanding of the ways in which ATP-dependent chromatin remodelers and histone chaperones can regulate chromatin structure. Taken together, the results of this study offer new insights into the functions of chromatin remodeling by CSB in transcription-coupled DNA repair as well as the underlying mechanisms of Cockayne syndrome. PMID- 23637613 TI - Six homeoproteins directly activate Myod expression in the gene regulatory networks that control early myogenesis. AB - In mammals, several genetic pathways have been characterized that govern engagement of multipotent embryonic progenitors into the myogenic program through the control of the key myogenic regulatory gene Myod. Here we demonstrate the involvement of Six homeoproteins. We first targeted into a Pax3 allele a sequence encoding a negative form of Six4 that binds DNA but cannot interact with essential Eya co-factors. The resulting embryos present hypoplasic skeletal muscles and impaired Myod activation in the trunk in the absence of Myf5/Mrf4. At the axial level, we further show that Myod is still expressed in compound Six1/Six4:Pax3 but not in Six1/Six4:Myf5 triple mutant embryos, demonstrating that Six1/4 participates in the Pax3-Myod genetic pathway. Myod expression and head myogenesis is preserved in Six1/Six4:Myf5 triple mutant embryos, illustrating that upstream regulators of Myod in different embryonic territories are distinct. We show that Myod regulatory regions are directly controlled by Six proteins and that, in the absence of Six1 and Six4, Six2 can compensate. PMID- 23637614 TI - Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality. AB - The ten-subunit transcription factor IIH (TFIIH) plays a crucial role in transcription and nucleotide excision repair (NER). Inactivating mutations in the smallest 8-kDa TFB5/TTDA subunit cause the neurodevelopmental progeroid repair syndrome trichothiodystrophy A (TTD-A). Previous studies have shown that TTDA is the only TFIIH subunit that appears not to be essential for NER, transcription, or viability. We studied the consequences of TTDA inactivation by generating a Ttda knock-out (Ttda(-/-) ) mouse-model resembling TTD-A patients. Unexpectedly, Ttda(-/-) mice were embryonic lethal. However, in contrast to full disruption of all other TFIIH subunits, viability of Ttda(-/-) cells was not affected. Surprisingly, Ttda(-/-) cells were completely NER deficient, contrary to the incomplete NER deficiency of TTD-A patient-derived cells. We further showed that TTD-A patient mutations only partially inactivate TTDA function, explaining the relatively mild repair phenotype of TTD-A cells. Moreover, Ttda(-/-) cells were also highly sensitive to oxidizing agents. These findings reveal an essential role of TTDA for life, nucleotide excision repair, and oxidative DNA damage repair and identify Ttda(-/-) cells as a unique class of TFIIH mutants. PMID- 23637616 TI - Insulators target active genes to transcription factories and polycomb-repressed genes to polycomb bodies. AB - Polycomb bodies are foci of Polycomb proteins in which different Polycomb target genes are thought to co-localize in the nucleus, looping out from their chromosomal context. We have shown previously that insulators, not Polycomb response elements (PREs), mediate associations among Polycomb Group (PcG) targets to form Polycomb bodies. Here we use live imaging and 3C interactions to show that transgenes containing PREs and endogenous PcG-regulated genes are targeted by insulator proteins to different nuclear structures depending on their state of activity. When two genes are repressed, they co-localize in Polycomb bodies. When both are active, they are targeted to transcription factories in a fashion dependent on Trithorax and enhancer specificity as well as the insulator protein CTCF. In the absence of CTCF, assembly of Polycomb bodies is essentially reduced to those representing genomic clusters of Polycomb target genes. The critical role of Trithorax suggests that stable association with a specialized transcription factory underlies the cellular memory of the active state. PMID- 23637615 TI - Rod monochromacy and the coevolution of cetacean retinal opsins. AB - Cetaceans have a long history of commitment to a fully aquatic lifestyle that extends back to the Eocene. Extant species have evolved a spectacular array of adaptations in conjunction with their deployment into a diverse array of aquatic habitats. Sensory systems are among those that have experienced radical transformations in the evolutionary history of this clade. In the case of vision, previous studies have demonstrated important changes in the genes encoding rod opsin (RH1), short-wavelength sensitive opsin 1 (SWS1), and long-wavelength sensitive opsin (LWS) in selected cetaceans, but have not examined the full complement of opsin genes across the complete range of cetacean families. Here, we report protein-coding sequences for RH1 and both color opsin genes (SWS1, LWS) from representatives of all extant cetacean families. We examine competing hypotheses pertaining to the timing of blue shifts in RH1 relative to SWS1 inactivation in the early history of Cetacea, and we test the hypothesis that some cetaceans are rod monochomats. Molecular evolutionary analyses contradict the "coastal" hypothesis, wherein SWS1 was pseudogenized in the common ancestor of Cetacea, and instead suggest that RH1 was blue-shifted in the common ancestor of Cetacea before SWS1 was independently knocked out in baleen whales (Mysticeti) and in toothed whales (Odontoceti). Further, molecular evidence implies that LWS was inactivated convergently on at least five occasions in Cetacea: (1) Balaenidae (bowhead and right whales), (2) Balaenopteroidea (rorquals plus gray whale), (3) Mesoplodon bidens (Sowerby's beaked whale), (4) Physeter macrocephalus (giant sperm whale), and (5) Kogia breviceps (pygmy sperm whale). All of these cetaceans are known to dive to depths of at least 100 m where the underwater light field is dim and dominated by blue light. The knockout of both SWS1 and LWS in multiple cetacean lineages renders these taxa rod monochromats, a condition previously unknown among mammalian species. PMID- 23637617 TI - Mouse oocyte methylomes at base resolution reveal genome-wide accumulation of non CpG methylation and role of DNA methyltransferases. AB - DNA methylation is an epigenetic modification that plays a crucial role in normal mammalian development, retrotransposon silencing, and cellular reprogramming. Although methylation mainly occurs on the cytosine in a CG site, non-CG methylation is prevalent in pluripotent stem cells, brain, and oocytes. We previously identified non-CG methylation in several CG-rich regions in mouse germinal vesicle oocytes (GVOs), but the overall distribution of non-CG methylation and the enzymes responsible for this modification are unknown. Using amplification-free whole-genome bisulfite sequencing, which can be used with minute amounts of DNA, we constructed the base-resolution methylome maps of GVOs, non-growing oocytes (NGOs), and mutant GVOs lacking the DNA methyltransferase Dnmt1, Dnmt3a, Dnmt3b, or Dnmt3L. We found that nearly two-thirds of all methylcytosines occur in a non-CG context in GVOs. The distribution of non-CG methylation closely resembled that of CG methylation throughout the genome and showed clear enrichment in gene bodies. Compared to NGOs, GVOs were over four times more methylated at non-CG sites, indicating that non-CG methylation accumulates during oocyte growth. Lack of Dnmt3a or Dnmt3L resulted in a global reduction in both CG and non-CG methylation, showing that non-CG methylation depends on the Dnmt3a-Dnmt3L complex. Dnmt3b was dispensable. Of note, lack of Dnmt1 resulted in a slight decrease in CG methylation, suggesting that this maintenance enzyme plays a role in non-dividing oocytes. Dnmt1 may act on CG sites that remain hemimethylated in the de novo methylation process. Our results provide a basis for understanding the mechanisms and significance of non-CG methylation in mammalian oocytes. PMID- 23637618 TI - Sex-differential selection and the evolution of X inactivation strategies. AB - X inactivation--the transcriptional silencing of one X chromosome copy per female somatic cell--is universal among therian mammals, yet the choice of which X to silence exhibits considerable variation among species. X inactivation strategies can range from strict paternally inherited X inactivation (PXI), which renders females haploid for all maternally inherited alleles, to unbiased random X inactivation (RXI), which equalizes expression of maternally and paternally inherited alleles in each female tissue. However, the underlying evolutionary processes that might account for this observed diversity of X inactivation strategies remain unclear. We present a theoretical population genetic analysis of X inactivation evolution and specifically consider how conditions of dominance, linkage, recombination, and sex-differential selection each influence evolutionary trajectories of X inactivation. The results indicate that a single, critical interaction between allelic dominance and sex-differential selection can select for a broad and continuous range of X inactivation strategies, including unequal rates of inactivation between maternally and paternally inherited X chromosomes. RXI is favored over complete PXI as long as alleles deleterious to female fitness are sufficiently recessive, and the criteria for RXI evolution is considerably more restrictive when fitness variation is sexually antagonistic (i.e., alleles deleterious to females are beneficial to males) relative to variation that is deleterious to both sexes. Evolutionary transitions from PXI to RXI also generally increase mean relative female fitness at the expense of decreased male fitness. These results provide a theoretical framework for predicting and interpreting the evolution of chromosome-wide expression of X linked genes and lead to several useful predictions that could motivate future studies of allele-specific gene expression variation. PMID- 23637619 TI - Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy. AB - We report the identification and characterization of a previously unknown suppressor of myopathy caused by expansion of CUG repeats, the mutation that triggers Myotonic Dystrophy Type 1 (DM1). We screened a collection of genes encoding RNA-binding proteins as candidates to modify DM1 pathogenesis using a well established Drosophila model of the disease. The screen revealed smaug as a powerful modulator of CUG-induced toxicity. Increasing smaug levels prevents muscle wasting and restores muscle function, while reducing its function exacerbates CUG-induced phenotypes. Using human myoblasts, we show physical interactions between human Smaug (SMAUG1/SMAD4A) and CUGBP1. Increased levels of SMAUG1 correct the abnormally high nuclear accumulation of CUGBP1 in myoblasts from DM1 patients. In addition, augmenting SMAUG1 levels leads to a reduction of inactive CUGBP1-eIF2alpha translational complexes and to a correction of translation of MRG15, a downstream target of CUGBP1. Therefore, Smaug suppresses CUG-mediated muscle wasting at least in part via restoration of translational activity of CUGBP1. PMID- 23637620 TI - The chromosomal passenger protein birc5b organizes microfilaments and germ plasm in the zebrafish embryo. AB - Microtubule-microfilament interactions are important for cytokinesis and subcellular localization of proteins and mRNAs. In the early zebrafish embryo, astral microtubule-microfilament interactions also facilitate a stereotypic segregation pattern of germ plasm ribonucleoparticles (GP RNPs), which is critical for their eventual selective inheritance by germ cells. The precise mechanisms and molecular mediators for both cytoskeletal interactions and GP RNPs segregation are the focus of intense research. Here, we report the molecular identification of a zebrafish maternal-effect mutation motley as Birc5b, a homolog of the mammalian Chromosomal Passenger Complex (CPC) component Survivin. The meiosis and mitosis defects in motley/birc5b mutant embryos are consistent with failed CPC function, and additional defects in astral microtubule remodeling contribute to failures in the initiation of cytokinesis furrow ingression. Unexpectedly, the motley/birc5b mutation also disrupts cortical microfilaments and GP RNP aggregation during early cell divisions. Birc5b localizes to the tips of astral microtubules along with polymerizing cortical F-actin and the GP RNPs. Mutant Birc5b co-localizes with cortical F-actin and GP RNPs, but fails to associate with astral microtubule tips, leading to disorganized microfilaments and GP RNP aggregation defects. Thus, maternal Birc5b localizes to astral microtubule tips and associates with cortical F-actin and GP RNPs, potentially linking the two cytoskeletons to mediate microtubule-microfilament reorganization and GP RNP aggregation during early embryonic cell cycles in zebrafish. In addition to the known mitotic function of CPC components, our analyses reveal a non-canonical role for an evolutionarily conserved CPC protein in microfilament reorganization and germ plasm aggregation. PMID- 23637622 TI - Sensory neuron-derived eph regulates glomerular arbors and modulatory function of a central serotonergic neuron. AB - Olfactory sensory neurons connect to the antennal lobe of the fly to create the primary units for processing odor cues, the glomeruli. Unique amongst antennal lobe neurons is an identified wide-field serotonergic neuron, the contralaterally projecting, serotonin-immunoreactive deutocerebral neuron (CSDn). The CSDn spreads its termini all over the contralateral antennal lobe, suggesting a diffuse neuromodulatory role. A closer examination, however, reveals a restricted pattern of the CSDn arborization in some glomeruli. We show that sensory neuron derived Eph interacts with Ephrin in the CSDn, to regulate these arborizations. Behavioural analysis of animals with altered Eph-ephrin signaling and with consequent arborization defects suggests that neuromodulation requires local glomerular-specific patterning of the CSDn termini. Our results show the importance of developmental regulation of terminal arborization of even the diffuse modulatory neurons to allow them to route sensory-inputs according to the behavioural contexts. PMID- 23637623 TI - Signatures of diversifying selection in European pig breeds. AB - Following domestication, livestock breeds have experienced intense selection pressures for the development of desirable traits. This has resulted in a large diversity of breeds that display variation in many phenotypic traits, such as coat colour, muscle composition, early maturity, growth rate, body size, reproduction, and behaviour. To better understand the relationship between genomic composition and phenotypic diversity arising from breed development, the genomes of 13 traditional and commercial European pig breeds were scanned for signatures of diversifying selection using the Porcine60K SNP chip, applying a between-population (differentiation) approach. Signatures of diversifying selection between breeds were found in genomic regions associated with traits related to breed standard criteria, such as coat colour and ear morphology. Amino acid differences in the EDNRB gene appear to be associated with one of these signatures, and variation in the KITLG gene may be associated with another. Other selection signals were found in genomic regions including QTLs and genes associated with production traits such as reproduction, growth, and fat deposition. Some selection signatures were associated with regions showing evidence of introgression from Asian breeds. When the European breeds were compared with wild boar, genomic regions with high levels of differentiation harboured genes related to bone formation, growth, and fat deposition. PMID- 23637624 TI - Cytotoxic chromosomal targeting by CRISPR/Cas systems can reshape bacterial genomes and expel or remodel pathogenicity islands. AB - In prokaryotes, clustered regularly interspaced short palindromic repeats (CRISPRs) and their associated (Cas) proteins constitute a defence system against bacteriophages and plasmids. CRISPR/Cas systems acquire short spacer sequences from foreign genetic elements and incorporate these into their CRISPR arrays, generating a memory of past invaders. Defence is provided by short non-coding RNAs that guide Cas proteins to cleave complementary nucleic acids. While most spacers are acquired from phages and plasmids, there are examples of spacers that match genes elsewhere in the host bacterial chromosome. In Pectobacterium atrosepticum the type I-F CRISPR/Cas system has acquired a self-complementary spacer that perfectly matches a protospacer target in a horizontally acquired island (HAI2) involved in plant pathogenicity. Given the paucity of experimental data about CRISPR/Cas-mediated chromosomal targeting, we examined this process by developing a tightly controlled system. Chromosomal targeting was highly toxic via targeting of DNA and resulted in growth inhibition and cellular filamentation. The toxic phenotype was avoided by mutations in the cas operon, the CRISPR repeats, the protospacer target, and protospacer-adjacent motif (PAM) beside the target. Indeed, the natural self-targeting spacer was non-toxic due to a single nucleotide mutation adjacent to the target in the PAM sequence. Furthermore, we show that chromosomal targeting can result in large-scale genomic alterations, including the remodelling or deletion of entire pre-existing pathogenicity islands. These features can be engineered for the targeted deletion of large regions of bacterial chromosomes. In conclusion, in DNA-targeting CRISPR/Cas systems, chromosomal interference is deleterious by causing DNA damage and providing a strong selective pressure for genome alterations, which may have consequences for bacterial evolution and pathogenicity. PMID- 23637625 TI - Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional false discovery rate. AB - Several lines of evidence suggest that genome-wide association studies (GWAS) have the potential to explain more of the "missing heritability" of common complex phenotypes. However, reliable methods to identify a larger proportion of single nucleotide polymorphisms (SNPs) that impact disease risk are currently lacking. Here, we use a genetic pleiotropy-informed conditional false discovery rate (FDR) method on GWAS summary statistics data to identify new loci associated with schizophrenia (SCZ) and bipolar disorders (BD), two highly heritable disorders with significant missing heritability. Epidemiological and clinical evidence suggest similar disease characteristics and overlapping genes between SCZ and BD. Here, we computed conditional Q-Q curves of data from the Psychiatric Genome Consortium (SCZ; n = 9,379 cases and n = 7,736 controls; BD: n = 6,990 cases and n = 4,820 controls) to show enrichment of SNPs associated with SCZ as a function of association with BD and vice versa with a corresponding reduction in FDR. Applying the conditional FDR method, we identified 58 loci associated with SCZ and 35 loci associated with BD below the conditional FDR level of 0.05. Of these, 14 loci were associated with both SCZ and BD (conjunction FDR). Together, these findings show the feasibility of genetic pleiotropy-informed methods to improve gene discovery in SCZ and BD and indicate overlapping genetic mechanisms between these two disorders. PMID- 23637626 TI - Comprehensive assignment of roles for Salmonella typhimurium genes in intestinal colonization of food-producing animals. AB - Chickens, pigs, and cattle are key reservoirs of Salmonella enterica, a foodborne pathogen of worldwide importance. Though a decade has elapsed since publication of the first Salmonella genome, thousands of genes remain of hypothetical or unknown function, and the basis of colonization of reservoir hosts is ill defined. Moreover, previous surveys of the role of Salmonella genes in vivo have focused on systemic virulence in murine typhoid models, and the genetic basis of intestinal persistence and thus zoonotic transmission have received little study. We therefore screened pools of random insertion mutants of S. enterica serovar Typhimurium in chickens, pigs, and cattle by transposon-directed insertion-site sequencing (TraDIS). The identity and relative fitness in each host of 7,702 mutants was simultaneously assigned by massively parallel sequencing of transposon-flanking regions. Phenotypes were assigned to 2,715 different genes, providing a phenotype-genotype map of unprecedented resolution. The data are self consistent in that multiple independent mutations in a given gene or pathway were observed to exert a similar fitness cost. Phenotypes were further validated by screening defined null mutants in chickens. Our data indicate that a core set of genes is required for infection of all three host species, and smaller sets of genes may mediate persistence in specific hosts. By assigning roles to thousands of Salmonella genes in key reservoir hosts, our data facilitate systems approaches to understand pathogenesis and the rational design of novel cross protective vaccines and inhibitors. Moreover, by simultaneously assigning the genotype and phenotype of over 90% of mutants screened in complex pools, our data establish TraDIS as a powerful tool to apply rich functional annotation to microbial genomes with minimal animal use. PMID- 23637627 TI - Dialects of the DNA uptake sequence in Neisseriaceae. AB - In all sexual organisms, adaptations exist that secure the safe reassortment of homologous alleles and prevent the intrusion of potentially hazardous alien DNA. Some bacteria engage in a simple form of sex known as transformation. In the human pathogen Neisseria meningitidis and in related bacterial species, transformation by exogenous DNA is regulated by the presence of a specific DNA Uptake Sequence (DUS), which is present in thousands of copies in the respective genomes. DUS affects transformation by limiting DNA uptake and recombination in favour of homologous DNA. The specific mechanisms of DUS-dependent genetic transformation have remained elusive. Bioinformatic analyses of family Neisseriaceae genomes reveal eight distinct variants of DUS. These variants are here termed DUS dialects, and their effect on interspecies commutation is demonstrated. Each of the DUS dialects is remarkably conserved within each species and is distributed consistent with a robust Neisseriaceae phylogeny based on core genome sequences. The impact of individual single nucleotide transversions in DUS on meningococcal transformation and on DNA binding and uptake is analysed. The results show that a DUS core 5'-CTG-3' is required for transformation and that transversions in this core reduce DNA uptake more than two orders of magnitude although the level of DNA binding remains less affected. Distinct DUS dialects are efficient barriers to interspecies recombination in N. meningitidis, N. elongata, Kingella denitrificans, and Eikenella corrodens, despite the presence of the core sequence. The degree of similarity between the DUS dialect of the recipient species and the donor DNA directly correlates with the level of transformation and DNA binding and uptake. Finally, DUS-dependent transformation is documented in the genera Eikenella and Kingella for the first time. The results presented here advance our understanding of the function and evolution of DUS and genetic transformation in bacteria, and define the phylogenetic relationships within the Neisseriaceae family. PMID- 23637628 TI - SNF5 is an essential executor of epigenetic regulation during differentiation. AB - Nucleosome occupancy controls the accessibility of the transcription machinery to DNA regulatory regions and serves an instructive role for gene expression. Chromatin remodelers, such as the BAF complexes, are responsible for establishing nucleosome occupancy patterns, which are key to epigenetic regulation along with DNA methylation and histone modifications. Some reports have assessed the roles of the BAF complex subunits and stemness in murine embryonic stem cells. However, the details of the relationships between remodelers and transcription factors in altering chromatin configuration, which ultimately affects gene expression during cell differentiation, remain unclear. Here for the first time we demonstrate that SNF5, a core subunit of the BAF complex, negatively regulates OCT4 levels in pluripotent cells and is essential for cell survival during differentiation. SNF5 is responsible for generating nucleosome-depleted regions (NDRs) at the regulatory sites of OCT4 repressed target genes such as PAX6 and NEUROG1, which are crucial for cell fate determination. Concurrently, SNF5 closes the NDRs at the regulatory regions of OCT4-activated target genes such as OCT4 itself and NANOG. Furthermore, using loss- and gain-of-function experiments followed by extensive genome-wide analyses including gene expression microarrays and ChIP sequencing, we highlight that SNF5 plays dual roles during differentiation by antagonizing the expression of genes that were either activated or repressed by OCT4, respectively. Together, we demonstrate that SNF5 executes the switch between pluripotency and differentiation. PMID- 23637629 TI - The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3. AB - Embryonic development is tightly regulated by transcription factors and chromatin associated proteins. H3K4me3 is associated with active transcription and H3K27me3 with gene repression, while the combination of both keeps genes required for development in a plastic state. Here we show that deletion of the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) results in major neonatal lethality due to respiratory failure. Jarid1b knockout embryos have several neural defects including disorganized cranial nerves, defects in eye development, and increased incidences of exencephaly. Moreover, in line with an overlap of Jarid1b and Polycomb target genes, Jarid1b knockout embryos display homeotic skeletal transformations typical for Polycomb mutants, supporting a functional interplay between Polycomb proteins and Jarid1b. To understand how Jarid1b regulates mouse development, we performed a genome-wide analysis of histone modifications, which demonstrated that normally inactive genes encoding developmental regulators acquire aberrant H3K4me3 during early embryogenesis in Jarid1b knockout embryos. H3K4me3 accumulates as embryonic development proceeds, leading to increased expression of neural master regulators like Pax6 and Otx2 in Jarid1b knockout brains. Taken together, these results suggest that Jarid1b regulates mouse development by protecting developmental genes from inappropriate acquisition of active histone modifications. PMID- 23637630 TI - Functional dissection of the Drosophila melanogaster condensin subunit Cap-G reveals its exclusive association with condensin I. AB - The heteropentameric condensin complexes have been shown to participate in mitotic chromosome condensation and to be required for unperturbed chromatid segregation in nuclear divisions. Vertebrates have two condensin complexes, condensin I and condensin II, which contain the same structural maintenance of chromosomes (SMC) subunits SMC2 and SMC4, but differ in their composition of non SMC subunits. While a clear biochemical and functional distinction between condensin I and condensin II has been established in vertebrates, the situation in Drosophila melanogaster is less defined. Since Drosophila lacks a clear homolog for the condensin II-specific subunit Cap-G2, the condensin I subunit Cap G has been hypothesized to be part of both complexes. In vivo microscopy revealed that a functional Cap-G-EGFP variant shows a distinct nuclear enrichment during interphase, which is reminiscent of condensin II localization in vertebrates and contrasts with the cytoplasmic enrichment observed for the other EGFP-fused condensin I subunits. However, we show that this nuclear localization is dispensable for Cap-G chromatin association, for its assembly into the condensin I complex and, importantly, for development into a viable and fertile adult animal. Immunoprecipitation analyses and complex formation studies provide evidence that Cap-G does not associate with condensin II-specific subunits, while it can be readily detected in complexes with condensin I-specific proteins in vitro and in vivo. Mass-spectrometric analyses of proteins associated with the condensin II-specific subunit Cap-H2 not only fail to identify Cap-G but also the other known condensin II-specific homolog Cap-D3. As condensin II-specific subunits are also not found associated with SMC2, our results question the existence of a soluble condensin II complex in Drosophila. PMID- 23637621 TI - All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs. AB - Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate (TDR = 1-FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in introns, and negative enrichment for intergenic SNPs. Stratified enrichment directly leads to increased TDR for a given p-value, mirrored by increased replication rates in independent samples. We show this in independent Crohn's disease GWAS, where we find a hundredfold variation in replication rate across genic categories. Applying a well established sFDR methodology we demonstrate the utility of stratification for improving power of GWAS in complex phenotypes, with increased rejection rates from 20% in height to 300% in schizophrenia with traditional FDR and sFDR both fixed at 0.05. Our analyses demonstrate an inherent stratification among GWAS SNPs with important conceptual implications that can be leveraged by statistical methods to improve the discovery of loci. PMID- 23637631 TI - Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types. AB - Gene fusions, like BCR/ABL1 in chronic myelogenous leukemia, have long been recognized in hematologic and mesenchymal malignancies. The recent finding of gene fusions in prostate and lung cancers has motivated the search for pathogenic gene fusions in other malignancies. Here, we developed a "breakpoint analysis" pipeline to discover candidate gene fusions by tell-tale transcript level or genomic DNA copy number transitions occurring within genes. Mining data from 974 diverse cancer samples, we identified 198 candidate fusions involving annotated cancer genes. From these, we validated and further characterized novel gene fusions involving ROS1 tyrosine kinase in angiosarcoma (CEP85L/ROS1), SLC1A2 glutamate transporter in colon cancer (APIP/SLC1A2), RAF1 kinase in pancreatic cancer (ATG7/RAF1) and anaplastic astrocytoma (BCL6/RAF1), EWSR1 in melanoma (EWSR1/CREM), CDK6 kinase in T-cell acute lymphoblastic leukemia (FAM133B/CDK6), and CLTC in breast cancer (CLTC/VMP1). Notably, while these fusions involved known cancer genes, all occurred with novel fusion partners and in previously unreported cancer types. Moreover, several constituted druggable targets (including kinases), with therapeutic implications for their respective malignancies. Lastly, breakpoint analysis identified new cell line models for known rearrangements, including EGFRvIII and FIP1L1/PDGFRA. Taken together, we provide a robust approach for gene fusion discovery, and our results highlight a more widespread role of fusion genes in cancer pathogenesis. PMID- 23637632 TI - Identification of a tissue-selective heat shock response regulatory network. AB - The heat shock response (HSR) is essential to survive acute proteotoxic stress and has been studied extensively in unicellular organisms and tissue culture cells, but to a lesser extent in intact metazoan animals. To identify the regulatory pathways that control the HSR in Caenorhabditis elegans, we performed a genome-wide RNAi screen and identified 59 genes corresponding to 7 positive activators required for the HSR and 52 negative regulators whose knockdown leads to constitutive activation of the HSR. These modifiers function in specific steps of gene expression, protein synthesis, protein folding, trafficking, and protein clearance, and comprise the metazoan heat shock regulatory network (HSN). Whereas the positive regulators function in all tissues of C. elegans, nearly all of the negative regulators exhibited tissue-selective effects. Knockdown of the subunits of the proteasome strongly induces HS reporter expression only in the intestine and spermatheca but not in muscle cells, while knockdown of subunits of the TRiC/CCT chaperonin induces HS reporter expression only in muscle cells. Yet, both the proteasome and TRiC/CCT chaperonin are ubiquitously expressed and are required for clearance and folding in all tissues. We propose that the HSN identifies a key subset of the proteostasis machinery that regulates the HSR according to the unique functional requirements of each tissue. PMID- 23637633 TI - The G4 genome. AB - Recent experiments provide fascinating examples of how G4 DNA and G4 RNA structures--aka quadruplexes--may contribute to normal biology and to genomic pathologies. Quadruplexes are transient and therefore difficult to identify directly in living cells, which initially caused skepticism regarding not only their biological relevance but even their existence. There is now compelling evidence for functions of some G4 motifs and the corresponding quadruplexes in essential processes, including initiation of DNA replication, telomere maintenance, regulated recombination in immune evasion and the immune response, control of gene expression, and genetic and epigenetic instability. Recognition and resolution of quadruplex structures is therefore an essential component of genome biology. We propose that G4 motifs and structures that participate in key processes compose the G4 genome, analogous to the transcriptome, proteome, or metabolome. This is a new view of the genome, which sees DNA as not only a simple alphabet but also a more complex geography. The challenge for the future is to systematically identify the G4 motifs that form quadruplexes in living cells and the features that confer on specific G4 motifs the ability to function as structural elements. PMID- 23637634 TI - Genetic and biochemical assays reveal a key role for replication restart proteins in group II intron retrohoming. AB - Mobile group II introns retrohome by an RNP-based mechanism in which the intron RNA reverse splices into a DNA site and is reverse transcribed by the associated intron-encoded protein. The resulting intron cDNA is then integrated into the genome by cellular mechanisms that have remained unclear. Here, we used an Escherichia coli genetic screen and Taqman qPCR assay that mitigate indirect effects to identify host factors that function in retrohoming. We then analyzed mutants identified in these and previous genetic screens by using a new biochemical assay that combines group II intron RNPs with cellular extracts to reconstitute the complete retrohoming reaction in vitro. The genetic and biochemical analyses indicate a retrohoming pathway involving degradation of the intron RNA template by a host RNase H and second-strand DNA synthesis by the host replicative DNA polymerase. Our results reveal ATP-dependent steps in both cDNA and second-strand synthesis and a surprising role for replication restart proteins in initiating second-strand synthesis in the absence of DNA replication. We also find an unsuspected requirement for host factors in initiating reverse transcription and a new RNA degradation pathway that suppresses retrohoming. Key features of the retrohoming mechanism may be used by human LINEs and other non LTR-retrotransposons, which are related evolutionarily to mobile group II introns. Our findings highlight a new role for replication restart proteins, which function not only to repair DNA damage caused by mobile element insertion, but have also been co-opted to become an integral part of the group II intron retrohoming mechanism. PMID- 23637635 TI - Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs. AB - Advances in vertebrate genomics have uncovered thousands of loci encoding long noncoding RNAs (lncRNAs). While progress has been made in elucidating the regulatory functions of lncRNAs, little is known about their origins and evolution. Here we explore the contribution of transposable elements (TEs) to the makeup and regulation of lncRNAs in human, mouse, and zebrafish. Surprisingly, TEs occur in more than two thirds of mature lncRNA transcripts and account for a substantial portion of total lncRNA sequence (~30% in human), whereas they seldom occur in protein-coding transcripts. While TEs contribute less to lncRNA exons than expected, several TE families are strongly enriched in lncRNAs. There is also substantial interspecific variation in the coverage and types of TEs embedded in lncRNAs, partially reflecting differences in the TE landscapes of the genomes surveyed. In human, TE sequences in lncRNAs evolve under greater evolutionary constraint than their non-TE sequences, than their intronic TEs, or than random DNA. Consistent with functional constraint, we found that TEs contribute signals essential for the biogenesis of many lncRNAs, including ~30,000 unique sites for transcription initiation, splicing, or polyadenylation in human. In addition, we identified ~35,000 TEs marked as open chromatin located within 10 kb upstream of lncRNA genes. The density of these marks in one cell type correlate with elevated expression of the downstream lncRNA in the same cell type, suggesting that these TEs contribute to cis-regulation. These global trends are recapitulated in several lncRNAs with established functions. Finally a subset of TEs embedded in lncRNAs are subject to RNA editing and predicted to form secondary structures likely important for function. In conclusion, TEs are nearly ubiquitous in lncRNAs and have played an important role in the lineage-specific diversification of vertebrate lncRNA repertoires. PMID- 23637636 TI - Neutral genomic microevolution of a recently emerged pathogen, Salmonella enterica serovar Agona. AB - Salmonella enterica serovar Agona has caused multiple food-borne outbreaks of gastroenteritis since it was first isolated in 1952. We analyzed the genomes of 73 isolates from global sources, comparing five distinct outbreaks with sporadic infections as well as food contamination and the environment. Agona consists of three lineages with minimal mutational diversity: only 846 single nucleotide polymorphisms (SNPs) have accumulated in the non-repetitive, core genome since Agona evolved in 1932 and subsequently underwent a major population expansion in the 1960s. Homologous recombination with other serovars of S. enterica imported 42 recombinational tracts (360 kb) in 5/143 nodes within the genealogy, which resulted in 3,164 additional SNPs. In contrast to this paucity of genetic diversity, Agona is highly diverse according to pulsed-field gel electrophoresis (PFGE), which is used to assign isolates to outbreaks. PFGE diversity reflects a highly dynamic accessory genome associated with the gain or loss (indels) of 51 bacteriophages, 10 plasmids, and 6 integrative conjugational elements (ICE/IMEs), but did not correlate uniquely with outbreaks. Unlike the core genome, indels occurred repeatedly in independent nodes (homoplasies), resulting in inaccurate PFGE genealogies. The accessory genome contained only few cargo genes relevant to infection, other than antibiotic resistance. Thus, most of the genetic diversity within this recently emerged pathogen reflects changes in the accessory genome, or is due to recombination, but these changes seemed to reflect neutral processes rather than Darwinian selection. Each outbreak was caused by an independent clade, without universal, outbreak-associated genomic features, and none of the variable genes in the pan-genome seemed to be associated with an ability to cause outbreaks. PMID- 23637638 TI - The tissue-specific RNA binding protein T-STAR controls regional splicing patterns of neurexin pre-mRNAs in the brain. AB - The RNA binding protein T-STAR was created following a gene triplication 520-610 million years ago, which also produced its two parologs Sam68 and SLM-1. Here we have created a T-STAR null mouse to identify the endogenous functions of this RNA binding protein. Mice null for T-STAR developed normally and were fertile, surprisingly, given the high expression of T-STAR in the testis and the brain, and the known infertility and pleiotropic defects of Sam68 null mice. Using a transcriptome-wide search for splicing targets in the adult brain, we identified T-STAR protein as a potent splicing repressor of the alternatively spliced segment 4 (AS4) exons from each of the Neurexin1-3 genes, and exon 23 of the Stxbp5l gene. T-STAR protein was most highly concentrated in forebrain-derived structures like the hippocampus, which also showed maximal Neurexin1-3 AS4 splicing repression. In the absence of endogenous T-STAR protein, Nrxn1-3 AS4 splicing repression dramatically decreased, despite physiological co-expression of Sam68. In transfected cells Neurexin3 AS4 alternative splicing was regulated by either T-STAR or Sam68 proteins. In contrast, Neurexin2 AS4 splicing was only regulated by T-STAR, through a UWAA-rich response element immediately downstream of the regulated exon conserved since the radiation of bony vertebrates. The AS4 exons in the Nrxn1 and Nrxn3 genes were also associated with distinct patterns of conserved UWAA repeats. Consistent with an ancient mechanism of splicing control, human T-STAR protein was able to repress splicing inclusion of the zebrafish Nrxn3 AS4 exon. Although Neurexin1-3 and Stxbp5l encode critical synaptic proteins, T-STAR null mice had no detectable spatial memory deficits, despite an almost complete absence of AS4 splicing repression in the hippocampus. Our work identifies T-STAR as an ancient and potent tissue-specific splicing regulator that uses a concentration-dependent mechanism to co-ordinately regulate regional splicing patterns of the Neurexin1-3 AS4 exons in the mouse brain. PMID- 23637637 TI - Scavenger receptors mediate the role of SUMO and Ftz-f1 in Drosophila steroidogenesis. AB - SUMOylation participates in ecdysteroid biosynthesis at the onset of metamorphosis in Drosophila melanogaster. Silencing the Drosophila SUMO homologue smt3 in the prothoracic gland leads to reduced lipid content, low ecdysone titers, and a block in the larval-pupal transition. Here we show that the SR-BI family of Scavenger Receptors mediates SUMO functions. Reduced levels of Snmp1 compromise lipid uptake in the prothoracic gland. In addition, overexpression of Snmp1 is able to recover lipid droplet levels in the smt3 knockdown prothoracic gland cells. Snmp1 expression depends on Ftz-f1 (an NR5A-type orphan nuclear receptor), the expression of which, in turn, depends on SUMO. Furthermore, we show by in vitro and in vivo experiments that Ftz-f1 is SUMOylated. RNAi-mediated knockdown of ftz-f1 phenocopies that of smt3 at the larval to pupal transition, thus Ftz-f1 is an interesting candidate to mediate some of the functions of SUMO at the onset of metamorphosis. Additionally, we demonstrate that the role of SUMOylation, Ftz-f1, and the Scavenger Receptors in lipid capture and mobilization is conserved in other steroidogenic tissues such as the follicle cells of the ovary. smt3 knockdown, as well as ftz-f1 or Scavenger knockdown, depleted the lipid content of the follicle cells, which could be rescued by Snmp1 overexpression. Therefore, our data provide new insights into the regulation of metamorphosis via lipid homeostasis, showing that Drosophila Smt3, Ftz-f1, and SR BIs are part of a general mechanism for uptake of lipids such as cholesterol, required during development in steroidogenic tissues. PMID- 23637639 TI - The hourglass and the early conservation models--co-existing patterns of developmental constraints in vertebrates. AB - Developmental constraints have been postulated to limit the space of feasible phenotypes and thus shape animal evolution. These constraints have been suggested to be the strongest during either early or mid-embryogenesis, which corresponds to the early conservation model or the hourglass model, respectively. Conflicting results have been reported, but in recent studies of animal transcriptomes the hourglass model has been favored. Studies usually report descriptive statistics calculated for all genes over all developmental time points. This introduces dependencies between the sets of compared genes and may lead to biased results. Here we overcome this problem using an alternative modular analysis. We used the Iterative Signature Algorithm to identify distinct modules of genes co-expressed specifically in consecutive stages of zebrafish development. We then performed a detailed comparison of several gene properties between modules, allowing for a less biased and more powerful analysis. Notably, our analysis corroborated the hourglass pattern at the regulatory level, with sequences of regulatory regions being most conserved for genes expressed in mid-development but not at the level of gene sequence, age, or expression, in contrast to some previous studies. The early conservation model was supported with gene duplication and birth that were the most rare for genes expressed in early development. Finally, for all gene properties, we observed the least conservation for genes expressed in late development or adult, consistent with both models. Overall, with the modular approach, we showed that different levels of molecular evolution follow different patterns of developmental constraints. Thus both models are valid, but with respect to different genomic features. PMID- 23637640 TI - Aconitase causes iron toxicity in Drosophila pink1 mutants. AB - The PTEN-induced kinase 1 (PINK1) is a mitochondrial kinase, and pink1 mutations cause early onset Parkinson's disease (PD) in humans. Loss of pink1 in Drosophila leads to defects in mitochondrial function, and genetic data suggest that another PD-related gene product, Parkin, acts with pink1 to regulate the clearance of dysfunctional mitochondria (mitophagy). Consequently, pink1 mutants show an accumulation of morphologically abnormal mitochondria, but it is unclear if other factors are involved in pink1 function in vivo and contribute to the mitochondrial morphological defects seen in specific cell types in pink1 mutants. To explore the molecular mechanisms of pink1 function, we performed a genetic modifier screen in Drosophila and identified aconitase (acon) as a dominant suppressor of pink1. Acon localizes to mitochondria and harbors a labile iron sulfur [4Fe-4S] cluster that can scavenge superoxide to release hydrogen peroxide and iron that combine to produce hydroxyl radicals. Using Acon enzymatic mutants, and expression of mitoferritin that scavenges free iron, we show that [4Fe-4S] cluster inactivation, as a result of increased superoxide in pink1 mutants, results in oxidative stress and mitochondrial swelling. We show that [4Fe-4S] inactivation acts downstream of pink1 in a pathway that affects mitochondrial morphology, but acts independently of parkin. Thus our data indicate that superoxide-dependent [4Fe-4S] inactivation defines a potential pathogenic cascade that acts independent of mitophagy and links iron toxicity to mitochondrial failure in a PD-relevant model. PMID- 23637641 TI - Genome-wide association studies identify two novel BMP15 mutations responsible for an atypical hyperprolificacy phenotype in sheep. AB - Some sheep breeds are naturally prolific, and they are very informative for the studies of reproductive genetics and physiology. Major genes increasing litter size (LS) and ovulation rate (OR) were suspected in the French Grivette and the Polish Olkuska sheep populations, respectively. To identify genetic variants responsible for the highly prolific phenotype in these two breeds, genome-wide association studies (GWAS) followed by complementary genetic and functional analyses were performed. Highly prolific ewes (cases) and normal prolific ewes (controls) from each breed were genotyped using the Illumina OvineSNP50 Genotyping Beadchip. In both populations, an X chromosome region, close to the BMP15 gene, harbored clusters of markers with suggestive evidence of association at significance levels between 1E(-05) and 1E(-07). The BMP15 candidate gene was then sequenced, and two novel non-conservative mutations called FecX(Gr) and FecX(O) were identified in the Grivette and Olkuska breeds, respectively. The two mutations were associated with the highly prolific phenotype (p FecX (Gr) = 5.98E(-06) and p FecX(O) = 2.55E(-08)). Homozygous ewes for the mutated allele showed a significantly increased prolificacy (FecX(Gr)/FecX(Gr), LS = 2.50 +/- 0.65 versus FecX(+)/FecX(Gr), LS = 1.93 +/- 0.42, p<1E(-03) and FecX(O)/FecX(O), OR = 3.28 +/- 0.85 versus FecX(+)/FecX(O), OR = 2.02 +/- 0.47, p<1E(-03)). Both mutations are located in very well conserved motifs of the protein and altered the BMP15 signaling activity in vitro using a BMP-responsive luciferase test in COV434 granulosa cells. Thus, we have identified two novel mutations in the BMP15 gene associated with increased LS and OR. Notably, homozygous FecX(Gr)/FecX(Gr) Grivette and homozygous FecX(O)/FecX(O) Olkuska ewes are hyperprolific in striking contrast with the sterility exhibited by all other known homozygous BMP15 mutations. Our results bring new insights into the key role played by the BMP15 protein in ovarian function and could contribute to a better understanding of the pathogenesis of women's fertility disorders. PMID- 23637643 TI - Using a birth cohort to study ageing: representativeness and response rates in the National Survey of Health and Development. AB - Britain's oldest birth cohort study, the MRC National Survey of Health and Development (NSHD) provides data to explore life time influences on ageing. The latest data collection was undertaken between 2006 and 2011 when study members were aged 60-64 and consisted of postal and pre-assessment questionnaires to eligible study members, followed by invitation to attend one of six clinical research facilities (CRFs) across the UK for clinical assessments, and dietary diaries and activity monitors in the days following the CRF visit. The option of a home visit for clinical assessments was provided if the study member refused or was unable to attend the CRF. We examined response and attrition, here describing rates overall and for postal and clinical assessment modes of data collection, identifying socioeconomic and health-related predictors of response, and assessing the continued representativeness of the sample. In total, 2,661 (84 % of the target sample) responded. Lower educational attainment, lower childhood cognition and lifelong smoking independently predicted lower likelihood of both overall response and CRF cooperation. At 53 years, not owning one's home and not being married predicted lower likelihood of overall response whereas manual social class and obesity predicted lower likelihood of CRF cooperation. Providing for collection of biomedical data in the home and use of assessment instruments and modes to retain study members with lower education attainment, lower cognition and poorer health behaviours should be priorities for helping reduce attrition amongst vulnerable ageing study members. PMID- 23637642 TI - The genome organization of Thermotoga maritima reflects its lifestyle. AB - The generation of genome-scale data is becoming more routine, yet the subsequent analysis of omics data remains a significant challenge. Here, an approach that integrates multiple omics datasets with bioinformatics tools was developed that produces a detailed annotation of several microbial genomic features. This methodology was used to characterize the genome of Thermotoga maritima--a phylogenetically deep-branching, hyperthermophilic bacterium. Experimental data were generated for whole-genome resequencing, transcription start site (TSS) determination, transcriptome profiling, and proteome profiling. These datasets, analyzed in combination with bioinformatics tools, served as a basis for the improvement of gene annotation, the elucidation of transcription units (TUs), the identification of putative non-coding RNAs (ncRNAs), and the determination of promoters and ribosome binding sites. This revealed many distinctive properties of the T. maritima genome organization relative to other bacteria. This genome has a high number of genes per TU (3.3), a paucity of putative ncRNAs (12), and few TUs with multiple TSSs (3.7%). Quantitative analysis of promoters and ribosome binding sites showed increased sequence conservation relative to other bacteria. The 5'UTRs follow an atypical bimodal length distribution comprised of "Short" 5'UTRs (11-17 nt) and "Common" 5'UTRs (26-32 nt). Transcriptional regulation is limited by a lack of intergenic space for the majority of TUs. Lastly, a high fraction of annotated genes are expressed independent of growth state and a linear correlation of mRNA/protein is observed (Pearson r = 0.63, p<2.2 * 10(-16) t-test). These distinctive properties are hypothesized to be a reflection of this organism's hyperthermophilic lifestyle and could yield novel insights into the evolutionary trajectory of microbial life on earth. PMID- 23637645 TI - Impact of selection of cord blood units from the United States and swiss registries on the cost of banking operations. AB - BACKGROUND: Over the last 2 decades, cord blood (CB) has become an important source of blood stem cells. Clinical experience has shown that CB is a viable source for blood stem cells in the field of unrelated hematopoietic blood stem cell transplantation. METHODS: Studies of CB units (CBUs) stored and ordered from the US (National Marrow Donor Program (NMDP) and Swiss (Swiss Blood Stem Cells (SBSQ)) CB registries were conducted to assess whether these CBUs met the needs of transplantation patients, as evidenced by units being selected for transplantation. These data were compared to international banking and selection data (Bone Marrow Donors Worldwide (BMDW), World Marrow Donor Association (WMDA)). Further analysis was conducted on whether current CB banking practices were economically viable given the units being selected from the registries for transplant. It should be mentioned that our analysis focused on usage, deliberately omitting any information about clinical outcomes of CB transplantation. RESULTS: A disproportionate number of units with high total nucleated cell (TNC) counts are selected, compared to the distribution of units by TNC available. Therefore, the decision to use a low threshold for banking purposes cannot be supported by economic analysis and may limit the economic viability of future public CB banking. CONCLUSIONS: We suggest significantly raising the TNC level used to determine a bankable unit. A level of 125 * 10(7) TNCs, maybe even 150 * 10(7) TNCs, might be a viable banking threshold. This would improve the return on inventory investments while meeting transplantation needs based on current selection criteria. PMID- 23637646 TI - Blood Transfusion Policies in Elective General Surgery: How to Optimise Cross Match-to-Transfusion Ratios. AB - OBJECTIVE: Preoperative over-ordering of blood is common and leads to the wastage of blood bank resources. The preoperative blood ordering and transfusion practices for common elective general surgical procedures were evaluated in our university hospital to formulate a maximum surgical blood order schedule (MSBOS) for those procedures where a cross-match appears necessary. METHODS: We evaluated blood ordering practices retrospectively in all elective general surgical procedures in our institution over a 6-month period. Cross-match-to-transfusion ratios (C:T) were calculated and compared to current trust and the British Society of Haematology (BSH) guidelines. The adjusted C:T ratio was also calculated and was defined as the C:T ratio when only cross-matched blood used intraoperatively was included in the calculation. RESULTS: 541 patients were identified during the 6-month period. There were 314 minor and 227 major surgeries carried out. 99.6% (n = 226) of the patients who underwent major surgery and 95.5% (n = 300) of the patients having minor surgery had at least a group and save (G and S) test preoperatively. A total of 507 units of blood were cross-matched and 238 units were used. The overall C:T ratio was therefore 2.1:1, which corresponds to a 46.9% red cell usage. There was considerable variation in the C:T ratio, depending on the type of surgery performed. The adjusted C:T ratio varied between 3.75 and 37. CONCLUSIONS: Compliance with transfusion policies is poor and over-ordering of blood products commonplace. Implementation of the updated recommended MSBOS and introduction of G and S for eligible surgical procedures is a safe, effective and cost-effective method to prevent preoperative over-ordering of blood in elective general surgery. Savings of GBP 8,596.00 per annum are achievable with the incorporation of updated evidence-based guidelines in our university hospital. PMID- 23637647 TI - No detection of the retrovirus xenotropic murine leukemia virus-related virus in individuals with hemophilia. AB - BACKGROUND: Xenotropic murine leukemia virus-related virus (XMRV) is a retrovirus that has recently been related to prostate cancers and chronic fatigue syndrome. Since other human-pathogenic retroviruses, such as HIV, human T-lymphotropic virus type I (HTLV-I) and -II, are known blood-transmitted pathogens, XMRV might present another hazard associated with products derived from in vitro cultures of human or animal origin, or blood component-based therapeutics. Here, we investigated whether XMRV was transmitted to individuals with hemophilia and frequent exposure to plasma-derived or recombinant clotting factors. METHODS: We used highly sensitive real-time PCR to test plasma samples from 127 consecutive individuals with hemophilia who consulted our hemophilia center either for treatment or for a standard check-up. RESULTS: From the 127 hemophiliacs, 80 had prior contact to persons with either hepatitis B (n = 30), hepatitis C (n = 74) and/or HIV (n = 21), and 30 were currently being treated with plasma-derived and 97 with recombinant factor concentrates. None of the individuals tested positive for XMRV. CONCLUSIONS: Independent of the ongoing discussion on whether the positive XMRV testing in initial reports was a result of reagent, sample, or tissue contamination, and whether XMRV is a real threat or a testing artifact, our data suggest that XMRV might not play an important role for hemophiliacs. PMID- 23637644 TI - Transfusion-Related Acute Lung Injury: The Work of DAMPs. AB - Current notions in immunology hold that not only pathogen-mediated tissue injury but any injury activates the innate immune system. In principle, this evolutionarily highly conserved, rapid first-line defense system responds to pathogen-induced injury with the creation of infectious inflammation, and non pathogen-induced tissue injury with 'sterile' tissue inflammation. In this review, evidence has been collected in support of the notion that the transfusion related acute lung injury induces a 'sterile' inflammation in the lung of transfused patients in terms of an acute innate inflammatory disease. The inflammatory response is mediated by the patient's innate immune cells including lung-passing neutrophils and pulmonary endothelial cells, which are equipped with pattern recognition receptors. These receptors are able to sense injury-induced, damage-associated molecular patterns (DAMPs) generated during collection, processing, and storage of blood/blood components. The recognition process leads to activation of these innate cells. A critical role for a protein complex known as the NLRP3 inflammasome has been suggested to be at the center of such a scenario. This complex undergoes an initial 'priming' step mediated by 1 class of DAMPs and then an 'activating' step mediated by another class of DAMPs to activate interleukin-1beta and interleukin-18. These 2 cytokines then promote, via transactivation, the formation of lung inflammation. PMID- 23637648 TI - Reliable Determination of Fetal RhD Status by RHD Genotyping from Maternal Plasma. AB - BACKGROUND: Immunoprophylaxis with IgG anti-D is a standard prevention of hemolytic disease of the fetus and newborn. Fetal Rhesus D (RhD) blood group genotyping from maternal plasma of RhD-negative pregnant women allows targeted prophylaxis with IgG anti-D in RhD-positive pregnancies only. We set up a reliable protocol for prenatal RHD genotyping. METHODS: 153 pregnant Caucasian RhD-negative women were tested in the 27th week (range 7-38th week) of pregnancy. 18 of them were alloimmunized to the RhD antigen. The fetal RHD genotype was determined based on an automated DNA extraction and real-time polymerase chain reaction method. Intron 4 and exons 5, 7 and 10 of the RHD gene and the SRY gene were targeted. RESULTS: The fetal RhD status and gender was 100% correctly predicted in all 153 pregnancies (55 RhD-positive males, 45 RhD-positive females; 23 RhD-negative males, 30 RhD-negative females). CONCLUSION: The accuracy and applicability of our protocol for non-invasive fetal RhD determination allows the correct management of RhD-incompatible pregnancies. Our protocol could prevent unnecessary immunoprophylaxis in 53 of 153 cases. We therefore recommend that non invasive fetal RHD genotyping is introduced as an obligatory part of prenatal screening. PMID- 23637649 TI - Treatment of buffy coat platelets in platelet additive solution with the mirasol((r)) pathogen reduction technology system. AB - BACKGROUND: The Mirasol pathogen reduction technology (PRT) system uses riboflavin and ultraviolet light and is currently approved and used in Europe for the treatment of platelets and plasma. Mirasol treatment is intended to reduce the infectious pathogen load and to inactivate leukocytes in blood products. Our objective was to evaluate buffy coat platelet concentrates (BCPCs) prepared with platelet additive solution (PAS) and treated with the Mirasol system and to examine the effects on platelet cell quality during storage. METHODS: 26 BCPCs were prepared and split, creating 13 paired control and test units. The test units were treated with the Mirasol system and the platelet quality was assessed in all units over 7 days of storage. RESULTS: All products met the incoming specifications for Mirasol treatment, and the pH of all Mirasol-treated BCPCs in PAS met the requirements of the Council of Europe guidelines throughout storage. Analysis of lactate production and glucose consumption rates, CD62p expression and cytokines indicates enhanced cellular metabolism in treated platelets, but the levels were within previously published ranges. CONCLUSION: While Mirasol treated BCPCs in PAS had increased metabolism and activation compared to controls, the results indicate that these units can be stored for 7 days with acceptable cell quality. PMID- 23637650 TI - Comparison of cytokine responses with anti-d and intravenous immunoglobulin in idiopathic thrombocytopenia. PMID- 23637651 TI - Arbonematodes - nematode infections transmissible by arthropods: arbeitskreis blut, untergruppe "bewertung blutassoziierter krankheitserreger"*. PMID- 23637653 TI - Unveiling the metric structure of internal representations of space. AB - How are neuronal representations of space organized in the hippocampus? The self organization of such representations, thought to be driven in the CA3 network by the strong randomizing input from the Dentate Gyrus, appears to run against preserving the topology and even less the exact metric of physical space. We present a way to assess this issue quantitatively, and find that in a simple neural network model of CA3, the average topology is largely preserved, but the local metric is loose, retaining e.g., 10% of the optimal spatial resolution. PMID- 23637654 TI - Distinct morphological features of NADPH diaphorase neurons across rodent's primary cortices. PMID- 23637655 TI - Exploiting biomechanical degrees of freedom for fast and accurate changes in movement direction: coordination underlying quick bow reversals during continuous cello bowing. AB - Theoretical and empirical evidence suggests that accurate and efficient motor performance may be achieved by task-specific exploitation of biomechanical degrees of freedom. We investigate coordination of the right arm in a task requiring a sudden yet precisely controlled reversal of movement direction: bow reversals during continuous ("legato") tone production on a stringed instrument. Ten advanced or professional cello players (at least 10 years of practice) and ten age-matched novice players took part in the study. Kinematic data from the bow and the right arm were analyzed in terms of velocity and acceleration profiles, as well as temporal coordination along the arm. As expected, experts' bow velocity and acceleration profiles differed markedly from those of novice participants, with higher peak accelerations and quicker direction changes. Importantly, experts achieved the change in movement direction with a single acceleration peak while novices tended to use multiple smaller acceleration peaks. Experts moreover showed a proximal-distal gradient in timing and amplitudes of acceleration peaks, with earlier and lower-amplitude reversals at more proximal joints. We suggest that this coordination pattern allows generating high accelerations at the end effector while reducing the required joint torques at the proximal joints. This may underlie experts' ability to produce fast bow reversals efficiently and with high spatiotemporal accuracy. The findings are discussed in terms of motor control theory as well as potential implications for musicians' performance and health. PMID- 23637656 TI - An intra-K-complex oscillation with independent and labile frequency and topography in NREM sleep. AB - NREM sleep is characterized by K-complexes (KCs), over the negative phase of which we identified brief activity in the theta range. We recorded high resolution EEG of whole-night sleep from seven healthy volunteers and visually identified 2nd and 3rd stage NREM spontaneous KCs. We identified three major categories: (1) KCs without intra-KC-activity (iKCa), (2) KCs with non oscillatory iKCa, and (3) KCs with oscillatory iKCa. The latter group of KCs with intra-KC-oscillation (iKCo), was clustered according to the duration of the iKCo. iKCa was observed in most KCs (1150/1522, 75%). iKCos with 2, 3, and 4 waves were observed in 52% (786/1522) of KCs in respective rates of 49% (386/786), 44%, and 7%. Successive waves of iKCos showed on average a shift of their maximal amplitude in the anterio-posterior axis, while the average amplitude of the slow KC showed no spatial shift in time. The iKCo spatial shift was accompanied by transient increases in instantaneous frequency from the theta band toward the alpha band, followed by decreases to upper theta. The study shows that the KC is most often concurrently accompanied by an independent brief iKCo exhibiting topographical relocation of amplitude maxima with every consecutive peak and transient increases in frequency. The iKCo features are potentially reflecting arousing processes taking place during the KC. PMID- 23637652 TI - Toward developmental models of psychiatric disorders in zebrafish. AB - Psychiatric disorders are a diverse set of diseases that affect all aspects of mental function including social interaction, thinking, feeling, and mood. Although psychiatric disorders place a large economic burden on society, the drugs available to treat them are often palliative with variable efficacy and intolerable side-effects. The development of novel drugs has been hindered by a lack of knowledge about the etiology of these diseases. It is thus necessary to further investigate psychiatric disorders using a combination of human molecular genetics, gene-by-environment studies, in vitro pharmacological and biochemistry experiments, animal models, and investigation of the non-biological basis of these diseases, such as environmental effects. Many psychiatric disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, mental retardation, and schizophrenia can be triggered by alterations to neural development. The zebrafish is a popular model for developmental biology that is increasingly used to study human disease. Recent work has extended this approach to examine psychiatric disorders as well. However, since psychiatric disorders affect complex mental functions that might be human specific, it is not possible to fully model them in fish. In this review, I will propose that the suitability of zebrafish for developmental studies, and the genetic tools available to manipulate them, provide a powerful model to study the roles of genes that are linked to psychiatric disorders during neural development. The relative speed and ease of conducting experiments in zebrafish can be used to address two areas of future research: the contribution of environmental factors to disease onset, and screening for novel therapeutic compounds. PMID- 23637657 TI - Emerging phenomena in neural networks with dynamic synapses and their computational implications. AB - In this paper we review our research on the effect and computational role of dynamical synapses on feed-forward and recurrent neural networks. Among others, we report on the appearance of a new class of dynamical memories which result from the destabilization of learned memory attractors. This has important consequences for dynamic information processing allowing the system to sequentially access the information stored in the memories under changing stimuli. Although storage capacity of stable memories also decreases, our study demonstrated the positive effect of synaptic facilitation to recover maximum storage capacity and to enlarge the capacity of the system for memory recall in noisy conditions. Possibly, the new dynamical behavior can be associated with the voltage transitions between up and down states observed in cortical areas in the brain. We investigated the conditions for which the permanence times in the up state are power-law distributed, which is a sign for criticality, and concluded that the experimentally observed large variability of permanence times could be explained as the result of noisy dynamic synapses with large recovery times. Finally, we report how short-term synaptic processes can transmit weak signals throughout more than one frequency range in noisy neural networks, displaying a kind of stochastic multi-resonance. This effect is due to competition between activity-dependent synaptic fluctuations (due to dynamic synapses) and the existence of neuron firing threshold which adapts to the incoming mean synaptic input. PMID- 23637658 TI - A model of electrophysiological heterogeneity in periglomerular cells. AB - Olfactory bulb (OB) periglomerular (PG) cells are heterogeneous with respect to several features, including morphology, connectivity, patterns of protein expression, and electrophysiological properties. However, these features rarely correlate with one another, suggesting that the differentiating properties of PG cells may arise from multiple independent adaptive variables rather than representing discrete cell classes. We use computational modeling to assess this hypothesis with respect to electrophysiological properties. Specifically, we show that the heterogeneous electrophysiological properties demonstrated in PG cell recordings can be explained solely by differences in the relative expression levels of ion channel species in the cell, without recourse to modifying channel kinetic properties themselves. This PG cell model can therefore be used as the basis for diverse cellular and network-level analyses of OB computations. Moreover, this simple basis for heterogeneity contributes to an emerging hypothesis that glomerular-layer interneurons may be better described as a single population expressing distributions of partially independent, potentially plastic properties, rather than as a set of discrete cell classes. PMID- 23637660 TI - "Building a foundation of trust". PMID- 23637659 TI - Astroglial networking contributes to neurometabolic coupling. AB - The strategic position of astrocytic processes between blood capillaries and neurons, provided the early insight that astrocytes play a key role in supplying energy substrates to neurons in an activity-dependent manner. The central role of astrocytes in neurometabolic coupling has been first established at the level of single cell. Since then, exciting recent work based on cellular imaging and electrophysiological recordings has provided new mechanistic insights into this phenomenon, revealing the crucial role of gap junction (GJ)-mediated networks of astrocytes. Indeed, astrocytes define the local availability of energy substrates by regulating blood flow. Subsequently, in order to efficiently reach distal neurons, these substrates can be taken up, and distributed through networks of astrocytes connected by GJs, a process modulated by neuronal activity. Astrocytic networks can be morphologically and/or functionally altered in the course of various pathological conditions, raising the intriguing possibility of a direct contribution from these networks to neuronal dysfunction. The present review upgrades the current view of neuroglial metabolic coupling, by including the recently unravelled properties of astroglial metabolic networks and their potential contribution to normal and pathological neuronal activity. PMID- 23637661 TI - Study types and bias-Don't judge a study by the abstract's conclusion alone. PMID- 23637662 TI - The influence of anatomy (normal versus scoliosis) on the free-hand placement of pedicle screws: Is misplacement more frequent in patients with anatomical deformity? AB - STUDY DESIGN: Retrospective prognostic study. OBJECTIVE: To evaluate whether patients with anatomical deformity due to scoliosis have a higher frequency of inaccurate pedicle screw insertion and related complications using the free-hand technique compared with those whose normal anatomy had been impacted by trauma. METHODS: Consecutively treated trauma patients with otherwise normal anatomy (48 patients instrumented with 291 screws, group A) and scoliosis patients (24 patients instrumented with 287 screws, group B) were evaluated. Screw position on CT was evaluated using the classification by Gertzbein and Robbins with modification by Karagoz Guzey. (See web appendix at www.aospine.org/ebsj for complete classification description.) Images were examined by two fellows and one junior staff member none of whom participated in patient management. Screw position was determined by consensus. RESULTS: In group A, five (1.7%) out of 289 screws were severely misplaced and 26 (9%) screws caused either medial (3.8%) or lateral (5.2%) cortical breeches. The other 258 (89.3%) screws were fully contained within the cortical boundaries of the pedicle. In group B, seven (2.8%) out of 256 screws were severely misplaced. Thirty-three (13%) screws caused cortical breeches, either medial (9%), lateral (2%), or anterior (2%), and 216 (84.3%) screws were fully contained within the cortical boundaries of the pedicle and the vertebra. Neurological complications were reported in one patient with scoliosis. No vascular complications were reported in either group. CONCLUSIONS: The percentage of incorrectly placed screws was similar in both groups, trauma and deformity patients. The presence of vertebral anatomical changes related to adult scoliosis was not associated with an increase in the screw-related neurological or vascular complications. [Table: see text] The definiton of the different classes of evidence is available on page 73. PMID- 23637663 TI - Risk factors for cardiac complications after spine surgery. AB - STUDY DESIGN: Registry study using prospectively collected data Objective: To determine risk factors for cardiac complications in spine surgery. METHODS: The Spine End RESULTS Registry 2003-2004 is an exhaustive database of 1,592 patients who underwent spine surgery at the University of Washington Medical Center or Harborview Medical Center. Detailed information regarding patient demographic, medical comorbidity, surgical invasiveness and adverse outcomes were prospectively recorded. The primary outcome of measure was the occurrence of a cardiac complication in the perioperative period. Relative risk (RR) and 95% confidence intervals were calculated for each of the categorical variables. Multiple log-binomial regression analysis was performed to investigate the independent factors associated with cardiac complication. RESULTS: The incidence of cardiac complication after spine surgery was 6.7%. There were 136 cardiac complications in 107 patients after spine surgery. Age, diabetes, previous cardiac history, elevated adjusted Charlson comorbidity score, revision surgery, combined anterior-posterior approaches, and surgical invasiveness were statistically significant risk factors for cardiac complication after spine surgery. CONCLUSIONS: The results of the present study suggest numerous statistically significant risk factors for cardiac complications after spine surgery. These results may aid the clinician with preoperative risk stratification and patient counseling. [Table: see text] The definiton of the different classes of evidence is available on page 73. PMID- 23637665 TI - Does lumbar decompression in overweight patients assist in postoperative weight loss? AB - STUDY DESIGN: Systematic review. OBJECTIVE: To determine if there is a weight change in overweight patients following lumbar decompression with or without fusion for lumbar degenerative conditions. SUMMARY OF BACKGROUND: Anecdotal evidence suggests obesity is a risk factor for recurrent disc herniation or adjacent segment degeneration after lumbar surgery. Weight loss after surgery therefore may be important to reduce risk of these problems. Theoretically, patients who recover may be able to increase exercise tolerance and therefore the possibility for weight loss is more likely. If spine patients are similar to knee arthroplasty then it is unlikely that substantial weight loss will occur after surgery. If true, then other patient centered programs need to be developed to help obese patient's loss weight after spine surgery. METHODS: A systematic review of the English language literature was undertaken for articles published between 1970 and March 2010. Electronic databases and reference lists of key articles were searched to identify studies evaluating weight change in overweight patients following lumbar decompression with or without fusion for lumbar degenerative conditions. Two independent reviewers assessed the strength of evidence using the GRADE criteria assessing quality, quantity, and consistency of results. Disagreements were resolved by consensus. RESULTS: We identified two articles meeting our inclusion criteria. Body weight change following lumbar surgery in overweight patients varied between the two included studies. One study reported 6% of patients lost weight 34 months following lumbar surgery, while 35% gained body weight. A second study reported 40% lost weight while 41% gained weight 20 months post surgery. Evidence from these two studies are limited due to small sample sizes, different definitions of overweight, and unequal lengths of follow up between the two studies. CONCLUSION: There is no evidence that overweight patients consistently lose weight as a result of lumbar decompression with or without fusion. Two small studies suggest that an overweight patient undergoing lumbar surgery is as likely to gain weight as to lose weight following surgery. PMID- 23637664 TI - Risk factors for pulmonary complications after spine surgery. AB - STUDY DESIGN: Registry study with prospectively collected data Objective: To determine risk factors for pulmonary complications in spine surgery. METHODS: The Spine End RESULTS Registry 2003-2004 is an exhaustive database of 1,592 patients who underwent spine surgery at the University of Washington Medical Center or Harborview Medical Center. Detailed information regarding patient demographic, medical comorbidity, and comorbidities, surgical invasiveness and adverse outcomes were prospectively recorded. The primary outcome measure was the occurrence of a pulmonary complication following surgery. Univariate relative risks and 95% confidence intervals for each of the risk factors were determined. Multivariate log binomial regression analysis was performed to investigate the association between each risk factor and a pulmonary complication, while controlling for other important risk factors. RESULTS: Altogether, there were 199 pulmonary complications after spine surgery. The cumulative incidence of a respiratory complication after spine surgery was 9% (144 patients). Multivariate analysis suggested gender, chronic obstructive pulmonary disease, congestive heart failure, diabetes, age, diagnosis, surgical invasiveness and surgery in the thoracic spine are significant risk factors for pulmonary complications after spinal surgery. CONCLUSIONS: The results of the present study suggest numerous statistically significant risk factors for pulmonary complications after spine surgery. These results may aid the clinician with preoperative risk stratification and patient counseling. [Table: see text] The definiton of the different classes of evidence is available on page 73. PMID- 23637666 TI - Is chemical antithrombotic prophylaxis effective in elective thoracolumbar spine surgery? Results of a systematic review. AB - STUDY DESIGN: Systematic review Study rationale and context: There is controversy regarding the efficacy and safety of chemical prophylaxis to prevent deep venous thrombosis (DVT) and pulmonary embolism (PE) in elective spinal procedures.Commonly performed elective spine surgeries done through a posterior approach have a very low associated risk of DVT/PE. The lack of consensus is due in part to a limited amount of quality evidence based literature dealing with this issue. OBJECTIVE: To compare chemical prophylaxis with no chemical prophylaxis in preventing venous thromboembolism in elective thoracolumbar spine surgery. METHODS: We undertook a systematic review of the literature to assess the efficacy and safety of chemical prophylaxis in preventing venous thromboembolism in elective thoracolumbar spine surgery. Pubmed, EMBASE, Cochrane, National Guideline Clearinghouse Databases as well as bibliographies of key articles were searched. Articles were reviewed by two independently working reviewers. Inclusion and exclusion criteria were set and each article was subject to a predefined quality rating scheme. RESULTS: We identified only two articles meeting our inclusion criteria. Neither study demonstrated a significant difference between chemical prophylaxis versus no prophylaxis in preventing thromboembolic events. There was an increased incidence of perioperative bleeding with low dose Coumadin in one of the studies. CONCLUSION: The incidence of DVT and PE in commonly performed elective posterior spinal procedures is very low. While there is a limited amount of randomized literature looking at this issue, the current literature does not support the routine use of chemical prophylaxis for low risk patients undergoing these procedures. PMID- 23637667 TI - Arachnoiditis ossificans associated with syringomyelia: An unusual cause of myelopathy. AB - OBJECTIVE: The pathophysiology of arachnoiditis ossificans (AO) and its association with syringomyelia remains a rare and poorly understood phenomenon. Here, we present a case of AO associated with syringomyelia, a review of literature, and a discussion of current understanding of disease pathophysiology. METHODS: A literature review was performed using MEDLINE (January 1900-May 2010) and Embase (January 1900-May 2010) to identify all English-language studies that described AO with syringomyelia. The current report was added to published cases. RESULTS: Over 50 cases of AO are reported in literature, of which only eight are associated with syringomyelia. The various presumptive etiologies of syrinx formation include abnormalities in blood circulation, ischemia, hydrodynamic alternations in cerebrospinal fluid (CSF) flow, tissue damage, or incidental coexistence. Changing CSF dynamics related to decreased compliance of the subarachnoid space and subsequent paracentral dissection of the spinal cord may be implicated in the disease process. magnetic resonance imaging (MRI) scanning may identify the syrinx but fail to diagnose the calcified arachnoid. Five patients, including the current case, improved clinically following laminectomy and decompression. CONCLUSIONS: Syringomyelia in association in AO is a rare phenomenon. A high index of suspicion is required and both MRI and computed tomography (CT) are recommended for diagnosis. The pathophysiology of syringomyelia in AO remains an area of ongoing research. PMID- 23637668 TI - Traumatic neuroma in continuity injury model in rodents: a preliminary report. AB - Consistent with EBSJ's commitment to fostering quality research, we are pleased to feature some of the most highly rated abstracts from the 8th Annual AOSpine North America Fellows Forum in Banff Canada. Enhancing the quality of evidence in spine care means acknowledging and supporting the efforts of young researchers within our AOSpine North America network. We look forward to seeing more from these promising researchers in the future. ABSTRACT: STUDY TYPE: Basic science research report Introduction: Spinal nerve-injury management and prevention constitute a substantial proportion of a spinal surgeon's practice. Functional recovery after peripheral nerve injuries is often unsatisfactory and to optimize the outcomes, an intimate understanding of these injuries is required. Sunderland classified peripheral nerve injuries into five grades.1 Grade 1 (neurapraxia) and grade 2 (axonal disruption) injuries usually recover with no or insignificant functional deficits within weeks to a few months, respectively. Injuries that are most difficult to manage clinically are the often mixed grade 3 (endoneurial disruption) and grade 4 (perineurial disruption) lesions where spontaneous functional recovery is limited or absent, resulting in neuroma in continuity (NIC). Traumatic NIC is characterized by aberrant intra- and extra- fascicular axonal regeneration and scar formation within an unsevered injured nerve, resulting in impaired and erroneous end-organ reinnervation.2,3 Animal models reproducing grade 1, 2, 3, and 5 lesions have been developed, but to our knowledge a clinically relevant rodent model of NIC has not been developed.4,5,6,7,8 The effective peripheral nerve regeneration and resilience of rodents make it challenging to recreate the NIC scenario. OBJECTIVE: Our goal was to develop a practical rodent model for focal traumatic NIC, demonstrating the characteristic histological features, supported by concordant functional deficits. Such a model may help us to identify this injury pattern earlier and allow development of intervention strategies to reduce neuronal misdirection, scar formation, and enhance regeneration for improved functional recovery. METHODS: Various injury techniques were tested on freshly harvested Lewis rat sciatic nerves ex vivo, and examined histologically before inflicting more refined injuries in vivo. The optimal experimental injuries combined a 50 g traction force applied with a spring scale hooked around the sciatic nerve, and focal three second maximal compression using a malleus nipper (Figure 1). Nerves were harvested at 0, 5, 13, 21, and 65 days, and processed for longitudinal 8 micron cryostat sectioning, H&E, laminin, neurofilament, and Masson's trichrome staining. Skilled locomotion (tapered beam, ladder rung) and flat plane locomotion for ground reaction force (GRF) analysis were performed serially up to 9 weeks with the experimental (n = 4) and simple (control) crush (n = 1) injuries by blinded animal behavior experts, using methods as recently described.9 Figure 1 Photograph illustrating the experimental injury. Fifty grams of traction is applied in a direction orthogonal to the native nerve course after external neurolysis, simultaneously, three second maximal compression is applied at the sciatic trifurcation, just distal to a mesoneurial suture. Malleus nipper with tip detail and 100 g spring scale in bottom left. In situ sciatic nerve immediately after injury (top right). RESULTS: Disruption of the endoneurium and perineurium with aberrant intra- and extrafascicular axonal regeneration and progressive fibrosis was consistently demonstrated histologically in ten out of ten nerves with experimental injuries. In contrast, crush injuries showed only signs of Wallerian degeneration (Figure 2). At 8 weeks, experimental animals made more errors during skilled locomotion as compared to nerve crush animals. GRFs revealed impaired vertical and fore-aft force generation by the injured limbs at week 9 in the experimental group, whereas GRFs from the simple crush animal revealed recovery at the same time point (Figure 3). Figure 2 Injury zones at five days (a-d, bar = 200 um) and 65 days (e-h, bar = 50 um), comparing crush (top) to experimental (bottom) injuries; Masson's trichrome and neurofilament. Note the aberrant axonal sprouting and regeneration in the experimental injury group, associated with increased intrafascicular collagen, in contrast to orderly regeneration and lack of scar in the simple crush group.Figure 3 Mean vertical and fore-aft ground reaction forces at both baseline and 9 weeks from representative animals. Compared to baseline and crush-injured animal at 9 weeks, animals in the experimental group bear less weight on both their right (surgical) hind limb (solid line), and fore limb (dotted line) at 9 weeks. Comparable with historical data, the crush animal have improved braking ((*)) and propulsive (#) forces in fore and hind limbs (injured side) compared to the experimental group, though these have not returned to baseline values. CONCLUSIONS: We have demonstrated histological features and poor functional recovery consistent with NIC formation in a rodent model. The injury mechanism employed combines traction and compression forces akin to the physical forces at play in clinical nerve injuries. Additional validating experiments are in progress. PMID- 23637669 TI - Accuracy and reliability of MRI quantitative measurements to assess spinal cord compression in cervical spondylotic myelopathy: a prospective study. AB - STUDY TYPE: Reliability study Introduction: Cervical spondylotic myelopathy (CSM) is the most common spinal cord disorder in persons more than 55 years old. Despite multiple neuroimaging approaches proposed to quantify the spinal cord compromise in CSM patients, magnetic resonance imaging (MRI) remains the procedure of choice by providing helpful information for clinical decision making, determining optimal subpopulations for treatment, and selecting the optimal treatment strategies. However, the validity, reliability, and accuracy of the MRI quantitative measurements have not yet been addressed. OBJECTIVE: To assess the intra- and inter-observer reliability of MRI quantitative measurements of the spinal cord compromise in CSM patients. METHODS: Seventeen CSM patients (13 male) of mean age 54.5 years old were selected from the AOSpine North America database. The patients had different combinations of stenotic levels (1-4 levels) and the clinical severity (range mJOA baseline: 8-18). Asymptomatic or previous surgically treated CSM, active infection, neoplastic disease, rheumatoid arthritis, ankylosing spondylitis, trauma, or concomitant lumbar stenosis were excluded. The patients underwent preoperative MRI using 1.5T (15 patients) and 3T (two patients) scanner, including mid-sagittal T1-weighted, axial and mid sagittal T2-weighted series. MRI data were analyzed (Mango 2.0 software; Multi Image Analysis GUI) by four blind raters in three different sessions. Four measurements were analysed: transverse area (TA) (Figure 1), compression ratio (CR) (Figure 2), maximal canal compromise (MCC), and maximal spinal cord compression (MSCC) (Figure 3). The differences for each measurement were evaluated using mixed-effect ANOVA models (ratter, session, ratter x session). The intra- and inter-rater reliability was evaluated with intraclass correlation coefficients (ICC) (Figure 4). Figure 1 Transverse area (TA)Figure 2 Compression ratio (CR = AP/W)Figure 3 Maximal canal compromise (MCC), and maximal spinal cord compression (MSCC). MCC(%) = 1-[Dx/(Da+Db)/2] * 100%; MSCC(%) = 1-[dx/(da+db)/2] * 100%Figure 4 Intraclass correlation coefficients (ICC) Results: The principal findings were: (i) for TA (71.48 +/- 12.99mm2), the intra-rater agreement was 0.97 (95% CI, range 0.94-0.99) and the inter-rater agreement was 0.76 (95% CI, range 0.49-0.90); (ii) for CR (0.35 +/- 0.04%), 0.94 (95% CI, range 0.88-0.98), and 0.79 (95% CI, range 0.57-0.91) respectively; (iii) for MCC (83.21 +/- 2.08%), 0.95 (95% CI, range 0.89-0.98), and 0.64 (95% CI, range 0.28-0.85) respectively; and (iv) for MSCC (82.87 +/- 1.52%), 0.93 (95% CI, range 0.86-0.97), and 0.84 (95% CI, range 0.65-0.93) respectively. CONCLUSIONS: Our data suggest that three out of four measurements (TA, CR and MSCC) have acceptable intra- and interreliability coefficients (ICC > 0.75). However, for the maximal canal compromise measure, although the intrareliability was acceptable, the inter-rater reliability was not acceptable (0.64). Based on this study, we recommend that three MRI measures: transverse area, compression ratio and maximal spinal cord compression should be used in the imaging assessment of the spinal cord in CSM patients. PMID- 23637670 TI - Intraoperative neuromonitoring: lessons learned from 32 case events in 2095 spine cases. AB - STUDY TYPE: Restrospective chart review Introduction: Intraoperative neuromonitoring is becoming the standard of care for many more spinal surgeries, especially with deformity correction and instrumentation. We reviewed our institution's neuromonitored spine cases over the past 4 years to see the immediate intraoperative and postoperative clinical findings when an intraoperative neuromonitoring event was noted. OBJECTIVE: The main question addressed in this review is how multimodality intraoperative neuromonitoring has affected our ability to avoid potential neurological injury during spine surgery. METHODS: We retrospectively reviewed 2,095 neuromonitored spine cases at one institution performed over a period of 4 years. Data from the single neuromonitoring provider (Impulse Monitoring, Inc.) at our institution was collected and any cases with possible intraoperative events were isolated. The intraoperative and immediate postoperative clinical documentation of these 32 cases were reviewed (Table 1). [Table: see text] RESULTS: There were 17 cases where changes noted on EMG, SSEP, and/or MEPs affected the course of the surgery, and prevented possible postoperative neurological deficits. Of these 17, five were related to hypotension, seven due to deformity correction, one screw had a low triggered EMG threshold and was repositioned, and four cases had changes related to patient positioning and external pressure (ie, brachial plexus stretch). None of the 17 cases had postoperative motor or sensory deficits (Figure 1). Figure 1 DURING THE INSERTION OF THE CONVEX ROD: decrease of the MEP amplitude in left foot by 80% amplitude (yellow arrow). The baseline recording is in blue, the current recording in purple. The right side (non represented) will remain normal. Four cases consisted of intradural cord biopsies or tumor resections that had various positive neuromonitoring findings that essentially serve as controls. These cases confirm that the expected changes were seen on neuromonitoring. Four cases had false-positive neuromonitoring findings due to one technical issue requiring needle repositioning, one low threshold with triggered EMG without a pedicle breach, one case had decreased MEP responses with stable SSEPs, and one case had decreased SSEPs after positioning the patient prone. None of these four cases had any postoperative deficits. Four cases showed improved SSEPs after decompression; three cervical corpectomies, and one thoracic discectomy. Three cases of lumbar instrumentation with spontaneous EMGs each had a medial screw breach without intraoperative findings (Figure 2). They all had a postoperative motor deficit (foot drop). None of these three cases had triggered EMGs performed with the index procedure. Figure 2 Left L4 pedicle screw medial breach. Triggered EMGs were not performed during the index procedure. Postoperative foot drop required a second surgery to reposition the screw. CONCLUSIONS: Overall, this review reinforces the importance of multimodality neuromonitoring for spinal surgery. The incidence of possible events in our series was 1.5%. It is difficult to determine the true incidence, since it is impossible to know of any missed events due to lack of complete documentation. In a majority of the cases with events, possible postoperative neurologic deficits were avoided by intraoperative intervention, but the possible outcomes without intervention are not known. Clearly, in the three cases with lumbar pedicle screw malposition, triggered EMGs would have likely shown low thresholds. This would allow for screw reposition, and thus avoid a postoperative lumbar radiculopathy and revision surgery. The incidence of false-positive findings was very low in this review, and unfortunately the true incidence of false-negative findings is not able to be elucidated with this database. PMID- 23637671 TI - Total disc replacement using a tissue-engineered intervertebral disc in vivo: new animal model and initial results. AB - STUDY TYPE: Basic science Introduction: Chronic back pain due to degenerative disc disease (DDD) is among the most important medical conditions causing morbidity and significant health care costs. Surgical treatment options include disc replacement or fusion surgery, but are associated with significant short- and long-term risks.1 Biological tissue-engineering of human intervertebral discs (IVD) could offer an important alternative.2 Recent in vitro data from our group have shown successful engineering and growth of ovine intervertebral disc composites with circumferentially aligned collagen fibrils in the annulus fibrosus (AF) (Figure 1).3 Figure 1 Tissue-engineered composite disc a Experimental steps to generate composite tissue-engineered IVDs3b Example of different AF formulations on collagen alignment in the AF. Second harmonic generation and two-photon excited fluorescence images of seeded collagen gels (for AF) of 1 and 2.5 mg/ml over time. At seeding, cells and collagen were homogenously distributed in the gels. Over time, AF cells elongated and collagen aligned parallel to cells. Less contraction and less alignment is noted after 3 days in the 2.5 mg/mL gel. c Imaging-based creation of a virtual disc model that will serve as template for the engineered disc. Total disc dimensions (AF and NP) were retrieved from micro-computer tomography (CT) (left images), and nucleus pulposus (NP) dimensions alone were retrieved from T2-weighted MRI images (right images). Merging of MRI and micro-CT models revealed a composite disc model (middle image)-Software: Microview, GE Healthcare Inc., Princeton, NJ; and slicOmatic v4.3, TomoVision, Montreal, Canada. d Flow chart describing the process for generating multi-lamellar tissue engineered IVDs. IVDs are produced by allowing cell-seeded collagen layers to contract around a cell-seeded alginate core (NP) over time Objective: The next step is to investigate if biological disc implants survive, integrate, and restore function to the spine in vivo. A model will be developed that allows efficient in vivo testing of tissue engineered discs of various compositions and characteristics. METHODS: Athymic rats were anesthetized and a dorsal approach was chosen to perform a microsurgical discectomy in the rat caudal spine (Fig. 2,Fig. 3). Control group I (n = 6) underwent discectomy only, Control group II (n = 6) underwent discectomy, followed by reimplantation of the autologous disc. Two treatment groups (group III, n = 6, 1 month survival; group IV, n = 6, 6 months survival) received a tissue-engineered composite disc implant. The rodents were followed clinically for signs of infection, pain level and wound healing. X-rays and magnetic resonance imaging (MRI) were assessed postoperatively and up to 6 months after surgery (Fig. 6,Fig. 7). A 7 Tesla MRI (Bruker) was implemented for assessment of the operated level as well as the adjacent disc (hydration). T2-weighted sequences were interpreted by a semiquantitative score (0 = no signal, 1 = weak signal, 2 = strong signal and anatomical features of a normal disc). Histology was performed with staining for proteoglycans (Alcian blue) and collagen (Picrosirius red) (Fig. 4,Fig. 5). Figure 2 Disc replacement surgery a Operative situs with native disc that has been disassociated from both adjacent vertebrae b Native disc (left) and tissue-engineered implant (right) c Implant in situ before wound closureAF: Annulus fi brosus, nP: nucleus pulposus, eP: endplate, M: Muscle, T: Tendon, s: skin, art: artery, GP: Growth plate, B: BoneFigure 3 Disc replacement surgery. Anatomy of the rat caudal disc space a Pircrosirius red stained axial cut of native disc space b Saffranin-O stained sagittal cut of native disc spaceFigure 4 Histologies of three separate motion segments from three different rats. Animal one = native IVD, Animal two = status after discectomy, Animal three = tissue-engineered implant (1 month) a-c H&E (overall tissue staining for light micrsocopy) d-f Alcian blue (proteoglycans) g-i Picrosirius red (collagen I and II)Figure 5 Histology from one motion segment four months after implantation of a bio-engineered disc construct a Picrosirius red staining (collagen) b Polarized light microscopy showing collagen staining and collagen organization in AF region c Increased Safranin-O staining (proteoglycans) in NP region of the disc implant d Higher magnification of figure 5c: Integration between implanted tissue-engineered total disc replacement and vertebral body boneFigure 6 MRI a Disc space height measurements in flash/T1 sequence (top: implant (714.0 micrometer), bottom: native disc (823.5 micrometer) b T2 sequence, red circle surrounding the implant NPFigure 7 7 Tesla MRI imaging of rat tail IVDs showing axial images (preliminary pilot data) a Diffusion tensor imaging (DTI) on two explanted rat tail discs in Formalin b Higher magnification of a, showing directional alignment of collagen fibers (red and green) when compared to the color ball on top which maps fibers' directional alignment (eg, fibers directing from left to right: red, from top to bottom: blue) c Native IVD in vivo (successful imaging of top and bottom of the IVD (red) d Gradient echo sequence (GE) showing differentiation between NP (light grey) and AF (dark margin) e GE of reimplanted tail IVD at the explantation level f T1Rho sequence demonstrating the NP (grey) within the AF (dark margin), containing the yellow marked region of interest for value acquisition (preliminary data are consistent with values reported in the literature). g T2 image of native IVD in vivo for monitoring of hydration (white: NP) Results: The model allowed reproducible and complete discectomies as well as disc implantation in the rat tail spine without any surgical or postoperative complications. Discectomy resulted in immediate collapse of the disc space. Preliminary results indicate that disc space height was maintained after disc implantation in groups II, III and IV over time. MRI revealed high resolution images of normal intervertebral discs in vivo. Eight out of twelve animals (groups III and IV) showed a positive signal in T2-weighted images after 1 month (grade 0 = 4, grade 1 = 4, grade 2 = 4). Positive staining was seen for collagen as well as proteoglycans at the site of disc implantation after 1 month in each of the six animals with engineered implants (group III). Analysis of group IV showed positive T2 signal in five out of six animals and disc-height preservation in all animals after 6 months. CONCLUSIONS: This study demonstrates for the first time that tissue-engineered composite IVDs with circumferentially aligned collagen fibrils survive and integrate with surrounding vertebral bodies when placed in the rat spine for up to 6 months. Tissue engineered composite IVDs restored function to the rat spine as indicated by maintenance of disc height and vertebral alignment. A significant finding was that maintenance of the composite structure in group III was observed, with increased proteoglycan staining in the nucleus pulposus region (Figure 4d-f). Proteoglycan and collagen matrix as well as disc height preservation and positive T2 signals in MRI are promising parameters and indicate functionality of the implants. PMID- 23637672 TI - Development of a whole disc organ culture system to study human intervertebral disc. AB - STUDY TYPE: Basic science Objective: Low back pain is one of the most common health problems1 and is strongly associated with intervertebral disc degeneration, (IVD). Current treatments remove the symptoms without reversing or even retarding the underlying problem. Development of new therapy for the regeneration of the degenerative IVD is complicated by the lack of a validated long-term organ culture model in which therapeutic candidates can be studied. The object of this study was to develop, optimize, and validate an organ culture model for human IVD, allowing for the study of degeneration and the potential for regeneration of the human IVD. METHODS: From eleven donors, an average of 5-6 IVDs were obtained. Inclusion criteria were; age between 50 and 70 years old, no history of cancer, chemotherapy, diabetes, or liver cirrhosis. An x-ray of the harvested spine was done to assess the grade of degeneration. Three different methods for isolating the discs were studied: with bony endplate (BEP), without endplate (NEP), and with cartilage endplate (CEP). Discs were cultured for 4 weeks without external load, in Dulbecco's modified eagle media with glucose and fetal bovine serum (FBS). Four different combinations of concentrations of glucose and FBS were compared: low glucose-low FBS, low glucose-high FBS, high glucose-low FBS, and high glucose-high FBS.2 Short-term cultures (1 week) were performed to compare the cell viability of the three methods of isolating the discs. Swelling potential on NEP and CEP discs from the same donor were evaluated. After four weeks of culture, a 4 mm punch was taken from CEP discs and cell viability was evaluated using a live/dead assay with confocal microscopy. RESULTS: Analyzing the potential of swelling in CEP discs, there was an increase in volume to a maximum of 25% and retention of shape and morphology. Whereas in NEP discs, there was an excessive deformation and a two-fold time increase in volume than CEP discs. The cell viability in short-term cultures is around 40% 50% in the BEP model, 50%-60% in the NEP model and > 96% in the CEP model. BEP isolated discs show endplate necrosis that begins after 4 days of culture. Cell viability in CEP discs was evaluated at 4 weeks in three different areas of the disc: nucleus pulposus, inner annulus fibrosus, and outer annulus fibrosus. We found no difference in live cells (> 96%) between the four different concentrations of FBS and glucose (Table 1). [Table: see text] CONCLUSIONS: We have developed a novel method to isolate human IVDs and optimized the culture conditions. The CEP method has been proven to be superior to the previous models (NEP and BEP) in cell viability and maintaining physiologic swelling.3 In the long-term cultures, the CEP system maintained sufficient nutrient supply and high cell survival in all regions of the discs even with low concentrations of FBS and glucose. The availability of an intact disc organ culture system has a considerable advantage over the culture of isolated disc cells, as it maintains the cells in their unique microenvironment, making any response to catabolic or anabolic agents more physiologically relevant. PMID- 23637674 TI - Evaluation of the sodium-glutamate blocker riluzole in a preclinical model of ervical spinal cord injury. AB - STUDY TYPE: Basic research Introduction: Because sodium and glutamate play integrated roles in the pathology of spinal cord injury (SCI), there is intense interest in the potential role of the sodium-glutamate blocker riluzole as a neuroprotective agent for spinal cord injury. A phase I safety clinical trial of riluzole is about to commence in the USA and Canada. OBJECTIVE: The key challenges in translating riluzole to the clinic relate to uncertainty regarding the time window for post-injury administration of riluzole and the optimal dose. Hence, the current study was undertaken to study these issues in a preclinical model of cervical SCI in rodents. METHODS: Adult female rats received moderate cervical spinal cord clip compression injury (35 g * 1 min at C7-T1) and were randomly assigned to one of the following three groups (n = 12/group): a) 8 mg/kg of riluzole intraperitoneally at 1 hour (P1 group) ; b) 3 hours (P3 group) after injury or c) a control group (vehicle). The P1 and P3 groups then received 6 mg/kg of riluzole intraperitoneally every 12 hours for 7 days. A smaller group of rats (n = 10) received a higher dose (8 mg/kg IP Q12 h for 7 days) of riluzole following the initial dosing. Functional recovery was tested by open field locomotion (BBB score, BBB subscore) and grid walk. Sensory function (tactile allodynia) was assessed by quantitative von Frey filament testing. Somatosensory evoked potentials (SSEP) were performed to quantitatively assess central axonal conduction. Western blotting for neurofilament 200 (NF200) was used to assess axonal integrity. Quantitative image analysis of lesion histology (HE/LFB stained sections) was undertaken to assess tissue sparing at the injury site. High performance liquid chromatography (HPLC) was used to test pharmacokinetics of riluzole. ANOVA followed by the Tukey's post-hoc testing was used to compare the results. RESULTS: A total of 92.3% of injured rats that received repeated dose of 6 mg/kg riluzole survived during the term of 6 weeks, showing tolerance to this dosage. In contrast, higher doses of riluzole (8mg/kg IP q12h post-injury) were associated with significant respiratory depression and high mortality (7/10 rats). Riluzole treatment (P1 group) decreased the functional deficit significantly (P < 0.05) at 6 weeks after injury by showing 11.4 in BBB, 3.8 in BBB subscore and 2.8 in grid walk test, compared with 10.25 in BBB, 1.1 in BBB subscore, and 8.0 in grid walk test of control group (Figure 1). Quantitative analysis of SSEPs confirmed the neuroprotective effects of riluzole (P1 group) by showing significantly larger amplitude (control = 20.67 uV, P1 = 42.67 uV and P3 = 37.00 uV, Figure 2) and reduced response latency (control = 4.05 ms and P1 = 3.9 ms). Western blotting of NF200 indicated greater axonal preservation with riluzole treatment (P1 group) at 1 week after injury. The P3 group showed trends to improved neurobehavioral recovery and axonal preservation that did not attain significance. HPLC showed riluzole penetrated into the spinal cord as fast as 15 minutes, accumulated in the spinal cord at a concentration six times higher than in plasma, and two times higher than in brain. The drug stayed in spinal cord with a high concentration before the next injection. Figure 1 Riluzole treatment improved functional recovery. The most robust effects were seen when the drug was injected at one hour after SCIFigure 2 Riluzole treatment increased amplitude of somatosensory evoked potentials Conclusions: The sodium-glutamate blocker riluzole confers neurobehavioral and anatomical neuroprotection when administered one hour after moderately severe cervical contusive/compressive injury. PMID- 23637673 TI - Diagnosis and treatment of craniocervical dissociation in 48 consecutive survivors. AB - STUDY TYPE: Case series Introduction: Craniocervical dissociation (CCD) is an uncommon and frequently fatal injury with few reports in the literature of survivors. Advances in automobile safety and improved emergency medical services have resulted in increased survival. Timely diagnosis and treatment are imperative for optimal outcome. Regrettably, the presence of multiple life threatening injuries, low clinical suspicion, and lack of familiarity with the upper cervical radiographic anatomy frequently lead to missed or delayed diagnosis. OBJECTIVE: This paper represents the largest series of surgically treated CCD survivors. The goal of this study is to determine if any improvements have been made in the timely diagnosis of CCD while performing a complete patient evaluation. METHODS: Following institutional review board approval, a search of the Harborview Medical Center (HMC) trauma registry was conducted for all surgically treated CCD patients between 1996 and 2008. Forty-eight consecutive cases were identified. A retrospective review of the radiological and clinical results with emphasis on timing of diagnosis, modality used for diagnosis (Figures 1 and 2), clinical effect of delayed diagnosis, potential clinical or imaging warning signs, and response to treatment was performed. Thirty-one patients treated from 2003 to 2008 were compared to 17 patients that were treated from 1996 to 2002 and reported previously.1 Figure 1 Initial lateral C-spine radiograph obtained as part of the initial ATLS survey demonstrating an occiput C1 distractive injury.Figure 2 Sagittal C-spine CT scan obtained as part of the initial ATLS survey demonstrating an occiput C2 distractive injury. All patients sustained high-energy injuries and were evaluated according to standard Advanced Trauma Life Support (ATLS) protocols. Once CCD was identified or suspected, provisional stabilization was applied and MRI evaluation performed (Figure 3). Definitive surgical management with rigid posterior instrumentation and fusion was performed as soon as physiologically possible (Figures 4 and 5). Figure 3a-b Preoperative coronal T2 MRI sequences demonstrating increased signal intensity on the occiput-C1 and C1-2 joints.Figure 4 Postoperative lateral C-spine x-ray showing rigid posterior instrumented fusion from occiput to C2.Figure 5 Postoperative sagittal C-spine x-ray showing rigid posterior instrumented fusion from occiput to C2. RESULTS: Craniocervical dissociation was identified on initial cervical spine imaging in 26 patients (84%). The remaining five patients (16%) were diagnosed by cervical spine MRI. Twenty-three patients (74.2%) were diagnosed within 24 hours of presentation, four (22.6%) were diagnosed between 24 and 48 hours, and one (3.2%) experienced a delay of greater than 48 hours (Table 1). In comparison, four (24%) of the previously treated 17 patients were diagnosed on initial cervical spine imaging. Four patients (24%) were diagnosed within 24 hours of presentation, nine (52%) were diagnosed between 24 and 48 hours, and four (24%) experienced a delay of greater than 48 hours. There were no cases of craniocervical pseudarthrosis or hardware failure during a mean nine month follow-up period. Four patients expired during their hospital course. The mean American Spinal Injury Association (ASIA) motor score of 47 improved to 60, and the number of patients with useful motor function (ASIA Grade D or E) increased from eight (26%) preoperatively to 17 (55%) postoperatively. CONCLUSIONS: Improvements have been made in time to diagnosis of CCD in recent years. Increased awareness and the routine use of CT scan as part of the initial ATLS evaluation account for this progress. Expedited diagnosis has decreased preoperative neurological deterioration. However, differences in length of follow up between the two groups preclude conclusions about its effect on long-term neurological outcome. [Table: see text]. PMID- 23637675 TI - Avarice, evidence, and the media. PMID- 23637676 TI - Heterogeneity of treatment effects: from "How to treat" to "Whom to treat". PMID- 23637677 TI - The influence of the energy of trauma, the timing of decompression, and the impact of grade of SCI on outcome. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To find out: (1) if the energy of trauma (high and low) influence the outcome after cervical spinal cord injury; (2) if time to decompression and degree of injury (complete and incomplete) influence the outcome after high- and low-energy cervical spinal cord injury. METHODS: Twenty-one consecutive patients with low-energy cervical spinal cord injury were identified from the spinal injuries unit database (eg, ball sports, diving, surfing, and falls). Twenty-one aged-matched patients with high energy cervical spinal cord injury (eg, motor vehicle trauma) were then randomly selected and the groups were compared. All patients had formal American Spinal Injuries Association assessment on admission and at 6 months. RESULTS: At the 6 month follow-up, the energy of the initial trauma was not found to influence the neurological outcome (P = .76). Early definitive intervention (<8 hours) for patients with incomplete cord lesions was shown to significantly affect outcome (P = .049). As expected, patients with an incomplete spinal cord injury at presentation showed significantly greater neurological improvement at follow-up compared with those with complete injuries (P = .006). CONCLUSIONS: We were unable to find a correlation between the energy of the initial trauma causing a spinal cord injury and the neurological outcome. Early definitive decompression improved outcomes for patients with spinal cord injury, especially those with incomplete spinal cord injury. [Table: see text] The definiton of the different classes of evidence is available on page 55. PMID- 23637678 TI - Interspinous devices: are they as attractive as they seem? An intermediate-term follow-up. AB - STUDY DESIGN: A retrospective cohort of 68 patients who underwent insertion of the DIAM (Medtronic Sofamor Danek, Switzerland) interspinous device (ISD) during 2006-2008 at one medical center. OBJECTIVES: To assess the short- and intermediate-term outcomes and complications associated with ISD. METHODS: Evaluation of files and all patients who underwent insertion of a DIAM ISD was performed. Patients walking distances and pain (visual analog scale score) were compared with data gathered before surgery. Outcome and all complications related to ISD have been identified and analyzed. RESULTS: All 68 patients were available for follow-up. Mean follow-up was 34 months (23-52 months). The average age was 57 (+/-13) years. Walking distance increased by 890% and patient's pain score improved by 3.27 points on visual analog scale. Twenty-one (32%) of the 68 patients had perioperative or late complications. Nine complications (75%) were unrelated to ISD and included 5 dura tears, 3 wound-related complications, and 1 transient ischemic attack. Spinous process fractures occurred in 5 cases, leading to revision in 2 cases. In total, 7 of the patients required revision surgery. These patients were older, with an average age of 69 years. CONCLUSION: The outcome of patients who had an implantation of the DIAM ISD is good. In this cohort, 6% developed recurrent claudication symptoms in the second postoperative year. In an older population, the combination of softer bone and rigid stenosis increase the risk of spinous process fracture, resulting in failure and leading to revision surgery. Other solutions should be sought for these patients. [Table: see text] The definiton of the different classes of evidence is available on page 55. PMID- 23637679 TI - Efficacy of bracing versus observation in the treatment of idiopathic scoliosis. AB - STUDY DESIGN: Systematic review. OBJECTIVES: (1) Does brace treatment compared with observation of curves lead to lower rates of surgery and failure for patients with idiopathic scoliosis? (2) Does brace treatment compared with observation of curves lead to better quality of life outcomes for patients with idiopathic scoliosis? (3) Does brace treatment compared with observation of curves lead to improved curve angle for patients with idiopathic scoliosis? METHODS: A systematic review of the English-language literature was undertaken for articles published between 1970 and December 2010. Electronic databases and reference lists of key articles were searched to identify studies comparing brace treatment with observation of curves in patients with idiopathic scoliosis. Two independent reviewers assessed the strength of evidence using the GRADE criteria assessing quality, quantity, and consistency of results. Disagreements were resolved by consensus. RESULTS: We identified eight studies meeting our inclusion criteria. The pooled studies comparing surgical rates between observation and brace treatment showed no statistical significance (P = .65). One study showed a statistically significant difference in failure rate between observation (45%) and brace (15%) treatment (P < .001). Findings with respect to posttreatment quality of life at 2 years were inconsistent. Two studies favored the brace group, and one the observation group using the SRS-22 and Quality of Life Profile for Spine Deformities (QLPSD) measures. Two of three studies reporting pretreatment and posttreatment curve angles demonstrated a treatment effect favoring bracing; however, statistical significance for these treatment effects could not be calculated. One study described a treatment effect favoring observation but the differences were not statistically significant (P = .26). CONCLUSION: This systematic review identified and summarized only the highest level of evidence by limiting to comparison studies. Case-series were not included. This allowed for comparisons among the same patient populations. Findings with respect to surgical rates, quality of life, and change in curve angle demonstrate either no significant differences or inconsistent findings favoring one treatment or the other. If bracing does not cause a positive treatment effect, then its rejection will lead to significant savings for healthcare providers and purchasers. Given the very low to low level of evidence and inconsistent findings, a randomized trial is necessary to determine if bracing should be recommended. PMID- 23637680 TI - Lumbar posterolateral fusion with local bone graft plus bone extender compared with iliac crest bone graft: a systematic review. AB - STUDY DESIGN: Systematic review. Study rationale and context: Bone graft from the iliac crest has been the gold standard in posterolateral spinal fusion procedures, but is associated with chronic pain at the harvest site. Bone graft harvested locally from the spine and combined with extenders may decrease the morbidity associated with iliac graft harvest, but questions remain on the success of this technique to achieve bone union. OBJECTIVES: Compare the fusion rate, functional outcomes, and safety of local bone graft plus bone extender compared with iliac crest bone graft in posterolateral spinal fusion procedures. METHODS: A systematic review of the literature was undertaken for articles published through January 2011. Pubmed, Cochrane, National Guideline Clearinghouse Databases, and bibliographies of key articles were searched. Two independent reviewers studied the articles. Inclusion and exclusion criteria were set and each article was subject to a predefined quality-rating scheme. RESULTS: We identified three articles meeting our inclusion criteria. Fusion rates were high across studies, with no significant differences between treatment groups in fusion, functional outcomes, or quality of life. There were two deep infections (5.3%) in one study among patients receiving local bone graft plus extender. CONCLUSION: Local bone graft plus bone extender has similar fusion rates, functional outcomes, and patient quality-of-life scores as iliac crest bone graft in posterolateral spinal fusion procedures. Additional randomized trials with standardized methods of measuring fusion and functional outcomes are needed. PMID- 23637681 TI - Dropped head syndrome: diagnosis and management. AB - Dropped head syndrome (DHS) is a relatively rare condition, with a broad differential diagnosis. This deformity has significant implications on the health and quality of life of affected individuals. While surgery seems to be an obvious therapeutic option, there is a paucity of information on surgical intervention with no clear consensus on an optimal approach or timing. We present a case of DHS in a young woman to illustrate this condition, and review the current literature. Although at present the only definitive solution for correction and stabilization of DHS is surgical intervention involving multilevel instrumented fixation and fusion, this condition requires a persistent medical workup and treatment of reversible causes before surgical intervention is contemplated. PMID- 23637682 TI - L5 vertebral osteomyelitis treated with L5 corpectomy and anterior instrumentation: case report. AB - STUDY DESIGN: A case report. OBJECTIVE: Pyogenic osteomyelitis is the most common form of vertebral infection and typically resolves following conservative treatment with antibiotics administered long term and immobilization. In cases of spinal instability, severe neurological deficit or disease refractory to medical management, neurosurgical intervention is warranted. Historically, these patients have undergone radical vertebral debridement and grafting with or without posterior instrumentation. We report the case of a 46-year-old female intravenous drug user presenting with L5 pyogenic osteomyelitis with L5 vertebral compression and cortex retropulsion following L2-L4 laminectomy for epidural abscess 8 weeks prior. METHODS: The patient underwent an anterior approach single-stage L5 corpectomy, L4/5 and L5/S1 discectomies, expandable titanium-cage insertion and anterior plating from L4 to the sacrum. RESULTS: The patient recovered without any complications. The infection was successfully eradicated and her fusion remains solid 18 months postoperatively. CONCLUSIONS: To our knowledge, this is the first case of L5 vertebral osteomyelitis treated with a single-stage corpectomy and anterior instrumentation. PMID- 23637683 TI - A view on EGFR-targeted therapies from the oncogene-addiction perspective. AB - Tumor cell growth and survival can often be impaired by inactivating a single oncogen- a phenomenon that has been called as "oncogene addiction." It is in such scenarios that molecular targeted therapies may succeed. among known oncogenes, the epidermal growth factor receptor (EGFR) has become the target of different cancer therapies. So far, however, the clinical benefit from EGFR-targeted therapies has been rather limited. a critical review of the large amount of clinical data obtained with anti-EGFR agents, carried out from the perspective of the oncogene addiction concept, may help to understand the causes of the unsatisfactory results. In this article we intend to do such an exercise taking as basis for the analysis a few case studies of anti-EGFR agents that are currently in the clinic. There, the "EGFR addiction" phenomenon becomes apparent in high-responder patients. We further discuss how the concept of oncogene addiction needs to be interpreted on the light of emerging experimental evidences and ideas; in particular, that EGFR addiction may reflect the interconnection of several cellular pathways. In this regard we set forth several hypotheses; namely, that requirement of higher glucose uptake by hypoxic tumor cells may reinforce EGFR addiction; and that chronic use of EGFR-targeted antibodies in EGFR-addicted tumors would induce stable disease by reversing the malignant phenotype of cancer stem cells and also by sustaining an anti-tumor T cell response. Finally, we discuss possible reasons for the failure of certain combinatorial therapies involving anti-EGFR agents, arguing that some of these agents might produce either a negative or a positive trans-modulation effect on other oncogenes. It becomes evident that we need operational definitions of EGFR addiction in order to determine which patient populations may benefit from treatment with anti-EGFR drugs, and to improve the design of these therapies. PMID- 23637685 TI - Physical activity and physical activity induced energy expenditure in humans: measurement, determinants, and effects. AB - Physical activity is defined as any bodily movement produced by skeletal muscles that results in energy expenditure. The doubly labeled water method for the measurement of total energy expenditure (TEE), in combination with resting energy expenditure, is the reference for physical activity under free-living conditions. To compare the physical activity level (PAL) within and between species, TEE is divided by resting energy expenditure resulting in a figure without dimension. The PAL for sustainable lifestyles ranges between a minimum of 1.1-1.2 and a maximum of 2.0-2.5. The average PAL increases from 1.4 at age 1 year to 1.7-1.8 at reproductive age and declines again to 1.4 at age 90 year. Exercise training increases PAL in young adults when energy balance is maintained by increasing energy intake. Professional endurance athletes can reach PAL values around 4.0. Most of the variation in PAL between subjects can be ascribed to predisposition. A higher weight implicates higher movement costs and less body movement but not necessarily a lower PAL. Changes in physical activity primarily affect body composition and to a lesser extent body weight. Modern man has a similar PAL as a wild mammal of a similar body size. PMID- 23637684 TI - Effects of pacing site and stimulation history on alternans dynamics and the development of complex spatiotemporal patterns in cardiac tissue. AB - Alternans of action potential duration has been associated with T wave alternans and the development of arrhythmias because it produces large gradients of repolarization. However, little is known about alternans dynamics in large mammalian hearts. Using optical mapping to record electrical activations simultaneously from the epicardium and endocardium of 9 canine right ventricles, we demonstrate novel arrhythmogenic complex spatiotemporal dynamics. (i) Alternans predominantly develops first on the endocardium. (ii) The postulated simple progression from normal rhythm to concordant to discordant alternans is not always observed; concordant alternans can develop from discordant alternans as the pacing period is decreased. (iii) In contrast to smaller tissue preparations, multiple stationary nodal lines may exist and need not be perpendicular to the pacing site or to each other. (iv) Alternans has fully three dimensional dynamics and the epicardium and endocardium can show significantly different dynamics: multiple nodal surfaces can be transmural or intramural and can form concave/convex surfaces resulting in islands of discordant alternans. (v) The complex spatiotemporal patterns observed during alternans are very sensitive to both the site of stimulation and the stimulation history. Alternans in canine ventricles not only exhibit larger amplitudes and persist for longer cycle length regimes compared to those found in smaller mammalian hearts, but also show novel dynamics not previously described that enhance dispersion and show high sensitivity to initial conditions. This indicates some underlying predisposition to chaos and can help to guide the design of new drugs and devices controlling and preventing arrhythmic events. PMID- 23637686 TI - Positively valenced stimuli facilitate creative novel metaphoric processes by enhancing medial prefrontal cortical activation. AB - A metaphor is a figure of speech in which a subject is symbolic of another unrelated object. In the present study, we examined neural patterns associated with both novel unfamiliar and conventional familiar metaphoric processing, and how these patterns are modulated by affective valence. Prior to fMRI scanning, participants received a list of word pairs (novel unfamiliar metaphors as well as conventional familiar metaphors) and were asked to denote the valence (positive, negative, or neutral) of each word pair. During scanning, participants had to decide whether the word pairs formed meaningful or meaningless expressions. Results indicate that participants were faster and more accurate at deciding that positively valenced metaphors were meaningful compared to neutral metaphors. These behavioral findings were accompanied by increased activation in the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), and the right inferior parietal lobe (RIPL). Specifically, positively valenced novel unfamiliar metaphors elicited activation in these brain regions in addition to the left superior temporal gyrus when compared to neutral novel metaphors. We also found that the mPFC and PCC mediated the processing of positively valenced metaphors when compared to negatively valenced metaphors. Positively valenced conventional metaphors, however, elicited different neural signatures when contrasted with either neutral or negatively valenced conventional metaphors. Together, our results indicate that positively valenced stimuli facilitate creative metaphoric processes (specifically novel metaphoric processes) by mediating attention and cognitive control processes required for the access, integration, and selection of semantic associations via modulation of the mPFC. The present study is important for the development of neural accounts of emotion-cognition interactions required for creativity, language, and successful social functioning in general. PMID- 23637687 TI - Processing of fear and anger facial expressions: the role of spatial frequency. AB - Spatial frequency (SF) components encode a portion of the affective value expressed in face images. The aim of this study was to estimate the relative weight of specific frequency spectrum bandwidth on the discrimination of anger and fear facial expressions. The general paradigm was a classification of the expression of faces morphed at varying proportions between anger and fear images in which SF adaptation and SF subtraction are expected to shift classification of facial emotion. A series of three experiments was conducted. In Experiment 1 subjects classified morphed face images that were unfiltered or filtered to remove either low (<8 cycles/face), middle (12-28 cycles/face), or high (>32 cycles/face) SF components. In Experiment 2 subjects were adapted to unfiltered or filtered prototypical (non-morphed) fear face images and subsequently classified morphed face images. In Experiment 3 subjects were adapted to unfiltered or filtered prototypical fear face images with the phase component randomized before classifying morphed face images. Removing mid frequency components from the target images shifted classification toward fear. The same shift was observed under adaptation condition to unfiltered and low- and middle range filtered fear images. However, when the phase spectrum of the same adaptation stimuli was randomized, no adaptation effect was observed. These results suggest that medium SF components support the perception of fear more than anger at both low and high level of processing. They also suggest that the effect at high-level processing stage is related more to high-level featural and/or configural information than to the low-level frequency spectrum. PMID- 23637688 TI - Pointing hand stimuli induce spatial compatibility effects and effector priming. AB - The present study investigated the automatic influence of perceiving a picture that indicates other's action on one's own task performance in terms of spatial compatibility and effector priming. Participants pressed left and right buttons with their left and right hands respectively, depending on the color of a central dot target. Preceding the target, a left or right hand stimulus (pointing either to the left or right with the index or little finger) was presented. In Experiment 1, with brief presentation of the pointing hand, a spatial compatibility effect was observed: responses were faster when the direction of the pointed finger and the response position were spatially congruent than when incongruent. The spatial compatibility effect was larger for the pointing index finger stimulus compared to the pointing little finger stimulus. Experiment 2 employed longer duration of the pointing hand stimuli. In addition to the spatial compatibility effect for the pointing index finger, the effector priming effect was observed: responses were faster when the anatomical left/right identity of the pointing and response hands matched than when the pointing and response hands differed in left/right identity. The results indicate that with sufficient processing time, both spatial/symbolic and anatomical features of a static body part implying another's action simultaneously influence different aspects of the perceiver's own action. Hierarchical coding, according to which an anatomical code is used only when a spatial code is unavailable, may not be applicable if stimuli as well as responses contain anatomical features. PMID- 23637690 TI - Production preferences cannot be understood without reference to communication. PMID- 23637692 TI - The appeal of the PDC program. PMID- 23637689 TI - How language production shapes language form and comprehension. AB - Language production processes can provide insight into how language comprehension works and language typology-why languages tend to have certain characteristics more often than others. Drawing on work in memory retrieval, motor planning, and serial order in action planning, the Production-Distribution-Comprehension (PDC) account links work in the fields of language production, typology, and comprehension: (1) faced with substantial computational burdens of planning and producing utterances, language producers implicitly follow three biases in utterance planning that promote word order choices that reduce these burdens, thereby improving production fluency. (2) These choices, repeated over many utterances and individuals, shape the distributions of utterance forms in language. The claim that language form stems in large degree from producers' attempts to mitigate utterance planning difficulty is contrasted with alternative accounts in which form is driven by language use more broadly, language acquisition processes, or producers' attempts to create language forms that are easily understood by comprehenders. (3) Language perceivers implicitly learn the statistical regularities in their linguistic input, and they use this prior experience to guide comprehension of subsequent language. In particular, they learn to predict the sequential structure of linguistic signals, based on the statistics of previously-encountered input. Thus, key aspects of comprehension behavior are tied to lexico-syntactic statistics in the language, which in turn derive from utterance planning biases promoting production of comparatively easy utterance forms over more difficult ones. This approach contrasts with classic theories in which comprehension behaviors are attributed to innate design features of the language comprehension system and associated working memory. The PDC instead links basic features of comprehension to a different source: production processes that shape language form. PMID- 23637691 TI - The PDC framework applied to prosody and disfluency. PMID- 23637693 TI - Say what you please? Really? PMID- 23637694 TI - How tightly are production and comprehension interwoven? PMID- 23637696 TI - Comparative analyses of nuclear proteome: extending its function. AB - Organeller proteomics is an emerging technology that is critical in determining the cellular signal transduction pathways. Nucleus, the regulatory hub of the eukaryotic cell is a dynamic system and a repository of various macromolecules that serve as modulators of such signaling that dictate cell fate decisions. Nuclear proteins (NPs) are predicted to comprise about 10-20% of the total cellular proteins, suggesting the involvement of the nucleus in a number of diverse functions. Indeed, NPs constitute a highly organized but complex network that plays diverse roles during development and physiological processes. In plants, relatively little is known about the nature of the molecular components and mechanisms involved in coordinating NP synthesis, their action and function. Proteomic study hold promise to understand the molecular basis of nuclear function using an unbiased comparative and differential approach. We identified a few hundred proteins that include classical and non-canonical nuclear components presumably associated with variety of cellular functions impinging on the complexity of nuclear proteome. Here, we review the nuclear proteome based on our own findings, available literature, and databases focusing on detailed comparative analysis of NPs and their functions in order to understand how plant nucleus works. The review also shed light on the current status of plant nuclear proteome and discusses the future prospect. PMID- 23637698 TI - Reliability, validity, and optimal cutoff score of the montreal cognitive assessment (changsha version) in ischemic cerebrovascular disease patients of hunan province, china. AB - BACKGROUND/AIMS: The goal of this study was to examine the reliability and validity of the Changsha version of the Montreal Cognitive Assessment (MoCA-CS) in ischemic cerebrovascular disease patients of Hunan Province, China, and to explore the optimal cutoff score for detecting vascular cognitive impairment-no dementia (VCI-ND) and vascular dementia (VD). METHODS: Three hundred and thirty eight ischemic cerebrovascular disease patients (131 with normal cognition, 111 with VCI-ND, and 96 with VD) and 132 healthy controls were recruited. All participants accepted examination by the MoCA-CS, Mini-Mental State Examination (MMSE), and other related scales. A detailed neuropsychological battery was used for making a final cognitive diagnosis. SPSS 16.0 statistical software was used for reliability, validity examination, and optimal cutoff score detection. RESULTS: Cronbach's alpha of the MoCA-CS was 0.884, and test-retest and interrater reliability of the MoCA-CS were 0.966 and 0.926, respectively. MoCA-CS scores were highly correlated with MMSE scores (r = 0.867) and simplified intelligence quotients (r = 0.822). The results indicate that 1 point should be added for subjects with less than 6 years of education, and that the optimal cutoff score for detecting VCI-ND is 26/27 (sensitivity 96.1%, specificity 75.6%), whereas the optimal cutoff score for detecting VD is 16/17 (sensitivity 92.7%, specificity 96.3%). CONCLUSION: The MoCA-CS has good reliability and validity, and is a useful cognitive screening instrument for detecting VCI in the Chinese population. PMID- 23637697 TI - Initial 'TTP Map-Defect' of Computed Tomography Perfusion as a Predictor of Hemorrhagic Transformation of Acute Ischemic Stroke. AB - BACKGROUND: Hemorrhagic transformation (HT) following acute ischemic stroke is a major problem, especially for the indication of reperfusion therapy including intravenous administration of recombinant tissue plasminogen activator (IV rt PA). The specific predictive factors of HT have not yet been established. The present study evaluated the findings of computed tomography perfusion (CTP) images as predictors of subsequent HT to identify patients with low HT risk for reperfusion therapy such as IV rt-PA. METHODS: We retrospectively reviewed 68 consecutive stroke patients (41 males; mean age 72.9 years) with steno-occlusive lesions in the major trunk, including 10 patients who underwent IV rt-PA. Each HT was detected on a follow-up T2*-weighted magnetic resonance image until 2 weeks after stroke onset and categorized into four groups [hemorrhagic infarction (HI) type 1 and 2, and parenchymal hematoma (PH) type 1 and 2] according to the European Cooperative Acute Stroke Study (ECASS) classification. We assessed clinical features and radiological findings between the HT and non-HT groups or the PH2 and non-PH2 groups. The efficacy of initial time to peak (TTP) mapping of CTP for predicting HT or PH2 was evaluated. RESULTS: Thirty-four patients (50%) developed subsequent HT: 18 (52.9%) had HI and 16 (47.1%) had PH, including 9 PH2 patients (13.2%). IV rt-PA was not significantly associated with HT or PH2 occurrence. Forty of the 68 patients (59%) revealed defect areas on the initial TTP mapping (TTP map-defect), and 34 of these 40 patients (85%) developed secondary HT and 9 patients (22.5%) developed PH2. Initial 'TTP map-defect' was significantly associated with the occurrence of HT (p < 0.0001) and PH2 (p = 0.0070). Thirty of the 34 patients (88.2%) in the HT group experienced delayed recanalization of the occluded vessels, in contrast to only 8 of the 34 patients (23.6%) in the non-HT group. All patients of the PH2 group showed recanalization (p = 0.0042). In 40 'TTP map-defect'-positive patients, delayed recanalization was associated with the occurrence of HT (p < 0.0001) and PH2 (p = 0.0491). All 28 patients without 'TTP map-defect' did not develop HT, including 8 patients (28.6%) with delayed recanalization. CONCLUSIONS: Initial 'TTP map-defect' of CTP could accurately predict HT risk including PH2 risk and identify low-risk patients even in the delayed period. PMID- 23637695 TI - The potential for bio-mediators and biomarkers in pediatric traumatic brain injury and neurocritical care. AB - The use of biomarkers of brain injury in pediatric neurocritical care has been explored for at least 15 years. Two general lines of research on biomarkers in pediatric brain injury have been pursued: (1) studies of "bio-mediators" in cerebrospinal fluid (CSF) of children after traumatic brain injury (TBI) to explore the components of the secondary injury cascades in an attempt to identify potential therapeutic targets and (2) studies of the release of structural proteins into the CSF, serum, or urine in order to diagnose, monitor, and/or prognosticate in patients with TBI or other pediatric neurocritical care conditions. Unique age-related differences in brain biology, disease processes, and clinical applications mandate the development and testing of brain injury bio mediators and biomarkers specifically in pediatric neurocritical care applications. Finally, although much of the early work on biomarkers of brain injury in pediatrics has focused on TBI, new applications are emerging across a wide range of conditions specifically for pediatric neurocritical care including abusive head trauma, cardiopulmonary arrest, septic shock, extracorporeal membrane oxygenation, hydrocephalus, and cardiac surgery. The potential scope of the utility of biomarkers in pediatric neurocritical care is thus also discussed. PMID- 23637699 TI - Persistence of cholinesterase inhibitor treatment in dementia: insights from a naturalistic study. AB - BACKGROUND: Cholinesterase inhibitors (ChEI) are widely used in dementia, but there is a lack of practice guidelines in case of intolerance or absence of perceived effect. METHODS: Two hundred and forty patients (mean age 77 years, SD 6.3, 66% female) with Alzheimer's disease or Lewy body dementia were prescribed a ChEI and evaluated annually under conditions of standard practice. Of these, 152 patients maintained, 36 switched, and 52 abandoned ChEI treatment. RESULTS: Less behavioural disturbance and less cognitive deterioration were observed, respectively, at the 3- and 4-year follow-up assessments in the patients who maintained the first prescribed ChEI (p < 0.05). Cognitive benefits were reinforced in the patients who experienced some adverse event, but no benefits were observed when the patient or caregiver did not perceive an effect. CONCLUSIONS: Maintenance of the first prescribed ChEI was supported when some benefit was perceived by the patient or caregiver, even in cases of nonserious adverse events. PMID- 23637700 TI - Altered expression of RNA splicing proteins in Alzheimer's disease patients: evidence from two microarray studies. AB - BACKGROUND/AIMS: Dysregulation of pre-mRNA splicing from an altered expression of RNA splice-regulatory proteins may act as the convergence point underlying aberrant gene expression changes in Alzheimer's disease (AD). METHODS: Two microarray datasets from a control/AD postmortem brain cohort of 31 subjects - 9 controls and 22 AD subjects (National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database) - were used. RESULTS: Between the two microarray studies, the expression of six splice-regulatory protein genes showed concordant changes in AD. These genes were then correlated with gene expression changes of transcripts reported to be altered in AD. Amyloid beta (A4) precursor protein and tropomyosin receptor kinase B transcripts were found to correlate significantly with the same splice-regulatory proteins in the two studies. CONCLUSION: This study highlights a susceptibility network that can potentially link a number of susceptibility genes. PMID- 23637701 TI - Predictors of time to discharge in patients hospitalized for behavioral and psychological symptoms of dementia. AB - BACKGROUND/AIMS: In Japan, more than 50,000 patients with dementia are housed in psychiatric facilities, a trend precipitated by prolonged hospitalizations. This study aimed to determine predictors for the time to discharge in patients hospitalized for behavioral and psychological symptoms of dementia (BPSD). METHODS: Medical charts of patients admitted to an acute psychogeriatric ward for treatment of BPSD were reviewed. Cox's proportional hazards model was used to evaluate relationships between active behavioral problems and/or demographics at the time of admission, and the time until favorable discharge (FD), defined as discharge to the patient's own home or a care facility. RESULTS: For the 402 study patients included in this study, median time to FD was 101 days. In addition to family and residential factors, multivariate analysis identified higher Mini-Mental State Examination scores as independent clinical predictors for a shorter hospital stay, whereas male gender and combative behavior as the primary reason for hospital admission were predictors for a longer hospital stay. CONCLUSION: Clinical characteristics can be predictive of the time to discharge for patients with BPSD. Earlier interventions and enhanced care strategies may be needed for patients with a lower likelihood of FD. PMID- 23637702 TI - Relationship between White Matter Lesions and Progression of Cognitive Decline in Alzheimer's Disease. AB - BACKGROUND: This study examined the relationship between baseline white matter lesions (WMLs) and the progression of cognitive decline in patients with late onset Alzheimer's disease (AD). METHODS: Fifty-six patients with AD were included in the study (23 men, 33 women; mean age, 77.8 years). All subjects were treated with acetylcholinesterase inhibitors and followed up for approximately 1 year. The Mini-Mental State Examination (MMSE) score was assessed at least twice to evaluate the progressive cognitive impairment. All subjects underwent brain MRI at baseline and were divided into WMLs(-), mild WMLs(+), and moderate WMLs(+) groups based on WML severity. Changes in MMSE scores between baseline and follow up were analyzed using the Wilcoxon signed-rank test. RESULTS: MMSE scores at baseline did not differ significantly among the three groups (p = 0.1658), whereas MMSE scores at the follow-up evaluation were significantly lower in the moderate WMLs(+) group than in the WMLs(-) group (p = 0.0257). The mean MMSE scores remained above baseline values during the approximately 1-year follow-up in the WMLs(-) group, whereas they were decreased in the mild and moderate WMLs(+) groups. Moreover, the frequency of improvement in patients from the WMLs( ) group tended to be higher than that in patients from the WMLs(+) groups. CONCLUSION: Baseline WMLs may be associated with the heterogeneous progression of cognitive decline in patients with AD. PMID- 23637703 TI - Cognitive profiles of patients with mild cognitive impairment or dementia in Alzheimer's or Parkinson's disease. AB - BACKGROUND: Alzheimer's disease (AD) and Parkinson's disease (PD) are associated with severe cognitive decline, but it is still unclear to what extent they become functionally more similar over time. METHODS: We compared amnestic mild cognitively impaired (aMCI; n = 29) patients to mild cognitively impaired (MCI) PD patients (n = 25), and patients with AD (n = 34) to patients with PD dementia (PDD; n = 15) with respect to cognitive functioning and mood. RESULTS: aMCI patients were impaired in episodic memory, while MCI PD patients showed deficits in visuoconstruction and attention. AD and PDD patients showed comparable deficits on tests for language, attention and visuoconstruction. However, unlike PDD patients but similar to aMCI patients, AD patients showed a characteristic memory impairment, especially commission errors on recognition tasks, whereas PDD patients scored higher on the depressive mood questionnaire. CONCLUSIONS: In advanced stages of both diseases, the pattern of functional deficits associated with parietal and temporal lobe functions (attention, visuoconstruction and language) is similar. However, specific differences, already present in the early stage (recognition errors in AD, associated with mediobasal temporal lobe functioning, and depressed mood in PDD, associated with non-motor basal ganglia loops), are also observed in the late stage. PMID- 23637704 TI - Potential Impact of miR-137 and Its Targets in Schizophrenia. AB - The significant impact of microRNAs (miRNAs) on disease pathology is becoming increasingly evident. These small non-coding RNAs have the ability to post transcriptionally silence the expression of thousands of genes. Therefore, dysregulation of even a single miRNA could confer a large polygenic effect. Schizophrenia is a genetically complex illness thought to involve multiple genes each contributing a small risk. Large genome-wide association studies identified miR-137, a miRNA shown to be involved in neuronal maturation, as one of the top risk genes. To assess the potential mechanism of impact of miR-137 in this disorder and identify its targets, we used a combination of literature searches, ingenuity pathway analysis (IPA), and freely accessible bioinformatics resources. Using TargetScan and the schizophrenia gene resource (SZGR) database, we found that in addition to CSMD1, C10orf26, CACNA1C, TCF4, and ZNF804A, five schizophrenia risk genes whose transcripts are also validated miR-137 targets, there are other schizophrenia-associated genes that may be targets of miR-137, including ERBB4, GABRA1, GRIN2A, GRM5, GSK3B, NRG2, and HTR2C. IPA analyses of all the potential targets identified several nervous system (NS) functions as the top canonical pathways including synaptic long-term potentiation, a process implicated in learning and memory mechanisms and recently shown to be altered in patients with schizophrenia. Among the subset of targets involved in NS development and function, the top scoring pathways were ephrin receptor signaling and axonal guidance, processes that are critical for proper circuitry formation and were shown to be disrupted in schizophrenia. These results suggest that miR 137 may indeed play a substantial role in the genetic etiology of schizophrenia by regulating networks involved in neural development and brain function. PMID- 23637705 TI - Use of the protein ontology for multi-faceted analysis of biological processes: a case study of the spindle checkpoint. AB - As a member of the Open Biomedical Ontologies (OBO) foundry, the Protein Ontology (PRO) provides an ontological representation of protein forms and complexes and their relationships. Annotations in PRO can be assigned to individual protein forms and complexes, each distinguishable down to the level of post-translational modification, thereby allowing for a more precise depiction of protein function than is possible with annotations to the gene as a whole. Moreover, PRO is fully interoperable with other OBO ontologies and integrates knowledge from other protein-centric resources such as UniProt and Reactome. Here we demonstrate the value of the PRO framework in the investigation of the spindle checkpoint, a highly conserved biological process that relies extensively on protein modification and protein complex formation. The spindle checkpoint maintains genomic integrity by monitoring the attachment of chromosomes to spindle microtubules and delaying cell cycle progression until the spindle is fully assembled. Using PRO in conjunction with other bioinformatics tools, we explored the cross-species conservation of spindle checkpoint proteins, including phosphorylated forms and complexes; studied the impact of phosphorylation on spindle checkpoint function; and examined the interactions of spindle checkpoint proteins with the kinetochore, the site of checkpoint activation. Our approach can be generalized to any biological process of interest. PMID- 23637707 TI - Long-term survival after hand-assisted laparoscopic approach of primary retroperitoneal mucinous cystadenocarcinoma in male: case report and review of literature. AB - BACKGROUND: Primary retroperitoneal mucinous cystadenocarcinoma (PRMC) is a rare disease and mostly occurs in females, and there are only three male cases described in the literatures without long-term follow-up. CASE REPORT: A 59-year old male presented with a left retroperitoneal cystic mass (7.5 ' 7 ' 3 cm) that upwardly displaced the left kidney and caused abdominal discomfort. The tumor was totally excised by the hand-assisted laparoscopic method without complications or recurrence in a follow-up period of 79 months. The etiology from coelomic metaplasia of peritoneal epithelium was proved by a spectrum of diverse cells (benign, borderline malignant, and malignant cells) during pathological examination. RESULTS: This is the fourth male case of PRMC in the world with a favorable outcome after hand-assisted laparoscopic excision, and this is also distinct by the longest follow-up period in this disease entity. CONCLUSIONS: Because of its low-malignant potential and recurrence rate, surgical excision is still the best choice of treatment, but the least invasion method should be adopted in front. PMID- 23637706 TI - Endonuclease domain of the Drosophila melanogaster R2 non-LTR retrotransposon and related retroelements: a new model for transposition. AB - The molecular mechanisms of the transposition of non-long terminal repeat (non LTR) retrotransposons are not well understood; the key questions of how the 3' ends of cDNA copies integrate and how site-specific integration occurs remain unresolved. Integration depends on properties of the endonuclease (EN) domain of retrotransposons. Using the EN domain of the Drosophila R2 retrotransposon as a model for other, closely related non-LTR retrotransposons, we investigated the EN domain and found that it resembles archaeal Holliday-junction resolvases. We suggest that these non-LTR retrotransposons are co-transcribed with the host transcript. Combined with the proposed resolvase activity of the EN domain, this model yields a novel mechanism for site-specific retrotransposition within this class of retrotransposons, with resolution proceeding via a Holliday junction intermediate. PMID- 23637709 TI - Motor stereotypies and volumetric brain alterations in children with Autistic Disorder. AB - Motor stereotypies are defined as patterned, repetitive, purposeless movements. These stigmatizing motor behaviors represent one manifestation of the third core criterion for an Autistic Disorder (AD) diagnosis, and are becoming viewed as potential early markers of autism. Moreover, motor stereotypies might be a tangible expression of the underlying neurobiology of this neurodevelopmental disorder. In this study, we videoscored stereotypies recorded during semi structured play sessions from school age children with AD. We examined the effect of severity and persistence over time of stereotypies on brain volumetric changes. Our findings confirmed that the brain volume of school age children with AD is, on average, larger than that of age-matched typically developing children. However, we have failed to detect any sign of volumetric differences in brain regions thought to be particularly linked to the pathophysiology of stereotypies. This negative finding may suggest that, at least with respect to motor stereotypies, functional rather than structural alterations might be the underpinning of these disruptive motor manifestations of autism. PMID- 23637708 TI - Relationship between executive functions and motor stereotypies in children with Autistic Disorder. AB - This study reports on the relationship between motor stereotypies and impairments in executive functions (EF) in children with Autistic Disorder (AD) and in children with Developmental Language Disorders (DLD). We hypothesized that low EF performance would predict higher frequency and longer durations of stereotypies in the AD group only. Twenty-two children (age range = 7-9 years, 6 months, girls = 5) with AD were recruited from a longitudinal multi-site study and compared to twenty-two non-autistic children with DLD (age range = 7-9 years, 6 months, girls = 5). The two groups were matched on non-verbal IQ and demographic characteristics. Frequency and duration of stereotypies were coded from videotaped semi-structured play sessions. EF measures included the Wisconsin Card Sorting Task (WCST) Categories, Wechsler Intelligence Scale for Children-Revised (WISC-R) Mazes, and Stanford-Binet Fourth Edition (SB-IV) Matrices. The scores for frequency and duration of stereotypies were higher in the AD group. Separate linear regressions revealed that group status, EF, and their interactions predict stereotypies. Specifically, lower EF scores predicted higher frequencies and longer durations of stereotypies in the AD group only. Analyses controlled for age, gender, and parent education. Findings suggest that in AD, EF impairments and stereotypies may be linked to shared brain pathways. PMID- 23637710 TI - The origins of duality of patterning in artificial whistled languages. AB - In human speech, a finite set of basic sounds is combined into a (potentially) unlimited set of well-formed morphemes. Hockett (1960) placed this phenomenon under the term 'duality of patterning' and included it as one of the basic design features of human language. Of the thirteen basic design features Hockett proposed, duality of patterning is the least studied and it is still unclear how it evolved in language. Recent work shedding light on this is summarized in this paper and experimental data is presented. This data shows that combinatorial structure can emerge in an artificial whistled language through cultural transmission as an adaptation to human cognitive biases and learning. In this work the method of experimental iterated learning (Kirby et al. 2008) is used, in which a participant is trained on the reproductions of the utterances the previous participant learned. Participants learn and recall a system of sounds that are produced with a slide whistle. Transmission from participant to participant causes the whistle systems to change and become more learnable and more structured. These findings follow from qualitative observations, quantitative measures and a follow-up experiment that tests how well participants can learn the emerged whistled languages by generalizing from a few examples. PMID- 23637712 TI - Phonetic convergence in spontaneous conversations as a function of interlocutor language distance. AB - This study explores phonetic convergence during conversations between pairs of talkers with varying language distance. Specifically, we examined conversations within two native English talkers and within two native Korean talkers who had either the same or different regional dialects, and between native and nonnative talkers of English. To measure phonetic convergence, an independent group of listeners judged the similarity of utterance samples from each talker through an XAB perception test, in which X was a sample of one talker's speech and A and B were samples from the other talker at either early or late portions of the conversation. The results showed greater convergence for same-dialect pairs than for either the different-dialect pairs or the different-L1 pairs. These results generally support the hypothesis that there is a relationship between phonetic convergence and interlocutor language distance. We interpret this pattern as suggesting that phonetic convergence between talker pairs that vary in the degree of their initial language alignment may be dynamically mediated by two parallel mechanisms: the need for intelligibility and the extra demands of nonnative speech production and perception. PMID- 23637711 TI - Safety, formulation, and in vitro antiviral activity of the antimicrobial peptide subtilosin against herpes simplex virus type 1. AB - In the present study the antiviral properties of the bacteriocin subtilosin against Herpes simplex virus type 1 (HSV-1) and the safety and efficacy of a subtilosin-based nanofiber formulation were determined. High concentrations of subtilosin, the cyclical antimicrobial peptide produced by Bacillus amyloliquefaciens, were virucidal against HSV-1. Interestingly, at non-virucidal concentrations, subtilosin inhibited wild type HSV-1 and aciclovir-resistant mutants in a dose-dependent manner. Although the exact antiviral mechanism is not fully understood, time of addition experiments and western blot analysis suggest that subtilosin does not affect viral multiplication steps prior to protein synthesis. Poly(vinyl alcohol) (PVOH)-based subtilosin nanofibers with a width of 278 nm were produced by the electrospinning process. The retained antimicrobial activity of the subtilosin-based fibers was determined via an agar well diffusion assay. The loading capacity of the fibers was 2.4 mg subtilosin/g fiber, and loading efficiency was 31.6%. Furthermore, the nanofibers with and without incorporated subtilosin were shown to be nontoxic to human epidermal tissues using an in vitro human tissue model. Taking together these results subtilosin based nanofibers should be further studied as a novel alternative method for treatment and/or control of HSV-1 infection. PMID- 23637731 TI - Elevated 12-month and lifetime prevalence and comorbidity rates of mood, anxiety, and alcohol use disorders in Chinese men who have sex with men. AB - BACKGROUND: This study aimed to assess whether Chinese men who have sex with men (MSM) had a significantly elevated prevalence of psychiatric disorders compared to urban males in China. METHODS: 807 MSM were recruited using a respondent driven sampling (RDS) method in urban area of northeast China. Psychiatric disorders were assessed employing the Composite International Diagnostic Interview (CIDI. Version 1.0) according to the criteria of the DSM-III-R. RESULTS: Chinese MSM had a significantly elevated standardized prevalence ratios (SPR) for lifetime prevalence of any disorder (SPR = 2.8; 95%CI: 2.5-3.2), mood disorder (SPR = 3.0; 95%CI: 2.3-3.7), anxiety disorder (SPR = 5.5; 95% CI: 4.6 6.5), alcohol use disorder (SPR = 2.4, 95%CI: 2.0-2.8), and combination of disorders (SPR = 4.2; 95%CI: 3.4-5.1). CONCLUSIONS: Chinese MSM had significantly elevated prevalence and comorbidity of psychiatric disorders. RDS is a suitable sampling method for psychiatric epidemiological survey in MSM population. PMID- 23637732 TI - Priming intelligent behavior: an elusive phenomenon. AB - Can behavior be unconsciously primed via the activation of attitudes, stereotypes, or other concepts? A number of studies have suggested that such priming effects can occur, and a prominent illustration is the claim that individuals' accuracy in answering general knowledge questions can be influenced by activating intelligence-related concepts such as professor or soccer hooligan. In 9 experiments with 475 participants we employed the procedures used in these studies, as well as a number of variants of those procedures, in an attempt to obtain this intelligence priming effect. None of the experiments obtained the effect, although financial incentives did boost performance. A Bayesian analysis reveals considerable evidential support for the null hypothesis. The results conform to the pattern typically obtained in word priming experiments in which priming is very narrow in its generalization and unconscious (subliminal) influences, if they occur at all, are extremely short-lived. We encourage others to explore the circumstances in which this phenomenon might be obtained. PMID- 23637733 TI - Altered response to A(H1N1)pnd09 vaccination in pregnant women: a single blinded randomized controlled trial. AB - BACKGROUND: Pregnant women were suspected to be at particular risk when H1N1pnd09 influenza became pandemic in 2009. Our primary objective was to compare the immune responses conferred by MF59(r)-adjuvanted vaccine (Focetria(r)) in H1N1pnd09-naive pregnant and non-pregnant women. The secondary aims were to compare influences of dose and adjuvant on the immune response. METHODS: The study was nested in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) pregnancy cohort in 2009-2010 and conducted as a single-blinded block-randomised [1?1?1] controlled clinical trial in pregnant women after gestational week 20: (1) 7.5 ug H1N1pnd09 antigen with MF59-adjuvant (Pa7.5 ug); (2) 3.75 ug antigen half MF59-adjuvanted (Pa3.75 ug); (3) 15 ug antigen unadjuvanted (P15 ug); and in non-pregnant women receiving (4) 7.5 ug antigen full adjuvanted (NPa7.5 ug). Blood samples were collected at baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were recorded prospectively. RESULTS: 58 pregnant women were allocated to Pa7.5 ug and 149 non-pregnant women were recruited to NPa7.5 ug. The sero-conversion rate was significantly increased in non-pregnant (NPa7.5 ug) compared with pregnant (Pa7.5 ug) women (OR = 2.48 [1.03-5.95], p = 0.04) and geometric mean titers trended towards being higher, but this difference was not statistically significant (ratio 1.27 [0.85-1.93], p = 0.23). The significant titer increase rate showed no difference between pregnant (Pa7.5 ug) and non-pregnant (NPa7.5 ug) groups (OR = 0.49 [0.13-1.85], p = 0.29). CONCLUSION: Our study suggests the immune response to the 7.5 ug MF59 adjuvanted Focetria(r) H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01012557. PMID- 23637734 TI - Closing the gap between single molecule and bulk FRET analysis of nucleosomes. AB - Nucleosome structure and stability affect genetic accessibility by altering the local chromatin morphology. Recent FRET experiments on nucleosomes have given valuable insight into the structural transformations they can adopt. Yet, even if performed under seemingly identical conditions, experiments performed in bulk and at the single molecule level have given mixed answers due to the limitations of each technique. To compare such experiments, however, they must be performed under identical conditions. Here we develop an experimental framework that overcomes the conventional limitations of each method: single molecule FRET experiments are carried out at bulk concentrations by adding unlabeled nucleosomes, while bulk FRET experiments are performed in microplates at concentrations near those used for single molecule detection. Additionally, the microplate can probe many conditions simultaneously before expending valuable instrument time for single molecule experiments. We highlight this experimental strategy by exploring the role of selective acetylation of histone H3 on nucleosome structure and stability; in bulk, H3-acetylated nucleosomes were significantly less stable than non-acetylated nucleosomes. Single molecule FRET analysis further revealed that acetylation of histone H3 promoted the formation of an additional conformational state, which is suppressed at higher nucleosome concentrations and which could be an important structural intermediate in nucleosome regulation. PMID- 23637736 TI - Nitrogen deposition reduces plant diversity and alters ecosystem functioning: field-scale evidence from a nationwide survey of UK heathlands. AB - Findings from nitrogen (N) manipulation studies have provided strong evidence of the detrimental impacts of elevated N deposition on the structure and functioning of heathland ecosystems. Few studies, however, have sought to establish whether experimentally observed responses are also apparent under natural, field conditions. This paper presents the findings of a nationwide field-scale evaluation of British heathlands, across broad geographical, climatic and pollution gradients. Fifty two heathlands were selected across an N deposition gradient of 5.9 to 32.4 kg ha(-1) yr(-1). The diversity and abundance of higher and lower plants and a suite of biogeochemical measures were evaluated in relation to climate and N deposition indices. Plant species richness declined with increasing temperature and N deposition, and the abundance of nitrophilous species increased with increasing N. Relationships were broadly similar between upland and lowland sites, with the biggest reductions in species number associated with increasing N inputs at the low end of the deposition range. Both oxidised and reduced forms of N were associated with species declines, although reduced N appears to be a stronger driver of species loss at the functional group level. Plant and soil biochemical indices were related to temperature, rainfall and N deposition. Litter C:N ratios and enzyme (phenol-oxidase and phosphomonoesterase) activities had the strongest relationships with site N inputs and appear to represent reliable field indicators of N deposition. This study provides strong, field-scale evidence of links between N deposition--in both oxidised and reduced forms--and widespread changes in the composition, diversity and functioning of British heathlands. The similarity of relationships between upland and lowland environments, across broad spatial and climatic gradients, highlights the ubiquity of relationships with N, and suggests that N deposition is contributing to biodiversity loss and changes in ecosystem functioning across European heathlands. PMID- 23637735 TI - The baboon kidney transcriptome: analysis of transcript sequence, splice variants, and abundance. AB - The baboon is an invaluable model for the study of human health and disease, including many complex diseases of the kidney. Although scientists have made great progress in developing this animal as a model for numerous areas of biomedical research, genomic resources for the baboon, such as a quality annotated genome, are still lacking. To this end, we characterized the baboon kidney transcriptome using high-throughput cDNA sequencing (RNA-Seq) to identify genes, gene variants, single nucleotide polymorphisms (SNPs), insertion-deletion polymorphisms (InDels), cellular functions, and key pathways in the baboon kidney to provide a genomic resource for the baboon. Analysis of our sequencing data revealed 45,499 high-confidence SNPs and 29,813 InDels comparing baboon cDNA sequences with the human hg18 reference assembly and identified 35,900 cDNAs in the baboon kidney, including 35,150 transcripts representing 15,369 genic genes that are novel for the baboon. Gene ontology analysis of our sequencing dataset also identified numerous biological functions and canonical pathways that were significant in the baboon kidney, including a large number of metabolic pathways that support known functions of the kidney. The results presented in this study catalogues the transcribed mRNAs, noncoding RNAs, and hypothetical proteins in the baboon kidney and establishes a genomic resource for scientists using the baboon as an experimental model. PMID- 23637737 TI - Cognitive inflexibility in obsessive-compulsive disorder and major depression is associated with distinct neural correlates. AB - Obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) are frequently co-morbid, and dysfunctional frontal-striatal circuits have been implicated in both disorders. Neurobiological distinctions between OCD and MDD are insufficiently clear, and comparative neuroimaging studies are extremely scarce. OCD and MDD may be characterized by cognitive rigidity at the phenotype level, and frontal-striatal brain circuits constitute the neural substrate of intact cognitive flexibility. In the present study, 18 non-medicated MDD-free patients with OCD, 19 non-medicated OCD-free patients with MDD, and 29 matched healthy controls underwent functional magnetic resonance imaging during performance of a self-paced letter/digit task switching paradigm. Results showed that both patient groups responded slower relative to controls during repeat events, but only in OCD patients slowing was associated with decreased error rates. During switching, patients with OCD showed increased activation of the putamen, anterior cingulate and insula, whereas MDD patients recruited inferior parietal cortex and precuneus to a lesser extent. Patients with OCD and MDD commonly failed to reveal anterior prefrontal cortex activation during switching. This study shows subtle behavioral abnormalities on a measure of cognitive flexibility in MDD and OCD, associated with differential frontal-striatal brain dysfunction in both disorders. These findings may add to the development of biological markers that more precisely characterize frequently co-morbid neuropsychiatric disorders such as OCD and MDD. PMID- 23637738 TI - cAMP response element binding protein1 is essential for activation of steroyl co enzyme a desaturase 1 (Scd1) in mouse lung type II epithelial cells. AB - Cyclic AMP Response Element-Binding Protein 1 (Creb1) is a transcription factor that mediates cyclic adenosine 3', 5'-monophosphate (cAMP) signalling in many tissues. Creb1(-/-) mice die at birth due to respiratory failure and previous genome-wide microarray analysis of E17.5 Creb1(-/-) fetal mouse lung identified important Creb1-regulated gene targets during lung development. The lipogenic enzymes stearoyl-CoA desaturase 1 (Scd1) and fatty acid synthase (Fasn) showed highly reduced gene expression in Creb1(-/-) lungs. We therefore hypothesized that Creb1 plays a crucial role in the transcriptional regulation of genes involved in pulmonary lipid biosynthetic pathways during lung development. In this study we confirmed that Scd1 and Fasn mRNA levels were down regulated in the E17.5 Creb1(-/-) mouse lung while the lipogenic-associated transcription factors SrebpF1, C/ebpalpha and Ppargamma were increased. In vivo studies using germline (Creb1(-/-) ) and lung epithelial-specific (Creb1(EpiDelta/Delta) ) Creb1 knockout mice showed strongly reduced Scd1, but not Fasn gene expression and protein levels in lung epithelial cells. In vitro studies using mouse MLE-15 epithelial cells showed that forskolin-mediated activation of Creb1 increased both Scd1 gene expression and protein synthesis. Additionally, MLE15 cells transfected with a dominant-negative ACreb vector blocked forskolin-mediated stimulation of Scd1 gene expression. Lipid profiling in MLE15 cells showed that dominant-negative ACreb suppressed forskolin-induced desaturation of ether linked lipids to produce plasmalogens, as well as levels of phosphatidylethanolamine, ceramide and lysophosphatidylcholine. Taken together these results demonstrate that Creb1 is essential for the induction and maintenance of Scd1 in developing fetal mouse lung epithelial cells. PMID- 23637739 TI - Menstrual cycle phase modulates emotional conflict processing in women with and without premenstrual syndrome (PMS)--a pilot study. AB - BACKGROUND: Premenstrual syndrome (PMS) is characterized by a cluster of psychological and somatic symptoms during the late luteal phase of the menstrual cycle that disappear after the onset of menses. Behavioral differences in emotional and cognitive processing have been reported in women with PMS, and it is of particular interest whether PMS affects the parallel execution of emotional and cognitive processing. Related to this is the question of how the performance of women with PMS relates to stress levels compared to women without PMS. Cortisol has been shown to affect emotional processing in general and it has also been shown that women with severe PMS have a particular cortisol profile. METHODS: We measured performance in an emotional conflict task and stress levels in women with PMS (n = 15) and women without PMS (n = 15) throughout their menstrual cycle. RESULTS: We found a significant increase (p = 0.001) in the mean reaction time for resolving emotional conflict from the follicular to the luteal cycle phase in all subjects. Only women with PMS demonstrated an increase in physiological and subjective stress measures during the luteal menstrual cycle phase. CONCLUSIONS: Our findings suggest that the menstrual cycle modulates the integration of emotional and cognitive processing in all women. Preliminary data are supportive of the secondary hypothesis that stress levels are mediated by the menstrual cycle phase only in women with PMS. The presented evidence for menstrual cycle-specific differences in integrating emotional and cognitive information highlights the importance of controlling for menstrual cycle phase in studies that aim to elucidate the interplay of emotion and cognition. PMID- 23637740 TI - Trends in ecological research during the last three decades--a systematic review. AB - It is thought that the science of ecology has experienced conceptual shifts in recent decades, chiefly from viewing nature as static and balanced to a conception of constantly changing, unpredictable, complex ecosystems. Here, we ask if these changes are reflected in actual ecological research over the last 30 years. We surveyed 750 articles from the entire pool of ecological literature and 750 articles from eight leading journals. Each article was characterized according to its type, ecological domain, and applicability, and major topics. We found that, in contrast to its common image, ecology is still mostly a study of single species (70% of the studies); while ecosystem and community studies together comprise only a quarter of ecological research. Ecological science is somewhat conservative in its topics of research (about a third of all topics changed significantly through time), as well as in its basic methodologies and approaches. However, the growing proportion of problem-solving studies (from 9% in the 1980s to 20% in the 2000 s) may represent a major transition in ecological science in the long run. PMID- 23637741 TI - Early weaning stress in pigs impairs innate mucosal immune responses to enterotoxigenic E. coli challenge and exacerbates intestinal injury and clinical disease. AB - BACKGROUND AND AIMS: The clinical onset and severity of intestinal disorders in humans and animals can be profoundly impacted by early life stress. Here we investigated the impact of early weaning stress in pigs on intestinal physiology, clinical disease, and immune response to subsequent challenge with enterotoxigenic F18 E. coli (ETEC). METHODOLOGY: Pigs weaned from their dam at 16 d, 18 d, and 20 d of age were given a direct oral challenge of F18 ETEC at 26 d of age. Pigs were monitored from days 0 to 4 post-infection for clinical signs of disease. On Day 4 post-ETEC challenge, ileal barrier function, histopathologic and inflammatory cytokine analysis were performed on ileal mucosa. RESULTS: Early weaned pigs (16 d and 18 d weaning age) exhibited a more rapid onset and severity of diarrhea and reductions in weight gain in response to ETEC challenge compared with late weaned pigs (20 d weaning age). ETEC challenge induced intestinal barrier injury in early weaned pigs, indicated by reductions in ileal transepithelial electrical resistance (TER) and elevated FD4 flux rates, in early weaned pig ileum but not in late weaned pigs. ETEC-induced marked elevations in IL-6 and IL-8, neutrophil recruitment, and mast cell activation in late-weaned pigs; these responses were attenuated in early weaned pigs. TNF levels elevated in ETEC challenged ileal mucosa from early weaned pigs but not in other weaning age groups. CONCLUSIONS: These data demonstrate the early weaning stress can profoundly alter subsequent immune and physiology responses and clinical outcomes to subsequent infectious pathogen challenge. Given the link between early life stress and gastrointestinal diseases of animals and humans, a more fundamental understanding of the mechanisms by which early life stress impacts subsequent pathophysiologic intestinal responses has implications for the prevention and management of important GI disorders in humans and animals. PMID- 23637742 TI - Lavender oil-potent anxiolytic properties via modulating voltage dependent calcium channels. AB - Recent clinical data support the clinical use of oral lavender oil in patients suffering from subsyndromal anxiety. We identified the molecular mechanism of action that will alter the perception of lavender oil as a nonspecific ingredient of aromatherapy to a potent anxiolytic inhibiting voltage dependent calcium channels (VOCCs) as highly selective drug target. In contrast to previous publications where exorbitant high concentrations were used, the effects of lavender oil in behavioral, biochemical, and electrophysiological experiments were investigated in physiological concentrations in the nanomolar range, which correlate to a single dosage of 80 mg/d in humans that was used in clinical trials. We show for the first time that lavender oil bears some similarities with the established anxiolytic pregabalin. Lavender oil inhibits VOCCs in synaptosomes, primary hippocampal neurons and stably overexpressing cell lines in the same range such as pregabalin. Interestingly, Silexan does not primarily bind to P/Q type calcium channels such as pregabalin and does not interact with the binding site of pregabalin, the alpha2delta subunit of VOCCs. Lavender oil reduces non-selectively the calcium influx through several different types of VOCCs such as the N-type, P/Q-type and T-type VOCCs. In the hippocampus, one brain region important for anxiety disorders, we show that inhibition by lavender oil is mainly mediated via N-type and P/Q-type VOCCs. Taken together, we provide a pharmacological and molecular rationale for the clinical use of the oral application of lavender oil in patients suffering from anxiety. PMID- 23637743 TI - Lifestyles and risk factors associated with adherence to the Mediterranean diet: a baseline assessment of the PREDIMED trial. AB - BACKGROUND: The traditional Mediterranean dietary pattern (MedDiet) is associated with longevity and low rates of cardiovascular disease (CVD). However, there is little information on who is more likely to follow this food pattern. AIM: To evaluate how different factors are associated with lower MedDiet adherence in older Spanish subjects. METHODS: We included 7305 participants (men aged 55-80 y, women 60-80 y) at high-risk of CVD recruited into the PREDIMED trial (ISRCTN35739639). Socioeconomic, anthropometric, lifestyle characteristics and CVD risk factors were recorded. A validated 14-item questionnaire was used to evaluate MedDiet adherence at baseline. Multivariate models were used to estimate odds ratios (OR) and 95% confidence intervals for lower adherence to the MedDiet (<9 points out of 14) and ascertain factors independently associated with it. RESULTS: Former smoking (OR = 0.87; 95% CI, 0.78-0.98), physical activity (OR for the 3(rd) vs. the 1(st)tertile: 0.69; 0.62-0.78), and higher educational level (OR for university vs. less than primary school: 0.54; 0.38-0.77) were associated with higher MedDiet adherence. Conversely, having a larger waist-to-height ratio (OR for 0.1 units, 1.35; 1.22-1.49), being diabetic (OR = 1.13; 1.03-1.24), being single (OR = 1.27; 1.01-1.61) or divorced or separated (OR = 1.44; 1.09-1.89), and current smoking (OR = 1.28; 1.11-1.47) were associated with lower adherence. CONCLUSIONS: Participants with little education, a larger waist-to-height ratio, or diabetes and those who were less physically active, single, divorced or separated, or smokers were less likely to adhere to the MedDiet, an ideal model for food choices. Stronger efforts of health promotion are needed in these groups to foster adoption of the MedDiet. PMID- 23637745 TI - A new dimension to relative age effects: constant year effects in German youth handball. AB - In this manuscript we argue for a broader use of the term 'relative age effect' due to the influence of varying development policies on the development of sport expertise. Two studies are presented on basis of data from Schorer, et al. [1]. The first showed clear 'constant year effects' in the German handball talent development system. A shift in year groupings for the female athletes resulted in a clear shift of birth year patterns. In the second study we investigated whether the constant year effect in the national talent development system carried over to professional handball. No patterns were observable. Together both studies show that a differentiation of varying effects that often happen simultaneously is necessary to understand the secondary mechanisms behind the development of sport expertise. PMID- 23637744 TI - Brainstem involvement as a cause of central sleep apnea: pattern of microstructural cerebral damage in patients with cerebral microangiopathy. AB - BACKGROUND: The exact underlying pathomechanism of central sleep apnea with Cheyne-Stokes respiration (CSA-CSR) is still unclear. Recent studies have demonstrated an association between cerebral white matter changes and CSA. A dysfunction of central respiratory control centers in the brainstem was suggested by some authors. Novel MR-imaging analysis tools now allow far more subtle assessment of microstructural cerebral changes. The aim of this study was to investigate whether and what severity of subtle structural cerebral changes could lead to CSA-CSR, and whether there is a specific pattern of neurodegenerative changes that cause CSR. Therefore, we examined patients with Fabry disease (FD), an inherited, lysosomal storage disease. White matter lesions are early and frequent findings in FD. Thus, FD can serve as a "model disease" of cerebral microangiopathy to study in more detail the impact of cerebral lesions on central sleep apnea. PATIENTS AND METHODS: Genetically proven FD patients (n = 23) and age-matched healthy controls (n = 44) underwent a cardio-respiratory polysomnography and brain MRI at 3.0 Tesla. We applied different MR-imaging techniques, ranging from semiquantitative measurement of white matter lesion (WML) volumes and automated calculation of brain tissue volumes to VBM of gray matter and voxel-based diffusion tensor imaging (DTI) analysis. RESULTS: In 5 of 23 Fabry patients (22%) CSA-CSR was detected. Voxel-based DTI analysis revealed widespread structural changes in FD patients when compared to the healthy controls. When calculated as a separate group, DTI changes of CSA-CSR patients were most prominent in the brainstem. Voxel-based regression analysis revealed a significant association between CSR severity and microstructural DTI changes within the brainstem. CONCLUSION: Subtle microstructural changes in the brainstem might be a neuroanatomical correlate of CSA-CSR in patients at risk of WML. DTI is more sensitive and specific than conventional structural MRI and other advanced MR analyses tools in demonstrating these abnormalities. PMID- 23637746 TI - A perspective on multiple waves of influenza pandemics. AB - BACKGROUND: A striking characteristic of the past four influenza pandemic outbreaks in the United States has been the multiple waves of infections. However, the mechanisms responsible for the multiple waves of influenza or other acute infectious diseases are uncertain. Understanding these mechanisms could provide knowledge for health authorities to develop and implement prevention and control strategies. MATERIALS AND METHODS: We exhibit five distinct mechanisms, each of which can generate two waves of infections for an acute infectious disease. The first two mechanisms capture changes in virus transmissibility and behavioral changes. The third mechanism involves population heterogeneity (e.g., demography, geography), where each wave spreads through one sub-population. The fourth mechanism is virus mutation which causes delayed susceptibility of individuals. The fifth mechanism is waning immunity. Each mechanism is incorporated into separate mathematical models, and outbreaks are then simulated. We use the models to examine the effects of the initial number of infected individuals (e.g., border control at the beginning of the outbreak) and the timing of and amount of available vaccinations. RESULTS: Four models, individually or in any combination, reproduce the two waves of the 2009 H1N1 pandemic in the United States, both qualitatively and quantitatively. One model reproduces the two waves only qualitatively. All models indicate that significantly reducing or delaying the initial numbers of infected individuals would have little impact on the attack rate. Instead, this reduction or delay results in a single wave as opposed to two waves. Furthermore, four of these models also indicate that a vaccination program started earlier than October 2009 (when the H1N1 vaccine was initially distributed) could have eliminated the second wave of infection, while more vaccine available starting in October would not have eliminated the second wave. PMID- 23637747 TI - Gene expression variability in human hepatic drug metabolizing enzymes and transporters. AB - Interindividual variability in the expression of drug-metabolizing enzymes and transporters (DMETs) in human liver may contribute to interindividual differences in drug efficacy and adverse reactions. Published studies that analyzed variability in the expression of DMET genes were limited by sample sizes and the number of genes profiled. We systematically analyzed the expression of 374 DMETs from a microarray data set consisting of gene expression profiles derived from 427 human liver samples. The standard deviation of interindividual expression for DMET genes was much higher than that for non-DMET genes. The 20 DMET genes with the largest variability in the expression provided examples of the interindividual variation. Gene expression data were also analyzed using network analysis methods, which delineates the similarities of biological functionalities and regulation mechanisms for these highly variable DMET genes. Expression variability of human hepatic DMET genes may affect drug-gene interactions and disease susceptibility, with concomitant clinical implications. PMID- 23637749 TI - Exploring default mode and information flow on the web. AB - Social networking services (e.g., Twitter, Facebook) are now major sources of World Wide Web (called "Web") dynamics, together with Web search services (e.g., Google). These two types of Web services mutually influence each other but generate different dynamics. In this paper, we distinguish two modes of Web dynamics: the reactive mode and the default mode. It is assumed that Twitter messages (called "tweets") and Google search queries react to significant social movements and events, but they also demonstrate signs of becoming self-activated, thereby forming a baseline Web activity. We define the former as the reactive mode and the latter as the default mode of the Web. In this paper, we investigate these reactive and default modes of the Web's dynamics using transfer entropy (TE). The amount of information transferred between a time series of 1,000 frequent keywords in Twitter and the same keywords in Google queries is investigated across an 11-month time period. Study of the information flow on Google and Twitter revealed that information is generally transferred from Twitter to Google, indicating that Twitter time series have some preceding information about Google time series. We also studied the information flow among different Twitter keywords time series by taking keywords as nodes and flow directions as edges of a network. An analysis of this network revealed that frequent keywords tend to become an information source and infrequent keywords tend to become sink for other keywords. Based on these findings, we hypothesize that frequent keywords form the Web's default mode, which becomes an information source for infrequent keywords that generally form the Web's reactive mode. We also found that the Web consists of different time resolutions with respect to TE among Twitter keywords, which will be another focal point of this paper. PMID- 23637750 TI - Absence of complementary sex determination in the parasitoid wasp genus Asobara (Hymenoptera: Braconidae). AB - An attractive way to improve our understanding of sex determination evolution is to study the underlying mechanisms in closely related species and in a phylogenetic perspective. Hymenopterans are well suited owing to the diverse sex determination mechanisms, including different types of Complementary Sex Determination (CSD) and maternal control sex determination. We investigated different types of CSD in four species within the braconid wasp genus Asobara that exhibit diverse life-history traits. Nine to thirteen generations of inbreeding were monitored for diploid male production, brood size, offspring sex ratio, and pupal mortality as indicators for CSD. In addition, simulation models were developed to compare these observations to predicted patterns for multilocus CSD with up to ten loci. The inbreeding regime did not result in diploid male production, decreased brood sizes, substantially increased offspring sex ratios nor in increased pupal mortality. The simulations further allowed us to reject CSD with up to ten loci, which is a strong refutation of the multilocus CSD model. We discuss how the absence of CSD can be reconciled with the variation in life-history traits among Asobara species, and the ramifications for the phylogenetic distribution of sex determination mechanisms in the Hymenoptera. PMID- 23637748 TI - MicroRNA-219-2-3p functions as a tumor suppressor in gastric cancer and is regulated by DNA methylation. AB - BACKGROUND AIMS: Gastric cancer is the most frequent gastrointestinal tumor in adults and is the most lethal form of human cancer. Despite of the improvements in treatments, the underlying mechanism of gastric carcinogenesis is not well known. To define novel modulators that regulate susceptibility to tumorgenesis, we focused on miR-219-2-3p. METHODS: Quantitative RT-PCR was employed to investigate the level of miR-219-2-3p in gastric cancer (GC) tissues (n = 113) and their matched adjacent normal tissues (n = 113). In vitro cell proliferation, apoptosis assays, cell migration, and invasion assays were performed to elucidate biological effects of miR-219-2-3p. Since silencing of miRNA by promoter CpG island methylation may be an important mechanism in tumorgenesis, GC cells were treated with 5-aza-2'-deoxycytidine and trichostatin A, and expression changes of miR-219-2-3p were subsequently examined by quantitative RT-PCR. Finally, the methylation status of CpG island upstream of miR-219-2-3p was analyzed by methylation-specific PCR in GC tissues (n = 22). RESULTS: miR-219-2-3p was down regulated in GC and cell lines. In addition, the experiments documented the lower expression of miR-219-2-3p in GC specimens with higher grade and later stage tumors. Meanwhile, miR-219-2-3p exerted antiproliferative, proapoptotic, and antimetastatic roles and reduced levels of p-ERK1/2 in GC cells. Furthermore, 5 aza-2'-deoxycytidine and trichostatin A increased the expression (~2 fold) of miR 219-2-3p in GC cells. By methylation-specific PCR, DNA methylation in the upstream region of miR-219-2-3p was detected in both adjacent normal tissues and cancer tissues. As expected, the methylation level was considerably higher in the miR-219-2-3p down-regulated group than up-regulated group. CONCLUSIONS: miR-219-2 3p is potentially involved in gastric cancer progression and metastasis by regulating ERK1/2-related signal pathways, which may provide a novel therapeutic strategy for treatment of gastric cancer. Methylation mechanism may be involved in modulating the expression level of miR-219-2-3p in gastric cancer. PMID- 23637751 TI - Network theory inspired analysis of time-resolved expression data reveals key players guiding P. patens stem cell development. AB - Transcription factors (TFs) often trigger developmental decisions, yet, their transcripts are often only moderately regulated and thus not easily detected by conventional statistics on expression data. Here we present a method that allows to determine such genes based on trajectory analysis of time-resolved transcriptome data. As a proof of principle, we have analysed apical stem cells of filamentous moss (P. patens) protonemata that develop from leaflets upon their detachment from the plant. By our novel correlation analysis of the post detachment transcriptome kinetics we predict five out of 1,058 TFs to be involved in the signaling leading to the establishment of pluripotency. Among the predicted regulators is the basic helix loop helix TF PpRSL1, which we show to be involved in the establishment of apical stem cells in P. patens. Our methodology is expected to aid analysis of key players of developmental decisions in complex plant and animal systems. PMID- 23637752 TI - Demonstration of cytotoxicity against wasps by pierisin-1: a possible defense factor in the cabbage white butterfly. AB - The cabbage white butterfly, Pieris rapae, produces pierisin-1, a protein inducing apoptosis of mammalian cells. In the present study, the biological activity of pierisin-1 as a protective agent against parasitic wasps for P. rapae was examined. Pierisin-1 caused detrimental effects on eggs and larvae of non habitual parasitoids for P. rapae, Glyptapanteles pallipes, Cotesia kariyai and Cotesia plutellae at 1-100 ug/ml, levels essentially equivalent to those found in P. rapae larvae. In contrast, eggs and larvae of the natural parasitoid of P. rapae, Cotesia glomerata proved resistant to the toxicity of pierisin-1 through inhibition of pierisin-1 penetration of the surface layer. The expression level of pierisin-1 mRNA in the larvae of P. rapae was increased by parasitization by C. plutellae, whereas it was decreased by C. glomerata. In addition, C. plutellae was associated with elevation of activated pierisin-1 in the hemolymph. From these observations, it is suggested that pierisin-1 could contribute as a defense factor against parasitization by some type of wasps in P. rapae. PMID- 23637754 TI - The susceptibility of Pseudomonas aeruginosa strains from cystic fibrosis patients to bacteriophages. AB - Phage therapy may become a complement to antibiotics in the treatment of chronic Pseudomonas aeruginosa infection. To design efficient therapeutic cocktails, the genetic diversity of the species and the spectrum of susceptibility to bacteriophages must be investigated. Bacterial strains showing high levels of phage resistance need to be identified in order to decipher the underlying mechanisms. Here we have selected genetically diverse P. aeruginosa strains from cystic fibrosis patients and tested their susceptibility to a large collection of phages. Based on plaque morphology and restriction profiles, six different phages were purified from "pyophage", a commercial cocktail directed against five different bacterial species, including P. aeruginosa. Characterization of these phages by electron microscopy and sequencing of genome fragments showed that they belong to 4 different genera. Among 47 P. aeruginosa strains, 13 were not lysed by any of the isolated phages individually or by pyophage. We isolated two new phages that could lyse some of these strains, and their genomes were sequenced. The presence/absence of a CRISPR-Cas system (Clustered Regularly Interspaced Short Palindromic Repeats and Crisper associated genes) was investigated to evaluate the role of the system in phage resistance. Altogether, the results show that some P. aeruginosa strains cannot support the growth of any of the tested phages belonging to 5 different genera, and suggest that the CRISPR-Cas system is not a major defence mechanism against these lytic phages. PMID- 23637755 TI - Outreach syphilis testing services by different health providers to female sex workers in southern China. AB - Health providers have played important roles on delivering prevention and care services to control syphilis in China. The current study was aimed to evaluate the performance of different health providers in providing outreach syphilis testing services to female sex workers (FSWs). The current study carried out during April to August 2009 in Liuzhou was aimed to investigate the services delivered by two different types of clinics in China. A total of 1,808 FSWs recruited from sex work venues were included in the study. Prevalence of positive syphilis test (6.4%) among FSWs accessed by the local center for disease control outreach teams (CDC teams) was significantly lower than that (9.3%) among FSWs accessed by the local reproductive health hospital outreach teams (RHH teams). As compared with CDC teams, RHH teams had more FSWs to be successfully referred to the designated STD clinics for further syphilis confirmation and intervention (85.7% vs. 26.7%, P<0.001). These findings indicate that RHH teams may be more efficient than CDC teams to provide outreach-based services to FSWs. Participation of the reproductive health providers or other medical facilities in outreach services to FSWs should be considered in developing intervention programs in China. PMID- 23637753 TI - A critical regulatory role for macrophage migration inhibitory factor in hyperoxia-induced injury in the developing murine lung. AB - BACKGROUND: The role and mechanism of action of MIF in hyperoxia-induced acute lung injury (HALI) in the newborn lung are not known. We hypothesized that MIF is a critical regulatory molecule in HALI in the developing lung. METHODOLOGY: We studied newborn wild type (WT), MIF knockout (MIFKO), and MIF lung transgenic (MIFTG) mice in room air and hyperoxia exposure for 7 postnatal (PN) days. Lung morphometry was performed and mRNA and protein expression of vascular mediators were analyzed. RESULTS: MIF mRNA and protein expression were significantly increased in WT lungs at PN7 of hyperoxia exposure. The pattern of expression of Angiopoietin 2 protein (in MIFKO>WT>MIFTG) was similar to the mortality pattern (MIFKO>WT>MIFTG) in hyperoxia at PN7. In room air, MIFKO and MIFTG had modest but significant increases in chord length, compared to WT. This was associated with decreased expression of Angiopoietin 1 and Tie 2 proteins in the MIFKO and MIFTG, as compared to the WT control lungs in room air. However, on hyperoxia exposure, while the chord length was increased from their respective room air controls, there were no differences between the 3 genotypes. CONCLUSION: These data point to the potential roles of Angiopoietins 1, 2 and their receptor Tie2 in the MIF regulated response in room air and upon hyperoxia exposure in the neonatal lung. PMID- 23637756 TI - Transmigration of neural stem cells across the blood brain barrier induced by glioma cells. AB - Transit of human neural stem cells, ReNcell CX, through the blood brain barrier (BBB) was evaluated in an in vitro model of BBB and in nude mice. The BBB model was based on rat brain microvascular endothelial cells (RBMECs) cultured on Millicell inserts bathed from the basolateral side with conditioned media (CM) from astrocytes or glioma C6 cells. Glioma C6 CM induced a significant transendothelial migration of ReNcells CX in comparison to astrocyte CM. The presence in glioma C6 CM of high amounts of HGF, VEGF, zonulin and PGE2, together with the low abundance of EGF, promoted ReNcells CX transmigration. In contrast cytokines IFN-alpha, TNF-alpha, IL-12p70, IL-1beta, IL-6, IL-8 and IL-10, as well as metalloproteinases -2 and -9 were present in equal amounts in glioma C6 and astrocyte CMs. ReNcells expressed the tight junction proteins occludin and claudins 1, 3 and 4, and the cell adhesion molecule CRTAM, while RBMECs expressed occludin, claudins 1 and 5 and CRTAM. Competing CRTAM mediated adhesion with soluble CRTAM, inhibited ReNcells CX transmigration, and at the sites of transmigration, the expression of occludin and claudin-5 diminished in RBMECs. In nude mice we found that ReNcells CX injected into systemic circulation passed the BBB and reached intracranial gliomas, which overexpressed HGF, VEGF and zonulin/prehaptoglobin 2. PMID- 23637757 TI - The impact of clinical social franchising on health services in low- and middle income countries: a systematic review. AB - BACKGROUND: The private sector plays a large role in health services delivery in low- and middle-income countries; yet significant gaps remain in the quality and accessibility of private sector services. Clinical social franchising, which applies the commercial franchising model to achieve social goals and improve health care, is increasingly used in developing countries to respond to these limitations. Despite the growth of this approach, limited evidence documents the effect of social franchising on improving health care quality and access. OBJECTIVES AND METHODS: We examined peer-reviewed and grey literature to evaluate the effect of social franchising on health care quality, equity, cost effectiveness, and health outcomes. We included all studies of clinical social franchise programs located in low- and middle-income countries. We assessed study bias using the WHO-Johns Hopkins Rigour Scale and used narrative synthesis to evaluate the findings. RESULTS: Of 113 identified articles, 23 were included in this review; these evaluated a small sample of franchises globally and focused on reproductive health franchises. Results varied widely across outcomes and programs. Social franchising was positively associated with increased client volume and client satisfaction. The findings on health care utilization and health impact were mixed; some studies find that franchises significantly outperform other models of health care, while others show franchises are equivalent to or worse than other private or public clinics. In two areas, cost effectiveness and equity, social franchises were generally found to have poorer outcomes. CONCLUSIONS: Our review indicates that social franchising may strengthen some elements of private sector health care. However, gaps in the evidence remain. Additional research should include: further documentation of the effect of social franchising, evaluating the equity and cost-effectiveness of this intervention, and assessing the role of franchising within the context of the greater healthcare delivery system. PMID- 23637758 TI - The ocular conjunctiva as a mucosal immunization route: a profile of the immune response to the model antigen tetanus toxoid. AB - BACKGROUND: In a quest for a needle-free vaccine administration strategy, we evaluated the ocular conjunctiva as an alternative mucosal immunization route by profiling and comparing the local and systemic immune responses to the subcutaneous or conjunctival administration of tetanus toxoid (TTd), a model antigen. MATERIALS AND METHODS: BALB/c and C57BL/6 mice were immunized either subcutaneously with TTd alone or via the conjunctiva with TTd alone, TTd mixed with 2% glycerol or TTd with merthiolate-inactivated whole-cell B. pertussis (wBP) as adjuvants. Mice were immunized on days 0, 7 and 14 via both routes, and an evaluation of the local and systemic immune responses was performed two weeks after the last immunization. Four weeks after the last immunization, the mice were challenged with a lethal dose (2 * LD50) of tetanus toxin. RESULTS: The conjunctival application of TTd in BALB/c mice induced TTd-specific secretory IgA production and skewed the TTd-specific immune response toward a Th1/Th17 profile, as determined by the stimulation of IFNgamma and IL-17A secretion and/or the concurrent pronounced reduction of IL-4 secretion, irrespective of the adjuvant. In conjunctivaly immunized C57BL/6 mice, only TTd administered with wBP promoted the establishment of a mixed Th1/Th17 TTd-specific immune response, whereas TTd alone or TTd in conjunction with glycerol initiated a dominant Th1 response against TTd. Immunization via the conjunctiva with TTd plus wBP adjuvant resulted in a 33% survival rate of challenged mice compared to a 0% survival rate in non immunized animals (p<0.05). CONCLUSION: Conjunctival immunization with TTd alone or with various adjuvants induced TTd-specific local and systemic immune responses, predominantly of the Th1 type. The strongest immune responses developed in mice that received TTd together with wBP, which implies that this alternative route might tailor the immune response to fight intracellular bacteria or viruses more effectively. PMID- 23637760 TI - Patterns of human papillomavirus DNA and antibody positivity in young males and females, suggesting a site-specific natural course of infection. AB - BACKGROUND: To monitor the impact of human papillomavirus types 16 and 18 vaccine on HPV infection dynamics in the Netherlands, we started an ongoing study in sexually transmitted infection (STI) clinics in 2009. Here, we analyze baseline type-specific HPV DNA and HPV-specific antibody positivity rates. METHODS: We enrolled 3569 men and women, 16-24 years of age, from 14 STI clinics, and estimated genital and anal HPV DNA and antibody positivity rates of 7 main carcinogenic HPV types. Generalized estimating equations regression analyses were applied to determine risk factors for, and associations between, type-specific HPV DNA and antibody positivity. RESULTS: Genital HPV DNA positivity rates were higher in women than in men; anal HPV DNA was especially high in men who have sex with men (MSM). HPV antibody seropositivity rates were also highest in women and MSM. High-risk sexual behavior was predictive of both HPV DNA and antibody positivity. Despite a strong correlation in serological profiles for multiple HPV types, seropositivity was independently associated with homologous HPV DNA detection. CONCLUSIONS: HPV DNA and antibody positivity rates are higher in women and MSM than in heterosexual men, but their association is similar across gender. This suggests a site-specific natural course of infection. PMID- 23637759 TI - Psychological distress during pregnancy in a multi-ethnic community: findings from the born in Bradford cohort study. AB - PURPOSE: Antenatal anxiety and depression are predictive of future mental distress, which has negative effects on children. Ethnic minority women are more likely to have a lower socio-economic status (SES) but it is unclear whether SES is an independent risk factor for mental health in pregnancy. We described the association between maternal mental distress and socio-demographic factors in a multi-ethnic cohort located in an economically deprived city in the UK. METHODS: We defined eight distinct ethno-language groups (total N = 8,454) and classified a threshold of distress as the 75th centile of within-group GHQ-28 scores, which we used as the outcome for univariate and multivariate logistic regression for each ethnic group and for the sample overall. RESULTS: Financial concerns were strongly and independently associated with worse mental health for six out of the eight ethnic groups, and for the cohort overall. In some groups, factors such as working status, education and family structure were associated with worse mental health, but for others these factors were of little importance. CONCLUSIONS: The diversity between and within ethnic groups in this sample underlines the need to take into consideration individual social, migration and economic circumstances and their potential effect on mental health in ethnically diverse areas. PMID- 23637762 TI - Diet-induced obesity exacerbates auditory degeneration via hypoxia, inflammation, and apoptosis signaling pathways in CD/1 mice. AB - The aim of this study was to investigate the mechanisms of diet-induced obesity on hearing degeneration in CD/1 mice. Sixty 4-week-old male CD/1 mice were randomly and equally divided into 2 groups. For 16 weeks, the diet-induced obesity (DIO) group was fed a high fat diet and the control group was fed a standard diet of 13.43 % kcal fat. The morphometry, biochemistry, auditory brainstem response thresholds, omental fat, and histopathology of the cochlea were compared between the beginning and end of the study (4 vs. 20 weeks old). The results show that the body weight, fasting plasma triglyceride concentrations, and omental fat weight were higher in the DIO group than in the control group at the end of experiment. The auditory brainstem response thresholds at high frequencies were significantly elevated in the DIO group compared to those of the control group. Histology studies showed that, compared to the control group, the DIO group had blood vessels with smaller diameters and thicker walls in the stria vascularis at the middle and basal turns of the cochlea. The cell densities in the spiral ganglion and spiral ligament at the basal turn of the cochlea were significantly lower in the DIO group. Immunohistochemical staining showed that hypoxia-induced factor 1 (HIF-1), tumor necrosis factor alpha (TNF-alpha), nuclear factor kappa B (NF-kappaB), caspase 3, poly(ADP-ribose) polymerase-1, and apoptosis inducing factor were all significantly more dense in the spiral ganglion and spiral ligament at the basal turn of cochlea in the DIO group. Our results suggest that diet-induced obesity exacerbates hearing degeneration via increased hypoxia, inflammatory responses, and cell loss in the spiral ganglion and spiral ligament and is associated with the activation of both caspase-dependent and -independent apoptosis signaling pathways in CD/1 mice. PMID- 23637761 TI - Recent geological events and intrinsic behavior influence the population genetic structure of the chiru and tibetan gazelle on the tibetan plateau. AB - The extent to which a species responds to environmental changes is mediated not only by extrinsic processes such as time and space, but also by species-specific ecology. The Qinghai-Tibetan Plateau uplifted approximately 3000 m and experienced at least four major glaciations during the Pleistocene epoch in the Quaternary Period. Consequently, the area experienced concurrent changes in geomorphological structure and climate. Two species, the Tibetan antelope (Pantholops hodgsonii, chiru) and Tibetan gazelle (Procapra picticaudata), both are endemic on the Qinghai-Tibetan Plateau, where their habitats overlap, but have different migratory behaviors: the chiru is inclined to have female-biased dispersal with a breeding migration during the calving season; in contrast, Tibetan gazelles are year-round residents and never migrate distantly. By using coalescence methods we compared mitochondrial control region DNA sequences and variation at nine microsatellite loci in these two species. Coalescent simulations indicate that the chiru and Tibetan gazelle do not share concordant patterns in their genealogies. The non-migratory Tibetan gazelle, that is more vulnerable to the impact of drastic geographic changes such as the elevation of the plateau, glaciations and so on, appears to have a strong population genetic structure with complicated demographic history. Specifically, the Tibetan gazelle population appears to have experienced isolation and divergence with population fluctuations since the Middle Pleistocene (0.781 Ma). However, it showed continued decline since the Upper Pleistocene (0.126 Ma), which may be attributed to the irreversible impact of increased human activities on the plateau. In contrast, the migratory chiru appears to have simply experienced population expansion. With substantial gene flow among regional populations, this species shows no historical population isolation and divergence. Thus, this study adds to many empirical studies that show historical and contemporary extrinsic and intrinsic processes shape the recent evolutionary history and population genetic structure of species. PMID- 23637763 TI - Variation of expression levels of seven housekeeping genes at different life history stages in Porphyra yezoensis. AB - In order to identify the optimal internal control for relative real-time PCR when studying target gene expression in the red alga Porphyra yezoensis, we quantified the expression of seven housekeeping genes (18S ribosomal RNA, 30S ribosomal protein S8, Polyubiquitin-2, Glyceraldehyde-3-phosphate dehydrogenase, Elongation factor 1-alpha, Beta-tubulin and Actin 3) at different life-history stages. Absolute quantification was done by normalization to total RNA quantity and by normalization to genomic DNA quantity. We used these two normalization approaches, comparing the differences of expression levels of all candidate housekeeping genes between any two generations and across three life-history stages (filamentous sporophytes, leafy gametophytes and conchospores). We found GAPDH had the best stability in all cases and we recommend that GAPDH be considered as a potential internal control for gene expression studies at different life-history stages in P. yezoensis. PMID- 23637764 TI - Land use explains the distribution of threatened New World amphibians better than climate. AB - BACKGROUND: We evaluated the direct and indirect influence of climate, land use, phylogenetic structure, species richness and endemism on the distribution of New World threatened amphibians. METHODOLOGY/PRINCIPAL FINDINGS: We used the WWF's New World ecoregions, the WWFs amphibian distributional data and the IUCN Red List Categories to obtain the number of threatened species per ecoregion. We analyzed three different scenarios urgent, moderate, and the most inclusive scenario. Using path analysis we evaluated the direct and indirect effects of climate, type of land use, phylogenetic structure, richness and endemism on the number of threatened amphibians in New World ecoregions. In all scenarios we found strong support for direct influences of endemism, the cover of villages and species richness on the number of threatened species in each ecoregion. The proportion of wild area had indirect effects in the moderate and the most inclusive scenario. Phylogenetic composition was important in determining the species richness and endemism in each ecoregion. Climate variables had complex and indirect effects on the number of threatened species. CONCLUSION/SIGNIFICANCE: Land use has a more direct influence than climate in determining the distribution of New World threatened amphibians. Independently of the scenario analyzed, the main variables influencing the distribution of threatened amphibians were consistent, with endemism having the largest magnitude path coefficient. The importance of phylogenetic composition could indicate that some clades may be more threatened than others, and their presence increases the number of threatened species. Our results highlight the importance of man-made land transformation, which is a local variable, as a critical factor underlying the distribution of threatened amphibians at a biogeographic scale. PMID- 23637765 TI - LMP1-induced cell death may contribute to the emergency of its oncogenic property. AB - BACKGROUND AND OBJECTIVES: Epstein-Barr Virus (EBV) Latent Membrane Protein 1 (LMP1) is linked to a variety of malignancies including Hodgkin's disease, lymphomas, nasopharyngeal and gastric carcinoma. LMP1 exerts its transforming or oncogenic activity mainly through the recruitment of intracellular adapters via LMP1 C-terminal Transformation Effector Sites (TES) 1 and 2. However, LMP1 is also reported to elicit significant cytotoxic effects in some other cell types. This cytotoxic effect is quite intriguing for an oncogenic protein, and it is unclear whether both functional aspects of the protein are related or mutually exclusive. METHODOLOGY AND PRINCIPAL FINDINGS: Using different ectopic expression systems in both Madin-Darby canine kidney (MDCK) epithelial cells and human embryonic kidney HEK-293 cells, we observe that LMP1 ectopic expression massively induces cell death. Furthermore, we show that LMP1-induced cytotoxicity mainly implies LMP1 C-terminal transformation effector sites and TRADD recruitment. However, stable expression of LMP1 in the same cells, is found to be associated with an increase of cell survival and an acquisition of epithelial mesenchymal transition phenotype as evidenced by morphological modifications, increased cell mobility, increased expression of MMP9 and decreased expression of E-cadherin. Our results demonstrate for the first time that the cytotoxic and oncogenic effects of LMP1 are not mutually exclusive but may operate sequentially. We suggest that in a total cell population, cells resistant to LMP1-induced cytotoxicity are those that could take advantage of LMP1 oncogenic activity by integrating LMP1 signaling into the pre-existent signaling network. Our findings thus reconcile the apparent opposite apoptotic and oncogenic effects described for LMP1 and might reflect what actually happens on LMP1-induced cell transformation after EBV infection in patients. PMID- 23637766 TI - Rapid mitochondrial genome evolution through invasion of mobile elements in two closely related species of arbuscular mycorrhizal fungi. AB - Arbuscular mycorrhizal fungi (AMF) are common and important plant symbionts. They have coenocytic hyphae and form multinucleated spores. The nuclear genome of AMF is polymorphic and its organization is not well understood, which makes the development of reliable molecular markers challenging. In stark contrast, their mitochondrial genome (mtDNA) is homogeneous. To assess the intra- and inter specific mitochondrial variability in closely related Glomus species, we performed 454 sequencing on total genomic DNA of Glomus sp. isolate DAOM-229456 and we compared its mtDNA with two G. irregulare isolates. We found that the mtDNA of Glomus sp. is homogeneous, identical in gene order and, with respect to the sequences of coding regions, almost identical to G. irregulare. However, certain genomic regions vary substantially, due to insertions/deletions of elements such as introns, mitochondrial plasmid-like DNA polymerase genes and mobile open reading frames. We found no evidence of mitochondrial or cytoplasmic plasmids in Glomus species, and mobile ORFs in Glomus are responsible for the formation of four gene hybrids in atp6, atp9, cox2, and nad3, which are most probably the result of horizontal gene transfer and are expressed at the mRNA level. We found evidence for substantial sequence variation in defined regions of mtDNA, even among closely related isolates with otherwise identical coding gene sequences. This variation makes it possible to design reliable intra- and inter specific markers. PMID- 23637767 TI - Annexin peptide Ac2-26 suppresses TNFalpha-induced inflammatory responses via inhibition of Rac1-dependent NADPH oxidase in human endothelial cells. AB - The anti-inflammatory peptide annexin-1 binds to formyl peptide receptors (FPR) but little is known about its mechanism of action in the vasculature. Here we investigate the effect of annexin peptide Ac2-26 on NADPH oxidase activity induced by tumour necrosis factor alpha (TNFalpha) in human endothelial cells. Superoxide release and intracellular reactive oxygen species (ROS) production from NADPH oxidase was measured with lucigenin-enhanced chemiluminescence and 2',7'-dichlorodihydrofluorescein diacetate, respectively. Expression of NADPH oxidase subunits and intracellular cell adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) were determined by real-time PCR and Western blot analysis. Promoter activity of nuclear factor kappa B (NFkappaB) was measured by luciferase activity assay. TNFalpha stimulated NADPH-dependent superoxide release, total ROS formation and expression of ICAM-1and VCAM-1. Pre-treatment with N-terminal peptide of annexin-1 (Ac2-26, 0.5-1.5 uM) reduced all these effects, and the inhibition was blocked by the FPRL-1 antagonist WRW4. Furthermore, TNFalpha-induced NFkappaB promoter activity was attenuated by both Ac2-26 and NADPH oxidase inhibitor diphenyliodonium (DPI). Surprisingly, Nox4 gene expression was reduced by TNFalpha whilst expression of Nox2, p22phox and p67phox remained unchanged. Inhibition of NADPH oxidase activity by either dominant negative Rac1 (N17Rac1) or DPI significantly attenuated TNFalpha-induced ICAM-1and VCAM-1 expression. Ac2-26 failed to suppress further TNFalpha-induced expression of ICAM-1 and VCAM-1 in N17Rac1-transfected cells. Thus, Ac2-26 peptide inhibits TNFalpha-activated, Rac1-dependent NADPH oxidase derived ROS formation, attenuates NFkappaB pathways and ICAM-1 and VCAM-1 expression in endothelial cells. This suggests that Ac2-26 peptide blocks NADPH oxidase activity and has anti-inflammatory properties in the vasculature which contributes to modulate in reperfusion injury inflammation and vascular disease. PMID- 23637768 TI - Protection of cells against oxidative stress by nanomolar levels of hydroxyflavones indicates a new type of intracellular antioxidant mechanism. AB - Natural polyphenol compounds are often good antioxidants, but they also cause damage to cells through more or less specific interactions with proteins. To distinguish antioxidant activity from cytotoxic effects we have tested four structurally related hydroxyflavones (baicalein, mosloflavone, negletein, and 5,6 dihydroxyflavone) at very low and physiologically relevant levels, using two different cell lines, L-6 myoblasts and THP-1 monocytes. Measurements using intracellular fluorescent probes and electron paramagnetic resonance spectroscopy in combination with cytotoxicity assays showed strong antioxidant activities for baicalein and 5,6-dihydroxyflavone at picomolar concentrations, while 10 nM partially protected monocytes against the strong oxidative stress induced by 200 uM cumene hydroperoxide. Wide range dose-dependence curves were introduced to characterize and distinguish the mechanism and targets of different flavone antioxidants, and identify cytotoxic effects which only became detectable at micromolar concentrations. Analysis of these dose-dependence curves made it possible to exclude a protein-mediated antioxidant response, as well as a mechanism based on the simple stoichiometric scavenging of radicals. The results demonstrate that these flavones do not act on the same radicals as the flavonol quercetin. Considering the normal concentrations of all the endogenous antioxidants in cells, the addition of picomolar or nanomolar levels of these flavones should not be expected to produce any detectable increase in the total cellular antioxidant capacity. The significant intracellular antioxidant activity observed with 1 pM baicalein means that it must be scavenging radicals that for some reason are not eliminated by the endogenous antioxidants. The strong antioxidant effects found suggest these flavones, as well as quercetin and similar polyphenolic antioxidants, at physiologically relevant concentrations act as redox mediators to enable endogenous antioxidants to reach and scavenge different pools of otherwise inaccessible radicals. PMID- 23637769 TI - Specific targeting of caspase-9/PP2A interaction as potential new anti-cancer therapy. AB - PURPOSE: PP2A is a serine/threonine phosphatase critical to physiological processes, including apoptosis. Cell penetrating peptides are molecules that can translocate into cells without causing membrane damage. Our goal was to develop cell-penetrating fusion peptides specifically designed to disrupt the caspase 9/PP2A interaction and evaluate their therapeutic potential in vitro and in vivo. EXPERIMENTAL DESIGN: We generated a peptide containing a penetrating sequence associated to the interaction motif between human caspase-9 and PP2A (DPT-C9h), in order to target their association. Using tumour cell lines, primary human cells and primary human breast cancer (BC) xenografts, we investigated the capacity of DPT-C9h to provoke apoptosis in vitro and inhibition of tumour growth (TGI) in vivo. DPT-C9h was intraperitoneally administered at doses from 1 to 25 mg/kg/day for 5 weeks. Relative Tumour Volume (RTV) was calculated. RESULTS: We demonstrated that DPT-C9h specifically target caspase-9/PP2A interaction in vitro and in vivo and induced caspase-9-dependent apoptosis in cancer cell lines. DPT C9h also induced significant TGI in BC xenografts models. The mouse-specific peptide DPT-C9 also induced TGI in lung (K-Ras model) and breast cancer (PyMT) models. DPT-C9h has a specific effect on transformed B cells isolated from chronic lymphocytic leukemia patients without any effect on primary healthy cells. Finally, neither toxicity nor immunogenic responses were observed. CONCLUSION: Using the cell-penetrating peptides blocking caspase-9/PP2A interactions, we have demonstrated that DPT-C9h had a strong therapeutic effect in vitro and in vivo in mouse models of tumour progression. PMID- 23637770 TI - Which environmental factors predict seasonal variation in the coral health of Acropora digitifera and Acropora spicifera at Ningaloo Reef? AB - The impact of physico-chemical factors on percent coral cover and coral health was examined on a spatial basis for two dominant Acropora species, A. digitifera and A. spicifera, at Ningaloo Reef (north-western Australia) in the southeast Indian Ocean. Coral health was investigated by measuring metabolic indices (RNA/DNA ratio and protein concentration), energy levels (lipid ratio) and autotrophic indices (chlorophyll a (chl a) and zooxanthellae density) at six stations during typical seasons (austral autumn 2010 (March and April), austral winter 2010 (August)) and during an extreme La Nina event in summer 2011 (February). These indices were correlated with 15 physico-chemical factors (measured immediately following coral sampling) to identify predictors for health indices. Variations in metabolic indices (protein concentration and RNA/DNA ratio) for A. spicifera were mainly explained by nitrogen, temperature and zooplankton concentrations under typical conditions, while for A. digitifera, light as well as phytoplankton, in particular picoeukaryotes, were important, possibly due to higher energy requirement for lipid synthesis and storage in A. digitifera. Optimum metabolic values occurred for both Acropora species at 26-28 degrees C when autotrophic indices (chl a and zooxanthellae density) were lowest. The extreme temperature during the La Nina event resulted in a shift of feeding modes, with an increased importance of water column plankton concentrations for metabolic rates of A. digitifera and light and plankton for A. spicifera. Our results suggest that impacts of high sea surface temperatures during extreme events such as La Nina may be mitigated via reduction on metabolic rates in coral host. The high water column plankton concentrations and associated low light levels resulted in a shift towards high symbiont densities, with lower metabolic rates and energy levels than the seasonal norm for the coral host. PMID- 23637772 TI - Objectively measured physical activity and sedentary time during childhood, adolescence and young adulthood: a cohort study. AB - BACKGROUND: To know how moderate-to-vigorous physical activity (MVPA) and sedentary time change across lifespan periods is needed for designing successful lifestyle interventions. We aimed to study changes in objectively measured (accelerometry) MVPA and sedentary time from childhood to adolescence and from adolescence to young adulthood. METHODS: Estonian and Swedish participants from the European Youth Heart Study aged 9 and 15 years at baseline (N = 2312) were asked to participate in a second examination 6 (Sweden) to 9/10 (Estonia) years later. 1800 participants with valid accelerometer data were analyzed. RESULTS: MVPA decreased from childhood to adolescence (-1 to -2.5 min/d per year of follow up, P = 0.01 and <0.001, for girls and boys respectively) and also from adolescence to young adulthood (-0.8 to -2.2 min/d per year, P = 0.02 and <0.001 for girls and boys, respectively). Sedentary time increased from childhood to adolescence (+15 and +20 min/d per year, for girls and boys respectively, P<0.001), with no substantial change from adolescence to young adulthood. Changes in both MVPA and sedentary time were greater in Swedish than in Estonian participants and in boys than in girls. The magnitude of the change observed in sedentary time was 3-6 time larger than the change observed in MVPA. CONCLUSIONS: The decline in MVPA (overall change = 30 min/d) and increase sedentary time (overall change = 2:45 h/d) observed from childhood to adolescence are of concern and might increase the risk of developing obesity and other chronic diseases later in life. These findings substantially contribute to understand how key health-related behaviors (physical activity and sedentary) change across important periods of life. PMID- 23637771 TI - Immune-complex mimics as a molecular platform for adjuvant-free vaccine delivery. AB - Protein-based vaccine development faces the difficult challenge of finding robust yet non-toxic adjuvants suitable for humans. Here, using a molecular engineering approach, we have developed a molecular platform for generating self-adjuvanting immunogens that do not depend on exogenous adjuvants for induction of immune responses. These are based on the concept of Immune Complex Mimics (ICM), structures that are formed between an oligomeric antigen and a monoclonal antibody (mAb) to that antigen. In this way, the roles of antigens and antibodies within the structure of immune complexes are reversed, so that a single monoclonal antibody, rather than polyclonal sera or expensive mAb cocktails can be used. We tested this approach in the context of Mycobacterium tuberculosis (MTB) infection by linking the highly immunogenic and potentially protective Ag85B with the oligomeric Acr (alpha crystallin, HspX) antigen. When combined with an anti-Acr monoclonal antibody, the fusion protein formed ICM which bound to C1q component of the complement system and were readily taken up by antigen presenting cells in vitro. ICM induced a strong Th1/Th2 mixed type antibody response, which was comparable to cholera toxin adjuvanted antigen, but only moderate levels of T cell proliferation and IFN-gamma secretion. Unfortunately, the systemic administration of ICM did not confer statistically significant protection against intranasal MTB challenge, although a small BCG-boosting effect was observed. We conclude that ICM are capable of inducing strong humoral responses to incorporated antigens and may be a suitable vaccination approach for pathogens other than MTB, where antibody-based immunity may play a more protective role. PMID- 23637773 TI - Accounting for age uncertainty in growth modeling, the case study of yellowfin tuna (Thunnus albacares) of the Indian Ocean. AB - Age estimates, typically determined by counting periodic growth increments in calcified structures of vertebrates, are the basis of population dynamics models used for managing exploited or threatened species. In fisheries research, the use of otolith growth rings as an indicator of fish age has increased considerably in recent decades. However, otolith readings include various sources of uncertainty. Current ageing methods, which converts an average count of rings into age, only provide periodic age estimates in which the range of uncertainty is fully ignored. In this study, we describe a hierarchical model for estimating individual ages from repeated otolith readings. The model was developed within a Bayesian framework to explicitly represent the sources of uncertainty associated with age estimation, to allow for individual variations and to include knowledge on parameters from expertise. The performance of the proposed model was examined through simulations, and then it was coupled to a two-stanza somatic growth model to evaluate the impact of the age estimation method on the age composition of commercial fisheries catches. We illustrate our approach using the sagittal otoliths of yellowfin tuna of the Indian Ocean collected through large-scale mark recapture experiments. The simulation performance suggested that the ageing error model was able to estimate the ageing biases and provide accurate age estimates, regardless of the age of the fish. Coupled with the growth model, this approach appeared suitable for modeling the growth of Indian Ocean yellowfin and is consistent with findings of previous studies. The simulations showed that the choice of the ageing method can strongly affect growth estimates with subsequent implications for age-structured data used as inputs for population models. Finally, our modeling approach revealed particularly useful to reflect uncertainty around age estimates into the process of growth estimation and it can be applied to any study relying on age estimation. PMID- 23637774 TI - miRNA biogenesis enzyme Drosha is required for vascular smooth muscle cell survival. AB - miRNA biogenesis enzyme Drosha cleaves double-stranded primary miRNA by interacting with double-stranded RNA binding protein DGCR8 and processes primary miRNA into precursor miRNA to participate in the miRNA biogenesis pathway. The role of Drosha in vascular smooth muscle cells (VSMCs) has not been well addressed. We generated Drosha conditional knockout (cKO) mice by crossing VSMC specific Cre mice, SM22-Cre, with Drosha (loxp/loxp) mice. Disruption of Drosha in VSMCs resulted in embryonic lethality at E14.5 with severe liver hemorrhage in mutant embryos. No obvious developmental delay was observed in Drosha cKO embryos. The vascular structure was absent in the yolk sac of Drosha homozygotes at E14.5. Loss of Drosha reduced VSMC proliferation in vitro and in vivo. The VSMC differentiation marker genes, including alphaSMA, SM22, and CNN1, and endothelial cell marker CD31 were significantly downregulated in Drosha cKO mice compared to controls. ERK1/2 mitogen-activated protein kinase and the phosphatidylinositol 3-kinase/AKT were attenuated in VSMCs in vitro and in vivo. Disruption of Drosha in VSMCs of mice leads to the dysregulation of miRNA expression. Using bioinformatics approach, the interactions between dysregulated miRNAs and their target genes were analyzed. Our data demonstrated that Drosha is required for VSMC survival by targeting multiple signaling pathways. PMID- 23637776 TI - Association of genetic markers in the BCL-2 family of apoptosis-related genes with endometrial cancer risk in a Chinese population. AB - BACKGROUND: In vitro studies have demonstrated the role of the BCL-2 family of genes in endometrial carcinogenesis. The role of genetic variants in BCL-2 genes and their interactions with non-genetic factors in the development of endometrial cancer has not been investigated in epidemiological studies. PATIENTS AND METHODS: We examined the relationship between BCL-2 gene family variants and endometrial cancer risk among 1,028 patients and 1,922 age-matched community controls from Shanghai, China. We also investigated possible interactions between genetic variants and established risk factors (demographic, lifestyle and clinical). Individuals were genotyped for 86 tagging single nucleotide polymorphisms (SNPs) in the BCL2, BAX, BAD and BAK1 genes. RESULTS: Significant associations with endometrial cancer risk were found for 9 SNPs in the BCL2 gene (P trend<0.05 for all). For SNPs rs17759659 and rs7243091 (minor allele for both: G), the associations were independent. The odds ratio was 1.27 (95% CI: 1.04 1.53) for women with AG genotype for the SNP rs17759659 and 1.82 (95% CI: 1.21 2.73) for women with the GG genotype for the SNP rs7243091. No interaction between these two SNPs and established non-genetic risk factors of endometrial cancer was noticed. CONCLUSION: Genetic polymorphisms in the BCL2 gene may be associated with the risk of endometrial cancer in Chinese women. PMID- 23637775 TI - A hypomorphic lsd1 allele results in heart development defects in mice. AB - Lysine-specific demethylase 1 (Lsd1/Aof2/Kdm1a), the first enzyme with specific lysine demethylase activity to be described, demethylates histone and non-histone proteins and is essential for mouse embryogenesis. Lsd1 interacts with numerous proteins through several different domains, most notably the tower domain, an extended helical structure that protrudes from the core of the protein. While there is evidence that Lsd1-interacting proteins regulate the activity and specificity of Lsd1, the significance and roles of such interactions in developmental processes remain largely unknown. Here we describe a hypomorphic Lsd1 allele that contains two point mutations in the tower domain, resulting in a protein with reduced interaction with known binding partners and decreased enzymatic activity. Mice homozygous for this allele die perinatally due to heart defects, with the majority of animals suffering from ventricular septal defects. Molecular analyses revealed hyperphosphorylation of E-cadherin in the hearts of mutant animals. These results identify a previously unknown role for Lsd1 in heart development, perhaps partly through the control of E-cadherin phosphorylation. PMID- 23637777 TI - Relative metabolic stability, but disrupted circadian cortisol secretion during the fasting month of Ramadan. AB - BACKGROUND: Chronic feeding and sleep schedule disturbances are stressors that exert damaging effects on the organism. Practicing Muslims in Saudi Arabia go through strict Ramadan fasting from dawn till sunset for one month yearly. Modern era Ramadan practices in Saudi Arabia are associated with disturbed feeding and sleep patterns, namely abstaining from food and water and increasing daytime sleep, and staying awake and receiving food and water till dawn. HYPOTHESIS: Strict Ramadan practices in Saudi Arabia may influence metabolism, sleep and circadian cortisol secretion. PROTOCOL: Young, male Ramadan practitioners were evaluated before and two weeks into the Ramadan. Blood samples were collected at 9.00 am and 9.00 pm for measurements of metabolic parameters and cortisol. Saliva was collected serially during the day for cortisol determinations. RESULTS: Ramadan practitioners had relative metabolic stability or changes expected by the pattern of feeding. However, the cortisol circadian rhythm was abolished and circulating insulin levels and HOMA index were increased during this period. DISCUSSION: The flattening of the cortisol rhythm is typical of conditions associated with chronic stress or endogenous hypercortisolism and associated with insulin resistance. CONCLUSIONS: Modern Ramadan practices in Saudi Arabia are associated with evening hypercortisolism and increased insulin resistance. These changes might contribute to the high prevalence of chronic stress-related conditions, such as central obesity, hypertension, metabolic syndrome and diabetes mellitus type 2, and their cardiovascular sequelae observed in the Kingdom. PMID- 23637778 TI - Network redundancy analysis of effective brain networks: a comparison of healthy controls and patients with major depression. AB - This study investigated electroencephalographic correlates in chronically depressed patients compared to healthy controls using intracutaneously applied electrical pain stimulus, to better understand the interaction between pain processing and depression. A close interaction between pain and depression is generally recognized although the precise mechanisms are not yet fully understood. The present study focuses on the hypothesis that effective brain connectivity in major depression patients is altered. Multifunctional interactions between brain regions represent a robust index of effective interactions within the brain, and can be quantified by network redundancy. Thus, structural network differences between 18 normal controls and 18 major depression patients before as well as during the processing of moderately painful intracutaneous electrical stimuli were investigated on the basis of network redundancy differences. In our sample, both patients and control subjects exhibit comparable network redundancies before stimulus application. Caused by the stimulus, there is a global increase of network redundancy in both groups. This increase is diminished in the group of major depression patients. We found clear differences between patients and controls during the stimulus processing, where the network redundancy in normal controls is larger in comparison to patients. The differences might be explained by the fact that major depression patients are more restricted to the affective component of the processing. The well established biasing to affective processing might suppress the somatosensory processing resulting in a lower number of connections within the considered network. This might then lead to a reduction in network redundancy during stimulus processing. PMID- 23637780 TI - Baseline gene expression signatures in monocytes from multiple sclerosis patients treated with interferon-beta. AB - BACKGROUND: A relatively large proportion of relapsing-remitting multiple sclerosis (RRMS) patients do not respond to interferon-beta (IFNb) treatment. In previous studies with peripheral blood mononuclear cells (PBMC), we identified a subgroup of IFNb non-responders that was characterized by a baseline over expression of type I IFN inducible genes. Additional mechanistic experiments carried out in IFNb non-responders suggested a selective alteration of the type I IFN signaling pathway in the population of blood monocytes. Here, we aimed (i) to investigate whether the type I IFN signaling pathway is up-regulated in isolated monocytes from IFNb non-responders at baseline; and (ii) to search for additional biological pathways in this cell population that may be implicated in the response to IFNb treatment. METHODS: Twenty RRMS patients classified according to their clinical response to IFNb treatment and 10 healthy controls were included in the study. Monocytes were purified from PBMC obtained before treatment by cell sorting and the gene expression profiling was determined with oligonucleotide microarrays. RESULTS AND DISCUSSION: Purified monocytes from IFNb non-responders were characterized by an over-expression of type I IFN responsive genes, which confirms the type I IFN signature in monocytes suggested from previous studies. Other relevant signaling pathways that were up-regulated in IFNb non-responders were related with the mitochondrial function and processes such as protein synthesis and antigen presentation, and together with the type I IFN signaling pathway, may also be playing roles in the response to IFNb. PMID- 23637781 TI - Elucidating novel serum biomarkers associated with pulmonary tuberculosis treatment. AB - In an unbiased approach to biomarker discovery, we applied a highly multiplexed proteomic technology (SOMAscan, SomaLogic, Inc, Boulder, CO) to understand changes in proteins from paired serum samples at enrollment and after 8 weeks of TB treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in the Center for Disease Control and Prevention's Tuberculosis Trials Consortium (TBTC) Study 29. This work represents the first large-scale proteomic analysis employing modified DNA aptamers in a study of active tuberculosis (TB). We identified multiple proteins that exhibit significant expression differences during the intensive phase of TB therapy. There was enrichment for proteins in conserved networks of biological processes and function including antimicrobial defense, tissue healing and remodeling, acute phase response, pattern recognition, protease/anti-proteases, complement and coagulation cascade, apoptosis, immunity and inflammation pathways. Members of cytokine pathways such as interferon-gamma, while present, were not as highly represented as might have been predicted. The top proteins that changed between baseline and 8 weeks of therapy were TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, and LBP. The novel proteins elucidated in this work may provide new insights for understanding TB disease, its treatment and subsequent healing processes that occur in response to effective therapy. PMID- 23637779 TI - Tyrosine kinase inhibitors induce down-regulation of c-Kit by targeting the ATP pocket. AB - The stem cell factor receptor (SCF) c-Kit plays a pivotal role in regulating cell proliferation and survival in many cell types. In particular, c-Kit is required for early amplification of erythroid progenitors, while it must disappear from cell surface for the cell entering the final steps of maturation in an erythropoietin-dependent manner. We initially observed that imatinib (IM), an inhibitor targeting the tyrosine kinase activity of c-Kit concomitantly down regulated the expression of c-Kit and accelerated the Epo-driven differentiation of erythroblasts in the absence of SCF. We investigated the mechanism by which IM or related masitinib (MA) induce c-Kit down-regulation in the human UT-7/Epo cell line. We found that the down-regulation of c-Kit in the presence of IM or MA was inhibited by a pre-incubation with methyl-beta-cyclodextrin suggesting that c-Kit was internalized in the absence of ligand. By contrast to SCF, the internalization induced by TKI was independent of the E3 ubiquitin ligase c-Cbl. Furthermore, c-Kit was degraded through lysosomal, but not proteasomal pathway. In pulse-chase experiments, IM did not modulate c-Kit synthesis or maturation. Analysis of phosphotyrosine peptides in UT-7/Epo cells treated or not with IM show that IM did not modify overall tyrosine phosphorylation in these cells. Furthermore, we showed that a T670I mutation preventing the full access of IM to the ATP binding pocket, did not allow the internalization process in the presence of IM. Altogether these data show that TKI-induced internalization of c-Kit is linked to a modification of the integrity of ATP binding pocket. PMID- 23637783 TI - Cross-translational studies in human and Drosophila identify markers of sleep loss. AB - Inadequate sleep has become endemic, which imposes a substantial burden for public health and safety. At present, there are no objective tests to determine if an individual has gone without sleep for an extended period of time. Here we describe a novel approach that takes advantage of the evolutionary conservation of sleep to identify markers of sleep loss. To begin, we demonstrate that IL-6 is increased in rats following chronic total sleep deprivation and in humans following 30 h of waking. Discovery experiments were then conducted on saliva taken from sleep-deprived human subjects to identify candidate markers. Given the relationship between sleep and immunity, we used Human Inflammation Low Density Arrays to screen saliva for novel markers of sleep deprivation. Integrin alphaM (ITGAM) and Anaxin A3 (AnxA3) were significantly elevated following 30 h of sleep loss. To confirm these results, we used QPCR to evaluate ITGAM and AnxA3 in independent samples collected after 24 h of waking; both transcripts were increased. The behavior of these markers was then evaluated further using the power of Drosophila genetics as a cost-effective means to determine whether the marker is associated with vulnerability to sleep loss or other confounding factors (e.g., stress). Transcript profiling in flies indicated that the Drosophila homologues of ITGAM were not predictive of sleep loss. Thus, we examined transcript levels of additional members of the integrin family in flies. Only transcript levels of scab, the Drosophila homologue of Integrin alpha5 (ITGA5), were associated with vulnerability to extended waking. Since ITGA5 was not included on the Low Density Array, we returned to human samples and found that ITGA5 transcript levels were increased following sleep deprivation. These cross-translational data indicate that fly and human discovery experiments are mutually reinforcing and can be used interchangeably to identify candidate biomarkers of sleep loss. PMID- 23637782 TI - Maize gene atlas developed by RNA sequencing and comparative evaluation of transcriptomes based on RNA sequencing and microarrays. AB - Transcriptome analysis is a valuable tool for identification and characterization of genes and pathways underlying plant growth and development. We previously published a microarray-based maize gene atlas from the analysis of 60 unique spatially and temporally separated tissues from 11 maize organs [1]. To enhance the coverage and resolution of the maize gene atlas, we have analyzed 18 selected tissues representing five organs using RNA sequencing (RNA-Seq). For a direct comparison of the two methodologies, the same RNA samples originally used for our microarray-based atlas were evaluated using RNA-Seq. Both technologies produced similar transcriptome profiles as evident from high Pearson's correlation statistics ranging from 0.70 to 0.83, and from nearly identical clustering of the tissues. RNA-Seq provided enhanced coverage of the transcriptome, with 82.1% of the filtered maize genes detected as expressed in at least one tissue by RNA-Seq compared to only 56.5% detected by microarrays. Further, from the set of 465 maize genes that have been historically well characterized by mutant analysis, 427 show significant expression in at least one tissue by RNA-Seq compared to 390 by microarray analysis. RNA-Seq provided higher resolution for identifying tissue specific expression as well as for distinguishing the expression profiles of closely related paralogs as compared to microarray-derived profiles. Co expression analysis derived from the microarray and RNA-Seq data revealed that broadly similar networks result from both platforms, and that co-expression estimates are stable even when constructed from mixed data including both RNA-Seq and microarray expression data. The RNA-Seq information provides a useful complement to the microarray-based maize gene atlas and helps to further understand the dynamics of transcription during maize development. PMID- 23637784 TI - Physical deconditioning as a cause of breathlessness among obese adolescents with a diagnosis of asthma. AB - BACKGROUND: Obese children frequently complain of breathlessness. Asthma and obesity can both contribute to the symptoms during exercise, and this symptom can contribute to a diagnosis of asthma in these children. Despite the high prevalence of obesity few studies have investigated the cardiopulmonary physiology of breathlessness in obese children with a diagnosis of asthma. METHODS: In this case-control study, thirty adolescents between age 12 and 19 were studied with baseline spirometry and a cardiopulmonary exercise test. Ten adolescents were normal controls, ten had obesity without a diagnosis of asthma, and ten had obesity with a history of physician-diagnosed asthma. RESULTS: Baseline characteristics including complete blood count and spirometry were comparable between obese adolescents with and without a diagnosis of asthma. During exercise, obese asthmatic and obese non-asthmatic adolescents had significantly reduced physical fitness compared to healthy controls as evidenced by decreased peak oxygen uptake after adjusting for actual body weight (21.7 +/- 4.5 vs. 21.4 +/- 5.4 vs. 35.3 +/- 5.8 ml/kg/min, respectively). However, pulmonary capacity at the peak of exercise was comparable among all three groups as evidenced by similar pulmonary reserve. CONCLUSION: In this study, breathlessness was primarily due to cardiopulmonary deconditioning in the majority of obese adolescents with or without a diagnosis of asthma. PMID- 23637785 TI - Role of hepcidin in the setting of hypoferremia during acute inflammation. AB - The anemia of chronic disease (also called anemia of inflammation) is an acquired disorder of iron homeostasis associated with infection, malignancy, organ failure, trauma, or other causes of inflammation. It is now widely accepted that induction of hepcidin expression in response to inflammation might explain the characteristic hypoferremia associated with this condition. To determine the role of hepcidin in acute inflammation and the regulation of its receptor, the iron exporter, ferroportin, wild-type, heterozygote and hepcidin knockout mice (Hepc-/ ) were challenged with sublethal doses of lipopolysaccharide (LPS). Six hours after injection, ferroportin mRNA and protein levels were assessed in the duodenum and the spleen and plasma iron was determined. Our results demonstrate that hepcidin is crucial, though not the sole mediator of LPS-mediated acute hypoferremia, and also that hepcidin major contribution relies on decreased ferroportin protein levels found in the spleen. Furthermore, we establish that LPS-mediated repression of the membrane iron transporter DMT1 and oxidoreductase Dcytb in the duodenum is independent of hepcidin. Finally, our results in the hepc+/- mice indicate that elevated hepcidin gene expression is not a prerequisite for the setting of hypoferremia during early inflammatory response, and they highlight the intimate crosstalk between inflammatory and iron responsive pathways for the control of hepcidin. PMID- 23637786 TI - Targeting of PBP1 by beta-lactams determines recA/SOS response activation in heterogeneous MRSA clinical strains. AB - The SOS response, a conserved regulatory network in bacteria that is induced in response to DNA damage, has been shown to be associated with the emergence of resistance to antibiotics. Previously, we demonstrated that heterogeneous (HeR) MRSA strains, when exposed to sub-inhibitory concentrations of oxacillin, were able to express a homogeneous high level of resistance (HoR). Moreover, we showed that oxacillin appeared to be the triggering factor of a beta-lactam-mediated SOS response through lexA/recA regulators, responsible for an increased mutation rate and selection of a HoR derivative. In this work, we demonstrated, by selectively exposing to beta-lactam and non-beta-lactam cell wall inhibitors, that PBP1 plays a critical role in SOS-mediated recA activation and HeR-HoR selection. Functional analysis of PBP1 using an inducible PBP1-specific antisense construct showed that PBP1 depletion abolished both beta-lactam-induced recA expression/activation and increased mutation rates during HeR/HoR selection. Furthermore, based on the observation that HeR/HoR selection is accompanied by compensatory increases in the expression of PBP1,-2, -2a, and -4, our study provides evidence that a combination of agents simultaneously targeting PBP1 and either PBP2 or PBP2a showed both in-vitro and in-vivo efficacy, thereby representing a therapeutic option for the treatment of highly resistant HoR-MRSA strains. The information gathered from these studies contributes to our understanding of beta-lactam mediated HeR/HoR selection and provides new insights, based on beta-lactam synergistic combinations, that mitigate drug resistance for the treatment of MRSA infections. PMID- 23637787 TI - Role of baseline antral follicle count and anti-Mullerian hormone in prediction of cumulative live birth in the first in vitro fertilisation cycle: a retrospective cohort analysis. AB - OBJECTIVE: This retrospective study determined for the first time the role of baseline antral follicle count (AFC) and serum anti-Mullerian hormone (AMH) level in the first in-vitro fertilisation (IVF) cycle in predicting cumulative live birth from one stimulation cycle. METHODS: We studied 1,156 women (median age 35 years) undergoing the first IVF cycle. Baseline AFC and AMH level on the day before ovarian stimulation were analysed. The main outcome measure was cumulative live birth in the fresh plus all the frozen embryo transfers after the same stimulation cycle. RESULTS: Serum AMH was significantly correlated with AFC. Both AMH and AFC showed significant correlation with age and ovarian response in the stimulated cycle and total number of transferrable embryos. Baseline AFC and serum AMH were significantly higher in subjects attaining a live birth than those who did not in the fresh stimulated cycle, as well as those attaining cumulative live birth. There was a significant trend of higher cumulative live birth rate in women with higher AMH or AFC. However, logistic regression revealed that both AMH and AFC were not significant predictors of cumulative live birth after adjusting for age and number of embryos available for transfer. Considering only one single predictor, the areas under the ROC curves for AMH (0.646, 95% CI 0.616-0.675) and age (0.648, 95% CI 0.618-0.677) were slightly higher than that for AFC (0.617, 95% CI 0.587-0.647) in predicting cumulative live birth. However, a model combining AMH (with or without AFC) and age of the women only classified an addition of less than 2% of subjects correctly compared to the model with age alone. CONCLUSION: Baseline AFC and serum AMH have only modest predictive performance on the occurrence of cumulative live birth, and may not give additional value on top of the women's age. PMID- 23637788 TI - Mannose-binding lectin 2 gene and risk of adult glioma. AB - BACKGROUND AND AIMS: The immune system is likely to play a key role in the etiology of gliomas. Genetic polymorphisms in the mannose-binding lectin gene, a key activator in the lectin complement pathway, have been associated with risk of several cancers. METHODS: To examine the role of the lectin complement pathway, we combined data from prospectively collected cohorts with available DNA specimens. Using a nested case-control design, we genotyped 85 single nucleotide polymorphisms (SNPs) in 9 genes in the lectin complement pathway and 3 additional SNPs in MBL2 were tested post hoc). Initial SNPs were selected using tagging SNPs for haplotypes; the second group of SNPs for MBL2 was selected based on functional SNPs related to phenotype. Associations were examined using logistic regression analysis. All statistical tests were two-sided. Nominal p-values are presented and are not corrected for multiple comparisons. RESULTS: A total of 143 glioma cases and 419 controls were available for this analysis. Statistically significant associations were observed for two SNPs in the mannose-binding lectin 2 (ML2) gene and risk of glioma (rs1982266 and rs1800450, test for trend p = 0.003 and p = 0.04, respectively, using the additive model). One of these SNPs, rs1800450, was associated with a 58% increase in glioma risk among those carrying one or two mutated alleles (odds ratio = 1.58, 95% confidence interval = 0.99 2.54), compared to those homozygous for the wild type allele. CONCLUSIONS: Overall, our findings suggest that MBL may play a role in the etiology of glioma. Future studies are needed to confirm these findings which may be due to chance, and if reproduced, to determine mechanisms that link glioma pathogenesis with the MBL complement pathway. PMID- 23637790 TI - Enhanced immune response and protective effects of nano-chitosan-based DNA vaccine encoding T cell epitopes of Esat-6 and FL against Mycobacterium tuberculosis infection. AB - Development of a novel and effective vaccine against Mycobacterium tuberculosis (M.tb) is a challenging for preventing TB infection. In this study, a novel nanoparticle-based recombinant DNA vaccine was developed, which contains Esat-6 three T cell epitopes (Esat-6/3e) and fms-like tyrosine kinase 3 ligand (FL) genes (termed Esat-6/3e-FL), and was enveloped with chitosan (CS) nanoparticles (nano-chitosan). The immunologic and protective efficacy of the nano-chitosan based DNA vaccine (termed nano-Esat-6/3e-FL) was assessed in C57BL/6 mice after intramuscular prime vaccination with the plasmids DNA and nasal boost with the Esat-6/3e peptides. The results showed that the immunized mice remarkably elicited enhanced T cell responses and protection against M.tb H37Rv challenge. These findings indicate that the nano-chitosan can significantly elevate the immunologic and protective effects of the DNA vaccine, and the nano-Esat-6/3e-FL is a useful vaccine for preventing M.tb infection in mice. PMID- 23637789 TI - From data towards knowledge: revealing the architecture of signaling systems by unifying knowledge mining and data mining of systematic perturbation data. AB - Genetic and pharmacological perturbation experiments, such as deleting a gene and monitoring gene expression responses, are powerful tools for studying cellular signal transduction pathways. However, it remains a challenge to automatically derive knowledge of a cellular signaling system at a conceptual level from systematic perturbation-response data. In this study, we explored a framework that unifies knowledge mining and data mining towards the goal. The framework consists of the following automated processes: 1) applying an ontology-driven knowledge mining approach to identify functional modules among the genes responding to a perturbation in order to reveal potential signals affected by the perturbation; 2) applying a graph-based data mining approach to search for perturbations that affect a common signal; and 3) revealing the architecture of a signaling system by organizing signaling units into a hierarchy based on their relationships. Applying this framework to a compendium of yeast perturbation response data, we have successfully recovered many well-known signal transduction pathways; in addition, our analysis has led to many new hypotheses regarding the yeast signal transduction system; finally, our analysis automatically organized perturbed genes as a graph reflecting the architecture of the yeast signaling system. Importantly, this framework transformed molecular findings from a gene level to a conceptual level, which can be readily translated into computable knowledge in the form of rules regarding the yeast signaling system, such as "if genes involved in the MAPK signaling are perturbed, genes involved in pheromone responses will be differentially expressed." PMID- 23637791 TI - A novel transport mechanism for MOMP in Chlamydophila pneumoniae and its putative role in immune-therapy. AB - Major outer membrane proteins (MOMPs) of Gram negative bacteria are one of the most intensively studied membrane proteins. MOMPs are essential for maintaining the structural integrity of bacterial outer membranes and in adaptation of parasites to their hosts. There is evidence to suggest a role for purified MOMP from Chlamydophila pneumoniae and corresponding MOMP-derived peptides in immune modulation, leading to a reduced atherosclerotic phenotype in apoE(-/-) mice via a characteristic dampening of MHC class II activity. The work reported herein tests this hypothesis by employing a combination of homology modelling and docking to examine the detailed molecular interactions that may be responsible. A three-dimensional homology model of the C. pneumoniae MOMP was constructed based on the 14 transmembrane beta-barrel crystal structure of the fatty acid transporter from Escherichia coli, which provides a plausible transport mechanism for MOMP. Ligand docking experiments were used to provide details of the possible molecular interactions driving the binding of MOMP-derived peptides to MHC class II alleles known to be strongly associated with inflammation. The docking experiments were corroborated by predictions from conventional immuno-informatic algorithms. This work supports further the use of MOMP in C. pneumoniae as a possible vaccine target and the role of MOMP-derived peptides as vaccine candidates for immune-therapy in chronic inflammation that can result in cardiovascular events. PMID- 23637792 TI - Intermediate coupling between aboveground and belowground biomass maximises the persistence of grasslands. AB - Aboveground and belowground biomass compartments of vegetation fulfil different functions and they are coupled by complex interactions. These compartments exchange water, carbon and nutrients and the belowground biomass compartment has the capacity to buffer vegetation dynamics when aboveground biomass is removed by disturbances such as herbivory or fire. However, despite their importance, root shoot interactions are often ignored in more heuristic vegetation models. Here, we present a simple two-compartment grassland model that couples aboveground and belowground biomass. In this model, the growth of belowground biomass is influenced by aboveground biomass and the growth of aboveground biomass is influenced by belowground biomass. We used the model to explore how the dynamics of a grassland ecosystem are influenced by fire and grazing. We show that the grassland system is most persistent at intermediate levels of aboveground belowground coupling. In this situation, the system can sustain more extreme fire or grazing regimes than in the case of strong coupling. In contrast, the productivity of the system is maximised at high levels of coupling. Our analysis suggests that the yield of a grassland ecosystem is maximised when coupling is strong, however, the intensity of disturbance that can be sustained increases dramatically when coupling is intermediate. Hence, the model predicts that intermediate coupling should be selected for as it maximises the chances of persistence in disturbance driven ecosystems. PMID- 23637793 TI - Tamoxifen ameliorates peritoneal membrane damage by blocking mesothelial to mesenchymal transition in peritoneal dialysis. AB - Mesothelial-to-mesenchymal transition (MMT) is an auto-regulated physiological process of tissue repair that in uncontrolled conditions such as peritoneal dialysis (PD) can lead to peritoneal fibrosis. The maximum expression of peritoneal fibrosis induced by PD fluids and other peritoneal processes is the encapsulating peritoneal sclerosis (EPS) for which no specific treatment exists. Tamoxifen, a synthetic estrogen, has successfully been used to treat retroperitoneal fibrosis and EPS associated with PD. Hence, we used in vitro and animal model approaches to evaluate the efficacy of Tamoxifen to inhibit the MMT as a trigger of peritoneal fibrosis. In vitro studies were carried out using omentum-derived mesothelial cells (MCs) and effluent-derived MCs. Tamoxifen blocked the MMT induced by transforming growth factor (TGF)-beta1, as it preserved the expression of E-cadherin and reduced the expression of mesenchymal associated molecules such as snail, fibronectin, collagen-I, alpha-smooth muscle actin, and matrix metalloproteinse-2. Tamoxifen-treatment preserved the fibrinolytic capacity of MCs treated with TGF-beta1 and decreased their migration capacity. Tamoxifen did not reverse the MMT of non-epitheliod MCs from effluents, but it reduced the expression of some mesenchymal molecules. In mice PD model, we demonstrated that MMT progressed in parallel with peritoneal membrane thickness. In addition, we observed that Tamoxifen significantly reduced peritoneal thickness, angiogenesis, invasion of the compact zone by mesenchymal MCs and improved peritoneal function. Tamoxifen also reduced the effluent levels of vascular endothelial growth factor and leptin. These results demonstrate that Tamoxifen is a therapeutic option to treat peritoneal fibrosis, and that its protective effect is mediated via modulation of the MMT process. PMID- 23637794 TI - Genome-wide association study identifies Loci and candidate genes for body composition and meat quality traits in Beijing-You chickens. AB - Body composition and meat quality traits are important economic traits of chickens. The development of high-throughput genotyping platforms and relevant statistical methods have enabled genome-wide association studies in chickens. In order to identify molecular markers and candidate genes associated with body composition and meat quality traits, genome-wide association studies were conducted using the Illumina 60 K SNP Beadchip to genotype 724 Beijing-You chickens. For each bird, a total of 16 traits were measured, including carcass weight (CW), eviscerated weight (EW), dressing percentage, breast muscle weight (BrW) and percentage (BrP), thigh muscle weight and percentage, abdominal fat weight and percentage, dry matter and intramuscular fat contents of breast and thigh muscle, ultimate pH, and shear force of the pectoralis major muscle at 100 d of age. The SNPs that were significantly associated with the phenotypic traits were identified using both simple (GLM) and compressed mixed linear (MLM) models. For nine of ten body composition traits studied, SNPs showing genome wide significance (P<2.59E-6) have been identified. A consistent region on chicken (Gallus gallus) chromosome 4 (GGA4), including seven significant SNPs and four candidate genes (LCORL, LAP3, LDB2, TAPT1), were found to be associated with CW and EW. Another 0.65 Mb region on GGA3 for BrW and BrP was identified. After measuring the mRNA content in beast muscle for five genes located in this region, the changes in GJA1 expression were found to be consistent with that of breast muscle weight across development. It is highly possible that GJA1 is a functional gene for breast muscle development in chickens. For meat quality traits, several SNPs reaching suggestive association were identified and possible candidate genes with their functions were discussed. PMID- 23637795 TI - Are stripes beneficial? Dazzle camouflage influences perceived speed and hit rates. AB - In the animal kingdom, camouflage refers to patterns that help potential prey avoid detection. Mostly camouflage is thought of as helping prey blend in with their background. In contrast, disruptive or dazzle patterns protect moving targets and have been suggested as an evolutionary force in shaping the dorsal patterns of animals. Dazzle patterns, such as stripes and zigzags, are thought to reduce the probability with which moving prey will be captured by impairing predators' perception of speed. We investigated how different patterns of stripes (longitudinal-i.e., parallel to movement direction-and vertical-i.e., perpendicular to movement direction) affect the probability with which humans can hit moving objects and if differences in hitting probability are caused by a misperception of speed. A first experiment showed that longitudinally striped objects were hit more often than unicolored objects. However, vertically striped objects did not differ from unicolored objects. A second study examining the link between perceived speed and hitting probability showed that longitudinally and vertically striped objects were both perceived as moving faster and were hit more often than unicolored objects. In sum, our results provide evidence that striped patterns disrupt the perception of speed, which in turn influences how often objects are hit. However, the magnitude and the direction of the effects depend on additional factors such as speed and the task setup. PMID- 23637796 TI - Empirical mode decomposition and k-nearest embedding vectors for timely analyses of antibiotic resistance trends. AB - BACKGROUND: Antibiotic resistance is a major worldwide public health concern. In clinical settings, timely antibiotic resistance information is key for care providers as it allows appropriate targeted treatment or improved empirical treatment when the specific results of the patient are not yet available. OBJECTIVE: To improve antibiotic resistance trend analysis algorithms by building a novel, fully data-driven forecasting method from the combination of trend extraction and machine learning models for enhanced biosurveillance systems. METHODS: We investigate a robust model for extraction and forecasting of antibiotic resistance trends using a decade of microbiology data. Our method consists of breaking down the resistance time series into independent oscillatory components via the empirical mode decomposition technique. The resulting waveforms describing intrinsic resistance trends serve as the input for the forecasting algorithm. The algorithm applies the delay coordinate embedding theorem together with the k-nearest neighbor framework to project mappings from past events into the future dimension and estimate the resistance levels. RESULTS: The algorithms that decompose the resistance time series and filter out high frequency components showed statistically significant performance improvements in comparison with a benchmark random walk model. We present further qualitative use-cases of antibiotic resistance trend extraction, where empirical mode decomposition was applied to highlight the specificities of the resistance trends. CONCLUSION: The decomposition of the raw signal was found not only to yield valuable insight into the resistance evolution, but also to produce novel models of resistance forecasters with boosted prediction performance, which could be utilized as a complementary method in the analysis of antibiotic resistance trends. PMID- 23637799 TI - Cyanine 5.5 conjugated nanobubbles as a tumor selective contrast agent for dual ultrasound-fluorescence imaging in a mouse model. AB - Nanobubbles and microbubbles are non-invasive ultrasound imaging contrast agents that may potentially enhance diagnosis of tumors. However, to date, both nanobubbles and microbubbles display poor in vivo tumor-selectivity over non targeted organs such as liver. We report here cyanine 5.5 conjugated nanobubbles (cy5.5-nanobubbles) of a biocompatible chitosan-vitamin C lipid system as a dual ultrasound-fluorescence contrast agent that achieved tumor-selective imaging in a mouse tumor model. Cy5.5-nanobubble suspension contained single bubble spheres and clusters of bubble spheres with the size ranging between 400-800 nm. In the in vivo mouse study, enhancement of ultrasound signals at tumor site was found to persist over 2 h while tumor-selective fluorescence emission was persistently observed over 24 h with intravenous injection of cy5.5-nanobubbles. In vitro cell study indicated that cy5.5-flurescence dye was able to accumulate in cancer cells due to the unique conjugated nanobubble structure. Further in vivo fluorescence study suggested that cy5.5-nanobubbles were mainly located at tumor site and in the bladder of mice. Subsequent analysis confirmed that accumulation of high fluorescence was present at the intact subcutaneous tumor site and in isolated tumor tissue but not in liver tissue post intravenous injection of cy5.5 nanobubbles. All these results led to the conclusion that cy5.5-nanobubbles with unique crosslinked chitosan-vitamin C lipid system have achieved tumor-selective imaging in vivo. PMID- 23637798 TI - Clostridium botulinum strain Af84 contains three neurotoxin gene clusters: bont/A2, bont/F4 and bont/F5. AB - Sanger and shotgun sequencing of Clostridium botulinum strain Af84 type Af and its botulinum neurotoxin gene (bont) clusters identified the presence of three bont gene clusters rather than the expected two. The three toxin gene clusters consisted of bont subtypes A2, F4 and F5. The bont/A2 and bont/F4 gene clusters were located within the chromosome (the latter in a novel location), while the bont/F5 toxin gene cluster was located within a large 246 kb plasmid. These findings are the first identification of a C. botulinum strain that contains three botulinum neurotoxin gene clusters. PMID- 23637797 TI - Individual variation in influenza A virus infection histories and long-term immune responses in Mallards. AB - Wild dabbling ducks (genus Anas) are the main reservoir for influenza A virus (IAV) in the Northern Hemisphere. Current understanding of disease dynamics and epidemiology in this virus-host system has primarily been based on population level surveillance studies and infection experiments conducted in laboratory settings. Using a combined experimental-natural approach with wild-strain captive mallards (Anas platyrhynchos), we monitored individual IAV infection histories and immunological responses of 10 birds over the course of 15 months. This is the first detailed study to track natural IAV infection histories over several seasons amongst the same individuals growing from juvenile to adults. The general trends in the infection histories of the monitored birds reflected seasonal variation in prevalence at the population level. However, within the study group there were significant differences between individuals in infection frequency as well as in short and long term anti-IAV antibody response. Further observations included individual variation in the number of infecting virus subtypes, and a strong tendency for long-lasting hemagglutinin-related homosubtypic immunity. Specifically, all infections in the second autumn, except one, were of different subtypes compared to the first autumn. The variation among birds concerning these epidemiologically important traits illustrates the necessity for IAV studies to move from the level of populations to examine individuals in order to further our understanding of IAV disease and epidemiology. PMID- 23637800 TI - MRI of neuronal recovery after low-dose methamphetamine treatment of traumatic brain injury in rats. AB - We assessed the effects of low dose methamphetamine treatment of traumatic brain injury (TBI) in rats by employing MRI, immunohistology, and neurological functional tests. Young male Wistar rats were subjected to TBI using the controlled cortical impact model. The treated rats (n = 10) received an intravenous (iv) bolus dose of 0.42 mg/kg of methamphetamine at eight hours after the TBI followed by continuous iv infusion for 24 hrs. The control rats (n = 10) received the same volume of saline using the same protocol. MRI scans, including T2-weighted imaging (T2WI) and diffusion tensor imaging (DTI), were performed one day prior to TBI, and at 1 and 3 days post TBI, and then weekly for 6 weeks. The lesion volumes of TBI damaged cerebral tissue were demarcated by elevated values in T2 maps and were histologically identified by hematoxylin and eosin (H&E) staining. The fractional anisotropy (FA) values within regions-of-interest (ROI) were measured in FA maps deduced from DTI, and were directly compared with Bielschowsky's silver and Luxol fast blue (BLFB) immunohistological staining. No therapeutic effect on lesion volumes was detected during 6 weeks after TBI. However, treatment significantly increased FA values in the recovery ROI compared with the control group at 5 and 6 weeks after TBI. Myelinated axons histologically measured using BLFB were significantly increased (p<0.001) in the treated group (25.84+/-1.41%) compared with the control group (17.05+/-2.95%). Significant correlations were detected between FA and BLFB measures in the recovery ROI (R = 0.54, p<0.02). Methamphetamine treatment significantly reduced modified neurological severity scores from 2 to 6 weeks (p<0.05) and foot-fault errors from 3 days to 6 weeks (p<0.05) after TBI. Thus, the FA data suggest that methamphetamine treatment improves white matter reorganization from 5 to 6 weeks after TBI in rats compared with saline treatment, which may contribute to the observed functional recovery. PMID- 23637801 TI - Cocaine inhibits dopamine D2 receptor signaling via sigma-1-D2 receptor heteromers. AB - Under normal conditions the brain maintains a delicate balance between inputs of reward seeking controlled by neurons containing the D1-like family of dopamine receptors and inputs of aversion coming from neurons containing the D2-like family of dopamine receptors. Cocaine is able to subvert these balanced inputs by altering the cell signaling of these two pathways such that D1 reward seeking pathway dominates. Here, we provide an explanation at the cellular and biochemical level how cocaine may achieve this. Exploring the effect of cocaine on dopamine D2 receptors function, we present evidence of sigma1 receptor molecular and functional interaction with dopamine D2 receptors. Using biophysical, biochemical, and cell biology approaches, we discovered that D2 receptors (the long isoform of the D2 receptor) can complex with sigma1 receptors, a result that is specific to D2 receptors, as D3 and D4 receptors did not form heteromers. We demonstrate that the sigma1-D2 receptor heteromers consist of higher order oligomers, are found in mouse striatum and that cocaine, by binding to sigma1 -D2 receptor heteromers, inhibits downstream signaling in both cultured cells and in mouse striatum. In contrast, in striatum from sigma1 knockout animals these complexes are not found and this inhibition is not seen. Taken together, these data illuminate the mechanism by which the initial exposure to cocaine can inhibit signaling via D2 receptor containing neurons, destabilizing the delicate signaling balance influencing drug seeking that emanates from the D1 and D2 receptor containing neurons in the brain. PMID- 23637802 TI - Coherent superposition in grating-based directional dark-field imaging. AB - X-ray dark-field scatter imaging allows to gain information on the average local direction and anisotropy of micro-structural features in a sample well below the actual detector resolution. For thin samples the morphological interpretation of the signal is straight forward, provided that only one average orientation of sub pixel features is present in the specimen. For thick samples, however, where the x-ray beam may pass structures of many different orientations and dimensions, this simple assumption in general does not hold and a quantitative description of the resulting directional dark-field signal is required to draw deductions on the morphology. Here we present a description of the signal formation for thick samples with many overlying structures and show its validity in experiment. In contrast to existing experimental work this description follows from theoretical predictions of a numerical study using a Fourier optics approach. One can easily extend this description and perform a quantitative structural analysis of clinical or materials science samples with directional dark-field imaging or even direction-dependent dark-field CT. PMID- 23637803 TI - Regulation of fibrochondrogenesis of mesenchymal stem cells in an integrated microfluidic platform embedded with biomimetic nanofibrous scaffolds. AB - In native fibrocartilage, mechanotransduction allows the cells to perceive the physical microenvironment not only through topographical cues from the extracellular matrix, but also through mechanical cues, such as interstitial flow. To create a microenvironment that simultaneously integrates nanotopography and flow stimulus, we developed a biomimetic microfluidic device embedded with aligned nanofibers to contain microchambers of different angles, which enabled the flow direction to form different angles with the fibers. Using this device, we investigated the effects of microfluidic and nanotopographical environment on the morphology and fibrochondrogenesis of mesenchymal stem cells (MSCs) and the involvement of RhoA/ROCK pathway and Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ). The results showed that the flow direction perpendicular to aligned nanofibers was conducive to fibrochondrogenesis of MSCs. In addition, ROCK inhibitor and knockdown of YAP/TAZ disrupted fibrochondrogenic differentiation of MSCs. In conclusion, our data suggest the crucial role of mechanotransduction in regulating fibrochondrogenic differentiation of MSCs, which may be mediated by RhoA/ROCK pathway and YAP/TAZ. PMID- 23637804 TI - Telomere length and genetic anticipation in Lynch syndrome. AB - Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families. Leukocyte telomere length was measured in 244 mismatch repair gene mutation carriers from 96 Lynch syndrome families and in 234 controls using a monochrome multiplex quantitative PCR method. Cancer-affected mutation carriers showed significantly shorter telomeres than cancer-free mutation carriers. In addition, cancer-affected carriers showed the most pronounced shortening of telomere length with age, compared with unaffected carriers. The anticipation in the age of cancer onset observed in successive generations was not associated with telomere shortening, although, interestingly, all mother-son pairs showed telomere shortening. In conclusion, cancer-affected mismatch repair gene mutation carriers have distinct telomere length pattern and dynamics. However, anticipation in the age of onset is not explained by telomere shortening. Pending further study, our findings suggest that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations. PMID- 23637805 TI - NFYA1 is involved in regulation of postgermination growth arrest under salt stress in Arabidopsis. AB - The nuclear factor Y (NF-Y), which is a ubiquitous transcription factor found in eukaryotes, is composed of three distinct subunits, namely, NF-YA, NF-YB, and NF YC. Here, we firstly characterized the detailed function of the Arabidopsis NFYA1 factor. It is found that the 35S::AtNFYA1-overexpressed lines were hypersensitive to salt stress and Abscisic acid (ABA) during the early-postgermination growth stages. The transgenic lines exhibited a severe postgermination growth arrest compared with the wild-type (WT) under salt stress and ABA treatment. Interestingly, sodium tungstate, which is an ABA synthesis inhibitor, restored the salt-sensitive phenotype of the 35S::AtNFYA1 lines. Results of the qRT-PCR analysis showed that the mRNA levels of ABI3 and ABI5, as well as their downstream genes AtEM1 and AtEM6, were more greatly upregulated under salt stress during seed germination in the transgenic lines compared with those in WT. On the other hand, the NFYA1-RNAi lines were found to be insensitive to salt stress and exhibited decreased levels of ABI3, ABI5, EM1, and EM6 transcripts. Our results provide clear evidence supporting a role of AtNFYA1 in regulating postgermination growth arrest under salt stress. PMID- 23637807 TI - Can humic water discharge counteract eutrophication in coastal waters? AB - A common and established view is that increased inputs of nutrients to the sea, for example via river flooding, will cause eutrophication and phytoplankton blooms in coastal areas. We here show that this concept may be questioned in certain scenarios. Climate change has been predicted to cause increased inflow of freshwater to coastal areas in northern Europe. River waters in these areas are often brown from the presence of high concentrations of allochthonous dissolved organic carbon (humic carbon), in addition to nitrogen and phosphorus. In this study we investigated whether increased inputs of humic carbon can change the structure and production of the pelagic food web in the recipient seawater. In a mesocosm experiment unfiltered seawater from the northern Baltic Sea was fertilized with inorganic nutrients and humic carbon (CNP), and only with inorganic nutrients (NP). The system responded differently to the humic carbon addition. In NP treatments bacterial, phytoplankton and zooplankton production increased and the systems turned net autotrophic, whereas the CNP-treatment only bacterial and zooplankton production increased driving the system to net heterotrophy. The size-structure of the food web showed large variations in the different treatments. In the enriched NP treatments the phytoplankton community was dominated by filamentous >20 um algae, while in the CNP treatments the phytoplankton was dominated by picocyanobacteria <5 um. Our results suggest that climate change scenarios, resulting in increased humic-rich river inflow, may counteract eutrophication in coastal waters, leading to a promotion of the microbial food web and other heterotrophic organisms, driving the recipient coastal waters to net-heterotrophy. PMID- 23637806 TI - On the power and the systematic biases of the detection of chromosomal inversions by paired-end genome sequencing. AB - One of the most used techniques to study structural variation at a genome level is paired-end mapping (PEM). PEM has the advantage of being able to detect balanced events, such as inversions and translocations. However, inversions are still quite difficult to predict reliably, especially from high-throughput sequencing data. We simulated realistic PEM experiments with different combinations of read and library fragment lengths, including sequencing errors and meaningful base-qualities, to quantify and track down the origin of false positives and negatives along sequencing, mapping, and downstream analysis. We show that PEM is very appropriate to detect a wide range of inversions, even with low coverage data. However, >=% of inversions located between segmental duplications are expected to go undetected by the most common sequencing strategies. In general, longer DNA libraries improve the detectability of inversions far better than increments of the coverage depth or the read length. Finally, we review the performance of three algorithms to detect inversions- SVDetect, GRIAL, and VariationHunter--, identify common pitfalls, and reveal important differences in their breakpoint precisions. These results stress the importance of the sequencing strategy for the detection of structural variants, especially inversions, and offer guidelines for the design of future genome sequencing projects. PMID- 23637810 TI - Vertical transmission of respiratory syncytial virus modulates pre- and postnatal innervation and reactivity of rat airways. AB - BACKGROUND: Environmental exposure to respiratory syncytial virus (RSV) is a leading cause of respiratory infections in infants, but it remains unknown whether this infection is transmitted transplacentally from the lungs of infected mothers to the offspring. We sought to test the hypothesis that RSV travels from the respiratory tract during pregnancy, crosses the placenta to the fetus, persists in the lung tissues of the offspring, and modulates pre- and postnatal expression of growth factors, thereby predisposing to airway hyperreactivity. METHODOLOGY: Pregnant rats were inoculated intratracheally at midterm using recombinant RSV expressing red fluorescent protein (RFP). Viral RNA was amplified by RT-PCR and confirmed by sequencing. RFP expression was analyzed by flow cytometry and viral culture. Developmental and pathophysiologic implications of prenatal infection were determined by analyzing the expression of genes encoding critical growth factors, particularly neurotrophic factors and receptors. We also measured the expression of key neurotransmitters and postnatal bronchial reactivity in vertically infected lungs, and assessed their dependence on neurotrophic signaling using selective biological or chemical inhibition. PRINCIPAL FINDINGS: RSV genome was found in 30% of fetuses, as well as in the lungs of 40% of newborns and 25% of adults. RFP expression was also shown by flow cytometry and replicating virus was cultured from exposed fetuses. Nerve growth factor and its TrkA receptor were upregulated in RSV- infected fetal lungs and co localized with increased cholinergic innervation. Acetylcholine expression and smooth muscle response to cholinergic stimulation increased in lungs exposed to RSV in utero and reinfected after birth, and blocking TrkA signaling inhibited both effects. CONCLUSIONS/SIGNIFICANCE: Our data show transplacental transmission of RSV from mother to offspring and persistence of vertically transmitted virus in lungs after birth. Exposure to RSV in utero is followed by dysregulation of neurotrophic pathways predisposing to postnatal airway hyperreactivity upon reinfection with the virus. PMID- 23637808 TI - Sex-specific effect of juvenile diet on adult disease resistance in a field cricket. AB - Food limitation is expected to reduce an individual's body condition (body mass scaled to body size) and cause a trade-off between growth and other fitness related traits, such as immunity. We tested the condition-dependence of growth and disease resistance in male and female Gryllus texensis field crickets by manipulating diet quality via nutrient content for their entire life and then subjecting individuals to a host resistance test using the live bacterium Serratia marcescens. As predicted, crickets on a high-quality diet eclosed more quickly, and at a larger body size and mass. Crickets on a high-quality diet were not in better condition at the time of eclosion, but they were in better condition 7-11 days after eclosion, with females also being in better condition than males. Despite being in better condition, however, females provided with a high-quality diet had significantly poorer disease resistance than females on a low-quality diet and in poor condition. Similarly, males on low- and high-quality diets did not differ in their disease resistance, despite differing in their body condition. A sex difference in disease resistance under diet-restriction suggests that females might allocate resources toward immunity during development if they expect harsh environmental conditions as an adult or it might suggest that females allocate resources toward other life history activities (i.e. reproduction) when food availability increases. We do not know what immune effectors were altered under diet-restriction to increase disease resistance, but our findings suggest that increased immune function might provide an explanation for the sexually-dimorphic increase in longevity generally observed in diet restricted animals. PMID- 23637811 TI - The relation of serum myeloperoxidase to disease progression and mortality in patients with chronic obstructive pulmonary disease (COPD). AB - Myeloperoxidase is a strong oxidant stored in primary granules of neutrophils with potent antibacterial and proatherogenic properties. Myeloperoxidase has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the relationship of myeloperoxidase to health outcomes in COPD is not well known. We measured serum myeloperoxidase levels from 4,677 subjects with mild to moderate airflow limitation in the Lung Health Study. Using a Cox proportional hazards model, we determined the relationship of serum myeloperoxidase concentration to the risk of all-cause and disease specific causes of mortality. We found that serum myeloperoxidase concentrations were significantly related to accelerated decline in forced expiratory volume in 1 second (FEV1) over 11 years of follow-up (p<0.0001), and this association persisted after adjustments for age, sex, race, baseline FEV1, and smoking status (p = 0.048). Serum myeloperoxidase concentrations were also associated with increased risk of cardiovascular mortality (p = 0.036). Individuals in the highest quintile of myeloperoxidase had a hazard ratio of cardiovascular mortality of 1.90 (95% confidence interval 1.00-3.58; p = 0.049) compared with those in the lowest quintile, which was particularly notable in patients who continued to smoke (adjusted p-value of 0.0396). However, serum myeloperoxidase concentration was not related to total mortality, respiratory mortality, or deaths from malignancies. In conclusion, increased serum myeloperoxidase levels are associated with rapid lung function decline and poor cardiovascular outcomes in COPD patients, which support the emerging role of myeloperoxidase in the pathogenesis of COPD progression and cardiovascular disease. PMID- 23637809 TI - Identification and characterization of a cis-encoded antisense RNA associated with the replication process of Salmonella enterica serovar Typhi. AB - Antisense RNAs that originate from the complementary strand of protein coding genes are involved in the regulation of gene expression in all domains of life. In bacteria, some of these antisense RNAs are transcriptional noise while others play a vital role to adapt the cell to changing environmental conditions. By deep sequencing analysis of transcriptome of Salmonella enterica serovar Typhi, a partial RNA sequence encoded in-cis to the dnaA gene was revealed. Northern blot and RACE analysis confirmed the transcription of this antisense RNA which was expressed mostly in the stationary phase of the bacterial growth and also under iron limitation and osmotic stress. Pulse expression analysis showed that overexpression of the antisense RNA resulted in a significant increase in the mRNA levels of dnaA, which will ultimately enhance their translation. Our findings have revealed that antisense RNA of dnaA is indeed transcribed not merely as a by-product of the cell's transcription machinery but plays a vital role as far as stability of dnaA mRNA is concerned. PMID- 23637812 TI - The distribution of henipaviruses in Southeast Asia and Australasia: is Wallace's line a barrier to Nipah virus? AB - Nipah virus (NiV) (Genus Henipavirus) is a recently emerged zoonotic virus that causes severe disease in humans and has been found in bats of the genus Pteropus. Whilst NiV has not been detected in Australia, evidence for NiV-infection has been found in pteropid bats in some of Australia's closest neighbours. The aim of this study was to determine the occurrence of henipaviruses in fruit bat (Family Pteropodidae) populations to the north of Australia. In particular we tested the hypothesis that Nipah virus is restricted to west of Wallace's Line. Fruit bats from Australia, Papua New Guinea, East Timor and Indonesia were tested for the presence of antibodies to Hendra virus (HeV) and Nipah virus, and tested for the presence of HeV, NiV or henipavirus RNA by PCR. Evidence was found for the presence of Nipah virus in both Pteropus vampyrus and Rousettus amplexicaudatus populations from East Timor. Serology and PCR also suggested the presence of a henipavirus that was neither HeV nor NiV in Pteropus alecto and Acerodon celebensis. The results demonstrate the presence of NiV in the fruit bat populations on the eastern side of Wallace's Line and within 500 km of Australia. They indicate the presence of non-NiV, non-HeV henipaviruses in fruit bat populations of Sulawesi and Sumba and possibly in Papua New Guinea. It appears that NiV is present where P. vampyrus occurs, such as in the fruit bat populations of Timor, but where this bat species is absent other henipaviruses may be present, as on Sulawesi and Sumba. Evidence was obtained for the presence henipaviruses in the non-Pteropid species R. amplexicaudatus and in A. celebensis. The findings of this work fill some gaps in knowledge in geographical and species distribution of henipaviruses in Australasia which will contribute to planning of risk management and surveillance activities. PMID- 23637814 TI - Evidence for biotrophic lifestyle and biocontrol potential of dark septate endophyte Harpophora oryzae to rice blast disease. AB - The mutualism pattern of the dark septate endophyte (DSE) Harpophora oryzae in rice roots and its biocontrol potential in rice blast disease caused by Magnaporthe oryzae were investigated. Fluorescent protein-expressing H. oryzae was used to monitor the colonization pattern. Hyphae invaded from the epidermis to the inner cortex, but not into the root stele. Fungal colonization increased with root tissue maturation, showing no colonization in the meristematic zone, slight colonization in the elongation zone, and heavy colonization in the differentiation zone. H. oryzae adopted a biotrophic lifestyle in roots accompanied by programmed cell death. Real-time PCR facilitated the accurate quantification of fungal growth and the respective plant response. The biocontrol potential of H. oryzae was visualized by inoculation with eGFP-tagged M. oryzae in rice. H. oryzae protected rice from M. oryzae root invasion by the accumulation of H2O2 and elevated antioxidative capacity. H. oryzae also induced systemic resistance against rice blast. This systemic resistance was mediated by the OsWRKY45-dependent salicylic acid (SA) signaling pathway, as indicated by the strongly upregulated expression of OsWRKY45. The colonization pattern of H. oryzae was consistent with the typical characteristics of DSEs. H. oryzae enhanced local resistance by reactive oxygen species (ROS) and high antioxidative level and induced OsWRKY45-dependent SA-mediated systemic resistance against rice blast. PMID- 23637813 TI - Crystal structures of E. coli native MenH and two active site mutants. AB - Recent revision of the biosynthetic pathway for menaquinone has led to the discovery of a previously unrecognized enzyme 2-succinyl-6-hydroxy-2,4 cyclohexadiene-1-carboxylate synthase, also known as MenH. This enzyme has an alpha/beta hydrolase fold with a catalytic triad comprising Ser86, His232, and Asp210. Mutational studies identified a number of conserved residues of importance to activity, and modeling further implicated the side chains of Tyr85 and Trp147 in formation of a non-standard oxyanion hole. We have solved the structure of E. coli MenH (EcMenH) at 2.75 A resolution, together with the structures of the active site mutant proteins Tyr85Phe and Arg124Ala, both at 2.5 A resolution. EcMenH has the predicted alpha/beta hydrolase fold with its core alpha/beta domain capped by a helical lid. The active site, a long groove beneath the cap, contains a number of conserved basic residues and is found to bind exogeneous anions, modeled as sulfate and chloride, in all three crystal structures. Docking studies with the MenH substrate and a transition state model indicate that the bound anions mark the binding sites for anionic groups on the substrate. The docking studies, and careful consideration of the active site geometry, further suggest that the oxyanion hole is of a conventional nature, involving peptide NH groups, rather than the proposed site involving Tyr85 and Trp147. This is in accord with conclusions from the structure of S. aureus MenH. Comparisons with the latter do, however, indicate differences in the periphery of the active site that could be of relevance to selective inhibition of MenH enzymes. PMID- 23637815 TI - Family planning knowledge, attitude and practice among married couples in Jimma Zone, Ethiopia. AB - BACKGROUND: Understanding why people do not use family planning is critical to address unmet needs and to increase contraceptive use. According to the Ethiopian Demographic and Health Survey 2011, most women and men had knowledge on some family planning methods but only about 29% of married women were using contraceptives. 20% women had an unmet need for family planning. We examined knowledge, attitudes and contraceptive practice as well as factors related to contraceptive use in Jimma zone, Ethiopia. METHODS: Data were collected from March to May 2010 among 854 married couples using a multi-stage sampling design. Quantitative data based on semi-structured questionnaires was triangulated with qualitative data collected during focus group discussions. We compared proportions and performed logistic regression analysis. RESULT: The concept of family planning was well known in the studied population. Sex-stratified analysis showed pills and injectables were commonly known by both sexes, while long-term contraceptive methods were better known by women, and traditional methods as well as emergency contraception by men. Formal education was the most important factor associated with better knowledge about contraceptive methods (aOR = 2.07, p<0.001), in particular among women (aOR(women )= 2.77 vs. aOR(men) = 1.49; p<0.001). In general only 4 out of 811 men ever used contraception, while 64% and 43% females ever used and were currently using contraception respectively. CONCLUSION: The high knowledge on contraceptives did not match with the high contraceptive practice in the study area. The study demonstrates that mere physical access (proximity to clinics for family planning) and awareness of contraceptives are not sufficient to ensure that contraceptive needs are met. Thus, projects aiming at increasing contraceptive use should contemplate and establish better counseling about contraceptive side effects and method switch. Furthermore in all family planning activities both wives' and husbands' participation should be considered. PMID- 23637816 TI - Cell death pathways in astrocytes with a modified model of oxygen-glucose deprivation. AB - Traditional oxygen-glucose deprivation (OGD) models do not produce sufficiently stable and continuous deprivation to induce cell death in the ischemic core. Therefore, we modified the OGD model to mimic the observed damage in the ischemic core following stroke and utilized this new model to study cell death pathways in astrocytes. The PO2 and pH levels in the astrocyte culture medium were compared between a physical OGD group, a chemical OGD group and a mixed OGD group. The mixed OGD group was able to maintain anaerobic conditions in astrocyte culture medium for 6 h, while the physical and the chemical groups failed to maintain such conditions. Astrocyte viability decreased and LDH release into in the medium increased as a function of exposure to OGD. Compared to the control group, the expression of active caspase-3 in the mixed OGD group increased within 2 h after OGD, but decreased after 2 h of OGD. Additionally, porimin mRNA levels did not significantly increase during the first 2 h of OGD, while bcl-2 mRNA levels decreased at 1 h. However, both porimin and bcl-2 mRNA levels increased after 2 h of OGD; interestingly, they both suddenly decreased at 4 h of OGD. Taken together, these results indicate that apoptosis and oncosis are the two cell death pathways responsible for astrocyte death in the ischemic core. However, the main death pathway varies depending on the OGD period. PMID- 23637817 TI - Salivary biomarkers for detection of systemic diseases. AB - BACKGROUND AND OBJECTIVE: Analysis of inflammatory biomarkers in saliva could offer an attractive opportunity for the diagnosis of different systemic conditions specifically in epidemiological surveys. The aim of this study was to investigate if certain salivary biomarkers could be used for detection of common systemic diseases. MATERIALS AND METHODS: A randomly selected sample of 1000 adults living in Skane, a county in the southern part of Sweden, was invited to participate in a clinical study of oral health. 451 individuals were enrolled in this investigation, 51% women. All participants were asked to fill out a questionnaire, history was taken, a clinical examination was made and stimulated saliva samples were collected. Salivary concentrations of IL-1beta, -6, -8, TNF alpha, lysozyme, MMP-8 and TIMP-1 were determined using ELISA, IFMA or Luminex assays. RESULTS: Salivary IL-8 concentration was found to be twice as high in subjects who had experience of tumour diseases. In addition, IL-8 levels were also elevated in patients with bowel disease. MMP-8 levels were elevated in saliva from patients after cardiac surgery or suffering from diabetes, and muscle and joint diseases. The levels of IL-1beta, IL-8 and MMP-8, as well as the MMP 8/TIMP-1 ratio were higher in subjects with muscle and joint diseases. CONCLUSION: Biomarkers in saliva have the potential to be used for screening purposes in epidemiological studies. The relatively unspecific inflammatory markers used in this study can not be used for diagnosis of specific diseases but can be seen as markers for increased systemic inflammation. PMID- 23637821 TI - Effect of aging on hedonic appreciation of pleasant and unpleasant odors. AB - Does hedonic appreciation evolve differently for pleasant odors and unpleasant odors during normal aging? To answer this question we combined psychophysics and electro-encephalographic recordings in young and old adults. A first study showed that pleasant odorants (but not unpleasant ones) were rated as less pleasant by old adults. A second study validated this decrease in hedonic appreciation for agreeable odors and further showed that smelling these odorants decreased beta event-related synchronization in aged participants. In conclusion, the study offers new insights into the evolution of odor hedonic perception during normal aging, highlighting for the first time a change in processing pleasant odors. PMID- 23637820 TI - Assessing the online social environment for surveillance of obesity prevalence. AB - BACKGROUND: Understanding the social environmental around obesity has been limited by available data. One promising approach used to bridge similar gaps elsewhere is to use passively generated digital data. PURPOSE: This article explores the relationship between online social environment via web-based social networks and population obesity prevalence. METHODS: We performed a cross sectional study using linear regression and cross validation to measure the relationship and predictive performance of user interests on the online social network Facebook to obesity prevalence in metros across the United States of America (USA) and neighborhoods within New York City (NYC). The outcomes, proportion of obese and/or overweight population in USA metros and NYC neighborhoods, were obtained via the Centers for Disease Control and Prevention Behavioral Risk Factor Surveillance and NYC EpiQuery systems. Predictors were geographically specific proportion of users with activity-related and sedentary related interests on Facebook. RESULTS: Higher proportion of the population with activity-related interests on Facebook was associated with a significant 12.0% (95% Confidence Interval (CI) 11.9 to 12.1) lower predicted prevalence of obese and/or overweight people across USA metros and 7.2% (95% CI: 6.8 to 7.7) across NYC neighborhoods. Conversely, greater proportion of the population with interest in television was associated with higher prevalence of obese and/or overweight people of 3.9% (95% CI: 3.7 to 4.0) (USA) and 27.5% (95% CI: 27.1 to 27.9, significant) (NYC). For activity-interests and national obesity outcomes, the average root mean square prediction error from 10-fold cross validation was comparable to the average root mean square error of a model developed using the entire data set. CONCLUSIONS: Activity-related interests across the USA and sedentary-related interests across NYC were significantly associated with obesity prevalence. Further research is needed to understand how the online social environment relates to health outcomes and how it can be used to identify or target interventions. PMID- 23637818 TI - Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders. AB - Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR = 2.59; p = 0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR = 5.62; p = 0.0002), but not in females (OR = 1.19, p = 0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR = 2.59; p = 0.0005), located in the 0.83 Mb genomic region between 15.49-16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus. PMID- 23637819 TI - Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21. AB - Bone is a dynamically remodeled tissue that requires gravity-mediated mechanical stimulation for maintenance of mineral content and structure. Homeostasis in bone occurs through a balance in the activities and signaling of osteoclasts, osteoblasts, and osteocytes, as well as proliferation and differentiation of their stem cell progenitors. Microgravity and unloading are known to cause osteoclast-mediated bone resorption; however, we hypothesize that osteocytic osteolysis, and cell cycle arrest during osteogenesis may also contribute to bone loss in space. To test this possibility, we exposed 16-week-old female C57BL/6J mice (n = 8) to microgravity for 15-days on the STS-131 space shuttle mission. Analysis of the pelvis by uCT shows decreases in bone volume fraction (BV/TV) of 6.29%, and bone thickness of 11.91%. TRAP-positive osteoclast-covered trabecular bone surfaces also increased in microgravity by 170% (p = 0.004), indicating osteoclastic bone degeneration. High-resolution X-ray nanoCT studies revealed signs of lacunar osteolysis, including increases in cross-sectional area (+17%, p = 0.022), perimeter (+14%, p = 0.008), and canalicular diameter (+6%, p = 0.037). Expression of matrix metalloproteinases (MMP) 1, 3, and 10 in bone, as measured by RT-qPCR, was also up-regulated in microgravity (+12.94, +2.98 and +16.85 fold respectively, p<0.01), with MMP10 localized to osteocytes, and consistent with induction of osteocytic osteolysis. Furthermore, expression of CDKN1a/p21 in bone increased 3.31 fold (p<0.01), and was localized to osteoblasts, possibly inhibiting the cell cycle during tissue regeneration as well as conferring apoptosis resistance to these cells. Finally the apoptosis inducer Trp53 was down regulated by -1.54 fold (p<0.01), possibly associated with the quiescent survival promoting function of CDKN1a/p21. In conclusion, our findings identify the pelvic and femoral region of the mouse skeleton as an active site of rapid bone loss in microgravity, and indicate that this loss is not limited to osteoclastic degradation. Therefore, this study offers new evidence for microgravity-induced osteocytic osteolysis, and CDKN1a/p21-mediated osteogenic cell cycle arrest. PMID- 23637825 TI - Dose-response analysis in the joint action of two effectors. A new approach to simulation, identification and modelling of some basic interactions. AB - In systems with several effectors, the results of dose-response (DR) experiments are usually assessed by checking them against two hypotheses: independent action (IA) and concentration addition (CA). Both are useful simplifications, but do not represent the only possible responses, and avoid to a large extent the analysis of the interactions that are possible in the system. In addition, these are often applied in such a way that they produce insufficient descriptions of the problem that raises them, frequent inconclusive cases and doubtful decisions. In this work a generative approach is attempted, starting from some simple mechanisms necessarily underlying the response of an elementary biological entity to an effector agent. A set of simulations is formulated next through an equally simple system of logical rules, and several families of virtual responses are thus generated. These families include typical responses of IA and CA modes of action, other ones not less probable from a physiological point of view, and even other derived from common and expectable forms of interactions. The analysis of these responses enabled, firstly, to relate some phenomenological regularities with some general mechanistic principles, and to detect several causes by which the IA CA dualism is necessarily ambiguous. Secondly, it allowed identifying different forms of synergy and antagonism that contribute to explain some controversial aspects of these notions. Finally, it led to propose two sets of explicit algebraic equations that describe accurately a wide diversity of possible and realistic responses. PMID- 23637823 TI - MHC multimer-guided and cell culture-independent isolation of functional T cell receptors from single cells facilitates TCR identification for immunotherapy. AB - Adoptive therapy using T cells redirected to target tumor- or infection associated antigens is a promising strategy that has curative potential and broad applicability. In order to accelerate the screening process for suitable antigen specific T cell receptors (TCRs), we developed a new approach circumventing conventional in vitro expansion-based strategies. Direct isolation of paired full length TCR sequences from non-expanded antigen-specific T cells was achieved by the establishment of a highly sensitive PCR-based T cell receptor single cell analysis method (TCR-SCAN). Using MHC multimer-labeled and single cell-sorted HCMV-specific T cells we demonstrate a high efficacy (approximately 25%) and target specificity of TCR-SCAN receptor identification. In combination with MHC multimer based pre-enrichment steps, we were able to isolate TCRs specific for the oncogenes Her2/neu and WT1 even from very small populations (original precursor frequencies of down to 0.00005% of CD3(+) T cells) without any cell culture step involved. Genetic re-expression of isolated receptors demonstrates their functionality and target specificity. We believe that this new strategy of TCR identification may provide broad access to specific TCRs for therapeutically relevant T cell epitopes. PMID- 23637824 TI - Gaze holding in healthy subjects. AB - Eccentric gaze in darkness evokes minor centripetal eye drifts in healthy subjects, as cerebellar control sufficiently compensates for the inherent deficiencies of the brainstem gaze-holding network. This behavior is commonly described using a leaky integrator model, which assumes that eye velocity grows linearly with gaze eccentricity. Results from previous studies in patients and healthy subjects suggest caution when this assumption is applied to eye eccentricities larger than 20 degrees. To obtain a detailed characterization of the centripetal gaze-evoked drift, we recorded horizontal eye position in 20 healthy subjects. With their head fixed, they were asked to fixate a flashing dot (50 ms every 2 s)that was quasi-stationary displacing(0.5 deg/s) between +/- 40 deg horizontally in otherwise complete darkness. Drift velocity was weak at all angles tested. Linearity was assessed by dividing the range of gaze eccentricity in four bins of 20 deg each, and comparing the slopes of a linear function fitted to the horizontal velocity in each bin. The slopes of single subjects for gaze eccentricities of +/- 0-20 deg were, in median,0.41 times the slopes obtained for gaze eccentricities of +/- 20-40 deg. By smoothing the individual subjects' eye velocity as a function of gaze eccentricity, we derived a population of position velocity curves. We show that a tangent function provides a better fit to the mean of these curves when large eccentricities are considered. This implies that the quasi-linear behavior within the typical ocular motor range is the result of a tuning procedure, which is optimized in the most commonly used range of gaze. We hypothesize that the observed non-linearity at eccentric gaze results from a saturation of the input that each neuron in the integrating network receives from the others. As a consequence, gaze-holding performance declines more rapidly at large eccentricities. PMID- 23637822 TI - Age- and light-dependent development of localised retinal atrophy in CCL2(-/ )CX3CR1(GFP/GFP) mice. AB - Previous studies have shown that CCL2/CX3CR1 deficient mice on C57BL/6N background (with rd8 mutation) have an early onset (6 weeks) of spontaneous retinal degeneration. In this study, we generated CCL2(-/-)CX3CR1(GFP/GFP) mice on the C57BL/6J background. Retinal degeneration was not detected in CCL2(-/ )CX3CR1(GFP/GFP) mice younger than 6 months. Patches of whitish/yellowish fundus lesions were observed in 17~60% of 12-month, and 30~100% of 18-month CCL2(-/ )CX3CR1(GFP/GFP) mice. Fluorescein angiography revealed no choroidal neovascularisation in these mice. Patches of retinal pigment epithelium (RPE) and photoreceptor damage were detected in 30% and 50% of 12- and 18-month CCL2(-/ )CX3CR1(GFP/GFP) mice respectively, but not in wild-type mice. All CCL2(-/ )CX3CR1(GFP/GFP) mice exposed to extra-light (~800lux, 6 h/day, 6 months) developed patches of retinal atrophy, and only 20-25% of WT mice which underwent the same light treatment developed atrophic lesions. In addition, synaptophysin expression was detected in the outer nucler layer (ONL) of area related to photoreceptor loss in CCL2(-/-)CX3CR1(GFP/GFP) mice. Markedly increased rhodopsin but reduced cone arrestin expression was observed in retinal outer layers in aged CCL2(-/-)CX3CR1(GFP/GFP) mice. GABA expression was reduced in the inner retina of aged CCL2(-/-)CX3CR1(GFP/GFP) mice. Significantly increased Muller glial and microglial activation was observed in CCL2(-/-)CX3CR1(GFP/GFP) mice compared to age-matched WT mice. Macrophages from CCL2(-/-)CX3CR1(GFP/GFP) mice were less phagocytic, but expressed higher levels of iNOS, IL-1beta, IL-12 and TNF-alpha under hypoxia conditions. Our results suggest that the deletions of CCL2 and CX3CR1 predispose mice to age- and light-mediated retinal damage. The CCL2/CX3CR1 deficient mouse may thus serve as a model for age-related atrophic degeneration of the RPE, including the dry type of macular degeneration, geographic atrophy. PMID- 23637826 TI - Inhibition of vascular smooth muscle cell proliferation by Gentiana lutea root extracts. AB - Gentiana lutea belonging to the Gentianaceae family of flowering plants are routinely used in traditional Serbian medicine for their beneficial gastro intestinal and anti-inflammatory properties. The aim of the study was to determine whether aqueous root extracts of Gentiana lutea consisting of gentiopicroside, gentisin, bellidifolin-8-O-glucoside, demethylbellidifolin-8-O glucoside, isovitexin, swertiamarin and amarogentin prevents proliferation of aortic smooth muscle cells in response to PDGF-BB. Cell proliferation and cell cycle analysis were performed based on alamar blue assay and propidium iodide labeling respectively. In primary cultures of rat aortic smooth muscle cells (RASMCs), PDGF-BB (20 ng/ml) induced a two-fold increase in cell proliferation which was significantly blocked by the root extract (1 mg/ml). The root extract also prevented the S-phase entry of synchronized cells in response to PDGF. Furthermore, PDGF-BB induced ERK1/2 activation and consequent increase in cellular nitric oxide (NO) levels were also blocked by the extract. These effects of extract were due to blockade of PDGF-BB induced expression of iNOS, cyclin D1 and proliferating cell nuclear antigen (PCNA). Docking analysis of the extract components on MEK1, the upstream ERK1/2 activating kinase using AutoDock4, indicated a likely binding of isovitexin to the inhibitor binding site of MEK1. Experiments performed with purified isovitexin demonstrated that it successfully blocks PDGF-induced ERK1/2 activation and proliferation of RASMCs in cell culture. Thus, Gentiana lutea can provide novel candidates for prevention and treatment of atherosclerosis. PMID- 23637827 TI - Glycosylation on hemagglutinin affects the virulence and pathogenicity of pandemic H1N1/2009 influenza A virus in mice. AB - The two glycosylation sites (Asn142 and Asn177) were observed in the HA of most human seasonal influenza A/H1N1 viruses, while none in pandemic H1N1/2009 influenza A (pH1N1) viruses. We investigated the effect of the two glycosylation sites on viral virulence and pathogenicity in mice using recombinant pH1N1. The H1N1/144 and H1N1/177 mutants which gained potential glycosylation sites Asn142 and Asn177 on HA respectively were generated from A/Mexico/4486/2009(H1N1) by site-directed mutagenesis and reverse genetics, the same as the H1N1/144+177 gained both glycosylation sites Asn142 and Asn177. The biological characteristics and antigenicity of the mutants were compared with wild-type pH1N1. The virulence and pathogenicity of recombinants were also detected in mice. Our results showed that HA antigenicity and viral affinity for receptor may change with introduction of the glycosylation sites. Compared with wild-type pH1N1, the mutant H1N1/177 displayed an equivalent virus titer in chicken embryos and mice, and increased virulence and pathogenicity in mice. The H1N1/144 displayed the highest virus titer in mice lung. However, the H1N1/144+177 displayed the most serious alveolar inflammation and pathogenicity in infected mice. The introduction of the glycosylation sites Asn144 and Asn177 resulted in the enhancement on virulence and pathogenicity of pH1N1 in mice, and was also associated with the change of HA antigenicity and the viral affinity for receptor. PMID- 23637829 TI - Dimethylfumarate suppresses adipogenic differentiation in 3T3-L1 preadipocytes through inhibition of STAT3 activity. AB - The excessive accumulation of adipocytes contributes to the development of obesity and obesity-related diseases. The interactions of several transcription factors, such as C/EBPbeta, PPARgamma, C/EBPalpha, Nrf2, and STAT3, are required for adipogenic differentiation. Dimethylfumarate (DMF), an immune modulator and antioxidant, may function as an inhibitor of STAT3 and an activator of Nrf2. This study examined whether DMF inhibits adipogenic differentiation of 3T3-L1 preadipocytes by inhibiting STAT3 or activating Nrf2. DMF suppressed 3T3-L1 preadipocyte differentiation to mature adipocytes in a dose-dependent manner as determined by Oil Red O staining. The mRNA and protein levels of adipogenic genes, including C/EBPbeta, C/EBPalpha, PPARgamma, SREBP-1c, FAS, and aP2, were significantly lower in DMF-treated 3T3-L1 preadipocytes. Suppression of adipogenic differentiation by DMF treatment resulted primarily from inhibition of the early stages of differentiation. DMF inhibits clonal expansion during adipogenic differentiation through induction of a G1 cell cycle arrest. Additionally, DMF regulates cell cycle-related proteins, such as p21, pRb, and cyclin D. DMF treatment markedly inhibited differentiation medium-induced STAT3 phosphorylation and inhibited STAT3 transcriptional activation of a reporter construct composed of four synthetic STAT3-response elements. Moreover, inhibition of endogenous Nrf2 activity using a dominant negative Nrf2 did not abolish the DMF-induced inhibition of adipogenic differentiation of 3T3-L1 preadipocytes. In summary, DMF is a negative regulator of adipogenic differentiation based on its regulation of adipogenic transcription factors and cell cycle proteins. This negative regulation by DMF is mediated by STAT3 inhibition, but is unlikely to involve Nrf2 activation. PMID- 23637828 TI - PIN2 turnover in Arabidopsis root epidermal cells explored by the photoconvertible protein Dendra2. AB - The steady state level of integral membrane proteins is dependent on a strictly controlled delivery and removal. Here we show that Dendra2, a green-to-red photoconvertible fluorescent protein, is a suitable tool to study protein turnover in plants. We characterized the fluorescence properties of Dendra2 expressed either as a free protein or as a tag in Arabidopsis thaliana roots and optimized photoconversion settings to study protein turnover. Dendra2 was fused to the PIN2 protein, an auxin transporter in the root tip, and by time-lapse imaging and assessment of red and green signal intensities in the membrane after photoconversion we quantified directly and simultaneously the rate of PIN2 delivery of the newly synthesized protein into the plasma membrane as well as the disappearance of the protein from the plasma membrane due to degradation. Additionally we have verified several factors which are expected to affect PIN2 protein turnover and therefore potentially regulate root growth. PMID- 23637830 TI - Therapeutic effects of 15 Hz pulsed electromagnetic field on diabetic peripheral neuropathy in streptozotocin-treated rats. AB - Although numerous clinical studies have reported that pulsed electromagnetic fields (PEMF) have a neuroprotective role in patients with diabetic peripheral neuropathy (DPN), the application of PEMF for clinic is still controversial. The present study was designed to investigate whether PEMF has therapeutic potential in relieving peripheral neuropathic symptoms in streptozotocin (STZ)-induced diabetic rats. Adult male Sprague-Dawley rats were randomly divided into three weight-matched groups (eight in each group): the non-diabetic control group (Control), diabetes mellitus with 15 Hz PEMF exposure group (DM+PEMF) which were subjected to daily 8-h PEMF exposure for 7 weeks and diabetes mellitus with sham PEMF exposure group (DM). Signs and symptoms of DPN in STZ-treated rats were investigated by using behavioral assays. Meanwhile, ultrastructural examination and immunohistochemical study for vascular endothelial growth factor (VEGF) of sciatic nerve were also performed. During a 7-week experimental observation, we found that PEMF stimulation did not alter hyperglycemia and weight loss in STZ treated rats with DPN. However, PEMF stimulation attenuated the development of the abnormalities observed in STZ-treated rats with DPN, which were demonstrated by increased hind paw withdrawal threshold to mechanical and thermal stimuli, slighter demyelination and axon enlargement and less VEGF immunostaining of sciatic nerve compared to those of the DM group. The current study demonstrates that treatment with PEMF might prevent the development of abnormalities observed in animal models for DPN. It is suggested that PEMF might have direct corrective effects on injured nerves and would be a potentially promising non-invasive therapeutic tool for the treatment of DPN. PMID- 23637831 TI - Effect of fruit juice on cholesterol and blood pressure in adults: a meta analysis of 19 randomized controlled trials. AB - BACKGROUND: The effect of fruit juice on serum cholesterol and blood pressure in humans has generated inconsistent results. We aimed to quantitatively evaluate the effect of fruit juice on serum cholesterol and blood pressure in adults. METHODS: We performed a strategic literature search of PubMed, EMBASE, and the Cochrane Library (updated to October, 2012) for randomized controlled trials that evaluated the effects of fruit juice on serum cholesterol and blood pressure. Study quality was assessed by using the Jadad scale. Weighted mean differences were calculated for net changes in cholesterol and blood pressure by using fixed effects model. Prespecified subgroup and sensitivity analyses were conducted to explore the potential heterogeneity. RESULTS: Nineteen trials comprising a total of 618 subjects were included in this meta-analysis. Fruit juice consumption borderlinely reduced the diastolic blood pressure (DBP) by 2.07 mm Hg (95% CI: 3.75, -0.39 mm Hg; p = 0.02), but did not show significant effects on total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) concentrations or systolic blood pressure (SBP) values. A significant reduction of TC concentration was observed in low-median intake of total polyphenols group. Subgroup analyses for HDL-C and LDL-C concentrations did not show statistically significant results. No significant heterogeneity was detected for all the measures. CONCLUSION: This meta-analysis suggested that fruit juice had a borderline significant effect on reducing DBP, but had no effect on TC, HDL-C, LDL-C concentrations or SBP. PMID- 23637832 TI - Regulator of G-protein signaling - 5 (RGS5) is a novel repressor of hedgehog signaling. AB - Hedgehog (Hh) signaling plays fundamental roles in morphogenesis, tissue repair, and human disease. Initiation of Hh signaling is controlled by the interaction of two multipass membrane proteins, patched (Ptc) and smoothened (Smo). Recent studies identify Smo as a G-protein coupled receptor (GPCR)-like protein that signals through large G-protein complexes which contain the Galphai subunit. We hypothesize Regulator of G-Protein Signaling (RGS) proteins, and specifically RGS5, are endogenous repressors of Hh signaling via their ability to act as GTPase activating proteins (GAPs) for GTP-bound Galphai, downstream of Smo. In support of this hypothesis, we demonstrate that RGS5 over-expression inhibits sonic hedgehog (Shh)-mediated signaling and osteogenesis in C3H10T1/2 cells. Conversely, signaling is potentiated by siRNA-mediated knock-down of RGS5 expression, but not RGS4 expression. Furthermore, using immuohistochemical analysis and co-immunoprecipitation (Co-IP), we demonstrate that RGS5 is present with Smo in primary cilia. This organelle is required for canonical Hh signaling in mammalian cells, and RGS5 is found in a physical complex with Smo in these cells. We therefore conclude that RGS5 is an endogenous regulator of Hh-mediated signaling and that RGS proteins are potential targets for novel therapeutics in Hh-mediated diseases. PMID- 23637833 TI - Interaction between oxytocin genotypes and early experience predicts quality of mothering and postpartum mood. AB - Individual differences in maternal behavior are affected by both early life experiences and oxytocin, but little is known about genetic variation in oxytocin genes and its effects on mothering. We examined two polymorphisms in the oxytocin peptide gene OXT (rs2740210 and rs4813627) and one polymorphism in the oxytocin receptor gene OXTR (rs237885) in 187 Caucasian mothers at six months postpartum. For OXT, both rs2740210 and rs4813627 significantly associated with maternal vocalizing to the infant. These polymorphisms also interacted with the quality of care mothers experienced in early life, to predict variation in maternal instrumental care and postpartum depression. However, postpartum depression did not mediate the gene-environment effects of the OXT SNPs on instrumental care. In contrast, the OXTR SNP rs237885 did not associate with maternal behavior, but it did associate with pre-natal (but not post-natal) depression score. The findings illustrate the importance of variation in oxytocin genes, both alone and in interaction with early environment, as predictors of individual differences in human mothering. Furthermore, depression does not appear to have a causal role on the variation we report in instrumental care. This suggests that variation in instrumental care varies in association with a gene-early environment effect regardless of current depressive symptomatology. Finally, our findings highlight the importance of examining multiple dimensions of human maternal behavior in studies of genetic associations. PMID- 23637835 TI - Hyperuricemia is an independent risk factor for new onset micro-albuminuria in a middle-aged and elderly population: a prospective cohort study in taiwan. AB - BACKGROUND: Hyperuricemia is now regarded as a risk factor for cardiovascular disease. Micro-albuminuria is associated with increased risk for cardiovascular disease and chronic kidney disease. We hypothesized that elevated serum uric acid (UA) is associated with development of micro-albuminuria in the general population. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a community-based prospective cohort study. A total of 1862 subjects from southern Taiwan, all older than 40 years, were screened and 993 of these participants without micro albuminuria were followed for 4 years. Urinary albumin-to-creatinine ratio was measured two times per year. A multiple linear regression model indicated that serum UA was independently associated with ln(ACR) after adjustment for 8 factors (age, sex, and 6 metabolic metrics) (beta = 0.194, p<0.01). Logistic regression analysis indicated that each 1 mg/dL increase of UA was associated with a 1.42 fold increased risk of micro-albuminuria after adjustment for the same 8 factors (OR = 1.42, 95% CI: 1.27-1.59, p<0.01). A Cox regression model using subjects with serum UA less than 5 mg/dL as reference group indicated higher hazard ratios (HRs) only found in subjects with serum UA more than 7 mg/dL (HR = 3.54, 95% CI: 2.11-5.93, p<0.01) and not in subjects with serum UA of 5 to 7 mg/dL (HR = 1.30, 95% CI: 0.82-2.07, p = 0.15). CONCLUSION: Hyperuricemia is significantly associated with micro-albuminuria in middle-aged and elderly males and females from a general population in Taiwan. Elevated serum UA is an independent predictor for development of micro-albuminuria in this population. PMID- 23637836 TI - The development and application of the two real-time RT-PCR assays to detect the pathogen of HFMD. AB - Large-scale Hand, Foot, and Mouth Disease (HFMD) outbreaks have frequently occurred in China since 2008, affecting more than one million children and causing several hundred children deaths every year. The pathogens of HFMD are mainly human enteroviruses (HEVs). Among them, human enterovirus 71 (HEV71) and coxsackievirus A16 (CVA16) are the most common pathogens of HFMD. However, other HEVs could also cause HFMD. To rapidly detect HEV71 and CVA16, and ensure detection of all HEVs causing HFMD, two real-time hybridization probe-based RT PCR assays were developed in this study. One is a multiplex real-time RT-PCR assay, which was developed to detect and differentiate HEV71 specifically from CVA16 directly from clinical specimens within 1-2 h, and the other is a broad spectrum real-time RT-PCR assay, which targeted almost all HEVs. The experiments confirmed that the two assays have high sensitivity and specificity, and the sensitivity was up to 0.1 TCID50/ml for detection of HEVs, HEV71, and CVA16, respectively. A total of 213 clinical specimens were simultaneously detected by three kinds of assays, including the two real-time RT-PCR assays, direct conventional RT-PCR assay, and virus isolation assay on human rhabdomyosarcoma cells (RD cells). The total positive rate of both HEV71 and CVA16 was 69.48% with real-time RT-PCR assay, 47.42% with RT-PCR assay, and 34.58% with virus isolation assay. One HFMD clinical specimen was positive for HEV, but negative for HEV71 or CVA16, which was identified as Echovirus 11 (Echo11) by virus isolation, RT-PCR, and sequencing for the VP1 gene. The two real-time RT-PCR assays had been applied in 31 provincial HFMD labs to detect the pathogens of HFMD, which has contributed to the rapid identification of the pathogens in the early stages of HFMD outbreaks, and helped to clarify the etiologic agents of HFMD in China. PMID- 23637834 TI - Ectopic expression of homeobox gene NKX2-1 in diffuse large B-cell lymphoma is mediated by aberrant chromatin modifications. AB - Homeobox genes encode transcription factors ubiquitously involved in basic developmental processes, deregulation of which promotes cell transformation in multiple cancers including hematopoietic malignancies. In particular, NKL-family homeobox genes TLX1, TLX3 and NKX2-5 are ectopically activated by chromosomal rearrangements in T-cell neoplasias. Here, using transcriptional microarray profiling and RQ-PCR we identified ectopic expression of NKL-family member NKX2 1, in a diffuse large B-cell lymphoma (DLBCL) cell line SU-DHL-5. Moreover, in silico analysis demonstrated NKX2-1 overexpression in 5% of examined DLBCL patient samples. NKX2-1 is physiologically expressed in lung and thyroid tissues where it regulates differentiation. Chromosomal and genomic analyses excluded rearrangements at the NKX2-1 locus in SU-DHL-5, implying alternative activation. Comparative expression profiling implicated several candidate genes in NKX2-1 regulation, variously encoding transcription factors, chromatin modifiers and signaling components. Accordingly, siRNA-mediated knockdown and overexpression studies confirmed involvement of transcription factor HEY1, histone methyltransferase MLL and ubiquitinated histone H2B in NKX2-1 deregulation. Chromosomal aberrations targeting MLL at 11q23 and the histone gene cluster HIST1 at 6p22 which we observed in SU-DHL-5 may, therefore, represent fundamental mutations mediating an aberrant chromatin structure at NKX2-1. Taken together, we identified ectopic expression of NKX2-1 in DLBCL cells, representing the central player in an oncogenic regulative network compromising B-cell differentiation. Thus, our data extend the paradigm of NKL homeobox gene deregulation in lymphoid malignancies. PMID- 23637837 TI - Roles of ApoB-100 gene polymorphisms and the risks of gallstones and gallbladder cancer: a meta-analysis. AB - BACKGROUND: Gallstones (GS) is the major manifestation of gallbladder disease, and is the most common risk factor for gallbladder cancer (GBC). Previous studies investigating the association between ApoB-100 gene polymorphisms and the risks of GS and GBC have yielded conflicting results. Therefore, we performed a meta analysis to clarify the effects of ApoB-100 gene polymorphisms on the risks of GS and GBC. METHODS: A computerized literature search was conducted to identify the relevant studies from PubMed and Embase. Fixed or random effects model was selected based on heterogeneity test. Publication bias was estimated using Begg's funnel plots and Egger's regression test. RESULTS: A total of 10, 3, and 3 studies were included in the analyses of the association between ApoB-100 XbaI, EcoRI, or insertion/deletion (ID) polymorphisms and the GS risks, respectively, while 3 studies were included in the analysis for the association between XbaI polymorphism and GBC risk. The combined results showed a significant association in Chinese (X+ vs. X-, OR = 2.37, 95%CI 1.52-3.70; X+X+/X+X- vs. X+X+, OR = 2.47, 95%CI 1.55-3.92), but not in Indians or Caucasians. Null association was observed between EcoRI or ID polymorphisms and GS risks. With regard to the association between XbaI polymorphism and GBC risk, a significant association was detected when GBC patients were compared with healthy persons and when GBC patients were compared with GS patients. A significant association was still detected when GBC patients (with GS) were compared with the GS patients (X+X+ vs. X-X-, OR = 0.33, 95%CI 0.12-0.90). CONCLUSION: The results of this meta-analysis suggest that the ApoB-100 X+ allele might be associated with increased risk of GS in Chinese but not in other populations, while the ApoB-100 X+X+ genotype might be associated with reduced risk of GBC. Further studies with larger sample sizes are needed to confirm these results. PMID- 23637838 TI - Tree species composition influences enzyme activities and microbial biomass in the rhizosphere: a rhizobox approach. AB - Monoculture causes nutrient losses and leads to declines in soil fertility and biomass production over successive cultivation. The rhizosphere, a zone of usually high microbial activities and clearly distinct from bulk soil, is defined as the volume of soil around living roots and influenced by root activities. Here we investigated enzyme activities and microbial biomass in the rhizosphere under different tree compositions. Six treatments with poplar, willow, and alder mono- or mixed seedlings were grown in rhizoboxes. Enzyme activities associated with nitrogen cycling and microbial biomass were measured in all rhizosphere and bulk soils. Both enzyme activities and microbial biomass in the rhizosphere differed significantly tree compositions. Microbial biomass contents were more sensitive to the changes of the rhizosphere environment than enzyme activities. Tree species coexistence did not consistently increase tested enzyme activities and microbial biomass, but varied depending on the complementarities of species traits. In general, impacts of tree species and coexistence were more pronounced on microbial composition than total biomass, evidenced by differences in microbial biomass C/N ratios stratified across the rhizosphere soils. Compared to poplar clone monoculture, other tree species addition obviously increased rhizosphere urease activity, but greatly reduced rhizosphere L-asparaginase activity. Poplar growth was enhanced only when coexisted with alder. Our results suggested that a highly productive or keystone plant species in a community had greater influence over soil functions than the contribution of diversity. PMID- 23637840 TI - Negative association between testosterone concentration and inflammatory markers in young men: a nested cross-sectional study. AB - OBJECTIVE: Low grade systemic inflammation (LGSI) as well as androgen deficiency has in older men been associated with several pathologies, including cardiovascular disease (CVD). We wanted to investigate whether low testosterone levels are linked to biomarkers of LGSI already in young age, before any concurrent manifestations of CVD or other systemic diseases. DESIGN: Nested cross sectional study. METHODS: Forty subfertile biochemically hypogonadal (n = 20) or eugonadal (n = 20) men (mean age 37 years, SD = 4.3) and 20 age-matched controls were randomly selected from an ongoing study on male subfertility. Subjects comprised male partners in infertile couples in whom also subnormal sperm concentration was present. Blood sampling, interviews, and anthropometric measures were undertaken. Serum levels of testosterone, LH, estradiol, SHBG, and 21 LGSI-markers were assessed. RESULTS: Among 21 inflammatory markers, macrophage inflammatory protein 1-alpha (MIP1a) (beta = -0.025; p = 0.028), 1-beta (MIP1B) (beta = -0.015; p = 0.049) and tumor necrosis factor alpha (TNFa) (beta = -0.015; p = 0.040) showed negative association to total testosterone (TT) levels. MIP1a (beta = -1.95; p = 0.001) and TNFa (beta = -0.95; p = 0.014) showed negative association to calculated free testosterone (cFT) levels. Compared to men with normal TT and cFT levels, TNFa levels were higher in men with subnormal levels of TT (mean ratio 1.61; p = 0.006) and cFT (mean ratio 1.58; p = 0.007). Also, MIP1a levels were higher in men with subnormal levels of TT (mean ratio 1.84; p = 0.030). CONCLUSIONS: Subnormal testosterone may already in young age associate to LGSI, which might be a part of the mechanism underlying adverse health outcomes of male hypogonadism. PMID- 23637839 TI - Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid mediated modulation of LPS-induced activation of BV-2 microglial cells. AB - Cannabinoids are known to exert immunosuppressive activities. However, the mechanisms which contribute to these effects are unknown. Using lipopolysaccharide (LPS) to activate BV-2 microglial cells, we examined how Delta(9)-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, and cannabidiol (CBD) the non-psychoactive component, modulate the inflammatory response. Microarray analysis of genome-wide mRNA levels was performed using Illumina platform and the resulting expression patterns analyzed using the Ingenuity Pathway Analysis to identify functional subsets of genes, and the Ingenuity System Database to denote the gene networks regulated by CBD and THC. From the 5338 transcripts that were differentially expressed across treatments, 400 transcripts were found to be upregulated by LPS, 502 by CBD+LPS and 424 by THC+LPS, while 145 were downregulated by LPS, 297 by CBD+LPS and 149 by THC+LPS, by 2-fold or more (p<=0.005). Results clearly link the effects of CBD and THC to inflammatory signaling pathways and identify new cannabinoid targets in the MAPK pathway (Dusp1, Dusp8, Dusp2), cell cycle related (Cdkn2b, Gadd45a) as well as JAK/STAT regulatory molecules (Socs3, Cish, Stat1). The impact of CBD on LPS-stimulated gene expression was greater than that of THC. We attribute this difference to the fact that CBD highly upregulated several genes encoding negative regulators of both NFkappaB and AP-1 transcriptional activities, such as Trib3 and Dusp1 known to be modulated through Nrf2 activation. The CBD-specific expression profile reflected changes associated with oxidative stress and glutathione depletion via Trib3 and expression of ATF4 target genes. Furthermore, the CBD affected genes were shown to be controlled by nuclear factors usually involved in regulation of stress response and inflammation, mainly via Nrf2/Hmox1 axis and the Nrf2/ATF4-Trib3 pathway. These observations indicate that CBD, and less so THC, induce a cellular stress response and that this response underlies their high immunosuppressant activities. PMID- 23637841 TI - Parallel tagged next-generation sequencing on pooled samples - a new approach for population genetics in ecology and conservation. AB - Next-generation sequencing (NGS) on pooled samples has already been broadly applied in human medical diagnostics and plant and animal breeding. However, thus far it has been only sparingly employed in ecology and conservation, where it may serve as a useful diagnostic tool for rapid assessment of species genetic diversity and structure at the population level. Here we undertake a comprehensive evaluation of the accuracy, practicality and limitations of parallel tagged amplicon NGS on pooled population samples for estimating species population diversity and structure. We obtained 16S and Cyt b data from 20 populations of Leiopelma hochstetteri, a frog species of conservation concern in New Zealand, using two approaches - parallel tagged NGS on pooled population samples and individual Sanger sequenced samples. Data from each approach were then used to estimate two standard population genetic parameters, nucleotide diversity (pi) and population differentiation (FST), that enable population genetic inference in a species conservation context. We found a positive correlation between our two approaches for population genetic estimates, showing that the pooled population NGS approach is a reliable, rapid and appropriate method for population genetic inference in an ecological and conservation context. Our experimental design also allowed us to identify both the strengths and weaknesses of the pooled population NGS approach and outline some guidelines and suggestions that might be considered when planning future projects. PMID- 23637842 TI - Imbalanced decision hierarchy in addicts emerging from drug-hijacked dopamine spiraling circuit. AB - Despite explicitly wanting to quit, long-term addicts find themselves powerless to resist drugs, despite knowing that drug-taking may be a harmful course of action. Such inconsistency between the explicit knowledge of negative consequences and the compulsive behavioral patterns represents a cognitive/behavioral conflict that is a central characteristic of addiction. Neurobiologically, differential cue-induced activity in distinct striatal subregions, as well as the dopamine connectivity spiraling from ventral striatal regions to the dorsal regions, play critical roles in compulsive drug seeking. However, the functional mechanism that integrates these neuropharmacological observations with the above-mentioned cognitive/behavioral conflict is unknown. Here we provide a formal computational explanation for the drug-induced cognitive inconsistency that is apparent in the addicts' "self-described mistake". We show that addictive drugs gradually produce a motivational bias toward drug-seeking at low-level habitual decision processes, despite the low abstract cognitive valuation of this behavior. This pathology emerges within the hierarchical reinforcement learning framework when chronic exposure to the drug pharmacologically produces pathologicaly persistent phasic dopamine signals. Thereby the drug hijacks the dopaminergic spirals that cascade the reinforcement signals down the ventro-dorsal cortico-striatal hierarchy. Neurobiologically, our theory accounts for rapid development of drug cue-elicited dopamine efflux in the ventral striatum and a delayed response in the dorsal striatum. Our theory also shows how this response pattern depends critically on the dopamine spiraling circuitry. Behaviorally, our framework explains gradual insensitivity of drug seeking to drug-associated punishments, the blocking phenomenon for drug outcomes, and the persistent preference for drugs over natural rewards by addicts. The model suggests testable predictions and beyond that, sets the stage for a view of addiction as a pathology of hierarchical decision-making processes. This view is complementary to the traditional interpretation of addiction as interaction between habitual and goal-directed decision systems. PMID- 23637844 TI - In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma. AB - Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the leading cause of cancer-related death in children. While it is clear that surgery (if possible), and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular. PMID- 23637845 TI - Pharmacokinetics and interspecies allometric scaling of ST-246, an oral antiviral therapeutic for treatment of orthopoxvirus infection. AB - Plasma pharmacokinetics of ST-246, smallpox therapeutic, was evaluated in mice, rabbits, monkeys and dogs following repeat oral administrations by gavage. The dog showed the lowest Tmax of 0.83 h and the monkey, the highest value of 3.25 h. A 2- to 4-fold greater dose-normalized Cmax was observed for the dog compared to the other species. The mouse showed the highest dose-normalized AUC, which was 2 fold greater than that for the rabbit and monkey both of which by approximation, recorded the lowest value. The Cl/F increased across species from 0.05 L/h for mouse to 42.52 L/h for dog. The mouse showed the lowest VD/F of 0.41 L and the monkey, the highest VD/F of 392.95 L. The calculated extraction ratios were 0.104, 0.363, 0.231 and 0.591 for mouse, rabbit, monkey and dog, respectively. The dog showed the lowest terminal half-life of 3.10 h and the monkey, the highest value of 9.94 h. The simple allometric human VD/F and MLP-corrected Cl/F were 2311.51 L and 51.35 L/h, respectively, with calculated human extraction ratio of 0.153 and terminal half-life of 31.20 h. Overall, a species-specific difference was observed for Cl/F with this parameter increasing across species from mouse to dog. The human MLP-corrected Cl/F, terminal half-life, extraction ratios were in close proximity to the observed estimates. In addition, the first in-humans (FIH) dose of 485 mg, determined from the MLP-corrected allometry Cl/F, was well within the dose range of 400 mg and 600 mg administered in healthy adult human volunteers. PMID- 23637843 TI - Gene expression changes in the motor cortex mediating motor skill learning. AB - The primary motor cortex (M1) supports motor skill learning, yet little is known about the genes that contribute to motor cortical plasticity. Such knowledge could identify candidate molecules whose targeting might enable a new understanding of motor cortical functions, and provide new drug targets for the treatment of diseases which impair motor function, such as ischemic stroke. Here, we assess changes in the motor-cortical transcriptome across different stages of motor skill acquisition. Adult rats were trained on a gradually acquired appetitive reach and grasp task that required different strategies for successful pellet retrieval, or a sham version of the task in which the rats received pellet reward without needing to develop the reach and grasp skill. Tissue was harvested from the forelimb motor-cortical area either before training commenced, prior to the initial rise in task performance, or at peak performance. Differential classes of gene expression were observed at the time point immediately preceding motor task improvement. Functional clustering revealed that gene expression changes were related to the synapse, development, intracellular signaling, and the fibroblast growth factor (FGF) family, with many modulated genes known to regulate synaptic plasticity, synaptogenesis, and cytoskeletal dynamics. The modulated expression of synaptic genes likely reflects ongoing network reorganization from commencement of training till the point of task improvement, suggesting that motor performance improves only after sufficient modifications in the cortical circuitry have accumulated. The regulated FGF-related genes may together contribute to M1 remodeling through their roles in synaptic growth and maturation. PMID- 23637848 TI - Analysis of PPARGC1B, RUNX3 and TBKBP1 polymorphisms in Chinese Han patients with ankylosing spondylitis: a case-control study. AB - BACKGROUND: Susceptibility to and severity of ankylosing spondylitis (AS) are largely genetically determined. PPARGC1B, RUNX3 and TBKBP1 have recently been found to be associated with AS in patients of western European descent. Our purpose is to examine the influence of PPARGC1B, RUNX3 and TBKBP1 polymorphisms on the susceptibility to and the severity of ankylosing spondylitis in Chinese ethnic majority Han population. METHODS: Blood samples are drawn from 396 AS patients and 404 unrelated healthy controls. All the patients and the controls are Han Chinese and the patients are HLA-B27 positive. The AS patients are classified based on the severity of the disease. Twelve tag single nucleotide polymorphisms (tagSNPs) in PPARGC1B, RUNX3 and TBKBP1 are selected and genotyped. Frequencies of different genotypes and alleles are analyzed among the different severity AS patients and the controls. RESULTS: After Bonferroni correction, the rs7379457 SNP in PPARGC1B shows significant difference when comparing all AS patients to controls (p = 0.005). This SNP also shows significant difference when comparing normal AS patients to controls (p = 0.002). The rs1395621 SNP in RUNX3 shows significant difference when comparing severe AS patients to controls (p = 0.007). The rs9438876 SNP in RUNX3 shows significant difference when comparing normal AS patients to controls (p = 0.007). The rs8070463 SNP in TBKBP1 shows significant difference in genotype distribution when comparing severe AS patients to controls (p = 0.003). CONCLUSIONS: The rs7379457 SNP in PPARGC1B is related to susceptibility to AS in Chinese Han population. The rs7379457 SNP in PPARGC1B, the rs1395621 and rs9438876 SNPs in RUNX3, and the rs8070463 SNP in TBKBP1 are related to the severity of AS in Chinese Han population. PMID- 23637846 TI - Molecular and immunological characterization of ragweed (Ambrosia artemisiifolia L.) pollen after exposure of the plants to elevated ozone over a whole growing season. AB - Climate change and air pollution, including ozone is known to affect plants and might also influence the ragweed pollen, known to carry strong allergens. We compared the transcriptome of ragweed pollen produced under ambient and elevated ozone by 454-sequencing. An enzyme-linked immunosorbent assay (ELISA) was carried out for the major ragweed allergen Amb a 1. Pollen surface was examined by scanning electron microscopy and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), and phenolics were analysed by high-performance liquid chromatography. Elevated ozone had no influence on the pollen size, shape, surface structure or amount of phenolics. ATR-FTIR indicated increased pectin like material in the exine. Transcriptomic analyses showed changes in expressed sequence tags (ESTs), including allergens. However, ELISA indicated no significantly increased amounts of Amb a 1 under elevated ozone concentrations. The data highlight a direct influence of ozone on the exine components and transcript level of allergens. As the total protein amount of Amb a 1 was not altered, a direct correlation to an increased risk to human health could not be derived. Additional, the 454-sequencing contributes to the identification of stress-related transcripts in mature pollen that could be grouped into distinct gene ontology terms. PMID- 23637849 TI - Investigating the effects of food available and climatic variables on the animal host density of hemorrhagic Fever with renal syndrome in changsha, china. AB - BACKGROUND: The transmission of hemorrhagic fever with renal syndrome (HFRS) is influenced by population dynamics of its main host, rodents. It is therefore important to better understand rodents' characteristic in epidemic areas. METHODOLOGY/PRINCIPAL FINDINGS: We examined the potential impact of food available and climatic variability on HFRS rodent host and developed forecasting models. Monthly rodent density of HFRS host and climate data in Changsha from January 2004 to December 2011 were obtained. Monthly normalized difference vegetation index (NDVI) and temperature vegetation dryness index (TVDI) for rice paddies were extracted from MODIS data. Cross-correlation analysis were carried out to explore correlation between climatic variables and food available with monthly rodent data. We used auto-regressive integrated moving average model with explanatory variables to examine the independent contribution of climatic variables and food supply to rodent density. The results indicated that relative rodent density of HFRS host was significantly correlated with monthly mean temperatures, monthly accumulative precipitation, TVDI and NDVI with lags of 1-6 months. CONCLUSIONS/SIGNIFICANCE: Food available plays a significant role in population fluctuations of HFRS host in Changsha. The model developed in this study has implications for HFRS control and prevention. PMID- 23637847 TI - Ca(2+) release events in cardiac myocytes up close: insights from fast confocal imaging. AB - The spatio-temporal properties of Ca(2+) transients during excitation-contraction coupling and elementary Ca(2+) release events (Ca(2+) sparks) were studied in atrial and ventricular myocytes with ultra-fast confocal microscopy using a Zeiss LSM 5 LIVE system that allows sampling rates of up to 60 kHz. Ca(2+) sparks which originated from subsarcolemmal junctional sarcoplasmic reticulum (j-SR) release sites in atrial myocytes were anisotropic and elongated in the longitudinal direction of the cell. Ca(2+) sparks in atrial cells originating from non junctional SR and in ventricular myocytes were symmetrical. Ca(2+) spark recording in line scan mode at 40,000 lines/s uncovered step-like increases of [Ca(2+)]i. 2-D imaging of Ca(2+) transients revealed an asynchronous activation of release sites and allowed the sequential recording of Ca(2+) entry through surface membrane Ca(2+) channels and subsequent activation of Ca(2+)-induced Ca(2+) release. With a latency of 2.5 ms after application of an electrical stimulus, Ca(2+) entry could be detected that was followed by SR Ca(2+) release after an additional 3 ms delay. Maximum Ca(2+) release was observed 4 ms after the beginning of release. The timing of Ca(2+) entry and release was confirmed by simultaneous [Ca(2+)]i and membrane current measurements using the whole cell voltage-clamp technique. In atrial cells activation of discrete individual release sites of the j-SR led to spatially restricted Ca(2+) release events that fused into a peripheral ring of elevated [Ca(2+)]i that subsequently propagated in a wave-like fashion towards the center of the cell. In ventricular myocytes asynchronous Ca(2+) release signals from discrete sites with no preferential subcellular location preceded the whole-cell Ca(2+) transient. In summary, ultra fast confocal imaging allows investigation of Ca(2+) signals with a time resolution similar to patch clamp technique, however in a less invasive fashion. PMID- 23637850 TI - RNA profiles of porcine embryos during genome activation reveal complex metabolic switch sensitive to in vitro conditions. AB - Fertilization is followed by complex changes in cytoplasmic composition and extensive chromatin reprogramming which results in the abundant activation of totipotent embryonic genome at embryonic genome activation (EGA). While chromatin reprogramming has been widely studied in several species, only a handful of reports characterize changing transcriptome profiles and resulting metabolic changes in cleavage stage embryos. The aims of the current study were to investigate RNA profiles of in vivo developed (ivv) and in vitro produced (ivt) porcine embryos before (2-cell stage) and after (late 4-cell stage) EGA and determine major metabolic changes that regulate totipotency. The period before EGA was dominated by transcripts responsible for cell cycle regulation, mitosis, RNA translation and processing (including ribosomal machinery), protein catabolism, and chromatin remodelling. Following EGA an increase in the abundance of transcripts involved in transcription, translation, DNA metabolism, histone and chromatin modification, as well as protein catabolism was detected. The further analysis of members of overlapping GO terms revealed that despite that comparable cellular processes are taking place before and after EGA (RNA splicing, protein catabolism), different metabolic pathways are involved. This strongly suggests that a complex metabolic switch accompanies EGA. In vitro conditions significantly altered RNA profiles before EGA, and the character of these changes indicates that they originate from oocyte and are imposed either before oocyte aspiration or during in vitro maturation. IVT embryos have altered content of apoptotic factors, cell cycle regulation factors and spindle components, and transcription factors, which all may contribute to reduced developmental competence of embryos produced in vitro. Overall, our data are in good accordance with previously published, genome-wide profiling data in other species. Moreover, comparison with mouse and human embryos showed striking overlap in functional annotation of transcripts during the EGA, suggesting conserved basic mechanisms regulating establishment of totipotency in mammalian development. PMID- 23637851 TI - Achievement of cardiometabolic goals among diabetic patients in Spain. A nationwide population-based study. AB - BACKGROUND: No previous study has reported a comprehensive assessment of the attainment of cardiometabolic goals in the diabetic population of a European country. We examined the achievement of cardiometabolic goals among diabetics in Spain. METHODS AND FINDINGS: A cross-sectional survey was performed in 2008-2010 among 12,077 individuals representative of the Spanish population aged >=18 years. Information on cardiometabolic characteristics was collected at the participants' homes through structured questionnaires, physical examination, and fasting blood samples. Attainment of cardiometabolic goals was evaluated according to the most well-known guidelines. A total of 834 individuals had diabetes (fasting serum glucose >=126 mg/dl, or glycosylated hemoglobin >=6.5%,) or were being treated with oral antidiabetic drugs or insulin). Among diabetic patients, 661 (79.2%) were aware of their condition. Among the aware diabetic patients, only 11.4% had neither general (body mass index <25 kg/m(2)) nor abdominal obesity (waist circumference <=102 cm in men and <=88 cm in women), 8.6% consumed <7% of calories daily from saturated fats, and 41.1% achieved the recommendation on weekly physical activity. About 71% had glycosylated hemoglobin <7%, 22% had blood pressure <130/80 mmHg, and 36% reached the LDL-cholesterol goal of <100 mg/dl. Although a large proportion of aware diabetic individuals received lifestyle medical advice, only 38% of overweight individuals and 20% of daily smokers were offered a specific strategy for weight loss or quitting smoking, respectively. CONCLUSIONS: In a European country with universal healthcare coverage, achievement of many cardiometabolic goals, in particular lifestyle, among aware diabetic individuals is poor. This suggests a need for improvement in both clinical guidelines' implementation and patients' adherence. PMID- 23637854 TI - Increased physical activity not decreased energy intake is associated with inpatient medical treatment for anorexia nervosa in adolescent females. AB - There is a dearth of data regarding changes in dietary intake and physical activity over time that lead to inpatient medical treatment for anorexia nervosa (AN). Without such data, more effective nutritional therapies for patients cannot be devised. This study was undertaken to describe changes in diet and physical activity that precede inpatient medical hospitalization for AN in female adolescents. This data can be used to understand factors contributing to medical instability in AN, and may advance rodent models of AN to investigate novel weight restoration strategies. It was hypothesized that hospitalization for AN would be associated with progressive energy restriction and increased physical activity over time. 20 females, 11-19 years (14.3+/-1.8 years), with restricting type AN, completed retrospective, self-report questionnaires to assess dietary intake and physical activity over the 6 month period prior to inpatient admission (food frequency questionnaire, Pediatric physical activity recall) and 1 week prior (24 hour food recall, modifiable activity questionnaire). Physical activity increased acutely prior to inpatient admission without any change in energy or macronutrient intake. However, there were significant changes in reported micronutrient intake causing inadequate intake of Vitamin A, Vitamin D, and pantothenic acid at 1 week versus high, potentially harmful, intake of Vitamin A over 6 months prior to admission. Subject report of significantly increased physical activity, not decreased energy intake, were associated with medical hospitalization for AN. Physical activity and Vitamin A and D intake should be carefully monitored following initial AN diagnosis, as markers of disease progression as to potentially minimize the risk of medical instability. PMID- 23637852 TI - The complete sequence of the mitochondrial genome of Butomus umbellatus--a member of an early branching lineage of monocotyledons. AB - In order to study the evolution of mitochondrial genomes in the early branching lineages of the monocotyledons, i.e., the Acorales and Alismatales, we are sequencing complete genomes from a suite of key taxa. As a starting point the present paper describes the mitochondrial genome of Butomus umbellatus (Butomaceae) based on next-generation sequencing data. The genome was assembled into a circular molecule, 450,826 bp in length. Coding sequences cover only 8.2% of the genome and include 28 protein coding genes, four rRNA genes, and 12 tRNA genes. Some of the tRNA genes and a 16S rRNA gene are transferred from the plastid genome. However, the total amount of recognized plastid sequences in the mitochondrial genome is only 1.5% and the amount of DNA transferred from the nucleus is also low. RNA editing is abundant and a total of 557 edited sites are predicted in the protein coding genes. Compared to the 40 angiosperm mitochondrial genomes sequenced to date, the GC content of the Butomus genome is uniquely high (49.1%). The overall similarity between the mitochondrial genomes of Butomus and Spirodela (Araceae), the closest relative yet sequenced, is low (less than 20%), and the two genomes differ in size by a factor 2. Gene order is also largely unconserved. However, based on its phylogenetic position within the core alismatids Butomus will serve as a good reference point for subsequent studies in the early branching lineages of the monocotyledons. PMID- 23637855 TI - A plea for neutral comparison studies in computational sciences. AB - In computational science literature including, e.g., bioinformatics, computational statistics or machine learning, most published articles are devoted to the development of "new methods", while comparison studies are generally appreciated by readers but surprisingly given poor consideration by many journals. This paper stresses the importance of neutral comparison studies for the objective evaluation of existing methods and the establishment of standards by drawing parallels with clinical research. The goal of the paper is twofold. Firstly, we present a survey of recent computational papers on supervised classification published in seven high-ranking computational science journals. The aim is to provide an up-to-date picture of current scientific practice with respect to the comparison of methods in both articles presenting new methods and articles focusing on the comparison study itself. Secondly, based on the results of our survey we critically discuss the necessity, impact and limitations of neutral comparison studies in computational sciences. We define three reasonable criteria a comparison study has to fulfill in order to be considered as neutral, and explicate general considerations on the individual components of a "tidy neutral comparison study". R codes for completely replicating our statistical analyses and figures are available from the companion website http://www.ibe.med.uni muenchen.de/organisation/mitarbeiter/020_professuren/boulesteix/plea2013. PMID- 23637853 TI - Proprotein convertase 1/3 (PC1/3) in the rat alveolar macrophage cell line NR8383: localization, trafficking and effects on cytokine secretion. AB - The proprotein convertase 1/3 (PC1/3) is an important post-translational processing enzyme for the activation of precursor proteins within the regulated secretory pathway. Well characterized for its role in the neural and endocrine systems, we recently reported an unconventional role of PC1/3 as a modulator of the Toll-like receptor innate immune response. There are only a few reports that have studied PC1/3 expression in macrophages, and more investigation is needed to better characterize its function. These studies would greatly benefit from model cell lines. Our study aims to identify and characterize PC1/3 in a relevant model macrophage cell line and to determine the links between PC1/3 and innate immune cellular responses. We describe the rat alveolar cell line, NR8383, as expressing PC1/3 and the most common Toll-like receptors. In NR8383 cells, PC1/3 is localized at the Trans-Golgi network and traffics to lysosome related vesicles upon lipopolysaccharide stimulation. Moreover, we report the co-localization of PC1/3 and Toll-like receptor 4 upon lipopolysaccharide stimulation. Down regulation of PC1/3 by shRNA produce a similar phenotype in NR8383 to what we previously reported in isolated peritoneal macrophages. PC1/3 shRNA induced changes in the cellular organization and expression of the specific trafficking regulator RAB GTPase. As a consequence, NR8383 down-regulated for PC1/3, present an abnormal cytokine secretion profile. We conclude that the NR8383 cell line represents a good model to study PC1/3 in macrophages and we present PC1/3 as an important regulator of vesicle trafficking and secretion in macrophages. PMID- 23637856 TI - Nonresponse to interferon-alpha based treatment for chronic hepatitis C infection is associated with increased hazard of cirrhosis. AB - BACKGROUND: The long-term consequences of unsuccessful interferon-alpha based hepatitis C treatment on liver disease progression and survival have not been fully explored. METHODS AND FINDINGS: We performed retrospective analyses to assess long-term clinical outcomes among treated and untreated patients with hepatitis C virus in two independent cohorts from a United States Veterans Affairs Medical Center and a University Teaching Hospital. Eligible patients underwent liver biopsy during consideration for interferon-alpha based treatment between 1992 and 2007. They were assessed for the probability of developing cirrhosis and of dying during follow-up using Cox proportional hazards models, stratified by pretreatment liver fibrosis stage and adjusted for known risk factors for cirrhosis and characteristics affecting treatment selection. The major predictor was a time-dependent covariate for treatment outcome among four patient groups: 1) patients with sustained virological response to treatment; 2) treatment relapsers; 3) treatment nonresponders; and 4) never treated patients. Treatment nonresponders in both cohorts had a statistically significantly increased hazard of cirrhosis compared to never treated patients, as stratified by pretreatment liver fibrosis stage and adjusted for clinical and psychosocial risk factors that disproportionately affect patients who were ineligible for treatment (Veterans Affairs HR=2.35, CI 1.18-4.69, mean follow-up 10 years, and University Hospital HR=5.90, CI 1.50-23.24, mean follow-up 7.7 years). Despite their increased risk for liver disease progression, the overall survival of nonresponders in both cohorts was not significantly different from that of never treated patients. CONCLUSION: These unexpected findings suggest that patients who receive interferon-alpha based therapies but fail to clear the hepatitis C virus may have an increased hazard of cirrhosis compared to untreated patients. PMID- 23637857 TI - Does taste matter? How anticipation of cola brands influences gustatory processing in the brain. AB - Brands surround us everywhere in daily life. Here we investigate the influences of brand cues on gustatory processing of the same beverage. Participants were led to believe that the brand that announced the administration of a Cola mixture provided correct information about the drink to come. We found stronger fMRI signal in right mOFC during weak compared to strong brand cues in a contrast of parametric modulation with subjective liking. When directly comparing the two strong brands cues, more activation in the right amygdala was found for Coca Cola cues compared with Pepsi Cola cues. During the taste phase the same beverage elicited stronger activation in left ventral striatum when it was previously announced by a strong compared with a weak brand. This effect was stronger in participants who drink Cola infrequently and might therefore point to a stronger reliance on brand cues in less experienced consumers. The present results reveal strong effects of brand labels on neural responses signalling reward. PMID- 23637858 TI - Defective lung macrophage function in lung cancer +/- chronic obstructive pulmonary disease (COPD/emphysema)-mediated by cancer cell production of PGE2? AB - In chronic obstructive pulmonary disease (COPD/emphysema) we have shown a reduced ability of lung and alveolar (AM) macrophages to phagocytose apoptotic cells (defective 'efferocytosis'), associated with evidence of secondary cellular necrosis and a resultant inflammatory response in the airway. It is unknown whether this defect is present in cancer (no COPD) and if so, whether this results from soluble mediators produced by cancer cells. We investigated efferocytosis in AM (26 controls, 15 healthy smokers, 37 COPD, 20 COPD+ non small cell lung cancer (NSCLC) and 8 patients with NSCLC without COPD) and tumor and tumor-free lung tissue macrophages (21 NSCLC with/13 without COPD). To investigate the effects of soluble mediators produced by lung cancer cells we then treated AM or U937 macrophages with cancer cell line supernatant and assessed their efferocytosis ability. We qualitatively identified Arachidonic Acid (AA) metabolites in cancer cells by LC-ESI-MSMS, and assessed the effects of COX inhibition (using indomethacin) on efferocytosis. Decreased efferocytosis was noted in all cancer/COPD groups in all compartments. Conditioned media from cancer cell cultures decreased the efferocytosis ability of both AM and U937 macrophages with the most pronounced effects occurring with supernatant from SCLC (an aggressive lung cancer type). AA metabolites identified in cancer cells included PGE2. The inhibitory effect of PGE2 on efferocytosis, and the involvement of the COX-2 pathway were shown. Efferocytosis is decreased in COPD/emphysema and lung cancer; the latter at least partially a result of inhibition by soluble mediators produced by cancer cells that include PGE2. PMID- 23637860 TI - Transcriptional and metabolic changes associated to the infection by Fusarium verticillioides in maize inbreds with contrasting ear rot resistance. AB - Fusarium verticillioides causes ear rot and grain mycotoxins in maize (Zea mays L.), which are harmful to human and animal health. Breeding and growing less susceptible plant genotypes is one alternative to reduce these detrimental effects. A better understanding of the resistance mechanisms would facilitate the implementation of strategic molecular agriculture to breeding of resistant germplasm. Our aim was to identify genes and metabolites that may be related to the Fusarium reaction in a resistant (L4637) and a susceptible (L4674) inbred. Gene expression data were obtained from microarray hybridizations in inoculated and non-inoculated kernels from both inbreds. Fungal inoculation did not produce considerable changes in gene expression and metabolites in L4637. Defense-related genes changed in L4674 kernels, responding specifically to the pathogen infection. These results indicate that L4637 resistance may be mainly due to constitutive defense mechanisms preventing fungal infection. These mechanisms seem to be poorly expressed in L4674; and despite the inoculation activate a defense response; this is not enough to prevent the disease progress in this susceptible line. Through this study, a global view of differential genes expressed and metabolites accumulated during resistance and susceptibility to F. verticillioides inoculation has been obtained, giving additional information about the mechanisms and pathways conferring resistance to this important disease in maize. PMID- 23637859 TI - Chronic restraint stress inhibits hair growth via substance P mediated by reactive oxygen species in mice. AB - BACKGROUNDS: Solid evidence has demonstrated that psychoemotional stress induced alteration of hair cycle through neuropeptide substance P (SP) mediated immune response, the role of reactive oxygen species (ROS) in brain-skin-axis regulation system remains unknown. OBJECTIVES: The present study aims to investigate possible mechanisms of ROS in regulation of SP-mast cell signal pathway in chronic restraint stress (CRS, a model of chronic psychoemotional stress) which induced abnormal of hair cycle. METHODS AND RESULTS: Our results have demonstrated that CRS actually altered hair cycle by inhibiting hair follicle growth in vivo, prolonging the telogen stage and delaying subsequent anagen and catagen stage. Up-regulation of SP protein expression in cutaneous peripheral nerve fibers and activation of mast cell were observed accompanied with increase of lipid peroxidation levels and reduction of the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in CRS mice skin. In addition, SP receptor antagonist (RP67580) reduced mast cell activations and lipid peroxidation levels as well as increased GSH-Px activity and normalized hair cycle. Furthermore, antioxidant Tempol (a free radical scavenger) also restored hair cycle, reduced SP protein expression and mast cell activation. CONCLUSIONS: Our study provides the first solid evidence for how ROS play a role in regulation of psychoemotional stress induced SP-Mast cell pathway which may provide a convincing rationale for antioxidant application in clinical treatment with psychological stress induced hair loss. PMID- 23637861 TI - Tumor angiogenesis after heated lipiodol infusion via the hepatic artery in a rabbit model of VX2 liver cancer. AB - OBJECTIVES: This study aimed to observe the changes in tumor angiogenesis after heated lipiodol (60 degrees C) infusion via the hepatic artery in a rabbit model of VX2 liver cancer. MATERIALS AND METHODS: Twenty rabbits with VX2 hepatic tumors were randomly divided into 2 groups (10 rabbits in each group). Under anesthesia, a trans-catheter hepatic arterial infusion was performed, and lipiodol (37 degrees C; control group) or heated lipiodol (60 degrees C; treated group) was injected into the hepatic arteries of the animals. Then, changes in tumor angiogenesis were assessed using the following markers and methods. 1. Vascular endothelial growth factor receptor (VEGFR) and vascular endothelial growth factor (VEGF) expression levels in the tumor were assessed using western blotting and real-time quantitative polymerase chain reaction (PCR). 2. Proliferating cell nuclear antigen (PCNA) expression in the tumor was assessed through immunohistochemical staining. 3. The morphological changes in tumor vascular endothelial cells were observed using transmission electron microscopy (TEM). RESULTS: VEGFR and VEGF mRNA and protein expression levels were reduced in the treated group compared to the control group. PCNA protein showed reduced expression levels in the treated group compared to the control group. TEM indicated that the endothelial cell endoplasmic reticulum expanded, the chondriosome was swollen, and the endothelial cell microvilli were decreased after heated lipiodol infusion. CONCLUSIONS: The tumor angiogenesis of rabbits with VX2 cancer was inhibited after arterial heated lipiodol infusion compared to lipiodol infusion. PMID- 23637862 TI - The influence of social support on hematopoietic stem cell transplantation survival: a systematic review of literature. AB - BACKGROUND: Hematopoietic Stem cell Transplantation (HSCT) can negatively impact the psychosocial well-being of the patient. Social support is a complex term that has been variably used to encompass perceived and objective support, including caregiver presence. Social support has been associated with superior psychosocial outcomes; however the influence of social support on HSCT survival remains unclear. We sought to summarize the literature on the influence of social support on HSCT survival. METHODS: MEDLINE, EMBASE, COCHRANE, CINAHL, AND PSYCINFO WERE SEARCHED USING THE FOLLOWING SEARCH CATEGORIES/CONCEPTS: 1) HSCT, 2) Social support, 3) Caregiver, 4) Survival, and 5) Treatment outcomes. RESULTS: We identified 6 relevant studies: 4 publications, 1 dissertation, and 1 abstract. Three studies were retrospective and 3, prospective. Sample size ranged between 92-272 with a mean/median patient age between 30-55 yrs. The duration of follow up ranged between 13.3-48 months. Social support was measured inconsistently: 2 by retrospective investigator assessment, 2 as patients' perceived support, 1 as caregiver presence, and 1 included caregiver presence and retrospective investigator assessment. The 4 published studies and 1 abstract demonstrate an association between better social support and survival. However, the unpublished dissertation, with the largest sample size found no association. CONCLUSIONS: There is a paucity of evidence examining social support with HSCT survival. Available studies are older, with the most recent publication in 2005. A heterogeneous group of HSCT patients were studied with variable follow-up times. Further, covariates were variably considered in HSCT survival analyses and we suggest that there may be publication bias, given the negative unpublished study with the largest sample size. Prospective studies using validated scales are necessary to better assess the influence of social support on HSCT mortality. Given the potential for improved HSCT survival with better social support, HSCT centres should routinely provide HSCT recipients and their caregivers with enhanced psychosocial services. PMID- 23637864 TI - Elevated t/e2 ratio is associated with an increased risk of cerebrovascular disease in elderly men. AB - OBJECTIVE: To investigate the relationship between sex hormones and the risk of vascular disease in elderly men and to evaluate the advantages and disadvantages of testosterone replacement. METHODS: A total of 337 men, aged 60 to 91 years, were enrolled in this single-center, cross-sectional study, and their sex hormone levels were assessed. Linear and logistic regression analyses were utilized to compare the sex hormone levels between patients with and without vascular disease. The nonparametric K-sample test was used for inter-group comparisons. RESULTS: Aging and abnormal metabolism were both significantly associated with an increased risk of vascular diseases and changes in sex hormone levels. Primary linear and logistic regression analyses showed no significant differences in sex hormone concentrations between patients with and without vascular diseases after adjusting for age. Logistic regression with abnormal metabolism as categorical variable showed that free testosterone (FT) and free estradiol (FE2) had significant relationships with CEVD risk (P<0.05). In further regression with all metabolic continuous variables included, the testosterone/estradiol (T/E2) ratio replaced FT and FE2 (P<0.05). Trend line analyses showed that T/E2 actually had a binomial linear correlation with the risk of cerebrovascular disease; its best protective effect occurred at values of 0.13-0.15, with an OR value extremely close to those of FT and FE2 (0.23 vs. 0.24-0.25). CONCLUSION: T/E2 balance plays a key role in the relationship between sex hormones and the risk of cerebrovascular disease. The balance between T and E2 may be more important than their absolute quantities. Extremely low T/E2 and inappropriately high T/E2 ratio can both harm the brain blood vessels. Careful consideration should be given before beginning testosterone replacement treatment, and supplementing with estrogen seems to be a good way to protect blood vessels of the brain in elderly men. PMID- 23637863 TI - Prevalence of p.V37I variant of GJB2 in mild or moderate hearing loss in a pediatric population and the interpretation of its pathogenicity. AB - A p.V37I variant of GJB2 has been reported from subjects with moderate or slight hearing loss especially in East Asian populations. This study aimed to estimate the prevalence of the p.V37I variant among such subjects and prove, epidemiologically, its pathogenic potential to cause mild hearing loss. A total of 380 subjects from 201 families with hearing loss were enrolled. From them, 103 families were selected who had autosomal recessive inheritance or sporadic occurrence of hearing loss and who were younger than 15 years old. GJB2 sequencing was carried out for the probands of all 103 families. The prevalence of the p.V37I variant was compared between the subtle, mild or moderate hearing loss (group I) and the severe or profound hearing loss (group II) groups. Where possible, a targeted next generation sequencing of 82 deafness genes was performed from the p.V37I carrier to exclude the existence of other pathogenic genes. Five (4.8%) of 103 probands were found to carry p.V37I. The carrier frequency of p.V37I among group I (18.2%) was significantly higher than that of group II (1.2%) or the reported Korean normal hearing control group (1.0%). Detection of the p.V37I variant of GJB2 in 18.2% of Koreans with mild hearing loss strongly suggests its contribution to the pathogenesis of milder hearing loss, which might justify sequencing of GJB2 from these subjects in the Korean population. PMID- 23637865 TI - A novel flow cytometric hemozoin detection assay for real-time sensitivity testing of Plasmodium falciparum. AB - Resistance of Plasmodium falciparum to almost all antimalarial drugs, including the first-line treatment with artemisinins, has been described, representing an obvious threat to malaria control. In vitro antimalarial sensitivity testing is crucial to detect and monitor drug resistance. Current assays have been successfully used to detect drug effects on parasites. However, they have some limitations, such as the use of radioactive or expensive reagents or long incubation times. Here we describe a novel assay to detect antimalarial drug effects, based on flow cytometric detection of hemozoin (Hz), which is rapid and does not require any additional reagents. Hz is an optimal parasite maturation indicator since its amount increases as the parasite matures. Due to its physical property of birefringence, Hz depolarizes light, hence it can be detected using optical methods such as flow cytometry. A common flow cytometer was adapted to detect light depolarization caused by Hz. Synchronized in vitro cultures of P. falciparum were incubated for 48 hours with several antimalarial drugs. Analysis of depolarizing events, corresponding to parasitized red blood cells containing Hz, allowed the detection of parasite maturation. Moreover, chloroquine resistance and the inhibitory effect of all antimalarial drugs tested, except for pyrimethamine, could be determined as early as 18 to 24 hours of incubation. At 24 hours incubation, 50% inhibitory concentrations (IC50) were comparable to previously reported values. These results indicate that the reagent-free, real time Hz detection assay could become a novel assay for the detection of drug effects on Plasmodium falciparum. PMID- 23637866 TI - Presence of human papilloma virus in a series of breast carcinoma from Argentina. AB - BACKGROUND: The etiology and the molecular mechanisms related to breast carcinogenesis remain poorly understood. Some recent reports have examined the role of Human Papillomavirus (HPV) in this disease. The purpose of this study was to determine the prevalence of HPV in breast cancer. METHODS: Sixty one fresh frozen breast cancers samples were analyzed. Samples were tested for HPV by PCR, and products were automatically sequenced. Findings were correlated with clinical and pathological characteristics. RESULTS: The HPV DNA prevalence in the breast cancer samples was 26% (16/61). Clinical parameters were not statistically associated with HPV presence (p>0.05 chi(2) test). Sequence analysis in a subgroup of cases indicates the prevalence of low risk HPV11, followed by high risk HPV16. We found no HPV transcriptional activity. CONCLUSION: The present study demonstrated for the first time in Argentina the presence of HPV in a proportion of the malignant breast tissues. This finding suggests that HPV may have a biological significance in breast carcinogenesis. PMID- 23637867 TI - Hypertonic saline reduces vascular leakage in a mouse model of severe dengue. AB - Dengue (DEN) is a mosquito-borne viral disease and represents a serious public health threat and an economical burden throughout the tropics. Dengue clinical manifestations range from mild acute febrile illness to severe DEN hemorrhagic fever/DEN shock syndrome (DHF/DSS). Currently, resuscitation with large volumes of isotonic fluid remains the gold standard of care for DEN patients who develop vascular leakage and shock. Here, we investigated the ability of small volume of hypertonic saline (HTS) suspensions to control vascular permeability in a mouse model of severe DEN associated with vascular leakage. Several HTS treatment regimens were considered and our results indicated that a single bolus of 7.5% NaCl at 4 mL per kg of body weight administered at the onset of detectable vascular leakage rapidly and significantly reduced vascular leak for several days after injection. This transient reduction of vascular leakage correlated with reduced intestine and liver damage with restoration of the hepatic functions, and resulted in delayed death of the infected animals. Mechanistically, we showed that HTS did not directly impact on the viral titers but resulted in lower immune cells counts and decreased systemic levels of soluble mediators involved in vascular permeability. In addition, we demonstrated that neutrophils do not play a critical role in DEN-associated vascular leakage and that the therapeutic effect of HTS is not mediated by its impact on the neutrophil counts. Together our data indicate that HTS treatment can transiently but rapidly reduce dengue associated vascular leakage, and support the findings of a recent clinical trial which evaluated the efficacy of a hypertonic suspension to impact on vascular permeability in DSS children. PMID- 23637868 TI - Identification of genes involved in Pseudomonas aeruginosa biofilm-specific resistance to antibiotics. AB - Pseudomonas aeruginosa is a key opportunistic pathogen characterized by its biofilm formation ability and high-level multiple antibiotic resistance. By screening a library of random transposon insertion mutants with an increased biofilm-specifc antibiotic susceptibility, we previously identified 3 genes or operons of P. aeruginosa UCBPP-PA14 (ndvB, PA1875-1877 and tssC1) that do not affect biofilm formation but are involved in biofilm-specific antibiotic resistance. In this study, we demonstrate that PA0756-0757 (encoding a putative two-component regulatory system), PA2070 and PA5033 (encoding hypothetical proteins of unknown function) display increased expression in biofilm cells and also have a role in biofilm-specific antibiotic resistance. Furthermore, deletion of each of PA0756, PA2070 and PA5033 resulted in a significant reduction of lethality in Caenorhabditis elegans, indicating a role for these genes in both biofilm-specific antibiotic resistance and persistence in vivo. Together, these data suggest that these genes are potential targets for antimicrobial agents. PMID- 23637869 TI - A simple technique based on a single optical trap for the determination of bacterial swimming pattern. AB - Bacterial motility is associated to a wide range of biological processes and it plays a key role in the virulence of many pathogens. Here we describe a method to distinguish the dynamic properties of bacteria by analyzing the statistical functions derived from the trajectories of a bacterium trapped by a single optical beam. The approach is based on the model of the rotation of a solid optically trapped sphere. The technique is easily implemented in a biological laboratory, since with only a small number of optical and electronic components a simple biological microscope can be converted into the required analyzer. To illustrate the functionality of this method, we probed several Salmonella enterica serovar Typhimurium mutants that differed from the wild-type with respect to their swimming patterns. In a further application, the motility dynamics of the S. Typhimurium cheV mutant were characterized. PMID- 23637870 TI - Paracrine effects of bone marrow soup restore organ function, regeneration, and repair in salivary glands damaged by irradiation. AB - BACKGROUND: There are reports that bone marrow cell (BM) transplants repaired irradiated salivary glands (SGs) and re-established saliva secretion. However, the mechanisms of action behind these reports have not been elucidated. METHODS: To test if a paracrine mechanism was the main effect behind this reported improvement in salivary organ function, whole BM cells were lysed and its soluble intracellular contents (termed as "BM Soup") injected into mice with irradiation injured SGs. The hypothesis was that BM Soup would protect salivary cells, increase tissue neovascularization, function, and regeneration. Two minor aims were also tested a) comparing two routes of delivering BM Soup, intravenous (I.V.) versus intra-glandular injections, and b) comparing the age of the BM Soup's donors. The treatment-comparison group consisted of irradiated mice receiving injections of living whole BM cells. Control mice received irradiation and injections of saline or sham-irradiation. All mice were followed for 8 weeks post-irradiation. RESULTS: BM Soup restored salivary flow rates to normal levels, protected salivary acinar, ductal, myoepithelial, and progenitor cells, increased cell proliferation and blood vessels, and up-regulated expression of tissue remodeling/repair/regenerative genes (MMP2, CyclinD1, BMP7, EGF, NGF). BM Soup was as an efficient therapeutic agent as injections of live BM cells. Both intra glandular or I.V. injections of BM Soup, and from both young and older mouse donors were as effective in repairing irradiated SGs. The intra-glandular route reduced injection frequency/dosage by four-fold. CONCLUSION: BM Soup, which contains only the cell by-products, can be advantageously used to repair irradiation-damaged SGs rather than transplanting whole live BM cells which carry the risk of differentiating into unwanted/tumorigenic cell types in SGs. PMID- 23637871 TI - Genetic variants and increased expression of Parascaris equorum P-glycoprotein-11 in populations with decreased ivermectin susceptibility. AB - Macrocyclic lactones (MLs) represent the major drug class for control of parasitic infections in humans and animals. However, recently reports of treatment failures became more frequent. In addition to human and ruminant parasitic nematodes this also is the case for the horse-nematode Parascaris equorum. Nevertheless, to date the molecular basis of ML resistance is still not understood. Unspecific resistance mechanisms involving transporters such as P glycoproteins (Pgps) are expected to contribute to ML resistance in nematodes. Here, complete sequences of two P. equorum Pgps were cloned and identified as orthologs of Caenorhabditis elegans Ppg-11 and an unnamed Caenorhabditis briggsae Pgp designated as Pgp-16 using phylogenetic analysis. Quantitative real-time PCR was used to compare expression between tissues. Significantly higher PeqPgp-11 expression was found in the gut for both genders, whereas for PeqPgp-16 the body wall was identified as predominant expression site. Furthermore, Pgps were analyzed regarding their participation in resistance development. Using SeqDoC analyses, Pgp-sequences of P. equorum populations with different ML susceptibility were compared. This approach revealed three single nucleotide polymorphisms (SNPs) causing missense mutations in the PeqPgp-11 sequence which correlated with decreased ML susceptibility. However, no resistance associated differences in mRNA expression levels were detected between embryonated eggs of these populations. In contrast, comparison of two pre-adult groups with different ivermectin (IVM) susceptibility revealed the presence of the three SNPs and in addition statistically significant PeqPgp-11 overexpression in the group of worms with reduced susceptibility. These results indicate that Pgp-11 might be involved in IVM resistance in P. equorum as it shows increased expression in an IVM exposed life-cycle stage of an IVM resistant population as well as occurrence of putatively resistance associated SNPs in populations with reduced IVM susceptibility. These SNPs are promising diagnostic candidates for detection of ML resistance with potential also for other parasitic nematode species. PMID- 23637872 TI - Higher risk perception of HIV than of chlamydia and HPV among secondary school students in two German cities. AB - BACKGROUND: Chlamydia and genital human papillomavirus (HPV) are the two most common sexually transmitted infections (STIs) among teens and young adults in industrialised countries. The majority of adolescents, however, have limited or no knowledge of these infections. Within the context of a cross-sectional survey on awareness and knowledge of sexually transmitted infections, secondary school students attending the 8th grade and above in Bremen and Bremerhaven, two cities in northern Germany, were asked to rate the risk of peers to get infected with HIV, HPV or chlamydia. METHODS: Between October and December 2011, students aged 12-20 years completed an anonymous, self-administered questionnaire at their school. In addition to answering questions on awareness and knowledge of sexually transmitted infections, all students were also asked to rate the risk of peers to get infected with HIV, HPV or chlamydia. Furthermore, those reporting ever having sexual intercourse were asked to rate their own risk of getting infected with each of the three infections. RESULTS: 1,148 students, 55% female, completed the questionnaire. 27% of the students reported having had sexual intercourse. 68% of all students rated the risk of same-aged students to get infected with HIV/AIDS as high/medium. The corresponding proportions for HPV and chlamydia were 19 and 25% respectively. Those reporting ever having sexual intercourse generally perceived their own risk of getting infected with HIV, chlamydia or HPV as lower than that of their peers. CONCLUSION: Generally, the risk of getting infected with HIV was perceived as being higher than that of getting infected with HPV or chlamydia, most likely due to the fact that the students were more aware of HIV than of the other two infections. Efforts should be made to improve awareness and knowledge of HPV and chlamydia among school going adolescents, and to make them realize that these are common infections that are preventable. PMID- 23637873 TI - Improved clinical outcomes of high risk beta thalassemia major patients undergoing a HLA matched related allogeneic stem cell transplant with a treosulfan based conditioning regimen and peripheral blood stem cell grafts. AB - Improving clinical outcomes among high risk Class III beta thalassemia major patients (Class IIIHR) receiving an allogeneic SCT remains a challenge. From October, 2009 a treosulfan based regimen (TreoFluT) was used for all consecutive Class III patients (n = 50). The clinical outcomes were compared with the historical conventional busulfan (BuCy) based regimen (n = 139). Use of TreoFluT was associated with a significantly reduced incidence of sinusoidal obstruction syndrome (SOS) among Class IIIHR cases (78% to 30%; P = 0.000) and early TRM (46% to 13%; p = 0.005). There was also a trend towards better engraftment in the Class IIIHR subset (P = 0.055). However, the use of bone marrow (BM) as source of stem cells along with the TreoFluT regimen was associated with 50% early mixed chimerism which reduced to 8.5% with the use of a peripheral blood stem cell graft (PBSC). Use of a PBSC graft was not associated with a significant increase in the incidence of acute or chronic graft versus host disease (GVHD). The overall and event free survival was significantly better among the Class IIIHR subset with the use of TreoFluT Vs. BuCy (86.6 +/- 7.3 Vs. 39.4 +/- 6.8%; P = 0.002 and 77.8 +/- 8.8 Vs. 32.4 +/- 6.5%; P = 0.003 respectively). A TreoFluT conditioning regimen with a PBSC graft can significantly improve clinical outcomes of Class IIIHR patients. PMID- 23637874 TI - Resveratrols in grape berry skins and leaves in vitis germplasm. AB - BACKGROUND: Resveratrol is an important stilbene that benefits human health. However, it is only distributed in a few species including grape and is very expensive. At present, grape has been an important source resveratrol. However, the details are scarce on resveratrol distribution in different Vitis species or cultivars. METHODOLOGY/PRINCIPAL FINDING: The composition and content of resveratrols were investigated by HPLC for assessing genotypic variation in berry skins and leaves of 75 grape cultivars, belonging to 3 species and 7 interspecific hybrids. Trans-resveratrol, cis-piceid and trans-piceid were detected in berry skins and leaves, but cis-resveratrol was not. Resveratrol content largely varied with genetic background as well as usage. In most cultivars, total resveratrol including the above three compounds was higher in berry skins than leaves. In berry skins of most cultivars and leaves of almost all cultivars, cis-piceid was the most abundant resveratrol; trans-resveratrol and trans-piceid were minor components. Some specific cultivars were found with extremely high levels of trans-resveratrol, cis- piceid, trans-piceid or total resveratrols in berry skins or leaves. In skins and leaves, rootstock cultivars had a higher content of total resveratrols, and the cultivated European type cultivars and their hybrids with V. labrusca had relatively low totals. There were no significant correlations of the amounts of total resveratrols or any individual resveratrol between berry skins and leaves. All 75 cultivars can be divided into four groups based on the composition of resveratrols and their concentration by principal component analysis. CONCLUSION: Resveratrol content of grape berries and leaves varied largely with their genetic background and usage. Rootstock cultivars had a higher content of total resveratrols than the other germplasm. Total resveratrols were lower in leaves than berry skins in most cultivars. Cis-piceid was the most abundant resveratrol in most cultivars, and trans-res and trans-pd were minor components. PMID- 23637875 TI - Genetic, functional and molecular features of glucocorticoid receptor binding. AB - Glucocorticoids (GCs) are key mediators of stress response and are widely used as pharmacological agents to treat immune diseases, such as asthma and inflammatory bowel disease, and certain types of cancer. GCs act mainly by activating the GC receptor (GR), which interacts with other transcription factors to regulate gene expression. Here, we combined different functional genomics approaches to gain molecular insights into the mechanisms of action of GC. By profiling the transcriptional response to GC over time in 4 Yoruba (YRI) and 4 Tuscans (TSI) lymphoblastoid cell lines (LCLs), we suggest that the transcriptional response to GC is variable not only in time, but also in direction (positive or negative) depending on the presence of specific interacting transcription factors. Accordingly, when we performed ChIP-seq for GR and NF-kappaB in two YRI LCLs treated with GC or with vehicle control, we observed that features of GR binding sites differ for up- and down-regulated genes. Finally, we show that eQTLs that affect expression patterns only in the presence of GC are 1.9-fold more likely to occur in GR binding sites, compared to eQTLs that affect expression only in its absence. Our results indicate that genetic variation at GR and interacting transcription factors binding sites influences variability in gene expression, and attest to the power of combining different functional genomic approaches. PMID- 23637876 TI - Inactivation of the CovR/S virulence regulator impairs infection in an improved murine model of Streptococcus pyogenes naso-pharyngeal infection. AB - Streptococcus pyogenes is a leading cause of pharyngeal infection, with an estimated 616 million cases per year. The human nasopharynx represents the major reservoir for all S. pyogenes infection, including severe invasive disease. To investigate bacterial and host factors that influence S. pyogenes infection, we have devised an improved murine model of nasopharyngeal colonization, with an optimized dosing volume to avoid fulminant infections and a sensitive host strain. In addition we have utilized a refined technique for longitudinal monitoring of bacterial burden that is non-invasive thereby reducing the numbers of animals required. The model was used to demonstrate that the two component regulatory system, CovR/S, is required for optimum infection and transmission from the nasopharynx. There is a fitness cost conferred by covR/S mutation that is specific to the nasopharynx. This may explain why S. pyogenes with altered covR/S have not become prevalent in community infections despite possessing a selective advantage in invasive infection. PMID- 23637877 TI - On the respiratory mechanics measured by forced oscillation technique in patients with systemic sclerosis. AB - BACKGROUND: Pulmonary complications are the most common cause of death and morbidity in systemic sclerosis (SSc). The forced oscillation technique (FOT) offers a simple and detailed approach to investigate the mechanical properties of the respiratory system. We hypothesized that SSc may introduce changes in the resistive and reactive properties of the respiratory system, and that FOT may help the diagnosis of these abnormalities. METHODOLOGY/PRINCIPAL FINDINGS: We tested these hypotheses in controls (n = 30) and patients with abnormalities classified using spirometry (n = 52) and pulmonary volumes (n = 29). Resistive data were interpreted with the zero-intercept resistance (Ri) and the slope of the resistance (S) as a function of frequency. Reactance changes were evaluated by the mean reactance between 4 and 32 Hz (Xm) and the dynamic compliance (Crs,dyn). The mechanical load was evaluated using the absolute value of the impedance in 4 Hz (Z4Hz). A compartmental model was used to obtain central (R) and peripheral (Rp) resistances, and alveolar compliance (C). The clinical usefulness was evaluated by investigating the area under the receiver operating characteristic curve (AUC). The presence of expiratory flow limitation (EFL) was also evaluated. For the groups classified using spirometry, SSc resulted in increased values in Ri, R, Rp and Z4Hz (p<0.003) and reductions in Crs,dyn, C and Xm (p<0.004). Z4Hz, C and Crs,dyn exhibited a high diagnostic accuracy (AUC>0.90). In groups classified by pulmonary volume, SSc resulted in reductions in S, Xm, C and Crs,dyn (p<0.01). Xm, C and Crs,dyn exhibited adequate diagnostic accuracy (AUC>0.80). It was also observed that EFL is not common in patients with SSc. CONCLUSIONS/SIGNIFICANCE: This study provides evidence that the respiratory resistance and reactance are changed in SSc. This analysis provides a useful description that is of particular significance for understanding respiratory pathophysiology and to ease the diagnosis of respiratory abnormalities in these patients. PMID- 23637878 TI - Serotype diversity of astroviruses in Rawalpindi, Pakistan during 2009-2010. AB - Astroviruses are globally known enteropathogens causing gastroenteritis and diarrhea, with eight well defined serotypes. Epidemiological studies have recognized serotype-1 as the most common subtype but no such data is available in Pakistan. During 2009-2010, we found astroviruses in 41 out of 535 (7%) samples collected from hospitalized children. Thirty one strains belonged to serotype-1 and clustered into two distinct lineages. Serotype-3, -4 and -6 were detected with 97-98% genetic homology to Indian and Chinese strains. PMID- 23637879 TI - An anti-phospholipase A2 receptor quantitative immunoassay and epitope analysis in membranous nephropathy reveals different antigenic domains of the receptor. AB - The phospholipase A2 receptor (PLA2R) was recently discovered as a target autoantigen in patients with idiopathic membranous nephropathy (IMN). Published evidence suggests that the autoantibodies directed towards a conformation dependent epitope are currently effectively detected by a cell based assay (CBA) utilizing indirect immunofluorescence (IIF) on tissue culture cells transfected with the PLA2R cDNA. Limitations of such IIF-CBA assays include observer dependent subjective evaluation of semi-quantitative test results and the protocols are not amenable to high throughput diagnostic testing. We developed a quantitative, observer independent, high throughput capture immunoassay for detecting PLA2R autoantibodies on an addressable laser bead immunoassay (ALBIA) platform. Since reactive domains of PLA2R (i.e. epitopes) could be used to improve diagnostic tests by using small peptides in various high throughput diagnostic platforms, we identified PLA2R epitopes that bound autoantibodies of IMN patients. These studies confirmed that inter-molecular epitope spreading occurs in IMN but use of the cognate synthetic peptides in immunoassays was unable to conclusively distinguish between IMN patients and normal controls. However, combinations of these peptides were able to effectively absorb anti PLA2R reactivity in IIF-CBA and an immunoassay that employed a lysate derived from HEK cells tranfected with and overexpressing PLA2R. While we provide evidence of intermolecular epitope spreading, our data indicates that in addition to conformational epitopes, human anti-PLA2R reactivity in a commercially available CBA and an addressable laser bead immunoassay is significantly absorbed by peptides representing epitopes of PLA2R. PMID- 23637880 TI - Smoking-specific parenting and smoking onset in adolescence: the role of genes from the dopaminergic system (DRD2, DRD4, DAT1 genotypes). AB - Although only few studies have shown direct links between dopaminergic system genes and smoking onset, this does not rule out the effect of a gene-environment interaction on smoking onset. Therefore, the aim of this study was to examine the associations between smoking-specific parenting (i.e., frequency and quality of communication and house rules) and smoking onset while considering the potential moderating role of dopaminergic system genes (i.e., DRD2, DRD4, and DAT1 genotypes). Data from five annual waves of the 'Family and Health' project were used. At time 1, the sample comprised 365 non-smoking adolescents (200 younger adolescents, mean age = 13.31, SD = .48; 165 older adolescents, mean age = 15.19, SD = .57). Advanced longitudinal analyses were used (i.e., logistic regression analyses, (dual) latent growth curves, and cross-lagged path models). The results showed a direct effect of quality of communication on smoking onset. No direct effects were found for frequency of communication and house rules. Furthermore, no direct and moderating effects of the DRD2, DRD4, or DAT1 genotypes were found. In conclusion, the findings indicated that the effects of smoking-specific parenting on smoking are similar for adolescent carriers and non-carriers of the dopaminergic system genes. PMID- 23637882 TI - Intervention effects of ganoderma lucidum spores on epileptiform discharge hippocampal neurons and expression of neurotrophin-4 and N-cadherin. AB - Epilepsy can cause cerebral transient dysfunctions. Ganoderma lucidum spores (GLS), a traditional Chinese medicinal herb, has shown some antiepileptic effects in our previous studies. This was the first study of the effects of GLS on cultured primary hippocampal neurons, treated with Mg(2+) free medium. This in vitro model of epileptiform discharge hippocampal neurons allowed us to investigate the anti-epileptic effects and mechanism of GLS activity. Primary hippocampal neurons from <1 day old rats were cultured and their morphologies observed under fluorescence microscope. Neurons were confirmed by immunofluorescent staining of neuron specific enolase (NSE). Sterile method for GLS generation was investigated and serial dilutions of GLS were used to test the maximum non-toxic concentration of GLS on hippocampal neurons. The optimized concentration of GLS of 0.122 mg/ml was identified and used for subsequent analysis. Using the in vitro model, hippocampal neurons were divided into 4 groups for subsequent treatment i) control, ii) model (incubated with Mg(2+) free medium for 3 hours), iii) GLS group I (incubated with Mg(2+) free medium containing GLS for 3 hours and replaced with normal medium and incubated for 6 hours) and iv) GLS group II (neurons incubated with Mg(2+) free medium for 3 hours then replaced with a normal medium containing GLS for 6 hours). Neurotrophin-4 and N-Cadherin protein expression were detected using Western blot. The results showed that the number of normal hippocampal neurons increased and the morphologies of hippocampal neurons were well preserved after GLS treatment. Furthermore, the expression of neurotrophin-4 was significantly increased while the expression of N-Cadherin was decreased in the GLS treated group compared with the model group. This data indicates that GLS may protect hippocampal neurons by promoting neurotrophin-4 expression and inhibiting N Cadherin expression. PMID- 23637881 TI - Single-cell dynamics reveals sustained growth during diauxic shifts. AB - Stochasticity in gene regulation has been characterized extensively, but how it affects cellular growth and fitness is less clear. We study the growth of E. coli cells as they shift from glucose to lactose metabolism, which is characterized by an obligatory growth arrest in bulk experiments that is termed the lag phase. Here, we follow the growth dynamics of individual cells at minute-resolution using a single-cell assay in a microfluidic device during this shift, while also monitoring lac expression. Mirroring the bulk results, the majority of cells displays a growth arrest upon glucose exhaustion, and resume when triggered by stochastic lac expression events. However, a significant fraction of cells maintains a high rate of elongation and displays no detectable growth lag during the shift. This ability to suppress the growth lag should provide important selective advantages when nutrients are scarce. Trajectories of individual cells display a highly non-linear relation between lac expression and growth, with only a fraction of fully induced levels being sufficient for achieving near maximal growth. A stochastic molecular model together with measured dependencies between nutrient concentration, lac expression level, and growth accurately reproduces the observed switching distributions. The results show that a growth arrest is not obligatory in the classic diauxic shift, and underscore that regulatory stochasticity ought to be considered in terms of its impact on growth and survival. PMID- 23637884 TI - beta-Glucan synthase gene overexpression and beta-glucans overproduction in Pleurotus ostreatus using promoter swapping. AB - Mushroom beta-glucans are potent immunological stimulators in medicine, but their productivities are very low. In this study, we successfully improved its production by promoter engineering in Pleurotus ostreatus. The promoter for beta 1,3-glucan synthase gene (GLS) was replaced by the promoter of glyceraldehyde-3 phosphate dehydrogenase gene of Aspergillus nidulans. The homologous recombination fragment for swapping GLS promoter comprised five segments, which were fused by two rounds of combined touchdown PCR and overlap extension PCR (TD OE PCR), and was introduced into P. ostreatus through PEG/CaCl2-mediated protoplast transformation. The transformants exhibited one to three fold higher transcription of GLS gene and produced 32% to 131% higher yield of beta-glucans than the wild type. The polysaccharide yields had a significant positive correlation to the GLS gene expression. The infrared spectra of the polysaccharides all displayed the typical absorption peaks of beta-glucans. This is the first report of successful swapping of promoters in filamentous fungi. PMID- 23637883 TI - Assembly-driven community genomics of a hypersaline microbial ecosystem. AB - Microbial populations inhabiting a natural hypersaline lake ecosystem in Lake Tyrrell, Victoria, Australia, have been characterized using deep metagenomic sampling, iterative de novo assembly, and multidimensional phylogenetic binning. Composite genomes representing habitat-specific microbial populations were reconstructed for eleven different archaea and one bacterium, comprising between 0.6 and 14.1% of the planktonic community. Eight of the eleven archaeal genomes were from microbial species without previously cultured representatives. These new genomes provide habitat-specific reference sequences enabling detailed, lineage-specific compartmentalization of predicted functional capabilities and cellular properties associated with both dominant and less abundant community members, including organisms previously known only by their 16S rRNA sequences. Together, these data provide a comprehensive, culture-independent genomic blueprint for ecosystem-wide analysis of protein functions, population structure, and lifestyles of co-existing, co-evolving microbial groups within the same natural habitat. The "assembly-driven" community genomic approach demonstrated in this study advances our ability to push beyond single gene investigations, and promotes genome-scale reconstructions as a tangible goal in the quest to define the metabolic, ecological, and evolutionary dynamics that underpin environmental microbial diversity. PMID- 23637885 TI - Permeabilization of the blood-brain barrier via mucosal engrafting: implications for drug delivery to the brain. AB - Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson's disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS. PMID- 23637886 TI - Atomic hydrogen surrounded by water molecules, H(H2O)m, modulates basal and UV induced gene expressions in human skin in vivo. AB - Recently, there has been much effort to find effective ingredients which can prevent or retard cutaneous skin aging after topical or systemic use. Here, we investigated the effects of the atomic hydrogen surrounded by water molecules, H(H2O)m, on acute UV-induced responses and as well as skin aging. Interestingly, we observed that H(H2O)m application to human skin prevented UV-induced erythema and DNA damage. And H(H2O)m significantly prevented UV-induced MMP-1, COX-2, IL-6 and IL-1beta mRNA expressions in human skin in vivo. We found that H(H2O)m prevented UV-induced ROS generation and inhibited UV-induced MMP-1, COX-2 and IL 6 expressions, and UV-induced JNK and c-Jun phosphorylation in HaCaT cells. Next, we investigated the effects of H(H2O)m on intrinsically aged or photoaged skin of elderly subjects. In intrinsically aged skin, H(H2O)m application significantly reduced constitutive expressions of MMP-1, IL-6, and IL-1beta mRNA. Additionally, H(H2O)m significantly increased procollagen mRNA and also decreased MMP-1 and IL 6 mRNA expressions in photoaged facial skin. These results demonstrated that local application of H(H2O)m may prevent UV-induced skin inflammation and can modulate intrinsic skin aging and photoaging processes. Therefore, we suggest that modifying the atmospheric gas environment within a room may be a new way to regulate skin functions or skin aging. PMID- 23637887 TI - Phosphorylation of mRNA decapping protein Dcp1a by the ERK signaling pathway during early differentiation of 3T3-L1 preadipocytes. AB - BACKGROUND: Turnover of mRNA is a critical step in the regulation of gene expression, and an important step in mRNA decay is removal of the 5' cap. We previously demonstrated that the expression of some immediate early gene mRNAs is controlled by RNA stability during early differentiation of 3T3-L1 preadipocytes. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that the mouse decapping protein Dcp1a is phosphorylated via the ERK signaling pathway during early differentiation of preadipocytes. Mass spectrometry analysis and site-directed mutagenesis combined with a kinase assay identified ERK pathway-mediated dual phosphorylation at Ser 315 and Ser 319 of Dcp1a. To understand the functional effects of Dcp1a phosphorylation, we examined protein-protein interactions between Dcp1a and other decapping components with co-immunoprecipitation. Dcp1a interacted with Ddx6 and Edc3 through its proline-rich C-terminal extension, whereas the conserved EVH1 (enabled vasodilator-stimulated protein homology 1) domain in the N terminus of Dcp1a showed a stronger interaction with Dcp2. Once ERK signaling was activated, the interaction between Dcp1a and Ddx6, Edc3, or Edc4 was not affected by Dcp1a phosphorylation. Phosphorylated Dcp1a did, however, enhanced interaction with Dcp2. Protein complexes immunoprecipitated with the recombinant phosphomimetic Dcp1a(S315D/S319D) mutant contained more Dcp2 than did those immunoprecipitated with the nonphosphorylated Dcp1a(S315A/S319A) mutant. In addition, Dcp1a associated with AU-rich element (ARE)-containing mRNAs such as MAPK phosphatase-1 (MKP-1), whose mRNA stability was analyzed under the overexpression of Dcp1a constructs in the Dcp1a knockdown 3T3-L1 cells. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that ERK-phosphorylated Dcp1a enhances its interaction with the decapping enzyme Dcp2 during early differentiation of 3T3-L1 cells. PMID- 23637888 TI - Bee venom and its component apamin as neuroprotective agents in a Parkinson disease mouse model. AB - Bee venom has recently been suggested to possess beneficial effects in the treatment of Parkinson disease (PD). For instance, it has been observed that bilateral acupoint stimulation of lower hind limbs with bee venom was protective in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In particular, a specific component of bee venom, apamin, has previously been shown to have protective effects on dopaminergic neurons in vitro. However, no information regarding a potential protective action of apamin in animal models of PD is available to date. The specific goals of the present study were to (i) establish that the protective effect of bee venom for dopaminergic neurons is not restricted to acupoint stimulation, but can also be observed using a more conventional mode of administration and to (ii) demonstrate that apamin can mimic the protective effects of a bee venom treatment on dopaminergic neurons. Using the chronic mouse model of MPTP/probenecid, we show that bee venom provides sustained protection in an animal model that mimics the chronic degenerative process of PD. Apamin, however, reproduced these protective effects only partially, suggesting that other components of bee venom enhance the protective action of the peptide. PMID- 23637890 TI - Visualizing the attack of RNase enzymes on dendriplexes and naked RNA using atomic force microscopy. AB - Cationic polymers such as poly(amidoamine), PAMAM, dendrimers have been used to electrostatically complex siRNA molecules forming dendriplexes for enhancing the cytoplasmic delivery of the encapsulated cargo. However, excess PAMAM dendrimers is typically used to protect the loaded siRNA against enzymatic attack, which results in systemic toxicity that hinders the in vivo use of these particles. In this paper, we evaluate the ability of G4 (flexible) and G5 (rigid) dendrimers to complex model siRNA molecules at low +/- ratio of 2/1 upon incubation for 20 minutes and 24 hours. We examine the ability of the formed G4 and G5 dendriplexes to shield the loaded siRNA molecules and protect them from degradation by RNase V1 enzymes using atomic force microscopy (AFM). Results show that G4 and G5 dendrimers form similar hexagonal complexes upon incubation with siRNA molecules for 20 minutes with average full width of 43+/-19.3 nm and 62+/-8.3 at half the maximum height, respectively. AFM images show that these G4 and G5 dendriplexes were attacked by RNase V1 enzyme leading to degradation of the exposed RNA molecules that increased with the increase in incubation time. In comparison, incubating G4 and G5 dendrimers with siRNA for 24 hours led to the formation of large particles with average full width of 263+/-60 nm and 48.3+/-2.5 nm at half the maximum height, respectively. Both G4 and G5 dendriplexes had a dense central core that proved to shield the loaded RNA molecules from enzymatic attack for up to 60 minutes. These results show the feasibility of formulating G4 and G5 dendriplexes at a low N/P (+/-) ratio that can resist degradation by RNase enzymes, which reduces the risk of inducing non-specific toxicity when used in vivo. PMID- 23637889 TI - 1,25-dihydroxyvitamin D3 protects against macrophage-induced activation of NFkappaB and MAPK signalling and chemokine release in human adipocytes. AB - Increased accumulation of macrophages in adipose tissue in obesity is linked to low-grade chronic inflammation, and associated with features of metabolic syndrome. Vitamin D3 may have immunoregulatory effects and reduce adipose tissue inflammation, although the molecular mechanisms remain to be established. This study investigated the effects of vitamin D3 on macrophage-elicited inflammatory responses in cultured human adipocytes, particularly the signalling pathways involved. Macrophage-conditioned (MC) medium (25% with adipocyte maintenance media) markedly inhibited protein expression of the nuclear factor-kappaB (NFkappaB) subunit inhibitor kappaBalpha (IkappaBalpha) (71%, P<0.001) and increased NFkappaB p65 (1.5-fold, P = 0.026) compared with controls. Treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) abolished macrophage-induced activation of NFkappaB signalling by increasing IkappaBalpha expression (2.7 fold, P = 0.005) and reducing NFkappaB p65 phosphorylation (68%; P<0.001). The mitogen-activated protein kinase (MAPK) signalling was activated by MC medium, which was also blunted by 1,25(OH)2D3 with a downregulation of phosphorylated p38 MAPK (32%, P = 0.005) and phosphorylated Erk1/2 (49%, P = 0.001). Furthermore, MC medium (12.5% or 25%) dose-dependently upregulated secretion of key proinflammatory chemokines/cytokines (22-368-fold; all P<0.001) and this was significantly decreased by 1,25(OH)2D3: IL-8 (61% and 31%, P<0.001), MCP-1 (37%, P<0.001 and 36%, P = 0.002), RANTES (78% and 62%, P<0.001) and IL-6 (29%, P<0.001 and 34%, P = 0.019). Monocyte migration-elicited by adipocytes treated with 1,25(OH)2D3 was also reduced (up to 25%, P<0.001). In conclusion, vitamin D3 could be anti-inflammatory in adipose tissue, decreasing macrophage-induced release of chemokines and cytokines by adipocytes and the chemotaxis of monocytes. Our data suggests these effects are mediated by inhibition of the NFkappaB and MAPK signalling pathways. PMID- 23637891 TI - The association between health system development and the burden of cardiovascular disease: an analysis of WHO country profiles. AB - BACKGROUND: Several risk factors for cardiovascular disease (CVD) have been identified in recent decades. However, the association between the health system and the burden of CVD has not yet been sufficiently researched. The objective of this study was to analyse the association between health system development and the burden of CVD, in particular CVD-related disability-adjusted life-years (DALYs). METHODS: Univariate and multivariate generalized linear mixed models were applied to country-level data collected by the World Bank and World Health Organization. Response variables were the age-standardized CVD mortality and age standardized CVD DALY rates. RESULTS: The amount of available health system resources, indicated by total health expenditures per capita, physician density, nurse density, dentistry density, pharmaceutical density and the density of hospital beds, was associated with reduced CVD DALY rates and CVD mortality. However, in the multivariate models, the density of nurses and midwives was positively associated with CVD. High out-of-pocket costs were associated with increased CVD mortality in both univariate and multivariate analyses. CONCLUSION: A highly developed health system with a low level of out-of-pocket costs seems to be the most appropriate to reduce the burden of CVD. Furthermore, an efficient balance between human health resources and health technologies is essential. PMID- 23637892 TI - The impact of the February 2012 cold spell on health in Italy using surveillance data. AB - In February 2012 Italy was hit by an exceptional cold spell with extremely low temperatures and heavy snowfall. The aim of this work is to estimate the impact of the cold spell on health in the Italian cities using data from the rapid surveillance systems. In Italy, a national mortality surveillance system has been operational since 2004 in 34 cities for the rapid monitoring of daily mortality. Data from this system were used to evaluate the impact of the February 2012 cold spell on mortality shortly after the occurrence of the event. Furthermore, a cause-specific analysis was conducted in Roma using the Regional Mortality Registry and the emergency visits (ER) surveillance system. Cold spell episodes were defined as days when mean temperatures were below the 10(th) percentile of February distribution for more than three days. To estimate the impact of the cold spell, excess mortality was calculated as the difference between observed and daily expected values. An overall 1578 (+25%) excess deaths among the 75+ age group was recorded in the 14 cities that registered a cold spell in February 2012. A statistically significant excess in mortality was observed in several cities ranging from +22% in Bologna to +58% in Torino. Cause-specific analysis conducted in Roma showed a statistically significant excess in mortality among the 75+ age group for respiratory disease (+64%), COPD (+57%), cardiovascular disease +20% ischemic heart disease (14%) and other heart disease (+33%). Similar results were observed for ER visits. Surveillance systems need to become are a key component of prevention plans as they can help improve public health response and are a valid data source to rapidly quantify the impact on health. Cold related mortality is still an important issue and should not be underestimated by public health Authorities. PMID- 23637893 TI - Social calls produced within and near the roost in two species of tent-making bats, Dermanura watsoni and Ectophylla alba. AB - Social animals regularly face the problem of relocating conspecifics when separated. Communication is one of the most important mechanisms facilitating group formation and cohesion. Known as contact calls, signals exchanged between conspecifics that permit group maintenance are widespread across many taxa. Foliage-roosting bats are an excellent model system for studying the evolution of contact calling, as there are opportunities to compare closely related species that exhibit major differences in ecology and behavior. Further, foliage-roosting bats rely on relatively ephemeral roosts, which leads to major challenges in maintaining group cohesion. Here, we report findings on the communication signals produced by two tent-making bats, Dermanura watsoni and Ectophylla alba. We found that both species produced calls in the early morning near the roost that were associated with roostmate recruitment. Calling often ended once other bats arrived at the tent, suggesting that calls may be involved in roostmate recruitment and group formation. The structure and function of these calls are described and future research directions are discussed. PMID- 23637895 TI - Simultaneous analysis and quality assurance for diffusion tensor imaging. AB - Diffusion tensor imaging (DTI) enables non-invasive, cyto-architectural mapping of in vivo tissue microarchitecture through voxel-wise mathematical modeling of multiple magnetic resonance imaging (MRI) acquisitions, each differently sensitized to water diffusion. DTI computations are fundamentally estimation processes and are sensitive to noise and artifacts. Despite widespread adoption in the neuroimaging community, maintaining consistent DTI data quality remains challenging given the propensity for patient motion, artifacts associated with fast imaging techniques, and the possibility of hardware changes/failures. Furthermore, the quantity of data acquired per voxel, the non-linear estimation process, and numerous potential use cases complicate traditional visual data inspection approaches. Currently, quality inspection of DTI data has relied on visual inspection and individual processing in DTI analysis software programs (e.g. DTIPrep, DTI-studio). However, recent advances in applied statistical methods have yielded several different metrics to assess noise level, artifact propensity, quality of tensor fit, variance of estimated measures, and bias in estimated measures. To date, these metrics have been largely studied in isolation. Herein, we select complementary metrics for integration into an automatic DTI analysis and quality assurance pipeline. The pipeline completes in 24 hours, stores statistical outputs, and produces a graphical summary quality analysis (QA) report. We assess the utility of this streamlined approach for empirical quality assessment on 608 DTI datasets from pediatric neuroimaging studies. The efficiency and accuracy of quality analysis using the proposed pipeline is compared with quality analysis based on visual inspection. The unified pipeline is found to save a statistically significant amount of time (over 70%) while improving the consistency of QA between a DTI expert and a pool of research associates. Projection of QA metrics to a low dimensional manifold reveal qualitative, but clear, QA-study associations and suggest that automated outlier/anomaly detection would be feasible. PMID- 23637894 TI - Partial agonism of taurine at gamma-containing native and recombinant GABAA receptors. AB - Taurine is a semi-essential sulfonic acid found at high concentrations in plasma and mammalian tissues which regulates osmolarity, ion channel activity and glucose homeostasis. The structural requirements of GABAA-receptors (GABAAR) gated by taurine are not yet known. We determined taurine potency and efficacy relative to GABA at different types of recombinant GABAAR occurring in central histaminergic neurons of the mouse hypothalamic tuberomamillary nucleus (TMN) which controls arousal. At binary alpha(1/2)beta(1/3) receptors taurine was as efficient as GABA, whereas incorporation of the gamma(1/2) subunit reduced taurine efficacy to 60-90% of GABA. The mutation gamma(2F77I), which abolishes zolpidem potentiation, significantly reduced taurine efficacy at recombinant and native receptors compared to the wild type controls. As taurine was a full- or super- agonist at recombinant alphaxbeta1delta-GABAAR, we generated a chimeric gamma(2) subunit carrying the delta subunit motif around F77 (MTVFLH). At alpha(1/2)beta(1)gamma2(MTVFLH) receptors taurine became a super-agonist, similar to delta-containing ternary receptors, but remained a partial agonist at beta3 containing receptors. In conclusion, using site-directed mutagenesis we found structural determinants of taurine's partial agonism at gamma-containing GABAA receptors. Our study sheds new light on the beta1 subunit conferring the widest range of taurine-efficacies modifying GABAAR function under (patho)physiological conditions. PMID- 23637897 TI - Genetic hitchhiking under heterogeneous spatial selection pressures. AB - During adaptive evolutionary processes substantial heterogeneity in selective pressure might act across local habitats in sympatry. Examples are selection for drug resistance in malaria or herbicide resistance in weeds. In such setups standard population-genetic assumptions (homogeneous constant selection pressures, random mating etc.) are likely to be violated. To avoid misinferences on the strength and pattern of natural selection it is therefore necessary to adjust population-genetic theory to meet the specifics driving adaptive processes in particular organisms. We introduce a deterministic model in which selection acts heterogeneously on a population of haploid individuals across different patches over which the population randomly disperses every generation. A fixed proportion of individuals mates exclusively within patches, whereas the rest mates randomly across all patches. We study how the allele frequencies at neutral markers are affected by the spread of a beneficial mutation at a closely linked locus (genetic hitchhiking). We provide an analytical solution for the frequency change and the expected heterozygosity at the neutral locus after a single copy of a beneficial mutation became fixed. We furthermore provide approximations of these solutions which allow for more obvious interpretations. In addition, we validate the results by stochastic simulations. Our results show that the application of standard population-genetic theory is accurate as long as differences across selective environments are moderate. However, if selective differences are substantial, as for drug resistance in malaria, herbicide resistance in weeds, or insecticide resistance in agriculture, it is necessary to adapt available theory to the specifics of particular organisms. PMID- 23637896 TI - Drosophila ste-20 family protein kinase, hippo, modulates fat cell proliferation. AB - BACKGROUND: Evolutionarily conserved Hippo (Hpo) pathway plays a pivotal role in the control of organ size. Although the Hpo pathway regulates proliferation of a variety of epidermal cells, its function in non-ectoderm-derived cells is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Through methods including fat quantification assays, starvation assays, in vivo labeling assays, we show that overexpression of Hpo in Drosophila melanogaster fat body restricts Drosophila body growth and reduces fat storage through regulation of adipocyte proliferation rather than through influencing the size of fat cells and lipid metabolism, whereas compromising Hpo activity results in weight gain and greater fat storage. Furthermore, we provide evidence that Yorkie (Yki, a transcriptional coactivator that functions in the Hpo pathway) antagonizes Hpo to modulate fat storage in Drosophila. CONCLUSIONS/SIGNIFICANCE: Our findings specify a role of Hpo in controlling mesoderm-derived cell proliferation. The observed anti-obesity effects of Hpo may indicate great potential for its utilization in anti-obesity therapeutics. PMID- 23637898 TI - Toxicological effects of the different substances in tobacco smoke on human embryonic development by a systems chemo-biology approach. AB - The physiological and molecular effects of tobacco smoke in adult humans and the development of cancer have been well described. In contrast, how tobacco smoke affects embryonic development remains poorly understood. Morphological studies of the fetuses of smoking pregnant women have shown various physical deformities induced by constant fetal exposure to tobacco components, especially nicotine. In addition, nicotine exposure decreases fetal body weight and bone/cartilage growth in addition to decreasing cranial diameter and tibia length. Unfortunately, the molecular pathways leading to these morphological anomalies are not completely understood. In this study, we applied interactome data mining tools and small compound interaction networks to elucidate possible molecular pathways associated with the effects of tobacco smoke components during embryonic development in pregnant female smokers. Our analysis showed a relationship between nicotine and 50 additional harmful substances involved in a variety of biological process that can cause abnormal proliferation, impaired cell differentiation, and increased oxidative stress. We also describe how nicotine can negatively affect retinoic acid signaling and cell differentiation through inhibition of retinoic acid receptors. In addition, nicotine causes a stress reaction and/or a pro inflammatory response that inhibits the agonistic action of retinoic acid. Moreover, we show that the effect of cigarette smoke on the developing fetus could represent systemic and aggressive impacts in the short term, causing malformations during certain stages of development. Our work provides the first approach describing how different tobacco constituents affect a broad range of biological process in human embryonic development. PMID- 23637899 TI - Vanillin inhibits translation and induces messenger ribonucleoprotein (mRNP) granule formation in saccharomyces cerevisiae: application and validation of high content, image-based profiling. AB - Vanillin, generated by acid hydrolysis of lignocellulose, acts as a potent inhibitor of the growth of the yeast Saccharomyces cerevisiae. Here, we investigated the cellular processes affected by vanillin using high-content, image-based profiling. Among 4,718 non-essential yeast deletion mutants, the morphology of those defective in the large ribosomal subunit showed significant similarity to that of vanillin-treated cells. The defects in these mutants were clustered in three domains of the ribosome: the mRNA tunnel entrance, exit and backbone required for small subunit attachment. To confirm that vanillin inhibited ribosomal function, we assessed polysome and messenger ribonucleoprotein granule formation after treatment with vanillin. Analysis of polysome profiles showed disassembly of the polysomes in the presence of vanillin. Processing bodies and stress granules, which are composed of non translating mRNAs and various proteins, were formed after treatment with vanillin. These results suggest that vanillin represses translation in yeast cells. PMID- 23637900 TI - Primary breast cancer tumours contain high amounts of IgA1 immunoglobulin: an immunohistochemical analysis of a possible carrier of the tumour-associated Tn antigen. AB - The Tn antigen (GalNAc alpha-O-Ser/Thr) as defined by the binding of the lectin, helix pomatia agglutinin (HPA) or anti-Tn monoclonal antibodies, is known to be exposed in a majority of cancers, and it has also been shown to correlate positively with the metastatic capacity in breast carcinoma. The short O-glycan that forms the antigen is carried by a number of different proteins. One potential carrier of the Tn antigen is immunoglobulin A1 (IgA1), which we surprisingly found in tumour cells of the invasive parts of primary breast carcinoma. Conventional immunohistochemical analysis of paraffin-embedded sections from primary breast cancers showed IgA1 to be present in the cytoplasm and plasma membrane of 35 out of 36 individual primary tumours. The immunohistochemical staining of HPA and anti-Tn antibody (GOD3-2C4) did to some extent overlap with the presence of IgA1 in the tumours, but differences were seen in the percentage of stained cells and in the staining pattern in the different breast cancers analysed. Anti-Tn antibody and HPA were also shown to specifically bind to a number of possible constellations of the Tn antigen in the hinge region of IgA1. Both reagents could also detect the presence of Tn positive IgA in serum. On average 51% of the tumour cells in the individual breast cancer tumour sections showed staining for IgA1. The overall amount of staining in the invasive part of the tumour with the anti Tn antibody was 67%, and 93% with HPA. The intra-expression or uptake of IgA1 in breast cancer makes it a new potential carrier of the tumour associated and immunogenic Tn antigen. PMID- 23637901 TI - Pyrazine analogues are active components of wolf urine that induce avoidance and freezing behaviours in mice. AB - BACKGROUND: The common grey wolf (Canis lupus) is found throughout the entire Northern hemisphere and preys on many kinds of mammals. The urine of the wolf contains a number of volatile constituents that can potentially be used for predator-prey chemosignalling. Although wolf urine is put to practical use to keep rabbits, rodents, deer and so on at bay, we are unaware of any prior behavioural studies or chemical analyses regarding the fear-inducing impact of wolf urine on laboratory mice. METHODOLOGY/PRINCIPAL FINDINGS: Three wolf urine samples harvested at different times were used in this study. All of them induced stereotypical fear-associated behaviors (i.e., avoidance and freezing) in female mice. The levels of certain urinary volatiles varied widely among the samples. To identify the volatiles that provoked avoidance and freezing, behavioural, chemical, and immunohistochemical analyses were performed. One of the urine samples (sample C) had higher levels of 2,6-dimethylpyrazine (DMP), trimethylpyrazine (TMP), and 3-ethyl-2,5-dimethyl pyrazine (EDMP) compared with the other two urine samples (samples A and B). In addition, sample C induced avoidance and freezing behaviours more effectively than samples A and B. Moreover, only sample C led to pronounced expression of Fos-immunoreactive cells in the accessory olfactory bulb (AOB) of female mice. Freezing behaviour and Fos immunoreactivity were markedly enhanced when the mice were confronted with a mixture of purified DMP, TMP, and EDMP vs. any one pyrazine alone. CONCLUSIONS/SIGNIFICANCE: The current results suggest that wolf urinary volatiles can engender aversive and fear-related responses in mice. Pyrazine analogues were identified as the predominant active components among these volatiles to induce avoidance and freezing behaviours via stimulation of the murine AOB. PMID- 23637902 TI - A comprehensive, multi-scale dynamical model of ErbB receptor signal transduction in human mammary epithelial cells. AB - The non-receptor tyrosine kinase Src and receptor tyrosine kinase epidermal growth factor receptor (EGFR/ErbB1) have been established as collaborators in cellular signaling and their combined dysregulation plays key roles in human cancers, including breast cancer. In part due to the complexity of the biochemical network associated with the regulation of these proteins as well as their cellular functions, the role of Src in EGFR regulation remains unclear. Herein we present a new comprehensive, multi-scale dynamical model of ErbB receptor signal transduction in human mammary epithelial cells. This model, constructed manually from published biochemical literature, consists of 245 nodes representing proteins and their post-translational modifications sites, and over 1,000 biochemical interactions. Using computer simulations of the model, we find it is able to reproduce a number of cellular phenomena. Furthermore, the model predicts that overexpression of Src results in increased endocytosis of EGFR in the absence/low amount of the epidermal growth factor (EGF). Our subsequent laboratory experiments also suggest increased internalization of EGFR upon Src overexpression under EGF-deprived conditions, further supporting this model generated hypothesis. PMID- 23637903 TI - Representation of early sensory experience in the adult auditory midbrain: implications for vocal learning. AB - Vocal learning in songbirds and humans occurs by imitation of adult vocalizations. In both groups, vocal learning includes a perceptual phase during which juveniles birds and infants memorize adult vocalizations. Despite intensive research, the neural mechanisms supporting this auditory memory are still poorly understood. The present functional MRI study demonstrates that in adult zebra finches, the right auditory midbrain nucleus responds selectively to the copied vocalizations. The selective signal is distinct from selectivity for the bird's own song and does not simply reflect acoustic differences between the stimuli. Furthermore, the amplitude of the selective signal is positively correlated with the strength of vocal learning, measured by the amount of song that experimental birds copied from the adult model. These results indicate that early sensory experience can generate a long-lasting memory trace in the auditory midbrain of songbirds that may support song learning. PMID- 23637904 TI - Donor safety in living donor liver transplantation: a single-center analysis of 300 cases. AB - AIM: To evaluate the safety to donors of living-donor liver transplantation. METHODS: This study included 300 consecutive living liver tissue donors who underwent operations at our center from July 2002 to December 2012. We evaluated the safety of donors with regard to three aspects complications were recorded prospectively and stratified by grade according to Clavien's classification, and the data were compared in two stages (the first 5 years' experience (pre-January 2008) and the latter 5 years' experience (post-January 2008); laboratory tests such as liver function and blood biochemistry were performed; and the health related quality of life was evaluated. RESULTS: There was no donor mortality at our center, and the overall morbidity rate was 25.3%. Most of the complications of living donors were either grade I or II. There were significantly fewer complications in the latter period of our study than in the initial period (19.9% vs 32.6%, P<0.001), and biliary complications were the most common complications, with an incidence of 9%. All of the liver dysfunction was temporary; however, the post-operative suppression of platelet count lasted for years. Although within the normal range, eight years after operation, 22 donors showed lower platelet levels (189 * 10(9)/L) compared with the pre-operative levels (267 * 10(9)/L) (P<0.05). A total of 98.4% of donors had returned to their previous levels of social activity and work, and 99.2% of donors would donate again if it was required and feasible. With the exception of two donors who experienced grade III complications (whose recipients died) and a few cases of abdominal discomfort, fatigue, chronic pain and scar itching, none of the living donors were affected by physical problems. CONCLUSION: With careful donor selection and specialized patient care, low morbidity rates and satisfactory long-term recovery can be achieved after hepatectomy for living-donor liver transplantation. PMID- 23637906 TI - Genetic variation in the HN and SH genes of mumps viruses: a comparison of strains from mumps cases with and without neurological symptoms. AB - BACKGROUND: It is known that mumps virus (MuV) strains may vary in their neurovirulent capacity, and certain MuV strains may be highly neurotropic. In animal models and epidemiological studies, mutations at specific amino acids (aa) have been proposed to be associated with neurovirulence. To assess whether these genetic variations can be observed in clinical samples from patients and if they correlate with neurovirulence as determined by clinical symptoms, 39 mumps patients with or without neurological symptoms were investigated. PRINCIPAL FINDINGS: Respiratory samples, oral fluids, throat swabs, and neurological and cerebrospinal fluid samples were tested by RT-PCR and products sequenced. Sequences of the entire small hydrophobic (SH) gene and the partial hemagglutinin neuraminidase (HN) gene were compared. CONCLUSIONS: The results showed there was no significant difference between the samples of the two groups of patients at the aa sites in either the HN protein or the SH protein, which have previously been hypothesized to be associated with neurovirulence or antigenicity. The occurrence of neurological symptoms of mumps does not appear to be due to a single point mutation in either the HN or SH gene. PMID- 23637905 TI - Serine proteolytic pathway activation reveals an expanded ensemble of wound response genes in Drosophila. AB - After injury to the animal epidermis, a variety of genes are transcriptionally activated in nearby cells to regenerate the missing cells and facilitate barrier repair. The range and types of diffusible wound signals that are produced by damaged epidermis and function to activate repair genes during epidermal regeneration remains a subject of very active study in many animals. In Drosophila embryos, we have discovered that serine protease function is locally activated around wound sites, and is also required for localized activation of epidermal repair genes. The serine protease trypsin is sufficient to induce a striking global epidermal wound response without inflicting cell death or compromising the integrity of the epithelial barrier. We developed a trypsin wounding treatment as an amplification tool to more fully understand the changes in the Drosophila transcriptome that occur after epidermal injury. By comparing our array results with similar results on mammalian skin wounding we can see which evolutionarily conserved pathways are activated after epidermal wounding in very diverse animals. Our innovative serine protease-mediated wounding protocol allowed us to identify 8 additional genes that are activated in epidermal cells in the immediate vicinity of puncture wounds, and the functions of many of these genes suggest novel genetic pathways that may control epidermal wound repair. Additionally, our data augments the evidence that clean puncture wounding can mount a powerful innate immune transcriptional response, with different innate immune genes being activated in an interesting variety of ways. These include puncture-induced activation only in epidermal cells in the immediate vicinity of wounds, or in all epidermal cells, or specifically in the fat body, or in multiple tissues. PMID- 23637907 TI - Diosmin alleviates retinal edema by protecting the blood-retinal barrier and reducing retinal vascular permeability during ischemia/reperfusion injury. AB - BACKGROUND AND PURPOSE: Retinal swelling, leading to irreversible visual impairment, is an important early complication in retinal ischemia/reperfusion (I/R) injury. Diosmin, a naturally occurring flavonoid glycoside, has been shown to have antioxidative and anti-inflammatory effects against I/R injury. The present study was performed to evaluate the retinal microvascular protective effect of diosmin in a model of I/R injury. METHODS: Unilateral retinal I/R was induced by increasing intraocular pressure to 110 mm Hg for 60 min followed by reperfusion. Diosmin (100 mg/kg) or vehicle solution was administered intragastrically 30 min before the onset of ischemia and then daily after I/R injury until the animals were sacrificed. Rats were evaluated for retinal functional injury by electroretinogram (ERG) just before sacrifice. Retinas were harvested for HE staining, immunohistochemistry assay, ELISA, and western blotting analysis. Evans blue (EB) extravasation was determined to assess blood retinal barrier (BRB) disruption and the structure of tight junctions (TJ) was examined by transmission electron microscopy. RESULTS: Diosmin significantly ameliorated the reduction of b-wave, a-wave, and b/a ratio in ERG, alleviated retinal edema, protected the TJ structure, and reduced EB extravasation. All of these effects of diosmin were associated with increased zonular occluden-1 (ZO-1) and occludin protein expression and decreased VEGF/PEDF ratio. CONCLUSIONS: Maintenance of TJ integrity and reduced permeability of capillaries as well as improvements in retinal edema were observed with diosmin treatment, which may contribute to preservation of retinal function. This protective effect of diosmin may be at least partly attributed to its ability to regulate the VEGF/PEDF ratio. PMID- 23637908 TI - Vaccination using recombinants influenza and adenoviruses encoding amastigote surface protein-2 are highly effective on protection against Trypanosoma cruzi infection. AB - In the present study we evaluated the protection raised by immunization with recombinant influenza viruses carrying sequences coding for polypeptides corresponding to medial and carboxi-terminal moieties of Trypanosoma cruzi 's amastigote surface protein 2 (ASP2). Those viruses were used in sequential immunization with recombinant adenovirus (heterologous prime-boost immunization protocol) encoding the complete sequence of ASP2 (Ad-ASP2) in two mouse strains (C57BL/6 and C3H/He). The CD8 effector response elicited by this protocol was comparable to that observed in mice immunized twice with Ad-ASP2 and more robust than that observed in mice that were immunized once with Ad-ASP2. Whereas a single immunization with Ad-ASP2 sufficed to completely protect C57BL/6 mice, a higher survival rate was observed in C3H/He mice that were primed with recombinant influenza virus and boosted with Ad-ASP2 after being challenged with T. cruzi. Analyzing the phenotype of CD8+ T cells obtained from spleen of vaccinated C3H/He mice we observed that heterologous prime-boost immunization protocol elicited more CD8+ T cells specific for the immunodominant epitope as well as a higher number of CD8+ T cells producing TNF-alpha and IFN-gamma and a higher mobilization of surface marker CD107a. Taken together, our results suggest that immunodominant subpopulations of CD8+ T elicited after immunization could be directly related to degree of protection achieved by different immunization protocols using different viral vectors. Overall, these results demonstrated the usefulness of recombinant influenza viruses in immunization protocols against Chagas Disease. PMID- 23637909 TI - Genetic susceptibility to refractive error: association of vasoactive intestinal peptide receptor 2 (VIPR2) with high myopia in Chinese. AB - Myopia is the most common ocular disease worldwide. We investigated the association of high myopia with the common single nucleotide polymorphisms (SNPs) of five candidate genes - early growth response 1 (EGR1), v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS), jun oncogene (JUN), vasoactive intestinal peptide (VIP), and vasoactive intestinal peptide receptor 2 (VIPR2). We recruited 1200 unrelated Chinese subjects with 600 cases (spherical equivalent <=-8.00 diopters) and 600 controls (spherical equivalent within +/-1.00 diopter). A discovery sample set was formed from 300 cases and 300 controls, and a replication sample set from the remaining samples. Tag SNPs were genotyped for the discovery sample set, and the most significant haplotypes and their constituent SNPs were followed up with the replication sample set. The allele and haplotype frequencies in cases and controls were compared by logistic regression adjusted for sex and age to give P a values, and multiple comparisons were corrected by permutation test to give P aemp values. Odd ratios (OR) were calculated accordingly. In the discovery phase, EGR1, JUN and VIP did not show any significant association while FOS and VIPR2 demonstrated significant haplotype association with high myopia. In the replication phase, the haplotype association for VIPR2 was successfully replicated, but not FOS. In analysis combining both sample sets, the most significant association signals of VIPR2 were the single marker rs2071625 (P a = 0.0008, P aemp = 0.0046 and OR = 0.75) and the 4-SNP haplotype window rs2071623-rs2071625-rs2730220-rs885863 (omnibus test, P a = 9.10e-10 and P aemp = 0.0001) with one protective haplotype (GGGG: P aemp = 0.0002 and OR = 0.52) and one high-risk haplotype (GAGA: P aemp = 0.0027 and OR = 4.68). This 4-SNP haplotype window was the most significant in all sample sets examined. This is the first study to suggest a role of VIPR2 in the genetic susceptibility to high myopia. EGR1, JUN, FOS and VIP are unlikely to be important in predisposing humans to high myopia. PMID- 23637910 TI - Epigenetic inactivation of Notch-Hes pathway in human B-cell acute lymphoblastic leukemia. AB - The Notch pathway can have both oncogenic and tumor suppressor roles, depending on cell context. For example, Notch signaling promotes T cell differentiation and is leukemogenic in T cells, whereas it inhibits early B cell differentiation and acts as a tumor suppressor in B cell leukemia where it induces growth arrest and apoptosis. The regulatory mechanisms that contribute to these opposing roles are not understood. Aberrant promoter DNA methylation and histone modifications are associated with silencing of tumor suppressor genes and have been implicated in leukemogenesis. Using methylated CpG island amplification (MCA)/DNA promoter microarray, we identified Notch3 and Hes5 as hypermethylated in human B cell acute lymphoblastic leukemia (ALL). We investigated the methylation status of other Notch pathway genes by bisulfite pyrosequencing. Notch3, JAG1, Hes2, Hes4 and Hes5 were frequently hypermethylated in B leukemia cell lines and primary B ALL, in contrast to T-ALL cell lines and patient samples. Aberrant methylation of Notch3 and Hes5 in B-ALL was associated with gene silencing and was accompanied by decrease of H3K4 trimethylation and H3K9 acetylation and gain of H3K9 trimethylation and H3K27 trimethylation. 5-aza-2'-deoxycytidine treatment restored Hes5 expression and decreased promoter hypermethylation in most leukemia cell lines and primary B-ALL samples. Restoration of Hes5 expression by lentiviral transduction resulted in growth arrest and apoptosis in Hes5 negative B-ALL cells but not in Hes5 expressing T-ALL cells. These data suggest that epigenetic modifications are implicated in silencing of tumor suppressor of Notch/Hes pathway in B-ALL. PMID- 23637913 TI - Quantifying collective attention from tweet stream. AB - Online social media are increasingly facilitating our social interactions, thereby making available a massive "digital fossil" of human behavior. Discovering and quantifying distinct patterns using these data is important for studying social behavior, although the rapid time-variant nature and large volumes of these data make this task difficult and challenging. In this study, we focused on the emergence of "collective attention" on Twitter, a popular social networking service. We propose a simple method for detecting and measuring the collective attention evoked by various types of events. This method exploits the fact that tweeting activity exhibits a burst-like increase and an irregular oscillation when a particular real-world event occurs; otherwise, it follows regular circadian rhythms. The difference between regular and irregular states in the tweet stream was measured using the Jensen-Shannon divergence, which corresponds to the intensity of collective attention. We then associated irregular incidents with their corresponding events that attracted the attention and elicited responses from large numbers of people, based on the popularity and the enhancement of key terms in posted messages or "tweets." Next, we demonstrate the effectiveness of this method using a large dataset that contained approximately 490 million Japanese tweets by over 400,000 users, in which we identified 60 cases of collective attentions, including one related to the Tohoku oki earthquake. "Retweet" networks were also investigated to understand collective attention in terms of social interactions. This simple method provides a retrospective summary of collective attention, thereby contributing to the fundamental understanding of social behavior in the digital era. PMID- 23637912 TI - Reactive oxygen species-activated nanoprodrug of Ibuprofen for targeting traumatic brain injury in mice. AB - Traumatic brain injury (TBI) is an enormous public health problem, with 1.7 million new cases of TBI recorded annually by the Centers for Disease Control. However, TBI has proven to be an extremely challenging condition to treat. Here, we apply a nanoprodrug strategy in a mouse model of TBI. The novel nanoprodrug contains a derivative of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen in an emulsion with the antioxidant alpha-tocopherol. The ibuprofen derivative, Ibu2TEG, contains a tetra ethylene glycol (TEG) spacer consisting of biodegradable ester bonds. The biodegradable ester bonds ensure that the prodrug molecules break down hydrolytically or enzymatically. The drug is labeled with the fluorescent reporter Cy5.5 using nonbiodegradable bonds to 1-octadecanethiol, allowing us to reliably track its accumulation in the brain after TBI. We delivered a moderate injury using a highly reproducible mouse model of closed skull controlled cortical impact to the parietal region of the cortex, followed by an injection of the nanoprodrug at a dose of 0.2 mg per mouse. The blood brain barrier is known to exhibit increased permeability at the site of injury. We tested for accumulation of the fluorescent drug particles at the site of injury using confocal and bioluminescence imaging of whole brains and brain slices 36 hours after administration. We demonstrated that the drug does accumulate preferentially in the region of injured tissue, likely due to an enhanced permeability and retention (EPR) phenomenon. The use of a nanoprodrug approach to deliver therapeutics in TBI represents a promising potential therapeutic modality. PMID- 23637911 TI - Identification of genes and pathways related to phenol degradation in metagenomic libraries from petroleum refinery wastewater. AB - Two fosmid libraries, totaling 13,200 clones, were obtained from bioreactor sludge of petroleum refinery wastewater treatment system. The library screening based on PCR and biological activity assays revealed more than 400 positive clones for phenol degradation. From these, 100 clones were randomly selected for pyrosequencing in order to evaluate the genetic potential of the microorganisms present in wastewater treatment plant for biodegradation, focusing mainly on novel genes and pathways of phenol and aromatic compound degradation. The sequence analysis of selected clones yielded 129,635 reads at an estimated 17 fold coverage. The phylogenetic analysis showed Burkholderiales and Rhodocyclales as the most abundant orders among the selected fosmid clones. The MG-RAST analysis revealed a broad metabolic profile with important functions for wastewater treatment, including metabolism of aromatic compounds, nitrogen, sulphur and phosphorus. The predicted 2,276 proteins included phenol hydroxylases and cathecol 2,3- dioxygenases, involved in the catabolism of aromatic compounds, such as phenol, byphenol, benzoate and phenylpropanoid. The sequencing of one fosmid insert of 33 kb unraveled the gene that permitted the host, Escherichia coli EPI300, to grow in the presence of aromatic compounds. Additionally, the comparison of the whole fosmid sequence against bacterial genomes deposited in GenBank showed that about 90% of sequence showed no identity to known sequences of Proteobacteria deposited in the NCBI database. This study surveyed the functional potential of fosmid clones for aromatic compound degradation and contributed to our knowledge of the biodegradative capacity and pathways of microbial assemblages present in refinery wastewater treatment system. PMID- 23637915 TI - Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis. AB - BACKGROUND: Differences in cytokine/chemokine profiles among patients with neuromyelitis optica (NMO), relapsing remitting multiple sclerosis (RRMS), and primary progressive MS (PPMS), and the relationships of these profiles with clinical and neuroimaging features are unclear. A greater understanding of these profiles may help in differential diagnosis. METHODS/PRINCIPAL FINDINGS: We measured 27 cytokines/chemokines and growth factors in CSF collected from 20 patients with NMO, 26 with RRMS, nine with PPMS, and 18 with other non inflammatory neurological diseases (OND) by multiplexed fluorescent bead-based immunoassay. Interleukin (IL)-17A, IL-6, CXCL8 and CXCL10 levels were significantly higher in NMO patients than in OND and RRMS patients at relapse, while granulocyte-colony stimulating factor (G-CSF) and CCL4 levels were significantly higher in NMO patients than in OND patients. In NMO patients, IL-6 and CXCL8 levels were positively correlated with disability and CSF protein concentration while IL-6, CXCL8, G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-gamma were positively correlated with CSF neutrophil counts at the time of sample collection. In RRMS patients, IL-6 levels were significantly higher than in OND patients at the relapse phase while CSF cell counts were negatively correlated with the levels of CCL2. Correlation coefficients of cytokines/chemokines in the relapse phase were significantly different in three combinations, IL-6 and GM-CSF, G-CSF and GM-CSF, and GM-CSF and IFN-gamma, between RRMS and NMO/NMOSD patients. In PPMS patients, CCL4 and CXCL10 levels were significantly higher than in OND patients. CONCLUSIONS: Our findings suggest distinct cytokine/chemokine alterations in CSF exist among NMO, RRMS and PPMS. In NMO, over-expression of a cluster of Th17- and Th1-related proinflammatory cytokines/chemokines is characteristic, while in PPMS, increased CCL4 and CXCL10 levels may reflect on-going low grade T cell and macrophage/microglia inflammation in the central nervous system. In RRMS, only a mild elevation of proinflammatory cytokines/chemokines was detectable at relapse. PMID- 23637914 TI - Minor hypospadias: the "tip of the iceberg" of the partial androgen insensitivity syndrome. AB - BACKGROUND: Androgens are critical in male external genital development. Alterations in the androgen sensitivity pathway have been identified in severely undermasculinized boys, and mutations of the androgen receptor gene (AR) are usually found in partial or complete androgen insensitivity syndrome (AIS). OBJECTIVE: The aim of this study was to determine whether even the most minor forms of isolated hypospadias are associated with AR mutations and thus whether all types of hypospadias warrant molecular analysis of the AR. MATERIALS AND METHODS: Two hundred and ninety-two Caucasian children presenting with isolated hypospadias without micropenis or cryptorchidism and 345 controls were included prospectively. Mutational analysis of the AR through direct sequencing (exons 1 8) was performed. In silico and luciferase functional assays were performed for unreported variants. RESULTS: Five missense mutations of the AR were identified in 9 patients with glandular or penile anterior (n = 5), penile midshaft (n = 2) and penile posterior (n = 2) hypospadias, i.e., 3%: p.Q58L (c.173A>T), 4 cases of p.P392S (c.1174C>T), 2 cases of p.A475V (c.1424C>T), p.D551H (c.1651G>C) and p.Q799E (c.2395C>G). None of these mutations was present in the control group. One mutation has never been reported to date (p.D551H). It was predicted to be damaging based on 6 in silico models, and in vitro functional studies confirmed the lowered transactivation function of the mutated protein. Three mutations have never been reported in patients with genital malformation but only in isolated infertility: p.Q58L, p.P392S, and p.A475V. It is notable that micropenis, a cardinal sign of AIS, was not present in any patient. CONCLUSION: AR mutations may play a role in the cause of isolated hypospadias, even in the most minor forms. Identification of this underlying genetic alteration may be important for proper diagnosis and longer follow-up is necessary to find out if the mutations cause differences in sexual function and fertility later in life. PMID- 23637916 TI - Non-steroidal anti-inflammatory drugs decrease E2F1 expression and inhibit cell growth in ovarian cancer cells. AB - Epidemiological studies have shown that the regular use of non-steroidal anti inflammatory (NSAIDs) drugs is associated with a reduced risk of various cancers. In addition, in vitro and experiments in mouse models have demonstrated that NSAIDs decrease tumor initiation and/or progression of several cancers. However, there are limited preclinical studies investigating the effects of NSAIDs in ovarian cancer. Here, we have studied the effects of two NSAIDs, diclofenac and indomethacin, in ovarian cancer cell lines and in a xenograft mouse model. Diclofenac and indomethacin treatment decreased cell growth by inducing cell cycle arrest and apoptosis. In addition, diclofenac and indomethacin reduced tumor volume in a xenograft model of ovarian cancer. To identify possible molecular pathways mediating the effects of NSAID treatment in ovarian cancer, we performed microarray analysis of ovarian cancer cells treated with indomethacin or diclofenac. Interestingly, several of the genes found downregulated following diclofenac or indomethacin treatment are transcriptional target genes of E2F1. E2F1 was downregulated at the mRNA and protein level upon treatment with diclofenac and indomethacin, and overexpression of E2F1 rescued cells from the growth inhibitory effects of diclofenac and indomethacin. In conclusion, NSAIDs diclofenac and indomethacin exert an anti-proliferative effect in ovarian cancer in vitro and in vivo and the effects of NSAIDs may be mediated, in part, by downregulation of E2F1. PMID- 23637918 TI - The association between pulse wave velocity and cognitive function: the Sydney Memory and Ageing Study. AB - OBJECTIVES: Pulse wave velocity (PWV) is a measure of arterial stiffness and its increase with ageing has been associated with damage to cerebral microvessels and cognitive impairment. This study examined the relationship between carotid femoral PWV and specific domains of cognitive function in a non-demented elderly sample. METHOD: Data were drawn from the Sydney Memory and Ageing Study, a cohort study of non-demented community-dwelling individuals aged 70-90 years, assessed in successive waves two years apart. In Wave 2, PWV and cognitive function were measured in 319 participants. Linear regression was used to analyse the cross sectional relationship between arterial stiffness and cognitive function in the whole sample, and separately for men and women. Analysis of covariance was used to assess potential differences in cognition between subjects with PWV measurements in the top and bottom tertiles of the cohort. Covariates were age, education, body mass index, pulse rate, systolic blood pressure, cholesterol, depression, alcohol, smoking, hormone replacement therapy, apolipoprotein E epsilon4 genotype, use of anti-hypertensive medications, history of stroke, transient ischemic attack, myocardial infarction, angina, diabetes, and also sex for the whole sample analyses. RESULTS: There was no association between PWV and cognition after Bonferroni correction for multiple testing. When examining this association for males and females separately, an association was found in males, with higher PWV being associated with lower global cognition and memory, however, a significant difference between PWV and cognition between males and females was not found. CONCLUSION: A higher level of PWV was not associated with lower cognitive function in the whole sample. PMID- 23637917 TI - Interventions for American cutaneous and mucocutaneous leishmaniasis: a systematic review update. AB - INTRODUCTION: Leishmaniasis is an important public health problem in the Americas. A Cochrane review published in 2009 analyzed 38 randomized controlled trials (RCT). We conducted a systematic review to evaluate the effects of therapeutic interventions for American cutaneous and mucocutaneous leishmaniasis. METHODS: All studies were extracted from PubMed, Embase, Lilacs (2009 to July, 2012 respectively), the Cochrane Central Register of Controlled Trials (6-2012) and references of identified publications. RCTs' risk of bias was assessed. RESULTS: We identified 1865 references of interest; we finally included 10 new RCTs. The risk of bias scored low or unclear for most domains. Miltefosine was not significantly different from meglumine antimoniate in the complete cure rate at 6 months (4 RCT; 584 participants; ITT; RR: 1.12; 95%CI: 0.85 to 1.47; I2 78%). However a significant difference in the rate of complete cure favoring miltefosine at 6 months was found in L. panamensis and L. guyanensis (2 RCTs, 206 participants; ITT; RR: 1.22; 95%CI: 1.02 to 1.46; I2 0%). One RCT found that meglumine antimoniate was superior to pentamidine in the rate of complete cure for L. braziliensis (80 participants, ITT; RR: 2.21; 95%CI: 1.41 to 3.49), while another RCT assessing L. guyanensis did not find any significant difference. Although meta-analysis of three studies found a significant difference in the rate of complete cure at 3 months favoring imiquimod versus placebo (134 participants; ITT; RR: 1.45; 95%CI: 1.12 to 1.88; I2 0%), no significant differences were found at 6 and 12 months. Thermotherapy and nitric oxide were not superior to meglumine antimoniate. CONCLUSION: Therapeutic interventions for American cutaneous and mucocutaneous leishmaniasis are varied and should be decided according to the context. Since mucosal disease is the more neglected form of leishmaniasis a multicentric trial should be urgently considered. PMID- 23637920 TI - GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. AB - Disseminated tumor cells (DTCs) are believed to lie dormant in the marrow before they can be activated to form metastases. How DTCs become dormant in the marrow and how dormant DTCs escape dormancy remains unclear. Recent work has shown that prostate cancer (PCa) cell lines express the growth-arrest specific 6 (GAS6) receptors Axl, Tyro3, and Mer, and become growth arrested in response to GAS6. We therefore hypothesized that GAS6 signaling regulates the proliferative activity of DTCs in the marrow. To explore this possibility, in vivo studies were performed where it was observed that when Tyro3 expression levels exceed Axl expression, the PCa cells exhibit rapid growth. When when Axl levels predominate, PCa cells remain largely quiescent. These findings suggest that a balance between the expression of Axl and Tyro3 is associated with a molecular switch between a dormant and a proliferative phenotype in PCa metastases. PMID- 23637919 TI - Extracellular matrix aggregates from differentiating embryoid bodies as a scaffold to support ESC proliferation and differentiation. AB - Embryonic stem cells (ESCs) have emerged as potential cell sources for tissue engineering and regeneration owing to its virtually unlimited replicative capacity and the potential to differentiate into a variety of cell types. Current differentiation strategies primarily involve various growth factor/inducer/repressor concoctions with less emphasis on the substrate. Developing biomaterials to promote stem cell proliferation and differentiation could aid in the realization of this goal. Extracellular matrix (ECM) components are important physiological regulators, and can provide cues to direct ESC expansion and differentiation. ECM undergoes constant remodeling with surrounding cells to accommodate specific developmental event. In this study, using ESC derived aggregates called embryoid bodies (EB) as a model, we characterized the biological nature of ECM in EB after exposure to different treatments: spontaneously differentiated and retinoic acid treated (denoted as SPT and RA, respectively). Next, we extracted this treatment-specific ECM by detergent decellularization methods (Triton X-100, DOC and SDS are compared). The resulting EB ECM scaffolds were seeded with undifferentiated ESCs using a novel cell seeding strategy, and the behavior of ESCs was studied. Our results showed that the optimized protocol efficiently removes cells while retaining crucial ECM and biochemical components. Decellularized ECM from SPT EB gave rise to a more favorable microenvironment for promoting ESC attachment, proliferation, and early differentiation, compared to native EB and decellularized ECM from RA EB. These findings suggest that various treatment conditions allow the formulation of unique ESC-ECM derived scaffolds to enhance ESC bioactivities, including proliferation and differentiation for tissue regeneration applications. PMID- 23637921 TI - Trends in breast cancer stage and mortality in Michigan (1992-2009) by race, socioeconomic status, and area healthcare resources. AB - The long-term effect of socioeconomic status (SES) and healthcare resources availability (HCA) on breast cancer stage of presentation and mortality rates among patients in Michigan is unclear. Using data from the Michigan Department of Community Health (MDCH) between 1992 and 2009, we calculated annual proportions of late-stage diagnosis and age-adjusted breast cancer mortality rates by race and zip code in Michigan. SES and HCA were defined at the zip-code level. Joinpoint regression was used to compare the Average Annual Percent Change (AAPC) in the median zip-code level percent late stage diagnosis and mortality rate for blacks and whites and for each level of SES and HCA. Between 1992 and 2009, the proportion of late stage diagnosis increased among white women [AAPC = 1.0 (0.4, 1.6)], but was statistically unchanged among black women [AAPC = -0.5 (-1.9, 0.8)]. The breast cancer mortality rate declined among whites [AAPC = -1.3% ( 1.8,-0.8)], but remained statistically unchanged among blacks [AAPC = -0.3% ( 0.3, 1.0)]. In all SES and HCA area types, disparities in percent late stage between blacks and whites appeared to narrow over time, while the differences in breast cancer mortality rates between blacks and whites appeared to increase over time. PMID- 23637923 TI - Dynamics of an infectious keratoconjunctivitis outbreak by Mycoplasma conjunctivae on Pyrenean Chamois Rupicapra p. pyrenaica. AB - Between 2006 and 2008, an outbreak of Infectious Keratoconjunctivitis (IKC) affected Pyrenean chamois Rupicapra p. pyrenaica, an endemic subspecies of mountain ungulate that lives in the Pyrenees. The study focused on 14 mountain massifs (180,000 ha) where the species' population is stable. Cases of IKC were detected in ten of the massifs and, in five of them, mortality was substantial. The outbreak spread quickly from the first location detected, with two peaks in mortality that affected one (2007) and three (2008) massifs. In the latter, the peak was seasonal (spring to autumn) and, in the former, the outbreak persisted through winter. To identify the outbreak's aetiology, we examined 105 Pyrenean chamois clinically affected with IKC. TaqMan rt-PCR identified Mycoplasma conjunctivae in 93 (88.5%) of the chamois. Another rt-PCR detected Chlamydophila spp. in 14 of chamois, and 12 of those had mixed infections with mycoplasmas. In the period 2000-2007, the chamois population increased slightly (lambda 1.026) but decreased significantly during the IKC outbreak (lambda 0.8, 2007-2008; lambda 0.85, 2008-2009) before increasing significantly after the outbreak (lambda 1.1, 2009-2010). Sex-biased mortality shifted the adult sex ratio toward males (from 0.6 to 0.7 males per female) and reduced productivity slightly. Hunting was practically banned in the massifs where chamois experienced significant mortality and allowed again after the outbreak ended. Long-term monitoring of wild populations provides a basis for understanding the impacts of disease outbreaks and improves management decisions, particularly when species are subject to extractive exploitation. PMID- 23637922 TI - A single-dose PLGA encapsulated protective antigen domain 4 nanoformulation protects mice against Bacillus anthracis spore challenge. AB - Bacillus anthracis, the etiological agent of anthrax, is a major bioterror agent. Vaccination is the most effective prophylactic measure available against anthrax. Currently available anthrax vaccines have issues of the multiple booster dose requirement, adjuvant-associated side effects and stability. Use of biocompatible and biodegradable nanoparticles to deliver the antigens to immune cells could solve the issues associated with anthrax vaccines. We hypothesized that the delivery of a stable immunogenic domain 4 of protective antigen (PAD4) of Bacillus anthracis encapsulated in a poly (lactide-co-glycolide) (PLGA)--an FDA approved biocompatible and biodegradable material, may alleviate the problems of booster dose, adjuvant toxicity and stability associated with anthrax vaccines. We made a PLGA based protective antigen domain 4 nanoparticle (PAD4-NP) formulation using water/oil/water solvent evaporation method. Nanoparticles were characterized for antigen content, morphology, size, polydispersity and zeta potential. The immune correlates and protective efficacy of the nanoparticle formulation was evaluated in Swiss Webster outbred mice. Mice were immunized with single dose of PAD4-NP or recombinant PAD4. The PAD4-NP elicited a robust IgG response with mixed IgG1 and IgG2a subtypes, whereas the control PAD4 immunized mice elicited low IgG response with predominant IgG1 subtype. The PAD4-NP generated mixed Th1/Th2 response, whereas PAD4 elicited predominantly Th2 response. When we compared the efficacy of this single-dose vaccine nanoformulation PAD4-NP with that of the recombinant PAD4 in providing protective immunity against a lethal challenge with Bacillus anthracis spores, the median survival of PAD4-NP immunized mice was 6 days as compared to 1 day for PAD4 immunized mice (p<0.001). Thus, we demonstrate, for the first time, the possibility of the development of a single-dose and adjuvant-free protective antigen based anthrax vaccine in the form of PAD4-NP. Further work in this direction may produce a better and safer candidate anthrax vaccine. PMID- 23637924 TI - Metagenomic identification of bacterioplankton taxa and pathways involved in microcystin degradation in lake erie. AB - Cyanobacterial harmful blooms (CyanoHABs) that produce microcystins are appearing in an increasing number of freshwater ecosystems worldwide, damaging quality of water for use by human and aquatic life. Heterotrophic bacteria assemblages are thought to be important in transforming and detoxifying microcystins in natural environments. However, little is known about their taxonomic composition or pathways involved in the process. To address this knowledge gap, we compared the metagenomes of Lake Erie free-living bacterioplankton assemblages in laboratory microcosms amended with microcystins relative to unamended controls. A diverse array of bacterial phyla were responsive to elevated supply of microcystins, including Acidobacteria, Actinobacteria, Bacteroidetes, Planctomycetes, Proteobacteria of the alpha, beta, gamma, delta and epsilon subdivisions and Verrucomicrobia. At more detailed taxonomic levels, Methylophilales (mainly in genus Methylotenera) and Burkholderiales (mainly in genera Bordetella, Burkholderia, Cupriavidus, Polaromonas, Ralstonia, Polynucleobacter and Variovorax) of Betaproteobacteria were suggested to be more important in microcystin degradation than Sphingomonadales of Alphaproteobacteria. The latter taxa were previously thought to be major microcystin degraders. Homologs to known microcystin-degrading genes (mlr) were not overrepresented in microcystin-amended metagenomes, indicating that Lake Erie bacterioplankton might employ alternative genes and/or pathways in microcystin degradation. Genes for xenobiotic metabolism were overrepresented in microcystin-amended microcosms, suggesting they are important in bacterial degradation of microcystin, a phenomenon that has been identified previously only in eukaryotic systems. PMID- 23637926 TI - IL-6 expression regulates tumorigenicity and correlates with prognosis in bladder cancer. AB - Identification of potential tumor markers will help stratify and identify a tumor's malignant potential and its response to specific therapies. IL-6 has been reported to be a predictor in various cancers. Therefore, the present study was performed to highlight the role of IL-6 in improving treatment and determining prognosis of bladder cancer. The human bladder cancer cell lines HT1376 and HT1197 were selected for cell and animal experiments, in which biological changes after experimental manipulation of IL-6 were explored, including tumor behavior and related signaling in bladder cancer. In addition, clinical specimens from 85 patients with muscle-invasive, and 50 with non-muscle invasive bladder cancers were selected for immunohistochemical staining to evaluate the predictive capacity of IL-6 in relation to clinical outcome. The data revealed that IL-6 was overexpressed in the bladder cancer specimens compared with non-malignant tissues at both mRNA and protein levels. Positive staining of IL-6 was significantly correlated with higher clinical stage, higher recurrence rate after curative treatment, and reduced survival rate. Tumor growth and invasive capability were attenuated when IL-6 was blocked. The underlying changes included decreased cell proliferation, less epithelial-mesenchymal transition (EMT), decreased DNA methyltransferase 1 expression and attenuated angiogenesis. In conclusion, our findings showed that IL-6 could be a significant predictor for clinical stage and prognosis of bladder cancer. Moreover, targeting IL-6 may be a promising strategy for treating bladder cancer. PMID- 23637925 TI - Infectious events prior to chemotherapy initiation in children with acute myeloid leukemia. AB - BACKGROUND: The primary objective was to describe infectious complications in children with acute myeloid leukemia from presentation to the healthcare system to initiation of chemotherapy and to describe how these infections differ depending on neutropenia. METHODS: We conducted a retrospective, population-based cohort study that included children and adolescents with acute myeloid leukemia diagnosed and treated at 15 Canadian centers. We evaluated infections that occurred between presentation to the healthcare system (for symptoms that led to the diagnosis of acute myeloid leukemia) until initiation of chemotherapy. RESULTS: Among 328 children, 92 (28.0%) were neutropenic at presentation. Eleven (3.4%) had sterile-site microbiologically documented infection and four had bacteremia (only one Gram negative). Infection rate was not influenced by neutropenia. No child died from an infectious cause prior to chemotherapy initiation. CONCLUSION: It may be reasonable to withhold empiric antibiotics in febrile non-neutropenic children with newly diagnosed acute myeloid leukemia until initiation of chemotherapy as long as they appear well without a clinical focus of infection. Future work could examine biomarkers or a clinical score to identify children presenting with leukemia and fever who are more likely to have an invasive infection. PMID- 23637928 TI - 2009 A(H1N1) seroconversion rates and risk factors among the general population in Vientiane Capital, Laos. AB - OBJECTIVE: To assess 2009 A(H1N1) seroconversion rates and their determinants within an unvaccinated population in Vientiane Capital, Laos. METHODS: CoPanFlu Laos, a general population cohort of 807 households and 4,072 participants was established in March 2010. Sociodemographic data, epidemiological data, and capillary blood samples were collected from all the household members in March, and again in October 2010, in order to assess the level of antibodies to 2009 A(H1N1) with the haemagglutination inhibition assay. 2009 A(H1N1) seroconversion was defined as a fourfold or greater increase in titre between inclusion and follow-up. Determinants for pandemic influenza infection were studied using the generalized estimating equations model, taking household clustering into account. RESULTS: Between March and November 2010, 3,524 paired sera were tested. Prior to the pandemic, our cohort was almost completely vaccine-naive for seasonal influenza. The overall seroconversion rate among nonvaccinated individuals (n = 2,810) was 14.3% (95%CI [13.0, 15.6]), with the highest rate for participants under 20 yo (19.8%, 95%CI [17.4, 22.4]) and the lowest rate for participants over 60 yo (6.5%, 95%CI [3.7, 10.4]). Participants with lower baseline titres had significantly higher infection rates, with a dose-effect relationship. Odds ratios (ORs) ranged from 76.5 (95%CI [27.1, 215.8]), for those with a titre at inclusion of 1?10, to 8.1 (95%CI [3.3, 20.4]), for those with a titre of 1?40. Having another household member with a titre >=1?80 was associated with a higher likelihood of immunity (OR = 3.3, 95%CI [2.8, 3.9]). CONCLUSION: The determinants and age distribution for seroconversion within a vaccine-naive population were similar to those found in developed countries. This pandemic was characterized by strong epidemiological determinants, regardless of geographical zone and level of development. Moreover, we detected pre-existing cross-reacting antibodies in participants over 60 yo, which could not have originated from former multiple vaccination as has been suggested elsewhere. PMID- 23637929 TI - Use of exposure history to identify patterns of immunity to pneumonia in bighorn sheep (Ovis canadensis). AB - Individual host immune responses to infectious agents drive epidemic behavior and are therefore central to understanding and controlling infectious diseases. However, important features of individual immune responses, such as the strength and longevity of immunity, can be challenging to characterize, particularly if they cannot be replicated or controlled in captive environments. Our research on bighorn sheep pneumonia elucidates how individual bighorn sheep respond to infection with pneumonia pathogens by examining the relationship between exposure history and survival in situ. Pneumonia is a poorly understood disease that has impeded the recovery of bighorn sheep (Ovis canadensis) following their widespread extirpation in the 1900s. We analyzed the effects of pneumonia exposure history on survival of 388 radio-collared adults and 753 ewe-lamb pairs. Results from Cox proportional hazards models suggested that surviving ewes develop protective immunity after exposure, but previous exposure in ewes does not protect their lambs during pneumonia outbreaks. Paradoxically, multiple exposures of ewes to pneumonia were associated with diminished survival of their offspring during pneumonia outbreaks. Although there was support for waning and boosting immunity in ewes, models with consistent immunizing exposure were similarly supported. Translocated animals that had not previously been exposed were more likely to die of pneumonia than residents. These results suggest that pneumonia in bighorn sheep can lead to aging populations of immune adults with limited recruitment. Recovery is unlikely to be enhanced by translocating naive healthy animals into or near populations infected with pneumonia pathogens. PMID- 23637927 TI - Common genetic variation in the human FNDC5 locus, encoding the novel muscle derived 'browning' factor irisin, determines insulin sensitivity. AB - AIMS/HYPOTHESIS: Recently, the novel myokine irisin was described to drive adipose tissue 'browning', to increase energy expenditure, and to improve obesity and insulin resistance in high fat-fed mice. Here, we assessed whether common single nucleotide polymorphisms (SNPs) in the FNDC5 locus, encoding the irisin precursor, contribute to human prediabetic phenotypes (overweight, glucose intolerance, insulin resistance, impaired insulin release). METHODS: A population of 1,976 individuals was characterized by oral glucose tolerance tests and genotyped for FNDC5 tagging SNPs. Subgroups underwent hyperinsulinaemic euglycaemic clamps, magnetic resonance imaging/spectroscopy, and intravenous glucose tolerance tests. From 37 young and 14 elderly participants recruited in two different centres, muscle biopsies were obtained for the preparation of human myotube cultures. RESULTS: After appropriate adjustment and Bonferroni correction for the number of tested variants, SNPs rs16835198 and rs726344 were associated with in vivo measures of insulin sensitivity. Via interrogation of publicly available data from the Meta-Analyses of Glucose and Insulin-related traits Consortium, rs726344's effect on insulin sensitivity was replicated. Moreover, novel data from human myotubes revealed a negative association between FNDC5 expression and appropriately adjusted in vivo measures of insulin sensitivity in young donors. This finding was replicated in myotubes from elderly men. CONCLUSIONS/INTERPRETATION: This study provides evidence that the FNDC5 gene, encoding the novel myokine irisin, determines insulin sensitivity in humans. Our gene expression data point to an unexpected insulin-desensitizing effect of irisin. PMID- 23637930 TI - Protease-activated receptor (PAR)2, but not PAR1, is involved in collateral formation and anti-inflammatory monocyte polarization in a mouse hind limb ischemia model. AB - AIMS: In collateral development (i.e. arteriogenesis), mononuclear cells are important and exist as a heterogeneous population consisting of pro-inflammatory and anti-inflammatory/repair-associated cells. Protease-activated receptor (PAR)1 and PAR2 are G-protein-coupled receptors that are both expressed by mononuclear cells and are involved in pro-inflammatory reactions, while PAR2 also plays a role in repair-associated responses. Here, we investigated the physiological role of PAR1 and PAR2 in arteriogenesis in a murine hind limb ischemia model. METHODS AND RESULTS: PAR1-deficient (PAR1-/-), PAR2-deficient (PAR2-/-) and wild-type (WT) mice underwent femoral artery ligation. Laser Doppler measurements revealed reduced post-ischemic blood flow recovery in PAR2-/- hind limbs when compared to WT, while PAR1-/- mice were not affected. Upon ischemia, reduced numbers of smooth muscle actin (SMA)-positive collaterals and CD31-positive capillaries were found in PAR2-/- mice when compared to WT mice, whereas these parameters in PAR1 /- mice did not differ from WT mice. The pool of circulating repair-associated (Ly6C-low) monocytes and the number of repair-associated (CD206-positive) macrophages surrounding collaterals in the hind limbs were increased in WT and PAR1-/- mice, but unaffected in PAR2-/- mice. The number of repair-associated macrophages in PAR2-/- hind limbs correlated with CD11b- and CD115-expression on the circulating monocytes in these animals, suggesting that monocyte extravasation and M-CSF-dependent differentiation into repair-associated cells are hampered. CONCLUSION: PAR2, but not PAR1, is involved in arteriogenesis and promotes the repair-associated response in ischemic tissues. Therefore, PAR2 potentially forms a new pro-arteriogenic target in coronary artery disease (CAD) patients. PMID- 23637931 TI - Metagenomic analysis of a tropical composting operation at the sao paulo zoo park reveals diversity of biomass degradation functions and organisms. AB - Composting operations are a rich source for prospection of biomass degradation enzymes. We have analyzed the microbiomes of two composting samples collected in a facility inside the Sao Paulo Zoo Park, in Brazil. All organic waste produced in the park is processed in this facility, at a rate of four tons/day. Total DNA was extracted and sequenced with Roche/454 technology, generating about 3 million reads per sample. To our knowledge this work is the first report of a composting whole-microbial community using high-throughput sequencing and analysis. The phylogenetic profiles of the two microbiomes analyzed are quite different, with a clear dominance of members of the Lactobacillus genus in one of them. We found a general agreement of the distribution of functional categories in the Zoo compost metagenomes compared with seven selected public metagenomes of biomass deconstruction environments, indicating the potential for different bacterial communities to provide alternative mechanisms for the same functional purposes. Our results indicate that biomass degradation in this composting process, including deconstruction of recalcitrant lignocellulose, is fully performed by bacterial enzymes, most likely by members of the Clostridiales and Actinomycetales orders. PMID- 23637933 TI - Cholesteryl esters accumulate in the heart in a porcine model of ischemia and reperfusion. AB - Myocardial ischemia is associated with intracellular accumulation of lipids and increased depots of myocardial lipids are linked to decreased heart function. Despite investigations in cell culture and animal models, there is little data available on where in the heart the lipids accumulate after myocardial ischemia and which lipid species that accumulate. The aim of this study was to investigate derangements of lipid metabolism that are associated with myocardial ischemia in a porcine model of ischemia and reperfusion. The large pig heart enables the separation of the infarct area with irreversible injury from the area at risk with reversible injury and the unaffected control area. The surviving myocardium bordering the infarct is exposed to mild ischemia and is stressed, but remains viable. We found that cholesteryl esters accumulated in the infarct area as well as in the bordering myocardium. In addition, we found that expression of the low density lipoprotein receptor (LDLr) and the low density lipoprotein receptor related protein 1 (LRP1) was up-regulated, suggesting that choleteryl ester uptake is mediated via these receptors. Furthermore, we found increased ceramide accumulation, inflammation and endoplasmatic reticulum (ER) stress in the infarcted area of the pig heart. In addition, we found increased levels of inflammation and ER stress in the myocardium bordering the infarct area. Our results indicate that lipid accumulation in the heart is one of the metabolic derangements remaining after ischemia, even in the myocardium bordering the infarct area. Normalizing lipid levels in the myocardium after ischemia would likely improve myocardial function and should therefore be considered as a target for treatment. PMID- 23637932 TI - Androgens upregulate Cdc25C protein by inhibiting its proteasomal and lysosomal degradation pathways. AB - Cdc25C is a cell cycle protein of the dual specificity phosphatase family essential for activating the cdk1/Cyclin B1 complex in cells entering into mitosis. Since altered cell cycle is a hallmark of human cancers, we investigated androgen regulation of Cdc25C protein in human prostate cancer (PCa) cells, including androgen-sensitive (AS) LNCaP C-33 cells and androgen-independent (AI) LNCaP C-81 as well as PC-3 cells. In the regular culture condition containing fetal bovine serum (FBS), Cdc25C protein levels were similar in these PCa cells. In a steroid-reduced condition, Cdc25C protein was greatly decreased in AS C-33 cells but not AI C-81 or PC-3 cells. In androgen-treated C-33 cells, the Cdc25C protein level was greatly elevated, following a dose- and a time-dependent manner, correlating with increased cell proliferation. This androgen effect was blocked by Casodex, an androgen receptor blocker. Nevertheless, epidermal growth factor (EGF), a growth stimulator of PCa cells, could only increase Cdc25C protein level by about 1.5-fold. Altered expression of Cdc25C in C-33 cells and PC-3 cells by cDNA and/or shRNA transfection is associated with the corresponding changes of cell growth and Cyclin B1 protein level. Actinomycin D and cycloheximide could only partially block androgen-induced Cdc25C protein level. Treatments with both proteasomal and lysosomal inhibitors resulted in elevated Cdc25C protein levels. Immunoprecipitation revealed that androgens reduced the ubiquitination of Cdc25C proteins. These results show for the first time that Cdc25C protein plays a role in regulating PCa cell growth, and androgen treatments, but not EGF, greatly increase Cdc25C protein levels in AS PCa cells, which is in part by decreasing its degradation. These results can lead to advanced PCa therapy via up-regulating the degradation pathways of Cdc25C protein. PMID- 23637934 TI - Transcriptome analysis of skin photoaging in chinese females reveals the involvement of skin homeostasis and metabolic changes. AB - BACKGROUND: Photoaging is cumulative damage to skin, caused by chronic, repeated solar radiation exposure. Its molecular mechanisms are poorly understood at the level of global gene expression. OBJECTIVE: This study set out to uncover genes and functional modules involved in photoaging at the level of transcription, with the use of skin samples from Chinese women. METHODS: Using the Illumina microarray platform, we compared the genome-wide expression profiles of 21 pairs of sun-exposed pre-auricular and sun-protected post-auricular skin samples from northern Chinese women. RESULTS: With microarray analysis, 1,621 significantly regulated genes due to photoaging were identified from skin samples. These genes were subjected to functional enrichment analyses with both the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation databases. As revealed by the functional analyses, the up-regulated functional modules in sun exposed pre-auricular skin were related to various cellular activities in regulation of the skin homeostasis (e.g., the KEGG pathways TGF-beta signaling pathway and ECM-receptor interaction), whereas the down-regulated functional modules were mostly metabolic-related. Additionally, five selected genes (HOXA5, LEPR, CLDN5, LAMC3, and CGA) identified as differentially-expressed were further confirmed by quantitative real-time PCR (Q-RT-PCR). CONCLUSION: Our findings suggest that disruption of skin homeostasis and down-regulation of skin metabolism may play important roles in the process of photoaging. PMID- 23637935 TI - Free testosterone drives cancer aggressiveness: evidence from US population studies. AB - Cancer incidence and mortality are higher in males than in females, suggesting that some gender-related factors are behind such a difference. To analyze this phenomenon the most recent Surveillance, Epidemiology and End Results (SEER) database served to access cancer survival data for the US population. Patients with gender-specific cancer and with limited information were excluded and this fact limited the sample size to 1,194,490 patients. NHANES III provided the distribution of physiologic variables in US population (n = 29,314). Cox model and Kaplan-Meier method were used to test the impact of gender on survival across age, and to calculate the gender-specific hazard ratio of dying from cancer five years following diagnosis. The distribution of the hazard ratio across age was then compared with the distribution of 65 physiological variables assessed in NHANES III. Spearman and Kolmogorov-Smirnov test assessed the homology. Cancer survival was lower in males than in females in the age range 17 to 61 years. The risk of death from cancer in males was about 30% higher than that of females of the same age. This effect was present only in sarcomas and epithelial solid tumors with distant disease and the effect was more prominent in African Americans than Caucasians. When compared to the variables assessed in the NHANES III study, the hazard ratio almost exactly matched the distribution of free testosterone in males; none of the other analyzed variables exhibited a similar homology. Our findings suggest that male sex hormones give rise to cancer aggressiveness in patients younger than 61 years. PMID- 23637936 TI - A temperature-stable cryo-system for high-temperature superconducting MR in-vivo imaging. AB - To perform a rat experiment using a high-temperature superconducting (HTS) surface resonator, a cryostat is essential to maintain the rat's temperature. In this work, a compact temperature-stable HTS cryo-system, keeping animal rectal temperature at 37.4 degrees C for more than 3 hours, was successfully developed. With this HTS cryo-system, a 40-mm-diameter Bi2Sr2Ca2Cu3Ox (Bi-2223) surface resonator at 77 K was demonstrated in a 3-Tesla MRI system. The proton resonant frequency (PRF) method was employed to monitor the rat's temperature. Moreover, the capacity of MR thermometry in the HTS experiments was evaluated by correlating with data from independent fiber-optic sensor temperature measurements. The PRF thermal coefficient was derived as 0.03 rad/ degrees C and the temperature-monitoring architecture can be implemented to upgrade the quality and safety in HTS experiments. The signal-to-noise ratio (SNR) of the HTS surface resonator at 77 K was higher than that of a professionally made copper surface resonator at 300 K, which has the same geometry, by a 3.79-fold SNR gain. Furthermore, the temperature-stable HTS cryo-system we developed can obtain stable SNR gain in every scan. A temperature-stable HTS cryo-system with an external air-blowing circulation system is demonstrated. PMID- 23637937 TI - Role of arginase 1 from myeloid cells in th2-dominated lung inflammation. AB - Th2-driven lung inflammation increases Arginase 1 (Arg1) expression in alternatively-activated macrophages (AAMs). AAMs modulate T cell and wound healing responses and Arg1 might contribute to asthma pathogenesis by inhibiting nitric oxide production, regulating fibrosis, modulating arginine metabolism and restricting T cell proliferation. We used mice lacking Arg1 in myeloid cells to investigate the contribution of Arg1 to lung inflammation and pathophysiology. In six model systems encompassing acute and chronic Th2-mediated lung inflammation we observed neither a pathogenic nor protective role for myeloid-expressed Arg1. The number and composition of inflammatory cells in the airways and lungs, mucus secretion, collagen deposition, airway hyper-responsiveness, and T cell cytokine production were not altered if AAMs were deficient in Arg1 or simultaneously in both Arg1 and NOS2. Our results argue that Arg1 is a general feature of alternative activation but only selectively regulates Th2 responses. Therefore, attempts to experimentally or therapeutically inhibit arginase activity in the lung should be examined with caution. PMID- 23637939 TI - Quantifying climatological ranges and anomalies for Pacific coral reef ecosystems. AB - Coral reef ecosystems are exposed to a range of environmental forcings that vary on daily to decadal time scales and across spatial scales spanning from reefs to archipelagos. Environmental variability is a major determinant of reef ecosystem structure and function, including coral reef extent and growth rates, and the abundance, diversity, and morphology of reef organisms. Proper characterization of environmental forcings on coral reef ecosystems is critical if we are to understand the dynamics and implications of abiotic-biotic interactions on reef ecosystems. This study combines high-resolution bathymetric information with remotely sensed sea surface temperature, chlorophyll-a and irradiance data, and modeled wave data to quantify environmental forcings on coral reefs. We present a methodological approach to develop spatially constrained, island- and atoll-scale metrics that quantify climatological range limits and anomalous environmental forcings across U.S. Pacific coral reef ecosystems. Our results indicate considerable spatial heterogeneity in climatological ranges and anomalies across 41 islands and atolls, with emergent spatial patterns specific to each environmental forcing. For example, wave energy was greatest at northern latitudes and generally decreased with latitude. In contrast, chlorophyll-a was greatest at reef ecosystems proximate to the equator and northern-most locations, showing little synchrony with latitude. In addition, we find that the reef ecosystems with the highest chlorophyll-a concentrations; Jarvis, Howland, Baker, Palmyra and Kingman are each uninhabited and are characterized by high hard coral cover and large numbers of predatory fishes. Finally, we find that scaling environmental data to the spatial footprint of individual islands and atolls is more likely to capture local environmental forcings, as chlorophyll-a concentrations decreased at relatively short distances (>7 km) from 85% of our study locations. These metrics will help identify reef ecosystems most exposed to environmental stress as well as systems that may be more resistant or resilient to future climate change. PMID- 23637938 TI - Induction of STAT1 phosphorylation at serine 727 and expression of proinflammatory cytokines by porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a viral pathogen that causes acute respiratory illnesses in young pigs. Since 1987, PRRSV has contributed substantial economic losses to the swine industry. Elevation of proinflammatory cytokines in PRRSV-infected pigs is thought to contribute to PRRSV pathogenesis. In this study, PRRSV VR-2385, a Type 2 strain with moderate virulence, was found to induce phosphorylation of signal transducer and activator of transcription 1 (STAT1) at serine 727 (pSTAT1-S727) in MARC-145 cells. No phosphorylated STAT1 at tyrosine 701 was detected, which indicates that the pSTAT1-S727 elevation was interferon-independent. The PRRSV-induced pSTAT1-S727, however, was dose-dependent and its levels increased with infection time. IngelVac PRRS MLV strain had a minimal effect on pSTAT1-S727. Compared to MLV infected cells, VR-2385 infection caused significantly higher level of expression of proinflammatory cytokines, including interleukin 1 beta (IL-1beta) and IL-8. The VR-2385-induced pSTAT1-S727 and cytokine expression were reduced after SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK), or methylthioadenosine (MTA), a methyl transferase inhibitor, was added to the cells. The SB203580 and MTA-mediated inhibition suggested that the virus-induced pSTAT1-S727 was dependent on p38 MAPK pathway. In primary porcine alveolar macrophages (PAMs), VR-2385 also induced pSTAT1-S727 and expression of proinflammatory cytokines and chemokines, including IL-1beta, IL-8, chemokine ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 10 (CXCL10). Similarly, SB203580 treatment of PAM cells blocked the elevation of pSTAT1-S727 and cytokine expression. Overexpression of individual viral proteins showed that non structural protein 12 (nsp12) was able to induce elevation of pSTAT1-S727 and the expression of IL-1beta and IL-8. These results indicated that PRRSV VR-2385 induces pSTAT1-S727 and the expression of proinflammatory cytokines, which contributes to the insight of PRRSV pathogenesis. PMID- 23637940 TI - The Twitter of Babel: mapping world languages through microblogging platforms. AB - Large scale analysis and statistics of socio-technical systems that just a few short years ago would have required the use of consistent economic and human resources can nowadays be conveniently performed by mining the enormous amount of digital data produced by human activities. Although a characterization of several aspects of our societies is emerging from the data revolution, a number of questions concerning the reliability and the biases inherent to the big data "proxies" of social life are still open. Here, we survey worldwide linguistic indicators and trends through the analysis of a large-scale dataset of microblogging posts. We show that available data allow for the study of language geography at scales ranging from country-level aggregation to specific city neighborhoods. The high resolution and coverage of the data allows us to investigate different indicators such as the linguistic homogeneity of different countries, the touristic seasonal patterns within countries and the geographical distribution of different languages in multilingual regions. This work highlights the potential of geolocalized studies of open data sources to improve current analysis and develop indicators for major social phenomena in specific communities. PMID- 23637941 TI - Emerging role of angiotensin type 2 receptor (AT2R)/Akt/NO pathway in vascular smooth muscle cell in the hyperthyroidism. AB - Hyperthyroidism is characterized by increased vascular relaxation and decreased vascular contraction and is associated with augmented levels of triiodothyronine (T3) that contribute to the diminished systemic vascular resistance found in this condition. T3 leads to augmented NO production via PI3K/Akt signaling pathway, which in turn causes vascular smooth muscle cell (VSMC) relaxation; however, the underlying mechanisms involved remain largely unknown. Evidence from human and animal studies demonstrates that the renin-angiotensin system (RAS) plays a crucial role in vascular function and also mediates some of cardiovascular effects found during hyperthyroidism. Thus, in this study, we hypothesized that type 2 angiotensin II receptor (AT2R), a key component of RAS vasodilatory actions, mediates T3 induced-decreased vascular contraction. Marked induction of AT2R expression was observed in aortas from T3-induced hyperthyroid rats (Hyper). These vessels showed decreased protein levels of the contractile apparatus: alpha actin, calponin and phosphorylated myosin light chain (p-MLC). Vascular reactivity studies showed that denuded aortic rings from Hyper rats exhibited decreased maximal contractile response to angiotensin II (AngII), which was attenuated in aortic rings pre-incubated with an AT2R blocker. Further study showed that cultured VSMC stimulated with T3 (0.1 umol/L) for 24 hours had increased AT2R gene and protein expression. Augmented NO levels and decreased p MLC levels were found in VSMC stimulated with T3, both of which were reversed by a PI3K/Akt inhibitor and AT2R blocker. These findings indicate for the first time that the AT2R/Akt/NO pathway contributes to decreased contractile responses in rat aorta, promoted by T3, and this mechanism is independent from the endothelium. PMID- 23637942 TI - A further analysis of the relationship between yellow ripe-fruit color and the capsanthin-capsorubin synthase gene in pepper (Capsicum sp.) indicated a new mutant variant in C. annuum and a tandem repeat structure in promoter region. AB - Mature pepper (Capsicum sp.) fruits come in a variety of colors, including red, orange, yellow, brown, and white. To better understand the genetic and regulatory relationships between the yellow fruit phenotype and the capsanthin-capsorubin synthase gene (Ccs), we examined 156 Capsicum varieties, most of which were collected from Northwest Chinese landraces. A new ccs variant was identified in the yellow fruit cultivar CK7. Cluster analysis revealed that CK7, which belongs to the C. annuum species, has low genetic similarity to other yellow C. annuum varieties. In the coding sequence of this ccs allele, we detected a premature stop codon derived from a C to G change, as well as a downstream frame-shift caused by a 1-bp nucleotide deletion. In addition, the expression of the gene was detected in mature CK7 fruit. Furthermore, the promoter sequences of Ccs from some pepper varieties were examined, and we detected a 176-bp tandem repeat sequence in the promoter region. In all C. annuum varieties examined in this study, the repeat number was three, compared with four in two C. chinense accessions. The sequence similarity ranged from 84.8% to 97.7% among the four types of repeats, and some putative cis-elements were also found in every repeat. This suggests that the transcriptional regulation of Ccs expression is complex. Based on the analysis of the novel C. annuum mutation reported here, along with the studies of three mutation types in yellow C. annuum and C. chinense accessions, we suggest that the mechanism leading to the production of yellow color fruit may be not as complex as that leading to orange fruit production. PMID- 23637943 TI - The evolution of bat vestibular systems in the face of potential antagonistic selection pressures for flight and echolocation. AB - The vestibular system maintains the body's sense of balance and, therefore, was probably subject to strong selection during evolutionary transitions in locomotion. Among mammals, bats possess unique traits that place unusual demands on their vestibular systems. First, bats are capable of powered flight, which in birds is associated with enlarged semicircular canals. Second, many bats have enlarged cochleae associated with echolocation, and both cochleae and semicircular canals share a space within the petrosal bone. To determine how bat vestibular systems have evolved in the face of these pressures, we used micro-CT scans to compare canal morphology across species with contrasting flight and echolocation capabilities. We found no increase in canal radius in bats associated with the acquisition of powered flight, but canal radius did correlate with body mass in bat species from the suborder Yangochiroptera, and also in non echolocating Old World fruit bats from the suborder Yinpterochiroptera. No such trend was seen in members of the Yinpterochiroptera that use laryngeal echolocation, although canal radius was associated with wing-tip roundedness in this group. We also found that the vestibular system scaled with cochlea size, although the relationship differed in species that use constant frequency echolocation. Across all bats, the shape of the anterior and lateral canals was associated with large cochlea size and small body size respectively, suggesting differential spatial constraints on each canal depending on its orientation within the skull. Thus in many echolocating bats, it seems that the combination of small body size and enlarged cochlea together act as a principal force on the vestibular system. The two main groups of echolocating bats displayed different canal morphologies, in terms of size and shape in relation to body mass and cochlear size, thus suggesting independent evolutionary pathways and offering tentative support for multiple acquisitions of echolocation. PMID- 23637944 TI - Hypothalamic ventricular ependymal thyroid hormone deiodinases are an important element of circannual timing in the Siberian hamster (Phodopus sungorus). AB - Exposure to short days (SD) induces profound changes in the physiology and behaviour of Siberian hamsters, including gonadal regression and up to 30% loss in body weight. In a continuous SD environment after approximately 20 weeks, Siberian hamsters spontaneously revert to a long day (LD) phenotype, a phenomenon referred to as the photorefractory response. Previously we have identified a number of genes that are regulated by short photoperiod in the neuropil and ventricular ependymal (VE) cells of the hypothalamus, although their importance and contribution to photoperiod induced physiology is unclear. In this refractory model we hypothesised that the return to LD physiology involves reversal of SD expression levels of key hypothalamic genes to their LD values and thereby implicate genes required for LD physiology. Male Siberian hamsters were kept in either LD or SD for up to 39 weeks during which time SD hamster body weight decreased before increasing, after more than 20 weeks, back to LD values. Brain tissue was collected between 14 and 39 weeks for in situ hybridization to determine hypothalamic gene expression. In VE cells lining the third ventricle, expression of nestin, vimentin, Crbp1 and Gpr50 were down-regulated at 18 weeks in SD photoperiod, but expression was not restored to the LD level in photorefractory hamsters. Dio2, Mct8 and Tsh-r expression were altered by SD photoperiod and were fully restored, or even exceeded values found in LD hamsters in the refractory state. In hypothalamic nuclei, expression of Srif and Mc3r mRNAs was altered at 18 weeks in SD, but were similar to LD expression values in photorefractory hamsters. We conclude that in refractory hamsters not all VE cell functions are required to establish LD physiology. However, thyroid hormone signalling from ependymal cells and reversal of neuronal gene expression appear to be essential for the SD refractory response. PMID- 23637945 TI - A systematic review of the health and social effects of menstrual hygiene management. AB - BACKGROUND: Differing approaches to menstrual hygiene management (MHM) have been associated with a wide range of health and psycho-social outcomes in lower income settings. This paper systematically collates, summarizes and critically appraises the available evidence. METHODS: Following the PRISMA guidelines a structured search strategy was used to identify articles investigating the effects of MHM on health and psycho-social outcomes. The search was conducted in May 2012 and had no date limit. Data was extracted and quality of methodology was independently assessed by two researchers. Where no measure of effect was provided, but sufficient data were available to calculate one, this was undertaken. Meta analysis was conducted where sufficient data were available. RESULTS: 14 articles were identified which looked at health outcomes, primarily reproductive tract infections (RTI). 11 articles were identified investigating associations between MHM, social restrictions and school attendance. MHM was found to be associated with RTI in 7 papers. Methodologies however varied greatly and overall quality was low. Meta-analysis of a subset of studies found no association between confirmed bacterial vaginosis and MHM (OR: 1.07, 95% CI: 0.52-2.24). No other substantial associations with health outcomes were found. Although there was good evidence that educational interventions can improve MHM practices and reduce social restrictions there was no quantitative evidence that improvements in management methods reduce school absenteeism. CONCLUSION: The management of menstruation presents significant challenges for women in lower income settings; the effect of poor MHM however remains unclear. It is plausible that MHM can affect the reproductive tract but the specific infections, the strength of effect, and the route of transmission, remain unclear. There is a gap in the evidence for high quality randomised intervention studies which combine hardware and software interventions, in particular for better understanding the nuanced effect improving MHM may have on girls' attendance at school. PMID- 23637946 TI - Assessment of the relationship between self-declared ethnicity, mitochondrial haplogroups and genomic ancestry in Brazilian individuals. AB - In populations that have a high degree of admixture, such as in Brazil, the sole use of ethnicity self-declaration information is not a good method for classifying individuals regarding their ethnicity. Here, we evaluate the relationship of self-declared ethnicities with genomic ancestry and mitochondrial haplogroups in 492 individuals from southeastern Brazil. Mitochondrial haplogroups were obtained by analyzing the hypervariable regions of the mitochondrial DNA (mtDNA), and the genomic ancestry was obtained using 48 autosomal insertion-deletion ancestry informative markers (AIM). Of the 492 individuals, 74.6% self-declared as White, 13.8% as Brown and 10.4% as Black. Classification of the mtDNA haplogroups showed that 46.3% had African mtDNA, and the genomic ancestry analysis showed that the main contribution was European (57.4%). When we looked at the distribution of mtDNA and genomic ancestry according to the self-declared ethnicities from 367 individuals who self-declared as White, 37.6% showed African mtDNA, and they had a high contribution of European genomic ancestry (63.3%) but also a significant contribution of African ancestry (22.2%). Of the 68 individuals who self-declared as Brown, 25% showed Amerindian mtDNA and similar contribution of European and African genomic ancestries. Of the 51 subjects who self-declared as black, 80.4% had African mtDNA, and the main contribution of genomic ancestry was African (55.6%), but they also had a significant proportion of European ancestry (32.1%). The Brazilian population had a uniform degree of Amerindian genomic ancestry, and it was only with the use of genetic markers (autosomal or mitochondrial) that we were able to capture Amerindian ancestry information. Additionally, it was possible to observe a high degree of heterogeneity in the ancestry for both types of genetic markers, which shows the high genetic admixture that is present in the Brazilian population. We suggest that in epidemiological studies, the use of these methods could provide complementary information. PMID- 23637947 TI - In vivo optical imaging of interscapular brown adipose tissue with (18)F-FDG via Cerenkov luminescence imaging. AB - OBJECTIVE: Brown adipose tissue (BAT), a specialized tissue for thermogenesis, plays important roles for metabolism and energy expenditure. Recent studies validated BAT's presence in human adults, making it an important re-emerging target for various pathologies. During this validation, PET images with (18)F-FDG showed significant uptake of (18)F-FDG by BAT under certain conditions. Here, we demonstrated that Cerenkov luminescence imaging (CLI) using (18)F-FDG could be utilized for in vivo optical imaging of BAT in mice. METHODS: Mice were injected with (18)F-FDG and imaged 60 minutes later with open filter and 2 minute acquisition. In vivo activation of BAT was performed by norepinephrine and cold treatment under isoflurane or ketamine anesthesia. Spectral unmixing and 3D imaging reconstruction were conducted with multiple-filter CLI images. RESULTS: 1) It was feasible to use CLI with (18)F-FDG to image interscapular BAT in mice, with the majority of the signal (>85%) at the interscapular site originating from BAT; 2) The method was reliable because excellent correlations between in vivo CLI, ex vivo CLI, and ex vivo radioactivity were observed; 3) CLI could be used for monitoring BAT activation under different conditions; 4) CLI signals from the group under short-term isoflurane anesthesia were significantly higher than that from the group under long-term anesthesia; 5) The CLI spectrum of (18)F-FDG with a peak at 640 nm in BAT after spectral unmixing reflected the actual context of BAT; 6) Finally 3D reconstruction images showed excellent correlation between the source of the light signal and the location and physical shape of BAT. CONCLUSION: CLI with (18)F-FDG is a feasible and reliable method for imaging BAT in mice. Compared to PET imaging, CLI is significantly cheaper, faster for 2D planar imaging and easier to use. We believe that this method could be used as an important tool for researchers investigating BAT. PMID- 23637949 TI - Optogenetic delay of status epilepticus onset in an in vivo rodent epilepsy model. AB - Epilepsy is a devastating disease, currently treated with medications, surgery or electrical stimulation. None of these approaches is totally effective and our ability to control seizures remains limited and complicated by frequent side effects. The emerging revolutionary technique of optogenetics enables manipulation of the activity of specific neuronal populations in vivo with exquisite spatiotemporal resolution using light. We used optogenetic approaches to test the role of hippocampal excitatory neurons in the lithium-pilocarpine model of acute elicited seizures in awake behaving rats. Hippocampal pyramidal neurons were transduced in vivo with a virus carrying an enhanced halorhodopsin (eNpHR), a yellow light activated chloride pump, and acute seizure progression was then monitored behaviorally and electrophysiologically in the presence and absence of illumination delivered via an optical fiber. Inhibition of those neurons with illumination prior to seizure onset significantly delayed electrographic and behavioral initiation of status epilepticus, and altered the dynamics of ictal activity development. These results reveal an essential role of hippocampal excitatory neurons in this model of ictogenesis and illustrate the power of optogenetic approaches for elucidation of seizure mechanisms. This early success in controlling seizures also suggests future therapeutic avenues. PMID- 23637948 TI - Identification and validation of novel contraction-regulated myokines released from primary human skeletal muscle cells. AB - Proteins secreted by skeletal muscle, so called myokines, have been shown to affect muscle physiology and additionally exert systemic effects on other tissues and organs. Although recent profiling studies have identified numerous myokines, the amount of overlap from these studies indicates that the secretome of skeletal muscle is still incompletely characterized. One limitation of the models used is the lack of contraction, a central characteristic of muscle cells. Here we aimed to characterize the secretome of primary human myotubes by cytokine antibody arrays and to identify myokines regulated by contraction, which was induced by electrical pulse stimulation (EPS). In this study, we validated the regulation and release of two selected myokines, namely pigment epithelium derived factor (PEDF) and dipeptidyl peptidase 4 (DPP4), which were recently described as adipokines. This study reveals that both factors, DPP4 and PEDF, are secreted by primary human myotubes. PEDF is a contraction-regulated myokine, although PEDF serum levels from healthy young men decrease after 60 min cycling at VO2max of 70%. Most interestingly, we identified 52 novel myokines which have not been described before to be secreted by skeletal muscle cells. For 48 myokines we show that their release is regulated by contractile activity. This profiling study of the human skeletal muscle secretome expands the number of myokines, identifies novel contraction-regulated myokines and underlines the overlap between proteins which are adipokines as well as myokines. PMID- 23637951 TI - Defining the subcellular interface of nanoparticles by live-cell imaging. AB - Understanding of nanoparticle-bio-interactions within living cells requires knowledge about the dynamic behavior of nanomaterials during their cellular uptake, intracellular traffic and mutual reactions with cell organelles. Here, we introduce a protocol of combined kinetic imaging techniques that enables investigation of exemplary fluorochrome-labelled nanoparticles concerning their intracellular fate. By time-lapse confocal microscopy we observe fast, dynamin dependent uptake of polystyrene and silica nanoparticles via the cell membrane within seconds. Fluorescence recovery after photobleaching (FRAP) experiments reveal fast and complete exchange of the investigated nanoparticles at mitochondria, cytoplasmic vesicles or the nuclear envelope. Nuclear translocation is observed within minutes by free diffusion and active transport. Fluorescence correlation spectroscopy (FCS) and raster image correlation spectroscopy (RICS) indicate diffusion coefficients of polystyrene and silica nanoparticles in the nucleus and the cytoplasm that are consistent with particle motion in living cells based on diffusion. Determination of the apparent hydrodynamic radii by FCS and RICS shows that nanoparticles exert their cytoplasmic and nuclear effects mainly as mobile, monodisperse entities. Thus, a complete toolkit of fluorescence fluctuation microscopy is presented for the investigation of nanomaterial biophysics in subcellular microenvironments that contributes to develop a framework of intracellular nanoparticle delivery routes. PMID- 23637950 TI - The response of human macrophages to beta-glucans depends on the inflammatory milieu. AB - BACKGROUND: beta-glucans are fungal cell wall components that bind to the C-type lectin-like receptor dectin-1. Polymorphisms of dectin-1 gene are associated with susceptibility to invasive fungal infection and medically refractory ulcerative colitis. The purpose of this study has been addressing the response of human macrophages to beta-glucans under different conditions mimicking the composition of the inflammatory milieu in view of the wide plasticity and large range of phenotypical changes showed by these cells, and the relevant role of dectin-1 in several pathophysiological conditions. PRINCIPAL FINDINGS: Serum-differentiated macrophages stimulated with beta-glucans showed a low production of TNFalpha and IL-1beta, a high production of IL-6 and IL-23, and a delayed induction of cyclooxygenase-2 and PGE2 biosynthesis that resembled the responses elicited by crystals and those produced when phagosomal degradation of the phagocytic cargo increases ligand access to intracellular pattern recognition receptors. Priming with a low concentration of LPS produced a rapid induction of cyclooxygenase-2 and a synergistic release of PGE2. When the differentiation of the macrophages was carried out in the presence of M-CSF, an increased expression of dectin-1 B isoform was observed. In addition, this treatment made the cells capable to release arachidonic acid in response to beta-glucan. CONCLUSIONS: These results indicate that the macrophage response to fungal beta-glucans is strongly influenced by cytokines and microbial-derived factors that are usual components of the inflammatory milieu. These responses can be sorted into three main patterns i) an elementary response dependent on phagosomal processing of pathogen associated molecular patterns and/or receptor-independent, direct membrane binding linked to the immunoreceptor tyrosine-based activation motif-bearing transmembrane adaptor DNAX-activating protein 12, ii) a response primed by TLR4 dependent signals, and iii) a response dependent on M-CSF and dectin-1 B isoform expression that mainly signals through the dectin-1 B/spleen tyrosine kinase/cytosolic phospholipase A2 route. PMID- 23637952 TI - Embryonic stem cells are redirected to non-tumorigenic epithelial cell fate by interaction with the mammary microenvironment. AB - Experiments were conducted to redirect mouse Embryonic Stem (ES) cells from a tumorigenic phenotype to a normal mammary epithelial phenotype in vivo. Mixing LacZ-labeled ES cells with normal mouse mammary epithelial cells at ratios of 1:5 and 1:50 in phosphate buffered saline and immediately inoculating them into epithelium-divested mammary fat pads of immune-compromised mice accomplished this. Our results indicate that tumorigenesis occurs only when normal mammary ductal growth is not achieved in the inoculated fat pads. When normal mammary gland growth occurs, we find ES cells (LacZ+) progeny interspersed with normal mammary cell progeny in the mammary epithelial structures. We demonstrate that these progeny, marked by LacZ expression, differentiate into multiple epithelial subtypes including steroid receptor positive luminal cells and myoepithelial cells indicating that the ES cells are capable of epithelial multipotency in this context but do not form teratomas. In addition, in secondary transplants, ES cell progeny proliferate, contribute apparently normal mammary progeny, maintain their multipotency and do not produce teratomas. PMID- 23637953 TI - Clinical and molecular epidemiology of methicillin-resistant Staphylococcus aureus in New Zealand: rapid emergence of sequence type 5 (ST5)-SCCmec-IV as the dominant community-associated MRSA clone. AB - The predominant community-associated MRSA strains vary between geographic settings, with ST8-IV USA300 being the commonest clone in North America, and the ST30-IV Southwest Pacific clone established as the dominant clone in New Zealand for the past two decades. Moreover, distinct epidemiological risk factors have been described for colonisation and/or infection with CA-MRSA strains, although these associations have not previously been characterized in New Zealand. Based on data from the annual New Zealand MRSA survey, we sought to describe the clinical and molecular epidemiology of MRSA in New Zealand. All non-duplicate clinical MRSA isolates from New Zealand diagnostic laboratories collected as part of the annual MRSA survey were included. Demographic data was collected for all patients, including age, gender, ethnicity, social deprivation index and hospitalization history. MRSA was isolated from clinical specimens from 3,323 patients during the 2005 to 2011 annual surveys. There were marked ethnic differences, with MRSA isolation rates significantly higher in Maori and Pacific Peoples. Over the study period, there was a significant increase in CA-MRSA, and a previously unidentified PVL-negative ST5-IV spa t002 clone replaced the PVL positive ST30-IV Southwest Pacific clone as the dominant CA-MRSA clone. Of particular concern was the finding of several successful and virulent MRSA clones from other geographic settings, including ST93-IV (Queensland CA-MRSA), ST8-IV (USA300) and ST772-V (Bengal Bay MRSA). Ongoing molecular surveillance is essential to prevent these MRSA strains becoming endemic in the New Zealand healthcare setting. PMID- 23637954 TI - Ophthalmoscopic assessment of the retinal nerve fiber layer. The Beijing Eye Study. AB - PURPOSE: To examine the retinal nerve fiber layer (RNFL) ophthalmoscopically, to search for localized RNFL defects, and to assess factors associated with RNFL visibility in a population-based setting. METHODS: The population-based cross sectional Beijing Eye Study 2006 included 3251 subjects. Using color fundus photographs, RNFL visibility was assessed in grades from 0 to 8 in 8 fundus sectors. Localized RNFL defects were defined as wedge-shaped defects running towards the optic disc. RESULTS: After exclusion of subjects with optic media opacities, 2602 subjects (mean age: 58.1+/-9.0 years) were included. RNFL visibility score was highest (P<0.001) in the temporal inferior region, followed by the temporal superior region, nasal superior region, and nasal inferior region. In multivariate analysis, higher RNFL visibility score was associated with younger age (P<0.001; standardized coefficient beta: -0.44; regression coefficient B: -0.22; 95%CI: -0.24, -0.20), female gender (P<0.001; beta: 0.11; B: 1.00; 95%CI: 0.67, 1.32), higher blood concentration of low-density lipoproteins (P = 0.002; beta: 0.07; B: 0.34; 95%CI: 0.13, 0.56), absence of dyslipidemia (P = 0.001; beta: -0.07; B: -0.58; 95%CI: -0.93, -0.24), lower blood glucose concentration (P = 0.006; beta: -0.05; B: -0.14; 95%CI: -0.24, -0.04), hyperopic refractive error (P<0.001; beta: 0.15; B: 0.45; 95%CI: 0.34, 0.56), smaller optic disc size (P<0.001; beta: -0.08; B: -0.72; 95% CI: -1.04, -0.40), absence of glaucomatous optic neuropathy (P<0.001; beta: -0.06; B: -2.69; 95%CI: 4.18, -1.21) and absence of non-glaucomatous optic nerve damage (P = 0.001; beta: -0.06; B: -4.80; 95%CI: 0. -7.64, -1.96). Localized RNFL defects were detected in 96 subjects (prevalence:3.7+/-0.45% (95% confidence interval (CI): 3.0, 4.4). In multivariate analysis, prevalence of localized RNFL defects was associated with higher blood pressure (P<0.001; odds ratio (OR): 1.07; 95%CI: 1.03, 1.10), higher concentration of low-density lipoproteins (P = 0.01; OR: 1.42; 95%CI: 1.08, 1.85), higher prevalence of glaucomatous optic neuropathy (P<0.001; OR: 46.8; 95%CI: 19.4, 113) and diabetic retinopathy (P = 0.002; OR: 3.20; 95%CI: 1.53, 6.67), and lower total RNFL visibility (P<0.001; OR: 0.92; 95%CI: 0.88, 0.96). CONCLUSIONS: In Chinese aged 45+ years, a decreased RNFL visibility was associated with older age, male gender, dyslipidemia, hyperglycemia, myopia, larger optic disc, and glaucomatous or non-glaucomatous optic neuropathy. Localized RNFL defects (prevalence: 3.7+/-0.45%) were correlated mainly with higher blood pressure, higher concentration of low-density lipoproteins, glaucomatous optic neuropathy and diabetic retinopathy. These data are helpful for the routine ophthalmoscopic examination of the RNFL. PMID- 23637957 TI - Impact of oral typhoid vaccination on the human gut microbiota and correlations with s. Typhi-specific immunological responses. AB - The resident microbial consortia of the human gastrointestinal tract play an integral role in modulating immune responses both locally and systemically. However, detailed information regarding the effector immune responses after vaccine administration in relation to the gastrointestinal microbiota is absent. In this study, the licensed oral live-attenuated typhoid vaccine Ty21a was administered in a clinical study to investigate whether oral immunization resulted in alterations of the microbiota and to identify whether a given microbiota composition, or subsets of the community, are associated with defined S. Typhi-specific immunological responses. The fecal microbiota composition and temporal dynamics were characterized using bacterial 16S rRNA pyrosequencing from individuals who were either immunized with the Ty21a typhoid vaccine (n = 13) or served as unvaccinated controls (n = 4). The analysis revealed considerable inter and intra-individual variability, yet no discernible perturbations of the bacterial assemblage related to vaccine administration were observed. S. Typhi specific cell mediated immune (CMI) responses were evaluated by measurement of intracellular cytokine production using multiparametric flow cytometry, and humoral responses were evaluated by measurement of serum anti-LPS IgA and IgG titers. Volunteers were categorized according to the kinetics and magnitude of their responses. While differences in microbial composition, diversity, or temporal stability were not observed among individuals able to mount a positive humoral response, individuals displaying multiphasic CMI responses harbored more diverse, complex communities. In line with this preliminary observation, over two hundred operational taxonomic units (OTUs) were found to differentiate multiphasic and late CMI responders, the vast majority of which classified within the order Clostridiales. These results provide an unprecedented view into the dramatic temporal heterogeneity of both the gut microbiota and host immune responses. PMID- 23637955 TI - Meta-analysis of MMP2, MMP3, and MMP9 promoter polymorphisms and head and neck cancer risk. AB - BACKGROUND: The 1306 C>T, 1171 5A>6A, and 1562C>T polymorphisms of matrix metalloproteinase (MMP) 2, MMP3, and MMP9 genes, respectively, have been found to be functional and may contribute to head and neck carcinogenesis. However, the results of case-control studies examining associations between MMP polymorphisms and head and neck cancer (HNC) risk remain inconclusive. Therefore, we performed a meta-analysis to further evaluate the role of these polymorphisms in HNC development. METHODS: We searched PubMed, ISI Web of Knowledge, MEDLINE, Embase, and Google Scholar to identify all published case-control studies of MMP2-1306 C>T, MMP3-1171 5A>6A, and MMP9-1562 C>T polymorphisms and HNC risk in the meta analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association between these polymorphisms and HNC risk. RESULTS: Thirteen studies were included in this meta-analysis. For MMP2-1306 C>T polymorphism, significant associations were observed under three genetic models both in overall comparison and in a hospital-based subgroup, and in oral cavity cancer and nasopharyngeal cancer under dominant model as well. For MMP3-1171 5A>6A and MMP9-1562 C>T polymorphisms, no association was found in overall comparison; however, in subgroup analyses based on ethnicity and tumor site, significant associations were detected between the MMP3-1171 5A>6A polymorphism and HNC risk in a European population and pharyngeal/laryngeal cancer under two genetic contrasts. CONCLUSION: This meta-analysis suggests that the MMP2-1306 C>T polymorphism is associated with HNC risk, as is the MMP3-1171 5A>6A polymorphism specifically in some subgroups. Further studies with larger sample sizes are warranted. PMID- 23637956 TI - Over-expression of nerve growth factor-beta in human cholangiocarcinoma QBC939 cells promote tumor progression. AB - AIMS: It has been shown that nerve growth factor-beta (NGF-beta) promoted the initiation and progression of many tumors, and we have previously demonstrated that the expression of NGF-beta was associated with tumor stage, nerve infiltration and lymph node metastasis in human hilar cholangiocarcinoma. However, whether NGF-beta promotes tumor progression in human cholangiocarcinoma requires further investigation. Therefore, we aimed to determine the effects of NGF-beta on the progression of human cholangiocarcinoma. METHODS: Human cholangiocarcinoma QBC939 stable cell lines with over-expressed or silenced NGF beta genes were generated with pEGFP-N1-NGF-beta and pGPU6/GFP/Neo-NGF-beta-shRNA recombinant plasmids. Cell proliferation assay, colony formation assay, cell cycle analysis, apoptosis assay and tumorigenicity assay were performed to evaluate the role of NGF-beta in the progression of human cholangiocarcinoma. In addition, human lymphatic endothelial cells were co-cultured with QBC939 culture supernatants, and the cell proliferation and migration abilities of the lymphatic endothelial cells were evaluated. RESULTS: Forced expression of NGF-beta in QBC939 cell lines promoted proliferation, colony formation and tumorigenicity in these cells and inhibited the apoptosis. However, down-regulation of NGF-beta inhibited proliferation, colony formation and tumorigenicity, and increased the apoptotic rate of QBC939 cells. In addition, the NGF-beta gain-of-function induced a high expression of vascular endothelial growth factor C and enhanced the proliferation and migration of lymphatic endothelial cells, while NGF-beta loss-of-function showed opposite effects. CONCLUSIONS: We concluded that NGF-beta promoted tumor progression in human cholangiocarcinoma QBC939 cells. Our results provided a new concept to understand the role of NGF-beta in cholangiocarcinoma progression, and might provide important information for the development of new targeted therapies in human cholangiocarcinoma. PMID- 23637959 TI - Hypertension and genetic variation in endothelial-specific genes. AB - Genome-wide association (GWA) studies usually detect common genetic variants with low-to-medium effect sizes. Many contributing variants are not revealed, since they fail to reach significance after strong correction for multiple comparisons. The WTCCC study for hypertension, for example, failed to identify genome-wide significant associations. We hypothesized that genetic variation in genes expressed specifically in the endothelium may be important for hypertension development. Results from the WTCCC study were combined with previously published gene expression data from mice to specifically investigate SNPs located within endothelial-specific genes, bypassing the requirement for genome-wide significance. Six SNPs from the WTCCC study were selected for independent replication in 5205 hypertensive patients and 5320 population-based controls, and successively in a cohort of 16,537 individuals. A common variant (rs10860812) in the DRAM (damage-regulated autophagy modulator) locus showed association with hypertension (P = 0.008) in the replication study. The minor allele (A) had a protective effect (OR = 0.93; 95% CI 0.88-0.98 per A-allele), which replicates the association in the WTCCC GWA study. However, a second follow-up, in the larger cohort, failed to reveal an association with blood pressure. We further tested the endothelial-specific genes for co-localization with a panel of newly discovered SNPs from large meta-GWAS on hypertension or blood pressure. There was no significant overlap between those genes and hypertension or blood pressure loci. The result does not support the hypothesis that genetic variation in genes expressed in endothelium plays an important role for hypertension development. Moreover, the discordant association of rs10860812 with blood pressure in the case control study versus the larger Malmo Preventive Project-study highlights the importance of rigorous replication in multiple large independent studies. PMID- 23637960 TI - Exopolymer diversity and the role of levan in Bacillus subtilis biofilms. AB - Exopolymeric substances (EPS) are important for biofilm formation and their chemical composition may influence biofilm properties. To explore these relationships the chemical composition of EPS from Bacillus subtilis NCIB 3610 biofilms grown in sucrose-rich (SYM) and sucrose-poor (MSgg and Czapek) media was studied. We observed marked differences in composition of EPS polymers isolated from all three biofilms or from spent media below the biofilms. The polysaccharide levan dominated the EPS of SYM grown biofilms, while EPS from biofilms grown in sucrose-poor media contained significant amounts of proteins and DNA in addition to polysaccharides. The EPS polymers differed also in size with very large polymers (Mw>2000 kDa) found only in biofilms, while small polymers (Mw<200 kD) dominated in the EPS isolated from spent media. Biofilms of the eps knockout were significantly thinner than those of the tasA knockout in all media. The biofilm defective phenotypes of tasA and eps mutants were, however, partially compensated in the sucrose-rich SYM medium. Sucrose supplementation of Czapek and MSgg media increased the thickness and stability of biofilms compared to non-supplemented controls. Since sucrose is essential for synthesis of levan and the presence of levan was confirmed in all biofilms grown in media containing sucrose, this study for the first time shows that levan, although not essential for biofilm formation, can be a structural and possibly stabilizing component of B. subtilis floating biofilms. In addition, we propose that this polysaccharide, when incorporated into the biofilm EPS, may also serve as a nutritional reserve. PMID- 23637962 TI - A universal vector for high-efficiency multi-fragment recombineering of BACs and knock-in constructs. AB - There is an increasing need for more efficient generation of transgenic constructs. Here we present a universal multi-site Gateway vector for use in recombineering reactions. Using transgenic mouse models, we show its use for the generation of BAC transgenics and targeting vectors. The modular nature of the vector allows for rapid modification of constructs to generate different versions of the same construct. As such it will help streamline the generation of series of related transgenic models. PMID- 23637958 TI - Impact of alginate composition: from bead mechanical properties to encapsulated HepG2/C3A cell activities for in vivo implantation. AB - Recently, interest has focused on hepatocytes' implantation to provide end stage liver failure patients with a temporary support until spontaneous recovery or a suitable donor becomes available. To avoid cell damage and use of an immunosuppressive treatment, hepatic cells could be implanted after encapsulation in a porous biomaterial of bead or capsule shape. The aim of this study was to compare the production and the physical properties of the beads, together with some hepatic cell functions, resulting from the use of different material combinations for cell microencapsulation: alginate alone or combined with type I collagen with or without poly-L-lysine and alginate coatings. Collagen and poly-L lysine increased the bead mechanical resistance but lowered the mass transfer kinetics of vitamin B12. Proliferation of encapsulated HepG2/C3A cells was shown to be improved in alginate-collagen beads. Finally, when the beads were subcutaneously implanted in mice, the inflammatory response was reduced in the case of alginate mixed with collagen. This in vitro and in vivo study clearly outlines, based on a systematic comparison, the necessity of compromising between material physical properties (mechanical stability and porosity) and cell behavior (viability, proliferation, functionalities) to define optima hepatic cell microencapsulation conditions before implantation. PMID- 23637961 TI - An abelisauroid theropod dinosaur from the Turonian of Madagascar. AB - Geophysical evidence strongly supports the complete isolation of India and Madagascar (Indo-Madagascar) by ~100 million years ago, though sparse terrestrial fossil records from these regions prior to ~70 million years ago have limited insights into their biogeographic history during the Cretaceous. A new theropod dinosaur, Dahalokely tokana, from Turonian-aged (~90 million years old) strata of northernmost Madagascar is represented by a partial axial column. Autapomorphies include a prominently convex prezygoepipophyseal lamina on cervical vertebrae and a divided infraprezygapophyseal fossa through the mid-dorsal region, among others. Phylogenetic analysis definitively recovers the species as an abelisauroid theropod and weakly as a noasaurid. Dahalokely is the only known dinosaur from the interval during which Indo-Madagascar likely existed as a distinct landmass, but more complete material is needed to evaluate whether or not it is more closely related to later abelisauroids of Indo-Madagascar or those known elsewhere in Gondwana. PMID- 23637963 TI - Association between gender, process of care measures, and outcomes in ACS in India: results from the detection and management of coronary heart disease (DEMAT) registry. AB - BACKGROUND: Studies from high-income countries have shown that women receive less aggressive diagnostics and treatment than men in acute coronary syndromes (ACS), though their short-term mortality does not appear to differ from men. Data on gender differences in ACS presentation, management, and outcomes are sparse in India. METHODS AND RESULTS: The Detection and Management of Coronary Heart Disease (DEMAT) Registry collected data from 1,565 suspected ACS patients (334 women; 1,231 men) from ten tertiary care centers throughout India between 2007 2008. We evaluated gender differences in presentation, in-hospital and discharge management, and 30-day death and major adverse cardiovascular event (MACE; death, re-hospitalization, and cardiac arrest) rates. Women were less likely to present with STEMI than men (38% vs. 55%, p<0.001). Overall inpatient diagnostics and treatment patterns were similar between men and women after adjustment for potential confounders. Optimal discharge management with aspirin, clopidogrel, beta-blockers, and statin therapy was lower for women than men, (58% vs. 65%, p = 0.03), but these differences were attenuated after adjustment (OR = 0.86 (0.62, 1.19)). Neither the outcome of 30-day mortality (OR = 1.40 (0.62, 3.16)) nor MACE (OR = 1.00 (0.67, 1.48)) differed significantly between men and women after adjustment. CONCLUSIONS: ACS in-hospital management, discharge management, and 30 day outcomes did not significantly differ between genders in the DEMAT registry, though consistently higher treatment rates and lower event rates in men compared to women were seen. These findings underscore the importance of further investigation of gender differences in cardiovascular care in India. PMID- 23637964 TI - Reductions in cardiovascular, cerebrovascular, and respiratory mortality following the national irish smoking ban: interrupted time-series analysis. AB - BACKGROUND: Previous studies have shown decreases in cardiovascular mortality following the implementation of comprehensive smoking bans. It is not known whether cerebrovascular or respiratory mortality decreases post-ban. On March 29, 2004, the Republic of Ireland became the first country in the world to implement a national workplace smoking ban. The aim of this study was to assess the effect of this policy on all-cause and cause-specific, non-trauma mortality. METHODS: A time-series epidemiologic assessment was conducted, utilizing Poisson regression to examine weekly age and gender-standardized rates for 215,878 non-trauma deaths in the Irish population, ages >=35 years. The study period was from January 1, 2000, to December 31, 2007, with a post-ban follow-up of 3.75 years. All models were adjusted for time trend, season, influenza, and smoking prevalence. RESULTS: Following ban implementation, an immediate 13% decrease in all-cause mortality (RR: 0.87; 95% CI: 0.76-0.99), a 26% reduction in ischemic heart disease (IHD) (RR: 0.74; 95% CI: 0.63-0.88), a 32% reduction in stroke (RR: 0.68; 95% CI: 0.54 0.85), and a 38% reduction in chronic obstructive pulmonary disease (COPD) (RR: 0.62; 95% CI: 0.46-0.83) mortality was observed. Post-ban reductions in IHD, stroke, and COPD mortalities were seen in ages >=65 years, but not in ages 35-64 years. COPD mortality reductions were found only in females (RR: 0.47; 95% CI: 0.32-0.70). Post-ban annual trend reductions were not detected for any smoking related causes of death. Unadjusted estimates indicate that 3,726 (95% CI: 2,305 4,629) smoking-related deaths were likely prevented post-ban. Mortality decreases were primarily due to reductions in passive smoking. CONCLUSIONS: The national Irish smoking ban was associated with immediate reductions in early mortality. Importantly, post-ban risk differences did not change with a longer follow-up period. This study corroborates previous evidence for cardiovascular causes, and is the first to demonstrate reductions in cerebrovascular and respiratory causes. PMID- 23637965 TI - Socio-demographic and geographical factors in esophageal and gastric cancer mortality in Sweden. AB - BACKGROUND: Socio-demographic factors and area of residence might influence the development of esophageal and gastric cancer. Large-scale population-based research can determine the role of such factors. METHODS: This population-based cohort study included all Swedish residents aged 30-84 years in 1990-2007. Educational level, marital status, place of birth, and place of residence were evaluated with regard to mortality from esophageal or gastric cancer. Cox regression yielded hazard ratios (HR) with 95% confidence intervals (CI), adjusted for potential confounding. RESULTS: Among 84 920 565 person-years, 5125 and 12 230 deaths occurred from esophageal cancer and gastric cancer, respectively. Higher educational level decreased the HR of esophageal cancer (HR = 0.61, 95%CI 0.42-0.90 in women, HR = 0.71, 95%CI 0.60-0.84 in men) and gastric cancer (HR = 0.80, 95%CI 0.63-1.03 in women, HR = 0.73, 95%CI 0.64-0.83 in men). Being unmarried increased HR of esophageal cancer (HR = 1.64, 95%CI 1.35-1.99 in women, HR = 1.64, 95%CI 1.50-1.80 in men), but not of gastric cancer. Being born in low density populated areas increased HR of gastric cancer (HR = 1.23, 95%CI 1.10-1.38 in women, HR = 1.37, 95%CI 1.25-1.50 in men), while no strong association was found with esophageal cancer. Living in densely populated areas increased HR of esophageal cancer (HR = 1.31, 95%CI 1.14-1.50 in women, HR = 1.40, 95%CI 1.29-1.51 in men), but not of gastric cancer. CONCLUSION: These socio demographic inequalities in cancer mortality warrant efforts to investigate possible preventable mechanisms and to promote and support healthier lifestyles among deprived groups. PMID- 23637966 TI - Celastrol, an NF-kappaB inhibitor, improves insulin resistance and attenuates renal injury in db/db mice. AB - The NF-kappaB pathway plays an important role in chronic inflammatory and autoimmune diseases. Recently, NF-kappaB has also been suggested as an important mechanism linking obesity, inflammation, and metabolic disorders. However, there is no current evidence regarding the mechanism of action of NF-kappaB inhibition in insulin resistance and diabetic nephropathy in type 2 diabetic animal models. We investigated the effects of the NF-kappaB inhibitor celastrol in db/db mice. The treatment with celastrol for 2 months significantly lowered fasting plasma glucose (FPG), HbA1C and homeostasis model assessment index (HOMA-IR) levels. Celastrol also exhibited significant decreases in body weight, kidney/body weight and adiposity. Celastrol reduced insulin resistance and lipid abnormalities and led to higher plasma adiponectin levels. Celastrol treatment also significantly mitigated lipid accumulation and oxidative stress in organs including the kidney, liver and adipose tissue. The treated group also exhibited significantly lower creatinine levels and urinary albumin excretion was markedly reduced. Celastrol treatment significantly lowered mesangial expansion and suppressed type IV collagen, PAI-1 and TGFbeta1 expressions in renal tissues. Celastrol also improved abnormal lipid metabolism, oxidative stress and proinflammatory cytokine activity in the kidney. In cultured podocytes, celastrol treatment abolished saturated fatty acid-induced proinflammatory cytokine synthesis. Taken together, celastrol treatment not only improved insulin resistance, glycemic control and oxidative stress, but also improved renal functional and structural changes through both metabolic and anti-inflammatory effects in the kidney. These results suggest that targeted therapy for NF-kappaB may be a useful new therapeutic approach for the management of type II diabetes and diabetic nephropathy. PMID- 23637968 TI - Tenascin C promiscuously binds growth factors via its fifth fibronectin type III like domain. AB - Tenascin C (TNC) is an extracellular matrix protein that is upregulated during development as well as tissue remodeling. TNC is comprised of multiple independent folding domains, including 15 fibronectin type III-like (TNCIII) domains. The fifth TNCIII domain (TNCIII5) has previously been shown to bind heparin. Our group has shown that the heparin-binding fibronectin type III domains of fibronectin (FNIII), specifically FNIII12-14, possess affinity towards a large number of growth factors. Here, we show that TNCIII5 binds growth factors promiscuously and with high affinity. We produced recombinant fragments of TNC representing the first five TNCIII repeats (TNCIII1-5), as well as subdomains, including TNCIII5, to study interactions with various growth factors. Multiple growth factors of the platelet-derived growth factor (PDGF) family, the fibroblast growth factor (FGF) family, the transforming growth factor beta (TGF beta) superfamily, the insulin-like growth factor binding proteins (IGF-BPs), and neurotrophins were found to bind with high affinity to this region of TNC, specifically to TNCIII5. Surface plasmon resonance was performed to analyze the kinetics of binding of TNCIII1-5 with TGF-beta1, PDGF-BB, NT-3, and FGF-2. The promiscuous yet high affinity of TNC for a wide array of growth factors, mediated mainly by TNCIII5, may play a role in multiple physiological and pathological processes involving TNC. PMID- 23637969 TI - The genome sequence of Lone Star virus, a highly divergent bunyavirus found in the Amblyomma americanum tick. AB - Viruses in the family Bunyaviridae infect a wide range of plant, insect, and animal hosts. Tick-borne bunyaviruses in the Phlebovirus genus, including Severe Fever with Thrombocytopenia Syndrome virus (SFTSV) in China, Heartland virus (HRTV) in the United States, and Bhanja virus in Eurasia and Africa have been associated with acute febrile illness in humans. Here we sought to characterize the growth characteristics and genome of Lone Star virus (LSV), an unclassified bunyavirus originally isolated from the lone star tick Amblyomma americanum. LSV was able to infect both human (HeLa) and monkey (Vero) cells. Cytopathic effects were seen within 72 h in both cell lines; vacuolization was observed in infected Vero, but not HeLa, cells. Viral culture supernatants were examined by unbiased deep sequencing and analysis using an in-house developed rapid computational pipeline for viral discovery, which definitively identified LSV as a phlebovirus. De novo assembly of the full genome revealed that LSV is highly divergent, sharing <61% overall amino acid identity with any other bunyavirus. Despite this sequence diversity, LSV was found by phylogenetic analysis to be part of a well supported clade that includes members of the Bhanja group viruses, which are most closely related to SFSTV/HRTV. The genome sequencing of LSV is a critical first step in developing diagnostic tools to determine the risk of arbovirus transmission by A. americanum, a tick of growing importance given its expanding geographic range and competence as a disease vector. This study also underscores the power of deep sequencing analysis in rapidly identifying and sequencing the genomes of viruses of potential clinical and public health significance. PMID- 23637967 TI - Administration of a Toll-like receptor 9 agonist decreases the proviral reservoir in virologically suppressed HIV-infected patients. AB - Toll-like receptor (TLR) agonists can reactivate HIV from latently infected cells in vitro. We aimed to investigate the TLR-9 agonist, CPG 7909's in vivo effect on the proviral HIV reservoir and HIV-specific immunity. This was a post-hoc analysis of a double-blind randomized controlled vaccine trial. HIV-infected adults were randomized 1:1 to receive pneumococcal vaccines with or without 1 mg CPG 7909 as adjuvant at 0, 3 and 9 months. In patients on suppressive antiretroviral therapy we quantified proviral DNA at 0, 3, 4, 9, and 10 months (31 subjects in the CPG group and 37 in the placebo-adjuvant group). Furthermore, we measured HIV-specific antibodies, characterized T cell phenotypes and HIV specific T cell immunity. We observed a mean reduction in proviral DNA in the CPG group of 12.6% (95% CI: -23.6-0.0) following each immunization whereas proviral DNA in the placebo-adjuvant group remained largely unchanged (6.7% increase; 95% CI: -4.2-19.0 after each immunization, p = 0.02). Among participants with additional cryo-preserved PBMCs, HIV-specific CD8+ T cell immunity as indicated by increased expression of degranulation marker CD107a and macrophage inflammatory protein 1beta (MIP1beta) tended to be up-regulated following immunization with CPG 7909 compared with placebo as adjuvant. Further, increasing proportion of HIV-specific CD107a and MIP1beta-expressing CD8+ T cells were strongly correlated with decreasing proviral load. No changes were observed in T cell phenotype distribution, HIV-specific CD4+ T cell immunity, or HIV-specific antibodies. TLR9-adjuvanted pneumococcal vaccination decreased proviral load. Reductions in proviral load correlated with increasing levels of HIV specific CD8+ T cells. Further investigation into the potential effect of TLR9 agonists on HIV latency is warranted. PMID- 23637970 TI - Salt stress encourages proline accumulation by regulating proline biosynthesis and degradation in Jerusalem artichoke plantlets. AB - Proline accumulation is an important mechanism for osmotic regulation under salt stress. In this study, we evaluated proline accumulation profiles in roots, stems and leaves of Jerusalem artichoke (Helianthus tuberosus L.) plantlets under NaCl stress. We also examined HtP5CS, HtOAT and HtPDH enzyme activities and gene expression patterns of putative HtP5CS1, HtP5CS2, HtOAT, HtPDH1, and HtPDH2 genes. The objective of our study was to characterize the proline regulation mechanisms of Jerusalem artichoke, a moderately salt tolerant species, under NaCl stress. Jerusalem artichoke plantlets were observed to accumulate proline in roots, stems and leaves during salt stress. HtP5CS enzyme activities were increased under NaCl stress, while HtOAT and HtPDH activities generally repressed. Transcript levels of HtP5CS2 increased while transcript levels of HtOAT, HtPDH1 and HtPDH2 generally decreased in response to NaCl stress. Our results supports that for Jerusalem artichoke, proline synthesis under salt stress is mainly through the Glu pathway, and HtP5CS2 is predominant in this process while HtOAT plays a less important role. Both HtPDH genes may function in proline degradation. PMID- 23637971 TI - S100A8 and S100A9 are associated with colorectal carcinoma progression and contribute to colorectal carcinoma cell survival and migration via Wnt/beta catenin pathway. AB - BACKGROUND AND OBJECTIVE: S100A8 and S100A9, two members of the S100 protein family, have been reported in association with the tumor cell differentiation and tumor progression. Previous study has showed that their expression in stromal cells of colorectal carcinoma (CRC) is associated with tumor size. Here, we investigated the clinical significances of S100A8 and S100A9 in tumor cells of CRC and their underlying molecular mechanisms. METHODS: Expression of S100A8 and S100A9 in colorectal carcinoma and matching distal normal tissues were measured by reverse transcriptase polymerase chain reaction (RT-PCR), immunohistochemistry and western blot. CRC cell lines treated with the recombinant S100A8 and S100A9 proteins were used to analyze the roles and molecular mechanisms of the two proteins in CRC in vitro. RESULTS: S100A8 and S100A9 were elevated in more than 50% of CRC tissues and their expression in tumor cells was associated with differentiation, Dukes stage and lymph node metastasis. The CRC cell lines treatment with recombinant S100A8 and S100A9 proteins promoted the viability and migration of CRC cells. Furthermore, the two recombinant proteins also resulted in the increased levels of beta-catenin and its target genes c-myc and MMP7. beta catenin over-expression in CRC cells by Adbeta-catenin increased cell viability and migration. beta-catenin knock-down by Adsibeta-catenin reduced cell viability and migration. Furthermore, beta-catenin knockdown also partially abolished the promotive effects of recombinant S100A8 and S100A9 proteins on the viability and migration of CRC cells. CONCLUSIONS: Our work demonstrated that S100A8 and S100A9 are linked to the CRC progression, and one of the underlying molecular mechanisms is that extracellular S100A8 and S100A9 proteins contribute to colorectal carcinoma cell survival and migration via Wnt/beta-catenin pathway. PMID- 23637972 TI - Targeting photoreceptors via intravitreal delivery using novel, capsid-mutated AAV vectors. AB - Development of viral vectors capable of transducing photoreceptors by less invasive methods than subretinal injection would provide a major advancement in retinal gene therapy. We sought to develop novel AAV vectors optimized for photoreceptor transduction following intravitreal delivery and to develop methodology for quantifying this transduction in vivo. Surface exposed tyrosine (Y) and threonine (T) residues on the capsids of AAV2, AAV5 and AAV8 were changed to phenylalanine (F) and valine (V), respectively. Transduction efficiencies of self-complimentary, capsid-mutant and unmodified AAV vectors containing the smCBA promoter and mCherry cDNA were initially scored in vitro using a cone photoreceptor cell line. Capsid mutants exhibiting the highest transduction efficiencies relative to unmodified vectors were then injected intravitreally into transgenic mice constitutively expressing a Rhodopsin-GFP fusion protein in rod photoreceptors (Rho-GFP mice). Photoreceptor transduction was quantified by fluorescent activated cell sorting (FACS) by counting cells positive for both GFP and mCherry. To explore the utility of the capsid mutants, standard, (non-self complementary) AAV vectors containing the human rhodopsin kinase promoter (hGRK1) were made. Vectors were intravitreally injected in wildtype mice to assess whether efficient expression exclusive to photoreceptors was achievable. To restrict off-target expression in cells of the inner and middle retina, subsequent vectors incorporated multiple target sequences for miR181, an miRNA endogenously expressed in the inner and middle retina. Results showed that AAV2 containing four Y to F mutations combined with a single T to V mutation (quadY F+T-V) transduced photoreceptors most efficiently. Robust photoreceptor expression was mediated by AAV2(quadY-F+T-V) -hGRK1-GFP. Observed off-target expression was reduced by incorporating target sequence for a miRNA highly expressed in inner/middle retina, miR181c. Thus we have identified a novel AAV vector capable of transducing photoreceptors following intravitreal delivery to mouse. Furthermore, we describe a robust methodology for quantifying photoreceptor transduction from intravitreally delivered AAV vectors. PMID- 23637973 TI - Seed structure characteristics to form ultrahigh oil content in rapeseed. AB - BACKGROUND: Rapeseed (Brassica napus L.) is an important oil crop in the world, and increasing its oil content is a major breeding goal. The studies on seed structure and characteristics of different oil content rapeseed could help us to understand the biological mechanism of lipid accumulation, and be helpful for rapeseed breeding. METHODOLOGY/PRINCIPAL FINDINGS: Here we report on the seed ultrastructure of an ultrahigh oil content rapeseed line YN171, whose oil content is 64.8%, and compared with other high and low oil content rapeseed lines. The results indicated that the cytoplasms of cotyledon, radicle, and aleuronic cells were completely filled with oil and protein bodies, and YN171 had a high oil body organelle to cell area ratio for all cell types. In the cotyledon cells, oil body organelles comprised 81% of the total cell area in YN171, but only 53 to 58% in three high oil content lines and 33 to 38% in three low oil content lines. The high oil body organelle to cotyledon cell area ratio and the cotyledon ratio in seed were the main reasons for the ultrahigh oil content of YN171. The correlation analysis indicated that oil content is significantly negatively correlated with protein content, but is not correlated with fatty acid composition. CONCLUSIONS/SIGNIFICANCE: Our results indicate that the oil content of YN171 could be enhanced by increasing the oil body organelle to cell ratio for some cell types. The oil body organelle to seed ratio significantly highly positively correlates with oil content, and could be used to predict seed oil content. Based on the structural analysis of different oil content rapeseed lines, we estimate the maximum of rapeseed oil content could reach 75%. Our results will help us to screen and identify high oil content lines in rapeseed breeding. PMID- 23637974 TI - Explicit mentalizing mechanisms and their adaptive role in memory conformity. AB - Memory conformity occurs when an individual endorses what other individuals remember about past events. Research on memory conformity is currently dominated by a 'forensic' perspective, which views the phenomenon as inherently undesirable. This is because conformity not only distorts the accuracy of an individual's memory, but also produces false corroboration between individuals, effects that act to undermine criminal justice systems. There is growing awareness, however, that memory conformity may be interpreted more generally as an adaptive social behavior regulated by explicit mentalizing mechanisms. Here, we provide novel evidence in support of this emerging alternative theoretical perspective. We carried out a memory conformity experiment which revealed that explicit belief-simulation (i.e. using one's own beliefs to model what other people believe) systematically biases conformity towards like-minded individuals, even when there is no objective evidence that they have a more accurate memory than dissimilar individuals. We suggest that this bias is functional, i.e. adaptive, to the extent that it fosters trust, and hence cooperation, between in group versus out-group individuals. We conclude that memory conformity is, in more fundamental terms, a highly desirable product of explicit mentalizing mechanisms that promote adaptive forms of social learning and cooperation. PMID- 23637975 TI - Microsporidia and its relation to Crohn's disease. A retrospective study. AB - BACKGROUND: The cause of Crohn's Disease (CD) remains unknown. Recently a decrease in the global lymphocyte population in the peripheral blood of CD patients has been reported. This decrease was more evident in gammadelta T lymphocytes, especially gammadelta CD8+T subsets. Furthermore, a decrease of IL-7 was also observed in these patients. We propose the hypothesis that microsporidia, an obligate intracellular opportunistic parasite recently related to fungi, in CD patients can take advantage of the lymphocytes and IL-7 deficits to proliferate and to contribute to the pathophysiology of this disease. METHODS AND FINDINGS: In this case-control study, serum samples were collected from 36 CD patients and from 36 healthy individuals (controls), IgE and IgG anti Encephalitozoon antibodies were determined by ELISA; and forty-four intestinal tissue samples were analyzed through real time Polymerase Chain Reaction (PCR), twenty CD patients, nine with others diseases and 15 healthy subjects. We observed that IgE anti-Encephalitozoon levels were significantly higher in patients with CD: 0.386(+/-0.256) vs control group, 0.201(+/-0.147), P<0.001. However, IgG anti-Encephalitozoon values were significantly lower in CD patients: 0.361(+/-0.256) vs control group, 0.876(+/-0.380), P<0.001. In the group of CD patients, 6/20 (30%) were positive by real time PCR for microsporidia and, all the patients of the control group were negative by real time PCR. CONCLUSIONS: These results suggest that CD patients are a group at risk for microsporidiasis and, moreover that microsporidia may be involved as a possible etiologic factor of CD. PMID- 23637976 TI - Diversity of methicillin-resistant Staphylococcus aureus (MRSA) strains isolated from inpatients of 30 hospitals in Orange County, California. AB - There is a need for a regional assessment of the frequency and diversity of MRSA to determine major circulating clones and the extent to which community and healthcare MRSA reservoirs have mixed. We conducted a prospective cohort study of inpatients in Orange County, California, systematically collecting clinical MRSA isolates from 30 hospitals, to assess MRSA diversity and distribution. All isolates were characterized by spa typing, with selective PFGE and MLST to relate spa types with major MRSA clones. We collected 2,246 MRSA isolates from hospital inpatients. This translated to 91/10,000 inpatients with MRSA and an Orange County population estimate of MRSA inpatient clinical cultures of 86/100,000 people. spa type genetic diversity was heterogeneous between hospitals, and relatively high overall (72%). USA300 (t008/ST8), USA100 (t002/ST5) and a previously reported USA100 variant (t242/ST5) were the dominant clones across all Orange County hospitals, representing 83% of isolates. Fifteen hospitals isolated more t008 (USA300) isolates than t002/242 (USA100) isolates, and 12 hospitals isolated more t242 isolates than t002 isolates. The majority of isolates were imported into hospitals. Community-based infection control strategies may still be helpful in stemming the influx of traditionally community-associated strains, particularly USA300, into the healthcare setting. PMID- 23637978 TI - Applied mixed generalized additive model to assess the effect of temperature on the incidence of bacillary dysentery and its forecast. AB - BACKGROUND: Association between bacillary dysentery (BD) disease and temperature has been reported in some studies applying Poisson regression model, however the effect estimation might be biased due to the data autocorrelation. Furthermore the temperature effect distributed in the time of different lags has not been studied either. The purpose of this work was to obtaining the association between the BD counts and the climatic factors such as temperature in the form of the weighted averages, concerning the autocorrelation pattern of the model residuals, and to make short term predictions using the model. The data was collected in the city of Shanghai from 2004 to 2008. METHODS: We used mixed generalized additive model (MGAM) to analyze data on bacillary dysentery, temperature and other covariates with autoregressive random effect. Short term predictions were made using MGAM with the moving average of the BD counts. MAIN RESULTS: Our results showed that temperature was significant linearly associated with the logarithm of BD count for temperature in the range from 12 degrees C to 22 degrees C. Optimal weights in the temperature effect have been obtained, in which the one of 1-day lag was close to 0, and the one of 2-days-lag was the maximum (p-value of the difference was less than 0.05). The predictive model was showing good fitness on the internal data with R(2) value 0.875, and the good short term prediction effect on the external data with correlation coefficient to be 0.859. CONCLUSION: According to the model estimation, corresponding Risk Ratio to affect BD was close to 1.1 when temperature effect goes up for 1 degrees C in the range from 12 degrees C to 22 degrees C. And the 1-day incubation period could be inferred from the model estimation. Good prediction has been made using the predictive MGAM. PMID- 23637977 TI - Gastrointestinal stromal tumors, somatic mutations and candidate genetic risk variants. AB - Gastrointestinal stromal tumors (GISTs) are rare but treatable soft tissue sarcomas. Nearly all GISTs have somatic mutations in either the KIT or PDGFRA gene, but there are no known inherited genetic risk factors. We assessed the relationship between KIT/PDGFRA mutations and select deletions or single nucleotide polymorphisms (SNPs) in 279 participants from a clinical trial of adjuvant imatinib mesylate. Given previous evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations, or "signatures" in other cancers, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may similarly be mutational signatures that are causally linked to specific mutagens or susceptibility loci. As previous epidemiologic studies suggest environmental risk factors such as dioxin and radiation exposure may be linked to sarcomas, we chose 208 variants in 39 candidate genes related to DNA repair and dioxin metabolism or response. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each variant and 7 categories of tumor mutation using logistic regression. We also evaluated gene-level effects using the sequence kernel association test (SKAT). Although none of the association p-values were statistically significant after adjustment for multiple comparisons, SNPs in CYP1B1 were strongly associated with KIT exon 11 codon 557-8 deletions (OR = 1.9, 95% CI: 1.3-2.9 for rs2855658 and OR = 1.8, 95% CI: 1.2-2.7 for rs1056836) and wild type GISTs (OR = 2.7, 95% CI: 1.5-4.8 for rs1800440 and OR = 0.5, 95% CI: 0.3-0.9 for rs1056836). CYP1B1 was also associated with these mutations categories in the SKAT analysis (p = 0.002 and p = 0.003, respectively). Other potential risk variants included GSTM1, RAD23B and ERCC2. This preliminary analysis of inherited genetic risk factors for GIST offers some clues about the disease's genetic origins and provides a starting point for future candidate gene or gene-environment research. PMID- 23637980 TI - The effect of spaceflight on growth of Ulocladium chartarum colonies on the international space station. AB - The objectives of this 14 days experiment were to investigate the effect of spaceflight on the growth of Ulocladium chartarum, to study the viability of the aerial and submerged mycelium and to put in evidence changes at the cellular level. U. chartarum was chosen for the spaceflight experiment because it is well known to be involved in biodeterioration of organic and inorganic substrates covered with organic deposits and expected to be a possible contaminant in Spaceships. Colonies grown on the International Space Station (ISS) and on Earth were analysed post-flight. This study clearly indicates that U. chartarum is able to grow under spaceflight conditions developing, as a response, a complex colony morphotype never mentioned previously. We observed that spaceflight reduced the rate of growth of aerial mycelium, but stimulated the growth of submerged mycelium and of new microcolonies. In Spaceships and Space Stations U. chartarum and other fungal species could find a favourable environment to grow invasively unnoticed in the depth of surfaces containing very small amount of substrate, posing a risk factor for biodegradation of structural components, as well as a direct threat for crew health. The colony growth cycle of U. chartarum provides a useful eukaryotic system for the study of fungal growth under spaceflight conditions. PMID- 23637979 TI - Cell cycle abnormalities associated with differential perturbations of the human U5 snRNP associated U5-200kD RNA helicase. AB - Splicing of pre-messenger RNAs into functional messages requires a concerted assembly of proteins and small RNAs that identify the splice junctions and facilitate cleavage of exon-intron boundaries and ligation of exons. One of the key steps in the splicing reaction is the recruitment of a tri-snRNP harboring the U5/U4/U6 snRNPs. The U5 snRNP is also required for both steps of splicing and exon-exon joining. One of the key components of the tri-snRNP is the U5 200kd helicase. The human U5-200kD gene isolated from Hela cells encodes a 200 kDa protein with putative RNA helicase function. Surprisingly, little is known about the functional role of this protein in humans. Therefore, we have investigated the role of the U5-200kD RNA helicase in mammalian cell culture. We created and expressed a dominant negative domain I mutant of the RNA helicase in HEK293 cells and used RNAi to downregulate expression of the endogenous protein. Transient and stable expression of the domain I mutant U5-200kD protein using an ecdysone inducible system and transient expression of an anti-U5-200kD short hairpin RNA (shRNA) resulted in differential splicing and growth defects in the 293/EcR cells. Cell cycle analysis of the dominant negative clones revealed delayed exit from the G2/M phase of the cell cycle due to a mild splicing defect. In contrast to the domain I dominant negative mutant expressing cells, transient expression of an anti-U5-200kD shRNA resulted in a pronounced S phase arrest and a minute splicing defect. Collectively, this work demonstrates for the first time establishment of differential human cell culture splicing and cell cycle defect models due to perturbed levels of an essential core splicing factor. PMID- 23637982 TI - Bimanual motor coordination in older adults is associated with increased functional brain connectivity--a graph-theoretical analysis. AB - In bimanual coordination, older and younger adults activate a common cerebral network but the elderly also have additional activation in a secondary network of brain areas to master task performance. It remains unclear whether the functional connectivity within these primary and secondary motor networks differs between the old and the young and whether task difficulty modulates connectivity. We applied graph-theoretical network analysis (GTNA) to task-driven fMRI data in 16 elderly and 16 young participants using a bimanual coordination task including in phase and anti-phase flexion/extension wrist movements. Network nodes for the GTNA comprised task-relevant brain areas as defined by fMRI activation foci. The elderly matched the motor performance of the young but showed an increased functional connectivity in both networks across a wide range of connectivity metrics, i.e., higher mean connectivity degree, connection strength, network density and efficiency, together with shorter mean communication path length between the network nodes and also a lower betweenness centrality. More difficult movements showed an increased connectivity in both groups. The network connectivity of both groups had "small world" character. The present findings indicate (a) that bimanual coordination in the aging brain is associated with a higher functional connectivity even between areas also activated in young adults, independently from task difficulty, and (b) that adequate motor coordination in the context of task-driven bimanual control in older adults may not be solely due to additional neural recruitment but also to aging-related changes of functional relationships between brain regions. PMID- 23637981 TI - Fooling the eyes: the influence of a sound-induced visual motion illusion on eye movements. AB - The question of whether perceptual illusions influence eye movements is critical for the long-standing debate regarding the separation between action and perception. To test the role of auditory context on a visual illusion and on eye movements, we took advantage of the fact that the presence of an auditory cue can successfully modulate illusory motion perception of an otherwise static flickering object (sound-induced visual motion effect). We found that illusory motion perception modulated by an auditory context consistently affected saccadic eye movements. Specifically, the landing positions of saccades performed towards flickering static bars in the periphery were biased in the direction of illusory motion. Moreover, the magnitude of this bias was strongly correlated with the effect size of the perceptual illusion. These results show that both an audio visual and a purely visual illusion can significantly affect visuo-motor behavior. Our findings are consistent with arguments for a tight link between perception and action in localization tasks. PMID- 23637983 TI - Classification of the adenylation and acyl-transferase activity of NRPS and PKS systems using ensembles of substrate specific hidden Markov models. AB - There is a growing interest in the Non-ribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) of microbes, fungi and plants because they can produce bioactive peptides such as antibiotics. The ability to identify the substrate specificity of the enzyme's adenylation (A) and acyl-transferase (AT) domains is essential to rationally deduce or engineer new products. We here report on a Hidden Markov Model (HMM)-based ensemble method to predict the substrate specificity at high quality. We collected a new reference set of experimentally validated sequences. An initial classification based on alignment and Neighbor Joining was performed in line with most of the previously published prediction methods. We then created and tested single substrate specific HMMs and found that their use improved the correct identification significantly for A as well as for AT domains. A major advantage of the use of HMMs is that it abolishes the dependency on multiple sequence alignment and residue selection that is hampering the alignment-based clustering methods. Using our models we obtained a high prediction quality for the substrate specificity of the A domains similar to two recently published tools that make use of HMMs or Support Vector Machines (NRPSsp and NRPS predictor2, respectively). Moreover, replacement of the single substrate specific HMMs by ensembles of models caused a clear increase in prediction quality. We argue that the superiority of the ensemble over the single model is caused by the way substrate specificity evolves for the studied systems. It is likely that this also holds true for other protein domains. The ensemble predictor has been implemented in a simple web-based tool that is available at http://www.cmbi.ru.nl/NRPS-PKS-substrate-predictor/. PMID- 23637987 TI - Autoantibodies against phospholipase A2 receptor in Korean patients with membranous nephropathy. AB - The data were presented in abstract form at the 45(th) meeting of the American Society of Nephrology, October 30-November 04 2012, San Diego, CA, USA. Circulating autoantibodies against M-type phospholipase A2 receptor (PLA2R) are important pathogenic antibodies of idiopathic membranous nephropathy (MN) in adults. However, previous studies on the clinical impact of anti-PLA2R antibodies demonstrated several limitations, including insufficient numbers of study subjects and different time points and methods for anti-PLA2R antibody measurement. To verify the clinical significance of anti-PLA2R antibodies in Korean patients with MN, we measured autoantibodies in serum samples obtained at the time of biopsy from a total of 100 patients with idiopathic MN who had not yet received immunosuppressive treatment. We detected anti-PLA2R antibody in 69 patients, and we observed that autoantibody reactivity reflected the severity of disease activity. Proteinuria and hypoalbuminemia were more severe in patients with anti-PLA2R than in those without the autoantibodies (2.95 g/g vs. 6.85 g/g, P = 0.003; 3.1 g/dL vs. 2.5 g/dL, P = 0.004, respectively). Additionally, the clinical severities worsened proportionally as the levels of anti-PLA2R antibodies increased (P = 0.015 and P for trend <0.001 for proteinuria and hypoalbuminemia, respectively). However, neither the levels nor the presence or absence of anti-PLA2R antibody showed a significant correlation with clinical outcomes, such as remission rate and time to remission. In conclusion, we observed that anti-PLA2R antibodies are highly prevalent in Korean patients with idiopathic MN and that they reflect the clinical disease activity before the administration of immunosuppressive treatment. However, the levels of anti-PLA2R antibody at the time of kidney biopsy may not predict the clinical outcomes in current clinical practice. PMID- 23637984 TI - A study of the mechanism of the chaperone-like function of an scFv of human creatine kinase by computer simulation. AB - A new application of antibodies is to use them as macromolecular chaperones. Protein antigens usually have multiple epitopes, thus, there may be a plurality of antibodies binding to one antigen. However, not all antibodies that bind to one antigen could act as a chaperone. Experiments show that some screened anti human creatine kinase single chain antibodies (scFV) could assist in the folding and stabilizing of the enzyme, while others could not. We built the model of the single chain antibody (scFv-A4) that increased the stability of human creatine kinase (HCK) by the homology modeling method. Epitopes of human creatine kinase were predicted by computer and then the binding of scFv-A4 and HCK was modeled with computer. The calculation results were further combined with the peptide array membrane experiment results to obtain reliable models for the scFv-A4-HCK complex. Based on the above study we gave an explanation about how scFv-A4 could act as a macromolecular chaperone assisting the folding of HCK. This study provides an approach for predicting antigen-antibody binding mode and also a useful theoretical guidance for the study of antibodies' chaperone-like function. PMID- 23637985 TI - Oxidized low density lipoprotein induced caspase-1 mediated pyroptotic cell death in macrophages: implication in lesion instability? AB - BACKGROUND: Macrophage death in advanced lesion has been confirmed to play an important role in plaque instability. However, the mechanism underlying lesion macrophage death still remains largely unknown. METHODS AND RESULTS: Immunohistochemistry showed that caspase-1 activated in advanced lesion and co located with macrophages and TUNEL positive reaction. In in-vitro experiments showed that ox-LDL induced caspase-1 activation and this activation was required for ox-LDL induced macrophages lysis, IL-1beta and IL-18 production as well as DNA fragmentation. Mechanism experiments showed that CD36 and NLRP3/caspase 1/pathway involved in ox-LDL induced macrophage pyroptosis. CONCLUSION: Our study here identified a novel cell death, pyroptosis in ox-LDL induced human macrophage, which may be implicated in lesion macrophages death and play an important role in lesion instability. PMID- 23637986 TI - Prominin 1/CD133 endothelium sustains growth of proneural glioma. AB - In glioblastoma high expression of the CD133 gene, also called Prominin1, is associated with poor prognosis. The PDGF-driven proneural group represents a subset of glioblastoma in which CD133 is not overexpressed. Interestingly, this particular subset shows a relatively good prognosis. As with many other tumors, gliobastoma is believed to arise and be maintained by a restricted population of stem-like cancer cells that express the CD133 transmembrane protein. The significance of CD133(+) cells for gliomagenesis is controversial because of conflicting supporting evidence. Contributing to this inconsistency is the fact that the isolation of CD133(+) cells has largely relied on the use of antibodies against ill-defined glycosylated epitopes of CD133. To overcome this problem, we used a knock-in lacZ reporter mouse, Prom1(lacZ/+) , to track Prom1(+) cells in the brain. We found that Prom1 (prominin1, murine CD133 homologue) is expressed by cells that express markers characteristic of the neuronal, glial or vascular lineages. In proneural tumors derived from injection of RCAS-PDGF into the brains of tv-a;Ink4a-Arf(-/-) Prom1(lacZ/+) mice, Prom1(+) cells expressed markers for astrocytes or endothelial cells. Mice co-transplanted with proneural tumor sphere cells and Prom1(+) endothelium had a significantly increased tumor burden and more vascular proliferation (angiogenesis) than those co-transplanted with Prom1( ) endothelium. We also identified specific genes in Prom1(+) endothelium that code for endothelial signaling modulators that were not overexpressed in Prom1(-) endothelium. These factors may support proneural tumor progression and could be potential targets for anti-angiogenic therapy. PMID- 23637991 TI - Factors associated with risky sexual practices among female sex workers in Karnataka, India. AB - INTRODUCTION: The objectives of this study are to develop a summary measure of risky sexual practice and examine the factors associated with this among female sex workers (FSWs) in Karnataka, India. MATERIALS AND METHODS: Data were drawn from special behavioral surveys (SBS) conducted in 2007 among 577 FSWs in two districts of Karnataka, India: Belgaum and Bangalore. FSWs were recruited using the two-stage probability sampling design. FSWs' sexual practice was considered risky if they reported inconsistent condom use with any sexual partner and reported experience of one of the following vulnerabilities to HIV risk: anal sex, alcohol consumption prior to sex and concurrent sexual relationships. RESULTS: About 51% of FSWs had engaged in risky sexual practice. The odds of engaging in risky sex were higher among FSWs who were older (35+ years) than younger (18-25 years) (58% vs. 45%, Adjusted Odds Ratio (AOR): 2.0, 95% confidence interval (CI): 1.2-3.4), who were currently married than never married (61% vs. 51%, AOR: 4.8, 95% CI: 2.5-9.3), who were in sex work for 10+ years than those who were in sex work for less than five years (66% vs. 39%, AOR: 2.6, 95% CI: 1.6-4.2), and who had sex with 3+ clients/day than those who had sex with fewer clients (67% vs. 38%, AOR: 3.7, 95% CI:2.5-5.5). CONCLUSION: FSWs who are older, currently married, practicing sex work for longer duration and with higher clientele were more likely to engage in risky sexual practices. HIV prevention programs should develop strategies to reach these most-at risk group of FSWs to optimize the effectiveness of such programs. PMID- 23637990 TI - An ultra high-throughput, whole-animal screen for small molecule modulators of a specific genetic pathway in Caenorhabditis elegans. AB - High-throughput screening (HTS) is a powerful approach to drug discovery, but many lead compounds are found to be unsuitable for use in vivo after initial screening. Screening in small animals like C. elegans can help avoid these problems, but this system has been limited to screens with low-throughput or no specific molecular target. We report the first in vivo 1536-well plate assay for a specific genetic pathway in C. elegans. Our assay measures induction of a gene regulated by SKN-1, a master regulator of detoxification genes. SKN-1 inhibitors will be used to study and potentially reverse multidrug resistance in parasitic nematodes. Screens of two small commercial libraries and the full Molecular Libraries Small Molecule Repository (MLSMR) of ~364,000 compounds validate our platform for ultra HTS. Our platform overcomes current limitations of many whole animal screens and can be widely adopted for other inducible genetic pathways in nematodes and humans. PMID- 23637992 TI - miR-221 promotes tumorigenesis in human triple negative breast cancer cells. AB - Patients with triple-negative breast cancers (TNBCs) typically have a poor prognosis. TNBCs are characterized by their resistance to apoptosis, aggressive cellular proliferation, migration and invasion, and currently lack molecular markers and effective targeted therapy. Recently, miR-221/miR-222 have been shown to regulate ERalpha expression and ERalpha-mediated signaling in luminal breast cancer cells, and also to promote EMT in TNBCs. In this study, we characterized the role of miR-221 in a panel of TNBCs as compared to other breast cancer types. miR-221 knockdown not only blocked cell cycle progression, induced cell apoptosis, and inhibited cell proliferation in-vitro but it also inhibited in vivo tumor growth by targeting p27(kip1). Furthermore, miR-221 knockdown inhibited cell migration and invasion by altering E-cadherin expression, and its regulatory transcription factors Snail and Slug in human TNBC cell lines. Therefore, miR-221 functions as an oncogene and is essential in regulating tumorigenesis in TNBCs both in vitro as well as in vivo. PMID- 23637988 TI - Molecular modeling studies of the novel inhibitors of DNA methyltransferases SGI 1027 and CBC12: implications for the mechanism of inhibition of DNMTs. AB - DNA methylation is an epigenetic modification that regulates gene expression by DNA methyltransferases (DNMTs). Inhibition of DNMTs is a promising approach for cancer therapy. Recently, novel classes of the quinolone-based compound, SGI 1027, and RG108-procainamide conjugates, CBC12, have been identified as potent DNMT inhibitors. In this work, we report comprehensive studies using induced-fit docking of SGI-1027 and CBC12 with human DNMT1 and DNMT3A. The docking was performed in the C-terminal MTase catalytic domain, which contains the substrate and cofactor binding sites, in the presence and absence of other domains. Induced fit docking predicts possible binding modes of the ligands through the appropriate structural changes in the receptor. This work suggests a hypothesis of the inhibitory mechanisms of the new inhibitors which is in agreement with the reported autoinhibitory mechanism. The insights obtained in this work can be used to design DNMT inhibitors with novel scaffolds. PMID- 23637993 TI - Local mechanical stimuli regulate bone formation and resorption in mice at the tissue level. AB - Bone is able to react to changing mechanical demands by adapting its internal microstructure through bone forming and resorbing cells. This process is called bone modeling and remodeling. It is evident that changes in mechanical demands at the organ level must be interpreted at the tissue level where bone (re)modeling takes place. Although assumed for a long time, the relationship between the locations of bone formation and resorption and the local mechanical environment is still under debate. The lack of suitable imaging modalities for measuring bone formation and resorption in vivo has made it difficult to assess the mechanoregulation of bone three-dimensionally by experiment. Using in vivo micro computed tomography and high resolution finite element analysis in living mice, we show that bone formation most likely occurs at sites of high local mechanical strain (p<0.0001) and resorption at sites of low local mechanical strain (p<0.0001). Furthermore, the probability of bone resorption decreases exponentially with increasing mechanical stimulus (R(2) = 0.99) whereas the probability of bone formation follows an exponential growth function to a maximum value (R(2) = 0.99). Moreover, resorption is more strictly controlled than formation in loaded animals, and ovariectomy increases the amount of non-targeted resorption. Our experimental assessment of mechanoregulation at the tissue level does not show any evidence of a lazy zone and suggests that around 80% of all (re)modeling can be linked to the mechanical micro-environment. These findings disclose how mechanical stimuli at the tissue level contribute to the regulation of bone adaptation at the organ level. PMID- 23637994 TI - Intercropping of green garlic (Allium sativum L.) induces nutrient concentration changes in the soil and plants in continuously cropped cucumber (Cucumis sativus L.) in a plastic tunnel. AB - A pot-based experiment was conducted to investigate nutrient concentrations in cucumber plants intercropped with various amounts of green garlic. In addition, the soil nutrient contents were studied over two consecutive growing seasons. The results revealed that the accumulation of biomass and the nutritional elements nitrogen (N), phosphorus (P), potassium (K), calcium (Ca) and manganese (Mn) in cucumber plants were significantly increased for intercropping treatments during the two growing seasons compared to monoculture. Conversely, magnesium (Mg) concentrations were decreased in the cucumber plants. Shoot iron (Fe) concentrations decreased whereas root Fe concentrations increased in the intercropping system. Shoot and root zinc (Zn) concentrations decreased during the fall of 2011 but increased during the spring of 2012. Soil organic matter and available N, P and K were significantly increased as the proportion of intercropped green garlic increasing. Medium levels of intercropping green garlic improved cucumber nutrient concentrations the most. The regression analysis showed that the concentrations of most elements were significantly related to the amounts of garlic bulbs, especially the microelements in the spring 2011. The available soil N and organic matter were linearly related to the amounts of garlic bulbs. The results indicate that the nutritional status of the soil and plants of continuously cropped cucumber could be improved by intercropping with green garlic. PMID- 23637995 TI - Earliest archaeological evidence of persistent hominin carnivory. AB - The emergence of lithic technology by ~ 2.6 million years ago (Ma) is often interpreted as a correlate of increasingly recurrent hominin acquisition and consumption of animal remains. Associated faunal evidence, however, is poorly preserved prior to ~ 1.8 Ma, limiting our understanding of early archaeological (Oldowan) hominin carnivory. Here, we detail three large well-preserved zooarchaeological assemblages from Kanjera South, Kenya. The assemblages date to 2.0 Ma, pre-dating all previously published archaeofaunas of appreciable size. At Kanjera, there is clear evidence that Oldowan hominins acquired and processed numerous, relatively complete, small ungulate carcasses. Moreover, they had at least occasional access to the fleshed remains of larger, wildebeest-sized animals. The overall record of hominin activities is consistent through the stratified sequence - spanning hundreds to thousands of years - and provides the earliest archaeological evidence of sustained hominin involvement with fleshed animal remains (i.e., persistent carnivory), a foraging adaptation central to many models of hominin evolution. PMID- 23637989 TI - Circulating brain microvascular endothelial cells (cBMECs) as potential biomarkers of the blood-brain barrier disorders caused by microbial and non microbial factors. AB - Despite aggressive research, central nervous system (CNS) disorders, including blood-brain barrier (BBB) injury caused by microbial infection, stroke, abused drugs [e.g., methamphetamine (METH) and nicotine], and other pathogenic insults, remain the world's leading cause of disabilities. In our previous work, we found that dysfunction of brain microvascular endothelial cells (BMECs), which are a major component of the BBB, could be caused by nicotine, meningitic pathogens and microbial factors, including HIV-1 virulence factors gp41 and gp120. One of the most challenging issues in this area is that there are no available cell-based biomarkers in peripheral blood for BBB disorders caused by microbial and non microbial insults. To identify such cellular biomarkers for BBB injuries, our studies have shown that mice treated with nicotine, METH and gp120 resulted in increased blood levels of CD146+(endothelial marker)/S100B+ (brain marker) circulating BMECs (cBMECs) and CD133+[progenitor cell (PC) marker]/CD146+ endothelial PCs (EPCs), along with enhanced Evans blue and albumin extravasation into the brain. Nicotine and gp120 were able to significantly increase the serum levels of ubiquitin C-terminal hydrolase 1 (UCHL1) (a new BBB marker) as well as S100B in mice, which are correlated with the changes in cBMECs and EPCs. Nicotine and meningitic E. coli K1-induced enhancement of cBMEC levels, leukocyte migration across the BBB and albumin extravasation into the brain were significantly reduced in alpha7 nAChR knockout mice, suggesting that this inflammatory regulator plays an important role in CNS inflammation and BBB disorders caused by microbial and non-microbial factors. These results demonstrated that cBMECs as well as EPCs may be used as potential cell-based biomarkers for indexing of BBB injury. PMID- 23637996 TI - Epidermal growth factor receptor (EGFR)-RAS signaling pathway in penile squamous cell carcinoma. AB - Penile Squamous Cell Carcinoma (SCC) is a rare cancer with poor prognosis and limited response to conventional chemotherapy. The genetic and epigenetic alterations of Epidermal Growth Factor Receptor (EGFR)-RAS-RAF signaling in penile SCC are unclear. This study aims to investigate four key members of this pathway in penile SCC. We examined the expression of EGFR and RAS-association domain family 1 A (RASSF1A) as well as the mutation status of K-RAS and BRAF in 150 cases of penile SCC. EGFR and RASSF1A expression was evaluated by immunohistochemistry. KRAS mutations at codons 12 and 13, and the BRAF mutation at codon 600 were analyzed on DNA isolated from formalin fixed paraffin embedded tissues by direct genomic sequencing. EGFR expression was positive in all specimens, and its over-expression rate was 92%. RASSF1A expression rate was only 3.42%. Significant correlation was not found between the expression of EGFR or RASSF1A and tumor grade, pT stage or lymph node metastases. The detection of KRAS and BRAF mutations analysis was performed in 94 and 83 tumor tissues, respectively. We found KRAS mutation in only one sample and found no BRAF V600E point mutation. In summary, we found over-expression of EGFR in the majority cases of penile SCC, but only rare expression of RASSF1A, rare KRAS mutation, and no BRAF mutation in penile SCC. These data suggest that anti-EGFR agents may be potentially considered as therapeutic options in penile SCC. PMID- 23637999 TI - Evolvability is inevitable: increasing evolvability without the pressure to adapt. AB - Why evolvability appears to have increased over evolutionary time is an important unresolved biological question. Unlike most candidate explanations, this paper proposes that increasing evolvability can result without any pressure to adapt. The insight is that if evolvability is heritable, then an unbiased drifting process across genotypes can still create a distribution of phenotypes biased towards evolvability, because evolvable organisms diffuse more quickly through the space of possible phenotypes. Furthermore, because phenotypic divergence often correlates with founding niches, niche founders may on average be more evolvable, which through population growth provides a genotypic bias towards evolvability. Interestingly, the combination of these two mechanisms can lead to increasing evolvability without any pressure to out-compete other organisms, as demonstrated through experiments with a series of simulated models. Thus rather than from pressure to adapt, evolvability may inevitably result from any drift through genotypic space combined with evolution's passive tendency to accumulate niches. PMID- 23637997 TI - Twin and sibling studies using health insurance data: the example of attention deficit/hyperactivity disorder (ADHD). AB - BACKGROUND AND AIMS: Twin studies are used to assess the contribution of genetic factors to the aetiology of diseases. To show the feasibility of such research on the basis of health insurance data, we analysed twin and sibling data on the attention deficit/hyperactivity disorder (ADHD) in the German Pharmacoepidemiological Research Database (GePaRD). METHODS: The GePaRD consists of data from four statutory health insurances, including around 17% of the total population of Germany. Among those insured in 2005, we identified 286,653 non twin sibling pairs and 12,486 twin pairs. Each pair consisted of an index child (6 to 12 years old) and a co-sibling of equal age or up to five years older. ADHD cases were identified by hospital or ambulatory ICD-10 diagnoses (F90.0 or F90.1) and prescriptions. We estimated tetrachoric correlations, percentage of concordant pairs, concordance rates, and heritability. Weighted estimates for the indirect assessment of mono- and dizygotic pairs were derived. RESULTS: TETRACHORIC CORRELATIONS WERE HIGHEST FOR TWIN PAIRS OF THE SAME SEX (MALES: 0.85, 95% CI 0.81-0.89; females: 0.81, 95% CI 0.73-0.88) and lowest for opposite sex non-twin sibling pairs (0.43, 95% CI 0.41-0.45). Heritability estimates were 0.88 (95% CI: 0.79-0.97) for males and 0.77 (95% CI: 0.60-0.95) for females. CONCLUSIONS: The study clearly reproduced the well-known strong genetic component in the aetiology of ADHD. This approach could be used for further assessments of genetic components in other diseases. PMID- 23638000 TI - The BTBR mouse model of autism spectrum disorders has learning and attentional impairments and alterations in acetylcholine and kynurenic acid in prefrontal cortex. AB - Autism is a complex spectrum of disorders characterized by core behavioral deficits in social interaction, communication, repetitive stereotyped behaviors and restricted interests. Autism frequently presents with additional cognitive symptoms, including attentional deficits and intellectual disability. Preclinical models are important tools for studying the behavioral domains and biological underpinnings of autism, and potential treatment targets. The inbred BTBR T+tf/J (BTBR) mouse strain has been used as an animal model of core behavioral deficits in autism. BTBR mice exhibit repetitive behaviors and deficits in sociability and communication, but other aspects of their cognitive phenotype, including attentional performance, are not well characterized. We examined the attentional abilities of BTBR mice in the 5-choice serial reaction time task (5-CSRTT) using an automated touchscreen testing apparatus. The 5-CSRTT is an analogue of the human continuous performance task of attention, and so both the task and apparatus have translational relevance to human touchscreen cognitive testing. We also measured basal extracellular levels of a panel of neurotransmitters within the medial prefrontal cortex, a brain region critically important for performing the 5-CSRTT. We found that BTBR mice have increased impulsivity, defined as an inability to withhold responding, and decreased motivation, as compared to C57Bl/6J mice. Both of these features characterize attentional deficit disorders in humans. BTBR mice also display decreased accuracy in detecting short stimuli, lower basal levels of extracellular acetylcholine and higher levels of kynurenic acid within the prefrontal cortex. Intact cholinergic transmission in prefrontal cortex is required for accurate performance of the 5-CSRTT, consequently this cholinergic deficit may underlie less accurate performance in BTBR mice. Based on our findings that BTBR mice have attentional impairments and alterations in a key neural substrate of attention, we propose that they may be valuable for studying mechanisms for treatment of cognitive dysfunction in individuals with attention deficits and autism. PMID- 23637998 TI - GSTT1 null genotype contributes to lung cancer risk in asian populations: a meta analysis of 23 studies. AB - BACKGROUND: Genetic variation in glutathione S-transferases (GSTs) may contribute to lung cancer risk. Many studies have investigated the correlation between the Glutathione S-transferase T1 (GSTT1) null genotype and lung cancer risk in Asian population but yielded inconclusive results. METHODOLOGY/PRINCIPAL FINDINGS: We performed a meta-analysis of 23 studies including 4065 cases and 5390 controls. We assessed the strength of the association of GSTT1 with lung cancer risk and performed sub-group analyses by source of controls, smoking status, histological types, and sample size. A statistically significant correlation between GSTT1 null genotype and lung cancer in Asian population was observed (OR = 1.28, 95% CI = 1.10, 1.49; Pheterogeneity<0.001 and I(2) = 62.0%). Sub-group analysis revealed there was a statistically increased lung cancer risk in ever-smokers who carried the GSTT1 null genotype (OR = 1.94, 95% CI = 1.27, 2.96; P heterogeneity = 0.02 and I(2) = 58.1%). It was also indicated that GSTT1 null genotype could increase lung cancer risk among population-based studies (OR = 1.25, 95% CI = 1.04, 1.50; Pheterogeneity = 0.003 and I(2) = 56.8%). The positive association was also found in studies of sample size (<=500 participants) (OR = 1.34, 95% CI = 1.10, 1.62; Pheterogeneity<0.001 and I(2) = 65.4%). CONCLUSIONS: These meta-analysis results suggest that GSTT1 null genotype is associated with a significantly increased risk of lung cancer in Asian population. PMID- 23638004 TI - Modulation of HJURP (Holliday Junction-Recognizing Protein) levels is correlated with glioblastoma cells survival. AB - BACKGROUND: Diffuse astrocytomas are the most common type of primary brain cancer in adults. They present a wide variation in differentiation and aggressiveness, being classified into three grades: low-grade diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (grade IV), the most frequent and the major lethal type. Recent studies have highlighted the molecular heterogeneity of astrocytomas and demonstrated that large-scale analysis of gene expression could help in their classification and treatment. In this context, we previously demonstrated that HJURP, a novel protein involved in the repair of DNA double-strand breaks, is highly overexpressed in glioblastoma. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that HJURP is remarkably overexpressed in a cohort composed of 40 patients with different grade astrocytomas. We also observed that tumors presenting the higher expression levels of HJURP are associated with poor survival prognosis, indicating HJURP overexpression as an independent prognostic factor of death risk for astrocytoma patients. More importantly, we found that HJURP knockdown strongly affects the maintenance of glioblastoma cells in a selective manner. Glioblastoma cells showed remarkable cell cycle arrest and premature senescence that culminated in elevated levels of cell death, differently from non-tumoral cells that were minimally affected. CONCLUSIONS: These data suggest that HJURP has an important role in the maintenance of extremely proliferative cells of high-grade gliomas and point to HJURP as a potential therapeutic target for the development of novel treatments for glioma patients. PMID- 23638005 TI - Combined effects of the North Atlantic Oscillation and the Arctic Oscillation on sea surface temperature in the Alboran Sea. AB - We explored the possible effects of the North Atlantic Oscillation (NAO) and Arctic Oscillation (AO) on interannual sea surface temperature (SST) variations in the Alboran Sea, both separately and combined. The probability of observing mean annual SST values higher than average was related to NAO and AO values of the previous year. The effect of NAO on SST was negative, while that of AO was positive. The pure effects of NAO and AO on SST are obscuring each other, due to the positive correlation between them. When decomposing SST, NAO and AO in seasonal values, we found that variation in mean annual SST and mean winter SST was significantly related to the mean autumn NAO of the previous year, while mean summer SST was related to mean autumn AO of the previous year. The one year delay in the effect of the NAO and AO on the SST could be partially related to the amount of accumulated snow, as we found a significant correlation between the total snow in the North Alboran watershed for a year with the annual average SST of the subsequent year. A positive AO implies a colder atmosphere in the Polar Regions, which could favour occasional cold waves over the Iberian Peninsula which, when coupled with precipitations favoured by a negative NAO, may result in snow precipitation. This snow may be accumulated in the high peaks and melt down in spring-summer of the following year, which consequently increases the runoff of freshwater to the sea, which in turn causes a diminution of sea surface salinity and density, and blocks the local upwelling of colder water, resulting in a higher SST. PMID- 23638001 TI - Adrenal gland infection by serotype 5 adenovirus requires coagulation factors. AB - Recombinant, replication-deficient serotype 5 adenovirus infects the liver upon in vivo, systemic injection in rodents. This infection requires the binding of factor X to the capsid of this adenovirus. Another organ, the adrenal gland is also infected upon systemic administration of Ad, however, whether this infection is dependent on the cocksackie adenovirus receptor (CAR) or depends on the binding of factor X to the viral capsid remained to be determined. In the present work, we have used a pharmacological agent (warfarin) as well as recombinant adenoviruses lacking the binding site of Factor X to elucidate this mechanism in mice. We demonstrate that, as observed in the liver, adenovirus infection of the adrenal glands in vivo requires Factor X. Considering that the level of transduction of the adrenal glands is well-below that of the liver and that capsid-modified adenoviruses are unlikely to selectively infect the adrenal glands, we have used single-photon emission computed tomography (SPECT) imaging of gene expression to determine whether local virus administration (direct injection in the kidney) could increase gene transfer to the adrenal glands. We demonstrate that direct injection of the virus in the kidney increases gene transfer in the adrenal gland but liver transduction remains important. These observations strongly suggest that serotype 5 adenovirus uses a similar mechanism to infect liver and adrenal gland and that selective transgene expression in the latter is more likely to be achieved through transcriptional targeting. PMID- 23638002 TI - Reduction of in-stent restenosis risk on nickel-free stainless steel by regulating cell apoptosis and cell cycle. AB - High nitrogen nickel-free austenitic stainless steel (HNNF SS) is one of the biomaterials developed recently for circumventing the in-stent restenosis (ISR) in coronary stent applications. To understand the ISR-resistance mechanism, we have conducted a comparative study of cellular and molecular responses of human umbilical vein endothelial cells (HUVECs) to HNNF SS and 316L SS (nickel containing austenitic 316L stainless steel) which is the stent material used currently. CCK-8 analysis and flow cytometric analysis were used to assess the cellular responses (proliferation, apoptosis, and cell cycle), and quantitative real-time PCR (qRT-PCR) was used to analyze the gene expression profile of HUVECs exposed to HNNF SS and 316L SS, respectively. Flow cytometry analysis revealed that 316L SS could activate the cellular apoptosis more efficiently and initiate an earlier entry into the S-phase of cell cycle than HNNF SS. At the molecular level, qRT-PCR results showed that the genes regulating cell apoptosis and autophagy were overexpressed on 316L SS. Further examination indicated that nickel released from 316L SS triggered the cell apoptosis via Fas-Caspase8 Caspase3 exogenous pathway. These molecular mechanisms of HUVECs present a good model for elucidating the observed cellular responses. The findings in this study furnish valuable information for understanding the mechanism of ISR-resistance on the cellular and molecular basis as well as for developing new biomedical materials for stent applications. PMID- 23638003 TI - Influence of mesenchymal stem cell transplantation on stereotypic behavior and dopamine levels in rats with Tourette syndrome. AB - CONTEXT: Tourette syndrome (TS) is a heterogeneous neuropsychiatric disorder. Chronic motor and phonic tics are central symptoms in TS patients. For some patients, tics are intractable to any traditional treatment and cause lifelong impairment and life-threatening symptoms. New therapies should be developed to address symptoms and overt manifestations of TS. Transplantation of neurogenic stem cells might be a viable approach in TS treatment. OBJECTIVE: We used mesenchymal stem cell (MSC) transplantation to treat TS. We discuss the mechanism of action, as well as the efficiency of this approach, in treating TS. SETTINGS AND DESIGN: An autoimmune TS animal model was adopted in the present study. Forty eight Wistar rats were randomly allocated to the control group and the 2 experimental groups, namely, TS rats+vehicle and TS rats+MSC. MSCs were co cultured with 5-bromodeoxyuridine (BrdU) for 24 h for labeling prior to grafting. METHODS: Stereotypic behaviors were recorded at 1, 7, 14, and 28 days after transplantation. Dopamine (DA) content in the striatum of rats in the 3 groups was measured using a high-performance liquid chromatography column equipped with an electrochemical detector (HPLC-ECD) on day 28 after transplantation. STATISTICAL ANALYSIS: Statistical analysis was performed by repeated measurements analysis of variance to evaluate stereotypic behavior counts at different time points. RESULTS: TS rats exhibited higher stereotypic behavioral counts compared with the control group. One week after transplantation, TS rats with MSC grafts exhibited significantly decreased stereotypic behavior. Rats with MSC grafts also showed reduced levels of DA in the striatum when compared with TS rats, which were exposed only to the vehicle. CONCLUSIONS: Intrastriatal transplantation of MSCs can provide relief from the stereotypic behavior of TS. Our results indicate that this approach may have potential for developing therapies against TS. The mechanism(s) of the observed effect may be related to the suppression of DA system by decreasing the content of DA in TS rats. PMID- 23638006 TI - Bioinformatics analysis identify novel OB fold protein coding genes in C. elegans. AB - BACKGROUND: The C. elegans genome has been extensively annotated by the WormBase consortium that uses state of the art bioinformatics pipelines, functional genomics and manual curation approaches. As a result, the identification of novel genes in silico in this model organism is becoming more challenging requiring new approaches. The Oligonucleotide-oligosaccharide binding (OB) fold is a highly divergent protein family, in which protein sequences, in spite of having the same fold, share very little sequence identity (5-25%). Therefore, evidence from sequence-based annotation may not be sufficient to identify all the members of this family. In C. elegans, the number of OB-fold proteins reported is remarkably low (n=46) compared to other evolutionary-related eukaryotes, such as yeast S. cerevisiae (n=344) or fruit fly D. melanogaster (n=84). Gene loss during evolution or differences in the level of annotation for this protein family, may explain these discrepancies. METHODOLOGY/PRINCIPAL FINDINGS: This study examines the possibility that novel OB-fold coding genes exist in the worm. We developed a bioinformatics approach that uses the most sensitive sequence-sequence, sequence profile and profile-profile similarity search methods followed by 3D-structure prediction as a filtering step to eliminate false positive candidate sequences. We have predicted 18 coding genes containing the OB-fold that have remarkably partially been characterized in C. elegans. CONCLUSIONS/SIGNIFICANCE: This study raises the possibility that the annotation of highly divergent protein fold families can be improved in C. elegans. Similar strategies could be implemented for large scale analysis by the WormBase consortium when novel versions of the genome sequence of C. elegans, or other evolutionary related species are being released. This approach is of general interest to the scientific community since it can be used to annotate any genome. PMID- 23638008 TI - Childhood malaria admission rates to four hospitals in Malawi between 2000 and 2010. AB - INTRODUCTION: The last few years have witnessed rapid scaling-up of key malaria interventions in several African countries following increases in development assistance. However, there is only limited country-specific information on the health impact of expanded coverage of these interventions. METHODS: Paediatric admission data were assembled from 4 hospitals in Malawi reflecting different malaria ecologies. Trends in monthly clinical malaria admissions between January 2000 and December 2010 were analysed using time-series models controlling for covariates related to climate and service use to establish whether changes in admissions can be related to expanded coverage of interventions aimed at reducing malaria infection. RESULTS: In 3 of 4 sites there was an increase in clinical malaria admission rates. Results from time series models indicate a significant month-to-month increase in the mean clinical malaria admission rates at two hospitals (trend P<0.05). At these hospitals clinical malaria admissions had increased from 2000 by 41% to 100%. Comparison of changes in malaria risk and ITN coverage appear to correspond to a lack of disease declines over the period. Changes in intervention coverage within hospital catchments showed minimal increases in ITN coverage from <6% across all sites in 2000 to maximum of 33% at one hospital site by 2010. Additionally, malaria transmission intensity remained unchanged between 2000-2010 across all sites. DISCUSSION: Despite modest increases in coverage of measures to reduce infection there has been minimal changes in paediatric clinical malaria cases in four hospitals in Malawi. Studies across Africa are increasingly showing a mixed set of impact results and it is important to assemble more data from more sites to understand the wider implications of malaria funding investment. We also caution that impact surveillance should continue in areas where intervention coverage is increasing with time, for example Malawi, as decline may become evident within a period when coverage reaches optimal levels. PMID- 23638007 TI - Colonic inflammation in mice is improved by cigarette smoke through iNKT cells recruitment. AB - Cigarette smoke (CS) protects against intestinal inflammation during ulcerative colitis. Immunoregulatory mechanisms sustaining this effect remain unknown. The aim of this study was to assess the effects of CS on experimental colitis and to characterize the intestinal inflammatory response at the cellular and molecular levels. Using the InExpose(r) System, a smoking device accurately reproducing human smoking habit, we pre-exposed C57BL/6 mice for 2 weeks to CS, and then we induced colitis by administration of dextran sodium sulfate (DSS). This system allowed us to demonstrate that CS exposure improved colonic inflammation (significant decrease in clinical score, body weight loss and weight/length colonic ratio). This improvement was associated with a significant decrease in colonic proinflammatory Th1/Th17 cytokine expression, as compared to unexposed mice (TNF (p=0.0169), IFNgamma (p<0.0001), and IL-17 (p=0.0008)). Smoke exposure also induced an increased expression of IL-10 mRNA (p=0.0035) and a marked recruitment of iNKT (invariant Natural Killer T; CD45+ TCRbeta+ CD1d tetramer+) cells in the colon of DSS-untreated mice. Demonstration of the role of iNKT cells in CS-dependent colitis improvement was performed using two different strains of NKT cells deficient mice. Indeed, in Jalpha18KO and CD1dKO animals, CS exposure failed to induce significant regulation of DSS-induced colitis both at the clinical and molecular levels. Thus, our study demonstrates that iNKT cells are pivotal actors in the CS-dependent protection of the colon. These results highlight the role of intestinal iNKT lymphocytes and their responsiveness to environmental stimuli. Targeting iNKT cells would represent a new therapeutic way for inflammatory bowel diseases. PMID- 23638010 TI - A satellite explosion in the genome of holocentric nematodes. AB - Centromere sequences in the genome are associated with the formation of kinetochores, where spindle microtubules grow in mitosis. Centromere sequences usually have long tandem repeats (satellites). In holocentric nematodes it is not clear how kinetochores are formed during mitosis; they are distributed throughout the chromosomes. For this reason it appeared of interest to study the satellites in nematodes in order to determine if they offer any clue on how kinetochores are assembled in these species. We have studied the satellites in the genome of six nematode species. We found that the presence of satellites depends on whether the nematode chromosomes are holocentric or monocentric. It turns out that holocentric nematodes are unique because they have a large number of satellites scattered throughout their genome. Their number, length and composition are different in each species: they apparently have very little evolutionary conservation. In contrast, no scattered satellites are found in the monocentric nematode Trichinella spiralis. It appears that the absence/presence of scattered satellites in the genome distinguishes monocentric from holocentric nematodes. We conclude that the presence of satellites is related to the holocentric nature of the chromosomes of most nematodes. Satellites may stabilize a higher order structure of chromatin and facilitate the formation of kinetochores. We also present a new program, SATFIND, which is suited to find satellite sequences. PMID- 23638011 TI - MicroRNA-146a is upregulated by and negatively regulates TLR2 signaling. AB - TLR signaling is a crucial component of the innate immune response to infection. MicroRNAs (miRNAs) have been shown to be upregulated during TLR signaling. Specifically, microRNA-146a (miR-146a) plays a key role in endotoxin tolerance by downregulating interleukin-1 receptor-associated kinase 1 (IRAK-1). The aim of this study was to assess the role of miR-146a in the TLR2 signaling and development of bacterial lipoprotein (BLP) self-tolerance and cross-tolerance to bacteria. Expression of miR-146a increased in a dose- and time-dependent manner in BLP-stimulated human THP-1 promonocytic cells. In BLP-tolerised cells miR-146a was even further upregulated in response to BLP re-stimulation (p<0.001). Re stimulation of BLP-tolerised cells with heat-killed gram-negative Salmonella typhimurium (S. typhimurium), but not gram-positive Staphylococcus aureus (S. aureus), led to significant overexpression of miR-146a (p<0.05). Transfection of naive cells with a miR-146a mimic substantially suppressed TNF-alpha production (p<0.05). Furthermore, overexpression of miR-146a resulted in strong reduction in IRAK-1 and phosphorylated IkappaBalpha expression in naive and S. typhimurium stimulated THP-1 cells. Collectively, miR-146a is upregulated in response to BLP and bacterial stimulation in both naive and BLP-tolerised cells. Overexpression of miR-146a induces a state analogous to tolerance in BLP-stimulated cells and therefore may represent a future target for exogenous modulation of tolerance during microbial infection and sepsis. PMID- 23638009 TI - Environmental particulate matter induces murine intestinal inflammatory responses and alters the gut microbiome. AB - BACKGROUND: Particulate matter (PM) is a key pollutant in ambient air that has been associated with negative health conditions in urban environments. The aim of this study was to examine the effects of orally administered PM on the gut microbiome and immune function under normal and inflammatory conditions. METHODS: Wild-type 129/SvEv mice were gavaged with Ottawa urban PM10 (EHC-93) for 7-14 days and mucosal gene expression analyzed using Ingenuity Pathways software. Intestinal permeability was measured by lactulose/mannitol excretion in urine. At sacrifice, segments of small and large intestine were cultured and cytokine secretion measured. Splenocytes were isolated and incubated with PM10 for measurement of proliferation. Long-term effects of exposure (35 days) on intestinal cytokine expression were measured in wild-type and IL-10 deficient (IL 10(-/-)) mice. Microbial composition of stool samples was assessed using terminal restriction fragment length polymorphism. Short chain fatty acids were measured in caecum. RESULTS: Short-term treatment of wild-type mice with PM10 altered immune gene expression, enhanced pro-inflammatory cytokine secretion in the small intestine, increased gut permeability, and induced hyporesponsiveness in splenocytes. Long-term treatment of wild-type and IL-10(-/-) mice increased pro inflammatory cytokine expression in the colon and altered short chain fatty acid concentrations and microbial composition. IL-10(-/-) mice had increased disease as evidenced by enhanced histological damage. CONCLUSIONS: Ingestion of airborne particulate matter alters the gut microbiome and induces acute and chronic inflammatory responses in the intestine. PMID- 23638013 TI - Longitudinal MRI evaluation of intracranial development and vascular characteristics of breast cancer brain metastases in a mouse model. AB - Longitudinal MRI was applied to monitor intracranial initiation and development of brain metastases and assess tumor vascular volume and permeability in a mouse model of breast cancer brain metastases. Using a 9.4T system, high resolution anatomic MRI and dynamic susceptibility contrast (DSC) perfusion MRI were acquired at different time points after an intracardiac injection of brain-tropic breast cancer MDA-MB231BR-EGFP cells. Three weeks post injection, multifocal brain metastases were first observed with hyperintensity on T2-weighted images, but isointensity on T1-weighted post contrast images, indicating that blood-tumor barrier (BTB) at early stage of brain metastases was impermeable. Follow-up MRI revealed intracranial tumor growth and increased number of metastases that distributed throughout the whole brain. At the last scan on week 5, T1-weighted post contrast images detected BTB disruption in 160 (34%) of a total of 464 brain metastases. Enhancement in some of the metastases was only seen in partial regions of the tumor, suggesting intratumoral heterogeneity of BTB disruption. DSC MRI measurements of relative cerebral blood volume (rCBV) showed that rCBV of brain metastases was significantly lower (mean= 0.89+/-0.03) than that of contralateral normal brain (mean= 1.00+/-0.03; p<0.005). Intriguingly, longitudinal measurements revealed that rCBV of individual metastases at early stage was similar to, but became significantly lower than that of contralateral normal brain with tumor growth (p<0.05). The rCBV data were concordant with histological analysis of microvascular density (MVD). Moreover, comprehensive analysis suggested no significant correlation among tumor size, rCBV and BTB permeability. In conclusion, longitudinal MRI provides non-invasive in vivo assessments of spatial and temporal development of brain metastases and their vascular volume and permeability. The characteristic rCBV of brain metastases may have a diagnostic value. PMID- 23638012 TI - DNA methylation profile distinguishes clear cell sarcoma of the kidney from other pediatric renal tumors. AB - A number of specific, distinct neoplastic entities occur in the pediatric kidney, including Wilms' tumor, clear cell sarcoma of the kidney (CCSK), congenital mesoblastic nephroma (CMN), rhabdoid tumor of the kidney (RTK), and the Ewing's sarcoma family of tumors (ESFT). By employing DNA methylation profiling using Illumina Infinium HumanMethylation27, we analyzed the epigenetic characteristics of the sarcomas including CCSK, RTK, and ESFT in comparison with those of the non neoplastic kidney (NK), and these tumors exhibited distinct DNA methylation profiles in a tumor-type-specific manner. CCSK is the most frequently hypermethylated, but least frequently hypomethylated, at CpG sites among these sarcomas, and exhibited 490 hypermethylated and 46 hypomethylated CpG sites in compared with NK. We further validated the results by MassARRAY, and revealed that a combination of four genes was sufficient for the DNA methylation profile based differentiation of these tumors by clustering analysis. Furthermore, THBS1 CpG sites were found to be specifically hypermethylated in CCSK and, thus, the DNA methylation status of these THBS1 sites alone was sufficient for the distinction of CCSK from other pediatric renal tumors, including Wilms' tumor and CMN. Moreover, combined bisulfite restriction analysis could be applied for the detection of hypermethylation of a THBS1 CpG site. Besides the biological significance in the pathogenesis, the DNA methylation profile should be useful for the differential diagnosis of pediatric renal tumors. PMID- 23638014 TI - Evolution of the Ainu language in space and time. AB - Languages evolve over space and time. Illuminating the evolutionary history of language is important because it provides a unique opportunity to shed light on the population history of the speakers. Spatial and temporal aspects of language evolution are particularly crucial for understanding demographic history, as they allow us to identify when and where the languages originated, as well as how they spread across the globe. Here we apply Bayesian phylogeographic methods to reconstruct spatiotemporal evolution of the Ainu language: an endangered language spoken by an indigenous group that once thrived in northern Japan. The conventional dual-structure model has long argued that modern Ainu are direct descendants of a single, Pleistocene human lineage from Southeast Asia, namely the Jomon people. In contrast, recent evidence from archaeological, anthropological and genetic evidence suggest that the Ainu are an outcome of significant genetic and cultural contributions from Siberian hunter-gatherers, the Okhotsk, who migrated into northern Hokkaido around 900-1600 years ago. Estimating from 19 Ainu language varieties preserved five decades ago, our analysis shows that they are descendants of a common ancestor who spread from northern Hokkaido around 1300 years ago. In addition to several lines of emerging evidence, our phylogeographic analysis strongly supports the hypothesis that recent expansion of the Okhotsk to northern Hokkaido had a profound impact on the origins of the Ainu people and their culture, and hence calls for a refinement to the dual-structure model. PMID- 23638015 TI - Chemical chaperones exceed the chaperone effects of RIC-3 in promoting assembly of functional alpha7 AChRs. AB - Functional alpha7 nicotinic acetylcholine receptors (AChRs) do not assemble efficiently in cells transfected with alpha7 subunits unless the cells are also transfected with the chaperone protein RIC-3. Despite the presence of RIC-3, large amounts of these subunits remain improperly assembled. Thus, additional chaperone proteins are probably required for efficient assembly of alpha7 AChRs. Cholinergic ligands can act as pharmacological chaperones to promote assembly of mature AChRs and upregulate the amount of functional AChRs. In addition, we have found that the chemical chaperones 4-phenylbutyric acid (PBA) and valproic acid (VPA) greatly increase the amount of functional alpha7 AChRs produced in a cell line expressing both alpha7 and RIC-3. Increased alpha7 AChR expression allows assay of drug action using a membrane potential-sensitive fluorescent indicator. Both PBA and VPA also increase alpha7 expression in the SH-SY5Y neuroblastoma cell line that endogenously expresses alpha7 AChRs. VPA increases expression of endogenous alpha7 AChRs in hippocampal neurons but PBA does not. RIC-3 is insufficient for optimal assembly of alpha7 AChRs, but provides assay conditions for detecting additional chaperones. Chemical chaperones are a useful pragmatic approach to express high levels of human alpha7 AChRs for drug selection and characterization and possibly to increase alpha7 expression in vivo. PMID- 23638016 TI - The complement anaphylatoxin C3a receptor (C3aR) contributes to the inflammatory response in dextran sulfate sodium (DSS)-induced colitis in mice. AB - Inflammatory bowel diseases are a critical public health issue, and as treatment options remain limited, there is a need to unravel the underlying pathomechanisms in order to identify new therapeutic targets. Complement activation was found in patients suffering from inflammatory bowel disease, and the complement anaphylatoxin C5a and its receptor C5aR have been implicated in disease pathogenesis in animal models of bowel inflammation. To further characterize complement-related pathomechanisms in inflammatory bowel disease, we have investigated the role of the anaphylatoxin C3a receptor in acute dextran sulfate sodium-induced colitis in mice. For this, colitis was induced in C3a receptor deficient BALB/c and C57BL/6 mice, and disease severity was evaluated by clinical and histological examination, and by measuring the mRNA expression or protein levels of inflammatory mediators in the tissue. C3a receptor deficiency was partially protective in BALB/c mice, which had significantly reduced weight loss, clinical and histological scores, colon shortening, and CXCL-1/KC mRNA, myeloperoxidase and interleukin-6 tissue levels compared to the corresponding wild type mice. In C57BL/6 mice the differences between wild type and C3a receptor-deficient animals were much smaller and reached no significance. Our data demonstrate that the contribution of C3a receptor to disease pathogenesis and severity of dextran sulfate sodium-induced colitis in mice depends on the genetic background. Further studies will be required to clarify whether targeting of C3a receptor, possibly in combination with C5a receptor, might be considered as a therapeutic strategy for inflammatory bowel disease. PMID- 23638018 TI - Invasion of the red seaweed Heterosiphonia japonica spans biogeographic provinces in the Western North Atlantic Ocean. AB - The recent invasion of the red alga Heterosiphonia japonica in the western North Atlantic Ocean has provided a unique opportunity to study invasion dynamics across a biogeographical barrier. Native to the western North Pacific Ocean, initial collections in 2007 and 2009 restricted the western North Atlantic range of this invader to Rhode Island, USA. However, through subtidal community surveys, we document the presence of Heterosiphonia in coastal waters from Maine to New York, USA, a distance of more than 700 km. This geographical distribution spans a well-known biogeographical barrier at Cape Cod, Massachusetts. Despite significant differences in subtidal community structure north and south of Cape Cod, Heterosiphonia was found at all but two sites surveyed in both biogeographic provinces, suggesting that this invader is capable of rapid expansion over broad geographic ranges. Across all sites surveyed, Heterosiphonia comprised 14% of the subtidal benthic community. However, average abundances of nearly 80% were found at some locations. As a drifting macrophyte, Heterosiphonia was found as intertidal wrack in abundances of up to 65% of the biomass washed up along beaches surveyed. Our surveys suggest that the high abundance of Heterosiphonia has already led to marked changes in subtidal community structure; we found significantly lower species richness in recipient communities with higher Heterosiphona abundances. Based on temperature and salinity tolerances of the European populations, we believe Heterosiphonia has the potential to invade and alter subtidal communities from Florida to Newfoundland in the western North Atlantic. PMID- 23638020 TI - The evolutionary paradox of tooth wear: simply destruction or inevitable adaptation? AB - Over the last century, humans from industrialized societies have witnessed a radical increase in some dental diseases. A severe problem concerns the loss of dental materials (enamel and dentine) at the buccal cervical region of the tooth. This "modern-day" pathology, called non-carious cervical lesions (NCCLs), is ubiquitous and worldwide spread, but is very sporadic in modern humans from pre industrialized societies. Scholars believe that several factors are involved, but the real dynamics behind this pathology are far from being understood. Here we use an engineering approach, finite element analysis (FEA), to suggest that the lack of dental wear, characteristic of industrialized societies, might be a major factor leading to NCCLs. Occlusal loads were applied to high resolution finite element models of lower second premolars (P2) to demonstrate that slightly worn P2s envisage high tensile stresses in the buccal cervical region, but when worn down artificially in the laboratory the pattern of stress distribution changes and the tensile stresses decrease, matching the results obtained in naturally worn P2s. In the modern industrialized world, individuals at advanced ages show very moderate dental wear when compared to past societies, and teeth are exposed to high tensile stresses at the buccal cervical region for decades longer. This is the most likely mechanism explaining enamel loss in the cervical region, and may favor the activity of other disruptive processes such as biocorrosion. Because of the lack of dental abrasion, our masticatory apparatus faces new challenges that can only be understood in an evolutionary perspective. PMID- 23638017 TI - Increased cortical activity in binge drinkers during working memory task: a preliminary assessment through a functional magnetic resonance imaging study. AB - BACKGROUND: Cerebral dysfunction is a common feature of both chronic alcohol abusers and binge drinkers. Here, we aimed to study whether, at equated behavioral performance levels, binge drinkers exhibited increased neural activity while performing simple cognitive tasks. METHODS: Thirty-two participants (16 binge drinkers and 16 matched controls) were scanned using functional magnetic resonance imaging (fMRI) while performing an n-back working memory task. In the control zero-back (N0) condition, subjects were required to press a button with the right hand when the number "2" was displayed. In the two-back (N2) condition, subjects had to press a button when the displayed number was identical to the number shown two trials before. RESULTS: fMRI analyses revealed higher bilateral activity in the pre-supplementary motor area in binge drinkers than matched controls, even though behavioral performances were similar. Moreover, binge drinkers showed specific positive correlations between the number of alcohol doses consumed per occasion and higher activity in the dorsomedial prefrontal cortex, as well as between the number of drinking occasions per week and higher activity in cerebellum, thalamus and insula while performing the N2 memory task. CONCLUSIONS: Binge alcohol consumption leads to possible compensatory cerebral changes in binge drinkers that facilitate normal behavioral performance. These changes in cerebral responses may be considered as vulnerability factors for developing adult substance use disorders. PMID- 23638022 TI - How the statistics of sequential presentation influence the learning of structure. AB - Recent work has shown that humans can learn or detect complex dependencies among variables. Even learning a simple dependency involves the identification of an underlying model and the learning of its parameters. This process represents learning a structured problem. We are interested in an empirical assessment of some of the factors that enable humans to learn such a dependency over time. More specifically, we look at how the statistics of the presentation of samples from a given structure influence learning. Participants engage in an experimental task where they are required to predict the timing of a target. At the outset, they are oblivious to the existence of a relationship between the position of a stimulus and the required temporal response to intercept it. Different groups of participants are either presented with a Random Walk where consecutive stimuli were correlated or with stimuli that were uncorrelated over time. We find that the structural relationship implicit in the task is only learned in the conditions where the stimuli are independently drawn. This leads us to believe that humans require rich and independent sampling to learn hidden structures among variables. PMID- 23638019 TI - Suicide ideation of individuals in online social networks. AB - Suicide explains the largest number of death tolls among Japanese adolescents in their twenties and thirties. Suicide is also a major cause of death for adolescents in many other countries. Although social isolation has been implicated to influence the tendency to suicidal behavior, the impact of social isolation on suicide in the context of explicit social networks of individuals is scarcely explored. To address this question, we examined a large data set obtained from a social networking service dominant in Japan. The social network is composed of a set of friendship ties between pairs of users created by mutual endorsement. We carried out the logistic regression to identify users' characteristics, both related and unrelated to social networks, which contribute to suicide ideation. We defined suicide ideation of a user as the membership to at least one active user-defined community related to suicide. We found that the number of communities to which a user belongs to, the intransitivity (i.e., paucity of triangles including the user), and the fraction of suicidal neighbors in the social network, contributed the most to suicide ideation in this order. Other characteristics including the age and gender contributed little to suicide ideation. We also found qualitatively the same results for depressive symptoms. PMID- 23638024 TI - Regulation of programmed ribosomal frameshifting by co-translational refolding RNA hairpins. AB - RNA structures are unwound for decoding. In the process, they can pause the elongating ribosome for regulation. An example is the stimulation of -1 programmed ribosomal frameshifting, leading to 3' direction slippage of the reading-frame during elongation, by specific pseudoknot stimulators downstream of the frameshifting site. By investigating a recently identified regulatory element upstream of the SARS coronavirus (SARS-CoV) -1 frameshifting site, it is shown that a minimal functional element with hairpin forming potential is sufficient to down-regulate-1 frameshifting activity. Mutagenesis to disrupt or restore base pairs in the potential hairpin stem reveals that base-pair formation is required for-1 frameshifting attenuation in vitro and in 293T cells. The attenuation efficiency of a hairpin is determined by its stability and proximity to the frameshifting site; however, it is insensitive to E site sequence variation. Additionally, using a dual luciferase assay, it can be shown that a hairpin stimulated +1 frameshifting when placed upstream of a +1 shifty site in yeast. The investigations indicate that the hairpin is indeed a cis-acting programmed reading-frame switch modulator. This result provides insight into mechanisms governing-1 frameshifting stimulation and attenuation. Since the upstream hairpin is unwound (by a marching ribosome) before the downstream stimulator, this study's findings suggest a new mode of translational regulation that is mediated by the reformed stem of a ribosomal unwound RNA hairpin during elongation. PMID- 23638023 TI - Climate change expands the spatial extent and duration of preferred thermal habitat for lake Superior fishes. AB - Climate change is expected to alter species distributions and habitat suitability across the globe. Understanding these shifting distributions is critical for adaptive resource management. The role of temperature in fish habitat and energetics is well established and can be used to evaluate climate change effects on habitat distributions and food web interactions. Lake Superior water temperatures are rising rapidly in response to climate change and this is likely influencing species distributions and interactions. We use a three-dimensional hydrodynamic model that captures temperature changes in Lake Superior over the last 3 decades to investigate shifts in habitat size and duration of preferred temperatures for four different fishes. We evaluated habitat changes in two native lake trout (Salvelinus namaycush) ecotypes, siscowet and lean lake trout, Chinook salmon (Oncorhynchus tshawytscha), and walleye (Sander vitreus). Between 1979 and 2006, days with available preferred thermal habitat increased at a mean rate of 6, 7, and 5 days per decade for lean lake trout, Chinook salmon, and walleye, respectively. Siscowet lake trout lost 3 days per decade. Consequently, preferred habitat spatial extents increased at a rate of 579, 495 and 419 km(2) per year for the lean lake trout, Chinook salmon, and walleye while siscowet lost 161 km(2) per year during the modeled period. Habitat increases could lead to increased growth and production for three of the four fishes. Consequently, greater habitat overlap may intensify interguild competition and food web interactions. Loss of cold-water habitat for siscowet, having the coldest thermal preference, could forecast potential changes from continued warming. Additionally, continued warming may render more suitable conditions for some invasive species. PMID- 23638025 TI - Volume quantification of acute infratentorial hemorrhage with computed tomography: validation of the formula 1/2ABC and 2/3SH. AB - OBJECTIVE: To compare the accuracy of formula 1/2ABC with 2/3SH on volume estimation for hypertensive infratentorial hematoma. METHODS: One hundred and forty-seven CT scans diagnosed as hypertensive infratentorial hemorrhage were reviewed. Based on the shape, hematomas were categorized as regular or irregular. Multilobular was defined as a special shape of irregular. Hematoma volume was calculated employing computer-assisted volumetric analysis (CAVA), 1/2ABC and 2/3SH, respectively. RESULTS: The correlation coefficients between 1/2ABC (or 2/3SH) and CAVA were greater than 0.900 in all subgroups. There were neither significant differences in absolute values of volume deviation nor percentage deviation between 1/2ABC and 2/3SH for regular hemorrhage (P>0.05). While for cerebellar, brainstem and irregular hemorrhages, the absolute values of volume deviation and percentage deviation by formula 1/2ABC were greater than 2/3SH (P<0.05). 1/2ABC and 2/3SH underestimated hematoma volume each by 10% and 5% for cerebellar hemorrhage, 14% and 9% for brainstem hemorrhage, 19% and 16% for regular hemorrhage, 9% and 3% for irregular hemorrhage, respectively. In addition, for the multilobular hemorrhage, 1/2ABC underestimated the volume by 9% while 2/3SH overestimated it by 2%. CONCLUSIONS: For regular hemorrhage volume calculation, the accuracy of 2/3SH is similar to 1/2ABC. While for cerebellar, brainstem or irregular hemorrhages (including multilobular), 2/3SH is more accurate than 1/2ABC. PMID- 23638021 TI - Transcriptomic analysis of murine embryos lacking endogenous retinoic acid signaling. AB - Retinoic acid (RA), an active derivative of the liposoluble vitamin A (retinol), acts as an important signaling molecule during embryonic development, regulating phenomenons as diverse as anterior-posterior axial patterning, forebrain and optic vesicle development, specification of hindbrain rhombomeres, pharyngeal arches and second heart field, somitogenesis, and differentiation of spinal cord neurons. This small molecule directly triggers gene activation by binding to nuclear receptors (RARs), switching them from potential repressors to transcriptional activators. The repertoire of RA-regulated genes in embryonic tissues is poorly characterized. We performed a comparative analysis of the transcriptomes of murine wild-type and Retinaldehyde Dehydrogenase 2 null-mutant (Raldh2 (-/-)) embryos - unable to synthesize RA from maternally-derived retinol using Affymetrix DNA microarrays. Transcriptomic changes were analyzed in two embryonic regions: anterior tissues including forebrain and optic vesicle, and posterior (trunk) tissues, at early stages preceding the appearance of overt phenotypic abnormalities. Several genes expected to be downregulated under RA deficiency appeared in the transcriptome data (e.g. Emx2, Foxg1 anteriorly, Cdx1, Hoxa1, Rarb posteriorly), whereas reverse-transcriptase-PCR and in situ hybridization performed for additional selected genes validated the changes identified through microarray analysis. Altogether, the affected genes belonged to numerous molecular pathways and cellular/organismal functions, demonstrating the pleiotropic nature of RA-dependent events. In both tissue samples, genes upregulated were more numerous than those downregulated, probably due to feedback regulatory loops. Bioinformatic analyses highlighted groups (clusters) of genes displaying similar behaviors in mutant tissues, and biological functions most significantly affected (e.g. mTOR, VEGF, ILK signaling in forebrain tissues; pyrimidine and purine metabolism, calcium signaling, one carbon metabolism in posterior tissues). Overall, these data give an overview of the gene expression changes resulting from embryonic RA deficiency, and provide new candidate genes and pathways that may help understanding retinoid-dependent molecular events. PMID- 23638026 TI - Genome-wide expression analysis of soybean MADS genes showing potential function in the seed development. AB - The MADS family is an ancient and best-studied transcription factor and plays fundamental roles in almost every developmental process in plants. In the plant evolutionary history, the whole genome duplication (WGD) events are important not only to the plant species evolution, but to expansion of members of the gene families. Soybean as a model legume crop has experience three rounds of WGD events. Members of some MIKC(C) subfamilies, such as SOC, AGL6, SQUA, SVP, AGL17 and DEF/GLO, were expanded after soybean three rounds of WGD events. And some MIKC(C) subfamilies, MIKC* and type I MADS families had experienced faster birth and-death evolution and their traces before the Glycine WGD event were not found. Transposed duplication played important roles in tandem arrangements among the members of different subfamilies. According to the expression profiles of type I and MIKC paralog pair genes, the fates of MIKC paralog gene pairs were subfunctionalization, and the fates of type I MADS paralog gene pairs were nonfunctionalization. 137 out of 163 MADS genes were close to 186 loci within 2 Mb genomic regions associated with seed-relative QTLs, among which 115 genes expressed during the seed development. Although MIKC(C) genes kept the important and conserved functions of the flower development, most MIKC(C) genes showed potentially essential roles in the seed development as well as the type I MADS. PMID- 23638029 TI - A novel beta-defensin antimicrobial peptide in Atlantic cod with stimulatory effect on phagocytic activity. AB - A novel defensin antimicrobial peptide gene was identified in Atlantic cod, Gadus morhua. This three exon/two intron defensin gene codes for a peptide precursor consisting of two domains: a signal peptide of 26 amino acids and a mature peptide of 40 residues. The mature cod defensin has six conserved cysteine residues that form 1-5, 2-4 and 3-6 disulphide bridges. This pattern is typical of beta-defensins and this gene was therefore named cod beta-defensin (defb). The tertiary structure of Defb exhibits an alpha/beta fold with one alpha helix and beta1beta2beta3 sheets. RT-PCR analysis indicated that defb transcripts were present mainly in the swim bladder and peritoneum wall but could also be detected at moderate to low levels in skin, head- and excretory kidneys. In situ hybridisation revealed that defb was specifically expressed by cells located in the swim bladder submucosa and the oocytes. During embryonic development, defb gene transcripts were detectable from the golden eye stage onwards and their expression was restricted to the swim bladder and retina. Defb was differentially expressed in several tissues following antigenic challenge with Vibrio anguillarum, being up-regulated up to 25-fold in head kidney. Recombinant Defb displayed antibacterial activity, with a minimal inhibitory concentration of 0.4 0.8 uM and 25-50 uM against the Gram-(+) bacteria Planococcus citreus and Micrococcus luteus, respectively. In addition, Defb stimulated phagocytic activity of cod head kidney leucocytes in vitro. These findings imply that beta defensins may play an important role in the innate immune response of Atlantic cod. PMID- 23638028 TI - The Escherichia coli translation-associated heat shock protein YbeY is involved in rRNA transcription antitermination. AB - A new group of translation-associated heat shock genes has been recently identified. One of these novel genes is ybeY which is highly conserved in bacteria. In Escherichia coli the YbeY protein is important for efficient translation at all temperatures and is essential at high temperatures. Deletion mutants of ybeY are defective in protein translation, due to impaired 30 S ribosomal subunits. Here we provide evidence which tie YbeY to the transcription antitermination process. Thus, in ybeY deletion mutants transcription is significantly inhibited when the "nut like" sequences required for transcriptional antitermination are present, while if these sequences are removed transcription is not affected by the mutation. PMID- 23638027 TI - Anti-Sclerostin antibody inhibits internalization of Sclerostin and Sclerostin mediated antagonism of Wnt/LRP6 signaling. AB - Sclerosteosis is a rare high bone mass disease that is caused by inactivating mutations in the SOST gene. Its gene product, Sclerostin, is a key negative regulator of bone formation and might therefore serve as a target for the anabolic treatment of osteoporosis. The exact molecular mechanism by which Sclerostin exerts its antagonistic effects on Wnt signaling in bone forming osteoblasts remains unclear. Here we show that Wnt3a-induced transcriptional responses and induction of alkaline phosphatase activity, an early marker of osteoblast differentiation, require the Wnt co-receptors LRP5 and LRP6. Unlike Dickkopf1 (DKK1), Sclerostin does not inhibit Wnt-3a-induced phosphorylation of LRP5 at serine 1503 or LRP6 at serine 1490. Affinity labeling of cell surface proteins with [(125)I]Sclerostin identified LRP6 as the main specific Sclerostin receptor in multiple mesenchymal cell lines. When cells were challenged with Sclerostin fused to recombinant green fluorescent protein (GFP) this was internalized, likely via a Clathrin-dependent process, and subsequently degraded in a temperature and proteasome-dependent manner. Ectopic expression of LRP6 greatly enhanced binding and cellular uptake of Sclerostin-GFP, which was reduced by the addition of an excess of non-GFP-fused Sclerostin. Finally, an anti Sclerostin antibody inhibited the internalization of Sclerostin-GFP and binding of Sclerostin to LRP6. Moreover, this antibody attenuated the antagonistic activity of Sclerostin on canonical Wnt-induced responses. PMID- 23638031 TI - Analysis of human protein replacement stable cell lines established using snoMEN PR vector. AB - The study of the function of many human proteins is often hampered by technical limitations, such as cytotoxicity and phenotypes that result from overexpression of the protein of interest together with the endogenous version. Here we present the snoMEN (snoRNA Modulator of gene ExpressioN) vector technology for generating stable cell lines where expression of the endogenous protein can be reduced and replaced by an exogenous protein, such as a fluorescent protein (FP)-tagged version. SnoMEN are snoRNAs engineered to contain complementary sequences that can promote knock-down of targeted RNAs. We have established and characterised two such partial protein replacement human cell lines (snoMEN-PR). Quantitative mass spectrometry was used to analyse the specificity of knock-down and replacement at the protein level and also showed an increased pull-down efficiency of protein complexes containing exogenous, tagged proteins in the protein replacement cell lines, as compared with conventional co-expression strategies. The snoMEN approach facilitates the study of mammalian proteins, particularly those that have so far been difficult to investigate by exogenous expression and has wide applications in basic and applied gene-expression research. PMID- 23638030 TI - Nuclear localization of CD26 induced by a humanized monoclonal antibody inhibits tumor cell growth by modulating of POLR2A transcription. AB - CD26 is a type II glycoprotein known as dipeptidyl peptidase IV and has been identified as one of the cell surface markers associated with various types of cancers and a subset of cancer stem cells. Recent studies have suggested that CD26 expression is involved in tumor growth, tumor invasion, and metastasis. The CD26 is shown in an extensive intracellular distribution, ranging from the cell surface to the nucleus. We have previously showed that the humanized anti-CD26 monoclonal antibody (mAb), YS110, exhibits inhibitory effects on various cancers. However, functions of CD26 on cancer cells and molecular mechanisms of impaired tumor growth by YS110 treatment are not well understood. In this study, we demonstrated that the treatment with YS110 induced nuclear translocation of both cell-surface CD26 and YS110 in cancer cells and xenografted tumor. It was shown that the CD26 and YS110 were co-localized in nucleus by immunoelectron microscopic analysis. In response to YS110 treatment, CD26 was translocated into the nucleus via caveolin-dependent endocytosis. It was revealed that the nuclear CD26 interacted with a genomic flanking region of the gene for POLR2A, a subunit of RNA polymerase II, using a chromatin immunoprecipitation assay. This interaction with nuclear CD26 and POLR2A gene consequently led to transcriptional repression of the POLR2A gene, resulting in retarded cell proliferation of cancer cells. Furthermore, the impaired nuclear transport of CD26 by treatment with an endocytosis inhibitor or expressions of deletion mutants of CD26 reversed the POLR2A repression induced by YS110 treatment. These findings reveal that the nuclear CD26 functions in the regulation of gene expression and tumor growth, and provide a novel mechanism of mAb-therapy related to inducible translocation of cell-surface target molecule into the nucleus. PMID- 23638034 TI - When can clades be potentially resolved with morphology? AB - Morphology-based phylogenetic analyses are the only option for reconstructing relationships among extinct lineages, but often find support for conflicting hypotheses of relationships. The resulting lack of phylogenetic resolution is generally explained in terms of data quality and methodological issues, such as character selection. A previous suggestion is that sampling ancestral morphotaxa or sampling multiple taxa descended from a long-lived, unchanging lineage can also yield clades which have no opportunity to share synapomorphies. This lack of character information leads to a lack of 'intrinsic' resolution, an issue that cannot be solved with additional morphological data. It is unclear how often we should expect clades to be intrinsically resolvable in realistic circumstances, as intrinsic resolution must increase as taxonomic sampling decreases. Using branching simulations, I quantify intrinsic resolution across several models of morphological differentiation and taxonomic sampling. Intrinsically unresolvable clades are found to be relatively frequent in simulations of both extinct and living taxa under realistic sampling scenarios, implying that intrinsic resolution is an issue for morphology-based analyses of phylogeny. Simulations which vary the rates of sampling and differentiation were tested for their agreement to observed distributions of durations from well-sampled fossil records and also having high intrinsic resolution. This combination only occurs in those datasets when differentiation and sampling rates are both unrealistically high relative to branching and extinction rates. Thus, the poor phylogenetic resolution occasionally observed in morphological phylogenetics may result from a lack of intrinsic resolvability within groups. PMID- 23638032 TI - Characterization of an invertase with pH tolerance and truncation of its N terminal to shift optimum activity toward neutral pH. AB - Most invertases identified to date have optimal activity at acidic pH, and are intolerant to neutral or alkaline environments. Here, an acid invertase named uninv2 is described. Uninv2 contained 586 amino acids, with a 100 amino acids N terminal domain, a catalytic domain and a C-terminal domain. With sucrose as the substrate, uninv2 activity was optimal at pH 4.5 and at 45 degrees C. Removal of N-terminal domain of uninv2 has shifted the optimum pH to 6.0 while retaining its optimum temperaure at 45 degrees C. Both uninv2 and the truncated enzyme retained highly stable at neutral pH at 37 degrees C, and they were stable at their optimum pH at 4 degrees C for as long as 30 days. These characteristics make them far superior to invertase from Saccharomyces cerevisiae, which is mostly used as industrial enzyme. PMID- 23638033 TI - Activation of AMPK by bitter melon triterpenoids involves CaMKKbeta. AB - We recently showed that bitter melon-derived triterpenoids (BMTs) activate AMPK and increase GLUT4 translocation to the plasma membrane in vitro, and improve glucose disposal in insulin resistant models in vivo. Here we interrogated the mechanism by which these novel compounds activate AMPK, a leading anti-diabetic drug target. BMTs did not activate AMPK directly in an allosteric manner as AMP or the Abbott compound (A-769662) does, nor did they activate AMPK by inhibiting cellular respiration like many commonly used anti-diabetic medications. BMTs increased AMPK activity in both L6 myotubes and LKB1-deficient HeLa cells by 20 35%. Incubation with the CaMKKbeta inhibitor, STO-609, completely attenuated this effect suggesting a key role for CaMKKbeta in this activation. Incubation of L6 myotubes with the calcium chelator EGTA-AM did not alter this activation suggesting that the BMT-dependent activation was Ca(2+)-independent. We therefore propose that CaMKKbeta is a key upstream kinase for BMT-induced activation of AMPK. PMID- 23638035 TI - Differential expression of CRH, UCN, CRHR1 and CRHR2 in eutopic and ectopic endometrium of women with endometriosis. AB - Endometriosis is considered as a benign aseptic inflammatory disease, characterised by the presence of ectopic endometrium-like tissue. Its symptoms (mostly pain and infertility) are reported as constant stressors. Corticotropin releasing hormone (CRH) and urocortin (UCN) are neuropeptides, strongly related to stress and inflammation. The effects of CRH and UCN are mediated through CRHR1 and CRHR2 receptors which are implicated in several reproductive functions acting as inflammatory components. However, the involvement of these molecules to endometriosis remains unknown. The aim of this study was to examine the expression of CRHR1 and CRHR2 in endometriotic sites and to compare the expression of CRHR1 and CRHR2 in eutopic endometrium of endometriotic women to that of healthy women. We further compared the expression of CRH, UCN, CRHR1 and CRHR2 in ectopic endometrium to that in eutopic endometrium of women with endometriosis. Endometrial biopsy specimens were taken from healthy women (10 patients) and endometrial and endometriotic biopsy specimens were taken from women with endometriosis (16 patients). Tauhe expression of CRH, UCN, CRHR1, and CRHR2 was tested via RT-PCR, immunohistochemistry and Western blotting. This study shows for the first time that CRH and UCN receptor subtypes CRHR1beta and CRHR2alpha are expressed in endometriotic sites and that they are more strongly expressed (p<0.01) in eutopic endometrium of women with endometriosis compared to healthy women endometrium at the mRNA and protein level. CRH, UCN, CRHR1 and CRHR2 mRNA were also more highly expressed in ectopic rather than eutopic endometrium (CRH, UCN, CRHR2alpha: p<0.01, CRHR1beta: p<0.05) and protein (CRH and UCN: p<0.05, CRHR1 and CRHR2: p<0.01) in women with endometriosis. These data indicate that CRH and UCN might play an immunoregulatory role in endometriotic sites by affecting reproductive functions such as decidualization and implantation of women with endometriosis. PMID- 23638036 TI - Likelihood of treatment in a coronary care unit for a first-time myocardial infarction in relation to sex, country of birth and socioeconomic position in Sweden. AB - OBJECTIVE: To examine the relationship between sex, country of birth, level of education as an indicator of socioeconomic position, and the likelihood of treatment in a coronary care unit (CCU) for a first-time myocardial infarction. DESIGN: Nationwide register based study. SETTING: Sweden. PATIENTS: 199 906 patients (114 387 men and 85,519 women) of all ages who were admitted to hospital for first-time myocardial infarction between 2001 and 2009. MAIN OUTCOME MEASURES: Admission to a coronary care unit due to myocardial infarction. RESULTS: Despite the observed increasing access to coronary care units over time, the proportion of women treated in a coronary care unit was 13% less than for men. As compared with men, the multivariable adjusted odds ratio among women was 0.80 (95% confidence interval 0.77 to 0.82). This lower proportion of women treated in a CCU varied by age and year of diagnosis and country of birth. Overall, there was no evidence of a difference in likelihood of treatment in a coronary care unit between Sweden-born and foreign-born patients. As compared with patients with high education, the adjusted odds ratio among patients with a low level of education was 0.93 (95% confidence interval 0.89 to 0.96). CONCLUSIONS: Foreign-born and Sweden-born first-time myocardial infarction patients had equal opportunity of being treated in a coronary care unit in Sweden; this is in contrast to the situation in many other countries with large immigrant populations. However, the apparent lower rate of coronary care unit admission after first-time myocardial infarction among women and patients with low socioeconomic position warrants further investigation. PMID- 23638038 TI - High human bocavirus viral load is associated with disease severity in children under five years of age. AB - Human bocavirus (HBoV) is a parvovirus and detected worldwide in lower respiratory tract infections (LRTIs), but its pathogenic role in respiratory illness is still debatable due to high incidence of co-infection with other respiratory viruses. To determine the prevalence of HBoV infection in patients with LRTI in Shanghai and its correlation with disease severity, we performed a 3 year prospective study of HBoV in healthy controls, outpatients and inpatients under five years of age with X-ray diagnosed LRTIs. Nasopharyngeal aspirates were tested by PCR for common respiratory viruses and by real time PCR for HBoV subtypes 1-4. Nasopharyngeal swabs from healthy controls and serum samples and stools from inpatients were also tested for HBoV1-4 by real time PCR. Viral loads were determined by quantitative real time PCR in all HBoV positive samples. HBoV1 was detected in 7.0% of inpatients, with annual rates of 5.1%, 8.0% and 4.8% in 2010, 2011 and 2012, respectively. Respiratory syncytial virus (RSV) subtype A was the most frequent co-infection detected; HBoV1 and RSVA appeared to co circulate with similar seasonal variations. High HBoV viral loads (>10(6) copies/ml) were significantly more frequent in inpatients and outpatients than in healthy controls. There was a direct correlation of high viral load with increasing disease severity in patients co-infected with HBoV1 and at least one other respiratory virus. In summary, our data suggest that HBoV1 can cause LRTIs, but symptomatic HBoV infection is only observed in the context of high viral load. PMID- 23638037 TI - Extensive microsatellite variation in rice induced by introgression from wild rice (Zizania latifolia Griseb.). AB - BACKGROUND: It is widely accepted that interspecific hybridization may induce genomic instability in the resultant hybrids. However, few studies have been performed on the genomic analysis of homoploid hybrids and introgression lines. We have reported previously that by introgressive hybridization, a set of introgression lines between rice (Oryza sativa L.) and wild rice (Zizania latifolia Griseb.) was successfully generated, and which have led to the release of several cultivars. METHODOLOGY: Using 96 microsatellite markers located in the nuclear and organelle genomes of rice, we investigated microsatellite stability in three typical introgression lines. Expression of a set of mismatch repair (MMR) genes and microsatellite-containing genes was also analyzed. RESULTS/CONCLUSIONS: Compared with the recipient rice cultivar (Matsumae), 55 of the 96 microsatellite loci revealed variation in one or more of the introgression lines, and 58.2% of the altered alleles were shared by at least two lines, indicating that most of the alterations had occurred in the early stages of introgression before their further differentiation. 73.9% of the non-shared variations were detected only in one introgression line, i.e. RZ2. Sequence alignment showed that the variations included substitutions and indels that occurred both within the repeat tracts and in the flanking regions. Interestingly, expression of a set of MMR genes altered dramatically in the introgression lines relative to their rice parent, suggesting participation of the MMR system in the generation of microsatellite variants. Some of the altered microsatellite loci are concordant with changed expression of the genes harboring them, suggesting their possible cis-regulatory roles in controlling gene expression. Because these genes bear meaningful homology to known-functional proteins, we conclude that the introgression-induced extensive variation of microsatellites may have contributed to the novel phenotypes in the introgression lines. PMID- 23638039 TI - Two distinct functional patterns of hepatitis C Virus (HCV)-specific T cell responses in seronegative, aviremic patients. AB - In hepatitis C Virus (HCV) high-risk groups, HCV-specific T cell responses have been detected in seronegative, aviremic persons who have no evidence of HCV infection. Herein, we investigated functional profiles of HCV-specific T-cell responses in seronegative, aviremic patients of a HCV high-risk group. Seventy seven hemodialysis patients with chronic renal disease were analyzed by IFN-gamma ELISpot assays, and eight of 71 (11.3%) seronegative, aviremic patients displayed HCV-specific T-cell responses. Their HCV-specific memory T cells were characterized by assessing cytokine polyfunctionality, known to provide antiviral protection. By intracellular staining of IFN-gamma, TNF-alpha, IL-2 and MIP 1beta, we identified two distinct populations in the seronegative, aviremic patients: polyfunctional responders and TNF-alpha-predominant responders. In further analysis, occult HCV infection was excluded as a cause of the HCV specific T cell response via secondary nested RT-PCR of HCV RNA in peripheral blood mononuclear cell samples. HCV-specific T cells targeted multiple epitopes including non-structural proteins in a single patient, implying that their T cells might have been primed by HCV proteins synthesized within the host. We conclude that HCV-specific memory T cells of seronegative, aviremic patients arise from authentic HCV replication in the host, but not from current occult HCV infection. By functional pattern of HCV-specific T cells, there are two distinct populations in these patients: polyfunctional responders and TNF-alpha predominant responders. PMID- 23638041 TI - Accounting for imperfect detection is critical for inferring marine turtle nesting population trends. AB - Assessments of population trends based on time-series counts of individuals are complicated by imperfect detection, which can lead to serious misinterpretations of data. Population trends of threatened marine turtles worldwide are usually based on counts of nests or nesting females. We analyze 39 years of nest-count, female-count, and capture-mark-recapture (CMR) data for nesting loggerhead turtles (Caretta caretta) on Wassaw Island, Georgia, USA. Annual counts of nests and females, not corrected for imperfect detection, yield significant, positive trends in abundance. However, multistate open robust design modeling of CMR data that accounts for changes in imperfect detection reveals that the annual abundance of nesting females has remained essentially constant over the 39-year period. The dichotomy could result from improvements in surveys or increased within-season nest-site fidelity in females, either of which would increase detection probability. For the first time in a marine turtle population, we compare results of population trend analyses that do and do not account for imperfect detection and demonstrate the potential for erroneous conclusions. Past assessments of marine turtle population trends based exclusively on count data should be interpreted with caution and re-evaluated when possible. These concerns apply equally to population assessments of all species with imperfect detection. PMID- 23638040 TI - Social cognitive role of schizophrenia candidate gene GABRB2. AB - The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition. PMID- 23638042 TI - Role of LytF and AtlS in eDNA release by Streptococcus gordonii. AB - Extracellular DNA (eDNA) is an important component of the biofilm matrix produced by many bacteria. In general, the release of eDNA is associated with the activity of muralytic enzymes leading to obvious cell lysis. In the Gram-positive oral commensal Streptococcus gordonii, eDNA release is dependent on pyruvate oxidase generated hydrogen peroxide (H2O2). Addition of H2O2 to cells grown under conditions non-permissive for H2O2 production causes eDNA release. Furthermore, eDNA release is maximal under aerobic growth conditions known to induce pyruvate oxidase gene expression and H2O2 production. Obvious cell lysis, however, does not occur. Two enzymes have been recently associated with eDNA release in S. gordonii. The autolysin AtlS and the competence regulated murein hydrolase LytF. In the present report, we investigated the role of both proteins in the H2O2 dependent eDNA release process. Single and double mutants in the respective genes for LytF and AtlS released less eDNA under normal growth conditions, but the AtlS mutant was still inducible for eDNA release by external H2O2. Moreover, we showed that the AtlS mutation interfered with the ability of S. gordonii to produce eDNA release inducing amounts of H2O2. Our data support a role of LytF in the H2O2 eDNA dependent release of S. gordonii as part of the competence stress pathway responding to oxidative stress. PMID- 23638043 TI - EGFR inhibitor erlotinib delays disease progression but does not extend survival in the SOD1 mouse model of ALS. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR) signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course. PMID- 23638044 TI - Multiplex detection of plant pathogens using a microsphere immunoassay technology. AB - Plant pathogens are a serious problem for seed export, plant disease control and plant quarantine. Rapid and accurate screening tests are urgently required to protect and prevent plant diseases spreading worldwide. A novel multiplex detection method was developed based on microsphere immunoassays to simultaneously detect four important plant pathogens: a fruit blotch bacterium Acidovorax avenae subsp. citrulli (Aac), chilli vein-banding mottle virus (CVbMV, potyvirus), watermelon silver mottle virus (WSMoV, tospovirus serogroup IV) and melon yellow spot virus (MYSV, tospovirus). An antibody for each plant pathogen was linked on a fluorescence-coded magnetic microsphere set which was used to capture corresponding pathogen. The presence of pathogens was detected by R phycoerythrin (RPE)-labeled antibodies specific to the pathogens. The assay conditions were optimized by identifying appropriate antibody pairs, blocking buffer, concentration of RPE-labeled antibodies and assay time. Once conditions were optimized, the assay was able to detect all four plant pathogens precisely and accurately with substantially higher sensitivity than enzyme-linked immunosorbent assay (ELISA) when spiked in buffer and in healthy watermelon leaf extract. The assay time of the microsphere immunoassay (1 hour) was much shorter than that of ELISA (4 hours). This system was also shown to be capable of detecting the pathogens in naturally infected plant samples and is a major advancement in plant pathogen detection. PMID- 23638045 TI - Immunolocalization of the tumor-sensitive calmodulin-like protein CALML3 in normal human skin and hyperproliferative skin disorders. AB - BACKGROUND AND OBJECTIVE: Calmodulin-like protein CALML3 is an epithelial specific protein regulated during keratinocyte differentiation in vitro. CALML3 expression is downregulated in breast cancers and transformed cell lines making it an attractive marker for tumor formation. The objective of this study was to survey CALML3 localization in normal epidermis and in hyperproliferative skin diseases including actinic keratosis, squamous and basal cell carcinoma as well as verruca and psoriasis and to compare CALML3 immunoreactivity with the proliferation marker Ki-67. METHODS: Paraffin-embedded tissue sections from normal human skin and hyperproliferative skin disorders were examined by immunohistochemistry and analyzed for localization and expression of CALML3 and Ki-67. RESULTS: CALML3 was strongly expressed in differentiating layers of normal skin, staining the periphery in suprabasal cells and exhibiting nuclear localization in the stratum granulosum. CALML3 nuclear localization was inversely correlated to Ki-67 staining in each disease, indicating that CALML3 nuclear presence is related to terminal cell differentiation and postmitotic state. CONCLUSIONS: Increased CALML3 expression in suprabasal layers is characteristic for differentiating keratinocytes in normal epidermis, and nuclear expression of CALML3 inversely correlates with expression of the proliferation marker Ki-67. This suggests that CALML3 is a useful marker for normal and benign hyperplastic epidermal development, whereas the loss of nuclear CALML3 indicates progression to a proliferative and potentially malignant phenotype. PMID- 23638046 TI - General cell-binding activity of intramolecular G-quadruplexes with parallel structure. AB - G-quadruplexes (G4s) are four-stranded nucleic acid structures adopted by some repetitive guanine-rich sequences. Putative G-quadruplex-forming sequences (PQSs) are highly prevalent in human genome. Recently some G4s have been reported to have cancer-selective antiproliferative activity. A G4 DNA, AS1411, is currently in phase II clinical trials as an anticancer agent, which is reported to bind tumor cells by targeting surface nucleolin. AS1411 also has been extensively investigated as a target-recognition element for cancer cell specific drug delivery or cancer cell imaging. Here we show that, in addition to AS1411, intramolecular G4s with parallel structure (including PQSs in genes) have general binding activity to many cell lines with different affinity. The binding of these G4s compete with each other, and their targets are certain cellular surface proteins. The tested G4s exhibit enhanced cellular uptake than non-G4 sequences. This uptake may be through the endosome/lysosome pathway, but it is independent of cellular binding of the G4s. The tested G4s also show selective antiproliferative activity that is independent of their cellular binding. Our findings provide new insight into the molecular recognition of G4s by cells; offer new clues for understanding the functions of G4s in vivo, and may extend the potential applications of G4s. PMID- 23638047 TI - Phytohormones related to host plant manipulation by a gall-inducing leafhopper. AB - The maize orange leafhopper Cicadulina bipunctata (Hemiptera: Cicadellidae) induces galls characterized by growth stunting and severe swelling of leaf veins on various plants of Poaceae. Previous studies revealed that galls are induced not on feeding site but on distant, newly extended leaves during the feeding, and strongly suggested that some chemicals injected by the leafhopper affect at the leaf primordia. To approach the mechanism underlying gall induction by C. bipunctata, we examined physiological response of plants to feeding by the leafhopper. We performed high-throughput and comprehensive plant hormone analyses using LC-ESI-MS/MS. Galled maize leaves contained higher contents of abscisic acid (ABA) and trans-Zeatin (tZ) and lower contents of gibberellins (GA1 and GA4) than ungalled maize leaves. Leafhopper treatment significantly increased ABA and tZ contents and decreased GA1 and GA4 contents in extending leaves. After the removal of leafhoppers, contents of tZ and gibberellins in extending leaves soon became similar to the control values. ABA content was gradually decreased after the removal of leafhoppers. Such hormonal changes were not observed in leafhopper treatment on leaves of resistant maize variety. Water contents of galled leaves were significantly lower than control leaves, suggesting water stress of galled leaves and possible reason of the increase in ABA content. These results imply that ABA, tZ, and gibberellins are related to gall induction by the leafhopper on susceptible variety of maize. PMID- 23638049 TI - Food access and diet quality are associated with quality of life outcomes among HIV-infected individuals in Uganda. AB - BACKGROUND: Food insecurity is associated with poor nutritional and clinical outcomes among people living with HIV/AIDS. Few studies investigate the link between food insecurity, dietary diversity and health-related quality of life among people living with HIV/AIDS. OBJECTIVE: We investigated whether household food access and individual dietary diversity are associated with health-related quality of life among people living with HIV/AIDS in Uganda. METHODS: We surveyed 902 people living with HIV/AIDS and their households from two clinics in Northern Uganda. Health-related quality of life outcomes were assessed using the Medical Outcomes Study (MOS)-HIV Survey. We performed multivariate regressions to investigate the relationship between health-related quality of life, household food insecurity and individual dietary diversity. RESULTS: People living with HIV/AIDS from severe food insecurity households have mean mental health status scores that are 1.7 points lower (p<.001) and physical health status scores that are 1.5 points lower (p<.01). Individuals with high dietary diversity have mean mental health status scores that were 3.6 points higher (p<.001) and physical health status scores that were 2.8 points higher (p<.05). CONCLUSIONS: Food access and diet quality are associated with health-related quality of life and may be considered as part of comprehensive interventions designed to mitigate psychosocial consequences of HIV. PMID- 23638048 TI - Molecular cloning and sequence analysis of a phenylalanine ammonia-lyase gene from dendrobium. AB - In this study, a phenylalanine ammonia-lyase (PAL) gene was cloned from Dendrobium candidum using homology cloning and RACE. The full-length sequence and catalytic active sites that appear in PAL proteins of Arabidopsis thaliana and Nicotiana tabacum are also found: PAL cDNA of D. candidum (designated Dc-PAL1, GenBank No. JQ765748) has 2,458 bps and contains a complete open reading frame (ORF) of 2,142 bps, which encodes 713 amino acid residues. The amino acid sequence of DcPAL1 has more than 80% sequence identity with the PAL genes of other plants, as indicated by multiple alignments. The dominant sites and catalytic active sites, which are similar to that showing in PAL proteins of Arabidopsis thaliana and Nicotiana tabacum, are also found in DcPAL1. Phylogenetic tree analysis revealed that DcPAL is more closely related to PALs from orchidaceae plants than to those of other plants. The differential expression patterns of PAL in protocorm-like body, leaf, stem, and root, suggest that the PAL gene performs multiple physiological functions in Dendrobium candidum. PMID- 23638050 TI - Can the neural basis of repression be studied in the MRI scanner? New insights from two free association paradigms. AB - BACKGROUND: The psychodynamic theory of repression suggests that experiences which are related to internal conflicts become unconscious. Previous attempts to investigate repression experimentally were based on voluntary, intentional suppression of stimulus material. Unconscious repression of conflict-related material is arguably due to different processes, but has never been studied with neuroimaging methods. METHODS: We used functional magnetic resonance imaging (fMRI) in addition with skin conductance recordings during two free association paradigms to identify the neural mechanisms underlying forgetting of freely associated words according to repression theory. RESULTS: In the first experiment, free association to subsequently forgotten words was accompanied by increases in skin conductance responses (SCRs) and reaction times (RTs), indicating autonomic arousal, and by activation of the anterior cingulate cortex. These findings are consistent with the hypothesis that these associations were repressed because they elicited internal conflicts. To test this idea more directly, we conducted a second experiment in which participants freely associated to conflict-related sentences. Indeed, these associations were more likely to be forgotten than associations to not conflict-related sentences and were accompanied by increases in SCRs and RTs. Furthermore, we observed enhanced activation of the anterior cingulate cortex and deactivation of hippocampus and parahippocampal cortex during association to conflict-related sentences. CONCLUSIONS: These two experiments demonstrate that high autonomic arousal during free association predicts subsequent memory failure, accompanied by increased activation of conflict-related and deactivation of memory-related brain regions. These results are consistent with the hypothesis that during repression, explicit memory systems are down-regulated by the anterior cingulate cortex. PMID- 23638052 TI - In vivo tracking and comparison of the therapeutic effects of MSCs and HSCs for liver injury. AB - BACKGROUND: Mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) have been studied for damaged liver repair; however, the conclusions drawn regarding their homing capacity to the injured liver are conflicting. Besides, the relative utility and synergistic effects of these two cell types on the injured liver remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: MSCs, HSCs and the combination of both cells were obtained from the bone marrow of male mice expressing enhanced green fluorescent protein(EGFP)and injected into the female mice with or without liver fibrosis. The distribution of the stem cells, survival rates, liver function, hepatocyte regeneration, growth factors and cytokines of the recipient mice were analyzed. We found that the liver content of the EGFP donor cells was significantly higher in the MSCs group than in the HSCs or MSCs+HSCs group. The survival rate for the MSCs group was significantly higher than that of the HSCs or MSCs+HSCs group; all surpassed the control group. After MSC-transplantation, the injured livers were maximally restored, with less collagen than the controls. The fibrotic areas had decreased to a lesser extent in the mice transplanted with HSCs or MSCs+HSCs. Compared with mice in the HSCs group, the mice that received MSCs had better improved liver function. MSCs exhibited more remarkable paracrine effects and immunomodulatory properties on hepatic stellate cells and native hepatocytes in the treatment of the liver pathology. Synergistic actions of MSCs and HSCs were most likely not observed because the stem cells in liver were detected mostly as single cells, and single MSCs are insufficient to provide a beneficial niche for HSCs. CONCLUSIONS/SIGNIFICANCE: MSCs exhibited a greater homing capability for the injured liver and modulated fibrosis and inflammation more effectively than did HSCs. Synergistic effects of MSCs and HSCs were not observed in liver injury. PMID- 23638051 TI - Occupational exposure to ultraviolet radiation and risk of non-melanoma skin cancer in a multinational European study. AB - BACKGROUND: Studies suggest that ambient sunlight plays an important role in the pathogenesis of non-melanoma skin cancers (NMSC). However, there is ongoing controversy regarding the relevance of occupational exposure to natural and artificial ultraviolet radiation (UV) radiation. OBJECTIVES: We investigated potential associations between natural and artificial UV radiation exposure at work with NMSC in a case-control study conducted in Hungary, Romania, and Slovakia. METHODS: Occupational exposures were classified by expert assessment for 527 controls and 618 NMSC cases (515 basal cell carcinoma, BCC). Covariate information was collected via interview and multiple logistic regression models were used to assess associations between UV exposure and NMSC. RESULTS: Lifetime prevalence of occupational exposure in the participants was 13% for natural UV radiation and 7% for artificial UV radiation. Significant negative associations between occupational exposure to natural UV radiation and NMSC were detected for all who had ever been exposed (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.27-0.80); similar results were detected using a semi-quantitative metric of cumulative exposure. The effects were modified by skin complexion, with significantly decreased risks of BCC among participants with light skin complexion. No associations were observed in relation to occupational artificial UV radiation exposure. CONCLUSIONS: The protective effect of occupational exposure to natural UV radiation was unexpected, but limited to light-skinned people, suggesting adequate sun-protection behaviors. Further investigations focusing on variations in the individual genetic susceptibility and potential interactions with environmental and other relevant factors are planned. PMID- 23638053 TI - Effects of in vitro low oxygen tension preconditioning of adipose stromal cells on their in vivo chondrogenic potential: application in cartilage tissue repair. AB - PURPOSE: Multipotent stromal cell (MSC)-based regenerative strategy has shown promise for the repair of cartilage, an avascular tissue in which cells experience hypoxia. Hypoxia is known to promote the early chondrogenic differentiation of MSC. The aim of our study was therefore to determine whether low oxygen tension could be used to enhance the regenerative potential of MSC for cartilage repair. METHODS: MSC from rabbit or human adipose stromal cells (ASC) were preconditioned in vitro in control or chondrogenic (ITS and TGF-beta) medium and in 21 or 5% O2. Chondrogenic commitment was monitored by measuring COL2A1 and ACAN expression (real-time PCR). Preconditioned rabbit and human ASC were then incorporated into an Si-HPMC hydrogel and injected (i) into rabbit articular cartilage defects for 18 weeks or (ii) subcutaneously into nude mice for five weeks. The newly formed tissue was qualitatively and quantitatively evaluated by cartilage-specific immunohistological staining and scoring. The phenotype of ASC cultured in a monolayer or within Si-HPMC in control or chondrogenic medium and in 21 or 5% O2 was finally evaluated using real-time PCR. RESULTS/CONCLUSIONS: 5% O2 increased the in vitro expression of chondrogenic markers in ASC cultured in induction medium. Cells implanted within Si-HPMC hydrogel and preconditioned in chondrogenic medium formed a cartilaginous tissue, regardless of the level of oxygen. In addition, the 3D in vitro culture of ASC within Si-HPMC hydrogel was found to reinforce the pro-chondrogenic effects of the induction medium and 5% O2. These data together indicate that although 5% O2 enhances the in vitro chondrogenic differentiation of ASC, it does not enhance their in vivo chondrogenesis. These results also highlight the in vivo chondrogenic potential of ASC and their potential value in cartilage repair. PMID- 23638054 TI - S100A12 suppresses pro-inflammatory, but not pro-thrombotic functions of serum amyloid A. AB - S100A12 is elevated in the circulation in patients with chronic inflammatory diseases and recent studies indicate pleiotropic functions. Serum amyloid A induces monocyte cytokines and tissue factor. S100A12 did not stimulate IL-6, IL 8, IL-1beta or TNF-alpha production by human peripheral blood mononuclear cells but low amounts consistently reduced cytokine mRNA and protein levels induced by serum amyloid A, by ~49% and ~46%, respectively. However, S100A12 did not affect serum amyloid A-induced monocyte tissue factor. In marked contrast, LPS-induced cytokines or tissue factor were not suppressed by S100A12. S100A12 did not alter cytokine mRNA stability or the cytokine secretory pathway. S100A12 and serum amyloid A did not appear to form complexes and although they may have common receptors, suppression was unlikely via receptor competition. Serum amyloid A induces cytokines via activation of NF-kappaB and the MAPK pathways. S100A12 reduced serum amyloid A-, but not LPS-induced ERK1/2 phosphorylation to baseline. It did not affect JNK or p38 phosphorylation or the NF-kappaB pathway. Reduction in ERK1/2 phosphorylation by S100A12 was unlikely due to changes in intracellular reactive oxygen species, Ca(2+) flux or to recruitment of phosphatases. We suggest that S100A12 may modulate sterile inflammation by blunting pro inflammatory properties of lipid-poor serum amyloid A deposited in chronic lesions where both proteins are elevated as a consequence of macrophage activation. PMID- 23638056 TI - Fine mapping and functional analysis of the multiple sclerosis risk gene CD6. AB - CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2(nd) SRCR domain with susceptibility to MS (P max(T) permutation = 1*10(-4)). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. - CD4(+) naive cells, P = 0.0001; CD8(+) naive cells, P<0.0001; CD4(+) and CD8(+) central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS associated CD6 risk haplotype significantly modifies expression of CD6 on CD4(+) and CD8(+) T cells. PMID- 23638057 TI - Simulation of E. coli gene regulation including overlapping cell cycles, growth, division, time delays and noise. AB - Due to the complexity of biological systems, simulation of biological networks is necessary but sometimes complicated. The classic stochastic simulation algorithm (SSA) by Gillespie and its modified versions are widely used to simulate the stochastic dynamics of biochemical reaction systems. However, it has remained a challenge to implement accurate and efficient simulation algorithms for general reaction schemes in growing cells. Here, we present a modeling and simulation tool, called 'GeneCircuits', which is specifically developed to simulate gene regulation in exponentially growing bacterial cells (such as E. coli) with overlapping cell cycles. Our tool integrates three specific features of these cells that are not generally included in SSA tools: 1) the time delay between the regulation and synthesis of proteins that is due to transcription and translation processes; 2) cell cycle-dependent periodic changes of gene dosage; and 3) variations in the propensities of chemical reactions that have time-dependent reaction rates as a consequence of volume expansion and cell division. We give three biologically relevant examples to illustrate the use of our simulation tool in quantitative studies of systems biology and synthetic biology. PMID- 23638055 TI - CpG-ODN attenuates pathological cardiac hypertrophy and heart failure by activation of PI3Kalpha-Akt signaling. AB - Phosphoinositide-3-kinase alpha (PI3Kalpha) represents a potential novel drug target for pathological cardiac hypertrophy (PCH) and heart failure. Oligodeoxynucleotides containing CpG motifs (CpG-ODN) are classic agonists of Toll-like receptor 9 (TLR9), which typically activates PI3K-Akt signaling in immune cells; however, the role of the nucleotide TLR9 agonists in cardiac myocytes is largely unknown. Here we report that CpG-ODN C274 could both attenuate PCH and improve cardiac dysfunction by activating PI3Kalpha-Akt signaling cascade. In vitro studies indicated that C274 could blunt reactivation of fetal cardiac genes and cell enlargement induced by a hypertrophic agent, isoproterenol. The anti-hypertrophic effect of C274 was suppressed by a pan-PI3K inhibitor, LY294002, or a small interfering RNA targeting PI3Kalpha. In vivo studies demonstrated that PCH, as marked by increased heart weight (HW) and cardiac ANF mRNA, was normalized by pre-administration with C274. In addition, Doppler echocardiography detected cardiac ventricular dilation, and contractile dysfunction in isoproterenol-treated animals, consistent with massive replacement fibrosis, reflecting cardiac cell death. As expected, pre-treatment of mice with C274 could prevent cardiac dysfunction associated with diminished cardiac cell death and fibrosis. In conclusion, CpG-ODNs are novel cardioprotective agents possessing antihypertrophic and anti-cell death activity afforded by engagement of the PI3Kalpha-Akt signaling. CpG-ODNs may have clinical use curbing the progression of PCH and preventing heart failure. PMID- 23638058 TI - In-the-bag intraocular lens placement via secondary capsulorhexis with radiofrequency diathermy in pediatric aphakic eyes. AB - Pediatric ophthalmologists increasingly recognize that the ideal site for intraocular lens (IOL) implantation is in the bag for aphakic eyes, but it is always very difficult via conventional technique. We conducted a prospective case series study to investigate the success rate and clinical outcomes of capsular bag reestablishment and in-the-bag IOL implantation via secondary capsulorhexis with radiofrequency diathermy (RFD) in pediatric aphakic eyes, in which twenty two consecutive aphakic pediatric patients (43 aphakic eyes) enrolled in the Childhood Cataract Program of the Chinese Ministry of Health were included. The included children underwent either our novel technique for secondary IOL implantation (with RFD) or the conventional technique (with a bent needle or forceps), depending on the type of preoperative proliferative capsular bag present. In total, secondary capsulorhexis with RFD was successfully applied in 32 eyes (32/43, 74.4%, age 5.6+/-2.3 years), of which capsular bag reestablishment and in-the-bag IOL implantation were both achieved in 30 eyes (30/43, 70.0%), but in the remaining 2 eyes (2/32, 6.2%) the IOLs were implanted in the sulcus with a capsular bag that was too small. Secondary capsulorhexis with conventional technique was applied in the other 11 eyes (11/43, 25.6%, age 6.9+/-2.3 years), of which capsular bag reestablishment and in-the-bag IOL implantation were both achieved only in 3 eyes(3/43, 7.0%), and the IOLs were implanted in the sulcus in the remaining 8 eyes. A doughnut-like proliferative capsular bag with an extensive Soemmering ring (32/43, 74.4%) was the main success factor for secondary capsulorhexis with RFD, and a sufficient capsular bag size (33/43, 76.7%) was an additional factor in successful in-the-bag IOL implantation. In conclusion, RFD secondary capsulorhexis technique has 70% success rate in the capsular bag reestablishment and in-the-bag IOL implantation in pediatric aphakic eyes, particularly effective in cases with a doughnut-like, extensively proliferative Soemmering ring. PMID- 23638059 TI - VPPIPP and IPPVPP: two hexapeptides innovated to exert antihypertensive activity. AB - In this study, two hexapeptides of IPPVPP and VPPIPP were innovated by using two commercial antihypertensive peptides IPP and VPP as two domains cis-linked and trans-linked, respectively. The IPPVPP and VPPIPP were chemically synthesized and evaluated for the antihypertensive activity in vitro/vivo. The in vitro ACE inhibitory study showed that VPPIPP (34.71 +/- 4.38%) has a significantly stronger activity than that of IPPVPP (13.17 +/- 0.25%) at a treatment concentration of 10 umol/L, but it was weaker than the commercial IPP (56.97 +/- 2.40%) (P<0.05). However, VPPIPP, IPPVPP, and IPP lowered the systolic blood pressure by 21 +/- 0.9%, 17.4 +/- 1.3% and 17.5 +/- 0.9%, respectively, in rats at 1.5 mg/kg body weight dosage. The result was consistent with the mRNA level of sarcoplasmic reticulum Ca(2+), Mg(2+) -ATPase Gene (SERCA 2a) in rat hearts. Additionally, VPPIPP and IPPVPP showed no negative impact on blood glycometabolism. The results suggested that the two hexapeptides could be potent bioactive peptides in functional foods for people with high blood pressure. PMID- 23638060 TI - Protective efficacy of selenite against lead-induced neurotoxicity in Caenorhabditis elegans. AB - BACKGROUND: Selenium is an essential micronutrient that has a narrow exposure window between its beneficial and toxic effects. This study investigated the protective potential of selenite (IV) against lead (Pb(II))-induced neurotoxicity in Caenorhabditis elegans. PRINCIPAL FINDINGS: The results showed that Se(IV) (0.01 uM) pretreatment ameliorated the decline of locomotion behaviors (frequencies of body bends, head thrashes, and reversal ) of C. elegans that are damaged by Pb(II) (100 uM) exposure. The intracellular ROS level of C. elegans induced by Pb(II) exposure was significantly lowered by Se(IV) supplementation prior to Pb(II) exposure. Finally, Se(IV) protects AFD sensory neurons from Pb(II)-induced toxicity. CONCLUSIONS: Our study suggests that Se(IV) has protective activities against Pb(II)-induced neurotoxicity through its antioxidant property. PMID- 23638061 TI - Homology of the fifth epibranchial and accessory elements of the ceratobranchials among gnathostomes: insights from the development of ostariophysans. AB - Epibranchials are among the main dorsal elements of the gill basket in jawed vertebrates (Gnathostomata). Among extant fishes, chondrichthyans most resemble the putative ancestral condition as all branchial arches possess every serially homologous piece. In osteichthyans, a primitive rod-like epibranchial 5, articulated to ceratobranchial 5, is absent. Instead, epibranchial 5 of many actinopterygians is here identified as an accessory element attached to ceratobranchial 4. Differences in shape and attachment of epibranchial 5 in chondrichthyans and actinopterygians raised suspicions about their homology, prompting us to conduct a detailed study of the morphology and development of the branchial basket of three ostariophysans (Prochilodus argenteus, Characiformes; Lophiosilurus alexandri and Pseudoplatystoma corruscans, Siluriformes). Results were interpreted within a phylogenetic context of major gnathostome lineages. Developmental series strongly suggest that the so-called epibranchial 5 of actinopterygians does not belong to the epal series because it shares the same chondroblastic layer with ceratobranchial 4 and its ontogenetic emergence is considerably late. This neomorphic structure is called accessory element of ceratobranchial 4. Its distribution among gnathostomes indicates it is a teleost synapomorphy, occurring homoplastically in Polypteriformes, whereas the loss of the true epibranchial 5 is an osteichthyan synapomorphy. The origin of the accessory element of ceratobranchial 4 appears to have occurred twice in osteichthyans, but it may have a single origin; in this case, the accessory element of ceratobranchial 4 would represent a remnant of a series of elements distally attached to ceratobranchials 1-4, a condition totally or partially retained in basal actinopterygians. Situations wherein a structure is lost while a similar neomorphic element is present may lead to erroneous homology assessments; these can be avoided by detailed morphological and ontogenetic investigations interpreted in the light of well-supported phylogenetic hypotheses. PMID- 23638062 TI - Sex bias in infectious disease epidemiology: patterns and processes. AB - BACKGROUND: Infectious disease incidence is often male-biased. Two main hypotheses have been proposed to explain this observation. The physiological hypothesis (PH) emphasizes differences in sex hormones and genetic architecture, while the behavioral hypothesis (BH) stresses gender-related differences in exposure. Surprisingly, the population-level predictions of these hypotheses are yet to be thoroughly tested in humans. METHODS AND FINDINGS: For ten major pathogens, we tested PH and BH predictions about incidence and exposure prevalence patterns. Compulsory-notification records (Brazil, 2006-2009) were used to estimate age-stratified ?:? incidence rate ratios for the general population and across selected sociological contrasts. Exposure-prevalence odds ratios were derived from 82 published surveys. We estimated summary effect-size measures using random-effects models; our analyses encompass ~0.5 million cases of disease or exposure. We found that, after puberty, disease incidence is male biased in cutaneous and visceral leishmaniasis, schistosomiasis, pulmonary tuberculosis, leptospirosis, meningococcal meningitis, and hepatitis A. Severe dengue is female-biased, and no clear pattern is evident for typhoid fever. In leprosy, milder tuberculoid forms are female-biased, whereas more severe lepromatous forms are male-biased. For most diseases, male bias emerges also during infancy, when behavior is unbiased but sex steroid levels transiently rise. Behavioral factors likely modulate male-female differences in some diseases (the leishmaniases, tuberculosis, leptospirosis, or schistosomiasis) and age classes; however, average exposure-prevalence is significantly sex-biased only for Schistosoma and Leptospira. CONCLUSIONS: Our results closely match some key PH predictions and contradict some crucial BH predictions, suggesting that gender specific behavior plays an overall secondary role in generating sex bias. Physiological differences, including the crosstalk between sex hormones and immune effectors, thus emerge as the main candidate drivers of gender differences in infectious disease susceptibility. PMID- 23638064 TI - Citation analysis may severely underestimate the impact of clinical research as compared to basic research. AB - BACKGROUND: Citation analysis has become an important tool for research performance assessment in the medical sciences. However, different areas of medical research may have considerably different citation practices, even within the same medical field. Because of this, it is unclear to what extent citation based bibliometric indicators allow for valid comparisons between research units active in different areas of medical research. METHODOLOGY: A visualization methodology is introduced that reveals differences in citation practices between medical research areas. The methodology extracts terms from the titles and abstracts of a large collection of publications and uses these terms to visualize the structure of a medical field and to indicate how research areas within this field differ from each other in their average citation impact. RESULTS: Visualizations are provided for 32 medical fields, defined based on journal subject categories in the Web of Science database. The analysis focuses on three fields: Cardiac & cardiovascular systems, Clinical neurology, and Surgery. In each of these fields, there turn out to be large differences in citation practices between research areas. Low-impact research areas tend to focus on clinical intervention research, while high-impact research areas are often more oriented on basic and diagnostic research. CONCLUSIONS: Popular bibliometric indicators, such as the h-index and the impact factor, do not correct for differences in citation practices between medical fields. These indicators therefore cannot be used to make accurate between-field comparisons. More sophisticated bibliometric indicators do correct for field differences but still fail to take into account within-field heterogeneity in citation practices. As a consequence, the citation impact of clinical intervention research may be substantially underestimated in comparison with basic and diagnostic research. PMID- 23638063 TI - On hepatitis C virus evolution: the interaction between virus and host towards treatment outcome. AB - BACKGROUND: Hepatitis C is a disease spread throughout the world. Hepatitis C virus (HCV), the etiological agent of this disease, is a single-stranded positive RNA virus. Its genome encodes a single precursor protein that yields ten proteins after processing. NS5A, one of the non-structural viral proteins, is most associated with interferon-based therapy response, the approved treatment for hepatitis C in Brazil. HCV has a high mutation rate and therefore high variability, which may be important for evading the immune system and response to therapy. The aim of this study was to analyze the evolution of NS5A quasispecies before, during, and after treatment in patients infected with HCV genotype 3a who presented different therapy responses. METHODS: Viral RNA was extracted, cDNA was synthesized, the NS5A region was amplified and cloned, and 15 clones from each time-point were sequenced. The sequences were analyzed for evolutionary history, genetic diversity and selection. RESULTS: This analysis shows that the viral population that persists after treatment for most non-responder patients is present in before-treatment samples, suggesting it is adapted to evade treatment. In contrast, the population found in before treatment samples from most end-of treatment responder patients either are selected out or appears in low frequency after relapse, therefore changing the population structure. The exceptions illustrate the uniqueness of the evolutionary process, and therefore the treatment resistance process, in each patient. CONCLUSION: Although evolutionary behavior throughout treatment showed that each patient presented different population dynamics unrelated to therapy outcome, it seems that the viral population from non-responders that resists the treatment already had strains that could evade therapy before it started. PMID- 23638066 TI - Variability in the labeling of asthma among pediatricians. AB - OBJECTIVE: Few studies have examined variability among physicians in the perception and interpretation of asthma symptoms. We report the results of a pilot study to investigate the variability of symptom description and diagnostic labeling and nomenclature among a group of clinicians using standardized audiovisual presentations of asthma. METHODS: Practicing pediatricians in Wisconsin recruited from an electronic mailing list were shown the International Study of Asthma and Allergies in Childhood (ISAAC) video questionnaire online, and asked to describe the symptoms and signs they observed and suggest possible diagnostic labels for each presentation. RESULTS: A total of 113 pediatricians (mean age = 43 years; 56% female) responded to >=1 of the 5 video scenes. The number of practitioners who described the principal symptom(s) of asthma depicted in the 5 sequences ranged from 5.5% for Scene 5 (featuring both dyspnea and wheeze), to 100% for Scene 4 (featuring cough). The number who suggested label of 'asthma' as a possible cause of the presentations ranged from 69.7% for Scene 3 (featuring nocturnal wheeze), to 92.7% for Scene 2 (featuring exercise induced wheeze). CONCLUSION: There is important unexplained variation in the perceptions and labeling of asthma symptoms among pediatricians. These differences may influence the likelihood of diagnosis and the apparent prevalence of asthma. Many participants suggested that the ISAAC video be used in the education and training of pediatricians. PMID- 23638065 TI - Human vocal attractiveness as signaled by body size projection. AB - Voice, as a secondary sexual characteristic, is known to affect the perceived attractiveness of human individuals. But the underlying mechanism of vocal attractiveness has remained unclear. Here, we presented human listeners with acoustically altered natural sentences and fully synthetic sentences with systematically manipulated pitch, formants and voice quality based on a principle of body size projection reported for animal calls and emotional human vocal expressions. The results show that male listeners preferred a female voice that signals a small body size, with relatively high pitch, wide formant dispersion and breathy voice, while female listeners preferred a male voice that signals a large body size with low pitch and narrow formant dispersion. Interestingly, however, male vocal attractiveness was also enhanced by breathiness, which presumably softened the aggressiveness associated with a large body size. These results, together with the additional finding that the same vocal dimensions also affect emotion judgment, indicate that humans still employ a vocal interaction strategy used in animal calls despite the development of complex language. PMID- 23638069 TI - Scientists popularizing science: characteristics and impact of TED talk presenters. AB - The TED (Technology, Entertainment, Design) conference and associated website of recorded conference presentations (TED Talks) is a highly successful disseminator of science-related videos, claiming over a billion online views. Although hundreds of scientists have presented at TED, little information is available regarding the presenters, their academic credentials, and the impact of TED Talks on the general population. This article uses bibliometric and webometric techniques to gather data on the characteristics of TED presenters and videos and analyze the relationship between these characteristics and the subsequent impact of the videos. The results show that the presenters were predominately male and non-academics. Male-authored videos were more popular and more liked when viewed on YouTube. Videos by academic presenters were more commented on than videos by others and were more liked on YouTube, although there was little difference in how frequently they were viewed. The majority of academic presenters were senior faculty, males, from United States-based institutions, were visible online, and were cited more frequently than average for their field. However, giving a TED presentation appeared to have no impact on the number of citations subsequently received by an academic, suggesting that although TED popularizes research, it may not promote the work of scientists within the academic community. PMID- 23638068 TI - Tau passive immunotherapy in mutant P301L mice: antibody affinity versus specificity. AB - The use of antibodies to treat neurodegenerative diseases has undergone rapid development in the past decade. To date, immunotherapeutic approaches to Alzheimer's disease have mostly targeted amyloid beta as it is a secreted protein that can be found in plasma and CSF and is consequently accessible to circulating antibodies. Few recent publications have suggested the utility of treatment of tau pathology with monoclonal antibodies to tau. Our laboratory has begun a systematic study of different classes of tau monoclonal antibodies using mutant P301L mice. Three or seven months old mutant tau mice were inoculated weekly with tau monoclonal antibodies at a dose of 10 mg/Kg, until seven or ten months of age were reached respectively. Our data strongly support the notion that in P301L animals treated with MC1, a conformational monoclonal antibody specific for PHF tau, the rate of development of tau pathology is effectively reduced, while injecting DA31, a high affinity tau sequence antibody, does not exert such benefit. MC1 appears superior to DA31 in overall effects, suggesting that specificity is more important than affinity in therapeutic applications. Unfortunately the survival rate of the P301L treated mice was not improved when immunizing either with MC1 or PHF1, a high affinity phospho-tau antibody previously reported to be efficacious in reducing pathological tau. These data demonstrate that passive immunotherapy in mutant tau models may be efficacious in reducing the development of tau pathology, but a great deal of work remains to be done to carefully select the tau epitopes to target. PMID- 23638067 TI - Loss of PINK1 increases the heart's vulnerability to ischemia-reperfusion injury. AB - OBJECTIVES: Mutations in PTEN inducible kinase-1 (PINK1) induce mitochondrial dysfunction in dopaminergic neurons resulting in an inherited form of Parkinson's disease. Although PINK1 is present in the heart its exact role there is unclear. We hypothesized that PINK1 protects the heart against acute ischemia reperfusion injury (IRI) by preventing mitochondrial dysfunction. METHODS AND RESULTS: Over expressing PINK1 in HL-1 cardiac cells reduced cell death following simulated IRI (29.2+/-5.2% PINK1 versus 49.0+/-2.4% control; N = 320 cells/group P<0.05), and delayed the onset of mitochondrial permeability transition pore (MPTP) opening (by 1.3 fold; P<0.05). Hearts excised from PINK1+/+, PINK1+/- and PINK1-/- mice were subjected to 35 minutes regional ischemia followed by 30 minutes reperfusion. Interestingly, myocardial infarct size was increased in PINK1-/- hearts compared to PINK1+/+ hearts with an intermediate infarct size in PINK1+/- hearts (25.1+/-2.0% PINK1+/+, 38.9+/-3.4% PINK1+/- versus 51.5+/-4.3% PINK1-/- hearts; N>5 animals/group; P<0.05). Cardiomyocytes isolated from PINK1-/- hearts had a lower resting mitochondrial membrane potential, had inhibited mitochondrial respiration, generated more oxidative stress during simulated IRI, and underwent rigor contracture more rapidly in response to an uncoupler when compared to PINK1+/+ cells suggesting mitochondrial dysfunction in hearts deficient in PINK1. CONCLUSIONS: We show that the loss of PINK1 increases the heart's vulnerability to ischemia-reperfusion injury. This may be due, in part, to increased mitochondrial dysfunction. These findings implicate PINK1 as a novel target for cardioprotection. PMID- 23638070 TI - The congruency effect in the posterior medial frontal cortex is more consistent with time on task than with response conflict. AB - The posterior medial frontal cortex (pMFC) is thought to play a pivotal role in enabling the control of attention during periods of distraction. In line with this view, pMFC activity is ubiquitously greater in incongruent trials of response-interference (e.g., Stroop) tasks than in congruent trials. Nonetheless, the process underlying this congruency effect remains highly controversial. We therefore sought to distinguish between two competing accounts of the congruency effect. The conflict monitoring account posits the effect indexes a process that detects conflict between competing response alternatives, which is indexed by trial-specific reaction time (RT). The time on task account posits the effect indexes a process whose recruitment increases with time on task independent of response conflict (e.g., sustained attention, arousal, effort, etc.). To distinguish between these accounts, we used functional MRI to record brain activity in twenty-four healthy adults while they performed two tasks: a response interference task and a simple RT task with only one possible response. We reasoned that demands on a process that detects response conflict should increase with RT in the response-interference task but not in the simple RT task. In contrast, demands on a process whose recruitment increases with time on task independent of response conflict should increase with RT in both tasks. Trial-by trial analyses revealed that pMFC activity increased with RT in both tasks. Moreover, pMFC activity increased with RT in the simple RT task enough to fully account for the congruency effect in the response-interference task. These findings appear more consistent with the time on task account of the congruency effect than with the conflict monitoring account. PMID- 23638071 TI - Detection and strain typing of ancient Mycobacterium leprae from a medieval leprosy hospital. AB - Nine burials excavated from the Magdalen Hill Archaeological Research Project (MHARP) in Winchester, UK, showing skeletal signs of lepromatous leprosy (LL) have been studied using a multidisciplinary approach including osteological, geochemical and biomolecular techniques. DNA from Mycobacterium leprae was amplified from all nine skeletons but not from control skeletons devoid of indicative pathology. In several specimens we corroborated the identification of M. leprae with detection of mycolic acids specific to the cell wall of M. leprae and persistent in the skeletal samples. In five cases, the preservation of the material allowed detailed genotyping using single-nucleotide polymorphism (SNP) and multiple locus variable number tandem repeat analysis (MLVA). Three of the five cases proved to be infected with SNP type 3I-1, ancestral to contemporary M. leprae isolates found in southern states of America and likely carried by European migrants. From the remaining two burials we identified, for the first time in the British Isles, the occurrence of SNP type 2F. Stable isotope analysis conducted on tooth enamel taken from two of the type 3I-1 and one of the type 2F remains revealed that all three individuals had probably spent their formative years in the Winchester area. Previously, type 2F has been implicated as the precursor strain that migrated from the Middle East to India and South-East Asia, subsequently evolving to type 1 strains. Thus we show that type 2F had also spread westwards to Britain by the early medieval period. PMID- 23638072 TI - Incidence and associated factors of HIV drug resistance in Chinese HIV-infected patients receiving antiretroviral treatment. AB - BACKGROUND: A critical indicator of the future success of highly active antiretroviral therapy (HAART) is the incidence of HIV drug resistance, which has not been studied in China on the national scale. METHODS: HIV drug resistance baseline survey was conducted in the eight provinces with the largest numbers of patients on HAART in 2009, and a prospective cohort study with 12-month follow-up was completed in 2010. Patients completed an interviewer-administrated questionnaire and provided blood for CD4+ T-lymphocyte count (CD4 count), HIV viral load (VL), and HIV drug resistance genotyping. Factors associated with incidence of HIVDR were identified by Cox regression analysis. RESULTS: The overall prevalence of HIV RNA >= 1000 copies/ml and HIVDR at baseline was 12.4% and 5.6%, respectively. Incidence of HIVDR in the one year follow-up was 3.5 per 100 person years. Independently associated factors were started treatment with a didanosine-based regimen, received care at township hospital or village clinic, low baseline CD4 counts, and high baseline VL. CONCLUSIONS: The incidence of HIVDR in China was higher than that of some developed countries. China urgently needs to provide comprehensive education and training to doctors at village clinics and township hospitals to improve quality community-based care and treatment. PMID- 23638073 TI - Comparative analysis of the gut microbiota in people with different levels of ginsenoside Rb1 degradation to compound K. AB - Panax ginseng (family Araliaceae) which contains ginsenoside Rb1 as a main constituent is traditionally used as a remedy for cancer, inflammation, stress, and ageing. The ginsenoside Rb1 in orally administered ginseng is metabolized to bioactive compounds by gut microbiota before their absorptions to the blood. However, its metabolizing activities in individuals are significantly different as we previously demonstrated. Here, we selected 5 samples with fecal activity potently metabolizing ginsenoside Rb1 to compound K (FPG; metabolic activity, 0.058+/-0.029 pmol/min/mg) and 5 samples with fecal activity non-metabolizing ginsenoside Rb1 to compound K (FNG) from a pool of 100 subjects investigated in a previous study and analyzed fecal microbiota by 16S rRNA gene pyrosequencing. Taxonomy-based analysis showed that the population levels of Firmicutes and Proteobacteria in FPG were lower than in FNG, but those of Bacteroidetes and Tenericutes in FPG were higher than in FNG. At the genus level, the population levels of Clostridiales_uc_g, Oscillibacter, Ruminococcus, Holdemania, and Sutterella in FPG were significantly higher than in FNG, but that of Leuconostoc in FPG was lower than in FNG. The population levels of Bacteroides and Bifidobacterium, which potently metabolizes ginsenoside Rb1 to compound K were dramatically increased in FPG. The gut microbiota compositions of FPG and FNG were segregated on PCO2 by Principal Coordinate Analysis. Intestinal bacterial metabolism of ginseng, particularly ginsenoside Rb1, may be dependent on the composition of gut microbiota, such as Ruminococcus spp., Bacteroides spp. and Bifidobacterium spp. PMID- 23638074 TI - Dynamic and static overloading induce early degenerative processes in caprine lumbar intervertebral discs. AB - Mechanical overloading of the spine is associated with low back pain and intervertebral disc (IVD) degeneration. How excessive loading elicits degenerative changes in the IVD is poorly understood. Comprehensive knowledge of the interaction between mechanical loading, cell responses and changes in the extracellular matrix of the disc is needed in order to successfully intervene in this process. The purpose of the current study was to investigate whether dynamic and static overloading affect caprine lumbar discs differently and what mechanisms lead to mechanically induced IVD degeneration. Lumbar caprine IVDs (n = 175) were cultured 7, 14 and 21 days under simulated-physiological loading (control), high dynamic or high static loading. Axial deformation and stiffness were continuously measured. Cell viability, cell density, and gene expression were assessed in the nucleus, inner- and outer annulus. The extracellular matrix (ECM) was analyzed for water, glycosaminoglycan and collagen content. IVD height loss and changes in axial deformation were gradual with dynamic and acute with static overloading. Dynamic overloading caused cell death in all IVD regions, whereas static overloading mostly affected the outer annulus. IVDs expression of catabolic and inflammation-related genes was up-regulated directly, whereas loss of water and glycosaminoglycan were significant only after 21 days. Static and dynamic overloading both induced pathological changes to caprine lumbar IVDs within 21 days. The mechanism by which they inflict biomechanical, cellular, and extracellular changes to the nucleus and annulus differed. The described cascades provide leads for the development of new pharmacological and rehabilitative therapies to halt the progression of DDD. PMID- 23638076 TI - Natural killer cell function, an important target for infection and tumor protection, is impaired in type 2 diabetes. AB - Patients with Type 2 diabetes (T2D) are highly susceptible to infection and have an increased incidence of some tumors, possibly due to immune system dysfunction. In the innate cellular immune system, Natural Killer (NK) lymphocytes are important effectors responsible for controlling infections and combating tumor development. We analyzed NK cell subsets in 51 patients with long-standing T2D. Compared with healthy blood donors, diabetic patients showed a profound decrease in both NKG2D-positive NK cells (44% vs. 55.5%, P<0.01) and NKp46-positive cells (26% vs. 50%, P<0.01). Decreased expression of these receptors was associated with functional defects, such as reduced NK degranulation capacity when challenged with the tumor target cell line K562 (10.3 vs. 15.8%, P<0.05). This defect could be restored in vitro by stimulating NK cells from T2D patients with IL-15 (P<0.05). NKG2D expression was found to be negatively correlated with HBA1c level (r=-0.50; P=0.009), suggesting that sustained hyperglycemia could directly influence NK cell defects. We demonstrated that endoplasmic reticulum (ER) stress, an important mediator in diabetes-associated complications, was inducible in vitro in normal NK cells and that tunicamycin treatment resulted in a significant decrease in NKG2D expression (P<0.05). Furthermore, markers of the Unfolded Protein Response (UPR) BiP, PDI and sXBP1 mRNAs were significantly increased in NK cells from T2D patients (P<0.05, P<0.01, P<0.05, respectively), indicating that ER stress is activated in vivo through both PERK and IRE1 sensors. These results demonstrate for the first time defects in NK cell activating receptors NKG2D and NKp46 in T2D patients, and implicate the UPR pathway as a potential mechanism. These defects may contribute to susceptibility to infections and malignancies and could be targetted therapeutically. PMID- 23638075 TI - Antibody to ricin a chain hinders intracellular routing of toxin and protects cells even after toxin has been internalized. AB - BACKGROUND: Mechanisms of antibody-mediated neutralization are of much interest. For plant and bacterial A-B toxins, A chain mediates toxicity and B chain binds target cells. It is generally accepted and taught that antibody (Ab) neutralizes by preventing toxin binding to cells. Yet for some toxins, ricin included, anti-A chain Abs afford greater protection than anti-B. The mechanism(s) whereby Abs to the A chain neutralize toxins are not understood. METHODOLOGY/PRINCIPAL FINDINGS: We use quantitative confocal imaging, neutralization assays, and other techniques to study how anti-A chain Abs function to protect cells. Without Ab, ricin enters cells and penetrates to the endoplasmic reticulum within 15 min. Within 45-60 min, ricin entering and being expelled from cells reaches equilibrium. These results are consistent with previous observations, and support the validity of our novel methodology. The addition of neutralizing Ab causes ricin accumulation at the cell surface, delays internalization, and postpones retrograde transport of ricin. Ab binds ricin for >6hr as they traffic together through the cell. Ab protects cells even when administered hours after exposure. CONCLUSIONS/KEY FINDINGS: We demonstrate the dynamic nature of the interaction between the host cell and toxin, and how Ab can alter the balance in favor of the cell. Ab blocks ricin's entry into cells, hinders its intracellular routing, and can protect even after ricin is present in the target organelle, providing evidence that the major site of neutralization is intracellular. These data add toxins to the list of pathogenic agents that can be neutralized intracellularly and explain the in vivo efficacy of delayed administration of anti-toxin Abs. The results encourage the use of post-exposure passive Ab therapy, and show the importance of the A chain as a target of Abs. PMID- 23638077 TI - Filling gaps in biodiversity knowledge for macrofungi: contributions and assessment of an herbarium collection DNA barcode sequencing project. AB - Despite recent advances spearheaded by molecular approaches and novel technologies, species description and DNA sequence information are significantly lagging for fungi compared to many other groups of organisms. Large scale sequencing of vouchered herbarium material can aid in closing this gap. Here, we describe an effort to obtain broad ITS sequence coverage of the approximately 6000 macrofungal-species-rich herbarium of the Museum of Natural History in Venice, Italy. Our goals were to investigate issues related to large sequencing projects, develop heuristic methods for assessing the overall performance of such a project, and evaluate the prospects of such efforts to reduce the current gap in fungal biodiversity knowledge. The effort generated 1107 sequences submitted to GenBank, including 416 previously unrepresented taxa and 398 sequences exhibiting a best BLAST match to an unidentified environmental sequence. Specimen age and taxon affected sequencing success, and subsequent work on failed specimens showed that an ITS1 mini-barcode greatly increased sequencing success without greatly reducing the discriminating power of the barcode. Similarity comparisons and nonmetric multidimensional scaling ordinations based on pairwise distance matrices proved to be useful heuristic tools for validating the overall accuracy of specimen identifications, flagging potential misidentifications, and identifying taxa in need of additional species-level revision. Comparison of within- and among-species nucleotide variation showed a strong increase in species discriminating power at 1-2% dissimilarity, and identified potential barcoding issues (same sequence for different species and vice-versa). All sequences are linked to a vouchered specimen, and results from this study have already prompted revisions of species-sequence assignments in several taxa. PMID- 23638078 TI - Components of the canonical and non-canonical Wnt pathways are not mis-expressed in pituitary tumors. AB - INTRODUCTION: Canonical and non-canonical Wnt pathways are involved in the genesis of multiple tumors; however, their role in pituitary tumorigenesis is mostly unknown. OBJECTIVE: This study evaluated gene and protein expression of Wnt pathways in pituitary tumors and whether these expression correlate to clinical outcome. MATERIALS AND METHODS: Genes of the WNT canonical pathway: activating ligands (WNT11, WNT4, WNT5A), binding inhibitors (DKK3, sFRP1), beta catenin (CTNNB1), beta-catenin degradation complex (APC, AXIN1, GSK3beta), inhibitor of beta-catenin degradation complex (AKT1), sequester of beta-catenin (CDH1), pathway effectors (TCF7, MAPK8, NFAT5), pathway mediators (DVL-1, DVL-2, DVL-3, PRICKLE, VANGL1), target genes (MYB, MYC, WISP2, SPRY1, TP53, CCND1); calcium dependent pathway (PLCB1, CAMK2A, PRKCA, CHP); and planar cell polarity pathway (PTK7, DAAM1, RHOA) were evaluated by QPCR, in 19 GH-, 18 ACTH-secreting, 21 non-secreting (NS) pituitary tumors, and 5 normal pituitaries. Also, the main effectors of canonical (beta-catenin), planar cell polarity (JNK), and calcium dependent (NFAT5) Wnt pathways were evaluated by immunohistochemistry. RESULTS: There are no differences in gene expression of canonical and non-canonical Wnt pathways between all studied subtypes of pituitary tumors and normal pituitaries, except for WISP2, which was over-expressed in ACTH-secreting tumors compared to normal pituitaries (4.8x; p = 0.02), NS pituitary tumors (7.7x; p = 0.004) and GH secreting tumors (5.0x; p = 0.05). beta-catenin, NFAT5 and JNK proteins showed no expression in normal pituitaries and in any of the pituitary tumor subtypes. Furthermore, no association of the studied gene or protein expression was observed with tumor size, recurrence, and progressive disease. The hierarchical clustering showed a regular pattern of genes of the canonical and non-canonical Wnt pathways randomly distributed throughout the dendrogram. CONCLUSIONS: Our data reinforce previous reports suggesting no activation of canonical Wnt pathway in pituitary tumorigenesis. Moreover, we describe, for the first time, evidence that non-canonical Wnt pathways are also not mis-expressed in the pituitary tumors. PMID- 23638080 TI - Monomeric banana lectin at acidic pH overrules conformational stability of its native dimeric form. AB - Banana lectin (BL) is a homodimeric protein categorized among jacalin-related family of lectins. The effect of acidic pH was examined on conformational stability of BL by using circular dichroism, intrinsic fluorescence, 1-anilino-8 napthalene sulfonate (ANS) binding, size exclusion chromatography (SEC) and dynamic light scattering (DLS). During acid denaturation of BL, the monomerization of native dimeric protein was found at pH 2.0. The elution profile from SEC showed two different peaks (59.65 ml & 87.98 ml) at pH 2.0 while single peak (61.45 ml) at pH 7.4. The hydrodynamic radii (R h) of native BL was 2.9 nm while at pH 2.0 two species were found with R h of 1.7 and 3.7 nm. Furthermore at, pH 2.0 the secondary structures of BL remained unaltered while tertiary structure was significantly disrupted with the exposure of hydrophobic clusters confirming the existence of molten globule like state. The unfolding of BL with different subunit status was further evaluated by urea and temperature mediated denaturation to check their stability. As inferred from high Cm and DeltaG values, the monomeric form of BL offers more resistance towards chemical denaturation than the native dimeric form. Besides, dimeric BL exhibited a Tm of 77 degrees C while no loss in secondary structures was observed in monomers even up to 95 degrees C. To the best of our knowledge, this is the first report on monomeric subunit of lectins showing more stability against denaturants than its native dimeric state. PMID- 23638079 TI - Selective targeting of brain tumors with gold nanoparticle-induced radiosensitization. AB - Successful treatment of brain tumors such as glioblastoma multiforme (GBM) is limited in large part by the cumulative dose of Radiation Therapy (RT) that can be safely given and the blood-brain barrier (BBB), which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs). GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ~1.3). Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature. PMID- 23638082 TI - Infra-slow oscillation (ISO) of the pupil size of urethane-anaesthetised rats. AB - Multiplicity of oscillatory phenomena in a range of infra-slow frequencies (<0.01 Hz) has been described in mammalian brains at different levels of organisation. The significance and manifestation in physiology and/or behaviour of many brain infra-slow oscillations (ISO) remain unknown. Examples of this phenomenon are two types of ISO observed in the brains of urethane-anaesthetised rats: infra-slow, rhythmic changes in the rate of action potential firing in a few nuclei of the subcortical visual system and a sleep-like cycle of activation/deactivation visible in the EEG signal. Because both of these rhythmic phenomena involve brain networks that can influence autonomic nervous system activity, we hypothesised that these two brain ISOs can be reflected by rhythmic changes of pupil size. Thus, in the present study, we used simultaneous pupillography and ECoG recording to verify the hypothesised existence of infra-slow oscillations in the pupil size of urethane-anaesthetised rats. The obtained results showed rhythmic changes in the size of the pupils and rhythmic eyeball movements in urethane-anaesthetised rats. The observed rhythms were characterised by two different dominant components in a range of infra-slow frequencies. First, the long component had a period of ~ 29 minutes and was present in both the irises and the eyeball movements. Second, the short component had a period of ~ 2 minutes and was observed only in the rhythmic constrictions and dilations of the pupils. Both ISOs were simultaneously present in both eyes, and they were synchronised between the left and right eye. The long ISO component was synchronised with the cyclic alternations of the brain state, as revealed by rhythmic changes in the pattern of the ECoG signal. Based on the obtained results, we propose a model of interference of ISO present in different brain systems involved in the control of pupil size. PMID- 23638081 TI - Recombinant adenovirus-mediated intestinal trefoil factor gene therapy for burn induced intestinal mucosal injury. AB - Intestinal trefoil factor (ITF) is a small polypeptide with potential medical values whose main pharmacological effects are to alleviate gastrointestinal mucosal injury caused by various injury factors and promote the repair of damaged mucosa. However, its low yield limits its application. The purpose of our study was to construct a recombinant adenoviral vector containing the hITF gene and observe the therapeutic effect of burn-induced intestinal mucosal injury using in vitro and in vivo analysis. First, a recombinant shuttle plasmid was constructed by ligating a pAdTrack-CMV vector with a full-length hITF gene containing a signal peptide and the mature peptide, followed by the recombinant Ad-hITF adenovirus vector after linearization and homologous recombination with the backbone plasmid in the competent BJ5183 strain. Second, the hITF expression level was detected using reverse transcription polymerase chain reaction and western blotting after Ad-hITF infection of colon cancer HT-29 cells. The recombinant adenovirus significantly promoted cell migration in an in vitro wounding model. Finally, we confirmed that the recombinant adenovirus could significantly expedite the healing of intestinal mucosal injury after establishing a mouse model in which severe burns were stimulated and the recombinant adenovirus was delivered by intragastric injection. In summary, we constructed a recombinant adenoviral vector containing the hITF gene and confirmed its role in promoting repair of the intestinal mucosa. Our study provides a novel way to treat burn-induced intestinal mucosal injury. PMID- 23638083 TI - The AgI/II family adhesin AspA is required for respiratory infection by Streptococcus pyogenes. AB - Streptococcus pyogenes (GAS) is a human pathogen that causes pharyngitis and invasive diseases such as toxic shock syndrome and sepsis. The upper respiratory tract is the primary reservoir from which GAS can infect new hosts and cause disease. The factors involved in colonisation are incompletely known however. Previous evidence in oral streptococci has shown that the AgI/II family proteins are involved. We hypothesized that the AspA member of this family might be involved in GAS colonization. We describe a novel mouse model of GAS colonization of the nasopharynx and lower respiratory tract to elucidate these interactions. We used two clinical M serotypes expressing AspA, and their aspA gene deletant isogenic mutants in experiments using adherence assays to respiratory epithelium, macrophage phagocytosis and neutrophil killing assays and in vivo models of respiratory tract colonisation and infection. We demonstrated the requirement for AspA in colonization of the respiratory tract. AspA mutants were cleared from the respiratory tract and were deficient in adherence to epithelial cells, and susceptible to phagocytosis. Expression of AspA in the surrogate host Lactococcus lactis protected bacteria from phagocytosis. Our results suggest that AspA has an essential role in respiratory infection, and may function as a novel anti phagocytic factor. PMID- 23638084 TI - No trade-off between growth rate and temperature stress resistance in four insect species. AB - Although fast growth seems to be generally favored by natural selection, growth rates are rarely maximized in nature. Consequently, fast growth is predicted to carry costs resulting in intrinsic trade-offs. Disentangling such trade-offs is of great ecological importance in order to fully understand the prospects and limitations of growth rate variation. A recent study provided evidence for a hitherto unknown cost of fast growth, namely reduced cold stress resistance. Such relationships could be especially important under climate change. Against this background we here investigate the relationships between individual larval growth rate and adult heat as well as cold stress resistance, using eleven data sets from four different insect species (three butterfly species: Bicyclus anynana, Lycaena tityrus, Pieris napi; one Dipteran species: Protophormia terraenovae). Despite using different species (and partly different populations within species) and an array of experimental manipulations (e.g. different temperatures, photoperiods, feeding regimes, inbreeding levels), we were not able to provide any consistent evidence for trade-offs between fast growth and temperature stress resistance in these four insect species. PMID- 23638087 TI - KCNQ channels regulate age-related memory impairment. AB - In humans KCNQ2/3 heteromeric channels form an M-current that acts as a brake on neuronal excitability, with mutations causing a form of epilepsy. The M-current has been shown to be a key regulator of neuronal plasticity underlying associative memory and ethanol response in mammals. Previous work has shown that many of the molecules and plasticity mechanisms underlying changes in alcohol behaviour and addiction are shared with those of memory. We show that the single KCNQ channel in Drosophila (dKCNQ) when mutated show decrements in associative short- and long-term memory, with KCNQ function in the mushroom body alpha/betaneurons being required for short-term memory. Ethanol disrupts memory in wildtype flies, but not in a KCNQ null mutant background suggesting KCNQ maybe a direct target of ethanol, the blockade of which interferes with the plasticity machinery required for memory formation. We show that as in humans, Drosophila display age-related memory impairment with the KCNQ mutant memory defect mimicking the effect of age on memory. Expression of KCNQ normally decreases in aging brains and KCNQ overexpression in the mushroom body neurons of KCNQ mutants restores age-related memory impairment. Therefore KCNQ is a central plasticity molecule that regulates age dependent memory impairment. PMID- 23638088 TI - Annexin A1 on the surface of early apoptotic cells suppresses CD8+ T cell immunity. AB - Prevention of an immune response against self-antigens derived from apoptotic cells is essential to preclude autoimmune and chronic inflammatory diseases. Here, we describe apoptosis induced externalization of endogenous cytosolic annexin 1 initiating an anti-inflammatory effector mechanism that suppresses the immune response against antigens of apoptotic cells. Cytosolic annexin 1 rapidly translocated to the apoptotic cell surface and inhibited dendritic cell (DC) activation induced by Toll like receptors (TLR). Annexin 1-inhibited DC showed strongly reduced secretion of pro-inflammatory cytokines (e.g. TNF and IL-12) and costimulatory surface molecules (e.g. CD40 and CD86), while anti-inflammatory mediators like PD-L1 remained unchanged. T cells stimulated by such DC lacked secretion of interferon-gamma (IFN-gamma) and TNF but retained IL-10 secretion. In mice, annexin 1 prevented the development of inflammatory DC and suppressed the cellular immune response against the model antigen ovalbumin (OVA) expressed in apoptotic cells. Furthermore, annexin 1 on apoptotic cells compromised OVA specific tumor vaccination and impaired rejection of an OVA-expressing tumor. Thus, our results provide a molecular mechanism for the suppressive activity of apoptotic cells on the immune response towards apoptotic cell-derived self antigens. This process may play an important role in prevention of autoimmune diseases and of the immune response against cancer. PMID- 23638085 TI - Novel algorithm for non-invasive assessment of fibrosis in NAFLD. AB - INTRODUCTION: Various conditions of liver disease and the downsides of liver biopsy call for a non-invasive option to assess liver fibrosis. A non-invasive score would be especially useful to identify patients with slow advancing fibrotic processes, as in Non-Alcoholic Fatty Liver Disease (NAFLD), which should undergo histological examination for fibrosis. PATIENTS/METHODS: Classic liver serum parameters, hyaluronic acid (HA) and cell death markers of 126 patients undergoing bariatric surgery for morbid obesity were analyzed by machine learning techniques (logistic regression, k-nearest neighbors, linear support vector machines, rule-based systems, decision trees and random forest (RF)). Specificity, sensitivity and accuracy of the evaluated datasets to predict fibrosis were assessed. RESULTS: None of the single parameters (ALT, AST, M30, M60, HA) did differ significantly between patients with a fibrosis score 1 or 2. However, combining these parameters using RFs reached 79% accuracy in fibrosis prediction with a sensitivity of more than 60% and specificity of 77%. Moreover, RFs identified the cell death markers M30 and M65 as more important for the decision than the classic liver parameters. CONCLUSION: On the basis of serum parameters the generation of a fibrosis scoring system seems feasible, even when only marginally fibrotic tissue is available. Prospective evaluation of novel markers, i.e. cell death parameters, should be performed to identify an optimal set of fibrosis predictors. PMID- 23638086 TI - Formation of Stylet Sheaths in aere (in air) from eight species of phytophagous hemipterans from six families (Suborders: Auchenorrhyncha and Sternorrhyncha). AB - Stylet sheath formation is a common feature among phytophagous hemipterans. These sheaths are considered essential to promote a successful feeding event. Stylet sheath compositions are largely unknown and their mode of solidification remains to be elucidated. This report demonstrates the formation and solidification of in aere (in air) produced stylet sheaths by six hemipteran families: Diaphorina citri (Psyllidae, Asian citrus psyllid), Aphis nerii (Aphididae, oleander/milkweed aphid), Toxoptera citricida (Aphididae, brown citrus aphid), Aphis gossypii (Aphididae, cotton melon aphid), Bemisia tabaci biotype B (Aleyrodidae, whitefly), Homalodisca vitripennis (Cicadellidae, glassy-winged sharpshooter), Ferrisia virgata (Pseudococcidae, striped mealybug), and Protopulvinaria pyriformis (Coccidae, pyriform scale). Examination of in aere produced stylet sheaths by confocal and scanning electron microscopy shows a common morphology of an initial flange laid down on the surface of the membrane followed by continuous hollow core structures with sequentially stacked hardened bulbous droplets. Single and multi-branched sheaths were common, whereas mealybug and scale insects typically produced multi-branched sheaths. Micrographs of the in aere formed flanges indicate flange sealing upon stylet bundle extraction in D. citri and the aphids, while the B. tabaci whitefly and H. vitripennis glassy winged sharpshooter flanges remain unsealed. Structural similarity of in aere sheaths are apparent in stylet sheaths formed in planta, in artificial diets, or in water. The use of 'Solvy', a dissolvable membrane, for intact stylet sheath isolation is reported. These observations illustrate for the first time this mode of stylet sheath synthesis adding to the understanding of stylet sheath formation in phytophagous hemipterans and providing tools for future use in structural and compositional analysis. PMID- 23638091 TI - Simultaneous transcriptome analysis of Sorghum and Bipolaris sorghicola by using RNA-seq in combination with de novo transcriptome assembly. AB - The recent development of RNA sequencing (RNA-seq) technology has enabled us to analyze the transcriptomes of plants and their pathogens simultaneously. However, RNA-seq often relies on aligning reads to a reference genome and is thus unsuitable for analyzing most plant pathogens, as their genomes have not been fully sequenced. Here, we analyzed the transcriptomes of Sorghum bicolor (L.) Moench and its pathogen Bipolaris sorghicola simultaneously by using RNA-seq in combination with de novo transcriptome assembly. We sequenced the mixed transcriptome of the disease-resistant sorghum cultivar SIL-05 and B. sorghicola in infected leaves in the early stages of infection (12 and 24 h post inoculation) by using Illumina mRNA-Seq technology. Sorghum gene expression was quantified by aligning reads to the sorghum reference genome. For B. sorghicola, reads that could not be aligned to the sorghum reference genome were subjected to de novo transcriptome assembly. We identified genes of B. sorghicola for growth of this fungus in sorghum, as well as genes in sorghum for the defense response. The genes of B. sorghicola included those encoding Woronin body major protein, LysM domain-containing intracellular hyphae protein, transcriptional factors CpcA and HacA, and plant cell-wall degrading enzymes. The sorghum genes included those encoding two receptors of the simple eLRR domain protein family, transcription factors that are putative orthologs of OsWRKY45 and OsWRKY28 in rice, and a class III peroxidase that is a homolog involved in disease resistance in the Poaceae. These defense-related genes were particularly strongly induced among paralogs annotated in the sorghum genome. Thus, in the absence of genome sequences for the pathogen, simultaneous transcriptome analysis of plant and pathogen by using de novo assembly was useful for identifying putative key genes in the plant-pathogen interaction. PMID- 23638089 TI - Association between SPARC mRNA expression, prognosis and response to neoadjuvant chemotherapy in early breast cancer: a pooled in-silico analysis. AB - INTRODUCTION: SPARC is an important regulator of the extracellular matrix and has been suggested to improve delivery of albumin-bound cytotoxics. However, little is known regarding its role in breast cancer (BC). METHODS: We conducted a pooled analysis of publically available datasets, in which BC patients who received no systemic therapy or received neoadjuvant chemotherapy were eligible. Patients were assigned to molecular subtypes using PAM-50. We computed a SPARC module (SPARC7), composed of genes with an absolute correlation with SPARC >0.7. In the systemically untreated cohort, we evaluated 1) expression of SPARC/SPARC7 according to breast cancer subtype, 2) association between SPARC/SPARC7 and biological processes related to proliferation, immune and stroma, and 3) association between SPARC/SPARC7 and relapse-free survival in a Cox model in all patients and in the different molecular subtypes adjusted for tumor size, nodal status, histological grade, and age. In the neoadjuvant cohort, we evaluated the association between SPARC and pCR in a logistic regression model, adjusted for the same clinicopathologic factors. RESULTS: 948 (10 datasets), and 791 (8 datasets) patients were included in the systemically untreated and neoadjuvant cohorts, respectively. High SPARC expression was associated with small tumor size, low histological grade and luminal-A tumors (all p<0.0001). There was a positive correlation between SPARC and stroma-related modules but negative correlation with proliferation modules. High SPARC expression was associated with poor prognosis in patients with basal and HER2+ breast cancer even after adjusting for clinicopathologic parameters. In the neoadjuvant cohort, a subgroup analysis suggested that high SPARC is associated with low rates of pCR in the HER2 subtype. Same results were observed on replacing SPARC by SPARC7. CONCLUSION: This analysis suggests a potential role of SPARC in determining prognosis and response to primary chemotherapy in early BC. This information could guide further development of albumin-bound cytotoxics in BC. PMID- 23638092 TI - Reference gene selection for real-time quantitative PCR analysis of the mouse uterus in the peri-implantation period. AB - The study of uterine gene expression patterns is valuable for understanding the biological and molecular mechanisms that occur during embryo implantation. Real time quantitative RT-PCR (qRT-PCR) is an extremely sensitive technique that allows for the precise quantification of mRNA abundance; however, selecting stable reference genes suitable for the normalization of qRT-PCR data is required to avoid the misinterpretation of experimental results and erroneous analyses. This study employs several mouse models, including an early pregnancy, a pseudopregnancy, a delayed implantation and activation, an artificial decidualization and a hormonal treatment model; ten candidate reference genes (PPIA, RPLP0, HPRT1, GAPDH, ACTB, TBP, B2M, 18S, UBC and TUBA) that are found in uterine tissues were assessed for their suitability as internal controls for relative qRT-PCR quantification. GeNorm(PLUS), NormFinder, and BestKeeper were used to evaluate these candidate reference genes, and all of these methods identified RPLP0 and GAPDH as the most stable candidates and B2M and 18S as the least stable candidates. However, when the different models were analyzed separately, the reference genes exhibited some variation in their expression levels. PMID- 23638090 TI - Age-mediated transcriptomic changes in adult mouse substantia nigra. AB - Substantia nigra pars compacta (SNpc) is highly sensitive to normal aging and selectively degenerates in Parkinson's disease (PD). Until now, molecular mechanisms behind SNpc aging have not been fully investigated using high throughput techniques. Here, we show early signs of aging in SNpc, which are more evident than in ventral tegmental area (VTA), a region adjacent to SNpc but less affected in PD. Aging-associated early changes in transcriptome were investigated comparing late middle-aged (18 months old) to young (2 months old) mice in both SNpc and VTA. A meta-analysis of published microarray studies allowed us to generate a common "transcriptional signature" of the aged (>= 24 months old) mouse brain. SNpc of late-middle aged mice shared characteristics with the transcriptional signature, suggesting an accelerated aging in SNpc. Age-dependent changes in gene expression specific to SNpc were also observed, which were related to neuronal functions and inflammation. Future studies could greatly help determine the contribution of these changes to SNpc aging. These data help understand the processes underlying SNpc aging and their potential contribution to age-related disorders like PD. PMID- 23638094 TI - Getting a grip on memory: unilateral hand clenching alters episodic recall. AB - Unilateral hand clenching increases neuronal activity in the frontal lobe of the contralateral hemisphere. Such hand clenching is also associated with increased experiencing of a given hemisphere's "mode of processing." Together, these findings suggest that unilateral hand clenching can be used to test hypotheses concerning the specializations of the cerebral hemispheres during memory encoding and retrieval. We investigated this possibility by testing effects of unilateral hand clenching on episodic memory. The hemispheric Encoding/Retrieval Asymmetry (HERA) model proposes left prefrontal regions are associated with encoding, and right prefrontal regions with retrieval, of episodic memories. It was hypothesized that right hand clenching (left hemisphere activation) pre-encoding, and left hand clenching (right hemisphere activation) pre-recall, would result in superior memory. Results supported the HERA model. Also supported was that simple unilateral hand clenching can be used as a means by which the functional specializations of the cerebral hemispheres can be investigated in intact humans. PMID- 23638095 TI - TCreERT2, a transgenic mouse line for temporal control of Cre-mediated recombination in lineages emerging from the primitive streak or tail bud. AB - The study of axis extension and somitogenesis has been greatly advanced through the use of genetic tools such as the TCre mouse line. In this line, Cre is controlled by a fragment of the T (Brachyury) promoter that is active in progenitor cells that reside within the primitive streak and tail bud and which give rise to lineages emerging from these tissues as the embryonic axis extends. However, because TCre-mediated recombination occurs early in development, gene inactivation can result in an axis truncation that precludes the study of gene function in later or more posterior tissues. To address this limitation, we have generated an inducible TCre transgenic mouse line, called TCreERT2, that provides temporal control, through tamoxifen administration, in all cells emerging from the primitive streak or tail bud throughout development. TCreERT2 activity is mostly silent in the absence of tamoxifen and, in its presence, results in near complete recombination of emerging mesoderm from E7.5 through E13.5. We demonstrate the utility of the TCreERT2 line for determining rate of posterior axis extension and somite formation, thus providing the first in vivo tool for such measurements. To test the usefulness of TCreERT2 for genetic manipulation, we demonstrate that an early deletion of beta-Catenin via TCreERT2 induction phenocopies the TCre-mediated deletion of beta-Catenin defect, whereas a later induction bypasses this early phenotype and produces a similar defect in more caudal tissues. TCreERT2 provides a useful and novel tool for the control of gene expression of emerging embryonic lineages throughout development. PMID- 23638093 TI - Sfrp5 modulates both Wnt and BMP signaling and regulates gastrointestinal organogenesis [corrected] in the zebrafish, Danio rerio. AB - Sfrp5 belongs to the family of secreted frizzled related proteins (Sfrp), secreted inhibitors of Wingless-MMTV Integration Site (Wnt) signaling, which play an important role in cancer and development. We selected sfrp5 because of its compelling expression profile in the developing endoderm in zebrafish, Danio rerio. In this study, overexpression of sfrp5 in embryos results in defects in both convergent extension (CE) by inhibition of non-canonical Wnt signaling and defects in dorsoventral patterning by inhibition of Tolloid-mediated proteolysis of the BMP inhibitor Chordin. From 25 hours post fertilization (hpf) to 3 days post fertilization (dpf), both overexpression and knockdown of Sfrp5 decrease the size of the endoderm, significantly reducing liver cell number. At 3 dpf, insulin positive endodermal cells fail to coalesce into a single pancreatic islet. We show that Sfrp5 inhibits both canonical and non-canonical Wnt signaling during embryonic and endodermal development, resulting in endodermal abnormalities. PMID- 23638097 TI - Sub-sets of cancer stem cells differ intrinsically in their patterns of oxygen metabolism. AB - The glycolytic response of hypoxic cells is primarily mediated by the hypoxia inducible factor alpha (HIF-1alpha) but even in the presence of abundant oxygen tumours typically show high rates of glycolysis. Higher levels of HIF-1alpha in tumours are associated with a poorer prognosis and up-regulation of markers of epithelial mesenchymal transition (EMT) due to HIF-1alpha actions. We have recently shown that EMT occurs within the CD44(high) cancer stem cell (CSC) fraction and that epithelial and EMT CSCs are distinguished by high and low ESA expression, respectively. We here show that hypoxia induces a marked shift of the CSC fraction towards EMT leading to altered cell morphology, an increased proportion of CD44(high)/ESA(low) cells, patterns of gene expression typical of EMT, and enhanced sphere-forming ability. The size of EMT fractions returned to control levels in normoxia indicating a reversible process. Surprisingly, however, even under normoxic conditions a fraction of EMT CSCs was present and maintained high levels of HIF-1alpha, apparently due to actions of cytokines such as TNFalpha. Functionally, this EMT CSC fraction showed decreased mitochondrial mass and membrane potential, consumed far less oxygen per cell, and produced markedly reduced levels of reactive oxygen species (ROS). These differences in the patterns of oxygen metabolism of sub-fractions of tumour cells provide an explanation for the general therapeutic resistance of CSCs and for the even greater resistance of EMT CSCs. They also identify potential mechanisms for manipulation of CSCs. PMID- 23638096 TI - Evidence against a role for the JIL-1 kinase in H3S28 phosphorylation and 14-3-3 recruitment to active genes in Drosophila. AB - JIL-1 is the major kinase controlling phosphorylation of histone H3S10 and has been demonstrated to function to counteract heterochromatization and gene silencing. However, an alternative model has been proposed in which JIL-1 is required for transcription to occur, additionally phosphorylates H3S28, and recruits 14-3-3 to active genes. Since these findings are incompatible with our previous demonstration that there are robust levels of transcription in the complete absence of JIL-1 and that JIL-1 is not present at developmental or heat shock-induced polytene chromosome puffs, we have reexamined JIL-1's possible role in H3S28 phosphorylation and 14-3-3 recruitment. Using two different H3S28ph antibodies we show by immunocytochemistry and immunoblotting that in Drosophila the H3S28ph mark is not present at detectable levels above background on polytene chromosomes at interphase but only on chromosomes at pro-, meta-, and anaphase during cell division in S2 cells and third instar larval neuroblasts. Moreover, this mitotic H3S28ph signal is also present in a JIL-1 null mutant background at undiminished levels suggesting that JIL-1 is not the mitotic H3S28ph kinase. We also demonstrate that H3S28ph is not enriched at heat shock puffs. Using two different pan-specific 14-3-3 antibodies as well as an enhancer trap 14-3 3epsilon-GFP line we show that 14-3-3, while present in salivary gland nuclei, does not localize to chromosomes but only to the nuclear matrix surrounding the chromosomes. In our hands 14-3-3 is not recruited to developmental or heat shock puffs. Furthermore, using a lacO repeat tethering system to target LacI-JIL-1 to ectopic sites on polytene chromosomes we show that only H3S10ph is present and upregulated at such sites, not H3S28ph or 14-3-3. Thus, our results argue strongly against a model where JIL-1 is required for H3S28 phosphorylation and 14 3-3 recruitment at active genes. PMID- 23638099 TI - Broadly protective adenovirus-based multivalent vaccines against highly pathogenic avian influenza viruses for pandemic preparedness. AB - Recurrent outbreaks of H5, H7 and H9 avian influenza viruses in domestic poultry accompanied by their occasional transmission to humans have highlighted the public health threat posed by these viruses. Newer vaccine approaches for pandemic preparedness against these viruses are needed, given the limitations of vaccines currently approved for H5N1 viruses in terms of their production timelines and the ability to induce protective immune responses in the absence of adjuvants. In this study, we evaluated the feasibility of an adenovirus (AdV) based multivalent vaccine approach for pandemic preparedness against H5, H7 and H9 avian influenza viruses in a mouse model. Replication-defective AdV vectors expressing hemagglutinin (HA) from different subtypes and nucleoprotein (NP) from one subtype induced high levels of humoral and cellular immune responses and conferred protection against virus replication following challenge with H5, H7 and H9 avian influenza virus subtypes. Inclusion of HA from the 2009 H1N1 pandemic virus in the vaccine formulation further broadened the vaccine coverage. Significantly high levels of HA stalk-specific antibodies were observed following immunization with the multivalent vaccine. Inclusion of NP into the multivalent HA vaccine formulation resulted in the induction of CD8 T cell responses. These results suggest that a multivalent vaccine strategy may provide reasonable protection in the event of a pandemic caused by H5, H7, or H9 avian influenza virus before a strain-matched vaccine can be produced. PMID- 23638100 TI - Learning to attend to threat accelerates and enhances memory consolidation. AB - Practice on a procedural task involves within-session learning and between session consolidation of learning, with the latter requiring a minimum of about four hours to evolve due to involvement of slower cellular processes. Learning to attend to threats is vital for survival and thus may involve faster memory consolidation than simple procedural learning. Here, we tested whether attention to threat modulates the time-course and magnitude of learning and memory consolidation effects associated with skill practice. All participants (N = 90) practiced in two sessions on a dot-probe task featuring pairs of neutral and angry faces followed by target probes which were to be discriminated as rapidly as possible. In the attend-threat training condition, targets always appeared at the angry face location, forming an association between threat and target location; target location was unrelated to valence in a control training condition. Within each attention training condition, duration of the between session rest interval was varied to establish the time-course for emergence of consolidation effects. During the first practice session, we observed robust improvement in task performance (online, within-session gains), followed by saturation of learning. Both training conditions exhibited similar overall learning capacities, but performance in the attend-threat condition was characterized by a faster learning rate relative to control. Consistent with the memory consolidation hypothesis, between-session performance gains (delayed gains) were observed only following a rest interval. However, rest intervals of 1 and 24 hours yielded similar delayed gains, suggesting accelerated consolidation processes. Moreover, attend-threat training resulted in greater delayed gains compared to the control condition. Auxiliary analyses revealed that enhanced performance was retained over several months, and that training to attend to neutral faces resulted in effects similar to control. These results provide a novel demonstration of how attention to threat can accelerate and enhance memory consolidation effects associated with skill acquisition. PMID- 23638098 TI - Comprehensive genomic analysis and expression profiling of phospholipase C gene family during abiotic stresses and development in rice. AB - BACKGROUND: Phospholipase C (PLC) is one of the major lipid hydrolysing enzymes, implicated in lipid mediated signaling. PLCs have been found to play a significant role in abiotic stress triggered signaling and developmental processes in various plant species. Genome wide identification and expression analysis have been carried out for this gene family in Arabidopsis, yet not much has been accomplished in crop plant rice. METHODOLOGY/PRINCIPAL FINDINGS: An exhaustive in-silico exploration of rice genome using various online databases and tools resulted in the identification of nine PLC encoding genes. Based on sequence, motif and phylogenetic analysis rice PLC gene family could be divided into phosphatidylinositol-specific PLCs (PI-PLCs) and phosphatidylcholine- PLCs (PC-PLC or NPC) classes with four and five members, respectively. A comparative analysis revealed that PLCs are conserved in Arabidopsis (dicots) and rice (monocot) at gene structure and protein level but they might have evolved through a separate evolutionary path. Transcript profiling using gene chip microarray and quantitative RT-PCR showed that most of the PLC members expressed significantly and differentially under abiotic stresses (salt, cold and drought) and during various developmental stages with condition/stage specific and overlapping expression. This finding suggested an important role of different rice PLC members in abiotic stress triggered signaling and plant development, which was also supported by the presence of relevant cis-regulatory elements in their promoters. Sub-cellular localization of few selected PLC members in Nicotiana benthamiana and onion epidermal cells has provided a clue about their site of action and functional behaviour. CONCLUSION/SIGNIFICANCE: The genome wide identification, structural and expression analysis and knowledge of sub-cellular localization of PLC gene family envisage the functional characterization of these genes in crop plants in near future. PMID- 23638101 TI - Differential susceptibility and response of primary human myeloid BDCA1(+) dendritic cells to infection with different Enteroviruses. AB - Coxsackie B viruses (CVBs) and echoviruses (EVs) form the Human Enterovirus-B (HEV-B) species within the family Picornaviridae. HEV-B infections are widespread and generally cause mild disease; however, severe infections occur and HEV-B are associated with various chronic diseases such as cardiomyopathy and type 1 diabetes. Dendritic cells (DCs) are the professional antigen-presenting cells of our immune system and initiate and control immune responses to invading pathogens, yet also maintain tolerance to self-antigens. We previously reported that EVs, but not CVBs, can productively infect in vitro generated monocyte derived DCs. The interactions between HEV-B and human myeloid DCs (mDCs) freshly isolated from blood, however, remain unknown. Here, we studied the susceptibility and responses of BDCA1(+) mDC to HEV-B species and found that these mDC are susceptible to EV, but not CVB infection. Productive EV7 infection resulted in massive, rapid cell death without DC activation. Contrary, EV1 infection, which resulted in lower virus input at the same MOI, resulted in DC activation as observed by production of type I interferon-stimulated genes (ISGs), upregulation of co-stimulatory and co-inhibitory molecules (CD80, CD86, PDL1) and production of IL-6 and TNF-alpha, with a relative moderate decrease in cell viability. EV1 induced ISG expression depended on virus replication. CVB infection did not affect DC viability and resulted in poor induction of ISGs and CD80 induction in part of the donors. These data show for the first time the interaction between HEV-B species and BDCA1(+) mDCs isolated freshly from blood. Our data indicate that different HEV-B species can influence DC homeostasis in various ways, possibly contributing to HEV-B associated pathology. PMID- 23638102 TI - Nutritional intervention restores muscle but not kidney phenotypes in adult calcineurin Aalpha null mice. AB - Mice lacking the alpha isoform of the catalytic subunit of calcineurin (CnAalpha) were first reported in 1996 and have been an important model to understand the role of calcineurin in the brain, immune system, bones, muscle, and kidney. Research using the mice has been limited, however, by failure to thrive and early lethality of most null pups. Work in our laboratory led to the rescue of CnAalpha /- mice by supplemental feeding to compensate for a defect in salivary enzyme secretion. The data revealed that, without intervention, knockout mice suffer from severe caloric restriction. Since nutritional deprivation is known to significantly alter development, it is imperative that previous conclusions based on CnAalpha-/- mice are revisited to determine which aspects of the phenotype were attributable to caloric restriction versus a direct role for CnAalpha. In this study, we find that defects in renal development and function persist in adult CnAalpha-/- mice including a significant decrease in glomerular filtration rate and an increase in blood urea nitrogen levels. These data indicate that impaired renal development we previously reported was not due to caloric restriction but rather a specific role for CnAalpha in renal development and function. In contrast, we find that rather than being hypoglycemic, rescued mice are mildly hyperglycemic and insulin resistant. Examination of muscle fiber types shows that previously reported reductions in type I muscle fibers are no longer evident in rescued null mice. Rather, loss of CnAalpha likely alters insulin response due to a reduction in insulin receptor substrate-2 (IRS2) expression and signaling in muscle. This study illustrates the importance of re-examining the phenotypes of CnAalpha-/- mice and the advances that are now possible with the use of adult, rescued knockout animals. PMID- 23638103 TI - Phylogeny of bacterial and archaeal genomes using conserved genes: supertrees and supermatrices. AB - Over 3000 microbial (bacterial and archaeal) genomes have been made publically available to date, providing an unprecedented opportunity to examine evolutionary genomic trends and offering valuable reference data for a variety of other studies such as metagenomics. The utility of these genome sequences is greatly enhanced when we have an understanding of how they are phylogenetically related to each other. Therefore, we here describe our efforts to reconstruct the phylogeny of all available bacterial and archaeal genomes. We identified 24, single-copy, ubiquitous genes suitable for this phylogenetic analysis. We used two approaches to combine the data for the 24 genes. First, we concatenated alignments of all genes into a single alignment from which a Maximum Likelihood (ML) tree was inferred using RAxML. Second, we used a relatively new approach to combining gene data, Bayesian Concordance Analysis (BCA), as implemented in the BUCKy software, in which the results of 24 single-gene phylogenetic analyses are used to generate a "primary concordance" tree. A comparison of the concatenated ML tree and the primary concordance (BUCKy) tree reveals that the two approaches give similar results, relative to a phylogenetic tree inferred from the 16S rRNA gene. After comparing the results and the methods used, we conclude that the current best approach for generating a single phylogenetic tree, suitable for use as a reference phylogeny for comparative analyses, is to perform a maximum likelihood analysis of a concatenated alignment of conserved, single-copy genes. PMID- 23638104 TI - The dynamics of mood and coping in bipolar disorder: longitudinal investigations of the inter-relationship between affect, self-esteem and response styles. AB - BACKGROUND: Previous research has suggested that the way bipolar patients respond to depressive mood impacts on the future course of the illness, with rumination prolonging depression and risk-taking possibly triggering hypomania. However, the relationship over time between variables such as mood, self-esteem, and response style to negative affect is complex and has not been directly examined in any previous study--an important limitation, which the present study seeks to address. METHODS: In order to maximize ecological validity, individuals diagnosed with bipolar disorder (N = 48) reported mood, self-esteem and response styles to depression, together with contextual information, up to 60 times over a period of six days, using experience sampling diaries. Entries were cued by quasi-random bleeps from digital watches. Longitudinal multilevel models were estimated, with mood and self-esteem as predictors of subsequent response styles. Similar models were then estimated with response styles as predictors of subsequent mood and self-esteem. Cross-sectional associations of daily-life correlates with symptoms were also examined. RESULTS: Cross-sectionally, symptoms of depression as well as mania were significantly related to low mood and self-esteem, and their increased fluctuations. Longitudinally, low mood significantly predicted rumination, and engaging in rumination dampened mood at the subsequent time point. Furthermore, high positive mood (marginally) instigated high risk-taking, and in turn engaging in risk-taking resulted in increased positive mood. Adaptive coping (i.e. problem solving and distraction) was found to be an effective coping style in improving mood and self-esteem. CONCLUSIONS: This study is the first to directly test the relevance of response style theory, originally developed to explain unipolar depression, to understand symptom changes in bipolar disorder patients. The findings show that response styles significantly impact on subsequent mood but some of these effects are modulated by current mood state. Theoretical and clinical implications are discussed. PMID- 23638105 TI - Effects of CO2 and temperature on tritrophic interactions. AB - There has been a significant increase in studies of how global change parameters affect interacting species or entire communities, yet the combined or interactive effects of increased atmospheric CO2 and associated increases in global mean temperatures on chemically mediated trophic interactions are mostly unknown. Thus, predictions of climate-induced changes on plant-insect interactions are still based primarily on studies of individual species, individual global change parameters, pairwise interactions, or parameters that summarize communities. A clear understanding of community response to global change will only emerge from studies that examine effects of multiple variables on biotic interactions. We examined the effects of increased CO2 and temperature on simple laboratory communities of interacting alfalfa, chemical defense, armyworm caterpillars, and parasitoid wasps. Higher temperatures and CO2 caused decreased plant quality, decreased caterpillar development times, developmental asynchrony between caterpillars and wasps, and complete wasp mortality. The effects measured here, along with other effects of global change on natural enemies suggest that biological control and other top-down effects of insect predators will decline over the coming decades. PMID- 23638106 TI - Prokaryotic ubiquitin-like ThiS fusion enhances the heterologous protein overexpression and aggregation in Escherichia coli. AB - Fusion tags are commonly employed to enhance target protein expression, improve their folding and solubility, and reduce protein degradation in expression of recombinant proteins. Ubiquitin (Ub) and SUMO are highly conserved small proteins in eukaryotes, and frequently used as fusion tags in prokaryotic expression. ThiS, a smaller sulfur-carrier protein involved in thiamin synthesis, is conserved among most prokaryotic species. The structural similarity between ThiS and Ub provoked us into expecting that the former could be used as a fusion tag. Hence, ThiS was fused to insulin A and B chains, murine Ribonuclease Inhibitor (mRI) and EGFP, respectively. When induced in Escherichia coli, ThiS-fused insulin A and B chains were overexpressed in inclusion bodies, and to higher levels in comparison to the same proteins fused with Ub. On the contrast, ThiS fusion of mRI, an unstable protein, resulted in enhanced degradation that was not alleviated in protease-deficient strains. While the degradation of Ub- and SUMO fused mRI was less and seemed protease-dependent. Enhanced degradation of mRI did not occur for the fusions with half-molecules of ThiS. When ThiS-tag was fused to the C-terminus of EGFP, higher expression, predominantly in inclusion bodies, was observed again. It was further found that ThiS fusion of EGFP significantly retarded its refolding process. These results indicated that prokaryotic ThiS is able to promote the expression of target proteins in E. coli, but enhanced degradation may occur in case of unstable targets. Unlike eukaryotic Ub-based tags usually increase the solubility and folding of proteins, ThiS fusion enhances the expression by augmenting the formation of inclusion bodies, probably through retardation of the folding of target proteins. PMID- 23638107 TI - Nonlinearities lead to qualitative differences in population dynamics of predator prey systems. AB - Since typically there are many predators feeding on most herbivores in natural communities, understanding multiple predator effects is critical for both community and applied ecology. Experiments of multiple predator effects on prey populations are extremely demanding, as the number of treatments and the amount of labour associated with these experiments increases exponentially with the number of species in question. Therefore, researchers tend to vary only presence/absence of the species and use only one (supposedly realistic) combination of their numbers in experiments. However, nonlinearities in density dependence, functional responses, interactions between natural enemies etc. are typical for such systems, and nonlinear models of population dynamics generally predict qualitatively different results, if initial absolute densities of the species studied differ, even if their relative densities are maintained. Therefore, testing combinations of natural enemies without varying their densities may not be sufficient. Here we test this prediction experimentally. We show that the population dynamics of a system consisting of 2 natural enemies (aphid predator Adalia bipunctata (L.), and aphid parasitoid, Aphidius colemani Viereck) and their shared prey (peach aphid, Myzus persicae Sulzer) are strongly affected by the absolute initial densities of the species in question. Even if their relative densities are kept constant, the natural enemy species or combination thereof that most effectively suppresses the prey may depend on the absolute initial densities used in the experiment. Future empirical studies of multiple predator - one prey interactions should therefore use a two-dimensional array of initial densities of the studied species. Varying only combinations of natural enemies without varying their densities is not sufficient and can lead to misleading results. PMID- 23638108 TI - MCT2 expression and lactate influx in anorexigenic and orexigenic neurons of the arcuate nucleus. AB - Hypothalamic neurons of the arcuate nucleus control food intake, releasing orexigenic and anorexigenic neuropeptides in response to changes in glucose concentration. Several studies have suggested that the glucosensing mechanism is governed by a metabolic interaction between neurons and glial cells via lactate flux through monocarboxylate transporters (MCTs). Hypothalamic glial cells (tanycytes) release lactate through MCT1 and MCT4; however, similar analyses in neuroendocrine neurons have yet to be undertaken. Using primary rat hypothalamic cell cultures and fluorimetric assays, lactate incorporation was detected. Furthermore, the expression and function of MCT2 was demonstrated in the hypothalamic neuronal cell line, GT1-7, using kinetic and inhibition assays. Moreover, MCT2 expression and localization in the Sprague Dawley rat hypothalamus was analyzed using RT-PCR, in situ hybridization and Western blot analyses. Confocal immunohistochemistry analyses revealed MCT2 localization in neuronal but not glial cells. Moreover, MCT2 was localized to ~90% of orexigenic and ~60% of anorexigenic neurons as determined by immunolocalization analysis of AgRP and POMC with MCT2-positives neurons. Thus, MCT2 distribution coupled with lactate uptake by hypothalamic neurons suggests that hypothalamic neurons control food intake using lactate to reflect changes in glucose levels. PMID- 23638109 TI - Paracoccidoides brasiliensis 30 kDa adhesin: identification as a 14-3-3 protein, cloning and subcellular localization in infection models. AB - Paracoccidoides brasiliensis adhesion to lung epithelial cells is considered an essential event for the establishment of infection and different proteins participate in this process. One of these proteins is a 30 kDa adhesin, pI 4.9 that was described as a laminin ligand in previous studies, and it was more highly expressed in more virulent P. brasiliensis isolates. This protein may contribute to the virulence of this important fungal pathogen. Using Edman degradation and mass spectrometry analysis, this 30 kDa adhesin was identified as a 14-3-3 protein. These proteins are a conserved group of small acidic proteins involved in a variety of processes in eukaryotic organisms. However, the exact function of these proteins in some processes remains unknown. Thus, the goal of the present study was to characterize the role of this protein during the interaction between the fungus and its host. To achieve this goal, we cloned, expressed the 14-3-3 protein in a heterologous system and determined its subcellular localization in in vitro and in vivo infection models. Immunocytochemical analysis revealed the ubiquitous distribution of this protein in the yeast form of P. brasiliensis, with some concentration in the cytoplasm. Additionally, this 14-3-3 protein was also present in P. brasiliensis cells at the sites of infection in C57BL/6 mice intratracheally infected with P. brasiliensis yeast cells for 72 h (acute infections) and 30 days (chronic infection). An apparent increase in the levels of the 14-3-3 protein in the cell wall of the fungus was also noted during the interaction between P. brasiliensis and A549 cells, suggesting that this protein may be involved in host-parasite interactions, since inhibition assays with the protein and this antibody decreased P. brasiliensis adhesion to A549 epithelial cells. Our data may lead to a better understanding of P. brasiliensis interactions with host tissues and paracoccidioidomycosis pathogenesis. PMID- 23638111 TI - Shared decision making does not influence physicians against clinical practice guidelines. AB - BACKGROUND: While shared decision making (SDM) and adherence to clinical practice guidelines (CPGs) are important, some believe they are incompatible. This study explored the mutual influence between physicians' intention to engage in SDM and their intention to follow CPGs. METHODS: Embedded within a clustered randomized trial to assess the impact of training physicians in SDM about using antibiotics to treat acute respiratory tract infections, this study evaluated physicians' intentions to both engage in SDM and follow CPGs. A self-administered questionnaire based on the theory of planned behavior evaluated both behavioral intentions and their respective determinants (attitude, subjective norm and perceived behavioral control) at study entry and exit. We used path analysis to explore the relationships between the intentions. We conducted statistical analyses using the maximum likelihood method and the variance-covariance matrix. Goodness of fit indices encompassed the chi-square statistic, the comparative fit index and the root mean square error of approximation. RESULTS: We analyzed 244 responses at entry and 236 at exit. In the control group, at entry we observed that physicians' intention to engage in SDM (r = 0, t = 0.03) did not affect their intention to follow CPGs; however, their intention to follow CPGs (r = 0.31 t = -2.82) did negatively influence their intention to engage in SDM. At exit, neither behavioral intention influenced the other. In the experimental group, at entry neither behavioral intention influenced the other; at exit, the intention to engage in SDM still did not influence the intention to use CPGs, although the intention to follow CPGs (r = -0.15 t = -2.02) slightly negatively influenced the intention to engage in SDM, but this was not clinically significant. CONCLUSION: Physicians' intention to engage in SDM does not affect their intention to adopt CPGs even after SDM training. Physicians' intention to adopt CPGs had no clinically significant influence on intention to engage in SDM. TRIAL REGISTRATION: ClinicalTrials.gov NCT01116076. PMID- 23638110 TI - A further look at porcine chromosome 7 reveals VRTN variants associated with vertebral number in Chinese and Western pigs. AB - The number of vertebrae is an economically important trait that affects carcass length and meat production in pigs. A major quantitative trait locus (QTL) for thoracic vertebral number has been repeatedly identified on pig chromosome (SSC) 7. To dissect the genetic basis of the major locus, we herein genotyped a large sample of animals from 3 experimental populations of Chinese and Western origins using 60K DNA chips. Genome-wide association studies consistently identified the locus across the 3 populations and mapped the locus to a 947-Kb region on SSC7. An identical-by-descent sharing assay refined the locus to a 100-Kb segment that harbors only two genes including VRTN and SYNDIG1L. Of them, VRNT has been proposed as a strong candidate of the major locus in Western modern breeds. Further, we resequenced the VRTN gene using DNA samples of 35 parental animals with known QTL genotypes by progeny testing. Concordance tests revealed 4 candidate causal variants as their genotypes showed the perfect segregation with QTL genotypes of the tested animals. An integrative analysis of evolutional constraints and functional elements supported two VRTN variants in a complete linkage disequilibrium phase as the most likely causal mutations. The promising variants significantly affect the number of thoracic vertebrae (one vertebra) in large scale outbred animals, and are segregating at rather high frequencies in Western pigs and at relatively low frequencies in a number of Chinese breeds. Altogether, we show that VRTN variants are significantly associated with the number of thoracic vertebrae in both Chinese and Western pigs. The finding advances our understanding of the genetic architecture of the vertebral number in pigs. Furthermore, our finding is of economical importance as it provides a robust breeding tool for the improvement of vertebral number and meat production in both Chinese indigenous pigs and Western present-day commercial pigs. PMID- 23638113 TI - Complete plastid genome sequence of the basal asterid Ardisia polysticta Miq. and comparative analyses of asterid plastid genomes. AB - Ardisia is a basal asterid genus well known for its medicinal values and has the potential for development of novel phytopharmaceuticals. In this genus of nearly 500 species, many ornamental species are commonly grown worldwide and some have become invasive species that caused ecological problems. As there is no completed plastid genome (plastome) sequence in related taxa, we sequenced and characterized the plastome of Ardisia polysticta to find plastid markers of potential utility for phylogenetic analyses at low taxonomic levels. The complete A. polysticta plastome is 156,506 bp in length and has gene content and organization typical of most asterids and other angiosperms. We identified seven intergenic regions as potentially informative markers with resolution for interspecific relationships. Additionally, we characterized the diversity of asterid plastomes with respect to GC content, plastome organization, gene content, and repetitive sequences through comparative analyses. The results demonstrated that the genome organizations near the boundaries between inverted repeats (IRs) and single-copy regions (SCs) are polymorphic. The boundary organization found in Ardisia appears to be the most common type among asterids, while six other types are also found in various asterid lineages. In general, the repetitive sequences in genic regions tend to be more conserved, whereas those in noncoding regions are usually lineage-specific. Finally, we inferred the whole plastome phylogeny with the available asterid sequences. With the improvement in taxon sampling of asterid orders and families, our result highlights the uncertainty of the position of Gentianales within euasterids I. PMID- 23638112 TI - Mammalian mucosal alpha-glucosidases coordinate with alpha-amylase in the initial starch hydrolysis stage to have a role in starch digestion beyond glucogenesis. AB - Starch digestion in the human body is typically viewed in a sequential manner beginning with alpha-amylase and followed by alpha-glucosidase to produce glucose. This report indicates that the two enzyme types can act synergistically to digest granular starch structure. The aim of this study was to investigate how the mucosal alpha-glucosidases act with alpha-amylase to digest granular starch. Two types of enzyme extracts, pancreatic and intestinal extracts, were applied. The pancreatic extract containing predominantly alpha-amylase, and intestinal extract containing a combination of alpha-amylase and mucosal alpha-glucosidase activities, were applied to three granular maize starches with different amylose contents in an in vitro system. Relative glucogenesis, released maltooligosaccharide amounts, and structural changes of degraded residues were examined. Pancreatic extract-treated starches showed a hydrolysis limit over the 12 h incubation period with residues having a higher gelatinization temperature than the native starch. alpha-Amylase combined with the mucosal alpha glucosidases in the intestinal extract showed higher glucogenesis as expected, but also higher maltooligosaccharide amounts indicating an overall greater degree of granular starch breakdown. Starch residues after intestinal extract digestion showed more starch fragmentation, higher gelatinization temperature, higher crystallinity (without any change in polymorph), and an increase of intermediate sized or small-sized fractions of starch molecules, but did not show preferential hydrolysis of either amylose or amylopectin. Direct digestion of granular starch by mammalian recombinant mucosal alpha-glucosidases was observed which shows that these enzymes may work either independently or together with alpha-amylase to digest starch. Thus, mucosal alpha-glucosidases can have a synergistic effect with alpha-amylase on granular starch digestion, consistent with a role in overall starch digestion beyond their primary glucogenesis function. PMID- 23638114 TI - Three-phase fuel deposition in a long-distance migrant, the red knot (Calidris canutus piersmai), before the flight to high Arctic breeding grounds. AB - Refuelling by migratory birds before take-off on long flights is generally considered a two-phase process, with protein accumulation preceding rapid fat deposition. The first phase expresses the demands for a large digestive system for nutrient storage after shrinkage during previous flights, the second phase the demands for fat stores to fuel the subsequent flight. At the last staging site in northward migration, this process may include expression of selection pressures both en route to and after arrival at the breeding grounds, which remains unascertained. Here we investigated changes in body composition during refuelling of High Arctic breeding red knots (Calidris canutus piersmai) in the northern Yellow Sea, before their flight to the tundra. These red knots followed a three-phase fuel deposition pattern, with protein being stored in the first and last phases, and fat being deposited mainly in the second phase. Thus, they did not shrink nutritional organs before take-off, and even showed hypertrophy of the nutritional organs. These suggest the build up of strategic protein stores before departure to cope with a protein shortage upon arrival on the breeding grounds. Further comparative studies are warranted to examine the degree to which the deposition of stores by migrant birds generally reflects a balance between concurrent and upcoming environmental selection pressures. PMID- 23638115 TI - A novel injectable calcium phosphate cement-bioactive glass composite for bone regeneration. AB - BACKGROUND: Calcium phosphate cement (CPC) can be molded or injected to form a scaffold in situ, which intimately conforms to complex bone defects. Bioactive glass (BG) is known for its unique ability to bond to living bone and promote bone growth. However, it was not until recently that literature was available regarding CPC-BG applied as an injectable graft. In this paper, we reported a novel injectable CPC-BG composite with improved properties caused by the incorporation of BG into CPC. MATERIALS AND METHODS: The novel injectable bioactive cement was evaluated to determine its composition, microstructure, setting time, injectability, compressive strength and behavior in a simulated body fluid (SBF). The in vitro cellular responses of osteoblasts and in vivo tissue responses after the implantation of CPC-BG in femoral condyle defects of rabbits were also investigated. RESULTS: CPC-BG possessed a retarded setting time and markedly better injectability and mechanical properties than CPC. Moreover, a new Ca-deficient apatite layer was deposited on the composite surface after immersing immersion in SBF for 7 days. CPC-BG samples showed significantly improved degradability and bioactivity compared to CPC in simulated body fluid (SBF). In addition, the degrees of cell attachment, proliferation and differentiation on CPC-BG were higher than those on CPC. Macroscopic evaluation, histological evaluation, and micro-computed tomography (micro-CT) analysis showed that CPC-BG enhanced the efficiency of new bone formation in comparison with CPC. CONCLUSIONS: A novel CPC-BG composite has been synthesized with improved properties exhibiting promising prospects for bone regeneration. PMID- 23638117 TI - Automated and accurate detection of soma location and surface morphology in large scale 3D neuron images. AB - Automated and accurate localization and morphometry of somas in 3D neuron images is essential for quantitative studies of neural networks in the brain. However, previous methods are limited in obtaining the location and surface morphology of somas with variable size and uneven staining in large-scale 3D neuron images. In this work, we proposed a method for automated soma locating in large-scale 3D neuron images that contain relatively sparse soma distributions. This method involves three steps: (i) deblocking the image with overlap between adjacent sub stacks; (ii) locating the somas in each small sub-stack using multi-scale morphological close and adaptive thresholds; and (iii) fusion of the repeatedly located somas in all sub-stacks. We also describe a new method for the accurate detection of the surface morphology of somas containing hollowness; this was achieved by improving the classical Rayburst Sampling with a new gradient-based criteria. Three 3D neuron image stacks of different sizes were used to quantitatively validate our methods. For the soma localization algorithm, the average recall and precision were greater than 93% and 96%, respectively. For the soma surface detection algorithm, the overlap of the volumes created by automatic detection of soma surfaces and manually segmenting soma volumes was more than 84% for 89% of all correctly detected somas. Our method for locating somas can reveal the soma distributions in large-scale neural networks more efficiently. The method for soma surface detection will serve as a valuable tool for systematic studies of neuron types based on neuron structure. PMID- 23638116 TI - Phylogenetic relationships of citrus and its relatives based on matK gene sequences. AB - The genus Citrus includes mandarin, orange, lemon, grapefruit and lime, which have high economic and nutritional value. The family Rutaceae can be divided into 7 subfamilies, including Aurantioideae. The genus Citrus belongs to the subfamily Aurantioideae. In this study, we sequenced the chloroplast matK genes of 135 accessions from 22 genera of Aurantioideae and analyzed them phylogenetically. Our study includes many accessions that have not been examined in other studies. The subfamily Aurantioideae has been classified into 2 tribes, Clauseneae and Citreae, and our current molecular analysis clearly discriminate Citreae from Clauseneae by using only 1 chloroplast DNA sequence. Our study confirms previous observations on the molecular phylogeny of Aurantioideae in many aspects. However, we have provided novel information on these genetic relationships. For example, inconsistent with the previous observation, and consistent with our preliminary study using the chloroplast rbcL genes, our analysis showed that Feroniella oblata is not nested in Citrus species and is closely related with Feronia limonia. Furthermore, we have shown that Murraya paniculata is similar to Merrillia caloxylon and is dissimilar to Murraya koenigii. We found that "true citrus fruit trees" could be divided into 2 subclusters. One subcluster included Citrus, Fortunella, and Poncirus, while the other cluster included Microcitrus and Eremocitrus. Compared to previous studies, our current study is the most extensive phylogenetic study of Citrus species since it includes 93 accessions. The results indicate that Citrus species can be classified into 3 clusters: a citron cluster, a pummelo cluster, and a mandarin cluster. Although most mandarin accessions belonged to the mandarin cluster, we found some exceptions. We also obtained the information on the genetic background of various species of acid citrus grown in Japan. Because the genus Citrus contains many important accessions, we have comprehensively discussed the classification of this genus. PMID- 23638118 TI - Hepatitis C virus NS2 protein inhibits DNA damage pathway by sequestering p53 to the cytoplasm. AB - Chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality globally, and often leads to end-stage liver disease. The DNA damage checkpoint pathway induces cell cycle arrest for repairing DNA in response to DNA damage. HCV infection has been involved in this pathway. In this study, we assess the effects of HCV NS2 on DNA damage checkpoint pathway. We have observed that HCV NS2 induces ataxia-telangiectasia mutated checkpoint pathway by inducing Chk2, however, fails to activate the subsequent downstream pathway. Further study suggested that p53 is retained in the cytoplasm of HCV NS2 expressing cells, and p21 expression is not enhanced. We further observed that HCV NS2 expressing cells induce cyclin E expression and promote cell growth. Together these results suggested that HCV NS2 inhibits DNA damage response by altering the localization of p53, and may play a role in the pathogenesis of HCV infection. PMID- 23638121 TI - Regional differences in dynamic cerebral autoregulation in the healthy brain assessed by magnetic resonance imaging. AB - A novel method is described for mapping dynamic cerebral blood flow autoregulation to assess autoregulatory efficiency throughout the brain, using magnetic resonance imaging (MRI). Global abnormalities in autoregulation occur in clinical conditions, including stroke and head injury, and are of prognostic significance. However, there is limited information about regional variations. A gradient-echo echo-planar pulse sequence was used to scan the brains of healthy subjects at a rate of 1 scan/second during a transient decrease in arterial blood pressure provoked by a sudden release of pressure in bilateral inflated thigh cuffs. The signal decrease and subsequent recovery were analyzed to provide an index of autoregulatory efficiency (MRARI). MRI time-series were successfully acquired and analyzed in eleven subjects. Autoregulatory efficiency was not uniform throughout the brain: white matter exhibited faster recovery than gray (MRARI = 0.702 vs. 0.672, p = 0.009) and the cerebral cortex exhibited faster recovery than the cerebellum (MRARI = 0.669 vs. 0.645, p = 0.016). However, there was no evidence for differences between different cortical regions. Differences in autoregulatory efficiency between white matter, gray matter and the cerebellum may be a result of differences in vessel density and vasodilation. The techniques described may have practical importance in detecting regional changes in autoregulation consequent to disease. PMID- 23638120 TI - A prospective study of LINE-1DNA methylation and development of adiposity in school-age children. AB - BACKGROUND: Repetitive element DNA methylation is related to prominent obesity related chronic diseases including cancer and cardiovascular disease; yet, little is known of its relation with weight status. We examined associations of LINE-1 DNA methylation with changes in adiposity and linear growth in a longitudinal study of school-age children from Bogota, Colombia. METHODS: We quantified methylation of LINE-1 elements from peripheral leukocytes of 553 children aged 5 12 years at baseline using pyrosequencing technology. Anthropometric characteristics were measured periodically for a median of 30 months. We estimated mean change in three age-and sex-standardized indicators of adiposity: body mass index (BMI)-for-age Z-score, waist circumference Z-score, and subscapular-to-triceps skinfold thickness ratio Z-score according to quartiles of LINE-1 methylation using mixed effects regression models. We also examined associations with height-for-age Z-score. RESULTS: There were non-linear, inverse relations of LINE-1 methylation with BMI-for-age Z-score and the skinfold thickness ratio Z-score. After adjustment for baseline age and socioeconomic status, boys in the lowest quartile of LINE-1 methylation experienced annual gains in BMI-for-age Z-score and skinfold thickness ratio Z-score that were 0.06 Z/year (P = 0.04) and 0.07 Z/year (P = 0.03), respectively, higher than those in the upper three quartiles. The relation of LINE-1 methylation and annual change in waist circumference followed a decreasing monotonic trend across the four quartiles (P trend = 0.02). DNA methylation was not related to any of the adiposity indicators in girls. There were no associations between LINE-1 methylation and linear growth in either sex. CONCLUSIONS: Lower LINE-1 DNA methylation is related to development of adiposity in boys. PMID- 23638119 TI - Structural insights into a wildtype domain of the oncoprotein E6 and its interaction with a PDZ domain. AB - The high-risk human papilloma virus (HPV) oncoproteins E6 and E7 interact with key cellular regulators and are etiological agents for tumorigenesis and tumor maintenance in cervical cancer and other malignant conditions. E6 induces degradation of the tumor suppressor p53, activates telomerase and deregulates cell polarity. Analysis of E6 derived from a number of high risk HPV finally yielded the first structure of a wild-type HPV E6 domain (PDB 2M3L) representing the second zinc-binding domain of HPV 51 E6 (termed 51Z2) determined by NMR spectroscopy. The 51Z2 structure provides clues about HPV-type specific structural differences between E6 proteins. The observed temperature sensitivity of the well-folded wild-type E6 domain implies a significant malleability of the oncoprotein in vivo. Hence, the structural differences between individual E6 and their malleability appear, together with HPV type-specific surface exposed side chains, to provide the structural basis for the different interaction networks reported for individual E6 proteins. Furthermore, the interaction of 51Z2 with a PDZ domain of hDlg was analyzed. Human Dlg constitutes a prototypic representative of the large family of PDZ proteins regulating cell polarity, which are common targets of high-risk HPV E6. Nine C-terminal residues of 51Z2 interact with the second PDZ domain of hDlg2. Surface plasmon resonance in conjunction with the NMR spectroscopy derived complex structure (PDB 2M3M) indicate that E6 residues N-terminal to the canonical PDZ-BM of E6 significantly contribute to this interaction and increase affinity. The structure of the complex reveals how residues outside of the classical PDZ-BM enhance the affinity of E6 towards PDZ domains. Such mechanism facilitates successful competition of E6 with cellular PDZ-binding proteins and may apply to PDZ-binding proteins of other viruses as well. PMID- 23638123 TI - Socio-demographic and clinical differences in subjects with tuberculosis with and without diabetes mellitus in Brazil--a multivariate analysis. AB - BACKGROUND: Several studies have evaluated the relationship between diabetes mellitus (DM) and tuberculosis (TB), but the nature of this relationship is not fully understood. TB incidence may be influenced by immunosuppression from DM, but this association may be confounded by other clinical and socioeconomic factors. We aimed to assess socio-demographic and clinical differences in TB patients with and without DM. METHODS: Using the Brazilian national surveillance system (SINAN), we compared 1,797 subjects with TB and DM with 29,275 subjects diagnosed with TB only in 2009. We performed multivariate analysis to identify factors associated with the presence of DM among TB patients. RESULTS: Subjects with TB - DM were older; have initial positive sputum smear test (OR = 1.42, 95% CI 1.26-1.60), and were more likely to die from TB (OR = 1.44, 95% CI 1.03-2.01). They were less likely to have been institutionalized [in prison, shelter, orphanage, psychiatric hospital (OR = 0.74, 95% CI 0.60-0.93)]; developed extra pulmonary TB (OR = 0.62, 95% CI 0.51-0.75) and to return to TB treatment after abandonment (OR = 0.66, 95% CI 0.51-0.86). CONCLUSIONS: Prevalence of NCD continues to rise in developing countries, especially with the rise of elderly population, the prevention and treatment of infectious diseases will be urgent. DM and TB represent a critical intersection between communicable and non communicable diseases in these countries and the effect of DM on TB incidence and outcomes provide numerous opportunities for collaboration and management of these complex diseases in the national public health programs. PMID- 23638122 TI - Activating transcription factor 4 and X box binding protein 1 of Litopenaeus vannamei transcriptional regulated white spot syndrome virus genes Wsv023 and Wsv083. AB - In response to endoplasmic reticulum (ER) stress, the signaling pathway termed unfolded protein response (UPR) is activated. To investigate the role of UPR in Litopenaeus vannamei immunity, the activating transcription factor 4 (designated as LvATF4) which belonged to a branch of the UPR, the [protein kinase RNA (PKR) like ER kinase, (PERK)]-[eukaryotic initiation factor 2 subunit alpha (eIF2alpha)] pathway, was identified and characterized. The full-length cDNA of LvATF4 was 1972 bp long, with an open reading frame of 1299 bp long that encoded a 432 amino acid protein. LvATF4 was highly expressed in gills, intestines and stomach. For the white spot syndrome virus (WSSV) challenge, LvATF4 was upregulated in the gills after 3 hpi and increased by 1.9-fold (96 hpi) compared to the mock-treated group. The LvATF4 knock-down by RNA interference resulted in a lower cumulative mortality of L. vannamei under WSSV infection. Reporter gene assays show that LvATF4 could upregulate the expression of the WSSV gene wsv023 based on the activating transcription factor/cyclic adenosine 3', 5' monophosphate response element (ATF/CRE). Another transcription factor of L. vannamei, X box binding protein 1 (designated as LvXBP1), has a significant function in [inositol-requiring enzyme-1(IRE1) - (XBP1)] pathway. This transcription factor upregulated the expression of the WSSV gene wsv083 based on the UPR element (UPRE). These results suggest that in L. vannamei UPR signaling pathway transcription factors are important for WSSV and might facilitate WSSV infection. PMID- 23638124 TI - Stand diameter distribution modelling and prediction based on Richards function. AB - The objective of this study was to introduce application of the Richards equation on modelling and prediction of stand diameter distribution. The long-term repeated measurement data sets, consisted of 309 diameter frequency distributions from Chinese fir (Cunninghamia lanceolata) plantations in the southern China, were used. Also, 150 stands were used as fitting data, the other 159 stands were used for testing. Nonlinear regression method (NRM) or maximum likelihood estimates method (MLEM) were applied to estimate the parameters of models, and the parameter prediction method (PPM) and parameter recovery method (PRM) were used to predict the diameter distributions of unknown stands. Four main conclusions were obtained: (1) R distribution presented a more accurate simulation than three-parametric Weibull function; (2) the parameters p, q and r of R distribution proved to be its scale, location and shape parameters, and have a deep relationship with stand characteristics, which means the parameters of R distribution have good theoretical interpretation; (3) the ordinate of inflection point of R distribution has significant relativity with its skewness and kurtosis, and the fitted main distribution range for the cumulative diameter distribution of Chinese fir plantations was 0.4~0.6; (4) the goodness-of-fit test showed diameter distributions of unknown stands can be well estimated by applying R distribution based on PRM or the combination of PPM and PRM under the condition that only quadratic mean DBH or plus stand age are known, and the non-rejection rates were near 80%, which are higher than the 72.33% non-rejection rate of three parametric Weibull function based on the combination of PPM and PRM. PMID- 23638125 TI - The stimulatory adenosine receptor ADORA2B regulates serotonin (5-HT) synthesis and release in oxygen-depleted EC cells in inflammatory bowel disease. AB - OBJECTIVE: We recently demonstrated that hypoxia, a key feature of IBD, increases enterochromaffin (EC) cell 5-HT secretion, which is also physiologically regulated by the ADORA2B mechanoreceptor. Since hypoxia is associated with increased extracellular adenosine, we wanted to examine whether this nucleotide amplifies HIF-1alpha-mediated 5-HT secretion. DESIGN: The effects of hypoxia were studied on IBD mucosa, isolated IBD-EC cells, isolated normal EC cells and the EC cell tumor derived cell line KRJ-1. Hypoxia (0.5% O2) was compared to NECA (adenosine agonist), MRS1754 (ADORA2B receptor antagonist) and SCH442146 (ADORA2A antagonist) on HIF signaling and 5-HT secretion. Antisense approaches were used to mechanistically evaluate EC cells in vitro. PCR and western blot were used to analyze transcript and protein levels of HIF-1alpha signaling and neuroendocrine cell function. An animal model of colitis was evaluated to confirm hypoxia:adenosine signaling in vivo. RESULTS: HIF-1alpha is upregulated in IBD mucosa and IBD-EC cells, the majority (~90%) of which express an activated phenotype in situ. Hypoxia stimulated 5-HT release maximally at 30 mins, an effect amplified by NECA and selectively inhibited by MRS1754, through phosphorylation of TPH-1 and activation of VMAT-1. Transient transfection with Renilla luciferase under hypoxia transcriptional response element (HRE) control identified that ADORA2B activated HIF-1alpha signaling under hypoxic conditions. Additional signaling pathways associated with hypoxia:adenosine included MAP kinase and CREB. Antisense approaches mechanistically confirmed that ADORA2B signaling was linked to these pathways and 5-HT release under hypoxic conditions. Hypoxia:adenosine activation which could be reversed by 5'-ASA treatment was confirmed in a TNBS-model. CONCLUSION: Hypoxia induced 5-HT synthesis and secretion is amplified by ADORA2B signaling via MAPK/CREB and TPH-1 activation. Targeting ADORA2s may decrease EC cell 5-HT production and secretion in IBD. PMID- 23638127 TI - Harnessing different motivational frames via mobile phones to promote daily physical activity and reduce sedentary behavior in aging adults. AB - Mobile devices are a promising channel for delivering just-in-time guidance and support for improving key daily health behaviors. Despite an explosion of mobile phone applications aimed at physical activity and other health behaviors, few have been based on theoretically derived constructs and empirical evidence. Eighty adults ages 45 years and older who were insufficiently physically active, engaged in prolonged daily sitting, and were new to smartphone technology, participated in iterative design development and feasibility testing of three daily activity smartphone applications based on motivational frames drawn from behavioral science theory and evidence. An "analytically" framed custom application focused on personalized goal setting, self-monitoring, and active problem solving around barriers to behavior change. A "socially" framed custom application focused on social comparisons, norms, and support. An "affectively" framed custom application focused on operant conditioning principles of reinforcement scheduling and emotional transference to an avatar, whose movements and behaviors reflected the physical activity and sedentary levels of the user. To explore the applications' initial efficacy in changing regular physical activity and leisure-time sitting, behavioral changes were assessed across eight weeks in 68 participants using the CHAMPS physical activity questionnaire and the Australian sedentary behavior questionnaire. User acceptability of and satisfaction with the applications was explored via a post-intervention user survey. The results indicated that the three applications were sufficiently robust to significantly improve regular moderate-to-vigorous intensity physical activity and decrease leisure-time sitting during the 8-week behavioral adoption period. Acceptability of the applications was confirmed in the post-intervention surveys for this sample of midlife and older adults new to smartphone technology. Preliminary data exploring sustained use of the applications across a longer time period yielded promising results. The results support further systematic investigation of the efficacy of the applications for changing these key health promoting behaviors. PMID- 23638128 TI - Inefficient TLR4/MD-2 heterotetramerization by monophosphoryl lipid A. AB - Synthetic forms of E. coli monophosphoryl lipid A (sMLA) weakly activate the MyD88 (myeloid differentiation primary response protein) branch of the bifurcated TLR4 (Toll-like receptor 4) signaling pathway, in contrast to diphosphoryl lipid A (sDLA), which is a strong activator of both branches of TLR4. sMLA's weak MyD88 signaling activity is apparent downstream of TLR4/MyD88 signaling as we show that sMLA, unlike sDLA, is unable to efficiently recruit the TNF receptor-associated factor 6 (TRAF6) to the Interleukin-1 receptor-associated kinase 1 (IRAK1). This reduced recruitment of TRAF6 explains MLA's lower MAPK (Mitogen Activated Protein Kinase) and NF-kappaB activity. As further tests of sMLA's ability to activate TLR4/Myeloid differentiation factor 2 (MD-2), we used the antibody MTS510 as an indicator for TLR4/MD-2 heterotetramer formation. Staining patterns with this antibody indicated that sMLA does not effectively drive heterotetramerization of TLR4/MD-2 when compared to sDLA. However, a F126A mutant of MD-2, which allows lipid A binding but interferes with TLR4/MD-2 heterotetramerization, revealed that while sMLA is unable to efficiently form TLR4/MD-2 heterotetramers, it still needs heterotetramer formation for the full extent of signaling it is able to achieve. Monophosphoryl lipid A's weak ability to form TLR4/MD-2 heterotetramers was not restricted to synthetic E. coli type because cells exposed to a biological preparation of S. minnesota monophosphoryl lipid A (MPLA) also showed reduced TLR4/MD-2 heterotetramer formation. The low potency with which sMLA and MPLA drive heterotetramerization of TLR4/MD-2 contributes to their weak MyD88 signaling activities. PMID- 23638126 TI - Susceptibility to transmitting HIV in patients initiating antiretroviral therapy in rural district hospitals in Cameroon (Stratall ANRS 12110/ESTHER Trial). AB - OBJECTIVES: Using cohort data nested in a randomized trial conducted in Cameroon, this study aimed to investigate time trends and predictors of the susceptibility to transmitting HIV during the first 24 months of treatment. METHODS: The outcome, susceptibility to transmitting HIV, was defined as reporting inconsistent condom use and experiencing incomplete virological suppression. Mixed logistic regressions were performed to identify predictors of this outcome among 250 patients reporting to have had sexual relationships either with HIV negative or unknown HIV status partner(s). RESULTS: Despite an initial decrease from 76% at M0 to 50% at M6, the rate of inconsistent condom use significantly increased from M12 (59%) to M24 (66%) (p = 0.017). However, the proportion of patients susceptible to transmitting HIV significantly decreased over follow-up from 76% at M0, to 50% at M6, 31% at M12 and 27% at M24 (p<0.001). After controlling for age, gender and intervention group, we found that perceiving healthcare staff's readiness to listen as poor (adjusted odds ratios (AOR) [95% Confidence Interval (CI)] = 1.87 [1.01-3.46]), reporting to have sexual relationships more than once per week (AOR [95%CI] = 2.52 [1.29-4.93]), having more than one sexual partner (AOR [95%CI] = 2.53 [1.21-5.30]) and desiring a/another child (AOR [95%CI] = 2.07 [1.10-3.87]) were all associated with a higher risk of being susceptible to transmitting HIV. Conversely, time since ART initiation (AOR [95%CI] = 0.66 [0.53-0.83] for an extra 6 months and ART adherence (AOR [95%CI] = 0.33 [0.15-0.72]) were significantly associated with a lower risk of being susceptible to transmitting HIV. CONCLUSIONS: The decrease observed in the susceptibility to transmitting HIV suggests that fear of behavioural disinhibition should not be a barrier to universal access to ART. However, developing adequate preventive interventions matching patients' expectations -like the desire to have children- and strengthening healthcare staff's counselling skills are urgently needed to maximize the impact of ART in slowing the HIV epidemic. PMID- 23638130 TI - A school-based human papillomavirus vaccination program in barretos, Brazil: final results of a demonstrative study. AB - INTRODUCTION: The implementation of a public HPV vaccination program in several developing countries, especially in Latin America, is a great challenge for health care specialists. AIM: To evaluate the uptake and the three-dose completion rates of a school-based HPV vaccination program in Barretos (Brazil). METHODS: THE STUDY INCLUDED GIRLS WHO WERE ENROLLED IN PUBLIC AND PRIVATE SCHOOLS AND WHO REGULARLY ATTENDED THE SIXTH AND SEVENTH GRADES OF ELEMENTARY SCHOOL (MEAN AGE: 11.9 years). A meeting with the parents or guardians occurred approximately one week before the vaccination in order to explain the project and clarify the doubts. The quadrivalent vaccine was administered using the same schedule as in the product package (0-2-6 months). The school visits for regular vaccination occurred on previously scheduled dates. The vaccine was also made available at Barretos Cancer Hospital for the girls who could not be vaccinated on the day when the team visited the school. RESULTS: Among the potential candidates for vaccination (n = 1,574), the parents or guardians of 1,513 girls (96.1%) responded to the invitation to participate in the study. A total of 1,389 parents or guardians agreed to participate in the program (acceptance rate = 91.8%). The main reason for refusing to participate in the vaccination program was fear of adverse events. The vaccine uptake rates for the first, second, and third doses were 87.5%, 86.3% and 85.0%, respectively. The three-dose completion rate was 97.2%. CONCLUSIONS: This demonstrative study achieved high rates of vaccination uptake and completion of three vaccine doses in children 10-16 years old from Brazil. The feasibility and success of an HPV vaccination program for adolescents in a developing country may depend on the integration between the public health and schooling systems. PMID- 23638129 TI - Regulation of retinoid-mediated signaling involved in skin homeostasis by RAR and RXR agonists/antagonists in mouse skin. AB - Endogenous retinoids like all-trans retinoic acid (ATRA) play important roles in skin homeostasis and skin-based immune responses. Moreover, retinoid signaling was found to be dysregulated in various skin diseases. The present study used topical application of selective agonists and antagonists for retinoic acid receptors (RARs) alpha and gamma and retinoid-X receptors (RXRs) for two weeks on mouse skin in order to determine the role of retinoid receptor subtypes in the gene regulation in skin. We observed pronounced epidermal hyperproliferation upon application of ATRA and synthetic agonists for RARgamma and RXR. ATRA and the RARgamma agonist further increased retinoid target gene expression (Rbp1, Crabp2, Krt4, Cyp26a1, Cyp26b1) and the chemokines Ccl17 and Ccl22. In contrast, a RARalpha agonist strongly decreased the expression of ATRA-synthesis enzymes, of retinoid target genes, markers of skin homeostasis, and various cytokines in the skin, thereby markedly resembling the expression profile induced by RXR and RAR antagonists. Our results indicate that RARalpha and RARgamma subtypes possess different roles in the skin and may be of relevance for the auto-regulation of endogenous retinoid signaling in skin. We suggest that dysregulated retinoid signaling in the skin mediated by RXR, RARalpha and/or RARgamma may promote skin based inflammation and dysregulation of skin barrier properties. PMID- 23638131 TI - First report of generalized face processing difficulties in mobius sequence. AB - Reverse simulation models of facial expression recognition suggest that we recognize the emotions of others by running implicit motor programmes responsible for the production of that expression. Previous work has tested this theory by examining facial expression recognition in participants with Mobius sequence, a condition characterized by congenital bilateral facial paralysis. However, a mixed pattern of findings has emerged, and it has not yet been tested whether these individuals can imagine facial expressions, a process also hypothesized to be underpinned by proprioceptive feedback from the face. We investigated this issue by examining expression recognition and imagery in six participants with Mobius sequence, and also carried out tests assessing facial identity and object recognition, as well as basic visual processing. While five of the six participants presented with expression recognition impairments, only one was impaired at the imagery of facial expressions. Further, five participants presented with other difficulties in the recognition of facial identity or objects, or in lower-level visual processing. We discuss the implications of our findings for the reverse simulation model, and suggest that facial identity recognition impairments may be more severe in the condition than has previously been noted. PMID- 23638132 TI - Efficacy of admission screening for extended-spectrum beta-lactamase producing Enterobacteriaceae. AB - OBJECTIVE: We hypothesized that admission screening for extended-spectrum beta lactamase-producing Enterobacteriaceae (ESBL-E) reduces the incidence of hospital acquired ESBL-E clinical isolates. DESIGN: Retrospective cohort study. SETTING: 12 hospitals (6 screening and 6 non-screening) in Toronto, Canada. PATIENTS: All adult inpatients with an ESBL-E positive culture collected from 2005-2009. METHODS: Cases were defined as hospital-onset (HO) or community-onset (CO) if cultures were positive after or before 72 hours. Efficacy of screening in reducing HO-ESBL-E incidence was assessed with a negative binomial model adjusting for study year and CO-ESBL-E incidence. The accuracy of the HO-ESBL-E definition was assessed by re-classifying HO-ESBL-E cases as confirmed nosocomial (negative admission screen), probable nosocomial (no admission screen) or not nosocomial (positive admission screen) using data from the screening hospitals. RESULTS: There were 2,088 ESBL-E positive patients and incidence of ESBL-E rose from 0.11 to 0.42 per 1,000 inpatient days between 2005 and 2009. CO-ESBL-E incidence was similar at screening and non-screening hospitals but screening hospitals had a lower incidence of HO-ESBL-E in all years. In the negative binomial model, screening was associated with a 49.1% reduction in HO-ESBL-E (p<0.001). A similar reduction was seen in the incidence of HO-ESBL-E bacteremia. When HO-ESBL-E cases were re-classified based on their admission screen result, 46.5% were positive on admission, 32.5% were confirmed as nosocomial and 21.0% were probable nosocomial cases. CONCLUSIONS: Admission screening for ESBL-E is associated with a reduced incidence of HO-ESBL-E. Controlled, prospective studies of admission screening for ESBL-E should be a priority. PMID- 23638133 TI - Understanding providers' offering and patients' acceptance of HIV screening in emergency departments: a multilevel analysis. ANRS 95008, Paris, France. AB - OBJECTIVE: We assessed the EDs' characteristics associated with the offer and acceptance rates of a nontargeted HIV rapid-test screening in 29 Emergency Departments (EDs) in the metropolitan Paris region (11.7 million inhabitants), where half of France's new HIV cases are diagnosed annually. METHODS: EDs nurses offered testing to all patients 18-64-year-old, able to provide consent, either with or without supplemental staff (hybrid staff model or indigenous staff model). The EDS' characteristics collected included structural characteristics (location, type, size), daily workload (patients' number and severity, length of stay in hours), staff's participation (training, support to the intervention, leadership), type of week day (weekends vs weekdays) and time (in days). Associations between these variables and the staff model, the offer and acceptance rates were studied using multilevel modeling. RESULTS: Indigenous staff model was more frequent in EDs with a lower daily patient flow and a higher staff support score to the intervention. In indigenous-model EDs, the offer rate was associated with the patient flow (OR = 0.838, 95% CI = 0.773-0.908), was lower during weekends (OR = 0.623, 95% CI = 0.581-0.667) and decreased over time (OR = 0.978, 95% CI = 0.975-0.981). Similar results were found in hybrid-model EDs. Acceptance was poorly associated with EDs characteristics in indigenous model EDs while in hybrid-model EDs it was lower during weekends (OR = 0.713, 95% CI = 0.623-0.816) and increased after the first positive test (OR = 1.526, 95% CI = 1.142-2.038). The EDs' characteristics explained respectively 38.5% and 15% of the total variance in the offer rate across indigenous model-EDs and hybrid model EDs vs 12% and 1% for the acceptance rate. CONCLUSION: Our findings suggest the need for taking into account EDs' characteristics while considering the implementation of an ED-based HIV screening program. Strategies allowing the optimization of human resources' utilization such as HIV targeted screening in the EDs might be privileged. PMID- 23638135 TI - Conserved N-terminal negative charges support optimally efficient N-type inactivation of Kv1 channels. AB - N-type inactivation is produced by the binding of a potassium channel's N terminus within the open pore, blocking conductance. Previous studies have found that introduction of negative charges into N-terminal inactivation domains disrupts inactivation; however, the Aplysia AKv1 N-type inactivation domain contains two negatively charged residues, E2 and E9. Rather than being unusual, sequence analysis shows that this N-terminal motif is highly conserved among Kv1 sequences across many phyla. Conservation analysis shows some tolerance at position 9 for other charged residues, like D9 and K9, whereas position 2 is highly conserved as E2. To examine the functional importance of these residues, site directed mutagenesis was performed and effects on inactivation were recorded by two electrode voltage clamp in Xenopus oocytes. We find that inclusion of charged residues at positions 2 and 9 prevents interactions with non-polar sites along the inactivation pathway increasing the efficiency of pore block. In addition, E2 appears to have additional specific electrostatic interactions that stabilize the inactivated state likely explaining its high level of conservation. One possible explanation for E2's unique importance, consistent with our data, is that E2 interacts electrostatically with a positive charge on the N-terminal amino group to stabilize the inactivation domain at the block site deep within the pore. Simple electrostatic modeling suggests that due to the non-polar environment in the pore in the blocked state, even a 1 A larger separation between these charges, produced by the E2D substitution, would be sufficient to explain the 65* reduced affinity of the E2D N-terminus for the pore. Finally, our studies support a multi-step, multi-site N-type inactivation model where the N terminus interacts deep within the pore in an extended like structure placing the most N-terminal residues 35% of the way across the electric field in the pore blocked state. PMID- 23638134 TI - New properties of Drosophila scs and scs' insulators. AB - Insulators are defined as a class of regulatory elements that delimit independent transcriptional domains within eukaryotic genomes. The first insulators to be identified were scs and scs', which flank the domain including two heat shock 70 genes. Zw5 and BEAF bind to scs and scs', respectively, and are responsible for the interaction between these insulators. Using the regulatory regions of yellow and white reporter genes, we have found that the interaction between scs and scs' improves the enhancer-blocking activity of the weak scs' insulator. The sequences of scs and scs' insulators include the promoters of genes that are strongly active in S2 cells but not in the eyes, in which the enhancer-blocking activity of these insulators has been extensively examined. Only the promoter of the Cad87A gene located at the end of the scs insulator drives white expression in the eyes, and the white enhancer can slightly stimulate this promoter. The scs insulator contains polyadenylation signals that may be important for preventing transcription through the insulator. As shown previously, scs and scs' can insulate transcription of the white transgene from the enhancing effects of the surrounding genome, a phenomenon known as the chromosomal position effect (CPE). After analyzing many independent transgenic lines, we have concluded that transgenes carrying the scs insulator are rarely inserted into genomic regions that stimulate the white reporter expression in the eyes. PMID- 23638136 TI - Exploring differentially expressed genes by RNA-Seq in cashmere goat (Capra hircus) skin during hair follicle development and cycling. AB - Cashmere goat (Capra hircus) hair follicle development and cycling can be divided into three stages: anagen, catagen and telogen. To elucidate the genes involved in hair follicle development and cycling in cashmere goats, transcriptome profiling of skin was carried out by analysing samples from three hair follicle developmental stages using RNA-Seq. The RNA-Seq analysis generated 8487344, 8142514 and 7345335 clean reads in anagen, catagen and telogen stages, respectively, which provided abundant data for further analysis. A total of 1332 differentially expressed genes (DEGs) were identified, providing evidence that the development of hair follicles among the three distinct stages changed considerably. A total of 683 genes with significant differential expression were detected between anagen and catagen, 530 DEGs were identified between anagen and telogen, and 119 DEGs were identified between catagen and telogen. A large number of DEGs were predominantly related to cellular process, cell & cell part, binding, biological regulation and metabolic process among the different stages of hair follicle development. In addition, the Wnt, Shh, TGF-beta and Notch signaling pathways may be involved in hair follicle development and the identified DEGs may play important roles in these signaling pathways. These results will expand our understanding of the complex molecular mechanisms of hair follicle development and cycling in cashmere goats and provide a foundation for future studies. PMID- 23638137 TI - Different auditory feedback control for echolocation and communication in horseshoe bats. AB - Auditory feedback from the animal's own voice is essential during bat echolocation: to optimize signal detection, bats continuously adjust various call parameters in response to changing echo signals. Auditory feedback seems also necessary for controlling many bat communication calls, although it remains unclear how auditory feedback control differs in echolocation and communication. We tackled this question by analyzing echolocation and communication in greater horseshoe bats, whose echolocation pulses are dominated by a constant frequency component that matches the frequency range they hear best. To maintain echoes within this "auditory fovea", horseshoe bats constantly adjust their echolocation call frequency depending on the frequency of the returning echo signal. This Doppler-shift compensation (DSC) behavior represents one of the most precise forms of sensory-motor feedback known. We examined the variability of echolocation pulses emitted at rest (resting frequencies, RFs) and one type of communication signal which resembles an echolocation pulse but is much shorter (short constant frequency communication calls, SCFs) and produced only during social interactions. We found that while RFs varied from day to day, corroborating earlier studies in other constant frequency bats, SCF-frequencies remained unchanged. In addition, RFs overlapped for some bats whereas SCF frequencies were always distinctly different. This indicates that auditory feedback during echolocation changed with varying RFs but remained constant or may have been absent during emission of SCF calls for communication. This fundamentally different feedback mechanism for echolocation and communication may have enabled these bats to use SCF calls for individual recognition whereas they adjusted RF calls to accommodate the daily shifts of their auditory fovea. PMID- 23638138 TI - Acid ceramidase maintains the chondrogenic phenotype of expanded primary chondrocytes and improves the chondrogenic differentiation of bone marrow-derived mesenchymal stem cells. AB - Acid ceramidase is required to maintain the metabolic balance of several important bioactive lipids, including ceramide, sphingosine and sphingosine-1 phosphate. Here we show that addition of recombinant acid ceramidase (rAC) to primary chondrocyte culture media maintained low levels of ceramide and led to elevated sphingosine by 48 hours. Surprisingly, after three weeks of expansion the chondrogenic phenotype of these cells also was markedly improved, as assessed by a combination of histochemical staining (Alcian Blue and Safranin-O), western blotting (e.g., Sox9, aggrecan, collagen 2A1), and/or qPCR. The same effects were evident in rat, equine and human cells, and were observed in monolayer and 3-D cultures. rAC also reduced the number of apoptotic cells in some culture conditions, contributing to overall improved cell quality. In addition to these effects on primary chondrocytes, when rAC was added to freshly harvested rat, equine or feline bone marrow cultures an ~2-fold enrichment of mesenchymal stem cells (MSCs) was observed by one week. rAC also improved the chondrogenic differentiation of MSCs, as revealed by histochemical and immunostaining. These latter effects were synergistic with TGF-beta1. Based on these results we propose that rAC could be used to improve the outcome of cell-based cartilage repair by maintaining the quality of the expanded cells, and also might be useful in vivo to induce endogenous cartilage repair in combination with other techniques. The results also suggest that short-term changes in sphingolipid metabolism may lead to longer-term effects on the chondrogenic phenotype. PMID- 23638139 TI - An efficient weighted graph strategy to identify differentiation associated genes in embryonic stem cells. AB - In the past few decades, embryonic stem cells (ESCs) were of great interest as a model system for studying early developmental processes and because of their potential therapeutic applications in regenerative medicine. However, the underlying mechanisms of ESC differentiation remain unclear, which limits our exploration of the therapeutic potential of stem cells. Fortunately, the increasing quantity and diversity of biological datasets can provide us with opportunities to explore the biological secrets. However, taking advantage of diverse biological information to facilitate the advancement of ESC research still remains a challenge. Here, we propose a scalable, efficient and flexible function prediction framework that integrates diverse biological information using a simple weighted strategy, for uncovering the genetic determinants of mouse ESC differentiation. The advantage of this approach is that it can make predictions based on dynamic information fusion, owing to the simple weighted strategy. With this approach, we identified 30 genes that had been reported to be associated with differentiation of stem cells, which we regard to be associated with differentiation or pluripotency in embryonic stem cells. We also predicted 70 genes as candidates for contributing to differentiation, which requires further confirmation. As a whole, our results showed that this strategy could be applied as a useful tool for ESC research. PMID- 23638140 TI - Molecular modeling study for inhibition mechanism of human chymase and its application in inhibitor design. AB - Human chymase catalyzes the hydrolysis of peptide bonds. Three chymase inhibitors with very similar chemical structures but highly different inhibitory profiles towards the hydrolase function of chymase were selected with the aim of elucidating the origin of disparities in their biological activities. As a substrate (angiotensin-I) bound crystal structure is not available, molecular docking was performed to dock the substrate into the active site. Molecular dynamics simulations of chymase complexes with inhibitors and substrate were performed to calculate the binding orientation of inhibitors and substrate as well as to characterize conformational changes in the active site. The results elucidate details of the 3D chymase structure as well as the importance of K40 in hydrolase function. Binding mode analysis showed that substitution of a heavier Cl atom at the phenyl ring of most active inhibitor produced a great deal of variation in its orientation causing the phosphinate group to interact strongly with residue K40. Dynamics simulations revealed the conformational variation in region of V36-F41 upon substrate and inhibitor binding induced a shift in the location of K40 thus changing its interactions with them. Chymase complexes with the most active compound and substrate were used for development of a hybrid pharmacophore model which was applied in databases screening. Finally, hits which bound well at the active site, exhibited key interactions and favorable electronic properties were identified as possible inhibitors for chymase. This study not only elucidates inhibitory mechanism of chymase inhibitors but also provides key structural insights which will aid in the rational design of novel potent inhibitors of the enzyme. In general, the strategy applied in the current study could be a promising computational approach and may be generally applicable to drug design for other enzymes. PMID- 23638142 TI - Ureaplasma parvum serovar 3 multiple banded antigen size variation after chronic intra-amniotic infection/colonization. AB - Ureaplasma species are the microorganisms most frequently associated with adverse pregnancy outcomes. The multiple banded antigen (MBA), a surface-exposed lipoprotein, is a key virulence factor of ureaplasmas. The MBA demonstrates size variation, which we have shown previously to be correlated with the severity of chorioamnion inflammation. We aimed to investigate U. parvum serovar 3 pathogenesis in vivo, using a sheep model, by investigating: MBA variation after long term (chronic) and short term (acute) durations of in utero ureaplasma infections, and the severity of chorioamnionitis and inflammation in other fetal tissues. Inocula of 2 * 10(7) colony-forming-units (CFU) of U. parvum serovar 3 (Up) or media controls (C) were injected intra-amniotically into pregnant ewes at one of three time points: day 55 (69d Up, n = 8; C69, n = 4); day 117 (7d Up, n = 8; C7, n = 2); and day 121 (3d Up, n = 8; C3, n = 2) of gestation (term = 145 150d). At day 124, preterm fetuses were delivered surgically. Samples of chorioamnion, fetal lung, and umbilical cord were: (i) snap frozen for subsequent ureaplasma culture, and (ii) fixed, embedded, sectioned and stained by haematoxylin and eosin stain for histological analysis. Selected fetal lung clinical ureaplasma isolates were cloned and filtered to obtain cultures from a single CFU. Passage 1 and clone 2 ureaplasma cultures were tested by western blot to demonstrate MBA variation. In acute durations of ureaplasma infection no MBA variants (3d Up) or very few MBA variants (7d Up) were present when compared to the original inoculum. However, numerous MBA size variants were generated in vivo (alike within contiguous tissues, amniotic fluid and fetal lung, but different variants were present within chorioamnion), during chronic, 69d exposure to ureaplasma infection. For the first time we have shown that the degree of ureaplasma MBA variation in vivo increased with the duration of gestation. PMID- 23638144 TI - Neuroanatomical evidence that kisspeptin directly regulates isotocin and vasotocin neurons. AB - Neuropeptide kisspeptin has been suggested to be an essential central regulator of reproduction in response to changes in serum gonadal steroid concentrations. However, in spite of wide kisspeptin receptor distribution in the brain, especially in the preoptic area and hypothalamus, the research focus has mostly been confined to the kisspeptin regulation on GnRH neurons. Here, by using medaka whose kisspeptin (kiss1) neurons have been clearly demonstrated to be regulated by sex steroids, we analyzed the anatomical distribution of kisspeptin receptors Gpr54-1 and Gpr54-2. Because the both receptors were shown to be activated by kisspeptins (Kiss1 and Kiss2), we analyzed the anatomical distribution of the both receptors by in situ hybridization. They were mainly expressed in the ventral telencephalon, preoptic area, and hypothalamus, which have been suggested to be involved in homeostatic functions including reproduction. First, we found gpr54-2 mRNA expression in nucleus preopticus pars magnocellularis and demonstrated that vasotocin and isotocin (Vasopressin and Oxytocin ortholog, respectively) neurons express gpr54-2 by dual in situ hybridization. Given that kisspeptin administration increases serum oxytocin and vasopressin concentration in mammals, the present finding are likely to be vertebrate-wide phenomenon, although direct regulation has not yet been demonstrated in mammals. We then analyzed co-expression of kisspeptin receptors in three types of GnRH neurons. It was clearly demonstrated that gpr54-expressing cells were located adjacent to GnRH1 neurons, although they were not GnRH1 neurons themselves. In contrast, there was no gpr54-expressing cell in the vicinities of neuromodulatory GnRH2 or GnRH3 neurons. From these results, we suggest that medaka kisspeptin neurons directly regulate some behavioral and neuroendocrine functions via vasotocin/isotocin neurons, whereas they do not regulate hypophysiotropic GnRH1 neurons at least in a direct manner. Thus, direct kisspeptin regulation of GnRH1 neurons proposed in mammals may not be the universal feature of vertebrate kisspeptin system in general. PMID- 23638141 TI - The potential regimen of target-controlled infusion of propofol in flexible bronchoscopy sedation: a randomized controlled trial. AB - OBJECTIVES: Target-controlled infusion (TCI) provides precise pharmacokinetic control of propofol concentration in the effect-site (Ce), eg. brain. This pilot study aims to evaluate the feasibility and optimal TCI regimen for flexible bronchoscopy (FB) sedation. METHODS: After alfentanil bolus, initial induction Ce of propofol was targeted at 2 MUg/ml. Patients were randomized into three titration groups (i.e., by 0.5, 0.2 and 0.1 MUg/ml, respectively) to maintain stable sedation levels and vital signs. Adverse events, frequency of adjustments, drug doses, and induction and recovery times were recorded. RESULTS: The study was closed early due to significantly severe hypoxemia events (oxyhemoglobin saturation <70%) in the group titrated at 0.5 MUg/ml. Forty-nine, 49 and 46 patients were enrolled into the 3 respective groups before study closure. The proportion of patients with hypoxemia events differed significantly between groups (67.3 vs. 46.9 vs. 41.3%, p = 0.027). Hypotension events, induction and recovery time and propofol doses were not different. The Ce of induction differed significantly between groups (2.4+/-0.5 vs. 2.1+/-0.4 vs. 2.1+/-0.3 MUg/ml, p = 0.005) and the Ce of procedures was higher at 0.5 MUg/ml titration (2.4+/-0.5 vs. 2.1+/-0.4 vs. 2.2+/-0.3 MUg/ml, p = 0.006). The adjustment frequency tended to be higher for titration at 0.1 MUg/ml but was not statistically significant (2 (0~6) vs. 3 (0~6) vs. 3 (0~11)). Subgroup analysis revealed 14% of all patients required no further adjustment during the whole sedation. Comparing patients requiring at least one adjustment with those who did not, they were observed to have a shorter induction time (87.6+/-34.9 vs. 226.9+/-147.9 sec, p<0.001), a smaller induction dose and Ce (32.5+/-4.1 vs. 56.8+/-22.7 mg, p<0.001; 1.76+/ 0.17 vs. 2.28 +/-0.41, p<0.001, respectively), and less hypoxemia and hypotension (15.8 vs.56.9%, p = 0.001; 0 vs. 24.1%, p = 0.008, respectively). CONCLUSION: Titration at 0.5 MUg/ml is risky for FB sedation. A subgroup of patients required no more TCI adjustment with fewer complications. Further studies are warranted to determine the optimal regimen of TCI for FB sedation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01101477. PMID- 23638143 TI - Determinants of medication adherence to antihypertensive medications among a Chinese population using Morisky Medication Adherence Scale. AB - BACKGROUND AND OBJECTIVES: Poor adherence to medications is one of the major public health challenges. Only one-third of the population reported successful control of blood pressure, mostly caused by poor drug adherence. However, there are relatively few reports studying the adherence levels and their associated factors among Chinese patients. This study aimed to study the adherence profiles and the factors associated with antihypertensive drug adherence among Chinese patients. METHODS: A cross-sectional study was conducted in an outpatient clinic located in the New Territories Region of Hong Kong. Adult patients who were currently taking at least one antihypertensive drug were invited to complete a self-administered questionnaire, consisting of basic socio-demographic profile, self-perceived health status, and self-reported medication adherence. The outcome measure was the Morisky Medication Adherence Scale (MMAS-8). Good adherence was defined as MMAS scores greater than 6 points (out of a total score of 8 points). RESULTS: From 1114 patients, 725 (65.1%) had good adherence to antihypertensive agents. Binary logistic regression analysis was conducted. Younger age, shorter duration of antihypertensive agents used, job status being employed, and poor or very poor self-perceived health status were negatively associated with drug adherence. CONCLUSION: This study reported a high proportion of poor medication adherence among hypertensive subjects. Patients with factors associated with poor adherence should be more closely monitored to optimize their drug taking behavior. PMID- 23638145 TI - Examining physical activity service provision to culturally and linguistically diverse (CALD) communities in Australia: a qualitative evaluation. AB - Strong evidence exists for the role of physical activity in preventing and managing a range of chronic health conditions. A particular challenge in promoting physical activity as a health strategy exists in culturally and linguistically diverse (CALD) groups, as such groups demonstrate high risk for a range of non-communicable diseases. The aim of this research was to examine the perspective of multicultural health service providers for CALD groups with respect to the physical activity services/initiatives on offer, access barriers to these services, and ideas for future service delivery in this area. Semi structured interviews were conducted with 15 multicultural health service providers across the capital cities of the three most populous states in Australia (New South Wales, Queensland, and Victoria), and thematic content analysis was used to examine the data. Findings indicated that the majority of physical activity initiatives were associated with organizations offering other social services for CALD communities but were greatly restrained by resources. As well, it was found that most services were not designed by taking into account specific cultural requirements for CALD communities or their cultural expectations. Common barriers identified to service uptake were classified as socio-cultural (e.g., gender, language, context of health) and environmental (e.g., transportation) in nature. These findings should be utilized when planning future physical activity and health promotion initiatives for increasing CALD participation. In particular, programs need to be culturally tailored to the specific expectations of CALD groups, addressing cultural safety and sensitivity, and should be in partnership with other organizations to extend the reach and capacity. PMID- 23638147 TI - A dynamical model of hierarchical selection and coordination in speech planning. AB - studies of the control of complex sequential movements have dissociated two aspects of movement planning: control over the sequential selection of movement plans, and control over the precise timing of movement execution. This distinction is particularly relevant in the production of speech: utterances contain sequentially ordered words and syllables, but articulatory movements are often executed in a non-sequential, overlapping manner with precisely coordinated relative timing. This study presents a hybrid dynamical model in which competitive activation controls selection of movement plans and coupled oscillatory systems govern coordination. The model departs from previous approaches by ascribing an important role to competitive selection of articulatory plans within a syllable. Numerical simulations show that the model reproduces a variety of speech production phenomena, such as effects of preparation and utterance composition on reaction time, and asymmetries in patterns of articulatory timing associated with onsets and codas. The model furthermore provides a unified understanding of a diverse group of phonetic and phonological phenomena which have not previously been related. PMID- 23638148 TI - Knowledge, attitudes, and practices related to uterotonic drugs during childbirth in Karnataka, India: a qualitative research study. AB - BACKGROUND AND OBJECTIVES: India has the highest annual number of maternal deaths of any country. As obstetric hemorrhage is the leading cause of maternal death in India, numerous efforts are under way to promote access to skilled attendance at birth and emergency obstetric care. Current initiatives also seek to increase access to active management of the third stage of labor for postpartum hemorrhage prevention, particularly through administration of an uterotonic after delivery. However, prior research suggests widespread inappropriate use of uterotonics at facilities and in communities-for example, without adequate monitoring or referral support for complications. This qualitative study aimed to document health providers' and community members' current knowledge, attitudes, and practices regarding uterotonic use during labor and delivery in India's Karnataka state. METHODS: 140 in-depth interviews were conducted from June to August 2011 in Bagalkot and Hassan districts with physicians, nurses, recently delivered women, mothers-in-law, traditional birth attendants (dais), unlicensed village doctors, and chemists (pharmacists). RESULTS: Many respondents reported use of uterotonics, particularly oxytocin, for labor augmentation in both facility-based and home-based deliveries. The study also identified contextual factors that promote inappropriate uterotonic use, including high value placed on pain during labor; perceived pressure to provide or receive uterotonics early in labor and delivery, perhaps leading to administration of uterotonics despite awareness of risks; and lack of consistent and correct knowledge regarding safe storage, dosing, and administration of oxytocin. CONCLUSIONS: These findings have significant implications for public health programs in a context of widespread and potentially increasing availability of uterotonics. Among other responses, efforts are needed to improve communication between community members and providers regarding uterotonic use during labor and delivery and to target training and other interventions to address identified gaps in knowledge and ensure that providers and pharmacists have up-to-date information regarding proper usage of uterotonic drugs. PMID- 23638146 TI - Skeletal lesions in human tuberculosis may sometimes heal: an aid to palaeopathological diagnoses. AB - In three to five percent of active cases of tuberculosis, skeletal lesions develop. Typically, these occur on the vertebrae and are destructive in nature. In this paper, we examined cases of skeletal tuberculosis from a skeletal collection (Galler Collection) with focus on the manifestation of bony changes due to tuberculosis in various body regions in association with antibiotic introduction. This skeletal collection was created in 1925-1977 by a pathologist at the University Hospital in Zurich, Ernst Galler. It includes the remains of 2426 individuals with documented clinical histories as well as autopsies. It contained 29 cases of skeletal tuberculosis lesions. We observed natural healing of vertebral lesions through several processes including fusion of vertebrae, bone deposition and fusion of posterior elements. In these cases, we observed a higher frequency and proportion of bone deposition and fusion of posterior vertebral elements where pharmacological agents were used. There were also four cases of artificial healing through surgically induced posterior spinal fusion. With the introduction of pharmaceutical treatments, the number of individuals with multiple tuberculous foci decreased from 80% to 25% when compared to individuals who did not receive any drug therapy. Investigation of comorbidities showed that pneumonia, pleuritis and being underweight were consistently present, even with pharmaceutical treatment. Our results have applications in palaeopathological diagnoses where healing and consequent bone deposition may complicate differential diagnoses. PMID- 23638150 TI - Occurrence patterns of lichens on stumps in young managed forests. AB - The increasing demand for forest-derived bio-fuel may decrease the amount of dead wood and hence also the amount of available substrate for saproxylic ( = dead wood dependent) organisms. Cut stumps constitute a large portion of dead wood in managed boreal forests. The lichen flora of such stumps has received little interest. Therefore, we investigated which lichens that occur on stumps in young (4-19 years), managed forests and analyzed how species richness and occurrence of individual species were related to stump and stand characteristics. We performed lichen inventories of 576 Norway spruce stumps in 48 forest stands in two study areas in Central Sweden, recording in total 77 lichen species. Of these, 14 were obligately lignicolous, while the remaining were generalists that also grow on bark, soil or rocks. We tested the effect of characteristics reflecting successional stage, microclimate, substrate patch size, and the species pool in the surrounding area on (1) total lichen species richness, (2) species richness of obligately lignicolous lichens and (3) the occurrence of four obligately lignicolous lichen species. The most important variables were stump age, with more species on old stumps, and study area, with similar total species richness but differences in occupancy for individual species. Responses for total lichen species richness and species richness of obligately lignicolous lichens were overall similar, indicating similar ecological requirements of these two groups. Our results indicate that species richness measurements serve as poor proxies for the responses of individual, obligately lignicolous lichen species. PMID- 23638151 TI - Defining the erythrocyte binding domains of Plasmodium vivax tryptophan rich antigen 33.5. AB - Tryptophan-rich antigens play important role in host-parasite interaction. One of the Plasmodium vivax tryptophan-rich antigens called PvTRAg33.5 had earlier been shown to be predominantly of alpha helical in nature with multidomain structure, induced immune responses in humans, binds to host erythrocytes, and its sequence is highly conserved in the parasite population. In the present study, we divided this protein into three different parts i.e. N-terminal (amino acid position 24 106), middle (amino acid position 107-192), and C-terminal region (amino acid position 185-275) and determined the erythrocyte binding activity of these fragments. This binding activity was retained by the middle and C-terminal fragments covering 107 to 275 amino acid region of the PvTRAg33.5 protein. Eight non-overlapping peptides covering this 107 to 275 amino acid region were then synthesized and tested for their erythrocyte binding activity to further define the binding domains. Only two peptides, peptide P4 (at 171-191 amino acid position) and peptide P8 (at 255-275 amino acid position), were found to contain the erythrocyte binding activity. Competition assay revealed that each peptide recognizes its own erythrocyte receptor. These two peptides were found to be located on two parallel helices at one end of the protein in the modelled structure and could be exposed on its surface to form a suitable site for protein protein interaction. Natural antibodies present in the sera of the P. vivax exposed individuals or the polyclonal rabbit antibodies against this protein were able to inhibit the erythrocyte binding activity of PvTRAg33.5, its fragments, and these two synthetic peptides P4 and P8. Further studies on receptor-ligand interaction might lead to the development of the therapeutic reagent. PMID- 23638149 TI - Cross-modal stimulus conflict: the behavioral effects of stimulus input timing in a visual-auditory Stroop task. AB - Cross-modal processing depends strongly on the compatibility between different sensory inputs, the relative timing of their arrival to brain processing components, and on how attention is allocated. In this behavioral study, we employed a cross-modal audio-visual Stroop task in which we manipulated the within-trial stimulus-onset-asynchronies (SOAs) of the stimulus-component inputs, the grouping of the SOAs (blocked vs. random), the attended modality (auditory or visual), and the congruency of the Stroop color-word stimuli (congruent, incongruent, neutral) to assess how these factors interact within a multisensory context. One main result was that visual distractors produced larger incongruency effects on auditory targets than vice versa. Moreover, as revealed by both overall shorter response times (RTs) and relative shifts in the psychometric incongruency-effect functions, visual-information processing was faster and produced stronger and longer-lasting incongruency effects than did auditory. When attending to either modality, stimulus incongruency from the other modality interacted with SOA, yielding larger effects when the irrelevant distractor occurred prior to the attended target, but no interaction with SOA grouping. Finally, relative to neutral-stimuli, and across the wide range of the SOAs employed, congruency led to substantially more behavioral facilitation than did incongruency to interference, in contrast to findings that within-modality stimulus-compatibility effects tend to be more evenly split between facilitation and interference. In sum, the present findings reveal several key characteristics of how we process the stimulus compatibility of cross-modal sensory inputs, reflecting stimulus processing patterns that are critical for successfully navigating our complex multisensory world. PMID- 23638152 TI - Aquaculture can promote the presence and spread of antibiotic-resistant Enterococci in marine sediments. AB - Aquaculture is an expanding activity worldwide. However its rapid growth can affect the aquatic environment through release of large amounts of chemicals, including antibiotics. Moreover, the presence of organic matter and bacteria of different origin can favor gene transfer and recombination. Whereas the consequences of such activities on environmental microbiota are well explored, little is known of their effects on allochthonous and potentially pathogenic bacteria, such as enterococci. Sediments from three sampling stations (two inside and one outside) collected in a fish farm in the Adriatic Sea were examined for enterococcal abundance and antibiotic resistance traits using the membrane filter technique and an improved quantitative PCR. Strains were tested for susceptibility to tetracycline, erythromycin, ampicillin and gentamicin; samples were directly screened for selected tetracycline [tet(M), tet(L), tet(O)] and macrolide [erm(A), erm(B) and mef] resistance genes by newly-developed multiplex PCRs. The abundance of benthic enterococci was higher inside than outside the farm. All isolates were susceptible to the four antimicrobials tested, although direct PCR evidenced tet(M) and tet(L) in sediment samples from all stations. Direct multiplex PCR of sediment samples cultured in rich broth supplemented with antibiotic (tetracycline, erythromycin, ampicillin or gentamicin) highlighted changes in resistance gene profiles, with amplification of previously undetected tet(O), erm(B) and mef genes and an increase in benthic enterococcal abundance after incubation in the presence of ampicillin and gentamicin. Despite being limited to a single farm, these data indicate that aquaculture may influence the abundance and spread of benthic enterococci and that farm sediments can be reservoirs of dormant antibiotic-resistant bacteria, including enterococci, which can rapidly revive in presence of new inputs of organic matter. This reservoir may constitute an underestimated health risk and deserves further investigation. PMID- 23638154 TI - Epstein Barr virus and Helicobacter pylori co-infection are positively associated with severe gastritis in pediatric patients. AB - BACKGROUND: H. pylori infection is acquired during childhood and causes a chronic inflammatory response in the gastric mucosa, which is considered the main risk factor to acquire gastric cancer (GC) later in life. More recently, infection by Epstein-Barr virus (EBV) have also been associated with GC. The role of EBV in early inflammatory responses and its relationship with H. pylori infection remains poorly studied. Here, we assessed whether EBV infection in children correlated with the stage of gastritis and whether co-infection with H. pylori affected the severity of inflammation. METHODOLOGY/PRINCIPAL FINDINGS: 333 pediatric patients with chronic abdominal pain were studied. From them, gastric biopsies were taken and inflammation graded according to the Sydney system; peripheral blood was drawn and antibodies against EBV (IgG and IgM anti-VCA) and H. pylori (IgG anti-whole bacteria and anti-CagA) were measured in sera. We found that children infected only by EBV presented mild mononuclear (MN) and none polymorphonuclear (PMN) cell infiltration, while those infected by H. pylori presented moderate MN and mild PMN. In contrast, patients co-infected with both pathogens were significantly associated with severe gastritis. Importantly, co infection of H. pylori CagA+/EBV+ had a stronger association with severe MN (PR 3.0) and PMN (PR 7.2) cells than cases with single H. pylori CagA+ infection. CONCLUSIONS/SIGNIFICANCE: Co-infection with EBV and H. pylori in pediatric patients is associated with severe gastritis. Even single infections with H. pylori CagA+ strains are associated with mild to moderate infiltration arguing for a cooperative effect of H. pylori and EBV in the gastric mucosa and revealing a critical role for EBV previously un-appreciated. This study points out the need to study both pathogens to understand the mechanism behind severe damage of the gastric mucosa, which could identified children with increased risk to present more serious lesions later in life. PMID- 23638153 TI - Use of natural products as chemical library for drug discovery and network pharmacology. AB - BACKGROUND: Natural products have been an important source of lead compounds for drug discovery. How to find and evaluate bioactive natural products is critical to the achievement of drug/lead discovery from natural products. METHODOLOGY: We collected 19,7201 natural products structures, reported biological activities and virtual screening results. Principal component analysis was employed to explore the chemical space, and we found that there was a large portion of overlap between natural products and FDA-approved drugs in the chemical space, which indicated that natural products had large quantity of potential lead compounds. We also explored the network properties of natural product-target networks and found that polypharmacology was greatly enriched to those compounds with large degree and high betweenness centrality. In order to make up for a lack of experimental data, high throughput virtual screening was employed. All natural products were docked to 332 target proteins of FDA-approved drugs. The most potential natural products for drug discovery and their indications were predicted based on a docking score-weighted prediction model. CONCLUSIONS: Analysis of molecular descriptors, distribution in chemical space and biological activities of natural products was conducted in this article. Natural products have vast chemical diversity, good drug-like properties and can interact with multiple cellular target proteins. PMID- 23638155 TI - Indicators of child health, service utilization and mortality in Zhejiang Province of China, 1998-2011. AB - OBJECTIVE: To investigate the levels of primary health care services for children and their changes in Zhejiang Province, China from 1998 to 2011. METHODS: The data were drawn from Zhejiang maternal and child health statistics collected under the supervision of the Health Bureau of Zhejiang Province. Primary health care coverage, hospital deliveries, low birth weight, postnatal visits, breastfeeding, underweight, early neonatal (<7 days) mortality, neonatal mortality, infant mortality and under-5 mortality were investigated. RESULTS: The coverage rates for children under 3 years old and children under 7 years old increased in the last 14 years. The hospital delivery rate was high during the study period, and the overall difference narrowed. There was a significant difference (P<0.001) between the prevalence of low birth weight in 1998 (2.03%) and the prevalence in 2011 (2.71%). The increase in low birth weight was more significant in urban areas than in rural areas. The postnatal visit rate increased from 95.00% to 98.45% with a significant difference (P<0.001). The breastfeeding rate was the highest in 2004 at 74.79% and lowest in 2008 at 53.86%. The prevalence of underweight in children under 5 years old decreased from 1.63% to 0.65%, and the prevalence was higher in rural areas. The early neonatal, neonatal, infant and under-5 mortality rates decreased from 6.660/00, 8.670/00, 11.990/00 and 15.280/00 to 1.690/00, 2.360/00, 3.890/00 and 5.420/00, respectively (P<0.001). The mortality rates in rural areas were slightly higher than those in urban areas each year, and the mortality rates were lower in Ningbo, Wenzhou, and Jiaxing regions and higher in Quzhou and Lishui regions. CONCLUSION: Primary health care services for children in Zhejiang Province improved from 1998 to 2011. Continued high rates of low birth weight in urban areas and mortality in rural areas may be addressed with improvements in health awareness and medical technology. PMID- 23638157 TI - Effects of GC bias in next-generation-sequencing data on de novo genome assembly. AB - Next-generation-sequencing (NGS) has revolutionized the field of genome assembly because of its much higher data throughput and much lower cost compared with traditional Sanger sequencing. However, NGS poses new computational challenges to de novo genome assembly. Among the challenges, GC bias in NGS data is known to aggravate genome assembly. However, it is not clear to what extent GC bias affects genome assembly in general. In this work, we conduct a systematic analysis on the effects of GC bias on genome assembly. Our analyses reveal that GC bias only lowers assembly completeness when the degree of GC bias is above a threshold. At a strong GC bias, the assembly fragmentation due to GC bias can be explained by the low coverage of reads in the GC-poor or GC-rich regions of a genome. This effect is observed for all the assemblers under study. Increasing the total amount of NGS data thus rescues the assembly fragmentation because of GC bias. However, the amount of data needed for a full rescue depends on the distribution of GC contents. Both low and high coverage depths due to GC bias lower the accuracy of assembly. These pieces of information provide guidance toward a better de novo genome assembly in the presence of GC bias. PMID- 23638156 TI - T follicular helper cells mediate expansion of regulatory B cells via IL-21 in Lupus-prone MRL/lpr mice. AB - T follicular helper (Tfh) cells can mediate humoral immune responses and augment autoimmunity, whereas the role of Tfh cells on regulatory B (B10) cells in autoimmunity diseases is not clear. Here, we investigated the percentages of Tfh cells and B10 cells in lupus-prone MRL/Mp-lpr/lpr (MRL/lpr) mice and examined the effects and mechanism of Tfh cell-derived interleukin-21 (IL-21) on IL-10 production during the differentiation of B10 cells. Both Tfh cells and B10 cells were expanded in spleens of MRL/lpr mice. In addition, a positive correlation between the proportions of Tfh cells and B10 cells was observed. Tfh cell-derived IL-21 from MRL/lpr mice could promote IL-10 production during the differentiation of B10 cells. Importantly, neutralization of IL-21 inhibited IL-10 production and expansion of B10 cells both in vitro and in vivo. IL-21 induced IL-10 production via activation of phosphorylated signal transduction and activator of transcription 3 (p-STAT3). Inhibition of p-STAT3 effectively blocked IL-10 production during the differentiation of B10 cells. Moreover, IL-21-induced IL-10 exerted a regulatory function by inhibiting the proliferation of T cells. These data suggest that Tfh cells not only mediate humoral immune responses and augment autoimmunity but also play a broader role in immune regulatory actions via the induction of IL-10 production. PMID- 23638158 TI - Potential of olfactory ensheathing cells from different sources for spinal cord repair. AB - Spinal cord injury (SCI) induces a permanent disability in patients. To this day no curative treatment can be proposed to restore lost functions. Therefore, extensive experimental studies have been conducted to induce recovery after SCI. One of the most promising therapies is based on the use of olfactory ensheathing cells (OECs). OECs can be obtained from either the olfactory bulbs (OB-OECs) or from olfactory mucosa (OM-OECs), involving a less invasive approach for autotransplantation. However the vast majority of experimental transplantations have been focusing on OB-OECs although the OM represents a more accessible source of OECs. Importantly, the ability of OM-OECs in comparison to OB-OECs to induce spinal cord recovery in the same lesion paradigm has never been described. We here present data using a multiparametric approach, based on electrophysiological, behavioral, histological and magnetic resonance imaging experiments on the repair potential of OB-OECs and OM-OECs from either primary or purified cultures after a severe model of SCI. Our data demonstrate that transplantation of OECs obtained from OB or OM induces electrophysiological and functional recovery, reduces astrocyte reactivity and glial scar formation and improves axonal regrowth. We also show that the purification step is essential for OM-OECs while not required for OB-OECs. Altogether, our study strongly indicates that transplantation of OECs from OM represents the best benefit/risk ratio according to the safety of access of OM and the results induced by transplantations of OM-OECs. Indeed, purified OM-OECs in addition to induce recovery can integrate and survive up to 60 days into the spinal cord. Therefore, our results provide strong support for these cells as a viable therapy for SCI. PMID- 23638159 TI - A central role for C1q/TNF-related protein 13 (CTRP13) in modulating food intake and body weight. AB - C1q/TNF-related protein 13 (CTRP13), a hormone secreted by adipose tissue (adipokines), helps regulate glucose metabolism in peripheral tissues. We previously reported that CTRP13 expression is increased in obese and hyperphagic leptin-deficient mice, suggesting that it may modulate food intake and body weight. CTRP13 is also expressed in the brain, although its role in modulating whole-body energy balance remains unknown. Here, we show that CTRP13 is a novel anorexigenic factor in the mouse brain. Quantitative PCR demonstrated that food restriction downregulates Ctrp13 expression in mouse hypothalamus, while high-fat feeding upregulates expression. Central administration of recombinant CTRP13 suppressed food intake and reduced body weight in mice. Further, CTRP13 and the orexigenic neuropeptide agouti-related protein (AgRP) reciprocally regulate each other's expression in the hypothalamus: central delivery of CTRP13 suppressed Agrp expression, while delivery of AgRP increased Ctrp13 expression. Food restriction alone reduced Ctrp13 and increased orexigenic neuropeptide gene (Npy and Agrp) expression in the hypothalamus; in contrast, when food restriction was coupled to enhanced physical activity in an activity-based anorexia (ABA) mouse model, hypothalamic expression of both Ctrp13 and Agrp were upregulated. Taken together, these results suggest that CTRP13 and AgRP form a hypothalamic feedback loop to modulate food intake and that this neural circuit may be disrupted in an anorexic-like condition. PMID- 23638160 TI - The role of protein interactions in mediating essentiality and synthetic lethality. AB - Genes are characterized as essential if their knockout is associated with a lethal phenotype, and these "essential genes" play a central role in biological function. In addition, some genes are only essential when deleted in pairs, a phenomenon known as synthetic lethality. Here we consider genes displaying synthetic lethality as "essential pairs" of genes, and analyze the properties of yeast essential genes and synthetic lethal pairs together. As gene duplication initially produces an identical pair or sets of genes, it is often invoked as an explanation for synthetic lethality. However, we find that duplication explains only a minority of cases of synthetic lethality. Similarly, disruption of metabolic pathways leads to relatively few examples of synthetic lethality. By contrast, the vast majority of synthetic lethal gene pairs code for proteins with related functions that share interaction partners. We also find that essential genes and synthetic lethal pairs cluster in the protein-protein interaction network. These results suggest that synthetic lethality is strongly dependent on the formation of protein-protein interactions. Compensation by duplicates does not usually occur mainly because the genes involved are recent duplicates, but is more commonly due to functional similarity that permits preservation of essential protein complexes. This unified view, combining genes that are individually essential with those that form essential pairs, suggests that essentiality is a feature of physical interactions between proteins protein-protein interactions, rather than being inherent in gene and protein products themselves. PMID- 23638161 TI - High expression of heat shock protein 90 is associated with tumor aggressiveness and poor prognosis in patients with advanced gastric cancer. AB - The heat shock protein 90 (HSP90) is overexpressed and highly associated with poor prognosis in many malignancies. However, the role of HSP90 in gastric cancer has not been thoroughly elucidated. The aim of this study is to investigate the relationship of HSP90 expression with clinicopathological parameters and prognosis in advanced gastric cancer, and estimate the alteration of HSP90 expression after neoadjuvant chemotherapy. HSP90 and matrix metallopeptidase 9 (MMP-9) antigen expression was evaluated by immunohistochemistry in 322 advanced gastric carcinoma samples. The relationships between HSP90 and clinicopathological parameters and prognosis were analyzed. The response of HSP90 level was assessed in chemotherapeutic effect in 54 patients received 1-2 cycles of neoadjuvant chemotherapy. The positive expression of HSP90 was found to be 69.6% in 322 advanced gastric carcinoma samples. HSP90 protein expression was significantly associated with depth invasion (P<0.001), lymph node metastasis (P<0.001) and stage of disease (P<0.001). The positive rates of HSP90 expression were higher in both prominent serosal invasion group (P<0.001) and lymph node metastasis group (P<0.001). Moreover, HSP90 was significantly correlated with MMP 9 among 322 gastric cancer tissues (P<0.001). In univariate and multivariate analyses, HSP90 was an independent prognostic factor for both recurrence-free survival (RFS) and overall survival (OS). These results suggested that HSP90 may play an important role on tumor invasion, metastasis and prognosis, and might act as a promising target for prognostic prediction. PMID- 23638163 TI - Modeling and automatic feedback control of tremor: adaptive estimation of deep brain stimulation. AB - This paper discusses modeling and automatic feedback control of (postural and rest) tremor for adaptive-control-methodology-based estimation of deep brain stimulation (DBS) parameters. The simplest linear oscillator-based tremor model, between stimulation amplitude and tremor, is investigated by utilizing input output knowledge. Further, a nonlinear generalization of the oscillator-based tremor model, useful for derivation of a control strategy involving incorporation of parametric-bound knowledge, is provided. Using the Lyapunov method, a robust adaptive output feedback control law, based on measurement of the tremor signal from the fingers of a patient, is formulated to estimate the stimulation amplitude required to control the tremor. By means of the proposed control strategy, an algorithm is developed for estimation of DBS parameters such as amplitude, frequency and pulse width, which provides a framework for development of an automatic clinical device for control of motor symptoms. The DBS parameter estimation results for the proposed control scheme are verified through numerical simulations. PMID- 23638162 TI - Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis--a longitudinal study. AB - BACKGROUND: The human gut microbiota has profound influence on host metabolism and immunity. This study characterized the fecal microbiota in patients with nonalcoholic steatohepatitis (NASH). The relationship between microbiota changes and changes in hepatic steatosis was also studied. METHODS: Fecal microbiota of histology-proven NASH patients and healthy controls was analyzed by 16S ribosomal RNA pyrosequencing. NASH patients were from a previously reported randomized trial on probiotic treatment. Proton-magnetic resonance spectroscopy was performed to monitor changes in intrahepatic triglyceride content (IHTG). RESULTS: A total of 420,344 16S sequences with acceptable quality were obtained from 16 NASH patients and 22 controls. NASH patients had lower fecal abundance of Faecalibacterium and Anaerosporobacter but higher abundance of Parabacteroides and Allisonella. Partial least-square discriminant analysis yielded a model of 10 genera that discriminated NASH patients from controls. At month 6, 6 of 7 patients in the probiotic group and 4 of 9 patients in the usual care group had improvement in IHTG (P=0.15). Improvement in IHTG was associated with a reduction in the abundance of Firmicutes (R(2)=0.4820, P=0.0028) and increase in Bacteroidetes (R(2)=0.4366, P=0.0053). This was accompanied by corresponding changes at the class, order and genus levels. In contrast, bacterial biodiversity did not differ between NASH patients and controls, and did not change with probiotic treatment. CONCLUSIONS: NASH patients have fecal dysbiosis, and changes in microbiota correlate with improvement in hepatic steatosis. Further studies are required to investigate the mechanism underlying the interaction between gut microbes and the liver. PMID- 23638164 TI - The impact and desirability of news of risk for schizophrenia. AB - In studies of schizotypy, investigators seldom inform participants that they are engaged in research designed to shed light on risk for schizophrenia. Such nondisclosure is justified in part by the argument that disclosure of risk status may be harmful. However, there is little evidence that this is the case. Harm arising from disclosure of risk status was examined in two experiments. In the first, participants (n = 114 psychology undergraduates) were asked to anticipate their reactions to news of risk for schizophrenia, depression, cancer, and diabetes, and also to indicate whether they would want to know their schizophrenia risk status. Participants anticipated schizophrenia risk would have a negative impact that was significantly greater than depression or diabetes risk but similar to cancer risk. The anticipated impact of schizophrenia risk was predicted by expectations of stigmatization as well as confidence in the accuracy of biological screening. Although 81% indicated a preference for knowing their risk status, just 11% were prepared to undergo an assessment to find out. In the second, a between-subjects deception paradigm was used to inform participants (n = 144 psychology undergraduates) they had an enzyme deficiency that placed them at increased risk for schizophrenia, cancer, or depression. Impact was assessed using prospective self-report and salivary cortisol and retrospective self report. Impact was modeled using measures of stigmatization and health locus of control. Retrospectively, schizophrenia, cancer, and depression risk had strong negative impacts relative to a control group, but there was no effect on prospective measures. Together, the findings suggest that news of risk for schizophrenia has the potential to engender distress, although participants' anticipations and reflections of responses are not corroborated in prospectively measured outcomes. PMID- 23638165 TI - Complex genetic architecture of cardiac disease in a wild type inbred strain of Drosophila melanogaster. AB - Natural populations of the fruit fly, Drosophila melanogaster, segregate genetic variation that leads to cardiac disease phenotypes. One nearly isogenic line from a North Carolina peach orchard, WE70, is shown to harbor two genetically distinct heart phenotypes: elevated incidence of arrhythmias, and a dramatically constricted heart diameter in both diastole and systole, with resemblance to restrictive cardiomyopathy in humans. Assuming the source to be rare variants of large effect, we performed Bulked Segregant Analysis using genomic DNA hybridization to Affymetrix chips to detect single feature polymorphisms, but found that the mutant phenotypes are more likely to have a polygenic basis. Further mapping efforts revealed a complex architecture wherein the constricted cardiomyopathy phenotype was observed in individual whole chromosome substitution lines, implying that variants on both major autosomes are sufficient to produce the phenotype. A panel of 170 Recombinant Inbred Lines (RIL) was generated, and a small subset of mutant lines selected, but these each complemented both whole chromosome substitutions, implying a non-additive (epistatic) contribution to the "disease" phenotype. Low coverage whole genome sequencing was also used to attempt to map chromosomal regions contributing to both the cardiomyopathy and arrhythmia, but a polygenic architecture had to be again inferred to be most likely. These results show that an apparently simple rare phenotype can have a complex genetic basis that would be refractory to mapping by deep sequencing in pedigrees. We present this as a cautionary tale regarding assumptions related to attempts to map new disease mutations on the assumption that probands carry a single causal mutation. PMID- 23638166 TI - Cholesterol depletion disorganizes oocyte membrane rafts altering mouse fertilization. AB - Drastic membrane reorganization occurs when mammalian sperm binds to and fuses with the oocyte membrane. Two oocyte protein families are essential for fertilization, tetraspanins and glycosylphosphatidylinositol-anchored proteins. The firsts are associated to tetraspanin-enriched microdomains and the seconds to lipid rafts. Here we report membrane raft involvement in mouse fertilization assessed by cholesterol modulation using methyl-beta-cyclodextrin. Cholesterol removal induced: (1) a decrease of the fertilization rate and index; and (2) a delay in the extrusion of the second polar body. Cholesterol repletion recovered the fertilization ability of cholesterol-depleted oocytes, indicating reversibility of these effects. In vivo time-lapse analyses using fluorescent cholesterol permitted to identify the time-point at which the probe is mainly located at the plasma membrane enabling the estimation of the extent of the cholesterol depletion. We confirmed that the mouse oocyte is rich in rafts according to the presence of the raft marker lipid, ganglioside GM1 on the membrane of living oocytes and we identified the coexistence of two types of microdomains, planar rafts and caveolae-like structures, by terms of two differential rafts markers, flotillin-2 and caveolin-1, respectively. Moreover, this is the first report that shows characteristic caveolae-like invaginations in the mouse oocyte identified by electron microscopy. Raft disruption by cholesterol depletion disturbed the subcellular localization of the signal molecule c-Src and the inhibition of Src kinase proteins prevented second polar body extrusion, consistent with a role of Src-related kinases in fertilization via signaling complexes. Our data highlight the functional importance of intact membrane rafts for mouse fertilization and its dependence on cholesterol. PMID- 23638168 TI - Improving but inferior survival in patients with chronic lymphocytic leukemia in taiwan: a population-based study, 1990-2004. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is much less prevalent in Asian countries. Whether there are differences in survival outcomes between the East and West, however, remain unclear. METHODS: The survival data for CLL patients identified in the Taiwan Cancer Registry database between 1990 and 2004, together with corresponding data in the US Surveillance, Epidemiology, and End Results database, were retrieved. The relative survivals (RS, adjusted for the expected survival in the general population) were estimated in patients diagnosed in three 5-year periods of time. RESULTS: CLL drastically shortened patients' life expectancy; more importantly, this negative impact in Taiwan was much larger than that in the US: the 5-year RS in Taiwan and US were 59% and 76%, and the 10-year RS, 45% and 56%, respectively. Nevertheless, survival in Taiwan was better in the periods after 1995 (5-year RS, from 53.0% to 60.6%), a time period corresponding to the introduction of the Taiwan National Health Insurance scheme. Such improvement was largely due to decreased mortality in patients younger than 65 (5 year RS, from 53.5% to 69.1%). Despite the improvement, patients' RS in Taiwan in recent periods remain steadily 15~20% inferior to that in the US in both younger and older patient groups. CONCLUSIONS: The improved RS in Taiwan implies that therapeutic advances are changing the prognosis of CLL. The stable RS gap between Taiwanese and the US patients suggests the existence of an ethnic difference in CLL patients' outcomes. PMID- 23638169 TI - DETECT: a MATLAB toolbox for event detection and identification in time series, with applications to artifact detection in EEG signals. AB - Recent advances in sensor and recording technology have allowed scientists to acquire very large time-series datasets. Researchers often analyze these datasets in the context of events, which are intervals of time where the properties of the signal change relative to a baseline signal. We have developed DETECT, a MATLAB toolbox for detecting event time intervals in long, multi-channel time series. Our primary goal is to produce a toolbox that is simple for researchers to use, allowing them to quickly train a model on multiple classes of events, assess the accuracy of the model, and determine how closely the results agree with their own manual identification of events without requiring extensive programming knowledge or machine learning experience. As an illustration, we discuss application of the DETECT toolbox for detecting signal artifacts found in continuous multi-channel EEG recordings and show the functionality of the tools found in the toolbox. We also discuss the application of DETECT for identifying irregular heartbeat waveforms found in electrocardiogram (ECG) data as an additional illustration. PMID- 23638167 TI - Transcriptome analysis of buds and leaves using 454 pyrosequencing to discover genes associated with the biosynthesis of active ingredients in Lonicera japonica Thunb. AB - BACKGROUND: Lonicera japonica Thunb. is a plant used in traditional Chinese medicine known for its anti-inflammatory, anti-oxidative, anti-carcinogenic, and antiviral pharmacological properties. The major active secondary metabolites of this plant are chlorogenic acid (CGA) and luteoloside. While the biosynthetic pathways of these metabolites are relatively well known, the genetic information available for this species, especially the biosynthetic pathways of its active ingredients, is limited. METHODOLOGY/PRINCIPAL FINDINGS: We obtained one million reads (average length of 400 bp) in a whole sequence run using a Roche/454 GS FLX titanium platform. Altogether, 85.69% of the unigenes covering the entire life cycle of the plant were annotated and 325 unigenes were assigned to secondary metabolic pathways. Moreover, 2039 unigenes were predicted as transcription factors. Nearly all of the possible enzymes involved in the biosynthesis of CGA and luteoloside were discovered in L. japonica. Three hydroxycinnamoyl transferase genes, including two hydroxycinnamoyl-CoA quinate hydroxycinnamoyl transferase genes and one hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyl transferase (HCT) gene featuring high similarity to known genes from other species, were cloned. The HCT gene was discovered for the first time in L. japonica. In addition, 188 candidate cytochrome P450 unigenes and 245 glycosyltransferase unigenes were found in the expressed sequence tag (EST) dataset. CONCLUSION: This study provides a high quality EST database for L. japonica by 454 pyrosequencing. Based on the EST annotation, a set of putative genes involved in CGA and luteoloside biosynthetic pathways were discovered. The database serves as an important source of public information on genetic markers, gene expression, genomics, and functional genomics in L. japonica. PMID- 23638170 TI - Arf1 and membrane curvature cooperate to recruit Arfaptin2 to liposomes. AB - Arfaptin2 contains a Bin/Amphiphysin/Rvs (BAR) domain and directly interacts with proteins of the Arf/Arl family in their active GTP-bound state. It has been proposed that BAR domains are able to sense membrane curvature and to induce membrane tubulation. We report here that active Arf1 is required for the recruitment of Arfaptin2 to artificial liposomes mimicking the Golgi apparatus lipid composition. The Arf1-dependent recruitment of Arfaptin2 increases with membrane curvature, while the recruitment of Arf1 itself is not sensitive to curvature. At high protein concentrations, the binding of Arfaptin2 induces membrane tubulation. Finally, membrane-bound Arfaptin2 is released from the liposome when ArfGAP1 catalyzes the hydrolysis of GTP to GDP in Arf1. These results show that both Arf1 activation and high membrane curvature are required for efficient recruitment of Arfaptin2 to membranes. PMID- 23638172 TI - Legionella pneumophila infection of Drosophila S2 cells induces only minor changes in mitochondrial dynamics. AB - During infection of cells by Legionella pneumophila, the bacterium secretes a large number of effector proteins into the host cell cytoplasm, allowing it to alter many cellular processes and make the vacuole and the host cell into more hospitable environments for bacterial replication. One major change induced by infection is the recruitment of ER-derived vesicles to the surface of the vacuole, where they fuse with the vacuole membrane and prevent it from becoming an acidified, degradative compartment. However, the recruitment of mitochondria to the region of the vacuole has also been suggested by ultrastructural studies. In order to test this idea in a controlled and quantitative experimental system, and to lay the groundwork for a genome-wide screen for factors involved in mitochondrial recruitment, we examined the behavior of mitochondria during the early stages of Legionella pneumophila infection of Drosophila S2 cells. We found that the density of mitochondria near vacuoles formed by infection with wild type Legionella was not different from that found in dotA(-) mutant-infected cells during the first 4 hours after infection. We then examined 4 parameters of mitochondrial motility in infected cells: velocity of movement, duty cycle of movement, directional persistence and net direction. In the 4 hours following infection, most of these measures were indistinguishable between wild type and dotA(-).infection. However, wild type Legionella did induce a modest shift in the velocity distribution toward faster movement compared dotA(-) infection, and a small downward shift in the duty cycle distribution. In addition, wild type infection produced mitochondrial movement that was biased in the direction of the bacterial vacuole relative to dotA-, although not enough to cause a significant accumulation within 10 um of the vacuole. We conclude that in this host cell, mitochondria are not strongly recruited to the vacuole, nor is their motility dramatically affected. PMID- 23638171 TI - New insights into the population structure of Anopheles gambiae s.s. in the Gulf of Guinea Islands revealed by Herves transposable elements. AB - Transposable elements (TEs) are mobile portions of DNA that are able to replicate and spread in the genome of many organisms. TEs can be used as a means to insert transgenes in insects, being stably inherited throughout generations. Anopheles gambiae is the main vector of human malaria in Sub-Saharan Africa. Given the extraordinary burden this disease imposes, the mosquito became a choice target for genetic control approaches with the purpose of reducing malaria transmission. In this study, we investigated the abundance and distribution of Herves TE in An. gambiae s.s. from Cameroon and four islands in the Gulf of Guinea, in order to determine their genetic structure. We have detected a population subdivision between Equatorial Guinea islands and the islands of Sao Tome, Principe and mainland. This partitioning associates more with political rather than geographic boundaries, possibly reflecting different mainland source populations colonizing the islands. PMID- 23638173 TI - Identification and analysis of multi-protein complexes in placenta. AB - Placental malfunction induces pregnancy disorders which contribute to life threatening complications for both the mother and the fetus. Identification and characterization of placental multi-protein complexes is an important step to integratedly understand the protein-protein interaction networks in placenta which determine placental function. In this study, blue native/sodium dodecyl sulfate polyacrylamide gel electrophoresis (BN/SDS-PAGE) and Liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to screen the multi protein complexes in placenta. 733 unique proteins and 34 known and novel heterooligomeric multi-protein complexes including mitochondrial respiratory chain complexes, integrin complexes, proteasome complexes, histone complex, and heat shock protein complexes were identified. A novel protein complex, which involves clathrin and small conductance calcium-activated potassium (SK) channel protein 2, was identified and validated by antibody based gel shift assay, co immunoprecipitation and immunofluorescence staining. These results suggest that BN/SDS-PAGE, when integrated with LC-MS/MS, is a very powerful and versatile tool for the investigation of placental protein complexes. This work paves the way for deeper functional characterization of the placental protein complexes associated with pregnancy disorders. PMID- 23638174 TI - Using hormones to manage dairy cow fertility: the clinical and ethical beliefs of veterinary practitioners. AB - In the face of a steady decline in dairy cow fertility over several decades, using hormones to assist reproduction has become common. In the European Union, hormones are prescription-only medicines, giving veterinary practitioners a central role in their deployment. This study explored the clinical and ethical beliefs of practitioners, and provides data on their current prescribing practices. During 2011, 93 practitioners working in England completed a questionnaire (95% response rate). Of the 714 non-organic farms they attended, only 4 farms (0.6%) never used hormones to assist the insemination of lactating dairy cows. Practitioners agreed (>80%) that hormones improve fertility and farm businesses profitability. They also agreed (>80%) that if farmers are able to tackle management issues contributing to poor oestrus expression, then over a five year period these outcomes would both improve, relative to using hormones instead. If management issues are addressed instead of prescribing hormones, practitioners envisaged a less favourable outcome for veterinary practices profitability (p<0.01), but an improvement in genetic selection for fertility (p<0.01) and overall cow welfare (p<0.01). On farms making no efforts to address underlying management problems, long-term routine use at the start of breeding for timing artificial insemination or inducing oestrus was judged "unacceptable" by 69% and 48% of practitioners, respectively. In contrast, practitioners agreed (>= 90%) that both these types of use are acceptable, provided a period of time has been allowed to elapse during which the cow is observed for natural oestrus. Issues discussed include: weighing quality versus length of cow life, fiscal factors, legal obligations, and balancing the interests of all stakeholders, including the increasing societal demand for food. This research fosters debate and critical appraisal, contributes to veterinary ethics, and encourages the pro active development of professional codes of conduct. PMID- 23638175 TI - Molecular modeling of the human hemoglobin-haptoglobin complex sheds light on the protective mechanisms of haptoglobin. AB - Hemoglobin (Hb) plays a critical role in human physiological function by transporting O2. Hb is safe and inert within the confinement of the red blood cell but becomes reactive and toxic upon hemolysis. Haptoglobin (Hp) is an acute phase serum protein that scavenges Hb and the resulting Hb-Hp complex is subjected to CD163-mediated endocytosis by macrophages. The interaction between Hb and Hp is extraordinarily strong and largely irreversible. As the structural details of the human Hb-Hp complex are not yet available, this study reports for the first time on insights of the binding modalities and molecular details of the human Hb-Hp interaction by means of protein-protein docking. Furthermore, residues that are pertinent for complex formation were identified by computational alanine scanning mutagenesis. Results revealed that the surface of the binding interface of Hb-Hp is not flat and protrudes into each binding partner. It was also observed that the secondary structures at the Hb-Hp interface are oriented as coils and alpha-helices. When dissecting the interface in more detail, it is obvious that several tyrosine residues of Hb, particularly beta145Tyr, alpha42Tyr and alpha140Tyr, are buried in the complex and protected from further oxidative reactions. Such finding opens up new avenues for the design of Hp mimics which may be used as alternative clinical Hb scavengers. PMID- 23638177 TI - A multi-parametric imaging investigation of the response of C6 glioma xenografts to MLN0518 (tandutinib) treatment. AB - Angiogenesis, the development of new blood vessels, is essential for tumour growth; this process is stimulated by the secretion of numerous growth factors including platelet derived growth factor (PDGF). PDGF signalling, through its receptor platelet derived growth factor receptor (PDGFR), is involved in vessel maturation, stimulation of angiogenesis and upregulation of other angiogenic factors, including vascular endothelial growth factor (VEGF). PDGFR is a promising target for anti-cancer therapy because it is expressed on both tumour cells and stromal cells associated with the vasculature. MLN0518 (tandutinib) is a potent inhibitor of type III receptor tyrosine kinases that demonstrates activity against PDGFRalpha/beta, FLT3 and c-KIT. In this study a multi parametric MRI and histopathological approach was used to interrogate changes in vascular haemodynamics, structural response and hypoxia in C6 glioma xenografts in response to treatment with MLN0518. The doubling time of tumours in mice treated with MLN0518 was significantly longer than tumours in vehicle treated mice. The perfused vessel area, number of alpha smooth muscle actin positive vessels and hypoxic area in MLN0518 treated tumours were also significantly lower after 10 days treatment. These changes were not accompanied by alterations in vessel calibre or fractional blood volume as assessed using susceptibility contrast MRI. Histological assessment of vessel size and total perfused area did not demonstrate any change with treatment. Intrinsic susceptibility MRI did not reveal any difference in baseline R2* or carbogen-induced change in R2*. Dynamic contrast-enhanced MRI revealed anti-vascular effects of MLN0518 following 3 days treatment. Hypoxia confers chemo- and radio-resistance, and alongside PDGF, is implicated in evasive resistance to agents targeted against VEGF signalling. PDGFR antagonists may improve potency and efficacy of other therapeutics in combination. This study highlights the challenges of identifying appropriate quantitative imaging response biomarkers in heterogeneous models, particularly considering the multifaceted roles of angiogenic growth factors. PMID- 23638176 TI - Impact of different group 2 sigma factors on light use efficiency and high salt stress in the cyanobacterium Synechocystis sp. PCC 6803. AB - Sigma factors of RNA polymerase recognize promoters and have a central role in controlling transcription initiation and acclimation to changing environmental conditions. The cyanobacterium Synechocystis sp. PCC 6803 encodes four non essential group 2 sigma factors, SigB, SigC, SigD and SigE that closely resemble the essential SigA factor. Three out of four group 2 sigma factors were simultaneously inactivated and acclimation responses of the triple inactivation strains were studied. All triple inactivation strains grew slowly in low light, and our analysis suggests that the reason is a reduced capacity to adjust the perception of light. Simultaneous inactivation of SigB and SigD hampered growth also in high light. SigB is the most important group 2 sigma factor for salt acclimation, and elimination of all the other group 2 sigma factors slightly improved the salt tolerance of Synechocystis. Presence of only SigE allowed full salt acclimation including up-regulation of hspA and ggpS genes, but more slowly than SigB. Cells with only SigD acclimated to high salt but the acclimation processes differed from those of the control strain. Presence of only SigC prevented salt acclimation. PMID- 23638179 TI - Prevalence of antidepressant use during pregnancy in Denmark, a nation-wide cohort study. AB - AIM: The aim of this study was to assess the prevalence and patterns of exposure to antidepressants before, during and after pregnancy in a cohort including all pregnant women in Denmark between 1997 and 2010. METHODS: We performed a retrospective cohort study including 912 322 pregnancies. Information was retrieved from the Danish Birth Registry and The Register of Medicinal Product Statistics to identify women redeeming an antidepressant prescription during pregnancy. Exposure periods were based on standard treatment doses and dispensed pack sizes. RESULTS: We identified 19 740 pregnancies exposed to an antidepressant at some point during pregnancy. The rate of exposure increased from 0.2% in 1997 to 3.2% in 2010. We found that the rate of exposure was halved during the first 3 months of pregnancy. In contrast, we describe a clear increase in exposure after pregnancy among pre-delivery treatment-naive women. CONCLUSIONS: In spite of uncertainty concerning antidepressants' safety during pregnancy we find a 16-fold increase in exposure rates between 1997 and 2010. The rates describe a sharp decrease in exposure during pregnancy that is probably caused by physicians' hesitation to prescribe antidepressants and women's fear of unwanted effects on the unborn child. More studies are needed to clarify the consequences of antidepressant discontinuation during pregnancy. PMID- 23638178 TI - Growth-promoting role of the miR-106a~363 cluster in Ewing sarcoma. AB - MicroRNAs (miRs) have been identified as potent regulators of both normal development and the hallmarks of cancer. Targeting of microRNAs has been shown to have preclinical promise, and select miR-based therapies are now in clinical trials. Ewing Sarcoma is a biologically aggressive pediatric cancer with little change in clinical outcomes despite improved chemotherapeutic regimens. There is a substantial need for new therapies to improve Ewing Sarcoma outcomes and to prevent chemotherapy-related secondary sequelae. Most Ewing Sarcoma tumors are driven by the EWS/Fli-1 fusion oncoprotein, acting as a gain-of-function transcription factor causing dysregulation of a variety of targets, including microRNAs. Our previous studies, and those of others, have identified upregulation of miRs belonging to the related miR-17~92a, miR-106b~25, and miR 106a~363 clusters in Ewing Sarcoma. However, the functional consequences of this have not been characterized, nor has miR blockade been explored as an anti-cancer strategy in Ewing Sarcoma. To simulate a potential therapeutic approach, we examined the effects of blockade of these clusters, and their component miRs. Using colony formation as a read-out, we find that blockade of selected individual cluster component miRs, using specific inhibitors, has little or no effect. Combinatorial inhibition using miR "sponge" methodology, on the other hand, is inhibitory to colony formation, with blockade of whole clusters generally more effective than blockade of miR families. We show that a miR blocking sponge directed against the poorly characterized miR-106a~363 cluster is a particularly potent inhibitor of clonogenic growth in a subset of Ewing Sarcoma cell lines. We further identify upregulation of miR-15a as a downstream mechanism contributing to the miR-106a~363 sponge growth-inhibitory effect. Taken together, our studies provide support for a pro-oncogenic role of the miR-106a~363 cluster in Ewing Sarcoma, and identify miR-106a~363 blockade, as well as miR-15a replacement, as possible strategies for inhibition of Ewing Sarcoma growth. PMID- 23638181 TI - How we know it hurts: item analysis of written narratives reveals distinct neural responses to others' physical pain and emotional suffering. AB - People are often called upon to witness, and to empathize with, the pain and suffering of others. In the current study, we directly compared neural responses to others' physical pain and emotional suffering by presenting participants (n = 41) with 96 verbal stories, each describing a protagonist's physical and/or emotional experience, ranging from neutral to extremely negative. A separate group of participants rated "how much physical pain", and "how much emotional suffering" the protagonist experienced in each story, as well as how "vivid and movie-like" the story was. Although ratings of Pain, Suffering and Vividness were positively correlated with each other across stories, item-analyses revealed that each scale was correlated with activity in distinct brain regions. Even within regions of the "Shared Pain network" identified using a separate data set, responses to others' physical pain and emotional suffering were distinct. More broadly, item analyses with continuous predictors provided a high-powered method for identifying brain regions associated with specific aspects of complex stimuli - like verbal descriptions of physical and emotional events. PMID- 23638180 TI - Reduced radiation exposure for face transplant surgical planning computed tomography angiography. AB - OBJECTIVE: To test the hypothesis that wide area detector face transplant surgical planning CT angiograms with simulated lower radiation dose and iterative reconstruction (AIDR3D) are comparable in image quality to those with standard tube current and filtered back projection (FBP) reconstruction. MATERIALS AND METHODS: The sinograms from 320-detector row CT angiography of four clinical candidates for face transplantation were processed utilizing standard FBP, FBP with simulated 75, 62, and 50% tube current, and AIDR3D with corresponding dose reduction. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were measured at muscle, fat, artery, and vein. Image quality for each reconstruction strategy was assessed by two independent readers using a 4-point scale. RESULTS: Compared to FBP, the median SNR and CNR for AIDR3D images were higher at all sites for all 4 different tube currents. The AIDR3D with simulated 50% tube current achieved comparable SNR and CNR to FBP with standard dose (median muscle SNR: 5.77 vs. 6.23; fat SNR: 6.40 vs. 5.75; artery SNR: 43.8 vs. 45.0; vein SNR: 54.9 vs. 55.7; artery CNR: 38.1 vs. 38.6; vein CNR: 49.0 vs. 48.7; all p-values >0.19). The interobserver agreement in the image quality score was good (weighted kappa = 0.7). The overall score and the scores for smaller arteries were significantly lower when FBP with 50% dose reduction was used. The AIDR3D reconstruction images with 4 different simulated doses achieved a mean score ranging from 3.68 to 3.82 that were comparable to the scores from images reconstructed using FBP with original dose (3.68-3.77). CONCLUSIONS: Simulated radiation dose reduction applied to clinical CT angiography for face transplant planning suggests that AIDR3D allows for a 50% reduction in radiation dose, as compared to FBP, while preserving image quality. PMID- 23638182 TI - HIV-1 Env C2-V4 diversification in a slow-progressor infant reveals a flat but rugged fitness landscape. AB - Human immunodeficiency virus type-1 (HIV-1) fitness has been associated with virus entry, a process mediated by the envelope glycoprotein (Env). We previously described Env genetic diversification in a Zambian, subtype C infected, slow progressor child (1157i) in parallel with an evolving neutralizing antibody response. Because of the role the Variable-3 loop (V3) plays in transmission, cell tropism, neutralization sensitivity, and fitness, longitudinally isolated 1157i C2-V4 alleles were cloned into HIV-1NL4-3-eGFP and -DsRed2 infectious molecular clones. The fluorescent reporters allowed for dual-infection competitions between all patient-derived C2-V4 chimeras to quantify the effect of V3 diversification and selection on fitness. 'Winners' and 'losers' were readily discriminated among the C2-V4 alleles. Exceptional sensitivity for detection of subtle fitness differences was revealed through analysis of two alleles differing in a single synonymous amino acid. However, when the outcomes of N = 33 competitions were averaged for each chimera, the aggregate analysis showed that despite increasing diversification and divergence with time, natural selection of C2-V4 sequences in this individual did not appear to be producing a 'survival of the fittest' evolutionary pattern. Rather, we detected a relatively flat fitness landscape consistent with mutational robustness. Fitness outcomes were then correlated with individual components of the entry process. Env incorporation into particles correlated best with fitness, suggesting a role for Env avidity, as opposed to receptor/coreceptor affinity, in defining fitness. Nevertheless, biochemical analyses did not identify any step in HIV-1 entry as a dominant determinant of fitness. Our results lead us to conclude that multiple aspects of entry contribute to maintaining adequate HIV-1 fitness, and there is no surrogate analysis for determining fitness. The capacity for subtle polymorphisms in Env to nevertheless significantly impact viral fitness suggests fitness is best defined by head-to-head competition. PMID- 23638183 TI - Prognostic factors of melanoma patients with satellite or in-transit metastasis at the time of stage III diagnosis. AB - BACKGROUND: Prognosis of patients with loco-regional skin metastases has not been analyzed in detail and the presence or absence of concurrent lymph node metastasis represents the only established prognostic factor thus far. Most studies were limited to patients already presenting with skin lesions at the time of initial diagnosis. We aimed to analyze the impact of a broad penal of prognostic factors in patients with skin metastases at the time of first metastatic spread, including patients with synchronous lesions already present at the time of initial diagnosis, stage I/II patients with loco-regional recurrence and patients initially presenting with skin metastasis but unknown primary melanoma. PATIENTS AND METHODS: We investigated disease-specific survival of 380 patients treated at our department between 1996 and 2010 using Kaplan Meier survival probabilities and Cox-proportional hazard analysis. RESULTS: Five-year survival probability was 60.1% for patients with skin metastases only and 36.3% for those with synchronous nodal metastases. The number of involved nodes and a tumor thickness of at least 3 mm had independent negative impact on prognosis. A strong relationship was identified between the risk of death and the number of involved nodes. Neither ulceration nor the timing of the first occurrence of metastases as either in stage I/II patients, at the time of excision of the primary melanoma or initially in patients with unknown primary tumor, had additional effects on survival. CONCLUSION: Lymph node involvement was confirmed as the most important prognostic factor for melanoma patients with loco-regional skin metastasis including those with unknown primary tumor and stage I/II patients with skin recurrence. Consideration of the tumor thickness and of the number of involved lymph nodes instead of the exclusive differentiation into presence vs. absence of nodal disease may allow a more accurate prediction of prognosis for patients with satellite or in-transit metastases. PMID- 23638185 TI - Hemispheric specialization varies with EEG brain resting states and phase of menstrual cycle. AB - A growing body of behavioral studies has demonstrated that women's hemispheric specialization varies as a function of their menstrual cycle, with hemispheric specialization enhanced during their menstruation period. Our recent high-density electroencephalogram (EEG) study with lateralized emotional versus neutral words extended these behavioral results by showing that hemispheric specialization in men, but not in women under birth-control, depends upon specific EEG resting brain states at stimulus arrival, suggesting that hemispheric specialization may be pre-determined at the moment of the stimulus onset. To investigate whether EEG brain resting state for hemispheric specialization could vary as a function of the menstrual phase, we tested 12 right-handed healthy women over different phases of their menstrual cycle combining high-density EEG recordings and the same lateralized lexical decision paradigm with emotional versus neutral words. Results showed the presence of specific EEG resting brain states, associated with hemispheric specialization for emotional words, at the moment of the stimulus onset during the menstruation period only. These results suggest that the pre stimulus EEG pattern influencing hemispheric specialization is modulated by the hormonal state. PMID- 23638184 TI - Rapamycin inhibits IGF-1-mediated up-regulation of MDM2 and sensitizes cancer cells to chemotherapy. AB - The Murine Double Minute 2 (MDM2) protein is a key regulator of cell proliferation and apoptosis that acts primarily by inhibiting the p53 tumor suppressor. Similarly, the PI3-Kinase (PI3K)/AKT pathway is critical for growth factor-mediated cell survival. Additionally, it has been reported that AKT can directly phosphorylate and activate MDM2. In this study, we show that IGF-1 up regulates MDM2 protein levels in a PI3K/AKT-dependent manner. Inhibition of mTOR by rapamycin or expression of a dominant negative eukaryotic initiation factor 4E binding protein 1 (4EBP1) mutant protein, as well as ablation of eukaryotic initiation factor 4E (eIF4E), efficiently abolishes IGF-1-mediated up-regulation of MDM2. In addition, we show that rapamycin effectively inhibits MDM2 expression and sensitizes cancer cells to chemotherapy. Taken together, this study reveals a novel mechanism by which IGF-1 activates MDM2 via the mTOR pathway, and that pharmacologic inhibition of mTOR combined with chemotherapy may be more effective in treatment of a subset of cancers harboring increased MDM2 activation. PMID- 23638186 TI - Small GTPase Rab40c associates with lipid droplets and modulates the biogenesis of lipid droplets. AB - The subcellular location and cell biological function of small GTPase Rab40c in mammalian cells have not been investigated in detail. In this study, we demonstrated that the exogenously expressed GFP-Rab40c associates with lipid droplets marked by neutral lipid specific dye Oil red or Nile red, but not with the Golgi or endosomal markers. Further examination demonstrated that Rab40c is also associated with ERGIC-53 containing structures, especially under the serum starvation condition. Rab40c is increasingly recruited to the surface of lipid droplets during lipid droplets formation and maturation in HepG2 cells. Rab40c knockdown moderately decreases the size of lipid droplets, suggesting that Rab40c is involved in the biogenesis of lipid droplets. Stimulation for adipocyte differentiation increases the expression of Rab40c in 3T3-L1 cells. Rab40c interacts with TIP47, and is appositionally associated with TIP47-labeled lipid droplets. In addition, over-expression of Rab40c causes the clustering of lipid droplets independent of its GTPase activity, but completely dependent of the intact SOCS box domain of Rab40c. In addition, Rab40c displayed self-interaction as well as interaction with TIP47 and the SOCS box is essential for its ability to induce clustering of lipid droplets. Our results suggest that Rab40c is a novel Rab protein associated with lipid droplets, and is likely involved in modulating the biogenesis of lipid droplets. PMID- 23638188 TI - Norovirus P particle efficiently elicits innate, humoral and cellular immunity. AB - Norovirus (NoV) P domain complexes, the 24 mer P particles and the P dimers, induced effective humoral immunity, but their role in the cellular immune responses remained unclear. We reported here a study on cellular immune responses of the two P domain complexes in comparison with the virus-like particle (VLP) of a GII.4 NoV (VA387) in mice. The P domain complexes induced significant central memory CD4(+) T cell phenotypes (CD4(+) CD44(+) CD62L(+) CCR7(+)) and activated polyclonal CD4(+) T cells as shown by production of Interleukin (IL)-2, Interferon (IFN)-gamma, and Tumor Necrosis Factor (TNF)-alpha. Most importantly, VA387-specific CD4(+) T cell epitope induced a production of IFN-gamma, indicating an antigen-specific CD4(+) T cell response in P domain complex immunized mice. Furthermore, P domain complexes efficiently induced bone marrow derived dendritic cell (BMDC) maturation, evidenced by up-regulation of co stimulatory and MHC class II molecules, as well as production of IL-12 and IL 1beta. Finally, P domain complex-induced mature dendritic cells (DCs) elicited proliferation of specific CD4(+) T cells targeting VA387 P domain. Overall, we conclude that the NoV P domain complexes are efficiently presented by DCs to elicit not only humoral but also cellular immune responses against NoVs. Since the P particle is highly effective for both humoral and cellular immune responses and easily produced in Escherichia coli (E. coli), it is a good choice of vaccine against NoVs and a vaccine platform against other diseases. PMID- 23638187 TI - Involvement of CD244 in regulating CD4+ T cell immunity in patients with active tuberculosis. AB - CD244 (2B4) is a member of the signaling lymphocyte activation molecule (SLAM) family of immune cell receptors and it plays an important role in modulating NK cell and CD8(+) T cell immunity. In this study, we investigated the expression and function of CD244/2B4 on CD4(+) T cells from active TB patients and latent infection individuals. Active TB patients had significantly elevated CD244/2B4 expression on M. tuberculosis antigen-specific CD4(+) T cells compared with latent infection individuals. The frequencies of CD244/2B4-expressing antigen specific CD4(+) T cells were significantly higher in retreatment active TB patients than in new active TB patients. Compared with CD244/2B4-dull and -middle CD4(+) T cells, CD244/2B4-bright CD4(+) T cell subset had significantly reduced expression of IFN-gamma, suggesting that CD244/2B4 expression may modulate IFN gamma production in M. tuberculosis antigen-responsive CD4(+) T cells. Activation of CD244/2B4 signaling by cross-linking led to significantly decreased production of IFN-gamma. Blockage of CD244/2B4 signaling pathway of T cells from patients with active TB resulted in significantly increased production of IFN-gamma, compared with isotype antibody control. In conclusion, CD244/2B4 signaling pathway has an inhibitory role on M. tuberculosis antigen-specific CD4(+) T cell function. PMID- 23638189 TI - Correction: Antigenicity and Protective Efficacy of a Leishmania Amastigote specific Protein, Member of the Super-oxygenase Family, against Visceral Leishmaniasis. AB - [This corrects the article on p. e2148 in vol. 7.]. PMID- 23638190 TI - Neurocysticercosis-more than a neglected disease. PMID- 23638192 TI - Transcriptional profiling of the circulating immune response to lassa virus in an aerosol model of exposure. AB - Lassa virus (LASV) is a significant human pathogen that is endemic to several countries in West Africa. Infection with LASV leads to the development of hemorrhagic fever in a significant number of cases, and it is estimated that thousands die each year from the disease. Little is known about the complex immune mechanisms governing the response to LASV or the genetic determinants of susceptibility and resistance to infection. In the study presented here, we have used a whole-genome, microarray-based approach to determine the temporal host response in the peripheral blood mononuclear cells (PBMCs) of non-human primates (NHP) following aerosol exposure to LASV. Sequential sampling over the entire disease course showed that there are strong transcriptional changes of the immune response to LASV exposure, including the early induction of interferon-responsive genes and Toll-like receptor signaling pathways. However, this increase in early innate responses was coupled with a lack of pro-inflammatory cytokine response in LASV exposed NHPs. There was a distinct lack of cytokines such as IL1beta and IL23alpha, while immunosuppressive cytokines such as IL27 and IL6 were upregulated. Comparison of IRF/STAT1-stimulated gene expression with the viral load in LASV exposed NHPs suggests that mRNA expression significantly precedes viremia, and thus might be used for early diagnostics of the disease. Our results provide a transcriptomic survey of the circulating immune response to hemorrhagic LASV exposure and provide a foundation for biomarker identification to allow clinical diagnosis of LASV infection through analysis of the host response. PMID- 23638193 TI - Whole genome sequence of the Treponema Fribourg-Blanc: unspecified simian isolate is highly similar to the yaws subspecies. AB - BACKGROUND: Unclassified simian strain Treponema Fribourg-Blanc was isolated in 1966 from baboons (Papio cynocephalus) in West Africa. This strain was morphologically indistinguishable from T. pallidum ssp. pallidum or ssp. pertenue strains, and it was shown to cause human infections. METHODOLOGY/PRINCIPAL FINDINGS: To precisely define genetic differences between Treponema Fribourg Blanc (unclassified simian isolate, FB) and T. pallidum ssp. pertenue strains (TPE), a high quality sequence of the whole Fribourg-Blanc genome was determined with 454-pyrosequencing and Illumina sequencing platforms. Combined average coverage of both methods was greater than 500*. Restriction target sites (n = 1,773), identified in silico, of selected restriction enzymes within the Fribourg Blanc genome were verified experimentally and no discrepancies were found. When compared to the other three sequenced TPE genomes (Samoa D, CDC-2, Gauthier), no major genome rearrangements were found. The Fribourg-Blanc genome clustered with other TPE strains (especially with the TPE CDC-2 strain), while T. pallidum ssp. pallidum strains clustered separately as well as the genome of T. paraluiscuniculi strain Cuniculi A. Within coding regions, 6 deletions, 5 insertions and 117 substitutions differentiated Fribourg-Blanc from other TPE genomes. CONCLUSIONS/SIGNIFICANCE: The Fribourg-Blanc genome showed similar genetic characteristics as other TPE strains. Therefore, we propose to rename the unclassified simian isolate to Treponema pallidum ssp. pertenue strain Fribourg Blanc. Since the Fribourg-Blanc strain was shown to cause experimental infection in human hosts, non-human primates could serve as possible reservoirs of TPE strains. This could considerably complicate recent efforts to eradicate yaws. Genetic differences specific for Fribourg-Blanc could then contribute for identification of cases of animal-derived yaws infections. PMID- 23638191 TI - Single-reaction, multiplex, real-time rt-PCR for the detection, quantitation, and serotyping of dengue viruses. AB - BACKGROUND: Dengue fever results from infection with one or more of four different serotypes of dengue virus (DENV). Despite the widespread nature of this infection, available molecular diagnostics have significant limitations. The aim of this study was to develop a multiplex, real-time, reverse transcriptase-PCR (rRT-PCR) for the detection, quantitation, and serotyping of dengue viruses in a single reaction. METHODOLOGY/PRINCIPAL FINDINGS: An rRT-PCR assay targeting the 5' untranslated region and capsid gene of the DENV genome was designed using molecular beacons to provide serotype specificity. Using reference DENV strains, the assay was linear from 7.0 to 1.0 log10 cDNA equivalents/uL for each serotype. The lower limit of detection using genomic RNA was 0.3, 13.8, 0.8, and 12.4 cDNA equivalents/uL for serotypes 1-4, respectively, which was 6- to 275-fold more analytically sensitive than a widely used hemi-nested RT-PCR. Using samples from Nicaragua collected within the first five days of illness, the multiplex rRT-PCR was positive in 100% (69/69) of specimens that were positive by the hemi-nested assay, with full serotype agreement. Furthermore, the multiplex rRT-PCR detected DENV RNA in 97.2% (35/36) of specimens from Sri Lanka positive for anti-DENV IgM antibodies compared to just 44.4% (16/36) by the hemi-nested RT-PCR. No amplification was observed in 80 clinical samples sent for routine quantitative hepatitis C virus testing or when genomic RNA from other flaviviruses was tested. CONCLUSIONS/SIGNIFICANCE: This single-reaction, quantitative, multiplex rRT-PCR for DENV serotyping demonstrates superior analytical and clinical performance, as well as simpler workflow compared to the hemi-nested RT-PCR reference. In particular, this multiplex rRT-PCR detects viral RNA and provides serotype information in specimens collected more than five days after fever onset and from patients who had already developed anti-DENV IgM antibodies. The implementation of this assay in dengue-endemic areas has the potential to improve both dengue diagnosis and epidemiologic surveillance. PMID- 23638194 TI - Protective role of acetylsalicylic acid in experimental Trypanosoma cruzi infection: evidence of a 15-epi-lipoxin A4-mediated effect. AB - Chagas' disease, produced by Trypanosoma cruzi, affects more than 8 million people, producing approximately 10,000 deaths each year in Latin America. Migration of people from endemic regions to developed countries has expanded the risk of infection, transforming this disease into a globally emerging problem. PGE2 and other eicosanoids contribute to cardiac functional deficits after infection with T. cruzi. Thus, the inhibition of host cyclooxygenase (COX) enzyme emerges as a potential therapeutic target. In vivo studies about the effect of acetylsalicylic acid (ASA) upon T. cruzi infection are controversial, and always report the effect of ASA at a single dose. Therefore, we aimed to analyze the effect of ASA at different doses in an in vivo model of infection and correlate it with the production of arachidonic acid metabolites. ASA decreased mortality, parasitemia, and heart damage in T. cruzi (Dm28c) infected mice, at the low doses of 25 and 50 mg/Kg. However, this effect disappeared when the high ASA doses of 75 and 100 mg/Kg were used. We explored whether this observation was related to the metabolic shift toward the production of 5-lipoxygenase derivatives, and although we did not observe an increase in LTB4 production in infected RAW cells and mice infected, we did find an increase in 15-epi-LXA4 (an ASA-triggered lipoxin). We also found high levels of 15-epi-LXA4 in T. cruzi infected mice treated with the low doses of ASA, while the high ASA doses decreased 15-epi-LXA4 levels. Importantly, 15-epi-LXA4 prevented parasitemia, mortality, and cardiac changes in vivo and restored the protective role in the treatment with a high dose of ASA. This is the first report showing the production of ASA-triggered lipoxins in T. cruzi infected mice, which demonstrates the role of this lipid as an anti-inflammatory molecule in the acute phase of the disease. PMID- 23638196 TI - Dual African origins of global Aedes aegypti s.l. populations revealed by mitochondrial DNA. AB - BACKGROUND: Aedes aegypti is the primary global vector to humans of yellow fever and dengue flaviviruses. Over the past 50 years, many population genetic studies have documented large genetic differences among global populations of this species. These studies initially used morphological polymorphisms, followed later by allozymes, and most recently various molecular genetic markers including microsatellites and mitochondrial markers. In particular, since 2000, fourteen publications and four unpublished datasets have used sequence data from the NADH dehydrogenase subunit 4 mitochondrial gene to compare Ae. aegypti collections and collectively 95 unique mtDNA haplotypes have been found. Phylogenetic analyses in these many studies consistently resolved two clades but no comprehensive study of mtDNA haplotypes have been made in Africa, the continent in which the species originated. METHODS AND FINDINGS: ND4 haplotypes were sequenced in 426 Ae. aegypti s.l. from Senegal, West Africa and Kenya, East Africa. In Senegal 15 and in Kenya 7 new haplotypes were discovered. When added to the 95 published haplotypes and including 6 African Aedes species as outgroups, phylogenetic analyses showed that all but one Senegal haplotype occurred in a basal clade while most East African haplotypes occurred in a second clade arising from the basal clade. Globally distributed haplotypes occurred in both clades demonstrating that populations outside Africa consist of mixtures of mosquitoes from both clades. CONCLUSIONS: Populations of Ae. aegypti outside Africa consist of mosquitoes arising from one of two ancestral clades. One clade is basal and primarily associated with West Africa while the second arises from the first and contains primarily mosquitoes from East Africa. PMID- 23638195 TI - Development of novel prime-boost strategies based on a tri-gene fusion recombinant L. tarentolae vaccine against experimental murine visceral leishmaniasis. AB - Visceral leishmaniasis (VL) is a vector-borne disease affecting humans and domestic animals that constitutes a serious public health problem in many countries. Although many antigens have been examined so far as protein- or DNA based vaccines, none of them conferred complete long-term protection. The use of the lizard non-pathogenic to humans Leishmania (L.) tarentolae species as a live vaccine vector to deliver specific Leishmania antigens is a recent approach that needs to be explored further. In this study, we evaluated the effectiveness of live vaccination in protecting BALB/c mice against L. infantum infection using prime-boost regimens, namely Live/Live and DNA/Live. As a live vaccine, we used recombinant L. tarentolae expressing the L. donovani A2 antigen along with cysteine proteinases (CPA and CPB without its unusual C-terminal extension (CPB( CTE))) as a tri-fusion gene. For DNA priming, the tri-fusion gene was encoded in pcDNA formulated with cationic solid lipid nanoparticles (cSLN) acting as an adjuvant. At different time points post-challenge, parasite burden and histopathological changes as well as humoral and cellular immune responses were assessed. Our results showed that immunization with both prime-boost A2-CPA-CPB( CTE)-recombinant L. tarentolae protects BALB/c mice against L. infantum challenge. This protective immunity is associated with a Th1-type immune response due to high levels of IFN-gamma production prior and after challenge and with lower levels of IL-10 production after challenge, leading to a significantly higher IFN-gamma/IL-10 ratio compared to the control groups. Moreover, this immunization elicited high IgG1 and IgG2a humoral immune responses. Protection in mice was also correlated with a high nitric oxide production and low parasite burden. Altogether, these results indicate the promise of the A2-CPA-CPB(-CTE) recombinant L. tarentolae as a safe live vaccine candidate against VL. PMID- 23638198 TI - Prevalence of latent and active tuberculosis among dairy farm workers exposed to cattle infected by Mycobacterium bovis. AB - BACKGROUND: Human tuberculosis caused by M. bovis is a zoonosis presently considered sporadic in developed countries, but remains a poorly studied problem in low and middle resource countries. The disease in humans is mainly attributed to unpasteurized dairy products consumption. However, transmission due to exposure of humans to infected animals has been also recognized. The prevalence of tuberculosis infection and associated risk factors have been insufficiently characterized among dairy farm workers (DFW) exposed in settings with poor control of bovine tuberculosis. METHODOLOGY/PRINCIPAL FINDINGS: Tuberculin skin test (TST) and Interferon-gamma release assay (IGRA) were administered to 311 dairy farm and abattoir workers and their household contacts linked to a dairy production and livestock facility in Mexico. Sputa of individuals with respiratory symptoms and samples from routine cattle necropsies were cultured for M. bovis and resulting spoligotypes were compared. The overall prevalence of latent tuberculosis infection (LTBI) was 76.2% (95% CI, 71.4-80.9%) by TST and 58.5% (95% CI, 53.0-64.0%) by IGRA. Occupational exposure was associated to TST (OR 2.72; 95% CI, 1.31-5.64) and IGRA (OR 2.38; 95% CI, 1.31-4.30) adjusting for relevant variables. Two subjects were diagnosed with pulmonary tuberculosis, both caused by M. bovis. In one case, the spoligotype was identical to a strain isolated from bovines. CONCLUSIONS: We documented a high prevalence of latent and pulmonary TB among workers exposed to cattle infected with M. bovis, and increased risk among those occupationally exposed in non-ventilated spaces. Interspecies transmission is frequent and represents an occupational hazard in this setting. PMID- 23638197 TI - Mode of death on Chagas heart disease: comparison with other etiologies. a subanalysis of the REMADHE prospective trial. AB - BACKGROUND: Sudden death has been considered the main cause of death in patients with Chagas heart disease. Nevertheless, this information comes from a period before the introduction of drugs that changed the natural history of heart failure. We sought to study the mode of death of patients with heart failure caused by Chagas heart disease, comparing with non-Chagas cardiomyopathy. METHODS AND RESULTS: We examined the REMADHE trial and grouped patients according to etiology (Chagas vs non-Chagas) and mode of death. The primary end-point was all cause, heart failure and sudden death mortality; 342 patients were analyzed and 185 (54.1%) died. Death occurred in 56.4% Chagas patients and 53.7% non-Chagas patients. The cumulative incidence of all-cause mortality and heart failure mortality was significantly higher in Chagas patients compared to non-Chagas. There was no difference in the cumulative incidence of sudden death mortality between the two groups. In the Cox regression model, Chagas etiology (HR 2.76; CI 1.34-5.69; p = 0.006), LVEDD (left ventricular end diastolic diameter) (HR 1.07; CI 1.04-1.10; p<0.001), creatinine clearance (HR 0.98; CI 0.97-0.99; p = 0.006) and use of amiodarone (HR 3.05; CI 1.47-6.34; p = 0.003) were independently associated with heart failure mortality. LVEDD (HR 1.04; CI 1.01-1.07; p = 0.005) and use of beta-blocker (HR 0.52; CI 0.34-0.94; p = 0.014) were independently associated with sudden death mortality. CONCLUSIONS: In severe Chagas heart disease, progressive heart failure is the most important mode of death. These data challenge the current understanding of Chagas heart disease and may have implications in the selection of treatment choices, considering the mode of death. TRIAL REGISTRATION: ClinicalTrials.gov NCT00505050 (REMADHE). PMID- 23638199 TI - Viperin is induced following dengue virus type-2 (DENV-2) infection and has anti viral actions requiring the C-terminal end of viperin. AB - The host protein viperin is an interferon stimulated gene (ISG) that is up regulated during a number of viral infections. In this study we have shown that dengue virus type-2 (DENV-2) infection significantly induced viperin, co-incident with production of viral RNA and via a mechanism requiring retinoic acid inducible gene I (RIG-I). Viperin did not inhibit DENV-2 entry but DENV-2 RNA and infectious virus release was inhibited in viperin expressing cells. Conversely, DENV-2 replicated to higher tires earlier in viperin shRNA expressing cells. The anti-DENV effect of viperin was mediated by residues within the C-terminal 17 amino acids of viperin and did not require the N-terminal residues, including the helix domain, leucine zipper and S-adenosylmethionine (SAM) motifs known to be involved in viperin intracellular membrane association. Viperin showed co localisation with lipid droplet markers, and was co-localised and interacted with DENV-2 capsid (CA), NS3 and viral RNA. The ability of viperin to interact with DENV-2 NS3 was associated with its anti-viral activity, while co-localisation of viperin with lipid droplets was not. Thus, DENV-2 infection induces viperin which has anti-viral properties residing in the C-terminal region of the protein that act to restrict early DENV-2 RNA production/accumulation, potentially via interaction of viperin with DENV-2 NS3 and replication complexes. These anti-DENV 2 actions of viperin show both contrasts and similarities with other described anti-viral mechanisms of viperin action and highlight the diverse nature of this unique anti-viral host protein. PMID- 23638200 TI - LABCG2, a new ABC transporter implicated in phosphatidylserine exposure, is involved in the infectivity and pathogenicity of Leishmania. AB - Leishmaniasis is a neglected disease produced by the intracellular protozoan parasite Leishmania. In the present study, we show that LABCG2, a new ATP-binding cassette half-transporter (ABCG subfamily) from Leishmania, is involved in parasite virulence. Down-regulation of LABCG2 function upon expression of an inactive mutant version of this half-transporter (LABCG2(K/M)) is shown to reduce the translocation of short-chain analogues of phosphatidylserine (PS). This dominant-negative phenotype is specific for the headgroup of the phospholipid, as the movement of phospholipid analogues of phosphatidylcholine, phosphatidylethanolamine or sphingomyelin is not affected. In addition, promastigotes expressing LABCG2(K/M) expose less endogenous PS in the stationary phase than control parasites. Transient exposure of PS at the outer leaflet of the plasma membrane is known to be one of the mechanisms used by Leishmania to infect macrophages and to silence their immune response. Stationary phase/metacyclic promastigotes expressing LABCG2(K/M) are less infective for macrophages and show decreased pathogenesis in a mouse model of cutaneous leishmaniasis. Thus, mice infected with parasites expressing LABCG2(K/M) did not develop any lesion and showed significantly lower inflammation and parasite burden than mice infected with control parasites. Our results indicate that LABCG2 function is required for the externalization of PS in Leishmania promastigotes, a process that is involved in the virulence of the parasite. PMID- 23638201 TI - False positivity of non-targeted infections in malaria rapid diagnostic tests: the case of human african trypanosomiasis. AB - BACKGROUND: In endemic settings, diagnosis of malaria increasingly relies on the use of rapid diagnostic tests (RDTs). False positivity of such RDTs is poorly documented, although it is especially relevant in those infections that resemble malaria, such as human African trypanosomiasis (HAT). We therefore examined specificity of malaria RDT products among patients infected with Trypanosoma brucei gambiense. METHODOLOGY/PRINCIPAL FINDINGS: Blood samples of 117 HAT patients and 117 matched non-HAT controls were prospectively collected in the Democratic Republic of the Congo. Reference malaria diagnosis was based on real time PCR. Ten commonly used malaria RDT products were assessed including three two-band and seven three-band products, targeting HRP-2, Pf-pLDH and/or pan-pLDH antigens. Rheumatoid factor was determined in PCR negative subjects. Specificity of the 10 malaria RDT products varied between 79.5 and 100% in HAT-negative controls and between 11.3 and 98.8% in HAT patients. For seven RDT products, specificity was significantly lower in HAT patients compared to controls. False positive reactions in HAT were mainly observed for pan-pLDH test lines (specificities between 13.8 and 97.5%), but also occurred frequently for the HRP 2 test line (specificities between 67.9 and 98.8%). The Pf-pLDH test line was not affected by false-positive lines in HAT patients (specificities between 97.5 and 100%). False positivity was not associated to rheumatoid factor, detected in 7.6% of controls and 1.2% of HAT patients. CONCLUSIONS/SIGNIFICANCE: Specificity of some malaria RDT products in HAT was surprisingly low, and constitutes a risk for misdiagnosis of a fatal but treatable infection. Our results show the importance to assess RDT specificity in non-targeted infections when evaluating diagnostic tests. PMID- 23638202 TI - Characterization of Rift Valley fever virus MP-12 strain encoding NSs of Punta Toro virus or sandfly fever Sicilian virus. AB - Rift Valley fever virus (RVFV; genus Phlebovirus, family Bunyaviridae) is a mosquito-borne zoonotic pathogen which can cause hemorrhagic fever, neurological disorders or blindness in humans, and a high rate of abortion in ruminants. MP-12 strain, a live-attenuated candidate vaccine, is attenuated in the M- and L segments, but the S-segment retains the virulent phenotype. MP-12 was manufactured as an Investigational New Drug vaccine by using MRC-5 cells and encodes a functional NSs gene, the major virulence factor of RVFV which 1) induces a shutoff of the host transcription, 2) inhibits interferon (IFN)-beta promoter activation, and 3) promotes the degradation of dsRNA-dependent protein kinase (PKR). MP-12 lacks a marker for differentiation of infected from vaccinated animals (DIVA). Although MP-12 lacking NSs works for DIVA, it does not replicate efficiently in type-I IFN-competent MRC-5 cells, while the use of type I IFN-incompetent cells may negatively affect its genetic stability. To generate modified MP-12 vaccine candidates encoding a DIVA marker, while still replicating efficiently in MRC-5 cells, we generated recombinant MP-12 encoding Punta Toro virus Adames strain NSs (rMP12-PTNSs) or Sandfly fever Sicilian virus NSs (rMP12 SFSNSs) in place of MP-12 NSs. We have demonstrated that those recombinant MP-12 viruses inhibit IFN-beta mRNA synthesis, yet do not promote the degradation of PKR. The rMP12-PTNSs, but not rMP12-SFSNSs, replicated more efficiently than recombinant MP-12 lacking NSs in MRC-5 cells. Mice vaccinated with rMP12-PTNSs or rMP12-SFSNSs induced neutralizing antibodies at a level equivalent to those vaccinated with MP-12, and were efficiently protected from wild-type RVFV challenge. The rMP12-PTNSs and rMP12-SFSNSs did not induce antibodies cross reactive to anti-RVFV NSs antibody and are therefore applicable to DIVA. Thus, rMP12-PTNSs is highly efficacious, replicates efficiently in MRC-5 cells, and encodes a DIVA marker, all of which are important for vaccine development for Rift Valley fever. PMID- 23638203 TI - Factors associated with visceral leishmaniasis in the americas: a systematic review and meta-analysis. AB - BACKGROUND: Still today, more than 30 years after the beginning of the process of visceral leishmaniasis' urbanization, there is little knowledge about the risk factors for its occurrence, despite their relevance to the control and understanding of disease dynamics. The present study is the first systematic review with meta-analysis about factors associated with Leishmania infantum infection in humans in the Americas. METHODS AND FINDINGS: After searching different databases, consultations to the reference lists of articles and to experts in the field, 51 studies were reviewed. Theoretical discussions or meta analysis of p-values or of effect sizes were used to pool information about each variable. The Q test and the I(2) statistic were used to assess heterogeneities among the studies. Male sex was associated with visceral leishmaniasis in studies which used the leishmanin skin test for diagnosis and in those where the outcome was the clinical disease; the opposite occurred when serological diagnosis was applied. Younger individuals were less frequently infected than adults, but were more prone to illness. Although with different levels of evidence and of heterogeneity, the presence of dogs at home, higher dog seropositivity in nearby areas, lower socioeconomic status and highly vegetated areas were associated with L. infantum infection. This was not noticed for the presence of chickens in the house and with nutritional status. Susceptibilities to bias and limitations in the analysis and in the description of results were often identified in the studies analyzed. CONCLUSIONS: Results showed the existence of consistent patterns for some of the factors analyzed and should be taken into account in developing more effective and well-targeted control measures. Studies must be conducted in new areas of the continent, with improved methodological quality and prioritizing the investigation of the patterns identified and their causes, as well as variables for which knowledge is poor. PMID- 23638204 TI - Phage therapy is effective against infection by Mycobacterium ulcerans in a murine footpad model. AB - BACKGROUND: Buruli Ulcer (BU) is a neglected, necrotizing skin disease caused by Mycobacterium ulcerans. Currently, there is no vaccine against M. ulcerans infection. Although the World Health Organization recommends a combination of rifampicin and streptomycin for the treatment of BU, clinical management of advanced stages is still based on the surgical resection of infected skin. The use of bacteriophages for the control of bacterial infections has been considered as an alternative or to be used in association with antibiotherapy. Additionally, the mycobacteriophage D29 has previously been shown to display lytic activity against M. ulcerans isolates. METHODOLOGY/PRINCIPAL FINDINGS: We used the mouse footpad model of M. ulcerans infection to evaluate the therapeutic efficacy of treatment with mycobacteriophage D29. Analyses of macroscopic lesions, bacterial burdens, histology and cytokine production were performed in both M. ulcerans infected footpads and draining lymph nodes (DLN). We have demonstrated that a single subcutaneous injection of the mycobacteriophage D29, administered 33 days after bacterial challenge, was sufficient to decrease pathology and to prevent ulceration. This protection resulted in a significant reduction of M. ulcerans numbers accompanied by an increase of cytokine levels (including IFN-gamma), both in footpads and DLN. Additionally, mycobacteriophage D29 treatment induced a cellular infiltrate of a lymphocytic/macrophagic profile. CONCLUSIONS/SIGNIFICANCE: Our observations demonstrate the potential of phage therapy against M. ulcerans infection, paving the way for future studies aiming at the development of novel phage-related therapeutic approaches against BU. PMID- 23638205 TI - Second international diagnostic accuracy study for the serological detection of West Nile virus infection. AB - BACKGROUND: In recent decades, sporadic cases and outbreaks in humans of West Nile virus (WNV) infection have increased. Serological diagnosis of WNV infection can be performed by enzyme-linked immunosorbent assay (ELISA), immunofluorescence assay (IFA) neutralization test (NT) and by hemagglutination-inhibition assay. The aim of this study is to collect updated information regarding the performance accuracy of WNV serological diagnostics. METHODOLOGY/PRINCIPAL FINDINGS: In 2011, the European Network for the Diagnostics of Imported Viral Diseases-Collaborative Laboratory Response Network (ENIVD-CLRN) organized the second external quality assurance (EQA) study for the serological diagnosis of WNV infection. A serum panel of 13 samples (included sera reactive against WNV, plus specificity and negative controls) was sent to 48 laboratories involved in WNV diagnostics. Forty seven of 48 laboratories from 30 countries participated in the study. Eight laboratories achieved 100% of concurrent and correct results. The main obstacle in other laboratories to achieving similar performances was the cross-reactivity of antibodies amongst heterologous flaviviruses. No differences were observed in performances of in-house and commercial test used by the laboratories. IFA was significantly more specific compared to ELISA in detecting IgG antibodies. The overall analytical sensitivity and specificity of diagnostic tests for IgM detection were 50% and 95%, respectively. In comparison, the overall sensitivity and specificity of diagnostic tests for IgG detection were 86% and 69%, respectively. CONCLUSIONS/SIGNIFICANCE: This EQA study demonstrates that there is still need to improve serological tests for WNV diagnosis. The low sensitivity of IgM detection suggests that there is a risk of overlooking WNV acute infections, whereas the low specificity for IgG detection demonstrates a high level of cross reactivity with heterologous flaviviruses. PMID- 23638206 TI - Socio-economic and cultural determinants of human african trypanosomiasis at the Kenya - Uganda transboundary. AB - BACKGROUND: Kenya and Uganda have reported different Human African Trypanosomiasis incidences in the past more than three decades, with the latter recording more cases. This cross-sectional study assessed the demographic characteristics, tsetse and trypanosomiasis control practices, socio-economic and cultural risk factors influencing Trypanosoma brucei rhodesiense (T.b.r.) infection in Teso and Busia Districts, Western Kenya and Tororo and Busia Districts, Southeast Uganda. A conceptual framework was postulated to explain interactions of various socio-economic, cultural and tsetse control factors that predispose individuals and populations to HAT. METHODS: A cross-sectional household survey was conducted between April and October 2008. Four administrative districts reporting T.b.r and lying adjacent to each other at the international boundary of Kenya and Uganda were purposely selected. Household data collection was carried out in two villages that had experienced HAT and one other village that had no reported HAT case from 1977 to 2008 in each district. A structured questionnaire was administered to 384 randomly selected household heads or their representatives in each country. The percent of respondents giving a specific answer was reported. Secondary data was also obtained on socio economic and political issues in both countries. RESULTS: Inadequate knowledge on the disease cycle and intervention measures contributed considerable barriers to HAT, and more so in Uganda than in Kenya. Gender-associated socio-cultural practices greatly predisposed individuals to HAT. Pesticides-based crop husbandry in the 1970's reportedly reduced vector population while vegetation of coffee and banana's and livestock husbandry directly increased occurrence of HAT. Livestock husbandry practices in the villages were strong predictors of HAT incidence. The residents in Kenya (6.7%) applied chemoprophylaxis and chemotherapeutic controls against trypanosomiasis to a larger extent than Uganda (2.1%). CONCLUSION: Knowledge on tsetse and its control methods, culture, farming practice, demographic and socio-economic variables explained occurrence of HAT better than landscape features. PMID- 23638207 TI - Phlebotomus orientalis sand flies from two geographically distant Ethiopian localities: biology, genetic analyses and susceptibility to Leishmania donovani. AB - BACKGROUND: Phlebotomus orientalis Parrot (Diptera: Psychodidae) is the main vector of visceral leishmaniasis (VL) caused by Leishmania donovani in East Africa. Here we report on life cycle parameters and susceptibility to L. donovani of two P. orientalis colonies originating from different sites in Ethiopia: a non endemic site in the lowlands - Melka Werer (MW), and an endemic focus of human VL in the highlands - Addis Zemen (AZ). METHODOLOGY/PRINCIPAL FINDINGS: Marked differences in life-cycle parameters between the two colonies included distinct requirements for larval food and humidity during pupation. However, analyses using Random Amplified Polymorphic DNA (RAPD) PCR and DNA sequencing of cytB and COI mitochondrial genes did not reveal any genetic differences. F1 hybrids developed successfully with higher fecundity than the parental colonies. Susceptibility of P. orientalis to L. donovani was studied by experimental infections. Even the lowest infective dose tested (2*10(3) per ml) was sufficient for successful establishment of L. donovani infections in about 50% of the P. orientalis females. Using higher infective doses, the infection rates were around 90% for both colonies. Leishmania development in P. orientalis was fast, the presence of metacyclic promastigotes in the thoracic midgut and the colonization of the stomodeal valve by haptomonads were recorded in most P. orientalis females by day five post-blood feeding. CONCLUSIONS: Both MW and AZ colonies of P. orientalis were highly susceptible to Ethiopian L. donovani strains. As the average volume of blood-meals taken by P. orientalis females are about 0.7 ul, the infective dose at the lowest concentration was one or two L. donovani promastigotes per sand fly blood-meal. The development of L. donovani was similar in both P. orientalis colonies; hence, the absence of visceral leishmaniasis in non-endemic area Melka Werer cannot be attributed to different susceptibility of local P. orientalis populations to L. donovani. PMID- 23638208 TI - Fluctuations at a low mean temperature accelerate dengue virus transmission by Aedes aegypti. AB - BACKGROUND: Environmental factors such as temperature can alter mosquito vector competence for arboviruses. Results from recent studies indicate that daily fluctuations around an intermediate mean temperature (26 degrees C) reduce vector competence of Aedes aeygpti for dengue viruses (DENV). Theoretical predictions suggest that the mean temperature in combination with the magnitude of the diurnal temperature range (DTR) mediate the direction of these effects. METHODOLOGY/PRINCIPAL FINDINGS: We tested the effect of temperature fluctuations on Ae. aegypti vector competence for DENV serotype-1 at high and low mean temperatures, and confirmed this theoretical prediction. A small DTR had no effect on vector competence around a high (30 degrees C) mean, but a large DTR at low temperature (20 degrees C) increased the proportion of infected mosquitoes with a disseminated infection by 60% at 21 and 28 days post-exposure compared to a constant 20 degrees C. This effect resulted from a marked shortening of DENV extrinsic incubation period (EIP) in its mosquito vector; i.e., a decrease from 29.6 to 18.9 days under the fluctuating vs. constant temperature treatment. CONCLUSIONS: Our results indicate that Ae. aegypti exposed to large fluctuations at low temperatures have a significantly shorter virus EIP than under constant temperature conditions at the same mean, leading to a considerably greater potential for DENV transmission. These results emphasize the value of accounting for daily temperature variation in an effort to more accurately understand and predict the risk of mosquito-borne pathogen transmission, provide a mechanism for sustained DENV transmission in endemic areas during cooler times of the year, and indicate that DENV transmission could be more efficient in temperate regions than previously anticipated. PMID- 23638209 TI - Factors affecting the propensity of tsetse flies to enter houses and attack humans inside: increased risk of sleeping sickness in warmer climates. AB - BACKGROUND: Sleeping sickness, or human African trypanosomiasis, is caused by two species of Trypanosoma brucei that are transmitted to humans by tsetse flies (Glossina spp.) when these insects take a bloodmeal. It is commonly assumed that humans must enter the normal woodland habitat of the flies to become infected, but recent studies found that tsetse frequently attack humans inside buildings. Factors affecting human/tsetse contact in buildings need identification. METHODOLOGY/PRINCIPAL FINDINGS: In Zimbabwe, tsetse were allowed access to a house via an open door. Those in the house at sunset, and those alighting on humans in the house during the day, were caught using hand-nets. Total catches were unaffected by: (i) the presence of humans in the house and at the door, (ii) wood smoke from a fire inside the house or just outside, (iii) open windows, and (iv) chemicals simulating the odor of cattle or of humans. Catches increased about 10-fold with rising ambient temperatures, and during the hottest months the proportion of the total catch that was taken from the humans increased from 5% to 13%. Of the tsetse caught from humans, 62% consisted of female G. morsitans morstans and both sexes of G. pallidipes, i.e., the group of tsetse that normally alight little on humans. Some of the tsetse caught were old enough to be effective vectors. CONCLUSION/SIGNIFICANCE: Present results confirm previous suggestions that buildings provide a distinctive and important venue for transmission of sleeping sickness, especially since the normal repellence of humans and smoke seems poorly effective in such places. The importance of the venue would be increased in warmer climates. PMID- 23638210 TI - Mechanisms involved in the nociception triggered by the venom of the armed spider Phoneutria nigriventer. AB - BACKGROUND: The frequency of accidental spider bites in Brazil is growing, and poisoning due to bites from the spider genus Phoneutria nigriventer is the second most frequent source of such accidents. Intense local pain is the major symptom reported after bites of P. nigriventer, although the mechanisms involved are still poorly understood. Therefore, the aim of this study was to identify the mechanisms involved in nociception triggered by the venom of Phoneutria nigriventer (PNV). METHODOLOGY/PRINCIPAL FINDINGS: Twenty microliters of PNV or PBS was injected into the mouse paw (intraplantar, i.pl.). The time spent licking the injected paw was considered indicative of the level of nociception. I.pl. injection of PNV produced spontaneous nociception, which was reduced by arachnid antivenin (ArAv), local anaesthetics, opioids, acetaminophen and dipyrone, but not indomethacin. Boiling or dialysing the venom reduced the nociception induced by the venom. PNV-induced nociception is not dependent on glutamate or histamine receptors or on mast cell degranulation, but it is mediated by the stimulation of sensory fibres that contain serotonin 4 (5-HT4) and vanilloid receptors (TRPV1). We detected a kallikrein-like kinin-generating enzyme activity in tissue treated with PNV, which also contributes to nociception. Inhibition of enzymatic activity or administration of a receptor antagonist for kinin B2 was able to inhibit the nociception induced by PNV. PNV nociception was also reduced by the blockade of tetrodotoxin-sensitive Na(+) channels, acid-sensitive ion channels (ASIC) and TRPV1 receptors. CONCLUSION/SIGNIFICANCE: Results suggest that both low- and high molecular-weight toxins of PNV produce spontaneous nociception through direct or indirect action of kinin B2, TRPV1, 5-HT4 or ASIC receptors and voltage-dependent sodium channels present in sensory neurons but not in mast cells. Understanding the mechanisms involved in nociception caused by PNV are of interest not only for better treating poisoning by P. nigriventer but also appreciating the diversity of targets triggered by PNV toxins. PMID- 23638212 TI - Unusual extrahepatic metastatic sites from hepatocellular carcinoma. AB - The author examined unusual extrahepatic metastatic sites from liver hepatocellular carcinomas (HCCs) in autopsy and surgical files at our laboratory in the last 10 years. In autopsy cases (n=31), extrahepatic metastases were present in 21 cases (68%). The most common metastatic sites were lung (n=18). Unusual extrahepatic metastatic sites in the autopsy series were abdominal regional lymph nodes (n=6), bones (n=5), diaphragma (n=2), pancreas (n=2), gall bladder (n=1), stomach (n=1), colon (n=1), adrenal gland (n=1), pleura (n=1), peritoneum (n=1), cervical lymph nodes (n=1), and shoulder soft tissue (n=1). In surgical cases (n=21), in which extrahepatic tumors were excised, the lung was the most common, and accounted for 16 cases. The unusual extrahepatic metastatic sites in the surgical series were bones (n=2), brain (n=1), skin (n=1), and oral cavity (n=1). Immunohistochemical demonstration of HepPar1 and AFP were recognized in 12 of 12 surgical cases examined and 8 of the 12 surgical cases examined, respectively. Cytokeratin 8 and 18 were expressed in 6 of 6 surgical cases and 7 of 7 surgical cases examined. These data shows that HCC can metastasize in various organs other than the lung, and HepPar1 and AFP were good markers of extrahepatic metastases of these unusual sites of metastatic foci from HCC. PMID- 23638211 TI - A qualitative study exploring barriers related to use of footwear in rural highland ethiopia: implications for neglected tropical disease control. AB - BACKGROUND: The role of footwear in protection against a range of Neglected Tropical Diseases (NTDs) is gaining increasing attention. Better understanding of the behaviors that influence use of footwear will lead to improved ability to measure shoe use and will be important for those implementing footwear programs. METHODOLOGY/PRINCIPAL FINDINGS: Using the PRECEDE-PROCEED model we assessed social, behavioral, environmental, educational and ecological needs influencing whether and when children wear shoes in a rural highland Ethiopian community endemic for podoconiosis. Information was gathered from 242 respondents using focus groups, semi-structured interviews and extended case studies. Shoe-wearing norms were said to be changing, with going barefoot increasingly seen as 'shameful'. Shoes were thought to confer dignity as well as protection against injury and cold. However, many practical and social barriers prevented the desire to wear shoes from being translated into practice. Limited financial resources meant that people were neither able to purchase more than one pair of shoes to ensure their longevity nor afford shoes of the preferred quality. As a result of this limited access, shoes were typically preserved for special occasions and might not be provided for children until they reached a certain age. While some barriers (for example fit of shoe and fear of labeling through use of a certain type of shoe) may be applicable only to certain diseases, underlying structural level barriers related to poverty (for example price, quality, unsuitability for daily activities and low risk perception) are likely to be relevant to a range of NTDs. CONCLUSIONS/SIGNIFICANCE: Using well established conceptual models of health behavior adoption, we identified several barriers to shoe wearing that are amenable to intervention and which we anticipate will be of benefit to those considering NTD prevention through shoe distribution. PMID- 23638213 TI - Effects of glycyl-glutamine dipeptide supplementation on myocardial damage and cardiac function in rats after severe burn injury. AB - Glutamine decreases myocardial damage in ischemia/reperfusion injury. However, the cardioprotective effect of glutamine after burn injury remains unclear. Present study was to explore the protective effect of glycyl-glutamine dipeptide on myocardial damage in severe burn rats. Seventy-two Wistar rats were randomly divided into three groups: normal control (C), burned control (B) and glycyl glutamine dipeptide-treated (GG) groups. B and GG groups were inflicted with 30% total body surface area of full thickness burn. The GG group was given 1.5 g/kg glycyl-glutamine dipeptide per day and the B group was given the same dose of alanine via intraperitoneal injection for 3 days. The serum CK, LDH, AST, and, blood lactic acid levels, as well as the myocardium ATP and GSH contents, were measured. The indices of cardiac contractile function and histopathological change were analyzed at 12, 24, 48, and 72 post-burn hours (PBH). The serum CK, LDH, AST and blood lactic acid levels increased, and the myocardium ATP and GSH content decreased in both burned groups. Compared with B group, the CK, LDH, AST and blood lactic acid levels reduced, myocardium ATP and GSH content increased in GG group. Moreover, the inhibition of cardiac contractile function and myocardial histopathological damage were reduced significantly in GG group. We conclude that myocardial histological structure and function were damaged significantly after burn injury, glycyl-glutamine dipeptide supplementation is beneficial to myocardial preservation by improving cardiocyte energy metabolism, increasing ATP and glutathione synthesis. PMID- 23638214 TI - Protective effect of mesenchymal stem cell-conditioned medium on hepatic cell apoptosis after acute liver injury. AB - The aim of this study was to investigate the role of Mesenchymal Stem Cell (MSC) conditioned medium (CM(MSC)) on apoptosis of cultured mouse primary hepatocytes after in vivo carbon tetrachloride (CCl4)-induced acute liver injury. The acute liver injury was induced by injecting CCl4 intraperitoneally in C57/BL6 mice. Hepatocytes were isolated by liver perfusion, cultured in a defined medium to maintain their differentiation and characterized by reverse transcriptase polymerase chain reaction (RT-PCR) using the hepatic cell specific genes albumin, hepatocyte nuclear factor 4 (HNF4) and cytokeratin 18 (CK18). CM(MSC) was generated from cultured bone marrow-derived MSCs (BM-MSCs). BM-MSCs were positive for CD73, CD90, CD44 by flow cytometry and able to differentiate into chondrocytes, adipocytes and osteocytes. Apoptosis was evaluated by both annexin V. CM(MSC) were examined by flow cytometry to detect MSC-derived annexin V- and CD54/CD44-positive microparticles (MPs). In the CCl4-CM(MSC) treated hepatocytes, interleukin-6 (IL-6) was increased on the first day of culture compared to control and CCl4 and was followed by upregulation of fibroblast-like-protein (FGL1) expression after 48 hrs. This was associated with a significant decrease of annexin V positive CCl4-CM(MSC) treated hepatocytes at day 3 post plating. Recombinant IL-6 was induced FGL1 expression in hepatocytes derived from CCl4 treated mice suggesting that CM(MSC), which is enriched also in microparticles, attenuates CCl4-induced early apoptosis in hepatocytes through activation of FGL1. PMID- 23638215 TI - Overexpression of integrin a2 promotes osteogenic differentiation of hBMSCs from senile osteoporosis through the ERK pathway. AB - Osteoporosis is a major health problem affecting the aging population, especially in patients 65 years of age and older. The imbalance between bone formation and bone resorption is generally accepted as the essential mechanism leading to osteoporosis. In addition to the abnormal activation of osteoclast-mediated bone resorption, the dysfunction of bone marrow stromal cells (BMSCs) in mediating bone formation has been accepted as a major contributor to the progression of senile osteoporosis. RESULTS: In our study, senile osteoporotic hBMSCs displayed a decreasing capacity for proliferation and osteoblast differentiation, which was associated with the downregulation of integrin alpha2. Forced ectopic integrin alpha2 expression using a lentivirus vector reversed the dysfunction of senile osteoporotic hBMSCs. Additionally, the overexpression of integrin alpha2 upregulated the levels of Runx2 and Osterix. Mechanically, Western blot analyses revealed that integrin alpha2 phosphorylated ERK1/2 and the inactivation of ERK by PD98059 suppressed the osteoblastic differentiation of hBMSCs, suggesting that integrin alpha2 promotes osteoblast proliferation through the activation of ERK1/2 MAPK. CONCLUSION: Taken together, our results show that hBMSCs obtained from senile osteoporotic patients gradually lose their capability to differentiate along the osteogenic lineage and proliferate, which might be associated with the abnormal regulation of the integrin alpha2/ERK/Runx2 signaling pathway undergoing senile osteoporosis. PMID- 23638216 TI - Galectin-3: a novel protein in cerebellar hemangioblastoma. AB - Hemangioblastoma (HB), a rare neoplasm of uncertain histogenesis, is characterized histologically by the presence of vacuolated; lipid-containing cells 'stromal cells' and a well developed, fine capillary network. Stromal cells are the neoplastic component of this tumor. Five-um sections were stained using streptavidin- biotin immunoperoxidase and immunofluorescent techniques. The stromal cells were uniformly "HIF-1alpha, Galectin-3, VEGF, VEGFR, WT-1, and bcl2," positive. Endothelial cells but not stromal cells were uniformly immunoreactive to CD31. Co-localization of HIF-1alpha with galectin-3 and VEGF as well as galectin-3 with VEGF in stromal cells is confirmed by immunofluorescent technique. In conclusion, the development of HB is multi-factorial and the expression of galectin-3 correlates with the expression of HIF-1alpha and VEGF. Galectin-3 can be used as a marker for the diagnosis of HB as well as it can be a valuable candidate for future targeting immunotherapy. PMID- 23638217 TI - Knocking down SMC1A inhibits growth and leads to G2/M arrest in human glioma cells. AB - Cohesin, a multiunit complex of SMC1A, SMC3 and Rad21, associates with chromatin after mitosis and holds sister chromatids together following DNA replication. It has been reported that SMC1A is mutated in some cancer types, leading to genomic instability and abnormal cell growth. In this study, we investigated the role of SMC1A in human glioma. We found that SMC1A was expressed at abnormally high levels in human glioma tissue and in cultured U251 glioma cells. Knocking down SMC1A expression in U251 cells with SMC1A-targeted interfering RNAs inhibited cell growth and induced G2/M cell cycle arrest. Furthermore, expression of the cell cycle associated gene CCNB1IP1 was dramatically increased, whereas expression of Cyclin B1 was decreased in SMC1A-deficienct U251 cells. These results suggest that SMC1A upregulation is involved in the pathogenesis of glioma. PMID- 23638218 TI - RNAi screening identifies KAT8 as a key molecule important for cancer cell survival. AB - Histone acetyltransferases (HATs) regulate many critical cancer events, including transcriptional regulation of oncogene and tumor suppressors, chromatin structure and DNA damage response. Abnormal expression of HATs has been reported in a number of cancers. However, cellular functions of HATs in cancer and molecular mechanisms remain largely unclear. Here, we performed a lentiviral vector mediated RNAi screen to systematically address the function of HATs in lung cancer cell growth and viability. We identified 8 HATs genes involved in A549 cell viability. Further experiments showed that KAT8 regulates G2/M cell cycle arrest through AKT/ERK-cyclin D1 signaling. Moreover, KAT8 inhibition led to p53 induction and subsequently reduced bcl-2 expression. Our results demonstrate an important role of KAT8 in cancer and suggest that KAT8 could be a novel cancer therapeutic target. PMID- 23638219 TI - Papillary meningioma: clinical and histopathological observations. AB - Papillary meningioma is a rare subtype of malignant meningiomas, which is classified by the World Health Organization as Grade III. Because of lack of large sample size case studies, many of the specific characteristics of papillary meningioma are unclear. This study investigated by retrospective analysis the clinical, radiological and histopathological findings of 17 papillary meningioma patients who underwent surgical resection or biopsy, to assess the characteristics of papillary meningioma. Eight female and nine male patients were included, with a mean age of 40 (range: 6 to 55) years. Tumors were mostly located in the cerebral convexity and showed irregular margins, absence of a peritumoral rim, heterogeneous enhancement and severe peritumoral brain edema on preoperative images. Brain invasion was often confirmed during the operations, with abundant to exceedingly abundant blood supply. Intratumoral necrosis and mitosis was frequently observed on routinely stained sections. The average MIB-1 labeling index was 6.9%. Seven cases experienced tumor recurrence or progression, while seven patients died 6 to 29 months after operation. Radiation therapy was given in 52.9% of all cases. Univariate analysis showed that only the existence of intratumoral necrosis and incomplete resection correlated with tumor recurrence. The 3-year progression free survival was 66.7% after gross total resection and 63.6% for other cases. The 3-year mortality rate was 50% after gross total resection and 63.6% for other cases. Papillary meningioma has specific clinical and histopathological characteristics. Tumor recurrence (or progression) and mortality are common. Gross total tumor resection resulted in less recurrence and mortality. PMID- 23638221 TI - Inhibitory effect of bone morphogenetic protein-7 on hepatic fibrosis in rats. AB - AIM: Hepatic cirrhosis is a serious clinical problem caused by the accumulation of extracellular matrix, which can ultimately progress into hepatic failure. Transforming growth factor-beta1 (TGF-beta1) plays a pivotal role in extracellular matrix production. Bone morphogenetic protein-7 (BMP-7), as a member of the TGF-beta1 superfamily, has been well proved to be capable of reversing renal fibrosis in mice. In this study, we aim to investigate the potential effect of BMP-7 on hepatic fibrosis in rats. METHODS: Sprague-Dawley rats were randomly divided into five groups. In the hepatic fibrosis model group (n=8), rats was treated with porcine serum at 0.5 ml each time, twice a week. In the negative control group (n=10), rats were intraperitoneally injected with equal amount and frequency saline. Rats were injected with BMP-7 (100 MUg/kg weight) before porcine serum intraperitoneal injection in the preventive group (n=9). For the early (n=10) and late (n=8) treatment group, rats were received with BMP-7 (100 MUg/kg weight) every other day since the second and fourth week respectively after porcine serum injection. After eight weeks, the degree of liver fibrosis in rats was evaluated and the expression of TGF-beta1 in liver tissues was detected by Western blot and immunohistochemistry. RESULTS: The grade of hepatic fibrosis was significant attenuated by BMP-7 prevention and treatment compared with the rats in negative control group (P<0.05). In addition, the expression of TGF-beta1 greatly decreased in the BMP-7 preventive and treatment groups detected by both Western blot and immunohistochemistry. CONCLUSIONS: BMP-7 can attenuate and even prevent the level of hepatic fibrosis in rats through inhibiting the expression of TGF-beta1 in the liver fibrotic tissues. Therefore, it may be a potential clinical drug for the prevention and treatment of hepatic fibrosis. PMID- 23638220 TI - Ductal plate in hepatoblasts in human fetal livers: I. ductal plate-like structures with cytokeratins 7 and 19 are occasionally seen within human fetal hepatoblasts. AB - The author has studied the organogenesis of human intrahepatic bile duct in fetal livers. The developmental studies of the liver have focused mainly on the development of intrahepatic bile ducts including the ductal plate (DP). The DP is a single or double layered structures composed of small cuboidal cells and located in the interface between the hepatoblasts and portal mesenchyme. Herein, the author discovered the DP within the parenchymal hepatocytes. The DP-like structures within the hepatoblasts were found in 17 human fetal livers out of the 32 human fetal livers. The gestational ages of the 17 fetal livers were as follows: 7, 8, 9, 10 (n=2), 11, 12, 13, 14 (n=2), 15, 16, 17, 18, 19, 21, and 23 weeks. The presence of intraparenchymal DP-like structures were mainly found in the fetus of early gestational ages. Morphologically, the DP-like structures within the hepatoblasts were composed of small cuboidal epithelial cells with normal chromatin patterns. The cytoplasm was scant and relatively basophilic. The nuclei were small and round, and had no nucleoli. These cells formed the DP-like structures. The DP-like structures frequently formed cords, tubules, and duplicating patterns. These DP-like structures were scattered and the remaining hepatoblasts are normal hepatoblasts. The density of these DP-structures was low (one or two per 5 low power fields), but varied from case to case and area to area in the same case. The overall appearances were very similar to the true DP. Comparative observations of HE and CK immunostaining were performed. The DP-like structures within the hepatoblasts were positive for biliary-type CK7 and CK19. They were also positive for CK8 and CK18 that are expressed in both hepatocyte and biliary lineages. The true DP was positive for biliary-type CK7 and CK19. They were also positive for CK8 and CK18. Thus, the intraparenchymal DP-like structures were the same as the true DP located in the interface. Thus, the author discovered the intraparenchymal DP in the human fetal livers. This discovery should be confirmed by other researchers. If it is true, many studies of the functions of these intraparenchymal DPs are need. PMID- 23638223 TI - Overexpression of IL-9 receptor in diffuse large B-cell lymphoma. AB - Interleukin-9 (IL-9) is initially described as a growth factor secreted by helper T cells. It acts on a variety of immune cells via its receptor (IL-9R). Recently, the oncogenic activities of IL-9 and IL-9R were reported in some lymphomas but not diffuse large B-cell lymphoma (DLBCL). The purpose of the present study is to investigate the expression of IL-9R in pathological tissues from patients with DLBCL and to evaluate its correlation with clinical characteristics. Tissue samples from patients with DLBCL and reactive lymphoid hyperplasia were analyzed using RT-PCR, western blot and immunohistochemical staining. There was a higher expression of IL-9R within DLBCL tissues compared with hyperplasic lymph nodes. Immunohistochemical analysis indicated membrane localization of IL-9R in 22 of 36 (61.1%) DLBCL cases. The upregulated IL-9R was correlated to the serum levels of beta2 microglobulin and albumin, International Prognostic Index (IPI) score as well as Ki-67 expression within tumor tissues. Our findings suggest that overexpression of IL-9R may contribute to the pathogenesis of DLBCL and is associated with some adverse prognostic parameters. PMID- 23638222 TI - Glomerular and tubular C4d depositions in IgA nephropathy: relations with histopathology and with albuminuria. AB - BACKGROUND: C4d has been used as an evaluation marker for antibody-mediated rejection for solid organ transplantation. Although some studies have proposed that complement activation is involved in renal diseases, very little information is available on pathogenesis. This study was conducted to investigate C4d deposition in IgA nephropathy and to find its relations with histopathology and albuminuria. METHODS: This retrospective study included 23 patients who underwent renal biopsy at our medical center. The WHO grade of IgA nephropathy, interstitial inflammation and fibrosis, C4d staining and medical records including sex, age, and urine albumin were reviewed. RESULTS: Thirteen patients (56.5%) were positive for C4d staining in the glomerulus and eleven patients (47.8%) were positive in the tubular epithelium. Glomerular C4d deposition was associated with albuminuria (p=0.044), and tubular C4d deposition was associated with a higher grade of IgA nephropathy (p=0.014). CONCLUSIONS: Activation of the complement system was involved in renal damage and was identified through deposition of C4d in the glomerulus and tubules. Positive C4d staining in the glomerulus and the tubules may be associated with functional damage related to glomerular filtration and poor renal outcome. PMID- 23638224 TI - Intestinal protein expression profile identifies inflammatory bowel disease and predicts relapse. AB - To date, most studies have applied individual factors as indicators of disease classification and prognosis. The aim of this study is to determine whether clustering analysis of protein expression profiles in intestinal epithelia improves classification and prognosis in patients with inflammatory bowel disease (IBD). One hundred and twenty Crohn's disease (CD) patients, 117 ulcerative colitis (UC) patients and 120 cases of nonspecific colitis provided intestinal biopsy samples for tissue microarray (TMA). Both unsupervised and supervised analyses were used for evaluation of clustering and association with relapse. There was a significant concordance between cluster groups based on immunostaining data of TMA and clinical classification in distinguishing IBD from nonspecific colitis (kappa= 0.498, p<0.001). CD27, CD70, CD40, TRAF3, TRAF4 and TRAF2 presented similar immunostaining features, which were different from clusters of CD154, CD80 and TRAF5. Moreover, higher expression of TRAF2 was a predictor of relapse in patients with UC (p=0.006).Thus, protein expression profiles can distinguish IBD and nonspecific colitis, and combination analysis protein expression profiles show that TRAF2 can predict relapse of UC. PMID- 23638225 TI - Diffuse hyperplastic mesothelial cells in multiple lymph nodes: case report with review of the literature. AB - We report a case of diffuse hyperplastic mesothelial cells in multiple lymph nodes. Microscopically, the lymph nodes had a normal follicular pattern. The lymphatic sinus was extremely expanded, within the sinuses the epithelial-like cells proliferated actively in the form of sheets and clusters. Epithelioid-like cells had eosinophilic cytoplasm, prominent nucleoli and vesicular nuclei. Mitotic figures were rarely observed. These cells were immunopositive for Calretinin, CK5/6, D2-40, MC and Ckpan and immunonegative for S-100, HMB45, MelanA, TTF-1, CDX-2, Villin, ALK, CD30, CD20, CD3, CD1a and CD68. In addition, during a 22 months follow-up period failed to identify any malignant neoplasms, thus confirming the benign nature of these cells. It is the first reported case of diffuse hyperplastic of mesothelial cells mainly in the cervical lymph nodes associated with systemic multiple lymph node involvement. Awareness of this event is important for the pathologist in preventing the misdiagnosis of malignancy. PMID- 23638226 TI - Adenoid cystic carcinoma of the oral cavity: immunohistochemical study of four cases. AB - Adenoid cystic carcinoma (ACC) in the oral cavity is rare, and no immunohistochemical studies of ACC in the oral cavity have been performed. This report describes the immunohistochemical study of four ACCs of the oral cavity. The male to female ratio was 1:3. The age was 43, 51, 59 and 64 years. The location was tongue (n=2), buccal mucosa (n=1), and gingiva (n=1). Histochemically, all ACCs were positive for neutral, carboxylated and sulfated mucins. Immunohistochemically, ACC was consistently positive for cytokeratin (CK) AE1/3, CK 34betaE12, CK5/6, CK7, CK14, CK18, p63, CA19-9, c-KIT (CD117), PDGFRA, MUC1, and Ki-67 (labeling index: 5%, 15%, 20% and 40%). ACC was consistently negative for CK8, CK20, desmin, S100 protein, CD34, chromogranin, MUC2, MUC5AC and MUC6. Some ACCs were positive for CK CAM5.2 (3/4), CK19 (1/4), EMA (2/4), CEA (2/4), vimentin (3/4), alpha-smooth muscle actin (2/4), p53 (2/4), CD10 (2/4), and synaptophysin (1/4). These results may provide basic knowledge of ACC of the oral cavity. PMID- 23638227 TI - Recurrent multifocal Langerhans cell histiocytosis of the mandible and maxilla in a 46-year-old man: a pathologic case report. AB - A 46-year-old man consulted to a private dental clinic for tooth extraction, where he was indicated to have abnormal shadow in the right mandible. The patient was referred to our clinic hospital. X-ray examination revealed an osteolytic lesion (3 x 2 x 1 cm), and tumor excision was performed. Pathological diagnosis was difficult. The tumor consisted of round cells with moderate atypia. Nuclear grooves were recognized. Immunohistochemistry showed positive CD1a and S100 protein. The Ki67 labeling was 16%. The author diagnosed the lesion as Langerhans cell histiocytosis (LCH). The patient became free of tumor, and discharged. However, the tumor recurred 5 years later. Two osteolytic lesions were found: one is mandible (3 x 1 x 1 cm), and another was maxilla (0.5 x 0.5 x 0.4 cm). Tumorectomy with wide margins were performed. The pathological diagnosis was LCH in both lesions. Whole body CT, MRI and PET were performed, but revealed no tumors. The patient is now free from tumor, and is followed up 7 years after the first presentation. PMID- 23638228 TI - Cystic lymphangioma-like adenomatoid tumor of the adrenal gland: report of a rare case and review of the literature. AB - Adenomatoid tumors (AT) are uncommon, benign tumors of mesothelial origination most frequently encountered in the genital tracts of both sexes. Their occurrences in the extragenital sites are much rarer and could elicit a variety of differential diagnosis both clinically and morphologically. With regard to the adrenal gland, to the best knowledge of us, only 31 cases of AT have been reported in the English literature. Several histologic growth patterns have been documented in AT, among which cystic type is the least common one. We herein present a further case of AT arising in the adrenal of a 62-year-old Chinese man with a medical history for systemic hypertensive disease. The tumor was incidentally identified during routine medical examination. An abdomen computed tomography scan revealed a solitary mass in the right adrenal. Grossly, the poorly-circumscribed mass measured 3.0 x 3.0 x 2.0 cm with a cut surface showing a gelatinous texture with numerous tiny cystic structures. Microscopic examination showed an infiltrated lesion with honeycomb appearance mimicking a lymphangioma, which composed predominantly of variably sized and shaped anastomosing small cystic spaces lined by flattened endothelial-like cells, without any epithelioid or signet-ring like components present. Foci of extraadrenal tumor extension, lymphoid aggregates with occasional germinal centre formation, intralesional fat tissue, stromal myoid proliferation and ossification were also observed. Immunohistochemical analyses confirmed the mesothelial differentiation of this tumor and indicated a diagnosis of cystic lymphangiomatoid AT of the adrenal. PMID- 23638229 TI - Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) of the ileum in a 35-year-old Japanese woman. AB - MALT lymphoma of the ileum is extremely rare: only several cases have been reported. A 34-year-old woman presented abdominal pain and melena. Colorectal and small intestinal endoscopes revealed multiple tumors and ulcers of the entire ileum. Biopsy was taken. Histologically, the biopsy consisted of 6 tissue specimens taken from the various sites of the ileum. All the tissue specimens showed infiltration of small atypical cells resembling centrocyte-like cells (CLC). Immunoblastic cells were scattered, though the number was scant. Monocytoid, plasma cell differentiation, and germinal centers were seen. Lymphoepithelial lesions (LEL) were scattered. Some small atypical lymphocyte were destructive the vessels and stromal tissues. Giemsa and Gram stains demonstrated no Helicobacter pylori and any bacteria. Immunohistochemically, the atypical small lymphocytes were positive for vimentin, but negative for various kinds of cytokeratins (CKs), EMA, CEA and CA19-9. The CK highlighted the LEL. They were positive for CD45, and B-cell markers (CD20, CD79a, CD10, CD23, bcl-2). CD138-positive plasma cells were seen in large number. CD68-positive macrophages were scattered. CD30- and CD15-positive immunoblastic cells were scattered. Most of the lymphoid cells were negative for T-cell markers (CD3, CD4, CD5, CD45RO, and CD43) and negative for NK cell markers (CD56 and CD57). The lymphoid cells were positive for kappa-chain but negative for lambda-chain; thus the light chain restriction was seen. TdT and cyclin D1 were negative. P53 was positive and Ki-67 labeling index was 67%. The lymphoid cells were negative for neuroendocrine markers (NCAM, NSE, chromogranin, and synaptophysin). The pathological diagnosis was MALT lymphoma of the ileum. Post-biopsy imaging techniques including CT, MRI, PET endoscope and gallium scintigraphy identified no tumors and no lymphadenopathy in the body except the ileum. The stomach was free from MALT lymphoma. She was treated by low dose chemotherapy and strictly followed up. PMID- 23638230 TI - Carcinoid tumor of the lung with massive ossification: report of a case showing the evidence of osteomimicry and review of the literature. AB - Carcinoid tumor is one of the commonly encountered primary pulmonary neoplasms. Although it has been known to be accompanied by calcification and/or ossification, presentation with a large ossified mass is rare. We describe here the case of a 29-year-old female with the radiological finding of a single bony nodular lesion. Pathological examination of the surgically resected specimen led to the diagnosis of carcinoid tumor of the lung with massive ossification. Although histological features showed the tumor of low grade malignancy, subcarinal and right hilar lymph nodes were found to be positive for metastasis. Further immunohistochemical analysis revealed that the tumor cells expressed the osteogenic inducer protein, bone morphogenic protrein-2 [BMP-2] and osteoblastic marker protein, osteocalcin. We interpreted this to mean that the carcinoid tumor cells had acquired an osteoblastic phenotype and had subsequently developed marked intratumoral ossification. The relevant literature is reviewed and possible mechanisms of tumor-related osteogenesis are discussed. PMID- 23638231 TI - Mucinous borderline tumor involving fallopian tube: case report and review of the literature. AB - We report the case of a 74-year-old woman with a primary mucinous borderline tumor of the fallopian tube coexisting with an ovarian mucinous borderline tumor. Data were obtained through histopathologic study of the excised surgical specimen. p53, estrogen receptor (ER) and PAX8 expression were evaluated by immunohistochemistry on the available right fallopian tube and ovary. Both the ovarian and fallopian tube borderline ovarian tumors were negative for p53, ER and PAX8. However, the staining pattern highlighted the transition from a normal ciliated cell to neoplastic epithelia in the fallopian tube fimbria. This is the first report to indicate that mucinous borderline tumors may arise from the ciliated cells at the fallopian tube fimbrial epithelia. ER and PAX8 are useful markers in identifying the transition and origination of these tumors. PMID- 23638232 TI - Cutaneous pseudolymphoma: a case report with an immunohistochemical study. AB - Cutaneous pseudolymphoma (C-PSL) is defined as reactive polyclonal benign lymphoproliferative process predominantly composed of either B-cells or T-cells, localized or disseminated. It heals spontaneously after cessation of the causative factor (e.g. drugs) or after non-aggressive treatment. The author herein presents a case of C-PSL with an immunohistochemical study. A 78-year-old man consulted our hospital because of slightly itching skin swelling on the arm. He denied insect bite and traumatic injury. His usual intake drugs were drugs of hypertension, hyperlipidemia, diabetes mellitus, and emotional disorders. Physical examination showed mildly erosive swelling of the am. The lesion measured 1 x 1 x 0.2 cm. Biopsy of the lesion was taken, and it revealed excessive proliferation of small lymphoid cells. The lymphoid cells lacked apparent atypical features and appeared matures. Lymphoblastic cells with nucleoli were scattered. Nodular structures were also seen in the lower dermis. Immunohistochemically, the lymphoid cells were positive for vimentin, CD3, CD4, CD5, CD8, CD10, CD15, CD20, CD23, CD30, CD43, CD38, CD138, CD45RO, CD79alpha, bcl 2, bcl-6, kappa-chain, lambda-chain, and Ki-67 (labeling index=7%). No light chain restriction is seen. The lymphoblastic cells were positively labeled for CD15 and CD30. Plasma cells positive for CD38, CK79alpha and CD138 were seen in a significant amounts. They were negative for cytokeratin (CK) CAM5.2, CKAE1/3, CK34BE12, CK5/6, CK7, CK8, CK18, CK19, CK20, EMA, CEA, CD56, CD57, p53, KIT, PDGFRA, and cyclin D1. Because the constituent cells were both B-cells including plasm cells and T-cells, no light-chain restriction was seen, and no histological atypia was seen, a diagnosis of cutaneous pseudolymphoma was made. The low Ki-67 labeling and negative p53 also suggested the diagnosis. The lesion slightly reduced in size (from 1 cm to 0.7 cm), the causative agent was still unknown 11 months after the biopsy. PMID- 23638233 TI - Good response of malignant pleural effusion from carcinoma of unknown primary site to the anti-tuberculosis therapy: a case report. AB - Malignant pleural effusion in patients with cancers or malignant pleural mesothelioma may often appear at the late stage of disease and significantly affect the patients' life quality and survival. However, there is still no very effective treatment to control malignant pleural effusion. Here we report that malignant pleural effusion in one patient was completely relieved for 15 months by the anti-tuberculosis therapy. CASE PRESENTATION: A 54-year-old female patient complained of cough, dyspnea, chest pain, night sweat and light fever in the afternoon. Computed tomography (CT) of the chest revealed bilateral pleural effusion. But no tumor was found in the lung, pleura and in other sites. Blood test revealed serum carcinoembryonic antigen (CEA) level at 300 ng/mL. One week after we tried anti-tuberculosis combined therapy with isoniazid, pyrazinamide, rifapentine and ethambutol. The pleural effusion in patient was eliminated, along with decreasing CEA. But the CEA increased gradually again when the anti tuberculosis treatment was forced to discontinuation. Sixteen months after anti tuberculosis treatment, the symptoms of cough and breathing difficulty relapsed. Chest CT revealed left pleural effusion, pleural thickness and pericardium nodules. Thoracoscopy and biopsy were conducted. The pleural nodules specimen was pathologically diagnosed as squamous cell carcinoma. CONCLUSION: We reported a rare case of successfully treating malignant pleural effusion caused by squamous cell carcinoma of unknown primary site with the anti-tuberculosis combined. This report provides useful evidences for that the anti-tubercular agents may have potential anticancer activity in some carcinomas. PMID- 23638234 TI - CD10-positive malignant spindle cell tumor of the lip in a child: a malignant myoepithelioma? AB - A 9-year-old girl consulted to our hospital because of lower lip tumor. Excision of the tumor was performed. Histologically, the tumor consisted of cellular spindle and round cells with hyperchromatic nuclei and nucleoli. Mitotic figure and apoptotic bodies were scattered. Immunohistochemically, the tumor cells were strongly and diffusely positive for CD10 and vimentin. The tumor was focally positive for S100 protein, alpha-smooth muscle actin, PDGFRA, HER2/neu, p53, and CD68. The Ki-67 labeling was 20%. In contrast, the tumor cells were negative for pancytokeratins (AE1/3, CAM5.2, WSS, KL-1, HNF116), cytokeratin (CK) 5/6, CK34betaE12, CK7, CK8, CK14, CK18, CK19, CK20, EMA, desmin, CD34, melanosome, KIT, p63, myoglobin, CD45, CD56, GFAP, D2-40, CEA and synaptophysin. The Histologies, positive p53 protein, and Ki-67 labeling of 20% suggested low grade malignancy. Although histological type was unclear, the author diagnosed this tumor as malignant myoepithelioma arising from the lip minor salivary gland because of positive reaction for S100 protein, alpha-smooth muscle actin, and CD10. The patient is now free from tumor 8 years after the first presentation. PMID- 23638235 TI - Peutz-Jeghers syndrome and family survey: a case report. AB - Peutz-Jeghers syndrome (PJS) is a rare inherited autosomal dominant disease characterized by mucocutaneous pigmentation and multiple polyps in the gastrointestinal tract. We report on an 18-year-old Chinese male who complained with pigmentation on face and extremities for over 10 years. Colonoscopy revealed more than ten polyps from transverse colon to rectum. The family survey included 15 family members from three generations, and 6 PJSs (4 males and 2 females) were found. This case is reported because of its rarity of Peutz-Jeghers syndrome and the survey of family history. PMID- 23638236 TI - Primary hepatosplenic CD5-positive diffuse large B-cell lymphoma: a case report with literature review. AB - De novo CD5-positive diffuse large B-cell lymphoma (CD5(+) DLBCL) accounts for approximately 10% of DLBCL, and is usually associated with aggressive clinical course. We report a case of CD5(+) DLBCL with primary involvement of the spleen and liver, and no distinct mass lesions or lymphadenopathy. The patient had stage IV disease with bone marrow involvement by lymphoma. The lymphoma cells showed characteristic portal and intrasinusoidal pattern of infiltrate in the liver. The literature was reviewed and the clinicopathologic features of 7 similar reported cases were summarized. All cases share the common features of hepatosplenomegaly without mass lesions, exclusive red pulp infiltrate with a diffuse and cordal pattern in the spleen, portal and intrasinusoidal pattern of infiltrate in the liver, and stage IV disease with poor response to conventional chemotherapy. This may represent a distinct subgroup of CD5(+) DLBCL and the diagnosis is important for prompt clinical treatment. PMID- 23638238 TI - Successful delivery after IVF-ET in an abdominal cocoon patient: case report and literature review. AB - Abdominal cocoon (AC) is a rare condition of uncertain etiology. We report the case of a 29-year-old infertile Chinese woman with AC, who successfully got twin pregnancy and delivery through in vitro fertilization (IVF) and embryo transfer (ET). And this review discusses the current concepts of its pathogenesis, diagnosis and treatments. AC might lead to tubal infertility and IVF-ET would be the most effective remedy for the patients desiring pregnancy. PMID- 23638237 TI - Primary pure squamous cell carcinoma of the endometrium: a case report. AB - Because primary pure squamous cell carcinoma (SCC) of the endometrium is very rare and its frequency is unknown, the author reviewed 142 archival hysterectomy specimens of endometrial cancers. As the results, one case of primary pure SCC was found. Thus, the frequency of SCC of the endometrium was 0.7% of all endometrial malignancies in our institution. The patient was a 72-year-old woman presenting with uterine bleeding. Uterine curettage biopsy and uterine discharge cytology revealed SCC. No malignancy was seen in cervical biopsy. Radical hysterectomy, bilateral salpingo-oophorectomy, omentectomy and lymph node dissection were performed. The endometrial carcinoma was an infiltrative polypoid tumor composed of non-keratinizing SCC with stratification and intercellular bridges. No adenocarcinoma element was recognized. The SCC cells were immunohistochemically positive for p53 protein and showed high Ki-67 antigen (labeling, 70%). The SCC was found to invade into the deeper third of the myometrium. No tumor cells were seen in other sites including the cervix, ovaries, omentum, and lymph nodes. The patients was FIGO stage IC (pT1C, N0, M0), and was treated with radiation and adjuvant chemotherapy. The patient is now alive without recurrence and metastasis 15 months after the operation. PMID- 23638239 TI - Cuterebral ophthalmomyiasis externa presenting as preseptal cellulitis. PMID- 23638240 TI - Reconstruction of a distal dorsal thumb defect. PMID- 23638241 TI - Management and reconstruction of a helical rim defect with exposed cartilage. PMID- 23638242 TI - Squamous cell carcinoma in an epidermoid cyst. PMID- 23638243 TI - Heterogeneity in Number and Type of Sexual Contacts in a Gay Urban Cohort. AB - HIV transmission models include heterogeneous individuals with different sexual behaviors including contact rates, mixing patterns, and sexual practices. However, heterogeneity can also exist within individuals over time. In this paper we analyze a two year prospective cohort of 882 gay men with observations at six month intervals focusing on heterogeneity both within and between individuals in sexual contact rates and sexual roles. The total number of sexual contacts made over the course of the study (mean 1.55 per month) are highly variable between individuals (standard deviation 9.82 per month) as expected. At the individual level, contacts were also heterogeneous over time. For a homogeneous count process the variance should scale with the mean; however, at the individual level the variance scaled with the square root of the mean implying the presence of heterogeneity within individuals over time. We also observed a high level of movement between dichotomous sexual roles (insertive/receptive, protected/unprotected, anal/oral, and HIV status of partners). On average periods of exclusively unprotected sexual contacted lasted 16 months. Our results suggest that future HIV models should consider heterogeneities both between and within individuals in sexual contact rates and sexual roles. PMID- 23638247 TI - Barriers to maternal health service use in Chikhwawa, Southern Malawi. AB - INTRODUCTION: Research was conducted to get a community's perspective on the factors contributing to continued maternal and neonatal deaths. The aim of the study was to identify and understand experiences, perceptions and needs of the community on maternal health service utilization. METHODS: Qualitative data was obtained through focus group discussions with community leaders, women, men and youth in the catchment areas of three remote health centres. A total of fourteen focus groups were held: three each with community leaders, men, women, boys and two with girls. Data was transcribed and analyzed manually through the use of thematic analysis. RESULTS: The discussions revealed the following as barriers to maternal health service utilization: walking long distances to access health facilities, lack of midwives, lack of or insufficient items to be used during delivery, long stay and rude health personnel. Seeking help from Traditional Birth Attendants (TBAs) during delivery was a common option because TBAs are within reach, do not demand many items for delivery, and treat the women with respect. CONCLUSION: This study suggests some factors that are contributing to the high burden of maternal deaths in Malawi. Interventions should be developed and implemented to improve the barriers reported. PMID- 23638244 TI - Characterizing at-Risk Voxels by Using Perfusion Magnetic Resonance Imaging for Cervical Cancer during Radiotherapy. AB - The number of voxels with low signal intensity (Low DCE voxels) might be potentially related to treatment failure, which might be associated with the tumor oxygenation status. Our goal was to investigate whether at-risk voxels can be used to predict treatment outcome during radiation therapy for cervical cancer. 80 patients with Stage IB2-IVB cervical cancer were included. Four sequential MRI scans were performed at pre-RT, every 2-2.5 weeks during RT, and post-radiotherapy. 3D volumetric data including tumor regression and tumor perfusion from dynamic contrast enhanced MRI (DCE-MRI) were analyzed. Based on the signal intensity (SI) curves of the DCE-MRI, the low-DCE tumor voxels was obtained for individual patients. The predictive power of low DCE voxels in predicting the treatment outcomes was evaluated by Kaplan-Meier survival analysis. Correlation of low DCE voxels with hemoglobin (Hgb) was checked by Pearson Correlation. The actuarial local control rate and survival rate in the patient group with a small number of low DCE voxels were 89.7% and 76.9%, compared with 75.6% and 51.2% in the patient group with a big number of low DCE voxels for the MRI study #1, and 94.1% and 80.4% compared with 62.1% and 34.5% for the MRI study #2, and 95.7% and 78.7% compared with 63.6% and 42.4% for the MRI study #3, respectively. Low DCE voxels were significantly correlated with Hgb. At-risk voxels can be used to predict the outcomes and help understand tumor heterogeneity of response to RT. The Hgb level and tumor perfusion during RT influence the radioresponsiveness and survival in cervical cancer patients. PMID- 23638248 TI - What do Malawi Polytechnic first year students know and do about HIV and AIDS? AB - BACKGROUND: The Polytechnic introduced a "WHY WAIT?" course to equip first year students with skills to help reduce transmission of Human Immune-deficiency Virus (HIV). Training is conducted during the first week of arrival at college. The study aimed to explore existing knowledge, beliefs and attitudes in order to tailor the training programme to students' needs. METHODS: This was a cross sectional study. During first day of arrival, first year students available on campus were given a structured self-administered questionnaire which was filled and submitted before the course. Out of 320 questionnaires distributed, 295 were returned representing 92% response rate. RESULTS: Ten percent (30) had more than one girlfriend or boyfriend. Ninety-seven percent (286) indicated that condoms are not 100% effective towards prevention of HIV while 72% (169) reported that they had never had sexual intercourse before. Of 66 students who had had sexual intercourse before, 30% indicated that they used condoms always during sexual intercourse, 40% used it occasionally while 30% never used condoms. Thirty-two percent (94) reported having an HIV test before and 19% (56) would feel uncomfortable to share a room with an HIV infected person. CONCLUSION: The Polytechnic first year students have varying knowledge and practices about HIV and AIDS. There is need to intensify "WHY WAIT?" course to first years during first week at College to help equip them with necessary knowledge and skills to protect themselves against HIV and AIDS. PMID- 23638249 TI - The effect of providing resuscitation training to frontline staff on rates of maternal and trauma mortality in two health districts in Malawi. PMID- 23638250 TI - Ward round--A patient with multi-organ failure. PMID- 23638251 TI - Ward round--A rare tumor of the kidney resulting in hypertension, renal failure and a cerebrovascular accident in a young female. AB - A 17-year-old girl was admitted to our hospital with severe refractory hypertension evolving over approximately 4 years. Despite not having the resources to identify plasma-renin levels and using standard imaging techniques, a juxtaglomerular cell tumor was suspected and was histologically confirmed after surgical excision. This is a potentially lethal condition if left untreated and surgical excision is curative. The benign nature of the tumor is emphasized and its chemical, radiological and microscopic appearance discussed according to the literature. To the best of our knowledge, this is the first reported case of a patient surviving a cerebrovascular accident associated with a juxtaglomerular cell tumor. PMID- 23638252 TI - Teaching corner: A new method of measuring mid upper arm circumference at Queen Elizabeth Central hospital, Blantyre, Malawi. PMID- 23638253 TI - Teaching corner: Adult asthma in Malawi. PMID- 23638254 TI - Opinions on distribution of condoms in primary and secondary schools: is it proper for government to enhance condom distribution exercise in schools? PMID- 23638255 TI - Thengo Kavinya talks to Dr Leo Masamba, Malawi's only oncologist. PMID- 23638256 TI - Report on site visit to JAMA. PMID- 23638259 TI - How much do Blantyre dispensers in hospital and community pharmacies know about the new malaria treatment guidelines? AB - OBJECTIVE: To determine the knowledge of dispensers in hospital and community pharmacies within Blantyre on new malaria treatment guidelines. METHODS: An interviewer administered questionnaire was used for data collection and the questions focused on the knowledge of dispensers on the new malaria treatment guidelines and whether the subjects were involved in the preparation or implementation of the guidelines or had undertaken any training on how to dispense the new anti-malarial medicines. RESULTS: None of the participants had been involved in the preparation of the treatment guidelines and only 45.5% of the participants had undertaken the pre-implementation training. Ninety percent of the interviewees had knowledge concerning the appropriate treatment of malaria in pregnancy. However, as many as 90.9% of the interviewed participants could not mention any possible five or more side-effects of LA and only 13.6% knew how to properly manage the possible effects. Only 27.3% knew the correct dose regimen of LA and none of them knew the condition of taking LA with a fatty meal for improved absorption. CONCLUSION AND RECOMMENDATIONS: Lack of involvement of the pharmaceutical personnel working in hospital and community pharmacies, from the preparation of new malaria treatment guidelines to their implementation, inadequate training and qualifications of the dispensing personnel contributed to their lack of knowledge and skill on how to rationally dispense the medicines. Pharmaceutical personnel dispensing in the pharmacies need to be involved from the beginning in the preparation of treatment guidelines. Adequate training should be provided and followed by continuous professional education. PMID- 23638260 TI - Improving palliative treatment of patients with non-operable cancer of the oesophagus: training doctors and nurses in the use of self-expanding metal stents (SEMS) in Malawi. AB - Cancer of the oesophagus is the 6th most common cancer in Malawi. Nationwide only three hospitals are able to perform oesophagectomies, and there is no radiotherapy or chemotherapy available. Owing to late presentation of the patients (sometimes in combination with co-morbidities such as HIV/AIDS or tuberculosis) the vast majority of patients are not suitable for surgery. Self expanding metal stents (SEMS) of the oesophagus provide a suitable palliative option to improve the quality of life for patients. This project took a nationwide approach, raising funds for both technical equipment and training of endoscopists and nursing staff throughout Malawi. PMID- 23638261 TI - Sexually Transmitted Infection (STI) screening, case and contact treatment, and condom promotion resulting in STI reduction two years later in rural Malawi. AB - As part of a longitudinal cohort study in rural Malawi in 2000, 469 men and 758 women were asked to respond to a series of surveys, were tested for gonorrhea and chlamydia, and received their results and treatment, if applicable, for themselves and up to 2 partners if positive for either sexually transmitted infection (STI). Two years later, in 2002, 328 men and 525 women were again asked to respond to survey questions, tested again for gonorrhea and chlamydia, and were also tested for HIV--of these, 247 men and 453 women had also given urine samples in 2000. In 2000, the gonorrhea and chlamydia prevalence was 6.2% and 5.8% among men, and 3.6% and 4.9% among women. Two years later, prevalence of gonorrhea and chlamydia was 0.7% and 1.4% among men, and 1.3% and 1.1% among women. Although we did not test for HIV in the first round, the HIV prevalence in 2002 was 19.2%. The implications of the findings are discussed in the context of interventions for STI prevention and to reduce HIV transmission in sub-Saharan Africa. PMID- 23638262 TI - Hip and knee replacement in the HIV positive patient. AB - Arthroplasty is used to relieve pain associated with degenerative or inflammatory joint disease, some post-traumatic joint problems, and avascular necrosis. Avascular necrosis, inflammatory and post-traumatic problems are seen on a regular basis in areas of high HIV seroprevalence. Degenerative arthritis is rare in younger HIV patients, however. Historically the only group of HIV patients in which arthroplasty has been common is that which received contaminated factor VIII transfusions in the 1980's. Haemophiliacs get a haemophilic arthropathy from repeated bleeds into joints and so is an additional complication. Much of the previous literature on this topic has focused on haemophiliac patients. This review examines the success of arthroplasty in HIV positive patients, with an emphasis on non-haemophiliac patients. We conclude that arthroplasty can be a safe procedure for HIV positive individuals if the surgery is carried out in good conditions, and early results are encouraging. PMID- 23638263 TI - Case report: An unusual case of priapism. PMID- 23638264 TI - Case report--A forgotten dermatological disease. PMID- 23638266 TI - CD4 testing at clinics to assess eligibility for antiretroviral therapy. AB - BACKGROUND: In 2011, the Ministry of Health raised the CD4 threshold for antiretroviral therapy (ART) eligibility from <250 cells/ul and <350 cells/ul, but at the same time only 8.8% of facilities in Malawi with HIV services provided CD4 testing. We conducted a record review at 10 rural clinics in Thyolo District to assess the impact of introducing CD4 testing on identifying patients eligible for ART. METHODS: We abstracted CD4 counts of all ART-naive, HIV-infected patients with WHO clinical stages 1 and 2 and an initial CD4 test between May 2008 and June 2009. At four clinics, we also abstracted CD4 counts of patients not initially eligible for ART who were retested before April 2010. RESULTS: Of 1,113 patients tested, the initial CD4 was "<=250 cells/ul" and "<=350 cells/ul" in 534 (48.0%). Of 203 patients with follow-up results, the most recent CD4 was <=250 cells/ul in 34 (24.5%), and <=350 cells/ul in 64 (46.0%). CONCLUSIONS: CD4 testing in rural clinics is feasible and identifies many patients eligible for ART who would not be identified without CD4 testing. CD4 testing needs to be scaled-up to identify patients eligible for ART. ART services need to be scaled up concurrently to meet the resulting increased demand. PMID- 23638265 TI - Tuberculosis drug resistance and outcomes among tuberculosis inpatients in Lilongwe, Malawi. AB - SETTING/OBJECTIVE: We evaluated clinical characteristics, yield of solid vs. liquid culture, polymerase chain reaction (PCR)-based drug-resistance profiles, and clinical outcomes of tuberculosis (TB) inpatients in Lilongwe, Malawi. DESIGN: We enrolled adult patients admitted to the Bwaila TB Ward from Jan Aug/2010. Evaluations included questionnaires, clinical exam, chest radiograph, HIV status, CD4 lymphocyte count, plasma HIVRNA and sputum analysis including Auramine-O stain, Lowenstein-Jensen (LJ) and Mycobacterial Growth Indicator Tube (MGIT) culture, and susceptibility testing using the HAIN GenoType(r) MTBDRplus. RESULTS: Eighty-eight patients were enrolled (88% re-treatment, 42% smear positive, 93% pulmonary TB, 74% HIV co-infected). At baseline, 44/88 (50%) MGIT and 28 (32%) LJ cultures were positive with a mean time to positivity of 12.1 (Range 1-42) and 21.5 (Range 7-58) days, respectively. Four percent (3/77) of retreatment patients or 8% of the 38 MGIT+ PCR-confirmed retreatment cases had multi-drug resistant tuberculosis (MDR TB). One MDR TB patient was smear negative and only one MDR patient was identified with LJ. Lower mean hemoglobin at admission was associated with mortality (10.5 vs. 7.5; p<0.01; CI 101 9.8-11.0). CONCLUSIONS: The MDR TB burden among the retreatment population in Lilongwe, Malawi is similar to regional estimates by the WHO (7.7% 95% CI 0-18.1). MDR TB patients are not routinely identified with sputum smear or LJ, suggesting more efficient technology should be adopted. PMID- 23638267 TI - Cholera outbreak in districts around Lake Chilwa, Malawi: lessons learned. AB - BACKGROUND: Cholera is endemic in Malawi with seasonal outbreaks during the wet season. People living around Lake Chilwa rely on the lake for their water supply. From May 2009 to May 2010, a cholera outbreak occurred in fishing communities around Lake Chilwa. This paper describes the outbreak response and lessons learned for prevention and management of future outbreaks. METHODS: Starting in January 2010, Medecins Sans Frontieres (MSF) helped District Health Management Teams (DHMTs) to distribute educational materials, water disinfectant and hygiene supplies, and oral rehydration solution (ORS) in fishing communities. MSF also supported case management by mentoring health workers and providing equipment and supplies. RESULTS: A total of 1,171 cholera cases and 21 deaths were reported in the districts around the lake, with cases also being reported on the Mozambican side of the lake. The attack rate was highest among people living on or around the lake, particularly among fishermen. Samples of lake water had high turbidity conducive to the propagation of Vibrio cholerae. CONCLUSION: A number of practical measures could be taken to prevent future outbreaks and to manage outbreaks more effectively. These measures should address surveillance, environmental management, outbreak preparedness, and case management. PMID- 23638268 TI - Clinical case: An atypical presentation of a common infection. PMID- 23638269 TI - A 54 year analysis of articles from Mpilo Central Hospital, Bulawayo, Zimbabwe- 168 articles cited 999 times. AB - PubMed and Google Scholar were searched to obtain articles originating from Mpilo Central Hospital, Bulawayo, Zimbabwe--1958 to August 2011 (54 years). 168 articles cited 999 times were retrieved giving about 6 citations per article. Analysis of publication trends over time as well as publication avenues is made. The full research dataset for this study is shared. This study adds to the body of knowledge on teaching hospital research performance assessment particularly in low-income settings, a topic with few studies. Africa needs data on research. PMID- 23638270 TI - Research report--Volunteer infant feeding and care counselors: a health education intervention to improve mother and child health and reduce mortality in rural Malawi. AB - The aim of this report is to describe a health education intervention involving volunteer infant feeding and care counselors being implemented in Mchinji district, Malawi. The intervention was established in January 2004 and involves 72 volunteer infant feeding and care counselors, supervised by 24 government Health Surveillance Assistants, covering 355 villages in Mchinji district. It aims to change the knowledge, attitudes and behaviour of women to promote exclusive breastfeeding and other infant care practices. The main target population are women of child bearing age who are visited at five key points during pregnancy and after birth. Where possible, their partners are also involved. The visits cover exclusive breastfeeding and other important neonatal and infant care practices. Volunteers are provided with an intervention manual and picture book. Resource inputs are low and include training allowances and equipment for counselors and supervisors, and a salary, equipment and materials for a coordinator. It is hypothesized that the counselors will encourage informational and attitudinal change to enhance motivation and risk reduction skills and self-efficacy to promote exclusive breastfeeding and other infant care practices and reduce infant mortality. The impact is being evaluated through a cluster randomised controlled trial and results will be reported in 2012. PMID- 23638272 TI - Opinions on directives by authorities to ban traditional birth attendants: should Malawi be done with traditional birth attendants? PMID- 23638271 TI - "This speciality is for all people who want to help others without strings attached".... Interview by Thengo Kavinya. PMID- 23638273 TI - "PHC leadership: are health centres in good hands? Perspectives from 3 districts in Malawi". AB - AIM: The study aimed to document the kinds of leadership styles are practiced at health centres (H/C) and how these styles can be explained by the contexts, characteristics of the health centre in charge (IC) and subordinate trained health staff (STHS). METHODS: A well-researched leadership style model was applied, which included task, relation and change styles. This is a cross sectional study using self-administered questionnaires in 47 H/C in 3 districts. 347 STHSs (95%) and 46 ICs (98%) responded. Questions explored background data and perceived leadership behaviour. Style items were factor analysed, and bivariate analyses and hierarchical regressions determined how styles could be explained. RESULTS: Two leadership styles were revealed: "Trans" style contained all relation and the majority of task and change items; "Control" style focused on health statistics (Health Management Information System), reporting and evaluation. STHS and IC had a median age/median work experience of 34/5 years and 38,5/2 years, respectively. 48% of IC reported having no management training. CHAM H/Cs had the lowest score on "Control" style. Distance to referral hospital had no impact on style scores. No contexts or STHS characteristics predicted any leadership styles. For ICs, young age and increasing work experience were significant predictors for both styles, while Nurse ICs were negative predictors for "Control style". Management training was not a significant predictor for any style. CONCLUSION: Frontline PHC leadership may be forced by situation and context to use a comprehensive style which could lack the diversity and flexibility needed for effective leadership. The missing associations between staff characteristics and leadership styles might indicate that this group is not sufficiently considered and included in leadership processes in the PHC organization. Leadership competency for the ICs seems not to be based on formal training, but substituted by young age and work experience. Health centre organization could also influence the options for leadership behaviour. In conclusion this calls for a reassessment of H/C leadership and formal leadership training. PMID- 23638274 TI - HIV and AIDS workplace interventions; gaps between policy and practice at the College of Medicine. AB - INTRODUCTION: This study set out to identify gaps between policy and practice of HIV and AIDS workplace interventions in the University of Malawi, in particular College of Medicine in line with the UNIMA HIV and AIDS policy. OBJECTIVES: The main objective was to establish whether the HIV and AIDS workplace interventions at College of Medicine were in line and guided by the University of Malawi HIV and AIDS policy. METHODS: This was a cross sectional qualitative study. A random sample of 25 students and 15 members of staff were interviewed using in-depth interviews. Interviews were tape-recorded and data was analyzed using thematic content analysis. RESULTS: There are a number of activities relating to HIV and AIDS in place while others are still in the pipeline, however the majority of respondents did not know about the UNIMA HIV and AIDS policy or any HIV and AIDS activities that are guided by the policy. This is due to lack of interest on their part or lack of knowledge on the existence of the workplace programme. CONCLUSION: The COM HIV and AIDS committee should strive to fast track key programme areas such as VCT centre and clinic and coordination of different activities to increase programme visibility and patronage. PMID- 23638276 TI - Case report: Evidence of rise in rabies cases in southern Malawi--better preventative measures are urgently required. AB - We describe five children who died of clinical rabies in a three month period (September to November 2011) in the Queen Elizabeth Central Hospital. From previous experience and hospital records, this number of cases is higher than expected. We are concerned that difficulty in accessing post-exposure prophylaxis (PEP) rabies vaccine may be partly responsible for this rise. We advocate: (a) prompt course of active immunisation for all patients with significant exposure to proven or suspected rabid animals. (b) the use of an intradermal immunisation regime that requires a smaller quantity of the vaccine than the intramuscular regime and gives a better antibody response. (c) improved dog rabies control measures. PMID- 23638275 TI - Association of the dominant hand and needle stick injuries for healthcare workers in Taiwan. AB - BACKGROUND: Healthcare workers face the risk of acquiring blood-borne infections from patients through needle stick injuries. Understanding the factors that are associated with increased risk, for example, the role of the dominant hand, is important so that preventive measures can be focused. METHODS: The EPINet (Exposure Prevention, Information Network--a trade mark of Virginia University) questionnaire was used to collect the data. The EPInet system started 2003 in Taiwan under C-MESH. When healthcare workers sustain sharp injury, they complete the injury report form, and report to infection control personnel, who then transmitted the data to EPINet website monthly. RESULTS: 93.5% of the healthcare workers reported being right handed and only 6.5% reported being left handed. About two-thirds (65%) of the reported injuries were by self, 30% injuries were by others and 5% were reported as injured by unknown.There was an association between the dominant hand injury and the needle stick original HCW user, p<0.0001. There is a significant difference between the dominant hand and the needlestick original HCW user. HCW whose dominant hand was the right hand were most likely at risk to be injured by "others" than "self" or "unknown HCW"; OR<= 18.39; CI (0.42 +/- 2.33). CONCLUSION: Needlestick injuries among health care workers in Taiwan continue to pose a serious occupational problem. Historically, prevention has focused on the use of protective wear than assessment of which hand may be at greater risk than the other. There is a greater need to prevent hand injuries as the dominant hand remains the most used and injured in process of patient care. PMID- 23638277 TI - View point: Ethical dilemmas in malaria vector research in Africa: making the difficult choice between mosquito, science and humans. AB - Malaria vector studies are a very important aspect of malaria research as they assist researchers to learn more about the malaria vector. Research programmes in various African countries include studies that assess various methods of preventing malaria transmission including controlling the malaria vector. Various institutions have also established mosquito colonies that are maintained by staff from the institutions. Malaria vector research presents several dilemmas relating to the various ways in which humans are used in the malaria vector research enterprise. A review of the past and present practices reveals much about the prevailing attitudes and assumptions with regard to the ethical conduct of research involving humans. The focus on the science of malaria vector research has led some researchers in African institutions to engage in questionable practices which reveal the ethical tensions inherent in the choice between science and the principles of justice, nonmaleficence and respect for individuals. The analysis of past and present choices in malaria vector research has relevance to broader questions of human dignity and are in line with the current emphasis on ethical research worldwide. PMID- 23638278 TI - Statistics corner: A guide to appropriate use of correlation coefficient in medical research. AB - Correlation is a statistical method used to assess a possible linear association between two continuous variables. It is simple both to calculate and to interpret. However, misuse of correlation is so common among researchers that some statisticians have wished that the method had never been devised at all. The aim of this article is to provide a guide to appropriate use of correlation in medical research and to highlight some misuse. Examples of the applications of the correlation coefficient have been provided using data from statistical simulations as well as real data. Rule of thumb for interpreting size of a correlation coefficient has been provided. PMID- 23638279 TI - Thengo Kavinya talks to Professor Address Malata the Principal of Kamuzu College of Nursing. PMID- 23638280 TI - Opinions on the circumcision campaign rolled out by the government: is circumcision a viable way of combating the HIV/AIDS pandemic? PMID- 23638281 TI - Utilization of family members to provide hospital care in Malawi: the role of Hospital Guardians. AB - AIM: Like most of sub-Saharan Africa, Malawi suffers from a paucity of human resources in the health sector. With an average of one physician for every 50,000 persons, and a health care professional to in-patient population ratio of 1:277, patient care suffers. At Kamuzu Central Hospital (KCH) of Lilongwe, Malawi, family members, termed Hospital Guardians, are utilized to provide basic care for patients. The aim of our study is to characterize this population and explore their role in the health care system of KCH. METHODS: Seventy three semi qualitative surveys and nineteen in-depth interviews were conducted with hospital administrators, Guardians, nurses, and physicians from these wards. The results were analyzed using descriptive analysis and emergent coding. RESULTS: It was found that Hospital Guardians were primarily female family members of patients and have a low literacy rate. They performed a wide range of daily tasks in patient care from wound care to advocacy. Despite their essential role in the health care system, the Guardians were provided with little support from the hospital. There was often conflict between the Guardians and hospital personnel due to overcrowding with more than one Guardian per patient; a lack of understanding of hospital rules and regulations; and a lack of respect for the Guardian role by hospital staff. CONCLUSIONS: Until their role can be reduced by additional trained health care professionals, patient care could be improved by institutional support including a clarification of the role of the Hospital Guardians. Recommendations include a one-patient one-guardian policy; Guardian education; and enhancing Guardian resources. PMID- 23638282 TI - Exploring the feasibility of engaging Traditional Birth Attendants in a prevention of mother to child HIV transmission program in Lilongwe, Malawi. AB - OBJECTIVE: To investigate the willingness of Traditional Birth Attendants (TBAs) to provide single dose antiretroviral prophylaxis to infants born to mothers with HIV and the feasibility of providing the TBAs with antiretroviral medication. DESIGN: 2 focus groups with a total of 17 registered TBAs. SETTING: Lilongwe, Malawi. METHODS: TBAs were recruited by local health workers and participated in focus groups assessing their attitudes towards participation in a PMTCT program. RESULTS: TBAs were willing to participate in this prevention of mother-to-child HIV transmission (PMTCT) program and helped identify barriers to their participation. CONCLUSIONS: Given appropriate support and training, TBAs' participation in PMTCT programs could be an additional way to deliver medication to mothers and neonates who might otherwise miss crucial doses of medication. PMID- 23638283 TI - Tricuspid endocarditis, in a 12 year old girl with a previously normal heart. PMID- 23638284 TI - Ward round: A 43-year-old diabetic man with multiple joint pains. PMID- 23638285 TI - View point: Economic growth and child health in Sub Saharan Africa. PMID- 23638287 TI - "It is time the masses are sensitize that men too, like women have reproductive problems ...". Interview by Thengo Kavinya. PMID- 23638286 TI - Teaching corner: Regional anaesthesia for ophthalmic surgery. AB - Performing safe and effective regional anaesthesia for ophthalmic surgery is an important skill for anaesthetic and ophthalmologic practitioners. Akinetic sharp needle blocks are generally safe but rare, sight and life threatening complications occur. Sub-Tenon's block using a blunt canula provides akinesa and is a safer alternative but serious complications have been reported. This review provides an introduction to the relevant anatomy, local anaesthetic drugs and commonly used techniques and a practical guide to their safe performance. PMID- 23638288 TI - A survey on saffron in major islamic traditional medicine books. AB - Islamic Traditional Medicine (ITM) is a holistic system of medicine. Saffron (Crocus sativus) is one of the most famous plants cultivated in Iran and has a wide range of activities such as oxytocic, anti-carcinogenic, exhilarant, anti depressant, and anti-asthma effects. In addition, saffron can increase the bioavailability and enhance absorption of other drugs. This study comprises a bibliographical survey of 13 major ITM books regarding different medical aspects of this species. Ferdows al-Hekmah fi'l-Tibb (The Paradise of Wisdom in Medicine), Al-Hawi fi'l-Tibb (Comprehensive Book of Medicine), Kamel al-Sanaat al Tibbyyah (Complete Book of the Medical Art), Al-Qanun fi'l-Tibb (Canon of Medicine), Zakhireh Kharazmshahi (Treasure of Kharazmshahi), and Makhzan al Adwiah (Drug Treasure) are some of the most important ITM books used in this survey. PMID- 23638289 TI - Safranal: from an aromatic natural product to a rewarding pharmacological agent. AB - Safranal, the main component of Crocus sativus essential oil, is thought to be the main cause of saffron unique odor. It is now about eighty years that this compound has been discovered and since then different scientific experiments have been done investigating its biological-pharmacological activities. Safranal effects in CNS have been more attractive to scientists and an escalating number of papers have been published regarding its neuropsychological effects. These promising properties of safranal propose its presence as a therapeutic agent in future, although there is a great need for further clinical trials and toxicological studies. In this review article, according to Scopus (r), Thomson Reuters Web of Knowledge(r), Scientific Information Database (SID) (r) and Pubmed (r) all papers published until July 2012 were thoroughly discussed and a brief note of each study was prepared. PMID- 23638290 TI - Saffron Aqueous Extract Inhibits the Chemically-induced Gastric Cancer Progression in the Wistar Albino Rat. AB - OBJECTIVE(S): Gastric cancer is the first and second leading cause of cancer related death in Iranian men and women, respectively. Gastric cancer management is based on the surgery, radiotherapy and chemotherapy. In the present study, for the first time, the beneficial effect of saffron (Crocus sativus L.) aqueous extract (SAE) on the 1-Methyl -3- nitro -1- nitrosoguanidine (MNNG)-induced gastric cancer in rat was investigated. MATERIALS AND METHODS: MNNG was used to induce gastric cancer and then, different concentrations of SAE were administered to rats. After sacrificing, the stomach tissue was investigated by both pathologist and flow cytometry, and several biochemical parameters was determined in the plasma (or serum) and stomach of rats. RESULTS: Pathologic data indicated the induction of cancer at different stages from hyperplasia to adenoma in rats; and the inhibition of cancer progression in the gastric tissue by SAE administration; so that, 20% of cancerous rats treated with higher doses of SAE was completely normal at the end of experiment and there was no rat with adenoma in the SAE treated groups. In addition, the results of the flow cytometry/ propidium iodide staining showed that the apoptosis/proliferation ratio was increased due to the SAE treatment of cancerous rats. Moreover, the significantly increased serum LDH and decreased plasma antioxidant activity due to cancer induction fell backwards after treatment of rats with SAE. But changes in the other parameters (Ca(2+), tyrosine kinase activity and carcino-embryonic antigen) were not significant. CONCLUSION: SAE inhibits the progression of gastric cancer in rats, in a dose dependent manner. PMID- 23638291 TI - Safety Evaluation of Crocin (a constituent of saffron) Tablets in Healthy Volunteers. AB - OBJECTIVE(S): Crocin is the chemical ingredient primarily responsible for the color of saffron. It has different pharmacological effects such as antioxidant, anticancer and memory improving activities. Crocin tablets were evaluated for short-term safety and tolerability in healthy adult volunteers. MATERIALS AND METHODS: The study was a randomized, double-blind, placebo-controlled design consisting of one month treatment of crocin tablets. Volunteers who fulfilled inclusion and exclusion criteria were randomized into 2 groups of 22 each (males and females) and received 20 mg crocin tablets or placebo. General measures of health were recorded during the study such as hematological, biochemical, hormonal and urinary parameters in pre and post-treatment periods. RESULTS: No major adverse events were reported during the trial. Crocin tablets did not change the above parameters except that it decreased amylase, mixed white blood cells and PTT in healthy volunteers after one month. CONCLUSION: This clinical safety evaluation showed a relatively safe and normal profile for crocin in healthy volunteers at the given doses within the trial period. PMID- 23638292 TI - Development and Validation of HPLC Method for Determination of Crocetin, a constituent of Saffron, in Human Serum Samples. AB - OBJECTIVE(S): The present study reports the development and validation of a sensitive and rapid extraction method beside high performance liquid chromatographic method for the determination of crocetin in human serum. MATERIALS AND METHODS: The HPLC method was carried out by using a C18 reversed phase column and a mobile phase composed of methanol/water/acetic acid (85:14.5:0.5 v/v/v) at the flow rate of 0.8 ml/min. The UV detector was set at 423 nm and 13-cis retinoic acid was used as the internal standard. Serum samples were pretreated with solid-phase extraction using Bond Elut C18 (200mg) cartridges or with direct precipitation using acetonitrile. RESULTS: The calibration curves were linear over the range of 0.05-1.25 ug/ml for direct precipitation method and 0.5-5 ug/ml for solid-phase extraction. The mean recoveries of crocetin over a concentration range of 0.05-5 ug/ml serum for direct precipitation method and 0.5-5 ug/ml for solid-phase extraction were above 70 % and 60 %, respectively. The intraday coefficients of variation were 0.37- 2.6% for direct precipitation method and 0.64 - 5.43% for solid-phase extraction. The inter day coefficients of variation were 1.69 - 6.03% for direct precipitation method and 5.13-12.74% for solid-phase extraction, respectively. The lower limit of quantification for crocetin was 0.05 ug/ml for direct precipitation method and 0.5 ug/ml for solid-phase extraction. CONCLUSION: The validated direct precipitation method for HPLC satisfied all of the criteria that were necessary for a bioanalytical method and could reliably quantitate crocetin in human serum for future clinical pharmacokinetic study. PMID- 23638293 TI - Cardioprotective effect of saffron extract and safranal in isoproterenol-induced myocardial infarction in wistar rats. AB - OBJECTIVE(S): This study was designed to evaluate the cardioprotective effect of Crocus sativus L. (saffron) aqueous extract and safranal, the major constituent of the essential oil of saffron, on lipid peroxidation, biochemical parameters and histopathological findings in isoproterenol (ISO)-induced myocardial infarction in Wistar rats. MATERIALS AND METHODS: The saffron extract (20, 40, 80 and 160 mg/kg/day IP) or control were administered for 9 days along with ISO (85 mg/kg, SC, at 24 hr interval) on 8th and 9th day in rats. Activities of creatine kinase-muscle, brain (CK-MB) and lactate dehydrogenase (LDH) were measured using standard commercial kits. The level of malondialdehyde in heart tissue was estimated with thiobarbituric acid reactive species test. For histopathological examination, hematoxylin and eosin (H&E) staining was used. RESULTS: ISO administration induced a statistically significant increase (P< 0.001) in serum LDH and CK-MB and a significant increase (P< 0.001) in the levels of thiobarbituric acid reactive substances (TBARs) in the heart as compared to vehicle control rats. Saffron pretreatment (20, 40, 80 and 160 mg/kg IP) or safranal pretreatment (0.025, 0.050, 0.075 ml/kg IP) for 8 days, significantly decreased (P< 0.001) the serum LDH and CK-MB and myocardial lipid peroxidation as compared to ISO- induced rats. Histological findings of the heart sections confirmed myocardial injury with ISO administration and preserved nearly normal tissue architecture with saffron or safranal pretreatment. CONCLUSION: Saffron and safranal may have cardioprotective effect in ISO-induced myocardial infarction through modulation of oxidative stress in such a way that they maintain the redox status of the cell. PMID- 23638294 TI - Crocin restores hypotensive effect of subchronic administration of diazinon in rats. AB - OBJECTIVE(S): In this study, the effects of crocin against subchronic toxicity of diazinon (DZN) on systolic blood pressure (SBP) and heart rate (HR) were evaluated in rats. MATERIALS AND METHODS: Rats were equally divided into 7 groups; control (corn oil), DZN (15 mg/kg), crocin (each group received 12.5, 25 or 50 mg/kg crocin plus DZN), vitamin E (200 IU/kg plus DZN) and crocin (50 mg/kg) treated groups. Rats were given DZN via gavage once a day for 4 weeks. Vitamin E (three times per week) and crocin (once a day) were intraperitoneally injected to rats for 4 weeks. Plasma cholinesterase activity (Elman method), malondealdehyde (MDA) levels in the aortic tissue (Thiobarbituric acid reactive substances or TBARS method); SBP and HR (tail cuff method) were evaluated at the end of 4th week. RESULTS: A significant decrease in cholinesterase activity was observed in DZN group (P< 0.001). Crocin did not show any effects on cholinesterase activity. DZN increased MDA levels in aortic tissue (P< 0.001) in comparison with control group. Crocin and vitamin E plus DZN decreased MDA elevation induced by DZN in aortic tissue. DZN significantly reduced SBP (P< 0.01) and increased HR (P< 0.001) in comparison with control. Concurrent administration of crocin and DZN, improved the reduction of SBP and the elevation of HR induced by DZN in rat. Crocin alone did not have any effect on SBP and HR. CONCLUSION: This study showed that concurrent administration of crocin and DZN could restore the effects of subchronic DZN administration on SBP and HR in rats. PMID- 23638295 TI - Protective Effect of Safranal, a Constituent of Crocus sativus, on Quinolinic Acid-induced Oxidative Damage in Rat Hippocampus. AB - OBJECTIVE(S): Quinolinic acid (QA)-mediated excitotoxicity has been widely used as a model for studying neurodegenerative disorders. Recent studies suggested that saffron (Crocus sativus) or its active metabolite, i.e. safranal, exerts pharmacological actions on central nervous system including anxiolytic, anticonvulsant, and neuroprotective properties. The present study aimed to investigate the effect safranal pretreatment on QA-induced oxidative damage in rat hippocampus. MATERIALS AND METHODS: Under anesthesia, a guide cannula was stereotaxically inserted into left ventral hippocampus of rats. The rats were then given either saline or safranal (72.75, 145.5, and 291 mg/kg, IP) 30 min before administration of QA (300 nmol, intrahippocampal injection). The markers of oxidative stress including thiobarbituric acid reactive substances (TBARS, as an index of lipid preoxidation), total sulfhydryl groups, antioxidant capacity of hippocampus (using FRAP assay), and oxidative DNA damage (%tail DNA, using comet assay) were measured in hippocampus. RESULTS: The QA induced a significant increase in TBARS levels and %tail DNA and remarkable decrease in antioxidant power (FRAP value) and total sulfhydryl content of hippocampus, in comparison with control animals. Systemic administration of safranal (291 mg/kg, IP), effectively and dose-dependently decreased the QA-induced lipid peroxidation (P<0.001) and oxidative DNA damage (P<0.001). Safranal also prevented the decrease of hippocampal thiol redox and antioxidant status (P<0.001) produced by QA. CONCLUSION: Safranal have protective effects on different markers of oxidative damage in hippocampal tissue following QA administration. Our findings might raise a possibility of potential therapeutic application of safranal for preventing and treating neurodegenerative disorders such as Alzheimer's disease. PMID- 23638296 TI - Crocin enhanced functional recovery after sciatic nerve crush injury in rats. AB - OBJECTIVE(S): Crocin is a constituent of saffron and has many biological functions. The present study aimed to investigate the effects of intraperitoneal (IP) injection of crocin on sciatic nerve regeneration in male Wistar rats. MATERIALS AND METHODS: Fifty-four rats were divided into 9 groups: groups 1-4 (intact + normal saline and intact + crocin at doses of 5, 20 and 80 mg/kg, respectively); group 5 (sham surgery + normal saline); groups 6-9 (crush + normal saline and crush + crocin at doses of 5, 20 and 80 mg/kg, respectively). Normal saline and crocin were IP injected for 10 consecutive days after induction of a standard crush injury in left sciatic nerve. Footprints were obtained 1 day before and weekly after induction of nerve injury for evaluation of sciatic functional index (SFI). Blood samples were taken for evaluation of malondialdehyde (MDA) levels. Histopathological changes of sciatic nerve were investigated by light microscopy. RESULTS: Sciatic nerve crush-injured rats showed SFI values reduction, increased plasma MDA levels and produced Wallerian degeneration in sciatic nerve. Crocin at a dose of 5 mg/kg had no significant effects. At doses of 20 and 80 mg/kg, crocin accelerated the SFI recovery, decreased MDA levels and reduced Wallerian degeneration severity. CONCLUSION: The present study suggests that the neuroprotective effects afforded by crocin may be due in part to reduction of free radicals-induced toxic effects. PMID- 23638297 TI - Crocin improved learning and memory impairments in streptozotocin-induced diabetic rats. AB - OBJECTIVE(S): Crocin influences many biological functions including memory and learning. The present study was aimed to investigate the effects of crocin on learning and memory impairments in streptozotocine-induced diabetic rats. MATERIALS AND METHODS: Diabetes was induced by intraperitoneal (IP) injection of streptozotocin (STZ, 45 mg/kg). Transfer latency (TL) paradigm in elevated plus maze (EPM) was used as an index of learning and memory. Plasma levels of total antioxidant capacity (TAC) and malondialdehyde (MDA), blood levels of glucose, and serum concentrations of insulin were measured. The number of hippocampal neurons was also counted. RESULTS: STZ increased acquisition transfer latency (TL1) and retention transfer latency (TL2), and MDA, decreased transfer latency shortening (TLs) and TCA, produced hyperglycemia and hypoinsulinemia, and reduced the number of neurons in the hippocampus. Learning and memory impairments and blood TCA, MDA, glucose, and insulin changes induced by streptozotocin were improved with long-term IP injection of crocin at doses of 15 and 30 mg/kg. Crocin prevented hippocampal neurons number loss in diabetic rats. CONCLUSION: The results indicate that oxidative stress, hyperglycemia, hypoinsulinemia, and reduction of hippocampal neurons may be involved in learning and memory impairments in STZ-induced diabetic rats. Antioxidant, antihyperglycemic, antihypoinsulinemic, and neuroprotective activities of crocin might be involved in improving learning and memory impairments. PMID- 23638298 TI - The effect of the crocus sativus L. Carotenoid, crocin, on the polymerization of microtubules, in vitro. AB - OBJECTIVE(S): Crocin, as the main carotenoid of saffron, has shown anti-tumor activity both in vitro and in vivo. Crocin might interact with cellular proteins and modulate their functions, but the exact target of this carotenoid and the other compounds of the saffron have not been discovered yet. Microtubular proteins, as one of the most important proteins inside the cells, have several functions in nearly all kinds of cellular processes. The aim of this study was to investigate whether crocin affects microtubule polymerization and tubulin structure. MATERIALS AND METHODS: Microtubules were extracted from sheep brains after two cycles of temperature-dependant assembly-disassembly in the polymerization buffer (PMG). Then phosphocellulose P11 column was used to prepare MAP-free tubulin. Turbidimetric assay of microtubules was performed by incubation of tubulins at 37 oC in PIPES buffer. To investigate the intrinsic fluorescence spectra of tubulins, the emission spectra of tryptophans was monitored. To test the interaction of crocin with tubulin in more details, ANS has been used. RESULTS: Crocin extremely affected the tubulin polymerization and structure. Ultraviolet spectroscopy indicated that crocin increased polymerization of microtubules by nearly a factor of two. Fluorescence spectroscopic data also pointed to significant conformational changes of tubulin. CONCLUSION: We showed that crocin increased tubulin polymerization and microtubule nucleation rate and this effect was concentration dependant. After entering cell, crocin can modulate cellular proteins and their functions. Concerning the results of this study, crocin would be able to affect several cell processes through interaction with tubulin proteins or microtubules. PMID- 23638299 TI - Accurate timekeeping is controlled by a cycling activator in Arabidopsis. AB - Transcriptional feedback loops are key to circadian clock function in many organisms. Current models of the Arabidopsis circadian network consist of several coupled feedback loops composed almost exclusively of transcriptional repressors. Indeed, a central regulatory mechanism is the repression of evening-phased clock genes via the binding of morning-phased Myb-like repressors to evening element (EE) promoter motifs. We now demonstrate that a related Myb-like protein, REVEILLE8 (RVE8), is a direct transcriptional activator of EE-containing clock and output genes. Loss of RVE8 and its close homologs causes a delay and reduction in levels of evening-phased clock gene transcripts and significant lengthening of clock pace. Our data suggest a substantially revised model of the circadian oscillator, with a clock-regulated activator essential both for clock progression and control of clock outputs. Further, our work suggests that the plant clock consists of a highly interconnected, complex regulatory network rather than of coupled morning and evening feedback loops. DOI:http://dx.doi.org/10.7554/eLife.00473.001. PMID- 23638300 TI - Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage. AB - Dengue Virus (DENV), a flavivirus spread by mosquito vectors, can cause vascular leakage and hemorrhaging. However, the processes that underlie increased vascular permeability and pathological plasma leakage during viral hemorrhagic fevers are largely unknown. Mast cells (MCs) are activated in vivo during DENV infection, and we show that this elevates systemic levels of their vasoactive products, including chymase, and promotes vascular leakage. Treatment of infected animals with MC-stabilizing drugs or a leukotriene receptor antagonist restores vascular integrity during experimental DENV infection. Validation of these findings using human clinical samples revealed a direct correlation between MC activation and DENV disease severity. In humans, the MC-specific product, chymase, is a predictive biomarker distinguishing dengue fever (DF) and dengue hemorrhagic fever (DHF). Additionally, our findings reveal MCs as potential therapeutic targets to prevent DENV-induced vasculopathy, suggesting MC-stabilizing drugs should be evaluated for their effectiveness in improving disease outcomes during viral hemorrhagic fevers. DOI:http://dx.doi.org/10.7554/eLife.00481.001. PMID- 23638302 TI - Unmasking the role of mast cells in dengue. AB - Immune cells called mast cells can hinder rather than help the body's response to dengue virus, which suggests that mast cell products could be used as biomarkers to identify severe forms of the disease. PMID- 23638303 TI - Time for a change. AB - The circadian clock of Arabidopsis, a popular model organism for plants, is more complex than expected, with negative feedback loops based on the repression of gene expression having a less exclusive role than previously thought. PMID- 23638301 TI - Native alpha-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2. AB - alpha-Synuclein is a presynaptic protein that is implicated in Parkinson's and other neurodegenerative diseases. Physiologically, native alpha-synuclein promotes presynaptic SNARE-complex assembly, but its molecular mechanism of action remains unknown. Here, we found that native alpha-synuclein promotes clustering of synaptic-vesicle mimics, using a single-vesicle optical microscopy system. This vesicle-clustering activity was observed for both recombinant and native alpha-synuclein purified from mouse brain. Clustering was dependent on specific interactions of native alpha-synuclein with both synaptobrevin-2/VAMP2 and anionic lipids. Out of the three familial Parkinson's disease-related point mutants of alpha-synuclein, only the lipid-binding deficient mutation A30P disrupted clustering, hinting at a possible loss of function phenotype for this mutant. alpha-Synuclein had little effect on Ca(2+)-triggered fusion in our reconstituted single-vesicle system, consistent with in vivo data. alpha Synuclein may therefore lead to accumulation of synaptic vesicles at the active zone, providing a 'buffer' of synaptic vesicles, without affecting neurotransmitter release itself. DOI:http://dx.doi.org/10.7554/eLife.00592.001. PMID- 23638304 TI - The eLife approach to peer review. AB - All editorial decisions at eLife are taken by working scientists in a process that emphasizes fairness, speed and transparency. PMID- 23638305 TI - Counting on co-transcriptional splicing. AB - Splicing is the removal of intron sequences from pre-mRNA by the spliceosome. Researchers working in multiple model organisms - notably yeast, insects and mammalian cells - have shown that pre-mRNA can be spliced during the process of transcription (i.e. co-transcriptionally), as well as after transcription termination (i.e. post-transcriptionally). Co-transcriptional splicing does not assume that transcription and splicing machineries are mechanistically coupled, yet it raises this possibility. Early studies were based on a limited number of genes, which were often chosen because of their experimental accessibility. Since 2010, eight studies have used global datasets as counting tools, in order to quantify co-transcriptional intron removal. The consensus view, based on four organisms, is that the majority of splicing events take place co transcriptionally in most cells and tissues. Here, we discuss the nature of the various global datasets and how bioinformatic analyses were conducted. Considering the broad differences in experimental approach and analysis, the level of agreement on the prevalence of co-transcriptional splicing is remarkable. PMID- 23638306 TI - SUSTAINED TL1A (TNFSF15) EXPRESSION ON BOTH LYMPHOID AND MYELOID CELLS LEADS TO MILD SPONTANEOUS INTESTINAL INFLAMMATION AND FIBROSIS. AB - TL1A is a member of the TNF superfamily, and its expression is increased in the mucosa of inflammatory bowel disease patients. Moreover, patients with certain TNFSF15 variants over-express TL1A and have a higher risk of developing strictures in the small intestine. Consistently, mice with sustained Tl1a expression in either lymphoid or myeloid cells develop spontaneous ileitis and increased intestinal collagen deposition. Transgenic (Tg) mice with constitutive Tl1a expression in both lymphoid and myeloid cells were generated to assess their in vivo consequence. Constitutive expression of Tl1a in both lymphoid and myeloid cells showed increased spontaneous ileitis and collagen deposition than WT mice. T cells with constitutive expression of Tl1a in both lymphoid and myeloid cells were found to have a more activated phenotype, increased gut homing marker CCR9 expression, and enhanced Th1 and Th17 cytokine activity than WT mice. Although no differences in T cell activation marker, Th1 or Th17 cytokine activity, ileitis, or collagen deposition were found between constitutive Tl1a expression in lymphoid only, myeloid only, or combined lymphoid and myeloid cells. Double hemizygous Tl1a-Tg mice appeared to have worsened ileitis and intestinal fibrosis. Our findings confirm that TL1A-DR3 interaction is involved in T cell dependent ileitis and fibrosis. PMID- 23638308 TI - Can Allergen-Specific IgE Antibodies Diagnose Egg Allergy Accurately? PMID- 23638307 TI - Translational strategies in peripheral neuroinflammation and neurovascular repair. AB - Current therapies for immune-mediated inflammatory disorders in peripheral nerves are non-specific, and partly efficacious. Peripheral nerve regeneration following axonal degeneration or injury is suboptimal, with current therapies focused on modulating the underlying etiology and treating the consequences, such as neuropathic pain and weakness. Despite significant advances in understanding mechanisms of peripheral nerve inflammation, as well as axonal degeneration and regeneration, there has been limited translation into effective new drugs for these disorders. A major limitation in the field has been the unavailability of reliable disease models or research tools that mimic some key essential features of these human conditions. A relatively overlooked aspect of peripheral nerve regeneration has been neurovascular repair required to restore the homeostatic microenvironment necessary for normal function. Using Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as examples of human acute and chronic immune-mediated peripheral neuroinflammatory disorders respectively, we have performed detailed studies in representative mouse models to demonstrate essential features of the human disorders. These models are important tools to develop and test treatment strategies using realistic outcomes measures applicable to affected patients. In vitro models of the human blood-nerve barrier using endothelial cells derived by endoneurial microvessels provide insights into pro-inflammatory leukocyte-endothelial cell interactions relevant to peripheral neuroinflammation, as well as potential mediators and signaling pathways required for vascular proliferation, angiogenesis, remodeling and tight junction specialization necessary to restore peripheral nerve function following injury. This review discusses the progress we are making in translational peripheral neurobiology and our future directions. PMID- 23638309 TI - Vitamin d, the cutaneous barrier, antimicrobial peptides and allergies: is there a link? AB - Atopic diseases such as atopic dermatitis (AD) are very common in industrialized countries. Up to 15%-30% of all children and 2%-10% of all adults suffer from AD. Already in early disease stages, a defective epidermal barrier is known to contribute to the pathogenesis of AD. Central elements in the epidermal barrier are antimicrobial peptides (AMPs), which are secreted by keratinocytes, sweat gland cells but also infiltrating immune cells. AMPs function as endogenous antibiotics and are able to kill bacteria, viruses, and fungi. Furthermore AMPs act as immune modulators with effects on the innate and adaptive immune system. The probably best studied AMPs in human skin are the defensins and cathelicidin. In atopic diseases the functions of AMPs such as cathelicidin might be impaired and microbial superinfections could serve as cofactors for allergic sensitization. Hence, induction of AMPs could be beneficial in these patients. Cathelicidin which is often referred to its peptide form hCAP18 or LL-37 can be induced by ultraviolet light B (UVB) irradiation and is upregulated in infected and injured skin. The cathelicidin gene carries a vitamin D response element and the vitamin D pathway could therefore be targeted for cathelicidin regulation. As the development and course of atopic diseases might be influenced by vitamin D signaling these pathomechanisms could explain the growing evidence connecting vitamin D to allergic diseases, including AD, allergic rhinitis, food allergies and asthma. In this review the role of vitamin D and the AMP cathelicidin in the pathogenesis of atopic diseases with impaired barrier function will be discussed. PMID- 23638310 TI - Management of insect sting hypersensitivity: an update. AB - Reactions to Hymenoptera insect stings are common. While most are self-limited, some induce systemic allergic reactions or anaphylaxis. Prompt recognition, diagnosis, and treatment of these reactions are important for improving quality of-life and reducing the risk of future sting reactions. This review summarizes the current recommendations to diagnose and treat Hymenoptera sting induced allergic reactions and highlights considerations for various populations throughout the world. PMID- 23638311 TI - The Clinical Usefulness of IgE Antibodies Against Egg White and Its Components in Korean Children. AB - PURPOSE: Egg (egg white) allergies are among the most common food allergies in infants and young children. Serum egg white-specific IgE (sIgE) levels have been shown to be correlated with clinical symptoms, and the predictive decision point of sIgE levels has been proposed and used widely in the clinical setting. However, some patients whose sIgE levels to egg white are higher than the predictive decision point value show no clinical symptoms, and vice versa. This study was conducted to evaluate the clinical usefulness of sIgE antibodies to egg white and its components in the diagnosis of egg allergies. METHODS: Forty-one patients younger than 2 years of age with no experience of egg intake due to concerns regarding allergies or a non-specific clinical response to eggs were enrolled. Total IgE levels and the levels of IgE antibodies specific for egg white and its components (ovomucoid, ovalbumin, and conalbumin) were measured by ImmunoCAP testing. The clinical response of the subjects was confirmed by an open oral food challenge (OFC). RESULTS: Fifteen (71.4%) out of 21 patients in the egg white-sIgE >=2 kU/L group showed a positive response, while 10 (50.0%) out of 20 patients in the egg white-sIgE <2 kU/L group showed a negative response to the OFC. There were no statistically significant differences in the levels of sIgE antibodies against egg white and its components between the positive and negative open OFC groups. In addition, there were no statistically significant differences in the levels of sIgE antibodies against egg white and its components based on an intra-group analysis. CONCLUSIONS: Our results show that the sensitivity and specificity of the predictive decision point values for egg white-sIgE antibodies by ImmunoCAP were relatively low in Korean children. In addition, no egg white component predicted the clinical reactivity of the subjects. We suggest that the predictive decision point value for a positive egg oral challenge test by ImmunoCAP should be re-evaluated. Moreover, we suggest that careful personal history recording and challenge tests are necessary for the correct diagnosis of an egg allergy. PMID- 23638312 TI - Impact of atopy on asthma and allergic rhinitis in the cohort for reality and evolution of adult asthma in Korea. AB - PURPOSE: Atopy is an important cause of asthma. Few data on the prevalence of atopy or comparisons with clinical characteristics of asthma in Korean patients have been published. We evaluated the effects of atopy on clinical profiles and airway inflammation in Korean asthmatics. METHODS: We retrospectively enrolled 1,492 asthmatics from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) cohort who had undergone skin prick tests for aeroallergens. The patients' clinical characteristics, lung function, PC20, and sputum and blood inflammatory cell counts were compared based on the presence or absence of atopy. Atopy was defined as one or more positive reactions (A/H ratio >1) on a skin prick test. RESULTS: Among 11 aeroallergens, house dust mites (Dermatophagoides farinae and Dermatophagoides pteronyssinus) were the most prevalent cause of a positive skin prick test. As compared with non-atopic asthmatics, atopic asthmatics showed early onset of the disease. Atopic patients with asthma had a higher FEV1, FVC, and FEV1/FVC as compared with non-atopic patients with asthma. In addition, asthmatics without atopy had more uncontrolled asthma (P=0.001) and severe rhinitis (P<0.05) as compared with atopic asthmatics. Smoking, as measured in pack years, was higher in the non-atopic asthmatics than in the atopic asthmatics. The erythrocyte sedimentation rate was higher in non-atopic asthmatics than in the atopic asthmatics and patients with non-atopic asthma had a higher sputum neutrophil count than did those with atopic asthma. CONCLUSIONS: Our data indicate that atopic asthmatics had an early onset of disease and high IgE levels, while the non-atopic asthmatics had decreased lung function and a high sputum neutrophil count, suggesting that a different approach is needed to treat atopic asthma. PMID- 23638313 TI - Evaluation of banana hypersensitivity among a group of atopic egyptian children: relation to parental/self reports. AB - PURPOSE: To evaluate the frequency of banana sensitization and allergy among a group of atopic Egyptian children in relation to parental/self reports. METHODS: This is a case-control study included 2 groups of allergic children with and without history of banana allergy, each included 40 patients. They were subjected to skin prick test (SPT) using commercial banana allergen extract and prick-prick test (PPT) using raw banana, in addition to measuring the serum banana-specific IgE. Oral banana challenge was performed in suspected cases. RESULTS: Banana allergy was diagnosed in 3 (7.5%) patients based on positive history of allergy on exposure to banana, positive SPT/PPT and elevated banana-specific IgE. The 3 patients had bronchial asthma with exacerbation upon banana exposure. The PPT results conform with those of SPT both in diagnosis of banana allergy and in the skin reactivity to banana. Serum banana-specific IgE was detectable in the whole studied sample with higher serum level among those without history of banana allergy (P=0.005). Oral banana challenge was negative for 20 patients with history of banana allergy and positive serum banana-specific IgE but negative SPT and PPT. CONCLUSIONS: Self/parental reports of banana allergy is high while the actual banana allergy is uncommon. The PPT seems as reliable as SPT in diagnosis of banana allergy unlike specific IgE which reflects sensitization rather than allergy. Oral food challenge remains the most helpful tool for diagnosis of food allergy in suspected cases. PMID- 23638314 TI - Relationships between exhaled nitric oxide and atopy profiles in children with asthma. AB - PURPOSE: We examined whether fractional exhaled nitric oxide (FeNO) levels are associated with atopy profiles in terms of mono-sensitization and poly sensitization in asthmatic children. METHODS: A total of 119 children underwent an assessment that included FeNO measurements, spirometry, methacholine challenge, and measurement of blood eosinophil count, serum total IgE, and serum eosinophil cationic protein (ECP). We also examined sensitization to five classes of aeroallergens (house dust mites, animal danders, pollens, molds, and cockroach) using skin prick testing. The children were divided into three groups according to their sensitization profiles to these aeroallergens (non-sensitized, mono-sensitized, and poly-sensitized). RESULTS: The geometric means (range of 1 SD) of FeNO were significantly different between the three groups (non sensitized, 18.6 ppb [10.0-34.7 ppb]; mono-sensitized, 28.8 ppb [16.6-50.1 ppb]; and poly-sensitized, 44.7 ppb [24.5-81.3 ppb], P=0.001). FeNO levels were correlated with serum total IgE concentrations, peripheral blood eosinophilia, and serum ECP levels to different degrees. CONCLUSIONS: FeNO levels vary according to the profile of atopy, as determined by positive skin prick test results to various classes of aeroallergens. FeNO is also moderately correlated with serum total IgE, blood eosinophilia, and serum ECP. These results suggest that poly-sensitized asthmatic children may have the highest risk of airway inflammation. PMID- 23638316 TI - The Age Impact on Serum Total and Allergen-Specific IgE. AB - Aging is accompanied by a progressive decline in almost all functions of the immune system. To investigate a possible impact of age on IgE production, this study evaluated total and allergen-specific serum IgE levels in a large cohort of allergic patients. This study included 6,370 allergic patients (2,961 females, 3,409 males; mean age, 21.7 years; age range, 0-96 years). Total and allergen specific serum IgE levels were measured by immunoenzymatic assay. The analysis of variance showed a significant difference (P<0.0001) in the mean value of total IgE among the different age groups of patients. Moreover, specific IgE levels for all allergens examined differed significantly among the age groups of patients (P<0.0001), with a specific trend pattern for each allergen. Total IgE increased with age, but allergen-specific IgE levels significantly decreased with age, with a trend specific for each allergen tested. PMID- 23638315 TI - Assessment of Total/Specific IgE Levels Against 7 Inhalant Allergens in Children Aged 3 to 6 Years in Seoul, Korea. AB - PURPOSE: Childhood allergies are a serious problem, as they may lead to lifetime chronic disease. Determination of total and specific IgE levels is known to be a diagnostic tool for allergic sensitization; however, IgE levels are affected by various factors, such as age, sex, ethnicity, and geographic area. Thus, we evaluated the distribution of total and specific serum IgE levels against seven inhalant allergens in preschool children and examined their association with allergic diseases in Seoul, Korea. METHODS: Total/specific serum IgE determination and skin prick tests for seven common allergens were performed on 509 children aged 3 to 6 years from 16 child care centers in Seoul, Korea. Demographic characteristics were surveyed from parents using a modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. A diagnosis of atopic dermatitis was made by physicians. RESULTS: The geometric mean of total IgE was 80.48+/-3.80 kU/L in preschool children. IgE levels were higher in boys (boys, 102.34+/-3.52 kU/L; girls, 62.37+/-3.93 kU/L; P<0.001) and atopic subjects (atopic, 158.00+/-3.35 kU/L; non-atopic, 52.75+/-3.44 kU/L; P<0.001). An increased prevalence of atopy was associated with a high monthly household income (P=0.004) and higher maternal education level (above university level education; P=0.009), as well as increased total IgE levels (P=0.036). Physician-diagnosed atopic dermatitis was associated with sensitization to inhalant allergens. CONCLUSIONS: Total IgE levels were very high as compared with those in previous reports from other countries. The most common sensitized allergen was Dermatophagoides farinae, and the positive response rate peaked at age 3 years and was maintained thereafter, particularly in boys. Specific IgE levels for seven inhalant allergens varied with age in preschool children. Although further investigations are needed with a broad range of ages and various allergens, the distribution of the total and specific serum IgE levels in preschool children might help to serve as a reference value to diagnose atopy. PMID- 23638317 TI - Improvement of eosinophilic otitis media by optimized asthma treatment. AB - Eosinophilic otitis media (EOM) shows a very high rate of association with asthma, and intractable otitis media involves marked eosinophil infiltration into the middle ear. The middle ear space is connected to the nasopharynx by the Eustachian tube, and it is considered a part of the upper respiratory tract. Allergic rhinitis and asthma often coexist as chronic inflammatory diseases of the upper and lower airways, respectively, and have an impact on each other. In fact, inhaled corticosteroids reduce seasonal eosinophilia systemically in the circulation and locally in the nasal mucosa, as well as attenuate seasonal nasal symptoms. We report a case of EOM associated with adult-onset asthma that improved following optimal asthma therapy after changing the treatment from inhaled fluticasone propionate (FP) (200 ug b.i.d.) to a combination of FP/salmeterol (250/50 ug b.i.d.). This result supports the hypothesis that EOM and asthma are closely linked, presenting as different manifestations of a similar disease syndrome. PMID- 23638318 TI - Relationship between the proteasomal system and autophagy. AB - TWO MAJOR PATHWAYS DEGRADE MOST CELLULAR PROTEINS IN EUKARYOTIC CELLS: the ubiquitin-proteasome system (UPS), which usually degrades the majority of proteins, and autophagy, primarily responsible for the degradation of most long lived or aggregated proteins and cellular organelles. Disruption of these processes can contribute to pathology of a variety of diseases. Further, both pathways are critical for the maintenance of several aspects of cellular homeostasis, but, until recently, were thought to be largely distinct. Recent advances in this field, however, now strongly suggest that their activities are carefully orchestrated through several interfacing elements that are presented and discussed in this review. PMID- 23638319 TI - RNA aptamers and their therapeutic and diagnostic applications. AB - RNA Aptamers refer to RNA oligonulceotides that are capable of binding to specific targets with high affinity and specificity. Through a process called Systematic Evolution of Ligands by EXponential enrichment (SELEX), a number of RNA aptamers have been identified against various targets including organic compounds, nucleotides, proteins and even whole cells and organisms. RNA aptamers have proven to be of high therapeutic and diagnostic value with recent FDA approval of the first aptamer drug and additional ones in the clinical pipelines. It has also been found to be a particularly useful tool for cell-type specific delivery of other RNA therapeutics like siRNA. All these establish RNA aptamers as one of the pivotal tools of the emerging RNA nanotechnology field in the fight against human diseases including cancer, viral infections and other diseases. This article summarizes the current advancement in the identification of RNA aptamers and also provides some examples of their therapeutic and diagnostic applications. PMID- 23638320 TI - Functional silencing of guanylyl cyclase/natriuretic peptide receptor-A by microRNA interference: analysis of receptor endocytosis. AB - Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) is the principal receptor for the regulatory action of atrial and brain natriuretic peptides (ANP and BNP) and an important effector molecule in controlling of extracellular fluid volume and blood pressure homeostasis. We have utilized RNA interference to silence the expression of GC-A/NPRA gene (Npr1), providing a novel system to study the internalization and trafficking of NPRA in intact cells. MicroRNA (miRNA)-mediated small interfering RNA (siRNA) elicited functional gene-knockdown of NPRA in stably transfected human embryonic kidney 293 (HEK-293) cells expressing a high density of recombinant NPRA. We artificially expressed three RNA polymerase II-driven miRNAs that specifically targeted the Npr1 gene, but shared no significant sequence homology with any other known mouse genes. Reverse transcription-PCR (RT-PCR) and Northern blot analyses identified two highly efficient Npr1 miRNA sequences to knockdown the expression of NPRA. The Npr1 miRNA in chains or clusters decreased NPRA expression more than 90% as compared with control cells. ANP-dependent stimulation of intracellular accumulation of cGMP and guanylyl cyclase activity of NPRA were significantly reduced in Npr1 miRNA-expressing cells by 90-95% as compared with control cells. Treatment with Npr1 miRNA caused a drastic reduction in the receptor density subsequently a deceased internalization of radiolabeled (125)I-ANP-NPRA ligand-receptor complexes. Only 12%-15% of receptor population was localized in the intracellular compartments of microRNA silenced cells as compared to 70%-80% in control cells. PMID- 23638321 TI - Purification and biochemical characterization of membrane-bound neutral ceramidase from camel brain (Camelus dromedarius). AB - Ceramidases cleave the N-acyl linkages of ceramide to generate sphingosine and its subsequent product sphingosine-1-phosphate (S1P). Ceramide and S1P are important bioactive lipids, and ceramidases are important in regulating the availability of these lipids. In this study, we report the purification and characterization of camel brain neutral ceramidase (CBCDase). The novel CBCDase was purified from camel brain using sequential chromatography of DEAE-Sepharose, Phenyl-Sepharose, Superdex, and Mono Q column. The Mono Q fractions containing ceramidase activity were used for enzyme characterization. The purified CBCDase showed a single band corresponding to a molecular weight of ~100 kDa, displaying classical Michaelis-Menten kinetics, with maximum enzymatic activity at pH 7.0. Deglycosylation of the enzyme yields an apparent molecular weight of ~80 kDa. The purified CBCDase was inhibited by Zn(2+) and Cu(2+), while Ca(2+) stimulates the activity. Phosphatidic acid, phosphatidylserine and phosphatidylcholine completely inhibited enzyme activity at low concentrations. Thiol-containing compounds inhibited the CBCDase activity. Among the nucleotides, ADP, UMP, and TMP inhibited the enzyme activity at low concentrations, whereas, ATP inhibited the activity at higher concentrations only. The CBCDase catalysed both ceramide hydrolysis and reverse CDase reactions. For the first time, we have purified to apparent homogeneity of a ~100 kDa nCDase from camel brain. PMID- 23638322 TI - Identification and association of TGFbeta-1 expression in patients with asthma in a Polish population - Lodz metropolitan area study. AB - OBJECTIVE: Interaction of genotype and environment results in a specific phenotype of the clinical course of asthma. TGFbeta-1 gene belongs to the important group of genes involved in the regulation of proliferation, differentiation, adhesion, and migration of a variety of cell types. TGFbeta-1 is inhibitory for B and T cells, as well as IgE production. In particular, it is engaged in inflammation of the bronchi and airway remodeling in asthma, which processes are critical in the pathogenesis of the disease. The aim of this study was to evaluate the correlation between the level of expression of TGFbeta-1 and the severity of asthma. METHODS: The study included 39 participants (20 healthy subjects and 19 patients with asthma). Each sample was analysed by using real time PCR. RESULTS: There was statistical associations between the control group and the group of patients (p = 0,00007). It was demonstrated strong correlation between healthy and patients with severe asthma according GINA guidelines (p = 0,017). It was found the strong statistical correlation between healthy and patients with severe corticosteroid dependent asthma (p = 0,013). Correlations were observed between levels of asthma severity according to the ATS guidelines and controls. The influence of the level of TGFbeta-1 mRNA expression and the severity of asthma (ATS) in the FEV1 (%) parameter value was found. CONCLUSION: It was found that an important role is played by TGFbeta-1 in the pathogenesis of asthma. PMID- 23638323 TI - Evaluation of a Patient Perspective Module in a Required Medication Safety and Quality Course at a College of Pharmacy. AB - OBJECTIVES: To develop and evaluate the impact of a module discussing the patient's perspective on medication errors in a required medication safety course at a college of pharmacy. METHODS: Students were required to read Josie's Story, a true story written by a mother after her daughter died from a medical error, and attend an in-class discussion regarding the book. A questionnaire, which employed a pre-post retrospective method and extracted items from the Caring Ability Inventory, was then administered to measure the change in students' perceptions of patient care. Additional questions gathered students' perceptions of the assignment, their personal experiences with the topic, and the importance of medication safety. RESULTS: 120 out of 138 students (response rate = 87%) completed the questionnaire. 56% of students indicated they would be more likely to speak with a patient directly about a medication error after reading the book, whereas only 3% were less likely, and 42% indicated they were just as likely. Most students (59%) reported that they felt more motivated to learn about medication safety after reading Josie's Story. IMPLICATIONS: This course previously addressed strategies to prevent medication errors. Successfully adding a component that introduces how a medication error impacted a patient and her family may help motivate students to recognize the importance and need for a culture of safety, personalize how medication errors impact patients, and provide a venue for students to gain patient centeredness and caring skills. PMID- 23638324 TI - The critical evaluation of laser Doppler imaging in determining burn depth. AB - This review article discusses the use of laser Doppler imaging as a clinimetric tool to determine burn depth in patients presenting to hospital. Laser Doppler imaging is a very sensitive and specific tool to measure burn depth, easy to use, reliable and acceptable to the patient due to its quick and non-invasive nature. Improvements in validity, cost and reproducibility would improve its use in clinical practice however it is difficult to satisfy the entire evaluation criterion all the time. It remains a widely accepted tool to assess burn depth, with an ever-increasing body of evidence to support its use, as discussed in this review. Close collaboration between clinicians, statisticians, epidemiologists and psychologists is necessary in order to develop the evidence base for the use of laser Doppler imaging as standard in burn depth assessment and therefore act as an influencing factor in management decisions. PMID- 23638325 TI - Burns functional disabilities among burn survivors: a study in Komfo Anokye Teaching Hospital, Ghana. AB - AIM: To determine the types of functional disabilities in adult and paediatric burns survivors, with specific emphasis on potential risk and socio-economic factors of burn disabilities present in Ghana. PATIENTS AND METHODS: The descriptive study was carried out in Komfo Anokye Teaching Hospital, Kumasi, Ghana from May 2011 to April 2012. Burn survivors who came for follow-up visits after been discharged home and had functional disability were the participants of the study. They were physically examined and interviewed using a pre-tested questionnaire after their informed consent/or that of their parents (in the cases of paediatrics burns survivors) was sought. RESULTS: A total of 70 participants consented for the study. Their ages ranged from 8/12 - 78 years, with a mean age of 12+/-1.7 years. Majority (60.0%, N=42) of the participants had third degree burns. The nature of disabilities of participants were mostly scar contractures (42.9%, N=30) of which 36.7% (N=11) had impeded arm elevation; 23.3% (N=7) could not fold the palm or move the digits. From the multiple regression analysis risk factors for burn victim to have disability were paediatric age (OR=11.1, P=0.043), third degree of burn (OR=6.2, P=0.001) and anatomical part affected (OR=18.3, P=0.031). Socio-economic factors that affected burn disability victims were nuclear family compensation (OR=4.2, P=0.021), community mockery/stigmatization (OR=0.1, P=0.052) and caretakers time and finance (OR=5.2, P=0.033). CONCLUSION: The commonest functional disabilities recorded were scar contractions of the axilla region which had impeded the ability of the patients to lift the arm. Risk factors for burns disability included childhood age, third degree of burn incurred and anatomical part affected. Social factors influencing the lives of burn survivors with disability were good family and negative community interactions. Significant economical factors recorded were caretakers' time and financial constrains. PMID- 23638326 TI - Treatment modalities in severe mento-sternal synechia. AB - OBJECTIVE: Scar contracture of the neck after a burn-injury can cause both functional and aesthetic problems, and still presents a challenge for plastic surgeons. The anatomic area and adjacent structures such as the lower lip, trachea and neuro-vascular structures which are affected by the scar make treatment diffucult. Scarring and contracture of the neck region may severely limit function, cause alterations of normal posture and make intubation for surgery difficult. When a burn scar extends toward the face, eating and swallowing may be restricted and facial distortion may develop as the scar pulls the mouthdownwards even the lower eyelids. METHOD: Following the upper extremity, the neck is the most common site affected by burn contracture. The method chosen for contracture release, depends on the severity of scarring and extent of involvement. If the contracture area is limited, z-plasties, skin grafts or local skin flaps are adequate for the treatment but when the whole anterior neck is affected, the treatment modalities are limited and mostly skin grafts either meshed or unmeshed are used. RESULTS: In this study we evaluated the usage of alternative teatment methods involving skin grafts and local flaps for severe neck contractures and tried to discuss oftenly encounered difficulties in treating these group of patients. CONCLUSION: Many techniques have been described for correction of neck contractures, including skin grafting, expanders, local regional flaps and free flaps. The treatment of choice should be modified for every patient. PMID- 23638327 TI - Enhancement of burn wounds healing by platelet dressing. AB - BACKGROUND AND AIMS: The goal of this study was to evaluate the efficacy of platelet dressing in the treatment of burn wounds and compare its results with silver sulfadiazine dressing. MATERIAL AND METHODS: Between 21 march 2011 to 21 September, 50 patients with burn injuries were selected by a randomized double blind controlled trial. In order to eliminate the biological and personal variables among the various treated burn wounds, in the same patient, distal or proximal, lateral or medial part of burn wound were selected for dressing with platelet or silver sulfadiazine. All patients were designated for homologous component use. The dressing was repeated every day up to complete healing. RESULTS: The results indicated that treatment with platelet enhanced epithelialization and accelerate epithelialization and granulation tissue formation. Platelet dressing to be most significant in this respect compared with silver sulfadiazine dressing. CONCLUSION: It is concluded that topical application of platelet enhanced the wound healing process in burn patients. PMID- 23638328 TI - Evolution of bacterial flora in burn wounds: key role of environmental disinfection in control of infection. AB - Bacterial flora in burn patients undergoes change over period of time and is dependent upon many factors. Study of burn flora is not only helpful in locating entry of multidrug resistant bacterial strains into the unit's usual flora but also in determining current antibiotic susceptibilities. Since no studies are available from India that have studied sequential emergence of different microorganisms in burn wound, present study was carried out to study evolution of bacterial flora in burn wounds and its correlation with invasive wound infection. Environmental sampling was also carried out for possible sources of infection. Patients with 20-70% of total burn surface were enrolled and followed up for entire duration of stay. Clinical & treatment details were noted. Surface wound swabs were collected on first, third, seventh, tenth and fourteenth day post admission. Environmental sampling was done every three months. Of 215 wound swabs collected from 71 patients, 72 were sterile and 143 yielded 214 isolates. Colonization rates were 33% on first day, 94% on 7th day and 100% by 14th day. 42% swabs grew gram negative bacteria. Overall Staphylococcus aureus was the predominant isolate (45%) followed by Pseudomonas aeruginosa (13.9%), beta hemolytic Streptococci (9.4%). Maximum invasive infections were seen at the seventh day. A high level of environmental contamination was seen with S. aureus, a substantial portion being MRSA. Better control of environmental contamination and disinfection along with rigorous hand washing and barrier precautions are recommended to prevent infection of wounds. PMID- 23638329 TI - Total intravenous anesthesia for major burn surgery. AB - Total intravenous anesthesia (TIVA) is frequently used for major operations requiring general anesthesia in critically ill burn patients. We reviewed our experience with this approach. METHODS: During a 22-month period, 547 major burn surgeries were performed in this center's operating room and were staffed by full time burn anesthesiologists. The records of all 123 TIVA cases were reviewed; 112 records were complete and were included. For comparison, 75 cases were selected at random from a total of 414 non-TIVA general anesthetics. Some patients had more than one operation during the study: as appropriate for the analysis in question, each operation or each patient was entered as an individual case. For inter-patient analysis, exposure to 1 or more TIVAs was used to categorize a patient as member of the TIVA group. RESULTS: Excision and grafting comprised 78.2% of the operations. 14 TIVA regimens were used, employing combinations of 4 i.v. drugs: ketamine (K, 91 cases); i.v. methadone (M, 62); fentanyl (F, 58); and propofol (P, 21). The most common regimens were KM (34 cases); KF (26); KMF (16); and K alone (8). Doses used often exceeded those used in non-burn patients. TIVA was preferred for those patients who were more critically ill prior to surgery, with a higher ASA score (3.87 vs. 3.11). Consistent with this, inhalation injury (26.7 vs. 1.6%), burn size (TBSA, 36.3 vs. 15.8%), and full-thickness burn size (FULL, 19.8 vs. 6.5%) were higher in TIVA than in non-TIVA patients. Despite this, intraoperative pressor use was as common in TIVA as in non-TIVA cases (23.9 vs. 22.7%). CONCLUSIONS: TIVA was used in patients whose inhalation injury rate and TBSA were greater than those of non-TIVA patients. TIVA cases were not associated with increased hemodynamic instability. TIVA is a viable approach to general anesthesia in critically ill burn patients. PMID- 23638331 TI - Detection of bla(IMP) and bla(VIM) metallo-beta-lactamases genes among Pseudomonas aeruginosa strains. AB - Acquired Metallo-beta-Lactamases (MBLs) are emerging resistance determinants in Pseudomonas aeruginosa and other gram-negative bacteria.Using Combination Disk Diffusion test, it was found that among 83 imipenem non-susceptible P. aeruginosa strains, 48 (57.9%) were MBL producers. PCR and Sequencing methods proved that these isolates were positive for blaIMP-1 genes, whereas none were positive for bla(VIM) genes. The mortality rate due to MBL-producing Pseudomonas infection was 4 (8.3%) among the hospitalized patients. Therefore, identification of drug resistance patterns in P. aeruginosa and detection of MBLs producing isolates are of great importance in the prevention and control of infections. PMID- 23638330 TI - The role of oxidized albumin in blood cell aggregation disturbance in burn disease. AB - The burn disease is found to be accompanied by increasing of the level of oxidized proteins of blood serum. We studied the influence of albumin oxidation rate on aggregation of platelets and erythrocytes, disaggregation of erythrocytes. The changes of blood cells aggregation associated with oxidation rate of albumin were found. Possible mechanisms of these effects are discussed. PMID- 23638332 TI - Multiple disseminated pyogenic granuloma after second degree scald burn: a rare two case. AB - Pyogenic granuloma is a benign lesion and usually occurs after trauma. Disseminated pyogenic granuloma, is a rare form of pyogenic granuloma. There are 9 cases of disseminated pyogenic granuloma in literature and most of them are hot milk burns. First case describes an 18- month-old girl who developed disseminated pyogenic granulomas on her right cheek, neck, and right nasal ala. Lesions on her right cheek and neck were excised and sutured primarily. Lesion on right nasal ala was excised and repaired with full thickness skin graft. Second case describes a 7-years- old boy who developed pyogenic granulomas on his left forearm. These lesions were excised and sutured primarily. In both cases lesions were developed after scald burn. During 6-month follow-up, no recurrence was observed in both cases. PMID- 23638334 TI - Intravascular near-infrared fluorescence molecular imaging of atherosclerosis. AB - Novel imaging modalities are required to better identify vulnerable atherosclerotic plaques before their dire consequences of myocardial infarction, sudden death, and stroke. Moving beyond traditional diagnostic methods, the field of molecular imaging offers an innovative approach to report upon critical in vivo biological features of high-risk plaques. Molecular imaging employs engineered, targeted imaging agents in conjunction with sophisticated, high resolution detection systems. While various modalities have been investigated for this purpose, intravascular near infrared fluorescence imaging (NIRF) strategies are uniquely poised to provide high-resolution readouts of human coronary artery plaques. To date, preclinical animal studies have demonstrated feasibility of both standalone NIRF intravascular imaging as well as dual-modality approaches detecting inflammation and fibrin deposition in coronary-sized arteries. This translatable catheter-based approach is positioned to advance the identification of biologically vulnerable coronary plaques and coronary stents at risk of thrombosis. PMID- 23638333 TI - PET radiopharmaceuticals for probing enzymes in the brain. AB - Biologically important processes in normal brain function and brain disease involve the action of various protein-based receptors, ion channels, transporters and enzymes. The ability to interrogate the location, abundance and activity of these entities in vivo using non-invasive molecular imaging can provide unprecedented information about the spatio-temporal dynamics of brain function. Indeed, positron emission tomography (PET) imaging is transforming our understanding of the central nervous system and brain disease. Great emphasis has historically been placed on developing radioligands for the non-invasive detection of neuroreceptors. In contrast, relatively few enzymes have been amenable to examination by PET imaging procedures based upon trapping or accumulation of enzymatic products, because only a subset of enzymes have sufficient catalytic rate to produce measureable accumulation within the practical time-limit of PET recordings. However, high affinity inhibitors are now serving as tracers for enzymes, particularly for measuring the abundance of enzymes mediating intracellular signal transduction in the brain, which offer a rich diversity of potential targets for drug discovery. The purpose of this review is to summarize well-known radiotracers for brain enzymes, and draw attention to recent developments in PET radiotracers for imaging signal transduction pathways in the brain. The review is organized by target class and focuses on structural chemistry of the best-established radiotracers identified in each class. PMID- 23638336 TI - Limitations of SRTM, Logan graphical method, and equilibrium analysis for measuring transient dopamine release with [(11)C]raclopride PET. AB - Conventional PET methods to estimate [(11)C]raclopride binding potential (BP ND) assume that endogenous dopamine concentration does not change during the scan time. However, this assumption is purposely violated in studies using pharmacological or behavioral stimuli to invoke acute dopamine release. When the assumption of steady-state dopamine is violated, conventional analysis methods may produce biased or even unusable estimates of BP ND. To illustrate this problem, we examined the effect of scan duration on DeltaBP ND estimated by three common analysis methods (simplified reference tissue model, Logan graphical reference method, and equilibrium analysis) applied to simulated and experimental single-scan activation studies. The activation - dopamine release - in both the simulated and experimental studies was brief. Simulations showed DeltaBP ND to be highly dependent on the window of data used to determine BP ND in the activation state. A similar pattern was seen in the data from human smoking studies. No such pattern of DeltaBP ND dependence on the window of data used was apparent in simulations where dopamine was held constant. The dependence of DeltaBP ND on the duration of data analyzed illustrates the inability of conventional methods to reliably quantify short-lived increases in endogenous dopamine. PMID- 23638335 TI - Stem cell tracking with optically active nanoparticles. AB - Stem-cell-based therapies hold promise and potential to address many unmet clinical needs. Cell tracking with modern imaging modalities offers insight into the underlying biological process of the stem-cell-based therapies, with the goal to reveal cell survival, migration, homing, engraftment, differentiation, and functions. Adaptability, sensitivity, resolution, and non-invasiveness have contributed to the longstanding use of optical imaging for stem cell tracking and analysis. To identify transplanted stem cells from the host tissue, optically active probes are usually used to label stem cells before the administration. In comparison to the traditional fluorescent probes like fluorescent proteins and dyes, nanoparticle-based probes are advantageous in terms of the photo stabilities and minimal changes to the cell phenotype. The main focus here is to overview the recent development of optically active nanoparticles for stem cells tracking. The related optical imaging modalities include fluorescence imaging, photoacoustic imaging, Raman and surface enhanced Raman spectroscopy imaging. PMID- 23638337 TI - Re-evaluating the potentials and limitations of (99m)Tc-aprotinin scintigraphy for amyloid imaging. AB - The definitive diagnosis of amyloidosis is made histologically with Congo red stain. Noninvasive imaging techniques for amyloidosis are beneficial for early and definite diagnosis of amyloid deposition in the body. (99m)Tc-aprotinin has the benefit of detecting amyloid deposits mainly in the heart, but it can also detect a wide range of lesions in other locations. The usefulness and limitations of (99m)Tc-Aprotinin scintigraphy for amyloid imaging were re-evaluated based on results from 25 patients (15 men and 10 women; median age, 62.9 y; range, 34-83 y). In addition, other nuclear tracers for imaging amyloidosis are discussed. Of the 25 patients with suspected amyloidosis, 19 patients were proven to have amyloid deposits by histopathological diagnosis. Major (99m)Tc-aprotinin positive sites were confirmed in the myocardium, thyroid, large joints, vertebrae, colon, and lungs. If (99m)Tc-Aprotinin images showed positive findings, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of existing amyloid deposits were 94.7, 33.3, 81.8, and 66.7%, respectively. For analysis based on biopsy region, the sensitivity, specificity, PPV, and NPV of existing amyloid deposition were 30.6, 82.6, 73.3, and 43.2%, respectively. (99m)Tc-Aprotinin has a high potential for diagnosis of amyloid deposition in body; however, due to its physiological uptake, its potential is limited for detection of amyloid deposits in the liver, kidney, and spleen. PMID- 23638338 TI - Baseline total lesion glycolysis measured with (18)F-FDG PET/CT as a predictor of progression-free survival in diffuse large B-cell lymphoma: a pilot study. AB - This pilot study investigates the value of baseline total lesion glycolysis (TLG) in (18)F-FDG PET/CT scans for prediction of progression-free survival (PFS) in patients with Diffuse Large B-Cell Lymphoma (DLBCL). We also evaluate the role of other quantitative parameters measured at baseline and interim PET/CT for prediction of PFS. A retrospective review (2003-2010) of patients with DLBCL who underwent (18)F-FDG PET/CT before, after cycle two, and after completion of R CHOP treatment, identified 84 patients. Twenty patients fulfilled the inclusion criteria. Standardized uptake values (SUVmax and SUVmean), total metabolic tumor volume (TMTV), and TLG were measured in baseline and interim PET/CT. Relationship between quantitative parameters and PFS was statistically analyzed using Log-rank test and univariate Cox-regression analysis. Of 20 patients (F/M: 7/13, range: 20 73 years), six patients (30%) developed recurrence after chemotherapy (mean follow-up: 51.35+/-17.05 months, range: 12-81 months). Results of statistical analysis showed TLG as the only discriminator of recurrence at baseline (cut point: 704.77 g, HR: 11.21, CI: 1.29-97, P=0.02). Among the interim PET/CT parameters, SUVmean (cut -point: 2.07, HR: 6.31, CI: 1.25-31.61), SUVmax (cut point: 2.3, HR: 6.31, CI: 1.25-31.61), and TLG (cut-point: 96.5 g, HR: 6.38, CI: 1.29 - 31.61) could all help predict PFS (P<0.05). Although not routinely reported, high baseline TLG may be a useful index to identify patients with DLBCL who are at increased risk for relapse after conventional R-CHOP. If confirmed in larger prospective studies, this may allow the selection of alternate therapeutic choices at the onset of treatment. PMID- 23638339 TI - Bilateral peripheral neural activity observed in vivo following unilateral nerve injury. AB - Manganese-enhanced magnetic resonance imaging (MRI) is a surrogate method to measure calcium content in nervous system since manganese physiologically follows calcium. Manganese is detectable in MRI and therefore visualizes structures and cell populations that actively regulate calcium. Since calcium is actively recruited for the transmission of action potentials, our purpose is to validate manganese-enhanced MRI for detection of changes in lumbar nerves related to nociception. A neuropathic pain model was created by chronic constrictive injury of the left sciatic nerve of Sprague-Dawley rats. Behavioral measurements, using von Frey's tests, confirmed the presence of significant allodynia in the left hind limb of animals in the injured group. T1-weighted fast spin echo images were obtained of the lumbar cord and plexus of animals with injured left sciatic nerve and uninjured animals (control) scanned in a 7 Tesla magnet after intraperitoneal manganese chloride administration four weeks after surgery. Lumbar nerve roots and sciatic nerves in the injured group show increased normalized manganese enhanced MRI signal, representing manganese enhancement, compared to the control group. In conclusion, animals with neuropathic pain in the left hind limb show increased manganese uptake in not only the injured sciatic nerve but also in the contralateral uninjured sciatic nerve on manganese-enhanced MRI in vivo. Although poorly understood, this finding corroborates ex vivo finding of bilateral nociceptive-related molecular changes in the nervous system of unilateral pain models. PMID- 23638341 TI - Physical Activity, Sedentary Behavior, and Dietary Patterns among Children. AB - Energy balance-related behavioral patterns find their origin in early childhood. The current paper provides an overview of studies that have examined such behavioral patterns, i.e., the clustering of dietary behaviors, physical activity, and/or sedentary behavior. The paper discusses the importance of examining energy balance-related behavioral patterns in children, outlines methods to examine these patterns, and provides examples of patterns that have been found (e.g., the universal sedentary-snacking and healthy intake patterns, as well as more unique or local patterns), child and parental characteristics predicting such patterns (e.g., child gender and maternal educational level), and the relationship of these patterns with overweight and related measures. PMID- 23638340 TI - Image quality assessment of automatic three-segment MR attenuation correction vs. CT attenuation correction. AB - The purpose of this study is to systematically evaluate the usefulness of Positron emission tomography/Magnetic resonance imaging (PET/MRI) images in a clinical setting by assessing the image quality of Positron emission tomography (PET) images using a three-segment MR attenuation correction (MRAC) versus the standard CT attenuation correction (CTAC). We prospectively studied 48 patients who had their clinically scheduled FDG-PET/CT followed by an FDG-PET/MRI. Three nuclear radiologists evaluated the image quality of CTAC vs. MRAC using a Likert scale (five-point scale). A two-sided, paired t-test was performed for comparison purposes. The image quality was further assessed by categorizing it as acceptable (equal to 4 and 5 on the five-point Likert scale) or unacceptable (equal to 1, 2, and 3 on the five-point Likert scale) quality using the McNemar test. When assessing the image quality using the Likert scale, one reader observed a significant difference between CTAC and MRAC (p=0.0015), whereas the other readers did not observe a difference (p=0.8924 and p=0.1880, respectively). When performing the grouping analysis, no significant difference was found between CTAC vs. MRAC for any of the readers (p=0.6137 for reader 1, p=1 for reader 2, and p=0.8137 for reader 3). All three readers more often reported artifacts on the MRAC images than on the CTAC images. There was no clinically significant difference in quality between PET images generated on a PET/MRI system and those from a Positron emission tomography/Computed tomography (PET/CT) system. PET images using the automatic three-segmented MR attenuation method provided diagnostic image quality. However, future research regarding the image quality obtained using different MR attenuation based methods is warranted before PET/MRI can be used clinically. PMID- 23638342 TI - Targeted Rejection Triggers Differential Pro- and Anti-Inflammatory Gene Expression in Adolescents as a Function of Social Status. AB - Social difficulties during adolescence influence life-span health. To elucidate underlying mechanisms, we examined whether a noxious social event, targeted rejection (TR), influences the signaling pathways that regulate inflammation, which is implicated in a number of health problems. For this study, 147 adolescent women at risk for developing a first episode of major depression were interviewed every 6 months for 2.5 years to assess recent TR exposure, and blood was drawn to quantify leukocyte messenger RNA (mRNA) for nuclear factor-kappaB (NF-kappaB) and inhibitor of kappaB (I-kappaB) and the inflammatory biomarkers C reactive protein and interleukin-6. Participants had more NF-kappaB and I-kappaB mRNA at visits when TR had occurred. These shifts in inflammatory signaling were most pronounced for adolescents high in perceived social status. These findings demonstrate that social rejection upregulates inflammatory gene expression in youth at risk for depression, particularly for those high in status. If sustained, this heightened inflammatory signaling could have implications for life-span health. PMID- 23638344 TI - Influence of the experimental design of gene expression studies on the inference of gene regulatory networks: environmental factors. AB - The inference of gene regulatory networks gained within recent years a considerable interest in the biology and biomedical community. The purpose of this paper is to investigate the influence that environmental conditions can exhibit on the inference performance of network inference algorithms. Specifically, we study five network inference methods, Aracne, BC3NET, CLR, C3NET and MRNET, and compare the results for three different conditions: (I) observational gene expression data: normal environmental condition, (II) interventional gene expression data: growth in rich media, (III) interventional gene expression data: normal environmental condition interrupted by a positive spike-in stimulation. Overall, we find that different statistical inference methods lead to comparable, but condition-specific results. Further, our results suggest that non-steady-state data enhance the inferability of regulatory networks. PMID- 23638343 TI - How long is a piece of loop? AB - Loops are irregular structures which connect two secondary structure elements in proteins. They often play important roles in function, including enzyme reactions and ligand binding. Despite their importance, their structure remains difficult to predict. Most protein loop structure prediction methods sample local loop segments and score them. In particular protein loop classifications and database search methods depend heavily on local properties of loops. Here we examine the distance between a loop's end points (span). We find that the distribution of loop span appears to be independent of the number of residues in the loop, in other words the separation between the anchors of a loop does not increase with an increase in the number of loop residues. Loop span is also unaffected by the secondary structures at the end points, unless the two anchors are part of an anti-parallel beta sheet. As loop span appears to be independent of global properties of the protein we suggest that its distribution can be described by a random fluctuation model based on the Maxwell-Boltzmann distribution. It is believed that the primary difficulty in protein loop structure prediction comes from the number of residues in the loop. Following the idea that loop span is an independent local property, we investigate its effect on protein loop structure prediction and show how normalised span (loop stretch) is related to the structural complexity of loops. Highly contracted loops are more difficult to predict than stretched loops. PMID- 23638346 TI - Novel control of lactate dehydrogenase from the freeze tolerant wood frog: role of posttranslational modifications. AB - Lactate dehydrogenase (LDH), the terminal enzyme of anaerobic glycolysis, plays a crucial role both in sustaining glycolytic ATP production under oxygen-limiting conditions and in facilitating the catabolism of accumulated lactate when stress conditions are relieved. In this study, the effects on LDH of in vivo freezing and dehydration stresses (both of which impose hypoxia/anoxia stress on tissues) were examined in skeletal muscle of the freeze-tolerant wood frog, Rana sylvatica. LDH from muscle of control, frozen and dehydrated wood frogs was purified to homogeneity in a two-step process. The kinetic properties and stability of purified LDH were analyzed, revealing no significant differences in V max, K m and I 50 values between control and frozen LDH. However, control and dehydrated LDH differed significantly in K m values for pyruvate, lactate, and NAD, I 50 urea, and in temperature, glucose, and urea effects on these parameters. The possibility that posttranslational modification of LDH was responsible for the stable differences in enzyme behavior between control and dehydrated states was assessed using ProQ diamond staining to detect phosphorylation and immunoblotting to detect acetylation, methylation, ubiquitination, SUMOylation and nitrosylation of the enzyme. LDH from muscle of dehydrated wood frogs showed significantly lower levels of acetylation, providing one of the first demonstrations of a potential role for protein acetylation in the stress-responsive control of a metabolic enzyme. PMID- 23638345 TI - Assessing insect responses to climate change: What are we testing for? Where should we be heading? AB - To understand how researchers are tackling globally important issues, it is crucial to identify whether current research is comprehensive enough to make substantive predictions about general responses. We examined how research on climate change affecting insects is being assessed, what factors are being tested and the localities of studies, from 1703 papers published between 1985 and August 2012. Most published research (64%) is generated from Europe and North America and being dedicated to core data analysis, with 29% of the studies analysed dedicated to Lepidoptera and 22% Diptera: which are well above their contribution to the currently identified insect species richness (estimated at 13% and 17% respectively). Research publications on Coleoptera fall well short of their proportional contribution (19% of publications but 39% of insect species identified), and to a lesser extent so do Hemiptera, and Hymenoptera. Species specific responses to changes in temperature by assessing distribution/range shifts or changes in abundance were the most commonly used methods of assessing the impact of climate change on insects. Research on insects and climate change to date is dominated by manuscripts assessing butterflies in Europe, insects of economic and/or environmental concern in forestry, agriculture, and model organisms. The research on understanding how insects will respond to a rapidly changing climate is still in its infancy, but the current trends of publications give a good basis for how we are attempting to assess insect responses. In particular, there is a crucial need for broader studies of ecological, behavioural, physiological and life history responses to be addressed across a greater range of geographic locations, particularly Asia, Africa and Australasia, and in areas of high human population growth and habitat modification. It is still too early in our understanding of taxa responses to climate change to know if charismatic taxa, such as butterflies, or disease vectors, including Diptera, can be used as keystone taxa to generalise other insect responses to climate change. This is critical as the basic biology of most species is still poorly known, and dominant, well studied taxa may show variable responses to climate change across their distribution due to regional biotic and abiotic influences. Indeed identifying if insect responses to climate change can be generalised using phylogeny, functional traits, or functional groups, or will populations and species exhibit idiosyncratic responses, should be a key priority for future research. PMID- 23638347 TI - Dissecting the mechanisms of squirrel monkey (Saimiri boliviensis) social learning. AB - Although the social learning abilities of monkeys have been well documented, this research has only focused on a few species. Furthermore, of those that also incorporated dissections of social learning mechanisms, the majority studied either capuchins (Cebus apella) or marmosets (Callithrix jacchus). To gain a broader understanding of how monkeys gain new skills, we tested squirrel monkeys (Saimiri boliviensis) which have never been studied in tests of social learning mechanisms. To determine whether S. boliviensis can socially learn, we ran "open diffusion" tests with monkeys housed in two social groups (N = 23). Over the course of 10 20-min sessions, the monkeys in each group observed a trained group member retrieving a mealworm from a bidirectional task (the "Slide-box"). Two thirds (67%) of these monkeys both learned how to operate the Slide-box and they also moved the door significantly more times in the direction modeled by the trained demonstrator than the alternative direction. To tease apart the underlying social learning mechanisms we ran a series of three control conditions with 35 squirrel monkeys that had no previous experience with the Slide-box. The first replicated the experimental open diffusion sessions but without the inclusion of a trained model, the second was a no-information control with dyads of monkeys, and the third was a 'ghost' display shown to individual monkeys. The first two controls tested for the importance of social support (mere presence effect) and the ghost display showed the affordances of the task to the monkeys. The monkeys showed a certain level of success in the group control (54% of subjects solved the task on one or more occasions) and paired controls (28% were successful) but none were successful in the ghost control. We propose that the squirrel monkeys' learning, observed in the experimental open diffusion tests, can be best described by a combination of social learning mechanisms in concert; in this case, those mechanisms are most likely object movement reenactment and social facilitation. We discuss the interplay of these mechanisms and how they related to learning shown by other primate species. PMID- 23638349 TI - Fluorescent protein tagging confirms the presence of ribosomal proteins at Drosophila polytene chromosomes. AB - Most ribosomal proteins (RPs) are stoichiometrically incorporated into ribosomal subunits and play essential roles in ribosome biogenesis and function. However, a number of RPs appear to have non-ribosomal functions, which involve direct association with pre-mRNA and transcription factors at transcription sites. The consensus is that the RPs found at these sites are off ribosomal subunits, but observation that different RPs are usually found together suggests that ribosomal or ribosomal-like subunits might be present. Notably, it has previously been reported that antibodies against 20 different RPs stain the same Pol II transcription sites in Drosophila polytene chromosomes. Some concerns, however, were raised about the specificity of the antibodies. To investigate further whether RPs are present at transcription sites in Drosophila, we have generated several transgenic flies expressing RPs (RpS2, RpS5a, RpS9, RpS11, RpS13, RpS18, RpL8, RpL11, RpL32, and RpL36) tagged with either green or red fluorescent protein. Imaging of salivary gland cells showed that these proteins are, as expected, abundant in the cytoplasm as well as in the nucleolus. However, these RPs are also apparent in the nucleus in the region occupied by the chromosomes. Indeed, polytene chromosome immunostaining of a representative subset of tagged RPs confirms the association with transcribed loci. Furthermore, characterization of a strain expressing RpL41 functionally tagged at its native genomic locus with YFP, also showed apparent nuclear accumulation and chromosomal association, suggesting that such a nuclear localization pattern might be a shared feature of RPs and is biologically important. We anticipate that the transgenes described here should provide a useful research tool to visualize ribosomal subunits in Drosophila tissues and to study the non-ribosomal functions of RPs. PMID- 23638348 TI - Simultaneous recordings of ocular microtremor and microsaccades with a piezoelectric sensor and a video-oculography system. AB - Our eyes are in continuous motion. Even when we attempt to fix our gaze, we produce so called "fixational eye movements", which include microsaccades, drift, and ocular microtremor (OMT). Microsaccades, the largest and fastest type of fixational eye movement, shift the retinal image from several dozen to several hundred photoreceptors and have equivalent physical characteristics to saccades, only on a smaller scale (Martinez-Conde, Otero-Millan & Macknik, 2013). OMT occurs simultaneously with drift and is the smallest of the fixational eye movements (~1 photoreceptor width, >0.5 arcmin), with dominant frequencies ranging from 70 Hz to 103 Hz (Martinez-Conde, Macknik & Hubel, 2004). Due to OMT's small amplitude and high frequency, the most accurate and stringent way to record it is the piezoelectric transduction method. Thus, OMT studies are far rarer than those focusing on microsaccades or drift. Here we conducted simultaneous recordings of OMT and microsaccades with a piezoelectric device and a commercial infrared video tracking system. We set out to determine whether OMT could help to restore perceptually faded targets during attempted fixation, and we also wondered whether the piezoelectric sensor could affect the characteristics of microsaccades. Our results showed that microsaccades, but not OMT, counteracted perceptual fading. We moreover found that the piezoelectric sensor affected microsaccades in a complex way, and that the oculomotor system adjusted to the stress brought on by the sensor by adjusting the magnitudes of microsaccades. PMID- 23638350 TI - Na(+)/Ca(2+) selectivity in the bacterial voltage-gated sodium channel NavAb. AB - The recent publication of a number of high resolution bacterial voltage-gated sodium channel structures has opened the door for the mechanisms employed by these channels to distinguish between ions to be elucidated. The way these channels select between Na(+) and K(+) has been investigated in computational studies, but the selectivity for Na(+) over Ca(2+) has not yet been studied in this way. Here we use molecular dynamics simulations to calculate the energetics of Na(+) and Ca(2+) transport through the channel. Single ion profiles show that Ca(2+) experiences a large barrier midway through the selectivity filter that is not seen by Na(+). This barrier is caused by the need for Ca(2+) to partly dehydrate to pass through this region and the lack of compensating interactions with the protein. Multi-ion profiles show that ions can pass each other in the channel, which is why the presence of Ca(2+) does not block Na(+) conduction despite binding more strongly in the pore. PMID- 23638351 TI - Timing of molt of barn swallows is delayed in a rare Clock genotype. AB - Photoperiodic responses are major factors entraining circannual life-cycles, functioning to adaptively synchronize annual routines to seasonal fluctuations in ecological conditions. Photoperiodism in physiology and behaviour is enforced by genes, including the vertebrate Clock orthologues, which are associated, for example, with phenology of migration in fish and breeding in birds. However, the role of Clock in photoperiodic plumage molt processes is unknown. We analyzed variation in molt schedules in relation to Clock genotype, using the long distance migratory barn swallow (Hirundo rustica) as a model and by identifying males and females using molecular sexing techniques. Consistently with previous studies, we found one very common (Q 7) and two rare (Q 6, Q 8) variants of a functionally significant Clock polyglutamine repeat. Molt schedules of primary wing feathers of swallows during their wintering period in Nigeria differed among Clock genotypes: rare (1.1%) Q 7/Q 8 heterozygotes had significantly delayed molt compared to the other genotypes. Molt schedules did not differ between males and females, and no differential association between molt and Clock in relation to sex emerged. The same rare Clock genotype that exhibited delayed breeding in Europe was here found to delay molt in Africa. Though based on a limited number of Q 7/Q 8 individuals from an otherwise very large sample, these novel results suggest that Clock is involved in the photoperiodic control of both molt and breeding, potentially also via reciprocal carry-over effects. If confirmed in species with higher Clock polymorphism, present results may have far-reaching consequences for the study of photoperiodic control of molt and expression of annual routines. PMID- 23638352 TI - Evaluation of animal control measures on pet demographics in Santa Clara County, California, 1993-2006. AB - The measurable benefits of animal control programs are unknown and the aim of this study was to determine the impact of these programs on pet population changes. A prospective cross-sectional study of 1000 households was implemented in 2005 to evaluate characteristics of the owned and unowned population of dogs and cats in Santa Clara County, California. The same population was previously studied 12 years earlier. During this time period, the county instituted in 1994 and then subsequently disestablished a municipal spay/neuter voucher program for cats. Dog intakes declined from 1992-2005, as they similarly did for an adjacent county (San Mateo). However, cat intakes declined significantly more in Santa Clara County than San Mateo, with an average annual decline of approximately 700 cats for the 12 year period. Time series analysis showed a greater than expected decline in the number of cats surrendered to shelters in Santa Clara County during the years the voucher program was in effect (1994-2005). The net savings to the county by reducing the number of cat shelter intakes was estimated at approximately $1.5 million. The measurable benefits of animal control programs are unknown and the aim of this study was to determine the impact of these programs on pet population changes. PMID- 23638353 TI - Perceptual elements in Penn & Teller's "Cups and Balls" magic trick. AB - Magic illusions provide the perceptual and cognitive scientist with a toolbox of experimental manipulations and testable hypotheses about the building blocks of conscious experience. Here we studied several sleight-of-hand manipulations in the performance of the classic "Cups and Balls" magic trick (where balls appear and disappear inside upside-down opaque cups). We examined a version inspired by the entertainment duo Penn & Teller, conducted with three opaque and subsequently with three transparent cups. Magician Teller used his right hand to load (i.e. introduce surreptitiously) a small ball inside each of two upside-down cups, one at a time, while using his left hand to remove a different ball from the upside down bottom of the cup. The sleight at the third cup involved one of six manipulations: (a) standard maneuver, (b) standard maneuver without a third ball, (c) ball placed on the table, (d) ball lifted, (e) ball dropped to the floor, and (f) ball stuck to the cup. Seven subjects watched the videos of the performances while reporting, via button press, whenever balls were removed from the cups/table (button "1") or placed inside the cups/on the table (button "2"). Subjects' perception was more accurate with transparent than with opaque cups. Perceptual performance was worse for the conditions where the ball was placed on the table, or stuck to the cup, than for the standard maneuver. The condition in which the ball was lifted displaced the subjects' gaze position the most, whereas the condition in which there was no ball caused the smallest gaze displacement. Training improved the subjects' perceptual performance. Occlusion of the magician's face did not affect the subjects' perception, suggesting that gaze misdirection does not play a strong role in the Cups and Balls illusion. Our results have implications for how to optimize the performance of this classic magic trick, and for the types of hand and object motion that maximize magic misdirection. PMID- 23638356 TI - Glucose-6-phosphate dehydrogenase regulation in the hepatopancreas of the anoxia tolerant marine mollusc, Littorina littorea. AB - Glucose-6-phosphate dehydrogenase (G6PDH) gates flux through the pentose phosphate pathway and is key to cellular antioxidant defense due to its role in producing NADPH. Good antioxidant defenses are crucial for anoxia-tolerant organisms that experience wide variations in oxygen availability. The marine mollusc, Littorina littorea, is an intertidal snail that experiences daily bouts of anoxia/hypoxia with the tide cycle and shows multiple metabolic and enzymatic adaptations that support anaerobiosis. This study investigated the kinetic, physical and regulatory properties of G6PDH from hepatopancreas of L. littorea to determine if the enzyme is differentially regulated in response to anoxia, thereby providing altered pentose phosphate pathway functionality under oxygen stress conditions. Several kinetic properties of G6PDH differed significantly between aerobic and 24 h anoxic conditions; compared with the aerobic state, anoxic G6PDH (assayed at pH 8) showed a 38% decrease in K m G6P and enhanced inhibition by urea, whereas in pH 6 assays K m NADP and maximal activity changed significantly between the two states. The mechanism underlying anoxia-responsive changes in enzyme properties proved to be a change in the phosphorylation state of G6PDH. This was documented with immunoblotting using an anti-phosphoserine antibody, in vitro incubations that stimulated endogenous protein kinases versus protein phosphatases and significantly changed K m G6P, and phosphorylation of the enzyme with (32)P-ATP. All these data indicated that the aerobic and anoxic forms of G6PDH were the high and low phosphate forms, respectively, and that phosphorylation state was modulated in response to selected endogenous protein kinases (PKA or PKG) and protein phosphatases (PP1 or PP2C). Anoxia-induced changes in the phosphorylation state of G6PDH may facilitate sustained or increased production of NADPH to enhance antioxidant defense during long term anaerobiosis and/or during the transition back to aerobic conditions when the reintroduction of oxygen causes a rapid increase in oxidative stress. PMID- 23638355 TI - Iodine nutrition and toxicity in Atlantic cod (Gadus morhua) larvae. AB - Copepods as feed promote better growth and development in marine fish larvae than rotifers. However, unlike rotifers, copepods contain several minerals such as iodine (I), at potentially toxic levels. Iodine is an essential trace element and both under and over supply of I can inhibit the production of the I containing thyroid hormones. It is unknown whether marine fish larvae require copepod levels of I or if mechanisms are present that prevent I toxicity. In this study, larval Atlantic cod (Gadus morhua) were fed rotifers enriched to intermediate (26 mg I kg(-1) dry weight; MI group) or copepod (129 mg I kg(-1) DW; HI group) I levels and compared to cod larvae fed control rotifers (0.6 mg I kg(-1) DW). Larval I concentrations were increased by 3 (MI) and 7 (HI) fold compared to controls during the rotifer feeding period. No differences in growth were observed, but the HI diet increased thyroid follicle colloid to epithelium ratios, and affected the essential element concentrations of larvae compared to the other groups. The thyroid follicle morphology in the HI larvae is typical of colloid goitre, a condition resulting from excessive I intake, even though whole body I levels were below those found previously in copepod fed cod larvae. This is the first observation of dietary induced I toxicity in fish, and suggests I toxicity may be determined to a greater extent by bioavailability and nutrient interactions than by total body I concentrations in fish larvae. Rotifers with 0.6 mg I kg(-1) DW appeared sufficient to prevent gross signs of I deficiency in cod larvae reared with continuous water exchange, while modelling of cod larvae versus rotifer I levels suggests that optimum I levels in rotifers for cod larvae is 3.5 mg I kg( 1) DW. PMID- 23638357 TI - Poorer verbal working memory for a second language selectively impacts academic achievement in university medical students. AB - Working memory (WM) is often poorer for a second language (L2). In low noise conditions, people listening to a language other than their first language (L1) may have similar auditory perception skills for that L2 as native listeners, but do worse in high noise conditions, and this has been attributed to the poorer WM for L2. Given that WM is critical for academic success in children and young adults, these speech in noise effects have implications for academic performance where the language of instruction is L2 for a student. We used a well-established Speech-in-Noise task as a verbal WM (vWM) test, and developed a model correlating vWM and measures of English proficiency and/or usage to scholastic outcomes in a multi-faceted assessment medical education program. Significant differences in Speech-Noise Ratio (SNR50) values were observed between medical undergraduates who had learned English before or after five years of age, with the latter group doing worse in the ability to extract whole connected speech in the presence of background multi-talker babble (Student-t tests, p < 0.001). Significant negative correlations were observed between the SNR50 and seven of the nine variables of English usage, learning styles, stress, and musical abilities in a questionnaire administered to the students previously. The remaining two variables, Perceived Stress Scale (PSS) and the Age of Acquisition of English (AoAoE) were significantly positively correlated with the SNR50, showing that those with a poorer capacity to discriminate simple English sentences from noise had learnt English later in life and had higher levels of stress - all characteristics of the international students. Local students exhibited significantly lower SNR50 scores and were significantly younger when they first learnt English. No significant correlation was detected between the SNR50 and the students' Visual/Verbal Learning Style (r = -0.023). Standard multiple regression was carried out to assess the relationship between language proficiency and verbal working memory (SNR50) using 5 variables of L2 proficiency, with the results showing that the variance in SNR50 was significantly predicted by this model (r (2) = 0.335). Hierarchical multiple regression was then used to test the ability of three independent variable measures (SNR50, age of acquisition of English and English proficiency) to predict academic performance as the dependent variable in a factor analysis model which predicted significant performance differences in an assessment requiring communications skills (p = 0.008), but not on a companion assessment requiring knowledge of procedural skills, or other assessments requiring factual knowledge. Thus, impaired vWM for an L2 appears to affect specific communications-based assessments in university medical students. PMID- 23638358 TI - A metagenomic insight into freshwater methane-utilizing communities and evidence for cooperation between the Methylococcaceae and the Methylophilaceae. AB - We investigated microbial communities active in methane oxidation in lake sediment at different oxygen tensions and their response to the addition of nitrate, via stable isotope probing combined with deep metagenomic sequencing. Communities from a total of four manipulated microcosms were analyzed, supplied with (13)C-methane in, respectively, ambient air, ambient air with the addition of nitrate, nitrogen atmosphere and nitrogen atmosphere with the addition of nitrate, and these were compared to the community from an unamended sediment sample. We found that the major group involved in methane oxidation in both aerobic and microaerobic conditions were members of the family Methylococcaceae, dominated by species of the genus Methylobacter, and these were stimulated by nitrate in aerobic but not microaerobic conditions. In aerobic conditions, we also noted a pronounced response to both methane and nitrate by members of the family Methylophilaceae that are non-methane-oxidizing methylotrophs, and predominantly by the members of the genus Methylotenera. The relevant abundances of the Methylococcaceae and the Methylophilaceae and their coordinated response to methane and nitrate suggest that these species may be engaged in cooperative behavior, the nature of which remains unknown. PMID- 23638354 TI - Malleable ribonucleoprotein machine: protein intrinsic disorder in the Saccharomyces cerevisiae spliceosome. AB - Recent studies revealed that a significant fraction of any given proteome is presented by proteins that do not have unique 3D structures as a whole or in significant parts. These intrinsically disordered proteins possess dramatic structural and functional variability, being especially enriched in signaling and regulatory functions since their lack of fixed structure defines their ability to be involved in interaction with several proteins and allows them to be re-used in multiple pathways. Among recognized disorder-based protein functions are interactions with nucleic acids and multi-target binding; i.e., the functions ascribed to many spliceosomal proteins. Therefore, the spliceosome, a multimegadalton ribonucleoprotein machine catalyzing the excision of introns from eukaryotic pre-mRNAs, represents an attractive target for the focused analysis of the abundance and functionality of intrinsic disorder in its proteinaceous components. In yeast cells, spliceosome consists of five small nuclear RNAs (U1, U2, U4, U5, and U6) and a range of associated proteins. Some of these proteins constitute cores of the corresponding snRNA-protein complexes known as small nuclear ribonucleoproteins (snRNPs). Other spliceosomal proteins have various auxiliary functions. To gain better understanding of the functional roles of intrinsic disorder, we have studied the prevalence of intrinsically disordered proteins in the yeast spliceosome using a wide array of bioinformatics methods. Our study revealed that similar to the proteins associated with human spliceosomes (Korneta & Bujnicki, 2012), proteins found in the yeast spliceosome are enriched in intrinsic disorder. PMID- 23638359 TI - Development and evolution of the unique cetacean dentition. AB - The evolutionary success of mammals is rooted in their high metabolic rate. A high metabolic rate is sustainable thanks to efficient food processing and that in turn is facilitated by precise occlusion of the teeth and the acquisition of rhythmic mastication. These major evolutionary innovations characterize most members of the Class Mammalia. Cetaceans are one of the few groups of mammals in which precise occlusion has been secondarily lost. Most toothed whales have an increased number of simple crowned teeth that are similar along the tooth row. Evolution toward these specializations began immediately after the time cetaceans transitioned from terrestrial-to-marine environments. The fossil record documents the critical aspects of occlusal evolution of cetaceans, and allows us to pinpoint the evolutionary timing of the macroevolutionary events leading to their unusual dental morphology among mammals. The developmental controls of tooth differentiation and tooth number have been studied in a few mammalian clades, but nothing is known about how these controls differ between cetaceans and mammals that retain functional occlusion. Here we show that pigs, a cetacean relative with regionalized tooth morphology and complex tooth crowns, retain the typical mammalian gene expression patterns that control early tooth differentiation, expressing Bmp4 in the rostral (mesial, anterior) domain of the jaw, and Fgf8 caudally (distal, posterior). By contrast, dolphins have lost these regional differences in dental morphology and the Bmp4 domain is extended into the caudal region of the developing jaw. We hypothesize that the functional constraints underlying mammalian occlusion have been released in cetaceans, facilitating changes in the genetic control of early dental development. Such major developmental changes drive morphological evolution and are correlated with major shifts in diet and food processing during cetacean evolution. PMID- 23638360 TI - Repeated hands-and-knees positioning during labour: a randomized pilot study. AB - Background. Caesarean birth rates in North America continue to rise, in the absence of benefit for mothers and babies. One reason may be that hospitalized labouring women spend most of their labours in recumbent or semi-recumbent positions. Although hands-and-knees position has theoretical advantages, efforts to encourage its adoption in practice are severely hampered by the lack of compelling evidence that it is beneficial. Before a definitive, large scale trial, with spontaneous vaginal birth as the primary outcome, could be justified in terms of time, effort, and expense, several feasibility and acceptability questions had to be addressed. We aimed to enrol 60 women in a pilot study to assess feasibility and acceptability of the trial protocol, and to obtain estimates of treatment effects on method of birth and persistent back pain. Methods. We conducted a pilot study at two North American hospitals. In ten months of recruitment, 30 nulliparous women in labour at term were randomly allocated to either usual care (use of any position during labour except hands and-knees) or to try hands-and-knees for 15 min every hour during labour. Data were collected about compliance, acceptability, persistent back pain, intrapartum interventions, and women's views of their experiences. Results. Although mean length of time from randomization to delivery was over 12 hours, only 9 of the 16 women allocated to repeated hands-and-knees used it more than twice. Two of the 14 in the usual care group used hands-and-knees once. Twenty-seven women had regional analgesia (15 in the hands-and-knees group and 12 in the usual care group). Eleven in the hands-and-knees group and 14 in the usual care group had spontaneous vaginal births. One woman (in the hands-and-knees group) had a vacuum extraction. Four women in the hands-and-knees group and none in the usual care group gave birth by caesarean section. Hourly back pain ratings were highly variable in both groups, covering the full range of possible scores. Given the low compliance with the hands-and-knees position, it was not possible to explore relationships between use of the position and persistent back pain scores. When asked to rate their overall satisfaction with their birth experiences, the hands and-knees group's ratings tended to be lower than those in the usual care group, although 11 in the hands-and-knees group and 8 in the usual care group stated they would probably or definitely try the position in a subsequent labour. Conclusion. We concluded that we could not justify the time and expense associated with a definitive trial. However such a trial could be feasible with modifications to eligibility criteria and careful selection of suitable settings. PMID- 23638361 TI - Organ homologies in orchid flowers re-interpreted using the Musk Orchid as a model. AB - Background and Aims. The presence of novel structures in orchid flowers, including auricles, rostellum and bursicles on the gynostemium and a lobed labellum, has prompted long-standing homology disputes, fuelled by conflicting evidence from a wide range of sources. Re-assessment of this debate using an improved model is timely, following recent phylogenetic insights and on the cusp of a revolution in developmental genetics. Methods. We use new data from floral development and anatomy in the small-flowered terrestrial orchid Herminium monorchis as a model to explore organ homologies in orchid flowers within the context of a review of recent literature on developmental genetics. Key Results. The apex of the median carpel of Herminium is trilobed, and the bursicles develop from its lateral lobes, relatively late in flower ontogeny. The bursicles enclose the viscidia, which adhere to the tapetal remnants to form a caudicle linking the viscidium with the pollinium. The auricles are initiated earlier than the bursicles, but they also remain unvascularized. The deeply trilobed labellum possesses three vascular traces, in contrast with the lateral petals, each of which contains a single vascular trace. The two lateral labellum traces diverge from the traces supplying the two adjacent lateral sepals. Data from flower ontogeny and anatomy conflict with respect to organ homologies. Conclusions. Much progress has recently been made in understanding the exceptional differentiation shown by orchids among perianth segments, focusing on multiple copies of the DEF/AP3 subclass of B-class MADS-box genes. In contrast, untangling homologies of profound congenital union of multiple floral organs forming the orchid gynostemium is hampered by their profound congenital union, which we ascribe to overlap in gene expression between organs. Thus, the functional morphology of the orchid flower could ultimately reflect extreme synorganization and associated genetic integration. Analogizing the deeply lobed orchid labellum with a compound leaf, we speculate that KNOX genes could be implicated not only in their demonstrated role in spur development but also in the development of both the characteristic lobed morphology of the orchid labellum and the lobing of the median carpel that differentiates the bursicles and rostellum. PMID- 23638362 TI - Novel enzyme-polymer conjugates for biotechnological applications. AB - In the present research, a rapid, simple and efficient chemoselective method for the site-directed incorporation of tailor-made polymers into protein to create biocatalysts with excellent properties for pharmaceutical industrial purpose has been performed. First we focused on the protein engineering of the Geobacillus thermocatenulatus lipase 2 (BTL2) to replace the two cysteines (Cys65, Cys296) in the wild type enzyme (BTL-WT) by two serines. Then, by similar mode, a unique cysteine was introduced in the lid area of the protein. For the site-directed polymer incorporation, a set of different tailor-made thiol-ionic-polymers were synthesized and the protein cysteine was previously activated with 2,2 dithiodipyridine (2-PDS) to allow the disulfide exchange. The protected BTL variants were specifically modified with the different polymers in excellent yields, creating a small library of new biocatalysts. Different and important changes in the catalytic properties, possible caused by structural changes in the lid region, were observed. The different modified biocatalysts were tested in the synthesis of intermediates of antiviral and antitumor drugs, like nucleoside analogues and derivatives of phenylglutaric acid. In the hydrolysis of per acetylated thymidine, the best biocatalyst was the BTL*-193-DextCOOH , where the activity was increased in 3-fold and the regioselectivity was improved, reaching a yield of 92% of 3'-O-acetyl-thymidine. In the case of the asymmetric hydrolysis of dimethyl phenylglutarate, the best result was found with BTL*-193-DextNH2 6000, where the enzyme activity was increased more than 5-fold and the enantiomeric excess was >99%. PMID- 23638363 TI - Reduced expression of glycolate oxidase leads to enhanced disease resistance in rice. AB - Glycolate oxidase (GLO) is a key enzyme in photorespiration, catalyzing the oxidation of glycolate to glyoxylate. Arabidopsis GLO is required for nonhost defense responses to Pseudomonas syringae and for tobacco Pto/AvrPto-mediated defense responses. We previously described identification of rice GLO1 that interacts with a glutaredoxin protein, which in turn interacts with TGA transcription factors. TGA transcription factors are well known to participate in NPR1/NH1-mediated defense signaling, which is crucial to systemic acquired resistance in plants. Here we demonstrate that reduction of rice GLO1 expression leads to enhanced resistance to Xanthomonas oryzae pv oryzae (Xoo). Constitutive silencing of GLO1 leads to programmed cell death, resulting in a lesion-mimic phenotype and lethality or reduced plant growth and development, consistent with previous reports. Inducible silencing of GLO1, employing a dexamethasone-GVG (Gal4 DNA binding domain-VP16 activation domain-glucocorticoid receptor fusion) inducible system, alleviates these detrimental effects. Silencing of GLO1 results in enhanced resistance to Xoo, increased expression of defense regulators NH1, NH3, and WRKY45, and activation of PR1 expression. PMID- 23638364 TI - Anti-apoptotic signaling as a cytoprotective mechanism in mammalian hibernation. AB - In the context of normal cell turnover, apoptosis is a natural phenomenon involved in making essential life and death decisions. Apoptotic pathways balance signals which promote cell death (pro-apoptotic pathways) or counteract these signals (anti-apoptotic pathways). We proposed that changes in anti-apoptotic proteins would occur during mammalian hibernation to aid cell preservation during prolonged torpor under cellular conditions that are highly injurious to most mammals (e.g. low body temperatures, ischemia). Immunoblotting was used to analyze the expression of proteins associated with pro-survival in six tissues of thirteen-lined ground squirrels, Ictidomys tridecemlineatus. The brain showed a concerted response to torpor with significant increases in the levels of all anti apoptotic targets analyzed (Bcl-2, Bcl-xL, BI-1, Mcl-1, cIAP1/2, xIAP) as well as enhanced phosphorylation of Bcl-2 at S70 and T56. Heart responded similarly with most anti-apoptotic proteins elevated significantly during torpor except for Bcl xL and xIAP that decreased and Mcl-1 that was unaltered. In liver, BI-1 increased whereas cIAP1/2 decreased. In kidney, there was an increase in BI-1, cIAP and xIAP but decreases in Bcl-xL and p-Bcl-2(T56) content. In brown adipose tissue, protein levels of BI-1, cIAP1/2, and xIAP decreased significantly during torpor (compared with euthermia) whereas Bcl-2, Bcl-xL, Mcl-1 were unaltered; however, Bcl-2 showed enhanced phosphorylation at Thr56 but not at Ser70. In skeletal muscle, only xIAP levels changed significantly during torpor (an increase). The data show that anti-apoptotic pathways have organ-specific responses in hibernators with a prominent potential role in heart and brain where coordinated enhancement of anti-apoptotic proteins occurred in response to torpor. PMID- 23638365 TI - The roles of STP and LTP in synaptic encoding. AB - Long-term potentiation (LTP), a cellular model of learning and memory, is generally regarded as a unitary phenomenon that alters the strength of synaptic transmission by increasing the postsynaptic response to the release of a quantum of neurotransmitter. LTP, at CA3-CA1 synapses in the hippocampus, contains a stimulation-labile phase of short-term potentiation (STP, or transient LTP, t LTP) that decays into stable LTP. By studying the responses of populations of neurons to brief bursts of high-frequency afferent stimulation before and after the induction of LTP, we found that synaptic responses during bursts are potentiated equally during LTP but not during STP. We show that STP modulates the frequency response of synaptic transmission whereas LTP preserves the fidelity. Thus, STP and LTP have different functional consequences for the transfer of synaptic information. PMID- 23638366 TI - A practical implementation of de-Pake-ing via weighted Fourier transformation. AB - We provide an NMRPipe macro to meet an increasing need in membrane biophysics for facile de-Pake-ing of axially symmetric deuterium, and to an extent phosphorous, static lineshapes. The macro implements the development of McCabe & Wassall (1997), and is run as a simple replacement for the usual Fourier transform step in an NMRPipe processing procedure. PMID- 23638367 TI - Analysis of innate and acquired resistance to anti-CD20 antibodies in malignant and nonmalignant B cells. AB - The anti-CD20 monoclonal antibody, rituximab, provides a significant therapeutic benefit for patients with B-cell disorders. However, response to therapy varies and relapses are common, so an understanding of both inherited and acquired rituximab resistance is needed. In order to identify mechanisms of inherited resistance, sensitive versus resistant individuals were selected from a survey of 92 immortalized lymphoblastoid B-cell lines from normal individuals. Levels of CD20 protein and surface expression were lower in the resistant group. In contrast, CD20 mRNA levels were not correlated with susceptibility, suggesting regulation at a post-transcriptional level. To examine acquired resistance, resistant sublines were selected from both lymphoblastoid as well as lymphoma cell lines. Confirming previous findings, there was significant down-regulation of CD20 protein expression in all the resistant sublines. CD20 mRNA splice variants are reported to be associated with development of resistance. Three splice variants were observed in our cell lines, each lacking the binding epitope for rituximab, but none were associated with rituximab resistance. The second generation anti-CD20 mAb, ofatumumab, was more active compared with rituximab in vitro in the survey of all B-cell lines, mirroring results that have been reported previously with malignant B-cells. These studies show that normal B lymphoblastoid cell lines can be used to model both innate and acquired mechanisms of resistance. They validate the important role of CD20 expression and enable future genetic studies to identify additional mediators of anti-CD20 mAb resistance. PMID- 23638369 TI - A perfusion study of the handling of urea and urea analogues by the gills of the dogfish shark (Squalus acanthias). AB - The branchial mechanism of urea retention in elasmobranchs was investigated using an in vitro isolated-perfused head preparation, as well as in vivo samples, in the spiny dogfish shark. Both in vivo and in control saline perfusions containing 350 mmol L(-1) urea, calculated intracellular urea concentrations in gill epithelial cells were close to extracellular concentrations. Urea efflux to the external water fell only non-significantly, and calculated gill intracellular urea concentration did not change when perfusate urea concentration was reduced from 350 to 175 mmol L(-1) with osmotic compensation by 175 mmol L(-1) mannitol. However, when the urea analogues thiourea or acetamide were present in the perfusate at concentrations equimolar (175 mmol L(-1)) to those of urea (175 mmol L(-1)), urea efflux rates were increased 4-fold and 6.5-fold respectively, and calculated gill intracellular urea concentrations were depressed by about 55%. Analogue efflux rates were similar to urea efflux rates. Previous studies have argued that either the basolateral or apical membranes provided the limiting permeability barrier, and/or that a back-transporter on the basolateral membranes of gill cells is responsible for urea retention. The present results provide new evidence that the apical membrane is the limiting factor in maintaining gill urea impermeability, and raise the prospect that a urea back-transporter, which can be competitively inhibited by thiourea and acetamide, operates at the apical membrane. PMID- 23638368 TI - Associations between the human intestinal microbiota, Lactobacillus rhamnosus GG and serum lipids indicated by integrated analysis of high-throughput profiling data. AB - Accumulating evidence indicates that the intestinal microbiota regulates our physiology and metabolism. Bacteria marketed as probiotics confer health benefits that may arise from their ability to affect the microbiota. Here high-throughput screening of the intestinal microbiota was carried out and integrated with serum lipidomic profiling data to study the impact of probiotic intervention on the intestinal ecosystem, and to explore the associations between the intestinal bacteria and serum lipids. We performed a comprehensive intestinal microbiota analysis using a phylogenetic microarray before and after Lactobacillus rhamnosus GG intervention. While a specific increase in the L. rhamnosus-related bacteria was observed during the intervention, no other changes in the composition or stability of the microbiota were detected. After the intervention, lactobacilli returned to their initial levels. As previously reported, also the serum lipid profiles remained unaltered during the intervention. Based on a high-resolution microbiota analysis, intake of L. rhamnosus GG did not modify the composition of the intestinal ecosystem in healthy adults, indicating that probiotics confer their health effects by other mechanisms. The most prevailing association between the gut microbiota and lipid profiles was a strong positive correlation between uncultured phylotypes of Ruminococcus gnavus-group and polyunsaturated serum triglycerides of dietary origin. Moreover, a positive correlation was detected between serum cholesterol and Collinsella (Coriobacteriaceae). These associations identified with the spectrometric lipidome profiling were corroborated by enzymatically determined cholesterol and triglyceride levels. Actinomycetaceae correlated negatively with triglycerides of highly unsaturated fatty acids while a set of Proteobacteria showed negative correlation with ether phosphatidylcholines. Our results suggest that several members of the Firmicutes, Actinobacteria and Proteobacteria may be involved in the metabolism of dietary and endogenous lipids, and provide a scientific rationale for further human studies to explore the role of intestinal microbes in host lipid metabolism. PMID- 23638370 TI - Coronatine inhibits stomatal closure and delays hypersensitive response cell death induced by nonhost bacterial pathogens. AB - Pseudomonas syringae is the most widespread bacterial pathogen in plants. Several strains of P. syringae produce a phytotoxin, coronatine (COR), which acts as a jasmonic acid mimic and inhibits plant defense responses and contributes to disease symptom development. In this study, we found that COR inhibits early defense responses during nonhost disease resistance. Stomatal closure induced by a nonhost pathogen, P. syringae pv. tabaci, was disrupted by COR in tomato epidermal peels. In addition, nonhost HR cell death triggered by P. syringae pv. tabaci on tomato was remarkably delayed when COR was supplemented along with P. syringae pv. tabaci inoculation. Using isochorismate synthase (ICS)-silenced tomato plants and transcript profiles of genes in SA- and JA-related defense pathways, we show that COR suppresses SA-mediated defense during nonhost resistance. PMID- 23638371 TI - Phenotypic characterization of patients with deletions in the 3'-flanking SHOX region. AB - Context. Leri-Weill dyschondrosteosis is a clinically variable skeletal dysplasia, caused by SHOX deletion or mutations, or a deletion of enhancer sequences in the 3'-flanking region. Recently, a 47.5 kb recurrent PAR1 deletion downstream of SHOX was reported, but its frequency and clinical importance are still unknown. Objective. This study aims to compare the clinical features of different sizes of deletions in the 3'-flanking SHOX region in order to determine the relevance of the regulatory sequences in this region. Design. We collected DNA from 28 families with deletions in the 3'-PAR1 region. Clinical data were available from 23 index patients and 21 relatives. Results. In 9 families (20 individuals) a large deletion ( ~ 200-900 kb) was found and in 19 families (35 individuals) a small deletion was demonstrated, equal to the recently described 47.5 kb PAR1 deletion. Median height SDS, sitting height/height ratio SDS and the presence of Madelung deformity in patients with the 47.5 kb deletion were not significantly different from patients with larger deletions. The index patients had a median height SDS which was slightly lower than in their affected family members (p = 0.08). No significant differences were observed between male and female patients. Conclusions. The phenotype of patients with deletions in the 3' PAR1 region is remarkably variable. Height, sitting height/height ratio and the presence of Madelung deformity were not significantly different between patients with the 47.5 kb recurrent PAR1 deletion and those with larger deletions, suggesting that this enhancer plays an important role in SHOX expression. PMID- 23638372 TI - Why sauropods had long necks; and why giraffes have short necks. AB - The necks of the sauropod dinosaurs reached 15 m in length: six times longer than that of the world record giraffe and five times longer than those of all other terrestrial animals. Several anatomical features enabled this extreme elongation, including: absolutely large body size and quadrupedal stance providing a stable platform for a long neck; a small, light head that did not orally process food; cervical vertebrae that were both numerous and individually elongate; an efficient air-sac-based respiratory system; and distinctive cervical architecture. Relevant features of sauropod cervical vertebrae include: pneumatic chambers that enabled the bone to be positioned in a mechanically efficient way within the envelope; and muscular attachments of varying importance to the neural spines, epipophyses and cervical ribs. Other long-necked tetrapods lacked important features of sauropods, preventing the evolution of longer necks: for example, giraffes have relatively small torsos and large, heavy heads, share the usual mammalian constraint of only seven cervical vertebrae, and lack an air-sac system and pneumatic bones. Among non-sauropods, their saurischian relatives the theropod dinosaurs seem to have been best placed to evolve long necks, and indeed their necks probably surpassed those of giraffes. But 150 million years of evolution did not suffice for them to exceed a relatively modest 2.5 m. PMID- 23638373 TI - Pain assessment in children undergoing venipuncture: the Wong-Baker faces scale versus skin conductance fluctuations. AB - The aim of this study was to evaluate the efficacy of the subjective Wong-Baker faces pain rating scale (WBFS) and of the objective skin conductance fluctuation (SCF) test in assessing pain in children undergoing venipuncture. One-hundred and fifty children (aged 5-16 years) entered the study. All underwent venipuncture at the antecubital fossa to collect blood specimens for routine testing in the same environmental conditions. After venipuncture, the children indicated their pain intensity using the WBFS, whereas the number of SCFs was recorded before, during and after venipuncture. So, pain level was measured in each child with WBFS and SCF. We found that the level of WBFS-assessed pain was lower in all children, particularly those above 8 years of age, than SCF-assessed pain (p < 0.0001). Moreover, the number of SCFs was significantly higher during venipuncture than before or after venipuncture (p < 0.0001). At multivariate regression analysis, age and previous experience of venipuncture influenced the WBFS (beta = -1.81, p < 0.001, and beta = -0.86, p < 0.001, respectively) but not SCFs. In conclusion, although both procedures can be useful for research and clinical practice, our findings show that WBFS was affected by age and previous venipuncture, whereas SCF produced uniform data. If verified in other studies, our results should be taken into account when using these tools to evaluate pain in children. PMID- 23638374 TI - Validation of the Emotiv EPOC((r)) EEG gaming system for measuring research quality auditory ERPs. AB - Background. Auditory event-related potentials (ERPs) have proved useful in investigating the role of auditory processing in cognitive disorders such as developmental dyslexia, specific language impairment (SLI), attention deficit hyperactivity disorder (ADHD), schizophrenia, and autism. However, laboratory recordings of auditory ERPs can be lengthy, uncomfortable, or threatening for some participants - particularly children. Recently, a commercial gaming electroencephalography (EEG) system has been developed that is portable, inexpensive, and easy to set up. In this study we tested if auditory ERPs measured using a gaming EEG system (Emotiv EPOC((r)), www.emotiv.com) were equivalent to those measured by a widely-used, laboratory-based, research EEG system (Neuroscan). Methods. We simultaneously recorded EEGs with the research and gaming EEG systems, whilst presenting 21 adults with 566 standard (1000 Hz) and 100 deviant (1200 Hz) tones under passive (non-attended) and active (attended) conditions. The onset of each tone was marked in the EEGs using a parallel port pulse (Neuroscan) or a stimulus-generated electrical pulse injected into the O1 and O2 channels (Emotiv EPOC((r))). These markers were used to calculate research and gaming EEG system late auditory ERPs (P1, N1, P2, N2, and P3 peaks) and the mismatch negativity (MMN) in active and passive listening conditions for each participant. Results. Analyses were restricted to frontal sites as these are most commonly reported in auditory ERP research. Intra-class correlations (ICCs) indicated that the morphology of the research and gaming EEG system late auditory ERP waveforms were similar across all participants, but that the research and gaming EEG system MMN waveforms were only similar for participants with non-noisy MMN waveforms (N = 11 out of 21). Peak amplitude and latency measures revealed no significant differences between the size or the timing of the auditory P1, N1, P2, N2, P3, and MMN peaks. Conclusions. Our findings suggest that the gaming EEG system may prove a valid alternative to laboratory ERP systems for recording reliable late auditory ERPs (P1, N1, P2, N2, and the P3) over the frontal cortices. In the future, the gaming EEG system may also prove useful for measuring less reliable ERPs, such as the MMN, if the reliability of such ERPs can be boosted to the same level as late auditory ERPs. PMID- 23638375 TI - Personality change after Internet-delivered cognitive behavior therapy for depression. AB - Background. The Temperament and Character Inventory (TCI) by Cloninger is a widely used instrument to measure personality dimensions. Two dimensions of the TCI, Harm avoidance (HA) and Self-Directedness (SD), are known to be influenced by depressed mood. This study investigated changes in HA and SD after 10 weeks of Internet-delivered cognitive behavior therapy (ICBT) in a sample of clinically depressed subjects (N = 108). Differences in personality changes among treatment responders and non-responders were also investigated. Exploratory investigations on changes for other TCI dimensions, were also conducted. Methods. Depressed subjects were randomized either to ICBT or to a moderated online discussion group, which served as an active control group. The interventions lasted for 10 weeks. TCI was measured at baseline and after treatment. Depressive symptoms were assessed using the Beck Depression Inventory-II. Results. There were significant changes on HA and SD after ICBT. However, when comparing post-treatment HA and SD to the control, no differences were found. Among responders, larger changes compared to non-responders were found in HA and in SD, as well as in Cooperativeness. Conclusions. The study showed that HA and SD changed after ICBT. The changes in personality seem related to improvement in depression rather than a direct effect of ICBT. PMID- 23638376 TI - Loss of CclA, required for histone 3 lysine 4 methylation, decreases growth but increases secondary metabolite production in Aspergillus fumigatus. AB - Secondary metabolite (SM) production in filamentous fungi is mechanistically associated with chromatin remodeling of specific SM clusters. One locus recently shown to be involved in SM suppression in Aspergillus nidulans was CclA, a member of the histone 3 lysine 4 methylating COMPASS complex. Here we examine loss of CclA and a putative H3K4 demethylase, HdmA, in the human pathogen Aspergillus fumigatus. Although deletion of hdmA showed no phenotype under the conditions tested, the cclA deletant was deficient in tri- and di-methylation of H3K4 and yielded a slowly growing strain that was rich in the production of several SMs, including gliotoxin. Similar to deletion of other chromatin modifying enzymes, DeltacclA was sensitive to 6-azauracil indicating a defect in transcriptional elongation. Despite the poor growth, the DeltacclA mutant had wild-type pathogenicity in a murine model and the Toll-deficient Drosophila model of invasive aspergillosis. These data indicate that tri- and di-methylation of H3K4 is involved in the regulation of several secondary metabolites in A. fumigatus, however does not contribute to pathogenicity under the conditions tested. PMID- 23638378 TI - Foundation species loss affects vegetation structure more than ecosystem function in a northeastern USA forest. AB - Loss of foundation tree species rapidly alters ecological processes in forested ecosystems. Tsuga canadensis, an hypothesized foundation species of eastern North American forests, is declining throughout much of its range due to infestation by the nonnative insect Adelges tsugae and by removal through pre-emptive salvage logging. In replicate 0.81-ha plots, T. canadensis was cut and removed, or killed in place by girdling to simulate adelgid damage. Control plots included undisturbed hemlock and mid-successional hardwood stands that represent expected forest composition in 50-100 years. Vegetation richness, understory vegetation cover, soil carbon flux, and nitrogen cycling were measured for two years prior to, and five years following, application of experimental treatments. Litterfall and coarse woody debris (CWD), including snags, stumps, and fallen logs and branches, have been measured since treatments were applied. Overstory basal area was reduced 60%-70% in girdled and logged plots. Mean cover and richness did not change in hardwood or hemlock control plots but increased rapidly in girdled and logged plots. Following logging, litterfall immediately decreased then slowly increased, whereas in girdled plots, there was a short pulse of hemlock litterfall as trees died. CWD volume remained relatively constant throughout but was 3-4* higher in logged plots. Logging and girdling resulted in small, short term changes in ecosystem dynamics due to rapid regrowth of vegetation but in general, interannual variability exceeded differences among treatments. Soil carbon flux in girdled plots showed the strongest response: 35% lower than controls after three years and slowly increasing thereafter. Ammonium availability increased immediately after logging and two years after girdling, due to increased light and soil temperatures and nutrient pulses from leaf-fall and reduced uptake following tree death. The results from this study illuminate ecological processes underlying patterns observed consistently in region-wide studies of adelgid-infested hemlock stands. Mechanisms of T. canadensis loss determine rates, magnitudes, and trajectories of ecological changes in hemlock forests. Logging causes abrupt, large changes in vegetation structure whereas girdling (and by inference, A. tsugae) causes sustained, smaller changes. Ecosystem processes depend more on vegetation cover per se than on species composition. We conclude that the loss of this late-successional foundation species will have long-lasting impacts on forest structure but subtle impacts on ecosystem function. PMID- 23638377 TI - A novel control of human keratin expression: cannabinoid receptor 1-mediated signaling down-regulates the expression of keratins K6 and K16 in human keratinocytes in vitro and in situ. AB - Cannabinoid receptors (CB) are expressed throughout human skin epithelium. CB1 activation inhibits human hair growth and decreases proliferation of epidermal keratinocytes. Since psoriasis is a chronic hyperproliferative, inflammatory skin disease, it is conceivable that the therapeutic modulation of CB signaling, which can inhibit both proliferation and inflammation, could win a place in future psoriasis management. Given that psoriasis is characterized by up-regulation of keratins K6 and K16, we have investigated whether CB1 stimulation modulates their expression in human epidermis. Treatment of organ-cultured human skin with the CB1-specific agonist, arachidonoyl-chloro-ethanolamide (ACEA), decreased K6 and K16 staining intensity in situ. At the gene and protein levels, ACEA also decreased K6 expression of cultured HaCaT keratinocytes, which show some similarities to psoriatic keratinocytes. These effects were partly antagonized by the CB1-specific antagonist, AM251. While CB1-mediated signaling also significantly inhibited human epidermal keratinocyte proliferation in situ, as shown by K6/Ki-67-double immunofluorescence, the inhibitory effect of ACEA on K6 expression in situ was independent of its anti-proliferative effect. Given recent appreciation of the role of K6 as a functionally important protein that regulates epithelial wound healing in mice, it is conceivable that the novel CB1-mediated regulation of keratin 6/16 revealed here also is relevant to wound healing. Taken together, our results suggest that cannabinoids and their receptors constitute a novel, clinically relevant control element of human K6 and K16 expression. PMID- 23638379 TI - Pattern classification of brain activation during emotional processing in subclinical depression: psychosis proneness as potential confounding factor. AB - We used Support Vector Machine (SVM) to perform multivariate pattern classification based on brain activation during emotional processing in healthy participants with subclinical depressive symptoms. Six-hundred undergraduate students completed the Beck Depression Inventory II (BDI-II). Two groups were subsequently formed: (i) subclinical (mild) mood disturbance (n = 17) and (ii) no mood disturbance (n = 17). Participants also completed a self-report questionnaire on subclinical psychotic symptoms, the Community Assessment of Psychic Experiences Questionnaire (CAPE) positive subscale. The functional magnetic resonance imaging (fMRI) paradigm entailed passive viewing of negative emotional and neutral scenes. The pattern of brain activity during emotional processing allowed correct group classification with an overall accuracy of 77% (p = 0.002), within a network of regions including the amygdala, insula, anterior cingulate cortex and medial prefrontal cortex. However, further analysis suggested that the classification accuracy could also be explained by subclinical psychotic symptom scores (correlation with SVM weights r = 0.459, p = 0.006). Psychosis proneness may thus be a confounding factor for neuroimaging studies in subclinical depression. PMID- 23638380 TI - Development of guidelines for tertiary education institutions to assist them in supporting students with a mental illness: a Delphi consensus study with Australian professionals and consumers. AB - Background. The age at which most young people are in tertiary education is also the age of peak onset for mental illness. Because mental health problems can have adverse effects on students' academic performance and welfare, institutions require guidance how they can best provide support. However, the scientific evidence for how best to do this is relatively limited. Therefore a Delphi expert consensus study was carried out with professional and consumer experts. Methods. A systematic review of websites, books and journal articles was conducted to develop a 172 item survey containing strategies that institutions might use to support students with a mental illness. Two panels of Australian experts (74 professionals and 35 consumers) were recruited and independently rated the items over three rounds, with strategies reaching consensus on importance written into the guidelines. Results. The overall response rate across three rounds was 83% (80% consumers, 85% professionals). 155 strategies were endorsed as essential or important by at least 80% of panel members. The endorsed strategies provided information on policy, measures to promote support services, service provision, accessibility of support services, relationships between services, other types of support and issues associated with reasonable adjustments. They also provided guidance on the procedures the institutions should have for making staff aware of issues associated with mental illness, mental illness training, support for staff and communicating with a student with a mental illness. They also covered student rights and responsibilities, the procedures the institutions should have for making students aware of issues associated with mental illness, dealing with mental health crises, funding and research and evaluation. Conclusions. The guidelines provide guidance for tertiary institutions to assist them in supporting students with a mental illness. It is hoped that they may be used to inform policy and practice in tertiary institutions. PMID- 23638381 TI - The co-evolution of multiply-informed dispersal: information transfer across landscapes from neighbors and immigrants. AB - Dispersal plays a key role in natural systems by shaping spatial population and evolutionary dynamics. Dispersal has been largely treated as a population process with little attention to individual decisions and the influence of information use on the fitness benefits of dispersal despite clear empirical evidence that dispersal behavior varies among individuals. While information on local density is common, more controversial is the notion that indirect information use can easily evolve. We used an individual-based model to ask under what conditions indirect information use in dispersal will evolve. We modeled indirect information provided by immigrant arrival into a population which should be linked to overall metapopulation density. We also modeled direct information use of density which directly impacts fitness. We show that immigrant-dependent dispersal evolves and does so even when density dependent information is available. Use of two sources of information also provides benefits at the metapopulation level by reducing extinction risk and prolonging the persistence of populations. Our results suggest that use of indirect information in dispersal can evolve under conservative conditions and thus could be widespread. PMID- 23638382 TI - Does haemosporidian infection affect hematological and biochemical profiles of the endangered Black-fronted piping-guan (Aburria jacutinga)? AB - Infectious diseases can cause deleterious effects on bird species, leading to population decline and extinction. Haemosporidia can be recognized by their negative effects on host fitness, including reproductive success and immune responses. In captivity, outbreaks of haemosporidian infection have been observed in birds in zoos and aviaries. The endemic Brazilian Atlantic rainforest species Aburria jacutinga is one of the most endangered species in the Cracidae family, and wild populations of this species are currently found mainly in conservation areas in only two Brazilian states. In this study, we aimed to evaluate the effects of avian haemosporidia on hematological and biochemical parameters in two captive populations of A. jacutinga. Forty-two animals were assessed, and the haemosporidian prevalence was similar for males and females. The occurrence of haemosporidian infection in captive A. jacutinga observed in this study was similar to results found in other captive and wild birds in Brazil. We found three different lineages of haemosporidia. Two lineages were identified as Plasmodium sp., one of which was previously detected in Europe and Asia, and the other is a new lineage closely related to P. gallinaceum. A new third lineage was identified as Haemoproteus sp. We found no significant differences in hematological and biochemical values between infected and non-infected birds, and the haemosporidian lineage did not seem to have an impact on the clinical and physiological parameters of A. jacutinga. This is the first report on an evaluation of natural haemosporidian infections diagnosed by microscopic and molecular methods in A. jacutinga by hematology, blood biochemistry, and serum protein values. Determining physiological parameters, occurrence and an estimation of the impact of haemosporidia in endangered avian species may contribute to the management of species rehabilitation and conservation. PMID- 23638383 TI - Cloning, expression and characterization of an ethanol tolerant GH3 beta glucosidase from Myceliophthora thermophila. AB - The beta-glucosidase gene bgl3a from Myceliophthora thermophila, member of the fungal glycosyl hydrolase (GH) family 3, was cloned and expressed in Pichia pastoris. The mature beta-glucosidase gene, which results after the excision of one intron and the secreting signal peptide, was placed under the control of the strong alcohol oxidase promoter (AOX1) in the plasmid pPICZalphaC. The recombinant enzyme (90 kDa) was purified and characterized in order to evaluate its biotechnological potential. Recombinant P. pastoris efficiently secreted beta glucosidase into the medium and produced high level of enzymatic activity (41 U/ml) after 192 h of growth, under methanol induction. MtBgl3a was able to hydrolyze low molecular weight substrates and polysaccharides containing beta glucosidic residues. The K m was found to be 0.39 mM on p-beta-NPG and 2.64 mM on cellobiose. Optimal pH and temperature for the p-beta-NPG hydrolysis were 5.0 and 70 degrees C. The beta-glucosidase exhibits a half life of 143 min at 60 degrees C. Kinetic parameters of inhibition were determined for D-glucose, D xylose and D-gluconic acid, indicating tolerance of the enzyme for these sugars and oxidized products. The recombinant enzyme was stimulated by short chain alcohols and has been shown to efficiently synthesize methyl-D-glucoside in the presence of methanol due to its transglycosylation activity. The stability of MtBgl3a in ethanol was prominent, and it retained most of its original activity after we exposed it to 50% ethanol for 6 h. The high catalytic performance, good thermal stability and tolerance to elevated concentrations of ethanol, D-xylose and D-glucose qualify this enzyme for use in the hydrolysis of lignocellulosic biomass for biofuel production, as part of an efficient complete multi-enzyme cocktail. PMID- 23638384 TI - Microbial secondary succession in soil microcosms of a desert oasis in the Cuatro Cienegas Basin, Mexico. AB - Ecological succession is one of the most important concepts in ecology. However for microbial community succession, there is a lack of a solid theoretical framework regarding succession in microorganisms. This is in part due to microbial community complexity and plasticity but also because little is known about temporal patterns of microbial community shifts in different kinds of ecosystems, including arid soils. The Cuatro Cienegas Basin (CCB) in Coahuila, Mexico, is an arid zone with high diversity and endemisms that has recently been threatened by aquifer overexploitation. The gypsum-based soil system of the CCB is one of the most oligotrophic places in the world. We undertook a comparative 16S rRNA 454 pyrosequencing study to evaluate microbial community succession and recovery over a year after disturbance at two sites. Results were related to concurrent measurements of humidity, organic matter and total C and N content. While each site differed in both biogeochemistry and biodiversity, both present similar pattern of change at the beginning of the succession that diverged in later stages. After one year, experimentally disturbed soil was not similar to established and undisturbed adjacent soil communities indicating recovery and succession in disturbed soils is a long process. PMID- 23638385 TI - A non-cardiomyocyte autonomous mechanism of cardioprotection involving the SLO1 BK channel. AB - Opening of BK-type Ca(2+) activated K(+) channels protects the heart against ischemia-reperfusion (IR) injury. However, the location of BK channels responsible for cardioprotection is debated. Herein we confirmed that openers of the SLO1 BK channel, NS1619 and NS11021, were protective in a mouse perfused heart model of IR injury. As anticipated, deletion of the Slo1 gene blocked this protection. However, in an isolated cardiomyocyte model of IR injury, protection by NS1619 and NS11021 was insensitive to Slo1 deletion. These data suggest that protection in intact hearts occurs by a non-cardiomyocyte autonomous, SLO1 dependent, mechanism. In this regard, an in-situ assay of intrinsic cardiac neuronal function (tachycardic response to nicotine) revealed that NS1619 preserved cardiac neurons following IR injury. Furthermore, blockade of synaptic transmission by hexamethonium suppressed cardioprotection by NS1619 in intact hearts. These results suggest that opening SLO1 protects the heart during IR injury, via a mechanism that involves intrinsic cardiac neurons. Cardiac neuronal ion channels may be useful therapeutic targets for eliciting cardioprotection. PMID- 23638386 TI - A new 12-gene diagnostic biomarker signature of melanoma revealed by integrated microarray analysis. AB - Genome-wide microarray technology has facilitated the systematic discovery of diagnostic biomarkers of cancers and other pathologies. However, meta-analyses of published arrays often uncover significant inconsistencies that hinder advances in clinical practice. Here we present an integrated microarray analysis framework, based on a genome-wide relative significance (GWRS) and genome-wide global significance (GWGS) model. When applied to five microarray datasets on melanoma published between 2000 and 2011, this method revealed a new signature of 200 genes. When these were linked to so-called 'melanoma driver' genes involved in MAPK, Ca(2+), and WNT signaling pathways we were able to produce a new 12-gene diagnostic biomarker signature for melanoma (i.e., EGFR, FGFR2, FGFR3, IL8, PTPRF, TNC, CXCL13, COL11A1, CHP2, SHC4, PPP2R2C, and WNT4). We have begun to experimentally validate a subset of these genes involved in MAPK signaling at the protein level, including CXCL13, COL11A1, PTPRF and SHC4 and found these to be over-expressed in metastatic and primary melanoma cells in vitro and in situ compared to melanocytes cultured from healthy skin epidermis and normal healthy human skin. While SHC4 has been reported previously to be associated to melanoma, this is the first time CXCL13, COL11A1, and PTPRF have been associated with melanoma on experimental validation. Our computational evaluation indicates that this 12-gene biomarker signature achieves excellent diagnostic power in distinguishing metastatic melanoma from normal skin and benign nevus. Further experimental validation of the role of these 12 genes in a new signaling network may provide new insights into the underlying biological mechanisms driving the progression of melanoma. PMID- 23638387 TI - Bacterial curli protein promotes the conversion of PAP248-286 into the amyloid SEVI: cross-seeding of dissimilar amyloid sequences. AB - Fragments of prostatic acid phosphatase (PAP248-286) in human semen dramatically increase HIV infection efficiency by increasing virus adhesion to target cells. PAP248-286 only enhances HIV infection in the form of amyloid aggregates termed SEVI (Semen Enhancer of Viral Infection), however monomeric PAP248-286 aggregates very slowly in isolation. It has therefore been suggested that SEVI fiber formation in vivo may be promoted by exogenous factors. We show here that a bacterially-produced extracellular amyloid (curli or Csg) acts as a catalytic agent for SEVI formation from PAP248-286 at low concentrations in vitro, producing fibers that retain the ability to enhance HIV (Human Immunodeficiency Virus) infection. Kinetic analysis of the cross-seeding effect shows an unusual pattern. Cross-seeding PAP248-286 with curli only moderately affects the nucleation rate while significantly enhancing the growth of fibers from existing nuclei. This pattern is in contrast to most previous observations of cross seeding, which show cross-seeding partially bypasses the nucleation step but has little effect on fiber elongation. Seeding other amyloidogenic proteins (IAPP (islet amyloid polypeptide) and Abeta1-40) with curli showed varied results. Curli cross-seeding decreased the lag-time of IAPP amyloid formation but strongly inhibited IAPP elongation. Curli cross-seeding exerted a complicated concentration dependent effect on Abeta1-40 fibrillogenesis kinetics. Combined, these results suggest that the interaction of amyloidogenic proteins with preformed fibers of a different type can take a variety of forms and is not limited to epitaxial nucleation between proteins of similar sequence. The ability of curli fibers to interact with proteins of dissimilar sequences suggests cross seeding may be a more general phenomenon than previously supposed. PMID- 23638388 TI - Virus-host co-evolution under a modified nuclear genetic code. AB - Among eukaryotes with modified nuclear genetic codes, viruses are unknown. However, here we provide evidence of an RNA virus that infects a fungal host (Scheffersomyces segobiensis) with a derived nuclear genetic code where CUG codes for serine. The genomic architecture and phylogeny are consistent with infection by a double-stranded RNA virus of the genus Totivirus. We provide evidence of past or present infection with totiviruses in five species of yeasts with modified genetic codes. All but one of the CUG codons in the viral genome have been eliminated, suggesting that avoidance of the modified codon was important to viral adaptation. Our mass spectroscopy analysis indicates that a congener of the host species has co-opted and expresses a capsid gene from totiviruses as a cellular protein. Viral avoidance of the host's modified codon and host co-option of a protein from totiviruses suggest that RNA viruses co-evolved with yeasts that underwent a major evolutionary transition from the standard genetic code. PMID- 23638389 TI - A critical role for suppressors of cytokine signaling 3 in regulating LPS-induced transcriptional activation of matrix metalloproteinase-13 in osteoblasts. AB - Suppressor of cytokine signaling 3 (SOCS3) is a key regulator of cytokine signaling in macrophages and T cells. Although SOCS3 seems to contribute to the balance between the pro-inflammatory actions of IL-6 family of cytokines and anti inflammatory signaling of IL-10 by negatively regulating gp130/Jak/Stat3 signal transduction, how and the molecular mechanisms whereby SOCS3 controls the downstream impact of TLR4 are largely unknown and current data are controversial. Furthermore, very little is known regarding SOCS3 function in cells other than myeloid cells and T cells. Our previous study demonstrates that SOCS3 is expressed in osteoblasts and functions as a critical inhibitor of LPS-induced IL 6 expression. However, the function of SOCS3 in osteoblasts remains largely unknown. In the current study, we report for the first time that LPS stimulation of osteoblasts induces the transcriptional activation of matrix metalloproteinase (MMP)-13, a central regulator of bone resorption. Importantly, we demonstrate that SOCS3 overexpression leads to a significant decrease of LPS-induced MMP-13 expression in both primary murine calvariae osteoblasts and a mouse osteoblast like cell line, MC3T3-E1. Our findings implicate SOCS3 as an important regulatory mediator in bone inflammatory diseases by targeting MMP-13. PMID- 23638390 TI - Hypothyroidism and diabetes mellitus - a risky dual gestational endocrinopathy. AB - Objectives. Diabetes mellitus (DM) and hypothyroidism are each associated with increased rate of pregnancy complications. However, their combined morbidity during gestation is poorly studied. Therefore, the aims of this study were to determine the prevalence of the combined morbidity of DM & hypothyroidism and whether it is associated with adverse maternal and neonatal outcome. Study design. This population based retrospective cohort study included 87,213 women who had 232,293 deliveries. All deliveries were divided into the following groups: (1) hypothyroidism & DM (n = 171); (2) hypothyroidism (n = 1502); (3) DM (n = 13,324); and (4) deliveries of women with neither endocrinopathy, who served as a control group (n = 217, 296). Results. The prevalence of DM & hypothyroidism in our population was 0.17%. In comparisons to the other study groups, women with DM & hypothyroidism had higher rates of infertility (p < 0.001), preeclampsia (p < 0.001), chronic hypertension (p < 0.001), preterm birth (p < 0.001), and cesarean deliveries (p < 0.001). In Generalized Estimating Equations (GEE) model, hypothyroidism & DM was an independent risk factor for cesarean section (OR 3.46; 95% CI 2.53-4.75) and for preeclampsia (OR 1.82; 95%CI 1.16-2.84). Conclusion. The combination of DM & hypothyroidism is rare, yet it is associated with higher rate of infertility, cesarean sections, preterm deliveries, and hypertensive disorders of pregnancy than the rest of the population. This dual endocrinological combination is an independent risk factor for preeclampsia and cesarean section. These findings suggest that these patients are at risk for perinatal complications and should be followed and delivered as high risk pregnancies. PMID- 23638391 TI - Significant changes in the skin microbiome mediated by the sport of roller derby. AB - Diverse bacterial communities live on and in human skin. These complex communities vary by skin location on the body, over time, between individuals, and between geographic regions. Culture-based studies have shown that human to human and human to surface contact mediates the dispersal of pathogens, yet little is currently known about the drivers of bacterial community assembly patterns on human skin. We hypothesized that participation in a sport involving skin to skin contact would result in detectable shifts in skin bacterial community composition. We conducted a study during a flat track roller derby tournament, and found that teammates shared distinct skin microbial communities before and after playing against another team, but that opposing teams' bacterial communities converged during the course of a roller derby bout. Our results are consistent with the hypothesis that the human skin microbiome shifts in composition during activities involving human to human contact, and that contact sports provide an ideal setting in which to evaluate dispersal of microorganisms between people. PMID- 23638392 TI - Quantifying inter-group variability in lactation curve shape and magnitude with the MilkBot((r)) lactation model. AB - Genetic selection programs have driven development of most lactation models, to estimate the magnitude of animals' productive capacity from sampled milk production data. There has been less attention to management and research applications, where it may also be important to quantify the shape of lactation curves, and predict future daily milk production for incomplete lactations since residuals between predicted and actual daily production can be used to quantify the response to an intervention. A model may decrease the confounding effects of lactation stage, parity, breed, and possibly other factors depending on how the model is constructed and used, thus increasing the power of statistical analyses. Models with a mechanistic derivation may allow direct inference about biology from fitted production data. The MilkBot((r)) lactation model is derived from abstract suppositions about growth of udder capacity. This permits inference about shape of the lactation curve directly from parameter values, but not direct conclusions about physiology. Individual parameters relate to the overall scale of the lactation, the ramp , or rate of growth around parturition, decay describing the senescence of productive capacity (inversely related to persistence ), and the relatively insignificant time offset between calving and the physiological start of milk secretion. A proprietary algorithm was used to fit monthly test data from two parity groups in 21 randomly selected herds, and results displayed in box-and-whisker charts and Z-test tables. Fitted curves are constrained by the MilkBot((r)) equation to a single peak that blends into an exponential decline in late lactation. This is seen as an abstraction of productive capacity, with actual daily production higher or lower due to random error plus short-term environmental effects. The four MilkBot((r)) parameters, and metrics calculated directly from them including fitting error, peak milk and cumulative production, can be used to describe and compare individual lactations or groups of lactations. There is considerable intra-herd and inter-herd variability in scale, ramp, decay, RMSE, peak milk, and cumulative production, suggesting that management and environment have significant influence on both shape and magnitude of normal lactation curves. PMID- 23638393 TI - Cattle and climate in Africa: How climate variability has influenced national cattle holdings from 1961-2008. AB - The role of cattle in developing countries is as a source of high-quality food, as draft animals, and as a source of manure and fuel. Cattle represent important contribution to household incomes, and in drought prone areas they can act as an insurance against weather risk. So far, no studies have addressed how historical variations in temperature and rainfall have influenced cattle populations in Africa. The focus of this study is to assess the historical impact of climate variability on national cattle holdings. We reconstruct the cattle density and distribution for two time periods; 1955-1960 and 2000-2005. Based on estimates from FAO and official numbers, we generated a time series of cattle densities from 1961-2008, and compared these data with precipitation and temperature anomalies for the same period. We show that from 1961-2008 rainfall and temperature have been modulating, and occasionally controlling, the number of cattle in Africa. PMID- 23638394 TI - Clever strategists: Australian Magpies vary mobbing strategies, not intensity, relative to different species of predator. AB - Anti-predator behaviour of magpies was investigated, using five species of model predators, at times of raising offspring. We predicted differences in mobbing strategies for each predator presented and also that raising juveniles would affect intensity of the mobbing event. Fourteen permanent resident family groups were tested using 5 different types of predator (avian and reptilian) known to be of varying degrees of risk to magpies and common in their habitat. In all, 210 trials were conducted (across three different stages of juvenile development). We found that the stage of juvenile development did not alter mobbing behaviour significantly, but predator type did. Aerial strategies (such as swooping) were elicited by taxidermic models of raptors, whereas a taxidermic model of a monitor lizard was approached on the ground and a model snake was rarely approached. Swooping patterns also changed according to which of the three raptors was presented. Our results show that, in contrast to findings in other species, magpies vary mobbing strategy depending on the predator rather than varying mobbing intensity. PMID- 23638395 TI - Effects of manipulating slowpoke calcium-dependent potassium channel expression on rhythmic locomotor activity in Drosophila larvae. AB - Rhythmic motor behaviors are generated by networks of neurons. The sequence and timing of muscle contractions depends on both synaptic connections between neurons and the neurons' intrinsic properties. In particular, motor neuron ion currents may contribute significantly to motor output. Large conductance Ca(2+) dependent K(+) (BK) currents play a role in action potential repolarization, interspike interval, repetitive and burst firing, burst termination and interburst interval in neurons. Mutations in slowpoke (slo) genes encoding BK channels result in motor disturbances. This study examined the effects of manipulating slo channel expression on rhythmic motor activity using Drosophila larva as a model system. Dual intracellular recordings from adjacent body wall muscles were made during spontaneous crawling-related activity in larvae expressing a slo mutation or a slo RNA interference construct. The incidence and duration of rhythmic activity in slo mutants were similar to wild-type control animals, while the timing of the motor pattern was altered. slo mutants showed decreased burst durations, cycle durations, and quiescence intervals, and increased duty cycles, relative to wild-type. Expressing slo RNAi in identified motor neurons phenocopied many of the effects observed in the mutant, including decreases in quiescence interval and cycle duration. Overall, these results show that altering slo expression in the whole larva, and specifically in motor neurons, changes the frequency of crawling activity. These results suggest an important role for motor neuron intrinsic properties in shaping the timing of motor output. PMID- 23638396 TI - Immunization with tegument nucleotidases associated with a subcurative praziquantel treatment reduces worm burden following Schistosoma mansoni challenge. AB - Schistosomiasis is a debilitating disease caused by flatworm parasites of the Schistosoma genus and remains a high public health impact disease around the world, although effective treatment with Praziquantel (PZQ) has been available since the 1970s. Control of this disease would be greatly improved by the development of a vaccine, which could be combined with chemotherapy. The sequencing of the Schistosoma mansoni transcriptome and genome identified a range of potential vaccine antigens. Among these, three nucleotidases from the tegument of the parasite, presumably involved in purinergic signaling and nucleotide metabolism, were proposed as promising vaccine candidates: an alkaline phosphatase (SmAP), a phosphodiesterase (SmNPP-5) and a diphosphohydrolase (SmNTPDase). Herein, we evaluate the potential of these enzymes as vaccine antigens, with or without subcurative PZQ treatment. Immunization of mice with the recombinant proteins alone or in combination demonstrated that SmAP is the most immunogenic of the three. It induced the highest antibody levels, particularly IgG1, associated with an inflammatory cellular immune response characterized by high TNF-alpha and a Th17 response, with high IL-17 expression levels. Despite the specific immune response induced, immunization with the isolated or combined proteins did not reduce the worm burden of challenged mice. Nonetheless, immunization with SmAP alone or with the three proteins combined, together with subcurative PZQ chemotherapy was able to reduce the worm burden by around 40%. The immunogenicity and relative exposure of SmAP to the host immune system are discussed, as key factors involved in the apparently synergistic effect of SmAP immunization and subcurative PZQ treatment. PMID- 23638398 TI - Soil carbon determination by thermogravimetrics. AB - Determination of soil constituents and structure has a vital role in agriculture generally. Methods for the determination of soil carbon have in particular gained greater currency in recent times because of the potential that soils offer in providing offsets for greenhouse gas (CO2-equivalent) emissions. Ideally, soil carbon which can also be quite diverse in its makeup and origin, should be measureable by readily accessible, affordable and reliable means. Loss-on ignition is still a widely used method being suitably simple and available but may have limitations for soil C monitoring. How can these limitations be better defined and understood where such a method is required to detect relatively small changes during soil-C building? Thermogravimetric (TGA) instrumentation to measure carbonaceous components has become more interesting because of its potential to separate carbon and other components using very precise and variable heating programs. TGA related studies were undertaken to assist our understanding in the quantification of soil carbon when using methods such as loss-on-ignition. Combining instrumentation so that mass changes can be monitored by mass spectrometer ion currents has elucidated otherwise hidden features of thermal methods enabling the interpretation and evaluation of mass-loss patterns. Soil thermogravimetric work has indicated that loss-on-ignition methods are best constrained to temperatures from 200 to 430 degrees C for reliable determination for soil organic carbon especially where clay content is higher. In the absence of C-specific detection where mass only changes are relied upon, exceeding this temperature incurs increasing contributions from inorganic sources adding to mass losses with diminishing contributions related to organic matter. The smaller amounts of probably more recalcitrant organic matter released at the higher temperatures may represent mineral associated material and/or simply more refractory forms. PMID- 23638397 TI - Regulation of the heat stress response in Arabidopsis by MPK6-targeted phosphorylation of the heat stress factor HsfA2. AB - So far little is known on the functional role of phosphorylation in the heat stress response of plants. Here we present evidence that heat stress activates the Arabidopsis mitogen-activated protein kinase MPK6. In vitro and in vivo evidence is provided that MPK6 specifically targets the major heat stress transcription factor HsfA2. Activation of MPK6 results in complex formation with HsfA2. MPK6 phosphorylates HsfA2 on T249 and changes its intracellular localisation. Protein kinase and phosphatase inhibitor studies indicate that HsfA2 protein stability is regulated in a phosphorylation-dependent manner, but this mechanism is independent of MPK6. Overall, our data show that heat stress induced targeting of HsfA2 by MPK6 participates in the complex regulatory mechanism how plants respond to heat stress. PMID- 23638399 TI - Pulmonary anatomy in the Nile crocodile and the evolution of unidirectional airflow in Archosauria. AB - The lungs of birds have long been known to move air in only one direction during both inspiration and expiration through most of the tubular gas-exchanging bronchi (parabronchi). Recently a similar pattern of airflow has been observed in American alligators, a sister taxon to birds. The pattern of flow appears to be due to the arrangement of the primary and secondary bronchi, which, via their branching angles, generate inspiratory and expiratory aerodynamic valves. Both the anatomical similarity of the avian and alligator lung and the similarity in the patterns of airflow raise the possibility that these features are plesiomorphic for Archosauria and therefore did not evolve in response to selection for flapping flight or an endothermic metabolism, as has been generally assumed. To further test the hypothesis that unidirectional airflow is ancestral for Archosauria, we measured airflow in the lungs of the Nile crocodile (Crocodylus niloticus). As in birds and alligators, air flows cranially to caudally in the cervical ventral bronchus, and caudally to cranially in the dorsobronchi in the lungs of Nile crocodiles. We also visualized the gross anatomy of the primary, secondary and tertiary pulmonary bronchi of C. niloticus using computed tomography (CT) and microCT. The cervical ventral bronchus, cranial dorsobronchi and cranial medial bronchi display similar characteristics to their proposed homologues in the alligator, while there is considerable variation in the tertiary and caudal group bronchi. Our data indicate that the aspects of the crocodilian bronchial tree that maintain the aerodynamic valves and thus generate unidirectional airflow, are ancestral for Archosauria. PMID- 23638400 TI - Multiple global radiations in tadpole shrimps challenge the concept of 'living fossils'. AB - 'Living fossils', a phrase first coined by Darwin, are defined as species with limited recent diversification and high morphological stasis over long periods of evolutionary time. Morphological stasis, however, can potentially lead to diversification rates being underestimated. Notostraca, or tadpole shrimps, is an ancient, globally distributed order of branchiopod crustaceans regarded as 'living fossils' because their rich fossil record dates back to the early Devonian and their morphology is highly conserved. Recent phylogenetic reconstructions have shown a strong biogeographic signal, suggesting diversification due to continental breakup, and widespread cryptic speciation. However, morphological conservatism makes it difficult to place fossil taxa in a phylogenetic context. Here we reveal for the first time the timing and tempo of tadpole shrimp diversification by inferring a robust multilocus phylogeny of Branchiopoda and applying Bayesian divergence dating techniques using reliable fossil calibrations external to Notostraca. Our results suggest at least two bouts of global radiation in Notostraca, one of them recent, so questioning the validity of the 'living fossils' concept in groups where cryptic speciation is widespread. PMID- 23638401 TI - Mutations changing tropomodulin affinity for tropomyosin alter neurite formation and extension. AB - Assembly of the actin cytoskeleton is an important part of formation of neurites in developing neurons. Tropomodulin, a tropomyosin-dependent capping protein for the pointed end of the actin filament, is one of the key players in this process. Tropomodulin binds tropomyosin in two binding sites. Tmod1 and Tmod2, tropomodulin isoforms found in neurons, were overexpressed in PC12 cells, a model system for neuronal differentiation. Tmod1 did not affect neuronal differentiation; while cells expressing Tmod2 showed a significant reduction in the number and the length of neurites. Both tropomodulins bind short alpha-, gamma- and delta-tropomyosin isoforms. Mutations in one of the tropomyosin binding sites of Tmod1, which increased its affinity to short gamma- and delta tropomyosin isoforms, caused a decrease in binding short alpha-tropomyosin isoforms along with a 2-fold decrease in the length of neurites. Our data demonstrate that Tmod1 is involved in neuronal differentiation for proper neurite formation and outgrowth, and that Tmod2 inhibits these processes. The mutations in the tropomyosin-binding site of Tmod1 impair neurite outgrowth, suggesting that the integrity of this binding site is critical for the proper function of Tmod1 during neuronal differentiation. PMID- 23638402 TI - Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing. AB - Background. Inherited BRCA gene mutations convey a high risk for breast and ovarian cancer, but current guidelines limit BRCA mutation testing to women with early-onset cancer and relatives of mutation-positive cases. Benefits and risks of providing this information directly to consumers are unknown. Methods. To assess and quantify emotional and behavioral reactions of consumers to their 23andMe Personal Genome Service((r)) report of three BRCA mutations that are common in Ashkenazi Jews, we invited all 136 BRCA1 and BRCA2 mutation-positive individuals in the 23andMe customer database who had chosen to view their BRCA reports to participate in this IRB-approved study. We also invited 160 mutation negative customers who were matched for age, sex and ancestry. Semi-structured phone interviews were completed for 32 mutation carriers, 16 women and 16 men, and 31 non-carriers. Questions addressed personal and family history of cancer, decision and timing of viewing the BRCA report, recollection of the result, emotional responses, perception of personal cancer risk, information sharing, and actions taken or planned. Results. Eleven women and 14 men had received the unexpected result that they are carriers of a BRCA1 185delAG or 5382insC, or BRCA2 6174delT mutation. None of them reported extreme anxiety and four experienced moderate anxiety that was transitory. Remarkably, five women and six men described their response as neutral. Most carrier women sought medical advice and four underwent risk-reducing procedures after confirmatory mutation testing. Male carriers realized that their test results implied genetic risk for female relatives, and several of them felt considerably burdened by this fact. Sharing mutation information with family members led to screening of at least 30 relatives and identification of 13 additional carriers. Non-carriers did not report inappropriate actions, such as foregoing cancer screening. All but one of the 32 mutation-positive participants appreciated learning their BRCA mutation status. Conclusions. Direct access to BRCA mutation tests, considered a model for high-risk actionable genetic tests of proven clinical utility, provided clear benefits to participants. The unexpected information demonstrated a cascade effect as relatives of newly identified carriers also sought testing and more mutation carriers were identified. Given the absence of evidence for serious emotional distress or inappropriate actions in this subset of mutation-positive customers who agreed to be interviewed for this study, broader screening of Ashkenazi Jewish women for these three BRCA mutations should be considered. PMID- 23638403 TI - The effects of fixation target size and luminance on microsaccades and square wave jerks. AB - A large amount of classic and contemporary vision studies require subjects to fixate a target. Target fixation serves as a normalizing factor across studies, promoting the field's ability to compare and contrast experiments. Yet, fixation target parameters, including luminance, contrast, size, shape and color, vary across studies, potentially affecting the interpretation of results. Previous research on the effects of fixation target size and luminance on the control of fixation position rendered conflicting results, and no study has examined the effects of fixation target characteristics on square-wave jerks, the most common type of saccadic intrusion. Here we set out to determine the effects of fixation target size and luminance on the characteristics of microsaccades and square-wave jerks, over a large range of stimulus parameters. Human subjects fixated a circular target with varying luminance and size while we recorded their eye movements with an infrared video tracker (EyeLink 1000, SR Research). We detected microsaccades and SWJs automatically with objective algorithms developed previously. Microsaccade rates decreased linearly and microsaccade magnitudes increased linearly with target size. The percent of microsaccades forming part of SWJs decreased, and the time from the end of the initial SWJ saccade to the beginning of the second SWJ saccade (SWJ inter-saccadic interval; ISI) increased with target size. The microsaccadic preference for horizontal direction also decreased moderately with target size . Target luminance did not affect significantly microsaccades or SWJs, however. In the absence of a fixation target, microsaccades became scarcer and larger, while SWJ prevalence decreased and SWJ ISIs increased. Thus, the choice of fixation target can affect experimental outcomes, especially in human factors and in visual and oculomotor studies. These results have implications for previous and future research conducted under fixation conditions, and should encourage forthcoming studies to report the size of fixation targets to aid the interpretation and replication of their results. PMID- 23638404 TI - Virtual screening for oseltamivir-resistant a (H5N1) influenza neuraminidase from traditional Chinese medicine database: a combined molecular docking with molecular dynamics approach. AB - The neuraminidase (NA) of the influenza virus is the target of antiviral drug, oseltamivir. Recently, cases are reported that Influenza virus becoming resistant to oseltamivir, necessitating the development of new long-acting antiviral compounds. Most importantly, H274Y mutation in neuraminidase exhibits high levels of resistance to oseltamivir. In this report, a novel class of lead molecule with potential NA inhibitory activity was found from the traditional Chinese medicine database (TCMD) using virtual screening approach. Initially ADME properties of the lead compounds were analyzed with respect to the Lipinski rule of five. Subsequently, the data reduction was carried out by employing molecular docking study. Final validation was done by means of molecular dynamic simulations. The toxicity profiles for the screened compound were also analyzed. The result indicates that neoglucobrassicin (a compound derived from TCMD) become a promising lead compound and be effective in treating oseltamivir-resistant influenza virus strains. PMID- 23638405 TI - High-multiple spontaneous otoacoustic emissions confirm theory of local tuned oscillators. AB - Understanding the origin of spontaneous otoacoustic emissions (SOAEs) in mammals has been a challenge for more than three decades. Right from the beginning two mutually exclusive concepts were explored. After 30 years this has now resulted in two well established but incompatible theories, the global standing-wave theory and the local oscillator theory. The outcome of this controversy will be important for our understanding of inner ear functions, because local tuned oscillators in the cochlea would indicate the possibility of frequency analysis via local resonance also in mammals. A previously unexploited opportunity to gain further information on this matter lies in the occasional cases of high-multiple SOAEs in human ears, which present a large number of adjacent small frequency intervals. Here, eight healthy ears of four subjects (12 to 32 SOAEs per ear) are compared with individually simulated ears where frequency spacing was random generated by two different techniques. Further, a group of 1000 ears was simulated presenting a mean of 21.3 SOAEs per ear. The simulations indicate that the typical frequency spacing of human SOAEs may be due to random distribution of emitters along the cochlea plus a graded probability of mutual close-range suppression between adjacent emitters. It was found that the distribution of frequency intervals of SOAEs shows no above-chance probability of multiples of the preferred minimum distance (PMD) between SOAEs and that the size of PMD is related to SOAE density. The variation in size between adjacent small intervals is not significantly different in random-generated than in measured data. These three results are not in agreement with the global standing-wave theory but are in line with the local oscillator theory. In conclusion, the results are consistent with intrinsic tuning of cochlear outer hair cells. PMID- 23638407 TI - Myopia induced by flickering light in guinea pigs: a detailed assessment on susceptibility of different frequencies. AB - AIM: To investigate the effectiveness and feasibility of inducing myopia in guinea pigs by flickering light (FL) stimulation with different frequencies. METHODS: Seventy 2-week-old guinea pigs were randomly assigned to six groups: five FL groups and a control group (n=12 for each). Animals in the five FL groups were raised under 500lx illumination with a duty diurnal cycle of 50% at a flash rate of 5, 1, 0.5, 0.25 and 0.1Hz respectively. Those in the control group were reared under steady 250lx illumination. Refraction, axial length, and radius of curvature were measured before and at 2, 4, 6, 8, 10 and 12 weeks after treatment. At week 12, the eyeballs were taken out and three ocular dimensions and dry weight of sclera were measured. RESULTS: A myopic shift and axial eye length increase developed in the five FL groups. Stimulation at 0.5Hz caused greater changes in myopic shift, axial elongation, eyeball dimension, and dry weight of sclera than stimulation at other frequencies. Compared with controls, eyes in 0.5Hz group were approximately -5.5+/-1.5D more myopic with increase in horizontal, vertical, axial dimensions by 0.89+/-0.3mm, 0.69+/-0.2mm, 1.12+/ 0.2mm respectively and with increase in dry weight of sclera by 0.44mg. CONCLUSION: Chronic exposure to periodic illumination at temporal frequency is attended by development of excessive ocular enlargement and myopic refractive error. Emmetropization could be disrupted differently by frequency alteration. PMID- 23638408 TI - Perineuronal nets increase inhibitory GABAergic currents during the critical period in rats. AB - AIM: To investigate inhibitory gamma-aminobutyric acid (GABA) ergic postsynaptic currents (IPSCs) and postsynaptic currents (PSCs) in layer IV of the rat visual cortex during the critical period and when plasticity was extended through dissolution of the perineuronal nets (PNNs). METHODS: We employed 24 normal Long Evans rats to study GABAA-PSC characteristics of neurons within layer IV of the visual cortex during development. The animals were divided into six groups of four rats according to ages at recording: PW3 (P21-23d), PW4 (P28-30d), PW5 (P35 37d), PW6 (P42-44d), PW7 (P49-51d), and PW8 (56-58d). An additional 24 chondroitin sulfate proteoglycan (CSPG) degradation rats (also Long-Evans) were generated by making a pattern of injections of chondroitinase ABC (chABC) into the visual cortex 1 week prior to recording at PW3, PW4, PW5, PW6, PW7, and PW8. Immunohistochemistry was used to identify the effect of chABC injection on CSPGs. PSCs were detected with whole-cell patch recordings, and GABAA receptor-mediated IPSCs were pharmacologically isolated. RESULTS: IPSC peak current showed a strong rise in the age-matched control group, peaked at PW5 and were maintained at a roughly constant value thereafter. Although there was a small increase in peak current for the chABC group with age, the peak currents continued to decrease with the delayed highest value at PW6, resulting in significantly different week by-week comparison with normal development. IPSC decay time continued to increase until PW7 in the control group, while those in the chABC group were maintained at a stable level after an initial increase at PW4. Compared with normal rats, the decay times recorded in the chABC rats were always shorter, which differed significantly at each age. We did not observe any differences in IPSC properties between the age-matched control and penicillinase (P-ase) group. However, the change in IPSCs after chABC treatment was not reflected in the total PSCs or in basic membrane properties in layer IV of the rat visual cortex. CONCLUSION: Our results demonstrate that rather than rapidly increasing during the critical period for neuronal plasticity, IPSCs in layer IV of rat visual cortex are maintained at an immature level when PNNs are removed by chABC. This suggests that GABA receptor maturation involves the conformation of the CSPGs in PNNs. PMID- 23638409 TI - Microscopic characteristics of the inferior tarsal muscle and its surroundings in Korean. AB - AIM: To investigate the detailed microscopic anatomic structures of the lower eyelid in Korean cadavers. METHODS: Eight lower eyelids of 4 formalin-fixed Asian cadavers (4 males; age range, 48-69 years; mean age, 60.2 years) were examined. Three perpendicular dissected sections with a 2mm thickness were obtained from each eyelid to investigate anatomic shapes, size and relationship with surrounding structures. One section was obtained from the midline and 2 the other sections were obtained from a 3mm apart from the lateral and medial tarsus margins. RESULTS: The inferior tarsal muscle fibers were not directly attached to the tarsus but were only linked to the tarsus with enclosed fibrous fascia. The inferior tarsal muscles connected loosely with the capsulopalpebral fascia anteriorly and the conjunctiva posteriorly. The inferior tarsal muscle runs horizontally to the tarsus according to the shape of muscle fibers. The capsulopalpebral fascia consisted of an anterior and posterior layer. The anterior layer reached the orbital septum and subcutaneous fat but the posterior layer forwarded into the tarsus. Lockwood's ligament was separated from the inferior tarsal muscle and capsulopalpebral fascia or fused into the capsulopalpebral fascia. CONCLUSION: This study suggests that the inferior tarsal muscle which runs horizontally and doesn't insert directly into the tarsus, plays an important role in the movement and localization of the lower eyelid. PMID- 23638410 TI - Heparanase-1 activities in the development of laser induced choroidal neovascularization. AB - AIM: To investigate the role of heparanase-1 in laser-induced choroidal neovascularization (CNV). METHODS: Experimental CNV was induced by krypton laser photocoagulation in 15 male Brown Norway rats. Fundus fluorescein angiography and histopathological examination were performed in observing the CNV development. The expression and distribution of heparanase-1 protein in the laser lesions were determined by immunohistochemistry and western blotting analysis. RESULTS: The success rate of laser induced CNV was approximately 75% on 3-4 weeks after laser photocoagulation. The protein levels of heparanase-1 increased significantly in the retina-choroidal complex of CNV models when compared to normal rat eyes (P<0.01). Immunostaining confirmed strong heparanase-1 expressions in all laser lesions, and it displayed to be highest at the newly formed blood vessels within the fibrovascular complex in the subretinal space. CONCLUSION: Heparanase-1 is closely involved in the development of laser induced CNV. PMID- 23638406 TI - Regulation of fim genes in uropathogenic Escherichia coli. AB - Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections in women, causing significant morbidity and mortality in this population. Adherence to host epithelial cells is a pivotal step in the pathogenesis of UPEC. One of the most important virulence factors involved in mediating this attachment is the type 1 pilus (type 1 fimbria) encoded by a set of fim genes arranged in an operon. The expression of type 1 pili is controlled by a phenomenon known as phase variation, which reversibly switches between the expression of type 1 pili (Phase-ON) and loss of expression (Phase-OFF). Phase-ON cells have the promoter for the fimA structural gene on an invertible DNA element called fimS, which lines up to allow transcription, whereas transcription of the structural gene is silenced in Phase-OFF cells. The orientation of the fimS invertible element is controlled by two site-specific recombinases, FimB and FimE. Environmental conditions cause transcriptional and post-transcriptional changes in UPEC cells that affect the level of regulatory proteins, which in turn play vital roles in modulating this phase switching ability. The role of fim gene regulation in UPEC pathogenesis will be discussed. PMID- 23638411 TI - Comparison of subconjunctivally injected bevacizumab, ranibizumab, and pegaptanib for inhibition of corneal neovascularization in a rat model. AB - AIM: To compare the efficacies of subconjunctival bevacizumab, ranibizumab, and pegaptanib sodium injections for the inhibition of corneal neovascularization in an experimental rat model. METHODS: Sixteen corneas of 16 rats were chemically cauterized and randomized into four groups: bevacizumab group that treated with 0.05mL/1.25mg bevacizumab, ranibizumab group that treated with 0.05mL/0.5mg ranibizumab, pegaptanib group that treated with 0.05mL/0.15mg pegaptanib sodium, and control group that treated with 0.05mL saline solution. Digital photographs of the corneas were taken and analyzed using an image analysis software program. All corneas were excised and examined histologically on the 15(th) day. RESULTS: Each treatment group had significantly less neovascularized corneal areas and fewer blood vessels than the control group (all P<0.05). In addition, bevacizumab group had significantly less neovascularized corneal areas and fewer blood vessels than ranibizumab and pegaptanib groups (both P<0.05). However, there was no significant difference between the ranibizumab and pegaptanib groups regarding percentage of neovascularized corneal areas and number of blood vessels (both P>0.05). CONCLUSION: Subconjunctival bevacizumab, ranibizumab, and pegaptanib sodium were effective with no corneal epitheliopathy for inhibiting corneal neovascularization after corneal burn in rats. Bevacizumab was more effective than ranibizumab and pegaptanib sodium. PMID- 23638412 TI - Effects of intensive control of blood glucose and blood pressure on microvascular complications in patients with type II diabetes mellitus. AB - AIM: To evaluate the effects of intensive control of blood glucose and blood pressure on microvascular complications in patients with type II diabetes by comparing the therapeutic effects of intensive and standard treatment in patients with type II diabetes. METHODS: A total of 107 patients with type II diabetes were randomly assigned into intensive and standard treatment groups. Patients in the intensive treatment group received preterax (perindopril/ indapamide) to control blood pressure, and gliclazide (diamicron) MR to control blood glucose. Patients in the standard treatment group received routine medications or placebo. Urinary microalbumin (UMA), urinary creatinine (UCR), the UMA/UCR ratio, and visual acuity were monitored according to the study design of the ADVANCE trial. Direct ophthalmoscopy and seven-field stereoscopic retinal photography were used to examine the fundi at baseline, and repeated after 5 years of treatment. RESULTS: The characteristics of patients in both groups were well balanced at baseline. After 5 years of treatment, visual acuity was found to be decreased in the standard group (P=0.04), but remained stable in the intensive group. The severity of diabetic retinopathy had not progressed in patients in the intensive group, but had deteriorated in the standard group (P=0.0006). The UMA/UCR ratio was not obviously changed in patients in the intensive group, whereas it was significantly increased in the standard group (P=0.00). CONCLUSION: Intensive control of blood glucose and blood pressure can decrease the incidence or slow the progression of microvascular complications in patients with type II diabetes, and maintain stable vision. PMID- 23638413 TI - CT features of exophthalmos in Chinese subjects with thyroid-associated ophthalmopathy. AB - AIM: : To investigate computed tomography (CT) features of exophthalmos in Chinese subjects with thyroid-associated ophthalmopathy (TAO). METHODS: A total of 605 eyes of 325 patients with exophthalmos due to TAO were classified as grade I (mild exophthalmos) or II (severe exophthalmos) based on orbital CT imaging. The increased orbital volume features, such as changes from extraocular muscles, orbital fat, or both, were analyzed. RESULTS: A total of 605 eyes were analyzed, among them 62.98% presented grade I exophthalmos, while 36.02% showed grade II exophthalmos. In grade I, 56.69% showed orbital fat change, and in grade II, 89.29% exhibited extraocular muscle enlargement. CONCLUSION: Orbital fat and extraocular muscle enlargement are likely to be observed on CTs of subjects with mild and severe exophthalmos, respectively. Our results suggest that CT findings may guide TAO clinical therapy recommendations and prognosis. PMID- 23638414 TI - Optical biometry intraocular lens power calculation using different formulas in patients with different axial lengths. AB - AIM: : To investigate the predictability of intraocular lens (IOL) power calculation using the IOLMaster and different IOL power calculation formulas in eyes with various axial length (AL). METHODS: : Patients were included who underwent uneventful phacoemulsification with IOL implantation in the Department of Ophthalmology, Far Eastern Memorial Hospital, Taipei, Taiwan, China from February 2007 to January 2009. Preoperative AL and keratometric values (Ks) were measured by IOLMaster optical biometry. Patients were divided into 3 groups based on AL less than 22mm (Group 1), 22-26mm (Group 2), and more than 26mm (Group 3). The power of the implanted IOL was used to calculate the predicted postoperative spherical equivalence (SE) by various formulas: the Haigis, Hoffer Q, Holladay 1, and SRK/T. The predictive accuracy of each formula was analyzed by comparing the difference between the actual and predicted postoperative SE (MedAE, median absolute error). All the patients had follow-up periods exceeding 3 months. RESULTS: : Totally, there were 200 eyes (33 eyes in Group 1, 92 eyes in Group 2, 75 eyes in Group 3). In all patients, the Haigis had the significantly lower MedAE generated by the other formulas (P<0.05). In Group 1 to 3, the MedAE calculated by the Haigis was either significantly lower or comparable to those calculated by the other formulas. CONCLUSION: : Compared with other formulas using IOLMaster biometric data, the Haigis formula yields superior refractive results in eyes with various AL. PMID- 23638415 TI - Long-term cost and efficacy analysis of latanoprost versus timolol in glaucoma patients in Germany. AB - AIM: To evaluate 5-year effectiveness and cost between latanoprost or timolol monotherapy in a pilot trial. METHODS: A retrospective, multi-center trial performed at 6 sites in Germany of patients who had a diagnosis of primary open angle or pigmentary glaucoma, in at least one eye, initiated on monotherapy with latanoprost or timolol maleate. Qualified consecutive charts were reviewed in which 5-year efficacy, safety and cost data was abstracted. RESULTS: Seventy seoen latanoprost and 49 timolol patients were included, at the final visit no difference existed between the two groups in disc parameters including: rim area, rim area/disc area ratio, cup volume or vertical cup/disc ratio (P>0.05). There was no difference in intraocular pressure (IOP) between the initial latanoprost (17.4+/-2.6) and timolol (16.3+/-2.8mmHg) groups. There was less change in medicines over the follow-up period (0.1 vs 0.8) and fewer medications at the final visit (1.2 vs 1.8) with latanoprost compared to timolol. No patient treated with latanoprost discontinued therapy during follow-up, while 12% discontinued timolol mostly due to inadequate IOP control. Cost/year was less with initial timolol ($458+/-236) as compared to latanoprost ($552+/-202). CONCLUSION: Patients begun on latanoprost or timolol and followed over 5 years may have similar clinical outcomes. However, timolol patients may require more medicines and medicine changes to control IOP for long-term, but at a lower cost. PMID- 23638416 TI - Pediatric traumatic cataract and surgery outcomes in eastern China: a hospital based study. AB - AIM: To evaluate the etiologies, management, and outcomes of pediatric traumatic cataract in eastern China. METHODS: Pediatric traumatic cataract were reviewed for demographic information, type of injury, mode of injury, time of injury, interval between injury and first visiting doctors, hospital of first visiting, surgeries, complications and prognosis. RESULTS: A total of 117 eyes of 117 patients (96 boys and 21 girls) with unilateral injuries (66 right and 51 left eyes) were included in the study. The mean (SEM) age at diagnosis was (6.6+/-3.2) years (range, 1.3-13.8 years). Each cataract was categorized according to the type of trauma: closed-globe (n=26) or open-globe (n=91) injuries. The most common injuring objects were sharp metal objects (37.61%). The most common complication in open-globe injuries was corneal laceration, whereas traumatic mydriasis was most common in closed-globe injuries. Of 68 eyes in patients with open-globe injuries who received cataract extraction, intraocular lens (IOLs) were primarily implanted in 47 eyes (68.12%), whereas 18 eyes with closed-globe injuries received cataract extraction, and IOLs were primarily implanted in 17 eyes (94.4%). The surgical procedures included reconstruction of the anterior segment, synechiolysis, excision of the membrane, lensectomy, vitrectomy and related techniques. Postoperative vision was significantly improved compared with preoperative vision. CONCLUSION: Pediatric traumatic cataract should be treated in time to attenuate the complications, and education on pediatric traumatic cataract and improvements in pediatric health care are needed for the early detection of cataract in children. PMID- 23638417 TI - Episcleral macular buckling for posterior retinal detachment in silicone oil filled eyes associated with myopic macular hole. AB - AIM: To evaluate anatomical and visual outcomes of episcleral macular buckling (EMB) for posterior retinal detachment in silicone oil filled eyes associated with myopic macular hole. METHODS: Five cases of EMB for initial failure of retinal reattachment after internal limiting membrane (ILM) peeling and silicone oil tamponade caused by myopic macular hole were retrospectively reviewed. A silicone sponge sutured directly across the macular region was performed on the silicone oil filled eyes. Silicone oil was removed no sooner than 1 month post EMB. The duration of follow-up time after removal of silicone oil was more than 3 months. RESULTS: Retinas of five eyes were all reattached at the last follow-up. The postoperative vision ranged from counting fingers to 0.08. CONCLUSION: Anatomical results improved after EBM for posterior retinal detachment in silicone oil filled eyes associated with myopic macular hole, which was not evident for visual outcome. PMID- 23638418 TI - Bevacizumab vs ranibizumab for neovascular age-related macular degeneration in Chinese patients. AB - AIM: To compare the clinical efficacy of intravitreal injections of bevacizumab and ranibizumab for treating Chinese patients with neovascular age-related macular degeneration (AMD). METHODS: Among 60 Chinese patients with exudative AMD (60 eyes), 28 received intravitreal bevacizumab injections (1.25mg) and 32 received intravitreal ranibizumab injections (0.5mg), once a month for 3 months and were followed for a total of 6 months. Monthly optical coherence tomography (OCT) was used to determine whether the patients received additional treatments during the follow-up. We compared the baseline and 6-month follow-up values of mean best-corrected visual acuity (BCVA) and central retinal thickness (CRT) in both groups of patients. We also compared the occurrence of adverse events. RESULTS: At the 6-month follow-up, the mean BCVA (logMAR) of the bevacizumab and ranibizumab treatment groups improved from the baseline measurements of 0.72+/ 0.23 and 0.73+/-0.22 to 0.47+/-0.14 and 0.45+/-0.20, respectively (P<0.05 for both groups). However, the change was not significantly different between the two groups. As evaluated by OCT, CRT decreased from 366.71+/-34.72um and 352+/-36.9um at baseline to 250.86+/-41.51um and 243.22+/-41.38um in the bevacizumab and ranibizumab groups, respectively (P<0.05 for both groups). However, the change was not significantly different between the two groups. There were no severe local adverse reactions or systemic adverse events. CONCLUSION: Intravitreal bevacizumab and ranibizumab have equivalent effects on BCVA and CRT and appeare safe over the short-term. PMID- 23638419 TI - Endoscope-assisted goniosynechialysis combined with phacoemulsification and intraocular lens implantation to manage primary angle-closure glaucoma. AB - AIM: To describe and evaluate a new ophthalmic endoscope surgical technique combined with phacoemulsification and intraocular lens (IOL) implantation to treat goniosynechialysis and manage primary angle-closure glaucoma (PACG). METHODS: Endoscope-assisted goniosynechialysis combined with phacoemulsification and IOL implantation was performed in 32 eyes of 29 patients with PACG. Regular follow-up was performed 1 week and 1 month, 3, and 6 months after surgery to assess complications, intraocular pressure (IOP), anterior chamber depth, visual acuity, and anterior chamber angle. RESULTS: Preoperative mean IOP was 24.88+/ 7.22mmHg with pharmacological treatment, and was 13.70+/-4.02, 13.06+/-3.74, 14.29+/-4.70, and 14.33+/-5.01mmHg 1 week, 1 month, 3 months, and 6 months after surgery, respectively. The postoperative decrease in IOP was significant (P<0.05). The rate for all eyes with IOP of 21mmHg or less was 93.8% (30 eyes) at the final visit without ocular hypotensive agents. The average preoperative anterior chamber depth was 1.60+/-0.64mm, and this value significantly increased to 2.72+/-0.62, 2.76+/-0.70, 2.73+/-0.68, and 2.74+/-0.71mm at 1 week, 1 month, 3 months, and 6 months, respectively. Visual acuity was improved in 28 eyes (87.5%) at 6 months postoperatively. The anterior chamber angle had increased in 25 eyes (78.1%) at the final visit; it was adhesive 90 degrees -180 degrees in 6 eyes, 180 degrees -270 degrees in only 1 eye. Two eyes exhibited minimal hyphema in the early postoperative period, but it could gradually be absorbed. Fibrinous reaction was observed in five eyes and spontaneously disappeared within 7 days. No shallow anterior chamber, iridodialysis, choroidal detachment, or malignant glaucoma was found in any eyes. CONCLUSION: Endoscope-assisted goniosynechialysis combined with phacoemulsification and IOL implantation to manage PACG has several advantages, including optimized visualization, greater accuracy, and improved safety. Our results suggest that it has certain curative effects and clinical application value. PMID- 23638420 TI - Aberration changes of the corneal anterior surface following discontinued use of rigid gas permeable contact lenses. AB - AIM: To record aberrations with a corneal topographic device on the anterior surface of the cornea at different time-points prior to wearing and following discontinued use of rigid gas permeable (RGP) contact lenses. The effect of wearing RGP on the anterior surface of the cornea was discussed to provide guidance for clinical refractive error correction. METHODS: The study objects were 24 eyes from 24 patients. All patients underwent identical examination procedures prior to lens use, as well as afterwards, including slit-lamp examination, non-contact tonometer measurement, computer optometry and corneal curvature measurement, subjective refraction test, and corneal topography analysis. The patients wore contact lenses everyday for 1 month and then discontinued. Corneal topographies were recorded at certain time points of 30 minutes, 1 day, 3, 7 and 14 days following use. RESULTS: Total corneal aberration at each time point following discontinued use of RGP contact lenses was less than the time point prior to use. Detailed results were as follows: root mean square (RMS) (pre)=(1.438+/-0.328)um, RMS (30 minutes)=(1.076+/-0.355)um, RMS (1 day)=(1.362+/-0.402)um, RMS (3 days)=(1.373+/-0.398)um, RMS (7 days)=(1.387+/ 0.415)um, and RMS (14 days)=(1.430+/-0.423)um. Results showed that at 30 minutes after discontinued use of RGP contact lenses, almost all 2(nd)- and 3(rd)-order aberrations change. Quadrafoil Z10 and spherical Z12 of the 4(th)-order were also changed. Alterations to Z5, Z6, and Z12 at 1 day after discontinued use were significant differences compared with the time period prior to RGP use: Z5 and Z6 decreased, and Z12 increased slightly. Z5 and Z6 remained decreased at 3 days after discontinued use, but Z9 and Z10 continued to increase and Z12 returned to levels prior to RGP use. At 14 days after discontinued use, all aberrations were not significantly different from the values prior to use. CONCLUSION: The use RGP contact lenses greatly reduced total aberration of the anterior surface of the cornea. Changes to 2(nd)- and 3(rd)-order aberrations (including Z3, Z4, Z5, Z6, Z7, and Z8) were more significant. Following discontinued use of RGP contact lenses, the majority of lower order aberrations returned to original levels in a short period of time. During this process, a transient higher order aberration appeared, but all changes disappeared within 14 days after discontinued use of RGP contact lenses. PMID- 23638421 TI - Black diaphragm intraocular lens implantation and penetrating keratoplasty in aphakic eyes with traumatic aniridia. AB - AIM: To evaluate the long-term outcome of implantation of black diaphragm intraocular (BDI) lens combined with penetrating keratoplasty (PKP) for managing aphakic eyes with traumatic aniridia and corneal damage. METHODS: Six aphakic eyes of six patients with traumatic aniridia and corneal damage had BDI lens implantation at Qingdao Eye Hospital, Shandong Eye Institute from June 2008 to November 2011. Medical records of the patients were reviewed. Three patients received PKP and after 12-18months were implanted with BDI lens. The other three patients completed PKP and BDI lens implantation at the same time. The corrected visual acuity, intraocular pressure and number of corneal endothelial cells were monitored. RESULTS: The patients were followed up for an average of 24.3+/ 12.1months (range 14-48 months). All BDI lenses were located well. The best corrected visual acuity got improved in 5 patients (0.1-1.0) and decreased in 1 patient from 0.4 to 0.2. Three patients had normal intraocular pressure (IOP) after implantation. Two patients required antiglaucoma medications to control IOP within the normal range and 1 patient implanted Ahmed glaucoma valve to control IOP. The corneal grafts kept transparent in all eyes and the corneal endothelial counting >1 000/mm(2), although two patients experienced acute graft rejection and loss more than 30% corneal endothelial cells. CONCLUSION: Implantation of BDI lens combined with PKP is an effective option for managing aphakic eyes with traumatic aniridia and corneal damage. Although the results in our study are encouraging, additional studies of the long-term safety and efficacy are required. A larger study population and longer follow-up may be beneficial. PMID- 23638422 TI - Cyclopexy versus vitrectomy combined with intraocular tamponade for treatment of cyclodialysis. AB - AIM: To compare the effects and complications of direct cyclopexy (DC) versus vitrectomy, endophotocoagulation, and gas/silicone oil endotamponade (VEE) treatment in patients with cyclodialysis and persistent hypotony. METHODS: This is a prospective, comparative, nonrandomized clinical trial which includes 52 patients with cyclodialysis and persisting hypotony. Fifty-two patients suffering from cyclodialysis and persistent hypotony in one eye were divided into 2 groups (groups DC and VEE) and treated, respectively, with direct cyclopexy or vitrectomy, endophotocoagulation, and gas/silicone oil endotamponade. The patients were followed up for 12 months. Assessments included best corrected visual acuity (BCVA), intraocular pressure (IOP), anterior chamber depth (ACD), anterior chamber volume (ACV) and subjective rating of the pain caused by the treatments. RESULTS: After a follow-up of 12 months, significant improvement was seen in postoperative mean BCVA, IOP, ACD and ACV in both treatment groups (which were not significantly different from each other). The success rates for the treatments were not significantly different (DC: 50.0% vs VEE: 62.5%, P=0.383). Postoperative morbidity of cataract and subjective pain rating were significantly higher in the VEE group vs the DC group (P= 0.003 and P<0.001 respectively). CONCLUSION: DC and VEE were effective surgical procedures in treating patients with cyclodialysis and persistent hypotony. Patients had better tolerance to DC treatment and VEE was more likely lead to cataract complications. Taking into consideration the ease of the operation, success rate, and patient comfort, DC treatment seems preferable to VEE treatment in patients with simple cyclodialysis. While VEE has the advantage of treating patients with cyclodialysis combined with vitreous hemorrhage. PMID- 23638423 TI - Treatment of intractable orbital implant exposure with a large conjunctival defect by secondary insertion of the implant after preceding dermis fat graft. AB - AIM: To report a procedure and results of a two-stage operation to manage intractable extensive orbital implant exposure with a large conjunctival defect which was difficult to treat with dermis fat grafts due to repeated graft necrosis. METHODS: A retrospective chart review of four patients who had extensive orbital implant exposures with large conjunctival defects and had past histories of repeated autologous or preserved dermis graft failures was done. As a first-stage operation, the problematic pre-existing orbital implants were removed and autologous dermis fat grafts alone were performed on the defect area. Four months later, new orbital implants were secondarily inserted after confirmation of graft survival. The size of the conjunctival defects and state of the extraocular muscles were checked preoperatively. Success of the operations and complications were investigated. RESULTS: The mean size of the conjuctival defects was 17.3mm*16.0mm, and the mean time from the initial diagnosis of orbital implant exposure to implant removal and autologous dermis fat graft was 20.8 months. After implant removal and autologous dermis fat graft, no graft necrosis was observed in any patients. Also, implant exposure or fornix shortening was not observed in any patients after new orbital implant insertion. CONCLUSION: The secondary insertion of a new orbital implant after pre-existing implant removal and preceding dermis fat graft is thought to be an another selective management of intractable orbital implant exposure in which dermis fat grafts persistently fail. PMID- 23638424 TI - Vitrectomy combined with silicone oil tamponade in the treatment of severely traumatized eyes with the visual acuity of no light perception. AB - AIM: To evaluate the efficacy of surgical treatment of vitrectomy combined with silicone oil tamponade in the treatment of severely traumatized eyes with the visual acuity of no light perception (NLP). METHODS: This was a retrospective uncontrolled interventional case-series of 19 patients of severely traumatized eyes with NLP who underwent vitrectomy surgery at the Affiliated Hospital of Medical College, Qingdao University (Qingdao, China) during a 3-year period. We recorded perioperative factors with the potential to influence functional outcome including duration from the injury to intervention; causes for ocular trauma; open globe or closed globe injury; grade of vitreous hemorrhage; grade of endophthalmitis; grade of retinal detachment; size and location of intraocular foreign body (IOFB); extent and position of retinal defect; grade of proliferative vitreoretinopathy (PVR); type of surgery; perioperative complications and tamponade agent. The follow-up time was from 3 to 18 months, and the mean time was 12 months. RESULTS: After a mean follow-up period of 12 months (3-18 months) 10.53% (2/19) of eyes had visual acuity of between 20/60 and 20/400, 52.63% (10/19) had visual acuity less than 20/400 but more than NLP, and 36.84% (7/19) remained NLP. Visual acuity was improved from NLP to light perception (LP) or better in 63.16% (12/19) of eyes and the rate of complete retinal reattachment was 73.68% (14/19). Good visual acuity all resulted from those patients of blunt trauma with intact eyewall (closed globe injury). The perioperative factors of poor visual acuity prognosis included delayed intervention; open globe injury; endophthalmitis; severe retinal detachment; large IOFB; macular defect; a wide range of retinal defects and severe PVR. CONCLUSION: The main reasons of NLP after ocular trauma are severe vitreous hemorrhage opacity; refractive media opacity; retinal detachment; retinal and uveal damages and defects, especially defects of the macula; PVR and endophthalmitis. NLP after ocular trauma in some cases does not mean permanent vision loss. Early intervention of vitrectomy combined with silicone oil tamponade and achieving retinal reattachment of the remaining retina, may make the severely traumatized eyes regain the VA of LP or better. PMID- 23638425 TI - Ocular disorders in children with spastic subtype of cerebral palsy. AB - AIM: To document common ocular abnormalities in children with spastic subtype of cerebral palsy (CP) and to find out whether any correlation exists between their occurance and etiologic factors. METHODS: Totally 194 patients with the diagnosis of spastic type CP were enrolled in this retrospective study. Detailed ophthalmic examinations were performed. Demographic data and neuroradiological findings were documented. Kruskal-Wallis, Mann Whitney U, Pearson Chi-square tests and Student's t tests were used in the statistical analysis. RESULTS: The mean age was 64.7+/-44.2 months on the first ophthalmic examination. Prevalences of diplegia (47.4%) and tetraplegia (36.1%) were found to be higher than the frequency of hemiplegia (16.5%) in our study population. Etiologic factor was asphyxia in 60.8% of the patients. Abnormal ocular findings were present in 78.9% of the patients. Statistically significant poor vision was detected in tetraplegia group among all the spastic ubtypes of CP (P=0.000). Anisometropia and significant refractive error were found in 14.4% and 70.1% of the patients, respectively. Thirty-six children (18.6%) had nystagmus and 107 children (55.2%) had strabismus. Lower gestational age and birth weight were statistically higher in patients with esotropia than exotropia (P=0.009 and P=0.024, respectively). Abnormal morphology of the optic disc was present in 152 eyes (39.2%). Severe periventricular leukomalacia (PVL) was found in 48 patients and statistically significant poor vision was detected in the presence of PVL (P=0.000). CONCLUSION: Spastic diplegic or tetraplegic CP patients with positive neuroradiological symptoms, younger gestational age and lower birth weight ought to have detailed ophthalmic examinations as early as possible to provide best visual rehabilitation. PMID- 23638426 TI - Effects of multiple intravitreal anti-VEGF injections on retinal nerve fiber layer and intraocular pressure: a comparative clinical study. AB - AIM: To determine the effect of multiple injections of ranibizumab or bevacizumab on retinal nerve fiber layer (RNFL) and intraocular pressure (IOP) in patients with age-related macular degeneration (AMD). METHODS: This retrospective study includes 35 eyes of 35 patients treated with intravitreal bevacizumab (IVB, 1.25mg/0.05mL) and 30 eyes of 30 patients with intravitreal ranibizumab (IVR, 0.5mg/0.05mL) who had Fast RNFL analysis (StratusTM); IOP measurements were taken 30 minutes and 24 hours after each injection. RESULTS: The mean ages were 68.0+/ 7.5 and 69.1+/-7.7 years in the IVR and IVB groups, respectively (P=0.55). They underwent (6.3+/-1.9) and (5.1+/-1.3) injections (P=0.07) over (13.6+/-2.1) and (14.05+/-2.6) months (P=0.45) in the IVR and IVB groups, respectively. Changes in overall and temporal RNFL thickness in IVR-treated eyes (105.3+/-6.9um and 74.4+/ 11.2um) were not different from those in untreated eyes in the IVR group (104.6+/ 8.4um and 75.1+/-12.6um) (P=0.57 and P=0.41, respectively). Similarly, overall and temporal RNFL thickness in IVB-treated eyes (105.8+/-8.1um and 74.5+/-11.8um) were not different from those in untreated eyes in the IVB group (104.6+/-8um and 74.8+/-12.9um) (P=0.42 and P=0.80, respectively). The frequencies of IOP rise (P=0.60) and changes in RNFL thickness from baseline (P=0.16) were comparable between groups. CONCLUSION: Repeated intravitreal injection of ranibizumab or bevacizumab does not seem have adverse effects on RNFL thickness or IOP in wet AMD patients. PMID- 23638427 TI - Secondary glaucoma after pediatric cataract surgery. AB - AIM: To determine the incidence and risk factors of secondary glaucoma after pediatric cataract surgery. METHODS: Two hundred and forty nine eyes of 148 patients underwent cataract surgery without intraocular lens (IOL) implantation (group 1), and 220 eyes of 129 patients underwent cataract surgery with IOL implantation (group 2) retrospectively, were evaluated between 2000 and 2011. The outcome measure was the presence or absence of post-cataract surgery glaucoma, defined as an intraocular pressure (IOP) >=26mmHg, as measured on at least two occasions along with corneal or optic nerve changes. RESULTS: The mean follow-up periods of group 1 and 2 were (60.86+/-30.95) months (12-123 months) and (62.11+/ 31.29) months (14-115 months) respectively. In group 1, 12 eyes of 8 patients (4.8%) developed glaucoma. None of the patients developed glaucoma after surgery in group 2. The mean age of the patients at the cataract surgery was (2.58+/ 0.90) months (1 month-4 months) and the average period for glaucoma development after surgery was (9.50+/-4.33) months (4-16 months) in group 1. Three of the 12 glaucomatous eyes were controlled with antiglaucomatous medication and 9 eyes underwent trabeculectomy+mitomycin C surgery. One patient underwent a second trabeculectomy + mitomycin C operation for both of his eyes. CONCLUSION: The incidence of glaucoma after pediatric cataract surgery is very low in patients in whom IOL is implanted. The aphakic eyes after pediatric cataract surgery are at an increased risk for glaucoma development particularly if they underwent surgery before 4 months of age. PMID- 23638428 TI - Potential therapeutic effects of pigment epithelium-derived factor for treatment of diabetic retinopathy. AB - Diabetic retinopathy (DR), a major micro-vascular complication of diabetes, has emerged as a leading cause of visual impairment and blindness among working adults in the worldwide. The pathobiology of DR involves multiple molecular pathways and is characterized chronic neurovascular degeneration. Current approaches to prevent or to treat DR are still far from satisfactory. Therefore, it is important to develop new therapeutic strategies for the prevention and treatment to DR. Pigment epithelium-derived factor (PEDF), a 50-kDa secreted glycoprotein, has been described as a multi-functional protein. Some emerging evidences indicate that PEDF are able to target multiple pathways exerting neurotropic, neuroprotective, anti-angiogenic, antivasopermeability, anti inflammation, anti-thrombogenic and anti-oxidative effects in DR. In this review, we addressed the functions of PEDF in different pathways, which could lead to potential therapeutics on the treatment to DR. PMID- 23638429 TI - Prevalence and risk factors for eye diseases, blindness, and low vision in Lhasa, Tibet. AB - AIM: To determine the prevalence and risk factors for eye diseases, blindness, and low vision in Tibet, and to assist the development of eye disease prevention and treatment schemes. METHODS: We carried out a survey of eye diseases among a population living at high altitude. A total of 1 115 Tibetan permanent residents aged 40 years or older from the towns and villages of Qushui County, Lhasa Prefecture, Tibet Autonomous Region, participated in this study. All participants completed a detailed questionnaire, and underwent presenting and pinhole visual acuity tests, and a comprehensive ophthalmic examination. RESULTS: There were 187 blind eyes (8.43%), 231 eyes with low vision (10.41%). The leading cause of visual impairment was cataract of 55.0% (101/187) blindness and of 50.2% (116/231) low vision, followed by fundus lesions of 22.9% blindness and 23.8% low vision, while only a low prevalence of glaucoma of 9.6% blindness and 1.7% low vision was observed. The analysis of 2 219 eyes showed that the most common external eye disease was pterygium (27.2%) in Tibet. CONCLUSION: The high prevalence of blindness and low vision in the Tibetan population at high altitude is a serious public health issue. There is a need to establish and maintain an appropriate effective eye care program in Tibet. PMID- 23638430 TI - Combine intravitreal bevacizumab with Nd: YAG laser hyaloidotomy for valsalva pre macular haemorrhage and observe the internal limiting membrane changes: a spectralis study. AB - Valsalva retinopathy was described as a particular form of retinopathy, pre retinal and subinternal limiting membrane haemorrhages in nature that rarely may break through and become subhyloid or intravitreal, secondary to a sudden increase in intrathoracic pressure. We reported a new way that Nd:YAG laser for ILM hyaloidotomy in order to drain the sub-ILM blood into vitreous cavity combined with intravitreal bevacizumab to improve the absorption of blood. Therapeutic alliance make significant outcome, protecting vision in time. We used spectralis OCT to observe sub-ILM mix cells and special ILM structure in this lesion for the first time, as the spectralis OCT can reach histology level imagination. PMID- 23638431 TI - Iris microhaemangioma: a management strategy. AB - AIM: To analyse previous literature and to formulate a management strategy for iris microhaemangiomas (IMH). METHODS: A review of the literature in English language articles on IMH. RESULTS: Thirty five English language articles fulfilled the criteria for inclusion to the study and based on the contents on these articles a management strategy was formulated. Age at presentation ranged from 42 to 80 years with no sex or racial predisposition. Most patients with IMH have no systemic disease but a higher incidence had been reported in patients with diabetes mellitus, myotonic dystrophy, chronic obstructive pulmonary disease (COPD) and several other systemic and ophthalmic co-morbidities. Most patients remained asymptomatic until they experienced a sudden blurring of vision due to a hyphaema. Some patients only develop a self-limiting single episode of hyphaema and therefore the laser or surgical photocoagulation of iris should be reserved for the cases complicated with recurrent hyphaema. In some patients, several laser photocoagulation sessions may be needed and the recurrent iris vascular tufts may require more aggressive treatment. Iris fluorescein angiography (IFA) is useful in identifying the true extent of the disease and helps to improve the precision of the laser treatment. Surgical excision (iridectomy) should only be considered in patients who fail to respond to repeated laser treatment. In some cases IMHs has been initially misdiagnosed as amaurosis fugax, iritis and Posner Schlossman syndrome. CONCLUSION: Owing to its scarcity, there is no good quality scientific evidence to support the management of IMH. The authors discuss the various treatment options and present a management strategy based on the previous literature for the management for this rare condition and its complications. PMID- 23638432 TI - Central corneal epithelium self-healing after ring-shaped glycerin-cryopreserved lamellar keratoplasty in Terrien marginal degeneration. PMID- 23638433 TI - Angiography reveals early hiding iris neovascularization after ischemic CRVO. PMID- 23638434 TI - Retained wooden foreign body in the orbit. PMID- 23638435 TI - Dissecting the PI3K Signaling Axis in Pediatric Solid Tumors: Novel Targets for Clinical Integration. AB - Children with solid tumors represent a unique population. Recent improvements in pediatric solid tumor survival rates have been confined to low- and moderate-risk cancers, whereas minimal to no notable improvement in survival have been observed in high-risk and advanced-stage childhood tumors. Treatments for patients with advanced disease are rarely curative, and responses to therapy are often followed by relapse, which highlights the large unmet need for novel therapies. Recent advances in cancer treatment have focused on personalized therapy, whereby patients are treated with agents that best target the molecular drivers of their disease. Thus, a better understanding of the pathways that drive cancer or drug resistance is of critical importance. One such example is the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which is activated in many solid cancer patients and represents a target for therapy. PI3K/Akt/mTOR pathway activation has also been observed in tumors resistant to agents targeting upstream receptor tyrosine kinases (RTKs). Agents that target this pathway have the potential to shut down survival pathways, and are being explored both in the setting of pathway-activating mutations and for their ability to restore sensitivity to upstream signaling targeted agents. Here, we examine the role of the PI3K/Akt/mTOR pathway in pediatric solid tumors, review the novel agents being explored to target this pathway, and explore the potential role of the inhibition of this pathway in the clinical development of these agents in children. PMID- 23638437 TI - Gun violence and mental illness: no clear path. PMID- 23638438 TI - Modifiable risk factors for depressed mood among farmers. AB - BACKGROUND: Risk for depression among farmers is not fully understood. DSM-IV considers sadness or depressed mood a critical symptom of depression. The aim of this study was to examine risk factors for depressed mood among farmers using a longitudinal study design. METHODS: Participants were principal farm operators in the Iowa Certified Safe Farm study. We identified risk factors for depressed mood by calculating relative risks (RR) using the generalized estimating equations method. RESULTS: In the multivariate model, pesticide exposure (RR = 1.26; 95% CI: 1.04 to 1.53), having an additional job off the farm (RR = 1.32; 95% CI: 1.08 to 1.62), stress (RR = 3.09; 95% CI: 2.55 to 3.75), and previous injury (RR = 1.41; 95% CI: 1.05 to 1.89) prospectively increased the risk of depressed mood. CONCLUSIONS: Consistent with earlier non-longitudinal studies, the results of this study suggest that reducing pesticide exposure, stress, and injury may reduce the risk of depression in the farm setting. PMID- 23638439 TI - Consumer advocacy meetings: an innovative therapeutic tool. AB - BACKGROUND: Consumer advocacy groups are fulfilling an increasingly important role in psychiatry. The Trichotillomania Learning Center (TLC) aims to improve the quality of life of individuals with body-focused repetitive behavioral (BFRB) disorders such as trichotillomania (hair pulling disorder [HPD]) and skin picking disorder. The annual TLC retreat is an educational event focused on experiential learning and building a supportive community. METHODS: We assessed attendees' impressions of and experiences from the 2010 TLC retreat. RESULTS: Sixty-two (57 female; mean age: 32.4, standard deviation: 14.6) attendees completed the survey. Fifty-five reported >=1 current BFRBs, 6 were family members of attendees, and 1 participant reported HPD in remission. Most attendees found the TLC retreat to be a helpful intervention that offered support and information on BFRB disorders. Attendance was accompanied by reduced stigma, shame, and loneliness. Attendance also increased many respondents' levels of motivation to stop pulling or picking (85%); 61% of respondents reported reduced pulling or picking. Most respondents (95%) reported learning new ways of managing the condition. CONCLUSIONS: Survey findings suggested most attendees found the annual TLC retreat to be a helpful intervention. The retreat may serve as a novel and innovative model for helping individuals suffering from a range of other psychiatric disorders. PMID- 23638436 TI - Saccharomyces cerevisiae as a Model to Study Replicative Senescence Triggered by Telomere Shortening. AB - In many somatic human tissues, telomeres shorten progressively because of the DNA end replication problem. Consequently, cells cease to proliferate and are maintained in a metabolically viable state called replicative senescence. These cells are characterized by an activation of DNA damage checkpoints stemming from eroded telomeres, which are bypassed in many cancer cells. Hence, replicative senescence has been considered one of the most potent tumor suppressor pathways. However, the mechanism through which short telomeres trigger this cellular response is far from being understood. When telomerase is removed experimentally in Saccharomyces cerevisiae, telomere shortening also results in a gradual arrest of population growth, suggesting that replicative senescence also occurs in this unicellular eukaryote. In this review, we present the key steps that have contributed to the understanding of the mechanisms underlying the establishment of replicative senescence in budding yeast. As in mammals, signals stemming from short telomeres activate the DNA damage checkpoints, suggesting that the early cellular response to the shortest telomere(s) is conserved in evolution. Yet closer analysis reveals a complex picture in which the apparent single checkpoint response may result from a variety of telomeric alterations expressed in the absence of telomerase. Accordingly, the DNA replication of eroding telomeres appears as a critical challenge for senescing budding yeast cells and the easy manipulation of S. cerevisiae is providing insights into the way short telomeres are integrated into their chromatin and nuclear environments. Finally, the loss of telomerase in budding yeast triggers a more general metabolic alteration that remains largely unexplored. Thus, telomerase-deficient S. cerevisiae cells may have more common points than anticipated with somatic cells, in which telomerase depletion is naturally programed, thus potentially inspiring investigations in mammalian cells. PMID- 23638440 TI - Treatment resistance in severe unipolar depression: no association with psychotic or melancholic features. AB - BACKGROUND: Depressive subtypes generally have been neglected in research on treatment efficacy. We studied a sample of 699 severe unipolar depressed patients to detect any association between depressive features and treatment resistance. METHODS: Participants were divided into psychotic (PSY, n = 90), melancholic (MEL, n = 430) and non-melancholic (n = 179) subjects according to clinical features. Formal diagnostic criteria (Mini International Neuropsychiatric Interview items), and items from 17-item Hamilton Rating Scale for Depression (HRSD17) were compared across groups. Non-responders were defined by a HRSD17 cut off score of >=17 after the last adequate antidepressant treatment. Treatment resistant depression (TRD) was defined as the failure to respond to >=2 adequate antidepressant trials. Non-linear regression models were designed to detect associations between depressive subtypes and TRD. RESULTS: PSY and MEL patients appeared to be more severely affected and to share some "core" melancholic symptoms. Both PSY and MEL patients reported a higher rate of seasonality. However, we found no clinical or illness course variable associated with TRD. CONCLUSIONS: Our results indicate that psychotic and melancholic depression share some "core" melancholia symptoms, while no distinguishing psychopathological feature appears to be associated with TRD in severely depressed patients. PMID- 23638442 TI - Is there a relationship between age at menarche and clinical and temperamental characteristics in bipolar disorder? AB - BACKGROUND: This study investigated whether age at menarche in women with bipolar disorder (BD) is different from that in healthy women and if there is a relationship between age at menarche and clinical and temperamental characteristics of BD. METHODS: We consecutively evaluated 126 euthymic women diagnosed with BD according to DSM-IV. The healthy control group comprised 100 individuals of similar mean age and socioeconomic level. After the diagnostic interview, BD patients completed the Mood Disorders Diagnosis and Follow-Up Form and Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire. RESULTS: Age at menarche in BD patients was similar to that in controls. A strong inverse correlation was found between age at menarche and total duration of depressive episodes (r = -0.532). In BD patients, an inverse correlation has been found between age at menarche and depressive and cyclothymic temperament scores (r = -0.384 and r = -0.421). However, a strong correlation has been found between age at menarche and irritable temperament scores (r = 0.488). CONCLUSIONS: Age at menarche is associated with the clinical course of BD. Moreover, age at menarche seems to be associated with traits related to mood. PMID- 23638443 TI - A case series of clozapine for borderline personality disorder. AB - BACKGROUND: Borderline personality disorder (BPD) is a common, debilitating disorder for which the evidence base for treatment is modest. This case series aimed to explore preliminary evidence of clozapine's effectiveness for patients with severe BPD. METHODS: We examined the case notes of 22 female inpatients with a primary diagnosis of BPD who had started treatment with clozapine. Baseline routine clinical data were extracted from the records and at 6 monthly intervals thereafter, up to a maximum of 18 months after starting treatment. Patients also were interviewed about their experiences. RESULTS: We found evidence for a beneficial effect of clozapine across several clinical domains. Symptom severity, need for enhanced observations, use of additional medication, and the number of aggressive incidents all significantly improved after clozapine. The greatest improvements appeared within the first 6 months of initiating treatment. There also was a significant increase in weight. CONCLUSIONS: The results suggest that clozapine, with suitable health monitoring, may be beneficial for this clinical population. Larger, randomized, blinded, and controlled prospective studies are needed to confirm these findings. PMID- 23638441 TI - Alexithymia, emotional empathy, and self-regulation in anorexia nervosa. AB - BACKGROUND: Individuals with anorexia nervosa (AN) who are starved have poor awareness (alexithymia), reduced understanding of others' mental states (cognitive empathy), and difficulty regulating personal emotions (self regulation). Despite its important role in social interaction, sympathy for others (emotional empathy) has not been measured in AN. Furthermore, it is unknown how restoring weight affects the relationship among alexithymia, empathy, and self-regulation in AN. METHODS: Women with AN were tested longitudinally during their starvation period (N = 26) and after weight was restored (N = 20) and compared with 16 age-matched healthy women. Alexithymia, empathy, and self regulation were assessed with the Toronto Alexithymia Scale, the Interpersonal Reactivity Index, and items measuring self-regulation from the Minnesota Multiphasic Personality Inventory-2, respectively. RESULTS: Relative to comparison participants, individuals with AN during both starvation and weight restoration reported greater alexithymia and emotional empathy in one domain, personal distress (vicarious negative arousal to others' suffering). Among AN participants, personal distress was positively correlated with alexithymia and negatively correlated with self-regulation, when accounting for depression. CONCLUSIONS: High levels of alexithymia and personal distress may be persistent features of AN because they do not resolve upon weight restoration. Greater personal distress in AN may be a function of poor emotional awareness and regulation. PMID- 23638444 TI - Rapid screening for perceived cognitive impairment in major depressive disorder. AB - BACKGROUND: Subjectively experienced cognitive impairment is common in patients with mood disorders. The British Columbia Cognitive Complaints Inventory (BC-CCI) is a 6-item scale that measures perceived cognitive problems. The purpose of this study is to examine the reliability of the scale in healthy volunteers and depressed patients and to evaluate the sensitivity of the measure to perceived cognitive problems in depression. METHODS: Participants were 62 physician diagnosed inpatients or outpatients with depression, who had independently confirmed diagnoses on the Structured Clinical Interview for DSM-IV, and a large sample of healthy community volunteers (n=112). RESULTS: The internal consistency reliability of the BC-CCI was alpha=.86 for patients with depression and alpha=.82 for healthy controls. Principal components analyses revealed a one factor solution accounting for 54% of the total variability in the control sample and a 2-factor solution (cognitive impairment and difficulty with expressive language) accounting for 76% of the variance in the depression sample. The total score difference between the groups was very large (Cohen's d=2.2). CONCLUSIONS: The BC-CCI has high internal consistency in both depressed patients and community controls, despite its small number of items. The test is sensitive to cognitive complaints in patients with depression. PMID- 23638445 TI - An exploratory study examining lipid-lowering medications in reducing fasting serum lipids in schizophrenia patients treated with atypical antipsychotics. AB - BACKGROUND: We present a retrospective study examining response to treatment with fibrates or statins in schizophrenia patients. METHODS: We identified the patient population using the Research Patient Data Registry. Demographic data, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and non-HDL cholesterol (non-HDL-C) levels were obtained before initiation of treatment with lipid-lowering medication (LLM) and after LLM treatment was initiated (N = 183). RESULTS: Treatment with LLMs resulted in a statistically significant decrease in total cholesterol, triglycerides, LDL-C, and non-HDL-C. An independent-samples t test comparing the statin treatment-alone group with the fibrate treatment-alone group showed a significant reduction in triglyceride levels from baseline to 1-year follow-up in the fibrate treatment-alone group. CONCLUSIONS: The results of this study indicate that schizophrenia patients respond to LLMs in a manner consistent with the general population. Future studies would benefit from a larger sample, as well as comparisons between more specific treatment groups, such as those defined by type of statin or fibrate, to observe differential effects on specific markers of dyslipidemia in this population. PMID- 23638446 TI - Duloxetine and hypothermia: possible summation of effect in QTc interval prolongation. PMID- 23638447 TI - A case of schizencephaly associated with obsessive-compulsive disorder. PMID- 23638448 TI - Antidepressant-induced excessive sweating: clinical features and treatment with terazosin. AB - BACKGROUND: Antidepressant-induced excessive sweating (ADIES) occurs in 5% to 14% of patients taking antidepressants, usually persists throughout treatment, and causes subjective distress and functional impairment. We conducted the first clinical trial of any treatment for ADIES. METHODS: Clinical features of ADIES were assessed using a semi-structured form. Twenty-three patients with moderate or greater ADIES were assessed for a 2-week baseline period , followed by 6 weeks of open-label treatment with flexible dose terazosin, 1 to 6 mg/d. Improvement in ADIES was measured by the Clinical Global Impressions (CGI) scale and other measures. RESULTS: ADIES commonly was prominent in the scalp (62%), face (95%), neck (48%), and chest (57%); usually occurred either episodically or with episodic bursts (82%); and was persistent (median 63 months). Twenty-two of the 23 patients responded to terazosin (CGI-I scores 1 or 2), with CGI-Severity improving from median of 5 to median of 2 (P < .0001). Patient-rated daytime and nighttime severity of ADIES and proportion of time in ADIES also improved significantly. The most common adverse effects of terazosin therapy were dizziness/lightheadedness (n = 9) and dry mouth (n = 4). No patient dropped out because of adverse effects. Sitting and standing systolic blood pressure decreased by median values of 3 (P = .044) and 5 (P = .063) mm Hg, respectively. CONCLUSIONS: Terazosin may be an effective treatment for ADIES. Although dizziness/lightheadedness may occur in some patients, the treatment generally was well tolerated. PMID- 23638449 TI - A prospective study of the onset of PTSD symptoms in the first month after trauma exposure. AB - BACKGROUND: The course of posttraumatic stress disorder (PTSD) symptoms in the month after trauma exposure has not been determined adequately. Symptom group C (avoidance/numbing) has been identified retrospectively as a marker for PTSD, but prospective studies are needed to determine whether these symptoms can provide substantially earlier identification of those who will have PTSD 1 month after trauma exposure. METHODS: We evaluated 42 patients hospitalized for traumatic injuries over the first post-injury month to track development of posttraumatic symptoms. RESULTS: Symptoms emerged rapidly, with group B (intrusion) and group D (hyperarousal) symptoms occurring earlier than group C symptoms. At 1 week, group C criteria accurately predicted who would develop PTSD by 1 month, and by 2 weeks, group C criteria also predicted who would not develop PTSD by 1 month. CONCLUSIONS: The findings, if replicated, may permit earlier identification of PTSD and more timely, appropriate treatment. PMID- 23638450 TI - Thoughts on malpractice. PMID- 23638451 TI - For now, we see through a glass, darkly. PMID- 23638453 TI - Descriptive study of opioid-acetaminophen prescription patterns at the providence VA Medical Center. AB - BACKGROUND: Prescription opioid-acetaminophen products account for the majority of cases of acetaminophen-related acute liver failure in the United States. We sought to examine the frequency of opioid-acetaminophen overuse at the Providence VA Medical Center and improve the quality and safety of opioid-acetaminophen prescription practices in a system employing electronic health records and e prescribing. RESULTS: During fiscal year 2011, the Providence VA pharmacy dispensed a total of 19,841 acetaminophen prescriptions to a total of 4455 different patients. There were only 15 acetaminophen prescriptions dispensed in excess of 4g/day, and there were only 14 patients exposed to a potential maximum daily dose of acetaminophen greater than 4g. CONCLUSIONS: The Providence VAMC appears to have a low rate of prescription acetaminophen misuse, in contrast to rates seen in previous studies. The VHA electronic health record, accessible to all healthcare providers, appears to offer considerable benefit in reducing the overuse of acetaminophen containing opioid products. PMID- 23638452 TI - Systematic review of caudal epidural injections in the management of chronic back pain. AB - Epidural steroids recently attracted world attention due to medication contamination resulting in many cases of fungal meningitis. What was rarely noted in these reports is that there is little data to support use of this treatment. This article reviews the literature on epidural steroids for various types of back pain and concludes that further testing should be performed to determine if and in what situations this intervention is useful before wide-spread use is resumed. PMID- 23638454 TI - Hepatocellular carcinoma in HIV-infected women: two case reports. AB - With the widespread availability of highly active antiretroviral therapy (HAART), and increased life expectancy among HIV-infected individuals, liver-related mortality has emerged as the leading cause of non-AIDS-related death. The incidence of hepatocellular carcinoma (HCC), a sequela of chronic liver disease, is rising among HIV-infected individuals. While women are increasingly and disproportionately affected by HIV, little is known about HCC in HIV-infected women given HCC's predilection for men. In 2007, 2 out of 398 HIV-infected women seen at a Rhode Island HIV clinic were diagnosed with HCC. Of 351 HIV-infected individuals with HCC described in the published literature, 12 (3.4%) were women. These 2 cases add to the existing literature on this topic. PMID- 23638455 TI - Adherence to American Diabetes Association guidelines in a volunteer-run free clinic for the uninsured: better than standards achieved by clinics for insured patients. AB - To determine whether Type 2 diabetes care for the uninsured is comparable to care provided to insured patients, we compared a free clinic's compliance with American Diabetes Association (ADA) clinical practice guidelines to 6 adherence evaluations in the literature. We examined diabetes management-related biomarkers, compliance with ADA-recommended health monitoring events, and presence of other health-promoting behaviors via retrospective chart review (n = 33). Results demonstrate that standards achieved by the free clinic were commensurate with, if not outperforming, published standards achieved in settings for insured patients. This evaluation emphasizes that free clinics can provide high-quality diabetes management care to patients with limited resources. This review also provides a benchmark against which results of future diabetes management interventions in both free and conventional clinic settings can be compared. PMID- 23638456 TI - Carcinoid tumor of the ileoanal pouch in a patient with ulcerative colitis. AB - Carcinoid tumors have been reported to occur in various locations, particularly in the gastrointestinal tract. The relationship between the development of carcinoids and ulcerative colitis has been an unclear and controversial one. The association of ulcerative colitis and the development of ileal-pouch carcinoids has not, however, been well documented. We report a case of carcinoid tumor arising in an ileoanal pouch and discuss its unique diagnostic and therapeutic considerations. PMID- 23638457 TI - Report on Data Improvement Project on Patient Ethnicity and Race (DIPPER): pilot design and proposed voluntary standard. AB - The Hospital Association of Rhode Island, in conjunction with the Rhode Island Cancer Registry, received funding for a special project to improve the validity and reliability of race and ethnicity data in hospital inpatient records. In the past year, five hospitals participated in a pilot to improve race/ethnicity data collection. This paper provides an overview of the design and initial implementation of the pilot, and reports on early feedback. Given that the Affordable Care Act strengthens federal data collection efforts, with a new standard issued which adds granularity, these policies can renew efforts to record more accurate and detailed race and ethnicity data. Improved race and ethnicity data will increase our understanding of the health needs of different racial and ethnic groups and health disparities between groups. Better data improves understanding, increases the likelihood of effective actions to address and monitor disparities, and ensure that every American has the opportunity to live the healthiest life possible. PMID- 23638459 TI - Retraction notice to "Erucylphosphocholine shows a strong anti-growth activity in human endometrial and ovarian cancer cells" [Gynecol. Oncol. 111 (2008) 336-343]. PMID- 23638458 TI - Whatever happened to the annual pap smear? PMID- 23638460 TI - Retraction notice to "beta-Hydroxyisovalerylshikonin has a profound anti- growth activity in human endometrial and ovarian cancer cells" [Gynecol. Oncol. 109 (2008) 107-114]. PMID- 23638461 TI - Retraction notice to "M344 is a novel synthesized histone deacetylase inhibitor that induces growth inhibition, cell cycle arrest, and apoptosis in human endometrial cancer and ovarian cancer cells" [Gynecol. Oncol. 101 (2006) 108 113]. PMID- 23638462 TI - RCVS Council elections. PMID- 23638463 TI - We need a new paradigm in gynecologic cancer care: SGO proposes solutions for delivery, quality and reimbursement policies. PMID- 23638464 TI - The Gynecologic Oncology Group (GOG) Report. PMID- 23638465 TI - Motor vehicle traffic crashes as a leading cause of death in the United States, 2008 and 2009. PMID- 23638467 TI - [Acta Reumatologica Portuguesa: last two years evaluation]. PMID- 23638466 TI - Saxagliptin vs. glipizide as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: long-term (52-week) extension of a 52-week randomised controlled trial. AB - AIM: To compare the long-term safety, tolerability and efficacy of saxagliptin vs. glipizide as add-on therapy to metformin. METHODS: Adults with glycated haemoglobin (HbA1c) > 6.5-10% (on stable metformin >= 1500 mg/day) were randomised to saxagliptin 5 mg/day (n = 428) or glipizide titrated from 5 to 20 mg/day (mean dose 15 mg/day; n = 430) for 52 weeks with a 52-week extension (NCT00575588). Assessment of the long-term safety, tolerability and efficacy of add-on saxagliptin vs. glipizide after 104 weeks was a tertiary objective of the initial 52-week study. RESULTS: Saxagliptin was well tolerated during the 104 week period; 67.1% of patients receiving saxagliptin vs. 72.6% receiving glipizide had >= 1 adverse event (AE), and few patients (4.9% vs. 5.6%) discontinued owing to AEs. Fewer patients treated with saxagliptin experienced hypoglycaemia (3.5% vs. 38.4% with glipizide; difference, -34.9%, 95% CI, -39.8 to -30.0) or confirmed hypoglycaemia (0 vs. 9.1% with glipizide). Weight loss was observed with saxagliptin (-1.5 kg) vs. weight gain with glipizide (+1.3 kg; between-group difference, -2.8 kg, 95% CI, -3.32 kg to -2.20 kg). Change from baseline in HbA1c was -0.41 +/- 0.04% with saxagliptin and -0.35 +/- 0.04% with glipizide (between-group difference, -0.05%, 95% CI, -0.17 to 0.06%). A post hoc analysis showed that the proportion of patients with baseline HbA1c >= 7% who achieved HbA1c < 7% (observed data) at week 104 was 23.1% for saxagliptin + metformin and 22.7% for glipizide + metformin. DISCUSSION AND CONCLUSION: A lower risk of hypoglycaemia and reduced body weight were observed with saxagliptin vs. glipizide. No other clinically significant differences were observed between groups in safety profile. No significant between-group differences were observed for reductions in glycaemic parameters. After week 24, a smaller weekly rise in HbA1c was observed with saxagliptin vs. glipizide as add-on therapy to metformin. PMID- 23638469 TI - Look on the bright side: progress in defining and treating depression and diabetes. PMID- 23638468 TI - [Brazilian Society of Urology. Guidelines on penile neoplasm]. PMID- 23638470 TI - Finding the nerve: diabetic neuropathy often goes undercover, but doctors have ways to unmask it. PMID- 23638471 TI - Straight up: climber Steve Richert's year of testing himself. PMID- 23638472 TI - Diabetes basics: true or false? These up-to-date diabetes management practices may surprise you. PMID- 23638473 TI - Mapping fat: where your flab is stored matters, spurring scientists to develop new ways to assess your health. PMID- 23638474 TI - Fresh pleasures. PMID- 23638475 TI - Decoding the food label: how to decide what products are best for you. PMID- 23638476 TI - The war on chronic diseases: how we can turn back the tide. PMID- 23638477 TI - What does "qualified" mean? PMID- 23638478 TI - Achieving a key purpose. PMID- 23638479 TI - Traffic light system for healed venous leg ulcer monitoring. AB - The purpose of this paper is to introduce the conceptualisation and evolution of a trialed Doppler traffic light system for healed venous leg ulceration. This tool aims to facilitate clinical decision-making and provides a systematic approach to the ongoing assessment of arterial disease in patients with healed venous leg ulcers when used in conjunction with other purposely-designed assessment documentation to ensure the novice registered and unregistered nurse contributes safely and effectively to the care of patients. The validation and trial of this clinical decision tool is discussed in terms of the use of a recognised methodology determining its fitness for purpose and robustness. PMID- 23638480 TI - Exudate assessment and management. AB - Good wound management must involve an holistic approach to care; without considering the whole person, appropriate management might not be as good as it could be. In a time of austerity, it is important that money is spent appropriately on the correct wound-management technologies. Exudate assessment and management are a vital part of wound management. In this article, the focus will be on exploring the nature of exudate and tools available to evaluate exudate. Finally, suggestions will be made on the management of exudate. PMID- 23638481 TI - Energise for excellence in care: a call to action for nurses and midwives. AB - Energise for Excellence in Care (E4E) is a nurse-led quality framework for nursing and midwifery advocated by the Chief Nursing Officer. It aims to support safe and effective care delivery, creating positive patient and staff experiences. Many nurses have the desire to make change but do not feel equipped to do so. Recognition of this is what inspired the development of this programme, which aims to provide easy access to tools, techniques and stories that will enable nurses and midwives to make the improvements to care they feel are necessary. E4E's vision is for at least 200000 nurses, midwives and health visitors to sign up and share their stories of best practice and cost savings. Through this programme, nurses can demonstrate their personal commitment to improving nursing care for their patients and reinforce their position as role models within the multidisciplinary team. This article provides an overview of E4E with examples of how it can be effectively put to use in practice. PMID- 23638482 TI - A personal journey towards any qualified provider in the NHS. AB - Any Qualified Provider (AQP) is a new and exciting way of organising health care that offers patient choice and cost-effective care. But there are many rumours and 'Chinese whispers' that are causing concern among healthcare workers throughout the UK. Although not all the rumours are false, there is a general misunderstanding of what AQP can provide and its potential to raise standards and lower costs throughout the NHS. This paper asks: can its promises be achieved? It also shows how AQP may work, through a personal experience of commissioning. PMID- 23638483 TI - Effective management of exudate with AQUACEL extra. AB - The management of patients with highly-exuding wounds can often lead to the use of unreliable and costly treatments. Patients are frequently found to be at increased risk of infection and delayed healing, which results in a huge negative impact on their quality of life. In the political and health arena, reducing health-care costs yet maintaining high quality and productivity is high on the list. With current economic, health-care and political targets, it is crucial to address the importance of effective wound management, particularly the importance of managing exudate. Inappropriate management of wound exudate can lead to prolonged wound healing, peri-wound maceration and excoriation, and can result in deterioration of the wound. PMID- 23638498 TI - Medical staff affairs: State peer review privilege not available in federal discrimination action. Adkins v. Christie, 488 F.3d 1324 (11th Cir. 2007). PMID- 23638499 TI - Vicarious liability: Hospitals in Florida under no obligation to ensure physician financial responsibility. Horowitz v. Plantation General Hospital, 959 So. 2d 176 (Fla. 2007). PMID- 23638500 TI - Risk management: Incident reports may not be privileged in North Carolina. Hayes v. Premier Living, Inc., 641 S.E.2d 316 (Ct. App. N.C. 2007). PMID- 23638501 TI - Equipment management: Equipment malfunction needs to be investigated thoroughly. Powell v. Hawkins, No. C-060685 (Ct. App. 1st Dist. Ohio July 13, 2007). PMID- 23638502 TI - Vicarious liability: Hospitals must perform some act to hold out practitioners as their agents. Boren v. Weeks, No. M2007-00628-COA-R9-CV (Ct. App. Tenn. June 12, 2007); DeWald v. HCA Health Services of Tennessee, No. M2006-02369-COA-R9-CV (Ct. App. Tenn. June 12, 2007). PMID- 23638503 TI - Emergency medicine: Peer review privilege not effective in EMTALA claims. Moses v. Providence Hospitals and Medical Centers, No. 04 CV 74889 DT (E.D. Mich. June 22, 2007). PMID- 23638504 TI - Emergency medicine: EMTALA may require production of records on other patients. Southard v. United Regional Health System, No. 7:06-CV-011-R (N. D. Tex. August 14, 2007). PMID- 23638505 TI - Negligent credentialing: Allegedly negligent practitioner need not be a party in negligent credentialing action. Schelling v. Humphrey, No. WM-07-001 (Ct. App. 6th Dist. Ohio October 12, 2007). PMID- 23638506 TI - Emergency medicine: Emergency providers may be liable under S1983 and EMTALA to pre-trial detainee. Lewellen v. Schneck Medical Center, No. 4:05-CV-0083-JDT-WGH (S.D. Ind. August 16, 2007). PMID- 23638507 TI - Medical information: Punitive damages may be imposed for unauthorized release of sensitive medical information. Randi A. J. v. Long Island Surgi-Center, No. 2005 04976 (Index No. 14150/01) (S. Ct. App. Div. NY September 25, 2007). PMID- 23638508 TI - [Dysenteric diarrhea in children: antibiotic use according to the demographic and health poll--Endes 2011]. PMID- 23638509 TI - Autoimmunity: Fade out, fade in. PMID- 23638510 TI - ATTORNEY-CLIENT PRIVILEGE: attorney-client privilege attaches to materials submitted to hospital attorney. St. Luke Hospitals, Inc. v. Kopowski. PMID- 23638511 TI - EMERGENCY MEDICINE: requiring a patient to sign payment guarantee does not violate EMTALA. Burton v. William Beaumont Hospital. PMID- 23638512 TI - MEDICAL RECORDS: more than mere relevance may be necessary for disclosure of medical records. Alcon v. Spicer. PMID- 23638513 TI - UNFAIR TRADE PRACTICES: cases illustrate allegations of unfair trade practices in health care. Vincent v. Essent Healthcare of Connecticut. Tipton v. William Beaumont Hospital. PMID- 23638514 TI - EMERGENCY MEDICINE: EMTALA only applies to hospitals that participate in Medicare. Rodriguez v. American International Insurance Co. of Puerto Rico. PMID- 23638515 TI - PEER REVIEW: statements made during peer review activity may not be defamatory. Davis v. Hildyard. PMID- 23638516 TI - Preventing occupational ill health in the construction industry. PMID- 23638517 TI - Occupational exposures to magnetic fields and neurodegenerative disease risks. PMID- 23638518 TI - The confounding effects of intraoral metals in salivary biomarkers. PMID- 23638519 TI - Closing the Swedish National Institute for Working Life. PMID- 23638520 TI - Unsafe abortion in Tanzania: a review of the evidence. AB - Although pregnancy termination is restricted by law in Tanzania, it is widely practiced and almost always unsafe,and contributes to the country's high maternal morbidity and mortality. Yet the majority of abortion-related deaths are preventable, as are the unintended pregnancies associated with abortion. Better access to contraceptives, more comprehensive postabortion care and greater availability of safe abortion services within the current legal framework are critical to achieving the Millennium Development Goal 5 of reducing maternal mortality and ensuring universal access to reproductive health care by 2015. PMID- 23638521 TI - Forensic odontology. PMID- 23638522 TI - Start smart: healthy weight in early childhood. PMID- 23638523 TI - Investing in dental practice management: key issues and notable transactions. PMID- 23638524 TI - Charting new waters in leadership development. PMID- 23638525 TI - It's a matter of taste. PMID- 23638526 TI - A refresher on social media policy. PMID- 23638527 TI - Oral health give people something to smile about. PMID- 23638528 TI - Effective oral health care requires effective collaboration. PMID- 23638529 TI - Will renal programs be included in exchanges? PMID- 23638530 TI - Advances in the treatment of diabetic nephropathy. AB - While renal and cardiovascular outcomes trials are required, several new therapies for patients with diabetes are promising. The diabetic nephropathy research community will hopefully continue to learn from recent experiences, through the step-wise design of clinical trials, including proof-of-principle and mechanistic studies, followed by investment in adequately powered clinical trials that will capture important renal and cardiovascular long-term outcomes. PMID- 23638531 TI - The impact of technology on nephrology social work practice. PMID- 23638532 TI - CROWNWeb: system enhancements, the ESRD QIP, and things to come. PMID- 23638533 TI - ORs modifying on-call practices to recruit and retain nursing staff. PMID- 23638534 TI - Safer surgery: six steps that aim for excellence in sterile processing. PMID- 23638535 TI - A 'cockpit checklist' reduces defects in instrument sets. PMID- 23638536 TI - Automating sterile processing for safety, efficiency. PMID- 23638537 TI - New on-call plan helps to stabilize the staff and budget. PMID- 23638538 TI - Team training, checklist equal better outcomes in pilot. PMID- 23638539 TI - Phone calls go away with a low-cost tracking system. PMID- 23638540 TI - Better business performance is a critical competency. PMID- 23638541 TI - Lesser souls. Caring for fat people. PMID- 23638542 TI - How to diagnose complacency. It can be a fatal condition. PMID- 23638543 TI - History's mysteries. With no background info, what's a crew to do? PMID- 23638544 TI - Q&A with Mike Taigman. How to improve the health of your community. Interview by Jenifer Goodwin. PMID- 23638545 TI - The patient compartment reimagined. How can it be ergonomically improved? PMID- 23638546 TI - Making the hard moves easier. What can reduce the injury risks of moving patients? PMID- 23638547 TI - Wilderness response. Ride along with the Canadian Air Force's search and rescue technicians. PMID- 23638548 TI - A matter of life and limb: get to know acute limb ischemia. What can cause it and what to do about it. PMID- 23638549 TI - Campus calls. University-based first response gives new meaning to "student EMT". PMID- 23638550 TI - Critical thinking. Criticism can help us improve--if we let it. PMID- 23638551 TI - [Collaboration between KNMVD and The Hague. It is playing chess on several boards at once]. PMID- 23638552 TI - [Get out of here]. PMID- 23638553 TI - [Trends from the GD-monitoring]. PMID- 23638554 TI - [What should the veterinarian know about the European Bat Lyssavirus?]. PMID- 23638555 TI - [What should the veterinarian know about the Ljungan virus]. PMID- 23638556 TI - [Tuberculosis spreads among lions in Krugerpark]. PMID- 23638557 TI - [Does the T4 measurement belong in the standard blood analysis in polyuria/polydipsia?]. PMID- 23638558 TI - [Contract or confrontation?]. PMID- 23638559 TI - [Animal welfare is deeply rooted in the Biomedical Primate Research Center]. PMID- 23638560 TI - [How profitable is your veterinary practice?]. PMID- 23638561 TI - [Chimpanzee veterinarian in Sierra Leone]. PMID- 23638562 TI - [Quality control hypersensitivity tests]. PMID- 23638563 TI - ['One Health"-forum Voorjaarsdagen]. PMID- 23638564 TI - How are the evolving initiatives in health care reform impacting your marketing and communications efforts? Interviewed by Rhoda Weiss. PMID- 23638565 TI - Becoming a change management expert. How communicators succeed in a new era of health care partnerships. PMID- 23638566 TI - One fewer headache for physicians. A strong online reputation management plan helps good reviews rise to the top. PMID- 23638567 TI - Information is power. Make your stakeholder database a powerful marketing tool. PMID- 23638568 TI - Modern marketing defined. Health care marketing's organizational impact can't be easily labeled. PMID- 23638569 TI - Rock your resources. Interviewed by Marguerite McNeal. PMID- 23638570 TI - Coming full circle. PMID- 23638571 TI - Getting better. PMID- 23638572 TI - A new road map. PMID- 23638573 TI - Good neighbors. The importance of community connections. PMID- 23638574 TI - Pricing radiology bundled CPT codes accurately. PMID- 23638575 TI - Why do we keep doing what we do? PMID- 23638576 TI - Quality improvement related to radiation safety chest radiography in the NICU. AB - Discussion includes radiation safety and radiographic quality management, continual quality improvement processes, and management review over a three year period. The results of radiation safety and radiographic quality audits conducted on random samples of chest radiographs are included. Specific measures and improvement strategies are presented as they relate to "babygrams" patient positioning, shielding, collimation, exposure technique, exposure index, and patient holding by NICU staff. Discussion of the change management process related to physician ordering, radiologic technologist training, and interdepartmental collaboration and team building. PMID- 23638577 TI - Peeling the onion: crying over edits. PMID- 23638578 TI - ICD-10: multiple pregnancy. PMID- 23638579 TI - New HIPAA rules: a guide for radiology providers. AB - The Office for Civil Rights issued its long awaited final regulations modifying the HIPAA privacy, security, enforcement, and breach notification rules--the HIPAA Megarule. The new HIPAA rules will require revisions to Notice of Privacy Practices, changes to business associate agreements, revisions to HIPAA privacy and security policies and procedures, and an overall assessment of HIPAA compliance. The HIPAA Megarule formalizes the HITECH Act requirements, and makes it clear that the OCRs ramp up of HIPAA enforcement is not merely a passing trend. The new rules underscore that both covered entities and business associates must reassess and strengthen HIPAA compliance. PMID- 23638580 TI - Effective radiology dashboards: key research findings. AB - Innovative organizations have access to information for business intelligence through the objectives displayed in dashboards. In healthcare organizations, where the goal is to improve quality of care along with reducing costs, the radiology department is important from both financial and clinical aspects. Therefore, how to manage this department has critical impact on the effectiveness and efficiency of the organization. Today, since the information in this department not only has different data structure but also is gathered from different data sources, a well defined, comprehensive dashboard can be an effective tool to enhance performance. PMID- 23638581 TI - Crashed. AB - Based on my experiences, I have a few recommendations to implement in a hospital and a radiology department: Recognize that your staff is the most important resource and invest in them. Adopt the "KIT Procedure". Remember that physicians need positive feedback, too. Make sure that high windows and ceilings are clean and repaired. Maintain safe and comfortable wheelchairs. Make training and inservices in your department a priority. Find a way for patients and technologists to make eye contact during an MRI. The radiology administrator should emulate the CNO described and spend a day on a regular basis with staff. I recently spent 10 days in a hospital as a patient. During my stay, I learned how hospitals really operate and I passed along a few recommendations that I hope you find helpful. I plan to implement these recommendations in my facility. "In your day, like mine, Stay Strong!"--Adapted from my friend Bubby Greene. PMID- 23638583 TI - Marketing in the imaging world. PMID- 23638582 TI - Patient satisfaction in imaging services. AB - This article is a brief summary of the use of patient satisfaction surveys in the imaging services department in a major hospital in Long island, New York. Secondary data was collected and analyzed from the surveys given to outpatients in the imaging services department for the time period from January 2010 up to and including December 2011. Statistical testing, including correlation and regression analysis, was performed on the data. Results revealed that patient satisfaction scores improved from 2010 to 2011. A continued focus on patient centered care should continue to show an improvement in these scores for the foreseeable future. PMID- 23638584 TI - Management help wanted. PMID- 23638585 TI - Majority of councils have cut their Child and Adolescent Mental Health Services. PMID- 23638586 TI - Mental health problems can have a huge impact on physical health. PMID- 23638587 TI - Targeting improvement. PMID- 23638588 TI - A case for suitable treatment? PMID- 23638589 TI - Keeping the faith. PMID- 23638590 TI - A welcome return for the welfare writes column. PMID- 23638591 TI - CQC's recent Mental Health Act report. PMID- 23638592 TI - Mental health problems who use alcohol to self-medicate. PMID- 23638594 TI - People focus on what is wrong with mental health services. PMID- 23638593 TI - Morale in the mental health workforce. PMID- 23638595 TI - Doctor's orders. PMID- 23638596 TI - People with a diagnosis of schizophrenia should be encouraged to aim high in life. PMID- 23638597 TI - Dementia behind bars: an unexpected yet predictable crisis. PMID- 23638598 TI - Green shoots of recovery. PMID- 23638599 TI - Looking at ordinary people's tales of living with their mental illness. Interviewed by Dan Parton. PMID- 23638600 TI - Annual Congress and Symposium--our guide to our future in leadership. PMID- 23638601 TI - Anaplastology: changing appearances/changing lives. AB - This is a synopsis of the presentation delivered at the Society of Otorhinolaryngology and Head-Neck Nurses' Annual Congress and Nursing Symposium, September 11, 2012 in Washington, DC. We all have imperfections in our faces and bodies that we would like to change. Consider, though, the cancer patient or the trauma victim who must deal with a facial disfigurement that completely changes their appearance, and often, their ability to function normally. Anaplastology, which combines art and science through creativity and functionality, can make monumental improvements in the quality of a person's life by giving acceptable appearance back to the patient. Custom-made appliances and prosthetic creations can bring hope and confidence back to the patient. Individualized adaptations can make the prosthetic a true work of art. Nurses work closely with patients who are benefitting from this creative process. Arriving at a successful and pleasing outcome is extremely satisfying for the entire team, the patient and family. PMID- 23638602 TI - Partners in accountability. PMID- 23638603 TI - My biggest mistake: hit leaders come clean. PMID- 23638604 TI - Workflow central. PMID- 23638605 TI - Inspired by intricacy. Interviewed by Elizabeth Gardner. PMID- 23638606 TI - [Pneumococcal vaccines: different types and their use in practice]. AB - Streptococcus pneumoniae is responsible for a large number of invasive infections and upper respiratory tract infections in infants, elderly and patients with high complication risk. Currently, two types of vaccine are available on the Belgian market. In the context of pharmaceutical care, it is important for pharmacists to know their specific characteristics and differences. In this article we try to explain these and to motivate their use in different patient populations. The 23 valent vaccine is different from the 13-valent vaccine, not only in number of serotypes, but also in its presentation as respectively polysaccharide- and conjugated vaccine which affects the immunogenicity. Moreover, their indication and use are also different. Finally we take a closer look at the specific use in infants and children at risk at one hand, and vaccination of eldery and adults with increased risk for severe pneumococcal infection on the other hand. PMID- 23638607 TI - [Diabetes and fasting during Ramadan. A observational study among Turkish immigrants in Belgium]. AB - AIMS: To investigate (i) Ramadan participation, (ii) provision of Ramadan related advice by healthcare providers (iii) medication use during Ramadan fasting among Turkish migrants with diabetes in Belgium. METHODS: This pilot observational study was conducted among a convenience sample of 52 Turkish migrants with diabetes in Belgium. Two questionnaires collected information on socio demographic characteristics, diabetes related characteristics, current hypoglycaemic medication with dosing regimen, participation in the past Ramadan, reasons for (non)participation, use of hypoglycaemic medication during the past Ramadan, advice from their healthcare providers about fasting during Ramadan and follow up of this advice. RESULTS: Sixteen patients (31%) had fasted during the past Ramadan. Main reason for Ramadan participation was reinforcement of faith (12/15), while the main reason for non participation was having diabetes (34/36). About 56% of the study population had received recommendations from their healthcare provider(s) about fasting and diabetes during Ramadan. The most commonly provided advice was not to participate in Ramadan, followed by modification of drug therapy. Only 3 patients ignored the advice of their healthcare professionals. In addition, only 60% of those who actually fasted received recommendations about intake of diabetes medication during the ramadan. Most fasters continued their medication dose unchanged (87% of OHA users and 80% of the insulin users). CONCLUSIONS: This pilot study found a low prevalence of Ramadan fasting among Turkish migrants with diabetes in Belgium. We also found that provision of advice by healthcare providers could be improved. Larger scale studies are warranted to confirm these findings. PMID- 23638608 TI - [Recommendations for the management of diabetes during Ramadan]. PMID- 23638609 TI - [Lack of compliance to topical corticosteroid therapy: possible cause and solutions]. AB - Adherence to therapy is low for topical therapy used in dermatological disorders. particularly in chronic diseases like atopic dermatitis and psoriasis. One of the reasons is that patients do not trust their therapy and fear side effects, particularly with topical corticosteroids. In order to make patients more confident, it is it important to provide correct and detailed information about the prescribed products and the amount to apply, to involve them in the implementation of therapy and to harmonize the information given by various care providers (physicians, nurses, pharmacists). The message needs to be clear and consistent between caregivers and not lead to unjustified worries. Poor adherence may result in the use of stronger preparations or switch to systemic treatment, which eventually will result in more severe side effects. PMID- 23638610 TI - [Rivaroxaban: Xarelto--recommendations for pharmacists]. AB - Rivaroxaban is one of the new oral anticoagulants (NOACs). It has many potential advantages in comparison with Vitamin K Antagonists (VKA). It has a predictable anticoagulant effect and does not theoretically require biological monitoring. It is also characterized by less food and drug interactions. However, due to major risks associated with over- and under-dosage, its optimal use in patients should be carefully followed by health care professionals. The aim of this article is to provide recommendations for pharmacists on the practical use of Xarelto in its different approved indications. This document is adapted from the practical user guide of rivaroxaban which was developed by an independent group of Belgian experts in the field of thrombosis and haemostasis. PMID- 23638611 TI - [Oral Rivaroxaban (Xarelto)]. PMID- 23638612 TI - [Oral Linagliptin (Trajenta)]. PMID- 23638614 TI - Theoretical investigations on the kinetics of H-abstraction reactions from CF3CH(OH)CF3 by OH radicals. AB - The kinetic studies of the H-abstraction reaction of CF3CH(OH)CF3 with the OH radical, which is predicted to have two classes of possible reaction channels, were carried out. The minimum energy path and energetics were calculated at M062X/6-31+G (d,p) method. The rate coefficients for each reaction channels were evaluated by canonical variational transition state theory (CVT) with the small curvature tunneling correction (SCT) and zero-curvature tunneling over the wide range of temperature of 200-3000 K. The temperature-dependent rate expression for the title reaction is obtained to be k(Total) = 2.60 * 10(-22)T(3.04) exp(372.45/T) cm(3) molecule(-1) s(-1); with k(298) = 3.54 * 10(-14) cm(3) molecule(-1) s(-1). The global warming potentials (GWPs) and atmospheric lifetimes of CF3CH(OH)CF3 are computed in the present investigation. The atmospheric implications and the degradation mechanism of CF3CH(OH)CF3 are discussed. It is concluded that this compound can be suggested as an acceptable substitute to HFCs in terms of its atmospheric lifetime and GWPs. PMID- 23638613 TI - Subcellular biochemical investigation of purkinje neurons using synchrotron radiation fourier transform infrared spectroscopic imaging with a focal plane array detector. AB - Coupling Fourier transform infrared spectroscopy with focal plane array detectors at synchrotron radiation sources (SR-FTIR-FPA) has provided a rapid method to simultaneously image numerous biochemical markers in situ at diffraction limited resolution. Since cells and nuclei are well resolved at this spatial resolution, a direct comparison can be made between FTIR functional group images and the histology of the same section. To allow histological analysis of the same section analyzed with infrared imaging, unfixed air-dried tissue sections are typically fixed (after infrared spectroscopic analysis is completed) via immersion fixation. This post fixation process is essential to allow histological staining of the tissue section. Although immersion fixation is a common practice in this filed, the initial rehydration of the dehydrated unfixed tissue can result in distortion of subcellular morphology and confound correlation between infrared images and histology. In this study, vapor fixation, a common choice in other research fields where postfixation of unfixed tissue sections is required, was employed in place of immersion fixation post spectroscopic analysis. This method provided more accurate histology with reduced distortions as the dehydrated tissue section is fixed in vapor rather than during rehydration in an aqueous fixation medium. With this approach, accurate correlation between infrared images and histology of the same section revealed that Purkinje neurons in the cerebellum are rich in cytosolic proteins and not depleted as once thought. In addition, we provide the first direct evidence of intracellular lactate within Purkinje neurons. This highlights the significant potential for future applications of SR-FTIR-FPA imaging to investigate cellular lactate under conditions of altered metabolic demand such as increased brain activity and hypoxia or ischemia. PMID- 23638615 TI - Volatile gas concentrations in turkey houses estimated by Fourier Transform Infrared Spectroscopy (FTIR). AB - 1. The aim of the present study was to estimate gas concentrations in commercial turkey houses by Fourier Transform Infrared Spectroscopy (FTIR). 2. The experiment was conducted in 5 buildings of a commercial turkey farm. The measurements of gases were carried out every 3 weeks of the growth cycle. 3. The results demonstrate that ammonia and carbon dioxide are the prevalent gases released during the entire production cycle in turkey houses. The mean concentrations of the above compounds ranged between 4-31 ppm and 220-2058 ppm, respectively. Thiols, nitriles, amines, aldehydes, hydrocarbons and other organic and inorganic compounds also occurred in turkey houses, but they were emitted periodically and their mean concentrations were significantly lower in comparison with CO2 and NH3. 4. Lower ventilation ratio and higher moisture of excreta in the first half of the growth period accelerated the release of some gases, whereas gradual faeces and urine accumulation contributed to an increase in the concentration of selected organic compounds. 5. A portable FTIR analyser is a useful device for measuring gas concentrations in commercial turkey farms, and it supports determinations of tolerable emission limits in turkey production. PMID- 23638616 TI - Development of novel methods to determine crystalline glucose content of honey based on DSC, HPLC, and Viscosity measurements, and their use to examine the setting propensity of honey. AB - Crystallization must occur in honey in order to produce set or creamed honey; however, the process must occur in a controlled manner in order to obtain an acceptable product. As a consequence, reliable methods are needed to measure the crystal content of honey (phi expressed as kg crystal per kg honey), which can also be implemented with relative ease in industrial production facilities. Unfortunately, suitable methods do not currently exist. This article reports on the development of 2 independent offline methods to measure the crystal content in honey based on differential scanning calorimetry and high-performance liquid chromatography. The 2 methods gave highly consistent results on the basis of paired t-test involving 143 experimental points (P > 0.05, r2 = 0.99). The crystal content also correlated with the relative viscosity, defined as the ratio of the viscosity of crystal containing honey to that of the same honey when all crystals are dissolved, giving the following correlation: MUr=1-1398.8?2.318. This correlation can be used to estimate the crystal content of honey in industrial production facilities. The crystal growth rate at a temperature of 14 degrees C-the normal crystallization temperature used in practice-was linear, and the growth rate also increased with the total glucose content in the honey. PMID- 23638617 TI - The longevity of adaptive memory: evidence for mnemonic advantages of survival processing 24 and 48 hours later. AB - Prior studies have convincingly demonstrated that survival-related processing of information enhances its subsequent retention. This phenomenon, known as the survival recall advantage, generalises to other stimuli, memory domains, and research populations, thereby underscoring its reliability. As previous studies used only short retention intervals between survival processing and the memory test, an important yet hitherto unanswered issue is whether this effect persists over time. The present experiment therefore examined whether survival processing also produces mnemonic benefits when retention is tested after longer delay periods. Participants (N =81) rated the relevance of words according to a survival and a moving scenario, and were then randomly assigned to the typical immediate (3-minute delay) retention test condition or conditions that included a 24- or 48-hour interval between survival processing and memory testing. In each of these conditions survival processing led to higher surprise free recall and recognition rates than processing words according to the moving scenario. Thus this study provides evidence that illustrates the longevity of survival processing advantages on memory performance. PMID- 23638619 TI - The predictors of suicidality in previous suicide attempters following case management services. AB - Suicide attempts constitute a serious clinical problem. People who have attempted suicide are at an elevated risk for additional suicide attempts, but there is limited evidence regarding the predictors of suicidality of suicide attempters following case management services. In the present study the indicators of suicidality after case management were examined. A total of 1,056 subjects who had recently attempted suicide were recruited from January 1, 2011, to June 30, 2011. The suicide prevention center of Kaohsiung City in Taiwan provided case management services and followed up on suicide attempt cases for 6 months. The salient factors for repeat suicide attempts were estimated using a logistic regression analysis. The results showed that multiple factors, including a "willingness to receive mental health services during a crisis," "social support," "a history of mental disorders," and "a history of suicide," could predict repeat suicide attempts with hazard ratios (0.58, 0.54, 3.84, 1.51) and 95% confidence interval (0.39-0.86, 0.36-0.83, 2.41-6.10, 1.03-2.21). The four factors mentioned above were the most accurate predictors of subsequent suicidality when case management services were utilized after 6 months of follow up. The findings of our study could help clarify future strategies for suicide prevention. PMID- 23638620 TI - Role of A1c in the postpartum screening of women with gestational diabetes. AB - OBJECTIVE: This study aimed to determine whether A1c detects a different prediabetes prevalence in women with a history of gestational diabetes mellitus (GDM) compared to those diagnosed with oral glucose tolerance test (OGTT) and the influence of haemoglobin concentrations on A1c levels. DESIGN AND PATIENTS: We evaluated carbohydrate metabolism status by performing OGTT and A1c tests in 141 postpartum women with prior GDM in the first year post-delivery. RESULTS: The overall prevalence of prediabetes was 41.8%. Prevalence of isolated A1c 5.7-6.4%, impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) was 10.6%, 7.1%, and 9.2%, respectively. Isolated A1c 5.7-6.4% was associated with Caucasian origin (66.7% versus 32.6%, p = 0.02) and with higher LDL cholesterol concentrations (123 +/- 28.4 mg/dl versus 101.6 +/- 19.2 mg/dl, p = 0.037) compared with patients diagnosed by OGTT (IFG or IGT). Women with postpartum anaemia had similar A1c levels to those with normal haemoglobin concentrations (5.5% +/- 0.6% versus 5.4% +/- 0.4%, p = 0.237). CONCLUSIONS: Use of A1c in postpartum screening of women with GDM detected an additional 10.6% of patients with prediabetes and a more adverse lipid profile. Haemoglobin concentrations did not influence A1c values. PMID- 23638621 TI - A prospective, randomised, investigator-blind, controlled, clinical study on the clinical efficacy and tolerability of two highly purified hMG preparations administered subcutaneously in women undergoing IVF. AB - The aim of this multicentre, prospective, randomised, investigator blind, controlled clinical trial was to evaluate the clinical efficacy and tolerability of a highly purified human menopausal gonadotrophin (hMG) preparation (Merional HG) when administered to patients undergoing controlled ovarian stimulation (COS) for in-vitro fertilisation (IVF) procedure enrolled in hospital departments. One hundred fifty-seven patients were randomised in two parallel groups: 78 started COS with Merional-HG and 79 with Menopur. Results of the study showed that both highly purified hMG preparations were equivalent in terms of number of oocytes retrieved (primary endpoint: 8.8 +/- 3.9 versus 8.4 +/- 3.8, p = 0.54). In the patients treated with Merional-HG, we observed a higher occurrence of mature oocytes (78.3% versus 71.4%, p = 0.005) and a reduced quantity of gonadotrophins administered per cycle (2.556 +/- 636 IU versus 2.969 +/- 855 IU, p < 0.001). Fertilisation, cleavage, implantation rates and the number of positive beta-human chorionic gonadotrophin (hCG; pregnancy) tests and the clinical pregnancy rate were comparable in the two groups. Both treatments were well tolerated. In conclusion, the results of this study support the efficacy and safety of Merional HG administered subcutaneously for assisted reproduction techniques. Efficiency of Merional-HG appears to be higher due to reduced quantity of drug used and the higher yield of mature oocytes retrieved. PMID- 23638622 TI - Raloxifene modifies the insulin sensitivity and lipid profile of postmenopausal insulin resistant women. AB - OBJECTIVE: To investigate the effects of raloxifene on the insulin sensitivity and lipid profile in insulin-sensitive and insulin-resistant postmenopausal women. STUDY DESIGN: This placebo-controlled, double-blind, randomized study involved 64 postmenopausal women aged between 45 and 55 years. All subjects were screened with the insulin resistance homeostasis model assessment (IR-HOMA) and those patients in the lowest quartile (n = 16) were assigned as insulin sensitive and those in the highest quartile as insulin resistant (n = 16). Patients in both groups received either raloxifene hydrochloride (60 mg/day) or a placebo for a period of 12 weeks. Insulin sensitivity, the serum lipid profile and anthropometric measurements were established before and after therapy. RESULTS: Women with the highest IR-HOMA scores were associated with a significantly higher weight, body mass index, waist and waist-to-hip ratio (p < 0.05). Raloxifene significantly reduced the IR-HOMA scores from 5.76 +/- 2.91 to 1.93 +/- 0.96 (p = 0.02) and modified the lipid profile in insulin-resistant patients when compared with the placebo group and those patients receiving raloxifene in the insulin sensitive group. CONCLUSION: Raloxifene reduced insulin resistance and modified the lipid profile in insulin-resistant postmenopausal women. PMID- 23638618 TI - NusG-Spt5 proteins-Universal tools for transcription modification and communication. PMID- 23638623 TI - Glucocorticoid therapy as a significant risk factor for osteoporosis and fractures in an Italian postmenopausal population. AB - OBJECTIVE: To analyze the potential effects of glucocorticoid treatment without an osteoporosis prevention strategy and to precociously identify patients at high risk of osteoporosis and fragility fractures in the postmenopausal period. METHODS: A total of 382 postmenopausal patients, 177 exposed and 205 not exposed to glucocorticoid therapy, were studied using a standard questionnaire. Epidemiological as well as clinical data that included the most recent absorptiometry test results were examined. RESULTS: Osteoporosis and fractures were frequent in the postmenopausal glucocorticoid-treated patients. Fragility fractures occurred more frequently in glucocorticoid-treated patients (vertebral fractures represented 45% of all fractures) than in the non-glucocorticoid treated patients. In particular, the highest fracture percentage was found in 50- to 65-year-old glucocorticoid-treated patients, a subset of patients showing a prevalence of osteoporosis similar to that of non-exposed menopausal subjects older than 65. Glucocorticoid therapy increases the risk of fragility fractures fivefold and doubles the risk of osteoporosis in menopausal patients. CONCLUSIONS: Glucocorticoid treatments put menopausal patients at a high risk of incurring fragility fractures even in the early postmenopausal period. The management of strategies for fracture prevention must take into consideration early intervention in patients undergoing or about to undergo glucocorticoid treatment. PMID- 23638624 TI - Molecular modelling, synthesis, cytotoxicity and anti-tumour mechanisms of 2-aryl 6-substituted quinazolinones as dual-targeted anti-cancer agents. AB - BACKGROUND AND PURPOSE: Our previous study demonstrated that 6-(pyrrolidin-1-yl) 2-(3-methoxyphenyl)quinazolin-4-one (HMJ38) was a potent anti-tubulin agent. Here, HMJ38 was used as a lead compound to develop more potent anti-cancer agents and to examine the anti-cancer mechanisms. EXPERIMENTAL APPROACH: Using computer aided drug design, 2-aryl-6-substituted quinazolinones (MJ compounds) were designed and synthesized by introducing substituents at C-2 and C-6 positions of HMJ38. The cytotoxicity of MJ compounds towards human cancer cells was examined by Trypan blue exclusion assay. Microtubule distribution was visualized using TubulinTracker(TM) Green reagent. Protein expression of cell cycle regulators and JNK was assessed by Western blot analysis. KEY RESULTS: Compounds MJ65-70 exhibited strong anti-proliferative effects towards melanoma M21, lung squamous carcinoma CH27, lung non-small carcinoma H460, hepatoma Hep3B and oral cancer HSC 3 cells, with one compund MJ66 (6-(pyrrolidin-1-yl)-2-(naphthalen-1-yl)quinazolin 4-one) highly active against M21 cells (IC50 about 0.033 MUM). Treatment of CH27 or HSC-3 cells with MJ65-70 resulted in significant mitotic arrest accompanied by increasing multiple asters of microtubules. JNK protein expression was involved in the MJ65-70-induced CH27 and M21 cell death. Consistent with the cell cycle arrest at G2/M phase, marked increases in cyclin B1 and Bcl-2 phosphorylation were also observed, after treatment with MJ65-70. CONCLUSIONS AND IMPLICATION: MJ65-70 are dual-targeted, tubulin- and JNK-binding, anti-cancer agents and induce cancer cell death through up-regulation of JNK and interfering in the dynamics of tubulin. Our work provides a new strategy and mechanism for developing dual-targeted anti-cancer drugs, contributing to clinical anti-cancer drug discovery and application. PMID- 23638626 TI - Species with a chemical defence, but not chemical offence, live longer. AB - Evolutionary hypotheses for ageing generally predict that delayed senescence should evolve in organisms that experience lower extrinsic mortality. Thus, one might expect species that are highly toxic or venomous (i.e. chemically protected) will have longer lifespans than related species that are not likewise protected. This remarkable relationship has been suggested to occur in amphibians and snakes. First, we show that chemical protection is highly conserved in several lineages of amphibians and snakes. Therefore, accounting for phylogenetic autocorrelation is critical when conservatively testing evolutionary hypotheses because species may possess similar longevities and defensive attributes simply through shared ancestry. Herein, we compare maximum longevity of chemically protected and nonprotected species, controlling for potential nonindependence of traits among species using recently available phylogenies. Our analyses confirm that longevity is positively correlated with body size in both groups which is consistent with life-history theory. We also show that maximum lifespan was positively associated with chemical protection in amphibian species but not in snakes. Chemical protection is defensive in amphibians, but primarily offensive (involved in prey capture) in snakes. Thus, we find that although chemical defence in amphibians favours long life, there is no evidence that chemical offence in snakes does the same. PMID- 23638625 TI - Sudden, unexpected death due to glioblastoma: report of three fatal cases and review of the literature. AB - Sudden death from an undiagnosed primary intracranial neoplasm is an exceptionally rare event, with reported frequencies in the range of 0.02% to 2.1% in medico-legal autopsy series and only 12% of all cases of sudden, unexpected death due to primary intracranial tumors are due to glioblastomas. We present three cases of sudden, unexpected death due to glioblastoma, with different brain localization and expression. A complete methodological forensic approach by means of autopsy, histological and immunohistochemical examinations let us to conclude for an acute central dysregulation caused by glioblastoma and relative complication with rapid increase of intracranial pressure as cause of death. Although modern diagnostic imaging techniques have revolutionized the diagnosis of brain tumors, the autopsy and the careful gross examination and section of the fixed brain (with coronal section) is still the final word in determining exact location, topography, mass effects and histology and secondary damage of brain tumor and contributed the elucidation of the cause of death. Immunohistochemistry and proteomic analysis are mandatory in such cases. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1218574899466985. PMID- 23638627 TI - Naloxone increases maturation rate and ratio of inner cell mass to total cells in blastocysts in pigs. AB - The purposes of the present study were to examine the effect of naloxone, a mu opioid receptor (MOR) antagonist, on porcine oocyte maturation and embryo development. MOR gene was expressed in germinal vesicle (GV) and metaphase II (M II) porcine oocytes, one-, four-cell stage embryos and blastocysts. In blastocysts, MOR gene was mainly expressed in inner cell mass (ICM) cells. Supplementation of 10(-8) mol/L naloxone in in vitro maturation (IVM) medium increased the maturation rate (P < 0.05). However, 10(-4) mol/L naloxone reduced the maturation rate (P < 0.05) compared with the control. The presence of naloxone during IVM had no effects on fertilization status and subsequent embryonic development after in vitro culture (IVC). The addition of 10(-3) mol/L dibutyryl cyclic adenosine monophosphate (dbcAMP), and 10(-8 ) mol/L naloxone together into IVM medium increased nuclear maturation (P < 0.05) compared with the addition of either dbcAMP or naloxone alone. Supplementation with naloxone in IVC medium did not improve embryonic development. However, at the concentrations of 10(-6) mol/L and 10(-8) mol/L, naloxone increased the ratio of ICM to total cells in blastocysts (P < 0.05). In conclusion, at low concentration, naloxone increases maturation rate and the ratio of ICM to total cells in blastocysts. Naloxone and cAMP have a synergistic effect on oocyte maturation. PMID- 23638628 TI - AULA virtual reality test as an attention measure: convergent validity with Conners' Continuous Performance Test. AB - The majority of neuropsychological tests used to evaluate attention processes in children lack ecological validity. The AULA Nesplora (AULA) is a continuous performance test, developed in a virtual setting, very similar to a school classroom. The aim of the present study is to analyze the convergent validity between the AULA and the Continuous Performance Test (CPT) of Conners. The AULA and CPT were administered correlatively to 57 children, aged 6-16 years (26.3% female) with average cognitive ability (IQ mean = 100.56, SD = 10.38) who had a diagnosis of attention deficit/hyperactivity disorder (ADHD) according to DSM-IV TR criteria. Spearman correlations analyses were conducted among the different variables. Significant correlations were observed between both tests in all the analyzed variables (omissions, commissions, reaction time, and variability of reaction time), including for those measures of the AULA based on different sensorial modalities, presentation of distractors, and task paradigms. Hence, convergent validity between both tests was confirmed. Moreover, the AULA showed differences by gender and correlation to Perceptual Reasoning and Working Memory indexes of the WISC-IV, supporting the relevance of IQ measures in the understanding of cognitive performance in ADHD. In addition, the AULA (but not Conners' CPT) was able to differentiate between ADHD children with and without pharmacological treatment for a wide range of measures related to inattention, impulsivity, processing speed, motor activity, and quality of attention focus. Additional measures and advantages of the AULA versus Conners' CPT are discussed. PMID- 23638629 TI - Cardiovascular changes during SCUBA diving: an underwater Doppler echocardiographic study. AB - AIM: Body immersion induces blood redistribution (from peripheral to intrathoracic vessels) and is a powerful autonomic stimulus (activating both parasympathetic and sympathetic systems). For these reasons, concerns have been raised about the safety of diving for subjects with previous heart disease. The aim of this study was to evaluate cardiovascular changes occurring during recreational SCUBA diving, as assessed by underwater Doppler echocardiography. METHODS: Eighteen healthy experienced divers underwent a 2D Doppler echocardiography basally, during two 15' steps of still SCUBA diving at different depths (10 m followed by 5 m) and shortly after the end of immersion. RESULTS: During dive, left ventricular (LV) diastolic volume and early left ventricular filling significantly increased (5 m vs. basal: P < 0.05 and P < 0.01, respectively), while both deceleration time of the early filling rate and late diastolic filling velocity significantly decreased (5 m and 10 m dive vs. basal: P < 0.01). LV volume increase and diastolic filling changes persisted at postdive evaluation, where a significant decrease in heart rate was also observed (P < 0.01 as compared to basal, 5-m and 10-m dive). CONCLUSION: This study documents that shallow-depth SCUBA diving induces LV enlargement and diastolic dysfunction. Direct underwater evaluation by Doppler echocardiography could be an appropriate tool for unmasking subjects at risk for underwater-related accidents. PMID- 23638630 TI - DNMT1 genetic polymorphisms affect breast cancer risk in the central European Caucasian population. AB - INTRODUCTION: DNA methylation of CpG islands within the promoter region of genes is an epigenetic modification with an important role in the development of cancer and it is typically mediated by DNA methyltransferases (DNMTs). In cancer cells, global hypomethylation of the genome as a whole and regional hypermethylation of CpG islands have been reported. Four groups of DNMTs have been identified: DNMT1, DNMT2 (TRDMT1), DNMT3A and DNMT3B. DNMT2 uses the catalytic mechanism of DNMTs, but does in fact methylate RNA. Little is known about the significance of these genes in human breast cancer. In the study presented herein, we analyzed five distinct DNMT single SNPs with regard to potential associations with breast cancer risk. CASE DESCRIPTION: In this study, we genotyped 221 female Caucasian breast cancer patients and 221 female Caucasian healthy controls, and we used five allele-specific real-time polymerase chain reaction (qPCR) assays. We selected one locus within the DNMT1 gene and two loci within the DNMT3A and DNMT3B genes, respectively. Statistics were calculated using the chi-squared and Fisher's exact tests, and correlated with clinical parameters such as age, diagnosis, histology, TNM stage, hormonal receptor status, human epidermal growth factor receptor 2 (HER2) status, response to treatment and survival. Statistically significant results were obtained for correlations with the DNMT1 gene. DISCUSSION AND EVALUATION: Five genomic loci within the DNMT1, DNMT3A and DNMT3B genes were assessed. Statistical significance (P = 0.030) was identified for DNMT1 SNP (A201G, rs2228612): six women within the control group were GG homozygous (variant), while this mutation was absent in the breast cancer group. CONCLUSIONS: We conclude that women with the DNMT1 SNP (A201G, rs2228612) GG homozygous genotype (variant) have a lower risk of developing breast cancer compared to heterozygous or wildtype genotypes. To date, alterations within the DNMT1 gene have not been reported to be associated with cancer in the Caucasian population. PMID- 23638631 TI - Hormone withdrawal-associated symptoms: comparison of oestradiol valerate/dienogest versus ethinylestradiol/norgestimate. AB - OBJECTIVES: To determine the effect of oestradiol valerate/dienogest (E2V/DNG) versus ethinylestradiol/norgestimate (EE/NGM) on hormone-withdrawal associated symptoms (HWAS) in otherwise healthy women who had experienced at least one of these symptoms when using 21/7-day combined oral contraceptives (COCs). METHODS: This phase III, parallel-group study randomised 409 women aged 18 to 50 years to E2V/DNG or EE/NGM. The primary efficacy variable was the change from baseline to cycle 6 in the average of the three highest visual analogue scale values for headache and/or pelvic pain during cycle days 22 to 28. RESULTS: In total, 395 were included in the full analysis set (E2V/DNG, n = 191; EE/NGM, n = 204). E2V/DNG reduced the symptoms of headache or pelvic pain during cycle days 22 to 28 from baseline to cycle 6 to a significantly greater extent than EE/NGM (mean decrease 43.6 vs. 35.5 mm; p = 0.0024). Both treatments were well tolerated with a similar proportion of women experiencing adverse events that were considered at least possibly related to treatment (35% E2V/DNG vs. 34% EE/NGM). CONCLUSIONS: E2V/DNG reduces the frequency and intensity of headache and pelvic pain to a greater extent than EE/NGM, and may be a good option for women susceptible to HWAS with conventional 21/7-day COCs. PMID- 23638632 TI - Effects of angiotensin II type 1 receptor antagonist and temperature on prolonged cardioplegic arrest in neonatal rat myocytes. AB - Cardioplegic arrest is a model of ischemia/reperfusion injury and results in the death of irreplaceable cardiac myocytes by a programmed cell death or apoptosis. Signal transducers and activators of transcription (STAT) signaling pathways play an important role in the modulation of apoptosis after ischemia and reperfusion. Angiotensin II type 1 (AT1) receptor antagonist added to cardioplegia could represent an additional modality for enhancing myocardial protection during cardioplegic arrest. To test that hypothesis, we studied the effect of AT1 receptor antagonism and cardioplegia temperature perfusion on STATs modulation during cardioplegic arrest in neonatal rat hearts. Isolated, nonworking hearts (n = 4 per group) from neonatal rats were perfused aerobically in the Langendorff mode according to the following scheme: Dulbecco's Modified Eagle's Medium solution (Group 1); cold (4 degrees C) modified St. Thomas' Hospital no. 2 (MSTH2) cardioplegic solution (Group 2); cold (4 degrees C) MSTH2 cardioplegic solution plus AT1 antagonist (Valsartan) (Group 3); and warm (34 degrees C) MSTH2 cardioplegic solution (Group 4). Thus, myocytes were isolated by enzymatic digestion, and STAT1, STAT2, STAT3, and STAT5 were investigated in Western blot studies. Times to arrest after cardioplegia were 6-10 s for all groups with the exception of Group 1 (spontaneous arrest after 12-16 s). Total cardioplegia delivery volume was about 300 mL in 15 min. Perfusion with cold MSTH2 supplemented with AT1 receptor antagonist (Group 3) induced a significant reduction in STAT1, STAT2, and STAT5 tyrosine phosphorylation versus other groups (P < 0.05). The decreased activation of STAT1, STAT2, and STAT5 observed in Group 3 was accompanied by reduction of interleukin-1beta (P < 0.05). On the other hand, STAT3 activation was significantly reduced in Groups 1 and 4 (P < 0.05). Only perfusion with AT1 receptor antagonist supplemented with cold MSTH2 significantly decreases the inflammatory response of the neonatal rat cardiomyocytes without affecting antiapoptotic influence provided by activation of STAT3. Therefore, AT1 receptor antagonist could play a pivotal role in cytoprotective effect and cardiac recovery in neonates and infants. PMID- 23638634 TI - Food marketing to children on U.S. Spanish-language television. AB - Latino children in particular are at risk of childhood obesity. Because exposure to televised food marketing is a contributor to childhood obesity, it is important to examine the nutritional quality of foods advertised on Spanish language children's programming. The authors analyzed a sample of 158 Spanish language children's television programs for its advertising content and compared them with an equivalent sample of English-language advertising. The authors evaluated nutritional quality of each advertised product using a food rating system from the U.S. Department of Health and Human Services. In addition, the authors assessed compliance with industry self-regulatory pledges. The authors found that amount of food advertising on Spanish-language channels (M = 2.2 ads/hour) was lower than on English-language programs, but the nutritional quality of food products on Spanish-language channels was substantially poorer than on English channels. Industry self-regulation was less effective on Spanish language channels. The study provides clear evidence of significant disparities. Food advertising targeted at Spanish-speaking children is more likely to promote nutritionally poor food products than advertising on English-language channels. Industry self-regulation is less effective on Spanish-language television channels. Given the disproportionately high rate of childhood obesity among Latinos, the study's findings hold important implications for public health policy. PMID- 23638636 TI - Molecular insights into clathrate hydrate nucleation at an ice-solution interface. AB - Clathrate hydrates are specific cage-like structures formed by water molecules around a guest molecule. Despite the many studies that have been performed on clathrate hydrates, the actual molecular mechanism of both their homogeneous and heterogeneous nucleation has yet to be fully clarified. Here, by means of molecular simulations, we demonstrate how the interface of hexagonal ice can facilitate the heterogeneous nucleation of methane clathrate hydrate from an aqueous methane solution. Our results indicate an initial accumulation of methane molecules, which promote induction of defective structures, particularly coupled 5-8 ring defects, at the ice surface. Structural fluctuations promoted by these defective motifs assist hydrate cage formation next to the interface. The cage like structures formed then act as a sink for methane molecules in the solution and enhance the stability and growth of an amorphous nucleus, which can evolve into a hydrate crystal upon annealing. These results are illustrative of how a surface that is structurally incompatible can serve to facilitate heterogeneous nucleation of a new crystalline phase. They should also further our general understanding of the formation of gas hydrates and their critical roles in various industrial and environmental processes, including carbon capture and storage. PMID- 23638635 TI - A hybrid seasonal prediction model for tuberculosis incidence in China. AB - BACKGROUND: Tuberculosis (TB) is a serious public health issue in developing countries. Early prediction of TB epidemic is very important for its control and intervention. We aimed to develop an appropriate model for predicting TB epidemics and analyze its seasonality in China. METHODS: Data of monthly TB incidence cases from January 2005 to December 2011 were obtained from the Ministry of Health, China. A seasonal autoregressive integrated moving average (SARIMA) model and a hybrid model which combined the SARIMA model and a generalized regression neural network model were used to fit the data from 2005 to 2010. Simulation performance parameters of mean square error (MSE), mean absolute error (MAE) and mean absolute percentage error (MAPE) were used to compare the goodness-of-fit between these two models. Data from 2011 TB incidence data was used to validate the chosen model. RESULTS: Although both two models could reasonably forecast the incidence of TB, the hybrid model demonstrated better goodness-of-fit than the SARIMA model. For the hybrid model, the MSE, MAE and MAPE were 38969150, 3406.593 and 0.030, respectively. For the SARIMA model, the corresponding figures were 161835310, 8781.971 and 0.076, respectively. The seasonal trend of TB incidence is predicted to have lower monthly incidence in January and February and higher incidence from March to June. CONCLUSIONS: The hybrid model showed better TB incidence forecasting than the SARIMA model. There is an obvious seasonal trend of TB incidence in China that differed from other countries. PMID- 23638637 TI - Assessment of the performance of long-range-corrected density functionals for calculating the absorption spectra of silver clusters. AB - We assess the accuracy of several long-range-corrected (LC-) density functionals for the prediction of absorption spectra of silver clusters by time-dependent density functional theory. Several types of LC-functionals, with the exact Hartree-Fock exchange at long-range, are used: those applying the long-range correction to a standard GGA-type functional (LC-BP86, LC-omegaPBE) or to a local meta-GGA functional (LC-M06L) and two global hybrid functionals (CAM-B3LYP and omegaB97x). The spectra calculated with those density functionals are in good agreement with the recent accurate experimental measurements. We show that CAM B3LYP and omegaB97x are some of the most accurate functionals for evaluating the electronic excitation energies, while LC-M06L is more effective in reducing the occurrence of spurious states. The long-range correction appears to be essential in describing the absorption spectra of large clusters. The description of the plasmon-like band with LC functionals as transitions associated with excitations from s orbitals to s + p orbitals is in fairly good agreement with the classical interpretation as a collective excitation of valence s electrons. PMID- 23638639 TI - Chiral conflict among different helicenes suppresses formation of one enantiomorph in 2D crystallization. AB - Diastereomeric interactions in 2D crystals formed at solid surfaces serve as excellent models for understanding molecular recognition in biomineralization. Adsorption of a pentahelicene racemate on a Au(111) surface leads to 2D conglomerate crystallization, i.e., homochiral mirror domains, as observed by scanning tunneling microscopy. Upon mixing 26% of (M)-heptahelicene into the racemate monolayer, only the (M)-pentahelicene enantiomorph is observed. This effect is explained by a preferred heterochiral interaction between the different helicene species, suppressing the formation of the pure (P)-pentahelicene enantiomorph. These results shine new light onto stereoselective molecular recognition mediated by van der Waals forces. PMID- 23638638 TI - ALS Untangled No. 20: the Deanna protocol. PMID- 23638640 TI - Matrix isolation study of the ozonolysis of 1,3- and 1,4-cyclohexadiene: identification of novel reaction pathways. AB - The ozonolysis reactions of 1,3- and 1,4-cyclohexadiene have been studied using a combination of matrix isolation, infrared spectroscopy, and theoretical calculations. Experimental and theoretical results demonstrate that these reactions predominantly do not follow the long-accepted Criegee mechanism. Rather, the reaction of O3 with 1,4-cyclohexadiene leads to the essentially barrierless formation of benzene, C6H6, and H2O3. These two species are then trapped in the same argon matrix cage and weakly interact to form a molecular complex. There is also evidence for the formation of a small amount of the primary ozonide as a minor product, formed through a transition state that is slightly higher in energy. The reaction of O3 with 1,3-cyclohexadiene follows two pathways, one of which is the Criegee mechanism through a low energy transition state leading to formation of the primary ozonide. In addition, with a similar barrier, ozone abstracts a single hydrogen from C5 while adding to C1, forming a hydroperoxy intermediate. This study presents two of the rare cases in which the Criegee mechanism is not the dominant pathway for the ozonolysis of an alkene as well as the first evidence for dehydrogenation of an alkene by ozone. PMID- 23638641 TI - Cysteine-conjugated metabolite of ginger component [6]-shogaol serves as a carrier of [6]-shogaol in cancer cells and in mice. AB - Shogaols, a series of major constituents in dried ginger (Zingiber officinale), show high anticancer potencies. Previously, we reported that a major metabolite resulting from the mercapturic acid pathway, 5-cysteinyl-[6]-shogaol (M2), showed comparable growth inhibitory effects toward cancer cells to [6]-shogaol (6S). Here, we probe the mechanism by which M2 exerts its bioactivity. We utilized a series of chemical stability tests in conjunction with bioassays to show that thiol-conjugates display chemopreventative potency by acting as carriers of active ginger component 6S. M2 chemical degradation to 6S was observed in an environment most resembling physiological conditions, with a pH of 7.4 at 37 degrees C. The metabolic profiles of M2 in cancer cells HCT-116 and H-1299 resembled those of 6S, indicating that its biotransformation route was initiated by deconjugation. Further, the presence of excess glutathione significantly delayed 6S and M2 metabolism and counteracted cell death induced by 6S and M2, suggesting that increasing available free thiols exogenously both promoted the formation of 5-glutathionyl-[6]-shogaol (M13) and inhibited the production of free 6S from M2 deconjugation, resulting in delayed 6S cell entry and bioactivity. Given the chemopreventative properties of M2 and our observations in vitro, we investigated its metabolism in mice. M2 and 6S showed similar metabolic profiles in mouse urine and fecal samples. Six new thiol-conjugated metabolites (M16-M21), together with previously reported ones, were identified by LC/MS. In particular, the increase of 5-N-acetylcystenyl-[6]-shogaol (M5) and its 3' demethylated product (M16) abundance in mouse feces after treatment with M2 indicates that in addition to acting as a carrier of 6S, M2 is also directly acetylated to M5, which is further demethylated to M16 in vivo. In conclusion, the cysteine-conjugated metabolite of [6]-shogaol M2 exerts its bioactivity by acting as a carrier of 6S in both cancer cells and in mice. PMID- 23638643 TI - Hyaluronan with dextran added to therapeutic lung surfactants improves effectiveness in vitro and in vivo. AB - Surfactants in current clinical use are largely ineffective in treating acute lung injury (ALI)/ acute respiratory distress syndrome. In part, this ineffectiveness is due to inactivation of surfactant by serum leakage into the alveoli. Previously, we reported that adding hyaluronan and some nonionic polymers to synthetic lipids combined with native SP-B and SP-C enhanced surface activity. In this study, we first tested two therapeutic lung surfactants and then retested after adding hyaluronan, polyethylene glycol or dextran alone or in two-polymer combinations including hyaluronan in the absence or presence of serum. Surface activities were measured in a modified bubble surfactometer. Results indicate that the inhibition threshold (defined as the amount of serum required to produce a minimum surface tension above 10 mN/m after 5 minutes of cycling) was 35 times higher with hyaluronan plus dextran added to Infasurf than with Infasurf alone, and better than all other mixtures tested. The threshold for Survanta with hyaluronan plus polyethylene glycol was 7 times higher than Survanta alone. We next tested selected surfactant mixtures in an animal model that mimicked ALI. All measurements of lung function showed significant improvement (P <= .05) with hyaluronan, or with hyaluronan and dextran added to Infasurf compared to Infasurf alone. Also, for these two groups, lung function was still improving at the end of the experiment. We conclude that certain polymers added to clinical surfactants can greatly increase resistance to inactivation in vitro, while in vivo, both Infasurf mixtures containing hyaluronan tended to normalize measures of lung function unlike other mixtures tested. PMID- 23638642 TI - Injectable nano-network for glucose-mediated insulin delivery. AB - Diabetes mellitus, a disorder of glucose regulation, is a global burden affecting 366 million people across the world. An artificial "closed-loop" system able to mimic pancreas activity and release insulin in response to glucose level changes has the potential to improve patient compliance and health. Herein we develop a glucose-mediated release strategy for the self-regulated delivery of insulin using an injectable and acid-degradable polymeric network. Formed by electrostatic interaction between oppositely charged dextran nanoparticles loaded with insulin and glucose-specific enzymes, the nanocomposite-based porous architecture can be dissociated and subsequently release insulin in a hyperglycemic state through the catalytic conversion of glucose into gluconic acid. In vitro insulin release can be modulated in a pulsatile profile in response to glucose concentrations. In vivo studies validated that these formulations provided improved glucose control in type 1 diabetic mice subcutaneously administered with a degradable nano-network. A single injection of the developed nano-network facilitated stabilization of the blood glucose levels in the normoglycemic state (<200 mg/dL) for up to 10 days. PMID- 23638644 TI - Cellular and molecular mechanisms of goblet cell metaplasia in the respiratory airways. AB - The mucociliary system, consisting of mucus-secreting goblet cells and ciliated cells, generates a constant overturning layer of protective mucus that lines the airway epithelium. Mucus hypersecretion and the pathophysiological changes associated are hallmarks of many pulmonary diseases including asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Excessive mucus production leads to airway obstruction and, because there is currently no effective treatment, contributes to morbidity and mortality of many patients. Goblet cell differentiation and mucus production are subject to extensive control. An emerging concept is that not all goblet cells are phenotypically identical suggesting that specific molecular pathways orchestrate mucin overproduction. This paper attempts to describe the cellular and molecular mechanisms governing the differentiation of goblet cells in pulmonary diseases, a prerequisite for the development of new therapeutic agents. PMID- 23638645 TI - Innovation in the post-MDG environment: advancing global health diplomacy in pursuit of the global good. PMID- 23638646 TI - Paucisymptomatic Marchiafava-Bignami disease with relevant diffusion-weighted MRI lesions. AB - Marchiafava-Bignami disease (MBD) is a rare alcohol-associated disorder characterized by demyelization and necrosis of the corpus callosum. Diffusion weighted (DW) MRI may reveal the lesions in patients showing serious clinical manifestations, high mortality rate and severe cognitive sequelae, though some cases with good outcome have been reported. We describe a case of a man with a history of chronic alcohol abuse associated with malabsorption; the man presented mild clinical signs on the first neurological exam, despite the presence of DW MRI lesions, bilaterally involving entire corpus callosum, that are compatible with MBD diagnosis. PMID- 23638647 TI - Anxiety disorders are associated with increased plasma adrenomedullin level and left ventricular hypertrophy in patients with hypertension. AB - OBJECTIVE: To investigate the association between anxiety disorders and left ventricular hypertrophy in patients with essential hypertension. METHODS: Left ventricular structure and function were assessed with echocardiography in 56 patients with essential hypertension and anxiety disorder (study group) and in 56 patients with hypertension only (control group). Serum adrenomedullin levels were also measured in these patients. RESULTS: There was no statistically significant difference in the left ventricular ejection fraction between the study and the control group (54.21 +/- 88.81% versus 56.01 +/- 7.85%, p>0.05). The left ventricular mass index (LVMI) in study group was higher than in control group (137.05 +/- 9.42 versus 123.57 +/- 7.01 g/m(2), p=0.001). The plasma levels of adrenomedullin in study group was higher than in control group (25.97 +/- 5.48 versus 18.32 +/- 6.97 ng/L, p=0.001). Levels of plasma adrenomedullin were positively correlated with LVMI in the study (r=0.734, p<0.05) and control group (r=0.592, p<0.05). CONCLUSION: Anxiety disorders are associated with elevated plasma adrenomedullin levels and increased left ventricular hypertrophy in patients with essential hypertension. The clinical significance of these changes requires further investigation. PMID- 23638648 TI - Murder must memorise. AB - Memory reports usually provide the evidence that is most determinative of guilt or innocence in criminal proceedings-including in the most serious proceedings, capital murder trials. Thus memory research is bedrock science when it comes to the reliability of legal evidence, and expert testimony on such research is a linchpin of just verdicts. This principle is illustrated with a capital murder trial in which several of the most powerful forms of memory distortion were present (e.g., phantom recollections, robust interrogation methods that stimulate false self-incrimination). A key question before the jury, whether to regard the defendant's confession as true or false, turned on a theoretical principle that is used to explain memory distortion in the laboratory, the verbatim-gist distinction, and on research showing that it is possible to create false memories that embody the gist of experience. The scientific testimony focused on instances in which false gist memories had been created under controlled conditions (e.g., of having been lost in a mall, of receiving surgery for a fictitious injury), as well as on real-life examples of false memory for the gist experience (e.g., recovered memories of sexual abuse, alien abduction memories). The defendant was found innocent of capital murder. PMID- 23638649 TI - Iodine-mediated highly regio- and stereoselective iodoamination of ferrocenyl allene: an approach for the synthesis of ferrocene-containing allylic amines. AB - A straightforward and efficient protocol for the highly regio- and stereoselective synthesis of ferrocene-containing allylic amine derivatives via an iodine-mediated iodoamination of ferrocenyl allene was developed. The regio- and stereoselectivity of this reaction may be controlled by the steric effect of the bulky ferrocene group. PMID- 23638650 TI - Prevalence and factors associated with a prolonged QTc interval in a cohort of asymptomatic HIV-infected patients. AB - We aimed to determine the prevalence of a prolonged QTc interval in HIV-infected patients and its related factors through an observational study of a cohort of asymptomatic HIV-infected outpatients. All patients underwent a standard 12-lead electrocardiogram and a transthoracic echocardiogram. Prolonged QTc was considered if it was >440 ms in men and >450 ms in women. Epidemiological, clinical, and laboratory data were collected and the patients completed a questionnaire about cardiovascular risk factors. The analysis of the potential risk factors for prolonged QTc was done by multivariate logistic regression. The study included 194 patients, 84% men, with a mean age of 46.3 years. The mean duration of HIV infection was 122.6 months and 27.8% had AIDS. Antiretroviral therapy was being taken by 185 (96.4%) patients, and 92.4% of them had an undetectable viral load. The mean CD4 lymphocyte count was 553/mm(3). A total of 24 (12.4%) patients had a prolonged QTc interval, with a mean QTc of 456 ms. The factors associated with a prolonged QTc were hyperlipidemia (OR 3.7, 95% CI: 1.3 10.3; p=0.01) and diastolic dysfunction (OR 6.7, 95% CI: 2.4-18.3; p=0.0001), while the use of atazanavir was associated with a lower likelihood of having a prolonged QTc (OR 0.11, 95% CI: 0.02-0.5; p=0.008). A prolonged QTc syndrome was not uncommon in this cohort of asymptomatic HIV-infected patients with good immunovirological control. It was associated with hyperlipidemia and diastolic dysfunction. The use of atazanavir, compared with other protease inhibitors, was associated with a lower likelihood of having a prolonged QTc. PMID- 23638651 TI - Mechanism and selectivity of bioinspired cinchona alkaloid derivatives catalyzed asymmetric olefin isomerization: a computational study. AB - Asymmetric olefin isomerization of beta,gamma- to alpha,beta-unsaturated butenolides catalyzed by novel cinchona alkaloid derivatives was investigated in depth using density functional theory (M05-2x and B2PLYP-D). Three possible mechanistic scenarios, differing in the binding modes of the substrate to the catalyst, have been evaluated. Computations revealed that both the protonated quinuclidine and the 6'-OH of catalysts may act as the proton donor in the stereocontrolling step. Variation of the catalytic activity and enantioselectivity by tuning the electronic effect of catalyst was well reproduced computationally. It suggested that, for certain acid-base bifunctional chiral catalysts, the acid-base active sites of catalysts may interconvert and give new catalyst varieties of higher activity and selectivity. In addition, the noncovalent interactions in the stereocontrolling transition-state structures were identified, and their strength was quantitatively estimated. The weak nonconventional C-H...O hydrogen-bonding interactions were found to be crucial to inducing the enantioselectivity of the cinchona alkaloid derivatives catalyzed asymmetric olefin isomerization. The computational results provided further theoretical evidence that the rate-limiting step of this bioinspired organocatalytic olefin isomerization is inconsistent with that of the enzyme catalyzed olefin isomerization. PMID- 23638652 TI - Quantum chemistry investigation of secondary reaction kinetics in acrylate-based copolymers. AB - Recently, a growing amount of attention has been focused on the influence of secondary reactions on the free radical polymerization features and the properties and microstructure of the final polymer, particularly in the context of acrylate copolymers. One of the most challenging aspects of this research is the accurate determination of the corresponding reaction kinetics. In this paper, this problem is addressed using quantum chemistry. The reaction rate coefficients of various backbiting, propagation, and beta-scission steps are estimated considering different chain configurations of a terpolymer system composed of methyl acrylate, styrene, and methyl methacrylate. The replacement of methyl acrylate radical units with styrene and methyl methacrylate globally decreases the backbiting probability and shifts the equilibrium toward the reactants, while the effect of replacing adjacent units is weaker and more dependent upon the specific substituting monomer. Propagation kinetics is affected primarily by the replacement of the radical units, while this effect appears to be particularly effective on midchain radical reactivity. The overall results clarify the different physicochemical behavior of chain-end, midchain, and short-branch radicals as a function of copolymer composition, providing new insights into free radical polymerization kinetics. PMID- 23638653 TI - Factors associated with sexual abstinence among out-of-school females in a transitional town in Oyo State, South-Western Nigeria. AB - One hundred and forty-three respondents participated in this cross-sectional study and 42 (29.4%) of them had never had sex. About 92% engaged in at least one leisure activity. Factors significantly associated with abstinence follow: living arrangement, type of occupation, mode of earning, self-esteem, alcohol use, and some leisure activities (p < .05). Factors predictive of abstinence were living with parents or other relatives, earning weekly and monthly wages as opposed to daily wages, high self-esteem, and reading of novels during leisure time. Intensified efforts are necessary to enhance the identified protective factors in order to promote abstinence among out-of-school females. PMID- 23638654 TI - Lymphocyte DNA damage in Turkish asphalt workers detected by the comet assay. AB - Asphalt has a highly complex structure and it contains several organic compounds including polycyclic aromatic hydrocarbons and heterocyclic compounds. In this study, comet assay was used to detect the DNA damage in blood lymphocytes of 30 workers exposed to asphalt fumes and 30 nonexposed controls. This is the first report on Turkish asphalt workers' investigated DNA damage using the alkaline single cell gel electrophoresis (SCGE). The DNA damage was evaluated by the percentage of DNA in the comet tail (% tail DNA) for each cell. According to our results, workers exposed to asphalt fumes had higher DNA damage than the control group (p < 0.01). The present study showed that asphalt fumes caused a significant increase in DNA damage and the comet assay is a suitable method for determining DNA damage in asphalt workers. PMID- 23638655 TI - Bradykinin in blood and cerebrospinal fluid after acute cerebral lesions: correlations with cerebral edema and intracranial pressure. AB - Bradykinin (BK) was shown to stimulate the production of physiologically active metabolites, blood-brain barrier disruption, and brain edema. The aim of this prospective study was to measure BK concentrations in blood and cerebrospinal fluid (CSF) of patients with traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and ischemic stroke and to correlate BK levels with the extent of cerebral edema and intracranial pressure (ICP). Blood and CSF samples of 29 patients suffering from acute cerebral lesions (TBI, 7; SAH,: 10; ICH, 8; ischemic stroke, 4) were collected for up to 8 days after insult. Seven patients with lumbar drainage were used as controls. Edema (5 point scale), ICP, and the GCS (Glasgow Coma Score) at the time of sample withdrawal were correlated with BK concentrations. Though all plasma-BK samples were not significantly elevated, CSF-BK levels of all patients were significantly elevated in overall (n=73) and early (<=72 h) measurements (n=55; 4.3+/-6.9 and 5.6+/-8.9 fmol/mL), compared to 1.2+/-0.7 fmol/mL of controls (p=0.05 and 0.006). Within 72 h after ictus, patients suffering from TBI (p=0.01), ICH (p=0.001), and ischemic stroke (p=0.02) showed significant increases. CSF-BK concentrations correlated with extent of edema formation (r=0.53; p<0.001) and with ICP (r=0.49; p<0.001). Our results demonstrate that acute cerebral lesions are associated with increased CSF-BK levels. Especially after TBI, subarachnoid and intracerebral hemorrhage CSF-BK levels correlate with extent of edema evolution and ICP. BK blocking agents may turn out to be effective remedies in brain injuries. PMID- 23638656 TI - Exploring the native chemical ligation concept for highly stereospecific glycosylation reactions. AB - Various O-alkyl glycosides were obtained in a highly stereospecific manner with retention of configuration at the anomeric center. Our method has customized native chemical ligation concept for glycoconjugates synthesis, utilizing a meticulously controlled activating system. To explain the origin of stereoselective preference, an S(N)i mechanism was proposed and corroborated by computational calculations. PMID- 23638657 TI - Genetic engineering of Lactobacillus diolivorans. AB - In this study, we developed a toolbox for genetic manipulation of Lactobacillus diolivorans, a promising production organism for 1,3-propanediol from glycerol. Two major findings play a key role for successful transformation of this organism: (1) the absence of a native plasmid, because a native plasmid is a major obstacle for transformation of L. diolivorans, and (2) the absence of DNA methylation. A suitable expression plasmid, pSHM, for homologous and heterologous protein expression in L. diolivorans was constructed. This plasmid is based on the replication origin repA of L. diolivorans. The native glyceraldehyde-3 phosphate dehydrogenase promoter is used for constitutive expression of the genes of interest. Functional expression of genes in L. diolivorans was shown with two examples: production of green fluorescent protein resulted in a 40- to 60-fold higher fluorescence of the obtained clones compared with the wild-type strain. Finally, the homologous overexpression of a putatively NADPH-dependent 1,3 propanediol oxidoreductase improved 1,3-propanediol production by 20% in batch cultures. PMID- 23638658 TI - Three-dimensional self-assembly of chalcopyrite copper indium diselenide nanocrystals into oriented films. AB - CuInSe2, which is one of the highest efficiency thin-film solar cell active layer materials, has been an attractive target for nanocrystal synthesis and manipulation. Here, we report unprecedented, simultaneous control of the synthesis and self-assembly behavior of CuInSe2 nanocrystals. These nanocrystals are solution-processable, monodisperse tetragonal bipyramids that exhibit photoconductivity and self-assemble into crystallographically oriented thin films. Structural characterization indicates that these nanocrystals are tetragonal phase, as is used in high-efficiency, second-generation, thin-film solar cells. Elemental analysis indicates that approximately 1:1:2 Cu/In/Se stoichiometry can be achieved, and that the elemental composition can be adjusted from copper-rich to indium-rich with reaction time. PMID- 23638660 TI - Longitudinal comparison of early speech and language milestones in children with cleft palate: a comparison of US and Slovak children. AB - The purpose of this study was to compare early speech and language development of children with and without cleft lip and/or palate (CLP) in the US and Slovakia from 6 to 24 months of age. Thirty-two children from the US (eight with CLP and eight noncleft) and Slovakia (eight with CLP and eight noncleft) participated in this study. The children were videotaped at four time points for 30 minutes during mother-child interaction with play sets controlled for early-developing sounds in each language. Mean Babbling Level, consonant inventories, number of different words and mean length of utterance were calculated for 6- to 24-month samples. Results indicated that the US and Slovak groups showed similar performance across the ages. Cleft and noncleft groups showed significant differences in acquisition of all of the speech and language measures. High pressure consonants, particularly alveolar place of articulation, were problematic for children with CLP. PMID- 23638661 TI - My psychoanalytic journey. PMID- 23638659 TI - Milk yield responses to changes in milking frequency during early lactation are associated with coordinated and persistent changes in mammary gene expression. AB - BACKGROUND: The lactating mammary gland responds to changes in milking frequency by modulating milk production. This response is locally regulated and, in dairy cows, the udder is particularly sensitive during early lactation. Relative to cows milked twice-daily throughout lactation, those milked four-times-daily for just the first 3 weeks of lactation produce more milk throughout that lactation. We hypothesized that the milk yield response would be associated with increased mammary cell turnover and changes in gene expression during frequent milking and persisting thereafter. Cows were assigned to unilateral frequent milking (UFM; left udder halves milked twice-daily; right udder halves milked four-times daily) on days 1 to 21 of lactation, followed by twice-daily milking for the remainder of lactation. Relative to udder halves milked twice-daily, those milked four times produced more milk during UFM; the difference in milk yield declined acutely upon cessation of UFM after day 21, but remained significantly elevated thereafter. We obtained mammary biopsies from both udder halves on days 21, 23, and 40 of lactation. RESULTS: Mammary cell proliferation and apoptosis were not affected by milking frequency. We identified 75 genes that were differentially expressed between paired udder halves on day 21 but exhibited a reversal of differential expression on day 23. Among those genes, we identified four clusters characterized by similar temporal patterns of differential expression. Two clusters (11 genes) were positively correlated with changes in milk yield and were differentially expressed on day 21 of lactation only, indicating involvement in the initial milk yield response. Two other clusters (64 genes) were negatively correlated with changes in milk yield. Twenty-nine of the 75 genes were also differentially expressed on day 40 of lactation. CONCLUSIONS: Changes in milking frequency during early lactation did not alter mammary cell population dynamics, but were associated with coordinated changes in mammary expression of at least 75 genes. Twenty-nine of those genes were differentially expressed 19 days after cessation of treatment, implicating them in the persistent milk yield response. We conclude that we have identified a novel transcriptional signature that may mediate the adaptive response to changes in milking frequency. PMID- 23638662 TI - The tragic and the metaphysical in philosophy and psychoanalysis. AB - This article elaborates a claim, first introduced by Wilhelm Dilthey, that metaphysics represents an illusory flight from the tragedy of human finitude. Metaphysics, of which psychoanalytic metapsychologies are a form, transforms the unbearable fragility and transience of all things human into an enduring, permanent, changeless reality, an illusory world of eternal truths. Three "clinical cases" illustrate this thesis in the work and lives of a philosopher and two psychoanalytic theorists: Friedrich Nietzsche and his metaphysical doctrine of the eternal return of the same, Sigmund Freud and his dual instinct theory, and Heinz Kohut and his theoretical language of the self. It is contended that the best safeguard against the pitfalls of metaphysical illusion lies in a shared commitment to reflection on the constitutive contexts of all our theoretical ideas. PMID- 23638663 TI - An alternative conception of termination and follow-up. AB - Traditional psychoanalytic theory prescribes total patient-analyst separation after termination to facilitate mourning the loss of the analyst. This paper provides a rationale derived from contemporary (especially relational/interpersonal) theory for an alternative conception of termination and follow-up based on the central role of the analyst as a real person involved in a mutually caring patient-analyst relationship. Patient-analyst follow-up may provide numerous positive benefits: The patient may reexperience the analyst's caring, may reinvigorate helpful introjections of the analyst, and may have additional opportunity to deal with unresolved idealization of the analyst. The analyst may learn about the patient's unpredictable, inevitable post-termination changes, positive and negative, and improve his or her understanding of the course and outcome of treatment. PMID- 23638664 TI - Theodor Reik: architect of the subjective approach to psychoanalytic treatment. AB - An overview of the life and work of Theodor Reik is presented. Because of the confluence of various personal qualities and circumstantial factors, Reik's contributions to twentieth-century psychoanalysis were significant, varied, and controversial. His major contributions include the following: (1) He demonstrated the critical importance of unconscious guilt and masochism in human affairs, on an individual basis as well as man's social institutions. In effect, all neuroses have underlying unconscious guilt and punishment issues. (2) He emphasized that the mission of the analyst is to create an intimate clinical relationship with the patient by utilizing his or her (the analyst's) unconscious in concert with the unconscious of the patient. (3) In establishing the National Psychological Association for Psychoanalysis in 1948, Reik became the father of nonmedical psychoanalytic training in America. (4) Over a thirty-year period after his arrival in New York City in 1938, Reik published over twenty books on psychoanalysis, Reikian style. The most read and influential was Listening With the Third Ear (1948). As a result, Reik became America's primary educator of psychoanalysis. PMID- 23638665 TI - The paranoid-masochistic character. PMID- 23638668 TI - NHS-funded IVF: consequences of NICE implementation. AB - The UK National Institute for Health and Clinical Excellence (NICE) recommends that all subfertile women of < 40 years should be entitled to up to three IVF treatment cycles funded by the NHS. The full criteria have been implemented at The Newcastle Fertility Centre at Life since August 2009. The aim of this study was to evaluate the clinical outcome in terms of analysing the cumulative pregnancy rates. A retrospective analysis of data from 812 couples who started their first NHS-funded treatment after August 2009 was undertaken until there were 100 couples who had completed the three treatments. Cumulative pregnancy rates were calculated using life table analysis, and time intervals between treatments were recorded. The number of couples having first, second and third treatment cycles was 812, 298 and 100, respectively. The cumulative clinical pregnancy rates per each fresh cycle were 30.1%, 50.2% and 60.2%, and when frozen embryo transfers were included, they were 33.5%, 53.4% and 62.7%. The median + 2SD time interval between treatments was 11 and 10 months; 90.2% of the women were likely to complete up to three NHS-funded treatment cycles until they achieved a pregnancy. The NICE criteria offer most couples a chance of pregnancy, and the majority will take up the opportunity of undergoing three treatment cycles if required. The time interval between treatments indicated that it will take < 2 years for couples to complete the full course of NHS-funded treatment. PMID- 23638669 TI - Robenacoxib versus meloxicam for the management of pain and inflammation associated with soft tissue surgery in dogs: a randomized, non-inferiority clinical trial. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are used routinely to control pain and inflammation after surgery in dogs. Robenacoxib is a new NSAID with high selectivity for the cyclo-oxygenase (COX)-2 isoform of COX. The objective of this study was to evaluate the efficacy and tolerability of robenacoxib for the management of peri-operative pain and inflammation associated with soft tissue surgery in dogs. The study was a prospective, randomized, blinded, positive-controlled, non-inferiority, multi-center clinical trial. A total of 174 dogs undergoing major soft tissue surgery were included and randomly allocated in a 2:1 ratio to receive either robenacoxib (n = 118) or the positive control, meloxicam (n = 56). Each dog received an initial dose subcutaneously prior to surgery (robenacoxib 2 mg/kg, meloxicam 0.2 mg/kg), followed by daily oral doses (robenacoxib 1-2 mg/kg, meloxicam 0.1 mg/kg) for 12 days (range 10-14) after surgery. Pain and inflammation were assessed subjectively using the Glasgow Composite Pain Scale (GCPS) by clinicians as the primary end point and additional evaluations by the clinicians and animal owners as secondary endpoints. RESULTS: Both treatments provided similar pain control, with no significant differences between groups for any efficacy variable using non-parametric analyses (Mann Whitney U test). In no dog was analgesic rescue therapy administered. Non inferior efficacy of robenacoxib compared to meloxicam was demonstrated statistically for the primary and all secondary endpoints using parametric analysis of variance, although the data were not normally distributed even after log transformation. For the primary endpoint (reciprocal of the modified GCPS score), the relative efficacy of robenacoxib/meloxicam was 1.12 with a 95% confidence interval of 0.97-1.29. CONCLUSION: A treatment regimen of robenacoxib by subcutaneous injection followed by oral tablets had good tolerability and non inferior efficacy compared to meloxicam for the management of peri-operative pain and inflammation associated with soft tissue surgery in dogs. PMID- 23638670 TI - An HIV type 2 case series in Italy: a phylogenetic analysis. AB - In recent years, the increase of migration from countries where human immunodeficiency virus type 2 (HIV-2) is endemic to industrialized countries has facilitated the spread of the virus in individuals previously unexposed to this threat. In this report, we performed a phylogenetic analysis on pol and env sequences of HIV-2 strains identified in foreigners and native citizens to trace the origin of infection. All but one of the 17 pol gene sequences were classified as group A. HIV-2 strains were aggregated in several clusters depending by the country of origin and/or infection. One patient (1AA) was classified as being infected with a recombinant between HIV-2 group A and HIV-2 group B, because the pol gene sequence was clearly in the group A, but an env V3 region sequence from this patient was more similar to group B viruses. Therefore, it is urgent to strengthen the surveillance and use adequate molecular virological tools to diagnose and monitor HIV-2 infection. PMID- 23638671 TI - MicroRNAs as tumour suppressors in canine and human melanoma cells and as a prognostic factor in canine melanomas. AB - Malignant melanoma (MM) is one of the most aggressive cancers in dogs and in humans. However, the molecular mechanisms of its development and progression remain unclear. Presently, we examined the expression profile of microRNAs (miRs) in canine oral MM tissues and paired normal oral mucosa tissues by using the microRNA-microarray assay and quantitative RT-PCR. Importantly, a decreased expression of miR-203 was significantly associated with a shorter survival time. Also, miR-203 and -205 were markedly down-regulated in canine and human MM cell lines tested. Furthermore, the ectopic expression of miR-205 had a significant inhibitory effect on the cell growth of canine and human melanoma cells tested by targeting erbb3. Our data suggest that miR-203 is a new prognostic factor in canine oral MMs and that miR-205 functions as a tumour suppressor by targeting erbb3 in both canine and human MM cells. PMID- 23638672 TI - Feline pleomorphic cutaneous mast cell tumors (CMCT) are not the same as feline diffuse CMCT. PMID- 23638673 TI - Response to letter by Dr Schulman regarding 'European consensus document on mast cell tumours in dogs and cats'. PMID- 23638674 TI - Ureteral stenting and retrograde pyelography in the office: clinical outcomes, cost effectiveness, and time savings. AB - OBJECTIVES: To examine the clinical outcomes and cost-effectiveness of endourologic procedures performed in the office using standard fluoroscopy and topical anesthesia. METHODS: We performed a retrospective review of all patients who underwent primary ureteral stent placement, ureteral stent exchange, or ureteral catheterization with retrograde pyeolography or Bacillus Calmette-Guerin (BCG) instillation under fluoroscopic guidance in the office. For an evaluation of potential time savings, we compared this to a cohort of similar procedures performed in the operating room during the same time period. RESULTS: Procedures were attempted in 65 renal units in 38 patients (13 male, 25 female) with a mean age of 62.2 years (range 29.1-95.4 years). Primary ureteral stent placement was successful in 23/24 (95.8%) renal units. Ureteral stent exchange was successful in 19/22 (86.4%) renal units. Ureteral catheterization with retrograde pyelography or BCG instillation was successful in 19/19 (100%) renal units. The total cost savings for the 38 patients in this study, including excess cost from failure in the office, was approximately $91,496, with an average cost savings of $1,551 per procedure. Office-based procedures were associated with a nearly three fold reduction in total hospital time as a result of reduced periprocedure waiting times. CONCLUSIONS: Ureteral stent placement, ureteral stent exchange, and ureteral catheterization can be performed safely and effectively in the office in both men and women. This avoids general anesthesia and provides significant savings of time and cost for both patients and the health care system. PMID- 23638677 TI - Unintentional injury mortality -The role of criminal offending. A Swedish longitudinal population based study. AB - The aim was to investigate life course criminality in relation to unintentional injury mortality and other causes of death among 49,398 male Swedish conscripts aged 18-20 years in 1969/70 and a follow-up through 35 years. All subjects completed two questionnaires at the time of conscription concerning family, social, behavioural risk factors including alcohol and drug use. The impacts of committed crimes, alcohol and drug use and other risk factors were estimated using proportional hazard ratios (HRs) from Cox regression analyses. Many adolescent offences entailed a nearly six-fold higher injury mortality risk (HR = 5.64) and a four-fold higher risk (HR = 3.93) for all other causes vs. no convictions. In multivariate analyses, adolescent criminality was still found to be significantly associated with time to unintentional injury mortality, while criminality limited to adulthood had a moderately higher risk for all other causes of deaths. Individuals with both adolescence and adult criminality showed elevated mortality from especially unintentional injury (HR = 5.06), with the hazards remaining elevated, even after adjustment for other behavioural risk factors. Men with behavioural risk factors including alcohol and/or drug misuse in combination with frequent criminality seem to be a vulnerable group of both unintentional and other causes of deaths. PMID- 23638678 TI - Effect of bromochloromethane and fumarate on phylogenetic diversity of the formyltetrahydrofolate synthetase gene in bovine rumen. AB - Effect of the methane inhibitor, bromochloromethane (BCM) and dietary substrate, fumarate, on microbial community structure of acetogen bacteria in the bovine rumen was investigated through analysis of the formyltetrahydrofolate synthetase gene (fhs). The fhs sequences obtained from BCM-untreated, BCM-treated, fumarate untreated and fumarate-treated bovine rumen were categorized into homoacetogens and nonhomoacetogenic bacteria by homoacetogen similarity scores. Phylogenetic tree analysis indicated that most of the fhs sequences categorized into homoacetogens were divided into nine clusters, which were in close agreement with a result shown in a self-organizing map. The diversity of the fhs sequences from the BCM-treated rumen was significantly different from those from BCM-non-treated rumen. Principal component analysis also showed that addition of BCM to the rumen altered the population structure of acetogenic bacteria significantly but the effect of fumarate was comparatively minor. These results indicate that BCM affects diversity of actogens in the bovine rumen, and changes in acetogenic community structure in response to methane inhibitors may be caused by different mechanisms. PMID- 23638680 TI - The availability, spatial accessibility, service utilisation and retrieval cost of paediatric intensive care services for children in rural, regional and remote Queensland: study protocol. AB - BACKGROUND: Specialist health services are often organised on a regionalised basis whereby clinical resources and expertise are concentrated in areas of high population. Through a high volume caseload, regionalised facilities may provide improved clinical outcomes for patients. In some cases, regionalisation may be the only economically viable way to organise specialist care. While regionalisation may have benefits, it may also disadvantage some population groups, particularly in circumstances where distance and time are impediments to access.Queensland is a large Australian state with a distributed population. Providing equitable access to specialist healthcare services to the population is challenging. Specialist care for critically ill or injured children is provided by the Queensland Paediatric Intensive Care Service which comprises two tertiary paediatric intensive care units. The two units are located 6 km (3.7 miles) apart by road in the state capital of Brisbane and provide state-wide telephone advice and specialist retrieval services. Services also extend into the northern area of the adjacent state of New South Wales. In some cases children may be managed locally in adult intensive care units in regional hospitals.The aim of this study is to describe the effect of geography and service organisation for children who need intensive care services but who present outside of metropolitan centres in Queensland. METHODS/DESIGN: Using health services and population data, the availability and spatial accessibility to paediatric intensive care services will be analysed. Retrieval utilisation and the associated costs to the health service will be analysed to provide an indication of service utilisation by non metropolitan patients. DISCUSSION: While the regionalisation or centralisation of specialist services is recognised as an economical way to provide specialist health services, the extent to which these models serve critically ill children who live some distance from tertiary care has not been described. This study will provide new information on the effect of the regionalisation of specialist healthcare for critically ill children in Queensland and will have relevance to other regionalised health services. This study, which is focussed on describing the organisation, supply and demands on the health service, will provide the foundation for future work to explore clinical outcomes for non-metropolitan children who require intensive care. PMID- 23638682 TI - Exercise studies in patients with rotary blood pumps: cause, effects, and implications for starling-like control of changes in pump flow. AB - This multicenter study examines in detail the spontaneous increase in pump flow at fixed speed that occurs in exercise. Eight patients implanted with the VentrAssist rotary blood pump were subjected to maximal and submaximal cycle ergometry studies, the latter being completed with patients supine and monitored with right heart catheter and echocardiography. Maximal exercise studies conducted in each patient at three different pump speeds on separate days established initially the magnitude and consistency of increases in pump flow that correlated well with changes in heart rate. However, there was considerable variation, coefficients of variation for mean heart rate and pump flow being 47.9 and 49.3%, respectively. Secondly, these studies indicated that increasing pump flows caused significant improvements in maximal exercise capacity. An increase of 2.1 L/min (35%) in maximum blood flow caused 12 W (16%) further increase in achievable work, 1.26 (9.3%) mL/kg/min in maximal oxygen uptake, and 2.3 (23%) mL/kg/min in anaerobic threshold. Mean increases in lactate were 0.85 mm (24%), but mean B-type natiuretic peptide fell by 126 mm, (-78%). From submaximal supine exercise studies, multiple linear regression of pump flow on factors thought to underlie the spontaneous increase in pump flow indicated that it was associated with increases in heart rate (P = 0.039), pressure gradient across the left ventricle (P = 0.032), and right atrial pressure (P = 0.003). These changes have implications for the recently reported Starling-like controller for pump flow based on pump pulsatility values, which emulates the Starling curve relating pump output to left ventricular preload. Unmodified, the controller would not permit the full benefits of this effect to be afforded to patients implanted with rotary blood pumps. A modification to the pump control algorithm is proposed to eliminate this problem. PMID- 23638683 TI - Charge transfer and penning ionization of dopants in or on helium nanodroplets exposed to EUV radiation. AB - Helium nanodroplets are widely used as a cold, weakly interacting matrix for spectroscopy of embedded species. In this work, we excite or ionize doped He droplets using synchrotron radiation and study the effect onto the dopant atoms depending on their location inside the droplets (rare gases) or outside at the droplet surface (alkali metals). Using photoelectron-photoion coincidence imaging spectroscopy at variable photon energies (20-25 eV), we compare the rates of charge-transfer to Penning ionization of the dopants in the two cases. The surprising finding is that alkali metals, in contrast to the rare gases, are efficiently Penning ionized upon excitation of the (n = 2)-bands of the host droplets. This indicates rapid migration of the excitation to the droplet surface, followed by relaxation, and eventually energy transfer to the alkali dopants. PMID- 23638679 TI - Functional interaction between pre-synaptic alpha6beta2-containing nicotinic and adenosine A2A receptors in the control of dopamine release in the rat striatum. AB - BACKGROUND AND PURPOSE: Pre-synaptic nicotinic ACh receptors (nAChRs) and adenosine A2A receptors (A2A Rs) are involved in the control of dopamine release and are putative therapeutic targets in Parkinson's disease and addiction. Since A2A Rs have been reported to interact with nAChRs, here we aimed at mapping the possible functional interaction between A2A Rs and nAChRs in rat striatal dopaminergic terminals. EXPERIMENTAL APPROACH: We pharmacologically characterized the release of dopamine and defined the localization of nAChR subunits in rat striatal nerve terminals in vitro and carried out locomotor behavioural sensitization in rats in vivo. KEY RESULTS: In striatal nerve terminals, the selective A2A R agonist CGS21680 inhibited, while the A2A R antagonist ZM241385 potentiated the nicotine-stimulated [(3) H]dopamine ([(3) H]DA) release. Upon blockade of the alpha6 subunit-containing nAChRs, the remaining nicotine stimulated [(3) H]DA release was no longer modulated by A2A R ligands. In the locomotor sensitization experiments, nicotine enhanced the locomotor activity on day 7 of repeated nicotine injection, an effect that no longer persisted after 1 week of drug withdrawal. Notably, ZM241385-injected rats developed locomotor sensitization to nicotine already on day 2, which remained persistent upon nicotine withdrawal. CONCLUSIONS AND IMPLICATIONS: These results provide the first evidence for a functional interaction between nicotinic and adenosine A2A R in striatal dopaminergic terminals, with likely therapeutic consequences for smoking, Parkinson's disease and other dopaminergic disorders. PMID- 23638685 TI - Enantioselective synthesis of (thiolan-2-yl)diphenylmethanol and its application in asymmetric, catalytic sulfur ylide-mediated epoxidation. AB - This work describes an expeditious and efficient preparation of enantiopure (thiolan-2-yl)diphenylmethanol (2) featuring a double nucleophilic substitution and Shi epoxidation as key steps. One of the applications of its benzyl ether derivative to asymmetric sulfur ylide-mediated epoxidation with up to 92% ee (14 examples) was also demonstrated herein. PMID- 23638684 TI - A study of the knowledge, attitudes, and practices (KAP) of the women referred to health centers for cardiovascular disease (CVDs) and their risk factors. AB - Hypertension, dyslipidemia, and diabetes are established risk factors for cardiovascular disease (CVD) morbidity and mortality. In the past decade a general increase in CVD risk factors in the population aged 65 and older, along with suboptimal control rates, have occurred. In this descriptive, cross sectional study, the authors describe the knowledge, attitudes, and practices (KAP) of Iranian females regarding risk factors for CVD, in an attempt to help with the development of strategies to control risk factors and CVD. Participants were 200 women ages 15-49 referred to health centers in Yazd, selected from four different centers. Data were gathered through a questionnaire consisting of demographics and questions related to KAP. The validity of the questionnaire was determined by a health education specialist, with its reliability determined by piloting and measuring the related Cronbach's alpha (Alpha = 0.720). Measuring knowledge of CVD on a scale of 0-20, the mean knowledge score was 10.203.91. More than 76% of the participants knew that CVD is preventable. Ninety-one percent liked exercising and believed that exercising would make them feel better. The average mean scores for attitudes of participants toward CVD were 30.31 +/- 3.21 out of 36. The authors conclude that there is a need for enhancing mothers' general knowledge about the disease, because of the increasing rates of CVD in females. This will lead to improvements in attitude and practice. Furthermore, learning in groups of 12 can be a beneficial educational method. PMID- 23638681 TI - Global analysis of apicomplexan protein S-acyl transferases reveals an enzyme essential for invasion. AB - The advent of techniques to study palmitoylation on a whole proteome scale has revealed that it is an important reversible modification that plays a role in regulating multiple biological processes. Palmitoylation can control the affinity of a protein for lipid membranes, which allows it to impact protein trafficking, stability, folding, signalling and interactions. The publication of the palmitome of the schizont stage of Plasmodium falciparum implicated a role for palmitoylation in host cell invasion, protein export and organelle biogenesis. However, nothing is known so far about the repertoire of protein S-acyl transferases (PATs) that catalyse this modification in Apicomplexa. We undertook a comprehensive analysis of the repertoire of Asp-His-His-Cys cysteine-rich domain (DHHC-CRD) PAT family in Toxoplasma gondii and Plasmodium berghei by assessing their localization and essentiality. Unlike functional redundancies reported in other eukaryotes, some apicomplexan-specific DHHCs are essential for parasite growth, and several are targeted to organelles unique to this phylum. Of particular interest is DHHC7, which localizes to rhoptry organelles in all parasites tested, including the major human pathogen P. falciparum. TgDHHC7 interferes with the localization of the rhoptry palmitoylated protein TgARO and affects the apical positioning of the rhoptry organelles. This PAT has a major impact on T. gondii host cell invasion, but not on the parasite's ability to egress. PMID- 23638686 TI - Evolution of pleiotropic costs in experimental populations. AB - The fitness of populations adapting to new environments is expected to decline in different environments, but empirical studies often do not lend support for such adaptation costs. We test the idea that the initial fitness of the selected populations in the environment where the cost is estimated is key for interpreting tests of ecological trade-offs. We isolated single clones of the yeast Saccharomyces cerevisiae every ~250 generations from replicate experimental lineages that had been selected during 5000 generations in a glucose-limited environment. We then selected these clones in a galactose-limited environment for ~120 generations. Finally, we estimated single-clone fitness in both environments, before and after selection on galactose. The pleiotropic effects on glucose of selection on galactose evolved from positive to negative as fitness in glucose increased, providing strong support for the importance of initial fitness for determining the sign and magnitude of pleiotropic effects. This demonstrates that the sign of pleiotropic effects for fitness following adaptation to a new environment can change during long-term adaptation to an original environment. We also found no relationship between the size of the fitness changes in galactose and glucose, such that pleiotropic effects in glucose became relatively smaller as the sizes of direct effects on galactose increased. PMID- 23638687 TI - Expression of Hox genes during regeneration of nereid polychaete Alitta (Nereis) virens (Annelida, Lophotrochozoa). AB - BACKGROUND: Hox genes are the key determinants of different morphogenetic events in all bilaterian animals. These genes are probably responsible for the maintenance of regenerative capacities by providing positional information in the regenerating animal body. Polychaetes are well known for their ability to regenerate the posterior as well as the anterior part of the body. We have recently described the expression of 10 out of 11 Hox genes during postlarval growth of Alitta (Nereis) virens. Hox genes form gradient overlapping expression patterns, which probably do not contribute to the morphological diversity of segments along the anterior-posterior axis of the homonomously segmented worm. We suggest that this gradient expression of Hox genes establishes positional information along the body that can be used to maintain coordinated growth and regeneration. RESULTS: We showed that most of the Hox gene expression patterns are reorganized in the central nervous system, segmental ectoderm and mesoderm. The reorganization takes place long before regeneration becomes apparent. The most rapid reorganization was observed for the genes with the largest differences in expression levels in the amputation site and the terminal structures (pygidium and growth zone). Moreover, we revealed the expression of two antisense Hox RNAs (Nvi-antiHox5 and Nvi-antiHox7) demonstrating unique expression patterns during regeneration. CONCLUSIONS: Hox genes probably participate in the maintenance and restoration of the positional information in A. virens. During postlarval growth and regeneration, Hox genes do not alter the diversity of segments but provide the positional information along the anterior-posterior axis. The reorganization of at least some Hox gene patterns during regeneration may be regulated by their anti-sense transcripts, providing a rapid response of Hox gene transcripts to positional failure. The capacity of Hox genes to maintain the positional information in the adult body is present in different bilaterian animals (planarias, polychaetes and mammals) and might be an ancestral function inherited from the common evolutionary remote ancestor. PMID- 23638688 TI - A subcellular tug of war involving three MYB-like proteins underlies a molecular antagonism in Antirrhinum flower asymmetry. AB - The establishment of meristematic domains with different transcriptional activity is essential for many developmental processes. The asymmetry of the Antirrhinum majus flower is established by transcription factors with an asymmetric pattern of activity. To understand how this asymmetrical pattern is established, we studied the molecular mechanism through which the dorsal MYB protein RADIALIS (RAD) restricts the activity of the MYB transcription factor DIVARICATA (DIV) to the ventral region of the flower meristem. We show that RAD competes with DIV for binding with other MYB-like proteins, termed DRIF1 and DRIF2 (DIV- and-RAD interacting-factors). DRIF1 and DIV interact to form a protein complex that binds to the DIV-DNA consensus region, suggesting that the DRIFs act as co-regulators of DIV transcriptional activity. In the presence of RAD, the interaction between DRIF1 and DIV bound to DNA is disrupted. Moreover, the DRIFs are sequestered in the cytoplasm by RAD, thus, preventing or reducing the formation of DRIF-DIV heterodimers in the nuclei. Our results suggest that in the dorsal region of the Antirrhinum flower meristem the dorsal protein RAD antagonises the activity of the ventral identity protein DIV in a subcellular competition for a DRIF protein promoting the establishment of the asymmetric pattern of gene activity in the Antirrhinum flower. PMID- 23638689 TI - Low phytic acid 1 mutation in maize modifies density, starch properties, cations, and fiber contents in the seed. AB - Monogastric animals are unable to digest phytic acid, so it represents an antinutritional factor and also an environmental problem. One strategy to solve this problem is the utilization of low phytic acid (lpa) mutants that accumulate low levels of phytic P and high levels of free phosphate in the seeds; among the lpa maize mutants lpa1 exhibited the highest reduction of phytic acid in the seed. This study indicated that the low phytic acid mutations exerted pleiotropic effects not directly connected to the phytic acid pathway, such as on seed density, content of ions, and the antioxidant compounds present in the kernels. Furthermore some nutritional properties of the flour were altered by the lpa1 mutations, in particular lignin and protein content, while the starch does not seem to be modified as to the total amount and in the amylose/amylopectin ratio, but alterations were noticed in the structure and size of granules. PMID- 23638691 TI - Room-temperature single-electron charging detected by electrostatic force microscopy. AB - We use atomic force microscopy to measure electron addition spectra of individual Au nanoparticles that exhibit Coulomb blockade at room temperature. The cantilever tip charges individual nanoparticles supported on an ultra-thin NaCl film via single-electron tunneling from the metal back electrode. The tunneling is detected by measuring frequency shift and damping of the oscillating cantilever. Finite element electrostatic calculations indicate that the total nanoparticle capacitance is dominated by mutual capacitance to the back electrode. PMID- 23638690 TI - Genome-wide analysis of the GH3 family in apple (Malus * domestica). AB - BACKGROUND: Auxin plays important roles in hormone crosstalk and the plant's stress response. The auxin-responsive Gretchen Hagen3 (GH3) gene family maintains hormonal homeostasis by conjugating excess indole-3-acetic acid (IAA), salicylic acid (SA), and jasmonic acids (JAs) to amino acids during hormone- and stress related signaling pathways. With the sequencing of the apple (Malus * domestica) genome completed, it is possible to carry out genomic studies on GH3 genes to indentify candidates with roles in abiotic/biotic stress responses. RESULTS: Malus sieversii Roem., an apple rootstock with strong drought tolerance and the ancestral species of cultivated apple species, was used as the experimental material. Following genome-wide computational and experimental identification of MdGH3 genes, we showed that MdGH3s were differentially expressed in the leaves and roots of M. sieversii and that some of these genes were significantly induced after various phytohormone and abiotic stress treatments. Given the role of GH3 in the negative feedback regulation of free IAA concentration, we examined whether phytohormones and abiotic stresses could alter the endogenous auxin level. By analyzing the GUS activity of DR5::GUS-transformed Arabidopsis seedlings, we showed that ABA, SA, salt, and cold treatments suppressed the auxin response. These findings suggest that other phytohormones and abiotic stress factors might alter endogenous auxin levels. CONCLUSION: Previous studies showed that GH3 genes regulate hormonal homeostasis. Our study indicated that some GH3 genes were significantly induced in M. sieversii after various phytohormone and abiotic stress treatments, and that ABA, SA, salt, and cold treatments reduce the endogenous level of axuin. Taken together, this study provides evidence that GH3 genes play important roles in the crosstalk between auxin, other phytohormones, and the abiotic stress response by maintaining auxin homeostasis. PMID- 23638692 TI - Bovine rod rhodopsin: 2. Bleaching in vitro upon 12C ions irradiation as source of effects as light flash for patients and for humans in space. AB - PURPOSE: In a previous paper, we showed that chemiluminescence from radical recombination (initiated by lipid peroxidation and propagated by polyunsaturated fatty acids [PUFA]) has a bleaching effect comparable to that caused by light on the rhodopsin of retinal rod outer segment (RdOS) prepared from bovine eyes. Photons generated by radical recombination were suggested to be the origin of phosphenes perceived as light flashes by the human eye. Irradiation with (12)C carbon ions was used in this study to stimulate radical production, propagation and recombination leading to photoluminescence. MATERIALS AND METHODS: (12)C radiation bleached RdOS rhodopsin, but structural damage increasing with the radiation dose was also observed. For this reason, only the effects on rhodopsin at doses producing next to negligible biodamage and permitting regeneration have been considered as bleaching effects. RESULTS: (12)C irradiation bleached RdOS rhodopsin, but increasing structural damage with radiation dose was also observed. For the measure of bleaching and to reveal dose response effects on rhodopsin that were able to be regenerated only results from doses producing nearly negligible biodamage have been considered. CONCLUSIONS: Recombination of radicals appears responsible for the release of photons with subsequent bleaching of rhodopsin. This effect could have an important role in the generation of the anomalous visual effects (phosphenes) experienced by patients during hadrotherapy or by astronauts in space. PMID- 23638693 TI - Clinical utility of viscoelastic tests of coagulation in patients with liver disease. AB - The prothrombin time (PT) and international normalised ratio (INR) are used in scoring systems (Child-Pugh, MELD, UKELD) in chronic liver disease and as a prognostic tool and for dynamic monitoring of hepatic function in acute liver disease. These tests are known to be poor predictors of bleeding risk in liver disease; however, they continue to influence clinical management decisions. Recent work on coagulation in liver disease, in particular thrombin generation studies, has led to a paradigm shift in our understanding and it is now recognised that haemostasis is relatively well preserved. Whole blood global viscoelastic tests (TEG((r)) /ROTEM((r)) ) produce a composite dynamic picture of the entire coagulation process and have the potential to provide more clinically relevant information in patients with liver disease. We performed a systematic review of all relevant studies that have used viscoelastic tests (VET) of coagulation in patients with liver disease. Although many studies are observational and small in size, it is clear that VET provide additional information that is in keeping with the new concepts of how coagulation is altered in these patients. This review provides the basis for large scale, prospective outcome studies to establish the clinical value of these tests. PMID- 23638694 TI - Production of an alkaline protease using Bacillus pumilus D3 without inactivation by SDS, its characterization and purification. AB - Abstract In this study, protease-producing capacity of Bacillus pumilus D3, isolated from hydrocarbon contaminated soil, was evaluated and optimized. Optimum growing conditions for B. pumilus D3 in terms of protease production were determined as 1% optimum inoculum size, 35 degrees C temperature, 11 pH and 48 h incubation time, respectively. Stability studies indicated that the mentioned protease was stable within the pH range of 7-10.5 and between 30 degrees C and 40 degrees C temperatures. Surprisingly, the activity of the enzyme increased in the presence of SDS with concentration up to 5 mM. The protease was concentrated 1.6-fold with ammonium sulfate precipitation and dialysis. At least six protein bands were obtained from dialysate by electrophoresis. Four clear protein bands with caseinolytic activity were detected by zymography. Dialysate was further purified by anion-exchange chromatography and the caseinolytic active fraction showed a single band between 29 and 36 kDa of reducing conditions. PMID- 23638695 TI - Predictors of return to work and duration of absence following work-related hand injury. AB - The aims of the study were to explore the situation and the potential determinants of return-to-work (RTW) and the absence duration following work related hand injury, and to provide evidence for the future intervention strategy of improving RTW. A prospective cohort of workers with work-related hand injury from three selected hospitals in East China was followed up on the outcomes of RTW up to 8 months after discharge. Demographic and clinical data were collected during admission; economic factors, psychological factors and RTW outcomes were, respectively, investigated using a structured questionnaire via phone call after discharge from the hospitals in 0.5 month, 2 months, 4 months and 8 months. Univariate analysis and Cox regression model were used to examine the associations between potential determinants and outcomes of the RTW. Out of the 246 cases, 192 (78.1%) eventually returned to work with the median duration of the absence of 44.0 days during the 8-month follow-up. Factors from demographic, clinical, economic and psychological domains affected RTW in the univariate analyses. Receiving timely treatment at outpatient clinics, less serious injury, no tendon trauma and no skin loss were found to be significantly beneficial to RTW, while workers with the decreased monthly salary during absence and lower pre injury salary were likely to take longer sick leave. Most of the workers successfully achieved RTW after work-related hand injury. Proper clinical treatment and rehabilitation, as well as economic and social support seem to have played vital roles in prompting RTW that should be prioritised for the intervention strategy. PMID- 23638696 TI - High prevalence of ATTR amyloidosis in endomyocardial biopsy-proven cardiac amyloidosis patients. AB - BACKGROUND: Cardiac amyloidosis had been considered to be an incurable disease; however, new disease-modifying therapeutic approaches have succeeded in ameliorating the disease. Therefore, early and precise diagnosis based on the amyloid precursor protein is extremely important. OBJECTIVE: To determine the prevalence rates of systemic amyloidoses underlying cardiac amyloidosis. METHODS: The types of amyloidosis in 53 consecutive patients with endomyocardial biopsy proven cardiac amyloidosis were analyzed by Congo red and immunohistochemical staining. If staining for TTR was positive, direct DNA sequencing of the entire TTR gene was performed. RESULTS: ATTR amyloidosis was the most common (32/53 patients, 60.4%). The ATTR amyloidosis subtypes were senile systemic amyloidosis (SSA) 11, familial ATTR 10, and genotype unknown 11. AL amyloidosis was the next most frequent (19/53, 35.8%). CONCLUSIONS: ATTR amyloidosis, especially SSA, might be much more common than previously thought. With the development of new drugs targeting the ATTR amyloidosis, major efforts should be made to increase awareness of senile systemic amyloidosis among cardiologists. PMID- 23638697 TI - Simultaneous ventral hernia repair in bariatric surgery. AB - BACKGROUND: Obesity is a significant risk factor in abdominal hernia occurrence and recurrence. In patients having bariatric surgery, there are no clear guidelines as to whether repair should be done simultaneously, especially if procedures involve division or resection of part of the gastrointestinal tract. METHODS: A retrospective case series review over a 6-year period to December 2012 from a prospective database was conducted. As per existing practice for bariatric procedures, patients were followed up indefinitely. Short- and long-term outcomes were analysed. RESULTS: Forty-five patients underwent combined laparoscopic bariatric surgery and abdominal wall hernia repair. Of these, 36 had resection procedures (gastric bypass or sleeve gastrectomy) and 9 had non-resection procedures (gastric banding). The mean operative time was 151 min and the mean length of stay was 3 days. Two patients developed post-operative mesh seroma infections. To date, there have been no mesh removals or recurrent hernias. There was no mortality in this series. DISCUSSION: This study demonstrated a low rate of mesh infection (4.44%) at a median follow-up of 13 months, even when a resectional procedure was performed (5.56%). These results suggest the possible viability and reasonable short-/long-term outcomes of simultaneous laparoscopic abdominal wall hernia repair during bariatric surgical procedures, even if the surgery involved division or resection of part of the gastrointestinal tract. This topic is an area of clinical research that warrants further study. PMID- 23638699 TI - State-resolved reactivity of methane (nu2 + nu4) on Ni(111). AB - Vibrational state-resolved experiments that probe methane dissociation on Ni(111) quantify the reactivity of CH4 excited to the nu2 + nu4 bending vibration. A comparison of these data and previous state-resolved measurements reveals that this bending vibration is significantly less reactive than the nu3 C-H stretching vibration in the same polyad of vibrations. Comparison with the 3nu4 bend overtone also suggests that the doubly degenerate bending state, nu2, is less effective than the triply degenerate bend (nu4) in promoting methane dissociative chemisorption on Ni(111). This observation of vibrational mode selectivity contradicts thermal statistical theories of gas-surface reactivity and provides direct experimental evidence of roles that different vibrational states can play in activating this gas-surface reaction. PMID- 23638700 TI - Abstracts of the Advancing the Methods in Health Quality Improvement Research 2012 Conference. Arlington, Virginia, USA. May 7-8, 2012. PMID- 23638698 TI - Functional and morphological characterization of glutamate transporters in the rat locus coeruleus. AB - BACKGROUND AND PURPOSE: Excitatory amino acid transporters (EAATs) in the CNS contribute to the clearance of glutamate released during neurotransmission. The aim of this study was to explore the role of EAATs in the regulation of locus coeruleus (LC) neurons by glutamate. EXPERIMENTAL APPROACH: We measured the effect of different EAAT subtype inhibitors/enhancers on glutamate- and KCl induced activation of LC neurons in rat slices. EAAT2-3 expression in the LC was also characterized by immunohistochemistry. KEY RESULTS: The EAAT2-5 inhibitor DL threo-beta-benzyloxaspartic acid (100 MUM), but not the EAAT2, 4, 5 inhibitor L trans-pyrrolidine-2,4-dicarboxylic acid (100 MUM) or the EAAT2 inhibitor dihydrokainic acid (DHK; 100 MUM), enhanced the glutamate- and KCl-induced activation of the firing rate of LC neurons. These effects were blocked by ionotropic, but not metabotrobic, glutamate receptor antagonists. DHK (100 MUM) was the only EAAT inhibitor that increased the spontaneous firing rate of LC cells, an effect that was due to inhibition of EAAT2 and subsequent AMPA receptor activation. Chronic treatment with ceftriaxone (200 mg.kg(-1) i.p., once daily, 7 days), an EAAT2 expression enhancer, increased the actions of glutamate and DHK, suggesting a functional impact of EAAT2 up-regulation on the glutamatergic system. Immuhistochemical data revealed the presence of EAAT2 and EAAT3 surrounding noradrenergic neurons and EAAT2 on glial cells in the LC. CONCLUSIONS AND IMPLICATIONS: These results remark the importance of EAAT2 and EAAT3 in the regulation of rat LC by glutamate. Neuronal EAAT3 would be responsible for terminating the action of synaptically released glutamate, whereas glial EAAT2 would regulate tonic glutamate concentrations in this nucleus. PMID- 23638702 TI - Effectiveness of telephone-based counseling for improving the quality of life among middle-aged women. AB - Perimenopausal women may encounter multidimensional changes that influence their quality of life. Our purpose in this study was to evaluate the long-term effects of telephone counseling as a method of intervention for menopausal women. A parallel group controlled trial was designed. The intervention group showed a significant increase in self-health management at the four- and eight-month follow-up evaluations. The quality of life in the intervention group was significantly improved when measured during the eighth and twelfth months. Results of this study can be used as a basis for practical implementation of the telephone counseling service in middle-aged women elsewhere. PMID- 23638701 TI - Modification of glucose import capacity in Escherichia coli: physiologic consequences and utility for improving DNA vaccine production. AB - BACKGROUND: The bacterium Escherichia coli can be grown employing various carbohydrates as sole carbon and energy source. Among them, glucose affords the highest growth rate. This sugar is nowadays widely employed as raw material in industrial fermentations. When E. coli grows in a medium containing non-limiting concentrations of glucose, a metabolic imbalance occurs whose main consequence is acetate secretion. The production of this toxic organic acid reduces strain productivity and viability. Solutions to this problem include reducing glucose concentration by substrate feeding strategies or the generation of mutant strains with impaired glucose import capacity. In this work, a collection of E. coli strains with inactive genes encoding proteins involved in glucose transport where generated to determine the effects of reduced glucose import capacity on growth rate, biomass yield, acetate and production of an experimental plasmid DNA vaccine (pHN). RESULTS: A group of 15 isogenic derivatives of E. coli W3110 were generated with single and multiple deletions of genes encoding glucose, mannose, beta-glucoside, maltose and N-acetylglucosamine components of the phosphoenolpyruvate:sugar phosphotransferase system (PTS), as well as the galactose symporter and the Mgl galactose/glucose ABC transporter. These strains were characterized by growing them in mineral salts medium supplemented with 2.5 g/L glucose. Maximum specific rates of glucose consumption (qs) spanning from 1.33 to 0.32 g/g h were displayed by the group of mutants and W3110, which resulted in specific growth rates ranging from 0.65-0.18 h(-1). Acetate accumulation was reduced or abolished in cultures with all mutant strains. W3110 and five selected mutant derivatives were transformed with pHN. A 3.2-fold increase in pHN yield on biomass was observed in cultures of a mutant strain with deletion of genes encoding the glucose and mannose PTS components, as well as Mgl. CONCLUSIONS: The group of E. coli mutants generated in this study displayed a reduction or elimination of overflow metabolism and a linear correlation between qs and the maximum specific growth rate as well as the acetate production rate. By comparing DNA vaccine production parameters among some of these mutants, it was possible to identify a near-optimal glucose import rate value for this particular application. The strains employed in this study should be a useful resource for studying the effects of different predefined qs values on production capacity for various biotechnological products. PMID- 23638703 TI - Massive occult infection of a left ventricular assist device with Candida albicans. PMID- 23638704 TI - Effects of photoperiod on secretory patterns of growth hormone in adult male goats. AB - The aim of the present study was to clarify the effect of photoperiod on secretory patterns of growth hormone (GH) in male goats. Adult male goats were kept at 20 degrees C with an 8-h or 16-h light photoperiod, and secretory patterns of GH secretion were compared. In addition, plasma profiles of prolactin (PRL), insulin-like growth factor-I (IGF-I) and testosterone (T) were also examined to characterize GH secretion. GH was secreted in a pulsatile manner. There was no significant difference in pulse frequency between the 8-h and 16-h photoperiods. However, GH pulse amplitude tended to be greater in the group with the 16-h photoperiod (P = 0.1), and mean GH concentrations were significantly greater in the 16-h photoperiod (P < 0.05). The GH-releasing response to GH releasing hormone was greater in the 16-h than 8-h photoperiod (P < 0.05). Plasma PRL and IGF-I levels were higher in the 16-h than 8-h photoperiod (P < 0.05). In contrast, plasma T levels were lower in the 16-h photoperiod (P < 0.05). These results show that a long light photoperiod enhances the secretion of GH as well as PRL and IGF-I, but reduces plasma T concentrations in male goats. PMID- 23638705 TI - Lifetime fitness and age-related female ornament signalling: evidence for survival and fecundity selection in the pied flycatcher. AB - Ornaments displayed by females have often been denied evolutionary interest due to their frequently reduced expression relative to males, habitually attributed to a genetic correlation between the sexes. We estimated annual and lifetime reproductive success of female pied flycatchers (Ficedula hypoleuca) and applied capture-mark-recapture models to analyse annual survival rates in relation to the patterns of expression (absence/presence) of an ornament displayed by all males and a fraction of females. Overall, the likelihood of expressing the ornament increased nonlinearly with female age and was due to within-individual variation, not to the selective appearance or disappearance of ornament-related expression of phenotypes in the population. Accordingly, expressing the forehead patch in a given year did not influence survival probability. However, those females expressing the ornament at early ages (1-2 years old) enjoyed survival advantages throughout lifetime. Although ornamented females had higher lifetime fecundity and fledging success, their yearly reproductive performance, in terms of fledging productivity, decreased as they aged so that, late in life, ornamented females reared fewer offspring than nonexpressing females of the same age. In addition, both strategies (expressing vs. not expressing the trait) returned similar fitness payoffs in terms of recruited offspring. Our results support the hypothesis that fecundity and survival selection are involved in the displaying of this 'male' ornament by females. PMID- 23638706 TI - Live cell imaging reveals marked variability in myoblast proliferation and fate. AB - BACKGROUND: During the process of muscle regeneration, activated stem cells termed satellite cells proliferate, and then differentiate to form new myofibers that restore the injured area. Yet not all satellite cells contribute to muscle repair. Some continue to proliferate, others die, and others become quiescent and are available for regeneration following subsequent injury. The mechanisms that regulate the adoption of different cell fates in a muscle cell precursor population remain unclear. METHODS: We have used live cell imaging and lineage tracing to study cell fate in the C2 myoblast line. RESULTS: Analyzing the behavior of individual myoblasts revealed marked variability in both cell cycle duration and viability, but similarities between cells derived from the same parental lineage. As a consequence, lineage sizes and outcomes differed dramatically, and individual lineages made uneven contributions toward the terminally differentiated population. Thus, the cohort of myoblasts undergoing differentiation at the end of an experiment differed dramatically from the lineages present at the beginning. Treatment with IGF-I increased myoblast number by maintaining viability and by stimulating a fraction of cells to complete one additional cell cycle in differentiation medium, and as a consequence reduced the variability of the terminal population compared with controls. CONCLUSION: Our results reveal that heterogeneity of responses to external cues is an intrinsic property of cultured myoblasts that may be explained in part by parental lineage, and demonstrate the power of live cell imaging for understanding how muscle differentiation is regulated. PMID- 23638708 TI - Carbon nanotube complementary wrap-gate transistors. AB - Among the challenges hindering the integration of carbon nanotube (CNT) transistors in digital technology are the lack of a scalable self-aligned gate and complementary n- and p-type devices. We report CNT transistors with self aligned gates scaled down to 20 nm in the ideal gate-all-around geometry. Uniformity of the gate wrapping the nanotube channels is confirmed, and the process is shown not to damage the CNTs. Further, both n- and p-type transistors were realized by using the appropriate gate dielectric-HfO2 yielded n-type and Al2O3 yielded p-type-with quantum simulations used to explore the impact of important device parameters on performance. These discoveries not only provide a promising platform for further research into gate-all-around CNT devices but also demonstrate that scalable digital switches with realistic technological potential can be achieved with carbon nanotubes. PMID- 23638707 TI - Asymmetric synthesis of nonracemic primary amines via spiroborate-catalyzed reduction of pure (E)- and (Z)-O-benzyloximes: applications toward the synthesis of calcimimetic agents. AB - Highly enantiopure (1-aryl)- and (1-naphthyl)-1-ethylamines were synthesized by the borane-mediated reduction of single-isomeric (E)- and (Z)-O-benzyloxime ethers using the stable spiroborate ester derived from (S)-diphenyl valinol and ethylene glycol as the chiral catalyst. Primary (R)-arylethylamines were prepared by the reduction of pure (Z)-ethanone oxime ethers in up to 99% ee using 15% of catalyst. Two convenient and facile approaches to the synthesis of new and known calcimimetic analogues employing enantiopure (1-naphthalen-1-yl)ethylamine as chiral precursor are described. PMID- 23638709 TI - 5' tRNA halves are present as abundant complexes in serum, concentrated in blood cells, and modulated by aging and calorie restriction. AB - BACKGROUND: Small RNAs complex with proteins to mediate a variety of functions in animals and plants. Some small RNAs, particularly miRNAs, circulate in mammalian blood and may carry out a signaling function by entering target cells and modulating gene expression. The subject of this study is a set of circulating 30 33 nt RNAs that are processed derivatives of the 5' ends of a small subset of tRNA genes, and closely resemble cellular tRNA derivatives (tRFs, tiRNAs, half tRNAs, 5' tRNA halves) previously shown to inhibit translation initiation in response to stress in cultured cells. RESULTS: In sequencing small RNAs extracted from mouse serum, we identified abundant 5' tRNA halves derived from a small subset of tRNAs, implying that they are produced by tRNA type-specific biogenesis and/or release. The 5' tRNA halves are not in exosomes or microvesicles, but circulate as particles of 100-300 kDa. The size of these particles suggest that the 5' tRNA halves are a component of a macromolecular complex; this is supported by the loss of 5' tRNA halves from serum or plasma treated with EDTA, a chelating agent, but their retention in plasma anticoagulated with heparin or citrate. A survey of somatic tissues reveals that 5' tRNA halves are concentrated within blood cells and hematopoietic tissues, but scant in other tissues, suggesting that they may be produced by blood cells. Serum levels of specific subtypes of 5' tRNA halves change markedly with age, either up or down, and these changes can be prevented by calorie restriction. CONCLUSIONS: We demonstrate that 5' tRNA halves circulate in the blood in a stable form, most likely as part of a nucleoprotein complex, and their serum levels are subject to regulation by age and calorie restriction. They may be produced by blood cells, but their cellular targets are not yet known. The characteristics of these circulating molecules, and their known function in suppression of translation initiation, suggest that they are a novel form of signaling molecule. PMID- 23638710 TI - De novo hepatitis B virus infection from anti-HBc-positive donors in pediatric living donor liver transplantation. AB - OBJECTIVE: The aim of this study was to analyze the incidence and risk factors of de novo hepatitis B virus (HBV) infection from hepatitis B core antibody (anti HBc)-positive donors in pediatric living donor liver transplantation (LDLT). METHODS: We retrospectively analyzed 46 recipients without pre-liver transplantation (LT) HBV infection evidence who underwent LDLT from October 2006 to May 2011 in our center. HBV markers, including hepatitis B surface antigen (HBsAg) and antibody (anti-HBs), anti-HBc, hepatitis B e antigen (HBeAg) and antibody (anti-HBe) were determined in both donors and recipients before LT and in recipients after LT. HBV DNA titer was measured if the recipients were strongly suspected of de novo HBV infection. RESULTS: Without prophylaxis, de novo HBV infection occurred in 11 of 46 recipients (23.9%) 6-36 months after LT. All 11 patients received grafts from anti-HBc-positive donors. The donors' baseline status and the characteristics of recipients at the time of transplantation were not associated with the acquisition of de novo hepatitis B infection. The overall 2-year survival rate of patients from anti-HBc-positive donors was 84.2%. Two de novo HBV-infected patients who had YMDD mutation were given adefovir combined with lamivudine, and their liver function gradually improved during the follow-up period. CONCLUSIONS: Anti-HBc-positive donors can significantly increase the incidence of de novo HBV infection in HBsAg-negative recipients. Administration with adefovir in patients who are resistant to lamivudine seems to be an effective and safe way for de novo HBV infection. PMID- 23638711 TI - Effects of exclusive breastfeeding intervention on child growth and body composition: the MINIMat trial, Bangladesh. AB - AIM: Exclusive breastfeeding (EBF) for 6 months is recommended for optimal infant health, but the evidence for longer-term impacts is weak. We examined whether randomization to receive EBF counselling (BFC) in rural Bangladeshi women had an impact on childhood growth trajectories and body composition. METHODS: In the Maternal and Infant Nutrition Interventions in Matlab trial, 4436 pregnant women were randomized to six equally sized, food and micronutrient groups. Of these, 3214 were randomized during the last trimester of pregnancy to receive either BFC or the usual/standard health message (UHM). Their infants were extensively followed up, with anthropometric measurements between 0 and 54 months and assessment of body composition at 54 months. RESULTS: The mean duration of EBF in the BFC group was 111 days compared to 76 days in the UHM group (mean difference: 35.0 days, 95% CI 30.6-39.5, p < 0.001). There was no difference in growth trajectories between the BFC and UHM groups and no difference in body composition at 54 months. Children exposed to prenatal multiple micronutrients (vs 60 mg iron and folate) combined with BFC (vs UHM), however, had slower linear growth (mean difference -0.17 SD score, p < 0.01). CONCLUSION: Exclusive breastfeeding counselling resulted in neither differential growth trajectories in infancy and childhood, nor body composition differences at 54 months. The combination of prenatal multiple micronutrient supplementation (MMS) and BFC was unfavourable for linear growth during 0-54 months, which raises questions about possible negative effects of MMS. PMID- 23638719 TI - Systemic transthyretin amyloidosis in a patient with bent spine syndrome. AB - Wild-type and mutant transthyretin (TTR) are implicated in systemic amyloidosis (ATTR). Myopathy is a rare complication of ATTR amyloidosis, however no patient with bent spine syndrome secondary to ATTR amyloidosis has been reported so far. We present the first case of bent spine syndrome in a patient with wild-type ATTR amyloidosis who also had concomitant Alzheimer's disease. PMID- 23638718 TI - Improvement of aortic valve stenosis by ApoA-I mimetic therapy is associated with decreased aortic root and valve remodelling in mice. AB - BACKGROUND AND PURPOSE: We have shown that infusions of apolipoprotein A-I (ApoA I) mimetic peptide induced regression of aortic valve stenosis (AVS) in rabbits. This study aimed at determining the effects of ApoA-I mimetic therapy in mice with calcific or fibrotic AVS. EXPERIMENTAL APPROACH: Apolipoprotein E-deficient (ApoE(-/-) ) mice and mice with Werner progeria gene deletion (Wrn(Deltahel/Deltahel) ) received high-fat diets for 20 weeks. After developing AVS, mice were randomized to receive saline (placebo group) or ApoA-I mimetic peptide infusions (ApoA-I treated groups, 100 mg.kg(-1) for ApoE(-/-) mice; 50 mg.kg(-1) for Wrn mice), three times per week for 4 weeks. We evaluated effects on AVS using serial echocardiograms and valve histology. KEY RESULTS: Aortic valve area (AVA) increased in both ApoE(-/-) and Wrn mice treated with the ApoA-I mimetic compared with placebo. Maximal sinus wall thickness was lower in ApoA-I treated ApoE(-/-) mice. The type I/III collagen ratio was lower in the sinus wall of ApoA-I treated ApoE(-/-) mice compared with placebo. Total collagen content was reduced in aortic valves of ApoA-I treated Wrn mice. Our 3D computer model and numerical simulations confirmed that the reduction in aortic root wall thickness resulted in improved AVA. CONCLUSIONS AND IMPLICATIONS: ApoA-I mimetic treatment reduced AVS by decreasing remodelling and fibrosis of the aortic root and valve in mice. PMID- 23638720 TI - Clinical decision making: how surgeons do it. AB - Clinical decision making is a core competency of surgical practice. It involves two distinct types of mental process best considered as the ends of a continuum, ranging from intuitive and subconscious to analytical and conscious. In practice, individual decisions are usually reached by a combination of each, according to the complexity of the situation and the experience/expertise of the surgeon. An expert moves effortlessly along this continuum, according to need, able to apply learned rules or algorithms to specific presentations, choosing these as a result of either pattern recognition or analytical thinking. The expert recognizes and responds quickly to any mismatch between what is observed and what was expected, coping with gaps in information and making decisions even where critical data may be uncertain or unknown. Even for experts, the cognitive processes involved are difficult to articulate as they tend to be very complex. However, if surgeons are to assist trainees in developing their decision-making skills, the processes need to be identified and defined, and the competency needs to be measurable. This paper examines the processes of clinical decision making in three contexts: making a decision about how to manage a patient; preparing for an operative procedure; and reviewing progress during an operative procedure. The models represented here are an exploration of the complexity of the processes, designed to assist surgeons understand how expert clinical decision making occurs and to highlight the challenge of teaching these skills to surgical trainees. PMID- 23638722 TI - Cytotoxicity of rigid gas-permeable lens care solutions. AB - PURPOSE: Reports on cytotoxic effects of rigid gas-permeable lens multipurpose solutions, which remain important because of increasing popularity of orthokeratology, are limited. This study determined cytotoxic effects of rigid gas-permeable lens multipurpose solutions on human corneal epithelial cells and assessed the proliferation rate at different levels of cell membrane damage. METHODS: The human corneal epithelial cells were exposed to multipurpose solutions containing chlorhexidine gluconate (0.003%) and polyaminopropyl biguanide (PHMB) (0.0005%) (MPS-A), PHMB (0.0005%) (MPS-B) and PHMB (0.0001%) (MPS-C) for one, five and 10 minutes. Following staining with Annexin V-FITC/7 AAD, cell viability and membrane integrity were assessed by flow cytometry. Effects of exposure to concentrations of 10 to 40 per cent multipurpose solutions for 12 hours on the metabolic rate of human corneal epithelial cells were assessed by 3-(4-,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay. Recovery rates were assessed after re-culture for 96 hours at 37 degrees C. RESULTS: MPS-A exposure caused the highest percentage of early and late necrotic cells for all exposure times and was significantly higher than other multipurpose solutions (p < 0.0001). After 10 minutes exposure, almost 40 per cent of cells in MPS-A but less than five per cent in MPS-B or MPS-C, were in late necrotic stage. After 12 hours of exposure, cell activity was significantly reduced in a dose-response manner for MPS-A treated cells only (p > 0.05). After 96 hours of re-culture, all exposed cells showed some reduction in viability but the effects of exposure to 30 and 40 per cent MPS-A resulted in loss of viability. CONCLUSION: The presence of chlorhexidine appeared to increase cytotoxicity of multipurpose solutions for rigid gas-permeable lenses. This was apparent in both increased levels of necrotic cells on initial exposure and reductions in viability after prolonged exposures at lower dilutions. Multipurpose solutions containing PHMB as a preservative, while not causing acute cytotoxicity, did affect cell viability following exposure to diluted solutions. This indicated it is inadvisable to expose the cornea to multipurpose solutions but rather to rinse lenses with saline before insertion and use artificial tears for rewetting. PMID- 23638721 TI - Elective lymph node irradiation late course accelerated hyper-fractionated radiotherapy plus concurrent cisplatin-based chemotherapy for esophageal squamous cell carcinoma: a phase II study. AB - BACKGROUND: In this phase II study, we evaluated the efficacy, toxicity, and patterns of failure of elective lymph node irradiation (ENI) late course accelerated hyper-fractionated radiotherapy (LCAHRT) concurrently with cisplatin based chemotherapy (CHT) for esophageal squamous cell carcinoma (ESCC). METHODS: Patients with clinical stage II-IVa (T1-4N0-1M0 or M1a) ESCC were enrolled between 2004 and 2011. Radiation therapy (RT) comprised two courses: The first course of radiation covered the primary and metastatic regional tumors and high risk lymph nodal regions, given at 2 Gy per fraction for a dose of 40 Gy. In the second course, LCAHRT was delivered to the boost volume twice a day for an additional 19.6 Gy in 7 treatment days, using 1.4 Gy per fraction. Two cycles of CHT were given at the beginning of RT. RESULTS: The median age and Karnofsky performance status were 63 years and 80, respectively. The American Joint Committee on Cancer stage was II in 14 (20.6%) patients, III in 32 (47.1%), and IVa in 22 (32.3%). With a median follow-up of 18.5 months, the overall survival at 1-, 3-, 5-year were 75.5%, 46.5%, 22.7% for whole group patients, versus 78.6%, 49.4%, 39.9% for patients with stage II-III. The patterns of first failure from local recurrence, regional failure, and distant metastasis were seen in 20.6%, 17.6%, and 19.1%, respectively. The most frequent acute high-grade (>= 3) toxicities were esophagitis and leucopenia, occurred in 26.4% and 32.4%. CONCLUSIONS: ENI LCAHRT concurrently with CHT was appeared to be an effective regimen for ESCC patient with a favorable and tolerated profile. Further observation with longer time and randomized phase III trial is currently underway. TRIAL REGISTRATION: ChiCTR-TRC-09000568. PMID- 23638723 TI - Shape and pharmacophore-based virtual screening to identify potential cytochrome P450 sterol 14alpha-demethylase inhibitors. AB - Sterol 14alpha-demethylase (CYP51) is a cytochrome P450 heme thiolate containing enzyme involved in biosynthesis of membrane sterols, including sterol in animals, ergosterol in fungi, and a variety of C24-modified sterols in plants and protozoa. Several clinical drugs have been developed to reduce the impact of fungal diseases, but their clinical uses have been limited by the emergence of drug resistance and insufficiencies in their antifungal activity. Therefore, in order to identify potential CYP51 inhibitors, we have implemented a virtual screening (VS) protocol by using both phase shape and pharmacophore model (AHHRR) against Asinex, ChemBridge and Maybridge databases. A filtering protocol, including Lipinski filter, number of rotatable bonds and different precisions of molecular docking was applied in hits selection. The results indicated that both shape-based and pharmacophore-based screening yielded the best result with potential inhibitors. The searched compounds were also evaluated with ADME properties, which show excellent pharmacokinetic properties under the acceptable range. We identified potential CYP51 inhibitors for further investigation, they could also be employed to design ligands with enhanced inhibitory potencies and to predict the potencies of analogs to guide synthesis/or prepare synthetic antifungal analogs against CYP51. PMID- 23638725 TI - A decade of change in the treatment of advanced soft tissue sarcoma. PMID- 23638724 TI - Screening and identification of genetic loci involved in producing more/denser inclusion bodies in Escherichia coli. AB - BACKGROUND: Many proteins and peptides have been used in therapeutic or industrial applications. They are often produced in microbial production hosts by fermentation. Robust protein production in the hosts and efficient downstream purification are two critical factors that could significantly reduce cost for microbial protein production by fermentation. Producing proteins/peptides as inclusion bodies in the hosts has the potential to achieve both high titers in fermentation and cost-effective downstream purification. Manipulation of the host cells such as overexpression/deletion of certain genes could lead to producing more and/or denser inclusion bodies. However, there are limited screening methods to help to identify beneficial genetic changes rendering more protein production and/or denser inclusion bodies. RESULTS: We report development and optimization of a simple density gradient method that can be used for distinguishing and sorting E. coli cells with different buoyant densities. We demonstrate utilization of the method to screen genetic libraries to identify a) expression of glyQS loci on plasmid that increased expression of a peptide of interest as well as the buoyant density of inclusion body producing E. coli cells; and b) deletion of a host gltA gene that increased the buoyant density of the inclusion body produced in the E. coli cells. CONCLUSION: A novel density gradient sorting method was developed to screen genetic libraries. Beneficial host genetic changes could be exploited to improve recombinant protein expression as well as downstream protein purification. PMID- 23638726 TI - 13 years of trabectedin, 5 years of Yondelis(r): what have we learnt? AB - Trabectedin (Yondelis((r)) [PharmaMar S.A., Madrid, Spain]) is one of the most promising agents tested in the last two decades in patients with anthracycline/ifosfamide-resistant sarcomas and is the first agent highlighting the notion of prolonged tumor control in advanced soft tissue sarcoma. Indeed, the unusual pattern of tumor response to trabectedin has raised queries about the appropriateness of conventional radiological evaluation of efficacy according to Response Evaluation Criteria in Solid Tumors and has prompted the search for new end points for Phase II studies. The safety profile of trabectedin is unique and much more favorable than that of doxorubicin and ifosfamide especially as regards neutropenia and alopecia. Its efficacy in translocation-related sarcomas suggests a targeted approach to tumor control in these sarcoma subtypes. With numerous Phase II and III studies of trabectedin underway, it appears certain that the current standard-of-care paradigm in advanced soft tissue sarcoma is set for change. PMID- 23638727 TI - The intriguing patterns of tumor response to trabectedin. AB - Among soft tissue sarcomas, myxoid liposarcomas are exceedingly sensitive to trabectedin. Obvious tumor shrinkage is seen in some patients, whereas nondimensional changes in tumor tissue are seen in others especially after the first cycles of therapy. These patterns of tumor response are reminiscent of the way in which solid tumors respond to targeted therapies. The finding of trabectedin's ability to target the FUS-CHOP-mediated transcriptional block, restoring adipogenic differentiation within the tumor in myxoid liposarcomas, confirmed a 'targeted' activity that differs from its well-known atypical alkylating mechanism of action. Uterine leiomyosarcoma may show similar patterns of dimensional and nondimensional responses to trabectedin. Unusual cases of delayed response are occasionally seen and suggest other mechanisms of action, including activity on the tumor microenvironment which has recently been reported. An intriguing question is whether the different patterns of response have clinically or therapeutically meaningful correlations. PMID- 23638728 TI - Current questions in soft tissue sarcoma: further steps with Yondelis(r). AB - Treatment of advanced soft tissue sarcoma remains a considerable therapeutic challenge. Doxorubicin-based combination therapy produces reasonable objective response rates but this comes at the cost of high associated toxicity in the absence of an overall survival benefit in the first-line setting. When selecting chemotherapeutic options for patients with advanced disease, it is important to define the goals and expectations of treatment. For the majority of patients with refractory soft tissue sarcoma, goals are long-term tumor stabilization with good quality of life. Trabectedin is an excellent choice in these patients. The fifth anniversary of the marketing authorization of Yondelis((r)) (PharmaMar S.A., Madrid, Spain; trabectedin) in Europe provides an excellent opportunity to recap current knowledge and see what the future holds with this novel treatment. Trabectedin has made possible new models of care, such as long-term treatment and rechallenge. Its use has also fueled important and necessary debate about the criteria currently used to evaluate tumor response. PMID- 23638729 TI - Trabectedin's contribution to the treatment of sarcomas. AB - Historically, treatment options for soft tissue sarcoma in adults have been limited. Prior to the introduction of trabectedin, only two main cytotoxic drugs were considered active: doxorubicin and ifosfamide (and to a lesser extent dacarbazine). Trabectedin is a unique marine-derived agent with a dual mechanism of action; it shares the mechanisms of action of cytotoxic agents and targeted therapies. The activity of trabectedin in advanced soft tissue sarcoma has been demonstrated in an extensive Phase II clinical trials program in which some interesting new models of use were identified, including maintenance treatment and rechallenge after treatment interruption. After 13 years since trabectedin was first investigated, it continues to be the subject of active research in both academia and industry. Numerous clinical studies currently underway with trabectedin are aiming to resolve a variety of questions in order to optimize its use in clinical practice. PMID- 23638731 TI - Enhanced resistance to the cellulose biosynthetic inhibitors, thaxtomin A and isoxaben in Arabidopsis thaliana mutants, also provides specific co-resistance to the auxin transport inhibitor, 1-NPA. AB - BACKGROUND: Thaxtomin A (TA) is a phytotoxin produced by plant pathogenic Streptomyces spp. responsible for potato common scab. TA inhibits cellulose biosynthesis in expanding plant tissues and is essential for disease induction. Auxin treatment of various plant tissues has been repeatedly demonstrated to inhibit TA toxicity and to reduce common scab. This work utilises Arabidopsis thaliana mutants with resistance to cellulose biosynthesis inhibitors (CBIs) to investigate the interaction between TA, other CBIs and auxins. RESULTS: Three CBI resistant A. thaliana mutants; txr1-1 (tolerance to TA), ixr1-1 (tolerance to isoxaben - IXB) and KOR1 (cellulose deficiency), showed no altered root growth response to treatment with natural or synthetic auxins, nor with the auxin efflux transport inhibitor 2,3,5-Triiodobenzoic acid (TIBA). However, all mutants had significantly enhanced tolerance to 1-napthylphthalamic acid (NPA), another auxin efflux transport inhibitor, which blocks polar auxin transport at a site distinct from TIBA. NPA tolerance of txr1-1 and ixr1-1 was further supported by electrophysiological analysis of net H+ fluxes in the mature, but not elongation zone of roots. All three mutants showed increased tolerance to IXB, but only txr1 1 showed tolerance to TA. No mutant showed enhanced tolerance to a third CBI, dichlobenil (DCB). CONCLUSIONS: We have demonstrated that plant tolerance to TA and IXB, as well as cell wall synthesis modifications in roots, have resulted in specific co-resistance to NPA but not TIBA. This suggests that CBI resistance has an impact on polar auxin efflux transport processes associated with the NPA binding protein. We also show that NPA inhibitory response in roots occurs in the mature root zone but not the elongation zone. Responses of mutants to CBIs indicate a similar, but not identical mode of action of TA and IXB, in contrast to DCB. PMID- 23638732 TI - Use of transcriptional profiling to delineate the initial response of mice to intravaginal herpes simplex virus type 2 infection. AB - Intravaginal (ivag) infection of mice with herpes simplex virus type 2 (HSV-2) causes genital tissue damage, quickly followed by development of fatal encephalopathy. To delineate initial host responses generated by HSV-2 infection, here oligonucleotide microarrays compared gene expression in vaginal tissue from uninfected mice and mice 1, 2, 3, 4, 5, 6, or 7 days after ivag infection with 10(4) pfu HSV-2. While comparison of mRNA expression in uninfected and HSV infected vaginal tissue detected few changes during the first 2 days post infection (dpi), there were 156 genes whose expression was first significantly altered 3 dpi that remained significantly modified at all later time points examined. These 156 genes were significantly enriched in canonical pathways associated with interferon (IFN) signaling, activation of IFN elements by intracellular pattern recognition receptors, and antiviral immunity induced by cytosolic RIG-like receptors. Evaluation of this gene set with the National Center for Biotechnology Information Gene and INTERFEROME databases corroborated pathway analysis, as function of most (53%) were linked to IFN-mediated host immunity. In the final set of experiments, ivag administration of the Toll-like receptor 3 agonist polyinosinic: polycytidylic acid (poly I:C) 24 h before ivag HSV-2 infection reduced the incidence of genital pathology and encephalopathy, while these poly I:C-treated mice were subsequently protected from ocular HSV-2 challenge lethal to uninfected controls. The latter results imply that the exuberant antiviral immunity produced in our experimental model is simply formed too late to prevent viral replication and dissemination, and that poly I:C induced formation of an antiviral state protecting against primary ivag infection also permits development of HSV-specific protective immunity. PMID- 23638733 TI - Trineopentylphosphine: a conformationally flexible ligand for the coupling of sterically demanding substrates in the Buchwald-Hartwig amination and Suzuki Miyaura reaction. AB - Trineopentylphosphine (TNpP) in combination with palladium provides a highly effective catalyst for the Buchwald-Hartwig coupling of sterically demanding aryl bromides and chlorides with sterically hindered aniline derivatives. Excellent yields are obtained even when both substrates include 2,6-diisopropyl substituents. Notably, the reaction rate is inversely related to the steric demand of the substrates. X-ray crystallographic structures of Pd(TNpP)2, [Pd(4-t Bu-C6H4)(TNpP)(MU-Br)]2, and [Pd(2-Me-C6H4)(TNpP)(MU-Br)]2 are reported. These structures suggest that the conformational flexibility of the TNpP ligand plays a key role in allowing the catalyst to couple hindered substrates. The Pd/TNpP system also shows good activity for the Suzuki coupling of hindered aryl bromides. PMID- 23638735 TI - Comment on Effect of drying of jujubes (Ziziphus jujuba Mill.) on the contents of sugars, organic acids, alpha-tocopherol, beta-carotene, and phenolic compounds. PMID- 23638734 TI - EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1alpha and NFkappaB, and VEGF expression. AB - The role of EGCG, a major green tea catechin in breast cancer therapy is poorly understood. The present study tests the hypothesis that EGCG can inhibit the activation of HIF-1alpha and NFkappaB, and VEGF expression, thereby suppressing tumor angiogenesis and breast cancer progression. Sixteen eight-wk-old female mice (C57BL/6 J) were inoculated with 10^6 E0771 (mouse breast cancer) cells in the left fourth mammary gland fat pad. Eight mice received EGCG at 50-100 mg/kg/d in drinking water for 4 weeks. 8 control mice received drinking water only. Tumor size was monitored using dial calipers. At the end of the experiment, blood samples, tumors, heart and limb muscles were collected for measuring VEGF expression using ELISA and capillary density (CD) using CD31 immunohistochemistry. EGCG treatment significantly reduced tumor weight over the control (0.37 +/- 0.15 vs. 1.16 +/- 0.30 g; P < 0.01), tumor CD (109 +/- 20 vs. 156 +/- 12 capillary #/mm^2; P < 0.01), tumor VEGF expression (45.72 +/- 1.4 vs. 59.03 +/- 3.8 pg/mg; P < 0.01), respectively. But, it has no effects on the body weight, heart weight, angiogenesis and VEGF expression in the heart and skeletal muscle of mice. EGCG at 50 MUg/ml significantly inhibited the activation of HIF 1alpha and NFkappaB as well as VEGF expression in cultured E0771 cells, compared to the control, respectively. These findings support the hypothesis that EGCG, a major green tea catechin, directly targets both tumor cells and tumor vasculature, thereby inhibiting tumor growth, proliferation, migration, and angiogenesis of breast cancer, which is mediated by the inhibition of HIF-1alpha and NFkappaB activation as well as VEGF expression. PMID- 23638736 TI - Estimation of variance components for carcass traits in Japanese Black cattle using 50K SNP genotype data. AB - Genomic selection using high-density single nucleotide polymorphism (SNP) genotype data may accelerate genetic improvements in livestock animals. In this study, we attempted to estimate the variance components of six carcass traits in fattened Japanese Black steers using SNP genotype data. Six hundred and seventy three steers were genotyped using an Illumina Bovine SNP50 BeadChip and phenotyped for cold carcass weight, ribeye area, rib thickness, subcutaneous fat thickness, estimated yield percent and marbling score. Additive polygenic variance and the variance attributable to a set of SNPs that had statistically significant effects on the trait were estimated via Gibbs sampling with two models: (i) a model with the chosen SNPs and the additive polygenic effects; and (ii) a model with the polygenic effects alone. The proportion of the estimated variance attributable to the SNPs became higher as the number of SNP effects that fit increased. High correlations between breeding values estimated with the model containing the polygenic effect alone and those estimated by chosen SNPs were obtained. No fraction of the total genetic variance was explained by SNPs associated with the trait at P >= 0.1. Our results suggest that for the carcass traits of Japanese Black cattle, a maximum of half of the total additive genetic variance may be explained by SNPs between 100 several tens to several 100s. PMID- 23638737 TI - Nanoparticles for the induction of antigen-specific Tregs. PMID- 23638738 TI - Do therapeutic antibodies hold the key to an effective treatment for Ebola hemorrhagic fever? PMID- 23638739 TI - New research in HIV immunity points way for vaccine. PMID- 23638740 TI - Interview: Investigating immunomodulators among the Actinomycetales. Interview by Hannah Wilson. AB - John L Stanford speaks to Hannah Wilson, Assistant Commissioning Editor John L Stanford is Chief Scientific Officer at BioEos Ltd (Kent, UK). Dr Stanford began his career as a senior lecturer and then reader in microbiology at Middlesex Hospital Medical School (London, UK), then University College London Medical School, where he became Professor in Medical Microbiology and Head of Department in 1997. He retired and became Professor Emeritus in 2004. Dr Stanford's career has been devoted to research into mycobacteria, the diseases that they cause and the practical uses of this research. His special interest in recent years has been the development of bacterial immunotherapeutics for a range of diseases including tuberculosis and cancer. Dr Stanford was one of the founding directors of Stanford Rook Ltd (London) and of BioEos Ltd, where he remains a director. He also played a part in the founding of Immodulon Therapeutics Ltd (London) and of a new company, ActinoPharma Ltd (London), and has published more than 200 peer reviewed scientific papers. PMID- 23638741 TI - HIV-1 vaccine antibody induction against a variable region of HIV-1: a possible link to protective immunity? AB - Evaluation of: Liao H, Bonsignori M, Alam M et al. Vaccine induction of antibodies against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2. Immunity 38, 176-186 (2013). In 2009, results from the Phase III HIV-1 vaccine clinical trial RV144 applying a prime/boost regimen with a canarypox vaccine vector ALVAC-HIV plus the AIDSVAX B/E subunit envelope vaccine conducted in Thailand were reported. The priming canarypox vector carried the HIV-1 vaccine genes gp120 linked to the transmembrane-anchoring portion of subtype B gp41, HIV-1 Gag and protease; the boosting vaccine was composed of clades B and E of HIV-1 gp120. A 31.2% vaccine efficacy could be seen in this trial, an encouraging result in HIV-1 vaccine research that had been previously plagued with little clinical efficacy. In this paper, results from tests of four monoclonal antibodies isolated from RV144 vaccinees are reported. The antibodies recognize a certain HIV-1 envelope residue (169), neutralize laboratory-adapted HIV-1 strains and mediate killing of CD4(+) cells infected with HIV-1 laboratory isolates. Crystal structure analysis suggests that the recognized HIV-1 envelope epitope can exist in different conformations. It is thought that the immune pressure elicited by the monoclonal antibodies targets a HIV-1 envelope region with variable sequence structure. PMID- 23638742 TI - Efficacy of adoptive immunotherapy with donor lymphocyte infusion in relapsed lymphoid malignancies. AB - AIMS: There is a perceived benefit associated with the administration of donor lymphocyte infusion (DLI) in patients with lymphoid malignancies relapsing after allogeneic hematopoietic cell transplantation. However, it is unclear if and how this benefit varies according to specific diseases. Because administration of DLI is not universally effective and could be associated with significant toxicities resulting in morbidity and mortality, it is imperative to identify cases where benefits outweigh harms of the procedure. MATERIALS & METHODS: We conducted a systematic review of the published literature and extracted and pooled data independently for each disease cohort: acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). RESULTS: In summary, 39 studies met inclusion criteria. The pooled proportion (95% CI) for complete response was 27% (16-40) in ALL, 55% (15-92) in CLL, 26% (19-33) in MM, 52% (33-71) in NHL and 37% (20-56) in HL. CONCLUSION: Complete response rates appear higher when DLI is used for relapsed CLL and lymphomas (NHL and HL), and less pronounced in ALL or MM. Absence of data pertaining to disease-specific prognostic determinants, such as adverse genetic or molecular abnormalities, or quantitative disease burden when applicable, limit our ability to identify cases in whom benefits from DLI outweigh risks associated with the procedure within a particular disease. PMID- 23638743 TI - General overview of radioimmunotherapy of solid tumors. AB - Radioimmunotherapy (RIT) represents an attractive tool for the treatment of local and/or diffuse tumors with radiation. In RIT, cytotoxic radionuclides are delivered by monoclonal antibodies that specifically target tumor-associated antigens or the tumor microenvironment. While RIT has been successfully employed for the treatment of lymphoma, mostly with radiolabeled antibodies against CD20 (Bexxar((r)); Corixa Corp., WA, USA and Zevalin((r)); Biogen Idec Inc., CA, USA and Schering AG, Berlin, Germany), its use in solid tumors is more challenging and, so far, few trials have progressed beyond Phase II. This review provides an update on antibody-radionuclide conjugates and their use in RIT. It also discusses possible optimization strategies to improve the clinical response by considering biological, radiobiological and physical features. PMID- 23638744 TI - Molecular imaging and carbonic anhydrase IX-targeted radioimmunotherapy in clear cell renal cell carcinoma. AB - Conventional imaging is suboptimal at evaluating disease status in renal cell carcinoma (RCC) because of poor sensitivity. Furthermore, there is an unmet need for the treatment of metastatic RCC, both in terms of improvement of progression free survival and limitation of toxicity. For this reason, radionuclide imaging and radionuclide therapy are extensively investigated. This review provides an overview of the current progress in molecular imaging and radionuclide therapy in clear cell RCC and will focus on promising detection and therapy strategies targeting the carbonic anhydrase IX antigen, which is expressed in clear cell RCC. PMID- 23638745 TI - Toll-like receptor agonists: current status and future perspective on their utility as adjuvants in improving anticancer vaccination strategies. AB - Toll-like receptor (TLR) agonists possess remarkable properties, particularly with regard to dendritic cell activation, promoting Th1-type cytokine production and optimizing cytotoxic T-cell responses. Preclinical and clinical studies conducted to date show that TLR agonists can improve currently applied anticancer vaccination protocols. Although these have resulted in the US FDA approval of three TLR agonists for use in humans, their abundant application encounters limitations, principally due to dose-limiting toxicity evoking from systemic cytokine production. Here, using selected examples of clinical studies, we provide a concise review regarding the knowledge acquired thus far on the adjuvant use of TLR agonists as cancer vaccine components. We also provide evidence on the exploitation of a novel TLR agonist, prothymosin-alpha, which enhances the efficacy of tumor-reactive effectors without causing severe adverse effects. PMID- 23638747 TI - Antibody-based therapy in colorectal cancer. AB - Treatment in patients with nonresectable and resectable colorectal cancer at the advanced stage is challenging, therefore intensive strategies such as chemotherapy, signaling inhibitors and monoclonal antibodies (mAbs) to control the disease are required. mAbs are particularly promising tools owing to their target specificities and strong antitumor activities through multiple mechanisms, as shown by rituximab in B-cell non-Hodgkin's lymphoma and trastuzumab in breast cancer. Three mAbs (cetuximab, bevacizumab and panitumumab) have been approved for the treatment of colorectal cancer in the USA and many other mAbs are being tested in clinical trials. The potential of antibody therapy is associated with several mechanisms including interference of vital signaling pathways targeted by the antibody and immune cytotoxicity selectively directed against tumor cells by tumor-bound antibody through the Fc portion of the antibody, such as antibody dependent cellular cytotoxicity and complement-dependent cytotoxicity. Moreover, recent experimental findings have shown that immune complexes formed by therapeutic mAbs with tumor-released antigens could augment the induction of tumor-specific cytotoxic CD8(+) T cells through activation of APCs. In addition, antibodies targeting immune checkpoints on hematopoietic cells have recently opened a new avenue for the treatment of cancer. In this review, we focus on mAb treatment in colorectal cancer and its immunological aspects. PMID- 23638749 TI - Comparing groups with ranks. PMID- 23638750 TI - Microsphere lithography on hydrophobic surfaces for generating gold films that exhibit infrared localized surface plasmon resonances. AB - Evaporation induced self-assembly is an established method for producing close packed two-dimensional sphere masks on hydrophilic surfaces such as glass. In sphere lithography, gold or silver is deposited over sphere masks to generate a film-over-nanospheres or a nanoprism array that can be used as a sensing surface in localized surface plasmon extinction and surface enhanced Raman spectroscopy experiments. Sphere lithography is less commonly used to prepare sphere masks on hydrophobic surfaces associated with infrared window materials, in part because it is challenging to find solvents with wetting and evaporation characteristics that are appropriate for such surfaces. This wetting challenge can be overcome with appropriate surfactants. However, surfactant residues are then left behind on the sensing surface. We report methods for depositing monolayer crystalline sphere masks onto CaF2 windows that minimize surfactant residue by either using ethanol as a volatile cosolvent that enhances wetting, or by increasing the concentration of colloid to compensate for the reduced attractions between spheres and surface. The rate of evaporation of solvents from the colloid drop is controlled by fixing the headspace partial pressure of ethanol and/or water. PMID- 23638751 TI - Screening for rheumatic heart disease in Aboriginal and Torres Strait Islander children. AB - Rheumatic heart disease is preventable but causes significant morbidity and mortality in Aboriginal Australian and Torres Strait Islander populations. Screening echocardiography has the potential to detect early rheumatic heart disease thereby enabling timely commencement of treatment (secondary prophylaxis) to halt disease progression. However, a number of issues prevent echocardiographic screening for rheumatic heart disease satisfying the Australian criteria for acceptable screening programs. Primarily, it is unclear what criteria should be used to define a positive screening result as questions remain regarding the significance, natural history and potential treatment of early and subclinical rheumatic heart disease. Furthermore, at present the delivery of secondary prophylaxis in Australia remains suboptimal such that the potential benefits of screening would be limited. Finally, the impact of echocardiographic screening for rheumatic heart disease on local health services and the psychosocial health of patients and families are yet to be ascertained. PMID- 23638752 TI - Cerebrospinal fluid levels of phosphorylated tau and Abeta1-38/Abeta1-40/Abeta1 42 in Alzheimer's disease with PS1 mutations. AB - We studied seven cases of Alzheimer's disease (AD). Six of the patients had presenilin 1 (PS1) mutations (PS1AD). Three novel PS1 mutations (T99A, H131R and L219R) and three other missense mutations (M233L, H163R and V272A) were found in the PS1AD group. We measured the levels of phosphorylated tau (ptau-181, ptau 199) and Abeta (Abeta1-42, Abeta1-40 and Abeta1-38) in the cerebrospinal fluid (CSF) of PS1AD patients, early-onset sporadic AD (EOSAD), late-onset sporadic AD (LOSAD) and non-demented subjects (ND). The CSF levels of Abeta1-42 in the three AD groups were significantly lower than those of the ND group (p < 0.0001). CSF levels of Abeta1-42 in the PS1AD group were significantly lower than those in the two sporadic AD groups. The Abeta1-40 and Abeta1-38 levels in the CSF of the PS1AD group were significantly lower than those of the three other groups (p < 0.0001, respectively). The levels of Abeta1-40, Abeta1-38 and Abeta1-42 in the CSF of the PS1AD group remained lower than those of the ND group for 4 years. Not only CSF Abeta1-42, but also Abeta1-40 and Abeta1-38 decreased in the advanced stages of PS1AD. PMID- 23638753 TI - Placenta accreta and maternal morbidity in the Republic of Ireland, 2005-2010. AB - OBJECTIVE: To describe the nationwide prevalence of placenta accreta and to quantify its impact on maternal morbidity. METHODS: Using discharge data for public hospitals in Ireland, years 2005-2010, deliveries with placenta accreta were identified using ICD-10-AM code for morbidly adherent placenta and compared with deliveries without the condition. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Placenta accreta prevalence increased 34% from 2005 to 2010 (7.9/10 000 deliveries versus 10.6/10 000 deliveries). This condition was associated with a substantial increased risk of hemorrhage (aOR: 16.6, 95% CI: 13.4-20.5), hysterectomy (aOR: 950.6, 95% CI: 632.9-1427.9), procedures to reduce uterine blood flow (aOR: 72.4, 95% CI: 35.1-149.4), transfusion (aOR: 41.8, 95% CI: 33.4 52.2), anemia (aOR 15.1, 95% CI: 10.8-21.0), abdominal organ injury (aOR: 8.2, 95% CI: 5.2-13.1), bladder surgery (aOR: 38.5, 95% CI: 21.8-68.1), mechanical ventilation (aOR: 63.2, 95% CI: 28.4-140.6), intensive care unit admission (aOR: 41.3, 95% CI: 30.0-56.9), and co-existing placenta previa (aOR: 23.2, 95% CI: 16.8-31.8) as well as increased risk of cesarean section, longer hospitalization and stillbirth. CONCLUSIONS: To our knowledge, this is the first study to use a comparison group of deliveries without placenta accreta and quantitatively illustrate with odds ratios the profound adverse health effects of this condition on the mother. PMID- 23638746 TI - T-cell tolerance in cancer. AB - T cells are the master regulators of adaptive immune responses and maintenance of their tolerance is critical to prevent autoimmunity. However, in the case of carcinogenesis, the tumor microenvironment aids T-cell tolerance, which contributes to uncontrolled tumor growth. Recently, there has been significant progress in understanding the intrinsic extracellular (positive and negative costimulatory molecules on APCs) and intracellular mechanisms (E3 ubiquitin ligases, transcriptional and epigenetic repressors), as well as extrinsic mechanisms (Tregs and tolerogenic dendritic cells) that are required for the implementation and maintenance of T-cell tolerance. Ultimately, understanding and manipulating T-cell tolerance will help to break the tolerance state in cancer. PMID- 23638755 TI - Brachytherapy-emulating robotic radiosurgery in patients with cervical carcinoma. AB - PURPOSE: To evaluate the technique, dosimetry, dose-volume-histograms (DVHs) and acute toxicity for CyberKnife(r) boost irradiation instead of intra-cervical brachytherapy in patients with cervical cancer. METHODS AND MATERIALS: Eleven who were not suitable for brachytherapy with FIGO stage IIB-IIIB cervical cancer underwent primary chemoradiation. After fiducial implantation, T2 contrast enhanced planning MRI and CT scans at 2-mm slice thickness were collected in the treatment position. The clinical target volume was defined as cervix + macroscopic residual tumour on MRI. Five fractions of 6 Gy each were prescribed to the target volume with a covering single dose 6 Gy. DVH parameters were evaluated for the target and organs at risk. Acute toxicity was documented once a week. RESULTS: DmeanPTV ranged from 33.6-40 Gy, median 36.7 Gy with a coverage of the PTV calculated to 100% of the prescribed dose ranging from 93.0-99.3% (median 97.7%). For the PTV the median CN was 0.78 (range, 0.66 to 0.87) and the median CI was 1.28 (range 1.15 to 1.52). Gastrointestinal (GI) and genitourinary (GU) toxicity was mild. There was no grade 3 or higher GI and GU toxicity. After 6 months of follow up, there were no local recurrences. For the complete treatment, a median EQD2 to 1 cc and 2 cc of the bladder wall was 98.8 Gy and 87.1 Gy, respectively. Median EQD2 to 1 cc and 2 cc of the rectal wall was 72.3 Gy and 64 Gy, respectively, correlating with a risk < 10% for Grade 2-4 late toxicity. CONCLUSIONS: CyberKnife robotic radiosurgery in patients with cervical cancer provides excellent target coverage with steep dose gradients toward normal tissues and safe DVH parameters for bladder, rectum and sigmoid. Acute toxicity was mild. Longer follow-up is needed to evaluate the oncological equality. PMID- 23638754 TI - Profiling of histamine H4 receptor agonists in native human monocytes. AB - BACKGROUND AND PURPOSE: Since the identification of the histamine H4 receptor, several ligands activating this receptor have been described and more compounds are in development. These ligands are well characterized in pharmacological assays, including radioligand competition binding studies, GTPgammaS and GTPase assays. In most cases, these experiments are performed in transfected cell lines, expressing unnaturally high levels of target receptors and G-protein signalling components. In this study we investigated the specific properties of H4 receptor ligands in native cells. EXPERIMENTAL APPROACH: Histamine and five different H4 receptor agonists - 4-methylhistamine, UR-PI376, clobenpropit, VUF8430 and ST 1006 - were characterized in freshly isolated human monocytes. The ligands (10 nM 10 MUM) were tested as inhibitors of IL-12p70 secretion from human monocytes and the effects of the H2 receptor antagonist ranitidine and the H4 receptor antagonist JNJ7777120 on their action was investigated. KEY RESULTS: Histamine and all the tested agonists reduced IL-12p70 secretion into monocyte supernatants by 40-70%. The potencies varied with pEC50 values ranging from 5.7 to 6.9, depending on the agonist used. All potencies were lower than those determined in the original investigations of the compounds. Pretreatment of monocytes with H2 or H4 receptor antagonists showed that some H4 receptor ligands also had low activity at the H2 receptor. CONCLUSIONS AND IMPLICATIONS: Our study demonstrates discrepancies between the potencies obtained from assays in transfected cell lines and assays in native human cells, indicating the importance of evaluating H4 receptor ligands in native cells. PMID- 23638756 TI - Cutaneous adverse reactions linked to targeted anticancer therapies bortezomib and lenalidomide for multiple myeloma: new drugs, old side effects. AB - CONTEXT: Cutaneous toxicity is a frequent side effect of new anticancer targeted therapies. Skin reactions can severely impact the patient's physical, psychological and social well-being and may sometimes lead to discontinuations either treatment dose reductions. OBJECTIVE: This study evaluates the impact of cutaneous adverse drug reactions (cADR) of the new therapies bortezomib and lenalidomide and presents a review of their skin side effects. MATERIALS AND METHOD: Type, frequency, severity, time of onset and management of cADR were collected and the medical records of all multiple myeloma patients receiving bortezomib or lenalidomide in the Hematology and Medical Oncology Institute of the University of Bologna, were analyzed. RESULTS: A total of 17 cADR occurred in 10 patients of 17 (58.8% of patients) treated with bortezomib: 5 rashes, 3 events of pruriginous rash, 1 purpuric rash, 2 records of mouth swelling, 1 stomatitis mucositis, 3 cases of edema in the lower limbs, 1 patient referred pruritus and another telogen effluvium. Eight skin manifestations were due to lenalidomide in 7 patients of 25 treated (28%): 2 pruriginous rashes, 3 cases of edema, 2 records of pruritus, 1 case of stomatitis-mucositis. Three adverse events linked to bortezomib and 4 to lenalidomide forced to a complete withdrawal of the drug, while 3 reactions due to bortezomib mandated a dose reduction. Dermatological evaluation was performed only in 2 patients treated with bortezomib and 1 with lenalidomide. DISCUSSION: Evaluations of cADR due to bortezomib and lenalidomide were performed. There are no other reports focused on skin events in patients treated with the triple regimen velcade (bortezomib)-thalidomide-dexamethasone (VTD) up to date. Our study suggests that cutaneous toxicities, when researched by Dermatologists, are a side effect even more frequent than the reported data. LIMITATIONS: As it is a single institute and retrospective study, ongoing cADR were rarely evaluated by dermatologists; thus, it is possible that cutaneous reactions (especially mild) may have been under reported by Hematologists and Oncologists in clinical records. CONCLUSIONS: Even with the development of new drugs for cancer treatment, "old" cutaneous side effects may still be present, compromising patients' quality of life. Physicians prescribing bortezomib and lenalidomide should monitor their patients for the spectrum of cADR, and they should involve dermatologists in consultations and management of these events. A multidisciplinary approach is necessary to oncologic patient in order to provide a tailored supportive clinical care. PMID- 23638758 TI - Formal examiner training reflects the increased expertise required of RACS examiners. AB - The Fellowship Examination is the final summative assessment before the Surgical Education and Training trainees are awarded Fellowship of the Royal Australasian College of Surgeons. Conducted in nine specialties, it is aligned with the curriculum of each specialty training programme. The Fellowship Examination focuses on specific surgical competencies; in particular, the clinical application of knowledge, operative decision making and professional judgement. As a true 'exit' examination, it has to be conducted at the correct cognitive level for surgeons about to enter practice without direct supervision. This requires examiners to have specific skills and expertise for which training is required. This paper outlines the process of training undertaken by newly appointed examiners, and describes some of the areas of knowledge that they have to master before examining at the consistently high level that is now expected. PMID- 23638757 TI - High level of resistance in the mosquito Anopheles gambiae to pyrethroid insecticides and reduced susceptibility to bendiocarb in north-western Tanzania. AB - BACKGROUND: To control malaria in Tanzania, two primary vector control interventions are being scaled up: long-lasting insecticide-treated nets (LLINs) and indoor residual spraying (IRS). The main threat to effective malaria control is the selection of insecticide resistance. While resistance to pyrethroids, the primary insecticide used for LLINs and IRS, has been reported among mosquito vectors in only a few sites in Tanzania, neighbouring East African countries are recording increasing levels of resistance. To monitor the rapidly evolving situation, the resistance status of the malaria vector Anopheles gambiae s.l to different insecticides and the prevalence of the kdr resistance allele involved in pyrethroid resistance were investigated in north-western Tanzania, an area that has been subject to several rounds of pyrethroid IRS since 2006. METHODS: Household collections of anopheline mosquitoes were exposed to diagnostic dosages of pyrethroid, DDT, and bendiocarb using WHO resistance test kits. The relative proportions of An. gambiae s.s and Anopheles arabiensis were also investigated among mosquitoes sampled using indoor CDC light traps. Anophelines were identified to species and the kdr mutation was detected using real time PCR TaqMan assays. RESULTS: From the light trap collections 80% of An. gambiae s.l were identified as An. gambiae s.s and 20% as An. arabiensis. There was cross resistance between pyrethroids and DDT with mortality no higher than 40% reported in any of the resistance tests. The kdr-eastern variant was present in homozygous form in 97% of An. gambiae s.s but was absent in An. arabiensis. Anopheles gambiae s.s showed reduced susceptibility to the carbamate insecticide, bendiocarb, the proportion surviving WHO tests ranging from 0% to 30% depending on season and location. CONCLUSION: Anopheles gambiae s.s has developed phenotypic resistance to pyrethroids and DDT and kdr frequency has almost reached fixation. Unlike in coastal Tanzania, where the ratio of An. gambiae s.s to An. arabiensis has decreased in response to vector control, An. gambiae s.s persists at high frequency in north-western Tanzania, probably due to selection of pyrethroid resistance, and this trend is likely to arise in other areas as resistance spreads or is subject to local selection from IRS or LLINs. PMID- 23638760 TI - Effect of surfactant on the drying patterns of graphite nanofluid droplets. AB - We investigate the effect of surfactant on the formation of nanoparticle aggregates that resulted from evaporation of sessile nanofluid droplets theoretically and experimentally. A Monte Carlo model is developed to explain the transition from the coffee-ring pattern to the uniform deposition in drying the pinned sessile nanofluid droplets. The model applies the diffusion limited cluster-cluster aggregation approach coupled with the biased random walk of nanoparticles. The experiments show that the addition of surfactant in nanofluids helps the formation of a coffee ring instead of the uniform domain coverage. The simulations suggest an explanation of this transition by controlling the sticking probability parameter between the particles. The simulated results statistically agree with the experimental observation of the finally dried graphite nanoparticle structures from the pinned nanofluid droplets. PMID- 23638759 TI - Distribution of radioactive cesium in edible parts of cattle. AB - After the disastrous incident of the Fukushima Daiichi Nuclear Power Station, various agricultural, livestock and fishery products have been inspected for radioactive contamination with cesium in Japan. In this study, radioactive cesium was measured in various edible parts of cattle to verify the current inspection method for cattle, in which the neck tissues are generally used as samples. Radioactive cesium concentration in the short plate, diaphragm, liver, lung, omasum, abomasum and small intestine were lower and sirloin, tenderloin, top round meat and tongue were higher than that in the neck. There was no significant difference between the other organs (heart, kidney, lumen and reticulum) and the neck. Ninety-five percent upper tolerance limits of the relative concentration to the neck were 1.88 for sirloin, 1.74 for tenderloin, 1.87 for top round and 1.45 for tongue. These results suggest that a safety factor of 2 is recommended for the radioactivity inspection of cattle to prevent a marketing of meat with higher cesium than the legal limit. Re-inspection should be conducted using another part of muscle, for example, top round, when suspicious levels of 50-100 Bq/kg are detected in the neck. PMID- 23638761 TI - Human alpha- and beta-NRXN1 isoforms rescue behavioral impairments of Caenorhabditis elegans neurexin-deficient mutants. AB - Neurexins are cell adhesion proteins that interact with neuroligin and other ligands at the synapse. In humans, mutations in neurexin or neuroligin genes have been associated with autism and other mental disorders. The human neurexin and neuroligin genes are orthologous to the Caenorhabditis elegans genes nrx-1 and nlg-1, respectively. Here we show that nrx-1-deficient mutants are defective in exploratory capacity, sinusoidal postural movements and gentle touch response. Interestingly, the exploratory behavioral phenotype observed in nrx-1 mutants was markedly different to nlg-1-deficient mutants; thus, while the former had a 'hyper-reversal' phenotype increasing the number of changes of direction with respect to the wild-type strain, the nlg-1 mutants presented a 'hypo-reversal' phenotype. On the other hand, the nrx-1- and nlg-1-defective mutants showed similar abnormal sinusoidal postural movement phenotypes. The response of these mutant strains to aldicarb (acetylcholinesterase inhibitor), levamisole (ACh agonist) and pentylenetetrazole [gamma-aminobutyric (GABA) receptor antagonist], suggested that the varying behavioral phenotypes were caused by defects in ACh and/or GABA inputs. The defective behavioral phenotypes of nrx-1-deficient mutants were rescued in transgenic strains expressing either human alpha- or beta NRXN-1 isoforms under the worm nrx-1 promoter. A previous report had shown that human and rat neuroligins were functional in C. elegans. Together, these results suggest that the functional mechanism underpinning both neuroligin and neurexin in the nematode are comparable to human. In this sense the nematode might constitute a simple in vivo model for understanding basic mechanisms involved in neurological diseases for which neuroligin and neurexin are implicated in having a role. PMID- 23638762 TI - Clinicopathological investigation of vascular endothelial growth factor and von Hippel-Lindau gene-related protein expression in immunohistochemically negative pituitary adenoma--possible involvement in tumor aggressiveness. AB - OBJECTIVES: Immunohistochemically negative pituitary adenoma is known to be relatively indolent, but a few aggressive and highly vascular cases have been reported, which sometimes show high expression of vascular endothelial growth factor (VEGF). METHODS: The present study investigated the relationship between high expression of VEGF and the clinical character of pituitary adenomas in 30 cases of immunohistochemically negative pituitary adenomas using immunohistochemical staining with monoclonal VEGF antibody and related upstream factors, including von Hippel-Lindau gene-related protein (pVHL). Correlations between the histological findings and the clinical characteristics were investigated. RESULTS: Immunohistochemical staining using VEGF antibody showed high expression in 7 (23.3%) and low expression in 23 (76.7%) cases, and pVHL staining showed high expression in 24 (80%) and low expression in 6 (20%) cases. The pVHL low expression group showed significantly higher expression of VEGF (p = 0.005019), and significantly higher recurrence or regrowth rate (p = 0.04535) than the pVHL high expression group, whereas Ki-67 labeling index of >3% also showed significant correlation with recurrence or regrowth rate (p = 0.01745). However, there was no significant correlation between pVHL staining and Ki-67 labeling index (p = 0.49978). CONCLUSION: Low expression of pVHL with high expression of VEGF may be involved in the unusual aggressive clinical course in some pituitary adenomas. PMID- 23638763 TI - Taurodontism: A minor diagnostic criterion in Laurence-Moon/Bardet-Biedl syndromes. AB - OBJECTIVE: The objective of the study was to present the prevalence of taurodontism in the permanent dentition in individuals with Laurence-Moon/Bardet Biedl syndromes (LM/BBS). METHODS AND PARTICIPANTS: Thirty-nine individuals were studied, which comprises the whole population of known LM/BBS patients in Norway. Data were collected retrospectively. Panoramic radiographs (OPG) were evaluated to document taurodontism. RESULTS: Taurodontism was found in 82.9% of the individuals with LM/BBS. The second mandibular molars had the highest (72.3%) prevalence of taurodontism and the first mandibular molars the lowest (58.2%). CONCLUSION: This study suggests that taurodontism should be included as a minor diagnostic criterion for the Laurence-Moon/Bardet-Biedl syndromes (LM/BBS). PMID- 23638764 TI - The plaque- and gingivitis-inhibiting capacity of a commercially available essential oil product. A parallel, split-mouth, single blind, randomized, placebo controlled clinical study. AB - BACKGROUND: Studies have reported commercially available essential oils with convincing plaque and gingivitis preventing properties. However, no tests have compared these essential oils, i.e. Listerine((r)), against their true vehicle controls. OBJECTIVE: To compare the plaque and gingivitis inhibiting effect of a commercially-available essential oil (Listerine((r)) Total Care) to a negative (22% hydro-alcohol solution) and a positive (0.2% chlorhexidine (CHX)) control in an experimental gingivitis model. MATERIALS AND METHODS: In three groups of 15 healthy volunteers, experimental gingivitis was induced and monitored over 21 days, simultaneously treated with Listerine((r)) Total Care (test), 22% hydro alcohol solution (negative control) and 0.2% chlorhexidine solution (positive control), respectively. The upper right quadrant of each individual received mouthwash only, whereas the upper left quadrant was subject to both rinses and mechanical oral hygiene. Plaque, gingivitis and side-effects were assessed at day 7, 14 and 21. RESULTS: After 21 days, the chlorhexidine group showed significantly lower average plaque and gingivitis scores than the Listerine((r)) and alcohol groups, whereas there was little difference between the two latter. CONCLUSION: Listerine((r)) Total Care had no statistically significant effect on plaque formation as compared to its vehicle control. PMID- 23638765 TI - A glimpse into the curricular format of comprehensive care clinics in Brazilian dental schools. AB - OBJECTIVE: This study aimed to describe some curricular aspects of comprehensive dental care clinics in Brazil. MATERIALS AND METHODS: An email survey was sent to all academic affairs deans of Brazilian undergraduate dental programmes. It contained questions regarding the (1) curricular format and (2) characteristics of comprehensive dental care clinics. RESULTS: Sixty-seven dental schools agreed to participate. It was observed that curricular changes have contributed to modify the structure of these clinics in 88.1% of the schools surveyed. The main alteration was related to an increase in credit hours and offer of this type of care at different levels of the dental curriculum. In 95.5% of the schools, clinical procedures were prioritized according to level of complexity. Inter disciplinarity (37.3%) and teaching innovation (58.2%) were frequent challenges in the process of change. Progress in combining teaching and clinical services was reported by 50.8% of schools. In 32.8%, clinical procedures were still being performed intra-murally. CONCLUSIONS: Changes in the curriculum of Brazilian comprehensive dental care clinics were observed by this survey. PMID- 23638766 TI - Temperature increase during orthodontic bonding with different curing units using an infrared camera. AB - AIM: To evaluate the effects of different curing units and light-tip tooth surface distances on the temperature increase generated during orthodontic bonding, using an infrared camera (IR) and artificial neural networks (ANN). MATERIALS AND METHODS: Fifty-two freshly extracted human premolar teeth were used. Metallic orthodontic brackets were bonded to the buccal surfaces of the teeth and thermal records were taken using an IR camera and ANN. Brackets were cured with a light-emitting diode (LED) and high intensity halogen (HQTH). Teeth were divided into four groups according to the curing units (LED and HQTH) and curing distances (from tooth surface and 10 mm away from tooth surface). The results were analyzed with analysis of variance (ANOVA) and the Tukey HSD test. RESULTS: The ANOVA and Tukey HSD tests revealed that temperature changes were influenced by the type of light source and exposure times. All groups revealed significant differences between each other (p < 0.001). The highest surface temperature increase was gained from curing with a LED unit from the tooth surface (11.35 degrees C +/- 0.91 degrees C). The lowest surface temperature increase was gained from curing with a HQTH unit 10 mm away from the tooth surface (2.57 degrees C +/- 0.6 degrees C). CONCLUSION: The LED unit induced significantly higher temperature changes than did the HQTH. The temperature increase during orthodontic bonding was increased with long exposure time. A shorter light-tip tooth surface distance leads to greater increases in temperature. PMID- 23638767 TI - Is congenital malformation a risk factor for caries development in Swedish adolescents? AB - OBJECTIVE: The aim of this study was to investigate whether various forms of congenital malformations are risk factors for approximal caries development in Swedish adolescents. MATERIALS AND METHODS: This longitudinal register-based cohort study included all adolescents (n = 18 142) of 13 years of age who resided in the county of Stockholm, Sweden, in 2000. The cohort was followed until individuals were 19 years of age. Dental caries (decayed, missing and filled teeth/surfaces (DMFT/S)) were collected from the Public Health Care Administration in Stockholm. Data concerning pre- and perinatal factors and parental socio-demographic determinants were collected from Swedish National Registers. RESULTS: In a logistic regression analysis, neither congenital malformation nor any sub-group of congenital malformation registered at birth were significantly associated with an enhanced risk of approximal caries increment in adolescents between 13-19 years of age. The final multivariate logistic regression model, adjusted for possible maternal and family socio demographic confounders, showed that congenital malformation of the 'circulatory system' was significantly associated with a decreased risk of approximal caries increment, between 13-19 years of age (OR = 0.33; 95% CI = 0.12-0.88). CONCLUSIONS: Congenital malformation should not be considered as a risk factor for approximal caries development in Swedish adolescents today. Noticeably, adolescents with congenital heart diseases exhibited less risk of developing approximal caries, which was probably related to prevention programs allocated to these children in Sweden. PMID- 23638768 TI - Antimicrobial efficacy of endodontic irrigants from Azadirachta indica: An in vitro study. AB - OBJECTIVE: This study analyzed the antimicrobial effect of five irrigants formulated from different parts of the tree Azadirachta indica (Neem) and compared with 2.5% sodium hypochlorite and 0.2% chlorhexidine gluconate through an agar diffusion test. MATERIALS AND METHODS: A clinical isolate of Candida albicans was innoculated on Sabourad Dextrose Agar and Enterococcus faecalis (ATCC 29212) on Sheep Blood Agar. Wells with 6 mm diameter were created in agar and 100 MUL aliquiots of each irrigant were introduced to five different wells. After incubation, the largest uniform diameter of the inhibition zone was recorded. RESULTS: The leaf extract of the tree and a mixture of the seed-bark powder dissolved in dimethyl sulfoxide were active against both organisms. The other neem-based irrigants, a leaf powder dissolved in dimethyl sulfoxide, aqueous bark decoction and neem oil, did not possess any antimicrobial efficacy. Sodium hypochlorite completely inhibited growth of C. albicans and the leaf extract had larger inhibition zones than chlorhexidine (p = 0.011) or the seed bark irrigant (p = 0.008). Against E. faecalis, inhibition zones with chlorhexidine were the largest and differed significantly from sodium hypochlorite (p = 0.039), leaf extract (p = 0.008) and seed-bark irrigant (p = 0.011). CONCLUSIONS: Two neem irrigants displayed antimicrobial properties. The efficacy of the standard endodontic irrigants varied depending on the organisms tested. CLINICAL RELEVANCE: Neem-based endodontic irrigants may be formulated for clinical application. PMID- 23638769 TI - Endoscopist specialty is associated with colonoscopy quality. AB - BACKGROUND: Some studies have shown that endoscopist specialty is associated with colorectal cancers missed by colonoscopy. We sought to examine the relationship between endoscopist specialty and polypectomy rate, a colonoscopy quality indicator. Polypectomy rate is defined as the proportion of colonoscopies that result in the removal of one or more polyps. METHODS: A cross-sectional study was conducted of endoscopists and their patients from 7 Montreal and 2 Calgary endoscopy clinics. Eligible patients were aged 50-75 and covered by provincial health insurance. A patient questionnaire assessed family history of colorectal cancer, history of large bowel conditions and symptoms, and previous colonoscopy. The outcome, polypectomy status, was obtained from provincial health administrative databases. For each city, Bayesian hierarchical logistic regression was used to estimate the odds ratio for polypectomy comparing surgeons to gastroenterologists. Model covariates included patient age, sex, family history of colorectal cancer, colonoscopy indication, and previous colonoscopy. RESULTS: In total, 2,113 and 538 colonoscopies were included from Montreal and Calgary, respectively. Colonoscopies were performed by 38 gastroenterologists and 6 surgeons in Montreal, and by 31 gastroenterologists and 5 surgeons in Calgary. The adjusted odds ratios comparing surgeons to gastroenterologists were 0.48 (95% CI: 0.32-0.71) in Montreal and 0.73 (95% CI: 0.43-1.21) in Calgary. CONCLUSIONS: An association between endoscopist specialty and polypectomy was observed in both cities after adjusting for patient-level covariates. Results from Montreal suggest that surgeons are half as likely as gastroenterologists to remove polyps, while those from Calgary were associated with a wide, non-significant Bayesian credible interval. However, residual confounding from patient-level variables is possible, and further investigation is required. PMID- 23638770 TI - Beneficial role of the probiotic mixture Ultrabiotique on maintaining the integrity of intestinal mucosal barrier in DSS-induced experimental colitis. AB - The etiology of inflammatory bowel diseases which include ulcerative colitis (UC) and Crohn disease has not yet been clarified. Several hypotheses suggest a change in composition of gut microflora along with an impaired mucosal barrier that lead to excessive mucosal immunologic responses. Increased production of nitric oxide (NO) contributes greatly to the tissue injury caused by chronic inflammation. Evidence indicates that the mucus layer covering the epithelium is altered during UC and experimental colitis. Our aim in this study was to investigate the potential therapeutic effect of probiotic during DSS-induced colitis by modulating the immune system and colonic mucus production. For that purpose, the probiotic formulation Ultrabiotique((r)) (Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus plantarum and Bifidobacterium breve) was administered daily for 7 d to mice with colitis. Probiotic supplementation improved clinical symptoms and histological alterations observed during DSS induced colitis. Ultrabiotique((r)) treatment down regulated the NO production by peritoneal macrophages of DSS-treated mice and enhanced mucus production in both DSS-treated and healthy mice. In conclusion, the modification of microflora by the Ultrabiotique((r)) played a beneficial role in maintaining the integrity of the intestinal mucosal barrier and promoted tissue repair. PMID- 23638771 TI - Changes of choroidal thickness, intraocular pressure and other optical coherence tomographic parameters after haemodialysis. AB - BACKGROUND: The aim was to evaluate changes in choroidal thickness, intraocular pressure (IOP) and other parameters of optical coherence tomography, such as central foveal thickness (CFT), macular volume, peripapillary retinal nerve fibre layer (RNFL) thickness after haemodialysis (HD). METHODS: Thirty-four eyes of 34 chronic renal failure patients (9 eyes with diabetic patients) who underwent haemodialysis in the Dialysis Unit of Gangneung Asan Hospital were included. CFT, macular volume, peripapillary RNFL and choroidal thickness were measured before and after haemodialysis by optical coherence tomography (OCT, Spectralis; Heidelberg Engineering). Changes in the IOP were evaluated with Goldmann applanation tonometry before and after haemodialysis. RESULTS: The average choroidal thickness decreased significantly, from 233.1 +/- 77.5 MUm to 219.1 +/- 76.8 MUm (paired t-test, p < 0.001). This change correlated with the amount of body weight lost (Pearson's correlation coefficient = 0.348, p = 0.044). The mean IOP decreased from 15.1 +/- 2.6 mmHg to 13.9 +/- 2.2 mmHg after haemodialysis (paired t-test, p = 0.03). The change in macular volume and the small decrease in CFT (214.0 +/- 21.0 MUm to 213.8 +/- 21.8 MUm) were not significant. The measured overall change in RNFL thickness from 93.6 +/- 15.5 MUm to 94.7 +/- 14.6 MUm was not significant. CONCLUSIONS: Haemodialysis can affect various ocular parameters, particularly choroidal thickness and IOP. PMID- 23638772 TI - Electrotriggered, spatioselective, quantitative gene delivery into a single cell nucleus by Au nanowire nanoinjector. AB - Delivery of bioactive materials into a cell is highly important in the study of cell biology and medical treatments. Ideal nanoinjectors should be able to deliver biomaterials with high spatial resolution while causing minimum cell damage. We developed a Au nanowire (NW) nanoinjector that has the thinnest diameter (100-150 nm) among the DNA delivering devices as well as optimum mechanical properties, minimizing cell damage. Well-defined (111) single crystalline Au surface and high electric conductivity of a Au NW nanoinjector allow precisely timed and efficient electrochemical release of DNA molecules attached on a Au NW surface. Both linear DNA and plasmid DNA were delivered separately and showed successful expression. The Au NW nanoinjector would find important biomedical applications in the fields such as gene therapy, DNA vaccination, targeted drug delivery, and probe/control of cell signaling events. PMID- 23638773 TI - Molecular binding behaviors of pyromellitic and naphthalene diimide derivatives by tetrasulfonated 1,5-dinaphtho-(3n+8)-crown-n (n = 8, 10) in aqueous solution. AB - The highly affinitive and selective binding processes of tetrasulfonated 1,5 dinaphtho-38-crown-10 (1(4-)) and tetrasulfonated 1,5-dinaphtho-32-crown-8 (2(4 )) with pyromellitic diimide and naphthalene diimide derivatives bearing cationic terminal groups (PMDI(2+) and NDI(2+)) are comprehensively investigated in aqueous solution by (1)H NMR and UV/vis experiments, mass spectrometry, microcalorimetric titration, and crystallographic analysis. The binding process of host-guest complexation is thermodynamically driven by the large enthalpic gain and favorable entropic change with the high association constants in the range of 10(4)-10(6) M(-1) order of magnitude. Combined with our previously reported thermodynamic data of ethyl viologen (EV(2+)), it is found that the exclusively selective binding behaviors originate from the size/shape matching effect, as well as the electrostatic interaction between negatively charged hosts and positively charged guests and aromatic pi-stacking interrelation between electron-rich donors and electron-deficient acceptors. PMID- 23638775 TI - Is cardiovascular disease in young women overlooked? PMID- 23638774 TI - Influence of navigation system updates on total knee arthroplasty. AB - BACKGROUND: The purpose of this study was to evaluate the influence of image-free computer-assisted navigation system update on outcome in total knee arthroplasty. METHODS: Thirty-three knees were replaced using the Stryker 3.1 image-free navigation system and 49 knees were replaced using the Stryker 4.0 system. One surgeon took part in all procedures as chief surgeon or first assistant. All patients received the Stryker Scopio NRG CR total knee prosthesis. We compared the accuracy of component positioning measured using radiographs and CT scans, operating time and clinical outcome 1 year after surgery. RESULTS: The mean hip knee-ankle, frontal femoral and tibial component angle were 179.8 degrees (ideally implanted 85%), 89.8 degrees (88%), 90.4 degrees (88%) respectively for the 3.1 group and 179.5 degrees (96%), 90.6 degrees (92%), 90.2 degrees (94%) for the 4.0 group. The mean sagittal tibial component angle was 85.5 degrees (82%) for the 3.1 group and 85.6 degrees (92%) for the 4.0 group. The mean rotational femoral and tibial component angle were -0.5 degrees (81%), -0.7 degrees (73%) for the 3.1 group and 0.0 degrees (84%), 0.4 degrees (72%) for the 4.0 group. There were no statistically significant findings with regard to component positioning. Operating time was significantly longer in the 3.1 group (3.1 group: 137 min, 4.1group: 125 min, P < 0.01). No significant difference was detected in postoperative clinical outcome. CONCLUSION: The navigation system update from Stryker 3.1 to Stryker 4.0 reduced operating time by 12 min. However, there were no statistically significant findings with regard to component positioning and clinical outcome. PMID- 23638776 TI - SWAN: key findings to date and more to come. PMID- 23638777 TI - The clinical choice between estrogen and bisphosphonates to prevent bone loss: are women being misled? PMID- 23638779 TI - Unintended pregnancies among U.S. active-duty women. AB - Evaluation of: Grindlay K, Grossman D. Unintended pregnancy among active-duty women in the United States military, 2008. Obstetr. Gynecol. 121(2), 241-246 (2013). This is a study comparing the unintended pregnancy rates of active-duty women in 2008 with those rates in 2005 and the general US population. The data were obtained from the results of the Department of Defense Survey of Health Related Behaviors among active-duty military personnel in 2005 and 2008. The 2008 survey had data from over 7000 surveys, and the 2005 survey had data from over 3000 surveys. The authors found that the unintended pregnancy rate increased from 2005 to 2008, and is approximately 50% greater than that of the US general population. Investigators also found that pregnancy rates were similar amongst women who were recently deployed. There were higher rates among younger, less educated, nonwhite and married/cohabitating women. PMID- 23638780 TI - Endometriosis: an update on management. AB - Endometriosis is an inflammatory disease that commonly occurs in women of reproductive age and is associated with pain and infertility. This disease can be challenging to manage given its propensity to progress and recur despite treatment. Although medical therapy is beneficial for controlling pain due to endometriosis, medical management has not proven to be effective in treating infertility resulting from endometriosis. Surgery has historically been performed to both improve pain and treat infertility in women with endometriosis. However, the optimal management of endometriosis in asymptomatic women who desire fertility is unclear. Intrauterine insemination with superovulation and IVF are other treatments that have proven to be effective in assisting women with endometriosis to conceive. As the underlying molecular mechanisms of this disease become better understood, promising new therapies for the treatment of endometriosis continue to be investigated. PMID- 23638781 TI - A psychological view of sexual pain among women: applying the fear-avoidance model. AB - AIM: The purpose of this paper is to examine how well research findings on dyspareunia (intercourse pain) fit the fear-avoidance (FA) model on pain. RESULTS: The evidence suggests that the experience of pain in dyspareunia functions similarly to the pain reported in other pain conditions. There are also accumulating data showing that the central mechanisms of the FA model, such as catastrophizing, fear, hypervigilance and disability, are central to the experience of sexual pain. However, there are also some potential differences between sexual pain and other pain conditions that demand further attention in terms of the role of the partner, specific emotional consequences of avoidance and the effect of hypervigilance on sexual arousal. CONCLUSION: The results demonstrate the relevance of the FA model in sexual pain. They also imply that treatment methods for fear and avoidance in other pain conditions offer new avenues for treating sexual pain problems in the clinic. Future studies should focus on expanding how the mechanisms in the FA model contribute to sexual pain, as well as how treatments based on the model may be applied clinically. PMID- 23638783 TI - Alzheimer's disease, dementia, mild cognitive impairment and the menopause: a 'window of opportunity'? AB - Alzheimer's disease (AD) is not an inevitable consequence of aging and may be modified by both adverse and protective factors. The pathological changes of AD commence in midlife and AD has a long preclinical phase that may be diagnosed by biomarkers in the cerebrospinal fluid and by brain MRI. New clinical criteria for the diagnosis of AD dementia and AD mild cognitive impairment (MCI) have been proposed. MCI and dementia are frequently the result of AD and cerebrovascular disease combined. Over the age of 85 years, MCI and dementia are more common in women than in men. Women with a surgical premature menopause have an increased risk of MCI and AD. Menopausal hormone therapy from the menopause to the age of 60 years, when any risks of menopausal hormone therapy are extremely small, may provide a 'window of opportunity' to reduce the risk of MCI and AD in later life. Many measures may help to prevent, delay or minimize AD in both women and men and should be actively encouraged. PMID- 23638782 TI - Vaginal childbirth and pelvic floor disorders. AB - Childbirth is an important event in a woman's life. Vaginal childbirth is the most common mode of delivery and it has been associated with increased incidence of pelvic floor disorders later in life. In this article, the authors review and summarize current literature associating pelvic floor disorders with vaginal childbirth. Stress urinary incontinence and pelvic organ prolapse are strongly associated with vaginal childbirth and parity. The exact mechanism of injury associating vaginal delivery with pelvic floor disorders is not known, but is likely multifactorial, potentially including mechanical and neurovascular injury to the pelvic floor. Observational studies have identified certain obstetrical exposures as risk factors for pelvic floor disorders. These factors often coexist in clusters; hence, the isolated effect of these variables on the pelvic floor is difficult to study. PMID- 23638784 TI - Difficulty associated with donning medical compression stockings: results from a survey comparing two different compression stockings. AB - AIM: Although medical compression stockings (MCSs) represent the cornerstone of conservative treatment for patients with chronic venous disease, high rates of noncompliance exist. This study compared comfort levels and the difficulty associated with putting on/removing two different MCSs; a conventional degressive MCS (ankle pressure: 24-28 mmHg; calf pressure: 14-18 mmHg) and a progressive MCS (ankle pressure: 8-12 mmHg; calf pressure: 21-25 mmHg). PATIENTS & METHODS: Women wearing class III MCSs in the past 3 months were recruited from across France to complete an at-home, investigator-led questionnaire, designed to evaluate their experience with putting on/taking off MCSs. Patients were randomized to two groups (group 1: controls, degressive stocking right leg, then left leg; group 2: degressive stocking right leg, then progressive stocking left leg). RESULTS & CONCLUSION: Patients (n = 102) in group 1 (controls) reported no differences after wearing the degressive MCS on the right leg then the left leg. By contrast, group 2 patients (n = 118) reported statistically significant improvements with the progressive MCS compared with the degressive MCS in all questionnaire parameters, including 'comfort' and 'ease of putting on/taking off' dimensions. Progressive MCSs were associated with significantly better outcomes (ease of putting on/taking off and comfort) than the conventional MCSs. PMID- 23638787 TI - Making the most of partnerships. PMID- 23638788 TI - Teaching patient safety with a functional electronic medication record. PMID- 23638785 TI - Developing an intervention to address physical activity barriers for African American women in the deep south (USA). AB - AIM: To address high rates of inactivity and related chronic diseases among African-American women. MATERIALS & METHODS: Eleven focus groups on physical activity barriers for African-American women in the deep south (USA) were conducted (n = 56). Feedback guided an intervention development process. The resulting Home-Based Individually Tailored Physical Activity Print intervention was vetted with the target population in a 1-month, single arm, pre-post test demonstration trial (n = 10). RESULTS: Retention was high (90%). Intent-to-treat analyses indicated increases in motivational readiness for physical activity (70% of sample) and physical activity (7-day Physical Activity Recall) from baseline (mean: 89.5 min/week, standard deviation: 61.17) to 1 month (mean: 155 min/week, standard deviation: 100.86). Small improvements in fitness (6-Min Walk Test), weight and psychosocial process measures were also found. CONCLUSION: Preliminary findings show promise and call for future randomized controlled trials with larger samples to determine efficacy. Such low-cost, high-reach approaches to promoting physical activity have great potential for addressing health disparities and benefiting public health. PMID- 23638789 TI - Use of children's literature to teach nursing students about stroke. PMID- 23638790 TI - Hypothesis of peripheral nerve regeneration induced by terminal effectors. AB - Peripheral nerve injury (PNI) is a common trauma in clinical practice. A number of techniques to deal with PNI repair have been designed in clinics. From these methods for nerve repairing shown to be effective in clinics, as well as related experiments, we formulated a hypothesis that PNI regeneration and functional repair are induced by terminal effectors. Regeneration of peripheral nerves is the process whereby the nerve fibers regenerated by the induction of terminal effectors establish connections with effector organs and induce the spinal cord and upper centers to recognize effector organs and to re-model them for effective innervations. The hypothesis has two major components: (1) after surgical repairing of the injured nerves, the functional localization of regenerated nerves is determined by the connected effector organs and (2) the upper nervous system enables structural remodeling and functional changes according to the functions of the effector organs. PMID- 23638791 TI - Validation of accuracy of three-dimensional left atrial CartoSoundTM and CT image integration: influence of respiratory phase and cardiac cycle. AB - BACKGROUND: CartoSoundTM (CS) module is useful in integrating 3-dimensional (3D) left atrial (LA) image with CT image. Integration method, however, has not been established. We reported the accuracy of LA electroanatomical (EA) and CT image integration by registering LA roof (LAR) and posterior wall (LAPW). METHODS: The consecutive 56 atrial fibrillation patients undergoing pulmonary vein isolation were studied. In the initial 29 patients, before the transseptal puncture, 3D CS LAR and LAPW image was created by registering a mean of 10 contour lines between the right and left pulmonary veins. After transseptally inserting a mapping catheter into LA, 3D EA image of LAR and LAPW was obtained by sampling a mean of 40 points. LA CT image was taken at the full-inspiratory position and 0% of R-R interval. After visual alignment of CS or EA and LA CT image, the 2 images were integrated with surface registration program. In the latter 27 patients, both CT and CS images were taken while matching the respiratory phase at the end-tidal position and cardiac cycle at 50% of R-R interval. RESULTS: In the initial 29 patients, the mean distances between EA and CT images and between CS and CT images were 1.53 +/- 0.27 and 1.59 +/- 0.23 mm, respectively (P = NS). In the latter 27, the mean distance was decreased to 1.08 +/- 0.14 mm (P < 0.0001). CONCLUSIONS: CS system is useful in image integration with 3D CT. Matching both respiratory phase and cardiac cycle between CS and CT image acquisition improves the image integration accuracy. PMID- 23638792 TI - Neutron encoded labeling for peptide identification. AB - Metabolic labeling of cells using heavy amino acids is most commonly used for relative quantitation; however, partner mass shifts also detail the number of heavy amino acids contained within the precursor species. Here, we use a recently developed metabolic labeling technique, NeuCode (neutron encoding) stable isotope labeling with amino acids in cell culture (SILAC), which produces precursor partners spaced ~40 mDa apart to enable amino acid counting. We implement large scale counting of amino acids through a program, "Amino Acid Counter", which determines the most likely combination of amino acids within a precursor based on NeuCode SILAC partner spacing and filters candidate peptide sequences during a database search using this information. Counting the number of lysine residues for precursors selected for MS/MS decreases the median number of candidate sequences from 44 to 14 as compared to an accurate mass search alone (20 ppm). Furthermore, the ability to co-isolate and fragment NeuCode SILAC partners enables counting of lysines in product ions, and when the information is used, the median number of candidates is reduced to 7. We then demonstrate counting leucine in addition to lysine results in a 6-fold decrease in search space, 43 to 7, when compared to an accurate mass search. We use this scheme to analyze a nanoLC-MS/MS experiment and demonstrate that accurate mass plus lysine and leucine counting reduces the number of candidate sequences to one for ~20% of all precursors selected, demonstrating an ability to identify precursors without MS/MS analysis. PMID- 23638795 TI - New graduate nurses as knowledge brokers in general practice in New Zealand: a constructivist grounded theory. AB - Practice nursing in New Zealand is not well described in the literature. One survey illustrated that most of the New Zealand practice nurses sampled did not know of the country's two premier evidence-based health websites. A recent review compared general practice in the UK, New Zealand and Australia and found that whereas there had been significant developments in empowering the practice nurse workforce to run nurse-led clinics in the UK, New Zealand and Australia lagged behind. The aim of this reported constructivist grounded theory study was to investigate practice nurses' use of information. Conducted in Auckland, New Zealand, data were collected through ethnographic techniques in one general practice between September 2009 and January 2010 to enhance theoretical sensitivity to the area of information use. Subsequently, six experienced practice nurses (one twice after moving jobs) and five new graduate nurses from five different general practices were interviewed, using open-ended questions, between January 2010 and August 2011. Concurrent data collection and analysis occurred throughout the study period. The use of memos, the constant comparative method, data categorisation and finally, data abstraction resulted in the final theory of reciprocal role modelling. Experienced practice nurses role modelled clinical skills to new graduate nurses. Unexpectedly, new graduate nurses were unconscious experts at sourcing information and role modelled this skill to experienced practice nurses. Once this attribute was acknowledged by the experienced practice nurse, mutual learning occurred that enabled both groups of nurses to become better practitioners. Graduate nurses of the millennial generation were identified as a resource for experienced practice nurses who belong to the baby boomer generation and generation X. PMID- 23638794 TI - PrP(C) regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells. AB - The prion protein (PrP) plays a key role in prion disease pathogenesis. Although the misfolded and pathologic variant of this protein (PrP(SC)) has been studied in depth, the physiological role of PrP(C) remains elusive and controversial. PrP(C) is a cell-surface glycoprotein involved in multiple cellular functions at the plasma membrane, where it interacts with a myriad of partners and regulates several intracellular signal transduction cascades. However, little is known about the gene expression changes modulated by PrP(C) in animals and in cellular models. In this article, we present PrP(C)-dependent gene expression signature in N2a cells and its implication in the most overrepresented functions: cell cycle, cell growth and proliferation, and maintenance of cell shape. PrP(C) over expression enhances cell proliferation and cell cycle re-entrance after serum stimulation, while PrP(C) silencing slows down cell cycle progression. In addition, MAP kinase and protein kinase B (AKT) pathway activation are under the regulation of PrP(C) in asynchronous cells and following mitogenic stimulation. These effects are due in part to the modulation of epidermal growth factor receptor (EGFR) by PrP(C) in the plasma membrane, where the two proteins interact in a multimeric complex. We also describe how PrP(C) over-expression modulates filopodia formation by Rho GTPase regulation mainly in an AKT-Cdc42-N-WASP dependent pathway. PMID- 23638793 TI - Efficacy of using cancer stem cell markers in isolating and characterizing liver cancer stem cells. AB - Recent evidence suggests that a subset of hepatocellular carcinomas (HCCs) are derived from liver cancer stem cells (LCSCs). In order to isolate and characterize LCSCs, reliable markers that are specific to these cells are required. We evaluated the efficacy of a range of cancer stem cell (CSC) markers in isolating and characterizing LCSCs. We show that the most widely used CSC markers are not specific to LCSCs. By western analysis, protein expression of the common markers showed no significant difference between HCC tumor tissues and adjacent non-cancerous liver. Further, isolation of LCSCs from common HCC cell lines using FACScan and microbeads showed no consistent marker expression pattern. We also show that LCSCs have unique subtypes. Immunohistochemistry of HCC tissues showed that different HCCs express unique combinations of LCSC markers. Quantitative real-time polymerase chain reaction analysis showed that LCSCs isolated using different markers in the same HCC phenotype had different expression profiles. Likewise, LCSCs isolated from different HCC phenotypes with the same marker also had unique expression profiles and displayed varying resistance profiles to Sorafenib. Thus, using a range of commonly used CSC markers in HCCs and cell lines, we demonstrate that currently available markers are not specific for LCSCs. LCSCs have unique subtypes that express distinctive combinations of LCSC markers and altered drug resistance profiles, making their identification problematic. PMID- 23638800 TI - Optimizing image guidance frequency and implications on margins for gynecologic malignancies. AB - BACKGROUND: To analyze setup deviations using daily megavoltage computed tomography (MVCT) and to evaluate three MVCT frequency reducing protocols for gynecologic cancer patients treated with helical tomotherapy. METHODS: We recorded the setup errors of 56 patients with gynecological cancer observed throughout their whole course by matching their daily MVCT with the planning CT. Systematic and random errors were calculated on a patient and population basis. We defined three different protocols corresponding to MVCTs from the first five fractions (FFF), the first ten fractions (FTF) or from the first and third weeks (505). We compared theoretical. setup errors calculated using these 5 or 10 early MVCT scans with the actual errors found with the remaining fractions to to analyze the residual deviations. RESULTS: The total systematic (random) deviations had means of -2.0 (3.8)mm, 0.5 (3.4)mm, 0.5 (6.1)mm and -0.5 degrees (0.9 degrees ) in vertical (V), longitudinal (LO), lateral (LA), and roll (R) directions, respectively. The proposed three MVCT protocols resulted in minor residual deviations. In all three protocols, 95% of all calculated residual deviations were less than or equal to 5 mm in all 3 directions. When examining the additional minimal CTV-PTV setup margins that were calculated based on these residual deviations, the 505 protocol would have allowed smaller margins than the FFF and FTF protocol, particularly in the V direction. CONCLUSIONS: For patients with gynecologic cancer, the 505-protocol led to the lowest residual deviations and therefore might offer the best approach in reducing the frequency of pre treatment MVCTs. PMID- 23638799 TI - Consumption of low-fat dairy foods for 6 months improves insulin resistance without adversely affecting lipids or bodyweight in healthy adults: a randomized free-living cross-over study. AB - BACKGROUND: Given the highly debated role of dairy food consumption in modulating biomarkers of metabolic syndrome, this study was conducted to examine the influence of long-term (6 month) dairy consumption on metabolic parameters in healthy volunteers under free-living conditions without energy restriction. METHODS: Twenty-three healthy subjects completed a randomized, crossover trial of 12 months. Participants consumed their habitual diets and were randomly assigned to one of two treatment groups: a high dairy supplemented group instructed to consume 4 servings of dairy per day (HD); or a low dairy supplemented group limited to no more than 2 servings of dairy per day (LD). Baseline, midpoint, and endpoint metabolic responses were examined. RESULTS: Endpoint measurements of body weight and composition, energy expenditure, blood pressure, blood glucose, and blood lipid and lipoprotein responses did not differ (p > 0.05) between the LD and HD groups. HD consumption improved (p < 0.05) plasma insulin (-9%) and insulin resistance (-11%, p = 0.03) as estimated by HOMA-IR compared with the LD group. CONCLUSIONS: Study results suggest that high dairy consumption (4 servings/d) may improve insulin resistance without negatively impacting bodyweight or lipid status under free-living conditions. TRIAL REGISTRATION: Clinical Trials.gov: NCT01761955. PMID- 23638801 TI - A survey of fermentation products and bacterial communities in corn silage produced in a bunker silo in China. AB - To evaluate the current practice of corn silage management in China, samples of bunker-made silage were collected from 14 farms within a 500-km radius of Beijing for the analysis of fermentation products and bacterial communities. Mean values for dry matter (DM) content were as low as 250 g/kg in both corn stover (St) and whole crop corn (Wc) silages, and pH values averaged 4.48 and 3.73, respectively. Only three of the 14 silages exhibited a lactic-to-acetic acid ratio > 1.0, indicating that the presence of acetic acid was predominant in fermentation. Although 1,2-propanediol content was marginal in most cases (< 5.0 g/kg dry matter (DM)), two Wc silages had 1,2-propanediol levels > 25 g/kg DM. In contrast, 3 St silages had large amounts (> 10 g/kg DM) of butyric acid, and two of the three butyrate silages also had high concentrations of 1-propanol. Denaturing gradient gel electrophoresis analysis demonstrated that the bacterial community appeared similar in 10 out of the 14 silage samples. Bands indicating Lactobacillus buchneri, L. acetotolerans and Acetobacter pasteurianus were found in both the St and Wc silages, accounting for the high acetic acid content found across silage samples. PMID- 23638798 TI - Death receptors as targets in cancer. AB - Anti-tumour therapies based on the use pro-apoptotic receptor agonists, including TNF-related apoptosis-inducing ligand (TRAIL) or monoclonal antibodies targeting TRAIL-R1 or TRAIL-R2, have been disappointing so far, despite clear evidence of clinical activity and lack of adverse events for the vast majority of these compounds, whether combined or not with conventional or targeted anti-cancer therapies. This brief review aims at discussing the possible reasons for the lack of apparent success of these therapeutic approaches and at providing hints in order to rationally design optimal protocols based on our current understanding of TRAIL signalling regulation or resistance for future clinical trials. LINKED ARTICLES: This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8. PMID- 23638802 TI - Assessment of ocular neurotoxicity in patients treated with systemic cancer chemotherapeutics. AB - PURPOSE: Cisplatin and Paclitaxel are two chemotherapeutic agents known to produce neurotoxicity when used for cumulative dose regimens. In this study we aim to assess their toxicity in the optic nerve, and to evaluate the retinal nerve fibre layer (RNFL) thickness and visual field changes in lung cancer patients treated with Cisplatin and Paclitaxel. METHODS: Fifteen patients who were treated intravenously with 75 mg/m(2) cisplatin and 175 mg/m(2) paclitaxel every 3 weeks, up to a maximum of six courses, were enrolled in this prospective clinical trial. All patients underwent complete ophthalmological assessments before their treatments began, as well as three months after the completion of their treatments. The RNFL thickness measurements were performed using optical coherence tomography (OCT). Functional testing included the use of frequency doubling technology (FDT) perimetry and the Humphrey visual field analyser (HFA). The main outcome measurements included the average RNFL thicknesses and visual field indices (mean deviation [MD] and pattern standard deviation [PSD]). RESULTS: The median age of the 15 patients (nine male and six female) was 63.49 years old (range: 53-77). The average RNFL thickness measurement during the baseline examination was 103.73 MUm (range: 97-111). Three months after the cessation of treatment the RNFL thickness declined to 97.4 MUm (range: 91-102). Statistical analysis showed a significant thinning between the two measurements (p = 0.032). The MD and PSD values recorded by the HFA demonstrated no statistically significant changes 3 months after the cessation of treatment (p > 0.207 and p > 0.186, respectively). There were statistically significant decreases in both the MD (0.48 to -1.13 dB) and PSD (2.13 to 0.65 dB) indices measured by the FDT perimetry (p = 0.041 and p = 0.025, respectively). CONCLUSIONS: In our study, the systemic administration of Cisplatin and Paclitaxel affected the peripapillary RNFL thicknesses and visual field indices as revealed by FDT perimetry. OCT and FDT perimetry may be adjunctive tools for the screening of ocular toxicity in patients treated with these agents. PMID- 23638803 TI - Functional and anatomical results after a single intravitreal Ozurdex injection in retinal vein occlusion: a 6-month follow-up -- the SOLO study. AB - PURPOSE: To evaluate the efficacy of intravitreal dexamethasone implants in eyes with cystoid macular oedema (CME) secondary to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) in the clinical everyday practice, examine the effects of early retreatment and compare the results with the GENEVA study. METHODS: The charts of 102 patients (102 eyes) with CME secondary to BRVO (n = 54) or CRVO (n = 48) treated with Ozurdex at 8 centres were retrospectively reviewed. The patients were examined monthly over a 24-week period. Slit-lamp biomicroscopy, measurement of best-corrected visual acuity (BCVA) and measurement of the central retinal thickness (CRT) with spectral domain optical coherence tomography (SD-OCT) were performed at baseline and at every follow-up examination. With progression of the disease (loss of one line or increased central retinal thickness (CRT) of 150 MUm), a reinjection of Ozurdex or anti-VEGF was offered. Additional supplementing sectorial or panretinal laser photocoagulation was considered based on the individual status of the retina. RESULTS: In the BRVO group, the median BCVA was 0.6 logMAR (Snellen equivalent of 0.25) at baseline and improved to 0.4 logMAR (Snellen equivalent of 0.40) after 4 weeks, 0.3 logMAR (Snellen equivalent of 0.50) after 8 weeks, 0.4 logMAR (Snellen equivalent of 0.40) after 12 weeks, 0.5 logMAR (Snellen equivalent of 0.32) after 16 weeks, 0.4 logMAR (Snellen equivalent of 0.40) after 20 weeks and 0.45 logMAR (Snellen equivalent of 0.35) after 24 weeks. The mean CRT was 559 +/- (SD) 209 MUm at baseline and it decreased to 335 +/- 148 MUm after 4 weeks, 316 +/- 137 MUm after 8 weeks, 369 +/- 126 MUm after 12 weeks, 407 +/- 161 MUm after 16 weeks, 399 +/- 191 MUm after 20 weeks and 419 +/- 196 MUm after 24 weeks. In the CRVO group, the median BCVA was 0.7 logMAR (Snellen equivalent of 0.20) at baseline and improved to 0.4 logMAR (Snellen equivalent of 0.40) after 4 weeks, 0.4 logMAR (Snellen equivalent of 0.40) after 8 weeks, 0.6 logMAR (Snellen equivalent of 0.25) after 12 weeks, 0.6 logMAR (Snellen equivalent of 0.25) after 16 weeks, 0.5 logMAR (Snellen equivalent of 0.32) after 20 weeks and 0.52 logMAR (Snellen equivalent of 0.30) after 24 weeks. The mean CRT at baseline was 740 +/- 351 MUm and it decreased to 419 +/- 315 MUm after 4 weeks, 352 +/- 261 MUm after 8 weeks, 455 +/- 251 MUm after 12 weeks, 497 +/- 280 MUm after 16 weeks, 468 +/- 301 MUm after 20 weeks and 395 +/- 234 MUm after 24 weeks. The BCVA improvement was statistically significantly better (p < 0.05) compared with baseline in both groups at every follow-up visit. The mean CRT maintained significantly better when compared with baseline in both groups at all follow-up visits. Early reinjection was indicated in BRVO in 40.7% after 17.5 +/- 4.2 weeks and in CRVO in 50% after 17.68 +/- 4.2. Six eyes (11%) with BRVO received a sectorial laser photocoagulation at a mean interval of 22 +/- 5.0 weeks. Seven eyes (15%) with CRVO received a panretinal laser photocoagulation after a mean interval of 18 +/- 7.0 weeks. The BCVA improvement and the mean CRT reduction were statistically significant (p < 0.05) compared with baseline in both groups at every follow-up visit. CONCLUSIONS: Dexamethasone intravitreal implant resulted in a significant improvement of the BCVA and reduction of CME in patients with BRVO or CRVO. Early retreatment after 16 weeks instead of 24 weeks, like in the GENEVA study, was indicated in 50% to stabilize the improved functional and anatomical results. PMID- 23638806 TI - Correlation between perceived experience of caries disease and recorded caries activity among adult patients at a Swedish Public Dental Clinic: A longitudinal study. AB - OBJECTIVE: To compare patients' perceived experiences of caries activity with recorded longitudinal caries prevalence, consequences of caries and length of recall intervals. MATERIALS AND METHODS: A questionnaire was mailed to 134 caries active (CA) and 40 caries inactive (CI) adult patients at a Swedish Public Dental Clinic. The overall response rate was 69%. The questionnaire included items regarding perceived caries activity, general health, dietary and oral hygiene habits, level of education and socioeconomic status. Questionnaire responses were studied for their association to clinical data extracted from patient dental records. RESULTS: There was a correlation between patient-perceived and documented caries activity for all respondents (rho = 0.65; p < 0.001). CA patients had significantly more perceived caries activity (p < 0.001), decayed teeth (p < 0.001), root fillings (p = 0.001) and extractions (p < 0.001) than CI patients. The mean recall interval was 1.5 years for CA and 2.1 years for CI (p < 0.001). In multiple logistic regression analysis, CA patients were at increased risk for xerostomia (OR = 22.66, p = 0.003), sleep disturbances (OR = 4.36, p = 0.04) and more frequent use of daily extra fluoride (OR = 3.58, p = 0.03). CONCLUSIONS: Patient-perceived experience of caries correlated well with recorded caries activity in this group of middle-aged Swedish adults. Individuals with active caries were aware of their disease and made more frequent attempts to reduce caries activity by use of daily extra fluoride. Individual risk-based recall intervals did not seem to eliminate consequences of disease activity such as root fillings and extractions during the follow-up period. PMID- 23638805 TI - Association between HLA genes and American cutaneous leishmaniasis in endemic regions of Southern Brazil. AB - BACKGROUND: The present study sought to investigate the association between HLA A, HLA-B and HLA-DRB1 genes and susceptibility or resistance to the different clinical manifestations of American cutaneous leishmaniasis (ACL) in southern Brazil. METHODS: The sample consisted of 169 patients with a diagnosis of ACL and 270 healthy subjects for comparison. HLA-A, HLA-B and HLA-DRB1 were typed by PCR SSO reverse dot blot. RESULTS: Results showed a trend towards susceptibility to cutaneous lesions for alleles HLA-DRB1*13 (P=0.0228; Pc=0.3420; OR=1.66; 95%CI=1.08 - 2.56), HLA-B*35 (P=0.0218; Pc=0.6758; OR=1.67; 95%CI=1.08 - 2.29) and HLA-B*44 (P=0.0290; Pc=0.8990; OR=1.67; 95%CI=1.05 - 2.64). Subjects with allele HLA-B*27 (P=0.0180; Pc=0.5580; OR=7.1111; 95%CI=1.7850 - 28.3286) tended towards susceptibility to mucocutaneous lesions, those with HLA-B*49 (P=0.0101; Pc=0.3131; OR=6.4000; 95%CI=1.8472 - 22.1743) to recurrent ACL, and HLA-B*52 (P=0.0044; Pc=0.1360; OR=12.61; 95%CI=3.08 - 51.66), to re-infection. Presence of HLA-B*45 (P=0.0107; Pc=0.3317) tended to provide protection against the cutaneous form of ACL. The most frequent haplotypes that may be associated with susceptibility to ACL were A*02 B*44 DRB1*07 (P = 0.0236) and A*24 B*35 DRB1*01 (P = 0.0236). CONCLUSION: Some Class I and Class II HLA genes appear to contribute towards susceptibility to and protection against different clinical manifestations of ACL. Other genetic marker studies may contribute toward future prophylactic and therapeutic interventions in ACL. PMID- 23638807 TI - Autotransplantation of maxillary second premolars to mandibular recipient sites where the primary second molars were impacted, predisposes for complications. AB - OBJECTIVE: The aim of the study was to elucidate whether ankylosis of a transplanted permanent tooth can be predicted based on an evaluation of the primary and permanent dentitions. MATERIALS AND METHODS: The study comprised 162 maxillary second premolars and 49 third molars transplanted to the mandibular second premolar region in 157 patients treated in the period 1980-2003. SELECTION CRITERIA: panoramic radiograph available; agenesis of the mandibular permanent premolar/s; persistence of the primary molar at the recipient site. The 211 transplanted teeth were observed for a period of between 1-29 years. RESULTS: Seven per cent (95% confidence interval, CI = 3-11%) of the transplanted second premolars ankylosed during the first 10 years after operation. The success rate for transplantation of the third molar to the mandibular second premolar region was significantly lower (p = 0.001), as 40% (95% CI = 24-57%) of the third molars had ankylosed 10 years after operation. A significant association (p = 0.022) was found between ankylosis of a second premolar and infra-position of the primary second molar located at the recipient site. The infraposition group had 13% (CI = 4-23%) ankylosis after 10 year, whereas the non-infraposition group had 5% (CI = 1-9%) ankylosis after 10 years. CONCLUSIONS: The present study concludes that there is an increased risk of ankylosis of the transplanted permanent tooth if the primary tooth at the recipient site is in infraposition. This observation may be decisive for treatment planning, especially in young individuals in whom excessive growth of the alveolar process is expected from the cephalometric analysis. PMID- 23638808 TI - Autotransplantation and surgical uprighting of impacted or retained teeth: A retrospective clinical study and evaluation of patient satisfaction. AB - OBJECTIVES: This retrospective clinical study aimed to determine the success rate of autotransplanted impacted or retained teeth along with a patient satisfaction survey and to analyze the influence of relevant clinical and radiographic parameters. SUBJECTS AND METHODS: Fifty-seven teeth (37 canines, 10 molars, seven premolars, three incisors) in 45 patients (median 15 years) were evaluated over a mean of 1.6 years. The success criteria were pocket probing depth <=3.5 mm, mobility grade <= II, Periotest <=30 and complete alveolar bone healing. The influencing parameters were oral hygiene, smoking, periodontal screening index, occlusal/proximal contacts, horizontal position, dental age, pulp obliteration and degree of displacement. Furthermore, bone height was measured. RESULTS: The overall success rate was 74%, along with a high patient satisfaction. The survival rate was 96% after a mean follow-up of 1.6 years. The favorable factors were proper oral hygiene, non-smoking, good general periodontal condition, proximal contacts and pulp obliteration. An increase in or maintenance of bone level was found in 96%. CONCLUSIONS: Autotransplantation of impacted or retained teeth is an appropriate treatment, if orthodontic alignment has failed, especially in growing patients. PMID- 23638809 TI - Effect of pine bark extract on bond strength of brackets bonded to bleached human tooth enamel. AB - AIM: The purpose was to investigate the effect of pine bark (proanthocyanidin, natural antioxidant) solution on the shear bond strength (SBS) of metal brackets bonded with composite resin to human enamel after bleaching with hydrogen peroxide (HP). MATERIALS AND METHODS: Sixty recently extracted premolars were divided into an experimental group (n = 45), which was bleached with 40% HP, and a control group (n = 15), which was not bleached. The experimental group was further divided into three sub-groups. Specimens in group IB (n = 15) were bonded immediately after bleaching; specimens in group SA (n = 15) were bleached, then treated with 10% sodium ascorbate and then bonded; group PB specimens (n = 15) were bleached, then treated with 5% pine bark solution and bonded. The specimens were debonded with Universal testing machine. The adhesive remnant index was calculated. RESULTS: No significant differences in shear bond strength were noted when the pine bark treated group was compared with the control group and sodium ascorbate group (p > 0.05). Treating the bleached enamel surface with 10% sodium ascorbate or 5% pine bark solution reverses the SBS reduction. CONCLUSION: So, as a natural antioxidant and less hazardous, clinicians can choose pine bark solution instead of sodium ascorbate. PMID- 23638810 TI - Detection of sulphate-reducing bacteria in human saliva. AB - OBJECTIVE: The aim of the current study was to investigate the presence of sulphate-reducing bacteria (SRB) in human saliva and correlate with oral and systemic conditions. METHODS: Saliva samples were collected from 118 patients and inoculated in 2 ml of modified Postgate's E medium culture. After 28 days of incubation at 30 degrees C the presence of SRB was identified by the production of sulphide. RESULTS: Of 118 saliva samples collected, 35 were positive for the presence of SRB. Three positive samples were randomly chosen to identify the species of SRB by PCR and sequenced. The three selected samples were identified as Desulfovibrio fairfieldensis, Desulfovibrio desulfuricans and Raoultella ornithinolytica. Gastritis (14.4%) was the most prevalent systemic disease, followed by diabetes (3.4%), while periodontitis (11%) and traumatic fibroma (4.2%) were the oral manifestations most frequently found. A bivariate analysis was performed to examine for the presence of SRB and the most prevalent systemic and oral manifestations. Only periodontitis showed a statistically significant association (p = 0.0003). CONCLUSIONS: The results showed SRB can be found in oral microbiota of healthy patients. Regarding the several conditions studied, there was a higher prevalence of SRB in patients with gastritis and patients with periodontal disease, with a possible correlation between the presence of SRB in the oral microbiota and periodontal disease. PMID- 23638811 TI - Synthesis of fluorine-labeled peptide nucleic acid building blocks as sensors for the 19F NMR spectroscopic detection of different hybridization modes. AB - Peptide nucleic acid (PNA) building blocks, bearing a fluorine sensor at C-5 of the uracil base [viz. trifluoromethyl and 3,3-bis(trifluoromethyl)-4,4,4 trifluorobut-1-ynyl], were synthesized and incorporated to a PNA strand, and their applicability for the monitoring of different hybridization modes by (19)F NMR spectroscopy was studied. Both sensors gave unique (19)F resonance shifts in NMR when the PNA was targeted to a complementary antiparallel DNA, antiparallel RNA, parallel DNA, and parallel RNA. The 5-trifluoromethyl-derived sensor was additionally applied for the monitoring of interconversions from a parallel DNA/PNA complex to an antiparallel RNA/PNA complex and from a PNA/PNA complex to two DNA/PNA complexes (i.e., double-duplex invasion). PMID- 23638812 TI - Diagnostics for tuberculosis: what test developers want to know. PMID- 23638815 TI - Distinct miRNA profiles are associated with malignant transformation of pancreatic cystic tumors revealing potential biomarkers for clinical use. AB - Pancreatic cysts are now being detected more frequently owing to increased recognition and the liberal use of cross-sectional imaging. There is a spectrum of pancreatic cystic lesions ranging from the completely benign inflammatory to the highly malignant. Pancreatic cystic tumors, especially those with a mucinous epithelial lining such as the intraductal papillary mucinous neoplasms (IPMNs), have the potential to become malignant. The evaluated paper provides further evidence for miRNAs as diagnostic biomarkers for detecting dysplastic and malignant change in IPMNs, which may be useful for future clinical decision making. IPMNs of varying degrees of dysplasia, as well as IPMN with carcinoma, pancreatic ductal adenocarcinoma and normal pancreas samples were examined by microarray. Upregulation of miR-21, miR-155 and miR-708 was found to occur during IPMN malignant transformation. Here, the authors evaluate the published miRNA profiles of premalignant pancreatic lesions in order to consolidate these data. PMID- 23638813 TI - Single molecular weight discrete PEG compounds: emerging roles in molecular diagnostics, imaging and therapeutics. PMID- 23638816 TI - Trends in diagnostic biochip development. AB - Technological advancements in biochips for diagnosis and prevention lead to improved healthcare cost containment with a decreasing birth rate and an aging population. Biochips have been attracting attention as a tool for improving healthcare costs. There are technological, standardization-related, ethical and societal problems in biochip development. For biochip market expansion, in addition to technological problems, it is necessary to overcome social, institutional, marketing and economic problems all together. It is expected that the application of biochip technologies will facilitate not only 'super' early diagnosis of diseases and disease prevention based on the diagnosis, but also early treatment. PMID- 23638817 TI - Metabolomics for tumor marker discovery and identification based on chromatography-mass spectrometry. AB - Early detection is the most effective way to improve the clinical outcome of malignancies. Although some tumor markers are now widely used in the clinic, their sensitivity and specificity are still not satisfactory. Thus, there is an urgent requirement for the discovery of new tumor markers. By measuring holistic endogenous metabolites, metabolomics can be used for delineating metabolic networks and discovering metabolic markers. Chromatography-mass spectrometry is the most widely used tool for metabolomics and has shown great potential for biomarker screening. In this review, the authors summarize: recent advances in the protocols and methodologies of chromatography-mass spectrometry-based metabolomics in the discovery of tumor markers; recently identified tumor metabolic markers for primary liver cancer, gynecologic cancer and genitourinary cancer and their applications; and commonly encountered problems in the translational research of metabolic markers. PMID- 23638818 TI - Impact of metabolizing enzymes on drug response of endocrine therapy in breast cancer. AB - Estrogen-receptor positive breast cancer accounts for 75% of diagnosed breast cancers worldwide. There are currently two major options for adjuvant treatment: tamoxifen and aromatase inhibitors. Variability in metabolizing enzymes determines their pharmacokinetic profile, possibly affecting treatment response. Therefore, prediction of therapy outcome based on genotypes would enable a more personalized medicine approach, providing optimal therapy for each patient. In this review, the authors will discuss the current evidence on the most important metabolizing enzymes in endocrine therapy, with a special focus on CYP2D6 and its role in tamoxifen metabolism. PMID- 23638819 TI - Quantum dot-based nanosensors for diagnosis via enzyme activity measurement. AB - Enzymes are essential in the human body, and the disorder of enzymatic activities has been associated with many different diseases and stages of disease. Luminescent semiconductor nanocrystals, also known as quantum dots (QDs), have garnered great attention in molecular diagnostics. Owing to their superior optical properties, tunable and narrow emissions, stable brightness and long lifetime, QD-based enzyme activity measurement has demonstrated improved detection sensitivity, which is considered particularly valuable for early disease diagnosis. Recent studies have also shown that QD-based nanosensors are capable of probing multiple enzyme activities simultaneously. This review highlights the current development of QD-based nanosensors for enzyme detection. The enzyme-QD hybrid system, equipped with unique electronic, optical and catalytic properties, is envisioned as a potential solution in addressing challenges in diagnostics and therapeutics. PMID- 23638821 TI - Genetic background of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by progressive fibrosing interstitial pneumonia. The histological pattern, which displays dense fibrosis with active areas of fibroblastic proliferation, suggests a pathogenetic role of aberrant response to healing of multiple microscopic, repeated alveolar epithelial injuries. Although the exact etiology of the disease is still under investigation, several studies suggest that a combination of genetic and environmental factors may play a causal role. The aim of this review is to describe the genetic background of IPF, reporting the latest advancements made possible by genomic techniques that allow a high throughput analysis and the identification of target genes implicated in IPF. This information may help to clarify pivotal aspects on prognosis and diagnosis, and may help to identify potential targets for future therapies. PMID- 23638820 TI - Application of mass spectrometry to molecular diagnostics of viral infections. AB - Mass spectrometry (MS) has found numerous applications in life sciences. It has high accuracy, sensitivity and wide dynamic range in addition to medium- to high throughput capabilities. These features make MS a superior platform for analysis of various biomolecules including proteins, lipids, nucleic acids and carbohydrates. Until recently, MS was applied for protein detection and characterization. During the last decade, however, MS has successfully been used for molecular diagnostics of microbial and viral infections with the most notable applications being identification of pathogens, genomic sequencing, mutation detection, DNA methylation analysis, tracking of transmissions, and characterization of genetic heterogeneity. These new developments vastly expand the MS application from experimental research to public health and clinical fields. Matching of molecular techniques with specific requirements of the major MS platforms has produced powerful technologies for molecular diagnostics, which will further benefit from coupling with computational tools for extracting clinical information from MS-derived data. PMID- 23638823 TI - Standardization of the functional syndesmosis widening by dynamic U.S examination. AB - BACKGROUND: Dynamic US examination is a convenient, accurate, inexpensive and reproducible diagnostic tool for assessing the integrity of the distal tibiofibular syndesmosis in ankle injuries. However normal values for physiological functional widening of the anterior tibiofibular clear space in healthy subjects has yet to be determined. The purpose of this study was to determine normal values for the syndesmosis clear space on ultrasound examination. METHODS: We evaluated 110 healthy subjects. A dynamic U.S examination was performed in neutral (N), forced internal rotation (IR) and external rotation (ER) of the ankle. In each position the anterior tibiofibular clear space was measured at the level of the anterior inferior tibio-fibular ligament (AITFL). Height and calf length were also recorded. Results were analyzed in relation to age, activity, dominant leg and gender. RESULTS: Mean age was 32 years (range 16-60). There were 59 males and 51 females. 60% were professional athletes. Mean height was 173 cm (range 149-192). Functional Mean position measurements for clear space opening were: N=3.7mm, IR=3.6mm and ER=4.0mm. In younger men and women the clear space was significantly wider in neutral (Men: Y=3.8, O=3.4 ? Women: Y=3.8, O=3.4) and with rotational force application (Men ER: Y=4.1, O=3.6 ? Women ER: Y=4.1, O=3.8) compared to older subjects (p<0.05). There was no correlation with activity, height or the leg length.Females had a higher syndesmosis widening ratio (ER/N) under stress than males (p<0.01) this tended to occur more commonly in active subjects. CONCLUSIONS: Normal values for the syndesmosis clear space on ultrasound examination were determined as 3.78mm in neutral, 3.64mm in internal rotation and 4.08mm in external rotation. The clear space was shown to decrease with age both as an absolute measure and when rotational stresses are applied. Females tend to have a larger clear space and a greater functional widening.These findings provide a useful reference for radiologists and sports physicians when performing ultrasound assessment of ankle syndesmotic injuries and we encourage use of this modality. PMID- 23638824 TI - Pharmacokinetics and tissue distribution of furanodiene W/O/W multiple emulsions in rats by a fast and sensitive HPLC-APCI-MS/MS method. AB - A sensitive and specific HPLC-APCI-MS/MS method was developed and validated for the quantification of furanodiene, a natural antitumor compound in rat plasma and tissues. W/O/W multiple emulsions of furanodiene, identified through microscope observation and eosin staining method, were prepared with a two-step-procedure. Pharmacokinetics and tissue distribution were studied in rats after oral, intraperitoneal and intravenous injection with the dose of 5, 10 and 50 mg/kg, respectively. The assay achieved a good sensitivity and specificity for the determination of furanodiene in biological samples. The results showed that the concentration-time curves of furanodiene in rats after intravenous injection were fitted to a two-compartment model and the linear pharmacokinetic characteristic. The highest concentration in rat tissue was observed in the spleen, followed by heart, liver, lung, kidney, small intestine and brain. Comparing with the low concentration in plasma, furanodiene could be detected in various tissue samples after oral or intraperitoneal injection which indicated furanodiene had good and rapid tissue uptake. The results suggested that the wide tissue distribution of furanodiene could conduce to the therapeutic effects, but the short biological half-life limited its further application as an antitumor agent. The results are helpful for the structure modification of furanodiene as an antitumor candidate. PMID- 23638826 TI - Understanding reproductive isolation based on the rice model. AB - Reproductive isolation is both an indicator of speciation and a mechanism for maintaining species identity. Here we review the progress in studies of hybrid sterility in rice to illustrate the present understanding of the molecular and evolutionary mechanisms underlying reproductive isolation. Findings from molecular characterization of genes controlling hybrid sterility can be summarized with three evolutionary genetic models. The parallel divergence model features duplicated loci generated by genome evolution; in this model, the gametes abort when the two copies of loss-of-function mutants meet in hybrids. In the sequential divergence model, mutations of two linked loci occur sequentially in one lineage, and negative interaction between the ancestral and nascent alleles of different genes causes incompatibility. The parallel-sequential divergence model involves three tightly linked loci, exemplified by a killer protector system formed of mutations in two steps. We discuss the significance of such findings and their implications for crop improvement. PMID- 23638825 TI - Intracellular SERS nanoprobes for distinction of different neuronal cell types. AB - Distinction between closely related and morphologically similar cells is difficult by conventional methods especially without labeling. Using nuclear targeted gold nanoparticles (AuNPs) as intracellular probes we demonstrate the ability to distinguish between progenitor and differentiated cell types in a human neuroblastoma cell line using surface-enhanced Raman spectroscopy (SERS). SERS spectra from the whole cell area as well as only the nucleus were analyzed using principal component analysis that allowed unambiguous distinction of the different cell types. SERS spectra from the nuclear region showed the developments during cellular differentiation by identifying an increase in DNA/RNA ratio and proteins transcribed. Our approach using nuclear-targeted AuNPs and SERS imaging provides label-free and noninvasive characterization that can play a vital role in identifying cell types in biomedical stem cell research. PMID- 23638827 TI - Membrane microdomains, rafts, and detergent-resistant membranes in plants and fungi. AB - The existence of specialized microdomains in plasma membranes, postulated for almost 25 years, has been popularized by the concept of lipid or membrane rafts. The idea that detergent-resistant membranes are equivalent to lipid rafts, which was generally abandoned after a decade of vigorous data accumulation, contributed to intense discussions about the validity of the raft concept. The existence of membrane microdomains, meanwhile, has been verified by unequivocal independent evidence. This review summarizes the current state of research in plants and fungi with respect to common aspects of both kingdoms. In these organisms, principally immobile microdomains large enough for microscopic detection have been visualized. These microdomains are found in the context of cell-cell interactions (plant symbionts and pathogens), membrane transport, stress, and polarized growth, and the data corroborate at least three mechanisms of formation. As documented in this review, modern methods of visualization of lateral membrane compartments are also able to uncover the functional relevance of membrane microdomains. PMID- 23638828 TI - Unraveling the heater: new insights into the structure of the alternative oxidase. AB - The alternative oxidase is a membrane-bound ubiquinol oxidase found in the majority of plants as well as many fungi and protists, including pathogenic organisms such as Trypanosoma brucei. It catalyzes a cyanide- and antimycin-A resistant oxidation of ubiquinol and the reduction of oxygen to water, short circuiting the mitochondrial electron-transport chain prior to proton translocation by complexes III and IV, thereby dramatically reducing ATP formation. In plants, it plays a key role in cellular metabolism, thermogenesis, and energy homeostasis and is generally considered to be a major stress-induced protein. We describe recent advances in our understanding of this protein's structure following the recent successful crystallization of the alternative oxidase from T. brucei. We focus on the nature of the active site and ubiquinol binding channels and propose a mechanism for the reduction of oxygen to water based on these structural insights. We also consider the regulation of activity at the posttranslational and retrograde levels and highlight challenges for future research. PMID- 23638830 TI - Determinants of human coronary collaterals. AB - The human coronary collateral circulation is prognostically relevant. The understanding of collateral formation and its determinants may guide future therapeutic strategies aiming at promoting collateral growth and functionality, and hence reducing the global burden of coronary artery disease (CAD). PMID- 23638829 TI - The future of collateral artery research. AB - In the event of obstructive coronary artery disease, collateral arteries have been deemed an alternative blood source to preserve myocardial tissue perfusion and function. Monocytes play an important role in modulating this process, by local secretion of growth factors and extracellular matrix degrading enzymes. Extensive efforts have focused on developing compounds for augmenting the growth of collateral vessels (arteriogenesis). Nonetheless, clinical trials investigating the therapeutic potential of these compounds resulted in disappointing outcomes. Previous studies focused on developing compounds that stimulated collateral vessel growth by enhancing monocyte survival and activity. The limited success of these compounds in clinical studies, led to a paradigm shift in arteriogenesis research. Recent studies have shown genetic heterogeneity between CAD patients with sufficient and insufficient collateral vessels. The genetic predispositions in patients with poorly developed collateral vessels include overexpression of arteriogenesis inhibiting signaling pathways. New directions of arteriogenesis research focus on attempting to block such inhibitory pathways to ultimately promote arteriogenesis. Methods to detect collateral vessel growth are also critical in realizing the therapeutic potential of newly developed compounds. Traditional invasive measurements of intracoronary derived collateral flow index remain the gold standard in quantifying functional capacity of collateral vessels. However, advancements made in hybrid diagnostic imaging modalities will also prove to be advantageous in detecting the effects of pro-arteriogenic compounds. PMID- 23638832 TI - The coronary collateral circulation--past, present and future. PMID- 23638833 TI - Resolution of Coccidioides immitis endophthalmitis with an aggressive surgical and medical therapeutic approach. AB - INTRODUCTION: Coccidioides immitis endophthalmitis usually results in enucleation, and there is evidence that vitrectomized eyes are more likely to become enucleated. METHODS: A 55-year-old man presented to us with steroid resistant granulomatous uveitis and was eventually diagnosed with C. immitis endophthalmitis. He was treated with an aggressive medical and surgical approach, receiving a total of 16 intravitreal antifungal injections and three vitrectomies, as well as lensectomy and penetrating keratoplasty. RESULTS: At 13 months after presentation, the patient's eye was free of inflammation, and his best corrected visual acuity was 20/25. DISCUSSION: This is the first reported case of culture-proven C. immitis endophthalmitis with a favorable final outcome. We propose that the good outcome may have been due to our aggressive therapeutic approach. PMID- 23638831 TI - Cellular and pharmacological targets to induce coronary arteriogenesis. AB - The formation of collateral vessels (arteriogenesis) to sustain perfusion in ischemic tissue is native to the body and can compensate for coronary stenosis. However, arteriogenesis is a complex process and is dependent on many different factors. Although animal studies on collateral formation and stimulation show promising data, clinical trials have failed to replicate these results. Further research to the exact mechanisms is needed in order to develop a pharmalogical stimulant. This review gives an overview of recent data in the field of arteriogenesis. PMID- 23638835 TI - Stability and metastability of bromine clathrate polymorphs. AB - Clathrate hydrates are crystals in which water forms a network of fully hydrogen bonded polyhedral cages that contain small guests. Clathrate hydrates occur mostly in two cubic crystal polymorphs, sI and sII. Bromine is one of two guests that yield a hydrate with the tetragonal structure (TS), the topological dual of the Frank-Kasper sigma phase. There has been a long-standing disagreement on whether bromine hydrate also forms metastable sI and sII crystals. To date there are no data on the thermodynamic range of stability (e.g., the melting temperatures) of the metastable polymorphs. Here we use molecular dynamics simulations with the coarse-grained model of water mW to (i) investigate the thermodynamic stability of the empty and guest-filled the sI, sII, TS, and HS-I hydrate polymorphs, (ii) develop a coarse-grained model of bromine compatible with mW water, and (iii) evaluate the stability of the bromine hydrate polymorphs. The mW model predicts the same relative energy of the empty clathrate polymorphs and the same phase diagram as a function of water-guest interaction than the fully atomistic TIP4P water model. There is a narrow region in water guest parameter space for which TS is marginally more stable than sI or sII. We parametrize a coarse-grained model of bromine compatible with mW water and use it to determine the order of stability of the bromine hydrate polymorphs. The melting temperatures of the bromine hydrate polymorphs predicted by the coarse grained model are 281 +/- 1 K for TS, 279 +/- 1 K for sII, and 276 +/- 1 K for sI. The closeness of the melting temperatures supports the plausibility of formation of metastable sII and sI bromine hydrates. PMID- 23638834 TI - Frequency and factors associated with carriage of multi-drug resistant commensal Escherichia coli among women attending antenatal clinics in central India. AB - BACKGROUND: Commensal Escherichia coli are a prominent reservoir of genes coding for antibiotic resistance and also responsible for endogenous infections in pregnant women. We studied the factors in pregnant women associated with carriage of multi-drug resistant (MDR) E. coli and genetic determinants of antibiotic resistance in them. METHODS: Women attending to Obstetric and Gynaecology department outpatient clinics for routine antenatal check-up were administered a questionnaire. Peri-anal swabs were collected for culture isolation and identification of E.coil. Antibiotic sensitivity was done using the Kirby-Bauer disc diffusion method as recommended by the CLSI guidelines. MICs for quinolones and third generation cephalosporins were done using the agar dilution method. Genes coding for production of beta lactamses and for the quinolone resistance determinant were screened by polymerase chain reaction. Rep-PCR was done on MDR isolates for detecting possible genetic similarity. Multiple logistic regression models were used to determine the independent factors associated with carriage of MDR isolates. RESULTS: A total of 710 isolates of E. coli from 710 women (mean age 26 years) were included in the study. Resistance to at least one antibiotic tested was detected in 94% of the E. coli isolates. A total of 109 isolates were ESBL producing and 35 isolates were MDR. In the MDR isolates MIC(50) and MIC(90) for quinolones and third generation cephalosporins were high for those isolates that carried bla(TEM) gene (26 isolates) and bla(CTX-M) gene (24 isolates). Both bla(TEM) and bla(CTX-M) genes were detected in 19 isolates. The commonest Plasmid Mediated Quinolone Resistance (PMQR) gene identified was aac(6')-Ib-cr (n = 23/25). All isolates carrying the PMQR genes were also positive for bla(CTX-M) and bla(TEM) gene. Mutations in gyr A and par C genes were present in all 35 MDR isolates. The statistically significant risk factors for carriage of MDR E. coli were graduate or post-graduate education, a self-employed status, a family size of more than 10 members, antibiotic usage in last four weeks, and history of hospitalization in the last four weeks. CONCLUSIONS: The presence of genes coding for extended spectrum of beta lactamases and plasmid mediated quinolone resistance in commensal E. coli is disconcerting. The study provides strong basis good antibiotic stewardship. PMID- 23638836 TI - Establishment of pacemaker activity in tissues allotransplanted with interstitial cells of Cajal. AB - BACKGROUND: Loss or disruption of Kit(+) -interstitial cells of Cajal (ICC) capable of generating pacemaker activity has been implicated in the development of numerous gastrointestinal motility disorders. We sought to develop a model where ICC could be allotransplanted into intestines naturally devoid of these cells. METHODS: Enzymatically dispersed cells from the intestinal tunica muscularis of Kit(+/copGFP) and Kit(V558Delta) /+ gain-of-function mice were allotransplanted into myenteric plexus regions of W/W(V) mutant intestines that lack ICC at the level of the myenteric plexus (ICC-MY) and pacemaker activity. Immunohistochemical analysis fate mapped the development of ICC-MY networks and intracellular microelectrode recordings provided evidence for the development of functional pacemaker activity. KEY RESULTS: Kit(+) -ICC developed into distinct networks at the level of the myenteric plexus in organotypic cultures over 28 days and displayed robust rhythmic pacemaker activity. CONCLUSIONS & INFERENCES: This study demonstrates the feasibility of allotransplantation of ICC into the myenteric region of the small intestine and the establishment of functional pacemaker activity into tissues normally devoid of ICC-MY and slow waves, thus providing a possible basis for the therapeutic treatment of patients where ICC networks have been disrupted due to a variety of pathophysiological conditions. PMID- 23638837 TI - Correlation between target motion and the dosimetric variance of breast and organ at risk during whole breast radiotherapy using 4DCT. AB - PURPOSE: The purpose of this study was to explore the correlation between the respiration-induced target motion and volume variation with the dosimetric variance on breast and organ at risk (OAR) during free breathing. METHODS AND MATERIALS: After breast-conserving surgery, seventeen patients underwent respiration-synchronized 4DCT simulation scans during free breathing. Treatment planning was constructed using the end inspiration scan, then copied and applied to the other phases and the dose distribution was calculated separately to evaluate the dose-volume histograms (DVH) parameters for the planning target volume (PTV), ipsilateral lung and heart. RESULTS: During free breathing, the treated breast motion vector was 2.09 +/- 0.74 mm, and the volume variation was 3.05 +/- 0.94%. There was no correlation between the breast volume and target/OAR dosimetric variation (|r| = 0.39 ~ 0.48). In the anteroposterior, superoinferior and vector directions, breast movement correlated well with the mean PTV dose, conformal index, and the lung volume receiving high dose (|r| = 0.651-0.975); in the superoinferior and vector directions, breast displacement only correlated with the heart volume receiving >5 Gy (V5) (r = -0.795, 0.687). The lung volume and the lung volume receiving high dose correlated reasonably well (r = 0.655 ~ 0.882), and a correlation only existed between heart volume and V5 (r = -0.701). CONCLUSION: Target movement correlated well with the target/OAR dosimetric variation in certain directions, indicating that whole breast IMRT assisted by breathing control or respiratory-adapted gated treatment promotes the accuracy of dose delivery during radiotherapy. During free breathing, the effect of breast volume variation can be ignored in whole breast IMRT. PMID- 23638839 TI - A Sonogashira cross-coupling/5-exo-dig cyclization/ionic hydrogenation sequence: synthesis of 4-substituted 3-azabicyclo[3.1.0]hexan-2-ones from 2 iodocyclopropanecarboxamides. AB - A variety of 4-substituted 3-azabicyclo[3.1.0]hexan-2-ones have been prepared from 2-iodocyclopropanecarboxamides by a three-step sequence involving a copper free Sonogashira coupling with terminal aryl- or heteroarylalkynes, followed by a 5-exo-dig cyclization and an ionic hydrogenation. PMID- 23638841 TI - Potential environmental and human health impacts of rechargeable lithium batteries in electronic waste. AB - Rechargeable lithium-ion (Li-ion) and lithium-polymer (Li-poly) batteries have recently become dominant in consumer electronic products because of advantages associated with energy density and product longevity. However, the small size of these batteries, the high rate of disposal of consumer products in which they are used, and the lack of uniform regulatory policy on their disposal means that lithium batteries may contribute substantially to environmental pollution and adverse human health impacts due to potentially toxic materials. In this research, we used standardized leaching tests, life-cycle impact assessment (LCIA), and hazard assessment models to evaluate hazardous waste classification, resource depletion potential, and toxicity potentials of lithium batteries used in cellphones. Our results demonstrate that according to U.S. federal regulations, defunct Li-ion batteries are classified hazardous due to their lead (Pb) content (average 6.29 mg/L; sigma = 11.1; limit 5). However, according to California regulations, all lithium batteries tested are classified hazardous due to excessive levels of cobalt (average 163,544 mg/kg; sigma = 62,897; limit 8000), copper (average 98,694 mg/kg; sigma = 28,734; limit 2500), and nickel (average 9525 mg/kg; sigma = 11,438; limit 2000). In some of the Li-ion batteries, the leached concentrations of chromium, lead, and thallium exceeded the California regulation limits. The environmental impact associated with resource depletion and human toxicity is mainly associated with cobalt, copper, nickel, thallium, and silver, whereas the ecotoxicity potential is primarily associated with cobalt, copper, nickel, thallium, and silver. However, the relative contribution of aluminum and lithium to human toxicity and ecotoxicity could not be estimated due to insufficient toxicity data in the models. These findings support the need for stronger government policy at the local, national, and international levels to encourage recovery, recycling, and reuse of lithium battery materials. PMID- 23638840 TI - Stapling of the botulinum type A protease to growth factors and neuropeptides allows selective targeting of neuroendocrine cells. AB - Precise cellular targeting of macromolecular cargos has important biotechnological and medical implications. Using a recently established 'protein stapling' method, we linked the proteolytic domain of botulinum neurotoxin type A (BoNT/A) to a selection of ligands to target neuroendocrine tumor cells. The botulinum proteolytic domain was chosen because of its well-known potency to block the release of neurotransmitters and hormones. Among nine tested stapled ligands, the epidermal growth factor was able to deliver the botulinum enzyme into pheochromocytoma PC12 and insulinoma Min6 cells; ciliary neurotrophic factor was effective on neuroblastoma SH-SY5Y and Neuro2A cells, whereas corticotropin releasing hormone was active on pituitary AtT-20 cells and the two neuroblastoma cell lines. In neuronal cultures, the epidermal growth factor- and ciliary neurotrophic factor-directed botulinum enzyme targeted distinct subsets of neurons whereas the whole native neurotoxin targeted the cortical neurons indiscriminately. At nanomolar concentrations, the retargeted botulinum molecules were able to inhibit stimulated release of hormones from tested cell lines suggesting their application for treatments of neuroendocrine disorders. PMID- 23638842 TI - Protective role of (RS )-glucoraphanin bioactivated with myrosinase in an experimental model of multiple sclerosis. AB - AIM: The discovery of new natural compounds with pharmacological properties is a field of interest widely growing. Recent literature shows that Brassica vegetables (Cruciferae) possess therapeutic effects particularly ascribed due to their content in glucosinolates, which upon myrosinase hydrolysis release the corresponding isothiocyanates. This study examines the potential neuroprotective and immunomodulatory effects of (RS )-glucoraphanin from Tuscan black kale (Brassica oleracea L. var. acephala sabellica) bioactivated with myrosinase (bioactive RS -GRA) (10 mg/kg/day intraperitoneally), in an experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. METHODS: EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG35-55 ) in mice. After immunization, mice were observed daily for signs of EAE and weight loss. Clinical score was evaluated using a standardized scoring system. RESULTS: By Western blot analysis of spinal cord tissues, we have demonstrated that treatment with bioactive RS -GRA significantly decreased nuclear factor (NF)-kB translocation, pro-inflammatory cytokine production such as interleukin-1beta (IL-1beta), and apoptosis (Bax and caspase 3 expression). CONCLUSION: Our results clearly demonstrate that bioactive RS -GRA treatment may represent a useful therapeutic perspective in the treatment of this disease. PMID- 23638843 TI - Carer and service providers' experiences of individual funding models for children with a disability in rural and remote areas. AB - There is a global movement for people with a disability towards person-centred practices with opportunities for self-determination and choice. Person-centred approaches may involve individual funding (IF) for the purchase of required support. A shift to a person-centred model and IF should allow people with a disability and their carers greater choice in therapy access. However, individuals who live in rural and remote areas have less choice and access to therapy services than their metropolitan counterparts. Drawing on data from a larger study into therapy service delivery in a rural and remote area of New South Wales, Australia, this study describes some benefits and barriers to using IF to access therapy services in rural areas. Ten carers and 60 service providers participated in audio-recorded focus groups and individual interviews during which IF was discussed. Transcribed data were analysed using thematic analysis and constant comparison. Greater access to and choice of therapy providers were identified as benefits of IF. Four barriers were identified: (i) lack of information and advice; (ii) limited local service options and capacity; (iii) higher costs and fewer services and (iv) complexity of self-managing packages. A range of strategies is required to address the barriers to using IF in rural and remote areas. Carers indicated a need for: accessible information; a local contact person for support and guidance; adequate financial compensation to offset additional travel expenses and coordinated eligibility and accountability systems. Service providers required: coordinated cross-sector approaches; local workforce planning to address therapist shortages; certainty around service viability and growth; clear policies and procedures around implementation of IF. This study highlights the need for further discussion and research about how to overcome the barriers to the optimal use of an IF model for those living in rural and remote areas. PMID- 23638844 TI - Effects of electrical stimulation of carotid baroreflex and renal denervation on atrial electrophysiology. AB - INTRODUCTION: This study was designed to compare the effect of electrical baroreflex stimulation (BRS) at an intensity used in hypertensive patients and renal denervation (RDN) on atrial electrophysiology. BRS and RDN reduce blood pressure and global sympathetic drive in patients with resistant hypertension. Whereas RDN decreases sympathetic renal afferent nerve activity, leading to decreased central sympathetic drive, BRS modulates autonomic balance by activation of the baroreflex, resulting in both reduced sympathetic drive and increased vagal activation. Increased vagal tone potentially shortens atrial refractoriness resulting in a stabilization of reentry circuits perpetuating atrial fibrillation (AF). METHODS AND RESULTS: In normotensive anesthetized pigs (n = 12), we compared the acute effect of BRS and RDN on blood pressure, atrial effective refractory period (AERP), and inducibility of AF. Electrical BRS was titrated to result in comparable heart rate and blood pressure reduction compared to irreversible RDN. BRS resulted in a rapid and pronounced shortening of AERP (from 162 +/- 8 milliseconds to 117 +/- 16 milliseconds, P = 0.001) associated with increased AF-inducibility from 0% to 82%. This shortening in AERP was completely reversible after stopping BRS. After administration of atropine, AF inducibility during BRS was attenuated. Ventricular repolarization was not modulated by BRS. In RDN, AF was not inducible; however, it did not prevent BRS induced shortening of AERP. CONCLUSION: RDN and BRS resulting in comparable blood pressure and heart rate reductions differently influence atrial electrophysiology. Vagally mediated shortening of AERP, resulting in increased AF inducibility, was observed with BRS but not with RDN. PMID- 23638845 TI - Unilateral rainbow glare after uncomplicated femto-LASIK using the FS-200 femtosecond laser. AB - PURPOSE: To report a case of rainbow glare following femtosecond laser-assisted LASIK (femto-LASIK) with the Wavelight FS-200 femtosecond laser (Alcon Laboratories, Inc., Fort Worth, TX). METHODS: A patient was treated bilaterally for myopia with femto-LASIK using the FS-200 femtosecond laser. Postoperatively, he complained of rainbow glare in his right eye. RESULTS: Three months postoperatively, the induced grating pattern (hyperreflective spot-like zones corresponding to the surgeon-programmed spot and line separation distance of the FS-200 femtosecond laser) was demonstrated with confocal microscopy at the level of the flap interface in the right eye. CONCLUSIONS: This is the first report of rainbow glare following femto-LASIK with the FS-200 femtosecond laser documented with in vivo confocal microscopy. PMID- 23638846 TI - In vivo modulation of Campylobacter jejuni virulence in response to environmental stress. AB - Campylobacters have developed a number of mechanisms for responding to environmental conditions, although the different virulence properties of these cells following exposure to stress are still poorly understood. We analyzed in vitro stress responses and the consequent in vivo modulation of Campylobacter jejuni pathogenicity in BALB/c mice, as a result of the exposure of the C. jejuni to environmental stress (starvation, oxidative stress, heat shock). In vitro, the influence of starvation and oxidative stress was milder than that of heat shock, although the majority of the stress conditions influenced the survival of C. jejuni. During starvation, C. jejuni viability was maintained longer than its culturability. Additionally, starvation elicited transformation of stressed bacteria to coccoid forms. In contrast, bacteria exposed to oxygen remained culturable, but their viability decreased. Pre-starvation did not contribute to improved survival of C. jejuni cells during oxygen exposure. Changes in bacteria numbers and the levels of several cytokines (interleukins 6 and 10, tumor necrosis factor-alpha, interferon-gamma) were followed in vivo, in liver homogenates from the mice intravenously infected with either control (untreated) or stressed C. jejuni. The systemic infection with the control or stressed C. jejuni occurred with different production dynamics of the cytokines investigated. Starvation was the most powerful stress factor, which significantly decreased infectious potential of C. jejuni during the first 3 days postinfection. The most pronounced differences in cytokine production were found in interferon-gamma and interleukin-10 production, which indicates that these have roles in the immune response to C. jejuni infection. These in vivo studies of environmental impact on bacterial virulence reveal that microbial adaptation during stress challenge is crucial not just for pathogen survival out of the host, but also during host pathogen interactions, and thus for the bacterial pathogenicity. PMID- 23638847 TI - Emergence of macrolide-resistant Campylobacter strains in chicken meat in Poland and the resistance mechanisms involved. AB - In this study, we investigated the molecular mechanisms involved in erythromycin resistance in the first resistant Campylobacter strains isolated from chicken meat in Poland, and analyzed their genetic relatedness. A total of 297 samples of raw chicken meat and giblets from retail trade in the Warsaw area collected between 2006 and 2009 were examined. Among 211 Campylobacter strains (52 C. jejuni and 159 C. coli), 10 C. coli isolates (4.7%) were resistant to erythromycin. All the C. jejuni strains were susceptible. Among the high-level macrolide-resistant isolates, two different point mutations within the domain V of the 23S rRNA gene were observed. Eight of the strains had adenine->guanine transitions at position 2075, two other isolates at position 2074. Sequence analysis of ribosomal proteins L4 (rplD) and L22 (rplV) indicated that ribosomal protein modifications did not contribute to macrolide resistance. A mutation in the inverted repeat in the cmeR and cmeABC intergenic region was found in a single resistant strain. The genetic relatedness of Campylobacter isolates showed that two resistant strains obtained from the same production plant in a 2-month interval were genetically identical. The risk of transmission of resistant strains via the food chain highlights the need for constant monitoring of resistance in Campylobacter isolates of human and animal hosts. PMID- 23638848 TI - Molecular typing of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) isolated from animals and retail meat in North Dakota, United States. AB - The objective of this study was to determine the prevalence and molecular typing of methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) in food-producing animals and retail meat in Fargo, North Dakota. A two-step enrichment followed by culture methods were used to isolate S. aureus from 167 nasal swabs from animals, 145 samples of retail raw meat, and 46 samples of deli meat. Positive isolates were subjected to multiplex polymerase chain reaction in order to identify the genes 16S rRNA, mecA, and Panton Valentine Leukocidin. Pulsed-field gel electrophoresis and multilocus sequence typing were used for molecular typing of S. aureus strains. Antimicrobial susceptibility testing was carried out using the broth microdilution method. The overall prevalence of S. aureus was 37.2% (n=133), with 34.7% (n=58) of the animals positive for the organism, and the highest prevalence observed in pigs (50.0%) and sheep (40.6%) (p<0.05); 47.6% (n=69) of raw meat samples were positive, with the highest prevalence in chicken (67.6%) and pork (49.3%) (p<0.05); and 13.0% (n=6) of deli meat was positive. Five pork samples (7.0%) were positive for MRSA, of which three were ST398 and two were ST5. All exhibited penicillin resistance and four were multidrug resistant (MDR). The Panton Valentine Leukocidin gene was not detected in any sample by multiplex polymerase chain reaction. The most common clones in sheep were ST398 and ST133, in pigs and pork both ST398 and ST9, and in chicken ST5. Most susceptible S. aureus strains were ST5 isolated from chicken. The MDR isolates were found in pigs, pork, and sheep. The presence of MRSA, MDR, and the subtype ST398 in the meat production chain and the genetic similarity between strains of porcine origin (meat and animals) suggest the possible contamination of meat during slaughtering and its potential transmission to humans. PMID- 23638849 TI - Noroviruses in seafood: a 9-year monitoring in Italy. AB - Norovirus (NoV) are increasingly important as etiological agents of gastrointestinal infections. Consumption of bivalve molluscs and ready-to-eat fishery products is one of the most common ways of acquiring NoV foodborne infections, and the rise of outbreaks of viral gastroenteritis represents an important health problem that is also responsible for economic losses. The aim of this work was to define the prevalence of NoV contamination in preserved fishery products and in shellfish commercialized in Italy, taking into account the results obtained during 9 years of survey (2003-2011) and paying special attention to the regions more involved in national production. A total of 4463 samples were examined (2310 mussels, 1517 clams, 510 oysters, 22 other shellfish species, 104 preserved seafood products) and the average positivity rate for NoV presence was 4.1% and ranged from 0.6% in 2007 to 9.8% in 2003 and from 1.9% in preserved seafood products to 4.7% in mussels. Genetic characterization of circulating strains showed a prevalence of genogroup II genotypes, including GII.b and GII.e polymerase types and different GII.4 variants. This information could contribute to the optimization of risk-based sampling strategies for NoV contamination in seafood, taking into account variability in different species and from year to year. PMID- 23638850 TI - Impact of management practices and distillers' grains feeding on the prevalence of Escherichia coli O157 in feedlot cattle in Minnesota. AB - Escherichia coli O157 is a foodborne pathogen that can be transmitted by contaminated ground beef and is shed naturally in cattle feces. Recent reports indicated that feeding distillers' grains (DG) to cattle increased fecal shedding and prevalence of E. coli O157. In Minnesota, feeding DG with solubles (DGS) to livestock became widespread within the last 10 years, but there is no report about the prevalence of E. coli O157 in beef cattle in this state. This study was undertaken to survey the fecal prevalence of E. coli O157 in cattle fed diets containing DG and its association with environmental conditions and management practices. Fecal samples were collected from three feedlots during a 1-year period. All animals in those feedlots were fed different DGS levels. E. coli O157 presence was determined using a combination of enrichment, immunomagnetic separation, plating onto sorbitol MacConkey agar, and confirmation of isolates by immunoassay and multiplex virulence genes polymerase chain reaction analysis. Overall, E. coli O157 was confirmed in 9.7% of samples. Prevalence during summer was 30% and declined to less than 10% the rest of the year. In animals grouped by dietary DGS concentration, no significant difference in prevalence (12.0 and 5.5%) was detected between the low and the high average groups (less and more than 20%). Previous feeding of DGS before arriving to the feedlot also had no influence on fecal prevalence. The presence of several interacting variables, uncontrolled in a real-life feedlot environment, was the likely reason for our observation and suggested that at the levels studied, DGS had no effect on the STEC O157 prevalence in cattle populations. PMID- 23638851 TI - Iatrogenic intestinal and mesenteric injuries with small bowel volvulus following use of barbed suture during laparoscopic myomectomy. AB - This is a case report of a patient who developed major intestinal complications after the utilization of barbed sutures for an off-label indication. The report serves as a warning for patients and surgeons of the potential injuries that may be caused by the use of new products in unapproved indications. PMID- 23638852 TI - Influence of dynamic shadowing on 2D and 3D laparoscopic visualization under visible light and infrared light. AB - BACKGROUND: Depth perception is a significant weakness in conventional two dimensional (2D) endoscopy. We hypothesize that dynamic shadowing improves endoscopic depth perception during laparoscopy. Two experiments were performed to investigate this hypothesis. The first experiment compared the effect of dynamic shadowing with 2D and three-dimensional (3D) displays. The second experiment compared the effect of dynamic shadowing under visible light and infrared light. MATERIALS AND METHODS: In the experiment, a box trainer was designed and built to house three laparoscopic tasks. Six settings were investigated: 2D display without dynamic shadows under visible light, 2D display with dynamic shadows under visible light, 3D display without dynamic shadows under visible light, 3D display with dynamic shadows under visible light, 2D display without dynamic shadows under infrared light, and 2D display with dynamic shadows under infrared light. Two types of illumination were used: static overhead illumination and dynamic grasper illumination. The execution time and number of errors committed by the volunteers with no formal laparoscopic experience were measured in the experiments. RESULTS: The experimental results showed that dynamic shadowing with 2D display under both visible light and infrared light reduced mean execution time. Dynamic shadowing with 3D display increased execution time for one of the tasks and increased the number of errors for all three tasks. CONCLUSIONS: Dynamic shadowing has the potential to be an inexpensive method to improve laparoscopic depth perception. However, subjects needed to pay special attention to the shadows, which suggests that better implementation is necessary to improve the dominance of shadows as an effective depth cue. PMID- 23638854 TI - Theory of coherent nucleation in phase-separating nanoparticles. AB - The basic physics of nucleation in solid single-crystal nanoparticles is revealed by a phase-field theory that includes surface energy, chemical reactions, and coherency strain. In contrast to binary fluids, which form arbitrary contact angles at surfaces, complete "wetting" by one phase is favored at binary solid surfaces. Nucleation occurs when surface wetting becomes unstable, as the chemical energy gain (scaling with area) overcomes the elastic energy penalty (scaling with volume). The nucleation barrier thus decreases with the area-to volume ratio and vanishes below a critical size. Thus nanoparticles tend to transform in order of increasing size, leaving the smallest particles homogeneous (in the phase of lowest surface energy). The model is used to simulate phase separation in realistic nanoparticle geometries for LiXFePO4, a popular cathode material for Li-ion batteries, and collapses disparate experimental data for the nucleation barrier with no adjustable parameters. Beyond energy storage, the theory shows how to tailor the elastic and surface properties of a solid nanostructure to achieve desired phase behavior. PMID- 23638853 TI - Ca(2+) signals evoked by histamine H1 receptors are attenuated by activation of prostaglandin EP2 and EP4 receptors in human aortic smooth muscle cells. AB - BACKGROUND AND PURPOSE: Histamine and prostaglandin E2 (PGE2 ), directly and via their effects on other cells, regulate the behaviour of vascular smooth muscle (VSM), but their effects on human VSM are incompletely resolved. EXPERIMENTAL APPROACH: The effects of PGE2 on histamine-evoked changes in intracellular free Ca(2+) concentration ([Ca(2+) ]i ) and adenylyl cyclase activity were measured in populations of cultured human aortic smooth muscle cells (ASMCs). Selective ligands of histamine and EP receptors were used to identify the receptors that mediate the responses. KEY RESULTS: Histamine, via H1 receptors, stimulates an increase in [Ca(2+) ]i that is entirely mediated by activation of inositol 1,4,5 trisphosphate receptors. Selective stimulation of EP2 or EP4 receptors attenuates histamine-evoked Ca(2+) signals, but the effects of PGE2 on both Ca(2+) signals and AC activity are largely mediated by EP2 receptors. CONCLUSIONS AND IMPLICATIONS: Two important inflammatory mediators, histamine via H1 receptors and PGE2 acting largely via EP2 receptors, exert opposing effects on [Ca(2+) ]i in human ASMCs. PMID- 23638855 TI - Genetic characterization of antimicrobial resistance of Shigella flexneri 1c isolates from patients in Egypt and Pakistan. AB - BACKGROUND: Shigella flexneri serotype 1c emerged as a critical isolate from children in Egypt and Pakistan. The pattern of antimicrobial susceptibility (AMS) and resistance genes of this serotype have yet to be characterized. FINDINGS: Sixty nine S. flexneri 1c isolates isolates were identified from both Egypt (n 46) and Pakistan (n = 23) and tested for AMS by disk diffusion method and minimal inhibitory concentrations were also determined. Isolates were genotyped by pulsed field gel electrophoresis (PFGE) and five relevant resistance genes (bla(TEM), bla(SHV), bla(OXA), sulI and sulII) were detected by polymerase chain reaction (PCR) and confirmed by DNA sequencing. High resistance was observed in all isolates for ampicillin (AM >96%); trimethoprim-sulphamethoxazole and tetracycline (>88%). Most AM-resistant isolates from Egypt (70%) harbored bla(TEM) resistance, while 52% of isolates from Pakistan expressed bla(OXA). All isolates were closely related by PFGE, irrespective of source or time of collection. The sulII gene was present in 100% of isolates from pediatric cases in Egypt, 65% of Pakistan isolates, and 53% of isolates from older Egyptian patients. CONCLUSIONS: While different Shigella serotypes gathered in specific genotypic groups, 1c serotype isolates formed multiple clusters. Although AMS was considerably high to most commonly used drugs, genetic determinants were variable between countries over time. The data stress the need for a more careful selection of antibiotics in the treatment of shigellosis. PMID- 23638856 TI - Durability of bond between an indirect composite veneering material and zirconium dioxide ceramics. AB - OBJECTIVE: The purpose of the present study was to evaluate the durability of bond strength between an indirect composite material and zirconia ceramics after thermocycling (100 000 cycles) and to assess the effect of various priming agents for zirconia surface treatments. MATERIALS AND METHODS: A CAD/CAM system (Katana, Noritake Dental Supply) was used to fabricate 96 zirconia disks as a bonding substrate. The specimens were randomly divided into six groups (n = 16) and treated with one of the following acidic priming agents: Alloy Primer (ALP, Kuraray), Clearfil Ceramic Primer (CCP, Kuraray), Clearfil Photo Bond (CPB, Kuraray), Clearfil Photo Bond with Clearfil Porcelain Bond Activator (CPB + Activator, Kuraray), Estenia Opaque Primer (EOP, Kuraray) and Porcelain Liner M Liquid A (PLA, Sun Medical). The specimens were bonded with an indirect composite material (Estenia C&B Dentin, Kuraray). Shear bond strengths were tested before and after 100 000 thermocycles and the data were analyzed by using the Steel Dwass test and Mann-Whitney U-test. RESULTS: After 100 000 thermocycles, the PLA group showed the lowest bond strength (p = 0.010), whereas the CPB + Activator (23.9 MPa; p < 0.014) and CPB (22.7 MPa; p < 0.028) groups had significantly higher bond strengths than the other groups. The Mann-Whitney U-test revealed that bond strengths did not significantly decrease after thermocycling, except for specimens in the PLA (p = 0.038) and CCP (p = 0.028) groups. CONCLUSIONS: Application of a combination of hydrophobic phosphate monomer (MDP) and initiator results in a durable long-term bond between Katana zirconia and Estenia C&B composite material. PMID- 23638857 TI - Influence of surface treatment on the wear of solid zirconia. AB - OBJECTIVE: Recently there has been talk of the use of full-contour solid zirconia crowns or bridge restorations with no porcelain overlay. This could be a useful solution for patients with bruxism or limited interocclusal space. However, the hardness of zirconia could affect the opposite natural dentition. The aim of this in-vitro study was to investigate the role of surface treatments on the wear of a zirconia material and its antagonist. MATERIALS AND METHODS: Fifty plates (10 * 10 * 1 mm) made of zirconia (LavaMulti(TM) ZrO2, 3M ESPE), divided into five equal groups, were sandblasted and ground under standardized conditions with a fine-grit diamond bur (Komet Brasseler, Germany) to simulate clinical conditions. Group (a) was only fired, (b) was fired and sandblasted, (c) only ground, (d) was ground and additionally polished (EVE Ceramic Polishing-Set, Pforzheim) and (e) was ground and glazed. Wear behavior was measured with a pin-on-disk apparatus ABREX against 6 mm steatite balls as antagonists (45 degrees , 5 N load, 5000 cycles, water). The amount of wear was determined topographically using a 3-D profilometer (Concept 3D, Mahr, Germany) by measuring the height loss of the antagonist and the depth of wear Pt of the zirconia. RESULTS: In groups (a), (b), (c) and (d) the wear value Pt could not be determined (<1 MUm). Wear values of the antagonists (steatite balls) revealed a similar outcome in contact with (b), (c) and (e) in the range of 81-85 MUm, whereas (e) was more abrasive but not significantly. A noticeable difference in the wear of the antagonist showed group (d) to have the smallest value. CONCLUSION: Polished zirconia seems to have the lowest wear on the antagonists, in contrast with the other kinds of surface treatment. PMID- 23638858 TI - Evaluation of periodontal pathogens in amniotic fluid and the role of periodontal disease in pre-term birth and low birth weight. AB - BACKGROUND: Pre-term birth and/or low birth weight (PTLBW) is a serious problem in developing countries. The absence of known risk factors in ~ 50% of PTLBW cases has resulted in a continued search for other causes. The aim of this study was to examine the effect of periodontitis on pregnancy outcomes. METHODS: Samples were taken from 50 pregnant women who underwent amniocentesis. Polymerase chain reaction was performed on amniotic fluid samples obtained during amniocentesis and on subgingival plaque samples to determine the presence of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Treponema denticola, Tannerella forsythia, Fusobacterium nucleatum, Prevotella intermedia, Campylobacter rectus and Eikenella corrodens. Plaque index, gingival index, bleeding on probing, probing depth and clinical attachment level were evaluated. Medical records were obtained after birth. RESULTS: Social and demographic variables were similar among the Gingivitis (G), Localized Periodontitis (LP) and Generalized Periodontitis (GP) groups. Four subjects gave birth to PTLBW neonates. Campylobacter rectus, T. forsythia, P. gingivalis and F. nucleatum were detected in the amniotic fluid and subgingival plaque samples of three patients who gave birth to PTLBW neonates. The amniotic fluid sample from the fourth patient was not positive for any of the tested pathogens. CONCLUSION: These findings suggest that the transmission of some periodontal pathogens from the oral cavity of the mother may cause adverse pregnancy outcomes. The results contribute to an understanding of the association between periodontal disease and PTLBW, but further studies are required to better clarify the possible relationship. PMID- 23638859 TI - Comparison of the wear and flexural characteristics of flowable resin composites for posterior lesions. AB - OBJECTIVES: To determine the localized wear and flexural properties of flowable resin composites for posterior lesions compared with universal resin composites produced by the same manufacturers. METHODS: Ten specimens of each of three flowable resins, G-aenial Universal Flo, G-aenial Flo and Clearfil Majesty Flow, and the corresponding resin composite materials, Kalore and Clearfil Majesty Esthetics, were prepared in custom fixtures and subjected to 400,000 wear machine cycles to simulate localized wear. The total maximum depth and volume loss of the wear facets was calculated for each specimen using a profilometer. A three-point bending test was performed to determine the flexural strength, modulus of elasticity and resilience. Values were statistically compared using one-way analysis of variance (ANOVA) followed by Tukey's Honestly Significant Difference (HSD) test. RESULTS: The wear depth ranged from 58.3-126.9 m and the volumetric loss ranged from 0.019-0.049 mm(3), with significant differences observed between restorative materials. The wear depth of G-aenial Universal Flo was significantly smaller than those of the other resin composites tested. The flexural strengths and elastic modulus ranged from 90.5-135.1 MPa and from 4.7-7.6 GPa, respectively. A significantly greater flexural strength and higher elastic modulus was found for G-aenial Universal Flo than the other composites. CONCLUSIONS: The wear and mechanical properties of the flowable resin composites tested suggested improved performance compared with universal resin composites. PMID- 23638861 TI - Occupational skin diseases in automotive industry workers. AB - CONTEXT: Studies on occupational skin diseases in workers of the automotive industry are few. AIM: To investigate the prevalence of occupational skin diseases in workers of the automotive industry. MATERIALS AND METHODS: Between September and December 2011, a total of 405 workers from the automotive repair industry in Diyarbakir were interviewed. They were active workers in the repair industry who had been employed for at least six months. Business owners, sellers of spare parts and accounting officers were not included. The employees were examined at their workplaces and the working conditions were observed. Detailed dermatological examination was performed. RESULTS: The mean age of the 405 workers who participated in the study was 27.7 +/- 10.3. The mean working time of employees was 13.3 +/- 10.4 years. All of the employees were male. Dermatological diseases were not detected in 144 out of 405 workers (35.6%) and at least one condition was diagnosed in 261 (64.4%). The most frequent diagnosis was callus, hyperkeratosis, clavus (27.7%), followed by nail changes (16.8%) and superficial mycoses (12.1%). Contact dermatitis was seen at a rate of 5.9%. DISCUSSION: Traumatic lesions such as hyperkeratotic lesions and nail changes were found most frequently. Traumatic lesions were common among individuals who did not use gloves. Most nail changes were localized leuconychia, a finding not reported in the studies on automotive industry workers. In accordance with the literature, irritant contact dermatitis was observed in patients with a history of atopy and who had been working for a long time. CONCLUSION: Occupational skin diseases comprise an important field in dermatology, deserving much attention. Further studies on occupational dermatology are necessary. PMID- 23638860 TI - What can rheumatologists learn from translational cancer therapy? AB - It is well established that an intimate connection exists between inflammation and neoplasia. Indeed, particular chronic infections and autoimmune processes giving rise to prolonged site-specific inflammation are known to increase the probability of the development of specific cancers. Molecular characterisation of these processes has revealed profound similarities in the specific molecules involved in persistence of inflammation and in both the primary induction of neoplastic processes and in specification of the preferred anatomic sites of metastatic spread. The therapeutic importance of these findings is underscored by the remarkable success in the treatment of autoimmune pathology using medications initially developed for use in oncology and this arena is one of considerable therapeutic promise for rheumatologists. PMID- 23638862 TI - Inhibitory activities of Ulva lactuca polysaccharides on digestive enzymes related to diabetes and obesity. AB - The aim of this study was to evaluate the effect of alga Ulva lactuca polysaccharides (ULPS) on key enzymes related to diabetes and obesity. This marine natural product, ULPS, exerted potential inhibition on key enzymes related to starch digestion and absorption in both plasma and small intestine mainly alpha-amylase by 53% and 34% and maltase by 97 and 164% respectively, leading to a significant decrease in blood glucose rate by 297%. Moreover, ULPS potentially inhibited key enzymes of lipid metabolism and absorption as lipase activity in both plasma and small intestine by 235 and 287% respectively, which led to a notable decrease of blood LDL-cholesterol and triglycerides levels, and in the counterpart an increase in HDL-cholesterol level in surviving diabetic rats. Additively, ULPS significantly protected the liver-kidney functions, by decreasing of aspartate transaminase (AST), alanine transaminase (ALT) and gamma glytamyl transpeptidase (GGT) activities and creatinine, urea and albumin rates in plasma. PMID- 23638863 TI - Association of cytokine gene polymorphisms (IL6, IL10, TNF-alpha, TGF-beta and IFN-gamma) and Graves' disease in Turkish population. AB - INTRODUCTION: Cytokines play a crucial role in the pathogenesis of autoimmune thyroid disease, and recent studies have demonstrated an association between cytokine gene polymorphisms and Graves' Disease (GD) in different ethnic groups. The aim of the present study was to investigate the relationship of interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), and interferon-gamma (INF-gamma) gene polymorphisms in the development of GD in Turkish population. MATERIAL AND METHODS: A total of 224 subjects were included in the study comprising of 100 patients with GD (70 female, 30 male; mean age, 43.9 +/-13.8 years) and 124 healthy subjects (81 female, 43 male); mean age, 37.8 +/-10.2 years) without antithyroid autoantibodies or family history of autoimmune disorders. Genotyping was conducted by using PCR and sequence-specific primers. RESULTS: Statistical analysis showed a significant association between high TNF-alpha -308GA and IL-6 174CC gene polymorphisms in patients with GD compared to control subjects (p=0.016, p=0.044, respectively). However, no significant differences were observed between GD and control subjects for IL-10, TGF-beta, and INF-gamma gene polymorphisms. CONCLUSION: TNF-alpha-308GA and IL-6 -174CC gene polymorphisms are involved in susceptibility to GD in Turkish population. The polymorphism hypothesis in pro-inflammatory cytokines might be involved in predisposition to GD. PMID- 23638865 TI - New insights on the effectiveness of Metarhizium anisopliae formulation and application against Aedes aegypti eggs. AB - Increasing needs for innovative control tools against the dengue vector Aedes aegypti have prompted investigations into the development of specific mycoinsecticides. The entomopathogenic fungus Metarhizium anisopliae attacks both larval and adult stages, but its ovicidal activity against A. aegypti is still little explored. This study reports important findings about the effectiveness of conidia formulated in water and oil-in-water emulsions and of direct and indirect application techniques against A. aegypti eggs. The ovicidal activity of M. anisopliae increased with higher conidial concentrations regardless of the application technique, and larvae elimination concentrations were lowest with oil in-water-formulated conidia (LEC50 <= 4.8 * 10(3) conidia cm(-2) and LEC90 <= 1.9 * 10(5) conidia cm(-2), respectively). Conidia eventually stimulated larval eclosion. Consequently, the indirect application of oil-based fungal formulations onto substrates where oviposition will later occur appears to be a more efficient means to infect those eggs than the direct fungal application to previously deposited eggs. PMID- 23638867 TI - Insight into older peoples' healthcare experiences with managing COPD, asthma, and asthma-COPD overlap. AB - OBJECTIVE: The aim of this study was to explore older peoples' experiences of asthma or COPD with reference to their journey in the healthcare system. METHODS: We recruited older patients with a confirmed diagnosis of asthma or COPD and invited them to participate in a qualitative interview. Interviews were conducted with 21 participants. A line-by-line analysis of the interviews was performed and they were coded for common themes. RESULTS: From the data, six main themes emerged, these were; "limits to being", "being with or without a diagnosis", "not being heard or recognized", "expectation, fears, and hopes", "to medicate or not: the underuse, abuse, and misuse", and "needing to understand more". The findings of these interviews provide an important understanding of the behaviors and healthcare needs of older people with asthma and COPD. Older patients' adherence patterns, desire for person-centeredness, and involvement in shared decisions as well as desire for increased objective assessment are described. CONCLUSIONS: These findings provide an important understanding of the behaviors and healthcare needs of older people with asthma and COPD, an area that has not been well defined. The knowledge gained about older patients' desire for person- centeredness and involvement in shared decisions, as well as desire for increased objective assessment is essential in improving care. PMID- 23638866 TI - Glassy dynamics, cell mechanics, and endothelial permeability. AB - A key feature of all inflammatory processes is disruption of the vascular endothelial barrier. Such disruption is initiated in part through active contraction of the cytoskeleton of the endothelial cell (EC). Because contractile forces are propagated from cell to cell across a great many cell-cell junctions, this contractile process is strongly cooperative and highly nonlocal. We show here that the characteristic length scale of propagation is modulated by agonists and antagonists that impact permeability of the endothelial barrier. In the presence of agonists including thrombin, histamine, and H2O2, force correlation length increases, whereas in the presence of antagonists including sphingosine-1 phosphate, hepatocyte growth factor, and the rho kinase inhibitor, Y27632, force correlation length decreases. Intercellular force chains and force clusters are also evident, both of which are reminiscent of soft glassy materials approaching a glass transition. PMID- 23638868 TI - The binomial symptom index: toward an optimal method for the evaluation of symptom association in gastroesophageal reflux. AB - BACKGROUND: The evaluation of symptom association in gastroesophageal reflux is an open problem. The scientific literature reports important deficiencies and clinicians are claiming a new methodology. This article provides an optimal method for the evaluation of symptom association, the binomial symptom index (BSI). METHODS: A mathematical description of the BSI was presented for the study of association and causality. A total of n = 850,000 patients were simulated using a Monte Carlo model to perform a two-way sensitivity analysis. The average and the standard deviation of the BSI were evaluated in groups of 5000 patients with the same values of the reflux rate, symptom rate, association ratio, window of association, and monitoring time in order to contrast their influence on the estimator. KEY RESULTS: The BSI decreased with the number of reflux episodes when there was association, and remained constant and below 40% when there was not. The standard deviation was no higher than 40% and decreased with the reflux or symptom rates, and more sharply with the monitoring time, reaching approximately 0% for 50 days. A window length matching the characteristic reflux-symptom lag maximized the overall BSI and minimized its dispersion. Twenty-four hour and 96-h monitorings allowed detecting association ratios of 50% and 25%, respectively. CONCLUSIONS & INFERENCES: The BSI is a simple and reliable index for the evaluation of symptom association that considers all the parameters under analysis. Defining an appropriate cut-off value, the BSI can provide a measure of probability and strength of association simultaneously. PMID- 23638869 TI - The metabolite chemotype of Nicotiana benthamiana transiently expressing artemisinin biosynthetic pathway genes is a function of CYP71AV1 type and relative gene dosage. AB - Artemisia annua, which produces the anti-malaria compound artemisinin, occurs as high-artemisinin production (HAP) and low-artemisinin production (LAP) chemotypes. Understanding the basis of the difference between these chemotypes would assist breeding and optimising artemisinin biosynthesis. Here we present a systematic comparison of artemisinin biosynthesis genes that may be involved in determining the chemotype (CYP71AV1, DBR2 and ALDH1). These genes were isolated from the two chemotypes and characterized using transient expression in planta. The enzyme activity of DBR2 and ALDH1 from the two chemotypes did not differ, but structural differences in CYP71AV1 from LAP and HAP chemotypes (AMOLAP and AMOHAP, respectively) resulted in altered enzyme activity. AMOLAP displays a seven amino acids N-terminal extension compared with AMOHAP. The GFP fusion of both proteins show equal localization to the ER but AMOHAP may have reduced stability. Upon transient expression in Nicotiana benthamiana, AMOLAP displayed a higher enzyme activity than AMOHAP. However, expression in combination with the other pathway genes also resulted in a qualitatively different product profile ('chemotype'); that is, in a shift in the ratio between the unsaturated and saturated (dihydro) branch of the pathway. PMID- 23638870 TI - Missed opportunities for HIV testing in newly-HIV-diagnosed patients, a cross sectional study. AB - BACKGROUND: In France, 1/3 HIV-infected patients is diagnosed at an advanced stage of the disease. We describe missed opportunities for earlier HIV testing in newly-HIV-diagnosed patients. METHODS: Cross sectional study. Adults living in France for >=1 year, diagnosed with HIV-infection <=6 months earlier, were included from 06/2009 to 10/2010. We collected information on patient characteristics at diagnosis, history of HIV testing, contacts with healthcare settings, and occurrence of HIV-related events 3 years prior to HIV diagnosis. During these 3 years, we assessed whether or not HIV testing had been proposed by the healthcare provider upon first contact in patients notifying that they were MSM or had HIV-related conditions. RESULTS: 1,008 newly HIV-diagnosed patients (mean age: 39 years; male: 79%; MSM: 53%; diagnosed with an AIDS-defining event: 16%). During the 3-year period prior to HIV diagnosis, 99% of participants had frequented a healthcare setting and 89% had seen a general practitioner at least once a year. During a contact with a healthcare setting, 91/191 MSM (48%) with no HIV-related conditions, said being MSM; 50 of these (55%) did not have any HIV test proposal. Only 21% (41/191) of overall MSM who visited a healthcare provider received a test proposal. Likewise, 299/364 patients (82%) who sought care for s had a missed opportunity for HIV testing. CONCLUSIONS: Under current screening policies, missed opportunities for HIV testing remain unacceptably high. This argues in favor of improving risk assessment, and HIV-related conditions recognition in all healthcare facilities. PMID- 23638872 TI - Exploring the mealtime experience in residential care settings for older people: an observational study. AB - Improving the mealtime experience in residential care can be a major facilitator in improving care, well-being and QoL. Evidence suggests that, despite guidance on the subject of food, nutrition and hydration, there are still concerns. Although there is a range of methods to research and assess the quality of food provision, there is a challenge in capturing the experiences of those residents who are unable or unwilling to describe their feelings and experiences because of frailty, impaired communication or other vulnerability. The aim of this exploratory study was to capture and describe individual residents' mealtime experience. In spring 2011, a small-scale, observational study was carried out in seven dining settings in four residential care homes in Manchester. An adapted dementia care mapping tool was used alongside field notes. Observations showed two major differences in the way the mealtimes were organised: 'pre-plated' and 'family-style' (where either bowls of food are placed in the centre of the table or food is served directly from a hotplate by a chef). These two styles of service are discussed in relation to the emerging themes of 'task versus resident centred mealtimes', 'fostering resident independence' and 'levels of interaction'. Although improving mealtimes alone is not enough to improve quality of life in care homes, findings showed that relatively small changes to mealtime delivery can potentially have an impact on resident well-being in these homes. Observation is a useful method of engaging residents in care settings for older people who may not otherwise be able to take part in research. PMID- 23638874 TI - Granulocyte-colony-stimulating factor treatment enhances Foxp3(+) T lymphocytes and modifies the proinflammatory response in experimental autoimmune neuritis. PMID- 23638873 TI - Contribution of three-dimensional conformal intensity-modulated radiation therapy for women affected by bulky stage II supradiaphragmatic Hodgkin disease. AB - PURPOSE: To analyze the outcome and dose distribution of intensity-modulated radiation therapy (IMRT) by helical tomotherapy in women treated for large supradiaphragmatic Hodgkin's disease. MATERIAL AND METHODS: A total of 13 patients received adjuvant radiation at a dose of 30 Gy to the initially involved sites with a boost of 6 Gy to those areas suspected of harboring residual disease on the simulation CT scan. RESULTS: With a median follow-up of 23 months, the two year progression-free survival was 91.6%, and the 2- and 3-year overall survivals were 100%. We did not report any heart or lung acute side effects. The conformity index of PTV (Planning Target Volume) was better for IMRT than for 3D-CRT (p=0.001). For the breasts, lungs, heart, thyroid and esophagus, the volume distributions favored the IMRT plans. For the breasts, the V(20Gy), V(25Gy) and V(30Gy) were 1.5, 2.5 and 3.5 times lower, respectively, for IMRT than for 3D CRT. For the lung tissues, the V(20Gy) and V(30Gy) were 2 times and 4.5 times lower, respectively, for IMRT than for 3D-CRT. For the heart, the V(20Gy) and V(30Gy) were 1.4 and 2 times lower, respectively, for IMRT than for 3D-CRT. For the esophagus, the V(35Gy) was 1.7 lower for IMRT than for 3D-CRT, and for the thyroid, the V(30Gy) was 1.2 times lower for IMRT. CONCLUSION: IMRT by helical tomotherapy improved the PTV coverage and dramatically decreased the dose in organs at risk. The treatment was well tolerated, but a longer follow-up is necessary to prove a translation of these dosimetric improvements in the outcome of the patients. PMID- 23638875 TI - Heat shock induces interferon-TAU gene expression by in vitro-produced bovine blastocysts. AB - PROBLEM: The type I interferon (IFN), IFN-tau (tau), is the primary embryonic signal for pregnancy maintenance in ruminants. This study determined the effects of heat shock upon IFN-tau (IFNT) gene expression by bovine blastocysts in vitro. METHOD OF STUDY: In vitro-produced blastocyst-stage embryos were exposed to 42 degrees C for 4 hr, and mRNA for heat-shock protein 70 (HSP70) and IFNT quantified. RESULTS: Heat shock increased both HSP70 and IFNT expression. There was a significant correlation between HSP70 and IFNT transcript levels irrespective of whether a blastocyst had been exposed to heat shock or not. CONCLUSION: The increase in IFNT as a result of heat shock suggests that a proportion of the variation in IFNT expression observed in blastocyst-stage embryos is a response to stress. PMID- 23638876 TI - Sensitivity limits and scaling of bioelectronic graphene transducers. AB - Semiconducting nanomaterials are being intensively studied as active elements in bioelectronic devices, with the aim of improving spatial resolution. Yet, the consequences of size-reduction on fundamental noise limits, or minimum resolvable signals, and their impact on device design considerations have not been defined. Here, we address these key issues by quantifying the size-dependent performance and limiting factors of graphene (Gra) transducers under physiological conditions. We show that suspended Gra devices represent the optimal configuration for cardiac extracellular electrophysiology in terms of both transducer sensitivity, systematically ~5* higher than substrate-supported devices, and forming tight bioelectronic interfaces. Significantly, noise measurements on free-standing Gra together with theoretical calculations yield a direct relationship between low-frequency 1/f noise and water dipole-induced disorders, which sets fundamental sensitivity limits for Gra devices in physiological media. As a consequence, a square-root-of-area scaling of Gra transducer sensitivity was experimentally revealed to provide a critical design rule for their implementation in bioelectronics. PMID- 23638879 TI - Detection of aflatoxin M1 in milk by dynamic light scattering coupled with superparamagnetic beads and gold nanoprobes. AB - This study aimed to develop a rapid and sensitive method for detection of aflatoxin M1 (AFM) by dynamic light scattering (DLS) coupled with superparamagnetic beads and gold nanoprobes. The nanoprobes were synthesized by the conjugate of AFM and bovine serum albumin (AFM-BSA), BSA, and gold nanoparticles. Magnetic beads-based immunosorbent assay (MBISA) was used to measure the concentration of AFM by direct competition between AFM and nanoprobes. DLS was used to determine the concentration of unattached nanoprobes that was positively proportional to the concentration of AFM in the sample. TEM images prove that the as-prepared nanoprobes were able to attach on the magnetic beads through the antibody-antigen reaction. Compared to conventional ELISA, MBISA could effectively reduce the incubation time to 15 min in buffer solution and completely eliminate the color development step, thus simplifying the analysis of AFM. A linear relationship was observed between the inhibition values and the concentrations of AFM in both buffer solution (0-1000 ng.L(-1)) and spiked milk samples (0-400 ng.L(-1)). The limit of detection was found to be 37.7 ng.L(-1) for AFM in buffer solution and 27.5 ng.L(-1) in milk samples. These results demonstrate that DLS coupled with magnetic beads and gold nanoprobes is a rapid and effective method to detect AFM. This method could also be easily extended to rapid detection of other mycotoxins and biological species. PMID- 23638877 TI - Calcium channel blockers and dementia. AB - Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid-beta. Recent studies suggest that soluble forms facilitate influx through calcium-conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid-beta-induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof-of-concept studies are now available. PMID- 23638878 TI - Role of p38 and JNK MAPK signaling pathways and tumor suppressor p53 on induction of apoptosis in response to Ad-eIF5A1 in A549 lung cancer cells. AB - BACKGROUND: The eukaryotic translation initiation factor 5A1 (eIF5A1) is a highly conserved protein involved in many cellular processes including cell division, translation, apoptosis, and inflammation. Induction of apoptosis is the only function of eIF5A1 that is known to be independent of post-translational hypusine modification. In the present study, we investigated the involvement of mitogen- and stress-activated protein kinases during apoptosis of A549 lung cancer cells infected with adenovirus expressing eIF5A1 or a mutant of eIF5A1 that cannot be hypusinated (eIF5A1K50A). METHODS: Using adenoviral-mediated transfection of human A549 lung cancer cells to over-express eIF5A1 and eIF5A1K50A, the mechanism by which unhypusinated eIF5A1 induces apoptosis was investigated by Western blotting, flow cytometry, and use of MAPK and p53 inhibitors. RESULTS: Phosphorylation of ERK, p38 MAPK, and JNK was observed in response to adenovirus mediated over-expression of eIF5A1 or eIF5A1K50A, along with phosphorylation and stabilization of the p53 tumor suppressor protein. Synthetic inhibitors of p38 and JNK kinase activity, but not inhibitors of ERK1/2 or p53 activity, significantly inhibited apoptosis induced by Ad-eIF5A1. Importantly, normal lung cells were more resistant to apoptosis induced by eIF5A1 and eIF5A1K50A than A549 lung cancer cells. CONCLUSIONS: Collectively these data indicate that p38 and JNK MAP kinase signaling are important for eIF5A1-induced cell death and that induction of apoptosis was not dependent on p53 activity. PMID- 23638880 TI - Structural insights into the theoretical model of Plasmodium falciparum NADH dehydrogenase and its interaction with artemisinin and derivatives: towards global health therapeutics. AB - It is a continuing quest to uncover the principal molecular targets of malarial parasites to understand the antimalarial activity and mechanism of action of artemisinin, a potent antimalarial. A series of parasite proteins are experimentally validated as potential targets, such as translationally controlled tumor protein (TCTP) and sarco/endoplasmic reticulum membrane calcium ATP-ase (SERCA). The present study addressed the development of a theoretical model of Plasmodium falciparum NADH dehydrogenase with inference from artemisinin in vivo inhibitory activity. We report here the predicted binding modes of artemisinin and its derivatives. The modeled protein resembled the structural architecture of flavoproteins and oxidoreductases, consisting of two Rossmann folds and dedicated binding sites for its cofactors. Docked poses of the ligand dataset revealed its interactions at or near the si face, indicating being activated. This may aid in generation of reactive oxygen species, thereby disrupting the membrane potential of parasite mitochondria and leading to the clearance from the blood. These observations open up new strategies for development of novel therapeutics, or improvement of existing pharmacotherapies against malaria, a major burden for global health. PMID- 23638881 TI - Mapping QTLs for traits related to salinity tolerance at seedling stage of rice (Oryza sativa L.): an agrigenomics study of an Iranian rice population. AB - Rice (Oryza sativa L.) is one of the most important food crops in the world, especially in Asian countries, and salinity is a major constraint to the sustainability and expansion of rice cultivation. Genetically improving salt tolerance of rice is a highly important objective of rice breeding programs. Traits such as salt tolerance are quantitatively inherited. Hence, mapping quantitative trait loci (QTL) with molecular markers can be very helpful to plant breeders in the field of agricultural genomics (AgriGenomics). In this investigation, QTL analysis of physiological traits related to salt tolerance was carried out using F2:4 population of rice derived from a cross between a salt tolerant variety, Gharib (indica), and a salt-sensitive variety, Sepidroud (indica). A linkage map based on 148 F2 individuals was constructed with 131 SSR markers and 105 AFLP markers, covering 2475.7 cM of rice genome with an average distance of 10.48 cM between flanking markers. A total of 41 QTLs for twelve physiological traits under salinity stress were detected distributed on all rice chromosomes, some of them being reported for the first time. Also, overlapping of QTLs related to salt tolerance were observed in this study. Some of the identified QTLs on specific chromosomal regions explaining high phenotypic variance could be used for marker-assisted selection (MAS) programs. New QTLs retrieved in this study play an important role in growth of rice at seedling stage in an Iranian local population under high salinity conditions. PMID- 23638882 TI - A case of phytodermatitis due to the Ceratocephalus falcatus. AB - Many people widely use herbal therapies for health problems in the world. Although these herbal therapies sometimes may be useful for some disorders they are not risk free. Ceratocephalus falcatus is an annual, wild plant which is a member of Ranunculaceae family. There are few case reports of phytodermatitis due to the Ranunculaceae family. We present a 58-year-old woman with irritant phytodermatitis due to C. falcatus. PMID- 23638883 TI - Isobaric protein-level labeling strategy for serum glycoprotein quantification analysis by liquid chromatography-tandem mass spectrometry. AB - While peptide-level labeling using isobaric tag reagents has been widely applied for quantitative proteomics experiments, there are comparatively few reports of protein-level labeling. Intact protein labeling could be broadly applied to quantification experiments utilizing protein-level separations or enrichment schemes. Here, protein-level isobaric labeling was explored as an alternative strategy to peptide-level labeling for serum glycoprotein quantification. Labeling and digestion conditions were optimized by comparing different organic solvents and enzymes. Digestions with Asp-N and trypsin were found highly complementary; combining the results enabled quantification of 30% more proteins than either enzyme alone. Three commercial reagents were compared for protein level labeling. Protein identification rates were highest with iTRAQ 4-plex when compared to TMT 6-plex and iTRAQ 8-plex using higher-energy collisional dissociation on an Orbitrap Elite mass spectrometer. The compatibility of isobaric protein-level labeling with lectin-based glycoprotein enrichment was also investigated. More than 74% of lectin-bound labeled proteins were known glycoproteins, which was similar to results from unlabeled and peptide-level labeled serum samples. Finally, protein-level and peptide-level labeling strategies were compared for serum glycoprotein quantification. Isobaric protein level labeling gave comparable identification levels and quantitative precision to peptide-level labeling. PMID- 23638884 TI - A complicated liaison: IL-33 and IL-33R in arthritis pathogenesis. AB - Interruption of cytokine signaling, by targeting either the cytokine itself or its cellular receptor, is a mainstay in the therapy for patients with rheumatic diseases. Interleukin (IL)-33, a member of the IL-1 cytokine family, has emerged as an important mediator of inflammatory responses. In a side-by-side examination of IL-33-deficient and IL-33 receptor (IL-33R)-deficient mice in the K/BxN serum transfer model, arthritis was ameliorated in the IL-33R knockout (KO) mice but not in the IL-33 KO mice. These findings complement previous knowledge on IL-33R signaling, demonstrating that the IL-33R cross-activates other signaling pathways in addition to IL-33-mediated signals. The results reported by Martin and colleagues in a previous issue of Arthritis Research & Therapy underline the clinical relevance of IL-33R cross-signaling and further illustrate that targeting a cytokine receptor (IL-33R) can have completely different clinical outcomes than targeting the respective cytokine. PMID- 23638885 TI - Short-chain fatty acid-modified hexosamine for tissue-engineering osteoarthritic cartilage. AB - Inflammation and tissue degeneration play key roles in numerous rheumatic diseases, including osteoarthritis (OA). Efforts to reduce and effectively repair articular cartilage damage in an osteoarthritic environment are limited in their success due to the diseased environment. Treatment strategies focused on both reducing inflammation and increasing tissue production are necessary to effectively treat OA from a tissue-engineering perspective. In this work, we investigated the anti-inflammatory and tissue production capacity of a small molecule 3,4,6-O-tributanoylated-N-acetylglucosamine (3,4,6-O-Bu3GlcNAc) previously shown to inhibit the nuclear factor kappaB (NFkappaB) activity, a key transcription factor regulating inflammation. To mimic an inflammatory environment, chondrocytes were stimulated with interleukin-1beta (IL-1beta), a potent inflammatory cytokine. 3,4,6-O-Bu3GlcNAc exposure decreased the expression of NFkappaB target genes relevant to OA by IL-1beta-stimulated chondrocytes after 24 h of exposure. The capacity of 3,4,6-O-Bu3GlcNAc to stimulate extracellular matrix (ECM) accumulation by IL-1beta-stimulated chondrocytes was evaluated in vitro utilizing a three-dimensional hydrogel culturing system. After 21 days, 3,4,6-O-Bu3GlcNAc exposure induced quantifiable increases in both sulfated glycosaminoglycan and total collagen. Histological staining for proteoglycans and type II collagen confirmed these findings. The increased ECM accumulation was not due to the hydrolysis products of the small molecule, n-butyrate and N acetylglucosamine (GlcNAc), as the isomeric 1,3,4-O-tributanoylated N acetylglucosamine (1,3,4-O-Bu3GlcNAc) did not elicit a similar response. These findings demonstrate that a novel butanoylated GlcNAc derivative, 3,4,6-O Bu3GlcNAc, has the potential to stimulate new tissue production and reduce inflammation in IL-1beta-induced chondrocytes with utility for OA and other forms of inflammatory arthritis. PMID- 23638887 TI - Quantum suppression of ratchet rectification in a Brownian system driven by a biharmonic force. AB - We rigorously investigate the quantum dissipative dynamics of a ratchet system described by a periodic potential model based on the Caldeira-Leggett Hamiltonian with a biharmonic force. In this model, we use the reduced hierarchy equations of motion in the Wigner space representation. These equations represent a generalization of the Gaussian-Markovian quantum Fokker-Planck equation introduced by Tanimura and Wolynes (1991), which was formulated to study non Markovian and nonperturbative thermal effects at finite temperature. This formalism allows us to treat both the classical limit and the tunneling regimes, and it is helpful for identifying purely quantum mechanical effects through the time evolution of the Wigner distribution. We carried out extensive calculations of the classical and quantum currents for various temperatures, coupling strengths, and barrier heights. Our results reveal that at low temperature, while the quantum current is larger than the classical current in the case of a high barrier, the opposite is true in the case of a low barrier. We find that this behavior results from the fact that the tunneling enhances the current in the case of a high barrier, while it suppresses the current in the case of a low barrier. This is because the effect of the ratchet potential is weak in the case of a low barrier due to the large dispersion of the distribution introduced by tunneling. This causes the spatiotemporal asymmetry, which is necessary for ratchet current, to be weak, and as a result, the net current is suppressed. PMID- 23638886 TI - Crohn's disease-specific pancreatic autoantibodies are specifically present in ruminants with paratuberculosis: implications for the pathogenesis of the human disease. AB - Mycobacterium avium subspecies paratuberculosis (MAP) induces paratuberculosis (ptb) in ruminants and has clinical and histological features resebling Crohn's disease (CD). Pancreatic autoantibodies (PAB) targeting glycoprotein 2 (GP2) are specifically found in CD, but it is currently unknown whether these autoantibodies can be found in ruminants with ptb. IgG anti-MAP and anti-GP2 antibodies were tested by ELISA in 286 ruminants (212 sheep and 74 cattle). PAB testing was performed by indirect immunofluorescence (IIF) using anti-sheep or anti-cattle specific antisera. PCR analysis confirmed the presence of MAP in anti MAP positive samples. Anti-GP2 antibodies were more prevalent in anti-MAP antibody positive (26.9%) than in anti-MAP negative ruminants (8.7%, p < 0.001). Anti-GP2 antibodies were found in 16/70 (22.9%) anti-MAP positive sheep compared to 10/142 (7%, p = 0.001) anti-MAP antibody negative and in anti-MAP positive cattle than in negative counterparts (5/8 versus 8/66, p = 0.003). Absorbance values for anti-GP2 antibodies were higher in cattle than in sheep (mean 21 AU/mL +/- 25.4SD versus 12.2 AU/mL +/- 23 SD, p < 0.001). There was no correlation between anti-GP2 and anti-MAP antibody concentrations. Anti-GP2 antibodies persisted up to 1/1000 and showed the characteristic IIF pancreatic pattern seen by anti-GP2 antibody positive CD samples. This is the first study to demonstrate the presence of CD-specific GP2-reactive pancreatic autoantibodies in MAP infected ruminants. Our data suggest that CD and ptb are characterised by an antigen-driven loss of immunological tolerance to GP2, implying commonalities in the immunopathogenesis of the human and ruminant inflammatory bowel disorder. PMID- 23638888 TI - Characterization of distribution of pesticide residues in crop units. AB - The characteristic features of distribution of pesticide residues in crop units and single sample increments were studied based on more than 19,000 residue concentrations measured in root vegetables, leafy vegetables, small-, medium- and large-size fruits representing 20 different crops and 46 pesticides. Log-normal, gamma and Weibull distributions were found to provide the best fit for the relative frequency distributions of individual residue data sets. The overall best fit was provided by lognormal distribution. The relative standard deviation of residues (CV) in various crops ranged from 15-170%. The 100-120 residue values being in one data set was too small to identify potential effects of various factors such as the chemical and physical properties of pesticides and the nature of crops. Therefore, the average of CV values, obtained from individual data sets, were calculated and considered to be the best estimate for the likely variability of unit crop residues for treated field (CV = 0.8) and market samples (CV = 1.1), respectively. The larger variation of residues in market samples was attributed to the potential mixing of lots and varying proportion of non-detects. The expectable average variability of residues in composited samples can be calculated from the typical values taking into account the sample size. PMID- 23638889 TI - Predictability by Box-Behnken model for carbaryl adsorption by soils of Indian origin. AB - This study was undertaken to investigate the adsorption capacity of carbaryl on four Indian soils with different physiochemical properties. A batch adsorption study was carried out in order to evaluate the maximum adsorption capacity of carbaryl using a Response Surface Methodology (RSM). The effects of operating parameter such as initial carbaryl concentration (1-20 mgL-1), adsorbent dosage (0.5-6 g) and contact time (10-180 min) were examined. The proposed quadratic model for Box-Behnken design fits very well to the experimental data because it may be used to navigate design space according to ANOVA results. The regression co-efficient (R2) of the models developed and the results of validation experiments conducted at optimal conditions strongly suggests that the predicted values are in good agreement with experimental results. Contour and response surface plots are used to determine the interactions effects of main factors and optimal conditions of the process. The experiment can be utilized as a guideline for better understanding of carbaryl adsorption onto soil under different operating conditions. The results show that the forest soil is most efficient in binding carbaryl (Sevin) than the other types of soil tested. PMID- 23638891 TI - Sorption and desorption of sulfentrazone in Brazilian soils. AB - This study was undertaken to obtain information about the behavior of sulfentrazone in soil by evaluating the sorption and desorption of the herbicide in different Brazilian soils. Batch equilibrium method was used and the samples were analyzed by high performance liquid chromatography. Based on the results obtained from the values of Freundlich constants (Kf), we determined the order of sorption (Haplic Planosol < Red-Yellow Latosol < Red Argisol < Humic Cambisol < Regolitic Neosol) and desorption (Regolitic Neosol < Red Argisol < Humic Cambisol < Haplic Planosol < Red-Yellow Latosol) of sulfentrazone in the soils. The process of pesticide sorption in soils was dependent on the levels of organic matter and clay, while desorption was influenced by the organic matter content and soil pH. Thus, the use of sulfentrazone in soils with low clay content and organic matter (low sorption) increases the probability of contaminating future crops. PMID- 23638890 TI - Immunotoxicity of atrazine in Balb/c mice. AB - The present study was designed to investigate the immunotoxicity of atrazine (ATZ) in male Balb/c mice. ATZ (175, 87.5, and 43.75 mg/kg bw/day) was administered by gavage method for 28 days. The following indexes were determined in various groups of mice: body and organ weight; antibody aggregation of serum hemolysin; proliferative response of splenocytes to ConA; delayed-type hypersensitivity (DTH); natural killer cell activity; clearance of neutral red and nitric oxide (NO) release from peritoneal macrophages; apostosis and necrosis of splenocytes and thymocytes; cytokine production; and serum lysozyme. Results showed that cell-mediated, humoral immunity, and non-specific immune function in the high-dose ATZ group were suppressed; NO release and interferon-gamma(IFN gamma)/interleukin-4 (IL-4) were also significantly decreased in the high-dose group. In the medium-dose group, the proliferation response and IFN-gamma production was significantly decreased. In the low-dose group, the proliferation response was significantly decreased. Serum lysozyme was decreased in the ATZ treated groups. The percentage of early apoptosis in thymocytes was increased significantly in high- and medium-dose ATZ groups. In conclusion, ATZ elicited an inhibitory effect on cell-mediated immunity, humoral immunity, and non-specific immune function of mice. PMID- 23638892 TI - Sublethal impact of paraquat on the life span and parasitic behavior of Diaeretiella rapae M'Intosh. AB - This study focuses on assessing the impact of sublethal doses of paraquat on the survival, the emergence, the life span and the parasitic behavior of Diaeretiella rapae M'Intosh (Hymenoptera: Braconidae). The impact of sublethal doses was measured at room temperature using different densities of the cabbage aphid Brevicoryne brassicae. The results reveal that the field dose of paraquat caused 100% mortality in D. rapae. The percentage emergence of D. rapae decreased from 80.5% in the control group to 71.5% when treated with the lowest concentration of paraquat. Similarly, the life span of parasitoids that emerged from the mummy treated with paraquat also decreased significantly. Oviposition capability and ovipositor thrusting frequency of D. rapae also treated with sublethal dose paraquat decreased significantly along with a shortened patch residence time in the foraging area. PMID- 23638893 TI - Occurrence and ecological hazard assessment of selected veterinary medicines in livestock wastewater treatment plants. AB - The occurrence of some veterinary medicines in the livestock wastewater plants (WWTPs) was investigated. This investigation represented the occurrence of veterinary medicines to treat in the livestock WWTPs or be discharged into the water system in Korea since the sampling sites were widely distributed across the nation and samples were collected from the 11 livestock WWTPs. Nine antibiotics, two analgesics, and two disinfectants occurred in the livestock wastewater plants (WWTPs). From 11 livestock WWTP influents, chlortetracycline, oxytetracycline, acetylsalicylic acid, and disinfectants frequently occurred with the high concentrations. Meanwhile, sulfamethoxazole, erythromycin-H2O, and trimethoprim did not occur during sampling periods. The values for log Kow of each chemical showed a high correlation with the number of hydrogen bonding acceptors and were important parameters to estimate and understand the biodegradability and toxicity of a compound in the environment. The biodegradability of each compound was proportional to the hydrophilicity of each compound and the toxicity was proportional to the number of hydrogen bonding acceptors of each compound. The expected introductory concentration (EIC), predicted exposure concentration (PEC), and hazard quotient showed that the livestock WWTP effluents were hazardous to ecosystems. PMID- 23638894 TI - Semisynthesis of N-acyl homoserinelactone derivatives and the antifeedant activity against Mythimna separata. AB - Seven homoserine-lactone (HL) acylated derivatives (HL1-HL7) were synthesized to determine the differences in antifeedant affects. The differences between these derivatives and tutin against Mythimna separata were tested. The structural assignments of these semisynthetic compounds were examined based on their infrared radiaion (IR), electrospray ionization mass spectrometry (ESIMS), and 1H and 13C-nuclear magnetic resonance (13C-NMR) spectral data. Compound HL1 (N-(4 nitrobenzoyl)-homoserinelactone) is the optimized insecticidal agent among these compounds. In addition, the antifeedant activities between homoserinelactone and 7-hydroxycoumarin, tutin derivatives with the same acidylated substitutions were compared, which could help design and synthesize stronger novel botanical insecticides. PMID- 23638895 TI - Development of controlled release formulations of thiram employing amphiphilic polymers and their bioefficacy evaluation in seed quality enhancement studies. AB - Controlled release formulations of Thiram (Dimethylcarbamothioylsulfanyl-N,N dimethylcarbamodithioate), a contact fungicide, have been prepared using laboratory synthesized poly(ethylene glycol) (PEG) based functionalized amphiphilic copolymers. The kinetics of thiram from developed controlled release (CR) formulations were studied in comparison with that of the commercially available 75 WS. Release from the commercial formulation was faster than with the developed CR formulations. Maximum amount of thiram was released on 35th day for PEG-2000 4d, 28th day for PEG-1500 4c, 21st day for PEG-1000 4b and 15th day for PEG-600 4a in comparison to commercial formulation (7th day). The diffusion exponent (n) of thiram in water ranged from 0.356 to 0.545 in the tested formulations. The half-release (t(1/2)) values ranged between 14.78 to 22.1 days, and the Period of Optimum Availability (POA) of thiram ranged from 7.79 to 25.15 days. An effort has also been made to identify the suitable polymers that could reduce the seed deterioration during storage and also act as an effective carrier of fungicide thiram. The results demonstrate that the seeds coated with the different formulations deteriorated at a slower pace as manifested in high germination percentage over control. Apart from the fungicidal effect of thiram, the polymers acted as barriers to moisture reducing the rate of seed deterioration and checked the degradation of thiram. The CR formulation 4d, with PEG 2000, was found to be most effective as seed coat. PMID- 23638896 TI - Photocatalytic degradation of malathion by TiO2 and Pt-TiO2 nanotube photocatalyst and kinetic study. AB - Photocatalytic degradation of malathion, is investigated using Titanium Nanotubes (TNT) and Pt modified TNT (Pt-TNT) photocatalyst in an aqueous solution under 365 nm UV lamp irradiation. The TNT photocatalyst is prepared on pretreated strong alkaline solution via the hydrothermal method. The Pt-TNT was prepared by light deposition. The variations in morphology, formation mechanism, phase structure, and pore structure of TNT and Pt-TNT are characterized using UV-Vis, transmission electron microscopy (TEM), and N2 adsorption/desorption isotherm analyzer, respectively. The effect of the initial malathion concentration, reaction temperature, catalyst loading, solution pH value, irradiation time and Pt loading are studied and the optimized values are obtained. Moreover, the photodegradation performance and kinetics of malathion onto TNT and Pt-TNT are also examined with the aid of model analysis by kinetic data. The results show that under acid conditions, the performance of photocatalysts for treating malathion is high. The time of complete degradation increases with an increase in the initial malathion concentration. The degradation rate decreases with increasing initial malathion concentration. The degradation efficiency can reach 100% under acid conditions for any initial malathion concentration when the reaction time is 70 min. In addition, experimental decoloration kinetics data follow the pseudo-first-order reaction model. PMID- 23638897 TI - The integration of in vivo and in vitro metabolism assays to investigate the stereoselective behaviors of benalaxyl in rainbow trout (Oncorhynchus mykiss). AB - The bioconcentration and elimination of racemic benalaxyl (BX) in trout liver microsomes and in juvenile rainbow trout (Oncorhynchus mykiss) were investigated to determine whether the fish can bioconcentrate and degrade this fungicide enantioselectively. Both enantiomers of BX were extracted with organic solvents and evaluated using high-performance liquid chromatography. In the microsomes, BX degradation followed first-order kinetics, and the S-(+) enantiomer of BX was eliminated twice as rapidly as the R-(-) enantiomer, resulting in residues enriched for R-(-)-BX. In vivo experiment, chiral analysis showed an obvious selective bioconcentration of BX based on statistically altered enantiomer fractions (EFs) in the fish compared with the values in the water. The R-(-)-BX was initially preferentially bioconcentrated by rainbow trout and then dissipated more slowly than its antipode. The mean half-lives for individual enantiomers were calculated as 31.6 h for R-(-)-BX and 20.3 h for the S-(+)-form. The results of the study showed that the degradation of BX enantiomers was stereoselective in rainbow trout. PMID- 23638898 TI - Step-down of budesonide/formoterol in early stages of asthma treatment leads to insufficient anti-inflammatory effect. AB - OBJECTIVE: Administration of the combination of an inhaled corticosteroid (ICS) and a long-acting beta agonist (LABA) is the main treatment strategy for bronchial asthma. The ICS/LABA dosage can be reduced (stepped down) when the patient's symptoms and lung functions are well-controlled. In this study, we obtained fractional exhaled nitric oxide (FeNO) measurements to clarify whether the anti-inflammatory effect of budesonide/formoterol is shortened by step-down. METHODS: Fifty-four patients who visited the Kawasaki Medical School Hospital with newly diagnosed asthma from November 2008 to July 2010 received budesonide/formoterol for 8 weeks or more. In 29 patients, the forced expiratory volume in 1 s% predicted increased to 80% or more, and the Asthma Control Questionnaire (ACQ) score decreased to 0.5 or less within 12 weeks. These 29 patients were randomly divided into two groups: the dosage-continued group (n = 14) and the step-down group (n = 15). Then, the impact of budesonide/formoterol step-down on ACQ score, pulmonary function and FeNO level was compared between the groups. RESULTS: In the step-down group, the dosage was stepped down from 538 mcg/day to 331 mcg/day. In both groups, pulmonary function indicators and symptoms did not change. However, the mean FeNO level decreased significantly in the dosage-continued group (from 50.9 ppb to 45.0 ppb), and increased significantly in the step-down group (from 51.0 ppb to 65.7 ppb). CONCLUSIONS: Clinicians should be more careful when stepping down budesonide/formoterol based solely on patients' symptoms and/or pulmonary function. PMID- 23638899 TI - Simple recessive mutation in ENAM is associated with amelogenesis imperfecta in Italian Greyhounds. AB - We report a familial enamel hypoplasia in Italian Greyhounds resembling non syndromic autosomal recessive amelogenesis imperfecta (AI) of humans. The condition uniformly affects deciduous and permanent teeth and is manifested by enamel roughening/thinning and brownish mottling. Affected teeth are often small and pointed with increased gaps. However, basic tooth structure is usually maintained throughout life, and fractures and dental cavities are not a serious problem as in humans. No tissues or organs other than teeth were affected by this mutation, and there was no relationship between enamel hypoplasia and either autoimmunity or periodontal disease, which also are prevalent in the breed. The enamel hypoplasia was associated with a 5-bp deletion in exon 10 of the enamelin (ENAM) gene. The prevalence of the enamel defect in Italian Greyhounds was 14%, and 30% of dogs with normal teeth were carriers. Genome analyses suggest that the trait is under inadvertent positive selection. Based on the deletion detected in the ENAM gene, a genetic test was developed for identifying mutation carriers, which would enable breeders to manage the trait. PMID- 23638900 TI - Curcumin acts via transient receptor potential vanilloid-1 receptors to inhibit gut nociception and reverses visceral hyperalgesia. AB - BACKGROUND: An antinociceptive effect has been reported for curcumin in animal models and in humans, but the molecular mechanisms of curcumin's effect remain undefined. In this study, we explored the possibility that curcumin inhibit visceral nociception via antagonizing the transient receptor potential vanilloid 1 (TRPV1) receptor. METHODS: The effects of curcumin were explored using two experimental models: viscero-motor response (VMR) to colorectal distension (CRD) in rats and jejunal afferent firing in the ex vivo mouse jejunum preparations [TRPV1 knockout (KO) and wild-type mice, naive and trinitrobenzene sulfonic acid (TNBS)-treated Kunming mice]. In addition, capsaicin-induced calcium transients and whole-cell currents were examined in acutely dissociated dorsal root ganglia (DRG) neurons. KEY RESULTS: In the anesthetized rat, curcumin (4 mg kg(-1) min( 1) for 3 min) caused a marked and rapidly reversible inhibition of CRD-induced VMRs. In the mouse jejunum, the mesenteric afferent nerve response to ramp distension was attenuated by curcumin (3, 10 MUmol L(-1) ), an effect that was significantly reduced in TRPV1 KO mice compared with wild-type (WT) controls. Moreover, in WT mice, curcumin (1-30 MUmol L(-1) ) was found to inhibit the afferent responses to capsaicin in a concentration-dependent manner. Trinitrobenzene sulfonic acid-induced hypersensitivity of jejunal afferents was also attenuated by curcumin. Curcumin potently inhibited capsaicin-induced rise in intracellular calcium and inward currents in mouse or rat DRG neurons. CONCLUSIONS & INFERENCES: Our results provide strong evidence that curcumin inhibit visceral nociception via antagonizing TRPV1 and may be a promising lead for the treatment of functional gastrointestinal diseases. PMID- 23638901 TI - Interfacial self-assembly and characterization of chiral coordination polymer multilayers with bidentate ligands of hydroquinine anthraquinone-1,4-diyl diether as linkers. AB - Chiral coordination polymers (CPs) have been prepared at the air-water interface by using the ligand of 1,4-bis(9-O-dihydroquininyl)anthraquinone [(DHQ)2AQN] and its enantiomer of 1,4-bis(9-O-dihydroquinidinyl)anthraquinone [(DHQD)2AQN] as linkers and AgNO3 as the connector. Surface pressure-area isotherms indicated that both ligands could form insoluble monomolecular layers on the pure water and AgNO3 subphase surfaces. Compared with the average molecular area on the pure water surface, that of the ligand increased about 10% when its monolayer was formed on the AgNO3 subphase surface due to the formation of Ag-(DHQ)2AQN and Ag (DHQD)2AQN chiral CPs. These monolayers were deposited on the quartz, Si, and indium tin oxide (ITO) substrate surfaces via the Langmuir-Blodgett (LB) method. The as-prepared LB films were characterized by using UV-vis absorption and fluorescence spectroscopy, circular dichroism and X-ray photoelectron spectroscopy, as well as by using a scanning electron microscope and atomic force microscope. Broad fluorescence emissions were measured at about 365 and 525 nm for the ligands in the methanol solutions. The second emission red shifted to about 555 nm in the LB films of both pure ligands and their Ag-directed CPs. A couple of well-reversible redox waves were recorded and centered at about -0.2 ~ 0.3 V (vs Ag/AgCl) for the ITO electrode covered by the LB films of (DHQ)2AQN, (DHQD)2AQN, or of the Ag(+)-directed CPs, which were designated to one electron transfer process of the ligands. Small aggregates were observed for the LB films prepared at the lower surface pressures, which were compressed to form more uniform two-dimensional layers at the higher surface pressures. PMID- 23638902 TI - An EJC factor RBM8a regulates anxiety behaviors. AB - Neuroplasticity depends on the precise timing of gene expression, which requires accurate control of mRNA stability and rapid elimination of abnormal mRNA. Nonsense-mediated mRNA decay (NMD) is an RNA surveillance mechanism that ensures the speedy degradation of mRNAs carrying premature termination codons (PTCs). This mechanism relies on several key Exon Junction Complex (EJC) factors to distinguish PTCs from normal stop codons. NMD degrades not only aberrant transcripts carrying PTCs, but also normal transcripts harboring a normal stop codon [1]. Intriguingly, mutations in an NMD factor, Upf3b, have been found in patients with autism [2, 3]. A binding partner of Upf3b, RBM8a, is located in the 1q21.1 copy-number variation (CNV) associated with mental retardation, autism [4], schizophrenia [5], and microcephaly [6]. However, the functions of EJC factors and their roles in behavioral regulation are still elusive. RBM8a protein is a core component of the EJC that plays an important role in NMD. Recent genetic study indicated that RBM8a gain-of-function significantly associated with intellectual disability [7]. In this study we investigated the effect of RBM8a overexpression on affective behaviors in mice. Lentivirus expressing RBM8a was infused into the hippocampus of adult mice to conduct behavioral studies including social interaction, open field, elevated plus maze, and forced swimming tests. Our results showed that overexpression of RBM8a in the mouse dentate gyrus (DG) leads to increased anxiety-like behavior, abnormal social interaction and decreased immobile time in forced swimming test (FST). To examine the underlying mechanism, we found that overexpressing RBM8a in cultured primary neurons lead to significant higher frequency of miniature excitatory postsynaptic currents (mEPSCs). To explore the underlying mechanism of RBM8a mediated behavioral changes, RNA-immunoprecipitation (RNA-IP) detected that RBM8a binds to CaMK2, GluR1 and Egr1 mRNA, suggesting that RBM8a may target neuronal genes to regulate behaviors. This is the first study that demonstrates the key role of RBM8a on the emotional behaviors in mice. These results reveal new neural mechanisms by which NMD modulates behaviors and potentially provide a better understanding of pathophysiology underlying psychiatric disorders. PMID- 23638903 TI - Antimicrobial potential of lycosin-I, a cationic and amphiphilic peptide from the venom of the spider Lycosa singorensis. AB - Antimicrobial peptides (AMPs) are significant components of the innate immune system and play indispensable roles in the resistance to bacterial infection. Here, we investigated the antimicrobial activity of lycosin-I, a 24-residue cationic anticancer peptide derived from Lycosa singorensis with high structural similarity to several cationic and amphiphilic antimicrobial peptides. The antimicrobial activity of lycosin-I against 27 strains of microbes including bacteria and fungi was examined and compared with that of the Xenopus-derived AMP magainin 2 using a microdilution assay. Lycosin-I inhibited the growth of most microorganisms at low micromolar concentrations, and was a more potent inhibitor than magainin 2. Lycosin-I showed rapid, selective and broad-spectrum bactericidal activity and a synergistic effect with traditional antibiotics. In vivo, it showed potent bactericidal activity in a mouse thigh infection model. High Mg2+ concentrations reduced the antibacterial effect of lycosin-I, implying that the peptide might directly interact with the bacterial cell membrane. Uptake of the fluorogenic dye SYTOX and changes in the surface of lycosin-Itreated bacterial cells observed by scanning electron microscopy confirmed that lycosin-I permeabilized the cell membrane, resulting in the rapid bactericidal effect. Taken together, our findings indicate that lycosin-I is a promising peptide with the potential for the development of novel antibacterial agents. PMID- 23638904 TI - Effect of a low glycaemic index diet in gestational diabetes mellitus on post natal outcomes after 3 months of birth: a pilot follow-up study. AB - A low glycaemic index (LGI) diet during pregnancy complicated by gestational diabetes mellitus (GDM) may offer benefits to the mother and infant pair beyond those during pregnancy. We aimed to investigate the effect of an LGI diet during pregnancy complicated with GDM on early post-natal outcomes. Fifty-eight women (age: 23-41 years; mean +/- SD pre-pregnancy body mass index: 24.5 +/- 5.6 kg m( 2) ) who had GDM and followed either an LGI diet (n = 33) or a conventional high fibre diet (HF; n = 25) during pregnancy had a 75-g oral glucose tolerance test and blood lipid tests at 3 months post-partum. Anthropometric assessments were conducted for 55 mother-infant pairs. The glycaemic index of the antenatal diets differed modestly (mean +/- SD: 46.8 +/- 5.4 vs. 52.4 +/- 4.4; P < 0.001), but there were no significant differences in any of the post-natal outcomes. In conclusion, an LGI diet during pregnancy complicated by GDM has outcomes similar to those of a conventional healthy diet. Adequately powered studies should explore the potential beneficial effects of LGI diet on risk factors for chronic disease. PMID- 23638905 TI - Evaluation of two single-factor models of metabolic syndrome: a confirmatory factor analysis for an adult population in Beijing. AB - BACKGROUND: Prevalence of metabolic syndrome is high and increasing in China. The causation of this disorder is, yet, to be fully understood. Several studies with confirmatory factor analysis have been performed to investigate the core of the disease in some races other than Chinese, and amongst the other studies, they have yielded a sound model fit. This study was to evaluate and compare two single factor models of the underlying factor structure of metabolic syndrome in a Chinese population using confirmatory factor analysis. RESULTS: Findings showed that in a Chinese sample of 7,472 individuals, Model 1 (with waist circumference, triglycerides/HDL-C ratio, fasting plasma glucose and mean artery pressure) yielded good level of fitness (SRMR < 0.08, CFI > 0.96 and RMSEA < 0.10) in men and women of all age groups; and Model 2 (with waist circumference, triglycerides, fasting plasma glucose and systolic blood pressure) fitted well in men aged 18-34 and over 60 and in all women, except in men of 35-59 (RMSEA = 0.142). In comparison, Model 2 were shown to be better fit (with relative larger GFI and smaller AIC, BIC, CAIC, and EVIC) in women of all age groups and in men of 18-34 and over 60 years old; Model 1 had a better fit in men between 35 and 59. CONCLUSIONS: This study suggests that the single-factor model of metabolic syndrome with waist circumference, triglycerides, fasting plasma glucose and systolic blood pressure are plausible in women of all age groups and young and senior men in Beijing. The model with waist circumference, triglycerides/HDL-C ratio, fasting plasma glucose and mean artery pressure fits middle-aged men. PMID- 23638906 TI - Continuity, commitment and context: adult siblings of people with autism plus learning disability. AB - Sibling relationships are usually lifelong and reciprocal. They can assume particular significance when a brother or sister has a learning disability. Until recently, adult siblings of people with disabilities such as severe autism have been ignored by policy, practice and research. This qualitative study contributes to an emerging literature by exploring how adult siblings, who have a brother or sister with autism (plus learning disability) and living in England, give meaning to their family (and caring) relationships and engage with service delivery. We spoke to 21 adult siblings using semi-structured interviews and met with 12 of their siblings with autism. Our analysis, using a broad narrative approach, demonstrates the continuity of the sibling relationship and an enduring personalised commitment. The nature of this relationship, however, is sensitive to context. How non-disabled adult siblings relate to their childhood experience is fundamental when making sense of this, as is their need to fulfil other social and family obligations, alongside their 'sense of duty' to support their disabled brother or sister. Sibling experience was further mediated by negotiating their 'perceived invisibility' in social care policy and practice. Our work concludes that by understanding the way relationships between siblings have developed over time, adult siblings' contribution to the lives of their brother or sister with autism can be better supported for the benefit of both parties. Such an approach would support current policy developments. PMID- 23638907 TI - Family burden of schizophrenic patients and the welfare system; the case of Cyprus. AB - BACKGROUND: The shift from asylum to community care for mental health patients has burdened the providers of primary health care and, more than all, families. As a result, numerous studies [Soc Psychiatry Psychiatr Epidemiol 31:345-348, 1995, J Health Socisl Behav 36:138-150, 1995] have focused on the burden of care experienced by family members living with individuals with severe mental disorders. This kind of provision, also extols a significant cost to the society at large in terms of significant direct and indirect costs. A cost that may be even higher in times of severe socio-economic crisis. METHODOLOGY: This study, firstly, aims to examine the burden that the family members experience by caring for individuals with schizophrenia and the identification of the parameters, in a micro and macro level, that affect family burden. Secondly, this study aims to investigate whether the welfare state will be fit to help vulnerable groups as the one studied, especially during economic crisis periods when austerity measures are being implemented into welfare systems. For data collection purposes this study employed the Involvement Evaluation Questionnaire [Schizophr Bull 1998, 24(4):609-618]. The sample consisted of caregivers either living in rural or urban areas of the district of Nicosia, the capital of the Republic of Cyprus. These people were attending regular meetings with their allocated Community Psychiatric Nurses (CPN) in Community Mental Health Centres (CMHC). RESULTS: Analysis of covariance (ANCOVA) was applied with the tension, the supervision, the worry, and the encouragement entering as dependent factors. In each case, participant's age, gender, marital status, income, number of people living in the same house with the participant, degree of relationship between the caregiver and the person suffering from severe mental disorder, the age of the relative, and the gender of the relative, were entered as independent factors. Four ANCOVAs were performed, one for each dimension of the family burden. The results from this analysis produced only one significant main effect of the gender of the relative on supervision [F(1,118) = 4.40, p = .011, etap2 = .053] with male relatives suffering from schizophrenia requiring higher supervision than female ones as their relative caregivers responses indicate. CONCLUSIONS: Consequently, families under great stress due to the reasons derived from the weaknesses of the welfare system described throughout this paper would give up and reject the mentally ill individuals who would become outcasts socially. Therefore, health systems need to aim to the development of psychosocial provisions for both family caregivers and patients as to decrease the family burden rates and increase the possibility of smooth transition to the society. PMID- 23638908 TI - Evaluation of primary and secondary stability of titanium implants using different surgical techniques. AB - OBJECTIVE: To investigate the influence of different surgical techniques on the primary and secondary implant stability using trabecular bone of goats as an implantation model. MATERIAL AND METHODS: In the iliac crest of eight goats, 48 cylindrical-screw-type implants with a diameter of 4.2 mm (Dyna((r)) ; Bergen op Zoom, the Netherlands) were installed, using three different surgical techniques: (i) 5% undersized, using a final drill diameter of 4 mm; (ii) 15% undersized, using a final drill diameter of 3.6 mm; and (iii) 25% undersized, using a final drill diameter of 3.2 mm. Peak insertion torque values were measured by a Digital((r)) (MARK-10 Corporation, New York, NY, USA) torque gauge instrument during placement. At 3 weeks after implantation, removal torque was measured. Histomorphometrically, the peri-implant bone volume was measured in three zones; the inner zone (0-500 MUm), the middle zone (500-1000 MUm) and the outer zone (1000-1500 MUm). RESULTS: Evaluation of the obtained data demonstrated no statistically significant difference between different surgical techniques regarding removal torque values. With respect to the percentage peri-implant bone volume (%BV), also no significant difference could be observed between all three applied surgical techniques for both the inner, middle and outer zone. However, irrespective of the surgical technique, it was noticed that the %BV was significantly higher for the inner zone as compared to middle and outer zone (P < 0.05) around the implant. CONCLUSION: At 3 weeks after implant installation, independent of the used undersized surgical technique, the %BV in the inner zone (0-500 MUm) peri-implant area was improved due to both condensation of the surrounding bone as also the translocation of host bone particles along the implant surface. Surprisingly, no mechanical beneficial effect of the 25% undersized surgical technique could be observed as compared to the 5% or 15% undersized surgical technique to improve primary or secondary implant stability. PMID- 23638909 TI - A transgenic medaka line with visible markers for genotypic and phenotypic sex. AB - Accurate genotyping of sex is required for correct interpretation in any in vivo assays with endocrine disrupting chemicals (EDCs). Visible markers for genotypic sex, if reliable, simplify assays because time-consuming PCR-based genotyping can be skipped. Here, we describe a line of Japanese medaka with a brain-expressed green fluorescent protein (GFP) transgene inserted near the sex-determining locus. When used with a white pigment cell marker, genotypic sex can be determined reliably as early as 3 days after fertilization (well before gonadal sex differentiation). No recombinants were found in more than 2000 progenies. We also introduced a strong ovarian GFP marker into the line with these genetic sex markers, so that phenotypic sex can also be determined reliably at 8 days after hatching. Well-known sex reversal protocols using exogenous steroid treatments of embryos were monitored by this transgenic line, demonstrating the line to be a useful tool for in vivo studies utilizing gonadal sex differentiation of the medaka, especially for screenings of potential estrogenic and androgenic EDCs. PMID- 23638910 TI - beta-phenethylamine--a phenylalanine derivative in brain--contributes to oxidative stress by inhibiting mitochondrial complexes and DT-diaphorase: an in silico study. AB - AIM: Till date, the mode of action of beta-PEA on neurons is not well illustrated. We tested the hypothesis that beta-PEA has the ability to cause oxidative stress by inhibiting the antioxidant enzyme DT-diaphorase and mitochondrial complexes (Complex-I and complex-III). METHODS: Using molecular docking as a tool, we here studied and compared the inhibitory capacity of beta PEA on DT-diaphorase and mitochondrial complexes. Three-dimensional structures of mitochondrial complexes and DT-diaphorase and their ligands were downloaded from the respective data banks, and free energy of binding (docking scores) were determined. RESULTS: The present finding demonstrated for the first time that beta-PEA potentiates reactive oxygen species generation by inhibiting the antioxidant enzyme DT-diaphorase, in addition to the mitochondrial complex-I and complex-III. CONCLUSION: As lowering of cellular antioxidant molecules is evident in many neurodegenerative disorders, beta-PEA-induced lowering of DT-diaphorase activity may have the capability to cause neurodegeneration, which may be potentiated by its ability to inhibit mitochondrial complexes. Thus, beta-PEA-due to its cumulative actions-may be more potent in causing neurodegeneration as compared to other endogenous neurotoxins. PMID- 23638911 TI - Salting-in with a salting-out agent: explaining the cation specific effects on the aqueous solubility of amino acids. AB - Although the understanding of ion specific effects on the aqueous solubilities of biomolecules is crucial for the development of many areas of biochemistry and life sciences, a consensual and well-supported molecular picture of the phenomena has not yet been established. Mostly, the influence of cations and the nature of the molecular interactions responsible for the reversal of the Hofmeister trend in aqueous solutions of amino acids and proteins are still defectively understood. Aiming at contributing to the understanding of the molecular-level mechanisms governing the cation specific effects on the aqueous solubilities of biocompounds, experimental solubility measurements and classical molecular dynamics simulations were performed for aqueous solutions of three amino acids (alanine, valine, and isoleucine), in the presence of a series of inorganic salts. The evidence gathered suggests that the mechanism by which salting-in inducing cations operate in aqueous solutions of amino acids is different from that of anions, and allows for a novel and consistent molecular description of the effect of the cation on the solubility based on specific interactions of the cations with the negatively charged moieties of the biomolecules. PMID- 23638912 TI - Adolescents' increasing stress response to social evaluation: pubertal effects on cortisol and alpha-amylase during public speaking. AB - Stress responses to social evaluation are thought to increase during adolescence, which may be due to pubertal maturation. However, empirical evidence is scarce. This study is the first to investigate the relation between pubertal development and biological responses to a social-evaluative stressor longitudinally. Participants performed the Leiden Public Speaking Task twice, with a 2-year interval (N = 217; age at Time 1: 8-17 years). The results support an increase in sensitivity to social evaluation during adolescence. The overall cortisol and alpha-amylase responses increased-both between and within participants-and were more strongly related to self-reported pubertal development than to age. The cortisol response shifted from speech delivery toward anticipation. The alpha amylase response increased in both phases. PMID- 23638913 TI - Protein actors sustaining arbuscular mycorrhizal symbiosis: underground artists break the silence. AB - The roots of most land plants can enter a relationship with soil-borne fungi belonging to the phylum Glomeromycota. This symbiosis with arbuscular mycorrhizal (AM) fungi belongs to the so-called biotrophic interactions, involving the intracellular accommodation of a microorganism by a living plant cell without causing the death of the host. Although profiling technologies have generated an increasing depository of plant and fungal proteins eligible for sustaining AM accommodation and functioning, a bottleneck exists for their functional analysis as these experiments are difficult to carry out with mycorrhiza. Nonetheless, the expansion of gene-to-phenotype reverse genetic tools, including RNA interference and transposon silencing, have recently succeeded in elucidating some of the plant-related protein candidates. Likewise, despite the ongoing absence of transformation tools for AM fungi, host-induced gene silencing has allowed knockdown of fungal gene expression in planta for the first time, thus unlocking a technological limitation in deciphering the functional pertinence of glomeromycotan proteins during mycorrhizal establishment. This review is thus intended to draw a picture of our current knowledge about the plant and fungal protein actors that have been demonstrated to be functionally implicated in sustaining AM symbiosis mostly on the basis of silencing approaches. PMID- 23638914 TI - Cleft Palate in a Mouse Model of SOX2 Haploinsufficiency. AB - OBJECTIVE: While SEX-determining region Y-Box 2 (SOX2) mutations are typically recognized as yielding ocular and central nervous system abnormalities, they have also been associated with other craniofacial defects. To elucidate the genesis of the latter, Sox2 hypomorphic (Sox2(HYP)) mice were examined, with particular attention to secondary palatal development. RESULTS: Clefts of the secondary palate were found to be highly penetrant in Sox2(HYP) mice. The palatal clefting occurred in the absence of mandibular hypoplasia and resulted from delayed or failed shelf elevation. CONCLUSIONS: Sox2 hypomorphism can result in clefting of the secondary palate, an effect that appears to be independent of mandibular hypoplasia and is thus expected to result from an abnormality that is inherent to the palatal shelves and/or their progenitor tissues. Further clinical attention relative to SOX2 mutations as a basis for secondary palatal clefts appears warranted. PMID- 23638915 TI - Parental consanguinity and nonsyndromic orofacial clefts in children: a systematic review and meta-analyses. AB - OBJECTIVE: To assess whether individuals born to consanguineous parents had a higher frequency of nonsyndromic orofacial clefts compared with those with no parental consanguinity. DESIGN: A prespecified plan for a search strategy, inclusion/exclusion criteria, and data extraction from studies reporting consanguinity in relation to nonsyndromic orofacial clefts (NSOFC) was carried out. Papers reporting observational studies with control populations were included, without language restrictions, and these reports were assessed for quality. Sensitivity analyses using subgroups, homogeneity evaluation, and assessment of publication bias were carried out, and meta-analyses of extracted data were performed. RESULTS: Sixteen studies fulfilled the selection criteria and were included in the meta-analyses. There were statistically significant relationships between consanguinity and NSOFC for all 16 studies combined (P = .0003), with odds ratio (OR) = 1.83 and 95% confidence interval (CI) = (1.31, 2.54); 10 case-control studies (P = .006), with OR = 2.06 and 95% CI = (1.23, 3.46); six cross-sectional studies (P = .03), with OR = 1.34 and 95% CI = (1.02, 1.76); first cousins consanguineous marriages (P = .04), with OR = 1.40 and 95% CI = (1.01, 1.93); cleft palate alone (P = .01), with OR = 1.89 and 95% CI = (1.14, 3.13); and cleft lip with or without cleft palate cases (P = .002), with OR = 1.56 and 95% CI = (1.18, 2.07). CONCLUSION: Although there was a high level of study heterogeneity, the evidence is consistent in suggesting that consanguinity is a risk factor for NSOFC, with an overall OR of 1.83 (95% CI, 1.31 to 2.54), implying that there was almost twice the risk of a child with NSOFC being born if there was parental consanguinity. PMID- 23638916 TI - Genetic variation of superoxide dismutases in patients with primary open-angle glaucoma. AB - PURPOSE: Oxidative stress has been described as an underlying pathogenetic mechanism in retinal ganglion cell apoptosis, which is a hallmark of primary open angle glaucoma (POAG). Superoxide dismutases (SODs) are enzymes involved in the protection against oxidative stress by detoxification of superoxide. In this study, we investigated a number of disease-associated single nucleotide polymorphisms (SNPs) in the copper-zinc-containing SOD1 and SOD3, and in the manganese superoxide dismutase SOD2, in POAG patients. METHODS: The study included 239 patients with POAG and 185 controls, all of Estonian origin, recruited at two ophthalmic clinics in Tartu, Estonia. Eleven SNPs, either functional, disease-associated or tag SNPs in SOD1, SOD2 and SOD3 were genotyped using TaqMan Allelic Discrimination. Haplotype analysis was performed on the SNPs in SOD2. RESULTS: Using binary logistic regression in an additive model, the rs2842980 SNP in SOD2 was significantly associated with POAG diagnosis (p = 0.03) at a univariate level. None of the studied SNPs showed an association with risk of POAG in a multivariate analysis, including age and current smoking as covariates. Analysis of SOD2 haplotypes did not show any association with risk of POAG. CONCLUSIONS: If oxidative stress is an important mechanism in POAG-related retinal ganglion cell death, genetic variations in SOD1, SOD2 and SOD3 are not major contributors in the pathogenesis. PMID- 23638918 TI - Damping of acoustic vibrations of immobilized single gold nanorods in different environments. AB - We present measurements of the acoustic vibrations of single gold nanorods deposited on a glass substrate immersed in air and water by ultrafast pump-probe spectroscopy. The nanorods display two vibration modes, the breathing mode and the extensional mode. The damping time of the two modes is influenced by the environment, and a reduction of the quality factor is observed when the particles are immersed in water. The reduced quality factor of the breathing mode is in good agreement with a model that takes into account viscous damping and radiation of sound waves into the medium. The extension mode, however, is heavily damped when the particles are immersed in water, which is attributed to hydrodynamic lubrication forces between the nanoparticle and the glass substrate. Our results identify a new mode of damping in supported nanoparticles and indicate that the immersion medium can have different effects on different modes of vibration. PMID- 23638917 TI - Leber's congenital amaurosis as the retinal degenerative phenotype in thiamine responsive megaloblastic anemia: a case report. AB - BACKGROUND: Thiamine responsive megaloblastic anemia syndrome (TRMA), an autosomal recessive disorder is caused by mutations in the SLC19A2 gene which encodes for thiamine transporter 1 (THTR1) protein. TRMA presents with a triad of clinical features that includes diabetes mellitus, megaloblastic anemia and sensorineural hearing loss. Apart from the triad, reported ophthalmic features include cone rod dystrophy, optic atropy and retinitis pigmentosa. MATERIALS AND METHODS: A female child presented with Leber's congenital amaurosis at 10 months of age, later diagnosed with hearing impairment at 1 year, diabetes mellitus and megaloblastic anemia at 3 and a half years of age and hence as a case of thiamine responsive megaloblastic anemia. Six exons of the candidate gene SLC19A2 were screened by PCR and direct sequencing. SIFT and PolyPhen analysis was done to predict the probable effect of the mutation. RESULTS: Sequence analysis of the SLC19A2 coding region revealed a novel missense mutation in exon 2; c.314 G > A (p.G105E). Segregation analysis revealed parents heterozygous for the mutation and unaffected sib homozygous for wild type. SIFT and PolyPhen analyses predicted the mutation to be "damaging" (score-0.02) and "probably damaging" (score-0.994), respectively. CONCLUSIONS: SLC19A2, the high-affinity thiamine transporter, is the only gene known to be associated with TRMA. Here we describe for the first time Leber's congenital amaurosis as the retinal phenotype and also report a novel point mutation in the SLC19A2 gene that co-segregated with the disease in a TRMA patient. PMID- 23638919 TI - Hippophins C-F, four new flavonoids, acylated with one monoterpenic acid from the seed residue of Hippophae rhamnoides subsp. sinensis. AB - Four new flavonol glycosides (1-4), hippophins C-F, together with one known flavonoid (5), were isolated from the seed residue of Hippophae rhamnoides subsp. sinensis. The chemical structures of these compounds were characterized by 1D and 2D NMR, and HR-ESI-MS data. This report is a continuous research work on the systematic chemical investigation of plants of the genus Hippophae in our laboratory. PMID- 23638920 TI - Production and assessment of decellularized pig and human lung scaffolds. AB - The authors have previously shown that acellular (AC) trachea-lung scaffolds can (1) be produced from natural rat lungs, (2) retain critical components of the extracellular matrix (ECM) such as collagen-1 and elastin, and (3) be used to produce lung tissue after recellularization with murine embryonic stem cells. The aim of this study was to produce large (porcine or human) AC lung scaffolds to determine the feasibility of producing scaffolds with potential clinical applicability. We report here the first attempt to produce AC pig or human trachea-lung scaffold. Using a combination of freezing and sodium dodecyl sulfate washes, pig trachea-lungs and human trachea-lungs were decellularized. Once decellularization was complete we evaluated the structural integrity of the AC lung scaffolds using bronchoscopy, multiphoton microscopy (MPM), assessment of the ECM utilizing immunocytochemistry and evaluation of mechanics through the use of pulmonary function tests (PFTs). Immunocytochemistry indicated that there was loss of collagen type IV and laminin in the AC lung scaffold, but retention of collagen-1, elastin, and fibronectin in some regions. MPM scoring was also used to examine the AC lung scaffold ECM structure and to evaluate the amount of collagen I in normal and AC lung. MPM was used to examine the physical arrangement of collagen-1 and elastin in the pleura, distal lung, lung borders, and trachea or bronchi. MPM and bronchoscopy of trachea and lung tissues showed that no cells or cell debris remained in the AC scaffolds. PFT measurements of the trachea-lungs showed no relevant differences in peak pressure, dynamic or static compliance, and a nonrestricted flow pattern in AC compared to normal lungs. Although there were changes in content of collagen I and elastin this did not affect the mechanics of lung function as evidenced by normal PFT values. When repopulated with a variety of stem or adult cells including human adult primary alveolar epithelial type II cells both pig and human AC scaffolds supported cell attachment and cell viability. Examination of scaffolds produced using a variety of detergents indicated that detergent choice influenced human immune response in terms of T cell activation and chemokine production. PMID- 23638922 TI - Polymer-assisted structural modification on nucleosides and nucleotides. AB - Nucleosides and their analogues play important roles in biological research and clinical therapeutics. Polymer-assisted structural modifications of nucleosides and nucleotides enable parallel and rapid construction of nucleoside library. For some nucleosides, higher chemical selectivity and regioselectivity can be achieved using solid-phase synthesis when compared to classic solution-phase synthesis. PMID- 23638921 TI - Changes in fetal and neonatal mortality during 40 years by offspring sex: a national registry-based study in Norway. AB - BACKGROUND: There has been a considerable decline in fetal and neonatal mortality in the Western world. The authors hypothesized that this decline has been largest for boys, since boys have a higher risk of fetal and neonatal death. METHODS: The authors used data from the Medical Birth Registry about all births in Norway to study changes during 1967-2005 in mortality for boys and girls from the 23rd week of pregnancy until one month after birth. Absolute and relative yearly changes in fetal and neonatal death rates were estimated separately for boys and girls. RESULTS: From 1967 to 2005, the average annual reduction in the overall death rate was greater for boys: 0.47 per 1000 boys (95% CI: 0.45, 0.48) and 0.37 per 1000 girls (95% CI: 0.35, 0.39). These estimates were not affected by adjustments made for changes over time in maternal characteristics. The convergence in death rates by sex was strongest for the first week after birth: average annual reduction in the early neonatal death rate was 0.24 per 1000 boys (95% CI: 0.23, 0.25) and 0.17 per 1000 girls (95% CI: 0.16, 0.18). The death rates for boys and girls also converged during pregnancy and from one week to one month after birth. The relative reduction in death rates was quite similar for boys and girls: the overall death rate fell annually by 4.4% (95% CI: 4.3, 4.6%) for boys and by 4.2% (95% CI: 4.0, 4.4%) for girls. CONCLUSIONS: During the period 1967-2005, the absolute reduction in fetal and neonatal death rates was greatest for boys. The relative reduction in mortality was about the same for both sexes, but the absolute reduction was greatest for boys since the mortality for boys began at a higher level. The convergence of death rates was not due to changes in the composition of mothers, suggesting that convergence has been caused by technological progress. PMID- 23638923 TI - Synthesis of new pyrazoline-nucleoside analogue derivatives. AB - In this work, a synthesis of pyrazoline nucleosides analogues is presented, using the stereospecific sodium salt glycosylation procedure. In the first step, chalcones were prepared using Claisen-Schmidt reaction by reacting benzaldehyde with enolizable ketones in ethanolic NaOH solutions. Next, these chalcones were immediately reacted with hydrazine hydrochloride in the presence of dry methanol to obtain the corresponding 2-pyrazolines. Finally, the coupling of the pyrazolines with 1-chloro-arabinofuranose leads to different beta-nucleosides as the major product (13-17) in good yields. The structures of these derivatives were characterized by infrared and 1HNMR spectroscopy and mass spectrometry. PMID- 23638924 TI - Oligonucleotide functionalization by a novel alkyne-modified nonnucleosidic reagent obtained by versatile building block chemistry. AB - A convenient synthetic strategy has been designed to prepare an alkyne-modified synthon for automated DNA synthesis. It is based on the key O-DMTr-protected 4-(2 hydroxyethyl)morpholin-2,3-dione and building blocks obtained by its functionalization by various aliphatic amines. A respective nonnucleosidic phosphoramidite monomer containing a terminal alkyne in the side-chain was synthesized, and corresponding oligothymidylates incorporating the modification in various positions were prepared. The presence of the alkyne group was confirmed by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) between the functionalized oligonucleotide and an azide derivative of 7-nitro-2,1,3 benzoxadiazole. PMID- 23638925 TI - Synthesis and NMR assignment of the two diastereomers of 8,6'-cyclo-2',6' dideoxyadenosine. AB - We herein present the first synthesis and characterization of the two C5' diastereomers of 8,6'-cyclo-2',6'-dideoxyadenosine. Starting from commercially available 2'-deoxyadenosine, the target cyclonucleosides were synthesized in 11 linear steps. Following a zinc-mediated cyclization reaction to form the seven membered ring, the stereochemistry of the newly formed chiral center was established using two-dimensional NOESY NMR experiments. PMID- 23638926 TI - Synthesis and evaluation of anti-inflammatory and analgesic activities of new 1,2,4-triazole derivatives. AB - In this study, the synthesis, anti-inflammatory and analgesic activities of eight new 5-thioalkyl-1,3-diaryl-1,2,4- triazole derivatives were reported. For the anti-inflammatory study, the carrageenan-induced rat paw edema model was used. The test compounds in 50 mg/kg and 100 mg/kg were injected as IP and paw edema was determined. The results showed that some of the compounds have good activity compared to the references drug, indomethacin. For analgesic activity, the test compounds were studied using the in Tail-flick test model in 50 and 100 mg/kg as IP injections. Their analgesic activities were determined after 30 min via latency time assay. Statistical analysis showed that all test compounds have antinociceptive activity in the range of 24% -47% as compared to the control with a dose of 50 mg/kg. However, all tested compounds have analgesic activity lower than the standard drug, morphine. PMID- 23638927 TI - Ginger in the prevention of nausea and vomiting: a review. AB - Nausea and vomiting are physiological processes experienced by every human being at some stage of their life. They are complex protective mechanisms and the symptoms are influenced by the emetogenic response and stimuli. However, when these symptoms recur frequently, they can significantly reduce the quality of life and can also be detrimental to health. The existing antiemetic agents are ineffective against certain stimuli, are expensive, and possess side effects. Herbal medicines have been shown to be effective antiemetics, and among the various plants studied, the rhizome of Zingiber officinale, commonly known as ginger, has been used as a broad-spectrum antiemetic in the various traditional systems of medicine for over 2000 years. Various preclinical and clinical studies have shown ginger to possess antiemetic effects against different emetogenic stimuli. However, conflicting reports especially in the prevention of chemotherapy-induced nausea and vomiting and motion sickness prevent us from drawing any firm conclusion. The current review for the first time summarizes the results. An attempt is also made to address the lacunae in these published studies and emphasize aspects that need further investigations for it to be of use in clinics in the future. PMID- 23638928 TI - Garlic in clinical practice: an evidence-based overview. AB - BACKGROUND AND OBJECTIVE: Garlic has been widely used in clinical practice, and there were many systematic reviews (SRs) describing its effects. But none reviewed the clinical utility comprehensively, so we aimed to evaluate its effects from every aspect of its effects. METHODS: We comprehensively searched medical electronic databases, asked the experts in this field, along with reference tracking, and manual searching. We included all kinds of SRs, including Cochrane SRs and non-Cochrane SRs. Two authors independently selected articles for relevant SRs, and extracted data of included SRs, resolved differences by consultation with a third reviewer. RESULTS: We described nine SRs about garlic. Available evidence showed that garlic can reduce blood pressure (BP) in hypertensive patients and patients with elevated systolic BP (SBP), but not in normotensive subjects. Evidence about the effects of garlic on lipid parameters was contentious, so we cannot make a decision whether garlic is effective enough for reducing total cholesterol (TC), triglycerides (TAG), and high-density lipoprotein (HDL). As evidence was very limited and insufficient, relations between garlic intake and reduced risks of all kinds of cancers, antiglycemic and antithrombotic effects of garlic, the effects of garlic on cardiovascular morbidity and mortality were unclear. Garlic as a preventative or treatment option for the common cold or peripheral arterial occlusive disease or pre eclampsia and its complications could not be recommended, as only one relatively small trial evaluated the effects separately. CONCLUSIONS: Garlic might be effective in some areas of clinical practice, but the evidence levels were low, so further researches should be well designed using rigorous method to avoid potential biases. PMID- 23638929 TI - Reinventing the role of consumer research in today's open innovation ecosystem. AB - Consumer research (CR) has played a key role in the food and beverage industry. Emerging from laboratory product-tests, it has evolved into a corporate testing service that measures the consumer reactions to products/concepts using a wide range of analyses/metrics. We propose that CR transform itself in light of accelerated knowledge expansion, mounting global, and local economic pressure on corporations and changing consumer needs. The transformation moves from its traditional testing into creating profoundly new knowledge of the product and understanding of the corporation's current and future customers. CR's tasks will involve: contributing/expanding science, applying open innovation principles, and driving consumer-centric innovation. We identify seven paradigm shifts that will change CR, namely: a different way of working--from testing to open sourcing; from good corporate citizen to change leader; open new product development (NPD) process; new management roles/cultures; universities and industry, new education curricula, and cooperation; from battle over control to sustainable sharing is winning model (SiW); and the central role of design. This integrative, innovative CR requires the implementation of three recommendations: start the change process now, fine-tune along the way; create a new marketing/CR department; and educate and professionalize. These recommendations provide the blueprint for jump starting the process and call for immediate actions to deal with the severity of the crises facing the CR profession. PMID- 23638930 TI - Review of Canadian literature to estimate risks associated with Salmonella in broilers from retail to consumption in Canadian homes. AB - The objective was to review the literature related to the risk of salmonellosis from chicken consumed in private homes in Canada. The pathway of concern was retail-to-consumption at private homes due to the direct link between this pathway and public health. A qualitative review was conducted by searching Canadian governmental agencies' webpages, published peer-reviewed journals, and by contacting experts in the field. Overall, with the data available, estimating risk from Salmonella in chicken breasts using only Canadian information was limited. Enumeration data for Salmonella in retail raw chicken at different regions across Canada are needed to be able to generalize the risk of salmonellosis in the Canadian population. Few Canadian surveys were found to describe consumers' food safety behaviors at Canadians' private homes. Observational designs to study food safety practices and Canadian consumers' behavior in private kitchens are needed to ensure that consumer behavior is consistent with consumer perceptions of their behavior. The results of such studies will give valuable input for designing educational programs needed to increase awareness of safe food handling practices by Canadian consumers when preparing food at their homes. PMID- 23638931 TI - Dietary intake of natural antioxidants: vitamins and polyphenols. AB - Oxidative stress is a condition in which oxidant metabolites exert their toxic effect because of an increased production or an altered cellular mechanism of protection; oxidative stress is rapidly gaining recognition as a key phenomenon in chronic diseases. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves. Endogenous defence mechanisms are inadequate for the complete prevention of oxidative damage, and different sources of dietary antioxidants may be especially important. This article calls attention to the dietary antioxidants, such as vitamins A, C, and E and polyphenols. Compelling evidence has led to the conclusion that diet is a key environmental factor and a potential tool for the control of chronic diseases. More specifically, fruits and vegetables have been shown to exert a protective effect. The high content of minerals and natural antioxidant as vitamins A, C, and E and polyphenols in fruits and vegetables may be a main factor responsible for these effects. PMID- 23638932 TI - Peanut allergens: an overview. AB - Peanut is recognized as a potent food allergen producing one of the most frequent food allergies. This fact has originated the publication of an elevated number of scientific reports dealing with peanut allergens and, especially, the prevalence of peanut allergy. For this reason, the information available on peanut allergens is increasing and the debate about peanut allergy is always renewed. This article reviews the information currently available on peanut allergens and on the techniques used for their chemical characterization. Moreover, a general overview on the current biotechnological approaches used to reduce or eliminate peanut allergens is also provided. PMID- 23638934 TI - Mass spectrometry-based fingerprinting of proteins & peptides in wine quality control: a critical overview. AB - In this work we have critically revised and updated the literature dealing with wine quality control based on protein or peptide mass spectrometry-based fingerprinting. A number of pitfalls in the experimental design of most work dealing with this subject are highlighted along with recommendations on how to circumvent them. As a general trend, the conclusions reported to date in the literature of the topic are inconclusive mainly due to the (i) low number of representative samples, (ii) lack of basic analytical concepts, and (iii) lack of adequate statistical and software tools. In addition, we have critically revised the sample treatments commonly used to separate proteins from wines, emphasizing that the majority of literature is devoted to white wines, probably because of difficulties in isolating the protein content in red wines. PMID- 23638933 TI - Hass avocado composition and potential health effects. AB - Hass avocados, the most common commercial avocado cultivars in the world, contain a variety of essential nutrients and important phytochemicals. Although the official avocado serving is one-fifth of a fruit (30 g), according to NHANES analysis the average consumption is one-half an avocado (68 g), which provides a nutrient and phytochemical dense food consisting of the following: dietary fiber (4.6 g), total sugar (0.2 g), potassium (345 mg), sodium (5.5 mg), magnesium (19.5 mg), vitamin A (43 MUg), vitamin C (6.0 mg), vitamin E (1.3 mg), vitamin K1 (14 MUg), folate (60 mg), vitamin B-6 (0.2 mg), niacin (1.3 mg), pantothenic acid (1.0 mg), riboflavin (0.1 mg), choline (10 mg), lutein/zeaxanthin (185 MUg), phytosterols (57 mg), and high-monounsaturated fatty acids (6.7 g) and 114 kcals or 1.7 kcal/g. The avocado oil consists of 71% monounsaturated fatty acids (MUFA), 13% polyunsaturated fatty acids (PUFA), and 16% saturated fatty acids (SFA), which helps to promote healthy blood lipid profiles and enhance the bioavailability of fat soluble vitamins and phytochemicals from the avocado or other fruits and vegetables, naturally low in fat, which are consumed with avocados. There are eight preliminary clinical studies showing that avocado consumption helps support cardiovascular health. Exploratory studies suggest that avocados may support weight management and healthy aging. PMID- 23638935 TI - Aroma and taste perceptions with Alzheimer disease and stroke. AB - Chemosensory disorders of smell or taste in humans have been attributed to various physiological and environmental factors including aging and disease conditions. Aroma and taste greatly condition our food preference, selection and, consumption; the decreased appetite in patients with known neurodegenerative diseases may lead to dietary restrictions that could negatively impact nutritional and health status. The decline in olfactory and gustatory systems in patients with Alzheimer disease and various types of stroke are described. PMID- 23638936 TI - Effect of high pressure on physicochemical properties of meat. AB - The application of high pressure offers some interesting opportunities in the processing of muscle-based food products. It is well known that high-pressure processing can prolong the shelf life of meat products in addition to chilling but the pressure-labile nature of protein systems limits the commercial range of applications. High pressure can affect the texture and gel-forming properties of myofibrillar proteins and, hence, has been suggested as a physical and additive free alternative to tenderize and soften or restructure meat and fish products. However, the rate and magnitude at which pressure and temperature effects take place in muscles are variable and depend on a number of circumstances and conditions that are still not precisely known. This review provides an overview of the current knowledge of the effects of high pressure on muscle tissue over a range of temperatures as it relates to meat texture, microstructure, color, enzymes, lipid oxidation, and pressure-induced gelation of myofibrillar proteins. PMID- 23638937 TI - A modified technique for removing earlobe keloids. PMID- 23638938 TI - Highly specific and sensitive measurements of human and monkey interleukin 21 using sequential protein and tryptic peptide immunoaffinity LC-MS/MS. AB - A highly specific and sensitive immunoaffinity LC-MS/MS assay for quantification of human and cynomolgus monkey interleukin 21 (IL-21) was developed, qualified, and implemented. The workflow includes offline enrichment of IL-21 using an anti IL-21 capture antibody, followed by isolation using magnetic beads, trypsin digestion, online enrichment of IL-21 derived tryptic peptides using antipeptide antibodies, and quantification using nanoflow LC-MS/MS. This assay was developed and qualified in human and cynomolgus monkey serum and tissues with a lower limit of quantitation of 0.78 pg/mL based on the intact cytokine. Both intra- and interbatch precision and accuracy, as well as stability and recovery, were found to be acceptable. IL-21 was not detected in serum from normal healthy volunteers or from autoimmune disease patients. However, IL-21 levels were quantified in cynomolgus monkey spleen and colon tissue and normal and inflammatory bowel disease (IBD) human colon tissue as well as hyperplasia human tonsils. PMID- 23638939 TI - Effect of functionalized gold nanoparticles on floating lipid bilayers. AB - The development of novel nano-engineered materials poses important questions regarding the impact of these new materials on living systems. Possible adverse effects must be assessed in order to prevent risks for health and the environment. On the other hand, a thorough understanding of their interaction with biological systems might also result in the creation of novel biomedical applications. We present a study on the interaction of model lipid membranes with gold nanoparticles (AuNP) of different surface modifications. Neutron reflectometry experiments on zwitterionic lipid double bilayers were performed in the presence of AuNP functionalized with cationic and anionic head groups. Structural information was obtained that provided insight into the fate of the AuNPs with regard to the integrity of the model cell membranes. The AuNPs functionalized with cationic head groups penetrate into the hydrophobic moiety of the lipid bilayers and cause membrane disruption at an increased concentration. In contrast, the AuNPs functionalized with anionic head groups do not enter but seem to impede the destruction of the lipid bilayer at an alkaline pH. The information obtained might influence the strategy for a better nanoparticle risk assessment based on a surface charge evaluation and contribute to nano-safety considerations during their design. PMID- 23638940 TI - Health professionals' beliefs about domestic abuse and the issue of disclosure: a critical incident technique study. AB - Domestic abuse is increasingly recognised as a serious, worldwide public health concern. There is a significant body of literature regarding domestic abuse, but little is known about health professionals' beliefs about domestic abuse disclosure. In addition, the intersection between health professionals' beliefs and abused women's views remains uninvestigated. We report on a two-phase, qualitative study using Critical Incident Technique (CIT) that aimed to explore community health professionals' beliefs about domestic abuse and the issue of disclosure. We investigated this from the perspectives of both health professionals and abused women. The study took place in Scotland during 2011. The study was informed theoretically by the Common Sense Model of Self-Regulation of Health and Illness (CSM). This model is typically used in disease-orientated research. In our innovative use, however, CSM was used to study the social phenomenon, domestic abuse. The study involved semi-structured, individual CIT interviews with health professionals and focus groups with women who had experienced domestic abuse. Twenty-nine health professionals (Midwives, Health Visitors and General Practitioners) participated in the first phase of the study. In the second phase, three focus groups were conducted with a total of 14 women. Data were analysed using a combination of an inductive classification and framework analysis. Findings highlight the points of convergence and divergence between abused women's and health professionals' beliefs about abuse. Although there was some agreement, they do not always share the same views. For example, women want to be asked about abuse, but many health professionals do not feel confident or comfortable discussing the issue. Overall, the study shows the dynamic interaction between women's and health professionals' beliefs about domestic abuse and readiness to discuss and respond to it. Understanding these complex dynamics assists in the employment of appropriate strategies to support women post-disclosure. PMID- 23638942 TI - Making the use of psychotropic drugs more rational through the development of GRADE recommendations in specialist mental healthcare. AB - INTRODUCTION: In recent years the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology has often been used by international or national health authorities, or scientific societies, for developing evidence-based treatment recommendations. However, the GRADE approach has never been used by practicing physicians who aim at harmonizing their prescribing behaviours paying due attention to the best available evidence. This paper describes the experience of a working group of psychiatrists who adopted the GRADE approach to develop clinical recommendations on the use of psychotropic drugs in specialist mental healthcare. CASE DESCRIPTION: The project was conducted in the Department of Mental Health of Verona, Italy, a city located in the north of Italy. At the beginning of 2012, psychiatrists with a specific interest in the rational use of psychotropic drugs were identified and appointed as members of a Guideline Development Group (GDG). The first task of the GDG was the identification of controversial areas in the use of psychotropic drugs, the definition of scoping questions, and the identification of outcomes of interest. The GDG was supported by a scientific secretariat, who searched the evidence, identified one or more systematic reviews matching the scoping questions, and drafted GRADE tables. DISCUSSION AND EVALUATION: On the basis of efficacy, acceptability, tolerability and safety data, considering the risk of bias and confidence in estimates, and taking also into consideration preferences, values and practical aspects in favour and against the intervention under scrutiny, a draft recommendation with its strength was formulated and agreed by GDG members. Recommendations were submitted for consideration to all specialists of the Department, discussed in two plenary sessions open to the whole staff, and finally approved at the end of 2012. CONCLUSION: The present project of guideline development raised several challenging and innovating aspects, including a "bottom-up" approach, as it was motivated by reasons that found agreement among specialists, those who developed the recommendations were those who were supposed to follow them, and values, preferences and feasibility issues were considered paying due attention to local context variables. PMID- 23638941 TI - NMR relaxation in proteins with fast internal motions and slow conformational exchange: model-free framework and Markov state simulations. AB - Calculating NMR relaxation effects for proteins with dynamics on multiple time scales generally requires very long trajectories based on conventional molecular dynamics simulations. In this report, we have built Markov state models from multiple MD trajectories and used the resulting MSM to capture the very fast internal motions of the protein within a free energy basin on a time scale up to hundreds of picoseconds and the more than 3 orders of magnitude slower conformational exchange between macrostates. To interpret the relaxation data, we derive new equations using the model-free framework which includes two slowly exchanging macrostates, each of which also exhibits fast local motions. Using simulations of HIV-1 protease as an example, we show how the populations of slowly exchanging conformational states as well as order parameters for the different states can be determined from the NMR relaxation data. PMID- 23638944 TI - Evaluation of triplet aromaticity by the isomerization stabilization energy. AB - The many manifestations of aromaticity have long fascinated both experimentalists and theoreticians. Due to their degenerate half-filled MOs, triplet [n]annulenes with 4n pi-electrons are also aromatic, but the degree of their stabilization has been difficult to quantify. The isomerization stabilization energy (ISE) method has been applied to evaluate the triplet aromaticity. The reliability of this approach is indicated by the strong correlation of the ISE results with NICS(1)zz, a magnetic indicator of triplet state aromaticity. PMID- 23638943 TI - Direct and legacy effects of long-term elevated CO2 on fine root growth and plant insect interactions. AB - Increasing atmospheric CO2 concentrations alter leaf physiology, with effects that cascade to communities and ecosystems. Yet, responses over cycles of disturbance and recovery are not well known, because most experiments span limited ecological time. We examined the effects of CO2 on root growth, herbivory and arthropod biodiversity in a woodland from 1996 to 2006, and the legacy of CO2 enrichment on these processes during the year after the CO2 treatment ceased. We used minirhizotrons to study root growth, leaf censuses to study herbivory and pitfall traps to determine the effects of elevated CO2 on arthropod biodiversity. Elevated CO2 increased fine root biomass, but decreased foliar nitrogen and herbivory on all plant species. Insect biodiversity was unchanged in elevated CO2. Legacy effects of elevated CO2 disappeared quickly as fine root growth, foliar nitrogen and herbivory levels recovered in the next growing season following the cessation of elevated CO2. Although the effects of elevated CO2 cascade through plants to herbivores, they do not reach other trophic levels, and biodiversity remains unchanged. The legacy of 10 yr of elevated CO2 on plant herbivore interactions in this system appear to be minimal, indicating that the effects of elevated CO2 may not accumulate over cycles of disturbance and recovery. PMID- 23638945 TI - Young children give priority to ownership when judging who should use an object. AB - This study provides evidence that children give priority to ownership when judging who should use an object. Children (N = 269) and adults (N = 154) considered disputes over objects. In disputes between a character using an object and the owner of the object, children, as young as 3 years and as old as 7 years, sided with the owner, and did so more than adults. However, children aged 4 and older disregarded owners' rights in dilemmas where these were pitted against the need to prevent harm. These findings suggest that ownership is central in children's judgments about object use and constrain developmental accounts of how children acquire an appreciation of ownership. PMID- 23638946 TI - Real-time continuous characterization of secondary organic aerosol derived from isoprene epoxydiols in downtown Atlanta, Georgia, using the Aerodyne Aerosol Chemical Speciation Monitor. AB - Real-time continuous chemical measurements of fine aerosol were made using an Aerodyne Aerosol Chemical Speciation Monitor (ACSM) during summer and fall 2011 in downtown Atlanta, Georgia. Organic mass spectra measured by the ACSM were analyzed by positive matrix factorization (PMF), yielding three conventional factors: hydrocarbon-like organic aerosol (HOA), semivolatile oxygenated organic aerosol (SV-OOA), and low-volatility oxygenated organic aerosol (LV-OOA). An additional OOA factor that contributed to 33 +/- 10% of the organic mass was resolved in summer. This factor had a mass spectrum that strongly correlated (r(2) = 0.74) to that obtained from laboratory-generated secondary organic aerosol (SOA) derived from synthetic isoprene epoxydiols (IEPOX). Time series of this additional factor is also well correlated (r(2) = 0.59) with IEPOX-derived SOA tracers from filters collected in Atlanta but less correlated (r(2) < 0.3) with a methacrylic acid epoxide (MAE)-derived SOA tracer, alpha-pinene SOA tracers, and a biomass burning tracer (i.e., levoglucosan), and primary emissions. Our analyses suggest IEPOX as the source of this additional factor, which has some correlation with aerosol acidity (r(2) = 0.3), measured as H(+) (nmol m(-3)), and sulfate mass loading (r(2) = 0.48), consistent with prior work showing that these two parameters promote heterogeneous chemistry of IEPOX to form SOA. PMID- 23638947 TI - The extremely resorbed mandible, 10-year results of a randomized controlled trial on 3 treatment strategies. AB - OBJECTIVES: To prospectively compare the clinical and radiographic results of three modes of implant treatment for implant-retained mandibular overdentures in patients with extremely resorbed mandibles. The three treatment strategies used were (1) a transmandibular implant, (2) augmentation of the mandible with an autologous bone graft followed by placement of four endosseous implants, and (3) placement of four short endosseous implants. MATERIALS AND METHODS: Sixty edentulous patients met the inclusion criteria and were assigned according to a balanced allocation method to 1 of the 3 treatment strategies. Implant survival, surgical retreatment rates, and peri-implant bone loss were assessed according to a standardized protocol during a 10-year evaluation period. RESULTS: During the evaluation period, significantly more implants were lost in the transmandibular implant (cumulative 10-year implant survival rate, 76.3%) and the augmentation groups (88%) compared to the group provided with short endosseous implants (98.8%). The 10-year retreatment rate was significantly more favorable in the endosseous implants only (0%) and augmentation groups (5%) compared to the transmandibular group (30%). In all three groups, there was minor peri-implant bone loss. DISCUSSION: Although implant loss is a frequently used outcome measure for success, the necessity of surgical retreatment seems to be of more relevance for both the patient and the clinician. CONCLUSION: Considering the favorable clinical and radiographic parameters and the fact that patients can be treated in outdoor clinic setting, the use of short endosseous implants in combination with an overdenture is the first choice of treatment in patients with extremely resorbed mandibles. PMID- 23638948 TI - Diluted gadoteridol (ProHance(r)) causes mild ototoxicity in cochlear outer hair cells. AB - CONCLUSION: Administration of diluted solutions of gadoteridol might cause considerably less toxic effects on cochlear outer hair cells (OHCs). OBJECTIVES: Visualization of endolymphatic hydrops is done by intratympanic injection of gadolinium-based contrast agents (GBCAs) and three-dimensional fluid-attenuated inversion recovery (3-D FLAIR) magnetic resonance imaging. Here, we investigated the physiological and morphological responses of guinea pig cochlear cells to gadoteridol. METHODS: Distortion product otoacoustic emission (DPOAE) levels were measured before and 1, 2, and 4 weeks after intratympanic injection of 1/8 or 1/16 dilution of gadoteridol in guinea pigs. Morphological changes in isolated cochlear OHCs were observed after application of gadoteridol and GdCl3. RESULTS: At the highest frequency (F2 = 12 000 Hz), DPOAE level was significantly (p < 0.05) lower in the 1/8 diluted gadoteridol group than in the control group. Cell shape changes were observed in 24% (6/25) and 3% (1/33) of OHCs after application of 1/8 and 1/16 diluted gadoteridol, respectively. The occurrence of morphological damage was significantly lower after application of saline compared with 1/8 diluted gadoteridol. Morphological damage was significantly lower after application of 1/16 diluted gadoteridol compared with 1/8 diluted gadoteridol (p < 0.05). Morphological damage was observed at a high rate (8/10 cells, 80%) after application of GdCl3. PMID- 23638949 TI - Novel mutations of SLC26A4 in Chinese patients with nonsyndromic hearing loss. AB - CONCLUSIONS: This study demonstrated high prevalence of GJB2, SLC26A4, and mtDNA A1555G mutations in Chinese patients with nonsyndromic hearing loss and discovered eight novel mutations in SLC26A4. Most of these novel mutations were predicted pathogenic variants. OBJECTIVES: Nonsyndromic hearing loss is the most common neurosensory deafness where the majority of patients have highly diversified genetic defects. This study aimed to define the genetic profile of deafness in a Chinese population with potential to discover novel mutations. METHODS: A total of 227 segregating deaf students and 200 individuals with normal hearing were enrolled. With the Sanger sequencing chemistry, direct sequencing was performed on entire coding regions of GJB2, GJB3, SLC26A4, and mtDNA m.C1494T and m.A1555G. RESULTS: Direct sequencing analysis revealed that 53 (23.35%) of 227 patients carried at least 1 mutant allele in GJB2, 40 (17.62%) patients in SLC26A4, 5 (2.20%) patients in mtDNA A1555G, and 1 (0.44%) patient in mtDNA C1494T mutations. Four patients carried three unclassified mutations in GJB3 genes. Overall 38 mutant variants were detected in this cohort of patients, including 8 novel mutations in SLC26A4. The eight novel variants were six missense substitutions (p.V163L, p.G222S, p.A456D, p.N457I, p.C466Y, p.F667L), one nonsense mutation (p.W472X), and one frameshift (p.Asn612Ilefs*23). PMID- 23638950 TI - Gene silencing with siRNA targeting E6/E7 as a therapeutic intervention against head and neck cancer-containing HPV16 cell lines. AB - CONCLUSION: Our results indicate that siRNA E6 and/or E7 may have potential as a gene-specific therapy for human papillomavirus (HPV) type 16 (HPV16)-related squamous cell carcinoma of the head and neck (HNSCC). OBJECTIVES: To evaluate the effectiveness of siRNA targeting E6 and/or E7 on the in vitro and in vivo growth suppression of HPV16-related HNSCC. METHODS: HPV16-related HNSCC (UM-SCC47) cell lines were used for the present study. Expression of HPV viral oncogenes E6 and/or E7 and their cellular targets, p53 and pRb, was evaluated by real-time PCR, Western blotting, and immunofluorescence staining. To study the effect of siRNA on tumor growth in vivo, we developed animal models. Representative tumors harvested from each group were processed for apoptosis analyses (TUNEL assay) and immunofluorescence staining for p53 and pRb. RESULTS: E6 and E7 oncogenes of HPV16 were down-regulated by E6 and/or E7 targeting siRNAs, respectively. The expression of p53 and pRb proteins in both the E6 siRNA group and E7 siRNA group was up-regulated compared with those of control groups. The cellular proliferation and apoptosis indexes of E6 and/or E7 siRNA groups were higher than those of controls. In vivo studies showed significant inhibitory effect of E6 and/or E7 siRNA compared with those of control groups, which was consistent with in vitro studies. PMID- 23638951 TI - The complete mitochondrial genome of Chinese green hydra, Hydra sinensis (Hydroida: Hydridae). AB - The complete mitochondrial genome of Chinese green hydra, Hydra sinensis (Hydroida: Hydridae) is a linear molecule of 16,189 bp in length, containing 13 protein-coding genes, small and large subunit ribosomal RNAs, methionine and tryptophan transfer RNAs, a pseudogene consisting of a partial copy of COI and terminal sequences at two ends of the linear mitochondrial DNA. The A + T content of the overall base composition of H-strand is 77.2% (T: 41.7%; C: 10.9%; A: 35.5%; and G: 11.9%). COI and ND1 genes begin with GTG as start codon, while other 11 protein-coding genes start with a typical ATG initiation codon. COII, ATP8, ATP6, COIII, ND5, ND6, ND3, ND1, ND4 and COI genes are terminated with TAA as stop codon, ND4L ends with TAG, ND2 ends with TA and Cyt b ends with T. PMID- 23638953 TI - Effect of inorganic and organic copper fertilizers on copper nutrition in Spinacia oleracea and on labile copper in soil. AB - To ensure an optimal concentration of Cu in food crops, the effectiveness of eight liquid Cu fertilizers was studied in a spinach ( Spinacia oleracea L.) crop grown on Cu-deficient soil under greenhouse conditions. Plant dry matter yields, Cu concentrations in spinach plants (total and morpholino acid (MES)- and ethylenediaminedisuccinic acid (EDDS)-extractable), and Cu uptakes were studied. The behavior of Cu in soil was evaluated by both single and sequential extraction procedures. The highest quantities of Cu in labile forms in the soil, total uptakes, and Cu concentrations in the plants were associated with the application of the two sources that contained Cu chelated by EDTA and/or DTPA. The fertilizers containing these Cu chelates represent a promising approach to achieve high levels of agronomic biofortification. The stronger correlations obtained between low-molecular-weight organic acid-extractable Cu in soil and the Cu concentrations and Cu uptakes by the plants show the suitability of this soil extraction method for predicting Cu available to spinach plants. PMID- 23638952 TI - Magnetic capture from blood rescues molecular motor function in diagnostic nanodevices. AB - BACKGROUND: Introduction of effective point-of-care devices for use in medical diagnostics is part of strategies to combat accelerating health-care costs. Molecular motor driven nanodevices have unique potentials in this regard due to unprecedented level of miniaturization and independence of external pumps. However motor function has been found to be inhibited by body fluids. RESULTS: We report here that a unique procedure, combining separation steps that rely on antibody-antigen interactions, magnetic forces applied to magnetic nanoparticles (MPs) and the specificity of the actomyosin bond, can circumvent the deleterious effects of body fluids (e.g. blood serum). The procedure encompasses the following steps: (i) capture of analyte molecules from serum by MP-antibody conjugates, (ii) pelleting of MP-antibody-analyte complexes, using a magnetic field, followed by exchange of serum for optimized biological buffer, (iii) mixing of MP-antibody-analyte complexes with actin filaments conjugated with same polyclonal antibodies as the magnetic nanoparticles. This causes complex formation: MP-antibody-analyte-antibody-actin, and magnetic separation is used to enrich the complexes. Finally (iv) the complexes are introduced into a nanodevice for specific binding via actin filaments to surface adsorbed molecular motors (heavy meromyosin). The number of actin filaments bound to the motors in the latter step was significantly increased above the control value if protein analyte (50-60 nM) was present in serum (in step i) suggesting appreciable formation and enrichment of the MP-antibody-analyte-antibody-actin complexes. Furthermore, addition of ATP demonstrated maintained heavy meromyosin driven propulsion of actin filaments showing that the serum induced inhibition was alleviated. Detailed analysis of the procedure i-iv, using fluorescence microscopy and spectroscopy identified main targets for future optimization. CONCLUSION: The results demonstrate a promising approach for capturing analytes from serum for subsequent motor driven separation/detection. Indeed, the observed increase in actin filament number, in itself, signals the presence of analyte at clinically relevant nM concentration without the need for further motor driven concentration. Our analysis suggests that exchange of polyclonal for monoclonal antibodies would be a critical improvement, opening for a first clinically useful molecular motor driven lab-on-a-chip device. PMID- 23638954 TI - Systematic review: MRI enterography for assessment of small bowel involvement in paediatric Crohn's disease. AB - BACKGROUND: Barium meal enteroclysis (BM) is the recommended imaging technique for small bowel inaccessible by ileo-colonoscopy when diagnosing paediatric-onset inflammatory bowel disease, but it has poor sensitivity and involves ionising radiation. MRI enterography (MRE) is an alternative methodology. AIMS: To critically appraise the published evidence on MRE in the assessment of Paediatric inflammatory bowel disease by systematic review. METHODS: Review of all English language data reporting MRE for the investigation of patients <18 years with known or suspected IBD. Primary searches of Medline (Jan 1950-April 2012), Cinahl (1966-April 2012) and Pubmed (Jan 1950-April 2012) were performed using keyword and MeSH terms; IBD; Magnetic resonance imaging; small bowel imaging; EMBASE was then searched. Two authors independently assessed the quality of studies using the quality assessment of diagnostic accuracy studies tool. RESULTS: Searches yielded 930 035 hits, combination word searches limited to 1983 titles. Fifty-two studies were fully reviewed, 41 were excluded due to lack of paediatric data. Eleven studies of 496 children were included. All studies used endoscopy as the reference test. 10/496 patients required jejunal intubation for bowel preparation. Meta-analysis of six comparable studies gave a pooled sensitivity and specificity for MRE detection of active terminal ileal Crohn's disease of 84% and 97% respectively. Studies displayed heterogeneity in bowel preparation, scanning technique, reporting methodology and timing of ileo-colonoscopy in relation to MRE. In three studies comparing BM, MRE had greater sensitivity and specificity. CONCLUSIONS: MRE is a sensitive and specific tool for diagnosis in paediatric inflammatory bowel disease. Technical considerations require refinement and standardisation; however, MRE has no radiation. Current data suggest that MRE should supersede BM as the SB imaging technique in centres with appropriate expertise. PMID- 23638955 TI - Asthma control, cost and race: results from a national survey. AB - OBJECTIVE: Although interventions have been shown to alleviate symptoms in most patients suffering from asthma, only one-third of asthma patients have disease that is well-controlled. The purpose of this study is to investigate whether partly and uncontrolled asthmas are associated with increased costs for asthma related healthcare utilization compared to well-controlled asthma and to determine whether these associations differed across racial groups. METHODS: We classified respondents from the Asthma Insights and Management survey into those with well-, partly and uncontrolled asthma and compared utilization of healthcare services and costs among these groups, as well as between whites and non-whites. RESULTS: Respondents categorized as having asthma that was not well-controlled reported lower income levels, higher rates of unemployment and more trouble paying for healthcare; similar results were found in analyses stratified by race. Patients whose asthma was partly or uncontrolled had greater use of asthma related medications and medical services compared to patients whose asthma was well-controlled. Total unadjusted and adjusted costs were greater in patients whose asthma was classified as partly and uncontrolled. Similar results were found in analyses stratified on race. Across all levels of asthma control, non whites had higher rates of utilization of emergency rooms and urgent care facilities and had greater rates of hospitalizations compared to whites. CONCLUSIONS: Our findings indicate that patients with asthma that is not well controlled utilized more healthcare resources and had greater medical costs, despite lacking of health insurance which may suggest less access to care. PMID- 23638956 TI - Surgical versus expectant management in women with an incomplete evacuation of the uterus after treatment with misoprostol for miscarriage: the MisoREST trial. AB - BACKGROUND: Medical treatment with misoprostol is a non-invasive and inexpensive treatment option in first trimester miscarriage. However, about 30% of women treated with misoprostol have incomplete evacuation of the uterus. Despite being relatively asymptomatic in most cases, this finding often leads to additional surgical treatment (curettage). A comparison of effectiveness and cost effectiveness of surgical management versus expectant management is lacking in women with incomplete miscarriage after misoprostol. METHODS/DESIGN: The proposed study is a multicentre randomized controlled trial that assesses the costs and effects of curettage versus expectant management in women with incomplete evacuation of the uterus after misoprostol treatment for first trimester miscarriage.Eligible women will be randomized, after informed consent, within 24 hours after identification of incomplete evacuation of the uterus by ultrasound scanning. Women are randomly allocated to surgical or expectant management. Curettage is performed within three days after randomization.Primary outcome is the sonographic finding of an empty uterus (maximal diameter of any contents of the uterine cavity < 10 millimeters) six weeks after study entry. Secondary outcomes are patients' quality of life, surgical outcome parameters, the type and number of re-interventions during the first three months and pregnancy rates and outcome 12 months after study entry. DISCUSSION: This trial will provide evidence for the (cost) effectiveness of surgical versus expectant management in women with incomplete evacuation of the uterus after misoprostol treatment for first trimester miscarriage. TRIAL REGISTRATION: Dutch Trial Register: NTR3110. PMID- 23638960 TI - Structural revision of methyl tortuoate D, a bis-cembranoid from Hainan Sarcophyton tortuosum and its absolute stereochemistry. AB - Methyl tortuoate D (1), together with five other known related bis-cembranoids, was isolated from Hainan soft coral Sarcophyton tortuosum. The structure of methyl tortuoate D (1a), firstly isolated and reported by Li et al. from the title organism, was corrected as 1 by an extensive analysis of its one dimensional and two-dimensional nuclear magnetic resonance data and by comparison with those reported in the literature. In addition, lobophytone K (1b), recently isolated from Hainan soft coral Lobophytum pauciflorum by Lin et al., was proved to be the same compound as 1 and 1a. The absolute configuration of 1 was determined by comparing its electronic circular dichroism curve with that of co occurring ximaolide A (2). PMID- 23638957 TI - Turbulent life: the experiences of the family members of patients suffering from depression. AB - Families of patients suffering from depression have an important role in provision of care to the patients, which also may impose a great amount of stress on them. The purpose of this study was to explore and describe the experiences of the family members of patients suffering from depression on the impact of provision of care to the patients. A qualitative design using a content analysis approach was used to gather and analyse data. Unstructured interviews were conducted with 26 family members of patients suffering from depression chosen using purposeful sampling. During data analysis, 'turbulent life' was developed as the main theme along with five other categories including: 'penetration of the illness in the family', 'daily life's hardship', 'too much attention to the patient', 'delay in the acceptation of the illness' and 'concern about the patient's current and future conditions'. Each category consisted of several subcategories. It is concluded that the psychological, physical and financial factors imposed on families result in 'turbulent life'. Nurses can reduce the burden of providing care to patients suffering from depression through improving the knowledge of family members about how to communicate with patients and increase emotional supportive resources to the patients and their family members. PMID- 23638961 TI - Usefulness of Cochrane intervention reviews for the practicing dermatologic surgeon. AB - BACKGROUND: The Cochrane Collaboration produces systematic, evidence-based reviews of clinically relevant topics in medicine, including those relevant to dermatologic surgery. OBJECTIVE: To assess the utility of Cochrane reviews for practicing dermatologic surgeons. METHODS: Search of the Cochrane Database of Systematic Reviews on February 20, 2012 for topics relevant to dermatologic surgery. Assessment of clinical recommendations with regard to their likelihood to affect medical decision-making in clinical dermatologic surgery. RESULTS: Fifteen Cochrane reviews met the search criteria; three offered positive conclusions regarding the comparative effectiveness of different therapies for the same indications. CONCLUSIONS: Cochrane reviews offer outstandingly complete evidence-based summaries of their topics. As such, the methodology of Cochrane reviews is a model for reviews in dermatologic surgery. Because of the dearth of high-level evidence in dermatologic surgery, the ability of Cochrane reviews to provide specific recommendations remains limited. Furthermore, dermatologic surgery may be inherently difficult to study because of the rapid evolution of procedures, intraprocedure complexity and variation, difficulties inherent in randomizing patients to interventions, and intersurgeon skill variation. That being said, the dermatologic surgery literature continues to improve and grow, and investigators are now broaching the special challenges associated with research in this area. PMID- 23638962 TI - Identification of ion series using ion mobility mass spectrometry: the example of alkyl-benzothiophene and alkyl-dibenzothiophene ions in diesel fuels. AB - Ion mobility-mass spectrometry (IMMS) has been presented as a promising method for analysis of highly complex mixtures. This coupling adds an additional postionization separation dimension to MS. The IM separation of ions is obtained in the millisecond time scale and can be particularly helpful when chromatographic separation is not possible. For obtaining relevant information about the samples, data processing is usually the bottleneck because of the high amount of data generated with IMMS. In the current work, we present a new workflow using specific comparison software dedicated to IMMS data, which allows one to compare m/z-drift time plots to highlight differences between samples. Two diesel fuels have been compared, i.e., the feed and the product of hydrodesulfurization (HDS) process, and this approach allowed us to clearly highlight the variation of intensity of several ions distributed along the plots of both samples. Accurate mass measurements and post IM collision induced dissociation experiments allowed us to identify two series of polycyclic aromatic sulfur-containing heterocycle (PASH) compounds among the matrix ions. PMID- 23638963 TI - The involvement of programmed cell death 5 (PDCD5) in the regulation of apoptosis in cerebral ischemia/reperfusion injury. AB - AIMS: Programmed Cell Death 5 (PDCD5) is a protein that accelerates apoptosis in different types of cells in response to various stimuli and is down-regulated in many cancer tissues. We hypothesized in this study that down-regulating PDCD5 can protect the brain from ischemic damage by inhibiting PDCD5-induced apoptotic pathway. METHODS: One hundred and sixty male Sprague-Dawley rats were randomly assigned to five groups: Sham surgery (n = 25), MCAO (n = 45), MCAO+rhPDCD5 (RhPDCD5) (n = 30), MCAO+control siRNA (n = 30), and MCAO+PDCD5 siRNA (n = 30). At 24 h following MCAO, immunohistochemistry and Western blot were performed. RESULTS: PDCD5 siRNA reduced the infarct volume, improved neurological deficits, improved cerebral blood flow (CBF), and reduced Evans blue extravasation. Meanwhile, over-expression of PDCD5 protein with recombinant human PDCD5 (rhPDCD5) had an opposite effect. Immunohistochemistry and Western blot demonstrated PDCD5 siRNA decreased the expressions of key proapoptotic proteins such as p53, Bax/Bcl-2, and cleaved caspase-3 in the penumbra areas, whereas rhPDCD5 increased cell apoptosis. Double fluorescence labeling showed the positive immunoreactive materials of PDCD5 were partly colocalized with MAP2, GFAP, CD34, p53, and caspase-3 in the penumbra areas in brain. CONCLUSIONS: PDCD5 induced apoptosis and over-expression of PDCD5 are harmful to the ischemic neurons in vivo. Meanwhile, the inhibition of PDCD5 may be protective via reducing the apoptotic-related protein such as p53, Bax, and caspase-3. This observation may have potential for the treatment of ischemic cerebral stroke. PMID- 23638964 TI - Hierarchical, guided self-assembly of preselected carbon nanotubes for the controlled fabrication of CNT structures by electrooxidative nanolithography. AB - A fully controllable process for the fabrication of carbon nanotube assemblies is presented on the basis of a sequential electrochemical oxidation lithography process. This approach utilizes the local chemical conversion of a n octadecyltrichlorosilane self-assembled monolayer into a template featuring polar acid groups. The capability to utilize such chemically active templates for the site-selective assembly of individual carbon nanotubes was demonstrated, and a hierarchical, sequential structuring routine to obtain crossed CNT configurations, formed by preselected carbon nanotubes, was implemented. The introduced process allows the reliable and well-controlled fabrication of tailor made nanoscopic assemblies of nanomaterials toward their integration into complex device frameworks and could provide control over the electrical properties of the fabricated assemblies. PMID- 23638965 TI - MtQRRS1, an R-locus required for Medicago truncatula quantitative resistance to Ralstonia solanacearum. AB - Ralstonia solanacearum is a major soilborne pathogen that attacks > 200 plant species, including major crops. To characterize MtQRRS1, a major quantitative trait locus (QTL) for resistance towards this bacterium in the model legume Medicago truncatula, genetic and functional approaches were combined. QTL analyses together with disease scoring of heterogeneous inbred families were used to define the locus. The candidate region was studied by physical mapping using a bacterial artificial chromosome (BAC) library of the resistant line, and sequencing. In planta bacterial growth measurements, grafting experiments and gene expression analysis were performed to investigate the mechanisms by which this locus confers resistance to R. solanacearum. The MtQRRS1 locus was localized to the same position in two recombinant inbred line populations and was narrowed down to a 64 kb region. Comparison of parental line sequences revealed 15 candidate genes with sequence polymorphisms, but no evidence of differential gene expression upon infection. A role for the hypocotyl in resistance establishment was shown. These data indicate that the quantitative resistance to bacterial wilt conferred by MtQRRS1, which contains a cluster of seven R genes, is shared by different accessions and may act through intralocus interactions to promote resistance. PMID- 23638966 TI - Experimental evidence of Fermi resonances in isotopically dilute water from ultrafast broadband IR spectroscopy. AB - The vibrational dynamics of liquid water, which result from a complex interplay between internal molecular vibrations and the fluctuating hydrogen bond network, are fundamental to many physicochemical and biological processes. Using a new ultrafast broadband mid-infrared light source with over 2000 cm(-1) of bandwidth, we performed ultrafast time-resolved infrared spectroscopy to study the vibrational couplings and relaxation dynamics of the stretching and bending vibrations of the mixed isotopologue, HOD, in D2O. Analysis of cross-peaks and induced absorptions in the two-dimensional infrared spectrum and transient absorption spectrum shows that the hydroxyl stretch of HOD is coupled to the HOD bending mode via Fermi resonance, with a 70 degrees angle between their transition dipole moments. We see that HOD is also anharmonically coupled to the D2O solvent modes. From transient absorption spectra, we conclude that vibrational relaxation occurs through a number of paths. The strongly hydrogen bonded OH oscillators have the highest propensity to relax through the bending mode, while the weakly hydrogen bonded oscillators relax through other modes. PMID- 23638967 TI - Mutation of the Xylanase regulator 1 causes a glucose blind hydrolase expressing phenotype in industrially used Trichoderma strains. AB - BACKGROUND: Trichoderma reesei is an organism involved in degradation of (hemi)cellulosic biomass. Consequently, the corresponding enzymes are commonly used in different types of industries, and recently gained considerable importance for production of second-generation biofuel. Many industrial T. reesei strains currently in use are derived from strain Rut-C30, in which cellulase and hemicellulase expression is released from carbon catabolite repression. Nevertheless, inducing substances are still necessary for a satisfactory amount of protein formation. RESULTS: Here, we report on a T. reesei strain, which exhibits a very high level of xylanase expression regardless if inducing substances (e.g. D-xylose, xylobiose) are used. We found that a single point mutation in the gene encoding the Xylanase regulator 1 (Xyr1) is responsible for this strong deregulation of endo-xylanase expression and, moreover, a highly elevated basal level of cellulase expression. This point mutation is localized in a domain that is common in binuclear zinc cluster transcription factors. Only the use of sophorose as inducer still leads to a slight induction of cellulase expression. Under all tested conditions, the formation of cbh1 and cbh2 transcript level strictly follows the transcript levels of xyr1. The correlation of xyr1 transcript levels and cbh1/cbh2 transcript levels and also their inducibility via sophorose is not restricted to this strain, but occurs in all ancestor strains up to the wild-type QM6a. CONCLUSIONS: Engineering a key transcription factor of a target regulon seems to be a promising strategy in order to increase enzymes yields independent of the used substrate or inducer. The regulatory domain where the described mutation is located is certainly an interesting research target for all organisms that also depend so far on certain inducing conditions. PMID- 23638968 TI - Prediction of micropollutant elimination during ozonation of municipal wastewater effluents: use of kinetic and water specific information. AB - Ozonation is effective in improving the quality of municipal wastewater effluents by eliminating organic micropollutants. Nevertheless, ozone process design is still limited by (i) the large number of structurally diverse micropollutants and (ii) the varying quality of wastewater matrices (especially dissolved organic matter). These issues were addressed by grouping 16 micropollutants according to their ozone and hydroxyl radical ((*)OH) rate constants and normalizing the applied ozone dose to the dissolved organic carbon concentration (i.e., g O3/g DOC). Consistent elimination of micropollutants was observed in 10 secondary municipal wastewater effluents spiked with 16 micropollutants (~2 MUg/L) in the absence of ozone demand exerted by nitrite. The elimination of ozone-refractory micropollutants was well predicted by measuring the (*)OH exposure by the decrease of the probe compound p-chlorobenzoic acid. The average molar (*)OH yields (moles of (*)OH produced per mole of ozone consumed) were 21 +/- 3% for g O3/g DOC = 1.0, and the average rate constant for the reaction of (*)OH with effluent organic matter was (2.1 +/- 0.6) * 10(4) (mg C/L)(-1) s(-1). On the basis of these results, a DOC-normalized ozone dose, together with the rate constants for the reaction of the selected micropollutants with ozone and (*)OH, and the measurement of the (*)OH exposure are proposed as key parameters for the prediction of the elimination efficiency of micropollutants during ozonation of municipal wastewater effluents with varying water quality. PMID- 23638969 TI - Cophylogeny of quill mites from the genus Syringophilopsis (Acari: Syringophilidae) and their North American passerine hosts. AB - Species of Syringophilopsis quill mites are found in the flight feathers of passerine birds. A phylogeny of species from this genus infecting North American passerines was inferred from the mitochondrial cytochrome oxidase I gene and the nuclear 28S ribosomal RNA gene. Based on the large genetic distance among lineages, the genus appears to be composed of several cryptic species. A reconciliation analysis of these mites and their avian hosts indicates a limited, but significant, degree of cophylogeny. However, strict cospeciation is not found to be occurring in this system. PMID- 23638970 TI - 'Where do I go from here'? A cultural perspective on challenges to the use of hospice services. AB - Do hospice services as shaped by a western perspective adequately fulfil the needs of persons from non-Western cultures? Based on a Western view of palliative care, the vision outlined in the New Zealand Palliative Care Strategy (2001) is to deliver palliative care services, including hospice services, to all patients and their families requiring them in the context of an increasingly pluralistic and multicultural society. It is predicted that over the next two decades the proportion of people identifying as Maori, Pacific and Asian will dramatically increase within New Zealand. Ministry of Health information provided through a GAP analysis identified hospices as facing access-to-care pressures for Maori, Pacific and Asian patients. It is therefore critical to identify the challenges to hospice service access for Maori, Asian and Pacific patients. This project involved qualitative interviews with 37 cancer patients (Maori, Pacific and Asian self-identified ethnicities), whanau/family and bereaved whanua/family, as well as 15 health professionals (e.g. referring GPs, oncologists, allied health professionals) within one District Health Board. Patients and their families included both those who utilised hospice services, as well as those non-users of hospice services identified by a health professional as having palliative care needs. Challenges to hospice service utilisation reported in the findings include a lack of awareness in the communities of available services, as well as continuing misconceptions concerning the nature of hospice services. Language barriers were particularly reported for Asian patients and their families. Issues concerning the ethnic representativeness of the hospice services staff were raised. The findings highlight the importance of patient and family knowledge of hospice care for utilisation of services. This information can be used for future planning to enable hospices to both provide high quality evidence based palliative care services for patients and families and provide consultative services to primary healthcare providers in the community. PMID- 23638971 TI - Postural influences on the development of infant lateralized and symmetric hand use. AB - Within-individual variability is such an apparent characteristic of infant handedness that handedness is believed to consolidate only in childhood. Research showed that manifest handedness is influenced by emerging postural skills (sitting, crawling, and walking). In this investigation, it was proposed that symmetric hand-use (tendency to acquire objects bimanually), rather than lateralized hand-use (the use of one hand more than the other), may be influenced by postural changes. Trajectories of lateralized and symmetric hand-use for object acquisition were examined in 275 infants tested monthly from 6 to 14 months. Multilevel modeling revealed that change in lateralized hand-use is unrelated to developmental transitions in infant posture, whereas the trajectory of symmetric hand-use changes significantly with the development of postural skills. PMID- 23638972 TI - Selective cytotoxic activity of new lipophilic hydroxytyrosol alkyl ether derivatives. AB - Recent data suggest that hydroxytyrosol, a phenolic compound of virgin olive oils, has anticancer activity. This communication reports the synthesis of decyl and hexadecyl hydroxytyrosyl ethers, as well as the cytotoxic activity of hydroxytyrosol and a series of seven hydroxytyrosol alkyl ether derivatives against A549 lung cancer cells and MRC5 non-malignant lung fibroblasts. Hydroxytyrosyl dodecyl ether (HTDE) showed the highest selective cytotoxicity, and possible mechanisms of action were investigated; results suggest that HTDE can moderately inhibit glycolysis, induce oxidative stress, and cause DNA damage in A549 cells. The combination of HTDE with the anticancer drug 5-fluorouracil induced a synergistic cytotoxicity in A549 cancer cells but not in non-malignant MRC5 cells. HTDE also displayed selective cytotoxicity against MCF7 breast cancer cells versus MCF10 normal breast epithelial cells in the 1-30 MUM range. These results suggest that the cytotoxicity of HTDE is more potent and selective than that of parent compound hydroxytyrosol. PMID- 23638974 TI - Ag-carbenoid-initiated catalytic hydration cascades: rapid construction of functionalized bicyclo[3.3.1]nonanes. AB - Remarkable Ag-carbenoid-initiated enone cyclopropanation-hydrolytic fragmentation competitive 1,2-vs-1,4 addition reaction cascades were uncovered on a range of propargylic esters tethered to cyclohexadienones, leading to the highly efficient and stereospecific construction of densely functionalized bicyclo[3.3.1]nonanes under mild conditions. PMID- 23638973 TI - Colon cancer cells adopt an invasive phenotype without mesenchymal transition in 3-D but not 2-D culture upon combined stimulation with EGF and crypt growth factors. AB - BACKGROUND: The intestinal crypt homeostasis is maintained by a combination of growth factors including Wnt, R-Spondin1, Noggin and the epidermal growth factor (EGF). In human colorectal cancer, the Wnt pathway is constitutively activated through genetic and epigenetic alterations in as many as 11 genes encoding components of this crypt stem-cell maintenance mechanism. Although the proliferation of colon cancer cells does not require Wnt, it is possible that colon cancer cells can still respond to the crypt growth factors in the colonic microenvironment. A number of studies have shown that epithelial cells behave differently in 3-D versus 2-D cultures. Because the 3-D conditions more closely mimic the in vivo environment, we examined the effects of Wnt and other crypt growth factors on colon cancer cell growth in 3-D culture. METHODS: Colon cancer cells were grown in 3-D matrigel supplemented with different combinations of crypt growth factors and colonies were examined for morphology and pathways. RESULTS: When colon cancer cells were cultured in 3-D with EGF, they grew as round spheroid colonies. However, colon cancer cells also grew as flat, disc-like colonies when cultured with EGF plus Wnt, R-Spondin1 and Noggin. Disc colonies were found to have comparable levels of E-cadherin as the spheroid colonies, but showed decreased E-cadherin at the cell-matrix contact sites. Disc colonies also elaborated F-actin rich protrusions (FRP) at the cell-matrix edge, reminiscent of an invasive phenotype but without the expression of vimentin. These E-cadherin and F-actin alterations were not induced by the four growth factors in 2-D culture. Formation of the disc colonies was inhibited by the knockdown of beta catenin and by protein kinase inhibitors such as gefitinib, imatinib and MK-2206. Furthermore, withdrawal of the crypt growth factors was able to revert the disc colonies to spheroid growth, showing that the invasive phenotype was reversible dependent on the availability of growth factors. CONCLUSIONS: These findings show that colon cancer cells remain responsive to the growth factors in the crypt microenvironment and can be induced to undergo morphological transformation in the more physiologically relevant 3-D culture. PMID- 23638975 TI - Levels of TNF, TNF autoantibodies and soluble TNF receptors in patients with bronchial asthma. AB - OBJECTIVES: The aim of the study was to evaluate the potential contribution made by tumor necrosis factor (TNF) autoantibodies to the pathogenesis of bronchial asthma (BA). METHODS: We used affinity chromatography methods and a magnetic separation procedure to purify human autoantibodies specific to TNF. The autoantibodies were used as a calibration material to determine the absolute content of autoantibodies to TNF using enzyme-linked immunosorbent assay (ELISA). TNF content and levels of soluble receptors to TNF were determined using the ELISA commercial test kits. RESULTS: We demonstrated significant increases in the levels of TNF and soluble TNF receptors in the sera of patients with uncontrolled and controlled BA, as compared with healthy donors. Levels of autoantibodies of the IgG2 and IgG4 subclasses were significantly higher in sera from patients with uncontrolled BA than in healthy donors. Levels of IgG2 autoantibodies were significantly higher in sera from patients with uncontrolled BA than in patients with controlled BA. CONCLUSIONS: BA is associated with changes in the levels of not only TNF and soluble receptors for TNF, but also autoantibodies to TNF. Given the magnitude of the changes in the levels of different subclasses of autoantibodies to TNF, we propose that these autoantibodies might contribute to the pathogenesis of BA. PMID- 23638976 TI - Semi-IPN chitosan/polyvinylpyrrolidone microspheres and films: sustained release and property optimisation. AB - A set of chitosan-polyvinylpyrrolidone (CH-PVP) microspheres were prepared as semi-inter penetrating networks (semi-IPN) and loaded with 5-fluorouracil. In vitro release studies showed faster release for semi-IPN microspheres compared to pure CH samples, and the total release was achieved in about 20-30 days, depending on the composition. In vitro cell studies were achieved against human breast adenocarcinoma cell line cells where adsorption of cells on microspheres with a significant decrease in their number was obtained. Meanwhile, the CH-PVP films, which were prepared with the same compositions as in the microspheres, demonstrated an increase in strength from 66 to 118 MPa as the PVP content was decreased. It can be concluded that the prepared CH-PVP semi-IPN microspheres are novel promising carriers compared to pure CH microspheres since it becomes possible to adjust stability and hydrophilicity of the microspheres as well as the release rates of the drugs from the microspheres by changing the ratio of CH/PVP composition. PMID- 23638977 TI - From distress to illness: a critical analysis of medicalization and its effects in clinical practice. AB - This paper is precisely aimed at exposing the limits of psychiatry's scientific claim-making and exploring how psychiatric diagnoses come to be utilized in practice and affect those who become pathologized. Drawing on research findings in the field of HIV/AIDS nursing, we portray the impact of psychiatric pathologization of women who see their bodies transformed by antiretroviral therapy and subsequently, must accept that their response to these changes become the target of psychiatric labelling and interventions. In this paper, we therefore engage with the reader in a critical analysis that exposes the tensions that exist between individual experiences of distress and psychiatric pathologization. The first section of the paper is dedicated to the presentation of a theoretical framework in which we explore the medicalization process and the ontological issues regarding psychiatric diagnoses. The second section seeks to present the results from a qualitative research study in the field of HIV/AIDS nursing and serves as a case example to foster discussions on the implications of psychiatric pathologization in clinical practice. PMID- 23638979 TI - Revisiting the prehypertension debate: increasing evidence for treatment yet randomized clinical trials are lacking. AB - In 2009, Blood Pressure featured a debate about whether to treat patients with prehypertension (Kiely et al., Blood Press. 2009;18:300-303; McInnes GT, Blood Press. 2009;18:304-307). Our group supported pharmacotherapy for this condition at that time. Since then, additional evidence linking prehypertension with associated morbidities has emerged. These studies are detailed below and provide further evidence for the treatment of prehypertension. PMID- 23638978 TI - A randomized controlled double-blind investigation of the effects of vitamin D dietary supplementation in subjects with atopic dermatitis. AB - BACKGROUND: Subjects with atopic dermatitis (AD) have defects in antimicrobial peptide (AMP) production possibly contributing to an increased risk of infections. In laboratory models, vitamin D can alter innate immunity by increasing AMP production. OBJECTIVE: To determine if AD severity correlates with baseline vitamin D levels, and to test whether supplementation with oral vitamin D alters AMP production in AD skin. METHODS: This was a multi-centre, placebo controlled, double-blind study in 30 subjects with AD, 30 non-atopic subjects, and 16 subjects with psoriasis. Subjects were randomized to receive either 4000 IU of cholecalciferol or placebo for 21 days. At baseline and day 21, levels of 25-hydroxyvitamin D (25OHD), cathelicidin, HBD-3, IL-13, and Eczema Area and Severity Index (EASI) and Rajka-Langeland scores were obtained. RESULTS: At baseline, 20% of AD subjects had serum 25OHD below 20 ng/mL. Low serum 25OHD correlated with increased Fitzpatrick Skin Type and elevated BMI, but not AD severity. After 21 days of oral cholecalciferol, mean serum 25OHD increased, but there was no significant change in skin cathelicidin, HBD-3, IL-13 or EASI scores. CONCLUSIONS: This study illustrated that darker skin types and elevated BMI are important risk factors for vitamin D deficiency in subjects with AD, and highlighted the possibility that seasonality and locale may be potent contributors to cathelicidin induction through their effect on steady state 25OHD levels. Given the molecular links between vitamin D and immune function, further study of vitamin D supplementation in subjects with AD is warranted. PMID- 23638980 TI - Phosphopeptide enrichment with TiO2-modified membranes and investigation of tau protein phosphorylation. AB - Selective enrichment of phosphopeptides prior to their analysis by mass spectrometry (MS) is vital for identifying protein phosphorylation sites involved in cellular regulation. This study describes modification of porous nylon substrates with TiO2 nanoparticles to create membranes that rapidly enrich phosphopeptides. Membranes with a 22-mm diameter bind 540 nmol of phosphoangiotensin and recover 70% of the phosphopeptides in mixtures with a 15 fold excess of nonphosphorylated proteins. Recovery is 90% for a pure phosphopeptide. Insertion of small membrane disks into HPLC fittings allows rapid enrichment from 5 mL of 1 fmol/MUL phosphoprotein digests and concentration into small-volume (tens of microliters) eluates. The combination of membrane enrichment with tandem mass spectrometry reveals seven phosphorylation sites from in vivo phosphorylated tau (p-tau) protein, which is associated with Alzheimer's disease. PMID- 23638981 TI - Age of onset in chronic diseases: new method and application to dementia in Germany. AB - BACKGROUND: Age of onset is an important outcome to characterize a population with a chronic disease. With respect to social, cognitive, and physical aspects for patients and families, dementia is especially burdensome. In Germany, like in many other countries, it is highly prevalent in the older population and imposes enormous efforts for caregivers and society. METHODS: We develop an incidence prevalence-mortality model to derive the mean and variance of the age of onset in chronic diseases. Age- and sex-specific incidence and prevalence of dementia is taken from published values based on health insurance data from 2002. Data about the age distribution in Germany in 2002 comes from the Federal Statistical Office. RESULTS: Mean age of onset of a chronic disease depends on a) the age specific incidence of the disease, b) the prevalence of the disease, and c) the age distribution of the population. The resulting age of onset of dementia in Germany in 2002 is 78.8 +/- 8.1 years (mean +/- standard deviation) for men and 81.9 +/- 7.6 years for women. CONCLUSIONS: Although incidence and prevalence of dementia in men are not greater than in women, men contract dementia approximately three years earlier than women. The reason lies in the different age distributions of the male and the female population in Germany. PMID- 23638982 TI - Review article: prescribing medications in patients with cirrhosis - a practical guide. AB - BACKGROUND: Most drugs have not been well studied in cirrhosis; recommendations on safe use are based largely on experience and/or expert opinion, with dosing recommendations often based on pharmacokinetic (PK) changes. AIM: To provide a practical approach to prescribing medications for cirrhotic patients. METHODS: An indexed MEDLINE search was conducted using keywords cirrhosis, drug-induced liver injury, pharmacodynamics (PDs), PKs, drug disposition and adverse drug reactions. Unpublished information from the Food and Drug Administration and industry was also reviewed. RESULTS: Most medications have not been adequately studied in cirrhosis, and specific prescribing information is often lacking. Lower doses are generally recommended based on PK changes, but data are limited in terms of correlating PD effects with the degree of liver impairment. Very few drugs have been documented to have their hepatotoxicity potential enhanced by cirrhosis; most of these involve antituberculosis or antiretroviral agents used for HIV or viral hepatitis. Paracetamol can be used safely when prescribed in relatively small doses (2-3 g or less/day) for short durations, and is recommended as first line treatment of pain. In contrast, NSAIDs should be used cautiously (or not at all) in advanced cirrhosis. Proton pump inhibitors have been linked to an increased risk of spontaneous bacterial peritonitis (SBP) in cirrhosis and should be used with care. CONCLUSIONS: Most drugs can be used safely in cirrhosis, including those that are potentially hepatotoxic, but lower doses or reduced dosing frequency is often recommended, due to altered PKs. Drugs that can precipitate renal failure, gastrointestinal bleeding, SBP and encephalopathy should be identified and avoided. PMID- 23638983 TI - Roles, regulation and inhibitors of sphingosine kinase 2. AB - The bioactive sphingolipids ceramide, sphingosine and sphingosine-1-phosphate (S1P) are important signalling molecules that regulate a diverse array of cellular processes. Most notably, the balance of the levels of these three sphingolipids in cells, termed the 'sphingolipid rheostat', can dictate cell fate, where ceramide and sphingosine enhance apoptosis and S1P promotes cell survival and proliferation. The sphingosine kinases (SKs) catalyse the production of S1P from sphingosine and are therefore central regulators of the sphingolipid rheostat and attractive targets for cancer therapy. Two SKs exist in humans: SK1 and SK2. SK1 has been extensively studied and there is a large body of evidence to demonstrate its role in promoting cell survival, proliferation and neoplastic transformation. SK1 is also elevated in many human cancers which appears to contribute to carcinogenesis, chemotherapeutic resistance and poor patient outcome. SK2, however, has not been as well characterized, and there are contradictions in the key physiological functions that have been proposed for this isoform. Despite this, many studies are now emerging that implicate SK2 in key roles in a variety of diseases, including the development of a range of solid tumours. Here, we review the literature examining SK2, its physiological and pathophysiological functions, the current knowledge of its regulation, and recent developments in targeting this complex enzyme. PMID- 23638984 TI - Correlating bilayer tablet delamination tendencies to micro-environmental thermodynamic conditions during pan coating. AB - OBJECTIVE: The objective of this study was to determine the impact that the micro environment, as measured by PyroButton data loggers, experienced by tablets during the pan coating unit operation had on the layer adhesion of bilayer tablets in open storage conditions. MATERIALS AND METHODS: A full factorial design of experiments (DOE) with three center points was conducted to study the impact of final tablet hardness, film coating spray rate and film coating exhaust temperature on the delamination tendencies of bilayer tablets. PyroButton data loggers were placed (fixed) at various locations in a pan coater and were also allowed to freely move with the tablet bed to measure the micro-environmental temperature and humidity conditions of the tablet bed. RESULTS: The variance in the measured micro-environment via PyroButton data loggers accounted for 75% of the variance in the delamination tendencies of bilayer tablets on storage (R(2 )= 0.75). A survival analysis suggested that tablet hardness and coating spray rate significantly impacted the delamination tendencies of the bilayer tablets under open storage conditions. The coating exhaust temperature did not show good correlation with the tablets' propensity to crack indicating that it was not representative of the coating micro-environment. Models created using data obtained from the PyroButton data loggers outperformed models created using primary DOE factors in the prediction of bilayer tablet strength, especially upon equipment or scale transfers. CONCLUSION: The coating micro-environment experienced by tablets during the pan coating unit operation significantly impacts the strength of the bilayer interface of tablets on storage. PMID- 23638985 TI - Ginsenjilinol, a new protopanaxatriol-type saponin with inhibitory activity on LPS-activated NO production in macrophage RAW 264.7 cells from the roots and rhizomes of Panax ginseng. AB - One new dammarane triterpene saponin named ginsenjilinol (1) was isolated from the roots and rhizomes of Panax ginseng C.A. Mey., together with two known saponins ginsenoside Rf (2) and ginsenoside Re5 ( = panajaponol A, 3). Based on IR, HR-ESI-MS, and 1D as well as 2D NMR ((1)H-(1)H COSY, NOESY, HSQC, and HMBC) spectral data, the chemical structure of the new saponin was elucidated as 3beta,12beta,20S,26-tetrahydroxydammar-24E-en-6alpha-O-beta-d-glucopyranosyl-(1 > 2)-O-beta-d-glucopyranoside. The ability of the isolated saponins to inhibit nitric oxide production by lipopolysaccharide-activated RAW 264.7 cells was also assayed. All of the isolated saponins exhibited the significant activity in a concentration-dependent manner at concentrations of 60-200 MUM with the half maximal inhibitory concentration (IC50) values of 70.96 +/- 2.05 MUM for 1, 74.14 +/- 2.65 MUM for 2, and 79.83 +/- 1.78 MUM for 3, respectively, whereas indomethacin had an IC50 of 63.75 +/- 3.33 MUM as a positive control drug. PMID- 23638986 TI - A pilot split-face study comparing conventional methyl aminolevulinate photodynamic therapy (PDT) with microneedling-assisted PDT on actinically damaged skin. AB - BACKGROUND: Topical photodynamic therapy (PDT) is an approved treatment for superficial nonmelanoma skin cancers. To enhance photosensitizer penetration into the epidermis, microneedling (MN) devices or ablative carbon dioxide lasers are combined with PDT. OBJECTIVES: To compare the efficacy and safety of MN-assisted PDT with that of conventional PDT in human skin field cancerization. MATERIALS AND METHODS: Ten patients with multiple actinic keratoses (AKs) and photodamage were randomized to receive conventional methyl aminolevulinate (MAL) with previous gentle curettage on one side of the face and MAL-PDT combined with 1.5 mm-length MN on the other side after MAL application. After a 90-minute incubation, patients were illuminated with a red light-emitting diode and evaluated for improvement of photodamage, clearance of AKs, and side effects before and after 30 and 90 days. RESULTS: At day 30, global scores for photodamage, mottled pigmentation, roughness, and sallowness improved on both sides (p < .05), but fine lines improved only on the MN-PDT side (p = .004). At day 90, facial erythema (p = .04) and coarse wrinkles (p = .002) also improved on the MN-PDT side, in addition to fine lines for conventional MAL-PDT (p = .01). Erythema (p = .009), edema (p = .01), crusting (p = .01), and pain (p = .004) were more common and intense on the MN-PDT side. One patient developed a secondary bacterial infection at day 7 on the MN-PDT side. Average AK clearance was 88.3%, with no difference between the sides. CONCLUSION: Microneedling assisted PDT is a safe and effective method and can produce superior cosmetic results to conventional MAL-PDT for improving photodamaged skin. Further larger prospective studies are needed to determine whether the addition of MN decreases actinic keratosis. PMID- 23638987 TI - A kinetic study of amyloid formation: fibril growth and length distributions. AB - We propose a kinetic model for the self-aggregation by amyloid proteins. By extending several well-known models for protein aggregation, the time evolution of aggregate concentrations containing r proteins, denoted c(r)(t), can be written in terms of generalized Smoluchowski kinetics. With this approach, we take into account all possible aggregation and fragmentation reactions involving clusters of any size. Correspondingly, an aggregate of size x + y could be formed by or break up into two smaller constituent aggregates of sizes x and y. The rates of each aggregation or fragmentation reaction, called kernels, are specified in terms of the aggregate size, and we solve c(r)(t) for large cluster sizes using numerical techniques. We show that by using Smoluchowski kinetics many pathways to fibrillation are possible and quantities, such as the aggregate length distribution at an arbitrary time, can be calculated. We show that the predicted results of the model are in agreement with the experimental observations. PMID- 23638988 TI - The regulation of cambial activity in Chinese fir (Cunninghamia lanceolata) involves extensive transcriptome remodeling. AB - Chinese fir (Cunninghamia lanceolata), a commercially important tree for the timber and pulp industry, is widely distributed in southern China and northern Vietnam, but its large and complex genome has hindered the development of genomic resources. Few efforts have focused on analysis of the modulation of transcriptional networks in vascular cambium during the transition from active growth to dormancy in conifers. Here, we used Illumina sequencing to analyze the global transcriptome alterations at the different stages of vascular cambium development in Chinese fir. By analyzing dynamic changes in the transcriptome of vascular cambium based on our RNA sequencing (RNA-Seq) data at the dormant, reactivating and active stages, many potentially interesting genes were identified that encoded putative regulators of cambial activity, cell division, cell expansion and cell wall biosynthesis and modification. In particular, the genes involved in transcriptional regulation and hormone signaling were highlighted to reveal their biological importance in the cambium development and wood formation. Our results reveal the dynamics of transcriptional networks and identify potential key components in the regulation of vascular cambium development in Chinese fir, which will contribute to the in-depth study of cambial differentiation and wood-forming candidate genes in conifers. PMID- 23638990 TI - Self-esteem revisited: performance on the implicit relational assessment procedure as a measure of self- versus ideal self-related cognitions in dysphoria. AB - Although depression is characterised by low self-esteem as measured by questionnaires, research using implicit measures of self-esteem has failed to reveal the expected differences between depressed and non-depressed individuals. In this study, we used an implicit measure which enables the differentiation of ideal self- and actual self-esteem, through the introduction of propositions: "I am" versus "I want to be". We measured implicit relational associations about actual and ideal self in low (N=27) versus high dysphoric (N=29) undergraduates. Our data revealed that dysphoric individuals have a higher ideal self-esteem, and lower actual self-esteem in comparison to healthy participants. The results underscore the need to go beyond simple associations and suggest that the use of individual-specific propositions could enhance our understanding of the implicit measurement of self-esteem. Furthermore, these results underscore the importance of actual versus ideal self-discrepancy theories, which might guide the content of therapeutic interventions. PMID- 23638989 TI - Stochastic molecular model of enzymatic hydrolysis of cellulose for ethanol production. AB - BACKGROUND: During cellulosic ethanol production, cellulose hydrolysis is achieved by synergistic action of cellulase enzyme complex consisting of multiple enzymes with different mode of actions. Enzymatic hydrolysis of cellulose is one of the bottlenecks in the commercialization of the process due to low hydrolysis rates and high cost of enzymes. A robust hydrolysis model that can predict hydrolysis profile under various scenarios can act as an important forecasting tool to improve the hydrolysis process. However, multiple factors affecting hydrolysis: cellulose structure and complex enzyme-substrate interactions during hydrolysis make it diffucult to develop mathematical kinetic models that can simulate hydrolysis in presence of multiple enzymes with high fidelity. In this study, a comprehensive hydrolysis model based on stochastic molecular modeling approch in which each hydrolysis event is translated into a discrete event is presented. The model captures the structural features of cellulose, enzyme properties (mode of actions, synergism, inhibition), and most importantly dynamic morphological changes in the substrate that directly affect the enzyme-substrate interactions during hydrolysis. RESULTS: Cellulose was modeled as a group of microfibrils consisting of elementary fibrils bundles, where each elementary fibril was represented as a three dimensional matrix of glucose molecules. Hydrolysis of cellulose was simulated based on Monte Carlo simulation technique. Cellulose hydrolysis results predicted by model simulations agree well with the experimental data from literature. Coefficients of determination for model predictions and experimental values were in the range of 0.75 to 0.96 for Avicel hydrolysis by CBH I action. Model was able to simulate the synergistic action of multiple enzymes during hydrolysis. The model simulations captured the important experimental observations: effect of structural properties, enzyme inhibition and enzyme loadings on the hydrolysis and degree of synergism among enzymes. CONCLUSIONS: The model was effective in capturing the dynamic behavior of cellulose hydrolysis during action of individual as well as multiple cellulases. Simulations were in qualitative and quantitative agreement with experimental data. Several experimentally observed phenomena were simulated without the need for any additional assumptions or parameter changes and confirmed the validity of using the stochastic molecular modeling approach to quantitatively and qualitatively describe the cellulose hydrolysis. PMID- 23638991 TI - Non-contact AFM imaging in water using electrically driven cantilever vibration. AB - An atomic force microscopy (AFM) imaging mode is presented that can simultaneously record surface topography and local electrical properties in aqueous solutions without mechanical contact between the AFM tip and the sample. The interaction between the electrically biased tip and the grounded sample in aqueous medium causes the AFM cantilever to vibrate. This operation mode is based on the previously developed SPFM technique, though using water as the medium instead of air introduces some important practical and theoretical differences, and also greatly extends the applicability of this technique. There are two vibration modes, one at the frequency of the applied voltage (omega) and one at twice this frequency (2omega). The surface topography can be imaged using feedback control of the 2omega vibration amplitude, which is very sensitive to the tip-sample separation distance in the range of 1-10 nm. The amplitude and phase of the 1omega vibration can be recorded simultaneously during imaging to obtain information on local surface charge or potential differences. Similar techniques exist for imaging in air or vacuum, but the addition of a polarizable medium such as water adds significant theoretical and practical complexities. This paper addresses those complexities and demonstrates the effectiveness of the technique for surface imaging and analysis in aqueous environments. PMID- 23638992 TI - Rho kinase inhibitor fasudil protects against beta-amyloid-induced hippocampal neurodegeneration in rats. AB - BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and Abeta-induced neuronal damage is the major pathology of AD. There is increasing evidence that neuroinflammation induced by Abeta is also involved in the pathogenesis of AD. Fasudil is a Rho kinase inhibitor and has been reported to have neuroprotective effects. In this study, the main purpose is to investigate whether fasudil has beneficial effects on cognitive impairment and neuronal toxicity induced by Abeta. METHODS AND RESULTS: In the present study, intracerebroventricular injection of Abeta1-42 to rats resulted in marked cognitive impairment, severe neuronal damage, as well as increased IL-1beta, tumor necrosis factor alpha (TNF-alpha) production, and NF kappaB activation. Administration of fasudil significantly ameliorated the spatial learning and memory impairment, attenuated neuronal loss, and neuronal injury induced by Abeta1-42 . In addition, fasudil inhibited IL-1beta and TNF alpha production and NF-kappaB activation in the rat brain. CONCLUSIONS: Fasudil can protect against Abeta-induced hippocampal neurodegeneration by suppressing inflammatory response, suggesting that fasudil might be a promising agent for the prevention and treatment of inflammation-related diseases, such as AD. PMID- 23638993 TI - Does integrated governance lead to integrated patient care? Findings from the innovation forum. AB - Good integration of services that aim to reduce avoidable acute hospital bed use by older people requires frontline staff to be aware of service options and access them in a timely manner. In three localities where closer inter organisational integration was taking place, this research sought patients' perceptions of the care received across and within organisational boundaries. Between February and July 2008, qualitative methods were used to map the care journeys of 18 patients (six from each site). Patient interviews (46) covered care received before, at the time of and following a health crisis. Additional interviews (66) were undertaken with carers and frontline staff. Grounded theory based approaches showed examples of well-integrated care against a background of underuse of services for preventing health crises and a reliance on 'traditional' referral patterns and services at the time of a health crisis. There was scope to raise both practitioner and patient awareness of alternative care options and to expand the availability and visibility of care 'closer to home' services such as rapid response teams. Concerns voiced by patients centred on the adequacy of arrangements for organising ongoing care, while family members reported being excluded from discussions about care arrangements and the roles they were expected to play. The coordination of care was also affected by communication difficulties between practitioners (particularly across organisational boundaries) and a lack of compatible technologies to facilitate information sharing. Finally, closer organisational integration seemed to have limited impact on care at the patient/practitioner interface. To improve care experienced by patients, organisational integration needs to be coupled with vertical integration within organisations to ensure that strategic goals influence the actions of frontline staff. As they experience the complete care journey, feedback from patients can play an important role in the service redesign agenda. PMID- 23638994 TI - Low-normal free thyroxine confers decreased serum bilirubin in type 2 diabetes mellitus. AB - BACKGROUND: Bilirubin may confer cardiovascular protection because of its strong antioxidative properties. Both thyroid dysfunction and the diabetic state affect bilirubin metabolism. Here we tested whether low-normal thyroid function affects serum bilirubin among euthyroid subjects with and without type 2 diabetes mellitus (T2DM). METHODS: Serum total bilirubin, thyrotropin and free thyroxine (free T4), transaminases, insulin sensitivity (homeostasis model assessment), and lipids were measured in 74 T2DM and 82 nondiabetic subjects with thyrotropin and free T4 levels within the euthyroid range. RESULTS: Bilirubin was positively related to free T4 in T2DM subjects (r = 0.370, p < 0.001), but not in nondiabetic subjects (r = 0.047, p = 0.68). In age- and sex-adjusted multiple linear regression analysis, free T4 was found to interact positively with the presence of T2DM on serum bilirubin (interaction term: beta = 0.251, p = 0.024). This interaction remained present after additional adjustment for alcohol intake, aspartate aminotransferase and insulin sensitivity (interaction term: beta = 0.222, p = 0.043), or alternatively for cholesterol and triglycerides (interaction term: beta = 0.203, p = 0.057). CONCLUSIONS: Lower free T4 levels within the euthyroid range confer decreased bilirubin in T2DM. Low-normal thyroid function could enhance atherosclerosis susceptibility in T2DM by decreasing serum bilirubin. PMID- 23638996 TI - Size-dependent changes in sea spray aerosol composition and properties with different seawater conditions. AB - A great deal of uncertainty exists regarding the chemical diversity of particles in sea spray aerosol (SSA), as well as the degree of mixing between inorganic and organic species in individual SSA particles. Therefore, in this study, single particle analysis was performed on SSA particles, integrating transmission electron microscopy with energy dispersive X-ray analysis and scanning transmission X-ray microscopy with near edge X-ray absorption fine structure spectroscopy, with a focus on quantifying the relative fractions of different particle types from 30 nm to 1 MUm. SSA particles were produced from seawater in a unique ocean-atmosphere facility equipped with breaking waves. Changes to the SSA composition and properties after the addition of biological (bacteria and phytoplankton) and organic material (ZoBell growth media) were probed. Submicrometer SSA particles could be separated into two distinct populations: one with a characteristic sea salt core composed primarily of NaCl and an organic carbon and Mg(2+) coating (SS-OC), and a second type consisting of organic carbon (OC) species which are more homogeneously mixed with cations and anions, but not chloride. SS-OC particles exhibit a wide range of sizes, compositions, morphologies, and distributions of elements within each particle. After addition of biological and organic material to the seawater, a change occurs in particle morphology and crystallization behavior associated with increasing organic content for SS-OC particles. The fraction of OC-type particles, which are mainly present below 180 nm, becomes dramatically enhanced with increased biological activity. These changes with size and seawater composition have important implications for atmospheric processes such as cloud droplet activation and heterogeneous reactivity. PMID- 23638997 TI - Efficacy of topical tacrolimus for the treatment of persistent pruritus ani in patients with atopic dermatitis. AB - BACKGROUND: Pruritus ani (PA) is defined as intense chronic itching affecting perianal skin. OBJECTIVE: We aimed to determine the efficacy of topical tacrolimus treatment in atopic dermatitis (AD) patients who have PA. METHODS: The study included 32 patients with AD who were suffering PA. Patients were randomized into two groups. In total, 16 patients used 0.03% tacrolimus ointment and 16 patients used vaseline as placebo. All groups applied topical treatments to their perianal area twice daily for 4 weeks. The treatments were then reversed for 4 weeks after a 2 weeks wash out period. RESULTS: In total, 32 patients with AD who had refractory anal itching were enrolled in this study. None of the patients had obtained successful results with previous treatments. There was a statistically significant decrease in the recorded EASI, DLQI and itching scores for the tacrolimus group compared to the placebo group at weeks 4 and 6 of treatment (p < 0.05). CONCLUSION: Topical tacrolimus treatment was well tolerated and effective in controlling persistent PA in AD patients. PMID- 23638995 TI - NKG2D blockade attenuated cardiac allograft vasculopathy in a mouse model of cardiac transplantation. AB - A previous paper has reported that blockade of NKG2D was effective in protecting allograft in murine models of cardiac transplantation, but the mechanism of NKG2D blockade on attenuated cardiac allograft vasculopathy (CAV) was still unknown. In our current study, we found that wild-type recipients treated with anti-NKG2D monoclonal antibody (mAb) plus cytotoxic T lymphocyte antigen (CTLA)-4 immunoglobulin (I)g showed prolonged allograft survivals (>90 days, P < 0.001) significantly and attenuated CAV. These in-vivo results correlated with reduced alloantibody production, low expression of interleukin (IL)-17 and IL-6, while infiltration of regulatory T cells increased. IL-6 administration induced shorter allograft survival and higher CAV grade in CTLA-4-Ig plus anti-NKG2D mAb-treated recipients, whereas IL-17 had no significant effect on allograft survival and CAV grade in CTLA-4-Ig plus anti-NKG2D mAb-treated recipients. Furthermore, the prolonged allograft survival induced by NKG2D blockade was abrogated partially with depletion of regulatory T cells. In conclusion, blockade of NKG2D combined with CTLA-4-Ig attenuated CAV and this effect was associated with lower alloantibody production, inhibited IL-6 expression and enhanced expansion of regulatory T cells. PMID- 23638998 TI - Prognostic significance of peripheral monocyte count in patients with extranodal natural killer/T-cell lymphoma. AB - BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKL) has heterogeneous clinical manifestations and prognosis. This study aims to evaluate the prognostic impact of absolute monocyte count (AMC) in ENKL, and provide some immunologically relevant information for better risk stratification in patients with ENKL. METHODS: Retrospective data from 163 patients newly diagnosed with ENKL were analyzed. The absolute monocyte count (AMC) at diagnosis was analyzed as continuous and dichotomized variables. Independent prognostic factors of survival were determined by Cox regression analysis. RESULTS: The AMC at diagnosis were related to overall survival (OS) and progression-free survival (PFS) in patients with ENKL. Multivariate analysis identified AMC as independent prognostic factors of survival, independent of International Prognostic Index (IPI) and Korean prognostic index (KPI). The prognostic index incorporating AMC and absolute lymphocyte count (ALC), another surrogate factor of immune status, could be used to stratify all 163 patients with ENKL into different prognostic groups. For patients who received chemotherapy followed by radiotherapy (102 cases), the three AMC/ALC index categories identified patients with significantly different survivals. When superimposed on IPI or KPI categories, the AMC/ALC index was better able to identify high-risk patients in the low-risk IPI or KPI category. CONCLUSION: The baseline peripheral monocyte count is shown to be an effective prognostic indicator of survival in ENKL patients. The prognostic index related to tumor microenvironment might be helpful to identify high-risk patients with ENKL. PMID- 23639000 TI - Interfacial charge separation and recombination in InP and quasi-type II InP/CdS core/shell quantum dot-molecular acceptor complexes. AB - Recent studies of group II-VI colloidal semiconductor heterostuctures, such as CdSe/CdS core/shell quantum dots (QDs) or dot-in-rod nanorods, show that type II and quasi-type II band alignment can facilitate electron transfer and slow down charge recombination in QD-molecular electron acceptor complexes. To explore the general applicability of this wave function engineering approach for controlling charge transfer properties, we investigate exciton relaxation and dissociation dynamics in InP (a group III-V semiconductor) and InP/CdS core/shell (a heterostructure beween group III-V and II-VI semiconductors) QDs by transient absorption spectroscopy. We show that InP/CdS QDs exhibit a quasi-type II band alignment with the 1S electron delocalized throughout the core and shell and the 1S hole confined in the InP core. In InP-methylviologen (MV(2+)) complexes, excitons in the QD can be dissociated by ultrafast electron transfer to MV(2+) from the 1S electron level (with an average time constant of 11.4 ps) as well as 1P and higher electron levels (with a time constant of 0.39 ps), which is followed by charge recombination to regenerate the complex in its ground state (with an average time constant of 47.1 ns). In comparison, InP/CdS-MV(2+) complexes show similar ultrafast charge separation and 5-fold slower charge recombination rates, consistent with the quasi-type II band alignment in these heterostructures. This result demonstrates that wave function engineering in nanoheterostructures of group III-V and II-VI semiconductors provides a promising approach for optimizing their light harvesting and charge separation for solar energy conversion applications. PMID- 23638999 TI - Cell wall components of Leptosphaeria maculans enhance resistance of Brassica napus. AB - Preparations with elicitation activity were obtained from the mycelium of Leptosphaeria maculans , a fungal pathogen of oilseed rape (Brassica napus). Crude delipidated and deproteinized extract from fungal cell walls induced expression of pathogenesis related gene 1 (PR1), hydrogen peroxide accumulation, and enhanced resistance of B. napus plants toward infection by L. maculans. Elicitation activity significantly decreased after treatment of a crude extract with alpha- or beta-glucanase. Monosaccharide composition analysis of a crude extract purified by ion-exchange chromatography revealed glucose (~58 mol %), mannose (~22 mol %), and galactose (~18 mol %) as the major sugars. FT-IR and NMR spectra confirmed the presence of both carbohydrate and polypeptide components in the purified product. Correlation NMR experiments defined trisaccharide bound to O-3 of serine residue alpha-D-Glcp-(1->2)-beta-D-Galf-(1->6)-alpha-D-Manp-(1->3) L-Ser. Terminal alpha-D-Glcp and (1->6)-beta-D-glucan were also detected. The obtained results strongly support the conclusion that these carbohydrates induce defense response in B. napus plants. PMID- 23639001 TI - Biosynthetic O-methylation protects cladoniamides from self-destruction. AB - Bisindole cladoniamides, nanomolar inhibitors of colon cancer cell line HCT-116, contain a rare, indolotryptoline substructure. In this report, the structures of xenocladoniamides A-E (9-13) are described. Compounds 9-13 are generated from a cladoniamide heterologous production system where O-methyltransferase gene claM3 has been inactivated. The results suggest that O-methylation, installed by enzyme ClaM3, is critical to maintaining the structural integrity of the indolotryptoline scaffold. Xenocladoniamides D and E are modestly cytotoxic against colon cancer cell line HCT-116. PMID- 23639003 TI - Origin of the vasculature supporting growth of primary patient tumor xenografts. AB - BACKGROUND: Studies of primary patient tumor xenografts grown in immunodeficient mice have shown that these tumors histologically and genetically closely resemble the original tumors. These patient xenograft models are becoming widely used for therapeutic efficacy studies. Because many therapies are directed at tumor stromal components and because the tumor microenvironment also is known to influence the response of a tumor to therapy, it is important to understand the nature of the stroma and, in particular, the vascular supply of patient xenografts. METHODS: Patient tumor xenografts were established by implanting undisrupted pieces of patient tumors in SCID mice. For this study, formalin fixed, paraffin embedded specimens from several types of solid tumors were selected and, using species-specific antibodies which react with formalin fixed antigens, we analyzed the species origin of the stroma and blood vessels that supported tumor growth in these models. Additionally, we investigated the kinetics of the vascularization process in a colon tumor and a mesothelioma xenograft. In mice bearing a head and neck xenograft, a perfusion study was performed to compare the functionality of the human and mouse tumor vessels. RESULTS: In patient tumors which successfully engrafted, the human stroma and vessels which were engrafted as part of the original tumor did not survive and were no longer detectable at the time of first passage (15-25 weeks). Uniformly, the stroma and vessels supporting the growth of these tumors were of murine origin. The results of the kinetic studies showed that the loss of the human vessels and vascularization by host vessels occurred more rapidly in a colon tumor (by 3 weeks) than in a mesothelioma (by 9 weeks). Finally, the perfusion studies revealed that while mouse vessels in the periphery of the tumor were perfused, those in the central regions were rarely perfused. No vessels of human origin were detected in this model. CONCLUSIONS: In the tumors we investigated, we found no evidence that the human stromal cells and vessels contained in the original implant either survived or contributed in any substantive way to the growth of these xenografts. PMID- 23639006 TI - Anti-HIV and NO production inhibition activities of epi-aleuritolic acid derivatives. AB - Fifteen epi-aleuritolic acid derivatives were synthesized and evaluated for anti HIV activity in 293 T cells and NO production inhibition activity. Of the derivatives, 1, 2, 3, 4, 11, and 13 showed relatively potent anti-HIV activity with EC50 values ranging from 5.80 to 13.30 MUM. The most potent compound, 3alpha 2',2'-dimethylsuccinic acyl epi-aleuritolic acid (11), displayed significant anti HIV activity with an EC50 value of 5.80 MUM. Compounds 1, 3, 4, and 11 showed NO inhibition activity, with IC50 values ranging from 3.40 to 7.10 MUM and compound 1 inhibited NO production with an IC50 value of 3.40 MUM. PMID- 23639004 TI - A new method for determining gastric acid output using a wireless pH-sensing capsule. AB - BACKGROUND: Gastro-oesophageal reflux disease (GERD) and gastric acid hypersecretion respond well to suppression of gastric acid secretion. However, clinical management and research in diseases of acid secretion have been hindered by the lack of a non-invasive, accurate and reproducible tool to measure gastric acid output (GAO). Thus, symptoms or, in refractory cases, invasive testing may guide acid suppression therapy. AIM: To present and validate a novel, non invasive method of GAO analysis in healthy subjects using a wireless pH sensor, SmartPill (SP) (SmartPill Corporation, Buffalo, NY, USA). METHODS: Twenty healthy subjects underwent conventional GAO studies with a nasogastric tube. Variables impacting liquid meal-stimulated GAO analysis were assessed by modelling and in vitro verification. Buffering capacity of Ensure Plus was empirically determined. SP GAO was calculated using the rate of acidification of the Ensure Plus meal. Gastric emptying scintigraphy and GAO studies with radiolabelled Ensure Plus and SP assessed emptying time, acidification rate and mixing. Twelve subjects had a second SP GAO study to assess reproducibility. RESULTS: Meal-stimulated SP GAO analysis was dependent on acid secretion rate and meal-buffering capacity, but not on gastric emptying time. On repeated studies, SP GAO strongly correlated with conventional basal acid output (BAO) (r = 0.51, P = 0.02), maximal acid output (MAO) (r = 0.72, P = 0.0004) and peak acid output (PAO) (r = 0.60, P = 0.006). The SP sampled the stomach well during meal acidification. CONCLUSIONS: SP GAO analysis is a non-invasive, accurate and reproducible method for the quantitative measurement of GAO in healthy subjects. SP GAO analysis could facilitate research and clinical management of GERD and other disorders of gastric acid secretion. PMID- 23639007 TI - Double-perovskite magnetic La2NiMnO6 nanoparticles for adsorption of bovine serum albumin applications. AB - Double-perovskite La2NiMnO6 (LNMO) nanoparticles were synthesized by co precipitation process, and the adsorption of bovine serum albumin (BSA) protein on these nanoparticles was carried out. The powder samples were annealed at 750, 850, 950, and 1,050 degrees C, respectively. X-ray diffraction (XRD) results reveal that there are double perovskites and exhibit mixed orientations, without any impurity phases. Transmission electron microscopy results as well as the XRD estimate results show that the crystalline size is about 34 to 40 nm. The adsorption of BSA on the magnetic nanoparticles was analyzed using a UV spectrophotometer at room temperature. The results show that the as-prepared LNMO nanoparticles display a good adsorbing ability for BSA, and the nanoparticle sintered at 850 degrees C has the highest value of 219.6 mg/g, which is much higher than others. PMID- 23639008 TI - Photo-fermentative bacteria aggregation triggered by L-cysteine during hydrogen production. AB - BACKGROUND: Hydrogen recovered from organic wastes and solar energy by photo fermentative bacteria (PFB) has been suggested as a promising bioenergy strategy. However, the use of PFB for hydrogen production generally suffers from a serious biomass washout from photobioreactor, due to poor flocculation of PFB. In the continuous operation, PFB cells cannot be efficiently separated from supernatant and rush out with effluent from reactor continuously, which increased the effluent turbidity, meanwhile led to increases in pollutants. Moreover, to replenish the biomass washout, substrate was continuously utilized for cell growth rather than hydrogen production. Consequently, the poor flocculability not only deteriorated the effluent quality, but also decreased the potential yield of hydrogen from substrate. Therefore, enhancing the flocculability of PFB is urgent necessary to further develop photo-fermentative process. RESULTS: Here, we demonstrated that L-cysteine could improve hydrogen production of Rhodopseudomonas faecalis RLD-53, and more importantly, simultaneously trigger remarkable aggregation of PFB. Experiments showed that L-cysteine greatly promoted the production of extracellular polymeric substances, especially secretion of protein containing more disulfide bonds, and help for enhancement stability of floc of PFB. Through formation of disulfide bonds, L-cysteine not only promoted production of EPS, in particular the secretion of protein, but also stabilized the final confirmation of protein in EPS. In addition, the cell surface elements and functional groups, especially surface charged groups, have also been changed by L-cysteine. Consequently, absolute zeta potential reached a minimum value at 1.0 g/l of L-cysteine, which obviously decreased electrostatic repulsion interaction energy based on DLVO theory. Total interaction energy barrier decreased from 389.77 KT at 0.0 g/l of L-cysteine to 127.21 kT at 1.0 g/l. CONCLUSIONS: Thus, the strain RLD-53 overcame the total energy barrier and flocculated effectively. After a short settlement, the biomass rush out will be significantly reduced and the effluent quality will be greatly improved in the continuous operation. Furthermore, aggregation of PFB could enable high biomass hold-up of photobioreactor, which allows the photobioreactor to operate at low hydraulic retention time and high organic loading rate. Therefore, the described flocculation behaviour during photo-hydrogen production is potentially suitable for practicable application. PMID- 23639009 TI - Controlled cell adhesion using a biocompatible anchor for membrane-conjugated bovine serum albumin/bovine serum albumin mixed layer. AB - We report here a method for controlling cell adhesion, allowing simple yet accurate cell detachment from the substrate, which is required for the establishment of new cytometry-based cell processing and analyzing methods. A biocompatible anchor for membrane (BAM) was conjugated with bovine serum albumin (BSA) to produce a cell-anchoring agent (BAM-BSA). By coating polystyrene substrates with a mixture of BAM-BSA and BSA, controlled suppression of the substrate's adhesive properties was achieved. Hook-shaped nanoneedles were used to pick up cells from the substrate, while recording the cell-substrate adhesion force, using an atomic force microscope (AFM). Due to the lipid bilayer targeting property of BAM, the coated surface showed constant adhesion forces for various cell lines, and controlling the BAM-BSA/BSA ratio enabled tuning of the adhesion force, ranging from several tens of nano-Newtons down to several nano-Newtons. Optimized tuning of the adhesion force also enabled the detachment of cells from BAM-BSA/BSA-coated dishes, using a shear flow. Moreover, the method was shown to be noncell type specific and similar results were observed using four different cell types, including nonadherent cells. The attenuation of cell adhesion was also used to enable the collection of single cells by capillary aspiration. Thus, this versatile and relatively simple method can be used to control the adhesion of various cell types to substrates. PMID- 23639010 TI - Complete Raman spectral assignment of methanol in the C-H stretching region. AB - In this work, the Raman spectrum of gaseous methanol in the C-H stretching region was investigated by polarized Photoacoustic Raman spectroscopy (PARS). On the basis of the depolarization ratio measurement and density functional theory (DFT) calculations, a complete spectral assignment has been presented. The band at ~2845 cm(-1) was assigned to CH3 symmetric stretching, the bands at ~2925 and ~2955 cm(-1) were assigned to two Fermi resonance modes of CH3 bending overtones, and the bands at ~2961 and ~3000 cm(-1) were assigned to out-of-plane and in plane vibrations of splitting CH3 antisymmetric stretching. Such assignments can clarify the confusions among the previous spectral studies from the different experimental methods and be confirmed by the Raman spectrum of liquid methanol. Furthermore, the large splitting of 39 cm(-1) between two antisymmetric stretching in gaseous methanol was ascribed to the strong coupling between CH3 and OH groups within methanol molecule because it decreased rapidly in other long chain alcohol, such as CH3CD2OH. PMID- 23639002 TI - Redox regulation of protein kinases. AB - Protein kinases represent one of the largest families of genes found in eukaryotes. Kinases mediate distinct cellular processes ranging from proliferation, differentiation, survival, and apoptosis. Ligand-mediated activation of receptor kinases can lead to the production of endogenous hydrogen peroxide (H2O2) by membrane-bound NADPH oxidases. In turn, H2O2 can be utilized as a secondary messenger in signal transduction pathways. This review presents an overview of the molecular mechanisms involved in redox regulation of protein kinases and its effects on signaling cascades. In the first half, we will focus primarily on receptor tyrosine kinases (RTKs), whereas the latter will concentrate on downstream non-receptor kinases involved in relaying stimulant response. Select examples from the literature are used to highlight the functional role of H2O2 regarding kinase activity, as well as the components involved in H2O2 production and regulation during cellular signaling. In addition, studies demonstrating direct modulation of protein kinases by H2O2 through cysteine oxidation will be emphasized. Identification of these redox sensitive residues may help uncover signaling mechanisms conserved within kinase subfamilies. In some cases, these residues can even be exploited as targets for the development of new therapeutics. Continued efforts in this field will further basic understanding of kinase redox regulation, and delineate the mechanisms involved in physiological and pathological H2O2 responses. PMID- 23639011 TI - Raw hulled shredded acorns from Downy Oak (Quercus pubescens) in the diet of pigs: effects on digestibility and faeces characteristics. AB - Faeces quality and composition are both of interest to veterinary practitioners dealing with pigs' health and disturbances in the alimentary tract, especially in free-range situations. In the Mediterranean basin, acorns are used as a starch source for fattening pigs, yet little information is available on how that affects faecal quality and digestibility. Therefore, a combined diet containing ripe hulled shredded acorns vs. a pelleted complete diet for finishers was evaluated for the digestibility and faecal consistency. The trial involved eight crossbred pigs, and a matched-pair approach was used to divide animals into two groups, which were fed with two different diets: acorns group (A): n = 4, 70% ripe hulled shredded acorns + 30% pelleted complete diet combined, as fed; control group (C): n = 4, 100% pelleted complete feed. The pigs were housed individually and fed the experimental diets for 8 days; daily feed intake and faeces amounts were recorded and faeces quality assessed. The digestibility of organic matter (OM) and starch of the two diets, as well as of pure acorns, were calculated and compared. Daily feed consumption was significantly higher in group A, but the mean dry matter intake (DMI) per pig was similar in both groups. Dark, firm and consistent faeces were reported for each pig from group A in comparison with group B, whose faeces were paler and softer. Digestibility of OM and starch were lower in group A than in group B (67.8 +/- 3.4 vs. 83.9 +/- 1.1 and 82.5 +/- 3.4 vs. 92.3 +/- 2.1 respectively): total tract digestibility of native starch from pure acorns was calculated at 77%. The peculiar consistency of faeces was related to macroscopic acorn hulls, constantly detected in the faeces of all animals sampled in group A. PMID- 23639012 TI - Effect of weaning and in-feed high doses of zinc oxide on zinc levels in different body compartments of piglets. AB - High doses of Zn are widely used for prevention and treatment of diarrhoea in weaning piglets; however, the mechanism of action of Zn against diarrhoea is still not well understood. The objective of this study was to evaluate whether weaning induces Zn deficiency in piglets. Eight litters of primiparous sows were selected for the experiment, and 3 piglets presenting similar weights were selected within each litter. Two of the three selected piglets from each litter were weaned at 21d of age and fed two different diets: a commercial control diet (WCt) and the same diet plus 2000 ppm of Zn as ZnO (WZn). The third selected pig from each litter was kept unweaned (Uw) with the sow and the rest of the litter. All 24 selected animals were killed at 28 d of age, and blood, gastrointestinal content, liver, pancreas and spleen were sampled for Zn, Fe and Cu analysis (mg/kg or L of sample). Data were analysed using anova including treatment as a fixed factor. Weaned pigs fed WCt diet presented a lower Zn concentration in plasma than Uw animals (0.76 +/- 0.091 vs. 1.10 +/- 0.099 mg/L, p = 0.05). Zinc levels in liver, pancreas and spleen were not affected by weaning. Total concentration of Zn was higher in gastrointestinal contents of weaned animals fed WCt diet than in Uw pigs (p <= 0.001 for stomach, jejunum, ileum, caecum and colon). Supplementation with high doses of ZnO increased levels of Zn in gastrointestinal content (p < 0.001), liver (p < 0.001) and pancreas (p < 0.001) compared to WCt diet. It also increased plasma Zn to non-deficient levels (1.32 +/- 0.086), but the increase was not as marked as in other locations and final concentration was not different than that in Uw animals (p = 0.231). Weaning creates a Zn deficiency situation in weaned pigs as observed by plasma Zn concentrations. ZnO supplementation counteracts Zn deficiency. PMID- 23639013 TI - Feeding a diet contaminated with ochratoxin A for chickens at the maximum level recommended by the EU for poultry feeds (0.1 mg/kg). 1. Effects on growth and slaughter performance, haematological and serum traits. AB - The European Commission Recommendation 2006/576/EC, suggests that the maximum level of Ochratoxin A (OTA) in poultry feeds should be set at 0.1 mg OTA/kg. Thirty-six one-day-old male Hubburd broiler chickens were divided into two groups, a Control (basal diet) and an Ochratoxin A (basal diet + 0.1 mg OTA/kg) group. The growth and slaughter performance traits were recorded. The liver, spleen, bursa of Fabricius and thymus weights were measured. The erythrocyte and leukocyte numbers were assayed in blood samples, and the heterophils to lymphocytes (H/L) ratio was determined. Alpha-1-acid glycoprotein (AGP), lysozyme, the total protein and the electrophoretic pattern were evaluated in serum samples. Liver enzymes (alanino aminotransferase, ALT and aspartate aminotransferase, AST) and kidney function parameters (uric acid and creatinine) were quantified. The results revealed that feeding a 0.1 mg OTA/kg contaminated diet to chicks caused a decrease in the absolute thymus weight (p < 0.05) and a lower total protein (p < 0.01), albumin (p < 0.01), alpha (p < 0.05), beta (p = 0.001) and gamma (p = 0.001) globulins serum concentration in the Ochratoxin A group. Moreover, the albumin-to-globulin (A/G) ratio of the OTA-treated animals resulted to be higher (p < 0.05). Feeding broiler chickens, a diet contaminated with the maximum level admitted by the European Commission Recommendation (0.1 mg OTA/kg), did not affect the animal performance, slaughter traits, organ weights, haematological parameters, liver enzyme or renal function parameters concentrations but had an overall immunosuppressant effect, with reduction in the thymus weight and of the total serum protein, albumin, alpha, beta and gamma globulins concentration. PMID- 23639014 TI - Feeding a diet contaminated with ochratoxin A for broiler chickens at the maximum level recommended by the EU for poultry feeds (0.1 mg/kg). 2. Effects on meat quality, oxidative stress, residues and histological traits. AB - The European Commission Recommendation 2006/576/EC indicates that the maximum tolerable level of ochratoxin A (OTA) in poultry feeds is 0.1 mg OTA/kg. Thirty six 1-day-old male broiler chicks were divided into two groups, a control (basal diet) and an OTA (basal diet + 0.1 mg OTA/kg) group. The OTA concentration was quantified in serum, liver, kidney, breast and thigh samples. The thiobarbituric acid reactive substances (TBARS) content were evaluated in the liver, kidney, breast and thigh samples. The glutathione (GSH) content, and catalase (CAT) and superoxide dismutase (SOD) activity were measured in the liver and kidney samples. Histopathological traits were evaluated for the spleen, bursa of Fabricius and liver samples. Moreover, the chemical composition of the meat was analysed in breast and thigh samples. In the OTA diet-fed animals, a serum OTA concentration of 1.15 +/- 0.35 ng/ml was found, and OTA was also detected in kidney and liver at 3.58 +/- 0.85 ng OTA/g f.w. and 1.92 +/- 0.21 ng OTA/g f.w., respectively. The TBARS content was higher in the kidney of the ochratoxin A group (1.53 +/- 0.18 nmol/mg protein vs. 0.91 +/- 0.25 nmol/mg protein). Feeding OTA at 0.1 mg OTA/kg also resulted in degenerative lesions in the spleen, bursa of Fabricius and liver. The maximum tolerable level of 0.1 mg OTA/kg, established for poultry feeds by the EU, represents a safe limit for the final consumer, because no OTA residues were found in breast and thigh meat. Even though no clinical signs were noticed in the birds fed the OTA-contaminated diet, moderate histological lesions were observed in the liver, spleen and bursa of Fabricius. PMID- 23639015 TI - Identification of undeclared sources of animal origin in canine dry foods used in dietary elimination trials. AB - Failure to respond to commercial limited antigen diets can occur in dogs kept on a dietary trial for the diagnosis of adverse food reaction (AFR). The aim of this study was to assess twelve canine dry limited antigen diets (eleven novel protein diets and one hydrolysed diet) for potential contamination by ingredients of animal origin not mentioned on the label. The validity of the two methods adopted for the detection of such food antigens was also evaluated. Each dietary product was analysed by microscopy analysis using the official method described in Commission Regulation EC 152/2009 with the aim of identifying bone fragments of different zoological classes (mammalian, avian and fish) and by polymerase chain reaction (PCR) for the identification of DNA of animal origin. Discrepancies between the results obtained by PCR and/or microscopy analysis and the ingredients listed on pet food packages were found. Only in two pet foods did the results of both analyses match the ingredients listed on the label. In the remaining ten samples, microscopy detected bone fragments from one or two unpredicted zoological classes, revealing avian fragments in six of ten samples followed by those of fish in five of ten and mammalian fragments in four of ten. In two samples, microscopy analysis identified a contamination that would have otherwise passed unobserved if only PCR had been used. However, PCR confirmed the presence of all the zoological classes detected by microscopy and also identified the DNA of an additional unexpected zoological class in two samples. Dogs might fail to respond to commercial limited antigen diets because such diets are contaminated with potential allergens. Both PCR and microscopy analysis are required to guarantee the absence of undeclared animal sources in pet foods. Before ruling out AFR, a novel protein home-made diet should be considered if the dog is unresponsive to a commercial regimen. PMID- 23639016 TI - Enzyme effects on extruded diets for dogs with soybean meal as a substitute for poultry by-product meal. AB - The effects of exogenous enzymes supplementation on kibble diets for dogs formulated with soybean meal (SBM) as a substitute for poultry by-product meal (PM) was investigated on nutrient digestibility, fermentation products formation, post-prandial urea response and selected faecal bacteria counts. Two kibble diets with similar compositions were used in two trials: PM-based diet (28.9% of PM; soybean hulls as a fibre source) and SBM-based diet (29.9% of SBM). In experiment 1, the SBM diet was divided into three diets: SBM-0, without enzyme addition; SBM 1, covered after extrusion with 7500 U protease/kg and 45 U cellulase/kg; and SBM 2, covered with 15,000 U protease/kg and 90 U cellulase/kg. In experiment 2, the SBM diet was divided into three diets: SBM-0; SBM-1, covered with 140 U protease/kg; 8 U cellulase/kg, 800 U pectinase/kg, 60 U phytase/kg, 40 U betaglucanase/kg and 20 U xylanase/kg; and SMB-2, covered with 700 U protease/kg, 40 U cellulase/kg, 4000 U pectinase/kg, 300 U phytase/kg, 200 U betaglucanase/kg and 100 U xylanase/kg. Each experiment followed a block design with six dogs per diet. Data were submitted to analysis of variance and means compared by orthogonal and polynomial contrasts (p < 0.05). In both experiments, nutrients and energy digestibility did not differ between diets (p > 0.05). SBM consumption resulted in increased faecal moisture and production (p < 0.05), without effect on faecal score. Higher concentration of propionate, acetate and lactate, and lower ammonia and pH were found in the faeces of dogs fed SBM (p < 0.05). Higher post-prandial urea was verified in dogs fed SBM (p < 0.05). In experiment 2, the addition of enzymes increased faecal concentration of propionate, acetate and total short-chain fatty acid (p < 0.05) and tended to reduce post-prandial urea concentration (p = 0.06). Although with similar digestibility, SBM shows a worse utilization of absorbed amino acids than the PM. Soybean oligosaccharides can beneficially change gut fermentation product formation. Enzymes can increase the gut fermentation activity and improve the SBM proteic value. PMID- 23639017 TI - Enzyme use in kibble diets formulated with wheat bran for dogs: effects on processing and digestibility. AB - Recently, there is an interest in technologies that favour the use of coproducts for animal nutrition. The effect of adding two enzyme mixtures in diets for dogs formulated with wheat bran (WB) was evaluated. Two foods with similar compositions were formulated: negative control (NC; without WB) and test diet (25% of WB). The test diet was divided into four treatments: without enzyme (positive control), enzyme mixture 1 (ENZ1; added before extrusion beta glucanase, xylanase, cellulase, glucoamylase, phytase); enzyme mixture 2 (ENZ2; added before extrusion the ENZ1 more alpha-amylase); enzyme mixture 2 added after the extrusion (ENZ2ex). ENZ1 and ENZ2 were used to evaluate the enzyme effect on extruder pre-conditioner (processing additive) and ENZ2ex to evaluate the effect of enzyme supplementation for the animal. Digestibility was measured through total collection of faeces and urine. The experiment followed a randomized block design with five treatments (diets) and six dogs per diet, totalling 30 dogs (7.0 +/- 1.2 years old and 11.0 +/- 2.2 kg of body weight). Data were submitted to analysis of variance and means compared by Tukey's test and orthogonal contrasts (p < 0.05). Reducing sugars showed an important reduction after extrusion, suggesting the formation of carbohydrate complexes. The apparent total tract digestibility (ATTD) of dry matter, organic matter, crude protein, acid hydrolysed fat and energy was higher in NC than in diets with WB (p < 0.001), without effects of enzyme additions. WB diets resulted in higher faecal production and concentration of short-chain fatty acids (SCFA) and reduced pH and ammonia concentration (p < 0.01), with no effect of enzyme addition. The enzyme addition did not result in improved digestibility of a diet high in non-starch polysaccharides; however, only ATTD was measured and nutrient fermentation in the large intestine may have interfered with the results obtained. WB modified fermentation product formation in the colon of dogs. PMID- 23639018 TI - Maintenance energy requirements in miniature colony dogs. AB - There are numerous reports of maintenance energy requirements (MER) in dogs, but little information is available about energy requirements of miniature dog breeds. In this prospective, observational, cohort study, we aimed to determine MER in dogs from a number of miniature breeds and to determine which factors were associated with it. Forty-two dogs participated in the study. MER was calculated by determining daily energy intake (EI) during a period of 196 days (28-359 days) when body weight did not change significantly (e.g. +/-2% in 12 weeks). Estimated median MER was 473 kJ/kg(0.75) /day (285-766 kJ/kg(0.75) /day), that is, median 113 kcal/kg(0.75) /day (68-183 kcal/kg(0.75) /day). In the obese dogs that lost weight, median MER after weight loss was completed was 360 kJ/kg(0.75) /day (285 515 kJ/kg(0.75) /day), that is, 86 kcal/kg(0.75) /day, (68-123 kcal/kg(0.75) /day). Simple linear regression analysis suggested that three breeds (e.g. Chihuahua, p = 0.002; Yorkshire terrier, p = 0.039; dachshund, p = 0.035) had an effect on MER. In addition to breed, simple linear regression revealed that neuter status (p = 0.079) and having previously been overweight (p = 0.002) were also of significance. However, with multiple linear regression analysis, only previous overweight status (MER less in dogs previously overweight p = 0.008) and breed (MER greater in Yorkshire terriers [p = 0.029] and less in Chihuahuas [p = 0.089]) remained in the final model. This study is the first to estimate MER in dogs of miniature breeds. Although further information from pet dogs is now needed, the current work will be useful for setting energy and nutrient requirement in such dogs for the future. PMID- 23639019 TI - Effect of dietary supplementation of prebiotics and probiotics on intestinal microarchitecture in broilers reared under cyclic heat stress. AB - This study was designed to evaluate the effect of dietary supplementation of prebiotics, mannanoligosaccharides (MOS) and/or probiotics (LBP) on intraepithelial lymphocytes (IEL) count, goblet cells (GC) count and differentiation and intestinal micro-architecture in broilers reared under cyclic heat stress. Day-old broilers (n = 250) were randomly divided into five groups. Fifty birds were reared within the thermoneutral zone (TNZ). Remaining birds were subjected to cyclic heat stress from day 21 to 42 (35 degrees C, 75% RH, 8 h/d). The birds were fed corn-soy-based basal diet or the same diet supplemented with 0.5% MOS (HS-MOS), or 0.1% LBP (HS-LBP), or their combination (HS-SYN). The birds were slaughtered on day 42. Tissue samples were collected from mid-duodenum, jejunum and ileum, and stained with haematoxylin and eosin or combined Alcian blue and PAS technique. All differences were considered significant at p < 0.05. The IEL count increased in all intestinal segments of the HS group compared with the TNZ group and decreased in all supplemented groups compared with the HS group. Compared with the TNZ, heat stress reduced villus height, crypt depth and surface area in duodenum and ileum, and increased crypt depth in ileum. Villus width decreased in duodenum and jejunum compared with the TNZ group. Supplementation of LBP, MOS and SYN reversed all these changes in duodenum, while only increased villus height and surface area in ileum. In jejunum, the villus height and surface area increased with HS-LBP, and crypt depth increased with HS MOS. The number of GC containing acid mucins (duodenum and ileum) and mixed mucins (ileum) were increased in the HS compared with the TNZ. Supplementation of MOS, LBP and SYN maintained the enhanced activity of goblet cells. In conclusion, dietary supplementation of MOS and/or LBP may be helpful in alleviating some of the detrimental effects of heat stress on microstructure of the broiler gut. PMID- 23639020 TI - Comparison of postprandial lipaemia between native and palm random esterified acid oils in two different monogastric species (dogs and broiler chickens). AB - It has been reported that applying a chemical reesterification process to a native fat results in a new fat source with different physicochemical properties due to their different fatty acid (FA) positional distribution within the glycerol moiety and their different proportions of mono (MAG)-, di (DAG)- and triacylglycerides (TAG). Thus, this reesterification could affect fat digestion, absorption and metabolism; and this effect could vary among species given their differences in fat metabolism. The aim of this study was to compare the effect of feeding two different random esterified acid oils (REAO), presenting different MAG, DAG and TAG proportions, with their corresponding native oil on postprandial lipaemia in broiler chickens and dogs. For this purpose, 18 dogs and 54 broiler chickens were fed a basal diet supplemented with palm native oil, palm REAO low MAG or palm REAO high MAG. The inclusion level of the oils was 10% of the diet in dogs and 6% in broiler chickens. Serum postprandial TAG concentration (mg/dl) after feeding a single meal was measured at different time points during 12 h in dogs and 3 h in chickens. Although fasting serum TAG concentration values were similar for both species (47 +/- 2.4 mg/dl for dogs and 44 +/- 3.0 mg/dl for broilers; p = 0.522), postprandial TAG concentrations tended to be higher in broilers than in dogs (p = 0.058). Treatment had no effect on TAG concentration at any time point in any species (p = 0.768 for dogs, p = 0.947 for broilers). However, the postprandial TAG curves were very different between species; in broiler chickens, TAG concentration returned to the fasting values 3 h after feeding while in dogs, the TAG concentration still had not returned to basal levels 12 h after feeding. PMID- 23639021 TI - Comparative study of fermentation and methanogen community structure in the digestive tract of goats and rabbits. AB - Methane is the most important anthropogenic contribution to climate change after carbon dioxide and represents a loss of feed energy for the animal, mainly for herbivorous species. However, our knowledge about the ecology of Archaea, the microbial group responsible for methane synthesis in the gut, is very poor. Moreover, it is well known that hindgut fermentation differs from rumen fermentation. The composition of archaeal communities in fermentation compartments of goats and rabbits were investigated using DGGE to generate fingerprints of archaeal 16S rRNA gene. Ruminal contents and faeces from five Murciano-Granadina goats and caecal contents of five commercial White New Zealand rabbits were compared. Diversity profile of methanogenic archaea was carried out by PCR-DGGE. Quantification of methanogenic archaea and the abundance relative to bacteria was determined by real-time PCR. Methanogenic archaeal species were relatively constant across species. Dendrogram from DGGE of the methanogen community showed one cluster for goat samples with two sub-clusters by type of sample (ruminal and faeces). In a second cluster, samples from rabbit were grouped. No differences were found either in richness or Shannon index as diversity indexes. Although the primer sets used was developed to investigate rumen methanogenic archaeal community, primers specificity did not affect the assessment of rabbit methanogen community structure. Rumen content showed the highest number or methanogenic archaea (log10 9.36), followed by faeces (log10 8.52) and showing rabbit caecum the lower values (log10 5.52). DGGE profile showed that pre-gastric and hindgut fermenters hold a very different methanogen community. Rabbits hold a microbial community of similar complexity than that in ruminants but less abundant, which agrees with the type of fermentation profile. PMID- 23639022 TI - Dietary effects of linseed on fatty acid composition of milk and on liver, adipose and mammary gland metabolism of periparturient dairy cows. AB - During the transition period in dairy cows, drastic adaptations within and between key tissues and cell types occur in a coordinated manner to support late gestation, the synthesis of large quantities of milk and metabolic homoeostasis. The start of lactation coincides with an increase of triacylglycerols in the liver, which has been associated with several economically important diseases in dairy cows (i.e. hepatic lipidiosis, mastitis). The polyunsaturated fatty acids have been used to improve liver metabolism and immune function in the mammary gland. Therefore, the effects of dietary linseed supplementation on milk quality and liver, adipose and mammary gland metabolism of periparturient dairy cows were studied in 14 cows that were randomly assigned to control or linseed supplementation. Animals were treated from 3 weeks antepartum until 6 weeks post partum. Linseed did not modify dry matter intake, but increased milk yield and lactose yield, and decreased milk fat concentration, which coincided with lower proportion of C16 and higher proportions of stearic acid, conjugated linoleic acid and alpha-linolenic acid in milk fat. Linseed supplementation did not significantly change the expression of key lipid metabolism genes in liver and adipose tissues, except of glucose transporter 2 (GLUT2) in liver, which was increased in cows supplemented with linseed, suggesting that more glucose was secreted and probably available for lactose synthesis compared with cows fed control diet. Large adaptations of transcription occurred in the mammary gland when dairy cows were supplemented with linseed. The main affected functional modules were related to energy metabolism, cell proliferation and remodelling, as well as the immune system response. PMID- 23639023 TI - Effect of timing of post-partum introduction to pasture and supplementation with Saccharomyces cerevisiae on milk production, metabolic status, energy balance and some reproductive parameters in early lactation dairy cows. AB - Dietary change, an inconsistent nutrient intake and high levels of milk production make the early post-partum period (PP) a challenging time for the lactating dairy cow. This experiment investigates the effects of two early PP nutritional management strategies (NM): abrupt introduction to pasture (AP) or a total mixed ration (TMR) for 21 days followed by a gradual introduction to pasture over 7 days (GP), with (Y) or without (C) live yeast (YS) on milk production, energy balance (EB) and selected metabolic and reproductive variables. Forty multiparous dairy cows were assigned to one of four dietary treatments in a two (AP vs. GP) by two (Y vs. C) factorial, randomized block design. The experiment was conducted from days 1 to 70 PP. Blood samples were taken on day 1, day 5 and every 10 days until day 45 to determine metabolites, whilst intake (DMI), and EB were determined during week 6 PP. Milk was sampled weekly for fat, protein and lactose. Trans-rectal scanning for reproductive variables commenced on day 10 PP. Animals in the GP group had a higher DMI (p = 0.04), higher fat yield (p = 0.08) and fewer days to first ovulation (p = 0.09) vs. those in the AP group. EB (-3.5 +/- 0.67 units of energy for milk production) and body condition score loss (0.70 +/- 0.09) were not affected by NM. However, non-esterified fatty acids (NEFA) (p < 0.01) were higher, and glucose (p = 0.02) was lower in the AP vs. the GP group. Supplementary YS tended to improve EB (p = 0.09) and reduced NEFA (p < 0.01) vs. non-supplemented animals. These data suggest that offering animals a nutritionally balanced TMR during the first 3 weeks PP followed by a gradual introduction to pasture can improve DMI vs. pasture-based diets. Additionally, the blood metabolic profile suggests a more favourable energy status in the GP group or where YS was supplemented during the early PP period. PMID- 23639024 TI - Effects of Saccharomyces cerevisiae supplementation on apparent total tract digestibility of nutrients and fermentation profile in healthy horses. AB - Supplementation with Saccharomyces cerevisiae (SC) in horses may have some potential to modify microbial populations and thereby improve fibre digestibility. The aim of this study was to investigate the effects of SC on apparent total tract digestibility (ATTD) of nutrients, with a special focus on fibre digestion in healthy horses. The fermentation profile of microbial populations was another focus of interest. Twelve geldings were randomly assigned to three groups. The basal diet consisted of cracked corn (2 g starch/kg body weight [BW]) and hay (1.2 kg/100 kg BW). During adaptation (3 weeks) and the total faecal collection period (5 days), cracked corn was fed once daily either as control (0 g SC) or supplemented with 1 or 3 g SC (1 g SC = 2 * 10(10) colony forming units [cfu]). There was a 4-week wash-out period between the different SC regimes. Faeces were sampled by rectal collection for the analysis of pH, nitrogen, lactic acid, short-chain fatty acids (SCFA) and SC. In faeces, mean SC cfu was significantly lower than the quantity supplemented: 0 g SC, no detection; 1 g SC, 1.1 * 10(6) cfu; 3 g SC, 3.6 * 10(6) cfu. Apparent total tract digestibility of crude fibre varied approximately 40% without any treatment related effects. Short-chain fatty acids, lactic acids and pH in faeces were not significantly affected by SC supplementation. Saccharomyces cerevisiae supplementation was not associated with any changes in the fermentation profiles, and fibre digestion accordingly remained unchanged in intact and healthy horses. Taking into account that fibre digestion remained unchanged and recovery rate of SC in faeces was mariginal, colonization and proliferation of SC in the healthy equine intestinal tract seems to be unlikely. PMID- 23639026 TI - Expanding functions of intracellular resident mono-ADP-ribosylation in cell physiology. AB - Poly-ADP-ribosylation functions in diverse signaling pathways, such as Wnt signaling and DNA damage repair, where its role is relatively well characterized. Contrarily, mono-ADP-ribosylation by for example ARTD10/PARP10 is much less understood. Recent developments hint at the involvement of mono-ADP-ribosylation in transcriptional regulation, the unfolded protein response, DNA repair, insulin secretion and immunity. Additionally, macrodomain-containing hydrolases, MacroD1, MacroD2 and C6orf130/TARG1, have been identified that make mono-ADP-ribosylation reversible. Complicating further progress is the lack of tools such as mono-ADP ribose-specific antibodies. The currently known functions of mono-ADP ribosylation are summarized here, as well as the available tools such as mass spectrometry to study this modification in vitro and in cells. PMID- 23639025 TI - Infection structure-specific reductive iron assimilation is required for cell wall integrity and full virulence of the maize pathogen Colletotrichum graminicola. AB - Ferroxidases are essential components of the high-affinity reductive iron assimilation pathway in fungi. Two ferroxidase genes, FET3-1 and FET3-2, have been identified in the genome of the maize anthracnose fungus Colletotrichum graminicola. Complementation of growth defects of the ferroxidase-deficient Saccharomyces cerevisiae strain Deltafet3fet4 showed that both Fet3-1 and Fet3-2 of C. graminicola represent functional ferroxidases. Expression of enhanced green fluorescent protein fusions in yeast and C. graminicola indicated that both ferroxidase proteins localize to the plasma membrane. Transcript abundance of FET3-1 increased dramatically under iron-limiting conditions but those of FET3-2 were hardly detectable. Deltafet3-1 and Deltafet3-2 single as well as Deltafet3 1/2 double-deletion strains were generated. Under iron-sufficient or deficient conditions, vegetative growth rates of these strains did not significantly differ from that of the wild type but Deltafet3-1 and Deltafet3-1/2 strains showed increased sensitivity to reactive oxygen species. Furthermore, under iron limiting conditions, appressoria of Deltafet3-1 and Deltafet3-1/2 strains showed significantly reduced transcript abundance of a class V chitin synthase and exhibited severe cell wall defects. Infection assays on intact and wounded maize leaves, quantitative data of infection structure differentiation, and infection stage-specific expression of FET3-1 showed that reductive iron assimilation is required for appressorial penetration, biotrophic development, and full virulence. PMID- 23639027 TI - Serum B-cell activating factor assessment in a population of Egyptian patients with systemic sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc) is a rare systemic connective tissue disease characterized by abnormal fibroblast proliferation and micro-vascular inflammatory changes. AIM: To assess serum B-cell activating factor (BAFF) levels in patients with systemic sclerosis and to correlate this with disease features and disease severity. METHODS: This is a case-control study in which patients with the established diagnosis of SSc were recruited. The diagnosis of SSc was established according to the American Rheumatology Association 1980 criteria for the classification of scleroderma. Patients' assessment included evaluation of skin involvement using the Modified Rodnan score and disease severity using the Medsger score. Twenty-five healthy matching controls were included. The sandwich enzyme-linked immunosorbent assay technique was used for direct assessment of serum BAFF in patients and controls. RESULTS: The study included 60 patients (54 female and 6 male), with a mean age of 38.18 +/- 12.06 years, with mean disease duration of 7.85 +/- 4.075 years. Serum BAFF in patients ranged 98.2-5015 pg/mL with mean BAFF 1100 +/- 835.4 pg/mL. In controls serum BAFF levels ranged 188.5 2314 pg/mL with mean BAFF 546.1 +/- 471.1 pg/mL, showing a statistically significant elevation of serum BAFF levels in SSc patients (P = 0.0001) with insignificant correlation to skin disease or total Medsgar Score of the study population (P > 0.05). Serum BAFF levels showed significant correlation with episodes of pseudo-obstruction and methotrexate (MTX) use in the patients studied (P < 0.05). CONCLUSION: Serum BAFF levels were significantly elevated in patients with SSc irrespective of disease subtype, disease duration or age of patients. This elevation in serum BAFF significantly related to gastrointestinal track involvement and MTX therapy. PMID- 23639029 TI - Preparation of Mohs micrographic surgery frozen sections: three new pearls leading to a simplified, more-effective process. PMID- 23639028 TI - Two new highly oxygenated and rearranged limonoids from Phyllanthus cochinchinensis. AB - A new 6/6/5/6-fused limonoid, phyllanthoid A (1), possessing both 19/30 and 19/29 oxygen bridges was isolated from Phyllanthus cochinchinensis (Euphorbiaceae), together with a new related limonoid, phyllanthoid B (2). Their structures were determined by spectroscopic analysis and single-crystal X-ray diffraction in the case of 1. Compound 1 displayed moderate antifeedant against the generalist plant feeding insect Spodoptera exigua and cytotoxicity against the MCF-7 cell line. PMID- 23639030 TI - A randomised controlled study to explore the effect of life story review on depression in older Chinese in Singapore. AB - There is little evidence to support the efficacy of the life storybook creation process, which incorporates the use of narratives, in mediating depression levels. The study aimed to examine the effects of the life storybook creation process on depressive symptoms among older community-dwelling Chinese adults in Singapore. A randomised controlled trial was conducted from January 2011 to March 2012. Twenty-six Chinese aged over 60 years, who were able to communicate in Chinese and/or English, and with mild to severe depression were randomly allocated to either the life storybook (intervention) group (n = 14) or the non life storybook (control) group (n = 12). Subjects in the intervention group were interviewed on a one to one basis on five sessions over 8 weeks. Depressive symptoms were measured using the Geriatric Depression Scale. Generalised estimating equations were used to examine the effects of the intervention on the elderly peoples' depression level. Significant reductions in depression scores were found in the intervention group from baseline (mean 7.9 [SD 3.0]) to week 8 (2.5 [1.7], chi(2) = 15.25, P < 0.001). At week 8, the intervention group showed a lower level of depression than the control (chi(2) = 4.33, P = 0.037). This study supports the life storybook creation process as an effective intervention for depressed older Chinese adults living in the community. The findings suggest that this intervention may enhance the quality of care provided by healthcare providers as the therapeutic relationship between provider and client is being established. PMID- 23639032 TI - Sequence-based SNP genotyping in durum wheat. AB - Marker development for marker-assisted selection in plant breeding is increasingly based on next-generation sequencing (NGS). However, marker development in crops with highly repetitive, complex genomes is still challenging. Here we applied sequence-based genotyping (SBG), which couples AFLP(r)-based complexity reduction to NGS, for de novo single nucleotide polymorphisms (SNP) marker discovery in and genotyping of a biparental durum wheat population. We identified 9983 putative SNPs in 6372 contigs between the two parents and used these SNPs for genotyping 91 recombinant inbred lines (RILs). Excluding redundant information from multiple SNPs per contig, 2606 (41%) markers were used for integration in a pre-existing framework map, resulting in the integration of 2365 markers over 2607 cM. Of the 2606 markers available for mapping, 91% were integrated in the pre-existing map, containing 708 SSRs, DArT markers, and SNPs from CRoPS technology, with a map-size increase of 492 cM (23%). These results demonstrate the high quality of the discovered SNP markers. With this methodology, it was possible to saturate the map at a final marker density of 0.8 cM/marker. Looking at the binned marker distribution (Figure 2), 63 of the 268 10-cM bins contained only SBG markers, showing that these markers are filling in gaps in the framework map. As to the markers that could not be used for mapping, the main reason was the low sequencing coverage used for genotyping. We conclude that SBG is a valuable tool for efficient, high throughput and high-quality marker discovery and genotyping for complex genomes such as that of durum wheat. PMID- 23639031 TI - Reversible folding of human peripheral myelin protein 22, a tetraspan membrane protein. AB - Misfolding of the alpha-helical membrane protein peripheral myelin protein 22 (PMP22) has been implicated in the pathogenesis of the common neurodegenerative disease known as Charcot-Marie-Tooth disease (CMTD) and also several other related peripheral neuropathies. Emerging evidence suggests that the propensity of PMP22 to misfold in the cell may be due to an intrinsic lack of conformational stability. Therefore, quantitative studies of the conformational equilibrium of PMP22 are needed to gain insight into the molecular basis of CMTD. In this work, we have investigated the folding and unfolding of wild type (WT) human PMP22 in mixed micelles. Both kinetic and thermodynamic measurements demonstrate that the denaturation of PMP22 by n-lauroyl sarcosine (LS) in dodecylphosphocholine (DPC) micelles is reversible. Assessment of the conformational equilibrium indicates that a significant fraction of unfolded PMP22 persists even in the absence of the denaturing detergent. However, we find the stability of PMP22 is increased by glycerol, which facilitates quantitation of thermodynamic parameters. To our knowledge, this work represents the first report of reversible unfolding of a eukaryotic multispan membrane protein. The results indicate that WT PMP22 possesses minimal conformational stability in micelles, which parallels its poor folding efficiency in the endoplasmic reticulum. Folding equilibrium measurements for PMP22 in micelles may provide an approach to assess the effects of cellular metabolites or potential therapeutic agents on its stability. Furthermore, these results pave the way for future investigation of the effects of pathogenic mutations on the conformational equilibrium of PMP22. PMID- 23639034 TI - Retrospective cohort study on combination therapy with the histamine H2-receptor antagonist lafutidine for antihistamine-resistant chronic urticaria. AB - We conducted a retrospective cohort study evaluating the efficacy and usefulness of the addition of lafutidine, a novel histamine H2-receptor antagonist, in treatment of patients with idiopathic chronic urticaria whose disease was not well controlled with histamine H1-receptor antagonists. Based on the assessment of global improvement, moderate or better improvement was achieved in 39 of 46 patients (85%) after 1-3 weeks of additional administration of lafutidine and 35 patients (76%) after 3 months. No incidence of drug-related adverse reactions was reported in any patient. Lafutidine was rated as useful or better in 34 patients (74%) after 3 months of treatment. The usefulness of the drug was not affected by differences in background factors, such as disease duration, previous treatment duration and the number of concomitant H1-receptor antagonists. Lafutidine appears to be a promising addition to histamine H1-receptor antagonist therapy for the treatment of chronic urticaria resistant to treatment with H1-receptor antagonists alone. PMID- 23639036 TI - Snapshot of the AAOHN APRN membership. AB - In 2012, the American Association of Occupational Health Nurses, Inc. (AAOHN) conducted an online membership survey. This article presents demographic, certification, educational, employment, priority issues, and membership data for advanced practice registered nurse (APRN) AAOHN members. Approximately 8% of the respondents identified themselves as nurse practitioners and/or clinical nurse specialists. The majority of these members are currently employed as APRNs (62.1%) and work full-time (85.7%) as employees of their organizations (85.8%). Critical issues that AAOHN APRN members identified in occupational health nursing practice today included the economy, government regulations, and health care reform. PMID- 23639035 TI - Neuropeptide YY(2)R blockade in the central amygdala reduces anxiety-like behavior but not alcohol drinking in alcohol-dependent rats. AB - Electrophysiological data suggest a dual role of Y2 receptors (Y2 Rs) as autoreceptors regulating neuropeptide Y release and heteroceptors regulating gamma-aminobutyric acid release in the central amygdala (CeA). Here, we report that neither systemic (JNJ-31020028) nor intra-CeA (BIIE0246) Y2 R antagonism altered operant alcohol responding by alcohol-dependent or non-dependent rats. Conversely, BIIE0246 in the CeA reduced anxiety-like behavior in alcohol dependent and alcohol-naive rats. The finding that Y2 R antagonism reduces anxiety-like behavior but not alcohol drinking suggests that these two effects may occur via different functions of the Y2 R (e.g. autoreceptor versus heteroceptor function). PMID- 23639037 TI - Health care reform and influenza immunization. AB - Health care reform calls for the nursing profession, with a focus on disease prevention and health restoration, to innovate and create new models of care that are client-centric, evidence-based, and cost-effective. To do so, nurses must develop a fundamentally different paradigm and epistemology. New care models are required that focus on issues such as evidence-based prevention. Among the prevention foci for hospitals are hospital-acquired infections, including influenza, which kills 36,000 Americans annually. One crucial step in eliminating hospital-acquired influenza is to require influenza vaccination of all health care workers. This article challenges nursing leadership to seize opportunities to lead health care initiatives and encourage courageous innovative actions that depart from old paradigms; these actions must be based on scientific evidence, reduce costs, and promote patient safety and quality care and outcomes. PMID- 23639038 TI - The prevalence of work-related neck, shoulder, and upper back musculoskeletal disorders among midwives, nurses, and physicians: a systematic review. AB - With the global shortage of health care workers predicted to worsen, attrition from the work force must be minimized. This review examined the incidence or prevalence of neck, shoulder, and upper back musculoskeletal disorders, a possible source of attrition, among midwives, nurses, and physicians. Four electronic databases were systematically searched for publications meeting inclusion criteria. Reference lists of retrieved articles were hand searched for additional articles. After eliminating articles that did not meet inclusion criteria, the remaining articles were assessed for quality and prevalence or incidence data were extracted. Twenty-nine articles published between 1990 and 2012 were included and assessed for quality. Median annual prevalence rates were 45% (neck), 40% (shoulder), and 35% (upper back). Methodological concerns included small sample size, inconsistency of outcome measures, likelihood of non response bias, and low response rates. Midwives, who have not been well studied, demonstrated prevalence somewhat lower than that of nurses and physicians. PMID- 23639040 TI - Wind energy presents new challenges for worker health and safety. AB - Wind technology jobs present uncertainties for worker health. More investigation is needed to ensure the safety of employees working on wind farms. PMID- 23639041 TI - The effect of strabismus on object detection in the ring scotoma of a monocular bioptic telescope. AB - PURPOSE: People with reduced visual acuity are permitted to drive with the aid of bioptic telescopes in the USA, the Netherlands, and Canada. When viewing through a monocular bioptic telescope, suppression of the deviating eye in strabismus may reduce the ability of the non-telescope eye to detect objects whose images fall in the ring scotoma area of the telescope eye, which could impair detection of traffic-relevant events. This ability to detect stimuli in the ring scotoma area was compared for strabismic and non-strabismic patients. METHODS: Ten strabismic and six non-strabismic patients with bilaterally reduced visual acuity (0.30-1.0 logMAR, 6/12 to 6/60) participated. A dichoptic perimeter presented stimuli to the fellow (non telescope) eye in the area of the ring scotoma under binocular viewing. Fellow-eye detection rates were determined with and without a bioptic, on uniform and patterned backgrounds, while performing passive (viewing a cross) and active (reading letters) fixation tasks. RESULTS: All strabismic patients were found to have anomalous retinal correspondence. Both non-strabismic and strabismic patients had lower fellow-eye detection rates on patterned than on uniform backgrounds, and while performing the active task. In addition, strabismic patients had lower detection with than without the bioptic on the patterned background. They also had a larger decrease in detection from the uniform to the patterned background than non-strabismic patients (26% vs 8%). Depending on the angle and direction of the deviation relative to the stimulus side, strabismus either increased or decreased fellow-eye stimulus eccentricity on the retina. Larger detection rate reductions between the uniform and patterned backgrounds were associated with more eccentric stimulus locations (rho = 0.61, p = 0.013). CONCLUSIONS: Both strabismic patients and non-strabismic patients were able to detect stimuli with the fellow eye in the ring scotoma area, demonstrating successful bi-ocular multiplexing. However, strabismic patients generally had a greater reduction in detection performance from the uniform to the patterned background than non-strabismic patients, which was accounted for in part by differences in stimulus eccentricities on the retina (that varied with the angle and direction of the strabismus). However, a study with a larger sample, including participants with strabismus and normal retinal correspondence, is needed before our findings can be generalized. PMID- 23639042 TI - Cytotoxicity and variant cellular internalization behavior of water-soluble sulfonated nanographene sheets in liver cancer cells. AB - Highly exfoliated sulfonated graphene sheets (SGSs), an alternative to graphene oxide and graphene derivatives, were synthesized, characterized, and applied to liver cancer cells in vitro. Cytotoxicity profiles were obtained using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, WST-1[2-(4-iodophenyl)-3 (4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, and lactate dehydrogenase release colorimetric assays. These particles were found to be non-toxic across the concentration range of 0.1 to 10 MUg/ml. Internalization of SGSs was also studied by means of optical and electron microscopy. Although not conclusive, high-resolution transmission and scanning electron microscopy revealed variant internalization behaviors where some of the SGS became folded and compartmentalized into tight bundles within cellular organelles. The ability for liver cancer cells to internalize, fold, and compartmentalize graphene structures is a phenomenon not previously documented for graphene cell biology and should be further investigated. PMID- 23639043 TI - Alcohol plus chlorhexidine is more efficient than alcohol alone for phenol-based chemical matricectomy: an in vitro study. AB - BACKGROUND: A phenolization approach is often chosen for treatment of ingrown toenails. Many reports describe lavage of the wound with alcohol to neutralize any residual phenol. The aim of our study was to compare the suitability and effectiveness of a solution consisting of alcohol plus chlorhexidine with that of alcohol alone in a lavage step during the treatment of ingrown toenails using a phenolization procedure. METHODS: We performed an in vitro study using human matrix and a diffusion cell apparatus to measure the amount of phenol remaining after various lavage washes. The effect of phenol evaporation was also examined. RESULTS: When phenol was irrigated with alcohol alone, total phenol recovered was 29.9 +/- 4.8 mg (62.9% of the initial amount). When the phenol was irrigated with isopropyl alcohol plus 0.5% chlorhexidine, 39.8 +/- 1.7 mg (83.8%) of phenol was recovered. CONCLUSION: A lavage step including alcohol and chlorhexidine is more effective than alcohol alone for removal of excess phenol. The addition of chlorhexidine also contributed to inhibition of the action of phenol. This approach provides a suitable and effective means of diluting and removing any excess or residual phenol from the exposed area. PMID- 23639044 TI - Post-stroke sexual dysfunction: an overlooked and under-addressed problem. AB - Sexual disorders after stroke are thought to be due to multiple etiologies, including both organic and psychosocial causes. Sexual function in post-stroke patients is often disregarded by healthcare professionals although sexuality is a fundamental part of quality of life. Beside pharmacological treatment, one of the most important, but underestimated, success factors of SD therapy is undeniably a proper counseling, which is mandatory to provide correct information on post stroke sexuality helping the patients and their partners to regain intimacy. PMID- 23639046 TI - Cryptococcus gattii in urban trees from cities in North-eastern Argentina. AB - In the city of Buenos Aires, Argentina, Cryptococcus gattii genotype AFLP4/VGI was found to be associated with decaying wood in hollows of different tree species. The aim of this study was to investigate the presence of C. gattii in the environment of riverside cities of the river Parana, and to describe its serotypes and molecular types. Five hundred samples were collected in 50 parks by swabbing tree hollows. The samples were inoculated on caffeic acid agar supplemented with chloramphenicol, and incubated at 28 degrees C for 1 week with a daily observation. The isolates were identified by conventional methods. The serotype was determined by slide agglutination with specific antisera. Molecular typing was carried out by PCR-RFLP of the URA5 gene. Four isolates of C. gattii were recovered: Cryptococcus gattii serotype B, genotype AFLP4/VGI, isolated from Eucalyptus sp. in the city of Rosario and from Grevillea robusta in the city of La Paz; and C. gattii serotype C, genotype AFLP5/VGIII, isolated from two different Tipuana tipu trees in the city of Resistencia. Here, we report for the first time the isolation of C. gattii serotype C, genotype AFLP5/VGIII, from environmental samples in Argentina. PMID- 23639045 TI - Lenalidomide at therapeutic and supratherapeutic doses does not prolong QTc intervals in the thorough QTc study conducted in healthy men. AB - The effect of lenalidomide on the corrected QT (QTc) interval was evaluated in healthy men and extended to patients based on the lenalidomide concentration-QTc (C-QTc) relationship. A rigorous assessment of the effect of lenalidomide on QTc intervals was conducted in healthy volunteers who each received, in randomized order, a single oral dose of 10 mg lenalidomide, 50 mg lenalidomide, 400 mg moxifloxacin (positive control) and placebo. Plasma lenalidomide exposure was compared between healthy volunteers and patients with multiple myeloma or myelodysplastic syndromes. In healthy volunteers, moxifloxacin produced the expected significant prolongation in QTcI (individual correction). For lenalidomide 10 mg and 50 mg, the time-matched changes from placebo in the baseline-adjusted least-squares mean QTcI were <3 ms with the upper limit of the two-sided 90% confidence interval for the change <10 ms at all time-points. No subjects experienced QTcI >450 ms or change from baseline >60 ms after lenalidomide administration. Similar results were seen with QT interval data corrected by Fridericia and Bazett methods. The C-QTc analysis yielded no significant association between lenalidomide concentrations and QTcI changes up to 1522 ng/mL; this range was close to that observed in patients receiving lenalidomide doses up to 50 mg, including those with reduced drug clearance due to renal impairment. In conclusion, single doses of lenalidomide up to 50 mg were not associated with prolonged QTc intervals in healthy males. The C-QTc analysis further assured that lenalidomide doses up to 50 mg are not expected to prolong QTc intervals in patients. PMID- 23639048 TI - Genotype-phenotype analysis of recombinant chromosome 4 syndrome: an array-CGH study and literature review. AB - BACKGROUND: Recombinant chromosome 4, a rare constitutional rearrangement arising from pericentric inversion, comprises a duplicated segment of 4p13~p15->4pter and a deleted segment of 4q35->4qter. To date, 10 cases of recombinant chromosome 4 have been reported. RESULT: We describe the second case in which array-CGH was used to characterize recombinant chromosome 4 syndrome. The patient was a one year old boy with consistent clinical features. Conventional cytogenetics and FISH documented a recombinant chromosome 4, derived from a paternal pericentric inversion, leading to partial trisomy 4p and partial monosomy of 4q. Array-CGH, performed to further characterize the rearranged chromosome 4 and delineate the breakpoints, documented a small (4.36 Mb) 4q35.1 terminal deletion and a large (23.81 Mb) 4p15.1 terminal duplication. Genotype-phenotype analysis of 10 previously reported cases and the present case indicated relatively consistent clinical features and breakpoints. This consistency was more evident in our case and another characterized by array-CGH, where both showed the common breakpoints of p15.1 and q35.1. A genotype-phenotype correlation study between rec(4), dup(4p), and del(4q) syndromes revealed that urogenital and cardiac defects are probably due to the deletion of 4q whereas the other clinical features are likely due to 4p duplication. CONCLUSION: Our findings support that the clinical features of patients with rec(4) are relatively consistent and specific to the regions of duplication or deletion. Recombinant chromosome 4 syndrome thus appears to be a discrete entity that can be suspected on the basis of clinical features or specific deleted and duplicated chromosomal regions. PMID- 23639049 TI - Organobase-catalyzed amidation of esters with amino alcohols. AB - A base-mediated procedure for the amidation of unactivated esters with amino alcohols is reported. Optimization and exemplification of the catalytic process are described, furnishing products in 40-100% isolated yield. PMID- 23639047 TI - Role of exhaled nitric oxide as a predictor of atopy. AB - BACKGROUND: The fractional exhaled nitric oxide (FeNO) is a quantitative, noninvasive and safe measure of airways inflammation that may complement the assessment of asthma. Elevations of FeNO have recently been found to correlate with allergic sensitization. Therefore, FeNO may be a useful predictor of atopy in the general population. We sought to determine the diagnostic accuracy of FeNO in predicting atopy in a population-based study. METHODS: We conducted a cross sectional study in an age- and sex- stratified random sample of 13 to 15 year olds in two communities in Peru. We asked participants about asthma symptoms, environmental exposures and sociodemographics, and underwent spirometry, assessment of FeNO and an allergy skin test. We used multivariable logistic regression to model the odds of atopy as a function of FeNO, and calculated area under-the-curves (AUC) to determine the diagnostic accuracy of FeNO as a predictor of atopy. RESULTS: Of 1441 recruited participants, 1119 (83%) completed all evaluations. Mean FeNO was 17.6 ppb (SD=0.6) in atopics and 11.6 ppb (SD=0.8) in non-atopics (p<0.001). In multivariable analyses, a FeNO>20 ppb was associated with an increase in the odds of atopy in non-asthmatics (OR=5.3, 95% CI 3.3 to 8.5) and asthmatics (OR=16.2, 95% CI 3.4 to 77.5). A FeNO>20 ppb was the best predictor for atopy with an AUC of 68% (95% CI 64% to 69%). Stratified by asthma, the AUC was 65% (95% CI 61% to 69%) in non-asthmatics and 82% (95% CI 71% to 91%) in asthmatics. CONCLUSIONS: FeNO had limited accuracy to identify atopy among the general population; however, it may be a useful indicator of atopic phenotype among asthmatics. PMID- 23639050 TI - Prebiotic chemistry within a simple impacting icy mixture. AB - We present results of prebiotic organic synthesis in shock compressed mixtures of simple ices from quantum molecular dynamics (MD) simulations extended to close to equilibrium time scales. Given the likelihood of an inhospitable prebiotic atmosphere on early Earth, it is possible that impact processes of comets or other icy bodies were a source of prebiotic chemical compounds on the primitive planet. We observe that moderate shock pressures and temperatures within a CO2 rich icy mixture (36 GPa and 2800 K) produce a number of nitrogen containing heterocycles, which dissociate to form functionalized aromatic hydrocarbons upon expansion and cooling to ambient conditions. In contrast, higher shock conditions (48-60 GPa, 3700-4800 K) resulted in the synthesis of long carbon-chain molecules, CH4, and formaldehyde. All shock compression simulations at these conditions have produced significant quantities of simple C-N bonded compounds such as HCN, HNC, and HNCO upon expansion and cooling to ambient conditions. Our results elucidate a mechanism for impact synthesis of prebiotic molecules at realistic impact conditions that is independent of external constraints such as the presence of a catalyst, illuminating UV radiation, or pre-existing conditions on a planet. PMID- 23639051 TI - Adverse events of non-ablative fractional laser photothermolysis: a retrospective study of 856 treatments in 362 patients. AB - BACKGROUND: Non-ablative fractional laser photothermolysis (NAFP) has been used effectively in the treatment of photodamaged skin and scars, with short post operative recovery times; but, studies evaluating its adverse events and complication rates in Asian population have been limited. OBJECTIVE: To determine the frequency and range of adverse events associated with NAFP treatment in Korean patients. MATERIALS AND METHODS: We retrospectively evaluated the outcomes of 754 1550-nm erbium-doped and 102 1927-nm thulium fiber fractional laser treatments in patients with skin phototypes III-IV treated at a single center. Adverse events were identified and tabulated, as were patient demographics and laser parameters. RESULTS: From 856 treatments, there were 43 adverse events (5.0%), the most frequent being prolonged erythema (1.8%), post-inflammatory hyperpigmentation (1.1%) and aggravation of melasma (0.9%). Less frequently observed adverse events included herpes simplex outbreak (0.6%) and acneiform eruption (0.2%). There were no reports of long-term adverse events. CONCLUSION: Non-ablative fractional laser skin treatment has a relatively low complication rate. The adverse events found were temporary and did not result in long-term or severe sequelae such as hypertrophic scarring, atrophic scarring or permanent pigmentary alteration. PMID- 23639052 TI - 'She's usually quicker than the calculator': financial management and decision making in couples living with dementia. AB - This article explores how married couples managed their finances and made financial decisions when one spouse had dementia, drawing comparisons with the approaches used prior to the illness. More specifically, the article examines the role of social factors in influencing the involvement of people with dementia in financial management and decision-making, particularly whether a gender dynamic adopted earlier in a marriage similarly influenced a gendered approach following dementia. The research formed part of a larger study of everyday decision-making by couples living with dementia which explored the role of non-cognitive factors in influencing whether people with dementia were involved in decision-making processes. Twenty-one married couples living at home took part; the recently diagnosed were excluded. Qualitative methods -including participant observation and interviews - were used to examine the couples' fiscal management and decision making-processes, the perceptions of people with dementia and their spouses about their current financial abilities and whether any support provided by spouse carers influenced their partners' financial capacity. The fieldwork was undertaken in the North of England between June 2010 and May 2011. Thematic analysis of the data showed that social factors influenced the perceived capacity of people with dementia and the financial practices adopted by the couples. In particular, gender influenced whether people with dementia were involved in financial decisions. The research demonstrated that non-cognitive factors need to be taken into account when assessing and facilitating the capacity of people with dementia. In addition, as people with dementia were somewhat marginalised in decisions about designating financial authority (Lasting Power of Attorney), spouse-carers may need guidance on how to undertake advance care planning and how to support their relatives with dementia in major decision-making, particularly when there are communication difficulties. PMID- 23639053 TI - Patient-reported outcomes in bariatric surgery: a systematic review of standards of reporting. AB - Bariatric surgery is increasingly being used to treat severe obesity, but little is known about its impact on patient-reported outcomes (PROs). For PRO data to influence practice, well-designed and reported studies are required. A systematic review identified prospective bariatric surgery studies that used validated PRO measures. Risk of bias in randomized controlled trials (RCTs) was assessed, and papers were examined for reporting of (i) who completed PRO measures; (ii) missing PRO data and (iii) clinical interpretation of PRO data. Studies meeting all criteria were classified as robust. Eighty-six studies were identified. Of the eight RCTs, risk of bias was high in one and unclear in seven. Sixty-eight different PRO measures were identified, with the Short Form (SF)-36 questionnaire most commonly used. Forty-one (48%) studies explicitly stated measures were completed by patients, 63 (73%) documented missing PRO data and 50 (58%) interpreted PRO data clinically. Twenty-six (30%) met all criteria. Although many bariatric surgery studies assess PROs, study design and reporting is often poor, limiting data interpretation and synthesis. Well-designed studies that include agreed PRO measures are needed with reporting to include integration with clinical outcomes to inform practice. PMID- 23639055 TI - Translation and validation of the wound-specific quality of life instrument Cardiff Wound Impact Schedule in a Swedish population. AB - PURPOSE: To translate and validate the wound-specific health-related quality of life instrument, the Cardiff Wound Impact Schedule (CWIS) in a Swedish population. METHODS: The instrument was first translated into Swedish, using the Standard Linguistic Validation Process. The Swedish version of the CWIS was then tested for its psychometric properties in a Swedish context. A total of 117 patients with acute and hard-to-heal wounds were included. The patients were asked to fill in the Swedish version of the CWIS and the generic instrument SF-36 at baseline and after 1 week. Patients with acute wounds were also asked to fill in both instruments after 6 weeks. RESULTS: Face validity and content validity were assessed by patients and an expert group, and judged as good. Criterion validity was calculated with correlation between CWIS and SF-36, reaching moderate to high values. Reliability of the three domains of the CWIS measured with internal consistency and test-retest stability was acceptable to excellent. Internal responsiveness was assessed with standardised response mean and showed moderate to high sensitivity. CONCLUSIONS: This study concludes that the Swedish version of CWIS is a valid and reliable tool for measuring health-related quality of life in patients with acute and hard-to-heal wounds. PMID- 23639054 TI - Developmental heterochrony and the evolution of autistic perception, cognition and behavior. AB - BACKGROUND: Autism is usually conceptualized as a disorder or disease that involves fundamentally abnormal neurodevelopment. In the present work, the hypothesis that a suite of core autism-related traits may commonly represent simple delays or non-completion of typical childhood developmental trajectories is evaluated. DISCUSSION: A comprehensive review of the literature indicates that, with regard to the four phenotypes of (1) restricted interests and repetitive behavior, (2) short-range and long-range structural and functional brain connectivity, (3) global and local visual perception and processing, and (4) the presence of absolute pitch, the differences between autistic individuals and typically developing individuals closely parallel the differences between younger and older children. SUMMARY: The results of this study are concordant with a model of 'developmental heterochrony', and suggest that evolutionary extension of child development along the human lineage has potentiated and structured genetic risk for autism and the expression of autistic perception, cognition and behavior. PMID- 23639057 TI - Specific and rapid diagnosis of Edwardsiella tarda by a novel loop-mediated isothermal amplification targeting the upstream region of hlyb gene. AB - Edwardsiella tarda has become one of the most severe pathogens in aquaculture industries throughout the world; therefore, a specific and rapid identification method for this bacterium is urgently needed. In the present study, a novel loop mediated isothermal amplification (LAMP) was developed by targeting the upstream region of the hlyb gene of E. tarda, which was then named as UH-LAMP. The Mg(2+) concentrations, the reaction temperature, and the reaction time of UH-LAMP were optimized to 10 mM, 65 degrees C, and 45 min, respectively. The detection limit of the UH-LAMP was 100-times higher than that of conventional polymerase chain reaction (10 versus 1000 CFU/test). Furthermore, the new UH-LAMP assay showed no cross-reactivity to the E. ictaluri belonging to the other species in the genus Edwardsiella. The high specificity of the assay was also confirmed by testing the nine strains of E. tarda collected from different geographical locations and the other 20 bacteria species. The assay can be performed in a simple water bath or a heat block and the detection result can be visualized by adding a fluorescent reagent to the reaction mixture. Taken together, our preliminary results indicate that this UH-LAMP assay provided a rapid, sensitive, and species-specific diagnostic tool for E. tarda and can easily be applied for the diagnosis under clinical or onsite conditions. PMID- 23639056 TI - Impact of repeated intravenous cocaine administration on incentive motivation depends on mode of drug delivery. AB - The incentive sensitization theory of addiction posits that repeated exposure to drugs of abuse, like cocaine, can lead to long-term adaptations in the neural circuits that support motivated behavior, providing an account of pathological drug-seeking behavior. Although pre-clinical findings provide strong support for this theory, much remains unknown about the conditions that support incentive sensitization. The current study examined whether the mode of cocaine administration is an important factor governing that drug's long-term impact on behavior. Separate groups of rats were allowed either to self-administer intravenous cocaine or were given an equivalent number and distribution of unsignaled cocaine or saline infusions. During the subsequent test of incentive motivation (Pavlovian-to-instrumental transfer), we found that rats with a history of cocaine self-administration showed strong cue-evoked food seeking, in contrast to rats given unsignaled cocaine or saline. This finding indicates that the manner in which cocaine is administered can determine its lasting behavioral effects, suggesting that subjective experiences during drug use play a critical role in the addiction process. Our findings may therefore have important implications for the study and treatment of compulsive drug seeking. PMID- 23639058 TI - Growth factor release from platelet concentrates: analytic quantification and characterization for clinical applications. AB - BACKGROUND AND OBJECTIVES: Clinical use of plasma rich in growth factors requires biochemical product control. We aimed to measure and modulate concentrations of growth factors in solutions deriving from platelet apheresis or whole blood. MATERIALS AND METHODS: Growth factor concentrations were measured 5', 10', 20', 30', 60' after CaCl2 was added at 40 degrees C to platelet-apheresis products (n = 39) or after 60' in platelet concentrates from whole blood (n = 13). Growth factor release was also obtained in platelet apheresis a) by incubation at 22 degrees C or 40 degrees C for 10' or 30' (n = 4); b) by repeated freeze-thaw (n = 9). RESULTS: Fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) isoforms AA and AB and transforming growth factor beta (TGF-beta) concentrations (pg/10(9 ) plt) were 25-60% higher in growth factors solutions from whole blood compared to platelet apheresis. Vascular endothelial growth factor (VEGF), TGF-beta and PDGF isoforms were released early (5-10') during incubation: TGF-beta concentration increased also at 30'. FGF and epidermal growth factor (EGF) were released only after 30'. Incubation at 40 degrees C/10' increased VEGF (+70%) and decreased EGF (-30%) and PDGF-BB (-50%) versus 22 degrees C/30'. Shock significantly increased TGF-beta (1.6-fold), EGF (1.5-fold), FGF (4.5-fold) and lowered PDGF isoforms (0.2- to 0.5-fold) versus prolonged incubation at 40 degrees C. CONCLUSION: Platelets from platelet apheresis and whole-blood release all investigated growth factors. The release can be regulated controlling incubation time and/or temperature and performing cell lysis. PMID- 23639059 TI - The potential health hazard due to elevated radioactivity in old uranium mines in Dolina Bialego, Tatra Mountains, Poland. AB - Natural radioactivity is one of the essential components of the environment. Unlike the Sudety mountains area in Poland, the Tatra Mountains were not the subject of wide survey as regards the levels of natural radioactivity. Especially, the concentrations of radon (natural radioactive gas) have not been investigated there in terms of their possible negative health impact. Within the frame of bilateral cooperation between the Institute of Nuclear Physics in Krakow, Poland, and the Jozef Stefan Institute in Ljubljana, Slovenia, the measurements of natural radioactive elements in old uranium mines in the Tatra National Park were performed in June 2010. The investigated sites were located in Dolina Bialego (The Valley of the White). One of the mines is situated near the tourist path. The paper presents the results of complex measurements of natural radioactivity in both uranium drifts. The concentration of radon gas inside the mining drifts exceeded 28,000 Bq m(-3). Also, very high gamma dose rates were observed (up to 5600 nSv h(-1)). The maximum concentrations of natural radioactive elements (potassium (40)K, radium (226)Ra, thorium (232)Th) in rock samples amounted to 535, 2137, and 18 Bq kg(-1), respectively. The effective dose rates due to radon and thoron inhalation have been assessed as 0.013 mSv h(-1) (for the lowest concentration) and 0.121 mSv h(-1) (for the highest concentration). PMID- 23639060 TI - Intravenous lipid emulsion entraps amitriptyline into plasma and can lower its brain concentration--an experimental intoxication study in pigs. AB - Intravenous lipid emulsion has been suggested as treatment for severe intoxications caused by lipophilic drugs, including tricyclic antidepressants. We investigated the effect of lipid infusion on plasma and tissue concentrations of amitriptyline and haemodynamic recovery, when lipid was given after amitriptyline distribution into well-perfused organs. Twenty anaesthetized pigs received amitriptyline intravenously 10 mg/kg for 15 min. Thirty minutes later, in random fashion, 20% Intralipid((r)) (Lipid group) or Ringer's acetate (Control group) was infused 1.5 ml/kg for 1 min. followed by 0.25 ml/kg/min. for 29 min. Arterial and venous plasma amitriptyline concentrations and haemodynamics were followed till 75 min. after amitriptyline infusion. Then, frontal brain and heart apex samples were taken for amitriptyline measurements. Arterial plasma total amitriptyline concentrations were higher in the Lipid than in the Control group (p < 0.03) from 20 min. on after the start of the treatment infusions. Lipid emulsion reduced brain amitriptyline concentration by 25% (p = 0.038) and amitriptyline concentration ratios brain/arterial plasma (p = 0.016) and heart/arterial plasma (p = 0.011). There were no differences in ECG parameters and no severe cardiac arrhythmias occurred. Two pigs developed severe hypotension during the lipid infusion and were given adrenaline. In conclusion, lipid infusion, given not earlier than after an initial amitriptyline tissue distribution, was able to entrap amitriptyline back into plasma from brain and possibly from other highly perfused, lipid-rich tissues. In spite of the entrapment, there was no difference in haemodynamics between the groups. PMID- 23639062 TI - Safety, tolerance, and patient satisfaction with noninvasive cryolipolysis. AB - BACKGROUND: Comprehensive assessment of safety, tolerance, and patient satisfaction has not been established from noninvasive body contouring techniques, such as low-level laser therapy, ultrasound, radiofrequency, and infrared light, for reduction of subcutaneous fat. OBJECTIVE: This multicenter study investigated the clinical outcomes of noninvasive cryolipolysis in European subjects. METHODS: A retrospective study was performed at clinical sites in Belgium and France. Safety was assessed according to reports of side effects. Tolerance was evaluated according to pain scores and patient perception of treatment duration. Clinical outcomes were assessed according to patient surveys, caliper measurements, and assessment of photographs. RESULTS: The investigators treated 518 patients. No significant side effects or adverse events were reported. The procedure was well-tolerated, with 89% of respondents reporting a positive perception of treatment duration and 96% reporting minimal to tolerable discomfort. Survey results demonstrated 73% patient satisfaction and that 82% of patients would recommend the cryolipolysis procedure to a friend. Caliper measurements demonstrated 23% reduction in fat layer thickness at 3 months. Abdomen, back, and flank treatment sites were most effective, with 86% of subjects showing improvement per investigator assessment. CONCLUSIONS: With proper patient selection, cryolipolysis is a safe, well-tolerated, and effective treatment method for reduction of subcutaneous fat. PMID- 23639061 TI - LSSP-PCR of Trypanosoma cruzi: how the single primer sequence affects the kDNA signature. AB - BACKGROUND: Low-stringency single specific primer PCR (LSSP-PCR) is a highly sensitive and discriminating technique that has been extensively used to genetically characterize Trypanosoma cruzi populations in the presence of large amounts of host DNA. To ensure high sensitivity, in most T. cruzi studies, the variable regions of the naturally amplified kinetoplast DNA (kDNA) minicircles were targeted, and this method translated the intraspecific polymorphisms of these molecules into specific and reproducible kDNA signatures. Although the LSSP PCR technique is reproducible under strict assay conditions, the complex banding pattern generated can be significantly altered by even a single-base change in the target DNA. Our survey of the literature identified eight different primers with similar, if not identical, names that have been used for kDNA amplification and LSSP-PCR of T. cruzi. Although different primer sequences were used in these studies, many of the authors cited the same reference report to justify their primer choice. We wondered whether these changes in the primer sequence could affect also the parasite LSSP-PCR profiles. FINDINGS: To answer this question we compared the kDNA signatures obtained from three different and extensively studied T. cruzi populations with the eight primers found in the literature. Our results clearly demonstrate that even minimal modifications in the oligonucleotide sequences, especially in the 3' or 5' end, can significantly change the kDNA signature of a T. cruzi strain. CONCLUSIONS: These results highlight the necessity of careful preservation of primer nomenclature and sequence when reproducing an LSSP-PCR work to avoid confusion and allow comparison of results among different laboratories. PMID- 23639064 TI - Ab initio studies of the structure and spectroscopy of CHNMg stoichiometry molecules and van der Waals complexes. AB - A high-level ab initio study was conducted over the range of tetraatomic molecules containing H, C, N, and Mg. Potential energy surfaces were analyzed, leading, for selected molecules, to the optimization of their geometry in the lowest singlet and triplet excited states. Reliable ground state rotational constants are given for the most stable species, namely, HMgNC and HMgCN, together with respective anharmonic vibrational frequencies of fundamental, overtone, and combination bands. In addition, potential energy surfaces describing the interaction of HCN or HNC with a single magnesium atom have been investigated. PMID- 23639063 TI - Progesterone protective effects in neurodegeneration and neuroinflammation. AB - Progesterone is a neuroprotective, promyelinating and anti-inflammatory factor for the nervous system. Here, we review the effects of progesterone in models of motoneurone degeneration and neuroinflammation. In neurodegeneration of the Wobbler mouse, a subset of spinal cord motoneurones showed increased activity of nitric oxide synthase (NOS), increased intramitochondrial NOS, decreased activity of respiratory chain complexes, and decreased activity and protein expression of Mn-superoxide dismutase type 2 (MnSOD2). Clinically, Wobblers suffered several degrees of motor impairment. Progesterone treatment restored the expression of neuronal markers, decreased the activity of NOS and enhanced complex I respiratory activity and MnSOD2. Long-term treatment with progesterone increased muscle strength, biceps weight and survival. Collectively, these data suggest that progesterone prevented neurodegeneration. To study the effects of progesterone in neuroinflammation, we employed mice with experimental autoimmune encephalomyelitis (EAE). EAE mice spinal cord showed increased mRNA levels of the inflammatory mediators tumour necrosis factor (TNF)alpha and its receptor TNFR1, the microglial marker CD11b, inducible NOS and the toll-like receptor 4. Progesterone pretreatment of EAE mice blocked the proinflammatory mediators, decreased Iba1+ microglial cells and attenuated clinical signs of EAE. Therefore, reactive glial cells became targets of progesterone anti-inflammatory effects. These results represent a starting point for testing the usefulness of neuroactive steroids in neurological disorders. PMID- 23639065 TI - SmI2-mediated couplings of alpha-amino acid derivatives. Formal synthesis of (-) pumiliotoxin 251D and (+/-)-epiquinamide. AB - The coupling between cyclic and acyclic alpha-amino acid derivatives and methyl acrylate, mediated by samarium diiodide, is described. The method constitutes a powerful tool to construct indolizidine, quinolizidine, and piperidine systems in a straightforward two-step fashion. The formal synthesis of (-)-pumiliotoxin 251D and (+/-)-epiquinamide is achieved after two or three steps from these amino acid derivatives. PMID- 23639067 TI - Participation in work in early rheumatoid arthritis: a qualitative interview study interpreted in terms of the ICF. AB - PURPOSE: To explore what work-related dilemmas are experienced by patients with early rheumatoid arthritis (RA), according to their own descriptions, and to interpret this in terms of participation categories of the International Classification of Functioning, Disability and Health (ICF). METHOD: In 48 patients with early RA, qualitative interviews were analyzed, followed by linking of concepts to the activity/participation component of the ICF and interpretation of general themes. RESULTS: Work-related dilemmas represented different societal perspectives on work related to acquiring, keeping and terminating a job, self employment, part-time, full-time and non-remunerative employment. Dilemmas also represented participation priorities in economic self-sufficiency, self-care such as health care, and avoiding social relationships and recreation in favor of work. Leisure time was influenced because efforts of working took energy and time of day-to-day procedures. Embedded actions in work-related dilemmas were carrying out daily routine, mobility including using transportation, self-care, domestic life and social interaction. CONCLUSION: The general themes societal perspectives, participation priorities and embedded actions, with the included ICF categories that are described in detail according to the experiences of the patients, can support clinical reasoning and research on quantitative relations to disease activity, body functions, ability and contextual factors. PMID- 23639068 TI - Community-university partnerships in occupational therapy education: a preliminary exploration of practice in a European context. AB - AIM: To explore community-university partnerships in occupational therapy education in Europe. METHOD: Educators from Europe were invited to participate in the study. Data were collected using a questionnaire designed for the study. Eleven completed questionnaires were included. Descriptive statistics were generated from quantitative data while qualitative data were analyzed using inductive content analysis. RESULTS: The majority of participants reported that community-university partnerships were part of the third year of undergraduate occupational therapy studies. Partners were from a broad range of sectors. The activities undertaken were typically focused on specific target groups within the community. Three main themes emerged from the qualitative analysis (i) instigating community-university partnerships, (ii) processes of creating and sustaining partnerships and (iii) perceived outcomes of community-university partnerships. CONCLUSIONS: This is the first study of community-university partnerships in Europe generating some useful findings. Clarification is needed regarding the use of the term community-university partnership. Educators are called upon to consider how partnerships are embedded into curricula and to address issues of sustainability. IMPLICATIONS FOR REHABILITATION: Healthcare education should prepare rehabilitation professionals to collaborate with diverse communities. Community--university collaborations appear to offer opportunities to support students to develop competences for future community orientated practice. Key issues to be considered include choice of pedagogical approach, issues of reciprocity and sustainability. PMID- 23639066 TI - Composite measures of multi-joint symptoms, but not of radiographic osteoarthritis, are associated with functional outcomes: the Johnston County Osteoarthritis Project. AB - PURPOSE: To determine associations between multiple joint symptoms and radiographic osteoarthritis (rOA) and functional outcomes. METHOD: Complete cross sectional data for multi-joint symptoms and radiographs, Health Assessment Questionnaire (HAQ) scores, and gait speed were available for 1307 Johnston County Osteoarthritis Project participants (34% men, 32% African American, mean age 66 years). Factor analysis of symptom scores and radiographic grades for the lumbosacral spine, bilateral hands, knees, and hips provided composite scores. Regression models were used to determine associations between composite scores, HAQ, and gait speed, adjusting for age, body mass index, gender, and race. RESULTS: Five rOA factors were identified: (1) IP/CMC factor (carpometacarpal [CMC] and all interphalangeal [IP] joints); (2) MCP factor (metacarpophalangeal joints 2-5); (3) Knee factor (tibiofemoral and patellofemoral joints); (4) Spine factor (L1/2 to L5/S1); and (5) Symptom factor. After adjustment, only the Symptom composite was significantly associated with HAQ and gait speed; a 1 standard deviation increase in Symptom score was associated with 9 times higher odds of having poorer function on the HAQ (odds ratio 9.32, 95% confidence interval [CI] 6.80, 12.77), and a clinically significant decline in gait speed (0.06 m/s, 95% CI -0.07, -0.05). CONCLUSIONS: A novel Symptom composite score was associated with poorer functional outcomes. IMPLICATIONS FOR REHABILITATION: Osteoarthritis (OA) commonly affects multiple joints and is the most common form of arthritis. Symptomatic assessments, which can be easily executed by rehabilitation practitioners, are more closely related to self-reported and performance-based functional status than are less accessible and more costly radiographs. Symptomatic assessments are likely to be more informative for understanding, treating, and potentially preventing functional limitations than radiographic assessments. PMID- 23639069 TI - Parent-only vs. parent-child (family-focused) approaches for weight loss in obese and overweight children: a systematic review and meta-analysis. AB - Families are recommended as the agents of change for weight loss in overweight and obese children; family approaches are more effective than those that focus on the child alone. However, interventions that focus on parents alone have not been summarized. The objective of this review was to assess the effectiveness of interventions that compared a parent-only (PO) condition with a parent-child (PC) condition. Four trials using a similar between-group background approaches to overweight and obese children's weight loss met the inclusion criteria, but only one trial reported sufficient data for meta-analysis. Further information was obtained from authors. Meta-analysis showed no significant difference in z-BMI from baseline to end of treatment between the conditions (three trials) or to end of follow up (two trials). The trials were at risk of bias and no single trial was at lower risk of bias than others. There is an absence of high quality evidence regarding the effect of parent-only interventions for weight loss in children compared to parent-child interventions, but current evidence suggests the need for further investigation. PMID- 23639070 TI - Working memory training improvements and gains in non-trained cognitive tasks in young and older adults. AB - Previous studies on working memory training have indicated that transfer to non trained tasks of other cognitive domains may be possible. The aim of this study is to compare working memory training and transfer effects between younger and older adults (n = 60). A novel approach to adaptive n-back training (12 sessions) was implemented by varying the working memory load and the presentation speed. All participants completed a neuropsychological battery of tests before and after the training. On average, younger training participants achieved difficulty level 12 after training, while older training participants only reached difficulty level 5. In younger participants, transfer to Verbal Fluency and Digit Symbol Substitution test was found. In older participants, we observed a transfer to Digit Span Forward, CERAD Delayed Recall, and Digit Symbol Substitution test. Results suggest that working memory training may be a beneficial intervention for maintaining and improving cognitive functioning in old age. PMID- 23639071 TI - Assessment without action; a randomised evaluation of the interRAI home care compared to a national assessment tool on identification of needs and service provision for older people in New Zealand. AB - Comprehensive geriatric assessment (CGA) is considered the cornerstone of good practice, as it identifies need across multiple domains such as social, physical and psychological. The interRAI home care (interRAI-HC), probably the most well researched and supported community-based CGA has been implemented globally, often at considerable expense. Policy-makers, managers and clinicians anticipate significant gains in health outcomes following such investment; however, the implementation of CGA is often undertaken in the absence of community service development. This study sought to compare the interRAI-HC with an existing CGA [the Support Needs Assessment (SNA)] in community-dwelling older people. A randomised controlled trial was undertaken from January 2006 to January 2007 comparing the interRAI-HC and the SNA in 316 people (65+) referred for assessment of needs with follow-up at 1 and 4 months. Outcomes included health-related quality of life, physical function, social support, cognitive status, mood and health service usage as well as identified need. The study found that significantly more support needs were identified using the interRAI-HC compared to the SNA. More social and carer support were recommended by SNA and more rehabilitation and preventive health screens were recommended by interRAI-HC. Despite these differences, the mean healthcare use was similar at 4 months, although interRAI-HC participants had more Emergency Department presentations and hospital admissions. No statistically significant differences between groups were reported in terms of outcomes. In conclusion, the interRAI-HC was found to identify more unmet support needs than the SNA though resulted in no favourable outcomes for the older person or their carer. The study highlights the need to invest attention around the service context to maximise outcomes based on identified needs. PMID- 23639072 TI - Determination of the mode of action of enterolysin A, produced by Enterococcus faecalis B9510. AB - AIM: The current study aimed to visualize the damage caused by enterolysin A to the cells of sensitive strains and to find out cleavage site within the peptidoglycan moiety of bacterial cell walls. METHODS AND RESULTS: Enterolysin A produced by a local isolate, Enterococcus faecalis B9510 was found to rapidly kill cells of the sensitive strain Lactococcus lactis ssp. cremoris 2144 during 120 min of treatment as compared to the untreated control where no such effect was observed. Transmission electron microscopy of the enterolysin A-treated cells revealed leaking of the cytoplasmic contents ultimately resulting in complete lysis of cell walls. To find the cleavage site, purified cell walls of L. lactis ssp. cremoris 2144, Pediococcus pentosaceus 43201 and Lactobacillus delbrueckii ssp. bulgaricus ATCC 11842 were treated with enterolysin A, and liberated amino acids were derivatized for N and C terminals and analysed using thin layer chromatography on silica gel with isopropanol as solvent. The results showed that enterolysin A cleaves the peptide bonds at two locations within peptidoglycan subunits. The first location is between L-alanine and D-glutamic acid of the stem peptide and the other location is between L-lysine of the stem peptide and D aspartic acid of the interpeptide bridge. CONCLUSIONS: Enterolysin A cleaves the peptide bonds within the stem peptide as well as in the interpeptide bridge of Gram-positive bacterial cell walls. This gives a possible reason for the broad spectrum of enterolysin A activity. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report identifying the cleavage site of enterolysin A within the cell walls of sensitive bacteria. This will help in identifying potential applications for enterolysin A. PMID- 23639074 TI - Prevalence of Francisella noatunensis subsp. orientalis in cultured tilapia on the island of Oahu, Hawaii. AB - Francisellosis is an emergent disease in cultured and wild aquatic animals. The causative agent, Francisella noatunensis subsp. orientalis (Fno), is a gram negative bacterium recognized as one of the most virulent pathogens of warmwater fish. The main objective of this project was to investigate the prevalence of Fno in cultured tilapia (specifically, Mozambique Tilapia Oreochromis mossambicus, Koilapia [also known as Wami Tilapia] O. hornorum, Blue Tilapia O. aureus, and Nile Tilapia O. niloticus hybrids) on the island of Oahu, Hawaii, using conventional and real-time PCR assays followed by statistical modeling to compare the different diagnostic methods and identify potential risk factors. During 2010 and 2012, 827 fish were collected from different geographical locations throughout the island of Oahu. Upon collection of fish, the water temperature in the rearing system and the length of individual fish were measured. Extraction of DNA from different tissues collected aseptically during necropsy served as a template for molecular diagnosis. High correlation between both molecular methods was observed. Moreover, the bacterium was isolated from infected tilapia on selective media and confirmed to be Fno utilizing a species-specific Taqman-based real-time PCR assay. Although a direct comparison of the prevalence of Fno between the different geographical areas was not possible, the results indicate a high prevalence of Fno DNA in cultured tilapia throughout the farm sites located on Oahu. Of the different tilapia species and hybrids currently cultured in Hawaii, Mozambique Tilapia were more susceptible to infection than Koilapia. Water temperature in the rearing systems and fish size also had a strong effect on the predicted level of infection, with fish held at lower temperatures and smaller fish being more susceptible to piscine francisellosis. PMID- 23639075 TI - Two new cytotoxic iridoid esters from the rhizomes and roots of Patrinia heterophylla Bunge. AB - Two new iridoid esters, named patriheterdoid B, C, have been isolated from the rhizomes and roots of Patrinia heterophylla Bunge. Their structures were elucidated by extensive spectroscopic technologies. Together with patriheterdoid B, C, two known analogues have been isolated and identified by means of mass spectrometry and (1)H and (13)C NMR spectrometry. These compounds showed cytotoxic activity against SGC-7901, PC3 cell lines. PMID- 23639073 TI - Differential expression of interferon-gamma and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response. AB - BACKGROUND: Rasmussen encephalitis (RE) is a rare complex inflammatory disease, primarily seen in young children, that is characterized by severe partial seizures and brain atrophy. Surgery is currently the only effective treatment option. To identify genes specifically associated with the immunopathology in RE, RNA transcripts of genes involved in inflammation and autoimmunity were measured in brain tissue from RE surgeries and compared with those in surgical specimens of cortical dysplasia (CD), a major cause of intractable pediatric epilepsy. METHODS: Quantitative polymerase chain reactions measured the relative expression of 84 genes related to inflammation and autoimmunity in 12 RE specimens and in the reference group of 12 CD surgical specimens. Data were analyzed by consensus clustering using the entire dataset, and by pairwise comparison of gene expression levels between the RE and CD cohorts using the Harrell-Davis distribution-free quantile estimator method. RESULTS: Consensus clustering identified six RE cases that were clearly distinguished from the CD cases and from other RE cases. Pairwise comparison showed that seven mRNAs encoding interferon-gamma, CCL5, CCL22, CCL23, CXCL9, CXCL10, and Fas ligand were higher in the RE specimens compared with the CD specimens, whereas the mRNA encoding hypoxanthine-guanine phosphoribosyltransferase was reduced. Interferon-gamma, CXCL5, CXCL9 and CXCL10 mRNA levels negatively correlated with time from seizure onset to surgery (P <0.05), whereas CCL23 and Fas ligand transcript levels positively correlated with the degree of tissue destruction and inflammation, respectively (P <0.05), as determined from magnetic resonance imaging (MRI) T2 and FLAIR images. Accumulation of CD4+ lymphocytes in leptomeninges and perivascular spaces was a prominent feature in RE specimens resected within a year of seizure onset. CONCLUSIONS: Active disease is characterized by a Th1 immune response that appears to involve both CD8+ and CD4+ T cells. Our findings suggest therapeutic intervention targeting specific chemokine/chemokine receptors may be useful in early stage RE. PMID- 23639076 TI - Non-surgical periodontal treatment reduces cardiovascular risk in refractory hypertensive patients: a pilot study. AB - AIM: To evaluate the effects of non-surgical periodontal treatment on left ventricular mass (LVM), arterial stiffness, systolic and diastolic blood pressure and plasma levels of inflammatory markers (C-reactive protein (CRP), fibrinogen and interleukin-6) in refractory hypertension patients. MATERIAL AND METHODS: This interventional prospective cohort pilot study included 26 patients (53.6 +/- 8.0 years old) diagnosed with refractory hypertension and generalized chronic periodontitis. Subjects received non-surgical periodontal treatment according to their needs. Plasma levels of systemic inflammation (CRP; fibrinogen and interleukin-6) and established cardiovascular risk factors [systolic and diastolic blood pressure (SBP and DBP), left ventricular mass (LVM) and arterial stiffness] were assessed at three time points (baseline, 3 months after baseline and 6 months after periodontal therapy). RESULTS: Periodontal therapy significantly reduced all cardiovascular risk markers evaluated. Median values of SBP and DBP were reduced by 12.5 mmHg and 10.0 mmHg, respectively, whereas left ventricular mass (LVM) reduced by 12.9 g and pulse wave velocity reduced by 0.9 m/s (p < 0.01). Levels of CRP, IL-6 and fibrinogen lowered by 0.5 mg/dl, 1.4 pg/dl and 37.5 mg/dl (p < 0.01), respectively, 6 months after periodontal therapy. CONCLUSIONS: Periodontal therapy significantly reduced levels of CRP, IL 6, fibrinogen, blood pressure, LVM and arterial stiffness, lowering cardiovascular risk in refractory hypertensive patients. PMID- 23639077 TI - The stem xylem of Patagonian shrubs operates far from the point of catastrophic dysfunction and is additionally protected from drought-induced embolism by leaves and roots. AB - Hydraulic architecture was studied in shrub species differing in rooting depth in a cold desert in Southern Argentina. All species exhibited strong hydraulic segmentation between leaves, stems and roots with leaves being the most vulnerable part of the hydraulic pathway. Two types of safety margins describing the degree of conservation of the hydraulic integrity were used: the difference between minimum stem or leaf water potential (Psi) and the Psi at which stem or leaf hydraulic function was reduced by 50% (Psi - Psi50), and the difference between leaf and stem Psi50. Leaf Psi50 - stem Psi50 increased with decreasing rooting depth. Large diurnal decreases in root-specific hydraulic conductivity suggested high root vulnerability to embolism across all species. Although stem Psi50 became more negative with decreasing species-specific Psisoil and minimum stem Psi, leaf Psi50 was independent of Psi and minimum leaf Psi. Species with embolism-resistant stems also had higher maximum stem hydraulic conductivity. Safety margins for stems were >2.1 MPa, whereas those for leaves were negative or only slightly positive. Leaves acted as safety valves to protect the integrity of the upstream hydraulic pathway, whereas embolism in lateral roots may help to decouple portions of the plant from the impact of drier soil layers. PMID- 23639078 TI - Description of the novel HLA-DPB1*137:01 allele found in an Italian subject. AB - In this report, we describe the identification and sequencing of a novel HLA-DPB1 allele, found in an Italian haematological patient. This allele is identical to DPB1*17:01 except for a single nucleotide substitution (GAC->GAG) at position 57, which changes the encoded amino acid from Asp to Glu. PMID- 23639080 TI - "Stereoelectronic umpolung": converting a p-donor into a sigma-acceptor via electron injection and a conformational change. AB - The para-OMe functional group, usually regarded as a conjugative p-donor, acts as an efficient hyperconjugative sigma-acceptor in reductive cycloaromatization reactions. This apparent reversal of electronic properties is associated with a conformational change that aligns the sigma*(O-C) orbital with the adjacent aromatic system and provides stabilization to the developing negative charge in the TS of the dianionic cyclization of enediynes. The chameleonic character of the OMe group illustrates the important role of negative hyperconjugation in anionic processes. PMID- 23639081 TI - Synthesis of sulfonic acid derivatives by oxidative deprotection of thiols using tert-butyl hypochlorite. AB - Starting from alkyl halides or Michael acceptors, thioacetates were prepared in situ and further treated with t-BuOCl, affording the corresponding sulfonyl chlorides which were trapped with nucleophiles such as water, alcohol, or amines. The three steps can be achieved in a one-pot procedure. Oxidative deprotection also proved to be efficient with S-trityl and S-tert-butyl groups, making it a convenient route toward cysteic acid derivatives. PMID- 23639079 TI - A human Dravet syndrome model from patient induced pluripotent stem cells. AB - BACKGROUND: Dravet syndrome is a devastating infantile-onset epilepsy syndrome with cognitive deficits and autistic traits caused by genetic alterations in SCN1A gene encoding the alpha-subunit of the voltage-gated sodium channel Na(v)1.1. Disease modeling using patient-derived induced pluripotent stem cells (iPSCs) can be a powerful tool to reproduce this syndrome's human pathology. However, no such effort has been reported to date. We here report a cellular model for DS that utilizes patient-derived iPSCs. RESULTS: We generated iPSCs from a Dravet syndrome patient with a c.4933C>T substitution in SCN1A, which is predicted to result in truncation in the fourth homologous domain of the protein (p.R1645*). Neurons derived from these iPSCs were primarily GABAergic (>50%), although glutamatergic neurons were observed as a minor population (<1%). Current clamp analyses revealed significant impairment in action potential generation when strong depolarizing currents were injected. CONCLUSIONS: Our results indicate a functional decline in Dravet neurons, especially in the GABAergic subtype, which supports previous findings in murine disease models, where loss-of function in GABAergic inhibition appears to be a main driver in epileptogenesis. Our data indicate that patient-derived iPSCs may serve as a new and powerful research platform for genetic disorders, including the epilepsies. PMID- 23639082 TI - The relationship of plumage colours with MC1R (Melanocortin 1 Receptor) and ASIP (Agouti Signaling Protein) in Japanese quail (Coturnix coturnix japonica). AB - 1. The relationship of polymorphisms in the Melanocortin 1 Receptor (MC1R) and Agouti Signalling Protein (ASIP) genes with plumage colour in Japanese quail was investigated by cloning and sequencing the entire coding regions from black, white and maroon Japanese quail embryos at 12 d of incubation. 2. Three SNPs were identified in the MC1R coding region by multiple alignment of sequences from individuals with different plumage colours. A missense C/T mutation located at 169 bp within the Open Reading Frame caused a Ile57Val mutation in the amino acid sequence, and had a significant relationship with the black colour. 3. The expression of MC1R was higher in black plumage quails than that in maroon plumage quails, whereas the expression of ASIP was higher in maroon plumage quails than that in black plumage quails. 4. It is concluded that the black plumage colour in Japanese quails may be caused by either increased production of MC1R or decreased production of ASIP. PMID- 23639083 TI - Changes in risk factors for preterm birth in Western Australia 1984-2006. AB - OBJECTIVE: To characterise changing risk factors of preterm birth in Western Australia between 1984 and 2006. DESIGN: Population-based study. SETTING: Western Australia. POPULATION: All non-Aboriginal women giving birth to live singleton infants between 1984 and 2006. METHODS: Multinomial, multivariable regression models were used to assess antecedent profiles by preterm status and labour onset types (spontaneous, medically indicated, prelabour rupture of membranes [PROM]). Population attributable fraction (PAF) estimates characterized the contribution of individual antecedents as well as the overall contribution of two antecedent groups: pre-existing medical conditions (including previous obstetric history) and pregnancy complications. MAIN OUTCOME MEASURE: Antecedent relationships with preterm birth, stratified by labour onset type. RESULTS: Marked increases in maternal age and primiparous births were observed. A four-fold increase in the rates of pre-existing medical complications over time was observed. Rates of pregnancy complications remained stable. Multinomial regression showed differences in antecedent profiles across labour onset types. PAF estimates indicated that 50% of medically indicated preterm deliveries could be eliminated after removing six antecedents from the population; estimates for PROM and spontaneous preterm reduction were between 10 and 20%. Variables pertaining to previous and current obstetric complications (previous preterm birth, previous caesarean section, pre-eclampsia and antepartum haemorrhage) were the most influential predictors of preterm birth and adverse labour onset (PROM and medically indicated). CONCLUSIONS: Preterm antecedent profiles have changed markedly over the 23 years studied. Some changes may be attributable to true change, others to advances in surveillance and detection. Still others may signify change in clinical practice. PMID- 23639085 TI - Artificial stool transplantation: progress towards a safer, more effective and acceptable alternative. PMID- 23639086 TI - Type 2 diabetes mellitus in chronic hepatitis C virus infection: risk factor or consequence? PMID- 23639088 TI - Endoscopic diagnosis of dysplasia in Barrett's esophagus. AB - Barrett's esophagus, or columnar metaplasia with gastric cardiac cells or intestinal cells, develops in the squamous epithelium of the esophageal mucosa in relation to gastroesophageal reflux. An increased risk of neoplasia justifies surveillance at regular intervals. Conventional guidelines recommend detection of areas with intestinal metaplasia or dysplasia by taking random four-quadrant biopsies at every 1 or 2 cm. Alternatively, image processing with narrow band imaging (NBI), is proposed to improve detection. This international and randomized study in persons with Barrett's esophagus compares conventional endoscopy in white light with random four-quadrant biopsies and NBI imaging with focused biopsies only. Randomization enrolled 123 patients with Barrett's esophagus who successively underwent exploration with the two methods. The study confirmed that NBI had the same efficacy as white light in the detection of intestinal metaplasia, with a higher proportion of dysplasia detected (30 vs 21%) and a lower number of biopsies per patient (3.6 vs 7.6). PMID- 23639089 TI - The surgical treatment of inflammatory bowel disease-associated dysplasia. AB - Surgical management of colonic dysplasia discovered in the inflammatory bowel disease patient is controversial. Total proctocolectomy (TPC) is the most definitive treatment for the eradication of undiagnosed synchronous dysplasias and/or carcinomas and the prevention of subsequent metachronous lesions in both Crohn's disease (CD) and ulcerative colitis (UC). However, TPC is not always an attractive option owing to patient comorbidities and patient preference. Historically, dysplasia has been most studied in patients with UC, where the option of reconstruction without a stoma makes TPC more acceptable. Due to a relative lack of research on CD-related dysplasia, surveillance and treatment of CD dysplasia has followed paradigms based on UC data. However, due to pathophysiological differences in CD versus UC, options for surgical management in CD may be more varied than simple TPC, particularly in the less healthy surgical candidate and those who refuse end ileostomy. PMID- 23639090 TI - Small bowel video capsule endoscopy: an overview. AB - Video capsule endoscopy (VCE) is being increasingly used to investigate small bowel pathology. It is the gold standard for obscure gastrointestinal bleeding and iron deficiency anemia. VCE has been in use since 2001 and indications for its use are expanding. VCE is also a useful diagnostic tool in small bowel Crohn's disease, celiac disease, surveillance of polyps, small bowel malignancy and drug-induced small bowel injury. Although VCE is considered a safe and easy procedure, there are a few limitations. These include cost, capsule retention and inability to take a biopsy and perform any therapeutic maneuvers. Contraindications for VCE include pregnancy, patients with a swallowing disorder, history of previous abdominal surgery or concurrent abdomino-pelvic irradiation. This is an overview of VCE, its role and indications in clinical practice, potential complications and contraindications, as well as the ongoing and expected advances in the field. PMID- 23639091 TI - Systemic sclerosis and the gut. AB - Gastrointestinal involvement (GI) is increasingly recognized as a major cause of both morbidity and mortality in systemic sclerosis (SSc). GI complications are common, second only to skin involvement, and affect up to 90% of patients. Although treatment modalities have changed little for upper gut symptoms such as GI reflux, there are emerging treatment modalities for the common lower gut symptoms (constipation and fecal incontinence), which will be reviewed. The important link between reflux and interstitial lung disease in SSc is also addressed. The aim of this review is to help the clinician understand and manage GI symptoms in SSc. PMID- 23639092 TI - Ulcerative colitis: prevention of relapse. AB - The clinical management of ulcerative colitis (UC) involves first treating the acute symptoms to induce remission, and then successfully maintaining it. Oral 5 aminosalicylic acids are safe and useful for maintaining remission in patients with UC. In terms of adherence, a once-daily form of 5-aminosalicylic acid is superior in maintaining remission as compared with split dosing. Patients at high risk of relapse may be candidates for treatment with thiopurines and/or biologics in the early stages of UC. Calcineurin inhibitors, such as cyclosporine and tacrolimus, are effective for severe, steroid-refractory UC patients. It is suggested that these patients use thiopurines as their maintenance therapy once they achieve remission with calcineurin inhibitors. Recent studies have confirmed that biologics are effective for inducing clinical and endoscopic remission of UC, and thus they may improve long-term prognosis of UC. PMID- 23639093 TI - Clinical decision making in the management of pancreatic cystic neoplasms. AB - Pancreatic cystic lesions continue to pose diagnostic and management dilemmas for physicians. This may be related, in part, to the fact that these lesions represent a range of diagnostic possibilities, from inflammatory cysts and nonmucinous cysts to mucinous cysts, which may or may not have foci of invasive malignancy. Adequate characterization of cystic lesions is necessary to help devise a management plan. Moreover, patient-related factors such as comorbid conditions are often essential in deciding whether patients should be managed by a conservative approach of watchful waiting versus surgical resection, if so indicated. This review summarizes the recent advances in the management of pancreatic cystic neoplasms. PMID- 23639094 TI - Cardiovascular risk, atherosclerosis and metabolic syndrome after liver transplantation: a mini review. AB - Liver transplantation is the standard of care for acute and chronic end-stage liver disease. Advances in medical therapy and surgical techniques have transformed the long-term survival of liver-transplant (LT) recipients. The prevalence of post-transplant cardiovascular complications has been rising with increased life expectancy after liver transplantation. Currently, deaths related to cardiovascular complications are one of the main causes of long-term mortality in LT recipients, as cardiovascular disease is the reason of 19-42% of non-liver related mortality after transplant. On the other hand, metabolic syndrome is common among LT recipients before and after transplantation. In fact, their components (abdominal obesity, diabetes mellitus, hypertension and dyslipidemia) are often exacerbated by transplant-specific factors, such as immunosuppression, inappropriate diet, smoking and a sedentary lifestyle, and add a significant risk of developing atherosclerosis. These aspects are discussed in this article. PMID- 23639095 TI - Autoimmune hepatitis in diverse ethnic populations and geographical regions. AB - Autoimmune hepatitis has diverse clinical phenotypes and outcomes in ethnic groups within a country and between countries, and these differences may reflect genetic predispositions, indigenous etiological agents, pharmacogenomic mechanisms and socioeconomic reasons. In the USA, African-American patients have cirrhosis more commonly, treatment failure more frequently and higher mortality than white American patients. Survival is poorest in Asian-American patients. Autoimmune hepatitis in other countries is frequently associated with genetic predispositions that may favor susceptibility to indigenous etiological agents. Cholestatic features influence treatment response; acute-on-chronic liver disease increases mortality and socioeconomic and cultural factors affect prognosis. Ethnic-based deviations from classical phenotypes and the frequency of late-stage disease can complicate the diagnosis and management of autoimmune hepatitis in non-white populations. PMID- 23639096 TI - Bioinspired, calcium-free alginate hydrogels with tunable physical and mechanical properties and improved biocompatibility. AB - Alginate hydrogels are for various biomedical applications including tissue engineering, cell therapy, and drug delivery. However, it is not easy to control swelling or viscoelastic and biophysical properties of alginate hydrogels prepared by conventional cross-linking methods (ionic interaction using divalent cations). In this study, we describe a bioinspired approach for preparing divalent ion-free alginate hydrogels that exhibit tunable physical and mechanical properties and improved biocompatibility due to the absence of cations in the gel matrices. We conjugated dopamine, a minimalized adhesive motif found in the holdfast pads of mussels, to alginate backbones (alginate-catechol) and the tethered catechols underwent oxidative cross-linking. This resulted in divalent cation-free alginate hydrogels. The swelling ratios and moduli of the alginate catechol hydrogels are readily tunable, which is difficult to achieve in ionic bond-based alginate hydrogels. Furthermore, alginate-catechol hydrogels enhanced the survival of various human primary cells including stem cells in the three dimensional gel matrix, indicating that intrinsic cytotoxicity caused by divalent cations becomes negligible when employing catechol oxidation for alginate cross linking. The inflammatory response in vivo was also significantly attenuated compared to conventional alginate hydrogels with calcium cross-linking. This biomimetic approach for the preparation of alginate hydrogels may provide a novel platform technology to develop tunable, functional, biocompatible, three dimensional scaffolds for tissue engineering and cell therapy. PMID- 23639097 TI - Quantifying the effects of migration and mutation on adaptation and demography in spatially heterogeneous environments. AB - How do mutation and gene flow influence population persistence, niche expansion and local adaptation in spatially heterogeneous environments? In this article, we analyse a demographic and evolutionary model of adaptation to an environment containing two habitats in equal frequencies, and we bridge the gap between different theoretical frameworks. Qualitatively, our model yields four qualitative types of outcomes: (i) global extinction of the population, (ii) adaptation to one habitat only, but also adaptation to both habitats with, (iii) specialized phenotypes or (iv) with generalized phenotypes, and we determine the conditions under which each equilibrium is reached. We derive new analytical approximations for the local densities and the distributions of traits in each habitat under a migration-selection-mutation balance, compute the equilibrium values of the means, variances and asymmetries of the local distributions of phenotypes, and contrast the effects of migration and mutation on the evolutionary outcome. We then check our analytical results by solving our model numerically, and also assess their robustness in the presence of demographic stochasticity. Although increased migration results in a decrease in local adaptation, mutation in our model does not influence the values of the local mean traits. Yet, both migration and mutation can have dramatic effects on population size and even lead to metapopulation extinction when selection is strong. Niche expansion, the ability for the population to adapt to both habitats, can also be prevented by small migration rates and a reduced evolutionary potential characterized by rare mutation events of small effects; however, niche expansion is otherwise the most likely outcome. Although our results are derived under the assumption of clonal reproduction, we finally show and discuss the links between our model and previous quantitative genetics models. PMID- 23639100 TI - Comparison of nondominant and dominant hand performances on the Wechsler Memory Scale-Fourth Edition Visual Reproduction subtest copy and memory components. AB - Using both clinical and nonclinical samples, we investigated the effects of nondominant hand completion of copy and memory components on the Wechsler Memory Scale-Fourth Edition (WMS-IV) Visual Reproduction (VR) subtest. Part I of the study revealed statistically significant intermanual differences on the copy component, though discrepancies were not clinically meaningful. Part II showed similar memory scores between the group who used their nondominant hand and the group who used their dominant hand. Findings suggest that when a standard administration is precluded, it is reasonable to use the nondominant hand to complete the VR subtest and to make use of the WMS-IV norms for interpretation. PMID- 23639099 TI - A biomarker based on gene expression indicates plant water status in controlled and natural environments. AB - Plant or soil water status is required in many scientific fields to understand plant responses to drought. Because the transcriptomic response to abiotic conditions, such as water deficit, reflects plant water status, genomic tools could be used to develop a new type of molecular biomarker. Using the sunflower (Helianthus annuus L.) as a model species to study the transcriptomic response to water deficit both in greenhouse and field conditions, we specifically identified three genes that showed an expression pattern highly correlated to plant water status as estimated by the pre-dawn leaf water potential, fraction of transpirable soil water, soil water content or fraction of total soil water in controlled conditions. We developed a generalized linear model to estimate these classical water status indicators from the expression levels of the three selected genes under controlled conditions. This estimation was independent of the four tested genotypes and the stage (pre- or post-flowering) of the plant. We further validated this gene expression biomarker under field conditions for four genotypes in three different trials, over a large range of water status, and we were able to correct their expression values for a large diurnal sampling period. PMID- 23639101 TI - Improving awareness of cancer clinical trials among Hispanic patients and families: audience segmentation decisions for a media intervention. AB - Clinical trials hold great promise for cancer treatment; yet, Hispanic cancer patients have low rates of clinical trial participation. Lack of awareness and knowledge of clinical trials and language barriers may account for low participation rates. Patient education through audiovisual materials can improve knowledge of and attitudes toward clinical trials among Hispanic populations. In this study, 36 Hispanic cancer patients/survivors and caregivers in Florida and Puerto Rico participated in focus groups to aid in developing a Spanish-language DVD and booklet intervention designed to increase knowledge about clinical trials. Focus group results showed (a) low levels of knowledge about clinical trials, (b) uncertainty about why a physician would expect a patient to make a choice about treatment, and (c) desire for family participation in decision making. Respondents expressed various preferences for aspects of the DVD such as showing extended family in the DVD and physician explanations about key terms. On the basis of these preferences, the authors developed a creative brief for a DVD. The content of the DVD was reviewed by Hispanic community leaders and key stakeholders. A final DVD was created, in Spanish, using Hispanic patients and physicians, which contained the information deemed important from the focus groups and stakeholder interviews. The DVD is complete with companion booklet and currently undergoing a randomized control trial. PMID- 23639102 TI - Prevalence and factors correlating with hyperoxia exposure following cardiac arrest--an observational single centre study. AB - PURPOSE OF THE STUDY: Arterial hyperoxia during care in the intensive care unit (ICU) has been found to correlate with mortality after cardiac arrest (CA). We examined the prevalence of hyperoxia following CA including pre-ICU values and studied differences between those exposed and those not exposed to define predictors of exposure. MATERIALS AND METHODS: A retrospective analysis of a prospectively collected cohort of cardiac arrest patients treated in an Australian tertiary hospital between August 2008 and July 2010. Arterial blood oxygen values and used fractions of oxygen were recorded during the first 24 hours after the arrest. Hyperoxia was defined as any arterial oxygen value greater than 300 mmHg. Chi-square test was used to compare categorical data and Mann-Whitney U-test to continuous data. Statistical methods were used to identify predictors of hyperoxia exposure. RESULTS: Of 122 patients treated in the ICU following cardiac arrest 119 had one or several arterial blood gases taken and were included in the study. Of these, 49 (41.2%) were exposed to hyperoxia and 70 (58.8%) were not during the first 24 hours after the CA. Those exposed had longer delays to return of spontaneous circulation (26 minutes vs. 10 minutes) and a longer interval to ICU admission after the arrest (4 hours compared to 1 hour). Location of the arrest was an independent predictor of exposure to hyperoxia (P value = 0,008) with out-of-hospital cardiac arrest patients being more likely to have been exposed (65%), than those with an in-hospital (21%) or ICU (30%) cardiac arrest. Out-of-hospital cardiac arrest patients had higher oxygen concentrations to the fraction of inspired oxygen ratios. CONCLUSIONS: Hyperoxia exposure was more common than previously reported and occurred more frequently in association with out-of-hospital cardiac arrest, longer times to ROSC and delays to ICU admission. PMID- 23639103 TI - Phytochemical investigation on Atriplex halimus L. from Sardinia. AB - In this study, we reported the phytochemical composition of the aerial parts of Atriplex halimus L. collected from Sardinia. This species is a halophytic shrub, typical of the Mediterranean Basin. Four new glycosylated flavonoids were isolated and their structures were elucidated on the basis of 1D, 2D NMR and MS spectra as 3',5'-dimethoxymyricetin-3-O-beta-D-xylopyranosyl-7-O-fucopyranosyl-(1 -> 3)-beta-D-glucopyranoside (1), 3'-methoxyquercetin-7-O-beta-D-fucopyranosyl-(1 -> 3)-beta-d-glucopyranosyl-3-O-beta-xylopyranosyl-(1 -> 4)-beta-xylopyranoside (2), 3'-methoxyquercetin-7-O-alpha-l-rhamnopyranosyl-3-O-alpha-arabinofuranosyl (1 -> 6)-beta-D-glucopyranoside (3) and 3',5'-dimethoxymyricetin-7-O fucopyranosyl-(1 -> 3)-beta-D-glucopyranoside (4). LC-MS(n) analysis on the extract revealed the presence of other myricetin, quercetin, isorhamnetin glycosides, simple phenolic acids and esters. PMID- 23639105 TI - The future of dermatopathology. PMID- 23639104 TI - Within-host and between-host evolutionary rates across the HIV-1 genome. AB - BACKGROUND: HIV evolves rapidly at the epidemiological level but also at the within-host level. The virus' within-host evolutionary rates have been argued to be much higher than its between-host evolutionary rates. However, this conclusion relies on analyses of a short portion of the virus envelope gene. Here, we study in detail these evolutionary rates across the HIV genome. RESULTS: We build phylogenies using a relaxed molecular clock assumption to estimate evolutionary rates in different regions of the HIV genome. We find that these rates vary strongly across the genome, with higher rates in the envelope gene (env). Within host evolutionary rates are consistently higher than between-host rates throughout the HIV genome. This difference is significantly more pronounced in env. Finally, we find weak differences between overlapping and non-overlapping regions. CONCLUSIONS: We provide a genome-wide overview of the differences in the HIV rates of molecular evolution at the within- and between-host levels. Contrary to hepatitis C virus, where differences are only located in the envelope gene, within-host evolutionary rates are higher than between-host evolutionary rates across the whole HIV genome. This supports the hypothesis that HIV strains that are less adapted to the host have an advantage during transmission. The most likely mechanism for this is storage and then preferential transmission of viruses in latent T-cells. These results shed a new light on the role of the transmission bottleneck in the evolutionary dynamics of HIV. PMID- 23639106 TI - Primary small cell carcinoma of the esophagus: review of 64 cases from a single institution. AB - Primary small cell carcinoma of esophagus (SCCE) is a rare disease with poor prognosis. The aims of this study are to review the clinical characteristics, treatment modalities, and outcomes of SCCE and to investigate the prognostic factors and optimal treatment options. Sixty-four patients diagnosed as SCCE in Sun Yat-sen University Cancer Center from 1990 to 2011 were retrospectively reviewed. There were 46 patients with limited disease (LD) and 18 with extensive disease. The median survival time (MST) and overall survival rate were calculated and compared by the Kaplan-Meier method and log-rank test, respectively. The prognostic factors were calculated by Cox hazards regression model. With a median follow up of 11.6 months, the MST of all the 64 patients was 12.6 months, 16.5 months for LD and 9.0 months for extensive disease. The 1-, 3-, and 5-year overall survivals were 52.5%, 20.9%, and 7.5%, respectively. In univariate analysis, patients with ECOG performance score <2 (P = 0.009), lesion length <=5 cm (P = 0.009), T stage <=2 (P = 0.004), LD (P = 0.000), and multimodality treatment (P = 0.016) had significant associations with MST. Multivariate analysis showed that ECOG performance score (P = 0.001), T stage (P = 0.023), limited-extensive stage (P = 0.007), and treatment modality (P = 0.008) were independent prognostic factors. Locoregional treatment combined with chemotherapy had a trend to increase MST from 15.3 to 20.0 months in LD patients (P = 0.126), while combined chemotherapy had a significant impact on MST in extensive disease patients (P = 0.000). SCCE is a highly malignant disease with poor prognosis. Patients might obtain survival benefit from the combination of locoregional treatment and systemic therapy. Prospective studies are needed to validate these factors. PMID- 23639107 TI - Social communication disorder outside autism? A diagnostic classification approach to delineating pragmatic language impairment, high functioning autism and specific language impairment. AB - BACKGROUND: Developmental disorders of language and communication present considerable diagnostic challenges due to overlapping of symptomatology and uncertain aetiology. We aimed to further elucidate the behavioural and linguistic profile associated with impairments of social communication occurring outside of an autism diagnosis. METHODS: Six to eleven year olds diagnosed with pragmatic language impairment (PLI), high functioning autism (HFA) or specific language impairment (SLI) were compared on measures of social interaction with peers (PI), restricted and repetitive behaviours/interests (RRBIs) and language ability. Odds ratios (OR) from a multinomial logistic regression were used to determine the importance of each measure to diagnostic grouping. MANOVA was used to investigate differences in subscale scores for the PI measure. RESULTS: Greater degrees of PI difficulties (OR = 1.22, 95% CI = 1.05-1.41), RRBI (OR = 1.23, 95% CI = 1.06 1.42) and expressive language ability (OR = 1.16, 95% CI = 1.03-1.30) discriminated HFA from PLI. PLI was differentiated from SLI by elevated PI difficulties (OR = 0.82, 95% CI = 0.70-0.96) and higher expressive language ability (OR = 0.88, 95% CI = 0.77-0.98), but indistinguishable from SLI using RRBI (OR = 1.01, 95% CI=0.94-1.09). A significant effect of group on PI subscales was observed (theta = 1.38, F(4, 56) = 19.26, p < .01) and PLI and HFA groups shared a similar PI subscale profile. CONCLUSIONS: Results provide empirical support for a conceptualisation of PLI as a developmental impairment distinguishable from HFA by absence of RRBIs and by the presence of expressive language difficulties. PI difficulties appear elevated in PLI compared with SLI, but may be less pervasive than in HFA. Findings are discussed with reference to the proposed new category of 'social communication disorder' in DSM-5. PMID- 23639109 TI - Hepatitis C virus relapse was suppressed by long-term self-injection of low-dose interferon in patients with chronic hepatitis C after pegylated interferon plus ribavirin treatment. AB - AIM: The recommended treatment for chronic hepatitis C is a combination of pegylated interferon (PEG IFN) plus ribavirin (RBV). However, the sustained virological response (SVR) rate of PEG IFN-RBV therapy was approximately 50% in patients with genotype 1b and a high viral load. Thus, we compared the efficiencies and side-effects of PEG IFN-RBV and self-injected low-dose natural (n) IFN-alpha in patients with hepatitis C virus (HCV). METHODS: A prospective, multicenter, open-label study was conducted in 12 Japanese institutions. A total of 129 patients with chronic hepatitis C and no detectable HCV after 24-72 weeks of PEG IFN-RBV treatment were assigned to the control (n = 82) or treated (n = 47) group. Treated patients received 3 million units of nIFN-alpha 2-3 times/week over 96 weeks. The groups were compared regarding treatment efficiency and side effects. RESULTS: Significant treatment success regarding virus negativation rates was found, with 89% and 73% for the treated and control groups, respectively (P = 0.039). In contrast, there was no difference in relapse rate between the groups 24 weeks after the 96-week nIFN-alpha treatment (P = 0.349). However, when early viral responders and late viral responders (LVR) were separated, LVR patients responded significantly to the treatment with 90% sustained virological response, compared to 53% for the control group (P = 0.044). The side-effects of nIFN-alpha were less than that of PEG IFN-RBV treatment. CONCLUSION: Self-injected nIFN-alpha has larger benefits than prolonged PEG IFN-RBV for chronic hepatitis C patients with high viral loads of genotype 1b who fail to achieve early viral response during initial combination treatment. PMID- 23639108 TI - FoxO6 and PGC-1alpha form a regulatory loop in myogenic cells. AB - Transcription factors of the FoxO (forkhead box O) family regulate a wide range of cellular physiological processes, including metabolic adaptation and myogenic differentiation. The transcriptional activity of most FoxO members is inhibitory to myogenic differentiation and overexpression of FoxO1 inhibits the development of oxidative type I fibres in vivo. In this study, we found that FoxO6, the last discovered FoxO family member, is expressed ubiquitously in various tissues but with higher expression levels in oxidative tissues, such as brain and oxidative muscles. Both the expression level and promoter activity of FoxO6 were found to be enhanced by PGC-1alpha (peroxisome-proliferator-activated receptor gamma co activator 1alpha), thus explained its enriched expression in oxidative tissues. We further demonstrated that FoxO6 represses the expression of PGC-1alpha via direct binding to an upstream A/T-rich element (AAGATATCAAAACA,-2228-2215) in the PGC-1alpha promoter. Oxidative low-intensity exercise induced PGC-1alpha but reduced FoxO6 expression levels in hind leg muscles, and the binding of FoxO6 to PGC-1alpha promoter was also prevented by exercise. As FoxO6 promoter can be co activated by PGC-1alpha and its promoter in turn can be repressed by FoxO6, it suggests that FoxO6 and PGC-1alpha form a regulatory loop for setting oxidative metabolism level in the skeletal muscle, which can be entrained by exercise. PMID- 23639110 TI - Perceptions and deflections: associations between attitudes towards people with hepatitis C and testing for hepatitis C among Australian gay and bisexual men. AB - BACKGROUND: Research indicates that the incidence of hepatitis C (HCV) among HIV positive men who have sex with men (MSM) is increasing. Although injecting drug use remains the predominant means of transmission of HCV in the developed world, there is evidence of sexual transmission of HCV among MSM. Stigma associated with HCV has been shown to negatively impact HCV testing and health-seeking behaviour. There is little research that addresses attitudes towards HCV testing among this population. METHODS: The current exploratory study focussed on HCV knowledge, HCV testing, sexual practices, perceptions of HCV risk and attitudes towards people with HCV among Australian MSM. The sample consisted of 590 men who completed an online survey. RESULTS: The findings suggest that attitudinal factors related to HCV were associated with HCV testing behaviour. The more negatively respondents felt about people with HCV, the less likely they were to have ever had an HCV test. Behavioural risk factors related to sexual practices (i.e. is condom use and sexual risk activities) were not associated with HCV testing. Testing for HCV was associated with HIV-positive status, more knowledge about HCV and a greater likelihood of ever having injected drugs. CONCLUSIONS: The attitudes of MSM towards those who inject drugs are negative, mirroring that of society more generally. Furthermore, these attitudes, coupled with a lack of knowledge of the risk of sexual transmission of HCV among gay men, especially those who are HIV positive, may act to prevent routine HCV testing among some MSM at potential risk of acquiring HCV. PMID- 23639111 TI - Risk of obstetric anal sphincter lacerations among obese women. AB - OBJECTIVE: To assess the risk for obstetric anal sphincter lacerations in relation to maternal obesity among primiparous women in Sweden. DESIGN: A population-based study. SETTING: Sweden. POPULATION: All women with vaginal delivery and singleton pregnancy in Sweden in the years 2003-2008 (n = 210,678). METHODS: The Medical Birth Registry, the National Board of Health and Welfare, was used to identify cases of rupture and body mass index (BMI) classes. The population was categorised into four classes with BMI of <25, 25 to <30, 30 to <35 and >35 kg/m2. MAIN OUTCOME MEASURES: Odds ratios were estimated with 95% confidence intervals. In order to estimate the effect of BMI on obstetric anal sphincter lacerations, with possible confounders accounted for, uni- and multivariate logistic regressions were performed. RESULTS: In total, 8958 (4.25%) cases of anal sphincter lacerations (grade III-IV) occurred; increasing BMI showed a significant near-dose-response type of protective effect against grade III-IV lacerations when compared with women with BMI <25 kg/m2: BMI 25 to <30 kg/m2, 0.89; BMI 30 to <35 kg/m2, 0.84; BMI > 35 kg/m2, 0.70. CONCLUSION: Overweight and obesity were associated with a decreased risk for obstetric anal sphincter lacerations. PMID- 23639113 TI - Polyandrous females acquire indirect benefits in a nuptial feeding species. AB - The relative force of direct and indirect selection underlying the evolution of polyandry is contentious. When females acquire direct benefits during mating, indirect benefits are often considered negligible. Although direct benefits are likely to play a prominent role in the evolution of polyandry, post-mating selection for indirect benefits may subsequently evolve. We examined whether polyandrous females acquire indirect benefits and quantified direct and indirect effects of multiple mating on female fitness in a nuptial gift-giving spider (Pisaura mirabilis). In this system, the food item donated by males during mating predicts direct benefits of polyandry. We compared fecundity, fertility and survival of singly mated females to that of females mated three times with the same (monogamy) or different (polyandry) males in a two-factorial design where females were kept under high and low feeding conditions. Greater access to nutrients and sperm had surprisingly little positive effect on fitness, apart from shortening the time until oviposition. In contrast, polyandry increased female reproductive success by increasing the probability of oviposition, and egg hatching success indicating that indirect benefits arise from mating with several different mating partners rather than resources transferred by males. The evolution of polyandry in a male-resource-based mating system may result from exploitation of the female foraging motivation and that indirect genetic benefits are subsequently derived resulting from co-evolutionary post-mating processes to gain a reproductive advantage or to counter costs of mating. Importantly, indirect benefits may represent an additional explanation for the maintenance of polyandry. PMID- 23639115 TI - Indanomycin-related antibiotics from marine Streptomyces antibioticus PTZ0016. AB - Four indanomycin-related antibiotics 2-5 were isolated from the cultured broth of marine Streptomyces antibioticus strain PTZ0016. Their structures were characterised as 16-deethylindanomycin (2), iso-16-deethylindanomycin (3), 16 deethylindanomycin methyl ester (4) and iso-16-deethylindanomycin methyl ester (5) on the basis of NMR, HR-ESI-MS and CD evidences. Compounds 3-5 are new additions to the class of indanomycin antibiotics. All isolated compounds showed in vitro activity against Staphylococcus aureus with minimal inhibitory concentration at 4.0-8.0 MUg/ml. PMID- 23639116 TI - GOLLUM [FeFe]-hydrogenase-like proteins are essential for plant development in normoxic conditions and modulate energy metabolism. AB - [FeFe]-hydrogenase-like genes encode [Fe4 S4]-containing proteins that are ubiquitous in eukaryotic cells. In humans, iron-only hydrogenase-like protein 1 (IOP1) represses hypoxia inducible factor-1alpha subunit (HIF1-alpha) at normal atmospheric partial O2 pressure (normoxia, 21 kPa O2). In yeasts, the nar1 mutant cannot grow at 21 kPa O2, but can develop at a lower O2 pressure (2 kPa O2). We show here that plant [FeFe]-hydrogenase-like GOLLUM genes are essential for plant development and cell cycle progression. The mutant phenotypes of these plants are seen in normoxic conditions, but not under conditions of mild hypoxia (5 kPa O2). Transcriptomic and metabolomic experiments showed that the mutation enhances the expression of some hypoxia-induced genes under normal atmospheric O2 conditions and changes the cellular content of metabolites related to energy metabolism. In conclusion, [FeFe]-hydrogenase-like proteins play a central role in eukaryotes including the adaptation of plants to the ambient O2 partial pressure. PMID- 23639117 TI - Computer assessment of indirect insight during an airflow interrupter maneuver of breathing. AB - The paper answers the questions if it is possible to conclude in objective way on more (than one -Rint - in a classical IT) number of parameters from the time domain post-interrupter signals during the occlusional measurement of respiratory mechanics and also verifies what accuracy can be achieved in such attempt. To obtain reported results, the time-domain enhanced interrupter technique (TD-EIT) was developed in this paper using computer simulations. Three-stage scheme of work was assumed in the project. First, the quality of the model identification was assessed for various combinations of pressure and flow signals recorded during the interruption. Then, the correlation between the working characteristics of the interrupter valve and the precision of the parameter estimation were assessed for the TD-EIT algorithm. Finally, a verification experiment by forward-inverse modeling was organized, in which the mechanical characteristics of a complex model were mapped with reduced analogs and with the use of neural networks for three typical modes: 'Normal state', 'Airway constriction' and 'Cheeks supported'. Obtained results show that to became effective in time-domain post-interrupter data exploration, both pressure and flow signals should be used in assessment of respiratory mechanics, taken in a range of at least 100ms and when both slopes (valve closing and opening) of quasi step excitation are included. What is more, the faster the valve the smaller error of parameter estimation in proposed TD-EIT was observed, and this uncertainty importantly falls down for the length of time window exceeding the limit of 100ms. The pioneering use of neural network for mapping the mechanical properties of lungs with the use of interrupter experiment methodology proves that it is possible to conclude about more (than one) number of parameters characterizing the complex system and that this insight is biased with the error not exceeding of 10%; only peripheral properties are estimated worse. Such observation has a potential to change the experimental protocol, which was used in interrupter measurements up to date and to make this technique more attractive in comparison to other method, i.e. forced oscillation technique or impulse oscillometry. As regards the practical meaning of reported results for engineers and end-users (physicians and patients), proposed solution can be applied in simple portable devices with a feature of easy operation (important for e monitoring). PMID- 23639118 TI - Pseudolymphomatous cutaneous angiosarcoma: a report of 2 new cases arising in an unusual setting. AB - Pseudolymphomatous cutaneous angiosarcoma represents a rare, relatively new variant of cutaneous angiosarcoma exhibiting a prominent inflammatory lymphoid infiltrate that can mask the underlying vascular malignant proliferation and mimic a lymphomatous or pseudolymphomatous process. We describe the clinicopathologic characteristics of two new cases of pseudolymphomatous cutaneous angiosarcoma whose originality lies in the unusual setting from which they have arisen. In fact, the first case was an exceedingly lymphocyte-rich recurrence of a typical epithelioid cutaneous angiosarcoma whose primary lesion that was almost devoid of inflammatory infiltrate underwent surgical excision and radiotherapy while the second one was an unexpected histopathological finding associated with a basal cell carcinoma. Immunohistochemically, most of the lymphocytes expressed immunoreactivity for T-cell markers, while the neoplastic endothelial lymphatic cells expressed CD31 and CD34. D2-40 immunoreactivity was observed lining some channels and some neoplastic cells. In the first case a possible relationship between radiotherapy and the pseudolymphomatous reactive pattern is discussed while the second case has been considered as a rare example of collision tumor. PMID- 23639119 TI - Methylphenidate improves some but not all measures of attention, as measured by the TEA-Ch in medication-naive children with ADHD. AB - The Test of Everyday Attention for Children (TEA-Ch) is a reliable neuropsychological assessment of attention control in children. Methylphenidate (MPH) is an effective treatment to improve attentional difficulties in children with attention deficit/hyperactivity disorder (ADHD). Previous studies investigating the effects of MPH on attention performance of children with ADHD have produced mixed results and prior MPH usage may have confounded these results. No previous study has tested the effects of MPH on the entire TEA-Ch battery. This study investigated the effects of MPH on attention performance using the entire TEA-Ch in 51 medication-naive children with ADHD compared with 35 nonmedicated typically developing children. All children were tested at baseline and after 6 weeks: The children with ADHD were medication-naive at baseline, received MPH for 6 weeks and were tested whilst on medication at the second testing session. A beneficial effect of MPH administration was found on at least one subtest of each of the three forms of attention (selective, sustained, and attentional control) assessed by the TEA-Ch, independent of practice effects. MPH aided performance on the TEA-Ch tasks that were inherently nonarousing and that might require top-down control of attention. It is recommended that the TEA Ch measures--Sky Search Count (selective attention),Score! (sustained attention), Creature Counting Time Taken for older children (attentional control), and Same Worlds (attentional control) be prioritized for use in future pharmacological studies using MPH. PMID- 23639120 TI - Children's callous-unemotional traits moderate links between their positive relationships with parents at preschool age and externalizing behavior problems at early school age. AB - BACKGROUND: Growing research on children's traits as moderators of links between parenting and developmental outcomes has shown that variations in positivity, warmth, or responsiveness in parent-child relationships are particularly consequential for temperamentally difficult or biologically vulnerable children. But very few studies have addressed the moderating role of children's callous unemotional (CU) traits, a known serious risk factor for antisocial cascades. We examined children's CU traits as moderators of links between parent-child Mutually Responsive Orientation (MRO) and shared positive affect and future externalizing behavior problems. METHODS: Participants included 100 two-parent community families of normally developing children, followed longitudinally. MRO and shared positive affect in mother-child and father-child dyads were observed in lengthy, diverse naturalistic contexts when children were 38 and 52 months. Both parents rated children's CU traits at 67 months and their externalizing behavior problems (Oppositional Defiant Disorder and Conduct Disorder) at 67, 80, and 100 months. RESULTS: Children's CU traits moderated links between early positive parent-child relationships and children's future externalizing behavior problems, even after controlling for strong continuity of those problems. For children with elevated CU traits, higher mother-child MRO and father-child shared positive affect predicted a decrease in mother-reported future behavior problems. There were no significant associations for children with relatively lower CU scores. CONCLUSIONS: Positive qualities for early relationships, potentially different for mother-child and father-child dyads, can serve as potent factors that decrease probability of antisocial developmental cascades for children who are at risk due to elevated CU traits. PMID- 23639121 TI - Transverse uterine fundal incision for placenta praevia with accreta, involving the entire anterior uterine wall: a case series. AB - OBJECTIVE: To determine the feasibility and safety of transverse fundal incision with manual placental removal in women with placenta praevia and possible placenta accreta. DESIGN: Case series. SETTING: Four level-three Japanese obstetric centres. POPULATION: Thirty-four women with prior caesarean section and placenta praevia that widely covers the anterior uterine wall, in whom placenta accreta cannot be ruled out. METHODS: A transverse fundal incision was performed at the time of caesarean section and manual placental removal was attempted under direct observation. MAIN OUTCOME MEASURE: Operative fluid loss. RESULTS: The total volume of fluid lost during our operative procedure compares favourably with the volume lost during our routine transverse lower-segment caesarean sections performed in patients without placenta praevia or accreta. The average fluid loss was 1370 g. No patients required transfer to intensive care, and there were no cases of fetal anaemia. CONCLUSIONS: This procedure has the potential to reduce the heavy bleeding that arises from caesarean deliveries in women with placenta praevia and placenta accreta. PMID- 23639122 TI - Rapid quantification of dimethyl methylphosphonate from activated carbon particles by static headspace gas chromatography mass spectrometry. AB - Activated carbon (AC) particles are utilized as an adsorbent for binding hazardous vapors in protective equipment. The binding affinity and utilization of these AC particles should be known to ensure effective and efficient use. Therefore, a simple and effective method was developed for the quantification of the chemical warfare agent simulant, dimethyl methylphosphonate (DMMP), from AC particles. Static headspace gas chromatography mass-spectrometry with internal standard, DMMP-d6, was used to perform the analysis. The method produced a linear dynamic range of 2.48-620g DMMP/kg carbon and a detection limit of 1.24g DMMP/kg carbon. Furthermore, the method produced a coefficient of variation of less than 16% for all intra- and inter-assay analyses. The method provided a simple and effective procedure for quantifying DMMP from AC particles and was applied to the analysis of a DMMP-exposed AC protective respirator filter. PMID- 23639123 TI - Ultrasound-assisted extraction and in situ derivatization. AB - Ultrasound (US) is a type of energy of growing interest for analytical chemists. The favorable effect of US on mass transfer between two phases in the same or different state has been widely demonstrated as did the number of chemical reactions accelerated/improved under ultrasonic influence. The action of US on both mass transfer and chemical reaction developed in a simultaneous manner results in a synergistic effect as a consequence of the "removal" of the target extracted species by conversion into a product. Both US-assisted solid-liquid extraction and liquid-liquid extraction have been developed with in situ derivatization at the meso- and microscale and the advantages involved in their implementation are discussed in this article. PMID- 23639124 TI - Ionic liquid based dispersive liquid-liquid microextraction coupled with micro solid phase extraction of antidepressant drugs from environmental water samples. AB - Ionic liquid-dispersive liquid-liquid microextraction combined with micro-solid phase extraction (IL-DLLME-MU-SPE), and high-performance liquid chromatography (HPLC) was developed for the determination of tricyclic antidepressants (TCAs) in water samples. Two hundred microliters of an organic solvent (as disperser solvent) and 20 MUl of 1-hexyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate were injected into a 5.0 ml sample for sonication-assisted DLLME. After this, a MU-SPE device, containing a novel material zeolite imidazolate framework 4 (ZIF-4), was added into the sample solution and 1 min of vortex-assisted extraction was performed. After 5 min of sonication-assisted desorption, 10 MUl of desorption solvent was injected into a HPLC system for analysis. A characteristic property of DLLME-VA-MU-SPE is that any organic solvent and solid sorbent immiscible with water can be used. Special apparatus, or conical-bottom test tubes, and tedious procedures conventionally associated with DLLME such as centrifugation, or refrigeration of solvent are not necessary in the present approach. A novel material, ZIF-4 was employed as MU-SPE sorbent. Under the optimized conditions, the calibration curves were linear in the range of 1-1000 MUg/L. The relative standard deviations and the limits of detection were in the range of 1.5% and 7.8% and 0.3 and 1 MUg/L, respectively. The relative recoveries of canal water samples, spiked with drugs, were in the range of 94.3% and 114.7%. The results showed that IL-DLLME-MU-SPE was suitable for the determination of TCAs in water samples. PMID- 23639125 TI - Specific recognition of tyrosine-phosphorylated peptides by epitope imprinting of phenylphosphonic acid. AB - Protein phosphorylation on tyrosine residues is an important cell signaling mechanism that regulates embryo development, cell growth, differentiation and migration. Here, we developed an epitope imprinting approach to selectively enrich tyrosine-phosphorylated (pTyr) peptides using molecularly imprinted polymers (MIPs). An artificial receptor based on MIPs was prepared by precipitation polymerization using phenylphosphonic acid (PPA) as a template, Ti(4+)-immobilized ethylene glycol methacrylate phosphate as functional monomer, poly(ethylene glycol) diacrylate and N,N'-methylenebisacrylamide as crosslinkers, and deionized water as a porogen. The performance of MIPs was first evaluated by rebinding PPA, and then a competition experiment was conducted to assess the selectivity and specificity for PPA when mixed with benzoic acid, a structural analog. The imprinting factor of the MIPs was up to 2.04, compared with just 0.24 for benzoic acid. The selectivity and capacity of the MIPs for pTyr peptides from a mixture of peptides were considerably higher than that of commercial TiO2. And after six rebinding cycles, there were still 95% adsorption efficiency retained. Finally, MIPs were used for pTyr enrichment from a complex sample containing pTyr peptide and tryptic digestion of beta-casein, where it demonstrated a clear preference for the pTyr peptide over ones containing phosphorylated serine. PMID- 23639126 TI - Pros and cons of peptide isolectric focusing in shotgun proteomics. AB - In shotgun proteomics, protein mixtures are proteolytically digested before tandem mass spectrometry (MS/MS) analysis. Biological samples are generally characterized by a very high complexity, therefore a step of peptides fractionation before the MS analysis is essential. This passage reduces the sample complexity and increases its compatibility with the sampling performance of the instrument. Among all the existing approaches for peptide fractionation, isoelectric focusing has several peculiarities that are theoretically known but practically rarely exploited by the proteomics community. The main aim of this review is to draw the readers' attention to these unique qualities, which are not accessible with other common approaches, and that represent important tools to increase confidence in the identification of proteins and some post-translational modifications. The general characteristics of different methods to perform peptide isoelectric focusing with natural and artificial pH gradients, the existing instrumentation, and the informatics tools available for isoelectric point calculation are also critically described. Finally, we give some general conclusions on this strategy, underlying its principal limitations. PMID- 23639127 TI - Assurance of safety of recycled paperboard for food packaging through comprehensive analysis of potential migrants is unrealistic. AB - A method for determining potentially health-relevant components in paperboard used for packaging dry foods as comprehensively as technically feasible was applied to a sample of recycled paperboard. The task was specified by a detection limit in food of 0.01mg/kg, from which a detection limit of 0.1mg/kg in paperboard was derived. Extracts from the paperboard were preseparated into seven fractions by high performance liquid chromatography (HPLC) and transferred on line to gas chromatography with flame ionization detection (GC-FID). The chromatograms visualize the high complexity of the material that may migrate into foods at toxicologically potentially relevant concentrations. Since only a minority of the substances was also detectable in fresh fiber board, most must have originated from chemicals used in the paper and board fed into the recycling process. Significant variability between recycled paperboards of four manufacturers was observed because of varying feedstocks. Using comprehensive two dimensional GC (GC*GC) with time of flight mass spectrometry (TOF-MS), more than 250 substances were counted that probably exceeded the detection limit and were probably of sufficient volatility for migration into dry food. It is concluded in three main messages to risk managers: (i) since most potential migrants have not been adequately evaluated, many not even identified, the safety required by Article 3 of EU Regulation 1935/2004 has not been ensured; (ii) the number of substances potentially migrating into food above 0.01mg/kg is too large to realistically be brought under control; (iii) a barrier reducing the migration into food by a factor of 100 over the life time of a product would keep the migration of all except a few well known substances below 0.01mg/kg in food. PMID- 23639128 TI - On-line surface plasmon resonance-high performance liquid chromatography-tandem mass spectrometry for analysis of human serum albumin binders from Radix Astragali. AB - Development of sensitive and effective methods that meet the demand of high throughput, high-fidelity screening of bioactive components from natural products are important to drug discovery. We describe here a novel surface plasmon resonance-high performance liquid chromatography-tandem mass spectrometry (SPR HPLC-MS/MS) system for rapid, continuous and effective screening and identification of human serum albumin (HSA) binders from Radix Astragali. The HPLC six-port valve was used as interface through which the dissociated HSA binders from SPR was collected and injected automatically to HPLC-MS/MS for analysis. Eleven isofalvonoids and nine astragalosides have been screened and identified as the main HSA binders in ethyl acetate extract of Radix Astragali. Compared with reverse ultrafiltration assay, the developed configuration is more cost effective and reproductive because of the higher reusability and stability of immobilized HSA on SPR chip. Furthermore, the assay minimized the matrix interference in MS because of the elimination of non-binding components before HPLC separation. It is concluded that this novel technology offers new perspectives for screening and identification of active components from complex mixtures. PMID- 23639129 TI - Accuracy profiles assessing the validity for routine use of high-performance thin layer chromatographic assays for drug formulations. AB - The accuracy profile, based on total error, integrates several validation parameters, such as trueness, precision and linearity, providing one statistic which enables decision on the suitability of a method for its intended purpose. Two assay methods for formulations are validated using accuracy profiles as an alternative approach to classic method validation. It concerns high-performance thin-layer chromatography (HPTLC) methods, which initially were validated using the classic approach. The first method assayed sulfamethoxazole and trimethoprim, and the second lamivudine, stavudine and nevirapine. Both formulations are fixed dose combination tablets. The resulting accuracy profiles showed that the 95% beta-expectation tolerance limits for all compounds fell well within the bias acceptance limits set at +/-5%. This means that the two analytical thin-layer chromatographic methods are capable of making accurate results at the studied concentration ranges of each compound. Measurement uncertainties of every compound at each concentration level could also be determined from the accuracy profile data. PMID- 23639130 TI - Evaluating antibody monomer separation from associated aggregates using mixed mode chromatography. AB - Aggregate level is a key factor when assessing quality attributes of antibody product, since the aggregation might impact the biological activity of biopharmaceutical. Effective separation methods are usually essential in manufacturing processes. In this study, three mixed-mode resins, i.e. Capto adhere and two home-made resins with benzylamine and butylamine as the functional ligands (named BA and AB), were used to investigate the separation performances of antibody aggregate removal processes. In addition, two traditional resins (Q Sepharose FF and Phenyl Sepharose 6 FF) were also investigated to explore the role of molecular interaction in the aggregate removal. The results indicated that the removal efficiency was highly dependent on the mass loading. With the sample load of 50mg/ml resin both Capto adhere and BA resins can significantly reduce the aggregate level from 20.5% to 2.6% and 2.4%, respectively, while a relatively low degree of aggregate reduction was found with the traditional resins. The research indicates that both hydrophobic interaction and electrostatic interaction are critical for the aggregate removal and the cooperativity of different molecular interactions is important for the effective aggregates removal with mixed-mode resins. PMID- 23639131 TI - Autism and the broad autism phenotype: familial patterns and intergenerational transmission. AB - BACKGROUND: Features of the Broad Autism Phenotype (BAP) are disproportionately prevalent in parents of a child with autism, highlighting familial patterns indicative of heritability. It is unclear, however, whether the presence of BAP features in both parents confers an increased liability for autism. The current study explores whether the presence of BAP features in two biological parents occurs more frequently in parents of a child with autism relative to comparison parents, whether parental pairs of a child with autism more commonly consist of one or two parents with BAP features, and whether these features are associated with severity of autism behaviors in probands. METHOD: Seven hundred eleven parents of a child with an autism spectrum disorder and 981 comparison parents completed the Broad Autism Phenotype Questionnaire. Parents of a child with autism also completed the Social Communication Questionnaire. RESULTS: Although parental pairs of a child with autism were more likely than comparison parental pairs to have both parents characterized by the presence of the BAP, they more commonly consisted of a single parent with BAP features. The presence of the BAP in parents was associated with the severity of autism behaviors in probands, with the lowest severity occurring for children of parental pairs in which neither parent exhibited a BAP feature. Severity did not differ between children of two affected parents and those of just one. CONCLUSIONS: Collectively, these findings indicate that parental pairs of children with autism frequently consist of a single parent with BAP characteristics and suggest that future studies searching for implicated genes may benefit from a more narrow focus that identifies the transmitting parent. The evidence of intergenerational transmission reported here also provides further confirmation of the high heritability of autism that is unaccounted for by the contribution of de novo mutations currently emphasized in the field of autism genetics. PMID- 23639133 TI - Interferon-beta, prednisolone and lamivudine combination in acute exacerbation of chronic hepatitis B during pregnancy. PMID- 23639132 TI - Long-term risk of glaucoma after congenital cataract surgery. AB - PURPOSE: To report the long-term risk of glaucoma development in children following congenital cataract surgery. DESIGN: Retrospective interventional consecutive case series. METHODS: We retrospectively reviewed the records of 62 eyes of 37 children who underwent congenital cataract surgery when <7 months of age by the same surgeon using a limbal approach. The Kaplan-Meier method was used to calculate the probability of an eye's developing glaucoma and/or becoming a glaucoma suspect over time. RESULTS: The median age of surgery was 2.0 months and the median follow-up after cataract surgery was 7.9 years (range, 3.2-23.5 years). Nine eyes (14.5%) developed glaucoma a median of 4.3 months after cataract surgery and an additional 16 eyes (25.8%) were diagnosed as glaucoma suspects a median of 8.0 years after cataract surgery. The probability of an eye's developing glaucoma was estimated to be 19.5% (95% CI: 10.0%-36.1%) by 10 years after congenital cataract surgery. When the probability of glaucoma and glaucoma suspect were combined, the risk increased to 63.0% (95% CI: 43.6% 82.3%). CONCLUSIONS: Long-term monitoring of eyes after congenital cataract surgery is important because we estimate that nearly two thirds of these eyes will develop glaucoma or become glaucoma suspects by 10 years after cataract surgery. PMID- 23639134 TI - Handover of patients: a topical review of ambulance crew to emergency department handover. AB - Handover has major implications for patient care. The handover process between ambulance and emergency department (ED) staff has been sparsely investigated. The purpose of this paper is, based on a literature review, to identify and elaborate on the major factors influencing the ambulance to ED handover, and to bring suggestions on how to optimize this process. A literature search on handovers to EDs was performed in PubMed, Embase, Web of Science and Cochrane databases. A total of 18 papers were included. Issues regarding transfer of information are highlighted. Newer studies suggest that implementing a structured handover format holds the possibilities for improving the process. Electronic equipment could play a part in reducing problems. Cultural and organizational factors impact the process in different ways. The professions perceive the value and quality of information given differently. Giving and taking over responsibility is an important issue. The handover of patients to the ED has the potential to be improved. Cultural issues and a lack of professional recognition of handover importance need to be approached. Multidisciplinary training in combination with a structured tool may have a potential for changing the culture and improving handover. PMID- 23639136 TI - Cutaneous presentation of chronic lymphocytic leukemia as unique extramedullar involvement in a patient with normal peripheral blood lymphocyte count (monoclonal B-cell lymphocytosis). AB - Skin infiltration by chronic lymphocytic leukemia (CLL) is very rare and almost all reported cases occur in advanced stage. We report a patient with no relevant past medical history who presented with cutaneous erythematous plaques. A punch biopsy showed typical CLL morphologic and immunophenotypic features. Subsequent studies revealed a normal lymphocyte count in peripheral blood, and there was no evidence of lymphadenopathy or organomegaly. Flow cytometry demonstrated a clonal B-cell population both in the bone marrow and peripheral blood (1.60 * 10(9)/l) with a CLL phenotype, but it did not fulfill required criteria for CLL diagnosis. Without cutaneous involvement, this case should be classified as monoclonal B cell lymphocytosis. PMID- 23639135 TI - Phospholipase C-related but catalytically inactive protein modulates pain behavior in a neuropathic pain model in mice. AB - BACKGROUND: An inositol 1,4,5-trisphosphate binding protein, comprising 2 isoforms termed PRIP-1 and PRIP-2, was identified as a novel modulator for GABAA receptor trafficking. It has been reported that naive PRIP-1 knockout mice have hyperalgesic responses. FINDINGS: To determine the involvement of PRIP in pain sensation, a hind paw withdrawal test was performed before and after partial sciatic nerve ligation (PSNL) in PRIP-1 and PRIP-2 double knockout (DKO) mice. We found that naive DKO mice exhibited normal pain sensitivity. However, DKO mice that underwent PSNL surgery showed increased ipsilateral paw withdrawal threshold. To further investigate the inverse phenotype in PRIP-1 KO and DKO mice, we produced mice with specific siRNA-mediated knockdown of PRIPs in the spinal cord. Consistent with the phenotypes of KO mice, PRIP-1 knockdown mice showed allodynia, while PRIP double knockdown (DKD) mice with PSNL showed decreased pain-related behavior. This indicates that reduced expression of both PRIPs in the spinal cord induces resistance towards a painful sensation. GABAA receptor subunit expression pattern was similar between PRIP-1 KO and DKO spinal cord, while expression of K(+)-Cl(-)-cotransporter-2 (KCC2), which controls the balance of neuronal excitation and inhibition, was significantly upregulated in DKO mice. Furthermore, in the DKD PSNL model, an inhibitor-induced KCC2 inhibition exhibited an altered phenotype from painless to painful sensations. CONCLUSIONS: Suppressed expression of PRIPs induces an elevated expression of KCC2 in the spinal cord, resulting in inhibition of nociception and amelioration of neuropathic pain in DKO mice. PMID- 23639137 TI - Co-evolutionary patterns and diversification of ant-fungus associations in the asexual fungus-farming ant Mycocepurus smithii in Panama. AB - Partner fidelity through vertical symbiont transmission is thought to be the primary mechanism stabilizing cooperation in the mutualism between fungus-farming (attine) ants and their cultivated fungal symbionts. An alternate or additional mechanism could be adaptive partner or symbiont choice mediating horizontal cultivar transmission or de novo domestication of free-living fungi. Using microsatellite genotyping for the attine ant Mycocepurus smithii and ITS rDNA sequencing for fungal cultivars, we provide the first detailed population genetic analysis of local ant-fungus associations to test for the relative importance of vertical vs. horizontal transmission in a single attine species. M. smithii is the only known asexual attine ant, and it is furthermore exceptional because it cultivates a far greater cultivar diversity than any other attine ant. Cultivar switching could permit the ants to re-acquire cultivars after garden loss, to purge inferior cultivars that are locally mal-adapted or that accumulated deleterious mutations under long-term asexuality. Compared to other attine ants, symbiont choice and local adaptation of ant-fungus combinations may play a more important role than partner-fidelity feedback in the co-evolutionary process of M. smithii and its fungal symbionts. PMID- 23639138 TI - Investigational drugs for schizophrenia targeting the dopamine receptor: phase II trials. AB - INTRODUCTION: For over half a century now, the dopamine hypothesis has provided the most widely accepted heuristic model linking pathophysiology and treatment in schizophrenia. Despite dopaminergic drugs being available for six decades, this system continues to represent a key target in schizophrenia drug discovery. The present article reviews the scientific rationale for dopaminergic medications historically and the shift in our thinking since, which is clearly reflected in the investigational drugs detailed. AREAS COVERED: We searched for investigational drugs using the key words 'dopamine,' 'schizophrenia,' and 'Phase II' in American and European clinical trial registers (clinicaltrials.gov; clinicaltrialsregister.eu), published articles using National Library of Medicine's PubMed database, and supplemented results with a manual search of cross-references and conference abstracts. We provide a brief description of drugs targeting dopamine synthesis, release or metabolism, and receptors (agonists/partial agonists/antagonists). EXPERT OPINION: There are prominent shifts in how we presently conceptualize schizophrenia and its treatment. Current efforts are not as much focused on developing better antipsychotics but, instead, on treatments that can improve other symptom domains, in particular cognitive and negative. This new era in the pharmacotherapy of schizophrenia moves us away from the older 'magic bullet' approach toward a strategy fostering polypharmacy and a more individualized approach shaped by the individual's specific symptom profile. PMID- 23639139 TI - Solubility of aqueous methane under metastable conditions: implications for gas hydrate nucleation. AB - To understand the prenucleation stage of methane hydrate formation, we measured methane solubility under metastable conditions using molecular dynamics simulations. Three factors that influence solubility are considered: temperature, pressure, and the strength of the modeled van der Waals attraction between methane and water. Moreover, the naturally formed water cages and methane clusters in the methane solutions are analyzed. We find that both lowering the temperature and increasing the pressure increase methane solubility, but lowering the temperature is more effective than increasing the pressure in promoting hydrate nucleation because the former induces more water cages to form while the latter makes them less prevalent. With an increase in methane solubility, the chance of forming large methane clusters increases, with the distribution of cluster sizes being exponential. The critical solubility, beyond which the metastable solutions spontaneously form hydrate, is estimated to be ~0.05 mole fraction in this work, corresponding to the concentration of 1.7 methane molecules/nm(3). This value agrees well with the cage adsorption hypothesis of hydrate nucleation. PMID- 23639140 TI - Antitumor effect of recombinant human interferon-beta adenovirus on esophageal squamous cell cancer in vitro. AB - Interferon (IFN)-beta has efficient antitumor effect both in vitro and in vivo, but its clinical implication is limited by short half-life and systemic toxicities. Gene therapy could be the choice to avoid the defects. Adenovirus vector containing human IFN-beta gene was transfected into esophageal squamous cell carcinoma KYSE150 cells. Expression of human (h)IFN-beta was detected by reverse transcription polymerase chain reaction and immunocytochemistry in KYSE150 cells. Cell growth and clonogenic assays, and flow cytometry were used to observe the antiproliferation effect and apoptosis on tumor cells, respectively. Reverse transcription polymerase chain reaction and immunocytochemistry showed obvious hIFN-beta expression in KYSE150 cells after transfection and the tumor cell proliferation was obviously inhibited through cell proliferation and clonogenic assays. Flow cytometry analysis showed 27.3% cell apoptosis in adenovirus vector containing human IFN-beta gene transfection group compared with 1.12% in empty vector control group. These findings indicate that hIFN-beta gene mediated by recombinant adenovirus may have antitumor activity against human esophageal carcinoma cell by inducing apoptosis in vitro. PMID- 23639141 TI - Magnesium phosphate cements for endodontic applications with improved long-term sealing ability. AB - AIM: To characterize three radiopaque Magnesium Phosphate Cements (MPCs) developed for endodontic purposes. METHODOLOGY: Three experimental MPCs containing Bi2 O3 were formulated. The experimental cements, which consisted of mixtures of magnesium oxide with different phosphate salts, were characterized for setting time, injectability, porosity, compressive strength and phase composition. The long-term sealing ability of the experimental MPCs applied in single-rooted teeth as root canal filling material or as sealer in combination with gutta-percha was also assessed using a highly sensitive fluid filtration system. A mineral trioxide aggregate (MTA) cement was used as control. Statistical analysis was performed with two- or three-way analysis of variance (anova) and Tukey's test was used for comparisons. RESULTS: The addition of 10 wt% Bi2 O3 within the composition of the MPCs provided an adequate radiopacity for endodontic applications according to ISO 6876 standard. The reaction products resulting from the MPCs were either struvite (MgNH4 PO4 .6H2 O) or an amorphous sodium magnesium phosphate. The porosity of the three MPCs ranged between 4% and 11%. The initial setting time of the experimental cements was between 6 and 9 min, attaining high early compressive strength values (17-34 MPa within 2 h). All MPC formulations achieved greater sealing ability than MTA (P < 0.05) after 3 months, which was maintained after 6 months for two of the experimental cements (P < 0.05). CONCLUSIONS: These MPCs had adequate handling and mechanical properties and low degradation rates. Furthermore, a stable sealing ability was demonstrated up to 6 months when using the cement both as root filling material and as sealer in conjunction with gutta-percha. PMID- 23639142 TI - Lanthanide clusters with azide capping ligands. AB - Weakly binding azide ligands have been used as surface caps in the synthesis of lanthanide oxo and selenido clusters. Addition of NaN3 and Na2O to in situ prepared solutions of Ln(SePh)3 in pyridine results in the formation of (py)18Sm6Na2O2(N3)16 or (py)10Ln6O2(N3)12(SePh)2 (Ln = Ho, Er), with the Sm and Er compounds characterized by low temperature single crystal X-ray diffraction. Attempts to prepare chalcogenido derivatives by ligand-based redox reactions using elemental Se were successful in the preparation of (py)10Er6O2(SeSe)2(N3)10, a diselenido cluster having crystallographic disorder due to some site sharing of both SeSe and N3 ligands. These compounds all detonate when heated. PMID- 23639143 TI - Giving voice to food insecurity in a remote indigenous community in subarctic Ontario, Canada: traditional ways, ways to cope, ways forward. AB - BACKGROUND: Food insecurity is a serious public health issue for Aboriginal people (First Nations [FN], Metis, and Inuit) living in Canada. Food security challenges faced by FN people are unique, especially for those living in remote and isolated communities. Conceptualizations of food insecurity by FN people are poorly understood. The purpose of this study was to explore the perceptions of food insecurity by FN adults living in a remote, on-reserve community in northern Ontario known to have a high prevalence of moderate to severe food insecurity. METHODS: A trained community research assistant conducted semi-directed interviews, and one adult from each household in the community was invited to participate. Questions addressed traditional food, coping strategies, and suggestions to improve community food security and were informed by the literature and a community advisory committee. Thematic data analyses were carried out and followed an inductive, data-driven approach. RESULTS: Fifty-one individuals participated, representing 67% of eligible households. The thematic analysis revealed that food sharing, especially with family, was regarded as one of the most significant ways to adapt to food shortages. The majority of participants reported consuming traditional food (wild meats) and suggested that hunting, preserving and storing traditional food has remained very important. However, numerous barriers to traditional food acquisition were mentioned. Other coping strategies included dietary change, rationing and changing food purchasing patterns. In order to improve access to healthy foods, improving income and food affordability, building community capacity and engagement, and community-level initiatives were suggested. CONCLUSIONS: Findings point to the continued importance of traditional food acquisition and food sharing, as well as community solutions for food systems change. These data highlight that traditional and store-bought food are both part of the strategies and solutions participants suggested for coping with food insecurity. Public health policies to improve food security for FN populations are urgently needed. PMID- 23639144 TI - Repetitive and self-injurious behaviors: associations with caudate volume in autism and fragile X syndrome. AB - BACKGROUND: Following from previous work suggesting that neurobehavioral features distinguish fragile X and idiopathic variants of autism, we investigated the relationships between four forms of repetitive behavior (stereotypy, self-injury, compulsivity, ritual behavior) and caudate nuclei volume in two groups: boys with fragile X syndrome, a subset of whom met criteria for autism, and a comparison group of boys with idiopathic autism. METHODS: Bilateral caudate nuclei volumes were measured in boys aged 3 to 6 years with fragile X syndrome (n = 41), the subset of boys with fragile X syndrome and autism (n = 16), and boys with idiopathic autism (n = 30). Repetitive behaviors were measured using the Repetitive Behavior Scales-Revised. RESULTS: For boys with idiopathic autism, left caudate volume was modestly associated with self-injury, while both compulsive and ritual behaviors showed significant positive correlations with bilateral caudate nuclei volumes, replicating previous results. For boys with fragile X syndrome, there was no such association between caudate volume and compulsive behaviors. However, we did identify significant positive correlations between self-injury total scores and number of self-injury topographies with bilateral caudate nuclei volumes. CONCLUSIONS: These findings suggest a specific role for the caudate nucleus in the early pathogenesis of self-injurious behavior associated with both idiopathic autism and fragile X syndrome. Results further indicate that the caudate may be differentially associated with compulsive behavior, highlighting the utility of isolating discrete brain-behavior associations within and between subtypes of autism spectrum disorder. PMID- 23639146 TI - Assessment of cognitive domains during treatment with OROS methylphenidate in adolescents with ADHD. AB - AIM: To psychometrically assess cognitive domains in adolescents with ADHD during long-term open treatment with robust dosing of extended-release methylphenidate (OROS MPH). METHODS: Data were derived from a prospective clinical study of adolescent ADHD, employing the Cambridge Neuropsychological Test Automated Battery (CANTAB), before and after up to one year of treatment with OROS MPH. In the absence of placebo control, a similar age and gender group of youth without ADHD served as comparators. RESULTS: During the course of treatment with OROS MPH, ADHD youth's performance significantly improved across multiple CANTAB tasks, including spatial working memory, rapid visual processing, verbal recognition memory, set shifting, and inhibition/vigilance. ADHD subjects' scores in several CANTAB tasks, including spatial working memory, planning, and set shifting, were significantly more impaired at baseline compared to the non-ADHD comparison group; these significant differences were no longer seen at endpoint. CONCLUSIONS: Statistically significant improvements in multiple cognitive domains were observed in a sample of adolescents with ADHD over the course of 12 months of robust treatment with extended-release methylphenidate. Rigorous, monitored stimulant treatment may be associated with objectively determined cognitive benefits; however, practice effects in this open trial cannot be ruled out. Further study on this important topic is warranted. PMID- 23639145 TI - Details of a prospective protocol for a collaborative meta-analysis of individual participant data from all randomized trials of intravenous rt-PA vs. control: statistical analysis plan for the Stroke Thrombolysis Trialists' Collaborative meta-analysis. AB - RATIONALE: Thrombolysis with intravenous alteplase is both effective and safe when administered to particular types of patient within 4.5 hours of having an ischemic stroke. However, the extent to which effects might vary in different types of patient is uncertain. AIMS AND DESIGN: We describe the protocol for an updated individual patient data meta-analysis of trials of intravenous alteplase, including results from the recently reported third International Stroke Trial, in which a wide range of patients enrolled up to six-hours after stroke onset were randomized to alteplase vs. control. STUDY OUTCOMES: This protocol will specify the primary outcome for efficacy, specified prior to knowledge of the results from the third International Stroke Trial, as the proportion of patients having a 'favorable' stroke outcome, defined by modified Rankin Score 0-1 at final follow up at three- to six-months. The primary analysis will be to estimate the extent to which the known benefit of alteplase on modified Rankin Score 0-1 diminishes with treatment delay, and the extent to which it is independently modified by age and stroke severity. Key secondary outcomes include effect of alteplase on death within 90 days; analyses of modified Rankin Score using ordinal, rather than dichotomous, methods; and effects of alteplase on symptomatic intracranial hemorrhage, fatal intracranial hemorrhage, symptomatic ischemic brain edema and early edema, effacement and/or midline shift. DISCUSSION: This collaborative meta analysis of individual participant data from all randomized trials of intravenous alteplase vs. control will demonstrate how the known benefits of alteplase on ischemic stroke outcome vary across different types of patient. PMID- 23639147 TI - Spatial population structure of the Neotropical tiger catfish Pseudoplatystoma metaense: skull and otolith shape variation. AB - Using geometric morphometrics, the skull and otolith of tiger catfish Pseudoplatystoma metaense were analysed to identify population structure in tributaries of the Apure River (i.e. the Sarare, Caparo, Guanare, Portuguesa and San Carlos Rivers) in the Orinoco basin, Venezuela. The analyses show uniformity in skull and otolith shapes of P. metaense within and among four tributaries, with only the Caparo River showing significant differences. Within the Apure basin, the stock of P. metaense was differentiated through spawning, refuge and nursery areas. This study concludes that populations of P. metaense from each major tributary in the Orinoco basin should be considered as part of a metapopulation system for management purposes. Human disturbances in the catchment have directly reduced the spawning areas available to this species, decreased the total biomass and changed the spatial distribution of spawning areas. PMID- 23639148 TI - Fine-scale movements and habitat use of juvenile southern flounder Paralichthys lethostigma in an estuarine seascape. AB - Habitat use of juvenile southern flounder Paralichthys lethostigma was examined within a shallow estuarine seascape during June and July 2011 using acoustic telemetry. Fine-scale movement and habitat use of P. lethostigma was investigated with an acoustic positioning system placed in a seascape that varied in habitat type, physicochemical conditions and bathymetry. The use of different habitat types was examined with Euclidean distance-based analyses, and generalized additive models were used to determine the relative importance of habitat type relative to physicochemical conditions and bathymetry. Tracks of P. lethostigma ranged in distance between 1477 and 8582 m and speed was 4.2 +/- 1.1 m min-1 (mean +/- s.e.) for all P. lethostigma combined. Depth, slope and habitat type had the most influence on P. lethostigma occurrence and deep sandy areas with shallow slopes were used most frequently. In addition, depth use by P. lethostigma was influenced by tidal cycles, indicating habitat use varies temporally and is dynamic. Finally, temperatures <30.5 degrees C were used more than warmer waters within the study area. The results successfully identify movements by juvenile P. lethostigma, and indicate that definitions of essential habitats need to account for dynamics in habitat use. PMID- 23639149 TI - How does coarse gravel augmentation affect early-stage Chinook salmon Oncorhynchus tshawytscha embryonic survivorship? AB - Early-stage Chinook salmon Oncorhynchus tshawytscha embryos were incubated in artificial redds that mimicked hyporheic conditions in gravel-augmented habitat to assess survivorship. Two complementary experiments were conducted where units varied along gradients of (1) increasing interstitial flow velocity (0.05-2.50 cm s-1) in a uniformly coarse (particles >=22 mm) sediment mixture and (2) increasing sediment porosity with interstitial flow velocity held constant. Embryonic survivorship increased moderately along a gradient of interstitial flow velocity, while survivorship among units with varying sediment porosities was consistent. No evidence for flow-induced agitation and mortality was observed. Results suggest that high interstitial flow velocities may confer a moderate advantage for incubating salmonid embryos when conditions that typically reduce embryonic mortality (i.e. low concentrations of fine particles) are ideal. PMID- 23639150 TI - Reach and catchment-scale characteristics are relatively uninfluential in explaining the occurrence of stream fish species. AB - The objectives of this study were (1) to determine whether the presence or absence of prairie fishes can be modelled using habitat and biotic characteristics measured at the reach and catchment scales and (2) to identify which scale (i.e. reach, catchment or a combination of variables measured at both scales) best explains the presence or absence of fishes. Reach and catchment information from 120 sites sampled from 1999 to 2004 were incorporated into tree classifiers for 20 prairie fish species, and multiple criteria were used to evaluate models. Fewer than six models were considered significant when modelling individual fish occurrences at the reach, catchment or combined scale, and only one species was successfully modelled at all three scales. The scarcity of significant models is probably related to the rigorous criteria by which these models were evaluated as well as the prevalence of tolerant, generalist fishes in these stochastic and intermittent streams. No significant differences in the amount of reduced deviance, mean misclassification error rates (MER), and mean improvement in MER metrics was detected among the three scales. Results from this study underscore the importance of continued habitat assessment at smaller scales to further understand prairie-fish occurrences as well as further evaluations of modelling methods to examine habitat relationships for tolerant, ubiquitous species. Incorporation of such suggestions in the future may help provide more accurate models that will allow for better management and conservation of prairie fish species. PMID- 23639151 TI - Kinship analysis of brook trout Salvelinus fontinalis during their breeding migration. AB - Microsatellite markers were used to test whether groups of pre-spawning adult brook trout Salvelinus fontinalis from the same population and captured at the same location during their breeding migration comprised kin. Only weak evidence for kin associations was found at the onset of breeding: the proportion of kin captured at the same location was low and similar to the proportion found across all locations and the average relatedness of S. fontinalis captured at the same location was low. A dilution of kin associations from the feeding to breeding phase is hypothesized to stem from mainly natural mortality that reduces family size by the adult stage. The results illustrate the dynamic nature of kin associations between consecutive life stages, even within the same fish population. PMID- 23639152 TI - Age estimation and validation for South Pacific albacore Thunnus alalunga. AB - Validated estimates of age are presented for albacore Thunnus alalunga, sampled from a large part of the south-western Pacific Ocean, based on counts of annual opaque growth zones from transverse sections of otoliths. Counts of daily increments were used to estimate the location of the first opaque growth zone, which was completed before the first assumed birthday. The periodicity of opaque zones was estimated by marginal increment analysis and an oxytetracycline mark recapture experiment. Both validation methods indicated that opaque zones formed over the austral summer and were completed by autumn to winter (April to August). The direct comparison of age estimates obtained from otoliths and dorsal-fin spines of the same fish indicated bias, which was assumed to be due to poor increment clarity and resorption of early growth zones in spines, resulting in imprecise age estimates. As such, age estimates from otoliths are considered to be more accurate than those from spines for T. alalunga. This is consistent with results for a growing number of tropical and temperate tuna Thunnini species. It is recommend that validated counts of annual growth zones from sectioned otoliths is used as the preferred method for estimating age-based parameters for assessment and management advice for these important stocks. PMID- 23639153 TI - A one-step molecular biology method for simple and rapid detection of grass carp Ctenopharyngodon idella reovirus (GCRV) HZ08 strain. AB - Six reverse-transcription loop-mediated isothermal amplification (RT-LAMP) primers designed against conserved regions of segment 6 (s6) gene were used for the detection of grass carp Ctenopharyngodon idella reovirus (GCRV) HZ08 subtype. The entire amplification could be completed within 40 min at 62.3 degrees C. The RT-LAMP showed higher sensitivity than reverse-transcription polymerase chain reaction (RT-PCR). The RNA detection limit was 10 copies ul-1 for RT-LAMP assay and 100 copies ul-1 for conventional RT-PCR. In specificity tests, no cross reactivity was detected in other viruses from common aquatic animals. In addition, the reaction results can be visualized by using calcein fluorescent dye. Furthermore, a total of 86 samples were tested by RT-LAMP, RT-PCR and virus isolation. The results demonstrated that all 54 specimens identified as positive by virus isolation were also positive when detected by RT-LAMP. Seven out of 54 samples, however, were misidentified by RT-PCR. The RT-LAMP method is more accurate than conventional RT-PCR. The results indicate that RT-LAMP has potential as a simple and rapid diagnosis technique for the detection of GCRV HZ08 subtype infection. PMID- 23639154 TI - Spatial and temporal variations in otolith chemistry and relationships with water chemistry: a useful tool to distinguish Atlantic salmon Salmo salar parr from different natal streams. AB - Otolith elemental (Sr:Ca, Ba:Ca, Mn:Ca, Mg:Ca and Rb:Ca) and isotopic (87Sr:86Sr) profiles from several annual cohorts of juvenile Atlantic salmon Salmo salar were related to the physico-chemical characteristics (chemical signatures, flow rate, temperature and conductivity) of their natal rivers over an annual hydrological cycle. Only Sr:Ca, Ba:Ca and 87Sr:86Sr in otoliths were determined by their respective ratios in the ambient water. Sr:Ca ratios in stream waters fluctuated strongly on a seasonal basis, but these fluctuations, mainly driven by water flow regimes, were not recorded in the otoliths. Otolith Sr:Ca ratios remained constant during freshwater residency at a given site and were exclusively related to water Sr:Ca ratios during low flow periods. While interannual differences in otolith elemental composition among rivers were observed, this variability was minor compared to geographic variability and did not limit classification of juveniles to their natal stream. Success in discriminating fish from different sites was greatest using Sr isotopes as it remained relatively constant across years at a given location. PMID- 23639155 TI - Biological observations on the bristly catshark Bythaelurus hispidus from deep waters off the south-west coast of India. AB - Biological data are presented for the poorly known bristly catshark Bythaelurus hispidus based on specimens collected from the by-catch of the commercial deep sea shrimp trawl fishery operating in the Arabian Sea at depths of 200-500 m off the south-west coast of India. One hundred and sixty-two individuals, which ranged from 120 to 366 mm total length (L(T)), were collected for this study. Size-at-maturity (L50) for females and males was estimated at 252 and 235 mm L(T), respectively. The reproductive mode of B. hispidus was aplacental viviparity, which is the rarest reproductive mode within the Scyliorhinidae and is considered to be the most advanced of the three reproductive modes occurring within this family. Dietary analysis of stomach contents revealed B. hispidus feeds on a variety of prey, primarily fishes. PMID- 23639156 TI - Using remote underwater video to estimate freshwater fish species richness. AB - Species richness records from replicated deployments of baited remote underwater video stations (BRUVS) and unbaited remote underwater video stations (UBRUVS) in shallow (<1 m) and deep (>1 m) water were compared with those obtained from using fyke nets, gillnets and beach seines. Maximum species richness (14 species) was achieved through a combination of conventional netting and camera-based techniques. Chanos chanos was the only species not recorded on camera, whereas Lutjanus argentimaculatus, Selenotoca multifasciata and Gerres filamentosus were recorded on camera in all three waterholes but were not detected by netting. BRUVSs and UBRUVSs provided versatile techniques that were effective at a range of depths and microhabitats. It is concluded that cameras warrant application in aquatic areas of high conservation value with high visibility. Non-extractive video methods are particularly desirable where threatened species are a focus of monitoring or might be encountered as by-catch in net meshes. PMID- 23639157 TI - Morphological and molecular evidence for two new species of Tetragonopterus (Characiformes: Characidae) from central Brazil. AB - The combination of morphological and molecular data of Tetragonopterus species collected in the Rio Araguaia basin allows the recognition of two undescribed species that are presented in this article. These species are distinguished from their congeners (Tetragonopterus anostomus, Tetragonopterus argenteus, Tetragonopterus carvalhoi, Tetragonopterus chalceus and Tetragonopterus rarus) by characters related to the number and morphology of the teeth, the numbers of gill rakers on the upper and lower limbs of the first gill arch, the number of predorsal scales and the overall colour pattern. In addition, the analysis of mitochondrial DNA sequences identified an accentuated genetic distance between these two new species and their congeners. A discussion of the phylogenetic relationships within Tetragonopterus is provided. PMID- 23639158 TI - Analysis of body shape for differentiating among species of rajids. AB - This study sought to differentiate the species of skates encountered in Gulf St Vincent (GSV), South Australia using normalized elliptical Fourier analysis of body shape. Significant intraspecific variation was observed among whole body shapes. This was overcome by limiting subsequent analyses to the anterior snout region, where significant differences in shape were detected among the species examined and provided a high degree of classification success for the skates of GSV. More generally, this approach has the potential to provide a cost- and time efficient means of discrimination among species of skates. Further research is required to investigate the potentially confounding effects of sexual dimorphism and ontogenetic variation in growth to improve the efficacy of the body shape analysis of the skates and batoids species in general. In addition, this approach requires considerable development to facilitate implementation in a fishery setting. PMID- 23639159 TI - Contrasting patterns of morphological variation with dietary preferences in Micropogonias furnieri: insights from stable-isotope and digestive-trait analyses. AB - The dietary preferences of populations of whitemouth croaker Micropogonias furnieri, which commonly inhabit estuarine and oceanic environments of the south western Atlantic Ocean, were investigated using stable-isotope analysis and digestive traits, and compared with previous genetic and morphometric surveys of this species. Isotopic and C:N-derived data suggested that individuals from coastal lagoons are the most differentiated from the remaining localities surveyed. In contrast, the analysis of the digestive traits did not show the same differentiation pattern. The overall correlation between isotopic, molecular and morphological variations suggests that genetic and phenotypic differences among populations are accompanied by differential resource use, supporting the idea that selective forces could be playing an important role in population differentiation. PMID- 23639160 TI - Upstream effects of a reservoir on fish assemblages 45 years following impoundment. AB - Fish assemblage structure, rarefied species richness, species diversity and evenness of assemblages upstream of a reservoir in Oklahoma, U.S.A., were compared pre and post-impoundment as well as in contemporary collections from streams above and below the reservoir. There were significant shifts in assemblage structure between historical and contemporary collections above the reservoir but not between contemporary assemblages above and below the impoundment. Indicator species analysis revealed that the sand shiner Notropis stramineus and fathead minnow Pimephales promelas have declined, whereas largemouth bass Micropterus salmoides and western mosquitofish Gambusia affinis have increased in relative abundance in assemblages upstream of the impoundment. Species richness was lower in contemporary assemblages compared with historical assemblages. Furthermore, contemporary assemblages below the dam had lower species richness, diversity and evenness compared with contemporary collections above the dam. These results highlight the spatial and temporal extent of reservoirs altering fish assemblages upstream of impoundments. PMID- 23639161 TI - Genetic characterization and in vivo image analysis of novel zebrafish Danio rerio pigment mutants. AB - This study reports the isolation and characterization of a new type of transparent zebrafish Danio rerio mutant called pinky (pk), which has been visually isolated from a spontaneous mutation in a D. rerio colony. The pk larvae possess complex mutations affecting pigmentation because of missing pigment cells or a dramatic reduction in the chromatophore number. The pk displays a totally colourless phenotype and adult body transplant with no other obvious external morphological abnormalities, except for a red retina. The molecular analysis results in several candidate genes, hps1, ap3m2 and rabggta, implicated in the Hermansky-Pudlak syndrome (HPS) genes associated with HPS in pk. To demonstrate its applications of deep-tissue imaging, this study examines green fluorescent protein alone or with other fluorescent proteins to investigate their capability for using multilabelling purposes in live adult pk. In this study, pk is particularly valuable for tissue cell labelling and internal organogenesis studies because of its optical clarity in the adult body. PMID- 23639162 TI - Epinephelus moara: a valid species of the family Epinephelidae (Pisces: Perciformes). AB - This study documents the major external and internal morphological differences between Epinephelus bruneus and Epinephelus moara, and analyses the complete mitogenomes of both species. The partial cytochrome oxidase subunit I (coI) sequence divergence between E. bruneus and E. moara is significantly higher than specimens within the same species (P < 0.05). Analyses of gene flow (Nm = 0.02) and genetic differentiation (phist = 0.92995, P > 0.05) reveal reproductive isolation between E. bruneus and E. moara. These results support the hypothesis that E. moara is a valid species. Further molecular comparisons between E. bruneus and E. moara obtained in this study and a specimen identified in GenBank as E. bruneus from South Korea reveal that the latter is identical to E. moara rather than to E. bruneus. PMID- 23639163 TI - Diel activity patterns of the fish community in a temperate stream. AB - The diel activity patterns of fishes in a temperate New Brunswick stream were studied during the summer over 5 years. Young-of-the year Atlantic salmon Salmo salar and blacknose dace Rhinichthys atratulus were more active during the day than at night, whereas lake chub Couesius plumbeus, brook trout Salvelinus fontinalis and adult white suckers Catostomus commersonii were more active at night than during the day. Because fishes were as likely to be nocturnal as diurnal, the data suggest that more night-time sampling is needed to provide an unbiased view of fish community structure in temperate streams. PMID- 23639164 TI - Evidence of a recent decline in river lamprey Lampetra fluviatilis parasitism of a nationally rare whitefish Coregonus lavaretus: is there a diamond in the ruffe Gymnocephalus cernuus? AB - Lamprey-induced scarring of the nationally rare Coregonus lavaretus, a known host of a freshwater-resident population of European river lamprey Lampetra fluviatilis, was found to have declined precipitously since the establishment of several non-native fishes in Loch Lomond. Evidence presented in this study points to the possibility that L. fluviatilis in this lake may have altered its trophic ecology in response to the negative impact that non-native species, in particular ruffe Gymnocephalus cernuus, have had on their favoured host. PMID- 23639165 TI - The old trout Salmo trutta in the pond. AB - The last of 12 brown trout Salmo trutta stocked in a small pond in south-east Norway in 1979 were caught in July 2011. These fish represent a curiosity regarding longevity and growth pattern, and ageing from otoliths was consistent with the known life history of this specimen. Despite almost total stagnation in growth since the age of 16 years, the testes were fully developed. PMID- 23639167 TI - Prediction of biological form at the adult stage of brown trout Salmo trutta using morphological or colorimetric criteria in migrating juveniles. AB - To assess the correlation between four visual morphological types based on body colour and shape (fario trout, FT; shiny fario, SFT; presmolt trout, PST; typical smolt ST) of juvenile brown trout Salmo trutta during downstream spring migration and the biological form at the adult stage (river or sea), mark-recapture experiments were carried out over a period of 23 years. Evidence is provided that the visual SFT type is not a relevant one, while objective colorimetric measurements using a black basin are the best way to determine the morphological type in migrating juveniles. PMID- 23639166 TI - Reproductive success in a natural population of male three-spined stickleback Gasterosteus aculeatus: effects of nuptial colour, parasites and body size. AB - The effects of nuptial colour, parasites and body size on reproductive success were examined in a natural population of three-spined stickleback Gasterosteus aculeatus. Reproductive males were collected, with the contents of their nests, during the embryo-guarding stage from Lynne Lake (Cook Inlet, Alaska, U.S.A.), and nuptial colour, infection status and body size were recorded. Regression analysis revealed that male body size was the only predictor, of those measured, of reproductive success in nature. PMID- 23639168 TI - Inducible transgenic expression in the short-lived fish Nothobranchius furzeri. AB - This study demonstrates inducible transgenic expression in the exceptionally short-lived turquoise killifish Nothobranchius furzeri, which is a useful vertebrate model for ageing research. Transgenic N. furzeri bearing a green fluorescent protein (Gfp) containing construct under the control of a heat shock protein 70 promoter were generated, heat shock-induced and reversible Gfp expression was demonstrated and germline transmission of the transgene to the F1 and F2 generations was achieved. The availability of this inducible transgenic expression system will make the study of ageing-related antagonistically pleiotropic genes possible using this unique vertebrate model organism. PMID- 23639169 TI - Haematophagous feeding of newly metamorphosed European sea lampreys Petromyzon marinus on strictly freshwater species. AB - Approximately 6% of the freshwater living northern straight-mouth nase Pseudochondrostoma duriense in two Spanish rivers had attached post-metamorphic sea lamprey Petromyzon marinus. Minimum prey size was 16.1 cm fork length and 56.3 g mass. The condition factor of attacked P. duriense was 16% lower than that of unattacked conspecifics. PMID- 23639170 TI - Application of otolith mass and shape for discriminating scabbardfishes Aphanopus spp. in the north-eastern Atlantic Ocean. AB - The otolith was used to investigate the variability between Aphanopus carbo and Aphanopus intermedius inhabiting the north-eastern Atlantic Ocean. The results indicate a high degree of morphological affinity between species and areas; a noticeable metabolic change in the otolith shape was noted in the specimens of A. carbo, which may be related to migrations of individuals from shallow water (closer to the continental coast) to deeper water (archipelagos of Madeira and the Canary Islands). The results suggest a single population for both species in the north-eastern Atlantic Ocean, although not conclusively. PMID- 23639171 TI - First record of a bicephalic embryo of smalltail shark Carcharhinus porosus. AB - This study reports the first bicephalic embryo of smalltail shark Carcharhinus porosus, which was removed from a pregnant female in coastal waters of the tropical eastern Pacific Ocean. The observation suggested that although the individual's body was well formed, the malformation of the head would have affected it survival. PMID- 23639172 TI - Sexual dimorphism of vertical bar patterning in the South European toothcarp Aphanius fasciatus. AB - Sexual dimorphism of vertical bar patterning along the ontogenetic gradient was investigated in the South European toothcarp Aphanius fasciatus through the analysis of field samples collected from four different Venice Lagoon sites. Results suggested that, after controlling for site effect, vertical bar number and density were more correlated with size in females than in males, yielding a higher number of less spaced bars in females than in males. Results are discussed with regard to the interplay between natural and sexual selection acting on vertical bar dimorphism, suggesting a role of disruptive colouration in females and a more pronounced role of sexual selection in males. PMID- 23639173 TI - Brightness differences influence the evaluation of affective pictures. AB - We explored the possibility of a general brightness bias: brighter pictures are evaluated more positively, while darker pictures are evaluated more negatively. In Study 1 we found that positive pictures are brighter than negative pictures in two affective picture databases (the IAPS and the GAPED). Study 2 revealed that because researchers select affective pictures on the extremity of their affective rating without controlling for brightness differences, pictures used in positive conditions of experiments were on average brighter than those used in negative conditions. Going beyond correlational support for our hypothesis, Studies 3 and 4 showed that brighter versions of neutral pictures were evaluated more positively than darker versions of the same picture. Study 5 revealed that people categorised positive words more quickly than negative words after a bright picture prime, and vice versa for negative pictures. Together, these studies provide strong support for the hypotheses that picture brightness influences evaluations. PMID- 23639174 TI - Longitudinal analysis of cardiovascular risk parameters in women with a history of hypertensive pregnancy disorders: the Doetinchem Cohort Study. AB - OBJECTIVE: Women with hypertensive pregnancy disorders (HPD) are at increased risk of developing hypertension and cardiovascular disease later in life; however, it is not known how cardiovascular risk develops throughout life. We evaluated the longitudinal trends in cardiovascular risk factors in women after hypertensive pregnancy disorders compared with women with normotensive pregnancies. DESIGN AND POPULATION: All women of the Doetinchem Cohort Study (1987-91), a population-based cohort study, were included. METHODS: Women were examined (questionnaires and physical examination) four times at 5-year intervals. History of HPD was assessed from questionnaires. We compared 5-year changes in risk factors between women with and without HPD, by analysing longitudinal trends using generalised estimating equation analysis to estimate the effects of HPD and mean age, adjusting for treatment, body mass index (BMI), smoking and socio-economic status. MAIN OUTCOME MEASURES: Change over time in traditional cardiovascular risk factors, including systolic blood pressure (SBP) and diastolic blood pressure (DBP), BMI, total and high-density lipoprotein (HDL) cholesterol for women with and without a history of HPD. RESULTS: A total of 2703 women with normotensive pregnancies (mean age 40.5 years, SD 10.4) and 689 women with a history of HPD (mean age 38.4 years, SD 9.5) were included. Compared with normotensive women, in women with a history of HPD, SBP was 2.8 mmHg higher (95% CI 1.7-3.9), DBP was 2.3 mmHg higher (95% CI 1.6-3.0) and BMI was 0.7 kg/m(2) higher (95% CI 0.4-1.1). Total cholesterol (-0.05; 95% CI -0.1 to 0.0) and HDL cholesterol (0.02; 95% CI -0.0 to 0.1) were similar in both groups. No difference in annual change in blood pressure or in the other risk factors was observed between women with and without a history of HPD. CONCLUSION: Women with a history of HPD have higher levels of SBP, DBP and BMI compared with normotensive women, but the increase with ageing is similar in both groups. PMID- 23639175 TI - In vitro muscle contracture investigations on the malignant hyperthermia like episodes in myotonia congenita. AB - BACKGROUND: A common form of congenital myotonia, myotonia congenita (MC), is caused by mutations in the skeletal muscle Cl(-) channel gene type 1 (CLCN1). Due to the reduced Cl(-) conductance of the mutated channels, the patients may develop generalized muscle rigidity and hypermetabolism during general anaesthesia. The clinical symptoms resemble malignant hyperthermia (MH), which may lead to mistreatment of the patient. METHODS: Muscle specimens of ADR mice (an animal model of MC) as well as of human individuals were used and exposed to potent ryanodine receptor type 1 (RyR1) activators and increasing K(+) concentration. Muscle force was monitored by a standardized diagnostic method for MH, the so-called in vitro contracture test. RESULTS: Neither muscle of ADR mice nor MC muscle (murine and human myotonic muscle) showed pathological contractures after exposure to the potent RyR1 agonists caffeine and halothane. Increasing concentrations of K(+) had a dose-dependent preventive effect on myotonic stiffness. CONCLUSION: We conclude that the adverse anaesthetic MH-like episodes observed in MC patients do not primarily originate from an altered Ca(2+) release in skeletal muscle. In MC muscle, this hypermetabolism is facilitated by a (pharmacologically induced) sustained depolarization due to an instable membrane potential. The in vitro results suggest that these patients benefit from tight K(+) monitoring because of the membrane potential stabilizing effect of K(+) . PMID- 23639176 TI - Study of zalema grape pomace: phenolic composition and biological effects in Caenorhabditis elegans. AB - The phenolic composition of the extractable fraction of Zalema grape pomace has been analyzed by HPLC-DAD-MS and consisted of mainly flavanols and flavonols (122.75 and 23.11 mg/100 g dry pomace, respectively). The antioxidant activity has been determined by in vitro FRAP, ABTS, and ORAC assays (11.7, 34.9, and 63.6 mmol of Trolox equivalents (TE) per 100 g of dry pomace, respectively) and in vivo using the model organism Caenorhabditis elegans . Cultivation of C. elegans in media containing 100 MUg/mL dry pomace extract increased the survival of worms submitted to thermally induced oxidative stress, whereas a decrease in the rate of worm survival was found for 300 MUg/mL extract. Interestingly, the levels of reactive oxygen species (ROS) were significantly decreased in stressed worms treated with the pomace extract at the two concentration levels. Further studies are required to explain this unexpected behavior, as well as to determine the compounds and mechanisms involved in the observed effects. PMID- 23639177 TI - Utility of knowledge, attitude, and practice survey, and prevalence of dental caries among 11- to 13-year-old children in an urban community in India. AB - BACKGROUND: The school oral health education program is believed to be a cost effective method for promoting oral health. The KAP (knowledge-attitude-practice) model of oral health education is often the foundation of most health education programs. OBJECTIVES: To assess the existing knowledge, attitude, and oral health care practices among 11- to 13-year-old children and the association of knowledge with attitude, oral health care practices, and dental caries prevalence. DESIGN: Cross-sectional design, involving 858 children studying in class seven at various schools in the city of Mangalore, India. The children were selected using stratified random sampling method. Prevalence of dental caries was determined using decayed, missing, and filled permanent teeth (DMFT) index. A self administered questionnaire on self-care practices in oral health, knowledge, and attitude toward oral health care was filled by children. The association of different variables with knowledge was analyzed using binary logistic regression analysis. RESULTS: The dental caries prevalence was 59.4%, and 54.5% had low knowledge. They lacked knowledge regarding use of fluoridated toothpaste and did not use them. Children with low knowledge had significantly higher odds of having DMFT >= 1, not using fluoridated toothpaste, and being afraid of going to the dentist due to possible pain. There was no association of other oral health care practices and attitudes with knowledge. CONCLUSION: Oral health care practices and attitudes are not fully explained by knowledge, and other models of health education need to be considered. PMID- 23639178 TI - Routine vaccination coverage in low- and middle-income countries: further arguments for accelerating support to child vaccination services. AB - BACKGROUND AND OBJECTIVE: The Expanded Programme on Immunization was introduced by the World Health Organization (WHO) in all countries during the 1970s. Currently, this effective public health intervention is still not accessible to all. This study evaluates the change in routine vaccination coverage over time based on survey data and compares it to estimations by the WHO and United Nations Children's Fund (UNICEF). DESIGN: Data of vaccination coverage of children less than 5 years of age was extracted from Demographic and Health Surveys (DHS) conducted in 71 low- and middle-income countries during 1986-2009. Overall trends for vaccination coverage of tuberculosis, diphtheria, tetanus, pertussis, polio and measles were analysed and compared to WHO and UNICEF estimates. RESULTS: From 1986 to 2009, the annual average increase in vaccination coverage of the studied diseases ranged between 1.53 and 1.96% units according to DHS data. Vaccination coverage of diphtheria, tetanus, pertussis, polio and measles was all under 80% in 2009. Non-significant differences in coverage were found between DHS data and WHO and UNICEF estimates. CONCLUSIONS: The coverage of routine vaccinations in low- and middle-income countries may be lower than that previously reported. Hence, it is important to maintain and increase current vaccination levels. PMID- 23639179 TI - A framework for stakeholder identification in concept mapping and health research: a novel process and its application to older adult mobility and the built environment. AB - BACKGROUND: Stakeholders, as originally defined in theory, are groups or individual who can affect or are affected by an issue. Stakeholders are an important source of information in health research, providing critical perspectives and new insights on the complex determinants of health. The intersection of built and social environments with older adult mobility is an area of research that is fundamentally interdisciplinary and would benefit from a better understanding of stakeholder perspectives. Although a rich body of literature surrounds stakeholder theory, a systematic process for identifying health stakeholders in practice does not exist. This paper presents a framework of stakeholders related to older adult mobility and the built environment, and further outlines a process for systematically identifying stakeholders that can be applied in other health contexts, with a particular emphasis on concept mapping research. METHODS: Informed by gaps in the relevant literature we developed a framework for identifying and categorizing health stakeholders. The framework was created through a novel iterative process of stakeholder identification and categorization. The development entailed a literature search to identify stakeholder categories, representation of identified stakeholders in a visual chart, and correspondence with expert informants to obtain practice based insight. RESULTS: The three-step, iterative creation process progressed from identifying stakeholder categories, to identifying specific stakeholder groups and soliciting feedback from expert informants. The result was a stakeholder framework comprised of seven categories with detailed sub-groups. The main categories of stakeholders were, (1) the Public, (2) Policy makers and governments, (3) Research community, (4) Practitioners and professionals, (5) Health and social service providers, (6) Civil society organizations, and (7) Private business. CONCLUSIONS: Stakeholders related to older adult mobility and the built environment span many disciplines and realms of practice. Researchers studying this issue may use the detailed stakeholder framework process we present to identify participants for future projects. Health researchers pursuing stakeholder-based projects in other contexts are encouraged to incorporate this process of stakeholder identification and categorization to ensure systematic consideration of relevant perspectives in their work. PMID- 23639180 TI - High genomic similarity between European type hepatitis E virus subgenotype 3e strains isolated from an acute hepatitis patient and a wild boar in Mie, Japan. AB - A 67-year-old male living in Tsu city, Mie prefecture, Japan was referred to our hospital for further examination of acute liver injury and was diagnosed as having clinical hepatitis E virus (HEV) infection in January 2010. The HEV strain (HE-JA11-1701) isolated from the patient belonged to genotype 3 and European-type subgenotype 3e. It was presumed that the patient had been infected from a wild boar (Sus scrofa leucomystax) because he consumed meat/viscera from a wild boar that he had captured himself as a hunter approximately 2 months before disease onset. A specimen of the boar meat/viscera that the patient had ingested was not available. However, the HE-JA11-1701 strain was 99.8% identical within the 412 nucleotide sequence of the open reading frame 2 region to a HEV strain (JBOAR012 Mie08) that had been recovered from a wild boar captured near the patient's hunting area in 2008. A phylogenetic analysis confirmed that the two HEV strains had a close genetic relationship and were segregated into subgenotype 3e, supported by a high bootstrap value of 99%. Of note, the HE-JA11-1701 and JBOAR012-Mie08 strains were remotely related to the 3e strains reported in Japan and European countries, with a nucleotide difference of 7.9-13.9%, reinforcing the uniqueness of the 3e strains obtained in the present study. These results strongly support our speculation that the patient developed acute hepatitis E via consumption of HEV-infected boar meat/viscera. Genetic analyses of HEV strains are useful for tracing infectious sources in sporadic cases of acute hepatitis E. PMID- 23639181 TI - Analysis of multiple phenotypes in genome-wide genetic mapping studies. AB - BACKGROUND: Complex traits may be defined by a range of different criteria. It would result in a loss of information to perform analyses simply on the basis of a final clinical dichotomized affected / unaffected variable. RESULTS: We assess the performance of four alternative approaches for the analysis of multiple phenotypes in genetic association studies. We describe the four methods in detail and discuss their relative theoretical merits and disadvantages. Using simulation we demonstrate that PCA provides the greatest power when applied to both correlated phenotypes and with large numbers of phenotypes. The multivariate approach had low type I error only with independent phenotypes or small numbers of phenotypes. In this study, our application of the four methods to schizophrenia data provides converging evidence of the relative performance of the methods. CONCLUSIONS: Via power analysis of simulated data and testing of experimental data, we conclude that PCA, creating one variable based on a linear combination of all the traits, performs optimally. We propose that our comparison will provide insight into the properties of the methods and help researchers to choose appropriate strategy in future experimental studies. PMID- 23639182 TI - Overdamped dynamics of folded protein domains within a locally harmonic basin using coarse graining based on a partition of compact flexible clusters. AB - A coarse-graining method based on the partitioning of atoms into compact flexible clusters is used to formulate the dynamics of the nonequilibrium response of a protein to ligand dissociation. The alpha-carbon positions are used as the degrees of freedom. The net stiffness between each pair of neighboring alpha carbons is calculated for the quasi-static, overdamped regime within the harmonic (quadratic potential energy surface) using the equivalent stiffness matrix of the network of atoms occupying the intervening space within the locally interacting region. This localized approach realizes a divide and conquer strategy that results in a substantial reduction in computational complexity while accurately predicting relaxations under general loading conditions. A close correlation between the shapes and time scales of the relaxation curves of the coarse-grained and all-atom instances of two medium-sized proteins, T4 lysozyme and ferric binding protein (each of which having known apo and holo structures), was observed for the holo to the apo transitions. Furthermore, for both proteins the dominant modes of motion and the decay rates of the temporal relaxation profiles monitoring the separation distance between select amino acid pairs were found to be nearly identical when calculated on the coarse-grained and all-atom scales. PMID- 23639183 TI - Dielectric breakdown in silica-amorphous polymer nanocomposite films: the role of the polymer matrix. AB - The ultimate energy storage performance of an electrostatic capacitor is determined by the dielectric characteristics of the material separating its conductive electrodes. Polymers are commonly employed due to their processability and high breakdown strength; however, demands for higher energy storage have encouraged investigations of ceramic-polymer composites. Maintaining dielectric strength, and thus minimizing flaw size and heterogeneities, has focused development toward nanocomposite (NC) films; but results lack consistency, potentially due to variations in polymer purity, nanoparticle surface treatments, nanoparticle size, and film morphology. To experimentally establish the dominant factors in broad structure-performance relationships, we compare the dielectric properties for four high-purity amorphous polymer films (polymethyl methacrylate, polystyrene, polyimide, and poly-4-vinylpyridine) incorporating uniformly dispersed silica colloids (up to 45% v/v). Factors known to contribute to premature breakdown-field exclusion and agglomeration-have been mitigated in this experiment to focus on what impact the polymer and polymer-nanoparticle interactions have on breakdown. Our findings indicate that adding colloidal silica to higher breakdown strength amorphous polymers (polymethyl methacrylate and polyimide) causes a reduction in dielectric strength as compared to the neat polymer. Alternatively, low breakdown strength amorphous polymers (poly-4 vinylpyridine and especially polystyrene) with comparable silica dispersion show similar or even improved breakdown strength for 7.5-15% v/v silica. At ~15% v/v or greater silica content, all the polymer NC films exhibit breakdown at similar electric fields, implying that at these loadings failure becomes independent of polymer matrix and is dominated by silica. PMID- 23639184 TI - Gender difference in antidepressant-related sexual dysfunction in Taiwan. AB - OBJECTIVE: Sexual dysfunction accompanied by depression may be altered by antidepressants. The effects of antidepressants on sexual dysfunction among males and females remain to be investigated. METHODS: Three groups of subjects, drug free patients with depression (N=125), medicated patients with depression (N=145) and healthy volunteers (N=255), were recruited. A Chinese version of the Changes in Sexual Functioning Questionnaire was employed to assess sexual function as the primary outcome. RESULTS: Drug-free depressed females and medicated depressed males had more sexual dysfunction than healthy controls. The desire for sexual behaviors among healthy females and medicated depressed females was higher than that of drug-free depressed females. CONCLUSION: Depression and antidepressants may have different impacts on the sexual function of males and females. PMID- 23639185 TI - Pain conditions among veterans with schizophrenia or bipolar disorder. AB - OBJECTIVE: The purpose of this study was to assess the rates of chronic, noncancer pain conditions in patients with schizophrenia or bipolar disorder within the Veterans Health Administration (VHA) System. METHOD: This cross sectional study used administrative data extracted from VHA treatment records of all individuals receiving VHA services in fiscal year 2008 (N=5,195,551). The associations between severe psychiatric disorders (schizophrenia and bipolar disorder) and chronic pain (arthritis, back pain, chronic pain, migraine, headache, psychogenic and neuropathic) were evaluated using a series of logistic regression analyses. RESULTS: Veterans with schizophrenia [odds ratio (OR)=1.21] and bipolar disorder (OR=2.17) were significantly more likely to have chronic pain overall relative to veterans without these psychiatric conditions. These associations were slightly lower than for the association between depression and pain in this sample (OR=2.61). The highest associations between specific psychiatric diagnosis and pain condition were found with chronic pain, headache and psychogenic pain. CONCLUSIONS: Noncancer pain conditions occur in elevated rates among patients with schizophrenia and bipolar disorder. Future research could further examine possible barriers to adequate pain treatment among people with serious mental illness, as well as the extent to which chronic pain might impact mental health recovery. PMID- 23639186 TI - Association between anxiety, health-related quality of life and functional impairment in primary care patients with chronic pain. AB - OBJECTIVE: Anxiety and chronic pain are prevalent and frequently co-occur. Our purpose was to examine the association between anxiety, health-related quality of life (HRQL) and functional impairment in primary care patients with chronic musculoskeletal pain. METHODS: Data were drawn from baseline interviews of the 250 primary care patients enrolled in the Stepped Care to Optimize Pain care Effectiveness trial. Validated measures were used to determine the proportion of patients screening positive for five common anxiety disorders: generalized anxiety, panic, social anxiety, posttraumatic stress and obsessive-compulsive disorder. Bivariate analyses examined associations between the type and number of anxiety disorders for which patients screened positive and representative pain, psychological and other HRQL outcomes. Multivariable models controlling for major depression and other covariates examined the association between the number of screen-positive anxiety conditions and functional impairment in psychological [SF 12 mental component summary (MCS) score], pain [Brief Pain Inventory (BPI) interference score] and work (disability days) domains. RESULTS: One hundred fourteen (45%) patients screened positive for at least one anxiety disorder and, compared to the 136 screen-negative patients, had significantly worse scores across multiple pain, psychological and other HRQL domains. Substantial impairment was seen for each of the five screen-positive anxiety conditions and progressively worsened as the number of conditions increased from one (n=54) to two (n=26) to >=3 (n=34). The number of screen-positive anxiety conditions was strongly associated (P<.0001) with worse BPI interference and MCS scores and more disability days in models adjusting for age, sex and medical comorbidity. After further adjusting for major depression, associations were attenuated but remained significant for BPI interference (P<.0001) and MCS (P=.018) and marginally significant for disability days (P=.062). CONCLUSION: Nearly half of primary care patients with chronic pain screen positive for one or more anxiety disorders, which in turn are adversely associated with impairment across multiple domains of HRQL. Detecting and treating anxiety may be an important component of pain management. PMID- 23639187 TI - Amelioration of palmitate-induced insulin resistance in C2C12 muscle cells by rooibos (Aspalathus linearis). AB - Increased levels of free fatty acids (FFAs), specifically saturated free fatty acids such as palmitate are associated with insulin resistance of muscle, fat and liver. Skeletal muscle, responsible for up to 80% of the glucose disposal from the peripheral circulation, is particularly vulnerable to increased levels of saturated FFAs. Rooibos (Aspalathus linearis) and its unique dihydrochalcone C glucoside, aspalathin, shown to reduce hyperglycemia in diabetic rats, could play a role in preventing or ameliorating the development of insulin resistance. This study aims to establish whether rooibos can ameliorate experimentally-induced insulin-resistance in C2C12 skeletal muscle cells. Palmitate-induced insulin resistant C2C12 cells were treated with an aspalathin-enriched green (unfermented) rooibos extract (GRE), previously shown for its blood glucose lowering effect in vitro and in vivo or an aqueous extract of fermented rooibos (FRE). Glucose uptake and mitochondrial activity were measured using 2-deoxy-[3H] D-glucose, MTT and ATP assays, respectively. Expression of proteins relevant to glucose metabolism was analysed by Western blot. GRE contained higher levels of all compounds, except the enolic phenylpyruvic acid-2-O-glucoside and luteolin-7 O-glucoside. Both rooibos extracts increased glucose uptake, mitochondrial activity and ATP production. Compared to FRE, GRE was more effective at increasing glucose uptake and ATP production. At a mechanistic level both extracts down-regulated PKC theta activation, which is associated with palmitate induced insulin resistance. Furthermore, the extracts increased activation of key regulatory proteins (AKT and AMPK) involved in insulin-dependent and non-insulin regulated signalling pathways. Protein levels of the glucose transporter (GLUT4) involved in glucose transport via these two pathways were also increased. This in vitro study therefore confirms that rooibos can ameliorate palmitate-induced insulin resistance in C2C12 skeletal muscle cells. Inhibition of PKC theta activation and increased activation of AMPK and AKT offer a plausible mechanistic explanation for this ameliorative effect. PMID- 23639188 TI - Antiangiogenetic effects of anthranoids from Alternaria sp., an endophytic fungus in a Thai medicinal plant Erythrina variegata. AB - Endophytic fungi are known as a prolific source for the discovery of structurally interesting and biologically active secondary metabolites, some of which are promising candidates for drug development. In the present study, three anthranoids were isolated from an Alternaria sp. endophytic fungus and evaluated for their antiangiogenic activity in a rat aortic sprouting assay, an ex vivo model of angiogenesis. Of these three compounds, altersolanol (2) was further characterized and found to show a promising activity in ex vivo, in vitro and in vivo angiogenesis asssays. Using human umbilical vein endothelial cells as an in vitro model, the angiogenic effect of 2 was found to occur via suppression of all three main functions of endothelial cells, namely proliferation, tube formation and migration. PMID- 23639189 TI - Lippia alba (Mill.) N. E. Brown hydroethanolic extract of the leaves is effective in the treatment of migraine in women. AB - BACKGROUND: There is no universally accepted and effective prophylaxis of migraine headache episodes. We aimed to investigate the effects of Lippia alba (Mill.) N. E. Brown (chemotype geranial-carvenone) in the treatment of migraine patients. METHODS: Twenty-one women were enrolled in a prospective, phase 2, non controlled cohort study to orally receive hydroethanolic extract of L. alba leaves. Symptom intensity and impact were assessed using MIDAS and HIT-6 instruments before and after 2 months of treatment. RESULTS: We observed a significant decrease on HIT-6 total score, as well as MIDAS number of missed days, number of headache days, and pain intensity. More than 70% of patients experienced a minimum 50% reduction on pain frequency. CONCLUSIONS: Treatment with L. alba leaves (geranial-carvenone) hydroethanolic extract is a cheap, safe, widely available, highly effective therapy to reduce both the intensity and the frequency of headache episodes of women with migraine. ClinicalTrials.gov Identifier: NCT01259947. PMID- 23639190 TI - Mikania laevigata: chemical characterization and selective cytotoxic activity of extracts on tumor cell lines. AB - Cancer is the second major cause of mortality worldwide, losing only to cardiovascular disease. Nowadays, around 50% of antineoplastic drugs were discovered and isolated by indications of plants in folk medicine. In Brazilian flora there are many species of plants which have great therapeutic importance, highlighting the Mikania laevigata (Asteraceae) that has been used for their valuable properties, especially in the respiratory tract. In the present study, the compounds of M. laevigata extracts were characterized by High Resolution Mass Spectrometry (HRMS) and Gas Chromatography with Mass analysis (GC/MS-EI). Therefore, the presence of some compounds with promising biological properties as antitumor activity was detected. Coumarin (1,2-benzopyrone) was previously reported as responsible for some biological activities of this plant species. Here, the extracts were evaluated by their cytotoxic activity against tumor (Hep 2, HeLa) and non tumor (MRC-5) cell lines, presenting significant inhibitory activity of cell growth in all extracts analyzed, chloroform, ethyl acetate, hexane, ethanol, which is related to its chemical composition. From the four different extracts here tested, two of them, hexane and ethanol, presented a clear selectivity against both tumor cells lines investigated. This can be explained by variances and increase of phenolic compounds in the ethanol fraction and an association of molecules with coumarin found in the hexane fraction. PMID- 23639191 TI - Involvement of p-CREB and phase II detoxifying enzyme system in neuroprotection mediated by the flavonoid calycopterin isolated from Dracocephalum kotschyi. AB - PURPOSE: There is an increasing amount of experimental evidence that oxidative stress has a central role in the neuropathology of neurodegenerative diseases. It has been suggested that the loss of cell function results from the increased oxidative damage to proteins and DNA. Herein, we investigated the effect of a natural neuroprotective flavonoid, calycopterin, on H2O2-induced disruption of phase II detoxifying enzyme system and cAMP response element binding protein (CREB) phosphorylation. METHODS: PC12 cells were treated with 25, 50 and 100 MUM of calycopterin for 3h, followed by adding H2O2 (150 MUM) for 24 h. The extent of apoptosis was assessed by comet assay. The level of phosphorylated CREB, nuclear factor erythroid 2-related factor 2 (Nrf2), glutamylcysteine synthetase (gamma GCS) and heme oxygenase 1 (HO-1) were measured by western blot method. The concentration of glutathione (GSH) was determined in whole cell lysate using dithionitrobenzoic acid method. Superoxide dismutase (SOD) activity was measured by colorimetric assay. RESULT: Morphological analysis of protection induced by calycopterin, determined by comet assay, showed that calycopterin reduced DNA in tail. We found that H2O2 decreased mitochondrial membrane potential (MMP), while, calycopterin prevented this decrease in MMP in presence of H2O2. In H2O2-treated cells, calycopterin also suppressed cytochrome C release to cytosol that is necessary for maintaining mitochondrial homeostasis in survived cells. Moreover, calycopterin, in presence of H2O2 inhibited the decrease caused by oxidative stress in stress-sensing transcription factors, CREB and Nrf2, which play an important role in antioxidant capacity of the cell. There was also an increase in gamma-GCS and HO-1 levels in calycopterin pretreated cells. In the presence of H2O2, calycopterin inhibited decrease in GSH level and SOD activity. CONCLUSION: We provided documentation of neuroprotective effect of a natural flavone, calycopterin, against H2O2-induced oxidative stress in differentiated PC12 cells by modulating the level of CREB phosphorylation and Nrf2 pathway. PMID- 23639192 TI - Puerarin stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation. AB - Puerarin, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that puerarin increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. Puerarin promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERalpha and ERbeta. Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis. PMID- 23639193 TI - Atypical generalized eruptive histiocytosis clonally related to chronic myelomonocytic leukemia with loss of Y chromosome. AB - Generalized eruptive histiocytosis, described in 1963 by Winklemann and Muller, is a reactive, self-healing form of non-Langerhans histiocytosis. Rare cases of atypical generalized eruptive histiocytosis have been reported in patients with hematopoietic malignancy, but the biological relationship between the two disorders is not known. We report an 84-year-old man with chronic myelomonocytic leukemia who presented with coalescing erythematous papules and plaques on the posterior neck, ear and lower lip, followed by development of blast crisis. Skin biopsy revealed a thick band-like dermal infiltrate of cells that exhibited morphologic features of macrophages or histiocytes and prominent elastolytic phagocytosis. These cells demonstrated a mature immunophenotype, expressing CD14 and CD68, with partial expression of CD13 but not CD1a, CD43, CD56, CD123, Langerin, or S-100 protein. Karyotype and fluorescence in situ hybridization analyses showed loss of the Y chromosome in bone marrow and skin specimens, providing evidence of a clonal relationship between the cutaneous eruption and the underlying chronic myelomonocytic leukemia. The presence of the same clone in skin and bone marrow specimens from our patient supports the possibility that atypical generalized eruptive histiocytosis is a marker for underlying hematopoietic malignancy. Discovery of additional cases may shed further light on the pathogenesis of this rare entity. PMID- 23639194 TI - In vivo evaluation of CaO-SiO2-P2O5-B2O3 glass-ceramics coating on Steinman pins. AB - Surface coating using ceramics improves the bone bonding strength of an implant. We questioned whether a new type of glass-ceramics (BGS-7) coating (CaO-SiO2 -P2 O5 -B2 O3 ) would improve the osseointegration of Steinman pins (S-pins) both biomechanically and histomorphometrically. An in vivo study was performed using rabbits by inserting three S-pins into each iliac bone. The pins were 2.2-mm S pins with a coating of 30-MUm-thick BGS-7 and 550-nm-thick hydroxyapatite (HA), as opposed to an S-pin without coating. A tensile strength test and histomorphometrical evaluation was performed. In the 2-week group, the BGS-7 implant showed a significantly higher tensile strength than the S-pin. In the 4- and 8-week groups, the BGS-7 implants had significantly higher tensile strengths than the S-pins and HA implants. The histomorphometrical study revealed that the BGS-7 implant had a significantly higher contact ratio than the S-pin and HA implants in the 4-week group. The biomechanical and histomorphometrical tests showed that the BGS-7 coating had superior bone bonding properties than the groups without the coating from the initial stage of insertion. The BGS-7 coating of an S-pin will enhance the bone bonding strength, and there might also be an advantage in human bone bonding. PMID- 23639195 TI - Summary of papers presented at the 2012 seventh international cough symposium. AB - Twenty six papers were presented as posters in the Seventh International Symposium on Cough; 12 papers were presented in the Basic Science of Cough session, and 14 papers presented in the Clinical Science of Cough session. These papers explored a wide spectrum of cough-related areas including pathophysiological mechanisms, treatment and detection of cough, and symptom assessment and perception, and were grouped into several general themes for facilitate the discussion. Studies presented in these posters have provided new information that should improve our knowledge on the basic physiology and pharmacology of cough, and the peripheral and central neural mechanisms involved in the generation of the cough motor pattern. In addition, in the clinical science section, studies reporting potential new anti-tussive agents and further characterisation of cough symptoms and perception have provided a base for the fruitful strategies for the development of novel anti-tussive therapies and cough management. PMID- 23639197 TI - Spatial distribution of nests constrains the strength of sexual selection in a warbler. AB - In socially monogamous species, extra-pair paternity may increase the strength of intersexual selection by allowing males with preferred phenotypes to monopolize matings. Several studies have found relationships between male signals and extra pair mating, but many others fail to explain variation in extra-pair mating success. A greater appreciation for the role that ecological contingencies play in structuring behavioural processes may help to reconcile contradictory results. We studied extra-pair mating in a spatial context in the common yellowthroat (Geothlypis trichas), a territorial wood warbler. Over the course of 6 years, we observed 158 breeding attempts by 99 males, resulting in a total of 369 nests and 520 sampled nestlings. The spatial distribution of territories varied greatly, with males having between 0 and 10 close neighbours and between three and 39 neighbouring nestlings close enough to represent extra-pair siring opportunities. Both within-pair and extra-pair reproductive success increased with breeding density, but the opportunity for sexual selection and strength of selection varied with density. Total variance in reproductive success was highest at low density and was mostly explained by variation in within-pair success. In contrast, at high density, both within-pair and extra-pair successes contributed substantially to variance in reproductive success. The relationships between plumage and extra-pair mating also varied by density; plumage was under strong sexual selection via extra-pair mating success at high density, but no selection was detected at low density. Thus, ecological factors that structure social interactions can drive patterns of sexual selection by facilitating or constraining the expression of mating preferences. PMID- 23639199 TI - In vitro effects of extracts and purified tannins of sainfoin (Onobrychis viciifolia) against two cattle nematodes. AB - Sainfoin (Onobrychis viciifolia) is a condensed tannin (CT)-containing legume and has anthelmintic potential against gastrointestinal nematodes of ruminants. This study investigated in vitro effects of acetone/water extracts and derived CT fractions from different types of sainfoin (i.e. accessions) against larvae of Cooperia oncophora and Ostertagia ostertagi by applying the larval feeding inhibition assay (LFIA). Seven sainfoin accessions were extracted and tested with L1 larvae at 10 and 40 MUg extract/ml. In addition, CT in extracts from 4 accessions were fractionated according to polymer size and tested by LFIA at two concentrations (2 and 10 MUg CT fraction/ml). All sainfoin extracts caused significant inhibition of L1-feeding of both C. oncophora and O. ostertagi with varying intensity compared to the control (phosphate buffered saline). For both nematode species the in vitro effect was positively correlated with CT content in the extracts, but not with any of the structural CT parameters. In contrast, the 16 CT fractions revealed significant correlations between in vitro effect and CT content, polymer size (mean degree of polymerisation, mDP) and monomeric composition (prodelphinidin percentage, % PD). These differences between crude extracts and purified fractions may stem from the fact that extracts contain complex CT mixtures, which may mask and thus suppress CT structural effects. This study provides the first indication that, apart from CT and % PD content, polymer size also contributes to anthelmintic activity of CTs. The results, therefore, suggest that the inter-accession variability in CT content and composition needs to be taken into account in future plant breeding programmes which seek to enhance the anthelmintic properties of sainfoin. PMID- 23639198 TI - Effects of Trypanosoma brucei infection and diminazene aceturate therapy on testicular morphology and function of Nigerian local dogs. AB - The effects of Trypanosoma brucei infection on testicular morphology and function and the changes associated with treatment of infected dogs with diminazene aceturate were studied using fifteen Nigerian adult male dogs. The dogs were randomly assigned into three groups A, B and C consisting of five dogs each. Groups A and B were infected with 1 * 10(6) trypanosomes and group C was the uninfected control. Following infection, parasitaemia levels were monitored daily whereas the rectal temperature, body weight, packed cell volume, scrotal circumference and serum testosterone levels were monitored weekly. At parasitaemia peak, dogs in group A were orchidectomised while dogs in group B were treated with 7.0mg/kg body weight of diminazene aceturate (DA). Dogs in groups B and C were later orchidectomised on day 73 of the experiment. The harvested testes and epididymides were weighed and the epididymal sperm reserves of all the dogs determined. Also the sperm quality (mass activity, sperm motility and sperm morphology) were determined. The testes were sectioned after processing and studied histomorphologically. Acute trypanosomosis was observed following infection. The low serum testosterone levels observed from day 14 post infection (pi) gradually improved following treatment. Testicular weight, epididymal weight and sperm quality were significantly low (p<0.05) in the infected dogs when compared to the control group but gradually improved following treatment. Histomorphological studies revealed testicular degeneration characterized by depopulation of seminiferous tubules and depletion of spermatogenic cells in dogs of group A whereas the tissue sections of the testes of dogs in group B were similar to those of the control group. It was therefore concluded that infection of dogs with T. brucei adversely affected testicular morphology and function. Treatment with diminazene aceturate reversed the reproductive abnormalities caused by the parasite. PMID- 23639200 TI - Outcomes with split liver transplantation are equivalent to those with whole organ transplantation. AB - BACKGROUND: Split liver transplantation is an excellent option for expansion of the donor organ pool. However, reports of increased morbidity in split liver recipients may limit use of this technique. STUDY DESIGN: This was a single center retrospective analysis investigating split liver transplantation. Between August 1, 1995 and March 30, 2012, 53 of 1,261 (4.2%) recipients received split liver grafts. RESULTS: The 1-, 5-, and 10-year patient and graft survivals in adult recipients of split grafts were 95.5%, 89.5%, and 89.5%, respectively. Survival was similar to that of whole organ recipients (p = 0.15). Twenty-three adults received split grafts: 18 (78%) were right trisegment grafts, 4 (17.4%) were right lobes, and 1 (4.3%) was a left lobe. The mean cold ischemic time was 5.7 hours (+/-2.4 hours [SD]) and warm ischemic time was 36 minutes (+/-5.5 minutes). Four (17%) recipients required hepatic artery reconstruction; 5 (21.7%) required a caval-venous patch, and 5 (21.7%) had Roux-en-Y reconstruction of the bile duct. No venous conduits were required. Thirty children received split grafts (median age 1.2 years, range 0.1 to 16.4 years) and had a median weight of 8.6 kg (range 3.6 to 45 kg). Pediatric split 1-, 5-, and 10-year overall and graft survival rates were 96.7%, 80.0%, 80.0%, and 93.3%, 76.8, and 76.8%, respectively. Complications included retransplantation in 3 (10.0%), bile leak in 5 (16.7%), hepatic arterial thrombosis in 2 (6.7%), bowel perforation in 2 (6.7%), and bleeding in 2 (6.7%). The mean donor age was 22.4 months (+/-8.9) months and body mass index was 22.8 kg/m(2) (+/-3.3 kg/m(2)). CONCLUSIONS: We demonstrated excellent outcomes in adult and pediatric recipients using carefully selected donors for liver splitting. We recommend escalation of the use of split liver transplants to expand the donor pool for cadaveric liver transplantation. PMID- 23639201 TI - Predictors of chronic groin discomfort after laparoscopic totally extraperitoneal inguinal hernia repair. AB - BACKGROUND: Chronic groin discomfort is an undesired complication of laparoscopic totally extraperitoneal (TEP) inguinal hernia repairs. We examined whether perioperative factors may be associated with an increased risk of developing this problem and if their recognition could lead to preventive strategies. STUDY DESIGN: We performed a retrospective review of 1 surgeon's experience with 1,479 TEP repairs on 976 patients from 1995 to 2009. A mailed survey, which included a groin discomfort questionnaire (Carolinas Comfort Scale), was distributed to all patients. Symptom severity grading (range 0, none to 5, severe) was used to sort individual responses. Perioperative factors were compared between asymptomatic and symptomatic patients with varying levels of discomfort. RESULTS: There were 691 patients (71%) who provided complete responses to the questionnaire. Median follow-up was 5.7 years (range 0 to 14.4 years). The majority (n = 543, 79%) denied any symptoms of mesh sensation, pain, or movement limitation. In the remaining 148 (21%) patients, symptoms were most often mild (n = 108), followed by mild but bothersome (n = 25), and 15 patients (2%) had moderate or severe symptoms. Symptomatic patients were younger (median age 52 vs 57 years, p = 0.002) and were more likely to have had the TEP repair for recurrent hernias (24% vs 17%, p = 0.035). Operative diagnosis, bilateral exploration, mesh fixation techniques, perioperative complications, American Society of Anesthesiologists grade, and length of hospital stay were not associated with chronic groin discomfort. CONCLUSIONS: The majority of patients are asymptomatic after a laparoscopic TEP inguinal hernia repair. Most of the symptomatic patients do not have any bothersome symptoms. Given that younger age and a repair for recurrent hernia were predictors of chronic groin discomfort, we counsel these patients about their increased risks. PMID- 23639203 TI - General strategy for the synthesis of rigid weak-link approach platinum(II) complexes: tweezers, triple-layer complexes, and macrocycles. AB - Air-stable, heteroligated platinum(II) weak-link approach (WLA) tweezer and triple-layer complexes that possess P,X-Aryl hemilabile ligands (P^ = Ph2PCH2CH2 , X = chalcoethers or amines) have been synthesized via the halide-induced ligand rearrangement (HILR) reaction, using a one-pot, partial chloride-abstraction method. The approach is general and works with a variety of phosphine-based hemilabile ligands; when a P,S-Ph ligand is used as the relatively strongly chelating ligand, heteroligated complexes are formed cleanly when an ether- (P,O Ph), amine- (P,N-Ph2), or fluorinated thioether-based (P,S-C6F4H) hemilabile ligand is used as the weakly chelating counterpart. The HILR reaction has also been used to synthesize bisplatinum(II) macrocycles free of oligomeric material without having to resort to the high-dilution conditions typical for macrocycle synthesis. This approach is complementary to the traditional WLA to the synthesis of macrocyclic complexes which typically proceeds via fully closed, chloride-free intermediates. The structures of the complexes may be toggled between semiopen (with only one chelating ligand) and fully closed (with both ligands chelating) via the abstraction and addition of chloride. PMID- 23639202 TI - A negative urinalysis rules out catheter-associated urinary tract infection in trauma patients in the intensive care unit. AB - BACKGROUND: Urinary tract infection (UTI) in trauma patients is associated with increased mortality. Whether the urinalysis (UA) is an adequate test for a urinary source of fever in the ICU trauma patient has not been demonstrated. We hypothesized that the UA is a valuable screen for UTI in the febrile, critically ill trauma patient. STUDY DESIGN: All trauma ICU patients in our surgical ICU who had a fever (temperature >38.0 degrees C), urinary catheter, UA, and a urine culture between January 1, 2011 and December 13, 2011 were reviewed. A positive UA was defined as positive leukocyte esterase, positive nitrite, WBC > 10/high power field, or presence of bacteria. A positive urine culture was defined as growth of >=10(5) colony forming units (cfu) of an organism irrespective of the UA result or >=10(3) cfu in the setting of a positive UA. A UTI was defined as positive urine culture without an alternative cause of the fever. RESULTS: There were 232 UAs from 112 patients that met criteria. The majority (75%) of patients were men; the mean age was 40 (+/-16) years. Of the 232 UAs, 90 (38.7%) were positive. There were 14 UTIs. The sensitivity, specificity, positive predictive value, and negative predictive value of the UA for UTI were 100%, 65.1%, 15.5%, and 100%, respectively. CONCLUSIONS: A negative UA reliably excludes a catheter associated UTI in the febrile, trauma ICU patient with a 100% negative predictive value, and it can rapidly direct the clinician toward more likely sources of fever and reduce unnecessary urine cultures. PMID- 23639204 TI - Expression pattern of protein kinase C epsilon during mouse embryogenesis. AB - BACKGROUND: Protein kinase C epsilon (PKCepsilon) belongs to the novel PKC subfamily, which consists of diacylglycerol dependent- and calcium independent PKCs. Previous studies have shown that PKCepsilon is important in different contexts, such as wound healing or cancer. In this study, we contribute to expand the knowledge on PKCepsilon by reporting its expression pattern during murine midgestation using the LacZ reporter gene and immunostaining procedures. RESULTS: Sites showing highest PKCepsilon expression were heart at ealier stages, and ganglia in older embryos. Other stained domains included somites, bone, stomach, kidney, and blood vessels. CONCLUSIONS: The seemingly strong expression of PKCepsilon in heart and ganglia shown in this study suggests a important role of this isoform in the vascular and nervous systems during mouse development. However, functional redundancy with other PKCs during midgestation within these domains and others reported here possibly exists since PKCepsilon deficient mice do not display obvious embryonic developmental defects. PMID- 23639205 TI - Influence of water vapour and carbon dioxide on free lime during storage at 80 degrees C, studied by Raman spectroscopy. AB - Micro-Raman spectroscopy has been used to follow the reaction of free lime (CaO) exposed for 24h to moist air at 80 degrees C under conditions of different relative humidities (10-80% RH). X-ray diffraction and SEM imaging were applied as complementary techniques. The conversion of lime to calcium hydroxide and its subsequent carbonation to various calcium carbonate polymorphs was found to strongly depend on the relative humidity. At low RH (10-20%), only Raman spectroscopy revealed the formation of early amorphous CaCO3 which in the XRD patterns was detected only at >=40% RH. However, XRD analysis could identify the crystalline polymorphs formed at higher relative humidities. Thus, between 20 and 60% RH, all three CaCO3 polymorphs (calcite, aragonite and vaterite) were observed via XRD whereas at high relative humidity (80%), calcite was the predominant reaction product. The results demonstrate the usefulness of Raman spectroscopy in the study of minor cement constituents and their reaction products on air, especially of amorphous character. PMID- 23639206 TI - Frailty and mortality are not influenced by mitochondrial DNA haplotypes in the very old. AB - Inherited genetic variation of mitochondrial DNA (mtDNA) could account for the missing heritability of human longevity and healthy aging. Here, we show no robust association between common genetic variants of mtDNA and frailty (an "unhealthy aging" phenotype) or mortality in 700, more than 85-year-old, participants of the Newcastle 85+ study. Conflicting data from different populations underscore our conclusion that there is currently no compelling link between inherited mtDNA variants and aging. PMID- 23639207 TI - Cerebrospinal fluid norepinephrine and cognition in subjects across the adult age span. AB - Adequate central nervous system noradrenergic activity enhances cognition, but excessive noradrenergic activity may have adverse effects on cognition. Previous studies have also demonstrated that noradrenergic activity is higher in older than younger adults. We aimed to determine relationships between cerebrospinal fluid (CSF) norepinephrine (NE) concentration and cognitive performance by using data from a CSF bank that includes samples from 258 cognitively normal participants aged 21-100 years. After adjusting for age, gender, education, and ethnicity, higher CSF NE levels (units of 100 pg/mL) are associated with poorer performance on tests of attention, processing speed, and executive function (Trail Making A: regression coefficient 1.5, standard error [SE] 0.77, p = 0.046; Trail Making B: regression coefficient 5.0, SE 2.2, p = 0.024; Stroop Word-Color Interference task: regression coefficient 6.1, SE 2.0, p = 0.003). Findings are consistent with the earlier literature relating excess noradrenergic activity with cognitive impairment. PMID- 23639208 TI - Differential effects of duration and age on the consequences of neuroinflammation in the hippocampus. AB - The current study investigated the hypothesis that the duration of the proinflammatory environment plays a critical role in the brain's response that results in negative consequences on cognition, biochemistry, and pathology. Lipopolysaccharide or artificial cerebrospinal fluid was slowly (250 etag/h) infused into the fourth ventricle of young (3-month-old), adult (9-month-old), or aged (23-month-old) male F-344 rats for 21 or 56 days. The rats were then tested in the water pool task and endogenous hippocampal levels of pro- and anti inflammatory proteins and genes and indicators of glutamatergic function were determined. The duration of the lipopolysaccharide infusion, compared with the age of the rat, had the greatest effect on (1) spatial working memory; (2) the density and distribution of activated microglia within the hippocampus; and (3) the cytokine protein and gene expression profiles within the hippocampus. The duration- and age-dependent consequences of neuroinflammation might explain why human adults respond positively to anti-inflammatory therapies and aged humans do not. PMID- 23639210 TI - Phosphorus-arsenic interactions in variable-charge soils in relation to arsenic mobility and bioavailability. AB - Phosphorus (P) influences arsenic (As) mobility and bioavailability which depends on the charge components of soil. The objective of this study was to examine P-As interaction in variable-charge allophanic soils in relation to P-induced As mobilization and bioavailability. In this work, the effect of P on arsenate [As(V)] adsorption and desorption was examined using a number of allophanic and non-allophanic soils which vary in their anion adsorption capacity. The effect of P on As uptake by Indian mustard (Brassica juncea L.) plants was examined using a solution culture, and a soil plant growth experiment involving two As-spiked allophanic and non-allophanic soils which vary in their anion adsorption capacity, and a field As-contaminated sheep dip soil. Arsenate adsorption increased with an increase in the anion adsorption capacity of soils. The addition of P resulted in an increase in As desorption, and the effect was more pronounced in the case of allophanic soil. In the case of both As-spiked soils and field contaminated sheep-dip soil, application of P increased the desorption of As, thereby increasing its bioavailability. The effect of P on As uptake was more pronounced in the high anion adsorbing allophanic than low adsorbing non allophanic soil. In the case of solution culture, As phytoavailability decreased with increasing concentration of P which is attributed to the competition of P for As uptake by roots. While increasing P concentration in solution decreased the uptake of As, it facilitated the translocation of As from root to shoot. The net effect of P on As phytoavailability in soils depends on the extent of P induced As mobilization in soils and P-induced competition for As uptake by roots. The P-induced mobilization of As could be employed in the phytoremediation of As-contaminated sites. However, care must be taken to minimize the leaching of As mobilized through the P-induced desorption, thereby resulting in groundwater and off site contamination. PMID- 23639211 TI - Body-image dissatisfaction is strongly associated with chronic dysphoria. AB - BACKGROUND: Individual depressive symptoms may contribute to the risk of chronic depression. This study aimed to explore which symptoms predict chronic dysphoria, a hallmark of depression. METHODS: 1057 participants from the population-based Young Finns study were examined for four times during a 16-year period. Those with a modified Beck's Depression Inventory score in the upper third at all four screenings were considered to have chronic dysphoria (n=135). Participants with only one high depression score formed the reference group of transient dysphoria (n=179). Individual items of the Inventory were analyzed in terms of their association with dysphoria status and chronicity, controlling for potential confounding factors, such as personality assessed using the Temperament and Character Inventory. RESULTS: Body-image dissatisfaction was strongly associated with chronically elevated dysphoria (Bonferroni-corrected p=0.006). The degree of body-image dissatisfaction was associated with the probability for chronic dysphoria in a dose-response manner, with the estimated probability ranging from 0.01 to 0.60 as a function of item response. The association remained after adjustments for a wide range of personality characteristics. LIMITATIONS: The study relied on self-reports of mood and personality, and lacked information on external opinion on participants appearances. The requirement of full time-series data may have resulted in attrition-related bias. CONCLUSIONS: Body-image dissatisfaction was a strong predictor of chronic depression characterized by dysphoria. This finding suggests that dysfunctional attitude towards oneself might represent a potentially important target for cognitive therapies and preventive interventions. PMID- 23639209 TI - Short-term treatment with tolfenamic acid improves cognitive functions in Alzheimer's disease mice. AB - Tolfenamic acid lowers the levels of the amyloid precursor protein (APP) and amyloid beta (Abeta) when administered to C57BL/6 mice by lowering their transcriptional regulator specificity protein 1 (SP1). To determine whether changes upstream in the amyloidogenic pathway that forms Abeta plaques would improve cognitive outcomes, we administered tolfenamic acid for 34 days to hemizygous R1.40 transgenic mice. After the characterization of cognitive deficits in these mice, assessment of spatial learning and memory functions revealed that treatment with tolfenamic acid attenuated long-term memory and working memory deficits, determined using Morris water maze and the Y-maze. These improvements occurred within a shorter period of exposure than that seen with clinically approved drugs. Cognitive enhancement was accompanied by reduction in the levels of the SP1 protein (but not messenger RNA [mRNA]), followed by lowering both the mRNA and the protein levels of APP and subsequent Abeta levels. These findings provide evidence that tolfenamic acid can disrupt the pathologic processes associated with Alzheimer's disease (AD) and are relevant to its scheduled biomarker study in AD patients. PMID- 23639212 TI - Effects of once-daily extended release quetiapine fumarate (quetiapine XR) on quality of life and sleep in elderly patients with major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) is frequently associated with reduced quality of life (QoL) and sleep disturbance. We investigated the effects of once daily extended release quetiapine fumarate (quetiapine XR) monotherapy on QoL and sleep in elderly patients with MDD. METHODS: Prospectively planned analysis of patient-reported data from an 11-week (9-week randomized; 2-week post-treatment), double-blind, placebo-controlled, Phase III study. Elderly patients (>=66 years; DSM-IV MDD; Hamilton Rating Scale for Depression [HAM-D] total score >=22, HAM-D Item 1 score >=2) were randomized to quetiapine XR (flexible dosing 50-300 mg/day) or placebo. PRIMARY OUTCOME: MADRS total score change from randomization at Week 9. Patient-reported outcomes: Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) % of maximum total score (Items 1-14), Q LES-Q-SF Item 15 ('satisfaction with medication'), Q-LES-Q-SF Item 16 ('overall life satisfaction'), and Pittsburgh Sleep Quality Index (PSQI) global score. RESULTS: In total, 338 patients were randomized (166 quetiapine XR; 172 placebo). At Week 9, quetiapine XR significantly reduced MADRS total score (-16.33; difference: -7.54; 95% CI: -9.23, -5.85; p<0.001) versus placebo (-8.79). Quetiapine XR significantly improved Q-LES-Q-SF % of maximum total score (16.86; difference: 7.69; 95% CI: 4.99, 10.39; p<0.001) versus placebo (9.17), with numerical improvement in Q-LES-Q-SF Item 15 and improvement in Item 16. Improvement in PSQI global score was observed with quetiapine XR (-6.42; difference: -3.52; 95% CI: -4.26, -2.79; p<0.001) versus placebo (-2.89). LIMITATIONS: Lack of active-comparator arm, flexible-dose design, acute treatment period. CONCLUSIONS: Quetiapine XR monotherapy improved QoL and sleep in elderly patients with MDD. PMID- 23639213 TI - Is bigger better? A retrospective analysis of native renal biopsies with 16 Gauge versus 18 Gauge automatic needles. AB - AIM: Percutaneous renal biopsy (PRB) remains the gold standard for the diagnosis of renal disease; however, the tissue yield which relates to the optimal needle size used for native-kidney biopsies has not been clearly established. Our study compares the sample adequacy and complication rates using 16 gauge (G) and 18 gauge (G) automatic needles on native kidney PRB. METHODS: A retrospective analysis was performed of native-kidney biopsies at two centres, one exclusively using 16G and the other exclusively using 18G needles. All samples were assessed by a single centralized pathology service. We compared patient characteristics, indications, diagnoses, adequacy of tissue samples, and complications. RESULTS: A total of 934 native-kidney biopsies were performed with real time ultrasound guidance: 753 with Bard Max Core 16G * 16 cm needles, and 181 with Bard Magnum 18G * 20 cm needles. The median (range) of total glomeruli count per biopsy was higher in the 16G group compared with the 18G group (19 (0-66) vs. 12 (0-35), P < 0.001), despite having fewer cores per biopsy (2 (0-4) vs. 3 (1-4), P < 0.001). The 16G group provided a greater proportion of adequate biopsy samples (94.7% vs. 89.4%, P = 0.001). There was no significant difference in the frequency of total complications between the 16G and 18G groups (3.7% vs. 2.2%, P = 0.49). CONCLUSION: This retrospective study demonstrates 16G needles provide more glomeruli, more diagnostically adequate renal tissue, with fewer cores without a significant increase in complications compared with 18G needles. Based on these observations, 16G needles should be considered as the first line option in native kidney PRB. PMID- 23639215 TI - Detection experiments with humans implicate visual predation as a driver of colour polymorphism dynamics in pygmy grasshoppers. AB - BACKGROUND: Animal colour patterns offer good model systems for studies of biodiversity and evolution of local adaptations. An increasingly popular approach to study the role of selection for camouflage for evolutionary trajectories of animal colour patterns is to present images of prey on paper or computer screens to human 'predators'. Yet, few attempts have been made to confirm that rates of detection by humans can predict patterns of selection and evolutionary modifications of prey colour patterns in nature. In this study, we first analyzed encounters between human 'predators' and images of natural black, grey and striped colour morphs of the polymorphic Tetrix subulata pygmy grasshoppers presented on background images of unburnt, intermediate or completely burnt natural habitats. Next, we compared detection rates with estimates of capture probabilities and survival of free-ranging grasshoppers, and with estimates of relative morph frequencies in natural populations. RESULTS: The proportion of grasshoppers that were detected and time to detection depended on both the colour pattern of the prey and on the type of visual background. Grasshoppers were detected more often and faster on unburnt backgrounds than on 50% and 100% burnt backgrounds. Striped prey were detected less often than grey or black prey on unburnt backgrounds; grey prey were detected more often than black or striped prey on 50% burnt backgrounds; and black prey were detected less often than grey prey on 100% burnt backgrounds. Rates of detection mirrored previously reported rates of capture by humans of free-ranging grasshoppers, as well as morph specific survival in the wild. Rates of detection were also correlated with frequencies of striped, black and grey morphs in samples of T. subulata from natural populations that occupied the three habitat types used for the detection experiment. CONCLUSIONS: Our findings demonstrate that crypsis is background dependent, and implicate visual predation as an important driver of evolutionary modifications of colour polymorphism in pygmy grasshoppers. Our study provides the clearest evidence to date that using humans as 'predators' in detection experiments may provide reliable information on the protective values of prey colour patterns and of natural selection and microevolution of camouflage in the wild. PMID- 23639216 TI - Income inequalities in unhealthy life styles in England and Spain. AB - Health inequalities in developed societies are persistent. Arguably, the rising inequalities in unhealthy lifestyles might underpin these inequality patterns, yet supportive empirical evidence is scarce. We examine the patterns of inequality in unhealthy lifestyles in England and Spain, two countries that exhibit rising obesity levels with a high prevalence of smoking and alcohol use. This study is unique in that it draws from health survey data spanning over a period in which major contextual and policy changes have taken place. We document persistent income-related inequalities in obesity and smoking; both unhealthy lifestyles appear to be disproportionately concentrated among the relatively poor in recent decades. In contrast, alcohol use appears to be concentrated among richer individuals in both periods and countries examined. PMID- 23639214 TI - Discovery of GW870086: a potent anti-inflammatory steroid with a unique pharmacological profile. AB - BACKGROUND AND PURPOSE: Glucocorticoids are highly effective therapies for a range of inflammatory diseases. Advances in the understanding of the diverse molecular mechanisms underpinning glucocorticoid action suggest that anti inflammatory molecules with reduced side effect liabilities can be discovered. Here we set out to explore whether modification of the 17alpha position of the steroid nucleus could generate molecules with a unique pharmacological profile and to determine whether such molecules would retain anti-inflammatory activity. EXPERIMENTAL APPROACH: The pharmacological properties of GW870086 were compared with fluticasone propionate (FP) using a range of cellular and in vivo model systems, including extensive gene expression profiling. KEY RESULTS: GW870086 repressed inflammatory cytokine release from lung epithelial cells in a similar manner to FP but antagonized the effect of dexamethasone on MMTV-driven reporter gene transactivation. GW870086 had a strong effect on the expression of some glucocorticoid-regulated genes (such as PTGS2), while having minimal impact on the expression of other known target genes (such as SGK). GW870086 retained the ability to strengthen tight junctions in epithelial cell culture but, unlike FP, was unable to protect the culture from elastase-mediated damage. In murine models of irritant-induced contact dermatitis and ovalbumin-induced allergic inflammation, GW870086 showed comparable anti-inflammatory efficacy to FP. CONCLUSION AND IMPLICATIONS: GW870086 is a potent anti-inflammatory compound with a unique ability to regulate only a subset of those genes that are normally affected by classical glucocorticoids. It has the potential to become a new topical steroid with a different safety profile to existing therapies. PMID- 23639217 TI - Facultative use of thelytokous parthenogenesis for queen production in the polyandrous ant Cataglyphis cursor. AB - The evolutionary paradox of sex remains one of the major debates in evolutionary biology. The study of species capable of both sexual and asexual reproduction can elucidate factors important in the evolution of sex. One such species is the ant Cataglyphis cursor, where the queen maximizes the transmission of her genes by producing new queens (gynes) asexually while simultaneously maintaining a genetically diverse workforce via the sexual production of workers. We show that the queen can also produce gynes sexually and may do so to offset the costs of asexual reproduction. We genotyped 235 gynes from 18 colonies and found that half were sexually produced. A few colonies contained both sexually and asexually produced gynes. Although workers in this species can also use thelytoky, we found no evidence of worker production of gynes based on genotypes of 471 workers from the six colonies producing sexual gynes. Gynes are thus mainly, and potentially exclusively, produced by the queen. Simulations of gynes inbreeding level following one to ten generations of automictic thelytoky suggest that the queen switches between or combines thelytoky and sex, which may reduce the costs of inbreeding. This is supported by the relatively small size of inbred gynes in one colony, although we found no relationship between the level of inbreeding and immune parameters. Such facultative use of sex and thelytoky by individual queens contrasts with other known forms of parthenogenesis in ants, which are typically characterized by distinct lineages specializing in one strategy or the other. PMID- 23639218 TI - Photoelectrochemical properties of electrostatically self-assembled multilayer films formed by a cobalt complex and graphene oxide. AB - The multilayer films consisting of graphene oxide and a cobalt complex were fabricated though electrostatic layer-by-layer self-assembly technique and characterized by UV-Vis absorption spectroscopy, X-ray photoelectron spectroscopy, scanning electron microscopy, and cyclic voltammetry. The results demonstrated that the hybrid films were successfully prepared and exhibited good electrochemical activity. The film was also subjected to photoelectrochemical studies and were found to exhibit large cathodic photocurrent density of 6.1 MUA/cm(2) while irradiated with 100 mW/cm(2) polychromatic light (730 nm>lambda>325 nm) at an applied potential of -0.4V versus saturated calomel electrode. PMID- 23639219 TI - Honeycomb-like thin films of polystyrene-block-poly(2-vinylpyridine) embedded with gold or silver nanoparticles formed at the planer liquid/liquid interface. AB - Composite thin films of polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP) decorated with Au or Ag nanoclusters and nanoparticles were fabricated at the interfaces of chloroform solution of PS-b-P2VP and aqueous solutions of HAuCl4 or AgNO3. Transmission electron microscopy (TEM) investigations indicated that large area of a single-layer honeycomb structure was formed, which is composed of polygons (most of them are hexagons) whose walls look like spindles with the length of several hundreds of nanometers. Large amount of Au or Ag nanoparticles are embedded in the walls and the undersides of the honeycomb structures. The formation of these novel composite structures was attributed to the adsorption of block copolymer molecules and inorganic species of AuCl4(-) and Ag(+) ions at the liquid-liquid interface, the combination of the polymer molecules and the inorganic ions, and the self-assembly of the composite molecules. After UV-light irradiation and KBH4 aqueous solution treatment, the inorganic species were reduced completely, as confirmed by UV-vis spectra and X-ray photoelectron spectra. These composite films exhibited high catalytic activities for the reduction of 4-nitrophenol (4-NP) by KBH4 in aqueous solutions. PMID- 23639220 TI - Facile assembly and properties of polystyrene microsphere/reduced graphene oxide/Ag composite. AB - A ternary assembly consisting of reduced graphene oxide (RGO), Ag nanoparticles, and polystyrene (PS) microsphere was prepared in aqueous solution by an electrostatic assembly combined with one-step reduction process. The composition and structure of the assembly (PS microsphere/RGO/Ag) were characterized by powder X-ray diffraction, transmission electron microscope, scanning electron microscope, X-ray photoelectron spectroscopy, and Raman spectroscopy. The interactions among RGO, Ag nanoparticles, and PS microsphere were investigated by surface enhanced Raman scattering spectroscopy. The results showed that there existed strong interactions among RGO, Ag nanoparticles, and PS microsphere. Importantly, the assembly showed high heat stability and good dispersion in water. PMID- 23639221 TI - Sorafenib in a hepatocellular carcinoma patient with end-stage renal failure: A pharmacokinetic study. AB - The efficacy of sorafenib against hepatocellular carcinoma (HCC) has been extensively reported. However, there is little information available about the use of sorafenib for HCC patients with end-stage renal failure. We herein report the safe introduction of sorafenib therapy for a HCC patient on hemodialysis. A 63-year-old man had received multidisciplinary treatments, including transarterial chemoembolization (TACE) and radiofrequency ablation, for HCC since 1996, and had been undergoing hemodialysis since 2005. He also underwent TACE for multiple liver recurrence of HCC in 2011. Sorafenib therapy (200 mg/day) started 8 days after the TACE. The pharmacokinetic parameters of sorafenib and its active metabolite, M-2, were within the reference levels observed in patients with normal renal function 8 and 9 days after the initiation of sorafenib. The dose of sorafenib was reduced to 200 mg every other day on day 154 due to hypertension and general fatigue. Because of the progression of disease after 5 months, sorafenib was withdrawn on day 180. He was admitted to the emergency department because of a high fever during hemodialysis on day 201, and died of septic shock induced by Staphylococcus lugdunensis on day 203. Sorafenib was well tolerated at an initial dose of 200 mg/day for a HCC patient undergoing hemodialysis, thus indicating that renal failure is not necessarily a contraindication for sorafenib therapy. PMID- 23639222 TI - Fire disaster following LPG tanker explosion at Chala in Kannur (Kerala, India): August 27, 2012. AB - A fire disaster following LPG tanker explosion occurred at Chala bypass, Kannur, Kerala, India on August 27, 2012. The three chambered tanker with total 16tonnes (162.57 quintal) LPG collided with a road divider and exploded thrice. A total of 41 people became victims during first blast; out of which 20 died in various hospitals. Five people remained inside the house after first blast and escaped unhurt from the zone of accident before second blast. All the victims were transferred to various hospitals; of these, six were transferred to the burns unit of the Kasturba Hospital, Manipal (320km from Chala). Five (5/6) were transferred within 1-5 days at our burns unit suffered 31-72% total body surface area (TBSA) burn, none had external injuries. One (1/6) was transferred on 20th day as a follow up case of 15% TBSA burn with 4% residual raw area and diabetes mellitus. Except one, all were managed conservatively using Limited access dressings (LAD; Negative Pressure Wound Therapy). One of the patient wound bed prepared under LAD and on 41 post burn day underwent split skin grafting under LAD. Out of the six patients admitted at the burns unit, two (2/6) admitted patients expired (one due to inhalation injury and another due to sepsis with multiple organ failure). One survivor (1/4) developed sepsis related liver dysfunction with hepatomegaly but recovered well. The total hospital stay of survivors at the burns unit varied from 8 to 60 days (mean hospital stay 36.5 days). All the victims who developed psychological symptoms were treated by psychiatrists and counselled before discharge. Three of survivors developed psychological symptoms. Two of them (2/3) developed mixed anxiety-depression disorder (ICD 10 code F41.8) and one of these two showed grief reaction too (ICD 10 code F43.23). One victim (1/3) developed non-organic insomnia (ICD 10 code F51.0) and responded to counselling. The article describes the incident, mechanism of the incident, injuries sustained, author, explanations on pattern of burn and suggestions in relation to future safety measures. PMID- 23639223 TI - Risk factors for scald injury in children under 5 years of age: a case-control study using routinely collected data. AB - Scald injury is common, accounting for half of all burns in pre-school children. Most scalds are preventable and health professionals can play an important role in targeting interventions to those at greatest risk. However, the potential for routinely collected medical data to be used to identify high risk children has not been well explored. We used a matched case-control study to identify risk factors for first scald injury in children under 5 using a large, nationally representative database of routinely collected primary care records. Among 986 cases and 9240 controls, male gender, age (2 years), higher birth order, single parent families and increasing index of material deprivation were associated with increased odds of scald injury. Older maternal age at childbirth was associated with decreased odds of scald injury. Children at risk of scald injury can be identified from routinely collected primary care data and primary care practitioners can use this information to target evidence-based safety interventions. PMID- 23639224 TI - Scar management by means of occlusion and hydration: a comparative study of silicones versus a hydrating gel-cream. AB - Despite the worldwide use of silicones in scar management, its exact working mechanism based on a balanced occlusion and hydration, is still not completely elucidated. Moreover, it seems peculiar that silicones with completely different occlusive and hydrating properties still could provide a similar therapeutic effect. The objective of the first part of this study was to compare the occlusive and hydrating properties of three fluid silicone gels and a hydrating gel-cream. In a second part of the study these results were compared with those of silicone gel sheets. Tape stripped skin was used as a standardized scar like model on both forearms of 40 healthy volunteers. At specific times, trans epidermal water loss (TEWL) and the hydration state of the stratum corneum were measured and compared with intact skin and a scar-like control over a 3-4h period. Our study clearly demonstrated that fluid silicone gels and a hydrating gel-cream have comparable occlusive and hydrating properties while silicone gel sheets are much more occlusive, reducing TEWL values far below those of normal skin. A well-balanced, hydrating gel-cream can provide the same occlusive and hydrating properties as fluid silicone gels, suggesting that it could eventually replace silicones in scar treatment. PMID- 23639225 TI - Treatment outcomes for keloid scar management in the pediatric burn population. PMID- 23639226 TI - Effects of growth hormone and ultrasound on mandibular growth in rats: MicroCT and toxicity analyses. AB - It has been shown by previous studies that mandibular growth can be enhanced by the systemic administration of recombinant growth hormone (rGH) and/or local application of therapeutic low intensity pulsed ultrasound (LIPUS). The purpose of this study was to determine if local injection of rGH and application of LIPUS to the temporomandibular joint (TMJ) would synergistically enhance mandibular growth. In an animal study, the effect of rGH, LIPUS, and combination of rGH and LIPUS on male Sprague-Dawley rats was observed. Mandibular growth was evaluated by measuring total hemimandibular and condylar bone volume and bone surface area as well as condylar bone mineral density (BMD) after 21 days on dissected rats' mandibles using micro-computed tomography (MicroCT). The expression of c-jun mRNA extracted from the liver of each of these rats was also quantified by real-time polymerase chain reaction to evaluate possible systemic effect of local rGH administration. Significant growth stimulation was observed in the mandibular and condylar bone of the animals treated with rGH, LIPUS, and rGH/LIPUS combined when compared with the control group. Bone volume, surface area, condylar bone mineral density, and c-jun expression were also compared between the treatment groups and the control in the liver. The results suggest that mandibular growth may be enhanced by injection of rGH or LIPUS application. The current study although showed synergetic effect of rGH and LIPUS application in increasing mandibular condylar head length, there was no significant changes in mandibular bone volume using both treatments together when compared to the two individual treatments. Moreover, combined rGH and LIPUS decreased condylar bone mineral density than each treatment separately. Future research could be directed to investigate the effects of different rGH doses and/or different LIPUS exposures parameters on lower jaw growth. PMID- 23639227 TI - The effects of combined treatment with sevoflurane and cisplatin on growth and invasion of human adenocarcinoma cell line A549. AB - Sevoflurane, an inhalational anesthetic, and cisplatin (DDP)-based chemotherapy have been widely used during lung cancer surgery. However, the effect of sevoflurane on the sensitivity of lung cancer cells to DDP chemotherapy remains unclear. In this study, the effects of combined treatment with sevoflurane and cisplatin on the growth and invasion of human lung adenocarcinoma A549 cell line have been investigated. The underlying mechanism has also been explored. In our experiment, A549 cells were treated with 2.5% sevoflurane, 10MUmol/L DDP, or the co-treatment of sevoflurane and DDP for 4h, respectively. Cell proliferation was evaluated by the MTT assay and colony formation assay. Apoptosis was assessed by flow cytometry. Cell invasion was detected by Transwell assay. The expressions of X-linked inhibitor of apoptosis protein (XIAP), Survivin, matrix metalloproteinase (MMP)-2 and MMP-9 were determined by western blotting. Our results showed that sevoflurane combined with DDP resulted in a more pronounced inhibition of tumor cells growth and invasion as compared with either drug alone. Besides, XIAP, Survivin, MMP-2, and MMP-9 were downregulated more significantly by the co-treatment of the two drugs as compared to sevoflurane treatment or DDP treatment alone. Taken together, the growth-inhibitory and invasion-inhibitory synergy between sevoflurane and DDP in human adenocarcinoma A549 cell line was found in this study. Furthermore, we showed that the growth-inhibitory synergy between sevoflurane and DDP might be associated with the downregulation of XIAP and Survivin, and the invasion-inhibitory synergy between sevoflurane and DDP might be involved in the downregulation of MMP-2 and MMP-9. PMID- 23639228 TI - Bioequivalence evaluation of two formulations of pidotimod using a limited sampling strategy. AB - The aim of this study was to develop a limited sampling strategy (LSS) to assess the bioequivalence of two formulations of pidotimod. A randomized, two-way, cross over study was conducted in healthy Chinese volunteers to compare two formulations of pidotimod. A limited sampling model was established using regression models to estimate the pharmacokinetic parameters and assess the bioequivalence of pidotimod. The model was internally validated by the Jack-knife method and graphical methods. The traditional non-compartmental method was also used to analyze the data and compared with LSS method. The results indicate that following oral administration of a single 800 mg dose, the plasma AUC(0-12 h) and C(max) of pidotimod can be predicted accurately using only two to four plasma samples. The bioequivalence assessment based on the LSS models provided results very similar to that obtained using all the observed concentration-time data points and indicate that the two pidotimod formulations were bioequivalent. A LSS method for assessing the bioequivalence of pidotimod formulations was established and proved to be applicable and accurate. This LSS method could be considered appropriate for a pidotimod bioequivalence study, providing an inexpensive cost of sampling acquisition and analysis. And the methodology presented here may also be applicable to bioequivalence evaluation of other medications. PMID- 23639229 TI - The comparison of chronic hepatitis C treatment outcome between intravenous drug users and non-intravenous drug users. AB - Despite the fact that the majority of prevalent and incident cases of HCV are associated with intravenous drug use (IVDU), these patients have largely been excluded from HCV care. The aim of this study was to examine the treatment outcome of chronic hepatitis C in IVDUs compared to non-IVDUs. PATIENTS AND METHODS: Patients with chronic hepatitis C (CHC) who initiated and completed combination antiviral therapy with pegilated interferon and ribavirin, at the Hepatology Department of the University Hospital for Infectious and Tropical Diseases in Belgrade, were retrospectively analyzed. The study included a series of 254 patients of which 100 (39.4%) were former IVDU. RESULTS: Sustained virological response (SVR) was recorded in a total of 172 patients (67.7%). The analyses of the favorable treatment outcome, regarding particular viral genotypes, revealed that among those with genotype 1 and/or 4, including patients with genotype 1 recombinants with genotype 3, SVR was achieved in 114 (63.3%), while it was almost equally distributed between subgroups of former IVDU and all others (P=0.079). Among patients infected with HCV genotypes 2 and/or 3 the SVR rate was as high as 86.6%. CONCLUSION: IVDU with CHC infection should be treated with standard combination antiviral therapy for CHC, since the success rate is equal or even better than in non-IVDU patients. PMID- 23639230 TI - Pentoxifylline inhibits melanoma tumor growth and angiogenesis by targeting STAT3 signaling pathway. AB - Pentoxifylline (PTX), a phosphodiesterase inhibitor, has been shown to have anti metastatic or anti-angiogenic activity against many human cancers. However, the underlying mechanisms are unknown. In this study, we report that, PTX at sub toxic doses can inhibit melanoma tumor growth and angiogenesis by targeting the STAT3 signaling pathway. Despite minimal cytotoxicity against normal cells, PTX suppressed phosphorylation and DNA binding of STAT3 in a dose-dependent manner. Also, PTX inhibited phosphorylation of the upstream kinases JAK1 and JAK2 and increased the expression of pSHP2 phosphatase. Expression of various STAT3 regulated gene products, such as cylinD1, CDK6, cMyc, BclXL, and VEGF was downregulated following PTX treatment. Tumor microenvironment favours tumor growth and metastasis. PTX alters tumor microenvironment by limiting IL-6 secretion and also by disrupting VEGF-VEGFR2 autocrine/paracrine signaling. PTX treatment significantly inhibited tumor growth and angiogenesis in intra-dermal xenograft mouse model in vivo without having any visible toxicity. These findings identified STAT3 signaling as a target of PTX and have thus, augmented its potential application in the treatment of melanoma and other cancers. PMID- 23639232 TI - Prokaryotic expression and refolding of EGFR extracellular domain and generation of phage display human scFv against EGFR. AB - The epidermal growth factor receptor (EGFR), overexpressed in many epithelial tumors, is emerging as an attractive target for cancer therapy. Antibodies to the extracellular region of EGFR play a key role in the development of a mechanistic understanding and cancer therapy. In the present study, we demonstrated for the first time that EGFR-truncated extracellular domain (EGFR-tED), which was expressed in Escherichia coli BL21 (DE3) cells in the form of inclusion bodies, could be purified and renatured. The EGFR-tED protein was purified by gel filtration and Ni-NTA affinity chromatography with high purity (>90%) and refolded by a urea gradient size-exclusion chromatography, which could bind its ligand EGF in a concentration-dependent manner. The renatured EGFR was used for biopanning anti-EGFR scFvs from a human synthetic antibody phage display library. Combined with an additional cell-based ELISA screen, a novel scFv, E10, was obtained with two-fold more potent on the binding to EGFR-bearing tumor cells (the epidermoid carcinoma cell line A431) and the inhibition of A431 cells proliferation than scFv 11F8, suggesting that the E10 has the potential to be developed as therapeutic agents to solid tumors associated with EGFR overexpression. PMID- 23639231 TI - Serum proteomic MRM identify peptide ions of transferrin as new fibrosis markers in chronic hepatitis B. AB - BACKGROUND AND AIM: Because of the limitations of liver biopsy, reliable non invasive serum biomarkers of liver fibrosis are needed. The aim of this study was to identify such markers by the use of serum proteomics in chronic hepatitis B (CHB). METHODS: Two-dimensional gel electrophoresis (2-DE) was used to identify differentially expressed protein spots in sera from 40 CHB patients [20 with mild fibrosis (S0-S1) and 20 with severe fibrosis (S3-S4)]. Mass spectrometry (MS) based multiple reaction monitoring (MRM) was used to quantify peptide ions of differential protein spots in another set of sera from 86 CHB patients with different liver fibrosis (S0-S4). RESULTS: Seven differentially expressed protein spots were found by 2-DE. Fourteen peptide ions of seven target protein spots were quantified by MS-based MRM. Summed peak areas ratio (SPAR) values of peptide ions from protein spot 1, 4 and 8, identified as apo serum transferrin, complement component C3c and transferrin, were significantly different from non fibrosis (S0) to fibrosis stage 4. AUROCs of models established by peptide ions (protein spot 1, 4, 8) and model consisting of a combination of all ions were 0.848~0.966 (S2-S4 versus S0-S1) and 0.785~0.875 (S3-S4 versus S0-S2). Only the peptide ions model of transferrin had better sensitivity and specificity for predicting fibrosis stages than did aspartate aminotransferase-to-platelet ratio index (APRI), FIB-4 and Forn's index. CONCLUSIONS: Serum peptide ions of transferrin, detected by proteomic MRM, are new and promising biomarkers for staging liver fibrosis in CHB patients. PMID- 23639233 TI - Monitoring conformational changes in peroxisome proliferator-activated receptor alpha by a genetically encoded photoamino acid, cross-linking, and mass spectrometry. AB - Chemical cross-linking combined with an enzymatic digestion and mass spectrometric analysis of the reaction products has evolved into an alternative strategy to structurally resolve protein complexes. We investigated conformational changes in peroxisome proliferator-activated receptor alpha (PPARalpha) upon ligand binding. Using E. coli cells with a special tRNA/aminoacyl-tRNA synthetase pair, two PPARalpha variants were prepared in which Leu-258 or Phe-273 were site-specifically replaced by the genetically encoded photoreactive amino acid p-benzoylphenylalanine (Bpa). PPARalpha variants were subjected to UV-induced cross-linking, both in the absence and in the presence of ligands. After the photo-cross-linking reaction, reaction mixtures were enzymatically digested and peptides were analyzed by mass spectrometry. The inter-residue distances disclosed by the photochemical cross-links served to monitor conformational changes in PPARalpha upon agonist and antagonist binding. The data obtained with our strategy emphasize the potential of genetically encoded internal photo-cross-linkers in combination with mass spectrometry as an alternative method to monitor in-solution 3D-protein structures. PMID- 23639234 TI - Evolution of the melanocortin-2 receptor in tetrapods: studies on Xenopus tropicalis MC2R and Anolis carolinensis MC2R. AB - The tetrapods are a diverse assemblage of vertebrates, and that diversity is reflected in the sequences of tetrapod melanocortin-2 receptors (MC2Rs). In this review, the features common to human (mammal), Gallus gallus (bird), Anolis carolinensis (reptile), and Xenopus tropicalis (amphibian) MC2Rs in terms of ligand selectivity, requirements for interaction with MRAP1, and the effects of alanine substitutions to three amino acid motifs in the ligand hACTH(1-24) are discussed. Analysis of the effects of alanine substitutions to the H(6)F(7)R(8)W(9) and the K(15)K(16)R(17)R(18)P(19) motifs of hACTH(1-24) indicated that activation of A. carolinensis MC2R and X. tropicalis MC2R was more adversely affected by alanine substitutions at these positions as compared to the response of human MC2R to these same analogs. Furthermore, single alanine substitutions in the G(10)K(11)P(12)V(13)G(14) motif of hACTH(1-24) had negative affects on activation of both A. carolinensis MC2R and X. tropicalis MC2R that were not observed for human MC2R. The implications of responses to the various analogs of hACTH(1-24) in terms of the mechanism for mediating the activation of these various tetrapod melanocortin-2 receptors are discussed. PMID- 23639236 TI - Correlation between the complex PSA/total PSA ratio and the free PSA/total PSA ratio, sensitivity and specificity of both markers for the diagnosis of prostate cancer. AB - OBJECTIVE: To compare the behaviour of the PSAcomplex/PSAtotal percentage (PSAc%) against the PSA free/PSA total (PSAl%) and analyse both markers for their usefulness in diagnosing prostate cancer. MATERIAL AND METHODS: We measured total PSA (PSAt), free PSA (PSAl), complex PSA (PSAc), PSAl% and PSAc% levels in 158 patients. Of these, 98 (62%) were biopsied for presenting PSAt>=3 ng/dl and PSAl%<20, PSAt>10, suspicious rectal examination or suspicious ultrasound node. We performed linear regression and Passing-Bablok regression analyses. The ROC curves were calculated to study the sensitivity and specificity of PSAl% and PSAc% and were compared to each other. The prostate cancer diagnoses were analysed by PSAl% and PSAc% by applying the chi(2) test. RESULTS: The correlation coefficient (r) was good (0.7447, P<.0001), and the index of determination (r(2)) was 0,5. The result of the Passing-Bablok analysis was a slope of 1.658 (1.452 to 1.897) and an intersection of 2.044 (-0,936 to 5.393). The optimal cutoff for PSAl% (<=14.7854) showed a sensitivity of 89.29% [95% CI, 0,642-0,823] and a specificity of 54.29% (95% CI, 0,642-0,823). The optimal cutoff for PSAc% (>89.7796) had a sensitivity of 71.43% (95% CI, 0,616-0,802) and a specificity of 71.43% (95% CI, 0,616-0,802). There were no significant differences when comparing the areas under the curve of both markers (P=.59). The PPV of PSAl% was less than that of PSAc% (45.7% vs. 71%). CONCLUSION: There was a good correlation between PSAl% and PSAc%. PSAc% has demonstrated greater specificity and efficacy than PSAl% in the diagnosis of prostate cancer. PMID- 23639235 TI - Contralateral carotid occlusion in endovascular and surgical carotid revascularization: a single centre experience with literature review and meta analysis. AB - OBJECTIVE/BACKGROUND: The influence of contralateral carotid occlusion (CCO) on the outcome of carotid endarterectomy (CEA) and stenting (CAS) is debated. This study aims to evaluate CEA and CAS results in patients with CCO. METHODS: All carotid revascularizations from 2005 to 2011 were analyzed, focusing on the role of CCO on 30-day cerebral events and death (CED). A meta-analysis was performed to evaluate the results of the literature by random effect. RESULTS: Of the 1,218 carotid revascularizations performed in our institution, 706 (57.9%) were CEA and 512 (42.1%) were CAS. CED occurred in 3.6% of the CEAs and 8.2% of the CASs (p = .001). CCO was present in 37 (5.2%) CEAs and 38 (7.4%) CASs. In CEA, CCO patients had a higher CED compared with the non-CCO patients (16.2% vs. 2.9%, p = .001), as confirmed by multiple regression analysis (OR [odds ratio]: 5.1[1.7-14.5]). In CAS, CED was not significantly different in the CCO and non-CCO patients (2.6% vs. 8.7%, p = 0.23). The comparative analysis of the CCO patients showed a higher CED in CEA compared with that in CAS (16.2% vs. 2.6%, p = 0.04). Meta-analysis of 33 papers (27 on CEA and 6 on CAS) revealed that CCO was associated with a higher CED in CEA, but not in CAS (OR: 1.82 [1.57-2.11]; OR: 1.22 [0.60-2.49], respectively). CONCLUSION: CCO can be considered as a risk factor for CED in CEA, but not in CAS. CAS appears to be associated with lower CED than CEA in CCO patients. PMID- 23639237 TI - Outpatient surgical treatment of female stress urinary incontinence under local anesthesia-sedation with contrasure needleless incision. AB - OBJECTIVE: To evaluate the results obtained from out-patient surgical treatment of female stress urinary incontinence (SUI) with the use of trans-obturator tape (TOT) of a single Contrasure-Needleless incision (Neomedic-International). PATIENTS AND METHOD: We performed an intervention with local anesthesia-sedation in outpatient regime between January 2007 to December 2011 on 96 patients affected by SUI using the placement of Needleless tension-free suburethral sling. Inclusion and discharge criteria and the results obtained as well as satisfaction grade were evaluated by a questionnaire. All the patients underwent a stress test, urodynamic study and quality of life questionnaire (ICIQ-SF) prior to and at least 3 months after the intervention. RESULTS: Tolerance to the procedure was good. Surgical time was less than 10 minutes and stay in the hospital up to discharge less than 2hours. The results obtained are superimposable to those reached with epidural anesthesia and hospitalization, the grade of satisfactions with the treatment received being superior to 90%. CONCLUSIONS: Almost all of the patients affected are candidates for inclusion in an outpatient surgery program. This noticeably improves the cost-efficacy ratio, without decreasing the health care or grade of satisfaction. Furthermore, the Contasure-Needleless system fulfills the criteria for minimally invasive surgery, providing better stability of the sling than the third generation "minibands" due to the greater length of the mesh and less post-operative pain regarding the conventional TOT as no cutaneous incisions are required. PMID- 23639238 TI - Editorial comment. PMID- 23639239 TI - Vesicouretral reflux with neuropathic bladder: studying the resolution rate after ileocystoplasty. AB - OBJECTIVE: To study vesicoureteral reflux (VUR) resolution and risk of pyelonephritis after augmentation ileocystoplasty in a cohort of patients with noncompliant neuropathic bladder. METHODS: We reviewed data for all children who underwent augmentation ileocystoplasty for noncompliant neuropathic bladder with associated VUR between July 2002 and July 2009. All patients were kept on oral antibiotic prophylaxis. Patients were followed up with renal/bladder ultrasound and voiding cystourethrography at 3 months postoperatively and annually thereafter. RESULTS: A total of 52 patients with mean age 8.7 years (range 4-17 years) were identified. VUR was unilateral in 21 patients (40%) and bilateral in 31 patients (60%). VUR was low-grade (1-3) in 20 patients (38.5%) and high-grade (4-5) in 32 patients (61.5%). Mean follow-up duration was 27 months (range 12-80 months). VUR resolved in 35 of 52 patients (67%). Low-grade VUR resolved in 18 of 20 patients (90%), whereas high-grade reflux resolved in 17 of 32 patients (53%). This difference is statistically significant (P = .006). Although no patient with initial low-grade VUR developed pyelonephritis during follow-up, 8 of 32 patients (25%) with initial high-grade VUR developed pyelonephritis. Only 1 of 17 patients (6%) with resolved high-grade VUR developed pyelonephritis vs 7 of 15 patients (47%) with persistent high-grade VUR. Again the difference is statistically significant (P = .008). CONCLUSION: Bilateral high-grade VUR in patients with neuropathic bladder persist after bladder augmentation in nearly half of patients. Half of those develop pyelonephritis during follow-up. Therefore, at the time of bladder augmentation for noncompliant neuropathic bladder, concomitant antireflux surgery should be performed for all patients with bilateral high-grade VUR. PMID- 23639240 TI - Renal rhabdomyosarcoma in a pancake kidney. AB - Renal rhabdomyosarcoma (RMS) is a rare pediatric tumor. Pancake kidneys are unusual anatomic anomalies resulting when both upper and lower poles of the embryonic kidney become fused. We report on a 4-year-old boy who was discovered to have a stage 4, group IV renal embryonal RMS arising from a pancake kidney with metastases to the lung, pelvis, and bone marrow. Treatment included multimodal therapy, consisting of neoadjuvant chemotherapy, complete surgical resection, and adjuvant chemotherapy. He remains in clinical remission 7 months after resection. PMID- 23639241 TI - SIU scholar: Dr. Benjamin Okafor Ayogu. PMID- 23639244 TI - Insights into the interfacial properties of low-voltage CuPc field-effect transistor. AB - The interfacial transport properties and density of states (DOS) of CuPc near the dielectric surface in an operating organic field-effect transistor (OFET) are investigated using Kelvin probe force microscopy. We find that the carrier mobility of CuPc on high-k Al2Oy/TiOx (ATO) dielectrics under a channel electrical field of 4.3 * 10(2) V/cm reaches 20 times as large as that of CuPc on SiO2. The DOS of the highest occupied molecular orbital (HOMO) of CuPc on the ATO substrate has a Gaussian width of 0.33 +/- 0.02 eV, and the traps DOS in the gap of CuPc on the ATO substrate is as small as 7 * 10(17) cm(-3). A gap state near the HOMO edge is observed and assigned to the doping level of oxygen. The measured HOMO DOS of CuPc on SiO2 decreases abruptly near E(V(GS) = V(T)), and the pinning of DOS is observed, suggesting a higher trap DOS of 10(19)-10(20) cm( 3) at the interface. The relationships between DOS and the structural, chemical, as well as electrical properties at the interface are discussed. The superior performance of CuPc/ATO OFET is attributed to the low trap DOS and doping effect. PMID- 23639245 TI - Neuronal mechanisms of visual perceptual learning. AB - Numerous psychophysical studies have described perceptual learning as long lasting improvements in perceptual discrimination and detection capabilities following practice. Where and how long-term plastic changes occur in the brain is central to understanding the neural basis of perceptual learning. Here, neurophysiological research using non-human primates is reviewed to address the neural mechanisms underlying visual perceptual learning. Previous studies have shown that training either has no effect on or only weakly alters the sensitivity of neurons in early visual areas, but more recent evidence indicates that training can cause long-term changes in how sensory signals are read out in the later stages of decision making. These results are discussed in the context of learning specificity, which has been crucial in interpreting the mechanisms underlying perceptual learning. The possible mechanisms that support learning related plasticity are also discussed. PMID- 23639243 TI - Early upper digestive tract side effects of zidovudine with tenofovir plus emtricitabine in West African adults with high CD4 counts. AB - INTRODUCTION: Tenofovir (TDF) with emtricitabine (FTC) and zidovudine (ZDV) is a recognized alternate first-line antiretroviral (ART) regimen for patients who cannot start treatment with non-nucleoside reverse transcriptase inhibitors (NNRTIs). Clinical studies comparing TDF+FTC+ZDV to other regimens are lacking. METHODS: Participants in a trial of early ART in Cote d'Ivoire (Temprano ANRS 12136) started treatment with TDF/FTC plus either efavirenz (EFV) or ZDV (HIV-1+2 dually infected patients and women refusing contraception or previously treated with nevirapine). We compared rates of upper digestive serious adverse events (sAEs) between TDF/FTC+EFV and TDF/FTC+ZDV patients during the first six months of treatment. sAEs were defined as either grade 3-4 AEs or persistent grade 1-2 AEs leading to drug discontinuation. RESULTS: A total of 197 patients (76% women, median CD4 count 395/mm(3)) started therapy with TDF/FTC, 126 with EFV and 71 with ZDV. During the first six months of ART, 94 patients had digestive AEs (nausea/vomiting) of any grade (EFV 36/126, 29%; ZDV 58/71, 82%, p<0.0001), including 20 sAEs (EFV 3/126, 5%; ZDV 17/71, 24%, p<0.0001). In-patients on TDF/FTC+ZDV with digestive AEs, the median time to the first symptom was two days (IQR: 1-4). Plasma ZDV (Cmax) distributions and pill ZDV dosages were normal. Patients with digestive AEs had higher haemoglobin levels and tended to have higher body mass indices and more frequent past histories of cotrimoxazole (CTX) prophylaxis. CONCLUSIONS: We observed an unexpectedly high rate of digestive sAEs in West African adults, mostly women, who started a 3-nuc ART with TDF/FTC+ZDV in Cote d'Ivoire. These adults were participating in a trial of early ART and had much higher CD4 counts than those who currently routinely start ART in sub Saharan Africa. They all received CTX concomitantly with ZDV. We suggest that further early prescriptions of TDF+XTC+ZDV should be carefully monitored and that whenever possible, the rate of early upper digestive adverse events should be compared to that occurring in-patients taking other drug regimens. CLINICAL TRIAL NUMBER: NCT00495651. PMID- 23639246 TI - Differential induction of cytochrome P450 isoforms and peroxisomal proliferation by cyfluthrin in male Wistar rats. AB - Cyfluthrin effects on in vivo drug metabolizing enzymes were evaluated using the oxidative substrate antipyrine. Antipyrine pharmacokinetics in plasma and urinary excretion of its major metabolites with and without cyfluthrin oral treatment (20mg/kg/day for 6 days) were investigated in rats. Cyfluthrin increased the apparent intrinsic clearance and decreased the antipyrine half-life at beta phase. Cyfluthrin also increased the clearance of the antipyrine metabolites, norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine and the formation rate constants for each of the three metabolites measured in urine. These results suggest that cyfluthrin affects hepatic cytochrome P450 (CYP) system. In order to confirm, a second experiment was carried out. We evaluated the effects of repeated exposure to cyfluthrin on hepatic and renal CYP2E, CYP1A and CYP4A subfamilies and peroxisomal proliferation in rats following oral administration (10 and 20mg/kg/day for 6 days). At the highest dose, cyfluthrin increased renal and hepatic O-deethylation of ethoxyresorufin and O-demethylation of methoxyresorufin, metabolism mediated by the CYP1A subfamily. Liver and kidney were susceptible to cyfluthrin-dependent induction of 12- and 11-hydroxylation of lauric acid, suggesting CYP4A subfamily induction. Also cyfluthrin increased the beta-oxidation of palmitoyl-coenzyme A and carnitine acetyltransferase activity, supporting cyfluthrin as a peroxisome proliferator. In conclusion, the demonstration that cyfluthrin induced hepatic CYP1A, CYP4A subfamilies and peroxisomal proliferation raises the possibility of cyfluthrin could produce changes in oxidative stress. PMID- 23639247 TI - PF-04691502 triggers cell cycle arrest, apoptosis and inhibits the angiogenesis in hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in the world. The aim of the present study is to determine the antitumor effect of PF 04691502, a potent inhibitor of PI3K and mTOR kinases, on the apoptosis and angiogenesis of the hepatoma cancer cells. Our results indicate that treatment of cancer cells with PF-04691502 reduces cell viability and inhibits cell growth in a dose-dependent manner. PF-04691502 triggers apoptosis via a mitochondrial pathway, accompanied by activation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP). Pre-treatment of hepatoma cells with the caspase-3 inhibitor (z-DEVD-fmk) blocks the PF-04691502-induced death of these cells. In addition, growth factors-induced tube formation and the migration of HUVECs are markedly inhibited by PF-04691502 treatment. The mechanisms of anti-angiogenesis of PF 04691502 are associated with inhibiting the expression of VEGF and HIF-1alpha. Based on the overall results, we suggest that PF-04691502 reduces hepatocellular carcinoma cell viability, induces cell apoptosis, and inhibits cell growth and tumor angiogenesis, implicating its potential therapeutic value in the treatment of HCC. PMID- 23639248 TI - Bone morphogenetic protein-7 inhibits silica-induced pulmonary fibrosis in rats. AB - Bone morphogenetic protein-7 (BMP-7) has been shown to inhibit liver and renal fibrosis in in vivo and vitro studies. There is no study to investigate BMP-7's role in the development of pulmonary fibrosis induced by silica. In the current study, we used the rat model to explore the potential antifibrotic role of BMP-7 and its underlying mechanism in silica-induced pulmonary fibrosis. Sixty Wistar rats were randomly assigned into three groups. Control group received saline, silica group received silica and BMP-7 treated group received silica and BMP-7. BMP-7 was administered to silica-treated rats intraperitoneally at a dose of 300MUg/kg/injection from day 8 to day 30 every other day. After the animals were sacrificed on day 15 and 30, hydroxyproline levels, the protein expressions of BMP/Smad and TGF-beta/Smad signaling, and histopathology in lung tissues were analyzed. The hydroxyproline contents in BMP-7 treated groups were significantly lower than the silica groups (P<0.05). Histopathological results showed BMP-7 could reduce the progression of silica induced fibrosis. Furthermore, the expression of p-Smad1/5/8, a marker of BMP/Smad signaling, was significantly up regulated in BMP-7 treated groups (P<0.05) compared with the silica groups. On the contrary, the expression of p-Smad2/3, a marker for TGF-beta/Smad signaling, reduced significantly in BMP-7-treated groups compared with silica groups (P<0.05). In conclusion, the pulmonary fibrosis induced by silica in rats was significantly reduced with the therapeutic treatment of BMP-7. The antifibrotic effect of BMP-7 could be related to the activation of BMP/Smad signaling and inhibition of TGF-beta/Smad pathways. PMID- 23639249 TI - Indoxyl 3-sulfate stimulates Th17 differentiation enhancing phosphorylation of c Src and STAT3 to worsen experimental autoimmune encephalomyelitis. AB - Although AhR activation regulates CD4T cell differentiation, how it works has yet to be elucidated. In the present study, using in vitro Th17 differentiation model, we examined effects of AhR activation by indoxyl 3-sulfate (I3S), a uremic toxin, on Th17 differentiation and investigated underlying mechanisms. I3S increased expression of RORgammat, the master transcription factor for Th17 differentiation, and stimulated Th17 differentiation, in a comparative manner as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a prototypical AhR ligand. Activation of STAT3, which is phosphorylated by the IL-6 signaling pathways and thus is necessary for Th17 differentiation, was strongly stimulated by I3S and TCDD. Phosphorylation of c-Src, which was shown to be activated by AhR ligands, was also increased by I3S and TCDD, and blocking of c-Src activity by 4-amino-5-(4 chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine (PP2) inhibited phosphorylation of both c-Src and STAT3, raising a possibility that stimulatory activities of I3S and TCDD on Th17 differentiation could be exerted via increased phosphorylation of c-Src, which in turn stimulates STAT3 activation. Finally, we found that I3S worsened experimental autoimmune encephalomyelitis (EAE), which is primarily mediated by Th17 cells, enhancing the frequency of IL-17-producing cells in draining lymph nodes. PMID- 23639250 TI - Dental caries among children visiting a mobile dental clinic in South Central Kentucky: a pooled cross-sectional study. AB - BACKGROUND: Dental caries is one of the most common chronic childhood diseases affecting a large portion of children in the United States. The prevalence of childhood dental caries in Kentucky is among the highest in the nation. The purposes of this study are to (1) compare sociodemographic differences between caries and no caries groups and (2) investigate factors associated with untreated dental caries among children who visited a mobile dental clinic in South Central Kentucky. METHODS: Study subjects were children aged 6 to 15 years who participated in the school-based dental sealant program through the mobile dental clinic operated by the Institute for Rural Health at Western Kentucky University between September 2006 and May 2011 (n = 2,453). Descriptive statistics were calculated for sociodemographic factors (age, gender, race/ethnicity, insurance status, and urban versus rural residential location) and caries status. We used chi-square tests to compare sociodemographic differences of children stratified by caries and no caries status as well as three levels of caries severity. We developed a logistic regression model to investigate factors associated with untreated dental caries while controlling for sociodemographic characteristics. RESULTS: The proportion of children having untreated dental caries was 49.7% and the mean number of untreated dental caries was 2.0. The proportion of untreated dental caries was higher in older children, children with no insurance and living in rural residential locations, and caries severity was also higher in these groups. Odds ratio indicated that older ages, not having private insurance (having only public, government-sponsored insurance or no insurance at all) and rural residential location were associated with having untreated dental caries after controlling for sociodemographic characteristics of children. CONCLUSIONS: Untreated dental caries was more likely to be present in older children living in rural areas without insurance. Health interventionists may use this information and target rural children without having proper insurance in order to reduce geographic disparities in untreated dental caries in South Central Kentucky. PMID- 23639251 TI - Genetic and environmental influences of daily and intra-individual variation in testosterone levels in middle-aged men. AB - BACKGROUND: Testosterone regulates numerous physiological processes, and evidence suggests that it plays a critical role in male aging. It has yet to be determined whether the heritability of testosterone varies in accordance with its diurnal rhythm. Similarly, it is unclear whether changes in testosterone level throughout the day are genetically influenced. The aim of the present study was to determine the degree to which genetic and environmental factors contribute to individual differences in testosterone throughout the day in middle-aged men. METHODS: Saliva-based measures of free testosterone, sampled at multiple time-points both at-home and in-lab, were collected from 783 male twins (193 monozygotic pairs, 196 dizygotic pairs, 5 unpaired twins) as part of the Vietnam Era Twin Study of Aging (VETSA). The average age of participants was 55.9 years (SD=2.6). RESULTS: Testosterone levels declined substantially over the course of the day, with 32 39% of the change occurring in the first 30min after waking. Heritability estimates for specific time-points ranged from .02 to .39. The heritability of the average at-home and in-lab testosterone values were notably higher (.42 and .47 respectively). Daily rates of change showed some evidence of genetic influence, with heritability estimates ranging from .15 to .29, whereas there were no observable genetic influences on coefficients of variation. CONCLUSIONS: Genetic influences account for a significant proportion of the variance in average testosterone levels, while environmental factors account for the majority of intra-individual variability. These results highlight the need to explore both genetic and individual-specific environmental factors as determinants of free testosterone levels in aging men. PMID- 23639253 TI - Effect of emulsification on the skin permeation and UV protection of catechin. AB - An anti-aging effect may be obtained by skin application of tea catechins (Camellia sinensis) since they have high ultraviolet (UV)-protection activity. In this study, the skin permeation of catechin (C), epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECg) and epigallocatechin gallate (EGCg) was determined and compared, and the effect of emulsification on the skin permeation of C was measured. The UV-protective effect of C was also determined. The in vitro skin permeability of each catechin derivative was determined using side-by-side diffusion of cells. The UV-protective effect of C was determined by applying different concentrations of C to the solution or emulsion on a three dimensional cultured human skin model or normal human epidermal keratinocytes with UV-irradiation. ECg and EGCg with gallate groups showed lower skin permeability than C, EC and EGC without gallate groups, suggesting that the skin permeability of catechin derivatives may be dependent on the existence of a gallate group. Interestingly, the skin permeation of C was increased by an o/w emulsification. In addition, the C emulsion showed a significantly higher UV protective effect by C than that with its aqueous solution. These results suggest that the o/w emulsion of catechin derivatives is probably useful as a cosmetic formulation with anti-aging efficacy. PMID- 23639252 TI - Stress and telomere biology: a lifespan perspective. AB - In the past decade, the growing field of telomere science has opened exciting new avenues for understanding the cellular and molecular substrates of stress and stress-related aging processes over the lifespan. Shorter telomere length is associated with advancing chronological age and also increased disease morbidity and mortality. Emerging studies suggest that stress accelerates the erosion of telomeres from very early in life and possibly even influences the initial (newborn) setting of telomere length. In this review, we highlight recent empirical evidence linking stress and mental illnesses at various times across the lifespan with telomere erosion. We first present findings in the developmental programming of telomere biology linking prenatal stress to newborn and adult telomere length. We then present findings linking exposure to childhood trauma and to certain mental disorders with telomere shortening. Last, we review studies that characterize the relationship between related health-risk behaviors with telomere shortening over the lifespan, and how this process may further buffer the negative effects of stress on telomeres. A better understanding of the mechanisms that govern and regulate telomere biology throughout the lifespan may inform our understanding of etiology and the long-term consequences of stress and mental illnesses on aging processes in diverse populations and settings. PMID- 23639254 TI - Associations between single-nucleotide polymorphism in the FNDC3A and autism spectrum disorder in a Korean population. AB - Autism spectrum disorder (ASD) is a neurodevelopmental syndrome associated with impairments of reciprocal communication and cognitive function. Associations between single-nucleotide polymorphisms (SNPs) and ASD were analysed by logistic regression. Polymorphisms in fibronectin type III domain-containing 3A (FNDC3A) exhibited significant associations in genotype and diplotype analyses. We conclude that FNDC3A influences the prevalence of ASD. PMID- 23639255 TI - Drop-out from adolescent and young adult inpatient treatment for anorexia nervosa. AB - We examined factors predictive of dropout from inpatient treatment for anorexia nervosa (AN) among adolescents in a prospective study of 359 consecutive hospitalizations for AN (DSM-IV). Patients were assessed at admission (clinical, socio-demographic, and psychological data). Multivariate analyses were performed. Drop-out (i.e. leaving hospital before the target weight is achieved) occurred in 24% (n=86) of hospitalizations; in 42.3% (n=30) of the cases, dropout was initiated by the treatment team and in 58.6% (n=41) by the patients and/or their parents. 18.6% (16/86) occurred during the first half of the inpatient program. Frequency of drop-out was significantly higher when the patient was living with only one parent, had been hospitalized previously, had a lower BMI at admission and was over 18 at admission. These elements should draw the attention of the clinician, so that he/she can prepare hospitalization with patients presenting lower admission BMI, particularly by motivational interventions for a better therapeutic alliance, and by the deployment of intensive accompaniment of single parents. Further studies aiming to replicate these results, and including the evaluation of other clinical dimensions such as impulsivity and other personality traits, are needed to elucidate this important topic. PMID- 23639256 TI - The enhanced effect of lupeol on the destruction of gastric cancer cells by NK cells. AB - Lupeol, a triterpene, was reported to possess beneficial effects as a therapeutic and preventive agent for a range of disorders. Many studies have confirmed that lupeol possesses strong activities such as antioxidative, antiinflammatory, antiarthritic, antimutagenic, and antimalarial, both in vitro and in vivo, and at its effective therapeutic doses exhibit no toxicity to normal cells and tissues. Lupeol was observed to inhibit the proliferation of gastric tumour cells in a dose-dependent manner, as assessed by MTT assay, and induce the proliferation of NK cells, as assessed by flow cytometry and Western blotting. The killing effect of NK cells on gastric tumour cells was assessed by LDH. Our experiment demonstrated that lupeol at appropriate concentrations could promote the proliferation of NK cells, inhibit the proliferation of gastric cancer cell lines BGC823, N87 and HGC27, and increase the killing effect of NK cells on gastric cancer cells. We speculated that lupeol might increase the expression of PFP, IFN gamma, and CD107a via the activation of PI3K/Akt and Wnt/beta-catenin signalling pathways. Lupeol could serve as a potential agent against gastric cancer; however, further in-depth in vivo studies are still required. PMID- 23639257 TI - Competing physiological pathways link individual differences in weight and abdominal adiposity to white matter microstructure. AB - Being overweight or obese is associated with reduced white matter integrity throughout the brain. It is not yet clear which physiological systems mediate the association between inter-individual variation in adiposity and white matter. We tested whether composite indicators of cardiovascular, lipid, glucose, and inflammatory factors would mediate the adiposity-related variation in white matter microstructure, measured with diffusion tensor imaging on a group of neurologically healthy adults (N=155). A composite factor representing adiposity (comprised of body mass index and waist circumference) was associated with smaller fractional anisotropy and greater radial diffusivity throughout the brain, a pattern previously linked to myelin structure changes in non-human animal models. A similar global negative association was found for factors representing inflammation and, to a lesser extent, glucose regulation. In contrast, factors for blood pressure and dyslipidemia had positive associations with white matter in isolated brain regions. Taken together, these competing influences on the diffusion signal were significant mediators linking adiposity to white matter and explained up to fifty-percent of the adiposity-white matter variance. These results provide the first evidence for contrasting physiological pathways, a globally distributed immunity-linked negative component and a more localized vascular-linked positive component, that associate adiposity to individual differences in the microstructure of white matter tracts in otherwise healthy adults. PMID- 23639258 TI - Methodology for improved detection of low concentration metabolites in MRS: optimised combination of signals from multi-element coil arrays. AB - State of the art magnetic resonance imaging (MRI) scanners are generally equipped with multi-element receive coils; 16 or 32 channel coils are common. Their development has been predominant for parallel imaging to enable faster scanning. Less consideration has been given to localized magnetic resonance spectroscopy (MRS). Multinuclear studies, for example (31)P or (13)C MRS, are often conducted with a single element coil located over the region of interest. (1)H MRS studies have generally employed the same multi-element coils used for MRI, but little consideration has been given as to how the spectroscopic data from the different channels are combined. In many cases it is simply co-added with detrimental effect on the signal to noise ratio. In this study, we derive the optimum method for combining multi-coil data, namely weighting with the ratio of signal to the square of the noise. We show that provided that the noise is uncorrelated, this is the theoretical optimal combination. The method is demonstrated for in vivo proton MRS data acquired using a 32 channel receive coil at 7T in four different brain areas; left motor and right motor, occipital cortex and medial frontal cortex. PMID- 23639259 TI - Minimum-norm cortical source estimation in layered head models is robust against skull conductivity error. AB - The conductivity profile of the head has a major effect on EEG signals, but unfortunately the conductivity for the most important compartment, skull, is only poorly known. In dipole modeling studies, errors in modeled skull conductivity have been considered to have a detrimental effect on EEG source estimation. However, as dipole models are very restrictive, those results cannot be generalized to other source estimation methods. In this work, we studied the sensitivity of EEG and combined MEG+EEG source estimation to errors in skull conductivity using a distributed source model and minimum-norm (MN) estimation. We used a MEG/EEG modeling set-up that reflected state-of-the-art practices of experimental research. Cortical surfaces were segmented and realistically-shaped three-layer anatomical head models were constructed, and forward models were built with Galerkin boundary element method while varying the skull conductivity. Lead-field topographies and MN spatial filter vectors were compared across conductivities, and the localization and spatial spread of the MN estimators were assessed using intuitive resolution metrics. The results showed that the MN estimator is robust against errors in skull conductivity: the conductivity had a moderate effect on amplitudes of lead fields and spatial filter vectors, but the effect on corresponding morphologies was small. The localization performance of the EEG or combined MEG+EEG MN estimator was only minimally affected by the conductivity error, while the spread of the estimate varied slightly. Thus, the uncertainty with respect to skull conductivity should not prevent researchers from applying minimum norm estimation to EEG or combined MEG+EEG data. Comparing our results to those obtained earlier with dipole models shows that general judgment on the performance of an imaging modality should not be based on analysis with one source estimation method only. PMID- 23639260 TI - Motion artifacts in functional near-infrared spectroscopy: a comparison of motion correction techniques applied to real cognitive data. AB - Motion artifacts are a significant source of noise in many functional near infrared spectroscopy (fNIRS) experiments. Despite this, there is no well established method for their removal. Instead, functional trials of fNIRS data containing a motion artifact are often rejected completely. However, in most experimental circumstances the number of trials is limited, and multiple motion artifacts are common, particularly in challenging populations. Many methods have been proposed recently to correct for motion artifacts, including principle component analysis, spline interpolation, Kalman filtering, wavelet filtering and correlation-based signal improvement. The performance of different techniques has been often compared in simulations, but only rarely has it been assessed on real functional data. Here, we compare the performance of these motion correction techniques on real functional data acquired during a cognitive task, which required the participant to speak aloud, leading to a low-frequency, low amplitude motion artifact that is correlated with the hemodynamic response. To compare the efficacy of these methods, objective metrics related to the physiology of the hemodynamic response have been derived. Our results show that it is always better to correct for motion artifacts than reject trials, and that wavelet filtering is the most effective approach to correcting this type of artifact, reducing the area under the curve where the artifact is present in 93% of the cases. Our results therefore support previous studies that have shown wavelet filtering to be the most promising and powerful technique for the correction of motion artifacts in fNIRS data. The analyses performed here can serve as a guide for others to objectively test the impact of different motion correction algorithms and therefore select the most appropriate for the analysis of their own fNIRS experiment. PMID- 23639261 TI - Dominant frequencies of resting human brain activity as measured by the electrocorticogram. AB - The brain's spontaneous, intrinsic activity is increasingly being shown to reveal brain function, delineate large scale brain networks, and diagnose brain disorders. One of the most studied and clinically utilized types of intrinsic brain activity are oscillations in the electrocorticogram (ECoG), a relatively localized measure of cortical synaptic activity. Here we objectively characterize the types of ECoG oscillations commonly observed over particular cortical areas when an individual is awake and immobile with eyes closed, using a surface-based cortical atlas and cluster analysis. Both methods show that [1] there is generally substantial variability in the dominant frequencies of cortical regions and substantial overlap in dominant frequencies across the areas sampled (primarily lateral central, temporal, and frontal areas), [2] theta (4-8 Hz) is the most dominant type of oscillation in the areas sampled with a mode around 7 Hz, [3] alpha (8-13 Hz) is largely limited to parietal and occipital regions, and [4] beta (13-30 Hz) is prominent peri-Rolandically, over the middle frontal gyrus, and the pars opercularis. In addition, the cluster analysis revealed seven types of ECoG spectral power densities (SPDs). Six of these have peaks at 3, 5, 7 (narrow), 7 (broad), 10, and 17 Hz, while the remaining cluster is broadly distributed with less pronounced peaks at 8, 19, and 42 Hz. These categories largely corroborate conventional sub-gamma frequency band distinctions (delta, theta, alpha, and beta) and suggest multiple sub-types of theta. Finally, we note that gamma/high gamma activity (30+ Hz) was at times prominently observed, but was too infrequent and variable across individuals to be reliably characterized. These results should help identify abnormal patterns of ECoG oscillations, inform the interpretation of EEG/MEG intrinsic activity, and provide insight into the functions of these different oscillations and the networks that produce them. Specifically, our results support theories of the importance of theta oscillations in general cortical function, suggest that alpha activity is primarily related to sensory processing/attention, and demonstrate that beta networks extend far beyond primary sensorimotor regions. PMID- 23639262 TI - A user-study measuring the effects of lexical simplification and coherence enhancement on perceived and actual text difficulty. AB - PURPOSE: Low patient health literacy has been associated with cost increases in medicine because it contributes to inadequate care. Providing explanatory text is a convenient approach to distribute medical information and increase health literacy. Unfortunately, writing text that is easily understood is challenging. This work tests two text features for their impact on understanding: lexical simplification and coherence enhancement. METHODS: A user study was conducted to test the features' effect on perceived and actual text difficulty. Individual sentences were used to test perceived difficulty. Using a 5-point Likert scale, participants compared eight pairs of original and simplified sentences. Abstracts were used to test actual difficulty. For each abstract, four versions were created: original, lexically simplified, coherence enhanced, and lexically simplified and coherence enhanced. Using a mixed design, one group of participants worked with the original and lexically simplified documents (no coherence enhancement) while a second group worked with the coherence enhanced versions. Actual difficulty was measured using a Cloze measure and multiple choice questions. RESULTS: Using Amazon's Mechanical Turk, 200 people participated of which 187 qualified based on our data qualification tests. A paired-samples t-test for the sentence ratings showed a significant reduction in difficulty after lexical simplification (p<.001). Results for actual difficulty are based on the abstracts and associated tasks. A two-way ANOVA for the Cloze test showed no effect of coherence enhancement but a main effect for lexical simplification, with the simplification leading to worse scores (p=.004). A follow-up ANOVA showed this effect exists only for function words when coherence was not enhanced (p=.008). In contrast, a two-way ANOVA for answering multiple choice questions showed a significant beneficial effect of coherence enhancement (p=.003) but no effect of lexical simplification. CONCLUSIONS: Lexical simplification reduced the perceived difficulty of texts. Coherence enhancement reduced the actual difficulty of text when measured using multiple-choice questions. However, the Cloze measure results showed that lexical simplification can negatively impact the flow of the text. PMID- 23639264 TI - Divergent nuclear 18S rDNA paralogs in a turkey coccidium, Eimeria meleagrimitis, complicate molecular systematics and identification. AB - Multiple 18S rDNA sequences were obtained from two single-oocyst-derived lines of each of Eimeria meleagrimitis and Eimeria adenoeides. After analysing the 15 new 18S rDNA sequences from two lines of E. meleagrimitis and 17 new sequences from two lines of E. adenoeides, there were clear indications that divergent, paralogous 18S rDNA copies existed within the nuclear genome of E. meleagrimitis. In contrast, mitochondrial cytochrome c oxidase subunit I (COI) partial sequences from all lines of a particular Eimeria sp. were identical and, in phylogenetic analyses, COI sequences clustered unambiguously in monophyletic and highly supported clades specific to individual Eimeria sp. Phylogenetic analysis of the new 18S rDNA sequences from E. meleagrimitis showed that they formed two distinct clades: Type A with four new sequences; and Type B with nine new sequences; both Types A and B sequences were obtained from each of the single-oocyst-derived lines of E. meleagrimitis. Together these rDNA types formed a well-supported E. meleagrimitis clade. Types A and B 18S rDNA sequences from E. meleagrimitis had a mean sequence identity of only 97.4% whereas mean sequence identity within types was 99.1-99.3%. The observed intraspecific sequence divergence among E. meleagrimitis 18S rDNA sequence types was even higher (approximately 2.6%) than the interspecific sequence divergence present between some well-recognized species such as Eimeria tenella and Eimeria necatrix (1.1%). Our observations suggest that, unlike COI sequences, 18S rDNA sequences are not reliable molecular markers to be used alone for species identification with coccidia, although 18S rDNA sequences have clear utility for phylogenetic reconstruction of apicomplexan parasites at the genus and higher taxonomic ranks. PMID- 23639263 TI - Framing the evidence for health smart homes and home-based consumer health technologies as a public health intervention for independent aging: a systematic review. AB - INTRODUCTION: There is a critical need for public health interventions to support the independence of older adults as the world's population ages. Health smart homes (HSH) and home-based consumer health (HCH) technologies may play a role in these interventions. METHODS: We conducted a systematic review of HSH and HCH literature from indexed repositories for health care and technology disciplines (e.g., MEDLINE, CINAHL, and IEEE Xplore) and classified included studies according to an evidence-based public health (EBPH) typology. RESULTS: One thousand, six hundred and thirty-nine candidate articles were identified. Thirty one studies from the years 1998-2011 were included. Twenty-one included studies were classified as emerging, 10 as promising and 3 as effective (first tier). CONCLUSION: The majority of included studies were published in the period beginning in the year 2005. All 3 effective (first tier) studies and 9 of 10 of promising studies were published during this period. Almost all studies included an activity sensing component and most of them used passive infrared motion sensors. The three effective (first tier) studies all used a multicomponent technology approach that included activity sensing, reminders and other technologies tailored to individual preferences. Future research should explore the use of technology for self-management of health by older adults; social support; and self-reported health measures incorporated into personal health records, electronic medical records, and community health registries. PMID- 23639266 TI - The nervous and prenervous roles of serotonin in Echinococcus spp. AB - Serotonin (5-hydroxytryptamine, 5-HT) is an important neuroactive and morphogenetic molecule in several metazoan phyla, including flatworms. Serotoninergic nervous system studies are incomplete and 5-HT function/s are unknown in Echinococcus spp., the flatworm parasites that cause hydatid disease. In the present work, we searched for genes of the serotoninergic pathway and performed immunocytochemical and functional analyses of 5-HT in Echinococcus spp. Bioinformatic analysis using the recently available Echinococcus multilocularis and Echinococcus granulosus genomes suggests the presence of genes encoding enzymes, receptors and transporters participating in 5-HT synthesis, sensing and transport in these parasites. However, some components of the pathway could not be identified, suggesting loss or divergence of parasite homologous genes. The serotoninergic neuroanatomy study performed by confocal scanning laser microscopy on different E. granulosus stages showed an increasing level of complexity when the protoscolex develops towards the adult stage and a progressive diminution when the parasite develops towards the metacestode stage. The role of 5-HT as a neurotransmitter in E. granulosus was evaluated by determining the effect of this substance on protoscolex motility. The addition of 5-HT to protoscoleces induced a significant increase in motility for short time periods. Preincubation with 100 MUM citalopram, a known 5-HT transporter inhibitor, abolished the 5-HT-induced increase in motility, indicating that the effect could be mediated by a 5-HT transporter. Incubation of protoscoleces with 5-HT for time periods of several days induced a progressive differentiation towards the metacestode stage. The results indicate that 5-HT could have nervous and prenervous roles during Echinococcus spp. development. Taking into account the important roles of 5-HT in parasite biology and the divergence of 5-HT pathway genes with respect to human counterparts, the serotoninergic system could be considered as an amenable drug target against hydatid disease. PMID- 23639265 TI - RNA-mediated gene suppression and in vitro culture in Hymenolepis microstoma. AB - Hymenolepis microstoma, the mouse bile-duct tapeworm, is a classical rodent hosted model that provides easy laboratory access to all stages of the life cycle. Recent characterisation of its genome has greatly advanced its utility for molecular research, albeit contemporary techniques such as those for assaying gene function have yet to be developed in the system. Here we present research on the development of RNA-mediated gene suppression via RNA interference (RNAi), and on in vitro culture of the enteric, adult phase of the life cycle to support this work. We demonstrate up to 80% quantitative suppression of a Hox transcript via soaking activated juvenile worms with double-stranded RNAs. However, we were unable to achieve segmentation of the worms in culture despite extensive manipulations of the culture media and supplements, preventing functional interpretation. An alternative, in vivo approach to RNAi was also tested by exposing cysticercoids prior to inoculation in mice, but fluorescent labelling showed that the RNAs did not sufficiently penetrate the cyst body and no difference in expression was found between exposed and control groups grown in vivo. Genomic and transcriptomic data revealed that H. microstoma has two orthologs each of Dicer, Drosha and Ago-1-like genes and that expression of one of the Ago-1 genes appears exclusive to germline development, suggesting that two or more independent RNA-mediated pathways are in operation. These studies demonstrate the viability of RNAi in H. microstoma and extend the utility of the model for research in the genomic era. PMID- 23639267 TI - Trigger-free anesthetic management in congenital long QT syndrome. PMID- 23639268 TI - Molecular and hematological studies in a large cohort of alpha(0)-thalassemia in northeast Thailand: data from a single referral center. AB - alpha(0)-thalassemia is the most severe form of alpha-thalassemia alleles found among Southeast Asian and Chinese populations and can cause a fatal condition known as hemoglobin Bart's hydrops fetalis and hemoglobin H disease. In order to provide the molecular epidemiological characteristic of alpha(0)-thalassemia in northeast Thailand, a total of 12,525 blood specimens referred to our center at Khon Kaen University in northeast Thailand during October 2008 to January 2012 were studied. Hematological parameters were recorded and DNA deletions causing alpha(0)-thalassemia were examined by PCR related techniques. Among 12,525 samples examined, alpha(0)-thalassemia alleles were identified in 1,873 (15.0%) samples, including 1855 (14.8%) cases with Southeast Asian (--(SEA)) deletion and 18 cases (0.2%) with THAI deletion (--(THAI)). As many as twenty genotypes were encountered. Hb profiles and hematological parameters were comparatively presented. Data on prevalence, molecular features and phenotypic expression of alpha(0)-thalassemia should prove useful in a carrier screening and a prevention and control program of this common genetic disorder in the region. PMID- 23639269 TI - Successful treatment of mechanical mitral valve thrombosis without thrombolytic therapy or surgery. AB - Prosthetic valve thrombosis is an uncommon, life-threatening complication that often mandates urgent repeat surgery or thrombolytic therapy. We present an alternative approach in a patient with rheumatic heart disease who presented with subacute thrombosis of a recently implanted On-X mechanical mitral valve (On-X Life Technologies Inc, Austin, TX), diagnosed on echocardiography and valve fluoroscopy. The patient refused surgery, hence we elected to treat the patient with high-dose antithrombotic therapy alone. Echocardiographic monitoring demonstrated complete reabsorption of the thrombus within 6 months without any embolic complications. Endogenous fibrinolysis with appropriate antithrombotic therapy might be a suitable option for select, high-risk patients with mechanical mitral valve thrombosis. PMID- 23639270 TI - Recent-onset atrial fibrillation in patients with left ventricular dysfunction: amiodarone or vernakalant? PMID- 23639271 TI - Guideline adherence in management of stable chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the only leading cause of death with rising morbidity and mortality. Clinical practice guidelines (CPGs) to optimize pharmacotherapy for patients with COPD have been updated based on promising results of randomized clinical trials. We examined the frequency of and factors associated with guideline adherence by physicians in clinical practice at an academic medical center. METHODS: Patients with a clinical diagnosis of COPD, confirmed by spirometry, who presented to the ambulatory clinics, were enrolled. The primary outcome was provider's adherence to the 2007 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Subjects were categorized as guideline-concordant who received a rescue inhaler (all patients), or at least one long-acting bronchodilator (stage II), or at least one long-acting bronchodilator plus an inhaled corticosteroid (stage III IV). Demographics, clinical information and type of provider were recorded. Provider type was classified as primary care physician (PCP), pulmonologist, or co-management by both. RESULTS: Among 450 subjects who met study criteria, 246 (54.7%) received guideline-concordant treatment. Age, sex, race, disease severity, and co-morbidities were not associated with guideline adherence. Multivariate analysis showed that patients co-managed by a PCP and pulmonologist had a higher likelihood of receiving guideline-concordant treatment than those managed by one or the other (Odds Ratio: 4.59; 95% Confidence Interval: 2.92, 7.22, p < 0.001). CONCLUSIONS: Just over half of stable COPD patients receive guideline-concordant care. Co-management by a PCP and pulmonologist increases the likelihood of receiving guideline-concordant inhaler therapy. PMID- 23639272 TI - CD8(+) T cells characterize early smoking-related airway pathology in patients with asthma. AB - BACKGROUND: Smoking in asthma occurs frequently and is associated with increased symptom severity, an impaired response to corticosteroids, and accelerated lung function decline. Airway pathology in smoking asthmatics is characterized by neutrophilia and epithelial changes such as goblet cell hyperplasia and increased proliferation. Bronchial CD8(+) T cells are implicated in lung function decline in asthma and COPD. We hypothesized that smoking modifies airway inflammation in asthma by increasing the number of CD8(+) T cells at an early stage. OBJECTIVES & METHODS: To study effects of smoking on airway pathology in bronchial biopsies from atopic patients with controlled intermittent or mild persistent asthma (12 smokers, 9.7 py and 11 never-smokers, 0.0 py; 20-50 yrs; FEV1 > 70% predicted; PC20MCh < 8 mg/mL, no ICS) using immunohistochemistry. RESULTS: Smoking asthmatics showed higher numbers of bronchial CD8(+) T cells (55.8 vs 23.9 cells/0.1 mm(2); p = 0.001) and CD68(+) macrophages (7.5 vs 4.6 cells/0.1 mm(2), p = 0.012), and a lower CD4(+)/CD8(+) cell ratio (0.16 vs 0.40; p = 0.007) compared with non-smoking asthmatics, but no difference in neutrophils. Furthermore, the % intact epithelium was higher in smoking asthmatics (49.3 vs 23.3, p = 0.001). CONCLUSION: Smoking asthmatics with a limited smoking history show a distinct pattern of airway pathology characterized by a bronchial infiltrate of CD8(+) T cells and CD68(+) macrophages, and epithelial remodelling resembling COPD-like features. This raises the hypothesis that early presence of CD8(+) T cells contributes to disease progression in smoking asthmatics. PMID- 23639274 TI - Modification and patterning of nanometer-thin poly(ethylene glycol) films by electron irradiation. AB - In this study, we analyzed the effect of electron irradiation on highly cross linked and nanometer-thin poly(ethylene glycol) (PEG) films and, in combination with electron beam lithography (EBL), tested the possibility to prepare different patterns on their basis. Using several complementary spectroscopic techniques, we demonstrated that electron irradiation results in significant chemical modification and partial desorption of the PEG material. The initially well defined films were progressively transformed in carbon-enriched and oxygen depleted aliphatic layers with, presumably, still a high percentage of intermolecular cross-linking bonds. The modification of the films occurred very rapidly at low doses, slowed down at moderate doses, and exhibited a leveling off behavior at higher doses. On the basis of these results, we demonstrated the fabrication of wettability patterns and sculpturing complex 3D microstructures on the PEG basis. The swelling behavior of such morphological patterns was studied in detail, and it was shown that, in contrast to the pristine material, irradiated areas of the PEG films reveal an almost complete absence of the hydrogel-typical swelling behavior. The associated sealing of the irradiated areas allows a controlled deposition of objects dissolved in water, such as metal nanoparticles or fluorophores, into the surrounding, pristine areas, resulting in the formation of nanocomposite patterns. In contrast, due to the distinct protein repelling properties of the PEG films, proteins are exclusively adsorbed onto the irradiated areas. This makes such films a suitable platform to prepare protein affinity patterns in a protein-repelling background. PMID- 23639273 TI - [Recommendations of the Spanish Pancreatic Club on the diagnosis and treatment of chronic pancreatitis: part 2 (treatment)]. AB - Chronic pancreatitis (CP) is a complex disease with a wide spectrum of clinical manifestations ranging from asymptomatic disease to disabling forms or serious complications. The management of CP frequently differs among geographical areas and even among centers. These differences are due to the scarcity of high-quality studies and clinical practice guidelines that focus on the diagnosis and treatment of this disease. The aim of the Spanish Pancreatic Club was to create evidence-based recommendations for the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. These experts were selected on the basis of their clinical and research experience in CP. A list of questions was drawn up and each question was then reviewed by two panelists. These questions were then used to produce a draft, which was discussed in a face to-face meeting with all the participants. Levels of evidence were based on the classification of the Oxford Centre for Evidence-Based Medicine. In the second part of the consensus process, recommendations were established for the management of pain, pseudocysts, biliary and duodenal stenosis, pancreatic fistula and ascites, left portal hypertension, diabetes mellitus, exocrine pancreatic insufficiency, and nutritional support in CP. PMID- 23639275 TI - Embodied health: the effects of a mind-body course for medical students. AB - OBJECTIVE: An effective career in medicine requires empathy and compassion, yet the demands of a medical education increase stress and decrease students' ability to connect with patients. However, research suggests mind-body practices improve psychological well-being. This study aimed to evaluate the psychological effects on medical students of an 11-week elective course, Embodied Health or EH, which combines yoga and meditation with neuroscience didactics. METHODS: The effects on 27 first- and second-year medical students were evaluated via surveys in four areas: empathy, perceived stress, self-regulation, and self-compassion. Scales used were 1. Jefferson Scale of Physician Empathy, which measures empathy among health students and professionals and medical students on a scale of 1 (least empathetic) to 7 (most empathetic); 2. Cohen's Perceived Stress Scale, a measure of the perceived uncontrollability of respondents' lives, from 0 (least stressed) to 4 (most stressed); 3. Self-Regulation Questionnaire, which measures the development and maintenance of planned behavior to achieve goals, from 1 (least self-regulated) to 5 (most self-regulated); and 4. Self-Compassion Scale, which measures self-criticism, from 1 (least self-compassionate) to 5 (most self compassionate). Students also reflected on EH's impact on their well-being in a post-course essay. RESULTS: Self-regulation and self-compassion rose 0.13 (SD 0.20, p=0.003) and 0.28 (SD 0.61, p=0.04), respectively. Favorable changes were also seen in empathy and perceived stress, which went up by 0.11 (SD 0.50, p=0.30) and down by 0.05 (SD 0.62, p=0.70), respectively; these changes did not reach statistical significance. Students' essays were found to discuss the following recurrent themes: 1) Reconnection between mind and body; 2) Community in a competitive environment; 3) Increased mindfulness; 4) Confidence in use of mind-body skills with patients; and 5) Stress management. These themes overlapped with the measures EH affected quantitatively. CONCLUSION: A mind-body course for medical students increased self-regulation and self-compassion. Qualitative themes discussed in students' post-course essays reflected these effects. PMID- 23639276 TI - Comments on "Physiological time: a hypothesis". PMID- 23639277 TI - Culture and the Constructal-Law evolution of the human and machine species: comment on "An evolutionary framework for cultural change: selectionism versus communal exchange" by L. Gabora. PMID- 23639278 TI - Is temporal scaling at the basis of allometry?: comment on "Physiologic time: a hypothesis" by West and West. PMID- 23639279 TI - Toward an integrated view of psychophysiological time: comment on "Physiologic time: a hypothesis" by West and West. PMID- 23639280 TI - Is cultural change adaptive?: comment on "An evolutionary framework for cultural change: selectionism versus communal exchange" by Liane Gabora. PMID- 23639281 TI - Posterior ligamentous complex healing following disruption in thoracolumbar fractures. AB - Classification schemes for thoracolumbar fractures attempt to categorize them as either stable or unstable. Stable fractures heal with conservative treatment strategies such as bracing, while unstable fractures require operative internal fixation. Until recently, most classification schemes recognized the importance of the pattern and location of bony disruption in segregating stable and unstable fractures. Recently, the integrity of the posterior ligamentous complex was found to influence the degree of the stability of thoracolumbar fractures. Disruption of the intervertebral disc and ligaments increases spinal instability. Unlike bone, it is thought that these ligaments do not have the capacity to heal. However, this notion is not founded by substantial evidence. It is, hence, important to determine the extent of ligamentous healing in the spine as this will influence directing therapy towards not only bony fusion, but also ligamentous union. PMID- 23639282 TI - Metabolic stress in infected cells may represent a therapeutic target for human immunodeficiency virus infection. AB - Worldwide, there are thousands of new cases of human immunodeficiency virus-1 (HIV-1) infection per day. The effectiveness of current combination antiretroviral therapy (ART) is relative; to prioritize finding vaccines and/or cure-oriented initiatives should be reinforced because there is little room, if any, for procrastination. Basic and clinical findings on HIV-1 reservoirs suggest that disruption of virus latency is feasible. Because the goal is curing HIV-1 infection, we should be aware that the challenge is to eradicate the viruses of every single infected cell and consequently acting upon virus latency is necessary but not sufficient. The large majority of the virus reservoir, CD4(+) T lymphocytes, is readily accessible but other minor reservoirs, where ART does not diffuse, require innovative strategies. The situation closely resembles that currently faced in the treatment of cancer. Exploiting the fact that histone deacetylase inhibitors, mainly vorinostat, may disrupt the latency of HIV-1, we propose to supplement this effect with a programmed interference in the metabolic stress of infected cells. Metformin and chloroquine are cheap and accessible modulators of pro-survival mechanisms to which viruses are constantly confronted to generate alternative energy sources and maximize virus production. Metformin restrains the use of the usurped cellular biosynthetic machinery by viral genes and chloroquine contributes to death of infected cells. We suggest that the combination of vorinostat, chloroquine and metformin should be combined with ART to pursue viral eradication in infected cells. PMID- 23639283 TI - Correcting lenticular astigmatism by reinstating the correct neuromuscular message. AB - THE PROBLEM: The spasm of the oblique muscles can contribute to lenticular astigmatism. The visual cortex interprets the tension of the oblique muscles as an eye that is in near focus mode. It overrides the response to the information generated by depth perception to bring a distant image into focus. Any excessive effort to bring it into focus will not be successful and continuing to make that effort can cause a misalignment in the tension of the rectus muscles. This in turn can directly induce corneal astigmatism and indirectly induce lenticular astigmatism. The astigmatic eye can still bring a near image into focus, but a distant image remains aberrant. METHODOLOGY: The design of a special contact lens to treat lenticular astigmatism is similar to the design of a contact lens to treat corneal astigmatism by means of orthoculogy (or ortho C) as outlined in the paper Correcting Corneal Astigmatism by Reinstating the Correct Neuromuscular Message. The ortho C lens is worn for about two minutes to attend to the blur and distorted aspects of "simple myopic astigmatism". Both of these refractive errors are corrected simultaneously. RESULTS: Once the oblique muscles become "loose" due to a "contact lens draw", it triggers the visual cortex to reinstate the proper neuromotor message to stimulate the ciliary muscle (the muscle that controls the shape of the crystalline lens) to relax along a certain meridian which in turn "flattens" the crystalline lens along that meridian to bring a blur and distorted image in the distance into focus. The correction only takes a few minutes because the ciliary muscle of an astigmatic eye was not compromised. CONCLUSION: The correction is not strictly due to an ortho C lens. Its design is the same for corneal astigmatism or lenticular astigmatism. The purpose of the design is to "loosen" the oblique muscles in a certain manner depending on the degree of astigmatism instead of a specific type of astigmatism. The visual cortex can discriminate whether to correct for corneal astigmatism or lenticular astigmatism after the "draw" from the lens relaxes the oblique muscles. PMID- 23639284 TI - MiR-17-92 cluster is a novel regulatory gene of cardiac ischemic/reperfusion injury. AB - The miR-17-92 cluster is an important microRNA cluster in the animals. It was mainly investigated as an oncogene in tumors but never studied in cardiovascular disease. On one aspect, miR-17-92 cluster is documented to play anti-apoptotic roles in tumor cells, including hypoxia-induced apoptosis. The families of miR 17, miR-19, and miR-92 promote resistance to apoptosis by directly inhibiting pro apoptotic protein, and by the two major cell survival signaling pathways PI3K/AKT, and MAPK/ERK. On the other aspect, the component members of miR-17-92 cluster are high expressed in the hearts of canine and mice, suggesting that there are effect targets of the cluster in the myocardium. So that, we hypothesized that the miR-17-92 cluster may protect the heart by diminishing the apoptosis and alleviating ischemia/reperfusion injury. This may be a new regulating target for patients with myocardial infarction and undergoing cardiac surgery. PMID- 23639285 TI - PC3 (BTG2/TIS21) possible role in chromosome instability syndromes. AB - Chromosome instability syndromes (CIS) are autosomal recessive genetic disorders associated with defects in cell cycle regulation following DNA damage. Although most of the proteins involved in these syndromes have been identified as part of the MRN complex, little is known about their physiological functions and their interactions with other molecules that might explain the wide clinical presentation found in CIS patients. Here we discuss several observations suggesting that PC3 (BTG2/TIS21) - a protein involved in G1-S checkpoint progression control - might play a role in these pathologies. PMID- 23639286 TI - The expression level of myocardial beta1-adrenergic receptor affects metoprolol antihypertensive effects: a novel mechanism for interindividual difference. AB - Numerous studies revealed that the effective rate of beta-blockers for hypertension treatment is about 50 ~ 60%, which was mainly due to interindividual difference in drug response, especially for beta-blocker metoprolol. Previous studies have demonstrated that cytochrome P450 2D6 (CYP2D6) and beta1-adrenergic receptor (ADRB1) gene polymorphisms could affect metoprolol antihypertensive efficacy. However, even for patients with essential hypertension who have the same genotype in CYP2D6 and ADRB1 genes, their response to metoprolol is still different. Recently, we found that antihypertensive effects of metoprolol would be improved by increasing the expression level of myocardial Adrb1 in spontaneously hypertensive rats which had the same genotype. Therefore, we present a hypothesis that the expression level of myocardial ADRB1 could affect the antihypertensive effects, which may be a novel mechanism for interindividual difference in patients with essential hypertension treated by metoprolol. PMID- 23639287 TI - A second generation cervico-vaginal lavage device shows similar performance as its preceding version with respect to DNA yield and HPV DNA results. AB - BACKGROUND: Attendance rates of cervical screening programs can be increased by offering HPV self-sampling to non-attendees. Acceptability, DNA yield, lavage volumes and choice of hrHPV test can influence effectiveness of the self-sampling procedures and could therefore play a role in recruiting non-attendees. To increase user-friendliness, a frequently used lavage sampler was modified. In this study, we compared this second generation lavage device with the first generation device within similar birth cohorts. METHODS: Within a large self sampling cohort-study among non-responders of the Dutch cervical screening program, a subset of 2,644 women received a second generation self-sampling lavage device, while 11,977 women, matched for age and ZIP-code, received the first generation model. The second generation device was different in shape, color, lavage volume, and packaging, in comparison to its first generation model. The Cochran's test was used to compare both devices for hrHPV positivity rate and response rate. To correct for possible heterogeneity between age and ZIP codes in both groups the Breslow-Day test of homogeneity was used. A T-test was utilized to compare DNA yields of the obtained material in both groups. RESULTS: Median DNA yields were 90.4 MUg/ml (95% CI 83.2-97.5) and 91.1 MUg/ml (95% CI 77.8 104.4, p= 0.726) and hrHPV positivity rates were 8.2% and 6.9% (p= 0.419) per sample self-collected by the second - and the first generation of the device (p= 0.726), respectively. In addition, response rates were comparable for the two models (35.4% versus 34.4%, p= 0.654). CONCLUSIONS: Replacing the first generation self-sampling device by an ergonomically improved, second generation device resulted in equal DNA yields, comparable hrHPV positivity rates and similar response rates. Therefore, it can be concluded that the clinical performance of the first and second generation models are similar. Moreover, participation of non-attendees in cervical cancer screening is probably not predominantly determined by the type of self-collection device. PMID- 23639289 TI - Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: differences between primary and cancer cells. AB - The molecular mechanism of Salinomycin's toxicity is not fully understood. Various studies reported that Ca(2+), cytochrome c, and caspase activation play a role in Salinomycin-induced cytotoxicity. Furthermore, Salinomycin may target Wnt/beta-catenin signaling pathway to promote differentiation and thus elimination of cancer stem cells. In this study, we show a massive autophagic response to Salinomycin (substantially stronger than to commonly used autophagic inducer Rapamycin) in prostrate-, breast cancer cells, and to lesser degree in human normal dermal fibroblasts. Interestingly, autophagy induced by Salinomycin is a cell protective mechanism in all tested cancer cell lines. Furthermore, Salinomycin induces mitophagy, mitoptosis and increased mitochondrial membrane potential (?Psi) in a subpopulation of cells. Salinomycin strongly, and in time dependent manner decreases cellular ATP level. Contrastingly, human normal dermal fibroblasts treated with Salinomycin show some initial decrease in mitochondrial mass, however they are largely resistant to Salinomycin-triggered ATP-depletion. Our data provide new insight into the molecular mechanism of preferential toxicity of Salinomycin towards cancer cells, and suggest possible clinical application of Salinomycin in combination with autophagy inhibitors (i.e. clinically-used Chloroquine). Furthermore, we discuss preferential Salinomycins toxicity in the context of Warburg effect. PMID- 23639290 TI - The effect of ultraviolet radiation on the anti-inflammatory effect of filters. AB - A certain number of filters have notable anti-inflammatory properties with percentage inhibition of PMA-induced edema in mice at over 70%. The question arose as to whether this effect was likely to continue after UV irradiation. It can be noted that 7 filters retain an equivalent anti-inflammatory effect before and after 2h of irradiation in a Suntest device (650 W/m(2)). For 9 filters, the anti-inflammatory effect decreases and for 5 filters, the anti-inflammatory effect increases. Various behaviors should be noted. 3 groups of substances can be distinguished: such as phenylbenzimidazole sulfonic acid which loses its anti inflammatory character after irradiation (the percentage inhibition falls from 80 to 44%), oxybenzone which retains a constant anti-inflammatory character (89% inhibition before and after irradiation and also octyl methoxycinnamate which becomes very anti-inflammatory (with a percentage inhibition of 93%). The same phenomenon is observed in the case of commercial products. This should be made known as it can have a considerable impact on the results which are displayed on the packaging of sun products. PMID- 23639288 TI - p27 suppresses cyclooxygenase-2 expression by inhibiting p38beta and p38delta mediated CREB phosphorylation upon arsenite exposure. AB - p27 is a cyclin-dependent kinase (CDK) inhibitor that suppresses a cell's transition from G0 to S phase, therefore acting as a tumor suppressor. Our most recent studies demonstrate that upon arsenite exposure, p27 suppresses Hsp27 and Hsp70 expressions through the JNK2/c-Jun- and HSF-1-dependent pathways, suggesting a novel molecular mechanism underlying the tumor suppressive function of p27 in a CDK-independent manner. We found that p27-deficiency (p27-/-) resulted in the elevation of cyclooxygenase-2 (COX-2) expression at transcriptional level, whereas the introduction of p27 brought back COX-2 expression to a level similar to that of p27+/+ cells, suggesting that p27 exhibits an inhibitory effect on COX-2 expression. Further studies identified that p27 inhibition of COX-2 expression was specifically due to phosphorylation of transcription factor cAMP response element binding (CREB) phosphorylation mediated by p38beta and p38delta. These results demonstrate a novel mechanism underlying tumor suppression effect of p27 and will contribute to the understanding of the overall mechanism of p27 tumor suppression in a CDK independent manner. PMID- 23639292 TI - Laser phototherapy at high energy densities do not stimulate pre-osteoblast growth and differentiation. AB - OBJECTIVE: The aim of this study is to evaluate the effects of red and infrared lasers at high energy densities on pre-osteoblast MC3T3 proliferation and differentiation. BACKGROUND DATA: The acceleration of bone regeneration by low intensity laser irradiation may hold potential benefits in clinical therapy in orthopedics and dentistry. MATERIALS AND METHODS: Cells were irradiated with red (660 nm) and infrared (780 nm) lasers (90 and 150 J/cm2, 40 mW). The control group did not receive irradiation. Cell growth was assessed by a colorimetric test (MTT) (24, 48, 72, 96 h) and cell differentiation was evaluated by alkaline phosphatase (ALP) quantification after growth in osteogenic medium (72, 96 h; 7, 14 days). RESULTS: None of the irradiation groups had an enhancement in cell growth (p<0.05). The production of ALP was not influenced by irradiation at any period of time (p>0.05). CONCLUSIONS: The low intensity laser stimulated neither cell growth nor the production of alkaline phosphatase. PMID- 23639291 TI - Functional benefits of PLGA particulates carrying VEGF and CoQ10 in an animal of myocardial ischemia. AB - Myocardial ischemia (MI) remains one of the leading causes of death worldwide. Angiogenic therapy with the vascular endothelial growth factor (VEGF) is a promising strategy to overcome hypoxia and its consequences. However, from the clinical data it is clear that fulfillment of the potential of VEGF warrants a better delivery strategy. On the other hand, the compelling evidences of the role of oxidative stress in diseases like MI encourage the use of antioxidant agents. Coenzyme Q10 (CoQ10) due to its role in the electron transport chain in the mitochondria seems to be a good candidate to manage MI but is associated with poor biopharmaceutical properties seeking better delivery approaches. The female Sprague Dawley rats were induced MI and were followed up with VEGF microparticles intramyocardially and CoQ10 nanoparticles orally or their combination with appropriate controls. Cardiac function was assessed by measuring ejection fraction before and after three months of therapy. Results demonstrate significant improvement in the ejection fraction after three months with both treatment forms individually; however the combination therapy failed to offer any synergism. In conclusion, VEGF microparticles and CoQ10 nanoparticles can be considered as promising strategies for managing MI. PMID- 23639293 TI - Zymographic patterns of MMP-2 and MMP-9 in the CSF and cerebellum of dogs with subacute distemper leukoencephalitis. AB - Distemper leukoencephalitis is a disease caused by the canine distemper virus (CDV) infection. It is a demyelinating disease affecting mainly the white matter of the cerebellum and areas adjacent to the fourth ventricle; the enzymes of the matrix metalloproteinases (MMPs) group, especially MMP-2 and MMP-9 have a key role in the myelin basic protein fragmentation and in demyelination, as well as in leukocyte traffic into the nervous milieu. To evaluate the involvement of MMPs during subacute distemper leukoencephalitis, we measured the levels of MMP-2 and MMP-9 by zymography in the cerebrospinal fluid (CSF) and in the cerebellum of 14 dogs naturally infected with CDV and 10 uninfected dogs. The infected dogs presented high levels of pro-MMP-2 in the CSF and elevated levels of pro-MMP-2 and pro-MMP-9 in the cerebellar tissue. Active MMP-2 was detected in the CSF of some infected dogs. As active MMP-2 and MMP-9 are required for cellular migration across the blood-brain barrier and any interference between MMPs and their inhibitors may result in an amplification of demyelination, this study gives additional support to the involvement of MMPs during subacute distemper leukoencephalitis and suggests that MMP-2 and MMP-9 may take part in the brain inflammatory changes of this disease. PMID- 23639294 TI - Early serum hepatitis B virus large surface protein level: a stronger predictor of virological response to peginterferon alfa-2a than that to entecavir in HBeAg positive patients with chronic hepatitis B. AB - BACKGROUND: The response rate to antiviral therapy varies greatly among individuals, and its prediction is still very challenging. OBJECTIVES: To evaluate the usefulness of serum hepatitis B virus large surface protein (LHBs) levels compared with HBsAg in prediction of the antiviral treatment effect. STUDY DESIGN: Quantification of LHBs, HBsAg and HBV DNA was carried out at baseline and during antiviral therapy (weeks 4, 12, 24, 36 and 48) in HBeAg-positive patients treated with peginterferon alfa-2a (n = 21) or entecavir (n = 41). RESULTS: The serum LHBs concentration was correlated positively with HBV DNA and HBsAg (r = 0.635 and 0.588, respectively). LHBs and HBV DNA levels decreased significantly in a biphasic manner and HBsAg level tended to decrease slowly in both treatment groups. In peginterferon alfa-2a group, the cutoff of 88.46 ng/ml in serum LHBs at week 4 gave the best AUC ( = 0.96) with positive and negative predictive values of 88.9% and 100%, in association with virological response (VR). Serum LHBs level at week 4 also showed an association with VR in entecavir group (AUC 0.78). The predictive model incorporating LHBs, HBsAg and HBV DNA could discriminate VR at baseline (AUC 0.79) and showed an association with serological response (SR) at week 12 (AUC 0.80) in peginterferon alfa-2a group. CONCLUSIONS: On-treatment quantification of serum LHBs may be a more useful parameter for predicting VR in patients on peginterferon alfa-2a than those on entecavir. Combining LHBs, HBsAg and HBV DNA can predict VR and SR more effectively and earlier. PMID- 23639295 TI - Brazilian marsupial frogs are diphyletic (Anura: Hemiphractidae: Gastrotheca). AB - Molecular phylogenetic analyses based on expanded taxonomic and geographic sampling support the monophyly of the marsupial frog genera (family Hemiphractidae), resolve six geographically circumscribed lineages within Gastrotheca, and, for the first time, reveal that two divergent lineages of Gastrotheca inhabit the Atlantic Coastal Forests of Brazil. Within Gastrotheca, the earliest diverging clade is confined to northeastern Brazil, whereas the three subsequent diverging lineages are restricted to northern Venezuela (G. walkeri), southeastern Brazil, and northwestern South America. All species in these clades inhabit humid forests at low to mid-elevations, and their life histories are characterized by lacking free-living tadpoles (i.e., direct development). Two derived clades inhabit the Andes, and both contain species with either direct development or tadpoles. One Andean clade of Gastrotheca ranges in the high Andes from Colombia to extreme northern Peru, whereas the other clade inhabits high elevations in the Andes of southern Ecuador, Peru, and Bolivia, and lower elevations in the Andes of northwestern Argentina. The presence of two non sister lineages on each side of the Amazon Basin suggests that vicariance across this central region played an important role in diversification within Gastrotheca. PMID- 23639296 TI - Geographical origin and sexual-system evolution of the androdioecious plant Gynochthodes boninensis (Rubiaceae), endemic to the Bonin Islands, Japan. AB - Gynochthodes boninensis is a woody climber endemic to the Bonin Islands, Japan. It is characterized by an androdioecious sexual system, which is rare in angiosperms. We conducted a molecular phylogenetic analysis of 29 taxa including 61 samples from the tribe Morindeae to elucidate the geographical origin of G. boninensis by determining its progenitor species. We also investigated evolutionary transitions among different sexual systems within this plant group. The combined ETS, ITS, and trnT-F sequence data showed that G. boninensis formed a monophyletic group, but it did not form a clade with G. umbellata, which was treated as the same species, whereas it formed a clade with G. parvifolia, which is distributed in southeastern Asia. This suggests that G. boninensis evolved independently from G. umbellata, and probably originated from a progenitor native to southeastern Asia. In the clade composed of the three species of G. boninensis, G. parvifolia, and G. umbellata, only G. boninensis is androdioecious, whereas the others are dioecious. Thus, the androdioecious sexual system of G. boninensis may have evolved from dioecy. PMID- 23639297 TI - ELISA for determination of total coagulation factor XII concentration in human plasma. AB - Human blood coagulation factor XII (FXII) is the one chain 80 kDa zymogen form of the active serine protease alpha-FXIIa, which consists of a heavy and light chain linked by a disulfide bond, the light chain being responsible for the proteolytical activity. FXII is the first component of the contact dependent pathway of coagulation, but its physiological role is still subject to debate. In the present study we utilized two monoclonal antibodies against the heavy chain of FXII to establish a sandwich enzyme linked immunosorbent assay (ELISA) for quantification of total FXII concentration in human plasma samples. A unique characteristic of this assay is its equal recognition of FXII and inhibitor bound FXII. This is important, as inhibitor complexes of alpha-FXIIa are formed in vivo as well as during blood sampling and handling. Validation of the assay demonstrated a high sensitivity, with a limit of detection and quantification of 1.2 ng/mL and 2.6 ng/mL respectively. The coefficients of variation for the repeatability and within-laboratory standard deviations were 2.6% and 5.2% respectively. The reference interval determined from healthy volunteers (n=240) was 10.6-43 mg/L. PMID- 23639299 TI - The association between meditation practice and treatment outcome in Mindfulness based Cognitive Therapy for bipolar disorder. AB - This study aimed to examine the impact of quantity of mindfulness meditation practice on the outcome of psychiatric symptoms following Mindfulness-based Cognitive Therapy (MBCT) for those diagnosed with bipolar disorder. Meditation homework was collected at the beginning of each session for the MBCT program to assess quantity of meditation practice. Clinician-administered measures of hypo/mania and depression along with self-report anxiety, depression and stress symptom questionnaires were administered pre-, post-treatment and at 12-month follow-up. A significant correlation was found between a greater number of days meditated throughout the 8-week trial and clinician-rated depression scores on the Montgomery-Asberg Depression Rating Scale at 12-month follow-up. There were significant differences found between those who meditated for 3 days a week or more and those who meditated less often on trait anxiety post-treatment and clinician-rated depression at 12-month follow-up whilst trends were noted for self-reported depression. A greater number of days meditated during the 8-week MBCT program was related to lower depression scores at 12-month follow-up, and there was evidence to suggest that mindfulness meditation practice was associated with improvements in depression and anxiety symptoms if a certain minimum amount (3 times a week or more) was practiced weekly throughout the 8-week MBCT program. PMID- 23639298 TI - False-positive immunogenicity responses are caused by CD20+ B cell membrane fragments in an anti-ofatumumab antibody bridging assay. AB - An electrochemiluminescent (ECL) bridging assay to detect anti-ofatumumab antibodies (ADA) in human serum samples was developed and validated. Using this assay format, clinical samples were first screened to identify potential ADA positive samples, which were then further tested by adding excess drug, confirming the positive signals as drug specific. However, when the method was implemented into clinical studies for ADA testing, a high positive rate was observed in the pre-dose samples collected from patients with chronic lymphocytic leukemia (CLL). Since the positive signals were not associated with ofatumumab (Ofa) treatment, and diminished after treatment, it was suspected that matrix interference might be responsible, resulting in false-positive responses. We performed a series of experimental investigations to identify, characterize, minimize or eliminate the possible false-positive responses. One possible source was identified to be CD20 (the target of Ofa) present on cell membrane fragments (CMFs). The false-positive responses caused by CD20(+) CMFs could be reduced by solid-phase immunodepletion, ultracentrifugation, or inhibited by adding another anti-CD20 antibody (rituximab). As a consequence, the ADA method was modified to minimize the matrix interference caused by CD20(+) CMFs and, then, validated for sample testing. PMID- 23639300 TI - Internet-based guided self-help for university students with anxiety, depression and stress: a randomized controlled clinical trial. AB - Anxiety, depression and stress, often co-occurring, are the psychological problems for which university students most often seek help. Moreover there are many distressed students who cannot, or choose not to, access professional help. The present study evaluated the efficacy of an internet-based guided self-help program for moderate anxiety, depression and stress. The program was based on standard cognitive behavior therapy principles and included 5 core modules, some of which involved options for focusing on anxiety and/or depression and/or stress. Trained student coaches provided encouragement and advice about using the program via e-mail or brief weekly phone calls. Sixty-six distressed university students were randomly assigned to either Immediate Access or a 6-week Delayed Access condition. Sixty-one percent of Immediate Access participants completed all 5 core modules, and 80% of all participants completed the second assessment. On the Depression, Anxiety and Stress Scales-21, Immediate Access participants reported significantly greater reductions in depression (etap(2)=. 07), anxiety (etap(2)=. 08) and stress (etap(2)=. 12) in comparison to participants waiting to do the program, and these improvements were maintained at a six month follow-up. The results suggest that the provision of individually-adaptable, internet-based, self-help programs can reduce psychological distress in university students. PMID- 23639302 TI - The widening of the gaze cone in patients with social anxiety disorder and its normalization after CBT. AB - Gaze plays a crucial role in social interactions. Social Anxiety Disorder (SAD), which is associated with severe impairment of social interactions, is thus likely to exhibit disturbances of gaze perception. We conducted two experiments with SAD patients and healthy control participants using a virtual head whose gaze could be interactively manipulated. We determined the subjective area of mutual gaze, the so-called gaze cone, and measured it prior to and after a psychotherapeutic intervention (Exp. 1). Patients exhibited larger gaze cones than control subjects. Exp. 2 varied the emotional expression of the virtual head. These data were validated using a real person (professional actor) as stimulus. Excellent reliability indices were found for our gaze cone measure. After Cognitive Behavioral Therapy, group differences in gaze cone width had disappeared. Emotional expressions were observed to modulate the gaze cone's width. Especially an angry expression caused the gaze cone to widen, possibly mediated by increased arousal. Finally, wider gaze cones in SAD-patients could be demonstrated for virtual and for real human heads confirming the ecological validity of virtual heads. The findings are of relevance for a more fine-grained understanding of perceptual processes in patients with SAD. PMID- 23639301 TI - Fear, avoidance and physiological symptoms during cognitive-behavioral therapy for social anxiety disorder. AB - We examined fear, avoidance and physiological symptoms during cognitive behavioral therapy (CBT) for social anxiety disorder (SAD). Participants were 177 individuals with generalized SAD who underwent a 14-week group CBT as part of a randomized controlled treatment trial. Participants filled out self-report measures of SAD symptoms at pre-treatment, week 4 of treatment, week 8 of treatment, and week 14 of treatment (post-treatment). Cross-lagged Structural Equation Modeling indicated that during the first 8 weeks of treatment avoidance predicted subsequent fear above and beyond previous fear, but fear did not predict subsequent avoidance beyond previous avoidance. However, during the last 6 weeks of treatment both fear and avoidance predicted changes in each other. In addition, changes in physiological symptoms occurred independently of changes in fear and avoidance. Our findings suggest that changes in avoidance spark the cycle of change in treatment of SAD, but the cycle may continue to maintain itself through reciprocal relationships between avoidance and fear. In addition, physiological symptoms may change through distinct processes that are independent from those involved in changes of fear and avoidance. PMID- 23639303 TI - The role of the therapeutic relationship in cognitive behaviour therapy for chronic fatigue syndrome. AB - Cognitive behaviour therapy (CBT) for chronic fatigue syndrome (CFS) can reduce fatigue and impairment. Recently, it was found that changes in fatigue perpetuating factors, i.e. focusing on symptoms, control over fatigue, perceived activity and physical functioning, are associated with and explain up to half of the variance in fatigue during CBT for CFS. The therapy relationship, e.g. outcome expectations and working alliance, may also contribute to treatment outcome. We aimed to examine the role of the therapy relationship in CBT and determine whether it exerts its effect independently of changes in fatigue perpetuating factors. We used a cohort of 217 CFS patients in which the pattern of change in fatigue-perpetuating factors was examined previously. Fatigue, therapy relationship and fatigue-perpetuating factors were measured at the start of therapy, three times during CBT and at the end of therapy. Baseline outcome expectations and agreement about the content of therapy predicted post therapy fatigue. A large part of the variance in post-treatment fatigue (25%) was jointly explained by outcome expectations, working alliance and changes in fatigue perpetuating factors. From this, we conclude that positive outcome expectations and task agreement seem to facilitate changes in fatigue-perpetuating factors during CBT for CFS. It is therefore important to establish a positive therapy relationship early in therapy. PMID- 23639304 TI - Referral for psychological therapy of people with long term conditions improves adherence to antidepressants and reduces emergency department attendance: controlled before and after study. AB - BACKGROUND: Referral to psychological therapies is recommended for people with common mental health problems (CMHP) however its impact on healthcare utilisation in people with long term conditions (LTCs) is not known. METHOD: Routinely collected primary care, psychological therapy clinic and hospital data were extracted for the registered population of 20 practices (N = 121,199). These data were linked using the SAPREL (Secure and Private Record Linkage) method. We linked the 1118 people referred to psychological therapies with 6711 controls, matched for age, gender and practice. We compared utilisation of healthcare resources by people with LTCs, 6 months before and after referral, and conducted a controlled before and after study to compare health utilisation with controls. We made the assumption that collection of a greater number of repeat prescriptions for antidepressants was associated with greater adherence. RESULTS: Overall 21.8% of people with an LTC had CMHP vs. 18.8% without (p < 0.001). People with LTCs before referral were more likely to use health care resources (2 tailed t-test p < 0.001). Cases with LTCs showed referral to the psychological therapies clinic was associated with increased antidepressant medication prescribing (mean differences 0.62, p < 0.001) and less use of emergency department than controls (mean difference -0.21, p = 0.003). CONCLUSIONS: Referral to improved access to psychological therapies (IAPT) services appears of value to people with LTC. It is associated with the issue of a greater number of prescriptions for anti-depressant medicines and less use of emergency services. Further studies are needed to explore bed occupancy and outpatient attendance. PMID- 23639305 TI - Mindfulness and heart rate variability in individuals with high and low generalized anxiety symptoms. AB - Mindfulness has been incorporated into several treatment approaches for psychopathology. Despite the popularity of this approach, relatively few empirical investigations have examined the relationship between mindfulness and autonomic indicators of flexible emotion regulation, such as heart rate variability (HRV). Generalized anxiety disorder (GAD) has been associated with both low levels of mindfulness and HRV. In this investigation, we examined the relationship between HRV and mindfulness in the context of elevated generalized anxiety (GA) symptoms--an analog for GAD--by examining whether GA level moderated this relationship. HRV was collected while participants completed self-report measures of GA and trait mindfulness. GA level interacted with mindfulness in the prediction of HRV; in the high GA, but not low GA group, mindfulness was positively associated with HRV. This suggests that for individuals with high GA, mindfulness may enhance parasympathetic influences on the heart rate. We address the limitations of the current investigation and suggest avenues for future research on mindfulness-related changes in tonic and phasic HRV over time. PMID- 23639306 TI - Alveolar nitric oxide and asthma control in mild untreated asthma. AB - BACKGROUND: The role of the peripheral airways in asthma is increasingly being recognized as a potential target for the achievement of optimal control of the disease. We postulated that the inflammatory changes of the small airways are implicated in the lack of asthma control in mild asthma. OBJECTIVE: To test this hypothesis, we measured the alveolar fraction of exhaled NO (CalvNO) in patients with mild asthma with different levels of control of symptoms. METHODS: Seventy eight patients with asthma (35 men, age, 37 +/- 15 years; FEV1 percentage of predicted, 100% +/- 9%) were studied. Asthma control was assessed by using the Asthma Control Test (ACT). Measurements of exhaled NO at multiple constant flows were performed. RESULTS: Bronchial NO concentrations were 27.1 +/- 20 nL/min, [corrected] and CalvNO levels were 5.7 +/- 3.4 ppb. The ACT score was 20 +/- 4.2. The level of asthma control was not associated with bronchial NO concentrations (rs = 0.16, P = .15). However, a significant correlation was found between the ACT score and CalvNO (rs = 0.25, P = .03). Moreover, CalvNO was significantly higher in patients with uncontrolled asthma than in patients with controlled/partially controlled asthma (6.7 +/- 2.6 ppb vs 4.9 +/- 2.6 nL/min, [corrected] respectively, P = .02). In the subgroup of patients with asthma who underwent extrafine inhaled corticosteroid treatment, the magnitude of the inhaled corticosteroid-induced improvement in asthma control positively correlated with baseline CalvNO at 1 month (rs = 0.39, P = .003) and at 3 months (rs = 0.49, P < .0001). CONCLUSIONS: The alveolar component of exhaled NO is associated with the lack of asthma control in patients with mild, untreated asthma. This observation supports the notion that abnormalities of the peripheral airways are implicated in the mildest forms of asthma. PMID- 23639308 TI - Tolerated wasp sting challenge improves health-related quality of life in patients allergic to wasp venom. PMID- 23639307 TI - Childhood allergic rhinitis, traffic-related air pollution, and variability in the GSTP1, TNF, TLR2, and TLR4 genes: results from the TAG Study. AB - BACKGROUND: Associations between traffic-related air pollution (TRAP) and allergic rhinitis remain inconsistent, possibly because of unexplored gene environment interactions. OBJECTIVE: In a pooled analysis of 6 birth cohorts (Ntotal = 15,299), we examined whether TRAP and genetic polymorphisms related to inflammation and oxidative stress predict allergic rhinitis and sensitization. METHODS: Allergic rhinitis was defined with a doctor diagnosis or reported symptoms at age 7 or 8 years. Associations between nitrogen dioxide, particulate matter 2.5 (PM2.5) mass, PM2.5 absorbance, and ozone, estimated for each child at the year of birth, and single nucleotide polymorphisms within the GSTP1, TNF, TLR2, or TLR4 genes with allergic rhinitis and aeroallergen sensitization were examined with logistic regression. Models were stratified by genotype and interaction terms tested for gene-environment associations. RESULTS: Point estimates for associations between nitrogen dioxide, PM2.5 mass, and PM2.5 absorbance with allergic rhinitis were elevated, but only that for PM2.5 mass was statistically significant (1.37 [1.01, 1.86] per 5 MUg/m(3)). This result was not robust to single-cohort exclusions. Carriers of at least 1 minor rs1800629 (TNF) or rs1927911 (TLR4) allele were consistently at an increased risk of developing allergic rhinitis (1.19 [1.00, 1.41] and 1.24 [1.01, 1.53], respectively), regardless of TRAP exposure. No evidence of gene-environment interactions was observed. CONCLUSION: The generally null effect of TRAP on allergic rhinitis and aeroallergen sensitization was not modified by the studied variants in the GSTP1, TNF, TLR2, or TLR4 genes. Children carrying a minor rs1800629 (TNF) or rs1927911 (TLR4) allele may be at a higher risk of allergic rhinitis. PMID- 23639310 TI - Membrane and actin dynamics interplay at lamellipodia leading edge. AB - The multimolecular WAVE regulatory (WRC) and Arp2/3 complexes are primarily responsible to generate pushing forces at migratory leading edges by promoting branch elongation of actin filaments. The architectural complexity of these units betrays the necessity to impose a tight control on their activity. This is exerted through temporally coordinated and coincident signals which limit the intensity and duration of this activity. In addition, interactions of the WRC and Arp2/3 complexes with membrane binding and surprisingly membrane trafficking proteins is also emerging, revealing the existence of an 'endocytic wiring system' that spatially restrict branched actin elongation for the execution of polarized functions during cell migration. PMID- 23639309 TI - Rab GTPase regulation of membrane identity. AB - A fundamental question in cell biology is how cells determine membrane compartment identity and the directionality with which cargoes pass through the secretory and endocytic pathways. The discovery of so-called 'Rab cascades' provides a satisfying molecular mechanism that helps to resolve this paradox. One Rab GTPase has the ability to template the localization of the subsequent acting Rab GTPase along a given transport pathway. Thus, in addition to determining compartment identity and functionality, Rab GTPases are likely able to order the events of membrane trafficking. This review will highlight recent advances in our understanding of Rabs and Rab cascades. PMID- 23639312 TI - Tumor suppressors status in cancer cell line Encyclopedia. AB - Tumor suppressors play a major role in the etiology of human cancer, and typically achieve a tumor-promoting effect upon complete functional inactivation. Bi-allelic inactivation of tumor suppressors may occur through genetic mechanisms (such as loss of function mutation, copy number (CN) loss, or loss of heterozygosity (LOH)), epigenetic mechanisms (such as promoter methylation or histone modification), or a combination of the two. We report systematically derived status of 69 known or putative tumor suppressors, across 799 samples of the Cancer Cell Line Encyclopedia. In order to generate such resource we constructed a novel comprehensive computational framework for the assessment of tumor suppressor functional "status". This approach utilizes several orthogonal genomic data types, including mutation data, copy number, LOH and expression. Through correlation with additional data types (compound sensitivity and gene set activity) we show that this integrative method provides a more accurate assessment of tumor suppressor status than can be inferred by expression, copy number, or mutation alone. This approach has the potential for a more realistic assessment of tumor suppressor genes for both basic and translational oncology research. PMID- 23639311 TI - Ultrastructure of protrusive actin filament arrays. AB - The actin cytoskeleton is the major force-generating machinery in the cell, which can produce pushing, pulling, and resistance forces. To accomplish these diverse functions, actin filaments, with help of numerous accessory proteins, form higher order ensembles, networks and bundles, adapted to specific tasks. Moreover, dynamic properties of the actin cytoskeleton allow a cell to constantly build, renew, and redesign actin structures according to its changing needs. High resolution architecture of actin filament arrays provides key information for understanding mechanisms of force generation. To generate pushing force, cells use coordinated polymerization of multiple actin filaments organized into branched (dendritic) networks or parallel bundles. This review summarizes our current knowledge of the structural organization of these two actin filament arrays. PMID- 23639313 TI - Is India ready to lead the battle for fair access to medicines? PMID- 23639314 TI - Chocolate: delicious beauty or harmful beast? PMID- 23639315 TI - Radiotherapy capacity in Europe. PMID- 23639316 TI - Radiotherapy capacity in Europe. PMID- 23639317 TI - Radiotherapy capacity in Europe--authors' reply. PMID- 23639318 TI - Non-invasive ventilation for end-of-life oncology patients. PMID- 23639319 TI - Non-invasive ventilation for end-of-life oncology patients. PMID- 23639320 TI - Non-invasive ventilation for end-of-life oncology patients--authors' reply. PMID- 23639321 TI - Relapsed childhood acute lymphoblastic leukaemia. AB - With steadily improved cure rates for children with newly diagnosed acute lymphoblastic leukaemia (ALL), treating relapsed ALL has become increasingly challenging largely due to resistance to salvage therapy. Improved biological understanding of mechanisms of relapse and drug resistance, the identification of actionable molecular targets by studying leukaemic cell and host genetics, precise risk stratification with minimum residual disease measurement, and the development of new therapeutic drugs and approaches are needed to improve outcomes of relapsed patients. Molecularly targeted therapies and innovative immunotherapeutic approaches that include specialised monoclonal antibodies and cellular therapies hold promise of enhanced leukaemia cell killing with non overlapping toxicities. Advances in preparative regimens, donor selection, and supportive care should improve the success of haemopoietic stem-cell transplantation for high-risk patients. PMID- 23639322 TI - Cytokine patterns in patients with cancer: a systematic review. AB - Active, but dysfunctional, immune responses in patients with cancer have been studied in several tumour types, but owing to the heterogeneity of cancer theories of common reaction mechanisms seem to be obsolete. In this Review of published clinical studies of patients with cancer, expression and interplay of the following cytokines are examined: interleukin 2, interleukin 6, interleukin 8, interleukin 10, interleukin 12, interleukin 18, tumour necrosis factor alpha (TNFalpha), transforming growth factor beta (TGFbeta), interferon-gamma, HLA-DR, macrophage migration inhibitory factor (MIF), and C-X-C motif chemokine receptor 4 (CXCR4). Clinical data were analysed in a non-quantitative descriptive manner and interpreted with regard to experimentally established physiological cytokine interactions. The clinical cytokine pattern that emerged suggests that simultaneous immunostimulation and immunosuppression occur in patients with cancer, with increased concentrations of the cytokines MIF, TNFalpha, interleukin 6, interleukin 8, interleukin 10, interleukin 18, and TGFbeta. This specific cytokine pattern seems to have a prognostic effect, since high interleukin 6 or interleukin 10 serum concentrations are associated with negative prognoses in independent cancer types. Although immunostimulatory cytokines are involved in local cancer-associated inflammation, cancer cells seem to be protected from immunological eradication by cytokine-mediated local immunosuppression and a resulting defect of the interleukin 12-interferon-gamma-HLA-DR axis. Cytokines produced by tumours might have a pivotal role in this defect. A working hypothesis is that the cancer-specific and histology-independent uniform cytokine cascade is one of the manifestations of the underlying paraneoplastic systemic disease, and this hypothesis links the stage of cancer with both the functional status of the immune system and the patient's prognosis. Neutralisation of this cytokine pattern could offer novel and so far unexploited treatment approaches for cancer. PMID- 23639324 TI - Has the time come for metronomics in low-income and middle-income countries? AB - In 2008, 72% of cancer deaths occurred in low-income and middle-income countries, where, although there is a lower incidence of cancer than in high-income countries, survival rates are also low. Many patients are sent home to die, and an even larger number of patients do not have access to treatment facilities. New constraint-adapted therapeutic strategies are therefore urgently needed. Metronomic chemotherapy--the chronic administration of chemotherapy at low, minimally toxic doses on a frequent schedule of administration, with no prolonged drug-free breaks--has recently emerged as a potential strategy to control advanced or refractory cancer and represents an alternative for patients with cancer living in developing countries. This low-cost, well-tolerated, and easy to access strategy is an attractive therapeutic option in resource-limited countries. Moreover, combined with drug repositioning, additional anticancer effects can be achieved, ultimately resulting in improved cancer control while maintaining minimum cost of treatment. In this Personal View, we will briefly review the rationale behind the combination of metronomic chemotherapy and drug repositioning-an approach we term metronomics. We assess the clinical experience obtained with this kind of anticancer treatment and describe potential new developments in countries with limited resources. We also highlight the need for adapted clinical study endpoints and innovative models of collaboration between for-profit and non-profit organisations, to address the growing problem of cancer in resource-limited countries. PMID- 23639325 TI - Percutaneous closure of the left atrial appendage for prevention of thromboembolism in atrial fibrillation for patients with contraindication to or failure of oral anticoagulation: a single-center experience. AB - INTRODUCTION: In non-valvular atrial fibrillation 90% of thrombi originate in the left atrial appendage (LAA). Percutaneous LAA closure has been shown to be non inferior to warfarin for prevention of thromboembolism. OBJECTIVE: To evaluate the initial experience of a single center in percutaneous LAA closure in patients with high thromboembolic risk and in whom oral anticoagulation was impractical or contraindicated or had failed. METHODS: Patients with non-valvular atrial fibrillation and CHADS2 score >=2 in whom oral anticoagulation was impractical or contraindicated or had failed underwent percutaneous LAA closure according to the standard technique. After the procedure, dual antiplatelet therapy was maintained for one month, followed by single antiplatelet therapy indefinitely. Patients were followed by clinical assessment and transthoracic and transesophageal echocardiography. RESULTS: The procedure was performed in 22 of the 23 selected patients (95.7%), mean age 70+/-9 years, CHADS2 score 3.2+/-0.9 and CHA2DS2-VASC score 4.7+/-1.4. Intraprocedural device replacement was necessary only in the first patient, due to oversizing. The following periprocedural complications were observed: one femoral pseudoaneurysm, three femoral hematomas and two minor oropharyngeal bleeds, resolved by local hemostatic measures. During a 12+/-8 month follow-up a mild peri-device flow and a thrombus adhering to the device, resolved under with enoxaparin therapy, were identified. The rate of transient ischemic attack (TIA)/stroke was lower than expected according to the CHADS2 score (0 vs. 6.7+/-2.2%). CONCLUSIONS: In our initial experience, this procedure proved to be a feasible, safe and effective alternative for atrial fibrillation patients in whom oral anticoagulation is not an option. Only relatively minor complications were observed, with a lower than expected TIA/stroke rate. PMID- 23639326 TI - Modification of silicon carbide surfaces by atmospheric pressure plasma for composite applications. AB - In this study, we explore the use of atmospheric pressure plasmas for enhancing the adhesion of SiC surfaces using a urethane adhesive, as an alternative to grit blasting. Surface analysis showed that He-O2 plasma treatments resulted in a hydrophilic surface mostly by producing SiOx. Four-point bending tests and bonding pull tests were carried out on control, grit-blasted, and plasma-treated surfaces. Grit-blasted samples showed enhanced bonding but also a decrease in flexural strength. Plasma treated samples did not affect the flexural strength of the material and showed an increase in bonding strength. These results suggest that atmospheric pressure plasma treatment of ceramic materials is an effective alternative to grit-blasting for adhesion enhancement. PMID- 23639323 TI - Protein phosphatase 2A: a target for anticancer therapy. AB - Protein phosphatase 2A (PP2A), one of the main serine-threonine phosphatases in mammalian cells, maintains cell homoeostasis by counteracting most of the kinase driven intracellular signalling pathways. Unrestrained activation of oncogenic kinases together with inhibition of tumour suppressors is often required for development of cancer. PP2A has been shown to be genetically altered or functionally inactivated in many solid cancers and leukaemias, and is therefore a tumour suppressor. For example, the phosphatase activity of PP2A is suppressed in chronic myeloid leukaemia and other malignancies characterised by aberrant activity of oncogenic kinases. Preclinical studies show that pharmacological restoration of PP2A tumour-suppressor activity by PP2A-activating drugs (eg, FTY720) effectively antagonises cancer development and progression. Here, we discuss PP2A as a druggable tumour suppressor in view of the possible introduction of PP2A-activating drugs into anticancer therapeutic protocols. PMID- 23639327 TI - Host and viral factors affecting clinical performance of a rapid diagnostic test for respiratory syncytial virus in hospitalized children. AB - Respiratory syncytial virus rapid antigen detection tests (RADT) are used widely. RADT exhibited high specificity (97%) and moderate sensitivity (80%) compared with reverse-transcriptase polymerase chain reaction in 720 hospitalized children <3 years old. Older age, prolonged symptoms, and respiratory syncytial virus genotype-B infection were significantly associated with false-negative results of RADT. PMID- 23639328 TI - [A muscular mass]. PMID- 23639329 TI - [Dyspnea and shortened phalanges]. PMID- 23639330 TI - Becoming a parent to a child with birth asphyxia-From a traumatic delivery to living with the experience at home. AB - The aim of this study is to describe the experiences of becoming a parent to a child with birth asphyxia treated with hypothermia in the neonatal intensive care unit (NICU). In line with the medical advances, the survival of critically ill infants with increased risk of morbidity is increasing. Children who survive birth asphyxia are at a higher risk of functional impairments, cerebral palsy (CP), or impaired vision and hearing. Since 2006, hypothermia treatment following birth asphyxia is used in many of the Swedish neonatal units to reduce the risk of brain injury. To date, research on the experience of parenthood of the child with birth asphyxia is sparse. To improve today's neonatal care delivery, health care providers need to better understand the experiences of becoming a parent to a child with birth asphyxia. A total of 26 parents of 16 children with birth asphyxia treated with hypothermia in a Swedish NICU were interviewed. The transcribed interview texts were analysed according to a qualitative latent content analysis. We found that the experience of becoming a parent to a child with birth asphyxia treated with hypothermia at the NICU was a strenuous journey of overriding an emotional rollercoaster, that is, from being thrown into a chaotic situation which started with a traumatic delivery to later processing the difficult situation of believing the child might not survive or was to be seriously affected by the asphyxia. The prolonged parent-infant separation due to the hypothermia treatment and parents' fear of touching the infant because of the high-tech equipment seemed to hamper the parent-infant bonding. The adaption of the everyday life at home seemed to be facilitated by the follow-up information of the doctor after discharge. The results of this study underline the importance of family-centered support during and also after the NICU discharge. PMID- 23639331 TI - [Blunt or sharp expansion of cesarean section: a comparative study]. AB - OBJECTIVE: The aim of this study was to determine if the method used to expand the hysterotomy during a cesarean section (c-section) could affect maternal blood loss and uterine laceration. MATERIAL AND METHODS: Prospective study including 214 c-sections divided into two groups. Hundred and thirty-six were assigned to have blunt expansion of the uterine incision (group 1) and 78 to have sharp expansion by scissors (group 2). Maternal blood loss, change in hemoglobin level, and uterine tears were studied. RESULTS: The median blood loss was (IQR) 475mL (300-700) and 500mL (300-800) (P=0.227) in groups 1 and 2 respectively. The decrease in hemoglobin level was 9.5g/L versus 6g/L (P=0.007) in groups 1 and 2. Nine lateral uterine extensions of uterine incision (5.88%) were found in the group 1, three of them were complicated by a wound of the uterine vascular pedicle. One lateral uterine tear with vascular wound was found in the group 2 (1.28%). CONCLUSION: Sharp expansions were associated with a lower shift in hemoglobin level and a trend to more uterine lacerations. PMID- 23639332 TI - Nasal symptoms and clinical findings in adult patients treated for unilateral cleft lip and palate. AB - The aim of the study was to investigate self-experienced nasal symptoms among adults treated for UCLP and the association to clinical findings, and to evaluate whether palate closure in one-stage or two-stages affected the symptoms or clinical findings. All people with UCLP born between 1960-1987, treated at Uppsala University Hospital, were considered for participation in this cross sectional population study with long-term follow-up. Eighty-three patients (76% participation rate) participated, a mean of 37 years after the first operation. Fifty-two patients were treated with one-stage palate closure and 31 with two stage palate closure. An age-matched group of 67 non-cleft controls completed the same study protocol, which included a questionnaire regarding nasal symptoms, nasal inspection, anterior rhinoscopy, and nasal endoscopy. Patients reported a higher frequency of nasal symptoms compared with the control group, e.g., nasal obstruction (81% compared with 60%) and mouth breathing (20% compared with 5%). Patients also rated their nasal symptoms as having a more negative impact on their daily life and physical activities than controls. Nasal examination revealed higher frequencies of nasal deformities among patients. No positive correlation was found between nasal symptoms and severity of findings at nasal examination. No differences were identified between patients treated with one stage and two-stage palate closure regarding symptoms or nasal findings. Adult patients treated for UCLP suffer from more nasal symptoms than controls. However, symptoms are not associated with findings at clinical nasal examination or method of palate closure. PMID- 23639333 TI - Applications of triangular glanular flap in hypospadias repairs for different purposes. AB - Hypospadias is a congenital anomaly of the penis with an ectopic, ventrally placed meatus due to insufficient development of the anterior urethra. Tubularisation of glanular flaps without plate incision is performed with addition of a triangular flap in order to move the meatus more distally and avoid meatal stenosis. Subcoronally, mid-shaft, and coronally placed 41 hypospadias cases were treated with the tubularisation of the glanular flaps without incision of the urethral plate, a technique similar to TIP technique. Triangular flaps were added at the most distal end of one of the glanular flaps in all cases for different purposes. A medially-based triangular flap was elevated at the distal end of the right-sided longitudinal flap to carry the last suture more distally. The flap increased meatal diameter and carried the last suture more distally. No meatal stenosis was observed for an average of 18.02 (12-30) months. The final localisation of the meatus was satisfactory in all patients. Meatal stenosis, demonstrated after hypospadias repair, is a challenge for both the surgeon and the patient. A distal triangular glanular flap is planned to avoid this challenge. Besides, it helps to carry the meatus more distally. Promising results support the use of the glanular flap while longer follow-up is required for better evaluation. PMID- 23639334 TI - Dyadic flexibility during the face-to-face still-face paradigm: a dynamic systems analysis of its temporal organization. AB - A dynamic systems analytical model was used to characterize infant-caregiver regulatory dynamics. Though stable, there was an increase in dyadic flexibility following a perturbation. Dyadic flexibility was positively related to infant negativity during the perturbation. Findings were qualified by infant sex and maternal depressive symptoms. PMID- 23639336 TI - A real-time PCR for the detection of infectious myonecrosis virus in penaeid shrimp. AB - Infectious myonecrosis virus (IMNV) is a recently observed shrimp virus, which threats the cultured Litopenaeus vannamei and can cause huge economic loss in shrimp farming industry. The specific aim of this study was to develop a new sensitive real-time PCR method for the specific detection of shrimp IMNV. A real time PCR assay with a pair of primers to specifically amplify a 101bp IMNV cDNA fragment and a corresponding TaqMan probe was developed, which shown to be specific for IMNV without cross reaction with DNA samples prepared from four other shrimp viruses including white spot syndrome virus (WSSV), hepatopancreatic parvovirus (HPV), monodon baculovirus (MBV), and infectious hypodermal and haematopoietic virus (IHHNV). The method could detect as low as one single copy of IMNV plasmid cDNA. PMID- 23639335 TI - Auditory evoked magnetic fields in individuals with tinnitus. AB - Some forms of tinnitus are likely to be perceptual consequences of altered neural activity in the central auditory system triggered by damage to the auditory periphery. Animal studies report changes in the evoked responses after noise exposure or ototoxic drugs in inferior colliculus and auditory cortex. However, human electrophysiological evidence is rather equivocal: increased, reduced or no difference in N1/N1m evoked amplitudes and latencies in tinnitus participants have been reported. The present study used magnetoencephalography to seek evidence for altered evoked responses in people with tinnitus compared to controls (hearing loss matched and normal hearing) in four different stimulus categories (a control tone, a tone corresponding to the audiometric edge, to the dominant tinnitus pitch and a tone within the area of hearing loss). Results revealed that amplitudes of the evoked responses differed depending on the tone category. N1m amplitude to the dominant tinnitus pitch and the frequency within the area of hearing loss were reduced compared to the other two categories. Given that tinnitus pitch is typically within the area of hearing loss, the differences in the evoked responses pattern in tinnitus participants seem to be related more to the hearing loss than to the presence of tinnitus. PMID- 23639338 TI - Performance after timely cochlear implantation in prelingually deaf children with cerebral palsy. AB - OBJECTIVES: To investigate auditory perception, speech production, and language ability of prelingually deaf toddlers with cerebral palsy (CP) who were implanted within a sensitive period and who received proper speech therapy. Comparison of their outcomes with age- and sex-matched CI recipients without additional disabilities was also performed. METHODS: We retrospectively reviewed a cohort of pediatric CI in Samsung Medical Center. Eight CP subjects who received CI before 3 years of age and age-sex matched control recipients who had no additional disabilities except idiopathic sensorineural hearing loss (SNHL) were included for the analysis. Preoperative evaluation included the Categories of Auditory Performance (CAP) score, Korean Version of the Ling's Stage (K-Ling), Sequenced Language Scale for Infants (SELSI), Bailey Scales of Infant Development II assessment, Social Maturity Scale test, and grading of CP severity using severity level and Gross Motor Function Classification System for CP (GMFCS). To measure the outcome, the CAP scores, K-Ling, and SELSI were performed at 3, 6, 12, and 24 months after implantation. RESULTS: Four CP children with outstanding performances showed comparable achievement with matched control recipients. These patients had less severe motor disabilities (mild-moderate severity, GMFCS level 1-3), better social quotient, and better cognitive abilities. Although the others showed poor language abilities and hardly produced meaningful speech, their CAP scores reached 1 or 2 in 24 months after implantation. CONCLUSIONS: Deaf children with CP could have various ranges of benefits up to the levels of normal peers whose only disability was hearing loss, when CI was performed within a critical period. Especially, children with mild or moderate CP had a favorable outcome after CI, equivalent to that of normal peers. PMID- 23639339 TI - Paediatric otogenic lateral sinus thrombosis: therapeutic management, outcome and thrombophilic evaluation. AB - OBJECTIVE: Otogenic lateral sinus thrombosis (LST) in children represents a serious condition with potential long-lasting morbidity. The role of adjunct anticoagulation therapy and the benefit of an analysis of prothrombotic factors are unclear. The aim of the study was to report therapeutic management and outcome, analyze prothrombotic factors in children with otogenic LST treated with mastoidectomy/antibiotics/anticoagulation and to evaluate the results with a review of the literature. METHODS: Retrospective chart review of 9 children with otogenic LST (2000-2009) and literature search in PubMed. RESULTS: The most frequent sign was fever in 88%, while neurologic findings were seen in 55%. Streptococci was the most common bacteria (55%). Prothrombotic factors were normal in all children. All patients received therapeutic anticoagulation, without experiencing bleeding complications. Eight children made a full recovery, neurologic sequelae persisted in one. The literature review of 115 children identified fever as the most prominent sign, reported the absence of neurologic findings in almost 50% of cases and confirmed the major role of streptococci. Anticoagulation, as adjunct therapy, was given to 38% of patients in the therapeutic range with a trend towards better neurologic outcome. A prothrombotic analysis was reported in 5 studies with positive results in 2. CONCLUSIONS: Surgery and antibiotics represent the mainstay of the therapy. Anticoagulation can be safely added in view of the high potential for morbidity and might reduce neurologic sequelae. Bacteria with thrombotic activity seem to be an important aetiology. In contrast, a prothrombotic disposition seems to play a minor role in the development of otogenic LST. PMID- 23639340 TI - Salivary endoscopy in a pediatric patient with HLA-B27 seropositivity and recurrent submandibular sialadenitis. AB - Patients with human leukocyte antigen (HLA)-B27 seropositivity have a genetic predisposition to form spondyloarthropathies, especially ankylosing spondylitis. Other related inflammatory or autoimmune disorders include reactive arthritis, uveitis, psoriatic arthritis, and Crohn's disease. Although juvenile recurrent parotitis is not uncommon, recurrent submandibular sialadenitis is rare in pediatric patients. Sialadenitis is typically caused by salivary stones, infection, or duct stricture. To our knowledge, there has not been report of HLA B27 positivity and recurrent sialadenitis described previously. We describe a patient with HLA-B27 seropositivity and multiple episodes of left submandibular sialadenitis who underwent diagnostic and therapeutic sialendoscopy. Previous treatment included antibiotics, sialogogues, warm compresses, and hydration before he underwent definitive sialendoscopy treatment at a tertiary care medical center. Salivary endoscopy showed salivary stasis and sludging within the left submandibular gland duct, with no salivary stones. Topical steroid was applied to the duct. At one year following his surgery, he has not had any recurrent episodes of sialadenitis. HLA-B27 seropositivity is associated with many inflammatory disorders; we report a case in which the patient had coexisting recurrent sialadenitis. In the pediatric population, sialadenitis is traditionally managed with antibiotics and supportive care, however our patient underwent salivary endoscopy. Sialendoscopy is an emerging modality that potentially avoids radiation exposure from CT or sialography and should be considered as another preferred treatment option. More investigation is required to prove a possible correlation between existing HLA-B27 and the propensity to develop this clinical problem. PMID- 23639341 TI - Transoral robotic resection of oropharyngeal synovial sarcoma in a pediatric patient. AB - Localized synovial cell sarcomas are treated with surgical resection followed by chemo-radiation. Surgical resection of synovial sarcoma of the oropharynx and hypopharynx involves lip-splitting mandibulotomy resulting in treatment related morbidity. We report the successful use of Trans Oral Robotic Surgery for resection of localized synovial sarcoma of the lateral pharyngeal wall in a 15 year old patient. We were able to achieve negative surgical margins and avoid open surgery with its associated morbidity. At 2 years follow-up, patient is disease free, with no deficits in speech or swallowing functions and no cosmetic deformity. PMID- 23639343 TI - Integrated three-dimensional system-on-chip for direct quantitative detection of mitochondrial DNA mutation in affected cells. AB - We report a microfluidic system for automatic mitochondrial mutation diagnostics from sample purification to quantitative analysis. The system achieved direct DNA (mtDNA) mutation quantification in affected cells using a new 3D-microfluidic system, which integrated a mtDNA extraction module and a mutation detection module. Effective direct mtDNA extraction from the cells was realized using magnetic field manipulation. The obtained mtDNAs were subject to a fully automatic processing for quantitative mutation detection using integrated micropumps, micromixer and microtemperature control modules capable of mutation sensing by restriction enzyme digestion and real-time on-chip micro-PCR. Compared with traditional methods, this microfluidic system demonstrates the advantages of faster detection, requirement of fewer amount of specimens and reagents, much compact design and lower cost as well as lower risks for human errors. Thus, such system-on-chip would encourage the future translational development of rapid pathogenic mtDNA defects detection to provide more efficient clinical diagnosis and disease management strategies. PMID- 23639337 TI - Immunosenescence and organ transplantation. AB - Increasing numbers of elderly transplant recipients and a growing demand for organs from older donors impose pressing challenges on transplantation medicine. Continuous and complex modifications of the immune system in parallel to aging have a major impact on transplant outcome and organ quality. Both, altered alloimmune responses and increased immunogenicity of organs present risk factors for inferior patient and graft survival. Moreover, a growing body of knowledge on age-dependent modifications of allorecognition and alloimmune responses may require age-adapted immunosuppression and organ allocation. Here, we summarize relevant aspects of immunosenescence and their possible clinical impact on organ transplantation. PMID- 23639342 TI - Chronic constipation: a critical review. AB - Chronic constipation is a very common symptom that is rarely associated with life threatening diseases, but has a substantial impact on patient quality of life and consumption of healthcare resources. Despite the large number of affected patients and the social relevance of the condition, no cost-effectiveness analysis has been made of any diagnostic or therapeutic algorithm, and there are few data comparing different diagnostic and therapeutic approaches in the long term. In this scenario, increasing emphasis has been placed on demonstrating that a number of older and new therapeutic options are effective in treating chronic constipation in well-performed randomised controlled trials, but there is still debate as to when these therapeutic options should be included in diagnostic and therapeutic algorithms. The aim of this review is to perform a critical evaluation of the current diagnostic and therapeutic options available for adult patients with chronic constipation in order to identify a rational patient approach; furthermore we attempt to clarify some of the more controversial points to aid clinicians in managing this symptom in a more efficacious and cost effective manner. PMID- 23639344 TI - Aptamer-based sensing for thrombin in red region via fluorescence resonant energy transfer between NaYF4:Yb,Er upconversion nanoparticles and gold nanorods. AB - In this work, we design a FRET system for sensitive and selective determination of thrombin in red region, in which NaYF4:Yb,Er upconversion nanoparticles (UCNPs) act as donor and gold nanorods (Au NRs) act as acceptor. NaYF4:Yb,Er UCNPs with a strong emission at 661 nm were successfully synthesized by tuning the doped ions ratio. Carboxyl-functionalized NaYF4:Yb,Er UCNPs and Au NRs were then prepared and conjugated with the thrombin aptamers, respectively. The fluorescence emission band of NaYF4:Yb,Er UCNPs (lambda(max)=661 nm) highly overlaps with the absorption band of Au NRs(lambda(max)=666 nm), which benefits from the large tunability of the spectrum band of Au NRs. A FRET system was then formed when thrombin was added to the mixture of NaYF4:Yb,Er UCNPs and Au NRs, which were both modified thrombin aptamers. The fluorescence quenching efficiency of NaYF4:Yb,Er UCNPs was increased in a thrombin concentration-dependent manner, which built the principle of thrombin quantification. The linear range was 2.5-90 nM in an aqueous buffer, and 3.75-112.5 nM in spiked human serum samples for thrombin. It also demonstrates a high selectivity to other biological species due to the specific binding. The measurement of thrombin in human plasma is satisfying, suggesting that the FRET system is of practical value in a complex biological sample matrix in red region. PMID- 23639345 TI - Bead assembly magnetorotation as a signal transduction method for protein detection. AB - This paper demonstrates a proof-of-principle for a new signal transduction method for protein detection called Bead Assembly Magnetorotation (BAM). BAM is based on using the target protein to mediate the formation of aptamer-coated 1 MUm magnetic beads into a bead assembly, formed at the bottom of a 1 MUL hanging droplet. The size, shape and fractal dimension of this bead assembly all depend on the protein concentration. The protein concentration can be measured in two ways: by magnetorotation, in which the rotational period of the assembly correlates with the protein concentration, or by fractal analysis. Additionally, a microscope-free magnetorotation detection method is introduced, based on a simple laser apparatus built from standard laboratory components. In this paper, we chose to focus on the protein thrombin, a popular choice for proof-of principle work in this field. PMID- 23639346 TI - Central nervous system tumors: a single center pathology review of 34,140 cases over 60 years. AB - BACKGROUND: Tumor epidemiology is a significant part of CNS (central nervous system) tumor studies. Reassessment of original sections can update our knowledge of tumor spectrum. Here, we discuss the features of CNS tumor pathology in a single center. METHODS: A total of 34140 cases from 1950 to 2009 were collected; sections from 1990 to 2009 were reassessed according to WHO 2007 classification, and cases from 1950 to 1989 were classified according to the previous pathological diagnosis. RESULTS: Seven CNS tumor categories during 1990 to 2009 were as follow: neuroepithelial tissue (38.0%), tumors of the meninges (36.5%), tumors of the sellar region (4.1%), germ cell tumors (1.3%), tumors of cranial and paraspinal nerves (13.3%), lymphomas and hematopoietic neoplasm (1.7%), metastatic tumors (5.1%), where histological types by age and sex were diverse. Overall, males exceeded females in distributions of most CNS tumor subtypes, while tumors of the meninges occurred more frequently in females. The case number of lymphomas and hematopoietic neoplasms grew the fastest during the past five years, and the distribution of neuroepithelial tumors remained stable over the past twenty years. CONCLUSIONS: Despite the possibilities of cross sample biases, the data in this series could suggest a similar CNS tumor spectrum as might occur in other developing countries. PMID- 23639347 TI - Childhood maternal support and social capital moderate the regulatory impact of social relationships in adulthood. AB - For this functional magnetic resonance imaging (fMRI) study, we assessed the impact of early social experiences on the social regulation of neural threat responding in a sample of 22 individuals that have been followed for over a decade. At 13 years old, a multidimensional measure of neighborhood quality was derived from parental reports. Three measures of neighborhood quality were used to estimate social capital-the level of trust, reciprocity, cooperation, and shared resources within a community. At 16 years old, an observational measure of maternal emotional support behavior was derived from a mother/child social interaction task. At 24 years old, participants were asked to visit our neuroimaging facility with an opposite-sex platonic friend. During their MRI visit, participants were subjected to the threat of electric shock while holding their friend's hand, the hand of an anonymous opposite-sex experimenter, or no hand at all. Higher adolescent maternal support corresponded with less threat related activation during friend handholding, but not during the stranger or alone conditions, in the bilateral orbitofrontal cortex, inferior frontal gyrus and left insula. Higher neighborhood social capital corresponded with less threat related activation during friend hand-holding in the superior frontal gyrus, supplementary motor cortex, insula, putamen and thalamus; but low childhood capital corresponded with less threat-related activation during stranger handholding in the same regions. Exploratory analyses suggest that this latter result is due to the increased threat responsiveness during stranger handholding among low social capital individuals, even during safety cues. Overall, early maternal support behavior and high neighborhood quality may potentiate soothing by relational partners, and low neighborhood quality may decrease the overall regulatory impact of access to social resources in adulthood. PMID- 23639348 TI - Intravenous solid tip ECG lead placement in telemetry implanted dogs: Part 2: High quality telemetry signals yield high sensitivity to drug-induced changes. AB - INTRODUCTION: Dogs are commonly used in cardiovascular drug safety assessment, and implanted telemetry models include subcutaneous or epicardial electrocardiogram (ECG) electrode placements. The purpose of this study was to determine the sensitivity of a canine telemetry model with intravenous ECG lead placement: the negative ECG lead (solid tip) inserted into the jugular vein and the positive lead sutured to the diaphragm. Reference drugs were administered to test the sensitivity to drug-induced changes. METHODS: Twenty-four dogs were implanted with PCT or PCTP transmitters [Data Sciences International (DSI)]. Three reference drugs were administered: sotalol to eight PCT and milrinone to eight PCTP transmitter-implanted dogs. Twenty-four dogs received moxifloxacin (12 dogs/transmitter type). Telemetry data were collected for 25h and analyzed using double Latin squares for sotalol and milrinone data or a 4*4 or 3*6 parallel design for moxifloxacin data. Evaluated parameters were PR, QT, corrected QT (QTc), QRS, heart rate, left ventricular function, and hemodynamic data. Various correction factors for QTc interval were tested. Retrospective power analysis was performed to detect minimal absolute changes comparing a single to a double Latin square or the two parallel designs. RESULTS: Expected changes on ECG and hemodynamic parameters were observed after administration of all reference drugs. The individual animal corrected QT (QTci) interval provided the optimal correction factor. Retrospective power analysis confirmed detection of smaller differences in double versus single Latin squares. Minimal detectable differences were smaller in both Latin squares compared to parallel designs, with smaller detectable differences in a 3*6 compared to a 4*4 parallel design. DISCUSSION: The solid tip intravenous ECG lead configuration in dogs is a viable radiotelemetry model to detect drug-induced changes with high sensitivity. This model yields comparable signal quality and represents a refinement over epicardial ECG leads and allows for possible reduction in the number of animals if study design and size are selected based on needed assay sensitivity. PMID- 23639349 TI - Chronic obstructive pulmonary disease in Portugal: Pneumobil (1995) and 2002 prevalence studies revisited. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) has been a leading cause of morbidity and mortality worldwide, over the years. In 1995, the implementation of a respiratory function survey seemed to be an adequate way to draw attention to neglected respiratory symptoms and increase the awareness of spirometry surveys. By 2002 there were new consensual guidelines in place and the awareness that prevalence of COPD depended on the criteria used for airway obstruction definition. The purpose of this study is to revisit the two studies and to turn public some of the data and respective methodologies. METHODS: From Pneumobil study database of 12,684 subjects, only the individuals with 40+ years old (n = 9.061) were selected. The 2002 study included a randomized representative sample of 1,384 individuals with 35-69 years old. RESULTS: The prevalence of COPD was 8.96% in Pneumobil and 5.34% in the 2002 study. In both studies, presence of COPD was greater in males and there was a positive association between presence of COPD and older age groups. Smokers and ex-smokers showed a higher proportion of cases of COPD. CONCLUSIONS: Prevalence in Portugal is lower than in other European countries. This may be related to lower smokers' prevalence. Globally, the most important risk factors associated with COPD were age over 60 years, male gender and smoking exposure. All aspects and limitations regarding different recruitment methodologies and different criteria for defining COPD cases highlight the need of a standardized method to evaluate COPD prevalence and associated risks factors, whose results can be compared across countries, as it is the case of BOLD project. PMID- 23639350 TI - Daytime sleepiness and attention in city bus drivers of two capitals of Brazil. AB - Brazil is one of the world leaders on traffic accidents. The present article studied the excessive daytime sleepiness of public transport drivers in two Brazilian's capitals and their level of attention. It was conducted here a descriptive transversal study of a convenient sample. For the evaluation were used: anthropometric variables, a Sleep Questionnaire, Epworth Scale of Sonolency (ESS), Diffused Attention Test (TADIM), and Concentrated Attention Test (TACOM A). There were evaluated 300 drivers from Brasilia and 104 from Florianopolis. The majority of the individuals were overweight and presented somnolence. The neck circumference was smaller in Brasilia, where the drivers were also more sleepiness and presented worst attention on TACOM-A. The analysis of correlation was significant between attention tests and age and between BMI and ESS. Factors as differences in work journeys as well differences between the traffic in these two cities may be associated to our findings. We concluded that sleepiness is a common factor of risk between professional bus drivers and that was correlated with BMI, as well as the attention was correlated with age. PMID- 23639352 TI - [Rectal stromal tumor: about a case]. AB - Gastro-intestinal stromal tumors are uncommon mesenchymal tumors. There are localized preferentially in the stomach. The rectal localization is exceedingly rare. Through a new case of rectal stromal tumour as well as a review of the literature, we propose to focus on clinical, radiological and therapeutic particularities of this rare entity. PMID- 23639351 TI - Hypoxia and cytoplasmic alkalinization upregulate growth hormone expression in lymphocytes. AB - We report here that culture of lymphoid cells under hypoxic conditions showed an increase in both luciferase expression from a GH-promoter luciferase construct and the levels of lymphocyte GH. The effect was mimicked by treatment of cells with cobalt chloride consistent with a specific oxygen-sensing mechanism. We identified a putative hypoxia response element (HRE) in the GH promoter at the region -176 bp to -172 bp that contains a copy of the hypoxia-inducible factor-1 (Hif-1) binding motif (5'-ACGTG-3'). The results also showed that culture of primary rat spleen cells with different doses of TMA induced a dose-dependent increase in lymphocyte GH by Western blot analysis. Greater levels of GH are induced in T cell-enriched populations compared to B cell-enriched populations after treatment with CoCl(2) or TMA. Our results suggest that the stressful cellular conditions likely to occur at sites of inflammation or tumor growth may induce the synthesis of lymphocyte GH. PMID- 23639353 TI - Using equivalent doses of medications to convert atrial fibrillation. PMID- 23639354 TI - Dabigatran and acute coronary syndromes. PMID- 23639356 TI - Human beta-defensin 3: a novel inhibitor of Staphylococcus-produced biofilm production. Commentary on "Human beta-defensin 3 inhibits antibiotic-resistant Staphylococcus biofilm formation". PMID- 23639355 TI - Glucagon-like peptide 2 increases efficacy of distraction enterogenesis. AB - BACKGROUND: Application of distractive forces to small bowel induces intestinal growth, or enterogenesis. This emerging area of research may provide treatment for short bowel syndrome. Glucagon-like peptide 2(GLP-2) has also been reported to induce small bowel growth after bowel resection. We hypothesized that exogenous GLP-2 will result in enhanced distraction-induced enterogenesis. METHODS: Distraction-induced model was performed in 10-wk-old C57BL/6 mice using osmotic forces with high molecular weight polyethylene glycol (PEG)-stretch. Four groups were studied: Control group (PEG-/GLP-2-); PEG-stretch (PEG+/GLP-2-); GLP 2 control (PEG-/GLP-2+); and GLP-2 stretch (PEG+/GLP-2+). GLP-2 was given via subcutaneous osmotic pump over the 5 d of experiment. Morphology was measured by histomicrography. Epithelial cell (EC) proliferation was measured with proliferating cell nuclear antigen immunofluorescent staining. Total intestinal growth and blood vessel volume was assessed with Micro computed tomography volumetry. Vascular endothelial growth factor, fibroblast growth factor 1 and 2, and platelet-derived growth factor were measured by reverse-transcriptase polymerase chain reaction. RESULTS: EC proliferation increased significantly in all groups compared with controls, but was greatest in the GLP-2 stretch group. Diameter and length significantly increased in the PEG-stretch and GLP-2 stretch groups. Moreover, there was statistically greater diameter, crypt depth and EC proliferation in the GLP-2 stretch versus PEG-stretch groups. GLP-2 stretch vessel volume was greater than all other groups and was significantly increased compared with controls. The relative expression of platelet-derived growth factor increased significantly in the PEG-stretch group versus the Control group. CONCLUSIONS: GLP-2 had an additive effect on EC proliferation, tissue growth, histomorphology, and vascularization. We also demonstrated a unique action of GLP 2, the enhancement of intestinal vascularization. The combination of enterogenesis and GLP-2 may yield an improved approach to treat short bowel syndrome. PMID- 23639357 TI - Origin of asymmetry at the intersubunit interfaces of V1-ATPase from Thermus thermophilus. AB - V-type ATPase (V-ATPase) is one of the rotary ATPase complexes that mediate energy conversion between the chemical energy of ATP and the ion gradient across the membrane through a rotary catalytic mechanism. Because V-ATPase has structural features similar to those of well-studied F-type ATPase, the structure is expected to highlight the common essence of the torque generation of rotary ATPases. Here, we report a complete model of the extra-membrane domain of the V ATPase (V1-ATPase) of a thermophilic bacterium, Thermus thermophilus, consisting of three A subunits, three B subunits, one D subunit, and one F subunit. The X ray structure at 3.9A resolution provides detailed information about the interactions between A3B3 and DF subcomplexes as well as interactions among the respective subunits, which are defined by the properties of side chains. Asymmetry at the intersubunit interfaces was detected from the structural differences among the three AB pairs in the different reaction states, while the large interdomain motion in the catalytic A subunits was not observed unlike F1 from various species and V1 from Enterococcus hirae. Asymmetry is mainly realized by rigid-body rearrangements of the relative position between A and B subunits. This is consistent with the previous observations by the high-resolution electron microscopy for the whole V-ATPase complexes. Therefore, our result plausibly implies that the essential motion for the torque generation is not the large interdomain movement of the catalytic subunits but the rigid-body rearrangement of subunits. PMID- 23639358 TI - Regulation of lipoprotein assembly, secretion and fatty acid beta-oxidation by Kruppel-like transcription factor, klf-3. AB - Lipid metabolism is coordinately regulated through signaling networks that integrate biochemical pathways of fat assimilation, mobilization and utilization. Excessive diversion of fat for storage is a key risk factor for many fat-related human diseases. Dietary lipids are absorbed from the intestines and transported to various organs and tissues to provide energy and maintain lipid homeostasis. In humans, disparity between triglycerides (TG) synthesis and removal, via mitochondrial beta-oxidation and VLDL (very low density lipoprotein) secretion, causes excessive TG accumulation in the liver. The mutation in Caenorhabditis elegans KLF-3 leads to high TG accumulation in the worm's intestine. Our previous data suggested that klf-3 regulates lipid metabolism by promoting fatty acid beta oxidation. Depletion of cholesterol in the diet has no effect on fat deposition in klf-3 (ok1975) mutants. Addition of vitamin D in the diet, however, increases fat levels in klf-3 worms. This suggests that excess vitamin D may be lowering the rate of fatty acid beta-oxidation, with the eventual increase in fat accumulation. We also demonstrate that mutation in klf-3 reduces expression of C. elegans dsc-4 and/or vit genes, the orthologs of mammalian microsomal triglyceride transfer protein and apolipoprotein B, respectively. Both microsomal triglyceride transfer protein and apolipoprotein B are essential for mammalian lipoprotein assembly and transport, and mutation in both dsc-4 (qm182) and vit-5 (ok3239) results in high fat accumulation in worm intestine. Genetic interactions between klf-3 and dsc-4, as well as vit-5 genes, suggest that klf-3 may have an important role in regulating lipid assembly and secretion. PMID- 23639360 TI - Rokumi-jio-gan-containing prescriptions regulate oxidative stress through improving dyslipidemia in a subtotal nephrectomized rat model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rokumi-jio-gan-containing prescriptions, traditional medicine, are widely used to treat renal dysfunction in Japan. AIM OF THE STUDY: The present study was conducted to examine whether two Rokumi-jio-gan containing prescriptions (Hachimi-jio-gan and Bakumi-jio-gan) have an ameliorative effect on dyslipidemia in nephrectomized rats. MATERIALS AND METHODS: Each prescription was orally administered to nephrectomized rats at 150mg/kg body weight per day for 10 weeks, and its effect was compared with vehicle-treated nephrectomized rats. RESULTS: Rats given Hachimi-jio-gan and Bakumi-jio-gan showed an improvement of renal functional parameters such as serum urea nitrogen, creatinine, creatinine clearance, and urinary protein. The increased triglyceride, total cholesterol, non-esterified fatty acid, high density lipoprotein cholesterol, and very low-density lipoprotein cholesterol/low density lipoprotein cholesterol levels in serum, and triglyceride and total cholesterol contents in the kidney of nephrectomized rats were significantly decreased by Hachimi-jio-gan and Bakumi-jio-gan administration. Furthermore, Hachimi-jio-gan acts as a regulator of peroxisome proliferator-activated receptor alpha, sterol regulatory element binding protein (SREBP)-1, and SREBP-2. On the contrary, the increased reactive oxygen species and thiobarbituric acid-reactive substance were decreased, while superoxide dismutase and the reduced glutathione/oxidized glutathione ratio were augmented by Hachimi-jio-gan rather than Bakumi-jio-gan. The improvement of nuclear factor-kappa Bp65, cyclooxygenase 2, inducible nitric oxide synthase, NF-E2-related factor 2, and heme oxygenase-1 was marked in the group administered Bakumi-jio-gan. However, oil red O staining showed that the increased lipid deposition in the kidney of nephrectomized rats improved on Hachimi-jio-gan and Bakumi-jio-gan administration. CONCLUSION: This study provides scientific evidence that two Rokumi-jio-gan-containing prescriptions (Hachimi-jio-gan and Bakumi-jio-gan) improve oxidative stress via dyslipidemia in the remnant kidney of nephrectomized rats. PMID- 23639359 TI - E. coli ClpA catalyzed polypeptide translocation is allosterically controlled by the protease ClpP. AB - There are five known ATP-dependent proteases in Escherichia coli (Lon, ClpAP, ClpXP, HslUV, and the membrane-associated FtsH) that catalyze the removal of both misfolded and properly folded proteins in cellular protein quality control pathways. Hexameric ClpA rings associate with one or both faces of the cylindrically shaped tetradecameric ClpP protease. ClpA catalyzes unfolding and translocation of polypeptide substrates into the proteolytic core of ClpP for degradation through repeated cycles of ATP binding and hydrolysis at two nucleotide binding domains on each ClpA monomer. We previously reported a molecular mechanism for ClpA catalyzed polypeptide translocation in the absence of ClpP, including elementary rate constants, overall rate, and the kinetic step size. However, the potential allosteric effect of ClpP on the mechanism of ClpA catalyzed translocation remains unclear. Using single-turnover fluorescence stopped-flow methods, here we report that ClpA, when associated with ClpP, translocates polypeptide with an overall rate of ~35 aa s(-1) and, on average, traverses ~5 aa between two rate-limiting steps with reduced cooperativity between ATP binding sites in the hexameric ring. This is in direct contrast to our previously reported observation that, in the absence of ClpP, ClpA translocates polypeptide substrates with a maximum translocation rate of ~20 aa s(-1) with cooperativity between ATPase sites. Our results demonstrate that ClpP allosterically impacts the polypeptide translocation activity of ClpA by reducing the cooperativity between ATP binding sites. PMID- 23639361 TI - Ghrelin receptor is activated by naringin and naringenin, constituents of a prokinetic agent Poncirus fructus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Poncirus fructus (PF), also known as a dried immature fruit of Poncirus trifoliata (L.) Raf. (Rutaceae), has long been traditionally used for the various gastrointestinal disorders in Eastern Asia. AIM OF STUDY: The aqueous extract of PF (PF-W) has the strong prokinetic effect, yet the underlying mechanism is still elusive. The present study investigated whether PF-W has any effect on motilin receptor or ghrelin receptor, since these receptors enhance intestinal motility when activated. MATERIALS AND METHODS: The effect of PF-W and its components on motilin or ghrelin receptor was determined by calcium imaging and whole-cell patch clamp methods. RESULTS: PF-W activates the ghrelin receptor, but not the motilin receptor, resulting in a transient increase of intracellular calcium levels. Furthermore, among various constituents of PF, only naringin and naringenin evoked the intracellular calcium augmentation via the ghrelin receptor. Moreover, cortistatin-8 - a ghrelin receptor inhibitor specifically blocked naringin- and naringenin-induced calcium increases. In addition, naringin and naringenin induced inward currents in ghrelin receptor expressing cells under whole-cell patch clamp configuration. CONCLUSION: PF-W activates the ghrelin receptor, and naringin and naringenin are key constituents responsible for the activation of ghrelin receptor. Therefore, the present study suggests that the ghrelin receptor is a molecular entity responsible for the strong prokinetic activity of PF-W. PMID- 23639362 TI - Cyperi Rhizoma inhibits the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced reduction in nigrostriatal dopaminergenic neurons in estrogen-deprived mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cyperi Rhizoma has commonly been used for the treatment of gynecological and neuropsychiatric disorders in traditional medicine. The aim of this study was to evaluate the estrogenic properties and neuroprotective effects of Cyperi Rhizoma under estrogen-deprived condition in female mice. MATERIALS AND METHODS: To determine the estrogen-like effect of Cyperi Rhizoma extract (CRE), we measured luciferase expression after transfection of a promoter construct containing an estrogen response element (ERE) and treatment of CRE. To evaluate the neuroprotective effect of CRE, we measured striatal dopamine, movement ability, tyrosine hydroxylase (TH) immunoreactivity, and apoptosis-related protein expression levels after treatment of CRE either with or without 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in ovariectomized female mice. RESULTS: CRE significantly induced the luciferase expression driven by an ERE in PC12 cells, a dopaminergic cell line, in a dose dependent manner. In mice, MPTP significantly decreased the levels of dopamine in the striatum and behavior performance; in contrast, both CRE and 17beta-estradiol benzoate (EB) recovered these parameters to normal levels. CRE and EB treatment also recovered TH immunopositive fibers and cells, respectively, from MPTP toxicity. Additionally, MPTP significantly down-regulated Bcl-2 expression in the mitochondria of dopaminergic cells in the SN, followed by an increase in Bax expression, cytochrome C translocation to the cytosol, and cleaved-caspase-3 expression, whereas these were inhibited by CRE or EB treatment. CONCLUSIONS: These findings provide the first evidence that CRE has estrogen-like and neuroprotective effects on dopaminergic neurons in estrogen-deprived mice treated with MPTP-toxin. PMID- 23639363 TI - Canna indica L. attenuates high-glucose- and lipopolysaccharide-induced inflammatory mediators in monocyte/macrophage. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Canna indica L. (CI) has been widely used as a folklore medicine in tropical and subtropical areas with beneficial effects in numerous diseases, including infection, rheumatism, hepatitis, and it has also been identified as an antioxidant. MATERIALS AND METHODS: The present study aimed to investigate the effect of Canna indica CI ethanolic extract (CIE) on productions of nitric oxide (NO), prostaglandin E2 (PGE2), and interleukin-1beta (IL-1beta) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. In addition, the effects of CIE in high glucose (HG)-induced U937 monocytes on mRNA expressions of IL-8 and monocyte chemoattractant protein-1 (MCP-1), and regulation of mitogen-activated protein kinase (MAPK) pathways were also identified. RESULTS: CIE was found to inhibit the production of inflammatory mediators including NO, IL-1beta, and PGE2 from LPS-induced RAW 264.7 macrophages. The increases in HG-induced mRNA expressions of IL-8 and MCP-1 were also significantly inhibited by CIE. Stimulation of HG in U937 monocytes resulted in activation of p38 MAPK, ERK1/2, and JNK. However, CIE treatment significantly decreased phosphorylation of p38 MAPK, ERK1/2, and JNK. CONCLUSION: The present study demonstrated that CIE suppressed the LPS-induced inflammatory mediator production and also inhibited HG-induced inflammatory mediator expression by the regulation of MAPK pathway. PMID- 23639365 TI - Fabrication of novel two-dimensional nanopatterned conductive PEDOT:PSS films for organic optoelectronic applications. AB - This paper presents a novel strategy to fabricate two-dimensional poly(3,4 ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) photonic crystals (PCs) combining electron beam lithography (EBL) and plasma etching (PE) processes. The surface morphology of PEDOT:PSS PCs after mild oxygen plasma treatment was investigated by scanning electron microscopy. The effects on light extraction are studied experimentally. Vertical extraction of light was found to be strongly dependent on the geometric parameters of the PCs. By changing the lattice type from triangular to square and the geometrical parameters of the photonic structures, the resonance peak could be tuned from a narrow blue emission at 445 nm up to a green emission at 525 nm with a full width at half maximum of 20 nm, which is in good agreement with Bragg's diffraction theory and free photon band structure. Both finite-difference time-domain and plane wave expansion methods are used to calculate the resonant frequencies and the photonic band structures in the two-dimensional photonic crystals showing a very good agreement with the experiment results. A 2D nanopatterned transparent anode was also fabricated onto a flexible polyethylene terephthalate (PET) substrate and it was integrated into an organic light-emitting diode (OLED). The obtained results fully confirm the feasibility of the developed process of micro/nano patterning PEDOT:PSS. Engineered polymer electrodes prepared by this unique method are useful in a wide variety of high-performance flexible organic optoelectronics. PMID- 23639364 TI - Hawkins Group I fracture of neck of talus and Salter Harris Type III tibial epiphyseal injury of medial malleolus. AB - We are reporting an unusual combination of Hawkins Group I fracture of the neck of left talus in association with Salter Harris Type III distal tibial epiphyseal injury of medial malleolus in a child with cerebral palsy and hemiplegia of contralateral limbs and discussed the possible mechanism as well as management. Fractures of medial malleolus usually occur in Hawkins Group III fracture dislocations in adults. Forced dorsiflexion of talus against the anterior edge of tibia appears to be the accepted common mechanism, despite limited experimental and clinical evidence incriminating axial compression. Fracture of medial malleolus implicates supination. We managed this unusual pattern of injury conservatively. At 15 months, the child was asymptomatic with no radiological evidence of avascular necrosis of body of talus or growth disturbance of distal tibial epiphysis. PMID- 23639366 TI - The effects of cryoablation on renal cell carcinoma perfusion and glomerular filtration rate measured using dynamic contrast-enhanced MRI: a feasibility study. AB - AIM: To assess the effect of cryoablation on renal cell carcinoma (RCC) perfusion and single kidney (SK) glomerular filtration rate (GFR) using dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI). MATERIALS AND METHODS: Eighteen patients undergoing percutaneous cryoablation of a solitary RCC between August 2010 and November 2011 were evaluated with DCE-MRI immediately before and 1 month post-cryoablation. DCE-MRI data were acquired with 2 s temporal resolution in a coronal plane during the first pass of a 0.1 mmol/kg bolus dose of Gd-DOTA. Perfusion of the RCC (in ml/min/100 ml tissue) was estimated using a maximum slope technique. An index of SK GFR (SK-GFRi) was assessed using data acquired every 30 s for the following 3 min in the axial plane and analysed using Rutland Patlak plots. This was compared to the GFR estimated by creatinine clearance (eGFR). RESULTS: Perfusion in the zone of ablation decreased significantly (p<0.001) from a mean of 98.0 +/- 37.5 ml/min/100 ml pre-cryoablation to 11.6 +/- 4.1 ml/min/100 ml post-cryoablation; a mean decrease of 88.2%. Functional analysis was performed in seventeen patients. eGFR was underestimated by SK-GFRi which decreased significantly in tumour-bearing (-31.7%, p = 0.011), but not in contralateral kidneys (-4.4%, p = 0.14). CONCLUSION: It is feasible to measure RCC perfusion pre- and post-cryoablation using DCE-MRI. The significant decrease within the zone of ablation suggests that this technique may be useful for assessment of treatment response. Further work is required to address the underestimation of eGFR by SK-GFRi and to validate the perfusion findings. PMID- 23639367 TI - The Normandy field study on juvenile osteochondral conditions: conclusions regarding the influence of genetics, environmental conditions and management, and the effect on performance. AB - Juvenile osteochondral conditions (JOCC) have a major impact on the equine industry and include many musculoskeletal disorders of the young horse, of which osteochondrosis (OC) is the most prominent. The Breeding, Osteochondral Status and Athletic Career (BOSAC) project is the first large, comprehensive, longitudinal field study on the subject conducted in three breeds of performance horses (Thoroughbreds, Standardbred Trotters and Warmbloods) that were monitored in their natural environment where they were reared under common field conditions. The BOSAC study used a radiographic protocol designed for field use coupled to an internally validated severity scoring system, providing weighted radiographic findings as the primary outcome measure. The natural courses of various JOCC appear to differ, according to the joint and condition involved. Genetically, there were also large differences with moderate heritabilities in the tarsocrural and metacarpophalangeal/metatarsophalangeal joints and virtually no heritability for femoropatellar OC. There was a strong influence of exercise history (as an environmental condition) on the manifestation and natural course of JOCC. In the younger age class (<6months) lack of exercise or irregular exercise had a negative effect, as had exposure to excessive exercise. In the yearling category, (exercise-associated) intrinsic trauma seemed to be the most important negative factor. In terms of later function, the association of a poor radiographic score with poorer performance in racing Trotters could be demonstrated. PMID- 23639368 TI - Development and validation of a survey for quality of life assessment by owners of healthy dogs. AB - Assessing and maintaining quality of life (QOL) is a growing concern in companion animal practice, as improved nutrition and healthcare have extended canine longevity. The objective of this study was to develop a validated survey for evaluating QOL in healthy dogs for use in clinical and research settings. A total of 174 dog owners completed an initial QOL survey containing 21 items grouped into seven domains (CHQLS-21). After factor analysis of the responses, a final survey was constructed containing 15 items grouped into four domains (happiness, physical functioning, hygiene and mental status), plus two questions on general health and an item asking for a direct QOL assessment (CHQLS-15). Psychometric analysis indicated that the CHQLS-15 had good validity, reliability, and internal consistency and was able to detect QOL changes affecting several domains across age groups in healthy dogs. The CHQLS-15 therefore provides a basis for dialog between clinicians and dog owners regarding the health of their pets, particularly in tracking changes in health status, evaluating response to treatment, and guiding end-of-life decisions. A validated QOL survey could be particularly useful in recognizing and managing functional decline as the healthy canine patient ages. PMID- 23639369 TI - Influence of juvenile osteochondral conditions on racing performance in Thoroughbreds born in Normandy. AB - The relationship between osteoarticular status and future athletic capacity is commonly accepted in equine practice, but there is little to support this belief in Thoroughbreds. The objective of this study was to assess the prevalence of juvenile osteochondral conditions (JOCC) in Thoroughbred yearlings and to investigate the significance of these with regard to subsequent racing performance. The radiographic files from 328 Thoroughbred yearlings born in Normandy were assessed in a consistent manner and entered into a database together with racing records. Logistic regression models were used to quantify the association between each radiographic parameter and racing performance (raced/not raced, placed/not placed, performer/not performer) at 2, 3, 4 and 5years of age. The front fetlock (30.2% of horses), the dorsal aspect of the hind fetlock (18%), the carpus (15.9%) and the distal part of the hock (15.5%) were the most commonly affected joints. Most horses (87.5%) raced either in turf flat races or in hurdle races. Starting a race at 2years old was more frequent for yearlings without radiographic findings (RF) on the carpus or with less than one RF of moderate severity. The proportions of horses placed at 3years old decreased with increasing number or severity of RF. In racing horses, there was no association between the presence of RF and earnings. The radiographic score, calculated as the sum of all the severity indices found on the radiographic file of the horse appeared well correlated with performance. Using this synthetic index might help veterinarians to evaluate radiographs of Thoroughbred yearlings for potential buyers. PMID- 23639370 TI - Genetic parameters of juvenile osteochondral conditions (JOCC) in French Trotters. AB - Juvenile osteochondral conditions (JOCC) have been defined as lesions resulting from biomechanical influences (compressive, tensional or shear forces) on the developing and growing musculoskeletal system. They include different types of osteochondrosis, osteochondral fragmentation of the articular surface or of the periarticular margins, juvenile subchondral bone cysts, osteochondral collapse, avulsion fractures of epiphyseal (or metaphyseal) ossifying bone and 'physitis'. The aim of this study was to estimate heritability of JOCC in a sample of 2106 French Trotters from four different sources, comprising representative samples of the Trotter population, as well as material from auctions. Horses were aged 6 24months and were either not yet in training or just beginning training. Radiographs were taken of fore and hind feet, including proximal interphalangeal (pastern) joints, metacarpophalangeal and metatarsophalangeal (fetlock) joints, tarsocrural (hock) joints, carpi and femoropatellar (stifle) joints. The threshold model used included sex, age, region and month of birth, sampling group and sire (n=159) with all inter-sire relationships. The main results were a moderate heritability for findings in the hind fetlock (0.29) and the hock (0.19). There was a weak genetic correlation between findings in fetlocks and hocks (0.26). Higher heritability was found for findings in the hock (0.37 for findings in the distal row and 0.49 for the proximal row of tarsal bones) in that part of the data (699 horses) in which it was possible to integrate the grade, bilateral occurrence or not, and distal or proximal location of the lesions. It is possible to use these genetic parameters in breeding selection with more efficiency when detailed phenotypes are considered. PMID- 23639371 TI - Problems and pointers in osteochondrosis: Twenty years on. AB - Twenty years ago a supplement of Equine Veterinary Journal was devoted to equine osteochondrosis (OC) and recognised the importance of this developmental disease to the equine industry. In the accompanying editorial several controversial issues were identified and a number of areas for further research were highlighted. Today, equine OC is still a major clinical problem, but the on-going research has resulted in much improved knowledge and understanding of this highly complicated disease. There is still conflicting evidence on the prevalence of OC due to the dynamic character of the condition, widely varying definitions in the literature, and the range of joints affected. Nevertheless there is now convincing evidence that early vascular damage, leading to chondronecrosis, is the major mechanism of onset. The aetiological factors that determine whether a horse will develop clinical signs of OC remain obscure and the complex nature of OC and its multi-factorial character has been clearly demonstrated by genetic studies. These have shown a multitude of loci on a variety of chromosomes linked to osteochondrotic phenotypes, depending on the type of manifestation of OC, the joint involved and the breed. The controversy surrounding the possible key role of copper in the pathogenesis of OC in the early 1990s has evolved into a more limited contribution to repair thus making it just one of the many environmental factors that may have an effect on the occurrence of OC, but not a decisive one. The semantic debate concerning the most appropriate nomenclature seems to have crystallised into a consensus on terminology at three levels: OC or osteochondritis dissecans (OCD) for the disturbance in the process of endochondral ossification, juvenile ostechondral conditions (JOCC) for all joint and growth plate related disorders, and developmental orthopaedic diseases (DOD) for the full range of skeletal conditions in young horses. Future progress in improved management of OC can be expected from more research on cellular and molecular processes and the influences that determine the process of endochondral ossification, the process of articular cartilage maturation, and from epidemiological studies quantifying the long-term effects of OC on health and performance. PMID- 23639372 TI - Multiple locus variable number tandem repeat analysis of Mycoplasma bovis isolated from local and imported cattle. AB - Mycoplasma bovis is an important and emerging pathogen of cattle. In this study, multiple locus variable number tandem repeat (VNTR) analysis was used to differentiate M. bovis type strain PG45 and 68 M. bovis field isolates, including 34 isolates from calves imported to Israel from Australia, Lithuania and Hungary in the period 2006-2011, 32 isolates from mastitic dairy cows in Israel in the period 2000-2011, one isolate from the pneumonic lungs of a calf in Israel in 2010 and one isolate from frozen bull semen in Israel in 2008. A total of 35 VNTR types were distinguished, including three, eight and 10 different VNTR types among isolates from calves imported from Australia, Hungary and Lithuania, respectively, and 17 VNTR types among isolates from dairy cows in Israel. The VNTR types in isolates from Lithuanian calves were not identified among isolates from Israeli dairy cows. VNTR type XX, present in the Hungarian group, was identified in one Israeli mastitis-associated isolate. A cluster of 16 M. bovis isolates from Israeli dairy cows possessed the same VNTR type III as three Australian isolates from a single shipment of calves in 2006. The other cluster of isolates contained M. bovis strain 883, isolated from a mastitic cow, strain 72236, isolated from a calf with pneumonia, two isolates from calves imported from Australia to the same farm 3 months previously and four isolates from calves in quarantine imported to Israel from Australia in 2009-2010. Multiple locus VNTR analysis is a useful tool for understanding the movement and spread of strains of M. bovis within and across international boundaries. PMID- 23639373 TI - Swainsonine differentially affects steroidogenesis and viability in caprine luteal cells in vitro. AB - Plants containing swainsonine (SW) have been reported to impair reproductive function and fertility after long-term ingestion by livestock. However, direct effects of SW on luteal cell steroidogenesis remain unclear. In this study, primary and transfected luteal cells were used to investigate the effects of SW on progesterone secretion and cell viability and the mechanisms involved in these processes. After treatment with various concentrations of SW for 24 or 48 hours, progesterone production and the number of living cells were assessed using radioimmunoassay and trypan blue dye exclusion assay, respectively. Lower concentrations of SW enhanced basal, 22R-hydroxycholesterol- or pregnenolone stimulated progesterone secretion (P < 0.05), whereas higher concentrations of SW inhibited progesterone secretion (P < 0.05). Lower concentrations of SW promoted expression of P450 side-chain cleavage enzyme and 3beta-hydroxysteroid dehydrogenase, two key enzymes involved in luteal cell steroidogenesis, at mRNA and protein levels (P < 0.05), but did not affect expression of steroidogenic acute regulatory protein and cell proliferation. In contrast, higher concentrations of SW inhibited luteal cell proliferation by inducing growth phase 1/quiescent state cell cycle arrest and apoptosis (P < 0.05). Taken together, these results demonstrated that lower concentrations of SW induced progesterone production through upregulation of P450 side-chain cleavage enzyme and 3beta hydroxysteroid dehydrogenase without affecting cell viability, whereas higher concentrations of SW induced cell cycle arrest and apoptosis and impaired steroidogenesis. These findings provided new insights into understanding the effect of SW on luteal cell steroidogenesis. PMID- 23639374 TI - Nodo-paranodopathy: beyond the demyelinating and axonal classification in anti ganglioside antibody-mediated neuropathies. AB - In some anti-ganglioside antibody-mediated neuropathies, human and experimental data suggest a common pathogenic mechanism of dysfunction/disruption at the node of Ranvier resulting in a pathophysiologic continuum from transitory nerve conduction failure to axonal degeneration. The traditional classification of polyneuropathies into demyelinating or axonal may generate some confusion in the electrophysiological diagnosis of Guillain-Barre syndrome subtypes associated with anti-ganglioside antibodies. The axonal forms show, besides axonal degeneration, promptly reversible nerve conduction failure. This may be interpreted, by a single electrophysiological study, as demyelinating conduction block or distal axonal degeneration leading to errors in classification and in establishing prognosis. Moreover the term axonal may be misleading as it is commonly associated to axonal degeneration and not to a transitory, promptly reversible, dysfunction of the excitable axolemma. To focus on the site of nerve injury and overcome the classification difficulties, we propose the new category of nodo-paranodopathy which seems appropriate to various acute and chronic neuropathies associated with anti-ganglioside antibodies and we think better systematizes the neuropathies characterized by an autoimmune attack targeting the nodal region. PMID- 23639376 TI - Sleep wake cycling in early preterm infants: comparison of polysomnographic recordings with a novel EEG-based index. AB - OBJECTIVE: To document the occurrence of genuine sleep stages in the early preterm babies, and to develop an EEG-based index for following sleep wake cyclicity. METHODS: Twelve preterm babies were recruited from a study that assessed ventilator strategies. We used altogether 18 polysomnography recordings that were collected at mean conceptional age of 29.3 (25.9-32.7) weeks. Spontaneous activity transients (SAT) were detected automatically and their cumulative coverage in each 20s interval was computed from the EEG derivations C3 A2 and O2-A1. Mean SAT% values between sleep stages were compared. RESULTS: All babies exhibited all sleep stages, however the sleep was remarkably fragmentary in infants due to their respiratory issues. The EEG index, SAT% showed temporal behavior that strikingly well compared with the sleep stage fluctuations in the hypnogram. In the statistical analysis we found significant differences in all recordings between the deep (quiet) sleep and the REM sleep. CONCLUSION: Genuine sleep states exist in the early preterm babies, and changes in sleep stages are reflected in the EEG activity in a way that can be readily measured by assessing fluctuation of the automatically detected, EEG based index, the SAT%. SIGNIFICANCE: The findings open a possibility to construct automated analysis or monitoring of sleep wake cyclicity into brain monitors in neonatal intensive care unit. PMID- 23639375 TI - Modulation of laser-evoked potentials and pain perception by transcutaneous electrical nerve stimulation (TENS): a placebo-controlled study in healthy volunteers. AB - OBJECTIVE: To investigate the effects of transcutaneous electrical nerve stimulation (TENS) on brain nociceptive responses (laser-evoked potentials, LEPs) and pain perception. METHODS: Twenty healthy subjects were included. Nociceptive CO(2)-laser pulses were sequentially delivered to the dorsum of both feet. The amplitude of LEPs and nociceptive thresholds were collected in three consecutive conditions: T1: "sham" TENS (2 Hz/low-intensity) positioned heterotopically, over the left thigh; T2: "active" TENS (120 Hz/low-intensity) applied homotopically, over the left common peroneal nerve; and T3: "sham" TENS (replication of condition T1). RESULTS: Compared with "sham" TENS, "active" TENS significantly decreased the LEPs amplitude. This effect was observed exclusively when "active" TENS was applied ipsilaterally to the painful stimulus. Nociceptive thresholds increased with sessions in both limbs, but the increase observed during the "active" condition of TENS (T2) exceeded significantly that observed during the condition T3 only on the foot ipsilateral to TENS. CONCLUSIONS: Compared with a credible placebo TENS, high-frequency TENS induced a significant attenuation of both the acute pain and LEPs induced by noxious stimuli applied on the same dermatome. SIGNIFICANCE: This modulation of subjective and objective concomitants of pain processing reflects a real neurophysiological TENS-related effect on nociceptive transmission. PMID- 23639377 TI - Activity-dependent block in single axon branches. PMID- 23639379 TI - Bias in a common EEG and MEG statistical analysis and how to avoid it. PMID- 23639380 TI - Laboratory diagnosis of leptospirosis: a challenge. AB - Leptospirosis is caused by pathogenic bacteria called leptospires that are transmitted directly or indirectly from animals to humans. It occurs worldwide but is most common in tropical and subtropical areas. It is a potentially serious but treatable disease. Its symptoms may mimic those of a number of other unrelated infections such as influenza, meningitis, hepatitis, dengue, or other viral hemorrhagic fevers. The spectrum of the disease is extremely wide, ranging from subclinical infection to a severe syndrome of multiorgan infection with high mortality. Laboratory diagnosis tests are not always available, especially in developing countries. Numerous tests have been developed, but availability of appropriate laboratory support is still a problem. Direct observation of leptospires by darkfield microscopy is unreliable and not recommended. Isolation of leptospires can take up to months and does not contribute to early diagnosis. Diagnosis is usually performed by serology; enzyme-linked immunosorbent assay and the microscopic agglutination tests are the laboratory methods generally used, rapid tests are also available. Limitation of serology is that antibodies are lacking at the acute phase of the disease. In recent years, several real-time polymerase chain reaction assays have been described. These can confirm the diagnosis in the early phase of the disease prior to antibody titers are at detectable levels, but molecular testing is not available in restricted resources areas. PMID- 23639378 TI - Display of consistent ictal networks in refractory mesial temporal lobe epilepsy. AB - OBJECTIVE: Exploration of emergent ictal networks was performed in homogeneous subjects with refractory medial temporal lobe epilepsy. METHODS: Maximal Synchrony Index (SI) values were calculated for all electrode pairs for each second during 25 seizures and displayed as connectivity animations. Consistent temporal patterns of SI value and spatial connectivity were observed across seizures and subjects, and used to define a sequence of network stages. RESULTS: Highest SI values were found in electrodes within the area of surgical resection. Analysis of these electrodes by network stage demonstrated lateral temporal cortex dominance at seizure initiation, giving way to hippocampal synchrony during the major portion of the seizure, with lateral temporal regions re emerging as the seizure terminated. SI values also corresponded to behavioral severity of seizures, and lower SI values were associated with post-surgical seizure freedom. CONCLUSION: SI based methods of network characterization consistently display the intrinsic MTLE ictal network and may be sensitive to clinical features. SIGNIFICANCE: Consistency of EEG-derived network patterns is an important step as network features are applied towards improvement of clinical management. These data confirm consistency of network patterns within and across subjects and support the potential for these methods to distinguish relevant clinical variables. PMID- 23639381 TI - Molecular characterization of Group A streptococcal isolates causing scarlet fever and pharyngitis among young children: a retrospective study from a northern Taiwan medical center. AB - BACKGROUND/PURPOSE: Little information is available on the differences in frequency of pyrogenic exotoxin genes between strains of group A streptococci that cause scarlet fever and those that cause pharyngotonsillitis in children in Taiwan. This study retrospectively monitored the presence of pyrogenic exotoxin genes, the emm typing, and the susceptibility of macrolide drugs in Streptococcus pyogenes isolated from children diagnosed with scarlet fever and pharyngotonsillitis in northern Taiwan. MATERIALS AND METHODS: Isolates of S. pyogenes were recovered from children with scarlet fever (n = 21) and acute pharyngotonsillitis (n = 29) during 2000-2011. The isolates were characterized according to the presence of spe genes and emm typing. Antibiograms were determined by the disk diffusion method and agar dilution test. Polymerase chain reaction was used to detect the presence of erm genes in isolates that showed nonsusceptibility to erythromycin. All isolates underwent additional genotyping by pulsed-field gel electrophoresis. RESULTS: In isolates from patients with scarlet fever, the frequencies of pyrogenic exotoxin genes were 9.5% for speA, 81.0% for speB, 4.8% for speC, and 71.4% for speF. In isolates from patients with pharyngotonsillitis, the frequencies were 17.2% for speA, 72.4% for speB, 13.8% for speC, and 69.0% for speF. There were no significant differences in frequencies of the exotoxin genes between the two groups of isolates. Eight emm sequence types were identified from all group A streptococci isolates. The most common types were emm12 followed by emm1 and emm4. The erythromycin resistant rate was 4/50 (8%). The ermB gene was detected in only one isolate from a patient with pharyngotonsillitis. Pulsed-field gel electrophoresis had a total of three sets of clustered strains, which showed >80% homology and belonged to the same emm type. CONCLUSION: There were no significant differences in frequencies of the spe genes between S. pyogenes isolates from patients with scarlet fever and patients with pharyngotonsillitis. The most common emm type was emm12. Low erythromycin resistance in S. pyogenes was observed. PMID- 23639382 TI - Metabolic signaling by lactate in the brain. AB - High-resolution molecular and imaging techniques are shedding light on the mechanisms and functional significance of the transient rise in tissue lactate that accompanies synaptic activity. Despite high energy needs, neurons have a truncated glycolytic pathway that favors antioxidation over energy production, whereas astrocytes team up with oligodendrocytes to extract glucose from the blood, mobilize glycogen, and release lactate under neuronal command. Lactate energizes neurons but also diffuses beyond the active zone and modifies the activity of neurons and astrocytes in neighboring regions. Involved in a hierarchy of processes from neurovascular coupling to memory formation, lactate has a dual role as metabolic fuel and an intercellular messenger. PMID- 23639385 TI - Postoperative pain and contracture following total knee arthroplasty comparing parapatellar and subvastus approaches. AB - The purpose of this study was to see if subvastus approach would decrease incidence of postoperative contracture and pain following TKA compared to standard parapatellar approach. Retrospective review of 546 patients in Group A undergoing TKA using parapatellar approach were compared to 255 patients in Group B undergoing subvastus approach. No statistically significant differences regarding OR time, blood loss, BMI, or LOS. Total of 23 (4%) manipulations under anesthesia for contracture in Group A compared to 6 (2%) in Group B (p>0.05). Postoperative pain scores at 6 weeks was greater in Group A, p<0.05. We feel that a subvastus approach minimizes trauma to the extensor mechanism, and therefore decreases the incidence of postoperative pain following TKA. PMID- 23639386 TI - A comparative study of four bearing couples of the same acetabular and femoral component: a mean follow-up of 11.5 years. AB - We present a retrospective evaluation of 1369 hip arthroplasties performed using the Bicon-Plus cups and SL-Plus stems, differing only in the bearing combination. Four bearing combination groups were used: metal-on-polyethylene (MoP) group with 587 hips, ceramic-on-polyethylene (CoP) group with 161 hips, metal-on-metal (MoM) group with 322 hips and ceramic-on-ceramic (CoC) group with 299 hips. The mean follow-up was 11.5 years (4.1 to 15.0). Radiological evaluation was performed on implants failed due to aseptic loosening. The survival for prosthesis with revision for any reason at ten years was 96.1% (95% confidence interval (CI) 94.3 to 97.9) for MoP, 98.1% (CI 95.9 to 100) for CoP, 90.2% (CI 86.8 to 93.6) for MoM, and 95.6% (CI 93.0 to 98.2) for CoC. Survival for aseptic loosening was also determined. PMID- 23639383 TI - Autophagy in axonal and dendritic degeneration. AB - Degeneration of axons and dendrites is a common and early pathological feature of many neurodegenerative disorders, and is thought to be regulated by mechanisms distinct from those determining death of the cell body. The unique structures of axons and dendrites (collectively neurites) may cause them to be particularly vulnerable to the accumulation of protein aggregates and damaged organelles. Autophagy is a catabolic mechanism in which cells clear protein aggregates and damaged organelles. Basal autophagy occurs continuously as a housekeeping function, and can be acutely expanded in response to stress or injury. Emerging evidence shows that insufficient or excessive autophagy contributes to neuritic degeneration. Here, we review the recent progress that has begun to reveal the role of autophagy in neurite function and degeneration. PMID- 23639387 TI - Molecular characterization of the first commercial transgenic common bean immune to the Bean golden mosaic virus. AB - Golden mosaic of common bean is caused by the Bean golden mosaic virus (BGMV). The disease is one of the greatest constraints on bean production in Latin America and causes significant yield losses. The RNAi concept was explored to silence the rep (AC1) viral gene and a transgenic bean line immune to BGMV upon inoculation at high pressure was previously generated. Identification of the transgene insert confirmed the presence of a single locus corresponding to two intact copies of the RNAi cassette in opposite orientation and three intact copies of the AtAhas gene. It is flanked by Phaseolus genomic sequences and interspersed by one nuclear and three chloroplastic genomic sequences. Southern analyses showed that the transgenes were structurally stable for eight self pollinated generations and after backcrosses with a non transgenic commercial variety. Transgene expression analyses revealed similar levels of siRNA in leaves of transgenic plants cultivated under field conditions in three distinct regions. siRNA were also analyzed during seed development in common bean transgenic plants. siRNA signals were also detected in seeds, albeit at significantly lower levels than those observed in leaves, and could not be detected in seeds cooked during 10 min. This information is relevant to demonstrate that GM beans are free of siRNA signals after cooking and therefore suitable for human consumption. Additionally, characterization of the locus where the transgene was integrated in the common bean genome provides a valuable tool to trace this GM bean material in the field and in the market. PMID- 23639388 TI - Prediction of transcribed PIWI-interacting RNAs from CHO RNAseq data. AB - Chinese hamster ovary (CHO) cells are currently the most important mammalian host for the manufacture of biopharmaceuticals. To enhance our understanding of cellular processes, pathways, and the genetic setup of CHO cell lines, we predicted PIWI interacting RNAs (piRNAs) from small RNA sequencing data. Although piRNAs are the least understood class of small non-coding RNAs that mediate RNA silencing, it is believed that they play a pivotal role in protecting genome integrity by repressing transposable elements. Since genomic integrity is the key to prolonged stability of recombinant CHO cell lines, we characterized piRNA sequences and expression in six CHO cell lines by computational analysis of an existing small RNA sequencing dataset using proTRAC and the published CHO genome as reference. Here we present the result of this analysis consisting of 25,626 piRNAs and 540 piRNA clusters. Moreover we provide first evidence for differential piRNA expression in adherent and suspension-adapted CHO-K1 and DUKXB11 host cell lines as well as their recombinant derivatives, indicating that piRNAs might be tools for cell line development and engineering. PMID- 23639389 TI - Childhood abuse and neglect and transitions in stages of alcohol involvement among women: a latent transition analysis approach. AB - BACKGROUND: Childhood abuse and neglect have been linked with alcohol disorders in adulthood yet less is known about the potential of early trauma to influence transitions in stages of alcohol involvement among women. Study aims were to (1) identify stages of women's alcohol involvement, (2) examine the probability of transitions between stages, and (3) investigate the influence of four domains of childhood abuse and neglect (sexual abuse, physical abuse, neglect, and witness to domestic violence), assessed individually and as poly-victimization, on transitions. METHODS: The sample consisted of 11,750 adult female current drinkers identified in Wave 1 (2001-2002) and re-interviewed in Wave 2 (2004 2005) of the National Epidemiological Survey on Alcohol and Related Conditions. RESULTS: Three stages of alcohol involvement emerged from latent class analysis of 11 DSM-IV abuse/dependence criteria: severe (1.5% at Wave 1, 1.9% at Wave 2), hazardous (13.6% at Wave 1, 16.0% at Wave 2), and non-problem drinking (82.1% at Wave 1, 84.5% at Wave 2). Adjusted latent transition analyses determined transition probabilities between stages across waves. Women reporting any childhood abuse and neglect were more likely to advance from the non-problem drinking class at Wave 1 to severe (AOR=3.90, 95% CI=1.78-8.53) and hazardous (AOR=1.56, 95% CI=1.22-2.01) drinking classes at Wave 2 relative to women without this history. Associations were also observed between individual domains and transition from no problems to severe alcohol stage. CONCLUSIONS: Results suggest a long-term impact of childhood abuse and neglect as drivers of progression in women's alcohol involvement. PMID- 23639390 TI - Resting state synchrony in long-term abstinent alcoholics with versus without comorbid drug dependence. AB - BACKGROUND: We previously reported that when long-term abstinent alcoholics (LTAA; with no drug comorbidity) are compared to controls, they show increased resting state synchrony (RSS) in the executive control network and reduced RSS in the appetitive drive network suggestive of compensatory mechanisms that may facilitate abstinence. The aim of the present study was to investigate whether long-term abstinent alcoholics with comorbid stimulants dependence (LTAAS) show similar RSS mechanisms. METHODS: Resting-state functional MRI data were collected on 36 LTAAS (20 females, age: 47.85+/-7.30), 23 LTAA (8 females, age: M=47.91+/ 6.76), and 23 non-substance abusing controls (NSAC; 8 females, age: M=47.99+/ 6.70). Using seed-based measures, we examined RSS with the nucleus accumbens (NAcc) and the subgenual anterior cingulate cortex (sgACC). RESULTS: Results showed commonalities in LTAA and LTAAS RSS (similar enhanced executive control RSS and left insula RSS) as well as differences (no attenuation of appetitive drive RSS in LTAAS and no enhancement of RSS in right insula in LTAA). CONCLUSIONS: We believe these differences are adaptive mechanisms that support abstinence. These findings suggest common as well as specific targets for treatment in chronic alcoholics with vs without comorbid stimulant dependence. PMID- 23639391 TI - Cerebral hemorrhages in CADASIL: report of four cases and a brief review. AB - BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease, clinically characterized by migraine, recurrent transient ischemic attacks or strokes, psychiatric disorders and cognitive decline. Strokes are typically ischemic, while hemorrhagic events have been only sporadically described. However, cerebral microbleeds have been found in 31-69% of CADASIL patients. METHODS: We describe four unrelated CADASIL patients who had hemorrhagic strokes. We also briefly review the literature on intracerebral hemorrhage (ICH) in CADASIL. RESULTS: Three patients had a thalamo-capsular hemorrhage (age at onset: 54, 67, 77) and one of these had a second hemispheric cerebellar hemorrhage. Another patient experienced an interpeduncular cistern subarachnoid hemorrhage when he was 39. None of these patients was receiving antiplatelets, anticoagulants or statins at the time of hemorrhage; all were hypertensive. NOTCH3 gene analysis revealed mutations on exons 14, 22 (two patients presenting the same mutation), and 24. MRI signs of previous hemorrhages were present in all these patients. CONCLUSIONS: Hemorrhagic stroke can occur in CADASIL similarly to sporadic cerebral small vessel diseases; this finding expands the phenotype of the disease. A diagnosis of CADASIL should probably be considered also in patients with ICH. These data bear potential implications in terms of need of better control of risk factors, particularly hypertension, and raise relevant questions about the use of antiplatelets as prevention measures in CADASIL patients. PMID- 23639392 TI - Enzyme activity measurement via spectral evolution profiling and PARAFAC. AB - The recent advances in multi-way analysis provide new solutions to traditional enzyme activity assessment. In the present study enzyme activity has been determined by monitoring spectral changes of substrates and products in real time. The method relies on measurement of distinct spectral fingerprints of the reaction mixture at specific time points during the course of the whole enzyme catalyzed reaction and employs multi-way analysis to detect the spectral changes. The methodology is demonstrated by spectral evolution profiling of Fourier Transform Infrared (FTIR) spectral fingerprints using parallel factor analysis (PARAFAC) for pectin lyase, glucose oxidase, and a cellulase preparation. PMID- 23639393 TI - Simultaneous determination of aflatoxins B2 and G2 in peanuts using spectrofluorescence coupled with parallel factor analysis. AB - In the present study a method for the simultaneous determination of aflatoxins B2 and G2 in peanuts has been developed. The method uses second order standard addition method and excitation-emission fluorescence data together with parallel factor analysis (PARAFAC). The aflatoxin analysis was based on extraction with methanol-water and carried out using immunoaffinity clean-up. The results of PARAFAC on a set of spiked and naturally contaminated peanuts indicated that the two aflatoxins could be successfully determined. The method was validated and analytical figures of merit were obtained for both analytes. The limits of detection (LOD) were 0.05 and 0.04 MUg kg(-1) for aflatoxins B2 and G2, respectively. The limits of quantification (LOQ) were 0.16 and 0.12 MUg kg(-1) for aflatoxins B2 and G2, respectively. Coupling of spectrofluorimetry with PARAFAC can be considered as an alternative method for quantification of aflatoxins in the presence of unknown interferences obtained through analysis of highly complex matrix of peanuts samples at a reduced cost per analysis. PMID- 23639394 TI - Efficient use of pure component and interferent spectra in multivariate calibration. AB - Partial Least Squares (PLS) is by far the most popular regression method for building multivariate calibration models for spectroscopic data. However, the success of the conventional PLS approach depends on the availability of a 'representative data set' as the model needs to be trained for all expected variation at the prediction stage. When the concentration of the known interferents and their correlation with the analyte of interest change in a fashion which is not covered in the calibration set, the predictive performance of inverse calibration approaches such as conventional PLS can deteriorate. This underscores the need for calibration methods that are capable of building multivariate calibration models which can be robustified against the unexpected variation in the concentrations and the correlations of the known interferents in the test set. Several methods incorporating 'a priori' information such as pure component spectra of the analyte of interest and/or the known interferents have been proposed to build more robust calibration models. In the present study, four such calibration techniques have been benchmarked on two data sets with respect to their predictive ability and robustness: Net Analyte Preprocessing (NAP), Improved Direct Calibration (IDC), Science Based Calibration (SBC) and Augmented Classical Least Squares (ACLS) Calibration. For both data sets, the alternative calibration techniques were found to give good prediction performance even when the interferent structure in the test set was different from the one in the calibration set. The best results were obtained by the ACLS model incorporating both the pure component spectra of the analyte of interest and the interferents, resulting in a reduction of the RMSEP by a factor 3 compared to conventional PLS for the situation when the test set had a different interferent structure than the one in the calibration set. PMID- 23639395 TI - Flow electrochemical biosensors based on enzymatic porous reactor and tubular detector of silver solid amalgam. AB - A flow amperometric enzymatic biosensor for the determination of glucose was constructed. The biosensor consists of a flow reactor based on porous silver solid amalgam (AgSA) and a flow tubular detector based on compact AgSA. The preparation of the sensor and the determination of glucose occurred in three steps. First, a self-assembled monolayer of 11-mercaptoundecanoic acid (MUA) was formed at the porous surface of the reactor. Second, enzyme glucose oxidase (GOx) was covalently immobilized at MUA-layer using N-ethyl-N'-(3-dimethylaminopropyl) carboimide and N-hydroxysuccinimide chemistry. Finally, a decrease of oxygen concentration (directly proportional to the concentration of glucose) during enzymatic reaction was amperometrically measured on the tubular detector under flow injection conditions. The following parameters of glucose determination were optimized with respect to amperometric response: composition of the mobile phase, its concentration, the potential of detection and the flow rate. The calibration curve of glucose was linear in the concentration range of 0.02-0.80 mmol L(-1) with detection limit of 0.01 mmol L(-1). The content of glucose in the sample of honey was determined as 35.5+/-1.0 mass % (number of the repeated measurements n=7; standard deviation SD=1.2%; relative standard deviation RSD=3.2%) which corresponds well with the declared values. The tested biosensor proved good long term stability (77% of the current response of glucose was retained after 35 days). PMID- 23639396 TI - Single-step extraction and cleanup of bisphenol A in soft drinks by hemimicellar magnetic solid phase extraction prior to liquid chromatography/tandem mass spectrometry. AB - Hemimicelles of tetradecanoate chemisorbed onto magnetic nanoparticles (MNPs) are here proposed as a sorbent for the single-step extraction and cleanup of bisphenol A (BPA) in soft drinks. The purpose of this work was to develop a simple, rapid and low-cost sample treatment suitable to assess the human exposure to BPA from this type of high consumption food. The nanoparticles were easily coated by mixing commercially available magnetite of 20-30 nm mean particle diameter with tetradecanoate at 85 degrees C for 30 min. The extraction/cleanup procedure involved stirring the samples (3 mL) with 200mg of tetradecanoate coated MNPs for 20 min, isolating the sorbent with a Nd-Fe-B magnet and eluting BPA with methanol. The extraction efficiency was not influenced by salt concentrations up to 1M and pH values over the range 4-9. No cleanup of the extracts was needed, and the method proved matrix-independent. The extracts were analyzed by liquid chromatography, electrospray ionization tandem mass spectrometry. Quantitation was performed by internal standard calibration using BPA-(13)C12. The limit of quantitation obtained for the method, 0.03 ng mL(-1), was below the usual range of concentrations reported for BPA in soft drinks (0.1 3.4 ng mL(-1)). The proposed method was successfully applied to the determination of BPA in different samples acquired from various supermarkets in southern Spain; the concentrations found ranged from 0.066 to 1.08 ng mL(-1). Recoveries from samples spiked with 0.33 ng mL(-1) of BPA ranged from 91% to 105% with relative standard deviations from 3% to 8%. PMID- 23639397 TI - Sequential injection methodology for carbon speciation in bathing waters. AB - A sequential injection method (SIA) for carbon speciation in inland bathing waters was developed comprising, in a single manifold, the determination of dissolved inorganic carbon (DIC), free dissolved carbon dioxide (CO2), total carbon (TC), dissolved organic carbon and alkalinity. The determination of DIC, CO2 and TC was based on colour change of bromothymol blue (660 nm) after CO2 diffusion through a hydrophobic membrane placed in a gas diffusion unit (GDU). For the DIC determination, an in-line acidification prior to the GDU was performed and, for the TC determination, an in-line UV photo-oxidation of the sample prior to GDU ensured the conversion of all carbon forms into CO2. Dissolved organic carbon (DOC) was determined by subtracting the obtained DIC value from the TC obtained value. The determination of alkalinity was based on the spectrophotometric measurement of bromocresol green colour change (611 nm) after reaction with acetic acid. The developed SIA method enabled the determination of DIC (0.24-3.5 mg C L(-1)), CO2 (1.0-10 mg C L(-1)), TC (0.50-4.0 mg C L(-1)) and alkalinity (1.2-4.7 mg C L(-1) and 4.7-19 mg C L(-1)) with limits of detection of: 9.5 MUg C L(-1), 20 MUg C L(-1), 0.21 mg C L(-1), 0.32 mg C L( 1), respectively. The SIA system was effectively applied to inland bathing waters and the results showed good agreement with reference procedures. PMID- 23639398 TI - Selective fluorimetric method for the determination of histamine in seafood samples based on the concept of zone fluidics. AB - In the present article we report our results on the development of a selective automated method for the determination of histamine in seafood using the concept of zone fluidics. The method is based on the sequential on-line reaction of the analyte with o-phthalaldehyde in the absence of a nucleophilic reagent, followed by acidification. The careful selection of the chemical and instrumental variables enabled the determination of the analyte with adequate sensitivity at the low micromolar level and with specificity against other biogenic amines and amino acids such as histidine. The LOD was 0.05 MUmol L(-1) (0.6 mg kg(-1)) and linearity was obeyed in the range of 0.5-15 MUmol L(-1) (5.5-170 mg kg(-1)). The proposed method offers a satisfactory sampling rate of 15 h(-1) and adequate accuracy and precision for the analysis of seafood products after minimum sample preparation and without employing a separation technique. PMID- 23639399 TI - Rapid automatic identification and quantification of compounds in complex matrices using comprehensive two-dimensional gas chromatography coupled to high resolution time-of-flight mass spectrometry with a peak sentinel tool. AB - Comprehensive two-dimensional gas chromatography coupled to mass spectrometry (GC*GC-MS) is a powerful tool for comprehensive analysis of organic pollutants. In this study, we developed a powerful analytical method using GC*GC for rapid and accurate identification and quantification of compounds in environmental samples with complex matrices. Specifically, we have developed an automatic peak sentinel tool, T-SEN, with free programming software, R. The tool, which consists of a simple algorithm for on peak finding and peak shape identification, allows rapid screening of target compounds, even for large data sets from GC*GC coupled to high resolution time of flight mass spectrometry (HRTOFMS). The software tool automatically assigns and quantifies compounds that are listed in user databases. T-SEN works on a typical 64 bit workstation, and the reference calculation speed is 10-20 min for approximately 170 compounds for peak finding (five ion count setting) and integration from 1-2GB of sample data acquired by GC*GC-HRTOFMS. We analyzed and quantified 17 PCDD/F congeners and 24 PCB congeners in a crude lake sediment extract by both GC*GC coupled to quadrupole mass spectrometry (qMS) and GC*GC-HRTOFMS with T-SEN. While GC*GC-qMS with T-SEN resulted in false identification and inaccurate quantification, GC*GC-HRTOFMS with T-SEN provided correct identification and accurate quantification of compounds without sample pre-treatment. The differences between the values measured by GC*GC-HRTOFMS with T-SEN and the certified values for the certified reference material ranged from 7.3 to 36.9% for compounds with concentrations above the limit of quantification. False positives/negatives were not observed, except for when co-elution occurred. The technique of GC*GC-HRTOFMS in combination with T-SEN provides rapid and accurate screening and represents a powerful new approach for comprehensive analysis. PMID- 23639400 TI - Highly sensitive and selective colorimetric sensing of antibiotics in milk. AB - Antibiotics residues in foods are very harmful to human beings. Determination of antibiotics residues relies largely on the availability of adequate analytical techniques. Currently, there is an urgent need for on site and real time detection of antibiotics in food. In this work, a novel one step synthesis of gold nanoparticles (AuNPs) was proposed using pyrocatechol violet (PCV) as a reducer agent. Highly sensitive and selective colorimetric detection of four antibiotics kanamycin mono sulfate (KA), neomycin sulfate (NE), streptomycin sulfate (ST) and bleomycin sulfate (BL) was realized during the formation of AuNPs. PCV has -OH groups and these antibiotics have -OH, -NH2, -NH- groups, so there may be some special hydrogen-bonding interactions between PCV and these antibiotics. Therefore, the presence of KA, NE, ST and BL would influence the synthesis of AuNPs, then the color and state of AuNPs would change, which could be observed with the naked eye or a UV-vis spectrophotometer. Results showed that A670 was linear with the logarithm of KA concentration in the range from 1.0*10( 8) to 5.0*10(-7)M and 5.0*10(-7) to 5.5*10(-5)M. The detection limit of KA was 1.0*10(-9)M (S/N=3). The coexisting substances including 1.0*10(-5)M phenylalanine, alanine, glycerol, glucose, Mg(2+), Ca(2+), Na(+), K(+), CO3(2-), SO4(2-), NO3(-), Cl(-) and Br(-) did not affect the determination of 1.0*10(-7)M antibiotics. In particular, the proposed method could be applied successfully to the detection of antibiotics in the pretreated liquid milk products. PMID- 23639401 TI - Multiple approaches for enhancing all-organic electronics photoluminescent sensors: simultaneous oxygen and pH monitoring. AB - Key issues in using organic light emitting diodes (OLEDs) as excitation sources in structurally integrated photoluminescence (PL)-based sensors are the low forward light outcoupling, the OLEDs' broad electroluminescence (EL) bands, and the long-lived remnant EL that follows an EL pulse. The outcoupling issue limits the detection sensitivity (S) as only ~20% of the light generated within standard OLEDs can be forward outcoupled and used for sensor probe excitation. The EL broad band interferes with the analyte-sensitive PL, leading to a background that reduces S and dynamic range. In particular, these issues hinder designing compact sensors, potentially miniaturizable, that are devoid of optical filters and couplers. We address these shortcomings by introducing easy-to-employ multiple approaches for outcoupling improvement, PL enhancement, and background EL reduction leading to novel, compact all-organic device architectures demonstrated for simultaneous monitoring of oxygen and pH. The sensor comprises simply fabricated, directionally-emitting, narrower-band, multicolor microcavity OLED excitation and small molecule- and polymer-based organic photodetectors (OPDs) with a more selective spectral response. Additionally, S and PL intensity for oxygen are enhanced by using polystyrene (PS):polyethylene glycol (PEG) blends as the sensing film matrix. By utilizing higher molecular weight PS, the ratio tau0/tau100 (PL decay time tau at 0% O2/tau at 100% O2) that is often used to express S increases *1.9 to 20.7 relative to the lower molecular weight PS, where this ratio is 11.0. This increase reduces to *1.7 when the PEG is added (tau0/tau100=18.2), but the latter results in an increase *2.7 in the PL intensity. The sensor's response time is <10s in all cases. The microporous structure of these blended films, with PEG decorating PS pores, serves a dual purpose. It results in light scattering that reduces the EL that is waveguided in the substrate of the OLEDs and consequently enhances light outcoupling from the OLEDs by ~60%, and it increases the PL directed toward the OPD. The multiple functional structures of multicolor microcavity OLED pixels/microporous scattering films/OPDs enable generation of enhanced individually addressable sensor arrays, devoid of interfering issues, for O2 and pH as well as for other analytes and biochemical parameters. PMID- 23639402 TI - Multi-signalling cation sensing behaviour of a bis(pyridin-2-yl methyl)aniline based hetarylazo dye. AB - We investigated the cation sensing behaviour of a bis(pyridin-2-yl methyl)aniline appended hetarylazo dye via chromogenic and electrochemical transduction channels. The binding pocket constituting both the pyridyl as well as aniline nitrogen atoms acts as recognition site for the cations and consequent perturbation in the intramolecular charge-transfer prevailing in the dye results in the chromogenic response manifested in the form of hypsochromic shift in the intramolecular charge-transfer band and the attendant naked-eye color changes. The dye exhibits significant changes in its electrochemical behaviour in the presence of cations. The experimental results are also rationalized by time dependent density functional theory (TD-DFT) calculations. PMID- 23639403 TI - Fasting or caloric restriction for healthy aging. AB - Aging is associated with a host of biological changes that contribute to a progressive decline in cognitive and physical function, ultimately leading to a loss of independence, and increased risk of mortality. To date, prolonged caloric restriction (i.e., a reduction in caloric intake without malnutrition) is the only non-genetic intervention that has consistently been found to extend both mean and maximal life span across a variety of species. Most individuals have difficulty sustaining prolonged caloric restriction, which has led to a search for alternative approaches that can produce similar to benefits as caloric restriction. A growing body of evidence indicates that fasting periods and intermittent fasting regimens in particular can trigger similar biological pathways as caloric restriction. For this reason, there is increasing scientific interest in further exploring the biological and metabolic effects of intermittent fasting periods, as well as whether long-term compliance may be improved by this type of dietary approach. This special will highlight the latest scientific findings related to the effects of both caloric restriction and intermittent fasting across various species including yeast, fruit flies, worms, rodents, primates, and humans. A specific emphasis is placed on translational research with findings from basic bench to bedside reviewed and practical clinical implications discussed. PMID- 23639404 TI - The role of enzyme compartmentalization on the regulation of steroid synthesis. AB - Steroidogenic enzymes can be compartmentalized at different levels, some by virtue of being membrane bound in specific intra-cellular compartments. Although both 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerase (3beta-HSD) and 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17) are expressed in the endoplasmic reticulum (ER) membrane, these proteins may still be spatially separated within this membrane system. Side chain cleavage cytochrome P450 (P450scc) is anchored to the inner mitochondrial membrane and this organelle is the major source of pregnenolone (P5) feeding steroidogenesis. Furthermore, steroidogenic enzymes can also be partitioned in different cells. Although well recognized, the effect of enzyme compartmentalization on the rate of steroid production and the balance of different steroids is unclear. This study uses mathematical modeling to investigate the effect of enzyme compartmentalization on steroid synthesis in a human-ovine-bovine model of steroid synthesis. The study shows that the spatial separation of steroidogenic enzymes within the ER has a minimal effect on the rate of steroid synthesis. The compartmentalization of the enzymes into different organelles of a cell creates cellular steroid gradients and can affect the balance of the different steroid products. The partitioning of steroidogenic enzymes in different cells reduces the rate of steroid synthesis. The greater is the distance between the cells that contain different enzymes, the more the rate of steroid synthesis is reduced. Additionally, when 3beta-HSD is not in the same cell with P450scc (the P5 source) and P450c17, the ratio of the Delta(5)-pathway products' concentrations to the Delta(4)-pathway products' concentrations is increased. However, none of these levels of compartmentalization of steroidogenic enzymes alter the qualitative behaviors of steroid synthesis in response to variation in an enzyme activity or P5 supply. PMID- 23639405 TI - Competition between trees and grasses for both soil water and mineral nitrogen in dry savannas. AB - The co-existence of trees and grasses in savannas in general can be the result of processes involving competition for resources (e.g. water and nutrients) or differential response to disturbances such as fire, animals and human activities; or a combination of both broad mechanisms. In moist savannas, the tree-grass coexistence is mainly attributed to of disturbances, while in dry savannas, limiting resources are considered the principal mechanism of co-existence. Virtually all theoretical explorations of tree-grass dynamics in dry savannas consider only competition for soil water. Here we investigate whether coexistence could result from a balanced competition for two resources, namely soil water and mineral nitrogen. We introduce a simple dynamical resource-competition model for trees and grasses. We consider two alternative hypotheses: (1) trees are the superior competitors for nitrogen while grasses are superior competitors for water, and (2) vice-versa. We study the model properties under the two hypotheses and test each hypothesis against data from 132 dry savannas in Africa using Kendall's test of independence. We find that Hypothesis 1 gets much more support than Hypothesis 2, and more support than the null hypothesis that neither is operative. We further consider gradients of rainfall and nitrogen availability and find that the Hypothesis 1 model reproduces the observed patterns in nature. We do not consider our results to definitively show that tree-grass coexistence in dry savannas is due to balanced competition for water and nitrogen, but show that this mechanism is a possibility, which cannot be a priori excluded and should thus be considered along with the more traditional explanations. PMID- 23639406 TI - Elevated specific peripheral cytokines found in major depressive disorder patients with childhood trauma exposure: a cytokine antibody array analysis. AB - Taking into consideration the previous evidence of revealing the relationship of early life adversity, major depressive disorder (MDD), and stress-linked immunological changes, we recruited 22 MDD patients with childhood trauma exposures (CTE), 21 MDD patients without CTE, and 22 healthy controls without CTE, and then utilized a novel cytokine antibody array methodology to detect potential biomarkers underlying MDD in 120 peripheral cytokines and to evaluate the effect of CTE on cytokine changes in MDD patients. Although 13 cytokines were identified with highly significant differences in expressions between MDD patients and normal controls, this relationship was significantly attenuated and no longer significant after consideration of the effect of CTE in MDD patients. Depressed individuals with CTE (TD patients) were more likely to have higher peripheral levels of those cytokines. Severity of depression was associated with plasma levels of certain increased cytokines; meanwhile, the increased cytokines led to a proper separation of TD patients from normal controls during clustering analyses. Our research outcomes add great strength to the relationship between depression and cytokine changes and suggest that childhood trauma may play a vital role in the co-appearance of cytokine changes and depression. PMID- 23639407 TI - Substantial weight gains are common prior to treatment-seeking in obese patients with binge eating disorder. AB - This study examined weight trajectories in obese patients with binge eating disorder (BED) during the year prior to treatment initiation and explored potential correlates of these weight changes. One hundred thirty (N=130) consecutive, treatment-seeking, obese patients with BED were assessed with structured interviews and self-report questionnaires. Eighty-three percent (83%; n=108) of treatment seeking obese BED patients gained weight, and 65% (n=84) gained a clinically significant amount of weight (greater than or equal to 5% body weight), in the year preceding treatment. Overall, participants reported a mean percent weight gain of 8% (16.6 pounds) during the 12months prior to treatment with a wide range of weight changes across participants (from a 52% weight gain to a 13% weight loss). A substantial proportion of patients (35%), categorized as High Weight Gainers (defined as gaining more than 10% of body weight during previous year), reported gaining an average of 16.7% of body weight. Low Weight Gainers (defined as gaining greater than 5%, but less than 10%) comprised 29% of the sample and were characterized by a mean gain of 6.9% of body weight. Weight Maintainers/Losers (defined as having maintained or lost weight during the 12months prior to treatment) comprised 17% of the sample and reported losing on average 2.8% of body weight. These three groups did not differ significantly in their current weight and eating behaviors or eating disorder psychopathology. The majority of treatment-seeking obese patients with BED reported having gained substantial amounts of weight during the previous year. These findings provide an important context for interpreting the modest weight losses typically reported in treatment studies of BED. Failure to produce weight loss in these studies may be reinterpreted as stabilization of weight and prevention of further weight gain. PMID- 23639408 TI - Characterization of anaerobic consortia coupled lignin depolymerization with biomethane generation. AB - Two sediment-free microbial consortia (LI3 and LP3) were established to depolymerize lignin under anaerobic conditions. During depolymerizing high molecular weight lignin to low molecular weight molecules, the two cultures produced biomethane up to 151.7 and 113.0 mL g(-1) total lignin. Furthermore, LI3 and LP3 could also utilize the biomass - oil palm empty fruit bunch fiber (OPEFB) to produce 190.6 and 195.6 mL methaneg(-1) total lignin in OPEFB, and at the same time improve the bioavailability of lignocellulosic matters for further enzymatic hydrolysis. The microbial community analysis by denature gradient gel electrophoresis (DGGE) and the high-density 16S rDNA gene microarray (PhyloChip) exhibited that Methanomethylovorans sp. (LI3) and Methanoculleus sp. (LP3) were the main methanogens present, and phylum Firmicutes and Bacteroidetes were mainly involved in the lignin depolymerization. The established microbial consortia with both lignin depolymerization and biomethane production provide profound application on the environmental friendly pretreatment of lignocellulosic materials. PMID- 23639410 TI - Intratumour variation of biomarker expression by immunohistochemistry in resectable non-small cell lung cancer. AB - BACKGROUND: Prognostic and predictive biomarkers are increasingly used to customise the treatment of patients with solid tumours. Intra- and inter-tumour heterogeneous distribution of biomarker expression is a potential confounder for the use of biomarkers, as small biopsies may not necessarily truly reflect the pattern of biomarker expression. It may also be an important factor in chemo resistance, as tumours with heterogeneous biomarker expression may potentially harbour chemo resistant tumour clones. MATERIALS AND METHODS: Immunohistochemical evaluation of the expression of excision repair cross complementation group 1 (ERCC1), epidermal growth factor receptor (EGFR), class III-beta-tubulin (TUBB 3), thymidylate synthase (TS), Ki-67 and ribonucleotide reductase M1 (RRM1) was performed in 15 separate areas in each of six small microscopically completely resected adenocarcinomas of the lung in order to elucidate any heterogeneous distribution. RESULTS: Clinically relevant biomarker heterogeneity with respect to the expression of EGFR, ERCC1, RRM1, TUBB-3 and Ki-67 was observed in four (66%), four (66%), one (16%), three (50%) and five (83%) out of six tumours, respectively. Thus, heterogeneity could potentially allocate these tumours erroneously into high or low expressers by chance alone, according to previously reported cut-off values. In contrast, TS was almost completely homogenously distributed. CONCLUSION: Most biomarkers examined, except for TS, showed clinically significant intratumour heterogeneity in 33-87% of tumours examined. This heterogeneity may influence results in studies investigating the therapeutic impact of predictive biomarkers in non-small cell lung cancer (NSCLC). PMID- 23639409 TI - Anaerobic-aerobic sequencing bioreactors improve energy efficiency for treatment of personal care product industry wastes. AB - Personal care product (PCP) industry liquid wastes contain shampoo residues, which are usually treated by aerobic activated sludge (AS). Unfortunately, AS is expensive for PCP wastes because of high aeration and energy demands, whereas potentially energy-positive anaerobic designs cannot meet effluent targets. Therefore, combined anaerobic-aerobic systems may be the best solution. Seven treatment systems were assessed in terms of energy and treatment performance for shampoo wastes, including one aerobic, three anaerobic (HUASB, AHR and AnCSTR) and three anaerobic-aerobic reactor designs. COD removals were highest in the HUASB-aerobic (87.9 +/- 0.4%) and AHR-aerobic (86.8+/-0.5%) systems, which used 69.2% and 62.5% less energy than aerobic AS. However, actual methane production rates were low relative to theoretical in the UASB and AHR units (~10% methane/COD removed) compared with the AnCSTR unit (~70%). Anaerobic-aerobic sequence reactors show promise for treating shampoo wastes, but optimal designs depend upon whether methane production or COD removal is most important to operations. PMID- 23639411 TI - Imaging biomarker validation and qualification report: sixth OARSI Workshop on Imaging in Osteoarthritis combined with third OA Biomarkers Workshop. AB - The sixth Osteoarthritis Research Society International (OARSI) Workshop on Imaging in Osteoarthritis combined with the third osteoarthritis (OA) Biomarkers Workshop is the first to bring together the imaging and molecular biomarker communities to focus on clinical validation and qualification of OA biomarkers. The workshop was held in Hilton Head, SC, USA, from June 12-14, 2012; 138 attendees participated, including representatives from academia, pharmaceutical and magnetic resonance imaging (MRI) industries, Food and Drug Administration (FDA), and National Institutes of Health (NIH). Presentations and discussions raised awareness, consolidated knowledge, and identified strategies to overcome challenges for the development and application of imaging and biochemical biomarkers in OA research studies and clinical trials. CONCLUSION: The OA research communities need to work alongside regulatory agencies across the world, to qualify and validate new chemical and imaging biomarkers for future research and clinical trials. PMID- 23639412 TI - Percutaneous sclerotherapy of sialoceles after parotidectomy with fibrin glue, OK 432, and bleomycin. AB - We evaluated the curative effect of fibrin glue combined with OK-432 (streptococcal pyrogenic exotoxin A, PicibanilTM) and bleomycin on 9 patients with sialoceles after parotidectomy. The primary lesions included pleomorphic adenomas in 6 cases and Warthin's tumours in 3 cases. After a sialocele had been diagnosed each patient had repeated aspirations and pressure dressings for 3-4 weeks, but these treatments failed. The patients were then treated with percutaneous sclerotherapy with the injection of fibrin glue 8-10 ml combined with OK-432 5 mg and bleomycin 15 mg. All the sialoceles disappeared completely after a single procedure in 2-3 weeks. The patients have been followed up for more than 6 months with no evidence of recurrent sialocele or injury to the facial nerve related to sclerotherapy. This simple, safe technique can be successfully used to treat sialoceles after parotidectomy. PMID- 23639413 TI - Review of orthognathic surgery and related papers published in the British Journal of Oral and Maxillofacial Surgery 2011-2012. AB - This review summarises all orthognathic and related papers published between January 2011 and December 2012 in the British Journal of Oral and Maxillofacial Surgery (BJOMS). A total of 36 articles were published, a high proportion of which (78%) were full-length papers. The remainder consisted of short communications and technical notes. The topics included operative planning and postoperative outcomes, and there was a strong focus on distraction osteogenesis. There were fewer orthognathic articles published in BJOMS than articles on other subspecialties such as trauma or head and neck oncology. Only 8 (29%) of the full length articles were prospective studies or randomised trials, which highlights a need for well-designed clinical studies in orthognathic research. PMID- 23639414 TI - Bmi1 expression in oral lichen planus and the risk of progression to oral squamous cell carcinoma. AB - Oral lichen planus (OLP) is a potentially malignant disorder associated with an increased risk of progression to oral squamous cell carcinoma (OSCC). The objective of this study was to determine protein expression of cancer stem cell factor Bmi1 in a longitudinal series of patients with OLP and evaluate the correlation between Bmi1 expression and the risk of progression to OSCC. In a retrospective study, Bmi1 expression was determined using immunohistochemistry in samples from 96 patients with OLP who received a mean follow-up of 54 months, including patients who did not progress to OSCC (n=87) and patients who had progressed to OSCC (n=9). Analysis of 10 cases of normal oral mucosa and 6 cases of postmalignant OSCC form previously diagnosed OLP was also performed. The results showed that Bmi1 expression was observed in 32 (36.8%) of 87 cases of nonprogressing OLP and in 8 (88.9%) of 9 cases of progressing OLP. Bmi1 was not expressed in normal oral mucosa, but it was positively expressed in the 6 (100%) cases of OSCC. Multivariate analysis revealed that the risk of malignant progression in the patients with Bmi1-positive expression was significantly higher than those with Bmi1 negativity (odds ratio, 20.75; 95% confidence interval, 2.21-194.57; P=.008). Collectively, Bmi1 expression was significantly associated with malignant transformation in a large series of patients with OLP who received a longitudinal observation. Our findings suggested that Bmi1 may serve as a useful marker for the identification of a high risk of malignant progression of OLP. PMID- 23639415 TI - Humidity-responsive bilayer actuators based on a liquid-crystalline polymer network. AB - A humidity-responsive bilayer actuator has been developed that consists of an oriented polyamide-6 substrate and a liquid-crystalline polymer coating. The oriented substrate acts as an alignment layer for the liquid crystal. The liquid crystalline polymer consists of a supramolecular network having hydrogen-bonded entities that, after activation with an alkaline solution, exhibit deformation in response to a change in humidity. The bending behavior of the bilayer actuator was analyzed, showing a large response to a change in the humidity. PMID- 23639417 TI - Registered nurse scope of practice and ED complaint-specific protocols. AB - INTRODUCTION: The use of complaint-specific protocols (CSPs) by emergency registered nurses (RNs) can improve ED efficiency. However, RN practice is influenced by regulatory environments that may facilitate or inhibit the use of protocols. The purpose of this policy analysis was to explore the language of state boards of nursing scope-of-practice documents related to the use of RN initiated CSPs in the ED setting. METHODS: A qualitative descriptive design was used to investigate how the RN's scope of practice relates to the use of CSPs in ED settings across states. Data were collected from state boards of nursing Web site documents. RESULTS: Three major themes emerged: cautiously within scope, intentionally vague/silent, and outside scope. Seven states (Connecticut, Illinois, Kansas, Louisiana, New Jersey, New York, and Oklahoma) were identified where RN-initiated CSPs appear to be currently outside the RN's scope of practice. Therefore 18% of the US population, or 55,973,900 people, resides in states where CSPs are not allowed. DISCUSSION: State-to-state inconsistencies in the RN's scope of practice may interfere with the implementation of practices that enhance ED efficiency. RNs in all states must ensure that they have the requisite knowledge, skill, and documented competency to implement CSPs, if supported by their employing facility. Efforts to standardize ED RN education and policy are warranted. Continued research is needed assess the impact of RN initiated CSPs on the efficiency of ED care. PMID- 23639416 TI - A home-birthed neonate in cardiogenic shock. PMID- 23639418 TI - Using skills validation and verification techniques to hardwire staff behaviors. PMID- 23639419 TI - Phospholipase D as a catalyst: application in phospholipid synthesis, molecular structure and protein engineering. AB - Phospholipase D (PLD) is a useful enzyme for its transphosphatidylation activity, which enables the enzymatic synthesis of various phospholipids (PLs). Many reports exist on PLD-mediated synthesis of natural and tailor-made PLs with functional head groups, from easily available lecithin or phosphatidylcholine. Early studies on PLD-mediated synthesis mainly employed enzymes of plant origin, which were later supplanted by ones from microorganisms, especially actinomycetes. Many PLDs are members of the PLD superfamily, having one or two copies of a signature sequence, HxKxxxxD or HKD motif, in the primary structures. PLD superfamily members share a common core structure, and thereby, a common catalytic mechanism. The catalysis proceeds via two-step reaction with the formation of phosphatidyl-enzyme intermediate. Both of the two catalytic His residues are critical in the reaction course, where one acts as a nucleophile, while the other functions as a general acid/base. PLD is being engineered to improve its activity and stability, alter head group specificity and further identify catalytically important residues. Since the knowledge on PLD enzymology is constantly expanding, this review focuses on recent advances in the field, regarding PLD-catalyzed synthesis of bioactive PLs, deeper understanding of substrate recognition and binding mechanism, altering substrate specificity, and improving thermostability. We introduced some of our recent results in combination with existing facts to further deepen the story on the nature of this useful enzyme. PMID- 23639420 TI - LuxS affects biofilm maturation and detachment of the periodontopathogenic bacterium Eikenella corrodens. AB - Previously, we reported that biofilm formation of Eikenella corrodens is regulated by autoinducer-2 (AI-2), based on observations that biofilm-forming efficiency of DeltaluxS mutant was greater than that of the wild type (Azakami et al., J. Biosci. Bioeng., 102, 110-117, 2006). To determine whether the AI-2 molecule affects biofilm formation directly, we added purified AI-2 to luxS mutant and wild-type E. corrodens and compared biofilm formations by using a static assay. Results indicated that biofilm formation in E. corrodens was enhanced by the addition of AI-2. We also compared the biofilms formed by flow cell system for the luxS mutant and the wild type by using scanning electron microscopy and confocal laser scanning microscopy. The number of viable bacteria in the luxS mutant biofilm was dramatically reduced and more sparsely distributed than that of the wild type, which suggested that AI-2 might enhance the mature biofilm. Conversely, further analysis by modified confocal reflection microscopy indicated that the wild-type biofilm was matured earlier than that of the luxS mutant, and became thinner and more sparsely distributed with time. These data suggest that LuxS may facilitate the maturation and detachment of biofilm in E. corrodens. PMID- 23639421 TI - Effect of trace elements on growth of marine eukaryotes, tharaustochytrids. AB - We determined the effect of trace elements on the growth of thraustochytrids. The growth of the strains cultured with the trace elements was much higher than that of the strains cultured without any trace element. Iron and zinc were particularly important to obtaining the optimum growth of thraustochytrids. PMID- 23639422 TI - [Breastfeeding prevalence during the first year of life in Aragon. CALINA study]. AB - OBJECTIVES: To study the current prevalence of breastfeeding (BF) in Aragon (Spain) during the first 12 months of life, and analyse its demographic, perinatal and social influential factors. MATERIAL AND METHODS: Obstetric, perinatal and feeding aspects were evaluated in a longitudinal and observational study, in a representative cohort of infant population from Aragon born between March 2009 to March 2010, controlled until 12 months of age (N=1.602). RESULTS: Exclusive or predominant BF was more frequent than the rest of feeding modalities during the first 4 months of life. Maintenance prevalence of any BF modality was 82.5% at 1(st) month of age, 71.8% at 3(rd), 54.3% at 6(th), and 27.8% at 12 months of age. Maternal variables that were significantly associated with BF maintenance both at 1 and 6 months of age were: delivery modality (higher probability in case of vaginal delivery), academic level (higher probability if university studies), origin (higher probability in mothers from Africa), adiposity (higher probability of normal weight or overweight mothers compared with obese ones), and not to smoke during gestation. CONCLUSIONS: BF prevalence in Aragon (Spain) during the first 12 months of age is high and has increased compared with previous data. BF continues in more than half of infants at six months and in a quarter of infants at 12 months of age. Maternal factors that significantly influence BF initiation and maintenance are, delivery modality, academic level, origin (immigration), adiposity and smoking habit. PMID- 23639423 TI - Gene flow vs. pollution pressure: genetic diversity of Mytilus galloprovincialis in eastern Adriatic. AB - Environmental pollution may modify all the evolutionary processes involved in shaping the genetic patterns of exposed populations. In order to evaluate the pollution impact on the genetic diversity of Mediterranean mussel Mytilus galloprovincialis ten populations inhabiting differently polluted sites along the eastern Adriatic coast, from pristine bays to heavily trafficked harbours, were studied. Pollution pressure was assessed through an integrated study of biological effects and responses across different levels of biological organization. Eight microsatellite markers were analysed to assess genetic diversity of investigated populations. Both the principal component analysis (PCA) of the biomarker data set as well as the biomarker response index (BRI) confirmed substantial pollution pressure at the highly polluted sites, and very low pollution exposure at the three reference sites. Very shallow genetic differentiation was found in respect to maritime distances or pollution status, and this was attributed to a high gene flow among the populations. However, populations inhabiting polluted sites exhibited higher levels of genetic diversity and evolutionary mechanisms underlying this phenomenon are discussed. PMID- 23639424 TI - Neuraminidase amino acids 149 and 347 determine the infectivity and oseltamivir sensitivity of pandemic influenza A/H1N1 (2009) and avian influenza A/H5N1. AB - Pandemic influenza A/H1N1 (2009) and avian influenza A/H5N1 neuraminidase (NA) differ at two critical residues, positions 149 and 347. Recombinant influenza A viruses were constructed in which these two residues in pandemic influenza A/H1N1 (2009) NA were changed to the corresponding amino acids of avian influenza A/H5N1 NA, and vice versa. Recombinant viruses bearing N1 NA with the oseltamivir resistance mutation H274Y in combination with mutations at residues 149 and 347 were also constructed. Recombinant viruses grew normally in allantoic fluid and were subsequently studied for viral infectivity (TCID50), substrate binding (Km) and sensitivity to oseltamivir (Ki). The data demonstrated that infectivity of mutant viruses in Madin Darby canine kidney cells was comparable to, or even greater than, the infectivity of the parental viruses harboring wild-type N1 NA. Furthermore, mutations at NA residues 149 and 347 altered Km and Ki values, and thus modulated oseltamivir sensitivity. Although these mutants have yet to be observed among natural isolates, the minimal costs to the growth of recombinant viruses indicate their possible viability. Reassortment between pandemic influenza A/H1N1 (2009) and avian influenza A/H5N1 viruses may therefore generate new influenza A viruses with increased infectivity and oseltamivir resistance, and continued surveillance will be crucial for public health preparedness. PMID- 23639426 TI - Reassortment ability of the 2009 pandemic H1N1 influenza virus with circulating human and avian influenza viruses: public health risk implications. AB - Exploring the reassortment ability of the 2009 pandemic H1N1 (A/H1N1pdm09) influenza virus with other circulating human or avian influenza viruses is the main concern related to the generation of more virulent or new variants having implications for public health. After different coinfection experiments in human A549 cells, by using the A/H1N1pdm09 virus plus one of human seasonal influenza viruses of H1N1 and H3N2 subtype or one of H11, H10, H9, H7 and H1 avian influenza viruses, several reassortant viruses were obtained. Among these, the HA of H1N1 was the main segment of human seasonal influenza virus reassorted in the A/H1N1pdm09 virus backbone. Conversely, HA and each of the three polymerase segments, alone or in combination, of the avian influenza viruses mainly reassorted in the A/H1N1pdm09 virus backbone. Of note, A/H1N1pdm09 viruses that reassorted with HA of H1N1 seasonal human or H11N6 avian viruses or carried different combination of avian origin polymerase segments, exerted a higher replication effectiveness than that of the parental viruses. These results confirm that reassortment of the A/H1N1pdm09 with circulating low pathogenic avian influenza viruses should not be misjudged in the prediction of the next pandemic. PMID- 23639425 TI - Differentiated phenotypes of primary murine alveolar epithelial cells and their susceptibility to infection by respiratory viruses. AB - Severe respiratory viral infections are associated with spread to the alveoli of the lungs. There are multiple murine models of severe respiratory viral infections that have been used to identify viral and host factors that contribute to disease severity. Primary cultures of murine alveolar epithelial cells provide a robust in vitro model to perform mechanistic studies that can be correlated with in vivo studies to identify cell type-specific factors that contribute to pathology within the alveoli of the lung during viral infection. In this study, we established an in vitro model to compare the responses of type I (ATI) and type II (ATII) alveolar epithelial cells to infection by respiratory viruses used in murine models: mouse-adapted severe acute respiratory syndrome-associated coronavirus (SARS-CoV, v2163), murine coronavirus MHV-1, and influenza A (H1N1) virus, strain PR8. Murine alveolar cells cultured to maintain an ATII cell phenotype, determined by expression of LBP180, were susceptible to infection by all three viruses. In contrast, ATII cells that were cultured to trans differentiate into an ATI-like cell phenotype were susceptible to MHV-1 and PR8, but not mouse-adapted SARS-CoV. Epithelial cells produce cytokines in response to viral infections, thereby activating immune responses. Thus, virus-induced cytokine expression was quantified in ATI and ATII cells. Both cell types had increased expression of IL-1beta mRNA upon viral infection, though at different levels. While MHV-1 and PR8 induced expression of a number of shared cytokines in ATI cells, there were several cytokines whose expression was induced uniquely by MHV-1 infection. In summary, ATI and ATII cells exhibited differential susceptibilities and cytokine responses to infection by respiratory viruses. This in vitro model will be critical for future studies to determine the roles of these specialized cell types in the pathogenesis of respiratory viral infection. PMID- 23639427 TI - Coagulation factors, fibrinogen and plasminogen activator inhibitor-1, are differentially regulated by yellow fever virus infection of hepatocytes. AB - Yellow fever virus (YFV) infection poses a great risk to un-vaccinated individuals living or traveling in the endemic regions of Africa and South America. It is estimated that approximately 30,000 people die each year of this disease. The liver is the main target of YFV, where as many as 80% of the hepatocytes may become involved in the infection. The overwhelming infection of the liver is associated with the observed hemorrhagic disease manifestations such as petechiae, ecchymoses, and hematemesis which are all thought to be linked with the observed coagulation abnormalities that include prolonged clotting times, reduction in clotting factors, fibrin-split products (D-dimers) and elevated prothrombin times. Many factors involved in the coagulation pathway are produced by hepatocytes, such as fibrinogen (FBG) and plasminogen activator inhibitor-1 (PAI-1). Both of these proteins have been indicated in another flavivirus related disease, dengue, as having roles related to the bleeding abnormalities observed and overall outcome of infection. In this study we wanted to determine if FBG and PAI-1 expression levels by human hepatocytes was disrupted or altered by infection with either wild-type Asibi or vaccine strain17-D YFVs. Our findings indicate that YFV infection does affect the transcriptional and translational expression of FBG and PAI-1 in human hepatocytes and that these results are further affected by IL-6 during early stages of infection. These results may lead to further understanding of the molecular mechanism associated with bleeding abnormalities observed during late stage YFV infection. PMID- 23639428 TI - Long-term follow-up evaluation of renal function in patients treated with peritoneal dialysis after cardiac surgery for correction of congenital anomalies. AB - BACKGROUND: Available data on the long-term renal outcome of patients who required renal replacement therapy after cardiac surgery for correction of congenital cardiac anomalies are scarce. The aim of the present study was to investigate the long-term renal prognosis of children treated with peritoneal dialysis after surgical correction of congenital heart anomalies. METHODS: The present single-center cohort study was based on clinical data from patients who underwent surgery for the correction of congenital heart disease between 1996 and 2004 at the Schneider's Children's Medical Center of Israel, and developed acute kidney injury (AKI) requiring peritoneal dialysis. Perioperative risk factors were analyzed. Survivors were followed up for 3.5 to 10.5 years after their surgery. Renal function was assessed in survivors by physical examination, including blood pressure, growth evaluation, urinalysis, glomerular filtration rate estimated from plasma creatinine using the Schwartz formula, and ultrasonographic examination of the kidneys. RESULTS: There were 2994 children who underwent surgery during the study period. Eighty-four children (2.84%) developed postoperative AKI that was managed with peritoneal dialysis. Seventy six children were included in our study, 8 were excluded because of a lack of complete data. Of the 76 children included, 35 died during the immediate postoperative period, 15 died during the interim of nonrenal causes, and 26 were alive at the time of follow-up evaluation. Twenty-five patients with a complete evaluation had blood pressure measurements in the normal range. Plasma creatinine levels were normal for age. Only 1 child, who had a pre-existing congenital renal anomaly, had an abnormal glomerular filtration rate. None of the children had proteinuria. Three children were treated with angiotensin-converting enzyme inhibitors and 2 were treated with furosemide for congestive heart failure. We found no risk factors associated with immediate postoperative death. CONCLUSIONS: Despite the development of AKI requiring dialysis after surgical correction of congenital cardiac anomalies, the long-term renal prognosis in survivors is good. PMID- 23639429 TI - Ischemia-modified albumin and adenosine plasma concentrations are associated with severe systemic inflammatory response syndrome after cardiopulmonary bypass. AB - PURPOSE: Severe systemic inflammatory response syndrome (SIRS) occurring after cardiopulmonary bypass (CPB) is a common cause of mortality during cardiac surgery. These syndromes are characterized by vasoplegia and ischemia-reperfusion phenomenom. Adenosine is a strong endogenous vasodilating agent, which may be involved in blood pressure failure during CPB induced by severe SIRS. Ischemia modified albumin (IMA) is considered as a sensitive marker of tissue ischemia. We examined whether the IMA or adenosine plasma concentrations (APCs) change during a severe SIRS-induced blood pressure failure during CPB. MATERIALS AND METHODS: Plasma concentration and IMA (median [range]) were measured before, during, and after surgery in 86 patients who underwent coronary revascularization under CBP and were correlated to postoperative clinical course. RESULTS: Preoperative APC values (1.45 [0.52-2.11] MUmol L(-1) vs 0.36 [0.12-0.66] MUmol L(-1)) and IMA (144 [91-198] IU mL(-1) vs 109 [61-183] U mL(-1)) were significantly increased in patients presenting postoperative severe SIRS. Mean durations of mechanical ventilation, stay in the intensive care unit, and requirement of vasoactive drugs were significantly higher in patients with higher APC and IMA, but APC was the best predictive marker a postoperative severe. CONCLUSIONS: Adenosine plasma concentration and IMA concentration are associated with postoperative severe SIRS after CPB. PMID- 23639432 TI - A benzodiazepine impairs the neurogenic and behavioural effects of fluoxetine in a rodent model of chronic stress. AB - Antidepressant agents such as fluoxetine have been shown to produce neurogenic effects involving transcriptional and translational changes that direct molecular and cellular plasticity. These cellular and molecular events appear necessary to mediate the therapeutic effects of fluoxetine and may be generated through the ability for fluoxetine to regulate BDNF levels. Clinically, benzodiazepines are frequently used in combination with standard antidepressants both for initial treatment and maintenance therapy, especially when comorbid anxiety is present. However, very little is known regarding the consequence of combined treatment of benzodiazepines and antidepressant on the development of clinical effect. The current study therefore examined the effect of co-administration of fluoxetine and the benzodiazepine, diazepam, on hippocampal neurogenesis in the social isolation rodent model of chronic stress. We demonstrate that 9 weeks of social isolation induces a deficit in motivational behaviour with increased anxiety as well as impairment in hippocampal neurogenesis. This was parallelled by reduced BDNF levels in the hippocampus. While treatment with fluoxetine alone for 3 weeks restored anxiety behaviour as well as progenitor cell proliferation and the generation of new hippocampal neurons, this effect was prevented by co administration with diazepam. This suggests that co-administering benzodiazepines with antidepressants could significantly delay or prevent the cellular and behavioural improvement needed by patients. These findings indicate the need for future clinical studies designed to investigate the combined effects of benzodiazepines and antidepressants in patients. PMID- 23639430 TI - When a good taste turns bad: Neural mechanisms underlying the emergence of negative affect and associated natural reward devaluation by cocaine. AB - An important feature of cocaine addiction in humans is the emergence of negative affect (e.g., dysphoria, irritability, anhedonia), postulated to play a key role in craving and relapse. Indeed, the DSM-IV recognizes that social, occupational and/or recreational activities become reduced as a consequence of repeated drug use where previously rewarding experiences (e.g., food, job, family) become devalued as the addict continues to seek and use drug despite serious negative consequences. Here, research in the Carelli laboratory is reviewed that examined neurobiological mechanisms that may underlie these processes using a novel animal model. Oromotor responses (taste reactivity) were examined as rats learned that intraoral infusion of a sweet (e.g., saccharin) predicts impending but delayed access to cocaine self-administration. We showed that rats exhibit aversive taste reactivity (i.e., gapes/rejection responses) during infusion of the sweet paired with impending cocaine, similar to aversive responses observed during infusion of quinine, a bitter tastant. Critically, the expression of this pronounced aversion to the sweet predicted the subsequent motivation to self-administer cocaine. Electrophysiology studies show that this shift in palatability corresponds to an alteration in nucleus accumbens (NAc) cell firing; neurons that previously responded with inhibition during infusion of the palatable sweet shifted to excitatory activity during infusion of the cocaine-devalued tastant. This excitatory response profile is typically observed during infusion of quinine, indicating that the once palatable sweet becomes aversive following its association with impending but delayed cocaine, and NAc neurons encode this aversive state. We also review electrochemical studies showing a shift (from increase to decrease) in rapid NAc dopamine release during infusion of the cocaine-paired tastant as the aversive state developed, again, resulting in responses similar to quinine infusion. Collectively, our findings suggest that cocaine-conditioned cues elicit a cocaine-need state that is aversive, is encoded by a distinct subset of NAc neurons and rapid dopamine signaling, and promotes cocaine-seeking behavior. Finally, we present data showing that experimentally induced abstinence (30 days) exacerbates this natural reward devaluation by cocaine, and this effect is correlated with a greater motivation to lever press during extinction. Dissecting the neural mechanisms underlying these detrimental consequences of addiction is critical since it may lead to novel treatments that ameliorate negative affective states associated with drug use and decrease the drive (craving) for the drug. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23639431 TI - Nedd4 is a specific E3 ubiquitin ligase for the NMDA receptor subunit GluN2D. AB - NMDA receptors are a family of glutamate-gated ion channels that regulate various CNS functions such as synaptic plasticity and learning. However hypo- or hyper activation of NMDA receptors is critically involved in many neurological and psychiatric conditions such as pain, stroke, epilepsy, neurodegeneration, schizophrenia, and depression. Thus, it is important to identify mechanisms (such as by targeted ubiquitination) that regulate the levels of individual subtypes of NMDA receptors. In this study, we used a series of tagged, carboxy terminal constructs of GluN2D to identify associating proteins from rat brain. Of seven different GluN2D C-terminal fragments used as bait, only the construct containing amino acids 983-1097 associated with an E3 ubiquitin ligase, Nedd4. A direct interaction between GluN2D and Nedd4 was confirmed both in vivo and in vitro. This association is mediated by an interaction between GluN2D's C-terminal PPXY motif and the 2nd and 3rd WW domains of Nedd4. Of the four GluN2 subunits, Nedd4 directly interacted with GluN2D and also weakly with GluN2A. Nedd4 coexpression with GluN2D enhances GluN2D ubiquitination and reduces GluN1/GluN2D NMDA receptor responses. These results identify Nedd4 as a novel binding partner for GluN2D and suggest a mechanism for the regulation of NMDA receptors that contain GluN2D subunits through ubiquitination-dependent downregulation. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. PMID- 23639433 TI - Ethanol self-administration and nicotine treatment induce brain levels of CYP2B6 and CYP2E1 in African green monkeys. AB - CYP2B6 and CYP2E1 are enzymes responsible for the metabolism of many centrally acting drugs, toxins and endogenous compounds. Human smokers and alcoholics have elevated levels of CYP2B6 and CYP2E1 in certain brain regions, which may contribute to altered drug efficacy, neurotoxicity and metabolic tolerance. The objective of this study was to determine the effects of ethanol self administration and nicotine treatment, alone and in combination, on brain CYP2B6 and CYP2E1 levels in monkeys. Monkeys were randomized into four groups (N = 10/group): an ethanol-only group, a nicotine-only group, an ethanol + nicotine group and a control (no drug) group. Ethanol (10% alcohol in sucrose solution) was voluntarily self-administered by the monkeys and nicotine was given as subcutaneous injections (0.5 mg/kg bid). Immunocytochemistry revealed induction of both CYP2B6 and CYP2E1 protein in certain brain regions and cells within monkey brain as a result of ethanol self-administration, nicotine treatment and combined exposure to both drugs. Immunoblotting analyses demonstrated CYP2B6 induction by ethanol in the caudate, putamen and cerebellum (1.5-3.2 fold, P < 0.05), and CYP2E1 induction by nicotine in the frontal cortex and putamen (1.6 2.0 fold, P < 0.05). Combined ethanol and nicotine exposure induced CYP2B6 in the caudate, putamen, thalamus and cerebellum (1.4-2.4 fold, P < 0.05), and CYP2E1 in the frontal cortex and putamen (1.5-1.8, P < 0.05). CYP2B6 and CYP2E1 mRNA levels were unaffected by ethanol or nicotine exposure. In summary, ethanol and nicotine can induce CYP2B6 and CYP2E1 protein in the primate brain, which could potentially result in altered sensitivity to centrally acting drugs and toxins. PMID- 23639435 TI - Therapeutic doses of antidepressants are projected not to inhibit human alpha4beta2 nicotinic acetylcholine receptors. AB - Inhibition of central alpha4beta2 nAChRs by antidepressants, proposed to contribute to their clinical efficacy, was assessed for monoamine reuptake inhibitors (amitriptyline, nortriptyline, fluoxetine, sertraline, paroxetine, citalopram) by comparing projected human unbound brain drug concentrations (Cu,b) at therapeutic doses with concentrations that inhibit human alpha4beta2 nAChRs in vitro. Inhibitory concentrations (IC50) were determined by patch clamp and ranged from 0.8-3.2 MUM, except for nortriptyline (IC50 = 100 nM). Cu,b values were calculated from human unbound plasma drug concentrations (Cu,p) and rat-derived brain-to-plasma and extracellular fluid-to-plasma ratios for the unbound drug, which are near unity, due to much higher brain tissue binding than plasma protein binding of these drugs. Accordingly in humans, antidepressant Cu,b are projected to essentially equal Cu,p, with average values from 3-87 nM, which are 30-to-250 fold below their IC50 concentrations. Based on our model, monoaminergic antidepressants minimally inhibit central nAChRs and it is unlikely that alpha4beta2 nAChR antagonism contributes to their antidepressant activity. Nortriptyline is an exception with a Cu,b that is 2-fold below its IC50, which is comparable to the nAChR antagonist (+/-)-mecamylamine, for which Cu,b is 4-fold below its IC50; both drugs will inhibit a substantial fraction of alpha4beta2 nAChRs. The Cu,b of the alpha4beta2 nAChR partial agonist varenicline, which has antidepressant-like activity in a murine model, is higher than its IC50 and varenicline is projected to cause ~70% inhibition of alpha4beta2 nAChRs. Taken together these data may help explain the negative outcome of recent antidepressant augmentation trials with mecamylamine and the partial agonist CP 601927. PMID- 23639434 TI - Antecedents and consequences of drug abuse in rats selectively bred for high and low response to novelty. AB - Human genetic and epidemiological studies provide evidence that only a subset of individuals who experiment with potentially addictive drugs become addicts. What renders some individuals susceptible to addiction remains to be determined, but most would agree that there is no single trait underlying the disorder. However, there is evidence in humans that addiction liability has a genetic component, and that certain personality characteristics related to temperament (e.g. the sensation-seeking trait) are associated with individual differences in addiction liability. Consequently, we have used a selective breeding strategy based on locomotor response to a novel environment to generate two lines of rats with distinct behavioral characteristics. We have found that the resulting phenotypes differ on a number of neurobehavioral dimensions relevant to addiction. Relative to bred low-responder (bLR) rats, bred high-responder (bHR) rats exhibit increased exploratory behavior, are more impulsive, more aggressive, seek stimuli associated with rewards, and show a greater tendency to relapse. We therefore utilize this unique animal model to parse the genetic, neural and environmental factors that contribute to addiction liability. Our work shows that the glucocorticoid receptor (GR), dopaminergic molecules, and members of the fibroblast growth factor family are among the neurotransmitters and neuromodulators that play a role in both the initial susceptibility to addiction as well as the altered neural responses that follow chronic drug exposure. Moreover, our findings suggest that the hippocampus plays a major role in mediating vulnerability to addiction. It is hoped that this work will emphasize the importance of personalized treatment strategies and identify novel therapeutic targets for humans suffering from addictive disorders. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23639438 TI - Linking morphogen and chromatin in the hair follicle. AB - In this issue of Developmental Cell, Xiong et al. (2013) identify a critical role for the chromatin remodeler Brg1 in hair follicle stem cell maintenance and epidermal repair. Brg1 interacts with the Shh signaling pathway to create a positive feedback loop that fuels hair follicle growth. PMID- 23639436 TI - Rapid, transient synaptic plasticity in addiction. AB - Chronic use of addictive drugs produces enduring neuroadaptations in the corticostriatal glutamatergic brain circuitry. The nucleus accumbens (NAc), which integrates cortical information and regulates goal-directed behavior, undergoes long-term morphological and electrophysiological changes that may underlie the increased susceptibility for relapse in drug-experienced individuals even after long periods of withdrawal. Additionally, it has recently been shown that exposure to cues associated with drug use elicits rapid and transient morphological and electrophysiological changes in glutamatergic synapses in the NAc. This review highlights these dynamic drug-induced changes in this pathway that are specific to a drug seeking neuropathology, as well as how these changes impair normal information processing and thereby contribute to the uncontrollable motivation to relapse. Future directions for relapse prevention and pharmacotherapeutic targeting of the rapid, transient synaptic plasticity in relapse are discussed. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23639439 TI - New ways to gather grains. AB - A crucial step in cereal grass domestication is acquisition of seed retention in the inflorescence/seed head for efficient harvesting. Reporting in Nature Genetics, Ishii and colleagues (2013) show that a change in inflorescence architecture is sufficient to increase seed retention, providing an alternative pathway toward cereal grass domestication. PMID- 23639440 TI - Autophagosome formation: tracing the source. AB - Although it is well appreciated that autophagy begins with phagophore formation and expansion through lipid acquisition to become the autophagosome, this process remains poorly understood, with the source of autophagosome membrane controversial. Reporting recently in Nature, Hamasaki et al. (2013) suggest that the ER-mitochondria contact sites are involved in phagophore assembly. PMID- 23639437 TI - Cognitive function during nicotine withdrawal: Implications for nicotine dependence treatment. AB - Nicotine withdrawal is associated with deficits in neurocognitive function including sustained attention, working memory, and response inhibition. Several convergent lines of evidence suggest that these deficits may represent a core dependence phenotype and a target for treatment development efforts. A better understanding of the mechanisms underlying withdrawal-related cognitive deficits may lead to improve nicotine dependence treatment. We begin with an overview of the neurocognitive effects of withdrawal in rodent and human models, followed by discussion of the neurobehavioral mechanisms that are thought to underlie these effects. We then review individual differences in withdrawal-related neurocognitive effects including genetics, gender, and psychiatric comorbidity. We conclude with a discussion of the implications of this research for developing improved therapies, both pharmacotherapy and behavioral treatments, that target cognitive symptoms of nicotine withdrawal. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23639441 TI - CASZ1 promotes vascular assembly and morphogenesis through the direct regulation of an EGFL7/RhoA-mediated pathway. AB - The formation of the vascular system is essential for embryonic development and homeostasis. However, transcriptional control of this process is not fully understood. Here we report an evolutionarily conserved role for the transcription factor CASZ1 (CASTOR) in blood vessel assembly and morphogenesis. In the absence of CASZ1, Xenopus embryos fail to develop a branched and lumenized vascular system, and CASZ1-depleted human endothelial cells display dramatic alterations in adhesion, morphology, and sprouting. Mechanistically, we show that CASZ1 directly regulates Epidermal Growth Factor-Like Domain 7 (Egfl7). We further demonstrate that defects of CASZ1- or EGFL7-depleted cells are in part due to diminished RhoA expression and impaired focal adhesion localization. Moreover, these abnormal endothelial cell behaviors in CASZ1-depleted cells can be rescued by restoration of Egfl7. Collectively, these studies show that CASZ1 is required to directly regulate an EGFL7/RhoA-mediated pathway to promote vertebrate vascular development. PMID- 23639443 TI - Prdm13 mediates the balance of inhibitory and excitatory neurons in somatosensory circuits. AB - Generating a balanced network of inhibitory and excitatory neurons during development requires precise transcriptional control. In the dorsal spinal cord, Ptf1a, a basic helix-loop-helix (bHLH) transcription activator, maintains this delicate balance by inducing homeodomain (HD) transcription factors such as Pax2 to specify the inhibitory lineage while suppressing HD factors such as Tlx1/3 that specify the excitatory lineage. We uncover the mechanism by which Ptf1a represses excitatory cell fate in the inhibitory lineage. We identify Prdm13 as a direct target of Ptf1a and reveal that Prdm13 actively represses excitatory cell fate by binding to regulatory sequences near the Tlx1 and Tlx3 genes to silence their expression. Prdm13 acts through multiple mechanisms, including interactions with the bHLH factor Ascl1, to repress Ascl1 activation of Tlx3. Thus, Prdm13 is a key component of a highly coordinated transcriptional network that determines the balance of inhibitory versus excitatory neurons in the dorsal spinal cord. PMID- 23639445 TI - A "balloon" on the mitral valve. PMID- 23639444 TI - Arterial and venous progenitors of the major axial vessels originate at distinct locations. AB - Currently, it remains controversial how vascular endothelial progenitor cells (angioblasts) establish their arterial or venous fates. We show using zebrafish that the arterial progenitors of the major axial vessels originate earlier and closer to the midline than the venous progenitors. Both medial and lateral progenitor populations migrate to distinct arterial and venous positions and not into a common precursor vessel as previously suggested. Overexpression of VEGF or Hedgehog (Hh) homologs results in the partially randomized distribution of arterial and venous progenitors within the axial vessels. We further demonstrate that the function of the Etv2 transcription factor is required at earlier stages for arterial development than for venous. Our results argue that the medial angioblasts undergo arterial differentiation because they receive higher concentration of Vegf and Hh morphogens than the lateral angioblasts. We propose a revised model of arterial-venous differentiation that explains how angioblasts choose between an arterial and venous fate. PMID- 23639446 TI - Massive right pulmonary embolism on cardiovascular magnetic resonance. PMID- 23639442 TI - The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis. AB - Neuropilin 1 (NRP1) plays an important but ill-defined role in VEGF-A signaling and vascular morphogenesis. We show that mice with a knockin mutation that ablates the NRP1 cytoplasmic tail (Nrp1(cyto)) have normal angiogenesis but impaired developmental and adult arteriogenesis. The arteriogenic defect was traced to the absence of a PDZ-dependent interaction between NRP1 and VEGF receptor 2 (VEGFR2) complex and synectin, which delayed trafficking of endocytosed VEGFR2 from Rab5+ to EAA1+ endosomes. This led to increased PTPN1 (PTP1b)-mediated dephosphorylation of VEGFR2 at Y(1175), the site involved in activating ERK signaling. The Nrp1(cyto) mutation also impaired endothelial tubulogenesis in vitro, which could be rescued by expressing full-length NRP1 or constitutively active ERK. These results demonstrate that the NRP1 cytoplasmic domain promotes VEGFR2 trafficking in a PDZ-dependent manner to regulate arteriogenic ERK signaling and establish a role for NRP1 in VEGF-A signaling during vascular morphogenesis. PMID- 23639447 TI - Retinal thinning in Gaucher disease patients and carriers: results of a pilot study. AB - Both Gaucher disease patients and heterozygous glucocerebrosidase mutation carriers are at increased risk of Parkinson's disease. Retinal thinning has been reported in early Parkinson's disease. Here we used optical coherence tomography to demonstrate thinning of the retinal ganglion cell layer in Gaucher disease patients and carriers who manifest clinical markers of potential early neurodegeneration. Optical coherence tomography may help identify Gaucher disease patients and carriers at increased risk of developing Parkinson's disease. PMID- 23639449 TI - Reconsolidation and extinction of an appetitive pavlovian memory. AB - When memories are retrieved, they can enter a labile state during which the memory may be modified and subsequently restabilized through the process of reconsolidation. However, this does not occur in all situations, and certain "boundary conditions" determine whether a memory will undergo reconsolidation. Naive male lister hooded rats were trained for 5 days to press a lever in order to retrieve a food reward associated with a pavlovian light stimulus. Three days post-training, animals were injected with either MK-801 (0.1 mgkg(-1); i.p.) or saline vehicle, 30 min before they were placed back into the training context for a retrieval session. Lever pressing was reinforced only by the light stimulus and was restricted to either 10, 30 or 50 presentations of the light conditioned stimulus. After 48 h, animals were again returned to the boxes and light reinforced lever-pressing activity was recorded. MK-801-treated animals in the 10CS group significantly reduced lever pressing at test, compared to saline controls. In contrast, MK-801-treated rats in the 50CS group demonstrated a significant increase. There was no effect of MK-801 in the 30CS group. Additionally, there were no effects of MK-801 in an analogous, pure instrumental, setting when the cue lights were omitted. The opposing effects of MK-801 under different parametric conditions likely reflect impairments of appetitive pavlovian memory reconsolidation and extinction, respectively. These results demonstrate a competition between reconsolidation and extinction. However, there are also conditions under which MK-801 fails to impair either process. PMID- 23639450 TI - Transcriptomic changes following the compatible interaction Vitis vinifera Erysiphe necator. Paving the way towards an enantioselective role in plant defence modulation. AB - The compatible interaction between Erysiphe necator and Vitis vinifera induces significant alterations in the host transcriptome, affecting essentially those genes involved in signalling and secondary metabolite biosynthetic pathways. The precise transcriptomic changes vary from the early events to later stages of infection. In the present work, suppressive subtraction hybridization (SSH) was used to identify several differentially expressed transcripts in symptomatic and asymptomatic leaves from powdery mildew infected grapevines following a long term interaction. The detected transcripts show little or no correlation with similar expression studies concerning the early stages of infection which suggests distinct host responses occur before and after the infection is established. The transcription level of thirteen genes was assessed through qRT-PCR using appropriately selected and validated normalization genes. With one exception, all these genes underwent moderate levels of differential transcription, with log2 fold change values ranging from -2.65 to 4.36. The exception, a dirigent-like (DIR) protein, was upregulated over 180 fold in symptomatic leaves, suggesting an important role for stereochemical selectivity in the compatible interaction E. necator-V. vinifera. DIR copy number was determined in the genome of three grapevine cultivars exhibiting high (Carignan), moderate (Fernao Pires) and low (Touriga Nacional) sensitivity to E. necator. It was found to be a two-copy gene in all cultivars analyzed. Further analysis involving DIR metabolic neighbourhood transcripts was performed. The possible physiological significance of the detected DIR upregulation is discussed. PMID- 23639448 TI - Differences between acylcarnitine profiles in plasma and bloodspots. AB - Quantification of acylcarnitines is used for screening and diagnosis of inborn error of metabolism (IEM). While newborn screening is performed in dried blood spots (DBSs), general metabolic investigation is often performed in plasma. Information on the correlation between plasma and DBS acylcarnitine profiles is scarce. In this study, we directly compared acylcarnitine concentrations measured in DBS with those in the corresponding plasma sample. Additionally, we tested whether ratios of acylcarnitines in both matrices are helpful for diagnostic purpose when primary markers fail. STUDY DESIGN: DBS and plasma were obtained from controls and patients with a known IEM. (Acyl)carnitines were converted to their corresponding butyl esters and analyzed using HPLC/MS/MS. RESULTS: Free carnitine concentrations were 36% higher in plasma compared to DBS. In contrast, in patients with carnitine palmitoyltransferase 1 (CPT-1) deficiency free carnitine concentration in DBS was 4 times the concentration measured in plasma. In carnitine palmitoyltransferase 2 (CPT-2) deficiency, primary diagnostic markers were abnormal in plasma but could also be normal in DBS. The calculated ratios for CPT-1 (C0/(C16+C18)) and CPT-2 ((C16+C18:1)/C2) revealed abnormal values in plasma. However, normal ratios were found in DBS of two (out of five) samples obtained from patients diagnosed with CPT-2. CONCLUSIONS: Relying on primary acylcarnitine markers, CPT-1 deficiency can be missed when analysis is performed in plasma, whereas CPT-2 deficiency can be missed when analysis is performed in DBS. Ratios of the primary markers to other acylcarnitines restore diagnostic recognition completely for CPT-1 and CPT-2 in plasma, while CPT-2 can still be missed in DBS. PMID- 23639451 TI - Fusidic acid and rifampicin co-loaded PLGA nanofibers for the prevention of orthopedic implant associated infections. AB - Implant-associated infections following invasive orthopedic surgery are a major clinical problem, and are one of the primary causes of joint failure following total joint arthroplasty. Current strategies using perioperative antibiotics have been met with little clinical success and have resulted in various systemic toxicities and the promotion of antibiotic resistant microorganisms. Here we report the development of a biodegradable localized delivery system using poly(D,L-lactic acid-co-glycolic acid) (PLGA) for the combinatorial release of fusidic acid (FA) (or its sodium salt; SF) and rifampicin (RIF) using electrospinning. The drug-loaded formulations showed good antibiotic encapsulation (~75%-100%), and a biphasic drug release profile. All dual-loaded formulations showed direct antimicrobial activity in vitro against Staphylococcus epidermidis, and two strains of methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, lead formulations containing 10% (w/w) FA/SF and 5% (w/w) RIF were able to prevent the adherence of MRSA to a titanium implant in an in vivo rodent model of subcutaneous implant-associated infection. PMID- 23639452 TI - Cell-penetrating cationic siRNA and lipophilic derivatives efficient at nanomolar concentrations in the presence of serum and albumin. AB - Despite its considerable interest in human therapy, in vivo siRNA delivery is still suffering from hurdles of vectorization. We have shown recently efficient gene silencing by non-vectorized cationic siRNA. Here, we describe the synthesis and in vitro evaluation of new amphiphilic cationic siRNA. C12-, (C12)2- and cholesteryl-spermine(x)-siRNA were capable of luciferase knockdown at nanomolar concentrations without vectorization (i.e. one to two orders of magnitude more potent than commercially available cholesteryl siRNA). Moreover, incubation in the presence of serum did not impair their efficiency. Finally, amphiphilic cationic siRNA was pre-loaded on albumin. In A549Luc cells in the presence of serum, these siRNA conjugates were highly effective and had low toxicity. PMID- 23639455 TI - Exploring graphene nanocolloids as potential substrates for the enhancement of Raman scattering. AB - Graphene, especially few-layer graphene solid film, has been found to strongly suppress fluorescence and enhance Raman signals of probe molecules. In this paper, we attempt to explore the possibility of using graphene nanocolloids as potential substrates for the enhancement of Raman scattering. Graphene nanocolloids chemically produced from the reduction of graphene oxide by sodium citrate are nearly all monolayers in solution and are also found to exhibit certain surface-enhanced Raman scattering (SERS) activity to common aromatic probe molecules. Interestingly, largely different from few-layer graphene solid film, graphene nanocolloids show maximal SERS activity only when the probe molecules are at resonant laser excitation. According to our analysis, this phenomenon should arise from a combined effect of fluorescence quenching of graphene and a photoinduced charge transfer mechanism, in which the strong charge transfer accounts for the main contribution from close coupling between graphenes and probe molecules photoinduced by resonant excitation as well as the desolvation of graphene sheets and probe molecules. PMID- 23639454 TI - Experimental etch-and-rinse adhesives doped with bioactive calcium silicate-based micro-fillers to generate therapeutic resin-dentin interfaces. AB - OBJECTIVES: This study aimed at evaluating the therapeutic bioactive effects on the bond strength of three experimental bonding agents containing modified Portland cement-based micro-fillers applied to acid-etched dentin and submitted to aging in simulated body fluid solution (SBS). Confocal laser (CLSM) and scanning electron microscopy (SEM) were also performed. METHODS: A type-I ordinary Portland cement was tailored using different compounds such as sodium calcium-aluminum-magnesium silicate hydroxide (HOPC), aluminum-magnesium carbonate hydroxide hydrates (HCPMM) and titanium oxide (HPCTO) to create three bioactive micro-fillers. A resin blend mainly constituted by Bis-GMA, PMDM and HEMA was used as control (RES-Ctr) or mixed with each micro-filler to create three experimental bonding agents: (i) Res-HOPC, (ii) Res-HCPMM and (iii) Res HPCTO. The bonding agents were applied onto 37% H3PO4-etched dentin and light cured for 30s. After build-ups, they were prepared for micro-tensile bond strength (MUTBS) and tested after 24h or 6 months of SBS storage. SEM analysis was performed after de-bonding, while CLSM was used to evaluate the ultra morphology/nanoleakage and the mineral deposition at the resin-dentin interface. RESULTS: High MUTBS values were achieved in all groups after 24h. Only Res-HOPC and Res-HCPMM showed stable MUTBS after SBS storage (6 months). All the resin dentin interfaces created using the bonding agents containing the bioactive micro fillers tested in this study showed an evident reduction of nanoleakage and mineral deposition after SBS storage. CONCLUSION: Resin bonding systems containing specifically tailored Portland cement micro-fillers may promote a therapeutic mineral deposition within the hybrid layer and increase the durability of the resin-dentin bond. PMID- 23639453 TI - A characterization of the mechanical behavior of resin-infiltrated dentin using nanoscopic Dynamic Mechanical Analysis. AB - This study explored the spatial variations in mechanical behavior of resin infiltrated dentin using nanoscopic Dynamic Mechanical Analysis (DMA). OBJECTIVE: The objectives were to: (1) evaluate the mechanical behavior of resin-infiltrated dentin using a scanning-based approach to nanoindentation, (2) identify contributions of the collagen matrix to time-dependent deformation of the hybrid layer, and (3) assess the importance of specimen hydration on the nanoDMA response. METHODS: Specimens of completely demineralized dentin infiltrated with commercial resin adhesive and control samples of resin adhesive were evaluated using a nanoindenter in scanning mode. The load and displacement responses were used to perform DMA and to estimate the complex (E*), storage (E') and loss (E") moduli over selected regions of evaluation. The importance of hydration on the mechanical behavior was also examined from a comparison of responses in the hydrated and dehydrated conditions. RESULTS: In the hydrated state the apparent complex, storage and loss moduli for the resin-infiltrated dentin samples were 3.5+/-0.3GPa, 3.4+/-0.2GPa and 0.9+/-0.3GPa, respectively. Those values for the resin adhesive control were 2.7+/-0.3GPa, 2.7+/-0.3GPa and 0.2+/-0.02GPa, respectively. Viscoelastic deformation of the resin-infiltrated collagen exceeded that occurring in regions of uniform resin adhesive. Though dehydration resulted in a significant increase in both the complex and storage moduli of the macro hybrid layer, the largest changes occurred to the resin adhesive. SIGNIFICANCE: The microstructure and hydration play critical roles on the mechanical behavior of the hybrid layer and nanoDMA provides a potent measurement tool for identifying the spatial variations. PMID- 23639456 TI - The national evolution of cardiovascular CT practice: a UK NHS perspective. PMID- 23639457 TI - Focal adhesion kinase mediates atrial fibrosis via the AKT/S6K signaling pathway in chronic atrial fibrillation patients with rheumatic mitral valve disease. AB - BACKGROUND: Atrial fibrosis, as a hallmark of atrial structural remodeling, plays a critical role in the maintenance of chronic atrial fibrillation (AF), but the mechanisms responsible for atrial fibrosis are still uncertain. Fibrogenesis represents a complex process in which focal adhesion kinase (FAK) plays an important role. Therefore, we investigated the role of FAK-mediated signaling in atrial fibrosis in patients with chronic AF related to rheumatic mitral valve disease (RMVD). METHODS: Atrial appendages were excised from 45 patients with RMVD and either chronic AF (n=25, AF >6 months) or sinus rhythm (n=20). Fibrosis was assessed by histology, and FAK and its two downstream pathways (AKT/S6K and ERK1/2) were evaluated by western blotting. We further evaluated the role of FAK in fibrogenesis by culturing neonatal rat cardiac fibroblasts to determine the importance of FAK-regulated signaling in cardiac myofibroblast differentiation induced by transforming growth factor-beta1 (TGFbeta1). RESULTS: Our study revealed that FAK can regulate its downstream signaling to cause fibrosis in atrial tissue and activate isolated fibroblasts. Histology revealed a significant increase in atrial fibrosis in AF patients. The phosphorylation of FAK and its downstream AKT/S6K signaling was increased secondary to TGFbeta1-induced high expression of alpha-SMA, a marker of myofibroblast activity. FAK and AKT inhibitors suppressed alpha-SMA expression in TGFbeta1-induced fibroblasts. However, ERK1/2 signaling seemed to be unrelated to the fibrotic process in AF patients. CONCLUSION: The FAK-mediated AKT/S6K signaling pathway participated in atrial fibrogenesis and this finding may contribute to the prevention of atrial fibrosis associated with chronic AF in patients with underlying cardiac disease. PMID- 23639458 TI - Anisakis simplex: a new etiological agent of Kounis syndrome. PMID- 23639459 TI - Cardioncology: state of the heart. AB - Cardiotoxicity caused by chemotherapy is a concerning reality plaguing oncologists and cardiologists. The coexistence of cancer and cardiovascular diseases in the same patient is more common due to the aging population and improvement of chemotherapeutic drug effectiveness. We review the incidence and clinical features of cardiotoxicity caused by some of the most common chemotherapeutic drugs to provide the cardiologist with information regarding general cardiovascular toxicity, early left ventricular dysfunction detection, cardiac damage prevention and follow-up. In conclusion, awareness of this emerging problem has important clinical implications as only highly specialized care will prevent patients who successfully overcome cancer from being defeated by the side effects of anticancer therapy. PMID- 23639460 TI - Left ventricle metastasis of esophageal cancer mimicking myocardial infarction in myocardial perfusion scintigraphy. PMID- 23639461 TI - Mitochondrial myopathy with disappearance of noncompaction within a thickening myocardium. PMID- 23639462 TI - Multiple 'crumbled' cardiac myxomas presenting as gait ataxia. PMID- 23639463 TI - Ventriculoatrial conduction and related pacemaker-mediated arrhythmias in patients implanted for atrioventricular block: an old problem revisited. AB - INTRODUCTION: Ventriculoatrial (VA) conduction and related pacemaker-mediated tachyarrhythmias (PMT) have not been systematically investigated in a large cohort of patients implanted for symptomatic atrioventricular (AV) block. METHODS AND RESULTS: Two hundred fifty consecutive patients (71+/-14 years, 63% male) implanted for symptomatic second- or third-degree AV block were screened for retrograde VA conduction and related PMTs including endless loop tachycardia (ELT) and repetitive nonreentrant VA synchrony (RNRVAS). After a mean post implantation period of 38+/-12 months, AV block was persistent in 137 (55%) and variable in 113 (45%) patients. Retrograde 1:1 conduction was present in 76 patients (30%) with a mean VA conduction time of 258+/-65 ms. The incidence of VA conduction varied considerably according to the presence and type of anterograde conduction block. Retrograde conduction was present in 24 of 137 patients (18%) with persistent AV block. Fifteen of the 76 patients (20%) with VA conduction had >=1 documented PMT. The recorded arrhythmias were ELT in 11 and RNRVAS in 4 patients. VA conduction time was significantly longer in patients with than without PMT (297+/-64 vs. 249+/-62 ms, resp., P<0.01). None of the patients without VA conduction had documented PMTs. CONCLUSIONS: Retrograde VA conduction and related PMTs are not uncommon in patients implanted for symptomatic AV block. Testing for retrograde conduction should therefore be performed in all patients with AV block in order to optimize device programming and prevent PMTs. PMID- 23639464 TI - Prognosis of Duchenne/Becker muscular dystrophy with noncompaction is worse than without noncompaction. PMID- 23639465 TI - A retrospective observational study to model the progression curve of aortic stenosis. PMID- 23639466 TI - Is catheter ablation the best way to restore endothelial function?: reply. PMID- 23639467 TI - Duration of vitamin K-antagonist treatment before DC cardioversion does not affect recurrence rate in patients with atrial fibrillation. PMID- 23639468 TI - Improvement in clinical signs and cellular immunity of dogs with visceral leishmaniasis using the immunomodulator P-MAPA. AB - This study investigated the immunotherapeutic potential of the protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride immuno-modulator (P MAPA) on canine visceral leishmaniasis. Twenty mongrel dogs presenting clinical symptoms compatible with leishmaniasis and diagnosis confirmed by the detection of anti-leishmania antibodies were studied. Ten dogs received 15 doses of the immunomodulator (2.0 mg/kg) intramuscularly, and 10 received saline as a placebo. Skin and peripheral blood samples were collected following administration of the immunomodulator. The groups were followed to observe for clinical signals of remission; parasite load in the skin biopsies using real-time PCR, the cytokines IL-2, IL-10 and IFN-gamma in the supernatant of peripheral blood mononuclear cells stimulated in vitro with either total promastigote antigen or phytohemagglutinin measured by capture ELISA, and changes in CD4+ and CD8+ T cell subpopulations evaluated by flow cytometry. Comparison between the groups showed that treatment with the immunomodulator promoted improvement in clinical signs and a significant reduction in parasite load in the skin. In peripheral blood mononuclear cell cultures, supernatants showed a decrease in IL-10 levels and an increase in IL-2 and IFN-gamma. An increase in CD8+ T cells was observed in peripheral blood. In addition, the in vitro leishmanicidal action of P-MAPA was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and no leishmanicidal activity was detected. These findings suggest that P MAPA has potential as an immunotherapeutic drug in canine visceral leishmaniasis, since it assists in reestablishing partial immunocompetence of infected dogs. PMID- 23639469 TI - A selective ALK inhibitor in ALK-rearranged patients. PMID- 23639470 TI - CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. AB - BACKGROUND: Currently, crizotinib is the only drug that has been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor. METHODS: In this multicentre, single-arm, open-label, phase 1-2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI 101264. FINDINGS: Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20-300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93.5%, 95% CI 82.1-98.6) including two complete responses (4.3%, 0.5-14.8) and 41 partial responses (89.1%, 76.4-96.4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment. INTERPRETATION: CH5424802 is well tolerated and highly active in patients with advanced ALK rearranged NSCLC. FUNDING: Chugai Pharmaceutical Co, Ltd. PMID- 23639471 TI - Biogenic volatile organic compounds from the urban forest of the Metropolitan Region, Chile. AB - Tropospheric ozone is a secondary pollutant whose primary sources are volatile organic compounds and nitrogen oxides. The national standard is exceeded on a third of summer days in some areas of the Chilean Metropolitan Region (MR). This study reports normalized springtime experimental emissions factors (EF) for biogenic volatile organic compounds from tree species corresponding to approximately 31% of urban trees in the MR. A Photochemical Ozone Creation Index (POCI) was calculated using Photochemical Ozone Creation Potential of quantified terpenes. Ten species, natives and exotics, were analysed using static enclosure technique. Terpene quantification was performed using GC-FID, thermal desorption, cryogenic concentration and automatic injection. Observed EF and POCI values for terpenes from exotic species were 78 times greater than native values; within the same family, exotic EF and POCI values were 28 and 26 times greater than natives. These results support reforestation with native species for improved urban pollution management. PMID- 23639472 TI - Evaluation of the pathogenicity of avipoxvirus strains isolated from wild birds in New Zealand and the efficacy of a fowlpox vaccine in passerines. AB - Avipoxvirus (APV) infection is a highly contagious disease of birds and has been reported in more than 200 bird species, affecting both domesticated and free ranging birds around the world. In New Zealand, at least three different strains of Avipoxvirus (APV) have been identified in a range of bird species.The pathogenicityof two APV strains isolated from wild birds in New Zealand, representing subclade A1 and subclade B1 were compared in zebra finches (Taeniopygia guttata). The efficacy of fowlpox vaccine at preventing clinical disease in passerines was also evaluated. Twenty-five zebra finches were divided into five groups (I-IV and a control group). Birds from Groups II and IV were vaccinated using fowl poxvirus vaccine prior to challenge. Subsequently two groups (I and II) were inoculated with a silvereye isolate (A1) and the other two groups (Group III and IV) were inoculated with a blackbird isolate (B1). Both inocula were previously propagated in chicken fibroblast cell culture. Birds in the control group were inoculated with sterile PBS. Skin thickness at the inoculation sites was measured and the development of additional skin lesions was monitored. Antibody development was measured by ELISA pre- and post virus inoculation. Both APV strains caused either swelling or hyperplasia at the inoculation site of non-vaccinated birds (4/5 in Group I and 5/5 in Group III). The swelling was milder and no foot lesions were observed in vaccinated birds before or after challenge with the silvereye or blackbird APV strains. These findings indicated that the fowlpox vaccine provided safe and appropriate protection for zebra finches exposed to the two wild APV strains and suggest that the vaccine has the potential to be used where APV threatens the captive management or translocation of endangered passerines. PMID- 23639474 TI - Mechanisms of Mycobacterium avium subsp. paratuberculosis induced apoptosis and necrosis in bovine macrophages. AB - The interaction between Mycobacterium avium subsp. paratuberculosis (Map) and macrophages is a complex process to maximize the chances of their respective survival. Previous studies have shown that Map induces cell death in macrophages, but the mechanism is not known. In the present study, we investigated the mechanism by which Map induces cell death in bovine macrophages using the fluorescent and electron microscopic techniques. The macrophages infected with an equal number of Map (i.e., multiplicity of infection, MOI=1) showed no changes of cell death, but those macrophages infected at MOI=10 showed the morphological changes consistent with apoptosis. Strikingly, the macrophages infected by Map at MOI=50 showed the changes of apoptosis and necrosis. The Map-induced apoptosis was a caspase-dependent mechanism at MOI=10 while it was caspase- and nitric oxide-independent at MOI=50. The results of the present study suggest that the mitochondrial damage following Map infection initiates the cell death processes in macrophages. PMID- 23639473 TI - Serological and molecular investigation of the prevalence of Aujeszky's disease in feral swine (Sus scrofa) in the subregions of the Pantanal wetland, Brazil. AB - The feral swine (FS) originated from the domestic pig and is present throughout the Brazilian wetland plain (the Pantanal). Aujeszky's disease (AD) was first serologically confirmed in the state of Mato Grosso do Sul (MS) in 2001; however, there was no viral confirmation. The aim of this study was to investigate antibodies against-SuHV-1 in the sera of feral swine in the studied areas, detect SuHV-1 through PCR and classify the viral genome. Among the 218 animals sampled, 186 were analyzed by ELISA, resulting in 88 (47.3%) reactive samples. In the serum neutralization test (SN), 57/179 (31.8%) samples presented antibodies against the AD virus (SuHV-1). By nested PCR, 104 DNA samples were extracted for analysis and confirmed with amplification of a fragment of glycoprotein B (gB) in five samples. The SuHV-1 was detected in 12 samples by using primers for glycoprotein E (gE) and viral genome was classified as Type I by ul44 partial sequencing. The amplification of SuHV-1 glycoprotein fragments in the fetuses of seropositive sows indicate that the vertical transmission contribute to maintain SuHV-1 in a free-living feral swine population. The origin of AD in the feral swine populations of the Pantanal is unknown, however, the determination of viral latency, the vertical transmission of the antigen by the amplification of SuHV-1 glycoprotein fragments in the fetuses of seropositive sows and genome typing contribute to the elucidation of the epidemiology of this disease in the wetlands of MS, Brazil. PMID- 23639476 TI - Genomic characterization of Felis catus papillomavirus-3: a novel papillomavirus detected in a feline Bowenoid in situ carcinoma. AB - There is increasing evidence that papillomaviruses (PVs) may cause skin cancer in cats. Neoplasms most frequently contain Felis domesticus PV type 2 (FdPV-2) DNA, but other PV DNA sequences have also been detected suggesting multiple PVs could cause disease. One of these sequences, FdPV-MY2, was previously detected in 5 of a series of 70 feline skin cancers. The aim was to determine the genome sequence of this PV. Using the circular nature of PV DNA, 'outward facing' primers specific for FdPV-MY2 were designed and amplified a 7300 bp length of DNA from a feline Bowenoid in situ carcinoma (BISC) that showed microscopic evidence of a viral etiology and tested positive for FdPV-MY2 DNA. The PCR product was sequenced using next generation sequencing technology. The full genomic sequence of the virus, comprising 7583 bp, was assembled and analyzed. As this is the third PV from a domestic cat, the virus was designated Felis catus PV type 3 (FcaPV-3). Consistent with other PVs, the putative coding regions of FcaPV-3 were predicted to produce 6 early proteins and 2 late ones. Classification was difficult as the virus contained over 60% nucleotide similarity within the ORF L1 with PVs from 3 different genera. However, based on phylogenetic analysis of ORF L1, FcaPV-3 was most closely related to the tau-PVs CPV-2 and CPV-7. As FcaPV-3 has over 60% nucleotide similarity with the ORF L1 of both tau-PVs, it is proposed that FcaPV-3 is classified in the genus Taupapillomavirus and is the first non-canine PV in this genus. PMID- 23639475 TI - Respiratory disease due to current egg drop syndrome virus in Pekin ducks. AB - Severe acute respiratory symptoms with coughing, dyspnea, and gasping were reported in two flocks of 9-day-old Pekin ducklings from different provinces. Gross lesions, white exudate and mucous membrane congestion in the trachea as well as blue to purple color changes and sclerosis in lungs were observed. Histological lesions revealed that the trachea and bronchial epithelium were hyperplastic and infiltrated by neutrophil granulocytes. Egg drop syndrome virus (EDSV) was differentially diagnosed using polymerase chain reaction, and the strains were isolated from tracheas and lungs by inoculation of 10-day-old embryonated duck eggs. The virus isolates were designated strain D11-JW-012 and D11-JW-017. The clinical and pathological signs were reproduced by intra-tracheal inoculation of the isolates in 3-day-old ducklings. Although the two isolates produced similar clinical signs, pathological lesions and ciliostasis, the D11-JW 017 strain resulted in more severe clinical signs with progressive symptoms compared to those of D11-JW-012 strain-infected ducklings. We suggest that different EDSV strains with mild or severe to moderate pathogenicity coexist and have potential risks in poultry. Hereby, we report an EDSV infection in ducklings. PMID- 23639477 TI - Dopamine modulates attentional control of auditory perception: DARPP-32 (PPP1R1B) genotype effects on behavior and cortical evoked potentials. AB - Using a specific variant of the dichotic listening paradigm, we studied the influence of dopamine on attentional modulation of auditory perception by assessing effects of allelic variation of a single-nucleotide polymorphism (SNP) rs907094 in the DARPP-32 gene (dopamine and adenosine 3', 5'-monophosphate regulated phosphoprotein 32 kilodations; also known as PPP1R1B) on behavior and cortical evoked potentials. A frequent DARPP-32 haplotype that includes the A allele of this SNP is associated with higher mRNA expression of DARPP-32 protein isoforms, striatal dopamine receptor function, and frontal-striatal connectivity. As we hypothesized, behaviorally the A homozygotes were more flexible in selectively attending to auditory inputs than any G carriers. Moreover, this genotype also affected auditory evoked cortical potentials that reflect early sensory and late attentional processes. Specifically, analyses of event-related potentials (ERPs) revealed that amplitudes of an early component of sensory selection (N1) and a late component (N450) reflecting attentional deployment for conflict resolution were larger in A homozygotes than in any G carriers. Taken together, our data lend support for dopamine's role in modulating auditory attention both during the early sensory selection and late conflict resolution stages. PMID- 23639478 TI - Genomic diversity of Bombyx mori nucleopolyhedrovirus strains. AB - Bombyx mori nucleopolyhedrovirus (BmNPV) is a baculovirus that selectively infects the domestic silkworm. In this study, six BmNPV strains were compared at the whole genome level. We found that the number of bro genes and the composition of the homologous regions (hrs) are the two primary areas of divergence within these genomes. When we compared the ORFs of these BmNPV variants, we noticed a high degree of sequence divergence in the ORFs that are not baculovirus core genes. This result is consistent with the results derived from phylogenetic trees and evolutionary pressure analyses of these ORFs, indicating that ORFs that are not core genes likely play important roles in the evolution of BmNPV strains. The evolutionary relationships of these BmNPV strains might be explained by their geographic origins or those of their hosts. In addition, the total number of hr palindromes seems to affect viral DNA replication in Bm5 cells. PMID- 23639479 TI - Exploring the utility of human DNA methylation arrays for profiling mouse genomic DNA. AB - Illumina Infinium Human Methylation (HM) BeadChips are widely used for measuring genome-scale DNA methylation, particularly in relation to epigenome-wide association studies (EWAS) studies. The methylation profile of human samples can be assessed accurately and reproducibly using the HM27 BeadChip (27,578 CpG sites) or its successor, the HM450 BeadChip (482,421 CpG sites). To date no mouse equivalent has been developed, greatly hindering the application of this methodology to the wide range of valuable murine models of disease and development currently in existence. We found 1308 and 13,715 probes from HM27 and HM450 BeadChip respectively, uniquely matched the bisulfite converted reference mouse genome (mm9). We demonstrate reproducible measurements of DNA methylation at these probes in a range of mouse tissue samples and in a murine cell line model of acute myeloid leukaemia. In the absence of a mouse counterpart, the Infinium Human Methylation BeadChip arrays have utility for methylation profiling in non-human species. PMID- 23639481 TI - Prospective multicenter randomized intermediate biomarker study of oral contraceptive versus depo-provera for prevention of endometrial cancer in women with Lynch syndrome. AB - Women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have shown that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown whether they are effective in women with Lynch syndrome. Asymptomatic women ages 25 to 50 with Lynch syndrome were randomized to receive the progestin compounds Depo-Provera (depo-MPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were conducted before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depo-MPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results show that women with Lynch syndrome do show an endometrial response to short-term exogenous progestins, suggesting that OCP and depo-MPA may be reasonable chemopreventive agents in this high-risk patient population. PMID- 23639480 TI - Grape seed extract efficacy against azoxymethane-induced colon tumorigenesis in A/J mice: interlinking miRNA with cytokine signaling and inflammation. AB - Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths, suggesting that additional strategies are needed to prevent/control this malignancy. As CRC growth and progression involve a large window (10-15 years), chemopreventive intervention could be a practical/translational strategy. Azoxymethane (AOM)-induced colon tumorigenesis in mice resembles human CRC in terms of progression of ACF to polyps, adenoma, and carcinomas and associated molecular mechanisms. Accordingly, herein we investigated grape seed extract (GSE) efficacy against AOM-induced colon tumorigenesis in A/J mice. GSE was fed in diet at 0.25% or 0.5% (w/w) dose starting 2 weeks after last AOM injection for 18 or 28 weeks. Our results showed that GSE feeding significantly decreases colon tumor multiplicity and overall tumor size. In biomarker analysis, GSE showed significant antiproliferative and pro-apoptotic activities. Detailed mechanistic studies highlighted that GSE strongly modulates cytokines/interleukins and miRNA expression profiles as well as miRNA processing machinery associated with alterations in NF-kappaB, beta-catenin, and mitogen-activated protein kinase (MAPK) signaling. Additional studies using immunohistochemical analyses found that indeed GSE inhibits NF-kappaB activation and decreases the expression of its downstream targets (COX-2, iNOS, VEGF) related to inflammatory signaling, downregulates beta-catenin signaling and decreases its target gene c-myc, and reduces phosphorylated extracellular signal-regulated kinase (ERK)1/2 levels. Together, these finding suggested that inflammation, proliferation, and apoptosis are targeted by GSE to prevent CRC. In summary, this study for the first time shows alterations in the expression of miRNAs and cytokines by GSE in its efficacy against AOM-induced colon tumorigenesis in A/J mouse sporadic CRC model, supporting its translational potential in CRC chemoprevention. PMID- 23639482 TI - Improving the identification of anaerobes in the clinical microbiology laboratory through MALDI-TOF mass spectrometry. AB - In this study, 1325 anaerobes were analyzed by MALDI-TOF MS. Of these, 92.5% were correctly identified at the species level. One unidentified species and several uncommon and rare species were identified. These results show that this technique has become the new gold standard for the routine identification of clinical anaerobes. PMID- 23639484 TI - Older HIV-infected patients--an underestimated population in northern Greece: epidemiology, risk of disease progression and death. AB - OBJECTIVES: HIV prevalence among older people is on the increase. The aim of this study was to evaluate the epidemiological and clinical features at diagnosis and survival of older patients. METHODS: This was a retrospective analysis of the data of 558 newly diagnosed antiretroviral-naive patients between January 1998 and December 2008. Patients were divided into two groups according to their age at diagnosis: >=50 years (n=103) and 18-49 years (n=455). RESULTS: The most common risk factor for older patients was heterosexual contact (p<0.013). Older patients were more likely to suffer from hypertension (33.0% vs. 5.1%, p<0.0005), cardiovascular disease (20.4% vs. 2.9%, p<0.0005), neurological disorders (11.7% vs. 5.5%, p=0.02), renal dysfunction (12.6% vs. 5.3%, p=0.01), and infections (66.0% vs. 49.7%, p=0.003) than their younger counterparts, and to have more hospital admissions during follow-up (47.5% vs. 19.6%, p<0.0005). Older patients had a shorter survival time (p<0.0005). A statistically significant increase in CD4+ cell number through time was observed in both groups (p<0.0005). Younger patients reached higher magnitudes of absolute numbers of CD4+ cells during follow-up (p<0.0005) after the initiation of antiretroviral therapy. The total number of patients with clinical AIDS from baseline throughout the study period was also higher in the older age group (35.9% vs. 25.0%). CONCLUSIONS: HIV infected people aged >=50 years differ in epidemiological and clinical features to younger HIV-infected people. The issue of increasing prevalence of HIV infection is a matter of concern due to existing comorbidities, which probably lead to higher mortality rates and faster progression to clinical AIDS. PMID- 23639483 TI - High prevalence of IgA class anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased risk of bacterial infection in patients with cirrhosis. AB - BACKGROUND & AIMS: Anti-neutrophil cytoplasmic antibodies (ANCA) are a non uniform family of antibodies recognizing diverse components of neutrophil granulocytes. ANCA formation might be induced by protracted bacterial infections or probably reflect an abnormal immune response to commensal microorganisms. Bacterial infections are common complications in cirrhosis with high incidence of episodes caused by enteric organisms, therefore, we sought to study the presence and clinical importance of ANCA in cirrhosis. METHODS: Sera of 385 patients with cirrhosis of different etiologies were assayed for ANCA of IgG, IgA, IgA1, IgA2, and secretory IgA subtypes by indirect immunofluorescence and ELISAs. The control group comprised 202 patients with chronic liver diseases without cirrhosis and 100 healthy subjects. In cirrhosis, a 2-year follow-up, observational study was conducted to assess a possible association between the presence of ANCA and clinically significant bacterial infections. RESULTS: Prevalence of ANCA IgA was significantly higher in cirrhosis (52.2%) compared to chronic liver diseases (18.6%) or healthy controls (0%, p<0.001 for both). ANCA IgA subtyping assays revealed marked increase in the proportion of IgA2 subtype (46% of total ANCA IgA) and presence of the secretory component concurrently. Presence of ANCA IgA was associated with disease-specific clinical characteristics (Child-Pugh stage and presence of ascites, p<0.001). During a 2-year follow-up period, risk of infections was higher among patients with ANCA IgA compared to those without (41.8% vs. 23.4%, p<0.001). ANCA IgA positivity was associated with a shorter time to the first infectious complication (pLogRank <0.001) in Kaplan-Meier analysis and was identified as an independent predictor in multivariate Cox regression analysis (HR:1.74, 95% CI: 1.18-2.56, p=0.006). CONCLUSIONS: Presence of IgA type ANCA is common in cirrhosis. Involvement of gut mucosal immune system is in center of their formation and probably reflects sustained exposure to bacterial constituents. PMID- 23639486 TI - Prolonged recovery of sea otters from the Exxon Valdez oil spill? A re examination of the evidence. AB - Sea otters (Enhydra lutris) suffered major mortality after the Exxon Valdez oil spill in Prince William Sound, Alaska, 1989. We evaluate the contention that their recovery spanned over two decades. A model based on the otter age-at-death distribution suggested a large, spill-related population sink, but this has never been found, and other model predictions failed to match empirical data. Studies focused on a previously-oiled area where otter numbers (~80) stagnated post spill; nevertheless, post-spill abundance exceeded the most recent pre-spill count, and population trends paralleled an adjacent, unoiled-lightly-oiled area. Some investigators posited that otters suffered chronic effects by digging up buried oil residues while foraging, but an ecological risk assessment indicated that exposure levels via this pathway were well below thresholds for toxicological effects. Significant confounding factors, including killer whale predation, subsistence harvests, human disturbances, and environmental regime shifts made it impossible to judge recovery at such a small scale. PMID- 23639485 TI - Seasonal humidity may influence Pseudomonas aeruginosa hospital-acquired infection rates. AB - OBJECTIVE: The objective of this study was to determine the association of seasonal climatic conditions with the incidence of Pseudomonas aeruginosa infections. METHODS: A retrospective study was carried out to evaluate all infections caused by P. aeruginosa in a 660-bed tertiary-care hospital in Brazil over a period of 5 years. To assess seasonal patterns, monthly temperature, relative humidity, and precipitation averages were obtained. Correlations of seasonal variations with infection rates (IR) were determined by Pearson correlation coefficient. Linear regression was used to determine trends, and multivariable linear regression was performed using a Poisson distribution. RESULTS: A total of 844 cases of P. aeruginosa infection were identified for 1 058 501 patient-days during 1826 days (overall IR 7.97/10 000 patient-days). The mean temperature was 18.2+/-2.8 degrees C, relative humidity was 80.3+/-3.6%, and precipitation was 104.7+/-64.38mm. The Pearson correlation was significant between urinary tract infection and temperature (R=0.29; p=0.021) and precipitation (R=0.27; p=0.036). A correlation was also significant between hospital-associated pneumonia and precipitation (R=0.29; p=0.022) and relative humidity (R=0.31; p=0.013). Relative humidity was associated with a higher IR of other infections caused by P. aeruginosa, but it was not possible to build a predictive model when multiple linear regression and Poisson regression were tested. CONCLUSION: Climatic conditions are another factor that may interfere with the IR of Pseudomonas aeruginosa. PMID- 23639487 TI - The first case of H7N9 influenza in Taiwan. PMID- 23639489 TI - Breast cancer prevention: SERMs come of age. PMID- 23639488 TI - Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. AB - BACKGROUND: Tamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of selective oestrogen receptor modulators (SERMs) on breast cancer incidence. METHODS: We did a meta-analysis with individual participant data from nine prevention trials comparing four selective oestrogen receptor modulators (SERMs; tamoxifen, raloxifene, arzoxifene, and lasofoxifene) with placebo, or in one study with tamoxifen. Our primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10 year follow-up period. Analysis was by intention to treat. RESULTS: We analysed data for 83,399 women with 306,617 women-years of follow-up. Median follow-up was 65 months (IQR 54-93). Overall, we noted a 38% reduction (hazard ratio [HR] 0.62, 95% CI 0.56 0.69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5-10 (42%, HR 0.58, 0.51-0.66; p<0.0001 vs 25%, 0.75, 0.61-0.93; p=0.007), but we noted no heterogeneity between time periods. Thromboembolic events were significantly increased with all SERMs (odds ratio 1.73, 95% CI 1.47-2.05; p<0.0001). We recorded a significant reduction of 34% in vertebral fractures (0.66, 0.59-0.73), but only a small effect for non-vertebral fractures (0.93, 0.87-0.99). INTERPRETATION: For all SERMs, incidence of invasive oestrogen (ER)-positive breast cancer was reduced both during treatment and for at least 5 years after completion. Similar to other preventive interventions, careful consideration of risks and benefits is needed to identify women who are most likely to benefit from these drugs. FUNDING: Cancer Research UK. PMID- 23639490 TI - Efficient harvesting of marine microalgae Nannochloropsis maritima using magnetic nanoparticles. AB - An efficient magnetic separation technology using Fe(3)O(4) nanoparticles was developed for harvesting marine microalgae Nannochloropsis maritima from culture broth. Recovery capacity of these nanoparticles was affected by microalgal growth phase and reached the peak value when the microalgal growth reached its maximal biomass after 18 days. The recovery efficiency of microalgal cells from the culture medium reached more than 95% at the particle dosage of 120 mg/L within 4 min. Electrostatic attraction at acidic pH and cell aggregation under neutral and alkaline conditions was beneficial for harvesting the algal cells. Higher operation temperature resulted in higher adsorption capacity of these nanoparticles for microalgawl cells. Reuse of the culture medium obtained from magnetic separation gave similar biomass production in comparison with that from centrifugation separation after 5 recycles. Together with these results provide a great potential in high-efficient and economical harvesting of tiny marine microalgae using magnetic separation technology in practice. PMID- 23639491 TI - Liquid chromatography and mass spectrometry with post-column partial reduction for the analysis of native and scrambled disulfide bonds. AB - A method capable of detecting both native and scrambled disulfide bonds has been established. Nonreduced protein digests were separated using a reversed-phase C18 column, partially reduced by post-column addition of a reducing reagent, and then analyzed by mass spectrometry. Disulfide bond linkage was established by matching the retention times of cysteine-containing peptides and confirmed by the detection of the molecular weight of the disulfide-linked peptides. The application of this method was demonstrated by determination of the disulfide bond structures of an immunoglobulin G1 (IgG1) molecule and lysozyme and by the detection of four scrambled disulfide bonds in the IgG1 molecule. PMID- 23639492 TI - Risk factors associated with infectious bursal disease in commercial chickens in Bangladesh. AB - To identify risk factors associated with infectious bursal disease (IBD) in commercial chickens in Bangladesh, we conducted a matched case-control study on 32 commercial farms affected with IBD and 96 IBD unaffected farms taking flock size (1000 vs. >1000 birds) and location of the farms (whether it is in rural or urban area) as matching variables. Epidemiological data from case and control farms were collected through the use of a pretested questionnaire, and analyzed by matched-pair analysis and multivariable conditional logistic regression. In the multivariable analysis, the variables 'receive visitors on the farm premises' (odds ratio [OR]=4.49; 95% confidence interval [CI]=1.50-13.42; p=0.007), 'purchase live poultry from the open market' (OR=7.59; 95% CI=2.69-21.45; p=<0.001), 'workers live outside the farms premises' (OR=5.89; 95% CI=1.87-18.60; p=0.002) and 'access of vendor vehicles on the farm premises' (OR=5.19; 95% CI=1.39-19.31; p=0.014) were identified as risk factors for IBD in commercial chicken farms. The proper management of the risk factors along with knowledge of the disease could help to reduce the incidence of IBDV infection in commercial chickens in Bangladesh. PMID- 23639493 TI - Professional responsibility and certifying examinations. PMID- 23639494 TI - Fixing research subjects protection in the United States: moving beyond consent. PMID- 23639495 TI - Exercise-based cardiac rehabilitation and improvements in cardiorespiratory fitness: implications regarding patient benefit. PMID- 23639496 TI - Trust in residents and board examinations: when sharing crosses the boundary. PMID- 23639497 TI - Increasing enrollment in drug trials: the need for greater transparency about the social value of research in recruitment efforts. PMID- 23639498 TI - Protocol understanding and anxiety in perioperative clinical trial patients approached for consent on the day of surgery. AB - OBJECTIVE: To determine whether approaching patients for consent on the day of surgery impairs understanding or produces unacceptable anxiety compared with obtaining consent before the day of surgery. PATIENTS AND METHODS: We assessed the effect of the timing of obtaining consent for a moderate- to high-risk factorial trial of clonidine and aspirin in patients having noncardiac surgery. Between February 1, 2011, and November 31, 2011, 2 study personnel used the same standardized script to recruit patients before the day of surgery or on the day of surgery. Patients eligible for the trial were preferentially approached to obtain consent before the day of surgery in the preoperative clinic. Patients who did not attend the preoperative clinic or could not be approached that day were approached for consent on the day of surgery. We evaluated anxiety before and after the trial was discussed, protocol knowledge, consent rates, and perceived obligation to participate. All comparisons were adjusted for differences in potentially confounding variables using inverse propensity score weighting. RESULTS: Patients approached on the day of surgery compared with before the day of surgery had noninferior understanding of the comprehension score (adjusted mean difference, -0.19; 90% CI, -0.47 to 0.10; P<.001 for noninferiority) and a noninferior mean increase in the postapproach anxiety score (adjusted mean difference, 0.19; 90% CI, -0.29 to 0.68; P=.003 for noninferiority). Perceived obligation to participate was not greater on the day of surgery (adjusted mean difference, 0.09; 95% CI, -0.21 to 0.40; P=.57 for superiority); however, consent rates were significantly lower (31% vs 59%; odds ratio, 0.49; 90% CI, 0.33 to 0.72; P=.46 for noninferiority). CONCLUSION: Approaching patients to obtain consent to participate in a perioperative interventional trial on the day of surgery does not compromise essential elements of the consent process. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01082874. PMID- 23639499 TI - Cardiovascular fitness and mortality after contemporary cardiac rehabilitation. AB - OBJECTIVE: To assess the association between cardiorespiratory fitness (CRF) and outcomes in a cardiac rehabilitation (CR) cohort. PATIENTS AND METHODS: We conducted a retrospective study of 5641 patients (4282 men [76%] and 1359 women [24%]; mean +/- SD age, 60.0+/-10.3 years) with coronary artery disease who participated in CR between July 1, 1996, and February 28, 2009. Based on peak metabolic equivalents (METs), patients were classified as low fitness (LFit) (<5 METs), moderate fitness (5-8 METs), or high fitness (>8 METs). RESULTS: Baseline fitness predicted long-term mortality: relative to the LFit group, patients with moderate fitness had an adjusted hazard ratio of 0.54 (95% CI, 0.42-0.69), and those with high fitness a hazard ratio of 0.32 (95% CI, 0.24-0.44). Improvement in CRF at 12 weeks was associated with decreased overall mortality, with a 13% point reduction with each MET increase (P<.001) and a 30% point reduction in those who started with LFit. At 1 year, each MET increase in CRF was associated with a 25% point reduction in overall mortality in the whole group (P<.001). CONCLUSION: In this study of contemporary CR patients, higher baseline fitness predicted lower mortality. The novel finding was that improvement in fitness during a CR program and improvements that persisted at 1 year were also associated with decreased mortality, most strongly in patients who start with LFit. PMID- 23639500 TI - The new oral anticoagulants in clinical practice. AB - Vitamin K antagonists were the only class of oral anticoagulants available to clinicians for decades. However, with the US Food and Drug Administration approval of new oral anticoagulants, such as dabigatran, rivaroxaban, and apixaban, clinicians now have a broader choice. Given the recent approval and availability of these medications, several questions arise while deciding which of them would be best suited for a particular patient. This article provides a concise review for clinicians entailing the main studies that evaluated the efficacy and safety of these drugs, their pharmacokinetic and pharmacodynamic properties, and a practical approach to their clinical use. For this review, we conducted searches of PubMed and MEDLINE for articles published between January 1, 2000, and January 30, 2013, using the following search terms: oral anticoagulants, dabigatran, apixaban, rivaroxaban, novel anticoagulants, bleeding complications, management of bleeding complications, pharmacodynamics, and pharmacokinetics. Studies published in English were selected for inclusion in this review, as were additional articles identified from bibliographies. PMID- 23639501 TI - Childhood food allergies: current diagnosis, treatment, and management strategies. AB - Food allergy is a growing public health concern in the United States that affects an estimated 8% of children. Food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a specific food. Nearly 40% of children with food allergy have a history of severe reactions that if not treated immediately with proper medication can lead to hospitalization or even death. The National Institute of Allergy and Infectious Diseases (NIAID) convened an expert panel in 2010 to develop guidelines outlining evidence-based practices in diagnosing and managing food allergy. The purpose of this review is to aid clinicians in translating the NIAID guidelines into primary care practice and includes the following content domains: (1) the definition and mechanism of childhood food allergy, (2) differences between food allergy and food intolerance, (3) the epidemiology of childhood food allergy in the United States, (4) best practices derived from the NIAID guidelines focused on primary care clinicians' management of childhood food allergy, (5) emerging food allergy treatments, and (6) future directions in food allergy research and practice. Articles focused on childhood food allergy were considered for inclusion in this review. Studies were restricted to the English language and to those published within the past 40 years. A cross-listed combination of the following words, phrases, and MeSH terms was searched in PubMed and Google Scholar to identify relevant articles: food allergy, food hypersensitivity, child, pediatric, prevalence, and epidemiology. Additional sources were identified through the bibliographies of the retrieved articles. PMID- 23639502 TI - 57-year-old man with flushing and fainting. PMID- 23639503 TI - Ian Wilmut--pioneer of cloning. PMID- 23639505 TI - An unusual cause of melena. PMID- 23639506 TI - Immune circuits in asthma. AB - Asthma is an inflammatory disorder of the conducting airways that has traditionally been classified according to severity. While this has been helpful in guiding treatment with drugs that are currently available such as beta2 adrenoceptor agonists and corticosteroids, it takes little account of disease heterogeneity and causal pathways. This review draws attention to subphenotypes of asthma involving different mechanisms and moves the focus away from the adaptive immune response more towards innate immune mechanisms. This mandates a new view of the disease in which causal pathways linked to biomarkers are found and treatments targeted to these pathways as described in a more personalised approach to medicine. PMID- 23639508 TI - Echogenic focus in the fetal left ventricular cavity: is it a false tendon? AB - OBJECTIVE: To draw attention to the left ventricular false tendon which can be misinterpreted as echogenic focus in the fetus. METHODS: The study group consisted of 9 fetuses out of the 161 who had been misdiagnosed for left ventricular false tendon as echogenic focus by obstetricians. Fetal echocardiography and 2-D color Doppler echocardiography were performed in the pre postnatal period. The standard fetal echocardiographic views (4,5 chamber views, long axis view of the left ventricle, short axis view of the ventricles and great arteries, three vessels and trachea view, long axis views of the duct and aortic arch) were obtained for each case. RESULTS: Of the 161 fetuses with echogenic focus in the left ventricle which underwent fetal echocardiography, 9 (5.6%) were diagnosed with false tendons present in the left ventricular cavity with no other cardiovascular anomaly. Six out of 9 patients underwent amniocentesis as follows: for age of over 35 years (two patients), abnormal double-triple screening tests plus echogenic focus (two patients) and soft ultrasonographic markers including echogenic focus (two patients). These fetuses revealed no cardiovascular and other systemic pathology or dysmorphism except for false tendons in the left ventricular cavity. CONCLUSION: False tendon should be taken into account as differential diagnosis of left ventricular echogenic focus in the fetus. Misinterpretation of false tendon as echogenic focus may cause unnecessary fetal invasive approach and maternal anxiety, especially when it arises with a background of borderline fetal findings and knowledge. PMID- 23639507 TI - Emerging targets for novel therapy of asthma. AB - Significant advances in understanding the cell and molecular biology of inflammation and airway smooth muscle (ASM) contractility have identified several potential novel targets for therapies of asthma. New agents targeting G-protein coupled receptors (GPCRs) including bitter taste receptors (TAS2R) agonists and prostaglandin EP4 receptor agonists elicit ASM relaxation. The cAMP/PKA pathway continues to be a promising drug target with the emergence of new PDE inhibitors and a novel PKA target protein, HSP20, which mediates smooth muscle relaxation via actin depolymerization. Smooth muscle relaxation can also be elicited by inhibitors of the RhoA/Rho kinase pathway via inhibition of myosin light chain phosphorylation and actin depolymerization. Targeting epigenetic processes that control chromatin remodeling and RNA-induced gene silencing in airway cells also holds great potential for novel asthma therapy. Further investigation may identify agents that inhibit smooth muscle contraction and/or restrain or reverse obstructive remodeling of the airways. PMID- 23639509 TI - Mechanisms of apple polyphenols-induced proliferation inhibiting and apoptosis in a metastatic oral adenoid cystic carcinoma cell line. AB - Adenoid cystic carcinoma (ACC) is characterized by intensive local invasion and high incidence of distant metastases. Conventional chemotherapy for ACC produces a poor result. We aimed to evaluate the effect of apple polyphenols (APs), a novel nutraceutical agent, on the proliferation and apoptosis levels in a metastatic oral ACC cell line. A metastatic ACC (ACC-M) cell line and control cells (MRC-5 cells derived from normal lung tissue) were treated with APs at different concentrations. MTT assay was used to determine the in vitro cytotoxicity. The cell cycle distribution and apoptosis levels were measured by flow cytometry. To evaluate the mechanism of APs, vascular endothelial growth factor receptor-2 (VEGFR-2) and caspase-3 messenger ribonucleic acid (mRNA) and protein levels were evaluated by reverse transcription-polymerase chain reaction and Western blots, respectively. After cells were cultured for 24 hours or 48 hours, the critical concentration of cytotoxicity of APs in MRC-5 cells was found to be 250 MUg/mL. In contrast, in the concentration range of 100-250 MUg/mL, the cytotoxicity of APs in ACC-M cells was time- and dose-dependent: ACC-M cell proliferation declined at 100 MUg/mL when cultured for 48 hours, whereas growth was not inhibited at the concentrations of APs below 200 MUg/mL when cultured for 24 hours. In selected time and dose patterns (ACC-M cells cultured at the concentrations of 150 and 250 MUg/mL for 48 hours), the flow cytometry performance showed that apoptosis and necrosis occurred in APs-treated ACC-M cells. Also, in these patterns, VEGFR-2 mRNA and protein levels decreased whereas the levels of caspase-3 increased. In summary, APs could inhibit proliferation and induce apoptosis in ACC-M cells in vitro. These effects may be related to the downregulation of VEGFR-2 expression and the activation of caspase-3 expression. PMID- 23639510 TI - In vivo magnetic resonance imaging of mice liver tumors using a new gadolinium based contrast agent. AB - We compared the enhancement effect between a newly synthesized tissue-specific contrast agent, [Gd-DOTA-FPbetaG], and a commercially available agent, [Gd(DOTA)](-), in a murine model of liver tumor using a clinical magnetic resonance imaging scanner. The colon cancer cell lines with and without beta glucuronidase (betaG) expression were implanted into the liver of mice. Self synthesized gadolinium-based magnetic resonance contrast agent, [Gd(DOTA FPbetaG)], was administered to measure enhancement on magnetic resonance images using a commercially available agent, [Gd(DOTA)](-), as control in a clinical 3.0 tesla (T) magnetic resonance scanner. In vivo fluorescence imaging and histopathology of the liver were also performed to compare and correlate with the magnetic resonance studies. The in vivo fluorescence imaging failed to depict a sufficiently intense signal for liver or liver tumor of mice without exposure of the liver following an incision on the abdominal wall. The tissue-specific magnetic resonance agent, [Gd(DOTA-FPbetaG)], caused significantly stronger enhancement in tumors expressing betaG (CT26/mbetaG-eB7) than in tumors not expressing betaG (CT26) (p < 0.05). In the magnetic resonance imaging studies using control agent [Gd(DOTA)](-), the tumors with and without betaG expression depicted no significant difference in enhancement on the T1-weighted images. The [Gd(DOTA-FPbetaG)] also provided significantly more contrast uptake in the CT26/mbetaG-eB7 tumor than in the normal liver parenchyma, whereas the [Gd(DOTA)](-) did not. This study confirms that better contrast enhancement can be readily detected in vivo by the use of a tissue-specific magnetic resonance contrast agent to target tumor cells with specific biomarkers in a clinical magnetic resonance imaging scanner. PMID- 23639511 TI - Plasma B-type natriuretic peptide in predicting outcomes of elective coronary artery bypass surgery. AB - The risks of surgery and its clinical outcome are of great importance for both patients and physicians when choosing coronary artery bypass (CABG) surgery for coronary artery disease. The purpose of the current study was to clarify the relationship between serum B-type natriuretic peptide (BNP) and patient clinical outcome. Seventy-six eligible patients who underwent CABG were enrolled into the prospective study. Venous blood samples were drawn for serum BNP and N-terminal (NT)-proBNP levels measurement on preoperative Day 1, postoperative Day 1, and postoperative Day 7. Clinical end points were: (1) intensive care unit (ICU) stay longer than 4 days postoperatively and/or hospital stay longer than 13 days postoperatively; (2) major complications and poor outcomes. Patients who had prolonged ICU stay and hospitalization had significantly higher postoperative Day 1 BNP and postoperative Day 1 NT-proBNP level (p = 0.02 and 0.005, respectively). Age was significantly older in patients with prolonged ICU stay and hospitalization than those without prolonged ICU stay and hospitalization (p = 0.03). Serum creatinine level was also significantly increased in patients with prolonged ICU stay and hospitalization (p = 0.009). However, age was the only remaining factor that correlated with prolonged ICU stay and hospitalization in the multivariate logistic regression model. These results suggest that research using BNP and NT-proBNP for predicting ICU stay and hospitalization in patients who have undergone CABG must adjust risk factors to present a more appropriate estimation of its clinical outcome. PMID- 23639512 TI - P53 codon 72 polymorphism in Taiwanese breast cancer patients. AB - There are clear discrepancies between ethnicity and geographic area regarding the peak age incidence and mortality of breast cancer. Underlying variances include genetic, environmental, and socioeconomic factors. The wild-type p53 codon has two common polymorphic variants from a single-base-pair substitution at codon 72, where either C-C-C encodes proline (p53-p72) or C-G-C encodes arginine (p53-R72). We aim to study the p53 codon 72 genotypes of patients with breast cancer in Taiwan and make a comparison with the published data to ascertain whether any difference exists between Taiwanese and Western patients with breast cancer. We also evaluated the effect of the p53 codon 72 polymorphism on clinicopathologic features. We examined blood from 170 Taiwanese women with breast cancer with polymerase chain reaction-restriction fragment length polymorphism for the genotypes of p53 codon 72. For the p53 codon 72 polymorphism, there were 31 p53 P/P72 (18.2%), 93 p53-R/P72 (54.7%), and 46 p53-R/R72 (27.1%) with the allele frequencies 0.54 for the p53-R72 and 0.46 for p53-P72, respectively. Our results indicate that there was more p53-P72 (40.6% in Asians vs. 26.4% in Caucasians) and twice the incidence of p53-P/P72 homozygotes (18% in Asians vs. 8% in Caucasians) among the Asian population. Patients with the p53-R/R72 variant were more likely to have a t1 tumor size status (55.2%) compared with patients with the P53-P/R72 (30.9%) or P53-P/P72 variant (36%). Our results support the hypothesis that genetic factors may contribute to the difference between Taiwanese or Asian breast cancer and Western breast cancer patient populations. PMID- 23639513 TI - Efficacy and tolerability between an olmesartan/amlodipine fixed-dose combination and an amlodipine double dose in mild to moderate hypertension. AB - Fixed-dose combinations (FDCs) are one of the options for improving blood pressure (BP) goal attainment. We enrolled 141 patients and evaluated the efficacy and safety between a fixed dose of olmesartan/amlodipine (OA) and a double dose of amlodipine (DA) for treating mild to moderate hypertension after amlodipine monotherapy failure. After at least 2 weeks of monotherapy failure, the patients were randomized to receive either OA or DA for 8 weeks. We compared the systolic blood pressure (SBP)-lowering efficacy of the OA and DA using both an office BP and an ambulatory blood pressure monitoring (ABPM) device. The intent-to-treat analysis found that the early (2nd week) and final visit (8th week) SBP reductions were significantly greater in those patients receiving OA (n = 70) than DA (n = 71) (17.57 +/- 15.49 vs. 10.46 +/- 13.36 and 24.89 +/- 14.09 vs. 17.03 +/- 13.27 mmHg, p = 0.002 and 0.001, respectively). Among those using ABPM, the patients with 8-week OA had a greater SBP-lowering effect in comparison with those on DA (14.08 +/- 10.74 vs. 6.32 +/- 10.21, p = 0.018). Both treatment strategies were well tolerated. This study showed that an OA FDC is more effective than DA in reducing SBP for mild to moderate hypertension after the failure of amlodipine monotherapy. PMID- 23639514 TI - Preoperative dexmedetomidine prevents tourniquet-induced hypertension in orthopedic operation during general anesthesia. AB - This study was a double-blinded randomized control trial designed to investigate the hemodynamic effects of dexmedetomidine on prolonged tourniquet inflation. Thirty-seven patients scheduled for elective orthopedic surgery of the lower limb under general anesthesia were recruited. They were randomly assigned to receive intravenous dexmedetomidine (DEX, 0.5 MUg/kg; n = 18) or normal saline (CON; n = 19) before tourniquet inflation. Arterial blood pressure and heart rate were recorded every 10 minutes until 60 minutes after the start of tourniquet inflation and again immediately after deflation. In the DEX group, arterial pressure was not significantly changed, but in the CON group arterial pressure was significantly increased at 40, 50, and 60 minutes after the start of tourniquet inflation. Development of more than 30% increase in arterial pressure during tourniquet inflation was more frequent in the CON group than in the DEX group. Preoperative intravenous dexmedetomidine could therefore prevent tourniquet-induced hypertension in patients undergoing general anesthesia. PMID- 23639515 TI - Complications of urologic laparoscopic surgery: a center surgeon's experience involving 601 procedures including the learning curve. AB - When indications for laparoscopy were expanded to include a variety of urologic diseases, this increased the importance of prevention of complications, especially during the surgeons' learning curve period. Therefore, we evaluated the complications of urologic laparoscopic surgery in the course of one surgeon's experience including the learning curve after completing his long-term fellowship program. From December 2004 to August 2010, a total of 601 urologic laparoscopic surgical procedures were performed by a single surgeon who had finished a 9-month fellowship program at an experienced center. The intra- and postoperative complications of these cases were documented and graded according to the modified Clavien classification system, and then compared with the first and second 3-year periods. Of these 601 laparoscopic procedures, 47 complications occurred in 38 patients, resulting in a total complication rate of 7.8%. Conversion to open surgery occurred in four (0.6%) patients. Clavien grades I and II accounted for minor complications and occurred in 36 (5.9%) patients, whereas grades III, IV, and V accounted for major complications, which occurred in 11 (1.8%) patients. The annual complication rates formed a plateau in the 3rd year. Complication rates were significantly lower in the second 3-year period compared with the first 3 years (p<0.05). Despite the well-organized training program and transferability, surgeons must practice caution in the early years until they become more experienced. In spite of the presence of experienced laparoscopic surgeons, the surgical team needs time to gain experience. These factors cause complication rates to form a plateau in terms of time and experience. PMID- 23639516 TI - Mixed epithelial and stromal tumor of the kidney. AB - A 44-year-old woman who underwent radical nephrectomy due to a left renal mass presented to our clinic. Results of the histopathological examination showed a mixed epithelial and stromal tumor of the kidney, a rare benign lesion of the kidney. The epidemiology, histopathological features, imaging features, possible pathogeneses, and treatment alternatives are discussed, and the relevant literature is reviewed. The postoperative course was uneventful, and the patient was free of local recurrence or metastasis until the last follow-up (12 months). PMID- 23639517 TI - Postobstructive pulmonary edema (POPE) after surgery for obstructive sleep apnea. PMID- 23639518 TI - Painful intraosseous leiomyoma of the distal femur. PMID- 23639520 TI - Assessment of energetic costs of AhR activation by beta-naphthoflavone in rainbow trout (Oncorhynchus mykiss) hepatocytes using metabolic flux analysis. AB - Exposure to environmental contaminants such as activators of the aryl hydrocarbon receptor (AhR) leads to the induction of defense and detoxification mechanisms. While these mechanisms allow organisms to metabolize and excrete at least some of these environmental contaminants, it has been proposed that these mechanisms lead to significant energetic challenges. This study tests the hypothesis that activation of the AhR by the model agonist beta-naphthoflavone (betaNF) results in increased energetic costs in rainbow trout (Oncorhynchus mykiss) hepatocytes. To address this hypothesis, we employed traditional biochemical approaches to examine energy allocation and metabolism including the adenylate energy charge (AEC), protein synthesis rates, Na(+)/K(+)-ATPase activity, and enzyme activities. Moreover, we have used for the first time in a fish cell preparation, metabolic flux analysis (MFA) an in silico approach for the estimation of intracellular metabolic fluxes. Exposure of trout hepatocytes to 1MUM betaNF for 48h did not alter hepatocyte AEC, protein synthesis, or Na(+)/K(+)-ATPase activity but did lead to sparing of glycogen reserves and changes in activities of alanine aminotransferase and citrate synthase suggesting altered metabolism. Conversely, MFA did not identify altered metabolic fluxes, although we do show that the dynamic metabolism of isolated trout hepatocytes poses a significant challenge for this type of approach which should be considered in future studies. PMID- 23639519 TI - Crosslinked ionic polysaccharides for stimuli-sensitive drug delivery. AB - Polysaccharides are gaining increasing attention as components of stimuli responsive drug delivery systems, particularly since they can be obtained in a well characterized and reproducible way from the natural sources. Ionic polysaccharides can be readily crosslinked to render hydrogel networks sensitive to a variety of internal and external variables, and thus suitable for switching drug release on-off through diverse mechanisms. Hybrids, composites and grafted polymers can reinforce the responsiveness and widen the range of stimuli to which polysaccharide-based systems can respond. This review analyzes the state of the art of crosslinked ionic polysaccharides as components of delivery systems that can regulate drug release as a function of changes in pH, ion nature and concentration, electric and magnetic field intensity, light wavelength, temperature, redox potential, and certain molecules (enzymes, illness markers, and so on). Examples of specific applications are provided. The information compiled demonstrates that crosslinked networks of ionic polysaccharides are suitable building blocks for developing advanced externally activated and feed back modulated drug delivery systems. PMID- 23639521 TI - Sustained induction of cytochrome P4501A1 in human hepatoma cells by co-exposure to benzo[a]pyrene and 7H-dibenzo[c,g]carbazole underlies the synergistic effects on DNA adduct formation. AB - To gain a deeper insight into the potential interactions between individual aromatic hydrocarbons in a mixture, several benzo[a]pyrene (B[a]P) and 7H dibenzo[c,g]carbazole (DBC) binary mixtures were studied. The biological activity of the binary mixtures was investigated in the HepG2 and WB-F344 liver cell lines and the Chinese hamster V79 cell line that stably expresses the human cytochrome P4501A1 (hCYP1A1). In the V79 cells, binary mixtures, in contrast to individual carcinogens, caused a significant decrease in the levels of micronuclei, DNA adducts and gene mutations, but not in cell survival. Similarly, a lower frequency of micronuclei and levels of DNA adducts were found in rat liver WB F344 cells treated with a binary mixture, regardless of the exposure time. The observed antagonism between B[a]P and DBC may be due to an inhibition of Cyp1a1 expression because cells exposed to B[a]P:DBC showed a decrease in Cyp1a1 mRNA levels. In human liver HepG2 cells exposed to binary mixtures for 2h, a reduction in micronuclei frequency was also found. However, after a 24h treatment, synergism between B[a]P and DBC was determined based on DNA adduct formation. Accordingly, the up-regulation of CYP1A1 expression was detected in HepG2 cells exposed to B[a]P:DBC. Our results show significant differences in the response of human and rat cells to B[a]P:DBC mixtures and stress the need to use multiple experimental systems when evaluating the potential risk of environmental pollutants. Our data also indicate that an increased expression of CYP1A1 results in a synergistic effect of B[a]P and DBC in human cells. As humans are exposed to a plethora of noxious chemicals, our results have important implications for human carcinogenesis. PMID- 23639522 TI - Inhibitory effects of myricitrin on oxidative stress-induced endothelial damage and early atherosclerosis in ApoE-/- mice. AB - Atherosclerosis (AS) is a state of heightened oxidative stress characterized by lipid and protein oxidation in vascular walls. Oxidative stress-induced vascular endothelial cell (VEC) injury is a major factor in the pathogenesis of AS. Myricitrin, a natural flavonoid isolated from the root bark of Myrica cerifera, was recently found to have a strong antioxidative effect. However, its use for treating cardiovascular diseases, especially AS is still unreported. Consequently, we evaluated the cytoprotective effect of myricitrin on AS by assessing oxidative stress-induced VEC damage. The in vivo study using an ApoE-/ mouse model of AS demonstrated that myricitrin treatment protects against VEC damage and inhibits early AS plaque formation. This effect is associated with the antioxidative effect of myricitrin, as observed in a hydrogen peroxide (H2O2) induced rat model of artery endothelial injury and primary cultured human VECs. Myricitrin treatment also prevents and attenuates H2O2-induced endothelial injury. Further investigation of the cytoprotective effects of myricitrin demonstrated that myricitrin exerts its function by scavenging for reactive oxygen species, as well as reducing lipid peroxidation, blocking NO release, and maintaining mitochondrial transmembrane potential. Myricitrin treatment also significantly decreased H2O2-induced apoptosis in VECs, which was associated with significant inhibition of p53 gene expression, activation of caspase-3 and the MAPK signaling pathway, and alteration of the patterns of pro-apoptotic and anti apoptotic gene expression. The resulting significantly increased bcl-2/bax ratio indicates that myricitrin may prevent the apoptosis induced by oxidative stress injury. PMID- 23639524 TI - Screening hospitalized injured older adults for cognitive impairment and pre injury functional impairment. AB - Cognitive and functional impairments are leading predictors of poor outcomes among older adults, yet few hospitals collect these variables for injured older adults (IOAs). In this prospective descriptive study, we sought to determine the feasibility of screening IOAs for cognitive and pre-injury functional impairment; and to examine the prevalence of impairment at two acute care hospitals, using the Mini-Cog or Informant Questionnaire on Cognitive Decline in the Elderly (IQCDE), and Vulnerable Elder Survey (VES-13). Eighty patients were screened. Demographics included: mean age 78.7; female gender 83%; falls 89%. Cognitive impairment was present in 36 (44%) patients, and pre-injury functional impairment was present in 62 (78%) patients. Screening respondents included: patients: 53 (66%); adult children: 18 (23%); spouses: 5 (6%), and other 4 (5%). A combination of brief screening instruments for use with IOAs or surrogates is useful for capturing important variables for risk adjustment and care management. PMID- 23639523 TI - Malaise, melancholia and madness: the evolutionary legacy of an inflammatory bias. AB - Evolutionary imperatives bred a vigorous and highly orchestrated behavioral and immune response to the microbial world that served to promote species survival and propagation. The resultant legacy is an inflammatory bias which goes largely unchecked in the modern world and is provoked not only by pathogens but also now by people. In this commentary, the authors' contributions to the special issue on Inflammation and Mental Health are described, beginning with the origins of the inflammatory bias, its roots in genetic predispositions to behavioral adaptations and ultimately maladaptations, and its consequences on the developing brain. In addition, the mechanisms by which the immune system engages behavior are described including a central role for the inflammasome which may serve to link psychological stress with inflammatory and behavioral responses. Neurotransmitter systems that mediate effects of the immune system on behavior are also described along with interactions of the inflammatory bias with depression and their convergent impact on the response to stress and medical illness. Finally, translational implications are discussed including data from a clinical trial using a cytokine antagonist in depressed patients, which suggests an interaction of the inflammatory bias with other evolutionary legacies including those related to food consumption and their modern consequences of obesity and the metabolic syndrome. Taken together, the articles offer a sampling of the rich literature that has evolved regarding the role of the immune system in behavioral disorders. The grounding of this relationship in our evolutionary past may serve to inform future research both theoretically and therapeutically. PMID- 23639525 TI - Influence of a high-glucose diet on the sensitivity of Caenorhabditis elegans towards Escherichia coli and Staphylococcus aureus strains. AB - It was recently observed that a glucose-enriched diet activates the insulin-like pathway in Caenorhabditis elegans, resulting in an inhibition of the FOXO transcription factor DAF-16. Because this signalling pathway is highly conserved from invertebrates to mammals and DAF-16 is a key player in innate immunity, we wondered whether a high-glucose diet, resembling the hyperglycaemic conditions in diabetic patients, would affect the susceptibility of C. elegans to bacterial pathogens isolated from different clinical situations (urinary tract or diabetic foot infections). We confirmed previous reports showing that such a diet decreases the lifespan of C. elegans fed with an avirulent Escherichia coli strain. However, glucose-fed nematodes appeared to be more resistant to most clinical isolates tested, showing that this invertebrate model does not mimic infections encountered in human diabetes, where patients show increased susceptibility to bacterial infections. This study also suggests that modulation of innate immunity in C. elegans, upon activation of the IGF1/insulin-like pathway by glucose, is not exclusively mediated by DAF-16, but also involves an additional factor that requires DAF-16 activity. PMID- 23639526 TI - Laccase-mediated oxidation of small organics: bifunctional roles for versatile applications. AB - Laccases have been widely used in several biotechnological areas, including organic synthesis, bioremediation, and pulp/textile bleaching. In most applications, the enzymatic actions start with single-electron oxidation of small organics followed by formation of the corresponding radicals. These radicals are subsequently involved in either oxidative coupling (i.e., bond formation) or bond cleavage of target organics. These bifunctional actions--catabolic versus anabolic--are readily identifiable in in vivo metabolic processes involving laccases. Here, we characterize the bifunctionality of laccase-mediated oxidation of small organics and present the view that knowledge of the biological functions of these metabolic processes in vivo can illuminate potential biotechnological applications of this bifunctionality. PMID- 23639527 TI - The effect of primary particle size on biodistribution of inhaled gold nano agglomerates. AB - Airborne engineered nanoparticles undergo agglomeration, and careful distinction must be made between primary and agglomerate size of particles, when assessing their health effects. This study compares the effects on rats undergoing 15-day inhalation exposure to airborne agglomerates of gold nanoparticles (AuNPs) of similar size distribution and number concentration (1 * 10(6) particles/cm(3)), but two different primary diameters of 7 nm or 20 nm. Inhalation of agglomerates containing 7-nm AuNPs resulted in highest deposition by mass concentration in the lungs, followed by brain regions including the olfactory bulb, hippocampus, striatum, frontal cortex, entorhinal cortex, septum, cerebellum; aorta, esophagus, and kidney. Eight organs/tissues especially the brain retained greater mass concentration of Au after inhalation exposure to agglomerates of 7-nm than 20-nm AuNPs. Macrophage mediated escalation followed by fecal excretion is the major pathway of clearing inhaled AuNPs in the lungs. Microarray analyses of the hippocampus showed mostly downregulated genes, related to the cytoskeleton and neurite outgrowth. Together, results in this study indicate disintegration of nanosized agglomerates after inhalation and show impact of primary size of particles on subsequent biodistribution. PMID- 23639528 TI - The application of pH-sensitive polymer-lipids to antigen delivery for cancer immunotherapy. AB - For production of pH-sensitive liposomes, we developed pH-sensitive polymer lipids that consists of pH-sensitive fusogenic polymer moieties such as 3-methyl glutarylated poly(glycidol) and 2-carboxycyclohexane-1-carboxylated poly(glycidol), connected to a phosphatidylethanolamine head group. Incorporation of these pH-sensitive polymer-lipids into egg yolk phosphatidylcholine liposomes produced highly pH-sensitive liposomes that were stable at neutral pH but which destabilized markedly in response to very small pH change in weakly acidic pH region. These liposomes delivered their contents (pyranine) into cytosol of dendritic cell-derived DC2.4 cells. When these polymer-lipid-incorporated liposomes loaded with antigenic protein ovalbumin (OVA) were administered subcutaneously to mice, the antigen-specific cellular immunity was induced efficiently in the mice. Furthermore, immunization of mice with these OVA-loaded pH-sensitive polymer-lipid-incorporated liposomes induced strong OVA-specific immunity, which achieved complete rejection of OVA-expressing E.G7-OVA cells and marked regression of E.G7-OVA tumors. PMID- 23639529 TI - Linear-dendritic drug conjugates forming long-circulating nanorods for cancer drug delivery. AB - Elongated micelles have many desirable characteristics for cancer-drug delivery, but they are difficult to obtain since amphiphilic polymers form such nanostructures only within narrow composition ranges depending on their own structures. Herein, we demonstrated a facile fabrication of different nanostructures via drug content-controlled self-assembly of amphiphilic linear dendritic drug conjugates - using the number of the conjugated hydrophobic drug molecule camptothecin (CPT) to tailor the hydrophobicity of amphiphilic PEG-block dendritic polylysine-CPT (PEG-xCPT) conjugates and thereby control their self assembled nanostructures - nanospheres or nanorods of different diameters and lengths. The shape and size of the nanostructures were found to strongly affect their in vitro and in vivo properties, particularly the blood clearance kinetics, biodistribution and tumor targeting. The nanorods with medium lengths (<500 nm) had a much longer blood circulation and faster cellular uptake than the nanospheres or long nanorods. Thus, polymeric nanorods with proper lengths may be ideal nanocarriers capable of uniting the opposite requirements in cancer-drug delivery. PMID- 23639530 TI - Glioma therapy using tumor homing and penetrating peptide-functionalized PEG-PLA nanoparticles loaded with paclitaxel. AB - By taking advantage of the excessively upregulated expression of neuropilin (NRP) on the surface of both glioma cells and endothelial cells of angiogenic blood vessels, the ligand of NRP with high affinity - tLyp-1 peptide, which also contains a CendR motif ((R/K)XX(R/K)), was functionalized to the surface of PEG PLA nanoparticles (tLyp-1-NP) to mediate its tumor homing, vascular extravasation and deep penetration into the glioma parenchyma. The tLyp-1-NP was prepared via a maleimide-thiol coupling reaction with uniformly spherical shape under TEM and particle size of 111.30 +/- 15.64 nm. tLyp-1-NP exhibited enhanced cellular uptake in both human umbilical vein endothelial cells and Rat C6 glioma cells, increased cytotoxicity of the loaded PTX, and improved penetration and growth inhibition in avascular C6 glioma spheroids. Selective accumulation and deep penetration of tLyp-1-NP at the glioma site was confirmed by in vivo imaging and glioma distribution analysis. The longest survival was achieved by those mice bearing intracranial C6 glioma treated with PTX-loaded tLyp-1-NP. The findings here strongly indicate that tLyp-1 peptide-functionalized nanoparticulate DDS could significantly improve the efficacy of paclitaxel glioma therapy. PMID- 23639531 TI - The combined use of cell sheet fragments of periodontal ligament stem cells and platelet-rich fibrin granules for avulsed tooth reimplantation. AB - The aim of this study was to construct a cell transplant method consisting of cell sheet fragments of periodontal ligament stem cells (PDLSCs) and platelet rich fibrin (PRF) granules to enhance periodontal healing in avulsed tooth reimplantation. To test this concept in vitro, human PDLSCs were isolated and characterized by colony forming unit assay, cell surface marker characterizations, and their osteogenic/adipogenic differentiation potential. The biological effects of autologous PRF as a growth factor-enriched endogenous scaffold on human PDLSCs were then investigated and quantified for statistical analyses, including cell viability and proliferation, alkaline phosphatase (ALP) activity, and the gene expression of bone sialoprotein (BSP), osteocalcin (OCN), collagen I (Col-I), and cementum protein 23 (CP23). It was found that the PRF induced a significant and continuous stimulation of proliferation in human PDLSCs throughout the 7-day incubation period. Furthermore, the PRF suppressed the osteoblastic differentiation of PDLSCs by decreasing ALP activity and the gene expression of BSP and OCN while up-regulating the mRNA expression levels of Col-I and CP23 during the testing period. To assess the potential application of the PDLSCs/PRF construct in tooth reimplantation, 36 incisors were extracted from 6 dogs. The incisors then underwent 2 h of dry storage and were randomly divided into four groups receiving different strategies of reimplantation, where the avulsed teeth were reimplanted with the use of the autologous PDLSCs/PRF construct (cell sheet fragments in combination with PRF granules), with the use of autologous PDLSCs or PRF alone, or without adjuvant use of PRF or PDLSCs. Eight weeks post-reimplantation, the PDLSCs/PRF group achieved a more effective periodontal healing, characterized by the regeneration of PDL-like tissues and a reduction of ankylosis and inflammation, compared with the other testing groups. These overall results suggest that the PDLSCs/PRF construct may be a useful tool for alveolar surgery that has the potential to improve the clinical outcomes in future avulsed tooth reimplantations. PMID- 23639532 TI - Tumor targeting and MR imaging with lipophilic cyanine-mediated near-infrared responsive porous Gd silicate nanoparticles. AB - We synthesize a NIR MHI-148 dye, a lipophilic heptamethine cyanine, with capability in tumor-targeting property to accumulate in the mitochondria of tumor. In the context of MHI-148 dye, we demonstrate effective tumor targeting and NIR fluorescence in vitro and in vivo for MHI-148 as compared to ICG. A series of porous Gd silicates related nanoparticles, i.e. Gd silicate, Gd silicate@mSiO(2) (mSiO(2): mesoporous silica shell), and Gd(3+)-chelated Gd silicate@mSiO(2) (Gd(3+)-DOTA chelated on the mSiO(2)) are fabricated to demonstrate their magnetic resonance (MR) contrast imaging effects. Those Gd silicates related nanoparticles exhibit dual MR effect, expressing T(1) brightened and T(2)-darkened effects, in lower magnetic field. In high magnetic field, an abnormal enhanced transverse relaxivity (r(2)) appears, showing an effective T(2)-lowering effect, possibly due to concentrated Gd amount and porous architecture. The r(2) value increases 4-5 times as the field strength increased from 3T to 7T. The Gd(3+)-chelated Gd silicate@mSiO(2) has given large r(2) (T(2) lowering effect) up to 343.8 s(-1) mM(-1), which is even larger than the reported magnetic Fe(3)O(4) nanoparticles measured at the same field. Using a 9.4T animal micro MRI system we have seen effectively darken in signal for those porous Gd silicates related NPs, while no such phenomenon appears in commercial Gd-DOTA agent. The MHI-148 is then conjugated on the porous Gd silicate@mSiO(2) nanoparticles for a new paradigm with three functionalities for in vivo tumor targeting, near-infrared fluorescent and MR imaging by means of only using MHI 148 dye. PMID- 23639535 TI - Modular, efficient synthesis of asymmetrically substituted piperazine scaffolds as potent calcium channel blockers. AB - A novel approach to the synthesis of substituted piperazines and their investigation as N-type calcium channel blockers is presented. A common scaffold exhibiting high activity as N-type blockers is N-substituted piperazine. Using recently developed titanium and zirconium catalysts, we describe the efficient and modular synthesis of 2,5-asymmetrically disubstituted piperazines from simple amines and alkynes. The method requires only three isolation/purification protocols and no protection/deprotection steps for the diastereoselective synthesis of 2,5-dialkylated piperazines in moderate to high yield. Screening of the synthesized piperazines for N-type channel blocking activity and selectivity shows the highest activity for a compound with a benzhydryl group on the nitrogen (position 1) and an unprotected alcohol-functionalized side chain. PMID- 23639533 TI - Engineered cell-laden human protein-based elastomer. AB - Elastic tissue equivalence is a vital requirement of synthetic materials proposed for many resilient, soft tissue engineering applications. Here we present a bioelastomer made from tropoelastin, the human protein that naturally facilitates elasticity and cell interactions in all elastic tissues. We combined this protein's innate versatility with fast non-toxic fabrication techniques to make highly extensible, cell compatible hydrogels. These hydrogels can be produced in less than a minute through photocrosslinking of methacrylated tropoelastin (MeTro) in an aqueous solution. The fabricated MeTro gels exhibited high extensibility (up to 400%) and superior mechanical properties that outperformed other photocrosslinkable hydrogels. MeTro gels were used to encapsulate cells within a flexible 3D environment and to manufacture highly elastic 2D films for cell attachment, growth, and proliferation. In addition, the physical properties of this fabricated bioelastomer such as elasticity, stiffness, and pore characteristics were tuned through manipulation of the methacrylation degree and protein concentration. This photocrosslinkable, functional tissue mimetic gel benefits from the innate biological properties of a human elastic protein and opens new opportunities in tissue engineering. PMID- 23639536 TI - Fluorogenic sialic acid glycosides for quantification of sialidase activity upon unnatural substrates. AB - Herein we report the synthesis of N-acetyl neuraminic acid derivatives as 4 methylumbelliferyl glycosides and their use in fluorometrically quantifying human and bacterial sialidase activity and substrate specificities. We found that sialidases in the human promyelocytic leukemic cell line HL60 were able to cleave sialic acid substrates with fluorinated C-5 modifications, in some cases to a greater degree than the natural N-acetyl functionality. Human sialidases isoforms were also able to cleave unnatural substrates with bulky and hydrophobic C-5 modifications. In contrast, we found that a bacterial sialidase isolated from Clostridium perfringens to be less tolerant of sialic acid derivatization at this position, with virtually no cleavage of these glycosides observed. From our results, we conclude that human sialidase activity is a significant factor in sialic acid metabolic glycoengineering efforts utilizing unnatural sialic acid derivatives. Our fluorogenic probes have enabled further understanding of the activities and substrate specificities of human sialidases in a cellular context. PMID- 23639537 TI - Design, synthesis and biological evaluation of indeno[1,2-d]thiazole derivatives as potent histone deacetylase inhibitors. AB - Novel indeno[1,2-d]thiazole hydroxamic acids were designed, synthesized, and evaluated for histone deacetylases (HDACs) inhibition and antiproliferative activities on tumor cell lines. Most of the tested compounds exhibited HDAC inhibition and antiproliferative activity against both MCF7 and HCT116 cells with GI50 values in the sub-micromolar range. Among them, compound 6o showed good inhibitory activity against pan-HDAC with IC50 value of 0.14 MUM and significant growth inhibition on MCF7 and HCT116 cells with GI50 values of 0.869 and 0.535 MUM, respectively. PMID- 23639538 TI - A dihydrochalcone and several homoisoflavonoids from Polygonatum odoratum are activators of adenosine monophosphate-activated protein kinase. AB - Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a major cellular energy sensor and master regulator of metabolic homeostasis; thus, AMPK plays a central role in studies on diabetes and related metabolic diseases. From the rhizomes of Polygonatum odoratum (Mill.) Druce, six homoisoflavonoids (1-6) and one dihydrochalcone (7) were isolated, and the structures of polygonatones A-D (4 7) were elucidated by various spectroscopic analyses. Compounds 1-7 were evaluated for their effect on AMPK activation. The amount of active phosphorylated AMPK and acetyl-CoA carboxylase in rat liver epithelial IAR-20 cells increased when the cells were incubated with the aforementioned compounds. Specifically, (3R)-5,7-dihydroxyl-6-methyl-8-methoxyl-3-(4'-hydroxylbenzyl) chroman-4-one (1), (3R)-5,7-dihydroxyl-6,8-dimethyl-3-(4'-hydroxylbenzyl)-chroman 4-one (2), (3R)-5,7-dihydroxyl-6-methyl-3-(4'-hydroxylbenzyl)-chroman-4-one (3), and polygonatone D (7) exhibited significant activation effects. PMID- 23639539 TI - Synthesis, spectral and antimicrobial evaluation of some novel 1-methyl-3-alkyl 2,6-diphenylpiperidin-4-one oxime carbonates. AB - Synthesis of some novel biologically active piperidin-4-one oxime carbonates from 1-methyl-3alkyl-2,6-diphenylpiperidin-4-one oximes and substituted chloroformates was carried out in the presence of potassium carbonate as base and tetrabutylammonium bromide (TBAB) as catalyst. The newly synthesized compounds were characterized by IR, (1)H, (13)C NMR and LC-mass spectra. Based on the (1)H NMR analysis, all the compounds were found to adopt normal chair conformation with equatorial orientation of all the substituents. For all the synthesized compounds (5a-5l) antimicrobial activity has been tested against bacterial and fungal strains using Streptomycin and Amphotericin B as standards. PMID- 23639541 TI - Synthesis and in vitro evaluation of a PDT active BODIPY-NLS conjugate. AB - Two new photosensitizers based on the BODIPY scaffold have been synthesized, of which one bears an NLS peptide, which is linked to the BODIPY's core using the copper catalysed azide-alkyne click reaction. The phototoxicities of these BODIPY based photosensitizers have been determined, as well as their dark toxicities. Although the conjugation of a single NLS peptide to the BODIPY did not lead to any observable nuclear localization, the photosensitizer did exhibit a superior photoxicity. Cellular co-localization experiments revealed a localization of both dyes in the lysosomes, as well as a partial localization within the ER (for the peptide-bearing BODIPY). PMID- 23639540 TI - Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5 a]pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe. AB - A structure-activity relationship of the 3- and 6-positions of the pyrazolo[1,5 a]pyrimidine scaffold of the known BMP inhibitors dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3. The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency. From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows >300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation. PMID- 23639543 TI - Evaluation of 2'-alpha-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase. AB - Ribonucleoside phosphonate analogues containing 2'-alpha-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The diphosphophosphonate (triphosphate equivalent) adenine and cytidine analogues displayed potent inhibition of the HCV polymerase in the range of 1.9-2.1 MUM, but only modest cell-based activity in the HCV replicon. Pro-drugs of the parent nucleoside phosphonates improved the cell-based activity. PMID- 23639542 TI - NO-donating tacrine derivatives as potential butyrylcholinesterase inhibitors with vasorelaxation activity. AB - To search for potent anti-Alzheimer's disease (AD) agents with multifunctional effects, 12 NO-donating tacrine-flurbiprofen hybrid compounds (2a-l) were synthesized and biologically evaluated. It was found that all the new target compounds showed selective butyrylcholinesterase (BuChE) inhibitory activity in vitro comparable or higher than tacrine and the tacrine-flurbiprofen hybrid compounds 1a-c, and released moderate amount of NO in vitro. The kinetic study suggests that one of the most active and highest BuChE selective compounds 2d may not only compete with the substrate for the same catalytic active site (CAS) but also interact with a second binding site. Furthermore, 2d and 2l exhibited significant vascular relaxation effect, which is beneficial for the treatment of AD. All the results suggest that 2d and 2l might be promising lead compounds for further research. PMID- 23639545 TI - Synthesis and ionophoric activities of functionalized bis(choloyl) conjugates with a rigid core. AB - Three bis(choloyl) conjugates bearing a rigid p-phenylenediamine/p bis(aminomethyl)benzene linker and amino/acetamido groups were synthesized, and fully characterized on the basis of (1)H NMR, ESI-MS and HRMS. Their ionophoric activities were investigated by means of pH discharge assay. The results indicate that these conjugates exhibit potent ionophoric activities across egg-yolk l alpha-phosphatidylcholine (EYPC)-based liposomal membranes, via a cation/proton antiport mechanism. They show moderate ion selectivity among alkali metal ions. Of the three conjugates, the ones having amino groups transport alkali metal ions in the order of Na(+)>Li(+)>K(+)~Rb(+)~Cs(+), whereas the one having acetamido groups functions in the order of Li(+)>Na(+)>K(+)~Rb(+)~Cs(+). PMID- 23639544 TI - Synthesis of proline analogues as potent and selective cathepsin S inhibitors. AB - Cathepsin S is a potential target of autoimmune disease. A series of proline derived compounds were synthesized and evaluated as cathepsin S inhibitors. We discovered potent cathepsin S inhibitors through structure-activity relationship studies of proline analogues. In particular, compound 19-(S) showed promising in vitro/vivo pharmacological activities and properties as a selective cathepsin S inhibitor. PMID- 23639546 TI - Cationic porphyrin-quinoxaline conjugate as a photochemically triggered novel cytotoxic agent. AB - A novel cationic porphyrin-quinoxaline conjugate 8 was prepared in good yield by the coupling of activated quinoxaline carboxylic acid 5 with an appropriate aminoporphyrin. The UV-vis spectra of conjugate 8 with the addition of ctDNA shows substantial hypochromicity (39%) and a red shift (12 nm) in the Soret band indicating intercalation and self stacking along the surface. The binding constant of conjugate 8 with ctDNA was determined to be 1.26*10(6) M(-1). The porphyrin-quinoxaline conjugate 8 displayed enhanced photocytotoxicity (IC50=0.06 MUM) when compared to TMPyP against A549 cancer cells. PMID- 23639547 TI - Rehabilitation outcomes of stroke patients with and without diabetes. AB - OBJECTIVE: To investigate the relation of diabetes comorbidity and the rehabilitation outcomes of patients with stroke. DESIGN: Secondary data analysis. SETTING: Inpatient rehabilitation facilities. PARTICIPANTS: Patients with stroke (N=35,243) who received inpatient rehabilitation in 2004 through 2008. INTERVENTIONS: None. MAIN OUTCOME MEASURES: FIM, length of stay, and discharge destination. RESULTS: Mean age +/- SD of the sample was 71.0 +/- 13.2 years. The percent of the sample of Medicare beneficiaries was 53.8%, whereas 46.2% had other sources of funding. Of the patients in the sample, 34.5% had a comorbidity of diabetes, with 17.2% classified as tier-eligible and 82.8% as nontier eligible. Findings included that patients in this sample with diabetes were admitted for rehabilitation services at a younger age than those without diabetes and support previous studies in which tier-eligible diabetes comorbidities moderated by patient age were found to be significant predictors of stroke rehabilitation outcomes. Furthermore, similar findings remained regardless of payer source. CONCLUSIONS: This study provides additional evidence that diabetes as a comorbidity is significantly related to stroke rehabilitation outcome, but the relation is moderated by patient age. PMID- 23639548 TI - The role of added feed enzymes in promoting gut health in swine and poultry. AB - The value of added feed enzymes (FE) in promoting growth and efficiency of nutrient utilisation is well recognised in single-stomached animal production. However, the effects of FE on the microbiome of the gastrointestinal tract (GIT) are largely unrecognised. A critical role in host nutrition, health, performance and quality of the products produced is played by the intestinal microbiota. FE can make an impact on GIT microbial ecology by reducing undigested substrates and anti-nutritive factors and producing oligosaccharides in situ from dietary NSP with potential prebiotic effects. Investigations with molecular microbiology techniques have demonstrated FE-mediated responses on energy utilisation in broiler chickens that were associated with certain clusters of GIT bacteria. Furthermore, investigations using specific enteric pathogen challenge models have demonstrated the efficacy of FE in modulating gut health. Because FE probably change the substrate characteristics along the GIT, subsequent microbiota responses will vary according to the populations present at the time of administration and their reaction to such changes. Therefore, the microbiota responses to FE administration, rather than being absolute, are a continuum or a population of responses. However, recognition that FE can make an impact on the gut microbiota and thus gut health will probably stimulate development of FE capable of modulating gut microbiota to the benefit of host health under specific production conditions. The present review brings to light opportunities and challenges for the role of major FE (carbohydrases and phytase) on the gut health of poultry and swine species with a specific focus on the impact on GIT microbiota. PMID- 23639549 TI - From genetics of inflammatory bowel disease towards mechanistic insights. AB - Advancements in human genetics now poise the field to illuminate the pathophysiology of complex genetic disease. In particular, genome-wide association studies (GWAS) have generated insights into the mechanisms driving inflammatory bowel disease (IBD) and implicated genes shared by multiple autoimmune and autoinflammatory diseases. Thus, emerging evidence suggests a central role for the mucosal immune system in mediating immune homeostasis and highlights the complexity of genetic and environmental interactions that collectively modulate the risk of disease. Nevertheless, the challenge remains to determine how genetic variation can precipitate and sustain the inappropriate inflammatory response to commensals that is observed in IBD. Here, we highlight recent advancements in immunogenetics and provide a forward-looking view of the innovations that will deliver mechanistic insights from human genetics. PMID- 23639551 TI - MYCN/LIN28B/Let-7/HMGA2 pathway implicated by meta-analysis of GWAS in suppression of post-natal proliferation thereby potentially contributing to aging. AB - Mammalian organ and body growth slows and finally terminates because of a progressive suppression of cell proliferation, however little is known about the genetic regulatory mechanisms responsible. A meta-analysis of genome-wide association studies using growth and development-related traits revealed that two genes, HMGA2 and LIN28B, had multiple associations. Altered HMGA2 expression has been shown to result in both overgrowth and pygmy phenotypes in mice and overgrowth in humans. These genes are members of the MYCN/LIN28B/Let-7/HMGA2 pathway and homologs of LIN28B and let-7 are known to regulate developmental timing in Caenorhabditis elegans. Strikingly, expression levels of let-7 and Hmga2 in murine stem cells continue to increase and decrease, respectively, after growth terminates, suggesting that this pathway may contribute to regulating the pace of both development and age-related degenerative phenotypes. PMID- 23639550 TI - Relationship between chronic obstructive pulmonary disease and subclinical coronary artery disease in long-term smokers. AB - AIMS: Cardiovascular conditions are reported to be the most frequent cause of death in patients with chronic obstructive pulmonary disease (COPD). However, it remains unsettled whether severity of COPD per se is associated with coronary artery disease (CAD) independent of traditional cardiovascular risk factors. The aim of this study was to examine the relationship between the presence and severity of COPD and the amount of coronary artery calcium deposit, an indicator of CAD and cardiac risk, in a large population of current and former long-term smokers. METHODS AND RESULTS: In this cross-sectional study, long-term smokers without clinically manifested CAD were recruited from the Danish Lung Cancer Screening Trial and classified according to lung function by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Coronary artery calcium deposit as a measure of subclinical CAD and cardiac risk was evaluated with multi detector computed tomography and the Agatston coronary artery calcium score (CACS). Participants were categorized into five CACS risk classification groups according to the CACS. The population (n = 1535) consisted of 41% participants without COPD, 28% with mild, and 31% with moderate-to-severe COPD (n = 46 with severe COPD). In addition to age, male gender, hypertension, hypercholesterolaemia, and continued smoking, COPD according to GOLD classification were independent predictors of a higher CACS risk classification group in multivariable analysis [odds ratio (OR): 1.28 (1.01-1.63) and OR: 1.32 (1.05-1.67), for mild and moderate-to-severe COPD, respectively, compared with no COPD]. CONCLUSION: COPD in long-term smokers is independently correlated with the CACS, while COPD severity per se does not show a dose-response relationship. PMID- 23639552 TI - Deposition of the lectin pathway of complement in renal biopsies of lupus nephritis patients. AB - BACKGROUND/AIMS: Lupus nephritis (LN) is one of the most serious manifestations of SLE occurring in 66-90% of these patients. The complement system is part of the innate immunity and modulator of inflammation and the adaptative immune response. Mannan-binding lectin (MBL) and Ficolin-2 (FCN-2) are important members of the lectin pathway of complement activation. Despite the significant participation of complement in the pathogenesis of the LN, there are few reports demonstrating "in situ" deposition of complement components in renal biopsy specimens in this disorder. The present study investigated the deposition of complement components in kidney specimens of LN patients. METHODS: Renal biopsies of 11 patients with SLE and LN were evaluated for immunofluorescence staining for IgG, IgA, IgM, C3, and C1q. Additionally, MBL, FCN-2 and C5b-9 were researched using monoclonal antibodies. RESULTS: All the biopsies were positive for IgG, C3, and C1q, eight were positive IgM and five had IgA deposition in glomerular tissue. The terminal complex of complement C5b9 was positive in all cases, MBL in nine (82%) cases; seven (63.6%) of them presenting concomitantly FCN-2 deposition. Patients presenting MBL deposition had higher mean of urinary proteins (9.0 g/day) than patients with negative MBL deposition (mean of 2.3g/day). CONCLUSIONS: In this study, we demonstrated in situ the participation of complement in the renal injury, including MBL and FCN-2 of the lectin pathway; also the strong role of C5b-9 in the pathogenesis of LN. PMID- 23639553 TI - Polymorphisms in metalloproteinase-9 are associated with the risk for asthma in Mexican pediatric patients. AB - Asthma is characterized by chronic airway inflammation, which induces airway remodelling of the extracellular matrix over time. Matrix metalloproteinases (MMPs) are involved in this process, and single-nucleotide polymorphisms (SNPs) in MMP genes may influence their mRNA expression levels or abilities to bind substrates and inhibitors, thereby contributing to asthma predisposition and severity. MMP-9 is highly expressed in airways and many studies support its involvement in asthma pathogenesis; however the contribution of MMP-9 SNPs is controversial. To investigate whether MMP-9 SNPs are associated with childhood onset asthma in Mexican patients we conducted a case-control study including 403 children with clinical asthma diagnoses and 426 healthy controls from Mexico. The cases and controls were matched by ethnicity and gender. We found that the SNPs rs2274755, rs17577, and rs3918249 were associated with asthma risk. The most significant associations were with rs2274755 (OR=2.10, 95% CI 1.31-3.39, P=0.001) and rs17577 (OR=2.07, 95% CI 1.29-3.30, P=0.001); which were in strong linkage disequilibrium. Both SNPs were also associated with atopic asthma (OR=2.38, 95% CI 1.44-3 . 96, P=0.0005). The SNP rs3918249 exhibited a female gender-dependent association with asthma (OR=1.66, 95% CI 1.14-2.43, P=0.007). Our results suggest that MMP-9 polymorphisms could play a role in the susceptibility to childhood onset asthma. PMID- 23639555 TI - Regarding "rate and prognosis of patients under conscious sedation requiring emergent intubation during neuroendovascular procedures". PMID- 23639554 TI - Activation of human natural killer cells by the novel innate immune modulator recombinant Eimeria antigen. AB - The safe and effective activation of the innate and adaptive immune systems are crucial in the implementation of immunotherapeutic modalities for the prevention and treatment of human diseases. Eimeria antigen (EA) and its recombinantly expressed analog (rEA) are extremely effective activators of innate immunity in mice. The effects of rEA in the mouse are primarily mediated through the TLR11/12 MyD88 signaling system. Human cells lack functional TLR11 and TLR12, suggesting that rEA would not be effective in providing beneficial immune activation in humans. In the current report we provide definitive evidence that the treatment of human peripheral blood mononuclear cell (PBMC) cultures with rEA significantly up regulates CD69, CD107, NKG2D levels on NK cells. Furthermore, rEA stimulates human NK cell effector functions including increasing intracellular levels of IFNgamma and Granzyme B. These responses are positively correlated with an improved capacity of rEA stimulated human PBMCs to kill NK cell-sensitive human K562 tumor cells. Importantly, rEA-triggered innate immune responses was not associated with increased pro-inflammatory cytokines and chemokines production. These data confirm a previously unidentified role for rEA in human immune cell activation, and suggests the utilization of rEA in immunotherapies against a variety of infectious diseases and cancers. PMID- 23639556 TI - Geniculocalcarine tract disintegration after ischemic stroke: a diffusion tensor imaging study. AB - BACKGROUND AND PURPOSE: Our aim was to investigate the disintegration of the geniculocalcarine tract by using DTI-derived parameters in cases of unilateral occipital or temporal-occipital ischemic stroke with geniculocalcarine tract involvement and to determine whether geniculocalcarine tract fibers affected by infarction and unaffected ipsilateral geniculocalcarine tract fibers have different disintegration processes. MATERIALS AND METHODS: Seventy-one patients underwent routine MR imaging and DTI of the brain. Fractional anisotropy and mean diffusivity of the geniculocalcarine tract fibers affected by infarction, ipsilateral unaffected GCT fibers, and the contralateral geniculocalcarine tract were measured and compared at 5 different time points (from <1 week to >1 year) poststroke. RESULTS: The fractional anisotropy of geniculocalcarine tract fibers affected by infarction (0.27 +/- 0.06) was lower than that of contralateral GCT fibers (0.49 +/- 0.03). The fractional anisotropy of geniculocalcarine tract fibers affected by infarction was not different in the first 3 weeks (P = .306). The mean diffusivity of geniculocalcarine tract fibers affected by infarction (0.53 +/- 0.14) was lower than that of the contralateral GCT fibers (0.79 +/- 0.07) in the first week but higher after the second week (0.95 +/- 0.20 to 0.79 +/- 0.06). The mean diffusivity gradually increased until it was equal to the mean diffusivity of CSF after the eighth week (2.43 +/- 0.26), at which time both the fractional anisotropy and mean diffusivity values stabilized. The fractional anisotropy (0.50 +/- 0.04) and mean diffusivity (0.77 +/- 0.06) of the ipsilateral unaffected GCT fibers were similar to those of the contralateral GCT fibers (0.50 +/- 0.03 and 0.79 +/- 0.07) during the first 3 weeks. The fractional anisotropy then gradually decreased (from 0.42 +/- 0.03 to 0.27 +/- 0.05), while the mean diffusivity increased (from 0.95 +/- 0.09 to 1.35 +/- 0.11), though to a lesser degree than in the corresponding geniculocalcarine tract fibers affected by infarction. CONCLUSIONS: The geniculocalcarine tract fibers affected by infarction and the ipsilateral unaffected GCT fibers showed different disintegration processes. The progressive disintegration of geniculocalcarine tract fibers affected by infarction was stable until the eighth week poststroke. The ipsilateral unaffected GCT fibers began to disintegrate at the fourth week, but to a lesser degree than the geniculocalcarine tract fibers affected by infarction. PMID- 23639557 TI - Negative predictive value of surveillance PET/CT in head and neck squamous cell cancer. AB - BACKGROUND AND PURPOSE: Optimizing the utilization of surveillance PET/CT in treated HNSCC is an area of ongoing research. Our aim was to determine the negative predictive value of PET/CT in patients with treated head and neck squamous cell cancer and to determine whether negative PET/CT reduces the need for further imaging surveillance. MATERIALS AND METHODS: We evaluated patients with treated HNSCC who underwent posttreatment surveillance PET/CT. During routine clinical readouts, scans were categorized as having negative, probably negative, probably malignant, or malignant findings. We followed patients clinically and radiographically for at least 12 months from their last PET/CT (mean, 26 months; median, 28 months; range, 12-89 months) to determine recurrence rates. All suspected recurrences underwent biopsy for confirmation. RESULTS: Five hundred twelve patients (1553 scans) were included in the study. Two hundred fourteen patients had at least 1 PET/CT with negative findings. Of the 214 patients with a scan with negative findings, 19 (9%) eventually experienced recurrence, resulting in a NPV of 91%. In addition, a subgroup of 114 patients with 2 consecutive PET/CT examinations with negative findings within a 6-month period was identified. Only 2 recurrences were found in this group, giving a NPV of 98%. CONCLUSIONS: In patients treated for HNSCC, a single PET/CT with negative findings carries a NPV of 91%, which is not adequate to defer further radiologic surveillance. Two consecutive PET/CT examinations with negative findings within a 6-month period, however, resulted in a NPV of 98%, which could obviate further radiologic imaging in the absence of clinical signs of recurrence. PMID- 23639558 TI - Optimal timing of cerebral MRI in preterm infants to predict long-term neurodevelopmental outcome: a systematic review. AB - SUMMARY: Advances in neonatal neuroimaging have improved detection of preterm brain injury responsible for abnormal neuromotor and cognitive development. Increasingly sophisticated MR imaging setups allow scanning during early preterm life. In this review, we investigated how brain MR imaging in preterm infants should be timed to best predict long-term outcome. Given the strong evidence that structural brain abnormalities are related to long-term neurodevelopment, MR imaging should preferably be performed at term-equivalent age. Early MR imaging is promising because it can guide early intervention studies and is indispensable in research on preterm brain injury. PMID- 23639559 TI - Neuroimaging in patients with abnormal blood glucose levels. AB - SUMMARY: Smooth neuronal functioning requires an uninterrupted supply of energy that is provided by glucose under normal physiologic conditions. Significant variations in plasma glucose levels, be it hypoglycemia or hyperglycemia, can present with myriad clinical manifestations and may mimic stroke. At times, the diagnosis is either not apparent or not clinically suspected. Imaging can suggest the diagnosis in unsuspected cases and can help in the assessment of the extent of neuronal damage in known cases, making it vital for the neuroradiologist to be aware of both common and atypical neuroimaging findings in hypoglycemia and hyperglycemia. PMID- 23639560 TI - Morphologic characteristics of atherosclerotic middle cerebral arteries on 3T high-resolution MRI. AB - BACKGROUND AND PURPOSE: There are limited studies on the morphologic characteristics of MCA atherosclerotic stenosis. Our aim was to quantitatively assess the remodeling pattern and plaque distribution of atherosclerotic MCAs with 3T high-resolution MR imaging. MATERIALS AND METHODS: Eighty-seven consecutive patients with symptomatic atherosclerotic stenoses at the M1 segment of the MCA on DSA (50%-99%) were enrolled. The remodeling index was calculated as the Vessel Area at Maximal Lumen Narrowing/Reference Vessel Area. A remodeling index >= 1.0 was defined as positive remodeling, and a remodeling index < 1.0, as negative remodeling. Plaque distribution at the maximal lumen narrowing site was classified on the basis of the involvement of the superior, inferior, dorsal, or ventral MCA wall. RESULTS: Forty-three of 87 patients were excluded due to poor imaging quality (n = 8) or scan plane obliquity secondary to a tortuous M1 segment of the MCA or an MCA ostium lesion or angled lesion (n = 35). Of 44 patients in the final analysis, negative remodeling was found in 19 (43.2%) lesions, and positive remodeling, in 25 (56.8%) lesions. At maximal lumen narrowing sites, lesions with negative remodeling had less vessel area, wall area, and percentage of plaque burden (P < .0001) and a lower eccentricity index (P = .023), compared with lesions with positive remodeling. The plaque involved the superior and dorsal walls in 15 (34.1%) of 44 patients. CONCLUSIONS: 2D high resolution MR imaging can help assess the remodeling pattern and plaque distribution of MCA stenosis, but the imaging and postprocessing protocol for remodeling assessment needs to be improved in the tortuous course of the MCA and in MCA ostium or angled lesions. PMID- 23639561 TI - Dynamic MR imaging patterns of cerebral fat embolism: a systematic review with illustrative cases. AB - Different MR imaging patterns of cerebral fat embolism have been reported in the literature without a systematic review. Our goal was to describe the patterns, explore the relationship between disease course and the imaging patterns, and discuss the underlying mechanism. We reveal 5 distinctive MR imaging patterns: 1) scattered embolic ischemia occurring dominantly at the acute stage; 2) confluent symmetric cytotoxic edema located at the cerebral white matter, which mainly occurs at the subacute stage; 3) vasogenic edematous lesions also occurring at the subacute stage; 4) petechial hemorrhage, which persists from the acute to the chronic stage; and 5) chronic sequelae, occurring at late stage, including cerebral atrophy, demyelinating change, and sequelae of infarction or necrosis. Underlying mechanisms of these imaging patterns are further discussed. Recognition of the 5 evolving MR imaging patterns of cerebral fat embolism may result in adjustment of the appropriate management and improve the outcome. PMID- 23639562 TI - Stent-assisted coiling versus balloon remodeling of wide-neck aneurysms: comparison of angiographic outcomes. AB - BACKGROUND AND PURPOSE: Stent-assisted coiling and balloon-assisted coiling are 2 well-established techniques for treatment of wide-neck intracranial aneurysms. A direct comparative analysis of angiographic outcomes with the 2 techniques has not been available. We compare the angiographic outcomes of wide-neck aneurysms treated with stent-assisted coiling versus balloon-assisted coiling. MATERIALS AND METHODS: A retrospective review was conducted on 101 consecutive patients treated at our institution, 69 with stent-assisted coiling and 32 with balloon assisted coiling. Two multivariate logistic regression analyses were performed to determine predictors of aneurysm obliteration and predictors of progressive aneurysm thrombosis at follow-up. RESULTS: The 2 groups were comparable with respect to all baseline characteristics with the exception of a higher proportion of ruptured aneurysms in the balloon-assisted coiling group (65.6%) than in the stent-assisted coiling group (11.5%, P < .001). Procedural complications did not differ between the stent-assisted coiling group (6%) and the balloon-assisted coiling group (9%, P = .5). The rates of complete aneurysm occlusion (Raymond score 1) at the most recent follow-up were significantly higher for the stent assisted coiling group (75.4%) compared with the balloon-assisted coiling group (50%, P = .01). Progressive occlusion of incompletely coiled aneurysms was noted in 76.6% of aneurysms in the stent-assisted coiling group versus 42.8% in the balloon-assisted coiling group (P = .02). Retreatment rates were significantly lower with stent-assisted coiling (4.3%) versus balloon-assisted coiling (15.6%, P = .05). In multivariate analysis, stented aneurysms independently predicted both complete aneurysm obliteration and progression of occlusion. CONCLUSIONS: Stent-assisted coiling may yield lower rates of retreatment and higher rates of aneurysm obliteration and progression of occlusion at follow-up than balloon assisted coiling with a similar morbidity rate. PMID- 23639563 TI - Brain MRI findings in neurologically asymptomatic patients with infective endocarditis. AB - BACKGROUND AND PURPOSE: Neurologic complications in infective endocarditis are frequent and affect patient prognosis negatively. Additionally, detection of asymptomatic lesions by MR imaging could help early management of this condition. The objective of our study was to describe MR imaging characteristics of cerebral lesions in a neurologically asymptomatic population with infective endocarditis. MATERIALS AND METHODS: One hundred nine patients at the acute phase of a definite or possible infective endocarditis according to the Duke modified criteria and without neurologic manifestations according to the NIHSS were prospectively included. Each patient underwent cerebral MR imaging and MRA within 7 days of admission. RESULTS: MR imaging showed abnormalities in 78 patients (71.5%). Acute ischemic lesions (40 patients, 37%) and cerebral microbleeds (62 patients, 57%) were the most frequent lesions. Eight patients had an acute SAH, 3 patients had brain microabscesses, 3 had a small cortical hemorrhage, and 3 had a mycotic aneurysm. Acute ischemic lesions mostly appeared as multiple small infarcts disseminated in watershed territories (25/40, 62.5%) and as lesions of different ages (21/40, 52.5%). Cerebral microbleeds were preferentially distributed in cortical areas (362/539 cerebral microbleeds, 67%). No significant correlation was found among lesions, in particular between acute ischemia and cerebral microbleeds. CONCLUSIONS: Occult cerebral lesions, in particular cerebral microbleeds and acute ischemic lesions, are frequent in infective endocarditis. The MR imaging pattern of acute small infarcts of different ages predominating in watershed territories and cortical cerebral microbleeds may represent a surrogate imaging marker of infective endocarditis. PMID- 23639564 TI - Intracranial 4D flow MRI: toward individualized assessment of arteriovenous malformation hemodynamics and treatment-induced changes. AB - BACKGROUND AND PURPOSE: Arteriovenous malformations are an important etiology of hemorrhagic stroke. However, current imaging modalities and risk do not provide insights into individual AVM hemodynamics and its role in pathophysiology. The aims of this study are to determine whether intracranial 4D flow MR imaging can provide insights into arteriovenous malformation hemodynamics independent of the Spetzler-Martin grade and to report the changes in flow observed during staged embolization. MATERIALS AND METHODS: Intracranial 3D blood flow was assessed in 20 patients with AVM (age = 39 +/- 15 years, Spetzler-Martin grade ranging from 1 4) with the use of 4D flow MR imaging (temporal resolution = 45 ms, spatial resolution = [1.2-1.6mm](3)). AVM hemodynamics were visualized by means of time integrated 3D pathlines depicting the AVM arterial feeding and venous draining patterns over the cardiac cycle. Analysis included the grading of feeding and draining velocities on a 3-point scale (0 = low <25 cm/s, 1 = medium <50 cm/s, 2 = high >50 cm/s). For 4 of 20 patients undergoing 4D flow MR imaging follow-up after staged embolization, peak velocities were quantified in arterial feeders, draining veins, the sagittal sinus, and contralateral arteries. RESULTS: In 50% of the cases with Spetzler-Martin grade >2, heterogeneous flow (velocity grade differences >1) was found across arteries and veins. Velocities in draining veins increased from Spetzler-Martin grade = 1 (grading = 0.5 +/- 0.6) to Spetzler Martin grade >=3 (1.1 +/- 0.6), whereas arterial velocities were similar (1.7 +/- 0.6 versus 1.5 +/- 0.6). In the postembolization subgroup of 4 patients, 4D flow MR imaging demonstrated successively more compact AVM and redistribution of velocities. Changes in arterial and venous velocities during treatment were highly different among individuals. CONCLUSIONS: Spetzler-Martin grade does not reflect differences in 3D AVM arterial and venous hemodynamics, and an individual assessment of AVM hemodynamics may be needed for improved lesion characterization. Four-dimensional flow MR imaging may have the potential to monitor and guide embolization treatment planning. PMID- 23639565 TI - Physician quality reporting system: 2013 update. PMID- 23639566 TI - Mechanisms for cellular NO oxidation and nitrite formation in lung epithelial cells. AB - Airway lining fluid contains relatively high concentrations of nitrite, and arterial blood levels of nitrite are higher than venous levels, suggesting the lung epithelium may represent an important source of nitrite in vivo. To investigate whether lung epithelial cells possess the ability to convert NO to nitrite by oxidation, and the effect of oxygen reactions on nitrite formation, the NO donor DETA NONOate was incubated with or without A549 cells or primary human bronchial epithelial (HBE) cells for 24 h under normoxic (21% O2) and hypoxic (1% O2) conditions. Nitrite production was significantly increased under all conditions in the presence of A549 or HBE cells, suggesting that both A549 and HBE cells have the capacity to oxidize NO to nitrite even under low-oxygen conditions. The addition of oxyhemoglobin to the A549 cell medium decreased the production of nitrite, consistent with NO scavenging limiting nitrite formation. Heat-denatured A549 cells produced much lower nitrite and nitrate, suggesting an enzymatic activity is required. This NO oxidation activity was highest in membrane-bound proteins with molecular size <100kDa. In addition, 1H [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one and cyanide inhibited formation of nitrite in A549 cells. It has been shown that ceruloplasmin (Cp) possesses an NO oxidase and nitrite synthase activity in plasma based on NO oxidation to nitrosonium cation. We observed that Cp is expressed intracellularly in lung epithelial A549 cells and secreted into the medium under basal conditions and during cytokine stimulation. However, an analysis of Cp expression level and activity measured via p-phenylenediamine oxidase activity assay revealed very low activity compared with plasma, suggesting that there is insufficient Cp to contribute to detectable NO oxidation to nitrite in A549 cells. Additionally, Cp levels were knocked down using siRNA by more than 75% in A549 cells, with no significant change in either nitrite or cellular S-nitrosothiol formation compared to scrambled siRNA control under basal conditions or cytokine stimulation. These data suggest that lung epithelial cells possess NO oxidase activity, which is enhanced in cell-membrane-associated proteins and not regulated by intracellular or secreted Cp, indicating that alternative NO oxidases determine hypoxic and normoxic nitrite formation from NO in human lung epithelial cells. PMID- 23639568 TI - A novel GATA6 mutation leading to congenital heart defects and permanent neonatal diabetes: a case report. AB - Permanent neonatal diabetes mellitus is a rare condition mostly due to heterozygous mutations in the KCNJ11, ABCC8 and INS genes. Neonatal diabetes due to pancreatic agenesis is extremely rare. Mutations in PDX1, PTF1A, HNF1B, EIF2AK3, RFX6 and GATA6 genes have been shown to result in pancreatic agenesis or hypoplasia. This report describes a 40-day-old male infant diagnosed with permanent neonatal diabetes associated with atrial septal defect, pulmonary stenosis, patent ductus arteriosus and a novel de novo heterozygous missense mutation (p.N466S) in the GATA6 gene with no evidence of exocrine pancreas insufficiency. In addition to permanent neonatal diabetes, the patient had transient idiopathic neonatal cholestasis and hypoglycaemic episodes unrelated to insulin treatment, features that are rarely described in children with permanent neonatal diabetes. PMID- 23639569 TI - Interference of the most frequent haemoglobin variants on quantification of HbA1c: comparison between the LC-MS (IFCC reference method) and three routinely used methods. AB - AIM: Assaying HbA1c in patients with haemoglobin variants has long been a technical challenge, despite methodological advances that have progressively limited the problem. The purpose of this study was to evaluate the impact of the most frequent haemoglobin variants on three routine separation methods compared with the IFCC reference method. PATIENTS: Blood samples from heterozygous patients (AS, AC, AD, AE) were analyzed using the IFCC reference method (LC-MS), and the results compared with those obtained by capillary electrophoresis (CAPILLARYS 2 Flex Piercing, Sebia) and two HPLC methods using cation-exchange (Variant II, Bio-Rad) and affinity chromatography (Ultra(2), Primus). RESULTS: HbA1c values obtained by the IFCC reference method were comparable to those obtained by the three tested methods whatever the haemoglobin variant. Mean relative biases did not exceed the threshold of 7% (above which differences are generally considered clinically significant), although some individual values were above this limit with Variant II in samples with HbS and for all three methods in samples with HbE. CONCLUSION: This comparative study of the LC-MS reference method and three field methods has demonstrated that these assays are not clinically influenced by the presence of the most common haemoglobin variants. The present results also confirm that the interpretation of HbA1c values in patients with Hb variants remains complex and depends on the assays used and should, in some cases, take into account parameters other than analytical ones (such as differences in glycation rates and half-lives of haemoglobin variants). PMID- 23639567 TI - Endothelial NO and O2.- production rates differentially regulate oxidative, nitroxidative, and nitrosative stress in the microcirculation. AB - Endothelial dysfunction causes an imbalance in endothelial NO and O2.- production rates and increased peroxynitrite formation. Peroxynitrite and its decomposition products cause multiple deleterious effects including tyrosine nitration of proteins, superoxide dismutase (SOD) inactivation, and tissue damage. Studies have shown that peroxynitrite formation during endothelial dysfunction is strongly dependent on the NO and O2.- production rates. Previous experimental and modeling studies examining the role of NO and O2.- production imbalance on peroxynitrite formation showed different results in biological and synthetic systems. However, there is a lack of quantitative information about the formation and biological relevance of peroxynitrite under oxidative, nitroxidative, and nitrosative stress conditions in the microcirculation. We developed a computational biotransport model to examine the role of endothelial NO and O2.- production on the complex biochemical NO and O2.- interactions in the microcirculation. We also modeled the effect of variability in SOD expression and activity during oxidative stress. The results showed that peroxynitrite concentration increased with increase in either O2.- to NO or NO to O2.- production rate ratio (QO2.-/QNO or QNO/QO2.-, respectively). The peroxynitrite concentrations were similar for both production rate ratios, indicating that peroxynitrite-related nitroxidative and nitrosative stresses may be similar in endothelial dysfunction or inducible NO synthase (iNOS)-induced NO production. The endothelial peroxynitrite concentration increased with increase in both QO2. /QNO and QNO/QO2.- ratios at SOD concentrations of 0.1-100 MUM. The absence of SOD may not mitigate the extent of peroxynitrite-mediated toxicity, as we predicted an insignificant increase in peroxynitrite levels beyond QO2.-/QNO and QNO/QO2.- ratios of 1. The results support the experimental observations of biological systems and show that peroxynitrite formation increases with increase in either NO or O2.- production, and excess NO production from iNOS or from NO donors during oxidative stress conditions does not reduce the extent of peroxynitrite mediated toxicity. PMID- 23639571 TI - President's page: Tweet all about it: ACC charting the digital future. PMID- 23639570 TI - The association of type 2 diabetes and insulin resistance/secretion with persistent organic pollutants in two First Nations communities in northern Ontario. AB - AIMS: Recent evidence suggests an association between persistent organic pollutants (POPs) and type 2 diabetes. In two First Nations communities where wild food is consumed by a large portion of the population, we compared pollutants in plasma between diabetic and non-diabetic individuals, and investigated the strength of association between pollutants and insulin resistance/secretion in non-diabetic individuals. METHODS: The study population consisted of 72 participants. Oral Glucose Tolerance Tests were used to assess diabetes status. Plasma was used to determine POP concentrations and mercury concentrations were determined from hair samples. RESULTS: Age-adjusted plasma concentrations of some pollutants were significantly higher in diabetic than in non-diabetic individuals. When taking into account age, adiposity levels, and smoking status, POP levels were not associated with insulin resistance nor with insulin secretion in non-diabetic individuals. CONCLUSIONS: These findings confirm that POP concentrations in plasma may be higher in diabetic than in non diabetic individuals. No association was however seen between POP concentrations and markers of insulin resistance/secretion in non-diabetic individuals. PMID- 23639573 TI - Cytogenetic damage in the blood lymphocytes of astronauts: effects of repeat long duration space missions. AB - Human missions onboard the International Space Station (ISS) are increasing in duration and several astronauts have now participated in second ISS increments. The radiation environment in space is very different from terrestrial radiation exposure and it is still unclear if space flight effects and radiation from repeat missions are simply additive, which potentially confounds the assessment of the cumulative risk of radiation exposure. It has been shown that single space missions of a few months or more on the ISS can induce measureable increases in the yield of chromosome damage in the blood lymphocytes of astronauts, and it appears that cytogenetic biodosimetry can be used reliably to estimate equivalent dose and radiation risk. We have now obtained direct in vivo measurements of chromosome damage in blood lymphocytes of five astronauts before and after their first and second long duration space flights. Chromosome damage was assessed by fluorescence in situ hybridization technique using three different chromosome painting probes. All astronauts showed an increase in total exchanges and translocations after both the first and second flight. Biological dose measured using either individual assessment or a population assessment supports an additive risk model. PMID- 23639574 TI - Fetal growth factors and fetal nutrition. AB - Optimal fetal growth is important for a healthy pregnancy outcome and also for lifelong health. Fetal growth is largely regulated by fetal nutrition, and mediated via the maternal and fetal glucose/insulin/insulin-like growth factor axes. Fetal nutrition may reflect maternal nutrition, but abnormalities of placental function can also affect fetal growth, as the placenta plays a key intermediary role in nutritional signalling between mother and fetus. Fetal nutrition also impacts on the development of key fetal endocrine systems such as the glucose-insulin and insulin-like growth factor axes. This is likely to contribute to the link between both fetal growth restriction and fetal overgrowth, and increased risks of obesity and impaired glucose tolerance in later life. This review focuses on the associations between maternal and fetal nutrition, fetal growth and later disease risk, with particular emphasis on the role of insulin-like growth factors and the importance of the periconceptional period. PMID- 23639572 TI - The preventive effect of uncarboxylated osteocalcin against free fatty acid induced endothelial apoptosis through the activation of phosphatidylinositol 3 kinase/Akt signaling pathway. AB - OBJECTIVE: Increasing evidence suggests that osteocalcin (OC), one of the osteoblast-specific proteins, has been associated with atherosclerosis, but results are conflicting. The aim of this study was to elucidate the independent effect of uncarboxylated osteocalcin (ucOC), an active form of osteocalcin which has been suggested to have an insulin sensitizing effect, on vascular endothelial cells. MATERIALS AND METHODS: We used human aortic endothelial cells and treated them with ucOC. Linoleic acid (LA) was used as a representative free fatty acid. Apoptosis was evaluated using various methods including a terminal deoxyribonucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling analysis kit and Western blotting for cleaved caspase 3, cleaved poly (ADP-ribose) polymerase and Bcl-xL. The phosphorylations of Akt and endothelial nitric oxide synthase (eNOS) as well as the level of NO were measured to confirm the effect of ucOC on insulin signaling pathway. RESULTS: Pretreatment of ucOC (30 ng/ml) prevented LA-induced apoptosis in insulin-stimulated endothelial cells; effects were abolished by pretreatment with the phosphatidylinositol 3 kinase (PI3-kinase) inhibitor, wortmannin. Treatment of ucOC (ranged from 0.3 to 30 ng/ml) significantly increased the phosphorylation of Akt and eNOS and nitric oxide secretion from endothelial cells in a PI3-kinase dependent manner. CONCLUSIONS: Our study is the first to demonstrate the independent effect of ucOC on vascular endothelial cells. Our results further suggest that ucOC could have beneficial effects on atherosclerosis. PMID- 23639575 TI - The inflammatory state of the rat placenta increases in late gestation and is further enhanced by glucocorticoids in the labyrinth zone. AB - INTRODUCTION: Inflammation plays central roles in key aspects of successful reproduction: ovulation, implantation and parturition. In this study we characterised the inflammatory profile of the rat placenta in late gestation with and without maternal glucocorticoid (dexamethasone) treatment. METHODS: Placentas (n = 6/group) were collected from untreated (Con) rats at days 16 and 22 (term = day 23) and from dexamethasone-treated (Dex) rats at day 22. mRNA and protein expression was determined for enzymes of prostaglandin synthesis and metabolism (Ptgs-1, Ptgs-2, 15-Pgdh), pro-inflammatory cytokines (Tnf-alpha, Il-1beta, Il 6), and the macrophage marker Emr-1 in the junctional (JZ) and labyrinth (LZ) zones of the placenta. RESULTS: Tnf-alpha, Il-1beta and Il-6 mRNAs all increased (2- to 4-fold) in both placental zones between days 16 and 22 (P < 0.01). Ptgs-2 mRNA (30-fold; P < 0.01) and PTGS-2 protein (2.4-fold; P < 0.05) similarly increased in LZ. In contrast, 15-Pdgh expression increased in JZ but decreased in LZ; these changes were accompanied by decreased levels of PGE2 in the JZ and a trend towards increased LZ levels. Dex treatment inhibited fetal and placental growth, but had minimal effects on expression of Ptgs-1, Ptgs-2 or 15-Pdgh. Nevertheless, Dex treatment increased LZ PGE2 levels (5-fold, P < 0.01) at the end of gestation. Dex treatment increased Tnf-alpha mRNA expression in LZ (40%; P < 0.05), but modestly suppressed cytokine protein expression in JZ. CONCLUSIONS: These data demonstrate that the inflammatory state of the LZ increases near term coincident with the known increase in local glucocorticoid levels. This suggests the classic anti-inflammatory actions of glucocorticoids do not occur in the placental LZ. PMID- 23639577 TI - Prevalence, size, number and localization of vascular anastomoses in monochorionic placentas. AB - INTRODUCTION: Most monochorionic (MC) twin pregnancies have an uncomplicated course, but some develop severe complications including selective intrauterine growth restriction (sIUGR), twintwin transfusion syndrome (TTTS) and twin anemia polycythemia sequence (TAPS). The underlying pathogenesis of these various complications is associated with the ubiquitous presence of vascular anastomoses in MC placentas. METHODS: The aim of this study was to estimate the prevalence, number, size and localization of the anastomoses in sIUGR, TTTS and TAPS placentas compared to normal MC placentas using color dye injection. We excluded MC twin pregnancies treated with fetoscopic laser surgery or selective feticide. RESULTS: A total of 235 placentas fulfilled the inclusion criteria: 126 normal MC, 47 TTTS, 46 sIUGR and 16 spontaneous TAPS. Median number of anastomoses in normal MC, sIUGR, TTTS and TAPS placentas was 8 (IQR: 4-12), 8 (IQR: 5-14), 7 (IQR: 5-11) and 4 (IQR: 3-5), respectively. The prevalence of arterio-arterial (AA) anastomoses in normal MC, sIUGR, TTTS and TAPS placentas was 96%, 98%, 47% and 19%, respectively. We found AV anastomoses to be evenly distributed along the vascular equator in all MC placentas except in TAPS cases, where anastomoses were mostly localized near the margin. We also found that, in sIUGR and TTTS placentas, AA anastomoses tended to be at the center of the placenta. CONCLUSION: The present study shows that the prevalence, size, number and localization of the various types of anastomoses differ between normal MC, sIUGR, TTTS and TAPS placentas. PMID- 23639576 TI - Differentially expressed microRNAs and affected biological pathways revealed by modulated modularity clustering (MMC) analysis of human preeclamptic and IUGR placentas. AB - INTRODUCTION: This study focuses on the implementation of modulated modularity clustering (MMC) a new cluster algorithm for the identification of molecular signatures of preeclampsia and intrauterine growth restriction (IUGR), and the identification of affected microRNAs METHODS: Eighty-six human placentas from normal (40), growth-restricted (27), and preeclamptic (19) term pregnancies were profiled using Illumina Human-6 Beadarrays. MMC was utilized to generate modules based on similarities in placental transcriptome. Gene Set Enrichment Analysis (GSEA) was used to predict affected microRNAs. Expression levels of these candidate microRNAs were investigated in seventy-one human term placentas as follows: control (29); IUGR (26); and preeclampsia (16). RESULTS: MMC identified two modules, one representing IUGR placentas and one representing preeclamptic placentas. 326 differentially expressed genes in the module representing IUGR and 889 differentially expressed genes in a module representing preeclampsia were identified. Functional analysis of molecular signatures associated with IUGR identified P13K/AKT, mTOR, p70S6K, apoptosis and IGF-1 signaling as being affected. Analysis of variance of GSEA-predicted microRNAs indicated that miR-194 was significantly down-regulated both in preeclampsia (p = 0.0001) and IUGR (p = 0.0304), and miR-149 was significantly down-regulated in preeclampsia (p = 0.0168). DISCUSSION: Implementation of MMC, allowed identification of genes disregulated in IUGR and preeclampsia. The reliability of MMC was validated by comparing to previous linear modeling analysis of preeclamptic placentas. CONCLUSION: MMC allowed the elucidation of a molecular signature associated with preeclampsia and a subset of IUGR samples. This allowed the identification of genes, pathways, and microRNAs affected in these diseases. PMID- 23639578 TI - Vaginal dose point reporting in cervical cancer patients treated with combined 2D/3D external beam radiotherapy and 2D/3D brachytherapy. AB - BACKGROUND AND PURPOSE: Traditionally, vaginal dose points have been defined at the vaginal source level, thus not providing dose information for the entire vagina. Since reliable vaginal dose volume/surface histograms are unavailable, a strategy for comprehensive vaginal dose reporting for combined EBRT and BT was established and investigated. MATERIAL AND METHODS: An anatomical vaginal reference point was defined at the level of the Posterior-Inferior Border of Symphysis (PIBS), plus two points +/-2 cm (mid/introitus vagina). For BT extra points were selected for the upper vagina at 12/3/6/9 o'clock, at the vaginal surface and 5 mm depth. A vaginal reference length (VRL) was defined from ring centre to PIBS. Fifty-nine patients treated for cervical cancer were included in this retrospective feasibility study. RESULTS: The method was applicable to all patients. Total EQD2 doses at PIBS and +/-2 cm were 36.7 Gy (3.1-68.2), 49.6 Gy (32.1-89.6) and 4.3 Gy (1.0-46.6). At the vaginal surface at ring level doses were respectively 266.1 Gy (67.6-814.5)/225.9 Gy (61.5-610.5) at 3/9 o'clock, and 85.1 Gy (55.4-140.3)/72.0 Gy (49.1-108.9) at 12/6 o'clock. Mean VRL on MRI was 5.6 cm (2.0-9.4). CONCLUSIONS: With this novel system, a comprehensive reporting of vaginal doses is feasible. The present study has demonstrated large dose variations between patients observed in all parts of the vagina, resulting from different contributions from EBRT and BT. PMID- 23639579 TI - MR guided applicator reconstruction for brachytherapy of cervical cancer using the novel titanium Rotterdam applicator. AB - A novel model of the titanium Rotterdam tandem and ovoid applicator is presented. As titanium produces artefacts in MR images, an MR sequence was sought and optimised for visualisation and accurate applicator reconstruction. The mean inter-observer (8 observers) variability for four patients was only 0.7 mm (maximum 1.7 mm). PMID- 23639581 TI - The effect of Laminaria japonic polysaccharide on sperm characteristics and biochemical parameters in cryopreserved boar sperm. AB - The aim of the present study was to evaluate the cryoprotective effect of Laminaria japonic polysaccharide (LJP) on boar sperm. Semen samples were collected from seven mature Yorkshire boars once a week by the gloved hand technique and frozen-thawed in the extender with LJP added. Extender with LJP added at concentrations of 0.25, 0.5, 1.0, 1.5 and 2.0mg/mL to the extender and its effects on the quality of frozen-thawed boar sperm were assessed. Results showed: (i) sperm motility and plasma membrane integrity were greater in the extender containing 0.5 and 1.0mg/mL LJP, as compared to other groups (P<0.05); (ii) extender added 1.0mg/mL LJP showed the greatest plasma membrane and acrosomal integrity percentages in comparison with other groups (P<0.05); (iii) mitochondrial activity was significantly higher at the concentration of 0.5 and 1.0mg/mL LJP than those of other groups (P<0.05); (iv) in terms of biochemical assessments, 0.5 and 1.0mg/mL LJP improved SOD (superoxide dismutase) and CAT (catalase) concentrations, compared to other groups (P<0.05). However, no significant difference was found in GSH-Px (glutathione peroxidase) concentration when supplemented with LJP. Interestingly, LJP exhibited a dose-related response and the lesser concentration represented greater protective effects. It is also important to note that 1.0mg/mL LJP provides for an enhanced cryoprotective effect in boar semen. PMID- 23639582 TI - Collagen VI in cancer and its biological mechanisms. AB - Collagen VI is a widely distributed extracellular matrix protein highly expressed in a variety of cancers that favors tumor growth and progression. A growing number of studies indicate that collagen VI directly affects malignant cells by acting on the Akt-GSK-3beta-beta-catenin-TCF/LEF axis, enhancing the production of protumorigenic factors and inducing epithelial-mesenchymal transition. Moreover, it affects the tumor microenvironment by increasing the recruitment of macrophages and endothelial cells, thus promoting tumor inflammation and angiogenesis. Furthermore, collagen VI promotes chemotherapy resistance and can be regarded as a potential biomarker for cancer diagnosis. Collectively, these findings strongly support a role for collagen VI as an important regulator in tumors and provide new targets for cancer therapies. PMID- 23639580 TI - Clinical outcome and dosimetric parameters of chemo-radiation including MRI guided adaptive brachytherapy with tandem-ovoid applicators for cervical cancer patients: a single institution experience. AB - PURPOSE: To evaluate dosimetric parameters and clinical outcome for cervical cancer patients treated with chemo-radiation and MR-image guided adaptive brachytherapy (MR-IGABT) using tandem-ovoid applicators for intracavitary or combined intracavitary/interstitial approaches. METHOD: This retrospective analysis includes 46 patients treated between 2006 and 2008. Dose-volume parameters D90 HR-CTV (high-risk clinical target volume) and D(2cc) OARs (organs at risk) were determined and converted into biologically equivalent doses in 2 Gy fractions (EQD2). Clinical outcome parameters (local control (LC), progression free survival (PFS) and overall survival (OS)) were analysed actuarially and late morbidity crude rates were scored using CTCAEv3.0. RESULTS: Mean D90 HR-CTV was 84 (SD9) Gy EQD2 for HR-CTV volumes of mean 57 (SD37) cm(3) at time of first brachytherapy (BT). Median follow-up was 41 (range, 4-67) months. Three year LC, PFS, and OS rates were 93, 71, and 65%, respectively. Node negative patients had significantly higher 3-year survival rates compared to node positive ones (PFS 85 versus 53% (p=0.013), OS 77 versus 50% (p=0.032), respectively) with an even larger difference for patients with FIGO stages IB-IIB (PFS 87 versus 42% (p=0.002), OS 83 versus 46% (p=0.007), respectively). Late grade 3-4 mainly gastrointestinal or vaginal morbidity was observed in 4 patients (9.5%). No correlations were seen between morbidity and D(2cc) OAR values. CONCLUSION: (Chemo-) radiation and MR-IGABT with tandem-ovoid applicators result in high LC and promising survival rates with reasonable morbidity. PMID- 23639583 TI - N-terminal AH2 segment of protein NS4B from hepatitis C virus. Binding to and interaction with model biomembranes. AB - HCV NS4B, a highly hydrophobic protein involved in the alteration of the intracellular host membranes forming the replication complex, plays a critical role in the HCV life cycle. NS4B is a multifunctional membrane protein that possesses different regions where diverse and significant functions are located. One of these important regions is the AH2 segment, which besides being highly conserved has been shown to play a significant role in NS4B functioning. We have carried out an in-depth biophysical study aimed at the elucidation of the capacity of this region to interact, modulate and disrupt membranes, as well as to study the structural and dynamic features relevant for that disruption. We show that a peptide derived from this region, NS4BAH2, is capable of specifically binding phosphatidyl inositol phosphates with high affinity, and its interfacial properties suggest that this segment could behave similarly to a pre transmembrane domain partitioning into and interacting with the membrane depending on the membrane composition and/or other proteins. Moreover, NS4BAH2 is capable of rupturing membranes even at very low peptide-to-lipid ratios and its membrane-activity is modulated by lipid composition. NS4BAH2 is located in a shallow position in the membrane but it is able to affect the lipid environment from the membrane surface down to the hydrophobic core. The NS4B region where peptide NS4BAH2 resides might have an essential role in the membrane replication and/or assembly of the viral particle through the modulation of the membrane structure and hence the replication complex. PMID- 23639584 TI - Prognostic role of caveolin in breast cancer: a meta-analysis. AB - INTRODUCTION: Recent studies have shown that Caveolin play a potential role as a prognostic biomarker of cancers. The aim of the present study was to clarify whether caveolin could be a prognostic factor for patients with breast cancer. MATERIALS AND METHODS: All eligible studies were identified using Medline and EMBASE system. The patients' clinical characteristics and survival outcome were extracted. The meta-analysis was performed to clarify the prognostic role of caveolin and the correlation between the caveolin expression and clinical characteristics. RESULTS: After full text review, 19 articles were identified as eligible articles. We found that negative stromal Caveolin-1 (Cav-1) expression could predict the poor prognosis of breast cancer. The combined HR (95% CI) for OS was 4.12[2.05, 8.28], while the combined HR (95% CI) for DFS/PFS was 3.69[2.57, 5.31]. The combined HR (95% CI) of tumor epithelial Cav-1 for OS was 0.78[0.54, 1.12], and the combined HR (95% CI) for DFS/PFS was 1.32[0.76, 2.29]. The combined HR (95% CI) of tumor epithelial Cav-2 for CSS was 2.04[0.91, 4.56]. Odds ratios (ORs) showed that the stromal Cav-1 expression was associated with the AJCC stage, T status, lymph metastasis, distant metastasis, and histological grade (G grade) and many biomarkers. We found ORs of Cav-1 and Cav-2 expression in tumor epithelial cells varied in clinical characteristics and biomarkers. CONCLUSION: Our results indicated that negative expression of stromal Cav-1 was associated with poor prognosis of breast cancer, while the detection of Cav-1 and Cav-2 in tumor epithelial cells was not. PMID- 23639585 TI - Self-reported hypoesthesia of the lower lip after sagittal split osteotomy. AB - Sagittal split osteotomy may result in sensory impairment of the inferior alveolar nerve; altered sensation in the lower lip varies from patient to patient. We evaluated individual and intraoperative risk factors of sagittal split osteotomy and correlated these findings with self-reported postoperative changes in lower-lip sensation. Follow-up data for 163 consecutive patients who underwent a bilateral sagittal split osteotomy were assessed for self-reported sensibility disturbances in the lower lip at the last follow-up visit. These self reports were categorized as normal, hypoesthesia, hyperesthesia, or slightly diminished sensation in the central area of the chin. The overall rate of self reported changed sensibility was 15.1% (49/324; 13.0% on the right side and 17.3% on the left side). Of 16 patients (9.9%) who experienced hypoesthesia on the right side and 25 patients (15.4%) who experienced hypoesthesia on the left side, 10 experienced bilateral hypoesthesia (31 patients total, 19.1%). Genioplasty and age at surgery were significant predictors of hypoesthesia; a 1-year increase in age at surgery increased the odds of hyposensitivity by 5%, and the odds of hypoesthesia in patients with concurrent genioplasty were 4.5 times higher than in patients without genioplasty. Detachment of the nerve at the left side, but not at the right side, was significantly correlated with hypoesthesia. PMID- 23639586 TI - Gene expression profiling and pathway analysis of hepatotoxicity induced by triptolide in Wistar rats. AB - Triptolide (TP), a major component of TWHF, is widely used to treat rheumatoid arthritis, systemic lupus erythematosus, nephritis and leprosy. However, its clinical use is limited by hepatotoxicity. To further elucidate the underlying mechanism of its hepatotoxic effects, hepatic gene expression profiles were analyzed. TP (1000 and 300 MUg/kg) was orally administered to Wistar rats for 14 days. Current study indicated that female rats were more sensitive to TP-induced hepatotoxicity than males. Genome-wide microarray analyses identified 3329 differentially expressed genes in liver of female rats. Analyses of these genes identified over-represented functions associated with insulin signaling pathway, glucose metabolism, cell cycle, oxidative stress and apoptosis, which were consistent with the results of significant increase of Caspase-3 activity and reduction of serum glucose, GSH/GSSG ratio, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities, liver glycogen. In addition, it was observed for the first time that glucocorticoids and IGF1 might get involved in TP-induced hepatotoxicity. These data suggest that TP treatment could alter the hepatic redox status, reduce serum glucose and induce hepatocyte apoptosis, consistent with the differential expression of genes involved in insulin signaling pathway, glucose metabolism pathway and cell stress pathway, all of which might contribute to the overall TP-induced hepatotoxicity. PMID- 23639587 TI - Modelling framework for assessment of dietary exposure to added flavouring substances within the FACET (Flavours, Additives, and Food Contact Material Exposure Task) project. AB - This paper provides a model to assess dietary exposure to flavouring substances intentionally added to food. The purpose is to describe the approaches currently available and their scientific basis. The proposed exposure model for flavouring substances envisages three different levels of refinement: basic, intermediate and refined. At the two first levels, the model may be applied to all 2543 substances actually in use in Europe, while the refined level has been applied to 41 target flavouring substances selected within the FACET project. The refined level entails the use of the probability of addition of the flavouring substance added to the food and of correction factors related to losses owing to the processing of a food. PMID- 23639588 TI - Anti-nociceptive effect of vitexin mediated by the opioid system in mice. AB - In the present study, we determined the potential anti-nociceptive activity of vitexin, a C-glycosylated flavone, by conducting some acute nociceptive tests in mice. Centrally mediated anti-nociceptive effect was evaluated by hot-plate and tail-clip tests, whereas peripherally mediated anti-nociception was assessed by acetic acid-induced writhing tests. Rota-rod test was performed to evaluate the probable effect of vitexin on the motor coordination of mice. Vitexin administered orally at doses of 10, 20, and 30 mg/kg significantly increased the reaction times of animals in the hot-plate and tail-clip tests and reduced the number of acetic acid-induced writhes and stretches in writhing tests, which clearly indicated the presence of the anti-nociceptive effect. This effect disappeared by pretreatment with naloxone (a non-selective opioid receptor antagonist, 5.48 mg/kg, i.p.), which indicated the involvement of opioid mechanisms in anti-nociception. We evaluated the contribution of mu, delta, and kappa subtypes of opioid receptors to the anti-nociceptive activity by using naloxonazine (7 mg/kg, s.c.), naltrindole (0.99 mg/kg, i.p.), and nor binaltorphimine (1.03 mg/kg, i.p.), respectively. Pretreatment using these antagonists reversed the anti-nociceptive effect of vitexin in all the nociceptive tests, which indicated that mu, delta, and kappa opioid receptors contributed to the anti-nociceptive effect of this flavonoid. Falling latencies of mice in the Rota-rod test did not change upon the administration of vitexin, which indicated that vitexin showed specific anti-nociceptive effect. To the best of our knowledge, this is the first study on centrally and peripherally mediated anti-nociceptive effect of vitexin via opioid-related mechanisms. PMID- 23639589 TI - Shorter time until return of spontaneous circulation is the only independent factor for a good neurological outcome in patients with postcardiac arrest syndrome. AB - OBJECTIVE: Few studies have reported factors that result in a better neurological outcome in patients with postcardiac arrest syndrome (PCAS) following return of spontaneous circulation (ROSC). We investigated the factors affecting neurological outcome in terms of both prehospital care and treatments after arrival at hospital in patients with PCAS. METHODS: The study enrolled patients with cardiogenic cardiac arrest who were admitted to an intensive care unit after ROSC with PCAS. We investigated the association of the following factors with outcome: age, gender, witness to event present, bystander cardiopulmonary resuscitation (CPR) performed, ECG waveform at the scene, time interval from receipt of call to arrival of emergency personnel, time interval from receipt of call to arrival at hospital, prehospital defibrillation performed, special procedures performed by emergency medical technician, and time interval from receipt of call to ROSC, coronary angiography/percutaneous coronary intervention (PCI) and therapeutic hypothermia performed. RESULTS: The study enrolled 227 patients with PCAS. Compared with the poor neurological outcome group, the good neurological outcome group had a statistically significant higher proportion of the following factors: younger age, male, witness present, bystander CPR performed, first ECG showed ventricular fibrillation/pulseless ventricular tachycardia, defibrillation performed during transportation, short time interval from receipt of call to ROSC, coronary angiography/PCI and therapeutic hypothermia performed. Of these factors, the only independent factor associated with good neurological outcome was the short time interval from receipt of the call to ROSC. CONCLUSIONS: In the present study, shortening time interval from receipt of call to ROSC was the only important independent factor to achieve good neurological outcome in patients with PCAS. PMID- 23639591 TI - Theoretical study on optical and electronic properties of bipolar molecules with 1,8-naphthalimide and triphenylamine moieties as organic light-emitting materials. AB - A series of D-pi-A bipolar molecules with triphenylamine (TPA) fragments as donors, 1,8-naphthalimide (NI) fragments as acceptors, and different pi conjugated bridges (CB) as pi-conjugated bridges have been designed to explore their optical, electronic, and charge transport properties as charge transport and luminescent materials for organic light-emitting diodes (OLEDs). The frontier molecular orbitals (FMOs), natural population analysis (NPA), and local density of states analysis have turned out that the vertical electronic transitions of absorption and emission are characterized as intramolecular charge transfer (ICT). The calculated results show that their optical and electronic properties are affected by the pi-conjugated bridges in bipolar molecules. The electron donating (-withdrawing) pi-conjugated bridges serve as donors (acceptors) for the compounds under investigation. Our results suggest that these bipolar molecules are expected to be promising candidates for holes transport and luminescent materials for OLEDs. The results presented show that varying the pi-conjugated bridges of bipolar molecules is a highly promising approach to develop this series of materials for OLEDs applications. PMID- 23639590 TI - Assessment of tissue viability following electroosmotic push-pull perfusion from organotypic hippocampal slice cultures. AB - We have developed a novel sampling technique that allows both introduction and removal of fluid from the extracellular space of living tissue. This method is based on the fluidics of push-pull perfusion but flow is driven by electroosmosis. We have applied this method to organotypic hippocampal cultures. A source capillary is inserted into the tissue and a collection capillary is in contact with the tissue surface through a thin layer of fluid. A voltage is applied across the proximal ends of source and collection capillary. In the applied field, fluid will move from source, into the tissue, and then be collected. In this process, damage to cells may occur. To understand better what sampling conditions influence damage most, we tested various sampling geometries and applied voltages, quantifying damage 16-24 h later using propidium iodide as a cell death marker. We found that damage correlates with both voltage drop and power dissipated in the tissue, but that voltage drop is a better indicator of damage when comparing models in which capillary arrangement and length are different. PMID- 23639592 TI - Cholera in Haiti: redefining emergency public health philosophy. PMID- 23639593 TI - Psychosocial characteristics and poly-drug use of pregnant women enrolled in methadone maintenance treatment. AB - Pregnant women with substance dependency are a high-risk psychiatric and obstetric population, with their infants also at elevated neonatal risk. This paper draws on prospective, longitudinal data from a regional cohort of 81 methadone-maintained (MM) and 107 comparison women and their infants to describe the obstetric, socio-familial and mental health needs of women in methadone maintenance treatment during pregnancy. Of particular interest was the extent and pattern of maternal licit and illicit drug use over the course of pregnancy. Results showed that MM women had complex reproductive histories, chronic health problems, and were subject to high rates of socioeconomic adversity and comorbid mental health problems. During pregnancy, more than half continued to use licit and illicit drugs, although there was a general trend for drug use to reduce over time. No differences were observed between women maintained on low (12.5 61.0mg/day) and high (61.1-195.0mg/day) doses of methadone, with the exception of opiate abuse which was higher in the low dose group (p=.07). Findings highlight that pregnant women enrolled in MMT and their infants represent a vulnerable group with complex, social, obstetric and psychiatric needs. They also reinforce the need for services that can provide on-going wrap-around, multidisciplinary and multiagency care for these high risk dyads, both during pregnancy and in the transition to parenthood. PMID- 23639594 TI - Efficacity and feasibility of vertebroplasty for severe vertebral fracture: a retrospective study of 12 vertebroplasties. AB - Vertebroplasty is commonly contraindicated for severe vertebral fractures, or vertebra plana. However, we decided after multidisciplinary staff decision to perform vertebroplasty for few severe vertebral fractures which were still painful after optimal medical treatment. We retrospectively studied the charts of patients who benefited from vertebroplasty for severe vertebral body compression fracture between May 2006 and January 2012 in a rheumatology department. Clinical and biological data were collected and patients were consulted to assess effectiveness of that technique. We performed vertebroplasty of 12 severe vertebral fractures in 10 patients (nine women and one man). Mean age was 74.9+/ 10.7 years. Mean VAS score was 9/10+/-1.15 before vertebroplasty and 2.4+/-2 after. Global improvement was 80% and patient satisfaction was 7/10. After vertebroplasty, use of drugs was significantly reduced or even stopped. The complications observed were: three infraclinical cement leakages, one haematoma at the site of the puncture, one atrial fibrillation and one classic pulmonary embolism. Mean follow-up was 28.6+/-22.3 months. Vertebroplasty is indeed a delicate procedure for severe vertebral fracture but quickly and sustainably effective. PMID- 23639595 TI - Concordance between clinical and ultrasound findings in rheumatoid arthritis. AB - BACKGROUND: Clinical joint examination is less time-consuming than ultrasound in rheumatoid arthritis. Knowledge of clinical and ultrasound concordance of joints groups could help in selecting joints for a best ultrasonographic assessment. OBJECTIVE: To evaluate concordance between clinical examination and ultrasound of joints in a heterogeneous group of patients with rheumatoid arthritis. METHOD: Forty patients were included in a prospective, transversal, single-center study, whatever disease activity, duration or treatment. In each patient, 40 joints were evaluated for a total of 1600 joints. Synovitis was scored using clinical examination, B-mode, power Doppler and both B-mode and power Doppler. Concordance between swelling joint by clinical examination, synovitis thickening by B-mode (grade 1 or higher) and inflammation by power Doppler (grade 1 or higher) was assessed by computing the kappa coefficient. RESULTS: Clinical joint examination and ultrasound concordance was very low at the shoulders and metatarsophalangeal joints (kappa < 0.1) and was low at wrists (kappa: 0.23 to 0.30). B-mode and power Doppler found 2.4 and 1.4 more synovitis than swollen joint count using clinical examination and up to 30 times more at metatarsophalangeal joints. Concordance was strong at tibio-talar joints (kappa: 0.65 to 0.82) and moderate at others joints sites (kappa: 0.4 to 0.6). CONCLUSION: Assessment of a heterogeneous group showed that ultrasound adds information to clinical examination, most notably at the shoulders, wrists and metatarsophalangeal joints. Concordance was moderate to strong at other joint sites. PMID- 23639596 TI - Mortality among patients who receive or defer gastrostomies. AB - BACKGROUND & AIMS: There are few data on outcomes and mortality of patients who have received gastrostomies. We assessed 30-day and 1-year mortalities of patients in the United Kingdom who were referred to hospitals for gastrostomies and of patients who deferred this intervention. METHODS: We collected data from 1327 patients referred to 2 hospitals in Sheffield, United Kingdom, for gastrostomies from February 2004 through May 2010. Data were analyzed to determine 30-day and 1-year mortalities. Predicted mortality by using the validated Sheffield Gastrostomy Scoring System (SGSS) was then compared with actual mortality by using area under the receiver operator curves to determine levels of agreement in patients referred for gastrostomy. RESULTS: Three hundred four patients (23%) did not undergo gastrostomy after multidisciplinary team discussion, which was based on physicians' recommendations. This group had 35.5% mortality at 30 days and 74.3% at 1 year, whereas mortality among patients who underwent gastrostomy (n = 1027) was 11.2% at 30 days and 41.1% at 1 year (P < .0001, compared with patients who deferred the procedure). The area under the receiver operator curves for the SGSS demonstrated acceptable agreement between predicted and actual mortality in patients who underwent or were deferred gastrostomy. CONCLUSIONS: On the basis of data from 1327 patients, those who undergo gastrostomy have significantly lower mortality than those who defer the procedure. Without applying the SGSS, clinicians are able to select patients most likely to benefit from gastrostomy. The SGSS could provide objective support to clinicians involved in making ethically contentious or potentially litigious decisions. PMID- 23639597 TI - A quantitative polymerase chain reaction assay for rapid detection of 9 pathogens directly from stools of travelers with diarrhea. AB - BACKGROUND & AIMS: Every year, 80 million tourists traveling to tropical and subtropical areas contract traveler's diarrhea (TD). Forty percent to 80% of cases are caused by bacteria, yet clinical diagnostic tests are available to identify only a few of the strains that cause TD. We aimed to develop a quantitative polymerase chain reaction (qPCR) assay to identify all major pathogens in stool samples. METHODS: We developed a low-cost, high-throughput, multiplex qPCR assay for simultaneous detection of 9 bacterial pathogens in stool samples: Salmonella, Yersinia, Campylobacter, and Vibrio cholerae, as well as Shigella or enteroinvasive Escherichia coli, enterohemorrhagic E coli, enterotoxigenic E coli (ETEC), enteroaggregative E coli (EAEC), and enteropathogenic E coli (EPEC). The assay was validated using positive (n = 245) and negative (n = 243) control strains, as well as preselected positive and negative stool samples. In addition, stool samples were collected from 96 returning travelers with TD. The findings were compared with those from routine diagnostic tests. RESULTS: The assay detected the bacterial strains with 100% sensitivity and specificity, compared with results from the reference tests. Of all stool samples collected from travelers with TD, EPEC was found in 47%, EAEC in 46%, ETEC in 22%, enterohemorrhagic E coli in 7%, Campylobacter in 6%, Shigella or enteroinvasive E coli in 2%, and Salmonella in 2%. Multiple pathogens were found in 37% of all samples. CONCLUSIONS: We developed a low-cost, high throughput qPCR assay for use in routine diagnostic analysis and research. It detects the pathogenic bacteria most commonly associated with TD in stool samples with 100% sensitivity and specificity, compared with reference methods. The assay requires 4 hours, whereas current detection methods require 1 to 7 days. At least 1 TD pathogen was identified in stool samples from 76% of returning travelers, whereas conventional methods found a pathogen in only 17%. The most commonly detected bacteria were EPEC, EAEC, and ETEC. PMID- 23639598 TI - The ghrelin agonist RM-131 accelerates gastric emptying of solids and reduces symptoms in patients with type 1 diabetes mellitus. AB - BACKGROUND & AIMS: RM-131, a synthetic ghrelin agonist, greatly accelerates gastric emptying of solids in patients with type 2 diabetes and delayed gastric emptying (DGE). We investigated the safety and effects of a single dose of RM-131 on gastric emptying and upper gastrointestinal (GI) symptoms in patients with type 1 diabetes and previously documented DGE. METHODS: In a double-blind cross over study, 10 patients with type 1 diabetes (age, 45.7 +/- 4.4 y; body mass index, 24.1 +/- 1.1 kg/m(2)) and previously documented DGE were assigned in random order to receive a single dose of RM-131 (100 MUg, subcutaneously) or placebo. Thirty minutes later, they ate a radiolabeled solid-liquid meal containing EggBeaters (ConAgra Foods, Omaha, NE), and then underwent 4 hours of gastric emptying and 6 hours of colonic filling analyses by scintigraphy. Upper GI symptoms were assessed using a daily diary, gastroparesis cardinal symptom index (total GCSI-DD) and a combination of nausea, vomiting, fullness, and pain (NVFP) scores (each rated on a 0-5 scale). RESULTS: At screening, participants' mean level of hemoglobin A1c was 9.1% +/- 0.5%; their total GCSI-DD score was 1.66 +/- 0.38 (median, 1.71), and their total NVFP score was 1.73 +/- 0.39 (median, 1.9). The t1/2 of solid gastric emptying was 84.9 +/- 31.6 minutes when subjects were given RM-131 and 118.7 +/- 26.7 when they were given a placebo. The median difference (Delta)was 33.9 minutes (interquartile range [IQR] -12, -49), or -54.7% (IQR, -21%,-110%). RM-131 decreased gastric retention of solids at 1 hour (P = .005) and 2 hours (P = .019). Numeric differences in t1/2 for gastric emptying of liquids, solid gastric emptying lag time, and colonic filling at 6 hours were not significant. Total GCSI-DD scores were 0.79 on placebo (IQR, 0.75, 2.08) and 0.17 on RM-131 (IQR, 0.00, 0.67; P = .026); NVFP scores were lower on RM-131 (P = .041). There were no significant adverse effects. CONCLUSIONS: RM-131 significantly accelerates gastric emptying of solids and reduces upper GI symptoms in patients with type 1 diabetes and documented DGE. PMID- 23639599 TI - Bowel functions, fecal unconjugated primary and secondary bile acids, and colonic transit in patients with irritable bowel syndrome. AB - BACKGROUND & AIMS: There is an unclear relationship among bowel symptoms, excretion of unconjugated fecal bile acid (UBA), and colonic transit in irritable bowel syndrome (IBS). We measured total and main individual UBA in fecal samples of patients with IBS and assessed relationships among stool frequency or consistency, fecal UBA (total and individual), and colonic transit. METHODS: In this study 30 healthy volunteers (controls), 31 subjects with IBS with diarrhea (IBS-D), and 30 with IBS with constipation (IBS-C) were placed on 4-day diets containing 100 g fat; we measured stool characteristics, total fecal UBA and fat levels, and overall colonic transit. We assessed univariate associations of total and individual levels of fecal UBA with phenotype (controls, IBS-D, IBS-C) by using the Kruskal-Wallis test; associations between end points were assessed by using Spearman correlations. With response surface regression models, we assessed relationships between stool, colonic transit, and fecal total and secretory UBA. RESULTS: There was a significant association between total fecal UBA and phenotype (P = .029); the association was greater for IBS-D than IBS-C, compared with controls. Fecal levels of primary UBAs (cholic and chenodeoxycholic acids) were higher in subjects with IBS-D, compared with controls (both P < .01). Levels of fecal secretory UBAs (chenodeoxycholic acid, P = .019; deoxycholic acid, P = .025) were lower in subjects with IBS-C compared with controls, whereas levels of the nonsecretory UBA, lithocholic acid, were higher (P = .020). There were significant univariate associations between stool number and form and total fecal UBA (including percentages of lithocholic acid, chenodeoxycholic acid and cholic acid), fecal fat, and colonic transit at 24 and 48 hours after eating. In the regression models, the relative contribution of colonic transit was consistently greater and largely independent of the contribution of bile acids. CONCLUSIONS: Measurements of individual UBAs identify changes associated with stool characteristics in patients with IBS; these effects are independent of the effects of colonic transit. PMID- 23639600 TI - Clinical performance of an automated stool DNA assay for detection of colorectal neoplasia. AB - BACKGROUND & AIMS: Colorectal cancer (CRC) and advanced precancers can be detected noninvasively by analyses of exfoliated DNA markers and hemoglobin in stool. Practical and cost-effective application of a stool DNA-based (sDNA) test for general CRC screening requires high levels of accuracy and high-capacity throughput. We optimized an automated sDNA assay and evaluated its clinical performance. METHODS: In a blinded, multicenter, case-control study, we collected stools from 459 asymptomatic patients before screening or surveillance colonoscopies and from 544 referred patients. Cases included CRC (n = 93), advanced adenoma (AA) (n = 84), or sessile serrated adenoma >=1 cm (SSA) (n = 30); controls included nonadvanced polyps (n = 155) or no colonic lesions (n = 641). Samples were analyzed by using an automated multi-target sDNA assay to measure beta-actin (a marker of total human DNA), mutant KRAS, aberrantly methylated BMP3 and NDRG4, and fecal hemoglobin. Data were analyzed by a logistic algorithm to categorize patients as positive or negative for advanced colorectal neoplasia (CRC, advanced adenoma, and/or SSA >=1 cm). RESULTS: At 90% specificity, sDNA analysis identified individuals with CRC with 98% sensitivity. Its sensitivity for stage I cancer was 95%, for stage II cancer it was 100%, for stage III cancer it was 96%, for stage IV cancer it was 100%, and for stages I III cancers it was 97% (nonsignificant P value). Its sensitivity for advanced precancers (AA and SSA) >=1 cm was 57%, for >2 cm it was 73%, and for >3 cm it was 83%. The assay detected AA with high-grade dysplasia with 83% sensitivity. CONCLUSIONS: We developed an automated, multi-target sDNA assay that detects CRC and premalignant lesions with levels of accuracy previously demonstrated with a manual process. This automated high-throughput system could be a widely accessible noninvasive approach to general CRC screening. PMID- 23639601 TI - Education provides significant benefits to patients with hepatitis B virus or hepatitis C virus infection: a systematic review. AB - BACKGROUND & AIMS: Education of individuals who are at risk for, or have been diagnosed with, chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections can improve their participation in disease management. We performed a systematic review to evaluate the effects of educational interventions for patients with HBV or HCV infections. METHODS: We searched multiple databases for peer-reviewed studies of individuals with HBV or HCV infection, or those at risk for infection. Our final analysis included 14 studies that evaluated any educational intervention and reported the effectiveness or patient outcomes relevant to the intervention (7 patients with HCV infection, 4 patients with HBV infection, and 3 patients with either). Data extracted from studies included details on educational interventions, patient populations, comparison groups, and outcome measures. The quality of each study was appraised. RESULTS: Types of educational interventions assessed ranged from information websites and nurse-led sessions to community-wide and institutional programs. The educational interventions showed significant (P < .05) improvements to patients' knowledge about their disease, behaviors (including testing and uptake of vaccination), willingness to commence and adhere to treatment, and other outcomes such as self efficacy and vitality or energy scores. These significant benefits were shown in 5 of 7 studies of HBV infection and 8 of 10 studies of HCV infection. On a 20 point quality scale, study scores ranged from 6 to 19. CONCLUSIONS: Simple educational interventions for patients with HBV or HCV infection significantly increase patients' knowledge about their disease. More complex, multimodal educational interventions seem to cause behavioral changes that increase rates of testing, vaccination (for HBV), and treatment. PMID- 23639602 TI - Prevention of interval colorectal cancers: what every clinician needs to know. AB - Colonoscopic screening and surveillance have been very effective tools in the fight against colorectal cancer (CRC). Colonoscopy is more than a cancer screening test; it also can prevent CRC by detecting and removing precancerous lesions. Despite this potential, there has been increasing concern about CRCs that occur after a previous colonoscopy and before the next screening/surveillance examination (interval CRCs). The etiology of interval CRC is thought to be caused mostly by missed or incompletely resected lesions on index colonoscopy with some contribution of rapidly progressive new lesions. If this is true, many interval cancers should be preventable by improving colonoscopy technique. There are a variety of strategies to decrease interval CRC rates including use of a split-dosed bowel preparation, optimizing withdrawal technique, ensuring complete polypectomy, and careful pathologic examination of the tissue removed. Furthermore, there should be an increased emphasis on how endoscopists are trained to cultivate high-quality technique throughout their careers. It is important to inform patients that even high-quality colonoscopy is not perfectly sensitive for the detection of advanced neoplasia. Improving colonoscopy quality can decrease interval CRC rates and further decrease CRC incidence and mortality. PMID- 23639603 TI - Gliadin does not induce mucosal inflammation or basophil activation in patients with nonceliac gluten sensitivity. AB - BACKGROUND & AIMS: Nonceliac gluten-sensitive (NCGS) patients report intestinal and extra-intestinal symptoms shortly after ingesting gluten; these symptoms disappear on gluten-free diets, although these patients have no serologic markers of celiac disease or intestinal damage. In fact, there is no evidence for mucosal or serologic modifications in those individuals. We investigated immunologic responses of duodenal mucosa samples and peripheral blood basophils, isolated from NCGS patients, after exposure to gliadin. METHODS: Participants underwent a complete clinical evaluation to exclude celiac disease while on a gluten containing diet, a skin prick test to exclude wheat allergy, and upper endoscopy (n = 119) at 2 tertiary medical centers in Italy. Patients were considered to have NCGS based on their symptoms and the current definition of the disorder. Subjects were assigned to the following groups: patients with celiac disease on gluten-free diets (n = 34), untreated patients with celiac disease (n = 35), patients with NCGS (n = 16), or controls (n = 34). Duodenal biopsy samples collected during endoscopy were incubated with gliadin peptides, and levels of inflammatory markers were assessed. Peripheral blood basophils were extracted and incubated with gliadin peptides or a mix of wheat proteins; activation was assessed based on levels of CD203c, CD63, and CD45. RESULTS: Duodenal mucosa samples collected from 69 patients with celiac disease showed markers of inflammation after incubation with gliadin. Some, but not all, markers of inflammation were detected weakly in biopsy samples from 3 controls and 3 NCGS patients (P = .00 for all markers). There were no significant increases in the levels of CD63 and CD203c in NCGS patients. CONCLUSIONS: Unlike the duodenal mucosa from patients with celiac disease, upon incubation with gliadin, mucosa from patients with NCGS does not express markers of inflammation, and their basophils are not activated by gliadin. The in vitro gliadin challenge therefore should not be used to diagnose NCGS. PMID- 23639604 TI - Esophageal tuberculosis during treatment of hepatitis C. PMID- 23639605 TI - Clinical utility of a standardized electronic order set for the management of acute upper gastrointestinal hemorrhage in patients with cirrhosis. AB - BACKGROUND & AIMS: Recent reductions in mortality after acute upper gastrointestinal hemorrhage among patients with cirrhosis have been attributed to early and aggressive use of guideline-recommended pharmacologic agents, antibiotics, and endoscopic therapy. Studies have shown, however, that adherence to recommended guidelines is low. We investigated whether use of a standardized electronic order set would improve adherence to treatment and timeliness of delivery. METHODS: We performed a prospective observational study, implementing an electronic order set for 123 patients with known or suspected cirrhosis who presented with symptoms/signs of upper gastrointestinal hemorrhage at Parkland Memorial Hospital (in Dallas, TX) from July 2011 through June 2012. The order set included standard nursing orders, laboratory tests, medications, orders for consultative services, and a brief evidence-based review of the benefits of octreotide and antibiotics in patients with cirrhosis. Primary outcomes included overall adherence to the administration of octreotide and antibiotics and the performance of upper endoscopy, as well as time to these interventions. RESULTS: Administration of antibiotics increased in patients for whom the order set was used (100% vs 89% for whom it was not used; P = .01); the use of the order set significantly reduced the time to administration of antibiotics (3 h 28 min vs 10 h 4 min; P < .001). The time to administration of octreotide also significantly was reduced for patients for whom the order set was used (2 h 16 min vs 6 h 21 min; P < .002). Although all patients underwent endoscopy, there was no significant difference in the time to procedure between patients for whom the order set was used and not used (17 h 54 min vs 18 h 5 min; P = .95). CONCLUSIONS: The use of a standardized electronic order set improved not only overall adherence, but also the timeliness of administration of recommended therapies for patients with known or suspected cirrhosis presenting with upper gastrointestinal hemorrhage. PMID- 23639606 TI - Cesarean section reduces perinatal transmission of hepatitis B virus infection from hepatitis B surface antigen-positive women to their infants. AB - BACKGROUND & AIMS: Despite appropriate passive and active immunization, perinatal transmission of hepatitis B virus (HBV) still occurs in 5%-10% of infants born to women with high levels of viremia who test positive for the hepatitis B e antigen (HBeAg). We evaluated the effects of cesarean section delivery on perinatal transmission of HBV from women who tested positive for the hepatitis B surface antigen (HBsAg). METHODS: We analyzed data from 1409 infants born to HBsAg positive mothers through vaginal delivery (VD) (n = 673), elective caesarean section (ECS) (n = 496), or urgent cesarean section (UCS) (n = 240) who completed appropriate immunization against HBV. The prevention was assumed to have failed for infants who were HBsAg positive when they were 7-12 months old; this information was used to assess transmission rates. RESULTS: HBV infection was transmitted to a smaller percentage of infants born by ECS (1.4%) than by VD (3.4%, P < .032) or UCS (4.2%, P < .020). UCS had no effect on vertical transmission, compared with VD (4.2% vs 3.4%, P = .593). Infants born by ECS had a significantly lower rate of vertical transmission than those born by non-ECS (1.4% vs 3.6%, P = .017). Women with HBV DNA levels <1,000,000 copies/mL did not transmit the infection to their infants, regardless of method of delivery. There were no differences in maternal or infant morbidity and mortality among the groups. CONCLUSIONS: There is a significantly lower rate of vertical transmission of HBV infection to infants delivered by ECS, compared with those delivered vaginally or by UCS. Elective cesarean sections for HBeAg-positive mothers with pre-delivery levels of HBV DNA >=1,000,000 copies/mL could reduce vertical transmission. PMID- 23639607 TI - Prevention of mother-to-child transmission of hepatitis B virus: is elective cesarean section in highly viremic mothers an appropriate adjunct to immunoprophylaxis? PMID- 23639608 TI - Impaired glucose metabolism and health related quality of life. AB - AIMS: We aimed at investigating whether different categories of glucose tolerance have any effect on a person's HRQoL. METHODS: Population-based cross-sectional study conducted as a community sample of apparently healthy middle-aged individuals living in Western Finland. The subjects of the study, 1383 individuals, aged 45-70 years, had at least one cardiovascular risk factor but no previous diagnoses of either diabetes or cardiovascular disease. They completed health related quality of life (HRQoL) questionnaire before the oral glucose tolerance test (OGTT) was performed to diagnose the gategories of glucose tolerance. RESULTS: Persons with newly diagnosed type 2 diabetes (NDM) had lower scores for physical functioning, general health and emotional role than subjects with normal glucose tolerance. CONCLUSION: The results of the HRQoL questionnaire demonstrated that NDM is negatively associated with HRQoL, but prediabetes - IFG or IGT - does not. PMID- 23639609 TI - Risk factors for foot ulcers--a cross sectional survey from a primary care setting in Brazil. AB - AIMS: To identify the prevalence of higher risk of foot ulceration and associated factors among patients with diabetes mellitus (DM) at primary health care services. METHODS: Individuals with DM, registered at primary health care services in a municipality in southern Brazil, were interviewed and underwent foot examinations. Their risk of ulceration was classified in accordance with the recommendations of the International Working Group on the Diabetic Foot. Poisson bivariate and multivariate analyses were performed and adjusted prevalence ratios (PR) and 95% confidence intervals (CI) were calculated. RESULTS: The prevalence of higher risk of foot ulceration among the 337 interviewees was 27.9% (95% CI 23.1-32.9). The following factors were associated with this risk: having been diagnosed with DM for more than 10 years (Adjusted-PR 1.669; 95% CI 1.175-2.373; p=0.004); having had previous diagnoses of acute myocardial infarction (Adjusted PR 1.873; 95% CI 1.330-2.638; p<0.001) and stroke (Adjusted-PR 1.684; 95% CI 1.089-2.604; p=0.019); presenting interdigital mycosis (Adjusted-PR 1.539; 95% CI 1.030-2.300; p=0.035) and calluses (Adjusted-PR 1.654; 95% CI 1.117-2.451; p=0.012). CONCLUSIONS: The prevalence of higher risk of ulceration was high, which reinforces the importance of continued education for health care professionals in order to prevent complications in the feet of these patients. PMID- 23639610 TI - Assessment of awareness of diabetic retinopathy and utilization of eye care services among Turkish diabetic patients. AB - AIMS: Raising awareness of diabetic retinopathy (DR) was shown to be a key element for early diagnosis and treatment of this blinding disease. There is very limited data about the knowledge level, attitude, and behavior of diabetic patients regarding DR in Turkey. This study was planned to assess the awareness of DR and the utilization of eye care services among Turkish diabetic patients. METHODS: Diabetic patients who were under the care of ophthalmologists, endocrinologists, and/or primary care physicians were administered a questionnaire in order to assess their awareness of diabetes and its ocular complications. RESULTS: A total of 437 patients (51.8% female and 48.2% male) with a mean age of 55.2 +/- 11.9 were included in the study. Of the 437 patients, 31.8% had not been educated about diabetes, 88.1% were aware that diabetes can affect the eyes, and 39.8% thought that diabetics with good glycaemic control might suffer from DR. While 86.7% thought that early diagnosis was possible in DR, 77.3% previously had eye examinations, and 41.9% stated that annual eye examinations were necessary for diabetics. An educational level of middle school or higher, duration of DM longer than 5 years, previous DM education, and recruitment from the university (ophthalmology department and endocrinology department) were associated with better awareness of DR. The independent factors associated with visiting an ophthalmologist on a regular basis were DM education, DM duration, and site of recruitment. CONCLUSION: Although most of the patients know that DM affects the eye, there is a lack of appropriate knowledge and behavior about the management of DR. The importance of better control of DM and regular eye examination in the prevention of DR should be emphasized. PMID- 23639611 TI - Cellular responses to TGFbeta and TGFbeta receptor expression in human colonic epithelial cells require CaSR expression and function. AB - CaSR and TGFbeta are robust promoters of differentiation in the colonic epithelium. Loss of cellular responses to TGFbeta or loss of CaSR expression is tightly linked to malignant progression. Human colonic epithelial CBS cells, originally developed from a differentiated human colon tumor, retain CaSR expression and function, TGFbeta responsiveness and TGFbeta receptor expression. Thus, these cells offer a unique opportunity in determining the functional linkage (if any) between CaSR and TGFbeta. Knocking down CaSR expression abrogated TGFbeta-mediated cellular responses and attenuated the expression of TGFbeta receptors. Ca2+ or vitamin D treatment induced CaSR expression with a concurrent up-regulation of TGFbeta receptor expression. Ca2+ or vitamin D, however, did not induce CaSR in CaSR knocked down cells and without CaSR; there was no up-regulation of TGFbeta receptor. It is concluded that TGFbeta receptor expression and TGFbeta mediated responses requires CaSR expression and function. PMID- 23639613 TI - The end of the road for empirical antifungal treatment? PMID- 23639612 TI - Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial. AB - BACKGROUND: Empirical treatment with antifungal drugs is often used in haematology patients at high risk of invasive aspergillosis. We compared a standard diagnostic strategy (culture and histology) with a rapid biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) for directing the use of antifungal treatment in this group of patients. METHODS: In this open-label, parallel-group, randomised controlled trial, eligible patients were adults undergoing allogeneic stem-cell transplantation or chemotherapy for acute leukaemia, with no history of invasive fungal disease. Enrolled patients were randomly assigned (1:1) by a computer-generated schedule to follow either a standard diagnostic strategy (based on culture and histology) or a biomarker based diagnostic strategy (aspergillus galactomannan and PCR) to direct treatment with antifungal drugs. Patients, were followed up for 26 weeks or until death. Masking of the use of different diagnostic tests was not possible for patients, treating physicians, or investigators. The primary endpoint was empirical treatment with antifungal drugs in the 26 weeks after enrolment (for the biomarker-based diagnostic strategy, a single postive galactomannan or PCR result was deemed insufficient to confirm invasive aspergillosis, so treatment in this context was classified as empirical). This outcome was assessed by an independent data review committee from which the study allocations were masked. Analyses were by intention to treat and included all enrolled patients. This study is registered with ClinicalTrial.gov, number NCT00163722. FINDINGS: 240 eligible patients were recruited from six Australian centres between Sept 30, 2005, and Nov 19, 2009. 122 were assigned the standard diagnostic strategy and 118 the biomarker-based diagnostic strategy. 39 patients (32%) in the standard diagnosis group and 18 (15%) in the biomarker diagnosis group received empirical antifungal treatment (difference 17%, 95% CI 4-26; p=0.002). The numbers of patients who had hepatotoxic and nephrotoxic effects did not differ significantly between the standard diagnosis and biomarker diagnosis groups (hepatotoxic effects: 21 [17%] vs 12 [10%], p=0.11; nephrotoxic effects: 52 [43%] vs 60 [51%], p=0.20). INTERPRETATION: Use of aspergillus galactomannan and PCR to direct treatment reduced use of empirical antifungal treatment. This approach is an effective strategy for the management of invasive aspergillosis in high-risk haematology patients. FUNDING: Australian National Health and Medical Research Council, Cancer Council New South Wales, Pfizer, Merck, Gilead Sciences. PMID- 23639614 TI - Frameworks and guidelines for research--three examples. PMID- 23639615 TI - Imitation of an action course in preschool and school-aged children: a hierarchical reconstruction. AB - Imitation is commonly considered as a hierarchical process. The current study explored the reproduction of a multi-task course in deferred imitation. Eighty five children between 3.5 and 7.5 years old were divided into five groups and instructed to watch a live human adult demonstrator who performed simple successive actions, such as walking, jumping, grasping, carrying objects from one location to another through six sessions. After a five-minute delay, the children were individually instructed to reproduce the course. Their responses were videotaped and coded in dichotomous data at two hierarchical levels, namely goals and their spatial location. The main findings showed no improvement in the replication of goals due either to age or trials. However, there was an improvement in the integration of the goals' spatial location over trials. This signifies that imitation is an active reconstruction mechanism hierarchically organized. PMID- 23639616 TI - The C-terminal region of Rad52 is essential for Rad52 nuclear and nucleolar localization, and accumulation at DNA damage sites immediately after irradiation. AB - Rad52 plays essential roles in homologous recombination (HR) and repair of DNA double-strand breaks (DSBs) in Saccharomyces cerevisiae. However, in vertebrates, knockouts of the Rad52 gene show no hypersensitivity to agents that induce DSBs. Rad52 localizes in the nucleus and forms foci at a late stage following irradiation. Ku70 and Ku80, which play an essential role in nonhomologous DNA-end joining (NHEJ), are essential for the accumulation of other core NHEJ factors, e.g., XRCC4, and a HR-related factor, e.g., BRCA1. Here, we show that the subcellular localization of EYFP-Rad52(1-418) changes dynamically during the cell cycle. In addition, EYFP-Rad52(1-418) accumulates rapidly at microirradiated sites and colocalizes with the DSB sensor protein Ku80. Moreover, the accumulation of EYFP-Rad52(1-418) at DSB sites is independent of the core NHEJ factors, i.e., Ku80 and XRCC4. Furthermore, we observed that EYFP-Rad52(1-418) localizes in nucleoli in CHO-K1 cells and XRCC4-deficient cells, but not in Ku80 deficient cells. We also found that Rad52 nuclear localization, nucleolar localization, and accumulation at DSB sites are dependent on eight amino acids (411-418) at the end of the C-terminal region of Rad52 (Rad52 CTR). Furthermore, basic amino acids on Rad52 CTR are highly conserved among mammalian, avian, and fish homologues, suggesting that Rad52 CTR is important for the regulation and function of Rad52 in vertebrates. These findings also suggest that the mechanism underlying the regulation of subcellular localization of Rad52 is important for the physiological function of Rad52 not only at a late stage following irradiation, but also at an early stage. PMID- 23639617 TI - An unusual manifestation of a rare pleuropulmonary blastoma presenting with spinal cord compression and its neurosurgical implications. AB - Pleuropulmonary blastomas (PPB) are rare and biologically aggressive paediatric tumours. Although central nervous system metastatic dissemination is a recognised complication of PPB, to our knowledge, spinal cord compression has been described only in six patients. We report a 5-year-old boy with a diagnosis of recurrent type III PPB that was initially thought to be an empyema, who developed features of thoracic spinal cord compression secondary to local tumour infiltration. Although PPB demonstrate significant biologically aggressive behaviour, aggressive surgical resections together with adjuvant chemotherapy can help limit disease progression without impacting on the quality of life. Spinal metastatic disease should also be treated vigorously. In this paper we discuss the treatment strategies available in the management of PPB. PMID- 23639618 TI - An accelerometry-based study of lower and upper limb tremor in Parkinson's disease. AB - Over the past two decades, several studies have aimed to quantify the kinetic properties of tremor with primary focus on the upper limbs. However, there is a lack of investigation into the properties of tremor in the lower limbs. The objective of this preliminary study was to investigate the properties of oscillatory movement, at rest and in posture, in both the upper and lower limbs of Parkinson's disease (PD) patients with clinically undetectable to modest rest/postural tremor and healthy controls. PD patients (N = 16) and controls (N = 8) were examined clinically by a movement disorders specialist and oscillatory movements in all four extremities were evaluated using a portable biaxial accelerometer. While tremor intensity and frequency did not differ between groups, the intraindividual variability of rest and postural tremor frequency in the dexterity-dominant lower limb was lower in people living with PD than in healthy adults. Additionally, rest tremor frequency was discrepant between upper and lower limbs in PD. Our work introduces the possibility that minute variations in lower limb movements, which are imperceptible upon expert clinical exam, can be used to differentiate a diseased sample from a healthy one. These preliminary findings suggest that additional work using objective tremor measurement may improve our understanding of lower limb motor dysfunction in PD and lead to the refinement of current, and the development of new, metrics to enhance early diagnosis, differential diagnosis, and symptom quantification. PMID- 23639619 TI - Clinical trial participation and outcome for patients with glioblastoma: multivariate analysis from a comprehensive dataset. AB - Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Although multiple clinical and tumor-related variables affect survival outcomes, the effect of clinical trial participation has not been explored. The aim of this study was to determine whether clinical trial participation improves outcome for patients with GBM. Data from patients with GBM were accessed from a dataset collected over 12 years (1998-2010) at two institutions. Univariable and multivariate logistic regression analyses were performed to look for relationships between clinical trial participation, other baseline clinical and sociodemographic variables and overall survival (OS). In total, 542 patients were identified and included in the analysis; median age was 62 years. Sixty-one patients (11%) were enrolled in a clinical trial. Clinical trial enrollment was associated with improved median survival (14.5 months compared to 6.3 months, p < 0.001) and this difference remained significant in multivariate analysis (hazard ratio 0.67, p = 0.046). Age, poor performance status and operation type were also independent predictors for OS in multivariate analysis. Disease site, socioeconomic status and co-morbidity did not affect survival outcome. This is the first study in patients with GBM to suggest a survival benefit from clinical trial participation, independent of age and performance status; while also confirming the importance of other previously reported prognostic factors. This should encourage clinicians to offer trial therapies to patients with GBM and encourage patients to participate in available studies. PMID- 23639620 TI - Factors associated with survival for patients with glioblastoma with poor pre operative functional status. AB - Patients with glioblastoma (GB) are known to have poor prognoses, and among these patients, those with poor neurological function have an even poorer prognosis. Consequently, aggressive surgeries and adjuvant therapies are often withheld because of this dismal outlook. The effects of aggressive therapies in this small subset of patients remain unknown. The goal of this study was to evaluate outcomes and factors associated with survival for poor functioning patients who underwent aggressive resection of their GB. Adult patients who underwent surgical resection of an intracranial primary GB at an academic tertiary-care institution between 1997 and 2007 were retrospectively reviewed. Patients with a Karnofsky Performance Scale (KPS) score of <=60 were included. A total of 100 patients with primary GB met the inclusion criteria. The average age (+/- standard deviation) and KPS score of this cohort were 54 +/- 15 years and 53 +/- 12, respectively. No patient (0%) experienced perioperative mortality, and 0 (0%), 10 (10%), and 3 (3%) of patients incurred a new or increasing language, motor, and visual deficit, respectively. At last follow-up, 88 (88%) patients died with a median survival of 6.6 months. The factors associated with improved survival were age <65 year (p = 0.005), tumor size >2 cm (p = 0.01), radical tumor resection (p=0.01), and temozolomide (p = 0.001). This study identifies a subset of patients with poor functional status who may benefit from aggressive surgical resection. PMID- 23639621 TI - Spontaneous seizures in a rat model of multiple prenatal freeze lesioning. AB - Focal cortical dysplasia (FCD) is an important cause of intractable epilepsy. Previous rat studies have utilized freeze lesioning of neonatal animals to model FCD; however, such models are unable to demonstrate spontaneous seizures without seizure-provoking events. Therefore, we created an animal model with multiple FCD, produced during embryonic development, and observed whether spontaneous seizures occurred. Furthermore, we examined the relationship between FCD and epileptogenesis using immunohistochemistry. At 18 days postconception, a frozen metal probe was placed bilaterally on the scalps of Sprague-Dawley rat embryos through the uterus wall to produce multiple FCD. Electroencephalogram (EEG) and video recording were performed from postnatal day (P) 35 to P77. Brain tissues were examined immunohistochemically at P28 and P78 using semiquantitative densitometry. Eleven of 16 rats (68.8%) showed spontaneous seizures arising in the hippocampus from P47. Movement cessation followed by sniffing and mastication, culminating in wet-dog shaking, was seen during the hippocampal EEG discharges. FCD was observed in the bilateral frontoparietal lobes. The expression levels of N-methyl-d-aspartate receptor (NMDAR) subunits 1, 2A, 2B, the glutamate/aspartate transporter and the glial glutamate transporter 1 (GLT1) at FCD sites were increased at P28 and P78. There were no major histological abnormalities in the hippocampi compared with those in the cortex. However, the expression levels of NMDAR 2A and 2B were increased at P28. Levels of NMDAR1, 2A and 2B, the glutamate/aspartate transporter and GLT1 were also increased at P78. We created an animal model showing spontaneous seizures without a provoking event except for the existence of cortical dysplasia, and without a genetic or general systematic cause like MAM injection or irradiation. The seizures resembled human temporal lobe epilepsy both clinically and on EEG. Alterations in the levels of glutamatergic and GABAergic receptors were investigated during growth. This model should enable better clarification of the mechanisms underlying the development of human epilepsy. PMID- 23639622 TI - Survey of factors affecting health care workers' perception towards institutional and individual disaster preparedness. AB - INTRODUCTION: Health care institutions constantly must be prepared for disaster response. However, there are deficiencies in the current level of preparedness. The aim of this study was to investigate the factors affecting the perception of health care workers (HCWs) towards individual and institutional preparedness for a disaster. METHODS: A survey on disaster incident preparedness was conducted among doctors, nurses, and allied health workers over a period of two months in 2010. The survey investigated perceptions of disaster preparedness at the individual and institutional level. Responses were measured using a five-point Likert scale. The primary outcomes were factors affecting HCWs' perception of institution and individual preparedness. Secondary outcomes were the proportions of staff willing to participate and to place importance on disaster response training and their knowledge of access to such training. Data was analyzed using descriptive statistics. Logistic regression was performed to determine the factors that influenced the HCWs' perception of their individual and institutional readiness. Odd ratios (ORs) of such factors were reported with their 95% confidence intervals (CIs). RESULTS: Of 1700 HCWs, 1534 (90.2%) completed the survey. 75.3% (1155/1534) felt that the institution was ready for a disaster incident, but only 36.4% (558/1534) felt that they (as individuals) were prepared. Some important factors associated with a positive perception of institution preparedness were leadership preparedness (OR = 13.19; 95% CI, 9.93 17.51), peer preparedness (OR = 6.11; 95% CI, 4.27-8.73) and availability of training opportunities (OR = 4.76; 95% CI, 3.65-6.22). Some important factors associated with a positive perception of individual preparedness were prior experience in disaster response (OR = 2.80; 95% CI, 1.99-3.93), institution preparedness (OR = 3.71; 95% CI, 2.68-5.14), peer preparedness (OR = 3.49; 95% CI, 2.75-4.26), previous training in disaster response (OR = 3.48; 95% CI, 2.76 4.39) and family support (OR = 3.22; 95% CI, 2.54-4.07). Most (80.7%, 1238/1534) were willing to participate in future disaster incident response training, while 74.5% (1143/1534) felt that being able to respond to a disaster incident constitutes part of their professional competency. However, only 27.8% (426/1534) knew how to access these training opportunities. CONCLUSIONS: This study demonstrated that HCWs fare poorly in their perception of their individual preparedness. Important factors that might contribute to improving this perception at the individual and institution level have been identified. These factors could guide the review and implementation of future disaster incident response training in health care institutions. PMID- 23639623 TI - Genetic variation in AKT1, PTEN and the 8q24 locus, and the risk of testicular germ cell tumor. AB - STUDY QUESTION: Is there an association between testicular germ cell tumor (TGCT) and genetic polymorphisms in AKT1, PTEN and the 8q24 locus? SUMMARY ANSWER: Our findings suggest that genetic variation in PTEN may influence the risk of TGCT. WHAT IS KNOWN ALREADY: There is strong evidence that genetic variation influences the risk of TGCT. The oncogene, AKT1, the tumor suppressor gene, PTEN and the chromosome 8q24 locus play important roles in cancer development in general. STUDY DESIGN, SIZE, DURATION: We have conducted a population-based Norwegian Swedish case-parent study, based on cases diagnosed in 1990-2008, including 831 triads (TGCT case and both parents), 474 dyads (TGCT case and one parent) and 712 singletons (only the TGCT case). In addition we expanded the study to include 3922 unrelated male controls from the TwinGene project. PARTICIPANTS/MATERIALS, SETTING, METHODS: We genotyped 26 single nucleotide polymorphisms (SNPs) in AKT1, PTEN and the 8q24 locus. First, triads and dyads were included in a likelihood based association test. To increase the statistical power, case singletons and controls from the TwinGene project were included in a single test for association. We examined if the allelic effect on TGCT risk differed by histological subgroup, country of origin or parent of origin. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated with Bonferroni correction (P bonf) for multiple testing. MAIN RESULTS AND THE ROLE OF CHANCE: In the case parent analyses, none of the 26 SNPs were significantly associated with TGCT. Of the 23 SNPs investigated in the combined study, one SNP in PTEN (rs11202586) remained associated with TGCT risk after adjusting for multiple testing (OR = 1.16, 95% CI = 1.06-1.28, P bonf = 0.040). We found no difference in risk according to histological subgroup, parent of origin or between countries. LIMITATIONS, REASONS FOR CAUTION: Our study is strengthened by the population based design and large sample size, which gives high power to detect risk alleles. The reported association was not highly significant, and although it was based on an a priori hypothesis of this tumor suppressor gene being implicated in the etiology of TGCT, replication studies, as well as functional studies of this polymorphism, are warranted. WIDER IMPLICATIONS OF THE FINDINGS: We report, to our knowledge, a novel association between TGCT and a marker in the tumor suppressor gene PTEN. Previous studies have linked PTEN to TGCT etiology, and there is also a link between PTEN and KITLG, which contains TGCT susceptibility loci revealed through recent genome-wide studies. PMID- 23639624 TI - Clinical significance of ventricular tachyarrhythmias in patients treated with CRT-D. AB - BACKGROUND: Data on the outcome of cardiac resynchronization therapy with defibrillator (CRT-D) in patients developing ventricular arrhythmias are limited. OBJECTIVE: To evaluate the prognostic value of ventricular tachycardia (VT) or ventricular fibrillation (VF) episodes by heart rate in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial. METHODS: Slow VT was defined as VTs with heart rate < 200 beats/min. Fast VT with a heart rate >=200 beats/min and VF (>250 beats/min) were considered as a combined category. Primary end point was heart failure (HF) or death. Secondary end point included all-cause mortality. RESULTS: There were 228 (12.7%) patients with slow VT and 198 (11.1%) with fast VT/VF. In time-dependent analysis, slow VT was associated with an increased risk of HF/death in CRT-D patients with left branch bundle block (LBBB; hazard ratio [HR] 3.19; 95% confidence interval [CI] 1.83-5.55; P < .001), but not in patients with implantable cardioverter-defibrillator (ICD) (HR 1.03; 95% CI 0.52-2.19; P = .867; interaction P value = .017). CRT-D patients with LBBB and fast VT/VF doubled their risk of HF/death compared to ICD patients (interaction P value = .06). Slow VT events were also predictive of death in CRT-D patients with LBBB (HR 3.48; 95% CI 1.66-7.28; P < .001), but not in ICD patients (interaction P value = .06). Slow VTs were highly predictive of subsequent fast VT/VF (HR 4.33; 95% CI 3.01-6.24; P < .001). CONCLUSIONS: Slow VT episodes are predictive of subsequent fast VT/VF. Slow VT and fast VT/VF episodes in CRT-D patients are associated with an increased risk of subsequent HF/death. CRT-D-treated LBBB patients with slow VTs have a significantly higher risk of mortality. PMID- 23639625 TI - A randomised controlled trial of financial incentives to increase hepatitis B vaccination completion among people who inject drugs in Australia. AB - OBJECTIVE: This study aimed to investigate the efficacy of modest financial incentives in increasing completion of an accelerated 3-dose hepatitis B virus (HBV) vaccination schedule (0, 7, 21days) among people who inject drugs (PWID). METHODS: Randomised controlled trial. Participants were randomly allocated to receive $30 Australian Dollars cash following receipt of vaccine doses two and three ('incentive condition'), or standard care ('control condition'). Serologically confirmed HBV-susceptible PWID. Two inner-city health services and a field study site in Sydney, Australia. The primary outcome was completion of the vaccination series. Additional assessments included self-reported demographic, drug use and treatment, and risk-taking histories. RESULTS: Compared to the control condition, significantly more participants in the incentive condition received all three vaccine doses, under intention-to-treat analyses (n=139; 87% versus 66%; p=.004); and within the specified window periods under per protocol analyses (n=107 received three vaccine doses; 92% versus 67%; p=.001). Multivariate analysis indicated that the incentive condition and longer injecting histories significantly increased the likelihood of series completion. Aboriginal/Torres Strait Islanders were significantly less likely to complete the series. CONCLUSIONS: Modest financial incentives, per-dose, increased adherence to the accelerated HBV vaccination schedule among PWID. Results have implications for increasing HBV and, potentially, other vaccine-preventable infections, among PWID. PMID- 23639626 TI - TCDD induces the expression of insulin-like growth factor binding protein 4 in 5L rat hepatoma cells: a cautionary tale of the use of this cell line in studies on dioxin toxicity. AB - Previous quantitative proteomic studies on the actions of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) in 5L rat hepatoma cells, a cell model frequently used for investigating the mechanisms of TCDD toxicity, had indicated that dioxin exposure reduced the abundance of numerous proteins which are regulated at the level of protein synthesis initiation. In the present study, we have analysed the mechanism mediating this inhibition. TCDD treatment of the cells largely prevented the activation of eukaryotic translation initiation factor 4E-binding protein 1, a regulator of translation initiation and substrate of the mammalian target of rapamycin (mTOR). By "working upwards" from mTOR, we observed that TCDD inhibited endogenous and IGF-I-induced AKT and ERK activation by interfering with tyrosine phosphorylation of insulin receptor substrate 1. This inhibition was mediated by a TCDD-induced secreted factor which was identified as insulin-like growth factor binding protein 4 (IGFBP-4). The induction of IGFBP-4 protein was dependent on a functional aryl hydrocarbon receptor and was preceded by a rapid increase in the level of IGFBP-4 mRNA indicating that IGFBP-4 is a previously unknown transcriptional target of TCDD in 5L cells. IGFBP-4 was not induced by TCDD in the parental cell line of 5L cells, Fao, and in various closely related rat hepatoma cell lines as well as in other unrelated cell types. Analysis of 5L cell chromosomes by multicolour spectral karyotyping (SKY) revealed that the cells carry several hitherto uncharacterised chromosomal translocations. The observations suggest that in 5L cells the Igfbp-4 gene may have got under the control of a promoter containing dioxin responsive element(s) leading to the induction of IGFBP-4 by TCDD. These findings emphasise a particular caution when interpreting and extrapolating results on the action mechanisms of TCDD obtained in studies using 5L cells as a model system. PMID- 23639627 TI - Doxorubicin induces protein ubiquitination and inhibits proteasome activity during cardiotoxicity. AB - Anthracycline-induced cardiotoxicity is a clinically complex syndrome that leads to substantial morbidity and mortality for cancer survivors. Despite several years of research, the underlying molecular mechanisms remain largely undefined and thus effective therapies to manage this condition are currently non-existent. This study therefore aimed to determine the contribution of the ubiquitin proteasome pathway (UPP) and endoplasmic reticulum (ER)-stress within this context. Cardiotoxicity was induced with the use of doxorubicin (DXR) in H9C2 rat cardiomyoblasts (3 MUM) for 24 h, whereas the tumour-bearing GFP-LC3 mouse model was treated with a cumulative dose of 20 mg/kg. Markers for proteasome-specific protein degradation were significantly upregulated in both models following DXR treatment, however proteasome activity was lost. Moreover, ER-stress as assessed by increased ER load was considerably augmented (in vitro) with modest binding of DXR with ER. These results suggest that DXR induces intrinsic activation of the UPP and ER stress which ultimately contributes to dysfunction of the myocardium during this phenomenon. PMID- 23639628 TI - Antibodies against glycoprotein 2 are novel markers of intestinal inflammation in patients with an ileal pouch. AB - BACKGROUND AND AIMS: The Crohn's disease (CD)-specific pancreatic auto-antibodies (PAB), have been recently identified to target glycoprotein 2 (GP2). Pouchitis is an inflammation of the small bowel developing in up to 60% of ulcerative colitis patients undergoing proctocolectomy and ileal pouch anal anastomosis. Occurrence of CD-specific antibodies was reported to be a predictor of pouchitis. We aimed to assess the prevalence of anti-GP2 antibodies (anti-GP2) in the serum and feces of pouch patients and to correlate them with clinical parameters. Furthermore, we examined mucosal expression of the GP2 protein in the pouch. METHODS: Pouch patients were prospectively recruited and checked for clinical, endoscopic, and laboratory markers of inflammation. IgG and IgA anti-GP2 levels in serum and fecal samples were determined using ELISA. GP2 protein was assessed by immunohistochemistry. RESULTS: Anti-GP2 was elevated in both serum and fecal samples of patients with inflamed compared to those with non-inflamed pouches and patients with familial-adenomatous polyposis after surgery (p<0.05, respectively). Moreover, patients with CD-like complications exhibited significantly higher anti-GP2 titers than those without CD-like complications (p<=0.01). High levels of anti-GP2 correlated with more frequent bowel movements per day and with the presence of at least one anti-glycan antibody (p<=0.05). GP2 itself was more abundant in the mucosa of patients with chronic pouchitis. CONCLUSIONS: Anti-GP2 exists in the serum and feces of pouch patients and correlates with pouch inflammation, and presence of other serological markers. Thus, anti-GP2 may contribute to better stratification of pouchitis, more-so when the inflammation exhibits CD-like complications. PMID- 23639629 TI - Defect in Runx2 gene accelerates ureteral obstruction-induced kidney fibrosis via increased TGF-beta signaling pathway. AB - Runt-related transcription factor 2 (Runx2) plays an important role in bone formation and de novo synthesis of proteins, including type 1 collagen. Runx2 has a potent effect on signaling of transforming growth factor (TGF)-beta and vice versa, implicating its significant role in fibrosis. Chronic renal failure comprises fibrosis, characterized as an increase in TGF-beta signaling, and expression of alpha-smooth muscle actin (alpha-SMA), and extracellular matrix proteins. Here, we evaluated the role of Runx2 in ureteral obstruction (UO) induced kidney fibrosis using mice whose Runx2 gene expression is genetically down-regulated. UO caused tubular atrophy and dilation, expansion of interstitium, and increased expression of collagens and alpha-SMA with a concomitant decrease in expression of Runx2. Deficiency of Runx2 gene (Runx2(+/-) mice) showed higher expression of collagens and alpha-SMA in the kidney following UO compared to wild type (Runx2(+/+)) mice. UO-induced activation of TGF-beta signaling was higher in the Runx2(+/-) kidney than Runx2(+/+) kidney, suggesting an inhibitory effect of Runx2 on TGF-beta signaling in kidney fibrosis. Besides, overexpression of the Runx2 gene using an adenoviral vector in kidney tubule cells resulted in attenuated TGF-beta-induced Smad3 phosphorylation and expressions of alpha-SMA and collagen I. Furthermore, Runx2 gene deficient mouse embryonic fibroblasts induced greater activation of Smad3 and expression of alpha SMA in response to TGF-beta. Collectively, Runx2 plays a protective role in UO induced kidney fibrosis by inhibition of TGF-beta signaling, suggesting Runx2 as a novel target for protection against fibrosis-related diseases such as chronic renal failure. PMID- 23639630 TI - Vacuolar ATPase driven potassium transport in highly metastatic breast cancer cells. AB - Breast cancer is the second leading cause of death in women and thus has received a great deal of attention by researchers. Recent studies suggested decreased occurrence of cancer in patients treated with cardiac glycosides (CGs) for heart conditions. Because CGs induce their cellular effects via the Na(+), K(+) ATPase (Na-K), we treated four breast cancer cell lines (MCF-7, T47D, MDA-MB453, and MDA MB231) and a non-cancerous breast ductal epithelial cell line (MCF-10A) with ouabain, a well-characterized CG, and measured cell proliferation by measuring bromodeoxyuridine incorporation. Ouabain (1MUM) decreased cell proliferation in all cell lines studied except MDA-MB453 cells. Western blot of Na-K alpha and beta subunits showed alpha1, alpha3, and beta1 expression in all cell lines except MDA-MB453 cells where Na-K protein and mRNA were absent. Potassium uptake, measured as rubidium ((86)Rb) flux, and intracellular potassium were both significantly higher in MDA-MB453 cells compared to MCF-10A cells. RT-qPCR suggested a 7 fold increase in voltage-gated potassium channel (KCNQ2) expression in MDA-MB453 cells compared to MCF-10A cells. Inhibition of KCNQ2 prevented cell growth and (86)Rb uptake in MDA-MB453 cells but not in MCF-10A cells. All cancer cells had significantly higher vacuolar H-ATPase (V-ATPase) activity than MCF-10A cells. Inhibition of V-ATPase decreased (86)Rb uptake and intracellular potassium in MDA-MB453 cells but not in MCF-10A cells. The findings point to the absence of Na-K, high hERG and KCNQ2 expression, elevated V-ATPase activity and sensitivity to V-ATPase inhibitors in MDA-MB453. We conclude that cancer cells exhibit fundamentally different metabolic pathways for maintenance of intracellular ion homeostasis. PMID- 23639631 TI - The role of p21 Waf1/Cip1 in large airway epithelium in smokers with and without COPD. AB - Airway epithelium alterations, including squamous cell metaplasia, characterize smokers with and without chronic obstructive pulmonary disease (COPD). The p21 regulates cell apoptosis and differentiation and its role in COPD is largely unknown. Molecules regulating apoptosis (cytoplasmic p21, caspase-3), cell cycle (nuclear p21), proliferation (Ki67/PCNA), and metaplasia (survivin) in central airways from smokers (S), smokers-COPD (s-COPD) and non-smokers (Controls) were studied. The role of cigarette smoke extracts (CSE) in p21, survivin, apoptosis (caspase-3 and annexin-V binding) and proliferation was assessed in a bronchial epithelial cell line (16HBE). Immunohistochemistry, image analysis in surgical samples and flow-cytometry and carboxyfluorescein succinimidyl ester proliferative assay in 16HBE with/without CSE were applied. Cytoplasmic and nuclear p21, survivin, and Ki67 expression significantly increased in large airway epithelium in S and in s-COPD in comparison to Controls. Caspase-3 was similar in all the studied groups. p21 correlated with epithelial metaplasia, PCNA, and Ki67 expression. CSE increased cytoplasmic p21 and survivin expression but not apoptosis and inhibited the cell proliferation in 16HBE. In large airway epithelium of smokers with and without COPD, the cytoplasmic p21 inhibits cell apoptosis, promotes cell proliferation and correlates with squamous cell metaplasia thus representing a potential pre-oncogenic hallmark. PMID- 23639632 TI - Renal ultrasound volume in children with primary vesicoureteral reflux allows functional assessment. AB - OBJECTIVE: Renal scintigraphy represents the current diagnostic standard to assess split kidney function. We tested the hypothesis that the relative renal volume assessed by ultrasound provides an equally reliable but less invasive tool for assessment of kidney function as compared to renal scintigraphy in patients with primary vesicoureteral reflux. METHODS: Renal ultrasound and renal scintigraphy were performed in 85 patients (median age 4.5 years, range 0.25-7.7) and repeated in 74 patients after 2-13 months (mean 7) of the primary investigation. Renal size was measured by ultrasound, and relative renal volume was calculated for each kidney by using the formula of a prolate ellipsoid. Renal function was estimated for each side (split renal function) by scintigraphy with (99m)Tc MAG3. RESULTS: The mean difference between relative renal volume measured by ultrasound and split renal function determined by renal scintigraphy was 2.8% (standard deviation +/- 4.1%; 95% confidence interval 10.8/-5.2%). There was a statistically significant correlation between relative renal volume estimated by ultrasound and split renal function estimated by renal scintigraphy at first examination (r = 0.98; p < 0.001) and at follow-up (r = 0.91; p < 0.001). CONCLUSION: We conclude that ultrasound measurement of relative renal volume is capable of assessing split renal function in children with primary vesicoureteral reflux and, thus, should be considered instead of the more invasive MAG3 scintigraphy. PMID- 23639633 TI - [Clinical and radiologic evaluation of a polylactic acid interposition arthroplasty after trapezectomy]. AB - Surgical management of trapeziometacarpal osteoarthritis does not obey to strict rules. The use of interposition implants made of different materials leads to enrichment of surgeon's resources. This prospective study reports the radiological and clinical results of 45 patients treated by total trapeziectomy with polylactic acid interposition implant, with an average follow-up of 31 months. Thirty-seven surgical treatments were carried out after ineffective medical treatment. According to Dell classification, there were five stages II, 30 stages III and two stages IV. Mean age was 66 years. Dominant side was involved in 60%. Thumbs were pain free at 5 months in average and 81% of the patients reported good results (Alnot stages 0 and 1). The average opposition was 9.1/10, the average M1M2 angle was 40 degrees , and the average key pinch strength was 4.4 kg. Six patients suffered from sympathetic dystrophy but neither infection nor local inflammatory reaction was observed. Collapse of the trapezium space was constant and the trapezium space ratio was 76% at the follow-up. Seventy-five per cent of patients returned back to their occupation. The satisfaction rate was 89%. The radioclinical results were very good in our series. The interposition of polylactic acid implant permits to avoid the presumed complications of tendon harvesting, and those of other types of material used in the same indication. Its safety seems excellent. PMID- 23639634 TI - Potential role of annexin A7 in cancers. AB - Annexin A7 (Anxa7) is a member of the multigene annexin superfamily of Ca(2+) regulated and phospholipid-binding proteins. Accumulated evidence indicates that the deregulation, loss of heterozygosity (LOH) and subcellular localization of Anxa7 are associated with the occurrence, invasion, metastasis and progression of a variety of cancers. Anxa7 appears to have a tumor-suppression role in glioblastoma, glioblastoma multiforme (GBM), melanoma and prostate cancer (CaP) but, controversially and interestingly, Anxa7 also appears to promote the development and malignancies of liver cancer, gastric cancer (GC), nasopharyngeal carcinoma (NPC), colorectal cancer (CRC) and breast cancer (BC). The associations between Anxa7 and malignant tumors as well as potential mechanisms of action are summarized and discussed in current review. Anxa7 has potential for use as a biomarker for the diagnosis, treatment and prognosis of certain tumors. PMID- 23639635 TI - Tissue kallikrein is related to the severity of coronary artery disease. AB - BACKGROUND: The impairment of the tissue kallikrein (KLK1)-kinin system (KKS) may result in atheroma development. However, it remains unclear if the KKS correlates with coronary artery disease (CAD). METHODS: KLK1, VEGF and hs-CRP plasma levels were measured in 100 patients newly diagnosed with CAD and 33 CAD-free controls. Patients were followed-up for the incidence of major adverse cardiovascular events (MACE) for 8months to 2y. Gene expression of KLK1, CD105 and CD68 was assessed in human coronary endarterectomy specimens. RESULTS: Patients with CAD and acute coronary syndrome (ACS) had significantly elevated KLK1 levels. In addition, the concentration of hs-CRP was increased in ACS patients. A strong positive correlation between plasma KLK1 and the severity of CAD was also demonstrated, suggesting that high KLK1 levels are an independent predictor for CAD. MACE during follow-up significantly correlated with KLK1 levels in the ACS group. Unstable coronary plaques demonstrated markedly increased KLK1 levels, macrophage infiltration and high microvessel density. Additionally, KLK1 staining primarily colocalized with macrophages. CONCLUSIONS: In the present study, plasma KLK1 levels were a useful predictor for the presence and extent of CAD. More extensive studies are, however, necessary in order to validate these findings. PMID- 23639636 TI - Poring over pores: nuclear pore complex insertion into the nuclear envelope. AB - The nuclear boundary is formed by the nuclear envelope (NE), a double membrane system that establishes a selective barrier between the nucleoplasm and the cytoplasm. Its barrier characteristics are determined by nuclear pore complexes (NPCs); huge protein assemblies that guard nucleocytoplasmic compartmentalization. In this review, we discuss the biogenesis of NPCs during interphase of the cell cycle. This process requires a mechanistically enigmatic fusion step between the inner and the outer nuclear membrane. We focus on the principle of membrane pore formation in the NE and consider existing paradigms of other cellular membrane remodeling events. The emerging roles of transmembrane proteins and membrane-shaping factors in NPC biogenesis are discussed. PMID- 23639637 TI - Gastric cancer: overview. AB - This review provides a state of the art description of gastric cancer etiology, the infectious agent, host factors, the precancerous cascade, clinical aspects, and prevention strategies. The biology of Helicobacter pylori, the primary causative agent, is discussed as well as the environmental factors that may modulate its effects. PMID- 23639638 TI - Gastric cancer: epidemiology and risk factors. AB - Gastric cancer is one of the major malignancies in the world. This article summarizes the current understanding of the worldwide burden of this disease, its geographic variation, and temporal trends. An overview is presented of known risk factors, including genetic, dietary, and behavioral, but focuses on Helicobacter pylori infection as the most important factor in noncardia gastric cancer. When the data and the literature allow, we distinguish between cardia and noncardia sub-sites, as it is now clear that these two anatomic locations present distinct and sometimes opposite epidemiological characteristics. PMID- 23639639 TI - Genetics/genomics/proteomics of gastric adenocarcinoma. AB - Hereditary diffuse gastric cancer can be caused by epithelial cadherin mutations for which genetic testing is available. Inherited cancer predisposition syndromes including Lynch, Li-Fraumeni, and Peutz-Jeghers syndromes, can be associated with gastric cancer. Chromosomal and microsatellite instability occur in gastric cancers. Several consistent genetic and molecular alterations including chromosomal instability, microsatellite instability, and epigenetic alterations have been identified in gastric cancers. Biomarkers and molecular profiles are being discovered with potential for diagnostic, prognostic, and treatment guidance implications. PMID- 23639640 TI - Pathology of gastric cancer and its precursor lesions. AB - Gastric cancers are a histologically heterogenous group of neoplasms arising from unique epidemiologic and molecular backgrounds. There is accumulating evidence that the intestinal type of gastric adenocarcinoma develops through a multistep process beginning with chronic gastritis triggered primarily by Helicobacter pylori and progressing through atrophy, intestinal metaplasia, and dysplasia (intraepithelial neoplasia) to carcinoma. Loss of E-cadherin expression resulting from CDH1 gene alterations is the primary carcinogenetic event in hereditary diffuse gastric cancer. Proximal gastric adenocarcinomas likely result from either gastroesophageal reflux or H pylori gastritis. This article provides an update of the histologic, immunohistochemical, and molecular pathways of gastric cancer and its precursors. PMID- 23639642 TI - Gastric cancer chemoprevention: the current evidence. AB - Chemoprevention may form the cornerstone in the management of gastric adenocarcinoma of the future. Helicobacter pylori eradication and aspirin and/or nonsteroidal anti-inflammatory drug therapy have emerged as front-runner chemotherapeutic agents due to the putative pathogenic mechanisms that they address. Before a population-based chemopreventive strategy can be recommended on a large scale, randomized controlled trials with follow-up of more than 10 years of these 2 agents in populations at high gastric adenocarcinoma risk is urgently awaited. PMID- 23639643 TI - Screening and treating intermediate lesions to prevent gastric cancer. AB - Early gastric cancer is defined as adenocarcinoma confined to the mucosa or submucosa irrespective of lymph node involvement. In Japan, mucosal high-grade neoplasia is diagnosed as intramucosal early gastric cancer. Some early gastric cancers progress to advanced gastric cancer after several years of follow-up. Image-enhanced endoscopy (chromoendoscopy), narrow-band imaging, and magnifying endoscopy increase the diagnostic yield in characterizing early gastric cancer. Endoscopic resection of intramucosal early gastric cancer with endoscopic mucosal resection or endoscopic submucosal dissection is currently performed in East Asian countries to prevent the development of advanced gastric cancer and preserve patients' quality of life after treatment. PMID- 23639641 TI - Helicobacter pylori in gastric carcinogenesis: mechanisms. AB - Helicobacter pylori infection induces chronic inflammation and is the strongest known risk factor for gastric cancer. The genomes of H pylori are highly diverse and therefore bacterial virulence factors play an important role in determining the outcome of H pylori infection, in combination with host responses that are augmented by environmental and dietary risk factors. It is important to gain further understanding of the pathogenesis of H pylori infection to develop more effective treatments for this common but deadly malignancy. This review focuses on the specific mechanisms used by H pylori to drive gastric carcinogenesis. PMID- 23639645 TI - Modern oncological approaches to gastric adenocarcinoma. AB - Gastric cancer (GC) is a major health burden throughout the world, especially in certain endemic regions. GC is commonly diagnosed at an advanced stage because of the lack of early detection strategies and is usually associated with a dismal outcome. For patients with localized GC (LGC), surgery is the best cure: cure rates are highly associated with the surgical pathology stage. Adjunctive therapies improve the cure rates by about an additional 10%. Therefore, a multimodality approach is highly recommended for all patients with LGC. This article highlights some of the therapeutic advances made against GC and features important ongoing trials. PMID- 23639644 TI - Surgical considerations in the treatment of gastric cancer. AB - Gastric cancer is one of the most common malignancies in the world and is a leading cause of cancer death. Surgical treatment remains the best treatment option for potential cure and can be beneficial in the palliation of advanced disease. Several neoadjuvant chemotherapy regimens have been recently evaluated as potential adjuncts to surgery. This review describes the current role of surgical therapy in staging, resection, and palliation of gastric cancer. PMID- 23639646 TI - Gastric mucosal-associated lymphoid tissue lymphoma. AB - Gastric marginal zone B-cell lymphoma of mucosal-associated lymphoid tissue (MALT) is the predominant entity within the primary gastrointestinal lymphomas. Helicobacter pylori represents the decisive pathogenetic factor for gastric MALT lymphoma. The goal of treating gastric MALT lymphoma should be complete cure. The first choice of treatment is H pylori eradication. Patients with histologically persistent residual lymphoma after successful H pylori eradication and normalization of endoscopic findings should be managed by a watch-and-wait strategy. Patients who do not respond to H pylori eradication should be referred for radiation or chemotherapy. PMID- 23639647 TI - Gastric carcinoids (neuroendocrine neoplasms). AB - Gastric neuroendocrine neoplasms of the stomach can be divided into the usually well-differentiated, hypergastrinemia-dependent type I and II lesions and the more aggressively behaving gastrin-independent type III lesions. Studying menin and its complex interrelationship with gastrin may provide insight into tumor biology at the clinical level and in terms of basic cell biology (eg, the role of the epigenome in neuroendocrine cell proliferation), and lead to potential consideration of other targets that are known candidates for molecular-based therapies in other adenocarcinomas. PMID- 23639649 TI - Gastroenterology Clinics of North America. Gastric cancer. Preface. PMID- 23639650 TI - Synthesis and antitumor activities of naturally occurring oleanolic acid triterpenoid saponins and their derivatives. AB - Twenty-six naturally occurring oleanolic acid saponins and their derivatives, 16 of which were synthesized in this study, were preliminarily evaluated against human cancer cells. From SAR studies, the presence of alpha-l-rhamnosyl residue at the terminal of both C-3 and C-28 position for oleanolic acid bidesmosides was important to enhance cytotoxicity, and introducing more sugar residues at C3-OH of compound 12 with C-28 carboxylic acid is a favorable modification to ameliorate the anticancer activity. Furthermore, alpha-l-rhamnosyl moiety linked to C2-OH of the first monosaccharide (alpha-l-alabinose, beta-d-xylose, beta-d galactose or beta-d-glucose) in C3-OH of oleanolic acid was helpful to improve the cytotoxicity. According to the predicted log P values, lipophilicity of the synthesized saponins was not an important factor for cytotoxicity. PMID- 23639651 TI - Development of peptidomimetic boronates as proteasome inhibitors. AB - Proteasome inhibition has emerged over the past decade as an effective therapeutic approach for the treatment of hematologic malignancies. It is a multicatalytic complex, whose proteolytic activity relies in three types of subunits: chymotrypsin-like (beta5), trypsin-like (beta2) and caspase-like (beta1). Most important for the development of effective antitumor agents is the inhibition of the beta5 subunits. In this context, the dipeptide boronate bortezomib (Velcade((r))) represents the first proteasome inhibitor approved by the FDA and the lead compound in drug discovery. This paper describes the synthesis and biological evaluation of a series of conformationally constrained pseudopeptide boronates (1-3) structurally related to bortezomib. The synthesized compounds showed a promising inhibitory profile by blocking primarily the chymotrypsin-like activity of the proteasome with Ki values in submicromolar/micromolar range. These compounds also resulted quite selective since no significant inhibition was recorded in the test against bovine pancreatic alpha-chymotrypsin. The obtained results were rationalized by means of docking experiments based on a model of the crystal structure of bortezomib bound to the yeast 20S proteasome providing essential insights for further optimization of this class of inhibitors. PMID- 23639648 TI - Gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract. Soon after GIST was recognized as a tumor driven by a KIT or platelet-derived growth factor receptor mutation, it became the first solid tumor target for tyrosine kinase inhibitor therapies. More recently, alternative molecular mechanisms for GIST pathogenesis have been discovered. These are related to deficiencies in the succinate dehydrogenase complex, NF1 gene alterations in connection with neurofibromatosis type 1 tumor syndrome, and mutational activation of the BRAF oncogene in very rare cases. PMID- 23639652 TI - Synthetic chalcones and sulfonamides as new classes of Yersinia enterocolitica YopH tyrosine phosphatase inhibitors. AB - YopH plays a relevant role in three pathogenic species of Yersinia. Due to its importance in the prevention of the inflammatory response of the host, this enzyme has become a valid target for the identification and development of new inhibitors. In this work, an in-house library of 283 synthetic compounds was assayed against recombinant YopH from Yersinia enterocolitica. From these, four chalcone derivatives and one sulfonamide were identified for the first time as competitive inhibitors of YopH with binding affinity in the low micromolar range. Molecular modeling investigations indicated that the new inhibitors showed similar binding modes, establishing polar and hydrophobic contacts with key residues of the YopH binding site. PMID- 23639653 TI - Pyrazole derivatives as inhibitors of arachidonic acid-induced platelet aggregation. AB - Antiplatelet drugs are promising therapeutics to intervene with platelet aggregation in arterial thrombosis, most prominently in myocardial infarction and ischemic stroke. Here, we describe the synthesis and structure-activity relationships of potent inhibitors of platelet aggregation based on the 1,5 diarylpyrazol-3-carboxamide scaffold. Analogs from this series demonstrated potent anti-aggregatory activities against arachidonic acid-induced platelet aggregation, as measured by turbidimetric method of Born. 1,5-Diarylpyrazole-3 carboxamides obtained with small-basic amines (7, 8, 50, 51, 61, 62) displayed the strongest activity with IC50 values in low nanomolar range (5.7-83 nM). On the basis of their high potency in cellular environment, these straightforward pyrazole derivatives may possess potential in the design of more potent compounds for intervention with cardiovascular diseases. PMID- 23639654 TI - The evolving model of pediatric critical care delivery in North America. AB - The past 50 years have witnessed the emergence and evolution of the modern pediatric ICU and the specialty of pediatric critical care medicine. ICUs have become key in the delivery of health care services. The patient population within pediatric ICUs is diverse. An assortment of providers, including intensivists, trainees, physician assistants, nurse practitioners, and hospitalists, perform a variety of roles. The evolution of critical care medicine also has seen the rise of critical care nursing and other critical care staff collaborating in multidisciplinary teams. Delivery of optimal critical care requires standardized, reliable, and evidence-based processes, such as bundles, checklists, and formalized communication processes. PMID- 23639655 TI - The high-reliability pediatric intensive care unit. AB - In health care, reliability is the measurable capability of a process, procedure, or health service to perform its intended function in the required time under actual or existing conditions (as opposed to the ideal circumstances under which they are often studied). This article outlines the current state of reliability in a clinical context, discusses general principles of reliability, and explores the characteristics of high-reliability organizations as a desirable future state for pediatric critical care. PMID- 23639656 TI - Telemedicine in the pediatric intensive care unit. AB - Telemedicine technologies involve real-time, live, interactive video and audio communication and allow pediatric critical care physicians to have a virtual presence at the bedside of any critically ill child. Telemedicine use is increasing and will be a common technology in remote emergency departments, inpatient wards, and pediatric intensive care units. There is mounting data that demonstrate that the use of telemedicine technologies can result in higher quality of care, more efficient resource use and improved cost-effectiveness, and higher satisfaction among patients, parents, and remote providers compared to current models of care. PMID- 23639657 TI - The pediatric intensive care unit business model. AB - All pediatric intensivists need a primer on ICU finance. The author describes potential alternate revenue sources for the division. Differentiating units by size or academic affiliation, the author describes drivers of expense. Strategies to manage the bottom line including negotiations for hospital services are covered. Some of the current trends in physician productivity and its described metrics, with particular focus on clinical FTE management is detailed. Methods of using this data to enhance revenue are discussed. Some of the other current trends in the ICU business related to changes at the federal and state level as well as in the insurance sector, moving away from fee-for-service are covered. PMID- 23639658 TI - Advances in recognition, resuscitation, and stabilization of the critically ill child. AB - Advances in early recognition, effective response, and high-quality resuscitation before, during, and after cardiac arrest have resulted in improved survival for infants and children over the past 10 years. This review addresses several key factors that can make a difference in survival outcomes, including the etiology of pediatric cardiac arrests in and out of hospital, mechanisms and techniques of circulation of blood flow during cardiopulmonary resuscitation (CPR), quality of CPR, meticulous postresuscitative care, and effective training. Monitoring and quality improvement of each element in the system of resuscitation care are increasingly recognized as key factors in saving lives. PMID- 23639659 TI - Advances in monitoring and management of pediatric acute lung injury. AB - This article focuses on the respiratory management and monitoring of pediatric acute lung injury (ALI) as a specific cause for respiratory failure. Definitive, randomized, controlled trials in pediatrics to guide optimal ventilatory management are few. The only adjunct therapy that has been proved to improve clinical outcome is low tidal volume ventilation, but only in adult patients. Careful monitoring of the patient's respiratory status with airway graphic analysis and capnography can be helpful. Definitive data are needed in the pediatric population to assist in the care of infants, children, and adolescents with ALI to improve survival and functional outcome. PMID- 23639661 TI - Advances in pediatric cardiac intensive care. AB - Pediatric cardiac critical care has made, and continues to make, significant strides in improving outcomes. It is a measure of these successes that much of the discussion in this article does not focus on the reduction of mortality, but rather on perioperative management strategies intended to improve neurologic outcomes. The care of children with critical cardiac disease will continue to rely on broad and collaborative efforts by specialists and primary care practitioners to build on this foundation of success. PMID- 23639660 TI - Advances in monitoring and management of shock. AB - Early recognition and treatment of pediatric shock, regardless of cause, decreases mortality and improves outcome. In addition to the conventional parameters (eg, heart rate, systolic blood pressure, urine output, and central venous pressure), biomarkers and noninvasive methods of measuring cardiac output are available to monitor and treat shock. This article emphasizes how fluid resuscitation is the cornerstone of shock resuscitation, although the choice and amount of fluid may vary based on the cause of shock. Other emerging treatments for shock (ie, temperature control, extracorporeal membrane oxygenation/ventricular assist devices) are also discussed. PMID- 23639662 TI - Acute kidney injury in children: an update on diagnosis and treatment. AB - The concept and definition of acute kidney injury (AKI) in adults and children has undergone significant change in recent years. Biomarker assessment is aiding in description, defining and understanding timing of AKI. AKI demonstrates unique characteristics in association with sepsis and septic shock, organ dysfunction, and fluid overload. Treatment remains problematic, but growing experience with pediatric continuous renal replacement therapies has improved the delivery of care in children. Increasingly, continuous renal replacement therapy is provided in combination with other extracorporeal technologies, and approaches are advancing to improve combined therapy use. PMID- 23639663 TI - Advances in critical care of the pediatric hematopoietic stem cell transplant patient. AB - Hematopoietic stem cell transplant (SCT) remains a curative option for a variety of malignant and non-malignant disorders in children. Following transplant a proportion of SCT recipients become critically ill and need intensive care. Critical illness may occur in the setting of transplant complications such as graft versus host disease (GVHD), idiopathic pneumonia syndrome (IPS), veno occlusive disease (VOD) and transplant associated thrombotic microangiopathy (TA TMA). Hence, familiarity with recent advances in the transplant process and complications is crucial for the intensivist. This article will highlight common complications encountered in the critically ill SCT recipient. PMID- 23639664 TI - Advances in pediatric neurocritical care. AB - Because pediatric intensive care units (PICUs) improve survival for a range of acute diseases, attention has turned toward ensuring the best possible functional outcomes after critical illness. The neurocritical care of children is of increasing interest. However, the pediatric population encompasses a heterogeneous set of neurologic conditions, with several possible models of how best to address them. This article reviews the special challenges faced by PICUs with regards to diseases, technologies, and skills and the progress that has been made in treatment, monitoring, and prognostication. Recent advances in translational research expected to modify the field in the near-term are described. PMID- 23639665 TI - End-of-life care in pediatrics: ethics, controversies, and optimizing the quality of death. AB - Hospitalized children constitute most annual pediatric deaths in the United States. The details of "how-to" provide end-of-life (EOL) care are not consistently taught to staff and therefore the actual delivery of EOL care is often inconsistent and invariably negatively associated with the long-term mental health of both the patient's family and care providers. This review describes the pertinent aspects of end-of-life care in pediatrics. Finally, a framework to optimize the quality of death is described, which underscores the importance of synchrony between the care team and the family at the end of a child's life. PMID- 23639666 TI - Pediatric delirium: monitoring and management in the pediatric intensive care unit. AB - This review article updates the pediatric medical community on the current literature regarding diagnosis and treatment of delirium in critically ill children. This information will be of value to pediatricians, intensivists, and anesthesiologists in developing delirium monitoring and management protocols in their pediatric critical care units. PMID- 23639669 TI - Care of the critically ill pediatric patient. PMID- 23639668 TI - A parents' perspective on the pediatric intensive care unit: our family's journey. AB - The pediatric intensive care unit (PICU) can be an intimidating and frightening place for parents and family members of critically ill children. Most parents experience a loss of control and feelings of utter helplessness. Many PICUs are working with family members to improve the quality of care provided through patient- and family-centered care, which is in fact 1 of the 6 tenets of the Institute of Medicine's definition of quality health care. However, as highlighted by the tragic and very personal experience described by one family, PICUs can and should be doing more to improve the patient and family experience. PMID- 23639670 TI - Clinimetric properties of Gourion Minor Physical Anomalies Scale. Internal consistency, construct and diagnostic validity in families with a schizophrenic relative and in healthy families. PMID- 23639667 TI - Family-centered care in the pediatric intensive care unit. AB - Patient-centered and family-centered care (PFCC) has been endorsed by many professional health care organizations. Although variably defined, PFCC is an approach to care that is respectful of and responsive to the preferences, needs, and values of individual patients and their families. Research regarding PFCC in the pediatric intensive care unit has focused on 4 areas including (1) family visitation; (2) family-centered rounding; (3) family presence during invasive procedures and cardiopulmonary resuscitation; and (4) family conferences. Although challenges to successful implementation exist, the growing body of evidence suggests that PFCC is beneficial to patients, families, and staff. PMID- 23639671 TI - Oligodendrocyte density is changed in the basolateral amygdala in schizophrenia but not depression. PMID- 23639672 TI - Characterization and prognostic implication of 17 chromosome abnormalities in myelodysplastic syndrome. AB - The prognosis of chromosome 17 (chr17) abnormalities in patients with primary myelodysplastic syndrome (MDS) remains unclear. The revised International Prognostic Scoring System (IPSS-R) includes these abnormalities within the intermediate cytogenetic risk group. This study assessed the impact on overall survival (OS) and risk of acute myeloid leukemia transformation (AMLt) of chr17 abnormalities in 88 patients with primary MDS. We have compared this group with 1346 patients with primary MDS and abnormal karyotype without chr17 involved. The alterations of chr17 should be considered within group of poor prognosis. The different types of alterations of chromosome 17 behave different prognosis. The study confirms the intermediate prognostic impact of the i(17q), as stated in IPSS-R. The results of the study, however, provide valuable new information on the prognostic impact of alterations of chromosome 17 in complex karyotypes. PMID- 23639673 TI - Unusual late sequela of excision surgery for sacrococcygeal teratoma: advanced pelvic organ prolapse in a woman in her early twenties. PMID- 23639674 TI - Spread of endometriosis to pelvic sentinel lymph nodes: gene expression analysis. AB - OBJECTIVE: Endometriotic spread to the lymphatic system has been described, but little is known about the molecular events and changes in gene expression associated with this process. We sought to determine the expression levels of a panel of 28 genes in samples of primary endometriosis lesions (EL), isolated endometriotic-like cells (IELC)-positive pelvic sentinel lymph nodes (PSLN), and IELC-negative PSLN, in order to identify candidate genes that may play a role in this process. STUDY DESIGN: Quantitative real-time PCR and immunohistochemistry (IHC) of primary EL and PSLN samples with and without IELC from patients with ovarian and/or peritoneal endometriosis. RESULTS: Gene expression was analyzed in EL (n=13), IELC-positive PSLN (PSLN+, n=11), and IELC-negative PSLN (PSLN-, n=8). Gene expression differences between PSLN+ and PSLN- were analyzed and evaluated in relation to their expression levels in EL. Genes expressed at high levels in EL but not in PSLN- and known to be expressed in IELC (such as ESR1, PGR) served as controls and the expected gene dilution effect was clearly observed. Expression of a set of genes (CXCR4, CD68, MKI67, and CD44) was found to be higher in PSLN+ vs. PSLN-, while lowest in EL, indicating upregulation in IELC. In contrast, EPCAM and E-cadherin, which were strongly expressed in EL, were not found to be expressed in PSLN+, and thus likely absent from IELC. IHC confirmed the expression of CXCR4, CD44s, and CD44v6 in IELC, as well as the absence of E cadherin from IELC. CONCLUSION: Our data indicate that spread of endometriosis to PSLN is accompanied by differential expression of several genes, including EPCAM, CDH1 (E-cadherin), CXCR4, and CD44, suggesting an involvement of CD44 splice variants as well as CXCR4 signalling in this process. PMID- 23639675 TI - Associations with asymptomatic colonization with Candida in women reporting past vaginal candidiasis: an observational study. AB - OBJECTIVE: Asymptomatic vaginal colonization with Candida species is a known risk factor for vulvovaginal candidiasis (VVC). Taking known risk factors for symptomatic VVC, the authors sought to identify factors associated with asymptomatic colonization. STUDY DESIGN: As part of a randomized controlled trial which compared vaginal candidal colony counts in women taking garlic tablets or placebo, 192 asymptomatic women collected a baseline screening swab for Candida species. Eligibility for this study included at least one self-reported episode of VVC in the previous 12 months and age 18-50 years. Known risk factors for VVC were compared in women colonized with candida and those without colonization. RESULTS: 37% of asymptomatic women who self-reported VVC in the previous 12 months were colonized with vaginal Candida species. Using multivariate analysis, two factors were associated with asymptomatic colonization: a current sexual partner (P=0.02) and being born outside of Australia (P=0.05). Use of oral contraceptives was not statistically significant (P=0.27). CONCLUSIONS: Clinical relevance of asymptomatic colonization with vaginal yeast and its link to episodes of VVC warrants further investigation. PMID- 23639676 TI - The accuracy of the anti-alpha-fodrin antibody test for diagnosis of Sjogren's syndrome: a meta-analysis. AB - OBJECTIVE: To evaluate the diagnostic value of anti-alpha-fodrin in patients with Sjogren's syndrome (SS). METHODS: By internet retrieval, all anti-alpha-fodrin data were considered. This analysis included studies showing anti-alpha-fodrin (IgA or IgG) results in patients with SS and the control group with other autoimmune diseases. The qualities of the involved studies were assessed by QUADAS. The pooled sensitivity and specificity of the IgA and IgG were calculated, respectively. Finally, stratified analysis was performed according to the possible heterogeneity sources. RESULTS: Twenty-three studies including seven Chinese and sixteen English reports met the entry criteria. The pooled sensitivity and specificity of all the involved studies anti-alpha-fodrin were 39.3% and 83%, respectively. In detail, the pooled sensitivity was 38% in IgG subtype and 41.9% in IgA subtype while the specificity was 83.1% in IgG subtype and 82.8% in IgA subtype. CONCLUSION: The anti-alpha-fodrin showed moderate accuracy for the diagnosis of SS with high specificity and relative low sensitivity. PMID- 23639677 TI - Lysyl oxidase like-2 reinforces unsatisfactory ossification induced by bone morphogenetic protein-2: relating nanomechanical properties and molecular changes. AB - Bone morphogenetic protein-2 (BMP2) is among the most popular anabolic agents and substantially increase bone volume related to enhanced osteoblast differentiation. Here we demonstrate a remarkable deterioration in the nanomechanical properties of mineralized tissue induced from osteoblasts solely by the function of BMP2. Mineralized tissue of primary osteoblasts cultured with BMP2 shows molecular features of both bone and cartilage, but depletion of lysyl oxidase family members leads to poor nanomechanical properties of the mineralized tissue. Lysyl oxidase like-2 supplementation reinforces the inferior mineralized tissue induced from osteoblasts by BMP2 through intermolecular cross-linking of type II or type X collagen-rich extracellular matrix. This may also mimic a consolidation of bone fracture gaps, despite the fact that the distribution of the bone properties in such microenvironments has been poorly elucidated. These findings confirm the importance of testing newly induced bone down to the microscale and nanoscale in bone tissue engineering. FROM THE CLINICAL EDITOR: Bone morphogenetic protein-2 is known to substantially increase bone volume related to enhanced osteoblast differentiation; however, this team of investigators report a remarkable deterioration in the nanomechanical properties of mineralized tissue induced from osteoblasts solely by the function of BMP2. PMID- 23639678 TI - Osseointegration of titanium with an antimicrobial nanostructured noble metal coating. AB - Nanometer scale surface features on implants and prostheses can potentially be used to enhance osseointegration and may also add further functionalities, such as infection resistance, to the implant. In this study, a nanostructured noble metal coating consisting of palladium, gold and silver, never previously used in bone applications, was applied to machined titanium screws to evaluate osseointegration after 6 and 12 weeks in rabbit tibiae and femurs. Infection resistance was confirmed by in vitro adhesion test. A qualitatively and quantitatively similar in vivo bone response was observed for the coated and uncoated control screws, using histology, histomorphometry and electron microscopy. The bone-implant interface analysis revealed an extensive bone formation and direct bone-implant contact. These results demonstrate that the nanostructured noble metal coating with antimicrobial properties promotes osseointegration and may therefore be used to add extra implant functionality in the form of increased resistance to infection without the use of antibiotics. FROM THE CLINICAL EDITOR: The authors of this paper demonstrate that nanostructured noble metal coating of implants and prostheses used in orthopedic procedures promotes osseointegration and may be used to add extra implant functionality in the form of increased resistance to infection without the use of antibiotics. PMID- 23639679 TI - Dendrimer-enabled DNA delivery and transformation of Chlamydia pneumoniae. AB - The chlamydiae are important human pathogens. Lack of a genetic manipulation system has impeded understanding of the molecular bases of virulence for these bacteria. We developed a dendrimer-enabled system for transformation of chlamydiae and used it to characterize the effects of inserting the C. trachomatis plasmid into C. pneumoniae, which lacks any plasmids. The plasmid was cloned into modified yeast vector pEG(KG) and the clone complexed to polyamidoamine dendrimers, producing 50-100 nm spherical particles. HEp-2 cell cultures were infected with C. pneumoniae strain AR-39. Twenty-four hours later, medium was replaced for 3 hours with dendrimer-plasmid complexes, then removed and the medium replaced. Cultures were harvested at various times post transformation. Real-time PCR and RT-PCR of nucleic acids from transformed cultures demonstrated plasmid replication and gene expression. The cloned plasmid was replicated and expressed in transformants over 5 passages. This system will allow study of chlamydial gene function, allowing development of novel dendrimer based therapies. FROM THE CLINICAL EDITOR: This team of investigators developed a dendrimer-enabled system for transformation of chlamydiae and successfully utilized it to characterize the effects of inserting the C. trachomatis plasmid into C. pneumonia. This system will allow study of chlamydial gene function, allowing development of novel dendrimer-based therapies. PMID- 23639680 TI - Getting nano tattoos right - a checklist of legal and ethical hurdles for an emerging nanomedical technology. AB - The nano tattoo represents a nascent technology designed to be implanted in the skin to provide continuous and reliable glucose detection for diabetics. Its potential benefits are compelling not only for its ability to prevent diabetic complications and decrease related social costs, but also for its ease of use and relative patient-user comfort. This Note aims to articulate a checklist of fundamental intellectual property, bioethical and system design issues that are appropriately considered in the pre-clinical, pre-commercialization phase of nano tattoo development. Early and regular consideration of these factors can increase the odds of a societally beneficial dissemination of this device by engaging relevant researcher, medical, patient-user and patient-advocate communities concerned with its appropriate application, as well as policymaking communities focused on effectively managing diabetes-related healthcare costs. The checklist of factors includes fundamental issues and is generally applicable to nanomedical inventions. FROM THE CLINICAL EDITOR: This paper presents a comprehensive list of fundamental intellectual property, bioethical, and system design issues to be considered in the pre-commercialization phase of nanomedicine development, through the specific example of nano tattoo development. Nano tattoo is designed to be implanted in the skin to provide reliable glucose monitoring for diabetics, enabling enhanced prevention of complications and decreased socioeconomic costs. PMID- 23639681 TI - Managing the risks of sepsis in pregnancy. AB - Sepsis is a major cause of maternal mortality and morbidity worldwide. In the UK, sepsis is now the leading cause of direct maternal deaths. Raising awareness among healthcare professionals about the risks of maternal sepsis and the importance of early management is urgently needed. The challenge in the management of maternal sepsis is the translation of the vast knowledge gained from sequential confidential enquiries into maternal death and research findings, into clinical practice, to ensure an improvement in patient quality of care and maternal mortality and morbidity. In this chapter, I give an overview of the management of the risks of sepsis, and discuss implementation strategies that may reduce these risks. PMID- 23639682 TI - Estimation of PMI depends on the changes in ATP and its degradation products. AB - Estimating the time since death, or postmortem interval (PMI), has been one of the biggest difficulties in modern forensic investigation. This study tests if the concentrations of breakdown products of adenosine triphosphate (ATP) correlate with PMI in multiple organs from rat. Brains, spleens, and kidneys of rats were harvested at different time points in carcasses maintained at 4 degrees C or 20 degrees C. High Performance Liquid Chromatography (HPLC) was used to quantify concentrations of metabolites related to ATP degradation. A K value (Kv=100*(Hx+HxR)/(ATP+ADP+AMP+IMP+HxR+Hx)) was calculated and correlated with PMI for each organ and temperature. The results indicate that the K value is a robust index for the estimation of PMI based on highly significant linear correlations between PMI and concentrations of ATP breakdown products. Compared with other current research methods, the changing tendency of ATP and its degradation products may be potentially a better way for the estimation of PMI in medico legal practice. PMID- 23639683 TI - Inulin-based glycopolymer: its preparation, lectin-affinity and gellation property. AB - The glycopolymer composed of an inulin scaffold and pendent beta-lactosides was developed from commercially available inulin through sequential chemical modification processes composed of tosylation, azidation, and the subsequent Huisgen cyclocoupling with an alkyne-terminated beta-lactoside. The resultant inulin-based glycopolymer has unique dual affinity towards beta-galactoside and alpha-glucoside specific lectins which is attributable to its pendent beta lactosides and terminal alpha-glucoside. Its gellation property was also accessed to find that the inulin-based glycopolymer forms hydrogels whose critical gellation concentration (CGC) was lower than that required for hydrogels made from native inulin. Drug release properties of the inulin-based glycopolymer were also discussed in this paper. PMID- 23639684 TI - Structure-activity relationships for 4-anilinoquinoline derivatives as inhibitors of the DNA methyltransferase enzyme DNMT1. AB - A series of 4-anilinoquinoline derivatives related to the known inhibitor SGI 1027, containing side chains of varying pK(a), were prepared by acid-catalysed coupling of the pre-formed side chains with 4-chloroquinolines. The compounds were evaluated for their ability to reduce the level of DNMT1 protein in HCT116 human colon carcinoma cells by Western blotting. With a very strongly basic N methylpyridinium side chain, only NHCO-linked compounds were effective, whereas less strongly basic ((diaminomethylene)hydrazono)ethyl or 3-methylpyrimidine-2,4 diamine side chains allowed both NHCO- and CONH-linked compounds to show activity. In contrast, the pK(a) of the quinoline unit had little apparent influence on activity. PMID- 23639685 TI - Investigation of 1H MRS for quantification of hepatic triglyceride in lean and obese cats. AB - (1)H magnetic resonance spectroscopy ((1)H MRS) is the preferred technique for noninvasive quantification of hepatic triglyceride in humans. Domestic cats are subject to liver lipid accumulation, but MRS has not been investigated for quantification of liver fat in cats. The purpose of this project was to explore a technique for (1)H MRS measurement of hepatic triglyceride in lean and obese cats. Hepatic (1)H MRS was performed, using a 3T imaging unit and a single-voxel spin-echo spectroscopy sequence, on 6 lean (3.3-4.6 kg) and 12 obese cats (5.2 9.8 kg). Median liver fat percentages in lean and obese cats were 1.3% and 6.8%, respectively. Results are biologically plausible, based on chemical assay in a separate group of cats; however, full validation of the method is necessary before other conclusions can be drawn. This report should provide a foundation for the further development of spectroscopic techniques for studying hepatic lipid accumulation in cats. PMID- 23639686 TI - [Rethinking the place of primary healthcare in France--role of general practice]. AB - Primary healthcare is poorly structured in France while it is well defined at the international level: it is the point of first medical contact of the population with the healthcare system. General practice is the clinical specialty oriented to primary healthcare. Data in the scientific literature highlight the need of refocusing the health system on primary care known to improve both morbi mortality and care efficiency. In France, health authorities acknowledge general practitioners as playing a key role in the health care system: its time to move from intention to action. Structural changes are needed to achieve this reinforcement of primary healthcare: to re-orientate medical studies towards primary care; to develop research in primary care; to promote cooperation between care providers; to ease the daily workload of practitioners; to diversify methods of payment; to propose a guide for patient's use of primary care. The transformation of the healthcare system in France requires a real strategy of primary healthcare implementation. Regardless of financial constraints, it is possible to redistribute the resources towards ambulatory care. Strengthening the role of general practice and favoring its societal recognition will be the major stages of this change. PMID- 23639687 TI - [Statistical and epidemiological methods used in biomedical research: implications for initial medical education]. AB - BACKGROUND: The main source of key medical information consists in original articles published in peer-reviewed biomedical journals. Reported studies use increasingly sophisticated statistical and epidemiological approaches that first require a solid understanding of core methods. However, such understanding is not widely shared among physicians. Our aim was to assess whether the basic statistical and epidemiological methods used in original articles published in general biomedical journals are taught during the first years of the medical curriculum in France. METHODS: We selected original articles published in The New England Journal of Medicine, The Lancet, and The Journal of the American Medical Association, over a period of six months in 2007 and in 2008. A standardized statistical content checklist was used to extract the necessary information in the "Abstract", "Methods", "Results", footnotes of tables, and legends of figures. The methods used in the selected articles were compared to the national program and the public health program of biostatistics and epidemiology taught during the first six years of medical school. RESULTS: The 237 analyzed original articles all used at least one statistical or epidemiological method. Descriptive statistics, confidence interval and Chi(2) or Fisher tests, methods used in more than 50% of articles, were repeatedly taught throughout the medicine curriculum. Measures of association, sample size, fit and Kaplan-Meier method, used in 40 to 50% of articles, were specifically taught during training sessions on critical reading methods. Cox model (41% of articles) and logistic regression (24% of articles) were never taught. The most widely used illustrations, contingency tables (92%) and flowcharts (48%), were not included in the national program. CONCLUSION: More teaching of the core methods underlying the understanding of sophisticated methods and illustrations should be included in the early medical curriculum so that physicians can read the scientific literature critically for their medical education. PMID- 23639688 TI - [Injuries in France: trends and risk factors]. AB - BACKGROUND: Whatever the type of injury considered, prevention requires an improvement in health services' awareness of risk factors. The Health Barometer is a general population survey conducted in France since 1992 to contribute to surveillance in this field. The survey's statistical power and the numerous health topics included in the questionnaire provide accurate information for healthcare professionals and decision-makers. METHODS: The Health Barometer 2010 was a nationwide telephone survey of 9110 persons representative of the 15-85 year-old population. One part of the questionnaire detailed injuries which had occurred during the past year. The numerous variables recorded enabled application of logistic regression models to explore risk factors related to different types of injury by age group. The findings were compared with the Health Barometer 2005 data to search for temporal trends of injury prevalence. RESULTS: The data analysis showed that 10.3% of the 15-85-year-olds reported an injury during the past year. This rate was higher than recorded in 2005; the increase was mainly due to domestic accidents and injuries occurring during recreational activities. Both type of injury and risk factors exhibited age related variability. Domestic accidents and injuries occurring during recreational activities predominated in the older population and were associated with physical or mental health problems (chronic disease, diability, sleep disorders). For younger people, injuries were related to cannabis use, drunkedness, and insufficient sleep. Risk factors were also depended on type of injury: occupational accident-related injuries were linked with social disadvantage (manual worker population) whereas sports injuries were more common in the socially advantaged population. CONCLUSION: This survey confirms established knowledge and highlights, at different stages of life, new risk factors that contribute to injuries in France. These findings should be helpful for the development of adapted injury prevention programs, by providing a better understanding of the characteristic features of this major public health issue. PMID- 23639689 TI - Simulation of radioactive cesium transfer in the southern Fukushima coastal biota using a dynamic food chain transfer model. AB - The Fukushima Dai-ichi Nuclear Power Plant (1F NPP) accident occurred on 11 March 2011. The accident introduced (137)Cs into the coastal waters which was subsequently transferred to the local coastal biota thereby elevating the concentration of this radionuclide in coastal organisms. In this study, the radioactive cesium levels in coastal biota from the southern Fukushima area were simulated using a dynamic biological compartment model. The simulation derived the possible maximum radioactive cesium levels in organisms, indicating that the maximum (137)Cs concentrations in invertebrates, benthic fish and predator fish occurred during late April, late May and late July, respectively in the studied area where the source was mainly the direct leakage of (137)Cs effluent from the 1F NPP. The delay of a (137)Cs increase in fish was explained by the gradual food chain transfer of (137)Cs introduced to the ecosystem from the initial contamination of the seawater. The model also provided the degree of radionuclide depuration in organisms, and it demonstrated the latest start of the decontamination phase in benthic fish. The ecological half-lives, derived both from model simulation and observation, were 1-4 months in invertebrates, and 2-9 months in plankton feeding fish and coastal predator fish from the studied area. In contrast, it was not possible to similarly calculate these parameters in benthic fish because of an unidentified additional radionuclide source which was deduced from the biological compartment model. To adequately reconstruct the in situ depuration of radiocesium in benthic fish in the natural ecosystem, a contamination source associated with the bottom sediments is necessary. PMID- 23639690 TI - Tritium as an indicator of venues for nuclear tests. AB - Currently, due to the Treaty on the Non-proliferation of Nuclear Weapons there is a highly topical issue of an accurate verification of nuclear explosion venues. This paper proposes to consider new method for verification by using tritium as an indicator. Detailed studies of the tritium content in the air were carried in the locations of underground nuclear tests - "Balapan" and "Degelen" testing sites located in Semipalatinsk Test Site. The paper presents data on the levels and distribution of tritium in the air where tunnels and boreholes are located - explosion epicentres, wellheads and tunnel portals, as well as in estuarine areas of the venues for the underground nuclear explosions (UNE). PMID- 23639691 TI - Demonstration of lightweight gamma spectrometry systems in urban environments. AB - Urban areas present highly complex radiation environments; with small scale features resulting from different construction materials, topographic effects and potential anthropogenic inputs from past industrial activity or other sources. Mapping of the radiation fields in urban areas allows a detailed assessment of exposure pathways for the people who live and work there, as well as locating discrete sources of activity that may warrant removal to mitigate dose to the general public. These areas also present access difficulties for radiometric mapping using vehicles or aircraft. A lightweight portable gamma spectrometry system has been used to survey sites in the vicinity of Glasgow to demonstrate the possibilities of radiometric mapping of urban areas, and to investigate the complex radiometric features such areas present. Variations in natural activity due to construction materials have been described, the presence of (137)Cs used to identify relatively undisturbed ground, and a previously unknown NORM feature identified. The effect of topographic enclosure on measurements of activity concentration has been quantified. The portable system is compared with the outputs that might be expected from larger vehicular or airborne systems. For large areas airborne surveys are the most cost effective approach, but provide limited spatial resolution, vehicular surveys can provide sparse exploratory data rapidly or detailed mapping of open areas where off-road access is possible. Backpack systems are ideally suited to detailed surveys of small areas, especially where vehicular access is difficult. PMID- 23639692 TI - Plutonium concentration and (240)Pu/(239)Pu atom ratio in biota collected from Amchitka Island, Alaska: recent measurements using ICP-SFMS. AB - Three underground nuclear tests, including the Unites States' largest, were conducted on Amchitka Island, Alaska. Monitoring of the radiological environment around the island is challenging because of its remote location. In 2008, the Department of Energy (DOE) Office of Legacy Management (LM) became responsible for the long term maintenance and surveillance of the Amchitka site. The first DOE LM environmental survey occurred in 2011 and is part of a cycle of activities that will occur every 5 years. The University of Alaska Fairbanks, a participant in the 2011 study, provided the lichen (Cladonia spp.), freshwater moss (Fontinalis neomexicanus), kelp (Eualaria fistulosa) and horse mussel (Modiolus modiolus) samples from Amchitka Island and Adak Island (a control site). These samples were analyzed for (239)Pu and (240)Pu concentration and (240)Pu/(239)Pu atom ratio using inductively coupled plasma sector field mass spectrometry (ICP SFMS). Plutonium concentrations and (240)Pu/(239)Pu atom ratios were generally consistent with previous terrestrial and marine studies in the region. The ((239)+)(240)Pu levels (mBq kg(-1), dry weight) ranged from 3.79 to 57.1 for lichen, 167-700 for kelp, 27.9-148 for horse mussel, and 560-573 for moss. Lichen from Adak Island had higher Pu concentrations than Amchitka Island, the difference was likely the result of the higher precipitation at Adak compared to Amchitka. The (240)Pu/(239)Pu atom ratios were significantly higher in marine samples compared to terrestrial and freshwater samples (t-test, p < 0.001); lichen and moss averaged 0.184 +/- 0.007, similar to the integrated global fallout ratio, whereas kelp and mussel (soft tissue) averaged 0.226 +/- 0.003. These observations provide supporting evidence that a large input of isotopically heavier Pu occurred into the North Pacific Ocean, likely from the Marshall Island high yield nuclear tests, but other potential sources, such as the Kamchatka Peninsula Rybachiy Naval Base and Amchitka Island underground nuclear test site cannot be ruled out. PMID- 23639693 TI - A fuzzy approach for modelling radionuclide in lake system. AB - Radioactive liquid waste is generated during operation and maintenance of Pressurised Heavy Water Reactors (PHWRs). Generally low level liquid waste is diluted and then discharged into the near by water-body through blowdown water discharge line as per the standard waste management practice. The effluents from nuclear installations are treated adequately and then released in a controlled manner under strict compliance of discharge criteria. An attempt was made to predict the concentration of (3)H released from Kakrapar Atomic Power Station at Ratania Regulator, about 2.5 km away from the discharge point, where human exposure is expected. Scarcity of data and complex geometry of the lake prompted the use of Heuristic approach. Under this condition, Fuzzy rule based approach was adopted to develop a model, which could predict (3)H concentration at Ratania Regulator. Three hundred data were generated for developing the fuzzy rules, in which input parameters were water flow from lake and (3)H concentration at discharge point. The Output was (3)H concentration at Ratania Regulator. These data points were generated by multiple regression analysis of the original data. Again by using same methodology hundred data were generated for the validation of the model, which were compared against the predicted output generated by using Fuzzy Rule based approach. Root Mean Square Error of the model came out to be 1.95, which showed good agreement by Fuzzy model of natural ecosystem. PMID- 23639694 TI - High activity concentrations of (210)Pb and (7)Be in sediments and their histories. AB - High activity concentrations of (210)Pb and (7)Be, in addition to (137)Cs, were found in a rooftop deposit in Japan. This deposit had activities of about 5 Bq/g from (210)Pb and 3.6 Bq/g from (7)Be, an order of magnitude greater than typically found in field soils and lake and sea bottom sediments. It is clear that under certain conditions aerosol particles can accumulate in deposits with little or no mixing and dilution by silicate materials, and that subsequent processes and factors result in a heterogeneous distribution pattern of activity concentration on the Earth's surface. A simple model suggests that the history of an environmental sample can be estimated by using the activities of (210)Pb and (7)Be. PMID- 23639695 TI - Secondary radioactive contamination of the Black Sea after Chernobyl accident: recent levels, pathways and trends. AB - The recent radionuclide measurements have showed that concentrations of the Chernobyl-derived (137)Cs and (90)Sr in the surface Black Sea waters are still relatively high, reaching 56 and 32 Bq m(-3), respectively. This is comparable or even exceeds the pre-Chernobyl levels (~16 Bq (137)Cs and 22 Bq (90)Sr per m(3) as the basin-wide average values). The measurements have revealed that the Black Sea continues to receive Chernobyl radionuclides, particularly (90)Sr, by the runoff from the Dnieper River. An additional source of (90)Sr and (137)Cs was found in the area adjacent to the Kerch Strait that connects the Black Sea and the Sea of Azov. This may be caused by the inflow of the contaminated Dnieper waters, which come to this area through the North-Crimean Canal. The long-term monitoring of (137)Cs and (90)Sr concentration in the Black Sea surface waters and in the benthic brown seaweed Cystoseira sp., in comparison with the earlier published sediment records of the radionuclides, have showed signs of a secondary radioactive contamination, which has started to increase since the late 1990's. This may be the result of the combined effect of a higher input of radionuclides from the rivers in 1995-1999 due to an increased runoff; and a slow transport of the particulate bound radionuclides from the watersheds followed by their desorption in seawater from the riverine suspended matter and remobilization from the sediments adjacent to the river mouths. PMID- 23639696 TI - Structural determination and NMR characterization of a bacterial exopolysaccharide. AB - A strain of Bacillus licheniformis with high exopolysaccharide (EPS) production ability was isolated and identified. A new type of EPS was isolated from the strain fermentation and its structural characteristics were investigated and elucidated by partial and total acid hydrolysis, Fourier transform infrared, and (1)H and (13)C NMR spectroscopy including 2D (1)H, COSY, NOESY, XHCOR and HMBC experiments. Based on obtained data, the EPS was found to be a levan composed of linear chains of (2->6)-linked beta-d-fructofuranosyl residues with connections beta (2->6). PMID- 23639697 TI - Substrate preference of a Geobacillus maltogenic amylase: a kinetic and thermodynamic analysis. AB - The gene encoding a maltogenic amylase (MAase) from a newly isolated strain of thermophilic Geobacillus has been isolated, cloned and expressed. Following purification, biochemical and structural characterization have been performed. The enzyme exhibited maximal activity at a broad temperature range between 55 and 65 degrees C, clearly higher than that of other dimeric MAses. The optimum pH was 6.0 and catalytic activity increased by of Li(+) and K(+). A noticeable preference was demonstrated for alpha-, beta- and gamma-cyclodextrin (CD) compared to polymeric substrates (amylose, amylopectin, glycogen and starch) possibly due to steric interference. The affinity for CD substrates increased in the order of gamma-CD>beta-CD>alpha-CD, but k(cat)/K(m) increased as alpha CD>beta-CD>gamma-CD, implying that increased substrate specificities are mainly attribute to kcat. Thermodynamic analysis of the activation process showed that improved activity (decrease in DeltaG(#)) is accompanied by increases in activation entropy (DeltaS(#)) for aforementioned substrates. Molecular docking on the binding interactions between substrates and active site residues revealed a considerably higher accessible surface area for the active site residues in the presence of alpha-CD than beta-CD, indicating that interactions in the transition state are stronger in the presence of alpha-CD. This result explains the increased DeltaH(#) of the activation process and increased K(m) of the enzyme in the presence of alpha-CD, compared to that of beta-CD. This study, which presents the first detailed comparative analysis on the substrate preference of dimeric MAases for different substrates, may shed some lights into the molecular mechanism of these enzymes. PMID- 23639698 TI - Marketing foods to children: a comparison of nutrient content between children's and non-children's products. AB - OBJECTIVE: The predominance of marketing of products high in fat, sugar and/or salt to children has been well documented and implicated in the incidence of obesity. The present study aimed to determine whether foods marketed to children in UK supermarkets are nutritionally similar to the non-children's equivalent, focusing on food categories that may be viewed as healthier options. DESIGN: Nutritional data were collected on yoghurts (n 147), cereal bars (n 145) and ready meals (n 144) from seven major UK supermarkets and categorised as children's or non-children's products based on the characteristics, promotional nature or information on the product packaging. Fat, sugar and salt content was compared per 100 g and per recommended portion size. SETTING: UK. RESULTS: Per 100 g, children's yoghurts and cereal bars were higher in total sugars, fat and saturated fat than the non-children's; this was significant for all except sugar and total fat in cereal bars. Per portion these differences remained, except for sugars in yoghurts. Conversely children's ready meals were significantly lower in these nutrients per portion than non-children's, but not when expressed per 100 g. Children's yoghurts and ready meals had significantly lower sodium content than non-children's both per portion and per 100 g. CONCLUSIONS: Significant differences between the nutritional composition of children's and non-children's products were observed but varied depending on the unit reference. A significant number of products marketed towards children were higher in fat, sugar and salt than those marketed to the general population. PMID- 23639699 TI - D1-like dopamine receptors antagonist inhibits cutaneous immune reactions mediated by Th2 and mast cells. AB - BACKGROUND: Dopamine transduces signals via five subtypes of G protein-coupled receptors. Among these subtypes, the D1 and D5 receptors belong to the D1-like group. Although dopamine is known to mediate immune responses, its involvement in cutaneous immunity remains unclear. OBJECTIVE: The aim of this study is to determine the role of dopamine and its D1-like receptors in cutaneous immune responses. METHODS: By using the D1-like receptor antagonist SCH 23390, we examined the role of D1-like receptors in murine models of Th1-type contact hypersensitivity and Th2-type atopic dermatitis in vivo, and in mast cells and Th2 cell differentiation in vitro. RESULTS: Administration of SCH 23390 did not affect Th1-type contact hypersensitivity but suppressed the immediate-type reaction (ITR) and the late phase reaction (LPR) in the atopic dermatitis model. In addition, SCH 23390-treated mice showed higher IFN-gamma and lower IL-4 mRNA levels in the ear skin of challenged mice than did non-treated mice as analyzed by real-time RT PCR. Consistently, the passive cutaneous anaphylaxis reaction was significantly reduced in SCH 23390-treated mice. Moreover, dopamine enhanced mast cell degranulation and Th2 cell differentiation, and both activities were abrogated by SCH 23390. CONCLUSION: These findings suggest that the D1-like receptors mediate immediate and late phase skin reactions by promoting Th2 induction and mast cell degranulation. PMID- 23639700 TI - IL-11, IL-1alpha, IL-6, and TNF-alpha are induced by solar radiation in vitro and may be involved in facial subcutaneous fat loss in vivo. AB - BACKGROUND: The loss of subcutaneous (sc) fat is associated with aging. Inflammatory cytokines, such as interleukin-1 alpha (IL-1alpha), interleukin-11 (IL-11) and tumor necrosis factor-alpha (TNF-alpha), are known to inhibit the differentiation of preadipocytes. OBJECTIVE: This study investigated the potential role of inflammatory cytokines in solar-radiation-induced facial fat loss. METHODS: Cultured fibroblasts, keratinocytes, and skin equivalents were exposed to various doses of radiation from a solar simulator. Inflammatory cytokines' mRNA production and protein secretion were examined by qRT-PCR and ELISA, respectively. In some experiments, epidermal-dermal equivalents were pretreated topically with a broad-spectrum sunscreen prior to solar simulated radiation (SSR). Human facial preadipocytes treated with recombinant IL-11 or with conditioned media from solar-irradiated equivalents were evaluated for the level of adipocyte differentiation by image analyses, Oil red O staining, and the expression of adipocyte differentiation markers. RESULTS: IL-11, IL-1alpha, IL-6, and TNF-alpha protein secretion were induced from epidermal-dermal equivalents by exposure to SSR. A sunscreen prevented SSR-induced inflammatory cytokines production from such equivalents. Exposure of facial preadipocytes to conditioned medium from solar-irradiated epidermal-dermal equivalents inhibited their differentiation into mature adipocytes. Consequently, conditioned medium from sunscreen-pretreated, solar-irradiated equivalents did not inhibit differentiation of preadipocytes. A cocktail of neutralizing antibodies to IL-11, IL-1alpha, IL-6 and TNF-alpha significantly reduced the SSR-induced inhibition of preadipocyte differentiation. CONCLUSION: These results support the hypothesis that SSR-induced inflammatory cytokine may be involved in the photoaging-induced loss of facial subcutaneous fat. Inhibition of this process, e.g. by sunscreens, might slow or prevent photoaging-induced changes in facial contouring. PMID- 23639702 TI - Ceramic inlays: is the inlay thickness an important factor influencing the fracture risk? AB - OBJECTIVES: It is still unclear whether the inlay thickness is an important factor influencing the fracture risk of ceramic inlays. As high tensile stresses increase the fracture risk of ceramic inlays, the objective of the present finite element method (FEM) study was to biomechanically analyze the correlation between inlay thickness (T) and the induced first principal stress. METHODS: Fourteen ceramic inlay models with varying thickness (0.7-2.0 mm) were generated. All inlays were combined with a CAD model of a first mandibular molar (tooth 46), including the PDL and a mandibular segment which was created by means of the CT data of an anatomical specimen. Two materials were defined for the ceramic inlays (e.max((r)) or empress((r))) and an occlusal force of 100 N was applied. The first principal stress was measured within each inlay and the peak values were considered and statistically analyzed. RESULTS: The stress medians ranged from 20.7 to 22.1 MPa in e.max((r)) and from 27.6 to 29.2 MPa in empress((r)) inlays. A relevant correlation between the first principal stress and thickness (T) could not be detected, neither for e.max((r)) (Spearman: r=0.028, p=0.001), nor for empress((r)) (Spearman: r=0.010, p=0.221). In contrast, a very significant difference (p<0.001) between the two inlay materials (M) was verified. CONCLUSIONS: Under the conditions of the present FEM study, the inlay thickness does not seem to be an important factor influencing the fracture risk of ceramic inlays. However, further studies are necessary to confirm this. PMID- 23639703 TI - Introduction: Szczeklik's contributions to our understanding of aspirin, NSAIDs, asthma, and allergy. AB - Andrew Szczeklik was born in 1938 and died on Feb 3rd, 2012. He was the most influential expert in the field of aspirin and NSAID sensitivity reactions and associated diseases in the world. This edition of NACAI is dedicated to Andrew. In the introductory chapter, we elected to highlight his accomplishments as reflected in his publications. Andrew published at least 503 articles including many invited review articles. We present 20 of his most important publications all of which contributed significantly to our understanding of these diseases. PMID- 23639701 TI - Effects of diphenyliodonium salt addition on the adhesive and mechanical properties of an experimental adhesive. AB - OBJECTIVES: The aim of this study was to assess the microtensile bond strength (MUTBS), nanoleakage (NL), nano-hardness (NH) and Young's modulus (YM) of resin dentine bonding components formed by an experimental adhesive system with or without inclusion of diphenyliodonium salt (DPIH) in the camphorquinone-amine (CQ) system. METHODS: On 12 human molars, a flat superficial dentine surface was exposed by wet abrasion. A model simplified adhesive system was formulated (40 wt.% UDMA/MDP, 30 wt.% HEMA and 30 wt.% ethanol). Two initiator systems were investigated: 0.5 mol% CQ+1.0 mol% EDMAB and 0.5 mol% CQ+1.0 mol% EDMAB+0.2 mol% DPIH. Each adhesive was applied and light-cured (10s; 600 mW/cm(2)). Composite build-ups were constructed incrementally and resin-dentine specimens (0.8mm(2)) were prepared. For NL, 3 bonded sticks from each tooth were coated with nail varnish, placed in the silver nitrate, polished down with SiC papers and analysed by EDX-SEM. NH and YM were performed on the hybrid layer in 2 bonded sticks from each teeth. The remaining bonded sticks were tested on MUTBS (0.5mm/min). The data from each test were submitted to a Student t-test (alpha=0.05). RESULTS: No significant difference was found for MUTBS between groups (p>0.05). Significant lower NL and higher NH and YM were found in the hybrid layer and adhesive layer produced with the iodinium salt-containing adhesive (p<0.05). CONCLUSIONS: The inclusion of the DPIH to the traditional CQ is a good strategy to improve the adhesive and mechanical properties of a simplified etch-and-rinse adhesive system. PMID- 23639704 TI - Classification of reactions to nonsteroidal antiinflammatory drugs. AB - Hypersensitivity reactions to NSAIDs may occur in susceptible individuals and vary in symptom (skin, respiratory tract, and solid organs), severity (from mild skin or respiratory reactions to severe generalized) and timing (from acute to delayed). The current classification of NSAID-induced reactions emerged with the understanding of the pathologic mechanism of reactions to NSAIDs which may be either non-allergic (related to cyclooxygenase inhibition) or immunologically mediated. In this chapter we discuss the implications of accurate NSAIDs hypersensitivity classification for proper diagnosis and patient management. PMID- 23639705 TI - Aspirin-exacerbated respiratory disease: clinical disease and diagnosis. AB - This article summarizes the current knowledge in the field of clinical presentation and diagnosis of aspirin-exacerbated respiratory disease (AERD). The definition, prevalence, natural history, and clinical presentation of this distinct clinical syndrome are described. The classification and tolerance of particular groups of cyclooxygenase inhibitors by patients with AERD are presented. The authors comprehensively discuss provocation tests with aspirin as the most reliable method to confirm the diagnosis of AERD. PMID- 23639706 TI - Rhinosinusitis and nasal polyps in aspirin-exacerbated respiratory disease. AB - The presence of aspirin-exacerbated respiratory disease (AERD) in a patient with chronic rhinosinusitis with nasal polyps and asthma is associated with severe eosinophilic upper and lower airway disease. This article deals with the inflammatory disease of the respiratory tract as it relates to the sinuses. Involvement of the sinuses in AERD is almost universal, depending on the stage of onset of the disease and evaluation by computed tomography. This article explores the clinical aspects, physiopathology, and treatment of rhinosinusitis as it relates to AERD. PMID- 23639707 TI - Genetics of hypersensitivity to aspirin and nonsteroidal anti-inflammatory drugs. AB - Various hypersensitivity reactions have been reported with aspirin and nonsteroidal anti-inflammatory drugs. Hypersensitivity can occur regardless of a chemical drug structure or its therapeutic potency. Allergic conditions include aspirin-exacerbated respiratory disease (AERD or aspirin-induced asthma), aspirin induced urticaria/angioedema (AIU), and anaphylaxis. Several genetic studies on aspirin hypersensitivity have been performed to discover the genetic predisposition to aspirin hypersensitivity and to gain insight into the phenotypic diversity. This article updates data on the genetic mechanisms that govern AERD and AIU and summarizes recent findings on the molecular genetic mechanism of aspirin hypersensitivity. PMID- 23639709 TI - Aspirin desensitization in aspirin-exacerbated respiratory disease. AB - Although aspirin desensitization was discovered in 1922, it was not until 1979 that a therapeutic use for aspirin treatment, under the protection of desensitization, was discovered. In the last 33 years, details of aspirin treatment have been refined to the point where it is now recognized and accepted as a major therapeutic intervention in the treatment of aspirin-exacerbated respiratory disease, with therapeutic efficacy in approximately two-thirds of patients. It is only effective in patients who have aspirin-exacerbated respiratory disease and none of the other nonsteroidal anti-inflammatory drugs, despite their cross-reactive inhibition of cyclooxygenase-1, can effectively take the place of aspirin. PMID- 23639710 TI - Mechanisms of aspirin desensitization. AB - Aspirin-exacerbated respiratory disease is a clinical syndrome characterized by severe, persistent asthma, hyperplastic eosinophilic sinusitis with nasal polyps, and reactions to aspirin and other nonsteroidal antiinflammatory drugs that preferentially inhibit cyclooxygenase 1. The mechanisms behind the therapeutic effects of aspirin desensitization remain poorly understood. Recent studies suggest that the clinical benefits may occur through direct inhibition of tyrosine kinases and the signal transducer and activator of transcription 6 signaling pathway, which results in inhibition of interleukin 4 production. In this article, the current understanding of the mechanisms of aspirin desensitization is reviewed and future areas of investigation are discussed. PMID- 23639708 TI - Pathogenesis of aspirin-exacerbated respiratory disease and reactions. AB - Physiologic and pharmacologic studies support the hypothesis that aspirin exacerbated respiratory disease (AERD) involves fundamental dysregulation in the production of and end-organ responsiveness to both antiinflammatory eicosanoids (prostaglandin E2) and proinflammatory effectors (cysteinyl leukotrienes). The acquired nature of AERD implies a disturbance in a potential epigenetic control mechanism of the relevant mediator systems, which may be a result of incompletely clarified environmental factors (eg, viral or bacterial infections, inhaled pollutants). PMID- 23639711 TI - NSAID single-drug-induced reactions. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are cyclooxygenase inhibitors with analgesic, anti-inflammatory, antipyretic, and antithrombotic effects. NSAIDs have been implicated in a variety of drug-induced reactions that are proved as or suspected of being mediated through a host immune response. Single-drug-induced reactions are the hallmark of these types of reactions. The types of single-drug induced reactions are the confluence of 2 variables, the structure of the drug and the specific types of immune responses. This article identifies reactions patterns and the NSAIDs most likely to elicit each immune response. PMID- 23639712 TI - Aspirin-exacerbated cutaneous disease. AB - It has been recognized that a high proportion of chronic urticaria patients experience symptom aggravation when exposed to aspirin and NSAIDs. This clinical picture is known as Aspirin-exacerbated cutaneous disease. The pathogenesis of these exacerbations is related to the inhibition of cyclooxygenase-1 leading to a decreased synthesis of PGE2 and an increased cysteinyl leukotriene production in the skin and subcutaneous tissues. Patient management comprises the treatment of the underlying cutaneous disease with nonsedating antihistamines and other medications, avoidance of COX-1 inhibitors, and the use of alternative NSAIDs that do not inhibit COX-1 for the relief of pain, inflammation and fever. PMID- 23639713 TI - Cardiovascular prophylaxis and aspirin "allergy". AB - Aspirin is an important antiplatelet agent in the treatment of cardiovascular disease. Aspirin "allergy" often directs the physician away from this potentially life-saving modality. The majority of patients with a history of "reactions to aspirin" have aspirin/nonsteroidal anti-inflammatory drug (NSAID)-induced gastritis, easy bruisability, or other side effects. The minority of these patients has a "true allergy," referred to as a hypersensitivity reaction. The former group can be started on aspirin without the need for special challenge. Adding a proton-pump inhibitor can often mitigate the gastrointestinal side effects. Patients with aspirin hypersensitivity can be safely challenged with aspirin. PMID- 23639714 TI - A dedication to Andrew Szczeklik, MD. PMID- 23639715 TI - Risks and benefits of bladder antimuscarinics among elderly residents of Veterans Affairs Community Living Centers. AB - OBJECTIVES: To evaluate risks and benefits of bladder antimuscarinics (BAMs) among elderly long term care nursing home residents. DESIGN: Retrospective cohort study using a new user design and propensity score matching. SETTING: Veterans Affairs (VA) Community Living Centers (Nursing Homes). PARTICIPANTS: Older adults (65 and older) admitted for long term care between October 1, 2002, and September 30, 2009. MEASUREMENTS: The study used multiple VA data sources (Minimum Data Set [MDS], inpatient, outpatient, and pharmacy prescriptions administrative files). The following outcomes were evaluated: (1) fractures (hip fracture and "any" fracture) identified from inpatient and/or outpatient data (ICD-9-CM codes) and from MDS; (2) cognitive performance measured using the validated MDS Cognitive Performance Scale; (3) improvement in urinary incontinence measured from MDS; (4) quality of life measured from MDS using 2 validated instruments: Index of Social Engagement and Health Status Index. Covariates included demographic characteristics, baseline continence status (bladder and bowel) and continence management, preexistent urinary tract infections, body mass index, comorbidities, other medication use, cognitive status, and mobility at baseline. These variables were used to calculate the predicted probability (propensity score) of being initiated on a BAM; the resulting propensity scores were used to match new users and nonusers. Outcomes were compared with Cox proportional hazards regression and generalized estimating equations methodology. RESULTS: BAMs were used by 9.8% of the residents 65 years and older admitted for long term care; 44% (1195) were new users. Of these, all but 53 received nonselective immediate release preparations, predominantly oxybutynin chloride (75%). BAM initiation resulted in improved urinary continence status (odds ratio = 1.27, 95% confidence interval [CI] 1.07 1.5) and better social engagement (difference in mean index of social engagement score = 0.2074, 95% CI 0.055-0.3598). The risk of fractures was significantly increased in new users as compared to nonusers (hip fracture: hazard ratio [HR] = 3.67, 95% CI 1.46-9.34; "any" fracture: HR = 2.64, 95% CI 1.37-5.10). The number needed to treat (NNT) to obtain improvement in urinary incontinence after 90 days of treatment (NNT = 32, 95% CI 17-125) was similar to the number needed to harm (NNH) at 90 days in the hip fracture analysis (NNH = 36, 95% CI 12-209). There were no differences in cognitive performance or overall quality of life scores associated with BAM use. CONCLUSION: These results question the continued use of BAMs, particularly immediate-release oxybutynin chloride in elderly nursing home residents. PMID- 23639716 TI - Factors associated with weight loss, low BMI, and malnutrition among nursing home patients: a systematic review of the literature. AB - BACKGROUND: Weight loss and poor nutrition are important quality measures in long term care. Long term care professionals need to identify factors associated with weight loss and poor nutrition to target high-risk patients. METHODS: The authors systematically searched Medline and CINAHL databases and included English language studies with more than 100 subjects analyzed, published after January 1, 1990, with data on factors associated with at least one of the following: weight loss, low body mass index (BMI), low Mini-Nutritional Assessment (MNA) score, or other standard measure of malnutrition. Data from all studies were systematically extracted onto a matrix table. The Critical Appraisal Skills Programme (CASP) questions were used to compare the quality of evidence extracted. Data from each article were then sorted and arranged into tables of factors associated with weight loss, low BMI, and malnutrition. RESULTS: Sixteen studies met the inclusion criteria for the review. The factors most consistently associated with weight loss were depression, poor oral intake, swallowing issues, and eating/chewing dependency. Staffing factors were associated with weight loss in most studies. The factors most consistently associated with low BMI included immobility, poor oral intake, chewing problems, dysphagia, female gender, and older age. The factors most consistently associated with poor nutrition included impaired function, dementia, swallowing/chewing difficulties, poor oral intake, and older age. CONCLUSION: Potentially modifiable factors consistently associated with increased likelihood of weight loss, low BMI, or poor nutrition included depression, impaired function, and poor oral intake. Nursing home medical directors may wish to target quality improvement efforts toward patients with these conditions who are at highest risk for weight loss and poor nutrition. PMID- 23639717 TI - Application of COSMO-RS as an excipient ranking tool in early formulation development. AB - The low amounts of drug available in early discovery often results in limited information on the physico-chemical (solubility etc.) properties of a compound being obtained. As a result, predictive tools and miniaturised screens have been investigated to aid formulation development in early discovery. This study looks at the potential application of the quantum chemistry program, Conductor Screening Model for Real Solvents (COSMO-RS) to help with the selection of excipients for formulation development in early discovery. The excipient solubility predictions obtained from COSMO-RS were compared to experimentally obtained solubilities. The results showed that in general, COSMO-RS was able to help formulators with the selection of the most appropriate excipients to solubilise the model compound. PMID- 23639719 TI - Sponge hybridomas: applications and implications. AB - Many sponge-derived natural products with applications to human health have been discovered over the past three decades. In vitro production has been proposed as one biological alternative to ensure adequate supply of marine natural products for preclinical and clinical development of drugs. Although primary cell cultures have been established for many marine phyla, no cell lines with an extended life span have been established for marine invertebrates. Hybridoma technology has been used for production of monoclonal antibodies for application to human health. We hypothesized that a sponge cell line could be formed by fusing sponge cells of one species with those of another, or by fusing sponge cells with rapidly dividing, marine-derived, non-sponge cells. Using standard methods for formation of hybridomas, with appropriate modifications for temperature and salinity, cells from individuals of the same sponge species, as well as cells from individuals of two different sponge species were successfully fused. Research in progress is focused on optimizing fusion to produce a cell line and to stimulate expression of natural products with therapeutic relevance. Experimental hybridomas may also be used as models to test hypotheses related to naturally occurring sponge chimeras and hybridomas. PMID- 23639718 TI - What the clock tells the eye: lessons from an ancient arthropod. AB - Circadian changes in visual sensitivity have been observed in a wide range of species, vertebrates, and invertebrates, but the processes impacted and the underlying mechanisms largely are unexplored. Among arthropods, effects of circadian signals on vision have been examined in most detail in the lateral compound eye (LE) of the American horseshoe crab, Limulus polyphemus, a chelicerate arthropod. As a consequence of processes influenced by a central circadian clock, Limulus can see at night nearly as well as they do during the day. The effects of the clock on horseshoe crab LE retinas are diverse and include changes in structure, gene expression, and rhabdom biochemistry. An examination of the known effects of circadian rhythms on LEs shows that the effects have three important outcomes: an increase in visual sensitivity at night, a rapid decrease in visual sensitivity at dawn, and maintenance of eyes in a relatively low state of sensitivity during the day, even in the dark. All three outcomes may be critically important for species' survival. Specific effects of circadian rhythms on vision will certainly vary with species and according to life styles. Studies of the circadian regulation of Limulus vision have revealed that these effects can be extremely diverse and profound and suggest that circadian clocks can play a critical role in the ability of animals to adapt to the dramatic daily changes in ambient illumination. PMID- 23639720 TI - General practitioners as first line of defense in benign prostatic hyperplasia screening. PMID- 23639721 TI - Three-year oncologic and renal functional outcomes after robot-assisted partial nephrectomy. AB - BACKGROUND: With the wider adoption of minimally invasive partial nephrectomy (PN), intermediate- and long-term outcomes data are needed to make firm conclusions about oncologic and functional efficacy, especially for robot assisted PN (RPN). OBJECTIVE: To report intermediate-term oncologic and renal functional outcomes of RPN. DESIGN, SETTING, AND PARTICIPANTS: We performed a chart review of patients who had undergone RPN since June 2006; patients with a minimum of 2 yr of follow-up were included in this study. Length of follow-up was calculated from the date of surgery to the date of last clinical follow-up. Patients who were either lost to follow-up or who had follow-up outside of our center were sent surveys. INTERVENTION: Transperitoneal RPN with or without hilar clamping. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The demographic, preoperative, and postoperative data were statistically analyzed. The Kaplan Meier method was used to calculate overall survival (OS), cancer-specific survival (CSS), and cancer-free survival (CFS). Upstaging of chronic kidney disease (CKD) was calculated, as well. Univariate and multivariate analyses were performed to show predicting factors for the latest estimated glomerular filtration rate (eGFR). RESULTS AND LIMITATIONS: Of 427 patients, 134 had a minimum follow-up of 2 yr, and 70 had a minimum of 3-6 yr of follow-up. The mean age was 59.1+/-12.5 yr, body mass index (BMI) was 29.8+/-6.2 kg/m(2), and Charlson comorbidity index (CCI) score was 4.2+/-1.6. The mean tumor size on computed tomography (CT) scan was 3.0+/-1.6 cm, RENAL score was 7.2+/-1.8, estimated blood loss (EBL) was 270.7+/-291.9 ml, operative time was 189.1+/-54.8 min, and warm ischemia time (WIT) was 17.9+/-10.3 min. A total of two intraoperative complications (1.5%) and five high-grade Clavien complications (3.7%) occurred. Patients stayed on average for 3.7+/-1.7 d in the hospital, and the average follow-up was 3.0+/-0.9 yr. OS was 97.01% at 3 yr and 90.20% at 5 yr; CFS was 98.92% at 3 yr and 98.92% at 5 yr; and CSS was 99.04%, as projected by the Kaplan-Meier method. The mean preoperative GFR was 88.2+/-0.8 ml/min per 1.73 m(2); the latest postoperative GFR was 80+/-24 ml/min per 1.73 m(2), with a 8+/ 17.4% change. There was a 20.2% upstaging of CKD postoperatively, but no patients started dialysis. CONCLUSIONS: This study reaffirms that RPN is effective in renal function preservation and oncologic control at an intermediate follow-up interval. PMID- 23639722 TI - Time-dependent movement and distribution of chlorothalonil and chlorpyrifos in tomatoes. AB - Determining the distribution of pesticides in fruits is essential to eliminate pesticide residues during food processing. In this study, the dynamic distribution of two pesticides, chlorothalonil (CHT) and chlorpyrifos (CHP), were determined in different tomato parts following immersion in pesticide solutions. The concentrations of CHT and CHP in tomato followed an order of cuticle>plasma>pulp. However, the plasma initially accumulated the highest pesticide concentration. And the ratio of CHT concentration to that of CHP in plasma was about 2.1:1, similar to the ratio in solution, which suggested carpopodium as the entry site for the pesticides tested. The ratio in the cuticle was 0.02:1-0.06:1. This was consistent with the ratio of Kow for the two pesticides, manifesting the direct pesticide transfer from solution to cuticle. Following pesticide injection into tomato, the degradation of CHT over 96h was described by a first-order decay equation, Ctomato(t)CHT=C0*e(-0.0239t). The CHP concentration in tomato remained nearly constant with little degradation detected. Deducting the amount of degradation and migration, volatilization appeared to contribute the most amount of migration of CHT and CHP in tomato. PMID- 23639723 TI - ICRP PUBLICATION 122: radiological protection in geological disposal of long lived solid radioactive waste. AB - This report updates and consolidates previous recommendations of the International Commission on Radiological Protection (ICRP) related to solid waste disposal (ICRP, 1985, 1997b, 1998). The recommendations given apply specifically to geological disposal of long-lived solid radioactive waste. The report explains how the ICRP system of radiological protection described in Publication 103 (ICRP, 2007) can be applied in the context of the geological disposal of long lived solid radioactive waste. Although the report is written as a standalone document, previous ICRP recommendations not dealt with in depth in the report are still valid. The 2007 ICRP system of radiological protection evolves from the previous process-based protection approach relying on the distinction between practices and interventions by moving to an approach based on the distinction between three types of exposure situation: planned, emergency and existing. The Recommendations maintains the Commission's three fundamental principles of radiological protection namely: justification, optimisation of protection and the application of dose limits. They also maintain the current individual dose limits for effective dose and equivalent dose from all regulated sources in planned exposure situations. They re-enforce the principle of optimisation of radiological protection, which applies in a similar way to all exposure situations, subject to restrictions on individual doses: constraints for planned exposure situations, and reference levels for emergency and existing exposure situations. The Recommendations also include an approach for developing a framework to demonstrate radiological protection of the environment. This report describes the different stages in the life time of a geological disposal facility, and addresses the application of relevant radiological protection principles for each stage depending on the various exposure situations that can be encountered. In particular, the crucial factor that influences the application of the protection system over the different phases in the life time of a disposal facility is the level of oversight or 'watchful care' that is present. The level of oversight affects the capability to control the source, i.e. the waste and the repository, and to avoid or reduce potential exposures. Three main time frames are considered: time of direct oversight, when the disposal facility is being implemented and is under active supervision; time of indirect oversight, when the disposal facility is sealed and oversight is being exercised by regulators or special administrative bodies or society at large to provide additional assurance on behalf of society; and time of no oversight, when oversight is no longer exercised in case memory of the disposal facility is lost. PMID- 23639726 TI - Characterization of the Campylobacter jejuni cryptic plasmid pTIW94 recovered from wild birds in the southeastern United States. AB - The complete nucleotide sequence was determined for a cryptic plasmid, pTIW94, recovered from several Campylobacter jejuni isolates from wild birds in the southeastern United States. pTIW94 is a circular molecule of 3860 nucleotides, with a G+C content (31.0%) similar to that of many Campylobacter spp. genomes. A typical origin of replication, with iteron sequences, was identified upstream of DNA sequences that demonstrated similarity to replication initiation proteins. A total of five open reading frames (ORFs) were identified; two of the five ORFs demonstrated significant similarity to plasmid pCC2228-2 found within Campylobacter coli. These two ORFs were similar to essential replication proteins RepA (100%; 26/26 aa identity) and RepB (95%; 327/346 aa identity). A third identified ORF demonstrated significant similarity (99%; 421/424 aa identity) to the MOB protein from C. coli 67-8, originally recovered from swine. The other two identified ORFs were either similar to hypothetical proteins from other Campylobacter spp., or exhibited no significant similarity to any DNA or protein sequence in the GenBank database. Promoter regions (-35 and -10 signal sites), ribosomal binding sites upstream of ORFs, and stem-loop structures were also identified within the plasmid. These results demonstrate that pTIW94 represents a previously un-reported small cryptic plasmid with unique sequences as well as highly similar sequences to other small plasmids found within Campylobacter spp., and that this cryptic plasmid is present among Campylobacter spp. recovered from different genera of wild birds. PMID- 23639727 TI - Abdominal mass. PMID- 23639725 TI - Widespread but tissue-specific patterns of interferon-induced transmembrane protein 3 (IFITM3, FRAGILIS, MIL-1) in the mouse gastrula. AB - Interferon-induced transmembrane protein 3 (IFITM3; FRAGILIS; MIL-1) is part of a larger family of important small interferon-induced transmembrane genes and proteins involved in early development, cell adhesion, and cell proliferation, and which also play a major role in response to bacterial and viral infections and, more recently, in pronounced malignancies. IFITM3, together with tissue nonspecific alkaline phosphatase (TNAP), PRDM1, and STELLA, has been claimed to be a hallmark of segregated primordial germ cells (PGCs) (Saitou et al., 2002). However, whether IFITM3, like STELLA, is part of a broader stem/progenitor pool that builds the posterior region of the mouse conceptus (Mikedis and Downs, 2012) is obscure. To discover the whereabouts of IFITM3 during mouse gastrulation (~E6.5-9.0), systematic immunohistochemical analysis was carried out at closely spaced 2-4-h intervals. Results revealed diverse, yet consistent, profiles of IFITM3 localization throughout the gastrula. Within the putative PGC trajectory and surrounding posterior tissues, IFITM3 localized as a large cytoplasmic spot with or without staining in the plasma membrane. IFITM3, like STELLA, was also found in the ventral ectodermal ridge (VER), a posterior progenitor pool that builds the tailbud. The large cytoplasmic spot with plasma membrane staining was exclusive to the posterior region; the visceral yolk sac, non-posterior tissues, and epithelial tissues exhibited spots of IFITM3 without cell surface staining. Colocalization of the intracellular IFITM3 spot with the endoplasmic reticulum, Golgi apparatus, or endolysosomes was not observed. That relatively high levels of IFITM3 were found throughout the posterior primitive streak and its derivatives is consistent with evidence that IFITM3, like STELLA, is part of a larger stem/progenitor cell pool at the posterior end of the primitive streak that forms the base of the allantois and builds the fetal-umbilical connection, thus further obfuscating practical phenotypic distinctions between so-called PGCs and surrounding soma. PMID- 23639728 TI - [Thymoma-associated myasthenia gravis: Clinical features and surgical results]. AB - OBJECTIVE: The aim of this study was to compare the characteristics of myasthenic patients with and without thymoma, and the results of thymectomy in both types of patients. MATERIAL AND METHODS: A retrospective study was conducted among 66 patients who underwent thymectomy for myasthenia gravis in our department over a 10-year period (2000-2010). The surgical approach was sternotomy or anterolateral thoracotomy. Patients were divided into two groups according to the presence of thymoma: with (T-MG) and without (NT-MG) thymoma. Complete stable remission (CSR) was the primary endpoint. RESULTS: Median age was 35.09+/-9.89 years. The NT-MG group had 38 patients (57.57%) and the T-MG group 28 patients (42.43%). There was no difference between the two groups regarding the surgical approach (P=0.52). T MG patients were older (40.54+/-15.16 vs. 31.37+/-9.46) (P=0.008) and predominantly male. There were more generalized forms (P=0.01) and more bulbar involvement (P=0.02) in the T-MG group. The rate of CSR at 5 years was 7% and 17% in the T-MG and NT-MG patients respectively (P=0.70). At 10 years, it was 36% and 94.73% respectively (P=0.03). CONCLUSION: Thymomatous myasthenia gravis is characterized by the severity of its clinical features. Remission rate at 10 years was significantly lower in the myasthenia with thymoma group. PMID- 23639730 TI - Compromised motor imagery ability in individuals with multiple sclerosis and mild physical disability: an ERP study. AB - BACKGROUND: Motor imagery (MI) impairment has been reported in individuals with multiple sclerosis (MS). The present study was designed to investigate neural evidence for MI impairment and its relationship to working memory in MS patients. METHODS: The study participants included 24 early stage MS patients (age: 22 40/mean=32.7 years; M/F=4/20; years since duration: 1-10/mean=5.8) and 24 age-, gender-, and education-matched controls (age: 21-40/mean=31.8 years; M/F=5/19). Event-related potentials were recorded during a mental hand rotation task, in which participants were instructed to judge the laterality of hands displayed in different orientations. Furthermore, the Paced Auditory Serial Addition Test (PASAT) was used for assessment of working memory. RESULTS: At the behavioral level, MS patients were significantly less accurate and much slower (accuracy: 83.80 +/- 7.72%; reaction time: 1665.95 +/- 269.82 ms) than controls (accuracy: 88.35 +/- 7.68%; reaction time: 1505.16 +/- 225.11 ms). At the neural level, MS patients showed a significantly reduced amplitude (MS: 0.99 +/- 0.89 MUv, controls: 1.46 +/- 1.00 MUv) and delayed peak latency (MS: 458.45 +/- 67.60 ms, controls: 417.91 +/- 62.47 ms) at P3 for mental rotation effect. Moreover, there were significant correlations between individuals' PASAT scores and performance of the hand rotation task. CONCLUSION: The results of the present study demonstrate MI impairment in patients with MS at both the behavioral and neural level. Neuronal activity dysfunction (decreased and delayed activity) in patients with MS provides new insights into MI impairment. Furthermore, our findings suggest the contribution of working memory dysfunction to compromised MI ability in patients with MS. PMID- 23639731 TI - Vascular endothelial growth factor in the CSF of elderly patients with ventriculomegaly: variability, periodicity and levels in drainage responders and non-responders. AB - OBJECTIVES: The aim of this study was to examine lumbar CSF-VEGF levels from elderly patients with ventriculomegaly to evaluate the possible circadian or periodic concentration profile and relevance to the prediction of drainage response. METHODS: Lumbar CSF samples were collected in 1-h interval over 35 h from 22 patients with ventriculomegaly. CSF-VEGF levels were measured to elucidate the possible circadian or periodic concentration profiles. These VEGF levels were evaluated for correlations with clinical response to CSF drainage, ventricle size and other clinical information. RESULTS: The 35-h CSF-VEGF levels demonstrated a periodic concentration pattern with significant episodic fluctuation with 3-5h intervals. CSF-VEGF levels in non-responder group in which patients did not show clinical improvement with CSF drainage were significantly higher than these in responder group. CONCLUSION: VEGF variation in hydrocephalus patients suggests its possible pathophysiological role in hydrocephalus. The periodic concentration pattern of CSF-VEGF must be considered when choosing the most appropriate time for sample collection or clinical manipulation. Increased VEGF level in patients who showed no improvement with CSF drainage suggests that a possible greater ischemic or vascular injury may play a role in these patients. Pending further studies, these results suggest that high VEGF levels have a potential application in predicting non-responder patients with CSF drainage and so reducing the morbidity and cost of drainage and shunting in these patients. PMID- 23639732 TI - Intradural cervical nerve root traumatic neuroma without a history of direct trauma. PMID- 23639729 TI - Myf5 expression during fetal myogenesis defines the developmental progenitors of adult satellite cells. AB - Myf5 is a member of the muscle-specific determination genes and plays a critical role in skeletal muscle development. Whereas the expression of Myf5 during embryonic and fetal myogenesis has been extensively studied, its expression in progenitors that will ultimately give rise to adult satellite cells, the stem cells responsible for muscle repair, is still largely unexplored. To investigate this aspect, we have generated a mouse strain carrying a CreER coding sequence in the Myf5 locus. In this strain, Tamoxifen-inducible Cre activity parallels endogenous Myf5 expression. Combining Myf5(CreER) and Cre reporter alleles, we were able to evaluate the contribution of cells expressing Myf5 at distinct developmental stages to the pool of satellite cells in adult hindlimb muscles. Although it was possible to trace back the origin of some rare satellite cells to a subpopulation of Myf5(+ve) progenitors in the limb buds at the late embryonic stage (~E12), a significant number of satellite cells arise from cells which expressed Myf5 for the first time at the fetal stage (~E15). These studies provide direct evidence that adult satellite cells derive from progenitors that first express the myogenic determination gene Myf5 during fetal stages of myogenesis. PMID- 23639733 TI - The role of self-regulation in voice therapy. AB - Self-regulation (SR) is the ability to voluntarily control one's thinking and behavior and is a core construct in research on learning and behavior. SR plays a significant role in mastering and generalizing new skills, including skills such as those taught in voice therapy. The ability to self-regulate thoughts and behaviors varies widely across adults, changes in response to factors such as the cognitive load of the task, and predicts the likelihood of pursuing goals and maintaining behavior change over time. We propose that self-regulatory capacity should be considered both in determining candidacy for voice therapy and also in treatment planning. Thus, the goals of this article are to (1) introduce concepts and models of SR; (2) apply these concepts to voice therapy from a motor learning framework; (3) discuss considerations regarding the effects of SR failure on short- and long-term outcomes; and (4) suggest strategies to improve SR and better facilitate vocal behavior change. PMID- 23639734 TI - Binding characteristics of salbutamol with DNA by spectral methods. AB - Salbutamol interacting with deoxyribonucleic acid (DNA) was examined by fluorescence, UV absorption, viscosity measurements, and DNA melting techniques. The binding constants and binding sites were obtained at different temperatures by fluorescence quenching. The Stern-Volmer plots showed that the quenching of fluorescence of salbutamol by DNA was a static quenching. To probe the binding mode, various analytical methods were performed and the results were as follows: hyperchromic effect was shown in the absorption spectra of salbutamol upon addition of DNA; there was no appreciable increase in melting temperature of DNA when salbutamol was presented in DNA solution; the fluorescence intensity of salbutamol-DNA decrease with the increasing ionic strength; the relative viscosity of DNA did not change in the presence of salbutamol; the binding constant of salbutamol with double strand DNA (dsDNA) was much higher than that of it with single strand DNA (ssDNA). All these results indicated that the binding mode of salbutamol to DNA should be groove binding. The thermodynamic parameters suggested that hydrogen bond or van der Waals force might play an important role in salbutamol binding to DNA. According to the Forster energy transference theory, the binding distance between the acceptor and donor was 3.70 nm. PMID- 23639735 TI - Production and spectral properties of lattice defects in natural fibrous gypsum colored electrolytically at near room temperature using a pointed anode. AB - Natural fibrous gypsum is colored electrolytically at near room temperatures and under various voltages using a pointed anode and a flat cathode. The SO4(-), SO3( ), SO2(-) and O(-) lattice defects are produced in the colored natural fibrous gypsum. No visible characteristic absorption band in the ultraviolet and visible wavelength regions is observed in the optical absorption spectrum of the natural fibrous gypsum before the electrolytic coloration. The characteristic absorption bands of the SO4(-), SO3(-), SO2(-) and O(-) lattice defects are observed in the optical absorption spectra of the colored natural fibrous gypsum. The production of the lattice defects is explained. Current-time curve for the electrolytic coloration of the natural fibrous gypsum and its relationship with the electrolytic coloration processes are given. PMID- 23639736 TI - Using terahertz time-domain spectroscopical technique to monitor cocrystal formation between piracetam and 2,5-dihydroxybenzoic acid. AB - Far-infrared vibrational absorption of cocrystal formation between 2,5 dihydroxybenzoic acid (2,5-DHBA) and piracetam compounds under solvent evaporation and grinding methods have been investigated using terahertz time domain spectroscopy (THz-TDS) at room temperature. The experimental results show large difference among absorption spectra of the formed cocrystals and the involved individual parent molecules in 0.20-1.50 THz region, which probably originated from the intra-molecular and inter-molecular hydrogen bonds due to the presence of two hydroxyl groups in 2,5-DHBA and amide moieties in piracetam compound. The THz absorption spectra of two formed cocrystals with different methods are almost identical. With grinding method, the reaction process can be monitored directly from both time-domain and frequency-domain spectra using THz TDS technique. The results indicate that THz-TDS technology can absolutely offer us a high potential method to identify and characterize the formed cocrystals, and also provide the rich information about their reaction dynamic process involving two or more molecular crystals in situ to better know the corresponding reaction mechanism in pharmaceutical fields. PMID- 23639737 TI - The effects of linear assembly of two carbazole groups on acid-base and DNA binding properties of a ruthenium(II) complex. AB - A novel Ru(II) complex of [Ru(bpy)2(Hbcpip)](ClO4)2 {where bpy=2,2-bipyridine, Hbcpip=2-(4-(9H-3,9'-bicarbazol-9-yl)phenyl)-1H-imidazo[4,5 f][1,10]phenanthroline} is synthesized and characterized. Calf-thymus DNA-binding properties of the complex were studied by UV-vis absorption and luminescence titrations, steady-state emission quenching by [Fe(CN)6](4-), DNA competitive binding with ethidium bromide, thermal denaturation and DNA viscosity measurements. The results indicate that the complex partially intercalated into the DNA with a binding constant of (5.5+/-1.4)*10(5) M(-1) in buffered 50 mM NaCl. The acid-base properties of the complex were also studied by UV-visible and luminescence spectrophotometric pH titrations, and ground- and excited-state acidity ionization constant values were derived. PMID- 23639738 TI - Enzyme-responsive surface erosion of poly(ethylene carbonate) for controlled drug release. AB - Cholesterol esterase (CE) induced surface erosion of poly(ethylene carbonate) (PEC) and drug release from PEC under mild physiological environment was investigated. The degradation process was monitored by changes of mass and molecular weight (MW) and surface morphology of polymer films. During the whole period of degradation, MW of PEC was unchanged. Water uptake of the polymer was only 2.8% and 0.2% for PEC with the MW of 200 kDa (PEC200) and PEC with the MW of 41 kDa (PEC41), respectively. Degradation of less hydrophilic PEC41 with higher density was slower than that of PEC200. By this mechanism, CE-responsive drug in vitro release from PEC in situ forming depots (ISFD) was conducted successfully. As expected, less bovine serum albumin (BSA) was released from PEC41 compared with that of PEC200 in the same time period. In conclusion, this work enabled the in vitro drug release evaluation of existing PEC devices and implied a new candidate for the development of enzyme-responsive systems. PMID- 23639739 TI - In vivo administration of VEGF- and GDNF-releasing biodegradable polymeric microspheres in a severe lesion model of Parkinson's disease. AB - In this work, the neuroregenerative potentials of microencapsulated VEGF, GDNF and their combination on a severely lesioned rat model were compared with the aim of developing a new strategy to treat advanced stages of Parkinson's disease. Both neurotrophic factors were separately encapsulated into polymeric microspheres (MSs) to obtain a continuous drug release over time. The regenerative effects of these growth factors were evaluated using a rotation behaviour test and quantified by the number of surviving TH+cells. The biological activities of encapsulated vascular endothelial growth factor (VEGF) and glial cell line-derived neurotrophic factor (GDNF) were investigated in HUVEC and PC12 cells, respectively. The treatment of 6-OHDA-lesioned rats with GDNF microspheres and with both VEGF and GDNF microspheres resulted in improved results in the rotation behaviour test. Both groups also showed higher levels of neuroregeneration/neuroreparation in the substantia nigra than the control group did. These results were confirmed by the pronounced TH+neuron recovery in the group receiving VEGF+GDNF-MS, demonstrating regenerative effects. PMID- 23639740 TI - Involvement of autotaxin/lysophosphatidic acid signaling in obesity and impaired glucose homeostasis. AB - Autotaxin (ATX) is a secreted lysophospholipase D involved in synthesis of lysophosphatidic acid (LPA), a phospholipid growth factor acting via specific receptors (LPA1R to LPA6R) and involved in several pathologies including obesity. ATX is secreted by adipocytes and contributes to circulating LPA. ATX expression is up-regulated in obese patients and mice in relationship with insulin resistance and impaired glucose tolerance. LPA1R is the most abundant subtype in adipose tissue. Its expression is higher in non-adipocyte cells than in adipocytes and is not altered in obesity. ATX increases and LPA1R decreases while preadipocytes differentiate into adipocytes (adipogenesis). LPA inhibits adipogenesis through down-regulation of the pro-adipogenic transcription factor PPARgamma2. Adipocyte-specific knockout (FATX-KO) mice or mice treated with the LPAR antagonist Ki16425 gain more weight and accumulate more adipose tissue than wild type or control mice fed a high fat diet (HFD). These observations suggest that LPA (via LPA1R) exerts a tonic inhibitory effect on adipose tissue expansion that could, at least in part, result from the anti-adipogenic activity of LPA. A possible negative impact of LPA on insulin-sensitivity might also be considered. Despite being more sensitive to nutritional obesity, FATX-KO and Ki16425-treated mice fed a HFD show improved glucose tolerance when compared to wild type mice. Moreover, exogenously injected LPA acutely impairs glucose tolerance and insulin secretion. These observations show that LPA exerts a tonic deleterious impact on glucose homeostasis. In conclusion, ATX and LPA1R represent potential interesting pharmacological targets for the treatment of obesity-associated metabolic diseases. PMID- 23639741 TI - Ultrasound-assisted extraction of Na and K from swine feed and its application in a digestibility assay: a green analytical procedure. AB - The study is aimed to evaluate the efficiency of ultrasound-assisted extraction (UAE) as a simple strategy focused on sample preparation for metal determination in biological samples. The extraction of sodium and potassium extraction was carried out from swine feed followed by determination of the concentration of these metals by flame atomic emission spectrometry (FAES). The experiment was performed to cover the study of the variables influencing the extraction process and its optimal conditions (sample mass, particle size, acid concentration, sonication time and ultrasound power); the determination of these analytical characteristics and method validation using certified reference material; and the analysis of pre-starter diets. The optimal conditions established conditions were as follows: mass: 100mg, particle size:<60 MUm, acid concentration: 0.10 mol L( 1) HCl, sonication time: 50s and ultrasound power: 102 W. The proposed method (UAE) was applied in digestibility assays of those nutrients present in different piglet pre-starter feeds and their results proved to be compatible with those obtained from mineralized samples (P<0.05). The ultrasound extraction method was demonstrated to be an excellent alternative for handless sampling and operational costs and the method also has the advantage of does not generating toxic residues that may negatively affect human health and contaminate the environment. PMID- 23639742 TI - Immunomodulation and hormonal disruption without compromised disease resistance in perfluorooctanoic acid (PFOA) exposed Japanese quail. AB - This study evaluated the impact of oral perfluorooctanoic acid (PFOA) on Japanese quail at concentrations found in American and Belgian workers at PFOA manufacturing facilities. Three arms of the immune system were tested; T cell, B cell, and innate immunity. After 6 weeks exposure, quail were challenged with E. coli infection to test the ultimate measure of immunotoxicity, disease resistance. The T cell response was lower in the high exposure groups. Antibody mediated, and innate immune responses were not different. Growth rate was higher, whereas thyroid hormone levels were lower in PFOA-exposed birds. Morbidity/mortality from disease challenge was not different among the control and PFOA-exposed groups, and no overt PFOA toxicity was observed pre-disease challenge. Although PFOA at 'worst case scenario' levels caused T cell immunosuppression, this did not translate into increased disease susceptibility, demonstrating that immunotoxicity testing must be interpreted with caution since disease resistance is the ultimate concern. PMID- 23639743 TI - Effects of elevated O3 exposure on nutrient elements and quality of winter wheat and rice grain in Yangtze River Delta, China. AB - With the open-top chambers (OTCs) in situ in Yangtze River Delta, China in 2007 and 2008, the effects of elevated O3 exposure on nutrient elements and quality of winter wheat and rice grain were investigated. Grain yield per plant of winter wheat and rice declined in both years. The N and S concentrations increased under elevated O3 exposure in both years and C-N ratios decreased significantly. The concentrations of K, Ca, Mg, P, Mn, Cu and Zn in winter wheat and the concentrations of Mg, K, Mn and Cu in rice increased. The concentrations of protein, amino acid and lysine in winter wheat and rice increased and the concentration of amylose decreased. The increase in the nutrient concentration was less than the reduction of grain yield in both winter wheat and rice, and, hence, the absolute amount of the nutrients was reduced by elevated O3. PMID- 23639744 TI - Histological chorioamnionitis: effects on premature delivery and neonatal prognosis. AB - BACKGROUND: Chorioamnionitis is closely related to premature birth and has negative effects on neonatal morbidity and mortality. METHODS: In this prospective study, 43 mothers who delivered earlier than 35 gestational weeks and their 57 infants were evaluated clinically and with laboratory findings. Placentas and umbilical cords were investigated histopathologically for chorioamnionitis and funisitis. RESULTS: The overall frequency of clinical and histological chorioamnionitis (HCA) was 8.3% and 23.2%, respectively. The frequency of HCA was 47.3% and 83.3% in mothers delivered <32 weeks and <30 weeks, respectively. Maternal demographic and clinical findings and also leukocyte and C-reactive protein values were not indicative of HCA. Infants of mothers with HCA had significantly lower Apgar scores together with higher SNAP PE-II and CRIB scores. These infants had increased mechanical ventilator and surfactant requirements, higher incidences of patent ductus arteriosus, early sepsis, and bronchopulmonary dysplasia, and higher mortality rates. The effect of HCA on neonatal morbidity and mortality was more prominent than the effect of low birthweight and lower gestational age. CONCLUSION: Chorioamnionitis not only causes premature deliveries, but is also associated with neonatal complications and increased mortality. Clinical findings and infectious markers in mother or infant do not predict the diagnosis of histological chorioamnionitis. Therefore, placental histopathology may have a role in predicting neonatal outcome in premature deliveries, especially those below 30 weeks. PMID- 23639745 TI - A Newborn with Congenital Mixed Phenotype Acute Leukemia After In Vitro Fertilization. AB - Congenital leukemia is a rare disease. The majority of cases of this disease are acute myelogenous leukemia (AML). Congenital acute lymphoblastic leukemia (ALL) is rare and most often is of B cell lineage. Rarely, some cases have been designated biphenotypic or mixed phenotype acute leukemia (MPAL). Herein, we report a preterm newborn referred to us as a result of the appearance of blue violaceous dermal nodules on her body at birth. She was a twin and the product of an in vitro fertilization (IVF) pregnancy. Physical examination showed jaundice, hepatosplenomegaly, and peripheral facial nerve palsy in addition to dermal nodules. Bone marrow aspiration showed 40% blasts of lymphoid lineage; skin biopsy and its immunohistochemistry revealed myeloblastic infiltration of the dermis. Cytogenetic analysis (46,XX), fluorescence in situ hybridization (FISH) analysis, and cranial magnetic resonance were normal. The patient was diagnosed with congenital MPAL, and an association between IVF and congenital leukemia was suggested. PMID- 23639746 TI - Hypertrophic Cardiomyopathy After a Single Dose of Dexamethasone in a Preterm Infant. AB - Dexamethasone is widely used in preterm infants with severe pulmonary disease. Hypertrophic cardiomyopathy (HCM) is a transient side effect observed after multiple doses of dexamethasone. We report a preterm infant with myocardial hypertrophy after a single dose of dexamethasone (0.5 mg/kg) used to treat laryngeal edema secondary to prolonged intubation. A benign course was observed without left ventricular outflow tract obstruction and with recovery within 4 weeks. Myocardial effects of dexamethasone may be independent of dose and duration of treatment. The risk/benefit ratio must be carefully considered before using even a single dose of dexamethasone in preterm infants. PMID- 23639747 TI - A case of prune belly syndrome. AB - Prune belly syndrome (PBS) is a rare congenital disorder characterized by deficient abdominal wall muscles, urinary tract malformation, and, in males, cryptorchidism. We present a case of PBS in China. The patient was a newborn baby boy who had wrinkled, "prune-like" abdominal skin, bilateral cryptorchidism, and urinary system malformation, complicated with hypoplasia of the lung and branch of the coronary artery-right ventricular fistula. His kidney function was inadequate. The patient subsequently died at age 28 days due to septicemia from a severe urinary tract infection. PMID- 23639748 TI - Successful large-volume leukapheresis for hematopoietic stem cell collection in a very-low-weight brain tumor infant with coagulopathy. AB - Peripheral apheresis has become a safe procedure to collect hematopoietic stem cells, even in pediatric patients and donors. However, the apheresis procedure for small and sick children is more complicated due to difficult venous access, relatively large extracorporeal volume, toxicity of citrate, and unstable hemostasis. We report a small and sick child with refractory medulloblastoma, impaired liver function, and coagulopathy after several major cycles of cisplatin based chemotherapy. She successfully received large-volume leukapheresis for hematopoietic stem cell collection, although the patient experienced severe coagulopathy during the procedures. Health care providers should be alert to this potential risk. PMID- 23639749 TI - Binding of bis-ANS to Bacillus subtilis lipase: a combined computational and experimental investigation. AB - 8-Anilino-1-naphthalene sulfonate (ANS) and its covalent dimer bis-ANS are widely used for titrating hydrophobic surfaces of proteins. Interest to understand the nature of interaction of these dyes with proteins was seriously pursued. However as the techniques used in these studies varied, they often provided varied information regarding stoichiometry, binding affinity, actual binding sites etc. In the present study, we used combination of computation methods (docking and MD simulation) and experimental methods (mutations, steady-state and time-resolved fluorescence) to investigate bis-ANS interaction with Bacillus subtilis lipase. We identified seven binding sites for bis-ANS on lipase using computational docking and MD simulation and verified these data using a set of single amino acid substituted mutants. Docking and MD simulation studies indicated that the binding sites were various indentations and grooves on protein surface with hydrophobic characteristics. Both hydrophobic and ionic interactions were involved in each of these binding events. We further examine the fluorescence properties of bis-ANS bound to mutant lipases that either gained or lost a binding site. Our results indicated that neither gain nor loss of single binding site caused any change in fluorescence lifetimes (and their relative amplitudes) of mutant lipase-bound bis-ANS in comparison to that bound to wild type; hence, it suggested that nature of bis-ANS binding to each of the sites in lipase was very similar. PMID- 23639750 TI - Neuroglobin involvement in visual pathways through the optic nerve. AB - Neuroglobin is a member of the globin superfamily proposed to be only expressed in neurons and involved in neuronal protection from hypoxia or oxidative stress. A significant fraction of the protein localizes within the mitochondria and is directly associated with mitochondrial metabolism and integrity. The retina is the site of the highest concentration for neuroglobin and has been reported to be up to 100-fold higher than in the brain. Since neuroglobin was especially abundant in retinal ganglion cell layer, we investigated its abundance in optic nerves. Remarkably in optic nerves, neuroglobin is observed, as expected, in retinal ganglion cell axon profiles but also astrocyte processes, in physiological conditions, possess high levels of the protein. Neuroglobin mRNA and protein levels are ~10-fold higher in optic nerves than in retinas, indicating an important accumulation of neuroglobin in these support cells. Additionally, neuroglobin levels increase in Muller cells during reactive gliosis in response to eye injury. This suggests the pivotal role of neuroglobin in retinal glia involved in neuronal support and/or healing. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. PMID- 23639751 TI - Warehousing re-annotated cancer genes for biomarker meta-analysis. AB - Translational research in cancer genomics assigns a fundamental role to bioinformatics in support of candidate gene prioritization with regard to both biomarker discovery and target identification for drug development. Efforts in both such directions rely on the existence and constant update of large repositories of gene expression data and omics records obtained from a variety of experiments. Users who interactively interrogate such repositories may have problems in retrieving sample fields that present limited associated information, due for instance to incomplete entries or sometimes unusable files. Cancer specific data sources present similar problems. Given that source integration usually improves data quality, one of the objectives is keeping the computational complexity sufficiently low to allow an optimal assimilation and mining of all the information. In particular, the scope of integrating intraomics data can be to improve the exploration of gene co-expression landscapes, while the scope of integrating interomics sources can be that of establishing genotype-phenotype associations. Both integrations are relevant to cancer biomarker meta-analysis, as the proposed study demonstrates. Our approach is based on re-annotating cancer specific data available at the EBI's ArrayExpress repository and building a data warehouse aimed to biomarker discovery and validation studies. Cancer genes are organized by tissue with biomedical and clinical evidences combined to increase reproducibility and consistency of results. For better comparative evaluation, multiple queries have been designed to efficiently address all types of experiments and platforms, and allow for retrieval of sample-related information, such as cell line, disease state and clinical aspects. PMID- 23639752 TI - Computer-aided diagnosis of breast masses using quantified BI-RADS findings. AB - The information from radiologists was utilized in the proposed computer-aided diagnosis (CAD) for breast tumor classification. The ultrasound (US) database used in this study contained 166 benign and 78 malignant masses. For each mass, six quantitative feature sets were used to describe the radiologists' grading of six Breast Imaging Reporting and Data System (BI-RADS) categories including shape, orientation, margins, lesion boundary, echo pattern, and posterior acoustic features on breast US. The descriptive abilities were between 76% and 82% and the predicted descriptors were then used for tumor classification. Using receiver operating characteristic curve for evaluation, the area under curve (AUC) of the proposed CAD was slightly better than that of a conventional CAD based on the combination of all quantitative features (0.96 vs. 0.93, p=0.18). The partial AUC over 90% sensitivity of the proposed CAD was significantly better than that of the conventional CAD (0.90 vs. 0.76, p<0.05). In conclusion, the computer-aided analysis with qualitative information from radiologists showed a promising result for breast tumor classification. PMID- 23639753 TI - Necessity of noise in physiology and medicine. AB - Noise is omnipresent in biomedical systems and signals. Conventional views assume that its presence is detrimental to systems' performance and accuracy. Hence, various analytic approaches and instrumentation have been designed to remove noise. On the contrary, recent contributions have shown that noise can play a beneficial role in biomedical systems. The results of this literature review indicate that noise is an essential part of biomedical systems and often plays a fundamental role in the performance of these systems. Furthermore, in preliminary work, noise has demonstrated therapeutic potential to alleviate the effects of various diseases. Further research into the role of noise and its applications in medicine is likely to lead to novel approaches to the treatment of diseases and prevention of disability. PMID- 23639755 TI - Knee angle-specific MVIC for triceps surae EMG signal normalization in weight and non weight-bearing conditions. AB - Varying the degree of weight-bearing (WB) and/or knee flexion (KF) angle during a plantar-flexion maximal voluntary isometric contraction (MVIC) has been proposed to alter soleus and/or gastrocnemius medialis and lateralis activation. This study compared the surface EMG signals from the triceps surae of 27 men and 27 women during WB and non weight bearing (NWB) plantar-flexion MVICs performed at 0 degrees and 45 degrees of KF. The aim was to determine which condition was most effective at eliciting the greatest EMG signals from soleus, gastrocnemius medialis, and gastrocnemius lateralis, respectively, for subsequent use for the normalization of EMG signals. WB was more effective than NWB at eliciting the greatest signals from soleus (p=0.0021), but there was no difference with respect to gastrocnemius medialis and lateralis (p?0.2482). Although the greatest EMG signals during MVICs were more frequently elicited at 0 degrees of KF from gastrocnemius medialis and lateralis, and at 45 degrees from soleus (p<0.001); neither angle consistently captured peak gastrocnemius medialis, gastrocnemius lateralis or soleus activity. The present findings encourage more consistent use of WB plantar flexion MVICs for soleus normalization; confirm that both WB and NWB procedures can elicit peak gastrocnemius activity; and emphasize the fact that no single KF angle consistently evokes selective maximal activity of any individual triceps surae muscle. PMID- 23639754 TI - Aldehyde dehydrogenase 3 converts farnesal into farnesoic acid in the corpora allata of mosquitoes. AB - The juvenile hormones (JHs) play a central role in insect reproduction, development and behavior. Interrupting JH biosynthesis has long been considered a promising strategy for the development of target-specific insecticides. Using a combination of RNAi, in vivo and in vitro studies we characterized the last unknown biosynthetic enzyme of the JH pathway, a fatty aldehyde dehydrogenase (AaALDH3) that oxidizes farnesal into farnesoic acid (FA) in the corpora allata (CA) of mosquitoes. The AaALDH3 is structurally and functionally a NAD(+) dependent class 3 ALDH showing tissue- and developmental-stage-specific splice variants. Members of the ALDH3 family play critical roles in the development of cancer and Sjogren-Larsson syndrome in humans, but have not been studies in groups other than mammals. Using a newly developed assay utilizing fluorescent tags, we demonstrated that AaALDH3 activity, as well as the concentrations of farnesol, farnesal and FA were different in CA of sugar and blood-fed females. In CA of blood-fed females the low catalytic activity of AaALDH3 limited the flux of precursors and caused a remarkable increase in the pool of farnesal with a decrease in FA and JH synthesis. The accumulation of the potentially toxic farnesal stimulated the activity of a reductase that converted farnesal back into farnesol, resulting in farnesol leaking out of the CA. Our studies indicated AaALDH3 plays a key role in the regulation of JH synthesis in blood-fed females and mosquitoes seem to have developed a "trade-off" system to balance the key role of farnesal as a JH precursor with its potential toxicity. PMID- 23639756 TI - Motor and non-motor symptoms of 1453 patients with Parkinson's disease: prevalence and risks. AB - PURPOSE: We examined the prevalence and risk of clinical symptoms in a large number of Japanese patients with Parkinson's disease (PD) (n = 1453; 650 males). METHODS: Events were analyzed using Kaplan-Meier survival curves, logistic regression, and Cox proportional-hazards models. RESULTS: The mean age (SD) was 67.7 (10.0), age of onset was 58.0 (11.5), and disease duration was 9.7 (6.6) years. The mean modified Hoehn and Yahr stage was 2.8 (1.2). Most patients (88.9%) received levodopa (547.7 (257.6) mg/day). A large proportion (81.3%) received dopamine agonists (136.2 (140.7) mg/day). About 23.4% received pain treatment 6.9 (5.1) years after the onset; females (p < 0.05) and patients with late-onset PD (>=60 years, p < 0.001) were more likely to be affected. About 44.7% of patients had wearing-off 7.5 (4.7) years after the onset, and it was more common in females (p < 0.001) and patients with early-onset PD (p < 0.001). Camptocormia was found in 9.5% of patients 8.1 (6.2) years after the onset, and it was more common in females (p < 0.05) and patients with late-onset PD (p < 0.05). About 28.6% of patients developed psychosis 9.0 (5.4) years after the onset, and it was more likely to occur in patients with late-onset PD (p < 0.001). Late-onset PD and cerebrovascular disease were also associated with increased risk of pneumonia. CONCLUSIONS: Considering that very few studies have assessed numerous clinical symptoms in the same report, these data provide a useful reference for the clinical course of PD. PMID- 23639758 TI - Irbesartan administration therapeutically influences circulating endothelial progenitor cell and microparticle mobilization by involvement of pro-inflammatory cytokines. AB - Circulating microparticles (MPs) and endothelial progenitor cells (EPCs) correlate with endothelial dysfunction and contribute to the pathogenesis of atherosclerosis. In this context, we explored whether the angiotensin II type I receptor antagonist, irbesartan, exerts a pharmacological control in the atherosclerotic process by the improvement of EPC mobilization and inhibitory effects on MP release and VEGF and SDF-1alpha levels in the hypertensive hypercholesterolemic (HH) hamster model. The HH hamsters were treated with irbesartan (50mg/kg b.w/day administered by gavage) for 4 month (HHI). We analyzed MP/EPC infiltration in vascular wall before and after irbesartan administration as well as the endothelial function and expression of VEGF/SDF 1alpha in plasma and tissue and of molecular pathways activated by them. The results showed that treatment with irbesartan significantly increased EPC infiltration and decreased MP infiltration. The mechanisms underlying this response include the reduction/increase of a number of specific membrane receptors exposed by MPs (TF, P-Selectin, E-Selectin, PSGL-1, Rantes), respectively, by EPCs (beta2-Integrins, alpha4beta1-integrin), the augmentation of endothelium-mediated vasodilation and the reduction of protein expression of VEGF/SDF-1alpha followed by: (1) the diminishment of pro-inflammatory endothelial cytokines: VEGFR1, VEGFR2, CXCR4, Tie2, PIGF with role in EPC homing to sites of damaged endothelium; and (2) the increase of protein expression of COX-2, PGI2 synthase molecules with role in the improvement of arterial wall vasodilatation. In conclusion, the study underlines that irbesartan administration therapeutically improves/reduces EPC, respectively, MP mobilization and this action may be of salutary relevance contributing to its beneficial cardiovascular effects. PMID- 23639757 TI - RBx10080307, a dual EGFR/IGF-1R inhibitor for anticancer therapy. AB - Pharmacological intervention of epidermal growth factor receptor (EGFR) family members by antibodies or small molecule inhibitors has been one of the most successful approaches for anticancer therapy. However this therapy has its own limitations due to the development of resistance, over a period of time. One of the possible causes of the development of resistance to the therapy with EGFR inhibitors could be the simultaneous activation of parallel pathways. Both EGFR and insulin like growth factor-1 receptor (IGF-1R) pathways are reported to act reciprocal to each other and converge into the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. Inhibiting one pathway alone may therefore not be sufficient and could be a cause of development of resistance. The other cause could be mutations of EGFR which would be less sensitive to the inhibitors. We, therefore, suggest that co-targeting IGF-1R and EGFR kinases by dual inhibitors can lead to improved efficacy and address the problems of resistance. In the present manuscript, we report the identification of a novel, small molecule dual EGFR/IGF-1R inhibitor, RBx10080307 which displayed in vitro activity at the molecular level and oral efficacy in mouse xenograft model. The compound also showed in vitro activity in an EGFR mutant cell line and may thus have the potential to show activity in resistant conditions. Additional efficacy studies are needed in EGFR resistant mouse cancer model and if found efficacious, this can be a major advantage over standalone erlotinib and other existing therapies. PMID- 23639759 TI - Treatment outcomes in 23 thoracic primitive neuroectodermal tumours: a retrospective study. AB - OBJECTIVES: Thoracic primitive neuroectodermal tumour is an aggressive malignancy with poor survival despite multimodality treatment regimens. Early diagnosis of the tumour by histological, immunohistochemical, ultrastructural and cytogenetic techniques and early total surgical resection of the tumour with intensive chemoradiation may improve outcomes. METHODS: Over 30 years, 23 patients (median age 29.5) with primitive neuroectodermal tumours (15 chest wall, 4 lung, 3 costovertebral sulcus and 1 anterior mediastinum) were diagnosed by transthoracic needle biopsy (43%) or excisional biopsy (57%). Treatment of a localized disease (Stage I and II) in 19 patients included surgery (wide excision of chest lesions in 11, 4 lung resections, excision of 3 costovertebral sulcus and 1 anterior mediastinal tumours, and resection of adjacent tissues involved by tumour en bloc) with adjuvant chemoradiation. Four metastatic chest wall tumours (Stage III) had chemotherapy and radiation alone. RESULTS: Tumour recurred in 5 (2 chest wall, 2 costovertebral sulcus and 1 lung) requiring further chemotherapy, radiation and completion pneumonectomy for a lung recurrence. The incidence of recurrent tumour in 7 years for Stage I was 21 vs 40% (P=0.4) for Stage II lesions and 16% after the neoadjuvant chemotherapy vs 30% (P=0.4) after adjuvant chemoradiation. Four with recurrence, except one with a chest recurrence, succumbed to second relapse (78-96 months). All four Stage III chest tumours succumbed to advanced disease (30 months). The Kaplan-Meier disease-free survival of the overall group (23 patients) was 82+/-2% at 5 years and 64+/-3% at 10 years. The 10-year disease-free survival of 19 patients with localized tumours was 76%, but was high at 90% for chest wall tumours and low 33% for costovertebral sulcus tumours (P<=0.01). The 10-year disease-free survival was 86% for Stage I vs 60% (P=0.02) for Stage II tumours; and 83% for neoadjuvant vs 76% (P=0.06) for adjuvant chemotherapy and radiation. CONCLUSIONS: The primitive neuroectodermal tumours are aggressive neoplasms with poor prognosis. Early diagnosis and total surgical excision of localized tumours with neoadjuvant or adjuvant chemotherapy and radiation improved disease-free survival. PMID- 23639760 TI - Percutaneous iliosacral screw fixation in unstable pelvic ring lesions: the interest of O-ARM CT-guided navigation. AB - INTRODUCTION: The reference surgical treatment for unstable posterior pelvic fracture is percutaneous iliosacral screw fixation, isolated or in association with other techniques. As there is a risk of passage outside the bone when performing screw fixation under fluoroscopy, new image-guidance techniques have been developed: fluoronavigation, peroperative 3D navigation, CT-linked navigation, etc. Since September 2011, our department has performed iliosacral screw fixation under CT control linked to navigation so as to optimize screw positioning. This innovative technology has been used in neurosurgery in our center since 2007, for disc implants, spinal fracture, vertebral arthrodesis and intracerebral localization. MATERIAL AND METHODS: Six patients were treated by iliosacral screw fixation for posterior pelvic ring fracture lesion. The O-ARM (Medtronic((r))) computer-assisted surgical navigation system was used, combining surgical navigation and peroperative 3D imaging. This kind of osteosynthesis is suitable for non-displaced or prereduced fracture. A radiation dose report is drawn up at end of surgery. DISCUSSION: Postoperative course does not differ from other percutaneous osteosynthesis techniques, combing the advantages of a percutaneous approach (reduced infection and blood-loss rates, etc.) while optimizing iliosacral screw positioning. To date, no radiation overexposure has been found. CONCLUSION: The precision and safety of iliosacral screw fixation are now unequalled, meeting the basic computer-assisted surgery principles of reduced morbidity without overexposure to ionizing radiation. Indications for computer assisted surgery should therefore be extended to iliosacral pathologies (arthritic, tumoral and inflammatory), non-displaced acetabular fracture, etc. PMID- 23639761 TI - Postoperative perceived health status in adolescent following idiopathic scoliosis surgical treatment: results using the adapted French version of Scoliosis Research Society Outcomes questionnaire (SRS-22). AB - PURPOSE: Assessing functional outcome from patient-based outcomes questionnaires are essential to the evaluation of adolescent idiopathic scoliosis surgical treatment METHODS: At the minimum follow-up of 2 years, 45 operated on adolescent idiopathic scoliosis patients were mailed the French version of the Scoliosis Research Society Outcome Instrument (SRS-22) questionnaires containing items on pain, activities of daily living, and satisfaction. RESULTS: Mean values of the SRS-22 domains were 3,66 for the Pain domain, 3,85 for the Self-perceived image domain, 4,32 for the Function domain, 3,52 for the Mental health domain and 4,12 for the Global satisfaction with management domain. Mean value of the global SRS 22 score was 3,88. We showed no differences in functional SRS-22 health status in patients according to the type of curve (Lenke classification). We showed statistically significant correlations between the gain of Cobb angle and Patients self-image and function domain scores. There was a statistically significant correlation between preoperative Cobb angle and patient satisfaction with management. CONCLUSIONS: Even if Function and Self-image scores in our patients are close to control group values, indicating good short to mid-term outcome of surgical treatment, scores for pain and mental health status were significantly lower in patients than controls. Long-term follow-up studies conducted by multiple surgeons over successive generations are mandatory to assess clinical significance of these differences. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 23639762 TI - Feasibility and acceptability of Internet grocery service in an urban food desert, Chicago, 2011-2012. AB - We explored the feasibility and acceptability of an Internet grocery service (IGS) as an approach to improving food access in urban neighborhoods. In our pilot study, caregivers residing in a documented Chicago food desert (N = 34, 79% ethnic minority) received a voucher to use a commercial IGS to purchase groceries for their household. Caregivers most frequently purchased fruits, vegetables, meats, and caloric beverages, and endorsed 4 factors as potentially important determinants of future IGS use. IGS programs could have a role in improving urban food access if they have competitive prices, provide rapid delivery, and incorporate strategies to discourage purchasing of discretionary caloric beverages. PMID- 23639763 TI - A multilevel approach to estimating small area childhood obesity prevalence at the census block-group level. AB - INTRODUCTION: Traditional survey methods for obtaining nationwide small-area estimates (SAEs) of childhood obesity are costly. This study applied a geocoded national health survey in a multilevel modeling framework to estimate prevalence of childhood obesity at the census block-group level. METHODS: We constructed a multilevel logistic regression model to evaluate the influence of individual demographic characteristics, zip code, county, and state on the childhood obesity measures from the 2007 National Survey of Children's Health. The obesity risk for a child in each census block group was then estimated on the basis of this multilevel model. We compared direct survey and model-based SAEs to evaluate the model specification. RESULTS: Multilevel models in this study explained about 60% of state-level variances associated with childhood obesity, 82.8% to 86.5% of county-level, and 93.1% of zip code-level. The 95% confidence intervals of block- group level SAEs have a wide range (0.795-20.0), a low median of 2.02, and a mean of 2.12. The model-based SAEs of childhood obesity prevalence ranged from 2.3% to 54.7% with a median of 16.0% at the block-group level. CONCLUSION: The geographic variances among census block groups, counties, and states demonstrate that locale may be as significant as individual characteristics such as race/ethnicity in the development of the childhood obesity epidemic. Our estimates provide data to identify priority areas for local health programs and to establish feasible local intervention goals. Model-based SAEs of population health outcomes could be a tool of public health assessment and surveillance. PMID- 23639764 TI - Incarceration of a household member and Hispanic health disparities: childhood exposure and adult chronic disease risk behaviors. AB - INTRODUCTION: Incarceration of a household member has been linked to poor mental and behavioral health outcomes in children, but less is known about the health behaviors of these children once they reach adulthood. METHODS: We analyzed data from 81,910 respondents to the 2009-2010 Behavioral Risk Factor Surveillance System to identify associations between the childhood experience of having a household member incarcerated and adult smoking status, weight status, physical activity, and drinking patterns. We used multivariable logistic regression to control for sex, age, education, and additional adverse childhood events in the whole population and in separate models for Hispanic, non-Hispanic white, and non Hispanic black adults. We also assessed for having multiple risk behaviors. RESULTS: People who lived with an incarcerated household member during childhood were more likely as adults than those who did not to engage in smoking (adjusted odds ratio [AOR] 1.50; 95% confidence interval [CI], 1.27-1.77) and heavy drinking (AOR 1.39; 95% CI, 1.03-1.87), after controlling for demographics and additional adverse childhood events. Exposure to incarceration in the household as a child among Hispanic adults was associated with being a smoker, being a heavy drinker, and having multiple risk behaviors and among white adults was associated with being a smoker and having multiple risk behaviors; among black adults there were no significant associations. CONCLUSION: Incarceration of a household member during childhood is associated with adult risk behaviors, and race/ethnicity may be a factor in this association. PMID- 23639765 TI - Local health department use of twitter to disseminate diabetes information, United States. AB - INTRODUCTION: Diabetes may affect one-third of US adults by 2050. Adopting a healthful diet and increasing physical activity are effective in preventing type 2 diabetes and decreasing the severity of diabetes-related complications. Educating and informing the public about health problems is a service provided by local health departments (LHDs). The objective of this study was to examine how LHDs are using social media to educate and inform the public about diabetes. METHODS: In June 2012 we used NVivo 10 to collect all tweets ever posted from every LHD with a Twitter account and identified tweets about diabetes. We used a 2010 National Association of County and City Health Officials survey to compare characteristics of LHDs that tweeted about diabetes with those that did not. Content analysis was used to classify each tweet topic. RESULTS: Of 217 LHDs with Twitter accounts, 126 had ever tweeted about diabetes, with 3 diabetes tweets being the median since adopting Twitter. LHDs tweeting about diabetes were in jurisdictions with larger populations and had more staff and higher spending than LHDs not tweeting about diabetes. They were significantly more likely to employ a public information specialist and provide programs in diabetes-related areas. There was also a weak positive association between jurisdiction diabetes rate and the percentage of all tweets that were about diabetes (r = .16; P = .049). CONCLUSION: LHDs are beginning to use social media to educate and inform their constituents about diabetes. An understanding of the reach and effectiveness of social media could enable public health practitioners to use them more effectively. PMID- 23639766 TI - A simple and economical method in purifying dairy goat luteal cells. AB - As an important cell model, luteal cells are used to study the reproductive cycle and pregnancy maintenance, but there has not yet had a simple and economical method in purifing goat luteal cells. In order to find a good method to isolate and purify the luteal cells from the Guan Zhong dairy goat corpus luteua, we compared the purification efficiency of Percoll density gradient centrifugation method with that of the differential detachment method using trypsin. After using these two methods for isolation, the purified cells were identified by staining for 3beta-hydroxy steroid dehydrogenase activity. Cell diameter measurements and cell counting were used to categorize isolated cells from both methods. Cell proliferation activity of purified cells from both methods were studied by Cell Counting Kit-8 for 8 days. The results showed that, after Percoll discontinuous density gradient centrifugation, the purity of luteal cells was 98.2+/-1.2% in Percoll density layer of 30-40%. In comparison, the purity of luteal cells isolated in differential detachment by trypsin was 74.3+/-1.8%. Luteal cells purified from both methods stained positive for 3beta-hydroxy steroid dehydrogenase activity, and cells purified by Percoll centrifugation showed a more rapid cell proliferation rate than cells purified by trypsin. In conclusion, this study has demonstrated that Percoll density gradient centrifugation was superior to the method of differential detachment in cell purification efficiency and in maintenance of cell proliferation activity. PMID- 23639767 TI - Immunolocalization of specific keratin associated beta-proteins (beta-keratins) in the adhesive setae of Gekko gecko. AB - The previous identification of 21 proteins in the digital setae transcriptome of Gekko gecko, 2 alpha-keratins of 52-53kDa and 19 beta-proteins (beta-keratins) of 10-21kDa, has indicated that most of setal corneous proteins are cysteine-rich. The production of specific antibodies for two of the main beta-protein subfamilies expressed in gecko setae has allowed the ultrastructural localization of two beta-proteins indicated as Ge-cprp-9 (cysteine-rich) and Ge-gprp-6 (glycine-rich). Only Ge-cprp-9, representing most of the 16 cysteine-rich beta proteins, is present in the oberhautchen, setae and in the terminal spatula where adhesion takes place, supporting the previous expression study. Instead, the glycine-rich beta-proteins (Ge-gprp-6), representing the 3 glycine-rich beta proteins of digital epidermis is only present in the stiff beta-layer of the digital scales and in the thin beta layer of the pad lamella sustaining the setae. Ge-cprp-9 is representative for most of the remaining 15 cys-rich proteins (Ge-cprp 1-16) and may have a structural and functional role in the process of adhesion. Most of the cysteine-rich setal proteins have a net positive charge and it is here hypothesized that these proteins may induce the formation of dipoles at the surface interface between the spatula and the substrate, enhancing the van der Waals forces and therefore adhesion to the substrate. The selection and improvement of these proteins during the evolution of geckos may have represented a successful factor for the survival and ecological adaptations of these climbing lizards. PMID- 23639769 TI - The role of intracellular calcium stores in synaptic plasticity and memory consolidation. AB - Memory processing requires tightly controlled signalling cascades, many of which are dependent upon intracellular calcium (Ca(2+)). Despite this, most work investigating calcium signalling in memory formation has focused on plasma membrane channels and extracellular sources of Ca(2+). The intracellular Ca(2+) release channels, ryanodine receptors (RyRs) and inositol (1,4,5)-trisphosphate receptors (IP3Rs) have a significant capacity to regulate intracellular Ca(2+) signalling. Evidence at both cellular and behavioural levels implicates both RyRs and IP3Rs in synaptic plasticity and memory formation. Pharmacobehavioural experiments using young chicks trained on a single-trial discrimination avoidance task have been particularly useful by demonstrating that RyRs and IP3Rs have distinct roles in memory formation. RyR-dependent Ca(2+) release appears to aid the consolidation of labile memory into a persistent long-term memory trace. In contrast, IP3Rs are required during long-term memory. This review discusses various functions for RyRs and IP3Rs in memory processing, including neuro- and glio-transmitter release, dendritic spine remodelling, facilitating vasodilation, and the regulation of gene transcription and dendritic excitability. Altered Ca(2+) release from intracellular stores also has significant implications for neurodegenerative conditions. PMID- 23639770 TI - Journal of Dermatological Science. Greetings from the new Editor-in-Chief. PMID- 23639768 TI - Attention deficit hyperactivity disorder in a Canadian prison population. AB - Previous research has shown that a significant percentage of offenders are affected by adult attention deficit hyperactivity disorder (ADHD) and its related symptoms, however it is unknown the extent to which this disorder affects federal inmates in Canada and the impact ADHD has on key correctional outcomes. Four hundred and ninety-seven male federal offenders were assessed at intake over a fourteen month period using the Adult ADHD Self-Report Scale (ASRS). Approximately 16.5% scored in the highest range, which is consistent with the clinical threshold for diagnosis for the disorder; a further 25.2% reported sub threshold symptoms in the moderate range. ADHD symptoms were found to be associated with unstable job history, presence of a learning disability, lower educational attainment, substance abuse, higher criminal risk and need levels, and other mental health problems. ADHD symptoms were also found to predict institutional misconduct. Additionally, offenders with high levels of ADHD symptomatology fared more poorly on release to the community. Implications for institutional behavior management and the need for additional resources and adapted interventions are discussed. PMID- 23639771 TI - Prediction of three-dimensional femoral offset from AP pelvis radiographs in primary hip osteoarthritis. AB - BACKGROUND: In pre-operative planning for total hip arthroplasty (THA), femoral offset (FO) is frequently underestimated on AP pelvis radiographs as a result of inaccurate patient positioning, imprecise magnification, and radiographic beam divergence. The aim of the present study was to evaluate the accuracy and reliability of predicting three-dimensional (3-D) FO from standardised AP pelvis radiographs. METHODS: In a retrospective cohort study, pre-operative AP pelvis radiographs, AP hip radiographs and CT scans of a consecutive series of 345 patients (345 hips, 146 males, 199 females, mean age 60 (range: 40-79) years, mean body-mass-index 27 (range: 19-57)kg/m(2)) with primary end-stage hip OA were reviewed. Patients were positioned according to a standardised protocol and all images were calibrated. Using validated custom programmes, FO was measured on corresponding radiographs and CT scans. Measurement reliability was evaluated using intra-class-correlation-coefficients. To predict 3-D FO from AP pelvis measurements and to assess the accuracy compared to CT, the entire cohort was randomly split into subgroups A and B. Gender specific regression equations were derived from group A (245 patients) and the accuracy of prediction was evaluated in group B (100 patients) using Bland-Altman plots. RESULTS: In the entire cohort, mean FO was 39.2mm (95%CI: 38.5-40.0mm) on AP pelvis radiographs, 44.1mm (95%CI: 43.4-44.9mm) on AP hip radiographs and 44.6mm (95%CI: 44.0-45.2mm) on CT scans. In group B, we observed no significant difference between gender specific predicted FO (males: 48.0mm, 95%CI: 47.1-48.8mm; females: 42.0mm, 95%CI: 41.1 42.8mm) and FO as measured on CT (males: 47.7mm, 95%CI: 46.1-49.4mm, p=0.689; females: 41.6mm, 95%CI: 40.3-43.0mm, p=0.607). CONCLUSIONS: The present study suggests that FO can be accurately and reliably predicted from AP pelvis radiographs in patients with primary end-stage hip osteoarthritis. Our findings support the surgeon in pre-operative templating on AP-pelvis radiographs and may improve offset and limb length restoration in THA without the routine performance of additional radiographs or CT. PMID- 23639772 TI - Unenhanced steady state free precession versus traditional MR imaging for congenital heart disease. AB - PURPOSE: To assess potential benefits of three dimensional (3D) steady state free precession (SSFP) magnetic resonance sequence for congenital heart disease (CHD). MATERIALS AND METHODS: Twenty consecutive patients with CHD (male:female ratio,14:6, mean age, 27.5 +/- 8.5 years) underwent both 3D SSFP and traditional MR imaging (TMRI) [including two dimensional (2D) SSFP and contrast enhanced magnetic resonance angiography (CEMRA)]. Image quality and diagnosis were compared, and Bland-Altman analysis was used to evaluate consistency of 3D SSFP and CEMRA for diameter measurements. RESULTS: A total of 35 intra and 81 extra cardiac anomalies were identified in all patients. The image quality of 3D SSFP and TMRI for either intra or extra cardiac anomalies of all patients scored >=3, which allowed an establishment of diagnosis for all cases. The diagnostic sensitivity, specificity, and accuracy of 3D SSFP for the detection of intra cardiac anomalies were all 100%, whereas for extra cardiac anomalies they were 93.8%, 93.8%, 100%, respectively. Mean differences (3D SSFP minus CEMRA) for aorta and pulmonary arteries were 0.5 +/- 1.2 mm and 0.0 +/- 1.7 mm, respectively, showing good consistency of 3D SSFP and CEMRA for diameter measurements. CONCLUSION: 3D SSFP MRI can be an alternative image modality to TMRI for patients with congenital heart disease, especially for those who have renal insufficiency, breath-hold difficulty or who are allergic to contrast agent. It can also provide powerful complementary information for patients who undergo TMRI, especially at ventriculoarterial connection site. PMID- 23639773 TI - Relationship between myocardial T2 values and cardiac volumetric and functional parameters in beta-thalassemia patients evaluated by cardiac magnetic resonance in association with serum ferritin levels. AB - PURPOSE: Myocardial T2 cardiovascular magnetic resonance provides a rapid and reproducible assessment of cardiac iron load in thalassemia patients. Although cardiac involvement is mainly characterized by left ventricular dysfunction caused by iron overload, little is known about right ventricular function. The aim of this study was to assess the relationship between T2 value in myocardium and left-right ventricular volumetric and functional parameters and to evaluate the existing associations between left-right ventricles volumetric and functional parameter, myocardial T2 values and blood ferritin levels. MATERIALS AND METHODS: A retrospective analysis of 208 patients with beta-thalassemia major and thalassemia intermedia was performed (109 males and 99 females; mean age 37.7 +/- 13 years; 143 thalassemia major, 65 thalassemia intermedia). Myocardial iron load was assessed by T2 measurements, and volumetric functions were analyzed using the steady state free precession sequence. RESULTS: A significant correlation was observed between EFLV and T2 (p=0.0001), EFRV and T2 (p=0.0279). An inverse correlation was present between DVLV and T2 (p=0.0468), SVLV and T2 (p=0.0003), SVRV and T2 (p=0.0001). There was no significant correlation between cardiac T2 and LV-RV mass indices. A significant correlation was observed between T2 and serum ferritin levels (p<0.001) and between EFLV and serum ferritin (p<0.05). CONCLUSION: Myocardial iron load assessed by T2 cardiac magnetic resonance is associated with deterioration in left-right ventricular function; this is more evident when T2 values fall below 14 ms. CMR appears to be a promising approach for cardiac risk evaluation in TM patients. PMID- 23639774 TI - Response to the letter of "intranerve cross sectional area variability of tibial nerve in diabetic neuropathy". PMID- 23639775 TI - Assessment of brain maturation in the preterm infants using diffusion tensor imaging (DTI) and enhanced T2 star weighted angiography (ESWAN). AB - PURPOSE: To assess the brain maturation of preterm infants using diffusion tensor imaging (DTI) and enhanced T2 star weighted angiography (ESWAN). MATERIALS AND METHODS: Conventional magnetic resonance imaging (MRI), DTI and ESWAN were performed in 60 preterm infants and 21 term controls. 60 preterm infants were subgrouped to two groups according to the age at imaging: before and at term equivalent age (TEA). Fractional anisotropy (FA), apparent diffusion coefficient (ADC) map from DTI, T2 and R2 maps from ESWAN were post-processed at an off-line workstation. The values of FA, ADC, T2 and R2 from the posterior limb of internal capsule (PLIC), frontal white matter (FWM), occipital white matter (OWM) and lentiform nuclei (LN) were determined. These parameters were compared between preterm and term infants. Correlations of DTI and ESWAN parameters with the gestational age, postmenstrual age and postnatal age were analyzed. RESULTS: ADCs of FWM, OWM and LN, and T2 values of the PLIC and LN were higher in the preterm infants at TEA compared with the term controls. The correlations were existed between the postmenstrual age and the values of FA, ADC, T2, R2 from the PLIC, values of ADC, T2, R2 from the LN, T2 value from the OWM. The correlations were also found between the postnatal age and the values of FA, ADC, T2 from the PLIC, and T2 value from the LN. CONCLUSION: The maturity of preterm brain around TEA was different from that of term controls and appeared to be independent of the prematurity at birth. T2 was one of valuable indices to evaluate brain maturation in preterm infants. PMID- 23639776 TI - Evaluation of 18F-FDG and 18F-FLT for monitoring therapeutic responses of colorectal cancer cells to radiotherapy. AB - In order to compare the efficacy of (18)F-fluorothymidine (FLT) and (18)F fluorodeoxyglucose (FDG) for monitoring early responses to irradiation, two human colorectal cancer (CRC) cell lines SW480 and SW620, which were derived from the primary lesions and the metastatic lymph node, underwent X-ray irradiation of 0, 10, or 20 Gy and were examined at 0, 24 and 72 h After irradiation, reduced proliferation of both SW480 and SW620 cells was observed in a dose-dependent manner (P<0.001), G0-G1 arrest was also noted in both cell types after 72 h in the 20 Gy group (P<0.001). Although increased apoptosis was observed in both cell lines after irradiation (P<0.001), a greater percentage of SW480 cells underwent apoptosis in response to irradiation than SW620 cells. Increased Hsp27 and decreased integrin beta3, Ki67 and VEGFR2 expression was observed over time via immunocytochemistry and Western blot analysis (P<0.001), however, no significant changes were noted in response to irradiation. Finally, reduced uptake of (18)F FLT by SW480 or SW620 cells was observed at 24-h post-irradiation, however, reduced (18)F-FDG uptake was only observed after 72 h. Therefore, we conclude that (18)F-FLT is a more suitable positron emission tomography (PET) tracer for monitoring early responses to irradiation in primary and metastatic lymph node CRC cells. PMID- 23639777 TI - HDAC3 interacts with sumoylated C/EBPalpha to negatively regulate the LXRalpha expression in rat hepatocytes. AB - The expression changes of liver X receptor alpha (LXRalpha), histone deacetylase 3 (HDAC3) and CCAAT/enhancer binding protein alpha (C/EBPalpha) were detected in liver tissues of our high-fat-diet E3 rat model. The aim of this study is to pinpoint the molecular mechanism of HDAC3 and C/EBPalpha to orchestrate LXRalpha expression in hepatocytes. We confirmed that LXRalpha and its target genes were negatively regulated by HDAC3 in stable expressed clones with pEGFP-Hdac3 or shRNA-Hdac3 vector. However, transient pEGFP-C/EBPalpha plasmid transfection showed an upregulation of LXRalpha expression and C/EBPalpha enhanced LXRalpha promoter activity in a dose-dependent manner in CBRH-7919 cells. By using 5' serial deletion reporter analysis, we identified that fragment from -2881 to 1181bp of LXRalpha promoter was responsible for C/EBPalpha binding to the promoter, especially CBS1 and CBS4 were identified essentially by using ChIP and luciferase reporter assay. Co-IP, qRT-PCR and ChIP revealed that HDAC3 interacted with C/EBPalpha co-regulated LXRalpha expression. Sumoylation of C/EBPalpha at lysine 159 was detected in CBRH-7919 cells with transient overexpressed C/EBPalpha, and Co-IP assay detected that sumoylated C/EBPalpha interacted with more HDAC3 than C/EBPalpha K159L mutant. Luciferase reporter assay demonstrated that C/EBPalpha participated in HDAC3-repressed LXRalpha transcription, and HDAC3 was involved in sumoylated C/EBPalpha-inactivated LXRalpha activity. Luciferase reporter assay demonstrated that sumoylation of C/EBPalpha by SUMO-1 directly reversed the activation of C/EBPalpha on LXRalpha promoter. The results suggested that HDAC3 interacts with sumoylated C/EBPalpha to negatively regulate the LXRalpha expression. PMID- 23639778 TI - Enhanced proliferation and differentiation of neural stem cells grown on PHA films coated with recombinant fusion proteins. AB - Polyhydroxyalkanoates (PHAs) belong to a family of copolyesters with demonstrated biocompatibility. We hypothesize that genetically fusing evolutionarily preserved cell binding motifs, such as RGD or IKVAV, to the PHA-binding protein phasin (PhaP) for surface functionalization of PHA materials could better support the growth and differentiation of neural stem cells (NSCs). This hypothesis is tested on three polyester materials of the same aliphatic family: poly(L-lactic acid) (PLA) and two PHB copolymers, poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) (PHBVHHx). Experimental results indicate that surface coating of the two fusion proteins, PhaP-RGD and PhaP-IKVAV, provides short-term advantages in promoting the adhesion, proliferation and neural differentiation of rat NSCs compared to the PhaP-coated or uncoated material. Among the tested samples, the combination of coating PhaP-IKVAV on an PHBVHHx surface yields the highest levels in cell adhesion and proliferation, while the PLA film coated with PhaP-IKVAV promotes better neural differentiation and neurite outgrowth in the early stage. Because both PhaP-RGD and PhaP-IKVAV could be produced in an inexpensive manner, our data suggest that PhaP-IKVAV is an ideal nonspecific coating agent to functionalize hydrophobic biomaterials in the application of neural tissue engineering. PMID- 23639779 TI - The effect of intravenous ferric carboxymaltose on red cell distribution width: a subanalysis of the FAIR-HF study. AB - AIMS: Red cell distribution width (RDW), a measure of variability in red blood cell size, is a novel prognostic marker in chronic heart failure (CHF). Iron deficiency contributes to elevated RDW. In the FAIR-HF trial, i.v. ferric carboxymaltose (FCM) improved the 6 min walk test (6MWT) distance in iron deficient CHF patients. We studied the effect of FCM on RDW and the relationship between RDW and 6MWT distance. METHODS AND RESULTS: In FAIR-HF, iron-deficient CHF patients were randomized to FCM or placebo in a 2:1 ratio. From the total cohort (n = 459), we included 415 patients in whom RDW values and 6MWT distance were available for baseline and at least one follow-up visit (after 4, 12, and 24 weeks). Baseline RDW was higher in anaemic (haemoglobin <12 g/dL) compared with non-anaemic patients [15.2% (14.0-16.8) vs. 14.2% (13.4-15.4), P < 0.0001, median (interquartile range)]. In multivariate analysis, RDW was significantly associated with transferrin saturation (P < 0.001) and C-reactive protein levels (P = 0.002). Treatment with FCM led to a biphasic response; RDW increased within 4 weeks (+0.54% absolute change from baseline, P = 0.01) but fell to values below the placebo group after 24 weeks (-1.0 %, P = 0.03). The 6MWT distance and RDW were inversely related at baseline (r = -0.30, P < 0.0001). In all patients, the increase in 6MWT distance after 24 weeks was significantly correlated with a decrease in RDW (r= -0.25, P < 0.0001), even after adjustment for changes in haemoglobin. CONCLUSIONS: Iron deficiency in CHF is associated with high RDW, even after adjustment for the presence of anaemia. Treatment with i.v. FCM in iron-deficient CHF patients decreases RDW. PMID- 23639780 TI - Targeting anti-beta-1-adrenergic receptor antibodies for dilated cardiomyopathy. AB - Anti-beta-1-adrenergic receptor antibodies (anti-beta1AR Abs) have long been implicated in the pathogenesis of dilated cardiomyopathy (DCM). It is believed that these autoantibodies bind to and constitutively stimulate the beta1AR to promote pathological cardiac remodelling and beta1AR desensitization and downregulation. The prevalence of anti-beta1AR Abs in patients with DCM ranges from 26% to 60%, and the presence of these autoantibodies correlates with a poor prognosis. Several small studies have shown improvements in functional status, haemodynamics, and biomarkers of heart failure upon removal or neutralization of these antibodies from the sera of affected patients. Traditionally, removal of anti-beta1AR Abs required immunoadsorption therapy with apheresis columns directed against human immunoglobulins (Igs) and subsequent i.v. Ig infusion, thereby essentially performing a plasma exchange transfusion. However, recent advances have allowed the development of small peptides and nucleotide sequences that specifically target and neutralize anti-beta1AR Abs, providing a hopeful avenue for future drug development to treat DCM. Herein, we briefly review the clinical literature of therapy directed against anti-beta1AR Abs and highlight the opportunity for further research and development in this area. PMID- 23639781 TI - Clinical and neurohormonal correlates and prognostic value of serum prolactin levels in patients with chronic heart failure. AB - AIMS: Hypothalamic axis deregulation is associated with clinical severity and depression in chronic heart failure (CHF). We investigated the relationship of serum prolactin, an indicator of hypothalamic axis function, to neurohomonal/immune activation and depressive symptoms in CHF as well as its prognostic value. METHODS AND RESULTS: Serum prolactin was determined in 180 patients with advanced CHF (aged 65 +/- 12 years, mean LVEF 27 +/- 7%) along with natriuretic peptides (BNP), inflammatory cytokines, endothelial adhesion molecules, 6 min walk test (6MWT), and the Zung self-rating depression scale (SDS). Patients were followed for all-cause death or hospitalization for cardiovascular reasons for up to 8 months. Prolactin levels were significantly correlated with NYHA class (r = 0.394, P < 0.001), LVEF (r = -0.314, P < 0.001), 6MWT (r = -0.353, P < 0.001), BNP (r = 0.374, P < 0.001), Zung SDS (r = 0.544, P < 0.001), interleukin-6 (IL-6) (r = 0.451, P < 0.001), IL-10 (r = -0.426, P < 0.001), tumour necrosis factor (TNF)-alpha (r = 0.310, P = 0.001), soluble Fas (r = 0.333, P < 0.001), soluble Fas-ligand (r = 0.517, P < 0.001), soluble intercellular adhesion molecule-1 (ICAM-1) (r = 0.409, P < 0.001), and soluble vascular cell adhesion molecule-1 (VCAM-1) (r = 0.480, P < 0.001). During follow up, 119 patients (66%) died or were hospitalized for cardiovascular events after a median time of 72 days (range 5-220 days); these patients had higher baseline prolactin levels (10.2 +/- 5.7 vs. 6.7 +/- 4.3 ng/mL, P < 0.001), and a prolactin value >=4.5 ng/mL was associated with a higher rate of death or hospitalization (116 +/- 7 vs. 181 +/- 11 days, P = 0.0001). In multivariate analysis, prolactin levels remained an independent predictor of death or hospitalization (<4.5 vs. >=4.5 ng/mL; odds ratio, 0.368; 95% confidence interval 0.148-0.913; P = 0.031), along with BNP (P < 0.001) and 6MWT (P = 0.020). CONCLUSIONS: Serum prolactin is associated with neurohormonal/immune activation and depressive symptoms and is an independent predictor of prognosis in advanced CHF. PMID- 23639782 TI - Repeated intermittent administration of a ubiquitous proteasome inhibitor leads to restrictive cardiomyopathy. PMID- 23639783 TI - Percutaneous autonomic neural modulation: a novel technique to treat cardiac arrhythmia. AB - Ablation and anti-arrhythmic medications have shown promise but have been met with varying success and unwanted side effects such as myocardial injury, arrhythmias, and morbidity from invasive surgical intervention. The answer to improving efficacy of ablation may include modulation of the cardiac aspect of the autonomic nervous system. Our lab has developed a novel approach and device to navigate the oblique sinus and to use DC current and saline/alcohol irrigation to selectively stimulate and block the autonomic ganglia found on the epicardial side of the heart. This novel approach minimizes myocardial damage from thermal injury and provides a less invasive and targeted approach. For feasibility, proof of-concept, and safety monitoring, we carried out canine studies to test this novel application. Our results suggest a safer and less invasive way of modulating arrhythmogenic substrate that may lead to improved treatment of AF in humans. PMID- 23639784 TI - Role of ultrasound-guided transbronchial biopsy in the diagnosis of peripheral pulmonary lesions. AB - INTRODUCTION: Endobronchial ultrasound (EBUS) can be used as an alternative to fluoroscopy to visualize a peripheral pulmonary lesion (PPL) and to provide an image guidance for transbronchial biopsy (TBB). The aim of this study was to verify the accuracy of EBUS-guided TBB in the diagnosis of PPLs. METHODS: All the patients with CT-scan evidence of PPL who underwent bronchoscopy with EBUS in the period between 2008 and 2011 were retrospectively evaluated. EBUS was performed using a radial-type miniature ultrasound probe. Once obtained an EBUS image of the PPL, we measured the distance of the PPL from the outer orifice of the working channel of the bronchoscope in order to perform TBB at PPL site. RESULTS: A total of 662 patients were examined. The mean diameter of lesions was 36 +/- 20 mm. PPLs were visualized in 494 patients (75%) and the TBB was performed in 479 patients. Thirty-two patients were lost in follow-up and data from 447 patients were analyzed. TBB results were 255 cancers and 192 non-malignant lesions. The final diagnosis reported was 359 cases of cancer and 88 of benign lesion. EBUS guided TBB had a sensitivity of 71% for the diagnosis of cancer, a negative predictive value of 46% and an overall diagnostic accuracy of 77%. CONCLUSIONS: These data obtained from a large series of patients and using an original method show that EBUS represents a valid support to bronchoscopy and that the EBUS guided TBB has a high diagnostic yield in the diagnosis of PPLs. PMID- 23639785 TI - Identification of novel mutations of TP53, ALK and RET gene in metastatic thymic squamous cell carcinoma and its therapeutic implication. AB - Thymic tumors are epithelial tumors of the thymus for which multimodal therapies are often ineffective because of a lack of standardized regimens. Due to the low incidence, the molecular pathology and genomic abnormalities of thymic epithelial tumors are largely unknown. In this study, we report our comprehensively genomic study on a case of metastatic thymic tumor. Using next generation deep DNA sequencing technology, we sequenced 190 segments of 46 cancer genes of the cancer genome to cover 739 COSMIC mutations in 604 loci. Among these sequenced cancer genes, we identified that three low frequency (~10% of cells) mutations in the TP53 gene (c.782+1G>T), ALK gene (c.3551C>T), and RET gene (c.2651A>T). To the best of our knowledge, this is the first study to show those mutations in thymic tumor. Of note, our study further indicates comprehensive molecular analysis may facilitate development of novel diagnostic and therapeutic strategies for thymic tumors. PMID- 23639786 TI - Norepinephrine inhibits the migratory activity of pancreatic cancer cells. AB - We have shown previously that norepinephrine induces migratory activity of tumour cells from breast, colon and prostate tissue via activation of beta-2 adrenergic receptors. Consequently, this effect can be inhibited pharmacologically by clinically established beta-blockers. Tumour cell migration is a prerequisite for metastasis formation, and accordingly we and others have shown that breast cancer patients, which take beta-blockers due to hypertension, have reduced metastasis formation and increased survival probability as compared to patients without hypertension or using other anti-hypertensive medication. Unlike the aforementioned tumour cells, pancreatic cancer cells show a reduced migratory activity upon norepinephrine treatment. By means of our three-dimensional, collagen-based cell migration assay, we have investigated the signal transduction pathways involved in this phenomenon. We have found that this conflicting effect of norepinephrine on pancreatic cancer cells is due to an imbalanced activation of the two pathways that usually mediate a pro-migratory effect of norepinephrine in other tumour cell types. Firstly, the inhibitory effect results from activation of a pathway which causes a strong increase of the secondary cell signalling molecule, cAMP. In addition, activation of phospholipase C gamma and the downstream protein kinase C alpha were shown to be already activated in pancreatic cancer cells and cannot be further activated by norepinephrine. We hypothesize that this constitutive activation of the phospholipase C gamma pathway is due to a cross-talk with receptor tyrosine kinase signalling, and this might also deliver an explanation for the unusual high spontaneous migratory activity of pancreatic cancer cells. PMID- 23639787 TI - Elevated serum autoantibody against high mobility group box 1 as a potent surrogate biomarker for amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a complicate and progressive onset devastating neurodegenerative disease. Its pathogenic mechanisms remain unclear and there is no specific test for diagnosis. For years, researchers have been vigorously searching for biomarkers associated with ALS to assist clinical diagnosis and monitor disease progression. Some specific inflammatory processes in the central nervous system have been reported to participate in the pathogenesis of ALS. As high mobility group box 1 (HMGB1) is elevated in spinal cord tissues of patients with ALS, we hypothesized, therefore, that serum autoantibody against HMGB1 (HMGB1 autoAb) might represent an effective biomarker for ALS. Patients with ALS, Alzheimer's disease, Parkinson's disease, and healthy age-matched control subjects were recruited for this study. ALS group consisted of 61 subjects, the other groups each consisted of forty subjects. We generated a polyclonal antibody against HMGB1 and developed an ELISA-based methodology for screening serum samples of these subjects. All samples were coded for masked comparison. For statistic analyses, two-tailed Student's t-test, ANOVA, Bonferroni multiple comparison test, Spearman correlation, and receiver operating characteristic curve were applied. We discovered that the level of HMGB1 autoAb significantly increased in patients with ALS as compared with that of patients with Alzheimer's disease, Parkinson's disease, and healthy control subjects. The differences between all groups were robust even at the early stages of ALS progression. More importantly, higher HMGB1 autoAb level was found in more severe disease status with significant correlation. Our study demonstrates that serum HMGB1 autoAb may serve as a biomarker for the diagnosis of ALS and can be used to monitor disease progression. PMID- 23639788 TI - Adhesion molecule L1 binds to amyloid beta and reduces Alzheimer's disease pathology in mice. AB - Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of elderly dementia. In an effort to contribute to the potential of molecular approaches to reduce degenerative processes we have tested the possibility that the neural adhesion molecule L1 ameliorates some characteristic cellular and molecular parameters associated with the disease in a mouse model of AD. Three-month-old mice overexpressing mutated forms of amyloid precursor protein and presenilin-1 under the control of a neuron-specific promoter received an injection of adeno-associated virus encoding the neuronal isoform of full length L1 (AAV-L1) or, as negative control, green fluorescent protein (AAV-GFP) into the hippocampus and occipital cortex. Four months after virus injection, the mice were analyzed for histological and biochemical parameters of AD. AAV-L1 injection decreased the Abeta plaque load, levels of Abeta42, Abeta42/40 ratio and astrogliosis compared with AAV-GFP controls. AAV-L1 injected mice also had increased densities of inhibitory synaptic terminals on pyramidal cells in the hippocampus when compared with AAV-GFP controls. Numbers of microglial cells/macrophages were similar in both groups, but numbers of microglial cells/macrophages per plaque were increased in AAV-L1 injected mice. To probe for a molecular mechanism that may underlie these effects, we analyzed whether L1 would directly and specifically interact with Abeta. In a label-free binding assay, concentration dependent binding of the extracellular domain of L1, but not of the close homolog of L1 to Abeta40 and Abeta42 was seen, with the fibronectin type III homologous repeats 1-3 of L1 mediating this effect. Aggregation of Abeta42 in vitro was reduced in the presence of the extracellular domain of L1. The combined observations indicate that L1, when overexpressed in neurons and glia, reduces several histopathological hallmarks of AD in mice, possibly by reduction of Abeta aggregation. L1 thus appears to be a candidate molecule to ameliorate the pathology of AD, when applied in therapeutically viable treatment schemes. PMID- 23639790 TI - Isonymy and repeated pairs of surnames among the Muslims of Manipur, India. AB - Surnames have been used for studying population structure in different parts of the globe. The present study is aimed at indirectly estimating the degree of inbreeding from surnames and understanding the influences of the clan-like structure on mate selection among Manipuri Muslims. The proportion of isonymy I was found to be 0.0144. The non-random and random components were -0.0226 and 0.0239, respectively. The total inbreeding coefficient was estimated to be 0.0018. The scores of random pairs (RP) and random repeated pairs (RPr) were 0.026 and 0.010, respectively. The score of RP was higher than the RPr which gives a ratio of 0.38, indicating that Manipuri Muslims have a tendency of acquiring mates from within a given set of surnames while not in favour of isonymy. To conclude, surname/clan is a criterion for mate selection for various reasons among this population. PMID- 23639789 TI - Neuroglobin overexpression inhibits oxygen-glucose deprivation-induced mitochondrial permeability transition pore opening in primary cultured mouse cortical neurons. AB - Neuroglobin (Ngb) is an endogenous neuroprotective molecule against hypoxic/ischemic brain injury, but the underlying mechanisms remain largely undefined. Our recent study revealed that Ngb can bind to voltage-dependent anion channel (VDAC), a regulator of mitochondria permeability transition (MPT). In this study we examined the role of Ngb in MPT pore (mPTP) opening following oxygen-glucose deprivation (OGD) in primary cultured mouse cortical neurons. Co immunoprecipitation (Co-IP) and immunocytochemistry showed that the binding between Ngb and VDAC was increased after OGD compared to normoxia, indicating the OGD-enhanced Ngb-VDAC interaction. Ngb overexpression protected primary mouse cortical neurons from OGD-induced neuronal death, to an extent comparable to mPTP opening inhibitor, cyclosporine A (CsA) pretreatment. We further measured the role of Ngb in OGD-induced mPTP opening using Ngb overexpression and knockdown approaches in primary cultured neurons, and recombinant Ngb exposure to isolated mitochondria. Same as CsA pretreatment, Ngb overexpression significantly reduced OGD-induced mPTP opening markers including mitochondria swelling, mitochondrial NAD(+) release, and cytochrome c (Cyt c) release in primary cultured neurons. Recombinant Ngb incubation significantly reduced OGD-induced NAD(+) release and Cyt c release from isolated mitochondria. In contrast, Ngb knockdown significantly increased OGD-induced neuron death, and increased OGD-induced mitochondrial NAD(+) release and Cyt c release as well, and these outcomes could be rescued by CsA pretreatment. In summary, our results demonstrated that Ngb overexpression can inhibit OGD-induced mPTP opening in primary cultured mouse cortical neurons, which may be one of the molecular mechanisms of Ngb's neuroprotection. PMID- 23639791 TI - Direct urine polymerase chain reaction for chlamydia and gonorrhoea: a simple means of bringing high-throughput rapid testing to remote settings? AB - Background Rapid point-of-care tests (POCTs) for chlamydia (Chlamydia trachomatis) and gonorrhoea (Neisseria gonorrhoeae) have the potential to confer health benefits in certain populations even at moderate sensitivities; however, suitable POCTs for these organisms are currently lacking. METHODS: In this study, we investigated the use of direct urine polymerase chain reaction (PCR), with the view of implementing a simplified PCR strategy for high-throughput chlamydia and gonorrhoea screening in remote settings. Briefly, a simple dilution of the urine was performed before adding it directly to a real-time PCR reaction. The method was evaluated using 134 stored urine specimens that had been submitted for chlamydia and gonorrhoea testing and had been tested using a commercial C. trachomatis and N. gonorrhoeae PCR method. These included samples that were PCR positive for chlamydia (n=87), gonorrhoea (n=16) or both (n=2). Direct urine testing was conducted using previously described in-house real-time PCR methods for C. trachomatis and N. gonorrhoeae as well as for recognised N.gonorrhoeae antimicrobial resistance mechanisms. RESULTS: The overall sensitivities and specificities of the direct urine PCR were 78% and 100% for chlamydia, and 83% and 100% for gonorrhoea. N.gonorrhoeae penicillin and quinolone resistance mechanisms were characterised in 14 of the 18 N. gonorrhoeae-positive samples. CONCLUSIONS: The results of this study show that the simplified PCR strategy may be a feasible approach for rapid screening and improving chlamydia and gonorrhoea treatment in remote settings. PMID- 23639792 TI - Molecular subtypes of ductal carcinoma in situ in African American and Caucasian American women: distribution and correlation with pathological features and outcome. AB - BACKGROUND: Molecular subtypes of breast cancer have been extensively studied in invasive carcinoma. They were shown to have a different distribution within the various ethnic populations. Few studies have applied the same classification to Ductal Carcinoma in Situ (DCIS). We report the distribution of the molecular breast cancer subtypes in DCIS between African American (AA) and Caucasian American (CA) women, their association with pathological features and outcome. MATERIALS AND METHODS: Tissue microarrays were constructed from paraffin blocks of 94 DCIS cases (67 AA and 27 CA) selected from a cohort of AA and CA patients diagnosed with DCIS between 1996 and 2000; mean age at diagnosis was 61+/-12 for the AA and 58+/-11 years for the CA group. TMA blocks were labeled with antibodies for ER, PR, HER2, Ki-67, and CK5/6. The cases were subtyped as Luminal A (ER+ and/or PR+; HER2-), Luminal B (ER+ and/or PR+; HER2+), HER2+ (ER-, PR-; HER2+), basal-like (BL) (ER-, PR-, HER2-; CK5/6+) or unclassified triple negative (UTN) (ER-, PR-, HER2-, CK5/6-). Information on grade, size and follow-up were obtained. RESULTS: (1) Most DCIS cases were Luminal A, comprising 80% of the DCIS cases in AA and 92.6% in CA patients. (2) HER2+, BL and UTN DCIS subtypes were not seen in the CA population, and formed 9% of the DCIS cases in the AA population; these cases were all high grade. (3) In the cases with recurrence (8 AA and 1 CA patients), DCIS was Luminal A in 6 AA and 1 CA and Luminal B in 2 AA patients. CONCLUSION: The distribution of the molecular subtypes of DCIS did not show a significant difference between the two ethnic groups in our study. In addition, the risk of recurrence might not be higher in the non-luminal subtypes than in Luminal A and B. PMID- 23639793 TI - The impact of trial characteristics on premature discontinuation of antipsychotics in schizophrenia. AB - Patient dropout is common in mental health trials. It is important to understand why patients drop out from trials, so that measures can be taken to minimize its occurrence. This research sought to identify trial characteristics that have an impact on premature discontinuation in antipsychotic trials for schizophrenia. METHODS: Poisson regression analysis was applied with dropout rate per patient week as the dependent variable and trial characteristics as independent variables. Multinomial logistic regression analysis was performed to examine whether the same characteristics predict whether patients drop out without providing any outcome data and whether they drop out with sufficient early data for a 'last observation carried forward' analysis to be performed. RESULTS: trials with adequate allocation concealment, double blinding, placebo as control, higher precision, larger trial size, at least three treatment arms, recent publication, conduct in the United States and enrollment of inpatients were all associated with higher dropout rates. Similar factors were associated with whether a patient was more likely to be evaluated at least once, or be excluded entirely from the analysis. However, blinding status did not predict the former type of dropout, and allocation concealment, higher precision and larger sample size, number of arms, recent publication and recruiting inpatient did not predict the latter type of dropout. CONCLUSIONS: high dropout rates in antipsychotic trials can be associated with various characteristics, and appears to be particularly associated with use of placebo and study size. PMID- 23639794 TI - A patient-specific model of the negative-feedback control of the hypothalamus pituitary-thyroid (HPT) axis in autoimmune (Hashimoto's) thyroiditis. AB - The purpose of modelling the negative-feedback control mechanism of the hypothalamus-pituitary-thyroid (HPT) axis in autoimmune (Hashimoto's) thyroiditis is to describe the clinical course of euthyroidism, subclinical hypothyroidism and overt hypothyroidism for patients. Thyroid hormone thyroxine (T4) and triiodothyronine (T3) levels are controlled by negative-feedback control through thyroid-stimulating hormone (TSH). T4, like other hormones, can be bound or unbound; the unbound T4 (FT4) is used as a marker for hypothyroidism. Autoimmune thyroiditis is a disease in which the thyroid-infiltrating lymphocytes attack autoantigens in follicle cells, destroying them over a long time. To describe the operation of the feedback control, we developed a mathematical model involving four clinical variables: TSH, FT4, anti-thyroid peroxidase antibodies and the thyroid gland's functional size. The first three variables are regularly measured while the last variable is determined through relationships between the other three variables. The problem of two different time scales for circulating hormones and thyroid damage is addressed using singular perturbation theory. Analysis of the mathematical model establishes stability and conditions under which the diseased state can maintain the slow movement toward diseased state equilibrium. Although we have used four variables in modelling the feedback control through the HPT axis, the predicted clinical course given any set of parameters is shown to depend on the steady-state levels of TSH and FT4. This observation makes possible the development of the clinical charts based only on the levels of TSH, time and potential steady-state values. To validate the model predictions, a dataset obtained from a Sicilian adult population has been employed. PMID- 23639795 TI - Phenotypic and genotypic characterization of enterotoxigenic Escherichia coli isolated from U.S. military personnel participating in Operation Bright Star, Egypt, from 2005 to 2009. AB - Enterotoxigenic Escherichia coli (ETEC) is a major health problem for travelers to the Middle East. During the autumn months of 2005, 2007, and 2009, U.S. military personnel participated in Operation Bright Star (OBS) exercises in Egypt. Out of 181 military personnel enrolled in a diarrheal surveillance study, E. coli-like colonies were isolated from 170 patients. Isolates were tested for the detection of ETEC enterotoxins and colonization factors (CFs) using phenotypic and genotypic methods. Additionally, we studied the secular trends of ETEC isolates obtained from OBS studies since 1999. ETEC was isolated from 51.2% and 60.0% of the patients based on enzyme-linked immunosorbent assay and polymerase chain reaction (PCR), respectively. Heat stable (ST) was the dominant enterotoxin detected followed by heat labile (LT) and LTST. Additionally, we detected a CF in 59.7% and 67.6% of the ETEC-positive isolates using dot blot and PCR assays, respectively. The predominant CF isolated was CS6 followed by CS3. PMID- 23639796 TI - Acinetobacter pittii and Acinetobacter nosocomialis among clinical isolates of the Acinetobacter calcoaceticus-baumannii complex in Sichuan, China. AB - Among 82 clinical isolates of the Acinetobacter calcoaceticus-baumannii complex recovered in 13 hospitals of Sichuan, China, in 2011, 13 were Acinetobacter pittii and 2 were Acinetobacter nosocomialis. Multilocus sequence typing revealed a novel sequence type (ST) of A. nosocomialis and 7 novel STs of A. pittii. Most isolates were hospital-acquired and colonized in the respiratory tract, while 6 cases with pneumonia due to A. pittii were identified. This study provided a snapshot of the local incidence of A. pittii and A. nosocomialis. PMID- 23639797 TI - Mono- and bis-phosphine-ligated H93G myoglobin: spectral models for ferrous phosphine and ferrous-CO cytochrome P450. AB - To further investigate the properties of phosphines as structural and functional probes of heme proteins, mono- and bis-phosphine [tris(hydroxymethyl)phosphine, THMP] adducts of H93G myoglobin (Mb) have been prepared by stepwise THMP titrations of exogenous ligand-free ferric and ferrous H93G Mb, respectively. Bubbling with CO or stepwise titration with imidazole (Im) of the bis-THMP ligated ferrous protein generated a mixed ligand (THMP/CO or THMP/Im, respectively) ferrous complexes. Stable oxyferrous H93G(THMP) Mb was formed at 40 degrees C by bubbling the mono-THMP-Fe(II) protein with O2. A THMP-ligated ferryl H93G Mb moiety has been partially formed upon addition of H2O2 to the ferric mono-THMP adduct. All the species prepared above have been characterized with UV-visible (UV-vis) absorption and magnetic circular dichroism (MCD) spectroscopy in this study. The six-coordinate ferrous bis-phosphine and mono phosphine/CO complexes of H93G Mb exhibit characteristic spectral features (red shifted Soret/unique-shaped MCD visible bands and hyperporphyrin spectra, respectively) that only have been seen for the analogous phosphine or CO complexes of thiolate-ligated heme proteins such as cytochrome P450 (P450) and Caldariomyces fumago chloroperoxidase (CPO). However, such resemblance is not seen in phosphine-ligated ferric H93G Mb even though phosphine-bound ferric P450 and CPO display hyperporphyrin spectra. In fact, bis-THMP-bound ferric H93G Mb exhibits MCD and UV-vis absorption spectra that are similar to those of bis-amine and bis-thioether-ligated H93G Mb complexes. This study also further demonstrates the utility of the H93G cavity mutant for preparing novel heme iron coordination structures. PMID- 23639798 TI - Valeriana officinalis attenuates the rotenone-induced toxicity in Drosophila melanogaster. AB - In this study, we investigated the potential protective effects of Valeriana officinalis (V. officinalis) against the toxicity induced by rotenone in Drosophila melanogaster (D. melanogaster). Adult wild-type flies were concomitantly exposed to rotenone (500 MUM) and V. officinalis aqueous extract (10mg/mL) in the food during 7 days. Rotenone-fed flies had a worse performance in the negative geotaxis assay (i.e. climbing capability) and open-field test (i.e. mobility time) as well as a higher incidence of mortality when compared to control group. V. officinalis treatment offered protection against these detrimental effects of rotenone. In contrast, the decreased number of crossings observed in the flies exposed to rotenone was not modified by V. officinalis. Rotenone toxicity was also associated with a marked decrease on the total-thiol content in the homogenates and cell viability of flies, which were reduced by V. officinalis treatment. Indeed, rotenone exposure caused a significant increase in the mRNA expression of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) and also in the tyrosine hydroxylase (TH) gene. The expression of SOD and CAT mRNAs was normalized by V. officinalis treatment. Our results suggest that V. officinalis extract was effective in reducing the toxicity induced by rotenone in D. melanogaster as well as confirm the utility of this model to investigate potential therapeutic strategies on movement disorders, including Parkinson disease (PD). PMID- 23639799 TI - Validation of an LC-MS bioanalytical method for quantification of phytate levels in rat, dog and human plasma. AB - Myo-inositol hexakisphosphate (phytate, IP6) is a naturally occuring compound whose determination in biological matrices is chanllenging. Several benefitial properties have been attributed to IP6 in parallel with the development of suitable analytical methodologies for its analytical determination in urine and some tissues. However, there is a lack of appropriate tools for its determination in plasma samples. In this paper, a direct, sensitive and selective bioanalytical method for the determination of IP6 based on LC-MS is presented. It is the first method published to quantify IP6 in plasma matrices directly through its molecular weight, being consequently a highly specific methodology. The method has been validated in rat, dog and human plasma, according to the acceptance criteria laid down in the FDA guidance Bioanalytical Method Validation. Accuracy and precision were not greater than 15% at medium and high concentrations and not greater than 20% at the LLOQ concentration. The mean absolute recovery obtained ranged from 78.74 to 102.44%, 62.10 to 87.21% and 61.61 to 86.99% for rat, dog and human plasma respectively. The LLOQ was 500ngmL(-1) due to the presence of endogenous IP6 in blank plasma samples and the limit of detection was within the range 30-80ngmL(-1). PMID- 23639800 TI - Basolateral uptake of nucleosides by Sertoli cells is mediated primarily by equilibrative nucleoside transporter 1. AB - The blood-testis barrier (BTB) prevents the entry of many xenobiotic compounds into seminiferous tubules thereby protecting developing germ cells. Understanding drug transport across the BTB may improve drug delivery into the testis. Members of one class of drug, nucleoside reverse transcriptase inhibitors (NRTIs), do penetrate the BTB, presumably through interaction with physiologic nucleoside transporters. By investigating the mechanism of nucleoside transport, it may be possible to design other drugs to bypass the BTB in a similar manner. We present a novel ex vivo technique to study transport at the BTB that employs isolated, intact seminiferous tubules. Using this system, we found that over 80% of total uptake by seminiferous tubules of the model nucleoside uridine could be inhibited by 100 nM nitrobenzylmercaptopurine riboside (NBMPR, 6-S-[(4-nitrophenyl)methyl] 6-thioinosine), a concentration that selectively inhibits equilibrative nucleoside transporter 1 (ENT1) activity. In primary cultured rat Sertoli cells, 100 nM NBMPR inhibited all transepithelial transport and basolateral uptake of uridine. Immunohistochemical staining showed ENT1 to be located on the basolateral membrane of human and rat Sertoli cells, whereas ENT2 was located on the apical membrane of Sertoli cells. Transepithelial transport of uridine by rat Sertoli cells was partially inhibited by the NRTIs zidovudine, didanosine, and tenofovir disoproxil fumarate, consistent with an interaction between these drugs and ENT transporters. These data indicate that ENT1 is the primary route for basolateral nucleoside uptake into Sertoli cells and a possible mechanism for nucleosides and nucleoside-based drugs to undergo transepithelial transport. PMID- 23639801 TI - A selective antagonist reveals a potential role of G protein-coupled receptor 55 in platelet and endothelial cell function. AB - The G protein-coupled receptor 55 (GPR55) is a lysophosphatidylinositol (LPI) receptor that is also responsive to certain cannabinoids. Although GPR55 has been implicated in several (patho)physiologic functions, its role remains enigmatic owing mainly to the lack of selective GPR55 antagonists. Here we show that the compound CID16020046 ((4-[4-(3-hydroxyphenyl)-3-(4-methylphenyl)-6-oxo 1H,4H,5H,6H-pyrrolo[3,4-c]pyrazol-5-yl] benzoic acid) is a selective GPR55 antagonist. In yeast cells expressing human GPR55, CID16020046 antagonized agonist-induced receptor activation. In human embryonic kidney (HEK293) cells stably expressing human GPR55, the compound behaved as an antagonist on LPI mediated Ca2+ release and extracellular signal-regulated kinases activation, but not in HEK293 cells expressing cannabinoid receptor 1 or 2 (CB1 or CB2). CID16020046 concentration dependently inhibited LPI-induced activation of nuclear factor of activated T-cells (NFAT), nuclear factor kappa of activated B cells (NF kappaB) and serum response element, translocation of NFAT and NF-kappaB, and GPR55 internalization. It reduced LPI-induced wound healing in primary human lung microvascular endothelial cells and reversed LPI-inhibited platelet aggregation, suggesting a novel role for GPR55 in platelet and endothelial cell function. CID16020046 is therefore a valuable tool to study GPR55-mediated mechanisms in primary cells and tissues. PMID- 23639803 TI - Comparison of short-term outcomes after elective surgery following endoscopic stent insertion and emergency surgery for obstructive colorectal cancer. AB - PURPOSE: The aim of this study was to compare short-term morbidities and mortalities of elective surgery after stent insertion and emergency surgery in obstructive colorectal cancer. METHODS: We retrospectively reviewed 77 patients with obstructive colorectal cancer that underwent elective surgery after stenting (stent group: SG, n = 49) or emergent surgery (emergency group: EG, n = 28) from January 2000 to July 2010. RESULTS: The American Society of Anesthesiologists (ASA) score of SG was lower than that of EG (p = 0.015). The percentages of open and laparoscopic surgery in SG were 73.5% (36/49) and 26.5% (13/49), respectively, whereas surgery in EG was performed using an open technique (p = 0.003). The rate of primary anastomosis, without constructing a stoma, was 87.8% in SG and 42.9% in EG (p < 0.001). There was no difference in a postoperative complication. Anastomotic leakage according to time between stent placement and surgery in SG were 3 cases for 1-9 days and 0 for more than 10 days (p = 0.037). Three-year overall survival rates were 68.8% and 51.3% (p = 0.430), respectively. CONCLUSION: Preoperative stent insertion in obstructive colorectal cancer seems to be safe and feasible, and may decrease second stage procedure. Waiting 10 days after stent placement may be a more optimal time for surgical intervention. Further prospective randomized studies are needed to determine the proper time bridge to surgery following stent insertion in obstructive colorectal cancer. PMID- 23639804 TI - Albumin as a versatile platform for drug half-life extension. AB - BACKGROUND: Albumin is the most abundant plasma protein, is highly soluble, very stable and has an extraordinarily long circulatory half-life as a direct result of its size and interaction with the FcRn mediated recycling pathway. In contrast, many therapeutic molecules are smaller than the renal filtration threshold and are rapidly lost from the circulation thereby limiting their therapeutic potential. Albumin can be used in a variety of ways to increase the circulatory half-life of such molecules. SCOPE OF REVIEW: This article will review the mechanisms which underpin albumin's extraordinarily long circulatory half-life and how the understanding of these processes are currently being employed to extend the circulatory half-life of drugs which can be engineered to bind to albumin, or are conjugated to, or genetically fused to, albumin. MAJOR CONCLUSIONS: The recent and growing understanding of the pivotal role of FcRn in maintaining the extended circulatory half-life of albumin will necessitate a greater and more thorough investigation of suitable pre-clinical model systems for assessing the pharmacokinetic profiles of drugs associated, conjugated or fused to albumin. GENERAL SIGNIFICANCE: Association, conjugation or fusion of therapeutic drugs to albumin is a well-accepted and established half-life extension technology. The manipulation of the albumin-FcRn interaction will facilitate the modulation of the circulatory half-life of albumin-enabled drugs, leading to superior pharmacokinetics tailored to the disease state and increased patient compliance. This article is part of a Special Issue entitled Serum Albumin. PMID- 23639805 TI - Zn(2+) rather than Ca(2+) or Mg(2+) used as a cofactor in non-muscular actin from the oyster to control protein polymerization. AB - BACKGROUND: The major cytoskeletal protein of most cells is actin, which polymerizes to form actin filaments (F-actin). Each actin monomer (G-actin) contains a divalent alkaline earth metal ion (in vivo Mg(2+); in vitro usually Ca(2+)) as a cofactor that is crucial for protein polymerization. Prior to this study, however, whether or not other types of metal ions can play the same role as Mg(2+) or Ca(2+) in actins remains unknown. METHODS: A new actin from the gills of oyster (AGO) was prepared and characterized by protein purification techniques, SDS- and native-PAGE, and LC-MS?MS for the first time. The property of this protein was studied by CD, fluorescence and UV/vis spectroscopy, laser light scattering, and TEM. RESULTS: AGO is a monomer with a MW of ~42kDa. AGO is unique among all known actins in that Zn(2+) is only a naturally binding metal in the protein, and that one native AGO molecule binds 8 zinc ions, which can be removed by EDTA treatment at pH7.2. The presence of zinc has a great effect on the secondary and tertiary structure of the protein. Correlated with such effect is that these zinc ions in native AGO facilitate protein polymerization, whereas removal of zinc ions from native AGO results in a loss of such polymerization property. CONCLUSIONS: The present work demonstrates that AGO is a novel zinc binding protein with high capacity, and high selectivity. GENERAL SIGNIFICANCE: This work extends an understanding of the function of zinc and actin. PMID- 23639802 TI - Nitric-oxide synthase knockout modulates Ca2+-sensing receptor expression and signaling in mouse mesenteric arteries. AB - Extracellular calcium (Ca2+(e))-induced relaxation of isolated, phenylephrine (PE)-contracted mesenteric arteries is dependent on an intact perivascular sensory nerve network that expresses the Ca2+-sensing receptor (CaSR). Activation of the receptor stimulates an endocannabinoid vasodilator pathway, which is dependent on cytochrome P450 and phospholipase A2 but largely independent of the endothelium. In the present study, we determined the role of nitric oxide (NO) in perivascular nerve CaSR-mediated relaxation of PE-contracted mesenteric resistance arteries isolated from mice. Using automated wire myography, we studied the effects of NO synthase (NOS) gene knockout (NOS(-/-)) and pharmacologic inhibition of NOS on Ca2+(e)-induced relaxation of PE-contracted arteries. Endothelial NOS knockout (eNOS(-/-)) upregulates but neuronal NOS knockout (nNOS(-/-)) downregulates CaSR expression. NOS(-/-) reduced maximum Ca2+(e)-induced relaxation with no change in EC50 values, with eNOS(-/-) having the largest effect. The responses of vessels to calindol and Calhex 231 indicate that the CaSR mediates relaxation. L-N5-(1-iminoethyl)-ornithine reduced Ca2+(e) induced relaxation of PE-contracted arteries from C57BL/6 control mice by ~38% but had a smaller effect in vessels from eNOS(-/-) mice. 7-Nitroindazole had no significant effect on relaxation of arteries from NOS(-/-) mice, but both N(G) nitro-L-arginine methylester and N(G)-monomethyl-L-arginine significantly reduced the relaxation maxima in all groups. Interestingly, the nNOS-selective inhibitor S-methyl-L-thiocitrulline significantly increased the EC50 value by ~60% in tissues from C57BL/6 mice but reduced the maximum response by ~80% in those from nNOS(-/-) mice. Ca2+-activated big potassium channels play a major role in the process, as demonstrated by the effect of iberiotoxin. We conclude that CaSR signaling in mesenteric arteries stimulates eNOS and NO production that regulates Ca2+(e)-induced relaxation. PMID- 23639806 TI - Hydrogen sulfide, another simple gas with complex biology. PMID- 23639807 TI - High vitamin D3 diet administered during active colitis negatively affects bone metabolism in an adoptive T cell transfer model. AB - Decreased bone mineral density (BMD) represents an extraintestinal complication of inflammatory bowel disease (IBD). Vitamin D3 has been considered a viable adjunctive therapy in IBD. However, vitamin D3 plays a pleiotropic role in bone modeling and regulates the bone formation-resorption balance, depending on the physiological environment, and supplementation during active IBD may have unintended consequences. We evaluated the effects of vitamin D3 supplementation during the active phase of disease on colonic inflammation, BMD, and bone metabolism in an adoptive IL-10-/- CD4+ T cell transfer model of chronic colitis. High-dose vitamin D3 supplementation for 12 days during established disease had negligible effects on mucosal inflammation. Plasma vitamin D3 metabolites correlated with diet, but not disease, status. Colitis significantly reduced BMD. High-dose vitamin D3 supplementation did not affect cortical bone but led to a further deterioration of trabecular bone morphology. In mice fed a high vitamin D3 diet, colitis more severely impacted bone formation markers (osteocalcin and bone alkaline phosphatase) and increased bone resorption markers, ratio of receptor activator of NF-kappaB ligand to osteoprotegrin transcript, plasma osteoprotegrin level, and the osteoclast activation marker tartrate-resistant acid phosphatase (ACp5). Bone vitamin D receptor expression was increased in mice with chronic colitis, especially in the high vitamin D3 group. Our data suggest that vitamin D3, at a dose that does not improve inflammation, has no beneficial effects on bone metabolism and density during active colitis or may adversely affect BMD and bone turnover. These observations should be taken into consideration in the planning of further clinical studies with high-dose vitamin D3 supplementation in patients with active IBD. PMID- 23639808 TI - TRPM5-dependent amiloride- and benzamil-insensitive NaCl chorda tympani taste nerve response. AB - Transient receptor potential (TRP) subfamily M member 5 (TRPM5) cation channel is involved in sensing sweet, bitter, umami, and fat taste stimuli, complex-tasting divalent salts, and temperature-induced changes in sweet taste. To investigate if the amiloride- and benzamil (Bz)-insensitive NaCl chorda tympani (CT) taste nerve response is also regulated in part by TRPM5, CT responses to 100 mM NaCl + 5 MUM Bz (NaCl + Bz) were monitored in Sprague-Dawley rats, wild-type (WT) mice, and TRP vanilloid subfamily member 1 (TRPV1) and TRPM5 knockout (KO) mice in the presence of resiniferatoxin (RTX), a TRPV1 agonist. In rats, NaCl + Bz + RTX CT responses were also monitored in the presence of triphenylphosphine oxide, a specific TRPM5 blocker, and capsazepine and N-(3-methoxyphenyl)-4-chlorocinnamid (SB-366791), specific TRPV1 blockers. In rats and WT mice, RTX produced biphasic effects on the NaCl + Bz CT response, enhancing the response at 0.5-1 MUM and inhibiting it at >1 MUM. The NaCl + Bz + SB-366791 CT response in rats and WT mice and the NaCl + Bz CT response in TRPV1 KO mice were inhibited to baseline level and were RTX-insensitive. In rats, blocking TRPV1 by capsazepine or TRPM5 by triphenylphosphine oxide inhibited the tonic NaCl + Bz CT response and shifted the relationship between RTX concentration and the magnitude of the tonic CT response to higher RTX concentrations. TRPM5 KO mice elicited no constitutive NaCl + Bz tonic CT response. The relationship between RTX concentration and the magnitude of the tonic NaCl + Bz CT response was significantly attenuated and shifted to higher RTX concentrations. The results suggest that pharmacological or genetic alteration of TRPM5 activity modulates the Bz-insensitive NaCl CT response and its modulation by TRPV1 agonists. PMID- 23639810 TI - Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo. AB - Increased intestinal permeability is often associated with epithelial inflammation, leaky gut, or other pathological conditions in the gastrointestinal tract. We recently found that melatonin decreases basal duodenal mucosal permeability, suggesting a mucosal protective mode of action of this agent. The aim of the present study was to elucidate the effects of melatonin on ethanol-, wine-, and HCl-induced changes of duodenal mucosal paracellular permeability and motility. Rats were anesthetized with thiobarbiturate and a ~30-mm segment of the proximal duodenum was perfused in situ. Effects on duodenal mucosal paracellular permeability, assessed by measuring the blood-to-lumen clearance of 51Cr-EDTA, motility, and morphology, were investigated. Perfusing the duodenal segment with ethanol (10 or 15% alcohol by volume), red wine, or HCl (25-100 mM) induced concentration-dependent increases in paracellular permeability. Luminal ethanol and wine increased, whereas HCl transiently decreased duodenal motility. Administration of melatonin significantly reduced ethanol- and wine-induced increases in permeability by a mechanism abolished by the nicotinic receptor antagonists hexamethonium (iv) or mecamylamine (luminally). Signs of mucosal injury (edema and beginning of desquamation of the epithelium) in response to ethanol exposure were seen only in a few villi, an effect that was histologically not changed by melatonin. Melatonin did not affect HCl-induced increases in mucosal permeability or decreases in motility. Our results show that melatonin reduces ethanol- and wine-induced increases in duodenal paracellular permeability partly via an enteric inhibitory nicotinic-receptor dependent neural pathway. In addition, melatonin inhibits ethanol-induced increases in duodenal motor activity. These results suggest that melatonin may serve important gastrointestinal barrier functions. PMID- 23639809 TI - Gastroesophageal reflux activates the NF-kappaB pathway and impairs esophageal barrier function in mice. AB - The barrier function of the esophageal epithelium is a major defense against gastroesophageal reflux disease. Previous studies have shown that reflux damage is reflected in a decrease in transepithelial electrical resistance associated with tight junction alterations in the esophageal epithelium. To develop novel therapies, it is critical to understand the molecular mechanisms whereby contact with a refluxate impairs esophageal barrier function. In this study, surgical models of duodenal and mixed reflux were developed in mice. Mouse esophageal epithelium was analyzed by gene microarray. Gene set enrichment analysis showed upregulation of inflammation-related gene sets and the NF-kappaB pathway due to reflux. Significance analysis of microarrays revealed upregulation of NF-kappaB target genes. Overexpression of NF-kappaB subunits (p50 and p65) and NF-kappaB target genes (matrix metalloproteinases-3 and -9, IL-1beta, IL-6, and IL-8) confirmed activation of the NF-kappaB pathway in the esophageal epithelium. In addition, real-time PCR, Western blotting, and immunohistochemical staining also showed downregulation and mislocalization of claudins-1 and -4. In a second animal experiment, treatment with an NF-kappaB inhibitor, BAY 11-7085 (20 mg.kg 1.day-1 ip for 10 days), counteracted the effects of duodenal and mixed reflux on epithelial resistance and NF-kappaB-regulated cytokines. We conclude that gastroesophageal reflux activates the NF-kappaB pathway and impairs esophageal barrier function in mice and that targeting the NF-kappaB pathway may strengthen esophageal barrier function against reflux. PMID- 23639811 TI - Hepatocytes produce TNF-alpha following hypoxia-reoxygenation and liver ischemia reperfusion in a NADPH oxidase- and c-Src-dependent manner. AB - Cell line studies have previously demonstrated that hypoxia-reoxygenation (H/R) leads to the production of NADPH oxidase 1 and 2 (NOX1 and NOX2)-dependent reactive oxygen species (ROS) required for the activation of c-Src and NF-kappaB. We now extend these studies into mouse models to evaluate the contribution of hepatocytes to the NOX- and c-Src-dependent TNF-alpha production that follows H/R in primary hepatocytes and liver ischemia-reperfusion (I/R). In vitro, c-Src deficient primary hepatocytes produced less ROS and TNF-alpha following H/R compared with controls. In vivo, c-Src-KO mice also had impaired TNF-alpha and NF kappaB responses following partial lobar liver I/R. Studies in NOX1 and p47phox knockout primary hepatocytes demonstrated that both NOX1 and p47phox are partially required for H/R-mediated TNF-alpha production. To further investigate the involvement of NADPH oxidases in the production of TNF-alpha following liver I/R, we performed additional in vivo experiments in knockout mice deficient for NOX1, NOX2, p47phox, Rac1, and/or Rac2. Cumulatively, these results demonstrate that NOX2 and its activator subunits (p47phox and Rac) control the secretion of TNF-alpha by the liver following I/R. Interestingly, in the absence of Kupffer cells and NOX2, NOX1 played a dominant role in TNF-alpha production following hepatic I/R. However, NOX1 deletion alone had little effect on I/R-induced TNF alpha. Thus Kupffer cell-derived factors and NOX2 act to suppress hepatic NOX1 dependent TNF-alpha production. We conclude that c-Src and NADPH oxidase components are necessary for redox-mediated production of TNF-alpha following liver I/R and that hepatocytes play an important role in this process. PMID- 23639812 TI - Cicletanine stimulates eNOS phosphorylation and NO production via Akt and MAP kinase/Erk signaling in sinusoidal endothelial cells. AB - The function of the endothelial isoform of nitric oxide synthase (eNOS) and production of nitric oxide (NO) is altered in a number of disease states. Pharmacological approaches to enhancing NO synthesis and thus perhaps endothelial function could have substantial benefits in patients. We analyzed the effect of cicletanine, a synthetic pyridine with potent vasodilatory characteristics, on eNOS function and NO production in normal (liver) and injured rat sinusoidal endothelial cells, and we studied the effect of cicletanine-induced NO on stellate cell contraction and portal pressure in an in vivo model of liver injury. Sinusoidal endothelial cells were isolated from normal and injured rat livers. After exposure to cicletanine, eNOS phosphorylation, NO synthesis, and the signaling pathway regulating eNOS activation were measured. Cicletanine led to an increase in eNOS (Ser1177) phosphorylation, cytochrome c reductase activity, L-arginine conversion to L-citrulline, as well as NO production. The mechanism of the effect of cicletanine appeared to be via the protein kinase B (Akt) and MAP kinase/Erk signaling pathways. Additionally, cicletanine improved NO synthesis in injured sinusoidal endothelial cells. NO production induced by cicletanine in sinusoidal endothelial cells increased protein kinase G (PKG) activity as well as relaxation of stellate cells. Finally, administration of cicletanine to mice with portal hypertension induced by bile duct ligation led to reduction of portal pressure. The data indicate that cicletanine might improve eNOS activity in injured sinusoidal endothelial cells and likely activates hepatic stellate cell NO/PKG signaling. It raises the possibility that cicletanine could improve intrahepatic vascular function in portal hypertensive patients. PMID- 23639813 TI - A disintegrin and metalloproteinase 17 regulates TNF and TNFR1 levels in inflammation and liver regeneration in mice. AB - A disintegrin and metalloproteinase 17 (ADAM17), or tumor necrosis factor (TNF) alpha-converting enzyme, is a key metalloproteinase and physiological convertase for a number of putative targets that play critical roles in cytokine and growth factor signaling. These interdependent pathways are essential components of the signaling network that links liver function with the compensatory growth that occurs during liver regeneration following 2/3 partial hepatectomy (PH) or chemically induced hepatotoxicity. Despite identification of many soluble factors needed for efficient liver regeneration, very little is known about how such ligands are regulated in the liver. To directly study the role of ADAM17 in the liver, we employed two cell-specific ADAM17 knockout (KO) mouse models. Using lipopolysaccharide (LPS) as a robust stimulus for TNF release, we found attenuated levels of circulating TNF in myeloid-specific ADAM17 KO mice (ADAM17 m KO) and, unexpectedly, in mice with hepatocyte-specific ADAM17 deletion (ADAM17 h KO), indicating that ADAM17 expression in both cell types plays a role in TNF shedding. After 2/3 PH, induction of TNF, TNFR1, and amphiregulin (AR) was significantly attenuated in ADAM17 h-KO mice, implicating ADAM17 as the primary sheddase for these factors in the liver. Surprisingly, the extent and timing of hepatocyte proliferation were not affected after PH or carbon tetrachloride injection in ADAM17 h-KO or ADAM17 m-KO mice. We conclude that ADAM17 regulates TNF, TNFR1, and AR in the liver, and its expression in both hepatocytes and myeloid cells is important for TNF regulation after LPS injury or 2/3 PH, but is not required for liver regeneration. PMID- 23639814 TI - Tetrahydrobiopterin deficiency induces gastroparesis in newborn mice. AB - Pyloric stenosis, the most common infant gastrointestinal disease, has no known etiology and clinically presents as abnormal gastric emptying with evidence of pyloric muscle hypertrophy. Whether abnormalities in gastric muscle contraction and/or relaxation have a role in this condition is poorly known, but gastroparesis is commonly observed in association with delayed gastric emptying in adults. Therefore, we evaluated the tetrahydrobiopterin (BH4)-deficient newborn mouse model of this disease (hph-1) and hypothesized that their gastric muscle properties are impaired, when compared with wild-type control animals. In vitro studies evaluating the age-dependent gastric fundus muscle contraction and relaxation potential were conducted. Compared with wild-type mice, the hph-1 stomach content/body weight ratio was significantly increased in newborn but not juvenile or adult animals, confirming abnormal gastric emptying. Gastric tissue neuronal nitric oxide synthase (nNOS) protein expression was upregulated in both newborn and adult hph-1 mice, but in the former there was evidence of enzyme uncoupling and higher tissue superoxide generation when compared with same age matched animals. As opposed to the lack of strain differences in the U46619 induced force, the newborn hph-1 gastric muscle carbachol-induced contraction and nNOS-dependent relaxation were significantly reduced (P < 0.01). These group differences were not present in juvenile or adult mice. Preincubation with BH4 significantly enhanced the newborn hph-1, but not wild-type, gastric muscle contraction. In conclusion, changes compatible with gastroparesis are present in the newborn mouse model of pyloric stenosis. The role of BH4 deficiency and possibly associated gastroparesis in the pathogenesis of infantile pyloric stenosis warrants further investigation. PMID- 23639816 TI - Prenatal development of the fetal thoracic sympathetic trunk in sheep (Ovis aries). AB - This study aims at clarifying the detailed morphological and topographical changes of the thoracic part of the sympathetic trunk of sheep during fetal development. Bilateral micro-dissection of the thoracic sympathetic trunk was performed on 40 sheep fetuses aged 6-20 weeks (18 males and 22 females) under a stereomicroscope. The cervicothoracic ganglion (CTG) was observed on 75/80 sides (93.7%) and was composed of the caudal cervical and the first thoracic ganglia on 45/80 sides (56.2%), and of the caudal cervical and the first two thoracic ganglia on 30/80 sides (37.5%). The presence of the two last (12th-13th) thoracic ganglia was not constant. The influence of the sex, the side of the body, and the ages of the fetus on the morphology and topography of the thoracic sympathetic trunk in sheep were identified. In spite of the differences in the morphology and topography of the thoracic sympathetic trunk between early and late fetal developments, the morphology and topography of the older fetal thoracic sympathetic trunk tended to be similar to that of the adult sheep. To comprehend the comparative morphology of the fetal thoracic sympathetic trunk more completely, our results were compared with previous studies. Consequently, differences and similarities in the composition and position of the CTG, presence of single caudal cervical ganglion without fusion to the thoracic ganglia, and absence of the thoracic ganglia, and presence of splitting of the interganglionic branch were found among sheep, pig, and human fetuses. Therefore, sheep might be the appropriate animal model to be applied in human sympathetic nervous system. PMID- 23639817 TI - Ambulatory blood pressure variation: allostasis and adaptation. AB - Allostasis is defined as achieving stability through change and was originally coined as a term to describe the adaptive variability of blood pressure. While there have been a growing number of studies using ambulatory blood pressure monitors that have examined the sources of blood pressure variation in everyday life, these studies have largely not conceptualized that variation in allostatic terms. This brief overview evaluates ambulatory blood pressure variability and its sources in the context of allostasis and adaptation. The effects of job strain and the impact of evolutionary aspects of population biology on blood pressure variation are also discussed. PMID- 23639818 TI - Reply to Wiegand et al.: proton pump inhibitor over-use and the ongoing battle to control Clostridium difficile infection in hospitals. PMID- 23639819 TI - Infections acquired in intensive care units: results of national surveillance in Belgium, 1997-2010. AB - BACKGROUND AND AIM: To describe the methodology and output of the Belgian surveillance for infections acquired in intensive care units (ICUs) between 1997 and 2010. METHODS: Since 1997, ICUs in acute care hospitals in Belgium have been encouraged by federal law to participate in a national multi-centre prospective observational surveillance programme. A protocol and software tool for data collection was developed, and the case definitions and methodology follow those of the European Centre for Disease Prevention and Control. FINDINGS: For 2010, 18 hospitals provided data on 59 observation quarters, 6478 ICU patients and 52,593 ICU patient-days. The mean incidence rates of ICU-acquired pneumonia and intubation-associated pneumonia were 13 per 1000 patient-days and 12 per 1000 intubation-days, respectively. The mean incidence rates of ICU-acquired bloodstream infections, central vascular catheter (CVC)-associated bloodstream infections and CVC-associated primary bloodstream infections were 3.2 per 1000 patient-days, 2.6 per 1000 catheter-days and 2.3 per 1000 catheter-days, respectively. Between 1997 and 2010, stable trends in ICU-acquired pneumonia and bloodstream infections were observed, together with decreasing trends for intubation-associated pneumonia and CVC-associated bloodstream infections, and a stable trend for CVC-associated primary bloodstream infections. CONCLUSIONS: In Belgium, national surveillance of ICU-acquired infections allows acute care hospitals to track the incidence of infections at local level, enabling comparison with national and European reference data. Between 1997 and 2010, the incidence of ICU-acquired infections increased and the incidence of device associated infections decreased. PMID- 23639815 TI - Enteric nervous system development: migration, differentiation, and disease. AB - The enteric nervous system (ENS) provides the intrinsic innervation of the bowel and is the most neurochemically diverse branch of the peripheral nervous system, consisting of two layers of ganglia and fibers encircling the gastrointestinal tract. The ENS is vital for life and is capable of autonomous regulation of motility and secretion. Developmental studies in model organisms and genetic studies of the most common congenital disease of the ENS, Hirschsprung disease, have provided a detailed understanding of ENS development. The ENS originates in the neural crest, mostly from the vagal levels of the neuraxis, which invades, proliferates, and migrates within the intestinal wall until the entire bowel is colonized with enteric neural crest-derived cells (ENCDCs). After initial migration, the ENS develops further by responding to guidance factors and morphogens that pattern the bowel concentrically, differentiating into glia and neuronal subtypes and wiring together to form a functional nervous system. Molecules controlling this process, including glial cell line-derived neurotrophic factor and its receptor RET, endothelin (ET)-3 and its receptor endothelin receptor type B, and transcription factors such as SOX10 and PHOX2B, are required for ENS development in humans. Important areas of active investigation include mechanisms that guide ENCDC migration, the role and signals downstream of endothelin receptor type B, and control of differentiation, neurochemical coding, and axonal targeting. Recent work also focuses on disease treatment by exploring the natural role of ENS stem cells and investigating potential therapeutic uses. Disease prevention may also be possible by modifying the fetal microenvironment to reduce the penetrance of Hirschsprung disease causing mutations. PMID- 23639820 TI - Inhibition of IL-6 signaling: A novel therapeutic approach to treating spinal cord injury pain. AB - To characterize the contribution of interleukin-6 (IL-6) to spinal cord injury pain (SCIP), we employed a clinically relevant rat contusion model of SCIP. Using Western blots, we measured IL-6 levels in lumbar segments (L1-L5), at the lesion site (T10), and in the corresponding lumbar and thoracic dorsal root ganglia (DRG) in 2 groups of similarly injured rats: (a) SCI rats that developed hind limb mechanical allodynia (SCIP), and (b) SCI rats that did not develop SCIP. Only in SCIP rats did we find significantly increased IL-6 levels. Immunocytochemistry showed elevated IL-6 predominantly in reactive astrocytes. Our data also showed that increased production of IL-6 in hyperreactive astrocytes in SCIP rats may explain still-poorly understood astrocytic contribution to SCIP. To test the hypothesis that IL-6 contributes to mechanical allodynia, we treated SCIP rats with neutralizing IL-6 receptor antibody (IL-6-R Ab), and found that one systemic injection abolished allodynia and associated weight loss; in contrast to gabapentin, the analgesic effect lasted for at least 2weeks after the injection, despite the shorter presence of the Ab in the circulation. We also showed that IL-6-R Ab partially reversed SCI-induced decreases in the protein levels of the glutamate transporter GLT-1 12hours and 8days after Ab injection, which may explain the lasting analgesic effect of the Ab in SCIP rats. A link between reactive astrocytes IL-6-GLT-1 has not been previously shown. Given that the humanized IL-6-R Ab tocilizumab is Food and Drug Administration-approved for rheumatoid arthritis, we are proposing tocilizumab as a novel and potentially effective treatment for SCIP. PMID- 23639822 TI - Effects of motion style acupuncture treatment in acute low back pain patients with severe disability: a multicenter, randomized, controlled, comparative effectiveness trial. AB - Reviews of the efficacy of acupuncture as a treatment for acute low back pain (aLBP) have shown that there is insufficient evidence for its effect and that more research is needed. Motion style acupuncture treatment (MSAT) is novel in that it requires a part of the patient's body to move passively or actively while acupuncture needles are retained. A multicenter, randomized, comparative effectiveness trial was conducted to evaluate the effects of MSAT in aLBP with severe disability. A total of 58 aLBP patients with severe functional disability (defined per Oswestry Disability Index [ODI] ?60%) were recruited and assigned randomly to receive 1 session of either conventional diclofenac injection (n=29) or MSAT (n=29). The primary outcome measured improvement in LBP using the 10 point numerical rating scale of LBP, and the secondary outcome assessed disability using the Oswestry Disability Index at 30minutes and at 2, 4, and 24weeks after treatment. Analyses were by intention to treat. The numerical rating scale of the MSAT group decreased 3.12 (95% confidence interval=2.26, 3.98; P<.0001) more than that of the injection group and the Oswestry Disability Index of the MSAT group decreased 32.95% (95% confidence interval=26.88, 39.03; P<.0001) more than that of the injection group, respectively. The difference between the 2 groups maintained statistical significance at 2 and 4weeks after treatment. These results suggest that MSAT has positive effects on immediate pain relief and the functional recovery of aLBP patients with severe disability. PMID- 23639824 TI - Time to surgery and 30-day morbidity and mortality of periprosthetic hip fractures. AB - BACKGROUND AND AIM: The management of femoral periprosthetic fractures following hip replacement surgery is a complex and challenging situation. Whilst the early complications for both primary hip arthroplasty and proximal femoral fracture surgery have been widely documented, there is a paucity of published data regarding early outcomes following periprosthetic fracture surgery. Delay to surgery for native proximal femoral fractures has been clearly documented as a predictor towards adverse outcome. This study therefore aims to correlate the timing of operative intervention with the complication rate following periprosthetic fracture surgery. In addition, the study aims to identify further factors in the perioperative period that positively predict a poor postoperative outcome. METHODS: Sixty patients who were operatively managed for a femoral implant periprosthetic fracture were identified and each case assessed retrospectively. RESULTS AND CONCLUSION: There was an overall complication rate of 45% including a 30-day mortality of 10%. An abbreviated mental test score of 8 out of 10 or less and a delay to surgery of >72h were found to be significant risk factors for adverse outcome. Both the patient cohort in this study and the predictors for poor postoperative outcome were comparable to those for native proximal femoral fractures. PMID- 23639821 TI - Deficits in glycinergic inhibition within adult spinal nociceptive circuits after neonatal tissue damage. AB - Tissue injury during a critical period of early postnatal development can alter pain sensitivity throughout life. However, the degree to which neonatal tissue damage exerts prolonged effects on synaptic signaling within adult spinal nociceptive circuits remains unknown. Here we provide evidence that a transient surgical injury of the hind paw during the neonatal period compromises inhibitory transmission within the adult mouse superficial dorsal horn (SDH), while the same incision occurring during the third week of life failed to evoke these long-term modifications of the SDH synaptic network. The decrease in phasic inhibitory signaling after early tissue damage reflected a selective reduction in glycine receptor (GlyR)-mediated input onto both GABAergic and presumed glutamatergic neurons within lamina II of the adult SDH. Meanwhile, neonatal incision significantly decreased the density of tonic GlyR-mediated current only in the presumed glutamatergic population during adulthood. These persistent changes in synaptic function following early injury occurred in the absence of significant alterations in the transcription of genes known to be important for glycinergic transmission. These findings suggest that aberrant sensory input during early life has permanent consequences for the functional organization of nociceptive synaptic circuits within the adult spinal cord. PMID- 23639825 TI - Surgical strategies in polytraumatized patients with femoral shaft fractures - comparing a German and an Australian level I trauma centre. AB - BACKGROUND: Femoral shaft fractures are one of the most common injuries in multiple trauma patients. Due to their prognostic relevance, there is an ongoing controversial discussion as to the optimal treatment strategy in terms of Damage Control Orthopaedics (DCO) and Early Total Care (ETC). We aimed to describe the differences in fracture management and clinical outcome of multiple trauma patients with concomitant femoral shaft fractures treated at a German and an Australian level I trauma centre using the same inclusion criteria. METHODS: Polytraumatized patients (ISS >= 16) with a femoral shaft fracture aged >= 16 years treated at a German and an Australian trauma centre between 2003 and 2007 were included. According to ETC and DCO management principles, we evaluated demographic parameters as well as posttraumatic complications and clinical outcome. RESULTS: Seventy-three patients were treated at the German and 134 patients at the Australian trauma centre. DCO was performed in case of increased injury severity in both hospitals. Prolonged mechanical ventilation time, and length of ICU and hospital stay were demonstrated in DCO treatment regardless of the trauma centre. No differences concerning posttraumatic complications and survival were found between both centres. Survival of patients after DCO was similar to those managed using ETC despite a greater severity of injury and lower probability of survival. There was no difference in the incidence of ARDS. DCO was, however, associated with a greatly increased length of time on mechanical ventilation and length of stay in the ICU. CONCLUSION: We found no differences concerning patient demographics or clinical outcomes in terms of incidence of ARDS, MODS, or mortality. As such, we propose that comparability between German and Australian trauma populations is justified. Despite a higher ISS in the DCO group, there were no differences in posttraumatic complications and survival depending on ETC or DCO treatment. Further research is required to confirm whether this is the case with other countries, too. PMID- 23639826 TI - Acute repair of traumatic abdominal muscle avulsion from iliac crest: a mesh-free technique using suture anchors. PMID- 23639827 TI - Clearance of the thoracolumbar spine--a clinical decision rule is needed. PMID- 23639828 TI - Reductive activation of mitomycins A and C by vitamin C. AB - The anticancer drug mitomycin C produces cytotoxic effects after being converted to a highly reactive bis-electrophile by a reductive activation, a reaction that a number of 1-electron or 2-electron oxidoreductase enzymes can perform in cells. Several reports in the literature indicate that ascorbic acid can modulate the cytotoxic effects of mitomycin C, either potentiating or inhibiting its effects. As ascorbic acid is a reducing agent that is known to be able to reduce quinones, it could be possible that the observed modulatory effects are a consequence of a direct redox reduction between mitomycin C and ascorbate. To determine if this is the case, the reaction between mitomycin C and ascorbate was studied using UV/Vis spectroscopy and LC/MS. We also studied the reaction of ascorbate with mitomycin A, a highly toxic member of the mitomycin family with a higher redox potential than mitomycin C. We found that ascorbate is capable to reduce mitomycin A efficiently, but it reduces mitomycin C rather inefficiently. The mechanisms of activation have been elucidated based on the kinetics of the reduction and on the analysis of the mitosene derivatives formed after the reaction. We found that the activation occurs by the interplay of three different mechanisms that contribute differently, depending on the pH of the reaction. As the reduction of mitomycin C by ascorbate is rather inefficiently at physiologically relevant pH values we conclude that the modulatory effect of ascorbate on the cytotoxicity of mitomycin C is not the result of a direct redox reaction and therefore this modulation must be the consequence of other biochemical mechanisms. PMID- 23639829 TI - PEG-mediated one-pot multicomponent reactions for the efficient synthesis of functionalized dihydropyridines and their functional group dependent DNA cleavage activity. AB - Polyethylene glycol (PEG) has been found to be an inexpensive, non-toxic and useful medium for the one pot synthesis of highly functionalized dihydropyridines using multicomponent reactions (MCRs) at room temperature under catalyst free conditions. The notable features of this protocol are: mild reaction condition, applicability to wide range of substrates, reusability of the PEG and good yields. The interaction of the synthesized compounds with pUC19 plasmid DNA was also analyzed. Some of the synthesized compounds showed interesting functional group dependent nuclease activity for plasmid DNA cleavage under physiological conditions. PMID- 23639830 TI - Synthesis and biological evaluation of new bis-indolone-N-oxides. AB - A series of bis-indolone-N-oxides, 1a-f, was prepared from bis(ethynyl)benzenes and o-halonitroaryls and studied for their in vitro antiplasmodial activities against Plasmodium falciparum and representative strains of bacteria and candida as well as for their cytotoxicity against a human tumor cell line (MCF7). They did not cause any haemolysis (300 MUgmL(-1)). Of the synthesized bis-indolones, compound 1a had the most potent antiplasmodial activity (IC50=0.763 MUmolL(-1) on the FcB1 strain) with a selectivity index (CC50 MCF7/IC50 FcB1) of 35.6. No potency against the tested microbial strains was observed. PMID- 23639833 TI - Locking plate fixation of proximal humeral fractures with impaction of the fracture site to restore medial column support: a biomechanical study. AB - BACKGROUND: Despite the advent of locking plate techniques, proximal humeral fracture fixation can fail due to varus collapse, especially in osteoporotic bone with medial cortex comminution. This study investigated the effect of restoring the integrity of the medial column by fracture impaction and shaft medialization with locking plate fixation. This construct was compared with a traditional locking plate construct under conditions of varus cyclical loading. MATERIALS AND METHODS: Proximal humeral fractures with medial comminution were simulated by performing wedge-shaped osteotomies at the surgical neck in cadaveric specimens and removing 1 cm of medial cortex. For each cadaver (n = 6), 1 humeral fracture was fixed with a traditional locking plate construct. The other was fixed with the locking plate construct plus fracture impaction and shaft medialization, resulting in medial column restoration. The humeral head was immobilized, and a repetitive, varus force was applied to the humeral shaft until construct collapse or until 25,000 cycles were completed. RESULTS: None of the constructs with fracture impaction collapsed, whereas 5 of 6 of the nonaugmented constructs collapsed before reaching 25,000 cycles (P = .008). Collapse of the 5 nonimpacted constructs that failed occurred after an average of 11,470 +/- 3589 cycles. CONCLUSION: Fracture impaction increased the ability of the locking plate to withstand repetitive varus loading. This technique provides a construct biomechanically superior to locking plate fixation alone. PMID- 23639832 TI - Chronic asthma results in cognitive dysfunction in immature mice. AB - Asthma is the most common chronic childhood illness today. However, little attention is paid for the impacts of chronic asthma-induced hypoxia on cognitive function in children. The present study used immature mice to establish ovalbumin induced chronic asthma model, and found that chronic asthma impaired learning and memory ability in Morris Water Maze test. Further study revealed that chronic asthma destroyed synaptic structure, impaired long-term potentiation (LTP) maintaining in the CA1 region of mouse hippocampal slices. We found that intermittent hypoxia during chronic asthma resulted in down-regulation of c-fos, Arc and neurogenesis, which was responsible for the impairment of learning and memory in immature mice. Moreover, our results showed that budesonide treatment alone was inadequate for attenuating chronic asthma-induced cognitive impairment. Therefore, our findings indicate that chronic asthma might result in cognitive dysfunction in children, and more attention should be paid for chronic asthma induced brain damage in the clinical therapy. PMID- 23639831 TI - Neurotrophin and Wnt signaling cooperatively regulate dendritic spine formation. AB - Dendritic spines are major sites of excitatory synaptic transmission and changes in their numbers and morphology have been associated with neurodevelopmental and neurodegenerative disorders. Brain-derived Neurotrophic Factor (BDNF) is a secreted growth factor that influences hippocampal, striatal and neocortical pyramidal neuron dendritic spine density. However, the mechanisms by which BDNF regulates dendritic spines and how BDNF interacts with other regulators of spines remain unclear. We propose that one mechanism by which BDNF promotes dendritic spine formation is through an interaction with Wnt signaling. Here, we show that Wnt signaling inhibition in cultured cortical neurons disrupts dendritic spine development, reduces dendritic arbor size and complexity, and blocks BDNF-induced dendritic spine formation and maturation. Additionally, we show that BDNF regulates expression of Wnt2, and that Wnt2 is sufficient to promote cortical dendrite growth and dendritic spine formation. Together, these data suggest that BDNF and Wnt signaling cooperatively regulate dendritic spine formation. PMID- 23639834 TI - Minimally displaced fractures of the greater tuberosity: outcome of non-operative treatment. AB - BACKGROUND: Minimally displaced (<3 mm) and non-displaced fractures of the proximal humerus are a common source of disability; nevertheless, there is no agreement on the recommended rehabilitation program in these patients. The purpose of this study was to evaluate the outcome of this group of patients and describe the rehabilitation protocol we have used for the treatment of this injury. METHODS: We retrospectively analyzed the records of patients diagnosed with minimally displaced (<3 mm) fractures of the greater tuberosity who were admitted to our institute between June 2007 and May 2008. Patients were treated with a three-phase protocol. In the first phase, patients were immobilized in a sling for 3 weeks. In the second phase, pendular and active assisted exercises were begun 3 to 6 weeks after the injury. In the third phase, active exercises were commenced starting 6 weeks after injury. RESULTS: Sixty-nine patients matched our inclusion and exclusion criteria. At an average follow-up of 31 months (range, 26-41 months), the average Constant score improved from 40 points (range, 33-58 points) to 95 points (range, 75-100 points). Average satisfaction score improved from 4.2 of 10 (range, 2-6) to 9.5 of 10 (range, 7-10). The reported average duration of pain and decreased range of motion from the time of injury was 8.1 months (range, 1-24 months). CONCLUSIONS: When the diagnosis of a minimally displaced fracture of the proximal humerus is made, the patient can be reassured that a favorable outcome is anticipated with a staged rehabilitation protocol. Nevertheless, clinicians and patients should be aware that full recovery from the injury may take an average of 8 months. PMID- 23639835 TI - [Consumption of light soft drinks in children]. PMID- 23639836 TI - [Urinary dribbling in girls: which investigations in 2012?]. AB - Continuous urinary leakage, despite normal deliberate voiding, must suggest the diagnosis of ectopic ureter, more specifically in girls. Ectopic ureter is usually associated with duplex kidney and complete ureteral duplication. The strategy of investigations has changed over the past few years, due to MRI development in the analysis of urinary tract malformations. We report the case of a 4-year-old girl who presented with these symptoms and had a suspicion of left duplex kidney on the prenatal ultrasonography (US). Two US examinations during the first months of life were compatible with a left duplex kidney without any complication. Another US at the age of 4 years was reported as normal. We completed the investigation with MR urography, which revealed a left duplex kidney with a poorly functioning dysplastic upper pole, and the orifice of the ureter of this upper pole inserting in the vagina. The surgical treatment, realized by celioscopy, was partial nephrectomy of the upper pole, removing most of the ectopic ureter. US is the first exam to investigate urinary tract malformations. However, duplex kidney with small dysplastic pole and ectopic insertion of a nondilated ureter may be difficult to see, and a normal US should never end the investigations. Intravenous urography and renal scintigraphy used to be the reference complementary exams, but are now replaced by MR urography. Without using ionizing radiation, MR urography can visualize duplex kidney and ectopic ureteral insertion with high resolution, and evaluates renal function of each kidney and each pole. These morphological and functional data are essential to determine the surgical treatment. PMID- 23639837 TI - [Value of lumbar puncture after a first febrile seizure in children aged less than 18 months. A retrospective study of 157 cases]. AB - AIM: Because meningitis symptoms are not very specific under the age of 18 months, lumbar puncture (LP) was widely recommended in children presenting a febrile seizure (FS). Recent retrospective studies have challenged this age criterion. In 2011, the American Academy of Pediatrics updated its guidelines for the first episode of simple FS: LP is indicated if signs suggestive of meningitis are present and remains "an option" in case of prior antibiotic treatment or between the age of 6 and 12 months if the child is not properly vaccinated against Haemophilus and Streptococcus pneumoniae. Because the meningitis epidemiology and the vaccination coverage are different, the objective of this study was to evaluate whether these new guidelines were applicable in France. PATIENTS AND METHODS: Between 2009 and 2010, we conducted a retrospective single center study including 157 children aged less than 18 months admitted to the pediatric emergency department (Children's Hospital, Toulouse, France) for their first febrile seizure. The data collected were: type of seizure, knowledge of prior antibiotic treatment, neurological status, signs of central nervous system infection, and biological results (LP, blood cultures). RESULTS: Lumbar puncture was performed in 40% of cases (n=63). The diagnosis of meningitis/encephalitis was selected in eight cases: three cases of viral meningitis, three bacterial meningitis (Streptococcus pneumoniae), and two non-herpetic viral encephalitis. The incidence of bacterial meningitis in our study was 1.9%. The risk of serious infection, bacterial meningitis or encephalitis, was increased when there was a complex FS (14% versus 0% with a simple FS, P=0.06). The presence of other suggestive clinical symptoms was strongly associated with a risk of bacterial meningitis/encephalitis (36% in case of clinical orientation versus 0% in the absence of such signs, P<0.001). DISCUSSION: All severe clinical presentations were associated with complex FS (prolonged, focal, and/or repeated seizures) and the presence of other suggestive clinical signs (impaired consciousness lasting longer than 1h after the seizure, septic aspect, behavior disorders, hypotonia, bulging fontanel, neck stiffness, petechial purpura). The risk of bacterial meningitis or encephalitis associated with a simple FS and followed by a strictly normal clinical examination is extremely low. CONCLUSION: After a simple febrile seizure without any other suggestive signs of meningitis, systematic lumbar puncture is not necessary even in children younger than 18 months. LP remains absolutely indicated if clinical symptoms concentrate on central nervous system infection and should be discussed in case of complex seizures, prior antibiotic treatment, or incomplete vaccination. PMID- 23639838 TI - [Parents' understanding and acceptance of medical prescriptions in a pediatric emergency ward]. PMID- 23639839 TI - Mechanical properties and in vitro evaluation of bioactivity and degradation of dexamethasone-releasing poly-D-L-lactide/nano-hydroxyapatite composite scaffolds. AB - The purpose of this study was to fabricate drug-release nano-composite scaffolds and perform in vitro evaluation of their mechanical properties, bioactivity, biodegradability and drug release behaviors. Porous drug-release poly-d-l-lactide (PDLLA) composite scaffolds filled with different amounts of nano-hydroxyapatite (nano-HAp) were prepared by a technique combining polymer coagulation, cold compression moulding, salt leaching and drug coating. Apatite detected on the scaffolds after exposure to a simulated body fluid showed improvement in bioactivity and the apatite formation ability through the addition of the nano HAp content in the composites. Nano-HAp incorporation and apatite formation made a positive impact on the mechanical properties of the scaffolds; however, plasticization and degradation of PDLLA had a negative impact. The pH compensation effect of the composite scaffolds can reduce the risk of chronic inflammation complications. The fabrication method in this study can produce scaffolds with controllable structure, appropriate mechanical properties and degradation rates for cancellous bone repair applications. PMID- 23639841 TI - 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. PMID- 23639842 TI - Fosfomycin susceptibility of isolates with blaKPC-2 from Brazil. PMID- 23639840 TI - A molecular rheostat at the interface of cancer and diabetes. AB - Epidemiology studies revealed the connection between several types of cancer and type 2 diabetes (T2D) and suggested that T2D is both a symptom and a risk factor of pancreatic cancer. High level of circulating insulin (hyperinsulinemia) in obesity has been implicated in promoting aggressive types of cancers. Insulin resistance, a symptom of T2D, pressures pancreatic beta-cells to increase insulin secretion, leading to hyperinsulinemia, which in turn leads to a gradual loss of functional beta-cell mass, thus indicating a fine balance and interplay between beta-cell function and mass. While the mechanisms of these connections are unclear, the mTORC1-Akt signaling pathway has been implicated in controlling beta cell function and mass, and in mediating the link of cancer and T2D. However, incomplete understating of how the pathway is regulated and how it integrates body metabolism has hindered its efficacy as a clinical target. The IQ motif containing GTPase activating protein 1 (IQGAP1)-Exocyst axis is a growth factor- and nutrient-sensor that couples cell growth and division. Here we discuss how IQGAP1-Exocyst, through differential interactions with Rho-type of small guanosine triphosphatases (GTPases), acts as a rheostat that modulates the mTORC1 Akt and MAPK signals, and integrates beta-cell function and mass with insulin signaling, thus providing a molecular mechanism for cancer initiation in diabetes. Delineating this regulatory pathway may have the potential of contributing to optimizing the efficacy and selectivity of future therapies for cancer and diabetes. PMID- 23639844 TI - Complement C3f serum levels may predict breast cancer risk in women with gross cystic disease of the breast. AB - Gross cystic disease (GCDB) is a breast benign condition predisposing to breast cancer. Cryopreserved sera from GCDB patients, some of whom later developed a cancer (cases), were studied to identify potential risk markers. A MALDI-TOF mass spectrometry analysis found several complement C3f fragments having a significant increased abundance in cases compared to controls. After multivariate analysis, the full-length form of C3f maintained a predictive value of breast cancer risk. Higher levels of C3f in the serum of women affected by a benign condition like GCDB thus appears to be correlated to the development of breast cancer even 20 years later. BIOLOGICAL SIGNIFICANCE: Increased complement system activation has been found in the sera of women affected by GCDB who developed a breast cancer, even twenty or more years later. C3f may predict an increased breast cancer risk in the healthy population and in women affected by predisposing conditions. PMID- 23639843 TI - Differential proteomic analysis of abnormal intramyoplasmic aggregates in desminopathy. AB - Desminopathy is a subtype of myofibrillar myopathy caused by desmin mutations and characterized by protein aggregates accumulating in muscle fibers. The aim of this study was to assess the protein composition of these aggregates. Aggregates and intact myofiber sections were obtained from skeletal muscle biopsies of five desminopathy patients by laser microdissection and analyzed by a label-free spectral count-based proteomic approach. We identified 397 proteins with 22 showing significantly higher spectral indices in aggregates (ratio >1.8, p<0.05). Fifteen of these proteins not previously reported as specific aggregate components provide new insights regarding pathomechanisms of desminopathy. Results of proteomic analysis were supported by immunolocalization studies and parallel reaction monitoring. Three mutant desmin variants were detected directly on the protein level as components of the aggregates, suggesting their direct involvement in aggregate-formation and demonstrating for the first time that proteomic analysis can be used for direct identification of a disease-causing mutation in myofibrillar myopathy. Comparison of the proteomic results in desminopathy with our previous analysis of aggregate composition in filaminopathy, another myofibrillar myopathy subtype, allows to determine subtype specific proteomic profile that facilitates identification of the specific disorder. BIOLOGICAL SIGNIFICANCE: Our proteomic analysis provides essential new insights in the composition of pathological protein aggregates in skeletal muscle fibers of desminopathy patients. The results contribute to a better understanding of pathomechanisms in myofibrillar myopathies and provide the basis for hypothesis-driven studies. The detection of specific proteomic profiles in different myofibrillar myopathy subtypes indicates that proteomic analysis may become a useful tool in differential diagnosis of protein aggregate myopathies. PMID- 23639845 TI - The inducers 1,3-diaminopropane and spermidine cause the reprogramming of metabolism in Penicillium chrysogenum, leading to multiple vesicles and penicillin overproduction. AB - In this article we studied the differential protein abundance of Penicillium chrysogenum in response to either 1,3-diaminopropane (1,3-DAP) or spermidine, which behave as inducers of the penicillin production process. Proteins were resolved in 2-DE gels and identified by tandem MS spectrometry. Both inducers produced largely identical changes in the proteome, suggesting that they may be interconverted and act by the same mechanism. The addition of either 1,3-DAP or spermidine led to the overrepresentation of the last enzyme of the penicillin pathway, isopenicillin N acyltransferase (IAT). A modified form of the IAT protein was newly detected in the polyamine-supplemented cultures. Both inducers produced a rearrangement of the proteome resulting in an overrepresentation of enzymes involved in the biosynthesis of valine and other precursors (e.g. coenzyme A) of penicillin. Interestingly, two enzymes of the homogentisate pathway involved in the degradation of phenylacetic acid (a well-known precursor of benzylpenicillin) were reduced following the addition of either of these two inducers, allowing an increase of the phenylacetic acid availability. Both inducers produced also an increase in the intracellular content of vesicles that derived to vacuoles in late stages and promoted sporulation of P. chrysogenum in solid medium. BIOLOGICAL SIGNIFICANCE: The analysis of global protein changes produced in response to polyamines 1,3-DAP and spermidine provides a valuable information for the understanding of the molecular mechanisms underlying the production of penicillin. This represents useful information to improve the production of this antibiotic and many other bioactive secondary metabolites not only in P. chrysogenum, but in other filamentous fungi as well. PMID- 23639846 TI - A peptidomic approach to biomarker discovery for bovine mastitis. AB - Bovine mastitis is usually caused by either Gram positive or Gram negative bacteria, reducing the quantity and quality of milk produced. This investigation using capillary electrophoresis and mass spectroscopy, studied peptides in milk from cows with clinical mastitis in comparison to milk from healthy cows to identify biomarkers for mastitis. In addition, the milk peptidome from udders infected with Gram positive Staphylococcus aureus (S. aureus) or with Gram negative Escherichia coli (E. coli), was examined to assess differential diagnosis between the causative agent. Comparison of the peptidome between healthy (n=10) and mastitic milk (n=27) identified 154 peptides for a biomarker panel which in a model for diagnosis of mastitis showed 100% sensitivity and specificity. beta-casein and alpha(s1) casein provided the majority of peptides identified in this model. The peptidome comparison of milk from mastitis cases caused by S. aureus (n=8) or E. coli (n=11) revealed a biomarker panel of 47 peptides which discriminated between cause of infection with a sensitivity of 75% and a specificity of 100%. beta-casein fragments were the most common of the peptides in this model. Peptide biomarkers of milk could be used in the diagnosis of mastitis and can discriminate between these two bacterial causes. BIOLOGICAL SIGNIFICANCE: The paper describes an innovative approach to the use of gel free proteomics to identify the peptides that are present in milk during clinical mastitis, which is a major cause of loss of production to dairy farmers worldwide. The use of capillary electrophoresis, liquid chromatography and mass spectrometry has been able to identify panels of peptides which can be used for disease diagnosis and for differential diagnosis of the causative bacteria of the infections of the mammary gland. As well as contributing to our knowledge of the pathophysiology of bovine mastitis the results could be the basis of improved detection and differential diagnosis of the disease. PMID- 23639847 TI - Men who have sex with men, infectious syphilis and HIV coinfection in inner Sydney: results of enhanced surveillance. AB - Background The resurgence of infectious syphilis in men who have sex with men (MSM) has been documented worldwide; however, HIV coinfection and syphilis reinfections in MSM in inner Sydney have not been published. METHODS: For all laboratory syphilis notifications assessed as a newly notified case or reinfection, a questionnaire was sent to the requesting physician seeking demographic data and disease classification. Sex of partner and HIV status were collected for all infectious syphilis notifications in men received from 1 April 2006 to March 2011. RESULTS: From April 2001 to March 2011, 3664 new notifications were received, 2278 (62%) were classified as infectious syphilis. Infectious syphilis notifications increased 12-fold from 25 to 303 in the first and last year respectively, and almost all notifications were in men (2220, 97.5%). During April 2006 to March 2011, 1562 infectious syphilis notifications in males were received and 765 (49%) of these men were HIV-positive and 1351 (86%) reported a male sex partner. Reinfections increased over time from 17 (9%) to 56 (19%) in the last year of the study and were significantly more likely to be in HIV-positive individuals (chi(2)=140.92, degrees of freedom= 1, P=<0.001). CONCLUSION: Inner Sydney is experiencing an epidemic of infectious syphilis in MSM and about half of these cases are in HIV-positive patients. Reinfections are increasing and occur predominantly in HIV-positive men. Accurate surveillance information is needed to inform effective prevention programs, and community and clinician education needs to continue until a sustained reduction is achieved. PMID- 23639848 TI - Assessing the psychometric properties of smoking-related attitudes, self efficacy, and intention among a diverse population of middle school students. AB - Large-scale surveys frequently assess smoking-related attitudes, self-efficacy and intention to understand differences in smoking behavior. However, a critical assumption is that measures of these determinants should be equivalent across different subgroups of a target population. The current study examined the factorial invariance of measures of smoking-related attitudes, self-efficacy, and intention with a large sample (N=13,733) of middle school students from 25 schools in Texas. We examined five levels of factorial invariance using a sequential process, in which increasingly constrained models assess the equivalence of a measure across subgroups. Strong factorial invariance provided a good fit for the model across all of the subgroups: race/ethnicity (CFI=.93), gender (CFI=.96), age (CFI=.95), and grade level (CFI=.95). Invariance results provide strong empirical support for the validity of smoking-related attitudes, self-efficacy, and intention measures across race/ethnicity, gender, age, and grade level for middle school students. PMID- 23639849 TI - Smoking and social anxiety: the roles of gender and smoking motives. AB - Although social anxiety appears to be a risk factor for smoking and nicotine dependence, little work has identified factors that may play a role in these relationships. The current study examined the role of gender and smoking motives in these relationships among 945 (73.0% female) undergraduates, 91 of whom were current daily smokers. Among women, social anxiety was related to daily smoking status, whereas it was related to dependence severity among men. After controlling for past-week smoking frequency, social anxiety was related to affiliative attachment and behavioral choice-melioration smoking motives. Both motives mediated the relationship between social anxiety and nicotine dependence severity, although affiliative attachment motives uniquely mediated this relationship. Results suggest that socially anxious individuals who view cigarettes as having some of the same characteristics as social interactions may be particularly vulnerable to more severe nicotine dependence. Results also highlight the importance of considering gender in the relationships between social anxiety and smoking behaviors. PMID- 23639850 TI - Substance use in young persons in Ireland, a systematic review. AB - Adolescence is a time of physical and mental development when small changes can impact on the rest of a person's life. Substance use in this crucial period can have long-lasting consequences for the individual and for society. The prevalence of substance use in young people is an area of concern for policy makers and health workers. This systematic review looked at prevalence for four substances: alcohol, tobacco, cannabis, and benzodiazepines, across the Republic of Ireland for persons between the ages of 13 and 24, and compared usage between 2000 and 2012. Eighteen articles were included in the review. It was seen that tobacco, alcohol, and cannabis use has fallen in the lifetime and previous month use. The level of benzodiazepine use has remained similar in the period of study. Future work should redress the imbalance in substance use research that sees the majority of researchers looking at a few substances while little work is done on the others. PMID- 23639851 TI - Immediate and six-month effects of Project EX Russia: a smoking cessation intervention pilot program. AB - This study evaluates the performance of the Project EX tobacco use cessation program in Russian summer recreational camps. An eight-session clinic-based tobacco use cessation program for adolescents was tested during the summer of 2011 in an experimental pilot trial that involved different youth that rotated through camps. Conditions were nested within camps. Two rotations of unique subject groups of smokers (program and standard care control) through each of five camps provided the means of controlling for campsite by condition. Assignment of condition by rotation was random (by a flip of a coin), achieving reasonable baseline comparability (total n=164 smokers at baseline, 76 program group, 88 standard care control group). Evaluation involved an immediate pretest and posttest and a six-month telephone follow-up. At immediate posttest, Project EX was moderately well-received, significantly reduced future smoking expectation (46% reduction in EX program condition versus 8% in control, p<.0001), decreased intention to not quit smoking (-5.2% in EX versus +1.4% in control, p<.05), and increased motivation to quit smoking (0.72 versus -0.04, p<.0001). At the six month follow-up, program subjects reported a higher intent-to-treat quit rate during the last 30days (7.5% versus 0.1%, p<.05). For the subjects who remained monthly smokers at the six-month follow-up, Project EX reduced subjects' level of nicotine dependence (-0.53 versus +0.15, p<.001). The results were quite promising for this program, which included motivation enhancement, coping skill, and alternative medicine material. However, further research on teen tobacco use cessation programming in Russia with larger sample sizes, involving other locations of the country, and with stronger research designs is needed. PMID- 23639852 TI - Imaging spin filter for electrons based on specular reflection from iridium (001). AB - As Stern-Gerlach type spin filters do not work with electrons, spin analysis of electron beams is accomplished by spin-dependent scattering processes based on spin-orbit or exchange interaction. Existing polarimeters are single-channel devices characterized by an inherently low figure of merit (FoM) of typically 10 4-10-3. This single-channel approach is not compatible with parallel imaging microscopes and also not with modern electron spectrometers that acquire a certain energy and angular interval simultaneously. We present a novel type of polarimeter that can transport a full image by making use of k-parallel conservation in low-energy electron diffraction. We studied specular reflection from Ir (001) because this spin-filter crystal provides a high analyzing power combined with a "lifetime" in UHV of a full day. One good working point is centered at 39 eV scattering energy with a broad maximum of 5 eV usable width. A second one at about 10 eV shows a narrower profile but much higher FoM. A relativistic layer-KKR SPLEED calculation shows good agreement with measurements. PMID- 23639853 TI - Geographic distribution and taxonomic circumscription of populations within Coryphantha section Robustispina (Cactaceae). AB - PREMISE OF STUDY: Taxonomic circumscription of subspecific taxa within Coryphantha robustispina was evaluated with morphological data and microsatellites. This study was the first to compare adequately sampled morphological and DNA analyses at the population level in the Cactaceae. This comparison was important to test reliability of both methods and to gain a better understanding of phytogeography, evolution, and systematics of the species, knowledge that could prove useful for other taxa as well. Populations of C. robustispina subsp. robustispina are listed as endangered by the U. S. Fish and Wildlife Service. Our primary goal was to explore correlations among geographical distribution, morphology, and genetics of selected populations throughout the range of the species and the outgroup, C. poselgeriana. * METHODS: Stem characters were measured for 638 individuals among 16 populations. Flower characters were measured for 180 individuals among 12 populations. Ten microsatellite DNA loci were isolated and characterized for 204 individuals among 13 populations. Data were analyzed using various multivariate analyses. * RESULTS: Our results indicated that, within Coryphantha robustispina, there were three morphologically, genetically, and geographically coherent groups represented by the names C. robustispina subsp. robustispina, C. robustispina subsp. uncinata, and C. robustispina subsp. scheeri. For most analyses, distinctions among the three groups were primarily not as great as those between any one of them and the outgroup. * CONCLUSIONS: Results suggested that the three subspecific taxa within Coryphantha robustispina are good subspecies but should not be elevated to species rank. The closely aligned results between morphology and microsatellite data support the design and utility of both methods. PMID- 23639854 TI - Approaches for improving continuity of care in medication management: a systematic review. AB - PURPOSE: Medication-related problems frequently occur during transitions and lead to patient harm, increased use of healthcare resources and increased costs. The objective of this systematic review is to synthesize the impact of approaches to optimize the continuity of care in medication management upon hospital admission and/or discharge. DATA SOURCES: MEDLINE, EMBASE, CINAHL, IPA and the Cochrane Database of Systematic Reviews from 1995 through December 2010. STUDY SELECTION: Controlled, parallel-group trials. Data extraction Data were extracted by one researcher and checked by another. Both reviewers independently assessed the study quality. RESULTS: Thirty studies met the inclusion criteria, but only 14 reached the predefined minimum quality score. Most studies focused on discharge and targeted the patients, sometimes together with primary care providers. The majority of studies found improvements in process measures. Patient education and counseling provided upon discharge and reinforced after discharge, sometimes together with improved communication with healthcare professionals, was shown to reduce the risk of adverse drug events and hospital re-admissions in some studies, but not all. Heterogeneity in study population as well as in intervention and outcome reporting precluded meta-analysis and limited interpretation. Most studies had important methodological limitations and were underpowered to show significant benefits on clinical outcomes. CONCLUSIONS: The evidence for an impact of approaches on optimization of continuity of care in medication management remains limited. Further research should better target high risk populations, use multicentered designs and have adequate sample size to evaluate the impact on process measures, clinical outcomes and cost effectiveness. PMID- 23639855 TI - Left ventricular function improvement after prophylactic implantable cardioverter defibrillator implantation in patients with non-ischaemic dilated cardiomyopathy. AB - AIMS: To assess the incidence and prognostic significance of left ventricular (LV) function improvement in patients with non-ischaemic dilated cardiomyopathy (DCM) and prophylactic implantable cardioverter-defibrillator (ICD). METHODS AND RESULTS: A total of 123 patients with DCM and echocardiographic follow-up assessments within 1 year after prophylactic ICD implant were retrospectively studied at our institution. All patients had New York Heart Association class II or III symptoms in the presence of a LV ejection fraction of 23 +/- 6% (range: 9 35%) despite optimized medical therapy for at least 3 months prior to ICD implant. Left ventricular function improvement was defined as an increase of LV ejection fraction of more than 5% to more than 35% combined with a decrease LV end-diastolic diameter of at least 5 mm. Left ventricular function improvement after prophylactic ICD implant was found in 30 of 123 patients (24%). Multivariate logistic regression revealed recent onset DCM with symptoms <=9 months as the only significant predictor of LV function improvement [odds ratio: 6.89; 95% confidence interval (CI): 2.43-21.99, P = 0.0002]. During 74 months mean follow-up, total mortality was higher in patients without vs. with LV function improvement [hazard ratio (HR): 3.75; 95% CI: 1.14-12.31, P = 0.0034], while the incidence of appropriate ICD therapies was similar in both groups in the early phase after prophylactic ICD implant (HR: 1.15; 95% CI: 0.57-2.33, P = 0.70). The incidence of appropriate ICD therapies decreased to ~1% per year after LV function improvement had occurred. CONCLUSION: Recently diagnosed DCM predicts LV function improvement after prophylactic ICD implant. Overall survival was significantly better in patients with vs. without LV function improvement, while appropriate ICD therapy rates were similar in both groups in the early phase after prophylactic ICD implantation before LV function improvement occurred. PMID- 23639856 TI - Non-invasive electrophysiological imaging of acute rejection in a transplanted heart. PMID- 23639857 TI - Multi-omic data integration links deleted in breast cancer 1 (DBC1) degradation to chromatin remodeling in inflammatory response. AB - This study investigated the dynamics of ubiquitinated proteins after the inflammatory stimulation of RAW 264.7 macrophage-like cells with bacterial lipopolysaccharide. Ubiquitination is a common protein post-translational modification that regulates many key cellular functions. We demonstrated that levels of global ubiquitination and K48 and K63 polyubiquitin chains change after lipopolysaccharide stimulation. Quantitative proteomic analysis identified 1199 ubiquitinated proteins, 78 of which exhibited significant changes in ubiquitination levels following stimulation. Integrating the ubiquitinome data with global proteomic and transcriptomic results allowed us to identify a subset of 88 proteins that were targeted for degradation after lipopolysaccharide stimulation. Using cellular assays and Western blot analyses, we biochemically validated DBC1 (a histone deacetylase inhibitor) as a degradation substrate that is targeted via an orchestrated mechanism utilizing caspases and the proteasome. The degradation of DBC1 releases histone deacetylase activity, linking lipopolysaccharide activation to chromatin remodeling in caspase- and proteasome mediated signaling. PMID- 23639858 TI - Paraoxonase1 (PON1) reduces insulin resistance in mice fed a high-fat diet, and promotes GLUT4 overexpression in myocytes, via the IRS-1/Akt pathway. AB - OBJECTIVE: To analyze Paraoxonase1 (PON1) impact on GLUT4 expression, glucose metabolism, and the insulin signaling pathway in skeletal muscle cells. METHODS AND RESULTS: We analyzed the effect of PON1 in high-fat-diet-induced insulin resistance in C57BL/6J and in PON1KO mice. Mice were fed normal diet (ND) or high Fat Diet (HFD) for 8 weeks. PON1 deficiency caused enhanced insulin resistance in both ND and HFD mice. PON1 deficiency was associated with increased oxidative stress (OS), increased p38MAPK activity and attenuated insulin-mediated tyrosine phosphorylation of muscle insulin receptor substrate-1 (IRS-1), with a corresponding increase in serine phosphorylation. These effects resulted in decreased glucose uptake in whole-body level, as reflected by glucose tolerance test (GTT), by insulin tolerance test (ITT) and by cellular glycogen accumulation in the liver and in the muscles. PON1 addition to cultured C2 muscle cells enhanced GLUT4 mRNA expression, in a time and concentration dependent manner, increased GLUT4 protein and cellular glycogen accumulation. These effects were mediated via inhibition of p38MAPK activity, resulting in reduced IRS-1 serine phosphorylation and in enhanced IRS-1 tyrosine phosphorylation. The ability of PON1 to increase myocytes GLUT4 expression was partially inhibited upon blocking PON1 SH group, and completely abolished upon PON1 mutation in HIS115 of its catalytic site. CONCLUSION: PON1 plays a beneficial role in glucose regulation and metabolism and may serve as an important tool in diabetes control. PMID- 23639859 TI - Serum carboxy-terminal telopeptide of type I collagen (ICTP) as a surrogate marker for vulnerable plaques in atherosclerotic patients: a pilot study. AB - Evaluation of atherosclerotic plaques depends on invasive intravascular ultrasonography (IVUS). Carboxy-terminal telopeptide of type I collagen (ICTP) is produced by matrix metalloproteinase (MMP)-dependent digestion of type I collagen. Because vulnerable plaques are rich in type I collagen and MMPs from macrophages, we examined the association between serum ICTP and coronary plaques in patients with coronary disease. We recruited 46 men and 17 women without renal failure or bone diseases affecting serum ICTP, who underwent coronary IVUS. Serum ICTP levels were higher in patients with coronary plaques containing more than 10% necrotic core area than in patients with less than 10% necrotic core area. A positive correlation was found between serum ICTP and necrotic core area. Only serum ICTP was positively correlated with necrotic core area by multivariate analysis (p < 0.05). These results suggest that serum ICTP can be used as a non invasive marker of vulnerable plaques in atherosclerotic patients. PMID- 23639860 TI - Not significant but important. AB - Armstrong and colleagues report the result of a large Phase IIb randomized trial evaluating the effectiveness of a preparation of the Bowman Birk Inhibitor compared with an oral placebo in reversing the extent of oral leukoplakia as measured visually by pathology or a battery of intermediate end points. In this editorial, we review the report of this negative clinical trials result to highlight the clinical trial process used in evaluating this previously promising chemoprevention agent. Publishing this report is important to address concerns with publication bias. The challenges in running a chemoprevention trial are reviewed with suggestions to enhance progress going forward. Conceptually, developing drugs to intercept the early stages of carcinogenesis is very attractive, but progress in this area has been slow. Two opportunities to overcome this reality are discussed. These measures include the broader use of neoadjuvant, window-of-opportunity trials with new candidate chemoprevention agents to get more textured information about the mechanistic impact of the drug exposure in previously untreated early tumor tissue. In addition, we discuss the use of new intermediate end point markers such as with optical imaging tools to obtain a more objective and quantitative assessment of drug response. PMID- 23639861 TI - Optimizing biomarkers and endpoints in oral cancer chemoprevention trials. AB - Chemoprevention, defined as the use of natural, synthetic, or biologic compounds to halt, reverse, or prevent the initial phases of carcinogenesis or the progression of neoplastic cells to cancer, has produced successes, but progress has been slow. Notably, in the field of oral cancer prevention and despite extensive clinical investigations, a standard systemic therapy for patients with oral premalignant lesions is yet to be developed. In view of safety concerns surrounding the use of pharmaceuticals, the use of phytochemicals derived from the diet has been considered but has not yet translated into clinical success. The Bowman Birk Inhibitor (BBI) is a serine protease inhibitor isolated from soybeans possessing domains with trypsin and chymotrypsin inhibitory activity. Encouraging results were previously reported in a phase IIa trial of BBI complex in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. In this issue of the journal, the less promising results of the randomized, placebo-controlled phase IIb trial are presented. In this commentary, the complexities involved in defining optimal biomarkers and endpoints for oral cancer prevention trials and the development of dietary chemoprevention agents are discussed. PMID- 23639863 TI - In vitro power profiles of daily disposable contact lenses. AB - PURPOSE: To evaluate and compare the distribution of refractive power within the optic zone of different soft contact lenses and to investigate the effect of lens decentration on the power profiles. METHODS: The Nimo TR1504 instrument was used to measure the optical power across different aperture diameters (from 1.5mm to 5.5mm in steps of 0.5mm) of four daily disposable contact lenses: DAILIES TOTAL1, Proclear 1-Day, SofLens daily disposable and 1-DAY ACUVUE MOIST. Measurements were performed using a wet cell. Power data were evaluated when contact lenses were in its centered position and after inducing different amounts of lens decentration (from 0.2mm to 1.0mm in steps of 0.2mm). RESULTS: All contact lenses showed an increase - more negative - in lens power with distance from the lens center. The amount of change varied depending on the lens. It was about 10% of lens power for DAILIES TOTAL1 (-0.29diopters (D)), SofLens daily disposable ( 0.36D), and Proclear 1-Day (-0.32D) whereas 1-DAY ACUVUE MOIST showed a percentage variation of 3.3% (-0.10D). After inducing a lens decentration up to 1mm, the power curves were shifted in the negative direction. However, the change obtained in lens power compared with well-centered position was always lower than a quarter of diopter both for all the lenses and aperture diameters. CONCLUSIONS: Our results showed a variation of the refractive power from the lens center, becoming more negative toward the periphery, with a negligible effect of the decentration for all disposable contact lenses studied. PMID- 23639862 TI - Bowman birk inhibitor concentrate and oral leukoplakia: a randomized phase IIb trial. AB - Oral premalignancy serves as an ideal model for study of chemopreventive agents. Although 13-cis-retinoic acid showed reversal of oral premalignancy, toxicity, and reversal of clinical response after cessation of therapy obviated its widespread use. A search for nontoxic agents with cancer preventive activity led us to evaluate Bowman Birk Inhibitor (BBI) formulated as BBI Concentrate (BBIC). We previously reported encouraging results in a phase IIa trial of BBIC in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. On the basis of these results, we undertook a randomized, placebo controlled phase IIb trial with patients receiving BBIC or placebo for 6 months, with assessment of clinical response and change in lesion area as primary end point and an intent-to-treat analysis. One hundred and thirty two subjects were randomized; and 89 subjects completed six months on study drug or placebo. Both placebo and BBIC showed a statistically significant decrease in mean lesion area of 17.1% and 20.6%, respectively, and partial or greater clinical responses of 30% and 28% respectively. No significant difference between placebo and study drug arms was observed. Histologic review, review of photographs of lesions, and comparison of serum neu protein and oral mucosal cell protease activity also did not show significant differences between study arms. Probable reasons for these negative results were considered, are discussed, and include a placebo with non BBIC clinical activity and reduced pharmacokinetic availability of the second batch of BBIC. This experience should be a strong cautionary note to those considering "Green" chemoprevention. PMID- 23639864 TI - Otosclerosis and vitamin D receptor gene polymorphism. AB - OBJECTIVE: The possible genetic relationship between otosclerosis and Vitamin D Receptor (VDR) gene polymorphism is uncertain. The aim of this study is to assess association between otosclerosis and VDR gene polymorphisms. STUDY DESIGN: Case control Studies. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Clinical diagnosis of stapes fixation was based on otoscopic, audiometric, tympanometric and surgical findings. We identified 25 eligible patient and 60 controls to investigate the association of the VDR gene polymorphisms FokI, BsmI, ApaI, and Taq I with otosclerosis. The patient and control DNA was genotyped for; VDR Bsm I (rs1544410), VDR Apa I (rs7975232), VDR Taq I (rs731236) and VDR Fok I (rs2228570) gene. Primer, simple probe sequences was genotyped by RT-PCR restriction fragment length polymorphism. RESULTS: There was a statistically significant association between VDR gene and otosclerosis in polymorphism Taq I, Apa I and Bsm I. There was no significant association between VDR gene and otosclerosis in polymorphism Foq I. CONCLUSION: Three polymorphisms (Taq I, Apa I and Bsm I) in the VDR gene appear to be associated to susceptibility to otosclerosis disorder with otosclerosis patients. PMID- 23639865 TI - Bulk deposition close to a Municipal Solid Waste incinerator: one source among many. AB - In order to assess the contribution of a Municipal Solid Waste incinerator to the area's total contamination, metals and soluble ions have been determined in bulk deposition collected at sites affected by different levels of plant emissions, according to the results of the Calpuff air dispersion model. Results show that in general fluxes monitored at the different sites during the same period are quite similar for each analyte. Deposition fluxes of nitrite and ammonium are significantly lower at the more distant site, while copper is significantly higher at this site, possibly because of copper fungicide used on the nearby agriculture land. The presence of sea spray and resuspended soil dust can be inferred from Pearson correlation coefficients, while enrichment factors indicate that Cu, Pb and Zn have a probable anthropogenic origin. A more complete evaluation of the sources affecting the area was obtained with PMF analysis. The sources associated with each factor were identified from the source profile and temporal trends. Six factors were identified, three sources associate with natural matrices, while three factors represent anthropogenic sources. The greatest contribution of heavy metals, the most toxic and persistent components determined, is associated with resuspended soil dust, especially when weighted according to their toxicity. The anthropogenic source contribution is similar at all sites, and therefore the incinerator's relative contribution to the total pollutant load appears to be negligible compared to other sources affecting the area. PMID- 23639866 TI - A new approach to characterization of the resistance of populations of Rhipicephalus microplus (Acari: Ixodidae) to organophosphate and pyrethroid in the state of Minas Gerais, Brazil. AB - The monitoring of resistance of cattle tick populations in Brazil to the chemical bases in use is largely limited to investigation of the phenotypic profile. There are few studies investigating the role played by the genotypic profile in acaricide resistance in the country. Therefore, the aim of the present study was to carry out molecular characterization and trace out the genetic profile of populations of Rhipicephalus microplus with respect to resistance to the organophosphate and pyrethroid chemical groups. For that purpose, larvae were genotyped belonging to 587 populations for pyrethroids and 306 for organophosphates, using the polymerase chain reaction technique. It was found that 75.49% and 97.44% of the larvae studied showed resistance to the organophosphates and pyrethroids, respectively. Among the populations resistant to pyrethroids, 91.9% were heterozygotes, showing that most of the resistant populations have only one allele responsible for resistance. Therefore, it is possible to conclude that the genotyped populations have high resistance to organophosphates, and even more so to pyrethroids. This information is fundamental for understanding the mechanisms of resistance of R. microplus to acaricides, to enable improvement of control techniques. PMID- 23639867 TI - Direct methods for detection of protein S-nitrosylation. AB - S-nitrosylation of protein cysteine residues is known to be an important mechanism for nitric oxide signaling. However, the detection of protein S nitrosylation is still challenging due to technical limitations of current methods. This chapter provides a brief review on recent developments of methods, which directly target S-nitroso moieties for detection. We also describe in detail the protocol of an organophosphine-based biotin labeling of protein S nitroso moieties. PMID- 23639868 TI - Virus-like particle formulation optimization by miniaturized high-throughput screening. AB - Virus-like particles (VLPs) are non-infectious and immunogenic virus-mimicking protein assemblies that are increasingly researched as vaccine candidates. Stability against aggregation is an important determinant dictating the viability of a pipeline VLP product, making multivariable stability data highly desirable especially in early product development stages. However, comprehensive formulation studies are challenging due to low sample availability early in developability assessment. This issue is exacerbated by industry-standard analytical techniques which are low-throughput and/or sample-consuming. This study presents a miniaturized high-throughput screening (MHTS) methodology for VLP formulation by integrating dynamic light scattering (DLS) and asymmetrical flow field-flow fractionation (AF4) in a formulation funnel analysis. Using only 2 MUg of sample and 100 s per measurement, a DLS plate reader was deployed to effectively pre-screen a large experimental space, allowing a smaller set of superior formulation conditions to be interrogated at high-resolution with AF4. The stabilizing effects of polysorbate 20, sucrose, trehalose, mannitol and sorbitol were investigated. MHTS data showed that addition of 0.5% w/v polysorbate 20 together with either 40% w/v sucrose or 40% w/v sorbitol could stabilize VLPs at elevated temperatures up to 58 degrees C. AF4 data further confirmed that the formulation containing 40% w/v sorbitol and 0.5% w/v polysorbate 20 effectively protected VLPs during freeze-thawing and freeze drying, increasing recoveries from these processes by 80 and 50 percentage points, respectively. The MHTS strategy presented here could be used to rapidly explore a large formulation development space using reduced amounts of sample, without sacrificing the analytical resolution needed for quality control. Such a method paves the way for rapid formulation development and could potentially hasten the commercialization of new VLP vaccines. PMID- 23639869 TI - Method for quantitative measurements of the elastic modulus of biological cells in AFM indentation experiments. AB - Here we overview and further develop a quantitative method to measure mechanics of biological cells in indentation experiments, which is based on the use of atomic force microscopy (AFM). We demonstrate how the elastic modulus of the cell body should be measured when the cellular brush is taken into account. The brush is an essential inelastic part of the cell, which surrounds all eukaryotic (the brush is mostly microvilli and glycocalyx) and gram-negative prokaryotic cells (the brush is polysaccharides). The other main feature of the described method is the use of a relatively dull AFM probe to stay in the linear stress-strain regime. In particular, we show that the elastic modulus (aka the Young's modulus) of cells is independent of the indentation depth up to 10-20% deformation for the eukaryotic cells studied here. Besides the elastic modulus, the method presented allows obtaining the parameters of cellular brush, such as the effective length and grafting density of the brush. Although the method is demonstrated on eukaryotic cells, it is directly applicable for all types of cells, and even non biological soft materials surrounded by either a brush or any field of long-range forces. PMID- 23639871 TI - Seizures and antiepileptic drugs in patients with spontaneous intracerebral hemorrhages. AB - PURPOSE: Patients with intracerebral hemorrhage (ICH) are often initiated on antiepileptic drugs without a clear indication. We compared the percentage of patients with spontaneous ICH who had seizures at onset or during hospitalization, and examined empiric use of antiepileptic drugs (AEDs) in these patients in 2 cohorts 10 years apart. METHODS: Using a clinical data registry at a tertiary care adult hospital, we retrospectively selected admissions for spontaneous ICH between 1/1/99-12/31/00 (Cohort A, n=30) and 1/1/09-12/31/10 (Cohort B, n=108). Clinical, neurophysiological and radiological data were collected in both cohorts. RESULTS: In Cohorts A and B respectively, AEDs were started in 53.3% and 50.0%, and continued on discharge in 50.0% and 20.4% of patients; 86.6% and 59.1% of patients discharged on AEDs did not have a clinical/electrographic seizure or epileptiform EEG findings. Seizures occurred in 6.6% and 13.0% in Cohorts A and B respectively. The presence of a seizure at presentation (p=0.01) and during hospitalization (p=0.02) were predictors for continuing AED on discharge. CONCLUSION: In both cohorts, a significant number of patients were discharged on AEDs without a clear indication, though there is a change in practice between the two cohorts. PMID- 23639872 TI - Microbial genetic diversity and ciliate community structure along an environmental gradient in coastal soil. AB - We investigated the microbial genetic diversity and ciliate community in coastal soil from five sites with an environmental gradient using denaturing gradient gel electrophoresis (DGGE), gene sequencing and the Ludox-QPS method. The analyses of both the 16S ribosomal RNA (rRNA) gene and 18S rRNA gene DGGE resulted in equal or even a higher number of bands found in the samples taken from the high salinity sites IV and V than in those taken from the low-to-moderate-salinity sites I-III. Cluster analysis of both DGGE profiles classified the five sites into three main groups (sites I, II and III and IV and V), which corresponded well to the analysis of environmental factors. There were 13 species observed at site I, three species at site II and nine species at site III, while no active ciliates were observed at the high-salinity sites IV and V. By contrast, the ciliate-specific DGGE revealed a higher number of bands in the samples taken from the high-salinity soil. Furthermore, gene sequencing suggested that the ciliates in the high-salinity soil comprised forms originating not only from soil but also from marine environments. The data indicate that saline soil may maintain a high diversity of ciliates and soil salinity might be the most influential factor regulating the community structure of ciliates. PMID- 23639870 TI - Levetiracetam but not valproate inhibits function of CD8+ T lymphocytes. AB - PURPOSE: To further elucidate possible immune-modulatory effects of valproate (VPA) or levetiracetam (LEV), we investigated their influence on apoptosis and cytotoxic function of CD8+ T lymphocytes in humans. METHODS: In 15 healthy subjects (9 female (60%), 35.7+/-12.1 years), apoptosis and cytotoxic function of CD8+ T lymphocytes were measured using flow cytometry following in vitro exposure to LEV (5 mg/L and 50 mg/L) and VPA (10mg/L and 100 mg/L). Apoptosis rates were determined after incubation with LEV or VPA for 1 h or 24 h. Cytotoxic function was assessed following 2h stimulation with mixed virus peptides, using perforin release, CD107a/b expression and proliferation. The presence of synaptic vesicle protein 2A (SV2A) was investigated in human CD8+ T lymphocytes by flow cytometry analysis, Western blot and real time polymerase chain reaction (rtPCR). RESULTS: High concentration of LEV decreased perforin release of CD8+ T lymphocytes (LEV 50 mg/L vs. CEF only: 21.4% (interquartile range (IQR) 16.5-35.9%) vs. 16.6% (IQR 12-24.9%), p=0.002). LEV had no influence on apoptosis and proliferation (p>0.05). VPA (100 mg/L) slowed apoptosis of CD8() T lymphocytes after 24h (VPA 100mg/L vs. control: 7.3% (IQR 5.4-9.5%) vs. 11.3% (IQR 8.2-15.1%), p<0.001), but had no effects on perforin release (p>0.05). SV2A protein was detected in CD8+ T lymphocytes. CONCLUSION: LEV decreased degranulation of CD8+ T lymphocytes which may contribute to the increased incidence of upper respiratory tract infections in LEV treated patients. Inhibition of SV2A may be responsible for this effect. PMID- 23639873 TI - O-GlcNAc modification of the coat protein of the potyvirus Plum pox virus enhances viral infection. AB - O-GlcNAcylation is a dynamic protein modification which has been studied mainly in metazoans. We reported previously that an Arabidopsis thaliana O-GlcNAc transferase modifies at least two threonine residues of the Plum pox virus (PPV) capsid protein (CP). Now, six additional residues were shown to be involved in O GlcNAc modification of PPV CP. CP O-GlcNAcylation was abolished in the PPV CP7 T/A mutant, in which seven threonines were mutated. PPV CP7-T/A infected Nicotiana clevelandii, Nicotiana benthamiana, and Prunus persica without noticeable defects. However, defects in infection of A. thaliana were readily apparent. In mixed infections of wild-type arabidopsis, the CP7-T/A mutant was outcompeted by wild-type virus. These results indicate that CP O-GlcNAcylation has a major role in the infection process. O-GlcNAc modification may have a role in virion assembly and/or stability as the CP of PPV CP7-T/A was more sensitive to protease digestion than that of the wild-type virus. PMID- 23639874 TI - Novel pharmacotherapies of familial hyperlipidemia. AB - Familial hyperlipidemia is an inherited metabolic disorder characterized by elevated lipid and/or lipoprotein levels in the blood. Despite improvements in lipid-lowering therapy during the last decades, it still remains a substantial contributor to the incidence of cardiovascular disease since patients on current conventional therapies do not achieve their target LDL-cholesterol levels. With a view to lower LDL-cholesterol levels, a number of new therapeutic strategies have been developed over recent years. In this review, we provide an overview of these treatment options that are currently in clinical development and may offer alternative or adjunctive therapies for this high-risk population. PMID- 23639877 TI - Evidences that maternal swimming exercise improves antioxidant defenses and induces mitochondrial biogenesis in the brain of young Wistar rats. AB - Physical exercise during pregnancy has been considered beneficial to mother and child. Recent studies showed that maternal swimming improves memory in the offspring, increases hippocampal neurogenesis and levels of neurotrophic factors. The objective of this work was to investigate the effect of maternal swimming during pregnancy on redox status and mitochondrial parameters in brain structures from the offspring. Adult female Wistar rats were submitted to five swimming sessions (30 min/day) prior to mating with adult male Wistar rats, and then trained during the pregnancy (five sessions of 30-min swimming/week). The litter was sacrificed when 7 days old, when cerebellum, parietal cortex, hippocampus, and striatum were dissected. We evaluated the production of reactive species and antioxidant status, measuring the activities of superoxide-dismutase (SOD), catalase (CAT) and glutathione-peroxidase (GPx), as well as non-enzymatic antioxidants. We also investigated a potential mitochondrial biogenesis regarding mitochondrion mass and membrane potential, through cytometric approaches. Our results showed that maternal swimming exercise promoted an increase in reactive species levels in cerebellum, parietal cortex, and hippocampus, demonstrated by an increase in dichlorofluorescein oxidation. Mitochondrial superoxide was reduced in cerebellum and parietal cortex, while nitrite levels were increased in cerebellum, parietal cortex, hippocampus, and striatum. Antioxidant status was improved in cerebellum, parietal cortex, and hippocampus. SOD activity was increased in parietal cortex, and was not altered in the remaining brain structures. CAT and GPx activities, as well as non-enzymatic antioxidant potential, were increased in cerebellum, parietal cortex, and hippocampus of rats whose mothers were exercised. Finally, we observed an increased mitochondrial mass and membrane potential, suggesting mitochondriogenesis, in cerebellum and parietal cortex of pups subjected to maternal swimming. In conclusion, maternal swimming exercise induced neurometabolic programing in the offspring that could be of benefit to the rats against future cerebral insults. PMID- 23639878 TI - Repeated restraint stress impairs auditory attention and GABAergic synaptic efficacy in the rat auditory cortex. AB - Chronic stress induces dendritic atrophy in the rat primary auditory cortex (A1), a key brain area for auditory attention. The aim of this study was to determine whether repeated restraint stress affects auditory attention and synaptic transmission in A1. Male Sprague-Dawley rats were trained in a two-alternative choice task (2-ACT), a behavioral paradigm to study auditory attention in rats. Trained animals that reached a performance over 80% of correct trials in the 2 ACT were randomly assigned to control and restraint stress experimental groups. To analyze the effects of restraint stress on the auditory attention, trained rats of both groups were subjected to 50 2-ACT trials one day before and one day after of the stress period. A difference score was determined by subtracting the number of correct trials after from those before the stress protocol. Another set of rats was used to study the synaptic transmission in A1. Restraint stress decreased the number of correct trials by 28% compared to the performance of control animals (p < 0.001). Furthermore, stress reduced the frequency of spontaneous inhibitory postsynaptic currents (sIPSC) and miniature IPSC in A1, whereas glutamatergic efficacy was not affected. Our results demonstrate that restraint stress decreased auditory attention and GABAergic synaptic efficacy in A1. PMID- 23639879 TI - Osteopontin inhibits osmotic swelling of retinal glial (Muller) cells by inducing release of VEGF. AB - Osmotic swelling of retinal neurons and glial cells is an important pathogenic factor of retinal edema formation. Here, we show that the neuroprotective factor osteopontin (OPN), which is released from retinal glial (Muller) cells after stimulation of the cells with glial cell line-derived neurotrophic factor (Del Rio et al., 2011, Glia 59:821-832), inhibits the swelling of rat Muller cells induced by hypoosmotic exposure of retinal slices in the presence of barium ions and H2O2, respectively, and in slices of postischemic retinas. OPN did not inhibit the hypoosmotic swelling of bipolar cells in slices of control and postischemic retinas. The inhibitory effect of OPN on Muller cell swelling was dose-dependent, with a half-maximal effect at ~0.6 ng/ml. The effect of OPN was abrogated in the presence of pharmacological blockers of vascular endothelial growth factor (VEGF) receptor-2, metabotropic glutamate receptors, and purinergic receptors (P2Y1, adenosine A1 receptors), as well as of a neutralizing anti-VEGF antibody. The data suggest that OPN induces the release of VEGF, glutamate, ATP, and adenosine from Muller cells. The effect of OPN was also prevented by blockers of voltage-gated sodium channels (tetrodotoxin), T-type voltage-gated calcium channels (kurtoxin), potassium channels (clofilium), and chloride channels 5 nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). The swelling-inhibitory effect of OPN was dependent on intracellular calcium signaling, activation of phospholipase C and protein kinase C, and vesicular exocytosis of glutamate. In retinal slices, Muller glial cells display immunoreactivity of OPN. The data suggest that Muller cell-derived OPN has (in addition to the effects on photoreceptors and retinal neurons) autocrine effects. The neuroprotective effects of OPN may be in part mediated by the prevention of cytotoxic Muller cell swelling and the release of VEGF and adenosine from Muller cells. PMID- 23639880 TI - Cerebellar activity and connectivity during the experience of disgust and happiness. AB - Previous research indicates that distinct subregions of the cerebellum are involved in the processing of different primary emotions. How this is achieved in terms of connectional specificity with other brain areas still needs to be elucidated. We employed functional magnetic resonance imaging in order to investigate cerebellar activation and connectivity relevant for the processing of two basic emotions. Thirty-four healthy women were presented with pictures that specifically elicited happiness and disgust with the instruction to rate the intensity of the experienced feelings. The contrasting of both affective conditions showed that disgust evoked activation of the vermis and the cerebellar hemispheres, whereas happiness-associated activation was restricted to the posterior cerebellum. Both emotions provoked increased connectivity of the cerebellum with limbic regions. The observed extended connectivity patterns can explain why cerebellar lesions are able to produce pronounced changes of affective experience in the afflicted patients. PMID- 23639876 TI - Remodeling sensory cortical maps implants specific behavioral memory. AB - Neural mechanisms underlying the capacity of memory to be rich in sensory detail are largely unknown. A candidate mechanism is learning-induced plasticity that remodels the adult sensory cortex. Here, expansion in the primary auditory cortical (A1) tonotopic map of rats was induced by pairing a 3.66-kHz tone with activation of the nucleus basalis, mimicking the effects of natural associative learning. Remodeling of A1 produced de novo specific behavioral memory, but neither memory nor plasticity was consistently at the frequency of the paired tone, which typically decreased in A1 representation. Rather, there was a specific match between individual subjects' area of expansion and the tone that was strongest in each animal's memory, as determined by post-training frequency generalization gradients. These findings provide the first demonstration of a match between the artificial induction of specific neural representational plasticity and artificial induction of behavioral memory. As such, together with prior and present findings for detection, correlation and mimicry of plasticity with the acquisition of memory, they satisfy a key criterion for neural substrates of memory. This demonstrates that directly remodeling sensory cortical maps is sufficient for the specificity of memory formation. PMID- 23639875 TI - Prostaglandin E2 acts via bone marrow macrophages to block PTH-stimulated osteoblast differentiation in vitro. AB - Intermittent PTH is the major anabolic therapy for osteoporosis while continuous PTH causes bone loss. PTH acts on the osteoblast (OB) lineage to regulate bone resorption and formation. PTH also induces cyclooxygenase-2 (COX-2), producing prostaglandin E2 (PGE(2)) that can act on both OBs and osteoclasts (OCs). Because intermittent PTH is more anabolic in Cox-2 knockout (KO) than wild type (WT) mice, we hypothesized COX-2 might contribute to the effects of continuous PTH by suppressing PTH-stimulated differentiation of mesenchymal stem cells into OBs. We compared effects of continuous PTH on bone marrow stromal cells (BMSCs) and primary OBs (POBs) from Cox-2 KO mice, mice with deletion of PGE(2) receptors (Ptger(4) and Ptger(2) KO mice), and WT controls. PTH increased OB differentiation in BMSCs only in the absence of COX-2 expression or activity. In the absence of COX-2, PTH stimulated differentiation if added during the first week of culture. In Cox-2 KO BMSCs, PTH-stimulated differentiation was prevented by adding PGE(2) to cultures. Co-culture of POBs with M-CSF-expanded bone marrow macrophages (BMMs) showed that the inhibition of PTH-stimulated OB differentiation required not only COX-2 or PGE(2) but also BMMs. Sufficient PGE(2) to mediate the inhibitory effect was made by either WT POBs or WT BMMs. The inhibitory effect mediated by COX-2/PGE(2) was transferred by conditioned media from RANKL-treated BMMs and could be blocked by osteoprotegerin, which interferes with RANKL binding to its receptor on OC lineage cells. Deletion of Ptger(4), but not Ptger(2), in BMMs prevented the inhibition of PTH-stimulated OB differentiation. As expected, PGE(2) also stimulated OB differentiation, but when given in combination with PTH, the stimulatory effects of both were abrogated. These data suggest that PGE(2), acting via EP4R on BMMs committed to the OC lineage, stimulated secretion of a factor or factors that acted to suppress PTH stimulated OB differentiation. This suppression of OB differentiation could contribute to the bone loss seen with continuous PTH in vivo. PMID- 23639881 TI - Vasopressin infusion into the lateral septum of adult male rats rescues progesterone-induced impairment in social recognition. AB - It is well established that social recognition memory is mediated, in part, by arginine vasopressin (AVP). AVP cells within the bed nucleus of the stria terminalis (BST) and medial amygdala (MeA) send AVP-ergic projections to the lateral septum (LS). We have demonstrated that progesterone treatment decreases AVP immunoreactivity within the BST, the MeA and the LS, and that progesterone treatment impairs social recognition. These data suggested that progesterone may impair social recognition memory by decreasing AVP. In the present experiment, we hypothesized that infusions of AVP into the LS would rescue the progesterone induced impairment in social recognition within adult male rats. One week after adult male rats underwent cannula surgery, they were given systemic injections of either a physiological dose of progesterone or oil control for 3 days. Four hours after the last injection, we tested social recognition memory using the social discrimination paradigm, a two-trial test that is based on the natural propensity for rats to be highly motivated to investigate novel conspecifics. Immediately after the first exposure to a juvenile, each animal received bilateral infusions of either AVP or artificial cerebrospinal fluid into the LS. Our results show that, as expected, control animals exhibited normal social discrimination. In corroboration with our previous results, animals given progesterone have impaired social discrimination. Interestingly, animals treated with progesterone and AVP exhibited normal social discrimination, suggesting that AVP treatment rescued the impairment in social recognition caused by progesterone. These data also further support a role for progesterone in modulating vasopressin-dependent behavior within the male brain. PMID- 23639882 TI - The role of galanin system in modulating depression, anxiety, and addiction-like behaviors after chronic restraint stress. AB - There is high comorbidity between stress-related psychiatric disorders and addiction, suggesting they may share one or more common neurobiological mechanisms. Because of its role in both depressive and addictive behaviors, the galanin system is a strong candidate for such a mechanism. In this study, we tested if galanin and its receptors are involved in stress-associated behaviors and drug addiction. Mice were exposed to 21 days of chronic restraint stress (CRS); subsequently, mRNA levels of galanin, galanin receptors (GalRs), the rate limiting enzymes for the synthesis of monoamines, and monoamine autoreceptors were measured in the nucleus accumbens by a quantitative real-time polymerase chain reaction. Moreover, we tested the effects of this stress on morphine induced addictive behaviors. We found that CRS induced anxiety and depression like behaviors, impaired the formation and facilitated the extinction process in morphine-induced conditioned place preference (CPP), and also blocked morphine induced behavioral sensitization. These behavioral results were accompanied by a CRS-dependent increase in the mRNA expression of galanin, GalR1, tyrosine hydroxylase (TH), tryptophan hydroxylase 2, and 5-HT1B receptor. Interestingly, treatment with a commonly used antidepressant, fluoxetine, normalized the CRS induced behavioral changes based on reversing the higher expression of galanin and TH while increasing the expression of GalR2 and alpha2A-adrenceptor. These results indicate that activating the galanin system, with corresponding changes to noradrenergic systems, following chronic stress may modulate stress-associated behaviors and opiate addiction. Our findings suggest that galanin and GalRs are worthy of further exploration as potential therapeutic targets to treat stress related disorders and drug addiction. PMID- 23639884 TI - An evaluation of the observer effect on treatment integrity in a day treatment center for children. AB - Treatment integrity is an important concern in treatment centers but is often overlooked. Performance feedback is a well-established approach to improving treatment integrity, but is underused and undervalued. One way to increase its value to treatment centers may be to expose unrealized benefits on the observer who collects the performance feedback data. This "observer effect" could increase the value of performance feedback and promote more consistent evaluation of treatment integrity. The purpose of this investigation was to evaluate the observer effect on treatment integrity. Five supervisors who worked in a day treatment center were asked to collect performance feedback data on staff members' integrity in following a standard treatment protocol that supervisors were also expected to follow. Results showed an immediate and marked improvement in treatment integrity in three supervisors who collected but never received performance feedback. For two supervisors, this effect was reversed and replicated. Implications are discussed. PMID- 23639883 TI - Scaling of compensatory eye movements during translations: virtual versus real depth. AB - Vestibulo-ocular reflexes are the fastest compensatory reflex systems. One of these is the translational vestibulo-ocular reflex (TVOR) which stabilizes the gaze at a given fixation point during whole body translations. For a proper response of the TVOR the eyes have to counter rotate in the head with a velocity that is inversely scaled to viewing distance of the target. It is generally assumed that scaling of the TVOR is automatically coupled to vergence angle at the brainstem level. However, different lines of evidence also argue that in humans scaling of the TVOR also depends on a mechanism that pre-sets gain on a priori knowledge of target distance. To discriminate between these two possibilities we used a real target paradigm with vergence angle coupled to distance and a virtual target paradigm with vergence angle dissociated from target distance. We compared TVOR responses in six subjects who underwent lateral sinusoidal whole-body translations at 1 and 2 Hz. Real targets varied between distance of 50 and 22.4 cm in front of the subjects, whereas the virtual targets consisting of a green and red light emitting diode (LED) were physically located at 50 cm from the subject. Red and green LED's were dichoptically viewed. By shifting the red LED relative to the green LED we created a range of virtual viewing distances where vergence angle changed but the ideal kinematic eye velocity was always the same. Eye velocity data recorded with virtual targets were compared to eye velocity data recorded with real targets. We also used flashing targets (flash frequency 1 Hz, duration 5 ms). During the real, continuous visible targets condition scaling of compensatory eye velocity with vergence angle was nearly perfect. During viewing of virtual targets, and with flashed targets compensatory eye velocity only weakly correlated to vergence angle, indicating that vergence angle is only partially coupled to compensatory eye velocity during translation. Our data suggest that in humans vergence angle as a measure of target distance estimation has only limited use for automatic TVOR scaling. PMID- 23639885 TI - Quantitative hepatitis B surface antigen titres in Chinese chronic hepatitis B patients over 4 years of entecavir treatment. AB - BACKGROUND: The clinical value of quantitative hepatitis B surface antigen (qHBsAg) titre in patients taking nucleotide/nucleoside analogues (NAs) is still controversial. This study aims to investigate the dynamic changes of qHBsAg titres and their significance for predicting virological response (VR) and serological response (SR) to long-term entecavir (ETV) treatment. METHODS: A total of 48 ETV-naive patients were enrolled and followed prospectively for 4 years, 32 of whom were hepatitis B e antigen (HBeAg)-positive at baseline. Serum alanine aminotransferase (ALT), qualitative HBV serological markers and HBV DNA were detected; qHBsAg titres were measured using Elecsys((r)) HBsAg II Quant Assay (Roche Diagnostics, Penzberg, Germany). RESULTS: The mean baseline HBV DNA and qHBsAg were 7.51 log10 copies/ml and 3.78 log10 IU/ml, respectively. After 48 months of ETV treatment, the rates of VR (<291 copies/ml), ALT normalization and SR (HBeAg/antibody to HBeAg [anti-HBe]) were 89.6% (43/48), 89.6% (43/48) and 34.4% (11/32), respectively. There was a decrease in qHBsAg titres from baseline to month 48, ranging from 3.78 to 3.10 log10 IU/ml. The greatest decrease of qHBsAg was observed in the first 3 months of treatment (0.47 log10 IU/ml), which was significantly correlated with corresponding HBV DNA decreases (3.89 log10 copies/ml; P=0.032). By using receiver operating characteristic (ROC) curve analysis, qHBsAg titres at baseline (area under the curve [AUROC]=0.647) and 3 months after treatment (AUROC=0.586) had poor power in predicting 48-month VR; qHBsAg titres at baseline (AUROC=0.779) and 3 months after ETV treatment (AUROC=0.658) had poor power in predicting 48-month SR in patients who were HBeAg positive at baseline. Additionally, the decrease of qHBsAg in the first 3 months of treatment also had poor power in predicting either 48 month VR or SR. CONCLUSIONS: ETV is efficacious in NA-naive patients, and qHBsAg titres decreased significantly in the first 3 months of ETV treatment. However, qHBsAg titre was not a good predictor of 4-year VR and HBeAg/anti-HBe SR in this cohort. PMID- 23639886 TI - Effects of buffered vinegar and sodium dodecyl sulfate plus levulinic acid on Salmonella Typhimurium survival, shelf-life, and sensory characteristics of ground beef patties. AB - The inclusion of two sources of buffered vinegar and sodium dodecyl sulfate plus levulinic acid were studied as interventions for Salmonella Typhimurium and for their effect on shelf-life and sensory characteristics of ground beef. For the Salmonella challenge, beef trimmings (80/20) were inoculated then treated with 2% (w/v) liquid buffered vinegar (LVIN), 2.5% (w/w) powdered buffered vinegar (PVIN), a solution containing 1.0% levulinic acid plus 0.1% sodium dodecyl sulfate (SDLA) at 10% (w/v), or had no intervention applied (CNT). The same trim source and production methods were followed during production of patties for shelf-life and sensory testing without inoculation. SDLA patties had the largest reduction (P<0.05; 0.70 log CFU/g) of Salmonella. However, LVIN and PVIN had the least (P<0.05) psychrotrophic growth. SDLA patties had more purge (P<0.05) and lower (P<0.05) subjective color scores. There were not large differences in sensory characteristics, except PVIN exhibited stronger off-flavor (P<0.05). PMID- 23639887 TI - Development and evaluation of a driving observation schedule (DOS) to study everyday driving performance of older drivers. AB - This paper describes the development and evaluation of an on-road procedure, the Driving Observation Schedule (DOS), for monitoring individual driving behavior. DOS was developed for use in the Candrive/Ozcandrive five-year prospective study of older drivers. Key features included observations in drivers' own vehicles, in familiar environments chosen by the driver, with start/end points at their own homes. Participants were 33 drivers aged 75+ years, who drove their selected route with observations recorded during intersection negotiation, lane-changing, merging, low speed maneuvers and maneuver-free driving. Driving behaviors were scored by a specialist occupational therapy driving assessor and another trained observer. Drivers also completed a post-drive survey about the acceptability of DOS. Vehicle position, speed, distance and specific roadways traveled were recorded by an in-vehicle device installed in the participant's vehicle; this device was also used to monitor participants' driving over several months, allowing comparison of DOS trips with their everyday driving. Inter-rater reliability and DOS feasibility, acceptability and ecological validity are reported here. On average, drivers completed the DOS trip in 30.48min (SD=7.99). Inter-rater reliability measures indicated strong agreement between the trained and the expert observers: intra-class correlations (ICC)=0.905, CI 95% 0.747 0.965, p<0.0001; Pearson product correlation, r (18)=.83, p<0.05. Standard error of the measurement (SEM), method error (ME) and coefficient of variation (CV) measures were consistently small (3.0, 2.9 & 3.3%, respectively). Most participants reported being 'completely at ease' (82%) with the driving task and 'highly familiar with the route' (97%). Vehicle data showed that DOS trips were similar to participants' everyday driving trips in roads used, roadway speed limits, drivers' average speed and speed limit compliance. In summary, preliminary findings suggest that DOS can be scored reliably, is of feasible duration, is acceptable to drivers and representative of everyday driving. Pending further research with a larger sample and other observers, DOS holds promise as a means of quantifying and monitoring changes in older drivers' performance in environments typical of their everyday driving. PMID- 23639888 TI - Determining the validity of the AMA guide: A historical cohort analysis of the assessment of driving related skills and crash rate among older drivers. AB - BACKGROUND: Chronic health conditions associated with ageing can lead to changes in driving ability. The Canadian Driving Research Initiative for Vehicular Safety in the Elderly (Candrive II) is a 5-year prospective study funded by the Canadian Institutes of Health Research aiming to develop an in-office screening tool that will help clinicians identify potentially at-risk older drivers. Currently, no tools exist to directly predict the risk of motor vehicle collision (MVC) in this population. The American Medical Association (AMA), in collaboration with the National Highway Traffic Safety Association, has designed an opinion-based guide for assessing medical fitness to drive in older adults and recommends that physicians use the Assessment of Driving Related Skills (ADReS) as a test battery to measure vision, cognition and motor/somatosensory functions related to driving. The ADReS consists of the Snellen visual acuity test, visual fields by confrontation test, Trail Making Test part B, clock drawing test, Rapid Pace Walk, and manual tests of range of motion and motor strength. We used baseline data from the Candrive/Ozcandrive common cohort of older drivers to evaluate the validity of the ADReS subtests. We hypothesized that participants who crashed in the 2 years before the baseline assessment would have poorer scores on the ADReS subtests than participants who had not crashed. METHODS: In the Candrive/Ozcandrive study, 1230 participants aged 70 years or older were recruited from 7 Canadian cities, 1 Australian city and 1 New Zealand city, all of whom completed a comprehensive clinical assessment at study entry. The assessment included all tests selected as part of the ADReS. For this historical cohort study, data on all crashes (at-fault and non-at-fault) that occurred within 2 years preceding the baseline assessment were obtained from the respective licensing jurisdictions. Those who crashed were compared to those who had not crashed on their ADReS subtest scores using Pearson's chi-squared test and Student's t-test. RESULTS: Sixty-three of the 1230 participants (5.1%) were involved in an MVC within the 2 years preceding the baseline assessment. Contrary to our hypothesis, there were no statistically significant associations between abnormal performance on the tests constituting the ADReS and history of crash in the previous 2 years (p>0.01). DISCUSSION: We found that a history of crash in the previous 2 years was not associated with abnormalities on the subtests comprising the ADReS. This suggests the need for prospective analyses of risk factors over time to establish sensitive, valid predictors of crash that can be incorporated in clinical practice guidelines. PMID- 23639890 TI - Are transcriptional responses to inbreeding a functional response to alleviate inbreeding depression? AB - Previous studies addressing the relationship between gene regulation and inbreeding depression did not allow for discerning the changes that alleviate the depression from those that generate it. We directly addressed this question by analyzing changes in gene expression, using Affymetrix 2.0 arrays in Drosophila melanogaster inbred sublines differing in their magnitudes of inbreeding depression relative to the expression in an outbred control. The total number of arrays analyzed was 27, with 9,133 probe sets showing a significant signal of expression. We found that for those genes differentially expressed between inbred and outbred sublines, most of them showed a pattern of expression consistent with a protective role against inbreeding effects. The observed increase in depression was presumably related to an inability of the genome to do the appropriate expression adjustments. Expression changes detected in our study showed a clear specificity of RNA-splicing and energy derivation functions. Thus, it appears that most of the observed changes in gene expression associated with inbreeding may occur predominantly to alleviate inbreeding depression, i.e., as a protection against the effects of inbreeding. PMID- 23639892 TI - To be or not to be a bipolar disorder patient: problems with diagnosis. AB - The diagnosis of bipolar disorder (BD) is predominantly clinical. Some authors have suggested that BD is underdiagnosed and that many patients, particularly those with major depressive disorder, actually have BD. Some studies have suggested that BD is wrongly diagnosed, probably because of the idea of a "bipolar spectrum." To address this potential overdiagnosis, clinicians should carefully and systematically assess whether symptoms are included in diagnostic criteria and include the individual context of the patient. PMID- 23639891 TI - Genomic resources for multiple species in the Drosophila ananassae species group. AB - The development of genomic resources in non-model taxa is essential for understanding the genetic basis of biological diversity. Although the genomes of many Drosophila species have been sequenced, most of the phenotypic diversity in this genus remains to be explored. To facilitate the genetic analysis of interspecific and intraspecific variation, we have generated new genomic resources for seven species and subspecies in the D. ananassae species subgroup. We have generated large amounts of transcriptome sequence data for D. ercepeae, D. merina, D. bipectinata, D. malerkotliana malerkotliana, D. m. pallens, D. pseudoananassae pseudoananassae, and D. p. nigrens. de novo assembly resulted in contigs covering more than half of the predicted transcriptome and matching an average of 59% of annotated genes in the complete genome of D. ananassae. Most contigs, corresponding to an average of 49% of D. ananassae genes, contain sequence polymorphisms that can be used as genetic markers. Subsets of these markers were validated by genotyping the progeny of inter- and intraspecific crosses. The ananassae subgroup is an excellent model system for examining the molecular basis of speciation and phenotypic evolution. The new genomic resources will facilitate the genetic analysis of inter- and intraspecific differences in this lineage. Transcriptome sequencing provides a simple and cost-effective way to identify molecular markers at nearly single-gene density, and is equally applicable to any non-model taxa. PMID- 23639893 TI - The weakness of the sociocognitive model of dissociative identity disorder. PMID- 23639894 TI - Sociocognitive and posttraumatic models of dissociation are not opposed. PMID- 23639895 TI - Patients with DID are found and researched more widely than Boysen and VanBergen recognized. PMID- 23639896 TI - A review of dissociative identity disorder research: response to critics. PMID- 23639898 TI - Role of glutamine supplementation in critical illness given the results of the REDOXS study. PMID- 23639897 TI - Composition of dietary fat source shapes gut microbiota architecture and alters host inflammatory mediators in mouse adipose tissue. AB - BACKGROUND: Growing evidence shows that dietary factors can dramatically alter the gut microbiome in ways that contribute to metabolic disturbance and progression of obesity. In this regard, mesenteric adipose tissue has been implicated in mediating these processes through the elaboration of proinflammatory adipokines. In this study, we examined the relationship of these events by determining the effects of dietary fat content and source on gut microbiota, as well as the effects on adipokine profiles of mesenteric and peripheral adipocytes. METHODS: Adult male C57Bl/6 mice were fed milk fat-based, lard-based (saturated fatty acid sources), or safflower oil (polyunsaturated fatty acid)-based high-fat diets for 4 weeks. Body mass and food consumption were measured. Stool 16S ribosomal RNA (rRNA) was isolated and analyzed via terminal restriction fragment length polymorphism as well as variable V3-4 sequence tags via next-generation sequencing. Mesenteric and gonadal adipose samples were analyzed for both lipogenic and inflammatory mediators via quantitative real-time polymerase chain reaction. RESULTS: High-fat feedings caused more weight gain with concomitant increases in caloric consumption relative to low-fat diets. In addition, each of the high-fat diets induced dramatic and specific 16S rRNA phylogenic profiles that were associated with different inflammatory and lipogenic mediator profiles of mesenteric and gonadal fat depots. CONCLUSIONS: Our findings support the notion that dietary fat composition can both reshape the gut microbiota and alter host adipose tissue inflammatory/lipogenic profiles. They also demonstrate the interdependency of dietary fat source, commensal gut microbiota, and inflammatory profile of mesenteric fat that can collectively affect the host metabolic state. PMID- 23639900 TI - Renal growth in isolated methylmalonic acidemia. AB - PURPOSE: We sought to predict renal growth based on clinical and metabolic parameters in patients with isolated methylmalonic acidemia, a group of disorders associated with chronic kidney disease. METHODS: Fifty patients with methylmalonic acidemia, followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared with that of healthy controls and modeled to other clinical parameters using multiple-regression analyses. RESULTS: Comparisons with age-matched controls showed that renal length in subjects with methylmalonic acidemia was significantly decreased (P < 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C, and serum methymalonic acid concentrations best predicted kidney size. The regression equations used to generate methylmalonic acidemia kidney nomograms were renal length (cm) = 6.79 + 0.22 * age for the controls and 6.80 + 0.09 * age for the methylmalonic acidemia cohort (P < 0.001; constant and slope). CONCLUSION: Renal length, reflective of kidney growth, significantly decreased in patients with methylmalonic acidemia over time as compared with controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population. PMID- 23639901 TI - Experiences and attitudes of genome investigators regarding return of individual genetic test results. AB - PURPOSE: Whether and how to return individual genetic results to study participants is among the most contentious policy issues in contemporary genomic research. METHODS: We surveyed corresponding authors of genome-wide association studies, identified through the National Human Genome Research Institute's Catalog of Published Genome-Wide Association Studies, to describe the experiences and attitudes of these stakeholders. RESULTS: Of 357 corresponding authors, 200 (56%) responded. One hundred twenty-six (63%) had been responsible for primary data and sample collection, whereas 74 (37%) had performed secondary analyses. Only 7 (4%) had returned individual results within their index genome-wide association studies. Most (69%) believed that return of results to individual participants was warranted under at least some circumstances. Most respondents identified a desire to benefit participants' health (63%) and respect for participants' desire for information (57%) as major motivations for returning results. Most also identified uncertain clinical utility (76%), the possibility that participants will misunderstand results (74%), the potential for emotional harm (61%), the need to ensure access to trained clinicians (59%), and the potential for loss of confidentiality (51%) as major barriers to return of results. CONCLUSION: Investigators have limited experience returning individual results from genome-scale research, yet most are motivated to do so in at least some circumstances. PMID- 23639899 TI - Underutilization of Lynch syndrome screening in a multisite study of patients with colorectal cancer. AB - PURPOSE: The aim of this study was to examine Lynch syndrome screening of patients with metastatic colorectal cancer in integrated health-care-delivery organizations. METHODS: We determined the availability of Lynch syndrome screening criteria and actual Lynch syndrome screening in the medical records of 1,188 patients diagnosed with metastatic colorectal cancer between 2004 and 2009 at seven institutions in the Cancer Research Network. RESULTS: We found infrequent use of Lynch syndrome screening (41/1,188). Family history was available for 937 of the 1,188 patients (79%). There was sufficient information to assess Lynch syndrome risk using family history-based criteria in 719 of the 937 patients (77%) with family history documentation. In 391 individuals with a family history of a Lynch syndrome-associated cancer, 107 (27%) could not be evaluated due to missing information such as age of cancer onset. Eleven percent of patients who met the Bethesda criteria and 25% of individuals who met the Amsterdam II criteria were screened for Lynch syndrome. Recommended guidelines were adhered to during screening, but no testing method was preferred. CONCLUSION: The information required for Lynch syndrome screening decisions is routinely collected but seldom used. There is a critical gap between collection of family history and its use to guide Lynch syndrome screening, which may support a case for implementation of universal screening guidelines. PMID- 23639902 TI - The challenge of determining handedness in electron tomography and the use of DNA origami gold nanoparticle helices as molecular standards. AB - The apparent handedness of an EM-tomography reconstruction depends on a number of conventions and can be confused in many ways. As the number of different hardware and software combinations being used for electron tomography continue to climb, and the reconstructions being produced reach higher and higher resolutions, the need to verify the hand of the results has increased. Here we enumerate various steps in a typical tomography experiment that affect handedness and show that DNA origami gold nanoparticle helices can be used as convenient and fail-safe handedness standards. PMID- 23639903 TI - Of mice, rats and men: trabecular bone architecture in mammals scales to body mass with negative allometry. AB - Body mass (BM) in mammal species spans over six orders of magnitude. Although trabecular bone contributes to the mechanical properties of bones, we know much less about how trabecular bone scales with BM than about how cortical bone scales with BM. We therefore conducted a meta-analysis of the existing literature to test in rodents, humans and other mammals, predicted scaling properties between BM and several trabecular parameters: bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), connectivity density (ConnD) and degree of anisotropy (DA). Our results show that BV/TV and DA are independent of BM and that Tb.N, Tb.Th and Tb.Sp scale with negative allometry relative to BM. Rodents appear to have relatively thicker and fewer trabeculae than humans, and we propose it that is due to a minimum thickness threshold "imposed" on mechanically functional trabeculae. Consequently, rodents (mice and rats) and humans demonstrate two distinct mechanisms to achieve variations in BV/TV. Although Tb.Th variation is the main contributing factor for differences in BV/TV in humans, Tb.N variation is the main contributing factor for differences in BV/TV in rodents. Our results also demonstrate no correlation between Tb.N and Tb.Th within each taxon (mice, rats and humans). Since rodents are a common animal model for research on bone biomechanics, the evidence that trabecular bone parameters scale and correlate differently in rodents than in humans suggests that care should be applied when extrapolating bone biomechanical results from small animals to large-bodied humans. PMID- 23639904 TI - Stabilizing membrane proteins through protein engineering. AB - Integral membrane proteins (IMPs) are crucial components of all cells but are difficult to study in vitro because they are generally unstable when removed from their native membranes using detergents. Despite the major biomedical relevance of IMPs, less than 1% of Protein Data Bank (PDB) entries are IMP structures, reflecting the technical gap between studies of soluble proteins compared to IMPs. Stability can be engineered into IMPs by inserting stabilizing mutations, thereby generating proteins that can be successfully applied to biochemical and structural studies when solubilized in detergent micelles. The identification of stabilizing mutations is not trivial, and this review will focus on the methods that have been used to identify stabilized membrane proteins, including alanine scanning and screening, directed evolution and computational design. PMID- 23639906 TI - A comparison of reanalysis techniques: applying optimal interpolation and Ensemble Kalman Filtering to improve air quality monitoring at mesoscale. AB - To fulfill the requirements of the 2008/50 Directive, which allows member states and regional authorities to use a combination of measurement and modeling to monitor air pollution concentration, a key approach to be properly developed and tested is the data assimilation one. In this paper, with a focus on regional domains, a comparison between optimal interpolation and Ensemble Kalman Filter is shown, to stress pros and drawbacks of the two techniques. These approaches can be used to implement a more accurate monitoring of the long-term pollution trends on a geographical domain, through an optimal combination of all the available sources of data. The two approaches are formalized and applied for a regional domain located in Northern Italy, where the PM10 level which is often higher than EU standard limits is measured. PMID- 23639905 TI - Associations between fine particle, coarse particle, black carbon and hospital visits in a Chinese city. AB - China is one of the countries with the highest ambient particle levels in the world; however, there have been no epidemiologic studies examining the effects of fine particle (PM2.5), coarse particle (PM10-2.5) and black carbon (BC) simultaneously on morbidity outcomes. In this study, we conducted a time-series analysis to evaluate the acute effects of PM2.5, PM10-2.5, and BC on daily hospital visits in Shanghai, China. During our study period, the mean daily concentrations of PM2.5, PM10-2.5 and BC were 53.9 MUg/m(3), 38.4 MUg/m(3) and 3.9 MUg/m(3), respectively. We found significant associations of PM2.5, PM 10 2.5, and BC with daily hospital visits. An inter-quartile range increase of the average concentrations of the current and previous days in PM2.5, PM10-2.5 and BC was associated with a 1.88% (95% CI: 0.69% to 3.06%), a 1.30% (95% CI: 0.25% to 2.34%) and a 1.33% (95% CI: 0.34% to 2.32%) increase in emergency-room visits, respectively. For outpatient visits, the corresponding estimated changes were 2.44% (95% CI: -6.62% to 1.74%), 1.09% (95% CI: -2.72% to 4.90%) and 3.34% (95% CI: 0.10% to 6.57%) respectively. The effects of BC were more robust than the effects of PM2.5 and PM10-2.5 in two-pollutant models. To our knowledge, this is the first study in China, or even in Asian developing countries, to report the effect of PM2.5, PM10-2.5, and BC simultaneously on morbidity. Our findings also suggest that BC could serve as a valuable air quality indicator that reflects the health risks of airborne particles. PMID- 23639907 TI - HBCD and TBBPA in particulate phase of indoor air in Shenzhen, China. AB - Hexabromocyclododecane diastereoisomers (alpha, beta, and gamma-HBCD) and tetrabromobisphenol A (TBBPA) were investigated in air conditioning filter dust (designated as particulate phase of indoor air, PPIA) collected from an office building in Shenzhen, China in 2009. Concentrations of SigmaHBCD (sum of alpha-, beta-, and gamma-HBCD) ranged from 652 to 122, 973 ng/g in PPIA. Generally, gamma HBCD was the most abundant diastereomer. Concentrations of TBBPA ranged from 30 to 59, 140 ng/g in PPIA. According to our results, approximate 61.9 pg/kg body weight/day (pg/kg/d) PM2.5 bound SigmaHBCD can be inhaled deep into the lungs and 31.3 pg/kg/d PM10 bound SigmaHBCD tends to be deposited in the upper parts of the respiratory system, and those values of TBBPA were 28.7 pg/kg/d and 14.5 pg/kg/d for the lower and upper respiratory tracts, respectively. The average intakes of SigmaHBCD via dust inhalation and ingestion were 37.92 pg/kg/d and 2, 079 pg/kg/d for adults, and those data of TBBPA were 17.62 pg/kg/d and 966.2 pg/kg/d, respectively. Our research found that exposure via indoor dust inhalation and ingestion contributed more than dietary pathway. Sensitivity analysis result suggests that the concentration of HBCD and TBBPA is the most significant parameter governing estimated results, and the other parameters, such as body weight and inhalation rate, do not affect the outcome much. PMID- 23639908 TI - Temporal dynamics of antibiotics in wastewater treatment plant influent. AB - A yearlong field experimental campaign was conducted to reveal time scales over which antibiotic fluxes vary in the influent of a wastewater treatment plant (WTP). In particular, sampling was carried out to ascertain the amplitudes of monthly, daily and hourly fluctuations of several antibiotics. A total of 180 samples was collected at the entrance of a WTP in Lausanne, Switzerland. Sample concentrations were multiplied by flow rate to obtain monthly, daily and hourly mass fluxes of six antibiotics (trimethoprim, norfloxacin, ciprofloxacin, ofloxacin, clindamycin and metronidazole). Seasonality in mass fluxes was observed for all substances, with maximum values in winter being up to an order of magnitude higher than in summer. The hourly measurements of the mass flux of antibiotics were found to have a period of 12h. This was due to peaks in toilet use in the morning and early evening. In particular, the morning peak in flushing coincided with high concentrations (and hence high mass fluxes) due to overnight accumulation of substances in urine. However, little variation was observed in the average daily flux. Consequently, fluctuations in mass fluxes of antibiotics were mainly evident at the monthly and hourly time scales, with little variation on the day-week time scale. These results can aid in optimizing removal strategies and future sampling campaigns focused on antibiotics in wastewater. PMID- 23639909 TI - Exposure to food contaminants during pregnancy. AB - During pregnancy, the fetus is exposed to contaminants from its mother's diet. This work provides an assessment of the dietary exposure of pregnant women to inorganic contaminants (aluminum, mercury, lead, inorganic arsenic, cobalt), polychlorodibenzodioxins, polychlorodibenzofurans, dioxin-like and non-dioxin like polychlorobiphenyls (DL-PCBs, NDL-PCBs), polybromodiphenyl ethers (PBDEs), perfluoroalkyl acids, mycotoxins (zearalenone, patulin, trichothecenes), and heat generated compounds (acrylamide and polycyclic aromatic hydrocarbons). Consumption data of 2002 pregnant women aged 18 to 45 from the EDEN cohort study were combined with contamination data from the second French total diet study to assess the exposure before pregnancy (n=1861) and during the third trimester of pregnancy (n=1775). Exposure was also assessed considering the season during which the third trimester of pregnancy occurred. Significant changes in consumptions during pregnancy and between seasons were associated with differences in exposures for some substances. Some contaminant exposures appeared to be of health concern. Margins of exposure to acrylamide (635 to 1094 for mean), inorganic arsenic, lead, and BDE-99 (<=100) were too low to exclude all risks. For NDL-PCBs, T-2 and HT-2 toxins, and deoxynivalenol, significant exceedings of toxicological reference values were found before pregnancy, but there was no significant exceeding in the third trimester. PMID- 23639910 TI - The effect of different transport modes on urban PM(10) levels in two European cities. AB - The aim of the study is to identify transport patterns that may have an important influence on PM10 levels in two European cities, namely Szeged in East-Central Europe and Bucharest in Eastern Europe. 4-Day, 6-hourly three-dimensional (3D) backward trajectories arriving at these locations at 1200 GMT are computed using the HYSPLIT model over a 5-year period from 2004 to 2008. A k-means clustering algorithm using the Mahalanobis metric is applied in order to develop trajectory types. Two statistical indices are used to evaluate and compare exceedances of critical daily PM10 levels corresponding to the trajectory clusters. For Bucharest, the major PM10 transport can be clearly associated with air masses arriving from Central and Southern Europe, as well as the Western Mediterranean. Occasional North African dust intrusions over Romania are also found. For Szeged, Southern Europe with North Africa, Central Europe and Eastern Europe with regions over the West Siberian Plain are the most important sources of PM10. The occasional appearance of North-African-origin dust over Hungary is also detected. A statistical procedure is developed in order to separate medium- and long-range PM10 transport for both cities. Considering the 500 m arrival height, long-range transport plays a higher role in the measured PM10 concentration both for non rainy and rainy days for Bucharest and Szeged, respectively. PMID- 23639911 TI - Effects of deltamethrin (pyrethroid insecticide) on growth, reproduction, embryonic development and sex differentiation in two strains of Daphnia magna (Crustacea, Cladocera). AB - Acute and different chronic ecotoxic effects of deltamethrin have been investigated on two strains (coming from two different laboratories) of Daphnia magna. The effective concentrations immobilizing 50% of daphnids (EC50s) after 24 h and 48 h were 9.40 and 0.32 MUg L(-1), 8.86 and 0.63 MUg L(-1) for first strain (strain 1) and second strain (strain 2), respectively. Thus, there was an increase of deltamethrin ecotoxicity with time of exposure as confirmed by chronic studies. After 21 days of exposure to deltamethrin, daphnids have showed significant effects on survival at deltamethrin concentrations of 0.16 MUg L(-1) and 0.31 MUg L(-1) for strains 1 and 2, respectively. Eleven other endpoints were examined: body length, population growth rate and various reproductive parameters (days to first brood, number of broods, number of cumulative molts and number of neonates), embryotoxicity and appearance of males. IC10 values related to the number of juveniles per live adult were 11 and 46 ng L(-1) for strains 1 and 2, respectively. Furthermore, an increase in embryo deformities was observed at the highest concentrations tested for both strains. Following deltamethrin exposure, undeveloped second antennae, curved or unextended shell spines, and curved post abdomen spines were observed in live neonates. The production of male juveniles was only registered with strain 1 at 0.16 MUg L(-1). Results suggest that deltamethrin could act as an endocrine disruptor in D. magna as it interferes with sex determination and development abnormality but there is a difference in sensitivity between the two tested strains. PMID- 23639912 TI - Family caregiving and caring for families of older adults during hospitalization. PMID- 23639913 TI - Office of inspector general report finds skilled nursing facilities "often" fail to meet care planning and discharge planning requirements. PMID- 23639914 TI - T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. AB - BACKGROUND & AIMS: Antiviral agents suppress hepatitis B virus (HBV) replication but do not clear the infection. A strong effector T-cell response is required to eradicate HBV, but this does not occur in patients with chronic infection. T cells might be directed toward virus-infected cells by expressing HBV-specific receptors and thereby clear HBV and help to prevent development of liver cancer. In mice, we studied whether redirected T cells can engraft after adoptive transfer, without prior T-cell depletion, and whether the large amounts of circulating viral antigens inactivate the transferred T cells or lead to uncontrolled immune-mediated damage. METHODS: CD8(+) T cells were isolated from mice and stimulated using an optimized protocol. Chimeric antigen receptors (CARs) that bind HBV envelope proteins (S-CAR) and activate T cells were expressed on the surface of cells using retroviral vectors. S-CAR-expressing CD8(+) T cells, which carried the marker CD45.1, were injected into CD45.2(+) HBV transgenic mice. We compared these mice with mice that received CD8(+) T cells induced by vaccination, cells that express a CAR without a proper signaling domain, or cells that express a CAR that does not bind HBV proteins (controls). RESULTS: CD8(+) T cells that expressed HBV-specific CARs recognized different HBV subtypes and were able to engraft and expand in immune-competent HBV transgenic mice. After adoptive transfer, the S-CAR-expressing T cells localized to and functioned in the liver and rapidly and efficiently controlled HBV replication compared with controls, causing only transient liver damage. The large amount of circulating viral antigen did not impair or overactivate the S-CAR-grafted T cells. CONCLUSIONS: T cells with a CAR specific for HBV envelope proteins localize to the liver in mice to reduce HBV replication, causing only transient liver damage. This immune cell therapy might be developed for patients with chronic hepatitis B, regardless of their HLA type. PMID- 23639916 TI - Influence of alternative lifestyles on self-reported body weight and health characteristics in women. AB - BACKGROUND: Alternative lifestyles are often associated with distinct practices with respect to nutrition, physical activity, smoking, alcohol use and usage of complementary medicine. Evidence concerning effects of these lifestyle-related practices on health status is still fragmentary. OBJECTIVE: To describe maternal health characteristics related to alternative lifestyles, with emphasis on body weight status, during pregnancy and maternity periods. METHODS: We compared self reported health-related features of mothers with alternative lifestyles and conventional lifestyles during pregnancy and maternity period in the KOALA Birth Cohort Study. This cohort comprises two recruitment groups of mother-infant pairs, one with a conventional (no selection based on lifestyle, n = 2333), the other with an alternative lifestyle (selected via organic food shops, anthroposophic clinicians and midwives, anthroposophic under-five clinics, Rudolf Steiner schools and relevant magazines, n = 485). Mothers in the alternative group more frequently chose organic foods, adhered to specific living rules, practised vegetarianism and identified themselves with anthroposophy. RESULTS: Mothers in the alternative group showed lower BMI and lower prevalence of overweight and obesity than the conventional group, before pregnancy as well as 4 5 years after delivery. This difference was partly retained after adjusting for potential confounders. Furthermore, women in the alternative group had a lower prevalence of pregnancy-related hypertension, more often started breastfeeding and gave exclusive and prolonged breastfeeding for a longer period. Finally, they smoked less often, but more often drunk alcohol during pregnancy. CONCLUSION: The results suggest that an alternative lifestyle is associated with favourable body weight and with several differences in other health features. PMID- 23639915 TI - Deleterious effect of suboptimal diet on rest-activity cycle in Anastrepha ludens manifests itself with age. AB - Activity patterns and sleep-wake cycles are among the physiological processes that change most prominently as animals age, and are often good indicators of healthspan. In this study, we used the video-based high-resolution behavioral monitoring system (BMS) to monitor the daily activity cycle of tephritid fruit flies Anastrepha ludens over their lifetime. Surprisingly, there was no dramatic change in activity profile with respect to age if flies were consistently fed with a nutritionally balanced diet. However, if flies were fed with sugar-only diet, their activity profile decreased in amplitude at old age, suggesting that suboptimal diet affected activity patterns, and its detrimental effect may not manifest itself until the animal ages. Moreover, by simulating different modes of behavior monitoring with a range of resolution and comparing the resulting conclusions, we confirmed the superior performance of video-based monitoring using high-resolution BMS in accurately representing activity patterns in an insect model. PMID- 23639917 TI - Identifying pregnancy episodes, outcomes, and mother-infant pairs in the Vaccine Safety Datalink. AB - BACKGROUND: The need for research on the safety of vaccination during pregnancy is widely recognized. Large, population-based data systems like the Vaccine Safety Datalink (VSD) may be useful for this research, but identifying pregnancies using electronic medical record (EMR) and claims data can be challenging. METHODS: We modified an existing data processing algorithm to identify pregnancies within seven of the ten VSD sites. We validated the algorithm by calculating the agreement in pregnancy outcome type, end date, and gestational age between the algorithm and manual medical record review. At each participating site, we randomly sampled 15 episodes within four outcome type strata (live births, spontaneous abortions, elective abortions, and other pregnancy outcomes) for a total of 60 episodes per site. We also developed and validated methods to link mothers to their infants in the electronic data. RESULTS: We identified 595,929 pregnancy episodes ending in 2002 through 2006 among women 12 through 55 years of age. Of these pregnancies, 75% ended in live births, 12% in spontaneous abortions, and 9% in elective abortions. We were able to confirm a pregnancy within 28 days of the algorithm-estimated pregnancy start date for 99% of live births, 93% of spontaneous abortions, 92% of elective abortions, and 90% of other outcomes sampled. The agreement between the algorithm identified and the abstractor-identified outcome date ranged from 70% (elective abortion) to 96% (live birth) depending on outcome type. When gestational age was available in the EMR, agreement ranged from 82% (other) to 98% (live birth) depending on outcome type. We confirmed 100% of the 350 sampled mother-infant linkages with manual medical record review. CONCLUSIONS: The VSD algorithm accurately identifies pregnancy episodes and mother-infant pairs across participating sites. Additional manual record review may be needed to improve the precision of the pregnancy date estimates depending on specific study needs. These algorithms will allow us to conduct large, population-based studies of the safety of vaccination during pregnancy. PMID- 23639918 TI - Network activity in hippocampal slice cultures revealed by long-term in vitro recordings. AB - Organotypic hippocampal slice cultures (OHSCs) are widely used for anatomical, molecular and electrophysiological studies of the development of neuronal networks. Electrophysiological recordings are usually limited to a single time point during development, and recording conditions differ greatly based on culture conditions. Consequently, little is known about the maturation of neuronal network activity in vitro. Here, we describe a simple method that allows long-term electrophysiological recordings during culture maintenance in a CO2 incubator. We compared the occurrence of spontaneous network activity, including epileptiform activity, in OHSCs (maintained in Neurobasal/B27 serum-free medium) prepared at different postnatal days and investigated the effects of changes in osmolality and pH. Recordings over 48 h revealed spontaneous network activity culminating in seizure-like events (SLEs) in 65.4% of the OHSCs (n=78). SLE incidence peaked during the first 6h following implantation of the microelectrodes and a secondary increase in SLE-incidence began after 9h of recording and averaged 2.65SLEs/h. The initial peak was likely initiated by transient alkalosis induced by the low pCO2 during the positioning of the electrodes, whereas successive changes in the composition of the culture medium might explain the secondary increase in SLE incidence. Notably, changes in osmolality had no effect on SLE induction. In conclusion, long-term recordings in OHSCs will help to reveal changes in spontaneous network activity during maturation. The extent to which the axonal reorganization known to occur in OHSCs contributes to the susceptibility to epileptogenesis remains to be determined. PMID- 23639919 TI - Detecting cell assemblies in large neuronal populations. AB - Recent progress in the technology for single unit recordings has given the neuroscientific community the opportunity to record the spiking activity of large neuronal populations. At the same pace, statistical and mathematical tools were developed to deal with high-dimensional datasets typical of such recordings. A major line of research investigates the functional role of subsets of neurons with significant co-firing behavior: the Hebbian cell assemblies. Here we review three linear methods for the detection of cell assemblies in large neuronal populations that rely on principal and independent component analysis. Based on their performance in spike train simulations, we propose a modified framework that incorporates multiple features of these previous methods. We apply the new framework to actual single unit recordings and show the existence of cell assemblies in the rat hippocampus, which typically oscillate at theta frequencies and couple to different phases of the underlying field rhythm. PMID- 23639920 TI - Restoring long-term potentiation impaired by amyloid-beta oligomers: comparison of an acetylcholinesterase inhibitior and selective neuronal nicotinic receptor agonists. AB - As nicotinic acetylcholine receptor (nAChR) agonists directly address cholinergic neurotransmission with potential impact on glutamatergic function, they are considered as potential new symptomatic treatment options for Alzheimer's disease compared to the indirectly operating acetylcholinesterase inhibitors such as the current gold standard donepezil. In order to evaluate the therapeutic value of nAChR activation to ameliorate cognitive dysfunction, a direct comparison between alpha4beta2, alpha7 nAChR agonists, and donepezil was performed on the level of an ex vivo experimental model of impaired memory formation. First, we demonstrated that amyloid beta (Abeta)42 oligomers, which are believed to be the synaptotoxic Abeta-species causally involved in the pathophysiology of Alzheimer's disease, have a detrimental effect on long-term potentiation (LTP) in the CA1 region of rat hippocampal slices, a widely used cellular model of learning and memory. Second, we investigated the potential of donepezil, the alpha4beta2 nAChR agonist TC-1827 and the alpha7 nAChR partial agonist SSR180711 to reverse Abeta42 oligomer induced LTP impairment. Donepezil showed only a slight reversal of Abeta42 oligomer induced impairment of early LTP, and had no effect on Abeta42 oligomer induced impairment of late LTP. The same was demonstrated for the alpha4beta2 nAChR agonist TC-1827. In contrast, the alpha7 nAChR partial agonist SSR180711 completely rescued early as well as late LTP impaired by Abeta42 oligomers. As activating alpha7 nAChRs was found to be most efficacious in restoring Abeta42 oligomer induced LTP deficits, targeting alpha7 nAChRs might represent a powerful alternative approach for symptomatic treatment of AD. PMID- 23639921 TI - False memories for aggressive acts. AB - Can people develop false memories for committing aggressive acts? How does this process compare to developing false memories for victimhood? In the current research we used a simple false feedback procedure to implant false memories for committing aggressive acts (causing a black eye or spreading malicious gossip) or for victimhood (receiving a black eye). We then compared these false memories to other subjects' true memories for equivalent events. False aggressive memories were all too easy to implant, particularly in the minds of individuals with a proclivity towards aggression. Once implanted, the false memories were indistinguishable from true memories for the same events, on several dimensions, including emotional content. Implications for aggression-related memory more generally as well as false confessions are discussed. PMID- 23639922 TI - On the dual emission of p-dimethylaminobenzonitrile and its photophysical implications. AB - A solvatochromic analysis of available absorption and LE and TICT emission data in p-dimethylaminobenzonitrile (DMABN) was conducted. Applying the Abe method to the results of a thermochromic analysis of DMABN in 1-chlorobutane (ClB) allowed us to determine the polarizability and dipole moment of the excited electronic states involved in the absorption and emission transitions. As shown herein, the LE -> TICT excited state reaction for DMABN is triggered by the solvent polarity but is additionally influenced by the viscosity. The experimental evidence negates the assumption that the radiative constant for the TICT fluorescence of DMABN is temperature-dependent. PMID- 23639923 TI - [The new German reimbursement system for psychiatric hospitals as a "learning system"]. PMID- 23639924 TI - The role of obsessive-compulsive symptoms in the psychopathological profile of children with chronic tic disorder and attention-deficit hyperactivity disorder. AB - OBJECTIVE: The study examines the role of obsessive-compulsive symptoms (OCS) as a part of the psychopathology of children with chronic tic disorders (CTD) and/or attention-deficit hyperactivity disorder (ADHD). METHOD: We assessed the psychopathology of four large patient groups without further psychiatric disorders: CTD (n = 112), CTD + ADHD (n = 82), ADHD (n = 129), and controls (n = 144)) by implementing the Child Behavior Checklist (CBCL). We compared the main effects for CTD and ADHD with and without including OCS as covariates. RESULTS: Including OCS led to substantially different main effects for CTD on seven out of eight CBCL subscales. Slightly different main effects for ADHD were determined with respect to ADHD, mainly on the subscale withdrawn. CONCLUSIONS: OCS are closely related to CTD-associated psychopathology and - to a lesser extent, but nevertheless of importance in daily clinical practice - on ADHD-related symptoms. This information can be helpful in implementing more precise diagnostics and treatment in daily routine care. PMID- 23639925 TI - ["Euthanasia" of children in Nazi Germany - the case of Gunter Nevermannn. On the responsibility of childhood and adolescent psychiatry in the past, the present, and the future]. AB - "Euthanasia" was the cynical euphemism used by the Nazis to refer to the systematic murder of hundreds of thousands of mentally sick and handicapped people between 1939 and 1945, at least 6,000 of whom were children. Based on the example of Gunter Nevermann, this paper provides insight into the complex acts of registering, selecting, and targeting children labelled as "inferior" and "unworthy to live." This case clearly shows that Nazi doctors were not necessarily enmeshed in some tragic conflict. Rather, apparently without any qualms, they sacrificed the sick children who had been entrusted to their care, for the ideal of obtaining a "racially healthy corpus," a term used without being questioned. Most of the perpetrators were never brought to justice, and not a few of them later held managerial positions in child and adolescent psychiatry in the two German states. Many of them were members or even honorary members of the "Deutsche Gesellschaft fur Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie e. V." in its present or previous form. We feel it is necessary to inform the public effectively about this state of affairs, to discover what really happened and to determine who was responsible. PMID- 23639926 TI - [Resource-oriented assessment using the German Competence Analysis Questionnaire (Kompetenzanalyseverfahren, KANN) - verification of the KANN's validity as measured by the Child Behavior Checklist (CBCL/4-18) in the context of child and youth welfare]. AB - OBJECTIVE: The German Competence Analysis Questionnaire (Kompetenzanalyseverfahren, KANN) is an external assessment tool used to determine observable personal resources (= competences) in children and adolescents. The present paper examines the validity of the KANN based on additionally collected data of behavior disorders as measured by the Child Behavior Checklist (CBCL/4-18). The main objective is to explore whether the KANN scales are able to differentiate between children and adolescents with or without internalizing and/or externalizing behavior disorders. METHOD: The sample consists of n = 450 young people (aged 6 to 22 years) under the care of child and youth welfare services assessed between 2010 and 2012 by their group careworkers using KANN and CBCL as part of the ongoing quality development system "moses." RESULTS: According to the discriminant analysis the KANN scale "Empathy & Fairness" differentiates very well between youths with or without behavior disorders, particularly those with externalizing problems. The KANN scale "Leisure Behavior & Peer Groups" contributes the highest rate of differentiation of internalizing problems. The hit ratios of the discriminant analyses reach values of up to 76.2 %. CONCLUSIONS: The ability of the KANN scales to differentiate behavior disorders underlines the validity of the KANN. PMID- 23639927 TI - [The Spider Phobia Questionnaire for Children and Adolescents (SPQ-CA) - development and validation of a German short scale]. AB - OBJECTIVE: Spider phobia is rather common in Western societies and mainly afflicts females. The disorder has a very early onset but is very rarely diagnosed and treated in children and adolescents. Thus, there is a need for a reliable, valid, and economic questionnaire for the assessment of the disorder in children and adolescents. METHOD: For the development (exploratory and confirmatory factor analysis) and validation purposes, 816 children and adolescents aged between 7 and 15 years answered the questionnaire. RESULTS: The resulting Spider Phobia Questionnaire for Children and Adolescents (SPQ-CA) consists of ten items and has a good internal consistency (Cronbach's alpha = .86). The scale correlates positively with overall anxiety, disgust proneness, and sensitivity. CONCLUSIONS: The short scale SPQ-CA is a reliable, valid and economic instrument for the assessment of spider fear and is particularly well suited for application in psychotherapeutic studies. PMID- 23639928 TI - [Effectiveness of neuropsychological training in children with attention-deficit hyperactivity disorder (ADHD)]. AB - Recently published studies on the effects of neuropsychological training in children with attention-deficit hyperactivity disorder (ADHD) reflect our present knowledge about the pathogenesis of the disorder. This review article collects the results of published treatment studies drawn from a MEDLINE search. Because of the restricted number of available studies we considered randomized studies as well as studies with a lower evidence level, including case reports. Due to the heterogeneous nature of the study samples, we restrict our interpretation of the study results to the application of various diagnostic criteria, to different levels of effect measurement, and to diverse, only partially comparable treatment contents and length. Despite these limitations, neuropsychological training may be effective in reducing some specific cognitive deficits in ADHD. In a next step replication studies on homogeneous samples would be required under application of comparable training modules. PMID- 23639931 TI - Baseline hepatitis B surface antigen (HBsAg) as predictor of sustained HBsAg loss in chronic hepatitis B patients treated with pegylated interferon-alpha2a and adefovir. AB - BACKGROUND: In this study, we aimed to identify baseline predictors of response in chronic hepatitis B patients treated with a combination of pegylated interferon (PEG-IFN)-alpha2a and adefovir. METHODS: We treated 92 chronic hepatitis B patients (44 hepatitis B e antigen [HBeAg]-positive and 48 HBeAg negative) with HBV DNA > 100,000 copies/ml (> 17,182 IU/ml) with PEG-IFN and adefovir for 48 weeks and followed them up for 2 years. Baseline markers for HBeAg loss, combined response (HBeAg negativity, HBV DNA levels <= 2,000 IU/ml and alanine aminotransferase [ALT] normalization) and hepatitis B surface antigen (HBsAg) loss were evaluated. RESULTS: Two years after the end of treatment, rates of HBeAg loss and HBsAg loss in HBeAg-positive patients were 18/44 (41%) and 5/44 (11%), respectively. In HBeAg-negative patients, rates of combined response and HBsAg loss were 12/48 (25%) and 8/48 (17%), respectively. HBeAg-negative patients with HBsAg loss had lower baseline HBsAg levels than those without HBsAg loss (mean HBsAg 2.35 versus 3.55 log10 IU/ml; P < 0.001). They also had lower HBV DNA levels and were more often (PEG-)IFN experienced. Baseline HBsAg was the only independent predictor of HBsAg loss (OR 0.02; P = 0.01). CONCLUSIONS: With combination therapy of PEG-IFN and adefovir for 48 weeks, a high rate of HBsAg loss was observed in both HBeAg-positive (11%) and HBeAg-negative (17%) patients 2 years after treatment ended. In HBeAg-negative patients, a low baseline HBsAg level was a strong predictor for HBsAg loss. PMID- 23639932 TI - Apoptosis in thymus of teleost fish. AB - The presence and distribution of apoptotic cells during thymus development and in adult were studied by in situ end-labelling of fragmented DNA in three temperate species carp (Cyprinus carpio), sea bass (Dicentrarchus labrax) and dusky grouper (Epinephelus marginatus) and in the adult thymus of three Antarctic species belonging to the genus Trematomus spp. During thymus development some few isolated apoptotic cell (AC) firstly appeared in the central-external part of the organ (carp: 5 days ph; sea bass: 35 days ph grouper: 43 days ph). Initially the cells were isolated and then increased in number and aggregated in small groups in the outer-cortical region of the thymus larvae. The high density of apoptotic cells was observed in the junction between cortex and medulla from its appearance (border between cortex and medulla, BCM). ACs decreased in number in juveniles and adult as well as the ACs average diameter. In late juveniles and in adulthood, the apoptosis were restricted to the cortex. In Antarctic species the thymus is highly adapted to low temperature (high vascularisation to effort the circulation of glycoproteins enriched plasma and strongly compact parenchyma). The apoptosis process was more extended (4-7 fold) as compare with the thymus of temperate species, even if the distribution of ACs was similar in all examined species. Data suggested a common process of T lymphocyte negative-selection in BCM of thymus during the ontogeny. The selection process seems to be still active in adult polar fish, but restricted mainly in the cortex zone. PMID- 23639933 TI - Four lysozymes (one c-type and three g-type) in catfish are drastically but differentially induced after bacterial infection. AB - Lysozyme is an important component of the innate immune system. In this study, four lysozyme genes including one c-type lysozyme and three g-type lysozymes were identified from channel catfish (Ictalurus punctatus). The lysozyme genes are highly conserved in their structural features as compared to those from other species. Phylogenetic analyses were conducted allowing annotation of these genes. Additional analyses using conserved syntenies allowed determination of orthologies for the c-type lysozyme. Phylogenetic analysis indicated that the g type lysozyme may have gone through species-specific gene duplications leading to multiple copies in some teleost species. Channel catfish possessed three copies of the g-type lysozyme genes. Expression analysis revealed that the catfish lysozyme genes were expressed in a broad range of tissues. The highest levels of expression were found in head kidney, liver, spleen, and trunk kidney, compatible with the immune functions of these tissues/organs. The c-type and g-type lysozymes were drastically induced after bacterial infection, but exhibited large differences in the extent of induction and the tissue with the highest level of induction, with the g-type lysozyme being most highly induced in the head kidney whereas the other three lysozymes being most highly induced in the liver, suggesting their cooperative actions in the immune responses but difference in their detailed functions. PMID- 23639934 TI - Dietary supplementation of honeysuckle improves the growth, survival and immunity of Penaeus monodon. AB - Two trials were conducted to determine the effects of honeysuckle on shrimp, Penaeus monodon, first on growth performance, secondly on the immune response of shrimp. In trial 1, shrimp (mean initial wet weight about 3.02 g) were fed with five diets containing 0% (basal diet), 0.1%, 0.2%, 0.4% and 0.8% honeysuckle in triplicate for 60 days. Growth performance (final body wet weight, FBW; weight gain, WG; biomass gain, BG) of shrimp fed honeysuckle diets were higher (P < 0.05) than that of shrimp fed the basal diet, shrimp fed 0.4% honeysuckle diet showed the highest value of growth performance. Shrimp fed 0.2% honeysuckle diet showed highest value of survival. The total antioxidant status (TAS) and glutathione peroxidase (GSH-Px) activity of shrimp fed 0.2%, 0.4% and 0.8% honeysuckle diets were higher (P < 0.05) than those of shrimp fed basal and 0.1% honeysuckle diets. Hepatopancreas malondialdehyde (MDA) of shrimp fed honeysuckle diets were lower (P < 0.05) than that of shrimp fed the basal diet. Total haemocyte count of shrimp fed the basal diet was lower (P < 0.05) than that of shrimp fed honeysuckle diets. Haemolymph clotting time of shrimp had the opposite trend with the total haemocyte count of shrimp. In trial 2, the shrimp were exposed to air during a simulated live transportation for 36 h after the rearing trial. The antioxidant responses were characterized by lower TAS and higher antioxidant enzyme activities (superoxide dismutase: SOD, GSH-Px) and higher oxidative stress level (MDA) in the hepatopancreas compared to levels found in trial 1. No mortalities were observed in any diet groups after 36 h of simulated live transportation. The glutathione (GSH) content and TAS of shrimp fed 0.2%, 0.4% and 0.8% honeysuckle diets were higher (P < 0.05) than those of shrimp fed the basal and 0.1% honeysuckle diets. The SOD activity of shrimp fed the basal diet was higher (P < 0.05) than that of shrimp fed honeysuckle diets. The GSH-Px activity of shrimp fed the basal diet was lower (P < 0.05) than that of shrimp fed 0.2%, 0.4% and 0.8% honeysuckle diets but without significant difference (P > 0.05) with shrimp fed 0.1% honeysuckle diet. Moreover, the oxidative stress level (MDA) recorded in the hepatopancreas with shrimp submitted to the honeysuckle diets were lower. In conclusion, results suggested that dietary intake containing honeysuckle could enhance the growth performance of P. monodon and improve its resistance to air exposure during simulated live transportation. Considering the effect of honeysuckle on both growth performance and survival of P. monodon, the level of honeysuckle supplemented in the diet should be between 0.2% and 0.4%. PMID- 23639936 TI - Impact of statistical adjustment for frequency of venue attendance in a venue based survey of men who have sex with men. AB - Venue sampling is a common sampling method for populations of men who have sex with men (MSM); however, men who visit venues frequently are more likely to be recruited. While statistical adjustment methods are recommended, these have received scant attention in the literature. We developed a novel approach to adjust for frequency of venue attendance (FVA) and assess the impact of associated bias in the ManCount Study, a venue-based survey of MSM conducted in Vancouver, British Columbia, Canada, in 2008-2009 to measure the prevalence of human immunodeficiency virus and other infections and associated behaviors. Sampling weights were determined from an abbreviated list of questions on venue attendance and were used to adjust estimates of prevalence for health and behavioral indicators using a Bayesian, model-based approach. We found little effect of FVA adjustment on biological or sexual behavior indicators (primary outcomes); however, adjustment for FVA did result in differences in the prevalence of demographic indicators, testing behaviors, and a small number of additional variables. While these findings are reassuring and lend credence to unadjusted prevalence estimates from this venue-based survey, adjustment for FVA did shed important insights on MSM subpopulations that were not well represented in the sample. PMID- 23639935 TI - Using pathway-specific comprehensive exposure scores in epidemiology: application to oxidative balance in a pooled case-control study of incident, sporadic colorectal adenomas. AB - Identifying associations of risk factors sharing the same pathway with disease risk is complicated by small individual effects and intercorrelated components; this can be addressed by creating comprehensive exposure scores. We developed and validated 3 novel weighting methods (literature review-derived, study data-based, and a Bayesian method that combines prior knowledge with study data) to incorporate components into a pathway score for oxidative balance in addition to a commonly used method that assumes all components contribute equally to the score. We illustrate our method using pooled data from 3 US case-control studies of sporadic colorectal adenoma (1991-2002). We created 4 oxidative balance scores (OBS) to reflect combined summary measures of dietary and nondietary antioxidant and prooxidant exposures. A higher score represents a predominance of antioxidant exposures over prooxidant exposures. In the pooled data, the odds ratios comparing the highest tertile of OBS with the lowest for adenoma risk ranged from 0.38 to 0.54 for the 4 measures; all were statistically significant. These findings suggest that 1) OBS are indicators of oxidative balance and may be inversely associated with colorectal adenoma risk and 2) using comprehensive exposure scores may be preferable to investigating individual component-disease associations for complex exposures, such as oxidative balance. PMID- 23639937 TI - Opioid use for noncancer pain and risk of fracture in adults: a nested case control study using the general practice research database. AB - Opioid use has been reported to be associated with increased fracture risks. In a nested case-control study using the United Kingdom-based General Practice Research Database, we tested the hypotheses that fracture risk was associated with 1) an elevated risk of falls caused by the acute central nervous system effects of opioids including sedation and dizziness, and 2) osteoporosis caused by chronic opioid-induced hypogonadism. Among a cohort of adults aged 18-80 years without cancer who received >=1 opioid prescription during 1990-2008, we selected cases with a first diagnosed fracture of the hip, humerus, or wrist; up to 4 controls, matched by age, sex, index date (date of the first diagnosed fracture), and general practice, were randomly selected for each case. Adjusted odds ratios and 95% confidence intervals were estimated by using conditional logistic regression. Current use of 1 prescription was associated with a strong risk of fracture (adjusted odds ratio = 2.70, 95% confidence interval: 2.34, 3.13). The risk decreased with increasing use. There was no association with current use of >20 opioid prescriptions. The findings were consistent for all study fractures and for most common opioids, suggesting that acute central nervous system effects of opioids rather than chronic opioid-induced hypogonadism play a key role in fracture risk. PMID- 23639938 TI - Maternal dietary patterns are associated with risk of neural tube and congenital heart defects. AB - Studying empirically derived dietary patterns is useful in understanding dietary practice. We classified women by their dietary patterns using latent class analysis of 66 foods and studied the association of these patterns with neural tube defects (NTDs) and congenital heart defects (CHDs) in the U.S. National Birth Defects Prevention Study (1997-2005). Logistic regression models used data from 1,047 with an NTD, 6,641 with a CHD, and 6,123 controls that were adjusted for maternal characteristics and tested the effect modification of multivitamin supplement use. Four latent dietary patterns were identified: prudent, Western, low-calorie Western, and Mexican. Among participants who did not use supplements, those in the Mexican, Western, and low-calorie Western classes were significantly more likely (odds ratios of 1.6, 1.5, and 1.4, respectively) to have offspring born with NTDs than were those in the prudent class after adjustment of for dietary folic acid intake. In contrast, among supplement users, there was no difference in the incidence of NTDs between classes. Associations between dietary class and CHD subgroups were not modified by supplement use except for tetralogy of Fallot; among supplement users, those in the Western class were twice as likely (95% confidence interval: 1.4, 2.8) as the prudent class to have offspring with tetralogy of Fallot. Women who adhered to a Western diet were 1.2 (95% confidence interval: 1.03, 1.35) times more likely to have an infant with septal heart defect than were women who adhered to a prudent diet. A prudent dietary pattern, even with folate fortification, may decrease the risk of NTDs and some heart defects. PMID- 23639940 TI - Combination of protein coding and noncoding gene expression as a robust prognostic classifier in stage I lung adenocarcinoma. AB - Prognostic tests for patients with early-stage lung cancer may provide needed guidance on postoperative surveillance and therapeutic decisions. We used a novel strategy to develop and validate a prognostic classifier for early-stage lung cancer. Specifically, we focused on 42 genes with roles in lung cancer or cancer prognosis. Expression of these biologically relevant genes and their association with relapse-free survival (RFS) were evaluated using microarray data from 148 patients with stage I lung adenocarcinoma. Seven genes associated with RFS were further examined by quantitative reverse transcription PCR in 291 lung adenocarcinoma tissues from Japan, the United States, and Norway. Only BRCA1, HIF1A, DLC1, and XPO1 were each significantly associated with prognosis in the Japan and US/Norway cohorts. A Cox regression-based classifier was developed using these four genes on the Japan cohort and validated in stage I lung adenocarcinoma from the US/Norway cohort and three publicly available lung adenocarcinoma expression profiling datasets. The results suggest that the classifier is robust across ethnically and geographically diverse populations regardless of the technology used to measure gene expression. We evaluated the combination of the four-gene classifier with miRNA miR-21 (MIR21) expression and found that the combination improved associations with prognosis, which were significant in stratified analyses on stage IA and stage IB patients. Thus, the four coding gene classifier, alone or with miR-21 expression, may provide a clinically useful tool to identify high-risk patients and guide recommendations regarding adjuvant therapy and postoperative surveillance of patients with stage I lung adenocarcinoma. PMID- 23639942 TI - Editorial comment. PMID- 23639943 TI - Editorial comment. PMID- 23639944 TI - Carbon nanotube electrodes in organic transistors. AB - The scope of this Minireview is to provide an overview of the recent progress on carbon nanotube electrodes applied to organic thin film transistors. After an introduction on the general aspects of the charge injection processes at various electrode-semiconductor interfaces, we discuss the great potential of carbon nanotube electrodes for organic thin film transistors and the recent achievements in the field. PMID- 23639941 TI - MEK1/2 inhibition decreases lactate in BRAF-driven human cancer cells. AB - The RAS/BRAF/MEK/ERK signaling pathway is a central driver in cancer with many BRAF and MEK inhibitors being evaluated in clinical trials. Identifying noninvasive biomarkers of early pharmacodynamic responses is important for development of these targeted drugs. As increased aerobic glycolysis is often observed in cancer, we hypothesized that MEK1/2 (MAP2K1/MAP2K2) inhibitors may reduce lactate levels as detected by magnetic resonance spectroscopy (MRS), as a metabolic biomarker for the pharmacodynamic response. MRS was used to monitor intracellular and extracellular levels of lactate in human cancer cells in vitro and in melanoma tumors ex vivo. In addition, we used (1)H MRS and a fluorescent glucose analog to evaluate the effect of MEK inhibition on glucose uptake. MEK1/2 signaling inhibition reduced extracellular lactate levels in BRAF-dependent cells but not BRAF-independent cells. The reduction in extracellular lactate in BRAF driven melanoma cells was time-dependent and associated with reduced expression of hexokinase-II driven by c-Myc depletion. Taken together, these results reveal how MEK1/2 inhibition affects cancer cell metabolism in the context of BRAF oncogene addiction. Furthermore, they offer a preclinical proof-of-concept for the use of MRS to measure lactate as a noninvasive metabolic biomarker for pharmacodynamic response to MEK1/2 inhibition in BRAF-driven cancers. PMID- 23639945 TI - The clinical profile of high-risk mentally disordered offenders. AB - PURPOSE: High-risk mentally disordered offenders present a diverse array of clinical characteristics. To contain and effectively treat this heterogeneous population requires a full understanding of the group's clinical profile. This study aimed to identify and validate clusters of clinically coherent profiles within one high-risk mentally disordered population in the UK. METHODS: Latent class analysis (a statistical technique to identify clustering of variance from a set of categorical variables) was applied to 174 cases using clinical diagnostic information to identify the most parsimonious model of best fit. Validity analyses were performed. RESULTS: Three identified classes were a 'delinquent' group (n = 119) characterised by poor educational history, strong criminal careers and high recidivism risk; a 'primary psychopathy' group (n = 38) characterised by good educational profiles and homicide offences and an 'expressive psychopathy' group (n = 17) presenting the lowest risk and characterised by more special educational needs and sexual offences. CONCLUSIONS: Individuals classed as high-risk mentally disordered offenders can be loosely segregated into three discrete subtypes: 'delinquent', 'psychopathic' or 'expressive psychopathic', respectively. These groups represent different levels of risk to society and reflect differing treatment needs. PMID- 23639946 TI - Optical imaging of non-fluorescent nanodiamonds in live cells using transient absorption microscopy. AB - We directly observe non-fluorescent nanodiamonds in living cells using transient absorption microscopy. This label-free technology provides a novel modality to study the dynamic behavior of nanodiamonds inside the cells with intrinsic three dimensional imaging capability. We apply this method to capture the cellular uptake of nanodiamonds under various conditions, confirming the endocytosis mechanism. PMID- 23639947 TI - ZnO nanoparticle based highly efficient CdS/CdSe quantum dot-sensitized solar cells. AB - 20 nm ZnO nanoparticles are used to fabricate the mesoporous photoanode of the CdS/CdSe quantum dot-sensitized solar cells by the simple doctor blade method. A maximum power conversion efficiency of 4.46% has been achieved, which indicated exciting prospects for ZnO nanoparticle based quantum dot-sensitized solar cells. PMID- 23639949 TI - Construction of small plasmid vectors for use in genetic improvement of the extremely acidophilic Acidithiobacillus caldus. AB - The genetic improvement of biomining bacteria including Acidithiobacillus caldus could facilitate the bioleaching process of sulfur-containing minerals. However, the available vectors for use in A. caldus are very scanty and limited to relatively large broad-host-range IncQ plasmids. In this study, a set of small, mobilizable plasmid vectors (pBBR1MCS-6, pMSD1 and pMSD2) were constructed based on plasmid pBBR1MCS-2, which does not belong to the IncQ, IncW, or IncP groups. The function of the tac promoter on 5.8-kb pMSD2 was determined by inserting a kanamycin-resistant reporter gene. The resulting recombinant pMSD2-Km was successfully transferred by conjugation into A. caldus MTH-04 with transfer frequency of 1.38+/-0.64*10(-5). The stability and plasmid copy number of pMSD2 Km in A. caldus MTH-04 were 75+/-2.7% and 5-6 copies per cell, respectively. By inserting an arsABC operon into pMSD2, an arsenic-resistant recombinant pMSD2-As was constructed and transferred into A. caldus MTH-04 by conjugation. The arsenic tolerance of A. caldus MTH-04 containing pMSD2-As was obviously increased up to 45mM of NaAsO2. These vectors could be applied in genetic improvement of A. caldus as well as other bioleaching bacteria. PMID- 23639948 TI - Psychotic experiences and psychotic disorders at age 18 in relation to psychotic experiences at age 12 in a longitudinal population-based cohort study. AB - OBJECTIVE The authors examined the development of psychotic experiences and psychotic disorders in a large population-based sample of young adults and explored their relationship to psychotic phenomena earlier in childhood. METHOD The authors conducted a longitudinal birth cohort study of individuals assessed with the semistructured Psychosis-Like Symptom Interviews at ages 12 and 18 years. RESULTS Of the 4,724 individuals interviewed at age 18, 433 (9.2%) had either suspected (N=203 [4.3%]) or definite (N=230 [4.9%]) psychotic experiences. Of these, 79 (1.7%) met criteria for a psychotic disorder, and of those, only 50% sought professional help. All psychotic outcomes were more likely in young women and in those from socioeconomically disadvantaged backgrounds. Of the participants who had psychotic experiences at age 12, 78.7% had remitted by age 18. The risk of psychotic disorders at age 18 was greater in those with suspected (odds ratio=5.6, 95% CI=2.6-12.1) and especially in those with definite (odds ratio=12.7, 95% CI=6.2-26.1) psychotic experiences at age 12, and also among those with psychotic experiences at age 12 attributed to sleep or fever or with nonpsychotic experiences such as depersonalization. The positive predictive values for increasing frequency of experiences at age 12 predicting psychotic disorders at age 18 ranged from 5.5% to 22.8%. CONCLUSIONS Despite evidence for a continuum of psychotic experiences from as early as age 12, positive predictive values for predicting psychotic disorders were too low to offer real potential for targeted interventions. Psychotic disorders in young adults are relatively uncommon, but they constitute an important unmet need for care given that half of the individuals in this study who met criteria for a psychiatric disorder had not sought help for these problems despite high levels of associated distress and impairment. PMID- 23639950 TI - Climate variability and outbreaks of infectious diseases in Europe. AB - Several studies provide evidence of a link between vector-borne disease outbreaks and El Nino driven climate anomalies. Less investigated are the effects of the North Atlantic Oscillation (NAO). Here, we test its impact on outbreak occurrences of 13 infectious diseases over Europe during the last fifty years, controlling for potential bias due to increased surveillance and detection. NAO variation statistically influenced the outbreak occurrence of eleven of the infectious diseases. Seven diseases were associated with winter NAO positive phases in northern Europe, and therefore with above-average temperatures and precipitation. Two diseases were associated with the summer or spring NAO negative phases in northern Europe, and therefore with below-average temperatures and precipitation. Two diseases were associated with summer positive or negative NAO phases in southern Mediterranean countries. These findings suggest that there is potential for developing early warning systems, based on climatic variation information, for improved outbreak control and management. PMID- 23639951 TI - Aberrant expression of signaling proteins in essential thrombocythemia. AB - Dysregulated expression of signaling proteins may contribute to the pathophysiology of essential thrombocythemia (ET). This study aimed to characterize protein expression in ET and to correlate the dysregulated proteins with phenotypes and prognosis of ET patients. The expression of 128 proteins in peripheral blood neutrophils from 74 ET patients was assessed and compared with those from 29 healthy subjects and 35 polycythemia vera (PV) patients using protein pathway array. Fifteen proteins were differentially expressed between ET patients and normal controls. These dysregulated proteins were involved in the signaling pathways related with apoptosis and inflammation. Our results showed a significant overlap in protein expression between ET patients with JAK2V617F mutation and PV patients. In addition, nine proteins were associated with JAK2V617F mutation status in ET patients. Furthermore, estrogen receptor beta (ERbeta) and Stat3 were independent risk factors for subsequent thrombosis during follow-up on multivariable analysis. Our study shows a broad dysregulation of signaling protein in ET patients, suggesting their roles in ET pathogenesis. The expression levels of ERbeta and Stat3 could be promising predictors of subsequent thrombosis in ET patients. PMID- 23639952 TI - The impact of group music therapy on depression and cognition in elderly persons with dementia: a randomized controlled study. AB - OBJECTIVE: The aims of this study were to determine the effectiveness of group music therapy for improving depression and delaying the deterioration of cognitive functions in elderly persons with dementia. METHOD: The study had a prospective, parallel-group design with permuted-block randomization. Older persons with dementia (N = 104) were randomly assigned to the experimental or control group. The experimental group received 12 sessions of group music therapy (two 30-min sessions per week for 6 weeks), and the control group received usual care. Data were collected 4 times: (1) 1 week before the intervention, (2) the 6th session of the intervention, (3) the 12th session of the intervention, and (4) 1 month after the final session. RESULTS: Group music therapy reduced depression in persons with dementia. Improvements in depression occurred immediately after music therapy and were apparent throughout the course of therapy. The cortisol level did not significantly decrease after the group music therapy. Cognitive function significantly improved slightly at the 6th session, the 12th session, and 1 month after the sessions ended; in particular, short-term recall function improved. The group music therapy intervention had the greatest impact in subjects with mild and moderate dementia. CONCLUSION: The group music intervention is a noninvasive and inexpensive therapy that appeared to reduce elders' depression. It also delayed the deterioration of cognitive functions, particularly short-term recall function. Group music therapy may be an appropriate intervention among elderly persons with mild and moderate dementia. PMID- 23639954 TI - Variation and evolution of herkogamy in Exochaenium (Gentianaceae): implications for the evolution of distyly. AB - BACKGROUNDS AND AIMS: The spatial separation of stigmas and anthers (herkogamy) in flowering plants functions to reduce self-pollination and avoid interference between pollen dispersal and receipt. Little is known about the evolutionary relationships among the three main forms of herkogamy - approach, reverse and reciprocal herkogamy (distyly) - or about transitions to and from a non herkogamous condition. This problem was examined in Exochaenium (Gentianaceae), a genus of African herbs that exhibits considerable variation in floral morphology, including the three forms of herkogamy. METHODS: Using maximum parsimony and maximum likelihood methods, the evolutionary history of herkogamic and non herkogamic conditions was reconstructed from a molecular phylogeny of 15 species of Exochaenium and four outgroup taxa, based on three chloroplast regions, the nuclear ribosomal internal transcribed spacer (ITS1 and 2) and the 5.8S gene. Ancestral character states were determined and the reconstructions were used to evaluate competing models for the origin of reciprocal herkogamy. KEY RESULTS: Reciprocal herkogamy originated once in Exochaenium from an ancestor with approach herkogamy. Reverse herkogamy and the non-herkogamic condition homostyly were derived from heterostyly. Distylous species possessed pendent, slightly zygomorphic flowers, and the single transition to reverse herkogamy was associated with the hawkmoth pollination syndrome. Reductions in flower size characterized three of four independent transitions from reciprocal herkogamy to homostyly. CONCLUSIONS: The results support Lloyd and Webb's model in which distyly originated from an ancestor with approach herkogamy. They also demonstrate the lability of sex organ deployment and implicate pollinators, or their absence, as playing an important role in driving transitions among herkogamic and non-herkogamic conditions. PMID- 23639955 TI - An analysis of performance evaluation for motor-imagery based BCI. AB - In recent years, numerous brain-computer interfaces (BCIs) based on motor-imagery have been proposed which incorporate features such as adaptive classification, error detection and correction, fusion with auxiliary signals and shared control capabilities. Due to the added complexity of such algorithms, the evaluation strategy and metrics used for analysis must be carefully chosen to accurately represent the performance of the BCI. In this article, metrics are reviewed and contrasted using both simulated examples and experimental data. Furthermore, a review of the recent literature is presented to determine how BCIs are evaluated, in particular, focusing on the relationship between how the data are used relative to the BCI subcomponent under investigation. From the analysis performed in this study, valuable guidelines are presented regarding the choice of metrics and evaluation strategy dependent upon any chosen BCI paradigm. PMID- 23639953 TI - Effects of perinatal testosterone on infant health, mother-infant interactions, and infant development. AB - OBJECTIVE: Many researchers and health care providers have noticed male vulnerability in infant health, mother-infant interactions, and some infant cognitive development, especially among very low birth weight (VLBW) preterm infants. However, factors beyond gender that could explain these observed differences have not been clear. The purpose of this article is to review the literature on the subject and to introduce a conceptual framework relating these factors. DISCUSSION: According to gender-difference theories, prenatal exposure to high levels of testosterone may influence infant health and mother-infant interactions by negatively affecting infant cognitive/motor/language development. We constructed a conceptual framework based on the associations among biological (perinatal testosterone), stress-related (perinatal and maternal cortisol), and developmental (infant cognitive/motor/language skills) factors. If research establishes these biological, environmental, and developmental associations in mother-VLBW preterm pairs, the results will highlight the importance of addressing gender differences in nursing research and encourage the development of nursing interventions designed to reduce stress among mothers of VLBW preterm infants, particularly male infants. CONCLUSION: From a psychobiosocial perspective, combining biophysiological factors such as perinatal testosterone and cortisol with socioenvironmental factors such as the quality of mother-infant interactions and infant temperament may provide a broader view of gender differences in infant health and development. PMID- 23639956 TI - Modelling the human response to saltiness. AB - Eating is a complex process with a range of phenomena occurring simultaneously, including fracture, temperature changes, mixing with saliva, flavour and aroma release. Sensory perception as experienced in the oral cavity has a strong effect on the overall acceptability of the food. Thus in an engineering sense one would want to be able to understand and predict phenomena for different food matrices in order to design more palatable foods through understanding food oral processing without the health concerns of adding salt, fat and sugar. In this work we seek to obtain such an understanding for salt release from food matrices and perception viewing the oral processing as a physical/chemical reactor. A set of equations was developed to account for mass balance and transfer. Data required for the model such as effective diffusivity and mixing times were obtained from the chemical engineering literature. The model predictions compared favourably with published TI data, managing to capture key phenomena including response to pulsed salt release. The model was used to predict response to a range of food matrices and indicated that for solids and thickened liquid food products there is the potential to modulate consumer response by pulsing the release of sodium. PMID- 23639957 TI - Incorporating a health policy practicum in a graduate training program to prepare advanced practice nursing health services researchers. AB - Health services research benefits from the active engagement of researchers and policy makers from generation through to application of research-based knowledge. One approach to help graduate students learn about the policy world is through participation in a policy practicum. This is an opportunity to work for a defined period of time in a setting where policy decisions are made. This article focuses on the integration of the policy practicum into graduate nursing education for advanced practice nurses. Ten graduate students and two postdoctoral fellows who had recently completed their practicums and three policy makers who had recently supervised students in provincial, federal, and international practicum projects were invited to submit a narrative about the experience. Based on qualitative analysis of the narratives, this article outlines objectives of the practicum, the policy practicum journey, student learning, and finally, the benefits and challenges of the experience. PMID- 23639958 TI - Managing up, down, and across the nursing home: roles and responsibilities of directors of nursing. AB - The director of nursing (DON) is an essential member of the top management team in nursing homes and in a key position to improve the quality and value of care. This article describes and examines the roles and responsibilities of DONs as perceived by a convenience sample of current/previous DONs and nursing home administrators (n = 29). Data were collected through in-depth semistructured interviews and analyzed using content analysis and thematic analysis. The findings reveal a broad scope and wide variation in the DON position across settings, with inextricable linkages between clinical care and other aspects of care delivery, such as managing fiscal and human resources (HR). As RN licensure is the only Federal requirement for the DON position, suggesting a clinical focus, the findings highlight a policy-practice gap. Research is needed to address this gap, focusing on the requisite preparation DONs need to effectively and cost-efficiently lead initiatives for quality improvement. PMID- 23639959 TI - De novo MECP2 disomy in a Mexican male carrying a supernumerary marker chromosome and no typical Lubs syndrome features. AB - Xq28 duplication, including the MECP2 gene, is among the most frequently identified Xq subtelomeric rearrangements. The resulting clinical phenotype is named Lubs syndrome and mainly consists of intellectual disability, congenital hypotonia, absent speech, recurrent infections, and seizures. Here we report a Mexican male patient carrying a supernumerary marker chromosome with de novo Xq28 gain. By MLPA, duplication of MECP2, GDI1, and SLC6A8 was found and a subsequent a-CGH analysis demonstrated that the gain spanned ~2.1Mb. Despite gain of the MECP2 gene, the features of this patient do not evoke Lubs syndrome. Probably the mosaicism of the supernumerary marker chromosome is modifying the phenotype in this patient. PMID- 23639960 TI - The impact of transcription on posttranscriptional processes in yeast. AB - In eukaryotes, three RNA polymerases are responsible for transcription. These complex enzymes show many similarities with one another, such as several common or highly homologue subunits, while some other features, such as transcript length, diversity, processing, and transcription regulation, are unique to each polymerase. The present article reviews recent publications focusing on the impact of transcription of various RNA species in yeast on posttranscriptional steps such as pre-RNA processing, transport and decay. Two major conclusions emerge from a critical analysis of the current knowledge. (1) The kinetics of transcription elongation affects cotranscriptional pre-RNA processing. (2) The efficiency of transcription, by saturating the proteins interacting with RNA, indirectly affects the processing, export and decay of transcripts. PMID- 23639961 TI - Uncoupling protein 2 -866G/A and uncoupling protein 3 -55C/T polymorphisms in young South African Indian coronary artery disease patients. AB - BACKGROUND: Uncoupling proteins (UCPs) 2 and 3 play an important role in the regulation of oxidative stress which contributes to chronic inflammation. Promoter polymorphisms of these genes have been linked to chronic diseases including heart disease and type II diabetes mellitus in several populations. This is the first investigation of the UCP2 -866G/A rs659366 and UCP3 -55C/T rs1800849 polymorphisms in young South African (SA) Indians with coronary artery disease (CAD). METHODS: A total of 300 subjects were recruited into this study of which 100 were SA Indian males with CAD, 100 age- (range 24-45 years), gender- and race-matched controls and 100 age-matched black SA males. The frequency of the UCP2 -866G/A and UPC3 -55C/T genotypes was assessed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS: The heterozygous UCP2 -866G/A and homozygous UCP3 -55C/C genotypes occurred at highest frequency in CAD patients (60% and 64%, respectively) compared to SA Indian controls (52% and 63%) and SA Black controls (50% and 58%). The UCP2 886G/A (OR=1.110; 95% CI=0.7438-1.655; p=0.6835) and UCP3 -55C/T (OR=0.788; 95% CI=0.482-1.289; p=0.382) polymorphisms did not influence the risk of CAD. The rare homozygous UCP3 -55T/T genotype was associated with highest fasting glucose (11.87 +/- 3.7 mmol/L vs. C/C:6.11 +/- 0.27 mmol/L and C/T:6.48 +/- 0.57 mmol/L, p=0.0025), HbA1c (10.05 +/- 2.57% vs. C/C:6.44 +/- 0.21% and C/T:6.76 +/- 0.35%, p=0.0006) and triglycerides (6.47 +/- 1.7 mmol/L vs. C/C:2.33 +/- 0.17 mmol/L and C/T:2.06 +/- 0.25 mmol/L, p<0.0001) in CAD patients. CONCLUSION: The frequency of the UCP2 -866G/A and UCP3 -55C/T polymorphisms was similar in our SA Indian and SA Black groups. The presence of the UCP2 -866G/A and UCP3 -55C/T polymorphisms does not influence the risk of CAD in young South African Indian CAD patients. PMID- 23639962 TI - Recurrent porphyria attacks in a Chinese patient with a heterozygous PBGD mutation. AB - We report here the case of a 32-year-old Chinese Han woman who presented with frequent severe abdominal pain, convulsion, numbness and confusion. She also had hypertension, hyponatremia, chronic renal failure, anemia and a high urinary delta-aminolevulinic acid concentration. We identified a heterozygous splicing mutation in intron 11 (IVS11-2A->G) of the porphobilinogen (PBG) deaminase gene (PBGD) in her genomic DNA. This mutation had previously been reported in a North American patient, but was absent from 50 healthy Chinese controls. PMID- 23639963 TI - Innate immunity functional gene polymorphisms and gout susceptibility. AB - Gout is a common autoinflammatory disease characterized with elevated serum urate and recurrent attacks of intra-articular crystal deposition of monosodium urate. Accumulating evidence has demonstrated that MSU crystal-induced inflammation is a paradigm of innate immunity and the TLRs, NALP3 inflammasome and IL1R pathways are involved in gout development. Innate immunity components containing TLR2, TLR4, CD14, NALP3, ASC, Caspase-1 and CARD-8 are essential in the development of gouty inflammation. Recent studies suggest that innate immunity component gene functional mutations contribute to the development of autoinflammatory diseases including hereditary periodic fever syndrome, arthritis as well as inflammatory bowel disease. Taking into account these genetic findings, we would like to propose a novel hypothesis that the gene functional mutations might make innate immunity components as attractive susceptibility candidates and genetic markers for gout. Further clinical genetic studies need to be performed to confirm the role of innate immunity in the etiology of gout. PMID- 23639964 TI - A 1.1Mb deletion in distal 13q deletion syndrome region with congenital heart defect and postaxial polydactyly: additional support for a CHD locus at distal 13q34 region. AB - 13q deletion syndrome is a rare genetic disorder, especially for group 3 deletion (13q33-q34 deletion). Previously we described a patient with congenital heart defect and mental retardation and proposed that a distal 6Mb region might contain the causative gene of congenital heart defect. Here we present a new patient with congenital heart defects (CHD), hand and foot anomalies and mild mental retardation. We identified a 1.1Mb deletion at chromosome 13q34 with high resolution SNP-array BeadChips (HumanOmni1-Quad, Illumina, USA). This chromosome region contains ten annotated genes, including GRK1, TFDP1, RASA3 and GAS6. To our knowledge, this represents the smallest 13q34 deletion identified to date. Our study provides additional support that distal 13q34 deletion region might contain key gene(s) responsible for cardiac development. PMID- 23639965 TI - A novel prophenoloxidase, hemocyanin encoded copper containing active enzyme from prawn: gene characterization. AB - The copper containing prophenoloxidase enzyme plays a crucial role in the defense system of arthropods, especially crustaceans and insects. In this study, we have reported a full length cDNA of prophenoloxidase identified from the constructed cDNA library of freshwater prawn Macrobrachium rosenbergii by genome sequence FLX technology. The identified full length M. rosenbergii prophenoloxidase (MrProPO) consists of 3378 base pairs (bp) with an open reading frame (ORF) of 2099 bp. This ORF encoded a polypeptide of 700 amino acids (aa) with an estimated molecular mass of 80 kDa and a predicted isoelectric point (pI) of 6.7. The motif analysis of MrProPO shows two copper binding sites (CuA and CuB) along with hemocyanin signatures and a thiol-ester like motif. MrProPO exhibited the maximum similarity (97%) with ProPO from Macrobrachium nipponense and is closely clustered with other crustacean ProPO in the phylogenetic tree. Bioinformatics analysis suggests that MrProPO is a member of the prophenoloxidase family, due to the conserved domains, motifs and similarity with other known ProPOs. The 3D structural analysis of MrProPO reveals that it has more random coils, moderate alpha-helices, few extended beta-sheets and a very few beta-turns. Among the 700 aa of MrProPO, 355 (50.71%), 206 (29.43%), 110 (15.71%) and 29 (4.14%) amino acids are responsible for random coils, alpha-helices, extended beta-sheets and beta-turns respectively. The gene expression results indicate MrProPO is widely distributed in all the tissues studied, but significantly (P<0.05) highest expression was observed in hepatopancreas. The relative expression of mRNA was quantified in hepatopancreas after being infected with virus [white spot syndrome baculovirus (WSBV) and M. rosenbergii nodovirus (MrNV)] and bacteria (Aeromonas hydrophila and Vibrio harveyi) using real-time PCR. MrProPO mRNA transcription significantly (P<0.05) increased at 24h post injection (p.i.) with subsequent decrease at 48 h p.i. in both viral and bacterial infected prawns. The highest enzyme activity was observed in hepatopancreas, which was also significantly higher (P<0.05) than detected in other tissues. Similar to gene expression results, the enzyme activity reached the peak at 24h p.i. and then the activity started decreasing. Overall results indicate that MrProPO is very likely to participate in the acute response against pathogen entry in prawns. PMID- 23639966 TI - Five-year clinical effects of donor bone marrow cells infusions in kidney allograft recipients: improved graft function and higher graft survival. AB - Augmentation of microchimerism in solid organ transplant recipients by donor bone marrow cells (DBMC) infusion may promote immune hyporesponsiveness and consequently improve long-term allograft survival. Between March 2005 and July 2007, outcomes for 20 living unrelated donor (LURD) primary kidney recipients with concurrent DBMC infusion (an average of 2.19 +/- 1.13 x 109 donor cells consisting of 2.66 +/- 1.70 x 107 CD34+ cells) were prospectively compared with 20 non-infused control allograft recipients given similar conventional immunosuppressive regimens. With five years of clinical follow up, a total of 11 cases experienced rejection episodes (3 DBMI patients vs. 8 controls, p = 0.15). One DBMC-infused patient experienced chronic rejection vs. two episodes (1 biopsy confirmed) in the control patients. Actuarial and death-censored 5-y graft survival was significantly higher in infused patients compared with controls (p = 0.01 and p = 0.03, respectively). Long-term graft survival was significantly associated with pre-transplant anti-HLA antibodies (p = 0.01), slightly with peripheral microchimerism (p = 0.09) and CD4+CD25+FoxP3+ T cells (p = 0.09). Immunosuppressant dosing was lower in infused patients than controls, particularly for mycophenolate mofetil (p = 0.001). The current findings as well as our previous reports on these patients indicates clinical improvement in long term graft survival of renal transplant patients resulting from low-dose DBMC infusion given without induction therapy. PMID- 23639967 TI - A feasibility study on the prediction of acute graft-vs.-host disease before hematopoietic stem cell transplantation based on fetomaternal tolerance. AB - The contact between the immune systems of mother and child during pregnancy affects an immune response of the child against noninherited maternal antigens (NIMA) and the mother against inherited paternal antigens (IPA). However, the immunologic effects of developmental exposure to NIMA or IPA are heterogeneous, and can be either tolerogenic or immunogenic. Although we have reported that prediction of acute graft-vs.-host disease (GVHD) is feasible in a murine model, there has been no literature in human. We devised a novel method for predicting a tolerogenic effect by using mixed lymphocyte reaction combined with enzyme-linked immunospot (MLR-ELISPOT) assay. The assay can evaluate reactivity of interferon gamma spot-forming cells of donor against the recipient. Although we have shown only two examples of mother to child reactivity so far, our preliminary results suggest that this pre-screened assay may be used to predict acute GVHD. The clinical trial is in progress to evaluate MLR-ELISPOT assay as a predicting measure of acute GVHD in haploidentical transplantation from NIMA or IPA mismatched family donor. PMID- 23639968 TI - Arginase II inhibited lipopolysaccharide-induced cell death by regulation of iNOS and Bcl-2 family proteins in macrophages. AB - Arginase II catalyzes the conversion of arginine to urea and ornithine in many extrahepatic tissues. We investigated the protective role of arginase II on lipopolysaccharide-mediated apoptosis in the macrophage cells. Adenoviral gene transfer of full length of arginase II was performed in the murine macrophage cell line RAW264.7. The role of arginase II was investigated with cell viability, cytoplasmic histone-associated DNA fragmentation assay, arginase activity, nitric oxide production, and Western blot analysis. Arginase II is localized in mitochondria of macrophage cells, and the expression of arginase II was increased by lipopolysaccharide (LPS). LPS significantly increased cell death which was inhibited by AMT, a specific inducible nitric oxide synthase (iNOS) inhibitor. In contrast, LPS-induced cell death and nitric oxide production were increased by 2 boronoethyl-L-cysteine, a specific inhibitor of arginase. Adenoviral overexpression of arginase II significantly inhibited LPS-induced cell death and cytoplasmic histone-associated DNA fragmentation. LPS-induced iNOS expression and poly ADP-ribose polymerase cleavage were significantly suppressed by arginase II overexpression. Furthermore, arginase II overexpression resulted in a decrease in the Bax protein level and the reverse induction of Bcl-2 protein. Our data demonstrated that inhibition of NO production by arginase II may be due to arginine depletion as well as iNOS suppression though its reaction products. Moreover, arginase II plays a protective role of LPS-induced apoptosis in RAW264.7 cells. PMID- 23639969 TI - The effect of amino density on the attachment, migration, and differentiation of rat neural stem cells in vitro. AB - Artificial extracellular matrices play important roles in the regulation of stem cell behavior. To generate materials for tissue engineering, active functional groups, such as amino, carboxyl, and hydroxyl, are often introduced to change the properties of the biomaterial surface. In this study, we chemically modified coverslips to create surfaces with different amino densities and investigated the adhesion, migration, and differentiation of neural stem cells (NSCs) under serum free culture conditions. We observed that a higher amino density significantly promoted NSCs attachment, enhanced neuronal differentiation and promoted excitatory synapse formation in vitro. These results indicate that the amino density significantly affected the biological behavior of NSCs. Thus, the density and impact of functional groups in extracellular matrices should be considered in the research and development of materials for tissue engineering. PMID- 23639970 TI - Identification of an isogenic semidwarf rice cultivar carrying the Green Revolution sd1 gene by multiplex codominant ASP-PCR and SSR markers. AB - The rice cultivar Hikarishinseiki, a semidwarf isogenotype of Koshihikari carrying the Green Revolution sd1 gene, is increasingly grown in both Japan and the United States. Here, we report DNA diagnosis for Hikarishinseiki targeting its Jukkoku-type sd1 locus, which codes for a defective gibberellin 20-oxidase, with a 1 bp substitution in exon 1 (Jukkoku-type GA20ox-2 mutant allele: Jukkoku_GA20ox-2). An allele-specific primer (ASP)-polymerase chain reaction (PCR) with primers SD1F3 and SD1JR gave a PCR product specific to Jukkoku_GA20ox 2. In addition, ASP-PCR with primers SD1F3 and SD1NRM (which contains a mismatch at the third nucleotide from the 3'-terminus of SD1NR) gave a PCR product specific to non-Jukkoku_GA20ox-2. Multiplex ASP-PCR using SD1F3, VIC dye-labeled SD1JR, and FAM dye-labeled SD1NRM enabled simultaneous codominant detection of Jukkoku_GA20ox-2 and non-Jukkoku_GA20ox-2 among 188 cultivars. Also, Hikarishinseiki is identifiable by RM253 polymorphism from 11 cultivars carrying Jukkoku_GA20ox-2. Taken together, our results establish a methodology for distinguishing Hikarishinseiki. PMID- 23639971 TI - Amphiphile nanoarchitectonics: from basic physical chemistry to advanced applications. AB - Amphiphiles, either synthetic or natural, are structurally simple molecules with the unprecedented capacity to self-assemble into complex, hierarchical geometries in nanospace. Effective self-assembly processes of amphiphiles are often used to mimic biological systems, such as assembly of lipids and proteins, which has paved a way for bottom-up nanotechnology with bio-like advanced functions. Recent developments in nanostructure formation combine simple processes of assembly with the more advanced concept of nanoarchitectonics. In this perspective, we summarize research on self-assembly of amphiphilic molecules such as lipids, surfactants or block copolymers that are a focus of interest for many colloid, polymer, and materials scientists and which have become increasingly important in emerging nanotechnology and practical applications, latter of which are often accomplished by amphiphile-like polymers. Because the fundamental science of amphiphiles was initially developed for their solution assembly then transferred to assemblies on surfaces as a development of nanotechnological techniques, this perspective attempts to mirror this development by introducing solution systems and progressing to interfacial systems, which are roughly categorized as (i) basic properties of amphiphiles, (ii) self-assembly of amphiphiles in bulk phases, (iii) assembly on static surfaces, (iv) assembly at dynamic interfaces, and (v) advanced topics from simulation to application. This progression also represents the evolution of amphiphile science and technology from simple assemblies to advanced assemblies to nanoarchitectonics. PMID- 23639972 TI - Contamination of blood pressure cuffs by methicillin-resistant Staphylococcus aureus and preventive measures. AB - BACKGROUND: Although blood pressure cuffs are commonly used and shared in medical facilities, their routine disinfection is performed infrequently. AIMS: We investigated the contamination of blood pressure cuffs by methicillin-resistant Staphylococcus aureus (MRSA). METHODS: The MRSA level on the inner side (the surface in contact with patients' skin) of blood pressure cuffs used in the wards and outpatient clinics of a university hospital (733 beds) was determined using the gauze and swab wiping methods. RESULTS: Using the gauze wiping method (n = 35), the MRSA contamination rate was 31.4 %, and the MRSA contamination level was 1,702.6 +/- 9,996.1 (0-58, 320) colony-forming units (cfu)/cuff. No MRSA was detected on blood pressure cuffs after washing (n = 30) or wiping with 80 vol% ethanol (n = 18). CONCLUSIONS: Blood pressure cuffs are frequently contaminated by MRSA. PMID- 23639973 TI - Retinoid acid receptor expression is helpful to distinguish between adenoma and well-differentiated carcinoma in the thyroid. AB - Retinoid receptors (RRs) play a key role in cell proliferation and differentiation. We characterized the expression of RA receptors and retinoid X receptors (RARs and RXRs) in a series of 111 thyroid tumors and investigated the mechanisms responsible for their deregulation: hypermethylation of the RARB2 promoter, loss of heterozygosity (LOH) in the regions of RARB and RXRA, and altered expression of CRBP1 and enzymes involved in RA biosynthesis (RDH10 and RALDH2). Expression of RALDH2 and RDH10 was conserved in 100 % of adenomas and in 90 and 98 %, respectively, of carcinomas, whereas staining for CRBP1 was decreased in 9 % of FAs and 28 % of carcinomas, mainly anaplastic carcinomas (55 %). We found an abnormal expression of RARA, RARB, RXRA, and RXRB in 67, 69, 66, and 73 %, respectively, of thyroid carcinomas (n = 78) and in 9, 9, 9, and 33 % of follicular adenomas (n = 33) (p < 0.001). An abnormal staining pattern of at least two of these markers had 90 % sensitivity and 91 % specificity for a diagnosis of malignancy. Promoter hypermethylation of RARB2 was observed in some anaplastic carcinomas (14 %). LOH was found to be common at the RARB locus (3p24 3p25) and the RXRA locus (9q34), respectively, in 44 and 55 % of carcinomas and in 27 and 43 % of adenomas. In conclusion, immunohistochemical staining for RARs and RXRs may help in the differential diagnosis between well-differentiated carcinoma and follicular adenoma. Further investigation should be carried out to determine whether the characterization of RR expression might identify patients who could benefit from therapy with RA derivatives. PMID- 23639974 TI - The adherens junction: a mosaic of cadherin and nectin clusters bundled by actin filaments. AB - Cadherin and nectin are distinct transmembrane proteins of adherens junctions. Their ectodomains mediate adhesion, whereas their cytosolic regions couple the adhesive contact to the cytoskeleton. Both these proteins are essential for adherens junction formation and maintenance. However, some basic aspects of these proteins, such as their organization in adherence junctions, have remained open. Therefore, using super-resolution microscopy and live imaging, we focused on the subjunctional distribution of these proteins. We showed that cadherin and nectin in the junctions of A431 cells and human keratinocytes are located in separate clusters. The size of each cluster is independent of that of the adjacent clusters and can significantly fluctuate over time. Several nectin and cadherin clusters that constitute an individual adherens junction are united by the same actin-filament bundle. Surprisingly, interactions between each cluster and F actin are not uniform, as neither vinculin nor LIM-domain actin-binding proteins match the boundaries of cadherin or nectin clusters. Thus, the adherens junction is not a uniform structure but a mosaic of different adhesive units with very diverse modes of interaction with the cytoskeleton. We propose that such a mosaic architecture of adherence junctions is important for the fast regulation of their dynamics. PMID- 23639975 TI - UVB induces HIF-1alpha-dependent TSLP expression via the JNK and ERK pathways. AB - Thymic stromal lymphopoietin (TSLP) may have a key role in the initiation and maintenance of allergic inflammatory diseases, including atopic dermatitis. The present study revealed that UVB radiation exposure could induce TSLP expression in human keratinocytes and a human skin equivalent model. In addition, we investigated the regulatory mechanism of UVB-induced TSLP expression in keratinocytes. TSLP expression was upregulated by transfection with pcDNA3 hypoxia-inducible factor (HIF)-1alpha (P402A and P564A), which stably expresses HIF-1alpha protein. UVB-induced TSLP induction in keratinocytes was suppressed in the treatment of mitogen-activated protein kinase inhibitors or small interfering RNAs against HIF-1alpha. The results of chromatin immunoprecipitation assays indicate the direct involvement of HIF-1alpha in UVB-mediated TSLP induction. Taken together, these findings indicate that UVB exposure may increase TSLP expression through a HIF-1alpha-dependent mechanism via the c-JUN N-terminal kinase and extracellular signal-regulated kinase pathways in human keratinocytes. Our data showed that UVB-induced TSLP might increase secretion of the T-helper type 2-attracting chemokine (c-c motif) ligand 17 by human dendritic cells. The present study suggests an important role of HIF-1alpha in UVB-mediated immune response in keratinocytes. PMID- 23639977 TI - Reply to Glossmann: vitamin D compounds and oral supplementation methods. PMID- 23639978 TI - Oral supplementation with calcitriol, calcidiol, vitamin D3 or moderate sun exposure? PMID- 23639976 TI - PPARdelta inhibits UVB-induced secretion of MMP-1 through MKP-7-mediated suppression of JNK signaling. AB - In the present study, we investigated the role of peroxisome proliferator activated receptor (PPAR) delta in modulating matrix-degrading metalloproteinases and other mechanisms underlying photoaging processes in the skin. In human dermal fibroblasts (HDFs), activation of PPARdelta by its specific ligand GW501516 markedly attenuated UVB-induced secretion of matrix metalloproteinase (MMP)-1, concomitant with decreased generation of reactive oxygen species. These effects were significantly reduced in the presence of PPARdelta small interfering RNA and GSK0660. Furthermore, c-Jun N-terminal kinase (JNK), but not p38 or extracellular signal-regulated kinase, mediated PPARdelta-dependent inhibition of MMP-1 secretion in HDFs exposed to UVB. PPARdelta-mediated messenger RNA stabilization of mitogen-activated protein kinase phosphatase (MKP)-7 was responsible for the GW501516-mediated inhibition of JNK signaling. Inhibition of UVB-induced secretion of MMP-1 by PPARdelta was associated with the restoration of types I and III collagen to levels approaching those in cells not exposed to UVB. Finally, in HR-1 hairless mice exposed to UVB, administration of GW501516 significantly reduced wrinkle formation and skin thickness, downregulated MMP-1 and JNK phosphorylation, and restored the levels of MKP-7, types I and III collagen. These results suggest that PPARdelta-mediated inhibition of MMP-1 secretion prevents some effects of photoaging and maintains the integrity of skin by inhibiting the degradation of the collagenous extracellular matrix. PMID- 23639979 TI - The digital divide among low-income homebound older adults: Internet use patterns, eHealth literacy, and attitudes toward computer/Internet use. AB - BACKGROUND: Internet technology can provide a diverse array of online resources for low-income disabled and homebound older adults to manage their health and mental health problems and maintain social connections. Despite many previous studies of older adults' Internet use, none focused on these most vulnerable older adults. OBJECTIVE: This study examined Internet use patterns, reasons for discontinued use, eHealth literacy, and attitudes toward computer/Internet use among low-income homebound individuals aged 60 and older in comparison to their younger counterparts-homebound adults under age 60. METHODS: Face-to-face or telephone surveys were conducted with 980 recipients of home-delivered meals in central Texas (78% were age 60 years and older and 22% under age 60). The eHealth Literacy Scale (eHEALS) and the efficacy and interest subscales of the Attitudes Toward Computer/Internet Questionnaire (ATC/IQ) were used to measure the respective constructs. Age groups were compared with chi-square tests and t tests. Correlates of Internet use were analyzed with multinomial logistic regression, and correlates of eHEALS and ATC/IQ scores were analyzed with OLS regression models. RESULTS: Only 34% of the under-60 group and 17% of the 60 years and older group currently used the Internet, and 35% and 16% of the respective group members reported discontinuing Internet use due to cost and disability. In addition to being older, never users were more likely to be black (OR 4.41; 95% CI 2.82-6.91, P<.001) or Hispanic (OR 4.69; 95% CI 2.61-8.44, P<.001), and to have lower incomes (OR 0.36; 95% CI 0.27-0.49, P<.001). Discontinued users were also more likely to be black or Hispanic and to have lower incomes. Among both age groups, approximately three-fourths of the current users used the Internet every day or every few days, and their eHEALS scores were negatively associated with age and positively associated with frequency of use. Among the 60 and older group, a depression diagnosis was also negatively associated with eHEALS scores. ATC/IQ efficacy among never users of all ages and among older adults was positively associated with living alone, income, and the number of medical conditions and inversely associated with age, Hispanic ethnicity, and Spanish as the primary language. Although ATC/IQ interest among older adults was also inversely associated with age, it was not associated with Hispanic ethnicity and Spanish as the primary language. CONCLUSIONS: This study is the first to describe in detail low-income disabled and homebound adults' and older adults' Internet use. It shows very low rates of Internet use compared to the US population, either due to lack of exposure to computer/Internet technology; lack of financial resources to obtain computers and technology; or medical conditions, disabilities, and associated pain that restrict use. Recommendations to reduce the digital divide among these individuals are provided. PMID- 23639980 TI - Typical trajectories of coupled degrade-and-fire oscillators: from dispersed populations to massive clustering. AB - We consider the dynamics of a piecewise affine system of degrade-and-fire oscillators with global repressive interaction, inspired by experiments on synchronization in colonies of bacteria-embedded genetic circuits. Due to global coupling, if any two oscillators happen to be in the same state at some time, they remain in sync at all subsequent times; thus clusters of synchronized oscillators cannot shrink as a result of the dynamics. Assuming that the system is initiated from random initial configurations of fully dispersed populations (no clusters), we estimate asymptotic cluster sizes as a function of the coupling strength. A sharp transition is proved to exist that separates a weak coupling regime of unclustered populations from a strong coupling phase where clusters of extensive size are formed. Each phenomena occurs with full probability in the thermodynamics limit. Moreover, the maximum number of asymptotic clusters is known to diverge linearly in this limit. In contrast, we show that with positive probability, the number of asymptotic clusters remains bounded, provided that the coupling strength is sufficiently large. PMID- 23639982 TI - Editorial to the themed issue on translational modeling in neuroscience. PMID- 23639981 TI - Production of Japanese encephalitis virus-like particles in insect cells. AB - Virus-like particles (VLPs) are composed of one or several recombinant viral surface proteins that spontaneously assemble into particulate structures without the incorporation of virus DNA or RNA. The baculovirus-insect cell system has been used extensively for the production of recombinant virus proteins including VLPs. While the baculovirus-insect cell system directs the transient expression of recombinant proteins in a batch culture, stably transformed insect cells allow constitutive production. In our recent study, a secretory form of Japanese encephalitis (JE) VLPs was successfully produced by Trichoplusia ni BTI-TN-5B1-4 (High Five) cells engineered to coexpress the JE virus (JEV) premembrane (prM) and envelope (E) proteins. A higher yield of E protein was attained with recombinant High Five cells than with the baculovirus-insect cell system. This study demonstrated that recombinant insect cells offer a promising approach to the high-level production of VLPs for use as vaccines and diagnostic antigens. PMID- 23639983 TI - High prevalence of occult hepatitis C virus infection in patients with chronic hepatitis B virus infection. AB - Hepatitis C virus (HCV) infection in the absence of detectable antibodies against HCV and of viral RNA in serum is called occult HCV infection. Its prevalence and clinical significance in chronic hepatitis B virus (HBV) infection is unknown. HCV RNA was tested for in the liver samples of 52 patients with chronic HBV infection and 21 (40 %) of them were positive for viral RNA (occult HCV infection). Liver fibrosis was found more frequently and the fibrosis score was significantly higher in patients with occult HCV than in negative ones, suggesting that occult HCV infection may have an impact on the clinical course of HBV infection. PMID- 23639984 TI - Prevalence of fusB in Staphylococcus aureus clinical isolates. AB - Fusidic acid (FA) resistance in Staphylococcus aureus markedly varied among different regions. Few data for FA resistance are available in China. In this study, FA susceptibility testing was performed, and the prevalence of fusB and fusC in 116 clinical isolates of S. aureus was investigated by PCR. Mutations in fusA were also determined by sequencing of PCR products. Molecular typing of fusB positive strains was based on multilocus sequence typing (MLST), spa typing and pulsed-field gel electrophoresis (PFGE). A DNA fragment flanking fusB was sequenced. Transformation experiments were carried out in fusB-positive S. aureus. Of 116 S. aureus including 19 meticillin-resistant S. aureus (MRSA) and 97 meticillin-susceptible S. aureus (MSSA), four (3.5 %) were resistant to FA with MICs of 6-12 ug ml(-1), including one MRSA from blood and three MSSA from wound exudates. All four FA-resistant isolates were found to be fusB gene positive. Three FA-resistant MSSA strains had the same MLST profile of ST630 and spa type of t377, whilst the MRSA strain belonged to ST630-t4549. Only one PFGE pattern was recognized for these four strains. No fusC and fusA mutations were detected in any of the isolates. FA resistance in fusB-positive clinical isolates could be transferred to S. aureus RN4220. The fusB gene was located in a transposon-like element, which had 99 % identity with that found in pUB101. In conclusion, the FA resistance rate is low in S. aureus, and the fusB gene is responsible for the resistance. PMID- 23639985 TI - High prevalence of VIM-4 and NDM-1 metallo-beta-lactamase among carbapenem resistant Enterobacteriaceae. AB - The purpose of this study was to identify the mechanisms leading to carbapenem resistance among multidrug-resistant Enterobacteriaceae isolates recovered from hospitalized patients with nosocomial infections in Mubarak Al Kabeer Hospital, Kuwait. Fourteen carbapenem-resistant Enterobacteriaceae isolates were obtained from inpatients in different wards and intensive care units between April 2009 and February 2011. Antibiotic susceptibilities were determined using the E-test method. Genes encoding beta-lactamases were characterized by specific PCR amplification, sequencing and conjugation assays. All isolates were identified as metallo-beta-lactamase (MBL) producers using phenotypic and molecular methods. Eleven of the 14 isolates produced VIM-4 (six Klebsiella pneumoniae, three Escherichia coli, one Enterobacter cloacae and one Klebsiella oxytoca). Three K. pneumoniae isolates produced the MBL NDM-1 and co-produced the plasmid-encoded AmpC CMY-4. The VIM-4-producing isolates co-produced extended-spectrum beta lactamases including CTX-M-15 and some SHV derivatives. The VIM-4 gene was not transferable by conjugation studies of six selected strains. We demonstrated here the emergence of VIM-4- and NDM-1-producing isolates in the largest teaching hospital in Kuwait. PMID- 23639986 TI - Effects of Copaifera duckei Dwyer oleoresin on the cell wall and cell division of Bacillus cereus. AB - The aim of this work was to evaluate the antibacterial activity of Copaifera duckei oleoresin and to determine its possible mechanism of action against bacteria of clinical and food interest. The antibacterial activity was determined by agar diffusion and dilution methods; the mechanism of action by transmission electron microscopy and by SDS-PAGE; the bioactive compounds by bioautography; and the chemical analysis by GC/MS. Oleoresin showed activity against nine of the 11 strains of bacteria tested. Bacillus cereus was the most sensitive, with a MIC corresponding to 0.03125 mg ml(-1) and with a bactericidal action. Oleoresin acted on the bacterial cell wall, removing proteins and the S-layer, and interfering with the cell-division process. This activity probably can be attributed to the action of terpenic compounds, among them the bisabolene compound. Gram-negative bacteria tested were not inhibited. C. duckei oleoresin is a potential antibacterial, suggesting that this oil could be used as a therapeutic alternative, mainly against B. cereus. PMID- 23639987 TI - Presence of Clostridium difficile PCR ribotype clusters related to 033, 078 and 045 in diarrhoeic calves in Germany. AB - This study provides data on the distribution and relationship of C. difficile PCR ribotypes in diarrhoeic calves in Germany. C. difficile was isolated from 176 of 999 (17.6 %) faecal samples or swabs of diarrhoeic calves from 603 farms collected between January 2010 and August 2012 by eight federal laboratories of six states. Strains were assigned to 17 PCR ribotypes. PCR ribotypes 033 (57 %), 078 (17 %) and 045/FLI01 (closest match to 045 in the WEBRIBO database; 9 %) were found the most frequently. Nine per cent of all culture-positive tested animals shed more than one multiple locus variable number tandem repeat analysis (MLVA) or PCR ribotype. Eight PCR ribotypes with related profiles (including 033, 078 and 045/FLI01) representing 92 % of all isolates were grouped into three clusters. Molecular relatedness was supported by the absence of the MLVA locus A6Cd only in clustered strains and identical toxin gene profiles for strains within each cluster. Previously reported mulitilocus sequence typing analysis for PCR ribotypes that were also recovered in this study found identical sequence types and a tcdC deletion (Delta39 bp) for 033, 045, 078 and 126 (ST-11), confirming this clustering. A different geographical occurrence of PCR ribotypes was shown for cluster 033 (found more frequently in southern Germany) and 045 (found more frequently in northern Germany). This study showed that clusters of C. difficile PCR ribotypes related to 033, 078 and 045 are predominant in diarrhoeic calves in Germany. The high number of strains belonging to PCR ribotype 078 demonstrated that diarrhoeic calves are also potential reservoirs for human pathogenic C. difficile strains. PMID- 23639988 TI - Identification of Actinomyces meyeri actinomycosis in middle ear and mastoid by 16S rRNA analysis. AB - Actinomycosis of the middle ear and mastoid is extremely rare. Here, we report a unique case of actinomycosis of the middle ear and mastoid caused by Actinomyces meyeri diagnosed by 16S rRNA gene sequence analysis. PMID- 23639989 TI - "Selfish spermatogonial selection": a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders. AB - There is robust evidence from epidemiological studies that the offspring of older fathers have an increased risk of neurodevelopmental disorders, such as schizophrenia and autism. The authors present a novel mechanism that may contribute to this association. Because the male germ cell undergoes many more cell divisions across the reproductive age range, copy errors taking place in the paternal germline are associated with de novo mutations in the offspring of older men. Recently it has been recognized that somatic mutations in male germ cells that modify proliferation through dysregulation of the RAS protein pathway can lead to within-testis expansion of mutant clonal lines. First identified in association with rare disorders related to paternal age (e.g., Apert syndrome, achondroplasia), this process is known as "selfish spermatogonial selection." This mechanism favors propagation of germ cells carrying pathogenic mutations, increasingly skews the mutational profile of sperm as men age, and enriches de novo mutations in the offspring of older fathers that preferentially affect specific cellular signaling pathways. This mechanism not only offers a parsimonious explanation for the association between advanced paternal age and various neurodevelopmental disorders but also provides insights into the genetic architecture (role of de novo mutations), neurobiological correlates (altered cell cycle), and some epidemiological features of these disorders. The authors outline hypotheses to test this model. Given the secular changes for delayed parenthood in most societies, this hypothesis has important public health implications. PMID- 23639990 TI - Fear of movement and avoidance behaviour toward physical activity in chronic fatigue syndrome and fibromyalgia: state of the art and implications for clinical practice. AB - Severe exacerbation of symptoms following physical activity is characteristic for chronic-fatigue syndrome (CFS) and fibromyalgia (FM). These exacerbations make it understandable for people with CFS and FM to develop fear of performing body movement or physical activity and consequently avoidance behaviour toward physical activity. The aims of this article were to review what measures are available for measuring fear of movement and avoidance behaviour, the prevalence fear of movement and avoidance behaviour toward physical activity and the therapeutic options with fear of movement and avoidance behaviour toward physical activity in patients with CFS and FM. The review revealed that fear of movement and avoidance behaviour toward physical activity is highly prevalent in both the CFS and FM population, and it is related to various clinical characteristics of CFS and FM, including symptom severity and self-reported quality of life and disability. It appears to be crucial for treatment (success) to identify CFS and FM patients displaying fear of movement and avoidance behaviour toward physical activity. Individually tailored cognitive behavioural therapy plus exercise training, depending on the patient's classification as avoiding or persisting, appears to be the most promising strategy for treating fear of movement and avoidance behaviour toward physical activity in patients with CFS and FM. PMID- 23639992 TI - Microfluidics on liquid handling stations (MUF-on-LHS): an industry compatible chip interface between microfluidics and automated liquid handling stations. AB - We describe a generic microfluidic interface design that allows the connection of microfluidic chips to established industrial liquid handling stations (LHS). A molding tool has been designed that allows fabrication of low-cost disposable polydimethylsiloxane (PDMS) chips with interfaces that provide convenient and reversible connection of the microfluidic chip to industrial LHS. The concept allows complete freedom of design for the microfluidic chip itself. In this setup all peripheral fluidic components (such as valves and pumps) usually required for microfluidic experiments are provided by the LHS. Experiments (including readout) can be carried out fully automated using the hardware and software provided by LHS manufacturer. Our approach uses a chip interface that is compatible with widely used and industrially established LHS which is a significant advancement towards near-industrial experimental design in microfluidics and will greatly facilitate the acceptance and translation of microfluidics technology in industry. PMID- 23639991 TI - Glycemic memories and the epigenetic component of diabetic nephropathy. AB - A strong case for the deregulation of epigenetic chromatin modifications in the development and progression of various chronic complications of diabetes has emerged from recent experimental observations. Clinical trials of type 1 and type 2 diabetes patients highlight the importance of early and intensive treatment and the prolonged damage of hyperglycemia on organs such as the kidney. The functional relationship between the regulation of chromatin architecture and persistent gene expression changes conferred by prior hyperglycemia represents an important avenue of investigation for explaining diabetic nephropathy. While several studies implicate epigenetic changes at the chromatin template in the deregulated gene expression associated with diabetic nephropathy, the molecular determinants of metabolic memory in renal cells remain poorly understood. There is now strong evidence from experimental animals and cell culture of persistent glucose-driven changes in vascular endothelial gene expression that may also have relevance for the microvasculature of the kidney. Exploration of epigenetic mechanisms underlying the hyperglycemic cue mediating persistent transcriptional changes in renal cells holds novel therapeutic potential for diabetic nephropathy. PMID- 23639993 TI - Decennial trends of social differences in smoking habits in Italy: a 30-year update. AB - PURPOSE: To update educational inequalities in smoking in Italy up to 2009, with an in-depth analysis of female prevalence. METHODS: Data from 15 national health surveys (1980, 1983, 1986-1987, 1990, 1994, 1999-2003, 2005-2009) were analyzed. The overall sample size was representative of the population older than 25 years of age (3,300,000 men and 3,620,000 women). Main measures smoking prevalence rates standardized to the 2,000 European population, prevalence ratios by educational level (high: university degree or high school diploma; low: primary or middle school diploma), area (north, center, south and islands), and age-group (25-44, 45-59, >=60 years). Trends in tobacco prevalence were also analyzed with a multivariate approach using the negative binomial distribution. RESULTS: Although male prevalence steadily declined of about 2% annually from 56.1% in 1980 to 30.2% in 2009, educational inequalities slightly widened, recording in 2009 a 53% higher prevalence in men with low educational level compared to graduates. Even though female prevalence stalled around 18% in the last three decades, this was the result of opposite trends by educational group. In fact, highly educated women, with the highest prevalence during 1980s, decreased their tobacco use, determining a reversal similar to men in educational inequalities in smoking. This reversal occurred from the 1980s onwards with a time gradient starting from north to south and from younger to older women. CONCLUSION: To achieve a fairer reduction in smoking habits, tobacco control policies focusing on lower social groups are needed. PMID- 23639994 TI - The answering system to yes-no truth-functional questions in Korean-English bilingual children. AB - This study presents an experiment that explores the patterns of answers to yes-no truth-functional questions in English and Korean. The answering patterns are examined from 12 Korean-English bilingual children and 10 Korean-monolingual children. Four types of sentences in relation to given situations (Wason in Br J Psychol 52:133-142, 1961) were provided as questions such as true affirmative (TA), true negative (TN), false affirmative (FA), and false negative (FN). The bilingual children's answers were observed in separate language settings, English and Korean. The results by the bilingual in the Korean setting were compared with those by the monolinguals. The results show that bilingual children can process two systems rather successfully by providing correct responses to the given questions. But difficulty patterns, measured from error rates in each setting, are found different in two languages. The bilinguals' difficulty patterns in English and Korean, however, show deviation from monolinguals' difficulty patterns suggested in previous studies (Wason in Br J Psychol 52:133-142, 1961, Akiyama in Dev Psychol 20:219-228, 1984, Kim in Dev Psychol 21(3):462-472, 1985, Choi in Dev Psychol 29(3):407-420, 1991). The present work also shows that negatives are not uniformly reported with more errors than affirmatives when the truth condition and the answering system are further involved. All in all, the current study suggests that bilingual children have two separate processing systems for yes-no truth-functional questions. However, the two systems cannot be understood as a simple coexistence of two monolingual systems. Interaction of the two competing linguistic systems is discussed further. PMID- 23639995 TI - Comment on Schecklmann et al.: a call to consider both "negative" and "positive" results in brain research on tinnitus. PMID- 23639996 TI - Radiochemistry on chip: towards dose-on-demand synthesis of PET radiopharmaceuticals. AB - We have developed an integrated microfluidic platform for producing 2-[(18)F] fluoro-2-deoxy-D-glucose ((18)F-FDG) in continuous flow from a single bolus of radioactive isotope solution, with constant product yields achieved throughout the operation that were comparable to those reported for commercially available vessel-based synthesisers (40-80%). The system would allow researchers to obtain radiopharmaceuticals in a dose-on-demand setting within a few minutes. The flexible architecture of the platform, based on a modular design, can potentially be applied to the synthesis of other radiotracers that require a two-step synthetic approach, and may be adaptable to more complex synthetic routes by implementing additional modules. It can therefore be employed for standard synthesis protocols as well as for research and development of new radiopharmaceuticals. PMID- 23639998 TI - Managing moral hazard in motor vehicle accident insurance claims. AB - Motor vehicle accident (MVA) insurance in Canada is based primarily on two different compensation systems: (i) no-fault, in which policyholders are unable to seek recovery for losses caused by other parties (unless they have specified dollar or verbal thresholds) and (ii) tort, in which policyholders may seek general damages. As insurance companies pay for MVA-related health care costs, excess use of health care services may occur as a result of consumers' (accident victims) and/or producers' (health care providers) behavior - often referred to as the moral hazard of insurance. In the United States, moral hazard is greater for low dollar threshold no-fault insurance compared with tort systems. In Canada, high dollar threshold or pure no-fault versus tort systems are associated with faster patient recovery and reduced MVA claims. These findings suggest that high threshold no-fault or pure no-fault compensation systems may be associated with improved outcomes for patients and reduced moral hazard. PMID- 23639999 TI - Public health in the Arab World: at a crossroads. PMID- 23640000 TI - Sequence-specific backbone 1H, 13C and 15N assignments of the 34 kDa catalytic domain of PTPN5 (STEP). AB - PTPN5 is a protein tyrosine phosphatase that plays an integral role in regulating excitatory postsynaptic activity. The sequence-specific backbone assignments of the murine PTPN5 catalytic domain have been determined based on triple-resonance experiments using uniformly [(2)H,(13)C,(15)N]-labeled protein. PMID- 23640001 TI - Design and development of a novel intra-vaginal pressure sensor. AB - INTRODUCTION AND HYPOTHESIS: The influence of intra-abdominal pressure (IAP) on prolapse development is poorly understood. Nonetheless, chronic cough, high BMI, or heavy lifting predisposes women to pelvic organ prolapse (POP). This study aims to develop and test a novel, wireless intra-vaginal pressure sensor (IVPS) to quantify intra-abdominal pressure changes across a range of well-defined activities. METHODS: The IVPS shape was based on silicone moulds of the vagina and was designed to sit in the proximal vagina. It is thin, compliant and negligibly distorts the surrounding tissues. Repeatability was assessed in 14 volunteers performing three sets of activities (cycles). Each cycle consisted of 18 activities. The IVPS was removed and reinserted after completing either the first or second of the three-cycle exercise routine (order). Participants independently inserted and removed the device. A nested split-plot, factorial ANOVA determined the effect of order using mean IAP increase (mean) and peak-to peak fluctuations in IAP (amplitude) as dependent variables. Descriptive analysis examined the relative change in IAP across the activities. Cronbach's alpha) determined repeatability. RESULTS: All women found the IVPS comfortable and easy to insert. There was excellent correlation between cycles across all variables, r > 0.935 (mean) and r > 0.964 (amplitude). The order was not statistically significant, demonstrating a highly repeatable measurement. CONCLUSION: This is the first device to measure IAP at high frequency with the freedom of a wireless system. The IVPS aims to provide information to advise women better on suitable pre- and post-operative activities. PMID- 23640002 TI - On pelvic reference lines and the MR evaluation of genital prolapse: a proposal for standardization using the Pelvic Inclination Correction System. AB - Five midsagittal pelvic reference lines have been employed to quantify prolapse using MRI. However, the lack of standardization makes study results difficult to compare. Using MRI scans from 149 women, we demonstrate how use of existing reference lines can systematically affect measurements in three distinct ways: in oblique line systems, distances measured to the reference line vary with antero posterior location; soft issue-based reference lines can underestimate organ movement relative to the pelvic bones; and systems defined relative to the MR scanner are affected by intra- and interindividual differences in the pelvic inclination angle at rest and strain. Thus, we propose a standardized approach called the Pelvic Inclination Correction System (PICS). Based on bony structures and the body axis, the PICS system corrects for variation in pelvic inclination, at rest of straining, and allows for the standardized measurement of organ displacement in the direction of prolapse. PMID- 23640003 TI - Trainee performance at robotic console and benchmark operative times. AB - INTRODUCTION AND HYPOTHESIS: It is an ongoing challenge to maintain surgical efficiency while integrating trainee participation. We hypothesize that a program of graduated surgical responsibility for trainees does not hinder operative efficiency. METHODS: This was a retrospective cohort study of trainee performance times, collected prospectively in real time, for robotic cases performed at one university hospital between September 2008 and August 2011. The primary aim was to compare overall operative times between cases performed by trainees versus attendings. Secondary aims were to compare operative times for major portions of each operation by level of training and to establish benchmark operative times for trainees. RESULTS: During the study period, 98 cases had recorded trainee performance times. Total robot docked time was longer for trainees than for attendings (155 vs 132 min, p = 0.011), but mean performance times for hysterectomy (70 vs 59 min, p = 0.096) and sacrocolpopexy (76 vs 79 min, p = 0.545) were similar. Within the trainees, there was no correlation between surgical time and rank for each step of the procedures. Utilizing mean performance times for all trainees, benchmark operative times were established for each step of hysterectomy in minutes: right side (21), left side (21), bladder flap (10), colpotomy (15), and cuff closure (19); similarly, for sacrocolpopexy: sacral and peritoneal dissection (12), anterior cuff dissection (10), posterior cuff dissection (8), anterior mesh attachment (15), posterior mesh attachment (18), sacral mesh attachment (12), and peritoneal closure (9). CONCLUSION: In a program of graduated surgical responsibility, robotic operative efficiency was comparable when trainees were involved as console surgeons. PMID- 23640004 TI - Visualization of synthetic mesh utilizing optical coherence tomography. AB - INTRODUCTION AND HYPOTHESIS: Owing to the recent upsurge in adverse events reported after mesh-augmented pelvic organ prolapse (POP) repairs, our aim was to determine whether the location and depth of synthetic mesh can be measured postoperatively within the vaginal tissue microstructure using optical coherence tomography (OCT). METHODS: Seventeen patients with prior mesh-augmented repairs were recruited for participation. Patients were included if they had undergone an abdominal sacral colpopexy (ASC) or vaginal repair with mesh. Exclusion criteria were a postoperative period of <6 months, or the finding of mesh exposure on examination. OCT was used to image the vaginal wall at various POP-Q sites. If mesh was visualized, its location and depth was calculated and recorded. RESULTS: Ten patients underwent ASC and 7 patients had 8 transvaginal mesh repairs. Mesh was visualized in 16 of the 17 patients using OCT. In all ASC patients, mesh was imaged centrally at the posterior apex. In patients with transvaginal mesh in the anterior and/or posterior compartments, the mesh was visualized directly anterior and/or posterior to the apex respectively. Mean depth of the mesh in the ASC, anterior, and posterior groups was 60.9, 146.7, and 125.7 MUm respectively. Mesh was visualized within the vaginal epithelial layer in all 16 patients despite the route of placement. CONCLUSION: In this pilot study we found that OCT can be used to visualize polypropylene mesh within the vaginal wall following mesh-augmented prolapse repair. Regardless of abdominal versus vaginal placement, the mesh was identified within the vaginal epithelial layer. PMID- 23640005 TI - A pilot randomised controlled trial of the pelvic toner device in female stress urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: To determine the feasibility of using the pelvic toner device (PTD) in aiding pelvic floor muscle training (PFMT) METHODS: Forty women, aged at least 18 years with symptoms of pure stress urinary incontinence (SUI) or stress-predominant mixed urinary incontinence were randomly assigned to standard PFMT (ST group), or to PFMT and additional PTD (PTD group). They were evaluated throughout a treatment period of 16 weeks, and followed up 6 months after the active treatment period, using International Consultation on Incontinence Questionnaires (ICIQ), bladder diaries, and other subjective outcome measures for symptom improvement. RESULTS: Twenty-four women were randomised to ST and 28 to PTD. Twelve women did not complete therapy and analysis was performed on 19 randomised to ST and 21 randomised to PTD on a per protocol basis. The two groups showed statistically significant symptom improvement in ICIQ responses, both at 16 weeks and at 6 months. There was no significant difference between the groups regarding improvement in SUI (ST 52.6%, PTD 52.4%) at 16 weeks. At 6 months after the active treatment period, 60% of women (50%, 8 in the PTD group and 71.4 %, 10 in the ST group) were still doing pelvic floor exercises. The sample difference observed was not statistically significant. Some women reported that the device helped with confidence that the correct muscles were being contracted, and helped motivation to sustain PFMT. CONCLUSIONS: This pilot study demonstrates the feasibility of PTD for aiding PFMT. It is a safe and well-tolerated adjunct in PFMT, which increases patient choice. PMID- 23640006 TI - Operation for recurrent cystocele with anterior colporrhaphy or non-absorbable mesh: patient reported outcomes. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to compare patient reported outcomes and complications after repair of recurrent anterior vaginal wall prolapse in routine health care settings using standard anterior colporrhaphy or non-absorbable mesh. METHODS: The study is based on prospective data from the Swedish National Register for Gynaecological Surgery. 286 women were operated on for recurrent anterior vaginal wall prolapse in 2008-2010; 157 women had an anterior colporrhaphy and 129 were operated on with a non-absorbable mesh. Pre-, and perioperative data were collected from doctors and patients. Patient reported outcomes were evaluated 2 months and 12 months after the operation. RESULTS: After 12 months, the odds ratio (OR) of patient reported cure was 2.90 (1.34-6.31) after mesh implants compared with anterior colporrhaphy. Both patient- and doctor-reported complications were found more often in the mesh group. However, no differences in serious complications were found. Thus, an organ lesion was found in 2.3% after mesh implant compared with 2.5% after anterior colporrhaphy (p = 0.58). Two patients in the mesh group (1.2%) were re operated compared with 1 patient (0.6%) in the anterior colporrhaphy group (p = 0.58). The infection rate was higher after mesh (8.5%) than after anterior colporrhaphy (2.5%; OR 3.19 ; 1.07-14.25). CONCLUSION: Implantation of synthetic mesh during operation for recurrent cystocele more than doubled the cure rate, whereas no differences in serious complications were found between the groups. However, mesh increased the risk of infection. PMID- 23640007 TI - Improving the accuracy of prolapse and incontinence procedure epidemiology by utilizing both inpatient and outpatient data. AB - INTRODUCTION AND HYPOTHESIS: The epidemiologic description of pelvic organ prolapse (POP) and stress urinary incontinence (SUI) procedures is documented in several large studies using national database cohorts. These studies, however, may underestimate the number of procedures performed because they only capture procedures performed in either the inpatient or outpatient settings alone. We present a complete annual description of all inpatient and outpatient surgeries for POP and SUI in California. METHODS: We reviewed a record of all inpatient and outpatient POP and SUI surgeries performed in California in 2008 using data from the Office of Statewide Health Planning (OSHPD). RESULTS: In 2008, 20,004 and 20,330 women in California underwent POP and SUI procedures, respectively. Of these, 3,134 (15.6%) and 9,016 (44.3%) were performed in an outpatient setting. The age-adjusted rates of POP and SUI were 1.20 and 1.20 per 1,000 US females, respectively. This correlates to 186,000 POP and 186,000 SUI procedures per year nationally. Vaginal apical suspensions were more common in those undergoing surgery as an inpatient (45.1 vs 19.4%). The use of mesh to augment prolapse repairs was similar (22.3% inpatient vs 19.3% outpatient). SUI procedures performed in the outpatient setting were more likely to be performed as stand alone procedures (82.9 vs 18.8%, respectively). CONCLUSIONS: In California, 16% of POP and 44% of SUI procedures were performed in an outpatient surgical setting in 2008. Epidemiologic studies of POP and SUI should account for the fact that a substantial number of repairs are performed in the outpatient setting in order to achieve accuracy. PMID- 23640008 TI - Fibre-selective recording from the peripheral nerves of frogs using a multi electrode cuff. AB - OBJECTIVE: We investigate the ability of the method of velocity selective recording (VSR) to determine the fibre types that contribute to a compound action potential (CAP) propagating along a peripheral nerve. Real-time identification of the active fibre types by determining the direction of action potential propagation (afferent or efferent) and velocity might allow future neural prostheses to make better use of biological sensor signals and provide a new and simple tool for use in fundamental neuroscience. APPROACH: Fibre activity was recorded from explanted Xenopus Laevis frog sciatic nerve using a single multi electrode cuff that records whole nerve activity with 11 equidistant ring-shaped electrodes. The recorded signals were amplified, delayed against each other with variable delay times, added and band-pass filtered. Finally, the resulting amplitudes were measured. MAIN RESULT: Our experiments showed that electrically evoked frog CAP was dominated by two fibre populations, propagating at around 20 and 40 m/s, respectively. The velocity selectivity, i.e. the ability of the system to discriminate between individual populations was increased by applying band-pass filtering. The method extracted an entire velocity spectrum from a 10 ms CAP recording sample in real time. SIGNIFICANCE: Unlike the techniques introduced in the 1970s and subsequently, VSR requires only a single nerve cuff and does not require averaging to provide velocity spectral information. This makes it potentially suitable for the generation of highly-selective real-time control-signals for future neural prostheses. In our study, electrically evoked CAPs were analysed and it remains to be proven whether the method can reliably classify physiological nerve traffic. PMID- 23640009 TI - Adapting smoking cessation treatment according to initial response to precessation nicotine patch. AB - OBJECTIVE The authors evaluated an adaptive smoking cessation treatment strategy in which nicotine patch treatment was initiated before a quit date, and then, depending on initial therapeutic response, either the nicotine patch was continued or alternative pharmacotherapies were provided. METHOD The study was a double-blind, parallel-arm adaptive treatment trial. A total of 606 cigarette smokers started open-label nicotine patch treatment 2 weeks before the quit date. Those whose ad lib smoking did not decrease by >50% after 1 week were randomly assigned to one of three double-blind treatments: nicotine patch alone (control condition); "rescue" treatment with bupropion augmentation of the patch; or rescue treatment with varenicline alone. Participants whose precessation smoking decreased >50% but who lapsed after the quit date were also randomly assigned to the two rescue treatments or to nicotine patch alone. Logistic regression analyses compared each rescue treatment against the control condition in terms of abstinence at the end of treatment (weeks 8-11) and at 6 months. RESULTS Smokers who did not respond adequately to precessation nicotine patch benefited from bupropion augmentation; abstinence rates at end of treatment were 16% with nicotine patch alone and 28% with bupropion augmentation (odds ratio=2.04, 95% CI=1.03-4.01). Switching to varenicline produced less robust effects, but point abstinence at 6 months was 6.6% with the patch alone and 16.5% with a switch to varenicline (odds ratio=2.80, 95% CI=1.11-7.06). Postquit adaptive changes in treatment had no significant effects on any abstinence outcome. CONCLUSIONS It is possible to rescue a significant portion of smokers who would have failed to achieve abstinence if left on nicotine patch alone by identifying these smokers before their quit date and implementing adaptive changes in treatment. PMID- 23640010 TI - COPD: Overview and survey of NP knowledge. AB - Chronic obstructive pulmonary disease (COPD) is quickly becoming one of the leading causes of morbidity and mortality. The purpose of this article is to review the clinical presentation, spirometry, and pharmacologic management of COPD, as well as the results of a survey examining nurse practitioners' (NPs) knowledge about COPD and its management. PMID- 23640011 TI - Chronic pain management in the cancer survivor: tips for primary care providers. AB - Many cancer survivors suffer from chronic pain related to treatment. Pain management in the survivor is similar to chronic noncancer pain, with the important caveat that new or worsening pain must be promptly assessed for malignancy. This article reviews cancer survivorship, identifies common pain problems, and discusses strategies for management. PMID- 23640012 TI - Life expectancy: what can we do to help? PMID- 23640013 TI - NeuroProtective effects of adenosine receptor agonist coadministration with ascorbic acid on CA1 hippocampus in a mouse model of ischemia reperfusion injury. AB - Ischemic brain injury is a leading cause of sever neurological and neurobehavioral deficits and death. The hippocampus plays vital roles in learning and memory processes and it is impaired by ischemic insults. Cerebral ischemia/reperfusion leads to Oxidative stress damage impairing the hippocampus. Here we tested whether ascorbic acid and adenosine receptor played a neuroprotective role in a mouse brain ischemia model induced by common carotid arteries occlusion. Adult male mice were randomly assigned into nine experimental groups. The animals were subjected to ischemia by the ligation of common carotid arteries for 15 min. Drugs were injected intrapritoneally once daily for 7 days. Behavioral tests performed at day 14 and then mice were killed at day 21 and their brains were fixed for microscopic studies and some samples were prepared for western blot analysis. Western blot analysis utilized to evaluate the expression of apoptosis-related proteinsin the hippocampus. Short-term memory was assessed by shuttle-box test. Our findings revealed that administration of vitamin C and N6-cyclopentyladenosine (CPA) significantly attenuated ischemia induced brain injury. Vitamin C and CPA administration increased the expression of anti-apoptotic protein Bcl-2 and decreased the expression of pro-apoptotic protein Bax in the ischemic mice. Ischemia caused short-term memory loss that was improved by vitamin c and CPA treatment. Our results demonstrate that treatment with vitamin C and adenosine receptor agonist attenuated cerebral ischemia/reperfusion-induced brain injury as a potential neuroprotective agent. PMID- 23640014 TI - Berberine chloride improved synaptic plasticity in STZ induced diabetic rats. AB - Previous studies indicated that diabetes affects synaptic transmission in the hippocampus, leading to impairments of synaptic plasticity and defects in learning and memory. Although berberine treatment ameliorates memory impairment and improves synaptic plasticity in streptozotocin (STZ) induced diabetic rats, it is not clear if the effects are pre- or post-synaptic or both. The aim of this study was to evaluate the effects of berberine chloride on short-term plasticity in inhibitory interneurons in the dentate gyrus of STZ-induced diabetic rats. Experimental groups included: The control, control berberine treated (100 mg/kg), diabetic and diabetic berberine treated (50,100 mg/kg/day for 12 weeks) groups. The paired pulse paradigm was used to stimulate the perforant pathway and field excitatory post-synaptic potentials (fEPSP) were recorded in dentate gyrus (DG). In comparison with control, paired pulse facilitation in the diabetic group was significantly increased (P < 0.01) and this effect prevented by chronic berberine treatment (50,100 mg/kg). However, there were no differences between responses of the control berberine 100 mg/kg treated and diabetes berberine treated (50 and 100 mg/kg) groups as compared to the control group. The present results suggest that the pre-synaptic component of synaptic plasticity in the dentate gyrus is affected under diabetic conditions and that berberine prevents this effect. PMID- 23640016 TI - Radial diffusivity in the cerebellar peduncles correlates with clinical severity in Friedreich ataxia. AB - Friedreich ataxia (FRDA) is a common inherited ataxia, caused by an expanded GAA repeat sequence in the Frataxin (FXN) gene. The proprioceptive system, which enters the cerebellum through the cerebellar peduncles, is a primary focus of pathology. In this study, we investigate the relationship of clinical and genetic data with diffusion-tensor imaging (DTI) indices reflecting white matter integrity of the cerebellar peduncles. Nine FRDA patients underwent DTI. After between-subject registration using tract-based spatial statistics, a white matter atlas was used for computing average values of DTI indices in the regions of interest. These were the inferior, middle and superior cerebellar peduncles (ICP, MCP, SCP). For Bonferroni correction, significance threshold was set to p < 0.0056. We found that radial diffusivity (D(?)) within the ICP significantly correlated with scores on the Friedreich Ataxia Rating Scale (FARS, Spearman's rho = 0.883, p = 0.0016, all two-sided) and, at trend level, with number of trinucleotide repeats (rho = 0.812, p = 0.008). D(?) in the SCP correlated with scores on the Scale for the Assessment and Rating of Ataxia (SARA, rho = 0.867, p = 0.0025). These findings support the role of DTI, and especially D(?), as an informative biomarker in FRDA. PMID- 23640015 TI - IL-10-producing B-cells limit CNS inflammation and infarct volume in experimental stroke. AB - Clinical stroke induces inflammatory processes leading to cerebral injury. IL-10 expression is elevated during major CNS diseases and limits inflammation in the brain. Recent evidence demonstrated that absence of B-cells led to larger infarct volumes and increased numbers of activated T-cells, monocytes and microglial cells in the brain, thus implicating a regulatory role of B-cell subpopulations in limiting CNS damage from stroke. The aim of this study was to determine whether the IL-10-producing regulatory B-cell subset can limit CNS inflammation and reduce infarct volume following ischemic stroke in B-cell deficient (MUMT(-/ )) mice. Five million IL-10-producing B-cells were obtained from IL-10-GFP reporter mice and transferred i.v. to MUMT(-/-)mice. After 24 h following this transfer, recipients were subjected to 60 min of middle cerebral artery occlusion (MCAO) followed by 48 h of reperfusion. Compared to vehicle-treated controls, the IL-10(+) B-cell-replenished MUMT(-/-)mice had reduced infarct volume and fewer infiltrating activated T-cells and monocytes in the affected brain hemisphere. These effects in CNS were accompanied by significant increases in regulatory T cells and expression of the co-inhibitory receptor, PD-1, with a significant reduction in the proinflammatory milieu in the periphery. These novel observations provide the first proof of both immunoregulatory and protective functions of IL-10-secreting B-cells in MCAO that potentially could impart significant benefit for stroke patients in the clinic. PMID- 23640017 TI - Many-body effects in silicene, silicane, germanene and germanane. AB - Silicene, which is the silicon equivalent of carbon-based graphene and shares some of the unique properties with graphene, has been attracting more and more attention since its synthesis and represents a breakthrough in current silicon based technology. In this work, many-body effects in silicene, silicane, germanene and germanane have been demonstrated based on the Green's function perturbation theory, i.e., GW + Bethe-Salpeter equation. Due to confinement, many body effects play a pivotal role in quasi-particle excitations and optical absorption spectra, which leads to excitonic resonance (pi->pi* excitation) in silicene and germanene, and strongly bound excitons in silicane and germanane with considerable binding energies. PMID- 23640018 TI - Novel NaCS-CS-PPS microcapsules as a potential enzyme-triggered release carrier for highly-loading 5-ASA. AB - In order to develop novel spherical micro-drug-carriers, an orifice polymerization method was used to prepare spherical microcapsules which were composed of chemically crosslinked chitosan (CS) with sodium cellulose sulfate (NaCS) and sodium polyphosphate (PPS). 5-Aminosalicylic acid (5-ASA) was chosen as a model drug. The microcapsules prepared had an average diameter of 1.90 mm with loading efficiency of 60.77% and encapsulation efficiency of 90.03%. SEM results showed that the microcapsules had a double-walled capsule structure with an outer wall thickness of approximately 4.40 MUm and inner wall (shell) thickness of approximately 187.14 MUm. SEM transection images of the microcapsules showed that 5-ASA entrapped in the microcapsule was in a crystal form. The results of in vitro swelling/erosion and release analysis showed that the drug was preferentially and completely released in simulated colonic fluid (SCF, pH 6.4) under the mechanism of Anomalous transport. All these results indicate that the microcapsules could be a good candidate as an enzyme-triggered controlled release drug carrier. PMID- 23640019 TI - Ratiometric/'turn-on' fluorescent chemosensor for CN-: mimicking XNOR logic function with Fe3+ ions. AB - The naphthyl-appended chemosensors 5-7 based on thiacalix[4]arene of cone and 1,3 alternate conformations have been synthesized which show high selectivity toward CN(-) ions by using hydrogen bonding and displacement approach. The presence of CN(-) induces quenching of fluorescence emission of compound 5 and ratiometric fluorescence behaviour of compounds 6 and 7 through hydrogen bonding interactions. Further, chemosensors 5-7 show high affinity for Fe(3+) ions with quenching of fluorescence emission, among all the metal ions tested. The 'in situ' prepared iron complexes of compounds 5-7 shows high "turn-on" selectivity toward CN(-) ions over the other anions. The molecular switching has been observed between chemical inputs of Fe(3+) and CN(-) ions which mimics the operation of an exclusive-NOR (XNOR) logic gate. PMID- 23640020 TI - Magnetic resonance imaging of pineal region tumours. AB - OBJECTIVES: Pineal lesions can present as a heterogeneous collection of benign and malignant disease conditions. Pineal lesions include germ cell tumours, neoplasms arising from the pineal parenchyma, as well as other pineal region masses. METHODS: A variety of cases of pineal lesions are presented. The important clinical features and typical imaging findings of each pineal lesion are described with emphasis on their morphological appearance and signal intensity characteristics on magnetic resonance imaging (MRI). CONCLUSION: Knowledge of the imaging characteristics and clinical features of varying pineal lesions can assist in narrowing the differential diagnosis for more accurate and rational therapeutic planning. TEACHING POINTS: * Pineal parenchymal tumours show an "explosion" of normal pineal calcifications towards the periphery. * Pineoblastomas often have restricted diffusion, with apparent diffusion coefficient (ADC) values lower than germinomas. * Pineal teratomas and pineal lipomas display fat signal characteristics and fat saturation on MRI. * Pineal lesions in patients with known malignancy should raise suspicion of metastatic involvement. * Pineal cysts and arachnoid cysts show MRI signal characteristics similar to cerebrospinal fluid (CSF). PMID- 23640021 TI - Pubertal characteristics among schoolgirls in Riyadh, Saudi Arabia. AB - Puberty is the gradual transition period between childhood and adulthood. Many factors may contribute to the onset of puberty. The objective of the study was to determine the age of onset of secondary pubertal characteristics among Saudi Arabian girls. A cross-sectional study was conducted using a cluster sample design. Seven hundred and twenty-five schoolgirls between the ages of 6 and 16 years from diverse socioeconomic levels were included. During physical examinations, the height and weight of the girls were recorded, and the stages of breast and pubic hair development were determined according to Tanner stages; axillary hair development was determined according to modified stages. The median age at Tanner stage 2 for breast and pubic hair development was 10 years. The median age at stage 2 in modified scales for axillary hair development was 12 years. In conclusion, the median age of the onset of breast development at Tanner stage 2 for Saudi girls in Riyadh is lower than what has been reported in some countries in Europe, South Africa, Turkey and India but similar to girls in Hong Kong, China and white girls in the USA, which may support secular trends of an earlier onset of puberty. PMID- 23640022 TI - Association between C-reactive protein levels and outcome in acute lung injury in children. AB - High plasma C-reactive protein (CRP) levels are associated with favorable outcome in adults with acute lung injury (ALI). The association between CRP levels and outcome has not been studied in ALI in children. We performed a historical cohort study in 93 mechanically ventilated children (0-18 years) with ALI. The CRP level within 48 h of disease onset was tested for association with 28-day mortality and ventilator-free days (VFD). Clinical parameters and ventilator settings were evaluated for possible confounding. Fourteen patients died within 28 days. The median (interquartile range) CRP level in nonsurvivors was 126 mg/L (64; 187) compared with 56 mg/L (20; 105) in survivors (p = 0.01). For every 10-mg/L rise in CRP level, the unadjusted odds (95% confidence interval (95% CI)) for mortality increased 8.7% (2.1-15.8%). Cardiovascular organ failure at onset of ALI was the strongest predictor for mortality (odds ratio, 30.5 (6.2-152.5)). After adjustment for cardiovascular organ failure, for every 10-mg/L rise in CRP level, the OR (95% CI) for mortality increased 4.7% (-2.7-12.6%; p = 0.22). Increased CRP levels were associated with a decrease in VFD (rho = -0.26, p = 0.01). CONCLUSION: increased plasma CRP levels are not associated with favorable outcome in ALI in children. This is in contrast with findings in adults with ALI. PMID- 23640023 TI - Density functional theory of a curved liquid-vapour interface: evaluation of the rigidity constants. AB - It is argued that to arrive at a quantitative description of the surface tension of a liquid drop as a function of its inverse radius, it is necessary to include the bending rigidity k and Gaussian rigidity k in its description. New formulae for k and k in the context of density functional theory with a non-local, integral expression for the interaction between molecules are presented. These expressions are used to investigate the influence of the choice of Gibbs dividing surface, and it is shown that for a one-component system, the equimolar surface has a special status in the sense that both k and k are then the least sensitive to a change in the location of the dividing surface. Furthermore, the equimolar value for k corresponds to its maximum value and the equimolar value for k corresponds to its minimum value. An explicit evaluation using a short-ranged interaction potential between molecules shows that k is negative with a value around minus 0.5-1.0 kBT and that k is positive with a value that is a bit more than half the magnitude of k. Finally, for dispersion forces between molecules, we show that a term proportional to log(R)/R(2) replaces the rigidity constants and we determine the (universal) proportionality constants. PMID- 23640024 TI - Genetic and non-genetic instability in tumor progression: link between the fitness landscape and the epigenetic landscape of cancer cells. AB - Genetic instability is invoked in explaining the cell phenotype changes that take place during cancer progression. However, the coexistence of a vast diversity of distinct clones, most prominently visible in the form of non-clonal chromosomal aberrations, suggests that Darwinian selection of mutant cells is not operating at maximal efficacy. Conversely, non-genetic instability of cancer cells must also be considered. Such mutation-independent instability of cell states is most prosaically manifest in the phenotypic heterogeneity within clonal cell populations or in the reversible switching between immature "cancer stem cell like" and more differentiated states. How are genetic and non-genetic instability related to each other? Here, we review basic theoretical foundations and offer a dynamical systems perspective in which cancer is the inevitable pathological manifestation of modes of malfunction that are immanent to the complex gene regulatory network of the genome. We explain in an accessible, qualitative, and permissively simplified manner the mathematical basis for the "epigenetic landscape" and how the latter relates to the better known "fitness landscape." We show that these two classical metaphors have a formal basis. By combining these two landscape concepts, we unite development and somatic evolution as the drivers of the relentless increase in malignancy. Herein, the cancer cells are pushed toward cancer attractors in the evolutionarily unused regions of the epigenetic landscape that encode more and more "dedifferentiated" states as a consequence of both genetic (mutagenic) and non-genetic (regulatory) perturbations-including therapy. This would explain why for the cancer cell, the principle of "What does not kill me makes me stronger" is as much a driving force in tumor progression and development of drug resistance as the simple principle of "survival of the fittest." PMID- 23640025 TI - A microfluidic system for cell type classification based on cellular size independent electrical properties. AB - This paper presents a microfluidic system enabling cell type classification based on continuous characterization of size-independent electrical properties (e.g., specific membrane capacitance (C(specific membrane)) and cytoplasm conductivity (sigma(cytoplasm)). In this study, cells were aspirated continuously through a constriction channel, while cell elongation and impedance profiles at two frequencies (1 kHz and 100 kHz) were measured simultaneously. Based on a proposed distributed equivalent circuit model, 1 kHz impedance data were used to evaluate cellular sealing properties with constriction channel walls and 100 kHz impedance data were translated to C(specific membrane) and sigma(cytoplasm). Two lung cancer cell lines of CRL-5803 cells (n(cell) = 489) and CCL-185 cells (n(cell) = 487) were used to evaluate this technique, producing a C(specific membrane) of 1.63 +/- 0.52 MUF cm(-2) vs. 2.00 +/- 0.60 MUF cm(-2), and sigma(cytoplasm) of 0.90 +/- 0.19 S m(-1)vs. 0.73 +/- 0.17 S m(-1). Neural network-based pattern recognition was used to classify CRL-5803 and CCL-185 cells, producing success rates of 65.4% (C(specific membrane)), 71.4% (sigma(cytoplasm)), and 74.4% (C(specific membrane) and sigma(cytoplasm)), suggesting that these two tumor cell lines can be classified based on their electrical properties. PMID- 23640026 TI - The role of interleukin-17 in the associations between systemic lupus erythematosus and ANCA-associated vasculitis : Comment on: systemic lupus erythematosus associated with ANCA-associated vasculitis: an overlapping syndrome? (Rheumatol Int. 2012 Oct; 32(10):3285-3290). PMID- 23640027 TI - Continuous correction of differential path length factor in near-infrared spectroscopy. AB - In continuous-wave near-infrared spectroscopy (CW-NIRS), changes in the concentration of oxyhemoglobin and deoxyhemoglobin can be calculated by solving a set of linear equations from the modified Beer-Lambert Law. Cross-talk error in the calculated hemodynamics can arise from inaccurate knowledge of the wavelength dependent differential path length factor (DPF). We apply the extended Kalman filter (EKF) with a dynamical systems model to calculate relative concentration changes in oxy- and deoxyhemoglobin while simultaneously estimating relative changes in DPF. Results from simulated and experimental CW-NIRS data are compared with results from a weighted least squares (WLSQ) method. The EKF method was found to effectively correct for artificially introduced errors in DPF and to reduce the cross-talk error in simulation. With experimental CW-NIRS data, the hemodynamic estimates from EKF differ significantly from the WLSQ (p < 0.001). The cross-correlations among residuals at different wavelengths were found to be significantly reduced by the EKF method compared to WLSQ in three physiologically relevant spectral bands 0.04 to 0.15 Hz, 0.15 to 0.4 Hz and 0.4 to 2.0 Hz (p < 0.001). This observed reduction in residual cross-correlation is consistent with reduced cross-talk error in the hemodynamic estimates from the proposed EKF method. PMID- 23640028 TI - Rapid two-step metallization through physicochemical conversion of Ag2O for printed "black" transparent conductive films. AB - A rapid two-step metallization for fabrication of a "black" transparent conductive film on a flexible substrate for display applications is presented, using a mixture of silver oxide (Ag2O) and silver neodecanoate (C10H19AgO2), and its electrical conductivity and colour transition behaviours are investigated. Silver nanoparticles, which are physicochemically converted from silver oxide microparticles in the presence of silver neodecanoate in the course of the first metallization step at 150 degrees C for 10 min, are chemically annealed by immersing them in an acidic ferric chloride (FeCl3) solution at room temperature for 10 s. During this second metallization step, silver nanoparticles are found to be tightly packed through Ostwald ripening, which eventually leads to the dramatic enhancement of electrical conductivity by six orders of magnitude from 1.33 S m(-1) to 1.0 * 10(7) S m(-1), which corresponds to 15.9% of the electrical conductivity of bulk silver. In addition to the enhancement of electrical conductivity, the silver chloride (AgCl) layer formed on the surface of the silver layer due to ferric ions (Fe(3+)) enhances the blackness of the transparent conductive film by a factor of 1.69, from 36.29 B to 61.51 B. The sheet resistance and optical transparency of a roll-to-roll printed black transparent conductive film for a touch screen panel are found to be as low as 0.9 Omega?(-1) and 81%, respectively, after conducting the proposed two-step metallization. PMID- 23640029 TI - A new program for highly reproducible automatic evaluation of the substantia nigra from transcranial sonographic images. AB - AIMS: Recent studies report increased echogenicity of the substantia nigra (SN) in patients with Parkinson's disease (PD) using transcranial sonography (TCS). However, the main limitation to TCS is its dependence on the sonographer's experience. Experimental software for quantitative evaluation of the echogenic SN area was thus developed by us. The aim of this study was to test the reliability of the data using developed B-Mode Assist software in patients with parkinsonism and in healthy volunteers. METHODS: The SN was imaged from the right temporal bone window in mesencephalic plane using TCS. DICOM images of SN were saved, converted into JPEG format, encoded and processed. Two observers performed 3 automatic evaluations of the SN area (measurements of SN area in each gray scale intensity inside the region of interest) by counting the standard deviation of all 6 measurements using developed software. The average value of all 3 measurements of each observer was used for computing Cohen's kappa coefficient to determine inter-observer correlations. Cohen's kappa coefficients as an intra observer correlation for observer 1 and observer 2 were counted from the first 2 measurements of both observers. RESULTS: In total, 92 images were evaluated using this software. The mean of the standard deviations was 3.87; Cohen's kappa for intra-observer agreement of two observers were 0.947, and 0.943, resp.; Cohen's kappa for inter-observers agreement was 0.880. The agreement between visual and automatic detection of SN pathology was in 97.8% images. The sensitivity, specificity, positive and negative predictive values of automatic measurement were 100, 96.2, 95.1, 100%, resp. CONCLUSIONS: The results show very reliable measurement of SN features using designed application with "almost perfect" inter observer and intra-observer agreements. PMID- 23640030 TI - Possible control of paternal imprinting of polymorphisms of the ADAM33 gene by epigenetic mechanisms and association with level of airway hyperresponsiveness in asthmatic children. AB - INTRODUCTION: ADAM33 is the candidate gene most commonly associated with asthma and airway hyperreactivity (AHR). AIM: The aim of this study was to determine whether level of AHR is associated with certain alleles or haplotypes of the ADAM33 gene in asthmatic children. METHODS: One hundred and nine asthmatic children and 46 controls from the general population were examined with spirometry before and after histamine and methacholine inhalation. All subjects were genotyped for single-nucleotide polymorphisms (SNPs) of the ADAM33 gene. Haplotypes were determined according to genotypes of the patient's parents. RESULTS: We found the three most frequent ADAM33 haplotypes (a1-3) were associated with the highest level of AHR to methacholine and histamine in 66% of asthmatic children. The paternally transmitted GGGCTTTCGCA haplotype was seen in 73.3% asthmatic children with serious AHR to methacholine challenge (paternal and maternal origin of haplotype 73.3% to 37.5, P=0.046) Significant differences in the relative frequency of paternal haplotypes with high levels of AHR to histamine were found (P=0.013). CONCLUSION: ADAM33 haplotypes (a1, a2, a3) are associated with severity of AHR and are significantly more often transmitted in the paternal line. PMID- 23640031 TI - The CRZ1/SP1-like gene links survival under limited aeration, cell integrity and biofilm formation in the pathogenic yeast Cryptococcus neoformans. AB - AIMS: Limited aeration has been demonstrated to cause slowdown in proliferation and delayed budding, resulting eventually in a unique unbudded G2-arrest in the obligate aerobic pathogenic yeast Cryptococcus neoformans. Also, the ability to adapt to decreased oxygen levels during pathogenesis has been identified as a virulence factor in C. neoformans. The aim of this study was to identify and characterize genes that are necessary for the proliferation slowdown and G2 arrest caused by limited aeration. METHODS: Random mutants were prepared and screened for lack of typical slowdown of proliferation under limited aeration. The CNAG_00156.2 gene coding for a zinc-finger transcription factor was identified in mutants showing most distinctive phenotype. Targeted deletion strain and reconstituted strain were prepared to characterize and confirm the gene functions. This gene was also identified in a parallel studies as homologous both to calcineurin responsive (Crz1) and PKC1-dependent (SP1-like) transcription factors. RESULTS: We have confirmed the role of the cryptococcal homologue of CRZ1/SP1-like transcription factor in cell integrity, and newly demonstrated its role in slowdown of proliferation and survival under reduced aeration, in biofilm formation and in susceptibility to fluconazole. CONCLUSIONS: Our data demonstrate a tight molecular link between slowdown of proliferation during hypoxic adaptation and maintenance of cell integrity in C. neoformans and present a new role for the CRZ1 family of transcription factors in fungi. The exact positioning of this protein in cryptococcal signalling cascades remains to be clarified. PMID- 23640033 TI - Aldol-type compounds from water-soluble indole-3,4-diones: synthesis, kinetics, and antiviral properties. AB - A straightforward transformation of indole-3,4-diones is reported. The reaction feasibility is evidenced by kinetic studies on a model substrate, revealing a double phase process with a first faster pseudo-first-order step (i.e., deprotonation of the dione and self-nucleophilic attack of the anion) and a subsequent slower dehydration of the intermediate. The overall process is faster at pH higher than the pK value of the investigated substrate. The biological relevance of new compounds has been assessed in vitro against herpes simplex virus type-1 (HSV-1), showing a more promising biological profile with respect to their precursors. PMID- 23640032 TI - The role of the environment in the development of pediatric inflammatory bowel disease. AB - The incidence of inflammatory bowel disease (IBD) is rising worldwide, with a particularly sharp increase in children. Rates are highest in North America and Europe, with rapid increases noted in developing nations adopting the Westernized environment. While many genetic risk loci have been identified that predispose people to IBD, incomplete penetrance and overlapping genotypes among patients with different phenotypes inadequately explain the etiology of these chronic diseases. Therefore, environmental risk factors have been the subject of much recent research. This article reviews the role of the environment in IBD, with particular focus on early-life exposures and pediatric-onset disease. The literature surrounding environmental risk factors is reviewed, including prenatal and perinatal exposures, the hygiene hypothesis, the urban environment, infection and antibiotic use, and secondhand tobacco smoke exposure. In addition, the possible role of the environment in altering the intestinal microbiome is addressed. PMID- 23640034 TI - Mechanism of BDE209-induced impaired glucose homeostasis based on gene microarray analysis of adult rat liver. AB - Several persistent organic pollutants are reported to be potentially associated with the risk of human diabetes that has become rapidly epidemic in China currently. 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE209) is commercially most important both in the production and in the use of polybrominated diphenyl ethers (PBDEs). It might bioaccumulate in wildlife and human and is the only PBDEs mixture still used today. In the present study, male adult rats treated with BDE209 (0, 0.05, 1, and 20 mg/kg) for 8 weeks were used to explore the effects of BDE209 on glucose homeostasis and possible mechanisms; 0.05 mg/kg of BDE209 induced dose-related hyperglycemia. Then, we performed the full-genome gene expression microarrays, gene ontology analysis, and pathway analysis in this group and control. BDE209 induced 1,257 liver gene transcript changes, and 18 canonical pathways were significantly enriched. Four of them were involved in immune diseases, including autoimmune thyroid disease, graft-versus host disease, allograft rejection, and type I diabetes mellitus (T1MD), which was confirmed by the decrease in serum insulin. Subsequently, gene act network and gene co-expression network found that some MHC molecules and TNF-alpha were involved in T1DM pathway, which was then confirmed by the increase in serum TNF alpha. Additionally, reduced glutathione and superoxide dismutase in plasma indicated that oxidative damage might partly contribute to BDE209-induced hyperglycemia. The results of this study provide some new experimental evidence that the exposure to high levels of BDE209 may contribute to the onset of diabetes in human populations. Further work needs to be done to confirm this link. PMID- 23640035 TI - Neutralization of interleukin-1 beta attenuates silica-induced lung inflammation and fibrosis in C57BL/6 mice. AB - The inflammation and fibrosis induced by silica dust are considered to be substantial responses in silicosis progression. Interleukin-1 beta (IL-1beta) plays an important role in silica-induced lung inflammation, but the mechanisms that underlie the influence of IL-1beta on the progression of silicosis remain unclear. In this study, the role of IL-1beta in silica-induced inflammation and fibrosis was evaluated by administering a suspension of 2.5-mg silica dust, either with or without 40 MUg anti-mouse IL-1beta monoclonal antibody (mAb), to the lungs of male C57BL/6 mice. Silica + anti-IL-1beta mAb-treated mice showed the depletion of IL-1beta as well as the attenuation of inflammation, as evaluated in the bronchoalveolar lavage fluid (BALF) and histological sections from 1 to 84 days after silica exposure. Further study of the BALF indicated that inhibition of IL-1beta could reduce the contents of tumor necrosis factor-alpha and monocyte chemoattractant protein-1. The real-time PCR and pathology results showed that the neutralization of IL-1beta attenuated silica-induced fibrosis by inhibiting the gene expression of transforming growth factor-beta 1, collagen I and fibronectin. The examination of Th1-cytokine and Th2-cytokine suggested that depletion of IL-1beta decelerated the Th1/Th2 balance toward a Th2-dominant response. In conclusion, the present study suggests that the neutralization of IL 1beta attenuates silica-induced inflammation and fibrosis by inhibiting other inflammatory and fibrogenic mediators and modulating the Th1/Th2 balance. PMID- 23640036 TI - Our perspective of the treatment of naevus of Ota with 1,064-, 755- and 532-nm wavelength lasers. AB - Naevus of Ota (NO) is a disfiguring pigmentary disorder affecting the face. Q switched neodymium-doped yttrium aluminium garnet (QS Nd:YAG)-1,064 nm is a standard laser treatment because it causes highly selective destruction of melanin within the aberrant dermal melanocytes. However, not all lesions respond. This study aims to evaluate the efficacy/safety of QS Nd:YAG-1,064 nm and the shorter wavelength QS Alexandrite-755 nm and QS Nd:YAG-532 nm lasers in treating NO. Data were evaluated from 21 patients treated in our laser centre from 2004 to 2012. Lesional skin was irradiated with QS-532 nm/QS-755 nm/QS-1,064 nm, with settings titrated according to responses. All received initial test patches to direct initial wavelength choice, with subsequent treatments at 3-monthly intervals until clearance/lack of further response. Laser modality was switched following repeated test patches if there was no or no sustained improvement. Two thirds of patients had >= 90% improvement compared to baseline photographs. In 20% of patients, QS-1,064 nm was most efficacious with 97% mean improvement. The mean improvement was 80% for those in whom QS-755 nm was superior, and 90% for QS 532 nm. Median number of overall laser treatments was 8 (range 4-13). Number of treatments required varied significantly according to lesional colour and site: grey lesions and those on the forehead/temple were most resistant. We confirm successful treatment of NO with QS Nd:YAG-1,064 nm and the shorter wavelength QS 755 nm/QS-532 nm lasers without serious or irreversible side effects. We recommend judicious test patch analysis before treatment and a modality switch if complete clearance is not obtained. PMID- 23640038 TI - Retinal Neurodegeneration in Type II Diabetic Otsuka Long-Evans Tokushima Fatty Rats. AB - PURPOSE: We evaluated whether diabetes causes longitudinal thinning of retinal layers as a sign of retinal neurodegeneration in a type II diabetic animal model, the Otuska Long-Evans Tokushima fatty rats (OLETF), using spectral domain-optical coherence tomography (SD-OCT) and investigated the corresponding histology. METHODS: Retinal thickness in OLETF and Long-Evans Tokushima Otsuka rats (LETO) was measured at 1300 MUm from the center of the optic nerve head (ONH) at 12, 20, 28, and 36 weeks using SD-OCT. Total retinal thickness (TRT) was measured automatically by built-in software. The retinal nerve fiber layer (RNFL) and other layers' thicknesses were measured manually. At 36 weeks, eyes were processed for morphometric analysis and detection of apoptosis based on active caspase-3(+) and TUNEL(+) analysis. RESULTS: TRT was significantly thinner in OLETF at 28 and 36 weeks (236.26 +/- 5.64 and 235.98 +/- 5.42 MUm, respectively) than in LETO (243.82 +/- 7.36 and 239.58 +/- 6.99 MUm, respectively; P = 0.042 and P = 0.01). At 28 weeks, RNFL thickness was significantly lower in OLETF (21.52 +/- 1.91 MUm) than in LETO (24.75 +/- 2.10 MUm, P = 0.042). The change of TRT correlated significantly with change of RNFL thickness. At 36 weeks, OLETF (24.0 +/- 3.1/cross-section) had significantly fewer ganglion cells than LETO (28.4 +/- 6.7/cross-section, P = 0.028). Active caspase-3(+) and TUNEL(+) cells in RNFL were observed significantly more frequently in OLETF (6.8 +/- 5.2/cross section and 3.75 +/- 0.96/cross-section, respectively) than in LETO (1.5 +/- 2.3/cross-section, P = 0.008 and 1.0 +/- 0.8/cross-section, P = 0.029, respectively). CONCLUSIONS: OLETF exhibited a significantly reduced TRT, especially RNFL thickness, based on SD-OCT. Further, histology revealed increased apoptosis and a decrease in the number of ganglion cells. These results suggest that retinal neurodegeneration occurs in type II diabetic OLETF. PMID- 23640037 TI - Glucocorticoid induction of occludin expression and endothelial barrier requires transcription factor p54 NONO. AB - PURPOSE: Glucocorticoids (GCs) effectively reduce retinal edema and induce vascular barrier properties but possess unwanted side effects. Understanding GC induction of barrier properties may lead to more effective and specific therapies. Previous work identified the occludin enhancer element (OEE) as a GC responsive cis-element in the promoters of multiple junctional genes, including occludin, claudin-5, and cadherin-9. Here, we identify two OEE-binding factors and determine their contribution to GC induction of tight junction (TJ) gene expression and endothelial barrier properties. METHODS: OEE-binding factors were isolated from human retinal endothelial cells (HREC) using DNA affinity purification followed by MALDI-TOF MS/MS. Chromatin immunoprecipitation (ChIP) assays determined in situ binding. siRNA was used to evaluate the role of trans acting factors in transcription of TJ genes in response to GC stimulation. Paracellular permeability was determined by quantifying flux through a cell monolayer, whereas transendothelial electrical resistance (TER) was measured using the ECIS system. RESULTS: MS/MS analysis of HREC nuclear extracts identified the heterodimer of transcription factors p54/NONO (p54) and polypyrimidine tract-binding protein-associated splicing factor (PSF) as OEE binding factors, which was confirmed by ChIP assay from GC-treated endothelial cells and rat retina. siRNA knockdown of p54 demonstrated that this factor is necessary for GC induction of occludin and claudin-5 expression. Further, p54 knockdown ablated the pro-barrier effects of GC treatment. CONCLUSIONS: p54 is essential for GC-mediated expression of occludin, claudin-5, and barrier induction, and the p54/PSF heterodimer may contribute to normal blood-retinal barrier (BRB) induction in vivo. Understanding the mechanism of GC induction of BRB properties may provide novel therapies for macular edema. PMID- 23640039 TI - Modulation of bevacizumab-induced toxicity for cultured human corneal fibroblasts. AB - PURPOSE: There are numerous reports describing the direct or indirect cellular toxicity of bevacizumab. In this study, we measured the direct toxicity of bevacizumab and determined its modulation by growth factors in cultured human corneal fibroblasts. METHODS: To measure the toxicity of bevacizumab and ranibizumab on corneal fibroblasts, lactate dehydrogenase (LDH) assays, fluorescence-activated cell sorting analyses, and Ki-67 staining were performed. The role of vascular endothelial growth factor (VEGF) in bevacizumab-related toxicity was evaluated after suppression of VEGF expression using small interfering RNA (siRNA) and VEGF receptor inhibition with SU1498. We evaluated alteration of cellular toxicity and anti-angiogenic function of bevacizumab with cotreatment of basic fibroblast growth factor (bFGF) or nerve growth factor (NGF) using human corneal fibroblasts and human umbilical vein endothelial cells (HUVECs). RESULTS: Application of bevacizumab induced cellular toxicity and delayed proliferation in a dose-dependent manner, but ranibizumab did not cause cellular damage. Elevated LDH observed after bevacizumab treatment was decreased by cotreatment with varying concentrations of fetal bovine serum. However, VEGF cotreatment, VEGF suppression, and VEGF receptor blocking did not influence bevacizumab-induced cell death. Cotreatment of cells with bFGF or NGF and 2 mg/mL bevacizumab reduced LDH elevation. Low-dose bFGF or NGF did not interfere with the antiangiogenic function of bevacizumab as measured by the tube formation assay and MTS (dimethylthiazol-diphenyltetrazolium bromide) assay of HUVECs. CONCLUSIONS: This study determined the cellular toxicity of bevacizumab and its modulation with bFGF or NGF. Cotreatment with bFGF or NGF with bevacizumab reduced cellular damage without interfering with the original antiangiogenic function. Some components of serum have a protective effect on bevacizumab induced corneal epithelial change. PMID- 23640040 TI - Nerve growth factor promotes corneal epithelial migration by enhancing expression of matrix metalloprotease-9. AB - PURPOSE: Nerve growth factor (NGF) is a neuropeptide essential for the development, survival, growth, and differentiation of corneal cells. Its effects are mediated by both TrkA and p75 receptors. Clinically relevant use of NGF was introduced to treat neurotrophic ulcerations in patients. Herein, we examine the mechanisms by which NGF enhances epithelial wound healing both in vivo and in vitro. METHODS: An animal model using adult hens was implemented for the in vivo experiments. Laser ablation keratectomy was performed and animals were observed for up to 7 days. Epithelial healing was measured with fluorescein. In addition, proliferation was measured using BrdU incorporation and both TrkA and matrix metalloprotease-9 (MMP-9) expression were measured by immunohistochemistry (IHC) and Western blot (WB). In vitro experiments were carried out with telomerase immortalized human corneal epithelial cells (HCLE). The rate of proliferation was measured using a colorimetric assay and BrdU incorporation. Real-time migration was evaluated with an inverted microscope. MMP-9 expression was evaluated by immunocytochemistry (ICC), WB, zymography, and RT-PCR. Finally, beta-4 integrin (beta4) expression was assessed by ICC and WB. RESULTS: Faster epithelial healing was observed in NGF-treated corneas compared with controls (P < 0.01). These corneas showed increased proliferation, TrkA upregulation, and enhanced MMP-9 presence (P < 0.01). In vitro, faster spreading and migration were observed in response to NGF (P < 0.01). Enhanced proliferation, as well as enhanced TrkA and MMP-9 expression, and decreased beta4 levels were observed after adding NGF (P < 0.01). CONCLUSIONS: NGF plays a major role during the epithelial healing process by promoting migration, a process that is accelerated by cell spreading. This effect is mediated by both the upregulation of MMP-9 and cleavage of beta4 integrin. PMID- 23640042 TI - Role of heparin-binding epidermal growth factor-like growth factor in light induced photoreceptor degeneration in mouse retina. AB - PURPOSE: Although heparin-binding epidermal growth factor-like growth factor (HB EGF) has been reported to have protective effects against various neuronal cell damage, its role in the retina has not been elucidated. Here, we investigated its role in light-induced photoreceptor degeneration using retinas and ventral forebrain-specific Hb-egf knockout (KO) mice. METHODS: Disruption of Hb-egf was confirmed by beta-galactosidase (LacZ) staining and RT-PCR. Time-dependent changes in retinal HB-EGF were measured using quantitative RT-PCR and Western blotting. Retinal damage was induced by exposure to light. Recombinant human HB EGF was injected intravitreally. Electroretinogram (ERG) and histological analyses were performed. To evaluate the effect of HB-EGF against light irradiation-induced cell death, 661W cells, a transformed mouse cone cell line, were used. RESULTS: LacZ-positive cells were observed and Hb-egf deletion was confirmed in the retinas of Hb-egf KO mice. Hb-egf and pro-HB-EGF levels were increased after light exposure in wild-type (WT) mice. Exposure to light reduced the a- and b-wave amplitudes of the dark-adapted ERG, and also outer nuclear layer (ONL) thickness, in Hb-egf KO mice versus WT mice. Treatment with HB-EGF improved both the a- and b-wave amplitudes and the thickness of the ONL. The 661W cell death induced by light irradiation was exacerbated by Hb-egf knockdown. HB EGF also protected against light-induced cell death and reduced reactive oxygen species (ROS) production in 661W cells. HB-EGF treatment improved the a-wave amplitudes and the thickness of the ONL in Hb-egf KO mice. CONCLUSIONS: These data suggest that HB-EGF plays a pivotal role in light-induced photoreceptor degeneration. It therefore warrants investigation as a potential therapeutic target for such light-induced retinal diseases as age-related macular degeneration. PMID- 23640041 TI - Choice of statistical method influences apparent association between structure and function in glaucoma. AB - PURPOSE: The aim of this study was to explore how different statistical methods may lead to inconsistent inferences about the association between structure and function in glaucoma. METHODS: Two datasets from published studies were selected for their illustrative value. The first consisted of measurements of neuroretinal rim area in the superior-temporal sector paired with the corresponding visual field sensitivity. The second consisted of measurements of average retinal nerve fiber layer thickness over all sectors paired with the corresponding visual field sensitivity. Statistical methods included linear and segmented regression, and a nonparametric local-linear fit known as loess. The analyses were repeated with all measurements expressed as percent of mean normal. RESULTS: Slopes from linear fits to the data changed by a factor of 10 depending on the linear regression method applied. Inferences about whether structural abnormality precedes functional abnormality varied with the statistical design and the units of measure used. CONCLUSIONS: The apparent association between structure and function in glaucoma, and consequent interpretation, varies with the statistical method and units of measure. Awareness of the limitations of any statistical analysis is necessary to avoid finding spurious results that ultimately may lead to inadequate clinical recommendations. PMID- 23640043 TI - Comparison of the optical image quality in the periphery of phakic and pseudophakic eyes. AB - PURPOSE: The natural lens may provide some compensatory optical effect in the periphery. When it is substituted by an IOL during cataract surgery, the quality of the peripheral optics will be modified. We compared the peripheral image quality in the eyes of patients with one eye implanted with a monofocal IOL and the fellow eye still with the natural precataract lens. METHODS: We used a scanning peripheral Hartmann-Shack wavefront sensor to measure the central 80 degrees of visual angle along the horizontal meridian. Twelve patients with ages ranging between 65 to 81 years were evaluated. The results of the phakic and pseudophakic eyes were compared using the spherical equivalent, astigmatism, higher order aberrations, and the Strehl ratio. The statistical differences at each angle between the two eyes were evaluated. RESULTS: In the eyes implanted with IOLs, the peripheral mean spherical equivalent was slightly more myopic than in the phakic eyes, although the differences were only significant for some angles. Astigmatism increased much faster in the periphery for the pseudophakic eyes as compared with the phakic eyes. The mean values were significantly different from 9 degrees and 17 degrees outwards at the temporal and nasal retina, respectively. As an example, at 30 degrees , eyes implanted with IOLs presented 1.5 diopters (D) of additional astigmatism. The higher order aberrations were not significantly different between the two groups. CONCLUSIONS: Eyes implanted with monofocal IOLs present more astigmatism in the periphery than the healthy older eyes. This suggests that the crystalline lens provides a beneficial effect to partially compensate off-axis astigmatism. The degradation of the peripheral retinal image may reduce the pseudophakic patient's performance in common visual tasks. PMID- 23640044 TI - Characteristics of on-road driving performance of persons with central vision loss who use bioptic telescopes. AB - PURPOSE: To compare the on-road driving performance of visually impaired drivers using bioptic telescopes with age-matched controls. METHODS: Participants included 23 persons (mean age = 33 +/- 12 years) with visual acuity of 20/63 to 20/200 who were legally licensed to drive through a state bioptic driving program, and 23 visually normal age-matched controls (mean age = 33 +/- 12 years). On-road driving was assessed in an instrumented dual-brake vehicle along 14.6 miles of city, suburban, and controlled-access highways. Two backseat evaluators independently rated driving performance using a standardized scoring system. Vehicle control was assessed through vehicle instrumentation and video recordings used to evaluate head movements, lane-keeping, pedestrian detection, and frequency of bioptic telescope use. RESULTS: Ninety-six percent (22/23) of bioptic drivers and 100% (23/23) of controls were rated as safe to drive by the evaluators. There were no group differences for pedestrian detection, or ratings for scanning, speed, gap judgments, braking, indicator use, or obeying signs/signals. Bioptic drivers received worse ratings than controls for lane position and steering steadiness and had lower rates of correct sign and traffic signal recognition. Bioptic drivers made significantly more right head movements, drove more often over the right-hand lane marking, and exhibited more sudden braking than controls. CONCLUSIONS: Drivers with central vision loss who are licensed to drive through a bioptic driving program can display proficient on road driving skills. This raises questions regarding the validity of denying such drivers a license without the opportunity to train with a bioptic telescope and undergo on-road evaluation. PMID- 23640045 TI - Deficiency of caveolin-1 in Apc(min/+) mice promotes colorectal tumorigenesis. AB - Caveolin-1 (Cav1), a scaffold protein of membrane caveolae and coactivator of peroxisome proliferator-activated receptor gamma (PPARg), inhibits oncogenic signaling through Ras and wingless. However, the in vivo role of Cav1 in colorectal cancer (CRC) remained unknown. To test whether loss of Cav1 accelerates tumorigenesis, we generated a novel mouse model of CRC by crossing C57BL/6 Apc(min/+) with B6129 Cav1 knockout (Cav1-/-) mice. Apc(min/+) Cav1-/- mice developed large, microinvasive and vascularized intraepithelial adenocarcinomas in the distal colon and rectum with higher incidence than Apc(min/+) Cav1+/- and Apc(min/+) Cav1+/+ littermates. Intratumoral gene signatures related to Ras and wingless signaling were elevated, nuclear localization of PPARg protein and expression of PPARg-target genes were reduced independently of Cav1. The PPARg-agonist rosiglitazone prevented tumor formation in mice irrespectively of the Cav1 status and upregulated expression of the Ras inhibitory protein docking protein-1. Thus, codeficiency of Cav1 and adenomatous polyposis coli facilitated formation of CRC, and activation of PPARg may offer novel strategies for treatment of CRC. PMID- 23640048 TI - Anionic 3D cage networks self-assembled by iodine and V-shaped pentaiodides using dimeric oxoammonium cations produced in situ as templates. AB - A novel co-crystal, [(BTEMPO)2(2+).4I2.2I5(-)] (BTEMPO(+) = 4-benzoyloxy-2,2,6,6 tetramethylpiperidinyl-1-oxoammonium cation), was successfully constructed using iodine and 4-benzoyloxy-2,2,6,6-tetramethylpiperidinyl-1-oxy free radical (BTEMPO) as starting materials and was well characterized by XRD, Raman and calculation. The co-crystal possesses a fascinating 3D anionic cage structure formed by V-shaped-pentaiodides and iodine via multiple halogen bonding and on a template of dimeric (BTEMPO)2(2+) cations. The cationic dimers are held together by a pair of reversed C-H...O=C hydrogen bonds and stabilized the 3D cage structure by C-H...I hydrogen bonds between methyl-protons of BTEMPO(+) and iodine in the framework. The reaction mechanism of producing BTEMPO(+) and I5(-) is proposed and verified by UV-Vis spectroscopy and ESI-MS, which initially goes through a halogen bonding complex between iodine and BTEMPO free radical and then Milliken inner charge transfer and charge separation reaction. UV-Vis absorption spectroscopy confirms the halogen bonding complex between I2 and BTEMPO with a formation constant of 6.94 M(-1) and a 1 : 1 stoichiometry in chloroform. The ESI MS directly led to observation of the less stable intermediates in the mechanism. It is believed that the mechanism proposed here is helpful in understanding the interactions between I2 and organic electron donors, which are debated frequently, and fills the gaps in the reaction mechanism of I2 with free radicals or analogues. PMID- 23640046 TI - Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway. AB - Melanoma is highly metastatic and resistant to chemotherapeutic drugs. Our previous studies have demonstrated that caffeic acid phenethyl ester (CAPE) suppresses the growth of melanoma cells and induces reactive oxygen species generation. However, the exact mechanism of the growth suppressive effects of CAPE was not clear. Here, we determined the potential mechanism of CAPE against melanoma in vivo and in vitro. Administration of 10 mg/kg/day CAPE substantially suppressed the growth of B16F0 tumor xenografts in C57BL/6 mice. Tumors from CAPE treated mice showed reduced phosphorylation of phosphoinositide 3-kinase, AKT, mammalian target of rapamycin and protein level of X-linked inhibitor of apoptosis protein (XIAP) and enhanced the cleavage of caspase-3 and poly (ADP ribose) polymerase. In order to confirm the in vivo observations, melanoma cells were treated with CAPE. CAPE treatment suppressed the activating phosphorylation of phosphoinositide 3-kinase at Tyr 458, phosphoinositide-dependent kinase-1 at Ser 241, mammalian target of rapamycin at Ser 2448 and AKT at Ser 473 in B16F0 and SK-MEL-28 cells in a concentration and time-dependent study. Furthermore, the expression of XIAP, survivin and BCL-2 was downregulated by CAPE treatment in both cell lines. Significant apoptosis was observed by CAPE treatment as indicated by cleavage of caspase-3 and poly (ADP ribose) polymerase. AKT kinase activity was inhibited by CAPE in a concentration-dependent manner. CAPE treatment increased the nuclear translocation of XIAP, indicating increased apoptosis in melanoma cells. To confirm the involvement of reactive oxygen species in the inhibition of AKT/XIAP pathway, cells were treated with antioxidant N-acetyl-cysteine (NAC) prior to CAPE treatment. Our results indicate that NAC blocked CAPE-mediated AKT/XIAP inhibition and protected the cells from apoptosis. Because AKT regulates XIAP, their interaction was examined by immunoprecipitation studies. Our results show that CAPE treatment decreased the interaction of AKT with XIAP. To establish the involvement of AKT in the apoptosis-inducing effects of CAPE, cells were transfected with AKT. Our results revealed that AKT overexpression attenuated the decrease in XIAP and significantly blocked CAPE-mediated apoptosis. Similarly, overexpression of XIAP further decreased CAPE-induced apoptosis. Taken together, our results suggest that CAPE suppresses phosphoinositide 3-kinase/AKT/XIAP pathway leading to apoptosis in melanoma tumor cells in vitro and in vivo. PMID- 23640049 TI - Alkaline polymer electrolyte membranes for fuel cell applications. AB - In this review, we examine the most recent progress and research trends in the area of alkaline polymer electrolyte membrane (PEM) development in terms of material selection, synthesis, characterization, and theoretical approach, as well as their fabrication into alkaline PEM-based membrane electrode assemblies (MEAs) and the corresponding performance/durability in alkaline polymer electrolyte membrane fuel cells (PEMFCs). Respective advantages and challenges are also reviewed. To overcome challenges hindering alkaline PEM technology advancement and commercialization, several research directions are then proposed. PMID- 23640047 TI - Survivin promotion of melanoma metastasis requires upregulation of alpha5 integrin. AB - Survivin is an apoptotic and mitotic regulator that is overexpressed in melanoma and a poor prognostic marker in patients with metastatic disease. We recently showed that Survivin enhances melanoma cell motility through Akt-dependent upregulation of alpha5 integrin. However, the functional role of Survivin in melanoma metastasis is not clearly understood. We found that overexpression of Survivin in LOX and YUSAC2 human melanoma cells increased colony formation in soft agar, and this effect was abrogated by knockdown of alpha5 integrin by RNA interference. We employed melanoma cell xenografts to determine the in vivo effect of Survivin overexpression on melanoma metastasis. Although Survivin overexpression did not affect primary tumor growth of YUSAC2 or LOX subcutaneous tumors, or indices of proliferation or apoptosis, it significantly increased expression of alpha5 integrin in the primary tumors and formation of metastatic colonies in the lungs. Additionally, Survivin overexpression resulted in enhanced lung colony formation following intravenous (i.v.) injection of tumor cells in vivo and increased adherence to fibronectin-coated plastic in vitro. Importantly, in vivo inhibition of alpha5 integrin via intraperitoneal injection of an alpha5beta1 integrin-blocking antibody significantly slowed tumor growth and reduced Survivin-enhanced pulmonary metastasis. Knockdown of alpha5 integrin in cells prior to i.v. injection also blocked Survivin-enhanced lung colony formation. These findings support a direct role for Survivin in melanoma metastasis, which requires alpha5 integrin and suggest that inhibitors of alpha5 integrin may be useful in combating this process. PMID- 23640050 TI - Exploring the perceptions of success in an exercise referral scheme: a mixed method investigation. AB - BACKGROUND: Exercise referral schemes feature as one of the prevalent primary care physical activity interventions in the United Kingdom, without extensive understanding of how those involved in providing and participating view success. The present research explores and reveals the constituents of "success," through comparison, contradiction, and integration of qualitative and quantitative research findings. METHOD: A population-based cohort design formed the basis for a mixed method approach to the research. The quantitative component used a three stage binary logistic regression to identify patient sociodemographic characteristics and referral reasons associated with three outcomes (n=1,315). The qualitative component (n=28) comprised four focus groups with patients (n=17), individual interviews with exercise providers (n=4), and referring health professionals (n=7). The research components were compared at discussion stage to offer insights into the concept of "success." RESULTS: The integrated findings highlighted the multidimensional nature of the concept of success, containing a wide range of concepts such as empowerment, inclusion, and confidence. The traditional notions of success such as, attendance, weight loss, and blood pressure reduction featured amid a more holistic view which incorporated psychological and social aspects as both influences and outcomes. CONCLUSION: These findings can enable future development of more representative evaluations of the benefits of exercise referral. This mixed methods research approach can facilitate the development of sophisticated, tailored, evidence-based interventions in the future. PMID- 23640051 TI - Increasing the degrees of freedom in future group randomized trials: the df * method revisited. AB - BACKGROUND: This article revisits an article published in Evaluation Review in 2005 on sample size estimation and power analysis for group-randomized trials. With help from a careful reader, we learned of an important error in the spreadsheet used to perform the calculations and generate the results presented in that article. As we studied the spreadsheet, we discovered other minor errors. When we corrected the errors, we found that the results were substantially different and that the conclusions reported in the original article were not always appropriate. OBJECTIVE: This article corrects the errors and reports the results as they should have been reported originally. METHOD: Using a random effects meta-analytic model, estimates of intraclass correlation were combined from two studies to guide sample size calculations for a new study. RESULTS: The df * method can result in improved power or smaller studies when used a priori to plan future group-randomized trials, though the improvements will be modest in larger studies and will likely be insufficient to provide adequate power to small studies. CONCLUSION: Smaller group-randomized trials are often desirable, for example, as pilot studies to help plan for a full-scale efficacy trial, as replication studies, or in situations in which resource constraints prohibit a larger trial. We discuss the circumstances under which the df * method will be most helpful and the risks associated with conducting smaller studies. PMID- 23640052 TI - Bounding the effects of social experiments: accounting for attrition in administrative data. AB - BACKGROUND: Social experiments frequently exploit data from administrative records. However, most administrative data systems are designed to track earnings or benefit payments among residents within a single state. When an experimental participant moves across state lines, his entries in the data system of his state of origin consist entirely of zeros. Such attrition may bias the estimated effect of the experiment. OBJECTIVE: To estimate the attrition arising from interstate mobility and provide bounds on the effect of the experiment. METHOD: Attrition is estimated from runs of zeros at the end of the sample period. Bounds are constructed from these estimates. These estimates can be refined by imposing a stationarity assumption. RESULTS: The width of the estimated bounds depends importantly on the nature of the data being analyzed. Negatively correlated outcomes provide tighter bounds than positively correlated outcomes. CONCLUSION: Attrition can introduce considerable ambiguity into the estimated effects of experimental programs. To reduce ambiguity, one should collect as much data as possible. Even data on outcomes of no direct interest to the objectives of the experiment may be valuable for reducing the ambiguity that arises due to attrition. PMID- 23640054 TI - Brain interstitial oligomeric amyloid beta increases with age and is resistant to clearance from brain in a mouse model of Alzheimer's disease. AB - There is a growing body of evidence that soluble oligomeric forms of amyloid beta (Abeta) play a critical role in Alzheimer's disease (AD). Despite the importance of soluble Abeta oligomers as a therapeutic target for AD, the dynamic metabolism of these Abeta species in vivo has not been elucidated because of the difficulty in monitoring brain Abeta oligomers in living animals. Here, using a unique large pore-sized membrane microdialysis, we characterized soluble Abeta oligomers in brain interstitial fluid (ISF) of awake, freely moving APP/PS1 transgenic and control WT mice. We could detect high-molecular-weight (HMW) and low-molecular weight (LMW) Abeta oligomers in the brain ISF of living animals, which increased dramatically in an age-dependent manner (5- to 8-fold increase, 4 vs. 17-18 mo). Notably, HMW Abeta decreased more slowly than other forms of Abeta after acute gamma-secretase inhibition [% decrease from the baseline (HMW vs. LMW) was 36.9 vs. 74.1% (Abeta40, P<0.05) and 25.4 vs. 88.0% (Abeta42, P<0.01)], suggesting that HMW Abeta oligomers clear more slowly than other forms from the brain. These data reveal the dynamic metabolism of neurotoxic Abeta oligomers in AD brain and could provide new insights into Abeta-targeted therapies for AD. PMID- 23640055 TI - Nuclear monomeric integrin alphav in cancer cells is a coactivator regulated by thyroid hormone. AB - Thyroid hormone induces tumor cell and blood vessel cell proliferation via a cell surface receptor on heterodimeric integrin alphavbeta3. We investigated the role of thyroid hormone-induced internalization of nuclear integrin alphav monomer. Physiological concentration of thyroxine (free T4, 10(-10) M), but not 3,5,3' triiodo-l-thyronine (T3), induced cellular internalization and nuclear translocation of integrin alphav monomer in human non-small-cell lung cancer (H522) and ovarian carcinoma (OVCAR-3) cells. T4 did not complex with integrin alphav monomer during its internalization. The alphav monomer was phosphorylated by activated ERK1/2 when it heterodimerized with integrin beta3 in vitro. Nuclear alphav complexed with transcriptional coactivator proteins, p300 and STAT1, and with corepressor proteins, NCoR and SMRT. Nuclear alphav monomer in T4-exposed cells, but not integrin beta3, bound to promoters of specific genes that have important roles in cancer cells, including estrogen receptor-alpha, cyclooxygenase-2, hypoxia-inducible factor-1alpha, and thyroid hormone receptor beta1 in chromatin immunoprecipitation assay. In summary, monomeric alphav is a novel coactivator regulated from the cell surface by thyroid hormone for the expression of genes involved in tumorigenesis and angiogenesis. This study also offers a mechanism for modulation of gene expression by thyroid hormone that is adjunctive to the nuclear hormone receptor (TR)-T3 pathway. PMID- 23640057 TI - Molecular components required for resting and stimulated endocytosis of botulinum neurotoxins by glutamatergic and peptidergic neurons. AB - Proteins responsible for basal and stimulated endocytosis in nerves containing small clear synaptic vesicles (SCSVs) or large dense-core vesicles (LDCVs) are revealed herein, using probes that exploit surface-exposed vesicle proteins as acceptors for internalization. Basal uptake of botulinum neurotoxins (BoNTs) by both SCSV-releasing cerebellar granule neurons (CGNs) and LDCV-enriched trigeminal ganglionic neurons (TGNs) was found to require protein acceptors and acidic compartments. In addition, dynamin, clathrin, adaptor protein complex-2 (AP2), and amphiphysin contribute to the depolarization-evoked entry. For fast recycling of SCSVs, knockdown and knockout strategies demonstrated that CGNs use predominantly dynamin 1, whereas isoform 2 and, to a smaller extent, isoform 3 support a less rapid mode of stimulated endocytosis. Accordingly, proximity ligation assay confirmed that dynamin 1 and 2 colocalize with amphiphysin 1 in CGNs, and the latter copurified with both dynamins from cell extracts. In contrast, LDCV-releasing TGNs preferentially employ dynamins 2 and 3 and amphiphysin 1 for evoked endocytosis and lack the fast phase. Hence, stimulation recruits dynamin, clathrin, AP2, and amphiphysin to augment BoNT internalization, and neurons match endocytosis mediators to the different demands for locally recycling SCSVs or replenishing distally synthesized LDCVs. PMID- 23640056 TI - Tissue transglutaminase regulates beta-catenin signaling through a c-Src dependent mechanism. AB - Tissue transglutaminase (TG2) is a multifunctional enzyme involved in protein cross-linking and cell adhesion to fibronectin (FN). In cancer, TG2 induces an epithelial to mesenchymal transition, contributing to metastasis. Because cadherins bind beta-catenin at cell-cell junctions, disruption of adherens junctions destabilizes cadherin-catenin complexes. The goal of the present study was to analyze whether and how TG2 interacts with and regulates beta-catenin signaling in ovarian cancer (OC) cells. We observed a significant correlation between TG2 and beta-catenin expression levels in OC cells and tumors. TG2 augmented Wnt/beta-catenin signaling, as evidenced by enhanced beta-catenin transcriptional activity, inducing transcription of target genes cyclin D1 and c Myc. By promoting integrin-mediated cell adhesion to FN, TG2 physically associates with and recruits c-Src, which in turn phosphorylates beta-catenin at Tyr(654), releasing it from E-cadherin and rendering it available for transcriptional regulation. By interacting with FN and enhancing beta-catenin signaling, complexed TG2 stimulates OC cell proliferation. In summary, our data demonstrate that TG2 regulates beta-catenin expression and function in OC cells and define the c-Src-dependent mechanism through which this occurs. PMID- 23640058 TI - Activated alpha2-macroglobulin induces Muller glial cell migration by regulating MT1-MMP activity through LRP1. AB - In retinal proliferative diseases, Muller glial cells (MGCs) acquire migratory abilities. However, the mechanisms that regulate this migration remain poorly understood. In addition, proliferative disorders associated with enhanced activities of matrix metalloprotease 2 (MMP-2) and MMP-9 also present increased levels of the protease inhibitor alpha2-macroglobulin (alpha2M) and its receptor, the low-density lipoprotein receptor-related protein 1 (LRP1). In the present work, we investigated whether the protease activated form of alpha2M, alpha2M*, and LRP1 are involved with the MGC migratory process. By performing wound-scratch migration and zymography assays, we demonstrated that alpha2M* induced cell migration and proMMP-2 activation in the human Muller glial cell line, MIO-M1. This induction was blocked when LRP1 and MT1-MMP were knocked down with siRNA techniques. Using fluorescence microscopy and biochemical procedures, we found that alpha2M* induced an increase in LRP1 and MT1-MMP accumulation in early endosomes, followed by endocytic recycling and intracellular distribution of MT1 MMP toward cellular protrusions. Moreover, Rab11-dominant negative mutant abrogated MT1-MMP recycling pathway, cell migration, and proMMP-2 activation induced by alpha2M*. In conclusion, alpha2M*, through its receptor LRP1, induces cellular migration of Muller glial cells by a mechanism that involves MT1-MMP intracellular traffic to the plasma membrane by a Rab11-dependent recycling pathway. PMID- 23640059 TI - Mitochondrial D310 instability in Asian Indian breast cancer patients. AB - Somatic mutations in mitochondrial DNA (mtDNA) have been demonstrated in various tumors. Mitochondrial D-loop is a non-coding region in the mitochondrial genome, which has essential transcription and replication elements, and alterations in this region may affect both these processes. The D-loop has a poly-C tract (PCT) located between 303 and 315 nucleotides known as D310, which has been identified as a frequent hot spot mutation region in human neoplasia. In the present study, 77 pairs of breast tumor and adjacent non-tumorous tissue samples were analyzed by polymerase chain reaction-single-strand conformational polymorphism, restriction fragment length polymorphism, and sequencing to evaluate the frequency of D310 (PCT) mutations and its association with clinicopathologic parameters of breast cancer. Alterations were detected in 25 of 77 (32.5 %) breast cancer samples; these included 7/25 (28 %) cases with heteroplasmy. This is the first study from Asian Indian breast cancer (BC) patients indicating a relatively high frequency of D310 mutations, suggesting that mtDNA instability at D310 may be a common characteristic of BC. However, 66.7 % of the alterations were observed in stage II BC, indicating that this may be a more important change for early progression of the disease rather than its initiation. PMID- 23640060 TI - Model of tumor-associated epigenetic changes of HER2, ER, and PgR expression in invasive breast cancer phenotypes. AB - This theoretic paper is an attempt to apply the epigenetic progenitor model of human cancer origin, proposed by Feinberg et al. (Nat Rev Genet 7:21-33, 2006), to the reported phenotype features of invasive breast cancer. The model is based on the idea that expression of estrogen receptors (ER), progesterone receptors (PgR), and HER2 molecules in breast tumors is either remnants of the tissue stem cell from which the tumor has developed or a newly acquired tumor-associated epigenetic feature. HER2 overexpression is considered as an example of the tumor associated epigenetic changes. The model makes a simple distinction regarding the possible types of ER and PgR expression: the "functional" steroid hormone receptors are inherited from pretumoral tissue stem cells, while the "dysfunctional" steroid hormone receptors are acquired during tumorigenesis from initially ER-PgR-negative cells. In the former, estrogen binding increases the PgR expression while progesterone binding decreases the expression of ER and PgR. Since the estrogen-dependent PgR expression works only in cells with functional ERs, the expected share of tumors with functional ER and PgR receptors is in the model calculated as the squared probability of expressing the PgRs. Reported data from various trials are pooled together to find out phenotype shares (ER+PgR+ makes 62.03 %, ER+PgR- 16.43 %, ER-PgR+ 3.06, and ER-PgR- 18.48 %). By applying the model on these shares, the proposed share of tumors with the functional ER+PgR+ phenotype was 38.48 %, while the share of tumors with the dysfunctional ER+PgR+ was 23.55 %. The presented model suggests that both luminal A and luminal B tumor types are heterogeneous regarding the steroid receptor expression. Some tumors have functional and some have dysfunctional steroid receptors. If these predicted subgroups exist, their detection in the clinical practice might substantially improve treatment options, particularly in the premenopausal setting. PMID- 23640061 TI - The diagnostic role of human epididymis protein 4 and serum amyloid-A in early stage endometrial cancer patients. AB - The aim of this study was to evaluate the prognostic and predictive efficacy of the human epididymis secretory protein 4 (HE4) and serum amyloid-A (S-AA) together with the other tumor markers (CA 125, CA 15-3, CEA, and CA 19-9) in endometrial cancer patients. The study group consisted of 64 patients with defined stage and grade of endometrial cancer and 60 women with benign uterine diseases. Thirty-four healthy women were defined as the control group. Fasting blood samples were collected prior to surgery and tumor marker levels were determined in blood samples by E170 autoanalyzer. S-AA concentrations were measured by particle-enhanced immunonephelometry. Preoperative serum HE4 and S-AA levels were significantly higher in endometrial cancer patients than in controls, whereas the other measured parameters were not significantly different. Serum levels of HE4 were related to both the stage and grade of tumor. The best cutoff point for HE4 was determined to be 59.7 pmol/L; with 75 % sensitivity and 65.5 % specificity. For S-AA, the cutoff point was 8.8 U/mL, with 68.7 % sensitivity and 58.6 % specificity. The combination of HE4, CA 125, CEA, and S-AA raised the sensitivity to 84 %. Preoperative measurement of serum HE4 and S-AA may be of help in early detection of endometrial cancer. Preoperative screening with these markers may provide important information about the patient's outcome and prognosis. PMID- 23640062 TI - Prognostic impact of LDH levels in patients with relapsed/refractory seminoma. AB - PURPOSE: To evaluate the impact of age and LDH levels in patients with relapsed seminoma. METHODS: Data on the 204 seminoma from the International Prognostic Factor Study Group (IPFSG) were analyzed. All patients experienced unequivocal relapse/progression after at least three cisplatin-based chemotherapy cycles. Age and LDH at relapse were assessed in addition to previously identified prognostic factors for all germ cell tumor patients from the database (J Clin Oncol 28:4906, 2010). RESULTS: The impact of the IPFSG score remained highly significant in multivariate analysis. In addition, LDH >=1.5 times the upper limit of normal (ULN) was significant in univariate (HR 1.96; CI 1.06-3.61) and multivariate analysis (HR 1.90; CI 1.00-3.62). Age, however, was not significant. Therefore, LDH was incorporated into a modified new IPFSG seminoma score by moving patients to the next unfavorable group for patients with LDH values >=1.5 * ULN. Three prognostic groups were thus generated, which better subdivided seminoma patients than the original IPFSG score. Progression-free survival at 2 years: "very low risk" (n = 23) 85.7% (95% CI 62-95), "low risk" (n = 44) 62.7 % (95% CI 46-75) and "intermediate risk" (n = 36) 35.1% (95% CI 20-51). Overall survival at 3 years: "very low risk" 88.8% (95% CI 62-97), "low risk" 71.3% (95% CI 55-83) and "intermediate risk" 51.3% (95% CI 33-67). CONCLUSION: The addition of LDH, but not age, improves the impact of the IPFSG prognostic score in seminoma patients relapsing or progressing after cisplatin-based chemotherapy. PMID- 23640063 TI - Groups weight outside information less than individuals do, although they shouldn't: response to Schultze, Mojzisch, and Schulz-Hardt (2013). PMID- 23640064 TI - Groups weight outside information less than individuals do because they should: response to Minson and Mueller (2012). PMID- 23640065 TI - Enduring links from childhood mathematics and reading achievement to adult socioeconomic status. AB - Understanding the determinants of socioeconomic status (SES) is an important economic and social goal. Several major influences on SES are known, yet much of the variance in SES remains unexplained. In a large, population-representative sample from the United Kingdom, we tested the effects of mathematics and reading achievement at age 7 on attained SES by age 42. Mathematics and reading ability both had substantial positive associations with adult SES, above and beyond the effects of SES at birth, and with other important factors, such as intelligence. Achievement in mathematics and reading was also significantly associated with intelligence scores, academic motivation, and duration of education. These findings suggest effects of improved early mathematics and reading on SES attainment across the life span. PMID- 23640066 TI - A Monte Carlo tool for evaluating VMAT and DIMRT treatment deliveries including planar detectors. AB - The aim of this work is to describe and validate a new general research tool that performs Monte Carlo (MC) simulations for volumetric modulated arc therapy (VMAT) and dynamic intensity modulated radiation therapy (DIMRT), simultaneously tracking dose deposition in both the patient CT geometry and an arbitrary planar detector system. The tool is generalized to handle either entrance or exit detectors and provides the simulated dose for the individual control-points of the time-dependent VMAT and DIMRT deliveries. The MC simulation tool was developed with the EGSnrc radiation transport. For the individual control point simulation, we rotate the patient/phantom volume only (i.e. independent of the gantry and planar detector geometries) using the gantry angle in the treatment planning system (TPS) DICOM RP file such that each control point has its own unique phantom file. After MC simulation, we obtained the total dose to the phantom by summing dose contributions for all control points. Scored dose to the sensitive layer of the planar detector is available for each control point. To validate the tool, three clinical treatment plans were used including VMAT plans for a prostate case and a head-and-neck case, and a DIMRT plan for a head-and neck case. An electronic portal imaging device operated in 'movie' mode was used with the VMAT plans delivered to cylindrical and anthropomorphic phantoms to validate the code using an exit detector. The DIMRT plan was delivered to a novel transmission detector, to validate the code using an entrance detector. The total MC 3D absolute doses in patient/phantom were compared with the TPS doses, while 2D MC doses were compared with planar detector doses for all individual control points, using the gamma evaluation test with 3%/3 mm criteria. The MC 3D absolute doses demonstrated excellent agreement with the TPS doses for all the tested plans, with about 95% of voxels having gamma <1 for the plans. For planar dosimetry image comparisons, we defined an acceptable pass rate of >90% of percentage pixels with gamma <1. We found that over 90% of control points in the plans passed this criterion. In general, our results indicate that the simulation tool is suitable for accurately calculating both patient/phantom doses and planar doses for VMAT dose delivery. The tool will be valuable to check performance and advance the development of in vivo planar detectors for use in measurement-based VMAT dose verification. In addition, the tool can be useful as an independent research tool for VMAT commissioning of the TPS and delivery system. PMID- 23640067 TI - Validation of the Tensoval Duo Control II blood pressure monitor for clinic use and self-measurement according to the British Hypertension Society protocol and the European Society of Hypertension International Protocol Revision 2010. AB - OBJECTIVE: The Tensoval Duo Control II is an automated upper arm device that uses a combination of oscillometric and auscultatory technology to determine blood pressure noninvasively. The accuracy of this device was assessed according to the British Hypertension Society (BHS) protocol and the European Society of Hypertension International Protocol revision 2010 (ESH-IP2) in an adult population. METHODS: Ethical approval was obtained. Eighty-five and 33 adult individuals, respectively, were recruited to fulfil the requirements of each protocol. Trained observers took nine sequential same-arm measurements alternating between a mercury sphygmomanometer and the device. The device had to achieve at least a B grade for both systolic and diastolic pressures to pass the BHS protocol and had to fulfil the criteria of all three phases of the ESH-IP2 protocol to receive recommendation. RESULTS: The device achieved an A/A grading for the BHS protocol and passed all three phases of the ESH-IP2 protocol. The mean difference+/-SD for the BHS/ESH protocols, respectively, was -1.8+/-6.5/ 0.7+/-5.7 mmHg for systolic pressure and 1.9+/-5.1/2.4+/-4.5 mmHg for diastolic pressure. The device maintained its A/A grading throughout the low-pressure, medium-pressure and high-pressure ranges. CONCLUSION: The Tensoval Duo Control II device is recommended for clinical and home use according to both the BHS and the ESH-IP2 standard. PMID- 23640068 TI - Impurity doping: a novel strategy for controllable synthesis of functional lanthanide nanomaterials. AB - Many technological nanomaterials are intentionally 'doped' by introducing appropriate amounts of foreign elements into hosts to impart electronic, magnetic and optical properties. In fact, impurity doping was recently found to have significant influence on nucleation and growth of many functional nanocrystals (NCs), and provide a fundamental approach to modify the crystallographic phase, size, morphology, and electronic configuration of nanomaterials. In this feature article, we provide an overview of the most recent progresses in doping-induced control of phase structures, sizes, shapes, as well as performances of functional nanomaterials for the first time. Two kinds of impurity doping strategies, including the homo-valence ion doping and hetero-valence ion doping, are discussed in detail. We lay emphases on impurity doping induced modifications of microstructures and optical properties of upconversion (UC) lanthanide (Ln(3+)) NCs, but do not limit to them. In addition, we also illustrate the control of Ln(3+) activator distribution in the core@shell architecture, which has recently provided scientists with new opportunities for designing and tuning the multi color emissions of Ln(3+)-doped UC NCs. Finally, the challenges and future perspectives of this novel impurity doping strategy are pointed out. PMID- 23640070 TI - Editorial political cartoons in Australia: social representations & and the visual depiction of essentialism. AB - Six million migrants from over 170 countries have resettled in Australia since 1945 ensuring religious diversity is now a hallmark of Australia's population. However, not all religious groups are perceived in the same way. In this paper, we explore how representational processes differentially essentialise religious groups, in particular how some groups are ascribed an underlying nature that irrevocably defines who they are and how they will behave, whilst other groups are conveyed merely as coherent entities with similarity in goals and structure. We elucidate this through an analysis of the depiction of religious markers in Australian Editorial political cartoons. We mirror the near-exclusive focus on the Muslim and Christian religions, in the religious cartoons we sampled, to present an analysis of 6 exemplar cartoons. Drawing from visual analysis techniques (van Leeuwen 2001) and social representations theory (Moscovici 1984) we highlight how essentialist perceptions of religious groups are unwittingly fostered in everyday media communications. We discuss the implications of our analysis for the transnationalisation of religion. PMID- 23640069 TI - Developmental therapeutics in acute myelogenous leukemia: are there any new effective cytotoxic chemotherapeutic agents out there? AB - Therapies for AML have remained mostly unchanged since the introduction of anthracyline- and cytarabine-based regimens in the 1970s. Though some changes have been made in the dosing of anthracylines, in the choice of consolidation regimens versus allogeneic stem cell transplant, and in supportive care, clinical outcomes remain poor for most patients. As we continue to strive for better treatment options to improve upon outcomes, different agents, both chemotherapeutic and targeted therapies, are being studied. Here we discuss new chemotherapeutic agents that show promise in recent clinical trials and attempt to answer the question if there are any new effective cytotoxic chemotherapy agents out there. PMID- 23640071 TI - The Myc 3' Wnt responsive element regulates neutrophil recruitment after acute colonic injury in mice. AB - BACKGROUND: The Wnt/beta-catenin pathway regulates intestinal development, homeostasis, and regeneration after injury. Wnt/beta-catenin signaling drives intestinal proliferation by activating expression of the c-Myc proto-oncogene (Myc) through the Myc 3' Wnt responsive DNA element (Myc 3' WRE). In a previous study, we found that deletion of the Myc 3' WRE in mice caused increased MYC expression and increased cellular proliferation in the colon. When damaged by dextran sodium sulfate (DSS), the increased proliferative capacity of Myc 3' WRE( /-) colonocytes resulted in a more rapid recovery compared with wild-type (WT) mice. In that study, we did not examine involvement of the immune system in colonic regeneration. PURPOSE: To characterize the innate immune response in Myc 3' WRE(-/-) and WT mice during and after DSS-induced colonic injury. METHODS: Mice were fed 2.5 % DSS in their drinking water for five days to induce colonic damage and were then returned to normal water for two or four days to recover. Colonic sections were prepared and neutrophils and macrophages were analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by probing a cytokine array with colonic lysates. RESULTS: In comparison with WT mice, there was enhanced leukocyte infiltration into the colonic mucosal and submucosal layers of Myc 3' WRE(-/-) mice after DSS damage. Levels of activated neutrophils were substantially increased in damaged Myc 3' WRE(-/-) colons as were levels of the neutrophil chemoattractants C5/C5a, CXCL1, and CXCL2. CONCLUSION: The Myc 3' WRE regulates neutrophil infiltration into DSS-damaged colons. PMID- 23640073 TI - Simultaneous characterization of pancreatic stellate cells and other pancreatic components within three-dimensional tissue environment during chronic pancreatitis. AB - Pancreatic stellate cells (PSCs) and other pancreatic components that play a critical role in exocrine pancreatic diseases are generally identified separately by conventional studies, which provide indirect links between these components. Here, nonlinear optical microscopy was evaluated for simultaneous characterization of these components within a three-dimensional (3-D) tissue environment, primarily based on multichannel detection of intrinsic optical emissions and cell morphology. Fresh rat pancreatic tissues harvested at 1 day, 7 days, and 28 days after induction of chronic pancreatitis were imaged, respectively. PSCs, inflammatory cells, blood vessels, and collagen fibers were identified simultaneously. The PSCs at day 1 of chronic pancreatitis showed significant enlargement compared with those in normal pancreas (p < 0.001, analysis of variance linear contrast; n=8 for each group). Pathological events relating to these components were observed, including presence of inflammatory cells, deposited collagen, and phenotype conversion of PSCs. We demonstrate that label-free nonlinear optical microscopy is an efficient tool for dissecting PSCs and other pancreatic components coincidently within 3-D pancreatic tissues. It is a prospect for intravital observation of dynamic events under natural physiological conditions, and might help uncover the key mechanisms of exocrine pancreatic diseases, leading to more effective treatments. PMID- 23640072 TI - A randomized, double-blind, placebo-controlled crossover study of alpha4beta 2* nicotinic acetylcholine receptor agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder. AB - RATIONALE: Stimulation of nicotinic cholinergic systems has been shown to alleviate ADHD symptoms and to improve cognitive performance. AZD1446 is a selective alpha4beta2* nicotinic acetylcholine receptor agonist with potential effect on the symptoms of ADHD. OBJECTIVES: The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of AZD1446 in adults with ADHD treated for 2 weeks. METHOD: This was a randomized, double-blind, placebo controlled crossover trial. Participants were 79 adults with ADHD, grouped according to their use of nicotine-containing products. Nicotine non-users received placebo and two of three AZD1446 treatment regimens (80 mg tid, 80 mg qd, 10 mg tid). Nicotine users received placebo, AZD1446 80 mg tid and 80 mg qd. Efficacy measures included the Conners' Adult ADHD Rating Scale and cognitive measures of immediate and delayed verbal episodic memory, learning, attention, working memory, executive functioning, and spatial problem solving (CogState computerized test battery). RESULTS: There was no significant effect of AZD1446 on any of the clinical scores irrespective of dose, schedule, or concomitant use of nicotine products. A statistically significant improvement was seen on the Groton Maze Learning Task, a measure of executive functioning, in nicotine non users after treatment with AZD1446 80 mg qd. CONCLUSIONS: AZD1446 was well tolerated, but did not significantly improve ADHD symptoms after 2 weeks of treatment compared to placebo. While the present study does not support the therapeutic utility of AZD1446 in ADHD, its potential pro-cognitive effects remain to be explored in other neuropsychiatric disorders. PMID- 23640074 TI - Automatic segmentation of anterior segment optical coherence tomography images. AB - Optical coherence tomography (OCT) images can provide quantitative measurements of the eye's entire anterior segment. A new technique founded on a newly proposed level set-based shape prior segmentation model has been developed for automatic segmentation of the cornea's anterior and posterior boundaries. This technique comprises three major steps: removal of regions containing irrelevant structures and artifacts, estimation of the cornea's location using a thresholding technique, and application of the new level set-based shape prior segmentation model to improve segmentation. The performance of our technique is compared to previously developed methods for analysis of the cornea in 33 OCT images of normal eyes, whereby manual annotations are used as a reference standard. The new technique achieves much improved concordance than previous methods, with a mean Dice's similarity coefficient of > 0.92. This demonstrates the technique's potential to provide accurate and reliable measurements of the anterior segment geometry, which is important for many applications, including the construction of representative numerical simulations of the eye's mechanical behavior. PMID- 23640075 TI - Photoacoustic lifetime contrast between methylene blue monomers and self-quenched dimers as a model for dual-labeled activatable probes. AB - Activatable photoacoustic probes efficiently combine the high spatial resolution and penetration depth of ultrasound with the high optical contrast and versatility of molecular imaging agents. Our approach is based on photoacoustic probing of the excited-state lifetime of methylene blue (MB), a fluorophore widely used in clinical therapeutic and diagnostic applications. Upon aggregation, static quenching between the bound molecules dramatically shortens their lifetime by three orders of magnitude. We present preliminary results demonstrating the ability of photoacoustic imaging to probe the lifetime contrast between monomers and dimers with high sensitivity in cylindrical phantoms. Gradual dimerization enhancement, driven by the addition of increasing concentrations of sodium sulfate to a MB solution, showed that lifetime-based photoacoustic probing decreases linearly with monomer concentration. Similarly, the addition of 4 mM sodium dodecyl sulfate, a concentration that amplifies MB aggregation and reduces the monomer concentration by more than 20-fold, led to a signal decrease of more than 20 dB compared to a solution free of surfactant. These results suggest that photoacoustic imaging can be used to selectively detect the presence of monomers. We conclude by discussing the implementation of the monomer-dimer contrast mechanism for the development of an enzyme-specific activatable probe. PMID- 23640077 TI - Fluorescence background subtraction technique for hybrid fluorescence molecular tomography/x-ray computed tomography imaging of a mouse model of early stage lung cancer. AB - The ability to visualize early stage lung cancer is important in the study of biomarkers and targeting agents that could lead to earlier diagnosis. The recent development of hybrid free-space 360-deg fluorescence molecular tomography (FMT) and x-ray computed tomography (XCT) imaging yields a superior optical imaging modality for three-dimensional small animal fluorescence imaging over stand-alone optical systems. Imaging accuracy was improved by using XCT information in the fluorescence reconstruction method. Despite this progress, the detection sensitivity of targeted fluorescence agents remains limited by nonspecific background accumulation of the fluorochrome employed, which complicates early detection of murine cancers. Therefore we examine whether x-ray CT information and bulk fluorescence detection can be combined to increase detection sensitivity. Correspondingly, we research the performance of a data-driven fluorescence background estimator employed for subtraction of background fluorescence from acquisition data. Using mice containing known fluorochromes ex vivo, we demonstrate the reduction of background signals from reconstructed images and sensitivity improvements. Finally, by applying the method to in vivo data from K-ras transgenic mice developing lung cancer, we find small tumors at an early stage compared with reconstructions performed using raw data. We conclude with the benefits of employing fluorescence subtraction in hybrid FMT XCT for early detection studies. PMID- 23640078 TI - In vivo diffuse correlation spectroscopy investigation of the ocular fundus. AB - Diffuse correlation spectroscopy (DCS) measurements in vivo recorded from rabbits' ocular fundus are presented. Despite the complexity of these ocular tissues, we provide a clear and simple demonstration of the DCS abilities to analyze variations in physiological quantities of clinical interest. Indeed, the reported experimental activities demonstrate that DCS can reveal both choroidal flow and temperature variations and detect nano- and micro-aggregates in ocular fundus circulation. Such abilities can be of great interest both in fundamental research and practical clinical applications. The proposed measuring system can be useful in: (a) monitoring choroidal blood flow variations, (b) determining the end-point for photo-dynamic therapy and transpupillary thermo therapy and, (c) managing the dye injection and determining an end-point for dye-enhanced photothrombosis. Moreover, it could allow both diagnoses when the presence of nano- and micro-aggregates is related to specific diseases and verifying the effects of nanoparticle injection in nanomedicine. Even though the reported results demonstrate the applicability of DCS to investigate ocular fundus, a detailed and accurate investigation of the limits of detection is beyond the scope of this article. PMID- 23640079 TI - Effects of pathology dyes on Raman bone spectra. AB - We report an overlooked source of artifacts for clinical specimens, where unexpected and normally negligible contaminants can skew the interpretation of results. During an ongoing study of bone fragments from diabetic osteomyelitis, strong Raman signatures were found, which did not correspond with normal bone mineral or matrix. In a bone biopsy from the calcaneus of a patient affected by diabetic osteomyelitis, Raman microspectroscopic analysis revealed regions with both abnormal mineral and degraded collagen in addition to normal bone. Additional bands indicated a pathological material. Stenotrophomonas maltophilia was identified in the wound culture by independent microbiologic examination. We initially assigned the unusual bands to xanthomonadin, a bacterial pigment from S. maltophilia. However, the same bands were also found more than a year later on a second specimen that had been noticeably contaminated with pathology marking dye. Drop deposition/Raman spectroscopy of commonly used pathology dyes revealed that a blue tissue-marking dye was responsible for the unusual bands in both specimens, even in the first specimen where there was no visible evidence of contamination. PMID- 23640076 TI - Dual-wavelength photothermal optical coherence tomography for imaging microvasculature blood oxygen saturation. AB - A swept-source dual-wavelength photothermal (DWP) optical coherence tomography (OCT) system is demonstrated for quantitative imaging of microvasculature oxygen saturation. DWP-OCT is capable of recording three-dimensional images of tissue and depth-resolved phase variation in response to photothermal excitation. A 1,064-nm OCT probe and 770-nm and 800-nm photothermal excitation beams are combined in a single-mode optical fiber to measure microvasculature hemoglobin oxygen saturation (SO(2)) levels in phantom blood vessels with a range of blood flow speeds (0 to 17 mm/s). A 50-MUm-diameter blood vessel phantom is imaged, and SO(2) levels are measured using DWP-OCT and compared with values provided by a commercial oximeter at various blood oxygen concentrations. The influences of blood flow speed and mechanisms of SNR phase degradation on the accuracy of SO(2) measurement are identified and investigated. PMID- 23640080 TI - Infrared laser thermal fusion of blood vessels: preliminary ex vivo tissue studies. AB - Suture ligation of blood vessels during surgery can be time-consuming and skill intensive. Energy-based, electrosurgical, and ultrasonic devices have recently replaced the use of sutures and mechanical clips (which leave foreign objects in the body) for many surgical procedures, providing rapid hemostasis during surgery. However, these devices have the potential to create an undesirably large collateral zone of thermal damage and tissue necrosis. We explore an alternative energy-based technology, infrared lasers, for rapid and precise thermal coagulation and fusion of the blood vessel walls. Seven near-infrared lasers (808, 980, 1075, 1470, 1550, 1850 to 1880, and 1908 nm) were tested during preliminary tissue studies. Studies were performed using fresh porcine renal vessels, ex vivo, with native diameters of 1 to 6 mm, and vessel walls flattened to a total thickness of 0.4 mm. A linear beam profile was applied normal to the vessel for narrow, full-width thermal coagulation. The laser irradiation time was 5 s. Vessel burst pressure measurements were used to determine seal strength. The 1470 nm laser wavelength demonstrated the capability of sealing a wide range of blood vessels from 1 to 6 mm diameter with burst strengths of 578 +/- 154, 530 +/ 171, and 426 +/- 174 mmHg for small, medium, and large vessel diameters, respectively. Lateral thermal coagulation zones (including the seal) measured 1.0 +/- 0.4 mm on vessels sealed at this wavelength. Other laser wavelengths (1550, 1850 to 1880, and 1908 nm) were also capable of sealing vessels, but were limited by lower vessel seal pressures, excessive charring, and/or limited power output preventing treatment of large vessels (>4 mm outer diameter). PMID- 23640081 TI - Chromatic changes to artificial irises produced using different techniques. AB - Ocular prostheses are important determinants of their users' aesthetic recovery and self-esteem. Because of use, ocular prostheses longevity is strongly affected by instability of the iris color due to polymerization. The goal of this study is to examine how the color of the artificial iris button is affected by different techniques of artificial wear and by the application of varnish following polymerization of the colorless acrylic resin that covers the colored paint. We produce 60 samples (n = 10) according to the wear technique applied: conventional technique without varnish (PE); conventional technique with varnish (PEV); technique involving a prefabricated cap without varnish (CA); technique involving a prefabricated cap with varnish (CAV); technique involving inverted painting without varnish (PI); and technique involving inverted painting with varnish (PIV). Color readings using a spectrophotometer are taken before and after polymerization. We submitted the data obtained to analyses of variance and Tukey's test (P < 0.05). The color test shows significant changes after polymerization in all groups. The PE and PI techniques have clinically acceptable values of DeltaE, independent of whether we apply varnish to protect the paint. The PI technique produces the least color change, whereas the PE and CA techniques significantly improve color stability. PMID- 23640083 TI - High throughput multilayer microfluidic particle separation platform using embedded thermoplastic-based micropumping. AB - We present an integrated thermoplastic elastomer (TPE) based multilayer microfluidic device with an embedded peristaltic micropump and through-holes membrane for high throughput particle sorting and separation. Fluidic and pneumatic layers of the device were fabricated using hot-embossing lithography and commercially available polycarbonate membranes were succcessfully sandwiched between two thermoplastic elastomer fluidic layers integrated to a peristaltic micropumping layer. The integrated peristaltic micropump induces turbulence at the top-microfluidic layer ring which successfully avoids particle aggregation and membrane blocking even at nanorange size. We present herein the general design of the device structure and pumping characteristics for three devices with membrane pore sizes of 10 MUm, 5 MUm and 800 nm. By using this design we have successfully demonstrated a separation efficiency as high as 99% of polystyrene microbeads with different sizes and most importantly the separation of 390 nm particles from 2 MUm beads was achieved. Using this device, we were also able to separate red blood cells with size of about 6-8 MUm from osteoblasts typically larger than 10 MUm to demonstrate the potential applicability of this platform for biological samples. The produced microfluidic chip operating at flow rates up to 100 MUl min(-1) allows us to achieve efficient high-throughput sorting and separation of target particles/cells. PMID- 23640082 TI - Molecular characterization and primary functional analysis of PeVDE, a violaxanthin de-epoxidase gene from bamboo (Phyllostachys edulis). AB - KEY MESSAGE: PeVDE was expressed primarily in bamboo leaves, which was up regulated under high light. The protein encoded by PeVDE had enzyme activity of catalyzing violaxanthin (V) to zeaxanthin (Z) through antheraxanthin (A) as assay shown in vitro. Violaxanthin de-epoxidase (VDE), a key enzyme of xanthophyll cycle, catalyzes conversion from violaxanthin (V) to zeaxanthin (Z) through antheraxanthin (A) to protect photosynthesis apparatus. A cDNA, PeVDE, encoding a VDE was isolated from bamboo (Phyllostachys edulis) by RT-PCR and RACE methods. PeVDE is 1,723 bp and contains an ORF encoding 451 amino acids, with a transit peptide of 103 amino acids. The mature protein is deduced to have 348 amino acids with a calculated molecular weight of 39.6 kDa and a theoretic isoelectric point of 4.5. Semi-quantitative RT-PCR assay indicated that the highest expression level of PeVDE was in leaf, which agreed with the accumulation pattern of PeVDE protein. Real time PCR results showed that PeVDE was up-regulated and reached the highest level after the treatment (1,200 MUmo1 m(-2) s(-1)) for 2 h, then decreased and kept at the level similar to that of 0.5 h after treatment for 8 h. To investigate the function of PeVDE, mature protein was heterologously expressed in Escherichia coli and the enzymatic activity assay was carried out using V as substrate. The pigments that formed in the reaction mixture were extracted and analyzed by HPLC method. Besides V, A and Z were detected in the reaction mixture, which indicated that the recombinant protein exhibited enzymatic activity of catalyzing V into Z through A. This study indicates that PeVDE functions through regulating the components of xanthophyll cycle, which might be one of the critical factors that contribute to the growth of bamboo under naturally varying light conditions. PMID- 23640084 TI - Photo-magnetic imaging: resolving optical contrast at MRI resolution. AB - In this paper, we establish the mathematical framework of a novel imaging technique, namely photo-magnetic imaging (PMI). PMI uses a laser to illuminate biological tissues and measure the induced temperature variations using magnetic resonance imaging (MRI). PMI overcomes the limitation of conventional optical imaging and allows imaging of the optical contrast at MRI spatial resolution. The image reconstruction for PMI, using a finite-element-based algorithm with an iterative approach, is presented in this paper. The quantitative accuracy of PMI is investigated for various inclusion sizes, depths and absorption values. Then, a comparison between conventional diffuse optical tomography (DOT) and PMI is carried out to illustrate the superior performance of PMI. An example is presented showing that two 2 mm diameter inclusions embedded 4.5 mm deep and located side by side in a 25 mm diameter circular geometry medium are recovered as a single 6 mm diameter object with DOT. However, these two objects are not only effectively resolved with PMI, but their true concentrations are also recovered successfully. PMID- 23640085 TI - Mismatch repair gene mutation analysis and colonoscopy surveillance in Chinese Lynch syndrome families. AB - BACKGROUND: Lynch syndrome (or HNPCC) is a colorectal cancer syndrome caused by germline mutations in either one of the DNA mismatch repair (MMR) genes hMLH1, hMSH2, hMSH6 or hPMS2. Mutations in hMLH1 and hMSH2 are most prevalent. Here we aimed to determine the cancer risk of MMR gene mutation carriers and, in addition, the efficacy of colonoscopy surveillance in Chinese Lynch syndrome family members with and without MMR gene mutations. METHODS: A Lynch syndrome family registry encompassing 106 families in Northern China was recently established. Detailed pedigree data for each family were collected and hMLH1 and hMSH2 gene mutation analyses were performed. Germ-line mutations were identified in probands from 42 of these families, and additional genetic analyses were performed in each member of these 42 families to identify mutation and non mutation carriers. Among the family members included, 180 received colonoscopy and the remaining cases were followed without colonoscopy. RESULTS: Overall 54.8 % of the Lynch syndrome family members carried MMR gene mutations, and these mutation carriers exhibited significantly higher colorectal cancer and other Lynch syndrome-associated cancer risks as compared to non-mutation carriers. The cumulative risk for all Lynch syndrome-related cancers at age 70 was 93.8 % for both hMLH1 and hMSH2 mutation carriers, and 81.7 % and 93.1 % for colorectal cancer at this age, respectively. Whereas 43 of 102 (42.2 %) mutation carriers exhibited significant colonoscopy findings, including 10 colorectal cancers, none of 78 non-mutation carriers exhibited significant findings, and no cancers were detected. In addition, in the mutation carriers, colonoscopy surveillance led to the detection of more early stage cancers than in the non-surveillance group (70.0 % versus 36.5 %, p < 0.01). CONCLUSION: In Lynch syndrome family members, we recommend pre-symptomatic MMR gene mutation analysis in order to identify high risk individuals for colonoscopy surveillance. PMID- 23640086 TI - Tinnitus in a single-sided deaf ear reduces speech reception in the nontinnitus ear. AB - BACKGROUND: The influence of tinnitus on speech reception is under debate. A few previous studies addressed this issue and compared speech reception in groups with and without tinnitus, with tinnitus arising in both ears or in the same test ear. Recently, we demonstrated that loudness of tinnitus in single-sided deafness (SSD) could be reduced dramatically by implanting and activating a cochlear implant (CI). PURPOSE: The aim of the study was to evaluate whether changing the level of tinnitus in the SSD ear by disenabling or enabling the CI changes the speech reception in noise in the non-tinnitus ear. METHODS AND PATIENTS: Fifteen CI users (MED-EL multichannel) with SSD and incapacitating tinnitus participated. They had an initial score of 6 or greater out of 10 on the Visual Analogue Scale (VAS) and an average total score of 58.05 (standard deviation [SD], 13.68) on the Tinnitus Questionnaire. The outcome measure, speech reception threshold (SRT) in noise using an adaptive procedure was measured in the nontinnitus ear using insert earphones. The measurements were performed with a high tinnitus level and a low tinnitus level in the SSD ear, realized by switching the CI off or on. Tinnitus loudness was assessed on a VAS, and tinnitus loudness was also matched using an audiometer. RESULTS: Speech reception in noise is significantly worse in case of high tinnitus loudness. The mean difference in SRT in the nontinnitus ear between the 2 conditions (SRTCI off-SRTCI on) of the 15 subjects was 1.98 dB SNR (SD, 3.01 dB SNR). The mean tinnitus loudness on the VAS was 7.2 (SD, 2.6) in the CI-off condition. In the CI-on condition, the mean VAS score significantly declined to 3.4 (SD, 2.5). Also, the tinnitus loudness match improved from 22 dB SL (SD, 14.4 dB SL) to 10 dB SL (SD, 10.1 dB SL) in the CI-on condition. CONCLUSION: Unilateral tinnitus can significantly decrease speech reception in noise in the nontinnitus ear. PMID- 23640087 TI - Hearing preservation surgery: cochleostomy or round window approach? A systematic review. AB - OBJECTIVES/HYPOTHESIS: An increasing number of patients with low-frequency residual hearing are fitted with a cochlear implant. The challenge is to optimize cochlear implant device properties and develop atraumatic surgical techniques to preserve residual hearing. In view of the ongoing debate about the optimal procedure for opening the cochlea during cochlear implantation, we reviewed the evidence on the round window and the cochleostomy insertion techniques and compared their effects on postoperative residual hearing. DESIGN: Systematic review. METHODS: Electronic databases were systematically searched for relevant studies published up to January 2012. All studies reporting on residual hearing and hearing preservation surgery were included. RESULTS: Sixteen studies, with a total of 170 patients, were included. There were no studies directly comparing both surgical insertion techniques. The methodologic quality of the studies was poor and might be subjected to a high risk of bias. Because there were no studies directly comparing the 2 techniques and controlling for possible influencing factors, differences between studies might also be influenced by intersurgeon variance in many facets regarding cochlear implantation surgery. The available data show a postoperative low-frequency hearing loss ranging from 10 to 30 dB at 125, 250, and 500 Hz, regardless of surgical technique. The number of patients with a postoperative complete hearing preservation ranged from 0% to 40% for the cochleostomy group and from 13% to 59% in the round window group. CONCLUSION: The available data do not show that there is a benefit of one surgical approach over the other regarding the preservation of residual hearing. To provide solid evidence, a double-blind randomized trial is needed, which compares the clinical outcomes, notably the degree of hearing preservation, of both surgical approaches. PMID- 23640088 TI - Can an incomplete ossicular discontinuity be predicted by audiometric and clinical findings? AB - OBJECTIVE: To investigate a pathology of conductive hearing loss caused by an incomplete ossicular discontinuity. It can manifest as a triad of the following: 1) conductive hearing loss most prominent in the high frequencies (hfCHL), defined as [ABG for 4 kHz] > [mean ABG for 0.25-0.5 kHz] + 10 dB or more; 2) fluctuating hearing loss; and 3) short-lasting improvement of hearing after Valsalva maneuver. STUDY DESIGN: Retrospective clinical trial. SETTING: Tertiary referral center. PATIENTS: Fourteen patients with an incomplete ossicular discontinuity who underwent incus interposition were included. INTERVENTION: Incus interposition, mathematical model. MAIN OUTCOME MEASURES: First, the prevalence of the triad was documented. Second, the hypothesis that mechanical ossicular compliance was responsible for the triad of symptoms was evaluated and simulated in a mathematical model. Finally, the postoperative hearing results with a follow-up of 12 months were analyzed and compared with those reported in the literature. RESULTS: The presence of the triad of symptoms is a strong indicator for detecting patients with an incomplete ossicular discontinuity. High frequency conductive hearing loss was present in 93% (13/14 patients). Ten (71%) of the 14 patients presented with fluctuating hearing loss and improvement of hearing after Valsalva maneuver. The hfCHL could be simulated adequately in the mathematical model. Success rate for surgical intervention (ABG < 20 dB; 0.5, 1, 2, and 3 kHz) was 93% and was comparable to the results reported in the literature. CONCLUSION: Patients with hfCHL, fluctuating hearing loss, and improvement of hearing after Valsalva maneuver are likely to have an incomplete ossicular discontinuity. A favorable postoperative hearing recovery by incus interposition can be expected. PMID- 23640089 TI - Functional status of hearing aids in bilateral-bimodal users. AB - OBJECTIVE: To assess the functional status of the hearing aid (HA) in bilateral bimodal users, in whom HA monitoring is often neglected because fitting efforts are focused on the cochlear implant (CI). Also, to define an audiometric pattern of residual hearing that might explain why, despite nonoptimal bimodal fitting, certain cochlear implantees still opt to use a HA. STUDY DESIGN: Retrospective case review. SETTING: Ambulatory care clinic. PARTICIPANTS: Experienced bimodal (CI/HA) adult users (N = 31) who use their HA during most of their waking hours. HA settings were required to meet a selected prescriptive (NAL-NL1) electro acoustical Verifit Speechmap target at low frequencies using the simulated real ear mode. INTERVENTION: After initial evaluation, HAs that did not meet the Speechmap target underwent appropriate fitting and reevaluation. MAIN OUTCOME MEASURE(S): Number of patients whose HAs met the defined Speechmap criteria after refitting; residual hearing levels in patients who achieved optimal bimodal fitting and in those who did not. RESULTS: At initial evaluation, the HA in 25 (81%) of the 31 participants was malfunctioning or poorly tuned. After HA replacement or retuning, 19 participants (61%) met the Speechmap targets, and 12 (39%) did not. However, the 2 groups had similar mean levels of unaided and aided residual hearing thresholds at 250 or 500 Hz. CONCLUSION: To maximize the benefit for bilateral-bimodal users, specific guidelines must be established also for fitting of their HAs. The focus should be on achieving the maximum amplification possible at low frequencies. PMID- 23640090 TI - Speech comprehension in children and adolescents after sequential bilateral cochlear implantation with long interimplant interval. AB - OBJECTIVE: Identify likely predictors for the outcome after contralateral cochlear implantation with a long interimplant delay. STUDY DESIGN: Retrospective case reviews. SETTING: Outpatient cochlear implant (CI) center. PATIENTS: Seventy three children and adolescents who underwent sequential bilateral cochlear implantation with an interval between both implantations of 5 years or longer. The mean age of the patients at the first and second cochlear implantations was 2.72 +/- 1.52 and 11.57 +/- 2.9 years, respectively. The mean duration of experience with both implants was 4.01 +/- 1.57 years. INTERVENTION: Rehabilitative. MAIN OUTCOME MEASURES: All 73 patients underwent periodic speech perception testing in quiet and noise. The most recent unilateral data for each side were statistically analyzed. The speech test results were evaluated by the age at first implantation, the interval between both implantations, the duration of hearing aid use in the second side, and the duration of the bilateral CI use. RESULTS: A statistically significant difference for speech test results was obtained between the early-implanted ears and the late-implanted ears for all children. These results were dependent on the interimplant interval. All age groups demonstrated significant differences (p > 0.05) for the second side between the speech test results and the interval between both cochlear implantations. In addition, statistically significant differences influenced by the duration of hearing aid use were found for speech test results for the second side. Experience was also a factor for the second CI, yielding significantly higher speech test scores with longer use. CONCLUSION: The development of hearing abilities in a second-implanted side depends on the interimplant interval, the hearing aid use, and the duration of the second CI use. PMID- 23640091 TI - Identification of a SNP in a regulatory region of GJB2 associated with idiopathic nonsyndromic autosomal recessive hearing loss in a multicenter study. AB - HYPOTHESIS: Additional genetic changes in the regulatory region of the human GJB2 gene encoding the gap junction protein (Connexin 26) may contribute to sensorineural hearing loss. BACKGROUND: Mutations in GJB2 cause up to 50% of autosomal recessive nonsyndromic hearing impairment (NSHI). METHODS: In the present study, we screened the putative 5' GJB2 regulatory region for novel alterations. RESULTS: In idiopathic familial cases of NSHI lacking known pathogenic alterations in GJB2, we identified a T->C transition (refSNP: rs117685390) in a putative transcription factor binding sequence 228 bp proximal to the transcriptional start site at a homozygous frequency of 0.125 (n = 40), significantly overrepresented in comparison to the homozygous allele frequencies of 0.043 in the normal-hearing Caucasian population (n = 211; p < 0.001). In a NSHI family, inheritance of the rs117685390 C allele segregated on independent chromosomes with NSHI in conjunction with heterozygous inheritance of c.35delG, the most common Caucasian mutation in the GJB2 coding region. In a patient group (n = 32) bearing heterozygous pathogenic c.35delG mutations, - rs117685390 C allele homozygosity was also highly overrepresented (0.25; p < 0.001) and not exclusively linked to the c.35delG mutation in cis in patients homozygous for c.35delG. However, in the majority of NSHI homozygous c.35delG chromosomes examined (91/94), c.35delG homozygosity was linked to the rs117685390 C allele in cis. CONCLUSION: These results suggest that the rs117685390 C allele could represent a biomarker for the development of NSHI in Caucasian populations and may be included in risk assessment for the development of NSHI. PMID- 23640092 TI - Sudden unilateral hearing loss as first sign of cerebral sinus venous thrombosis? A 3-year retrospective analysis. AB - INTRODUCTION: Recently, several studies and case reports have dealt with the topic of cerebral sinus venous thrombosis (CSVT) and focused on sudden hearing loss as an early and rare symptom, to diminish the delay in diagnosing this serious disease. MATERIALS AND METHODS: We conducted a retrospective analysis over 3 years and investigated MRIs of all inpatients who were treated for sudden sensorineural hearing loss. The aim of the study was to evaluate whether sudden hearing loss could be an early indicator, or the first sign, of CSVT. RESULTS: In total, 554 patients were included. Only 2 patients with CSVT could be identified. In both, sudden unilateral sensorineural hearing loss was not the only symptom. They also reported headache, and 1 patient also reported tinnitus and vertigo. CONCLUSION: In our opinion, sudden unilateral sensorineural hearing loss alone is not a reliable indicator of CSVT. In combination with headache or visual impairment, this rare vascular disease should be taken into account. PMID- 23640093 TI - Hearing aid tolerance after revision and obliteration of canal wall down mastoidectomy cavities. AB - OBJECTIVE: To review the tolerance of hearing aid use after revision and obliteration of a previously unstable canal wall down mastoidectomy cavity. STUDY DESIGN: Retrospective case series. SETTING: Academic tertiary referral center. PATIENTS: Adults and children who underwent the described surgical procedure followed by attempted hearing aid use. INTERVENTION(S): Surgical revision and obliteration of a chronically unstable canal wall down mastoidectomy cavity and subsequent attempted use of a conventional, ear-level hearing aid. MAIN OUTCOME MEASURE(S): Stability of mastoid cavity after starting conventional hearing aid usage. RESULTS: From a review of 87 consecutive mastoid obliteration procedures performed on previously unstable open cavities, 20 ears in 19 subjects were identified for study inclusion. The indication for hearing aid use was mixed hearing loss in the majority of subjects (85%). Among included ears, 7 (35%) had at least one documented temporary period of hearing aid nonuse because of otorrhea; however, permanent discontinuation of hearing aid use in favor of bone anchored hearing implant placement only occurred in 3 ears (15%). The mean follow up from the start of hearing aid use was 49 months. CONCLUSION: Although failures do exist, attempted use of a hearing aid after revision of an unstable canal wall down mastoidectomy cavity seems feasible and generally well tolerated. However, the exact likelihood of achieving this result is yet uncertain, and hearing performance was not assessed in this study. PMID- 23640094 TI - Osseointegrated hearing device placement in congenital lamellar ichthyosis. AB - OBJECTIVE: To present a case of osseointegrated hearing device placement in a child with conductive hearing loss related to manifestations of congenital lamellar ichthyosis. PATIENT: A 5-year-old female patient with congenital lamellar ichthyosis resulting in conductive hearing loss because of bilateral external auditory canal stenosis and tympanic membrane blunting. INTERVENTION: Unilateral osseointegrated hearing device placement using a traditional skin flap technique. MAIN OUTCOME MEASURES: Frequency and severity of adverse skin reactions, device usage, and audiometric testing. RESULTS: After 51 months of follow-up postoperatively, the patient has only required 2 treatments for minor skin reactions (Holgers Grade I). Aided speech reception threshold was 15 dB hearing level (HL) compared to 35 dB HL unaided. The subject has used the device continuously with parental report of improvement in school performance. CONCLUSION: Osseointegrated hearing device placement may be a viable option in patients with congenital lamellar ichthyosis despite the skin-related comorbidities known to be associated with this disease condition. PMID- 23640095 TI - Magnesium - its role in CKD. AB - Magnesium containing compounds present promising oral phosphate binders for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD). However, the impact of magnesium in CKD patients still remains unclear in clinical routine practice. Therefore, this publication provides a practicable overview of knowledge about the physiological role of magnesium in general and in particular in CKD patients. Prevalence of hypomagnesaemia is high in the general population and especially in intensive care unit patients, but often not being detected. Magnesium deficiency increases the risk for several diseases, like diabetes mellitus type 2, hypertension and atherosclerosis. Moderate hypermagnesaemia, however, seems to have beneficial effects on vascular calcification and mortality rates in CKD patients. On the other hand, higher serum magnesium levels are reported to be linked to lower PTH levels and results on the effects on bone are controversial. In addition, low magnesium levels are associated with low bone mass, osteoporosis and vascular calcification. In dialysis patients serum magnesium levels are dependent mainly on the dialysate magnesium concentration. To confirm the potential delay of arterial calcification and improved survival outcomes by long-term intervention with magnesium powered randomized studies are required in dialysis patients. Since a recent trial revealed that a phosphate binder containing a combination of magnesium carbonate and calcium acetate was as effective as the polymer-based agent sevelamer hydrochloride and had an equally good tolerability profile, it is time for a re examination of the role of magnesium in CKD patients. PMID- 23640096 TI - Angular craniometry in craniocervical junction malformation. AB - The craniometric linear dimensions of the posterior fossa have been relatively well studied, but angular craniometry has been poorly studied and may reveal differences in the several types of craniocervical junction malformation. The objectives of this study were to evaluate craniometric angles compared with normal subjects and elucidate the main angular differences among the types of craniocervical junction malformation and the correlation between craniocervical and cervical angles. Angular craniometries were studied using primary cranial angles (basal and Boogard's) and secondary craniocervical angles (clivus canal and cervical spine lordosis). Patients with basilar invagination had significantly wider basal angles, sharper clivus canal angles, larger Boogard's angles, and greater cervical lordosis than the Chiari malformation and control groups. The Chiari malformation group does not show significant differences when compared with normal controls. Platybasia occurred only in basilar invagination and is suggested to be more prevalent in type II than in type I. Platybasic patients have a more acute clivus canal angle and show greater cervical lordosis than non-platybasics. The Chiari group does not show significant differences when compared with the control, but the basilar invagination groups had craniometric variables significantly different from normal controls. Hyperlordosis observed in the basilar inavagination group was associated with craniocervical kyphosis conditioned by acute clivus canal angles. PMID- 23640097 TI - The prevalence and prognostic significance of KRAS mutation in bladder cancer, chronic myeloid leukemia and colorectal cancer. AB - Mutations in the KRAS gene have been shown to play a key role in the pathogenesis of a variety of human tumours. However the mutational spectrum of KRAS gene differs by organ site. In this study, we have analysed the mutational spectrum of KRAS exon 1 in bladder tumours, colorectal cancer (CRC) and chronic myeloid leukemia (CML). A total of 366 patients were included in the present study (234 bladder tumours, 48 CRC and 84 CML). The KRAS mutations are absent in BCR/ABL1 positive CML. This result suggests that BCR/ABL1 fusion gene and KRAS mutations were mutually exclusive. The frequency of KRAS mutations in bladder cancer was estimated at 4.27 %. All of mutations were found in codon 12 and 90 % of them were detected in advanced bladder tumours. However the correlation between KRAS mutations and tumour stage and grade does not report a statistical significant association. The KRAS mutations occur in 35.41 % of patients with CRC. The most frequent mutations were G12C, G12D and G13D. These mutations were significantly correlated with histological differentiation of CRC (p = 0.024). Although the high frequency of KRAS in CRC in comparison to bladder cancer, these two cancers appear to have the same mutational spectrum (p > 0.05). PMID- 23640098 TI - Expression and functions of dopa decarboxylase in the silkworm, Bombyx mori was regulated by molting hormone. AB - Insect molting is an important developmental process of metamorphosis, which is initiated by molting hormone. Molting includes the activation of dermal cells, epidermal cells separation, molting fluid secretion, the formation of new epidermis and old epidermis shed and other series of continuous processes. Polyphenol oxidases, dopa decarboxylase and acetyltransferase are necessary enzymes for this process. Traditionally, the dopa decarboxylase (BmDdc) was considered as an enzyme for epidermal layer's tanning and melanization. This work suggested that dopa decarboxylase is one set of the key enzymes in molting, which closely related with the regulation of ecdysone at the time of biological molting processes. The data showed that the expression peak of dopa decarboxylase in silkworm is higher during molting stage, and decreases after molting. The significant increase in the ecdysone levels of haemolymph was also observed in the artificially fed silkworm larvae with ecdysone hormone. Consistently, the dopa decarboxylase expression was significantly elevated compared to the control. BmDdc RNAi induced dopa decarboxylase expression obviously declined in the silkworm larvae, and caused the pupae appeared no pupation or incomplete pupation. BmDdc was mainly expressed and stored in the peripheral plasma area near the nucleus in BmN cells. In larval, BmDdc was mainly located in the brain and epidermis, which is consisted with its function in sclerotization and melanization. Overall, the results described that the dopa decarboxylase expression is regulated by the molting hormone, and is a necessary enzyme for the silkworm molting. PMID- 23640099 TI - Identification of an intronic regulatory mutation at the buffalo alphaS1-casein gene that triggers the skipping of exon 6. AB - The characterization of casein polymorphism is an essential step in order to understand the genetic basis of milk quality in dairy ruminants. In this work, we report the identification of a regulatory mutation at the buffalo alphas1-casein (CSN1S1) gene that alters the normal processing of the primary transcript. Sequencing of CSN1S1 cDNA from individuals harbouring this new variant revealed that its most distinctive feature is the loss of exon 6 that encodes eight amino acids between positions 35-42 of mature protein. In an effort to map the causal mutation, we sequenced a genomic region spanning exons 5-7 of the buffalo CSN1S1 gene. This experiment allowed us to establish that exon 6-skipping is produced by a G to C substitution at the first position of intron 6 that inactivates the donor splice site. This mutation can be typed by PCR-RFLP by using either TaaI or Bpu10I diagnostic restriction enzymes, and it has a frequency of 0.18 in Romanian buffaloes. This exon skipping phenomenon is the first one described in buffalo CSN1S1 locus. PMID- 23640100 TI - Genetic diversity and maternal origin of Bangladeshi chicken. AB - Local domestic chicken populations are of paramount importance as a source of protein in developing countries. Bangladesh possesses a large number of native chicken populations which display a broad range of phenotypes well adapted to the extreme wet and hot environments of this region. This and the fact that wild jungle fowls (JFs) are still available in some regions of the country, it urges to study the present genetic diversity and relationships between Bangladeshi autochthonous chicken populations. Here, we report the results of the mitochondrial DNA (mtDNA) sequence polymorphisms analyses to assess the genetic diversity and possible maternal origin of Bangladeshi indigenous chickens. A 648 bp fragment of mtDNA control region (D-loop) was analyzed in 96 samples from four different chicken populations and one red JF population. Sequence analysis revealed 39 variable sites that defined 25 haplotypes. Estimates of haplotype and nucleotide diversities ranged from 0.745 to 0.901 and from 0.011 to 0.016, respectively. The pairwise differences between populations ranged from 0.091 to 1.459 while most of the PhiST (PhiST) values were significant. Furthermore, AMOVA analysis revealed 89.16 % of the total genetic diversity was accounted for within population variation, indicating little genetic differentiation among the studied populations. The median network analysis from haplotypes of Bangladeshi chickens illustrated five distinct mitochondrial haplogroups (A, D, E, F and I). Individuals from all Bangladeshi chicken populations were represented in the major clades D and E; those maternal origins are presumed to be from Indian Subcontinent and Southeast Asian countries, more particularly from South China, Vietnam, Myanmar and Thailand. Further, phylogenetic analysis between indigenous chicken populations and sub-species of red JFs showed G. g. gallus and G. g. spadiceus shared with almost all haplogroups and had major influence than G. g. murghi in the origin of indigenous chicken of Bangladesh. These results suggest that Bangladeshi indigenous chickens still have abundant genetic diversity and have originated from multiple maternal lineages, and further conservation efforts are warranted to maintain the diversity. PMID- 23640101 TI - Novel naphthalimide polyamine derivatives as potential antitumor agents. AB - A novel series of naphthalimide polyamine conjugates were designed, synthesized and evaluated for in vitro antiproliferative activity against human leukemia (Jurkat), human cervical adenocarcinoma (HeLa), human breast adenocarcinoma (MCF 7) and human lung adenocarcinoma (A549) cell lines. From the six derivatives, the new I1 and A3 exhibited highest antiproliferative activity with the IC50 values of 5.67-11.02 MUmol . L(-1). Cell cycle analysis of Jurkat cells exposed to I1 at a concentration of 30 MUmol * L(-1) for 24 h exhibited a mild increase in S and G2/M fraction caused by accumulation of cells. This arrest was followed by an increase in sub-G0/G1 after 48 h of incubation. Jurkat cells exposed to A3 at a concentration of 30 MUmol * L(-1) for 24 h showed an increase in G0/G1 fraction and after 48 h an increase in G2/M fraction followed by an increase in sub-G0/G1 after 72 h of incubation. Moreover, the A3 compound was observed to displace the intercalating agent ethidium bromide from calf thymus DNA using fluorescence spectroscopy. The apparent binding constant was estimated to be 3.1 * 10(6) M(-1) what indicates non-intercalating mode of DNA binding. On the other hand, we found no inhibitory effect of studied compounds on topoisomerase I and topoisomerase II activity. Finally, the localization of these compounds in the cells due to their inherent fluorescence was investigated with the fluorescence microscopy. Our results suggest that the naphthalimide polyamine conjugates rapidly penetrate to the cancer cells. Further studies are necessary to investigate the precise mechanism of action and to find out the relationship between the structure, character and position of substituents of naphthalimide polyamine conjugates and their biological activities. PMID- 23640102 TI - The development and validation of a decision-analytic model representing the full disease course of acute myeloid leukemia. AB - BACKGROUND: The treatment of acute myeloid leukemia (AML) is moving towards personalized medicine. However, due to the low incidence of AML, it is not always feasible to evaluate the cost-effectiveness of personalized medicine using clinical trials. Decision analytic models provide an alternative data source. OBJECTIVE: The aim of this study was to develop and validate a decision analytic model that represents the full disease course of AML. METHODS: We used a micro simulation with discrete event components to incorporate both patient and disease heterogeneity. Input parameters were calculated from patient-level data. Two hematologists critically evaluated the model to ensure face validity. Internal and external validity was tested by comparing complete remission (CR) rates and survival outcomes of the model with original data, other clinical trials and a population-based study. RESULTS: No significant differences in patient and treatment characteristics, CR rate, 5-year overall and disease-free survival were found between the simulated and original data. External validation showed no significant differences in survival between simulated data and other clinical trials. However, differences existed between the simulated data and a population based study. CONCLUSIONS: The model developed in this study is proved to be valid for analysis of an AML population participating in a clinical trial. The generalizability of the model to a broader patient population has not been proven yet. Further research is needed to identify differences between the clinical trial population and other AML patients and to incorporate these differences in the model. PMID- 23640104 TI - Gossypol overcomes stroma-mediated resistance to the BCL2 inhibitor ABT-737 in chronic lymphocytic leukemia cells ex vivo. PMID- 23640103 TI - Modelling the cost effectiveness of disease-modifying treatments for multiple sclerosis: issues to consider. AB - Several cost-effectiveness models of disease-modifying treatments (DMTs) for multiple sclerosis (MS) have been developed for different populations and different countries. Vast differences in the approaches and discrepancies in the results give rise to heated discussions and limit the use of these models. Our main objective is to discuss the methodological challenges in modelling the cost effectiveness of treatments for MS. We conducted a review of published models to describe the approaches taken to date, to identify the key parameters that influence the cost effectiveness of DMTs, and to point out major areas of weakness and uncertainty. Thirty-six published models and analyses were identified. The greatest source of uncertainty is the absence of head-to-head randomized clinical trials. Modellers have used various techniques to compensate, including utilizing extension trials. The use of large observational cohorts in recent studies aids in identifying population-based, 'real-world' treatment effects. Major drivers of results include the time horizon modelled and DMT acquisition costs. Model endpoints must target either policy makers (using cost utility analysis) or clinicians (conducting cost-effectiveness analyses). Lastly, the cost effectiveness of DMTs outside North America and Europe is currently unknown, with the lack of country-specific data as the major limiting factor. We suggest that limited data should not preclude analyses, as models may be built and updated in the future as data become available. Disclosure of modelling methods and assumptions could improve the transferability and applicability of models designed to reflect different healthcare systems. PMID- 23640105 TI - Preoperative evaluation and perioperative management of right ventricular failure after left ventricular assist device implantation. AB - Right ventricular (RV) failure continues to be a major cause of morbidity and mortality after left ventricular assist device (LVAD) implantation. Preoperative evaluation of RV function with a variety of clinical, laboratory, echocardiographic, and hemodynamic variables is essential to ensure appropriate patient selection for LVAD therapy but remains imperfect. Therefore, clinicians involved in the care of these patients need to be prepared to manage RV failure after LVAD placement. Perioperative management of RV failure after LVAD implantation requires minimization of intraoperative RV ischemia, maintenance of appropriate filling pressure, supportive therapy with pulmonary vasodilators and inotropes, and surgical interventions such as RV assist devices in select cases. This article reviews the incidence of RV failure with LVAD implantation, preoperative predictors of RV failure, and perioperative management strategies. PMID- 23640106 TI - Tool-use reshapes the boundaries of body and peripersonal space representations. AB - Interaction with objects in the environment typically requires integrating information concerning the object location with the position and size of body parts. The former information is coded in a multisensory representation of the space around the body, a representation of peripersonal space (PPS), whereas the latter is enabled by an online, constantly updated, action-orientated multisensory representation of the body (BR). Using a tool to act upon relatively distant objects extends PPS representation. This effect has been interpreted as indicating that tools can be incorporated into BR. However, empirical data showing that tool-use simultaneously affects PPS representation and BR are lacking. To study this issue, we assessed the extent of PPS representation by means of an audio-tactile interaction task and BR by means of a tactile distance perception task and a body-landmarks localisation task, before and after using a 1-m-long tool to reach far objects. Tool-use extended the representation of PPS along the tool axis and concurrently shaped BR; after tool-use, subjects perceived their forearm narrower and longer compared to before tool-use, a shape more similar to the one of the tool. Tool-use was necessary to induce these effects, since a pointing task did not affect PPS and BR. These results show that a brief training with a tool induces plastic changes both to the perceived dimensions of the body part acting upon the tool and to the space around it, suggesting a strong overlap between peripersonal space and body representation. PMID- 23640107 TI - Screening for long-lived genes identifies Oga1, a guanine-quadruplex associated protein that affects the chronological lifespan of the fission yeast Schizosaccharomyces pombe. AB - Schizosaccharomyces pombe and Saccharomyces cerevisiae are excellent model organisms to study lifespan. We conducted screening to identify novel genes that, when overexpressed, extended the chronological lifespan of fission yeast. We identified seven genes, among which we focused on SPBC16A3.08c. The gene product showed similarity to Ylr150w of S. cerevisiae, which has affinity for guanine quadruplex nucleic acids (G4). The SPBC16A3.08c product associated with G4 in vitro and complemented the phenotype of an S. cerevisiae Ylr150w deletion mutant. From these results, we proposed that SPBC16A3.08c encoded for a functional homolog of Ylr150w, which we designated ortholog of G4-associated protein (oga1 (+)). oga1 (+) overexpression extended the chronological lifespan and also decreased mating efficiency and caused both high and low temperature-sensitive growth. Deleting oga1 (+) resulted in caffeine-sensitive and canavanine-resistant phenotypes. Based on these results, we discuss the function of Oga1 on the chronological lifespan of fission yeast. PMID- 23640109 TI - Underestimated survival predictions of the prognostic tools Adjuvant! Online and PREDICT in BRCA1-associated breast cancer patients. AB - BRCA1-associated breast cancer is considered an unique clinical entity with its own specific histopathological characteristics. Several recently published large studies have shown that overall survival of BRCA1 mutation carriers having breast cancer is similar to sporadic breast cancer patients. It was also suggested that better response to chemotherapy is one of the most important factors that improves the clinical outcome of breast cancers with unfavorable histopathological subtypes in BRCA1 mutation carriers. Adjuvant! Online and PREDICT are web-based prognostic tools that estimate the survival benefit of adjuvant chemotherapy in primary breast cancer patients. These tools have been extensively validated in different populations; however, the accuracy of the predictions made by Adjuvant! Online and PREDICT among BRCA1 mutation carriers has not yet been investigated. In this study we have found, that predictions of overall and breast cancer-specific survival obtained from Adjuvant! Online and PREDICT were significantly lower than the observed survival percentages in the study population [predicted--observed difference for 10-year overall survival: 9.75%, P < 0.0001 (Adjuvant! Online); -10.21%, P < 0.0001 (PREDICT)]. Thus this study suggests that Adjuvant! Online and PREDICT should be used with caution in this group of patients. Further updating of adjuvant therapy benefit calculation tools by inclusion of the information about inherited genetic alterations should be considered to improve the performance of the prognostic programs among hereditary breast cancer patients. PMID- 23640110 TI - First clinical evaluation of a new innovative ureteral access sheath (Re TraceTM): a European study. AB - PURPOSE: The use of a ureteral access sheath (UAS) during flexible retrograde intrarenal surgery (RIRS) has become increasingly popular. Our aim was to evaluate the accessibility of a new UAS device, allowing the transformation of the working guidewire into a safety guidewire. METHODS: A prospective, multicenter study was conducted between January and February 2010 in six European tertiary reference centers. Patients needing flexible RIRS were eligible to participate in the study. In all cases, insertion of the Re-TraceTM (12/14Fr, Coloplast, Denmark) was attempted at the beginning of the procedure. Insertion success was defined as placement of the UAS in the lumbar ureter with successful disengagement of the working guidewire, which turned into a safety guidewire. Influence of gender and pre-stenting status was analyzed by univariate analysis. RESULTS: 137 UASs were used in 75 male and 62 female patients. 25.5% of ureters were pre-stented: men were 2.17 more often pre-stented than women. The overall Re TraceTM insertion rate was 82.5%. Success rate was not significantly different between men and women (77.3 vs. 88.7%, respectively, p = 0.11). Pre-stenting status did not significantly influence the success rate (p = 0.31). When analyzing the combined influence of pre-stenting status and gender, the worst success rates seemed to be obtained in men without pre-stenting, but no significant differences were found between groups. CONCLUSIONS: Re-TraceTM UAS showed good overall insertion rates. This evaluation validated the new concept of guidewire disengagement: A single wire automatically switches from working to safety role. PMID- 23640111 TI - Could millisecond timing errors in commonly used equipment be a cause of replication failure in some neuroscience studies? AB - Neuroscience is a rapidly expanding field in which complex studies and equipment setups are the norm. Often these push boundaries in terms of what technology can offer, and increasingly they make use of a wide range of stimulus materials and interconnected equipment (e.g., magnetic resonance imaging, electroencephalography, magnetoencephalography, eyetrackers, biofeedback, etc.). The software that bonds the various constituent parts together itself allows for ever more elaborate investigations to be carried out with apparent ease. However, research over the last decade has suggested a growing, yet underacknowledged, problem with obtaining millisecond-accurate timing in some computer-based studies. Crucially, timing inaccuracies can affect not just response time measurements, but also stimulus presentation and the synchronization between equipment. This is not a new problem, but rather one that researchers may have assumed had been solved with the advent of faster computers, state-of-the-art equipment, and more advanced software. In this article, we highlight the potential sources of error, their causes, and their likely impact on replication. Unfortunately, in many applications, inaccurate timing is not easily resolved by utilizing ever-faster computers, newer equipment, or post-hoc statistical manipulation. To ensure consistency across the field, we advocate that researchers self-validate the timing accuracy of their own equipment whilst running the actual paradigm in situ. PMID- 23640113 TI - Off-the-shelf microsponge arrays for facile and efficient construction of miniaturized 3D cellular microenvironments for versatile cell-based assays. AB - The integration of microfabrication and biomaterials enables construction of miniaturized 3D microenvironments with biomimetic micro-architectural and functional features to advance cell-based assays for mechanism investigation of physio/pathology and for prediction of drug responses. However, current biomaterials-assisted constructions of miniaturized 3D cellular microenvironments usually involve cells in the microfabrication process, limiting their wide application in most biomedical labs, where expertise and facilities are not readily available. Here we tackle this challenge by developing off-the-shelf microsponge arrays as pre-formed micro-patterned templates which can separate the microfabrication steps from the cell-handling steps and miniaturize the cell based assays. The microsponge arrays with tailored microarchitectures (e.g. micropillar/well arrays or bifurcated vascular network) could be stored and delivered to distant locations as ready-to-use chips. The highly porous and microscale sponges enabled automatic and uniform loading of cellular niche components (cells, matrices and soluble factors) by simply pipetting, making it accessible to any lab with basic cell culture setups. Meanwhile, the chips containing miniaturized 3D cellular microenvironments with versatile micro architectural designs could be integrated (i.e. by autoloading and sandwiching) to enable novel 3D cell-based assays (e.g. discrete gradient-based cytotoxicity test and horizontal 3D invasion assay) in an efficient and parallel manner. The off-the-shelf platform based on microsponge array is expected to be widely applicable across multiple disciplines in cell biology, cell/tissue engineering and pharmacological science. PMID- 23640114 TI - Probabilistic objective functions for margin-less IMRT planning. AB - We present a method to implement probabilistic treatment planning of intensity modulated radiation therapy using custom software plugins in a commercial treatment planning system. Our method avoids the definition of safety-margins by directly including the effect of geometrical uncertainties during optimization when objective functions are evaluated. Because the shape of the resulting dose distribution implicitly defines the robustness of the plan, the optimizer has much more flexibility than with a margin-based approach. We expect that this added flexibility helps to automatically strike a better balance between target coverage and dose reduction for surrounding healthy tissue, especially for cases where the planning target volume overlaps organs at risk. Prostate cancer treatment planning was chosen to develop our method, including a novel technique to include rotational uncertainties. Based on population statistics, translations and rotations are simulated independently following a marker-based IGRT correction strategy. The effects of random and systematic errors are incorporated by first blurring and then shifting the dose distribution with respect to the clinical target volume. For simplicity and efficiency, dose-shift invariance and a rigid-body approximation are assumed. Three prostate cases were replanned using our probabilistic objective functions. To compare clinical and probabilistic plans, an evaluation tool was used that explicitly incorporates geometric uncertainties using Monte-Carlo methods. The new plans achieved similar or better dose distributions than the original clinical plans in terms of expected target coverage and rectum wall sparing. Plan optimization times were only about a factor of two higher than in the original clinical system. In conclusion, we have developed a practical planning tool that enables margin-less probability-based treatment planning with acceptable planning times, achieving the first system that is feasible for clinical implementation. PMID- 23640115 TI - The usefulness of intracellular adenosine-5'-triphosphate measurement in CD4+ cells in renal transplant. AB - ImmuKnow is an in vitro diagnosis method that uses patient samples of whole blood polyclonally stimulated with phytohaemagglutinin. It also measures adenosine triphosphate (ATP) production by CD4+ T cells. The test aims to offer an objective and overall measurement of each individual's cellular immune response. The assay was designed with the idea of individually monitoring the immunosuppression administered to transplant patients. At the same time, it aims to help achieve a balance as a way of avoiding immunosuppression excess and the associated adverse effects (infections, cancer, etc.) or an immunosuppression defect and the subsequent risk of allograft rejection. The majority of studies that have evaluated its clinical usefulness display great diversity in terms of patient recruitment, the immunosuppressant treatment received, the clinical variables analysed and, above all, the time between performing ImmuKnow and the evaluated clinical event. The most consistent data show that this assay on CD4+ T cell functioning is useful for predicting the risk of infection in renal transplant patients. However, its use as a rejection risk indicator is unclear. Lastly, given the great variability of immune response amongst individuals and that of existing publications, it can be deduced that the isolated ImmuKnow value does not have diagnostic capacity and only individual serial monitoring could provide definitive assistance in clinical decision making and immunosuppressant treatment changes. Other aspects of ImmuKnow application in the clinical routine, such as assay cycles, require randomised prospective studies for more comprehensive information. PMID- 23640116 TI - The first molecular genetics analysis of individuals suffering from nephropatic cystinosis in the Southwestern Iran. AB - OBJECTIVE: Nephropatic Cystinosis (NC) is a rare metabolic disorder due to mutation in the CTNS gene in which more than 90 different mutations have already been reported so far. This study was performed to investigate mutations of the CTNS gene and its promoter in a number of Iranian patients with NC. METHODS: Polymerase chain reaction and direct sequencing were performed for molecular characterization of the CTNS gene in 25 patients from 24 unrelated Iranian families with NC. RESULTS: None of the patients showed the 57 kb deletion in heterozygous or homozygous manner. One was homozygous for a novel mutation, which was termed as "c.153-155insCT", while one of the cases was homozygous and another was compound heterozygous for the second novel mutation c.923G>A. Moreover three known mutations c.18-21delGACT, c.1017G>A, and c.681G>A in 11 of the patients were detected. No apparent mutation was observed in the rest of patients (44%, n=11). CONCLUSION: The present data exhibit a fundament for molecular carrier detection and prenatal diagnosis of a relatively large percentage of Iranian patients suffering from NC, at least in the Southwestern Iran, where Arab ethnicity is one of the common ethnicities of the region. PMID- 23640112 TI - Role of the hippocampus and orbitofrontal cortex during the disambiguation of social cues in working memory. AB - Human social interactions are complex behaviors requiring the concerted effort of multiple neural systems to track and monitor the individuals around us. Cognitively, adjusting our behavior on the basis of changing social cues such as facial expressions relies on working memory and the ability to disambiguate, or separate, the representations of overlapping stimuli resulting from viewing the same individual with different facial expressions. We conducted an fMRI experiment examining the brain regions contributing to the encoding, maintenance, and retrieval of overlapping identity information during working memory using a delayed match-to-sample task. In the overlapping condition, two faces from the same individual with different facial expressions were presented at sample. In the nonoverlapping condition, the two sample faces were from two different individuals with different expressions. fMRI activity was assessed by contrasting the overlapping and nonoverlapping conditions at sample, delay, and test. The lateral orbitofrontal cortex showed increased fMRI signal in the overlapping condition in all three phases of the delayed match-to-sample task and increased functional connectivity with the hippocampus when encoding overlapping stimuli. The hippocampus showed increased fMRI signal at test. These data suggest that lateral orbitofrontal cortex helps encode and maintain representations of overlapping stimuli in working memory, whereas the orbitofrontal cortex and hippocampus contribute to the successful retrieval of overlapping stimuli. We suggest that the lateral orbitofrontal cortex and hippocampus play a role in encoding, maintaining, and retrieving social cues, especially when multiple interactions with an individual need to be disambiguated in a rapidly changing social context in order to make appropriate social responses. PMID- 23640117 TI - Distal renal tubular acidosis: a hereditary disease with an inadequate urinary H+ excretion. AB - Distal renal tubular acidosis (dRTA) or RTA type I is characterised by reduced H+ hydrogen ions and ammonium urinary excretion. In children affected by dRTA there is stunted growth, vomiting, constipation, loss of appetite, polydipsia and polyuria, nephrocalcinosis, weakness and muscle paralysis due to hypokalaemia. This work summarises progress made in dRTA genetic studies in populations studied so far. DRTA is heterogeneous and as such, transporters and ion channels are analysed which have been identified in alpha-intercalated cells of the collecting duct, which could explain cases of dRTA not associated with the hitherto studied genes. DRTA can be autosomal dominant or autosomal recessive. Autosomal recessive dRTA appears in the first months of life and progresses with nephrocalcinosis and early or late hearing loss. Autosomal dominant dRTA is less severe and appears during adolescence or adulthood and may or may not develop nephrocalcinosis. In alpha-intercalated cells of the collecting duct, the acid load is deposited into the urine as titratable acids (phosphates) and ammonium. Autosomal recessive dRTA is associated with mutations in genes ATP6V1B1, ATP6V0A4 and SLC4A1, which encode subunits a4 and B1 of V-ATPase and the AE1 bicarbonate/chloride exchanger respectively. By contrast, autosomal dominant dRTA is only related to mutations in AE1. PMID- 23640118 TI - Dehydration upon admission is a risk factor for incomplete recovery of renal function in children with haemolytic uremic syndrome. AB - BACKGROUND: Haemolytic uremic syndrome (HUS) is the most common cause of acute renal failure and the second leading cause of chronic renal failure in children. The factors that affect incomplete renal function recovery prior to hospital admission are poorly understood. OBJECTIVE: To analyse the risk factors that determine incomplete recovery of renal function prior to hospitalisation in children with HUS. METHOD: A retrospective case-control study. VARIABLES: age, sex, duration of diarrhoea, bloody stools, vomiting, fever, dehydration, previous use of antibiotics, and incomplete recovery of renal function (proteinuria, hypertension, reduced creatinine clearance, and chronic renal failure during follow-up). Patients of both sexes under 15 years of age were included. RESULTS: Of 36 patients, 23 were males (65.3%; 95%CI: 45.8 to 80.9), with an average age of 2.5 +/- 1.4 years. Twenty-one patients required dialysis (58%; 95% CI: 40.8 to 75.8), and 13 (36.1%; 95% CI: 19.0 to 53.1) did not recover renal function. In the bivariate model, the only significant risk factor was dehydration (defined as weight loss >5%) [(OR: 5.3; 95% CI: 1.4 to 12.3; P=.0220]. In the multivariate analysis (Cox multiple regression), only dehydration was marginally significant (HR: 95.823; 95% CI: 93.175 to 109.948; P=.085). CONCLUSIONS: Our data suggest that dehydration prior to admission may be a factor that increases the risk of incomplete recovery of renal function during long-term follow-up in children who develop HUS D+. Consequently, in patients with diarrhoea who are at risk of HUS, dehydration should be strongly avoided during outpatient care to preserve long term renal function. These results must be confirmed by larger prospective studies. PMID- 23640119 TI - Acute and sub-acute effect of ferric carboxymaltose on inflammation and adhesion molecules in patients with predialysis chronic renal failure. AB - BACKGROUND: Treatment with parenteral iron causes oxidative stress, inflammation and endothelial dysfunction. Ferric carboxymaltose (FCM) is a new preparation of non-dextran iron which, due to its pharmacokinetics and stability, may induce less toxicity than other iron molecules. The aim of this study was to analyse the effect of FCM on inflammation and adhesion molecules in chronic kidney disease (CKD). METHODS: Forty-seven patients with predialysis CKD and iron-deficiency anaemia received a single dose of FCM (15 mg/kg, maximum dose 1 gram). At baseline and after 60 minutes (acute effect) and after 3 weeks and 3 months (sub acute effect), we determined inflammatory markers: C-reactive protein (CRP), interleukin-6 (IL-6) and endothelial dysfunction: intercellular adhesion molecule (ICAM) and vascular adhesion molecule (VCAM). RESULTS: Treatment with FCM was associated with a significant increase in haemoglobin levels: 10 (0.7) vs. 11.4 (1.3)g/dl, p<.0001. CRP, IL-6, ICAM and VCAM levels did not correlate with baseline haemoglobin or ferritin levels and there was no relationship between changes in these markers and those of haemoglobin after administration of FCM. No significant, acute or sub-acute changes occurred in any of the inflammatory or endothelial markers studied. Statin therapy was associated with lower VCAM concentrations. CONCLUSIONS: Treatment with high doses of FCM in patients with predialysis CKD has no proinflammatory effect and does not alter levels of adhesion molecules ICAM and VCAM in this population. PMID- 23640120 TI - Table showing dietary phosphorus/protein ratio for the Spanish population. Usefulness in chronic kidney disease. AB - BACKGROUND: The K/DOQI guidelines recommend the use of phosphorus/protein food ratios for proper control of dietary phosphorus. Evidence exists from tables with phosphorus to protein ratios for common foods. No such table exists for common foods consumed by the Spanish population with ratio estimations. OBJECTIVES: To estimate the phosphorus to protein ratio in foods commonly used by the Spanish population and to establish its usefulness in the selection of foods for patients with chronic kidney disease. METHOD: Tables with the phosphorus to protein ratio were prepared from two data sources concerning Spanish food composition. We evaluated chemical composition per 100g of raw food. The tables do not include phosphorus additives. No foods with high ratio of phosphorus to protein were eliminated in order to allow comparisons between different foods from each group. RESULTS: Shown in the tables. CONCLUSIONS: The dietary prescription for patients with chronic kidney disease should take into consideration not only the absolute phosphorus value of food consumed, but also the phosphorus to protein ratio of each food and the total amount of phosphorus in the diet. The more "natural" a diet is, the more likely that the patient will reach an acceptable phosphorus to protein ratio of less than 16mg/g, which does not increase mortality. There is clearly a need for an educational program on nutrition and phosphorus sources in which food ratio tables could be a useful tool for the multidisciplinary teams caring for renal patients. PMID- 23640121 TI - Clinicopathologic characteristics and survival of male breast cancer. AB - BACKGROUNDS: Male breast cancer (MBC) is a rare disease and accounts for <1 % of all breast cancers. METHODS: We retrospectively analyzed clinicopathologic characteristics and prognosis of MBC patients who were diagnosed in our hospital between March 2002 and March 2012. RESULTS: The median age of diagnosis of MBC was 62 years, which was 9 years older than female breast cancer (FBC) patients. The highest proportion of MBC patients was in the 50-59-year age group. The percentage of invasive ductal carcinoma in MBC was much higher than in FBC (P = 0.000). The positive rate of estrogen receptors in MBC patients (87.9 %) was significantly higher than in FBC patients (P = 0.048), whereas HER-2 was positive in 17.2 % of MBC patients, which was significantly lower than in FBC patients (P = 0.001). There was a consistent significant difference in luminal subtypes of FBC and MBC patients (P = 0.000). The overall survival rates of MBC were significantly higher than FBC (P = 0.004). HER-2-positive patients had a statistically worse prognosis than HER-2-negative patients (P = 0.040). Lymph node metastasis and larger tumor size were also associated with poorer prognosis (P = 0.056 and P = 0.088). The level of hormones was examined in 7 patients, and abnormal hormone levels were detected in 4. CONCLUSION: The FBC patients were significantly different from the MBC in clinicopathologic and prognostic characteristics. HER-2 positivity was an important factor for prognosis. PMID- 23640123 TI - Facilitators and barriers to engagement in parenting programs: a qualitative systematic review. AB - Parenting programs have the potential to improve the health and well-being of parents and children. A challenge for providers is to recruit and retain parents in programs. Studies researching engagement with programs have largely focused on providers', policy makers', or researchers' reflections of their experience of parents' participation. We conducted a systematic review of qualitative studies where parents had been asked why they did or did not choose to commence, or complete programs, and compared these perceptions with those of researchers and those delivering programs. We used data-mining techniques to identify relevant studies and summarized findings using framework synthesis methods. Six facilitator and five barrier themes were identified as important influences on participation, with a total of 33 subthemes. Participants focused on the opportunity to learn new skills, working with trusted people, in a setting that was convenient in time and place. Researchers and deliverers focused on tailoring the program to individuals and on the training of staff. Participants and researchers/deliverers therefore differ in their opinions of the most important features of programs that act as facilitators and barriers to engagement and retention. Program developers need to seek the views of both participants and deliverers when evaluating programs. PMID- 23640122 TI - Psychosocial correlates of physical and sedentary activities of early adolescent youth. AB - This study examines physical and sedentary activities of early adolescent boys and girls using Ecological Momentary Assessment (EMA), a method that can link mood and behaviors in specific social situations. Twenty-seven assessments were collected across 7 days from 82 participating adolescents, three times in seventh grade and one time in eighth grade. Assessments were completed during nonschool hours when youth had "free time." Gender differences, longitudinal trends, and associations of physical activities (PA) and small screen recreation (SSR) with moods and peer presence are examined. Boys were engaged in PA more than girls. Patterns of PA differed by gender; boys significantly decreased PA from seventh to eighth grade, whereas girls had increased PA only during the spring. PA was associated with happier mood and was more likely to occur in the presence of peers. SSR significantly increased from seventh grade to eighth grade for both boys and girls. SSR occurred more when youth were alone and was not associated with mood. Neither PA nor SSR was more likely to occur during weekdays or weekends. Implications for intervention efforts to increase PA in youth are discussed. PMID- 23640124 TI - Conservation and functional element discovery in 20 angiosperm plant genomes. AB - Here, we describe the construction of a phylogenetically deep, whole-genome alignment of 20 flowering plants, along with an analysis of plant genome conservation. Each included angiosperm genome was aligned to a reference genome, Arabidopsis thaliana, using the LASTZ/MULTIZ paradigm and tools from the University of California-Santa Cruz Genome Browser source code. In addition to the multiple alignment, we created a local genome browser displaying multiple tracks of newly generated genome annotation, as well as annotation sourced from published data of other research groups. An investigation into A. thaliana gene features present in the aligned A. lyrata genome revealed better conservation of start codons, stop codons, and splice sites within our alignments (51% of features from A. thaliana conserved without interruption in A. lyrata) when compared with previous publicly available plant pairwise alignments (34% of features conserved). The detailed view of conservation across angiosperms revealed not only high coding-sequence conservation but also a large set of previously uncharacterized intergenic conservation. From this, we annotated the collection of conserved features, revealing dozens of putative noncoding RNAs, including some with recorded small RNA expression. Comparing conservation between kingdoms revealed a faster decay of vertebrate genome features when compared with angiosperm genomes. Finally, conserved sequences were searched for folding RNA features, including but not limited to noncoding RNA (ncRNA) genes. Among these, we highlight a double hairpin in the 5'-untranslated region (5'-UTR) of the PRIN2 gene and a putative ncRNA with homology targeting the LAF3 protein. PMID- 23640125 TI - Inhibition of infection and transmission of HIV-1 and lack of significant impact on the vaginal commensal lactobacilli by carbohydrate-binding agents. AB - OBJECTIVES: A selection of carbohydrate-binding agents (CBAs) with different glycan specificities were evaluated for their inhibitory effect against HIV infection and transmission, and their interaction with vaginal commensal bacteria. METHODS: Several assays were used for the antiviral evaluation: (i) cell-free virus infection of human CD4+ T lymphocyte C8166 cells; (ii) syncytium formation in co-cultures of persistently HIV-1-infected HUT-78/HIV-1 and non infected CD4+ SupT1 cells; (iii) DC-SIGN-directed capture of HIV-1 particles; and (iv) transmission of DC-SIGN-captured HIV-1 particles to uninfected CD4+ C8166 cells. CBAs were also examined for their interaction with vaginal commensal lactobacilli using several viability, proliferation and adhesion assays. RESULTS: The CBAs showed efficient inhibitory activity in the nanomolar to low-micromolar range against four events that play a crucial role in HIV-1 infection and transmission: cell-free virus infection, fusion between HIV-1-infected and non infected cells, HIV-1 capture by DC-SIGN and transmission of DC-SIGN-captured virus to T cells. As candidate microbicides should not interfere with the normal human microbiota, we examined the effect of CBAs against Lactobacillus strains, including a variety of vaginal strains, a gastrointestinal strain and several non human isolates. None of the CBAs included in our studies inhibited the growth of these bacteria in several media, affected their viability or had any significant impact on their adhesion to HeLa cell monolayers. CONCLUSIONS: The CBAs in this study were inhibitory to HIV-1 in several in vitro infection and transmission models, and may therefore qualify as potential microbicide candidates. The lack of significant impact on commensal vaginal lactobacilli is an important property of these CBAs in view of their potential microbicidal use. PMID- 23640126 TI - High genetic diversity of nitrofurantoin- or mecillinam-resistant Escherichia coli indicates low propensity for clonal spread. AB - OBJECTIVES: The empirical treatment with trimethoprim or ciprofloxacin of urinary tract infections (UTIs) is now questioned, partly due to the global expansion of a few resistant clonal groups of Escherichia coli. METHODS: In this study we investigated the clonal structure of 34 strains of E. coli (collected from non pregnant women aged 18-65 years with uncomplicated UTIs in Europe and Canada) resistant to either of two other common treatment alternatives for uncomplicated UTIs, mecillinam or nitrofurantoin, using multilocus sequence typing (MLST). RESULT: The 34 isolates were, despite high levels of multiresistance, distributed all over the E. coli genetic diversity spectrum with little association of antibiotic resistance to specific clonal groups. CONCLUSIONS: The results of this study indicate a low probability of a future clonal spread of resistance to mecillinam and nitrofurantoin. PMID- 23640128 TI - A low cost and high throughput magnetic bead-based immuno-agglutination assay in confined droplets. AB - Although passive immuno-agglutination assays consist of one step and simple procedures, they are usually not adapted for high throughput analyses and they require expensive and bulky equipment for quantitation steps. Here we demonstrate a low cost, multimodal and high throughput immuno-agglutination assay that relies on a combination of magnetic beads (MBs), droplets microfluidics and magnetic tweezers. Antibody coated MBs were used as a capture support in the homogeneous phase. Following the immune interaction, water in oil droplets containing MBs and analytes were generated and transported in Teflon tubing. When passing in between magnetic tweezers, the MBs contained in the droplets were magnetically confined in order to enhance the agglutination rate and kinetics. When releasing the magnetic field, the internal recirculation flows in the droplet induce shear forces that favor MBs redispersion. In the presence of the analyte, the system preserves specific interactions and MBs stay in the aggregated state while in the case of a non-specific analyte, redispersion of particles occurs. The analyte quantitation procedure relies on the MBs redispersion rate within the droplet. The influence of different parameters such as magnetic field intensity, flow rate and MBs concentration on the agglutination performances have been investigated and optimized. Although the immuno-agglutination assay described in this work may not compete with enzyme linked immunosorbent assay (ELISA) in terms of sensitivity, it offers major advantages regarding the reagents consumption (analysis is performed in sub microliter droplet) and the platform cost that yields to very cheap analyses. Moreover the fully automated analysis procedure provides reproducible analyses with throughput well above those of existing technologies. We demonstrated the detection of biotinylated phosphatase alkaline in 100 nL sample volumes with an analysis rate of 300 assays per hour and a limit of detection of 100 pM. PMID- 23640127 TI - Probiotics and prebiotics in infants and children. AB - Probiotics and prebiotics have a major influence on gastrointestinal flora composition. This review analyses the relationship between this change in flora composition and health benefits in children. Literature databases were searched for relevant articles. Despite exhaustive research on the subject in different indications, such as prevention and treatment of acute gastroenteritis, antibiotic associated diarrhea (AAD), traveler's diarrhea, inflammatory bowel disease, irritable bowel syndrome, Helicobacter pylori, necrotizing enterocolitis, constipation, allergy and atopic dermatitis, colic and extraintestinal infections, reports of clear benefits for the use of prebiotics and probiotics in pediatric disorders remain scarce. The best evidence has been provided for the use of probiotics in acute gastroenteritis and in prevention of AAD. However, AAD in children is in general mild, and only seldom necessitates additional interventions. Overall, the duration of acute infectious diarrhea is reduced by approximately 24 hours. Evidence for clinically relevant benefit in all other indications (inflammatory bowel disease, irritable bowel syndrome, constipation, allergy) is weak to nonexistent. Selected probiotic strains given during late pregnancy and early infancy decrease atopic dermatitis. Adverse effects have very seldom been reported. Since the risk seems minimal to nonexistent, prebiotics and probiotics may be helpful in the prevention and treatment of some disorders in children, although the evidence for benefit is limited. The best evidence has been accumulated for some lactobacilli strains and for Saccharomyces boulardii in the reduction of the duration of acute diarrhea due to gastroenteritis and prevention of AAD. PMID- 23640129 TI - Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features. AB - Hepatocellular carcinomas exhibit heterogeneous morphologies by routine light microscopy. Although some morphologies represent insignificant variations in growth patterns, others may represent unrecognized subtypes of hepatocellular carcinoma. Identification of these subtypes could lead to separation of hepatocellular carcinomas into discrete groups with unique underlying genetic changes, prognosis, or therapeutic responses. In order to identify potential subtypes, two pathologists independently screened a cohort of 219 unselected hepatocellular carcinoma resection specimens and divided cases into potential subtypes. One of these promising candidate subtypes was further evaluated using histological and molecular techniques. This subtype was characterized by a unique and consistent set of histological features: smooth chromophobic cytoplasm, abrupt focal nuclear anaplasia (small clusters of tumor cells with marked nuclear anaplasia in a background of tumor cells with bland nuclear cytology), and scattered microscopic pseudocysts--we designate this variant as 'chromophobe hepatocellular carcinoma with abrupt anaplasia'. Thirteen cases were identified (6% of all hepatocellular carcinomas), including 6 men and 7 women with an average age of 61 years. Six cases occurred in cirrhotic livers. Serum AFP was elevated in 6 out of 10 cases. There were a variety of underlying liver diseases, but cases were enrichment for chronic hepatitis B, P=0.006. Interestingly, at the molecular level, this variant was strongly associated with the alternative lengthening of telomere (ALT) phenotype by telomere FISH. ALT is a telomerase independent mechanism of telomere maintenance and is found in approximately 8% of unselected hepatocellular carcinomas. In contrast, 11/12 (92%) of the cases of chromophobe hepatocellular carcinoma with abrupt anaplasia were ALT-positive. In summary, we propose that chromophobe hepatocellular carcinoma with abrupt anaplasia represents a new subtype of hepatocellular carcinoma with unique morphological and molecular features. PMID- 23640130 TI - Using mental imagery to deliver self-regulation techniques to improve sleep behaviors. AB - BACKGROUND: Poor sleep habits and insufficient sleep represent significant workplace health issues. PURPOSE: Applying self-regulation theory, we conducted a randomized, controlled trial testing the efficacy of mental imagery techniques promoting arousal reduction and implementation intentions to improve sleep behavior. METHOD: We randomly assigned 104 business employees to four imagery based interventions: arousal reduction, implementation intentions, combined arousal reduction and implementation intentions, or control imagery. Participants practiced their techniques daily for 21 days. They completed online measures of sleep quality, behaviors, and self-efficacy at baseline and Day 21; and daily measures of sleep behaviors. RESULTS: Participants using implementation intention imagery exhibited greater improvements in self-efficacy, sleep behaviors, sleep quality, and time to sleep relative to participants using arousal reduction and control imagery. CONCLUSIONS: Implementation intention imagery can improve sleep behavior for daytime employees. Use of arousal reduction imagery was unsupported. Self-regulation imagery techniques show promise for improving sleep behaviors. PMID- 23640131 TI - Conceptualizing and examining the role of stress in arthritis: a comment on Harris et al. PMID- 23640132 TI - Role of the subcommissural organ in the pathogenesis of congenital hydrocephalus in the HTx rat. AB - The present investigation was designed to clarify the role of the subcommissural organ (SCO) in the pathogenesis of hydrocephalus occurring in the HTx rat. The brains of non-affected and hydrocephalic HTx rats from embryonic day 15 (E15) to postnatal day 10 (PN10) were processed for electron microscopy, lectin binding and immunocytochemistry by using a series of antibodies. Cerebrospinal fluid (CSF) samples of non-affected and hydrocephalic HTx rats were collected at PN1, PN7 and PN30 and analysed by one- and two-dimensional electrophoresis, immunoblotting and nanoLC-ESI-MS/MS. A distinct malformation of the SCO is present as early as E15. Since stenosis of the Sylvius aqueduct (SA) occurs at E18 and dilation of the lateral ventricles starts at E19, the malformation of the SCO clearly precedes the onset of hydrocephalus. In the affected rats, the cephalic and caudal thirds of the SCO showed high secretory activity with all methods used, whereas the middle third showed no signs of secretion. At E18, the middle non-secretory third of the SCO progressively fused with the ventral wall of SA, resulting in marked aqueduct stenosis and severe hydrocephalus. The abnormal development of the SCO resulted in the permanent absence of Reissner's fibre (RF) and led to changes in the protein composition of the CSF. Since the SCO is the source of a large mass of sialilated glycoproteins that form the RF and of those that remain CSF-soluble, we hypothesize that the absence of this large mass of negatively charged molecules from the SA domain results in SA stenosis and impairs the bulk flow of CSF through the aqueduct. PMID- 23640133 TI - Quantification and localization of erythropoietin-receptor-expressing cells in the liver of Xenopus laevis. AB - Erythropoiesis occurs in the African clawed frog, Xenopus laevis and is mediated by erythropoietin (xlEPO), a primary regulator of this process. Previously, we have shown that the xlEPO receptor (xlEPOR), which is expressed by erythroid progenitors that respond to xlEPO, is found predominantly in the liver. The aim of the present study was to determine the dynamics of erythropoiesis in the livers of normal and anemic X. laevis by identifying the number and precise location of mature and immature erythrocytes. We quantified mature and immature erythrocyte numbers by o-dianisidine staining or immunohistochemistry and investigated the dynamics of erythropoiesis in normal, acute hemolytic and blood loss states by in vivo cell proliferation assays with 5-bromo-2'-deoxyuridine (BrdU). We detected 0.12*10(8) xlEPOR(+) BrdU(+) cells in the liver of the normal X. laevis at 24 h after BrdU injection. Frogs presenting with acute hemolytic anemia and pancytopenia show a 10-fold increase in the number of xlEPOR(+)/BrdU(+) cells (approximately 1.30*10(8) cells) in the liver. The xlEPOR(+) cells are found predominantly on the inner wall of hepatic sinusoids. Hematopoietic progenitors that undergo slow cell cycling were also observed in the hepatic sinusoids. This study clarifies the rate of production of mature and immature erythrocytes per day in the liver of X. laevis and the way that these cell numbers change in response to anemia. PMID- 23640134 TI - Regulation and effects of GDF-15 in the retina following optic nerve crush. AB - Growth/differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor-beta superfamily and is ubiquitously expressed in the central nervous system. It is prominently upregulated in cerebral cortical and ischemic lesion paradigms. GDF-15 robustly promotes the survival of lesioned nigrostriatal dopaminergic neurons in vivo; GDF-15-deficient mice exhibit progressive postnatal motor and sensory neuron losses implying essential functions of GDF-15 in neuronal survival. We show that GDF-15 mRNA and protein are, respectively, six fold and three-fold upregulated in the murine retina at 1 day after optic nerve crush, slightly elevated mRNA levels being maintained until day 28. However, the magnitude and time course of retinal ganglion cell (RGC) death are indistinguishable in knockout and control mice. Selected mRNAs implicated in the regulation of the death vs. survival of RGCs, including ATF3, Bad, Bcl-2 and caspase-8, were similarly regulated in both knockout and control retinae. Immunohistochemistry for tyrosine hydroxylase and choline acetyltransferase revealed no differences in staining patterns in the two genotypes. mRNA and protein levels of galanin, a putative neuroprotective factor and positive regulator of neuron survival and axonal regeneration, were prominently upregulated after crush in knockout retinae at day 3, as compared with control retinae, suggesting that GDF-15 acts as a physiological regulator of galanin. GDF 15 is therefore prominently upregulated in the retina after optic nerve crush but does not directly interfere with the magnitude and temporal progression of RGC death. PMID- 23640135 TI - Exploring the spectroscopic differences of Caki-2 cells progressing through the cell cycle while proliferating in vitro. AB - FTIR micro-spectral images of Caki-2 cells cytospun onto calcium fluoride (CaF2) slides were used to build a computational model in order to discriminate between the biochemical events of the continuous cell cycle during proliferation. Multivariate analysis and machine learning techniques such as PCA, PLSR and SVMs were used to highlight the chemical differences among the cell cycle phases and also to point out the need for removing the distortion of the spectra due to the morphology of the cells. Results showed cell cycle dependant scattering profiles that enabled the training of a SVM in order to recognise, with a relative high accuracy, each cell cycle phase purely with the scattering curve removed from the FTIR data after being subject to the RMieS-EMSC algorithm. PMID- 23640136 TI - SCOUT: a fast Monte-Carlo modeling tool of scintillation camera output. AB - We have developed a Monte-Carlo photon-tracking and readout simulator called SCOUT to study the stochastic behavior of signals output from a simplified rectangular scintillation-camera design. SCOUT models the salient processes affecting signal generation, transport, and readout of a scintillation camera. In this work, we compare output signal statistics from SCOUT to experimental results for both a discrete and a monolithic camera. We also benchmark the speed of this simulation tool and compare it to existing simulation tools. We find this modeling tool to be relatively fast and predictive of experimental results. Depending on the modeled camera geometry, we found SCOUT to be 4 to 140 times faster than other modeling tools. PMID- 23640137 TI - Neurocognitive functioning and health-related quality of life in patients with radiologically suspected meningiomas. AB - Few data are available concerning the neurocognitive outcome and health-related quality of life (HRQOL) following neurosurgery in meningioma patients, and even less is known about neurocognitive functioning and HRQOL in untreated patients with stable lesions. The present study aims at quantifying the nature and extent of neurocognitive deficits and HRQOL in suspected WHO grade I meningioma patients who have not received surgery and/or radiotherapy and compare outcome to that of healthy controls. Neurocognitive functioning was assessed by using a standardized test battery in 21 radiologically suspected WHO grade I meningioma patients with a wait-and-scan approach. HRQOL was assessed with the MOS SF-36 questionnaire. These patients were matched for age, sex, and education with 21 healthy controls. Associations between neurocognitive functioning on the one hand and HRQOL and tumor characteristics on the other were determined. Compared to healthy controls, meningioma patients had lower psychomotor speed (p = 0.011) and working memory capacity (p = 0.034) and furthermore attained lower levels of self-perceived general health and vitality. Neurocognitive functioning in untreated patients was not related to tumor volume, edema or tumor lateralization. No correlations were found between psychomotor speed or working memory and HRQOL. Untreated meningioma patients with stable lesions have limitations in neurocognitive functioning and HRQOL. In deciding upon a treatment strategy these reductions in functioning should be taken into consideration and communicated with the patient. PMID- 23640138 TI - Lyophilized brain tumor specimens can be used for histologic, nucleic acid, and protein analyses after 1 year of room temperature storage. AB - Frozen tissue, a gold standard biospecimen, can yield well preserved nucleic acids and proteins after over a decade but is vulnerable to thawing and has substantial fiscal, spatial, and environmental costs. A long-term room temperature biospecimen storage alternative that preserves broad analytical utility can potentially empower tissue-based research. As there is scant data on the analytical utility of lyophilized brain tumor biospecimens, we evaluated lyophilized (freeze-dried) samples stored for 1 year at room temperature. Lyophilized tumor tissue processed into paraffin sections produced good histology. Yields of extracted DNA, RNA, and protein approximated those of frozen tissue. After 1 year, lyophilized samples yielded high molecular weight DNA that permitted copy number variation analysis, IDH 1 mutation detection, and MGMT promoter methylation PCR. A 27 % decrease in RIN scores over the 1 year suggests that RNA degradation was inhibited though incompletely. Nevertheless, RT-PCR studies on lyophilized tissue performed similarly to frozen tissue. In contrast to FFPE tissues where protein bands were absent or shifted to a lower molecular weight, lyophilized samples showed similar protein bands as frozen tissue on SDS PAGE analysis. Lyophilized tissue performed similarly to frozen tissue for Western blots and enzyme activity assays. Immunohistochemistry of lyophilized tissue that were processed into FFPE blocks often required longer incubation times for staining than standard FFPE samples but generally provided robust antigen detection. This preliminary study suggests that lyophilization has promise for long-term room temperature storage while permitting varied tests; however, further work is required to better stabilize nucleic acids particularly RNA. PMID- 23640139 TI - Whole-body protein turnover reveals the cost of detoxification of secondary metabolites in a vertebrate browser. AB - The detoxification limitation hypothesis predicts that the metabolism and biotransformation of plant secondary metabolites (PSMs) elicit a cost to herbivores. There have been many attempts to estimate these costs to mammalian herbivores in terms of energy, but this ignores what may be a more important cost increases in protein turnover and concomitant losses of amino acids. We measured the effect of varying dietary protein concentrations on the ingestion of two PSMs (1,8 cineole-a monoterpene, and benzoic acid-an aromatic carboxylic acid) by common brushtail possums (Trichosurus vulpecula). The dietary protein concentration had a small effect on how much cineole possums ingested. In contrast, protein had a large effect on how much benzoate they ingested, especially at high dietary concentrations of benzoate. This prompted us to measure the effects of dietary protein and benzoate on whole-body protein turnover using the end-product method following an oral dose of [(15)N] glycine. Increasing the concentration of dietary protein in diets without PSMs improved N balance but did not influence whole-body protein turnover. In contrast, feeding benzoate in a low-protein diet pushed animals into negative N balance. The concomitant increases in the rates of whole-body protein turnover in possums eating diets with more benzoate were indicative of a protein cost of detoxification. This was about 30 % of the dietary N intake and highlights the significant effects that PSMs can have on nutrient metabolism and retention. PMID- 23640141 TI - Small is beautiful: the view from Seattle. PMID- 23640140 TI - Mechanisms of acetylcholine-mediated vasodilation in systemic arteries from mourning doves (Zenaida macroura). AB - For mammals, acetylcholine (ACh) promotes endothelium-dependent vasodilation primarily through nitric oxide (NO) and prostaglandin-mediated pathways, with varying reliance on endothelial-derived hyperpolarizing factors. Currently, no studies have been conducted on small systemic arteries from wild birds. We hypothesized that ACh-mediated vasodilation of isolated small arteries from mourning doves (Zenaida macroura) would likewise depend on endothelial-derived factors. Small resistance mesenteric and cranial tibial (c. tibial) arteries (80 150 MUm, inner diameter) were cannulated and pre-constricted to 50 % of resting inner diameter with phenylephrine then exposed to increasing concentrations of ACh (10(-9)-10(-5) M) or the NO donor, sodium nitroprusside (SNP; 10(-12)-10(-3) M). For mesenteric arteries, ACh-mediated vasodilation was significantly blunted with the potassium channel antagonist tetraethylammonium chloride (TEA, 10 mM); whereas responses were only moderately impaired with endothelial disruption or inhibition of prostaglandins (indomethacin, 10 MUM). In contrast, endothelial disruption as well as exposure to TEA largely abolished vasodilatory responses to ACh in c. tibial arteries while no effect of prostaglandin inhibition was observed. For both vascular beds, responses to ACh were moderately dependent on the NO signaling pathway. Inhibition of NO synthase had no impact, despite complete reversal of phenylephrine-mediated tone with SNP, whereas inhibition of soluble guanylate cyclase (sGC) caused minor impairments. Endothelium-independent vasodilation also relied on potassium channels. In summary, ACh-mediated vasodilation of mesenteric and c. tibial arteries occurs through the activation of potassium channels to induce hyperpolarization with moderate reliance on sGC. Prostaglandins likewise play a small role in the vasodilatory response to ACh in mesenteric arteries. PMID- 23640143 TI - An unusual case of neck pain. AB - The complaint of nontraumatic neck pain in a pediatric patient without fever or any other symptoms is unusual and can be very challenging. We present the case of a 4-year-old boy with imaging consistent with a rare diagnosis. This report discusses this diagnosis as well as the utility of advanced imaging and laboratory evaluations in the presentation of pediatric neck pain. PMID- 23640142 TI - IGF-1R targeting increases the antitumor effects of DNA-damaging agents in SCLC model: an opportunity to increase the efficacy of standard therapy. AB - Insulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146, and H526 cells in vitro and in vivo. Innovative genomic and functional approaches were conducted to analyze the molecular behavior under the different treatment conditions. A total of 53% and 37% of human specimens expressed IGF-1R and pAkt, respectively. R1507 showed single-agent activity in H146 and H526 cells but not in H69 cells. R1507 exhibited synergistic effects with both cisplatin and IR in vitro. The triple combination R1507-cisplatin-IR led to a dramatic delay in tumor growth compared with cisplatin-IR in H526 cells. Analyzing the apparent absence of antitumoral effect of R1507 alone in vivo, we observed a transient reduction of IGF-1R staining intensity in vivo, concomitant to the activation of multiple cell surface receptors and intracellular proteins involved in proliferation, angiogenesis, and survival. Finally, we identified that the nucleotide excision repair pathway was mediated after exposure to R1507-CDDP and R1507-IR in vitro and in vivo. In conclusion, adding R1507 to the current standard cisplatin-IR doublet reveals remarkable chemo- and radiosensitizing effects in selected SCLC models and warrants to be investigated in the clinical setting. PMID- 23640144 TI - Organophosphate poisoning-induced acute renal failure. AB - BACKGROUND: Acute kidney injury as a direct complication of organophosphate poisoning has rarely been described and its etiology is unclear. CASE: A 17-year old adolescent girl was admitted to the pediatric intensive care unit after a suicidal attempt with chlorpyrifos, an organophosphate insecticide compound. The patient developed acute kidney injury followed by renal failure, necessitating renal replacement therapy. She was treated with continuous venovenous hemofiltration with full resolution of her renal function. CONCLUSIONS: Organophosphate poisoning can lead to renal failure, which, with proper treatment, may be reversible but, if left unattended, might aggravate the clinical course of the disease. Physicians should be aware of this rare complication. PMID- 23640145 TI - An interesting case of a unilaterally dilated pupil. AB - Facial lacerations from minor trauma are a common presenting complaint to the emergency department. With the increasing availability of topical anesthetics, there is a decrease in the need for injectable local anesthetic and sedation services, facilitating the ease of facial laceration repairs for young children. One such topical anesthetic is a widely used pharmacy preparation of lidocaine 4% epinephrine 0.1%-tetracaine 0.5% gel (LET). Although the use of LET has decreased the need for injectable lidocaine and sedation for facial lacerations, both of which can be unpleasant for children with potentially life-threatening adverse events, it may still lead to unexpected and untoward adverse events. We explore here a little-known adverse effect of LET in a child who presented to a pediatric emergency department with an eyelid laceration after minor head trauma. PMID- 23640146 TI - Hyperkalemia and ventricular tachycardia after outpatient ureteral valve reimplantation: a case report. AB - OBJECTIVE: This study aimed to report on a toddler who presented with progressively worsening abdominal pain and obstructive uropathy 1 week after ureteral valve reimplantation. Acute renal failure resulted in critical hyperkalemia. METHODS: Chart review of presentation, physical examination, laboratory tests, and treatment. RESULTS: Initial potassium level was 10 mEq/L; ventricular tachycardia was observed and treated. CONCLUSIONS: More commonly, hyperkalemia results from overuse/overdose of supplementation or in patients with known renal failure. Although less common, obstructive uropathy should be considered in any patient with recent instrumentation of the urinary tract and coincident complications can be significant. PMID- 23640147 TI - Homicidal acute formalin poisoning in an infant from a rural sericulture family presenting with multisystem failure. AB - Acute poisoning of formalin is rare because of its strong irritating effect and alarming odor. Although few cases of acute poisoning in adults have been reported in literature, to our knowledge, this is the first case report of formalin poisoning in an infant presenting with multisystem failure. Despite proper supportive treatment in the absence of antidote, the infant died within 13 hours after deliberate poisoning. PMID- 23640149 TI - Valproic acid-induced acute pancreatitis and multiorgan failure in a child. AB - Valproic acid (VPA) is still an important antiepileptic drug, with the broadest spectrum used in all types of seizures and syndromes. It has serious adverse effects such as hepatotoxicity, hyperammonemic encephalopathy, coagulation disorders, and pancreatitis. The incidence of VPA-associated pancreatitis has been estimated to be 1:40,000. We present a 6-year-old boy who developed acute pancreatitis (AP) and multiple-organ failure after 3 months of VPA therapy. The patient's laboratory values showed that his kidney and hepatic function had impaired and thrombocytopenia, and coagulopathy had developed. The patient's abdominal tomography showed a suspected appearance, which was consistent with pancreatitis. Because amylase and lipase levels were found to be high, AP was considered. The patient improved after cessation of VPA treatment. Ten days later, the patient recovered both clinically and laboratorial. Consequently, the patient was discharged with cure. In conclusion, AP is a rare, severe adverse reaction to VPA treatment. If a child, who is receiving VPA, develops abdominal pain and vomits, VPA-associated pancreatitis must be considered. PMID- 23640148 TI - Successful early management of a female patient with a metabolic stroke due to ornithine transcarbamylase deficiency. AB - BACKGROUND: Ornithine transcarbamylase deficiency (OTC-D) is a urea cycle disorder caused by dysfunction of ornithine transcarbamylase, which frequently leads to hyperammonemia. Hyperammonemia represents a medical emergency requiring prompt treatment to reduce plasma ammonia levels and prevent severe neurological damage, coma, and death, particularly in patients with acute decompensation related coma. The clinical symptoms of OTC-D can manifest themselves either at an early stage, which is often associated with severe symptoms, or in later life (late-onset OTC-D), when symptoms may be less severe. There is currently little agreement over diagnostic signs of the condition or the most appropriate therapeutic approach. Hyperammonemia is usually treated with ammonia scavengers, continuous venovenous hemodialysis, and dietary changes. N-carbamylglutamate is approved for the treatment of hyperammonemia in N-acetylglutamate synthetase deficiency and may have efficacy in other urea cycle disorders. METHODS/RESULTS: Here, we report a 13-year-old girl who was diagnosed with OTC-D at the age of 3 years. On this occasion, the patient presented with vomiting, lethargy, and mental confusion. Despite biochemical parameters being within normal ranges, she was comatose within a few hours. She was promptly treated with a combined therapy of continuous venovenous hemodialysis and N-carbamylglutamate, resulting in a gradual normalization of clinical symptoms within 30 hours. No neurological damage was apparent at 18 months after treatment. CONCLUSIONS: This case demonstrates that clinical benefits can be obtained by beginning aggressive treatment of OTC-D within a few hours of the onset of severe neurological symptoms even in the absence of altered biochemical markers. PMID- 23640150 TI - Status epilepticus in a child secondary to ingestion of skin-lightening cream. AB - The popularity of the Internet and online media has led to the increased availability of prescription-strength, skin-lightening products contributing to a rise in their use among people with various skin pigment disorders. These products may contain a wide variety of active ingredients such as heavy metals, hydroquinone, and corticosteroids that can be highly toxic, especially after prolonged application. For decades, there have been case reports of both corticosteroid and heavy metal toxicity related to skin-lightening cream use. We report a case of a child who developed status epilepticus after ingesting a skin lightening solution containing 2% hydroquinone. The toxicodynamics of hydroquinone and its effects on the central nervous system are discussed. PMID- 23640151 TI - A review of dengue fever: a resurging tropical disease. AB - Dengue is a resurging mosquito-borne disease that is often contracted in U.S. travelers to Latin America, Asia, and the Caribbean. The clinical symptoms range from a simple febrile illness to hemorrhagic fever or shock. The clinical course has a wide range of outcomes, and adequate supportive care can reduce mortality rates dramatically. Repeated exposures to the virus can lead to a more complicated clinical course. PMID- 23640153 TI - Brief emergency department interventions for youth who use alcohol and other drugs: a systematic review. AB - OBJECTIVE: Brief intervention (BI) is recommended for use with youth who use alcohol and other drugs. Emergency departments (EDs) can provide BIs at a time directly linked to harmful and hazardous use. The objective of this systematic review was to determine the effectiveness of ED-based BIs. METHODS: We searched 14 electronic databases, a clinical trial registry, conference proceedings, and study references. We included randomized controlled trials with youth 21 years or younger. Two reviewers independently selected studies and assessed methodological quality. One reviewer extracted and a second verified data. We summarized findings qualitatively. RESULTS: Two trials with low risk of bias, 2 trials with unclear risk of bias, and 5 trials with high risk of bias were included. Trials evaluated targeted BIs for alcohol-positive (n = 3) and alcohol/other drug positive youth (n = 1) and universal BIs for youth reporting recent alcohol (n = 4) or cannabis use (n = 1). Few differences were found in favor of ED-based BIs, and variation in outcome measurement and poor study quality precluded firm conclusions for many comparisons. Universal and targeted BIs did not significantly reduce alcohol use more than other care. In one targeted BI trial with high risk of bias, motivational interviewing (MI) that involved parents reduced drinking quantity per occasion and high-volume alcohol use compared with MI that was delivered to youth only. Another trial with high risk of bias reported an increase in abstinence and reduction in physical altercations when youth received peer-delivered universal MI for cannabis use. In 2 trials with unclear risk of bias, MI reduced drinking and driving and alcohol-related injuries after the ED visit. Computer-based MI delivered universally in 1 trial with low risk of bias reduced alcohol-related consequences 6 months after the ED visit. CONCLUSIONS: Clear benefits of using ED-based BI to reduce alcohol and other drug use and associated injuries or high-risk behaviours remain inconclusive because of variation in assessing outcomes and poor study quality. PMID- 23640154 TI - Missed opportunities in fatal child abuse. PMID- 23640155 TI - ECGs in the ED. PMID- 23640156 TI - Comparative performance of GlideScope video laryngoscope and Macintosh laryngoscope in children with immobilized cervical spine. PMID- 23640157 TI - Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes. AB - Hyperostosis cranialis interna (HCI) is a rare autosomal dominant disorder characterized by intracranial hyperostosis and osteosclerosis, which is confined to the skull, especially the calvarium and the skull base. The rest of the skeleton is not affected. Progressive bone overgrowth causes nerve entrapment that leads to recurrent facial nerve palsy, disturbance of the sense of smell, hearing and vision impairments, impairment of facial sensibility, and disturbance of balance due to vestibular areflexia. The treatment is symptomatic. Histomorphological investigations showed increased bone formation with a normal tissue structure. Biochemical parameters were normal. Until today the disease has been described in only three related Dutch families with common progenitors and which consist of 32 individuals over five generations. HCI was observed in 12 family members over four generations. Patients are mildly to severely affected. Besides HCI, several bone dysplasias with hyperostosis and sclerosis of the craniofacial bones are known. Examples are Van Buchem disease, sclerosteosis, craniometaphyseal dysplasia, and Camurati-Engelmann disease. However, in these cases the long bones are affected as well. Linkage analysis in a family with HCI resulted in the localization of the disease-causing gene to a region on chromosome 8p21 delineated by markers D8S282 and D8S382. Interesting candidate genes in this region are BMP1, LOXL2, and ADAM28. Sequence analysis of these genes did not reveal any putative mutations. This suggests that a gene not previously involved in a sclerosing bone dysplasia is responsible for the abnormal growth in the skull of these patients. PMID- 23640158 TI - Influences on pregnancy-termination decisions in Matlab, Bangladesh. AB - We investigate factors affecting women's decisions to terminate pregnancies in Matlab, Bangladesh, using logistic regression on high-quality data from the Demographic Surveillance System on more than 215,000 pregnancies that occurred between 1978 and 2008. Variables associated with the desire not to have another birth soon (very young and older maternal age, a greater number of living children, the recent birth of twins or of a son, a short interval since a recent live birth) are associated with a greater likelihood of pregnancy termination, and the effects of many of these explanatory variables are stronger in more recent years. Women are less likely to terminate a pregnancy if they don't have any living sons or recently experienced a miscarriage, a stillbirth, or the death of a child. The higher the woman's level of education, the more likely she is to terminate a pregnancy. Between 1982 and the mid-2000s, pregnancy termination was significantly less likely in the area of Matlab with better family planning services. PMID- 23640159 TI - Total mesorectal preserving proctectomy. PMID- 23640161 TI - The synthesis of molecular imprinted chitosan-gels copolymerized with multiform functional monomers at three different temperatures and the recognition for the template ovalbumin. AB - In this paper, the molecularly imprinted polymers (MIPs) were prepared to recognize the template ovalbumin. The graft copolymerization was conducted based on chitosan (CS) and several types of functional monomers, while choosing N,N methylenebisacrylamide as the cross-linking agent. The influence of the synthesis temperature was investigated. The effect of different kinds of functional monomers was compared and optimized. The properties of the obtained gels were characterized by using the FT-IR spectrometer, field emission scanning electron microscope (FESEM) and Zeta-meter. The adsorption isotherms of the imprinted chitosan gels were determined and well fitted by a Langmuir model. The maximum theoretical adsorption capacities (Q(max)) was determined to be 9.74 mg g(-1) for the MIP (CS-g-AAm) and 22.94 mg g(-1) for the MIP (CS-g-MAA). Several types of reference protein with different molecular weights and isoelectric points were selected to examine the selectivity of the chitosan based gels. The results implied that the charge effect and the shape memory were the critical factors affecting the rebinding process. Finally, the selectivity for the protein mixture adsorption was evaluated by the high efficiency liquid chromatography (HPLC) analysis choosing lysozyme as the competitive protein. These results demonstrate the potential selectivity of the prepared chitosan gels. PMID- 23640160 TI - IL10 and TNF variants and risk of non-Hodgkin lymphoma among three Asian populations. AB - Genetic variation in immune-related genes, such as IL10 and TNF, have been associated with the development of non-Hodgkin lymphoma (NHL) in Caucasian populations. To test the hypothesis that IL10 and TNF polymorphisms may be associated with NHL risk in Asian populations, we genotyped 20 single nucleotide polymorphisms (SNPs) within the IL10 and TNF/LTA loci in three independent case control studies (2635 cases and 4234 controls). IL10 rs1800871, rs1800872, and rs1800896 were genotyped in all three studies, while 5 of the remaining SNPs were genotyped in two studies, and 12 in a single study. IL10 rs1800896 was associated with B cell lymphoma [per-allele odds ratio (OR) = 1.25, 95 % confidence interval (CI) 1.08-1.45; p trend = 0.003], specifically diffuse large B cell lymphoma (DLBCL) (per-allele OR = 1.29, 95 % CI 1.08-1.53; p trend = 0.004), as well as T cell lymphoma (per-allele OR = 1.44, 95 % CI 1.13-1.82; p trend = 0.003). TNF rs1800629, which was genotyped in only two of our studies, was also associated with B cell lymphoma (per-allele OR = 0.77, 95 % CI 0.64-0.91; p trend = 0.003), specifically DLBCL (per-allele OR = 0.69, 95 % CI 0.55-0.86; p trend = 0.001). Our findings suggest that genetic variation in IL10 and TNF may also play a role in lymphomagenesis in Asian populations. PMID- 23640162 TI - Cigarette smoking among Asian American and Pacific Islander college students: implications for college health promotion. AB - Asian Americans (AA) and Pacific Islanders (PI) are an understudied population for health and tobacco use, which is alarming for a fast growing U.S. population. Research in smoking among AA and PI college students is limited, despite 50% of AA and 20% of PI having obtained a college degree. A cross-sectional tobacco survey was administered in a large racially diverse Southern California university (N = 490) that examined smoking behavior, psychosocial, and perceptual factors related to smoking among AA and PI compared with Caucasians. Overall, 19% of participants were smokers. The prevalence of current smoking by race was 26% PI, 19% AA, and 17% Caucasian. AA and PI are light, infrequent smokers who smoke mainly for social reasons and in social locations. Most AA and PI made quit attempts and reported intention to quit smoking. Low to moderate risk perceptions for addiction, disease and difficulty in quitting were observed. Social norms center on family influences, therefore it is recommended that cessation approaches target cigarette smoking norms within this social environment to increase perceptual risks of smoking. Smoking cessation should be placed in college health outreach programs based on culturally tailored approaches for AA and PI that target their unique smoking characteristics. PMID- 23640163 TI - Note on "simulation optimization of PSA-threshold based prostate cancer screening policies". PMID- 23640164 TI - From atoms to layers: in situ gold cluster growth kinetics during sputter deposition. AB - The adjustment of size-dependent catalytic, electrical and optical properties of gold cluster assemblies is a very significant issue in modern applied nanotechnology. We present a real-time investigation of the growth kinetics of gold nanostructures from small nuclei to a complete gold layer during magnetron sputter deposition with high time resolution by means of in situ microbeam grazing incidence small-angle X-ray scattering (MUGISAXS). We specify the four stage growth including their thresholds with sub-monolayer resolution and identify phase transitions monitored in Yoneda intensity as a material-specific characteristic. An innovative and flexible geometrical model enables the extraction of morphological real space parameters, such as cluster size and shape, correlation distance, layer porosity and surface coverage, directly from reciprocal space scattering data. This approach enables a large variety of future investigations of the influence of different process parameters on the thin metal film morphology. Furthermore, our study allows for deducing the wetting behavior of gold cluster films on solid substrates and provides a better understanding of the growth kinetics in general, which is essential for optimization of manufacturing parameters, saving energy and resources. PMID- 23640165 TI - Hirsutellones and beyond: figuring out the biological and synthetic logics toward chemical complexity in fungal PKS-NRPS compounds. AB - Covering: up to early 2013. Fungal polyketides and their hybrid non ribosomal peptide derivatives are characterized by often striking structural features and biological activities. Their diversity and their complexity arise from highly organized and programmable biosynthetic pathways and have been challenged by many synthetic chemists. This review will conceptually illustrate how complexity can be generated, starting from a general biosynthetic purpose (the fundaments of PKS NRPS assembly lines) and finally showing how the particular class of hirsutellone compounds has emerged from such processes in relation to post-elongation and secondary tailoring events. Synthetic efforts to produce these natural products will be described with a special emphasis on complexity-generating strategies and steps. Thus, the biosynthetic and synthetic works will be analyzed in a continuous flow, focusing on both the logic of Nature and organic chemists. PMID- 23640166 TI - Construction and use of a microfluidic dissection platform for long-term imaging of cellular processes in budding yeast. AB - This protocol describes the production and operation of a microfluidic dissection platform for long-term, high-resolution imaging of budding yeast cells. At the core of this platform is an array of micropads that trap yeast cells in a single focal plane. Newly formed daughter cells are subsequently washed away by a continuous flow of fresh culture medium. In a typical experiment, 50-100 cells can be tracked during their entire replicative lifespan. Apart from aging-related research, the microfluidic platform can also be a valuable tool for other studies requiring the monitoring of single cells over time. Here we provide step-by-step instructions on how to fabricate the silicon wafer mold, how to produce and operate the microfluidic device and how to analyze the obtained data. Production of the microfluidic dissection platform and setting up an aging experiment takes ~7 h. PMID- 23640167 TI - Derivation of extraembryonic endoderm stem (XEN) cells from mouse embryos and embryonic stem cells. AB - At the time of implantation in the maternal uterus, the mouse blastocyst possesses an inner cell mass comprising two lineages: epiblast (Epi) and primitive endoderm (PrE). Representative stem cells derived from these two cell lineages can be expanded and maintained indefinitely in vitro as either embryonic stem (ES) or XEN cells, respectively. Here we describe protocols that can be used to establish XEN cell lines. These include the establishment of XEN cells from blastocyst-stage embryos in either standard embryonic or trophoblast stem (TS) cell culture conditions. We also describe protocols for establishing XEN cells directly from ES cells by either retinoic acid and activin-based conversion or by overexpression of the GATA transcription factor Gata6. XEN cells are a useful model of PrE cells, with which they share gene expression, differentiation potential and lineage restriction. The robust protocols for deriving XEN cells described here can be completed within 2-3 weeks. PMID- 23640168 TI - Preparation and purification of zinc sulfinate reagents for drug discovery. AB - The present protocol details the synthesis of zinc bis(alkanesulfinate)s that can be used as general reagents for the formation of radical species. The zinc sulfinates described herein are generated from the corresponding sulfonyl chlorides by treatment with zinc dust. The products may be used crude, or a simple purification procedure may be performed to minimize incorporation of water and zinc chloride. Although the synthesis of the zinc sulfinate salts can generally be completed within 3 h, workup can take up to 24 h and purification can take up to 3 h. Following the steps in this protocol would enable the user to generate a small toolkit of zinc sulfinate reagents over the course of 1 week. PMID- 23640171 TI - [Aging and social inequality]. PMID- 23640170 TI - [Ideal types of interaction patterns of psychosomatic patients in geriatric inpatient treatment]. AB - BACKGROUND: Cooperation between psychosomatic and geriatric medicine is still sporadic and rarely institutionally integrated. At the same time, however, nearly half of geriatric inpatients suffer from psychopathological symptoms of clinical relevance. The patterns of interactions between patients and professionals of the geriatric team prior to a psychosomatic intervention that lead to a specific consultation are still rarely known. The aim of this paper was to identify these relational patterns, which can again occur during interaction with the psychosomatic patient. MATERIAL AND METHODS: Protocols from the consultation sessions of 76 geriatric in-patients, treated over a period of 1 year, were used as the basis data for the development of interactional patterns with the systematic, qualitative method of forming ideal types by understanding. RESULTS: Three groups with a total of 11 interactional patterns were formed: (1) "conflictuous interaction" with patients who re-enact their inner conflicts (e.g., autonomy or conflicts on power and subjugation), (2) "the problem can not be dealt with" with patients who forget or deny and repress their mental problems in other ways, and (3) "avoiding contact" with patients who have different forms of psychosocial withdrawal. CONCLUSION: Extension of the geriatric functional diagnostic approach on interactional-psychodynamic aspects is possible and fosters a differentiated view on the psychosomatic situation of geriatric patients. PMID- 23640169 TI - Constructing droplet interface bilayers from the contact of aqueous droplets in oil. AB - We describe a protocol for forming an artificial lipid bilayer by contacting nanoliter aqueous droplets in an oil solution in the presence of phospholipids. A lipid monolayer forms at each oil-water interface, and when two such monolayers touch, a bilayer is created. Droplet interface bilayers (DIBs) are a simple way to generate stable bilayers suitable for single-channel electrophysiology and optical imaging from a wide variety of preparations, ranging from purified proteins to reconstituted eukaryotic cell membrane fragments. Examples include purified proteins from the alpha-hemolysin pore from Staphylococcus aureus, the anthrax toxin pore and the 1.2-MDa mouse mechanosensitive channel MmPiezo1. Ion channels and ionotropic receptors can also be reconstituted from membrane fragments without further purification. We describe two approaches for forming DIBs. In one approach, a lipid bilayer is created between two aqueous droplets submerged in oil. In the other approach, a membrane is formed between an aqueous droplet and an agarose hydrogel, which allows imaging in addition to electrical recordings. The protocol takes <30 min, including droplet generation, monolayer assembly and bilayer formation. In addition to the main protocol, we also describe the preparation of Ag/AgCl electrodes and sample preparation. PMID- 23640172 TI - In vitro electrical conductivity of seizing and non-seizing mouse brain slices at 10 kHz. AB - The electrical conductivity of small samples of mouse cortex (in vitro) has been measured at 10 kHz through the four-electrode method of van der Pauw. Brain slices from three mice were prepared under seizing and non-seizing conditions by changing the concentration of magnesium in the artificial cerebrospinal fluid used to maintain the tissue. These slices provided 121 square samples of cortical tissue; the conductivity of these samples was measured with an Agilent E4980A four-point impedance monitor. Of these, 73 samples were considered acceptable on the grounds of having good electrical contact between electrodes and tissue excluding outlier measurements. Results show that there is a significant difference (p = 0.03) in the conductivities of the samples under the two conditions. The seizing and non-seizing samples have mean conductivities of 0.33 and 0.36 S m(-1), respectively; however, these quantitative values should be used with caution as they are both subject to similar systematic uncertainties due to non-ideal temperature conditions and non-ideal placement of electrodes. We hypothesize that the difference between them, which is more robust to uncertainty, is due to the changing gap junction connectivity during seizures. PMID- 23640173 TI - Association of personality, neighbourhood, and civic participation with the level of perceived social support: the HUNT study, a cross-sectional survey. AB - AIM: The aim of the current study was to examine the association of personality, neighbourhood, and civic participation with the level of perceived social support if needed. METHODS: The sample consists of a total of 35,797 men (16,035) and women (19,762) drawn from the Nord-Trondelag Health Study 3 (HUNT3), aged 20-89, with a fully completed short version of the Eysenck Personality Questionnaire (EPQ) including a complete response to questions regarding perceived social support. A multinomial logistic regression model was used to investigate the association between the three-category outcomes (high, medium, and low) of perceived social support. RESULTS: The Chi-square test detected a significant (p < 0.001) association between personality, sense of community, civic participation, self-rated health, living arrangement, age groups, gender, and perceived social support, except between perceived social support and loss of social network, in which no significance was found. The crude and adjusted multinomial logistic regression models show a relation between medium and low scores on perceived social support, personality, and sources of social support. Interactions were observed between gender and self-rated health. CONCLUSIONS: There is an association between the level of perceived social support and personality, sense of community in the neighbourhood, and civic participation. Even if the interaction between men and self-reported health decreases the odds for low and medium social support, health professionals should be aware of men with poor health and their lack of social support. PMID- 23640174 TI - In response to the editorial entitled "On the use of the concept of "fairness" in ethics". PMID- 23640175 TI - New Cd2+, Pb2+ complexes with acylhydrazidate molecules from in situ acylation reactions. AB - Through employing the hydrothermal in situ acylation of N2H4 with aromatic dicarboxylic acids, four new acylhydrazidate-coordinated complexes, [Cd2(pth)4(phen)2(H2O)2].H2O (pth = phthalhydrazidate; phen = 1,10 phenanthroline) 1, [Cd3(dcpth)6(phen)2(H2O)2] (dcpth = 4,5 dichlorophthalhydrazidate) 2, [Cd(pdh)2(H2O)2] (pdh = pyridine-2,3 dicarboxylhydrazidate) 3 and [Pb(sdpth)(phen)] (sdpth = 4,4' sulfoyldiphthalhydrazidate) 4, were obtained. X-ray analysis revealed that (i) isomerization and deprotonation of acylhydrazide molecules also occurred; (ii) compound 2 possesses a one-dimensional (1-D) double-chain structure, in which dcpth exhibits three types of coordination modes; (iii) compound 4 shows a 1-D castellated single-chain structure; (iv) the adjacent uncoordinated acylamino groups form a hydrogen-bonded dimer, via which compounds 2-4 self-assemble into different two-dimensional (2-D) supramolecular networks. In the solid state, only compound 3 emits green light (lambda(em) = 525 nm), while in an aqueous solution, compounds 1, 3 and 4 all emit light. Density functional theory (DFT) calculations indicate that the emission at 470 nm for compound 1 corresponds to a charge transfer within the phen molecule, whereas the emission at 400 nm for compound 3 corresponds to a charge transfer within the pdh molecule. PMID- 23640176 TI - A rapid facilitation of acid-sensing ion channels current by corticosterone in cultured hippocampal neurons. AB - Acid-sensing ion channels (ASIC) play an important role in the central neuronal system and excessive activation of ASICs induces neuronal damage. Recent studies show that ASIC1a, a subunit of ASIC, is involved in stress processes but the mechanisms by which ASIC1a is regulated by corticosterone (CORT), a stress induced hormone, are as yet unelucidated. In the present study, to explore the effects of CORT on ASIC1a in cultured hippocampal neurons, the whole-cell patch clamp technique was used. We present data showing that extracellular application of 1 and 10 MUM CORT increase the inward current when solution of pH 6.0 is applied to the exterior of the cell. Moreover, extracellular application of membrane-impermeable CORT-BSA (1 MUM) maintains current elevation induced by the action of ASIC1a. However, intracellular application of CORT (1 MUM) did not increase ASIC1a current. Subsequent extracellular application of CORT enhanced the amplitude of ASIC1a current. Also, RU38486 (10 MUM), an antagonist of nuclear glucocorticoids receptor, did not block an increase of ASIC1a current induced by CORT. In addition, CORT application further resulted in a significant enhancement of ASIC1a current in the presence of phorbol 12-myristate 13-acetate (0.5 MUM) or bryostatin1 (1 MUM), which are both protein kinase C (PKC) agonists. On the contrary, after pretreatment with GF109203X (3 MUM), an antagonist of PKC, CORT did not elevate ASIC1a current. These data indicate that the rapid increase of ASIC1a current induced by CORT may be caused by the activation of corticosteroid receptors found on the cell membranes of hippocampal neurons and it may involve a PKC-dependent mechanism. PMID- 23640177 TI - Glia maturation factor expression in hippocampus of human Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by the presence of neuropathological lesions containing amyloid plaques (APs) and neurofibrillary tangles (NFTs) associated with neuroinflammation and neuronal degeneration. Hippocampus is one of the earliest and severely damaged areas in AD brain. Glia maturation factor (GMF), a known proinflammatory molecule is up-regulated in AD. Here, we have investigated the expression and distribution of GMF in relation to the distribution of APs and NFTs in the hippocampus of AD brains. Our immunohistochemical results showed GMF is expressed specifically in the vicinity of high density of APs and NFTs in the hippocampus of AD patients. Moreover, reactive astrocytes and activated microglia surrounds the APs and NFTs. We further demonstrate that GMF immunoreactive glial cells were increased at the sites of Tau containing NFTs and APs of hippocampus in AD brains. In conclusion, up-regulated expression of GMF in the hippocampus, and the co-localization of GMF and thioflavin-S stained NFTs and APs suggest that GMF may play important role in the pathogenesis of AD. PMID- 23640178 TI - Intravitreal fasudil combined with bevacizumab for persistent diabetic macular edema: a novel treatment. PMID- 23640179 TI - Comparison of biomass production and total lipid content of freshwater green microalgae cultivated under various culture conditions. AB - The growth and total lipid content of four green microalgae (Chlorella sp., Chlorella vulgaris CCAP211/11B, Botryococcus braunii FC124 and Scenedesmus obliquus R8) were investigated under different culture conditions. Among the various carbon sources tested, glucose produced the largest biomass or microalgae grown heterotrophically. It was found that 1% (w/v) glucose was actively utilized by Chlorella sp., C. vulgaris CCAP211/11B and B. braunii FC124, whereas S. obliquus R8 preferred 2% (w/v) glucose. No significant difference in biomass production was noted between heterotrophic and mixotrophic (heterotrophic with light illumination/exposure) growth conditions, however, less production was observed for autotrophic cultivation. Total lipid content in cells increased by approximately two-fold under mixotrophic cultivation with respect to heterotrophic and autotrophic cultivation. In addition, light intensity had an impact on microalgal growth and total lipid content. The highest total lipid content was observed at 100 MUmol m(-2)s(-1) for Chlorella sp. (22.5%) and S. obliquus R8 (23.7%) and 80 MUmol m(-2)s(-1) for C. vulgaris CCAP211/11B (20.1%) and B. braunii FC124 (34.9%). PMID- 23640181 TI - Honouring Folke Sjoqvist. PMID- 23640180 TI - Three ubiquitination sites of organic anion transporter-1 synergistically mediate protein kinase C-dependent endocytosis of the transporter. AB - Organic anion transporter-1 (OAT1) mediates the body disposition of a diverse array of clinically important drugs, including anti-HIV therapeutics, antitumor drugs, antibiotics, antihypertensives, and anti-inflammatories. Therefore, understanding the regulation of OAT1 has profound clinical significance. We previously established that OAT1 constitutively internalizes from and recycles back to cell surface and that activation of protein kinase C (PKC) inhibits OAT1 activity by promoting ubiquitination of the transporter, which then leads to an accelerated internalization of the transporter from cell surface to intracellular compartments. In the current study, we showed that PKC isoform PKCalpha was responsible for OAT1 ubiquitination. To directly address the role of OAT1 ubiquitination, we then generated two OAT1 mutants, each having multiple lysines (K) simultaneously mutated to arginine (R). One mutant K163/297/303/315/321R lost sensitivities to PKC-induced inhibition of transport activity, to PKC-induced ubiquitination, and to PKC-induced acceleration of transporter internalization. Further dissecting each lysine in this mutant, we identified Lys297, Lys303, and Lys315 as being the ubiquitin conjugation sites. Of interest, mutating any one of the three lysines prevented the ubiquitin conjugation to the other two lysines, suggesting that Lys297, Lys303, and Lys315 may form an optimal structure to interact with ubiquitination machineries. This is the first demonstration that Lys297, Lys303, and Lys315 play a synergistic role in PKC-regulated OAT1 ubiquitination, trafficking, and transport activity. PMID- 23640182 TI - Efforts and success world-wide in the field of clinical pharmacology. A personal review on the occasion of Folke Sjoqvist's 80th birthday. AB - In this personal review I describe my early expectations and experiences when I first came to work with Prof. Folke Sjoqvist as a training fellow in the early 1970s. At that time Prof. Sjoqvist and his unit had already earned an international reputation, and in the following decades this success has been magnified many times. Although a description of the research performed by Prof. Sjoqvist during his long career is not the main objective of this article, it is clear that the research carried out in his unit has been instrumental in the development of his international reputation. Over an 18-year period from 1994 onwards, some 272 papers bearing the name of Folke Sjoqvist have been cited over 13,000 times, with an average of over 50 citations per paper. In terms of training clinical pharmacologists from around the world, at the last count 112 individuals from 37 different countries have received a substantial part of their training in his unit. As another measure of his world-wide success, 33 individuals from 18 different countries who received a substantial part of their training in his unit between 1968 and 1996 have gone on to become professors of clinical pharmacology. Prof. Sjoqvist has been requested to consult on various aspects of clinical pharmacology in 15 different countries, from Russia to Spain and from Egypt to Latvia. Here I describe the long-term involvement that Prof. Sjoqvist has had with IUPHAR (now the International Union of Basic and Clinical Pharmacology) and with institutions such as the World Health Organisation (WHO). In particular, I recount his role in the long-term saga involved in updating the original WHO manifesto on clinical pharmacology published in 1970 up to the eventual success of the new manifesto published by WHO in 2012. Finally, I briefly describe the international honours that have been bestowed on Prof. Sjoqvist, including various prizes, designated lectureships and honorary Doctorates (5). Taken together, these honours provide a magnificent measure of Prof. Sjoqvist's world wide-success-a success that has been emulated by very few clinical pharmacologists. PMID- 23640183 TI - Pharmacopolitics: reflections on a subspecialty of clinical pharmacology? PMID- 23640184 TI - Challenges in pharmacogenetics. AB - The attempt to optimize drug treatment of patients by using evidenced-based medicine considering individual physiological and disease-related conditions is standard of modern medicine. Pharmacogenetics (PGx) has contributed to individualization considering hereditary genetic information; however, increasingly, pharmacogenomics is becoming essential, particularly in relation to modern oncology. New technologies such as next-generation sequencing and rapid development of computational and information sciences will help to better elucidate the consequences of genetic variation, considering also epigenetics and gene-environmental interactions and their translation into clinically relevant individual phenotypes. This review highlights the current challenging and most promising examples of PGx. PMID- 23640185 TI - Therapeutic drug monitoring for tomorrow. AB - Therapeutic drug monitoring (TDM) represents an early approach to personalised medicine. It helps the clinician to individualise drug treatment and guide dosage to reach systemic drug concentrations associated with therapeutic efficacy and/or to reduce the risk of concentration-dependent adverse effects. Well into the fifth decade of TDM as a service to healthcare, this concept is still expanding, and new areas for clinical implementation continue to emerge. The aim of this overview is to discuss promising new therapeutic areas in future TDM services, how to improve the clinical interpretation of single drug measurements and how recent technology development opens the doors to research and new applications. PMID- 23640187 TI - The intriguing future of pharmacoepidemiology. AB - Over the years more and more data have become available in the constantly growing databases on prescription drugs. This has facilitated the development of pharmacoepidemiology, a dynamic research field that has undergone a more rapid development than many other research areas. There are several reasons why pharmacoepidemiology will remain recognized as one of the most dynamic and challenging research areas of clinical pharmacology. The data explosion in modern society will continue, and observational studies aimed at assessing the value of medicines will be increasingly requested by payers, professionals and patients. Future studies in pharmacoepidemiology must include specialist drugs used in the hospital setting and also be designed to address obstacles hindering the delivery of effective medicines to the patient. Pharmacoepidemiological methods may also be valuable tools to address new challenges, such as the environmental impact of medicines. A potential threat is that the increasing amounts of data available in registries may add fuel to the debate on confidentiality. The too strict application of privacy rules might hinder the further development of pharmacoepidemiology. PMID- 23640186 TI - The past, present and perhaps future of pharmacovigilance: homage to Folke Sjoqvist. AB - Over the years since 1961 and the identification of thalidomide as the common link in thousands of birth defects, daily pharmacovigilance activities and signal generation have evolved from the analysis of individual case reports and imputology, to case series and underreporting, to spontaneous report databases and disproportionality analyses, to data mining in population databases. Regulatory requirements have also changed from purely passive monitoring and reacting to alerts to a proactive approach that includes risk management plans and risk minimization, and from reporting only by healthcare professionals to patient reporting and exploration of social media. The emphasis only on risk assessment is changing towards assessment of the risk/benefit ratio and the exploration of real-life efficacy studies to complement the measure of real-life risk. The interactions between industry and regulators have been amplified and strengthened. However, most adverse reactions, including severe ones, are related to well-known and often pharmacological effects of the older drugs, possibly with genetic predispositions. Prevention is the next frontier for pharmacovigilance, beyond simply generating alerts, and it involves not only the removal of drugs from the market, but also promotion of proper drug prescribing by better trained physicians and the proper use of drugs by better informed patients. PMID- 23640188 TI - Treating older people. PMID- 23640189 TI - Reflection: medicines for children--science alone is not enough. AB - PURPOSE: Access to medicines filling children's therapeutic needs is a long standing global problem. The problem has been recognised and initiatives for correction were adopted in the USA in the late 1990s, and in the European Union in the first decade of this century. Paediatric medicines are particularly problematic in middle- and low-income countries, where most of the children of the world live. METHODS: A paediatric medicines initiative involving the WHO in parallel with the US and EU initiatives was seen as important by the global paediatric and paediatric clinical pharmacology community, but the WHO was resistant to getting involved. RESULTS: Advocacy, networking, cooperation, persistence, hard work and some luck were needed to get the "Better medicines for children" resolution 60.20 adopted by the World Health Assembly in May 2007. CONCLUSION: Science has been a key enabler of the developments leading to and following the adoption of the paediatric initiatives, but as the example of the WHO shows, science alone was not enough to make the change. PMID- 23640190 TI - The continuing challenge of providing drug information services to diminish the knowledge--practice gap in medical practice. AB - Information must be collected, evaluated and utilized to support every qualified activity. Medicine, with a written scientific tradition stretching back more than 2,000 years, is no exception. Here, we discuss a number of important items associated with the establishment of a drug information centre run by clinical pharmacologists and information pharmacists, serving a broad demand, mainly among clinical specialists. The working methods include a professional literature search, critical evaluation of the material, writing a structured answer, quality control, feedback to the inquirer and storage in a database which is publicly available. One can foresee even more complex systems wherein a number of active and specialized databases communicate to provide relevant advice and support at the point of care, supplying information on drug recommendations, reimbursement, environmental aspects, antimicrobial resistance, pharmacogenetics and adverse effects, and linked to a list of prescribed drugs for the individual patient. This will be possible in both rich and poor countries through the application of modern and developing information technology. However, research on the best and safest methods of such decision support systems will be needed to ensure that they really do improve the quality of drug prescribing and use. PMID- 23640191 TI - Interface management of pharmacotherapy. Joint hospital and primary care drug recommendations. AB - PURPOSE: In September 2012 an interactive course on the "Interface Management of Pharmacotherapy" was organized by the Stockholm Drug and Therapeutics Committee in cooperation with Department of Clinical Pharmacology at Karolinska Institutet and at Karolinska University Hospital in Stockholm, Sweden, in collaboration with the WHO. The basis for the course was the "Stockholm model" for the rational use of medicines but also contained presentations about successful models in interface management of pharmacotherapy in other European countries. METHODS: The "Stockholm model" consists of 8 components: 1) Independent Drug and Therapeutics Committee with key role for respected drug experts with policy for "interest of conflicts", 2) The "Wise List", recommendations of medicines jointly for primary and hospital care, 3) Communication strategy with continuous medical education, 4) Systematic introduction of new expensive medicines, 5) E-pharmacological support at "point of care", 6) Methods and tools for follow-up of medicines use, 7) Medicines policy strategy and 8) Operative resources. RESULTS: The course highlighted the importance of efficient and targeted communication of drug recommendations building on trust among prescribers and patients for the guidelines to achieve high adherence. Trust is achieved by independent Drug and Therapeutics Committees with a key role for respected experts and a strict policy for "conflicts of interest". Representations of GPs are also crucial for successful implementation, being the link between evidence based medicine and practice. CONCLUSION: The successful models in Scotland and in Stockholm as well as the ongoing work in Catalonia were considered as examples of multifaceted approaches to improve the quality of medicine use across primary and hospital care. PMID- 23640192 TI - The right drug, but from whose perspective? A framework for analysing the structure and activities of drug and therapeutics committees. AB - PURPOSE: During the last five decades drug and therapeutics committees (DTCs), have evolved from mainly hospital-based groups of experts in pharmacotherapy and drug logistics into an arena for healthcare professionals employing evidence based methods of promoting rational drug use. The purpose of this study was to suggest a framework for analysing the structure and activities of DTCs. METHODS: A literature search was carried out in the Medline, Cinahl and Web of Sciences databases for the period 1993-2012. RESULTS: A total of 207 articles were included. Based on these articles a framework for the analysis of the DTCs based on the role of the DTC, target groups, budget perspective and type of economic decisions could be suggested. CONCLUSIONS: In order to respond to future demands the DTCs will have to develop their skill in pharmacoeconomics. Their processes will have to be standardised and made more transparent in order to be better adapted to evidence-based decision-making. They will also have to embrace the possibilities created by electronic health records in both influencing the decisions of physicians, and in improving quality assurance programmes and longitudinal follow-up of drug therapy and outcomes. They will have to find new ways of interacting with the public and policy makers in order to get the resources needed for their work. Finally, they will have to handle the conflict among national, regional and local decision-making processes and the relationship between formularies and therapeutic guidelines. PMID- 23640193 TI - Clinical pharmacology in everyday clinical care. AB - Since direct patient care is only one of the many fields of clinical pharmacologists world wide, the contribution of the discipline to the provision of healthcare is frequently underestimated. Besides therapeutic monitoring and pharmacogenetic services, particularly drug information services run by clinical pharmacology departments have been established in many countries. Despite the fact that electronic prescribing support may prevent physicians from major medication errors due to drug-drug interactions and inadequate dosages, a substantial number of questions addressed to drug information services include clinical expertise and judgement. Furthermore, a high number of requests deal with adverse drug interactions and involve requests for alternative drugs in the individual clinical context. Using information technology, an international web based clinical pharmacology service using existing knowledge databases seems to be a promising option to demonstrate the excellence of the discipline. PMID- 23640194 TI - Characteristics and apprehensions of clinical pharmacologists in Swedish healthcare--a questionnaire study. AB - PURPOSE: To describe the discipline clinical pharmacology of today in the Swedish healthcare system from the performers' point of view. METHODS: A questionnaire was administered in December 2012 to physicians working within the specialty clinical pharmacology in the Swedish healthcare system (7 sites; 1-26 physicians per site). The questionnaire included questions pertaining to the characteristics of the responder and statements to which the responder indicated his/her level of agreement using a score ranging from 1 (total disagreement) to 5 (total agreement). RESULTS: A total of 61 completed questionnaires were returned (response rate: 97 %; 55 % male; 74 % specialists and/or consultants). In the preceding month, 79 % of the responders had performed educational activities, 74 % had functioned as an "expert", and 75 % had performed research. The academic merits of the responders were high, with 72 % having at least a PhD degree and 23 % being professors. Among those performing research, the focus of 83 % was related to the field of clinical pharmacology, with the main sub-areas being pharmacoepidemiology (59 %) and/or pharmacogenetics (41 %). Regarding the apprehension questions, the responders strongly agreed that the specialty clinical pharmacology meets a need in the healthcare system (4.5 +/- 0.7), that they wanted to continue to work within the specialty (4.5 +/- 0.7), that their personal professional prospects were good (3.9 +/- 1.0), and that they would recommend a colleague to specialize within the field (3.9 +/- 1.1). The responders from the largest and first established site (Karolinska University Hospital) agreed with these points to a significantly greater extent than responders from other sites. CONCLUSIONS: The majority of the performers of clinical pharmacology in Swedish healthcare consider this specialty to be important to the medical community. By carrying out educational activities, providing expertise, and performing research, the performers seem to be content with their work and future prospects. Performers within the largest and oldest site in Sweden, generally held the most positive view of the specialty. PMID- 23640195 TI - Genome Sequences of Two Klebsiella pneumoniae Isolates from Different Geographical Regions, Argentina (Strain JHCK1) and the United States (Strain VA360). AB - We report the sequences of two Klebsiella pneumoniae clinical isolates, strains JHCK1 and VA360, from a newborn with meningitis in Buenos Aires, Argentina, and from a tertiary care medical center in Cleveland, OH, respectively. Both isolates contain one chromosome and at least five plasmids; isolate VA360 contains the Klebsiella pneumoniae carbapenemase (KPC) gene. PMID- 23640196 TI - Complete Genome Sequence of a Chinese Strain of "Candidatus Liberibacter asiaticus". AB - We report here the complete genome sequence of "Candidatus Liberibacter asiaticus" (strain Guangxi-1). The 1,268,237-bp genome with a 36.5% G+C content comprises 1,141 open reading frames, 44 tRNAs, and 3 complete rRNAs in a circular chromosome. PMID- 23640197 TI - Genome Sequence of Halanaerobium saccharolyticum subsp. saccharolyticum Strain DSM 6643T, a Halophilic Hydrogen-Producing Bacterium. AB - Halanaerobium saccharolyticum is a halophilic anaerobic fermentative bacterium capable of producing hydrogen, a potential future energy carrier molecule. The high-quality draft genome of H. saccharolyticum subsp. saccharolyticum strain DSM 6643(T) consists of 24 contigs for 2,873,865 bp with a G+C content of 32.3%. PMID- 23640198 TI - Whole-Genome Sequences of Streptococcus tigurinus Type Strain AZ_3a and S. tigurinus 1366, a Strain Causing Prosthetic Joint Infection. AB - Streptococcus tigurinus, a novel member of the Streptococcus mitis group, was recently identified as a causative agent of invasive infections. We report the complete genome sequences of the S. tigurinus type strain AZ_3a and S. tigurinus strain 1366. The genome sequences assist in the characterization of virulence determinants of S. tigurinus. PMID- 23640199 TI - Association of ambient air pollution and meteorological factors with primary care visits at night due to asthma attack. AB - AIM: The association of outdoor air pollution and meteorological elements with primary care visits at night due to asthma attack was studied. METHODS: A case crossover study was conducted in a primary care clinic in Himeji City, Japan. The subjects were 956 children aged 0-14 years who visited the clinic with an asthma attack between the hours of 9 p.m. and 6 a.m. Daily concentrations of particulate matter, ozone, nitrogen dioxide, and a number of meteorological elements were measured, and a conditional logistic regression model was used to estimate odds ratios (ORs) of primary care visits per unit increment of air pollutants or meteorological elements. The analyses took into consideration the effects of seasonality. RESULTS: Of the 956 children, 73 (7.6 %) were aged <2 years and 417 (43.6 %) were aged 2-5 years. No association between daily ozone levels and primary care visits due to asthma attack at night in the spring or summer was found. An inverse relation between suspended particulate matter and primary care visits due to asthma attack was detected in the winter. ORs in the summer per degree increment in daily mean temperature was 1.31 [95 % confidential interval (CI) 1.09-1.56], and ORs in the autumn per hourly increment in daily hours of sunshine was 0.94 (95 % CI 0.90-0.99). CONCLUSION: The findings of our study fail to support any association between daily mean concentration of air pollutant and primary care visits at night. However, we did find evidence indicating that certain meteorological elements may be associated with primary care visits. PMID- 23640200 TI - Clinical characteristics and antibiotic susceptibility of viridans streptococcal bacteremia in children with febrile neutropenia. AB - PURPOSE: This retrospective study was performed in order to investigate the clinical characteristics and antibiotic susceptibility of viridans streptococcal bacteremia (VSB) in febrile neutropenic children in the context of the increase in incidence and antibiotic resistance of VSB. METHODS: We conducted this study among neutropenic children with underlying hematology/oncology diseases who were diagnosed with VSB at a single institution from April 2009 to June 2012. Clinical and laboratory characteristics of the children as well as antibiotic susceptibility of the causative viridans streptococci were evaluated. RESULTS: Fifty-seven episodes of VSB were diagnosed in 50 children. Severe complications occurred in four children (7.0%), and a death of one child (1.8%) was attributable to VSB. Acute myeloid leukemia was the most common underlying disease (70.2% of all cases), and 71.9% of all cases received chemotherapy including high-dose cytarabine. VSB occurred at a median of 13 days (range 8-21 days) after the beginning of chemotherapy, and fever lasted for a median of 4 days (range 1-21 days). The C-reactive protein level significantly increased within a week after the occurrence of VSB (p < 0.001) and the maximum C-reactive protein level showed a positive correlation with fever duration (r = 0.362, p = 0.007). Second blood cultures were done before the use of glycopeptides in 33 children, and negative results were observed in 30 children (90.9%). Susceptibilities to cefotaxime, cefepime, and vancomycin were 58.9, 69.1, and 100%, respectively. CONCLUSIONS: Severe complications of VSB in neutropenic febrile children were rare. We suggest glycopeptide use according to the results of blood culture and antibiotic susceptibility tests based on the susceptibility to cefepime and the microbiologic response to empirical antibiotic treatment not including glycopeptides in this study. PMID- 23640201 TI - BML-11, a lipoxin receptor agonist, protected carbon tetrachloride-induced hepatic fibrosis in rats. AB - Inflammation plays an important role in the occurrence and development of fibrosis. Lipoxins (LXs) and BML-111 (lipoxin A4 agonist) have been approved for potent anti-inflammatory properties. Previously, we and others had showed LXs and BML-111 could protect acute hepatic injury, inhibit the growth and invasion of hepatic tumor. However, there are few reports dealing with their effects on hepatic fibrosis. To explore whether LXs and the analog could interrupt the process of hepatic fibrosis, the effects of BML-111 on tetrachloride-induced hepatic fibrosis were observed and the possible mechanism were discussed. Sprague Dawley rats were induced liver fibrosis by carbon tetrachloride (CCl4) for 10 weeks with or without BML-111, and the histopathology and collagen content were employed to quantify hepatic necro-inflammation and fibrosis. Moreover, the expression levels of alpha-smooth muscle actin (alpha-SMA), transforming growth factor-beta1 (TGF-beta1), and platelet-derived growth factor (PDGF) were examined via Western blot or ELISA. Rats treated with BML-111 improved hepatic necro inflammation and inhibited hepatic fibrosis in association with reduction of alpha-SMA expression and decreased collagen deposition. Furthermore, BML-111 could downregulate the expressions of TGF-beta1 and PDGF significantly. BML-111 played a critical protective role in CCl4-induced hepatic fibrosis through inhibiting the levels of TGF-beta1 and PDGF in rats. PMID- 23640202 TI - Transition metal-free one-pot synthesis of 2-substituted 3-carboxy-4-quinolone and chromone derivatives. AB - A novel one-pot synthesis of the 2-substituted 3-carboxy-4-quinolone/chromone derivatives from readily available 3-oxo-3-arylpropanoates and amides/acyl chlorides is reported, without any transition metal aid. PMID- 23640203 TI - Nationwide surveillance of bacterial pathogens from patients with acute uncomplicated cystitis conducted by the Japanese surveillance committee during 2009 and 2010: antimicrobial susceptibility of Escherichia coli and Staphylococcus saprophyticus. AB - The Japanese surveillance committee conducted the first nationwide surveillance of antimicrobial susceptibility patterns of uropathogens responsible for female acute uncomplicated cystitis at 43 hospitals throughout Japan from April 2009 to November 2010. In this study, the causative bacteria (Escherichia coli and Staphylococcus saprophyticus) and their susceptibility to various antimicrobial agents were investigated by isolation and culturing of bacteria from urine samples. In total, 387 strains were isolated from 461 patients, including E. coli (n = 301, 77.8 %), S. saprophyticus (n = 20, 5.2 %), Klebsiella pneumoniae (n = 13, 3.4 %), and Enterococcus faecalis (n = 11, 2.8 %). S. saprophyticus was significantly more common in premenopausal women (P = 0.00095). The minimum inhibitory concentrations of 19 antibacterial agents used for these strains were determined according to the Clinical and Laboratory Standards Institute manual. At least 87 % of E. coli isolates showed susceptibility to fluoroquinolones and cephalosporins, and 100 % of S. saprophyticus isolates showed susceptibility to fluoroquinolones and aminoglycosides. The proportions of fluoroquinolone resistant E. coli strains and extended-spectrum beta-lactamase (ESBL)-producing E. coli strains were 13.3 % and 4.7 %, respectively. It is important to confirm the susceptibility of causative bacteria for optimal antimicrobial therapy, and empiric antimicrobial agents should be selected by considering patient characteristics and other factors. However, the number of isolates of fluoroquinolone-resistant or ESBL-producing strains in gram-negative bacilli may be increasing in patients with urinary tract infections (UTIs) in Japan. Therefore, these data present important information for the proper treatment of UTIs and will serve as a useful reference for future surveillance studies. PMID- 23640204 TI - No difference in gait recovery after THA with different head diameters: a prospective randomized study. AB - BACKGROUND: Larger femoral heads are commonly presumed to improve joint stability and hip biomechanics; some studies have suggested they may hasten recovery of a normal gait. To our knowledge, no gait analysis studies have compared different size head diameters in THA. QUESTIONS/PURPOSES: We compared (1) spatiotemporal gait parameters, (2) kinematic and kinetic gait parameters, and (3) Harris hip scores in patients undergoing THA randomized to receive a 28-, 36-, or >= 42-mm bearing couple. We hypothesized a larger femoral head would restore an earlier, more physiologic gait pattern. METHODS: This randomized, blinded study involved 60 patients who received the same cementless THA except for the size of the bearing. Inclusion criteria were primary hip arthritis, female sex, and age between 55 and 70 years. Exclusion criteria were other problems influencing walking ability. The patients were randomized into three groups of 20 each (28- and 36-mm ceramic-on-crosslinked polyethylene, >= 42-mm metal-on-metal). All patients underwent the same postoperative rehabilitation protocol. Gait evaluation using an optoelectronic system was performed preoperatively and at 2 and 4 months postoperatively. RESULTS: With the numbers available, no differences in spatiotemporal gait parameters, kinematic or kinetic gait parameters, or Harris hip scores emerged among the three groups. All variables assessed at 4 months postoperatively showed improvements across all groups, but the differences among them were not significant. CONCLUSIONS: The hypothesis that a larger femoral head results in improved early gait performance was not supported by this study. PMID- 23640205 TI - Treatment and displacement affect the reoperation rate for femoral neck fracture. AB - BACKGROUND: Femoral neck fractures (FNFs) comprise 50% of geriatric hip fractures. Appropriate management requires surgeons to balance potential risks and associated healthcare costs with surgical treatment. Treatment complications can lead to reoperation resulting in increased patient risks and costs. Understanding etiologies of treatment failure and the population at risk may decrease reoperation rates. QUESTIONS/PURPOSES: We therefore (1) determined if treatment modality and/or displacement affected reoperation rates after FNF; and (2) identified factors associated with increased reoperation and timing and reasons for reoperation. METHODS: We reviewed 1411 records of patients older than 60 years treated for FNF with internal fixation or hemiarthroplasty between 1998 and 2009. We extracted patient age, sex, fracture classification, treatment modality and date, occurrence of and reasons for reoperation, comorbid conditions at the time of each surgery, and dates of death or last contact. Minimum followup was 12 months (median, 45 months; range, 12-157 months). RESULTS: Internal fixation (hazard ratio [HR], 6.38) and displacement (HR, 2.92) were independently associated with increased reoperation rates. The reoperation rate for nondisplaced fractures treated with fixation was 15% and for displaced fractures 38% after fixation and 7% after hemiarthroplasty. Most fractures treated with fixation underwent reoperation within 1 year primarily for nonunion. Most fractures treated with hemiarthroplasty underwent reoperation within 3 months, primarily for infection. CONCLUSIONS: Overall, hemiarthroplasty resulted in fewer reoperations versus internal fixation and displaced fractures underwent reoperation more than nondisplaced. Our data suggest there are fewer reoperations when treating elderly patients with displaced FNFs with hemiarthroplasty than with internal fixation. PMID- 23640207 TI - High-throughput microwave-assisted discovery of new metal phosphonates. AB - A systematic study was carried out to investigate the influence of linker geometry, metal ionic radius as well as the nature of the counter ions on the structure formation of metal tetraphosphonates. Two tetraphosphonic acids p- and m-(H2O3PCH2)2N-CH2-C6H4-CH2-N(CH2PO3H2)2, six metal ions (Ca(2+), Mn(2+), Co(2+), Ni(2+), Zn(2+), and Cd(2+)) and two different counter ions (Cl(-) and NO3(-)) were employed using high throughput methods. Microwave (MW)-assisted heating led to the discovery of ten new metal-phosphonates which crystallize in three different crystal structures. The combination of direct methods and force field calculations allowed us to establish the crystal structures. The counter ion and the ionic radii of the metal ions have a profound influence on the crystallinity and the formed crystal structure. All compounds were characterized in detail by thermogravimetric analyses, IR spectroscopy and magnetic susceptibility measurements. The proton conductivity of two selected compounds is also reported. PMID- 23640206 TI - Chemotherapy influences the pseudocapsule composition in soft tissue sarcomas. AB - BACKGROUND: Soft tissue sarcomas are a heterogeneous group of malignant tumors. Standard treatment for soft tissue sarcoma of the extremity is surgical excision and adjuvant therapy; however, the role of neoadjuvant chemotherapy is controversial. QUESTIONS/PURPOSES: We sought to (1) define the histologic characteristics of the pseudocapsule in soft tissue sarcomas; (2) compare the appearance of this structure in chemotherapy-treated versus untreated soft tissue sarcomas; and (3) evaluate the effect of chemotherapy on the presence and viability of tumor cells at the host-sarcoma interface. METHODS: Twenty-eight patients with biopsy-proven, deep, high-grade extremity soft tissue sarcomas greater than 5 cm (AJCC stage III) treated with chemotherapy and surgical excision were compared histologically with 47 matched control subjects treated with surgery alone. RESULTS: A pseudocapsule was identifiable in the majority of tumors and consisted of two identifiable layers, each with specific histological characteristics suggesting the biologic processes occurring in these layers are different. The pseudocapsule was more frequently observed in the group treated with chemotherapy and it was more frequently continuous, thicker, and better developed in this group. Chemotherapy decreased the number of tumors with malignant cells identified within and beyond the pseudocapsule. CONCLUSIONS: Neoadjuvant chemotherapy contributed to the development of a pseudocapsule and decreased the number of tumors with malignant cells identified within and beyond the pseudocapsule. CLINICAL RELEVANCE: These findings may provide a histological explanation for the clinical effect of chemotherapy in soft tissue sarcoma. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23640208 TI - Prognostic models: rising to the challenge. PMID- 23640209 TI - Gene expression: colorectal cancer classifications. PMID- 23640211 TI - Therapeutics: targeting an oncometabolite. PMID- 23640212 TI - A novel CT acquisition and analysis technique for breathing motion modeling. AB - To report on a novel technique for providing artifact-free quantitative four dimensional computed tomography (4DCT) image datasets for breathing motion modeling. Commercial clinical 4DCT methods have difficulty managing irregular breathing. The resulting images contain motion-induced artifacts that can distort structures and inaccurately characterize breathing motion. We have developed a novel scanning and analysis method for motion-correlated CT that utilizes standard repeated fast helical acquisitions, a simultaneous breathing surrogate measurement, deformable image registration, and a published breathing motion model. The motion model differs from the CT-measured motion by an average of 0.65 mm, indicating the precision of the motion model. The integral of the divergence of one of the motion model parameters is predicted to be a constant 1.11 and is found in this case to be 1.09, indicating the accuracy of the motion model. The proposed technique shows promise for providing motion-artifact free images at user-selected breathing phases, accurate Hounsfield units, and noise characteristics similar to non-4D CT techniques, at a patient dose similar to or less than current 4DCT techniques. PMID- 23640210 TI - The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer. AB - Aberrant expression and activity of G proteins and G-protein-coupled receptors (GPCRs) are frequently associated with tumorigenesis. Deep sequencing studies show that 4.2% of tumours carry activating mutations in GNAS (encoding Galphas), and that oncogenic activating mutations in genes encoding Galphaq family members (GNAQ or GNA11) are present in ~66% and ~6% of melanomas arising in the eye and skin, respectively. Furthermore, nearly 20% of human tumours harbour mutations in GPCRs. Many human cancer-associated viruses also express constitutively active viral GPCRs. These studies indicate that G proteins, GPCRs and their linked signalling circuitry represent novel therapeutic targets for cancer prevention and treatment. PMID- 23640213 TI - FDG PET images in a patient with Erdheim-Chester disease. AB - Erdheim-Chester disease is an uncommon non-Langerhans-cell histiocytosis, due to excessive production of histiocytes deposited in various organs and tissues in the human body. FDG PET was performed in a 68-year-old man with documented active Erdheim-Chester disease to evaluate the extent of the disease. The patient was previously treated with high-dose subcutaneous Interferon alpha2b, 1,000,000 units 3 times a week, but treatment was interrupted approximately 5 weeks before evaluation at the National Institutes of Health because of adverse effects of the medication. FDG PET/CT showed lesions were imaged in brain, heart, mediastinum, abdomen, and skeleton. PMID- 23640214 TI - Acute lymphocytic leukemia presented as back pain and revealed by bone scintigraphy. AB - A previously healthy 8-year-old girl underwent MDP bone scintigraphy to evaluate possible spondylolysis due to worsening back pain. Unexpectedly, the bone scan images revealed intense activity in several thoracic and lumbar vertebrae, which was not consistent with spondylolysis. Further examinations proved that the patient had acute lymphocytic leukemia. PMID- 23640215 TI - Bone marrow evaluation in initial staging of lymphoma: 18F-FDG PET/CT versus bone marrow biopsy. AB - PURPOSE: The evaluation of bone marrow infiltration (BMI) is of crucial importance in the staging of lymphoma. Although bone marrow biopsy (BMB) is the reference standard for the evaluation of BMI, it has limitations. PET/CT has become an excellent tool in staging of lymphoma, and bone marrow uptake is correlated with the involvement of lymphoma. The aim of this study was to assess the utility of PET/CT and its concordance with BMB in the detection of BMI in patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). PATIENTS AND METHODS: One hundred forty-seven patients with DLBCL (84) and HL (63) were referred for a PET/CT and a BMB (unilateral) at the initial staging. The reference standard was BMB. RESULTS: Bone marrow infiltration was detected by PET/CT in 39 (26%) and by BMB in 21 (14%) cases. There was concordance between PET/CT and BMB in 128 patients (87%) (74 DLBCL, 54 HL), 21 with positive PET/CT and BMB results and 107 with negative PET/CT and BMB results. Discordant results were observed in 19 patients (14%); 18 of them with positive PET/CT and negative standard BMB results (not performed in active sites). The sensitivity, specificity, accuracy, as well as positive and negative predictive values of FDG PET/CT for the detection of BMI were 95%, 86%, 87%, 54%, and 99%, respectively. CONCLUSIONS: PET/CT detects more bone marrow involvement in DLBCL and HL compared with BMB. Its good concordance with BMB makes it a complementary technique, as it helps select the biopsy site in cases with negative results. PMID- 23640216 TI - Multiple liver amoebic abscesses detected on FDG PET/CT. AB - We report a case of liver amoebic abscesses in a 58-year-old man referred for a FDG PET/CT with an initial diagnosis of secondary hepatic lesions. This patient, coming from Sri Lanka, presented with fever and shivers, pain in the right flank, vomiting, and diarrhea for a month. The FDG PET/CT showed a hepatic heterogeneous uptake with multiple cold lesions surrounded by a faint hypermetabolism. As this result was not typical of hepatic metastases, a hepatic biopsy was performed leading to the diagnosis of amoebic abscess. PMID- 23640217 TI - Validation of 18F-FDG PET at conventional and delayed intervals for the discrimination of high-grade from low-grade gliomas: a stereotactic PET and MRI study. AB - AIM: The aim of this study was to validate 18F-FDG PET imaging for differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs). METHODS: Twenty-one patients with gliomas undergoing a stereotactic biopsy underwent PET scanning at conventional and delayed intervals, diagnostic and stereotactic MR examinations. To calculate the uptake at the biopsy site, a 2-mm voxel was selected. Uptake in this voxel was expressed as a percentage of the average uptake per voxel in the normal brain. The difference in uptake between HGG and LGG at conventional and late intervals and the difference in uptake difference between HGG and LGG at both intervals were analyzed using t tests as well as a mixed-model analysis of variance. RESULTS: At conventional intervals, uptake in LGG was 67% of that in the normal brain. Between early and late intervals, a significant decrease in uptake of 11% (+/-2.5%) was noted (P = 0.001). Uptake in HGG at conventional intervals was 138% of that in the normal brain. Between early and late intervals, a significant increase in uptake of 43% (+/-11%) was noted (P = 0.005). The difference in uptake between HGG and LGG was significant both at conventional and delayed intervals (P < 0.001). Moreover, the difference in uptake between both groups was significantly greater (31%) at delayed than at conventional intervals (2%) (P < 0.001). CONCLUSIONS: The results of this correlative study between tumor grade and 18F-FDG uptake both determined at the stereotactic biopsy site indicate that PET, particularly at delayed intervals, is valid for discriminating LGG from HGG. PMID- 23640218 TI - 18F-FDG PET/CT metabolic activity assessment in infective and neoplastic diseases: a patient with systemic hydatidosis and concomitant Burkitt lymphoma. AB - We report a case of a 73-year-old-man with systemic hydatidosis and concomitant Burkitt lymphoma. He came at our attention for fever and weight loss suspected for parasitic cyst discharge and also for lymphoproliferative disorder. We performed US, which showed disseminated parasitic cysts. CECT showed parasitic cysts and also several abdominal and thoracic lymphnodes and adrenal hypodense tissue. 18F-FDG PET/CT was performed and showed lack of 18F-FDG uptake in cysts and high 18F-FDG uptake in lymphnodes and adrenal glands. These findings permitted us to exclude the cyst discharge, to localize a site for biopsy, and to define and stage the Burkitt lymphoma. PMID- 23640219 TI - Granulosa cell tumor of the ovary with high FDG uptake. AB - Granulosa cell tumor (GCT) of the ovary is a rare tumor accounting for 2%-5% of ovarian malignancies. Although the usefulness of 18F-FDG PET/CT is well demonstrated in the staging and follow-up of the great majority of ovarian cancers, GCTs are known to cause false-negative results on FDG PET because of very low FDG avidity. We present a case of a GCT in which an 18F-FDG PET/CT proved very useful in the detection of recurrence. PMID- 23640220 TI - 18F-fluorothymidine PET is a potential predictive imaging biomarker of the response to gemcitabine-based chemotherapeutic treatment for recurrent ovarian cancer: preliminary results in three patients. AB - In order to establish early and precise methods for evaluating the effect of secondary chemotherapy in patients with recurrent ovarian cancer, both the clinical course of 3 women treated with gemcitabine-based secondary chemotherapy and the potential for early and accurate evaluation of the secondary chemotherapeutic effect of 18F-fluorothymidine (FLT) PET are reported. Standard uptake value with FLT PET decreased earlier than with 18F-fluorodeoxyglucose PET and was better correlated with a reduction in size as measured by CT. FLT PET could become a new standard for monitoring response to gemcitabine-based secondary chemotherapy treatment for recurrent ovarian cancer. PMID- 23640221 TI - Differential washout of FDG activity in two different inflammatory lesions: implications for delayed imaging. AB - We describe the changes of FDG uptake in different inflammatory lesions on multiple time point FDG PET/CT. FDG uptake in granulomatous lesions was more intense and focal, with higher intensity on delayed images. In contrast, FDG uptake in chronic arthritic joint inflammation was diffuse and mild, without significant change over time, while FDG uptake in nonarthritic joints was at near background level with decreased activity on delayed images. The retention index was significantly higher in patients with granulomatous lesions than that in other groups. Our finding indicates differential FDG uptake and clearance in active granulomas versus chronic inflammation. PMID- 23640222 TI - Recruitment of new physicians, part II: the interview. AB - A careful, expertly done recruitment process is very important in having a successful group. Selecting a search committee, deciding what characteristics the group wants in a new person, evaluating the candidate's curriculum vitae, speaking to the individual on the phone or during a meeting, and calling references are important steps in selecting the top candidates for a group. The interview at the practice site is the next step, and it is critical. Many tips for planning and conducting a successful interview are given in this article. PMID- 23640223 TI - Radionuclide shunt patency study for suspected ventriculoatrial shunt malfunction. AB - OBJECTIVE: Radionuclide shunt studies have been used for decades to evaluate intracranial shunt patency (SP); however, the methodology is neither standardized nor well validated. The purpose of this study was to determine the clinical utility of radionuclide ventriculoatrial (VA) SP study for diagnosis of suspected shunt malfunction. METHODS: A retrospective review was undertaken of all patients who had a VA radionuclide SP study between 2001 and 2009. All had a 20-minute gamma camera acquisition (1 min/frame) immediately following injection of 99mTc DTPA into the shunt reservoir. Time-activity curves were generated and a half time (T1/2) of emptying quantified. The results were correlated with the final clinical diagnoses. RESULTS: Forty-nine studies in 40 adult patients with a minimum of 6 months' follow-up were analyzed. Thirteen shunt studies had a T1/2 of 3.9 to 8.0 minutes, had final diagnosis of normal functioning shunt, and did not need revision surgery for a mean follow-up of 15.1 months. Fourteen patient studies had a T1/2 of less than 3.9 minutes; 13 had final diagnosis of overdraining shunts, and 1 required revision surgery. Twenty-two had a T1/2 longer than 8 minutes: 13 had final diagnosis of shunt obstruction, 4 had overdrainage, and 5 had underdrainage. CONCLUSIONS: The radionuclide SP study is valuable for evaluation of VA SP. Results can be interpreted using a single variable (T1/2). T1/2 of 3.9 to 8 minutes indicates a patent shunt; T1/2 less than 3.9 minutes is consistent with overdrainage. T1/2 of >8 requires further evaluation to differentiate between obstruction and overdrainage/underdrainage. PMID- 23640224 TI - Easy-to-use online software package for internal dose assessment after radionuclide treatment in clinical routine. AB - BACKGROUND: Internal dose assessment after radionuclide therapy is usually performed using home-made software packages. The dose assessment includes image registration, region-of-interest drawing, time-activity curve generation, and manual calculation of residence times followed by dose calculation with the OLINDA/MIRD software. The drawback of these methods is that several steps have to be performed using various software products possibly installed on different workstations. The aforementioned approaches are error-prone as well as difficult and time-consuming. In this article, we present a commercial software package that implements all the required dose calculation steps in 1 application, which greatly facilitates the internal dose assessment. METHODS AND RESULTS: The workflow of the newly developed software package "Hybrid Dosimetry" proceeds from automatic image registration to region-of-interest drawing, followed by time activity curve fitting and dose calculation according to the MIRD method. The software is available online and can be run on independent computers using images in the common DICOM format. We used the package for internal dosimetry of 8 patients treated with Lu-DOTATATE and compared the results with manual dose calculation. CONCLUSIONS: The online software package presented is platform independent and allows fast dose calculations. The results obtained with the new package were in perfect agreement with manual methods. PMID- 23640225 TI - Ipilimumab-induced immunomediated adverse events: possible pitfalls in (18)F-FDG PET/CT interpretation. AB - A 42-year-old woman underwent resection of a high-risk melanoma of the right thigh. Adjuvant treatment with ipilimumab was then started within a phase III randomised, double-blind clinical trial. F-FDG PET/CT scan showed intense uptake in mediastinal hilar lymph nodes, bilaterally, and in rectus abdominis muscle. Biopsy at the abdominal wall revealed a chronic granulomatous inflammation. After oral steroid treatment, all the areas of abnormal tracer uptake disappeared. Ipilimumab can induce inflammatory immunomediated reactions that should be taken into account to avoid misinterpretation. PMID- 23640226 TI - Pediatric presentation of splenic marginal zone lymphoma on FDG PET/CT scan. AB - Splenic marginal zone lymphoma (SMZL) comprises about 1% of B-cell lymphomas and typically occurs after the age of 50 years. Pediatric SMZL is very rare, and no FDG PET/CT imaging of the disease has been reported. In the current study, a 4 year-old boy with biopsy-proven SMZL had FDG PET/CT for staging, which showed increased metabolic activity in the spleen and left cervical lymph nodes. A second FDG PET/CT for evaluation of treatment response showed complete resolution of abnormal FDG uptake in the nodes and spleen with decrease in size of the nodes. PMID- 23640227 TI - 68Ga-DOTANOC somatostatin receptor PET-CT imaging in multiple myeloma. AB - Multiple myeloma cells express somatostatin receptors, and somatostatin receptor scintigraphy with 111In-pentetreotide has been used for imaging multiple myeloma with variable success. We here present 68Ga-DOTANOC somatostatin receptor PET-CT findings in a 57-year-old man with multiple myeloma. PET-CT showed 2 expansile lytic lesions with increased 68Ga-DOTANOC. This case highlights the potential use of 68Ga-DOTANOC PET-CT as an alternative imaging modality in multiple myeloma. PMID- 23640228 TI - Dramatic change in 18F-FDG uptake in a sarcoidosis case showing spontaneous recovery. AB - A 47-year-old man with treatment-naive sarcoidosis underwent 18F-FDG PET/CT. The image revealed clearly abnormal uptakes in his lymph nodes, muscles, and lungs, consistent with lesions of sarcoidosis. The patient had no symptoms and was under observation without treatment for sarcoidosis. At a 2-year follow-up, he underwent another 18F-FDG PET/CT scan, which revealed that several lesions with abnormal FDG uptake had significantly decreased, and some lesions had completely disappeared. Because sarcoidosis frequently shows spontaneous recovery, FDG uptake may show spontaneously dynamic changes in the associated lesions. PMID- 23640229 TI - A rare case of solitary fibrous tumor of the adrenal gland detected by (18)F-FDG PET/CT. AB - A 33-year old man underwent an F-FDG PET/CT searching for the cause of a fever of unknown origin. F-FDG PET/CT incidentally detected a focal area of markedly increased radiopharmaceutical uptake corresponding to a 2.5-cm nodule in the right adrenal gland. Laboratory data ruled out the presence of a functioning adrenal lesion. All these findings were suggestive of adrenal malignancy. After right adrenalectomy, histology showed a benign solitary fibrous tumor of the adrenal gland. This case highlights that benign solitary fibrous tumor should be considered as possible false-positive F-FDG PET/CT finding for malignancy in evaluating adrenal incidentalomas. PMID- 23640230 TI - Isolated splenic metastasis of ovarian cancer detected with 18F-FDG PET/CT. AB - We report a case of isolated splenic metastasis from ovarian cancer detected with 18F-FDG PET/CT. A 66-year-old woman with ovarian cancer was referred for 18F-FDG PET/CT to determine the cause of elevated serum CA-125 levels about 48 months after surgery. 18F-FDG PET/CT showed focal, intense uptake in the spleen, with no other abnormal findings. A splenectomy was performed, and the lesion was confirmed as metastasis from ovarian cancer pathologically. PMID- 23640231 TI - Pheochromocytoma presenting with remote bony recurrence twenty years after initial surgery: detection with 68Ga-DOTANOC PET/CT. AB - Pheochromocytomas are rare tumors which can be malignant in 10% of cases. We present the case of a 75-year-old woman who presented with headache and palpitation for 1 year. She had a past history of right adrenalectomy for pheochromocytoma 20 years back. In between, the patient was asymptomatic. Twenty four-hour urinary vanillylmandelic acid was raised. Noncontrast CT and ultrasound of abdomen were unremarkable. The patient underwent 68Ga-DOTANOC PET/CT that showed metastasis to left ilium, which was confirmed on biopsy. PMID- 23640232 TI - Incidental focal uptake in oropharynx due to lingual thyroid on diagnostic 131I whole-body scan after total thyroidectomy. AB - After total thyroidectomy for papillary thyroid carcinoma, a 37-year-old woman underwent a 2-mCi (131)I whole-body scan which demonstrated focal uptake in the anterior neck and in the oropharynx. Preoperative contrast-enhanced neck computed tomography demonstrated a small enhancing nodule typical for ectopic thyroid at the tongue base. She was then treated with 150 mCi (131)I. Small asymptomatic lingual thyroid remnants typically do not affect high-dose (131)I therapy. PMID- 23640233 TI - Diffuse FDG uptake due to fat necrosis following transverse rectus abdominus myocutaneous (TRAM) flap reconstruction. AB - We report a case of a 57-year-old female patient with right breast invasive ductal carcinoma. Bilateral mastectomy and TRAM flap reconstructions were performed. Postoperatively, a palpable focus was identified within the left breast. PET/CT showed hypermetabolism throughout the reconstructed left breast, correlating with mixed fat attenuation and inflammatory soft tissue. MRI showed extensive fat necrosis/oil cyst formation in the left breast. As a TRAM flap reconstruction with fat-rich tissue can be damaged intraoperatively due to surgical manipulation, abnormal FDG uptake in this setting is more likely related to fat necrosis than recurrent tumor. PMID- 23640234 TI - A rare case of follicular dendritic cell sarcoma involving multiple bones. AB - A 36-year-old female patient with recurrent fever and abdominal pain for 20 days underwent a whole-body FDG PET/CT to detect the potential source of the fever. The images showed intense FDG uptake in multiple bones. Eventually, follicular dendritic cell sarcoma was diagnosed following the biopsy from the lesion in the left iliac bone. PMID- 23640235 TI - "Witch's milk" and 99mTc-pertechnetate uptake in neonatal breast tissue: an uncommon but not unexpected finding. AB - Milk coming from the breast of newborn is called "witch's milk", and it results from transplacental transfer of maternal hormones. We present a case of a 5-day old female neonate with secretion of "witch's milk", prominent breast nodules, and uptake of 99mTc-perchnetate in bilateral breast nodules on Meckel scan. Familiarity with this uncommon though not unexpected finding is needed to avoid confusion while interpreting Meckel scintigraphy. PMID- 23640236 TI - Less may be as good as more: feasible and effective method to differentiate gastric uptake solely on planar gallium scan in the era of SPECT/CT. AB - We presented a patient with abnormal focal accumulation of 67Ga in the left upper abdomen. After drinking water, we successfully identified the abnormal radioactivity that was from the stomach. Subsequent endoscopic examination did not reveal gastric pathological condition. Gastric accumulation of 67Ga may relate to pathological conditions or physiological uptake, confounding interpretation of 67Ga scintigraphy. Simple water ingestion method can rapidly identify gastric 67Ga uptake, and the shape of distended stomach can also help to differentiate pathological conditions from physiological uptake, which is especially helpful for a busy nuclear medicine department and for places where the SPECT/CT systems are not available. PMID- 23640237 TI - Gastric neuroendocrine carcinoma staged and followed with (18)F-FDG PET/CT--a report of 3 cases. AB - Gastric neuroendocrine carcinomas (NEC) are very rare, aggressive tumors of the stomach that are distinct from the more benign neuroendocrine tumors, sometimes referred to as "gastric carcinoids." We present 3 cases of gastric NEC representing various histological subtypes that were successfully staged and followed with F-FDG PET/CT, impacting therapeutic management in each case. PMID- 23640238 TI - Regional cerebral metabolic rate of glucose evaluation and clinical assessment in patients with idiopathic normal-pressure hydrocephalus before and after ventricular shunt placement: a prospective analysis. AB - PURPOSE: We prospectively evaluated the regional cerebral metabolic rate of glucose (CMRglu) before and after ventricular shunt placement in idiopathic normal-pressure hydrocephalus (iNPH) patients, to investigate whether some brain regions are more involved than others; we also correlated the individual variations of CMRglu with the clinical scale score assessment after shunting. METHODS: Twenty iNPH patients (12 men; mean age 73 +/- 9 years) underwent clinical scale score assessment and F-FDG PET-CT before and 1 week after shunting. RESULTS: Before shunting, CMRglu values were similar in right and left brain regions, as well as after shunting. After shunting, 17 of 20 iNPH patients were clinically improved; all scale scores decreased, and CMRglu significantly increased in all regions (P < 10). In 3 of 20 iNPH patients, the symptoms persisted, the scale scores did not change, and CMRglu increased only in 3 regions: left frontal, left putamen, and right thalamus. Before shunting, no difference in global CMRglu between clinically improved (n = 17) and not improved (n = 3) iNPH patients was found. After shunting, a significant (P = 0.01) correlation between individual variations of CMRglu and clinical assessment was found. CONCLUSIONS: These findings confirm that iNPH is a disease involving all cerebral regions almost in the same way, and shunt procedure has a similar effect on regional cerebral metabolism almost in the same way. Individual variations of CMRglu are more important than absolute values and correlate with clinical status after shunting. Clinical improvement depends not only on the capability to restore the cerebrospinal fluid dynamic, but also on the ability of cerebral parenchyma to recover the metabolic function. PMID- 23640239 TI - Incidental detection of clinically nondiagnosed inguinal hernia in (131)I whole body scan. AB - I whole-body bone scan was performed for an adult male patient after postradioactive iodine ablation of thyroid carcinoma. Besides the small thyroid remnants in the neck region, an incidental detection of left inguinal hernia was made in the scan, which was later confirmed by clinical examination. Despite the large size of the hernia, the patient was unaware of the condition. It can be concluded that, similar to other imaging procedures, incidental detection of unrelated clinical problems is possible in I scan also, and such early diagnosis prevents further complications that the patient may develop in the future. PMID- 23640240 TI - Breast implant foreign body reaction mimicking breast cancer recurrence on FDG PET/CT. AB - A woman with bilateral breast cancer treated with bilateral mastectomies, implant reconstructions, chemotherapy, and hormonal therapy underwent FDG PET/CT imaging. Imaging demonstrated sternal, nodal, and lung lesions which were stable or slowly increasing, as well as a parasternal chest wall mass which was enlarging much more rapidly and was excised. Pathology of the chest wall mass demonstrated only benign soft tissue with fat necrosis and foreign body giant cell reaction, without evidence of malignancy or implant rupture. This case demonstrates how a benign FDG-avid foreign body reaction, induced by an intact breast prosthesis, could easily be mistaken for malignancy. PMID- 23640241 TI - Nodular fasciitis on (18)F-FDG PET. PMID- 23640243 TI - Exercise training attenuates postoperative pain and expression of cytokines and N methyl-D-aspartate receptor subunit 1 in rats. AB - BACKGROUND: Exercise creates a variety of psychophysical effects, including altered pain perception. We investigated whether physical exercise reduces postincisional pain and cytokine and N-methyl-D-aspartate receptor 1 (NR1) expression in a rat model of skin/muscle incision and retraction (SMIR)-evoked pain. METHODS: Male Sprague-Dawley rats were divided randomly into 4 groups: sham operated, SMIR-sedentary (SS), SMIR-exercise, and sham operated-exercise. On postoperative day 8, trained rats started to run on a treadmill 55 min/d with an intensity of 18 meter/minute (m/min), 5 days per week for 4 weeks. NR1, tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) expressions in the spinal cord as well as mechanical hypersensitivity following SMIR surgery were assessed for 6 to 35 days. RESULTS: On postoperative day 6, SMIR-sedentary rats exhibited a marked hypersensitivity to von Frey stimuli. By contrast, SMIR operated rats undergoing exercise demonstrated a quick recovery of mechanical hypersensitivity. The levels of TNF-alpha, IL-6, and NR1 in the spinal cord were significantly increased in SS rats when compared with sham-operated rats on postoperative days 6, 21, and 35 after SMIR surgery. After the 4-week exercise intervention, the SMIR-exercise group showed lower NR1, TNF-alpha, and IL-6 expression in the spinal cord than those in the SS group. CONCLUSIONS: These results suggest that exercise training decreases persistent postsurgical pain caused by SMIR surgery. There appears to be a protective effect, probably relating to the decrease of NR1, TNF-alpha, and IL-6 expression in the spinal cord of SMIR rats, after exercise intervention. PMID- 23640244 TI - [Histopathology and microbiology of joint infections: extension of diagnostic safety in patients with chronic polyarthritis]. AB - BACKGROUND: It can be difficult to distinguish between synovitis due to rheumatism and synovitis due to a bacterial infection. Microbiological detection of bacteria is not always successful and the clinical significance of low virulent bacteria often remains uncertain. Therefore, the histopathological finding of inflammatory reactions is very important. STUDY DESIGN AND METHODS: From patients with clinically clear signs of infections and rheumatoid arthritis who underwent surgery between April and August 2011, samples were taken during surgery. Histopathological diagnosis was carried out by conventional enzyme and immunohistochemical techniques based on defined criteria of bacterial infection in tissues, synovial tissue and bone. RESULTS: A total of 20 patients were included, 10 males and 10 females with a mean age of 61.7 years. Staphylococcus aureus was the most commonly detected bacteria and in 4 cases bacteria could not be demonstrated. The correlation between the histopathological signs of an infection and microbiological detection of bacteria was 93.3 %. CONCLUSIONS: In patients with rheumatoid arthritis the combination of histopathology and microbiology significantly increased the safety of detecting an infection or contamination. PMID- 23640242 TI - Autobiographical memory, self, and stress-related psychiatric disorders: which implications in cancer patients? AB - Autobiographical memory refers to information and memories of personal life events, accumulated since childhood, which enable the construction of a feeling of identity and continuity. Autobiographical memory retrieval is a dynamic and reconstructive process, as mental representations change with the passage of time. This flexible aspect of memory is linked to one's changing self and aspirations over time, that evolve according to our personal status and environment. Hence, any breakdown in the continuity of life involves a distortion of memory. Such distortions can be observed in stress-related psychiatric disorders, such as major depression or post-traumatic stress disorder, where autobiographical memory retrieval is characterized by overgenerality (i.e., the tendency to recall generic memories rather than specific events in response to cue words). Such memory disorders can be observed at different degrees in cancer patients. We will report studies focusing on the above-mentioned psychiatric disorders and cancer, and will attempt to establish a relation with autobiographical memory disturbances. The better understanding of such memory deficits could permit new pathophysiological hypotheses to emerge. Recommendations for future research that will enhance understanding of the factors that contribute to autobiographical memory in cancer are suggested. PMID- 23640245 TI - Amiodarone monitoring practices in pediatric hospitals in the United States. AB - Laboratory monitoring of amiodarone therapy is recommended due to the high incidence of adverse events associated with the drug. The use of appropriate monitoring is unknown at pediatric hospitals. The Pediatric Health Information System database was queried during a 5-year period for all patients who received amiodarone while hospitalized. Use of thyroid function testing, hepatic function testing, electrocardiogram, pulmonary function testing, and chest X-ray for patients was identified. Incidence of individual monitoring tests and complete monitoring profile was identified and compared across patient demographic and clinical factors and pediatric hospital. A total of 1,703 patients met the study criteria, and the incidence of complete amiodarone monitoring for all patients was 7.6 %. The least common monitoring test performed was triiodothyronine at 19.4 %, and the most common was electrocardiogram at 89.7 %. Critically ill patients and neonates were more likely to have amiodarone monitoring. Considerable variation in monitoring practices between pediatric hospitals was identified. Monitoring of amiodarone therapy in patients admitted to pediatric hospitals is low. Future efforts to standardize care are warranted. PMID- 23640246 TI - Varicella-zoster virus-associated multifocal chorioretinitis in 2 boys. PMID- 23640247 TI - Synergic insulin sensitizing effect of rimonabant and BGP-15 in Zucker-obese rats. AB - Abdominal obesity is referred for as a common pathogenic root of multiple risk factors, which include insulin resistance, dyslipidemia, hypertension, and a pro atherogenic and pro-inflammatory state. Irrespective of its psychiatric side effects, rimonabant through blocking cannabinoid-1 receptor (CB1R) induces an increase in whole body insulin sensitivity. The aim of this work was to study the effect of selected doses of another insulin sensitizer compound BGP-15, and rimonabant on insulin resistance in Zucker obese rats with a promise of inducing insulin sensitization together at lower doses than would have been expected by rimonabant alone. We found that BGP-15 potentiates the insulin sensitizing effect of rimonabant. The combination at doses, which do not induce insulin sensitization by themselves, improved insulin signaling. Furthermore our results suggest that capsaicin-induced signal may play a role in insulin sensitizing effect of both molecules. Our data might indicate that a lower dose of rimonabant in the treatment of insulin resistance and type 2 diabetes is sufficient to administer, thus a lower incidence of the unfavorable psychiatric side effects of rimonabant are to be expected. PMID- 23640249 TI - Phenological differences among selected residents and long-distance migrant bird species in central Europe. AB - The phenological responses to climate of residents and migrants (short- and long distance) differ. Although few previous studies have focussed on this topic, the agree that changes in phenology are more apparent for residents than for long distance migrants. We analysed the breeding times of two selected residents (Sitta europaea, Parus major) and one long-distance migrant (Ficedula albicollis) from 1961 to 2007 in central Europe. The timing of the phenophases of all three bird species showed a significant advance to earlier times. Nevertheless, the most marked shift was observed for the long-distance migrant (1.9 days per decade on average in mean laying date with linearity at the 99.9% confidence level). In contrast, the shifts shown by the residents were smaller (1.6 days for S. europaea and 1.5 days for P. major also on average in mean laying date for both, with linearity at the 95% confidence level). Spearman rank correlation coefficients calculated for pairs of phenophases of given bird species in 20-year subsamples (e.g. 1961-1980, 1962-1981) showed higher phenological separation between the residents and the migrant. This separation is most apparent after the 1980s. Thus, our results indicate that the interconnections between the studied phenological stages of the three bird species are becoming weaker. PMID- 23640248 TI - miR-135a/b modulate cisplatin resistance of human lung cancer cell line by targeting MCL1. AB - microRNAs (miRNAs) are short non-coding RNA molecules, which post transcriptionally regulate genes expression and play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. Here, we investigated the possible role of miRNAs in the development of drug resistance in human lung cancer cell line. We found that miR 135a/b were downregulated while MCL1 was upregulated in A549/CDDP (cisplatin) cells, compared with the parental A549 cells. In vitro drug sensitivity assay demonstrated that overexpression of miR-135a/b sensitized A549/CDDP cells to cisplatin. The luciferase activity of MCL1 3'-untranslated region-based reporter constructed in A549/CDDP cells suggested that MCL1 was the direct target gene of miR-135a/b. Enforced miR-135a/b expression reduced MCL1 protein level and sensitized A549/CDDP cells to CDDP-induced apoptosis. Taken together, our findings first suggested that hsa-miR-135a/b could play a role in the development of CDDP resistance in lung cancer cell line at least in part by modulation of apoptosis via targeting MCL1. PMID- 23640251 TI - Labeling and tracking of human mesenchymal stem cells using near-infrared technology. AB - The recently developed near-infrared (NIR) light imaging technology combines low background noise with deep tissue penetration and readily allows imaging and tracking of NIR-labeled cells, following transplantation in small animal model of diseases. The real-time and longitudinal detection of grafted cells in vivo, as well as their rapid ex vivo localization, may further clarify graft interactions with the surrounding, in target and nontarget organs throughout the body, over time. The present chapter describes a protocol for (1) the efficient labeling of human mesenchymal stem cells (hMSCs) using a membrane intercalating dye, emitting in the NIR 815 nm spectrum; (2) the stereotaxic transplantation of NIR 815-hMSCs in rodent model of Parkinson's disease; and (3) the longitudinal in vivo detection of the grafted cells and the subsequent ex vivo imaging in selected tissues. PMID- 23640250 TI - Live imaging, identifying, and tracking single cells in complex populations in vivo and ex vivo. AB - Advances in optical imaging technologies combined with the use of genetically encoded fluorescent proteins have enabled the visualization of stem cells over extensive periods of time in vivo and ex vivo. The generation of genetically encoded fluorescent protein reporters that are fused with subcellularly localized proteins, such as human histone H2B, has made it possible to direct fluorescent protein reporters to specific subcellular structures and identify single cells in complex populations. This facilitates the visualization of cellular behaviors such as division, movement, and apoptosis at a single-cell resolution and, in principle, allows the prospective and retrospective tracking towards determining the lineage of each cell. PMID- 23640252 TI - Primary culture and live imaging of adult neural stem cells and their progeny. AB - Adult neural stem cells (NSC) generate neurons throughout life, but little is known about the sequence of events involved in the transition from NSC to neurons. Studying the intermediary steps involved in the specification of neuronal cells from NSCs requires observation of cells in real time. Here we describe a primary culture of the adult subependymal zone (SEZ) which allows for continuous live imaging to characterize the mode of cell division and lineage progression of adult NSCs and their progeny. To this end, cells are cultured at low density under adherent conditions and without growth factors. Under these conditions, NSCs display classical hallmarks of adult SEZ NSCs in vivo, such as astroglial marker expression and promoter activity, a slow cell cycle, and a predominantly neurogenic potential. Video time-lapse microscopy experiments using this cell preparation allow for studying the steps involved in the generation of fast-dividing precursors and neuroblasts from slow-dividing astroglia/NSCs. PMID- 23640253 TI - Micro-CT technique for three-dimensional visualization of human stem cells. AB - Micro-CT offers high spatial resolution of the distribution of stem cells and provides rapid reconstruction of 3D images and quantitative volumetric analysis. Together with real-time PCR analysis, micro-CT offers the possibility to obtain a quantification of the number of cells that are able to migrate from the bloodstream inside the muscular tissues. Here, we studied for the first time the kinetics of the human cells injected into the femoral artery of DMD animal model. It is fundamental to determine whether the cells disseminate and entrap only within the capillary system of downstream muscles and/or they are able to reach the non-injected muscles and other organs through blood flow. The efficient transplantation of stem cells to dystrophic-deficient muscle reinforced the utility of intra-arterial delivery of cells as a viable approach for cell-based clinical therapies of neuromuscular diseases. PMID- 23640254 TI - Conversion of primordial germ cells to pluripotent stem cells: methods for cell tracking and culture conditions. AB - Primordial germ cells (PGCs) are unipotent cells committed to germ lineage: PGCs can only differentiate into gametes in vivo. However, upon fertilization, germ cells acquire the capacity to differentiate into all cell types in the body, including germ cells. Therefore, germ cells are thought to have the potential for pluripotency. PGCs can convert to pluripotent stem cells in vitro when cultured under specific conditions that include bFGF, LIF, and the membrane-bound form of SCF (mSCF). Here, the culture conditions which efficiently convert PGCs to pluripotent embryonic germ (EG) cells are described, as well as methods used for identifying pluripotent candidate cells during culture. PMID- 23640255 TI - High-content imaging and analysis of pluripotent stem cell-derived cardiomyocytes. AB - Human pluripotent stem cells (hPSC) are investigated as a source of authentic human cardiac cells for drug discovery and toxicological tests. Cell-based assays using automated fluorescence imaging platform and high-content analysis characterize hypertrophic and toxicity profiles of compounds in hPSC-derived cardiomyocytes (hPSC-CM) at the cellular and subcellular levels. In purified population of hPSC-CM loaded with cell tracer probe and cell death markers, both hypertrophic and toxicity profiles can be assessed in live cardiomyocyte cultures. Alternatively, in non-purified cultures of hPSC-CM, hypertrophy, proliferation, and cell death assays can be performed specifically in the cardiomyocyte subpopulation using antibodies directed against cardiac proteins and a combination of cell death- and proliferation-specific fluorescent probes. PMID- 23640256 TI - Noninvasive imaging of myocardial blood flow recovery in response to stem cell intervention. AB - The recovery of myocardial blood flow is a major indicator of the effectiveness of cell-based therapies for ischemic heart diseases including myocardial infarction. Blood flow (also called perfusion) of the heart muscle can be noninvasively measured via imaging methods such as ultrasound, positron emission tomography (PET), or magnetic resonance imaging (MRI). Here, we describe an MRI technique, namely, spin labeling, to measure the volumetric blood flow (mL/min/g) in the heart. Specifically, we demonstrate how impaired blood flow in the infarcted region of the heart was recovered transiently (>= 2 weeks) after the injection of endothelial progenitor cells. PMID- 23640257 TI - Molecular imaging and tracking stem cells in neurosciences. AB - Stem cell transplantation is a promising new therapeutic option in different neurological diseases. However, it is not yet possible to translate its potential from animal models to clinical application. One of the main problems of applying stem cell transplantation in clinical medium is the difficulty of detection, localization, and examination of the stem cells in vivo at both cellular and molecular levels. State-of-the-art molecular imaging techniques provide new and better means for noninvasive, repeated, and quantitative tracking of stem cell implant or transplant. From initial deposition to the survival, migration, and differentiation of the transplant/implanted stem cells, current molecular imaging methods allow monitoring of the infused cells in the same live recipient over time. The present review briefly summarizes and compares these molecular imaging methods for cell labeling and imaging in animal models as well as in clinical application and sheds light on consecutive new therapeutic options if appropriate. PMID- 23640258 TI - Single-nucleotide polymorphisms in genes encoding for CC chemokines were not associated with the risk of non-Hodgkin lymphoma. AB - BACKGROUND: Chemokines play a pivotal role in immune regulation and response, and previous studies suggest an association between immune deficiency and non-Hodgkin lymphoma (NHL). METHODS: We evaluated the association between NHL and polymorphisms in 18 genes (CCL1, CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL18, CCL20, CCL24, CCL26, CCR1, CCR3, CCR4, CCR6, CCR7, CCR8, and CCR9) encoding for the CC chemokines using data from a population-based case-control study of NHL conducted in Connecticut women. RESULTS: CCR8 was associated with diffuse large B cell lymphoma (DLBCL; P = 0.012), and CCL13 was associated with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL; P = 0.003) at gene level. After adjustment for multiple comparisons, none of the genes or single nucleotide polymorphisms (SNP) were associated with risk of overall NHL or NHL subtypes. CONCLUSIONS: Our results suggest that the genes encoding for CC chemokines are not significantly associated with the risk of NHL, and further studies are needed to verify these findings. IMPACT: Our data indicate that CC chemokine genes were not associated with NHL risk. PMID- 23640259 TI - Catalase and superoxide dismutase activities and the total protein content of protocorm-like bodies of Dendrobium sonia-28 subjected to vitrification. AB - Dendrobium sonia-28 is an important ornamental orchid in the Malaysian flower industry. However, the genus faces both low germination rates and the risk of producing heterozygous progenies. Cryopreservation is currently the favoured long term storage method for orchids with propagation problems. Vitrification, a frequently used cryopreservation technique, involves the application of pretreatments and cryoprotectants to protect and recover explants during and after storage in liquid nitrogen. However, cryopreservation may cause osmotic injuries and toxicity to cryopreserved explants from the use of highly concentrated additives, and cellular injuries from thawing, devitrification and ice formation. Reactive oxygen species (ROS), occurring during dehydration and cryopreservation, may also cause membrane damage. Plants possess efficient antioxidant systems such as the superoxide dismutase (SOD) and catalase (CAT) enzymes to scavenge ROS during low temperature stress. In this study, protocorm like bodies (PLBs) of Dendrobium sonia-28 were assayed for the total protein content, and both SOD and CAT activities, at each stage of a vitrification exercise to observe for deleterious stages in the protocol. The results indicated that cryopreserved PLBs of Dendrobium sonia-28 underwent excessive post-thawing oxidative stress due to decreased levels of the CAT enzyme at the post-thawing recovery stage, which contributed to the poor survival rates of the cryopreserved PLBs. PMID- 23640260 TI - Rhamnolipids production by multi-metal-resistant and plant-growth-promoting rhizobacteria. AB - The biosurfactant-producing Pseudomonas aeruginosa A11, with plant-growth promoting (PGP) and multi-metal-resistant (MMR) features was isolated from the rhizosphere of a wild plant Parthenium hysterophorus. The strain A11 was able to utilize glycerol as a carbon source and produce 4,436.9 mg/L of biosurfactant after 120 h of incubation. The biosurfactants was characterized as rhamnolipids (RLs) by thin layer chromatography, Fourier transform infrared spectroscopy, nuclear magnetic resonance, and liquid chromatography-mass spectrometry analysis. Eight different RLs congeners were detected with RhaRhaC10C10 being most abundant. The purified rhamnolipid, dirhamnolipid, and monorhamnolipid reduced the surface tension of water to 29, 36, and 42 mN/m with critical micelle concentration of 83, 125, and 150 mg/L, respectively. The strain A11 demonstrated resistance against all the metals detected in rhizosphere except Hg and Ni. The strain A11 also possessed plant-growth-promoting features like siderophores, hydrogen cyanide, catalase, ammonia production, and phosphate solubilization. The dirhamnolipids formed crystals upon incubation at 4 degrees C, thus making separation of dirhamnolipids easy. Biosurfactant-producing ability along with MMR and PGP traits of the strain A11 makes it a potential candidate for application in the bacterial assisted enhancement of phytoremediation of heavy-metal contaminated sites. PMID- 23640261 TI - Production of microbial rhamnolipid by Pseudomonas aeruginosa MM1011 for ex situ enhanced oil recovery. AB - Recently, several investigations have been carried out on the in situ bacteria flooding, but the ex situ biosurfactant production and addition to the sand pack as agents for microbial enhanced oil recovery (MEOR) has little been studied. In order to develop suitable technology for ex situ MEOR processes, it is essential to carry out tests about it. Therefore, this work tries to fill the gap. The intention of this study was to investigate whether the rhamnolipid mix could be produced in high enough quantities for enhanced oil recovery in the laboratory scale and prove its potential use as an effective material for field application. In this work, the ability of Pseudomonas aeruginosa MM1011 to grow and produce rhamnolipid on sunflower as sole carbon source under nitrogen limitation was shown. The production of Rha-C10-C10 and Rha2-C10-C10 was confirmed by thin-layer chromatography and high-performance liquid chromatography analysis. The rhamnolipid mixture obtained was able to reduce the surface and interfacial tension of water to 26 and 2 mN/m, respectively. The critical micelle concentration was 120 mg/L. Maximum rhamnolipid production reached to about 0.7 g/L in a shake flask. The yield of rhamnolipid per biomass (Y RL/x ), rhamnolipid per sunflower oil (Y RL/s ), and the biomass per sunflower oil (Y x/s ) for shake flask were obtained about 0.01, 0.0035, and 0.035 g g(-1), respectively. The stability of the rhamnolipid at different salinities, pH and temperature, and also, its emulsifying activity has been investigated. It is an effective surfactant at very low concentrations over a wide range of temperatures, pHs, and salt concentrations, and it also has the ability to emulsify oil, which is essential for enhanced oil recovery. With 120 mg/L rhamnolipid, 27 % of original oil in place was recovered after water flooding from a sand pack. This result not only suggests rhamnolipids as appropriate model biosurfactants for MEOR, but it even shows the potential as a biosurfactant of choice for actual MEOR applications. PMID- 23640262 TI - Two-staged temperature and agitation strategy for the production of transglutaminase from a Streptomyces sp. isolated from Brazilian soils. AB - Transglutaminase catalyzes the cross-linking reaction between a glutamine residue and a free amine residue of proteins leading to the formation of protein aggregates. In this research, the effects of temperature, agitation, and aeration on the production of transglutaminase in a bench reactor by a newly isolated Streptomyces sp. from Brazilian soils were investigated using a factorial experimental design. The parameters evaluated influenced the enzyme production, and the data showed that the best conditions to enhance cell growth were different from those leading to enhanced transglutaminase production. Thus, a temperature and agitation shift strategy was adopted to increase transglutaminase productivity. The temperature and agitation were first set at 34 degrees C and 350 rpm, respectively, and after 24 h decreasing to 26 degrees C and 150 rpm until the end of fermentation. The transglutaminase activity obtained was 2.18 U/mL after 42 h of fermentation, which was twice than that obtained using a constant temperature and agitation fermentation strategy. PMID- 23640263 TI - Three-phase partitioning as a rapid and easy method for the purification and recovery of catalase from sweet potato tubers (Solanum tuberosum). AB - Three-phase partitioning (TPP) was used to purify and recover catalase from potato crude extract. The method consists of ammonium sulfate saturation, t butanol addition, and adjustment of pH, respectively. The best catalase recovery (262 %) and 14.1-fold purification were seen in the interfacial phase in the presence of 40 % (w/v) ammonium sulfate saturation with 1.0:1.0 crude extract/t butanol ratio (v/v) at pH 7 in a single step. The sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the enzyme showed comparatively purification and protein molecular weight was nearly found to be 56 kDa. This study shows that TPP is a simple, economical, and quick method for the recovering of catalase and can be used for the purification process. PMID- 23640264 TI - Sulfide-oxidizing autotrophic denitrification: an evaluation for nitrogen removal from anaerobically pretreated domestic sewage. AB - Nitrogen removal from effluents of anaerobic reactors using conventional nitrification/denitrification processes depends on the availability of electron donors for denitrification. As sulfide is normally present in such effluents, autotrophic denitrification using sulfide can be an alternative to avoid or reduce the requirements of exogenous organic carbon sources. This study evaluated the application of sulfide-oxidizing autotrophic denitrification to anaerobically pretreated domestic sewage. A denitrifying reactor was fed with a mixture, at different proportions, of anaerobically pretreated (containing sulfides and residual organic matter) and nitrified (containing nitrates) effluents produced by reactors treating synthetic domestic sewage. Autotrophic denitrification was responsible for most of the nitrogen removal and coexisted with heterotrophic activity, resulting in high denitrification efficiencies. Efficient denitrification could be attained at a molar NO3 (-)/S(2-) ratio of 2.1, higher than values reported before, and this represents an important parameter for the strategic application of the process. Under the experimental conditions studied, autotrophic denitrification showed to be an efficient and feasible alternative to conventional denitrification using exogenous electron donors. PMID- 23640265 TI - Chestnut shell as unexploited source of fermentable sugars: effect of different pretreatment methods on enzymatic saccharification. AB - Chestnut shell (CS) is an agronomic residue mainly used for extraction of antioxidants or as adsorbent of metal ions. It also contains some polysaccharide that has not been considered as potential source of fermentable sugars for biofuel production until now. In this study, the effect of different pretreatment methods on CS was evaluated in order to obtain the greatest conversion of cellulose and xylan into fermentable sugars. Hot acid impregnation, steam explosion (acid-catalysed or not), and aqueous ammonia soaking (AAS) were selected as pretreatments. The pretreated biomass was subjected to saccharification with two enzyme cocktails prepared from commercial preparations, and evaluation of the best pretreatment and enzyme cocktail was based on the yield of fermentable sugars produced. As AAS provided the best result after preliminary experiments, enhancement of sugar production was attempted by changing the concentrations of ammonium hydroxide, enzymes, and CS. The optimal pretreatment condition was 10 % ammonium hydroxide, 70 degrees C, 22 h with CS at 5 % solid loading. After saccharification of the pretreated CS for 72 h at 50 degrees C and pH 5.0 with a cocktail containing cellulase (Accellerase 1500), beta-glucosidase (Accellerase BG), and xylanase (Accellerase XY), glucose and xylose yields were 67.8 and 92.7 %, respectively. PMID- 23640266 TI - Bilateral endogenous fungal endophthalmitis. AB - Endogenous endophthalmitis is a rare and severe intraocular infection which can be vision-threatening. We describe a case of bilateral fungal endogenous endophthalmitis in a 64-year-old male which was successfully treated with systemic administration of fluconazole followed by pars plana vitrectomy with an intravitreous injection of amphotericin B. PMID- 23640267 TI - Iridodialysis repair: stroke and dock technique. AB - Iridodialysis needs to be repaired if it is symptomatic. We describe a new bimanual technique for repair of iridodialysis where a bent 26 gauge (G) needle is used to lift the peripheral iris first. The bevel of the needle then acts as a platform for the 9-0 prolene suture with a straight needle to enable unfolding of the curled up iris by stroking before finally docking the suture needle into the bevel of the 26 G needle. This technique ensures precise scleral fixation. PMID- 23640268 TI - Platinum CCC-NHC benzimidazolyl pincer complexes: synthesis, characterization, photostability, and theoretical investigation of a blue-green emitter. AB - The recently reported metallation/transmetallation route for the synthesis of CCC bis(NHC) pincer ligand architectures was extended to 1,3-bis(3' (trimethylsilylmethyl)-benzimidizol-1'-yl)benzene. The precursor was metallated with Zr(NMe2)4 and transmetallated to Pt using [Pt(COD)Cl2]. This Pt complex was found to resist photobleaching under UV irradiation in ambient conditions. Density functional theory (DFT) computations were used to generate the emission spectrum of the complex and reveal that this spectrum is the result of a transition from the triplet excited state (T1) to the ground state (S0). The Pt complex's molecular structure was determined by X-ray crystallography. The UV-vis absorption and emission spectra in solution and the solid-state emission spectra are reported. The solid-state photostability data and the radiative lifetime is also reported. PMID- 23640269 TI - Contemporary drug treatment of infective endocarditis. AB - Infective endocarditis (IE) occurs at a rate of approximately 0.9-6.2 per 100,000 people per year and is associated with a high morbidity and mortality despite advancements in antibiotic and surgical treatments. The general approach to the treatment of IE is initial clinical stabilization, early acquisition of blood cultures, and definitive medical and/or surgical treatment. Surgical consultation should be obtained early when indicated in order to determine the best treatment approach for each individual patient. Surgery is indicated in most cases of prosthetic valve endocarditis, Staphylococcus aureus endocarditis, fungal endocarditis, and endocarditis associated with large vegetations (>=10 mm). Initial antibiotic therapy for IE should be targeted to the culprit microorganism; however, in some cases, empiric therapy must be initiated prior to definitive culture diagnosis. Empiric antibiotics should be targeted toward the most likely pathogens, including staphylococci, streptococci, and enterococci species. Here we discuss the recommended antibiotic regimens for the most common causes of IE as indicated by the American Heart Association and European Society of Cardiology. In 2008, the ACC/AHA published guideline updates on the treatment of valvular heart disease, which included a focused update on endocarditis prophylaxis. According to the most recent guidelines, the number of patients who require antibiotic prophylaxis has decreased substantially. Treatment of IE should be targeted toward the causative microorganism and must be based on the type and location of valve involved (native, prosthetic, left or right sided), the clinical status of the patient, and the likelihood for clinical success. This requires a collaborative effort from multiple medical specialties including infectious disease specialists, cardiologists, and cardiothoracic surgeons. PMID- 23640271 TI - Note from editor-in-chief. PMID- 23640272 TI - The tenacity and tenuousness of hope: parental experiences of hope when their child has a poor cancer prognosis. AB - BACKGROUND: The meaning and role of hope in parents of children with life threatening illnesses remain relatively unstudied. OBJECTIVE: The objectives of this study were to explore parental hope when a child is being treated for a malignancy resistant to treatment and to identify facilitators and barriers to maintaining hope in this context. METHODS: Thirty-five parents of children with difficult-to-treat cancer were interviewed 3 months after diagnosis. Line-by-line coding of transcripts was used to establish categories and themes. Constant comparison was used to examine relationships within and across codes and categories. RESULTS: Parental hope was related to the child's cure and future. The concept, however, oscillated between being tenacious and robust, and tenuous and elusive, depending on how the child was responding to treatment and the psychosocial context. Focusing on positive outcomes and experiences, spirituality, and social support facilitated being hopeful. Awareness of negative outcomes, information overload, physical and emotional depletion, and fear and uncertainty challenged parental hope. CONCLUSIONS: Developing a model that identifies the nature of parental hope as well as barriers and facilitators to maintaining hope shortly after childhood cancer diagnosis may assist healthcare professionals in supporting parents. IMPLICATIONS FOR PRACTICE: Understanding parental hope may assist healthcare professionals to avoid overloading parents with too much information at once. Healthcare professionals can also ensure that social support from family, community, and the medical center is available for parents and that their physical and emotional needs are being met to ensure that they maintain hope to best care for their child with cancer. PMID- 23640274 TI - A new framework to accurately quantify soil bacterial community diversity from DGGE. AB - Denaturing gradient gel electrophoresis (DGGE) has been and remains extensively used to assess and monitor the effects of various treatments on soil bacterial communities. Considering only abundant phylotypes, the diversity estimates produced by this technique have been proven to be uncorrelated to true community diversity. The aim of this paper was to develop a framework to estimate a community's true diversity from DGGE. Developed using in silico DGGE profiles generated from published pyrosequencing datasets, this framework elongates the rank-abundance distributions (RADs) drawn by band quantification using the peak to-signal ratio (PSR) parameter, which was proven to be related to bacterial richness. The ability to compare DGGE-based diversity estimates to the true diversity of communities led to a unique opportunity to identify potential pitfalls when analyzing DGGE gels with commercial analysis software programs and gain insight into the process of DNA band clustering in the profiles. Bacterial diversity was compared through richness, Shannon, and Simpson's 1/D indices. Intermediate results demonstrated that, even though commercial gel analysis software programs were unable to produce consistent results throughout all samples, a newly developed Matlab-based framework unraveled the dominance profiles of communities from band quantification. Elongating these partial RADs using the PSRs extracted from the DGGE profiles chiefly made it possible to accurately estimate the true diversity of communities. For all the samples analyzed, the estimated Shannon and Simpson's 1/D were accurate at +/-10 %. Richness estimations were less accurate, ranging from -11 to 31 % of the expected values. The framework showed great potential to study the structure and diversity of soil bacterial communities. PMID- 23640273 TI - Positive muscle protein net balance and differential regulation of atrogene expression after resistance exercise and milk protein supplementation. AB - PURPOSE: Resistance exercise and amino acid availability are positive regulators of muscle protein net balance (NB). However, anabolic responses to resistance exercise and protein supplementation deserve further elucidation. The purpose was to compare intakes of whey, caseinate (both: 0.30 g/kg lean body mass), or a non caloric control after heavy resistance exercise on protein turnover and mRNA expressions of forkhead homeobox type O (FOXO) isoforms, muscle RING finger 1 (MuRF1), and Atrogin1 in young healthy males. METHODS: Protein turnover was determined by stable isotope-labeled leucine and femoral arteriovenous blood samples at rest and during 6-h recovery. Muscle biopsies were collected at -60 min (rest) and at 60, 210, and 360 min in the recovery period. RESULTS: During recovery, leucine NB was significantly higher in the protein groups compared to control (P < 0.001). Differences in leucine NB, rate of disappearance, and oxidation were observed in the early recovery period between whey and caseinate. FOXO1A and MuRF1 were upregulated at 60 and 210 min, and, in contrast, FOXO3 and Atrogin1 were downregulated at 210 and 360 min. For leucine rate of appearance and all FOXO and atrogene mRNA expressions, no differences were observed between groups. CONCLUSIONS: Whey and caseinate were equally superior to control in the 6 h recovery period and displayed temporal differences with whey having a fast and superior effect in the early part of the recovery period. Effects on mRNA expressions indicate different regulatory mechanisms on the ubiquitin ligases MuRF1 and Atrogin1 in recovery from heavy resistance exercise. PMID- 23640277 TI - Optimization of the modelling of longitudinal dose distributions for double scattered proton beams in a commercially-available treatment planning system. AB - The configuration of a treatment planning system (TPS) for double-scattering based proton therapy requires many user inputs. Most of these are either gathered during the routine collection of commissioning data, or can be supplied by the equipment vendor; however, this is not true of all. In this study we developed a technique both to (a) expedite the extraction of those undetermined TPS parameters related to the range modulator wheels that can only otherwise be obtained by the time-consuming process of trial-and-error, and (b) demonstrate how, for a commonly-employed, commercially-available TPS, the judicious determination of such parameters can be used to optimize the resultant modelling of longitudinal dose distributions delivered by a double scattering proton therapy system. Our technique is simple to implement, robust in nature and also provides insight allowing parameters that must be contrived in that model to be related directly to physical aspects of the beam delivery system. PMID- 23640275 TI - Diversity of planktonic and attached bacterial communities in a phenol contaminated sandstone aquifer. AB - Polluted aquifers contain indigenous microbial communities with the potential for in situ bioremediation. However, the effect of hydrogeochemical gradients on in situ microbial communities (especially at the plume fringe, where natural attenuation is higher) is still not clear. In this study, we used culture independent techniques to investigate the diversity of in situ planktonic and attached bacterial communities in a phenol-contaminated sandstone aquifer. Within the upper and lower plume fringes, denaturing gradient gel electrophoresis profiles indicated that planktonic community structure was influenced by the steep hydrogeochemical gradient of the plume rather than the spatial location in the aquifer. Under the same hydrogeochemical conditions (in the lower plume fringe, 30 m below ground level), 16S rRNA gene cloning and sequencing showed that planktonic and attached bacterial communities differed markedly and that the attached community was more diverse. The 16S rRNA gene phylogeny also suggested that a phylogenetically diverse bacterial community operated at this depth (30 mbgl), with biodegradation of phenolic compounds by nitrate-reducing Azoarcus and Acidovorax strains potentially being an important process. The presence of acetogenic and sulphate-reducing bacteria only in the planktonic clone library indicates that some natural attenuation processes may occur preferentially in one of the two growth phases (attached or planktonic). Therefore, this study has provided a better understanding of the microbial ecology of this phenol contaminated aquifer, and it highlights the need for investigating both planktonic and attached microbial communities when assessing the potential for natural attenuation in contaminated aquifers. PMID- 23640276 TI - Feedstocks affect the diversity and distribution of propionate CoA-transferase genes (pct) in anaerobic digesters. AB - Anaerobic digestion (AD) is an attractive microbiological technology for both waste treatment and energy production. Syntrophic acetogenic bacteria are an important guild because they are essential for maintaining efficient and stable AD operation. However, this guild is poorly understood due to difficulties to culture them. In this study, we developed specific PCR assays targeting the propionate-CoA transferase genes (pct) to investigate their diversity and distribution in several mesophilic anaerobic digesters and a bench-scale temperature-phased AD (TPAD) system. Phylogenetic analysis of sequenced pct amplicons revealed the occurrence of Syntrophobacter fumaroxidans and six other clusters of putative pct genes. Principal coordinate analysis (PCoA) showed that pct diversity and abundance were largely correlated to the feedstocks of the digesters, while little difference was seen between the granular and the liquid fractions of each digester or between the two digesters of the TPAD system. Cluster-specific qPCR analysis revealed major impact of feedstocks and fractions on the abundance of pct genes. Readily fermentable substrates such as sugar- or starch-rich feedstocks selected for pct genes (Cluster I) related to Syntrophobacter, while manure feedstock selected for pct clusters related to pct of Clostridium spp. These results suggest that propionate metabolism can be affected by feedstocks and partition differently between solid and liquid phases in digesters. The PCR assays developed in this study may serve as a tool to investigate propionate-oxidizing bacteria in anaerobic digesters and other anaerobic environments. PMID- 23640278 TI - Hypothalamitis: a diagnostic and therapeutic challenge. AB - To report an unusual case of biopsy-proven autoimmune hypophysitis with predominant hypothalamic involvement associated with empty sella, panhypopituitarism, visual disturbances and antipituitary antibodies positivity. We present the history, physical findings, hormonal assay results, imaging, surgical findings and pathology at presentation, together with a 2-year follow up. A literature review on the hypothalamic involvement of autoimmune hypophysitis with empty sella was performed. A 48-year-old woman presented with polyuria, polydipsia, asthenia, diarrhea and vomiting. The magnetic resonance imaging (MRI) revealed a clear suprasellar (hypothalamic) mass, while the pituitary gland appeared atrophic. Hormonal testing showed panhypopituitarism and hyperprolactinemia; visual field examination was normal. Pituitary serum antibodies were positive. Two months later an MRI documented a mild increase of the lesion. The patient underwent biopsy of the lesion via a transsphenoidal approach. Histological diagnosis was lymphocytic "hypothalamitis". Despite 6 months of corticosteroid therapy, the patient developed bitemporal hemianopia and blurred vision, without radiological evidence of chiasm compression, suggesting autoimmune optic neuritis with uveitis. Immunosuppressive treatment with azathioprine was then instituted. Two months later, an MRI documented a striking reduction of the hypothalamic lesion and visual field examination showed a significant improvement. The lesion is stable at the 2-year follow-up. For the first time we demonstrated that "hypothalamitis" might be the possible evolution of an autoimmune hypophysitis, resulting in pituitary atrophy, secondary empty sella and panhypopituitarism. Although steroid treatment is advisable as a first line therapy, immunosuppressive therapy with azathioprine might be necessary to achieve disease control. PMID- 23640279 TI - Chirality in DNA-pi-conjugated polymer supramolecular structures: insights into the self-assembly. AB - The self-assembly of DNA and pi-conjugated polyelectrolytes leads to chiral structures, with specific right- or left-handed assemblies ruled by the DNA sequence and topology. PMID- 23640280 TI - A combination of a dairy product fermented by lactobacilli and galactooligosaccharides shows additive effects on mineral balances in growing rats with hypochlorhydria induced by a proton pump inhibitor. AB - This study aimed to investigate the effects of a combination of a dairy product fermented by lactobacilli (DFL) and galactooligosaccharides (GOS) on mineral balances in growing rats with hypochlorhydria induced by a proton pump inhibitor (PPI). Three-week-old male rats were assigned to receive one of six diets: a control diet, control diets containing 1.6 or 5.0 % GOS, a DFL diet and DFL diets containing 1.6 or 5.0 % GOS for 9 days. From day 5 of the feeding period, half of the rats fed with control diets were subcutaneously administered with saline, whereas the remaining rats were administered with PPI for 5 days. Calcium (Ca), phosphorus (P), magnesium (Mg), iron (Fe) and zinc (Zn) balances were determined from days 6 to 9. PPI administration significantly decreased the apparent absorption of Ca and Fe and increased urinary P excretion, resulting in decreased Ca, Fe and P retention. GOS dose-dependently increased the apparent absorption of Ca, Mg and Fe and urinary Mg excretion and decreased urinary P excretion. DFL significantly increased the apparent absorption of Ca and Mg and urinary Mg excretion. The combination of DFL and GOS additively affected these parameters, resulting in increased Ca, P and Fe retention, and it further increased the apparent absorption and retention of Zn at 5.0 % GOS. In conclusion, the combination of DFL and GOS improves Ca, P and Fe retention in an additive manner and increases the Zn retention in growing rats with hypochlorhydria induced by PPI. PMID- 23640281 TI - Zinc and copper levels in bladder cancer: a systematic review and meta-analysis. AB - It is well documented that oxidative stress is involved in the pathogenesis of bladder cancer. Zinc (Zn) and copper (Cu) are important components of antioxidants. However, the association between Zn or Cu levels and bladder cancer remains elusive. The present study was designed to investigate the alteration of serum and urinary levels of Zn or Cu in bladder cancer patients compared with controls by performing a systematic review. We searched the PubMed, Embase, and Cochrane databases from January 1990 to March 2013 to identify studies that met our predefined criteria. Six studies were included. Bladder cancer patients demonstrated significantly lower levels of serum Zn (three studies, random effects standard mean deviation (SMD): -1.072, 95 % CI: -1.489 to -0.656, P <0.0001), markedly higher levels of serum Cu (three studies, random effects SMD: 1.069, 95 % CI: 0.302 to 1.836, P = 0.006) and urinary Zn (three studies, random effects SMD: 2.114, 95 % CI: 0.328 to 3.899, P = 0.02) compared with controls. No obvious difference was observed in urinary Cu levels between bladder cancer patients and controls (two studies, random effects SMD: 0.153, 95 % CI: -0.244 to 0.55, P = 0.449). No evidence of publication bias was observed. In conclusion, the disorder of Zn and Cu is closely associated with bladder cancer. Frequent monitoring and early intervention should be recommended. PMID- 23640282 TI - Characterization of surface ligands on functionalized magnetic nanoparticles using laser desorption/ionization mass spectrometry (LDI-MS). AB - Functionalized magnetic nanoparticles (MNPs) have been characterized by laser desorption/ionization mass spectrometry (LDI-MS). Quantitative information about surface ligand composition and structure for monolayer and mixed monolayer protected Fe3O4 and FePt NPs can be obtained rapidly with very little sample consumption. PMID- 23640283 TI - The design and realization of a large-area flexible nanofiber-based mat for pollutant degradation: an application in photocatalysis. AB - This work demonstrates a novel multifunctional nanofibrous mat for photocatalytic applications based on TiO2 nanocables functionalized by Ag nanoparticles and coated with a thin (~2 nm) graphitic shell. In this mat, which was realized by an electrospinning technique, each component serves a unique function: the carbon coating acts as both an adsorption material for capturing pollutants and as a charge-transfer material, the Ag nanoparticles act as a visible-light sensitizing agent and also as a charge-transfer material, finally the TiO2 nanocable mat acts as a UV sensitive photocatalytic matrix and as the flexible substrate for the other functional components. This multicomponent nanocable mat exhibits excellent photocatalytic activity under simulated solar irradiation for the degradation of model pollutants including RhB and phenol. The significant photocatalytic properties are attributed to the synergetic effect of the three functional components and the unique charge transport "freeway" property of the nanofibrous mat. In addition, the porous carbon coating infiltrated into the nanocable matrix endows the mat with excellent flexibility and enables robust, large-area (10 * 10 cm) fabrication, representing a significant advantage over previous brittle ceramic nanofibrous mat photocatalyst substrates. This study provides new insight into the design and preparation of an advanced, yet commercially practical and scaleable photocatalytic composite membrane material. The as-prepared photocatalytic mat might also be of interest in solar cell, catalysis, separation technology, biomedical engineering, and nanotechnology. PMID- 23640284 TI - Management of occult necrotic melanomas. PMID- 23640285 TI - What specific facets of executive function are associated with academic functioning in youth with attention-deficit/hyperactivity disorder? AB - The purpose of the study was to evaluate the relation between ratings of Executive Function (EF) and academic functioning in a sample of 94 middle-school aged youth with Attention-Deficit/Hyperactivity Disorder (ADHD; Mage = 11.9; 78 % male; 21 % minority). This study builds on prior work by evaluating associations between multiple specific aspects of EF (e.g., working memory, inhibition, and planning and organization) as rated by both parents and teachers on the Behavior Rating Inventory of Executive Function (BRIEF), with multiple academic outcomes, including school grades and homework problems. Further, this study examined the relationship between EF and academic outcomes above and beyond ADHD symptoms and controlled for a number of potentially important covariates, including intelligence and achievement scores. The EF Planning and Organization subscale as rated by both parents and teachers predicted school grades above and beyond symptoms of ADHD and relevant covariates. Parent ratings of youth's ability to transition effectively between tasks/situations (Shift subscale) also predicted school grades. Parent-rated symptoms of inattention, hyperactivity/impulsivity, and planning and organization abilities were significant in the final model predicting homework problems. In contrast, only symptoms of inattention and the Organization of Materials subscale from the BRIEF were significant in the teacher model predicting homework problems. Organization and planning abilities are highly important aspects academic functioning for middle-school-aged youth with ADHD. Implications of these findings for the measurement of EF, and organization and planning abilities in particular, are discussed along with potential implications for intervention. PMID- 23640286 TI - P2X(7) receptors in cerebral ischemia. AB - Cerebral ischemia is one of the most common diseases resulting in death and disability in aged people. It leads immediately to rapid energy failure, ATP depletion, and ionic imbalance, which increase extracellular ATP levels and accordingly activate P2X7 receptors. These receptors are ATP-gated cation channels and widely distributed in nerve cells, especially in the immunocompetent cells of the brain. Currently, interest in the roles of P2X7 receptors in ischemic brain injury is growing. In this review, we discuss recent research progress on the actions of P2X7 receptors, their possible mechanisms in cerebral ischemia, and the potential therapeutic value of P2X7 receptor antagonists which may provide a new target both for clinical and for research purposes. PMID- 23640287 TI - Development of PEGylated KMnF3 nanoparticles as a T1-weighted contrast agent: chemical synthesis, in vivo brain MR imaging, and accounting for high relaxivity. AB - Magnetic nanoparticles consisting of manganese-based T1-weighted contrast agents have rapidly achieved clinical application, however low proton relaxivity impedes further development. In this report, by analyzing nanoparticles' surface oxidation states we propose the possible reason for the low r1 relaxivity of common MnO nanoparticles and develop PEGylated fluoroperovskite KMnF3 nanoparticles as new T1-weighted contrast agents, which exhibit the highest longitudinal relaxivity (r1 = 23.15 mM(-1) s(-1)) among all the reported manganese-based T1-weighted contrast agents. We, for the first time, illustrate a typical example showing that the surface oxidation states of metal ions exposed on the nanoparticles' surfaces are able to influence not only the optical, magnetic, electronic or catalytic properties but also water proton longitudinal relaxivity when applied as an MRI contrast agent. Cytotoxicity tests demonstrate that the PEGylated KMnF3 nanoparticles are free from toxicity. Further in vivo MRI experiments distinctively depict fine anatomical features in brain imaging at a low dose of 5 mg of Mn per kg and possible removal from the kidneys due to their small size and biocompatibility. PMID- 23640288 TI - Serum prolidase may not accurately provide information to clinicians about the psoriasis activity. PMID- 23640289 TI - Study of an S = 1 Ni(II) pincer electrocatalyst precursor for aqueous hydrogen production based on paramagnetic 1H NMR. AB - A tridentate NNN Ni(II) complex, shown to be an electrocatalyst for aqueous H2 production at low overpotentials, is studied by using temperature-dependent paramagnetic (1)H NMR. The NMR T1 relaxation rates, temperature dependence of the chemical shifts, and dc SQUID magnetic susceptibility are correlated to DFT chemical shifts and compared with the properties of a diamagnetic Zn analogue complex. The resulting characterization provides an unambiguous assignment of the six proton environments in the meridionally coordinating tridentate NNN ligand. The demonstrated NMR/DFT methodology should be valuable in the search for appropriate ligands to optimize the reactivity of 3d metal complexes bound to attract increasing attention in catalytic applications. PMID- 23640290 TI - Results after wisdom tooth transplantation. A retrospective study. AB - Wisdom tooth transplants offer youth the possibility of biologically fixed tooth replacement in cases of premolar agenesis or premature loss of a molar. In the present study, 57 transplants of third molars were reviewed and evaluated retrospectively on preoperative findings (root growth stages, extraction sites, indication for transplantation), on postoperative clinical findings (local gingivitis, periodontal probing values, tooth mobility, percussion sound and percussion pain) and on radiological findings (tertiary build-up of dentin, osseous periradicular conditions, progress of root growth). Only the transplants which healed with a vital pulp and in a periodontally healthy state were considered successful. Upper and lower wisdom teeth having 50% to 75% root growth progression were transplanted. The postoperative follow-up observation period averaged 26.4 months. The success of a wisdom tooth transplantation was not influenced by the root growth stage (p = 1), the extraction location of wisdom teeth (p = 0.45), or the feasibility for a transplantation (p = 0.56). Three teeth showed pulpal necrosis with apical periodontitis and were counted as failures. The success rate was rather high with 54 out of 57 transplants (94.7%), therefore wisdom tooth transplantations, with careful selection of a suitable graft and its gentle removal, can be described as a good predictable treatment. PMID- 23640291 TI - Fibroblast growth factor receptor 2 expression may be involved in transformation of ovarian endometrioma to clear cell carcinoma of the ovary. AB - OBJECTIVE: The objective of this study was to determine the genes that may be associated with malignant transformation of ovarian endometrioma. METHODS: Endometriotic epithelial cells were isolated from tissues derived from chocolate cyst linings by laser capture microdissection. A Gene Chip Human Genome U133 Plus 2.0 Array was applied to evaluate levels of gene expression in 3 different groups of epithelial cells: epithelial cells of endometrioma, epithelial cells of endometrioma adjacent to clear cell carcinoma, and epithelial cells of clear cell carcinoma. As a validation assay, real-time reverse transcriptase-polymerase chain reaction and immunohistochemical analyses were performed. RESULTS: Gene expression analysis identified differential expressions among the 3 groups of epithelial cells. Using the classification of a signaling pathways database, 9 genes (12 gene probes) were selected from among 39 up-regulated genes indicating more than 2-fold higher expression between any comparisons of the 3 groups in the comprehensive microarray. Enhancement of fibroblast growth factor receptor 2 (FGFR2) gene expression was detected by microarray using 3 distinct probes. Gene and protein expression of FGFR2 differed significantly between epithelial cells of endometrioma and the epithelial component of clear cell carcinoma. CONCLUSIONS: We demonstrated that FGFR2 may play a significant role in the carcinogenesis of endometriosis and thus represents a potential therapeutic target. PMID- 23640292 TI - Should bevacizumab be continued after progression on bevacizumab in recurrent ovarian cancer? AB - OBJECTIVE: The optimal role of bevacizumab (Bev) in the treatment of ovarian cancer has not yet been established. Furthermore, it is unclear whether there is a benefit of Bev after progression on a Bev-containing regimen in ovarian cancer. The objective of this study was to compare response rates, progression-free survival (PFS), and overall survival between patients who were treated with chemotherapy and Bev after progression on Bev (BAB) versus patients who were treated with chemotherapy without Bev (CWOB). METHODS: We conducted a retrospective chart review of all patients who received treatment with Bev (with or without cytotoxic chemotherapy) for recurrent ovarian cancer at a single institution. Patients who received additional therapy after progression while on Bev were included. RESULTS: Forty-six patients were included (16 CWOB group and 30 BAB). The median number of previous chemotherapy regimens was 2.5 for CWOB compared with 4 for BAB (P = 0.11). Fifty-two percent of patients had an objective response to the first Bev regimen before progressing on Bev. Response rates for the regimen after progression on Bev were 19% (3/16) in the CWOB group and 23% (7/30) in the BAB group (P = 1). Twenty-five percent of the patients who responded to the first Bev regimen and 18% of those who did not respond to the first Bev regimen responded to the second Bev regimen (P = 0.72). The median PFS for patients in the CWOB group was 2.6 months (95% confidence interval [CI], 1.3 5 months), compared with 5.0 months (95% CI, 3.5-7.3 months) for patients in the BAB group (P = 0.01). Overall survival was similar, 9.4 months (95% CI, 5.0-12.0 months) for CWOB versus 8.6 months (95% CI, 5.8-15.5 months) for BAB (P = 0.19). One patient in the BAB group died of a bowel perforation. CONCLUSIONS: In patients previously treated with Bev for recurrent ovarian cancer, the subsequent addition of Bev to cytotoxic chemotherapy increased the PFS compared with patients not receiving a second course of Bev, but did so without an impact on overall survival. The response to the first Bev regimen did not predict whether a patient would respond again to the next Bev regimen. Randomized, larger studies will have to be performed to confirm this observation. PMID- 23640293 TI - Interobserver variability of the International Federation of Gynecology and Obstetrics staging in cervical cancer. AB - OBJECTIVE: The objective of this study was to assess the interobserver variability of pelvic examination under anesthesia (EUA) in cervical cancer. METHODS: Subsequent patients undergoing a staging procedure under anesthesia for primary cervical cancer were enrolled in the study. All clinicians assessed "blinded" tumor size, and the involvement of vagina, parametria, sacrouterine ligaments, pelvic sidewalls, bladder, and/or rectum. Items were scored varying from 1 ("certainly no involvement"), 2 ("not sure about involvement"), to 3 ("involvement"). Each individual decided on the International Federation of Gynecology and Obstetrics (FIGO) stage; also, the urge for imaging and treatment proposal were accounted for. Final FIGO staging was obtained by consensus of the team. Investigators were classified as experienced after more than 50 EUAs. All others were classified less experienced. The free-marginal kappa values between experienced and less experienced investigators were calculated for all previously mentioned items. RESULTS: Between February 2009 and December 2010, a total of 86 patients were enrolled. Among experienced investigators, a moderate interobserver agreement was found with regard to FIGO stage (free-marginal kappa value of 0.49) and an excellent interobserver agreement on their proposed therapy (free-marginal kappa value of 0.84). A lower level of agreement was found when comparing experienced with less experienced investigators: only a slight level of agreement on FIGO stage and a substantial agreement on their therapy proposal (free marginal kappa values of 0.03 and 0.66). CONCLUSIONS: We describe only a moderate interobserver agreement on clinical staging of patients with cervical cancer. The interobserver agreement increases in the group of experienced doctors, indicating that EUA can be learned. PMID- 23640294 TI - Constitutive activation of nuclear factor kappaB contributes to cystic fibrosis transmembrane conductance regulator expression and promotes human cervical cancer progression and poor prognosis. AB - OBJECTIVE: Cystic fibrosis transmembrane conductance regulator (CFTR) and nuclear factor kappaB (NF-kappaB) have been known to play important roles in the development and progression of many types of cancer including cervical cancer. The study aimed to verify the relevance and significance of CFTR and NF-kappaB expressions in cervical cancer tissues and cell lines. METHODS: The expressions of CFTR and NF-kappaB p65 were analyzed respectively by immunohistochemistry in total of 135 cervical tissue samples. The correlation to clinicopathologic characteristics and prognostic value was evaluated. The coexpression of CFTR and NF-kappaB was detected in cervical cancer cell lines. Nuclear factor kappaB signaling was inhibited by siRNA for NF-kappaB p65 and activated by stimulation of cells with interleukin beta or tumor necrosis factor alpha. RESULTS: We found both the membrane expression of CFTR and nuclear translocation of NF-kappaB p65 were progressively increased from normal cervical tissue, cervical intraepithelial neoplasm, to cervical cancer (overall R2 = 0.74, P < 0.001). Cystic fibrosis transmembrane conductance regulator expression and NF-kappaB activation were also positively associated with stage, histological grade, lymph node metastasis, and invasive interstitial depth. Multivariate analysis showed that coexpression of CFTR and NF-kappaB was an independent prognostic factor for survival (relative risk, 5.16; P = 0.003). Dual-immunofluorescence analysis showed CFTR and NF-kappaB were coexpressed in cervical cancer. Studies in vitro revealed that the expression levels of CFTR mRNA and protein were positively related to NF-kappaB activation. CONCLUSIONS: Cystic fibrosis transmembrane conductance regulator and NF-kappaB were coexpressed in cervical cancer, and the activation of NF-kappaB mediated the expression of CFTR. Multivariate analysis revealed that coexpression of CFTR and NF-kappaB was associated with poor prognosis in patients with cervical cancer. PMID- 23640295 TI - Pre-harvest methyl jasmonate treatment enhances cauliflower chemoprotective attributes without a loss in postharvest quality. AB - Methyl jasmonate (MeJA) treatment can significantly increase glucosinolate (GS) concentrations in Brassica vegetables and potentially enhance anticancer bioactivity. Although MeJA treatment may promote ethylene biosynthesis, which can be detrimental to postharvest quality, there are no previous reports of its effect on cauliflower postharvest quality. To address this, cauliflower curds in field plots were sprayed with either 0.1 % Triton X-100 (control) or 500 MUM MeJA solutions four days prior to harvest, then stored at 4 degrees C. Tissue subsamples were collected after 0, 10, 20, and 30 days of postharvest storage and assayed for visual color change, ethylene production, GS concentrations, and extract quinone reductase inductive activity. MeJA treatment increased curd GS concentrations of glucoraphanin, glucobrassicin, and neoglucobrassicin by 1.5, 2.4, and 4.6-fold over controls, respectively. MeJA treated cauliflower showed significantly higher quinone reductase activity, a biomarker for anticancer bioactivity, without reducing visual color and postharvest quality for 10 days at 4 degrees C storage. PMID- 23640296 TI - Extruded flaxseed meal enhances the nutritional quality of cereal-based products. AB - Human consumption of flaxseed is increasing due to its health benefit properties and extrusion processes can enhance its nutritional quality. Extruded flaxseed meal (EFM) obtained in a pilot plant was characterized and incorporated in flour mixes and cereal-based bars to demonstrate its nutritious usefulness. Amino acid content was not affected by extrusion and, despite lysine was the limitating amino acid, the chemical score (CS) was 83 %. Thiamin and riboflavin decreased slightly as consequence of extrusion, phytic acid did not change and trypsin inhibitor activity was undetectable. Proximate composition and nutritional quality determined by biological and chemical indexes were compared among EFM, flour mixes (FM) and cereal bars (CB). They presented high protein levels (26, 20 and 17 %, respectively), good biological value (BV) (80, 79 and 65, respectively), acceptable true protein digestibility (TD) (73, 79 and 78, respectively), and high dietary fiber (33, 20.5 and 18 %, respectively). The ratio of omega6:omega3 for CB was within the WHO/FAO recommendations. These results open a new venue for the usefulsess of nutritious/healthy extruded flaxseed flours into ready-to-eat cereal-based products with improved nutritional quality. PMID- 23640298 TI - International survey of cytomegalovirus management in solid organ transplantation after the publication of consensus guidelines. AB - BACKGROUND: The Transplantation Society published guidelines on cytomegalovirus (CMV) management after solid organ transplantation in 2010, which provide recommendations on prevention, treatment, diagnostics, and resistance. We aimed to survey international clinicians on their posttransplantation CMV management practices with reference to these guidelines to see if they altered the management of clinicians caring for transplant patients. METHODS: The members of The Transplantation Society were emailed an electronic survey 12 months after the guideline publication. RESULTS: A total of 155 clinicians responded, representing 126 centers in 41 countries. Overall, there was a high uptake of usage of the guidelines. High rates of initial CMV prevention were used (93%), with 46% using only universal prophylaxis, 21% only preemptive therapy, and 33% a hybrid combination dependent on recipient risk for CMV. Socioeconomic and geographic influence was evident, with 26% of respondents from developing countries using no CMV prevention, and more preemptive therapy used in Asia. Valganciclovir was the most common antiviral used, with dosing often below recommendations (33% in infection). Molecular monitoring was used by 84% of clinicians. Management of antiviral-associated neutropenia commonly included antiviral dose reduction or withdrawal (51%). CONCLUSIONS: We conclude that there is significant geographic variation in CMV management after solid organ transplantation. Although the majority of clinicians adhere to consensus guidelines, opportunity exists to encourage better guideline uptake. PMID- 23640299 TI - Accidental falls in home care hematological patients. PMID- 23640300 TI - Characteristics of American young adults with increased risk for type 2 diabetes: a pilot study. AB - PURPOSE: The purpose of the study was to examine the characteristics of American young adults with increased risk for type 2 diabetes (T2D). METHODS: Participants ages 18 to 29, overweight/obese, and sedentary were recruited from the metro Atlanta area in the United States. Variables included demographics, anthropometric and clinical variables, and physical activity. Of 107 participants, 3 participants had undiagnosed diabetes and 1 participant did not complete the modifiable activity questionnaire. Thus, 103 young adults remained for the final data analysis. RESULTS: Most participants were females and African Americans. About 30% of participants had prediabetes, either impaired fasting glucose, an A1C of 5.7% to 6.4%, or both. Overall, prediabetes young adults were heavier and did less physical activity than Diabetes Prevention Program (DPP) trial participants. In addition, these young adults had a higher prevalence of parental T2D history and lower level of physical activity compared to young adults with normoglycemia. CONCLUSIONS: Physical activity and parent T2D history are key risk factors for identifying young adults with prediabetes. Multilevel strategies are necessary to raise awareness of diabetes risk and to prevent T2D in young adults. PMID- 23640302 TI - The impact of diabetes counseling and education: clinical and cost outcomes from a large population of US managed care patients with type 2 diabetes. AB - PURPOSE: The purpose of this study is to examine outcomes in adult patients with type 2 diabetes mellitus who received diabetes counseling and education (C/E) services compared with those who did not. METHODS: A matched, retrospective cohort study of 17 483 C/E recipients and 17 470 non-C/E controls was followed for up to 12 months. Outcomes included glycemic control (glycosylated hemoglobin A1C levels <7.0%), hypoglycemic events, and health care utilization and costs. RESULTS: Compared with the non-C/E group, patients in the C/E group had significantly lower A1C (7.7% vs 7.2%) and were more likely to achieve glycemic control at 6 months' follow-up; they were also more likely to have a hypoglycemic event. During the 1-year period following the index date, C/E recipients had more inpatient visits (0.21 vs 0.20 visits per patient) and ambulatory visits (21.5 vs 18.6 visits per patient) compared with non-C/E controls. The increased use of health care services in the C/E groups was associated with $2388 higher annual overall costs and $827 higher diabetes-related costs. CONCLUSIONS: Diabetes C/E is associated with improved glycemic control, albeit with a slight increase in the risk of hypoglycemia. C/E was associated with higher health care costs across 12 months. Further analyses are needed to evaluate long-term cost-effectiveness of diabetes counseling and education. PMID- 23640301 TI - Perceptions of barriers in managing diabetes: perspectives of Hispanic immigrant patients and family members. AB - PURPOSE: Hispanics show poorer self-management of type 2 diabetes than non Hispanic whites. Although previous studies have reported socioeconomic and cultural barriers to diabetes self-management by Hispanics, little is known about perceived barriers to diabetes self-management from the perspectives of both Hispanics and their family members. The purpose of the study was to explore perceived barriers among Hispanic immigrants with diabetes and their family members. METHODS: A qualitative study using 5 focus groups was conducted. A total of 73 Hispanic immigrants with type 2 diabetes (n = 36) and family members (n = 37) were recruited in the southeastern United States for a family-based intervention study of diabetes-self management. Participants were asked to describe their perceptions of barriers to self-management. The 5 sessions were audiotaped and transcribed, translated from Spanish into English, and analyzed using standard content analysis. Demographics, hemoglobin A1C levels, blood pressure, and body mass index (BMI) were obtained both for participants with diabetes and for their family members. RESULTS: Barriers to diabetes self management identified by participants with diabetes were in 3 major themes categorized as: suffering from diabetes, difficulties in managing the disease, and lack of resources/support. Two key themes emerged pertaining to family members: we can provide support and we lack knowledge. CONCLUSIONS: Perceived barriers to diabetes self-management described by Hispanic immigrants with diabetes and family members indicate a lack of intervention strategies to meet their needs. Interventions should include culturally relevant resources, family support, and diabetes self-management skills education. PMID- 23640304 TI - Brief report: an evaluation of the AQ-10 as a brief screening instrument for ASD in adults. AB - There is a need for brief screening instruments for autistic spectrum disorders (ASD) that can be used by frontline healthcare professionals to aid in the decision as to whether an individual should be referred for a full diagnostic assessment. In this study we evaluated the ability of a short form of the autism spectrum quotient (AQ) questionnaire, the 10 item AQ-10, to correctly classify individuals as having or not having ASD. In a sample of 149 individuals with ASD and 134 controls without an ASD diagnosis, we found that the full AQ (AQ-50) abridged AQ (AQ-S) and AQ-10 all performed well as a screen for ASD. ROC analysis indicated that sensitivity, specificity and area under the curve were very similar at suggested cut-off's for ASD across measures, with little difference in performance between the AQ-10 and full AQ-50. Results indicate the potential usefulness of the AQ-10 as a brief screen for ASD. PMID- 23640303 TI - Impact of reinforcement of diabetes self-care on poorly controlled diabetes: a randomized controlled trial. AB - PURPOSE: The purpose of the study was to assess the value of reinforcing diabetes self-management for improving glycemia and self-care among adults with type 2 diabetes who had at least 3 hours of prior diabetes education. METHODS: In this randomized controlled trial, 134 participants (75% white, 51% female, 59 +/- 9 years old, 13 +/- 8 years with diabetes, A1C = 8.4% +/- 1.2%) were randomized to either a group map-based program (intervention) or group education on cholesterol and blood pressure (control). Participants were assessed for A1C levels, diabetes self-care behaviors (3-day pedometer readings, 6-minute walk test, blood glucose checks, frequency of self-care), and psychosocial factors (distress, frustration, quality of life) at baseline, 3, 6, and 12 months post intervention and health literacy at baseline. RESULTS: Groups did not differ on baseline characteristics including A1C levels, health literacy, or self-care; however, the intervention group had more years of education than controls. Intervention arm participants modestly improved A1C levels at 3 months post intervention but did not maintain that improvement at 6 and 12 months while control patients did not improve A1C levels at any time during follow-up. Importantly, frequency of self-reported self care, diabetes quality of life, diabetes-related distress, and frustration with diabetes self-care improved in both groups over time. CONCLUSIONS: Reinforcing self-care with diabetes education for patients who have not met glycemic targets helps improve A1C and could be considered a necessary component of ongoing diabetes care. The best method to accomplish reinforcement needs to be established. PMID- 23640306 TI - Characterization of the internal dynamics and conformational space of zinc-bound amyloid beta peptides by replica-exchange molecular dynamics simulations. AB - Amyloid beta (Abeta) peptides and metal ions have been associated with the pathogenesis of Alzheimer's disease. The conformational space of Abeta fragments of different length with and without binding of metal ions has been extensively investigated by replica-exchange molecular dynamics (REMD) simulation. However, only trajectories extracted at relatively low temperatures have been used for this analysis. The capability of REMD simulations to characterize the internal dynamics of such intrinsically disordered proteins (IDPs) as Abeta has been overlooked. In this work, we use an approach recently developed by Xue and Skrynnikov (J Am Chem Soc 133:14614-14628, 2011) to calculate NMR observables, including (15)N relaxation rates and (15)N-(1)H nuclear Overhauser enhancement (NOE), from the high-temperature trajectory of REMD simulations for zinc-bound Abeta peptides. The time axis of the trajectory was rescaled to correct for the effect of the high temperature (408 K) compared with the experimental temperature (278 K). Near-quantitative agreement between simulated values and experimental results was obtained. When the structural properties and free-energy surfaces of zinc-bound Abeta(1-40) and Abeta(1-42) were compared at the physiological temperature 310 K it was found that zinc-bound Abeta(1-42) was more rigid than Abeta(1-40) at the C terminus, and its conformational transitions were also more preferred. The self-consistent results derived from trajectories at high and low temperatures demonstrate the capability of REMD simulations to capture the internal dynamics of IDPs. PMID- 23640307 TI - Over-expression of small ubiquitin-related modifier-1 and sumoylated p53 in colon cancer. AB - Here we investigated whether the cellular accumulation of p53 protein caused by over-expression of small ubiquitin-related modifier-1 (SUMO-1) could be used as a predictive marker for prognosis in colon cancer. We detected SUMO-1 and p53 protein levels in 46 cases of colon cancer and adjacent tissues by immunohistochemistry and found that SUMO-1 was expressed at much higher levels in colon cancer compared with that in normal colon tissue. Immunoprecipitation and Western blot analysis revealed that the tumor suppressor p53 was present predominantly in the sumoylated rather than the non-sumoylated form in the colon cancer cell lines. A small interfering RNA targeted to SUMO-1 mRNA sequences was used to observe the levels of the p53 protein. Patients who showed high dual expressions of SUMO-1 and p53 tended to experience metastasis more frequently. These results suggest that the cellular accumulation of p53 protein caused by over-expression of SUMO-1 may be involved in tumor aggressiveness. Multivariate analysis confirmed that the high dual expression of SUMO-1 and p53 was an independent factor for evaluating prognosis. SUMO-1 may be useful as a novel target for therapy in colon cancer as well as a clinical indicator for tumor aggressiveness. PMID- 23640310 TI - Observation of mesenteric microcirculatory disturbance in rat by laser oblique scanning optical microscopy. AB - Ischemia-reperfusion (I/R) injury model has been widely applied to the study of microcirculation disturbance. In this work, we used laser oblique scanning optical microscopy (LOSOM) to observe the microcirculation system in the mesentery of rat model. Utilizing a localized point-scanning detection scheme, high-contrast images of leukocytes were obtained. The extended detection capability facilitated both the automatic in vivo cell counting and the accurate measurement of the rolling velocity of leukocytes. Statistical analysis of the different treatment groups suggested that the distinction between I/R and sham groups with time lapse is significant. PMID- 23640309 TI - Incidence and associated endocrine and neurologic abnormalities of optic nerve hypoplasia. AB - IMPORTANCE: Optic nerve hypoplasia (ONH) is an increasingly recognized cause of congenital blindness in children; however, there is significant discord regarding its incidence and the rate of associated conditions. OBJECTIVE: To determine the incidence of ONH and the rate of associated endocrine, neurologic, and developmental abnormalities among a population-based cohort of pediatric patients. DESIGN: Retrospective, population-based study. SETTING: Olmsted County, Minnesota (95.7% white in 1990). PARTICIPANTS: All pediatric residents (aged <19 years) of Olmstead County, diagnosed as having ONH from January 1, 1984, through December 31, 2008. MAIN OUTCOMES AND MEASURES: Incidence of ONH and the rate of associated endocrine, neurologic, and developmental abnormalities. RESULTS: Optic nerve hypoplasia was diagnosed in 19 pediatric patients during the 25-year study period, for an annual incidence of 2.4 (95% CI, 1.2-3.5) per 100,000 residents younger than 19 years or 1 in 2287 live births. The mean age at diagnosis was 2.1 years, and 10 (53%) patients were male. Commonly associated perinatal conditions included primiparity in 8 patients (42%), premature birth in 6 (32%), and maternal diabetes mellitus in 3 (16%). Of the 19 study patients, 16 (84%) had bilateral involvement at initial examination, 9 (47%) had decreased visual acuity, 8 (42%) had strabismus, and 5 (26%) had nystagmus. Systemic conditions included developmental delay in 12 (63%), neurologic deficits in 10 (53%), and endocrine dysfunction in 5 (26%). CONCLUSIONS AND RELEVANCE: This population based study demonstrated an incidence of ONH of 1 in 2287 live births. More than half of the patients had developmental and neurologic deficits, and one-fourth had a diagnosis of endocrine dysfunction. PMID- 23640311 TI - Factors influencing the evaluation and management outcomes of coccygodynia: a literature review. AB - BACKGROUND: This paper reviews various methods for the assessment and management of the coccygodynia. It included review of both conservative as well as operative methods. Goal of conservative methods in coccygodynia is to restore the functional status of the patients and to eliminate or at least minimize the discomfort associated with this disabling condition. Though various conservative methods have been used traditionally, yet not all patients respond positively to them. In such cases operative interventions are used, yet previous literature does suggest that even this method is not absolutely promising as not all patients do respond positively to it. METHODOLOGY: The purpose of this article is to review various literatures available for the assessment and the management of coccygodynia. It tends to identify the factors which could guide the selection of best intervention strategy for its management. English literature databases were searched to find the studies matching the predetermined inclusion criteria. CONCLUSION: Multiple factors (pathology, duration of pain, Body mass index, neurotic personality, associated disc pathologies, amount of inter-coccygeal movement) influence the outcomes of the remedial interventions. This study highlights multiple treatment approaches for the rehabilitation of the coccygodynia management. PMID- 23640308 TI - Multi-ligand poly(L-lactic-co-glycolic acid) nanoparticles inhibit activation of endothelial cells. AB - Endothelial cell (EC) activation and inflammation is a key step in the initiation and progression of many cardiovascular diseases. Targeted delivery of therapeutic reagents to inflamed EC using nanoparticles is challenging as nanoparticles do not arrest on EC efficiently under high shear stress. In this study, we developed a novel polymeric platelet-mimicking nanoparticle for strong particle adhesion onto ECs and enhanced particle internalization by ECs. This nanoparticle was encapsulated with dexamethasone as the anti-inflammatory drug, and conjugated with polyethylene glycol, glycoprotein 1b, and trans-activating transcriptional peptide. The multi-ligand nanoparticle showed significantly greater adhesion on P selectin, von Willebrand Factor, than the unmodified particles, and activated EC in vitro under both static and flow conditions. Treatment of injured rat carotid arteries with these multi-ligand nanoparticles suppressed neointimal stenosis more than unconjugated nanoparticles did. These results indicate that this novel multi-ligand nanoparticle is efficient to target inflamed EC and inhibit inflammation and subsequent stenosis. PMID- 23640312 TI - A systematic review: the effects of podiatrical deviations on nonspecific chronic low back pain. AB - Lower back pain (LBP) is a widespread, expensive, and debilitating problem in Western industrialized countries. Though LBP can be caused by acute injuries, biomechanical discrepancies have also been indicated to cause chronic LBP. A possible link between podiatrical deviations and LBP has been established in the literature; yet, no comprehensive review investigating the effects of foot and ankle deviations on low back pain has been published. The aim of this study was to assess the relevant literature concerning the effects of foot and ankle deviations on LBP. After review, it was determined that there is limited research regarding ankle and foot deviations and their connection to LBP. Reviewed studies have linked flat feet, ankle instability, sagittal plane blockage and excessive pronation to LBP. Specifically, excessive pronation has been shown to cause leg length discrepancies leading to pelvic tilts and LBP. Based on these results, ankle and foot deviations can be considered a potential cause for LBP due to the disruption of the kinetic chain from the foot to the back. Clinicians should consider the foot and ankle when addressing LBP, especially if more conventional etiologies fail to describe the condition. PMID- 23640313 TI - Systematic review of the effects of fatigue on spatiotemporal gait parameters. AB - PURPOSE: This systematic review aimed to assess changes on spatiotemporal gait parameters due to fatigue. MATERIAL AND METHOD: A search was carried out in literature published from 1950 to December 2010 and retrieved 771 articles using terms referring to walking and fatigue in the title, abstract or keywords. Two researchers assessed the selection and quality of each article independently. RESULTS: Seven studies were selected for this systematic review, two of which reported on the same data set. Several spatiotemporal parameters were reported to change with fatigue, but the few variables studied in multiple studies, gait speed and stride or step length and stride time, were affected only in single studies. Fatigue appears to modulate spatiotemporal gait parameters, but the effects of fatigue appear to be dependent on the muscles that were fatigued, and age that appears to be a moderator of the effects of fatigue on gait. PMID- 23640314 TI - Comparison between the effect of lumbopelvic belt and home based pelvic stabilizing exercise on pregnant women with pelvic girdle pain; a randomized controlled trial. AB - OBJECTIVE: Pelvic girdle pain is a common complaint of pregnant women. There are limited data on comparison between the effectiveness of stabilizing exercises and lumbopelvic belt on the treatment of these patients. The objective of this study was to compare the effect of lumbopelvic belt plus information, home based pelvic girdle stabilizing exercises plus information and information alone on pain intensity, functional status and quality of life of pregnant women with pelvic girdle pain. METHODS: In this randomized clinical trial pregnant women with pelvic girdle pain (n=105) were randomly allocated to three groups; Control group (n=35) that received general information, exercise group (n=31) that in addition to general information were asked to perform specific pelvic stabilizing exercises at home and belt group (n=31) that received non-rigid lumbopelvic belt and the information. The primary outcome variables were pain intensity and functional status of the participants which were measured using visual analogue scale and Oswestry Disability Index (ODI) respectively. Quality of life of participants was measured using WHOQOL-BREF questionnaire. All measurements were performed at baseline, 3 and 6 weeks after the study conduction. RESULTS: The pain intensity of patients in belt group in comparison to other groups was decreased significantly at both 3 and 6 weeks follow-ups. The mean score of ODI of patients in belt group was also improved more than exercise and control groups significantly. CONCLUSIONS: On base of our results, it can be found that in short term lumbopelvic belt and information in treatment of pregnant women with pelvic girdle pain is superior to exercise plus information or information alone. PMID- 23640315 TI - Measurement of cervical range of motion (CROM) by electronic CROM goniometer: a test of reliability and validity. AB - PURPOSE: To investigate the reliability and validity of the Electronic Cervical Range of Motion (CROM) Goniometer in measurement of cervical spine mobility in adults with and without neck pain. METHODS: A cross-sectional reliability study was conducted on 54 subjects (26 neck pain and 26 non-neck pain) aged from 20-70 years old. The Numerical Pain Rating Scale and Chinese version of Northwick Park Neck Pain Questionnaire were used to assess neck pain severity and disability respectively. The CROM was measured in sitting position except left to right rotation was measured in supine lying. All the cervical active movements were measured by using the Electronic CROM Goniometer from ARCON TM Functional Capacity Evaluation (FCE) systems. RESULTS: The intra-tester and inter-tester reliability were high in both normal and chronic neck pain groups with ICC coefficients ranged from 0.75-*0.92. There was significant difference in the total CROM between the normal (374.7 degrees ) and chronic neck pain group (292.6 degrees ). CONCLUSION: The ACRON cervical goniometer was found to be reliable for measuring cervical mobility in 3 planes for both normal and patient subjects. Construct validity of the goniometer was supported as the test's result documented significant difference in CROM between the control and the neck pain groups. PMID- 23640316 TI - Gluteus medius muscle activation on stance phase according to various vertical load. AB - BACKGROUND AND OBJECTIVES: This study aims to analyze muscle activity of the lower limbs during stance phase of gait in accordance with the application of various vertical loadings. MATERIAL AND METHODS: Participants who met the criterion for this study (n=11). During their gait, various vertical loadings (0 kg, 0.5 kg, 1 kg) were provided and their muscle activities in the lower limbs during stance phase were measured. In order to accurately measure their gait, they were instructed to walk 5 gait cycles, and 3 gait cycles excluding the front and back 1 cycle were used for analysis. For the objectivity of data, measurements were made three times under each condition and average values were employed for statistic analysis. RESULTS: The intervention of applying various vertical loadings of 0 kg, 0.5 kg, 1 kg to the lower limbs during swing phase in order to compare muscle activities of the lower limbs during stance phase of gait resulted in the following outcomes. Tibialis anterior and peroneus longus muscle activities did not significantly differ with the application of various vertical loadings to the lower limbs during swing phase, while gluteus medius muscle activities significantly differed according to the levels of loadings applied. There were significant differences in muscle activities between the loading of 0 kg and the loading of 0.5 kg. CONCLUSIONS: Clinicians may use these results to effectively progress strengthening for gluteus medius in the rehabilitation of lower extremity injuries. PMID- 23640317 TI - Comparison of muscle activities of abductor hallucis and adductor hallucis between the short foot and toe-spread-out exercises in subjects with mild hallux valgus. AB - BACKGROUND AND OBJECTIVE: Muscle imbalance between the abductor hallucis (AbdH) and adductor hallucis (AddH) has been demonstrated in hallux valgus (HV). Clinically, the short-foot (SF) is performed for strengthening foot intrinsic muscle. The toes-spread-out (TSO), the newly introduced, was devised to correct HV deformity. However, there was no study to determine which exercise is effective in balancing the ratio of activation between AbdH and AddH muscles. The purpose of this study was to compare the muscle activities of the AbdH and AddH between SF and TSO exercises in subjects with mild HV. METHODS: Eighteen subjects with mild HV participated. The muscle activity of AbdH and AddH and the angle of first metatarsophalangeal (MTP) joint in the horizontal plane were measured during the SF and TSO exercises. Values of dependent variables were compared using a paired t-test between the SF and TSO exercises. RESULTS: The TSO exercise showed significantly greater activation of the AbdH than did the SF exercise (mean difference=44.96% of maximum voluntary isometric contraction; p< 0.001). There was no significant difference between the SF and TSO exercises in activating the AddH (mean difference=8.28% of maximum voluntary isometric contraction; p=0.271). The ratio of AbdH to AddH muscle activity was significantly higher in the TSO exercise than in the SF exercise (mean difference=0.54; p=0.001). The angle of the first MTP joint in the horizontal plane during the TSO was significantly greater than that in the SF exercise (mean difference=9.60 degrees ; p<0.001). CONCLUSIONS: These results suggest that the TSO exercise can be recommended for preventing or correcting HV deformity at an early stage. PMID- 23640318 TI - Comparison of clinical and electrophysiological findings in patients with suspected radiculopathies. AB - Cervical and lumbar roots may be irritated or compressed due to the pathological conditions such as disc herniations, degenerative foraminal stenosis, trauma and tumors. Electrophysiologic tests are frequently used in conjunction with imaging modalities for evaluation of low back and neck pain radiating to extremities, primarily for the purpose of establishing the presence or absence of a radiculopathy. In this study, we aimed to evalulate the relationship between clinic and electroneuromyographic (ENMG) findings in patients with suspected radiculopathies. Forty one patients with radicular complaints in the upper extremities and 51 patients with radicular complaints in the lower extremities were included in this study. McNemar test and Kappa coefficients between the two methods were applied to each group of patients, in order to test the significance of the difference between the two diagnostic procedures' ability on finding out the pathology. The McNemar test identified a significant difference between the two diagnostic approaches both for cervical and lumbar radiculopathies (p<0.001). The Kappa coefficients between the two methods were determined as 0.08 and 0.07, respectively. This means, efficacy of anamnesis and neurological examination for the prediction of electrodiagnostic tests was found to be limited. Normal neurological examination results in a patient with suspected radiculopathy can not eliminate abnormal electrodiagnostic test results; likewise, abnormal findings in the neurological examination would not mean finding pathologies in the electrodiagnostic tests. For more accurate approach to a patient, neurological examination and electrodiagnostic tests must be used and interpreted together. PMID- 23640319 TI - Association between radiculopathy and lumbar multifidus atrophy in magnetic resonance imaging. AB - BACKGROUND AND OBJECTIVES: Many studies have evaluated factors related to lumbar multifidus (MF) muscle atrophy. However, few studies have investigated radiculopathy and the MF muscle. In this study, the association between radiculopathy and lumbar MF muscle atrophy in magnetic resonance imaging (MRI) was evaluated. MATERIALS AND METHODS: In total, 100 patients with low back pain or radiating leg pain were examined. Their lumbar MRIs were visually analyzed semi-quantitatively for signs of lumbar MF muscle atrophy. The severity and extent of MF atrophy were compared between non-radiculopathy (Non-rad) and radiculopathy (Rad) groups. Asymmetry of MF atrophy was also compared between unilateral radiculopathy (UniR) and bilateral radiculopathy (BiR) groups. RESULTS: Significantly more severe and extensive MF atrophy was observed in the Rad group than in the Non-rad group (p< 0.01). However, no difference in the asymmetry of MF atrophy was found between the UniR and BiR groups (p> 0.05). CONCLUSION: More severe and extensive atrophy in the lumbar MF muscle was associated with radiculopathy. Thus, we might consider the presence of radiculopathy when severe and extensive multi-level involvement of MF atrophy is seen in MRI. PMID- 23640320 TI - Lumbosacral transforaminal epidural steroid injections are equally effective for treatment of lumbosacral radicular pain in the obese compared to non-obese population: a pilot study. AB - BACKGROUND AND OBJECTIVES: Current evidence suggests that lumbosacral transforaminal epidural steroid injection (TFESI) is an effective treatment for lumbosacral radicular pain. However, practitioners may be reluctant to attempt this intervention in obese patients because of a perceived reduction in the chance of providing pain relief due to the increased technical difficulty of TFESI in individuals with a larger body habitus. No study to date has compared the effectiveness of TFESI in groups stratified by BMI. We report pilot data addressing whether lumbosacral transforaminal epidural steroid injection is as effective in treating lumbosacral radicular pain in the obese and overweight population as it is in the non-overweight population. MATERIAL AND METHODS: This study consisted of 9 normal weight (18.5 < BMI < 25), 9 overweight (25 < BMI < 30), and 6 obese (BMI > 30) patients who presented with lumbosacral radicular pain and received a TFESI. For each group, percent reduction in pain and the proportion of individuals with a 50% or greater reduction in pain 2-4 weeks after TFESI was determined. RESULTS: Comparing the overweight and obese groups to the normal weight group, no significant differences were found in the percent improvement in pain after TFESI (p=0.7154, p=0.4566) or in the proportion of each group with a 50% or greater reduction in lower back pain after TFESI (p=0.2968). CONCLUSION: Our pilot data indicates that lumbosacral TFESI is as effective in providing short-term relief of lumbosacral radicular pain in obese and overweight patients as it is in non-overweight patients. However, our sample size was not large enough to find a significant difference at a power of 80%. We plan to perform a larger prospective study to confirm the findings of this study. LEVEL OF EVIDENCE: Case-control study, Level II-2. PMID- 23640321 TI - Training effects of combined resistance and proprioceptive neck muscle exercising. AB - OBJECTIVES: To investigate training effects of two different resistance and proprioceptive exercising concepts of neck muscles. MATERIAL AND METHOD: Twenty six healthy women participated in a randomized pilot trial. The test persons were randomized to two different neck-training programs (resistance training (RT) and proprioceptive resistance training (PRT)). They performed a standardized training program for the duration of ten weeks two times weekly. The neck strength, the cross-sectional area of three neck muscle groups (1. sternocleidomastoid muscles; 2. multifidus and semispinalis cervicis muscles; 3. semispinalis capitis and splenius muscles) and the proprioceptive capability evaluated by the dynamic joint repositioning error (DJRE) of the head were assessed pre- and post intervention. RESULTS: Strength gain did not differ significantly between the two resistance training groups (PRT group: 8.2% to 29.3%; RT group: 1.4% to 19.8%). Change of hypertrophy of all neck muscle groups was significantly (p< 0.001 to p=0.013) greater in the PRT group (18.9% to 32.3%) than in the RT group (1.5% to 12.9%). The DJRE deteriorated with 35% in the RT group and did not change in PRT group (-2.0%). CONCLUSION: In combination with resistance training, proprioceptive training led to a significantly higher muscle hypertrophy and didn't effect a significant deterioration of the proprioceptive capability compared to isolated resistance training. PMID- 23640322 TI - Static and dynamic balance performance in patients with osteoporotic vertebral compression fracture. AB - OBJECTIVE: Patients with osteoporotic vertebral compression fracture (OVCF) have postural changes and increased risk of falling. The aim of this study is to compare balance characteristics between patients with OVCF and healthy control subjects. METHODS: Patients with severe OVCF and control subjects underwent computerised dynamic posturography (CDP) in this case-control study. RESULTS: Forty-seven OVCF patients and 45 controls were recruited. Compared with the control group, the OVCF group had significantly decreased average stability; maximal stability under the 'eye open with swayed support surface' (CDP subtest 4) and 'eye closed with swayed support surface' conditions (subtest 5); and decreased ankle strategy during subtests 4 and 5 and under the 'swayed vision with swayed support surface' condition (subtest 6). The OVCF group fell more frequently during subtests 5 and 6 and had longer overall reaction time and longer reaction time when moving backward during the directional control test. CONCLUSION: OVCF patients had poorer static and dynamic balance performance compared with normal control. They had decreased postural stability and ankle strategy with increased fall frequency on a swayed surface; they also had longer reaction times overall and in the backward direction. Therefore, we suggest balance rehabilitation for patients with OVCF to prevent fall. PMID- 23640323 TI - The impact of knee osteoarthritis on rehabilitation outcomes in hemiparetic stroke patients. AB - BACKGROUND AND OBJECTIVE: To investigate the effects of knee osteoarthritis (OA) on activities of daily living and motor and functional improvement in stroke patients with hemiparesis. METHODS: This prospective case-controlled study included 60 inpatients (44 women, 16 men; mean age 66.1 +/- 7.6 years, range 51 79 years) with hemiparesis after stroke. Main outcome measures included the Brunnstrom motor recovery stages of the lower extremity, Functional Ambulation Category (FAC), Barthel index, knee pain as assessed by a VAS, and radiographic severity of knee OA based on the Kellgren-Lawrence (K/L) criteria. RESULTS: Between improvements in FAC score and time since stroke , Barthel score, knee pain at rest, K/L radiological grade revealed weak but significant correlations (r: 0.254-0.393) (p< 0.05). Regression analysis revealed that time since stroke, knee pain at rest and radiologically knee osteoarthritis had a significant effect on the improvement in ambulation level (r=0.134, p=0.001; r=0.137, p<0.05; r= 0.007, p< 0.05; respectively). CONCLUSIONS: The present study shows that knee OA had a negative effect on ambulation levels in hemiplegic patients after stroke. Thus, knee pain at rest and knee osteoarthritis could be evaluated as a functional outcome factor for the improvement of the ambulation levels within stroke patients. PMID- 23640324 TI - The efficacy of lumbar extension traction for sagittal alignment in mechanical low back pain: a randomized trial. AB - BACKGROUND: There is growing interest in the role of abnormal asymmetrical posture, which is considered one of the most important etiological factors reported to be associated with mechanical low back pain. OBJECTIVE: This study was conducted to investigate the effect of lumbar extension traction on the pain, function and whole spine sagittal balance as represented in lumbar curvature, thoracic curvature, C7 plumb line, and sacral slope. METHODS: Eighty patients with chronic mechanical low back pain (CMLBP) and definite hypolordosis were randomly assigned to traction or a control group. The control group (n=40) received stretching exercises and infrared radiation, whereas the traction group (n=40) received lumbar extension traction in addition to stretching exercises and infrared radiation three times a week for 10 weeks. Back pain rating scale, Oswestry Disability Index, and radiological spine sagittal balance parameters in terms of lumbar lordosis, thoracic kyphosis, sacral slope, and positioning of C7 plumb line were measured for all patients at three intervals (before treatment, after 10 weeks of treatment, and at six months follow-up). RESULTS: There was a significant difference between the traction and control groups adjusted to baseline value of outcome at 10 weeks post treatment with respect to lumbar lordotic curve (P=0.000), thoracic kyphosis (P=0.013), sacral slope (P=0.001), C7 plump line distance (p=0.001), while there was no significant difference with respect to pain (p=0.29) and Oswestry Disability Index (ODI) (p=0.1). At 6-months follow-up, there were significant differences between both groups for all the previous variables (p< 0.05). CONCLUSIONS: Lumbar extension traction in addition to stretching exercises and infrared radiation improved the spine sagittal balance parameters and decreased the pain and disability in CMLBP. PMID- 23640325 TI - A study of therapeutic ultrasound and exercise treatment for muscle fatigue in patients with chronic non specific low back pain: a preliminary report. AB - AIM: The aim of this study was to investigate the effect of continuous ultrasound (US) plus exercise on the endurance of paravertebral muscles of patients with chronic non specific low back pain (CNSLBP). METHODS AND MATERIALS: In this pilot, pretest-posttest study, 22 patients with CNSLBP participated. Patients received 10 sessions of treatment, including continuous US plus exercise therapy, over a period of four consecutive weeks. Median frequency slopes of Iliocostalis and Multifidus muscles as well as holding time during Biering-Sorensen test were measured using surface electromyography. In addition, function and pain were measured using Functional Rating Index (FRI) questionnaire and VAS. RESULTS: Five females and 15 males with a mean age of 31.7 years completed the treatment. Descriptive data showed a decrease of 0.01 and 0.02 mean in median frequency slope of right and left Iliocostalis respectively and a mean of 0.08 decrease for both right and left Multifidus muscles. Endurance time increased 1.8 seconds mean. Both function (17%) and pain (24%) improved post treatment. CONCLUSION: Larger population studies in the context of high quality, randomized clinical trial are needed to validate the results. PMID- 23640326 TI - Test-retest reliability of the 6-min walk test in patients with postpolio syndrome. AB - This study describes the test-retest reliability of the 6-min walk test (6MWT) and evaluates the possibility to perform the test three times on the same day in patients with postpolio syndrome (PPS). This was an intrarater test-retest reliability study. A total of 23 PPS patients (nine men, 14 women), mean age 67 years, participated in the study. The patients performed three 6MWT with a 30-min rest between each test. Borg scales were used to evaluate leg tiredness, dyspnea, and exertion before and after each test. The influence of walking aids on the outcome of the 6MWT was also evaluated. All patients (n=23) were able to complete the three 6MWT. The individual distances varied from 140-395 m. The relative reliability was high. The intraclass correlation coefficient (ICC2.1) (95% confidence interval) values ranged from 0.98 (0.95-0.99) (T1-T2) to 0.99 (0.97 0.99) (T2-T3) for the total number of participants. The SEM ranged from 12 to 9 m and the smallest real difference (SRD) ranged from 33 to 26 m for the total number of participants. Data indicate that the 6MWT is reliable for patients with PPS. For the high test-retest reliability, one test may be required. However, as a small learning effect was observed, the best result of two tests can be recommended when evaluating walking ability for research purposes. PMID- 23640327 TI - Changing the awareness of physiatrists on musculoskeletal ultrasound: Italy in EURO-MUSCULUS. AB - The interest of physical and rehabilitation medicine (PRM) physicians in musculoskeletal ultrasonography (MSUS) is increasing. In this study, we aimed to explore the attitudes of a group of Italian physiatrists on this topic before and after a 21/2-day MSUS course. A 15-question survey (designed ad-hoc for this study) was administered before the first session of an MSUS course held in the PRM Department of Tor Vergata University, Rome. At the end of the course, a repeat questionnaire with eight of the original 15 questions (on awareness) was administered. The survey contained multiple-choice and open-ended questions addressing three main aspects: personal background, MSUS experience, and awareness about MSUS. All of the course participants (17 physiatrists) completed the precourse and postcourse questionnaires. Almost two-thirds of the participants (11/17) reported that they had never received education on MSUS. Overall, the participants rated MSUS as either 'essential' (8/16) or 'useful to some of my practice' (8/16). All of them stated at both times that physiatrists should perform MSUS themselves and that MSUS education is necessary for physiatrists. Participants' awareness significantly increased on the indications for MSUS, the advantages and the structures that could be evaluated with it. We draw attention to the fact that PRM physicians are increasingly becoming aware of the need for MSUS in clinical practice. Unfortunately, the two barriers (i.e. lack of education and lack of device) against the use of MSUS by physiatrists still seem to exist. Finally, we acknowledge the paramount role of international collaborative efforts (e.g., EURO-MUSCULUS) to speed up and standardize the education process and the clinical application of MSUS in our field. PMID- 23640329 TI - [Dentinogenesis imperfecta. Genetically determined dentin dysplasia]. PMID- 23640330 TI - Repression of class I transcription by cadmium is mediated by the protein phosphatase 2A. AB - Toxic metals are part of our environment, and undue exposure to them leads to a variety of pathologies. In response, most organisms adapt their metabolism and have evolved systems to limit this toxicity and to acquire tolerance. Ribosome biosynthesis being central for protein synthesis, we analyzed in yeast the effects of a moderate concentration of cadmium (Cd(2+)) on Pol I transcription that represents >60% of the transcriptional activity of the cells. We show that Cd(2+) rapidly and drastically shuts down the expression of the 35S rRNA. Repression does not result from a poisoning of any of the components of the class I transcriptional machinery by Cd(2+), but rather involves a protein phosphatase 2A (PP2A)-dependent cellular signaling pathway that targets the formation/dissociation of the Pol I-Rrn3 complex. We also show that Pol I transcription is repressed by other toxic metals, such as Ag(+) and Hg(2+), which likewise perturb the Pol I-Rrn3 complex, but through PP2A-independent mechanisms. Taken together, our results point to a central role for the Pol I-Rrn3 complex as molecular switch for regulating Pol I transcription in response to toxic metals. PMID- 23640332 TI - Memoir: template-based structure prediction for membrane proteins. AB - Membrane proteins are estimated to be the targets of 50% of drugs that are currently in development, yet we have few membrane protein crystal structures. As a result, for a membrane protein of interest, the much-needed structural information usually comes from a homology model. Current homology modelling software is optimized for globular proteins, and ignores the constraints that the membrane is known to place on protein structure. Our Memoir server produces homology models using alignment and coordinate generation software that has been designed specifically for transmembrane proteins. Memoir is easy to use, with the only inputs being a structural template and the sequence that is to be modelled. We provide a video tutorial and a guide to assessing model quality. Supporting data aid manual refinement of the models. These data include a set of alternative conformations for each modelled loop, and a multiple sequence alignment that incorporates the query and template. Memoir works with both alpha-helical and beta-barrel types of membrane proteins and is freely available at http://opig.stats.ox.ac.uk/webapps/memoir. PMID- 23640331 TI - Progesterone receptor induces bcl-x expression through intragenic binding sites favoring RNA polymerase II elongation. AB - Steroid receptors were classically described for regulating transcription by binding to target gene promoters. However, genome-wide studies reveal that steroid receptors-binding sites are mainly located at intragenic regions. To determine the role of these sites, we examined the effect of progestins on the transcription of the bcl-x gene, where only intragenic progesterone receptor binding sites (PRbs) were identified. We found that in response to hormone treatment, the PR is recruited to these sites along with two histone acetyltransferases CREB-binding protein (CBP) and GCN5, leading to an increase in histone H3 and H4 acetylation and to the binding of the SWI/SNF complex. Concomitant, a more relaxed chromatin was detected along bcl-x gene mainly in the regions surrounding the intragenic PRbs. PR also mediated the recruitment of the positive elongation factor pTEFb, favoring RNA polymerase II (Pol II) elongation activity. Together these events promoted the re-distribution of the active Pol II toward the 3'-end of the gene and a decrease in the ratio between proximal and distal transcription. These results suggest a novel mechanism by which PR regulates gene expression by facilitating the proper passage of the polymerase along hormone-dependent genes. PMID- 23640333 TI - The HIV-2 Rev-response element: determining secondary structure and defining folding intermediates. AB - Interaction between the viral protein Rev and the RNA motifs known as Rev response elements (RREs) is required for transport of unspliced and partially spliced human immunodeficiency virus (HIV)-1 and HIV-2 RNAs from the nucleus to the cytoplasm during the later stages of virus replication. A more detailed understanding of these nucleoprotein complexes and the host factors with which they interact should accelerate the development of new antiviral drugs targeting cis-acting RNA regulatory signals. In this communication, the secondary structures of the HIV-2 RRE and two RNA folding precursors have been identified using the SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) chemical probing methodology together with a novel mathematical approach for determining the secondary structures of RNA conformers present in a mixture. A complementary chemical probing technique was also used to support these secondary structure models, to confirm that the RRE2 RNA undergoes a folding transition and to obtain information about the relative positioning of RRE2 substructures in three dimensions. Our analysis collectively suggests that the HIV-2 RRE undergoes two conformational transitions before assuming the energetically most favorable conformer. The 3D models for the HIV-2 RRE and folding intermediates are also presented, wherein the Rev-binding stem-loops (IIB and I) are located coaxially in the former, which is in agreement with previous models for HIV-1 Rev-RRE binding. PMID- 23640335 TI - CMCompare webserver: comparing RNA families via covariance models. AB - A standard method for the identification of novel non-coding RNAs is homology search by covariance models. Covariance models are constructed for specific RNA families with common sequence and structure (e.g. transfer RNAs). Currently, there are models for 2208 families available from Rfam. Before being included into a database, a proposed family should be tested for specificity (finding only true homolog sequences), sensitivity (finding remote homologs) and uniqueness. The CMCompare webserver (CMCws) compares Infernal RNA family models to (i) identify models with poor specificity and (ii) explore the relationship between models. The CMCws provides options to compare new models against all existing models in the current Rfam database to avoid the construction of duplicate models for the same non-coding RNA family. In addition, the user can explore the relationship between two or more models, including whole sets of user-created family models. Visualization of family relationships provides help in evaluating candidates for clusters of biologically related families, called clans. The CMCws is freely available, without any login requirements, at http://rna.tbi.univie.ac.at/cmcws, and the underlying software is available under the GPL-3 license. PMID- 23640334 TI - The Taverna workflow suite: designing and executing workflows of Web Services on the desktop, web or in the cloud. AB - The Taverna workflow tool suite (http://www.taverna.org.uk) is designed to combine distributed Web Services and/or local tools into complex analysis pipelines. These pipelines can be executed on local desktop machines or through larger infrastructure (such as supercomputers, Grids or cloud environments), using the Taverna Server. In bioinformatics, Taverna workflows are typically used in the areas of high-throughput omics analyses (for example, proteomics or transcriptomics), or for evidence gathering methods involving text mining or data mining. Through Taverna, scientists have access to several thousand different tools and resources that are freely available from a large range of life science institutions. Once constructed, the workflows are reusable, executable bioinformatics protocols that can be shared, reused and repurposed. A repository of public workflows is available at http://www.myexperiment.org. This article provides an update to the Taverna tool suite, highlighting new features and developments in the workbench and the Taverna Server. PMID- 23640336 TI - Anion-driven structures of radially arranged anion receptor oligomers. AB - Radially arranged oligomers of pi-conjugated acyclic anion receptors showed various anion-driven structures depending on the positions and numbers of the receptor units. PMID- 23640337 TI - Canagliflozin approved for type 2 diabetes. PMID- 23640338 TI - Virginia passes nation's first biosimilar substitution law. PMID- 23640339 TI - Pharmacists work to boost patient satisfaction scores. PMID- 23640341 TI - California bill would accord pharmacists provider status. PMID- 23640343 TI - Pharmacist involvement in establishing a patient-centered medical home. PMID- 23640344 TI - Pharmacy practice model change: lean thinking provides a place to start. PMID- 23640346 TI - New treatment options for castration-resistant prostate cancer. AB - PURPOSE: Published efficacy and safety data from clinical trials of three recently approved agents for the management of metastatic castration-resistant prostate cancer (CRPC) are reviewed. SUMMARY: Sipuleucel-T is approved by the Food and Drug Administration (FDA) for the treatment of asymptomatic or minimally symptomatic patients with CRPC. In a placebo-controlled Phase III clinical trial, the use of sipuleucel-T was associated with an average improvement in median overall survival of 4.1 months. Abiraterone acetate and cabazitaxel are approved by FDA as second-line treatments for patients with CRPC who experience disease progression during first-line docetaxel therapy. In Phase III trials, abiraterone acetate was associated with improved overall survival relative to placebo use (14.8 months versus 10.9 months), and cabazitaxel was found to confer an overall survival advantage over mitoxantrone therapy (median survival, 15.1 months versus 12.7 months), corresponding to a 30% reduction in the relative risk of death (hazard ratio, 0.7; 95% confidence interval, 0.59-0.83; p < 0.0001). The three agents range in cost from $40,000 to $93,000 for a full course of therapy. Sipuleucel therapy entails leukapheresis procedures for the collection of autologous cells used in dose preparation, requiring careful planning and coordination of care. CONCLUSION: Sipuleucel-T, abiraterone acetate, and cabazitaxel offer new options for the treatment of patients with CRPC, including those with disease resistant to standard first-line therapies. The agents' varying administration requirements, as well as patient-specific factors and cost issues, are key considerations in the drug selection process. PMID- 23640345 TI - Vandetanib: a novel targeted therapy for the treatment of metastatic or locally advanced medullary thyroid cancer. AB - PURPOSE: The pharmacology, pharmacokinetics, efficacy, safety and tolerability, drug and food interactions, cost, and place in therapy of vandetanib are reviewed. SUMMARY: Vandetanib is a small-molecule inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and receptor tyrosine kinase signaling pathways, which are involved in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib is currently approved as an alternative to local therapies for both unresectable and disseminated disease. Vandetanib was evaluated in a randomized, placebo-controlled, double blind Phase III study comparing vandetanib with placebo in adult patients with unresectable locally advanced or metastatic hereditary or sporadic MTC. Vandetanib demonstrated a statistically significant longer progression-free survival (predicted median of 30.5 months) compared with placebo (median of 19.3 months) (hazard ratio, 0.46; 95% confidence interval, 0.31-0.69; p = 0.0001). The most commonly observed adverse effects of vandetanib include nausea, diarrhea, headache, rash, prolongation of the Q-T interval, and hypertension. Because it can prolong the Q-T interval, vandetanib is contraindicated for use in patients with serious cardiac complications, including congenital long QT syndrome, bradyarrhythmias, uncompensated heart failure, and a history of torsades de pointes. CONCLUSION: Vandetanib has been shown to be more effective than placebo in the treatment of advanced MTC; however, it has not been compared with radiation, resection, or embolization. Vandetanib also has significant and fairly common cardiac toxicities. The cost, benefits, and risks of vandetanib for patients with MTC should be weighed, as alternative treatments remain an option for most patients. PMID- 23640347 TI - Managing depression in patients with advanced heart failure awaiting transplantation. AB - PURPOSE: The relative merits of various forms of antidepressant therapy in patients with heart failure (HF) are discussed, including disease-specific pharmacokinetic changes and drug-interaction challenges in current or likely future candidates for heart transplantation. SUMMARY: There is a growing emphasis on the use of antidepressants in patients with chronic HF, as depression can have a negative impact on HF progression and morbidity and mortality after heart transplants or other invasive cardiac surgery. Evidence from one small study of patients with concomitant end-stage HF and major depression indicated a reduced risk of cardiovascular death in those receiving beta-blockers in combination with selective serotonin-reuptake inhibitor (SSRI) therapy. In addition to pharmacokinetic changes caused by HF itself, which can decrease medication absorption and distribution, other issues to consider in the drug selection process include the potential for antidepressants to interact with posttransplant immunosuppressive therapy and the possible effects of antidepressant use on surgical transfusion requirements. The SSRIs are generally recommended as first line therapies for depressed patients with HF; however, fluvoxamine and fluoxetine should be avoided due to interactions with immunosuppressant agents. If SSRI therapy is not well tolerated or adjunctive therapy is required, bupropion, mirtazapine, venlafaxine, and duloxetine may be suitable alternatives for certain patients. CONCLUSION: Key considerations in antidepressant selection in the context of advanced HF include HF-related changes in drug pharmacokinetics that may affect initial dosing or dosage adjustment, possible drug interactions, adverse effects that may potentiate those induced by immunosuppressants added after transplantation, and tolerability issues. PMID- 23640348 TI - Toxic epidermal necrolysis associated with rifaximin. AB - PURPOSE: The case of a patient who developed toxic epidermal necrolysis (TEN) after treatment with rifaximin for hepatic encephalopathy is reported. SUMMARY: A 62-year-old Caucasian woman with a history of alcohol abuse arrived at the emergency room with complaints of abdominal pain and acute onset of jaundice, likely secondary to alcoholic hepatitis. Laboratory tests and multiple imaging studies conducted in the emergency department revealed signs of chronic liver disease and common bile duct dilation with ascites. At admission, she had low concentrations of serum sodium, serum chloride, serum creatinine, and serum albumin and elevated liver function test values. On hospital day 7, the patient developed an altered mental status, which was diagnosed as toxic metabolic encephalopathy, primarily hepatic in origin. The patient was given lactulose 20 g via nasogastric tube every 12 hours and rifaximin 400 mg orally every 8 hours. The patient received only two doses of the rifaximin before it was discontinued. On hospital day 27, oral rifaximin 550 mg twice daily was initiated. After 12 days of rifaximin therapy, the patient developed a diffuse, erythematous, maculopapular, and desquamating cutaneous reaction on her chest, arms, and legs. The suspected diagnosis was determined to be a severe cutaneous adverse drug reaction, possibly TEN. Use of the Naranjo et al. scale revealed that rifaximin was a possible cause of the reaction. Rifaximin was discontinued, and antihistamines and i.v. corticosteroids were initiated. The reaction completely resolved after one week. CONCLUSION: A 62-year-old woman developed possible TEN after receiving rifaximin to treat hepatic encephalopathy. PMID- 23640349 TI - Enhancing diabetes care by adding a pharmacist to the primary care team. AB - PURPOSE: The impact of pharmacist interventions on short-term clinical markers and long-term cardiovascular risk in patients with type 2 diabetes is investigated. METHODS: Selected health outcomes were retrospectively analyzed in 147 adults with type 2 diabetes whose care was managed by a team of providers including a pharmacist (the enhanced care group) and a matched sample of patients (n = 147) managed by a primary care physician only (the control group). All patients received services through the same health maintenance organization (HMO). The primary study endpoints were (1) the changes from baseline to 12-month follow-up in glycosylated hemoglobin (HbA(1c)), low-density lipoprotein cholesterol (LDL-C), and blood pressure (BP) values, (2) rates of attainment of HbA(1c), LDL-C and BP goals, and (3) changes from baseline in predicted 10-year risks of coronary heart disease (CHD) and stroke. RESULTS: During the 12-month study period, the mean HbA(1c) value was decreased from 9.5% to 6.9% in the enhanced care group and from 9.3% to 8.4% in the control group (p < 0.001); patients in the enhanced care group were significantly more likely to attain goals for HbA(1c) (odds ratio [OR], 3.9), LDL-C (OR, 2.0), and BP reduction (OR, 2.0) and three times more likely to attain all three goals (OR, 3.2). The estimated 10-year risk of CHD was decreased from 16.4% to 9.3% with enhanced care versus a reduction from 17.4% to 14.8% with usual care (p < 0.001). CONCLUSION: The addition of a pharmacist to an HMO primary care team improved short-term surrogate markers as well as long-term cardiovascular risk in adult patients with type 2 diabetes. PMID- 23640350 TI - Resources used to support postgraduate year 1 pharmacy residencies: survey of residency program directors. AB - PURPOSE: The results of a survey to identify personnel time, funding, and other resources used to support existing postgraduate year 1 (PGY1) pharmacy residencies and to determine potential residency program expansion are reported. METHODS: An electronic survey was distributed to PGY1 residency program directors (RPDs). Respondents were asked to provide demographic information and to characterize resources used to support their training programs. RESULTS: The survey response rate was 62%, representing 493 respondents. About 21% indicated their formal job descriptions identified them as a PGY1 RPD, and 8% replied that time expectations to perform the residency functions were specified. Up to 69% of respondents estimated that the time spent performing residency functions was 5-16 hours weekly. Other personnel who facilitated pharmacy residency logistics included administrative assistants, coordinators, and pharmacists, devoting approximately 1-8 hours weekly to the residency program. Half of respondents indicated their PGY1 programs received funding through the Centers for Medicare and Medicaid Services (CMS) pass-through reimbursement; 30% were not eligible, 11% had not considered such reimbursement due to the amount of work required, and 9% did not know if their sites received such funding. CONCLUSION: A survey of PGY1 RPDs collected a wide range of information about the resources used to support their programs and about future plans. Almost half of respondents anticipated expanding their PGY1 residency program capacity, and responses made it clear that adequate documentation was important for programs applying for CMS pass-through reimbursement and facing an audit. PMID- 23640351 TI - Stability of extemporaneously compounded diltiazem hydrochloride infusions stored in polyolefin bags. AB - PURPOSE: The stability of extemporaneously compounded diltiazem hydrochloride infusions stored in polyolefin bags was studied. METHODS: Sterile preparations of diltiazem hydrochloride were compounded to a concentration of 1 mg/mL in 5% dextrose solutions in accordance with United States Pharmacopeia chapter 797. The infusions were stored at -20 degrees C, 2-6 degrees C, and 22-25 degrees C. Three samples from each temperature were withdrawn and assessed for stability immediately after preparation (day 0) and on days 7, 15, 21, and 30 using a high performance liquid chromatography (HPLC) assay. The physical stability of diltiazem samples was assessed by visual examination. Infusions were evaluated against black and white backgrounds for evidence of visible particulate matter, cloudiness, and color changes. The concentration of diltiazem hydrochloride in all samples was examined using a stability-indicating HPLC method at each time point. Diltiazem was considered stable if the solution retained over 90% of the initial concentration. RESULTS: No precipitation, cloudiness, or color change was observed at any of the temperatures studied. pH did not significantly increase or decrease among the samples, regardless of temperature, over the study period. The diltiazem hydrochloride infusions retained greater than 90% of the initial concentrations for at least 30 days. CONCLUSION: Diltiazem hydrochloride diluted to 1 mg/mL in 5% dextrose injection was stable for 30 days when stored at -20 degrees C, 2-6 degrees C, and 22-25 degrees C. PMID- 23640353 TI - Clinical decision support for drug-drug interactions: improvement needed. PMID- 23640352 TI - Changing transplant recipient education and inpatient transplant pharmacy practices: a single-center perspective. AB - PURPOSE: Pharmacists' contributions to improved inpatient medication practices and educational services for kidney transplant recipients at a community hospital were evaluated. SUMMARY: A retrospective observational analysis was conducted using demographic and case data collected during the year before (2007) and three years after (2011) the inclusion of pharmacists on the hospital's interdisciplinary kidney transplant team. Qualitative variables assessed included changes in prescribing practices, inpatient and outpatient transplant personnel, discharge planning processes, medication reconciliation, educational practices, and transplant program workflow; quantitative variables included average hospital length of stay (LOS), Scientific Registry of Transplant Recipients data, readmission rates, and reimbursement data. A comparison of data on kidney transplant procedures performed at the hospital in 2007 (n = 60) and 2011 (n = 54) indicated that the implementation of specialized transplant pharmacy services was particularly beneficial in the areas of inpatient medication management, medication reconciliation, discharge planning, and patient education. Program outcomes related to the inclusion of pharmacists on the kidney transplant team included a decrease in the mean LOS among transplant recipients (from 7.8 days in 2007 to 3.4 days in 2011, p < 0.001), with no adverse effect on all-cause 30-, 90 , and >90-day readmission rates (all p > 0.09). Annual cost savings attributable to the reduction in LOS were estimated at $279,180. CONCLUSION: The participation of pharmacists on the kidney transplant team enhanced a hospital's medication management, discharge planning, and patient education services for transplant recipients, helping to reduce their average LOS and yielding substantial cost savings. PMID- 23640354 TI - Drug eluting stents in the treatment of below the knee arterial occlusive disease. AB - The use of endovascular techniques for the treatment of occlusive arterial disease below the knee has gained widespread acceptance and is considered by many as the first line treatment for patients with critical limb ischaemia. Tibial angioplasty and stenting have a high rate of technical success and are relatively low risk procedures, which has widened their applicability to include treatment for the elderly and those with comorbidities unsuitable for open bypass surgery. Despite these advantages the durability of the percutaneous revascularisation remains inferior to that of open surgery for diffusely diseased arteries. In the search to improve their long term performance we have sought to investigate the role of coronary drug eluting stents (DES) in the tibial vasculature in the hope that they may reduce recurrent stenosis, the leading threat to interventional patency. Ample data now exists in the form of registries and randomised trials designed to evaluate the use of DES in the crural arteries below the knee. This article reviews this body of research, explores the use of these devices in more complex lesions, speculates on their future development and examines their cost effectiveness. PMID- 23640355 TI - First- and second-generation drug-eluting balloons for femoro-popliteal arterial obstructions: update of technique and results. AB - The use of drug-eluting balloons for treatment of long-segment femoropopliteal artery obstructions has become widespread in recent years. The possibility to deliver a drug into the arterial wall with sustained antiproliferative effects, without leaving behind metal scaffolding, seems very promising. The current generation of drug-eluting balloons differs in the formulation of the drug (usually paclitaxel), technique of coating, and the elution excipients. Results of published randomized trials are reviewed in this report. A new innovative coating technique has been introduced recently. The PRIMUS(r) coronary drug eluting balloon and the Legflow(r) peripheral drug-eluting balloon consist of paclitaxel nanoparticles that are embedded underneath the surface of the balloon as well as inside a new shellolic acid drug-release matrix. Risk for dislodgement of the paclitaxel particles is minimized in the newest generation of drug-eluting balloons. Short-term in vitro and in vivo results of this stable, coated balloon are promising, and large randomized trials have been started recently to gather more long-term and robust clinical data. PMID- 23640356 TI - Femoropopliteal in-stent restenosis: review and potential for drug based therapy. AB - Endovascular treatment of symptomatic peripheral arterial disease in the femoropopliteal (FP) artery is fraught with high rates of restenosis. Success of the antiproliferative drug, paclitaxel, in the coronary arteries, has lead to the investigation of paclitaxel in the peripheral arteries to treat restenosis. This article reviews restenosis rates for the major treatment modalities used in the FP segment. Use of drug-elution for restenosis is also reviewed, including the use of drug-eluting balloons and drug-eluting stents. PMID- 23640357 TI - Covered endovascular reconstruction of aortic bifurcation (CERAB) technique: a new approach in treating extensive aortoiliac occlusive disease. AB - Endovascular treatment of occlusive disease of the aortic bifurcation is challenging. We developed the Covered Endovascular Reconstruction of Aortic Bifurcation or CERAB-technique, as a new approach for extensive and/or recurrent aortoiliac occlusive disease using three covered balloon expandable stents to reconstruct the aortic bifurcation. This configuration provides the ability to deal with TransAtlantic Inter-Society Consensus (TASC II) C and D lesions, simulating a neo-bifurcation or flow divider in combination with the benefits of covered stents. The intervention can be performed percutaneously or as a hybrid procedure. Initial results are encouraging and further studies are indicated. PMID- 23640358 TI - Access site bleeding after transcatheter aortic valve implantation. AB - Surgical aortic valve replacement improves morbidity and mortality in patients with severe aortic valve stenosis and is treatment of choice for symptomatic patients. As high, one-third of patients with severe AS are considered inoperable due to associated high surgical risk. Recently, transcatheter aortic valve implantation (TAVI) has been demonstrated to improve survival, quality of life, and functional status in patients who are considered inoperable due to high risk of surgery. However, access site and non-access site bleeding are major procedural complications after TAVI and are associated with worse clinical outcomes. In this review, we systematically study the access site complication associated with TAVI and approaches that can minimize these complications. PMID- 23640360 TI - A shift in the dominant phenotype governs the pH-induced metabolic switch of Clostridium acetobutylicumin phosphate-limited continuous cultures. AB - In response to changing extracellular pH levels, phosphate-limited continuous cultures of Clostridium acetobutylicum reversibly switches its metabolism from the dominant formation of acids to the prevalent production of solvents. Previous experimental and theoretical studies have revealed that this pH-induced metabolic switch involves a rearrangement of the intracellular transcriptomic, proteomic and metabolomic composition of the clostridial cells. However, the influence of the population dynamics on the observations reported has so far been neglected. Here, we present a method for linking the pH shift, clostridial growth and the acetone-butanol-ethanol fermentation metabolic network systematically into a model which combines the dynamics of the external pH and optical density with a metabolic model. Furthermore, the recently found antagonistic expression pattern of the aldehyde/alcohol dehydrogenases AdhE1/2 and pH-dependent enzyme activities have been included into this combined model. Our model predictions reveal that the pH-induced metabolic shift under these experimental conditions is governed by a phenotypic switch of predominantly acidogenic subpopulation towards a predominantly solventogenic subpopulation. This model-driven explanation of the pH-induced shift from acidogenesis to solventogenesis by population dynamics casts an entirely new light on the clostridial response to changing pH levels. Moreover, the results presented here underline that pH-dependent growth and pH dependent specific enzymatic activity play a crucial role in this adaptation. In particular, the behaviour of AdhE1 and AdhE2 seems to be the key factor for the product formation of the two phenotypes, their pH-dependent growth, and thus, the pH-induced metabolic switch in C. acetobutylicum. PMID- 23640361 TI - Characterization of four TCE-dechlorinating microbial enrichments grown with different cobalamin stress and methanogenic conditions. AB - To investigate the important supportive microorganisms responsible for trichloroethene (TCE) bioremediation under specific environmental conditions and their relationship with Dehalococcoides (Dhc), four stable and robust enrichment cultures were generated using contaminated groundwater. Enrichments were maintained under four different conditions exploring two parameters: high and low TCE amendments (resulting in inhibited and uninhibited methanogenic activity, respectively) and with and without vitamin B12 amendment. Lactate was supplied as the electron donor. All enrichments were capable of reductively dechlorinating TCE to vinyl chloride and ethene. The dechlorination rate and ethene generation were higher, and the proportion of electrons used for dechlorination increased when methanogenesis was inhibited. Biologically significant cobalamin biosynthesis was detected in the enrichments without B12 amendment. Comparative genomics using a genus-wide microarray revealed a Dhc genome similar to that of strain 195 in all enrichments, a strain that lacks the major upstream corrin ring biosynthesis pathway. Seven other bacterial operational taxonomic units (OTUs) were detected using clone libraries. OTUs closest to Pelosinus, Dendrosporobacter, and Sporotalea (PDS) were most dominant. The Clostridium-like OTU was most affected by B12 amendment and active methanogenesis. Principal component analysis revealed that active methanogenesis, rather than vitamin B12 limitation, exerted a greater effect on the community structures even though methanogens did not seem to play an essential role in providing corrinoids to Dhc. In contrast, acetogenic bacteria that were abundant in the enrichments, such as PDS and Clostridium sp., may be potential corrinoid providers for Dhc. PMID- 23640363 TI - Marine bacteria: potential sources for compounds to overcome antibiotic resistance. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is the most problematic Gram positive bacterium in the context of public health due to its resistance against almost all available antibiotics except vancomycin and teicoplanin. Moreover, glycopeptide-resistant S. aureus have been emerging with the increasing use of glycopeptides. Recently, resistant strains against linezolid and daptomycin, which are alternative drugs to treat MRSA infection, have also been reported. Thus, the development of new drugs or alternative therapies is clearly a matter of urgency. In response to the antibiotic resistance, many researchers have studied for alternative antibiotics and therapies. In this review, anti-MRSA substances isolated from marine bacteria, with their potential antibacterial effect against MRSA as potential anti-MRSA agents, are discussed and several strategies for overcoming the antibiotic resistance are also introduced. Our objective was to highlight marine bacteria that have potential to lead in developing novel antibiotics or clinically useful alternative therapeutic treatments. PMID- 23640364 TI - Metabolic flux analysis of Gluconacetobacter xylinus for bacterial cellulose production. AB - Metabolic flux analysis was used to reveal the metabolic distributions in Gluconacetobacter xylinus (CGMCC no. 2955) cultured on different carbon sources. Compared with other sources, glucose, fructose, and glycerol could achieve much higher bacterial cellulose (BC) yields from G. xylinus (CGMCC no. 2955). The glycerol led to the highest BC production with a metabolic yield of 14.7 g/mol C, which was approximately 1.69-fold and 2.38-fold greater than that produced using fructose and glucose medium, respectively. The highest BC productivity from G. xylinus CGMCC 2955 was 5.97 g BC/L (dry weight) when using glycerol as the sole carbon source. Metabolic flux analysis for the central carbon metabolism revealed that about 47.96 % of glycerol was transformed into BC, while only 19.05 % of glucose and 24.78 % of fructose were transformed into BC. Instead, when glucose was used as the sole carbon source, 40.03 % of glucose was turned into the by product gluconic acid. Compared with BC from glucose and fructose, BC from the glycerol medium showed the highest tensile strength at 83.5 MPa, with thinner fibers and lower porosity. As a main byproduct of biodiesel production, glycerol holds great potential to produce BC with superior mechanical and microstructural characteristics. PMID- 23640362 TI - Construction and analysis of a genetically tuneable lytic phage display system. AB - The Bacteriophage lambda capsid protein gpD has been used extensively for fusion polypeptides that can be expressed from plasmids in Escherichia coli and remain soluble. In this study, a genetically controlled dual expression system for the display of enhanced green fluorescent protein (eGFP) was developed and characterized. Wild-type D protein (gpD) expression is encoded by lambda Dam15 infecting phage particles, which can only produce a functional gpD protein when translated in amber suppressor strains of E. coli in the absence of complementing gpD from a plasmid. However, the isogenic suppressors vary dramatically in their ability to restore functional packaging to lambdaDam15, imparting the first dimension of decorative control. In combination, the D-fusion protein, gpD::eGFP, was supplied in trans from a multicopy temperature-inducible expression plasmid, influencing D::eGFP expression and hence the availability of gpD::eGFP to complement for the Dam15 mutation and decorate viable phage progeny. Despite being the worst suppressor, maximal incorporation of gpD::eGFP into the lambdaDam15 phage capsid was imparted by the SupD strain, conferring a gpDQ68S substitution, induced for plasmid expression of pD::eGFP. Differences in size, fluorescence and absolute protein decoration between phage preparations could be achieved by varying the temperature of and the suppressor host carrying the pD::eGFP plasmid. The effective preparation with these two variables provides a simple means by which to manage fusion decoration on the surface of phage lambda. PMID- 23640365 TI - LPS-protein aggregation influences protein partitioning in aqueous two-phase micellar systems. AB - Lipopolysaccharide endotoxins (LPS) are the most common pyrogenic substances in recombinant peptides and proteins purified from Gram-negative bacteria, such as Escherichia coli. In this respect, aqueous two-phase micellar systems (ATPMS) have already proven to be a good strategy to purify recombinant proteins of pharmaceutical interest and remove high LPS concentrations. In this paper, we review our recent experimental work in protein partitioning in Triton X-114 ATPMS altogether with some new results and show that LPS-protein aggregation can influence both protein and LPS partitioning. Green fluorescent protein (GFPuv) was employed as a model protein. The ATPMS technology proved to be effective for high loads of LPS removal into the micelle-rich phase (%REM(LPS) > 98 %) while GFPuv partitioned preferentially to the micelle-poor phase (K GFP(uv) < 1.00) due to the excluded-volume interactions. However, theoretically predicted protein partition coefficient values were compared with experimentally obtained ones, and good agreement was found only in the absence of LPS. Dynamic light scattering measurements showed that protein-LPS interactions were taking place and influenced the partitioning process. We believe that this phenomenon should be considered in LPS removal employing any kind of aqueous two-phase system. Nonetheless, ATPMS can still be considered as an efficient strategy for high loads of LPS removal, but being aware that the excluded-volume partitioning theory available might overestimate partition coefficient values due to the presence of protein-LPS aggregation. PMID- 23640366 TI - Flavoprotein oxidases: classification and applications. AB - This review provides an overview of oxidases that utilise a flavin cofactor for catalysis. This class of oxidative flavoenzymes has shown to harbour a large number of biotechnologically interesting enzymes. Applications range from their use as biocatalysts for the synthesis of pharmaceutical compounds to the integration in biosensors. Through the recent developments in genome sequencing, the number of newly discovered oxidases is steadily growing. Recent progress in the field of flavoprotein oxidase discovery and the obtained biochemical knowledge on these enzymes are reviewed. Except for a structure-based classification of known flavoprotein oxidases, also their potential in recent biotechnological applications is discussed. PMID- 23640367 TI - Building self-ordered tubular macro- and mesoporous nitridated titania from gas bubbles towards high-performance lithium-ion batteries. AB - Robust well-defined tubular structural materials based on macro- and mesoporous nitridated titania (TMMN-TiO2) were obtained by a simple solution-phase approach in ammonia solution. In this approach, the gas bubbles derived from ammonia solution play the role of templates that direct the ordered growth in the form of a tubular structure. The results demonstrated that the volume ratio of ammonia to water can be favorable for the formation of TMMN-TiO2, which are characterized by FESEM and FTIR. What is more, ammonia was used not only as the template but also as the nitrogen source. Interestingly, it was found that the TiO2 nanocrystals building blocks were assembled into an interconnected mesoporous skeleton and built in ordered tubular macroporous channels. This unique architecture provides many important features that are required for high-performance anodes, such as fast ion transport, high conductivity, and structure stability, thus enabling an electrode with outstanding lithium storage performance. For example, such an electrode delivers 112 mA h g(-1) capacity at 5100 mA g(-1) (30 C) even after 1200 cycles. PMID- 23640368 TI - Distribution of health-related social surplus in pharmaceuticals: an estimation of consumer and producer surplus in the management of high blood lipids and COPD. AB - BACKGROUND: Following suggestions that developers should be allowed to capture a defined share of the total value generated by their technologies, the amount of surplus accruing to the pharmaceutical industry has become an important concept when discussing policies to encourage innovation in healthcare. METHODS: Observational clinical and market data spanning over a period of 20 years were applied in order to estimate the social surplus generated by pharmaceuticals used in the management of high cholesterol and chronic obstructive pulmonary disease (COPD). The distribution of social surplus between consumers and producers was also computed and the dynamics of rent extraction examined. RESULTS: Health related social surplus increased consistently over time for both disease areas, mostly due to the launch of more effective technologies and a greater number of patients being treated for the conditions. However, the growth rate of social surplus differed for each disease and dissimilar patterns of distribution between consumer and producer surplus emerged across the years. For lipid-lowering therapies, yearly consumer surplus reaches 85 % of total health-related social surplus after the loss of exclusivity of major molecules, whilst for COPD it ranges from 54 to 69 %. Average producer surplus is approximately 25 % of total health-related social surplus in the lipid-lowering market between 1990 and 2010, and 37 % for COPD between 2001 and 2010. The share of surplus captured by non innovative generic producers also varies differently across periods for both markets, reaching 11.12 % in the case of lipid-lowering therapies but just 1.55 % in the case of COPD. CONCLUSION: A considerable amount of the value may be recouped by consumers only towards the end of the lifecycle. Elements affecting the distribution of social surplus vary across disease areas and include the market pricing structure and the pattern of clinical effectiveness observed over time. The application of a longer-term disease specific perspective may be required when assessing the cost-effectiveness of health technologies at launch. PMID- 23640370 TI - Effects of battery type and age on performance of rechargeable laryngoscopes. AB - Optimal visualization of the glottis can be crucial to successful laryngoscopy. Limited information has been published on the light intensity delivered from laryngoscopes powered by rechargeable batteries. In this study the laryngoscope light intensity delivered from 10 nickel metal hydride (NiMH), 7 nickel cadmium (NiCAD), and 2 lithium (LI) batteries with 3-5 or more years of clinical usage were tested in comparison to 5 new NiMH batteries. Each battery was charged in a new laryngoscope handle and recharging unit for 24 h before testing. Light intensity (lux) from the bulb in the laryngoscope handle was recorded at 3-min intervals under continuous loading until battery depletion. The mean times +/-1 standard deviation (SD) to minimum acceptable light output (2,000 lux from the handle) were new NiMH 70 +/- 1 min, 3-year-old NiMH 96 +/- 2 min, 5+ year-old NiCAD 45 +/- 22 min, and 5+ year-old LI 117 +/- 4 min. There were significant differences in the time to minimum light intensity among all groups (p = 0.00 0.04). All new and used batteries exceeded the minimum ISO standard of light intensity for more than 10 min. These data demonstrate that rechargeable laryngoscope batteries can safely be used for several years before requiring replacement. PMID- 23640372 TI - Metabolic syndrome and endometrial cancer: a meta-analysis. AB - We performed a systematic review and meta-analysis on the association of metabolic syndrome with endometrial cancer. A systematic literature search of electronic databases (Medline, ISI Web of Knowledge and Scopus) was conducted and complemented by cross-referencing to identify studies published before 31 January 2013. Core items of identified studies were independently extracted by two reviewers, and results were summarized by random effects meta-analysis. We identified six studies, which reported on 3,132 cancer cases. Metabolic syndrome was associated with an increased risk of endometrial cancer (RR: 1.89, 95 % CI 1.34-2.67, P < 0.001), with significant heterogeneity among studies (I (2) = 92 %, P < 0.001), but no indication for publication bias in the Egger's test (P = 0.240). A sensitivity analysis omitting two studies produced no heterogeneity (I (2) = 0 %) and attenuated the association (RR: 1.39, 1.31-1.48, P < 0.001). The risk estimates for any single factor of the syndrome were 2.21 (P < 0.001) for higher values of body mass index and/or waist, 1.81 (P = 0.044) for hyperglycemia, 1.81 (P = 0.024) for higher blood pressure values, and 1.17 (P < 0.001) for high triglyceride levels; there was no significant association with low HDL-cholesterol. Metabolic syndrome is associated with an increased risk of endometrial cancer; among the components of the syndrome, obesity/high waist is that more strongly associated with endometrial cancer. PMID- 23640371 TI - Requirement of phosphorylatable endothelial nitric oxide synthase at Ser-1177 for vasoinhibin-mediated inhibition of endothelial cell migration and proliferation in vitro. AB - Endothelial nitric oxide synthase (eNOS)-derived nitric oxide is a major vasorelaxing factor and a mediator of vasopermeability and angiogenesis. Vasoinhibins, a family of antiangiogenic prolactin fragments that include 16 K prolactin, block most eNOS-mediated vascular effects. Vasoinhibins activate protein phosphatase 2A, causing eNOS inactivation through dephosphorylation of eNOS at serine residue 1179 in bovine endothelial cells and thereby blocking vascular permeability. In this study, we examined whether human eNOS phosphorylation at S1177 (analogous to bovine S1179) influences other actions of vasoinhibins. Bovine umbilical vein endothelial cells were stably transfected with human wild-type eNOS (WT) or with phospho-mimetic (S1177D) or non phosphorylatable (S1177A) eNOS mutants. Vasoinhibins inhibited the increases in eNOS activity, migration, and proliferation following the overexpression of WT eNOS but did not affect these responses in cells expressing S1177D and S1177A eNOS mutants. We conclude that eNOS inhibition by dephosphorylation of S1177 is fundamental for the inhibition of endothelial cell migration and proliferation by vasoinhibins. PMID- 23640373 TI - Partial molar pregnancy after intracytoplasmic sperm injection occurring as a result of diploid sperm usage. AB - PURPOSE: Partial molar pregnancies are rare conceptions characterized by having 69 rather than 46 chromosomes, the additional chromosome complement usually occurring as a result of fertilization of the ovum by two sperm. Although assisted conception with intracytoplasmic sperm injection (ICSI) should prevent the development of a partial molar pregnancy, occasional cases have been described after assisted conception using ICSI. The objective of this study was to investigate the cause of partial molar pregnancy in a couple who had undertaken assisted conception with ICSI. METHODS: Fluorescent microsatellite genotyping of DNA from the couple and tissue from their partial molar pregnancy was performed in order to confirm diagnosis and investigate the origin of the additional chromosome set. RESULTS: Genotyping confirmed that the partial molar tissue was triploid with an additional chromosome complement from the father. Genotyping of additional loci proximal to the centromere demonstrated that the two paternal sets of chromosomes originated in a single sperm with a double complement of paternal DNA resulting from non-reduction at the second meiotic division. CONCLUSIONS: This study confirms that partial molar pregnancy may occur after assisted conception with ICSI and that this occurs as a result of fertilization with a diploid sperm. PMID- 23640375 TI - Divergent picornavirus from a Turkey with gastrointestinal disease. AB - A novel picornavirus, turkey avisivirus (TuASV), was identified from the feces of turkeys (Meleagris gallopavo) with gastrointestinal disease from a farm in Indiana. Its genome organization is as follows: 5' untranslated region (UTR)(IRES II) [VP0, VP3, VP1, 2A, 2B, 2C, 3A, 3B, 3C(pro), 3D(pol)] 3' UTR-poly(A). TuASV shares only 34% (P1), 36% (P2), and 35% (P3) amino acid identities with avihepatoviruses, indicating that it potentially represents a novel picornavirus genus. PMID- 23640374 TI - The significance of serum anti-Mullerian hormone (AMH) levels in patients over age 40 in first IVF treatment. AB - PURPOSE: Although studies of serum anti-Mullerian hormone (AMH) in predicting ovarian reserve are numerous, many studies utilized patients under age 40. However, the assessment of ovarian reserve is especially critical in older infertile women. This study evaluates the significance of AMH level in patients over age 40 at the time of their first in vitro fertilization (IVF) treatment. METHODS: Forty-nine women over age 40 were studied. Although serum samples were taken prior to their IVF treatments, the data of serum AMH of patients were not taken into consideration to determine the therapy strategy, including follicle induction in which clomiphene citrate and human menopausal gonadotropin were used. RESULT(S): Twelve out of 49 patients achieved a clinical pregnancy (24.4 %). There was a positive correlation between serum AMH levels and the number of oocytes retrieved (P < 0.0001). The ROC curve analysis for prediction of poor ovarian response, <=3 retrieved oocytes, showed that the optimum cut-off level was < 1.0 ng/mL for AMH. The lower AMH group (AMH < 1.0 ng/ml) showed less chance of undergoing embryo transfer than the higher AMH group (AMH >=1.0 ng/ml). There was no difference in pregnancy rate between the two groups. Five out of 12 pregnant women exhibited AMH levels of less than 0.4 ng/ml. CONCLUSION(S): Assessment of serum AMH concentration in older patients is useful for the prediction of oocytes numbers which may be obtained in IVF. A cut-off level of 1.0 ng/ml AMH can be used to predict poor ovarian response. This cut-off level of AMH of 1.0 ng/ml might be useful to predict whether patients could have an embryo transfer, but had no power to predict achieving pregnancy. On the other hand, our data also showed that patients over age 40 with extreme low levels of AMH still had a chance of pregnancy. PMID- 23640376 TI - Draft Genome Sequence of Meiothermus ruber H328, Which Degrades Chicken Feathers, and Identification of Proteases and Peptidases Responsible for Degradation. AB - Meiothermus ruber H328 was isolated from Arima Hot Springs, Kobe, Japan, as a moderate thermophile. It has a strong ability to degrade intact chicken feathers. The enzymatic mechanism of the strain for feather degradation is unclear. The draft genome suggests potent enzyme candidates for degradation of keratin, a hard to-degrade protein found in feathers. PMID- 23640377 TI - Complete Genome Sequence of the Probiotic Bifidobacterium thermophilum Strain RBL67. AB - Bifidobacterium thermophilum RBL67, an isolate from infant feces, exhibits bacteriocin-like antimicrobial activity against Listeria spp. and Salmonella spp. and protects HT29-MTX cells against Salmonella infection. Here, the complete genome sequence of the probiotic B. thermophilum strain RBL67 is presented. PMID- 23640378 TI - Genome Sequence of Stenotrophomonas maltophilia Strain AU12-09, Isolated from an Intravascular Catheter. AB - Stenotrophomonas maltophilia is an opportunistic nosocomial pathogen that is characterized by its high-level intrinsic resistance to a variety of antibiotics and its ability to form biofilms. Here, we report the draft genome sequence of Stenotrophomonas maltophilia AU12-09, isolated from an intravascular catheter tip. PMID- 23640379 TI - Complete Genome Sequence of Glaciecola psychrophila Strain 170T. AB - Here, we report the complete genome sequence of Glaciecola psychrophila strain 170(T), a novel species of the genus Glaciecola, isolated from sea ice at high latitude Arctic locations. The genome consists of a single chromosome (5,413,691 bp) and 5,363 genes. The genomics information will facilitate the study of the physiology, cold adaptation, and evolution of this genus. PMID- 23640380 TI - Draft Genome Sequence of Bacillus stratosphericus LAMA 585, Isolated from the Atlantic Deep Sea. AB - Bacillus stratosphericus LAMA 585 was isolated from the Mid-Atlantic-Ridge seafloor (5,500-m depth). This bacterium presents the capacity for cellulase, xylanase, and lipase production when growing aerobically in marine-broth media. Genes involved in the tolerance of oligotrophic and extreme conditions and prospection of biotechnological products were annotated in the draft genome (3.7 Mb). PMID- 23640381 TI - Autophagy in pancreatic acinar cells in caerulein-treated mice: immunolocalization of related proteins and their potential as markers of pancreatitis. AB - Drug-induced pancreatitis (DIP) is an underdiagnosed condition that lacks sensitive and specific biomarkers. To better understand the mechanisms of DIP and to identify potential tissue biomarkers, we studied experimental pancreatitis induced in male C57BL/6 mice by intraperitoneal injection of caerulein (10 or 50 MUg/kg) at 1-hr intervals for a total of 7 injections. Pancreata from caerulein treated mice exhibited consistent acinar cell autophagy and apoptosis with infrequent necrosis. Kinetic assays for serum amylase and lipase also showed a dose-dependent increase. Terminal deoxynucleotidyl transferase-mediated biotin dNTP nick labeling (TUNEL) detected dose-dependent acinar cell apoptosis. By light microscopy, autophagy was characterized by the formation of autophagosomes and autolysosomes (ALs) within the cytoplasm of acinar cells. Immunohistochemical studies with specific antibodies for proteins related to autophagy and pancreatic stress were conducted to evaluate these proteins as potential biomarkers of pancreatitis. Western blots were used to confirm immunohistochemical results using pancreatic lysates from control and treated animals. Autophagy was identified as a contributing process in caerulein-induced pancreatitis and proteins previously associated with autophagy were upregulated following caerulein treatment. Autophagosomes and ALs were found to be a common pathway, in which cathepsins, lysosome-associated membrane protein 2, vacuole membrane protein 1, microtubule-associated protein 1 light chain 3 (LC3), autophagy related protein 9, Beclin1, and pancreatitis-associated proteins were simultaneously involved in response to caerulein stimulus. Regenerating islet derived 3 gamma (Reg3gamma), a pancreatic acute response protein, was dose dependently induced in caerulein-treated mice and colocalized with the autophagosomal marker, LC3. This finding supports Reg3gamma as a candidate biomarker for pancreatic injury. PMID- 23640382 TI - Stereoselectivity in the cytochrome P450-dependent N-demethylation and flavin monooxygenase-dependent N-oxidation of N,N-dimethylamphetamine. AB - N,N-dimethylamphetamine (DMA), a methamphetamine (MA) analog, is known as a weak central nervous system stimulant. As DMA possesses a chiral center, we investigated the enantioselective formation of N,N-dimethylamphetamine N-oxide (DMANO) and MA from DMA using human liver microsomes, recombinant cytochrome P450 (CYP) 2D6, and flavin monooxygenases (FMO) 1 and 3. d-DMA was preferentially metabolized to MA, whereas l-DMA was more rapidly transformed to DMANO in human liver microsomes. CYP2D6 showed a preference for catalyzing N-demethylation of d DMA, and the intrinsic clearance (Clint) ratio of d-isomer to l-isomer was 1.41. FMO1 catalyzed the formation of slightly less d-DMANO than l-DMANO, and the Clint ratio of the D- to L-isomer was 0.78. The reverse was observed for the formation of DMANO by FMO3. However, given the minor contribution of FMO3 compared with FMO1, it would not affect the overall enantioselective formation of DMANO in human liver microsomes. Enantioselectivities in the formation of MA and DMANO in human liver microsomes were consistent with those of CYP2D6 and FMO1, respectively. PMID- 23640383 TI - Synthesis and antifungal activity of the novel triazole derivatives containing 1,2,3-triazole fragment. AB - A series of fluconazole analogues containing 1,2,3-triazole fragment have been designed and synthesized on the basis of the active site of the cytochrome P450 14alpha-demethylase (CYP51). Their structures were characterized by (1)H NMR, (13)C NMR and LC-MS. The MIC80 values indicate that the target compounds 1a-r showed higher activities against nearly all the fungi tested to some extent except against Aspergillus fumigatus. Compounds 1c, e, f, l and p showed 128 times higher activity (with the MIC80 value of 0.0039 mg/mL) than that of fluconazole against Candida albicans and also showed higher activity than that of the other positive controls. PMID- 23640384 TI - An outbreak of fungal endophthalmitis after intravitreal injection of compounded combined bevacizumab and triamcinolone. AB - IMPORTANCE: Our experience may be useful to other practitioners using compounded intravitreal agents, those suspecting infectious outbreaks, and those managing fungal endophthalmitis. OBJECTIVE: To describe a series of patients with fungal endophthalmitis following intravitreal injection of combined bevacizumab and triamcinolone acetonide prepared by the same compounding pharmacy. DESIGN AND SETTING: Noncomparative case series. PARTICIPANTS: Eight eyes of 8 patients who received an intravitreal injection of compounded combined bevacizumab triamcinolone in a period of 3 weeks had subtle, nonspecific findings that were later diagnosed as fungal endophthalmitis. MAIN OUTCOME MEASURES: Visual acuity, response to antimicrobial therapy, and number of vitreoretinal surgical operations after diagnosis of fungal endophthalmitis. RESULTS: Eight patients developed endophthalmitis 41 to 97 days after receiving the intravitreal injection, which was prepared by the same compounding pharmacy. The injections occurred at the same location in New York. Treatment was based on clinical examination findings and knowledge of the etiology of the endophthalmitis. Eventually, all patients were treated with oral voriconazole. Five of 8 patients were initially treated with intravitreal antimicrobial agents. After 3 months of follow-up, visual acuities ranged from 20/50 to hand motions. Local, state, and federal health department officials were involved in investigating the source of the outbreak. CONCLUSIONS AND RELEVANCE: In the current study, we report a fungal endophthalmitis outbreak after intravitreal injection of contaminated, compounded combined bevacizumab-triamcinolone. In this series, Bipolaris hawaiiensis was the identified causative agent. The challenge of medical diagnosis, identification of the source of the outbreak, and management experience are highlighted in our series. Our experience may be useful to other practitioners using compounded intravitreal agents, those suspecting infectious outbreaks, and those managing fungal endophthalmitis. PMID- 23640385 TI - Reply: To PMID 22941439. PMID- 23640386 TI - Surgical capping of superior semicircular canal dehiscence. AB - Surgical plugging and resurfacing are well established treatments of superior semicircular canal dehiscence, while capping with hydroxyapatite cement has been little discussed in literature. The aim of this study was to prove the efficacy of the capping technique. Charts of patients diagnosed with superior semicircular canal dehiscence were reviewed retrospectively. All patients answered the dizziness handicap inventory, a survey analyzing the impact of their symptoms on their quality of life. Capping of the dehiscent canal was performed via the middle fossa approach in all cases. Ten out of 22 patients diagnosed with superior semicircular canal dehiscence were treated with surgical capping, nine of which were included in this study. No major perioperative complications occurred. In 8 out of 9 (89%) patients, capping led to a satisfying reduction of the main symptoms. One patient underwent revision surgery 1 year after the initial intervention. Scores in the dizziness handicap inventory were lower in the surgically treated group than in the non-surgically treated group, but results were not statistically significant (P = 0.45). Overall, capping is a safe and efficient alternative to plugging and resurfacing of superior semicircular canal dehiscence. PMID- 23640387 TI - Gridded inventories of historical usage for selected organochlorine pesticides in Gansu Province, China. AB - HCHs and DDTs were banned in 1983 in China; however, they are still remaining in various environmental media. Since endosulfan was introduced in China in 1994, it is widely used in agriculture. In this study, temporal and spatial uses of endosulfan, HCHs, and DDTs in Gansu province of China have been presented. It is estimated that the total usage is 701 tons for endosulfan between 1994 and 2007, 1,712 tons for HCHs between 1952 and 1983, and 462 tons for DDTs between 1951 and 1983, respectively. Endosulfan usage increased dramatically in 1998 due to its application on other crops except on cotton. The HCH and DDT usage displayed a rapid increase after 1972, reaching the peak in 1976 and in 1975, respectively; since then, they declined until being banned in 1983. The gridded usage inventories of these three kinds of organochlorine pesticides in Gansu province, with a 1/4 degrees longitude by 1/6 degrees latitude resolution, have been created by using different crops for endosulfan and the area of dry farmland for HCHs and DDTs as surrogate data. The most intensive use was in northwestern regions for endosulfan and southeastern regions for HCHs and DDTs in Gansu province. PMID- 23640388 TI - Is an assessment factor of 10 appropriate to account for the variation in chemical toxicity to freshwater ectotherms under different thermal conditions? AB - Ecotoxicity tests are often conducted following standard methods, and thus carried out at a fixed water temperature under controlled laboratory conditions. Yet, toxicity of a chemical contaminant may vary in a temperature-dependent manner, depending on the physiology of the test organism and physicochemical properties of the chemical. Although an assessment factor of 10 (AF10) is commonly adopted to account for variability in toxicity data related to temperature in the development of water quality guidelines and/or ecological risk assessment, no one has ever rigorously assessed the appropriateness of AF10 to account for potential variation in temperature-dependent chemical toxicity to aquatic organisms. This study, therefore, aims to address this issue through a meta-analysis by comparing median lethal concentration data for nine chemicals (cadmium, copper, nickel, lead, silver, zinc, arsenic, selenium and DDT) on a range of freshwater ectothermic animal species at different temperatures, and to assess whether AF10 is under- or over-protective for tropical and temperate freshwater ecosystems. Our results reveal varying extents of interaction between temperature and different chemicals on organisms and the complexity of these interactions. Applying AF10 sufficiently protects 90% of the animal species tested over a range of temperatures for cadmium, copper, nickel, silver, zinc and DDT in the tropics, but it is insufficient to adequately encompass a larger temperature variation for most studied chemicals in temperate regions. It is therefore important to set specific AFs for different climatic zones in order to achieve the desired level of ecosystem protection. PMID- 23640389 TI - Assessment of DNA damage in Brazilian workers occupationally exposed to pesticides: a study from Central Brazil. AB - We evaluated 41 rural workers occupationally exposed to pesticides and 32 subjects as a control group, using the micronucleus (MN) and the comet assay. For the comet assay, we evaluated the peripheral blood, and for the MN, we sampled cells from the oral epithelium. Damage to DNA was measured by tail length, % DNA in tail (% tail), olive tail moment (OTM), and tail moment (TM). The exposed group presented an 8* increase in MN frequency, when compared to the control group (p <0.05). When we contrasted the MN frequencies between the individuals that use and do not use personal protective equipment, we found a mean of 7.5 MN (57 % variance) and 12.1 MN (130 % variance), respectively. The binucleated cells were 0.04 and 0.005, in the exposed and control groups, respectively, indicating 8* increase in the number of binucleated cells, when comparing the groups (p <0.05). In the comet assay, we demonstrated statistically significant differences in three parameters (% DNA, OTM, and TM) indicating that the rural workers presented high levels of genomic damages. Our results indicate that occupational exposure to pesticides could cause genome damage in somatic cells, representing a potential health risk to Brazilian rural workers that deal constantly with agrochemicals without adequate personal protection equipment. PMID- 23640390 TI - Assessment of Arthrobacter viscosus as reactive medium for forming permeable reactive biobarrier applied to PAHs remediation. AB - Polycyclic aromatic hydrocarbons (PAHs) are significant environmental contaminants as they are present naturally as well as anthropogenically in soil, air and water. In spite of their low solubility, PAHs are spread to the environment, and they are present in surface water, industrial effluent or groundwater. Amongst all remediation technologies for treating groundwater contaminated with PAHs, the use of a permeable reactive biobarrier (PRBB) appears to be the most cost-effective, energy efficient, and environmentally sound approach. In this technology, the microorganisms are used as reactive medium to degrade or stabilize the contaminants. The main limits of this approach are that the microorganisms or consortium used for forming the PRBB should show adequate characteristics. They must be retained in the barrier-forming biofilm, and they should also have degradative ability for the target pollutants. The aim of the present work is to evaluate the viability of Arthrobacter viscosus as bioreactive medium for forming PRBB. Initially, the ability of A. viscosus to remove PAHs, benzo[a]anthracene 100 MUM and phenanthrene 100 MUM was evaluated operating in a batch bench-scale bioreactor. In both cases, total benzo[a]anthracene and phenanthrene removals were obtained after 7 and 3 days, respectively. Furthermore, the viability of the microorganisms was evaluated in the presence of chromium in a continuous mode. As a final point, the adhesion of A. viscosus to sepiolite forming a bioreactive material to build PRBB was demonstrated. In view of the attained results, it can be concluded that A. viscosus could be a suitable microorganism to form a bioreactive medium for PAHs remediation. PMID- 23640391 TI - Mutagenicity and genotoxicity assessment of industrial wastewaters. AB - The genotoxicity of industrial wastewaters from Jajmau (Kanpur), was carried out by Ames Salmonella/microsome test, DNA repair-defective mutants, and Allium cepa anaphase-telophase test. Test samples showed maximum response with TA98 strain with and without metabolic activation. Amberlite resins concentrated wastewater samples were found to be more mutagenic as compared to those of liquid-liquid extracts (hexane and dichloromethane extracts). The damage in the DNA repair defective mutants in the presence of Amberlite resins concentrated water samples were found to be higher to that of liquid-liquid-extracted water samples at the dose level of 20 MUl/ml culture. Among all the mutants, polA exhibited maximum decline with test samples. Mitotic index (MI) of root tip meristematic cells of A. cepa treated with 5, 10, 25, 50, and 100 % (v/v) wastewaters were significantly lower than the control. Complementary to the lower levels of MI, the wastewaters showed higher chromosomal aberration levels in all cases investigated. PMID- 23640392 TI - [Traumatic cyst of the mandible. From development to therapy - a case report]. AB - Traumatic bone cysts, also referred to as simple bone cysts, solitary bone cysts and haemorrhagic bone cysts, are intraosseous pseudocysts and are categorized by the WHO (2005) as benign, bone-related lesions. Most often young patients under the age of twenty are affected. Symptoms are uncommon and normally the lesion is found in routine radiographic examinations in the mandible. The etiology is still unknown and it has been discussed that trauma, benign tumours or abnormal bone growth might be the cause. Surgical treatment is recommended and recurrence is rare. Histologic features of pseudocysts are a lack of lining epithelium and often an empty bone cavity can be found. The following case report presents a traumatic cyst in the mandible of a 14-year old female patient. Clinical, radiological and histopathological characteristics of this entity will be discussed as well as therapy and follow-up. PMID- 23640393 TI - Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102). AB - BACKGROUND: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival. METHODS: Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1-5, vincristine 0.7 mg m(-2) day 5, mitomycin 7 mg m(-2) day 5, cisplatin 14 mg m(-2) days 1-5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival. RESULTS: A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85). CONCLUSION: Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT. PMID- 23640394 TI - Body size in relation to incidence of subtypes of haematological malignancy in the prospective Million Women Study. AB - BACKGROUND: Greater adiposity and height have been associated with increased risk of haematological malignancies. Associations for disease subtypes are uncertain. METHODS: A cohort of 1.3 million middle-aged U.K. women was recruited in 1996 2001 and followed for 10 years on average. Potential risk factors were assessed by questionnaire. Death, emigration, and incident cancer were ascertained by linkage to national registers. Adjusted relative risks were estimated by Cox regression. RESULTS: During follow-up, 9162 participants were diagnosed with lymphatic or haematopoietic cancers. Each 10 kg m(-2) increase in body mass index was associated with relative risk of 1.20 (95% confidence interval: 1.13-1.28) for lymphoid and 1.37 (1.22-1.53) for myeloid malignancy (P=0.06 for heterogeneity); similarly, Hodgkin lymphoma 1.64 (1.21-2.21), diffuse large B cell lymphoma 1.36 (1.17-1.58), plasma cell neoplasms 1.21 (1.06-1.39), acute myeloid leukaemia 1.47 (1.19-1.81), and myeloproliferative/myelodysplastic syndromes 1.32 (1.15-1.52). Each 10 cm increase in height was associated with relative risk of 1.21 (1.16-1.27) for lymphoid and 1.11 (1.02-1.21) for myeloid malignancy (P=0.07 for heterogeneity); similarly, mature T-cell malignancies 1.36 (1.03-1.79), diffuse large B-cell lymphoma 1.28 (1.14-1.43), follicular lymphoma 1.28 (1.13-1.44), plasma cell neoplasms 1.12 (1.01-1.24), chronic lymphocytic leukaemia/small lymphocytic lymphoma 1.23 (1.08-1.40), and acute myeloid leukaemia 1.22 (1.04-1.42). There was no significant heterogeneity between subtypes. CONCLUSION: In middle-aged women, greater body mass index and height were associated with modestly increased risks of many subtypes of haematological malignancy. PMID- 23640395 TI - Myeloid-derived suppressor cells have a central role in attenuated Listeria monocytogenes-based immunotherapy against metastatic breast cancer in young and old mice. AB - BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are present in large numbers in blood of mice and humans with cancer, and they strongly inhibit T-cell and natural killer (NK) cell responses, at young and old age. We found that a highly attenuated bacterium Listeria monocytogenes (Listeria(at))-infected MDSC and altered the immune-suppressing function of MDSC. METHODS: Young (3 months) and old (18 months) BALB/cByJ mice with metastatic breast cancer (4T1 model) were immunised with Listeria(at) semi-therapeutically (once before and twice after tumour development), and analysed for growth of metastases and primary tumour, in relation to MDSC-, CD8 T-cell and NK cell responses. RESULTS: We found that Listeria(at)-infected MDSC, which delivered Listeria(at) predominantly to the microenvironment of metastases and primary tumours, where they spread from MDSC into tumour cells (infected tumour cells will ultimately become a target for Listeria-activated immune cells). Immunotherapy with Listeria(at) significantly reduced the population of MDSC in blood and primary tumours, and converted a remaining subpopulation of MDSC into an immune-stimulating phenotype producing IL 12, in correlation with significantly improved T-cell and NK cell responses to Listeria(at) at both ages. This was accompanied with a dramatic reduction in the number of metastases and tumour growth at young and old age. CONCLUSIONS: Although preclinical studies show that immunotherapy is less effective at old than at young age, our study demonstrates that Listeria(at)-based immunotherapy can be equally effective against metastatic breast cancer at both young and old age by targeting MDSC. PMID- 23640396 TI - Measures of promptness of cancer diagnosis in primary care. PMID- 23640397 TI - Reply: Timeliness, risk communication and patient preferences for investigations or referral. PMID- 23640400 TI - ShearWave elastography: repeatability for measurement of tendon stiffness. PMID- 23640401 TI - How to interpret current-voltage relationships of blocking grain boundaries in oxygen ionic conductors. AB - A new model based on a linear diffusion equation is proposed to explain the current-voltage characteristics of blocking grain boundaries in Y-doped CeO2 in particular. One can also expect that the model can be applicable to the ionic conductors with blocking grain boundaries, in general. The model considers an infinitely long chain of identical grains separated by grain boundaries, which are treated as regions in which depletion layers of mobile ions are formed due to trapping of immobile charges that do not depend on the applied voltage as well as temperature. The model assumes that (1) the grain boundaries do not represent physical blocking layers, which implies that if there is a second phase at the grain boundaries, then it is too thin to impede ion diffusion and (2) the ions follow Boltzmann distribution throughout the materials. Despite its simplicity, the model successfully reproduces the "power law": current proportional to voltage power n and illustrated with the experimental example of Y-doped ceria. The model also correctly predicts that the product nT, where T is the temperature in K, is constant and is proportional to the grain boundary potential as long as the charge at the grain boundaries remains trapped. The latter allows its direct determination from the current-voltage characteristics and promises considerable simplification in the analysis of the electrical characteristics of the grain boundaries with respect to the models currently in use. PMID- 23640402 TI - Oxorhenium(V) complexes of quinoline and isoquinoline carboxylic acids- synthesis, structural characterization and catalytic application in epoxidation reactions. AB - Six novel oxorhenium(V) complexes incorporating quinoline and isoquinoline carboxylic acid derivatives were prepared in good yields. Relying on the experimental conditions, compounds with two chelate ligands [ReOCl(iqc)2].MeOH (1), [ReO(OMe)(iqc)2] (2), [ReO(OMe)(mqc)2] (3) and [ReO(OMe)(8-qc)2] (4) and compounds incorporating one bidentate ligand [ReOCl2(iqc)(PPh3)] (5) and [ReOCl2(mqc)(PPh3)] (6) were synthesized (iqcH = isoquinoline-1-carboxylic acid, mqcH = 4-methoxy-2-quinolinecarboxylic acid and 8-qcH = 8-quinolinecarboxylic acid). The reported compounds were characterized by spectroscopic methods and single crystal X-ray diffraction analysis. In compounds 1 and 2, one chelate ligand occupies an axial and an equatorial position, while the other one occupies two equatorial positions, forming a cis-(N,N) isomer. In turn, complexes 3 and 4 show a rare ligand arrangement with two trans-N, trans-O chelate ligands in the equatorial plane and a linear axial [O=Re-OMe] unit. The complexes with one chelate ligand 5 and 6 are cis-(Cl,Cl)-isomers. All compounds were tested as potential catalysts in the epoxidation of cyclooctene with 3 equiv. of tert butylhydroperoxide. The yield of cyclooctane oxide varies between 16 and 68% (50 degrees C, 24 h), and the catalytic competency of compounds 1-6 was discussed with regard to the structure of each complex. PMID- 23640403 TI - Estimation of in situ mating systems in wild sorghum (Sorghum bicolor (L.) Moench) in Ethiopia using SSR-based progeny array data: implications for the spread of crop genes into the wild. AB - Because transgenic sorghum (Sorghum bicolor L.) is being developed for Africa, we investigated the potential for transgenes to spread to conspecific wild/weedy sorghum populations in Ethiopia, which is considered the centre of origin of cultivated sorghum. In the current study, the extent of outcrossing, and uniparental and biparental inbreeding were investigated in seven wild/weedy sorghum populations collected at elevations ranging from 631 to 1709 m. Based on allele frequency data of 1120 progenies and 140 maternal plants from five polymorphic microsatellite markers, outcrossing rates were estimated using standard procedures. The average multilocus outcrossing rate was 0.51, with a range of 0.31-0.65 among populations, and the family outcrossing rate was in the extreme range of 0 to 100%. The highest outcrossing (t(m) = 0.65) was recorded in a weedy population that was intermixed with an improved crop variety in Abuare (Wello region). It was also observed that the inbreeding coefficient of the progenies (F(p)) tend to be more than the inbreeding coefficient of both their maternal parents (F(m)) and the level of inbreeding expected at equilibrium (F(eq)), which is a characteristic of predominantly outbreeding species. Biparental inbreeding was evident in all populations and averaged 0.24 (range = 0.10-0.33). The high outcrossing rates of wild/weedy sorghum populations in Ethiopia indicate a high potential for crop genes (including transgenes) to spread within the wild pool. Therefore, effective risk management strategies may be needed if the introgression of transgenes or other crop genes from improved cultivars into wild or weedy populations is deemed to be undesirable. PMID- 23640404 TI - Molecular adaptation within the coat protein-encoding gene of Tunisian almond isolates of Prunus necrotic ringspot virus. AB - The sequence alignments of five Tunisian isolates of Prunus necrotic ringspot virus (PNRSV) were searched for evidence of recombination and diversifying selection. Since failing to account for recombination can elevate the false positive error rate in positive selection inference, a genetic algorithm (GARD) was used first and led to the detection of potential recombination events in the coat protein-encoding gene of that virus. The Recco algorithm confirmed these results by identifying, additionally, the potential recombinants. For neutrality testing and evaluation of nucleotide polymorphism in PNRSV CP gene, Tajima's D, and Fu and Li's D and F statistical tests were used. About selection inference, eight algorithms (SLAC, FEL, IFEL, REL, FUBAR, MEME, PARRIS, and GA branch) incorporated in HyPhy package were utilized to assess the selection pressure exerted on the expression of PNRSV capsid. Inferred phylogenies pointed out, in addition to the three classical groups (PE-5, PV-32, and PV-96), the delineation of a fourth cluster having the new proposed designation SW6, and a fifth clade comprising four Tunisian PNRSV isolates which underwent recombination and selective pressure and to which the name Tunisian outgroup was allocated. PMID- 23640406 TI - Functional analysis of a Lemna gibba rbcS promoter regulated by abscisic acid and sugar. AB - Photosynthesis-associated nuclear genes (PhANGs) are able to respond to multiple environmental and developmental signals, including light, sugar and abscisic acid (ABA). PhANGs have been extensively studied at the level of transcriptional regulation, and several cis-acting elements important for light responsiveness have been identified in their promoter sequences. However, the regulatory elements involved in sugar and ABA regulation of PhANGs have not been completely characterized. A ribulose-1,5-bisphosphate carboxylase small subunit gene (rbcS) promoter (SSU5C promoter) was isolated from duckweed (Lemna gibba). A series of SSU5C promoter 5' deletion fragments were fused to an intron-gus gene, and transgenic tobacco suspension cell lines were generated. Assay of tobacco suspension cell line harbouring the complete promoter in the fusion construct indicated that SSU5C promoter was negatively regulated by sugar and ABA under the condition of regular photoperiod. 5' deletion analysis of SSU5C promoter in transgenic tobacco suspension cell lines confirmed that a region between positions -310 and -152 included the ABA-response region, and that sugar-response cis-acting elements might be located in the region between -152 and -117. Taken together, our results confirmed that the cis-regulatory region responsible for repression by ABA and sugar in the SSU5C promoter was located between -310 and 117. PMID- 23640405 TI - Auxin transport inhibitor induced low complexity petiolated leaves and sessile leaf-like stipules and architectures of heritable leaf and stipule mutants in Pisum sativum suggest that its simple lobed stipules and compound leaf represent ancestral forms in angiosperms. AB - In angiosperms, leaf and stipule architectures are inherited species-specific traits. Variation in leaf and stipule sizes, and forms result from the interaction between abiotic and biotic stimuli, and gene regulatory network(s) that underlie the leaf and stipule developmental programme(s). Here, correspondence between variation in leaf and stipule architectures described for extant angiosperms and that induced mutationally and by imposition of stress in model angiosperm species, especially in Pisum sativum, was detected. Following inferences were drawn from the observations. (i) Several leaf forms in P. sativum have origin in fusion of stipule and leaf primordia. Perfoliate (and amplexicaul and connate) simple sessile leaves and sessile adnate leaves are the result of such primordial fusions. Reversal of changes in the gene regulatory network responsible for fusion products are thought to restore original stipule and leaf conditions. (ii) Compound leaf formation in several different model plants, is a result of promotion of pathways for such condition by gene regulatory networks directed by KNOx1 and LEAFY transcription factors or intercalation of the gene networks directed by them. (iii) Gene regulatory network for compound leaves in P. sativum when mutated generates highly complex compound leaves on one hand and simple leaves on other hand. These altered conditions are mutationally reversible. (vi) Simple leaves in model plants such as Arabidopsis thaliana despite overexpression of KNOx1 orthologues do not become compound. (v) All forms of leaves, including simple leaf, probably have origins in a gene regulatory network of the kind present in P. sativum. PMID- 23640407 TI - Genetic dissection reveals effects of interaction between high-molecular-weight glutenin subunits and waxy alleles on dough-mixing properties in common wheat. AB - The glutenin and waxy loci of wheat are important determinants of dough quality. This study was conducted to evaluate the effects of high-molecular-weight glutenin (HMW-GS) and waxy alleles on dough-mixing properties. Molecular mapping was used to investigate these effects on Mixograph properties in a population of 290 (Nuomai1 x Gaocheng8901) recombinant inbred lines (RILs) from three environments in the harvest years 2008, 2009 and 2011. The results indicated the following: (i) the Glu-A1 and Glu-D1 loci have greater impacts on Mixograph properties compared to the Wx-1 loci and the effects of Glu-D1d and Glu-D1h on dough mixing are better than those of Glu-D1f and Glu-D1new1 in this population; (ii) the interactions between the Glu-1 and Wx-1 loci affected some traits, especially the midline peak value (MPV), and the lack of Wx-B1 or Wx-D1 led to increased MPV for all types of Glu-1 loci; and (iii) 30 quantitative-trait loci (QTL) over nine wheat chromosomes were identified with ICIM analysis based on the genetic map of 498 loci. Eight major QTL and 16 QTL in the Glu-1 loci from the three environments were found. The major QTL clusters were associated with the Glu-1 loci, and also were found in two regions on chromosome 3B and one region on chromosome 6A, which is one of the novel chromosome regions influencing dough mixing strength. The two QTL for MPV are located around Wx-B1 on chromosome 4A. QMPT-1D.1, QMPI-1D.1 and Q8MW-1D.1 were stable in different environments and could potentially be used in molecular marker-assisted breeding. PMID- 23640408 TI - New frameshift CF mutation 3729delAinsTCT in a Tunisian cystic fibrosis patient. PMID- 23640409 TI - Genome association study of human chromosome 13 and susceptibility to coronary artery disease in a Chinese population. PMID- 23640410 TI - Validation of PPP1R12B as a candidate gene for childhood asthma in Russians. PMID- 23640411 TI - Holoprosencephaly: report of four cases and genotype-phenotype correlations. PMID- 23640412 TI - Characterization of a genome-specific Gypsy-like retrotransposon sequence and development of a molecular marker specific for Dasypyrum villosum (L.). PMID- 23640413 TI - A study of the frequency of methylation of gene promoter regions in colorectal cancer in the Taiwanese population. PMID- 23640414 TI - Male-biased recombination in odonates: insights from a linkage map of the damselfly Ischnura elegans. PMID- 23640415 TI - Genomewide analysis of the chitinase gene family in Populus trichocarpa. PMID- 23640416 TI - Physical mapping of (GATA)n and (TTAGGG)n sequences in species of Hypostomus (Siluriformes, Loricariidae). PMID- 23640417 TI - Screening for genomic rearrangements at BRCA1 locus in Iranian women with breast cancer using multiplex ligation-dependent probe amplification. PMID- 23640418 TI - Polymorphisms of four pigmentation genes (SLC45A2, SLC24A5, MC1R and TYRP1) among eleven endogamous populations of India. PMID- 23640419 TI - Changes in genetic diversity parameters in unimproved and improved populations of teak (Tectona grandis L.f.) in Karnataka state, India. PMID- 23640420 TI - A single recessive gene controls fragrance in cucumber (Cucumis sativus L.). PMID- 23640421 TI - Identification of 40k gamma-secalin genes. PMID- 23640422 TI - Gene duplication as a major force in evolution. AB - Gene duplication is an important mechanism for acquiring new genes and creating genetic novelty in organisms. Many new gene functions have evolved through gene duplication and it has contributed tremendously to the evolution of developmental programmes in various organisms. Gene duplication can result from unequal crossing over, retroposition or chromosomal (or genome) duplication. Understanding the mechanisms that generate duplicate gene copies and the subsequent dynamics among gene duplicates is vital because these investigations shed light on localized and genomewide aspects of evolutionary forces shaping intra-specific and inter-specific genome contents, evolutionary relationships, and interactions. Based on whole-genome analysis of Arabidopsis thaliana, there is compelling evidence that angiosperms underwent two whole-genome duplication events early during their evolutionary history. Recent studies have shown that these events were crucial for creation of many important developmental and regulatory genes found in extant angiosperm genomes. Recent studies also provide strong indications that even yeast (Saccharomyces cerevisiae), with its compact genome, is in fact an ancient tetraploid. Gene duplication can provide new genetic material for mutation, drift and selection to act upon, the result of which is specialized or new gene functions. Without gene duplication the plasticity of a genome or species in adapting to changing environments would be severely limited. Whether a duplicate is retained depends upon its function, its mode of duplication, (i.e. whether it was duplicated during a whole-genome duplication event), the species in which it occurs, and its expression rate. The exaptation of preexisting secondary functions is an important feature in gene evolution, just as it is in morphological evolution. PMID- 23640424 TI - Pharmacotherapeutic management of actinic keratosis: focus on newer topical agents. AB - Actinic (solar) keratoses (AK) have the potential for malignant transformation and are the second most common diagnosis in dermatologic practices. No well established clinical criteria are available to determine which AK are more likely to undergo malignant transformation; therefore, many dermatologists utilize field directed approaches to treat all visible and subclinical AK on an affected skin surface. Current topical therapeutic agents require lengthy treatment regimens and are less well tolerated than many newer and investigational agents. We review and compare the efficacy and tolerability of well-established topical agents for the management of AK in the United States including 5-fluorouracil, imiquimod 5% cream as well as the newer 2.5 and 3.75% formulations, diclofenac 3% gel, photodynamic therapy, and the recently approved ingenol mebutate gel and discuss the therapeutic potential of investigational agents. Cryotherapy and 5 fluorouracil are efficacious at treating AK but less tolerable than imiquimod cream, particularly at its lower concentrations. The newer agents, diclofenac gel and ingenol mebutate, appear to be more tolerable than cryotherapy and 5- fluorouracil; however, comparative studies regarding efficacy are not available. PMID- 23640423 TI - Genetic polymorphism in FOXP3 gene: imbalance in regulatory T-cell role and development of human diseases. AB - The FOXP3 gene encodes a transcription factor thought to be important for the development and function of regulatory T cells (Treg cells). These cells are involved in the regulation of T cell activation and therefore are essential for normal immune homeostasis. Signals from microenvironment have a profound influence on the maintenance or progression of diseases. Thus, Tregs have an important marker protein, FOXP3, though it does not necessarily confer a Treg phenotype when expressed. FOXP3 polymorphisms that occur with high frequency in the general populations have been studied in common multifactorial human diseases. Dysfunction of FOXP3 gene product could result in lack of Treg cells and subsequently chronically activated CD4+ T cells which express increased levels of several activation markers and cytokines, resulting in some autoimmune diseases. In contrast, high Treg levels have been reported in peripheral blood, lymph nodes, and tumour specimens from patients with different types of cancer. The present study discusses the polymorphisms located in intron, exon and promoter regions of FOXP3 which have already been investigated by many researchers. FOXP3 has received considerable attention in attempts to understand the molecular aspect of Treg cells. Therefore, in the present study, the relationship between genetic polymorphism of FOXP3 in Treg-cell role and in disease development are reviewed considering the interactive effect of genetic factors. PMID- 23640425 TI - Phospholipid composition and longevity: lessons from Ames dwarf mice. AB - Membrane fatty acid (FA) composition is correlated with longevity in mammals. The "membrane pacemaker hypothesis of ageing" proposes that animals which cellular membranes contain high amounts of polyunsaturated FAs (PUFAs) have shorter life spans because their membranes are more susceptible to peroxidation and further oxidative damage. It remains to be shown, however, that long-lived phenotypes such as the Ames dwarf mouse have membranes containing fewer PUFAs and thus being less prone to peroxidation, as would be predicted from the membrane pacemaker hypothesis of ageing. Here, we show that across four different tissues, i.e., muscle, heart, liver and brain as well as in liver mitochondria, Ames dwarf mice possess membrane phospholipids containing between 30 and 60 % PUFAs (depending on the tissue), which is similar to PUFA contents of their normal-sized, short-lived siblings. However, we found that that Ames dwarf mice membrane phospholipids were significantly poorer in n-3 PUFAs. While lack of a difference in PUFA contents is contradicting the membrane pacemaker hypothesis, the lower n-3 PUFAs content in the long-lived mice provides some support for the membrane pacemaker hypothesis of ageing, as n-3 PUFAs comprise those FAs being blamed most for causing oxidative damage. By comparing tissue composition between 1-, 2- and 6-month-old mice in both phenotypes, we found that membranes differed both in quantity of PUFAs and in the prevalence of certain PUFAs. In sum, membrane composition in the Ames dwarf mouse supports the concept that tissue FA composition is related to longevity. PMID- 23640427 TI - Abstracts of the Twenty-Third Meeting of the European Neurological Society. June 8-11, 2013. Barcelona, Spain. PMID- 23640426 TI - Pituitary adenoma with mucin cells in a man with an unusual presentation of Carney complex. AB - We describe a 44-year-old man with infertility, acromegaly, and hypergonadotropic hypogonadism. Clinical examination of the patient revealed hyperpigmented macules on the lips, buccal mucosa, and face which were histologically confirmed as cutaneous myxomas and blue nevi. Ultrasound revealed testicular calcifications and multiple hypoechoic thyroid nodules. MR imaging showed a pituitary microadenoma and resection revealed it to be a growth hormone and prolactin secreting adenoma with the unusual finding of admixed individual mucin-producing cells. We discuss mucin cells in pituitary adenoma, an unreported pathologic finding in a patient with Carney complex. PMID- 23640428 TI - Effect of pH and ligand charge state on BACE-1 fragment docking performance. AB - In this work we propose a protocol for estimating the effect of pH on the docking performance to BACE-1, which affords the charge state of the inhibitor as well as the protonation state of all ionisable residues in the protein at a given pH value. To the best of our knowledge, this is the first report of a protocol predicting the BACE-1 ligand docking poses not only at the neutral pH at which most crystallographic structures were obtained, but also at the optimal pH of the enzyme (in the acidic range), at which most of the BACE-1 binding affinity assays are performed. We have applied this protocol to a set of 23 fragment-like BACE-1 ligands that span four orders of magnitude in their binding affinities. The pK a values of the BACE-1 acidic residues deviate substantially from the estimates for model compounds in solution and display a ligand dependent variability, especially in the case of the catalytic Asp dyad residues. This outcome should have a strong bearing on the design of protocols for docking based BACE-1 screening campaigns. Finally, we were able to find an explanation for the poor docking success rate of some fragments based on the availability of anchoring points, a rationale that could help to improve hit rates in BACE-1 screening campaigns. PMID- 23640429 TI - The acetylation degree of alginates in Azotobacter vinelandii ATCC9046 is determined by dissolved oxygen and specific growth rate: studies in glucose limited chemostat cultivations. AB - Alginates are polysaccharides that may be used as viscosifiers and gel or film forming agents with a great diversity of applications. The alginates produced by bacteria such as Azotobacter vinelandii are acetylated. The presence of acetyl groups in this type of alginate increases its solubility, viscosity, and swelling capability. The aim of this study was to evaluate, in glucose-limited chemostat cultivations of A. vinelandii ATCC9046, the influence of dissolved oxygen tension (DO) and specific growth rate (MU) on the degree of acetylation of alginates produced by this bacterium. In glucose-limited chemostat cultivations, the degree of alginate acetylation was evaluated under two conditions of DO (1 and 9 %) and for a range of specific growth rates (0.02-0.15 h-1). In addition, the alginate yields and PHB production were evaluated. High DO in the culture resulted in a high degree of alginate acetylation, reaching a maximum acetylation degree of 6.88 % at 9 % DO. In contrast, the increment of MU had a negative effect on the production and acetylation of the polymer. It was found that at high DO (9 %) and low MU, there was a reduction of the respiration rate, and the PHB accumulation was negligible, suggesting that the flux of acetyl-CoA (the acetyl donor) was diverted to alginate acetylation. PMID- 23640430 TI - Prevention of steroid-induced low bone mineral density in children with renal diseases: a systematic review. AB - BACKGROUND: Children with renal diseases who are treated with glucocorticoids are at increased risk of developing osteoporosis and fractures. However, there is no common strategy for prevention of corticosteroid-induced osteoporosis. The present systematic review was performed to determine whether prevention of bone loss by calcium (Ca), vitamin D (vit D) and/or bisphosphonates is justified, safe and efficacious in children treated with steroids for various renal diseases. METHODS: DATA SOURCES: Medline, Embase, Central were searched from 1961 up to 2012. Randomized controlled trials (RCTs) and observational studies concerning children <=18 years with renal diseases requiring steroids were included. RESULTS: The search strategy retrieved 2482 studies. Four RCTs including 166 patients and one observational study including 100 children met our eligibility criteria. One RCT and the observational study concerned treatment with Ca/vit D, one RCT with bisphosphonates and two RCTs with a combination of both therapies. All described a significant improvement in bone mineral density (BMD) in the treatment group compared with the control group. CONCLUSIONS: Ca combined with vit D is recommended to prevent bone disease in children with renal diseases treated with steroids. Because of side effects, bisphosphonates should be reserved for the treatment of severe osteoporosis when Ca and/or vit D supplementation has failed. PMID- 23640431 TI - GnRH antagonists in assisted reproductive techniques: a review on the Italian experience. AB - Current Controlled Ovarian Stimulation (COH) for Assisted Reproductive Techniques (ART) pursues three main objectives: hypophyseal activity suppression, multiple follicle growth stimulation, and ovulation induction. By suppressing hypophyseal activity, it is possible to prevent untimely LH surge and allow the appropriate development of the leading follicle. The classical GnRH agonist long protocol is the most widely used in COH for ART. However, an alternative regimen based on GnRH antagonist has been recently introduced in clinical practice. As competitive antagonists, these drugs display an immediate and quickly reversible effect and they avoid hormonal withdrawal side effects. Moreover, this protocol shows undeniable advantages, including the shorter duration of the treatment, the lower amount of gonadotropin required, the shorter hormonal and ultrasound monitoring of patients, milder physical and emotional stress, and a lower risk of Ovarian Hyperstimulation Syndrome (OHSS). The use of GnRH antagonists was traditionally restricted to selected patients, as "poor responders" and women at high-risk of developing OHSS such as Polycystic Ovary Syndrome (PCOS) and patients who had previously experienced OHSS. These findings could prompt a trend to change from the standard agonist protocol to the antagonist protocol in all categories of patients. This review provides a comprehensive overview of the use of GnRH antagonist protocols applied both to IVF techniques and to IUI procedures in the Italian experience. PMID- 23640432 TI - Placental expression of vimentin, desmin and ultrastructural changes in the villi in patients with HELLP syndrome. AB - OBJECTIVES: To examine placental expression of vimentin and desmin in relation to ultrastructural changes within the placental villi in cases of HELLP syndrome. STUDY DESIGN: Formaldehyde-fixed and paraffin-embedded specimens of 15 healthy pregnant and 13 Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, placentas were used for Harris hematoxylin staining, vimentin and desmin immunohistochemistry, and transmission electron microscopy (TEM). RESULTS: Increased of fibrinoid necrosis in vascular wall and the periphery of villi were observed in sections of the placentas with HELLP syndrome. Increased expression of vimentin in the intravillous area and increased expression of desmin on blood vessel wall, were seen in placentas of patients with HELLP syndrome when compared to placentas of healthy pregnant. CONCLUSIONS: Augmentation of intermediate filaments, desmin, vimentin may disturb normal movements of endothelial cells, and may display placental dysfunction that is unable to compensate the endothelial instability and the related hypertension in HELLP syndrome. Further studies are needed to get more definit results and also to compare HELLP syndrome with preeclampsia. PMID- 23640433 TI - Study of the mechanism of pulmonary protection strategy on pulmonary injury with deep hypothermia low flow. AB - BACKGROUND: The influence of deep hypothermia low-flow (DHLF) perfusion on inflammatory response of pulmonary injury in mammals undergoing the cardiopulmonary bypass (CPB) remains unknown. OBJECTIVES: This study was conducted to determine the feasibility and mechanism of pulmonary protection strategy on preventing pulmonary function from ischemia reperfusion injury with piglet model. MATERIALS AND METHODS: Eighteen piglets were divided randomly into three groups: control group with DHLF; continuous perfusion of pulmonary arteries (CPP) with DHLF group (CPP group) and partial liquid ventilation (PLV) with perfluorocarbon (PFC) after CPP with DHLF group (PLV group). Pulmonary ventilation functions in arterial blood samples were measured at pre-CPB, 0h, 1h and 2h until the end of CPB. Inflammatory factor TNF-alpha, IL-8 and IL-6, adherence factor ICAM-1 were also measured. RESULTS: After CPB, PaO2 increased but PaCO2 decreased significantly in the PLV group compared with control group. Pulmonary gas exchange in PLV group also improved more significantly than that in CPP group. The expression of TNF-alpha, IL-8 and IL-6 in serum increased more significantly in PVL group after CPB 1h than control group. The extent of lung injury was decreased significantly in PLV than that in CPP group and control group. CONCLUSIONS: CPP had a protective effect in lung ischemia reperfusion injury during DHLF, and the role of protection lung with maintaining PLV after CPP during DHLF is better than that of single CPP perfusion. PMID- 23640434 TI - Uncontrolled hypertension among black Africans in the city of Brussels: a case control study. AB - AIM: The aim of this study is to identify determinants that are associated with uncontrolled hypertension among black Africans in the city of Brussels. DESIGN: A not-matched case-control study. METHODS: Seventy-five black Africans were assigned to a case group with uncontrolled hypertension and a control group with controlled hypertension. Demographic characteristics, lifestyle and compliance were recorded as well as their blood pressure. Compliance in patients was evaluated by means of the Morisky Medication Adherence Scale-4 (MMAS-4). RESULTS: The mean age of the case group was 52 years (SD 7.8) and for the control group 49 years (SD 6.2). Almost 60% were women. Uncontrolled hypertension was associated with obesity (p = 0.01) and sedentary lifestyle (p = 0.034). About 50% of women were obese and 70% of these had uncontrolled hypertension. Patients with type 2 diabetes had a 4.5 times higher risk for uncontrolled hypertension and lower compliance to the medication regimen compared to non-diabetics. Patients were often treated with diuretics (29%), renin-angiotensin inhibitors (25%), and calcium-channel inhibitors (23%). According to the MMAS4-score uncontrolled patients had an intermediate compliance and the controlled patients had a high compliance. CONCLUSIONS: Black obese women and diabetics had the highest risk for uncontrolled hypertension. Compliance was significantly lower among uncontrolled patients. PMID- 23640435 TI - The prolonged effect of pneumoperitoneum on cardiac autonomic functions during laparoscopic surgery; are we aware? AB - BACKGROUND: The gynecological laparoscopic surgery requires pneumoperitoneum (PP) with CO2 gas insufflation. CO2 PP may influence cardiac automic function (CAF). This study was conducted to assess its significance and the prolonged effects of CO2 PP on the activity of the cardiac autonomic function 24 hours after the operation by heart rate turbulence (HRT) and heart rate variability (HRV), first time in the literature. PATIENTS AND METHODS: Fifty patients scheduled for elective gynecologic laparoscopy were evaluated. The patients had no preexisting lung or heart disease or pathologic lung function. Conventional general anesthesia with midazolam, propofol, fentanyl, rocuronium, and sevoflurane was administered. ECG recordings were carried out between before 4 h from surgery and the beginning of anesthesia (T1), induction of PP and CO2 evacuation (T2) and a 24-h period postoperatively (T3). The Holter recordings of all patients were analyzed by HRT and HRV. RESULTS: There were significant reductions in in HRV and HRT parameters peri-op period compared to the pre-op values (p < 0.05). In the first 3 h of post-op period, were calculated all HRT and some HRV (SDNN, LF) parameters were also found to be significantly reduced than the values of pre-op period (p < 0.05). CONCLUSIONS: This study described adverse effects of CO2 PP on cardiac autonomic regulation in the early postoperative period according to the long-term HRV and HRT frequency analysis, for the first time in the literature. The early postoperative monitorization may supply efficacious information for arrhythmic complications. PMID- 23640436 TI - Re-analysis of expression profiles for revealing new potential candidate genes of heart failure. AB - BACKGROUND: Chronic heart failure (HF) is characterized by diminished cardiac output and pooling of blood in the venous system. AIM: We used the GSE1145 microarray data to identify potential genes that related to heart failure to construct a regulation network. MATERIALS AND METHODS: In the network, some of transcription factors (TFs) and target genes have been proved to be related to heart failure in previous study. The gene MYC, RELA, HIF1A, NFkappaB1 and SMAD3 are as hub nodes in our transcriptional network and have a close relationship with heart failure. RESULTS: The study did not address regulation network but researched for the significant pathways related to chronic heart failure. Besides, RELA and NFkappaB1 interfere with each other in response to HF. CONCLUSIONS: It is demonstrated that transcriptional network analysis is useful in identification of the candidate genes in heart failure. PMID- 23640437 TI - Clinical characteristics of hypertension among victims in temporary shield district after Wenchuan earthquake in China. AB - AIM: The frequency of hypertension events increases after a strong stress, but the mechanism has not been fully investigated. This study aimed to investigate its prevalence and risk factors after the Wenchuan earthquake (8.0 on the Richter scale), so as to provide a scientific basis for the prevention of hypertension in natural disasters or unforeseen accidents. SUBJECTS AND METHODS: Victims staying in temporary shelter for more than 1 year between March to May 2009 were randomly selected by multi-stage stratified cluster sampling method. And predetermined questionnaire survey and physical examination were carried out. In this study, all participants signed informed consent form. RESULTS: A total of 3230 victims aged over 20 years participated in this study, and the prevalence rate of hypertension among those victims was 24.08% (778/3230), most of whom had first level hypertension; and the standardized rate was 18.44%. Moreover, the rates of hypertension awareness, dosing and controlling was only 34.58%, 53.43% and 17.84%, respectively. Among this cohort, the prevalence rate of hypertension increased with age (p < 0.01), but its distribution was similar between male and female victims (25.0% versus 23.58, p > 0.05). Logistic regression analysis showed that age, family history of hypertension, sleep quality, waist-to-hip ratio, body mass index and blood glucose level were risk factors of earthquake induced hypertension among victims in temporary shield district, but mental stress was not. CONCLUSIONS: Though mental stress was not a risk factor of hypertension in this study, earthquake-induced hypertension should not be ignored. For victims after earthquake, the education of the prevention and treatment of hypertension should be strengthened. PMID- 23640438 TI - Echocardiographic evaluation of right ventricular functions after successful percutaneous recanalization of right coronary artery chronic total occlusions. AB - BACKGROUND: No data exist on regarding possible improvement will occur in right ventricular (RV) functions after successful recanalization of right coronary artery chronic total occlusions (RCA CTOs). AIM: Our aim was to evaluate the revascularization induced changes in RV functions by novel echocardiographic techniques like tissue Doppler imaging (TDI) and two dimensional speckle tracking echocardiography (2DSTE). PATIENTS AND METHODS: Forty-one consecutive successfully recanalized patients with RCA CTOs were included in our study. All included patients underwent standard echocardiography with TDI and 2DSTE to assess RV function before procedure and repeated after 24 hours and 1 month. RESULTS: There were no significant changes in tricuspid annular plane systolic excursion, systolic myocardial velocities, and fractional area change values. However, RV global longitudinal strain and systolic strain rate values showed a significant increase at 24 hours after percutaneous coronary intervention compared to baseline (-23.6+/-4.1% vs. -19.7+/-3.9%, p < 0.001 and -1.55+/-0.18s 1 vs. -1.18+/-0.17s-1, p < 0.001, respectively). Moreover, improvement of the RV functions in patients with RCA CTOs was further suggested by the higher RV isovolumic acceleration values at 1-month compared with baseline (2.29+/-0.62 vs. 2.05+/-0.5 m/s2, p = 0.014). CONCLUSIONS: TDI derived isovolumic acceleration and 2DSTE derived global longitudinal strain and systolic strain rate values showed improvement in RV functions after successful percutaneous recanalization of RCACTOs suggesting viability of RV in chronic ischemia. PMID- 23640439 TI - Accuracy of Doppler echocardiography in the assessment of pulmonary arterial hypertension in patients with congenital heart disease. AB - BACKGROUND AND OBJECTIVES: Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality among patients with congenital heart disease (CHD). Earlier diagnosis of PAH would be of great benefit for the estimation of the CHD, the grasp of the indications for surgery and prognosis. PATIENTS AND METHODS: We assessed the diagnostic accuracy of Doppler echocardiography (D-ECHO) in detecting PAH in patients with CHD and the value of estimation about ventricular morphology and function of PAH-CHD patients. 123 CHD patients evaluated for suspected PAH were prospectively recruited. D-ECHO was performed and estimated right ventricular systolic pressure (RVSP) was measured to screen for PAH. Subsequently, pulmonary hemodynamic parameters were measured by right heart catheterization (RHC) for definitive diagnosis of PAH. RESULTS: RHC identified 66/123 (54%) patients with PAH. The noninvasive cut-point was: estimated right ventricular systolic pressure (RVSP) > 36.5 mm Hg by D-ECHO. D-ECHO classified 107 subjects correctly (sensitivity 89.4%, specificity 84.2%). The area under receiver-operating characteristic curve (AUC) was 0.96 for D-ECHO. A positive significant correlation (r = 0.853, p < 0.01) was found between RVSP measured by D-ECHO and systolic pulmonary arterial pressure (sPAP) measured by RHC. In addition, D-ECHO showed higher RVSP, left ventricular internal diameter (LV), right atrial diameter (RA), right ventricular internal diameter (RV), left ventricular end-diastolic diameter (EDD), left ventricular diastolic end diastolic volume (EDV) and mitral velocity A wave (AMV) values in the PAH-CHD group than in the CHD group (p < 0.05). CONCLUSIONS: D-ECHO is not only an important noninvasive diagnostic technique for PAH-CHD patients, but also a tool which can indicate the ventricular remodeling and diastolic dysfunction induced by PAH to some extent. PMID- 23640440 TI - Pelvic lymphedema in rectal cancer: a magnetic resonance feasibility study: a preliminary report. AB - BACKGROUND: Functional pelvic disorders in patients undergoing conservative surgical approach for rectal cancer are considered a major public health issue and represent one third of cost of colorectal cancer. We investigated the hypothesis that lymphadenectomy, involves the pelvic floor results in a localized hides or silent pelvic lymphedema characterized by symptoms without signs. PATIENTS AND METHODS: We examined 13 colo-rectal cancer patients: five intra peritoneal adenocarcinoma: 1 sigmoid and 4 upper third rectal cancer (1 male and 3 female) and 9 extra-peritoneal adenocarcinoma: 3 middle and 5 lower third rectal cancer (4 male and 5 female) using 1.5-T magnetic resonance, one week before and twelve months after discharged from hospital. RESULTS: Lymphedema was discovered on post-operative magnetic resonance imaging of all 9 patients with extra-pertitoneal cancer, whereas preoperative magnetic resonance imaging as well as a post-operative examination of 4 intra-peritoneal adenocarcinoma, revealed no evidence of lymphedema. Unlike the common clinical skin signs that typify all other sites of lymphedema, pelvic lymphedema is hides or silent, with no skin changes or any single symptom manifested. Magnetic resonance imaging showed that pelvic illness alone is accompanied by lymphedema related exclusively to venous congestion, and accumulation of liquid in adipose tissue or lipedema. CONCLUSIONS: Alteration of the pelvic lymphatic network during pelvic surgery can lead to lymphedema and, pelvic floor disease. Patients should be routinely examined for the possibility of developing this post-surgical syndrome and further studies are needed to establish diagnosis and to evaluate treatment preferences. PMID- 23640441 TI - Imiquimod 5% cream versus cold knife excision for treatment of VIN 2/3: a five year follow-up. AB - BACKGROUND: Vulvar intraepithelial neoplasia (VIN) is a premalingnant condition. For long time, surgery was considered the first-line therapy in the treatment of high grade VIN. Imiquimod was recently introduced as an alternative to surgery. AIM: To compare the overall complete response, the recurrence rate and the risk factors for relapse among patients with VIN 2/3 treated with Imiquimod or surgical excision. PATIENTS AND METHODS: Eighty women who had histological diagnosis of VIN 2 and VIN 3 were enrolled in this prospective study. Patients immunocompromised, with recurrent VIN, with well differentiated type VIN or VIN 1 and women treated more than once were excluded from the study. Patients were divided into two groups: group A was treated with Imiquimod, group B underwent surgical excision. Patients' characteristics analyzed were: age, smoking, degree of the primary lesion, state of margins, multifocal disease. We have evaluated the recurrence rate, the relapse rate, and the overall complete response, considering as recurrence the onset of a lesion after an initial complete response to Imiquimod and/or after the surgical treatment and as relapse all patients who had a recurrence plus those with medical treatment failure. RESULTS: Multifocal lesions (p = 0.03) and VIN 3 (p = 0.002) were associated with a higher risk of relapse. The recurrence rate was higher in the group B (p = 0.009), but the relapse rate was higher in the group A (p = 0.04). The overall complete response was better in the group B (p = 0.04). CONCLUSIONS: Although the advent of new medical options can decrease the morbidity associated with invasive surgical procedures, surgical treatments remain the best treatment modality for VIN with regard to relapse and overall complete response. PMID- 23640442 TI - Neonatal sevoflurane anesthesia induces long-term memory impairment and decreases hippocampal PSD-95 expression without neuronal loss. AB - AIM: Volatile anesthetics are widely used in the clinic, and sevoflurane is the most prevalent volatile anesthetic in pediatric anesthesia. Recent findings question the potential risks of volatile anesthetics on brain development. Evidence suggests that sevoflurane may cause neuronal deficiency. This study investigates the long-term effect of sevoflurane in the developing brain. MATERIALS AND METHODS: We anesthetized 7 day-old rats for 4 h with 2.5% sevoflurane. A Morris water maze was used to evaluate hippocampal function 7 weeks after sevoflurane exposure. Nissl staining was performed to analyze neuronal loss. PSD-95 (postsynaptic density protein-95) expression in the hippocampus was measured using a western blot. RESULTS: The exposure to 2.5% sevoflurane caused long-term deficits in hippocampal function and decreased hippocampal PSD-95 expression without neuronal loss. This study demonstrates that P7 rats exposed for 4 h to 2.5% sevoflurane have significant spatial learning and memory impairment 7 weeks after anesthesia. In addition, PSD-95 expression in the hippocampus decreased at P56 without neuronal loss. CONCLUSIONS: These data suggest that sevoflurane causes neurotoxicity in the developing brain, which may be attributed to decreased PSD-95 in the hippocampus. PMID- 23640443 TI - Risk factors for mortality in patients with nosocomial Gram-negative rod bacteremia. AB - BACKGROUND: The percentage of hospital-acquired bloodstream infections associated with Gram-negative bacilles has decreased during last decade but it is still a major cause of morbidity and mortality. OBJECTIVES: The aim of this study was to determine the outcome of Gram-negative rod (GNR) bacteremia, which is an important clinical problem with high mortality rates, and the risk factors for GNR related mortality in our Clinic. MATERIALS AND METHODS: During the study period, 520 episodes of bacteremia were detected in 411 patients. Only patients with GNR bacteremia in blood cultures were included in the study (n = 197). Among 197 patients fulfilling study criteria, GNR were grown in 239 samples. RESULTS: Escherichia coli (n = 97, 40.5%), Klebsiella pneumoniae (n = 54, 22.5%), Pseudomonas aeruginosa (n= 24, 10%), Acinetobacter baumannii (n = 24, 10%) were the most commonly isolated bacteria. The most frequently identified infection sources of bacteremia were pneumonia (n = 35, 17.7%), catheter-related infections (n = 24, 12.2%), urinary tract infections (n = 20, 10%). In multivariate analysis, it was found that the GNR bacteremia mortality risk increased in patients treated in intensive care units (ICU) (OR: 0.2, p = 0.03) and patients with ventilatory support (OR: 20.8, p = 0.05). CONCLUSIONS: In clinical practice of the hospital settings, efforts should concentrate on preventive measures for nosocomial infections since pneumonia, catheter-related infections, and urinary infections appear to be the most frequent causes of secondary bacteremia. PMID- 23640444 TI - Assesment life quality of familial Mediterranean fever patients by short form-36 and its relationship with disease parameters. AB - BACKGROUND: Familial Mediterranean fever is an auto-inflammatory disorder. Long term complications of the disease include decreased quality of life. The measurement of quality of life in the patients with chronic disease has become an important research topic during the last years. AIM: We aimed to evaluate life quality of the FMF patients by SF-36, and examine its relationship with the disease parameters. PATIENTS AND METHODS: One hundred voluntary patients (69 female, 31 male) admitted to the rheumatology clinic were included in the study. The control group consisted of 100 healthy individuals. All subjects in the study were asked to complete SF-36 questionnaire. Age of onset of FMF, age at diagnosis, age at the beginning of colchicine therapy, number of attacks per month, family history of FMF and dialysis were inquired of patients with FMF. Disease severity was determined using the FMF severity score. RESULTS: The mean age of the patient group was 31+/-12 and that of the control group was 29+/-9. Sixty-nine patients (69%) were female, and 31 patients were male (31%) in both groups. The mean scores of the physical function, physical role function, emotional role function, mental health, and general health parameters of the patients were statistically significantly lower than those of healthy volunteers (p < 0.05). The difference in social function and vitality between two groups was found to be insignificant (p > 0.05). CONCLUSIONS: We have shown that FMF had a negative impact on SF-36. FMF reduces quality of life both in physical and mental dimensions. PMID- 23640445 TI - Nitric oxide and peroxynitrite serum levels in Parkinson's disease: correlation of oxidative stress and the severity of the disease. AB - BACKGROUND: Nitric oxide (NO) and its toxic product peroxynitrite contribute to oxidative stress and neurodegeneration in Parkinson's disease (PD). The relationship of serum levels of these oxidants with the severity of the disease [evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS)] is not established. AIM: This study was designed to evaluate whether patients with PD had higher NO and peroxynitrite serum level or not. PATIENTS AND METHODS: Fifty eight patients with PD and 15 healthy volunteers entered this study. The concentrations of serum NO and peroxynitrite were assayed and their correlation with the UPDRS score was assessed. RESULTS: Mean serum NO levels in patient group was 29.8 +/- 21.631 versus 7.49 +/- 2.573 in control group, which was significantly higher in patients (p <= 0.0001). Peroxynitrite levels in patient and control groups were 7.37+/-3.501 umol/L and 3.94 +/-1.389 umol/L respectively. Patients had a significantly higher peroxynitrite level (p = 0.0004). CONCLUSIONS: Higher levels of NO and peroxynitrite leads to higher UPDRS scores. It seems since current PD treatments do not affect the pathology of the disease, using drugs that exert neuroprotective properties should be considered for the treatment of PD in order to prevent further neuronal cell loss. PMID- 23640447 TI - Correction of tuberous breast with small volume asymmetry by using a new adjustable implant. AB - BACKGROUND: The tuberous breast syndrome is a rare anomaly of breast shape, which can be associated to volume breast asymmetry. We report our caseload in the correction of tuberous breasts with small volume asymmetry by using the Muti's technique associated to the implantation of a new adjustable implant. AIM: Purpose of the study is to evaluate the efficacy of treating tuberous breast deformity with two different types of implants (a textured round high profile cohesive I implant in the larger breast and a SpectraTM implant in the smaller breast). PATIENTS AND METHODS: Since May 2008, patients affected by tuberous breast combined to small breast volume asymmetry were enrolled in a prospective study. After gland deformity correction, the adjustable implant was positioned in the smaller breast. A textured round implant was positioned in the contralateral breast. Standard pictures were taken before surgery and during follow-up visits over one year. A visual analogue scale (VAS) scale was used to evaluate patients' and external physicians' judgment. Standardized objective measurements of breast and chest were also taken. Statistical significance of any value variation was assessed with the Wilconxon's rank sum test. RESULTS: Eleven patients were treated with the proposed surgical approach. VAS scores from patients and external physicians were high. Deformity correction was obtained in all patients as evidenced by the significant modifications of objective measurements. No major late complications occurred. CONCLUSIONS: The new adjustable implant provides a reliable corrective option for hypoplastic tuberous breasts with small volume asymmetry. This device allows intra-operative modification of implant volume according to breast volume discrepancy. Although our findings are satisfying, a longer follow-up is required to evaluate long term results. PMID- 23640446 TI - Community-acquired urinary tract infections in children: pathogens, antibiotic susceptibility and seasonal changes. AB - AIM: Urinary tract infections (UTIs) are common infections affecting children. The aim of our study is to determine microorganisms that cause community-acquired urinary tract infections and their antibiotic susceptibility in children. MATERIALS AND METHODS: Our investigation includes 150 cases which has positive urine culture. The cases are detected at Pediatric Polyclinics of Dicle University between June 2010 and June 2011. RESULTS: The study included 118 (78.7%) female and 32 (21.3%) male children. Urinary tract infections were seen in autumn 10.7% (n = 16), summer 35.3% (n = 53), winter 30.7% (n = 46) and spring 23.3% (n = 35). The culture results indicated 75.3% (n = 113) Escherichia coli; 20.7% (n = 31) Klebsiella; 2.7% (n = 4) Proteus and % 1.3 (n = 2) Pseudomonas. The antibiotic resistance against Escherichia coli was found out is amikacin (3%), ertapenem (7%), imipenem (0%), meropenem (0%), nitrofurantoin (9%), trimethoprim/sulfamethoxazole (58%), piperacillin (83%), amoxicillin/clavulanate (50%), ampicillin/sulbactam (65%), cefazolin (54%), cefotaxime (51%), cefuroxime sodium (51% ) and tetracycline (68%). The resistance ratios of Klebsiella are amikacin (0%), imipenem (0%), levofloxacin (0%), meropenem (0%), amoxicillin/clavulanate (57%), ampicillin/sulbactam (79%), ceftriaxone (68%), cefuroxime sodium (74%) and trimethoprim/sulfamethoxazole (61%). CONCLUSIONS: The results represent the increasing antibiotic resistance against microorganisms among the community-acquired UTI patients in a developing country such as Turkey. So, the physicians should consider resistance status of the infectious agent and choose effective antibiotics which are nitrofurantoin and cefoxitin for their empirical antibiotic treatment. Furthermore, they should be trained about selection of more effective antibiotics and check the regional studies regularly. PMID- 23640448 TI - Cytotoxicity of hemostatic agents on the human gingival fibroblast. AB - BACKGROUND: Achieving of moisture control especially gingival bleeding control is great challenge in clinical practice. Various hemostatic agents and techniques have been promoted for bleeding control during dental operation. But few studies have focused on the cytotoxicity of hemostatic solutions. AIM: The aim of this study was to evaluate cytotoxic effect of hemostatic agents on human gingival fibroblast cells by using real-time cell analysis method. MATERIALS AND METHODS: Two hemostatic solutions, Hemoban (Sultan Healthcare, Hackensack, NJ, USA) and Hemasatic Solutions (W.P. Dental, Hamburg, Germany) that includes mainly aluminum chloride were used with different concentration. Gingival fibroblasts were isolated from gingival connective tissue during crown lengthening surgery of systemically healthy subjects. Gingival fibroblasts were maintained with Dulbecco's modified eagle medium containing 10% fetal bovine serum. A real-time cell analyzer (RT-CES, xCELLigence; Roche Applied Science, Mannheim, Germany, and ACEA Biosciences, San Diego, CA, USA) was used to evaluate cell survival. After seeding 200 mL of the cell suspensions into the wells (10,000 cells/well) of the E-plate 96, gingival fibroblasts were treated with hemostatic solutions (1/2, 1/4 and 1/8 dilutions) and monitored every 15 minutes for 72 hours. For the proliferation experiments, the statistical analyses used were 1-way analysis of variance (ANOVA) and Tukey HSD multiple comparisons tests. RESULTS: According to statistically analysis, when evaluated at 48 and 72 hours, there were significant differences between the cell indexes of the control and all hemostatic agents groups (p < 0.001). Agent reduced cell index value significantly when compared to untreated control group. CONCLUSIONS: The results indicate that using of Hemoban or Hemostatic Solutions as astringent solutions have a significant cytotoxic effect on gingival fibroblast cells. PMID- 23640449 TI - Otorrhea in Kawasaki disease diagnosis complicated by an EBV infection: coincidental disease or a true association. AB - The Authors report on two children affected by Kawasaki disease (KD). The diagnosis of KD was made after exclusion of conditions with similar presentation. At admission these children (cases 1 and 2) presented fever, purulent caseous pharyngotonsillitis, and cervical bilateral lymphadenopathy, as well as an erythematous non-vesicular rash over the face and trunk, and a mild bilateral non exudative conjunctivitis in case 1. After respectively three and two days corticosteroid therapy was started without any significant improvement of the general condition and any diminutions of the fever. Two days later in case 1 the child presented a clear otorrhea, a cutaneous non vesicular rash, and soon after all the remaining signs of Kawasaki disease, in case 2 otorrhea was found after 4 days and then the other signs of the KD. These patients were treated with intravenous immunoglobulin (2 g/kg day), with an improvement of their general condition. To our knowledge we report the first cases of otorrhea in the setting of Kawasaki disease. We cannot exclude that the presence of Kawasaki disease in the context of otorrhea in children positive for Epstein-Barr virus (EBV) is merely coincidental. Besides, recent acquisitions show that KD is due to a new virus that could cross-react with the EBV. The Authors conclude that the presence of EBV infection or similar condition in a febrile child may not exclude Kawasaki disease and a differential diagnosis has to be performed for a timely commencement of intravenous immunoglobulin therapy. PMID- 23640450 TI - Protective role of G6PD deficiency in poisoning by aluminum phosphide; are there possible new treatments? PMID- 23640451 TI - Anxiety and adverse health outcomes among cardiac patients: a biobehavioral model. AB - BACKGROUND: Anxiety is a common experience among patients with acute coronary syndrome (ACS) that can have a negative impact on health outcomes. Nonetheless, the negative role of anxiety remains underappreciated, as reflected by clinicians' underrecognition and undertreatment of anxious hospitalized and nonhospitalized patients with ACS. Underappreciation of the role of anxiety is possibly related to inadequate understanding of the mechanisms whereby anxiety may adversely affect health outcomes. PURPOSE: The aim of this study was to synthesize the evidence about potential mechanisms by which anxiety and adverse health outcomes are related. CONCLUSIONS: A biobehavioral model links anxiety to the development of thrombogenic and arrhythmic events in patients with ACS. Biologically, anxiety may interfere with the immune system, lipid profile, automatic nervous system balance, and the coagulation cascade, whereas behaviorally, anxiety may adversely affect adoption of healthy habits and cardiac risk-reducing behaviors. The biological and behavioral pathways complement each other in the production of poor outcomes. CLINICAL IMPLICATIONS: Anxiety requires more attention from clinical cardiology. The adverse impact of anxiety on health outcomes could be avoided by efficient assessment and treatment of anxiety. PMID- 23640454 TI - Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals. AB - Recent studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia. Insulin resistance is often associated with T2DM and can induce defective insulin signaling in the central nervous system as well as increase the risk of cognitive impairment in the elderly. Glucagone like peptide-1 (GLP-1) is an incretin hormone and, like GLP-1 analogs, stimulates insulin secretion and has been employed in the treatment of T2DM. GLP 1 and GLP-1 analogs also enhance synaptic plasticity and counteract cognitive deficits in mouse models of neuronal dysfunction and/or degeneration. In this study, we investigated the potential neuroprotective effects of long-term treatment with exenatide, a GLP-1 analog, in two animal models of neuronal dysfunction: the PS1-KI and 3xTg-AD mice. We found that exenatide promoted beneficial effects on short- and long-term memory performances in PS1-KI but not in 3xTg-AD animals. In PS1-KI mice, the drug increased brain lactate dehydrogenase activity leading to a net increase in lactate levels, while no effects were observed on mitochondrial respiration. On the contrary, exenatide had no effects on brain metabolism of 3xTg-AD mice. In summary, our data indicate that exenatide improves cognition in PS1-KI mice, an effect likely driven by increasing the brain anaerobic glycolysis rate. PMID- 23640455 TI - A caspase-3 'death-switch' in colorectal cancer cells for induced and synchronous tumor apoptosis in vitro and in vivo facilitates the development of minimally invasive cell death biomarkers. AB - Novel anticancer drugs targeting key apoptosis regulators have been developed and are undergoing clinical trials. Pharmacodynamic biomarkers to define the optimum dose of drug that provokes tumor apoptosis are in demand; acquisition of longitudinal tumor biopsies is a significant challenge and minimally invasive biomarkers are required. Considering this, we have developed and validated a preclinical 'death-switch' model for the discovery of secreted biomarkers of tumour apoptosis using in vitro proteomics and in vivo evaluation of the novel imaging probe [(18)F]ML-10 for non-invasive detection of apoptosis using positron emission tomography (PET). The 'death-switch' is a constitutively active mutant caspase-3 that is robustly induced by doxycycline to drive synchronous apoptosis in human colorectal cancer cells in vitro or grown as tumor xenografts. Death switch induction caused caspase-dependent apoptosis between 3 and 24 hours in vitro and regression of 'death-switched' xenografts occurred within 24 h correlating with the percentage of apoptotic cells in tumor and levels of an established cell death biomarker (cleaved cytokeratin-18) in the blood. We sought to define secreted biomarkers of tumor apoptosis from cultured cells using Discovery Isobaric Tag proteomics, which may provide candidates to validate in blood. Early after caspase-3 activation, levels of normally secreted proteins were decreased (e.g. Gelsolin and Midkine) and proteins including CD44 and High Mobility Group protein B1 (HMGB1) that were released into cell culture media in vitro were also identified in the bloodstream of mice bearing death-switched tumors. We also exemplify the utility of the death-switch model for the validation of apoptotic imaging probes using [(18)F]ML-10, a PET tracer currently in clinical trials. Results showed increased tracer uptake of [(18)F]ML-10 in tumours undergoing apoptosis, compared with matched tumour controls imaged in the same animal. Overall, the death-switch model represents a robust and versatile tool for the discovery and validation of apoptosis biomarkers. PMID- 23640456 TI - Pyrvinium targets autophagy addiction to promote cancer cell death. AB - Autophagy is a cellular catabolic process by which long-lived proteins and damaged organelles are degradated by lysosomes. Activation of autophagy is an important survival mechanism that protects cancer cells from various stresses, including anticancer agents. Recent studies indicate that pyrvinium pamoate, an FDA-approved antihelminthic drug, exhibits wide-ranging anticancer activity. Here we demonstrate that pyrvinium inhibits autophagy both in vitro and in vivo. We further demonstrate that the inhibition of autophagy is mammalian target of rapamycin independent but depends on the transcriptional inhibition of autophagy genes. Moreover, the combination of pyrvinium with autophagy stimuli improves its toxicity against cancer cells, and pretreatment of cells with 3-MA or siBeclin1 partially protects cells from pyrvinium-induced cell death under glucose starvation, suggesting that targeted autophagy addiction is involved in pyrvinium mediated cytotoxicity. Finally, in vivo studies show that the combination therapy of pyrvinium with the anticancer and autophagy stimulus agent, 2-deoxy-D-glucose (2-DG), is significantly more effective in inhibiting tumor growth than pyrvinium or 2-DG alone. This study supports a novel cancer therapeutic strategy based on targeting autophagy addiction and implicates using pyrvinium as an autophagy inhibitor in combination with chemotherapeutic agents to improve their therapeutic efficacy. PMID- 23640457 TI - ATM-NFkappaB axis-driven TIGAR regulates sensitivity of glioma cells to radiomimetics in the presence of TNFalpha. AB - Gliomas are resistant to radiation therapy, as well as to TNFalpha induced killing. Radiation-induced TNFalpha triggers Nuclear factor kappaB (NFkappaB) mediated radioresistance. As inhibition of NFkappaB activation sensitizes glioma cells to TNFalpha-induced apoptosis, we investigated whether TNFalpha modulates the responsiveness of glioma cells to ionizing radiation-mimetic Neocarzinostatin (NCS). TNFalpha enhanced the ability of NCS to induce glioma cell apoptosis. NCS mediated death involved caspase-9 activation, reduction of mitochondrial copy number and lactate production. Death was concurrent with NFkappaB, Akt and Erk activation. Abrogation of Akt and NFkappaB activation further potentiated the death inducing ability of NCS in TNFalpha cotreated cells. NCS-induced p53 expression was accompanied by increase in TP53-induced glycolysis and apoptosis regulator (TIGAR) levels and ATM phosphorylation. siRNA-mediated knockdown of TIGAR abrogated NCS-induced apoptosis. While DN-IkappaB abrogated NCS-induced TIGAR both in the presence and absence of TNFalpha, TIGAR had no effect on NFkappaB activation. Transfection with TIGAR mutant (i) decreased apoptosis and gammaH2AX foci formation (ii) decreased p53 (iii) elevated ROS and (iv) increased Akt/Erk activation in cells cotreated with NCS and TNFalpha. Heightened TIGAR expression was observed in GBM tumors. While NCS induced ATM phosphorylation in a NFkappaB independent manner, ATM inhibition abrogated TIGAR and NFkappaB activation. Metabolic gene profiling indicated that TNFalpha affects NCS-mediated regulation of several genes associated with glycolysis. The existence of ATM NFkappaB axis that regulate metabolic modeler TIGAR to overcome prosurvival response in NCS and TNFalpha cotreated cells, suggests mechanisms through which inflammation could affect resistance and adaptation to radiomimetics despite concurrent induction of death. PMID- 23640458 TI - Glucose 6-phosphate dehydrogenase deficiency enhances germ cell apoptosis and causes defective embryogenesis in Caenorhabditis elegans. AB - Glucose 6-phosphate dehydrogenase (G6PD) deficiency, known as favism, is classically manifested by hemolytic anemia in human. More recently, it has been shown that mild G6PD deficiency moderately affects cardiac function, whereas severe G6PD deficiency leads to embryonic lethality in mice. How G6PD deficiency affects organisms has not been fully elucidated due to the lack of a suitable animal model. In this study, G6PD-deficient Caenorhabditis elegans was established by RNA interference (RNAi) knockdown to delineate the role of G6PD in animal physiology. Upon G6PD RNAi knockdown, G6PD activity was significantly hampered in C. elegans in parallel with increased oxidative stress and DNA oxidative damage. Phenotypically, G6PD-knockdown enhanced germ cell apoptosis (2 fold increase), reduced egg production (65% of mock), and hatching (10% of mock). To determine whether oxidative stress is associated with G6PD knockdown-induced reproduction defects, C. elegans was challenged with a short-term hydrogen peroxide (H2O2). The early phase egg production of both mock and G6PD-knockdown C. elegans were significantly affected by H2O2. However, H2O2-induced germ cell apoptosis was more dramatic in mock than that in G6PD-deficient C. elegans. To investigate the signaling pathways involved in defective oogenesis and embryogenesis caused by G6PD knockdown, mutants of p53 and mitogen-activated protein kinase (MAPK) pathways were examined. Despite the upregulation of CEP-1 (p53), cep-1 mutation did not affect egg production and hatching in G6PD deficient C. elegans. Neither pmk-1 nor mek-1 mutation significantly affected egg production, whereas sek-1 mutation further decreased egg production in G6PD deficient C. elegans. Intriguingly, loss of function of sek-1 or mek-1 dramatically rescued defective hatching (8.3- and 9.6-fold increase, respectively) induced by G6PD knockdown. Taken together, these findings show that G6PD knockdown reduces egg production and hatching in C. elegans, which are possibly associated with enhanced oxidative stress and altered MAPK pathways, respectively. PMID- 23640459 TI - The targeting and functions of miRNA-383 are mediated by FMRP during spermatogenesis. AB - Our previous studies have shown that microRNA-383 (miR-383) expression is downregulated in the testes of infertile men with maturation arrest (MA). Abnormal testicular miR-383 expression may potentiate the connections between male infertility and testicular germ cell tumors. However, the mechanisms underlying the targeting and functions of miR-383 during spermatogenesis remain unknown. In this study, we found that fragile X mental retardation protein (FMRP) was associated with 88 miRNAs in mouse testis including miR-383. Knockdown of FMRP in NTERA-2 (NT2) (testicular embryonal carcinoma) cells enhanced miR-383 induced suppression of cell proliferation by decreasing the interaction between FMRP and miR-383, and then affecting miR-383 binding to the 3'-untranslated region of its target genes, including interferon regulatory factor-1 (IRF1) and Cyclin D1 both in vivo and in vitro. On the other hand, FMRP levels were also downregulated by overexpression of miR-383 in NT2 cells and GC1 (spermatogonia germ cell line). miR-383 targeted to Cyclin D1 directly, and then inhibited its downstream effectors, including phosphorylated pRb and E2F1, which ultimately resulted in decreased FMRP expression. Reduced miR-383 expression, dysregulated cyclin-dependent kinase 4 expression (one of the downstream genes of miR-383) and increased DNA damage were also observed in the testes of Fmr1 knockout mice and of MA patients with a downregulation of FMRP. A potential feedback loop between FMRP and miR-383 during spermatogenesis is proposed, and FMRP acts as a negative regulator of miR-383 functions. Our data also indicate that dysregulation of the FMRP-miR-383 pathway may partially contribute to human spermatogenic failure with MA. PMID- 23640460 TI - Involvement of PPARgamma in the antitumoral action of cannabinoids on hepatocellular carcinoma. AB - Cannabinoids exert antiproliferative effects in a wide range of tumoral cells, including hepatocellular carcinoma (HCC) cells. In this study, we examined whether the PPARgamma-activated pathway contributed to the antitumor effect of two cannabinoids, Delta9-tetrahydrocannabinol (THC) and JWH-015, against HepG2 and HUH-7 HCC cells. Both cannabinoids increased the activity and intracellular level of PPARgamma mRNA and protein, which was abolished by the PPARgamma inhibitor GW9662. Moreover, genetic ablation with small interfering RNA (siRNA), as well as pharmacological inhibition of PPARgamma decreased the cannabinoid induced cell death and apoptosis. Likewise, GW9662 totally blocked the antitumoral action of cannabinoids in xenograft-induced HCC tumors in mice. In addition, PPARgamma knockdown with siRNA caused accumulation of the autophagy markers LC3-II and p62, suggesting that PPARgamma is necessary for the autophagy flux promoted by cannabinoids. Interestingly, downregulation of the endoplasmic reticulum stress-related protein tribbles homolog 3 (TRIB3) markedly reduced PPARgamma expression and induced p62 accumulation, which was counteracted by overexpression of PPARgamma in TRIB3-knocked down cells. Taken together, we demonstrate for the first time that the antiproliferative action of the cannabinoids THC and JWH-015 on HCC, in vitro and in vivo, are modulated by upregulation of PPARgamma-dependent pathways. PMID- 23640461 TI - Yeast techniques for modeling drugs targeting Bcl-2 and caspase family members. AB - Development of drugs targeting Bcl-2 relatives and caspases, for treating diseases including cancer and inflammatory disorders, often involves measuring interactions with recombinant target molecules, and/or monitoring cancer cell killing in vitro. Here, we present yeast-based methods for evaluating drug mediated inhibition of Bcl-2 relatives or caspases. Active Bax and caspases kill Saccharomyces cerevisiae, and pro-survival Bcl-2 proteins can inhibit Bax-induced yeast death. By measuring the growth or adenosine triphosphate content of transformants co-expressing Bax with pro-survival Bcl-2 relatives, we found that the Bcl-2 antagonist drugs ABT-737 or ABT-263 abolished Bcl-2 or Bcl-xL function and reduced Bcl-w activity, but failed to inhibit Mcl-1, A1 or the poxvirus orthologs DPV022 and SPPV14. Using this technique, we also demonstrated that adenoviral E1B19K was resistant to these agents. The caspase inhibitor Q-VD-OPh suppressed yeast death induced by caspases 1 and 3. Yeast engineered to express human apoptotic regulators enable simple, automatable assessment of the activity and specificity of candidate drugs targeting Bcl-2 relatives or caspases. PMID- 23640462 TI - TGF-beta1 exposure induces epithelial to mesenchymal transition both in CSCs and non-CSCs of the A549 cell line, leading to an increase of migration ability in the CD133+ A549 cell fraction. AB - Metastasis is the leading cause of death by cancer. Non-small-cell lung cancer (NSCLC) represents nearly 85% of primary malignant lung tumours. Recent researches have demonstrated that epithelial-to-mesenchymal transition (EMT) plays a key role in the early process of metastasis of cancer cells. Transforming growth factor-beta1 (TGF-beta1) is the major inductor of EMT. The aim of this study is to investigate TGF-beta1's effect on cancer stem cells (CSCs) identified as cells positive for CD133, side population (SP) and non-cancer stem cells (non CSCs) identified as cells negative for CD133, and SP in the A549 cell line. We demonstrate that TGF-beta1 induces EMT in both CSC and non-CSC A549 sublines, upregulating the expression of mesenchymal markers such as vimentin and Slug, and downregulating levels of epithelial markers such as e-cadherin and cytokeratins. CSC and non-CSC A549 sublines undergoing EMT show a strong migration and strong levels of MMP9 except for the CD133(-) cell fraction. OCT4 levels are strongly upregulated in all cell fractions except CD133(-) cells. On the contrary, wound size reveals that TGF-beta1 enhances motility in wild-type A549 as well as CD133(+) and SP(+) cells. For CD133(-) and SP(-) cells, TGF-beta1 exposure does not change the motility. Finally, assessment of growth kinetics reveals major colony-forming efficiency in CD133(+) A549 cells. In particular, SP(+) and SP(-) A549 cells show more efficiency to form colonies than untreated corresponding cells, while for CD133(-) cells no change in colony number was observable after TGF-beta1 exposure. We conclude that it is possible to highlight different cell subpopulations with different grades of stemness. Each population seems to be involved in different biological mechanisms such as stemness maintenance, tumorigenicity, invasion and migration. PMID- 23640463 TI - Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts. AB - Although the recruitment of fibroblasts to areas of injury is critical for wound healing, their subsequent apoptosis is necessary in order to prevent excessive scarring. Fibroproliferative diseases, such as pulmonary fibrosis, are often characterized by fibroblast resistance to apoptosis, but the mechanism(s) for this resistance remains elusive. Here, we employed a murine model of pulmonary fibrosis and cells from patients with idiopathic pulmonary fibrosis (IPF) to explore epigenetic mechanisms that may be responsible for the decreased expression of Fas, a cell surface death receptor whose expression has been observed to be decreased in pulmonary fibrosis. Murine pulmonary fibrosis was elicited by intratracheal injection of bleomycin. Fibroblasts cultured from bleomycin-treated mice exhibited decreased Fas expression and resistance to Fas mediated apoptosis compared with cells from saline-treated control mice. Although there were no differences in DNA methylation, the Fas promoter in fibroblasts from bleomycin-treated mice exhibited decreased histone acetylation and increased histone 3 lysine 9 trimethylation (H3K9Me3). This was associated with increased histone deacetylase (HDAC)-2 and HDAC4 expression. Treatment with HDAC inhibitors increased Fas expression and restored susceptibility to Fas-mediated apoptosis. Fibroblasts from patients with IPF likewise exhibited decreased histone acetylation and increased H3K9Me3 at the Fas promoter and increased their expression of Fas in the presence of an HDAC inhibitor. These findings demonstrate the critical role of histone modifications in the development of fibroblast resistance to apoptosis in both a murine model and in patients with pulmonary fibrosis and suggest novel approaches to therapy for progressive fibroproliferative disorders. PMID- 23640464 TI - Resistance to hypoxia-induced necroptosis is conferred by glycolytic pyruvate scavenging of mitochondrial superoxide in colorectal cancer cells. AB - Cancer cells may survive under oxygen and nutrient deprivation by metabolic reprogramming for high levels of anaerobic glycolysis, which contributes to tumor growth and drug resistance. Abnormally expressed glucose transporters (GLUTs) are colocalized with hypoxia (Hx) inducible factor (HIF)1alpha in peri-necrotic regions in human colorectal carcinoma. However, the underlying mechanisms of anti necrotic resistance conferred by glucose metabolism in hypoxic cancer cells remain poorly understood. Our aim was to investigate signaling pathways of Hx induced necroptosis and explore the role of glucose pyruvate metabolite in mechanisms of death resistance. Human colorectal carcinoma cells were Hx exposed with or without glucose, and cell necroptosis was examined by receptor interacting protein (RIP)1/3 kinase immunoprecipitation and (32)P kinase assays. Our results showed increased RIP1/3 complex formation and phosphorylation in hypoxic, but not normoxic cells in glucose-free media. Blocking RIP1 signaling, by necrostatin-1 or gene silencing, decreased lactodehydrogenase (LDH) leakage and plasma membrane disintegration. Generation of mitochondrial superoxide was noted after hypoxic challenge; its reduction by antioxidants inhibited RIP signaling and cell necrosis. Supplementation of glucose diminished the RIP dependent LDH leakage and morphological damage in hypoxic cells, whereas non metabolizable sugar analogs did not. Hypoxic cells given glucose showed nuclear translocation of HIF1alpha associated with upregulation of GLUT-1 and GLUT-4 expression, as well as increase of intracellular ATP, pyruvate and lactate levels. The glucose-mediated death resistance was ablated by iodoacetate (an inhibitor to glyceraldehyde-3-phosphate dehydrogenase), but not by UK5099 (an inhibitor to mitochondrial pyruvate carrier), suggesting that glycolytic pathway was involved in anti-necrotic mechanism. Lastly, replacing glucose with cell permeable pyruvate derivative also led to decrease of Hx-induced necroptosis by suppression of mitochondrial superoxide in an energy-independent manner. In conclusion, glycolytic metabolism confers resistance to RIP-dependent necroptosis in hypoxic cancer cells partly through pyruvate scavenging of mitochondrial free radicals. PMID- 23640466 TI - Investigation of 90Y-avidin for prostate cancer brachytherapy: a dosimetric model for a phase I-II clinical study. AB - PURPOSE: A novel method for prostate irradiation is investigated. Similarly to (125)I or (103)Pd seed brachytherapy, (90)Y-avidin could be injected via the perineum under ultrasound image guidance. This study inspects the theoretical feasibility with a dosimetric model based on Monte Carlo simulation. METHODS: A geometrical model of the prostate, urethra and rectum was designed. The linear quadratic model was applied to convert (125)I absorbed dose prescription/constraints into (90)Y dose through biological effective dose (BED) calculation. The optimal (90)Y-avidin injection strategy for the present model was obtained. Dose distribution was calculated by Monte Carlo simulation (PENELOPE,GEANT4). Dose volume histograms (DVH) for the prostate, urethra and rectum were compared to typical DVHs of (125)I seed brachytherapy, used routinely in our institute. RESULTS: With (90)Y-avidin, at least 95% of the prostate must receive more than 70 Gy. The absorbed dose to 10% of the urethra (D(10%_urethra)) and the maximum absorbed dose to the rectum (D(max_rectum)) must be lower than 122 Gy. For the present model, the optimum strategy consists in multiple injections of (90)Y-avidin 50 MUl drops, for a total volume of 3.1 ml. The minimum activity to deliver the prescribed absorbed dose is 0.7 GBq, which also fully respects urethral and rectal constraints. The resulting dose map has a maximum in the central region with a sharp decrease towards the urethra and the prostate edge. Notably, D(10%_urethra) is 95 Gy and D(max_rectum) is below 2 Gy. Prostate absorbed dose is higher with (90)Y-avidin than (125)I seeds, although the total volume receiving the prescribed absorbed dose is 1-2% lower. Urethral DVH strictly depends on the (90)Y distribution, to be optimized according to prostate shape; in our model, BED(30%_urethra) is 90 Gy with (90)Y-avidin, whereas for patients receiving (125)I seeds it ranges between 150 and 230 Gy. The rectal DVH is always more favourable with (90)Y. CONCLUSION: The methodology is theoretically feasible and can deliver an effective treatment in T1-T2 prostate cancer. Pharmacokinetic and biodistribution studies in prostate cancer patients are needed for validation. PMID- 23640467 TI - 18F-FDG PET/CT imaging versus dynamic contrast-enhanced CT for staging and prognosis of inflammatory breast cancer. AB - PURPOSE: Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer with a poor prognosis. Locoregional staging is based on dynamic contrast enhanced (DCE) CT or MRI. The aim of this study was to compare the performances of FDG PET/CT and DCE CT in locoregional staging of IBC and to assess their respective prognostic values. METHODS: The study group comprised 50 women (median age: 51 +/- 11 years) followed in our institution for IBC who underwent FDG PET/CT and DCE CT scans (median interval 5 +/- 9 days). CT enhancement parameters were net maximal enhancement, net early enhancement and perfusion. RESULTS: The PET/CT scans showed intense FDG uptake in all primary tumours. Concordance rate between PET/CT and DCE CT for breast tumour localization was 92%. No significant correlation was found between SUVmax and CT enhancement parameters in primary tumours (p > 0.6). PET/CT and DCE CT results were poorly correlated for skin infiltration (kappa = 0.19). Ipsilateral foci of increased axillary FDG uptake were found in 47 patients (median SUV: 7.9 +/- 5.4), whereas enlarged axillary lymph nodes were observed on DCE CT in 43 patients. Results for axillary node involvement were fairly well correlated (kappa = 0.55). Nineteen patients (38%) were found to be metastatic on PET/CT scan with a significant shorter progression free survival than patients without distant lesions (p = 0.01). In the primary tumour, no statistically significant difference was observed between high and moderate tumour FDG uptake on survival, using an SUVmax cut-off of 5 (p = 0.7 and 0.9), or between high and low tumour enhancement on DCE CT (p > 0.8). CONCLUSION: FDG PET/CT imaging provided additional information concerning locoregional involvement to that provided by DCE CT on and allowed detection of distant metastases in the same whole-body procedure. Tumour FDG uptake or CT enhancement parameters were not correlated and were not found to have any prognostic value. PMID- 23640468 TI - Interventional nuclear medicine. PMID- 23640469 TI - Factors influencing the sensitivity of 18F-FDG PET/CT in the detection of infective endocarditis. PMID- 23640470 TI - Reply to comment by Treglia and Bertagna: FDG PET/CT for detection of infectious endocarditis. PMID- 23640471 TI - Free volume in ionic liquids: a connection of experimentally accessible observables from PALS and PVT experiments with the molecular structure from XRD data. AB - In the current work, free volume concepts, primarily applied to glass formers in the literature, were transferred to ionic liquids (ILs). A series of 1-butyl-3 methylimidazolium ([C4MIM](+)) based ILs was investigated by Positron Annihilation Lifetime Spectroscopy (PALS). The phase transition and dynamic properties of the ILs [C4MIM][X] with [X](-) = [Cl](-), [BF4](-), [PF6](-), [OTf](-), [NTf2](-) and [B(hfip)4](-) were reported recently (Yu et al., Phys. Chem. Chem. Phys., 2012, 14, 6856-6868). In this subsequent work, attention was paid to the connection of the free volume from PALS (here the mean hole volume, ) with the molecular structure, represented by volumes derived from X-ray diffraction (XRD) data. These were the scaled molecular volume Vm,scaled and the van der Waals volume V(vdw). Linear correlations of at the "knee" temperature ((T(k))) with V(m,scaled) and V(vdw) gave good results for the [C4MIM](+) series. Further relationships between volumes from XRD data with the occupied volume Vocc determined from PALS/PVT (Pressure Volume Temperature) measurements and from Sanchez-Lacombe Equation of State (SL-EOS) fits were elaborated (V(occ)(SL-EOS) ~ 1.63 V(vdw), R(2) = 0.981 and V(occ)(SL-EOS) ~ 1.12 V(m,scaled), R(2) = 0.980). Finally, the usability of V(m,scaled) was justified in terms of the Cohen-Turnbull (CT) free volume theory. Empirical CT type plots of viscosity and electrical conductivity showed a systematic increase in the critical free volume with molecular size. Such correlations allow descriptions of IL properties with the easily accessible quantity V(m,scaled) within the context of the free volume. PMID- 23640472 TI - Crystal structure and magnetic properties of Cr3Te5O13Cl3. AB - A new chromium tellurite oxochloride, Cr3Te5O13Cl3, has been prepared by solid state reaction and the crystal structure was determined by single crystal X-ray diffraction. The compound crystallizes in the non-centrosymmetric space group P2(1)2(1)2(1) with the unit cell a = 4.90180(10) A, b = 17.3394(2) A, c = 17.5405(2) A, Z = 4, R1 = 0.0282. The Cr(3+) ions have octahedral [CrO6] oxygen coordination, the Te(4+) ions have one sided [TeO3] and [TeO3Cl] coordinations. The [CrO6] octahedra are edge sharing and form chains extending along [100]. These are connected by corner sharing [TeO3] and [TeO3Cl] groups to form layers parallel to (110). The layers are connected by weak interactions in between Te(4+) in the layers and Cl(-) ions located in between. The compound undergoes antiferromagnetic ordering at ~34 K with a Weiss constant of -230 K. Isothermal magnetization measurements reveal a critical field of about 0.25 T above which the magnetization versus field changes from linear to a Brillouin-like saturation behaviour. The frustration ratio amounts to ~6.8 indicative of sizable competing antiferromagnetic spin-exchange interaction. The dielectric constant epsilon (6 kHz) amounts to ~7.9 and decreases by about 1% on cooling from 50 K to liquid helium temperatures. PMID- 23640473 TI - Intraluminal crossing of near-impenetrable occlusions by balloon-assisted battering ram technique. AB - PURPOSE: Subintimal crossing of total occlusions and acquiring reentry into the true lumen may be hazardous in highly calcified lesions, with or without the use of expensive reentry devices. Even when desirable, intraluminal crossing may not be feasible, because the guidewire tends to follow a path of least resistance between the intimal plaque and the adventitia. TECHNIQUE: A standard percutaneous transluminal angioplasty balloon is positioned just above the proximal cap of the occlusion and insufflated to 6 atmosphere. The balloon is used (1) to increase guidewire support close to the lesion and (2) for centralization purposes (limiting lateral movement of the guidewire). The ultra stiff back end of a regular guidewire can then be used to target the center of the cap while repeatedly pounding against it until it breaches. CONCLUSIONS: The balloon assisted battering ram technique may be attempted if intraluminal crossing is warranted before resorting to other complicated, expensive devices. PMID- 23640474 TI - The success and safety of endovenous ablation in patients with previous superficial venous thrombosis: a retrospective case-control study. AB - OBJECTIVES: Retrospective case-control study to determine the failure and endovenous heat-induced thrombosis (EHIT) rates of endovenous ablation (EVA) in patients with a history of superficial venous thrombosis (SVT). METHODS: Study and control groups each consisted of 73 patients with or without the history of SVT, who underwent EVA between June 2010 and July 2012. All patients were followed with venous duplex ultrasound. Procedural failure and EHIT rates were considered primary outcomes. RESULTS: There was no difference in EHIT or failure rates between study and control groups (P = 1.00). There was no difference in EHIT or failure rates between patients with and without the history of venous thromboembolism (VTE), with and without the history of VTE and/or SVT, with and without the history of thrombophilia, and on and off anticoagulation for either group or the combined study population. For the combined study population, failure rate was higher in patients with a history of VTE. CONCLUSIONS: Although EVA seems to be safe and effective in patients with a history of SVT, vein access in this patient group might require multiple attempts. PMID- 23640475 TI - Abstracts of the 11th International Conference of Non-invasive Cardiovascular Imaging. May 5-8, 2013. Berlin, Germany. PMID- 23640477 TI - Advocacy: Defining quality in the field. President's Page. PMID- 23640480 TI - Fluctuating mastectomy rates across time and geography. AB - In 2009, 2 single-institution studies from the United States reported increasing mastectomy rates during the last decade. We have recently reported unilateral mastectomy trends from a European database and demonstrated a significant trend of decreasing mastectomy rates from 38.1 % in 2005 to 13.1 % in 2010. A recent study from the SEER registry in the United States confirmed a previously reported decrease in mastectomy rates from 40.1 % in year 2000 to 35.6 % in 2005, but showed a statistically significant increase in mastectomy rates up to 38.4 % in 2008. This report provides evidence that mastectomy trends may be in opposite directions in different geographical areas. The sharpest increase in mastectomy rates across all ages in the recent SEER study occurs right after year 2005, which interestingly corresponds with the time of publication of the meta-analysis by the EBCTCG that highlighted the importance of local control in breast cancer. The coincident timing raises the question of whether this evidence may have indirectly triggered an increase in mastectomy rates in the United States that would partially explain the observed trend, and more importantly, of whether an increase would be justified on this basis. Multiple factors influence the proportion between mastectomy and breast conservation, so it may be unreasonable to think of an optimal cutoff. There is not necessarily a right or wrong direction for mastectomy trends, but aiming to determine explanations for these differences may help provide a clearer insight of the decision-making process involved in the surgical management of breast cancer. PMID- 23640479 TI - Increase of bone morphogenetic protein-7 expressing pulmonary resident cells in pneumonectomized rats. AB - PURPOSE: Compensatory lung growth (CLG) is recognized in rodents subjected to major pulmonary resection; however, the source of cells constituting regenerated tissues during the CLG is still unknown. We investigated the differentiation of lung resident cells and the participation of bone marrow (BM)-derived cells in the remnant lung of pneumonectomized rats. METHODS: After left pneumonectomy, the right remnant lung of Wistar rats was subjected to morphologic and molecular experiments at several time points. We studied the expression of bone morphogenic protein 7 (BMP-7), an accelerator of epithelial differentiation, based on the gene expression profile data of the remnant lung. Next, we evaluated the presence of GFP-positive cells in the remnant lung of Wistar rats that had received BM transplantation from green fluorescent protein (GFP) gene-transgenic Wistar rats prior to left pneumonectomy. RESULTS: We observed progression of emphysematous change, modulation of gene expression profile, and proliferating cellular nuclear antigen-positive cells in the alveoli of the remnant lungs. BMP-7 protein positive cells were detected in the alveolar septa, which increased significantly over time with the progression of emphysematous change. No bone marrow-derived cells were detected in the right remnant lung of the GFP-BM transferred rats by fluorescence microscopy, immunohistochemistry, or polymerase chain reaction at any time. CONCLUSION: Lung resident cells appear to contribute to CLG, possibly via a trans-differentiation pathway. PMID- 23640481 TI - Cholangiocarcinoma presenting as Sister Mary Joseph's nodule: case report and short review of the literature. PMID- 23640482 TI - Transcriptional control of macrophage polarization. AB - Macrophages are key regulators of many organ systems, including innate and adaptive immunity, systemic metabolism, hematopoiesis, vasculogenesis, malignancy, and reproduction. The pleiotropic roles of macrophages are mirrored by similarly diverse cellular phenotypes. A simplified schema classifies macrophages as M1, classically activated macrophages, or M2, alternatively activated macrophages. These cells are characterized by their expression of cell surface markers, secreted cytokines and chemokines, and transcription and epigenetic pathways. Transcriptional regulation is central to the differential speciation of macrophages, and several major pathways have been described as essential for subset differentiation. In this review, we discuss the transcriptional regulation of macrophages. PMID- 23640483 TI - 4-Hydroxy-2-nonenal enhances tissue factor activity in human monocytic cells via p38 mitogen-activated protein kinase activation-dependent phosphatidylserine exposure. AB - OBJECTIVE: 4-hydroxy-2-nonenal (HNE) is one of the major aldehydes formed during lipid peroxidation and is believed to play a role in the pathogenesis of atherosclerosis. The objective of the present study is to investigate the effect of HNE on tissue factor (TF) procoagulant activity expressed on cell surfaces. APPROACH AND RESULTS: TF activity and antigen levels on intact cells were measured using factor Xa generation and TF monoclonal antibody binding assays, respectively. Exposure of phosphatidylserine on the cell surface was analyzed using thrombin generation assay or by binding of a fluorescent dye-conjugated annexin V. 2',7'-dichlorodihydrofluorescein diacetate was used to detect the generation of reactive oxygen species. Our data showed that HNE increased the procoagulant activity of unperturbed THP-1 cells that express traces of TF antigen, but had no effect on unperturbed endothelial cells that express no measurable TF antigen. HNE increased TF procoagulant activity but not TF antigen of both activated monocytic and endothelial cells. HNE treatment generated reactive oxygen species, activated p38 mitogen-activated protein kinase, and increased the exposure of phosphatidylserine at the outer leaflet in THP-1 cells. Treatment of THP-1 cells with an antioxidant, N-acetyl cysteine, suppressed the above HNE-induced responses and negated the HNE-mediated increase in TF activity. Blockade of p38 mitogen-activated protein kinase activation inhibited HNE-induced phosphatidylserine exposure and increased TF activity. CONCLUSIONS: HNE increases TF coagulant activity in monocytic cells through a novel mechanism involving p38 mitogen-activated protein kinase activation that leads to enhanced phosphatidylserine exposure at the cell surface. PMID- 23640484 TI - KRP-203, sphingosine 1-phosphate receptor type 1 agonist, ameliorates atherosclerosis in LDL-R-/- mice. AB - OBJECTIVE: Sphingosine 1-phosphate (S1P) partly accounts for antiatherogenic properties of high-density lipoproteins. We previously demonstrated that FTY720, a synthetic S1P analog targeting all S1P receptors but S1P receptor type 2, inhibits murine atherosclerosis. Here, we addressed the identity of S1P receptor mediating atheroprotective effects of S1P. APPROACH AND RESULTS: Low-density lipoprotein receptor-deficient mice on cholesterol-rich diet were given selective S1P receptor type 1 agonist KRP-203 (3.0 mg/kg per day; 6 and 16 weeks). KRP-203 substantially reduced atherosclerotic lesion formation without affecting plasma lipid concentrations. However, KRP-203 induced lymphopenia, reduced total (CD4(+), CD8(+)) and activated (CD69(+)/CD8(+), CD69(+)/CD4(+)) T cells in peripheral lymphoid organs, and interfered with lymphocyte function, as evidenced by decreased T-cell proliferation and interleukin-2 and interferon-gamma production in activated splenocytes. Cyto- and chemokine (tumor necrosis factor alpha, regulated and normal T cell expressed and secreted) levels in plasma and aortas were reduced by KRP-203 administration. Moreover, macrophages from KRP-203 treated mice showed reduced expression of activation marker MCH-II and poly(I:C) elicited production of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interleukin-6. In vitro studies demonstrated that KRP-203 reduced tumor necrosis factor-alpha, interleukin-6, and interferon-gamma-induced protein 10 production; IkappaB and signal transducer and activator of transcription-1 phosphorylation; and nuclear factor kappaB and signal transducer and activator of transcription-1 activation in poly(I:C)-, lipopolysaccharide-, or interferon gamma-stimulated bone marrow macrophages, respectively. CONCLUSIONS: Present results demonstrate that activation of S1P signaling pathways inhibit atherosclerosis by modulating lymphocyte and macrophage function and suggest that S1P receptor type 1 at least partially mediates antiatherogenic effects of S1P. PMID- 23640486 TI - Impaired lipoprotein processing in HIV patients on antiretroviral therapy: aberrant high-density lipoprotein lipids, stability, and function. AB - OBJECTIVE: HIV patients on antiretroviral therapy (HIV/ART) exhibit a unique atherogenic dyslipidemic profile with hypertriglyceridemia (HTG) and low plasma concentrations of high-density lipoprotein (HDL) cholesterol. In the Heart Positive Study of HIV/ART patients, a hypolipidemic therapy of fenofibrate, niacin, diet, and exercise reduced HTG and plasma non-HDL cholesterol concentrations and raised plasma HDL cholesterol and adiponectin concentrations. We tested the hypothesis that HIV/ART HDL have abnormal structures and properties and are dysfunctional. APPROACH AND RESULTS: Hypolipidemic therapy reduced the TG contents of low-density lipoprotein and HDL. At baseline, HIV/ART low-density lipoproteins were more triglyceride (TG)-rich and HDL were more TG- and cholesteryl ester-rich than the corresponding lipoproteins from normolipidemic (NL) subjects. Very-low-density lipoproteins, low-density lipoprotein, and HDL were larger than the corresponding lipoproteins from NL subjects; HIV/ART HDL were less stable than NL HDL. HDL-[(3)H]cholesteryl ester uptake by Huh7 hepatocytes was used to assess HDL functionality. HIV/ART plasma were found to contain significantly less competitive inhibition activity for hepatocyte HDL cholesteryl ester uptake than NL plasma were found to contain (P<0.001). CONCLUSIONS: Compared with NL subjects, lipoproteins from HIV/ART patients are larger and more neutral lipid-rich, and their HDL are less stable and less receptor-competent. On the basis of this work and previous studies of lipase activity in HIV, we present a model in which plasma lipolytic activities or hepatic cholesteryl ester uptake are impaired in HIV/ART patients. These findings provide a rationale to determine whether the distinctive lipoprotein structure, properties, and function of HIV/ART HDL predict atherosclerosis as assessed by carotid artery intimal medial thickness. PMID- 23640485 TI - Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation. AB - OBJECTIVE: The pleiotropic effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) independent of cholesterol-lowering effects are thought to be mediated through inhibition of the Rho/Rho-kinase pathway. However, we have previously demonstrated that the pleiotropic effects of regular-dose statins are mediated mainly through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway, although the molecular mechanisms of the selective inhibition of the Rac1 signaling pathway by regular-dose statins remain to be elucidated. In this study, we tested our hypothesis that small GTP-binding protein GDP dissociation stimulator (SmgGDS) plays a crucial role in the molecular mechanisms of the Rac1 signaling pathway inhibition by statins in endothelial cells. APPROACH AND RESULTS: In cultured human umbilical venous endothelial cells, statins concentration-dependently increased SmgGDS expression and decreased nuclear Rac1. Statins also enhanced SmgGDS expression in mouse aorta. In control mice, the protective effects of statins against angiotensin II induced medial thickening of coronary arteries and fibrosis were noted, whereas in SmgGDS-deficient mice, the protective effects of statins were absent. When SmgGDS was knocked down by its small interfering RNA in human umbilical venous endothelial cells, statins were no longer able to induce Rac1 degradation or inhibit angiotensin II-induced production of reactive oxygen species. Finally, in normal healthy volunteers, statins significantly increased SmgGDS expression with a significant negative correlation between SmgGDS expression and oxidative stress markers, whereas no correlation was noted with total or low-density lipoprotein cholesterol. CONCLUSIONS: These results indicate that statins exert their pleiotropic effects through SmgGDS upregulation with a resultant Rac1 degradation and reduced oxidative stress in animals and humans. PMID- 23640489 TI - Macrophages: much more than big eaters! PMID- 23640488 TI - Notch1 promotes the pro-osteogenic response of human aortic valve interstitial cells via modulation of ERK1/2 and nuclear factor-kappaB activation. AB - OBJECTIVE: Calcific aortic valve disease is a leading cardiovascular disease in the elderly, and progressive calcification results in the failure of valvular function. Aortic valve interstitial cells (AVICs) from stenotic valves express higher levels of bone morphogenetic protein-2 in response to Toll-like receptor 4 stimulation. We recently found that Toll-like receptor 4 interacts with Notch1 in human AVICs. This study tests the hypothesis that Notch1 promotes the pro osteogenic response of human AVICs. APPROACH AND RESULTS: AVICs isolated from diseased human valves expressed higher levels of bone morphogenetic protein-2 and alkaline phosphatase after lipopolysaccharide stimulation. The augmented pro osteogenic response is associated with elevated cellular levels of Notch1 and enhanced Notch1 cleavage in response to lipopolysaccharide stimulation. Inhibition or silencing of Notch1 suppressed the pro-osteogenic response in diseased cells, and the Notch 1 ligand, Jagged1, enhanced the response in AVICs isolated from normal human valves. Interestingly, extracellular signal-regulated protein kinases 1/2 (ERK1/2) and nuclear factor-kappaB phosphorylation induced by lipopolysaccharide was markedly reduced by inhibition or silencing of Notch1 and enhanced by Jagged1. Inhibition of ERK1/2 or nuclear factor-kappaB also reduced bone morphogenetic protein-2 and alkaline phosphatase expression induced by lipopolysaccharide. CONCLUSIONS: Notch1 mediates the pro-osteogenic response to Toll-like receptor 4 stimulation in human AVICs. Elevated Notch1 levels and enhanced Notch1 activation play a major role in augmentation of the pro osteogenic response of AVICs of stenotic valves through modulation of ERK1/2 and nuclear factor-kappaB activation. These pathways could be potential therapeutic targets for prevention of the progression of calcific aortic valve disease. PMID- 23640490 TI - Current genetics and epigenetics of smoking/tobacco-related cardiovascular disease. AB - Genetic and epigenetic factors are of great importance in cardiovascular biology and disease. Tobacco-smoking, one of the most important cardiovascular risk factors, is itself partially determined by genetic background and is associated with altered epigenetic patterns. This could render the genetics and epigenetics of smoking-related cardiovascular disease a textbook example of environmental epigenetics and modern approaches to multimodal data analysis. A pronounced association of smoking-related methylation patterns in the F2RL3 gene with prognosis in patients with stable coronary heart disease has recently been described. Nonetheless, surprisingly little concrete knowledge on the role of specific genetic variants and epigenetic modifications in the development of cardiovascular diseases in people who smoke has been accumulated. Beyond the current knowledge, the present review briefly outlines some chief challenges and priorities for moving forward in this field. PMID- 23640487 TI - Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development. AB - OBJECTIVE: Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development. APPROACH AND RESULTS: Macrophage activation elicited by pathogen-recognition receptor agonists decreased Angptl4 expression, whereas lipid loading by intralipid and oxidized low-density lipoprotein increased Angptl4 expression. Consistent with an antilipotoxic role of Angptl4, recombinant Angptl4 significantly decreased uptake of oxidized low density lipoprotein by macrophages, via lipolysis-dependent and -independent mechanisms. Angptl4 protein was detectable in human atherosclerotic lesions and localized to macrophages. Transgenic overexpression of Angptl4 in atherosclerosis prone apolipoprotein E*3-Leiden mice did not significantly alter plasma cholesterol and triglyceride levels. Nevertheless, Angptl4 overexpression reduced lesion area by 34% (P<0.05). In addition, Angptl4 overexpression decreased macrophage content (-41%; P<0.05) and numbers of monocytes adhering to the endothelium wall (-37%; P<0.01). Finally, plasma Angptl4 was independently and negatively associated with carotid artery sclerosis measured by 3-T MRI in subjects with metabolic syndrome and low-grade systemic inflammation. CONCLUSIONS: Angptl4 suppresses foam cell formation to reduce atherosclerosis development. Stimulation of Angptl4 in macrophages by oxidized low-density lipoprotein may protect against lipid overload. PMID- 23640491 TI - CD34 hybrid cells promote endothelial colony-forming cell bioactivity and therapeutic potential for ischemic diseases. AB - OBJECTIVE: Although endothelial progenitor cells (EPCs) have been reported to promote neovessel formation during vascular injury, the function of supporting cells of EPCs and their interaction with EPCs during EPC isolation remain unclear. APPROACH AND RESULTS: We investigated the functional properties of 2 types of EPCs, also known as endothelial colony-forming cells (ECFCs), CD34( )/CD34(+) cell-derived ECFCs (hybrid-dECFCs) and CD34(+) cell-derived ECFCs (stem dECFCs), isolated using different methods, to elucidate the role of CD34(-) cell populations as cell-supporting niches. Using EPC colony-forming and insert coculture assays, we found that CD34(-) accessory cells dynamically modulate hematopoietic stem cell-derived endothelial cell progenitor commitment via angiogenic cytokines secreted by CD34(-)/CD11b(+) macrophages. On the basis of these findings, we isolated 2 types of ECFCs and investigated their bioactivities. We found that stem-dECFCs showed remarkably retarded cell growth, enhanced senescence, and decreased characteristics of ECFCs, whereas hybrid dECFCs showed greater proliferative properties but delayed senescence. In a murine hind-limb ischemia model, hybrid-dECFCs showed significantly enhanced blood perfusion, capillary density, transplanted cell survival and proliferation, and angiogenic cytokine secretion compared with stem-dECFCs. In particular, the migratory capacity of hybrid-dECFCs was significantly enhanced, in part mediated via an augmented phosphorylation cascade of focal adhesion kinase and Src, resulting in a highly increased incorporation capacity of hybrid-dECFCs compared with stem-dECFCs. CD34(-) accessory cells of hybrid-dECFCs might be niche supporting cells that facilitate cell survival, increase the secretion of angiogenic cytokines, and increase incorporation. CONCLUSIONS: This study provided important insight into blood vessel formation and repair in ischemic diseases for ECFC-based cell therapy. PMID- 23640493 TI - Male-specific region of the Y chromosome and cardiovascular risk: phylogenetic analysis and gene expression studies. AB - OBJECTIVE: Haplogroup I of male-specific region of the human Y chromosome is associated with 50% increased risk of coronary artery disease. It is not clear to what extent conventional cardiovascular risk factors and genes of the male specific region may explain this association. APPROACH AND RESULTS: A total of 1988 biologically unrelated men from 4 white European populations were genotyped using 11 Y chromosome single nucleotide polymorphisms and classified into 13 most common European haplogroups. Approximately 75% to 93% of the haplotypic variation of the Y chromosome in all cohorts was attributable to I, R1a, and R1b1b2 lineages. None of traditional cardiovascular risk factors, including body mass index, blood pressures, lipids, glucose, C-reactive protein, creatinine, and insulin resistance, was associated with haplogroup I of the Y chromosome in the joint inverse variance meta-analysis. Fourteen of 15 ubiquitous single-copy genes of the male-specific region were expressed in human macrophages. When compared with men with other haplogroups, carriers of haplogroup I had ~ 0.61- and 0.64 fold lower expression of ubiquitously transcribed tetratricopeptide repeat, Y linked gene (UTY) and protein kinase, Y-linked, pseudogene (PRKY) in macrophages (P=0.0001 and P=0.002, respectively). CONCLUSIONS: Coronary artery disease predisposing haplogroup I of the Y chromosome is associated with downregulation of UTY and PRKY genes in macrophages but not with conventional cardiovascular risk factors. PMID- 23640492 TI - Phenotypic polarization of macrophages in atherosclerosis. AB - Macrophages orchestrate the inflammatory response in inflamed tissues, and recent work indicates that these cells can alter their phenotypes and functions accordingly in response to changes in the microenvironment. Initial work in models of cardiovascular disease used immunologic markers to characterize macrophage phenotypes present in atherosclerotic plaque, and these studies have lately been extended through the use of markers that are more specific for atherosclerosis and metabolic disease. Together, these studies have led to a novel view of the function of macrophages in the development of atherosclerosis that suggests dynamic plasticity. Understanding this plasticity and the ensuing macrophage heterogeneity could lead to novel strategies of pharmacological intervention to combat chronic inflammation in metabolic diseases. Most importantly, revealing the functional characteristics of individual macrophage phenotypes will lead to a better understanding of their contribution to lesion development and plaque stability. PMID- 23640494 TI - Macrophage function and polarization in cardiovascular disease: a role of estrogen signaling? AB - Macrophages are plastic and versatile cells adapting their function/phenotype to the microenvironment. Distinct macrophage subpopulations with different functions, including classically (M1) and (M2) activated macrophages, have been described. Reciprocal skewing of macrophage polarization between the M1 and M2 state is a process modulated by transcription factors, such as the nuclear peroxisome proliferator-activated receptors. However, whether the estrogen/estrogen receptor pathways control the balance between M1/M2 macrophages is only partially understood. Estrogen-dependent effects on the macrophage system may be regarded as potential targets of pharmacological approaches to protect postmenopausal women from the elevated risk of cardiovascular disease. PMID- 23640495 TI - Thin-capped atheromata with reduced collagen content in pigs develop in coronary arterial regions exposed to persistently low endothelial shear stress. AB - OBJECTIVE: The mechanisms promoting the focal formation of rupture-prone coronary plaques in vivo remain incompletely understood. This study tested the hypothesis that coronary regions exposed to low endothelial shear stress (ESS) favor subsequent development of collagen-poor, thin-capped plaques. APPROACH AND RESULTS: Coronary angiography and 3-vessel intravascular ultrasound were serially performed at 5 consecutive time points in vivo in 5 diabetic, hypercholesterolemic pigs. ESS was calculated along the course of each artery with computational fluid dynamics at all 5 time points. At follow-up, 184 arterial segments with previously identified in vivo ESS underwent histopathologic analysis. Compared with other plaque types, eccentric thin-capped atheromata developed more in segments that experienced lower ESS during their evolution. Compared with lesions with higher preceding ESS, segments persistently exposed to low ESS (<1.2 Pa) exhibited reduced intimal smooth muscle cell content; marked intimal smooth muscle cell phenotypic modulation; attenuated procollagen-I gene expression; increased gene and protein expression of the interstitial collagenases matrix-metalloproteinase-1, -8, -13, and -14; increased collagenolytic activity; reduced collagen content; and marked thinning of the fibrous cap. CONCLUSIONS: Eccentric thin-capped atheromata, lesions particularly prone to rupture, form more frequently in coronary regions exposed to low ESS throughout their evolution. By promoting an imbalance of attenuated synthesis and augmented collagen breakdown, low ESS favors the focal evolution of early lesions toward plaques with reduced collagen content and thin fibrous caps-2 critical determinants of coronary plaque vulnerability. PMID- 23640497 TI - High precision platelet releasate definition by quantitative reversed protein profiling--brief report. AB - OBJECTIVE: Platelet activation and subsequent protein release play an important role in healthy hemostasis and inflammatory responses, yet the identity and quantity of proteins in the platelet releasate are still debated. Here, we present a reversed releasate proteomics approach to determine unambiguously and quantitatively proteins released from activated platelets. APPROACH AND RESULTS: Isolated platelets were mock and fully stimulated after which the released proteins in the supernatant were removed. Using high-end proteomics technology (2D chromatography, stable isotope labeling, electron transfer dissociation, and high collision dissociation fragmentation) allowed us to quantitatively discriminate the released proteins from uncontrolled lysis products. Monitoring the copy numbers of ~ 4500 platelet proteins, we observed that after stimulation via thrombin and collagen, only 124 (<3%) proteins were significantly released (P<0.05). The released proteins span a concentration range of >= 5 orders, as confirmed by ELISA. The released proteins were highly enriched in secretion tags and contained all known factors at high concentrations (>100 ng/mL, eg, thrombospondin, von Willebrand factor, and platelet factor 4). Interestingly, in the lower concentration range of the releasate many novel factors were identified. CONCLUSIONS: Our reversed releasate dataset forms the first unambiguous, in depth repository for molecular factors released by platelets. PMID- 23640496 TI - p21 activated kinase signaling coordinates glycoprotein receptor VI-mediated platelet aggregation, lamellipodia formation, and aggregate stability under shear. AB - OBJECTIVE: Rho GTPase proteins play a central role in regulating the dynamics of the platelet actin cytoskeleton. Yet, little is known regarding how Rho GTPase activation coordinates platelet activation and function. In this study, we aimed to characterize the role of the Rho GTPase effector, p21 activated kinase (PAK), in platelet activation, lamellipodia formation, and aggregate formation under shear. APPROACH AND RESULTS: Stimulation of platelets with the glycoprotein receptor VI agonist, collagen-related peptide, rapidly activated PAK in a time course preceding phosphorylation of PAK substrates, LIM domain kinase LIMK1 and the MAPK/ERK kinase MEK, and the subsequent activation of MAPKs and Akt. Pharmacological inhibitors of PAK blocked signaling events downstream of PAK and prevented platelet secretion as well as platelet aggregation in response to collagen-related peptide. PAK inhibitors also prevented PAK activation and platelet spreading on collagen surfaces. PAK was also required for the formation of platelet aggregates and to maintain aggregate stability under physiological shear flow conditions. CONCLUSIONS: These results suggest that PAK serves as an orchestrator of platelet functional responses after activation downstream of the platelet collagen receptor, glycoprotein receptor VI. PMID- 23640498 TI - Sphingomyelin synthase 2 activity and liver steatosis: an effect of ceramide mediated peroxisome proliferator-activated receptor gamma2 suppression. AB - OBJECTIVE: Sphingolipid de novo biosynthesis is related to nonalcoholic fatty liver disease or hepatic steatosis. However, the mechanism is still unclear. Sphingomyelin synthase (SMS), using ceramide as one of the substrates to produce sphingomyelin, sits at the crossroads of sphingolipid biosynthesis. SMS has 2 isoforms: SMS1 and SMS2. SMS2 is the major isoform in liver. APPROACH AND RESULTS: To investigate the relationship between liver SMS2 activity-mediated sphingolipid changes and hepatic steatosis, we used 2 mouse models: Sms2 liver specific transgenic and Sms2 knockout mice. We found that Sms2 liver-specific transgenic livers have lower ceramide and higher sphingomyelin, whereas Sms2 knockout livers have higher ceramide and lower sphingomyelin. We also found that liver Sms2 overexpression promoted fatty acid uptake and liver steatosis, whereas Sms2 deficiency had an opposite effect in comparison with their respective controls. Importantly, the exogenous ceramide supplementation to Huh7 cells, a human hepatoma cell line, reduced the expression of peroxisome proliferator activated receptor gamma2 and its target genes, Cd36 and Fsp27. Peroxisome proliferator-activated receptor gamma reporter analysis confirmed this phenomenon. Furthermore, peroxisome proliferator-activated receptor gamma antagonist treatment significantly decreased triglyceride accumulation in Sms2 liver-specific transgenic liver. CONCLUSIONS: We attributed these effects to ceramide that can suppress peroxisome proliferator-activated receptor gamma2, thus reducing the expression of Cd36 and Fsp27 and reducing liver steatosis. After all, SMS2 inhibition in the liver could diminish liver steatosis. PMID- 23640501 TI - Do clinical practice guidelines do enough to help clinicians identify patients at high risk of osteoporotic fracture? PMID- 23640499 TI - Multiple inflammatory biomarkers in relation to cardiovascular events and mortality in the community. AB - OBJECTIVE: Evidence suggests that chronic low-grade inflammation and oxidative stress are related to cardiovascular disease (CVD) and mortality. APPROACH AND RESULTS: We examined 11 established and novel biomarkers representing inflammation and oxidative stress (C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase-A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, P-selectin, and tumor necrosis factor receptor II [TNFRII]) in relation to incident major CVD and mortality in the community. We studied 3035 participants (mean age, 61 +/- 9 years; 53% women). During follow-up (median, 8.9 years), 253 participants experienced a CVD event and 343 died. C-reactive protein (hazard ratio [HR] reported per SD ln-transformed biomarker, 1.18; 95% confidence interval [CI], 1.02-1.35; nominal P=0.02) and TNFRII (HR, 1.15; 95% CI, 1.01 1.32; nominal P=0.04) were retained in multivariable-adjusted models for major CVD, but were not significant after adjustment for multiple testing. The biomarkers related to mortality were TNFRII (HR, 1.33; 95% CI, 1.19-1.49; P<0.0001), ICAM-1 (HR, 1.24; 95% CI, 1.12-1.37; P<0.0001), and interleukin-6 (HR, 1.25; 95% CI, 1.12-1.39; P<0.0001). The addition of these markers to the model, including traditional risk factors, increased discrimination and reclassification for risk of death (P<0.0001), but not for CVD. CONCLUSIONS: Of 11 inflammatory biomarkers tumor necrosis factor receptor II was related to cardiovascular disease and mortality in the Framingham Heart Study. The combination of TNFRII with C-reactive protein in relation to CVD and with interleukin-6 to mortality increased the predictive ability in addition to CVD risk factors for total mortality but not for incident CVD. PMID- 23640500 TI - Molecular basis of antiangiogenic thrombospondin-1 type 1 repeat domain interactions with CD36. AB - OBJECTIVE: Antiangiogenic activity of thrombospondin-1 and related proteins is mediated by interactions between thrombospondin type 1 repeat (TSR) domains and the CD36, LIMP-2, Emp sequence homology (CLESH) domain of the endothelial cell receptor CD36. We sought to characterize key molecular determinants of the interaction between thrombospondin-1 TSR domains and the CD36 CLESH domain. APPROACH AND RESULTS: Recombinant thrombospondin-1 TSR2 and TSR(2,3) constructs inhibited microvascular endothelial cell migration, microvascular endothelial cell tube formation, and vessel sprouting in aortic ring assays. Interaction with CD36 CLESH decoy peptides negated these effects. Mutational analyses identified a cluster of residues that confer positive charge to the TSR2 surface and mediate interaction with CD36 CLESH. Antiangiogenic activity was significantly reduced by charge-neutralizing mutations of the Arg-Trp ladder in TSR2, but not TSR3. Additionally, I438 and K464 of TSR2 were shown to be required for CD36 CLESH binding to TSR2. A complementary acidic cluster within CD36 CLESH is also required for antiangiogenic activity. CONCLUSIONS: Thrombospondin-1 interacts with CD36 CLESH through electrostatic interactions mediated by a positively charged TSR2 surface and multiple negatively charged CD36 CLESH residues. Two key residues serve as specificity determinants that identify other TSR domains that interact with CD36 CLESH. PMID- 23640502 TI - Defining high risk of osteoporotic fracture: a cross talk between clinical experience and guidelines recommendations. AB - BACKGROUND: : There is no universally accepted definition for patients at high risk of osteoporotic fracture. OBJECTIVES: : This study aimed to survey Spanish rheumatologists; to obtain opinions about risk factors, and an acceptable definition for patients at high risk of osteoporotic fracture; and to compare daily practice patterns with current osteoporosis guidelines. METHODS: : A total of 174 rheumatologists from throughout Spain completed an online survey about various risk factors for fragility fracture and about the management of patients with osteoporosis in clinical practice. Results were reviewed by a coordinating committee of osteoporosis experts and were compared with published national and international guideline recommendations. RESULTS: : Almost all rheumatologists who completed the survey (99%) consider that a group of patients exists with a high risk of osteoporotic fracture and that this group should be managed appropriately. Previous fracture is considered the most important risk factor, particularly in cases of multiple fracture, severe vertebral fracture, hip fracture, or fracture despite osteoporosis treatment. However, in osteoporosis guidelines, age, bone mineral density, and previous fragility fracture are the most important risk factors for new fracture. Furthermore, Spanish rheumatologists tend to treat patients at high risk of fracture with anabolic therapy (e.g., teriparatide), whereas guidelines make no such recommendation. CONCLUSIONS: : In osteoporosis, a large gap exists between implementation of guideline recommendations and actual clinical practice; this may be due, in part, to heterogeneity among existing guidelines. Thus, inclusion in guidelines of a practical definition of high risk of osteoporotic fracture may provide significant opportunities to improve patient care and prevent future fragility fractures. KEY POINTS: : PMID- 23640504 TI - Purtscher-like retinopathy in septicemic disseminated intravascular coagulation associated with nephrotic syndrome. AB - PURPOSE: To describe a case of severe Purtscher-like retinopathy during an episode of septicemic diffused intravascular coagulation (DIC) in a child with severe nephrotic syndrome. ?Method: Case report.?Results: A 5-year-old girl with a history of steroid-sensitive nephrotic syndrome was admitted for worsening symptoms of the systemic disease. Laboratory studies revealed evidence of DIC during an episode of septicemia. Ten days later, she had a sudden and severe bilateral visual loss. Her visual acuity was hand motion in either eye. Fundus examination showed ischemic retinal whitening and retinal hemorrhages. Fluorescein angiography revealed obstruction of arterioles and venules at the posterior pole. Three weeks later, ischemic retinal blanching and hemorrhages resolved in both eyes; visual acuity improved to 20/250 and 20/200 in right and left eye, respectively. No further functional improvement was noted after 3 months, due to diffuse thinning of the inner retina architecture as shown by optical coherence tomography. ?Conclusions: Purtscher-like retinopathy can occur in patients with septicemic DIC and nephrotic syndrome. PMID- 23640503 TI - Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age: an update. AB - Epilepsies occur across the entire age range, and their incidence peaks in the first years of life and in the elderly. Therefore, antiepileptic drugs (AEDs) are commonly used at the extremes of age. Rational prescribing in these age groups requires not only an understanding of the drugs' pharmacodynamic properties, but also careful consideration of potential age-related changes in their pharmacokinetic profile. The present article, which updates a review published in 2006 in this journal, focuses on recent findings on the pharmacokinetics of new generation AEDs in neonates, infants, children, and the elderly. Significant new information on the pharmacokinetics of new AEDs in the perinatal period has been acquired, particularly for lamotrigine and levetiracetam. As a result of slow maturation of the enzymes involved in glucuronide conjugation, lamotrigine elimination occurs at a particularly slow rate in neonates, and becomes gradually more efficient during the first months of life. In the case of levetiracetam, elimination occurs primarily by renal excretion and is also slow at birth, but drug clearance increases rapidly thereafter and can even double within 1 week. In general, infants older than 2-3 months and children show higher drug clearance (normalized for body weight) than adults. This pattern was confirmed in recent studies that investigated the pediatric pharmacokinetics of several new AEDs, including levetiracetam, rufinamide, stiripentol, and eslicarbazepine acetate. At the other extreme of age, in the elderly, drug clearance is generally reduced compared with younger adults because of less efficient drug-metabolizing activity, decreased renal function, or both. This general pattern, described previously for several AEDs, was confirmed in recent studies on the effect of old age on the clearance of felbamate, levetiracetam, pregabalin, lacosamide, and retigabine. For those drugs which are predominantly eliminated by renal excretion, aging-related pharmacokinetic changes could be predicted by measuring creatinine clearance (CLCR). Overall, most recent findings confirm that age is a major factor influencing the pharmacokinetic profile of AEDs. However, pharmacokinetic variability at any age can be considerable, and the importance of other factors should not be disregarded. These include genetic factors, co morbidities, and drug interactions, particularly those caused by concomitantly administered AEDs which induce or inhibit drug-metabolizing enzymes. PMID- 23640505 TI - Preventable visual impairment in children ?with nonprofound intellectual disability. AB - PURPOSE: To assess the preventable visual impairment in children with nonprofound intellectual disability (ID). ? METHODS: A total of 215 children with IDs (90 Down syndrome [DS], 125 nonprofound ID) and 116 age- and sex-matched healthy subjects were enrolled in this study. All participants underwent ophthalmologic examinations including cycloplegic refraction measurements, ocular movement evaluation, screening for strabismus (Hirschberg, Krimsky, or prism cover test), slit-lamp biomicroscopy, funduscopy, and intraocular pressure measurements. All data were recorded for statistical analysis.? RESULTS: Ocular findings in decreasing prevalence were as follows: refractive errors 55 (61.1%), strabismus 30 (33.2%), cataract 7 (7.8%), and nystagmus 7 (7.8%) in children with DS; refractive errors 57 (45.6%), strabismus 19 (15.2%), cataract 7 (6.4%), nystagmus 5 (4%), and glaucoma 1 (0.8%) in children with other ID; and refractive errors 13 (11.2%) and strabismus 4 (3.5%) in controls. Cataracts, glaucoma, and nystagmus were not observed in the control group. The most common ophthalmic findings in children with DS compared with other ID and controls were with hyperopia (p<0.03 and ?p<0.001, respectively) and esotropia (p<0.01 and p<0.01, respectively).? CONCLUSION: The pediatric population with ID has a high prevalence of preventable visual impairments, refractive errors, strabismus, and cataracts. The prevalence of strabismus and refractive errors was more frequent in children with DS. The importance of further health screenings including ophthalmic examinations should be utilized to implement appropriate care management and improve quality of life. PMID- 23640506 TI - Astigmatism prevalence and biometric analysis in normal population. AB - PURPOSE: To analyze the magnitude, orientation, and age-related changes of corneal astigmatism and its correlation with biometric parameters in healthy eyes.? METHODS: Patients over 15 years of age were enrolled in our study. Exclusion criteria were previous ocular surgery, corneal disease, or contact lens wear. Axial length (AL), keratometric readings, and anterior chamber depth (ACD) were assessed using IOLMaster.? RESULTS: In our study, 1092 eyes were examined. The mean age was 69.64 +/- 15.25 years (range ?15-100 years). The AL was 23.32 +/ 1.49 mm and ACD was 3.17 +/- 2.03 mm. Higher AL and ACD values were observed in male patients. The overall astigmatism was 0.89 +/- 0.72 D. The magnitude of astigmatism was =0.5 D in 73.53% of the cases, =1.0 D in 32.78%, =1.5 D in 13.55%, and =2.0 D in 6.86%. In our population, 582 eyes (53.3%) showed with-the rule astigmatism, 309 (28.3%) against-the-rule, and 201 (18.4%) oblique astigmatism, regardless of sex. Significant against-the-rule astigmatic shift was verified with aging. Significant correlation was found between age and ACD (r = <0.39, p<0.001), age and AL (r = <0.15, p<0.001), and AL and flat (r = <0.54, p<0.001) and steep keratometric readings ?(r = <0.49, p<0.001). ? CONCLUSIONS: In order to obtain adequate refraction results, at the time of cataract surgery distinct attention should be drawn to ophthalmologic biometric parameters, which are continuously changing even in adulthood, and to astigmatism above 1.0 D, present in >32% of the population. PMID- 23640507 TI - Correlation between cataract grading by Scheimpflug imaging and phaco time in phacoemulsification using peristaltic and venturi pumps. AB - PURPOSE: To study the correlation among cataract grading system by Scheimpflug imaging (Oculus Pentacam(r) Nucleus Grading System [PNS]), effective phaco time (EPT), and surgical time (ST) using peristaltic and venturi pumps on the Whitestar Signature Phaco System (Abbott Medical Optics, Inc., Santa Ana, California, USA). ? METHODS: Patients scheduled to have bimanual microincision phacoemulsification by the same surgeon (T.F.) had Pentacam(r) Scheimpflug assessment using PNS and were randomly distributed into ?2 groups. In group 1, surgery was performed using peristaltic pump, and in group 2, using venturi pump. Parameters assessed in both groups included EPT and ST. ? RESULTS: Sixty eyes that had uneventful clear cornea phacoemulsification with implantation of foldable intraocular lens (IOL) were evaluated, 30 in each group. The EPT was statistically superior with higher nuclear density grades for both groups 1 and 2 (group 1 Spearman R = 0.739, p<0.001; group 2 Spearman R = 0.924, p<0.001). The ST statistically increased with nucleus density for both groups 1 and 2 (group ?1 Spearman R = 0.620, p<0.001; group 2 Spearman R = 0.643, p<0.001). Group 2 presented statistically significant reduction on median ST compared with group 1 for nucleus grading 2, 3, 4, and 5. CONCLUSIONS: The PNS is an objective and reproducible method of grading nuclear cataract density and had a correlation with EPT. Peristaltic and venturi pumps in Signature Phaco System were similar in EPT but venturi pump reduced the median ST in nucleus with higher PNS, without repercussion on complications or anterior chamber stability. PMID- 23640508 TI - Biofeedback rehabilitation of eccentric fixation in patients with Stargardt disease. AB - PURPOSE: To evaluate the efficacy of biofeedback (BF) microperimetric rehabilitation in patients with Stargardt disease (STGD). ? METHODS: Eighteen patients with STGD with unstable fixation located in the superior retina and best corrected visual acuity (BCVA) between 20/100 and 20/320 in the better eye were recruited. All the patients underwent Nidek MP-1 microperimetry and fixation analysis. Twelve patients underwent 8 consecutive BF training sessions of 10 minutes each, performed once a week in the better eye. Six patients did not receive any training and were used as controls. In both groups, BCVA, reading speed, contrast sensitivity, bivariate contour ellipse area (BCEA), and retinal sensitivity were evaluated in the better eye at baseline and after 10 weeks. Paired and unpaired t tests were used as appropriate. ? RESULTS: In the control group, after the follow-up period, fixation pattern did not show any modification and the other parameters worsened or remained unchanged. On the contrary, the BF group showed significantly improved stabilization of fixation (mean BCEA 68.2% from 5.63 degrees 2 to 1.58 degrees 2), improved mean BCVA (from 34.00 to 37.67 letters), higher mean reading speed (from 66.67 to 84.00 words/min), higher contrast sensitivity (from 16.33 to 18.75 letters), and improved retinal sensitivity (from 10.68 to 12.29 dB). The comparison of the results obtained in the 2 groups was statistically significant for all the considered parameters except for retinal sensitivity. CONCLUSIONS: Biofeedback rehabilitation with the MP-1 increases quality of vision in patients with STGD, leading to a stabilization of fixation and a consequent improvement of patients' visual function and reading abilities PMID- 23640509 TI - Changes in anterior segment morphology after intravitreal injection of bevacizumab and bevacizumab-triamcinolone acetate combination. AB - PURPOSE: To evaluate the effects of 2 different amounts of commonly used intravitreal agents on anterior segment morphology in conjunction with intraocular pressure (IOP) changes. METHODS: Two groups of 46 patients who received intravitreal injection of bevacizumab (group 1, 0.05 mL) or bevacizumab triamcinolone acetate (TA) combination (group 2, 0.1 mL) were included in this prospective study. All patients underwent anterior segment optical coherence tomography ?(AS-OCT) imaging with Visante OCT and IOP measurement before and at 5 minutes, 1 hour, and 3 hours after injection. Anterior chamber depth (ACD), angle opening distance (AOD 500-750), trabecular-iris space area (TISA 500-750), and anterior chamber angle (ACA) were measured. Results were compared between groups and measurement time points. RESULTS: The mean change in IOP showed significant difference between baseline and first measurements after the injection in group 1 and group 2 (p = 0.012, p = 0.008, respectively). There was a statistically significant difference from baseline in ACD at the first and second measurements in group 2 (p = 0.005, p = 0.018, respectively). All angle parameters showed insignificant decrease from baseline at all measurement time points in both groups (p>0.05 for each). The difference of angle parameters after injection was not statistically significant between the groups (p>0.05 for each). CONCLUSION: Intravitreal injection of bevacizumab (0.05 mL) or bevacizumab-TA combination (0.1 mL) caused a change in anterior segment configuration determined by AS-OCT. The changes in anterior chamber parameters returned to baseline values with the normalization of IOP values after the first few minutes of injection. PMID- 23640510 TI - Large-area versus small-area application of mitomycin C during trabeculectomy. AB - PURPOSE: To compare 2 different application methods of mitomycin C (MMC) in patients undergoing trabeculectomy.? METHODS: This retrospective trial compared outcomes of 191 eyes that underwent trabeculectomy with small-area (96 eyes; 50.3%) and large-area (95 eyes; 49.7%) MMC application. Main outcome measures were changes in intraocular pressure (IOP), required glaucoma medications, the frequency of complications, and postsurgical interventions.? RESULTS: Within both treatment groups, a highly significant IOP reduction was seen during follow-up (p < 0.0001). Statistical analyses revealed a significant difference in IOP between both groups. Patients treated with a larger size of surface area had a higher IOP reduction within the first postoperative year. Choroidal detachment, shallow anterior chamber, and bleb leak were seen more often in the large-area group with more aggressive MMC use. In contrast, complications associated with bleb failure such as bleb scarring were higher in the small-area group. Success rate was higher in the large-area MMC application group after 12 months.? CONCLUSIONS: Large-area treatment seems to be a more efficient application method of MMC during trabeculectomy. PMID- 23640512 TI - Retinoblastoma with unusual association of postaxial polydactyly. AB - BACKGROUND: Retinoblastoma is the most common primary intraocular malignancy of childhood, arising from retinal progenitor cells. The most common presenting feature is leucocoria, followed by strabismus, defective vision, and rarely nystagmus. The unusual associations reported with retinoblastoma are well differentiated liposarcoma and lipomatous tissues, chromosome breakage syndromes, and the myriad findings of rare 13q deletion syndrome.? METHOD: Case report.? RESULTS: An 8-year-old boy presented with features of retinoblastoma, having leucocoria in the left eye and an unusual association of postaxial polydactyly in the left hand.? CONCLUSIONS: Postaxial polydactyly should be considered as an association of retinoblastoma. PMID- 23640511 TI - Retinal oxygen saturation and metabolism: how does it pertain to glaucoma? An update on the application of retinal oximetry in glaucoma. AB - PURPOSE: To discuss the techniques and mechanisms of retinal oximetry with a focus on utilization of retinal oximetry in the assessment of retinal oxygen saturation in glaucoma. METHODS: We reviewed recent literature found by searching combinations of the following search terms: glaucoma, retinal oximetry, ocular blood flow, retinal blood flow, oxygen saturation. We also reviewed pertinent references from articles found in this search. RESULTS: Retinal oximetry offers the potential for directly assessing oxygen saturation in retinal tissue. This capability can contribute to the knowledge of ocular blood flow and its role in the pathogenesis of glaucoma. CONCLUSIONS: Recent research has shown that retinal oximetry could become an important clinical tool in glaucoma. However, more research is needed to validate the reliability and reproducibility of retinal oximetry, and to fully deduce its clinical role in ocular diseases. PMID- 23640513 TI - Efficacy of timolol 0.1% gel and a prostaglandin ?analog in an unfixed combination compared to the corresponding fixed combinations. AB - Purpose: To investigate the intraocular pressure (IOP) reduction with prostaglandin analogs (PGAs)-timolol fixed combinations versus the unfixed combination of the same PGAs and timolol 0.1% in gel-forming carbomer. ?Methods: Patients with primary open-angle glaucoma (POAG) receiving for at least 4 weeks the fixed combinations of PGA-timolol, administered once a day in the evening (0.005% latanoprost with 0.5% timolol, 0.004% travoprost with 0.5% timolol, 0.03% bimatoprost with 0.5% timolol) were switched to an unfixed combination of the same PGA (once a day in the evening) with timolol 0.1% in gel-forming carbomer (once a day in the morning) for at least 4 weeks. The primary endpoint was to compare efficacy of fixed vs unfixed combinations in lowering IOP. The effects of both regimens on short-term IOP fluctuations were also assessed. ?Results: A total of 32 patients (64 eyes) fulfilled inclusion criteria: 17 patients received latanoprost-timolol fixed combination, 9 travoprost-timolol fixed combination, 6 bimatoprost-timolol fixed combination. For all considered time periods each unfixed combination induced an IOP reduction significantly higher than the corresponding fixed combination (paired t test: p<0.05 in all measurements). The diurnal IOP reduction was significantly higher during the unfixed combinations (p<0.001). Unfixed combinations significantly decreased IOP diurnal fluctuations and increased the percentage of patients with daily IOP fluctuation <=2 mm Hg.?Conclusion: In this pilot study, PGA and timolol seems to be more effective in POAG treatment when administered as unfixed combinations, reducing both IOP and daily fluctuations. The once a day timolol 0.1% gel-forming carbomer may be a valuable option in PGA-timolol unfixed combination regimen. PMID- 23640514 TI - Persistent plus disease after laser in retinopathy of prematurity with tetralogy of Fallot. AB - INTRODUCTION: We present a patient with retinopathy of prematurity (ROP) who received panretinal photocoagulation (PRP), but in whom plus disease developed, likely secondary to a complicated cardiovascular history, including DiGeorge syndrome and tetralogy of Fallot.? METHOD: Interventional case report with clinical and angiographic correlation. ? RESULTS: Our patient had been born at 29 weeks and 2 days gestational age with a birthweight of 940 grams, tetralogy of Fallot, DiGeorge syndrome, and major aortopulmonary collaterals. Type 1 Early Treatment for Retinopathy of Prematurity ROP (zone 2, stage 2 with plus) developed, requiring PRP. Worsening plus disease developed and mild further PRP was performed. Despite this, plus disease persisted.? CONCLUSIONS: We report plus disease even after appropriate PRP therapy for ROP. In this case, it is likely the patient's cardiovascular diseases that caused the persistent plus disease. Vascular tortuosity can be due to a number of different systemic disorders, so it is important to consider an infant's systemic conditions in the evaluation of ROP. PMID- 23640516 TI - Aerosol delivery of eukaryotic translation initiation factor 4E-binding protein 1 effectively suppresses lung tumorigenesis in K-rasLA1 mice. AB - Conventional radiotherapy or chemotherapy for the long-term survival of patients with lung cancer is still difficult for treatment in metastatic and advanced tumors. Therefore, the safe and effective approaches to the treatment of lung cancer are needed. In this study, the effect of delivered eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) on lung cancer progression was evaluated. Recombinant adeno-associated virus (rAAV)-M3/4E-BP1 was delivered into 6-week-old K-rasLA1 lung cancer model mice through a nose-only inhalation system twice a week for 4 weeks. Long-term repeated delivery of 4E-BP1 effectively reduced tumor progression in the lungs of K-rasLA1 mice. Reduction of eIF4E by overexpression of 4E-BP1 resulted in suppression of cap-dependent protein expression of basic fibroblast growth factor (bFGF or FGF-2) and vascular endothelial growth factor (VEGF). In addition, delivered 4E-BP1 inhibited the proliferation of lung cancer cells in K-rasLA1 mice model. Our results suggest that long-term repeated viral delivery of 4E-BP1 may provide a useful tool for designing lung cancer treatment. PMID- 23640518 TI - CVD formation of graphene on SiC surface in argon atmosphere. AB - We investigate the microscopic processes leading to graphene growth by the chemical vapor deposition of propane in an argon atmosphere at the SiC surface. Experimentally, it is known that the presence of argon fastens the dehydrogenation processes at the surface, at high temperatures of about 2000 K. We perform ab initio calculations, at zero temperature, to check whether chemical reactions can explain this phenomenon. Density functional theory and supporting quantum chemistry methods qualitatively describe formation of the graphene wafers. We find that the 4H-SiC(0001) surface exhibits a large catalytic effect in the adsorption process of hydrocarbon molecules, this is also supported by preliminary molecular dynamics results. The existence of the ArH(+) molecule, and an observation from the Raman spectra that the negative charge transfers into the SiC surface, would suggest that presence of argon atoms leads to a deprotonization on the surface, which is necessary to obtain a pure carbon adlayer. But the zero-temperature description shows that the cold environment is insufficient to promote argon-assisted surface cleaning. PMID- 23640517 TI - Genomic BLUP decoded: a look into the black box of genomic prediction. AB - Genomic best linear unbiased prediction (BLUP) is a statistical method that uses relationships between individuals calculated from single-nucleotide polymorphisms (SNPs) to capture relationships at quantitative trait loci (QTL). We show that genomic BLUP exploits not only linkage disequilibrium (LD) and additive-genetic relationships, but also cosegregation to capture relationships at QTL. Simulations were used to study the contributions of those types of information to accuracy of genomic estimated breeding values (GEBVs), their persistence over generations without retraining, and their effect on the correlation of GEBVs within families. We show that accuracy of GEBVs based on additive-genetic relationships can decline with increasing training data size and speculate that modeling polygenic effects via pedigree relationships jointly with genomic breeding values using Bayesian methods may prevent that decline. Cosegregation information from half sibs contributes little to accuracy of GEBVs in current dairy cattle breeding schemes but from full sibs it contributes considerably to accuracy within family in corn breeding. Cosegregation information also declines with increasing training data size, and its persistence over generations is lower than that of LD, suggesting the need to model LD and cosegregation explicitly. The correlation between GEBVs within families depends largely on additive-genetic relationship information, which is determined by the effective number of SNPs and training data size. As genomic BLUP cannot capture short-range LD information well, we recommend Bayesian methods with t-distributed priors. PMID- 23640519 TI - Concise synthesis of (-)-steviamine and analogues and their glycosidase inhibitory activities. AB - A concise synthesis of (-)-steviamine is reported along with the synthesis of its analogues 10-nor-steviamine, 10-nor-ent-steviamine and 5-epi-ent-steviamine. These compounds were tested against twelve glycosidases (at 143 MUg mL(-1) concentrations) and were found to have in general poor inhibitory activity against most enzymes. The 10-nor analogues however, showed 50-54% inhibition of alpha-L-rhamnosidase from Penicillium decumbens while one of these, 10-nor steviamine, showed 51% inhibition of N-acetyl-beta-D-glucosaminidase (from Jack bean) at the same concentration (760 MUM). PMID- 23640520 TI - Fluoxetine reduces murine graft-versus-host disease by induction of T cell immunosuppression. AB - Serotonin reuptake inhibitors (SRIs) are widely used drugs in the treatment of depression and anxiety disorders. Although SRIs are generally regarded as safe drugs with relatively few side effects, literature suggests that high concentrations of SRIs may alter immune function. We investigated whether high dose treatment with fluoxetine was able to suppress acute graft-versus-host disease (GvHD) in a MHC-matched, minor histocompatibility antigen mismatched murine bone marrow transplantation model. We found that high doses fluoxetine induce a significant reduction of clinical symptoms and increase survival of these animals. The amelioration of clinical GvHD was accompanied by a reduced expansion of alloreactive T cells. We further analyzed the direct in vitro effect of six SRIs on the viability and proliferation of human T cells and found an anti proliferative and pro-apoptotic effect that was significantly larger in activated than in resting T cells. We discuss these results in the light of potential future exploration of SRIs as a novel class of T cell immunosuppressive drugs. PMID- 23640522 TI - Synthesis of three-dimensional AgI@TiO2 nanoparticles with improved photocatalytic performance. AB - Three-dimensional (3D) TiO2 with an acanthosphere-like morphology composed of nanothorns has been used as a suitable support to fabricate a visible-light induced 3D AgI@TiO2 nanophotocatalyst. The structural characterization revealed that the size of the obtained AgI@TiO2 nanocomposite was close to that of pristine TiO2 particles, where AgI nanoparticles were evenly dispersed on the surfaces of "thorns" of TiO2. The as-achieved 3D AgI@TiO2 nanophotocatalyst exhibited enhanced photocatalytic performance towards photodegradation of organic pollutants, e.g., rhodamine B (RhB), in comparison with TiO2, P25, AgI and AgI@P25 with the same quantity. The enhanced photocatalytic performance is attributed to the strong visible light absorption and the defined interfaces between AgI nanoparticles and TiO2 nanothorns with efficient separation of photogenerated carriers. The excellent performance of the 3D AgI@TiO2 nanophotocatalyst suggests its promising applications in water treatment and environmental remediation. PMID- 23640521 TI - Subclinical CNS inflammation as response to a myelin antigen in humanized mice. AB - Multiple sclerosis is a demyelinating autoimmune disease of the CNS. Its animal model experimental autoimmune encephalomyelitis is commonly induced by active immunization with myelin antigens. To investigate human immune responses against myelin antigens in vivo we established a new subclinical experimental autoimmune encephalomyelitis model in humanized mice. NOD/Scidgammac-/- animals were transferred with peripheral blood mononuclear cells from healthy human donors and immunized with myelin antigens in complete Freund's adjuvant and antigen-pulsed autologous dendritic cells. Human T cells recovered from these animals reacted specifically to the soluble domain of myelin oligodendrocyte glycoprotein and secreted proinflammatory cytokines. Furthermore, immunized animals developed subclinical CNS inflammation with infiltrating CD4+ and CD8+ T cells and production of encephalitogenic cytokines. Thus, this model of myelin-induced CNS inflammation by human T cells may allow testing of new human-specific therapeuticals for multiple sclerosis. PMID- 23640523 TI - Primary solid pancreatic tumors: recent imaging findings updates with pathology correlation. AB - The imaging findings of primary solid pancreatic tumors have long been studied and are generally well-established. However, interestingly enough, a wealth of new information has recently appeared in the literature, including the imaging findings of novel or previously seldom-addressed pathological entities as well as atypical imaging findings of common tumors, both of which are well-correlated with the pathology findings. 5 %-14 % of pancreatic ductal adenocarcinomas have been reported on dynamic contrast-enhanced computed tomography to be isoattenuating, and thus making the imaging diagnosis challenging. The imaging pathology correlation in such isoattenuating tumors is presented along with a discussion regarding the early imaging detection of pancreatic cancers. Colloid (or mucinous non-cystic) pancreatic cancer may resemble a less harmful cystic lesion due to its abundant extracellular mucin, and thus requiring caution in the image interpretation. Serotonin-producing neuroendocrine tumors have recently been recognized as a separate entity from usual neuroendocrine tumors. Exuberant fibrosis caused by serotonin metabolites and scarce tumor cells creates a unique pattern of pancreatic ductal obstruction seen on imaging. Small solid pseudopapillary tumors appear as unencapsulated, completely solid lesions with gradually increasing enhancement after contrast administration, unlike typical solid pseudopapillary neoplasms that present as a large mixed solid and degenerated cystic or hemorrhagic mass encapsulated by a thick capsule and which, therefore, tend to be misdiagnosed on imaging. Solid serous adenoma is a rare, solid variant of serous cystadenoma and appears on imaging as a hypervascular, solid nodule due to its genuinely microscopic cystic, alveolar, and ectatic tubular tumor architecture. PMID- 23640524 TI - The effect of foot strike pattern on achilles tendon load during running. AB - In this study we compared Achilles tendon loading parameters during barefoot running among females with different foot strike patterns using open-source computer muscle modeling software to provide dynamic simulations of running. Muscle forces of the gastrocnemius and soleus were estimated from experimental data collected in a motion capture laboratory during barefoot running for 11 runners utilizing a rearfoot strike (RFS) and 8 runners utilizing a non-RFS (NRFS) pattern. Our results show that peak Achilles tendon force occurred earlier in stance phase (p = 0.007), which contributed to a 15% increase in average Achilles tendon loading rate among participants adopting a NRFS pattern (p = 0.06). Stance time, step length, and the estimated number of steps per mile were similar between groups. However, runners with a NRFS pattern experienced 11% greater Achilles tendon impulse each step (p = 0.05) and nearly significantly greater Achilles tendon impulse per mile run (p = 0.06). This difference equates to an additional 47.7 body weights for each mile run with a NRFS pattern. Runners considering a NRFS pattern may want to account for these novel stressors and adapt training programs accordingly. PMID- 23640526 TI - Intraventricular ganglioglioma prognosis and hydrocephalus: the largest case series and systematic literature review. AB - BACKGROUND: Ganglioglioma is mostly found in cerebral parenchymal, and it is rarely located in the ventricular system. To date, ganglioglioma within the ventricular system has been reported in only 10 cases. Its prognosis and relationship with complicating hydrocephalus are unclear. METHODS: A total of 7 cases with intraventricular ganglioglioma diagnosed by the surgical pathology examination from June 2004 to April 2011 in our center were retrospectively analyzed. The clinical data were collected from the clinical medical records, and the tumor site, size and basement of tumor were analyzed. Follow up was performed to obtain the clinical outcomes. RESULTS: The 7 cases included 5 males and 2 females, with disease onset at 23.6 +/- 14.9 years old. Epilepsy as the initial symptom was observed in 1 case. Reduced hearing, dizziness and weakness of both lower limbs were found in 1 case. Intracranial hypertension were detected in 5 cases, including 1 case complicating by decreased visual acuity. Tumors were located in the lateral ventricle in 5 cases, while 2 cases in the third ventricle. Hydrocephalus was observed in 5 cases, including 2 cases with severe hydrocephalus, and both underwent ventriculoperitoneal shunting. Total resection of tumors was performed in 5 cases, and 2 cases underwent gross total resection. The mean duration of follow-up was 28.7 months (8-90 months). Intracranial hypertension in all cases disappeared. Even radiotherapy post-surgery, one case with GTR relapsed 1 year later. However, the other 6 cases didn't relapse. CONCLUSIONS: Ganglioglioma in ventricular system is extremely rare, mainly with the symptoms of intracranial hypertension or seizure. The degree of hydrocephalus is closely related to the site of tumor's basement. The prognosis is good after total resection. The patients with GTR should be followed-up. PMID- 23640527 TI - New approaches to reversing oral anticoagulant therapy. Introduction. PMID- 23640528 TI - Pharmacologic interventions for reversing the effects of oral anticoagulants. AB - PURPOSE: To describe the pharmacologic agents and strategies used for urgent reversal of warfarin and the target-specific oral anticoagulants dabigatran, rivaroxaban, and apixaban. SUMMARY: To reverse the anticoagulant effects of warfarin in patients who are bleeding or need surgery, exogenous vitamin K (phytonadione) may be used in combination with another, shorter-acting intervention, such as fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), recombinant factor VIIa, or activated PCC (aPCC). Three-factor PCC contains factors II, IX, and X in an inactivated form, and four-factor PCC also includes factor VII in an inactivated form. No four-factor PCC products are available in the United States, but aPCC, which contains the same four factors with factor VII provided in an activated form, is available. The intervention depends on the International Normalized Ratio, presence of bleeding, and need for and timing of surgery. Research suggests that clotting factor concentrates are more effective than FFP alone for warfarin reversal. These products also may be useful for reversing the effects of target-specific oral anticoagulants, but limited efficacy and safety data are available to support their use. The risks and benefits associated with these products need to be weighed before their use for reversal of dabigatran, rivaroxaban, or apixaban. Additional clinical data are needed to clearly define the role of concentrated clotting factor products in reversal and to determine the optimal clotting factor concentrate product and dose for urgent reversal of oral anticoagulation. CONCLUSION: Phytonadione and clotting factor concentrates appear to have a role for reversal of warfarin, and limited evidence suggests that clotting factor concentrates could have a role in reversal of target-specific oral anticoagulants in an emergency situation. PMID- 23640529 TI - Developing a management plan for oral anticoagulant reversal. AB - PURPOSE: To describe a process for prompt evaluation and management- including reversal of the effects of warfarin and target-specific oral anticoagulants-of patients with or at high risk for bleeding during oral anticoagulant therapy or when such therapy is interrupted for an urgent invasive procedure or surgery. SUMMARY: The use of pharmacologic interventions for anticoagulant reversal may depend on the measured level of anticoagulation, time since the last anticoagulant dose, target level of coagulation, reliability of laboratory tests of coagulation, severity of or risk for bleeding, the agents' mechanism of action and pharmacokinetics, and pharmacodynamics of the reversal agent. The patient's age, weight, renal function, comorbid conditions, and other drug therapy, as well as the risk for thromboembolism and other adverse effects of the reversal therapies, also enter into therapeutic decisions. Hemodialysis may be used to remove the direct thrombin (factor IIa) inhibitor dabigatran and reverse its anticoagulant effects. Limited experience with clotting factor concentrates suggests that activated prothrombin complex concentrate may be useful for reversing the anticoagulant effects of dabigatran. The activity of oral factor Xa inhibitors (i.e., rivaroxaban and apixaban) is higher up the common pathway of the coagulation cascade and thus may be easier to reverse than that of direct thrombin inhibitors. Additional clinical experience is needed to identify the optimal reversal agents, dosage, and impact on thrombosis or bleeding outcomes for both classes of agents. CONCLUSION: A comprehensive plan individualized to each agent should be developed to promptly reverse the effects of oral anticoagulants and optimize outcomes in patients with bleeding or an urgent need for surgery. PMID- 23640530 TI - Oral anticoagulant therapies: balancing the risks. AB - PURPOSE: To describe the mechanisms of action, pharmacokinetics, and rate of bleeding complications from warfarin and target-specific oral anticoagulants; methods for assessing the risk for thromboembolism and bleeding in patients receiving oral anticoagulants or temporarily interrupting such therapy to undergo elective invasive procedures or surgery; therapeutic strategies for balancing these risks; and coagulation assays used to monitor oral anticoagulation therapy. SUMMARY: The target-specific oral anticoagulants have a more specific mechanism of action and shorter elimination half-lives than warfarin, but the half-lives of these target-specific agents may be prolonged in patients with renal impairment or elderly patients, resulting in the potential for drug accumulation and bleeding complications. The rate of bleeding complications in the community setting may be higher than in the clinical trial setting. In patients receiving oral anticoagulants or temporarily interrupting oral anticoagulant therapy to undergo elective invasive procedures or surgery, the risks for thromboembolism and bleeding should be assessed by using validated risk scoring systems and patient stratification schemes. The time during which an oral anticoagulant should be withheld before an invasive procedure or surgery and the time until resumption of therapy after the procedure depend on the drug, risk of thrombosis, type of procedure (i.e., risk for bleeding), and patient-specific variables, especially renal function for the target-specific agents. New coagulation assays are in development for use in monitoring oral anticoagulant therapy. CONCLUSION: An individualized approach is needed to balance the risks for thromboembolism and bleeding in patients receiving oral anticoagulants. PMID- 23640532 TI - Bifocal intracranial tumors of nongerminomatous germ cell etiology: diagnostic and therapeutic implications. AB - BACKGROUND: Patients presenting with synchronous bifocal intracranial tumors (masses in the pineal and neurohypophyseal region), detectable human chorionic gonadotropin (hCG) levels (5-100 mIU/mL), and normal alpha feto-protein (AFP) levels (<=10 ng/mL) are often diagnosed empirically with pure germinoma. In such scenarios, pathologic confirmation is often deferred, given that bifocal nongerminomatous germ cell tumors (NGGCTs) are considered rare and because available literature and research protocols support such an approach. We sought to characterize the association between bifocal intracranial tumors and NGGCT histology. METHODS: Seventy-one patients treated for intracranial germ cell tumors at Massachusetts General Hospital in 1998-2012 were identified. Patients presenting with synchronous bifocal disease were selected for further review. RESULTS: Of the 71 patients presenting with intracranial germ cell tumors, 14 (19.7%) had synchronous bifocal disease. Of these 14 patients, 7 (50.0%) had germinoma, 3 (21.4%) had NGGCT, and 4 (28.6%) had hCG levels <200 mIU/mL and normal AFP levels and were treated without pathologic confirmation. Of the 3 patients with confirmed bifocal NGGCT, 2 had detectable hCG levels with AFP <10 ng/mL and 1 patient had a detectable hCG level with a modest elevation in AFP. CONCLUSIONS: NGGCTs should be considered in the differential diagnosis for patients presenting with bifocal intracranial tumors. Given differences in the management of germinomas and NGGCTs, clinicians should strongly consider a biopsy in patients presenting with bifocal masses and normal or modestly elevated biomarkers. Misclassification of such cases as germinomas could result in undertreatment and a possible increased risk for recurrence. PMID- 23640534 TI - How effective are the current treatments for children diagnosed with manic/mixed bipolar disorder? PMID- 23640533 TI - Enhancing drug delivery for boron neutron capture therapy of brain tumors with focused ultrasound. AB - BACKGROUND: Glioblastoma is a notoriously difficult tumor to treat because of its relative sanctuary in the brain and infiltrative behavior. Therapies need to penetrate the CNS but avoid collateral tissue injury. Boron neutron capture therapy (BNCT) is a treatment whereby a (10)B-containing drug preferentially accumulates in malignant cells and causes highly localized damage when exposed to epithermal neutron irradiation. Studies have suggested that (10)B-enriched L-4 boronophenylalanine-fructose (BPA-f) complex uptake can be improved by enhancing the permeability of the cerebrovasculature with osmotic agents. We investigated the use of MRI-guided focused ultrasound, in combination with injectable microbubbles, to noninvasively and focally augment the uptake of BPA-f. METHODS: With the use of a 9L gliosarcoma tumor model in Fisher 344 rats, the blood-brain and blood-tumor barriers were disrupted with pulsed ultrasound using a 558 kHz transducer and Definity microbubbles, and BPA-f (250 mg/kg) was delivered intravenously over 2 h. (10)B concentrations were estimated with imaging mass spectrometry and inductively coupled plasma atomic emission spectroscopy. RESULTS: The tumor to brain ratio of (10)B was 6.7 +/- 0.5 with focused ultrasound and only 4.1 +/- 0.4 in the control group (P < .01), corresponding to a mean tumor [(10)B] of 123 +/- 25 ppm and 85 +/- 29 ppm, respectively. (10)B uptake in infiltrating clusters treated with ultrasound was 0.86 +/- 0.10 times the main tumor concentration, compared with only 0.29 +/- 0.08 in controls. CONCLUSIONS: Ultrasound increases the accumulation of (10)B in the main tumor and infiltrating cells. These findings, in combination with the expanding clinical use of focused ultrasound, may offer improvements in BNCT and the treatment of glioblastoma. PMID- 23640536 TI - Biased homozygous haplotypes across the human caveolin 1 upstream purine complex in Parkinson's disease. AB - The alpha-synuclein-caveolin 1 axis is suggested to be of role in the pathogenesis of Parkinson's disease in cell line models. The objective of this study was to analyze the homozygous haplotype compartment of the human caveolin 1 gene upstream purine complex in patients afflicted with Parkinson's disease. This complex was screened in patients with Parkinson's disease (n = 141) and compared with a group of controls (n = 760) using polymerase chain reaction and sequencing. The expression activity of the homozygous haplotypes was then examined using luciferase Dual-Glo system in human neuronal cell line, LAN-5. Six haplotypes were found to be homozygous in the patients, and not in the control pool (Fisher exact p < 1 * 10(-6)). Three of those haplotypes were specific to Parkinson's disease (Fisher exact p < 0.002), and the remaining three overlapped with homozygous haplotypes in Alzheimer's disease and multiple sclerosis (Fisher exact p < 0.002). The disease haplotypes contained motif lengths that were nonexistent in the control homozygous haplotype pool and significantly increased gene expression (p < 9 * 10(-6)). We conclude that skew in the caveolin 1 purine complex homozygous haplotype compartment and an additive effect of those haplotypes may be linked with Parkinson's disease. PMID- 23640535 TI - The role of hypothalamic H1 receptor antagonism in antipsychotic-induced weight gain. AB - Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK-carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity. PMID- 23640537 TI - Magnesium lithospermate B protects neurons from N-methyl-D-aspartic acid injury and attenuates kainic acid-induced neurodegeration in FVB mice. AB - Magnesium lithospermate B (MLB) is one of the major bioactive components of Radix Salviae miltiorrhizae (Dan Shen), which is a Chinese traditional herbal medicine with therapeutic effects on cardiovascular and cerebrovascular diseases. The aim of this study was to investigate the neuroprotective effects of MLB on N-methyl-D aspartic acid (NMDA)-injured neurons and against kainic acid (KA)-induced neurodegeneration in mice. In cultured mouse primary hippocampal neurons, MLB significantly reduced NMDA-induced cell death and promoted neurite growth in a dose-dependent manner. In FVB mice, MLB attenuated KA-induced neurodegeneration. Additionally, MLB prevented the decrease in phosphorylated Akt and glycogen synthase kinase-3beta (GSK-3beta) levels both in NMDA-injured neurons and KA injured mouse brain. This effect was blocked by phosphoinositide 3-kinase (PI3K) inhibitor LY294002 and Akt inhibitor triciribine, thus indicating the neuroprotective effects of MLB are most likely mediated by the PI3K/Akt/GSK-3beta pathway. Taken together, these results show the efficacy and underlying mechanism of MLB against neuronal injury and raise its therapeutic potential in neurodegenerative diseases. PMID- 23640538 TI - Effects of dexamethasone on human trabecular meshwork cells in vitro. AB - PURPOSE: To study the effects of dexamethasone sodium phosphate (Dex) on human trabecular meshwork (HTM) cells in vitro. METHODS: HTM cells were treated with Dex 2 mg/ml, 1 mg/ml, 0.5 mg/ml, 0.25 mg/ml, 0.1 mg/ml, or 0.05 mg/ml for 24 h. Cell viability was measured by a trypan blue exclusion test. Caspase-3/7, -8, -9 and -12 activities were measured by fluorochrome assays as mean signal intensity (msi) to assess apoptosis. Mitochondrial dehydrogenase activity was determined by a WST assay to quantify mitochondrial damage. RESULTS: Mean cell viabilities of HTM cells exposed to Dex at the higher doses of 2 mg/ml, 1 mg/ml, and 0.5 mg/ml were reduced: 11.9 % +/- 3.5 (P < 0.001), 31.2 % +/- 3.2 (P < 0.001), and 76.6 % +/- 4.4 (P < 0.01). At the lower doses of 0.25 mg/ml, 0.1 mg/ml or 0.05 mg/ml, no significant cell viability reductions were seen: 96.3 % +/- 0.7 (P > 0.05), 95.3 % +/- 2.5 (P > 0.05) and 93.8 % +/- 2.3 (P > 0.05), respectively compared to untreated HTM cells (97.0 % +/- 1.9). Caspase-3/7 activity (msi) of HTM cells exposed to Dex 2, 1 or 0.5 mg/ml was 21068 +/- 2498 (P < 0.001), 26994 +/- 3104 (P < 0.001) and 20416 +/- 1150 (P < 0.001) compared to untreated HTM cells 1148 +/- 803. Caspase-9 activity (msi) of HTM cells after exposure to Dex 2, 1 or 0.5 mg/ml was 14188 +/- 1203 (P < 0.001), 13256 +/- 1564 (P < 0.001) and 15041 +/- 1584 (P < 0.001) compared to untreated HTM cells 1748 +/- 524. The lower doses of Dex did not significantly increase caspase-3/7 or -9 activities. There were no increases for caspase-8 or -12 activities at any of the tested Dex doses. The WST assay showed mitochondrial dehydrogenase activities of 14.3 +/- 0.7 (P < 0.001), 9.6 +/- 0.3 (P < 0.001) and 56.0 +/- 7.6 (P < 0.001) at 2 mg/ml, 1 mg/ml and 0.5 mg/ml Dex compared to untreated HTM cells (186.1 +/- 15.0). CONCLUSIONS: Dex at 0.25, 0.1 and 0.05 mg/ml clinical dose did not cause significant reduction in cell viability, increased apoptosis, or mitochondrial dysfunction of HTM cells in vitro. At high doses (2, 1 or 0.5 mg/ml) Dex caused apoptosis via mitochondrial pathways. PMID- 23640540 TI - The effect of injury diagnosis on illness perceptions and expected postconcussion syndrome and posttraumatic stress disorder symptoms. AB - OBJECTIVE: To determine if systematic variation of diagnostic terminology (ie, concussion, minor head injury [MHI], mild traumatic brain injury [mTBI]) following a standardized injury description produced different expected symptoms and illness perceptions. We hypothesized that worse outcomes would be expected of mTBI, compared with other diagnoses, and that MHI would be perceived as worse than concussion. METHOD: 108 volunteers were randomly allocated to conditions in which they read a vignette describing a motor vehicle accident-related mTBI followed by a diagnosis of mTBI (n = 27), MHI (n = 24), concussion (n = 31), or, no diagnosis (n = 26). All groups rated (a) event "undesirability," (b) illness perception, and (c) expected postconcussion syndrome (PCS) and posttraumatic stress disorder (PTSD) symptoms 6 months after injury. RESULTS: There was a statistically significant group effect on undesirability (mTBI > concussion and MHI), PTSD symptomatology (mTBI and no diagnosis > concussion), and negative illness perception (mTBI and no diagnosis > concussion). CONCLUSION: In general, diagnostic terminology did not affect anticipated PCS symptoms 6 months after injury, but other outcomes were affected. Given that these diagnostic terms are used interchangeably, this study suggests that changing terminology can influence known contributors to poor mTBI outcome. PMID- 23640539 TI - White matter integrity in veterans with mild traumatic brain injury: associations with executive function and loss of consciousness. AB - OBJECTIVE: We investigated using diffusion tensor imaging (DTI) and the association between white matter integrity and executive function (EF) performance in postacute mild traumatic brain injury (mTBI). In addition, we examined whether injury severity, as measured by loss of consciousness (LOC) versus alterations in consciousness (AOC), is related to white matter microstructural alterations and neuropsychological outcome. PARTICIPANTS: Thirty Iraq and Afghanistan War era veterans with a history of mTBI and 15 healthy veteran control participants. RESULTS: There were no significant overall group differences between control and mTBI participants on DTI measures. However, a subgroup of mTBI participants with EF decrements (n = 13) demonstrated significantly decreased fractional anisotropy of prefrontal white matter, corpus callosum, and cingulum bundle structures compared with mTBI participants without EF decrements (n = 17) and control participants. Participants having mTBI with LOC were more likely to evidence reduced EF performances and disrupted ventral prefrontal white matter integrity when compared with either mTBI participants without LOC or control participants. CONCLUSIONS: Findings suggest that altered white matter integrity contributes to reduced EF in subgroups of veterans with a history of mTBI and that LOC may be a risk factor for reduced EF as well as associated changes to ventral prefrontal white matter. PMID- 23640541 TI - Prevalence, comorbidities, and correlates of challenging behavior among community dwelling adults with severe traumatic brain injury: a multicenter study. AB - OBJECTIVE: Investigate the prevalence, comorbidities, and correlates of challenging behaviors among clients of the New South Wales Brain Injury Rehabilitation Program. SETTING: All community-based rehabilitation services of the statewide program. PARTICIPANTS: Five hundred seven active clients with severe traumatic brain injury. DESIGN: Prospective multicenter study. MAIN MEASURES: Eighty-eight clinicians from the 11 services rated clients on the Overt Behaviour Scale, Disability Rating Scale, Sydney Psychosocial Reintegration Scale 2, Care and Needs Scale, and Health of the Nation Outcome Scale-Acquired Brain Injury. RESULTS: Overall prevalence rate of challenging behaviors was 54%. Inappropriate social behavior (33.3%), aggression (31.9%), and adynamia (23.1%) were the 3 most common individual behaviors, with 35.5% of the sample displaying more than 1 challenging behavior. Significant associations were found between increasing levels of challenging behavior and longer duration of posttraumatic amnesia, increasing functional disability, greater restrictions in participation, increased support needs, and greater degrees of psychiatric disturbance, respectively (P < 0.004). Multivariate binomial logistic regression found that premorbid alcohol abuse, postinjury restrictions in participation, and higher levels of postinjury psychiatric disturbance were independent predictors of challenging behavior. CONCLUSIONS: Challenging behaviors are widespread among community-dwelling adults with severe traumatic brain injury. Services need to deliver integrated anger management, social skills, and motivational treatments. PMID- 23640542 TI - Assessments of coping after acquired brain injury: a systematic review of instrument conceptualization, feasibility, and psychometric properties. AB - OBJECTIVE: To identify measures of coping styles used by patients with acquired brain injury; to evaluate the conceptualization, feasibility, and psychometric properties of the instruments; and to provide guidance for researchers and clinicians in the choice of a suitable instrument. DESIGN: Systematic review. RESULTS: The search identified 47 instruments, of which 14 were selected. The instruments focused on dispositional coping, situation-specific coping, or domain specific coping. Psychometric properties were scarcely investigated. The COPE stood out in terms of psychometric properties but had low feasibility. The brief COPE, Coping Scale for Adults-short form, and Utrecht Coping List stood out in terms of feasibility, and the available psychometric properties of these instruments were good. Only the Coping With Health Injuries and Problems was used as other report. CONCLUSION: Information on psychometric properties of coping instruments in acquired brain injury is scarcely available and limits the strength of our recommendations. For patients with mild injuries, we cautiously recommend the COPE and for patients with more severe injuries the brief COPE, Coping Scale for Adults-short form, Utrecht Coping List, and Coping With Health Injuries and Problems-other-report. Other instruments may be used to address particular issues such as coping with a specific stressful situation or illness. PMID- 23640543 TI - Counselor-assisted problem solving (CAPS) improves behavioral outcomes in older adolescents with complicated mild to severe TBI. AB - OBJECTIVE: To test the efficacy of Counselor-Assisted Problem Solving (CAPS) versus an Internet resource comparison (IRC) condition in reducing behavior problems in adolescents following traumatic brain injury (TBI). DESIGN: Randomized clinical trial with interviewers naive to treatment condition. SETTING: Three large tertiary children's hospitals and 2 general hospitals with pediatric commitment. PARTICIPANTS: A total of 132 children and adolescents aged 12 to 17 years hospitalized during the previous 6 months for moderate to severe TBI. INTERVENTIONS: Participants in CAPS (n = 65) completed 8 to 12 online modules providing training in problem solving, communication skills, and self regulation and subsequent synchronous videoconferencing with a therapist. Participants in the IRC group (n = 67) received links to Internet resources about pediatric TBI. MAIN OUTCOME MEASURES: Child Behavior Checklist administered before and after completion of treatment (ie, approximately 6 months after treatment initiation). RESULTS: Post hoc analysis of covariance, controlling for pretreatment scores, was used to examine group differences in behavior problems in the entire sample and among older (n = 59) and younger adolescents (n = 53). Among older but not younger adolescents, CAPS resulted in greater improvements on multiple dimensions of externalizing behavior problems than IRC. CONCLUSION: Online problem-solving therapy may be effective in reducing behavior problems in older adolescent survivors of moderate-severe TBI. PMID- 23640544 TI - Cognitive-behavioral prevention of postconcussion syndrome in at-risk patients: a pilot randomized controlled trial. AB - OBJECTIVE: To examine the tolerability and estimate the treatment effect of cognitive-behavioral therapy (CBT) delivered soon after mild traumatic brain injury to patients at risk for chronic postconcussion syndrome (PCS). SETTING: Tertiary rehabilitation center. PARTICIPANTS: Twenty-eight patients with uncomplicated mild traumatic brain injury, determined to be at risk for chronic PCS based on a published algorithm that incorporates subacute postconcussion symptoms and maladaptive illness beliefs (recovery expectations and perceived consequences). They were enrolled within 6 weeks postinjury. DESIGN: Open-label, parallel-group, randomized controlled trial, with masked outcome assessment 3 months after enrolment. Interventions were (1) treatment as usual (education, reassurance, and symptom management strategies) from an occupational therapist, or (2) treatment as usual plus CBT delivered by a psychologist. MAIN MEASURES: Rivermead Postconcussion Symptoms Questionnaire. RESULTS: Four participants (2:2) withdrew. Treatment credibility and satisfaction ratings were high in the CBT group. Treatment effect sizes were moderate for postconcussion symptoms (Cohen d = 0.74) and moderate-large for most secondary outcome measures (Cohen d = 0.62 1.61). Fewer participants receiving CBT had a diagnosis of PCS at follow-up (54% vs 91%, P < .05). CONCLUSION: Our preliminary data suggest that CBT delivered soon after mild traumatic brain injury is well tolerated and may facilitate recovery in patients who are at risk for chronic PCS. A definitive clinical trial is warranted. PMID- 23640546 TI - A comparison of antemortem tooth loss in human hunter-gatherers and non-human catarrhines: implications for the identification of behavioral evolution in the human fossil record. AB - Middle and Late Pleistocene fossil hominin specimens with severe antemortem tooth loss are often regarded as evidence for the precocious evolution of human-like behaviors, such as conspecific care or cooking, in ancient hominin species. The goal of this project was to ask whether the theoretical association between antemortem tooth loss and uniquely human behaviors is supported empirically in a large skeletal sample of human hunter-gatherers, chimpanzees, orangutans, and baboons. Binomial regression modeling in a Bayesian framework allows for the investigation of the effects of tooth class, genus, age, and sex on the likelihood of tooth loss. The results strongly suggest that modern humans experience more antemortem tooth loss than non-human primates and identify age in years as an important predictor. Once age is accounted for, the difference between the humans and the closest non-human genus (chimpanzees) is less pronounced; humans are still more likely on average to experience antemortem tooth loss though 95% uncertainty envelopes around the average prediction for each genus show some overlap. These analyses support theoretical links between antemortem tooth loss and modern human characteristics; humans' significantly longer life history and a positive correlation between age and antemortem tooth loss explain, in part, the reason why humans are more likely to experience tooth loss than non-human primates, but the results do not exclude behavioral differences as a contributing factor. PMID- 23640545 TI - Pitt-Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription. AB - TCF4 (transcription factor 4; E2-2, ITF2) is a transcription factor that when haplo-insufficient causes Pitt-Hopkins Syndrome (PTHS), an autism-spectrum disorder that is associated with pervasive developmental delay and severe intellectual disability. The TCF4 gene is also a risk factor with highly significant linkage to schizophrenia, presumably via overexpression of the TCF4 gene product in the central nervous system. This review will present an overview of the clinical manifestations of PTHS and relate those clinical attributes to the underlying molecular genetics of TCF4. In order to provide a molecular biological context for the loss of function of TCF4 in PTHS, the review will also present a brief overview of the basic biochemistry of TCF4-mediated regulation of cellular and neuronal gene expression. In the final section of this review, I will discuss and speculate upon possible roles for the TCF4 transcription factor in neuronal function and comment upon how understanding these roles may give new insights into the molecular neurobiology of human cognition. PMID- 23640547 TI - Seawater-driven magnesium based Janus micromotors for environmental remediation. AB - We describe the use of seawater as fuel to propel Janus micromotors. The new micromotors consist of biodegradable and environmentally friendly magnesium microparticles and a nickel-gold bilayer patch for magnetic guidance and surface modification. Such seawater-driven micromotors, which utilize macrogalvanic corrosion and chloride pitting corrosion processes, eliminate the need for external fuels to offer efficient and prolonged propulsion towards diverse applications in aquatic environments. PMID- 23640549 TI - Legal aid in hospitals: an innovative approach. PMID- 23640548 TI - It is health that is real wealth & not pieces of gold & silver. PMID- 23640550 TI - Sputum smear microscopy in tuberculosis: is it still relevant? PMID- 23640551 TI - Cytogenetics in paediatric aplastic anaemia: does it give an insight on the evolution of the disease? PMID- 23640552 TI - Unravelling the role of ADAM 33 in asthma. PMID- 23640553 TI - Exercise as a promising intervention in head & neck cancer patients. PMID- 23640555 TI - Global comparative healthcare effectiveness research: evaluating sustainable programmes in low & middle resource settings. AB - The need to focus healthcare expenditures on innovative and sustainable health systems that efficiently use existing effective therapies are the major drivers stimulating Comparative Effectiveness Research (CER) across the globe. Lack of adequate access and high cost of essential medicines and technologies in many countries increases morbidity and mortality and cost of care that forces people and families into poverty due to disability and out-of-pocket expenses. This review illustrates the potential of value-added global health care comparative effectiveness research in shaping health systems and health care delivery paradigms in the "global south". Enabling the development of effective CER systems globally paves the way for tangible local and regional definitions of equity in health care because CER fosters the sharing of critical assets, resources, skills, and capabilities and the development of collaborative of multi sectorial frameworks to improve health outcomes and metrics globally. PMID- 23640556 TI - Cytogenetic profile of aplastic anaemia in Indian children. AB - BACKGROUND & OBJECTIVES: Aplastic anaemia is a rare haematological disorder characterized by pancytopenia with a hypocellular bone marrow. It may be inherited/genetic or acquired. Acquired aplastic anaemia has been linked to many drugs, chemicals and viruses. Cytogenetic abnormalities have been reported infrequently with acquired aplastic anaemia. Majority of the studies are in adult patients from the West. We report here cytogenetic studies on paediatric patients with acquired aplastic anaemia seen in a tertiary care hospital in north India. METHODS: Patients (n=71, age 4-14 yr) were diagnosed according to the guidelines of International Agranulocytosis and Aplastic Anaemia Study. Conventional cytogenetics with Giemsa Trypsin Giemsa (GTG) banding was performed. Karyotyping was done according to the International System for Human Cytogenetics Nomenclature (ISCN). RESULTS: Of the 71 patients, 42 had successful karyotyping where median age was 9 yr; of these 42, 27 (64.3%) patients had severe, nine (21.4%) had very severe and six (14.3%) had non severe aplastic anaemia. Five patients had karyotypic abnormalities with trisomy 12 (1), trisomy 8 (1) and monosomy 7 (1). Two patients had non numerical abnormalities with del 7 q - and t (5:12) in one each. Twenty nine patients had uninformative results. There was no difference in the clinical and haematological profile of patients with normal versus abnormal cytogenetics although the number of patients was small in the two groups. INTERPRETATION & CONCLUSIONS: Five (11.9%) patients with acquired aplastic anaemia had chromosomal abnormalities. Trisomy was found to be the commonest abnormality. Cytogenetic abnormalities may be significant in acquired aplastic anaemia although further studies on a large sample are required to confirm the findings. PMID- 23640554 TI - Tuberculosis: From an incurable scourge to a curable disease - journey over a millennium. AB - Globally, tuberculosis (TB) still remains a major public health problem. India is a high TB burden country contributing to 26 per cent of global TB burden. During 1944-1980, TB became treatable and short-course chemotherapy emerged as the standard of care. When TB elimination seemed possible in the early 1980s, global human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS) pandemic resulted in a resurgence of TB. Widespread occurrence of multidrug-resistant and extensively drug-resistant TB (M/XDR-TB) is threatening to destabilize TB control globally. Atypical clinical presentation still poses a challenge. Disseminated, miliary and cryptic TB are being increasingly recognized. Availability of newer imaging modalities has allowed more efficient localization of lesions and use of image guided procedures has facilitated definitive diagnosis of extrapulmonary TB. Introduction of liquid culture, rapid drug-susceptibility testing (DST), molecular diagnostic methods has helped in rapid detection, speciation and DST profiling of Mycobacterium tuberculosis isolates. While treatment of TB and HIV-TB co-infection has become simpler, efforts are on to shorten the treatment duration. However, drug toxicities and drug-drug interactions still constitute a significant challenge. Recently, there has been better understanding of anti-TB drug-induced hepatotoxicity and its frequent confounding by viral hepatitis, especially, in resource-constrained settings; and immune reconstitution inflammatory syndrome (IRIS) in HIV-TB. Quest for newer biomarkers for predicting a durable cure, relapse, discovery/repurposing of newer anti-TB drugs, development of newer vaccines continues to achieve the goal of eliminating TB altogether by 2050. PMID- 23640558 TI - Effect of exercise training on functional capacity & quality of life in head & neck cancer patients receiving chemoradiotherapy. AB - BACKGROUND & OBJECTIVES: Patients with head and neck cancer (HNC) undergoing chemoradiotherapy (CRT) suffer from fatigue causing a decrease in functional capacity and quality of life (QoL). Limited research in the field of exercise training among these patients demanded the need for this study to assess the effects of exercise training on functional capacity and quality of life. METHODS: A randomized controlled trial was conducted on 48 patients with HNC undergoing CRT. The exercise group received an individually tailored, supervised, exercise programme for six weeks, while the control group did not receive any form of exercise. Functional capacity and QoL were assessed at baseline and at the end of the intervention using the six minute walk distance (6MWD) and medical outcomes survey short form 36 (SF 36). RESULTS: The mean age of patients was 52 yr with 42 males. After six weeks, the 6MWD improved by 42 metres (P<0.05) in the exercise group while the control group showed a decrease by 96 metres (P<0.001). There was an improvement on the mental component score (MCS) of SF36 for the exercise group (4.8; P<0.05) and the physical component score (PCS) remained almost the same, while a decrease in PCS and MCS was seen in the control group (-5.9; P=0.064 and 17.3; P<0.05). When 6MWD and SF36 were compared between the groups, there was a statistically significant difference (P<0.001) seen after six weeks. INTERPRETATION & CONCLUSIONS: Our results showed that the functional capacity and QoL decreased among those not receiving a supervised exercise program, while exercise training improved functional capacity and QoL in HNC patients undergoing CRT. PMID- 23640557 TI - Increased expression of ADAM33 protein in asthmatic patients as compared to non asthmatic controls. AB - BACKGROUND & OBJECTIVES: ADAM33 is a member of a family of genes that encode membrane-anchored proteins with a disintegrin and a metalloprotease domain, primarily expressed in lung fibroblasts and bronchial smooth muscle cells. ADAM33 has been identified as a risk factor for asthma and is known as a gene associated with airway remodelling. The present study was conducted with the aims to investigate the expression of ADAM33 protein in patients of asthma and non asthmatic controls, and to assess if the expression of ADAM33 protein relates with severity of asthma. METHODS: A total of 35 subjects, including 27 patients with asthma and eight non-asthmatic controls were included using Global Initiative for Asthma guidelines 2005. Bronchial biopsy tissues were collected and paraffin sections were made to store all study samples. Immunohistochemistry was performed using standardized protocol. RESULTS: An increase in expression of ADAM33 protein was observed in the epithelium, smooth muscle and mesenchymal cells of asthma cases when compared to controls but there was no relationship with severity of asthma. INTERPRETATION & CONCLUSIONS: A higher expression of ADAM33 protein was seen in asthma patients compared to controls. Large prospective studies need to be done with adequate study design to confirm these preliminary finding. PMID- 23640559 TI - Prevalence of Rh, Duffy, Kell, Kidd & MNSs blood group antigens in the Indian blood donor population. AB - BACKGROUND & OBJECTIVES: Little data are available regarding the frequencies of the blood group antigens other than ABO and RhD in the Indian population. Knowledge of the antigen frequencies is important to assess risk of antibody formation and to guide the probability of finding antigen-negative donor blood, which is especially useful when blood is required for a patient who has multiple red cell alloantibodies. This study was carried out to determine the frequencies of the D, C, c, E, e, K, k, Fy(a), Fy(b), Jk(a), Jk(b), M, N, S and s antigens in over 3,000 blood donors. METHODS: Samples from randomly selected blood donors from Delhi and nearby areas (both voluntary and replacement) were collected for extended antigen typing during the period January 2009 to January 2010. Antigens were typed via automated testing on the Galileo instrument using commercial antisera. RESULTS: A total of 3073 blood samples from donors were phenotyped. The prevalence of these antigens was found to be as follows in %: D: 93.6, C: 87, c: 58, E: 20, e: 98, K: 3.5, k: 99.97, F(a) : 87.4, Fy(b) : 57.6, Jk(a) : 81.5, Jk(b) : 67.4, M: 88.7, N: 65.4, S: 54.8 and s: 88.7. INTERPRETATION & CONCLUSIONS: This study found the prevalence of the typed antigens among Indian blood donors to be statistically different to those in the Caucasian, Black and Chinese populations, but more similar to Caucasians than to the other racial groups. PMID- 23640560 TI - Effects of poly (ADP-ribosyl) polymerase (PARP) inhibitor on cisplatin resistance & proliferation of the ovarian cancer C13* cells. AB - BACKGROUND & OBJECTIVES: Drug resistance is the primary cause of failure in the treatment of cancers. It has been suggested that the enhancement of DNA repair capability may be responsible for the drug resistance of the tumour cells, and poly(ADP-ribosyl)ation plays an important role in DNA repair. This study investigated the effect of PARP inhibitor 3-aminobenzamide (3-AB) on the cisplatin resistance and proliferation of the cisplatin-resistant ovarian cancer C13 FNx01 cells in vitro. METHODS: C13 FNx01 cells were treated with various concentrations of 3-AB in vitro. MTT assay was used to determine the effect of 3 AB on the cisplatin sensitivity and proliferation of cells. The expression levels of PARP-1 mRNA and protein in the C13 FNx01 cells were examined using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, and changes caused by 3-AB treatment were investigated. Immunofluorescence microscopy was used to detect the localization and expression of the PARP-1 proteins before and after treatment with 5 mmol/l 3-AB. RESULTS: The inhibitory ratio and the cisplatin sensitivity of C13 FNx01 cells significantly increased with the increase of the concentration of 3-AB (P<0.05). The RT-PCR analysis revealed that the expression of PARP-1 mRNA was decreased when platinum (Pt) and 3-AB were combined. The expression levels of PARP-1 protein were decreased by 23.15 +/- 2.53, 59.11 +/- 2.23 and 73.24 +/- 3.88 per cent, respectively, in C13 FNx01 cells with the increase of the concentration of 3-AB (P<0.05). The immunofluorescence microscopy results indicated that the expression level of PARP 1 protein was significantly decreased after treatment with 3-AB (P,<0.05). INTERPRETATION & CONCLUSIONS: 3-AB inhibited the proliferation activity of C13 FNx01 cells, and increased the cellular sensitivity to cisplatin. Our findings show that the PARP inhibitor 3-AB can downregulate the expression of PARP-1 at transcriptional and translational levels in C13 FNx01 cells. PMID- 23640561 TI - Association of Chlamydia trachomatis infection with human papillomavirus (HPV) & cervical intraepithelial neoplasia - a pilot study. AB - BACKGROUND & OBJECTIVES: Human papillomavirus (HPV) is the necessary cause of cervical cancer and Chlamydia trachomatis (CT) is considered a potential cofactor in the development of cervical intraepithelial neoplasia (CIN). The objective of this pilot study was to determine the association of CT infection with HPV, other risk factors for cervical cancer, and CIN in symptomatic women. METHODS: A total of 600 consecutively selected women aged 30-74 yr with persistent vaginal discharge, intermenstrual/postcoital bleeding or unhealthy cervix underwent conventional Pap smear, Hybrid Capture 2 (HC2) testing for HPV and CT DNA and colposcopy, with directed biopsy of all lesions. RESULTS: HPV DNA was positive in 108 (18.0%) women, CT DNA in 29 (4.8%) women. HPV/CT co-infection was observed in only four (0.7%) women. Of the 127 (21.2%) women with Pap >ASCUS, 60 (47.2%) were HPV positive and four (3.1%) were CT positive. Of the 41 women with CIN1 lesions, 11 (26.8%) were HPV positive, while two were CT positive. Of the 46 women with CIN2+ on histopathology, 41 (89.1%) were HPV positive, two (4.3%) were CT positive and one was positive for both. The risk of CIN2+ disease was significantly increased (P<0.05) by the following factors: age <18 yr at first coitus, HPV infection and a positive Pap smear. Older age (>35 yr), higher parity, use of oral contraceptives or smoking did not show any significant association with HPV or abnormal histopathology. Parity >5 was the only risk factor positivity associated with CT infection (P<0.05). INTERPRETATION & CONCLUSIONS: Our findings showed that CT infection was not significantly associated with CIN, and most of its risk factors, including HPV infection, in symptomatic women. Longitudinal studies with carefully selected study sample would be able to answer these questions. PMID- 23640562 TI - Ellagic acid & gallic acid from Lagerstroemia speciosa L. inhibit HIV-1 infection through inhibition of HIV-1 protease & reverse transcriptase activity. AB - BACKGROUND & OBJECTIVES: Banaba (Lagerstroemia speciosa L.) extracts have been used as traditional medicines and are effective in controlling diabetes and obesity. The aim of this study was to evaluate the anti-HIV property of the extracts prepared from the leaves and stems of banaba, and further purification and characterization of the active components. METHODS: Aqueous and 50 per cent ethanolic extracts were prepared from leaves and stems of banaba and were evaluated for cytotoxicity and anti-HIV activity using in vitro reporter gene based assays. Further, three compounds were isolated from the 50 per cent ethanolic extract of banaba leaves using silica gel column chromatography and characterization done by HPLC, NMR and MS analysis. To delineate the mode of action of the active compounds, reverse transcriptase assay and protease assay were performed using commercially available kits. RESULTS: All the extracts showed a dose dependent inhibition of HIV-1-infection in TZM-bl and CEM-GFP cell lines with a maximum from the 50 per cent ethanolic extract from leaves (IC 50 = 1 to 25 MUg/ml). This observation was confirmed by the virus load (p24) estimation in infected CEM-GFP cells when treated with the extracts. Gallic acid showed an inhibition in reverse transcriptase whereas ellagic acid inhibited the HIV-1 protease activity. INTERPRETATION & CONCLUSIONS: The present study shows a novel anti-HIV activity of banaba. The active components responsible for anti-HIV activity were gallic acid and ellagic acid, through inhibition of reverse transcriptase and HIV protease, respectively and hence could be regarded as promising candidates for the development of topical anti-HIV-1 agents. PMID- 23640563 TI - Pupal productivity of dengue vectors in Kolkata, India: implications for vector management. AB - BACKGROUND & OBJECTIVES: Entomological surveillance of the dengue vectors using pupal productivity as indicators can be helpful in effective management. On this basis, an assessment was made on the relative importance of the larval habitats of Aedes mosquitoes in Kolkata, an endemic zone for dengue in West Bengal, India. METHODS: Monthly collection of larvae and pupae of Aedes from larval habitats categorized as earthen, plastic and porcelain containers and tyres, was carried out from selected sites. Pupal weight was recorded and degree of sexual dimorphism was calculated. The data on pupal weight, sexual dimorphism and immature density were used for regression analysis. RESULTS: The number of positive sites for each type of larval habitats varied with months and mosquito species. Based on mean density per month, the plastic containers were the most productive habitats and the tyres were least productive for both Aedes species. The pupal weight of both Ae. aegypti and Ae. albopictus varied with the relative density and type of larval habitats. Significant differences in pupal productivity, positive sites and the proportion of pupae were observed in the habitats. Species-specific differences in the degree of dimorphism were noted with the females being larger in size than males, irrespective of the habitats. INTERPRETATION & CONCLUSIONS: Pupal productivity of Aedes mosquitoes in Kolkata differed in terms of the type of the larval habitats with the immature density affecting the body size of the adults. This habitat-based study is a pioneer effort considering Kolkata and calls for a management plan for source reduction of these habitats to minimize Aedes mosquitoes and thus potential risk of dengue. PMID- 23640564 TI - Serological survey of toxoplasmosis in a district in Tamil Nadu: hospital-based study. PMID- 23640565 TI - Phenotypic screening of resistance mechanism in Staphylococcus aureus. PMID- 23640566 TI - Tophaceous gout of the spine masquerading as spondylodiscitis. PMID- 23640567 TI - Elephantiasic pretibial myxoedema. PMID- 23640568 TI - Synthetic prodigiosenes and the influence of C-ring substitution on DNA cleavage, transmembrane chloride transport and basicity. AB - Analogues of the tripyrrolic natural product prodigiosin bearing an additional methyl and a carbonyl group at the C-ring were synthesised and evaluated. In vitro anticancer activity screening (NCI) and the study of modes of action (copper-mediated cleavage of double-stranded DNA and transmembrane transport of chloride anions) showed that the presence of the methyl group is not detrimental to activity. Furthermore, although the presence of an ester conjugated to the prodigiosene C-ring seems to decrease both pK(a) and chloride transport efficiency compared to the natural product, these analogues still exhibit a high rate of chloride transport. All analogues exhibit good in vitro anticancer activity and reduced toxicity compared to the natural product: compare an acute systemic toxicity of 100 mg kg(-1) in mice vs. 4 mg kg(-1) for prodigiosin, pointing towards a larger therapeutic window than for the natural product. PMID- 23640569 TI - Are all of the human exons alternatively spliced? AB - Alternative mRNA splicing (AS) is a major mechanism for increasing regulatory complexity. A key concept in AS is the distinction between alternatively and constitutively spliced exons (ASEs and CSEs, respectively). ASEs and CSEs have been reported to be differentially regulated, and to have distinct biological properties. However, the recent flood of RNA-sequencing data has obscured the boundary between ASEs and CSEs. Researchers are beginning to question whether 'authentic CSEs' do exist, and whether the ASE/CSE distinction is biologically invalid. Here, I examine the influences of increasing transcriptome data on the human ASE/CSE classification and our past understanding of the properties of these two types of exons. Interestingly, although the percentage of human ASEs has increased dramatically in recent years, the overall distinction between ASEs and CSEs remain valid. For example, CSEs are longer, evolve more slowly, and less frequently correspond to intrinsically disordered protein regions than ASEs. In addition, only a relatively small number of human genes have their transcripts composed entirely of ASEs despite the large amount of high-throughput transcriptome information. Therefore, the 'backbone' concept of AS, in which CSEs constitute the invariant part and ASEs the flexible part of the transcript, appears to be generally true despite the increasing percentage of ASEs in the human exome. PMID- 23640570 TI - Teaching the bioinformatics of signaling networks: an integrated approach to facilitate multi-disciplinary learning. AB - The number of bioinformatics tools and resources that support molecular and cell biology approaches is continuously expanding. Moreover, systems and network biology analyses are accompanied more and more by integrated bioinformatics methods. Traditional information-centered university teaching methods often fail, as (1) it is impossible to cover all existing approaches in the frame of a single course, and (2) a large segment of the current bioinformation can become obsolete in a few years. Signaling network offers an excellent example for teaching bioinformatics resources and tools, as it is both focused and complex at the same time. Here, we present an outline of a university bioinformatics course with four sample practices to demonstrate how signaling network studies can integrate biochemistry, genetics, cell biology and network sciences. We show that several bioinformatics resources and tools, as well as important concepts and current trends, can also be integrated to signaling network studies. The research-type hands-on experiences we show enable the students to improve key competences such as teamworking, creative and critical thinking and problem solving. Our classroom course curriculum can be re-formulated as an e-learning material or applied as a part of a specific training course. The multi-disciplinary approach and the mosaic setup of the course have the additional benefit to support the advanced teaching of talented students. PMID- 23640572 TI - Role of p21-activated kinases in cardiovascular development and function. AB - p21-activated kinases (Paks) are a group of six serine/threonine kinases (Pak1-6) that are involved in a variety of biological processes. Recently, Paks, more specifically Pak1, -2, and -4, have been shown to play important roles in cardiovascular development and function in a range of model organisms including zebrafish and mice. These functions include proper morphogenesis and conductance of the heart, cardiac contractility, and development and integrity of the vasculature. The mechanisms underlying these effects are not fully known, but they likely differ among the various Pak isoforms and include both kinase dependent and -independent functions. In this review, we discuss aspects of Pak function relevant to cardiovascular biology as well as potential therapeutic implications of small-molecule Pak inhibitors in cardiovascular disease. PMID- 23640574 TI - Multiscale stochastic reaction-diffusion modeling: application to actin dynamics in filopodia. AB - Two multiscale (hybrid) stochastic reaction-diffusion models of actin dynamics in a filopodium are investigated. Both hybrid algorithms combine compartment-based and molecular-based stochastic reaction-diffusion models. The first hybrid model is based on the models previously developed in the literature. The second hybrid model is based on the application of a recently developed two-regime method (TRM) to a fully molecular-based model, which is also developed in this paper. The results of hybrid models are compared with the results of the molecular-based model. It is shown that both approaches give comparable results, although the TRM model better agrees quantitatively with the molecular-based model. PMID- 23640571 TI - Regulatory mechanisms for the development of growth plate cartilage. AB - In vertebrates, most of the skeleton is formed through endochondral ossification. Endochondral bone formation is a complex process involving the mesenchymal condensation of undifferentiated cells, the proliferation of chondrocytes and their differentiation into hypertrophic chondrocytes, and mineralization. This process is tightly regulated by various factors including transcription factors, soluble mediators, extracellular matrices, and cell-cell and cell-matrix interactions. Defects of these factors often lead to skeletal dysplasias and short stature. Moreover, there is growing evidence that epigenetic and microRNA mediated mechanisms also play critical roles in chondrogenesis. This review provides an overview of our current understanding of the regulators for the development of growth plate cartilage and their molecular mechanisms of action. A knowledge of the regulatory mechanisms underlying the proliferation and differentiation of chondrocytes will provide insights into future therapeutic options for skeletal disorders. PMID- 23640576 TI - Latent pulmonary hypertension in atrial septal defect: Dynamic stress echocardiography reveals unapparent pulmonary hypertension and confirms rapid normalisation after ASD closure. AB - OBJECTIVE: Closure of atrial septal defects (ASD) prevents pulmonary hypertension, right heart failure and thromboembolic stroke. The exact timing for ASD closure is controversial. METHODS: In a prospective study to address the question whether unapparent pulmonary hypertension can be revealed prior to right ventricular (RV) remodelling, patients were investigated before and 6, 12, and 24 months after ASD closure using exercise stress echocardiography (ESE) and ergospirometry (n = 24). RESULTS: At rest, RV systolic pressure (RVSP) was normal in 58.8 %, slightly elevated in 26.5 %, and moderately elevated in 11.8 %. One patient showed severe pulmonary hypertension. During ESE, all patients with normal RVSP at rest exhibited an increase (25.7 +/- 1.2 mmHg vs. 45.3 +/- 2.3 mmHg, p < 0.001). After closure the RVSP was lower, both at rest and ESE. RV diameters decreased too. Tricuspid annulus plane systolic excursion (TAPSE) at rest remained lower after closure (24.0 +/- 0.9 vs. 22.0 +/- 0.9 mm, p < 0.05). TAPSE in ESE was elevated, and stayed stable after closure (30.1 +/- 1.8 mm vs. 29.3 +/- 1.6 mm). Before closure, RV systolic tissue velocities (s(a)) at rest were normal and decreased after closure (14.0 +/- 1.0 cm/s vs. 11.5 +/- 0.7 (6 month) vs. 10.6 +/- 0.5 cm/s (12 month), p < 0.05). During ESE, s(a) velocity was similar before and after closure (23.0 +/- 1.3 cm/s vs. 23.3 +/- 1.9 cm/s). Maximal oxygen uptake (VO2/kg) did not differ between baseline and follow-ups. CONCLUSION: Latent pulmonary hypertension may become apparent in ESE. ASD closure leads to a significant reduction in this stress-induced pulmonary hypertension and to a decrease in the right heart diameters indicating reverse RV remodelling. RV functional parameters at rest did not improve. The VO2/kg did not change after ASD closure. PMID- 23640575 TI - Inhibition of apelin expression switches endothelial cells from proliferative to mature state in pathological retinal angiogenesis. AB - The recruitment of mural cells such as pericytes to patent vessels with an endothelial lumen is a key factor for the maturation of blood vessels and the prevention of hemorrhage in pathological angiogenesis. To date, our understanding of the specific trigger underlying the transition from cell growth to the maturation phase remains incomplete. Since rapid endothelial cell growth causes pericyte loss, we hypothesized that suppression of endothelial growth factors would both promote pericyte recruitment, in addition to inhibiting pathological angiogenesis. Here, we demonstrate that targeted knockdown of apelin in endothelial cells using siRNA induced the expression of monocyte chemoattractant protein-1 (MCP-1) through activation of Smad3, via suppression of the PI3K/Akt pathway. The conditioned medium of endothelial cells treated with apelin siRNA enhanced the migration of vascular smooth muscle cells, through MCP-1 and its receptor pathway. Moreover, in vivo delivery of siRNA targeting apelin, which causes exuberant endothelial cell proliferation and pathological angiogenesis through its receptor APJ, led to increased pericyte coverage and suppressed pathological angiogenesis in an oxygen-induced retinopathy model. These data demonstrate that apelin is not only a potent endothelial growth factor, but also restricts pericyte recruitment, establishing a new connection between endothelial cell proliferation signaling and a trigger of mural recruitment. PMID- 23640577 TI - A calcified sinutubular junction: the discovery of a supravalvular aortic stenosis in an elderly woman. AB - We report a case of a 64 year old woman with a calcified ring at the level of the sinotubular junction. Echocardiography and Computed Tomography showed a supravalvular aortic stenosis, without known associated lesions, except for the existence of an aberrant right subclavian artery. These combination of abnormalities makes it an unique case. Differential diagnosis of sinutubular calcification is added. From the literature a short review of supravalvular aortic stenosis is presented with indications for surgical intervention. Lifelong and regular follow up is necessary. PMID- 23640578 TI - Crown years for non-invasive cardiovascular imaging (Part IV): 30 years of cardiac computed tomography. PMID- 23640581 TI - Sieving di-branched from mono-branched and linear alkanes using ZIF-8: experimental proof and theoretical explanation. AB - We study the adsorption equilibrium isotherms and differential heats of adsorption of hexane isomers on the zeolitic imidazolate framework ZIF-8. The studies are carried out at 373 K using a manometric set-up combined with a micro calorimeter. We see that the Langmuir model describes well the isotherms for all four isomers (n-hexane, 2-methylpentane, 2,2-dimethylbutane and 2,3 dimethylbutane). The linear and mono-branched isomers adsorb well, but 2,2 dimethylbutane is totally excluded. Plotting the differential heat of adsorption against the loading shows an initial plateau for n-hexane and 2-methylpentane. This is followed by a slow rise, indicating adsorbate-adsorbate interactions. For the di-branched isomers the differential heat of adsorption decreases with loading. To gain further insight, we ran molecular simulations using the grand canonical Monte Carlo approach. Comparing the simulation and the experimental results shows that the ZIF framework model requires blocking of the cages, since 2,2-dimethylbutane cannot fit through the sodalite-type windows. Practically speaking, this means that ZIF-8 is a highly promising candidate for enhancing gasoline octane numbers at 373 K, as it can separate 2,2-dimethylbutane and 2,3 dimethylbutane from 2-methylpentane. Our results prove the potential of ZIF-8 as a new adsorbent that can be employed in the upgrade of the Total Isomerization Process for the production of high octane number gasoline, by blending di branched alkanes in the gasoline. PMID- 23640582 TI - Genetic diversity of early (1998) and recent (2010) avian influenza H9N2 virus strains isolated from poultry in Iran. AB - Infection with avian influenza H9N2 virus is widespread in the Asian poultry industry, resulting in great economic losses due to mortality and a severe decline in egg production. To obtain more-comprehensive genomic data from circulating H9N2 viruses in Iran, we sequenced the whole genomes of early (Ck/IR/ZMT-101/98) and recent (Ck/IR/EBGV-88/10) isolates of this virus in Iran. The M and NS genes of Ck/IR/EBGV-88/10 shared a high level of similarity with a highly pathogenic H7N3 virus isolated from Pakistan. The cleavage site within the HA protein of these viruses contained two different motifs, RSSR and KSSR, which are similar to those found in low-pathogenic viruses. The deduced amino acid sequence of the new isolate contained the mutation Q226L, which is a characteristic of human-type sialic acid influenza receptor binding. An analysis of the viral amino acid sequence of the M2 protein of the recent strain revealed a V27A mutation, which is associated with amantadine resistance in avian influenza virus. The present results emphasize the need for continuous surveillance of H9N2 viruses in poultry and the human population to obtain more information about the nature and evolution of future pandemic influenza viruses. PMID- 23640583 TI - Complete coding sequences of European brown hare syndrome virus (EBHSV) strains isolated in 1982 in Sweden. AB - European brown hare syndrome (EBHS) is characterised by high mortality of European brown hares (Lepus europaeus) and mountain hares (Lepus timidus). European brown hare syndrome virus (EBHSV) and the closely related rabbit haemorrhagic disease virus (RHDV) comprise the genus Lagovirus, family Caliciviridae. In contrast to RHDV, which is well studied, with more than 30 complete genome sequences available, the only complete genome sequence available for EBHSV was obtained from a strain isolated in 1989 in France. EBHS was originally diagnosed in Sweden in 1980. Here, we report the complete coding sequences of two EBHSV strains isolated from European brown hares that died with liver lesions characteristic of EBHS in Sweden in 1982. These sequences represent the oldest complete coding sequences of EBHSV isolated from the original area of virus diagnosis. The genomic organisation is similar to that of the published French sequence. Comparison with this sequence revealed several nucleotide substitutions, corresponding to 6 % divergence. At the amino acid level, the Swedish strains are 2 % different from the French strain. Most amino acid substitutions were located within the major capsid protein VP60, but when considering the amino acid sequence length of each protein, VP10 is the protein with the highest percentage of amino acid differences. The same result was obtained when Swedish strains were compared. This evolutionary pattern has not been described previously for members of the genus Lagovirus. PMID- 23640584 TI - Fragility of pulmonary capillaries. AB - Although the pulmonary capillaries were discovered in 1661, the ultrastructure of the wall was not elucidated until 60 years ago. Electron micrographs then showed that only 0.2 MUm of tissue separated the capillary endothelium from the alveolar space over much of the area. In retrospect this vanishingly small protective layer should have alerted physiologists to the potential fragility of the capillaries, but this was not appreciated until almost 40 years later. This predicament is unique to pulmonary capillaries. No other capillaries in the body are shielded from the outside environment by such a minute amount of tissue. Reasons why the fragility of the capillaries was not recognized earlier include an inappropriate comparison with the properties of systemic capillaries, the mistaken view that the pulmonary capillary pressure is always low, and a misleading use of the Laplace equation. Evidence for the fragility comes from physiological, pathological, and laboratory observations. As expected from evolutionary considerations, the fragility only becomes evident in the normal lung under exceptional conditions. These include elite human athletes at maximal exercise and animals that have developed the capacity for extreme aerobic activity. However, lung and heart diseases frequently cause capillary disruption. Remodeling of pulmonary capillaries occurs in humans in whom the capillary pressure rises over a long period. Neonatal capillaries are extremely fragile, presumably because they have never been exposed to increased transmural pressures. The capillaries conform to the general biological rule that tissue adapts its structure to carry out its required function. PMID- 23640585 TI - The heterogeneity of regional specific ventilation is unchanged following heavy exercise in athletes. AB - Heavy exercise increases ventilation-perfusion mismatch and decreases pulmonary gas exchange efficiency. Previous work using magnetic resonance imaging (MRI) arterial spin labeling in athletes has shown that, after 45 min of heavy exercise, the spatial heterogeneity of pulmonary blood flow was increased in recovery. We hypothesized that the heterogeneity of regional specific ventilation (SV, the local tidal volume over functional residual capacity ratio) would also be increased following sustained exercise, consistent with the previously documented changes in blood flow heterogeneity. Trained subjects (n = 6, maximal O2 consumption = 61 +/- 7 ml.kg(-1).min(-1)) cycled 45 min at their individually determined ventilatory threshold. Oxygen-enhanced MRI was used to quantify SV in a sagittal slice of the right lung in supine posture pre- (preexercise) and 15- and 60-min postexercise. Arterial spin labeling was used to measure pulmonary blood flow in the same slice bracketing the SV measures. Heterogeneity of SV and blood flow were quantified by relative dispersion (RD = SD/mean). The alveolar arterial oxygen difference was increased during exercise, 23.3 +/- 5.3 Torr, compared with rest, 6.3 +/- 3.7 Torr, indicating a gas exchange impairment during exercise. No significant change in RD of SV was seen after exercise: preexercise 0.78 +/- 0.15, 15 min postexercise 0.81 +/- 0.13, 60 min postexercise 0.78 +/- 0.08 (P = 0.5). The RD of blood flow increased significantly postexercise: preexercise 1.00 +/- 0.12, 15 min postexercise 1.15 +/- 0.10, 45 min postexercise 1.10 +/- 0.10, 60 min postexercise 1.19 +/- 0.11, 90 min postexercise 1.11 +/- 0.12 (P < 0.005). The lack of a significant change in RD of SV postexercise, despite an increase in the RD of blood flow, suggests that airways may be less susceptible to the effects of exercise than blood vessels. PMID- 23640586 TI - Analysis of patient-specific surgical ventricular restoration: importance of an ellipsoidal left ventricular geometry for diastolic and systolic function. AB - Surgical ventricular restoration (SVR) is a procedure designed to treat heart failure by surgically excluding infarcted tissues from the dilated failing left ventricle. To elucidate and predict the effects of geometrical changes from SVR on cardiac function, we created patient-specific mathematical (finite-element) left ventricular models before and after surgery using untagged magnetic resonance images. Our results predict that the postsurgical improvement in systolic function was compromised by a decrease in diastolic distensibility in patients. These two conflicting effects typically manifested as a more depressed Starling relationship (stroke volume vs. end-diastolic pressure) after surgery. By simulating a restoration of the left ventricle back to its measured baseline sphericity, we show that both diastolic and systolic function improved. This result confirms that the increase in left ventricular sphericity commonly observed after SVR (endoventricular circular patch plasty) has a negative impact and contributes partly to the depressed Starling relationship. On the other hand, peak myofiber stress was reduced substantially (by 50%) after SVR, and the resultant left ventricular myofiber stress distribution became more uniform. This significant reduction in myofiber stress after SVR may help reduce adverse remodeling of the left ventricle. These results are consistent with the speculation proposed in the Surgical Treatment for Ischemic Heart Failure trial (20) for the neutral outcome, that "the lack of benefit seen with surgical ventricular reconstruction is that benefits anticipated from surgical reduction of left ventricular volume (reduced wall stress and improvement in systolic function) are counter-balanced by a reduction in diastolic distensibility." PMID- 23640588 TI - Lymphatic regulation in nonmammalian vertebrates. AB - All vertebrate animals share in common the production of lymph through net capillary filtration from their closed circulatory system into their tissues. The balance of forces responsible for net capillary filtration and lymph formation is described by the Starling equation, but additional factors such as vascular and interstitial compliance, which vary markedly among vertebrates, also have a significant impact on rates of lymph formation. Why vertebrates show extreme variability in rates of lymph formation and how nonmammalian vertebrates maintain plasma volume homeostasis is unclear. This gap hampers our understanding of the evolution of the lymphatic system and its interaction with the cardiovascular system. The evolutionary origin of the vertebrate lymphatic system is not clear, but recent advances suggest common developmental factors for lymphangiogenesis in teleost fishes, amphibians, and mammals with some significant changes in the water-land transition. The lymphatic system of anuran amphibians is characterized by large lymphatic sacs and two pairs of lymph hearts that return lymph into the venous circulation but no lymph vessels per se. The lymphatic systems of reptiles and some birds have lymph hearts, and both groups have extensive lymph vessels, but their functional role in both lymph movement and plasma volume homeostasis is almost completely unknown. The purpose of this review is to present an evolutionary perspective in how different vertebrates have solved the common problem of the inevitable formation of lymph from their closed circulatory systems and to point out the many gaps in our knowledge of this evolutionary progression. PMID- 23640589 TI - Beetroot juice and exercise: pharmacodynamic and dose-response relationships. AB - Dietary supplementation with beetroot juice (BR), containing approximately 5-8 mmol inorganic nitrate (NO3(-)), increases plasma nitrite concentration ([NO2( )]), reduces blood pressure, and may positively influence the physiological responses to exercise. However, the dose-response relationship between the volume of BR ingested and the physiological effects invoked has not been investigated. In a balanced crossover design, 10 healthy men ingested 70, 140, or 280 ml concentrated BR (containing 4.2, 8.4, and 16.8 mmol NO3(-), respectively) or no supplement to establish the effects of BR on resting plasma [NO3(-)] and [NO2(-)] over 24 h. Subsequently, on six separate occasions, 10 subjects completed moderate-intensity and severe-intensity cycle exercise tests, 2.5 h postingestion of 70, 140, and 280 ml BR or NO3(-)-depleted BR as placebo (PL). Following acute BR ingestion, plasma [NO2(-)] increased in a dose-dependent manner, with the peak changes occurring at approximately 2-3 h. Compared with PL, 70 ml BR did not alter the physiological responses to exercise. However, 140 and 280 ml BR reduced the steady-state oxygen (O2) uptake during moderate-intensity exercise by 1.7% (P = 0.06) and 3.0% (P < 0.05), whereas time-to-task failure was extended by 14% and 12% (both P < 0.05), respectively, compared with PL. The results indicate that whereas plasma [NO2(-)] and the O2 cost of moderate-intensity exercise are altered dose dependently with NO3(-)-rich BR, there is no additional improvement in exercise tolerance after ingesting BR containing 16.8 compared with 8.4 mmol NO3(-). These findings have important implications for the use of BR to enhance cardiovascular health and exercise performance in young adults. PMID- 23640590 TI - The effect of diaphragm contraction on upper airway collapsibility. AB - Increasing lung volume increases upper airway patency and decreases airway resistance and collapsibility. The role of diaphragm contraction in producing these changes remains unclear. This study was undertaken to determine the effect of selective diaphragm contraction, induced by phrenic nerve stimulation, on upper airway collapsibility and the extent to which any observed change was attributable to lung volume-related changes in pressure gradients or to diaphragm descent-related mediastinal traction. Continuous bilateral transcutaneous cervical phrenic nerve stimulation (30 Hz) was applied to nine supine, anesthetized human subjects during transient decreases in airway pressure to levels sufficient to produce flow limitation when unstimulated. Stimulation was applied at two intensities (low and high) and its effects on lung volume and airflow quantified relative to unstimulated conditions. Lung volume increased by 386 +/- 269 ml (means +/- SD) and 761 +/- 556 ml during low and high stimulation, respectively (P < 0.05 for the difference between these values), which was associated with peak inspiratory flow increases of 69 +/- 57 and 137 +/- 108 ml/s, respectively (P < 0.05 for the difference). Stimulation-induced change in lung volume correlated with change in peak flow (r = 0.65, P < 0.01). Diaphragm descent-related outward displacement of the abdominal wall produced no change in airflow unless accompanied by lung volume change. We conclude that phrenic nerve stimulation-induced diaphragm contraction increases lung volume and reduces airway collapsibility in a dose-dependent manner. The effect appears primarily mediated by changes in lung volume rather than mediastinal traction from diaphragm descent. The study provides a rationale for use of continuous phrenic stimulation to treat obstructive sleep apnea. PMID- 23640587 TI - Effect of healthy aging on renal vascular responses to local cooling and apnea. AB - Sympathetically mediated renal vasoconstriction may contribute to the pathogenesis of hypertension in older adults, but empirical data in support of this concept are lacking. In 10 young (26 +/- 1 yr) and 11 older (67 +/- 2 yr) subjects, we quantified acute hemodynamic responses to three sympathoexcitatory stimuli: local cooling of the forehead, cold pressor test (CPT), and voluntary apnea. We hypothesized that all stimuli would increase mean arterial blood pressure (MAP) and renal vascular resistance index (RVRI) and that aging would augment these effects. Beat-by-beat MAP, heart rate (HR), and renal blood flow velocity (from Doppler) were measured in the supine posture, and changes from baseline were compared between groups. In response to 1 degrees C forehead cooling, aging was associated with an augmented MAP (20 +/- 3 vs. 6 +/- 2 mmHg) and RVRI (35 +/- 6 vs. 16 +/- 9%) but not HR. In older adults, there was a positive correlation between the cold-induced pressor response and forehead pain (R = 0.726), but this effect was not observed in young subjects. The CPT raised RVRI in both young (56 +/- 13%) and older (45 +/- 8%) subjects, but this was not different between groups. Relative to baseline, end-expiratory apnea increased RVRI to a similar extent in both young (46 +/- 14%) and older (41 +/- 9%) subjects. During sympathetic activation, renal vasoconstriction occurred in both groups. Forehead cooling caused an augmented pressor response in older adults that was related to pain perception. PMID- 23640591 TI - Modeling energy expenditure in children and adolescents using quantile regression. AB - Advanced mathematical models have the potential to capture the complex metabolic and physiological processes that result in energy expenditure (EE). Study objective is to apply quantile regression (QR) to predict EE and determine quantile-dependent variation in covariate effects in nonobese and obese children. First, QR models will be developed to predict minute-by-minute awake EE at different quantile levels based on heart rate (HR) and physical activity (PA) accelerometry counts, and child characteristics of age, sex, weight, and height. Second, the QR models will be used to evaluate the covariate effects of weight, PA, and HR across the conditional EE distribution. QR and ordinary least squares (OLS) regressions are estimated in 109 children, aged 5-18 yr. QR modeling of EE outperformed OLS regression for both nonobese and obese populations. Average prediction errors for QR compared with OLS were not only smaller at the median tau = 0.5 (18.6 vs. 21.4%), but also substantially smaller at the tails of the distribution (10.2 vs. 39.2% at tau = 0.1 and 8.7 vs. 19.8% at tau = 0.9). Covariate effects of weight, PA, and HR on EE for the nonobese and obese children differed across quantiles (P < 0.05). The associations (linear and quadratic) between PA and HR with EE were stronger for the obese than nonobese population (P < 0.05). In conclusion, QR provided more accurate predictions of EE compared with conventional OLS regression, especially at the tails of the distribution, and revealed substantially different covariate effects of weight, PA, and HR on EE in nonobese and obese children. PMID- 23640592 TI - Role of neuronal nitric oxide in the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle of healthy rats. AB - Isoform-specific nitric oxide (NO) synthase (NOS) contributions to NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle are incompletely understood. The purpose of the present study was to investigate the role of neuronal NOS (nNOS) in the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle of healthy rats. We hypothesized that acute pharmacological inhibition of nNOS would augment sympathetic vasoconstriction in resting and contracting skeletal muscle, demonstrating that nNOS is primarily responsible for NO-mediated inhibition of sympathetic vasoconstriction. Sprague-Dawley rats (n = 13) were anesthetized and instrumented with an indwelling brachial artery catheter, femoral artery flow probe, and lumbar sympathetic chain stimulating electrodes. Triceps surae muscles were stimulated to contract rhythmically at 60% of maximal contractile force. In series 1 (n = 9), the percent change in femoral vascular conductance (%FVC) in response to sympathetic stimulations delivered at 2 and 5 Hz was determined at rest and during muscle contraction before and after selective nNOS blockade with S-methyl-l-thiocitrulline (SMTC, 0.6 mg/kg iv) and subsequent nonselective NOS blockade with N(omega)-nitro-l-arginine methyl ester (l-NAME, 5 mg/kg iv). In series 2 (n = 4), l-NAME was injected first, and then SMTC was injected to determine if the effect of l-NAME on constrictor responses was influenced by selective nNOS inhibition. Sympathetic stimulation decreased FVC at rest (-25 +/- 7 and -44 +/- 8%FVC at 2 and 5 Hz, respectively) and during contraction (-7 +/- 3 and -19 +/- 5%FVC at 2 and 5 Hz, respectively). The decrease in FVC in response to sympathetic stimulation was greater in the presence of SMTC at rest (-32 +/- 6 and -49 +/- 8%FVC at 2 and 5 Hz, respectively) and during contraction (-21 +/- 4 and -28 +/- 4%FVC at 2 and 5 Hz, respectively). l-NAME further increased (P < 0.05) the sympathetic vasoconstrictor response at rest (-47 +/- 4 and -60 +/- 6%FVC at 2 and 5 Hz, respectively) and during muscle contraction (-33 +/- 3 and 40 +/- 6%FVC at 2 and 5 Hz, respectively). The effect of l-NAME was not altered by the order of nNOS inhibition. These data demonstrate that NO derived from nNOS and endothelial NOS contribute to the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. PMID- 23640593 TI - 3D fascicle orientations in triceps surae. AB - The aim of this study was to determine the three-dimensional (3D) muscle fascicle architecture in human triceps surae muscles at different contraction levels and muscle lengths. Six male subjects were tested for three contraction levels (0, 30, and 60% of maximal voluntary contraction) and four ankle angles (-15, 0, 15, and 30 degrees of plantar flexion), and the muscles were imaged with B-mode ultrasound coupled to 3D position sensors. 3D fascicle orientations were represented in terms of pennation angle relative to the major axis of the muscle and azimuthal angle (a new architectural parameter introduced in this study representing the radial angle around the major axis). 3D orientations of the fascicles, and the sheets along which they lie, were regionalized in all the three muscles (medial and lateral gastrocnemius and the soleus) and changed significantly with contraction level and ankle angle. Changes in the azimuthal angle were of similar magnitude to the changes in pennation angle. The 3D information was used for an error analysis to determine the errors in predictions of pennation that would occur in purely two-dimensional studies. A comparison was made for assessing pennation in the same plane for different contraction levels, or for adjusting the scanning plane orientation for different contractions: there was no significant difference between the two simulated scanning conditions for the gastrocnemii; however, a significant difference of 4.5 degrees was obtained for the soleus. Correct probe orientation is thus more critical during estimations of pennation for the soleus than the gastrocnemii due to its more complex fascicle arrangement. PMID- 23640594 TI - Regional effects of low-intensity endurance training on structural and mechanical properties of rat ventricular myocytes. AB - We tested the effects of low-intensity endurance training (LIET) on the structural and mechanical properties of right (RV) and left ventricular (LV) myocytes. Male Wistar rats (4 mo old) were randomly divided into control (C, n = 7) and trained (T, n = 7, treadmill running at 50-60% of maximal running speed for 8 wk) groups. Isolated ventricular myocyte dimensions, contractility, Ca(2+) transients {intracellular Ca(2+) concentration ([Ca(2+)]i)}, and ventricular [Ca(2+)]i regulatory proteins were measured. LIET augmented cell length (C, 152.5 +/- 2.0 MUm vs. T, 162.2 +/- 2.1 MUm; P < 0.05) and volume (C, 5,162 +/- 131 MUm(3) vs. T, 5,506 +/- 132 MUm(3); P < 0.05) in the LV but not in the RV. LIET increased cell shortening (C, 7.5 +/- 0.3% vs. T, 8.6 +/- 0.3%; P < 0.05), the [Ca(2+)]i transient amplitude (C, 2.49 +/- 0.06 F/F0 vs. T, 2.82 +/- 0.06 F/F0; P < 0.05), the expression of sarcoplasmic reticulum Ca(2+)-ATPase 2a (C, 1.07 +/- 0.13 vs. T, 1.59 +/- 0.12; P < 0.05), and the levels of phosphorylated phospholamban at serine 16 (C, 0.99 +/- 0.11 vs. T, 1.34 +/- 0.10; P < 0.05), and reduced the total phospholamban-to-sarcoplasmic reticulum Ca(2+)-ATPase 2a ratio (C, 1.19 +/- 0.15 vs. T, 0.40 +/- 0.16; P < 0.05) in the LV without changing such parameters in the RV. In conclusion, LIET affected the structure and improved the mechanical properties of LV but not of RV myocytes in rats, helping to characterize the functional and morphological changes that accompany the endurance training-induced cardiac remodeling. PMID- 23640595 TI - MMP inhibition as a potential method to augment the healing of skeletal muscle and tendon extracellular matrix. AB - The extracellular matrix (ECM) of skeletal muscle and tendon is composed of different types of collagen molecules that play important roles in the transmission of forces throughout the body, and in the repair and regeneration of injured tissues. Fibroblasts are the primary cells in muscle and tendon that maintain, repair, and modify the ECM in response to mechanical loading, injury, and inactivity. Matrix metalloproteinases (MMPs) are enzymes that digest collagen and other structural molecules, which are synthesized and excreted by fibroblasts. MMPs are required for baseline ECM homeostasis, but disruption of MMP regulation due to injury or disease can alter the normal ECM architecture and prevent proper force transmission. Chronic injuries and diseases of muscles and tendons can be severely debilitating, and current therapeutic modalities to enhance healing are quite limited. This review will discuss the mechanobiology of MMPs, and the potential use of MMP inhibitors to improve the treatment of injured and diseased skeletal muscle and tendon tissue. PMID- 23640598 TI - Training the brain and its connections to muscles. PMID- 23640597 TI - Comparison of cardiovascular and biomechanical parameters of supine lower body negative pressure and upright lower body positive pressure to simulate activity in 1/6 G and 3/8 G. AB - For future space exploration missions, it is important to determine the best method of simulating on Earth cardiovascular and biomechanical conditions for lunar and Martian gravities. For this purpose, we compared exercise performed within a lower body negative pressure (LBNP) and a lower body positive pressure (LBPP) chamber. Twelve subjects underwent a protocol of resting and walking (0.25 Froude) within supine LBNP and upright LBPP simulation. Each protocol was performed in simulated 1/6 G and 3/8 G. We assessed heart rate (HR), mean arterial blood pressure, oxygen consumption (Vo2), normalized stride length, normalized vertical peak ground reaction force, duty factor, cadence, perceived exertion (Borg), and comfort of the subject. A mixed linear model was employed to determine effects of the simulation on the respective parameters. Furthermore, parameters were compared with predicted values for lunar and Martian gravities to determine the method that showed the best agreement. During walking, all cardiovascular and biomechanical parameters were unaffected by the simulation used for lunar and Martian gravities. During rest, HR and Vo2 were lower in supine LBNP compared with upright LBPP. HR, Vo2, and normalized vertical peak ground reaction force obtained with supine LBNP and upright LBPP showed good agreement with predicted values. Since supine LBNP and upright LBPP are lacking significant differences, we conclude that both simulations are suited to simulate the cardiovascular and biomechanical conditions during activity in lunar and Martian gravities. Operational characteristics and the intended application should be considered when choosing either supine LBNP or upright LBPP to simulate partial gravities on Earth. PMID- 23640596 TI - The role of trigeminal nasal TRPM8-expressing afferent neurons in the antitussive effects of menthol. AB - The cold-sensitive cation channel TRPM8 is a target for menthol, which is used routinely as a cough suppressant and as an additive to tobacco and food products. Given that cold temperatures and menthol activate neurons through gating of TRPM8, it is unclear how menthol actively suppresses cough. In this study we describe the antitussive effects of (-)-menthol in conscious and anesthetized guinea pigs. In anesthetized guinea pigs, cough evoked by citric acid applied topically to the tracheal mucosa was suppressed by menthol only when it was selectively administered as vapors to the upper airways. Menthol applied topically to the tracheal mucosa prior to and during citric acid application or administered continuously as vapors or as an aerosol to the lower airways was without effect on cough. These actions of upper airway menthol treatment were mimicked by cold air delivered to the upper airways but not by (+)-menthol, the inactive isomer of menthol, or by the TRPM8/TRPA1 agonist icilin administered directly to the trachea. Subsequent molecular analyses confirmed the expression of TRPM8 in a subset of nasal trigeminal afferent neurons that do not coincidently express TRPA1 or TRPV1. We conclude that menthol suppresses cough evoked in the lower airways primarily through a reflex initiated from the nose. PMID- 23640599 TI - A unified survival theory of the functioning of the hypocretinergic system. AB - This article advances the theory that the hypocretinergic (orexinergic) system initiates, coordinates, and maintains survival behaviors and survival-related processes (i.e., the Unified Survival Theory of the Functioning of the Hypocretinergic System or "Unified Hypocretinergic Survival Theory"). A priori presumptive support for the Unified Hypocretinergic Survival Theory emanates from the fact that neurons that contain hypocretin are located in the key executive central nervous system (CNS) site, the lateral hypothalamus, that for decades has been well-documented to govern core survival behaviors such as fight, flight, and food consumption. In addition, the hypocretinergic system exhibits the requisite morphological and electrophysiological capabilities to control survival behaviors and related processes. Complementary behavioral data demonstrate that all facets of "survival" are coordinated by the hypocretinergic system and that hypocretinergic directives are not promulgated except during survival behaviors. Importantly, it has been shown that survival behaviors are selectively impacted when the hypocretinergic system is impaired or rendered nonfunctional, whereas other behaviors are relatively unaffected. The Unified Hypocretinergic Survival Theory resolves the disparate, perplexing, and often paradoxical-appearing results of previous studies; it also provides a foundation for future hypothesis driven basic science and clinical explorations of the hypocretinergic system. PMID- 23640600 TI - Consequences of age-related splanchnic sequestration of leucine on interorgan glutamine metabolism in old rats. AB - Dietary leucine (Leu) serves as a nitrogen donor for de novo glutamine (Gln) synthesis in muscle. However, aging is characterized by an increase in the splanchnic extraction of Leu (SPELeu), i.e., splanchnic sequestration (SSLeu), which may affect muscle Gln metabolism and its subsequent homeostasis at the whole-body level. The aim of the work was to assess the effect of age-related SSLeu on Gln metabolism in the muscle, gut, liver, kidney, and Gln exchanges among these organs during fed conditions. Young-adult (3-mo-old) or aged (24-mo old), male Sprague-Dawley rats were studied during fed condition [infusion of amino acids (AA) into the duodenum from time 0 min (T0) to T60] under anesthesia. L-[5-(15)N]Gln and L[1-(13)C]Leu were infused into the jugular vein and L-[5,5,5 (2)H3]Leu into the duodenum. At T60, blood samples were taken from carotid artery, portal vein, hepatic vein, renal vein, and inferior vena cava for tracer tracee ratio and AA level measurements. SSLeu was observed in old rats and was negatively correlated with muscle Gln production (r = -0.501, P < 0.01). In addition, reduced Gln muscle release in old rats was accompanied by reduced Gln uptake by the gut and kidney. However, net Gln balance across organs was not different between young adult and old rats. During fed conditions in old rats, muscle Gln production and release are reduced in relation to the observed, increased SPELeu and reduced renal and intestinal Gln uptake to maintain whole body Gln homeostasis. Our results demonstrate the existence of an age-related change of interorgan Gln metabolism, which may be, in part, driven by SSLeu. PMID- 23640601 TI - Muscle metabolic determinants of exercise tolerance following exhaustion: relationship to the "critical power". AB - We tested the hypothesis that muscle high-energy phosphate compounds and metabolites related to the fatigue process would be recovered after exhaustion during recovery exercise performed below but not above critical power (CP) and that these changes would influence the capacity to continue exercise. Eight male subjects completed single-leg, knee-extension exercise to exhaustion (for ~180 s) on three occasions, followed by a work-rate reduction to severe-intensity exercise, heavy-intensity exercise (CP conditions (at least 10 min and 39 +/- 31 s, respectively; P < 0.05). During passive recovery and CP recovery exercise, neither muscle [PCr] nor pH recovered, reaching ~37% of the initial baseline and 6.6 +/- 0.2, respectively. These results indicate that the muscle metabolic dynamics in recovery from exhaustive >CP differ according to whether the recovery exercise is performed below or above the CP. These findings confirm the importance of the CP as an intramuscular metabolic threshold that dictates the accumulation of fatigue-related metabolites and the capacity to tolerate high-intensity exercise. PMID- 23640602 TI - A novel recombinant protein of IP10-EGFRvIIIscFv and CD8(+) cytotoxic T lymphocytes synergistically inhibits the growth of implanted glioma in mice. AB - The epidermal growth factor receptor (EGFR) mutant of EGFRvIII is highly expressed on glioma cells and has been thought to be an excellent target molecule for immunotherapy. IP-10 is a potent chemokine and can recruit CXCR3(+) T cells, including CD8(+) T cells that are important for the control of tumor growth. This study is aimed at investigating the therapeutic efficacy of a novel fusion protein of IP10-EGFRvIIIscFv (IP10-scFv) in combination with glioma lysate-pulsed DCs-activated CD8(+) cytotoxic T lymphocytes (CTLs) in a mouse model of glioma. A plasmid of pET-IP10-scFv was generated by linking mouse IP-10 gene with the DNA fragment for anti-EGFRvIIIscFv, a (Gly4Ser)3 flexible linker and a His-tag. The recombinant IP10-scFv in E. coli was purified by affinity chromatography and characterized for its anti-EGFRvIII immunoreactivity and chemotactic activity. C57BL/6 mice were inoculated with mouse glioma GL261 cells in the brain and treated intracranially with IP10-scFv and/or intravenously with CTL for evaluating the therapeutic effect. The glioma-specific immune responses were examined. The IP10-scFv retained anti-EGFRvIII immunoreactivity and IP-10-like chemotactic activity. Treatment with both IP10-scFv and CTL synergistically inhibited the growth of glioma and prolonged the survival of tumor-bearing mice, accompanied by increasing the numbers of brain-infiltrating lymphocytes (BILs) and the frequency of CXCR3(+)CD8(+) T cells, enhancing glioma-specific IFN-gamma responses and cytotoxicity, and promoting glioma cell apoptosis in mice. Our novel data indicate that IP10-scFv and CTL have synergistic therapeutic effects on inhibiting the growth of mouse glioma in vivo. PMID- 23640603 TI - Ex vivo analysis of pancreatic cancer-infiltrating T lymphocytes reveals that ENO specific Tregs accumulate in tumor tissue and inhibit Th1/Th17 effector cell functions. AB - Pancreatic cancer (PC) is an aggressive disease with dismal prognosis. Surgical resection is the recommended treatment for long-term survival, but patients with resectable PC are in the minority (with a 5-year survival rate of 20 %). Therefore, development of novel therapeutic strategies, such as anti-PC immunotherapy, is crucial. alpha-Enolase (ENO1) is an enzyme expressed on the surface of pancreatic cancer cells and is able to promote cell migration and cancer metastasis. The capacity of ENO1 to induce an immune response in PC patients renders it a true tumor-associated antigen. In this study, we characterized the effector functions of ENO1-specific T cells isolated from PC patients, and we specifically evaluated the successful role of intra-tumoral T helper 17 (Th17) cells and the inhibitory role of regulatory T (Tregs) cells in respectively promoting or reducing the cancer-specific immune response. In this ex vivo study, we have demonstrated, for the first time, that ENO1-specific Th17 cells have a specific anti-cancer effector function in PC patients, and that there are decreased levels of these cells in cancer compared to healthy mucosa. Conversely, there are elevated levels of ENO1-specific Tregs in PC patients which lead to inhibition of the antigen-specific effector T cells, thus highlighting a possible role in promoting PC progression. These results may be relevant for the design of novel immunotherapeutic strategies in pancreatic cancer. PMID- 23640605 TI - Occult chronic kidney disease among persons with hypertension in the United States: data from the National Health and Nutrition Surveys 1988-1994 and 1999 2002. AB - OBJECTIVES: Hypertension guidelines recommend screening for chronic kidney disease (CKD) using serum creatinine and urine dipstick; this strategy may lead to misclassification. Persons with occult CKD [i.e. missed by creatinine but detected by cystatin C or albumin-to-creatinine ratio (ACR)] have higher risks for death, cardiovascular events, and end-stage renal disease. METHODS: We studied occult CKD prevalence among nondiabetic, hypertensive adults in National Health and Nutrition Examination Survey 1988-1994 (N = 2088) and 1999-2002 (N = 737). We defined occult CKD as estimated glomerular filtration rate by cystatin C (eGFRcys) less than 60 ml/min per 1.73 m and/or ACR at least 30 mg/g among persons with eGFRcreat more than 60 ml/min per 1.73 m. We studied occult CKD prevalence by either marker, stratified by age, race/ethnicity, and assessed clinical predictors associated with occult CKD presence. RESULTS: In 1988-1994, occult CKD was prevalent among 25% of nondiabetic hypertensive persons, and it was 22% in 1999-2002. Each marker's ability to detect occult CKD varied by age and race. Cystatin C detected occult CKD among 8.9% of persons more than 65 years, and among 3.8% of whites. ACR detected occult CKD among 9.3% of persons less than 45 years, 16.6% of Blacks, and 20.6% of Mexican-Americans. In multivariate models, each decade of advancing age was associated with a higher occult CKD prevalence by cystatin C (OR 3.1, 95% CI 2.5-3.8) in 1988-1994 and 1999-2002 (OR 2.9, 1.8-4.6). CONCLUSION: Current hypertension guidelines may fail to detect a large proportion of high-risk individuals with CKD who can be identified by cystatin C or ACR. Future studies are needed to evaluate targeted use of multimarker renal panels among hypertensives. PMID- 23640604 TI - Sexual activity and function among middle-aged and older men and women with hypertension. AB - OBJECTIVE: To determine the association of hypertension (HTN) and its treatment with sexual function in middle-aged and older adults. METHODS: We studied a nationally representative sample of community-residing adults aged 57-85 years (n = 3005) from the National Social Health, Life and Aging Project. Adults were categorized by HTN status (treated, untreated, and no HTN). Antihypertensive medication use was classified into calcium channel blocker; beta-blocker; angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; diuretic; and alpha-blocker. For each HTN and medication group, we determined the prevalence and adjusted odds of being sexually active and of having any sexual problem. RESULTS: Among men, comparing treated HTN with untreated HTN and no HTN, sexual activity was less prevalent (66.5 vs. 75.9 vs.71.5%, P <0.01) and sexual problems were more prevalent (69.1 vs. 57.7 vs. 54.3%; P <= 0.01). There was no association between treated HTN and sexual activity [odds ratio, OR = 0.86 (95% confidence interval 0.51-1.45)] and a nonsignificant association between treated HTN and sexual problems [OR = 1.49 (0.94-2.37)]. Among women, the prevalence of sexual activity was lower in the treated and untreated HTN groups than the no HTN group (35.2 vs. 38.3 vs. 58.0%, P <0.01); the prevalence of sexual problems was similar (73.7 vs. 65.3 vs. 71.7%; P = 0.301). Women in the treated HTN [OR = 0.61 (0.39-0.95)] and untreated HTN [0.54 (0.30-0.96)] groups had a lower odds of sexual activity compared with no HTN. There were no significant associations between antihypertensive medication class and sexual activity or problems in men or women. CONCLUSION: The relationship between HTN and sexual health is different for older men and women. Prospective, comparative effectiveness trials are needed. PMID- 23640606 TI - Diurnal variation in excitation-contraction coupling is lost in the adult spontaneously hypertensive rat heart. AB - BACKGROUND: Excitation-contraction coupling of the normotensive rat heart exhibits a time-of-day variation in its response to isoproterenol (ISO), with a decrease during the animal's active period. Pressure-induced hypertrophy is known to adversely affect the circadian clock in the heart and this study sets out to determine whether this alters the time-of-day variation in E-C coupling. METHOD AND RESULTS: Hearts from juvenile (6-8 week) and adult (24-28 week) spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats were isolated during the animals active and resting periods. Left ventricular developed pressure (LVDP) recorded from isolated perfused adult SHR hearts did not show the night-time dip in response to ISO that was present in normotensive hearts. Left ventricular myocytes isolated from juvenile WKY and SHRs during the resting period had a higher systolic [Ca]i and faster rate of decay of the Ca- transient, under basal conditions and in response to 10 nmol/l ISO, than the active period. LV-myocytes isolated from adult WKYs had a similar time-of-day variation in their Ca-transient. However, LV-myocytes from adult SHRs had lost this diurnal variation in both basal systolic [Ca]i and in response to ISO. Adult SHR hearts were hypertrophic in comparison to age-matched WKYs, had disrupted cycling of the circadian genes CLOCK and Per2, and this was matched by depressed nNOS cycling. CONCLUSION: The dip in response of the heart to ISO stimulation during the animal's active period is absent in adult SHRs. This may result from disruption to the circadian clock mechanism, which depresses the cycling of nNOS expression. PMID- 23640607 TI - Overexpression of long noncoding RNA PCAT-1 is a novel biomarker of poor prognosis in patients with colorectal cancer. AB - Long noncoding RNAs (lncRNA) are emerging as key molecules in human cancer. Prostate cancer-associated ncRNA transcripts 1 (PCAT-1), a lncRNA, has been recently revealed involving in human prostate cancer progression. However, whether PCAT-1 could serve as novel biomarker to predict prognosis in colorectal cancer (CRC) or not is unknown. We therefore carried out the present study to explore the correlation between PCAT-1 expression and the progression of CRC. In this study, the expression of PCAT-1 in 108 cases of CRC tissues and matched 81 adjacent normal tissues were determined by quantitative real-time PCR. Furthermore, the copy number variation of PCAT-1 was also measured in 17 tumor tissues and matched normal tissues. Our results showed that PCAT-1 expression in CRC tissues was significantly upregulated compared with the matched normal tissues (p < 0.001) and the overexpression of PCAT-1(upregulated by more than 50 %) was found in 64 % (62/81) of CRC. Moreover, PCAT-1 gene copy number variation explains only a few percent of observed overexpression. In addition, there was a significant association between PCAT-1 expression and distant metastasis (p = 0.04), but not other clinical characteristics. More important, CRC patients with PCAT-1 higher expression have shown significantly poorer overall survival than those with lower PCAT-1 expression (p < 0.001). Also, multivariable Cox regression analysis identified PCAT-1 overexpression as an independent prognostic factor for CRC (p = 0.007, HR = 3.12 95 %CI = 1.355-7.185). In conclusion, our results suggest that high expression of PCAT-1 is involved in CRC progression and could be a novel biomarker of poor prognosis in patient with colorectal cancer. PMID- 23640609 TI - Correlation of transient vision loss with outer retinal disruption following intravitreal ocriplasmin. PMID- 23640608 TI - Postoperative peripheral blood monocyte count correlates with postoperative bile leakage in patients with colorectal liver metastases after hepatic resection. AB - PURPOSE: Postoperative bile leakage is one of the most common complications after hepatic surgery. The relationship between the inflammatory response and postoperative bile leakage has not been fully investigated. Therefore, we retrospectively investigated the relation between postoperative peripheral blood monocyte count and bile leakage in patients with colorectal liver metastases (CRLM) after elective hepatic resection. METHODS: The study comprised 105 patients who had undergone hepatic resection for CRLM between January 2000 and March 2012. Perioperative risk factors pertinent to development of bile leakage were investigated using univariate and multivariate analyses. RESULTS: Bile leakage developed in 9 (8.6 %) of 105 patients. In multivariate analysis, intraoperative fresh frozen plasma (FFP) transfusion (p = 0.009) and lower monocyte count of the peripheral blood on postoperative day 1 (p = 0.038) were found as independent risk factors of bile leakage. CONCLUSIONS: Postoperative lower monocyte count and intraoperative FFP transfusion were associated with the development of postoperative bile leakage after elective hepatic resection in patients with CRLM. PMID- 23640610 TI - Medulloepithelioma in DICER1 syndrome treated with resection. PMID- 23640611 TI - Corneal cross-linking service survey in England. PMID- 23640612 TI - Fixed-combination brinzolamide 1%/brimonidine 0.2% vs monotherapy with brinzolamide or brimonidine in patients with open-angle glaucoma or ocular hypertension: results of a pooled analysis of two phase 3 studies. AB - PURPOSE: To describe pooled efficacy and safety data from two phase 3 studies comparing brinzolamide 1%/brimonidine 0.2% fixed combination (BBFC) with its component medications, brinzolamide and brimonidine, in patients with open-angle glaucoma or ocular hypertension. METHODS: Data were pooled from two nearly identical clinical trials comparing BBFC with its component medications, each given three times daily. The 3-month efficacy outcome was mean intraocular pressure (IOP) at 0800, 1000, 1500, and 1700 hours. Safety outcomes included adverse events (AEs), best-corrected visual acuity, examination of ocular structures, pachymetry, perimetry, and vital signs. RESULTS: A total of 1350 patients were enrolled and included in this analysis (BBFC, n=437; brinzolamide, n=458; brimonidine, n=455). Baseline mean IOP levels were similar among the three treatment groups. At 3 months, mean IOP of the BBFC group was significantly lower than that of either monotherapy group (P<0.0001) at all the four time points. A total of 272 patients (20.1%) experienced at least one treatment-related AE (BBFC, 24.6%; brinzolamide, 18.7%; brimonidine, 17.4%), the majority of which were ocular AEs. One serious AE, moderate intensity chest pain, was considered related to brinzolamide treatment and resulted in study discontinuation. CONCLUSIONS: This analysis strengthens the conclusions drawn from the two individual phase 3 studies showing that, in patients with open-angle glaucoma or ocular hypertension, BBFC had significantly superior IOP-lowering activity compared with either brinzolamide or brimonidine alone and a safety profile consistent with that of its individual components. PMID- 23640613 TI - In vivo confocal microscopy detects preclinical corneal lattice dystrophy. PMID- 23640614 TI - Combined subconjunctival and subscleral ologen implant insertion in trabeculectomy. PMID- 23640615 TI - Copper silicide/silicon nanowire heterostructures: in situ TEM observation of growth behaviors and electron transport properties. AB - Copper silicide has been studied in the applications of electronic devices and catalysts. In this study, Cu3Si/Si nanowire heterostructures were fabricated through solid state reaction in an in situ transmission electron microscope (TEM). The dynamic diffusion of the copper atoms in the growth process and the formation mechanism are characterized. We found that two dimensional stacking faults (SF) may retard the growth of Cu3Si. Due to the evidence of the block of edge-nucleation (heterogeneous) by the surface oxide, center-nucleation (homogeneous) is suggested to dominate the silicidation. Furthermore, the electrical transport properties of various silicon channel length with Cu3Si/Si heterostructure interfaces and metallic Cu3Si NWs have been investigated. The observations not only provided an alternative pathway to explore the formation mechanisms and interface properties of Cu3Si/Si, but also suggested the potential application of Cu3Si at nanoscale for future processing in nanotechnology. PMID- 23640616 TI - ABO-Incompatible kidney transplantation. AB - HLA sensitization and ABO incompatibility continue to pose a significant barrier to expansion of living donation. In fact, either anti-blood or anti-donor HLA antibodies result in the occurrence of hyperacute rejection and graft loss. Reducing this early rejection risk by planned desensitization protocols has clearly improved the outcome of ABO-incompatible (ABOi) kidney transplantation. B cell depletive therapy has replaced splenectomy, overcoming the disadvantages of the latter. Plasma exchange techniques have considerably reduced antibody titers, allowing better results. Thus, newer immunosuppressive protocols reduced early graft loss and early rejections episodes and, consequently, improved the long term graft survival. Therefore, ABOi kidney transplantation can be more broadly practiced, especially to expand the pool donor and to reduce the waiting time for transplantation. PMID- 23640617 TI - Basiliximab induction in renal transplantation: long-term outcome. AB - Anti-IL-2 receptor has been proven to be effective in reducing the rate of acute rejection in kidney transplantation and also in improving the graft and patient survival rates. In this study, we retrospectively reviewed the role of the anti IL-2 receptor, basiliximab, as an induction immunosuppression. Fifty-seven kidney transplant recipients from living donors who received the IL-2 blocker basiliximab (Group 1) as induction therapy in combination with cyclosporine (CsA), steroids and mycophenolate mofetil (MMF) or azathioprine (AZA) were compared with similarly matched renal transplant recipients (N = 312) who did not receive induction therapy (Group 2). Survival analysis was performed using the Kaplan-Meir method. Chi-square test was used to compare the outcome difference of various parameters between the two groups. Both the groups were similar in terms of demographic characteristcs and maintenance immunosuppression used. The total number of rejections was significantly less in Group 1, 14% vs 25% in Group 2 (P = 0.04, Odds ratio = 0.44). A higher number of patients in Group 2 had steroid resistant rejections, although the difference was not statistically significant (9.9% in Group 2 vs 5.3% in Group 1). Death-censored graft survival was not significantly better in Group 1 at five years as compared with Group 2 (79.4% vs 47.2%, P = 0.09). On multivariate analysis for association with graft survival, only late acute rejections and steroid-resistant rejections were independently associated with poor graft survival, while the type of maintenance immuno suppression (MMF vs AZA), use of basiliximab induction therapy and total number of acute rejection episodes had no association. Our study suggests that the use of anti-IL-2 receptor antibody basiliximab as induction immuno-suppression results in significantly better prevention of acute rejection, but it does not result in a significantly improved graft survival at five years. It also results in reduced severity of acute rejection. PMID- 23640618 TI - Transcription factor activity profile of acute rejection after kidney transplantation. AB - Transcription factors (TFs) play a central role in regulating gene expression and in providing an interconnecting regulatory between related pathway elements. Currently, the wide-spread use of kidney transplantation to treat end-stage renal disease has evolved rapidly since the initial successful transplantations from both cadaveric and living donors. However, acute rejection is still a strong risk factor for chronic rejection in recipients of renal grafts. To investigate the possible mechanisms, we describe a comparison between TF' activity profile of acute rejection and controls. Through TF assay analysis and electrophoretic mobility shaft assay confirmation, we identified the activities of TFs in acute rejection after kidney transplantation. From a total of 345 screened TFs, 99 activity-differential TFs were found, of which 95 showed increased activity and four showed decreased activity. Our data indicate that TFs may be potentially involved in the pathogenesis of acute rejection, and can help to prevent, diagnose and treat acute rejection after kidney transplantation. The TF array methods could simplify the assay of multiple TFs and may facilitate high throughout profiling of large numbers of TFs. PMID- 23640619 TI - Small intestinal involvement by lymphoproliferative disorders post-renal transplantation: a report from the post-transplant lymphoproliferative disorder international survey. AB - In this study, data on post-renal transplant lymphoproliferative disorders (PTLD) collected from the existing literature were pooled and analyzed to compare the characteristics, predictors and prognosis of small intestinal PTLDs. We performed a comprehensive search for the available data by Pubmed and Google scholar search engines for reports on this subject. Data from 18 previously published studies, comprising 120 renal allograft recipients, were included in the analysis. Renal transplant recipients with intestinal PTLD were significantly less likely to have Hogkin's and Hogkin's-like lesions (P = 0.044) and to be younger at the time of transplantation (P = 0.07). Except for Hodgkin's-like lesions, histopathological evaluations elsewhere were comparable between the group with PTLD in the small intestine and age- and sex-matched renal transplant recipients with PTLD in other sites. The overall mortality was relatively higher in the control group (P = 0.09). When death only due to PTLD was used as the outcome, a trend toward better outcome was seen for the intestinal PTLD group compared with the other localizations (P = 0.1). The 1- and 5-year survival rates for intestinal PTLD patients were 57% and 37%, respectively, compared with 54% and 21%, respectively, for the control group. According to our findings based on analysis of international data, renal transplant patients with small intestinal PTLD are more likely to be of younger age but less frequently represent Hodgkin's and Hodgkin's like lesions. They also have better patient survival compared with transplant recipients with PTLD in other locations. Further multi-center prospective studies are needed to confirm our results. PMID- 23640620 TI - Significance of panel reactive antibodies in patients requiring kidney transplantation. AB - Presence of antibodies against human leukocyte antigen (HLA) molecules, which may be may be directed against HLA class I or/and class II antigens, is a known risk factor for acute rejections and graft loss. Pre-transplantation panel reactive antibody (PRA) estimation is done to identify sensitized patients prior to solid organ transplantation and also forms the basis of cadaver organ allocation. The aim of this study is to evaluate the PRA in 52 patients awaiting first renal transplant, identify various factors contributing to high PRA, and observe its influence on graft survival. This was a case control study performed in a tertiary care hospital. Eighty-five samples including 63 from 52 patients with end-stage renal disease (ESRD), 10 from healthy volunteers, and 12 from presumed sensitized individuals were tested for class I and/or II PRA by enzyme-linked immunosorbent assay (ELISA) using Quik ID (r) GTI kits. PRA for both class I and II was zero in all healthy controls and 19/46 (37%) patient samples; while individually, PRA class I and II were zero in 32/60 (53%) and 39/45 (86.3%) samples, respectively. PRA exceeded 10% in 16 samples from 12 patients with peak class I and II PRA of 100% and 46%, respectively. Post-transplantation, 27/31 patients are doing well, while four died with a functioning graft. Patient reactivity to antigen stimulation is the most important factor determining the PRA levels, and class I PRA is more relevant for detection of sensitization in first-time recipients and adversely affects the graft outcome. PMID- 23640621 TI - Prevalence and associated risk factors of male erectile dysfunction among patients on hemodialysis and kidney transplant recipients: a cross-sectional survey from Sudan. AB - Male erectile dysfunction (ED) is an important issue worldwide occurring in 5-69% of men in community-based studies. It is more common in patients with chronic kidney disease (CKD) and those on peritoneal as well as hemodialysis (HD), occurring in more than 80% of patients. In Sudan, there is no previous report on ED among patients with CKD. A cross-sectional study was done to determine the prevalence of ED and its associated risk factors among Sudanese CKD patients on HD and those who underwent renal transplant. This was conducted in Khartoum, Sudan from October 2005 to July 2006 including all married men who were on maintenance HD for more than three months and all married men who had received renal transplantation at least three months earlier. Single, divorced/separated men, those whose wives were living away, those who were bed-bound and those with cognitive impairment were also excluded. After obtaining consent for participation, demographic and clinical data were collected by using anonymous questionnaires and the Arabic version of International Index of Erectile Function (IIEF; the Egyptian version). Patients who did not participate in full and proper manner were considered as "non-responders." A total of 146 patients, 106 HD patients, and 40 renal transplant recipients completed the IIEF questionnaire. Non-responders constituted 43.7% and 54.5% of HD and transplant recipient patients, respectively. Blood samples were taken after completion of the IIEF questionnaire to determine the required investigations. ED prevalence was high among our study patients, 83% among the HD patients and 67.5% among the renal transplant recipients. Univariate analysis showed that there was a trend, although non-significant, of older age being associated with ED in both groups. Similar association was seen in those who were under-dialyzed in the HD group and DM in the transplant recipient group. Previous history of ED was significantly associated with current presence of ED in both groups. More studies with larger sample size are needed to clarify the results of this study. PMID- 23640622 TI - Outcome of individualized dialysate sodium concentration for hemodialysis patients. AB - To evaluate the individualization of dialysate sodium (Na + ) concentration in hemodialysis (HD), we studied 40 stable chronic HD patients in a single-blind crossover design. They underwent 36 consecutive HD sessions with the dialysate Na + concentration set at 138 mmol/L, followed by 36 sessions of dialysate Na + set to match the patients average pre-HD plasma Na + levels. We multiplied the midweek pre-HD measured Na + by the Donnan coefficient of 0.95 (individualized Na + ). Pre-HD Na + dialysis sodium levels were nearly constant, with no variation between the two phases and a mean of 137.45 +/- 2.04 mmol/L. Post-HD serum Na + was significantly higher during the standard phase (139.7 +/- 2 mmol/L) than during the individualized phase (137.1 +/- 1.6 mmol/L). Also, interdialytic weight gain (IDWG) was significantly more reduced during the individualized phase (3.25 +/- 0.56%) than during the standard phase (3.94 +/- 0.92%), P <0.001. Episodes of distressing symptoms including headache, muscle cramps and hypotension were significantly less frequent in the individualized phase. The mean of the pre-HD and post-HD systolic and diastolic blood pressures significantly decreased during the individualized phase, and we could reduce the doses of antihypertensive drugs in 10 (33.33%) patients. Individualized dialysate Na + concentration was associated with a decrease in IDWG and dialysis hypotension and related symptoms and better BP control in stable chronic HD patients. PMID- 23640624 TI - Health-related quality of life in patients on hemodialysis and peritoneal dialysis. AB - Chronic kidney disease (CKD) is a worldwide public health problem, and its treatment imposes a considerable burden on patients and their families. Limitations in everyday activity may worsen the situation and affect the health related quality of life (HRQOL) of patients with CKD. There are no studies on the HRQOL of dialysis patients in South Africa. We assessed the HRQOL of patients undergoing hemodialysis (HD) and continuous ambulatory peritoneal dialysis (PD) attending the Groote Schuur Hospital renal unit by using the Kidney Disease Quality of Life-Short Form version 1.3 questionnaire. Baseline demographic and clinical details of the participants were recorded. Analysis was performed (unpaired t test and univariate analysis) to compare the HRQOL between HD and PD patients and to identify factors influencing HRQOL. The HRQOL was low but not significantly different between HD and PD patients. In PD patients, the use of erythropoiesis-stimulating agents (ESA) significantly contributed to the emotional well-being (r 2 = 0.267; P = 0.01) and alleviation of pain (r 2 = 0.073; P = 0.049); in HD patients also, ESA use was associated with emotional well-being (r 2 = 0.258; P <0.0001) as well as improvement in energy/fatigue (r 2 = 0.390; P <0.0001). Systolic and diastolic blood pressures significantly influenced cognitive function in PD patients (P <0.05). Parathyroid hormone level significantly influenced the physical functioning and energy/fatigue domains in HD patients (P <0.0001). Serum ferritin (r 2 = 0.441; P = 0.002) and level of hemoglobin concentration (r 2 = 0.180; P = 0.006) were significantly associated with the domain role emotional in PD and HD patients, respectively. Although HRQOL is low in dialysis patients in Cape Town, the factors that have been identified to be associated with these scores (such as anemia and hyperparathyroidism) if aggressively managed and corrected may assist in improving patients' HRQOL. PMID- 23640623 TI - Quality of life and sleep in hemodialysis patients. AB - The purpose of this study was to determine the quality of life and sleep of chronic hemodialysis (HD) patients. Quality of sleep was measured using the Pittsburgh Sleep Quality Index (PSQI) and quality of life (QoL) was measured using the Medical Outcomes Study 36-item Short Form (SF-36) in 115 HD patients. One hundred (87%) patients were "poor sleepers" (global PSQI >=5). The SF-36 mental component summary and physical component summary (PCS) scores were higher than 50 only in 43% and 32% of the subjects, respectively. No significant differences were found in QoL and sleep according to the patient's gender, presence of diabetes and time on HD. Correlation between total SF-36 score and global PSQI was statistically significant (r = -0.227, P <0.05). Poor sleep is common in dialysis patients and is associated with lower QoL, especially with mental health component of life quality. PMID- 23640625 TI - Dialysis for acute kidney injury associated with influenza a (H1N1) infection. AB - In June 2009, the World Health Organization declared a novel influenza A, S-OIV (H1N1), pandemic. We observed 44 consecutive patients during the "first wave" of the pandemic. 70.5% of them showed co-morbidities (hypertension, obesity, chronic respiratory diseases, chronic renal disease, diabetes, pregnancy). Serious cases were admitted to the intensive care unit (ICU), particularly those with severe acute respiratory failure. Some of them developed acute kidney injury (AKI) and required renal replacement therapy (RRT). The average time between admission to the ICU and initiation of RRT was 3.16 +/- 2.6 days. At initiation of RRT, most patients required mechanical ventilation. No relationship was found with creatinine-kinase levels. Seventy-five percent of the cases were observed during a 3-week period and mortality, related to respiratory failure, doubling of alanine amino transferase and use of inotropics was 81.8%. In conclusion, the H1N1-infected patients who developed RRT-requiring AKI, in the context of multi organ failure, showed a high mortality rate. Thus, it is mandatory that elaborate strategies aimed at anticipating potential renal complications associated to future pandemics are implemented. PMID- 23640626 TI - Screening for chronic kidney diseases among an adult population. AB - Chronic kidney disease (CKD) is now one of the major health problems all over the world and its early screening is vital to prevent the development of end-stage renal failure. This study was designed to evaluate the proportion of urban adults suffering from CKD as well as to have a preliminary idea about the determinants of this disorder. The screening program for CKD was arranged in a public place in Dhaka city, Bangladesh, and involved 634 adult participants (>18 years of age) selected on first-come first-served basis. Socio-demographic, anthropometric, and clinical data were collected. Urinary protein was tested by the dipstick method, and serum glucose and creatinine were measured by an auto-analyzer. Estimated glomerular filtrate rate (eGFR) was calculated by using standard formula. CKD was diagnosed and classified according to the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines. A total of 12.8% of the subjects were found to have CKD of whom 2.7% were in Stage 1, 4.1% in Stage 2, and 6% were in Stage 3. The proportion was strongly influenced by age, with the highest prevalence (38.5%) found at 60 years and above. The CKD group showed higher body mass index, waist-hip ratio, and systolic blood pressure, compared with their non-CKD counterparts (P = 0.02). On multiple regression analysis (after adjustment of some confounding variables), age, random blood sugar, and education showed significant association with the development of CKD. A substantial number of urban adults in Dhaka were found to be unaware about the existence of CKD and large-scale prevention programs should be undertaken to reduce the classical risk factors of these disorders. PMID- 23640627 TI - The impact of donor myelofibrosis on outcome of renal transplantation. AB - In donors known to have medical conditions associated with kidney damage, caution is exercised when accepting donor kidneys. Myelofibrosis can affect kidney function in a variety of ways, but is not generally considered a contraindication to donation. We present the case of a 27-year-old woman with known myelofibrosis who died from an upper gastrointestinal bleed. After cardiac death, both the kidneys were donated. The first recipient was a 34-year-old lady with focal segmental glomerular sclerosis in her single pelvic kidney. There was delayed graft function and the kidney continued to function poorly due to a significant donor vascular disease. The second recipient was a 27-year-old man with posterior urethral valves. Similar donor vascular disease caused this transplant to fail. The kidney damage did not fit any pattern reported in myelofibrosis, but may represent part of a spectrum of damage seen with this disease. This case highlights the need for caution when accepting kidneys from donors with chronic medical conditions even when young, and may be of use to transplant teams when considering accepting future donations from patients with myelofibrosis. PMID- 23640628 TI - Severe acute post-streptococcal glomerulonephritis in an infant. AB - Acute post-streptococcal glomerulonephritis (APSGN) is very rare below the age of two years. We report a 14-month-old girl who presented with frank hematuria and nephrotic syndrome following group A streptococcal pharyngitis (GAS), which was confirmed by laboratory investigations. The patient underwent a renal biopsy to confirm the diagnosis and was treated with prednisolone. The proteinuria and hematuria resolved completely in eight weeks. Our case demonstrates that APSGN should be considered in evaluating hematuria and nephrotic syndrome in infants and children below two years of age. PMID- 23640629 TI - Post-partum bilateral renal cortical necrosis in antiphospholipid syndrome and systemic lupus erythematosus. AB - In the presence of systemic lupus erythematosus or related autoimmune disorders, antiphospholipid syndrome (APS) is termed secondary APS. Pregnancy-related renal failure due to SAPS is rarely reported in the literature. We present the case of a young primgravida woman with bilateral renal cortical necrosis due to secondary APS in late pregnancy. PMID- 23640630 TI - Acute renal failure and intravascular hemolysis following henna ingestion. AB - The powder of henna plant (Lawsonia inermis Linn.) is extensively used as a decorative skin paint for nail coloring and as a hair dye. Most reports of henna toxicity have been attributed to adding a synthetic dye para-phenylenediamine (PPD). PPD is marketed as black henna added to natural henna to accentuate the dark color and shorten the application time. PPD toxicity is well known and extensively reported in medical literature. We report a case of a young Saudi male who presented with characteristic features of acute renal failure and intravascular hemolysis following ingestion of henna mixture. Management of PPD poisoning is only supportive and helpful only if instituted early. Diagnosis requires a high degree of clinical suspicion, as the clinical features are quite distinctive. PMID- 23640631 TI - Mucinous tubular and spindle cell carcinoma of the kidney with sarcomatoid transformation. AB - Mucinous tubular and spindle cell carcinoma (MTSCC) of the kidney is a recently described entity in the World Health Organization (WHO) 2004 classification and has a relatively indolent behavior. Sarcomatoid differentiation has been well documented in most histologic variants of renal cell carcinoma and its presence is known to have a worse prognosis. Its occurrence in an otherwise benign MTSCC is extremely rare. Here, we report a unique case of MTSCC in a 64-year-old patient with multiple areas of high-grade spindle cells and large areas of necrosis in it. The patient had a rapidly fatal clinical outcome. PMID- 23640632 TI - Cerebral calcification, osteopetrosis and renal tubular acidosis: is it carbonic anhydrase-II deficiency? AB - Carbonic anhydrase-II deficiency is an autosomal recessive disorder with a triad of cerebral calcification, osteopetrosis and renal tubular acidosis (often combined proximal and distal). Mental retardation, growth failure, complications of osteopetrosis and other features were all recorded in this syndrome. We present a case of an Iraqi male with all these features and a positive family history. PMID- 23640633 TI - Unusual presentation of renal vein thrombosis with pulmonary artery embolism. AB - A young 23-year-old male patient presented with a two-day history of right flank pain. He had no history of any significant illnesses in the past. His investigations showed nephrotic range proteinuria with hypoalbuminemia. The patient developed cough and shortness of breath after having a left kidney biopsy. He did not respond to regular respiratory tract infection treatment. The kidney biopsy revealed membranoproliferative glomerulonephritis. Further investigations for the cough showed thromboembolism of the posterior and lateral basal segments of the right lower lobe. Moreover he was found to have thrombosis of the right upper pole renal vein. The patient was started on full anticoagulation along with three days pulse steroid, followed by 1 mg/kg oral steroid. Clinical improvement was noticed within 48 h. After eight weeks the proteinuria decreased from 8.5 gm/day to 1.1 gm/day. The kidney function was normal with eGFR 145 mL/min through the course of the disease. This case represent one of the unusual presentation of nephrotic syndrome with pulmonary and renal vascular thromboembolic events. The response to the combination of anticoagulation and steroid was remarkable. PMID- 23640634 TI - Acute renal failure by ingestion of Euphorbia paralias. AB - Euphorbia paralias is known in traditional medicine as an anti-inflammatory agent, a purgative and for its local anesthetic property. To the best our knowledge, renal toxicity of this substance has not been previously reported. In this paper, we report the case of a 29-year-old male who developed renal damage following ingestion of Euphorbia paralias. He had been on follow-up for nephrotic syndrome since 1986, although irregularly, with several relapses but each responding well to steroid therapy. A kidney biopsy had not been performed earlier due to refusal by the patient. He was off steroids since April 2008 because the patient developed osteoporosis. He was admitted with general malaise and oliguria to our department in May 2009, following repeated vomiting and watery diarrhea for three days. On examination, he was edematous but had normal vital signs except for a pulse rate of 120/min. Hemoglobin was only 5.5 g/dL but with normal white cell and platelet counts. Blood biochemistry showed evidence of advanced renal failure with a serum creatinine level of 1835 MUmol/L and urea at 44.6 mmol/L, sodium of 132 MUmol/L and potassium at 4.3 mmol/L. He had features of nephrotic syndrome with severe hypoproteinamia and 24-h urinary protein of 10.45 g. Ultrasonography revealed enlarged kidneys with a reduced echogenecity of the medulla and the papillae. Subsequently, after hemodialysis with blood transfusion, a kidney biopsy was performed that showed focal segmental glomerulosclerosis associated with an acute tubular injury. On intensive interrogation, the patient gave a history of ingesting boiled Euphorbia paralias as a native treatment for edema, ten days prior to the onset of the current illness. A diagnosis of acute renal failure (ARF) resulting from the possible nephrotoxic effect of Euphorbia paralias poisoning was made. He was treated with intermittent hemodialysis and corticosteroids. Serum creatinine values improved after 48 days. At six months following the intoxication, serum creatinine of the patient was 240 MUmol/L. In cases of unexplained ARF, a toxic mechanism should always be considered and acute renal failure caused by Euphorbia paralias should be included as a cause if renal toxicity is suspected in those places where it is being used as a native medicine. PMID- 23640635 TI - Mucormycosis after kidney transplantation. PMID- 23640636 TI - Favorable outcome of living donor kidney transplantation following use of grafts with multiple renal arteries. PMID- 23640637 TI - Fatal outcome due to sirolimus-induced acute hepatitis, myelosuppression and fever in a kidney allograft recipient. PMID- 23640638 TI - Morbidity and mortality in Tunisian patients with post-transplant diabetes mellitus. PMID- 23640639 TI - Hepatitis B virus infection: need for more attention in hemodialysis patients. PMID- 23640640 TI - Response to steroids in early-onset nephrotic syndrome. PMID- 23640641 TI - Acute kidney injury in endosulfan poisoning. PMID- 23640642 TI - Regional disparities in etiology of end-stage renal disease in Africa. PMID- 23640643 TI - The role of interleukin-23/interleukin-17 axis in coexisting anti-glomerular basement membrane disease and lupus nephritis. PMID- 23640644 TI - Another face of type-1 diabetes. PMID- 23640645 TI - Risk factors for renal scarring in children with primary vesicoureteral reflux disease. PMID- 23640646 TI - Bilateral ureterocystoplasty: a new technique for augmentation of bladder in transplant patients. PMID- 23640647 TI - Fate of patients during the first year of dialysis. AB - Care in dialysis is often associated with significant morbidity and mortality during the first year. Knowledge of its magnitude and causes could improve the prognosis of these patients. The aim of this study was to evaluate the survival and morbidity during the first year of dialysis for patients who initiated their dialysis between January 1, 2009 and December 31, 2009 and to study their possible correlation with baseline status at the beginning of treatment. A multi center retrospective study was conducted in 11 dialysis centers. Clinical data at the beginning of dialysis and during the following year were collected. Mortality and morbidity risk factors were assessed by comparing different groups. Statistical analysis was performed with SPSS version 11. This study involved 134 patients, 79 men and 55 women, of whom 132 were on hemodialysis and two patients were on peritoneal dialysis. The mean age at initiation of treatment was 54.37 +/ 18.09 years. Initial causes of nephropathy were dominated by diabetes (44.02%) and hypertension (11.19%). Among these patients, 39.55% had never received prior nephrological follow-up and 64.92% had started renal replacement therapy on an emergency basis. The initial clinical state was dominated by the presence of hypertension (50.74%), diabetes (44.02%), coronary insufficiency (13.43%) and heart failure (7.46%). Only 26.86% of the incident patients showed no comorbidity. During the first year of follow-up, 37.31% of the patients experienced at least one episode of comorbidity. Hospitalization was necessary in about half of these cases (17.91% of all patients). The overall mortality rate was 14.17%. One patient received a kidney transplant. The mortality rate in the first year of dialysis was lower in our study than in other series. Regular nephrological follow-up of these patients before they reach end-stage could have a significant influence on survival in dialysis. PMID- 23640648 TI - The relation between stone disease and obesity in Jordan. AB - Obesity forms a growing challenge in medicine worldwide. In Jordan, the obese and the overweight population form 49.7% of the total population. The latest national male to female ratio in Jordan is 1:1.06. There is a relation between obesity and renal stone formation. This study is conducted to study the relation of renal stone and obesity in the Jordanian population. All patients with urolithiasis that attended the urology clinic at Prince Hussein Bin Abdullah Urology Center at King Hussein Medical Center, Jordan, over the period from January 2006 to January 2011 were included in the study and analyzed for age, gender, body weight, number of visits to the clinic and number of procedures. Over a period of 60 months from January 2006 through January 2011, 8346 patients were treated for urolithiasis. The median age was 43.2 years. The male to female ratio was 1.46:1. 42.3% of the patients were obese, with body mass index (BMI) >30 kg/m 2 and 25.8% of the patients were overweight, with BMI >25 kg/m 2 . The normal body weight population formed 31.9% of the total population. The majority of our urolithiasis patients were obese and overweight, forming 68.1% of the population, with a higher number of clinical visits and higher number of surgical procedures. In the Jordanian population, there is a clear relation between obesity and stone formation, where the majority of stone formers was obese. PMID- 23640649 TI - The outcome of living related kidney transplantation with multiple renal arteries. AB - The aim of our study was to compare the surgical complications and short-term outcome of renal transplants with single and multiple renal artery grafts. We reviewed the records of 105 kidney transplantations performed consecutively at our institution from July 2006 to May 2010. The data of 33 (31.4%) renal transplants with multiple arteries were compared with the 72 transplants with single artery (68.6%), and the incidence of surgical complications, post transplant hypertension, acute tubular necrosis, acute graft rejection, mean creatinine level, and patient and graft survival was analyzed. We further subdivided the study recipients into three groups: group A (n = 72) with one renal-artery allografts and one-artery anastomosis, group B (n = 6) with multiple artery allografts with single-artery anastomosis, and group C (n = 27) with multiple-artery allografts with multiple arterial anasatomosis, and compared their outcome. No significant differences were observed among the recipients of all the three groups regarding early vascular and urological complications, post transplant hypertension, acute tubular necrosis, acute rejection, creatinine level, and graft and patient survival. The mean cold ischemia time in groups B and C was significantly higher (P <0.05). One patient in group A developed renal vein thrombosis resulting in graft nephrectomy. None of the patients with multiple renal arteries developed either vascular or urological complications. In conclusion, kidney transplantation using grafts with multiple renal arteries is equally safe as using grafts with single renal artery, regarding vascular, urological complications, as well as patient and graft survival. PMID- 23640650 TI - Renal involvement in sepsis: a prospective single-center study of 136 cases. AB - Acute kidney injury (AKI) is an independent risk factor for mortality in sepsis syndrome. Few Indian studies have focused on describing the epidemiology of sepsis with AKI. Adult patients with sepsis-induced AKI were evaluated for the clinical characteristics and outcome and to correlate various parameters associated with sepsis to the outcome of patients. This prospective study included 136 patients with sepsis-induced AKI between 2007 and 2009. All patients required renal replacement therapy. Males comprised 44% of the patients while 56% were females; their mean age was 38.6 years. When we compared the survivor and non-survivor groups, it was found that mortality was associated with delayed presentation (6.8 vs 9.4 days), presence of hypotension (132/80 vs 112/70 mmHg), oliguria (300 vs 130 mL), anemia (8 vs 9.3 gm/dL), prolonged prothrombin time (15 vs 29 s) and activated partial thrombin time (38 vs 46 s), creatinine (7.8 vs 6.4 mg/dL), blood urea (161 vs 135 mg/dL), higher D-dimer (1603 vs 2185), short hospital stay (27.9 vs 8.3 days), number of hemodialysis sessions (11.9 vs 6 times), need for vasopressors (14% vs 52%) and ventilator (7.2% vs 75%) and higher Sequential Organ Failure Assessment (SOFA) score (6.7 vs 11.4) (P <0.05). The most com-mon source of infection in this study was urogenital tract (34%). About 51.4% showed complete recovery of renal function. The overall hospital mortality rate was 38.9%. Less than 10% of the patients developed impaired renal function following septic AKI. In conclusion, the most common renal manifestation of sepsis was AKI, which is a risk factor for mortality in sepsis syndrome. SOFA score >11 and multi-organ dysfunction are the risk factors for mortality. PMID- 23640651 TI - Twenty-four-hour urine constituents in stone formers: a study from the northeast part of Peninsular Malaysia. AB - Urolithiasis is a common disease with increasing incidence and prevalence world wide, probably more common in industrialized countries. The metabolic evaluation of 24-h urine collection has been considered as part of the management of urinary stone patients. The aim of this study was to evaluate the 24-h urine constituents in stone formers and its relation to demographic data in the northeast part of Peninsular Malaysia. One hundred and six patients were recruited in this study from two hospitals in the same geographical region; 96 patients fulfilled the inclusion criteria and an informed consent was obtained from all subjects. The 24 h urine was collected in sterile bottles with a preservative agent and calcium, oxalate, citrate, uric acid, magnesium and phosphate were tested using commercial kits on a Roche Hitachi 912 chemistry analyzer. The age (mean +/- SD) of 96 patients was 56.45 +/- 13.43 years and 82.3% of the patients were male while 17.7% were female. The 24-h urine abnormalities were hypercalciuria (14.5%), hyperoxaluria (61.4%), hypocitraturia (57.2%), hyperuricouria (19.7%), hypomagnesuria (59.3%) and hyperphosphaturia (12.5%). Hyperoxaluria (61.4%) was the most common abnormality detected during the analysis of 24-h urine constituents in contradiction to industrial countries, where hypercalciuria was the most common finding. The high frequencies of hypomagnesuria and hypocitraturia reflect the important role of magnesium and citrate in stone formation and their prophylactic role in the treatment of urinary stone disease in the given population. PMID- 23640652 TI - Prospective predictors of unprotected anal intercourse among HIV-seropositive men who have sex with men initiating antiretroviral therapy. AB - Contemporary HIV prevention efforts are increasingly focused on those already living with HIV/AIDS (i.e., "prevention with positives"). Key to these initiatives is research identifying the most risky behavioral targets. Using a longitudinal design, we examined socio-demographic and psychosocial factors that prospectively predicted unprotected anal intercourse (UAI) in a sample of 134 HIV seropositive men who have sex with men (MSM) initiating, changing, or re-starting an antiretroviral therapy regimen as part of a behavioral intervention study. Computer-based questionnaires were given at baseline and 6 months. In a sequential logistic regression, baseline measures of UAI (step 1), socio demographic factors such as Latino ethnicity (step 2), and psychosocial factors such as crystal methamphetamine use, greater life stress, and lower trait anxiety (step 3) were predictors of UAI at 6 months. Problem drinking was not a significant predictor. Prevention efforts among MSM living with HIV/AIDS might focus on multiple psychosocial targets, like decreasing their crystal methamphetamine use and teaching coping skills to deal with life stress. PMID- 23640653 TI - Context matters: the moderating role of bar context in the association between substance use during sex and condom use among male clients of female sex workers in Tijuana, Mexico. AB - Tijuana is situated on Mexico's northern border with the U.S., where sex work is quasi-legal. Whereas previous work has focused on the risk behaviors of female sex workers (FSWs), less is known about the risk behaviors of their male clients. Further, research has not examined structural factors as moderators of the association between substance use and condom use, including the contexts in which sex takes place. The purpose of the current study is to examine whether having sex with FSWs in a bar moderates the link between alcohol intoxication during sex and condom use. We recruited 375 male clients of FSWs in Tijuana, Mexico from San Diego, California and Tijuana. Using computer assisted interviewing, we surveyed participants on their alcohol use, condom use, and physical contexts of sex with FSWs in the past 4 months. Results showed that more frequent intoxication during sex with FSWs is associated with more unprotected sex, but only among clients having sex with FSWs in a bar context. Results point to potential reasons for inconsistent condom use with FSWs in this context, including lower risk perceptions of sex with FSWs in bars. Future research should examine structural factors that underlie clients' risk behavior in bars in order to inform structural-level HIV prevention interventions. PMID- 23640655 TI - Synthesis and evaluation of an 18F-labelled norbornene derivative for copper-free click chemistry reactions. AB - The copper-free click chemistry reaction between norbornene and tetrazine species is known to proceed in a rapid, reliable and selective manner under mild conditions. Due to these attractive properties, this reaction has recently been explored as a generally applicable method of bioconjugation. Here, we report a convenient synthetic procedure towards a novel (18)F-labelled norbornene derivative ([(18)F]NFB) and have evaluated its ability to undergo strain-promoted copper-free click chemistry reactions with two model tetrazine species: an asymmetric dipyridyl tetrazine derivative (Tz) and a tetrazine thiourea-coupled stabilised bombesin peptide (TT-BBN). In both cases, [(18)F]NFB was found to undergo rapid and high-yielding click chemistry reactions. Furthermore, as reactions of this type could also potentially be used in vivo to facilitate the development of a novel pretargeting approach for tumour imaging and therapy, we have also assessed the radiopharmacological profile (bioavailability, biodistribution, blood clearance and metabolic stability) of [(18)F]NFB in normal BALB/c mice. This radiolabelled compound exhibits both high bioavailability and metabolic stability with approximately 90% remaining intact up to 30 min following administration. PMID- 23640654 TI - Dual HIV risk: receptive syringe sharing and unprotected sex among HIV-negative injection drug users in New York City. AB - HIV-negative injection drug users (IDUs) who engage in both receptive syringe sharing and unprotected sex ("dual HIV risk") are at high risk of HIV infection. In a cross-sectional study conducted in New York City in 2009, active IDUs aged >=18 years were recruited using respondent-driven sampling, interviewed, and tested for HIV. Participants who tested HIV-negative and did not self-report as positive were analyzed (N = 439). Adjusted odds ratios (aOR) and 95 % confidence intervals (95 % CI) were estimated using multinomial logistic regression. The sample was: 77.7 % male; 54.4 % Hispanic, 36.9 % white, and 8.7 % African American/black. Dual risk was engaged in by 26.2 %, receptive syringe sharing only by 3.2 %, unprotected sex only by 49.4 %, and neither by 21.2 %. Variables independently associated with engaging in dual risk versus neither included Hispanic ethnicity (vs. white) (aOR = 2.0, 95 % CI = 1.0-4.0), married or cohabiting (aOR = 6.3, 95 % CI = 2.5-15.9), homelessness (aOR = 3.4, 95 % CI = 1.6-7.1), >=2 sex partners (aOR = 8.7, 95 % CI = 4.4-17.3), >=2 injecting partners (aOR = 2.9, 95 % CI = 1.5-5.8), and using only sterile syringe sources (protective) (aOR = 0.5, 95 % CI = 0.2-0.9). A majority of IDUs engaged in HIV risk behaviors, and a quarter in dual risk. Interventions among IDUs should simultaneously promote the consistent use of sterile syringes and of condoms. PMID- 23640656 TI - Single-step solvothermal synthesis of mesoporous Ag-TiO2-reduced graphene oxide ternary composites with enhanced photocatalytic activity. AB - With growing interest in the photocatalytic performance of TiO2-graphene composite systems, the ternary phase of TiO2, graphene, and Ag is expected to exhibit improved photocatalytic characteristics because of the improved recombination rate of photogenerated charge carriers and potential contribution of the generation of localized surface plasmon resonance at Ag sites on a surface of the TiO2-graphene binary matrix. In this work, Ag-TiO2-reduced graphene oxide ternary nanocomposites were successfully synthesized by a simple solvothermal process. In a single-step synthetic procedure, the reduction of AgNO3 and graphene oxide and the hydrolysis of titanium tetraisopropoxide were spontaneously performed in a mixed solvent system of ethylene glycol, N,N dimethylformamide and a stoichiometric amount of water without resorting to the use of typical reducing agents. The nanocomposites were characterized by X-ray diffraction, X-ray photoelectron spectroscopy, along with different microscopic and spectroscopic techniques, enabling us to confirm the successful reduction of AgNO3 and graphite oxide to metallic Ag and reduced graphene oxide, respectively. Due to the highly facilitated electron transport of well distributed Ag nanoparticles, the synthesized ternary nanocomposite showed enhanced photocatalytic activity for degradation of rhodamine B dye under visible light irradiation. PMID- 23640657 TI - The development and evaluation of triage algorithms for early discovery of adverse drug interactions. AB - BACKGROUND: Around 20 % of all adverse drug reactions (ADRs) are due to drug interactions. Some of these will only be detected in the postmarketing setting. Effective screening in large collections of individual case safety reports (ICSRs) requires automated triages to identify signals of adverse drug interactions. Research so far has focused on statistical measures, but clinical information and pharmacological characteristics are essential in the clinical assessment and may be of great value in first-pass filtering of potential adverse drug interaction signals. OBJECTIVE: The aim of this study was to develop triages for adverse drug interaction surveillance, and to evaluate these prospectively relative to clinical assessment. METHODS: A broad set of variables were considered for inclusion in the triages, including cytochrome P450 (CYP) activity, explicit suspicions of drug interactions as noted by the reporter, dose and treatment overlap, and a measure of interaction disproportionality. Their unique contributions in predicting signals of adverse drug interactions were determined through logistic regression. This was based on the reporting in the WHO global ICSR database, VigiBaseTM, for a set of known adverse drug interactions and corresponding negative controls. Three triages were developed, each producing an estimated probability that a given drug-drug-ADR triplet constitutes an adverse drug interaction signal. The triages were evaluated against two separate benchmarks derived from expert clinical assessment: adverse drug interactions known in the literature and prospective adverse drug interaction signals. For reference, the triages were compared with disproportionality analysis alone using the same benchmarks. RESULTS: The following were identified as valuable predictors of adverse drug interaction signals: plausible CYP metabolism; notes of suspected interaction by the reporter; and reports of unexpected therapeutic response, altered therapeutic effect with dose information and altered therapeutic effect when only two drugs had been used. The new triages identified reporting patterns corresponding to both prospective signals of adverse drug interactions and already established ones. They perform better than disproportionality analysis alone relative to both benchmarks. CONCLUSIONS: A range of predictors for adverse drug interaction signals have been identified. They substantially improve signal detection capacity compared with disproportionality analysis alone. The value of incorporating clinical and pharmacological information in first-pass screening is clear. PMID- 23640659 TI - Strategies to improve adverse drug reaction reporting: a critical and systematic review. AB - BACKGROUND: Underreporting is the major limitation of a voluntary adverse drug reaction (ADR) reporting system. Many studies have assessed the effectiveness of different interventions designed to reduce underreporting. OBJECTIVE: We aimed to conduct a critical review of papers that assessed the effectiveness of different strategies to increase ADR reporting, regardless of the health professionals or patients included. DATA SOURCES: Scientific papers were selected after a search of the MEDLINE-PubMed and EMBASE scientific databases up to 7 December 2010. STUDY SELECTION: We included papers in English, French or Spanish that analysed an intervention aimed at increasing the number of reported ADRs, and quantify the results of the intervention in terms of number of reports. DATA EXTRACTION: The abstracts retrieved in both computerized searches were reviewed independently by two of the authors. Initially selected papers were thoroughly read to evaluate if they met inclusion and exclusion criteria. Data in finally selected papers were independently extracted by both authors and set in pre-designed tables. A third author took the final decision in case of disagreement. For each study, we analysed study design, type of intervention, assessment period, and results of the intervention. RESULTS: Of the 4,221 papers located that fulfilled the search criteria, 43 met the selection criteria. With the exception of one study, the interventions assessed were deemed to be effective. The vast majority of papers displayed methodological and formal limitations that lowered the grade of evidence. Multiple interventions seem to have had more impact than did single interventions. There were very few cases in which interventions were designed on the basis of inappropriate attitudes and mistaken beliefs about ADRs. CONCLUSIONS: In general, there is a need for studies of better methodological quality in this topic, so that more evidence of the effectiveness of the respective strategies can be collected for the purpose of improving ADR reporting by health professionals. It is probable that multiple interventions cause greater increases in the ADR reporting rates than single. PMID- 23640660 TI - Antiproton induced DNA damage: proton like in flight, carbon-ion like near rest. AB - Biological validation of new radiotherapy modalities is essential to understand their therapeutic potential. Antiprotons have been proposed for cancer therapy due to enhanced dose deposition provided by antiproton-nucleon annihilation. We assessed cellular DNA damage and relative biological effectiveness (RBE) of a clinically relevant antiproton beam. Despite a modest LET (~19 keV/MUm), antiproton spread out Bragg peak (SOBP) irradiation caused significant residual gamma-H2AX foci compared to X-ray, proton and antiproton plateau irradiation. RBE of ~1.48 in the SOBP and ~1 in the plateau were measured and used for a qualitative effective dose curve comparison with proton and carbon-ions. Foci in the antiproton SOBP were larger and more structured compared to X-rays, protons and carbon-ions. This is likely due to overlapping particle tracks near the annihilation vertex, creating spatially correlated DNA lesions. No biological effects were observed at 28-42 mm away from the primary beam suggesting minimal risk from long-range secondary particles. PMID- 23640661 TI - The association between tracheostomy and sternal wound infection in postoperative cardiac surgery patients. AB - PURPOSE: To investigate whether tracheostomy increases the risk of sternal wound infection (SWI) post cardiac surgery. METHODS: All patients undergoing cardiac surgery via median sternotomy from September 1997 to October 2010 were included in this retrospective observational study. Primary exposure was tracheostomy performed during admission to the cardiac surgical intensive care unit. The primary outcome was SWI during hospital admission. Multivariable logistic regression was used to determine if tracheostomy was an independent predictor of SWI. Restriction and propensity score analyses were then used to assess if tracheostomy is a causal risk factor for SWI. RESULTS: Four hundred and eleven of 18,845 patients (2.2%) were treated with tracheostomy. Incidences of SWI in tracheostomy and non-tracheostomy groups were 19.5% (80/411) and 0.8% (154/18,434), respectively. Using multivariable logistic regression analysis, tracheostomy was found to be an independent predictor of SWI (odds ratio [OR] 2.8; 95% confidence interval [CI] 1.9 to 4.2). In an analysis restricted to respiratory failure patients, tracheostomy was associated with sternal wound infection (OR 3.4; 95% CI 2.4 to 4.9). When the analysis was stratified by the risk of receiving tracheostomy as represented by propensity score (PS), 46 patients (12%) in the intermediate risk category (PS 0.2-0.4) had SWIs (adjusted OR 2.97; 95% CI 1.6 to 5.6), and 52 patients (14%) in the highest risk category (PS > 0.4) had SWIs (OR 1.52; 95% CI 0.85 to 2.87). DISCUSSION: Our single-centre observational study of cardiac surgery patients found tracheostomy to be an independent risk factor for SWI. Our analysis showed a robust association when restricted to patients with respiratory failure and after the population was stratified by the propensity to have a tracheostomy. PMID- 23640662 TI - Electrically driven ultraviolet random lasing from an n-MgZnO/i-ZnO/SiO2/p-Si asymmetric double heterojunction. AB - Electrically pumped lasing action has been realized in ZnO from an n-MgZnO/i ZnO/SiO2/p-Si asymmetric double heterostructure, an ultralow threshold of 3.9 mA was obtained. The mechanism of the laser is associated with the in-plane random resonator cavities formed in the ZnO films and the elaborate hollow-shaped SiO2 cladding pattern, which prevent the lateral diffusion of injection current and ultimately lower the threshold current of the laser diode. In addition, a waveguide mechanism due to different refractive indices of three epilayers enhances the guided optical field on the ZnO side, resulting in an improved light extraction efficiency. PMID- 23640658 TI - Drug-induced thrombosis: an update. AB - Drugs may play an important role in development of thrombosis, and in recent years there has been increased attention to the importance of this issue. Although drug-induced thrombosis usually causes venous thrombotic events, arterial events are also noted due to drug administration. Here we review the different mechanisms through which drugs can exert thrombosis. Drugs can cause direct endothelial damage and expose the underlying subendothelium thus leading to platelet adherence and subsequent thrombus formation. Such an effect is seen by contrast media and chemotherapeutic cytotoxic drugs. Drugs may also attenuate the secretion of pro- and anticoagulation mediators by the endothelial cells and may have prothrombotic effects on platelets by increasing adhesion and aggregation, as for example seen after heparin administration in an immune mediated mechanism. Red and white cells can also be affected by drugs, by increasing their aggregation or adhesion to the endothelial wall. Some drugs, such as oral contraceptive pills, may promote thrombosis by altering the balance between the different coagulation factors, and many drugs can lead to decreased blood flow by increasing blood viscosity, as seen for example after intravenous immunoglobulin administration. Better understanding of the mechanisms through which drugs exert thrombosis may facilitate their safe use in patients. Additionally, awareness of the drugs that are known to induce thrombosis is important in order to stop their administration in case of a thrombotic event. This review further emphasizes the fact that drug administration is a risk factor that should always be considered together with additional known thromboembolic risk factors such as genetic predisposition or cancer. PMID- 23640663 TI - Thoracic aortic aneurysms. PMID- 23640664 TI - Systematic review of central pancreatectomy and meta-analysis of central versus distal pancreatectomy. AB - BACKGROUND: Central pancreatectomy (CP) is a parenchyma-sparing surgical procedure that enables the removal of benign and/or low-grade malignant lesions from the neck and proximal body of the pancreas. The aim of this review was to evaluate the short- and long-term surgical results of CP from all published studies, and the results of comparative studies of CP versus distal pancreatectomy (DP). METHODS: Eligible studies published between 1988 and 2010 were reviewed systematically. Comparisons between CP and DP were pooled and analysed by meta-analytical techniques using random- or fixed-effects models, as appropriate. RESULTS: Ninety-four studies, involving 963 patients undergoing CP, were identified. Postoperative morbidity and pancreatic fistula rates were 45.3 and 40.9 per cent respectively. Endocrine and exocrine pancreatic insufficiency was reported in 5.0 and 9.9 per cent of patients. The overall mortality rate was 0.8 per cent. Compared with DP, CP had a higher postoperative morbidity rate and a higher incidence of pancreatic fistula, but a lower risk of endocrine insufficiency (relative risk (RR) 0.22, 95 per cent confidence interval 0.14 to 0.35; P < 0.001). The risk of exocrine failure was also lower after CP, although this was not significant (RR 0.59, 0.32 to 1.07; P = 0.082). CONCLUSION: CP is a safe procedure with good long-term functional reserve. In situations where DP represents an alternative, CP is associated with a slightly higher risk of early complications. PMID- 23640665 TI - Expertise-based randomized clinical trial of laparoscopic versus small-incision open cholecystectomy. AB - BACKGROUND: Several randomized clinical trials have compared laparoscopic cholecystectomy (LC) and small-incision open cholecystectomy (SIOC). Most have had wide exclusion criteria and none was expertise-based. The aim of this expertise-based randomized trial was to compare healthcare costs, quality of life (QoL), pain and clinical outcomes after LC and SIOC. METHODS: Patients scheduled for cholecystectomy were randomized to treatment by one of two teams of surgeons with a preference for either LC or SIOC. Each team performed their specific method (SIOC or LC) as a first-choice operation, but converted to open cholecystectomy and common bile duct exploration when necessary. Intraoperative cholangiography was carried out routinely. The intention was to include all patients undergoing cholecystectomy, including emergency operations and procedures involving surgical training for residents. RESULTS: Some 74.9 per cent of all patients undergoing cholecystectomy were included. Of 355 patients randomized, 333 were analysed. Self-estimated QoL scores in 258 patients, analysed by the area under the curve method, were significantly lower in the SIOC group at 1 month after surgery: median 2326 (95 per cent confidence interval 2187 to 2391) compared with 2411 (2334 to 2502) for the LC group (P = 0.030). The mean(s.d.) duration of operation was shorter for SIOC: 97(41) versus 120(48) min (P < 0.001). There were no significant differences between the groups in conversion rate, pain, complications, length of hospital stay or readmissions. CONCLUSION: SIOC had comparable surgical results but slightly worse short-term QoL compared with LC. REGISTRATION NUMBER: NCT00370344 (http://www.clinicaltrials.gov). PMID- 23640666 TI - Lymphangiogenesis in abdominal aortic aneurysm. AB - BACKGROUND: Ongoing angiogenesis is implicated in the inflammatory environment that characterizes abdominal aortic aneurysm (AAA). Although lymphangiogenesis has been associated with chronic inflammatory conditions, it has yet to be demonstrated in AAA. The aim was to determine the presence of lymphangiogenesis and to delineate the relationship between inflammation and neovascularization in AAA tissue. METHODS: AAA samples and preoperative computed tomography images were obtained from patients undergoing elective AAA repair. Control samples were age matched abdominal aortic tissue. Specific immunostains for blood vessels (CD31, CD105), lymphatic vessels (D2-40), vascular endothelial growth factor (VEGF) A and VEGF receptor (VEGFR) 3 allowed characterization and quantitation of vasculature. RESULTS: The AAA wall contained high levels of inflammatory infiltrate; microvascular densities of blood (P < 0.001) and lymphatic (P = 0.003) vessels were significantly increased in AAA samples compared with controls. Maximal AAA vascularity was observed in inflammatory areas, with vessels that stained positively for CD31 (rho = 0.625, P = 0.017), CD105 (rho = 0.692, P = 0.009) and D2-40 (rho = 0.675, P = 0.008) correlating positively with the extent of inflammation. Increased VEGFR-3 and VEGF-A expression was also evident within inflammatory AAA areas. CONCLUSION: These findings demonstrated lymphatic vessel involvement in end-stage AAA disease, which was associated with the degree of inflammation, and confirmed the involvement of neovascularization. PMID- 23640667 TI - Transgastric appendicectomy (Br J Surg 2013; 100: 911-915). PMID- 23640668 TI - Feasibility of robotic pancreaticoduodenectomy. AB - BACKGROUND: Laparoscopic pancreaticoduodenectomy is feasible, but requires adaptations to established surgical techniques. The improved dexterity offered by robotic assistance provides the opportunity to see whether laparoscopic pancreaticoduodenectomy can be performed safely when faithfully reproducing the open operation. METHODS: Patients were selected for robotic pancreaticoduodenectomy when generally suitable for laparoscopy. Obese patients were excluded, and those with pancreatic cancer were highly selected. A prospectively designed database was used for data collection and analysis. RESULTS: Of 238 patients undergoing pancreaticoduodenectomy, 34 (14.3 per cent) were operated on robotically. No procedure was converted to conventional laparoscopy or open surgery, despite three patients requiring segmental resection of the superior mesenteric/portal vein and reconstruction. The mean duration of operation was 597 (range 420-960) min. The mean number of lymph nodes retrieved and analysed from patients with neoplasia was 32 (range 15-76). Four patients required blood transfusions and five developed postoperative complications exceeding Clavien-Dindo grade II. There were four grade B pancreatic fistulas. One patient died on postoperative day 40. Excess mean operative cost compared with open resection was ?6193. CONCLUSION: Selected patients can safely undergo robotic pancreaticoduodenectomy. The main downsides are high costs and prolonged operating times compared with open resection. PMID- 23640669 TI - Repeat liver resection for colorectal metastases. AB - BACKGROUND: Following resection of colorectal liver metastases (CLMs) up to 75 per cent of patients develop recurrent liver metastases. Although repeat resection remains the only curative therapy, data evaluating the outcome are deficient. This study analysed postoperative morbidity, mortality and independent predictors of survival following repeat resection of CLMs. METHODS: Data on surgical treatment of primary and recurrent CLMs between 1994 and 2010 were collected retrospectively, and compared with those for single hepatic resections carried out during the same period. Independent predictors of survival were evaluated by means of univariable and multivariable Cox regression models. RESULTS: In this interval 1026 primary resections of CLMs were performed and 94 patients underwent repeat CLM excision. Overall postoperative morbidity and mortality rates were low (15.8 and 1.3 per cent respectively), with no statistical difference in patients undergoing repeat surgery (P = 0.072). Compared with single liver resections, overall survival was improved in repeat resections (P = 0.003). Multivariable analysis revealed that size of primary CLM over 50 mm was an independent predictor of survival (hazard ratio (HR) 2.61; P = 0.008). Only major hepatic resection was associated with poorer outcome following repeat surgery (HR 2.62; P = 0.009). International Union Against Cancer stage, number of CLMs, age at surgery and need for intraoperative transfusion had no impact on survival after repeat resection. CONCLUSION: Recurrent CLM surgery is feasible with similar morbidity and mortality rates to those of initial or single CLM resections. PMID- 23640670 TI - Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer (Br J Surg 2013; 100: 933-939). PMID- 23640672 TI - Impaired postoperative leucocyte counts after preoperative radiotherapy for rectal cancer in the Stockholm III Trial (Br J Surg 2013; 100: 970-975). PMID- 23640671 TI - Health-related quality of life after laparoscopic and open surgery for rectal cancer in a randomized trial. AB - BACKGROUND: Previous studies comparing laparoscopic and open surgical techniques have reported improved health-related quality of life (HRQL). This analysis compared HRQL 12 months after laparoscopic versus open surgery for rectal cancer in a subset of a randomized trial. METHODS: The setting was a multicentre randomized trial (COLOR II) comparing laparoscopic and open surgery for rectal cancer. Involvement in the HRQL study of COLOR II was optional. Patients completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR38, and EuroQol - 5D (EQ-5DTM) before surgery, and 4 weeks, 6, 12 and 24 months after operation. Analysis was done according to the manual for each instrument. RESULTS: Of 617 patients in hospitals participating in the HRQL study of COLOR II, 385 were included. The HRQL deteriorated to moderate/severe degrees after surgery, gradually returning to preoperative values over time. Changes in EORTC QLQ-C30 and QLQ-CR38, and EQ-5DTM were not significantly different between the groups regarding global health score or any of the dimensions or symptoms at 4 weeks, 6 or 12 months after surgery. CONCLUSION: In contrast to previous studies in patients with colonic cancer, HRQL after rectal cancer surgery was not affected by surgical approach. REGISTRATION NUMBER: NCT00297791 (http://www.clinicaltrials.gov). PMID- 23640673 TI - Systematic review of five feeding routes after pancreatoduodenectomy (Br J Surg 2013; 100: 589-598). PMID- 23640674 TI - Author's reply: exhaled volatile organic compounds identify patients with colorectal cancer (Br J Surg 2013; 100: 144-150). PMID- 23640675 TI - Exhaled volatile organic compounds identify patients with colorectal cancer (Br J Surg 2013; 100: 144-150). PMID- 23640676 TI - Authors' reply: systematic review of five feeding routes after pancreatoduodenectomy (Br J Surg 2013; 100: 589-598). PMID- 23640679 TI - Self-discharge of electrochemical double layer capacitors. AB - Spontaneous voltage drop between EDLC electrodes, when it is kept under the open circuit condition, is commonly called 'self-discharge' and is interpreted as a result of energy loss by the device. Three mechanisms of self-discharge were proposed: due to a leakage-current, faradaic reactions and charge redistribution. According to the law of energy preservation, if the voltage drop is associated with the energy loss, the energy would more likely be exchanged with the environment. While heat generation was measured during EDLC charging and discharging, the corresponding effect during storage under open-circuit conditions has not been reported. This may support the conclusion that voltage changes during 'self-discharge' are not related to a considerable energy loss. Moreover, it has been shown that a two-stage charging process, i.e. first galvanostatic charging followed by a potentiostatic charge redistribution, resulted in considerably slower potential changes when the device was switched to the open circuit. All discussed models were based on the assumption that the energy accumulated by EDLCs is proportional to the voltage in the second power, with capacitance (C/2) as the proportionality constant. However, it has been shown that during EDLC charging or discharging through a resistance R, equations valid for 'dielectric' and electrolytic capacitors, do not hold in the case of EDLCs. Consequently, the assumption that the energetic state of the EDLC is proportional at any time to the voltage in the second power may not be valid due to considerable variability of the 'constant' C. Therefore, voltage changes may not reflect the energetic state of the device. PMID- 23640678 TI - Bone turnover markers in patients with prostate carcinoma: influence of sex steroids levels. AB - There are limited data about bone turnover markers (BTM) in androgen deprivation therapy (ADT)-treated prostate cancer (PCa) patients, and the relationship between sex steroids, bone mass, and BTM has not been explored. Our objective was to analyze the influence of sex steroids levels on BTM in patients with PCa treated with or without ADT. We performed a cross-sectional study including 83 subjects with PCa (54% with ADT). BTM, bone mineral density (BMD), and sex steroids were determined. BTM were inversely related to serum level of estrogens. Tartrate-specific acid phosphatase (TRAP-5b) showed a negative correlation with free estradiol (Free E) (r = -0.274, p = 0.014) and Bio E (r = -0.256, p = 0.022) that remained after adjustment for age: Free E (beta = -0.241, p = 0.03) and Bio E (beta = -0.213, p = 0.063). Bone-specific alkaline phosphatase (BSAP) concentrations were inversely related to Free E (r = -0.281, p = 0.011, age adjusted beta = -0.256, p = 0.024). There was a negative correlation between osteocalcin (OC) levels and Free E (r = -0.195, p = 0.082; age-adjusted beta = 0.203, p = 0.076) and Bio E (r = -0.215, p = 0.054; age-adjusted beta = -0.240, p = 0.039). BTM and androgens were inversely related to TRAP-5b: total testosterone (total T) (r = -0.238, p = 0.033), Free T (r = -0.309, p = 0.05), and Bio T (r = 0.310, p = 0.05), but these correlations disappeared after age-adjustment. We did not find any relationship between BMD at different locations and sex steroids. In conclusion, in patients with PCa, estrogen levels influence bone resorption and bone formation whereas androgens may exert actions only in bone resorption. These results suggest that estradiol is the main sex steroid that regulates bone metabolism in males with prostate carcinoma. PMID- 23640680 TI - Hip score and disease activity correlation in patients with rheumatoid arthritis after total hip arthroplasty. AB - PURPOSE: The disease activity score including 28 joints (DAS28), the simplified disease activity index and the clinical disease activity index (CDAI) were developed in order to provide a quantifiable measure of rheumatoid arthritis (RA) activity. Although inflamed hip joints greatly impact activities of daily living (ADL) and walking ability, the hip joint was not included in the DAS28, SDAI or CDAI assessments. Although excellent clinical results have been reported for total hip arthroplasty (THA) in RA patients, correlations between disease activity and hip function in RA patients after THA remain unknown. METHODS: We analysed the effect of RA disease activity on a hip function score in an observational cohort of RA patients after THA. Twenty-five registered RA patients who had undergone THA (33 joints) were included. Hip function was recorded and RA disease activity was measured on the same day. The mean age of the patients was 65.17 years. They were followed up for a mean of 5.24 years after surgery. The mean duration of disease following RA diagnosis for this patient group was 19.47 years. The Japanese Orthopaedic Association (JOA) hip score was used as a clinical outcome measure for hip dysfunction. RA disease activity and health related quality of life were measured using the DAS28, SDAI, CDAI and the modified health assessment questionnaire (MHAQ). RESULTS: The mean JOA score for hip function was 80.48 at the final follow-up. The mean DAS28-ESR, DAS28-CRP, SDAI, CDAI and MHAQ measuring RA disease activity levels were 3.38, 2.65, 9.59, 8.63 and 0.44, respectively, at the final follow-up. There was a significant negative correlation between the JOA hip score and all disease activity assessments observed after THA (DAS-ESR [P = 0.0067], DAS-CRP [P = 0.0008]), SDAI [P = 0.0034], CDAI [P = 0.0003]) and MHAQ [P = 0.0002]). CONCLUSION: We found significant negative correlations between JOA hip scores and all disease activity assessments in RA patients treated with THA. PMID- 23640681 TI - Consistency of dominance rank order: a comparison of David's Scores with I&SI and Bayesian methods in macaques. AB - In nonhuman primate social groups, dominance ranks are usually assigned to individuals based on outcomes of dyadic agonistic encounters. Multiple approaches have been used, but currently there is no consensus. One approach, David's Scores (DS), offers dual advantages of yielding cardinal scores that may in turn be used to compute hierarchical steepness. Here we correlate rank orders yielded by DS with those yielded by both the traditionally used I&SI approach and the recently proposed parametric Bayesian approach. We use six datasets for female macaques (three despotic and three tolerant groups), and 90 artificially generated datasets modeling macaque groups. We also use the artificial datasets to determine the impact of three characteristics (group size, interaction frequency, and directional asymmetry of aggression) on the magnitude of correlation coefficients, and assess the relative utility of two indices used to compute DS: Dij versus Pij. DS-based rank orders were strongly positively correlated with those yielded by the other two approaches for five out of the six macaque datasets, and for the majority of artificial datasets. Magnitudes of correlation coefficients were unrelated to group size or interaction frequency, but increased with directional asymmetry, suggesting methodological inconsistencies were more likely when dyads had more frequent reversals in directions of aggression. Finally, rank orders calculated using the Dij and Pij indices were similarly consistent with orders from other methods. We conclude that DS offers consistent estimates of rank orders, except perhaps in groups with very low levels of aggression asymmetry. In such "tolerant" groups, we suggest that the relatively greater methodological variability in rank orders may reflect behavioral characteristics of tolerant groups rather than computational inconsistencies between methods. We hypothesize that this quality may be quantified using posterior probability scores of Bayesian rank orders and may also index macaque social styles. PMID- 23640682 TI - Bedside rounding strategies used by bedside teachers. The authors' reply. PMID- 23640683 TI - Construction of an expression vector for production and purification of human somatostatin in Escherichia coli. AB - Somatostatin/growth hormone-inhibiting hormone is the peptide that inhibits secretion of somatotropin/growth hormone. Solid-phase synthesis methods are being currently used to produce somatostatin. Recombinant peptide synthesis is widely described for the production of small proteins and peptides; however, the production at industrial scale of peptides for biopharmaceutical applications is limited for economic reasons. Here, we propose the use of a new pGB-SMT plasmid to produce Somatostatin, as a C-terminal fusion protein with a Kluyveromyces lactis beta-galactosidase fragment. To facilitate removal of that fragment by CNBr cleavage, a methionine residue was introduced at the N-terminal of the hormone peptide. The use of this construction enables an IPTG-free expression system. The suitability of this procedure has been assessed in a 15 l scale-up experiment yielding almost 300 mg, with purity >99 % and it is being implemented for commercial scale. The plasmid pGB-SMT here described is an alternative option for a cheap and high expression of other short peptide hormones. PMID- 23640684 TI - Spatial and temporal expression modes of MicroRNAs in an elite rice hybrid and its parental lines. AB - Heterosis is a commonly observed phenomenon in nature and refers to the superior performance of hybrids relative to both parents. The molecular mechanisms of heterosis are mostly unknown. Quantitative trait locus (QTL) mapping has been used to explain the genetic basis of heterosis, and large amounts of QTLs have been mapped for various agronomic traits, but the nature of QTL contributing to heterosis is still enigmatic. MicroRNAs (miRNAs) are master regulators in the processes of plant development and trait performance, and many miRNAs are predicted to reside in QTL intervals. We analyzed the expression modes of miRNAs, which were picked up from miRNA databases and chosen from those predicted from QTL intervals by bioinformatic approaches, in different organs at developmental stages of an elite rice hybrid and its parents. All possible modes of action for miRNA expression were detected, but most miRNAs showed nonadditive mode, and different stages and distinct organs displayed different patterns of miRNA expression. A large proportion of miRNAs were not detected for expression in leaves but expressed in the culms and roots of the hybrid at tillering stage. MiRNAs from grain-weight QTL intervals have multiple effects on grain development. Together, our results reveal that miRNAs, especially those from QTL intervals, play roles in heterotic performance in this elite rice hybrid, our results also shade new light on understanding the molecular mechanisms of heterosis. PMID- 23640685 TI - In situ atom-resolved tracing of element diffusion in NiAu nanospindles. AB - The structure evolution behaviors of NiAu nanospindles in oxidizing/vacuum conditions were studied by in situ scanning transmission electron microscopy. The spindle structure transforms into Ni@Au@NiO multi-shell structure in the oxidizing atmosphere following an oxidation-driving multilayer reconstruction mechanism. In the vacuum condition, the NiAu nanospindles evolve along four distinct stages: (i) polyhedron recrystallization of Ni matrix; (ii) facets selected segregation and recrystallization of Au component; (iii) single crystallization of Ni matrix; (iv) wrapping diffusion of Au component. The investigation here provides a practical insight into the structural stability of NiAu bimetallic catalysts through a thermal processes. PMID- 23640688 TI - [Diagnostics and therapy of ischemia in chronic stable angina pectoris. Role of echocardiography]. AB - Early detection of prognostically significant coronary artery disease (CAD) using ischemic tests, including noninvasive cardiac imaging, are fundamental approaches of optimized patient treatment guidelines to lower morbidity and mortality of these patients. Current international guidelines and the national standard of care guidelines from 2006 and 2011 as well as the third universal definition of myocardial infarction stress the increasing role of echocardiography as a favorable noninvasive imaging test. Echocardiography at rest, ergometric and pharmacologic stress echocardiography are established and readily available diagnostic tools with the potential to evaluate global and regional left ventricular function at rest and during exercise combined with information regarding regional perfusion. Especially new data on perfusion analysis allow further extension of the indications spectrum of reperfusion analysis and sensitivity increases in chest pain unit settings. The noninvasive detection of significant and prognostic stenosis burden in CAD without radiation is possible with high sensitivity and good specificity and encompasses functional cardiovascular parameters as well as extension of the ischemic area.The likelihood of future cardiac events can be assessed with high negative predictive accuracy, giving a high safety aspect in the treatment options of patients. The diagnostic potential of stress echocardiography is best in patients with intermediate and higher pretest probabilities. In patients under concurrent antiischemic medication identification of high risk patients seems feasible. Stress echocardiography has an excellent specificity and prognostic value for either indications for revascularization or survival prediction as well as survival benefits after revascularization in test positive patients.The detection of pathologic findings is not impaired by gender differences. New technical approaches include 2-D and 3-D speckle analysis of the myocardial wall and contrast-enhanced improvements in myocardial border delineation and perfusion. A new European multicenter study published in 2013 could demonstrate comparable to improved sensitivities in intermediate to severe coronary stenosis from 50% to 70% and in highly obstructive proximal stenoses compared to a reference electrocardiogram (ECG)-gated single photon emission computed tomography (SPECT). PMID- 23640687 TI - Drug-induced macular edema. AB - Macular edema constitutes a serious pathologic entity of ophthalmology resulting in vision loss with a remarkable impact on the quality of life of patients. It is the final common pathway of various systemic diseases and underlying intraocular conditions, with diabetes mellitus being the most frequent cause. Other causes include venous occlusive disease, intraocular surgery, and inflammatory conditions of the posterior segment of the eye. Macular edema is a recognized side effect of various systemic and local medications and requires special consideration among ophthalmologists and other clinicians. Recently, antidiabetic thiazolidinediones have been implicated in the development of macular edema, and a review of the English literature revealed that other systemically administered drugs like fingolimod, recently approved for relapsing forms of multiple sclerosis, the anticancer agents tamoxifen and the taxanes, as well as niacin and interferons have been reported to cause macular edema. Ophthalmologic pharmaceutical agents, like prostaglandin analogs, epinephrine, timolol, and ophthalmic preparation preservatives have also been reported to cause macular edema as an adverse event. The purpose of this article is to provide a short, balanced overview of the available evidence in this regard. The available data and the possible pathophysiologic mechanisms leading to the development of macular edema are discussed. Possible therapeutic strategies for drug-induced macular edema are also proposed. PMID- 23640690 TI - Characterisation of the first actinobacterial group isolated from a Mexican extremophile environment. AB - The "Cave of Crystals" (aka 'Naica') in Chihuahua Mexico is a natural unique subterranean ecosystem which mainly consists of crystals made of calcium sulfate. The main system of caves are found at a depth of 300 meters (m) below sea level with crystals that range in size from a few centimeters to 15 m. The crystals date from nearly 400,000 years old and are thought to be formed when the cave was fully covered by water. At present time, this place shows a nearly constant temperature of 55 degrees C over the year and a humidity of 100 % which makes this place incomparable and unbearable to animal and/or human life. In the present study, two actinobacterial groups were isolated from within this system of caves and subjected to a systematic study to establish their phylogenetic relationship to microorganisms belonging to this vast group of Gram positive bacteria. Phenotypic properties, chemotaxonomic and 16S rRNA gene sequencing show that the microorganisms are members of the family Pseudonocardiaceae and are most closely related to the genus Prauserella. The present study is the first to report the isolation and presence of Actinobacteria or any other microbial form of life in this exceptional place. Moreover, this unexpected biodiversity can also provide an insight of the antibiotic resistome present in the isolates reported in this study. PMID- 23640689 TI - Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. AB - OBJECTIVE: A recent Food and Drug Administration (FDA) warning cautioned that citalopram dosages exceeding 40 mg/day may cause abnormal heart rhythms, including torsade de pointes. The authors assessed relationships between citalopram use and ventricular arrhythmias and mortality. METHOD: A cohort study was conducted using Veterans Health Administration data between 2004 and 2009 from depressed patients who received a prescription for citalopram (N=618,450) or for sertraline (N=365,898), a comparison medication with no FDA warning. Cox regression models, adjusted for demographic and clinical characteristics, were used to examine associations of antidepressant dosing with ventricular arrhythmia and cardiac, noncardiac, and all-cause mortality. RESULTS: Citalopram daily doses >40 mg were associated with lower risks of ventricular arrhythmia (adjusted hazard ratio=0.68, 95% CI=0.61-0.76), all-cause mortality (adjusted hazard ratio=0.94, 95% CI=0.90-0.99), and noncardiac mortality (adjusted hazard ratio=0.90, 95% CI=0.86-0.96) compared with daily doses of 1-20 mg. No increased risks of cardiac mortality were found. Citalopram daily doses of 21-40 mg were associated with lower risks of ventricular arrhythmia (adjusted hazard ratio=0.80, 95% CI=0.74-0.86) compared with dosages of 1-20 mg/day but did not have significantly different risks of any cause of mortality. The sertraline cohort revealed similar findings, except there were no significant associations between daily dose and either all-cause or noncardiac mortality. CONCLUSIONS: This large study found no elevated risks of ventricular arrhythmia or all-cause, cardiac, or noncardiac mortality associated with citalopram dosages >40 mg/day. Higher dosages were associated with fewer adverse outcomes, and similar findings were observed for a comparison medication, sertraline, not subject to the FDA warning. These results raise questions regarding the continued merit of the FDA warning. PMID- 23640691 TI - Holocene footprints in Namibia: the influence of substrate on footprint variability. AB - We report a Holocene human and animal footprint site from the Namib Sand Sea, south of Walvis Bay, Namibia. Using these data, we explore intratrail footprint variability associated with small variations in substrate properties using a "whole foot" analytical technique developed for the studies in human ichnology. We demonstrate high levels of intratrail variability as a result of variations in grain size, depositional moisture content, and the degree of sediment disturbance, all of which determine the bearing capacity of the substrate. The two principal trails were examined, which had consistent stride and step lengths, and as such variations in print typology were primarily controlled by substrate rather than locomotor mechanics. Footprint typology varies with bearing capacity such that firm substrates show limited impressions associated with areas of peak plantar pressure, whereas softer substrates are associated with deep prints with narrow heels and reduced medial longitudinal arches. Substrates of medium bearing capacity give displacement rims and proximal movement of sediment, which obscures the true form of the medial longitudinal arch. A simple conceptual model is offered which summarizes these conclusions and is presented as a basis for further investigation into the control of substrate on footprint typology. The method, model, and results presented here are essential in the interpretation of any sites of greater paleoanthropological significance, such as recently reported from Ileret (1.5 Ma, Kenya; Bennett et al.: Science 323 (2009) 1197-1201). PMID- 23640693 TI - Cell dualism: presence of cells with alternative membrane potentials in growing populations of bacteria and yeasts. AB - It is considered that all growing cells, for exception of acidophilic bacteria, have negatively charged inside cytoplasmic membrane (Deltapsi--cells). Here we show that growing populations of microbial cells contain a small portion of cells with positively charged inside cytoplasmic membrane (Deltapsi+-cells). These cells were detected after simultaneous application of the fluorescent probes for positive membrane potential (anionic dye DIBAC-) and membrane integrity (propidium iodide, PI). We found in exponentially growing cell populations of Escherichia coli and Saccharomyces cerevisiae that the content of live Deltapsi- cells was 93.6 +/- 1.8 % for bacteria and 90.4 +/- 4.0 % for yeasts and the content of live Deltapsi+-cells was 0.9 +/- 0.3 % for bacteria and 2.4 +/- 0.7 % for yeasts. Hypothetically, existence of Deltapsi+-cells could be due to short term, about 1 min for bacteria and 5 min for yeasts, change of membrane potential from negative to positive value during the cell cycle. This change has been shown by the reversions of K+, Na+, and Ca2+ ions fluxes across the cell membrane during synchronous yeast culture. The transformation of Deltapsi(--cells to Deltapsi+-cells can be explained by slow influx of K+ ions into Deltapsi--cell to the trigger level of K+ concentration ("compression of potassium spring"), which is forming "alternative" Deltapsi+-cell for a short period, following with fast efflux of K+ ions out of Deltapsi+-cell ("release of potassium spring") returning cell to normal Deltapsi- state. We anticipate our results to be a starting point to reveal the biological role of cell dualism in form of Deltapsi-- and Deltapsi+ cells. PMID- 23640692 TI - Long-term administration of rosuvastatin prevents contractile and electrical remodelling of diabetic rat heart. AB - In recent years, many findings have been presented about the potential benefit of statin therapy on diabetes-induced cardiovascular complications. Cardioprotective effects of statins were suggested to be mediated at least in part through inhibition of small GTPases, particularly those of the Rho family. The present study was designed to examine whether rosuvastatin can improve electrical remodeling and contractile dysfunction in type 1 diabetic rat heart via modulation of RhoA pathway. Type 1 diabetes was induced by single dose injection of STZ (50 mg/kg). One week after injection rosuvastatin (10 mg/kg/day) and sham treatment was given for 5 weeks in the diabetic rats, as well as in control groups. Shortening and Ca2+ transients were recorded in myocytes loaded with Fura2-AM. Membrane currents and Ca2+ transients were measured synchronously via whole-cell patch clamping. In untreated diabetic rats, relaxation of shortening and decay of the matched Ca2+ transients were prolonged. Fractional shortening and Ca2+ transients were also decreased. Rosuvastatin treatment reversed those changes. I(CaL) density did not change in either group but rosuvastatin recovered the loss of sarcoplasmic reticulum Ca2+ and Na+/Ca2+ exchange as evidenced from amplitude and decay of caffeine-induced Ca2+ transients, peak INCX and calculated sarcoplasmic reticulum Ca2+ content. Diabetes-induced attenuation of I(to) and I(sus) was also reversed, whilst I(K1) was unchanged in diabetes and unaffected by treatment. Rosuvastatin prevented the diabetes-induced increase in RhoA expression. Plasma cholesterol and triglyceride levels were higher in diabetic rats, but rosuvastatin reduced only the latter. In conclusion, HMG-CoA reductase inhibitor rosuvastatin can prevent diabetes-induced electrical and functional remodeling of heart due to inhibition of RhoA signalling rather than reduction of cholesterol level. PMID- 23640695 TI - Nitrogen budget in a lowland coastal area within the Po River basin (northern Italy): multiple evidences of equilibrium between sources and internal sinks. AB - Detailed studies on pollutants genesis, path and transformation are needed in agricultural catchments facing coastal areas. Here, loss of nutrients should be minimized in order to protect valuable aquatic ecosystems from eutrophication phenomena. A soil system N budget was calculated for a lowland coastal area, the Po di Volano basin (Po River Delta, Northern Italy), characterized by extremely flat topography and fine soil texture and bordering a network of lagoon ecosystems. Main features of this area are the scarce relevance of livestock farming, the intense agriculture, mainly sustained by chemical fertilizers, and the developed network of artificial canals with long water residence time. Average nitrogen input exceeds output terms by ~60 kg N ha(-1) year(-1), a relatively small amount if compared to sub-basins of the same hydrological system. Analysis of dissolved inorganic nitrogen in groundwater suggests limited vertical loss and no accumulation of this element, while a nitrogen mass balance in surface waters indicates a net and significant removal within the watershed. Our data provide multiple evidences of efficient control of the nitrogen excess in this geographical area and we speculate that denitrification in soil and in the secondary drainage system performs this ecosystemic function. Additionally, the significant difference between nitrogen input and nitrogen output loads associated to the irrigation system, which is fed by the N-rich Po River, suggests that this basin metabolizes part of the nitrogen excess produced upstream. The traditionally absent livestock farming practices and consequent low use of manure as fertilizer pose the risk of excess soil mineralization and progressive loss of denitrification capacity in this area. PMID- 23640696 TI - Science-driven management of protected areas: a Philippine case study. AB - The lack of scientific baseline information hinders appropriate design and management of protected areas. To illustrate the value of science to management, we consider five scenarios for the 202.0 km2 Puerto Princesa Subterranean River National Park, Philippines: (1) closure to human activities, (2) and (3) two levels of increase in unplanned human activities, (4) creation of a forest corridor and (5) additional allocation of land for permanent or shifting agriculture. We then use habitat-specific bird density estimates to simulate the net effect of each scenario on 18 focal bird populations. Closure has significant benefits-populations of five species are predicted to increase by >50 % and nine by >25 %, but two secondary forest flycatchers, including the endemic and 'Vulnerable' Palawan flycatcher, decline dramatically, while the creation of a 4.0 km2 forest corridor yields average increases across species of 2 +/- 4 % (SD). In contrast, heavier unplanned park usage produces declines in all but a few species, while the negative effects of an extra 2.0 km2 of shifting cultivation are 3-5 times higher than for a similar area of permanent agriculture and affect species whose densities are highest in primary habitats. Relatively small changes within the park, especially those associated with agricultural expansion, has serious predicted implications for local bird populations. Our models do not take into account the full complexities of bird ecology at a site, but they do provide park managers with an evidence base from which to make better decisions relating to biodiversity conservation obligations which their parks are intended to meet. PMID- 23640697 TI - Effect of birth asphyxia on p wave dispersion. AB - OBJECTIVES: To evaluate the cardiac conduction system using P wave dispersion on electrocardiogram and its relationship with the short term mortality and development of arrhythmia in asphyxiated neonates. METHODS: Thirty term babies with evidence of asphyxia and without any congenital abnormalities were consecutively evaluated as cases. They were compared with thirty healthy term babies without asphyxia. Twelve-lead surface electrocardiography was obtained from all the patients and the controls, and P wave dispersion was calculated according to its definition as the difference between P maximum duration and P minimum duration in 12-lead electrocardiogram. RESULTS: A statically significant difference of P wave dispersion was observed between the patients and the control group (0.027 +/- 0.011 mm/s and 0.016 +/- 0.006 mm/s, respectively; P value = 0.0001). The P wave dispersion had a statistically significant correlation with the grade of asphyxia (P = 0.004, r = 0.62), the P wave dispersion had no statistically significant correlation with Apgar scores, short term arrhythmia, and troponin I level in asphyxiated neonates (P < 0.05). CONCLUSIONS: The P wave dispersion increased in asphyxiated neonates and correlated with grade of asphyxia; however, the increased P wave dispersion was not correlated with the short term mortality, arrhythmia and troponin I level of the asphyxiated neonates. PMID- 23640698 TI - A national survey of price and affordability of key essential medicines for children in Sri Lanka. AB - OBJECTIVE: To investigate the price and affordability of key essential medicines for children in Sri Lanka. METHODS: This national survey investigated the prices and affordability of 25 key essential medicines for children in private sector pharmacies using the WHO/Health Action International (HAI) medicine price methodology. Data were collected from a representative sample of 48 private sector pharmacies selected from 8 Provinces using a multistage clustered approach. At each pharmacy prices of originator brand (OB) and lowest priced generics (LPG) of the selected medicines were collected. Medicine prices were compared with international reference prices to obtain a median price ratio (MPR). Income of the lowest paid unskilled government worker was used to establish the affordability. RESULTS: The median MPR of retail prices to patients was 3.7 for OB (range 0.23-20) and 1.35 for LPG (range 0.05-3.75). MPR >5 was observed for OBs of 5 medicines: ceftriaxone injection, diazepam injection, mebendazole syrup, mebendazole chewable tablet and metronidazole tablet whereas MPR >2.5 was observed only for LPGs of 3 medicines: chlorphenamine syrup, clotrimazole topical cream, and paracetamol syrup. Mean percent difference in price between OB and LPG products was 365 % (range -21, 2343). Rational treatment for acute infections such as mild lower respiratory tract infections and acute gastroenteritis seems to be affordable but treatment for chronic illnesses requiring liquid or inhaled dosage forms were largely unaffordable. CONCLUSIONS: Intervention is needed to improve the economic access to key essential medicines for children indicated in the treatment of chronic diseases. PMID- 23640700 TI - Risk factors for incomplete immunization in children with HIV infection. AB - OBJECTIVE: To document the immunization rates, factors associated with incomplete immunization, and missed opportunities for immunizations in children affected by HIV presenting for routine outpatient follow-up. METHODS: A cross-sectional study of immunization status of children affected by HIV presenting for routine outpatient care was conducted. RESULTS: Two hundred and six HIV affected children were enrolled. The median age of children in this cohort was 6 y. One hundred ninety seven of 206 children were HIV infected, nine were HIV exposed, but indeterminate. Fifty (25 %) children had incomplete immunizations per the Universal Immunization Program (UIP) of India. Hundred percent of children had received OPV. Ninety three percent of children got their UIP vaccines from a government clinic. Children with incomplete immunization were older, median age of 8 compared to 5 (p = 0.003). Each year of maternal education increased the odds of having a child with complete UIP immunizations by 1.18 (p = 0.008) children of mothers with 6 y of education compared to those with no education were seven times more likely to have complete UIP vaccine status. The average number of visits to the clinic by an individual child in a year was 4. This represents 200 missed opportunities for immunizations. CONCLUSIONS: HIV infected children are at risk for incomplete immunization coverage though they regularly access medical care. Including routine immunizations, particularly catch-up immunizations in programs for HIV infected children maybe an effective way of protecting these children from vaccine preventable disease. PMID- 23640699 TI - Consensus on timing of intervention for common congenital heart diseases: part II - cyanotic heart defects. AB - The purpose of this review/editorial is to discuss how and when to treat the most common cyanotic congenital heart defects (CHDs); the discussion of acyanotic heart defects was presented in a previous editorial. By and large, the indications and timing of intervention are decided by the severity of the lesion. While some patients with acyanotic CHD may not require surgical or transcatheter intervention because of spontaneous resolution of the defect or mildness of the defect, the majority of cyanotic CHD will require intervention, mostly surgical. Total surgical correction is the treatment of choice for tetralogy of Fallot patients although some patients may need to be palliated initially by performing a modified Blalock-Taussig shunt. For transposition of the great arteries, arterial switch (Jatene) procedure is the treatment of choice, although Rastelli procedure is required for patients who have associated ventricular septal defect (VSD) and pulmonary stenosis (PS). Some of these babies may require Prostaglandin E1 infusion and/or balloon atrial septostomy prior to corrective surgery. In tricuspid atresia patients, most babies require palliation at presentation either with a modified Blalock-Taussig shunt or pulmonary artery banding followed later by staged Fontan (bidirectional Glenn followed later by extracardiac conduit Fontan conversion usually with fenestration). Truncus arteriosus babies are treated by closure of VSD along with right ventricle to pulmonary artery conduit; palliative banding of the pulmonary artery is no longer recommended. Total anomalous pulmonary venous connection babies require anastomosis of the common pulmonary vein with the left atrium at presentation. Other defects should also be addressed by staged correction or complete repair depending upon the anatomy/physiology. Feasibility, safety and effectiveness of treatment of cyanotic CHD with currently available medical, transcatheter and surgical methods are well established and should be performed at an appropriate age in order to prevent damage to cardiovascular structures. PMID- 23640701 TI - Giant coronary aneurysms in Kawasaki Disease. PMID- 23640703 TI - Suicidal crises because of diminishing tolerance to psychological pain. PMID- 23640702 TI - Glycine intracerebroventricular administration disrupts mitochondrial energy homeostasis in cerebral cortex and striatum of young rats. AB - High tissue levels of glycine (GLY) are the biochemical hallmark of nonketotic hyperglycinemia (NKH), an inherited metabolic disease clinically characterized by severe neurological symptoms and brain abnormalities. Considering that the mechanisms underlying the neuropathology of this disease are not fully established, the present work investigated the in vivo effects of intracerebroventricular administration of GLY on important parameters of energy metabolism in cerebral cortex and striatum from young rats. Our results show that GLY reduced CO2 production using glucose as substrate and inhibited the activities of citrate synthase and isocitrate dehydrogenase in striatum, whereas no alterations of these parameters were verified in cerebral cortex 30 min after GLY injection. We also observed that GLY diminished the activities of complex IV in cerebral cortex and complex I-III in striatum at 30 min and inhibited complex I-III activity in striatum at 24 h after its injection. Furthermore, GLY reduced the activity of total and mitochondrial creatine kinase in both brain structures 30 min and 24 h after its administration. In contrast, the activity of Na+, K+ ATPase was not altered by GLY. Finally, the antioxidants N-acetylcysteine and creatine, and the NMDA receptor antagonist MK-801 attenuated or fully prevented the inhibitory effects of GLY on creatine kinase and respiratory complexes in cerebral cortex and striatum. Our data indicate that crucial pathways for energy production and intracellular energy transfer are severely compromised by GLY. It is proposed that bioenergetic impairment induced by GLY in vivo may contribute to the neurological dysfunction found in patients affected by NKH. PMID- 23640704 TI - Common variants near BDNF and SH2B1 show nominal evidence of association with snacking behavior in European populations. AB - We investigated the effect of 24 obesity-predisposing single nucleotide polymorphisms (SNPs), separately and in combination, on snacking behavior in three European populations. The 24 SNPs were genotyped in 7,502 subjects (1,868 snackers and 5,634 non-snackers). We tested the hypothesis that obesity risk variants or a genetic risk score increases snacking using a logistic regression adjusted for sex, age, and body mass index. The obesity genetic risk score was not associated with snacking (odds ratio (OR) = 1.00 [0.98-1.02], P value = 0.48). The obesity risk variants of two SNPs (rs925946 and rs7498665) close to the BDNF and SH2B1 genes showed nominal evidence of association with increased snacking (OR = 1.09 [1.01-1.17], P value = 0.0348 and OR = 1.11 [1.04-1.19], P value = 0.00703, respectively) but did not survive Bonferroni corrections for multiple testing. The associations of rs925946 and rs7498665 obesity risk variants with increased BMI (beta = 0.180 [0.022-0.339], P value = 0.0258 and beta = 0.166 [0.019-0.313], P value = 0.0271, respectively) were slightly attenuated after adjusting for snacking (beta = 0.151 [-0.006 to 0.309], P value = 0.0591 and beta = 0.152 [0.006-0.297], P value = 0.0413). Our data suggest that genetic predisposition to obesity does not significantly contribute to snacking behavior. The nominal associations of rs925946 and rs7498665 obesity risk variants near the BDNF and SH2B1 genes with increased snacking deserve further investigation. PMID- 23640706 TI - Enviromental impact of a hospital waste incineration plant in Krakow (Poland). AB - The environmental impact of a hospital waste incineration plant in Krakow was investigated. The objective of this study was to assess the degree of environmental effect of the secondary solid waste generated during the incineration process of medical waste. The analysis of pollution of the air emissions and leaching test of ashes and slag were carried out. The obtained results allowed us to conclude that (i) the hospital waste incineration plant significantly solves the problems of medical waste treatment in Krakow; (ii) the detected contaminant concentrations were generally lower than the permissible values; (iii) the generated ashes and slag contained considerable concentrations of heavy metals, mainly zinc, and chloride and sulfate anions. Ashes and slag constituted 10-15% of the mass of incinerated wastes; they are more harmful for the environment when compared with untreated waste, and after solidification they can be deposited in the hazardous waste disposal. PMID- 23640705 TI - Risk factors for stereotypic behavior and self-biting in rhesus macaques (Macaca mulatta): animal's history, current environment, and personality. AB - Captive rhesus macaques sometimes exhibit undesirable abnormal behaviors, such as motor stereotypic behavior (MSB) and self-abuse. Many risk factors for these behaviors have been identified but the list is far from comprehensive, and large individual differences in rate of behavior expression remain. The goal of the current study was to determine which experiences predict expression of MSB and self-biting, and if individual differences in personality can account for additional variation in MSB expression. A risk factor analysis was performed utilizing data from over 4,000 rhesus monkeys at the California National Primate Research Center. Data were analyzed using model selection, with the best fitting models evaluated using Akaike Information Criterion. Results confirmed previous research that males exhibit more MSB and self-biting than females, MSB decreases with age, and indoor reared animals exhibit more MSB and self-biting than outdoor reared animals. Additionally, results indicated that animals exhibited less MSB and self-biting for each year spent outdoors; frequency of room moves and number of projects positively predicted MSB; pair separations positively predicted MSB and self-biting; pair housed animals expressed less MSB than single housed and grate paired animals; and that animals expressed more MSB and self-biting when in bottom rack cages, or cages near the room entrance. Based on these results we recommend limiting exposure to these risk factors when possible. Our results also demonstrated a relationship between personality and MSB expression, with animals low on gentle temperament, active in response to a human intruder, and high on novel object contact expressing more MSB. From these results we propose that an animal's MSB is related to its predisposition for an active personality, with active animals expressing higher rates of MSB. PMID- 23640707 TI - Possible adverse reactions to herbal products: a study with individuals who resort to popular medicine in the city of Diadema, SP, Brazil. AB - The present study aimed to investigate the occurrence of adverse reactions (ADRs) related to herbal products (HPs), which are purchased over-the-counter for self treatment, reported by 100 users. Samples of the HPs related to those ADRs were purchased for their pharmacobotanical identification. The ADRs reported were evaluated based on specialized literature and were analyzed according to causality into probable (PR), possible (PO), unrelated (UR) or unclassifiable (UC); according to expectance into unexpected adverse reaction (UNEX) and expected adverse reaction (EX); seriousness into serious adverse event or reaction (S) and non-serious (NS); and severity into mild (MI), moderate (MO) and severe (SE). Among 100 interviews, five complaints of ADRs were reported in relation to HPs: Senna alexandrina, with a report of cramps (PR; MI; EX; NS); Camellia sinensis, associated with tachycardia (PO; MI; EX; NS); Bauhinia sp., a strong allergic reaction that led to hospitalization (UC; MO; UNEX; S); Picrasma crenata, with several symptoms and hospitalization (UR; MO; UNEX; S); and 21-herb tea, related to an allergic reaction (UC; MI; EX; NS). The strategies used in this study allowed us to carry out an analysis of ADRs attributed to HPs. This analysis could serve as a model in the study of similar cases. PMID- 23640708 TI - Ang(1-7) treatment attenuates beta-cell dysfunction by improving pancreatic microcirculation in a rat model of Type 2 diabetes. AB - AIMS: Pancreatic microcirculation plays a pivotal role in the physiological function and survival of beta-cells. Ang(1- 7) is a novel component of the renin angiotensin system (RAS) that has beneficial effects on microcirculation. In the present study, we investigated the effects of systemic Ang(1-7) administration (with or without its receptor Mas antagonist A- 779) on pancreatic microcirculation and beta-cell function. METHODS: These effects were studied in vivo using a rat model of Type 2 diabetes (T2DM). Pancreatic microcirculation and islet microvessel density were measured; and beta-cell function, insulin content, and the apoptosis of islet cells were assessed, respectively. Additionally, we evaluated endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) concentration in islets. RESULTS: After Ang(1-7) intervention, pancreatic microcirculation and intra-islet microvessel density were significantly improved (p<0.05), and more importantly, first-phase insulin secretion of beta-cells as well as relative insulin content in islets were increased, and the amount of apoptotic islet cells was decreased (p<0.05). And eNOS expression and NO release were up-regulated in pancreatic islets by Ang(1-7) administration (p<0.05). These positive effects of Ang(1-7) were prevented by the addition of A-779 (p<0.05). CONCLUSIONS: Our findings suggest that systemic Ang(1-7) treatment could attenuate beta-cell dysfunction and ameliorate islet cell apoptosis in T2DM rats by improving pancreatic microcirculation, perhaps through the mechanism of endothelial vasodilation. PMID- 23640711 TI - Sexual dimorphism of the bony labyrinth: a new age-independent method. AB - Currently in physical anthropology there is a need for reliable methods of sex estimation for immature individuals and highly fragmented remains. This study develops a sex estimation technique from discriminant function analysis of the bony labyrinth as it matures before puberty and can survive taphonomic conditions that would destroy most other skeletal material. The bony labyrinth contains the organs of hearing and balance. For this reason biologists and paleoanthropologists have undertaken research in this area to understand evolutionary changes in locomotion. Prior studies have found clear differences between species, but within-species variation has not been satisfactorily investigated. 3D segmentations of the left and right labyrinths of 94 individuals from a Cretan collection were generated and measured. Mean measurements of height, width, size, and shape indices were analyzed for sexual dimorphism, bilateral asymmetry, and measurement error. Significant sexual dimorphism was detected for several measurements. For sex estimation, the single best variable was the radius of curvature of the posterior semicircular canal, which achieved 76% accuracy. Two multivariate functions increased accuracy to 84%. Although these equations are less accurate than equations for complete long bones and crania, they appear to be as accurate as or better than other techniques for sexing immature individuals and temporal bones. PMID- 23640712 TI - Prey preference and life tables of the predatory mite Parasitus bituberosus (Acari: Parasitidae) when offered various prey combinations. AB - Parasitus bituberosus Karg (Acari: Parasitidae) is one of the predatory mite species inhabiting mushroom houses. It is known to accept a wide range of prey, suggesting that it may be a promising candidate for the biological control of key pests of mushroom culture. In our study it did not show any prey preference among four groups of small organisms often occurring in mushroom growth medium, namely rhabditid nematodes, pygmephorid mites, and sciarid and phorid fly larvae. Nevertheless, the type of food these predators fed on affects their development. The shortest egg-to-adult development time was obtained on a nematode diet. On a diet of phorid larvae, mite development stopped at the deutonymph stage; none reached adulthood. All other diets sufficed to reach the adult phase. Female fecundity when fed nematodes and sciarid larvae did not differ, but it was much lower when fed pygmephorid mites. Other life table parameters confirmed that pygmephorid mites constituted the worst diet for P. bituberosus. The highest intrinsic rate of population increase (r m = 0.34) was obtained on the nematode diet; when fed sciarid larvae and pygmephorid mites it was 0.25 and 0.14, respectively. Our study provides good reasons to further test P. bituberosus as biocontrol agent of especially sciarid flies and nematodes, especially when the compost is well colonized by mushroom mycelium (which retards nematode growth). PMID- 23640713 TI - Proteins and endotoxin in house dust mite extracts modulate cytokine secretion and gene expression by dermal fibroblasts. AB - House dust mite extracts used for diagnostic tests and immunotherapy contain bioreactive molecules including proteins and endotoxin. These extracts can influence the cytokine secretion and adhesion molecule expression by cells in the skin and lung airways. The aim of this study was to determine the role of proteins and endotoxin in mite extracts in modulating gene expression and cytokine secretion by human dermal fibroblasts. Cultured normal human dermal fibroblasts were stimulated with whole mite extracts, mite extracts boiled to denature proteins, or mite extracts treated with polymyxin B to inactivate lipopolysaccharide. Gene expression and secretion of interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1) were determined after 6 h of stimulation. Whole Dermatophagoides farinae, D. pteronyssinus and Euroglyphus maynei extracts induced dose-dependent IL-6 and IL-8 secretion. In addition, D. farinae and E. maynei induced secretion of MCP-1. Dermatophagoides farinae and E. maynei also induced parallel cytokine gene expression. Cells stimulated with boiled D. farinae extract showed moderate to marked reductions in IL-6 and IL-8 secretion. In contrast, boiled D. pteronyssinus and E. maynei extracts induced equal or greater cytokine secretions than untreated extracts. The stimulating properties were reduced for all three extracts following treatment with polymyxin B. Our data suggest that both endotoxin and proteins in mite extracts modulate the secretion of cytokines by dermal fibroblasts. The biological activities of D. farinae, D. pteronyssinus, and E. maynei extracts are not equivalent. There appears to be a lipopolysaccharide-binding protein in some mite extracts. PMID- 23640715 TI - Sensitivity of salmonid freshwater life history in western US streams to future climate conditions. AB - We projected effects of mid-21st century climate on the early life growth of Chinook salmon (Oncorhynchus tshawytscha) and steelhead (O. mykiss) in western United States streams. Air temperature and snowpack trends projected from observed 20th century trends were used to predict future seasonal stream temperatures. Fish growth from winter to summer was projected with temperature dependent models of egg development and juvenile growth. Based on temperature data from 115 sites, by mid-21st century, the effects of climate change are projected to be mixed. Fish in warm-region streams that are currently cooled by snow melt will grow less, and fish in suboptimally cool streams will grow more. Relative to 20th century conditions, by mid-21st century juvenile salmonids' weights are expected to be lower in the Columbia Basin and California Central Valley, but unchanged or greater in coastal and mountain streams. Because fish weight affects fish survival, the predicted changes in weight could impact population fitness depending on other factors such as density effects, food quality and quantity changes, habitat alterations, etc. The level of year-to-year variability in stream temperatures is high and our analysis suggests that identifying effects of climate change over the natural variability will be difficult except in a few streams. PMID- 23640714 TI - Detection of in vivo enzyme activity with CatalyCEST MRI. AB - PURPOSE: CatalyCEST MRI compares the detection of an enzyme-responsive chemical exchange saturation transfer (CEST) agent with the detection of an unresponsive "control" CEST agent that accounts for other conditions that influence CEST. The purpose of this study was to investigate the feasibility of in vivo catalyCEST MRI. METHODS: CEST agents that were responsive and unresponsive to the activity of urokinase plasminogen activator were shown to have negligible interaction with each other. A CEST-fast imaging with steady state precession (FISP) MRI protocol was used to acquire MR CEST spectroscopic images with a Capan-2 pancreatic tumor model after intravenous injection of the CEST agents. A function of (super) Lorentzian line shapes was fit to CEST spectra of a region-of-interest that represented the tumor. RESULTS: The CEST effects from each agent showed the same initial uptake into tumor tissues, indicating that both agents had the same pharmacokinetic transport rates. Starting 5 min after injection, CEST from the enzyme-responsive agent disappeared more quickly than CEST from the unresponsive agent, indicating that the enzyme responsive agent was being catalyzed by urokinase plasminogen activator, while both agents also experienced net pharmacokinetic washout from the tumor. CONCLUSION: CatalyCEST MRI demonstrates that dynamic tracking of enzyme-responsive and unresponsive CEST agents during the same in vivo MRI study is feasible. PMID- 23640716 TI - Comparison of magnetic resonance imaging findings in temporomandibular joints of the two sides. AB - OBJECTIVES: The aim of this investigation was to assess the association of magnetic resonance imaging (MRI)-diagnosed temporomandibular joint (TMJ) disorders [i.e., disc displacement with reduction, disc displacement without reduction (DDNR), osseous changes (OC), joint effusion] on the same side as well as in the joints of the two sides of the same individual. MATERIALS AND METHODS: A total of 199 patients undergoing bilateral MRI of the TMJs were included in the study. A single variable correlation matrix was created to assess the within- and between-side correlation of single diagnoses. Then, based on 12 possible combinations of diagnoses per each side, a contingency table was created to assess the chi-square values of the differences between the observed and expected frequencies of the different cross-combinations. Multiple variable permutation test was performed to assess the null hypothesis that the diagnoses in the right and left joints are not related. RESULTS: Within the signs of the same side, DDNR was positively correlated with OC. As for combination of diagnoses, the presence of a specific combination of signs on one side implied the same combination of signs on the other side. The global multivariate permutation test with Tippett combination was significant at p < 0.001, showing that the null hypothesis of independence between diagnoses of the two sides was rejected. CONCLUSIONS: It can be suggested that disc displacement without reduction is associated with osseous changes of the same joint and that joints of the two sides are likely to be affected by the same combinations of MRI signs. CLINICAL RELEVANCE: This investigation supports the concept that the two temporomandibular joints work as a unit. PMID- 23640718 TI - miMsg: a target enrichment algorithm for predicted miR-mRNA interactions based on relative ranking of matched expression data. AB - MOTIVATION: Algorithms predicting microRNA (miR)-mRNA interactions generate high numbers of possible interactions, many of which might be non-existent or irrelevant in a certain biological context. It is desirable to develop a transparent, user-friendly, unbiased tool to enrich miR-mRNA predictions. RESULTS: The miMsg algorithm uses matched miR/mRNA expression data to enrich miR mRNA predictions. It grades interactions by the number, magnitude and significance of misplacements in the combined ranking profiles of miR/mRNA expression assessed over multiple biological samples. miMsg requires minimal user input and makes no statistical assumptions. It identified 921 out of 56 262 interactions as top scoring and significant in an actual germ cell cancer dataset. Twenty-eight miR-mRNA pairs were deemed of highest interest based on ranking by miMsg and supported by current knowledge about validated interactions and biological function. To conclude, miMsg is an effective algorithm to reduce a high number of predicted interactions to a small set of high confidence interactions for further study. AVAILABILITY AND IMPLEMENTATION: Matlab source code and datasets available at www.martinrijlaarsdam.nl/mimsg . SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23640717 TI - Parathyroid hormone-related protein specifies the mammary mesenchyme and regulates embryonic mammary development. AB - Parathyroid Hormone related Protein (PTHrP) is a critical regulator of mammary gland morphogenesis in the mouse embryo. Loss of PTHrP, or its receptor, PTHR1, results in arrested mammary buds at day 15 of embryonic development (E15). In contrast, overexpression of PTHrP converts the ventral epidermis into hairless nipple skin. PTHrP signaling appears to be critical for mammary mesenchyme specification, which in turn maintains mammary epithelial identity, directs bud outgrowth, disrupts the male mammary rudiment and specifies the formation of the nipple. In the embryonic mammary bud, PTHrP exerts its effects on morphogenesis, in part, through epithelial-stromal crosstalk mediated by Wnt and BMP signaling. Recently, PTHLH has been identified as a strong candidate for a novel breast cancer susceptibility locus, although PTHrP's role in breast cancer has not been clearly defined. The effects of PTHrP on the growth of the embryonic mammary rudiment and its invasion into the dermis may, in turn, have connections to the role of PTHrP in breast cancer. PMID- 23640719 TI - Self-interaction of transmembrane helices representing pre-clusters from the human single-span membrane proteins. AB - MOTIVATION: Most integral membrane proteins form dimeric or oligomeric complexes. Oligomerization is frequently supported by the non-covalent interaction of transmembrane helices. It is currently not clear how many high-affinity transmembrane domains (TMD) exist in a proteome and how specific their interactions are with respect to preferred contacting faces and their underlying residue motifs. RESULTS: We first identify a threshold of 55% sequence similarity, which demarcates the border between meaningful alignments of TMDs and chance alignments. Clustering the human single-span membrane proteome using this threshold groups ~40% of the TMDs. The homotypic interaction of the TMDs representing the 33 largest clusters was systematically investigated under standardized conditions. The results reveal a broad distribution of relative affinities. High relative affinity frequently coincides with (i) the existence of a preferred helix-helix interface and (ii) sequence specificity as indicated by reduced affinity after mutating conserved residues. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23640720 TI - Arboretum: reconstruction and analysis of the evolutionary history of condition specific transcriptional modules. AB - Comparative functional genomics studies the evolution of biological processes by analyzing functional data, such as gene expression profiles, across species. A major challenge is to compare profiles collected in a complex phylogeny. Here, we present Arboretum, a novel scalable computational algorithm that integrates expression data from multiple species with species and gene phylogenies to infer modules of coexpressed genes in extant species and their evolutionary histories. We also develop new, generally applicable measures of conservation and divergence in gene regulatory modules to assess the impact of changes in gene content and expression on module evolution. We used Arboretum to study the evolution of the transcriptional response to heat shock in eight species of Ascomycota fungi and to reconstruct modules of the ancestral environmental stress response (ESR). We found substantial conservation in the stress response across species and in the reconstructed components of the ancestral ESR modules. The greatest divergence was in the most induced stress, primarily through module expansion. The divergence of the heat stress response exceeds that observed in the response to glucose depletion in the same species. Arboretum and its associated analyses provide a comprehensive framework to systematically study regulatory evolution of condition-specific responses. PMID- 23640721 TI - A patient with oliguria and hemoptysis: do not forget the lung-kidney connection! PMID- 23640722 TI - Structure-activity relationships of quinoxaline-based 5-HT3A and 5-HT3AB receptor selective ligands. AB - Until recently, discriminating between homomeric 5-HT3A and heteromeric 5-HT3AB receptors was only possible with ligands that bind in the receptor pore. This study describes the first series of ligands that can discriminate between these receptor types at the level of the orthosteric binding site. During a recent fragment screen, 2-chloro-3-(4-methylpiperazin-1-yl)quinoxaline (VUF10166) was identified as a ligand that displays an 83-fold difference in [(3)H]granisetron binding affinity between 5-HT3A and 5-HT3AB receptors. Fragment hit exploration, initiated from VUF10166 and 3-(4-methylpiperazin-1-yl)quinoxalin-2-ol, resulted in a series of compounds with higher affinity at either 5-HT3A or 5-HT3AB receptors. These ligands reveal that a single atom is sufficient to change the selectivity profile of a compound. At the extremes of the new compounds were 2 amino-3-(4-methylpiperazin-1-yl)quinoxaline, which showed 11-fold selectivity for the 5-HT3A receptor, and 2-(4-methylpiperazin-1-yl)quinoxaline, which showed an 8.3-fold selectivity for the 5-HT3AB receptor. These compounds represent novel molecular tools for studying 5-HT3 receptor subtypes and could help elucidate their physiological roles. PMID- 23640723 TI - Iatrogenic vascular injuries with lethal outcome. AB - BACKGROUND: The aim was to study the nature of iatrogenic vascular injuries (IVIs) associated with postoperative death within 30 days. METHODS: Patients who had undergone vascular surgery for IVIs and were reported prospectively to the Swedish national vascular registry during 1987-2008 were identified. They were cross-checked with the national population registry. Those who died within 30 days of surgery were studied regarding case records and death certificates. RESULTS: A total of 56 patients with postoperative death within 30 days after IVI were identified. Among them, 52 case records were retrieved (93 %). In 24 cases the IVIs were caused by puncture during endovascular procedures (13 hemorrhage, 11 occlusive thrombosis), 11 by penetrating trauma during open surgery, 6 by occlusion after external compression, 6 by percutaneous accidental arterial puncture. Main symptoms were peripheral ischemia (19/52, 37 %), external bleeding (14, 27 %), and hypovolemic shock without external bleeding (10, 19 %). Main specialties involved were interventional radiology (n = 18), general surgery (n = 9), and interventional cardiology (n = 8). Overall, 22 (42 %) were avoidable, and only 13 (25 %) underwent autopsy. Within 2 weeks, 36 patients (69 %) were dead. Also, there was a higher proportion with uncertain correlation between IVI and death. CONCLUSIONS: Interventional radiology, general surgery, and cardiology are the main specialities involved in IVIs with lethal outcome. Not all fatalities after IVI are attributable to the injury itself, but almost half of the injuries were considered avoidable. PMID- 23640724 TI - Learning tools and simulation in robotic surgery: state of the art. AB - Robotic surgery has emerged as a new technology over the last decade and has brought with it new challenges, particularly in terms of teaching and training. To overcome these challenges, robotic courses, virtual simulation, and dual consoles have been successfully introduced. In fact, there are several simulators currently on the market that have proven to be a valid option for training, especially for the novice trainee. Robotic courses have also found success around the world, allowing participants to implement robotic programs at their institution, typically with the help of a proctor. More recently, the dual console has enabled two surgeons to be operating at the same time. Having one experienced surgeon and one trainee each at his or her own console has made it an obvious choice for training. Although these methods have been successfully introduced, the data remain relatively scarce concerning their role in training. The aim of this article was to review the various methods and tools involved in the training of surgeons in robotic surgery. PMID- 23640725 TI - Robotic and remote access thyroidectomy: a time to pause. PMID- 23640727 TI - The effect of short-term overfeeding on serum lipids in healthy humans. AB - OBJECTIVES: While chronic obesity is associated with alterations in circulating glycerolipids, sphingolipids and plasmalogens, the effects of short-term overfeeding in humans are unclear. DESIGN AND METHODS: Healthy individuals (n = 40) were overfed by 1,250 kcal day(-1) for 28 days. Insulin sensitivity (hyperinsulinemic-euglycemic clamp), abdominal fat distribution and serum lipidomics (mass spectrometry) were assessed. RESULTS: Overfeeding increased liver fat, insulin resistance, serum C-reactive protein and urinary F2 isoprostanes. HDL increased (11% +/- 2%, P < 0.001) while LDL, triglycerides and nonesterified fatty acids were unchanged. Three hundred and thirty three serum lipids were detected, of which 13% increased and 20% decreased with overfeeding. Total diacylglycerol and lysoalkylphosphatidylcholine (LPC(O)) concentrations decreased (P < 0.01), while total ceramide, Cer22:0 and Cer24:0 increased (P <= 0.01). The most notable increases were observed in the HDL-associated phosphatidylethanolamine-based plasmalogens and their precursors alkylhosphatidylethanolamine (18 +/- 5% and 38 +/- 8% respectively, P <= 0.01). CONCLUSIONS: Overfeeding led to weight gain and changes in the serum lipid profile. Increases in ceramides were noted, which left unchecked may promote systemic insulin resistance. Uniform increases were observed in plasmalogens and their precursors. Because plasmalogens are powerful antioxidants, this may be an appropriate response against increased oxidative stress generated by over nutrition. The metabolic consequences of changes in concentrations of many circulating lipid species with overfeeding require further study. Copyright (c) 2013 The Obesity Society. PMID- 23640728 TI - [Prognosis of polytraumatized patients: estimates in the shock room and intensive care station]. AB - Treatment of patients with multiple trauma is known to require validated established algorithms, experienced medical staff and intensive interdisciplinary cooperation between the medical disciplines. In order to predict the risk for potential complications and mortality, adequate assessment of patients with multiple trauma is crucial for further treatment decisions. Therefore, different scoring systems have been developed to assess injury severity and to predict the potential outcome after multiple trauma. These scores have in common that the severity of trauma is converted to a numeric value simplifying the physiological reality in general. But the anatomic as well as physiological impact after multiple trauma can hardly be represented comprehensively by a single numeric value. Consequently, the established scores can only be safely interpreted, if the individual limitations of each scoring system are known. PMID- 23640729 TI - Impact of correlation on predictive ability of biomarkers. AB - In this paper, we investigate how the correlation structure of independent variables affects the discrimination of risk prediction model. Using multivariate normal data and binary outcome, we prove that zero correlation among predictors is often detrimental for discrimination in a risk prediction model and negatively correlated predictors with positive effect sizes are beneficial. A very high multiple R-squared from regressing the new predictor on the old ones can also be beneficial. As a practical guide to new variable selection, we recommend to select predictors that have negative correlation with the risk score based on the existing variables. This step is easy to implement even when the number of new predictors is large. We illustrate our results by using real-life Framingham data suggesting that the conclusions hold outside of normality. The findings presented in this paper might be useful for preliminary selection of potentially important predictors, especially is situations where the number of predictors is large. PMID- 23640730 TI - Effects of extrusion, infrared and microwave processing on Maillard reaction products and phenolic compounds in soybean. AB - BACKGROUND: The Maillard reaction indicators furosine, hydroxymethylfurfural (HMF), acrylamide and color were determined to evaluate heat effects induced during extrusion, infrared and microwave heating of soybean. In addition, the present paper aimed to study changes in the phenolic compounds, as well as in the overall antioxidant properties of different soybean products in relation to heating at 45-140 degrees C during the processes. RESULTS: Soybean proteins were highly sensible to Maillard reaction and furosine was rapidly formed under slight heating conditions during extrusion and infrared heating. Microwave heating at lower temperatures for a longer time yielded lower acrylamide levels in the final soybean products, as a result of its partial degradation. However, during infrared heating, acrylamide formation greatly increased with decreasing moisture content. After a short time of extrusion and infrared heating at 140 degrees C and microwave heating at 135 degrees C for 5 min, concentrations of HMF increased to 11.34, 26.21 and 34.97 ug g(-1), respectively. CONCLUSION: The heating conditions caused formation of acrylamide, HMF and furosine in high concentration. The results indicate that the complex structure of soybeans provides protection of phenolic compounds from thermal degradation, and that Maillard reaction products improved the antioxidant properties of heat-treated soybean. PMID- 23640731 TI - The utility of upfront double wire guided biliary cannulation following early unintentional pancreatic cannulation in patients undergoing ERCP. AB - This study aims to assess the impact of upfront double-guidewire technique (DGT) following inadvertent early pancreatic duct (PD) cannulation or biliary cannulation and post-endoscopic retrograde cholangiopancreatography (ERCP) complications. A pilot non-randomized cohort study was performed in patients undergoing ERCP. DGT was utilized in the first 25 patients followed by standard cannulation technique (SCT) in the subsequent 25. A significantly lower PD cannulation rate [median (range)] was noted in the DGT group [1 (0-5) vs. 3 (0 6); p=0.013]; however, the pancreatitis rate was similar [2 (9 %) DGT, 1 (4 %) SCT; p=0.601]. In the SCT group, 15/25 (60 %) required DGT to achieve biliary cannulation. The majority of our cohort proceeding to an SCT following early PD cannulation required a DGT to achieve biliary cannulation. Early DGT resulted in a significant reduction in unintentional pancreatic cannulation but did not translate into a reduction in pancreatitis in our cohort. PMID- 23640732 TI - Differences in predictors of traditional and cyber-bullying: a 2-year longitudinal study in Korean school children. AB - Traditional bullying has received considerable research but the emerging phenomenon of cyber-bullying much less so. Our study aims to investigate environmental and psychological factors associated with traditional and cyber bullying. In a school-based 2-year prospective survey, information was collected on 1,344 children aged 10 including bullying behavior/experience, depression, anxiety, coping strategies, self-esteem, and psychopathology. Parents reported demographic data, general health, and attention-deficit hyperactivity disorder (ADHD) symptoms. These were investigated in relation to traditional and cyber bullying perpetration and victimization at age 12. Male gender and depressive symptoms were associated with all types of bullying behavior and experience. Living with a single parent was associated with perpetration of traditional bullying while higher ADHD symptoms were associated with victimization from this. Lower academic achievement and lower self esteem were associated with cyber bullying perpetration and victimization, and anxiety symptoms with cyber-bullying perpetration. After adjustment, previous bullying perpetration was associated with victimization from cyber-bullying but not other outcomes. Cyber-bullying has differences in predictors from traditional bullying and intervention programmes need to take these into consideration. PMID- 23640734 TI - u-Healthcare system: state-of-the-art review and challenges. AB - With the increase of an ageing population and chronic diseases, society becomes more health conscious and patients become "health consumers" looking for better health management. People's perception is shifting towards patient-centered, rather than the classical, hospital-centered health services which has been propelling the evolution of telemedicine research from the classic e-Health to m Health and now is to ubiquitous healthcare (u-Health). It is expected that mobile & ubiquitous Telemedicine, integrated with Wireless Body Area Network (WBAN), have a great potential in fostering the provision of next-generation u-Health. Despite the recent efforts and achievements, current u-Health proposed solutions still suffer from shortcomings hampering their adoption today. This paper presents a comprehensive review of up-to-date requirements in hardware, communication, and computing for next-generation u-Health systems. It compares new technological and technical trends and discusses how they address expected u Health requirements. A thorough survey on various worldwide recent system implementations is presented in an attempt to identify shortcomings in state-of the art solutions. In particular, challenges in WBAN and ubiquitous computing were emphasized. The purpose of this survey is not only to help beginners with a holistic approach toward understanding u-Health systems but also present to researchers new technological trends and design challenges they have to cope with, while designing such systems. PMID- 23640735 TI - Susceptibility to a metal under global warming is shaped by thermal adaptation along a latitudinal gradient. AB - Global warming and contamination represent two major threats to biodiversity that have the potential to interact synergistically. There is the potential for gradual local thermal adaptation and dispersal to higher latitudes to mitigate the susceptibility of organisms to contaminants and global warming at high latitudes. Here, we applied a space-for-time substitution approach to study the thermal dependence of the susceptibility of Ischnura elegans damselfly larvae to zinc in a common garden warming experiment (20 and 24 degrees C) with replicated populations from three latitudes spanning >1500 km in Europe. We observed a striking latitude-specific effect of temperature on the zinc-induced mortality pattern; local thermal adaptation along the latitudinal gradient made Swedish, but not French, damselfly larvae more susceptible to zinc at 24 degrees C. Latitude- and temperature-specific differences in zinc susceptibility may be related to the amount of energy available to defend against and repair damage since Swedish larvae showed a much stronger zinc-induced reduction of food intake at 24 degrees C. The pattern of local thermal adaptation indicates that the predicted temperature increase of 4 degrees C by 2100 will strongly magnify the impact of a contaminant such as zinc at higher latitudes unless there is thermal evolution and/or migration of lower latitude genotypes. Our results underscore the critical importance of studying the susceptibility to contaminants under realistic warming scenarios taking into account local thermal adaptation across natural temperature gradients. PMID- 23640736 TI - Annexin II receptor induces apoptosis independent of Annexin II. AB - Annexin II receptor (AXIIR) is also known as chromosome 5 open reading frame 39 (C5orf39), it was originally identified as a cell surface receptor for Annexin II. AXIIR gene is peculiar to human. So far, the only known function about AXIIR is mediating Annexin II signal. In this study, we find that over-expression of AXIIR induces apoptosis, and this phenomenon is found in multiple human cell types. AXIIR is located in cytoplasm, binds to and activates pro-Caspase-8, which subsequently activates Caspase-3/7. AXIIR also down-regulates BCL2, BCL-XL, and activates Caspase-9, which finally activates Caspase-3/7 as well. Over-expression of BCL-XL does not affect AXIIR-induced apoptosis, whereas inhibition of Caspase 8 partially abolished AXIIR-induced apoptosis. AXIIR induces apoptosis independent of Annexin II and FADD. AXIIR is neither required for TRAIL-induced Caspase-8 activation. Although the transcriptional level of AXIIR in multiple cell types is considerably high, the translational level of AXIIR can hardly be detected. And inhibition of protein degradation pathways does not elevate AXIIR expression. Taken together, our observations reveal that besides being a cell surface receptor of Annexin II, AXIIR can also be located in cytoplasm and act as a novel inducer of apoptosis in human cells, partially through activating Caspase 8 in a manner that is different from conventional apoptotic pathways. The translation of AXIIR is generally tightly inhibited in cells. The physiological significance of such inhibition might be to prevent cells from apoptosis. PMID- 23640737 TI - Late dysphagia after radiotherapy-based treatment of head and neck cancer. AB - BACKGROUND: Changing trends in head and neck cancer (HNC) merit an understanding of the late effects of therapy, but few studies examine dysphagia beyond 2 years of treatment. METHODS: A case series was examined to describe the pathophysiology and outcomes in dysphagic HNC survivors referred for modified barium swallow (MBS) studies >= 5 years after definitive radiotherapy or chemoradiotherapy (January 2001 through May 2011). Functional measures included the penetration aspiration scale (PAS), performance status scale-head and neck (PSS-HN), National Institutes of Health Swallowing Safety Scale (NIH-SSS), and MBS impairment profile (MBSImp). RESULTS: Twenty-nine patients previously treated with radiotherapy (38%) or chemoradiotherapy (62%) were included (median years posttreatment, 9; range, 5-19). The majority (86%) had oropharyngeal cancer; 52% were never-smokers. Seventy-five percent had T2 or T3 tumors; 52% were N+. The median age at diagnosis was 55 (range, 38-72). Abnormal late examination findings included: dysarthria/dysphonia (76%), cranial neuropathy (48%), trismus (38%), and radionecrosis (10%). MBS studies confirmed pharyngeal residue and aspiration in all dysphagic cases owing to physiologic impairment (median PAS, 8; median NIH SSS, 10; median MBSImp, 18), whereas stricture was confirmed endoscopically in 7 (24%). Twenty-five (86%) developed pneumonia, half requiring hospitalization. Swallow postures/strategies helped 69% of cases, but no patient achieved durable improvement across functional measures at last follow-up. Ultimately, 19 (66%) were gastrostomy-dependent. CONCLUSIONS: Although functional organ preservation is commonly achieved, severe dysphagia represents a challenging late effect that may develop or progress years after radiation-based therapy for HNC. These data suggest that novel approaches are needed to minimize and better address this complication that is commonly refractory to many standard dysphagia therapies. PMID- 23640738 TI - In vivo imaging of islet transplantation using PLGA nanoparticles containing iron oxide and indocyanine green. AB - PURPOSE: We determined whether poly(lactic-co-glycolic acid) nanoparticles would be a useful reagent for the successful monitoring of isolated islets by magnetic resonance imaging and optical imaging systems, without clinically relevant toxicity in vitro or in vivo. METHODS: We used iron oxide for MR imaging and a cyanide dye approved by the Food and Drug Administration (indocyanine green) for optical imaging and estimated the in vivo detection of transplanted pancreatic islets. RESULTS: The poly(lactic-co-glycolic acid) nanoparticles were associated with the islets in vitro and were successfully detected by 4.7 T (MR) and optical imaging, without other toxic effects. When labeled islets were transplanted under the mouse kidney capsule, in vivo T2/ T2*-weighted scans with 4.7 T MR detected as few as 300 labeled islets by 4 weeks. Optical in vivo imaging revealed indocyanine green fluorescence by 2 and 4 days after transplantation of islets containing 250 and 500 ug/mL poly(lactic-co-glycolic acid) nanoparticles, respectively. These results were further supported by the immunohistochemical results for insulin and iron in the recipient mouse kidney and pancreas. CONCLUSIONS: Taken together, these data indicate that poly(lactic-co-glycolic acid) nanoparticles may be used to label transplanted islets and may be imaged with in vivo MR and optical imaging systems. PMID- 23640739 TI - The convergent evolution of blue iris pigmentation in primates took distinct molecular paths. AB - How many distinct molecular paths lead to the same phenotype? One approach to this question has been to examine the genetic basis of convergent traits, which likely evolved repeatedly under a shared selective pressure. We investigated the convergent phenotype of blue iris pigmentation, which has arisen independently in four primate lineages: humans, blue-eyed black lemurs, Japanese macaques, and spider monkeys. Characterizing the phenotype across these species, we found that the variation within the blue-eyed subsets of each species occupies strongly overlapping regions of CIE L*a*b* color space. Yet whereas Japanese macaques and humans display continuous variation, the phenotypes of blue-eyed black lemurs and their sister species (whose irises are brown) occupy more clustered subspaces. Variation in an enhancer of OCA2 is primarily responsible for the phenotypic difference between humans with blue and brown irises. In the orthologous region, we found no variant that distinguishes the two lemur species or associates with quantitative phenotypic variation in Japanese macaques. Given the high similarity between the blue iris phenotypes in these species and that in humans, this finding implies that evolution has used different molecular paths to reach the same end. PMID- 23640741 TI - Synthesis and evaluation of water-soluble prodrugs of ursodeoxycholic acid (UDCA), an anti-apoptotic bile acid. AB - Ursodeoxycholic acid (UDCA) is a bile acid with demonstrated anti-apoptotic activity in both in vitro and in vivo models. However, its utility is hampered by limited aqueous solubility. As such, water-soluble prodrugs of UDCA could have an advantage over the parent bile acid in indications where intravenous administration might be preferable, such as decreasing damage from stroke or acute kidney injury. Five phosphate prodrugs were synthesized, including one incorporating a novel phosphoryloxymethyl carboxylate (POMC) moiety. These prodrugs were highly water-soluble, but showed significant differences in chemical stability, with oxymethylphosphate prodrugs being the most unstable. In a series of NMR experiments, the POMC prodrug was bioactivated to UDCA by alkaline phosphatase (AP) faster than a prodrug containing a phosphate directly attached to the alcohol at the 3-position of UDCA. Both of these prodrugs showed significant anti-apoptotic activity in a series of in vitro assays, although the POMC prodrug required the addition of AP for activity, while the other compound was active without exogenous AP. PMID- 23640740 TI - Multisociety consensus quality improvement guidelines for intraarterial catheter directed treatment of acute ischemic stroke, from the American Society of Neuroradiology, Canadian Interventional Radiology Association, Cardiovascular and Interventional Radiological Society of Europe, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, European Society of Minimally Invasive Neurological Therapy, and Society of Vascular and Interventional Neurology. AB - PURPOSE: In this international multispecialty document, quality benchmarks for processes of care and clinical outcomes are defined. It is intended that these benchmarks be used in a quality assurance program to assess and improve processes and outcomes in acute stroke revascularization. MATERIALS AND METHODS: Members of the writing group were appointed by the American Society of Neuroradiology, Canadian Interventional Radiology Association, Cardiovascular and Interventional Radiological Society of Europe, Society of Cardiac Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, European Society of Minimally Invasive Neurological Therapy, and Society of Vascular and Interventional Neurology. The writing group reviewed the relevant literature from 1986 through February 2012 to create an evidence table summarizing processes and outcomes of care. Performance metrics and thresholds were then created by consensus. The guideline was approved by the sponsoring societies. It is intended that this guideline be fully updated in 3 years. RESULTS: In this international multispecialty document, quality benchmarks for processes of care and clinical outcomes are defined. These include process measures of time to imaging, arterial puncture, and revascularization and measures of clinical outcome up to 90 days. CONCLUSIONS: Quality improvement guidelines are provided for endovascular acute ischemic stroke revascularization procedures. PMID- 23640742 TI - Persistent stapedial arteries in human: from phylogeny to surgical consequences. AB - The stapedial artery is an embryonic artery which disappears during the tenth week in utero, in human species. During its short life, this artery shapes the stapes and transforms the middle meningeal artery from the internal carotid artery to a branch of the external carotid system. Nevertheless, a persistent stapedial artery is seen in 0.2-4.8 per thousand of human adults. This persistence is usually asymptomatic but can sometimes cause pulsatile tinnitus or conductive hearing loss. Despite the risk of facial palsy, hearing loss and even hemiplegia argued by several authors, some surgeons have succeeded in coagulation without side effects. Reviewing the literature, we seek to enlighten the actual knowledge about the persistent stapedial artery to evaluate the risk to coagulate it. Embryologic studies explain the four types of persistent stapedial arteries: the hyoido-stapedial artery, the pharyngo-stapedial artery, the pharyngo-hyo stapedial artery and aberrant internal carotid with persistent stapedial artery. Phylogenetic studies show that the stapedial artery persists in adulthood in many vertebrates. Its disappearance is therefore either a random effect or an adaptative convergence. This adaptation could be partially linked to the negative allometry of the stapes. Practically, the risk to coagulate a stapedial artery seems limited thanks to anastomoses, for example with the stylomastoid artery. The risk of hemiplegia reported is in fact an extrapolation of variation in rats' embryos. A persistent stapedial artery can therefore reasonably be coagulated, with special attention to the facial nerve, because the facial canal is always dehiscent where the artery penetrates. PMID- 23640744 TI - Characterization of volatile compounds and olfactory profile of red minority varietal wines from La Rioja. AB - BACKGROUND: The aim of this work was to study for the first time the volatile compounds and olfactory profile of La Rioja red wines made with the local varieties Vitis vinifera cv. Monastel and Maturana Tinta de Navarrete, using Tempranillo as a reference variety. The impact of vintage on these compounds was also evaluated, and chemometric techniques were applied to achieve a possible differentiation of the wines. RESULTS: A clear classification of wines according to grape variety and vintage was obtained. Volatile compounds that differentiated wines by grape variety were varietal aromas whereas vintage was mainly differentiated by compounds formed during the alcoholic fermentation and extracted from wood during the elaboration process in wooden barrels. Sensory analysis also allowed differentiation of wines by grape variety. Tempranillo wines were characterized by liquorice notes, whereas Maturana Tinta de Navarrete wines were the least fruity and showed herbaceous and pepper notes. The sensory profile of Monastel varied between vintages. CONCLUSION: These minor grape varieties could provide a good alternative to the most widespread variety in La Rioja: Tempranillo. The use of these varieties produced wines with their own personality and different aromatic profile from other wines on the market. PMID- 23640743 TI - Independent and combined effects of dietary weight loss and exercise on leukocyte telomere length in postmenopausal women. AB - OBJECTIVE: Investigate the effects of 12 months of dietary weight loss and/or aerobic exercise on leukocyte telomere length in postmenopausal women. DESIGN AND METHODS: Four hundred and thirty nine overweight or obese women (50-75 years) were randomized to: (i) dietary weight loss (N = 118); (ii) aerobic exercise (N = 117), (iii) diet + exercise (N = 117), or (iv) control (N = 87). The diet intervention was a group-based program with a 10% weight loss goal. The exercise intervention was 45 min day(-1) , 5 days week(-1) of moderate-to-vigorous aerobic activity. Fasting blood samples were taken at baseline and 12 months. DNA was extracted from isolated leukocytes and telomere length was measured by quantitative-polymerase chain reaction (qPCR). Mean changes were compared between groups (intent-to-treat) using generalized estimating equations. RESULTS: Baseline telomere length was inversely associated with age (r = -0.12 P < 0.01) and positively associated with maximal oxygen uptake (r = 0.11, P = 0.03), but not with BMI or %body fat. Change in telomere length was inversely correlated with baseline telomere length (r = -0.47, P < 0.0001). No significant difference in leukocyte telomere length was detected in any intervention group compared to controls, nor was the magnitude of weight loss associated with telomere length at 12 months. CONCLUSIONS: Twelve months of dietary weight loss and exercise did not change telomere length in postmenopausal women. PMID- 23640745 TI - Measuring anisotropic muscle stiffness properties using elastography. AB - Physiological and pathological changes to the anisotropic mechanical properties of skeletal muscle are still largely unknown, with only a few studies quantifying changes in vivo. This study used the noninvasive MR elastography (MRE) technique, in combination with diffusion tensor imaging (DTI), to measure shear modulus anisotropy in the human skeletal muscle in the lower leg. Shear modulus measurements parallel and perpendicular to the fibre direction were made in 10 healthy subjects in the medial gastrocnemius, soleus and tibialis anterior muscles. The results showed significant differences in the medial gastrocnemius (MU|| = 0.86 +/- 0.15 kPa; MU? = 0.66 +/- 0.19 kPa, P < 0.001), soleus (MU|| = 0.83 +/- 0.22 kPa; MU? = 0.65 +/- 0.13 kPa, P < 0.001) and the tibialis anterior (MU|| = 0.78 +/- 0.24 kPa; MU? = 0.66 +/- 0.16 kPa, P = 0.03) muscles, where the shear modulus measured in the direction parallel is greater than that measured in the direction perpendicular to the muscle fibres. No significant differences were measured across muscle groups. This study provides the first direct estimates of the anisotropic shear modulus in the triceps surae muscle group, and shows that the technique may be useful for the probing of mechanical anisotropy changes caused by disease, aging and injury. PMID- 23640746 TI - A latent factor linear mixed model for high-dimensional longitudinal data analysis. AB - High-dimensional longitudinal data involving latent variables such as depression and anxiety that cannot be quantified directly are often encountered in biomedical and social sciences. Multiple responses are used to characterize these latent quantities, and repeated measures are collected to capture their trends over time. Furthermore, substantive research questions may concern issues such as interrelated trends among latent variables that can only be addressed by modeling them jointly. Although statistical analysis of univariate longitudinal data has been well developed, methods for modeling multivariate high-dimensional longitudinal data are still under development. In this paper, we propose a latent factor linear mixed model (LFLMM) for analyzing this type of data. This model is a combination of the factor analysis and multivariate linear mixed models. Under this modeling framework, we reduced the high-dimensional responses to low dimensional latent factors by the factor analysis model, and then we used the multivariate linear mixed model to study the longitudinal trends of these latent factors. We developed an expectation-maximization algorithm to estimate the model. We used simulation studies to investigate the computational properties of the expectation-maximization algorithm and compare the LFLMM model with other approaches for high-dimensional longitudinal data analysis. We used a real data example to illustrate the practical usefulness of the model. PMID- 23640747 TI - Improved baseline in 29Si NMR spectra of water glasses. AB - It is shown by experiments that replacing one-pulse sequence by RIDE (ring down elimination) pulse sequence may dramatically improve the baseline of (29)Si NMR spectra and eliminate the signal from the probe. PMID- 23640748 TI - Kinetic modeling of native Cassava starch thermo-oxidative degradation using Weibull and Weibull-derived models. AB - A new approach in kinetic modeling of thermo-oxidative degradation process of starch granules extracted from the Cassava roots was developed. Based on the thermoanalytical measurements, three reaction stages were detected. Using Weibull and Weibull-derived (inverse) models, it was found that the first two reaction stages could be described with the change of apparent activation energy (Ea) on conversion fraction (alpha(T)) (using "Model-free" analysis). It was found that first reaction stage, which involves dehydration and evaporation of lower molecular mass fractions, can be described with an inverse Weibull model. This model with its distribution of Ea values and derived distribution parameters includes the occurrence of three-dimensional diffusion mechanism. The second reaction stage is very complex, and it was found to contain the system of simultaneous reactions (where depolymerization occurs), and can be described with standard Weibull model. Identified statistical model with its distribution of Ea values and derived distribution parameters includes the kinetic model that gives the variable reaction order values. Based on the established models, shelf-life studies for first two stages were carried out. Shelf-life testing has shown that optimal dehydration time is achieved by a programmed heating at medium heating rate, whereas optimal time of degradation is achieved at highest heating rate. PMID- 23640749 TI - Stent implantation for chronic total occlusion in the iliac artery using intravascular ultrasound-guided carbon dioxide angiography without iodinated contrast medium. AB - A 68-year-old male presented with claudication. His kidney function was impaired. Carbon dioxide angiography revealed the left external iliac artery was occluded. A retrograde approach was attempted from the left CFA. The wire was advanced into the subintimal and failed to re-enter the true lumen. An IVUS catheter was then introduced and positioned near the proximal site of the occlusion. A 0.018-in. wire was advanced with the antegrade approach under the guidance of IVUS image which is located in the false lumen. In this approach, true lumen wiring was achieved. Stenting was performed successfully without injecting any iodinated contrast medium. PMID- 23640751 TI - Climate warming affects biological invasions by shifting interactions of plants and herbivores. AB - Plants and herbivorous insects can each be dramatically affected by temperature. Climate warming may impact plant invasion success directly but also indirectly through changes in their natural enemies. To date, however, there are no tests of how climate warming shifts the interactions among invasive plants and their natural enemies to affect invasion success. Field surveys covering the full latitudinal range of invasive Alternanthera philoxeroides in China showed that a beetle introduced for biocontrol was rare or absent at higher latitudes. In contrast, plant cover and mass increased with latitude. In a 2-year field experiment near the northern limit of beetle distribution, we found the beetle sustained populations across years under elevated temperature, dramatically decreasing A. philoxeroides growth, but it failed to overwinter in ambient temperature. Together, these results suggest that warming will allow the natural enemy to expand its range, potentially benefiting biocontrol in regions that are currently too cold for the natural enemy. However, the invader may also expand its range further north in response to warming. In such cases where plants tolerate cold better than their natural enemies, the geographical gap between plant and herbivorous insect ranges may not disappear but will shift to higher latitudes, leading to a new zone of enemy release. Therefore, warming will not only affect plant invasions directly but also drive either enemy release or increase that will result in contrasting effects on invasive plants. The findings are also critical for future management of invasive species under climate change. PMID- 23640750 TI - Clinical significance of cell cycle inhibitors in hepatocellular carcinoma. AB - It is well accepted that cell cycle regulators are strongly implicated in the progression of cancer development. p16 and p27 are potent cyclin-dependent kinase (CDK) inhibitors involved in G1 phase progression, and are regarded as adverse prognostic biomarkers for various types of cancers. It has been reported that the main mechanism for p16 inactivation is aberrant DNA methylation, while p27 is exclusively inactivated by proteasome-mediated protein degradation. We have found that p27 is decreased in around half of hepatocellular carcinomas (HCCs), and in some cases p27 is inactivated by inappropriate interaction with cyclin D1/CDK4 complexes. In such cases, p16 is concomitantly inactivated through DNA methylation. Taking into consideration the complex interaction between p16 and p27, a comprehensive analysis including p16 and p27 would be useful for predicting the prognosis of HCC patients. PMID- 23640752 TI - 4-1BB signal stimulates the activation, expansion, and effector functions of gammadelta T cells in mice and humans. AB - We show here that the expression of 4-1BB is rapidly induced in gammadelta T cells following antigenic stimulation in both mice and humans, and ligation of the newly acquired 4-1BB with an agonistic anti-4-1BB augments cell division and cytokine production. We further demonstrate that gammadelta rather than alphabeta T cells protect mice from Listeria monocytogenes (LM) infection and 4-1BB stimulation enhances the gammadelta T-cell activities in the acute phase of LM infection. IFN-gamma produced from gammadelta T cells was the major soluble factor regulating LM infection. Vgamma1(+) T cells were expanded in LM-infected mice and 4-1BB signal triggered an exclusive expansion of Vgamma1(+) T cells and induced IFN-gamma in these Vgamma1(+) T cells. Similarly, 4-1BB was induced on human gammadelta T cells and shown to be fully functional. Combination treatment with human gammadelta T cells and anti-hu4-1BB effectively protected against LM infection in human gammadelta T cell-transferred NOD-SCID mice. Taken together, these data provide evidence that the 4-1BB signal is an important regulator of gammadelta T cells and induces robust host defense against LM infection. PMID- 23640753 TI - Fluorescence quenching investigation on the interaction of glutathione-CdTe/CdS quantum dots with sanguinarine and its analytical application. AB - Water-soluble glutathione (GSH)-capped core/shell CdTe/CdS quantum dots (QDs) were synthesized. In pH5.4 sodium phosphate buffer medium, the interaction between GSH-CdTe/CdS QDs and sanguinarine (SA) was investigated by spectroscopic methods, including fluorescence spectroscopy and ultraviolet-visible absorption spectroscopy. Addition of SA to GSH-CdTe/CdS QDs results in fluorescence quenching of GSH-CdTe/CdS QDs. Quenching intensity was in proportion to the concentration of SA in a certain range. Investigation of the quenching mechanism, proved that the fluorescence quenching of GSH-CdTe/CdS QDs by SA is a result of electron transfer. Based on the quenching of the fluorescence of GSH-CdTe/CdS QDs by SA, a novel, simple, rapid and specific method for SA determination was proposed. The detection limit for SA was 3.4 ng/mL and the quantitative determination range was 0.2-40.0 ug/mL with a correlation coefficient of 0.9988. The method has been applied to the determination of SA in synthetic samples and fresh urine samples of healthy human with satisfactory results. PMID- 23640754 TI - Synthesis, antitumor evaluation and docking study of novel 4-anilinoquinazoline derivatives as potential epidermal growth factor receptor (EGFR) inhibitors. AB - Strike a pose! A series of 4-anilinoquinazolines were designed, synthesized and evaluated in vitro against lung and breast cancer cell lines. Several compounds were found to be endowed with cytotoxicity in the low micromolar range. Molecular docking suggests that these compounds bind to EGFR in a similar manner to known EGFR inhibitors. PMID- 23640756 TI - Functional characterization and determination of the physiological role of a calcium-dependent potassium channel from cyanobacteria. AB - Despite the important achievement of the high-resolution structures of several prokaryotic channels, current understanding of their physiological roles in bacteria themselves is still far from complete. We have identified a putative two transmembrane domain-containing channel, SynCaK, in the genome of the freshwater cyanobacterium Synechocystis sp. PCC 6803, a model photosynthetic organism. SynCaK displays significant sequence homology to MthK, a calcium-dependent potassium channel isolated from Methanobacterium thermoautotrophicum. Expression of SynCaK in fusion with enhanced GFP in mammalian Chinese hamster ovary cells' plasma membrane gave rise to a calcium-activated, potassium-selective activity in patch clamp experiments. In cyanobacteria, Western blotting of isolated membrane fractions located SynCaK mainly to the plasma membrane. To understand its physiological function, a SynCaK-deficient mutant of Synechocystis sp. PCC 6803, DeltaSynCaK, has been obtained. Although the potassium content in the mutant organisms was comparable to that observed in the wild type, DeltaSynCaK was characterized by a depolarized resting membrane potential, as determined by a potential-sensitive fluorescent probe. Growth of the mutant under various conditions revealed that lack of SynCaK does not impair growth under osmotic or salt stress and that SynCaK is not involved in the regulation of photosynthesis. Instead, its lack conferred an increased resistance to the heavy metal zinc, an environmental pollutant. A similar result was obtained using barium, a general potassium channel inhibitor that also caused depolarization. Our findings thus indicate that SynCaK is a functional channel and identify the physiological consequences of its deletion in cyanobacteria. PMID- 23640757 TI - A change in SHATTERPROOF protein lies at the origin of a fruit morphological novelty and a new strategy for seed dispersal in medicago genus. AB - Angiosperms are the most diverse and numerous group of plants, and it is generally accepted that this evolutionary success owes in part to the diversity found in fruits, key for protecting the developing seeds and ensuring seed dispersal. Although studies on the molecular basis of morphological innovations are few, they all illustrate the central role played by transcription factors acting as developmental regulators. Here, we show that a small change in the protein sequence of a MADS-box transcription factor correlates with the origin of a highly modified fruit morphology and the change in seed dispersal strategies that occurred in Medicago, a genus belonging to the large legume family. This protein sequence modification alters the functional properties of the protein, affecting the affinities for other protein partners involved in high-order complexes. Our work illustrates that variation in coding regions can generate evolutionary novelties not based on gene duplication/subfunctionalization but by interactions in complex networks, contributing also to the current debate on the relative importance of changes in regulatory or coding regions of master regulators in generating morphological novelties. PMID- 23640755 TI - Responses to light intensity in a genome-scale model of rice metabolism. AB - We describe the construction and analysis of a genome-scale metabolic model representing a developing leaf cell of rice (Oryza sativa) primarily derived from the annotations in the RiceCyc database. We used flux balance analysis to determine that the model represents a network capable of producing biomass precursors (amino acids, nucleotides, lipid, starch, cellulose, and lignin) in experimentally reported proportions, using carbon dioxide as the sole carbon source. We then repeated the analysis over a range of photon flux values to examine responses in the solutions. The resulting flux distributions show that (1) redox shuttles between the chloroplast, cytosol, and mitochondrion may play a significant role at low light levels, (2) photorespiration can act to dissipate excess energy at high light levels, and (3) the role of mitochondrial metabolism is likely to vary considerably according to the balance between energy demand and availability. It is notable that these organelle interactions, consistent with many experimental observations, arise solely as a result of the need for mass and energy balancing without any explicit assumptions concerning kinetic or other regulatory mechanisms. PMID- 23640758 TI - Effects of natural phytochemicals in Angelica sinensis (Danggui) on Nrf2-mediated gene expression of phase II drug metabolizing enzymes and anti-inflammation. AB - The root of Angelica sinensis (Oliv.) Diels (abbreviated as AS) (Danggui) has a long history in Asian herbal medicine. Recently, it was demonstrated that AS possesses anti-cancer and anti-oxidant activities. Because the transcription factor Nrf2 mediates the expression of many cellular anti-oxidative stress genes, including genes that are involved in phase II drug metabolism and anti-oxidative stress, this study sought to investigate whether pure compounds from AS or an AS extract could activate antioxidant response element (ARE)-mediated gene expression and induce anti-inflammatory activities. Z-Ligustilide (Ligu), 3 butylidenephthalide (Buty) and CO2 supercritical fluid-extracted lipophilic AS extract (SFE) were tested in HepG2-C8 cells stabilized with ARE luciferase reporter gene. Ligu and Buty caused significant toxicity only at 100 MUm. All three samples induced ARE-luciferase activity; however, SFE at 8.5 ug/ml induced ARE-luciferase activity 2-3 fold more potently than did either of the pure compounds. SFE also significantly increased the endogenous mRNA of Nrf2 and the Nrf2 target anti-oxidative gene NAD(P)H dehydrogenase, quinone 1 (NQO1). The protein expression of NQO1 was also significantly induced by SFE. In RAW 264.7 cells, SFE suppressed lipopolysaccharide (LPS)-induced IL-1beta and TNF-alpha expression about 2 fold stronger than sulforaphane, whereas both pure compounds and SFE suppressed inflammatory nitric oxide (NO) production. In summary, this study demonstrates that AS has anti-inflammatory effects and activates the Nrf2 pathway, which protects against oxidative stress. PMID- 23640759 TI - Supercoiled pseudocircular domains in single-twisted DNAs under tension: Elastic constants and unwinding dynamics in complexes with Topo I. AB - Extension versus twist data of Koster et al. (Nature 2005, 434, 671-674) are analyzed to obtain C for the main-chain segments and the twist energy parameter (ET ) for the supercoiled pseudocircular (sp) domain(s) from which C is estimated via simulations. The torsional rigidity in the tension-free sp domain(s) (C = 163 fJ fm) is typical of the unstrained DNA and is less than half the value in the main-chain segments under tension (C = 350-410 fJ fm). Tension is suggested to induce a structural transition to a torsionally stiffer state. Data of Koster et al. for the rate of extension owing to unwinding of a covalent complex of DNA with human Topoisomerase Ib (H Topo I) are analyzed to determine the torque and rate of rotation from which an effective friction coefficient is obtained. A Langevin equation for the unwinding motion in a supercoiled DNA:H Topo I complex is solved to obtain the temporal trajectory of the average winding angle and the time-dependent distribution of winding angles. The mean rate constant for the religation reaction is estimated from the measured probability of reaction per turn. We predict that unwinding proceeds rather far during a single-cleavage and religation cycle, and is effectively completely equilibrated during the 3.2 cleavage and religation cycles that occur during each noncovalent binding and dissociation event. H Topo I is predicted to be completely processive as in accord with observations on calf-thymus Topo I (Brewood et al., Biochemistry 2010, 49, 3367-3380). PMID- 23640760 TI - Synthesis and characterization of sulfated Gal-beta-1,3/4-GlcNAc disaccharides through consecutive protection/glycosylation steps. AB - We have developed an expeditious procedure to yield large amounts of orthogonally protected Gal-beta1,3/4-GlcNAc, which allowed for the systematic introduction of a sulfate group onto the C3/C6 positions of Gal and/or the C6 position of GlcNAc. In particular, the disaccharide precursors were prepared in five or six steps and high overall yield from para-tolyl-6-O-tert-butyldiphenylsilyl-1-thio-beta-D galactopyranoside. After deprotection and sulfation steps, the final products were characterized by using several NMR methods to unambiguously confirm the location of each introduced sulfate group and they were examined for their binding specificity of human galectin-1 and galectin-8. PMID- 23640762 TI - Midlife obesity and risk of frailty in old age during a 22-year follow-up in men and women: the Mini-Finland Follow-up Survey. AB - BACKGROUND: Long-term predictors of geriatric syndrome of frailty are unclear. Several obesity-related conditions are associated with frailty. This study examines the predictive role of midlife overweight and obesity on development of frailty more than 22 years of follow-up. METHODS: Data are from 1,119 men and women aged 30 or older without frailty at baseline participating in a population based Mini-Finland Health Examination Survey (1978-1980) with follow-up measurement in 2000-2001. At baseline (1978-1980), body weight and height were measured. At follow-up (2000-2001), the dependent variable prefrailty was defined as the presence of one or two of five frailty indicators (shrinking, weakness, exhaustion, slowness, and low physical activity) and frailty was defined as three or more indicators. RESULTS: The mean age at the baseline was 43.6 (SD 9.7) years, and majority of the participants (95%) were 30-60 years old. Incidence of prefrailty was 5% and frailty 36%. Based on adjusted multinomial logistic regression, persons with overweight (body mass index 25-29.9kg/m(2)) and obesity (body mass index >= 30kg/m(2)) at baseline had increased risk of prefrailty (odds ratio 1.45, 95% CI 1.08, 1.96; odds ratio 2.36, 95% CI 1.41, 3.93) and frailty (odds ratio 2.49, 95% CI 1.22, 5.06; odds ratio 5.02, 95% CI 1.89, 13.33) at follow-up in comparison to normal-weight persons after adjusting for age, sex, lifestyle factors and chronic conditions. CONCLUSIONS: Development of frailty may start already in midlife, and obesity is one of the underlying causes of frailty. PMID- 23640761 TI - Implementing frailty into clinical practice: a cautionary tale. AB - BACKGROUND: Little is known about the contribution of frailty in improving patient-level prediction beyond readily available clinical information. The objective of this study is to compare the predictive ability of 129 combinations of seven frailty markers (cognition, energy, mobility, mood, nutrition, physical activity, and strength) and quantify their contribution to predictive accuracy beyond age, sex, and number of chronic diseases. METHODS: Two cohorts from the Established Populations for Epidemiologic Studies of the Elderly were used. The model with the best predictive fit in predicting 6-year incidence of disability was determined using the Akaike Information Criterion. Predictive accuracy was measured by the C statistic. RESULTS: Incident disability was 23% in one cohort and 20% in the other cohort. The "best model" in each cohort was found to be a model including between five and seven frailty markers including cognition, mobility, nutrition, physical activity, and strength. Predictive accuracy of the 129 models ranged from 0.73 to 0.77 across both cohorts. Adding frailty markers to age, sex, and chronic disease increased predictive accuracy by up to 3% in both cohorts (p < .001). The contribution of frailty increased up to 9% in the oldest age group. CONCLUSIONS: Adding frailty markers provided a modest increase in patient-level prediction of disability. Such a modest increase may still be worthwhile because while age, sex, and the number of chronic diseases are not modifiable, frailty may be. Further studies examining the contribution of frailty in improving prediction are needed before adopting frailty as a prognostic tool. PMID- 23640764 TI - Phosphorylations of Sds23/Psp1/Moc1 by stress-activated kinase and cAMP-dependent kinase are essential for regulating cell viability in prolonged stationary phase. AB - Under nutritional deprivation caused by prolonged culture, actively growing cells prepare to enter stationary phase. We showed here that Sds23/Psp1/Moc1 was phosphorylated by both cAMP-dependent kinase and stress-activated MAP kinase Sty1 upon entry into stationary phase. Overexpression of the phosphorylation-defective mutant Sds23/Psp1/Moc1 induced cell death in prolonged culture and blocked re entry into the cell division cycle. These phosphorylations are likely to be required for cell survival during stationary phase and for binding of Ufd2, a Schizosaccharomyces pombe homologue of multi-ubiquitin chain assembly factor E4. Deletion of the Ufd2 gene and overexpression of Sds23/Psp1/Moc1 increased cell viability in prolonged stationary phase. These results suggested that Ufd2 induces cell death in prolonged nutrient deprivation, that Sds23/Psp1/Moc1 may be a target protein of the ubiquitin-fusion degradation pathway for regulation of cell viability under this stress condition, and that Sty1 and PKA activity in stationary phase is essential for interaction between Sds23/Psp1/Moc1 and Ufd2. PMID- 23640763 TI - Lack of adiponectin leads to increased lymphocyte activation and increased disease severity in a mouse model of multiple sclerosis. AB - Multiple sclerosis (MS) is a presumed autoimmune disease directed against central nervous system (CNS) myelin, in which diet and obesity are implicated as risk factors. Immune responses can be influenced by molecules produced by fat cells, called adipokines. Adiponectin is an adipokine with anti-inflammatory effects. We tested the hypothesis that adiponectin has a protective role in the EAE model for MS, that can be induced by immunization with myelin antigens or transfer of myelin-specific T lymphocytes. Adiponectin deficient (ADPKO) mice developed worse EAE with greater CNS inflammation, demyelination, and axon injury. Lymphocytes from myelin-immunized ADPKO mice proliferated more, produced higher amounts of IFN-gamma, IL-17, TNF-alpha, IL-6, and transferred more severe EAE than wild type (WT) lymphocytes. At EAE peak, the spleen and CNS of ADPKO had fewer regulatory T (Treg) cells than WT mice and during EAE recovery, Foxp3, IL-10 and TGF-beta expression levels in the CNS were reduced in ADPKO compared with WT mice. Treatment with globular adiponectin in vivo ameliorated EAE, and was associated with an increase in Treg cells. These data indicate that adiponectin is an important regulator of T-cell functions during EAE, suggesting a new avenue of investigation for MS treatment. PMID- 23640765 TI - Anomalous, extreme weather disrupts obligate seed dispersal mutualism: snow in a subtropical forest ecosystem. AB - Ongoing global climate change is predicted to increase the frequency and magnitude of extreme weather events, impacting population dynamics and community structure. There is, however, a critical lack of case studies considering how climatic perturbations affect biotic interactions. Here, we document how an obligate seed dispersal mutualism was disrupted by a temporally anomalous and meteorologically extreme interlude of unseasonably frigid weather, with accompanying snowstorms, in subtropical China, during January-February 2008. Based on the analysis of 5892 fecal samples (representing six mammalian seed dispersers), this event caused a substantial disruption to the relative seed dispersal function for the raisin tree Hovenia dulcis from prestorm 6.29 (2006) and 11.47 (2007), down to 0.35 during the storm (2008). Crucially, this was due to impacts on mammalian seed dispersers and not due to a paucity of fruit, where 4.63 fruit per branch were available in January 2008, vs. 3.73 in 2006 and 3.58 in 2007. An induced dietary shift occurred among omnivorous carnivores during this event, from the consumption fruit to small mammals and birds, reducing their role in seed dispersal substantially. Induced range shift extinguished the functionality of herbivorous mammals completely, however, seed dispersal function was compensated in part by three omnivorous carnivores during poststorm years, and thus while the mutualism remained intact it was enacted by a narrower assemblage of species, rendering the system more vulnerable to extrinsic perturbations. The storm's extended effects also had anthropogenic corollaries - migrating ungulates becoming exposed to heightened levels of illegal hunting - causing long-term modification to the seed dispersal community and mutualism dynamics. Furthermore, degraded forests proved especially vulnerable to the storm's effects. Considering increasing climate variability and anthropogenic disturbance, the impacts of such massive, aberrant events warrant conservation concern, while affording unique insights into the stability of mutualisms and the processes that structure biodiversity and mediate ecosystem dynamics. PMID- 23640766 TI - Effectiveness of second corticosteroid injections for carpal tunnel syndrome. AB - INTRODUCTION: A single local corticosteroid injection is an effective treatment for carpal tunnel syndrome. No study has specifically examined the effectiveness of a second injection on relapse after primary injection. METHODS: We identified a cohort of patients who had received an initial corticosteroid injection into 1 wrist and then, at a later date, a second injection into the same wrist. We compared the change in the Boston Symptom Severity Scale (SSS) and Functional Status Scale (FSS) between first and second injections. RESULTS: In 229 patients who received 2 injections the mean improvement on the SSS was 1.2 (SD = 0.8) for the first injection and 1.3 (SD = 0.9) for the second, which was not statistically significant. Improvement in FSS for the first injection was 0.4 (SD = 0.8) and 0.7 (SD = 0.8) for the second, which was statistically significant (P < 0.001). CONCLUSION: Second corticosteroid injections appear to be at least as effective as the first. PMID- 23640767 TI - Cell proliferation and cell sheet detachment from the positively and negatively charged nanocomposite hydrogels. AB - The charged nanocomposite hydrogels (NC gels) were synthesized by copolymerization of positively or negatively chargeable monomer with N isopropylacrylamide (NIPAm) in the aqueous suspension of hectorite clay. The ionic NC gels preserved the thermo-responsibility with the phase-transition temperature below 37 degrees C. The L929 cell proliferation was sensitive to charge polarity and charge density. As compared to the PNIPAm NC gel, the cationic NC gels with <5 mol % of 2-(dimethylamino)ethyl methacrylate (DMAEMA) showed improved cell proliferation, whereas the cells grew slowly on the gels with negatively charged 2-acrylamido-2-methylpropane sulfonic acid (AMPSNa). By lowering temperature, rapid cell sheet detachment was observed from the surface of ionic NC gels with 1 mol % of ionizable monomers. However, lager amount of AMPSNa or DMAEMA did not support rapid cell sheet detachment, probably owing to the adverse swelling effects and/or enhanced electrostatic attraction. PMID- 23640768 TI - Receipt of maintenance therapy is most predictive of survival in older acute lymphoblastic leukemia patients treated with intensive induction chemotherapy regimens. AB - While the prognosis for older adults diagnosed with acute lymphoblastic leukemia (ALL) is frequently poor, long-term survival can be achieved in patients treated with curative intent. We reviewed the outcomes of 37 patients age >=60 treated at our institution with either DVP- or hyperCVAD-based chemotherapy regimens from 2003-2011. In this patient population, a complete response rate of 92%, relapse rate of 56% and median overall survival of 18.1 months was experienced. Univariate analysis revealed that receipt of maintenance therapy vs. no maintenance therapy was associated with a statistically-significant impact on overall survival (p = 0.001, HR 0.15 for death), while disease-related characteristics including high-risk white blood cell count at diagnosis and Philadelphia chromosome status as well as treatment-related factors including chemotherapy regimen or completion of intensive therapy were not. Many patients were unable to initiate or remain on maintenance therapy due to toxicities including infections and cytopenias. Our analysis reveals the benefit of prolonged therapy in the treatment of older adults with ALL as well as the high incidence of treatment-related toxicity experienced by these patients. PMID- 23640769 TI - Polymer brushes: promises and challenges. AB - Surface-tethered polymers, or "polymer brushes", are emerging as key elements in the context of regulating the surface characteristics of materials. Their properties, such as biocompatibility, antifouling, colloidal stability, wettability, and corrosion resistance, play a vital role in ascertaining their potential applications. The availability of straightforward procedures for polymer brush synthesis, which are applicable to a wide range of monomers and are adaptable to a range of substrates, is a clear advantage over other surface modification strategies. Herein, the important advancements that are pertinent to the fabrication of polymer brushes are outlined. Furthermore, an exhaustive up-to date overview of the developments in different application domains, including smart drug-delivery systems, biosensing, antifouling, stimuli-responsive surfaces, and ion-conducting membranes, that benefit from the developments in the field of polymer brushes, is presented. PMID- 23640770 TI - Isolated generalized dystonia in biallelic missense mutations of the ATM gene. PMID- 23640771 TI - Intrafetal laser treatment for twin reversed arterial perfusion sequence: cohort study and meta-analysis. AB - OBJECTIVES: To ascertain the outcome of twin reversed arterial perfusion (TRAP) sequence cases managed in our unit and to review systematically cases reported in the literature treated with intrafetal laser therapy. METHODS: This was a retrospective cohort study of all TRAP sequence cases identified from 2000 to 2012 at our center. Pregnancy management and outcomes were ascertained from maternal and neonatal records. We also performed a meta-analysis of the literature on the use of intrafetal laser therapy for the treatment of TRAP. Adverse pregnancy outcome was defined as a composite of intrauterine death (IUD) and preterm birth before 37 weeks' gestation. RESULTS: Twenty-three cases of TRAP were identified during the study period. Six were managed conservatively and 17 were treated with laser therapy. All cases managed conservatively were complicated by IUD at a median gestational age of 14 + 4 (interquartile range (IQR), 12 + 4 to 16 + 5) weeks. Among the treated cases, 14 (82%) delivered a healthy twin at a median gestational age of 37 + 1 (IQR, 34 + 0 to 38 + 3) weeks. Ten studies were reviewed in detail and the data were combined with those from the current study. The overall neonatal survival was 80%. Adverse pregnancy outcome was significantly lower when the treatment was performed before 16 weeks' gestation (19 vs 66%, P = 0.0025). CONCLUSION: The study data demonstrate a high risk of spontaneous fetal demise in early pregnancy, lack of accurate prognostic markers and improved pregnancy outcome after laser therapy in cases of TRAP. In these cases we recommend elective treatment with intrafetal laser therapy at between 13 and 16 weeks' gestation. PMID- 23640772 TI - Maintenance of temporal synchrony between syrphid flies and floral resources despite differential phenological responses to climate. AB - Variation in species' responses to abiotic phenological cues under climate change may cause changes in temporal overlap among interacting taxa, with potential demographic consequences. Here, we examine associations between the abiotic environment and plant-pollinator phenological synchrony using a long-term syrphid fly-flowering phenology dataset (1992-2011). Degree-days above freezing, precipitation, and timing of snow melt were investigated as predictors of phenology. Syrphids generally emerge after flowering onset and end their activity before the end of flowering. Neither flowering nor syrphid phenology has changed significantly over our 20-year record, consistent with a lack of directional change in climate variables over the same time frame. Instead we document interannual variability in the abiotic environment and phenology. Timing of snow melt was the best predictor of flowering onset and syrphid emergence. Snow melt and degree-days were the best predictors of the end of flowering, whereas degree days and precipitation best predicted the end of the syrphid period. Flowering advanced at a faster rate than syrphids in response to both advancing snow melt and increasing temperature. Different rates of phenological advancements resulted in more days of temporal overlap between the flower-syrphid community in years of early snow melt because of extended activity periods. Phenological synchrony at the community level is therefore likely to be maintained for some time, even under advancing snow melt conditions that are evident over longer term records at our site. These results show that interacting taxa may respond to different phenological cues and to the same cues at different rates but still maintain phenological synchrony over a range of abiotic conditions. However, our results also indicate that some individual plant species may overlap with the syrphid community for fewer days under continued climate change. This highlights the role of interannual variation in these flower-syrphid interactions and shows that species-level responses can differ from community-level responses in nonintuitive ways. PMID- 23640774 TI - Selective stimulation of human tooth-pulp with a new stable method: responses and validation. AB - INTRODUCTION: The aims of this study were to establish a safe technique for selective stimulation of nerves in human tooth-pulp during long experiments and to validate its use even with stimuli of high intensities. METHODS: A custom-made veneer containing 2 silver wire-conductive cream electrodes was attached with cement to the labial surface of an upper central incisor tooth. A variety of stimulus intensities were applied, and sensory and reflex responses from jaw closing muscles were recorded. RESULTS: In 15 participants, the stimuli evoked predominantly sharp or painful sensations and reflex inhibitions of activity in the jaw muscles. Stimulation of 3 non-vital teeth evoked no sensations or reflexes, even at intensities that evoked maximal reflexes in vital teeth. The electrodes had reasonably stable resistances throughout experiments lasting up to 90 min. CONCLUSION: The method described enables responses to low- or high intensity stimulation of human pulpal nerves to be investigated in long experiments. PMID- 23640777 TI - Outcomes of myocardial infarction hydrogel injection therapy in the human left ventricle dependent on injectate distribution. AB - Myocardial infarction therapies involving biomaterial injections have shown benefits in inhibiting progression towards heart failure. However, the underlying mechanisms remain unclear. A finite element model of the human left ventricle was developed from magnetic resonance images. An anteroapical infarct was represented at acute (AI) and fibrotic (FI) stage. Hydrogel injections in the infarct region were modelled with layered (L) and bulk (B) distribution. In the FI, injectates reduced end-systolic myofibre stresses from 291.6% to 117.6% (FI-L) and 115.3% (FI-B) of the healthy value, whereas all AI models exhibited sub-healthy stress levels (AI: 90.9%, AI-L: 20.9%, AI-B: 30.5%). Reduction in end-diastolic infarct stress were less pronounced for both FI (FI: 294.1%, FI-L: 176.5%, FI-B: 188.2%) and AI (AI: 94.1%, AI-L: 35.3%, AI-B: 41.2%). In the border zone, injectates reduced end-systolic fibre stress by 8-10% and strain from positive (AI) and zero (FI) to negative. Layered and bulk injectates increased ejection fraction by 7.4% and 8.4% in AI and 14.1% and 13.7% in FI. The layered injectate had a greater impact on infarct stress and strain at acute stage, whereas the bulk injectate exhibited greater benefits at FI stage. These findings were confirmed by our previous in vivo results. PMID- 23640773 TI - The interaction between CD300a and phosphatidylserine inhibits tumor cell killing by NK cells. AB - The activity of NK cells is controlled by inhibitory and activating receptors. The inhibitory receptors interact mostly with MHC class I proteins, however, inhibitory receptors such as CD300a, which bind to non-MHC class I ligands, also exist. Recently, it was discovered that phosphatidylserine (PS) is a ligand for CD300a and that the interaction between PS expressed on apoptotic cells and CD300a inhibits the uptake of apoptotic cells by phagocytic cells. Whether PS can inhibit NK-cell activity through CD300a is unknown. Here, we have generated specific antibodies directed against CD300a and we used these mAbs to demonstrate that various NK-cell clones express different levels of CD300a. We further demonstrated that both CD300a and its highly homologous molecule CD300c bind to the tumor cells equally well and that they recognize PS and additional unknown ligand(s) expressed by tumor cells. Finally, we showed that blocking the PS CD300a interaction resulted in increased NK-cell killing of tumor cells. Collectively, we demonstrate a new tumor immune evasion mechanism that is mediated through the interaction between PS and CD300a and we suggest that CD300c, similarly to CD300a, also interacts with PS. PMID- 23640776 TI - Story in a sample-the potential (and limitations) of cryo-electron microscopy applied to molecular machines. AB - This article addresses recent developments in cryo-electron microscopy and single particle reconstruction of macromolecules. With the advent of powerful classification techniques, it is now possible to extract and visualize multiple conformers contained within the same dataset. It is discussed how and to what extent this technique can be used in the study of the dynamics of molecular machines. PMID- 23640778 TI - Longitudinal monitoring of cardiac siderosis using cardiovascular magnetic resonance T2* in patients with thalassemia major on various chelation regimens: a 6-year study. AB - Cardiovascular magnetic resonance (CMR) and hepatic magnetic resonance imaging (MRI) have become reliable noninvasive tools to monitor iron excess in thalassemia major (TM) patients. However, long-term studies are lacking. We reviewed CMR and hepatic MRI T2* imaging on 54 TM patients who had three or more annual measurements. They were managed on various chelation regimens. Patients were grouped according to their degree of cardiac siderosis: severe (T2*, <10 msec), mild to moderate (T2* = 10-20 msec), and no cardiac siderosis (T2*, >20 msec). We looked at the change in cardiac T2*, liver iron concentration (LIC) and left ventricular ejection fraction (LVEF) at years 3 and 5. In patients with severe cardiac siderosis, cardiac T2* (mean +/- SD) improved from 6.9 +/- 1.6 at baseline to 13.6 +/- 10.0 by year 5, mean DeltaT2* = 6.7 (P = 0.04). Change in cardiac T2* at year 3 was not significant in the severe group. Patients with mild to moderate cardiac siderosis had mean cardiac T2* of 14.6 +/- 2.9 at baseline which improved to 26.3 +/- 9.5 by year 3, mean DeltaT2* = 1.7 (P = 0.01). At baseline, median LICs (mg/g dry weight) in patients with severe, mild-moderate, and no cardiac siderosis were 3.6, 2.8, and 3.3, whereas LVEFs (mean +/- SD) (%) were 56.3 +/- 10.1, 60 +/- 5, and 66 +/- 7.6, respectively. No significant correlation was noted between Delta cardiac T2* and Delta LIC, Delta cardiac T2*, and Delta LVEF at years 3 and 5. Throughout the observation period, patients with no cardiac siderosis maintained their cardiac T2* above 20 msec. The majority of patients with cardiac siderosis improve cardiac T2* over time with optimal chelation. PMID- 23640780 TI - Differential detection of Zn2+ and Cd2+ ions by BODIPY-based fluorescent sensors. AB - Two monostyryl BODIPY derivatives that contain one or two bis(hydroxyamido)amino group(s) as the metal chelator have been prepared. The effects of various metal ions on their electronic absorption and fluorescence properties have been studied in detail in MeCN or in phosphate buffered saline (PBS). The results show that the derivative with two hydroxyamide chains can selectively detect Zn(2+) ions in MeCN. The compound and ions bind in a 1:1 stoichiometry with an association constant of 2.2(+/-0.1)*10(4) M(-1). The intensity of the fluorescence emission increases remarkably and is substantially blue-shifted from 624 to 572 nm, owing to the inhibition of intramolecular charge transfer, thus allowing its use as a ratiometric fluorescent sensor for Zn(2+) ions. The derivative with four hydroxyamide chains behaves differently: It responds selectively toward Cd(2+) ions in phosphate buffered saline. The compound and ions bind in a 1:2 stoichiometry, with first and second association constants of 4.4(+/-0.9)*10(4) M(-1) and 1.3(+/-0.1)*10(4) M(-1), respectively. Upon the addition of 80 equivalents of Cd(2+) ions, the fluorescence quantum yield increases 15-fold. Both of these compounds exhibit differential sensing of Zn(2+) and Cd(2+) ions and the associated color changes can be easily seen by the naked eye. PMID- 23640779 TI - Evidence for core 2 to core 1 O-glycan remodeling during the recycling of MUC1. AB - The apical transmembrane glycoprotein MUC1 is endocytosed to recycle through the trans-Golgi network (TGN) or Golgi complex to the plasma membrane. We followed the hypothesis that not only the known follow-up sialylation of MUC1 in the TGN is associated with this process, but also a remodeling of O-glycan core structures, which would explain the previously described differential core 2- vs core 1-based O-glycosylation of secreted, single Golgi passage and recycling membrane MUC1 isoforms (Engelmann K, Kinlough CL, Muller S, Razawi H, Baldus SE, Hughey RP, Hanisch F-G. 2005. Glycobiology. 15:1111-1124). Transmembrane and secreted MUC1 probes show trafficking-dependent changes in O-glycan core profiles. To address this novel observation, we used recombinant epitope-tagged MUC1 (MUC1-M) and mutant forms with abrogated clathrin-mediated endocytosis (MUC1 M-Y20,60N) or blocked recycling (palmitoylation-defective MUC1-M-CQC/AQA). We show that the CQC/AQA mutant transits the TGN at significantly lower levels, concomitant with a strongly reduced shedding from the plasma membrane and its accumulation in endosomal compartments. Intriguingly, the O-glycosylation of the shed MUC1 ectodomain subunit changes from preponderant sialylated core 1 (MUC1-M) to core 2 glycans on the non-recycling CQC/AQA mutant. The O-glycoprofile of the non-recycling CQC/AQA mutant resembles the core 2 glycoprofile on a secretory MUC1 probe that transits the Golgi complex only once. In contrast, the MUC1-M Y20,60N mutant recycles via flotillin-dependent pathways and shows the wild-type phenotype with dominant core 1 expression. Differential radiolabeling of protein with [(35)S]Met/Cys or glycans with [(3)H]GlcNH2 in pulse-chase experiments of surface biotinylated MUC1 revealed a significantly shorter half-life of [(3)H]MUC1 when compared with [(35)S]MUC1, whereas the same ratio for the CQC/AQA mutant was close to one. This finding further supports the novel possibility of a recycling-associated O-glycan processing from Gal1-4GlcNAc1-6(Gal1-3)GalNAc (core 2) to Gal1-3GalNAc (core 1). PMID- 23640781 TI - Distortion of the anterior part of the interhemispheric fissure: significance and implications for prenatal diagnosis. AB - In order to illustrate the significance of a new anatomical finding, distortion of the interhemispheric fissure (DIHF) associated with impacted medial borders of the frontal lobes, we report a retrospective observational study of 13 fetuses in which DIHF was identified on prenatal imaging. In 10 cases there were associated anatomical anomalies, including mainly midline anomalies (syntelencephaly (n=2), lobar holoprosencephaly (n=1), Aicardi syndrome (n=2)), but also schizencephaly (n=1), cortical dysplasia (n=1) and more complex cerebral malformations (n=3), including neural tube defect in two cases. Chromosomal anomaly was identified in two cases, including 6p deletion in a case without associated central nervous system anomalies and a complex mosaicism in one of the cases with syntelencephaly. In two cases, the finding was apparently isolated on both pre- and postnatal imaging, and the children were doing well at follow-up, aged 4 and 5 years. The presence of DIHF on prenatal imaging may help in the diagnosis of cerebral anomalies, especially those involving the midline. If DIHF is apparently isolated on prenatal ultrasound, magnetic resonance imaging is recommended for careful analysis of gyration and midline, especially optic and olfactory structures. Karyotyping is also recommended. PMID- 23640783 TI - How effective is the cognitive interview when used with adults with intellectual disabilities specifically with conversation recall? AB - BACKGROUND: The cognitive interview (CI) has been shown to increase correct memory recall of a diverse range of participant types, without an increase in the number of incorrect or confabulated details. However, it has rarely been examined for use with adults with intellectual disability. MEASURES AND METHOD: This study compared the memory recall of twenty-one adults with a mild intellectual disability (ID) (IQ 70-50) and twenty-one adults from the general population (GP). Participants viewed a film of a staged distraction theft and were interviewed using either the CI or the structured interview (SI). RESULTS: The CI, when compared to the SI, enhanced the correct recall of person, action and conversation (gist) detail for both participant types, without increasing the number of incorrect or confabulated details reported. The ID group reported significantly less correct information than the GP regardless of the interview used. CONCLUSION: The findings suggest that the CI can enable adults with intellectual disability to provide a fuller picture about an experienced event. Implications of this research are discussed. PMID- 23640782 TI - Early gene expression changes by Epstein-Barr virus infection of B-cells indicate CDKs and survivin as therapeutic targets for post-transplant lymphoproliferative diseases. AB - Lymphoproliferative diseases (LPDs) associated with Epstein-Barr virus (EBV) infection cause significant morbidity and mortality in bone marrow and solid organ transplant recipients. To gain insight into LPD pathogenesis and to identify potential effective therapeutic approaches, we investigated early molecular events leading to B-cell transformation by gene expression profiling of EBV-infected B-cells from tonsils by Affymetrix microarray 72 hr postinfection when the B-cells hyperproliferation phase starts. Cell cycle and apoptosis were the most significantly affected pathways and enriched gene sets. In particular, we found significantly increased expression of cyclin-dependent kinase (CDK)1 and CCNB1 (cyclin B1) and of one of their downstream targets BIRC5 (survivin). Importantly, the strong upregulation of the antiapoptotic protein survivin was confirmed in lymphoblastoid cell lines (LCLs) and 71% of EBV-positive post transplant EBV-LPD lesions scored positive for survivin. The validity of early transforming events for the identification of therapeutic targets for EBV-LPD was confirmed by the marked antiproliferative effect of the CDK inhibitor flavopiridol on LCLs and by the strong induction of apoptosis by survivin inhibition with YM155 or terameprocol. Our results suggest that targeting of CDKs and/or survivin in post-transplant EBV-LPD by specific inhibitors might be an important approach to control and eliminate EBV-transformed B-cells that should be further considered. PMID- 23640784 TI - Adipose tissue-derived mesenchymal stem cells as monocultures or cocultures with human umbilical vein endothelial cells: performance in vitro and in rat cranial defects. AB - The aim of this study was to compare the osteogenic capacity between human adipose tissue-derived mesenchymal stem cells (AT-MSCs) and their cocultures with human umbilical vein endothelial cells (HUVECs) in vitro and their biological performance in vivo. First, the optimal cell ratio in cocultures for osteogenic differentiation was determined by seeding AT-MSCs and HUVECs in ratios varying from 100:0 to 0:100 on tissue culture plates. Afterward, AT-MSCs and AT MSCs/HUVECs (50:50) were seeded on porous titanium fiber mesh scaffolds (Ti) for both in vitro and in vivo osteogenic evaluation. For in vitro evaluation, cell osteogenic differentiation was assessed by alkaline phosphatase (ALP) activity and calcium assay. For in vivo evaluation, the scaffolds were implanted bilaterally into rat cranial defects (5 mm diameter) and bone formation was assessed histologically and histomorphometrically after 8 weeks. The ratio of 50:50 was chosen in the cocultures because this coculture condition retained similar amount of calcium deposition while using the least amount of AT-MSCs. Moreover, AT-MSCs showed higher osteogenic differentiation in comparison to AT MSCs/HUVECs on Ti in vitro. Furthermore, superior bone formation was observed in AT-MSCs compared to AT-MSCs/HUVECs in rat cranial defects. In conclusion, AT-MSCs showed significantly higher osteogenic potential compared to AT-MSCs/HUVECs both in vitro and in vivo. PMID- 23640786 TI - Reconstruction of retrospective cardiac activity--numerical study in a single cell and in a linear strand. AB - Although computational modeling of the prospective electrical activity in the cardiac tissue is well established and robust, the retrospective extrapolation of this activity has not been explored to date. Here, we establish an algorithm for the backward-in-time extrapolation of electrical activity from measurements taken in the present. Using minimal human cardiac kinetic models and a modified Newton Raphson algorithm, we demonstrate the feasibility of past activity reconstruction in a single cell and in a linear strand. In a single cell, reconstruction of state variables' shape, the action potential morphology, and the time of stimulation was successful for up to 1300 ms poststimulation and for data with signal-to-noise ratio levels higher than 40 dB. For linear strands, the action potential morphology was reconstructed for 500 ms poststimulation, and the reconstructed conduction velocity remained unaffected for signal-to-noise ratio levels higher than 50 dB. Moreover, tissue restitution properties due to various pacing rates were successfully reconstructed by the backward-in-time algorithm. These preliminary results demonstrate that past cardiac activity may be reconstructed from measurements in the present. We envision that this methodology could be implemented in future clinical applications, for example to trace the location and timing of ectopic foci during ablation procedures. PMID- 23640785 TI - Physician factors affecting cardiac rehabilitation referral and patient enrollment: a systematic review. AB - Physicians play an important role in CR referral and enrollment. Despite established benefits and recommendations, cardiac rehabilitation (CR) enrollment rates are pervasively low. The reasons cardiac patients are missing from CR programs are multifactorial and include provider factors. A number of studies have now investigated physician factors associated with referral to CR programs and patient enrollment. The objective of this study was to qualitatively and systematically review this literature. A literature search of MEDLINE, PsycINFO, CINAHL, Embase, and EBM was conducted for published articles from database inception to October 2011. Overall, 17 articles were included following a process of independent review of each article by 2 authors. Seven (41.2%) were graded as good quality according to Downs and Black criteria. There were no randomized controlled trials. Results showed that medical specialty (ie, cardiac specialists more likely to refer; n = 8 studies) and other physician-reported reasons (eg, physician report of their reasons for CR referral and physician sex) were related to referral. Physician factors related to patient enrollment in CR were physician endorsement, medical specialty, being referred, and physician attitudes toward CR. Physician factors are consistently related to CR referral and enrollment. The role of physician endorsements in promoting patient enrollment should be optimized and exploited. PMID- 23640787 TI - Catalase has a key role in protecting cells from the genotoxic effects of monomethylarsonous acid: a highly active metabolite of arsenic. AB - Although it is widely known that arsenic-contaminated drinking water causes many diseases, arsenic's exact mode of action (MOA) is not fully understood. Induction of oxidative stress has been proposed as an important key event in the toxic MOA of arsenic. The authors' studies are centered on identifying a reactive species involved in the genotoxicity of arsenic using a catalase (CAT) knockout mouse model that is impaired in its ability to breakdown hydrogen peroxide (H2 O2 ). The authors assessed the induction of DNA damage using the Comet assay following exposure of mouse Cat(+/) (+) and Cat(-) (/) (-) primary splenic lymphocytes to monomethylarsonous acid (MMA(III) ) to identify the potential role of H2 O2 in mediating cellular effects of this metalloid. The results showed that the Cat(-) (/) (-) lymphocytes are more susceptible to MMA(III) than the Cat(+/) (+) lymphocytes by a small (1.5-fold) but statistically significant difference. CAT activity assays demonstrated that liver tissue has approximately three times more CAT activity than lymphocytes. Therefore, Comet assays were performed on primary Cat(+/) (+) , Cat(+/) (-) , and Cat(-) (/) (-) hepatocytes to determine if the Cat(-) (/) (-) cells were more susceptible to MMA(III) than lymphocytes. The results showed that the Cat(-) (/) (-) hepatocytes exhibit higher levels of DNA strand breakage than the Cat(+/) (+) (approximately fivefold) and Cat(+/) (-) (approximately twofold) hepatocytes exposed to MMA(III) . Electron spin resonance using 5,5-dimethyl-1-pyrroline-N-oxide as the spin-trap agent detected the generation of .OH via MMA(III) when H2 O2 was present. These experiments suggest that CAT is involved in protecting cells against the genotoxic effects of the .OH generated by MMA(III) . PMID- 23640788 TI - Material and structural properties of fin whale (Balaenoptera physalus) Zwischensubstanz. AB - The oral anatomy of the fin whale (Balaenoptera physalus) consists of several major structures crucial to its engulfment method of feeding, such as stiff keratinized baleen plates, a large flaccid tongue, and a prominent vomer. One under-documented part of this anatomy is the cream white Zwischensubstanz that holds the baleen plates to the rostrum at their dorsal base. The mechanical and structural properties of Zwischensubstanz play a key role in baleen plate dynamics and, on the grand scale, contribute to baleen whales' filtration efficiency and attainment of large body size. Compression and tensile tests on the Zwischensubstanz sampled from an 18 m fin whale showed that this material unexpectedly exhibits linear isotropic behaviour with Elastic Modulus of 2.56 +/- 0.60 MPa and hysteresis of 0.44 +/- 0.02 in compression despite apparent unidirectional growth. Acting similar to a soft rubber, the Zwischensubstanz absorbs and dissipates the enormous forces acting on baleen plates during engulfment feeding while maintaining spacing between the plates to maximize filtration efficiency. Microscopic analysis provided images of connective tissue papillae penetrating the base of the Zwischensubstanz and developing within it to emerge as fully formed, keratinized baleen plates. The plates develop from the papillae and a connective tissue sheet within the 5-7 cm deep Zwischensubstanz. The Zwischensubstanz provides a keratin matrix of concentrically oriented fibers around each papilla forming the hard baleen plates and frayed fringes used for filter feeding. During this formation, the Zwischensubstanz remains unchanged and appears to slough away to allow the baleen plate to grow unhindered. PMID- 23640789 TI - 2,3-Di(2-pyridyl)-5-phenylpyrazine: a NN-CNN-type bridging ligand for dinuclear transition-metal complexes. AB - A new bridging ligand, 2,3-di(2-pyridyl)-5-phenylpyrazine (dpppzH), has been synthesized. This ligand was designed so that it could bind two metals through a NN-CNN-type coordination mode. The reaction of dpppzH with cis-[(bpy)2RuCl2] (bpy = 2,2'-bipyridine) affords monoruthenium complex [(bpy)2Ru(dpppzH)](2+) (1(2+)) in 64 % yield, in which dpppzH behaves as a NN bidentate ligand. The asymmetric biruthenium complex [(bpy)2Ru(dpppz)Ru(Mebip)](3+) (2(3+)) was prepared from complex 1(2+) and [(Mebip)RuCl3] (Mebip = bis(N-methylbenzimidazolyl)pyridine), in which one hydrogen atom on the phenyl ring of dpppzH is lost and the bridging ligand binds to the second ruthenium atom in a CNN tridentate fashion. In addition, the RuPt heterobimetallic complex [(bpy)2Ru(dpppz)Pt(C=CPh)](2+) (4(2+)) has been prepared from complex 1(2+), in which the bridging ligand binds to the platinum atom through a CNN binding mode. The electronic properties of these complexes have been probed by using electrochemical and spectroscopic techniques and studied by theoretical calculations. Complex 1(2+) is emissive at room temperature, with an emission lambdamax = 695 nm. No emission was detected for complex 2(3+) at room temperature in MeCN, whereas complex 4(2+) displayed an emission at about 750 nm. The emission properties of these complexes are compared to those of previously reported Ru and RuPt bimetallic complexes with a related ligand, 2,3-di(2-pyridyl)-5,6-diphenylpyrazine. PMID- 23640790 TI - Evaluating myometrial and cervical invasion in women with endometrial cancer: comparing subjective assessment with objective measurement techniques. AB - OBJECTIVE: To compare the diagnostic accuracy of subjective ultrasound assessment with that of objective measurement techniques in the evaluation of myometrial and cervical invasion in women with endometrial cancer. METHODS: This was a prospective multicenter study including 144 women with endometrial cancer undergoing transvaginal ultrasound. Myometrial and cervical invasion was evaluated subjectively, as well as objectively measured in different ways: endometrial thickness, tumor/uterine anteroposterior (AP) diameter ratio, minimal tumor-free margin, minimal tumor-free margin/uterine AP diameter ratio, tumor volume (three-dimensional (3D)), tumor/uterine volume (3D) ratio, and distance from outer cervical os to lower margin of tumor (Dist-OCO). Histological assessment following hysterectomy was the gold standard. RESULTS: The sensitivity (72%) and specificity (76%) of tumor/uterine AP diameter (at cut-off, 0.53) were not significantly different from those of subjective evaluation (sensitivity, 77% (P = 0.44); specificity, 81% (P = 0.32)) for the prediction of deep myometrial invasion; all other objective measurement techniques had either a significantly lower sensitivity or a lower specificity. For all objective measurement techniques, except minimal tumor-free margin/uterine AP diameter ratio, fixing the sensitivity at the same level as that of subjective evaluation (i.e. 77%) gave a significantly lower specificity. Dist-OCO was the only parameter that might have potential to predict cervical invasion; it had a non-significantly higher sensitivity than did subjective evaluation (73% vs 54%, P = 0.06), but a significantly lower specificity (63% vs 93%, P < 0.001). CONCLUSION: Subjective assessment of cervical and myometrial invasion is as good as or better than any objective measurement technique. The tumor/uterine AP diameter ratio and minimal tumor-free margin/uterine AP diameter ratio seem to be the best objective measurement techniques to predict deep myometrial invasion. It remains to be shown if objective measurements are useful to predict cervical invasion. PMID- 23640791 TI - Adjusting for matching and covariates in linear discriminant analysis. AB - In studies that compare several diagnostic or treatment groups, subjects may not only be measured on a certain set of feature variables, but also be matched on a number of demographic characteristics and measured on additional covariates. Linear discriminant analysis (LDA) is sometimes used to identify which feature variables best discriminate among groups, while accounting for the dependencies among the feature variables. We present a new approach to LDA for multivariate normal data that accounts for the subject matching used in a particular study design, as well as covariates not used in the matching. Applications are given for post-mortem tissue data with the aim of comparing neurobiological characteristics of subjects with schizophrenia with those of normal controls, and for a post-mortem tissue primate study comparing brain biomarker measurements across three treatment groups. We also investigate the performance of our approach using a simulation study. PMID- 23640792 TI - In vitro response to alkaline phosphatase coatings immobilized onto titanium implants using electrospray deposition or polydopamine-assisted deposition. AB - Immobilization of biomolecules onto implant surfaces is one of the most straightforward strategies to control the interaction between an implant and its biological environment. Recently, it was shown that the enzyme alkaline phosphatase (ALP) could be efficiently immobilized onto titanium implants in a single step using polydopamine. We hypothesized that such polydopamine-ALP coatings can enhance the early attachment of cells and increase mineralization. Therefore, the current study aimed at immobilization of ALP onto titanium by means of either one- or two-step polydopamine-assisted immobilization or electrospray deposition, the comparative characterization of these experimental substrates and subsequent cell behavioral analysis using primary osteoblast-like cells. Uncoated titanium and ALP-free polydopamine coatings served as controls. Despite significant ALP surface activity and lower water contact for angles ALP containing surface modifications, only marginal effects on early cell behavior (i.e., cell spreading) and osteogenic differentiation (i.e., proliferation, differentiation and mineralization) were observed in comparison to uncoated titanium. PMID- 23640793 TI - Skin wound healing in different aged Xenopus laevis. AB - Xenopus froglets can perfectly heal skin wounds without scarring. To explore whether this capacity is maintained as development proceeds, we examined the cellular responses during the repair of skin injury in 8- and 15-month-old Xenopus laevis. The morphology and sequence of healing phases (i.e., inflammation, new tissue formation, and remodeling) were independent of age, while the timing was delayed in older frogs. At the beginning of postinjury, wound re-epithelialization occurred in form of a thin epithelium followed by a multilayered epidermis containing cells with apoptotic patterns and keratinocytes stained by anti-inducible nitric oxide synthase (iNOS) antibody. The inflammatory response, early activated by recruitment of blood cells immunoreactive to anti tumor necrosis factor (TNF)-alpha, iNOS, transforming growth factor (TGF)-beta1, and matrix metalloproteinase (MMP)-9, persisted over time. The dermis repaired by a granulation tissue with extensive angiogenesis, inflammatory cells, fibroblasts, and anti-alpha-SMA positive myofibroblasts. As the healing progressed, wounded areas displayed vascular regression, decrease in cellularity, and rearrangement of provisional matrix. The epidermis restored to a prewound morphology while granulation tissue was replaced by a fibrous tissue in a scar like pattern. The quantitative PCR analysis demonstrated an up-regulated expression of Xenopus suppressor of cytokine signaling 3 (XSOCS-3) and Xenopus transforming growth factor-beta2 (XTGF-beta2) soon after wounding and peak levels were detected when granulation tissue was well developed with a large number of inflammatory cells. The findings indicate that X. laevis skin wound healing occurred by a combination of regeneration (in epidermis) and repair (in dermis) and, in contrast to froglet scarless wound healing, the growth to a more mature adult stage is associated with a decrease in regenerative capacity with scar-like tissue formation. PMID- 23640794 TI - Reconstruction of a robust glycodiagnostic agent supported by multiple lectin assisted glycan profiling. AB - PURPOSE: Wisteria floribunda agglutinin positive human Mac-2-binding protein (WFA(+)-hM2BP) was recently validated as a liver fibrosis glycobiomarker with a fully automated lectin-antibody sandwich immunoassay. In this study, we supplied recombinant WFA(+)-hM2BP as the standard glycoprotein and the overlaid antibody to enhance the robustness of WFA(+)-hM2BP quantification. EXPERIMENTAL DESIGN: The optimum conditions for producing recombinant WFA(+)-hM2BP were selected by cell glycome analysis based on a lectin microarray. Interlot variability of recombinant WFA(+)-hM2BP was determined using an antibody-overlay lectin microarray. Screening of anti-M2BP mAb was completed by incorporating a WFA antibody sandwich ELISA and an antibody-overlay lectin microarray. RESULTS: The lectin microarray analysis revealed that human embryonic kidney 293 cells efficiently and stably produced WFA(+)-hM2BP in DMEM containing 10% FCS without any variation in the M2BP glycosylation level. A spiking experiment with recombinant WFA(+)-hM2BP was mostly effective for antibody screening. The reconstituted sandwich immunoassay was useful for the continuous quantification and cutoff index expression of serum WFA(+)-hM2BP. CONCLUSIONS AND CLINICAL RELEVANCE: The multiple use of lectin-assisted glycan profiling enabled us to construct a reliable sandwich assay kit for monitoring liver fibrosis in patients with viral hepatitis. This will assist in the development pipeline for other glycodiagnostic agents. PMID- 23640795 TI - Characterization of B-cell subpopulations in patients with chronic rhinosinusitis. AB - BACKGROUND: Recent research suggest that B and plasma cells may play an important role in the pathogenesis of chronic rhinosinusitis with nasal polyposis (CRSwNP). The purpose of this study was to subcharacterize the B cell response in the sinus mucosa of control and CRS patients. METHODS: Representative tissue samples and peripheral blood samples were obtained from controls, CRS without nasal polyps (CRSsNP) and CRSwNP. Using single-cell suspension flow cytometry these samples were analyzed for overall and stage-specific B and plasma cell percentages. RESULTS: Both atopic and nonatopic CRSwNP patients showed an increase in local numbers of naive, active, and memory B cells compared to controls. CRSsNP patients only showed local elevations of naive B cells. Plasma cells were only significantly elevated in the sinus tissue of atopic CRSwNP patients. These local tissue increases did not correlate with increased numbers of circulating B cells. CONCLUSION: This study provides further evidence of an important role of B cells in CRSwNP patients. The local increase appears to be independent of a systemic response. PMID- 23640797 TI - Effect of exposure to Special Olympic Games on attitudes of volunteers towards inclusion of people with intellectual disabilities. AB - BACKGROUND: The aim of this study was to examine the effect of volunteering for Special Olympics Games (SOG) on the attitudes of volunteers towards inclusion of people with intellectual disabilities. METHOD: A repeated measures design with 3 week follow-up was used. There were 100 volunteers recruited for the study and 90 of them completed the study. RESULTS: It was revealed that a 1-week exposure to the SOG improved volunteers' attitudes towards inclusion of people with intellectual disabilities significantly (P = 0.016). Females had more positive attitudes than males at all three time points of measures. The interaction effect of gender was not significant. CONCLUSIONS: A 1-week exposure to the SOG can enhance volunteers' positive attitudes towards inclusion of people with intellectual disabilities and this effect can maintain for up to a month. PMID- 23640796 TI - Distinct glutamatergic and GABAergic subsets of hypothalamic pro-opiomelanocortin neurons revealed by in situ hybridization in male rats and mice. AB - Pro-opiomelanocortin (POMC) and agouti-related protein (AGRP) neurons in the hypothalamus regulate various aspects of energy homeostasis and metabolism. POMC and AGRP neurons, respectively, agonize and antagonize melanocortin receptors on their common downstream neurons. However, it is unknown whether they also reciprocally stimulate and inhibit the same neurons by amino acid transmitters. Whereas AGRP neurons are mostly GABAergic, surprisingly, only a small population of POMC neurons has been found to be glutamatergic, and a significantly larger subpopulation to be GABAergic. To further examine amino acid phenotypes of POMC neurons, we studied mRNA expression for the glutamatergic marker, type 2 vesicular glutamate transporter (VGLUT2), and the GABA synthetic enzyme, glutamic acid decarboxylase 67 (GAD67), in POMC neurons of both rats and mice by using in situ hybridization techniques. In rats, approximately 58% of POMC neurons were labeled for VGLUT2 and 37% for GAD67 mRNA. In mice, approximately 43% of POMC neurons contained VGLUT2, and 54% contained GAD67 mRNA. In both species, a prominent mediolateral distribution pattern was observed at rostral and mid levels of the POMC cell group with VGLUT2-POMC neurons dominating in lateral portions and GAD67-POMC neurons in medial portions. These data demonstrate that both glutamatergic and GABAergic cells are present in comparably significant numbers among POMC neurons. Their glutamatergic or GABAergic phenotype may represent a major functional division within the POMC cell group. PMID- 23640798 TI - UDP-glucose enhances outward K(+) currents necessary for cell differentiation and stimulates cell migration by activating the GPR17 receptor in oligodendrocyte precursors. AB - In the developing and mature central nervous system, NG2 expressing cells comprise a population of cycling oligodendrocyte progenitor cells (OPCs) that differentiate into mature, myelinating oligodendrocytes (OLGs). OPCs are also characterized by high motility and respond to injury by migrating into the lesioned area to support remyelination. K(+) currents in OPCs are developmentally regulated during differentiation. However, the mechanisms regulating these currents at different stages of oligodendrocyte lineage are poorly understood. Here we show that, in cultured primary OPCs, the purinergic G-protein coupled receptor GPR17, that has recently emerged as a key player in oligodendrogliogenesis, crucially regulates K(+) currents. Specifically, receptor stimulation by its agonist UDP-glucose enhances delayed rectifier K(+) currents without affecting transient K(+) conductances. This effect was observed in a subpopulation of OPCs and immature pre-OLGs whereas it was absent in mature OLGs, in line with GPR17 expression, that peaks at intermediate phases of oligodendrocyte differentiation and is thereafter downregulated to allow terminal maturation. The effect of UDP-glucose on K(+) currents is concentration dependent, blocked by the GPR17 antagonists MRS2179 and cangrelor, and sensitive to the K(+) channel blocker tetraethyl-ammonium, which also inhibits oligodendrocyte maturation. We propose that stimulation of K(+) currents is responsible for GPR17-induced oligodendrocyte differentiation. Moreover, we demonstrate, for the first time, that GPR17 activation stimulates OPC migration, suggesting an important role for this receptor after brain injury. Our data indicate that modulation of GPR17 may represent a strategy to potentiate the post traumatic response of OPCs under demyelinating conditions, such as multiple sclerosis, stroke, and brain trauma. PMID- 23640799 TI - Ligand promiscuity through the eyes of the aminoglycoside N3 acetyltransferase IIa. AB - Aminoglycoside-modifying enzymes (AGMEs) are expressed in many pathogenic bacteria and cause resistance to aminoglycoside (AG) antibiotics. Remarkably, the substrate promiscuity of AGMEs is quite variable. The molecular basis for such ligand promiscuity is largely unknown as there is not an obvious link between amino acid sequence or structure and the antibiotic profiles of AGMEs. To address this issue, this article presents the first kinetic and thermodynamic characterization of one of the least promiscuous AGMEs, the AG N3 acetyltransferase-IIa (AAC-IIa) and its comparison to two highly promiscuous AGMEs, the AG N3-acetyltransferase-IIIb (AAC-IIIb) and the AG phosphotransferase(3')-IIIa (APH). Despite having similar antibiotic selectivities, AAC-IIIb and APH catalyze different reactions and share no homology to one another. AAC-IIa and AAC-IIIb catalyze the same reaction and are very similar in both amino acid sequence and structure. However, they demonstrate strong differences in their substrate profiles and kinetic and thermodynamic properties. AAC-IIa and APH are also polar opposites in terms of ligand promiscuity but share no sequence or apparent structural homology. However, they both are highly dynamic and may even contain disordered segments and both adopt well-defined conformations when AGs are bound. Contrary to this AAC-IIIb maintains a well-defined structure even in apo form. Data presented herein suggest that the antibiotic promiscuity of AGMEs may be determined neither by the flexibility of the protein nor the size of the active site cavity alone but strongly modulated or controlled by the effects of the cosubstrate on the dynamic and thermodynamic properties of the enzyme. PMID- 23640800 TI - CD8A gene polymorphisms predict severity factors in chronic rhinosinusitis. AB - BACKGROUND: A genetic basis to chronic rhinosinusitis (CRS) is postulated, but remains elusive. We have recently identified low levels of circulating CD8 lymphocytes as a frequent finding in difficult-to-treat or refractory CRS. In major histocompatibility complex 1 class 1 (MHC1) deficiency, low circulating levels of CD8 lymphocytes secondary to mutations in the cluster of differentiation 8a (CD8A), tapasin 1 (TAP1), tapasin 2 (TAP2), or tapasin binding protein (TAPBP) genes lead to a clinical syndrome, which is associated with severe CRS. The objective of this work was to identify whether genetic factors associated with MHC1 deficiency are present in CRS. METHODS: Previous results from a genomewide association study of CRS were screened for polymorphisms in the CD8A, TAP1, TAP2, and TAPBP genes associated with MHC1 immunodeficiency syndrome. Significant polymorphisms were tested for associations with demographic factors characterizing severe CRS. RESULTS: Polymorphisms in the CD8A (rs3810831) and TAPBP (rs2282851) genes were significantly associated with CRS. Major allele homozygosity for CD8A (rs3810831) was associated with a higher frequency of affected relatives (p = 0.052), increased severity as characterized by age at diagnosis (p = 0.009), age at first surgery (p = 0.004), and number of surgeries (p = 0.008), whereas TAPBP (rs2282851) was associated increased risk for CRS (odds ratio [OR] = 2.48, p = 0.0076). CONCLUSION: Modified CD8A or TAPBP gene function may contribute to the development of refractory CRS via altered MHC1 function and reduction of circulating CD8 lymphocytes. Identification of markers in the CD8A or TAPBP genes via sequencing may offer a basis for genetic testing in CRS. PMID- 23640801 TI - C-arm CT for histomorphometric evaluation of lumbar spine trabecular microarchitecture: a study on anorexia nervosa patients. AB - Bone histomorphometry measurements require high spatial resolution that may not be feasible using multidetector CT (MDCT). This study evaluated the trabecular microarchitecture of lumbar spine using MDCT and C-arm CT in a series of young adult patients with anorexia nervosa (AN). 11 young females with AN underwent MDCT (anisotropic resolution with a slice thickness of ~626 MUm) and C-arm CT (isotropic resolution of ~200 um). Standard histomorphometric parameters the of L1 vertebral body, namely the apparent trabecular bone volume fraction (BV/TV), trabecular thickness (TbTh), trabecular number (TbN) and trabecular separation (TbSp), were analysed using MicroView software (GE Healthcare, Piscataway, NJ). Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Trabecular parameters derived from MDCT and C-arm CT were compared, and their association with BMD parameters was evaluated. Histomorphometric parameters derived from C-arm CT, namely TbTh, TbN and TbSp, were significantly different from the corresponding MDCT parameters. There were no significant correlations between C-arm CT-derived parameters and the corresponding MDCT-derived parameters. C-arm CT-derived parameters were significantly (p<0.001) correlated with anteroposterior L1 spine BMD and Z-scores: TbTh (r=0.723, r=0.744, respectively), TbN (r=-0.720, r=-0.712, respectively) and TbSp (r=0.656, r=0.648, respectively). BV/TV, derived from C-arm CT, was significantly associated with body mass index (r=0.636) and ideal body weight (r=0.730) (p<0.05). These associations were not present in MDCT-derived parameters. This study suggests that the spatial resolution offered by C-arm CT more accurately captures the histomorphometric parameters of trabecular morphology than MDCT in patients with AN. PMID- 23640802 TI - The use of X-shaped cross-link in posterior spinal constructs improves stability in thoracolumbar burst fracture: a finite element analysis. AB - Posterior instrumentation is a common fixation method used to treat thoracolumbar burst fractures. However, the role of different cross-link configurations in improving fixation stability in these fractures has not been established. A 3D finite element model of T11-L3 was used to investigate the biomechanical behavior of short (2 level) and long (4 level) segmental spine pedicle screw fixation with various cross-links to treat a hypothetical L1 vertebra burst fracture. Three types of cross-link configurations with an applied moment of 7.5 Nm and 200 N axial force were evaluated. The long construct was stiffer than the short construct irrespective of whether the cross-links were used (p < 0.05). The short constructs showed no significant differences between the cross-link configurations. The XL cross-link provided the highest stiffness and was 14.9% stiffer than the one without a cross-link. The long construct resulted in reduced stress to the adjacent vertebral bodies and screw necks, with 66.7% reduction in bending stress on L2 when the XL cross-link was used. Thus, the stability for L1 burst fracture fixation was best achieved by using long segmental posterior instrumentation constructs and an XL cross-link configuration. Cross-links did not improved stability when a short structure was used. PMID- 23640804 TI - Nucleic acid-modified nanostructures as programmable atom equivalents: forging a new "table of elements". PMID- 23640803 TI - Characterization of the trunk neural crest in the bamboo shark, Chiloscyllium punctatum. AB - The neural crest is a population of mesenchymal cells that after migrating from the neural tube gives rise to structure and cell types: the jaw, part of the peripheral ganglia, and melanocytes. Although much is known about neural crest development in jawed vertebrates, a clear picture of trunk neural crest development for elasmobranchs is yet to be developed. Here we present a detailed study of trunk neural crest development in the bamboo shark, Chiloscyllium punctatum. Vital labeling with dioctadecyl tetramethylindocarbocyanine perchlorate (DiI) and in situ hybridization using cloned Sox8 and Sox9 probes demonstrated that trunk neural crest cells follow a pattern similar to the migratory paths already described in zebrafish and amphibians. We found shark trunk neural crest along the rostral side of the somites, the ventromedial pathway, the branchial arches, the gut, the sensory ganglia, and the nerves. Interestingly, C. punctatum Sox8 and Sox9 sequences aligned with vertebrate SoxE genes, but appeared to be more ancient than the corresponding vertebrate paralogs. The expression of these two SoxE genes in trunk neural crest cells, especially Sox9, matched the Sox10 migratory patterns observed in teleosts. Also of interest, we observed DiI cells and Sox9 labeling along the lateral line, suggesting that in C. punctatum, glial cells in the lateral line are likely of neural crest origin. Although this has been observed in other vertebrates, we are the first to show that the pattern is present in cartilaginous fishes. These findings demonstrate that trunk neural crest cell development in C. punctatum follows the same highly conserved migratory pattern observed in jawed vertebrates. PMID- 23640806 TI - Biodegradable radiopaque iodinated poly(ester urethane)s containing poly(epsilon caprolactone) blocks: synthesis, characterization, and biocompatibility. AB - Biodegradable radiopaque iodinated poly(ester-urethane) (I-PU), consisting of poly(epsilon-caprolactone) (PCL) diol and iodinated bisphenol A (IBPA), has been successfully synthesized via a coupling reaction of PCL-diisocyanate and IBPA with varying compositions. The IBPA with four iodine atoms per molecule was applied as a chain extender to endow the I-PUs with intrinsic X-ray visibility. The chemical structure and molecular weights of I-PUs were characterized by Fourier transform infrared spectroscopy (FT-IR), proton-nuclear magnetic resonance, and gel permeation chromatography (GPC). The effects of IBPA on the physical properties of I-PUs were systematically studied by means of differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and wide-angle X ray diffraction (WAXD). The DSC results showed that the crystallization of PCL segments in I-PUs was restrained with increasing amount of IBPA, which was also confirmed by WAXD. In the X-radiography analysis, all the synthesized I-PUs exhibited high radiopacity compared with an aluminum wedge of equivalent thickness. Enzymatic degradation tests showed that the incorporation of IBPA prolonged the degradation of I-PUs and distinct mass loss and degradation happened in the third month. Basic cytocompatibility conducted using rat adipose derived cells proved that all the I-PUs and their biodegradation products were nontoxic. The radiopaque I-PUs is expected to possess a significant advantage over the traditional polymer counterparts in some related biomedical fields. PMID- 23640805 TI - O-GlcNAcomics--Revealing roles of O-GlcNAcylation in disease mechanisms and development of potential diagnostics. AB - O-linked-beta-N-acetylglucosamine (O-GlcNAc) is a dynamic PTM of the 3'-hydroxyl groups of serine or threonine residues of nuclear, cytoplasmic, and mitochondrial proteins. The cycling of this modification is regulated in response to nutrients, stress, and other extracellular stimuli by the catalytic activities of O-GlcNAc transferase and O-GlcNAcase. O-GlcNAc is functionally similar to phosphorylation and has been demonstrated to play critical roles in numerous biological processes, including cell signaling, transcription, and disease etiology. Since its discovery nearly 30 years ago, studies have demonstrated that the O-GlcNAc is highly abundant and widespread, like phosphorylation however, the development of methodologies to study O-GlcNAc at the site level has been challenging. Recently, a number of studies have overcome these challenges and describe new tagging, enrichment, and mass spectrometric-based approaches to study O-GlcNAc in terms of its site identification, stoichiometry, and dynamics on proteins. The development of these methods are key for elucidation of O-GlcNAc's functional crosstalk with phosphorylation and other PTMs, and will serve to provide the necessary information for the development of site-specific antibodies, which will aid in the determination of a particular protein's site-specific function. In this review, we describe these methods and summarize results obtained from them demonstrating the roles of O-GlcNAc in diabetes, cancer, Alzheimer's, and in learning and memory, while also describing how these new strategies have implicated O-GlcNAc as a potential diagnostic for the screening of patients for prediabetes. PMID- 23640807 TI - Brain-derived neurotrophic factor/TrkB signaling regulates daily astroglial plasticity in the suprachiasmatic nucleus: electron-microscopic evidence in mouse. AB - Synchronization of circadian rhythms to the 24-h light/dark (L/D) cycle is associated with daily rearrangements of the neuronal-glial network of the suprachiasmatic nucleus of the hypothalamus (SCN), the central master clock orchestrating biological functions in mammals. These anatomical plastic events involve neurons synthesizing vasoactive intestinal peptide (VIP), known as major integrators of photic signals in the retinorecipient region of the SCN. Using an analog-sensitive kinase allele murine model (TrkB(F616A) ), we presently show that the pharmacological blockade of the tropomyosin-related kinase receptor type B (TrkB), the high-affinity receptor of brain-derived neurotrophic factor (BDNF), abolished day/night changes in the dendrite enwrapping of VIP neurons by astrocytic processes (glial coverage), used as an index of SCN plasticity on electron-microscopic sections. Therefore, the BDNF/TrkB signaling pathway exerts a permissive role on the ultrastructural rearrangements that occur in SCN under L/D alternance, an action that could be a critical determinant of the well established role played by BDNF in the photic regulation of the SCN. In contrast, the extent of glial coverage of non-VIP neighboring dendrites was not different at daytime and nighttime in TrkB(F616A) mice submitted to TrkB inactivation or not receiving any pharmacological treatment. These data not only show that BDNF regulates SCN structural plasticity across the 24-h cycle but also reinforce the view that the daily changes in SCN architecture subserve the light synchronization process. PMID- 23640808 TI - Mental health diagnoses and recidivism in paroled offenders. AB - Although the issue of mental illness among offender populations has received attention in the last number of years, there are a number of issues related to mental illness among such groups that require more study. One such topic relates to the association between mental illness, actuarially assessed risk of recidivism, and observed rates of reoffending. In the present investigation, file information was reviewed to determine the presence of a variety of mental health conditions. Actuarially based risk assessment data were also collected for participants as well as information regarding suspension, new charges, and convictions. A sample of 136 offenders housed in a halfway house operated by Correctional Service of Canada was included in the present investigation. Results indicated very high rates of serious mental illness in this high-risk population. Offenders with borderline personality disorder and attention deficit hyperactivity disorder were significantly more likely to recidivate or be suspended. Suspensions refer to administrative decisions to place an offender in jail due to problematic behaviour (typically involving a breach of his release conditions or new charges/convictions). Offenders with a diagnosis of paraphilic disorder were significantly less likely to recidivate or be suspended. Results are discussed in light of the available literature. PMID- 23640809 TI - Exploring parenting as a predictor of criminogenic thinking in college students. AB - Crime-promoting cognitions and attitudes, globally labeled as criminogenic thinking, are shown to perpetuate maladaptive and antisocial behavior in criminals and nonoffenders. In the nonoffender population, these thinking patterns may not lead to illegal behavior, but can result in irresponsible or maladaptive behavioral consequences. Theories suggest that early childhood parent child interactions may be partly responsible for the development of criminogenic thinking. While the relationship between parenting and antisocial behavior is well documented, the connection between parenting and the development of criminogenic thinking styles has not yet been explored. The current study examined the nature of the relationship between exposure to parenting behaviors and subsequent criminogenic thoughts in a nonoffender, college population. The sample included 119 undergraduates. Results indicate that parenting may affect general criminogenic thinking as well as specific types of criminogenic thinking styles. Relevance and importance of the findings with regard to clinical work and parenting are also discussed. PMID- 23640811 TI - beta-Hairpin peptides: heme binding, catalysis, and structure in detergent micelles. PMID- 23640810 TI - Vascularized free forearm flap versus free anterolateral thigh perforator flaps for reconstruction in patients with head and neck cancer: assessment of quality of life. AB - BACKGROUND: This study investigated the quality of life of Chinese patients with malignant tumors who had undergone immediate free flap reconstruction surgery. In addition, we compared 2 groups of patients: those who had received radial forearm free flap surgery and others who had received free anterolateral thigh perforator flap surgery. METHODS: Quality of life was assessed using the Medical Outcomes Study-Short Form-36 (MOS SF-36) and the University of Washington Quality of Life (UW-QOL) questionnaires 12 months after reconstruction. RESULTS: A total of 121 of 163 questionnaires were returned (74.2%). There were significant differences between the 2 groups in the T classification (p < .005). Patients reconstructed with free anterolateral thigh perforator flaps performed better in the appearance and shoulder domains, and the role emotion and social functioning domains. CONCLUSIONS: Using either radial forearm free flaps or free anterolateral thigh perforator flaps for reconstruction of head and neck defects after cancer resection significantly influences a patient's quality of life. PMID- 23640813 TI - Morphology of the olivocerebellar projection of the chick: an axonal reconstruction study. AB - The projection pattern of the olivocerebellar (OC) axons, which terminate mainly as climbing fibers (CFs) in the cerebellar cortex, tightly reflects the compartmental and developmental organization of the cerebellum as revealed by mapping and reconstruction studies in the rat. The avian cerebellum is well lobulated and longitudinally compartmentalized like the mammalian cerebellum. However, the projection pattern of the OC axons has not been studied in detail for most areas of the avian cerebellum. In the present study, we reconstructed labeled chick OC axons resulting from a small focal injection of biotinylated dextran amine into the inferior olive to investigate their morphological characteristics, and to determine their relationship to the general morphology of the chick cerebellum. Labeled CFs were distributed basically in a single longitudinally elongated narrow band-shaped area in lobules I-VIII, but in multiple, transversely widened, band-shaped areas in lobules IX-X. Three of the four reconstructed OC axons terminated in a single longitudinally band-shaped area in lobules IXa-c, whereas the other one terminated in multiple mediolaterally separated areas in lobule IXc, which is part of the flocculus. Single OC axons branched into 14 CFs on average. Two CFs occasionally merged to form a single terminal arbor. Axons also had thin, non-CF collaterals that projected either to a cerebellar nucleus or to the cortex. The results indicate that the morphological characteristics of OC axons, including branching and termination, are basically conserved between the chick and the rat. PMID- 23640812 TI - Enrichment strategies in glycomics-based lung cancer biomarker development. AB - PURPOSE: There is a need to identify better glycan biomarkers for diagnosis, early detection, and treatment monitoring in lung cancer using biofluids such as blood. Biofluids are complex mixtures of proteins dominated by a few high abundance proteins that may not have specificity for lung cancer. Therefore, two methods for protein enrichment were evaluated; affinity capturing of IgG and enrichment of medium abundance proteins, thus allowing us to determine which method yields the best candidate glycan biomarkers for lung cancer. EXPERIMENTAL DESIGN: N-glycans isolated from plasma samples from 20 cases of lung adenocarcinoma and 20 matched controls were analyzed using nLC-PGC-chip-TOF-MS (where PGC is porous-graphitized carbon). N-glycan profiles were obtained for five different fractions: total plasma, isolated IgG, IgG-depleted plasma, and the bound and flow-through fractions of protein enrichment. RESULTS: Four glycans differed significantly (false discovery rate, FDR < 0.05) between cases and controls in whole unfractionated plasma, while four other glycans differed significantly by cancer status in the IgG fraction. No significant glycan differences were observed in the other fractions. CONCLUSIONS AND CLINICAL RELEVANCE: These results confirm that the N-glycan profile in plasma of lung cancer patients is different from healthy controls and appears to be dominated by alterations in relatively abundant proteins. PMID- 23640814 TI - A highly crystalline manganese-doped iron oxide nanocontainer with predesigned void volume and shape for theranostic applications. AB - Hollow Mn-doped iron oxide nanocontainers, formed by a novel one-pot synthetic process, fulfill the dual requirements of delivering an effective dose of an anticancer drug to tumor tissue and enabling image-contrast monitoring of the nanocontainer fate through T2 -weighted magnetic resonance imaging, thereby determining the optimal balance between diagnostic and therapeutic moieties in an all-in-one theranostic nanoplatform. PMID- 23640816 TI - Multicompartment micelle-structured peptide nanoparticles: a new biocompatible gene- and drug-delivery tool. AB - Self-assembled, biodegradable materials that embed fragile, soluble, or insoluble compounds of therapeutic interest have potential use as drug delivery systems. The bead-forming peptide Ac-X3-gT can embed hydrophobic and hydrophilic payloads. Loaded peptide beads were internalized by human acute monocytic leukemia cell line (THP-1) macrophages, THP-1 monocytes, and hepatocellular carcinoma cells (Huh7). Furthermore, paclitaxel and doxorubicin coencapsulated in the peptide beads were delivered to THP-1 monocytes, causing a decrease in cell viability due to the activity of the anticancer drugs. In addition to the bead-forming peptide Ac-X3-gT, the use of a positively charged peptide analogue increased the RNA/DNA embedding efficiency to 99% by charge compensation and micellar complexation. Internalization of the resulting gene delivery systems by Huh7 cells led to specific gene silencing either by embedded small interfering RNA or by plasmid encoding small hairpin RNA delivered in cells. The new class of purely peptidic material caused no measurable toxicity during in vitro experiments, thereby indicating potential use as a drug delivery system for multidrug delivery and gene therapy. PMID- 23640815 TI - Expression of c-fos in hilar mossy cells of the dentate gyrus in vivo. AB - Granule cells (GCs) of the dentate gyrus (DG) are considered to be quiescent- they rarely fire action potentials. In contrast, the other glutamatergic cell type in the DG, hilar mossy cells (MCs) often have a high level of spontaneous activity based on recordings in hippocampal slices. MCs project to GCs, so activity in MCs could play an important role in activating GCs. Therefore, we investigated whether MCs were active under basal conditions in vivo, using the immediate early gene c-fos as a tool. We hypothesized that MCs would exhibit c fos expression even if rats were examined randomly, under normal housing conditions. Therefore, adult male rats were perfused shortly after removal from their home cage and transfer to the laboratory. Remarkably, most c-fos immunoreactivity (ir) was in the hilus, especially temporal hippocampus. C-fos-ir hilar cells co-expressed GluR2/3, suggesting that they were MCs. C-fos-ir MCs were robust even when the animal was habituated to the investigator and laboratory where they were euthanized. However, c-fos-ir in dorsal MCs was reduced under these circumstances, suggesting that ventral and dorsal MCs are functionally distinct. Interestingly, there was an inverse relationship between MC and GC layer c-fos expression, with little c-fos expression in the GC layer in ventral sections where MC expression was strong, and the opposite in dorsal hippocampus. The results support the hypothesis that a subset of hilar MCs are spontaneously active in vivo and provide other DG neurons with tonic depolarizing input. PMID- 23640817 TI - Pain and use of alcohol in later life: prospective evidence from the health and retirement study. AB - OBJECTIVE: To determine whether (a) late-life pain predicts growth in older adults' use of alcohol, and elevated risk of drinking problems; and (b) sociodemographic characteristics moderate these relationships. METHOD: Five times over an 8-year interval, N = 5,446 Health and Retirement Study (HRS) participants provided information about their pain and alcohol use. Two-part latent growth modeling and logistic regression were used to analyze these data. RESULTS: Participants with more pain at baseline had lower initial levels and a faster rate of decline over the next 8 years in alcohol consumption, but they also were at elevated risk of having drinking problems. Income and African American background interacted with pain to predict 8-year change in alcohol consumption and presence of drinking problems. DISCUSSION: Late-life pain does not predict growth in older adults' alcohol consumption, but is nonetheless linked to elevated risk of drinking problems, especially among African Americans. PMID- 23640818 TI - Optimizing P,N-bidentate ligands for oxidative gold catalysis: efficient intermolecular trapping of alpha-oxo gold carbenes by carboxylic acids. PMID- 23640819 TI - Glycoproteomic strategies: From discovery to clinical application of cancer carbohydrate biomarkers. AB - Carbohydrate antigens are the most frequently and traditionally used biomarkers for cancer, such as CA19-9, CA125, DUPAN-II, AFP-L3, and many others. The diagnostic potential of them was simply based on the cancer-specific alterations of glycan structures on particular glycoproteins in serum/plasma. In spite of the facts that glycosylation disorders are feasible for cancer biomarkers and glycomic analysis technologies to explore them have been rapidly developed, it remains difficult to sensitively screen glycan structure changes on cancer associated glycoproteins from clinical specimens. Moreover, a lot of additional issues should be appropriately addressed for the clinical application of newly identified glycosylation biomarkers, including analytical throughput, quantitative confirmation of structural changes, and biological explanation for the alterations. In the last decade, significant improvement of mass spectrometric techniques is being made in the aspects of both hardware spec and preanalytical purification procedures for glycoprotein analysis. Here we review potential approaches to perform comprehensive analysis of glycoproteomic biomarker screening from serum/plasma and to realize high-throughput validation of site-specific oligosaccharide variations. The power and problems of mass spectrometric applications on the clinical use of carbohydrate biomarkers are also discussed in this review. PMID- 23640820 TI - Four-dimensional analysis of nucleogenesis of the pontine nucleus in the hindbrain. AB - Nuclei in the central nervous system are 3D aggregates of neurons that have common physiological properties, functionalities, and connectivities. To form specific nuclei, neurons migrate from their birthplace towards the presumptive nuclear region where they change their dynamics to aggregate and rearrange into a distinct 3D structure, a process that we term nucleogenesis. Nuclei, together with the laminar structure, form the basic cytoarchitectonic unit for information processing. However, in contrast to much-studied laminar structures, the neuronal dynamics that contribute to the aggregation process to form nuclei are poorly understood. Here, we analyze nucleogenesis by observing the mouse precerebellar pontine nucleus (PN), and provide the first 4D view of nucleogenesis by tracking neuronal behaviors along the three spatial axes over time. Early- and late-born PN neurons were labeled by in utero electroporation and their behaviors on cultured brain slices were recorded by time-lapse imaging. We find that when PN neurons migrate medially into the nuclear region, many of them switch to migrate radially and laterally, to populate the dorsal and lateral PN regions, respectively. The tendency to switch to radial migration is much less in later born neurons, whereas that to switch to lateral migration is comparable between the two groups. In contrast to the radial and mediolateral axes, very few PN neurons switch to migrate rostrocaudally. These results could thus provide a framework for understanding the mechanisms that regulate this complex yet important process. PMID- 23640822 TI - Highly electrically conductive Ag-doped graphene fibers as stretchable conductors. AB - Ag-doped graphene fibers show remarkable electrical conductivity, high current capacity, good mechanical strength and fine flexibility. The integration of these merits promises Ag-doped graphene fibers expanding applications as stretchable conductors, wearable electronics, and actual microcables. PMID- 23640821 TI - Global gene expression analysis of amniotic fluid cell-free RNA from recipient twins with twin-twin transfusion syndrome. AB - OBJECTIVE: The objective of this study was to understand the biological pathways involved in twin-twin transfusion syndrome (TTTS) by performing global gene expression analysis of amniotic fluid (AF) cell-free RNA. METHODS: A prospective whole transcriptome microarray study analyzing cell-free RNA in AF from TTTS recipient twins and singleton controls was carried out. Significantly differentially regulated genes in TTTS cases (N = 8) versus matched controls (N = 8) were identified and pathways analyses performed. Significant gene expression differences between stage II TTTS recipients (N = 5) and stage III TTTS recipients with abnormal Doppler measurements (N = 5) were also analyzed. RESULTS: Analysis of paired data from TTTS cases and controls revealed differential expression of 801 genes, which were significantly enriched for neurological disease and cardiovascular system pathways. We also identified cardiovascular genes and pathways associated with the presence of critically abnormal Doppler measurements in stage III TTTS recipients. CONCLUSIONS: This study provides the first transcriptome-wide data on the impact of TTTS on fetal development. Our results show that gene expression involving neurological and cardiovascular pathways are altered in recipient fetuses prior to surgical treatment. This has relevance for the origins of long-term complications seen in survivors and for the development of future fetal biomarkers. PMID- 23640823 TI - Can diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch (positive diffusion-weighted imaging/negative fluid-attenuated inversion recovery) at 3 Tesla identify patients with stroke at <4.5 hours? AB - BACKGROUND AND PURPOSE: At 1.5 T, diffusion-weighted imaging-fluid-attenuated inversion recovery (DWI-FLAIR) mismatch helps identify strokes within 4.5 hours of onset. However, at 3T, studies have found divergent results. The goal of this study was to determine whether DWI-FLAIR mismatch at 3T would also be helpful for identifying patients within 4.5 hours of symptom onset. METHODS: All patients presenting with an ischemic stroke in the middle cerebral artery territory and explored with 3T MRI within 12 hours between November 2007 and April 2012 were included in this retrospective study. Two readers analyzed the DWI and FLAIR images. Logistic regression was performed to determine independent predictors of FLAIR visibility. Also, the predictive values of a mismatch for identifying patients with stroke onset <=4.5 hours were estimated. RESULTS: The study included 194 patients. The only predictive factor of FLAIR visibility was delayed MRI acquisition. The DWI-FLAIR mismatch was able to identify patients within 4.5 hours of stroke onset with relatively low sensitivity (0.55; 95% confidence interval, 0.48-0.63), low specificity (0.60; 95% confidence interval, 0.42-0.77), high positive predictive value (0.88; 95% confidence interval, 0.82-0.94), and very low negative predictive value (0.19; 95% confidence interval, 0.11-0.28). In addition, 44.5% of patients had a positive FLAIR sequence within 4.5 hours. CONCLUSIONS: This study improves our understanding of DWI-FLAIR mismatch as an imaging biomarker for wake-up management of patients with stroke. At 3T, the presence of a DWI-FLAIR mismatch was able to identify stroke onset of <4.5 hours. However, 44.5% of such stroke cases demonstrated FLAIR signal changes. PMID- 23640825 TI - White-coat and masked hypertension are associated with carotid atherosclerosis in a general population: the Hisayama study. AB - BACKGROUND AND PURPOSE: On the basis of combined measurements of clinic blood pressure (CBP) and home blood pressure (HBP), blood pressure status can be divided into normotension, white-coat hypertension (WCHT), masked hypertension (MHT), and sustained hypertension (SHT). Despite the clear impact of MHT and SHT on clinical and subclinical arterial disease, uncertainty about the influence of WCHT remains. The objective of this study was to investigate the associations of WCHT, MHT, and SHT with carotid atherosclerosis in a general population. METHODS: This is a cross-sectional survey of 2915 community-dwelling Japanese aged >= 40 years. Normotension was defined as CBP<140/90 and HBP<135/85 mm Hg; WCHT, CBP >= 140/90 and HBP<135/85 mm Hg; MHT, CBP<140/90 and HBP >= 135/85 mm Hg; and SHT, CBP >= 140/90 and HBP >= 135/85 mm Hg. Mean intima-media thickness of carotid arteries was measured using a computer-automated system, and carotid stenosis was defined as diameter stenosis >= 30%. RESULTS: There were 1374 subjects (47.1%) with normotension, 200 (6.9%) with WCHT, 639 (21.9%) with MHT, and 702 (24.1%) with SHT. The geometric average of mean intima-media thickness was significantly higher among subjects with WCHT (0.73 mm), MHT (0.77 mm), and SHT (0.77 mm) than those with normotension (0.67 mm; all P<0.001 versus normotension). Compared with normotension, all types of hypertension were also associated with increased likelihood of carotid stenosis (age- and sex-adjusted odds ratio, 2.36 [95% confidence interval, 1.27-4.37] for WCHT, 1.95 [1.25-3.03] for MHT, and 3.02 [2.01-4.54] for SHT). These associations remained significant even after adjustment for other cardiovascular risk factors. CONCLUSIONS: WCHT, as well as MHT, and SHT were associated with carotid atherosclerosis in a general Japanese population. PMID- 23640824 TI - Influence of the great East Japan earthquake and tsunami 2011 on occurrence of cerebrovascular diseases in Iwate, Japan. AB - BACKGROUND AND PURPOSE: Little information is available regarding the occurrence of cerebrovascular diseases after tsunamis. This study was performed to determine the influence of the tsunami damage caused by the Great East Japan earthquake on occurrence of cerebrovascular diseases. METHODS: Subjects from the coastline and inland areas of Iwate Prefecture who developed cerebrovascular diseases before and after the disaster were included in the analysis. Standardized incidence ratios of 2011 against the previous 3 years were calculated in two 4-week periods before and four 4-week periods after the disaster, according to stroke subtype, sex, age group, and flood damage. RESULTS: The standard incidence ratio for cerebrovascular diseases was 1.20 (1.00-1.40) in the first 4-week period after the disaster and was not significant in other periods. The standard incidence ratios in the first 4-week period for cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage were 1.22 (0.98-1.46), 1.15 (0.76-1.55), and 1.20 (0.52-1.88), respectively. These values were 1.51 (1.19-1.88) for men, 1.35 (1.06-1.64) for subjects aged >= 75 years, and 1.35 (1.06-1.64) for the high flooding areas. The standard incidence ratio of cerebral infarction in the first 4-week period for men aged >= 75 years in the high flooding areas was 2.34 (1.34 3.34). CONCLUSIONS: In the areas highly flooded by the tsunami caused by the Great East Japan earthquake, the occurrence of cerebral infarction among elderly men more than doubled in the first 4 weeks after the disaster. PMID- 23640826 TI - Cardiovascular risk profile and cognitive function in young, middle-aged, and elderly subjects. AB - BACKGROUND AND PURPOSE: Cognitive decline occurs earlier than previously realized and is already evident at the age of 45. Because cardiovascular risk factors are established risk factors for cognitive decline in old age, we investigated whether cardiovascular risk factors are also associated with cognitive decline in young and middle-aged groups. METHODS: The cross-sectional study included 3778 participants aged 35 to 82 years (mean age, 54 years) and free of cardiovascular disease and stroke. Cognitive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0; best score, 175 points) and the Visual Association Test (VAT; worst score, 0; best score, 12 points). Overall cardiovascular risk was assessed with the Framingham Risk Score (FRS) for general cardiovascular disease (best score, -5; worst score, 33 points). RESULTS: Mean RFFT score (SD) was 70 (26) points, median VAT score (interquartile range) was 10 (9-11) points, and mean FRS (SD) was 10 (6) points. Using linear regression analysis adjusting for educational level, RFFT was negatively associated with FRS. RFFT score decreased by 1.54 points (95% confidence interval, -1.66 to -1.44; P<0.001) per point increase in FRS. This negative association was not only limited to older age groups, but also found in the young (35-44 years). The main influencing components of the FRS were age (P<0.001), diabetes mellitus (P=0.001), and smoking (P<0.001). Similar results were found for VAT score as outcome measure. CONCLUSIONS: In this large population-based cohort, a worse overall cardiovascular risk profile was associated with poorer cognitive function. This association was already present in young adults aged 35 to 44 years. PMID- 23640827 TI - Disparities in evaluation at certified primary stroke centers: reasons for geographic and racial differences in stroke. AB - BACKGROUND AND PURPOSE: Evaluation at primary stroke centers (PSCs) has the potential to improve outcomes for patients with stroke. We looked for differences in evaluation at Joint Commission certified PSCs by race, education, income, and geography (urban versus nonurban; Southeastern Stroke Belt versus non-Stroke Belt). METHODS: Community-dwelling, black and white participants from the national Reasons for Geographic And Racial Differences in Stroke (REGARDS) prospective population-based cohort were enrolled between January 2003 and October 2007. Participants were contacted at 6-month intervals for suspected stroke events. For suspected stroke events, it was determined whether the evaluating hospital was a certified PSC. RESULTS: Of 1000 suspected strokes, 204 (20.4%) strokes were evaluated at a PSC. A smaller proportion of women than men (17.8% versus 23.0%; P=0.04), those with a previous stroke (15.1% versus 21.6%; P=0.04), those living in the Stroke Belt (14.7% versus 27.3%; P<0.001), and those in a nonurban area (9.1% versus 23.1%; P<0.001) were evaluated at a PSC. There were no differences by race, education, or income. In multivariable analysis, subjects were less likely to be evaluated at a PSC if they lived in a nonurban area (odds ratio, 0.39; 95% confidence interval, 0.22-0.67) or lived in the Stroke Belt (odds ratio, 0.54; 95% confidence interval, 0.38-0.77) or had a previous stroke (odds ratio, 0.46; 95% confidence interval, 0.27-0.78). CONCLUSIONS: Disparities in evaluation by PSCs are predominately related to geographic factors but not to race, education, or low income. Despite an increased burden of cerebrovascular disease in the Stroke Belt, subjects there were less likely to be evaluated at certified hospitals. PMID- 23640828 TI - CYP2C19 polymorphisms and antiplatelet effects of clopidogrel in acute ischemic stroke in China. AB - BACKGROUND AND PURPOSE: Little research regarding genotypes and clopidogrel response related to acute ischemic stroke has been published. This study was conducted to investigate whether the polymorphisms of receptors or enzymes involved in the metabolic process of clopidogrel affect clopidogrel response and prognosis related to acute stroke. METHODS: A total of 259 patients with acute ischemic stroke were enrolled in this study; all received follow-up evaluations 3 and 6 months after clopidogrel treatment. CYP2C19, CYP3A4, and P2Y12 were screened. The adenosine diphosphate-induced platelet aggregation test, the National Institutes of Health Stroke Scale (NIHSS), and the modified Rankin Scale (mRS) were used, and blood vascular events were evaluated. RESULTS: The difference before and after clopidogrel treatment on adenosine diphosphate induced platelet aggregation was significantly smaller in patients carrying 1 or 2 CYP2C19 loss-of-function alleles (*2, *3) compared with patients carrying none. Patients with none had better outcomes than patients with CYP2C19 loss-of function alleles, as demonstrated by NIHSS and mRS scores at 3 and 6 months after treatment. Regression analysis showed that CYP2C19 was an independent predictor of clopidogrel resistance. CONCLUSIONS: CYP2C19 genotypes had significant impact on clopidogrel response and prognosis of patients with stroke. Clinical Trial Registration Information- URL: http://www.chictr.org/. Unique Identifier: ChiCTR OCH-12002681. PMID- 23640829 TI - Foot drop stimulation versus ankle foot orthosis after stroke: 30-week outcomes. AB - BACKGROUND AND PURPOSE: Drop foot after stroke may be addressed using an ankle foot orthosis (AFO) or a foot drop stimulator (FDS). The Functional Ambulation: Standard Treatment versus Electric Stimulation Therapy (FASTEST) trial was a multicenter, randomized, single-blinded trial comparing FDS and AFO for drop foot among people >= 3 months after stroke with gait speed <= 0.8 m/s. METHODS: Participants (n=197; 79 females and 118 males; 61.14 +/- 11.61 years of age; time after stroke 4.55 +/- 4.72 years) were randomized to 30 weeks of either FDS or a standard AFO. Eight dose-matched physical therapy sessions were provided to both groups during the first 6 weeks of the trial. RESULTS: There was significant improvement within both groups from baseline to 30 weeks in comfortable gait speed (95% confidence interval for mean change, 0.11-0.17 m/s for FDS and 0.12 0.18 m/s for AFO) and fast gait speed. However, no significant differences in gait speed were found in the between-group comparisons. Secondary outcomes (standard measures of body structure and function, activity, and participation) improved significantly in both groups, whereas user satisfaction was significantly higher in the FDS group than in the control group. CONCLUSIONS: Using either an FDS or an AFO for 30 weeks yielded clinically and statistically significant improvements in gait speed and other functional outcomes. User satisfaction was higher in the FDS group. Although both groups did receive intervention, this large clinical trial provides evidence that FDS or AFO with initial physical therapy sessions can provide a significant and clinically meaningful benefit even years after stroke. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01138995. PMID- 23640830 TI - Hemodynamic changes by flow diverters in rabbit aneurysm models: a computational fluid dynamic study based on micro-computed tomography reconstruction. AB - BACKGROUND AND PURPOSE: The effect of flow diverter (FD) on hemodynamic changes observed in aneurysms is inevitably affected by the actual structural configuration of deployed FD. We studied the resultant hemodynamic changes after implantation of FDs using computational fluid dynamic simulations based on micro computed tomography reconstructions in rabbit aneurysm model. METHODS: The FDs by micro-computed tomography images and vascular model based on rabbit-specific angiograms in 14 rabbits were reconstructed for computational fluid dynamic studies, and rabbit-specific inlet flow waveforms were used as boundary conditions. The occluded group (n=10) and unoccluded group (n=4) were divided according to the follow-up angiography. Hemodynamic parameters were separately evaluated for significance with respect to FD implantation and healing. RESULTS: The normalized mean wall shear stress of the aneurysm sac and inflow volume were significantly reduced after FD deployment, and the relative residence time was significantly increased after treatment, without significant differences in mean pressure of aneurysm sac. When compared with the unoccluded group, the average relative residence time increment and percentage of inflow volume reduction in occluded group were higher. Additionally, the inlet of stream after FD deployment in the occluded group was more prevalent near the central region of the neck, whereas in the unoccluded group, it was more likely to occur near the proximal part of the neck. CONCLUSIONS: This study provided the real structural configurations of fully deployed FDs in vivo. We demonstrated the decrease of wall shear stress, inflow volume, increase of relative residence time, and change of inflow stream induced by FD implantation. The higher relative residence time increment, percentage of inflow volume reduction, and location of stream inlet near the central part of the neck may be closely related to healing. PMID- 23640831 TI - Rating method for dilated Virchow-Robin spaces on magnetic resonance imaging. AB - BACKGROUND AND PURPOSE: Dilated Virchow-Robin spaces are an emerging neuroimaging biomarker, but their assessment on MRI needs standardization. METHODS: We developed a rating method for dilated Virchow-Robin spaces in 4 brain regions (centrum semiovale, basal ganglia, hippocampus, and mesencephalon) and tested its reliability in a total of 125 MRI scans from 2 population-based studies. Six investigators with varying levels of experience performed the ratings. Intraclass correlation coefficients were calculated to determine intra- and interrater reliability. RESULTS: Intrarater reliability was excellent for all 4 regions (intraclass correlation coefficient, >0.8). Interrater reliability was excellent for the centrum semiovale and hippocampus (intraclass correlation coefficient, >0.8) and good for the basal ganglia and mesencephalon (intraclass correlation coefficient, 0.6-0.8). This did not differ between the cohorts or experience levels. CONCLUSIONS: We describe a reliable rating method that can facilitate pathogenic and prognostic research on dilated Virchow-Robin spaces using MRI. PMID- 23640832 TI - Incidence and predictors of late seizures in intracerebral hemorrhages. AB - BACKGROUND AND PURPOSE: To identify incidence and predictors of late seizures (LS, occurring >1 week of stroke) in a cohort of patients with intracerebral hemorrhage (ICH). METHODS: Prospective cohort of consecutive adults with spontaneous ICH. Incidence and predictors were identified with Cox regression. We included multivariate analyses on MRI biomarkers (global cortical atrophy, leukoaraiosis, brain microbleeds). RESULTS: Our study population consisted of 325 patients: 54% men, median age 70 years (interquartile range, 58-79). During 778 person-years of follow-up, the incidence rate was 4 new cases/100 person-years (95% confidence interval, 3-6). The median delay between ICH and LS was 9 months (interquartile range, 3-23). The only factor independently associated with the occurrence of LS was a cortical involvement of the ICH (hazard ratio, 2.8; 95% confidence interval, 1.3-6.1). Concerning MRI biomarkers, multivariate analyses found lobar brain microbleeds to be associated with LS (hazard ratio, 2.4; 95% confidence interval, 1.1-5.4), especially if >= 3 (hazard ratio, 2.7; 95% confidence interval, 1.1-6.8). LS were associated with a worse functional outcome after 3 years of follow-up (P=0.009). CONCLUSIONS: LS frequently occur >9 months after ICH onset, imposing a long-term follow-up. The association of lobar brain microbleeds with the risk of LS might suggest a link with the underlying vasculopathy (cerebral amyloid angiopathy). PMID- 23640833 TI - Delivery of S1P receptor-targeted drugs via biodegradable polymer scaffolds enhances bone regeneration in a critical size cranial defect. AB - Biodegradable polymer scaffolds can be used to deliver soluble factors to enhance osseous remodeling in bone defects. To this end, we designed a poly(lactic-co glycolic acid) (PLAGA) microsphere scaffold to sustain the release of FTY720, a selective agonist for sphingosine 1-phosphate (S1P) receptors. The microsphere scaffolds were created from fast degrading 50:50 PLAGA and/or from slow-degrading 85:15 PLAGA. Temporal and spatial regulation of bone remodeling depended on the use of appropriate scaffolds for drug delivery. The release profiles from the scaffolds were used to design an optimal delivery system to treat critical size cranial defects in a rodent model. The ability of local FTY720 delivery to maximize bone regeneration was evaluated with micro-computed tomography (microCT) and histology. Following 4 weeks of defect healing, FTY720 delivery from 85:15 PLAGA scaffolds resulted in a significant increase in bone volumes in the defect region compared to the controls. A 85:15 microsphere scaffolds maintain their structural integrity over a longer period of time, and cause an initial burst release of FTY720 due to surface localization of the drug. This encourages cellular in-growth and an increase in new bone formation. PMID- 23640835 TI - Secondary splitting of a free deep inferior epigastric perforator flap with pedicled transfer to the contralateral breast for staged reconstruction of two breasts: the split DIEP flap. AB - Free tissue transfer has become popularized for post-mastectomy autologous breast reconstruction, particularly with the abdominal wall donor site. However, in the setting of previous autologous breast reconstruction, options for later contralateral reconstruction are limited. We present a case of breast reconstruction with a free deep inferior epigastric artery perforator (DIEP) flap, which was split from the initially reconstructed breast and shared to reconstruct the opposite breast after the occurrence of a metachronous contralateral second primary breast cancer. There were no operative complications, no flap-related complications, and at two years follow-up, the patient subjectively described bilateral soft and supple breasts, which were symmetrical in a bra, and with which she has reported high satisfaction. An account of the "split DIEP flap" is provided, highlighting the planning, technique, and vascular rationale. The technique comprises partition of a previously transferred DIEP flap breast reconstruction into two parts based on preoperative computed tomographic angiography, performed to guide surgical planning in avoiding pedicle damage and identifying the portion of the flap to island. The split DIEP flap for staged bilateral autologous breast reconstruction offers two soft-tissue flaps for the price of one donor site, offering new possibilities in breast reconstruction and the broader field of tissue transplantation. PMID- 23640839 TI - Behavior of an adsorbed phospholipid monolayer submitted to prolonged periodical surface density variations. PMID- 23640834 TI - Long-term effects of neonatal hippocampal lesions on novelty preference in monkeys. AB - In a recent longitudinal study to assess the development of incidental recognition memory processes in monkeys, we showed that the effects of neonatal hippocampal lesions did alter incidental recognition memory only when the animals reached the juvenile period (Zeamer et al., ). The current follow-up study tested whether this incidental memory loss was long-lasting, i.e., present in adulthood, or only transitory, due to functional compensation with further brain maturation. The same animals with neonatal hippocampal lesions and their sham-operated controls were re-tested in the visual paired-comparison task when they reached adulthood (48 months). The results demonstrated that, at least for easily discriminable color pictures of objects, the involvement of the hippocampus was only transitory, given that when re-tested as adults, animals with neonatal hippocampal lesions performed as well as sham-operated controls at all delays. Yet, significant recognition memory impairment was re-instated when the discriminability of the stimuli was made more difficult (black/white pictures of similar objects). The data demonstrate profound functional remodeling within the hippocampus and its interactions with different medial temporal lobe structures from the juvenile period to adulthood, which is substantiated by a parallel morphological maturation of hippocampal intrinsic circuits (Lavenex et al., ; Jabes et al., ). PMID- 23640840 TI - The biological impact of concurrent exposure to metallic nanoparticles and a static magnetic field. AB - The rapid advancement of technology has led to an exponential increase of both nanomaterial and magnetic field utilization in applications spanning a variety of sectors. While extensive work has focused on the impact of these two variables on biological systems independently, the existence of any synergistic effects following concurrent exposure has yet to be investigated. This study sought to ascertain the induced alterations to the stress and proliferation responses of the human adult low calcium, high temperature keratinocyte (HaCaT) cell line by the application of a static magnetic field (approximately 0.5 or 30 mT) in conjunction with either gold or iron oxide nanoparticles for a duration of 24 h. By evaluating targets at a cellular, protein, and genetic level a complete assessment of the HaCaT response was generated. A magnetic field-dependent proliferative effect was found (~15%), which correlated with a decrease in reactive oxygen species and a simultaneous increase in ki67 expression, all occurring independently of nanoparticle presence. Furthermore, the application of a static magnetic field was able to counteract the cellular stress response induced by nanoparticle exposure through a combination of decreased reactive oxygen species production and modification of gene regulation. Therefore, we conclude that while these variables each introduce the potential to uniquely influence physiological events, no negative synergistic reactions were identified. PMID- 23640841 TI - Organization of multisynaptic circuits within and between the medial and the central extended amygdala. AB - The central and medial extended amygdala comprises the central (CEA) and medial nuclei of the amygdala (MEA), respectively, together with anatomically connected regions of the bed nucleus of the stria terminalis (BST). To reveal direct and multisynaptic connections within the central and medial extended amygdala, monosynaptic and transneuronal viral tracing experiments were performed in adult male rats. In the first set of experiments, a cocktail of anterograde and retrograde tracers was iontophoretically delivered into the medial CEA (CEAm), anterodorsal MEA (MEAad), or posterodorsal MEA (MEApd), revealing direct, topographically organized projections between distinct amygdalar and BST subnuclei. In the second set of experiments, the retrograde transneuronal tracer pseudorabies virus (PRV) was microinjected into the CEAm or MEAad. After 48 hours of survival, there were no significant differences between monosynaptic and PRV cases in the subnuclear distribution or proportions of retrogradely labeled BST neurons. However, after 60 hours of survival, CEAm-injected cases displayed an increased proportion of labeled neurons within the anteromedial group of BST subnuclei (amgBST) and within the posterior BST, which do not directly innervate the CEA. MEApd-injected 60-hour cases displayed a significantly increased proportion of retrograde labeling in the amgBST compared with monosynaptic and 48 hour cases, whereas MEAad-injected cases displayed no proportional changes over time. Thus, multisynaptic circuits within the medial extended amygdala overlap the direct connections making up this anatomical unit, whereas the multisynaptic boundaries of the central extended amygdala extend into BST subnuclei previously identified as part of the medial extended amygdala. PMID- 23640844 TI - Salvage of a free radial forearm flap by creation of an arteriovenous fistula at the distal arterial pedicle. AB - Interdisciplinary approaches with infrainguinal bypass grafts and free flaps between the plastic and vascular surgery may well offer an opportunity for diabetic patients with peripheral vascular disease to salvage their critically affected limbs. A free flap transfer combined with an autologous vein graft can cover large tissue defects and simultaneously improve distal perfusion even in patients with arterial occlusive disease. We are presenting a case of bypass-free radial forearm flap used to cover a foot defect in an old diabetic patient with peripheral arterial disease. The flap perfusion deteriorated significantly during the early postoperative period. The patient was brought back to the operating room with acute thrombosis of the popliteal-radial venous graft and the arterial pedicle of the flap. The flap was salvaged by thrombectomy and creation of an additional arteriovenous fistula at the distal arterial pedicle. The procedure improved the flap perfusion and decreased the high internal resistance that was noticed in the flap when trying to flush the radial artery during the revision surgery and was evident by continuous wave -Doppler sonography. The successful salvage of the flap in the presented case and the convenient long-term follow up suggest that this technique may be safe and helpful as a last effort to salvage a bypass-free flap with a suspected high internal resistance. PMID- 23640842 TI - Memory accuracy predicts hippocampal mTOR pathway activation following retrieval of contextual fear memory. AB - Prior work suggests that hippocampus-dependent memory undergoes a systems consolidation process such that recent memories are stored in the hippocampus, while older memories are independent of the hippocampus and instead dependent on cortical areas. One problem with interpreting these studies is that memory for the contextual stimuli weakens as time passes between the training event and testing and older memories are often less detailed, making it difficult to determine if memory storage in the hippocampus is related to the age or to the accuracy of the memory. Activity of the mammalian target of rapamycin (mTOR) signaling pathway is known to be important for controlling protein translation necessary for both memory consolidation after initial learning and for the reconsolidation of memory after retrieval. We tested whether p70s6 kinase (p70s6K), a key component of the mTOR signaling pathway, is activated following retrieval of context fear memory in the dorsal hippocampus (DH) and anterior cingulate cortex (ACC) at 1, 10, or 36 days after context fear conditioning. We also tested whether strengthening memory for the contextual stimuli changed p70s6K phosphorylation in these structures 36 days after training. We show that under standard training conditions retrieval of a recently formed memory is initially precise and involves the DH. Over time it loses detail, becomes independent of the DH and depends on the ACC. In a subsequent experiment, we preserved the accuracy of older memories through pre-exposure to the training context. We show that remote memory still involved the DH in animals given pre exposure. These data support the notion that detailed memories depend on the DH regardless of their age. PMID- 23640845 TI - Absence of post-lesion reactive gliosis in elasmobranchs and turtles and its bearing on the evolution of astroglia. AB - In the mature mammalian and avian central nervous systems, neuronal destructions are followed by reactive gliosis, but data on other vertebrates are rather controversial. Mammals and birds belong to different amniote groups (Synapsida and Diapsida, respectively), but exhibit common general features in their glial architecture, mainly the predominance of astrocytes. Two vertebrate groups seem to be in special positions of glial evolution: turtles (Testudiniformes) and skates and rays (Batoidea). The purely ependymoglial system of turtles seems to be the simplest one among the extant amniotes. In skates and rays, true astrocytes are preponderant glial elements, in contrast to the other "anamniotes" (and even to reptiles). We investigated stab wounds by the immunohistochemical detection of GFAP in turtles (Trachemys-formerly Pseudemys-scripta elegans), a skate (Raja clavata) and rays (Dasyatis akajei and Torpedo marmorata). Sharks (Scyliorhinus canicula) as ependymoglia-predominated chondrichthyans, and-for positive controls-rats were also studied. In the elasmobranchs, other astroglial markers: glutamine synthetase and S100 protein were also applied. Neither turtles nor elasmobranchs presented considerable astroglial reactions. Critically surveying the former reports on different vertebrates, these results complete the picture that typical post-lesion reactive gliosis is confined to mammals and birds. Analysis of the astroglial systems from phylogenetic perspective suggests that the capability of forming glial demarcation and scar formation evolved independently in mammals and birds. Predominance of astrocytes is a necessary condition but not sufficient for reactive gliosis. The intense glial reactivity of mammals and birds may be attributed to their complex cerebralization. PMID- 23640848 TI - Self-assembling neodymium/sodium heterobimetallic asymmetric catalyst confined in a carbon nanotube network. PMID- 23640849 TI - Writing under the microscope to obtain binocular vision. PMID- 23640850 TI - Metapodial or phalanx? An evolutionary and developmental perspective on the homology of the first ray's proximal segment. AB - The first mammalian metapodial (MP1) has periodically been argued to actually be a phalanx, because the first ray has one less element than the four posterior rays, and because the MP1 growth plate is proximal like those of all phalanges, rather than distal as in metapodials 2-5. However, growth plates are formed at both ends in non-therian tetrapod metapodials, and phylogenetic analysis demonstrates that growth plate loss is a therian synapomorphy that postdates the establishment of the mammalian phalangeal formula. These data, along with results of developmental and morphological studies, suggest that the MP1 is not a phalanx. The singular, proximal growth plates in MPs 2-5 are likely to be an adaptation to dynamic erect quadrupedal gait which was characterized by conversion of the posterior metapodials into rigid struts with the carpus/tarsus. While the adaptive significance of the reversed ossification of MP1 is less clear, we present three functional/developmental hypotheses. PMID- 23640851 TI - Experimental system for real-time assessment of potential changes in protein conformation induced by electromagnetic fields. AB - A novel experimental system to distinguish between potential thermal and non thermal effects of electromagnetic fields (EMFs) on the conformational equilibrium and folding kinetics of proteins is presented. The system comprises an exposure chamber installed within the measurement compartment of a spectropolarimeter and allows real-time observation of the circular dichroism (CD) signal of the protein during EMF exposure. An optical temperature probe monitors the temperature of the protein solution at the site of irradiation. The electromagnetic, thermal, and fluid-dynamic behavior of the system is characterized by numerical and experimental means. The number of repeated EMF on/off cycles needed for achieving a certain detection limit is determined on the basis of the experimentally assessed precision of the CD measurements. The isolated thermosensor protein GrpE of the Hsp70 chaperone system of Eschericha coli serves as the test protein. Long-term experiments show high thermal reproducibility as well as thermal stability of the experimental setup. PMID- 23640853 TI - Time-to-onset in spontaneous reports: the possibility to detect the unexpected. PMID- 23640852 TI - Monosynaptic convergence of chorda tympani and glossopharyngeal afferents onto ascending relay neurons in the nucleus of the solitary tract: a high-resolution confocal and correlative electron microscopy approach. AB - Physiological studies suggest convergence of chorda tympani and glossopharyngeal afferent axons onto single neurons of the rostral nucleus of the solitary tract (rNTS), but anatomical evidence has been elusive. The current study uses high magnification confocal microscopy to identify putative synaptic contacts from afferent fibers of the two nerves onto individual projection neurons. Imaged tissue is revisualized with electron microscopy, confirming that overlapping fluorescent signals in confocal z-stacks accurately identify appositions between labeled terminal and dendrite pairs. Monte Carlo modeling reveals that the probability of overlapping fluorophores is stochastically unrelated to the density of afferent label, suggesting that convergent innervation in the rNTS is selective rather than opportunistic. Putative synaptic contacts from each nerve are often compartmentalized onto dendrite segments of convergently innervated neurons. These results have important implications for orosensory processing in the rNTS, and the techniques presented here have applications in investigations of neural microcircuitry with an emphasis on innervation patterning. PMID- 23640855 TI - Microvascular salvage of a thrombosed total ear replant. AB - Microvascular replantation, when possible, is the treatment of choice for total ear amputations. Both arterial and venous reconstruction should be attempted. The present case report describes a successful total ear replantation in a 45-year old woman whose ear was amputated due to a horse accident. Venous thrombosis subsequently occurred and was managed with anticoagulation and leech therapy. Eighty hours after the replantation, arterial thrombosis took place. The posterior auricular artery thrombosed anastomosis was resected and reconstructed with an interposition vein graft. This report illustrates the feasibility of the successful microvascular salvage of a thrombosed total ear replant. It suggests the need for close clinical monitoring of the replanted ear and prompt microvascular reexploration in an event of the loss of arterial flow. PMID- 23640856 TI - A prototypical small-molecule modulator uncouples mitochondria in response to endogenous hydrogen peroxide production. AB - A high membrane potential across the mitochondrial inner membrane leads to the production of the reactive oxygen species (ROS) implicated in aging and age related diseases. A prototypical drug for the correction of this type of mitochondrial dysfunction is presented. MitoDNP-SUM accumulates in mitochondria in response to the membrane potential due to its mitochondria-targeting alkyltriphenylphosphonium (TPP) cation and is uncaged by endogenous hydrogen peroxide to release the mitochondrial uncoupler, 2,4-dinitrophenol (DNP). DNP is known to reduce the high membrane potential responsible for the production of ROS. The approach potentially represents a general method for the delivery of drugs to the mitochondrial matrix through mitochondria targeting and H(2)O(2) induced uncaging. PMID- 23640857 TI - Ruthenium catalysts for hydrogenation of aromatic and aliphatic esters: make use of bidentate carbene ligands. AB - Committed carbenes: The convenient application of bidentate carbene ligands is described for the hydrogenation of carboxylic acid esters. The ligand precursors are easily synthesized through the dimerization of N-substituted imidazoles with diiodomethane. The catalyst is generated in situ and exhibits good activity and functional group tolerance for the hydrogenation of aromatic and aliphatic carboxylic acid esters. PMID- 23640858 TI - Simvastatin-activated implant surface promotes osteoblast differentiation in vitro. AB - The bone growth promoting effects of statins suggest that these bioactive molecules can be used to improve the integration of bone-anchored implants. This study aimed at the application of simvastatin with dental implants for use in patients with low bone density. Coin-shaped titanium zirconium samples with grit blasted and acid-etched surface were coated with simvastatin, using a novel anodic oxidation setup under alkaline conditions. The presence of intact simvastatin attached to the surface was confirmed by infrared spectroscopy. A binding site on the aliphatic O-H group was discovered and the integration of (1)H, (18)O and (12)C in the depth of the surface were observed by secondary ion mass spectroscopy. A simvastatin concentration of about 60 g/cm(2) was found in a release study over 72 h. The simvastatin-coated surfaces promoted alkaline phosphatase, collagen type I and osteocalcin gene expression of MC3T3-E1 cells. This suggested that the demonstrated coating holds potential for use in patients with compromised bone. PMID- 23640859 TI - Development of nanofibrous cellulose acetate/gelatin skin substitutes for variety wound treatment applications. AB - The major component of fibrous extracellular matrix of dermis is composed of a complex combination of proteins and polysaccharides. Electrospun cellulose acetate/gelatin might be an effective simulator of the structure and composition of native skin and during this study, we electrospun cellulose acetate/gelatin membranes in various compositions and their performance as a scaffold for either skin tissue engineering or as a wound dressing was evaluated. Skin treatment products, whether tissue-engineered scaffolds or wound dressings, should be sufficiently hydrophilic to allow for gas and fluid exchange and absorb excess exudates while controlling the fluid loss. However, a wound dressing should be easily removable without causing tissue damage and a tissue-engineered scaffold should be able to adhere to the wound, and support cell proliferation during skin regeneration. We showed that these distinct adherency features are feasible just by changing the composition of cellulose acetate and gelatin in composite cellulose acetate/gelatin scaffolds. High proliferation of human dermal fibroblasts on electrospun cellulose acetate/gelatin 25:75 confirmed the capability of cellulose acetate/gelatin 25:75 nanofibers as a tissue-engineered scaffold, while the electrospun cellulose acetate/gelatin 75:25 can be a potential low-adherent wound dressing. PMID- 23640860 TI - Engineering bone tissue using human dental pulp stem cells and an osteogenic collagen-hydroxyapatite-poly (L-lactide-co-epsilon-caprolactone) scaffold. AB - The aim of this study was to design a new natural/synthetic bioactive bone scaffold for potential use in bone replacement applications. We developed a tri component osteogenic composite scaffold made of collagen (Coll), hydroxyapatite (HA) and poly(l-lactide-co-epsilon-caprolactone) (PLCL). This Coll/HA/PLCL composite scaffold was combined with human osteoblast-like cells obtained by differentiation of dental pulp stem cells (DPSCs) to engineer bone tissue in vitro. Results show that the 3D Coll/HA/PLCL composite scaffold was highly porous, thereby enabling osteoblast-like cell adhesion and growth. Cultured in the Coll/HA/PLCL scaffold, the osteoblast-like cells expressed different osteogenic genes, produced alkaline phosphatase and formed nodules more than did PLCL alone. Micro-CT analyses revealed a significant (30%) increase of tissue mineralisation on the surface as well as inside of the Coll/HA/PLCL scaffold, thus confirming its effectiveness as a bone regeneration platform. PMID- 23640861 TI - Environmental toxin-linked nonalcoholic steatohepatitis and hepatic metabolic reprogramming in obese mice. AB - Obesity is associated with strong risks of development of chronic inflammatory liver disease and metabolic syndrome following a second hit. This study tests the hypothesis that free radical metabolism of low chronic exposure to bromodichloromethane (BDCM), a disinfection byproduct of drinking water, causes nonalcoholic steatohepatitis (NASH), mediated by cytochrome P450 isoform CYP2E1 and adipokine leptin. Using diet-induced obese mice (DIO), mice deficient in CYP2E1, and mice with spontaneous knockout of the leptin gene, we show that BDCM caused increased lipid peroxidation and increased tyrosine nitration in DIO mice, events dependent on reductive metabolism by CYP2E1. DIO mice, exposed to BDCM, exhibited increased hepatic leptin levels and higher levels of proinflammatory gene expression and Kupffer cell activation. Obese mice exposed to BDCM also showed profound hepatic necrosis, Mallory body formation, collagen deposition, and higher alpha smooth muscle actin expression, events that are hallmarks of NASH. The absence of CYP2E1 gene in mice that were fed with a high-fat diet did not show NASH symptoms and were also protected from hepatic metabolic alterations in Glut-1, Glut-4, phosphofructokinase and phosphoenolpyruvate carboxykinase gene expressions (involved in carbohydrate metabolism), and UCP-1, PGC-1alpha, SREBP 1c, and PPAR-gamma genes (involved in hepatic fat metabolism). Mice lacking the leptin gene were significantly protected from both NASH and metabolic alterations following BDCM exposure, suggesting that higher levels of leptin induction by BDCM in the liver contribute to the development of NASH and metabolic alterations in obesity. These results provide novel insights into BDCM-induced NASH and hepatic metabolic reprogramming and show the regulation of obesity-linked susceptibility to NASH by environmental factors, CYP2E1, and leptin. PMID- 23640863 TI - Toxic shock syndrome: characterization of human immune responses to TSST-1 and evidence for sensitivity thresholds. AB - Noninvasive vaginal infections by Staphylococcus aureus strains producing the superantigen TSST-1 can cause menstrual toxic shock syndrome (mTSS). With the objective of exploring the basis for differential susceptibility to mTSS, the relative responsiveness to TSST-1 of healthy women has been investigated. Peripheral blood mononuclear cells from healthy donors were incubated with purified TSST-1 or with the T-cell mitogen phytohemmaglutinin (PHA), and proliferation was measured. The concentrations of TSST-1 and PHA required to elicit a response equivalent to 15% of the maximal achievable response (EC15) were determined. Although with PHA, EC15 values were comparable between donors, subjects could be classified as being of high, medium, or low sensitivity based on responsiveness to TSST-1. Sensitivity to TSST-1-induced proliferation was associated with increased production of the cytokines interleukin-2 and interferon-gamma. When the entire T lymphocyte population was considered, there were no differences between sensitivity groups with respect to the frequency of cells known to be responsive to TSST-1 (those bearing CD3(+) Vbeta2(+)). However, there was an association between sensitivity to TSST-1 and certain HLA-class II haplotypes. Thus, the frequencies of DR7DQ2, DR14DQ5, DR4DQ8, and DR8DQ4 haplotypes were greater among those with high sensitivity, a finding confirmed by analysis of responses to immortalized homozygous B cell lines. Collectively, the results reveal that factors other than neutralizing antibody and the frequency of Vbeta2(+) T lymphocytes determine immunological responsiveness to TSST-1. Differential responsiveness of lymphocytes to TSST-1 may form the basis of interindividual variations in susceptibility to mTSS. PMID- 23640862 TI - Nucleoside reverse transcriptase inhibitors induce a mitophagy-associated endothelial cytotoxicity that is reversed by coenzyme Q10 cotreatment. AB - Cardiovascular complications have been documented in HIV-1 infected populations, and antiretroviral therapy may play a role. Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals known to induce mitochondrial damage in endothelial cells, culminating in endothelial dysfunction, an initiating event in atherogenesis. Though the mechanism for NRTI-induced endothelial toxicity is not yet clear, our prior work suggested that a mitochondrial oxidative stress may be involved. To further delineate the mechanism of toxicity, endothelial cells were treated with NRTIs of varying subclasses, and the level of reactive oxygen species (ROS) and mitochondrial function were assessed. To test whether rescue of mitochondrial electron transport attenuated NRTI-induced endothelial cytotoxicity, in some cases, cells were cotreated with the electron transport cofactor coenzyme Q10 (Q10). At 4-6h, NRTIs increased levels of ROS but decreased the activities of electron transport chain complexes I-IV, levels of ATP and the NAD/NADH ratio. Moreover, nitric oxide levels were decreased, whereas endothelin 1 release was increased. Q10 abolished NRTI-induced mitochondria injury and effects on endothelial agonist production. Interestingly, in cells treated with NRTIs only, markers for mitochondrial toxicity returned to baseline levels by 18 24h, suggesting a compensatory mechanism for clearing damaged mitochondria. Using confocal microscopy, with confirmation utilizing the autophagy and mitophagy markers LC-3 and Nix, respectively, we observed autophagy of mitochondria at 8 10h after treatment. Q10 prevented NRTI-mediated increase in LC-3. These findings suggest that NRTI-induced mitophagy may be involved in NRTI-induced endothelial dysfunction and that this damage likely results from oxidant injury. Further, Q10 supplementation could potentially prevent NRTI-induced endothelial dysfunction. PMID- 23640864 TI - Inferring the evolution of teleostean zp genes based on their sites of expression. AB - Fish egg envelopes consist of several glycoproteins, called zona pellucida (ZP) proteins, which are conserved among chordates. Euteleosts synthesize ZP proteins in the liver, while elopomorphs synthesize them in the ovaries. In Cypriniformes, zp genes are expressed in the ovaries. We investigated the zp genes of two Otocephalan orders: Clupeiformes (Pacific herring and Japanese anchovy) and Gonorynchiformes (milkfish), which diverged earlier than Cypriniformes. cDNA cloning of zp gene homologs revealed that Pacific herring and Japanese anchovy possessed both ovary- and liver-expressed zp genes; however, the zp genes of milkfish were only expressed in the ovaries. Molecular phylogenetic analysis showed that ovary- and liver-expressed zpc genes of two the Clupeiformes formed independent clades. Based on this, we hypothesized the evolution of teleostean zp genes, focusing on the organ expressing zp gene. As in other chordates, the original site of expression of zp genes was likely the ovary. In the early stage of teleostean evolution, the ancestral zp genes acquired the ability to express in the liver. Later, one of the two expression sites became dominant. The liver expressed zp genes are component proteins of the egg envelope in the Euteleostei. In Otocephala, Clupeiformes possess both ovary- and liver-expressed genes that presumably participate in egg envelope formation, whereas the Gonorynchiformes and Cypriniformes have primarily preserved ovary expressed zp genes. PMID- 23640866 TI - Hybrid in silico models for drug-induced liver injury using chemical descriptors and in vitro cell-imaging information. AB - Drug-induced liver injury (DILI) is a major adverse drug reaction that accounts for one-third of post-marketing drug withdrawals. Several classifiers for human hepatotoxicity using chemical descriptors with limited prediction accuracies have been published. In this study, we developed predictive in silico models based on a set of 156 DILI positive and 136 DILI negative compounds for DILI prediction. First, models based on a chemical descriptor (CDK, Dragon and MOE) and in vitro cell-imaging endpoints [human hepatocyte imaging assay technology (HIAT) descriptors] were built using random forest (RF) and five-fold cross-validation procedure. Then three hybrid models were built using HIAT and a single type of chemical descriptors. Generally, the models based only on chemical descriptors were poor, with a correct classification rate (CCR) around 0.60 when the default threshold value (i.e. threshold = 0.50) was used. The hybrid models afforded a CCR of 0.73 with a specificity of 0.74 and a better true positive rate (sensitivity of 0.71), which is crucial in drug toxicity screening for the purpose of patient safety. The benefit of hybrid models was even more drastic when stricter classification thresholds were employed (e.g. CCR would be 0.83 when double thresholds (non-toxic < 0.40 and toxic > 0.60) were used for the hybrid model). We have developed rigorously validated hybrid models which can be used in virtual screening of lead compounds with potential hepatotoxicity. Our study also showed a chemical structure and in vitro biological data can be complementary in enhancing the prediction accuracy of human hepatotoxicity and can afford rational mechanistic interpretation. PMID- 23640865 TI - Retinotopic maps in the pulvinar of bush baby (Otolemur garnettii). AB - Despite its anatomical prominence, the function of the primate pulvinar is poorly understood. A few electrophysiological studies in simian primates have investigated the functional organization of pulvinar by examining visuotopic maps. Multiple visuotopic maps have been found for all studied simians, with differences in organization reported between New and Old World simians. Given that prosimians are considered closer to the common ancestors of New and Old World primates, we investigated the visuotopic organization of pulvinar in the prosimian bush baby (Otolemur garnettii). Single-electrode extracellular recording was used to find the retinotopic maps in the lateral (PL) and inferior (PI) pulvinar. Based on recordings across cases, a 3D model of the map was constructed. From sections stained for Nissl bodies, myelin, acetylcholinesterase, calbindin, or cytochrome oxidase, we identified three PI chemoarchitectonic subdivisions, lateral central (PIcl), medial central (PIcm), and medial (PIm) inferior pulvinar. Two major retinotopic maps were identified that cover PL and PIcl, the dorsal one in dorsal PL and the ventral one in PIcl and ventral PL. Both maps represent central vision at the posterior end of the border between the maps, the upper visual field in the lateral half and the lower visual field in the medial half. They share many features with the maps reported for the pulvinar of simians, including the location in pulvinar and the representation of the upper-lower and central-peripheral visual field axes. The second-order representation in the lateral map and a laminar organization are likely features specific to Old World simians. PMID- 23640867 TI - Facile fluorescence-based detection of PAD4-mediated citrullination. AB - The post-translational modifications of histone proteins are highly diverse and dynamic processes. It is becoming increasingly evident that modifying histone proteins can have a direct influence on both cellular homeostasis and disease states. Protein arginine deiminase 4 (PAD4) is an enzyme that converts peptidyl arginine to citrulline. The overexpression of PAD4 has been found in numerous types of human cancer and autoimmune diseases. We report a new, facile, fluorescence-based assay for the detection of PAD4 activity that exploits the substrate specificity of trypsin to monitor the citrullination reaction carried out by PAD4 based on the fact that, upon citrullination, the positively charged arginine side chain is converted to the neutral citrulline. We show that the assay can be performed rapidly with readily available reagents and that it responds accordingly to a known PAD4 inhibitor. PMID- 23640868 TI - New insights into the oxygen reduction reaction mechanism on Pt(111): a detailed electrochemical study. AB - The oxygen reduction reaction (ORR) is undoubtedly the most important fuel-cell cathodic reaction. In this work, a detailed electrochemical analysis of the ORR on Pt(111) in nonadsorbing electrolytes was performed, which included the high potential region Eup =1.15 V while ensuring the electrode surface structure stability. Our results suggest that the reduction of a soluble intermediate species formed during the ORR is the rate-determining step in the whole reaction mechanism. This species does not undergo any other electrochemical reaction at E>0.9 V and may accumulate close to the electrode surface. Together with dissolved O2, this intermediate may modify the oxide-growth dynamics on Pt(111). Hence, both species interact with the electrode surface through complex catalytic networks. Under certain experimental conditions, oxygenated species from the oxidation of Pt(111) may enhance the overall ORR current. These results propose an alternative to explain the current state of the art for this fundamental process. PMID- 23640869 TI - Formation and properties of self-assembly-driven fluorescent nanoparticle sensors. AB - Fluorescent nanoparticles (FNPs) are obtained in water by self-assembly from a polymeric ionic liquid, fluorescent carboxylate moiety, and a surfactant through two main supramolecular interactions, that is, ionic bonds and hydrophobic/hydrophilic interactions. The hydrophobicity of the surfactant is tunable and a highly hydrophobic surfactant increases the fluorescence intensity and stability of the FNPs. The fluorescence of the FNPs is sensitive to a quenching effect by various ions with high selectivity, and consequently, they may be used as sensors. The self-assembly approach used to generate the FNPs is considerably simpler than other methods based on more challenging synthetic methods and the flexibility of the approach should allow a wide and diverse range of FNPs to be prepared with specific sensor applications. PMID- 23640870 TI - The role of the anterolateral thigh flap in complex defects of the scalp and cranium. AB - In this study, we introduced scalp reconstruction using free anterolateral thigh (ALT) flaps and evaluated postoperative outcomes in nine patients between March 2000 and April 2012. Five patients had problems of exposed prosthesis, three required reconstruction after resection of scalp tumor and one patient presented with third degree flame burns of the scalp. All flaps survived without re exploration, except three flaps with tip necrosis requiring secondary procedures of debridement and small Z-plasty reconstructions. The superficial temporal artery and its concomitant vein were used as recipient vessels, apart from two cases where previous surgery and flame burns excluded these choices, for which facial arteries and veins were used instead. Primary closure of the donor-site was possible in six cases; with skin grafting performed for the other three patients. All donor sites healed without complications. The ALT flap offers the advantage of customizable size, option of fascia lata as vascularized dural replacement, and minimal flap atrophy typical of muscle flaps. Indications include very large defects, defects with exposed prosthesis, or defects with bone or dural loss. Our experience lends credible support to the use of customized free ALT flaps to achieve functional and cosmetically superior result for the reconstruction of large scalp defects, especially with bone exposure. PMID- 23640871 TI - GC models for separation optimization in pressure-tuneable tandem capillary columns operated isothermally. Part 1: Theoretical aspects. AB - GC column selectivity can be continuously adapted to suit analytical needs using a flow-tuneable tandem system. Its application for the separation of complex mixtures requires a deep understanding of the theory in this area. Although a number of researchers have developed specific models, a general and exhaustive theory is still missing. In this paper, we have made an implementation of pre existing models on tandem-column assemblies operated isothermally. In particular, we have investigated the effect of column length and diameter, phase thickness, and oven temperature on chromatographic parameters, such as capacity factor, selectivity, and intrinsic resolution. A new approach for the correct choice of the working temperature has been proposed. PMID- 23640872 TI - The distorted tropane of scopoline. AB - The structural isomerization of scopine into scopoline (oscine) has been observed in a supersonic jet expansion using microwave spectroscopy. The rotational spectrum evidences a single structure in the gas phase, providing a first description of the (three-ring) structurally distorted tropane in scopoline. The absence of rotational signatures of any scopine conformation suggests a practically quantitative isomerization at the vaporization temperatures of the experiment (ca. 90 degrees C). The determined rotational parameters of scopoline reveal the structural consequences of the intramolecular cyclation of scopine, which breaks the original epoxy group and creates a new ether bridge and a 7beta hydroxytropane configuration. The hydroxy group further stabilizes the molecule by an O-H???N intramolecular hydrogen bond, which, in turn, forces the N-methyl group to the less stable axial form. Supporting ab initio (MP2) and DFT (B3LYP, M06-2X) calculations are included. PMID- 23640873 TI - Nodal status of central lymph nodes as a negative prognostic factor for papillary thyroid carcinoma. AB - BACKGROUND: The status of metastatic lymph nodes, including the size and extracapsular spread (ECS), in papillary thyroid cancer (PTC) has not been well established. This study evaluated the correlation between the specific status of central lymph node metastases (CLNM) and negative prognostic factors. METHODS: We reviewed 243 patients who underwent total thyroidectomy and neck dissection. The CLNM slides were reviewed and the relationship between the CLNM status and risk factors was analyzed. RESULTS: CLNM were found in 111 patients. ECS (+) was related to a large tumor, high number of CLNM, and large node (P < 0.05). Tumor size and number of CLNM were related to the ECS rate (OR = 3.861 and 2.491, respectively; P < 0.01) in a multivariate analysis. Large nodes (>= 6 mm) were related to large tumor size, extrathyroidal extension, number of CLNM, and lateral cervical lymph node metastasis (LNM). Tumor size and LNM (OR = 4.519 and 7.811, respectively; P < 0.05) were related to large nodes in a multivariate analysis. CONCLUSIONS: ECS was related to node size, tumor size, and number of CLNM. Node size was related to tumor size and LNM. Thus, specific nodal status is a possible prognostic factor for PTC. PMID- 23640874 TI - Azimuthal and radial variations in sap flux density and effects on stand-scale transpiration estimates in a Japanese cedar forest. AB - Understanding radial and azimuthal variation, and tree-to-tree variation, in sap flux density (Fd) as sources of uncertainty is important for estimating transpiration using sap flow techniques. In a Japanese cedar (Cryptomeria japonica D. Don.) forest, Fd was measured at several depths and aspects for 18 trees, using heat dissipation (Granier-type) sensors. We observed considerable azimuthal variation in Fd. The coefficient of variation (CV) calculated from Fd at a depth of 0-20 mm (Fd1) and Fd at a depth of 20-40 mm (Fd2) ranged from 6.7 to 37.6% (mean = 28.3%) and from 19.6 to 62.5% (mean = 34.6%) for the -azimuthal directions. Fd at the north aspect averaged for nine trees, for which azimuthal measurements were made, was -obviously smaller than Fd at the other three aspects (i.e., west, south and east) averaged for the nine trees. Fd1 averaged for the nine trees was significantly larger than Fd2 averaged for the nine trees. The error for stand-scale transpiration (E) estimates caused by ignoring the azimuthal variation was larger than that caused by ignoring the radial variation. The error caused by ignoring tree-to-tree variation was larger than that caused by ignoring both radial and azimuthal variations. Thus, tree-to-tree variation in Fd would be more important than both radial and azimuthal variations in Fd for E estimation. However, Fd for each tree should not be measured at a consistent aspect but should be measured at various aspects to make accurate E estimates and to avoid a risk of error caused by the relationship of Fd to aspect. PMID- 23640876 TI - SAPs as novel regulators of abiotic stress response in plants. AB - Stress associated proteins (SAPs), novel A20/AN1 zinc-finger domain-containing proteins, are fast emerging as potential candidates for biotechnological approaches in order to improve abiotic stress tolerance in plants - the ultimate aim of which is crop-yield protection. Until relatively recently, such proteins had only been identified in humans, where they had been shown to be key regulators of innate immunity. Their phylogenetic relationship and recruitment of diverse protein domains reflect an architectural and mechanistic diversity. Emerging evidence suggests that SAPs may act as ubiquitin ligase, redox sensor, and regulator of gene expression during stress. Here, we evaluate the new knowledge on SAPs with a view to understand their mechanism of action. Furthermore, we set an agenda for investigating hitherto unexplored roles of these proteins. PMID- 23640875 TI - High-throughput screen for pharmacoperones of the vasopressin type 2 receptor. AB - Pharmacoperone drugs correct the folding of misfolded protein mutants and restore function (i.e., "rescue") by correcting the routing of (otherwise) misrouted mutants. Assays for pharmacoperones have not been applied to screen large libraries previously. Currently, most pharmacoperones possess intrinsic agonist or antagonist activities since these were identified using high-throughput screens aimed at discovering direct agonists or antagonists. Here we describe an ultra-high-throughput compatible no-wash assay system designed to specifically identify pharmacoperones of the vasopressin type 2 receptor (V2R). Development of such assays is important and novel since useful chemical structures with the ability to control cellular trafficking but lacking intrinsic agonist or antagonist properties have not likely been identified using existing screens. In the described assay, the level of functional human V2R (hV2R) (mutant) present in each test well is quantitated by stimulation with saturating levels of agonist followed by use of a luminescent-based cyclic adenosine monophosphate assay. This allows the assay to identify compounds that increase the trafficking of mutant hV2R[L(83)Q] in our model system. PMID- 23640877 TI - Reactivity of azole anions with CO2 from the DFT perspective. AB - Azole anions are key components in CO2 capture materials that include ionic liquids and porous solids. Herein, we use density functional theory (DFT) and a Langmuir-type adsorption model to study azole anion-CO2 interactions. Linear CO2 has to be bent by approximately 45 degrees to form an N-C bond within the azole ring. The energy cost of bending renders CO2 absorption much more difficult compared to SO2 absorption. For different azole anions, the number of nitrogen atoms in the ring and the natural bond orbital energy of the reacting nitrogen lone pair, both linearly correlate with the calculated reaction enthalpy and are useful handles for new sorbent designs. Unlike for SO2, the azole parent architecture (unsubstituted) does not allow successive CO2 absorption under mild conditions (<0.12 MPa and at room temperature). Experimental CO2 and SO2 absorption isotherms are reproduced by using the Langmuir model parameterized with the calibrated DFT reaction enthalpies. This study provides insight for designing azole-based CO2-capture materials. PMID- 23640878 TI - Aptamer-based SERS assay of ATP and lysozyme by using primer self-generation. AB - A simple bifunctional surface-enhanced Raman scattering (SERS) assay based on primer self-generation strand-displacement polymerization (PS-SDP) is developed to detect small molecules or proteins in parallel. Triphosphate (ATP) and lysozyme are used as the models of small molecules and proteins. Compared to traditional bifunctional methods, the method possesses some remarkable features as follows: 1) by virtue of the simple PS-SDP reaction, a bifunctional aptamer assembly binding of trigger 1 and trigger 2 was used as a functional structure for the simultaneous sensing of ATP or lysozyme. 2) The concept of isothermal amplification bifunctional detection has been first introduced into SERS biosensing applications as a signal-amplification tool. 3) The problem of high background induced by excess bio-barcodes is circumvented by using magnetic beads (MBs) as the carrier of signal-output products and massive of hairpin DNA binding with SERS active bio-barcodes relied on Au nanoparticles (Au NPs), SERS signal is significantly enhanced. Overall, with multiple amplification steps and one magnetic-separation procedure, this flexible biosensing system exhibited not only high sensitivity and specificity, with the detection limits of ATP and lysozyme of 0.05 nM and 10 fM, respectively. PMID- 23640879 TI - Effect of Platelet Rich Plasma and Platelet Rich Fibrin on sciatic nerve regeneration in a rat model. AB - The aim of this study was to evaluate the effect of Platelet Rich Plasma (PRP) and Platelet Rich Fibrin (PRF) on peripheral nerve repair. Thirty-two Wistar rats were randomly divided into four equal treatments groups: autologous nerve grafts (ANG), silicon tube plus saline solution (SS), silicon tube plus PRP, and silicon tube plus PRF. In ANG group, 10 mm segment from sciatic nerve was excised and reimplanted between the nerve stumps. In the SS, PRP, and PRF groups, 5 mm segment from sciatic nerve was excised and bridged with a 12 mm silicone conduit to create a 10 mm nerve gap. The conduit was filled in accordance with the different treatments. Walking track analysis was performed periodically and on the 90th post-operative day histomorphometric analysis was performed. The ANG, PRF, and PRP groups presented a significant functional improvement in relation to the SS group (P = 0.001) on 90 days after surgery. Histomorphometric analysis demonstrated that the ANG group achieved a larger nerve fiber diameter in proximal stump while comparing with the SS group (P =0.037) and showed larger fiber diameter in median stump in comparison to the PRP group (P = 0.002) and PRF group (P = 0.001). Axonal diameter and myelin sheath thickness showed no statistical significant difference between the groups in the three stumps (P >= 0.05). This study suggests that PRP and PRF have positive effects on the functional nerve recovery; however, these groups don't achieve a significant improvement on the histomorphometric analysis. PMID- 23640880 TI - Propofol binding to the resting state of the gloeobacter violaceus ligand-gated ion channel (GLIC) induces structural changes in the inter- and intrasubunit transmembrane domain (TMD) cavities. AB - General anesthetics exert many of their CNS actions by binding to and modulating membrane-embedded pentameric ligand-gated ion channels (pLGICs). The structural mechanisms underlying how anesthetics modulate pLGIC function remain largely unknown. GLIC, a prokaryotic pLGIC homologue, is inhibited by general anesthetics, suggesting anesthetics stabilize a closed channel state, but in anesthetic-bound GLIC crystal structures the channel appears open. Here, using functional GLIC channels expressed in oocytes, we examined whether propofol induces structural rearrangements in the GLIC transmembrane domain (TMD). Residues in the GLIC TMD that frame intrasubunit and intersubunit water accessible cavities were individually mutated to cysteine. We measured and compared the rates of modification of the introduced cysteines by sulfhydryl reactive reagents in the absence and presence of propofol. Propofol slowed the rate of modification of L240C (intersubunit) and increased the rate of modification of T254C (intrasubunit), indicating that propofol binding induces structural rearrangements in these cavities that alter the local environment near these residues. Propofol acceleration of T254C modification suggests that in the resting state propofol does not bind in the TMD intrasubunit cavity as observed in the crystal structure of GLIC with bound propofol (Nury, H., Van Renterghem, C., Weng, Y., Tran, A., Baaden, M., Dufresne, V., Changeux, J. P., Sonner, J. M., Delarue, M., and Corringer, P. J. (2011) Nature 469, 428-431). In silico docking using a GLIC closed channel homology model suggests propofol binds to intersubunit sites in the TMD in the resting state. Propofol-induced motions in the intersubunit cavity were distinct from motions associated with channel activation, indicating propofol stabilizes a novel closed state. PMID- 23640881 TI - Ferroportin and exocytoplasmic ferroxidase activity are required for brain microvascular endothelial cell iron efflux. AB - The mechanism(s) of iron flux across the brain microvasculature endothelial cells (BMVEC) of the blood-brain barrier remains unknown. Although both hephaestin (Hp) and the ferrous iron permease ferroportin (Fpn) have been identified in BMVEC, their roles in iron efflux have not been examined. Using a human BMVEC line (hBMVEC), we have demonstrated that these proteins are required for iron efflux from these cells. Expression of both Hp and Fpn protein was confirmed in hBMVEC by immunoblot and indirect immunofluorescence; we show that hBMVEC express soluble ceruloplasmin (Cp) transcript as well. Depletion of endogenous Hp and Cp via copper chelation leads to the reduction of hBMVEC Fpn protein levels as well as a complete inhibition of (59)Fe efflux. Both hBMVEC Fpn protein and (59)Fe efflux activity are restored upon incubation with 6.6 nm soluble plasma Cp. These results are independent of the source of cell iron, whether delivered as transferrin- or non-transferrin-bound (59)Fe. Our results demonstrate that iron efflux from hBMVEC Fpn requires the action of an exocytoplasmic ferroxidase, which can be either endogenous Hp or extracellular Cp. PMID- 23640882 TI - Protein tyrosine phosphatase 1B regulates pyruvate kinase M2 tyrosine phosphorylation. AB - Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and adiposity and is a drug target for the treatment of obesity and diabetes. Here we identify pyruvate kinase M2 (PKM2) as a novel PTP1B substrate in adipocytes. PTP1B deficiency leads to increased PKM2 total tyrosine and Tyr(105) phosphorylation in cultured adipocytes and in vivo. Substrate trapping and mutagenesis studies identify PKM2 Tyr-105 and Tyr-148 as key sites that mediate PTP1B-PKM2 interaction. In addition, in vitro analyses illustrate a direct effect of Tyr-105 phosphorylation on PKM2 activity in adipocytes. Importantly, PTP1B pharmacological inhibition increased PKM2 Tyr-105 phosphorylation and decreased PKM2 activity. Moreover, PKM2 Tyr-105 phosphorylation is regulated nutritionally, decreasing in adipose tissue depots after high-fat feeding. Further, decreased PKM2 Tyr-105 phosphorylation correlates with the development of glucose intolerance and insulin resistance in rodents, non-human primates, and humans. Together, these findings identify PKM2 as a novel substrate of PTP1B and provide new insights into the regulation of adipose PKM2 activity. PMID- 23640883 TI - Proteasomal degradation of eukaryotic elongation factor-2 kinase (EF2K) is regulated by cAMP-PKA signaling and the SCFbetaTRCP ubiquitin E3 ligase. AB - Protein translation and degradation are critical for proper protein homeostasis, yet it remains unclear how these processes are dynamically regulated, or how they may directly balance or synergize with each other. An important translational control mechanism is the Ca(2+)/calmodulin-dependent phosphorylation of eukaryotic elongation factor-2 (eEF-2) by eukaryotic elongation factor-2 kinase (EF2K), which inhibits elongation of nascent polypeptide chains during translation. We previously described a reduction of EF2K activity in PC12 cells treated with NGF or forskolin. Here, we show that both forskolin- and IGF-1 mediated reductions of EF2K activity in PC12 cells are due to decreased EF2K protein levels, and this is attenuated by application of the proteasome inhibitor, MG132. We further demonstrate that proteasome-mediated degradation of EF2K occurs in response to A2A-type adenosine receptor stimulation, and that activation of protein kinase A (PKA) or phospho-mimetic mutation of the previously characterized PKA site, Ser-499, were sufficient to induce EF2K turnover in PC12 cells. A similar EF2K degradation mechanism was observed in primary neurons and HEK cells. Expression of a dominant-negative form of Cul1 in HEK cells demonstrated that EF2K levels are regulated by an SCF-type ubiquitin E3 ligase. Specifically, EF2K binds to the F-box proteins, betaTRCP1 and betaTRCP2, and betaTRCP regulates EF2K levels and polyubiquitylation. We propose that the proteasomal degradation of EF2K provides a mechanistic link between activity dependent protein synthesis and degradation. PMID- 23640884 TI - Distinct role of Pyk2 in mediating thromboxane generation downstream of both G12/13 and integrin alphaIIbbeta3 in platelets. AB - Proline-rich tyrosine kinase 2 (Pyk2) is activated by various agonists in platelets. We evaluated the signaling mechanism and the functional role of Pyk2 in platelets by using pharmacological inhibitors and Pyk2-deficient platelets. We found that platelet aggregation and secretion in response to 2-methylthio-ADP (2 MeSADP) and AYPGKF were diminished in the presence of Pyk2 inhibitors or in Pyk2 deficient platelets, suggesting that Pyk2 plays a positive regulatory role in platelet functional responses. It has been shown that ADP-, but not thrombin induced thromboxane (TxA2) generation depends on integrin signaling. Unlike ADP, thrombin activates G12/13 pathways, and G12/13 pathways can substitute for integrin signaling for TxA2 generation. We found that Pyk2 was activated downstream of both G12/13 and integrin-mediated pathways, and both 2-MeSADP- and AYPGKF-induced TxA2 generation was significantly diminished in Pyk2-deficient platelets. In addition, TxA2 generation induced by co-stimulation of Gi and Gz pathways, which is dependent on integrin signaling, was inhibited by blocking Pyk2. Furthermore, inhibition of 2-MeSADP-induced TxA2 generation by fibrinogen receptor antagonist was not rescued by co-stimulation of G12/13 pathways in the presence of Pyk2 inhibitor. We conclude that Pyk2 is a common signaling effector downstream of both G12/13 and integrin alphaIIbbeta3 signaling, which contributes to thromboxane generation. PMID- 23640885 TI - The fibroblast growth factor 14.voltage-gated sodium channel complex is a new target of glycogen synthase kinase 3 (GSK3). AB - The FGF14 protein controls biophysical properties and subcellular distribution of neuronal voltage-gated Na(+) (Nav) channels through direct binding to the channel C terminus. To gain insights into the dynamic regulation of this protein/protein interaction complex, we employed the split luciferase complementation assay to screen a small molecule library of kinase inhibitors against the FGF14.Nav1.6 channel complex and identified inhibitors of GSK3 as hits. Through a combination of a luminescence-based counter-screening, co-immunoprecipitation, patch clamp electrophysiology, and quantitative confocal immunofluorescence, we demonstrate that inhibition of GSK3 reduces the assembly of the FGF14.Nav channel complex, modifies FGF14-dependent regulation of Na(+) currents, and induces dissociation and subcellular redistribution of the native FGF14.Nav channel complex in hippocampal neurons. These results further emphasize the role of FGF14 as a critical component of the Nav channel macromolecular complex, providing evidence for a novel GSK3-dependent signaling pathway that might control excitability through specific protein/protein interactions. PMID- 23640886 TI - Obesity induces hypothalamic endoplasmic reticulum stress and impairs proopiomelanocortin (POMC) post-translational processing. AB - It was shown previously that abnormal prohormone processing or inactive proconverting enzymes that are responsible for this processing cause profound obesity. Our laboratory demonstrated earlier that in the diet-induced obesity (DIO) state, the appetite-suppressing neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) is reduced, yet the mRNA of its precursor protein proopiomelanocortin (POMC) remained unaltered. It was also shown that the DIO condition promotes the development of endoplasmic reticulum (ER) stress and leptin resistance. In the current study, using an in vivo model combined with in vitro experiments, we demonstrate that obesity-induced ER stress obstructs the post-translational processing of POMC by decreasing proconverting enzyme 2, which catalyzes the conversion of adrenocorticotropin to alpha-MSH, thereby decreasing alpha-MSH peptide production. This novel mechanism of ER stress affecting POMC processing in DIO highlights the importance of ER stress in regulating central energy balance in obesity. PMID- 23640887 TI - Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease. AB - Neurofibrillary pathology of abnormally hyperphosphorylated Tau is a key lesion of Alzheimer disease and other tauopathies, and its density in the brain directly correlates with dementia. The phosphorylation of Tau is regulated by protein phosphatase 2A, which in turn is regulated by inhibitor 2, I2(PP2A). In acidic conditions such as generated by brain ischemia and hypoxia, especially in association with hyperglycemia as in diabetes, I2(PP2A) is cleaved by asparaginyl endopeptidase at Asn-175 into the N-terminal fragment (I2NTF) and the C-terminal fragment (I2CTF). Both I2NTF and I2CTF are known to bind to the catalytic subunit of protein phosphatase 2A and inhibit its activity. Here we show that the level of activated asparaginyl endopeptidase is significantly increased, and this enzyme and I2(PP2A) translocate, respectively, from neuronal lysosomes and nucleus to the cytoplasm where they interact and are associated with hyperphosphorylated Tau in Alzheimer disease brain. Asparaginyl endopeptidase from Alzheimer disease brain could cleave GST-I2(PP2A), except when I2(PP2A) was mutated at the cleavage site Asn-175 to Gln. Finally, an induction of acidosis by treatment with kainic acid or pH 6.0 medium activated asparaginyl endopeptidase and consequently produced the cleavage of I2(PP2A), inhibition of protein phosphatase 2A, and hyperphosphorylation of Tau, and the knockdown of asparaginyl endopeptidase with siRNA abolished this pathway in SH-SY5Y cells. These findings suggest the involvement of brain acidosis in the etiopathogenesis of Alzheimer disease, and asparaginyl endopeptidase-I2(PP2A)-protein phosphatase 2A-Tau hyperphosphorylation pathway as a therapeutic target. PMID- 23640888 TI - The interaction of caveolin 3 protein with the potassium inward rectifier channel Kir2.1: physiology and pathology related to long qt syndrome 9 (LQT9). AB - Mutations in CAV3 cause LQT syndrome 9 (LQT9). A previously reported LQT9 patient had prominent U waves on ECG, a feature that has been correlated with Kir2.1 loss of function. Our objective was to determine whether caveolin 3 (Cav3) associates with Kir2.1 and whether LQT9-associated CAV3 mutations affect the biophysical properties of Kir2.1. Kir2.1 current (IK1) density was measured using the whole cell voltage clamp technique. WT-Cav3 did not affect IK1. However, F97C-Cav3 and T78M-Cav3 decreased IK1 density significantly by ~60%, and P104L-Cav3 decreased IK1 density significantly by ~30% at -60 mV. Immunostained rat heart cryosections and HEK293 cells cotransfected with Kir2.1 and WT-Cav3 both demonstrated colocalization of Kir2.1 and WT-Cav3 by confocal imaging. Cav3 coimmunoprecipitated with Kir2.1 in human ventricular myocytes and in heterologous expression systems. Additionally, FRET efficiency was highly specific, with a molecular distance of 5.6 +/- 0.4 nm, indicating close protein location. Colocalization experiments found that Cav3 and Kir2.1 accumulated in the Golgi compartment. On-cell Western blot analysis showed decreased Kir2.1 cell surface expression by 60% when expressed with F97C-Cav3 and by 20% when expressed with P104L-Cav3 compared with WT-Cav3. This is the first report of an association between Cav3 and Kir2.1. The Cav3 mutations F97C-Cav3, P104L-Cav3, and T78M-Cav3 decreased IK1 density significantly. This effect was related to a reduced cell surface expression of Kir2.1. Kir2.1 loss of function is additive to the increase described previously in late INa, prolonging repolarization and leading to arrhythmia generation in Cav3-mediated LQT9. PMID- 23640889 TI - Sepiapterin reductase mediates chemical redox cycling in lung epithelial cells. AB - In the lung, chemical redox cycling generates highly toxic reactive oxygen species that can cause alveolar inflammation and damage to the epithelium, as well as fibrosis. In this study, we identified a cytosolic NADPH-dependent redox cycling activity in mouse lung epithelial cells as sepiapterin reductase (SPR), an enzyme important for the biosynthesis of tetrahydrobiopterin. Human SPR was cloned and characterized. In addition to reducing sepiapterin, SPR mediated chemical redox cycling of bipyridinium herbicides and various quinones; this activity was greatest for 1,2-naphthoquinone followed by 9,10 phenanthrenequinone, 1,4-naphthoquinone, menadione, and 2,3-dimethyl-1,4 naphthoquinone. Whereas redox cycling chemicals inhibited sepiapterin reduction, sepiapterin had no effect on redox cycling. Additionally, inhibitors such as dicoumarol, N-acetylserotonin, and indomethacin blocked sepiapterin reduction, with no effect on redox cycling. Non-redox cycling quinones, including benzoquinone and phenylquinone, were competitive inhibitors of sepiapterin reduction but noncompetitive redox cycling inhibitors. Site-directed mutagenesis of the SPR C-terminal substrate-binding site (D257H) completely inhibited sepiapterin reduction but had minimal effects on redox cycling. These data indicate that SPR-mediated reduction of sepiapterin and redox cycling occur by distinct mechanisms. The identification of SPR as a key enzyme mediating chemical redox cycling suggests that it may be important in generating cytotoxic reactive oxygen species in the lung. This activity, together with inhibition of sepiapterin reduction by redox-active chemicals and consequent deficiencies in tetrahydrobiopterin, may contribute to tissue injury. PMID- 23640890 TI - Erythrocytosis and pulmonary hypertension in a mouse model of human HIF2A gain of function mutation. AB - The central pathway for oxygen-dependent control of red cell mass is the prolyl hydroxylase domain protein (PHD):hypoxia inducible factor (HIF) pathway. PHD site specifically prolyl hydroxylates the transcription factor HIF-alpha, thereby targeting the latter for degradation. Under hypoxia, this modification is attenuated, allowing stabilized HIF-alpha to activate target genes, including that for erythropoietin (EPO). Studies employing genetically modified mice point to Hif-2alpha, one of two main Hif-alpha isoforms, as being the critical regulator of Epo in the adult mouse. More recently, erythrocytosis patients with heterozygous point mutations in the HIF2A gene have been identified; whether these mutations were polymorphisms unrelated to the phenotype could not be ruled out. In the present report, we characterize a mouse line bearing a G536W missense mutation in the Hif2a gene that corresponds to the first such human mutation identified (G537W). We obtained mice bearing both heterozygous and homozygous mutations at this locus. We find that these mice display, in a mutation dose dependent manner, erythrocytosis and pulmonary hypertension with a high degree of penetrance. These findings firmly establish missense mutations in HIF-2alpha as a cause of erythrocytosis, highlight the importance of this HIF-alpha isoform in erythropoiesis, and point to physiologic consequences of HIF-2alpha dysregulation. PMID- 23640891 TI - Biosynthesis, characterization, and efficacy in retinal degenerative diseases of lens epithelium-derived growth factor fragment (LEDGF1-326), a novel therapeutic protein. AB - For vision-threatening retinitis pigmentosa and dry age-related macular degeneration, there are no United States Food and Drug Administration (FDA) approved treatments. We identified, biosynthesized, purified, and characterized lens epithelium-derived growth factor fragment (LEDGF1-326) as a novel protein therapeutic. LEDGF1-326 was produced at about 20 mg/liter of culture when expressed in the Escherichia coli system, with about 95% purity and aggregate free homogeneous population with a mean hydrodynamic diameter of 9 +/- 1 nm. The free energy of unfolding of LEDGF1-326 was 3.3 +/- 0.5 kcal mol(-1), and melting temperature was 44.8 +/- 0.2 degrees C. LEDGF1-326 increased human retinal pigment epithelial cell viability from 48.3 +/- 5.6 to 119.3 +/- 21.1% in the presence of P23H mutant rhodopsin-mediated aggregation stress. LEDGF1-326 also increased retinal pigment epithelial cell FluoSphere uptake to 140 +/- 10%. Eight weeks after single intravitreal injection in Royal College of Surgeons (RCS) rats, LEDGF1-326 increased the b-wave amplitude significantly from 9.4 +/- 4.6 to 57.6 +/- 8.8 MUV for scotopic electroretinogram and from 10.9 +/- 5.6 to 45.8 +/- 15.2 MUV for photopic electroretinogram. LEDGF1-326 significantly increased the retinal outer nuclear layer thickness from 6.34 +/- 1.6 to 11.7 +/- 0.7 MUm. LEDGF1-326 is a potential new therapeutic agent for treating retinal degenerative diseases. PMID- 23640892 TI - Endogenous APOBEC3A DNA cytosine deaminase is cytoplasmic and nongenotoxic. AB - APOBEC3A (A3A) is a myeloid lineage-specific DNA cytosine deaminase with a role in innate immunity to foreign DNA. Previous studies have shown that heterologously expressed A3A is genotoxic, suggesting that monocytes may have a mechanism to regulate this enzyme. Indeed, we observed no significant cytotoxicity when interferon was used to induce the expression of endogenous A3A in CD14(+)-enriched primary cells or the monocytic cell line THP-1. In contrast, doxycycline-induced A3A in HEK293 cells caused major cytotoxicity at protein levels lower than those observed when CD14(+) cells were stimulated with interferon. Immunofluorescent microscopy of interferon-stimulated CD14(+) and THP 1 cells revealed that endogenous A3A is cytoplasmic, in stark contrast to stably or transiently transfected A3A, which has a cell-wide localization. A3A constructs engineered to be cytoplasmic are also nontoxic in HEK293 cells. These data combine to suggest that monocytic cells use a cytoplasmic retention mechanism to control A3A and avert genotoxicity during innate immune responses. PMID- 23640894 TI - X-ray structure analysis and characterization of AFUEI, an elastase inhibitor from Aspergillus fumigatus. AB - Elastase from Aspergillus sp. is an important factor for aspergillosis. AFUEI is an inhibitor of the elastase derived from Aspergillus fumigatus. AFUEI is a member of the I78 inhibitor family and has a high inhibitory activity against elastases of Aspergillus fumigatus and Aspergillus flavus, human neutrophil elastase and bovine chymotrypsin, but does not inhibit bovine trypsin. Here we report the crystal structure of AFUEI in two crystal forms. AFUEI is a wedge shaped protein composed of an extended loop and a scaffold protein core. The structure of AFUEI shows remarkable similarity to serine protease inhibitors of the potato inhibitor I family, although they are classified into different inhibitor families. A structural comparison with the potato I family inhibitors suggests that the extended loop of AFUEI corresponds to the binding loop of the potato inhibitor I family, and AFUEI inhibits its cognate proteases through the same mechanism as the potato I family inhibitors. PMID- 23640893 TI - Interleukin-2 inhibits HIV-1 replication in some human T cell lymphotrophic virus 1-infected cell lines via the induction and incorporation of APOBEC3G into the virion. AB - IL-2 has been used in culture of primary T cells to maintain cell proliferation. We have previously reported that IL-27 inhibits HIV-1 replication in primary T cells in the presence of IL-2. To gain a better understanding of the mechanisms involved in this inhibitory effect, we attempted to investigate in detail the effects of IL-27 and IL-2 using several cell lines. Unexpectedly, IL-27 did not inhibit HIV-1 in T cell lines, whereas IL-2 inhibited HIV-1 replication in the human T cell lymphotrophic virus (HTLV)-1-transformed T cell lines, MT-2, MT-4, SLB-1, and ATL-2. No effects were seen in HTLV-1-negative cell lines. Utilizing MT-2 cells, we demonstrated that IL-2 treatment inhibited HIV-1 syncytia-inducing ability and dose-dependently decreased supernatant p24 antigen levels by >90%. Using real time PCR and Western blot analysis, we observed that IL-2 treatment induced the host restriction factor, APOBEC3G with accumulation into the lower molecular mass active form as characterized by FPLC. Further analysis revealed that the virus recovered from IL-2-treated MT-2 cells had impaired replication competency. This was found to be due to incorporation of APOBEC3G into the virion despite the presence of Vif. These findings demonstrate a novel role for IL-2 in regulating production of infectious HIV-1 virions in HTLV-1-infected cells through the induction of APOBEC3G. PMID- 23640895 TI - Fibroblast growth factor receptor like-1 (FGFRL1) interacts with SHP-1 phosphatase at insulin secretory granules and induces beta-cell ERK1/2 protein activation. AB - FGFRL1 is a newly identified member of the fibroblast growth factor receptor (FGFR) family expressed in adult pancreas. Unlike canonical FGFRs that initiate signaling via tyrosine kinase domains, the short intracellular sequence of FGFRL1 consists of a putative Src homology domain-2 (SH2)-binding motif adjacent to a histidine-rich C terminus. As a consequence of nonexistent kinase domains, FGFRL1 has been postulated to act as a decoy receptor to inhibit canonical FGFR ligand induced signaling. In pancreatic islet beta-cells, canonical FGFR1 signaling affects metabolism and insulin processing. This study determined beta-cell expression of FGFRL1 as well as consequent effects on FGFR1 signaling and biological responses. We confirmed FGFRL1 expression at the plasma membrane and within distinct intracellular granules of both primary beta-cells and betaTC3 cells. Fluorescent protein-tagged FGFRL1 (RL1) induced a significant ligand independent increase in MAPK signaling. Removal of the histidine-rich domain (RL1 DeltaHis) or entire intracellular sequence (RL1-DeltaC) resulted in greater retention at the plasma membrane and significantly reduced ligand-independent ERK1/2 responses. The SHP-1 phosphatase was identified as an RL1-binding substrate. Point mutation of the SH2-binding motif reduced the ability of FGFRL1 to bind SHP-1 and activate ERK1/2 but did not affect receptor localization to insulin secretory granules. Finally, overexpression of RL1 increased cellular insulin content and matrix adhesion. Overall, these data suggest that FGFRL1 does not function as a decoy receptor in beta-cells, but rather it enhances ERK1/2 signaling through association of SHP-1 with the receptor's intracellular SH2 binding motif. PMID- 23640899 TI - Comparison of robotic adrenalectomy with traditional laparoscopic adrenalectomy with a lateral transperitoneal approach: a single-surgeon experience. AB - BACKGROUND: Although several recent studies have demonstrated the feasibility and safety of robotic adrenalectomy, it is unknown whether this procedure has advantages over the traditional laparoscopic approach. This study compared our initial experience using the da Vinci-S(r) robotic surgical system during laparoscopic adrenalectomy with our experience with traditional laparoscopic adrenalectomy. METHODS: From October 2009 to May 2012, 23 consecutive patients (13 women, 10 men) underwent laparoscopic adrenalectomy by the same surgeon at Anam Hospital, Korea University Medical Center. Fifteen patients (9 women, 6 men) underwent robot-assisted adrenalectomy (right-sided, 4 patients; left-sided, 11 patients). Eight patients (4 women, 4 men) underwent traditional laparoscopic adrenalectomy (right-sided, 5 patients; left-sided, 3 patients). The lateral transperitoneal approach was used for all patients. RESULTS: There were no cases of conversion to traditional laparoscopic or open surgery. The mean operative time was longer in the robotic group (208.2 minutes, range 120-320) than the laparoscopic group (181.13 minutes, range 75-270). There were no cases of intraoperative complications or mortality. The mean hospital stay did not differ significantly between groups (robotic group, 5.86 days (SD 1.16); laparoscopic group, 6.71 days (SD 1.38)). CONCLUSIONS: With its magnified stereoscopic three dimensional vision, elimination of tremor, and ability to articulate and rotate surgical instruments, the da Vinci-S(r) robotic system may be an ideal surgical tool for the operation of adrenal lesions. Robotic adrenalectomy appears to be a safe and effective alternative to traditional laparoscopic adrenalectomy. PMID- 23640897 TI - Lacritin rescues stressed epithelia via rapid forkhead box O3 (FOXO3)-associated autophagy that restores metabolism. AB - Homeostasis is essential for cell survival. However, homeostatic regulation of surface epithelia is poorly understood. The eye surface, lacking the cornified barrier of skin, provides an excellent model. Tears cover the surface of the eye and are deficient in dry eye, the most common eye disease affecting at least 5% of the world's population. Only a tiny fraction of the tear proteome appears to be affected, including lacritin, an epithelium-selective mitogen that promotes basal tearing when topically applied to rabbit eyes. Here we show that homeostasis of cultured corneal epithelia is entirely lacritin-dependent and elucidate the mechanism as a rapid autophagic flux to promptly restore cellular metabolism and mitochondrial fusion in keeping with the short residence time of lacritin on the eye. Accelerated flux appears to be derived from lacritin stimulated acetylation of FOXO3 as a novel ligand for ATG101 and coupling of stress-acetylated FOXO1 with ATG7 (which remains uncoupled without lacritin) and be sufficient to selectively divert huntingtin mutant Htt103Q aggregates largely without affecting non-aggregated Htt25Q. This is in keeping with stress as a prerequisite for lacritin-stimulated autophagy. Lacritin targets the cell surface proteoglycan syndecan-1 via its C-terminal amino acids Leu(108)-Leu(109)-Phe(112) and is also available in saliva, plasma, and lung lavage. Thus, lacritin may promote epithelial homeostasis widely. PMID- 23640898 TI - Each member of the poly-r(C)-binding protein 1 (PCBP) family exhibits iron chaperone activity toward ferritin. AB - The mechanisms through which iron-dependent enzymes receive their metal cofactors are largely unknown. Poly r(C)-binding protein 1 (PCBP1) is an iron chaperone for ferritin; both PCBP1 and its paralog PCBP2 are required for iron delivery to the prolyl hydroxylase that regulates HIF1. Here we show that PCBP2 is also an iron chaperone for ferritin. Co-expression of PCBP2 and human ferritins in yeast activated the iron deficiency response and increased iron deposition into ferritin. Depletion of PCBP2 in Huh7 cells diminished iron incorporation into ferritin. Both PCBP1 and PCBP2 were co-immunoprecipitated with ferritin in HEK293 cells, and expression of both PCBPs was required for ferritin complex formation in cells. PCBP1 and -2 exhibited high affinity binding to ferritin in vitro. Mammalian genomes encode 4 PCBPs, including the minimally expressed PCBPs 3 and 4. Expression of PCBP3 and -4 in yeast activated the iron deficiency response, but only PCBP3 exhibited strong interactions with ferritin. Expression of PCBP1 and ferritin in an iron-sensitive, ccc1 yeast strain intensified the toxic effects of iron, whereas expression of PCBP4 protected the cells from iron toxicity. Thus, PCBP1 and -2 form a complex for iron delivery to ferritin, and all PCBPs may share iron chaperone activity. PMID- 23640900 TI - Enhanced expression of MYF5 and MYOD1 in fibroblast cells via the forced expression of bos taurus MYF5. AB - The formation of vertebrate skeletal muscles widely thought to be under the control of hierarchy of regulatory genes. MYF5 is one of the myogenic determination gene expressed in the developing mouse dermomyotome which control skeletal muscle differentiation. In the current work, we had obtained the cDNA sequence including the full coding region of the bos taurus myogenic factor MYF5 by reverse transcription polymerase chain reaction. Furthermore, we examined whether fibroblast cell derived from mouse and bos taurus can be transduced using plasmid vectors carrying bos taurus MYF5. Bos taurus MYF5 activates MYF5 and MYOD1 expression after 1 day culture. The concerted upregulation of the myogenic regulatory factors enhanced myosin (skeletal fast) expression. These observation show that MYF5 is essential for myogenic differentiation and provides candidates for regulation bos taurus skeletal muscle development. PMID- 23640896 TI - Rac-1 superactivation triggers insulin-independent glucose transporter 4 (GLUT4) translocation that bypasses signaling defects exerted by c-Jun N-terminal kinase (JNK)- and ceramide-induced insulin resistance. AB - Insulin activates a cascade of signaling molecules, including Rac-1, Akt, and AS160, to promote the net gain of glucose transporter 4 (GLUT4) at the plasma membrane of muscle cells. Interestingly, constitutively active Rac-1 expression results in a hormone-independent increase in surface GLUT4; however, the molecular mechanism and significance behind this effect remain unresolved. Using L6 myoblasts stably expressing myc-tagged GLUT4, we found that overexpression of constitutively active but not wild-type Rac-1 sufficed to drive GLUT4 translocation to the membrane of comparable magnitude with that elicited by insulin. Stimulation of endogenous Rac-1 by Tiam1 overexpression elicited a similar hormone-independent gain in surface GLUT4. This effect on GLUT4 traffic could also be reproduced by acutely activating a Rac-1 construct via rapamycin mediated heterodimerization. Strategies triggering Rac-1 "superactivation" (i.e. to levels above those attained by insulin alone) produced a modest gain in plasma membrane phosphatidylinositol 3,4,5-trisphosphate, moderate Akt activation, and substantial AS160 phosphorylation, which translated into GLUT4 translocation and negated the requirement for IRS-1. This unique signaling capacity exerted by Rac 1 superactivation bypassed the defects imposed by JNK- and ceramide-induced insulin resistance and allowed full and partial restoration of the GLUT4 translocation response, respectively. We propose that potent elevation of Rac-1 activation alone suffices to drive insulin-independent GLUT4 translocation in muscle cells, and such a strategy might be exploited to bypass signaling defects during insulin resistance. PMID- 23640901 TI - Solanidine isolation from Solanum tuberosum by centrifugal partition chromatography. AB - The aim of this investigation was the preparative isolation of solanidine (aglycone of the two main potato glycoalkaloids: alpha-chaconine and alpha solanine) from fresh Solanum tuberosum (cv. Pompadour) material by implementing a new preparation scheme using centrifugal partition chromatography (CPC). A setup for obtaining solanidine by hydrolysis of the glycoalkaloids found in the skin and sprouts of S. tuberosum was first developed. Then its isolation was carried out by the development of CPC conditions: the solvent system used for separation was ethyl acetate/butanol/water in the ratio 42.5:7.5:50 v/v/v, 0.6 g of crude extract were separated with a 8 mL/min flow rate of mobile phase while rotating at 2500 rpm. A run yielded 98 mg of solanidine (86.7% recovery from the crude extract) in a one-step separation. The purity of the isolated solanidine was over 98%. Thus, CPC has proven to be the method of choice to get solanidine of very high purity from S. tuberosum biomass in large quantities. PMID- 23640903 TI - The basophil: resolved questions and new avenues of investigation. PMID- 23640905 TI - 1,2,3,4-Tetrasubstituted cyclopentadienes and their applications for metallocenes: efficient synthesis through zirconocene- and CuCl-mediated intermolecular coupling of two alkynes and one diiodomethane. AB - 1,2,3,4-Tetrasubstituted cyclopentadienes and indene derivatives with identical or different substituents were obtained in good to excellent isolated yields through a zirconocene- and CuCl-mediated intermolecular coupling process. This synthetic procedure involved three organic partners, including one CH2 I2 , and two different or identical alkynes. Two alkynes or one diyne undergo Cp2Zr(II) mediated (Cp = eta(5)-C5H5) pair-selective reductive coupling to afford the corresponding zirconacyclopentadiene derivatives, which react, in the presence of CuCl and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPU), with CH2I2 through intermolecular followed by intramolecular coupling to afford the cyclopentadiene derivatives. An application of the prepared tetrasubstituted cyclopentadiene derivatives was demonstrated by the facile synthesis of the corresponding zirconocene complexes [((4R)Cp)2ZrCl2] and [((4R)Cp)2ZrR'2] (R' = Me, Et, or nBu). The unique 1,2,3,4-tetrasubstituted cyclopentadiene ligands and the corresponding metallocenes are expected to have further applications in organometallic chemistry and organic synthesis. PMID- 23640906 TI - Posterior trunk reconstruction using an anteromedial thigh free flap and arteriovenous loop. PMID- 23640904 TI - Cyclooxygenase inhibition improves endothelial vasomotor dysfunction of visceral adipose arterioles in human obesity. AB - OBJECTIVE: The purpose of this study was to determine whether cyclooxygenase inhibition improves vascular dysfunction of adipose microvessels from obese humans. DESIGN AND METHODS: In 20 obese subjects (age 37 +/- 12 years, BMI 47 +/- 8 kg/m2), subcutaneous and visceral fat were collected during bariatric surgery and characterized for adipose depot-specific gene expression, endothelial cell phenotype, and microvascular function. Vasomotor function was assessed in response to endothelium-dependent agonists using videomicroscopy of small arterioles from fat. RESULTS: Arterioles from visceral fat exhibited impaired endothelium-dependent, acetylcholine-mediated vasodilation, compared to the subcutaneous depot (P < 0.001). Expression of mRNA transcripts relevant to the cyclooxygenase pathway was upregulated in visceral compared to subcutaneous fat. Pharmacological inhibition of cyclooxygenase with indomethacin improved endothelium-dependent vasodilator function of arterioles from visceral fat by twofold (P = 0.01), whereas indomethacin had no effect in the subcutaneous depot. Indomethacin increased activation via serine-1177 phosphorylation of endothelial nitric oxide synthase in response to acetylcholine in endothelial cells from visceral fat. Inhibition of endothelial nitric oxide synthase with N(omega)-nitro L-arginine methyl ester abrogated the effects of cyclooxygenase-inhibition suggesting that vascular actions of indomethacin were related to increased nitric oxide bioavailability. CONCLUSIONS: Our findings suggest that cyclooxygenase mediated vasoconstrictor prostanoids partly contribute to endothelial dysfunction of visceral adipose arterioles in human obesity. PMID- 23640907 TI - Risk factors associated with unconjugated neonatal hyperbilirubinemia in Malaysian neonates. AB - OBJECTIVE: To investigate the risk factors associated with neonatal hyperbilirubinemia in Malaysian neonates. METHODS: A prospective study was conducted to investigate the effects of glucose-6-phosphate dehydrogenase (G6PD) mutation, variant uridine diphosphate glucuronosyltransferase UGT1A1 gene and hepatic organic anion transporter protein (OATP2) gene on a group of neonates. Hyperbilirubinemia was defined as a total serum bilirubin level of >=250 umol/l. RESULTS: Of 318 neonates, 52 (16.4%) had hyperbilirubinemia. The incidence of G6PD mutation was 5.4% (15/280) among these infants. The incidence of G6PD mutation was significantly higher in the male neonates with hyperbilirubinemia (7.8%) when compared with the normal male neonates without hyperbilirubinemia (1.8%; p = 0.03). Logistic regression analysis showed that the significant risk factors for neonatal hyperbilirubinemia were Malay ethnicity [adjusted odds ratio (OR), 2.77; 95% confidence interval (CI): 1.31-5.86; p = 0.007] and G6PD mutation (adjusted OR, 3.29; 95% CI: 1.06-10.1820; p = 0.039). The gender, birth weight and gestation age of neonates, variant c.211G > A and variant of OATP2 gene were not significant. CONCLUSIONS: Neonates with Malay ethnicity and G6PD mutation were at risk for hyperbilirubinemia. PMID- 23640908 TI - An actuated force feedback-enabled laparoscopic instrument for robotic-assisted surgery. AB - BACKGROUND: Robotic-assisted minimally invasive surgery systems not only have the advantages of traditional laparoscopic instruments but also have other important advantages, including restoring the surgeon's hand-eye coordination and improving the surgeon's precision by filtering hand tremors. Unfortunately, these benefits have come at the expense of the surgeon's ability to feel. Various solutions for restoring this feature have been proposed. METHODS: An actuated modular force feedback-enabled laparoscopic instrument was proposed that is able to measure tip tissue lateral interaction forces as well as normal grasping forces. The instrument has also the capability to adjust the grasping direction inside the patient body. In order to measure the interaction forces, strain gauges were employed. A series of finite element analyses were performed to gain an understanding of the actual magnitude of surface strains where gauges are applied. The strain gauge bridge configurations were calibrated. A series of experiments was conducted and the results were analysed. RESULTS: The modularity feature of the proposed instrument makes it interchangeable between various tip types of different functionalities (e.g. cutter, grasper, dissector). Calibration results of the strain gauges incorporated into the tube and at the base of the instrument presented the monotonic responses for these strain gauge configurations. Experimental results from tissue probing and tissue characterization experiments verified the capability of the proposed instrument in measuring lateral probing forces and characterizing artificial tissue samples of varying stiffness. CONCLUSION: The proposed instrument can improve the quality of palpation and characterization of soft tissues of varying stiffness by restoring sense of touch in robotic assisted minimally invasive surgery operations. PMID- 23640909 TI - Development of a solid-phase microextraction fiber coated with poly(methacrylic acid-ethylene glycol dimethacrylate) and its application for the determination of chlorophenols in water coupled with GC. AB - A solid-phase microextraction (SPME) fiber coated with poly(methacrylic acid ethylene glycol dimethacrylate) coupled to GC with a micro electron-capture detector was developed for the determination of four chlorphenols in water samples for the first time. A novel and simple method for the preparation of this novel SPME fiber was proposed by copolymerization of methacrylic acid and ethylene glycol dimethacrylate in an appropriate solvent using a glass capillary as a "mold". The factors affecting the polymerization were optimized in detail. Furthermore, the extraction performance of the poly(methacrylic acid-ethylene glycol dimethacrylate) fiber was evaluated. Moreover, experimental headspace-SPME parameters, such as extraction temperature, extraction time, salt concentration, stirring speed, and pH, were optimized by orthogonal array experimental designs. Under the optimized conditions, the target analytes were linear in the range of 0.2-50 ng/mL, and the correlation coefficients were all greater than 0.99. RSD was less than 8.9%, and the detection limits were in the range of 0.1-10 ng/L. Four cholorphenols were detected from tap and lake water samples using the proposed method, with the recoveries of spiked natural water samples were ranged from 91.8 to 110.8, and 90.6 to 111.4% for tap and lake water samples, respectively. PMID- 23640910 TI - Development of an LC/MS/MS method in order to determine arctigenin in rat plasma: its application to a pharmacokinetic study. AB - In this study, a simple and sensitive LC/MS/MS method was developed and validated for the determination of arctigenin in rat plasma. The MS detection was performed using multiple reaction monitoring at the transitions of m/z 373.2 -> 137.3 for arctigenin and m/z 187.1 -> 131.0 for psoralen (internal standard) with a Turbo IonSpray electrospray in positive mode. The calibration curves fitted a good linear relationship over the concentration range of 0.2-500 ng/mL. It was found that arctigenin is not stable enough at both room temperature and -80 degrees C unless mixed with methanol before storage. The validated LC/MS/MS method was successfully applied for the pharmacokinetic study of arctigenin in rats. After intravenous injection of 0.3 mg/kg arctigenin injection to rats, the maximum concentration, half-life and area under the concentration-time curve were 323 +/- 65.2 ng/mL, 0.830 +/- 0.166 and 81.0 +/- 22.1 h ng/mL, respectively. PMID- 23640911 TI - AEG-1 participates in TGF-beta1-induced EMT through p38 MAPK activation. AB - Epithelial-mesenchymal transition (EMT) is an important cellular event in organogenesis, cancer and renal tubulointerstitial fibrosis. Transforming growth factor-beta1 (TGF-beta1) is the key inducer of EMT and the p38 mitogen-activated protein kinases (p38 MAPK), an major intracellular signal transduction pathway is involved in TGF-beta1-induced EMT. Astrocyte elevated gene-1 (AEG-1) represents an chief genetic determinant regulating multiple events in tumorigenesis. Our present study is to explore the role of AEG-1 in TGF-beta1-induced p38 MAPK activation and EMT process in human renal tubular epithelial (HK-2) cells. The protein expressions of AEG-1, the markers of EMT and p38 phosphorylation were measured by Western blot. The protein expression of AEG-1 was increased in HK-2 cells treated with TGF-beta1. Knockdown of AEG-1 potently inhibited phosphorylation of p38 MAPK and reversed TGF-beta1-induced EMT. Over-expression of AEG-1 via AEG-1 transfection elicited p38 MAPK phosphorylation and promoted EMT. The effects of AEG-1 during EMT were blocked by a p38-specific inhibitor. Our findings suggest that AEG-1 plays an important role in TGF-beta1-induced EMT through activation of p38 MAPK in proximal tubular epithelial cells. PMID- 23640913 TI - Use of dietary therapy for status epilepticus. AB - One of the newest and yet fastest growing indications for dietary therapy is the emergency treatment of refractory status epilepticus. Ten retrospective publications since 2008 have reported benefits in 32 children and adults, of whom 25 (78%) became seizure-free. Most of the patients who responded did so within 7 to 10 days of the initiation of nasogastrically administered ketogenic formulas. Encephalitis and febrile-illness related epilepsy syndrome causing status epilepticus highly refractory to antiepileptic drugs may be particularly amenable to dietary treatment. Prospective, multicenter studies are under way to help clarify who best will respond, how quickly, and the optimal diet duration after success. PMID- 23640912 TI - Greater weight loss with increasing age in the weight loss maintenance trial. AB - OBJECTIVE: To determine the effect of age on weight loss and weight loss maintenance in participants in the Weight Loss Maintenance trial (WLM). DESIGN AND METHODS: Secondary analysis of a randomized controlled trial of overweight/obese adults with CVD risk factors was conducted. Participants were 1685 adults with baseline BMI 25-45 kg m(2) with hypertension and/or dyslipidemia. Those who lost at least 4kg in an initial 6-month behavioral weight loss intervention (N = 1,032) were randomly assigned to a 30-month maintenance phase of self-directed control (SD), monthly personal counseling (PC), or unlimited access to an internet-based intervention (IT). Age groups were defined post-hoc and weight change was compared among age groups. RESULTS: Participants >=60 years old initially lost more weight than younger individuals, and sustained greater weight loss in IT and PC but not in SD (P value for trend 0.024, 0.002, and 0.36, respectively). CONCLUSIONS: In WLM, adults age >=60 years had greater initial weight loss and greater sustained weight loss over 3 years, compared to younger adults. Older adults had greater weight loss maintenance with either personal counseling or internet-based intervention. Future research should determine optimal implementation strategies and effects of weight loss on health outcomes in older adults. PMID- 23640914 TI - Single-site robotic cholecystectomy: efficiency and cost analysis. AB - BACKGROUND: Single-incision surgery has gained in popularity, and the recent development of specialized robotic and laparoscopic instruments may remove some of the ergonomic and technical difficulties associated with this approach. However, questions of cost and efficiency remain. METHODS: We prospectively collected perioperative outcome and efficiency (operative time, case volume) data for our single-site robotic cholecystectomy cases and retrospectively reviewed data for our single-incision laparoscopic cholecystectomy cases. RESULTS: There were no differences in patient characteristics or perioperative outcomes between the robotic (n = 20) and laparoscopic (n = 10) groups; operative times were equivalent (84.6 vs 85.5 min; p = 0.8737) and blood loss and complications were minimal. There was a higher robotic case volume, with an average of two robotic cases (range 1-4)/day vs one/day for laparoscopic cases (range 1-1; p = 0.0306). Streamlined instrument costs were essentially equivalent. CONCLUSIONS: Robotic single-site cholecystectomy is a safe, cost-effective alternative to single incision laparoscopic cholecystectomy in a robot-existing model. PMID- 23640916 TI - Functionalization of metal-organic frameworks through the postsynthetic transformation of olefin side groups. AB - For the first time, the adaptability of the C=C double bond as a versatile precursor for the postsynthetic modification (PSM) of microporous materials was extensively investigated and evaluated. Therefore, an olefin-tagged 4,4' bipyridine linker was synthesized and successfully introduced as pillar linker within a 9,10-triptycenedicarboxylate (TDC) zinc paddle-wheel metal-organic framework (MOF) through microwave-assisted synthesis. Different reactions, predominately used in organic chemistry, were tested, leading to the development of new postsynthetic reactions for the functionalization of solid materials. The postsynthetic oxidation of the olefin side groups applying osmium tetroxide (OsO4) as a catalyst led to the formation of a microporous material with free vicinal diol functionalities. The epoxidation with dimethyldioxirane (DMDO) enabled the synthesis of epoxy-functionalized MOFs. In addition to that, reaction procedures for a postsynthetic hydroboration with borane dimethyl sulfide as well as a photoinduced thiol-ene click reaction with ethyl mercaptan were developed. For all of these PSMs, yields of more than 90% were obtained, entirely maintaining the crystallinity of the MOFs. Since the direct introduction of the corresponding groups by means of pre-synthetic approaches is hardly possible, these new PSMs are useful tools for the functionalization of porous solids towards applications such as selective adsorption, separation, and catalysis. PMID- 23640915 TI - Cerebral TOF angiography at 7T: Impact of B1 (+) shimming with a 16-channel transceiver array. AB - PURPOSE: Time-of-flight (TOF) MR imaging is clinically among the most common cerebral noncontrast enhanced MR angiography techniques allowing for high spatial resolution. As shown by several groups TOF contrast significantly improves at ultrahigh field of B0 = 7T, however, spatially varying transmit B1 (B1 (+)) fields at 7T reduce TOF contrast uniformity, typically resulting in suboptimal contrast and reduced vessel conspicuity in the brain periphery. METHODS: Using a 16-channel B1 (+) shimming system, we compare different dynamically applied B1 (+) phase shimming approaches on the radiofrequency excitation to improve contrast homogeneity for a (0.5 mm)(3) resolution multislab TOF acquisition. In addition, B1 (+) shimming applied on the venous saturation pulse was investigated to improve venous suppression, subcutaneous fat signal reduction and enhanced background suppression originating from MT effect. RESULTS: B1 (+) excitation homogeneity was improved by a factor 2.2-2.6 on average depending on the shimming approach, compared to a standard CP-like phase setting, leading to improved vessel conspicuity particularly in the periphery. Stronger saturation, higher fat suppression and improved background suppression were observed when dynamically applying B1 (+) shimming on the venous saturation pulse. CONCLUSION: B1+ shimming can significantly improve high resolution TOF vascular investigations at ultrahigh field, holding strong promise for non contrast-enhanced clinical applications. PMID- 23640917 TI - Researching the reliability of accreditation survey teams: lessons learnt when things went awry. AB - Accreditation of health organisations, occurring in over 70 countries, is predicated upon the reliability of survey teams judgements, but we do not know the extent to which survey teams are reliable. To contribute evidence to this issue, we investigated the reliability of two survey teams simultaneously assessing an organisation. The setting was a large Australian teaching hospital, and data were derived from interviews, observations and survey documents. Participants were from four groups: hospital staff, accreditation agency personnel and surveyors, and research staff. Thematic analysis was employed to identify significant factors that influenced the study. The two survey teams ratings and recommendations demonstrated high levels of agreement. However, while a common understanding of the study existed, the research was compromised. There were difficulties enacting the study. Contrary to negotiated arrangements, the pressure of the study resulted in surveyors discussing evidence and their interpretation of standards. Uncontrollable circumstances (late changes of personnel), and unexpected events (a breakdown of working relationships), challenged the study. The twin lessons learnt are that a consistent survey outcome is likely to be reached when reliability of process and consistent application of standards are pursued, and research requires negotiating challenges and relationships. PMID- 23640918 TI - Perinatal data collection: current practice in the Australian nursing and midwifery healthcare context. AB - The collection of perinatal data within Queensland, Australia, has traditionally been achieved via a paper form completed by midwives after each birth. Recently, with an increase in the use of e-health systems in healthcare, perinatal data collection has migrated to an online system. It is suggested that this move from paper to an ehealth platform has resulted in improvement to error rates, completion levels, timeliness of data transfer from healthcare institutions to the perinatal data collection and subsequent publication of data items. Worldwide, perinatal data are collected utilising a variety of methods, but essentially data are used for similar purposes: to monitor outcome patterns within obstetrics and midwifery. This paper discusses current practice in relation to perinatal data collection worldwide and within Australia, with a specific focus on Queensland, highlights relevant issues for midwives, and points to the need for further research into the efficient use of an e-health platform for perinatal data collection. PMID- 23640919 TI - The roles of users personal characteristics and organisational support in the attitude towards using ERP systems in a Spanish public hospital. AB - Enterprise resources planning (ERP) systems enable central and integrative control over all processes throughout an organisation by ensuring one data entry point and the use of a common database. T his paper analyses the attitude of healthcare personnel towards the use of an ERP system in a Spanish public hospital, identifying influencing factors. This research is based on a regression analysis of latent variables using the optimisation technique of partial least squares. We propose a research model including possible relationships among different constructs using the technology acceptance model. Our results show that the personal characteristics of potential users are key factors in explaining attitude towards using ERP systems. PMID- 23640920 TI - Service quality and perceived value of technology-based service encounters: evaluation of clinical staff satisfaction in Taiwan. AB - Previous research has evaluated technology-based service encounters (TBSEs) in the delivery of health care by assessing patient satisfaction. This study examined service quality and perceived value of TBSEs used in health organisations from the perspective of clinical staff, with staff technology readiness as a moderator. A quantitative survey was conducted in Taiwan, across private and public healthcare organisations. Results showed that TBSEs had a direct effect on service quality and perceived value, which in turn had a direct effect on staff satisfaction in using TBSEs. However, service quality had no effect on perceived value when moderated by technology readiness. Theoretical and managerial implications of these findings are discussed. PMID- 23640921 TI - Global change effects on the long-term feeding ecology and contaminant exposures of East Greenland polar bears. AB - Rapid climate changes are occurring in the Arctic, with substantial repercussions for arctic ecosystems. It is challenging to assess ecosystem changes in remote polar environments, but one successful approach has entailed monitoring the diets of upper trophic level consumers. Quantitative fatty acid signature analysis (QFASA) and fatty acid carbon isotope (delta(13) C-FA) patterns were used to assess diets of East Greenland (EG) polar bears (Ursus maritimus) (n = 310) over the past three decades. QFASA-generated diet estimates indicated that, on average, EG bears mainly consumed arctic ringed seals (47.5 +/- 2.1%), migratory subarctic harp (30.6 +/- 1.5%) and hooded (16.7 +/- 1.3%) seals and rarely, if ever, consumed bearded seals, narwhals or walruses. Ringed seal consumption declined by 14%/decade over 28 years (90.1 +/- 2.5% in 1984 to 33.9 +/- 11.1% in 2011). Hooded seal consumption increased by 9.5%/decade (0.0 +/- 0.0% in 1984 to 25.9 +/- 9.1% in 2011). This increase may include harp seal, since hooded and harp seal FA signatures were not as well differentiated relative to other prey species. Declining delta(13) C-FA ratios supported shifts from more nearshore/benthic/ice-associated prey to more offshore/pelagic/open-water associated prey, consistent with diet estimates. Increased hooded seal and decreased ringed seal consumption occurred during years when the North Atlantic Oscillation (NAO) was lower. Thus, periods with warmer temperatures and less sea ice were associated with more subarctic and less arctic seal species consumption. These changes in the relative abundance, accessibility, or distribution of arctic and subarctic marine mammals may have health consequences for EG polar bears. For example, the diet change resulted in consistently slower temporal declines in adipose levels of legacy persistent organic pollutants, as the subarctic seals have higher contaminant burdens than arctic seals. Overall, considerable changes are occurring in the EG marine ecosystem, with consequences for contaminant dynamics. PMID- 23640922 TI - Simultaneous screening of four epidermal growth factor receptor antagonists from Curcuma longa via cell membrane chromatography online coupled with HPLC-MS. AB - The epidermal growth factor receptors (EGFRs) are significant targets for screening active compounds. In this work, an analytical method was established for rapid screening, separation, and identification of EGFRs antagonists from Curcuma longa. Human embryonic kidney 293 cells with a steadily high expression of EGFRs were used to prepare the cell membrane stationary phase in a cell membrane chromatography model for screening active compounds. Separation and identification of the retention chromatographic peaks was achieved by HPLC-MS. The active sites, docking extents and inhibitory effects of the active compounds were also demonstrated. The screening result found that ar-turmerone, curcumin, demethoxycurcumin, and bisdemethoxycurcumin from Curcuma longa could be active components in a similar manner to gefitinib. Biological trials showed that all of four compounds can inhibit EGFRs protein secretion and cell growth in a dose dependent manner, and downregulate the phosphorylation of EGFRs. This analytical method demonstrated fast and effective characteristics for screening, separation and identification of the active compounds from a complex system and should be useful for drug discovery with natural medicinal herbs. PMID- 23640923 TI - Lipocalin-2 increases fat oxidation in vitro and is correlated with energy expenditure in normal weight but not obese women. AB - OBJECTIVE: The role of lipocalin-2 (Lcn2) was determined in regulating metabolism in cell, animal, and human models. DESIGN AND METHODS: Adipocytes were treated with recombinant lipocalin-2 (rLcn2) to determine the effect on lipid metabolism. rLcn2 was injected into mice to determine the effect on metabolism in vivo. To assess the relationship between Lcn2 and fat oxidation (FatOx) in humans, normal weight (NW) and obese (OB) women were given three separate high fat (HF) meals followed by indirect calorimetry. The relationship between postprandial Lcn2 with macronutrient metabolism and total energy expenditure (TEE) using Pearson correlations was determined. RESULTS: Lcn2 increased expression of genes involved in beta-oxidation including peroxisome proliferator-activated receptor-delta in adipocytes, as well as (3) H labeled oleate beta-oxidation. Lcn2 injected into chow-fed mice directly increased TEE by 18% after the first dark cycle (232 +/- 1.4 cal vs. 341 +/- 1.4 cal; PBS vs. Lcn2) and remained significantly elevated by 10% after the second dark cycle (296 +/- 1.4 cal vs. 326 +/- 1.4 cal; PBS vs. Lcn2). Lcn2 was correlated with TEE in all three HF meal challenges in NW but not OB females. CONCLUSIONS: Lipocalin-2 is a novel adipokine that promotes FatOx and TEE and its function may be impaired in obesity. PMID- 23640924 TI - Rapid quantification of amlodipine enantiomers in human plasma by LC-MS/MS: application to a clinical pharmacokinetic study. AB - A rapid, simple, specific and sensitive LC-MS/MS method has been developed and validated for the enantiomeric quantification of amlodipine (AML) isomers [R amlodipine (R-AML) and S-amlodipine (S-AML)] with 200 MUL of human plasma using R AML-d4 and S-AML-d4 as corresponding internal standards as per regulatory guidelines. A simple liquid-liquid extraction process was used to extract these analytes from human plasma. The total run time was 3.5 min and the elution of R AML, S-AML, R-AML-d4 and S-AML-d4 occurred at 1.62, 2.51, 1.63 and 2.53 min, respectively. This was achieved with a mobile phase consisting of 0.2% ammonia acetonitrile (20:80, v/v) at a flow rate of 1 mL/min on a Chiralcel OJ RH column. A linear response function was established for the range of concentrations 0.1-10 ng/mL (r >0.998) for each enantiomer. The intra- and inter-day precision values for both enantiomers met the acceptance criteria. Both enantiomers were stable in a set of stability studies, viz. bench-top, auto-sampler, freeze-thaw cycles and long-term. The current assay was successfully applied to a pharmacokinetic study to quantitate AML enantiomers following oral administration of 10 mg AML tablet to humans. PMID- 23640925 TI - Anastomotic aneurysms--20-years of experience from one center. AB - Anastomotic aneurysms may develop after any type of vascular surgery, in different areas of the arterial system, and require reoperation. The frequency of occurrence of the above-mentioned is estimated at 1-5%. MATERIAL AND METHODS: During the period between 1989 and 2010, 180 patients with 230 anastomotic aneurysms were subject to surgical intervention at the Department of General and Thoracic Surgery, Warsaw Medical University. The study group comprised 21 (11.7%) female and 159 (88.3%) male patients, aged between 30 and 87 years (mean age - 62.8 years). In relation to the number of anastomoses aneurysms were diagnosed in 2.1% of cases. Twenty-four (10.4%) patients were diagnosed with recurrent aneurysms. RESULTS: Surgical procedures performed were as follows: artificial prosthesis implantation (119), reanastomosis (40), patch plasty (25), graftectomy (19), prosthesis replacement (9), and stent-graft (7) implantation. 195 (84.8%) aneurysms were subject to planned surgery, while 35 (15.2%) required emergency intervention. 77.8% of patients were diagnosed with aseptic aneurysms, while the remaining 22.2% with infected perioperative aneurysms. Good treatment results were obtained in 149 (82.8%) patients. Limb amputations were performed in 19 (10.5%) cases. Twelve (6.7%) patients died as a consequence of infection and general complications. CONCLUSIONS: Vascular reoperations are a difficult clinical problem and are burdened with a high rate of complications. The above mentioned often require complex treatment, in order to improve therapeutic results. PMID- 23640926 TI - Treatment possibilities of reverse-flow sural flap in covering the defects of lower extremities. AB - Soft tissue defects of the lower extremity pose an important surgical challenge, often because of inviability of primary covering. Therapeutic modalities of choice comprise of local perforator flaps, as well as of free flaps created with the use of microsurgical skills. However, these methods cannot be applied in patients with important comorbidities, and it is in such cases where the reverse sural flap proves to be the best solution. THE AIM OF THE STUDY: To present the results of treating lower extremity defects with various modifications of the reverse sural flap. MATERIAL AND METHODS: Sixteen patients, males aged 17-56 years, were operated on from 2007 to 2013. Diabetes with multiple complications, disseminated atheromatosis, and extensive soft tissue trauma involving the arteries crucial for microsurgica anastomoses were the most common reason disqualifying from the free and perforator-based flap techniques. RESULTS: All of the patients achieved very good results; in two cases distal and marginal flap necrosis was observed which, once exiced, covered with granulation, and was successfully covered with a partial-thickness skin graft. CONCLUSIONS: The reverse sural flap, technically easy, offers a viable, low-risk alternative to free and perforator-based flaps. PMID- 23640927 TI - Evaluation of inflammatory markers as predictors of hospital stay and unplanned readmission after colorectal surgery. AB - Hospital length of stay (LOS) and readmissions continue to be expensive and unexpected events following colorectal surgery (CRS) whether patients follow enhanced recovery pathways or traditional care. Predictors of these adverse events could facilitate identification and optimization of CRS patients. THE AIM OF THE STUDY: To examine the impact of white blood cell count (WBC) and C reactive protein (CRP) levels as predictors of delayed recovery or hospital readmission following CRS. MATERIAL AND METHODS: Patients undergoing laparoscopic or open abdominal colorectal surgery by a single surgeon were managed using standardized enhanced recovery pathways. Those with postoperative day 2 CRP and white blood cell values were evaluated. Outcomes included 30-day hospital readmission rates and postoperative length of hospital stay. RESULTS: CRP values were available for 193 patients (86 Male, mean age 58.6 years). Ninety-nine patients had surgery for colon cancer, 23 for Crohn's disease, 19 for ulcerative colitis, 31 for diverticulitis and 18 for other reasons. Twenty patients (10.4%) were readmitted to the hospital within 30 days of surgery. POD2 CRP accurately predicted short length of hospital stay (p< 0.01). Average CRP was 6.3 in the LOS of < 3 days or less, and 11.7 in patients with LOS >4 days. The mean CRP of the readmission and non-readmission groups was 11.8 and 9.9, respectively (p=0.29). The average POD 2 WBC of the readmission and non-readmission groups was 10.6 and 9 respectively (p=0.01). CONCLUSION: A low POD2 CRP level was correlated with a shorter LOS, but it did not predict readmission. Conversely, POD2 WBC, and the difference in WBC from baseline were associated with readmission. These markers may be useful indicators to predict suitability of early discharge in an ERP. Further evaluation in prospective trials is warranted. PMID- 23640928 TI - Evaluation of the effects of mammography screening program on cancer progression and implemented treatment in patients with breast cancer. AB - The primary goal of mammography screening is to decrease mortality in patients with breast cancer. THE AIM OF THE STUDY: Evaluation of the screening program results on course of implemented therapy and its results in breast carcinoma patients. MATERIAL AND METHODS: Evidence includes data on the group of 1818 patients with breast cancer that were subject to surgical treatment at the Clinic of Breast Cancer and Reconstructive Surgery of the Oncology Center in Bydgoszcz (558 patients hospitalized from January 2006 to December 2006 and 1260 patients treated from January 2011 to June 2012). Analysis included type of diagnostic procedure implemented before surgical treatment, as well as grade of cancer progression, results of pathology tests done on specimens and type of surgical procedure. Additionally, the screening group (tumor diagnosed based on screening mammography) and symptomatic group (cancer diagnosed otherwise that within the screening program) were identified. RESULTS: In 2006, in 28.4% of patients included in the study, primary tumor was discover in screening process (vs 61.5% in 2011-2012). In the first period, 35.7% of changes did not exceed 2 cm--cT1 (vs 48.3% in 2011-2012), while the percentage of cT4 was 9.9% (vs 4.7% in 2011-2012). In 2006, 30.8% of patients were treated in the grade I of clinical progression (vs 44.2% in 2011-2012), 53.4% in the grade II, 14% in grade III and 0.2% in grade IV (vs 45.7%, 9.7%, and 0.4%, respectively). In 45.5% (2006) and 39.9% (in 2011-2012) of patients, metastases were found in axillary lymph nodes. Differences were similar both in screening and symptomatic group. In 2006, in 12.4% of surgical patients breast conserving therapy (BCT) was implemented (vs 49.8% in 2011-2012). In the screening group, it was applied in 15.2% of patients (in 2006) and in 63% (in 2011- 2012), while in symptomatic group the percentages were 11.8% and 41%, respectively. CONCLUSIONS: In both periods of analysis, significant differences were observed as to implementation of breast cancer screening program, as well as to grade of clinical and pathological progression of the cancer. Observable increase of screening tests allowed for significantly more frequent implementation of breast conserving surgical procedures. PMID- 23640929 TI - Mammotome biopsy in diagnosing and treatment of intraductal papilloma of the breast. AB - Intraductal papilloma is a benign breast tumor which needs histopathological verification because of the risk of cancer coincidence. THE AIM OF THE STUDY: To assess the value of the mammography-guided and ultrasound-guided vacuum-assisted core biopsy in the diagnosis and treatment of intraductal papillomas of breast and to answer the question if mammotome biopsy allows to avoid surgery in these patients. MATERIAL AND METHODS: In the period 2000-2011, a total of 2246 vacuum assisted core biopsies were performed, of which 1495 were ultrasound-guided and 751 were mammography-guided (stereotaxic). In 76/2246 patients (3.4%), aged 19-88 years (mean age was 51,5) histopathological examination confirmed intraductal papilloma. RESULTS: Atypical lesions were accompanying intraductal papilloma in 16/76 cases (21%). Open surgical biopsy performed in these group revealed invasive cancer in 3 women. In all 60 cases (79%) with benign papilloma in biopsy specimens, further clinical observation did not show recurrence or malignant transformation of lesions. CONCLUSIONS: Vacuum-assisted core biopsy is a minimally invasive and efficient method used for diagnosing intraductal papilloma of the breast. If histopathological examination confirms a benign character of the lesion, surgery may be avoided but regular follow-up is recommended. However, in all cases histopathological diagnosis of papilloma with atypical hyperplasia, should always be indication for surgical excision. PMID- 23640930 TI - Diffuse cavernous hemangioma of the rectum (DCHR)--diagnosis and treatment--case report and review of available literature. AB - Diffuse cavernous hemangioma of the rectum (DCHR) is a rare benign tumor of vascular origin. Approximately 200 such cases have been reported in the literature. Here we present a case of a 49-year old female patient who underwent a surgical procedure due to a mass of the rectum with a history of recurrent, painless gastrointestinal bleeding and anemia in whom DCHR was diagnosed postoperatively. This paper is intended as a metaanalysis of available diagnostic and therapeutic methods to be used in patients with DCHR. PMID- 23640931 TI - Rectal endometriosis--rare case of intestinal obstruction. Case report. AB - The study presented a case of a 32-year old female patient admitted to the department of surgery with symptoms of abdominal pain and retention of gas and stool. The abdominal X-ray examination showed signs of intestinal obstruction. Abdominal CT suggested the possibility of a cancerous lesion located in the colon. The patient was qualified for surgical intervention. An anterior rectal resection was performed. The histopathological examination revealed the presence of colorectal endometriosis. After two months the patient was subject to gastrointestinal continuity restoration. Endometriosis is a rare cause of intestinal obstruction, considering patients hospitalized in the department of general surgery. PMID- 23640932 TI - The use of heparin in the treatment of acute pancreatitis. PMID- 23640934 TI - Success has many fathers, failure is orphan. PMID- 23640933 TI - Introduction of new technique of single-port transgastric access for repeated debridement of infected pancreatic necrosis. AB - In this article we introduce a novel technique of repeated single-port transgastric debritment of walledoff pancreatic necrosis using TriPortTM Access System. The presented technique seems an appealing and innovative approach to the treatment of walled-off pancreatic necrosis in acute pancreatitis patients. Studies proving feasibility, safety and efficiency are necessary to elucidate real value of the technique. PMID- 23640935 TI - Normosmic idiopathic hypogonadotropic hypogonadism: update on the genetic background and future challenges. AB - PURPOSE OF REVIEW: What controls puberty remains largely unknown, and current gene mutations account for only about one-third of the apparently genetic cases of idiopathic hypogonadotropic hypogonadism. Lately, important developments have occurred in this field. RECENT FINDINGS: The neuroendocrine control of reproduction in all mammals is governed by a hypothalamic neural network of approximately 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that control the activity of the reproductive axis across life. Recently, the syndrome of human GnRH deficiency, either with anosmia, termed Kallmann syndrome, or with a normal sense of smell, termed normosmic idiopathic hypogonadotropic hypogonadism, has proven to be important disease models that have revealed much about the abnormalities that can befall the GnRH neurons as they differentiate, migrate, form networks, mature and senesce. Mutations in several genes responsible for these highly coordinated developmental processes have thus been unearthed by the study of this prismatic disease model. These genetic studies have opened up a new chapter in the physiology and the pharmacology of the gonadotropic axis. PMID- 23640936 TI - KCNJ11 in-frame 15-bp deletion leading to glibenclamide- responsive neonatal diabetes mellitus in a Chinese child. AB - The ATP-sensitive K+ channel controls insulin secretion from the islet. Mutations in KCNJ11 can cause permanent and transient neonatal diabetes. To date, more than 30 KCNJ11 mutations have been revealed as related to the onset of neonatal diabetes mellitus (NDM), most of which are responsive to glibenclamide treatment. In the present study, we sequenced the KCNJ11 gene in a Chinese girl diagnosed with NDM and in her parents. An in-frame 15-bp KCNJ11 deletion was identified in the patient, whereas no KCNJ11 deletions were found in her parents, indicating that this deletion was de novo. The patient was responsive to the treatment of glibenclamide. Ten months of follow-up showed that, besides permanent NDM, the motor and intelligence development of the girl was normal and she suffered no onset of convulsions. The result, to some degree, improved our knowledge on NDM. PMID- 23640937 TI - Vaginal bleeding in a 4-month-old preterm girl: extreme minipuberty mimicking central precocious puberty. AB - We present a 4-month-old girl who showed vaginal bleeding and breast development. She was born preterm at 25 weeks and 4 days of gestation. Luteinizing hormone and follicle-stimulating hormone levels were extremely elevated. Magnetic resonance imaging showed a lesion of unknown nature in the pituitary gland, most likely a Rathke's cleft cyst. Because central precocious puberty (CPP) was suspected, a gonadotropin-releasing hormone analogue was started. At the age of 18 months, the treatment was stopped. Thereafter, no signs of puberty developed. The pituitary lesion remained unchanged. Therefore, the initial diagnosis of CPP was incorrect, and instead, an extreme minipuberty had occurred. If treatment for idiopathic CPP in girls younger than 2 years is started, we recommend the treatment be stopped after a certain period, for reevaluation of the diagnosis of CPP. PMID- 23640938 TI - A rare case of isolated Cushing syndrome in a 3-month-old boy. AB - Adrenocortical carcinoma (ACC) is a rare malignancy in children. Most of these are endocrinologically active tumors, with virilizing features being typically dominant. Its presentation with isolated Cushing syndrome is rare. We report a 3 month-old infant with Cushing syndrome without the clinical features of androgen or mineralocorticoid excess consequently diagnosed with ACC. We discuss the different presentations, diagnosis, and management of this rare tumor with a rarer presentation. PMID- 23640939 TI - p0071/PKP4, a multifunctional protein coordinating cell adhesion with cytoskeletal organization. AB - P0071 is a member of a subfamily of armadillo proteins that also comprises p120 catenin (p120ctn), delta-catenin/NPRAP, ARVCF and the more distantly related plakophilins 1-3. These proteins share a conserved central domain consisting of a series of repeated motifs, the armadillo repeats, which is flanked by more diverse amino- and carboxy-terminal domains. P0071 and the related proteins were first described as components of adherens junctions with a function in clustering and stabilizing cadherins, thereby controlling intercellular adhesion. In addition, these proteins show a cytoplasmic and a nuclear localization. Major progress in understanding their cytoplasmic role has been made in recent years. One common theme appears to be the spatiotemporal control of the small GTPases of the Rho family in various cellular contexts, such as cell adhesion and motility, cell division or neurite outgrowth. In this review article, we focus on the functions of the p0071 protein and its closest relatives in regulating cell adhesion and cytoskeletal organization, which are critically involved in the control of cell polarity. Understanding p0071's multiple functions requires assigning specific functions to particular binding partners and subcellular compartments. The identification of several new p0071 interacting proteins has promoted our understanding of the complex functions of this protein. Moreover, an initial analysis of its regulation begins to shed light on how these functions are coordinated in a cellular context. PMID- 23640940 TI - Functional ribosome biogenesis is a prerequisite for p53 destabilization: impact of chemotherapy on nucleolar functions and RNA metabolism. AB - The production and processing of ribosomal RNA is a complex and well-coordinated nucleolar process for ribosome biogenesis. Progress in understanding nucleolar structure and function has lead to the unexpected discovery of the nucleolus as a highly sensitive sensor of cellular stress and an important regulator of the tumor suppressor p53. Inhibition of ribosomal RNA metabolism has been shown to activate a signaling pathway for p53 induction. This review elucidates the potential of classical and recently developed chemotherapeutic drugs to stabilize p53 by inhibiting nucleolar functions. PMID- 23640941 TI - Zinc-dependent contact system activation induces vascular leakage and hypotension in rodents. AB - Contact to polyanions induces autoactivation of the serine protease factor XII that triggers the kallikrei-kinin system. Recent studies indicate that polysaccharide-induced autoactivation of factor XII has a role in allergy-related vascular leakage, and angioedema. Here, we characterize in vivo effects of the synthetic polysaccharide dextran sulfate in human plasma and in rodent models. Minute amounts of high-molecular-weight dextran sulfate-initiated factor XII autoactivation and triggered formation of the inflammatory mediator bradykinin via plasma kallikrein-mediated cleavage of high-molecular-weight kininogen. High molecular-weight kininogen fragments, containing the HKH20 sequence in domain D5H, blocked dextran sulfate-initiated bradykinin-generation by depleting plasma Zn2+ ions. Topical application of high molecular weight dextran sulfate increased leakage in murine skin microvessels, in a bradykinin-dependent manner. Intravital laser scanning microscopy showed a greater than two-fold elevated and accelerated fluid extravasation in C1 esterase inhibitor deficient mice that lack the major inhibitor of factor XII, compared to wild-type controls. Intra-arterial infusion of dextran sulfate induced a rapid transient drop in arterial blood pressure in rats and preinjection of kinin B2 receptor antagonists or HKH20 peptide blunted dextran sulfate-triggered hypotensive reactions. The data characterize dextran sulfate as a potent in vivo activator of factor XII with implications for bradykinin-mediated vascular permeability and blood pressure control. PMID- 23640942 TI - Subcellular localization and RNP formation of IGF2BPs (IGF2 mRNA-binding proteins) is modulated by distinct RNA-binding domains. AB - The IGF2 mRNA-binding protein family (IGF2BPs) directs the cytoplasmic fate of various target mRNAs and controls essential cellular functions. The three IGF2BP paralogues expressed in mammals comprise two RNA-recognition motifs (RRM) as well as four KH domains. How these domains direct IGF2BP paralogue-dependent protein function remains largely elusive. In this study, we analyze the role of KH domains in IGF2BPs by the mutational GXXG-GEEG conversion of single KH domain loops in the context of full-length polypeptides. These analyses reveal that all four KH domains of IGF2BP1 and IGF2BP2 are essentially involved in RNA-binding in vitro and the cellular association with RNA-binding proteins (RBPs). Moreover the KH domains prevent the nuclear accumulation of these two paralogues and facilitate their recruitment to stress granules. The role of KH domains appears less pronounced in IGF2BP3, because GxxG-GEEG conversion in all four KH domains only modestly affects RNA-binding, subcellular localization and RNA-dependent protein association of this paralogue. These findings indicate paralogue dependent RNA-binding properties of IGF2BPs which likely direct distinct cellular functions. Our findings suggest that IGF2BPs contact target RNAs via all four KH domains. This implies significant structural constraints, which presumably allow the formation of exceedingly stable protein-RNA complexes. PMID- 23640943 TI - Interactions between an M. tuberculosis strain overexpressing mtrA and mononuclear phagocytes. AB - PURPOSE: It was previously shown that the bacterial two-component regulatory signal transduction (2CR) system MtrAB may be associated with the ability of M. tuberculosis (Mtb) to survive in macrophages. In the present work Mtb mutants: Rv 78 with overexpression of mtrA and Rv-129 with elevated level of phosphorylation defective MtrA were used for further investigation of the potential influence of the MtrAB system on Mtb interaction with human monocytes. MATERIAL/METHODS: Flow cytometry was used to determine the expression of MHC class II molecules. The expression of genes for inducible nitric oxide synthase (iNOS) and cathepsin G was quantified by RT-PCR. The association of Mtb strains with Rab5 and Rab7 positive vacuoles was investigated applying confocal microscopy. IL-10 and IL-12 secretion by monocytes as well as the Mtb susceptibility to cathepsin G were investigated. RESULTS: Mutation-carried and wild type Mtb strains inhibited MHC class II expression on monocytes to a similar extent. Monocyte stimulation with mycobacteria led to the increased production of IL-10 but no detectable amounts of IL-12 or NO were observed. Expression of the gene for iNOS was not detected while that for cathepsin G was shown, however its intensity was not associated with MtrA mutation. Mtb mutant strains were more effectively enclosed in phagosomes containing the late endosome marker Rab7 as compared to the control. CONCLUSIONS: The results may confirm the importance of the MtrAB system in mycobacterial capacity for successful survival in phagocytes, especially in the context of high degree of colocalization of Mtb Rv-78 to mature phagosomes. PMID- 23640944 TI - Increased release of soluble CD163 by the peripheral blood mononuclear cells is associated with worse prognosis in patients with systemic sclerosis. AB - PURPOSE: CD163 is a scavenger receptor which is exclusively expressed on monocytes/macrophages and participates in modulation of inflammatory response. We aimed to evaluate ex vivo production of soluble CD163 (sCD163) by peripheral blood mononuclear cells (PBMC) from patients with systemic sclerosis (scleroderma, SSc). MATERIAL/METHODS: Concentration of sCD163 was measured by commercially available ELISA kit in the PBMC suparnates from 23 SSc patients and 16 age- and sex-matched healthy controls (HC). Eighteen SSc patients were subsequently followed for at least three years or until death whichever happened earlier. Disease progression was defined as death due to SSc-related organ complication, development of a new or progression of pre-existing SSc-related organ involvement. RESULTS: PBMC from SSc patients released significantly greater amounts of sCD163 as compared with HC (p<0.05). No significant associations between release of sCD163 by PBMC and baseline clinical or laboratory parameters of the disease could be found. However, concentration of sCD163 in cell culture supernates was significantly higher in 6 SSc patients who experienced subsequent progression of the disease as compared with 12 SSc patients with stable disease course over a 3-year follow-up period (p<0.05). CONCLUSIONS: We show, for the first time, that PBMC from SSc release significantly greater amounts of sCD163 than do PBMC from healthy subjects. Evaluation of sCD163 production by PBMC ex vivo may serve as a new biomarker of disease progression. Further studies are required to evaluate the role of sCD163 in the development of SSc. PMID- 23640945 TI - Can melatonin delay oxidative damage of human erythrocytes during prolonged incubation? AB - PURPOSE: Melatonin (MEL) is an effective antioxidant in numerous experimental models, both in vitro and in vivo. However, it should be stressed that there are also papers reporting limited antioxidative activity of MEL or even giving evidence for its pro-oxidative properties. In the present paper we investigated the influence of MEL on the oxidative damage of human erythrocytes during prolonged incubation. MATERIAL/METHODS: Human erythrocytes suspended in phosphate buffered saline (PBS), pH 7.4 were incubated at 37oC either in absence or presence of melatonin at concentration range 0.02 mM-3 mM for up to 96 hrs. The influence of MEL on erythrocyte damage was assessed on the basis of the intensity of intracellular oxidation processes (the oxidation of HbO2, GSH, fluorescent label DCFH2) as well as damage to the plasma membrane (lipid peroxidation, the potassium leakage) and the kinetics of hemolysis. RESULTS: The prolonged incubation of erythrocytes induced a progressive destruction of erythrocytes. Melatonin prevented lipid peroxidation and hemolysis whereas the oxidation of HbO2 and DCFH2 was enhanced by melatonin at concentrations higher than 0.6 mM. In the case of erythrocytes incubated with 3 mM of MEL, the hemolysis rate constant (0.0498+/-0.0039 H%*h-1) was 50% lower than that of the control while the HbO2 oxidation rate constants were about 1.4 and 1.5 times higher for 1.5 and 3 mM of MEL, respectively. Melatonin had no influence on the oxidation of GSH and the potassium leakage. CONCLUSIONS: Probably, MEL can stabilize the erythrocyte membrane due to interaction with lipids, thus prolonging the existence of cells. On the contrary, in the presence of MEL the accelerated oxidation of HbO2 and generally, increased oxidative stress was observed in erythrocytes. Pro- and antioxidative properties of melatonin depend on the type of cells, redox state, as well as experimental conditions. PMID- 23640946 TI - Comparative efficacy of exenatide versus insulin glargine on glycemic control in type 2 diabetes mellitus patients inadequately treated with metformin monotherapy. AB - PURPOSE: Comparative efficacy of exenatide versus insulin glargine primarily on glucemic control, and secondarily on body mass index (BMI), lipid profile and blood pressure, in type 2 diabetes mellitus (T2DM) patients suboptimally treated with metformin monotherapy. MATERIAL/METHODS: Forty-seven inadequately treated T2DM patients on metformin assigned to exenatide (n=18) or insulin glargine (n=29) for 26 weeks. Glycosylated hemoglobin (HbA1c), serum lipids, BMI, systolic and diastolic blood pressure, and adverse events, including episodes of hypoglycemia and gastrointestinal symptoms, were recorded. RESULTS: Either treatment had a similar favorable mean reduction in HbA1c. However, more patients in exenatide group achieved HbA1c <= 7% at the 26th week compared with insulin glargine group (p=0.036). Insulin glargine group had significantly more episodes of hypoglycemia compared with exenatide group (p=0.039). Gastrointestinal adverse events were non-significantly higher in the exenatide group. A significantly greater BMI reduction was observed in exenatide group, whereas BetaMUIota was not altered in insulin glargine group. Total and LDL cholesterol (p=0.012), and triglycerides (p=0.016) significantly decreased, whereas HDL cholesterol increased (p=0.021) in the exenatide group, whereas only total cholesterol decreased in insulin glargine group. Changes in systolic and diastolic blood pressure were insignificant in both groups. CONCLUSIONS: Exenatide provided similar reduction in HbA1c, but fewer episodes of hypoglycemia, compared with insulin glargine. Exenatide had also a favorable effect on weight loss, although more gastrointestinal adverse events. Exenatide may provide a justified alternative in second line treatment of T2DM, but more trials are required to elucidate its long-term safety and cost-effectiveness. PMID- 23640947 TI - The impact of genetic factors on response to anaesthetics. AB - In recent years, exceptional progress has been observed in pharmacogenetics, i.e. investigations of inherited conditioning of the organism's response to drugs or xenobiotics. On the other hand, modern molecular biology techniques have been implemented, making it possible to perform studies determining the involvement of genetic factors in differing responses to agents employed in general anaesthesia. Unexpected and incorrect response of the organism to the administration of specific anaesthetics is most commonly associated with a genetic defect of the metabolic pathway of a given agent or its receptor. The majority of agents used in anaesthesia are metabolised in the liver by the cytochrome P450 superfamily enzymes (CYPs) and phase II drug-metabolising enzymes: glutathione S-transferases (GSTs), sulphotransferases (SULTs), UDP-glucuronosyltransferases (UGTs) and NAD(P)H:quinone oxidoreductase (NQO1). Propofol is presently widely used for gastrointestinal (GI) and several other procedures. Among genes associated with metabolism of the most commonly applied anaesthetics such as propofol and sevoflurane, the following ones can be mentioned: CYP2E1, CYP2B6, CYP2C9, GSTP1, UGT1A9, SULT1A1 and NQO1. Moreover, the basic mechanism of propofol action involves its interaction with an ionotropic receptor GABAA inhibiting transfer of nerve impulses. Molecular studies have shown that polymorphic changes in GABRG2 receptor gene turn out to be important in the propofol anaesthesia. Planning of optimal anaesthesia can be considerably assisted by the determination of genetic factors of prognostic value taking advantage of genotyping and making it possible to select anaesthetics and reduce risk of side effects as well as undesirable actions. PMID- 23640948 TI - Metronidazole affects breast cancer cell lines. AB - PURPOSE: The aim of our study was to evaluate the impact of metronidazole (MTZ) on cytotoxicity and DNA synthesis in MCF-7 (estrogen receptor positive) and MDA MB-231 (estrogen receptor negative) breast cancer cell lines. MATERIAL/METHODS: Toxicity of MTZ was determined by MTT test. MCF-7 and MDA-MB-231 cells were incubated with metronidazole used in different concentrations for 24, 48 and 72 hours. The effect of MTZ on DNA synthesis was measured as [3H]-thymidine incorporation. RESULTS: We showed that MTZ in concentration 250 MUg/ml significantly increases the growth of MCF-7 cell lines after 24 hours of incubation, but it reduces cell viability in concentrations 1 and 10 MUg/ml 72 hours after the drug application. Significant increase of MDA-MB-231 cell viability was obtained in MTZ concentration of 250 MUg/ml after 24 and 72 hours. The increase of [3H]-thymidine incorporation in MCF-7 cell line treated with MTZ in concentration 250 MUg/ml was statistically significant after 24 hours. Great suppression of cell proliferation was obtained in MDA-MB-231 breast cell line after application of the following concentrations of MTZ: 0.1 MUg/ml (after 24 hours) and 0.1, 10, 50, 250 MUg/ml (after 72h). CONCLUSIONS: We found that metronidazole exerts different dose- and time- dependent effects on human breast cancer cell lines characterized by presence or absence of estrogen receptors. We suggest that these discrepancies may be influenced by the estrogen signaling. PMID- 23640949 TI - The value of MMP-9 for breast and non-small cell lung cancer patients' survival. AB - PURPOSE: Matrix metalloproteinases (MMPs) are implicated in cancer cells invasion and metastasis processes and have been investigated as potential cancer biomarkers. In this study MMP-9 gene expression and MMP-9 -1562 C/T polymorphism in breast and non-small cell lung cancer patients' blood and tumor samples and its correlation with clinicopathological parameters were investigated. MATERIAL/METHODS: MMP-9 gene expression was assessed by reverse transcription - polymerase chain reaction method in 108 cancer patients' blood and tumor samples. MMP-9 -1562 C/T polymorphism was determined by the polymerase chain reaction - based restriction fragment length polymorphism method. RESULTS: Significant relationship of MMP-9 gene expression and tumor differentiation grade was found only between groups with G1 and G3 breast tumors. Low survival rates were identified among positive MMP-9 expression in blood and ductal carcinoma of the breast (p=0.01) and negative progesterone receptor reaction (p=0.04). Significant differences in the distribution among genotypes were found between groups with stage I and stages III/IV (p=0.005) as well as between groups with lymph node status N0 and N1 (p<0.001). Breast cancer patients with tumor differentiation grade G3 and identified CC variant had a longer survival time (p=0.014). Shorter survival time was found among positive MMP-9 expression in tumor and stage I non small cell lung cancer patients with negative lymph node (p=0.012) and squamous cell carcinoma (p=0.019). CONCLUSIONS: Expression of MMP-9 in blood and tumor together indicates worse prognosis for breast cancer patients. PMID- 23640950 TI - Myocardial perfusion and intima-media thickness in patients with subclinical hypothyroidism. AB - PURPOSE: The data concerning the relation between subclinical hypothyroidism (SH) and the risk of cardiovascular disease are divergent. We aimed to assess myocardial perfusion in contrast-enhanced echocardiography and intima-media thickness (IMT) in patients with SH. MATERIAL/METHODS: Forty females with SH without symptoms of coronary artery disease and 15 healthy female volunteers were examined. Echocardiographic evaluation of the left ventricle function as well as carotid and femoral IMT complex measurements were performed at baseline. Thereafter, dobutamine stress echocardiography with myocardial perfusion assessment at rest and on the peak of stress test was performed. SonoVue(r) intravenous bolus as a contrast medium was used. The myocardial perfusion was assessed by quantitative method using Q-LAB Philips software (ROI modality). The perfusion index was calculated (a number of left ventricle segments with improved perfusion/a number of all segments). RESULTS: A mean IMT value in the SH group was significantly higher than in the controls (0.7 mm vs. 0.38 mm, p=0.001). Myocardial perfusion at rest and at the peak of stress test was significantly lower in the SH patients as compared to the controls (at rest 120 Db in SH vs. 181 Db in controls, p=0.039 and at the peak of stress 115 Db and 188 Db, p=0.01, respectively). The perfusion index was not significantly worse in the SH group (p=0.6). IMT values negatively correlated with the myocardial perfusion index at the peak of stress (r=-0.54, p=0.014). CONCLUSIONS: In patients with SH contrast enhanced echocardiographic examination revealed myocardial hypoperfusion and increased IMT. Our results may suggest that the patients with SH are at risk of the development of cardiovascular disease. PMID- 23640951 TI - Plasma vascular endothelial growth factor and angiogenin are positively related to erythropoietin dose in hemodialysis patients. AB - PURPOSE: Experimental data confirmed that erythropoietin (EPO) administration alters the course of various pathological situations such as heart failure and tumor growth by inducing vascular endothelial growth factor-A (VEGF-A) expression. The effect of EPO dose on plasma VEGF-A level in hemodialysis (HD) patients was evaluated. The effect of EPO dose on plasma angiogenin level in HD patients was also evaluated, since angiogenin is necessary for angiogenesis induced by VEGF-A. METHODS: Thirty two HD patients (10 diabetics) enrolled into the study. Patients were iron replete and did not suffer from infections, autoimmune diseases or malignancies. Plasma VEGF-A and angiogenin, as well as serum interleukin-6 and tumor necrosis factor-alpha were measured by means of ELISA. RESULTS: Weekly EPO dose per kg of dry body weight was positively related to both VEGF-A and angiogenin, whereas no relation was detected among VEGF-A or angiogenin and hemoglobin, inflammation or presence of diabetes mellitus. These relations among EPO dose and VEGF-A or angiogenin remained after adjustment for hemoglobin concentration or inflammation or presence of diabetes mellitus. CONCLUSIONS: EPO dose may affect plasma VEGF-A and angiogenin concentrations in HD patients. PMID- 23640954 TI - Nickel-catalyzed direct alkylation of heterocycles with alpha-bromo carbonyl compounds: C3-selective functionalization of 2-pyridones. AB - Nickel HAS it: A Ni(cod)2/dppp catalyst system promotes the direct alkylation of electron-rich heterocycles with alpha-bromo carbonyl compounds and involves an alkyl radical intermediate (see scheme; cod = 1,5-cyclooctadiene, dppp = 1,3 bis(diphenylphosphino)propane). This homolytic radical aromatic substitution (HAS)-type reaction enables the C3-selective direct functionalization of 2 pyridones. PMID- 23640952 TI - Oral arginine metabolism may decrease the risk for dental caries in children. AB - Arginine metabolism by oral bacteria via the arginine deiminase system (ADS) increases the local pH, which can neutralize the effects of acidification from sugar metabolism and reduce the cariogenicity of oral biofilms. To explore the relationship between oral arginine metabolism and dental caries experience in children, we measured ADS activity in oral samples from 100 children and correlated it with their caries status and type of dentition. Supragingival dental plaque was collected from tooth surfaces that were caries-lesion-free (PF) and from dentinal (PD) and enamel (PE) caries lesions. Regardless of children's caries status or type of dentition, PF (378.6) had significantly higher ADS activity compared with PD (208.4; p < .001) and PE (194.8; p = .005). There was no significant difference in the salivary arginolytic activity among children with different caries status. Mixed-model analysis showed that plaque caries status is significantly associated with ADS activity despite children's age, caries status, and dentition (p < .001), with healthy plaque predicting higher ADS activity compared with diseased plaque. Plaque arginine metabolism varies greatly among children and tooth sites, which may affect their susceptibility to caries. PMID- 23640955 TI - Significant testicular enlargement in a 6.5-year-old boy with monorchism and testicular microlithiasis. AB - We report a testicular enlargement that mimics precocious puberty in a boy aged 6.5 years with monorchism and testicular microlithiasis. PMID- 23640956 TI - Pathophysiology of critical illness hyperglycemia in children. AB - Causes of hyperglycemia in critically ill non-diabetic children may differ from those in adults. The objective of this study was to investigate the pathogenesis of critical illness hyperglycemia (CIH) in terms of insulin resistance and beta cell dysfunction. Critically ill children with blood glucose (BG) levels of >150 mg/dL (8.3 mmol/L) were enrolled in the study. Insulin sensitivity and beta-cell function in the hyperglycemic and euglycemic periods were analyzed with BG/insulin and BG/C-peptide ratios, and utilizing homeostasis model assessment (HOMA). A total of 40 patients were enrolled in the study. BG/insulin and BG/C peptide ratios were significantly higher in the hyperglycemic period. The HOMA-B and S scores for the hyperglycemic period revealed that out of all the patients who survived (n=30), 20 had beta-cell dysfunction, while the remaining (n=11) had insulin resistance. beta-cell dysfunction was significantly higher in the hyperglycemic period (p<0.001). As in adults, beta-cell dysfunction may play a major role in the pathophysiology of CIH in children. PMID- 23640957 TI - Reactive oxygen species-mediated activation of AMP-activated protein kinase and c Jun N-terminal kinase plays a critical role in beta-sitosterol-induced apoptosis in multiple myeloma U266 cells. AB - Although beta-sitosterol has been well known to have anti-tumor activity in liver, lung, colon, stomach, breast and prostate cancers via cell cycle arrest and apoptosis induction, the underlying mechanism of anti-cancer effect of beta sitosterol in multiple myeloma cells was never elucidated until now. Thus, in the present study, the role of reactive oxygen species (ROS) in association with AMP activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) pathways was demonstrated in beta-sitosterol-treated multiple myeloma U266 cells. Beta sitosterol exerted cytotoxicity, increased sub-G1 apoptotic population and activated caspase-9 and -3, cleaved poly (ADP-ribose) polymerase (PARP) followed by decrease in mitochondrial potential in U266 cells. Beta-sitosterol promoted ROS production, activated AMPK, acetyl-CoA carboxylase (ACC) and JNK in U266 cells. Also, beta-sitosterol attenuated the phosphorylation of AKT, mammalian target of rapamycin and S6K, and the expression of cyclooxygenase-2 and VEGF in U266 cells. Conversely, AMPK inhibitor compound C and JNK inhibitor SP600125 suppressed apoptosis induced by beta-sitosterol in U266 cells. Furthermore, ROS scavenger N-acetyl L-cysteine attenuated beta-sitosterol-mediated sub-G1 accumulation, PARP cleavage, JNK and AMPK activation in U266 cells. Overall, these findings for the first time suggest that ROS-mediated activation of cancer metabolism-related genes such as AMPK and JNK plays an important role in beta sitosterol-induced apoptosis in U266 multiple myeloma cells. PMID- 23640958 TI - Efavirenz intoxication due to a new CYP2B6 constellation. AB - Here, we describe severe neuropsychiatric symptoms in an HIV-positive Asian man with extremely high efavirenz plasma levels while receiving standard treatment with efavirenz/tenofovir/emtricitabine fixed-dose regimen. Genetic examination revealed compound homozygosity for loss-of-function alleles of CYP2B6, including coding for a rare truncated protein. Neuropsychiatric symptoms resolved completely after efavirenz discontinuation. PMID- 23640959 TI - PHOTO QUIZ. A generalized eruption in a rancher. PMID- 23640962 TI - Anti-inflammatory activities of an active fraction isolated from the root of Astragalus membranaceus in RAW 264.7 macrophages. AB - The root of Astragalus membranaceus (AR), which has been widely used in Traditional Chinese herbal formulae for treating foot ulcer, was found to exhibit anti-inflammatory property, but its molecular mechanism still remains unknown. We previously identified the anti-inflammatory sub-fraction using bioassay-guided fractionation. The objective of the present study was to investigate the anti inflammatory mechanism of the major active fraction (MAF) (0.039 to 0.156 mg/mL) using lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells. MAF was shown to inhibit LPS-induced mRNA and protein expression of inducible nitric oxide synthase by 54.7% and 65.1%, respectively. Additionally, MAF down-regulated the protein expression of cyclooxygenase-2 and MAPK regulator by 45.0% to 74.6%, as well as the reduction of DNA binding activity of nuclear factor kappa B (NFkappaB) by 66.5%. It also attenuated the production of prostaglandin E2 , interleukin-1 beta (IL-1beta), IL-6 and tumor necrosis factor alpha by 21.2% to 86.2%. Furthermore, the chemical constituents of MAF were identified. A total of 13 known chemical compounds were found in MAF, including five isoflavonoids and eight saponins. In conclusion, a bioactive fraction of AR was identified which possessed anti-inflammatory property by reducing the release of inflammatory mediators and inactivation of NFkappaB through MAPK signalling pathway. PMID- 23640963 TI - Safety and efficacy of CHOP for treatment of diffuse large B-cell lymphoma with different combination antiretroviral therapy regimens: SCULPT study. AB - BACKGROUND: Use of combination antiretroviral therapy (cART) and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) with or without rituximab for treatment of diffuse large B-cell lymphoma (DLBCL) in HIV substantially increases response rates but may also increase toxicity, possibly due to antiretroviral-antineoplastic drug interactions. The objective of this study was to evaluate the frequency of complete remission (CR) of DLBCL in patients treated with CHOP while receiving a protease inhibitor (PI) versus a non PI-based cART. METHODS: A retrospective multicentre pilot study was conducted in HIV-infected patients on cART treated for DLBCL with CHOP between 2002-2010 in three academic hospitals. RESULTS: A total of 34 patients were included with 65% and 35% of patients receiving a PI and non-PI-based cART, respectively. Baseline characteristics between groups were similar; overall 85% were male, median age was 43 years, 50% had an International Prognostic Index (IPI) of 2-3 and median CD4(+) T-cell count was 225 cells/mm(3). CR was achieved in 77% and 58% of patients in the PI and non-PI groups, respectively (P=0.21), with 65% and 63% of patients achieving 2-year overall survival (P=1.00). A multivariate analysis showed that lower IPI score alone was significantly associated with higher CR rates (P=0.05). Toxicity was similar between both groups. CONCLUSIONS: Similar efficacy and toxicity of CHOP was observed in patients receiving a PI and non-PI based cART. PMID- 23640964 TI - Post-transcriptional regulation of alpha-1-antichymotrypsin by microRNA-137 in chronic heart failure and mechanical support. AB - BACKGROUND: Better understanding of the molecular mechanisms of remodeling has become a major objective of heart failure (HF) research to stop or reverse its progression. Left ventricular assist devices (LVADs) are being used in patients with HF, leading to partial reverse remodeling. In the present study, proteomics identified significant changes in alpha-1-antichymotrypsin (ACT) levels during LVAD support. Moreover, the potential role of ACT in reverse remodeling was studied in detail. METHODS AND RESULTS: Expression of ACT mRNA (quantitative polymerase chain reaction) decreased significantly in post-LVAD myocardial tissue compared with pre-LVAD tissue (n=15; P<0.01). Immunohistochemistry revealed that ACT expression and localization changed during LVAD support. Circulating ACT levels were elevated in HF patients (n=18) as compared with healthy controls (n=6; P=0.001) and normalized by 6 months of LVAD support. Because increasing evidence implicates that microRNAs (miRs) are involved in myocardial disease processes, we also investigated whether ACT is post-transcriptionally regulated by miRs. Bioinformatics analysis pointed miR-137 as a potential regulator of ACT. The miR-137 expression is inversely correlated with ACT mRNA in myocardial tissue. Luciferase activity assays confirmed ACT as a direct target for miR-137, and in situ hybridization indicated that ACT and miR-137 were mainly localized in cardiomyocytes and stromal cells. CONCLUSIONS: High ACT plasma levels in HF normalized during LVAD support, which coincides with decreased ACT mRNA in heart tissue, whereas miR-137 levels increased. MiR-137 directly targeted ACT, thereby indicating that ACT and miR-137 play a role in the pathophysiology of HF and reverse remodeling during mechanical support. PMID- 23640965 TI - Complex rhythmicity and age dependence of growth hormone secretion are preserved in patients with acromegaly: further evidence for a present hypothalamic control of pituitary somatotropinomas. AB - CONTEXT: Traditionally, acromegaly is viewed as a disease resulting from GH hypersecretion from an autonomous pituitary somatotropinoma. OBJECTIVE: To test the hypothesis that GH secretion in acromegaly is still subjected to normal hypothalamic control, we studied the daily rhythmicity of GH secretion in normal controls and patients with newly diagnosed, untreated acromegaly. DESIGN AND SETTING: This was an observational inpatient study in the General Clinical Research Center at the University of Michigan. PATIENTS OR OTHER PARTICIPANTS: One hundred four normal controls and 67 acromegalic patients were included in the study. INTERVENTION: The intervention consisted of frequent blood sampling over 24 hours. MAIN OUTCOME MEASURE(S): We hypothesized that acromegalic patients would show rhythmicity, sexual dimorphism, and age-related decline of GH secretion similar to normal controls. RESULTS: Both normal controls and the patients exhibited 3 major GH waves with the highest values at 12:00 pm, 5:00 pm, and 1:00 am (P < .001 for all). Both controls and patients exhibited a clear appearance of the nocturnal GH waves, irrespective of the gender (P < .001 for all). The amplitude of the maximal (nocturnal) GH secretory wave (1:00 am) as compared with the nadir GH secretion (9:00 am) was clearly different between the 2 groups, with a significantly smaller magnitude in acromegaly (P < .001). A subsequent subanalysis of both groups was performed separately for both genders. Similar to the entire groups, both controls and patients exhibited a clear appearance of the nocturnal GH waves, irrespective of the gender (P < .001 for all). Patients with clearly elevated GH values have shown an age-related decline of GH secretion (r = -0.35, P < .001), similar to controls. CONCLUSIONS: The analysis of GH profiles in multiple patients with untreated acromegaly discloses the persistence of the hallmarks of the central control of GH regulation, ie, nictohemeral rhythmicity, sexual dimorphism, and an age-related decline of GH output. PMID- 23640966 TI - Successful visualization of an indeterminate hepatic metastasis from thyroid carcinoma using contrast-enhanced CT and contrast-enhanced ultrasound. PMID- 23640967 TI - Two novel functional single nucleotide polymorphisms of ADRB3 are associated with type 2 diabetes in the Chinese population. AB - AIMS: The purpose of this study was to investigate the association of two novel beta3-adrenergic receptor (ADRB3) gene polymorphisms (Ser165Pro and Ser257Pro) with type 2 diabetes (T2DM) in the Chinese population. METHODS: A total of 650 patients with T2DM and 1337 health volunteers were enrolled to conduct the association study. Two candidate polymorphisms were recreated by site-directed mutagenesis and tested for their effect on ADRB3 expression and function in stable transfected human embryonic kidney 293 and Chinese hamster ovary-K1 cells. Real-time PCR, Western blot, confocal microscopy, and cAMP assay were used to determine mRNA, protein expression, trafficking, and ADRB3 function, respectively. RESULTS: We found that both polymorphisms were significantly associated with T2DM (odds ratio = 2.060 and 95% confidence interval = 1.303 3.258 for Ser165Pro and odds ratio = 7.588, 95% confidence interval = 1.639 35.138 for Ser257Pro). Patients with T2DM with the Ser165Pro C allele had higher hemoglobin A1c, fasting plasma glucose and postprandial plasma glucose values than those in TT genotypes. We also found that patients with T2DM with the Ser257Pro C allele had lower fasting serum insulin, postprandial serum insulin, and homeostasis model assessment for insulin resistance levels than TT genotype carriers. Further in vitro study indicated that cell lines stably expressing Ser165Pro and Ser257Pro mutants of the ADRB3 gene showed impaired cAMP accumulation activity. However, both polymorphisms had no effect on ADRB3 expression and trafficking. CONCLUSIONS: Ser165Pro and Ser257Pro polymorphisms affected ADRB3 function and were significantly associated with susceptibility to and development of T2DM. PMID- 23640968 TI - Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing. AB - CONTEXT: Up to 60% of pheochromocytoma (PCC) and paraganglioma (PGL) are associated with either somatic or germline mutations in established PCC and PGL susceptibility loci. Most unexplained cases are characterized by an increased activity of the RAS/RAF/ERK signaling pathway. Mutations in RAS subtypes H, K, and N are common in human cancers; however, previous studies have been inconsistent regarding the mutational status of RAS in PCC and PGL. OBJECTIVES: The aim of this study was to identify novel disease causing genes in PCC and PGL tumors. DESIGN, SETTING, AND PARTICIPANTS: Four benign and sporadic PCC and PGL tumors were subjected to whole exome sequencing using the Illumina HiSeq Platform. Sequences were processed by CLC genomics 4.9 bioinformatics software and the acquired list of genetic variants was filtered against the Catalogue of Somatic Mutations in Cancer database. Findings were validated in an additional 78 PCC and PGL tumor lesions. RESULTS: Exome sequencing identified 2 cases with somatic mutations in the H-RAS. In total, 6.9% (n = 4/58) of tumors negative for mutations in major PCC and PGL loci had mutations in H-RAS: G13R, Q61K, and Q61R. There were 3 PCC and 1 PGL; all had sporadic presentation with benign tumor characteristics and substantial increases in norepinephrine and/or epinephrine. H RAS tumors were exclusively found in male patients (P = .007). CONCLUSIONS: We identified recurrent somatic H-RAS mutations in pheochromocytoma and paraganglioma. Tumors with H-RAS mutations had activation of the RAS/RAF/ERK signaling pathway and were associated with male PCC patients having benign and sporadic disease characteristics. H-RAS could serve as a prognostic and predictive marker as well as a novel therapeutic target. PMID- 23640969 TI - Genetic variation in NR1H4 encoding the bile acid receptor FXR determines fasting glucose and free fatty acid levels in humans. AB - CONTEXT: Bile acid signaling via farnesoid X receptor (FXR) regulates glucose and lipid levels, fat mass, and hepatic steatosis in animal models. OBJECTIVE: To understand the role of FXR in human metabolism, we investigated associations of common single-nucleotide polymorphisms (SNPs) in the FXR-encoding gene NR1H4 with glucose and lipid metabolism, body fat mass, and liver fat content. DESIGN: We genotyped 2166 healthy German subjects for 7 tagging SNPs within NR1H4 (rs35735, rs1030454, rs11110415, rs11610264, rs17030285, rs4764980, and rs11110390) covering 100% of common genetic variation (minor allele frequency > 10%). OUTCOME MEASURES: Subjects were metabolically characterized by an oral glucose tolerance test. In subgroups, hyperinsulinemic-euglycemic clamp and liver fat quantification by (1)H-magnetic resonance spectroscopy were performed. RESULTS: SNP rs4764980 was significantly associated with fasting glycemia (P = .0043) and nominally associated with fasting and postglucose load free fatty acid (FFA) levels (P = .01). Upon interrogation of publicly available Meta-Analyses of Glucose and Insulin-related traits Consortium data, the association of rs4764980 with fasting glycemia was replicated (Meta-Analyses of Glucose and Insulin related traits Consortium, P = .005). Additionally, SNP rs11110390 showed significant associations with fasting (P = .0054) and postload (P = .0051) FFA levels. For none of the investigated SNPs, associations with insulin secretion or sensitivity, body fat mass, or liver fat content were detected. CONCLUSIONS: We conclude that FXR contributes to fasting glucose and FFA levels in humans independent of unhealthy body fat accumulation. The receptor represents an interesting target to influence lipid and glucose metabolism. PMID- 23640972 TI - Apixaban compared with warfarin for stroke prevention in atrial fibrillation: implications of time in therapeutic range. PMID- 23640970 TI - Quality of life and other outcomes in children treated for Cushing syndrome. AB - CONTEXT: Cushing syndrome (CS) in children is associated with residual impairment in measures of health-related quality of life, even after successful resolution of hypercortisolemia, highlighting the need for early identification of morbidities and improvements in long-term management of these patients. EVIDENCE ACQUISITION AND SYNTHESIS: A PubMed, Scopus, and Web of Science search of articles from 1900 onward identified available studies related to quality of life and complications of pediatric CS as well as important historical articles. This review summarizes studies through November 2012 and highlights recent developments. CONCLUSIONS: A review of the literature identifies significant morbidities associated with CS of pediatric onset, which must not be treated in isolation. CS affects children and adolescents in many ways that are different than adults. Post-treatment challenges for the child or adolescent treated for CS include: optimize growth and pubertal development, normalize body composition, and promote psychological health and cognitive maturation. All these factors impact health-related quality of life, which is an important outcome measure to assess the burden of disease as well as the effect of treatment. Future research efforts are needed to improve management of the physical, psychological, and emotional aspects of this disease in order to diminish the residual impairments experienced by the pediatric CS patient population. PMID- 23640971 TI - Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation. AB - BACKGROUND: In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR). METHODS AND RESULTS: The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53-1.00) and 0.88 (95% CI, 0.57-1.35) (Pinteraction=0.078), for mortality were 0.91 (95% CI, 0.74-1.13) and 0.91 (95% CI, 0.71-1.16) (Pinteraction=0.34), and for major bleeding were 0.50 (95% CI, 0.36-0.70) and 0.75 (95% CI, 0.58-0.97) (Pinteraction=0.095), respectively. Similar results were seen for quartiles of individual TTR. CONCLUSIONS: The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers' and patients' predicted quality of international normalized ratio control. PMID- 23640973 TI - microRNA expression profiles identify subtypes of mantle cell lymphoma with different clinicobiological characteristics. AB - PURPOSE: microRNAs (miRNA) are posttranscriptional gene regulators that may be useful as diagnostic and/or prognostic biomarkers. We aim to study the expression profiles of a high number of miRNAs and their relationship with clinicopathologic and biologic relevant features in leukemic mantle cell lymphomas (MCL). EXPERIMENTAL DESIGN: Expression profiling of 664 miRNAs was investigated using a high-throughput quantitative real-time PCR platform in 30 leukemic MCLs. Statistical and bioinformatic analyses were conducted to define miRNAs associated with different clinicopathologic parameters. Gene expression profiling was investigated by microarrays in 16 matching cases to study the potential genes and pathways targeted by selected miRNAs. The prognostic value of miR-34a was investigated in 2 independent series of 29 leukemic and 50 nodal MCLs. RESULTS: Robust consensus clustering defined 2 main MCL subgroups with significant differences in the immunoglobulin (IGHV) mutational status, SOX11 expression, genomic complexity, and nodal clinical presentation. Supervised analyses of IGHV and SOX11 categories identified 17 and 22 miRNAs differentially expressed, respectively. Enriched targets of these miRNAs corresponded to relevant pathways in MCL pathogenesis such as DNA stress response, CD40 signaling, and chromatin modification. In addition, we found 7 miRNAs showing prognostic significance independently of IGHV status and SOX11 expression. Among them, miR-34a was also associated with poor prognosis in 2 independent series of leukemic and nodal MCL, and in cooperation with high expression of the MYC oncogene. CONCLUSION: We have identified miRNAs and target pathways related to clinical and biologic variants of leukemic MCL, and validated miR-34a as a prognostic marker in MCL. PMID- 23640974 TI - CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity. AB - PURPOSE: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. EXPERIMENTAL DESIGN: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239). RESULTS: Exposure to paclitaxel (logAUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, Cmax, or T>0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001). CONCLUSIONS: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment. PMID- 23640975 TI - PI3K/mTOR inhibitor PF-04691502 antitumor activity is enhanced with induction of wild-type TP53 in human xenograft and murine knockout models of head and neck cancer. AB - PURPOSE: Phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway activation is often associated with altered expression or mutations of PIK3CA, TP53/p73, PTEN, and TGF-beta receptors (TGFBR) in head and neck squamous cell carcinomas (HNSCC). However, little is known about how these alterations affect response to PI3K/mTOR-targeted agents. EXPERIMENTAL DESIGN: In this preclinical study, PI3K/Akt/mTOR signaling was characterized in nine HNSCC (UM SCC) cell lines and human oral keratinocytes. We investigated the molecular and anticancer effects of dual PI3K/mTOR inhibitor PF-04691502(PF-502) in UM-SCC expressing PIK3CA with decreased wild-type TP53, mutant TP53-/+ mutantTGFBR2, and in HNSCC of a conditional Pten/Tgfbr1 double knockout mouse model displaying PI3K/Akt/mTOR activation. RESULTS: UM-SCC showed increased PIK3CA expression and Akt/mTOR activation, and PF-502 inhibited PI3K/mTORC1/2 targets. In human HNSCC expressing PIK3CA and decreased wtTP53 and p73, PF-502 reciprocally enhanced TP53/p73 expression and growth inhibition, which was partially reversible by p53 inhibitor pifithrin-alpha. Most UM-SCC with wtTP53 exhibited a lower IC50 than those with mtTP53 status. PF-502 blocked growth in G0-G1 and increased apoptotic sub-G0 DNA. PF-502 suppressed tumorigenesis and showed combinatorial activity with radiation in a wild-type TP53 UM-SCC xenograft model. PF-502 also significantly delayed HNSCC tumorigenesis and prolonged survival of Pten/Tgfbr1 deficient mice. Significant inhibition of p-Akt, p-4EBP1, p-S6, and Ki67, as well as increased p53 and TUNEL were observed in tumor specimens. CONCLUSIONS: PI3K mTOR inhibition can enhance TP53/p73 expression and significantly inhibit tumor growth alone or when combined with radiation in HNSCC with wild-type TP53. PIK3CA, TP53/p73, PTEN, and TGF-beta alterations are potential modifiers of response and merit investigation in future clinical trials with PI3K-mTOR inhibitors. PMID- 23640976 TI - 4FISH-IF, a four-color dual-gene FISH combined with p63 immunofluorescence to evaluate NKX3.1 and MYC status in prostate cancer. AB - NKX3.1 allelic loss and MYC amplification are common events during prostate cancer progression and have been recognized as potential prognostic factors in prostate cancer after radical prostatectomy or precision radiotherapy. We have developed a 4FISH-IF assay (a dual-gene fluorescence in situ hybridization combined with immunofluorescence) to measure both NKX3.1 and MYC status on the same slide. The 4FISH-IF assay contains four probes complementary to chromosome 8 centromere, 8p telomere, 8p21, and 8q24, as well as an antibody targeting the basal cell marker p63 visualized by immunofluorescence. The major advantages of the 4FISH-IF include the distinction between benign and malignant glands directly on the 4FISH-IF slide and the control of truncation artifact. Importantly, this specialized and innovative combined multiprobe and immunofluorescence technique can be performed on diagnostic biopsy specimens, increasing its clinical relevance. Moreover, the assay can be easily performed in a standard clinical molecular pathology laboratory. Globally, the use of 4FISH-IF decreases analytic time, increases confidence in obtained results, and maintains the tissue morphology of the diagnostic specimen. PMID- 23640977 TI - Diaphragm muscle remodeling in a rat model of chronic intermittent hypoxia. AB - Respiratory muscle remodeling occurs in human sleep apnea--a common respiratory disorder characterized by chronic intermittent hypoxia (CIH) due to recurrent apnea during sleep. We sought to determine if CIH causes remodeling in rat sternohyoid (upper airway dilator) and diaphragm muscles. Adult male Wistar rats were exposed to CIH (n=8), consisting of 90 sec of hypoxia (5% at the nadir; SaO2 ~80%)/90 sec of normoxia, 8 hr per day, for 7 consecutive days. Sham animals (n=8) were exposed to alternating air/air cycles in parallel. The effect of CIH on myosin heavy-chain (MHC) isoform (1, 2a, 2x, 2b) distribution, sarcoplasmic reticulum calcium ATPase (SERCA) isoform distribution, succinate dehydrogenase activity, glycerol phosphate dehydrogenase activity, and Na+/K+ ATPase pump content was determined. Sternohyoid muscle structure was unaffected by CIH treatment. CIH did not alter oxidative/glycolytic capacity or the Na+/K+-ATPase pump content of the diaphragm. CIH significantly increased the areal density of MHC 2b fibers in the rat diaphragm, and this was associated with a shift in SERCA proteins from SERCA2 to SERCA1. We conclude that CIH causes a slow-to-fast fiber transition in the rat diaphragm after just 7 days of treatment. Respiratory muscle functional remodeling may drive aberrant functional plasticity such as decreased muscle endurance, which is a feature of human sleep apnea. PMID- 23640978 TI - Mitochondrial coenzyme Q10 determination by isotope-dilution liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: Coenzyme Q10 (CoQ10) is an essential part of the mitochondrial respiratory chain. Unlike most other respiratory chain disorders, CoQ10 deficiency is potentially treatable. We aimed to develop and validate an accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of mitochondrial CoQ10 in clinical samples. METHODS: We used mitochondria isolated from muscle biopsies of patients (n = 166) suspected to have oxidative phosphorylation deficiency. We also used fibroblast mitochondria from 1 patient with CoQ10 deficiency and 3 healthy individuals. Samples were spiked with nonphysiologic CoQ10-[(2)H6] internal standard, extracted with 1 propanol and with ethanol and hexane (2 mL/5 mL), and CoQ10 quantified by LC MS/MS. The method and sample stability were validated. A reference interval was established from the patient data. RESULTS: The method had a limit of quantification of 0.5 nmol/L. The assay range was 0.5-1000 nmol/L and the CVs were 7.5%-8.2%. CoQ10 was stable in concentrated mitochondrial suspensions. In isolated mitochondria, the mean ratio of CoQ10 to citrate synthase (CS) activity (CoQ10/CS) was 1.7 nmol/U (95% CI, 1.6-1.7 nmol/U). We suggest a CoQ10/CS reference interval of 1.1-2.8 nmol/U for both sexes and all ages. The CoQ10/CS ratio was 5-fold decreased in fibroblast mitochondria from a patient with known CoQ10 deficiency due to recessive prenyl (decaprenyl) diphosphate synthase, subunit 2 (PDSS2) mutations. CONCLUSIONS: Normalization of mitochondrial CoQ10 concentration against citrate synthase activity is likely to reflect most accurately the CoQ10 content available for the respiratory chain. Our assay and the established reference range should facilitate the diagnosis of respiratory chain disorders and treatment of patients with CoQ10 deficiency. PMID- 23640979 TI - Prevalence of andropausal symptoms among Kuwaiti males. AB - Andropause is a syndrome that usually occurs during men's midlife. It is associated with clinical short-term and long-term effects, as well as some physiological and psychological symptoms due to subnormal levels of testosterone serum. The objective of this study was to identify the factors that significantly contribute to the prevalence of symptoms that may be related to androgen deficiency. The study used a cross-sectional structured questionnaire and a sample of 214 Kuwaiti men aged 40 years and older. The questionnaire consisted of the sociodemographic characteristics of the participants and the Androgen Deficiency of the Aging Male Scale of Andropausal Symptoms. The results of the study indicate that Kuwaiti men who were 40 to 49 years old reported fewer symptoms than did Kuwaiti men aged 50 years and older, including deterioration in their ability to play sports, easily falling asleep after dinner, anger, and hot flushes (p < .05); and Kuwaiti men aged 50 years and older reported experiencing decrease in muscle strength, decrease in sport performance, sweating, loss of height, decreased libido, as well as falling asleep after dinner. For those aged 40 to 49 years, lower education levels, marital status, and employment status were significantly associated with the men's symptoms (p < .05). On the other hand, in the case of respondents aged 50 years and older, only education level was significantly associated with their symptoms (p < .05). This is a preliminary study that reports the prevalence of aging male symptoms among Kuwaiti men. The findings will offer insight into the necessary health care provisions to educate, treat, and provide information related to andropause for the general public. PMID- 23640981 TI - Multimodal imaging in systemic lupus erythematosus patients with diffuse neuropsychiatric involvement. AB - OBJECTIVES: The objective of this paper is to investigate conventional and nonconventional brain magnetic resonance imaging (MRI) findings in systemic lupus erythematosus (SLE) patients with diffuse neuropsychiatric involvement (dNPSLE) compared to healthy controls (HCs). METHODS: Twenty-six (26) SLE patients with one or more diffuse NP syndromes related to the central nervous system (CNS) (dNPSLE) and 36 age- and sex-matched HCs were scanned on a 3T MRI using a multimodal imaging approach. Univariate and multivariate analyses were used to determine MRI-specific measure differences between dNPSLE and HCs for lesion burden, tissue-specific atrophy, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) outcomes. RESULTS: In univariate analyses, dNPSLE patients showed significantly increased T1 lesion number (p = .001) and T1-lesion volume (LV, p = .008) compared to HCs. dNPSLE patients showed decreased whole brain volume (p < .0001), gray matter volume (p < .0001), cortical volume (p < .0001) and increased lateral ventricle volume (p = .004) compared to HCs. dNPSLE patients had increased axial diffusivity (AD) of NAWM (p = .008) and NA brain tissue (p = .017) compared to HCs. In the multivariate regression analysis, decreased cortical volume was associated with SLE (R (2) = 0.59, p < .0001). CONCLUSIONS: This study shows that cortical and central atrophy are associated with SLE patients with diffuse CNS syndromes. Microscopic tissue injury in the NAWM on AD DTI measures in SLE patients indicates a predominant reduction of axonal density. PMID- 23640980 TI - Relation between asymptomatic proteinase 3 antibodies and future granulomatosis with polyangiitis. AB - BACKGROUND AND OBJECTIVES: The subclinical pathogenesis of granulomatosis with polyangiitis (GPA) has not been completely elucidated. Proteinase 3 (PR3) antibodies are strongly associated with GPA, but have not been evaluated before disease presentation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective case-control serum bank study in which PR3 antibodies and C reactive protein (CRP) in up to three longitudinal serum samples for 27 GPA patients before diagnosis (1 day-19 years) were compared with 27 controls whose serum samples were matched for age, sex, and race. This study analyzed all patients with American College of Rheumatology criteria-confirmed disease identified in the Department of Defense electronic medical records between 1990 and 2008. RESULTS: A greater percentage of GPA patients had at least one elevated PR3 antibody level (>=6 U/ml) as well as at least one detectable PR3 antibody level (>1 U/ml) before diagnosis compared with matching controls (63% [17 of 27] versus 0% [0 of 27], P<0.001; and 85% [23 of 27] versus 4% [1 of 27], P<0.001, respectively). A greater percentage of GPA patients had a >1 U/ml per year rate of increase in PR3 antibody level compared with matching controls (62% [21 of 26] versus 0% [0 of 26], P<0.001). PR3 antibody more frequently became elevated before CRP (67% [12 of 18] versus 33% [6 of 18], P=0.04). CONCLUSIONS: Subclinical PR3 antibody presence, trajectory, and temporal relationship to CRP associates with the future diagnosis of GPA. This data set further elucidates the pathogenesis of GPA. PMID- 23640982 TI - Interleukin-10 promoter polymorphisms and expression in Thai children with juvenile systemic lupus erythematosus. AB - Interleukin (IL)-10 expression is regulated by its promoter and correlated with the activity of adult-onset lupus (systemic lupus erythematosus (SLE)). As the pathogenesis of adult-onset SLE may differ from SLE with the age at onset <18 years old (juvenile SLE or JSLE), we evaluated polymorphisms at positions 1082A/G, -819T/C and -592A/C of the IL-10 promoter and serum IL-10 levels in 71 patients with JSLE. Disease activity was determined by the SLE disease activity index (SLEDAI). Active SLE was defined by SLEDAI >= 6 and inactive SLE was defined by SLEDAI equal to zero. The mean age was 14.5 +/- 2.8 years. Nephritis occurred in 57 patients. In JSLE patients, -592 CC and -819 CC were identified with a higher frequency than in controls with the odds ratio (OR) of 2.75 (95% confidence interval (CI) 1.11-6.81, p = 0.04). GCC increased the susceptibility to nephritis in patients with JSLE (OR 2.16, 95% CI 1.07-4.35, p = 0.03). Serum IL-10 levels were significantly higher in 20 JSLE patients with active disease than in 27 patients with inactive disease and in 15 healthy children (p < 0.001). In conclusion, IL-10 expression was upregulated in active JSLE. The -819 CC and 592 CC genotypes increased the susceptibility to JSLE and GCC increased the susceptibility to nephritis. PMID- 23640983 TI - Retraction. Low sodium versus normal sodium diets in systolic heart failure: systematic review and meta-analysis. Heart. Published Online First: 21 August 2012 doi:10.1136/heartjnl-2012-302337. PMID- 23640984 TI - PCorral--interactive mining of protein interactions from MEDLINE. AB - The extraction of information from the scientific literature is a complex task for researchers doing manual curation and for automatic text processing solutions. The identification of protein-protein interactions (PPIs) requires the extraction of protein named entities and their relations. Semi-automatic interactive support is one approach to combine both solutions for efficient working processes to generate reliable database content. In principle, the extraction of PPIs can be achieved with different methods that can be combined to deliver high precision and/or high recall results in different combinations at the same time. Interactive use can be achieved, if the analytical methods are fast enough to process the retrieved documents. PCorral provides interactive mining of PPIs from the scientific literature allowing curators to skim MEDLINE for PPIs at low overheads. The keyword query to PCorral steers the selection of documents, and the subsequent text analysis generates high recall and high precision results for the curator. The underlying components of PCorral process the documents on-the-fly and are available, as well, as web service from the Whatizit infrastructure. The human interface summarizes the identified PPI results, and the involved entities are linked to relevant resources and databases. Altogether, PCorral serves curator at both the beginning and the end of the curation workflow for information retrieval and information extraction. Database URL: http://www.ebi.ac.uk/Rebholz-srv/pcorral. PMID- 23640985 TI - Attitudes towards SMS text message smoking cessation support: a qualitative study of pregnant smokers. AB - SMS text messaging shows promise for delivering smoking cessation support. However, little is known about smokers' feelings towards receiving behavioural advice and support on their mobile phones. This article explores the attitudes of women with experience of prenatal smoking towards receiving pregnancy-related smoking cessation support by text message. Data collected by semi-structured interviews and focus group from women who received either tailored smoking cessation texts or no text support (N = 33) were analysed using thematic analysis. Three themes emerged: convenience, high expectations and perceived source. Texting was regarded as a highly convenient mode of support delivery leading to high levels of attention to messages, although high convenience sometimes resulted in the value of a text being short-lived. Many who did not receive texts had high expectations for text support to intervene with routine smoking behaviour in real time. Those who received texts (with no real-time intervention element), however, felt they were helpful and supportive. Participants discussed how factors relating to perceived source, including personalization, personal relevance and salience of text automatization, could affect message attention and impact. Our findings provide insight into how maximizing personalization and personal relevance can increase the value of text message support and reduce the risk of disengagement. PMID- 23640986 TI - Impact of point-of-sale tobacco display bans: findings from the International Tobacco Control Four Country Survey. AB - This study examined the impact of point-of-sale (POS) tobacco marketing restrictions in Australia and Canada, in relation to the United Kingdom and the United States where there were no such restrictions during the study period (2006 10). The data came from the International Tobacco Control Four Country Survey, a prospective multi-country cohort survey of adult smokers. In jurisdictions where POS display bans were implemented, smokers' reported exposure to tobacco marketing declined markedly. From 2006 to 2010, in Canada, the percentages noticing POS tobacco displays declined from 74.1 to 6.1% [adjusted odds ratio (OR) = 0.26, P < 0.001]; and reported exposure to POS tobacco advertising decreased from 40.3 to 14.1% (adjusted OR = 0.61, P < 0.001). Similarly, in Australia, noticing of POS displays decreased from 73.9 to 42.9%. In contrast, exposure to POS marketing in the United States and United Kingdom remained high during this period. In parallel, there were declines in reported exposures to other forms of advertising/promotion in Canada and Australia, but again, not in the United States or United Kingdom. Impulse purchasing of cigarettes was lower in places that enacted POS display bans. These findings indicate that implementing POS tobacco display bans does result in lower exposure to tobacco marketing and less frequent impulse purchasing of cigarettes. PMID- 23640987 TI - Integrated approach of in vivo and in vitro evaluation of the involvement of hepatic uptake organic anion transporters in the drug disposition in rats using rifampicin as an inhibitor. AB - Cumulative studies describe the importance of drug transporters as one of the key determinants of pharmacokinetics that necessitate investigation and assessment of the involvement of drug transporters in drug discovery and development. The present study investigated an integrated in vivo and in vitro approach to determine the involvement of organic anion transporting polypeptides (Oatps) in the disposition of drugs in rats using rifampicin as an inhibitor. When bromosulfophthalein (BSP) and HMG-CoA reductase inhibitors (statins), which were used as model substrates for Oatps, were administered intravenously (3 and 1 mg/kg, respectively) to rats pretreated with rifampicin orally (30 mg/kg), the total plasma clearance of BSP and statins was attenuated compared with that in control rats, suggesting the involvement of Oatps in the disposition of these drugs in vivo. On the other hand, the pharmacokinetics of midazolam, used as a model substrate of cytochrome P450 3a (Cyp3a), was unchanged between control rats and rifampicin-pretreated rats. The involvement of Oatps in the disposition of statins observed in vivo was further clarified by employing an in vitro hepatic uptake study and media-loss assay in the presence or absence of 100 MUM rifampicin. Hepatic intrinsic clearance was reduced in the presence of rifampicin in both the media-loss assay and hepatocyte uptake study. The present study suggests in vivo investigations in rats using rifampicin together with in vitro investigations with a media-loss assay and/or uptake assay using rat hepatocytes can help determine whether a clinical drug-drug interaction study is necessary in drug development. PMID- 23640988 TI - Multiobjective optimization framework for landmark measurement error correction in three-dimensional cephalometric tomography. AB - The purpose of this study is to minimize errors that occur when using a four vs six landmark superimpositioning method in the cranial base to define the co ordinate system. Cone beam CT volumetric data from ten patients were used for this study. Co-ordinate system transformations were performed. A co-ordinate system was constructed using two planes defined by four anatomical landmarks located by an orthodontist. A second co-ordinate system was constructed using four anatomical landmarks that are corrected using a numerical optimization algorithm for any landmark location operator error using information from six landmarks. The optimization algorithm minimizes the relative distance and angle between the known fixed points in the two images to find the correction. Measurement errors and co-ordinates in all axes were obtained for each co ordinate system. Significant improvement is observed after using the landmark correction algorithm to position the final co-ordinate system. The errors found in a previous study are significantly reduced. Errors found were between 1 mm and 2 mm. When analysing real patient data, it was found that the 6-point correction algorithm reduced errors between images and increased intrapoint reliability. A novel method of optimizing the overlay of three-dimensional images using a 6 point correction algorithm was introduced and examined. This method demonstrated greater reliability and reproducibility than the previous 4-point correction algorithm. PMID- 23640989 TI - Study of edge detection task in dental panoramic radiographs. AB - The purpose of this study is (1) to introduce a new approach for edge detection in orthopantograms (OPGs) and an improved automatic parameter selector for common edge detectors, (2) to present a comparison between our novel approach with common edge detectors and (3) to provide faster outputs without compromising quality. A new approach for edge detection based on statistical measures was introduced: (1) a set of N edge detection results is calculated from a given input image and a selected type of edge detector, (2) N correspondence maps are constructed from N edge detection results, (3) probabilities and average probabilities are computed, (4) an overall correspondence is evaluated for each correspondence map and (5) the correspondence map providing the best overall correspondence is taken as the result of edge detection procedure. A comparison with common edge detectors (the Roberts, Prewitt, Sobel, Laplacian of the Gaussian and Canny methods) with various parameter settings (304 combinations for each test image) was carried out. The methods were assessed objectively [edge mismatch error (EME), modified Hausdorff distance (MHD) and principal component analysis] and subjectively by experts in dentistry and based on time demands. The suitability of the new approach for edge detection in OPGs was confirmed by experts. The current conventional methods in edge detection in OPGs are inadequate (none of the tested methods reach an EME value or MHD value below 0.1). Our proposed approach for edge detection shows promising potential for its implementation in clinical dentistry. It enhances the accuracy of OPG interpretation and advances diagnosis and treatment planning. PMID- 23640990 TI - Functional implications of splicing polymorphisms in the human genome. AB - Proper splicing is often crucial for gene functioning and its disruption may be strongly deleterious. Nevertheless, even the essential for splicing canonical dinucleotides of the splice sites are often polymorphic. Here, we use data from The 1000 Genomes Project to study single-nucleotide polymorphisms (SNPs) in the canonical dinucleotides. Splice sites carrying SNPs are enriched in weakly expressed genes and in rarely used alternative splice sites. Genes with disrupted splice sites tend to have low selective constraint, and the splice sites disrupted by SNPs are less likely to be conserved in mouse. Furthermore, SNPs are enriched in splice sites whose effects on gene function are minor: splice sites located outside of protein-coding regions, in shorter exons, closer to the 3' ends of proteins, and outside of functional protein domains. Most of these effects are more pronounced for high-frequency SNPs. Despite these trends, many of the polymorphic sites may still substantially affect the function of the corresponding genes. A number of the observed splice site-disrupting SNPs, including several high-frequency ones, were found among mutations described in OMIM. PMID- 23640991 TI - Investigation of six testicular germ cell tumor susceptibility genes suggests a parent-of-origin effect in SPRY4. AB - Recent genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with testicular germ cell tumor (TGCT) risk in the genes ATF7IP, BAK1, DMRT1, KITLG, SPRY4 and TERT. In the present study, we validate these associations in a Scandinavian population, and explore effect modification by parental sex and differences in associations between the major histological subtypes seminoma and non-seminoma. A total of 118 SNPs in the six genes were genotyped in a population-based Swedish-Norwegian sample comprising 831 TGCT case-parent triads, 474 dyads, 712 singletons and 3919 population controls. Seven hundred and thirty-four additional SNPs were imputed using reference haplotypes from the 1000 genomes project. SNP-TGCT association was investigated using a likelihood-based association test for nuclear families and unrelated subjects implemented in the software package UNPHASED. Forward stepwise regression within each gene was applied to determine independent association signals. Effect modifications by parent-of-origin and effect differences between histological subtypes were explored. We observed strong association between SNPs in all six genes and TGCT (lowest P-value per gene: ATF7IP 6.2 * 10(-6); BAK1 2.1 * 10(-10); DMRT1 6.7 * 10(-25); KITLG 2.1 * 10(-48); SPRY4 1.4 * 10(-29); TERT 1.8 * 10(-18)). Stepwise regression indicated three independent signals for BAK1 and TERT, two for SPRY4 and one each for DMRT1, ATF7IP and KITLG. A significant parent-of-origin effect was observed for rs10463352 in SPRY4 (maternal odds ratio = 1.72, paternal odds ratio = 0.99, interaction P = 0.0013). No significant effect differences between seminomas and non-seminomas were found. In summary, we validated previously reported genetic associations with TGCT in a Scandinavian population, and observed suggestive evidence of a parent-of-origin effect in SPRY4. PMID- 23640992 TI - Divergence within and among 3 varieties of the endemic tree, 'Ohi'a Lehua (Metrosideros polymorpha) on the eastern slope of Hawai'i Island. AB - Examination of neutral genetic structure within young, hypervariable tree species over heterogeneous landscapes can yield insight into the causes of divergence within trees. Three varieties of the Hawaiian-forest-dominant, Metrosideros polymorpha, occur across the main islands and partition 2 striking environmental gradients on young Hawai'i Island. In an examination of 6 nuclear microsatellite loci across 10 populations on east Hawai'i, we found differentiation among varieties (mean F ST = 0.065; max = 0.081) that exceeded that observed among populations of some continental tree species over much broader spatial scales. High-elevation var. polymorpha exhibited the strongest average differentiation (F ST = 0.071). Weaker differentiation between the early- and late-successional varieties was consistent with previous records of high hybridization between these varieties coupled with differential selection favoring var. incana in early successional or dry environments, and var. glaberrima in late-successional environments. A comparison of within-variety F ST values suggests that active volcanoes shape the genetic structure of early- and late-successional varieties differently. Examination of genetic structure of these same varieties on older islands is required to assess the degree to which the differentiation observed on Hawai'i Island is attributable to multiple colonizations of this young island by partially diverged forms versus divergence in situ. PMID- 23640993 TI - EBV DNA: a Hodgkin lymphoma biomarker? AB - In this issue of Blood, Kanakry and colleagues report that increased pretreatment levels of plasma Epstein Barr virus DNA (EBV-DNA), as determined by quantitative real-time polymerase chain reaction (QRT-PCR), are associated with inferior outcomes among patients with previously untreated, advanced-stage Hodgkin lymphoma. PMID- 23640994 TI - Blocking direct inhibitor bleeding. AB - In this issue of Blood, Schiele et al report the development of a monoclonal antibody that reverses the anticoagulant effect of the direct thrombin inhibitor dabigatran. PMID- 23640995 TI - Pharmacotherapy versus T lymphocytes for CMV. AB - In this issue of Blood, Blyth et al report a phase 2 study in 50 allogeneic hematopoietic stem cell transplant (HSCT) recipients who received donorderived cytomegalovirus (CMV)-specific cytotoxic T cells (CTLs) and compare outcomes with a group of concomitant controls who were transplanted at the trial centers but who did not receive CTLs. PMID- 23640997 TI - Pandey MK, Sung B, Ahn KS, Kunnumakkara AB, Chaturvedi MM, Aggarwal BB. Gambogic acid, a novel ligand for transferrin receptor, potentiates TNF-induced apoptosis through modulation of the nuclear factor-kappaB signaling pathway. Blood. 2007;110(10):3517-3525. PMID- 23640998 TI - Harikumar KB, Kunnumakkara AB, Ahn KS, Anand P, Krishnan S, Guha S, Aggarwal BB. Modification of the cysteine residues in IkappaBalpha kinase and NF-kappaB (p65) by xanthohumol leads to suppression of NF-kappaB-regulated gene products and potentiation of apoptosis in leukemia cells. Blood. 2009;113(9):2003-2013. PMID- 23640996 TI - Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. AB - Recent studies of the spectrum of somatic genetic alterations in acute myeloid leukemia (AML) have identified frequent somatic mutations in genes that encode proteins important in the epigenetic regulation of gene transcription. This includes proteins involved in the modification of DNA cytosine residues and enzymes which catalyze posttranslational modifications of histones. Here we describe the clinical, biological, and therapeutic relevance of mutations in epigenetic regulators in AML. In particular, we focus on the role of loss-of function mutations in TET2, gain-of-function mutations in IDH1 and IDH2, and loss of-function mutations in ASXL1 and mutations of unclear impact in DNMT3A in AML pathogenesis and therapy. Multiple studies have consistently identified that mutations in these genes have prognostic relevance, particularly in intermediate risk AML patients, arguing for inclusion of mutational testing of these genetic abnormalities in routine clinical practice. Moreover, biochemical, biological, and epigenomic analyses of the effects of these mutations have informed the development of novel therapies which target pathways deregulated by these mutations. Our understanding of the effects of these mutations on hematopoiesis and potential for therapeutic targeting of specific AML subsets is also reviewed here. PMID- 23640999 TI - The good death. PMID- 23641002 TI - Dynamic gradients of an intermediate filament-like cytoskeleton are recruited by a polarity landmark during apical growth. AB - Intermediate filament (IF)-like cytoskeleton emerges as a versatile tool for cellular organization in all kingdoms of life, underscoring the importance of mechanistically understanding its diverse manifestations. We showed previously that, in Streptomyces (a bacterium with a mycelial lifestyle similar to that of filamentous fungi, including extreme cell and growth polarity), the IF protein FilP confers rigidity to the hyphae by an unknown mechanism. Here, we provide a possible explanation for the IF-like function of FilP by demonstrating its ability to self-assemble into a cis-interconnected regular network in vitro and its localization into structures consistent with a cytoskeletal network in vivo. Furthermore, we reveal that a spatially restricted interaction between FilP and DivIVA, the main component of the Streptomyces polarisome complex, leads to formation of apical gradients of FilP in hyphae undergoing active tip extension. We propose that the coupling between the mechanism driving polar growth and the assembly of an IF cytoskeleton provides each new hypha with an additional stress bearing structure at its tip, where the nascent cell wall is inevitably more flexible and compliant while it is being assembled and matured. Our data suggest that recruitment of cytoskeleton around a cell polarity landmark is a broadly conserved strategy in tip-growing cells. PMID- 23641004 TI - Chloride binding site of neurotransmitter sodium symporters. AB - Neurotransmitter:sodium symporters (NSSs) play a critical role in signaling by reuptake of neurotransmitters. Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT are chloride-independent but contain an acidic residue (Glu290 in LeuT) at a site where eukaryotic NSSs have a serine. The LeuT E290S mutant displays chloride-dependent activity. We show that, in LeuT-E290S cocrystallized with bromide or chloride, the anion is coordinated by side chain hydroxyls from Tyr47, Ser290, and Thr254 and the side chain amide of Gln250. The bound anion and the nearby sodium ion in the Na1 site organize a connection between their coordinating residues and the extracellular gate of LeuT through a continuous H-bond network. The specific insights from the structures, combined with results from substrate binding studies and molecular dynamics simulations, reveal an anion-dependent occlusion mechanism for NSS and shed light on the functional role of chloride binding. PMID- 23641003 TI - Dnmt2-dependent methylomes lack defined DNA methylation patterns. AB - Several organisms have retained methyltransferase 2 (Dnmt2) as their only candidate DNA methyltransferase gene. However, information about Dnmt2-dependent methylation patterns has been limited to a few isolated loci and the results have been discussed controversially. In addition, recent studies have shown that Dnmt2 functions as a tRNA methyltransferase, which raised the possibility that Dnmt2 only genomes might be unmethylated. We have now used whole-genome bisulfite sequencing to analyze the methylomes of Dnmt2-only organisms at single-base resolution. Our results show that the genomes of Schistosoma mansoni and Drosophila melanogaster lack detectable DNA methylation patterns. Residual unconverted cytosine residues shared many attributes with bisulfite deamination artifacts and were observed at comparable levels in Dnmt2-deficient flies. Furthermore, genetically modified Dnmt2-only mouse embryonic stem cells lost the DNA methylation patterns found in wild-type cells. Our results thus uncover fundamental differences among animal methylomes and suggest that DNA methylation is dispensable for a considerable number of eukaryotic organisms. PMID- 23641006 TI - Long-term impact of cardiac resynchronization therapy in mild heart failure: 5 year results from the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study. AB - BACKGROUND: The benefit of cardiac resynchronization therapy (CRT) among patients with mild heart failure (HF), reduced left ventricular (LV) function and wide QRS is well established. We studied the long-term stability of CRT. METHODS: REVERSE was a randomized, double-blind study on CRT in NYHA Class I and II HF patients with QRS >=120 ms and left ventricular ejection fraction (LVEF) <=40%. After the randomized phase, all were programmed to CRT ON and prospectively followed through 5 years for functional capacity, echocardiography, HF hospitalizations, mortality, and adverse events. We report the results of the 419 patients initially assigned to CRT ON. FINDINGS: The mean follow-up time was 54.8 +/- 13.0 months. After 2 years, the functional and LV remodelling improvements were maximal. The 6-min hall walk increased by 18.8 +/- 102.3 m and the Minnesota and Kansas City scores improved by 8.2 +/- 17.8 and 8.2 +/- 17.2 units, respectively. The mean decrease in left ventricular end-systolic volume index and left ventricular end-diastolic volume index was 23.5 +/- 34.1 mL/m(2) (P < 0.0001) and 25.4 +/- 37.0 mL/m2 (P < 0.0001) and the mean increase in LVEF 6.0 +/- 10.8% (P < 0.0001) with sustained improvement thereafter. The annualized and 5-year mortality was 2.9 and 13.5% and the annualized and 5-year rate of death or first HF hospitalization 6.4, and 28.1%. The 5-year LV lead-related complication rate was 12.5%. CONCLUSION: In patients with mild HF, CRT produced reverse LV remodelling accompanied by very low mortality and need for heart failure hospitalization. These effects were sustained over 5 years. Cardiac resynchronization therapy in addition to optimal medical therapy produces long standing clinical benefits in mild heart failure. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00271154. PMID- 23641008 TI - Scimitar syndrome associated with complete transposition of the great arteries. PMID- 23641009 TI - Preserved ejection fraction can accompany low gradient severe aortic stenosis: impact of pathophysiology on diagnostic imaging. PMID- 23641007 TI - Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. AB - Hyperglycemia and insulin resistance are key players in the development of atherosclerosis and its complications. A large body of evidence suggest that metabolic abnormalities cause overproduction of reactive oxygen species (ROS). In turn, ROS, via endothelial dysfunction and inflammation, play a major role in precipitating diabetic vascular disease. A better understanding of ROS-generating pathways may provide the basis to develop novel therapeutic strategies against vascular complications in this setting. Part I of this review will focus on the most current advances in the pathophysiological mechanisms of vascular disease: (i) emerging role of endothelium in obesity-induced insulin resistance; (ii) hyperglycemia-dependent microRNAs deregulation and impairment of vascular repair capacities; (iii) alterations of coagulation, platelet reactivity, and microparticle release; (iv) epigenetic-driven transcription of ROS-generating and proinflammatory genes. Taken together these novel insights point to the development of mechanism-based therapeutic strategies as a promising option to prevent cardiovascular complications in diabetes. PMID- 23641010 TI - Influence of high cardiovascular risk in asymptomatic people on the duration and cost of sick leave: results of the ICARIA study. AB - AIMS: We investigated the potential influence of a moderate-to-high cardiovascular (CV) risk (CVR) (defined as a Systematic COronary Risk Evaluation model, or SCORE >= 4%), in the absence of an established CV disease, on the duration and cost of CV and non-CV sick leave (SL) resulting from common and occupational accidents or diseases. METHODS AND RESULTS: We conducted a prospective cohort study on 690 135 workers with a 1-year follow-up and examined CV- and non-CV-related SL episodes. To obtain baseline values, CVR factors were initially assessed at the beginning of the year during routine medical examination. The CVR was calculated with the SCORE charts for all subjects. Moderate-to-high CVR was defined as SCORE >= 4%. A baseline SCORE >= 4% was associated with a higher risk for long-term CV and non-CV SL, as revealed by follow-up assessment. This translated into an increased cost, estimated at ?5 801 464.18 per year. Furthermore, pharmacological treatment for hypertension or hyperlipidaemia was significantly associated with longer SL duration. CONCLUSION: Moderate-to-high CVR in asymptomatic subjects was significantly associated with the duration and cost of CV and non-CV SL. These results constitute the first body of evidence that the SCORE charts can be used to identify people with a non established CV disease, which might ultimately translate into more lost workdays and therefore increased cost for society. PMID- 23641011 TI - A jogger with tightness of the chest. PMID- 23641012 TI - Vanishing right ventricular outflow obstruction: an unusual presentation of mediastinal lymphoma. PMID- 23641013 TI - The impact of mechanical circulatory support on outcomes in paediatric heart transplantation. AB - OBJECTIVES: Internationally, the number of donors for cardiac transplantation has remained static, while the number of patients requiring transplantation for congenital heart disease (CHD) has increased. Although the availability of mechanical circulatory support (MCS) may increase the number of transplants performed by reducing deaths while waiting, it may also lead to increased morbidity post-transplantation. We sought to assess the impact of mechanical support on post-transplant outcomes in a single centre. METHODS: We assessed the outcomes of paediatric (age <=16 years) heart transplantation in a single unit in the era of mechanical support (1998-2012) by retrospective cohort study. Outcomes before (1998-2005) and after (2005-2012) the routine use of the Berlin Heart EXCOR device were contrasted. RESULTS: A total of 167 patients underwent heart transplantation during this period. The diagnosis was dilated cardiomyopathy in 61.7%, two-ventricle CHD in 11.4%, single ventricle CHD in 16.8% and miscellaneous in 10.1%. Sixty-nine (41%) were bridged to transplant by mechanical support; with extracorporeal membrane oxygenation in 19 (28%), ventricular assist device in 40 (58%) and a combination in 10 (14.0%). Post-transplant mortality at 30 days was significantly greater in those supported by MCS than without (7 vs 1%, P < 0.05), and a greater proportion of patients had neurological (23 vs 8%, P < 0.01) and major respiratory sequelae (20 vs 4%, P < 0.001). There was no significant increase in the need for post-transplant mechanical support (10 vs 6%, P = 0.3) in those supported prior to transplant. The number of transplants performed increased from 67 in 1998-2005 to 100 in the most recent era (2005 2012), and an increased proportion of these patients have been supported mechanically prior to transplantation (51 vs 27%, P < 0.01). CONCLUSION: Along with strategies to increase donor utilization, MCS has allowed an increase in cardiac transplant activity at the expense of a higher early mortality and morbidity. PMID- 23641014 TI - Development of a novel redirected T-cell-based adoptive immunotherapy targeting human telomerase reverse transcriptase for adult T-cell leukemia. AB - Although adult T-cell leukemia (ATL) has a poor prognosis, successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) in some cases suggests that a cellular immune-mediated strategy can be effective. So far, however, no effective target for anti-ATL immunotherapy has been defined. Here we demonstrated for the first time that human telomerase reverse transcriptase (hTERT) is a promising therapeutic target for ATL, and we developed a novel redirected T-cell-based immunotherapy targeting hTERT. hTERT messenger RNA was produced abundantly in ATL tumor cells but not in steady-state normal cells. Rearranged human leukocyte antigen-A*24:02 (HLA-A*24:02) -restricted and hTERT461-469 nonameric peptide specific T-cell receptor (TCR) alpha/beta genes were cloned from our previously established cytotoxic T lymphocyte clone (K3-1) and inserted into a novel retroviral TCR expression vector encoding small interfering RNAs for endogenous TCR genes in redirected T cells (hTERT-siTCR vector). Consequently, allogeneic or autologous gene-modified CD8(+) T cells prepared using the hTERT-siTCR vector successfully killed ATL tumor cells, but not normal cells including steady-state hematopoietic progenitors, in an HLA-A*24:02-restricted manner both in vitro and in vivo. Our experimental observations support the development of a novel hTERT targeting redirected T-cell-based adoptive immunotherapy for ATL patients, especially those for whom suitable allo-HSCT donors are lacking. PMID- 23641015 TI - Trends in survival of patients with Burkitt lymphoma/leukemia in the USA: an analysis of 3691 cases. AB - It is unknown whether the high rates of cure reported for Burkitt lymphoma/leukemia (BL) patients treated with chemoimmunotherapy can be verified outside published series and clinical trials. We used the Surveillance Epidemiology and End Results (SEER) database to describe time trends in outcomes of BL in the United States. Cases were divided into 2 eras based on year of diagnosis, reflecting improvements in HIV management, BL treatment, and supportive care. There was a marked improvement in survival among BL cases diagnosed in the 2002-2008 era (n = 1922) relative to 1973-2001 (n = 1769) with 5 year relative survival estimates of 56% and 43%, respectively (P < .001). Five year relative survival improved from 71% to 87% for ages 0 to 19 (n = 970), 35% to 60% for ages 20 to 39 (n = 897), 28% to 48% for ages 40 to 59 (n = 1047), and from 25% to 33% for ages >=60 (n = 777). In multivariable analysis, the 2002-2008 era (HR = 0.76, P < .001) was associated with lower mortality. Conversely, older age, black race, and advanced stage were associated with higher mortality. More effective therapies are needed for older patients with BL, along with improved access to modern therapy for younger patients. PMID- 23641017 TI - Associations of TSH levels within the reference range with future blood pressure and lipid concentrations: 11-year follow-up of the HUNT study. AB - OBJECTIVE: In cross-sectional studies, TSH levels within the reference range have been positively associated with blood pressure and adverse serum lipid levels. In a prospective study, we aimed to determine whether differences in TSH levels within the reference range are associated with future levels of blood pressure and lipids. DESIGN: We conducted a prospective population-based study. METHODS: In 9709 women and 4644 men without previous thyroid disease who had a baseline TSH level of 0.45-4.5 mU/l, we studied the associations of baseline TSH levels with blood pressure and lipid levels at follow-up 11 years later. RESULTS: Higher TSH levels at baseline were associated with higher systolic (P=0.002 in women) and diastolic (P=0.03 in women) blood pressure, non-HDL cholesterol (P=0.01 in men) and triglyceride (P=0.008 in men) levels and lower HDL cholesterol levels (P<0.001 in women and men) at follow-up, but the associations were very modest and not consistent between the sexes. Among people who remained free of thyroid disease, changes in TSH levels during follow-up were associated with concomitant changes in systolic and diastolic blood pressure, non-HDL cholesterol and triglyceride levels (all P<0.001), with similar results being observed for women and men. Thus, blood pressure and lipid levels increased among people with an increase in TSH levels and decreased among people with a decrease in TSH levels compared with people with no change in TSH levels. CONCLUSIONS: High TSH levels within the reference range may be associated with modestly higher future levels of blood pressure and adverse serum lipids. TSH levels may co-vary with blood pressure and lipid levels among people with apparently normal thyroid function. PMID- 23641016 TI - Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. AB - Cancer-associated isocitrate dehydrogenase (IDH) mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of 2HG has not been established. We studied whether 2HG measurements in acute myeloid leukemia (AML) patients correlate with IDH mutations, and whether diagnostic or remission 2HG measurements predict survival. Sera from 223 de novo AML patients were analyzed for 2HG concentration by reverse-phase liquid chromatography-mass spectrometry. Pretreatment 2HG levels ranged from 10 to 30 000 ng/mL and were elevated in IDH mutants (median, 3004 ng/mL), compared to wild-type IDH (median, 61 ng/mL) (P < .0005). 2HG levels did not differ among IDH1 or IDH2 allelic variants. In receiver operating characteristic analysis, a discriminatory level of 700 ng/mL optimally segregated patients with and without IDH mutations, and on subsequent mutational analysis of the 13 IDH wild-type samples with 2HG levels >700 ng/mL, 9 were identified to have IDH mutations. IDH-mutant patients with 2HG levels >200 at complete remission had shorter overall survival compared to 2HG <=200 ng/mL (hazard ratio, 3.9; P = .02). We establish a firm association between IDH mutations and serum 2HG concentration in AML, and confirm that serum oncometabolite measurements provide useful diagnostic and prognostic information that can improve patient selection for IDH-targeted therapies. PMID- 23641018 TI - Surgery for adrenocortical carcinoma in The Netherlands: analysis of the national cancer registry data. AB - OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare disease with an estimated incidence of one to two cases per 1 million inhabitants. The Dutch Adrenal Network (DAN) was initiated with the aim to improve patient care and to stimulate scientific research on ACC. Currently, not all patients with ACC are treated in specialized DAN hospitals. The objective of the current investigation was to determine whether there are differences in survival between patients operated on in DAN hospitals and those operated on in non-DAN hospitals. DESIGN: The study was set up as a retrospective and population-based survival analysis. METHODS: Data on all adult ACC patients diagnosed between 1999 and 2009 were obtained from The Netherlands Cancer Registry (NCR). Overall survival was calculated and a comparison was made between DAN and non-DAN hospitals. RESULTS: The NCR contained data of 189 patients. The median survival of patients with European Network for the Study of Adrenal Tumors stages I-III disease was significantly longer for patients operated on in a DAN hospital (n=46) than for those operated on in a non DAN hospital (n=37, 5-year survival 63 vs 42%). Survival remained significantly different after correction for sex, age, year of diagnosis, and stage of disease in the multivariate analysis (hazard ratio 1.96 (95% CI 1.01-3.81), P=0.047). CONCLUSION: The results associate surgery in a DAN center with a survival benefit for patients with local or locally advanced ACC. We hypothesize that a multidisciplinary approach for these patients explains the observed survival benefit. These findings should be carefully considered in view of the aim for further centralization of ACC treatment. PMID- 23641019 TI - Fatal neurological respiratory insufficiency is common among viral encephalitides. AB - BACKGROUND: Neurological respiratory insufficiency strongly correlates with mortality among rodents infected with West Nile virus (WNV), which suggests that this is a primary mechanism of death in rodents and possibly fatal West Nile neurological disease in human patients. METHODS: To explore the possibility that neurological respiratory insufficiency is a broad mechanism of death in cases of viral encephalitis, plethysmography was evaluated in mice infected with 3 flaviviruses and 2 alphaviruses. Pathology was investigated by challenging the diaphragm, using electromyography with hypercapnia and optogenetic photoactivation. RESULTS: Among infections due to all but 1 alphavirus, death was strongly associated with a suppressed minute volume. Virally infected mice with a very low minute volume did not neurologically respond to hypercapnia or optogenetic photoactivation of the C4 cervical cord. Neurons with the orexin 1 receptor protein in the ventral C3-5 cervical cord were statistically diminished in WNV-infected mice with a low minute volume as compared to WNV-infected or sham infected mice without respiratory insufficiency. Also, WNV-infected cells were adjacent to neurons with respiratory functions in the medulla. CONCLUSIONS: Detection of a common neurological mechanism of death among viral encephalitides creates opportunities to create broad-spectrum therapies that target relevant neurological cells in patients with types of viral encephalitis that have not been treatable in the past. PMID- 23641022 TI - The method of removing hardly soluble organic material from metallic specimen used in fracture surface analysis by scanning electron microscope. AB - Epoxy resin attached to a fatigue fracture surface of Ti-Al-Nb alloy was removed using a removal method for hardly soluble organic material attached to metallic material, which has been developed by the author. In the removal method process, the epoxy resin attached to the fracture surface was treated with an organic solvent, 'tetrahydrofuran', and cold concentrated sulfuric acid of nearly 100% purity. After the epoxy resin was removed from the fracture surface with the removal method, damage of the microscopic feature of the fracture surface was investigated using a scanning electron microscope (SEM). For the first time, the degree of the removal of the epoxy resin with the method was investigated by energy dispersive X-ray spectroscopy (EDS) in this research. After the removal, no damage of the fracture surface was found with SEM observation. In addition, C Kalpha derived from the epoxy resin was not detected with the EDS after removal. The result of the EDS analysis clarified that the epoxy resin was completely removed with the removal method. PMID- 23641020 TI - Adjuvant host-directed therapy with types 3 and 5 but not type 4 phosphodiesterase inhibitors shortens the duration of tuberculosis treatment. AB - BACKGROUND: Shortening tuberculosis treatment could significantly improve patient adherence and decrease the development of drug resistance. Phosphodiesterase inhibitors (PDE-Is) have been shown to be beneficial in animal models of tuberculosis. We assessed the impact of PDE-Is on the duration of treatment in tuberculous mice. METHODS: We analyzed the time to death in Mycobacterium tuberculosis-infected mice receiving type 4 PDE-Is (rolipram and cilomilast) and the impact on bacterial burden, time to clearance, and relapse when types 3 and 5 PDE-Is (cilostazol and sildenafil, respectively) and rolipram were added to the standard treatment. We investigated pharmacokinetic interactions between PDE-Is (cilostazol and sildenafil) and rifampin. RESULTS: The type 4 PDE-Is rolipram and cilomilast accelerated the time to death in tuberculous mice. The addition of rolipram to standard tuberculosis treatment increased bacterial burden and did not decrease the time to bacterial clearance in the lung, while the addition of the cilostazol and sildenafil reduced the time to clearance by 1 month. Cilostazol and sildenafil did not have negative pharmacokinetic interactions with rifampin. CONCLUSIONS: Type 4 PDE-Is may increase the severity of tuberculosis and should be carefully investigated for use in patients with latent or active tuberculosis. Cilostazol and sildenafil may benefit tuberculosis patients by shortening the duration of therapy. PMID- 23641021 TI - Daily rhythms of glycerophospholipid synthesis in fibroblast cultures involve differential enzyme contributions. AB - Circadian clocks regulate the temporal organization of several biochemical processes, including lipid metabolism, and their disruption leads to severe metabolic disorders. Immortalized cell lines acting as circadian clocks display daily variations in [(32)P]phospholipid labeling; however, the regulation of glycerophospholipid (GPL) synthesis by internal clocks remains unknown. Here we found that arrested NIH 3T3 cells synchronized with a 2 h-serum shock exhibited temporal oscillations in a) the labeling of total [(3)H] GPLs, with lowest levels around 28 and 56 h, and b) the activity of GPL-synthesizing and GPL-remodeling enzymes, such as phosphatidate phosphohydrolase 1 (PAP-1) and lysophospholipid acyltransferases (LPLAT), respectively, with antiphase profiles. In addition, we investigated the temporal regulation of phosphatidylcholine (PC) biosynthesis. PC is mainly synthesized through the Kennedy pathway with choline kinase (ChoK) and CTP:phosphocholine cytidylyltranferase (CCT) as key regulatory enzymes. We observed that the PC labeling exhibited daily changes, with the lowest levels every ~28 h, that were accompanied by brief increases in CCT activity and the oscillation in ChoK mRNA expression and activity. Results demonstrate that the metabolisms of GPLs and particularly of PC in synchronized fibroblasts are subject to a complex temporal control involving concerted changes in the expression and/or activities of specific synthesizing enzymes. PMID- 23641023 TI - Cost collection and analysis for health economic evaluation. AB - OBJECTIVE: To improve the understanding of common health care cost collection, estimation, analysis, and reporting methodologies. DATA SOURCES: Ovid MEDLINE (1947 to December 2012), Cochrane Central register of Controlled Trials, Database of Systematic Reviews, Health Technology Assessment, and National Health Service Economic Evaluation Database. REVIEW METHODS: This article discusses the following cost collection methods: defining relevant resources, quantification of consumed resources, and resource valuation. It outlines the recommendations for cost reporting in economic evaluations and reviews the techniques on how to handle cost data uncertainty. Last, it discusses the controversial topics of future costs and patient productivity losses. CONCLUSION: Health care cost collection and estimation can be challenging, and an organized approach is required to optimize accuracy of economic evaluation outcomes. IMPLICATIONS FOR PRACTICE: Understanding health care cost collection and estimation techniques will improve both critical appraisal and development of future economic evaluations. PMID- 23641024 TI - Implementation of shared decision making in physical therapy: observed level of involvement and patient preference. AB - BACKGROUND: Shared decision making (SDM) reduces the asymmetrical power between the therapist and the patient. Patient involvement improves patient satisfaction, adherence, and health outcomes and is a prerequisite for good clinical practice. The opportunities for using SDM in physical therapy have been previously considered. OBJECTIVE: The objective of this study was to examine the status of SDM in physical therapy, patients' preferred levels of involvement, and the agreement between therapist perception and patient preferred level of involvement. DESIGN: This was an observational study of real consultations in physical therapy. METHODS: In total, 237 consultations, undertaken by 13 physical therapists, were audiorecorded, and 210 records were analyzed using the Observing Patient Involvement (OPTION) instrument. Before the consultation, the patient and therapist completed the Control Preference Scale (CPS). Multilevel analysis was used to study the association between individual variables and the level of SDM. Agreement on preferences was calculated using kappa coefficients. RESULTS: The mean OPTION score was 5.2 (SD=6.8), out of a total score of 100. Female therapists achieved a higher OPTION score (b=-0.86, P=0.01). In total, 36.7% of the patients wanted to share decisions, and 36.2% preferred to give their opinion before delegating the decisions. In the majority of cases, therapists believed that they had to decide. The kappa coefficient for agreement was poor at .062 (95% confidence interval=-.018 to .144). LIMITATIONS: Only 13 out of 125 therapists who were personally contacted agreed to participate. CONCLUSION: Shared decision making was not applied; although patients preferred to share decisions or at least provide their opinion about the treatment, physical therapists did not often recognize this factor. The participating physical therapists were more likely to make decisions in the best interest of their patients; that is, these therapists tended to apply a paternalistic approach rather than involving the patient. PMID- 23641025 TI - Quality in physical therapist clinical education: a systematic review. AB - BACKGROUND: Many factors affect student learning throughout the clinical education (CE) component of professional (entry-level) physical therapist education curricula. Physical therapist education programs (PTEPs) manage CE, yet the material and human resources required to provide CE are generally overseen by community-based physical therapist practices. PURPOSE: The purposes of this systematic review were: (1) to examine how the construct of quality is defined in CE literature and (2) to determine the methodological rigor of the available evidence on quality in physical therapist CE. METHODS: This study was a systematic review of English-language journals using the American Physical Therapy Association's Open Door Portal to Evidence-Based Practice as the computer search engine. The search was categorized using terms for physical therapy and quality and for CE pedagogy and models or roles. Summary findings were characterized by 5 primary themes and 14 subthemes using a qualitative-directed content analysis. RESULTS: Fifty-four articles were included in the study. The primary quality themes were: CE framework, CE sites, structure of CE, assessment in CE, and CE faculty. The methodological rigor of the studies was critically appraised using a binary system based on the McMaster appraisal tools. Scores ranged from 3 to 14. LIMITATIONS: Publication bias and outcome reporting bias may be inherent limitations to the results. CONCLUSION: The review found inconclusive evidence about what constitutes quality or best practice for physical therapist CE. Five key constructs of CE were identified that, when aggregated, could construe quality. PMID- 23641026 TI - Validity of the dynamic gait index in people with multiple sclerosis. AB - BACKGROUND: Evaluation of walking capacity and risk of falls in people with multiple sclerosis often are performed in rehabilitation. The Dynamic Gait Index (DGI) evaluates walking during different tasks, but the feasibility in identifying people at risk for falls needs to be further investigated. OBJECTIVE: The objective of this study was to investigate (1) the construct validity (known groups, convergent, and discriminant) of the DGI and (2) the accuracy of predicting falls and establishing a cutoff point to identify fallers. DESIGN: This trial was a multicenter, cross-sectional study. METHODS: A convenience sample was composed of 81 people with multiple sclerosis with subjective gait and balance impairment who were able to walk 100 m (comparable to Expanded Disability Status Scale 1-6). Mean age of the participants was 49 years; 76% were women. The 25-Foot Timed Walk Test, Timed "Up & Go" Test, Four Square Step Test, Timed Sit to-Stand Test, MS Walking Scale, Multiple Sclerosis Impact Scale, and self reported falls during the previous 2 months were used for validation, to establish cutoff points for identifying fallers, and to investigate predictive values. RESULTS: Significantly lower DGI scores (P<=.001) were found for participants reporting falls (n=31). High sensitivity (87%) in identifying fallers was found, with a cutoff score <=19. The positive predictive value was 50%, and the negative predictive value was 87%. The positive likelihood ratio was 1.77, and the negative likelihood ratio was 0.26. The convergent validity was moderate to strong (rho=0.58-0.80), with the highest correlation coefficient found for the 25-Foot Timed Walk Test. Discriminant validity was shown with low correlation for the psychological subscale of the Multiple Sclerosis Impact Scale. LIMITATIONS: The sample included ambulatory people participating in a randomized controlled trial investigating balance training. CONCLUSIONS: The DGI is a valid measure of dynamic balance during walking for ambulatory people with multiple sclerosis. With the cutoff point of <=19, sensitivity was high in identifying people at risk of falls. PMID- 23641027 TI - Comparative kinematic and electromyographic assessment of clinician- and device assisted sit-to-stand transfers in patients with stroke. AB - BACKGROUND: Workplace injuries from patient handling are prevalent. With the adoption of no-lift policies, sit-to-stand transfer devices have emerged as one tool to combat injuries. However, the therapeutic value associated with sit-to stand transfers with the use of an assistive apparatus cannot be determined due to a lack of evidence-based data. OBJECTIVE: The aim of this study was to compare clinician-assisted, device-assisted, and the combination of clinician- and device assisted sit-to-stand transfers in individuals who recently had a stroke. DESIGN: This cross-sectional, controlled laboratory study used a repeated-measures design. METHODS: The duration, joint kinematics, and muscle activity of 4 sit-to stand transfer conditions were compared for 10 patients with stroke. Each patient performed 4 randomized sit-to-stand transfer conditions: clinician-assisted, device-assisted with no patient effort, device-assisted with the patient's best effort, and device- and clinician-assisted. RESULTS: Device-assisted transfers took nearly twice as long as clinician-assisted transfers. Hip and knee joint movement patterns were similar across all conditions. Forward trunk flexion was lacking and ankle motion was restrained during device-assisted transfers. Encouragement and guidance from the clinician during device-assisted transfers led to increased lower extremity muscle activation levels. LIMITATIONS: One lifting device and one clinician were evaluated. Clinician effort could not be controlled. CONCLUSIONS: Lack of forward trunk flexion and restrained ankle movement during device-assisted transfers may dissuade clinicians from selecting this device for use as a dedicated rehabilitation tool. However, with clinician encouragement, muscle activation increased, which suggests that it is possible to safely practice transfers while challenging key leg muscles essential for standing. Future sit-to-stand devices should promote safety for the patient and clinician and encourage a movement pattern that more closely mimics normal sit-to stand biomechanics. PMID- 23641028 TI - Structure of the physical therapy benefit in a typical Blue Cross Blue Shield preferred provider organization plan available in the individual insurance market in 2011. AB - BACKGROUND: The Affordable Care Act of 2010 establishes American Health Benefit Exchanges. The benefit design of insurance plans in state health insurance exchanges will be based on the structure of existing small-employer-sponsored plans. OBJECTIVE: The purpose of this study was to describe the structure of the physical therapy benefit in a typical Blue Cross Blue Shield (BCBS) preferred provider organization (PPO) health insurance plan available in the individual insurance market in 2011. DESIGN: A cross-sectional survey design was used. METHODS: The physical therapy benefit within 39 BCBS PPO plans in 2011 was studied for a standard consumer with a standard budget. First, whether physical therapy was a benefit in the plan was determined. If so, then the structure of the benefit was described in terms of whether the physical therapy benefit was a stand-alone benefit or part of a combined-discipline benefit and whether a visit or financial limit was placed on the physical therapy benefit. RESULTS: Physical therapy was included in all BCBS plans that were studied. Ninety-three percent of plans combined physical therapy with other disciplines. Two thirds of plans placed a limit on the number of visits covered. LIMITATIONS: The results of the study are limited to 1 standard consumer, 1 association of insurance companies, 1 form of insurance (a PPO), and 1 PPO plan in each of the 39 states that were studied. CONCLUSIONS: Physical therapy is a covered benefit in a typical BCBS PPO health insurance plan. Physical therapy most often is combined with other therapy disciplines, and the number of covered visits is limited in two thirds of plans. PMID- 23641029 TI - Factors associated with utilization of preoperative and postoperative rehabilitation services by patients with amputation in the VA system: an observational study. AB - BACKGROUND: The Department of Veterans Affairs (VA) and the Department of Defense published evidence-based guidelines to standardize and improve rehabilitation of veterans with lower limb amputations; however, no studies have examined the guidelines' impact. OBJECTIVES: The purposes of this study were: (1) to describe the utilization of rehabilitative services in the acute care setting by people who underwent major lower limb amputation in the VA from 2005 to 2010, (2) to identify factors associated with receipt of rehabilitation services, and (3) to examine the impact of the guidelines on service receipt. DESIGN: A cross sectional study of 12,599 patients, who underwent major surgical amputation of the lower limb at a VA medical center from January 1, 2005, to December 31, 2010, was conducted. Data were obtained from main and surgical inpatient datasets and the inpatient encounters files of the Veterans Health Administration databases. METHODS: Rehabilitation services were categorized as physical therapy, occupational therapy, and either (any therapy), before or after amputation. Separate multivariate logistic regressions examined the impact of guideline implementation and identified factors associated with service receipt. RESULTS: Patients were 1.45 and 1.73 times more likely to receive preoperative physical therapy and occupational therapy and 1.68 and 1.79 times more likely to receive postoperative physical therapy and occupational therapy after guideline implementation. Patients in the Northeast had the lowest likelihood of receiving preoperative and postoperative rehabilitation services, whereas patients in the West had the highest likelihood. Other patient characteristics associated with service receipt were identified. LIMITATIONS: The sample included only veterans who had surgeries at VA Medical Centers and cannot be generalized to veterans with surgeries outside the VA or to nonveteran patients and settings. CONCLUSIONS: Further quality improvement efforts are needed to standardize delivery of rehabilitation services for veterans with amputations in the acute care setting. PMID- 23641030 TI - The role of U.S. military physical therapists during recent combat campaigns. AB - U.S. military physical therapists have a proud history of providing medical care during operational deployments ranging from war to complex humanitarian emergencies. Regardless of austerity of environment or intensity of hostility, U.S. military physical therapists serve as autonomous providers, evaluating and treating service members with and without physician referral. This perspective article suggests that the versatility of U.S. military physical therapist practice enables them not only to diagnose musculoskeletal injuries but also to provide a wide range of definitive care and rehabilitation, reducing the need for costly evacuation. War is not sport, but the delivery of skilled musculoskeletal physical therapy services as close to the point of injury as possible parallels the sports medicine model for on- or near-field practice. This model that mixes direct access with near-immediate access enhances outcomes, reduces costs, and allows other health care team members to work at the highest levels of their licensure. PMID- 23641032 TI - Better management of patients with multimorbidity. PMID- 23641031 TI - What makes transcutaneous electrical nerve stimulation work? Making sense of the mixed results in the clinical literature. AB - Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacological treatment for control of pain. It has come under much scrutiny lately with the Center for Medicare Services rendering a recent decision stating that "TENS is not reasonable and necessary for the treatment of CLBP [chronic low back pain]." When reading and analyzing the existing literature for which systematic reviews show that TENS is inconclusive or ineffective, it is clear that a number of variables related to TENS application have not been considered. Although many of the trials were designed with the highest of standards, recent evidence suggests that factors related to TENS application need to be considered in an assessment of efficacy. These factors include dosing of TENS, negative interactions with long-term opioid use, the population and outcome assessed, timing of outcome measurement, and comparison groups. The purpose of this perspective is to highlight and interpret recent evidence to help improve the design of clinical trials and the efficacy of TENS in the clinical setting. PMID- 23641034 TI - Metabolic alkalosis in a patient with dyspnoea. PMID- 23641033 TI - Derivation and validation of QStroke score for predicting risk of ischaemic stroke in primary care and comparison with other risk scores: a prospective open cohort study. AB - OBJECTIVE: To develop and validate a risk algorithm (QStroke) to estimate risk of stroke or transient ischaemic attack in patients without prior stroke or transient ischaemic attack at baseline; to compare (a) QStroke with CHADS2 and CHA2DS2VASc scores in patients with atrial fibrillation and (b) the performance of QStroke with the Framingham stroke score in the full population free of stroke or transient ischaemic attack. DESIGN: Prospective open cohort study using routinely collected data from general practice during the study period 1 January 1998 to 1 August 2012. SETTING: 451 general practices in England and Wales contributing to the national QResearch database to develop the algorithm and 225 different QResearch practices to validate the algorithm. PARTICIPANTS: 3.5 million patients aged 25-84 years with 24.8 million person years in the derivation cohort who experienced 77,578 stroke events. For the validation cohort, we identified 1.9 million patients aged 25-84 years with 12.7 million person years who experienced 38,404 stroke events. We excluded patients with a prior diagnosis of stroke or transient ischaemic attack and those prescribed oral anticoagulants at study entry. MAIN OUTCOME MEASURES: Incident diagnosis of stroke or transient ischaemic attack recorded in general practice records or linked death certificates during follow-up. RISK FACTORS: Self assigned ethnicity, age, sex, smoking status, systolic blood pressure, ratio of total serum cholesterol to high density lipoprotein cholesterol concentrations, body mass index, family history of coronary heart disease in first degree relative under 60 years, Townsend deprivation score, treated hypertension, type 1 diabetes, type 2 diabetes, renal disease, rheumatoid arthritis, coronary heart disease, congestive cardiac failure, valvular heart disease, and atrial fibrillation RESULTS: The QStroke algorithm explained 57% of the variation in women and 55% in men without a prior stroke. The D statistic for QStroke was 2.4 in women and 2.3 in men. QStroke had improved performance on all measures of discrimination and calibration compared with the Framingham score in patients without a prior stroke. Among patients with atrial fibrillation, levels of discrimination were lower, but QStroke had some improved performance on all measures of discrimination compared with CHADS2 and CHA2DS2VASc. CONCLUSION: QStroke provides a valid measure of absolute stroke risk in the general population of patients free of stroke or transient ischaemic attack as shown by its performance in a separate validation cohort. QStroke also shows some improvement on current risk scoring methods, CHADS2 and CHA2DS2VASc, for the subset of patients with atrial fibrillation for whom anticoagulation may be required. Further research is needed to evaluate the cost effectiveness of using these algorithms in primary care. PMID- 23641035 TI - Nearly half of UK young doctors say stress levels rose last year. PMID- 23641036 TI - Bone morphogenetic protein 15 and fibroblast growth factor 10 enhance cumulus expansion, glucose uptake, and expression of genes in the ovulatory cascade during in vitro maturation of bovine cumulus-oocyte complexes. AB - Oocyte-secreted factors (OSFs) regulate differentiation of cumulus cells and are of pivotal relevance for fertility. Bone morphogenetic protein 15 (BMP15) and fibroblast growth factor 10 (FGF10) are OSFs and enhance oocyte competence by unknown mechanisms. We tested the hypothesis that BMP15 and FGF10, alone or combined in the maturation medium, enhance cumulus expansion and expression of genes in the preovulatory cascade and regulate glucose metabolism favouring hyaluronic acid production in bovine cumulus-oocyte complexes (COCs). BMP15 or FGF10 increased the percentage of fully expanded COCs, but the combination did not further stimulate it. BMP15 increased cumulus cell levels of mRNA encoding a disintegrin and metalloprotease 10 (ADAM10), ADAM17, amphiregulin (AREG), and epiregulin (EREG) at 12 h of culture and of prostaglandin (PG)-endoperoxide synthase 2 (PTGS2), pentraxin 3 (PTX3) and tumor necrosis factor alpha-induced protein 6 (TNFAIP6 (TSG6)) at 22 h of culture. FGF10 did not alter the expression of epidermal growth factor-like factors but enhanced the mRNA expression of PTGS2 at 4 h, PTX3 at 12 h, and TNFAIP6 at 22 h. FGF10 and BMP15 stimulated glucose consumption by cumulus cells but did not affect lactate production or levels of mRNA encoding glycolytic enzymes phosphofructokinase and lactate dehydrogenase A. Each growth factor increased mRNA encoding glucosamine:fructose-6-PO4 transaminases, key enzymes in the hexosamine pathway leading to hyaluronic acid production, and BMP15 also stimulated hyaluronan synthase 2 (HAS2) mRNA expression. This study provides evidence that BMP15 and FGF10 stimulate expansion of in vitro-matured bovine COCs by driving glucose metabolism toward hyaluronic acid production and controlling the expression of genes in the ovulatory cascade, the first acting upon ADAM10, ADAM17, AREG, and EREG and the second on downstream genes, particularly PTGS2. PMID- 23641037 TI - Report shows wide variation in intrapartum care in England. PMID- 23641038 TI - Effect of gender on clinical presentation in systemic lupus erythematosus. AB - The incidence of SLE is markedly increased in females of child-bearing age. Although males are protected in terms of incidence of disease, it is unclear whether a distinct phenotype of male lupus exists in those who do develop SLE. We sought to explore through a detailed literature review whether gender exerts an influence on the clinical presentation and outcome of SLE. We found that males experience less of the typical mucocutaneous and musculoskeletal symptoms commonly present at diagnosis in women. On the other hand, there is limited evidence to support a negative prognostic association between male gender and disease activity or mortality. PMID- 23641040 TI - Resolving the ductal carcinoma in situ treatment conundrum. PMID- 23641039 TI - A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. AB - BACKGROUND: For women with ductal carcinoma in situ (DCIS) of the breast, the risk of developing an ipsilateral breast event (IBE; defined as local recurrence of DCIS or invasive carcinoma) after surgical excision without radiation is not well defined by clinical and pathologic characteristics. METHODS: The Oncotype DX breast cancer assay was performed for patients with DCIS treated with surgical excision without radiation in the Eastern Cooperative Oncology Group (ECOG) E5194 study. The association of the prospectively defined DCIS Score (calculated from seven cancer-related genes and five reference genes) with the risk of developing an IBE was analyzed using Cox regression. All statistical tests were two-sided. RESULTS: There were 327 patients with adequate tissue for analysis. The continuous DCIS Score was statistically significantly associated with the risk of developing an IBE (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.15 to 4.49; P = .02) when adjusted for tamoxifen use (prespecified primary analysis) and with invasive IBE (unadjusted HR = 3.68, 95% CI = 1.34 to 9.62; P = .01). For the prespecified DCIS risk groups of low, intermediate, and high, the 10-year risks of developing an IBE were 10.6%, 26.7%, and 25.9%, respectively, and for an invasive IBE, 3.7%, 12.3%, and 19.2%, respectively (both log rank P <= .006). In multivariable analyses, factors associated with IBE risk were DCIS Score, tumor size, and menopausal status (all P <= .02). CONCLUSIONS: The DCIS Score quantifies IBE risk and invasive IBE risk, complements traditional clinical and pathologic factors, and provides a new clinical tool to improve selecting individualized treatment for women with DCIS who meet the ECOG E5194 criteria. PMID- 23641041 TI - A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ. PMID- 23641042 TI - Re: Annual report to the nation on the status of cancer, 1975-2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels and Re: Inequalities in human papillomavirus (HPV) associated cancers: implications for the success of HPV vaccination. PMID- 23641043 TI - Molecular profiling diagnosis in unknown primary cancer: accuracy and ability to complement standard pathology. AB - BACKGROUND: Molecular tumor profiling (MTP) is a potentially powerful diagnostic tool for identifying the tissue of origin in patients with cancer of unknown primary (CUP). However, validation of the accuracy and clinical value of MTP has been difficult because the anatomic primary site in most patients is never identified. METHODS: From March 2008 through January 2010, clinicopathologic data from 171 CUP patients who had MTP (CancerTYPE ID; bioTheranostics, Inc, San Diego, CA) performed on archived material were evaluated. The accuracy of MTP diagnoses was evaluated by comparison with (1) latent primary tumor sites found months/years later; (2) initial single diagnoses by immunohistochemistry (IHC); and (3) additional directed IHC and/or clinicopathologic findings evaluated after MTP diagnoses. RESULTS: A single MTP diagnosis was made in 144 of 149 patients with adequate tumor specimens. Eighteen of 24 patients with latent primaries discovered months to years later had correct diagnoses by MTP (75%), and these diagnoses compared favorably with IHC. Single IHC diagnoses matched MTP diagnoses in 40 of 52 patients (77%). IHC predictions of 2 or more possible primaries compared poorly with MTP diagnoses. However, additional targeted IHC and clinical/histologic evaluation supported the MTP diagnosis in 26 of 35 patients (74%). Clinical features were usually consistent with MTP diagnoses (70%). CONCLUSIONS: The diagnostic accuracy of this MTP assay was supported by a high level of agreement with identified latent primaries (75%), single IHC diagnoses (77%), and additional directed IHC and/or clinical/histologic findings (74%) prompted by the MTP diagnoses. MTP complements standard pathologic evaluation in determining the tissue of origin in patients with CUP, particularly when IHC is inconclusive. PMID- 23641044 TI - A primary approach to cancers of unknown primary. PMID- 23641045 TI - Medical council asks India's Central Bureau of Investigation to investigate scam of bidding for postgraduate places. PMID- 23641046 TI - Cancer risk before schizophrenia diagnosis in Taiwan, 1995-2009. PMID- 23641049 TI - European regulator is ordered not to release clinical study documents. PMID- 23641050 TI - Most religious followers support assisted suicide for the dying. PMID- 23641047 TI - Meta-analysis of olfactory function in schizophrenia, first-degree family members, and youths at-risk for psychosis. AB - BACKGROUND: Previous research has provided compelling support for olfactory dysfunction in schizophrenia patients, their first-degree relatives, and youth at risk for psychosis. A previous meta-analysis revealed large effect sizes across olfactory tasks but was limited to 2 olfactory tasks and did not examine moderator variables. Thus, the current meta-analysis was undertaken to incorporate additional studies, risk cohorts, olfactory test domains, and moderator variable analyses. METHOD: A meta-analysis was conducted on 67 publications examining olfactory function in schizophrenia patients and 15 publications examining olfactory functioning in youth at-risk for psychosis, first-degree relatives of schizophrenia patients, and individuals with schizotypy. RESULTS: Results revealed medium-to-large olfactory deficits in schizophrenia patients though significant heterogeneity was evident. Several variables moderated overall study effects. At-risk youths similarly demonstrated medium-to-large effect sizes, whereas first-degree relatives and individuals with schizotypy showed small effects. CONCLUSIONS: Findings suggest robust olfactory deficits in schizophrenia and at-risk youths. In schizophrenia, several variables had significant impact on these deficits and warrant consideration in prospective studies. Our findings also indicate that olfactory measures may be a useful marker of schizophrenia risk status. PMID- 23641051 TI - Study shows Medicaid coverage has little clinical benefit. PMID- 23641052 TI - Regulatory T cell-derived IL-10 ameliorates crescentic GN. AB - Regulatory T cells (Tregs) exert their immunosuppressive activity through several immunoregulatory mechanisms, including the production of anti-inflammatory cytokines such as IL-10. Although several studies suggest a role for Tregs in modulating crescentic GN, the underlying mechanisms are not well understood. Here, using IL-10 reporter mice, we detected IL-10-producing Foxp3(+) T cells in the kidney, blood, and secondary lymphoid tissue in a mouse model of crescentic GN. Specific inactivation of Il10 in Foxp3(+) Tregs eliminated the ability of these cells to suppress renal and systemic production of IFNgamma and IL-17; these IL-10-deficient Tregs lost their capacity to attenuate renal tissue injury. These data highlight the suppressive functions of Tregs in crescentic GN and suggest the importance of Treg-derived IL-10 in ameliorating disease severity and in modulating both the Th1 and most notably Th17 immune response. PMID- 23641053 TI - Islet1 deletion causes kidney agenesis and hydroureter resembling CAKUT. AB - Islet1 (Isl1) is a transcription factor transiently expressed in a subset of heart and limb progenitors. During studies of limb development, conditional Isl1 deletion produced unexpected kidney abnormalities. Here, we studied the renal expression of Isl1 and whether it has a role in kidney development. In situ hybridization revealed Isl1 expression in the mesenchymal cells surrounding the base of the ureteric bud in mice. Conditional deletion of Isl1 caused kidney agenesis or hypoplasia and hydroureter, a phenotype resembling human congenital anomalies of the kidney and urinary tract (CAKUT). The absence of Isl1 led to ectopic branching of the ureteric bud out from the nephric duct or to the formation of accessory buds, both of which could lead to obstruction of the ureter-bladder junction and consequent hydroureter. The abnormal elongation and poor branching of the ureteric buds were the likely causes of the kidney agenesis or hypoplasia. Furthermore, the lack of Isl1 reduced the expression of Bmp4, a gene implicated in the CAKUT-like phenotype, in the metanephric region before ureteric budding. In conclusion, Isl1 is essential for proper development of the kidney and ureter by repressing the aberrant formation of the ureteric bud. These observations call for further studies to investigate whether Isl1 may be a causative gene for human CAKUT. PMID- 23641054 TI - Integrins in kidney disease. AB - A major hallmark of chronic kidney injury is fibrosis, which is characterized by increased accumulation of extracellular matrix components that replace the damaged tissue. Normally, the synthesis and degradation of extracellular matrix components are finely regulated; however, when matrix replacement goes unchecked, there is unwanted and irreversible tissue scarring with consequent organ damage, organ failure, and, in certain cases, death. Many factors, including cell-matrix interactions, play a role in the development of renal fibrosis. Cell-matrix interactions are made possible by integrins, a family of transmembrane receptors that, upon binding to the extracellular matrix, activate intracellular signaling. Thus, they control various cell functions, including survival, proliferation, migration, and matrix homeostasis. Genetic mutations in humans and the development of animal models lacking integrins in selective parts of the kidney have improved our understanding of molecular mechanisms and pathways controlling matrix remodeling in kidney disease. Here we outline the major integrins involved in kidney disease and some of the major molecular mechanisms whereby integrins contribute to kidney fibrosis. PMID- 23641055 TI - Renal ischemia-reperfusion injury amplifies the humoral immune response. AB - Renal transplant recipients who experience delayed graft function have increased risks of rejection and long-term graft failure. Ischemic damage is the most common cause of delayed graft function, and although it is known that tissue inflammation accompanies renal ischemia, it is unknown whether renal ischemia affects the production of antibodies by B lymphocytes, which may lead to chronic humoral rejection and allograft failure. Here, mice immunized with a foreign antigen 24-96 hours after renal ischemia-reperfusion injury developed increased levels of antigen-specific IgG1 compared with sham-treated controls. This amplified IgG1 response did not follow unilateral ischemia, and it did not occur in response to a T-independent antigen. To test whether innate immune activation in the kidney after ischemia affects the systemic immune response to antigen, we repeated the immunization experiment using mice deficient in factor B that lack a functional alternative pathway of complement. Renal ischemia-reperfusion injury did not cause amplification of the antigen-specific antibodies in these mice, suggesting that the increased immune response requires a functional alternative pathway of complement. Taken together, these data suggest that ischemic renal injury leads to a rise in antibody production, which may be harmful to renal allografts, possibly explaining a mechanism underlying the link between delayed graft function and long-term allograft failure. PMID- 23641056 TI - Reversibility of structural and functional damage in a model of advanced diabetic nephropathy. AB - The reversibility of diabetic nephropathy remains controversial. Here, we tested whether replacing leptin could reverse the advanced diabetic nephropathy modeled by the leptin-deficient BTBR ob/ob mouse. Leptin replacement, but not inhibition of the renin-angiotensin-aldosterone system (RAAS), resulted in near-complete reversal of both structural (mesangial matrix expansion, mesangiolysis, basement membrane thickening, podocyte loss) and functional (proteinuria, accumulation of reactive oxygen species) measures of advanced diabetic nephropathy. Immunohistochemical labeling with the podocyte markers Wilms tumor 1 and p57 identified parietal epithelial cells as a possible source of regenerating podocytes. Thus, the leptin-deficient BTBR ob/ob mouse provides a model of advanced but reversible diabetic nephropathy for further study. These results also suggest that restoration of lost podocytes is possible but is not induced by RAAS inhibition, possibly explaining the limited efficacy of RAAS inhibitors in promoting repair of diabetic nephropathy. PMID- 23641058 TI - An airborne transmissible avian influenza H5 hemagglutinin seen at the atomic level. AB - Recent studies have identified several mutations in the hemagglutinin (HA) protein that allow the highly pathogenic avian H5N1 influenza A virus to transmit between mammals by airborne route. Here, we determined the complex structures of wild-type and mutant HAs derived from an Indonesia H5N1 virus bound to either avian or human receptor sialic acid analogs. A cis/trans conformational change in the glycosidic linkage of the receptor analog was observed, which explains how the H5N1 virus alters its receptor-binding preference. Furthermore, the mutant HA possessed low affinities for both avian and human receptors. Our findings provide a structural and biophysical basis for the H5N1 adaptation to acquire human, but maintain avian, receptor-binding properties. PMID- 23641057 TI - Androgen-sensitive hypertension associates with upregulated vascular CYP4A12-20 HETE synthase. AB - Although the mechanism underlying the effect of androgen on BP and cardiovascular disease is not well understood, recent studies suggest that 20-hydroxy-5,8,11,14 eicosatetraenoic acid (20-HETE), a primary cytochrome P450 4 (Cyp4)-derived eicosanoid, may mediate androgen-induced hypertension. Here, treatment of normotensive mice with 5alpha-dihydrotestosterone increased BP and induced both Cyp4a12 expression and 20-HETE levels in preglomerular microvessels. Administration of a 20-HETE antagonist prevented and reversed the effects of dihydrotestosterone on BP. Cyp4a14(-/-) mice, which exhibit androgen-sensitive hypertension in the male mice, produced increased levels of vascular 20-HETE; furthermore, administration of a 20-HETE antagonist normalized BP. To examine whether androgen-independent increases in 20-HETE are sufficient to cause hypertension, we studied Cyp4a12-transgenic mice, which express the CYP4A12-20 HETE synthase under the control of a doxycycline-sensitive promoter. Administration of doxycycline increased BP by 40%, and administration of a 20 HETE antagonist prevented this increase. Levels of CYP4A12 and 20-HETE in preglomerular microvessels of doxycycline-treated transgenic mice approximately doubled, correlating with increased 20-HETE-dependent sensitivity to phenylephrine-mediated vasoconstriction and with decreased acetylcholine-mediated vasodilation in the renal microvasculature. We observed a similar contribution of 20-HETE to myogenic tone in the mesenteric microvasculature. Taken together, these results suggest that 20-HETE both mediates androgen-induced hypertension and can cause hypertension independent of androgen. PMID- 23641059 TI - Widespread production of extracellular superoxide by heterotrophic bacteria. AB - Superoxide and other reactive oxygen species (ROS) originate from several natural sources and profoundly influence numerous elemental cycles, including carbon and trace metals. In the deep ocean, the permanent absence of light precludes currently known ROS sources, yet ROS production mysteriously occurs. Here, we show that taxonomically and ecologically diverse heterotrophic bacteria from aquatic and terrestrial environments are a vast, unrecognized, and light independent source of superoxide, and perhaps other ROS derived from superoxide. Superoxide production by a model bacterium within the ubiquitous Roseobacter clade involves an extracellular oxidoreductase that is stimulated by the reduced form of nicotinamide adenine dinucleotide (NADH), suggesting a surprising homology with eukaryotic organisms. The consequences of ROS cycling in immense aphotic zones representing key sites of nutrient regeneration and carbon export must now be considered, including potential control of carbon remineralization and metal bioavailability. PMID- 23641060 TI - Redox heterogeneity in mid-ocean ridge basalts as a function of mantle source. AB - The oxidation state of Earth's upper mantle both influences and records mantle evolution, but systematic fine-scale variations in upper mantle oxidation state have not previously been recognized in mantle-derived lavas from mid-ocean ridges. Through a global survey of mid-ocean ridge basalt glasses, we show that mantle oxidation state varies systematically as a function of mantle source composition. Negative correlations between Fe(3+)/SigmaFe ratios and indices of mantle enrichment--such as (87)Sr/(86)Sr, (208)Pb/(204)Pb, Ba/La, and Nb/Zr ratios--reveal that enriched mantle is more reduced than depleted mantle. Because carbon may act to simultaneously reduce iron and generate melts that share geochemical traits with our reduced samples, we propose that carbon creates magmas at ridges that are reduced and enriched. PMID- 23641061 TI - H5N1 hybrid viruses bearing 2009/H1N1 virus genes transmit in guinea pigs by respiratory droplet. AB - In the past, avian influenza viruses have crossed species barriers to trigger human pandemics by reassorting with mammal-infective viruses in intermediate livestock hosts. H5N1 viruses are able to infect pigs, and some of them have affinity for the mammalian type alpha-2,6-linked sialic acid airway receptor. Using reverse genetics, we systematically created 127 reassortant viruses between a duck isolate of H5N1, specifically retaining its hemagglutinin (HA) gene throughout, and a highly transmissible, human-infective H1N1 virus. We tested the virulence of the reassortants in mice as a correlate for virulence in humans and tested transmissibility in guinea pigs, which have both avian and mammalian types of airway receptor. Transmission studies showed that the H1N1 virus genes encoding acidic polymerase and nonstructural protein made the H5N1 virus transmissible by respiratory droplet between guinea pigs without killing them. Further experiments implicated other H1N1 genes in the enhancement of mammal-to mammal transmission, including those that encode nucleoprotein, neuraminidase, and matrix, as well as mutations in H5 HA that improve affinity for humanlike airway receptors. Hence, avian H5N1 subtype viruses do have the potential to acquire mammalian transmissibility by reassortment in current agricultural scenarios. PMID- 23641062 TI - Strong light-matter interactions in heterostructures of atomically thin films. AB - The isolation of various two-dimensional (2D) materials, and the possibility to combine them in vertical stacks, has created a new paradigm in materials science: heterostructures based on 2D crystals. Such a concept has already proven fruitful for a number of electronic applications in the area of ultrathin and flexible devices. Here, we expand the range of such structures to photoactive ones by using semiconducting transition metal dichalcogenides (TMDCs)/graphene stacks. Van Hove singularities in the electronic density of states of TMDC guarantees enhanced light-matter interactions, leading to enhanced photon absorption and electron-hole creation (which are collected in transparent graphene electrodes). This allows development of extremely efficient flexible photovoltaic devices with photoresponsivity above 0.1 ampere per watt (corresponding to an external quantum efficiency of above 30%). PMID- 23641063 TI - Multisensory control of hippocampal spatiotemporal selectivity. AB - The hippocampal cognitive map is thought to be driven by distal visual cues and self-motion cues. However, other sensory cues also influence place cells. Hence, we measured rat hippocampal activity in virtual reality (VR), where only distal visual and nonvestibular self-motion cues provided spatial information, and in the real world (RW). In VR, place cells showed robust spatial selectivity; however, only 20% were track active, compared with 45% in the RW. This indicates that distal visual and nonvestibular self-motion cues are sufficient to provide selectivity, but vestibular and other sensory cues present in RW are necessary to fully activate the place-cell population. In addition, bidirectional cells preferentially encoded distance along the track in VR, while encoding absolute position in RW. Taken together, these results suggest the differential contributions of these sensory cues in shaping the hippocampal population code. Theta frequency was reduced, and its speed dependence was abolished in VR, but phase precession was unaffected, constraining mechanisms governing both hippocampal theta oscillations and temporal coding. These results reveal cooperative and competitive interactions between sensory cues for control over hippocampal spatiotemporal selectivity and theta rhythm. PMID- 23641064 TI - The composition and role of cross links in mechanoelectrical transduction in vertebrate sensory hair cells. AB - The key components of acousticolateralis systems (lateral line, hearing and balance) are sensory hair cells. At their apex, these cells have a bundle of specialized cellular protrusions, which are modified actin-containing microvilli, connected together by extracellular filaments called cross links. Stereociliary deflections open nonselective cation channels allowing ions from the extracellular environment into the cell, a process called mechanoelectrical transduction. This produces a receptor potential that causes the release of the excitatory neurotransmitter glutamate onto the terminals of the sensory nerve fibres, which connect to the cell base, causing nerve signals to be sent to the brain. Identification of the cellular mechanisms underlying mechanoelectrical transduction and of some of the proteins involved has been assisted by research into the genetics of deafness, molecular biology and mechanical measurements of function. It is thought that one type of cross link, the tip link, is composed of cadherin 23 and protocadherin 15, and gates the transduction channel when the bundle is deflected. Another type of link, called lateral (or horizontal) links, maintains optimal bundle cohesion and stiffness for transduction. This Commentary summarizes the information currently available about the structure, function and composition of the links and how they might be relevant to human hearing impairment. PMID- 23641066 TI - Virus entry at a glance. PMID- 23641065 TI - Regulation of mTORC1 and its impact on gene expression at a glance. AB - The mechanistic (or mammalian) target of rapamycin (mTOR) is a kinase that regulates key cellular functions linked to the promotion of cell growth and metabolism. This kinase, which is part of two protein complexes termed mTOR complex 1 (mTORC1) and 2 (mTORC2), has a fundamental role in coordinating anabolic and catabolic processes in response to growth factors and nutrients. Of the two mTOR complexes, mTORC1 is by far the best characterized. When active, mTORC1 triggers cell growth and proliferation by promoting protein synthesis, lipid biogenesis, and metabolism, and by reducing autophagy. The fact that mTORC1 deregulation is associated with several human diseases, such as type 2 diabetes, cancer, obesity and neurodegeneration, highlights its importance in the maintenance of cellular homeostasis. Over the last years, several groups observed that mTORC1 inhibition, in addition to reducing protein synthesis, deeply affects gene transcription. Here, we review the connections between mTORC1 and gene transcription by focusing on its impact in regulating the activation of specific transcription factors including including STAT3, SREBPs, PPARgamma, PPARalpha, HIF1alpha, YY1-PGC1alpha and TFEB. We also discuss the importance of these transcription factors in mediating the effects of mTORC1 on various cellular processes in physiological and pathological contexts. PMID- 23641067 TI - Germline deletion of Cetn1 causes infertility in male mice. AB - Centrins are calmodulin-like Ca(2+)-binding proteins that can be found in all ciliated eukaryotic cells from yeast to mammals. Expressed in male germ cells and photoreceptors, centrin 1 (CETN1) resides in the photoreceptor transition zone and connecting cilium. To identify its function in mammals, we deleted Cetn1 by homologous recombination. Cetn1(-/-) mice were viable and showed no sign of retina degeneration suggesting that CETN1 is nonessential for photoreceptor ciliogenesis or structural maintenance. Phototransduction components localized normally to the Cetn1(-/-) photoreceptor outer segments, and loss of CETN1 had no effect on light-induced translocation of transducin to the inner segment. Although Cetn1(-/-) females and Cetn1(+/-) males had normal fertility, Cetn1(-/-) males were infertile. The Cetn1(-/-) testes size was normal, and spermatogonia as well as spermatocytes developed normally. However, spermatids lacked tails suggesting severe defects at the late maturation phase of spermiogenesis. Viable sperm cells were absent and the few surviving spermatozoa were malformed. Light and electron microscopy analyses of Cetn1(-/-) spermatids revealed failures in centriole rearrangement during basal body maturation and in the basal-body nucleus connection. These results confirm an essential role for CETN1 in late steps of spermiogenesis and spermatid maturation. PMID- 23641068 TI - Antagonism and synergy between extracellular BMP modulators Tsg and BMPER balance blood vessel formation. AB - Growth and regeneration of blood vessels are crucial processes during embryonic development and in adult disease. Members of the bone morphogenetic protein (BMP) family are growth factors known to play a key role in vascular development. The BMP pathway is controlled by extracellular BMP modulators such as BMP endothelial cell precursor derived regulator (BMPER), which we reported previously acts proangiogenically on endothelial cells in a concentration-dependent manner. Here, we explore the function of other BMP modulators, especially Tsg, on endothelial cell behaviour and compare them to BMPER. In Matrigel assays, BMP modulators chordin and noggin had no stimulatory effect; however, gremlin and Tsg enhanced human umbilical vein endothelial cell (HUVEC) sprouting. As the activation dynamics of Tsg were similar to those of BMPER, we further investigated the proangiogenic effect of Tsg on endothelial cells. Tsg enhanced endothelial cell ingrowth in the mouse Matrigel plug assay as well as HUVEC sprouting, migration and proliferation in vitro, dependent on Akt, Erk and Smad signalling pathway activation in a concentration-dependent manner. Surprisingly, silencing of Tsg also increased HUVEC sprouting, migration and proliferation, which is again associated with Akt, Erk and Smad signalling pathway activation. Furthermore, we reveal that Tsg and BMPER interfere with each other to enhance proangiogenic events. However, in vivo the presence of Tsg as well as of BMPER is mandatory for regular development of the zebrafish vasculature. Taken together, our results suggest that BMPER and Tsg maintain a fine-tuned equilibrium that controls BMP pathway activity and is necessary for vascular cell homeostasis. PMID- 23641069 TI - Intermolecular disulfide bonds between nucleoporins regulate karyopherin dependent nuclear transport. AB - Disulfide (S-S) bonds play important roles in the regulation of protein function and cellular stress responses. In this study, we demonstrate that distinct sets of nucleoporins (Nups), components of the nuclear pore complex (NPC), form S-S bonds and regulate nuclear transport through the NPC. Kinetic analysis of importin beta demonstrated that the permeability of the NPC was increased by dithiothreitol treatment and reduced by oxidative stress. The permeability of small proteins such as GFP was not affected by either oxidative stress or a reducing reagent. Immunoblot analysis revealed that the oxidative stress significantly induced S-S bond formation in Nups 358, 155, 153 and 62 but not 88 and 160. The direct involvement of cysteine residues in the formation of S-S bonds was confirmed by mutating conserved cysteine residues in Nup62, which abolished the formation of S-S bonds and enhanced the permeability of the NPC. Knocking down Nup62 reduced the stress-inducible S-S bonds of Nup155, suggesting that Nup62 and Nup155 are covalently coupled via S-S bonds. From these results, we propose that the inner channel of the NPC is somehow insulated from the cytoplasm and is more sensitive than the cytoplasm to the intracellular redox state. PMID- 23641071 TI - The yeast cell cortical protein Num1 integrates mitochondrial dynamics into cellular architecture. AB - During the cell cycle each organelle has to be faithfully partitioned to the daughter cells. However, the mechanisms controlling organellar inheritance remain poorly understood. We studied the contribution of the cell cortex protein, Num1, to mitochondrial partitioning in yeast. Live-cell microscopy revealed that Num1 is required for attachment of mitochondria to the cell cortex and retention in mother cells. Electron tomography of anchoring sites revealed plasma membrane invaginations directly contacting the mitochondrial outer membrane. Expression of chimeric plasma membrane tethers rescued mitochondrial fission defects in Deltanum1 and Deltamdm36 mutants. These findings provide new insights into the coupling of mitochondrial dynamics, immobilization, and retention during inheritance. PMID- 23641070 TI - Evidence of a triosephosphate isomerase non-catalytic function crucial to behavior and longevity. AB - Triosephosphate isomerase (TPI) is a glycolytic enzyme that converts dihydroxyacetone phosphate (DHAP) into glyceraldehyde 3-phosphate (GAP). Glycolytic enzyme dysfunction leads to metabolic diseases collectively known as glycolytic enzymopathies. Of these enzymopathies, TPI deficiency is unique in the severity of neurological symptoms. The Drosophila sugarkill mutant closely models TPI deficiency and encodes a protein prematurely degraded by the proteasome. This led us to question whether enzyme catalytic activity was crucial to the pathogenesis of TPI sugarkill neurological phenotypes. To study TPI deficiency in vivo we developed a genomic engineering system for the TPI locus that enables the efficient generation of novel TPI genetic variants. Using this system we demonstrate that TPI sugarkill can be genetically complemented by TPI encoding a catalytically inactive enzyme. Furthermore, our results demonstrate a non metabolic function for TPI, the loss of which contributes significantly to the neurological dysfunction in this animal model. PMID- 23641073 TI - Human Cep192 and Cep152 cooperate in Plk4 recruitment and centriole duplication. AB - Polo-like kinase 4 (Plk4) is a key regulator of centriole duplication, but the mechanism underlying its recruitment to mammalian centrioles is not understood. In flies, Plk4 recruitment depends on Asterless, whereas nematodes rely on a distinct protein, Spd-2. Here, we have explored the roles of two homologous mammalian proteins, Cep152 and Cep192, in the centriole recruitment of human Plk4. We demonstrate that Cep192 plays a key role in centrosome recruitment of both Cep152 and Plk4. Double-depletion of Cep192 and Cep152 completely abolishes Plk4 binding to centrioles as well as centriole duplication, indicating that the two proteins cooperate. Most importantly, we show that Cep192 binds Plk4 through an N-terminal extension that is specific to the largest isoform. The Plk4 binding regions of Cep192 and Cep152 (residues 190-240 and 1-46, respectively) are rich in negatively charged amino acids, suggesting that Plk4 localization to centrioles depends on electrostatic interactions with the positively charged polo box domain. We conclude that cooperation between Cep192 and Cep152 is crucial for centriole recruitment of Plk4 and centriole duplication during the cell cycle. PMID- 23641072 TI - Direct binding of TUBB3 with DCC couples netrin-1 signaling to intracellular microtubule dynamics in axon outgrowth and guidance. AB - The coupling of axon guidance cues, such as netrin-1, to microtubule (MT) dynamics is essential for growth cone navigation in the developing nervous system. However, whether axon guidance signaling regulates MT dynamics directly or indirectly is unclear. Here, we report that TUBB3, the most dynamic beta tubulin isoform in neurons, directly interacts with the netrin receptor DCC, and that netrin-1 induces this interaction in primary neurons. TUBB3 colocalizes with DCC in the growth cones of primary neurons and MT dynamics is required for netrin 1-promoted association of TUBB3 with DCC. Netrin-1 not only increases co sedimentation of DCC with polymerized MT, but also promotes MT dynamics in the growth cone. Knocking down TUBB3 inhibits netrin-1-induced MT dynamics, axon outgrowth and attraction in vitro and causes defects in commissural axon projection in the embryo. These results indicate that TUBB3 directly links netrin signaling pathways to MT dynamics and plays an important role in guiding commissural axons in vivo. PMID- 23641074 TI - Tracking Ca2+-dependent and Ca2+-independent conformational transitions in syntaxin 1A during exocytosis in neuroendocrine cells. AB - A key issue for understanding exocytosis is elucidating the various protein interactions and the associated conformational transitions underlying soluble N ethylmeleimide-sensitive factor attachment protein receptor (SNARE) protein assembly. To monitor dynamic changes in syntaxin 1A (Syx) conformation along exocytosis, we constructed a novel fluorescent Syx-based probe that can be efficiently incorporated within endogenous SNARE complexes, support exocytosis, and report shifts in Syx between 'closed' and 'open' conformations by fluorescence resonance energy transfer analysis. Using this probe we resolve two distinct Syx conformational transitions during membrane depolarization-induced exocytosis in PC12 cells: a partial 'opening' in the absence of Ca(2+) entry and an additional 'opening' upon Ca(2+) entry. The Ca(2+)-dependent transition is abolished upon neutralization of the basic charges in the juxtamembrane regions of Syx, which also impairs exocytosis. These novel findings provide evidence of two conformational transitions in Syx during exocytosis, which have not been reported before: one transition directly induced by depolarization and an additional transition that involves the juxtamembrane region of Syx. The superior sensitivity of our probe also enabled detection of subtle Syx conformational changes upon interaction with VAMP2, which were absolutely dependent on the basic charges of the juxtamembrane region. Hence, our results further suggest that the Ca(2+)-dependent transition in Syx involves zippering between the membrane proximal juxtamembrane regions of Syx and VAMP2 and support the recently implied existence of this zippering in the final phase of SNARE assembly to catalyze exocytosis. PMID- 23641076 TI - A unitary focus of spatial attention during attentional capture: Evidence from event-related brain potentials. AB - We studied whether attentional capture in vision can be elicited simultaneously at multiple locations in the visual field or whether it is always restricted to a single location. Participants searched for color singleton targets in search arrays that were preceded by spatially uninformative color cue arrays. Single cue arrays contained a unique color singleton among gray background items, and double cue arrays included two different-colored objects. Behavioral spatial cueing effects and N2pc components indicative of attentional capture were triggered by single as well as double cue arrays, but these capture effects were smaller with double cues. Response latencies were used to distinguish double cue trials where attention was captured by a left or right cue and trials where it was attracted by a cue on the vertical meridian. The N2pc was only present on horizontal capture trials, indicating that attentional capture is not triggered in parallel and equally at different locations, but is strongly weighted towards one object and one location at a time. Results show that when multiple salient visual objects compete for attentional selection, the capacity of each object to capture attention is reduced, but the focus of spatial attention tends to remain unitary. PMID- 23641075 TI - Lamin aggregation is an early sensor of porphyria-induced liver injury. AB - Oxidative liver injury during steatohepatitis results in aggregation and transglutaminase-2 (TG2)-mediated crosslinking of the keratin cytoplasmic intermediate filament proteins (IFs) to form Mallory-Denk body (MDB) inclusions. The effect of liver injury on lamin nuclear IFs is unknown, though lamin mutations in several human diseases result in lamin disorganization and nuclear shape changes. We tested the hypothesis that lamins undergo aggregation during oxidative liver injury using two MDB mouse models: (i) mice fed the porphyrinogenic drug 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and (ii) mice that harbor a mutation in ferrochelatase (fch), which converts protoporphyrin IX to heme. Dramatic aggregation of lamin A/C and B1 was noted in the livers of both models in association with changes in lamin organization and nuclear shape, as determined by immunostaining and electron microscopy. The lamin aggregates sequester other nuclear proteins including transcription factors and ribosomal and nuclear pore components into high molecular weight complexes, as determined by mass-spectrometry and confirmed biochemically. Lamin aggregate formation is rapid and precedes keratin aggregation in fch livers, and is seen in liver explants of patients with alcoholic cirrhosis. Exposure of cultured cells to DDC, protoporphyrin IX or N-methyl-protoporphyrin, or incubation of purified lamins with protoporphyrin IX, also results in lamin aggregation. In contrast, lamin aggregation is ameliorated by TG2 inhibition. Therefore, lamin aggregation is an early sensor of porphyria-associated liver injury and might serve to buffer oxidative stress. The nuclear shape and lamin defects associated with porphyria phenocopy the changes seen in laminopathies and could result in transcriptional alterations due to sequestration of nuclear proteins. PMID- 23641078 TI - Is any science safe? PMID- 23641077 TI - When is it time to move to the next raspberry bush? Foraging rules in human visual search. AB - Animals, including humans, engage in many forms of foraging behavior in which resources are collected from the world. This paper examines human foraging in a visual search context. A real-world analog would be berry picking. The selection of individual berries is not the most interesting problem in such a task. Of more interest is when does a forager leave one patch or berry bush for the next one? Marginal Value Theorem (MVT; Charnov, 1976) predicts that observers will leave a patch when the instantaneous yield from that patch drops below the average yield from the entire "field." Experiments 1, 2, 3, and 4 show that MVT gives a good description of human behavior for roughly uniform collections of patches. Experiments 5 and 6 show strong departures from MVT when patch quality varies and when visual information is degraded. PMID- 23641083 TI - U.S. science policy. Bill would set new rules for choosing NSF grants. PMID- 23641084 TI - Primate studies. Research in limbo as Harvard moves to close center. PMID- 23641085 TI - Newsmaker interview. Bill and Melinda Gates talk science. Interview by Leslie Roberts. PMID- 23641086 TI - Science debate. Scientists clash swords over future of GM food crops in India. PMID- 23641087 TI - Climate change. Hansen's retirement from NASA spurs look at his legacy. PMID- 23641088 TI - Mr. Borucki's lonely road to the light. PMID- 23641089 TI - Taking the pulse of a ravaged ocean. PMID- 23641090 TI - The Pacific swallows Fukushima's fallout. PMID- 23641091 TI - Geoengineering: guidance exists. PMID- 23641092 TI - Geoengineering: perilous particles. PMID- 23641093 TI - Comment on "Bateman in nature: predation on offspring reduces the potential for sexual selection". AB - Byers and Dunn (Reports, 9 November 2012, p. 802) claimed that predation on offspring reduced the potential for sexual selection in pronghorn. We argue that the potential for sexual selection is not affected by random offspring mortality when relative reproductive success is considered and increases when measured with the opportunity for selection, a metric that describes the potential for selection. PMID- 23641094 TI - Comment on "Bateman in nature: predation on offspring reduces the potential for sexual selection". AB - Byers and Dunn's (Reports, 9 November 2012, p.802) conclusion that predation constrains sexual selection is problematic for three reasons: their nonstandard calculation of Bateman slopes; their assertion that random processes do not influence reproductive success; and the statistically unjustifiable use of 6 variables to explain just 10 observations. PMID- 23641095 TI - Comment on "Bateman in nature: predation on offspring reduces the potential for sexual selection". AB - Byers and Dunn (Reports, 9 November 2012, p. 802) reported that sexual selection and natural selection are closely related in a wild population of pronghorns. Here, I argue that this conclusion is incorrect. Their main finding is due to the fact that, unsurprisingly, juvenile mortality and juvenile survival are negatively related across years. PMID- 23641096 TI - Response to comments on "Bateman in nature: predation on offspring reduces the potential for sexual selection". AB - Commenters objected to the way that we counted matings and offspring to calculate Bateman slopes and disagreed with our contention that predation on offspring can decrease the potential for sexual selection. We clarify what may have been misunderstandings to argue that our methods, analyses, and conclusions are correct. PMID- 23641098 TI - Life in science. All in the family. PMID- 23641099 TI - Research ethics. Global research integrity training. PMID- 23641100 TI - Engineering. Recombinatorial logic. PMID- 23641101 TI - Astrophysics. Seeing gravitational waves. PMID- 23641102 TI - Environmental science. Tracking marine pollution. PMID- 23641103 TI - Cancer. Silencing a metabolic oncogene. PMID- 23641105 TI - Materials science. Obey the peptide assembly rules. PMID- 23641104 TI - Cell biology. Unconventional secretion, unconventional solutions. PMID- 23641107 TI - Exoplanets. Alien worlds galore. Introduction. PMID- 23641106 TI - Biochemistry. As good as chocolate. PMID- 23641108 TI - A gallery of planet hunters. PMID- 23641109 TI - ...And a glossary of their quarry. PMID- 23641110 TI - Observed properties of extrasolar planets. AB - Observational surveys for extrasolar planets probe the diverse outcomes of planet formation and evolution. These surveys measure the frequency of planets with different masses, sizes, orbital characteristics, and host star properties. Small planets between the sizes of Earth and Neptune substantially outnumber Jupiter sized planets. The survey measurements support the core accretion model, in which planets form by the accumulation of solids and then gas in protoplanetary disks. The diversity of exoplanetary characteristics demonstrates that most of the gross features of the solar system are one outcome in a continuum of possibilities. The most common class of planetary system detectable today consists of one or more planets approximately one to three times Earth's size orbiting within a fraction of the Earth-Sun distance. PMID- 23641111 TI - Exoplanet habitability. AB - The search for exoplanets includes the promise to eventually find and identify habitable worlds. The thousands of known exoplanets and planet candidates are extremely diverse in terms of their masses or sizes, orbits, and host star type. The diversity extends to new kinds of planets, which are very common yet have no solar system counterparts. Even with the requirement that a planet's surface temperature must be compatible with liquid water (because all life on Earth requires liquid water), a new emerging view is that planets very different from Earth may have the right conditions for life. The broadened possibilities will increase the future chances of discovering an inhabited world. PMID- 23641112 TI - Emergence and frustration of magnetism with variable-range interactions in a quantum simulator. AB - Frustration, or the competition between interacting components of a network, is often responsible for the emergent complexity of many-body systems. For instance, frustrated magnetism is a hallmark of poorly understood systems such as quantum spin liquids, spin glasses, and spin ices, whose ground states can be massively degenerate and carry high degrees of quantum entanglement. Here, we engineer frustrated antiferromagnetic interactions between spins stored in a crystal of up to 16 trapped (171)Yb(+) atoms. We control the amount of frustration by continuously tuning the range of interaction and directly measure spin correlation functions and their coherent dynamics. This prototypical quantum simulation points the way toward a new probe of frustrated quantum magnetism and perhaps the design of new quantum materials. PMID- 23641113 TI - Complex N-heterocycle synthesis via iron-catalyzed, direct C-H bond amination. AB - The manipulation of traditionally unreactive functional groups is of paramount importance in modern chemical synthesis. We have developed an iron-dipyrrinato catalyst that leverages the reactivity of iron-borne metal-ligand multiple bonds to promote the direct amination of aliphatic C-H bonds. Exposure of organic azides to the iron dipyrrinato catalyst furnishes saturated, cyclic amine products (N-heterocycles) bearing complex core-substitution patterns. This study highlights the development of C-H bond functionalization chemistry for the formation of saturated, cyclic amine products and should find broad application in the context of both pharmaceuticals and natural product synthesis. PMID- 23641114 TI - Controlled flight of a biologically inspired, insect-scale robot. AB - Flies are among the most agile flying creatures on Earth. To mimic this aerial prowess in a similarly sized robot requires tiny, high-efficiency mechanical components that pose miniaturization challenges governed by force-scaling laws, suggesting unconventional solutions for propulsion, actuation, and manufacturing. To this end, we developed high-power-density piezoelectric flight muscles and a manufacturing methodology capable of rapidly prototyping articulated, flexure based sub-millimeter mechanisms. We built an 80-milligram, insect-scale, flapping wing robot modeled loosely on the morphology of flies. Using a modular approach to flight control that relies on limited information about the robot's dynamics, we demonstrated tethered but unconstrained stable hovering and basic controlled flight maneuvers. The result validates a sufficient suite of innovations for achieving artificial, insect-like flight. PMID- 23641115 TI - R-loop stabilization represses antisense transcription at the Arabidopsis FLC locus. AB - Roles for long noncoding RNAs (lncRNAs) in gene expression are emerging, but regulation of the lncRNA itself is poorly understood. We have identified a homeodomain protein, AtNDX, that regulates COOLAIR, a set of antisense transcripts originating from the 3' end of Arabidopsis FLOWERING LOCUS C (FLC). AtNDX associates with single-stranded DNA rather than double-stranded DNA non sequence-specifically in vitro, and localizes to a heterochromatic region in the COOLAIR promoter in vivo. Single-stranded DNA was detected in vivo as part of an RNA-DNA hybrid, or R-loop, that covers the COOLAIR promoter. R-loop stabilization mediated by AtNDX inhibits COOLAIR transcription, which in turn modifies FLC expression. Differential stabilization of R-loops could be a general mechanism influencing gene expression in many organisms. PMID- 23641116 TI - The Fluid Mechanics of Genome Mapping. PMID- 23641117 TI - Carbon pools of an intact forest in Gabon. AB - : Quantitative and qualitative loss of tropical forests prompted international policy agendas to slow down forest loss through reducing emissions from deforestation and forest degradation (REDD)+, ensuring carbon offset payments to developing countries. So far, many African countries lack reliable forest carbon data and monitoring systems as required by REDD+. In this study, we estimate the carbon stocks of a naturally forested landscape unaffected by direct human impact. We used data collected from 34 plots randomly distributed across the Mount Birougou National Park (690 km2) in southern Gabon. We used tree-level data on species, diameter, height, species-specific wood density and carbon fraction as well as site-level data on dead wood, soil and litter carbon to calculate carbon content in aboveground, belowground, dead wood, soil and litter as 146, 28, 14, 186 and 7 Mg ha-1, respectively. Results may serve as a benchmark to assess ecosystem carbon loss/gain for the Massif du Chaillu in Gabon and the Republic of Congo, provide field data for remote sensing and also may contribute to establish national monitoring systems. RESUME: Les pertes qualitatives et quantitatives de foret tropicale ont pousse les calendriers politiques internationaux a ralentir la perte de forets au moyen des mecanismes REDD+, qui garantissent le paiement compensatoire des emissions de carbone aux pays en developpement. Jusqu'a present, de nombreux pays africains ne disposent pas encore de donnees fiables sur le carbone forestier, pas plus que de systemes de suivi exiges par les REDD+. Dans cet article, nous estimons les stocks de carbone d'un paysage de foret naturelle non affecte par des impacts humains directs. Nous avons utilise les donnees provenant de 34 parcelles reparties au hasard dans le Parc National du Mont Birougou (690 km2), dans le sud du Gabon. Nous avons utilise trois niveaux de donnees pour les especes, le diametre, la hauteur et la densite specifique du bois par espece, et la fraction de carbone ainsi que des donnees au niveau du site sur le carbone du bois mort, du sol et de la litiere pour calculer le contenu en carbone au-dessus du sol, en dessous, dans le bois mort, le sol et la litiere, a savoir, respectivement, 146, 28, 14, 186 et 7 mg ha 1. Ces resultats peuvent servir de donnees de reference pour evaluer la perte ou le gain de carbone de l'ecosysteme pour le Massif du Chaillu, au Gabon, et en Republique du Congo, constituer des donnees de terrain pour la detection a distance et aussi contribuer a etablir des systemes de suivi au niveau national. PMID- 23641118 TI - Picophytoplankton during the ice-free season in five temperate-zone rivers. AB - Although picophytoplankton (PP) (0.2-2 um) are ubiquitous in lakes and oceans, their importance in rivers has rarely been studied. We examined PP assemblages during the ice-free period in five rivers of a temperate region varying in trophic state (9-107 ug/L total phosphorus) and water discharge (1-87 m3/s). In these rivers, PP abundance reached concentrations as high as those observed in lakes and oceans (~104-105 cells/mL). The highest density of PP (4.9 * 105 cells/mL) was observed in the most eutrophic river when the water temperature (28 degrees C) and total phosphorus (293 ug/L) were highest. For the most part, PP abundance was dominated by non-phycoerythrin-containing cyanobacteria; phycocyanin-rich cells accounted for ~75% of PP abundance in all the rivers. In multiple regression analyses, water temperature and nitrate concentrations explained about half of the variation in PP abundance across the rivers. Discharge had no effect on PP abundance or biomass, whereas it had a significant negative effect on total algal biomass among the rivers. The PP contribution to total chlorophyll-a averaged 27% (ranging 16-46%) and did not decline with increasing nutrients as found in lakes and oceans. The PP biomass from microscopic enumerations reached a maximum of 9% of total phytoplankton biomass, comparable with that observed in lakes. The results of this study demonstrate the importance of including picophytoplankton when analysing phytoplankton communities in rivers. PMID- 23641119 TI - Business Cycles and Divorce: Evidence from Microdata. AB - We use individual-level data to show that divorce is pro-cyclical on average, a finding robust to the inclusion of a wide range of controls. Pro-cyclical divorce is concentrated among women who married young and/or do not have a college degree. PMID- 23641121 TI - A direct D-bar reconstruction algorithm for recovering a complex conductivity in 2-D. AB - A direct reconstruction algorithm for complex conductivities in W2,infinity (Omega), where Omega is a bounded, simply connected Lipschitz domain in R2, is presented. The framework is based on the uniqueness proof by Francini [Inverse Problems 20 2000], but equations relating the Dirichlet-to-Neumann to the scattering transform and the exponentially growing solutions are not present in that work, and are derived here. The algorithm constitutes the first D-bar method for the reconstruction of conductivities and permittivities in two dimensions. Reconstructions of numerically simulated chest phantoms with discontinuities at the organ boundaries are included. PMID- 23641120 TI - Substance Use among Adolescent Mothers: A Review. AB - Maternal substance abuse is a critical problem, and adolescent mothers appear to be at high risk for such behaviors. We review studies on postpartum adolescent substance use to explore the extent of this problem and avenues for new research. Authors screened 1,300 studies, identifying 12 articles on substance use among postpartum adolescent mothers for this review. Adolescent mothers reported greater substance use before pregnancy compared to other adolescent females. Although some adolescents continued substance use during pregnancy, most stopped using only to resume within six months after birth. Comparisons of use to national samples of nulliparous adolescent females showed a higher prevalence of substance use in this population. Substances used often varied by race/ethnicity, with white mothers more likely to smoke cigarettes and use marijuana, and Black mothers more likely than whites to drink and use drugs. Of all identified studies, only one focused on Hispanics. Beliefs about drug use grew less negative as girls transitioned from pregnancy to parenthood. As they transitioned to adulthood, substance use remained prevalent and stable. Psychological distress and low self-esteem appeared to influence continued use. Friends' cigarette smoking predicted early initiation of and persistent smoking, while increased education predicted quitting. Early initiation of substances often predicted problem behaviors. Adolescent mothers are a vulnerable population, implicating use of problem behavior theory or the self-medication hypothesis in future research. Multiple avenues for new studies are needed to help identify effective treatment and intervention for this understudied population. PMID- 23641122 TI - Gender Dynamics in Mexican American Families: Connecting Mothers', Fathers', and Youths' Experiences. AB - Study goals were to examine the conditions under which congruent and incongruent patterns of parents' division of household labor and gender role attitudes emerged, and the implications of these patterns for youth gender development. Questionnaire and phone diary data were collected from mothers, fathers, and youths from 236 Mexican American families in the southwestern US. Preliminary cluster analysis identified three patterns: Traditional divisions of labor and traditional attitudes, egalitarian divisions of labor and egalitarian attitudes, and an incongruent pattern, with a traditional division of labor but egalitarian attitudes. MANOVAs, and follow-up, mixed- and between-group ANOVAs, revealed that these groups of families differed in parents' time constraints, socioeconomic resources, and cultural orientations. Mothers in the congruent egalitarian group worked more hours and earned higher incomes as compared to mothers in the congruent traditional and incongruent groups, and the emergence of the incongruent group was grounded in within-family, inter-parental differences in work hours and incomes. Parents' patterns of gendered practices and beliefs were linked to their youths' housework participation, time with mothers versus fathers, and gender role attitudes. Youths in the congruent traditional group had more traditional gender role attitudes than those in the congruent egalitarian and incongruent groups, and gender atypical housework participation and time with parents were only observed in the congruent egalitarian group. Findings demonstrate the utility of a within-family design to understand complex gendered phenomena, and highlight the multidimensional nature of gender and the importance of contextualizing the study of ethnic minorities. PMID- 23641123 TI - Now for Me, Later for Us? Effects of Group Context on Temporal Discounting. AB - Delayed rewards are less valuable than immediate rewards. This well-established finding has focused almost entirely on individual outcomes. However, are delayed rewards similarly discounted if they are shared by a group? The current article reports on three experiments exploring the effect of group context on delay discounting. Results indicate that discount rates of individual and group rewards were highly correlated, but that respondents were more willing to wait (decreased discounting) for shared outcomes than for individual outcomes. An explanatory model is proposed suggesting that decreased discount rates in group contexts may be due to the way the effects of both delay and social discounting are combined. That is, in a group context, a person values both a future reward (discounted by delay) and a present reward to another person (discounted by the social distance between them). The results are explained by a combined discount function containing a delay factor and a factor representing the social distance between the decision maker and group members. Practical implications of the fact that shared consequences can increase individual self-control are also discussed. PMID- 23641124 TI - Chirality-Mediated Mechanical and Structural Properties of Oligopeptide Hydrogels. AB - The origin and the effects of homochirality in the biological world continuously stimulate numerous hypotheses and much debate. This work attempts to look at the biohomochirality issue from a different angle-the mechanical properties of the bulk biomaterial and their relation to nanoscale structures. Using a pair of oppositely charged peptides that co-assemble into hydrogels, we systematically investigated the effect of chirality on the mechanical properties of these hydrogels through different combinations of syndiotactic and isotactic peptides. It was found that homochirality confers mechanical advantage, resulting in higher elastic modulus and strain yield value. Yet, heterochirality confer kinetic advantage, resulting in faster gelation. Structurally, both homochiral and heterochiral hydrogels are made of fibers interconnected by lappet-like webs, but the homochiral peptide fibers are thicker and denser. The result highlights the possible role of biohomochirality in the evolution and/or natural selection of biomaterials. PMID- 23641125 TI - Piezo-thermal Probe Array for High Throughput Applications. AB - Microcantilevers are used in a number of applications including atomic-force microscopy (AFM). In this work, deflection-sensing elements along with heating elements are integrated onto micromachined cantilever arrays to increase sensitivity, and reduce complexity and cost. An array of probes with 5-10 nm gold ultrathin film sensors on silicon substrates for high throughput scanning probe microscopy is developed. The deflection sensitivity is 0.2 ppm/nm. Plots of the change in resistance of the sensing element with displacement are used to calibrate the probes and determine probe contact with the substrate. Topographical scans demonstrate high throughput and nanometer resolution. The heating elements are calibrated and the thermal coefficient of resistance (TCR) is 655 ppm/K. The melting temperature of a material is measured by locally heating the material with the heating element of the cantilever while monitoring the bending with the deflection sensing element. The melting point value measured with this method is in close agreement with the reported value in literature. PMID- 23641126 TI - The Use of Tertiary Alkylmagnesium Nucleophiles in Ni-Catalyzed Cross-Coupling Reactions. AB - Nickel-catalyzed cross-coupling reactions of unactivated tertiary alkyl nucleophiles and aryl bromides have been developed using N-heterocyclic carbene ligands. These processes are reviewed alongside earlier attempts to employ unactivated tertiary alkyl nucleophiles in cross-coupling reactions. Potential mechanisms for the transformations, and future challenges in this field are discussed. PMID- 23641127 TI - Legalization of medical marijuana and marijuana use among youths. AB - AIMS: This study examined the relationship of youth marijuana use and perceived ease of access with the number of medical marijuana cards at the county-level, and marijuana norms as indicated by percent of voters approving legalization of medical marijuana in 2004. METHODS: Survey data from 17,482 youths (ages 13 - 19) in Montana and county-level archival data, including votes for the legalization of medical marijuana and the number of medical marijuana cards were analyzed using hierarchical linear modeling. FINDINGS: Living in a county with more medical marijuana cards was not related to lifetime or 30 day marijuana use. However, voter approval of medical marijuana was positively related to lifetime and 30 day use. Perceived ease of access to marijuana was positively related to medical marijuana cards, but this relation became non-significant when voter approval was controlled. Among marijuana users, marijuana cards and voter approval were positively related to perceived ease of access. CONCLUSIONS: The relation between medical marijuana cards and youth use may be related to an overall normative environment that is more tolerant of marijuana use. Interventions to prevent youth marijuana use should focus on adult norms regarding use by and provision of marijuana to youths. PMID- 23641128 TI - Graduate Socialization in the Responsible Conduct of Research: A National Survey on the Research Ethics Training Experiences of Psychology Doctoral Students. AB - Little is known about the mechanisms by which psychology graduate programs transmit responsible conduct of research (RCR) values. A national sample of 968 current students and recent graduates of mission-diverse doctoral psychology programs, completed a web-based survey on their research ethics challenges, perceptions of RCR mentoring and department climate, their ability to conduct research responsibility, and whether they believed psychology as a discipline promotes scientific integrity. Research experience, mentor RCR instruction and modeling, and department RCR policies predicted student RCR preparedness. Mentor RCR instruction, department RCR policies, and faculty modeling of RCR behaviors predicted confidence in the RCR integrity of the discipline. Implications for training are discussed. PMID- 23641129 TI - 'Neither a borrower nor a lender be' when drugs are involved. AB - Borrowing and lending drugs is a dangerous business. PMID- 23641130 TI - DHHS Pushes to Expand E-Prescribing: Accessing Formularies in Health Plans Is a Major Problem. AB - The DHS pushes to expand e-prescribing. Pharmacy groups push back. PMID- 23641132 TI - Pharmaceutical approval update. AB - Bedaquiline for multiresistant pulmonary tuberculosis; Flublok influenza vaccine; and Octaplas for coagulation factor deficiency. PMID- 23641134 TI - Transforming the p&t committee. PMID- 23641133 TI - Linaclotide (Linzess) for Irritable Bowel syndrome With Constipation and For Chronic Idiopathic Constipation. AB - Linaclotide (Linzess) for irritable bowel syndrome with constipation and for chronic idiopathic constipation. PMID- 23641135 TI - Do antidepressant medications work? AB - Treatment-resistant depression is extremely common-but does that mean there is no place for antidepressants? PMID- 23641136 TI - The affordable care act: new features in 2013. AB - Among the health care changes this year: revenues to hospitals will be lower, payments to physicians will be modified, and more patients will be covered by Medicaid. PMID- 23641137 TI - Differing views on 'essential health benefits' extend to drug coverage: composition of formularies is a point of contention. AB - it is unclear how the final rule on "clinically appropriate" and "medically necessary" drugs will apply to hospital formularies and Part B drugs given in the doctor's office. PMID- 23641138 TI - ACE Inhibitor-Related Angioedema: Are Your Patients at Risk? AB - The author presents 4 case histories of patients who experienced angioedema after treatment with various ACE inhibitors in what some have called a "silent epidemic." PMID- 23641139 TI - Improving anticoagulation management in patients with atrial fibrillation. AB - Three agents have recently been approved to reduce the risk of stroke and embolism, and one agent is in phase 3 trials. These drugs cause less serious bleeding and are simpler to manage, compared with warfarin, but they are not without their risks. PMID- 23641140 TI - Circulation of human respiratory syncytial virus strains among hospitalized children with acute lower respiratory infection in malaysia. AB - Human respiratory syncytial virus (RSV) is a major viral pathogen associated with acute lower respiratory tract infections (ALRTIs) among hospitalized children. In this study, the genetic diversity of the RSV strains was investigated among nasopharyngeal aspirates (NPA) taken from children less than 5 years of age hospitalized with ALRTIs in Hospital Serdang, Malaysia. A total of 165 NPA samples were tested for the presence of RSV and other respiratory viruses from June until December 2009. RSV was found positive in 83 (50%) of the samples using reverse transcription polymerase chain reaction (RT-PCR). Further classification of 67 RSV strains showed that subgroups A and B comprised 11/67 (16.4%) and 56/67 (83.6%) of the strains, respectively. The second hypervariable region at the carboxyl-terminal of the G gene was amplified and sequenced in order to do phylogenetic study. The phylogenetic relationships of the samples were determined separately for subgroups A and B using neighbor joining (NJ), maximum parsimony (MP), and Bayesian inference (BI). Phylogenetic analysis of the 32 sequenced samples showed that all 9 RSV-A strains were clustered within NA1 genotype while the remaining 23 strains of the RSV-B subgroup could be grouped into a clade consisted of strains with 60-nucleotide duplication region. They were further classified into newly discovered BA10 and BA9 genotypes. The present finding suggests the emergence of RSV genotypes of NA1 and BA. This is the first documentation of the phylogenetic relationship and genetic diversity of RSV strains among hospitalized children diagnosed with ALRTI in Serdang, Malaysia. PMID- 23641141 TI - A Tool Preference Choice Method for RNA Secondary Structure Prediction by SVM with Statistical Tests. AB - The Prediction of RNA secondary structures has drawn much attention from both biologists and computer scientists. Many useful tools have been developed for this purpose. These tools have their individual strengths and weaknesses. As a result, based on support vector machines (SVM), we propose a tool choice method which integrates three prediction tools: pknotsRG, RNAStructure, and NUPACK. Our method first extracts features from the target RNA sequence, and adopts two information-theoretic feature selection methods for feature ranking. We propose a method to combine feature selection and classifier fusion in an incremental manner. Our test data set contains 720 RNA sequences, where 225 pseudoknotted RNA sequences are obtained from PseudoBase, and 495 nested RNA sequences are obtained from RNA SSTRAND. The method serves as a preprocessing way in analyzing RNA sequences before the RNA secondary structure prediction tools are employed. In addition, the performance of various configurations is subject to statistical tests to examine their significance. The best base-pair accuracy achieved is 75.5%, which is obtained by the proposed incremental method, and is significantly higher than 68.8%, which is associated with the best predictor, pknotsRG. PMID- 23641142 TI - In Silico Promoter Analysis can Predict Genes of Functional Relevance in Cell Proliferation: Validation in a Colon Cancer Model. AB - Specific combinations of transcription-factor binding sites in the promoter regions of genes regulate gene expression, and thus key functional processes in cells. Analysis of such promoter regions in specific functional contexts can be used to delineate novel disease-associated genes based on shared phenotypic properties. The aim of this study was to utilize promoter analysis to predict cell proliferation-associated genes and to test this method in colon cancer cell lines. We used freely-available bioinformatic techniques to identify cell proliferation-associated genes expressed in colon cancer, extract a shared promoter module, and identify novel genes that also contain this module in the human genome. An EGRF/ETSF promoter module was identified as prevalent in proliferation-associated genes from a colon cancer cDNA library. We detected 30 other genes, from the known promoters of the human genome, which contained this proliferation-associated module. This group included known proliferation associated genes, such as HERG1 and MCM7, and a number of genes not previously implicated in cell proliferation in cancer, such as TSPAN3, Necdin and APLP2. Suppression of TSPAN3 and APLP2 by siRNA was performed and confirmed by RT-PCR. Inhibition of these genes significantly inhibited cell proliferation in colon cancer cell lines. This study demonstrates that promoter analysis can be used to identify novel cancer-associated genes based on shared functional processes. PMID- 23641143 TI - Epigenetic markers for bladder cancer in urine. AB - Many tumor markers for bladder cancer have been evaluated for use in detecting and monitoring bladder cancers tissue specimens, bladder washes, and urine specimens. However, none of the biomarkers reported to date has shown sufficient sensitivity and specificity to detect the entire spectrum of bladder cancers in routine clinical practice. The limited value of the established prognostic markers demands analysis of new molecular parameters having the potential to predict the prognosis of bladder cancer patients, particularly, the high-risk patients at risk of cancer progression and recurrence. Abnormal methylation of CpG islands can efficiently repress transcription of the associated gene in a manner akin to mutations and deletions. Several tumor suppressor genes correlated with bladder cancer contain CpG islands in their promoters. Markers for aberrant methylation may be a potential gateway for monitoring bladder cancer. Hypermethylation of several gene promoters was detected in urine sediment DNA from bladder cancer patients. Detection of DNA methylation in voided urine is feasible and noninvasive. Methylation is an important molecular mechanism in the development of bladder cancer and could be used as a prognostic and diagnostic marker. Aberrant patterns of epigenetic modification could, in the near future, be crucial indicators in cancer diagnosis, prognosis, and may additionally be good targets for developing novel therapies while maintaining quality of life. PMID- 23641144 TI - Tumor suppressor role of notch1 and raf-1 signaling in medullary thyroid cancer cells. AB - There is a growing body of literature suggesting that signaling based therapy might be a potential approach for medullary thyroid cancer (MTC). In this review we focus on the tumor suppressor role of Notch1 and Raf-1 signaling in MTC. Interestingly these two pathways are minimally active or absent in these tumors and activation of Notch1 and Raf-1 significantly reduces tumor growth in vitro. Therefore, identification of compounds that induce these pathways could be a potential strategy to treat patients with MTC. PMID- 23641145 TI - YB-1 is a Transcription/Translation Factor that Orchestrates the Oncogenome by Hardwiring Signal Transduction to Gene Expression. AB - The Y-box Binding Protein-1 (YB-1) is a highly conserved oncogenic transcription/translation factor that is expressed in cancers affecting adults and children. It is now believed that YB-1 plays a causal role in the development of cancer given recent work showing that its expression drives the tumorigenesis in the mammary gland. In human breast cancers, YB-1 is associated with rapidly proliferating tumors that are highly aggressive. Moreover, expression of YB-1 promotes the growth of breast cancer cell lines both in monolayer and anchorage independent conditions. The involvement of YB-1 in breast cancer pathogenesis has made it a putative therapeutic target; however, the mechanism(s) that regulate YB 1 are poorly understood. This review first describes the oncogenic properties of YB-1 in cancer. It also highlights the importance of YB-1 in hardwiring signal transduction pathways to the regulation of genes involved in the development of cancer. PMID- 23641146 TI - The role of SRC family kinases in prostate cancer. PMID- 23641147 TI - A STAT3 Gene Expression Signature in Gliomas is Associated with a Poor Prognosis. AB - Gliomas frequently display constitutive activation of the transcription factor STAT3, a protein that is known to be able to mediate neoplastic transformation. STAT3 regulates genes that play a central role in cellular survival, proliferation, self-renewal, and invasion, and a cohort of STAT3 target genes have been found that are commonly coexpressed in human cancers. Thus, these genes likely subserve the transforming ability of constitutively activated STAT3. To determine whether the coordinated expression of STAT3 target genes is present in a subset of human gliomas, and whether this changes the biology of these tumors in patients, gene expression analysis was performed in four distinct human glioma data sets for which patient survival information was available. Coordinate expression of STAT3 targets was significantly associated with poor patient outcome in each data set. Specifically, patients with tumors displaying high expression of STAT3 targets had a shorter median survival time compared to patients whose tumors had low expression of STAT3 targets. These data suggest that constitutively activated STAT3 in gliomas can alter the biology of these tumors, and that development of targeted STAT3 inhibitors would likely be of particular benefit in treatment of this disease. PMID- 23641149 TI - Retinal vascular tortuosity in obstructive sleep apnea. AB - PURPOSE: Endothelial dysfunction and vascular disease are common in obstructive sleep apnea (OSA). We sought to examine the retinal vascular manifestations of OSA. METHODS: Nine consecutive patients with OSA underwent ophthalmic examination regardless of any ocular complaints. Seven patients without OSA matched for demographics were used as controls. Fundus photographs from both eyes were used to quantitate retinal vascular tortuosity of the temporal arterial and venous arcades using ImageJ digital analysis software. The tortuosity of each vessel from the optic disc rim to the crossing point of a 5 disc diameter (5DD) circle and 10 disc diameter (10DD) circle centered on the optic disc were quantitated. RESULTS: The mean age of patients with OSA in the study was 52 years +/- SD of 10 years and 67 years +/- SD of 10 years in the control group. The apnea-hypopnea index in patients with OSA ranged from 12 to 102 events/hr of sleep. The nadir saturation during sleep in patients with OSA ranged from 60% to 87%. There was no significant difference in the frequency of diabetes or hypertension between the groups. Total tortuosity was increased at the 5DD (P = 0.011) and 10DD (P = 0.004) marks. Arterial tortuosity was significantly increased at the 10DD mark (P = 0.016). Venular tortuosity was increased at both the 5DD (P = 0.001) and 10DD (P = 0.028) marks. CONCLUSION: Patients with OSA have increased retinal vascular tortuosity as compared to matched controls. Increased tortuosity of the retinal vasculature may be a novel association with OSA. A larger prospective study will be necessary to further explore this relationship and its clinical significance. PMID- 23641150 TI - Assessment of the quality of existing patient educational tools focused on sudden cardiac arrest: a systematic evaluation by the Sudden Cardiac Arrest Thought Leadership Alliance. AB - BACKGROUND: Conveying contemporary treatment options for those at risk of sudden cardiac arrest (SCA) is challenging. The purpose of the present research was to evaluate the quality and usability of available patient educational tools relevant to SCA and its treatment options, such as implantable cardioverter defibrillators (ICDs). We hypothesized that this review would identify gaps in areas of information for the enhancement of patient education and decision-making materials. METHODS: We used a formal instrument to assess specific domains of content, development, and effectiveness of 18 available SCA and ICD educational tools. The multidisciplinary review panel included two electrophysiologists, two general cardiologists, a cardiac psychologist, a health services researcher, and a patient advocate. RESULTS: Of the 18 education tools, four were rated as "good, may need revisions, but sufficient for use", 12 were rated as "marginal, needs revision prior to use", and two were rated as "poor, inadequate for use". None of the tools were rated as being of "very good" or "excellent" quality. CONCLUSION: There appear to be opportunities to improve the quality and completeness of existing educational tools for patients with SCA and ICD. While many tools have been developed, they fall below current standards for supporting informed medical decision-making. PMID- 23641148 TI - bHLH-Orange Transcription Factors in Development and Cancer. AB - Basic helix-loop-helix (bHLH) proteins are a large superfamily of transcription factors that play critical roles in many physiological processes including cellular differentiation, cell cycle arrest and apoptosis. Based on structural and phylogenetic analysis, mammalian bHLH-Orange (bHLH-O) proteins, which constitute the repressor family of bHLH factors, can be grouped into four subfamilies: Hes, Hey, Helt and Stra13/Dec. In addition to the bHLH domain that mediates DNA-binding and protein dimerization, all members of this family are characterized by a distinctive motif called the "Orange domain" which is present exclusively in these factors. Genetic studies using targeted mutagenesis in mice have revealed essential roles for many bHLH-O genes in embryonic development, cell fate decisions, differentiation of a number of cell types and in apoptosis. Furthermore, growing evidence of crosstalk between bHLH-O proteins with the tumor suppressors p53 and hypoxia-inducible factor, have started to shed light on their possible roles in oncogenesis. Consistently, deregulated expression of several bHLH-O factors is associated with various human cancers. Here, we review the structure and biological functions of bHLH-O factors, and discuss recent studies that suggest a potential role for these factors in tumorigenesis and tumor progression. PMID- 23641151 TI - Ustekinumab in chronic immune-mediated diseases: a review of long term safety and patient improvement. AB - Ustekinumab is a fully human monoclonal antibody targeting the common p40 subunit shared by interleukin (IL)-12 and IL-23. Ustekinumab prevents the interaction of IL-12 and IL-23 with their cell surface receptors, and thus blocks T helper (Th) 1 IL-12 and Th-17 IL-23 inflammatory pathways. Ustekinumab has been evaluated in the treatment of various chronic immune-mediated diseases including, psoriasis, psoriatic arthritis, Crohn's disease, and multiple sclerosis. It led to a rapid and durable improvement in psoriasis area and severity index in patients with moderate to severe psoriasis. Ustekinumab also improved joint symptoms of psoriatic arthritis. Results in Crohn's disease were more mitigated, albeit with a symptomatic improvement in patients refractory to tumor necrosis factor-alpha inhibitors. Ustekinumab did not reduce the number of magnetic resonance imaging brain lesions in multiple sclerosis. The most common adverse events to have been observed during clinical trials are mild in intensity, and include respiratory tract infections, nasopharyngitis, headaches, and injection site reactions. A pooled analysis of clinical trial data indicated no specific patterns of infection or malignancy under long-term ustekinumab administration. Ustekinumab is easy to use, has a comfortable therapeutic regimen, improves quality of life in patients, and thus appears to be an attractive biological treatment that is adapted and accepted by patients with moderate to severe psoriasis. PMID- 23641152 TI - The relationship between self-management abilities, quality of chronic care delivery, and wellbeing among patients with chronic obstructive pulmonary disease in The Netherlands. AB - BACKGROUND: This cross-sectional study aimed to identify the relationship between quality of chronic care delivery, self-management abilities, and wellbeing among patients with chronic obstructive pulmonary disease (COPD). METHODS: The study was conducted in 2012 and included 548 (out of 1303; 42% response rate) patients with COPD enrolled in a COPD care program in the region of Noord-Kennemerland in The Netherlands. We employed a multilevel random-effects model (548 patients nested in 47 healthcare practices) to investigate the relationship between quality of chronic care delivery, self-management abilities, and patients' wellbeing. In the multilevel analyses we controlled for patients' background characteristics and health behaviors. RESULTS: Multilevel analyses clearly showed a significant relationship between quality of chronic care delivery and wellbeing of patients with COPD (P <= 0.001). When self-management abilities were included in the equation while controlling for background characteristics, health behaviors, and quality of chronic care delivery, these abilities were found to have a strong positive relationship with patients' wellbeing (P <= 0.001). Low educational level, single marital status, and physical exercise were not significantly associated with wellbeing when self-management abilities were included in the equation. CONCLUSION: Self-management abilities and the quality of chronic care delivery are important for the wellbeing of patients with COPD. Furthermore, self-management abilities acted as mediators between wellbeing and low educational level, single status, and physical exercise among these patients. PMID- 23641154 TI - Bile salt/phospholipid mixed micelle precursor pellets prepared by fluid-bed coating. AB - Bile salt/phospholipid mixed micelles (MMs) are potent carriers used for oral absorption of drugs that are poorly soluble in water; however, there are many limitations associated with liquid formulations. In the current study, the feasibility of preparing bile salt/phospholipid MM precursor (preMM) pellets with high oral bioavailability, using fluid-bed coating technology, was examined. In this study, fenofibrate (FB) and sodium deoxycholate (SDC) were used as the model drug and the bile salt, respectively. To prepare the MMs and to serve as the micellular carrier, a weight ratio of 4:6 was selected for the sodium deoxycholate/phospholipids based on the ternary phase diagram. Polyethylene glycol (PEG) 6000 was selected as the dispersion matrix for precipitation of the MMs onto pellets, since it can enhance the solubilizing ability of the MMs. Coating of the MMs onto the pellets using the fluid-bed coating technology was efficient and the pellets were spherical and intact. MMs could be easily reconstituted from preMM pellets in water. Although they existed in a crystalline state in the preMM pellets, FB could be encapsulated into the reconstituted MMs, and the MMs were redispersed better than solid dispersion pellets (FB:PEG = 1:3) and Lipanthyl(r). The redispersibility of the preMM pellets increased with the increase of the FB/PEG/micellar carrier. PreMM pellets with a FB:PEG:micellar carrier ratio of 1:1.5:1.5 showed 284% and 145% bioavailability relative to Lipanthyl(r) and solid dispersion pellets (FB:PEG = 1:3), respectively. Fluid-bed coating technology has considerable potential for use in preparing sodium deoxycholate/phospholipid preMM pellets, with enhanced oral bioavailability for poorly water-soluble drugs. PMID- 23641155 TI - Multilayer bioactive glass/zirconium titanate thin films in bone tissue engineering and regenerative dentistry. AB - Surface modification, particularly coatings deposition, is beneficial to tissue engineering applications. In this work, bioactive glass/zirconium titanate composite thin films were prepared by a sol-gel spin-coating method. The surface features of the coatings were studied by scanning electron microscopy, atomic force microscopy, and spectroscopic reflection analyses. The results show that uniform and sound multilayer thin films were successfully prepared through the optimization of the process variables and the application of carboxymethyl cellulose as a dispersing agent. Also, it was found that the thickness and roughness of the multilayer coatings increase nonlinearly with increasing the number of the layers. This new class of nanocomposite coatings, comprising the bioactive and inert components, is expected not only to enhance bioactivity and biocompatibility, but also to protect the surface of metallic implants against wear and corrosion. PMID- 23641157 TI - Prevalence of hypertension in the rural adult population of Osun State, southwestern Nigeria. AB - BACKGROUND: The purpose of this study was to determine the prevalence of hypertension in two rural communities of Osun State, Nigeria. METHODS: A consenting adult population of the Alajue and Obokun rural communities in southwestern Nigeria that presented for the screening exercise participated in this community-based cross-sectional descriptive study. Two hundred and fifty nine respondents aged older than 18 years completed a standardized, pretested, structured questionnaire as part of activities celebrating World Kidney Day and World Glaucoma Day in 2011. Anthropometric data and blood pressure were recorded, and the data were analyzed using the Statistical Package for Social Sciences version 17. RESULTS: The mean age of the respondents was 49.7 +/- 1.6 years, 100 (38.6%) were males, 84 (32.4%) were farmers, and 111 (42.9%) were traders. The prevalence of hypertension was 13.16% (present in 34 respondents). Seventeen (6.6%) had isolated systolic hypertension, while 11 (4.2%) had isolated diastolic hypertension. Two hundred and thirty-six (91.1%) undertook daily exercise lasting at least 30 minutes and 48 (18.5%) had ever taken antihypertensive drugs on a regular basis. Four respondents (1.6%) claimed a family history of hypertension. The average body mass index (BMI) among respondents was 23.4 +/- 4.9 kg/m(2), 51 (19.6%) had a BMI of 25.0-29.9, and 30 (11.5%) had a BMI >= 30. A significant association existed between age older than 40 years and having hypertension (P < 0.05), while no relationship existed between age and BMI or between gender and hypertension (P > 0.05). Rates of older age and high BMI were significantly higher among hypertensives than among normotensives. Respondents with BMI >= 25 had at least a three times greater likelihood of developing hypertension than those with BMI < 25 (odds ratio 2.9, 95% confidence interval 0.007-0.056, P = 0.011). CONCLUSION: The prevalence of hypertension is high in this study population and we recommend scaling up primary prevention efforts to reduce this in Nigerian communities. PMID- 23641158 TI - Forgotten drugs: long-term prescriptions of thyroid hormones - a cross-sectional study. AB - BACKGROUND: Thyroid hormones are among the most prescribed drugs in Germany. Although iodine supply has been improving in the last decade, annual prescriptions for thyroid hormones are rising. The aim of this study was to provide prevalence of thyroid hormone prescribing and to explore reasons for thyroid hormone prescription in primary care settings. STUDY DESIGN: A cross sectional study. METHODS: Data collection took place in six general practitioner (GP) practices in Hesse, Germany. We used the records of six GP practices to estimate prevalence of thyroid hormone prescribing. All patients who received a prescription of the active ingredient levotyroxine during the preceding 3 months were mailed a study invitation. A proportion of the identified patients were interviewed. In addition, demographical data and all medical findings related to thyroid disease were recorded. RESULTS: On average, 9.2% (SD 4.6) of all patients from participating practices were taking thyroid hormones. The majority were female (82.5%). In 47.7% of the study participants, the GP's diagnosis, according to their records, was nonexistent. In 13.6% of cases, the documentation of the diagnostic information was incomplete. While 25% of interviewed patients with high educational background initiated further diagnostic investigation, only 4.4% of the patients with lower education did so. CONCLUSION: In the majority of patients treated with thyroid hormones, doctors had not documented the precise indication for prescription. PMID- 23641156 TI - Optimized formulation of solid self-microemulsifying sirolimus delivery systems. AB - BACKGROUND: The aim of this study was to develop an optimized solid self microemulsifying drug delivery system (SMEDDS) formulation for sirolimus to enhance its solubility, stability, and bioavailability. METHODS: Excipients used for enhancing the solubility and stability of sirolimus were screened. A phase separation test, visual observation for emulsifying efficiency, and droplet size analysis were performed. Ternary phase diagrams were constructed to optimize the liquid SMEDDS formulation. The selected liquid SMEDDS formulations were prepared into solid form. The dissolution profiles and pharmacokinetic profiles in rats were analyzed. RESULTS: In the results of the oil and cosolvent screening studies, CapryolTM Propylene glycol monocapry late (PGMC) and glycofurol exhibited the highest solubility of all oils and cosolvents, respectively. In the surfactant screening test, D-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) was determined to be the most effective stabilizer of sirolimus in pH 1.2 simulated gastric fluids. The optimal formulation determined by the construction of ternary phase diagrams was the T32 (CapryolTM PGMC:glycofurol:vitamin E TPGS = 30:30:40 weight ratio) formulation with a mean droplet size of 108.2 +/- 11.4 nm. The solid SMEDDS formulations were prepared with Sucroester 15 and mannitol. The droplet size of the reconstituted solid SMEDDS showed no significant difference compared with the liquid SMEDDS. In the dissolution study, the release amounts of sirolimus from the SMEDDS formulation were significantly higher than the raw sirolimus powder. In addition, the solid SMEDDS formulation was in a more stable state than liquid SMEDDS in pH 1.2 simulated gastric fluids. The results of the pharmacokinetic study indicate that the SMEDDS formulation shows significantly greater bioavailability than the raw sirolimus powder or commercial product (Rapamune(r) oral solution). CONCLUSION: The results of this study suggest the potential use of a solid SMEDDS formulation for the delivery of poorly water-soluble drugs, such as sirolimus, through oral administration. PMID- 23641159 TI - A case of left main coronary artery disease in an octogenarian treated surgically and complicated by myocardial infarction: decisions, techniques, rescue and final outcome. AB - We report on an octogenarian patient presenting with an acute coronary syndrome due to significant left main coronary artery disease and severe ostial stenosis of the left anterior descending artery disease. Emergent bypass graft performed with "beating heart" consisted of left internal mammary graft to the mid left anterior descending artery with an "over-stent" anastomosis. The immediate post operative phase was simple, however the patient presented on post-operative day 8 with extensive anterior myocardial infarction and cardiogenic shock. Emergent coronary angiogram showed subocclusive anastomotic stenosis. Percutaneous coronary intervention was performed on left main, proximal left anterior descending, and proximal circumflex arteries. Subsequently, the patient restored a satisfactory hemodynamic condition. A focus on the importance of decision for management of left main disease especially in octogenarian is presented, along with a review of the pertinent literature. PMID- 23641160 TI - Emerging Therapeutic Options for the Management of COPD. AB - Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and is projected to be the third by 2020. COPD is characterized by chronic airflow limitation caused by airway inflammation and parenchymal destruction that is usually progressive. Inhaled bronchodilators continue to be the mainstay of the current management of COPD. Safety and efficacy data of the recently approved medications including aclidinium, glycopyrronium, roflumilast, and indacaterol are reviewed here. PMID- 23641161 TI - Risk factors for infection with coagulase-negative staphylococci in newborns from the neonatal unit of a brazilian university hospital. AB - BACKGROUND: Coagulase-negative staphylococci (CoNS) are one of the most frequent causative agents of neonatal nosocomial infections, especially in premature and low-weight newborns. Risk factors for infection include extracellular polysaccharide production and consequent biofilm formation that permit adhesion to the smooth surface of catheters and other medical devices. The objective of this study was to identify CoNS strains isolated from 105 newborns admitted to the Neonatal Unit of our hospital, and to evaluate the association of biofilm production and host risk factors with the occurrence of infection. METHODS: CoNS isolates were identified and classified as significant or contaminant based on clinical and laboratory data of the newborn medical records. Perinatal risk factors for infection, neonatal clinical evolution, and antibiotic treatment were analysed. In addition, the presence of genes (icaA, icaC and icaD) responsible for biofilm production in CoNS was investigated. RESULTS: Among the 130 CoNS strains studied, 66 (50.8%) were classified as clinically significant and 64 (49.2%) as contaminant. There was no difference in the detection of biofilm specific genes between CoNS strains isolated from newborns with (81.8%) and without infection (84.3%), although 11 (91.7%) of the 12 children whose death was related to CoNS were infected with strains that were positive for these genes. Forty-five (83.3%) of the 54 newborns infected with CoNS were premature and 33 (61.1%) had a birth weight <= 1,500 g. Most newborns infected with CoNS had been submitted to invasive procedures, including catheter use (85.2%), parenteral nutrition (61.1%), and mechanical ventilation (57.4%). S. epidermidis was the most frequently isolated species (81.5%) and was more related to infection (86.3%) than to contamination (76.5%). CONCLUSION: Most newborns infected with CoNS presented factors that contributed to the colonization and development of infection with these microorganisms, including a birth weight <= 1,500 g, catheter complications, use of a drain, and previous antibiotic treatment. The fact that most children who died of CoNS-related infection carried strains positive for biofilm-specific genes indicates the importance of this virulence factor for the outcome of staphylococcal infections. PMID- 23641162 TI - Sleep deficiency and sleep health problems in chinese adolescents. AB - A survey of sleep schedules, sleep health, and the impact on school performance was conducted in 585 adolescents in a high school in China. A high level of early and circadian-disadvantaged sleep/wake schedules during weekdays was observed. Significantly shorter sleep duration on weekdays was reported (P < 0.0001). Older teenagers slept significantly less than the younger teenagers (P < 0.0001). Complaints of inadequate sleep and sleepiness during weekdays were prevalent. Night awakenings were reported in 32.2% of students. Students with a sleep length of less than 7 hours, complaint of inadequate sleep, or excessive daytime sleepiness during weekdays were more likely to report an adverse effect of poor sleep on performance. The present observations are qualitatively similar to those reported in our study in American adolescents, particularly with respect to Chinese adolescents exhibiting a similar sleep deficiency on weekdays. We concluded that sleep deficiency and sleep health problems were prevalent in the participating adolescents in China, and were perceived to adversely affect school performance. PMID- 23641163 TI - Caspofungin for the treatment of immunocompromised and severely ill children and neonates with invasive fungal infections. AB - Caspofungin is the first member of the echinocandin class of antifungals to receive an indication for the use in infants, children, and adolescents from the United States Food and Drug Administration. Daily doses of 50 mg/m(2) result in pharmacokinetic parameters that are similar to those observed in adults. Although fewer data are available, the response rates in pediatric patients who received caspofungin either as treatment or empiric therapy in clinical trials are similar to those reported in adults. In addition, caspofungin appears to be generally safe and well tolerated in this population. This represents a significant step forward in the treatment of invasive fungal infections within this population, as caspofungin is associated with few clinically significant drug-interactions and toxicities compared to other antifungals, such as the azoles and amphotericin B. PMID- 23641164 TI - Minimal difference in the prevalence of asthma in the urban and rural environment. AB - Multiple risk factors can be modified to decrease asthma incidence. It is important to understand early risks to decrease exposure to harmful conditions in the environment that can trigger asthma which may not be clinically evident in children until they reach adulthood. A retrospective literature review of articles on the prevalence of asthma in the urban versus rural environment was initiated in order to understand the effect of the environment on asthma. The urban-living effect is a global problem in the face of growing population, industrialization and pollution. The socioeconomic dichotomy in the urban versus rural environment also affects access and quality of health care. Articles reviewed had differences in the urban versus rural prevalence of asthma. However, further analysis of specific risk factors and socioeconomic trends that increased susceptibility to asthma was the same in these studies. Some rural areas may have similar environmental and socioeconomic issues that place them at the same risk for the development of asthma as their urban counterparts. Urban locations generally tend to have the prototype environment that can lead to the predisposition of asthma. Ultimately, the incidence of asthma can be decreased if these environmental and socioeconomic issues are addressed. However, every effort is needed from the level of the individual to the community at large. PMID- 23641165 TI - Alport Syndrome: De Novo Mutation in the COL4A5 Gene Converting Glycine 1205 to Valine. AB - BACKGROUND: Alport syndrome is a primary basement membrane disorder arising from mutations in genes encoding the type IV collagen protein family. It is a genetically heterogeneous disease with different mutations and forms of inheritance that presents with renal affection, hearing loss and eye defects. Several new mutations related to X-linked forms have been previously determined. METHODS: We report the case of a 12 years old male and his family diagnosed with Alport syndrome after genetic analysis was performed. RESULT: A new mutation determining a nucleotide change c.3614G > T (p.Gly1205Val) in hemizygosis in the COL4A5 gene was found. This molecular defect has not been previously described. CONCLUSION: Molecular biology has helped us to comprehend the mechanisms of pathophysiology in Alport syndrome. Genetic analysis provides the only conclusive diagnosis of the disorder at the moment. Our contribution with a new mutation further supports the need of more sophisticated molecular methods to increase the mutation detection rates with lower costs and less time. PMID- 23641166 TI - Nasal and buccal treatment of midazolam in epileptic seizures in pediatrics. AB - Acute seizure and status epilepticus constitute major medical emergencies in children. Four to six percent of children will have at least one seizure in the first 16 years of life. Status epilepticus is a common neurological emergency in childhood and is associated with significant morbidity and mortality. The early application of antiepileptic treatment is very important. Because early treatment prevents the status epilepticus formation and shortens the duration of seizure activity. For this reason administration of anticonvulsant therapy in the prehospital setting is very important. Seizures generally begin outside the hospital, and thus parents and caregivers need simple, safe and effective treatment options to ensure early intervention. The only special preparation used for this purpose is rectal diazepam but has some disadvantages. Midazolam is a safe, short-acting benzodiazepin. It is suitable to use oral, buccal, nasal, im and iv routes. This provides a wide area for clinical applications. Recently there are many clinical studies about the usage of nasal and buccal midazolam for treatment of pediatric epileptic seizures. The nasal and buccal applications in pediatric seizures are very practical and effective. Parents and caregivers can apply easily outside the hospital. PMID- 23641167 TI - Hypertension and Biliary Ductopenia in a Patient with Duplication of Exon 6 of the JAG1 Gene. AB - We describe a neonatal patient with biliary ductopenia featuring duplication of exon 6 of the JAG1 gene. Facial alterations were observed, consisting of a prominent forehead, sunken eyes, upward slanting palpebral fissures, hypertelorism, flat nasal root and prominent chin. From birth, these were accompanied by the development of haematuria and renal failure and by renal Doppler findings indicative of peripheral renal artery stenosis. JAG1 gene mutations on chromosome 20 have been associated with various anomalies, including biliary cholestasis, vertebral abnormalities, eye disorders, heart defects and facial dysmorphia. This syndrome, first described by Alagille, is an infrequent congenital disorder caused by a dominant autosomal inheritance with variable expressivity. Anatomopathological effects include the destruction and disappearance of hepatic bile ducts (ductopenia). The duplication of exon 6 of JAG1 has not previously been described as an alteration related to the Alagille syndrome with peripheral renal artery stenosis. PMID- 23641168 TI - Urinary excretion of phenolic acids by infants and children: a randomised double blind clinical assay. AB - OBJECTIVES: The present study, which is part of the ISRCTN16968287 clinical assay, is aimed at determining the effects of cranberry syrup or trimethoprim treatment for UTI. METHODS: This Phase III randomised clinical trial was conducted at the San Cecilio Clinical Hospital (Granada, Spain) with a study population of 192 patients, aged between 1 month and 13 years. Criteria for inclusion were a background of recurrent UTI, associated or otherwise with vesico ureteral reflux of any degree, or renal pelvic dilatation associated with urinary infection. Each child was randomly given 0.2 mL/Kg/day of either cranberry syrup or trimethoprim (8 mg/mL). The primary and secondary objectives, respectively, were to determine the risk of UTI and the levels of phenolic acids in urine associated with each intervention. RESULTS: With respect to UTI, the cranberry treatment was non-inferior to trimethoprim. Increased urinary excretion of ferulic acid was associated with a greater risk of UTI developing in infants aged under 1 year (RR 1.06; CI 95% 1.024-1.1; P = 0.001). CONCLUSIONS: The results obtained show the excretion of ferulic acid is higher in infants aged under 1 year, giving rise to an increased risk of UTI, for both treatment options. PMID- 23641169 TI - The nursing dimension of providing palliative care to children and adolescents with cancer. AB - Palliative care for children and adolescents with cancer includes interventions that focus on the relief of suffering, optimization of function, and improvement of quality of life at any and all stages of disease. This care is most effectively provided by a multidisciplinary team. Nurses perform an integral role on that team by identifying symptoms, providing care coordination, and assuring clear communication. Several basic tenets appear essential to the provision of optimal palliative care. First, palliative care should be administered concurrently with curative therapy beginning at diagnosis and assuming a more significant role at end of life. This treatment approach, recommended by many medical societies, has been associated with numerous benefits including longer survival. Second, realistic, objective goals of care must be developed. A clear understanding of the prognosis by the patient, family, and all members of the medical team is essential to the development of these goals. The pediatric oncology nurse is pivotal in developing these goals and assuring that they are adhered to across all specialties. Third, effective therapies to prevent and relieve the symptoms of suffering must be provided. This can only be accomplished with accurate and repeated assessments. The pediatric oncology nurse is vital in providing these assessments and must possess a working knowledge of the most common symptoms associated with suffering. With a basic understanding of these palliative care principles and competency in the core skills required for this care, the pediatric oncology nurse will optimize quality of life for children and adolescents with cancer. PMID- 23641170 TI - Mannose binding lectin deficiency: more than meets the eye. AB - This case report describes a 5-year-old boy who presented to the emergency department with clinical symptoms and chest X-ray findings suggestive of pneumonia. Further history revealed multiple other infections, and workup for immunodeficiency revealed a deficiency of mannose-binding lectin (MBL), a pattern recognition receptor involved in activation of the complement system. Innate immunodeficiency may be more common than currently appreciated, with mutations of MBL affecting up to 50% of individuals in some populations. While pneumonia is a common presentation in the Pediatric Emergency Department, clinical presentations of children with defects of innate immunity can be unpredictable. Children may initially appear well with sudden deterioration. These cases pose particular challenges to physicians, and the level of suspicion for innate defects must remain high. It is crucial to identify patients with such impairments to better manage and prevent future complications. PMID- 23641172 TI - Utility of blood culture in uncomplicated pneumonia in children. AB - BACKGROUND: It is believed to be the standard of care to obtain a blood culture in a child who is hospitalized for pneumonia. In recent years, many studies have questioned the utility of this practice in the presence of age appropriate immunization. We conducted this study to determine the current prevalence of bacteremia in children with uncomplicated pneumonia and the utility of obtaining blood cultures in these children. OBJECTIVE: To evaluate the risk of bacteremia in hospitalized young children with pneumonia. METHODS: This was a retrospective review from July 2003 until July 2008. The setting was the pediatric emergency department of an urban teaching hospital. The study population included children under 36 months of age who had been fully immunized and who had been hospitalized with radiographic evidence of uncomplicated pneumonia. Excluded were children who were currently using antibiotics or who had used antibiotics within the previous 48 hours, as well as children with immunodeficiency status such as sickle cell anemia, immunoglobulin deficiency, or children on steroid therapy. The radiologist's interpretation of each chest radiograph was reviewed and recorded. The variables studied were age (in months), gender, race, birth history, pneumococcal vaccination status, appearance on arrival, temperature on arrival, respiratory rate, oxygen saturation, white blood cell (WBC) count, neutrophil count, band count, and urine culture. The chi-square test and logistic regression were used to analyze the data. RESULTS: A blood culture was obtained in 535 children hospitalized with radiographic pneumonia. Bacteremia was present in 12 children (2.2%). All organisms isolated from the blood cultures were considered contaminants. CONCLUSION: Children hospitalized with uncomplicated pneumonia have a low rate of positive blood cultures. None of the variables studied predicted bacteremia. The absence of true-positive cultures among the organisms isolated suggests little value in obtaining blood cultures in children hospitalized due to uncomplicated pneumonia. PMID- 23641173 TI - Invasive fungal infections in infants-focus on anidulafungin. AB - INTRODUCTION: Invasive fungal infection in pediatric intensive care units (PICU) is a rising challenge. Candida species are the most common microorganisms in these infections. Due to growing resistance against fluconazole, echinocandins are being used for the appropriate therapy. However, the recent IDSA guidelines recommend them only in cases where fluconazole or Amphotericin B cause treatment failure or are contraindicated. In a literature review, the importance of invasive fungal infections in PICU settings and the role of anidulafungin shall be examined. MATERIALS AND METHODS: Articles were retrieved form PubMed covering the years 2000-2012. Various search terms were used. Then the articles were clustered in different types like 'review,' 'pharmacokinetics,' 'case reports' and others. RESULTS: From 67 search results, 14 articles were selected. Of these, 7 were related to anidulafungin, while 7 were related to echinocandins or fungal infections in the PICU. Anidulafungin was examined in 4 PK/PD studies where a good safety profile was found. No serious adverse events occurred. The articles reporting risk factors show that central venous catheters, receipt of antibiotics, receipt of parenteral nutrition, and neutropenia are the most important independent risk factors for invasive fungal infections in PICU. Three reviews of antifungal agents show that echinocandins may be useful due to their safety profile; micafungin is the best examined one and further trials are needed. DISCUSSION: The published literature on invasive fungal infections in PICU settings has grown over the years. There are only a few articles, however, which are directly related to the use of anidulafungin in this setting. A most recent publication showed good PK/PD dynamics and a good safety profile for anidulafungin. So far, no RCT in the area of invasive candidiasis in infants and neonates has been published. A review of currently registered trials at ClinicalTrials.gov has shown one more trial related to PK/PD and two trials that investigate the use of anidulafungin or anidulafungin in combination with Voriconazole in pediatrics. CONCLUSION: The small body of existing literature on anidulafungin in infants shows success in treatment, no drug-related adverse events, and good pharmacodynamics. A dosing of 0.75 mg/kg/day or 1.5 mg/kg/day is as effective as 50 mg/day or 100 mg/day in adults. More trials on the use in clinical reality of PICU or NICU should follow. PMID- 23641171 TI - Efficacy and safety of atomoxetine in the treatment of children and adolescents with attention deficit hyperactivity disorder. AB - Several non-stimulant medications have been used in the treatment of attention deficit hyperactivity disorder (ADHD). Atomoxetine, was introduced in 2002. The safety and efficacy of atomoxetine in the treatment of ADHD for children, adolescents, and adults has been evaluated in over 4000 patients in randomized controlled studies and double blinded studies as well as in recent large longitudinal studies. This paper provides an updated summary of the literature on atomoxetine, particularly in relation to findings on the short- and long-term safety of atomoxetine in children and adolescents arising from recent large longitudinal cohort studies. Information is presented about the efficacy, safety, and tolerability of this medication. PMID- 23641175 TI - From randomly to inevitable: Accelerating tomato breeding by comprehensive tools and information. PMID- 23641174 TI - Outpatient management of asthma in children. AB - The principal aims of asthma management in childhood are to obtain symptom control that allows individuals to engage in unrestricted physical activities and to normalize lung function. These aims should be achieved using the fewest possible medications. Ensuring a correct diagnosis is the first priority. The mainstay of asthma management remains pharmacotherapy. Various treatment options are discussed. Asthma monitoring includes the regular assessment of asthma severity and asthma control, which then informs decisions regarding the stepping up or stepping down of therapy. Delivery systems and devices for inhaled therapy are discussed, as are the factors influencing adherence to prescribed treatment. The role of the pediatric health care provider is to establish a functional partnership with the child and their family in order to minimize the impact of asthma symptoms and exacerbations during childhood. PMID- 23641176 TI - Genes that influence yield in tomato. AB - Yield is the most important breeding trait of crops. For fruit-bearing plants such as Solanum lycopersicum (tomato), fruit formation directly affects yield. The final fruit size depends on the number and volume of cell layers in the pericarp of the fruit, which is determined by the degree of cell division and expansion in the fertilized ovaries. Thus, fruit yield in tomato is predominantly determined by the efficiency of fruit set and the final cell number and size of the fruits. Through domestication, tomato fruit yield has been markedly increased as a result of mutations associated with fruit size and genetic studies have identified the genes that influence the cell cycle, carpel number and fruit set. Additionally, several lines of evidence have demonstrated that plant hormones control fruit set and size through the delicate regulation of genes that trigger physiological responses associated with fruit expansion. In this review, we introduce the key genes involved in tomato breeding and describe how they affect the physiological processes that contribute to tomato yield. PMID- 23641177 TI - Functional genomics of tomato in a post-genome-sequencing phase. AB - Completion of tomato genome sequencing project has broad impacts on genetic and genomic studies of tomato and Solanaceae plants. The reference genome sequence derived from Solanum lycopersicum cv 'Heinz 1706' serves as the firm basis for sequencing-based approaches to tomato genomics. In this article, we first present a brief summary of the genome sequencing project and a summary of the reference genome sequence. We then focus on recent progress in transcriptome sequencing and small RNA sequencing and show how the reference genome sequence makes these analyses more comprehensive than before. We discuss the potential of in-depth analysis that is based on DNA methylome sequencing and transcription start-site detection. Finally, we describe the current status of efforts to resequence S. lycopersicum cultivars to demonstrate how resequencing can allow the use of intraspecific genomic diversity for detailed phenotyping and breeding. PMID- 23641178 TI - DNA marker applications to molecular genetics and genomics in tomato. AB - Tomato is an important crop and regarded as an experimental model of the Solanaceae family and of fruiting plants in general. To enhance breeding efficiency and advance the field of genetics, tomato has been subjected to DNA marker studies as one of the earliest targets in plants. The developed DNA markers have been applied to the construction of genetic linkage maps and the resultant maps have contributed to quantitative trait locus (QTL) and gene mappings for agronomically important traits, as well as to comparative genomics of Solanaceae. The recently released whole genome sequences of tomato enable us to develop large numbers of DNA markers comparatively easily, and even promote new genotyping methods without DNA markers. In addition, databases for genomes, DNA markers, genetic linkage maps and other omics data, e.g., transcriptome, proteome, metabolome and phenome information, will provide useful information for molecular breeding in tomatoes. The use of DNA marker technologies in conjunction with new breeding techniques will promise to advance tomato breeding. PMID- 23641180 TI - Updating the Micro-Tom TILLING platform. AB - The dwarf tomato variety Micro-Tom is regarded as a model system for functional genomics studies in tomato. Various tomato genomic tools in the genetic background of Micro-Tom have been established, such as mutant collections, genome information and a metabolomic database. Recent advances in tomato genome sequencing have brought about a significant need for reverse genetics tools that are accessible to the larger community, because a great number of gene sequences have become available from public databases. To meet the requests from the tomato research community, we have developed the Micro-Tom Targeting-Induced Local Lesions IN Genomes (TILLING) platform, which is comprised of more than 5000 EMS mutagenized lines. The platform serves as a reverse genetics tool for efficiently identifying mutant alleles in parallel with the development of Micro-Tom mutant collections. The combination of Micro-Tom mutant libraries and the TILLING approach enables researchers to accelerate the isolation of desirable mutants for unraveling gene function or breeding. To upgrade the genomic tool of Micro-Tom, the development of a new mutagenized population is underway. In this paper, the current status of the Micro-Tom TILLING platform and its future prospects are described. PMID- 23641181 TI - Population structure in Japanese rice population. AB - It is essential to elucidate genetic diversity and relationships among even related individuals and populations for plant breeding and genetic analysis. Since Japanese rice breeding has improved agronomic traits such as yield and eating quality, modern Japanese rice cultivars originated from narrow genetic resource and closely related. To resolve the population structure and genetic diversity in Japanese rice population, we used a total of 706 alleles detected by 134 simple sequence repeat markers in a total of 114 cultivars composed of 94 improved varieties and 20 landraces, which are representative and important for Japanese rice breeding. The landraces exhibit greater gene diversity than improved lines, suggesting that landraces can provide additional genetic diversity for future breeding. Model-based Bayesian clustering analysis revealed six subgroups and admixture situation in the cultivars, showing good agreement with pedigree information. This method could be superior to phylogenetic method in classifying a related population. The leading Japanese rice cultivar, Koshihikari is unique due to the specific genome constitution. We defined Japanese rice diverse sets that capture the maximum number of alleles for given sample sizes. These sets are useful for a variety of genetic application in Japanese rice cultivars. PMID- 23641179 TI - Current challenges and future potential of tomato breeding using omics approaches. AB - As tomatoes are one of the most important vegetables in the world, improvements in the quality and yield of tomato are strongly required. For this purpose, omics approaches such as metabolomics and transcriptomics are used not only for basic research to understand relationships between important traits and metabolism but also for the development of next generation breeding strategies of tomato plants, because an increase in the knowledge improves the taste and quality, stress resistance and/or potentially health-beneficial metabolites and is connected to improvements in the biochemical composition of tomatoes. Such omics data can be applied to network analyses to potentially reveal unknown cellular regulatory networks in tomato plants. The high-quality tomato genome that was sequenced in 2012 will likely accelerate the application of omics strategies, including next generation sequencing for tomato breeding. In this review, we highlight the current studies of omics network analyses of tomatoes and other plant species, in particular, a gene coexpression network. Key applications of omics approaches are also presented as case examples to improve economically important traits for tomato breeding. PMID- 23641182 TI - A major quantitative trait locus for cold-responsive gene expression is linked to frost-resistance gene Fr-A2 in common wheat. AB - Low temperature induces expression of Cor (cold-responsive)/Lea (late embryogenesis-abundant) gene family members through C-repeat binding factor (CBF) transcription factors in common wheat. However, the relationship between the genetic loci controlling cold-responsive gene expression and freezing tolerance is unclear. In expression quantitative trait locus (eQTL) analysis, accumulated transcripts of Cor/Lea and CBF genes were quantified in recombinant inbred lines derived from a cross between two common wheat cultivars with different levels of freezing tolerance. Four eQTLs controlling five cold-responsive genes were found, and the major eQTL with the greatest effect was located on the long arm of chromosome 5A. At least the 1D and 5A eQTLs played important roles in development of freezing tolerance in common wheat. The chromosomal location of the 5A eQTL, controlling four cold-responsive genes, coincided with a region homoeologous to a frost-tolerance locus (Fr-A (m) 2) reported as a CBF cluster region in einkorn wheat. The 5A eQTL plays a significant role through Cor/Lea gene expression in cold acclimation of wheat. In addition, our results suggest that one or more CBF copies at the Fr-2 region positively regulate other copies, which might amplify the positive effects of the CBF cluster on downstream Cor/Lea gene activation. PMID- 23641183 TI - Cloning of allene oxide cyclase gene from Leymus mollis and analysis of its expression in wheat-Leymus chromosome addition lines. AB - Leymus mollis (Triticeae; Poaceae) is a useful genetic resource for wheat (Triticum aestivum L.) breeding via wide hybridization to introduce its chromosomes and integrate its useful traits into wheat. Leymus mollis is highly tolerant to abiotic stresses such as drought and salinity and resistant to various diseases, but the genetic mechanisms controlling its physiological tolerance remain largely unexplored. We identified and cloned an allene oxide cyclase (AOC) gene from L. mollis that was strongly expressed under salt stress. AOC is involved in biosynthesis of jasmonic acid, an important signaling compound that mediates a wide range of adaptive responses. LmAOC cDNA consisted of 717 bp, coding for a protein with 238 amino acids that was highly similar to AOCs from barley (Hordeum vulgare) and other monocots. Subcellular localization using Nicotiana benthamiana confirmed it as a chloroplast-localized protein. LmAOC was found to be a multiple-copy gene, and that some copies were conserved and efficiently expressed in wheat-Leymus chromosome addition lines. LmAOC expression was upregulated under drought, heat, cold and wounding stresses, and by jasmonic acid and abscisic acid. Our results suggest that LmAOC plays an important role in L. mollis adaptation to abiotic stresses and it could be useful for wheat improvement. PMID- 23641184 TI - Multiple and independent origins of short seeded alleles of GS3 in rice. AB - GRAIN SIZE 3 (GS3) is a cloned gene that is related to seed length. Here we report the discovery of new deletion alleles at the GS3 locus, each of which confer short seed. We selected ten short seeded cultivars from a collection of 282 diverse cultivars. Sequence analysis across the GS3 gene in these ten cultivars identified three novel alleles and a known allele that contain several independent deletion(s) in the fifth exon of GS. These independent deletion variants each resulted in a frameshift mutation that caused a premature stop codon, and they were functionally similar to one another. Each coded for a truncated gene product that behaved as an incomplete dominant allele and conferred a short seeded phenotype. Haplotype analysis of these sequence variants indicated that two of the variants were of japonica origin, and two were from indica. Transformation experiments demonstrated that one of the deletion alleles of GS3 decrease the cell number in the upper epidermis of the glume, resulting in a significant reduction in seed length. The multiple and independent origins of these short seeded alleles indicate that farmers and early breeders imposed artificial selection favoring short seeds. PMID- 23641185 TI - Diversity of odor-active compounds from local cultivars and wild accessions of Iwateyamanashi (Pyrus ussuriensis var. aromatica) revealed by Aroma Extract Dilution Analysis (AEDA). AB - Some local cultivars and wilds of Iwateyamanashi (Pyrus ussuriensis var. aromatica) that grows wild in Northern Tohoku, Japan have good aromatic fruit. Iwateyamanashi may be valuable germplasms as a donor of odor compounds in breeding of Japanese pear (Pyrus pyrifolia), because almost all Japanese pear cultivars have faint odor. Fruits odors from a local cultivar 'Sanenashi', a wild accession (i0830) in Iwateyamanashi, cultivars of 'Kosui' and 'La France' were characterized at first with comparative Aroma Extract Dilution Analysis (AEDA). Application of AEDA, based on Gas chromatography/Olfactometry analysis (GC/O), on the odor concentration prepared from 'Sanenashi' indicated the presence of 33 odor-active compounds including methyl and ethyl esters, aldehydes and alcohol. The eleven odor compounds from 16 accessions of Iwateyamanashi showed various combinations and wide range of odor concentrations by Principal Component Analysis (PCA). Especially 2 accessions of local cultivar 'Natsunashi' plotted in the highly ethyl ester group might be useful for Japanese pear breeding. PMID- 23641186 TI - Induction of 2n female gametes in Populus adenopoda Maxim by high temperature exposure during female gametophyte development. AB - In order to produce triploid plants, 2n female gametes were induced by treating female buds and developing embryo sacs of Populus adenopoda Maxim with high temperature exposure. During megasporogenesis, tests were conducted on the relationship between female gametophyte development and morphological changes of female catkins. In the resulting progeny, 12 triploids were produced, and the highest rate of triploid production was 40%. Cytological observation revealed that the pachytene to diakinesis phase of meiotic stages may be a suitable period for inducing megaspore chromosome doubling through high temperature exposure. On the other hand, catkins of 6-72 h after pollination were treated for inducing embryo sac chromosome doubling. In the offspring seedlings, 51 triploids were detected and the highest efficiency of triploid production was 83.33%. Correlation analysis between the proportion of each embryo sac's developmental stage and the percentage of triploid production indicated that the second mitotic division may be the most effective stage for 2n female gamete induction. Our findings showed that high temperature exposure is an ideal method for 2n female gamete induction. Heterozygous offspring are valuable for breeding programs of P. adenopoda. PMID- 23641187 TI - Isolation of a wheat (Triticum aestivum L.) mutant in ABA 8'-hydroxylase gene: effect of reduced ABA catabolism on germination inhibition under field condition. AB - Pre-harvest sprouting, the germination of mature seeds on the mother plant under moist condition, is a serious problem in cereals. To investigate the effect of reduced abscisic acid (ABA) catabolism on germination in hexaploid wheat (Triticum aestivum L.), we cloned the wheat ABA 8'-hydroxyase gene which was highly expressed during seed development (TaABA8'OH1) and screened for mutations that lead to reduced ABA catabolism. In a screen for natural variation, one insertion mutation in exon 5 of TaABA8'OH1 on the D genome (TaABA8'OH1-D) was identified in Japanese cultivars including 'Tamaizumi'. However, a single mutation in TaABA8'OH1-D had no clear effect on germination inhibition in double haploid lines. In a screen for a mutation, one deletion mutant lacking the entire TaABA8'OH1 on the A genome (TaABA8'OH1-A), TM1833, was identified from gamma-ray irradiation lines of 'Tamaizumi'. TM1833 (a double mutant in TaABA8'OH1-A and TaABA8'OH1-D) showed lower TaABA8'OH1 expression, higher ABA content in embryos during seed development under field condition and lower germination than those in 'Tamaizumi' (a single mutant in TaABA8'OH1-D). These results indicate that reduced ABA catabolism through mutations in TaABA8'OH1 may be effective in germination inhibition in field-grown wheat. PMID- 23641188 TI - Fine mapping of the clubroot resistance gene CRb and development of a useful selectable marker in Brassica rapa. AB - In Chinese cabbage (Brassica rapa), the clubroot resistance (CR) gene CRb is effective against Plasmodiophora brassicae isolate No. 14, which is classified as pathotype group 3. Although markers linked to CRb have been reported, an accurate position in the genome and the gene structure are unknown. To determine the genomic location and estimate the structure of CRb, we developed 28 markers (average distance, 20.4 kb) around CRb and constructed a high-density partial map. The precise position of CRb was determined by using a population of 2,032 F2 plants generated by selfing B. rapa 'CR Shinki.' We determined that CRb is located in the 140-kb genomic region between markers KB59N07 and B1005 and found candidate resistance genes. Among other CR genes on chromosome R3, a genotype of CRa closest marker clearly matched those of CRb and Crr3 did not confer resistance to isolate No. 14. Based on the genotypes of 11 markers developed near CRb and resistance to isolate No. 14, 82 of 108 cultivars showed a strong correlation between genotypes and phenotypes. The results of this study will be useful for isolating CRb and breeding cultivars with resistance to pathotype group 3 by introducing CRb into susceptible cultivars through marker-assisted selection. PMID- 23641189 TI - Potential assessment of genome-wide association study and genomic selection in Japanese pear Pyrus pyrifolia. AB - Although the potential of marker-assisted selection (MAS) in fruit tree breeding has been reported, bi-parental QTL mapping before MAS has hindered the introduction of MAS to fruit tree breeding programs. Genome-wide association studies (GWAS) are an alternative to bi-parental QTL mapping in long-lived perennials. Selection based on genomic predictions of breeding values (genomic selection: GS) is another alternative for MAS. This study examined the potential of GWAS and GS in pear breeding with 76 Japanese pear cultivars to detect significant associations of 162 markers with nine agronomic traits. We applied multilocus Bayesian models accounting for ordinal categorical phenotypes for GWAS and GS model training. Significant associations were detected at harvest time, black spot resistance and the number of spurs and two of the associations were closely linked to known loci. Genome-wide predictions for GS were accurate at the highest level (0.75) in harvest time, at medium levels (0.38-0.61) in resistance to black spot, firmness of flesh, fruit shape in longitudinal section, fruit size, acid content and number of spurs and at low levels (<0.2) in all soluble solid content and vigor of tree. Results suggest the potential of GWAS and GS for use in future breeding programs in Japanese pear. PMID- 23641190 TI - Molecular mapping of a sunflower rust resistance gene from HAR6. AB - Sunflower rust, caused by Puccinia helianthi Schw., can result in significant yield losses in cultivated sunflower (Helianthus annuus L. var. macrocarpus Ckll.). HAR6 is a germplasm population resistant to most predominant rust races. The objectives of this study were to map the resistance factor present in HAR6 (R HAR6 ), and to provide and validate molecular tools for the identification of this gene for marker assisted selection purposes. Virulence reaction of seedlings for the F2 population and F2:3 families suggested that a single dominant gene confers rust resistance in HAR6-1, a selected rust resistance line from the original population. Genetic mapping with eight markers covered 97.4 cM of genetic distance on linkage group 13 of the sunflower consensus map. A co dominant marker ZVG61 is the closest marker distal to R HAR6 at a genetic distance of 0.7 cM, while ORS581, a dominant marker linked in the coupling phase, is proximal to R HAR6 at a genetic distance of 1.5 cM. Validation of these markers was assessed by converting a susceptible line into a rust resistant isoline by means of marker assisted backcrossing. The application of these results to assist the breeding process and to design new strategies for rust control in sunflower is discussed. PMID- 23641191 TI - Taking Stock of Parent Education in the Family Courts: Envisioning a Public Health Model. AB - The paper reviewed the development and current status of the parent education movement in the Family Courts. Parent education programs are now being implemented in courts throughout the United States and have a high level of public acceptance; however, a stronger research methodology to evaluate the effects and continued work to align the goals with the content and teaching strategies of these programs are needed. A new conceptual framework is proposed for parent education, which views divorce as a public health problem for children as well as a legal issue. The three-level framework uses concepts from public health to align the goals, content and format of parent education programs and to enable rigorous evaluations of the outcomes achieved by these programs. PMID- 23641192 TI - STRATEGIES TO REDUCE BARRIERS TO RECRUITMENT AND PARTICIPATION. AB - PURPOSE: To identify barriers encountered and solutions employed to improve research recruitment and retention of rural subjects for participation in the Promoting Heart Health in Rural Women (PHH) study. METHODS: This article provides an examination of experiences encountered by nurse researchers in recruiting rural women from two locations to a randomized, controlled trial. Problem solving through broadening recruitment areas and inclusion criteria, community liaison assistance, identification of rural-specific strategies in the literature, and perseverance helped to overcome barriers to subject recruitment and retention in this rural Phase-II nurse-run intervention study. CLINICAL RELEVANCE: Research studies need to be conducted in order to build a body of evidence for nursing interventions to reduce cardiovascular disease risk factors in rural women. A study is strengthened by a robust sample that provides power to statistical analysis. Without discussion of real-world experiences and appropriate and effective recruitment and retention strategies in nursing research, there is little chance of conducting research with appropriate power to build evidence based practice. PMID- 23641193 TI - Adult hippocampal neurogenesis reduces memory interference in humans: opposing effects of aerobic exercise and depression. AB - Since the remarkable discovery of adult neurogenesis in the mammalian hippocampus, considerable effort has been devoted to unraveling the functional significance of these new neurons. Our group has proposed that a continual turnover of neurons in the DG could contribute to the development of event-unique memory traces that act to reduce interference between highly similar inputs. To test this theory, we implemented a recognition task containing some objects that were repeated across trials as well as some objects that were highly similar, but not identical, to ones previously observed. The similar objects, termed lures, overlap substantially with previously viewed stimuli, and thus, may require hippocampal neurogenesis in order to avoid catastrophic interference. Lifestyle factors such as aerobic exercise and stress have been shown to impact the local neurogenic microenvironment, leading to enhanced and reduced levels of DG neurogenesis, respectively. Accordingly, we hypothesized that healthy young adults who take part in a long-term aerobic exercise regime would demonstrate enhanced performance on the visual pattern separation task, specifically at correctly categorizing lures as "similar." Indeed, those who experienced a proportionally large change in fitness demonstrated a significantly greater improvement in their ability to correctly identify lure stimuli as "similar." Conversely, we expected that those who score high on depression scales, an indicator of chronic stress, would exhibit selective deficits at appropriately categorizing lures. As expected, those who scored high on the Beck Depression Inventory (BDI) were significantly worse than those with relatively lower BDI scores at correctly identifying lures as "similar," while performance on novel and repeated stimuli was identical. Taken together, our results support the hypothesis that adult-born neurons in the DG contribute to the orthogonalization of incoming information. PMID- 23641195 TI - Chemokines induce axon outgrowth downstream of Hepatocyte Growth Factor and TCF/beta-catenin signaling. AB - Axon morphogenesis is a complex process regulated by a variety of secreted molecules, including morphogens and growth factors, resulting in the establishment of the neuronal circuitry. Our previous work demonstrated that growth factors [Neurotrophins (NT) and Hepatocyte Growth Factor (HGF)] signal through beta-catenin during axon morphogenesis. HGF signaling promotes axon outgrowth and branching by inducing beta-catenin phosphorylation at Y142 and transcriptional regulation of T-Cell Factor (TCF) target genes. Here, we asked which genes are regulated by HGF signaling during axon morphogenesis. An array screening indicated that HGF signaling elevates the expression of chemokines of the CC and CXC families. In line with this, CCL7, CCL20, and CXCL2 significantly increase axon outgrowth in hippocampal neurons. Experiments using blocking antibodies and chemokine receptor antagonists demonstrate that chemokines act downstream of HGF signaling during axon morphogenesis. In addition, qPCR data demonstrates that CXCL2 and CCL5 expression is stimulated by HGF through Met/b catenin/TCF pathway. These results identify CC family members and CXCL2 chemokines as novel regulators of axon morphogenesis downstream of HGF signaling. PMID- 23641197 TI - FMRP: a triple threat to PSD-95. PMID- 23641196 TI - Interleukin-1beta and tumor necrosis factor-alpha: reliable targets for protective therapies in Parkinson's Disease? AB - Neuroinflammation has received increased attention as a target for putative neuroprotective therapies in Parkinson's Disease (PD). Two prototypic pro inflammatory cytokines interleukin-1beta (IL-1) and tumor necrosis factor-alpha (TNF) have been implicated as main effectors of the functional consequences of neuroinflammation on neurodegeneration in PD models. In this review, we describe that the functional interaction between these cytokines in the brain differs from the periphery (e.g., their expression is not induced by each other) and present data showing predominantly a toxic effect of these cytokines when expressed at high doses and for a sustained period of time in the substantia nigra pars compacta (SN). In addition, we highlight opposite evidence showing protective effects of these two main cytokines when conditions of duration, amount of expression or state of activation of the target or neighboring cells are changed. Furthermore, we discuss these results in the frame of previous disappointing results from anti-TNF-alpha clinical trials against Multiple Sclerosis, another neurodegenerative disease with a clear neuroinflammatory component. In conclusion, we hypothesize that the available evidence suggests that the duration and dose of IL-1beta or TNF-alpha expression is crucial to predict their functional effect on the SN. Since these parameters are not amenable for measurement in the SN of PD patients, we call for an in-depth analysis to identify downstream mediators that could be common to the toxic (and not the protective) effects of these cytokines in the SN. This strategy could spare the possible neuroprotective effect of these cytokines operative in the patient at the time of treatment, increasing the probability of efficacy in a clinical setting. Alternatively, receptor-specific agonists or antagonists could also provide a way to circumvent undesired effects of general anti-inflammatory or specific anti-IL-1beta or TNF-alpha therapies against PD. PMID- 23641199 TI - Fluoxetine impairs GABAergic signaling in hippocampal slices from neonatal rats. AB - Fluoxetine (Prozac), an antidepressant known to selectively inhibit serotonin reuptake, is widely used to treat mood disorders in women suffering from depression during pregnancy and postpartum period. Several lines of evidence suggest that this drug, which crosses the human placenta and is secreted into milk during lactation, exerts its action not only by interfering with serotoninergic but also with GABAergic transmission. GABA is known to play a crucial role in the construction of neuronal circuits early in postnatal development. The immature hippocampus is characterized by an early type of network activity, the so-called Giant Depolarizing Potentials (GDPs), generated by the synergistic action of glutamate and GABA, both depolarizing and excitatory. Here we tested the hypothesis that fluoxetine may interfere with GABAergic signaling during the first postnatal week, thus producing harmful effects on brain development. At micromolar concentrations fluoxetine severely depressed GDPs frequency (IC50 22 MUM) in a reversible manner and independently of its action on serotonin reuptake. This effect was dependent on a reduced GABAergic (but not glutamatergic) drive to principal cells most probably from parvalbumin-positive fast spiking neurons. Cholecystokinin-positive GABAergic interneurons were not involved since the effects of the drug persisted when cannabinoid receptors were occluded with WIN55,212-2, a CB1/CB2 receptor agonist. Fluoxetine effects on GABAergic transmission were associated with a reduced firing rate of both principal cells and interneurons further suggesting that changes in network excitability account for GDPs disruption. This may have critical consequences on the functional organization and stabilization of neuronal circuits early in postnatal development. PMID- 23641198 TI - Imaging the microanatomy of astrocyte-T-cell interactions in immune-mediated inflammation. AB - The role of astrocytes in the immune-mediated inflammatory response in the brain is more prominent than previously thought. Astrocytes become reactive in response to neuro-inflammatory stimuli through multiple pathways, contributing significantly to the machinery that modifies the parenchymal environment. In particular, astrocytic signaling induces the establishment of critical relationships with infiltrating blood cells, such as lymphocytes, which is a fundamental process for an effective immune response. The interaction between astrocytes and T-cells involves complex modifications to both cell types, which undergo micro-anatomical changes and the redistribution of their binding and secretory domains. These modifications are critical for different immunological responses, such as for the effectiveness of the T-cell response, for the specific infiltration of these cells and their homing in the brain parenchyma, and for their correct apposition with antigen-presenting cells (APCs) to form immunological synapses (ISs). In this article, we review the current knowledge of the interactions between T-cells and astrocytes in the context of immune-mediated inflammation in the brain, based on the micro-anatomical imaging of these appositions by high-resolution confocal microscopy and three-dimensional rendering. The study of these dynamic interactions using detailed technical approaches contributes to understanding the function of astrocytes in inflammatory responses and paves the way for new therapeutic strategies. PMID- 23641200 TI - Control of a specific motor program by a small brain area in zebrafish. AB - Complex motor behaviors are thought to be coordinated by networks of brain nuclei that may control different elementary motor programs. Transparent zebrafish larvae offer the opportunity to analyze the functional organization of motor control networks by optical manipulations of neuronal activity during behavior. We examined motor behavior in transgenic larvae expressing channelrhodopsin-2 throughout many neurons in the brain. Wide-field optical stimulation triggered backward and rotating movements caused by the repeated execution of J-turns, a specific motor program that normally occurs during prey capture. Although optically-evoked activity was widespread, behavioral responses were highly coordinated and lateralized. 3-D mapping of behavioral responses to local optical stimuli revealed that J-turns can be triggered specifically in the anterior ventral optic tectum (avOT) and/or the adjacent pretectum. These results suggest that the execution of J-turns is controlled by a small group of neurons in the midbrain that may act as a command center. The identification of a brain area controlling a defined motor program involved in prey capture is a step toward a comprehensive analysis of neuronal circuits mediating sensorimotor behaviors of zebrafish. PMID- 23641202 TI - Empirical testing of hypotheses about the evolution of genomic imprinting in mammals. AB - The close interaction between mother and offspring in mammals is thought to contribute to the evolution of genomic imprinting or parent-of-origin dependent gene expression. Empirical tests of theories about the evolution of imprinting have been scant for several reasons. Models make different assumptions about the traits affected by imprinted genes and the scenarios in which imprinting is predicted to have been selected for. Thus, competing hypotheses cannot readily be tested against each other. Further, it is far from clear how predictions about expression patterns of genes with specific phenotypic effects can be tested given current methodology of assaying gene expression levels, be it in the brain or in other tissues. We first set out a scenario for testing competing hypotheses and delineate the different assumptions and predictions of models. We then outline how predictions may be tested using mouse models such as intercrosses or recombinant inbred (RI) systems that can be phenotyped for traits relevant to imprinting theories. Further, we briefly discuss different molecular approaches that may be used in conjunction with experiments to ascertain expression patterns of imprinted genes and thus the testing of predictions. PMID- 23641201 TI - Tonotopic and localized pathways from primary auditory cortex to the central nucleus of the inferior colliculus. AB - Descending projections from the cortex to subcortical structures are critical for auditory plasticity, including the ability for central neurons to adjust their frequency tuning to relevant and meaningful stimuli. We show that focal electrical stimulation of primary auditory cortex in guinea pigs produces excitatory responses in the central nucleus of the inferior colliculus (CNIC) with two tonotopic patterns: a narrow tuned pattern that is consistent with previous findings showing direct frequency-aligned projections; and a broad tuned pattern in which the auditory cortex can influence multiple frequency regions. Moreover, excitatory responses could be elicited in the caudomedial portion along the isofrequency laminae of the CNIC but not in the rostrolateral portion. This descending organization may underlie or contribute to the ability of the auditory cortex to induce changes in frequency tuning of subcortical neurons as shown extensively in previous studies. PMID- 23641203 TI - A unified framework for the organization of the primate auditory cortex. AB - In non-human primates a scheme for the organization of the auditory cortex is frequently used to localize auditory processes. The scheme allows a common basis for comparison of functional organization across non-human primate species. However, although a body of functional and structural data in non-human primates supports an accepted scheme of nearly a dozen neighboring functional areas, can this scheme be directly applied to humans? Attempts to expand the scheme of auditory cortical fields in humans have been severely hampered by a recent controversy about the organization of tonotopic maps in humans, centered on two different models with radically different organization. We point out observations that reconcile the previous models and suggest a distinct model in which the human cortical organization is much more like that of other primates. This unified framework allows a more robust and detailed comparison of auditory cortex organization across primate species including humans. PMID- 23641204 TI - Female vulnerability to the development of depression-like behavior in a rat model of intimate partner violence is related to anxious temperament, coping responses, and amygdala vasopressin receptor 1a expression. AB - Exposure to violence is traumatic and an important source of mental health disturbance, yet the factors associated with victimization remain incompletely understood. The aim of the present study was to investigate factors related to vulnerability to depression-like behaviors in females. An animal model of intimate partner violence, which was previously shown to produce long-lasting behavioral effects in females as a result of male partner aggression, was used. The associations among the degree of partner aggression, the long-term consequences on depressive-like behavior, and the impact of the anxious temperament of the female were examined. In a separate group, pre-selected neural markers were evaluated in the amygdala and the lateral septum of females. Expression was examined by analyses of targeted candidate genes, serotonin transporter (slc6a4), vasopressin receptor 1a, (avpr1a), and oxytocin receptor (oxtr). Structural equation modeling revealed that the female's temperament moderated depressive-like behavior that was induced by cohabitation aggression from the male partner. More specifically, increased floating in the forced swim test following male aggression was most apparent in females exhibiting more anxiety-like behavior (i.e., less open arm exploration in an elevated plus-maze) prior to the cohabitation. Aggression reduced slc6a4 levels in the lateral septum. However, the interaction between partner aggression and the anxious temperament of the female affected the expression of avpr1a in the amygdala. Although, aggression reduced levels of this marker in females with high anxiety, no such pattern was observed in females with low anxiety. These results identify important characteristics in females that moderate the impact of male aggression. Furthermore, these results provide potential therapeutic targets of interest in the amygdala and the lateral septum to help improve post-stress behavioral pathology and increase resilience to social adversity. PMID- 23641205 TI - Preserved tool knowledge in the context of impaired action knowledge: implications for models of semantic memory. AB - A number of studies have observed that the motor system is activated when processing the semantics of manipulable objects. Such phenomena have been taken as evidence that simulation over motor representations is a necessary and intermediary step in the process of conceptual understanding. Cognitive neuropsychological evaluations of patients with impairments for action knowledge permit a direct test of the necessity of motor simulation in conceptual processing. Here, we report the performance of a 47-year-old male individual (Case AA) and six age-matched control participants on a number of tests probing action and object knowledge. Case AA had a large left-hemisphere frontal-parietal lesion and hemiplegia affecting his right arm and leg. Case AA presented with impairments for object-associated action production, and his conceptual knowledge of actions was severely impaired. In contrast, his knowledge of objects such as tools and other manipulable objects was largely preserved. The dissociation between action and object knowledge is difficult to reconcile with strong forms of the embodied cognition hypothesis. We suggest that these, and other similar findings, point to the need to develop tractable hypotheses about the dynamics of information exchange among sensory, motor and conceptual processes. PMID- 23641207 TI - Hemispatial neglect: computer-based testing allows more sensitive quantification of attentional disorders and recovery and might lead to better evaluation of rehabilitation. PMID- 23641206 TI - Orchestrating neuronal networks: sustained after-effects of transcranial alternating current stimulation depend upon brain states. AB - The interest in transcranial alternating current stimulation (tACS) has significantly increased in the past decade. It has potential to modulate brain oscillations in a frequency specific manner, offering the possibility to demonstrate a causal nature of oscillation behavior relationships. TACS is a strong candidate as a tool for clinical applications, however, to fulfill this potential, certain parameters have yet to be evaluated. First, little is known about long-lasting after-effects of tACS with respect to the modulations of rhythmic brain activity. Second, the power of endogenous brain oscillations might play a crucial role in the efficacy of tACS. We hypothesize that the after effects of tACS depend on the endogenous power of oscillations. To this end, we modulated the power of endogenous occipital alpha oscillations via tACS. In two experiments, participants either had their eyes open or closed to keep endogenous alpha power either low or high while they were stimulated for 20 min with their individual alpha frequency (IAF) and simultaneously performing a vigilance task. After-effects on IAF power were evaluated over a course of 30 min with a pre stimulation period serving as baseline. After-effects were strongly dependent on IAF power. Enhanced IAF power was observed for at least 30 min after tACS under conditions of low endogenous IAF power, whereas, IAF power could not be further enhanced by tACS under conditions of high IAF power. The current study demonstrates, for the first time, a long lasting effect after tACS on endogenous EEG power in the range of the stimulation frequency. Additionally, we present conclusive evidence that the power of the endogenous oscillations has a critical impact on tACS efficacy. Long lasting after-effects foster the role of tACS as a tool for non-invasive brain stimulation and demonstrate the potential for therapeutic application to reestablish the balance of altered brain oscillations. PMID- 23641208 TI - Beyond Noise: Using Temporal ICA to Extract Meaningful Information from High Frequency fMRI Signal Fluctuations during Rest. AB - Analysis of resting-state networks using fMRI usually ignores high-frequency fluctuations in the BOLD signal - be it because of low TR prohibiting the analysis of fluctuations with frequencies higher than 0.25 Hz (for a typical TR of 2 s), or because of the application of a bandpass filter (commonly restricting the signal to frequencies lower than 0.1 Hz). While the standard model of convolving neuronal activity with a hemodynamic response function suggests that the signal of interest in fMRI is characterized by slow fluctuation, it is in fact unclear whether the high-frequency dynamics of the signal consists of noise only. In this study, 10 subjects were scanned at 3 T during 6 min of rest using a multiband EPI sequence with a TR of 354 ms to critically sample fluctuations of up to 1.4 Hz. Preprocessed data were high-pass filtered to include only frequencies above 0.25 Hz, and voxelwise whole-brain temporal ICA (tICA) was used to identify consistent high-frequency signals. The resulting components include physiological background signal sources, most notably pulsation and heart-beat components, that can be specifically identified and localized with the method presented here. Perhaps more surprisingly, common resting-state networks like the default-mode network also emerge as separate tICA components. This means that high-frequency oscillations sampled with a rather T1-weighted contrast still contain specific information on these resting-state networks to consistently identify them, not consistent with the commonly held view that these networks operate on low-frequency fluctuations alone. Consequently, the use of bandpass filters in resting-state data analysis should be reconsidered, since this step eliminates potentially relevant information. Instead, more specific methods for the elimination of physiological background signals, for example by regression of physiological noise components, might prove to be viable alternatives. PMID- 23641209 TI - A supplementary circuit rule-set for the neuronal wiring. AB - Limitations of known anatomical circuit rules necessitate the identification of supplementary rules. This is essential for explaining how associative sensory stimuli induce nervous system changes that generate internal sensations of memory, concurrent with triggering specific motor activities in response to specific cue stimuli. A candidate mechanism is rapidly reversible, yet stabilizable membrane hemi-fusion formed between the closely apposed postsynaptic membranes of different neurons at locations of convergence of sensory inputs during associative learning. The lateral entry of activity from the cue stimulus activated postsynapse re-activates the opposite postsynapse through the hemi fused area and induces the basic units of internal sensation (namely, semblions) as a systems property. Working, short-term and long-term memories can be viewed as functions of the number of re-activatible hemi-fusions present at the time of memory retrieval. Blocking membrane hemi-fusion either by the insertion of the herpes simplex virus (HSV) glycoproteins or by the deposition of insoluble intermediates of amyloid protein in the inter-postsynaptic extracellular matrix (ECM) space leads to cognitive impairments, supporting this mechanism. The introduction of membrane fusion blockers into the postsynaptic cell cytoplasm that attenuates long-term potentiation (LTP), a correlate of behavioral motor activities in response to memory retrieval, provides further support. The lateral spread of activity through the inter-postsynaptic membrane is capable of contributing to oscillating neuronal activity at certain neuronal orders. At the resting state these oscillations provide sub-threshold activation to many neurons at higher orders, including motor neurons maintaining them at a low initiation threshold for motor activity. PMID- 23641210 TI - Synaptic encoding of temporal contiguity. AB - Often we need to perform tasks in an environment that changes stochastically. In these situations it is important to learn the statistics of sequences of events in order to predict the future and the outcome of our actions. The statistical description of many of these sequences can be reduced to the set of probabilities that a particular event follows another event (temporal contiguity). Under these conditions, it is important to encode and store in our memory these transition probabilities. Here we show that for a large class of synaptic plasticity models, the distribution of synaptic strengths encodes transitions probabilities. Specifically, when the synaptic dynamics depend on pairs of contiguous events and the synapses can remember multiple instances of the transitions, then the average synaptic weights are a monotonic function of the transition probabilities. The synaptic weights converge to the distribution encoding the probabilities also when the correlations between consecutive synaptic modifications are considered. We studied how this distribution depends on the number of synaptic states for a specific model of a multi-state synapse with hard bounds. In the case of bistable synapses, the average synaptic weights are a smooth function of the transition probabilities and the accuracy of the encoding depends on the learning rate. As the number of synaptic states increases, the average synaptic weights become a step function of the transition probabilities. We finally show that the information stored in the synaptic weights can be read out by a simple rate-based neural network. Our study shows that synapses encode transition probabilities under general assumptions and this indicates that temporal contiguity is likely to be encoded and harnessed in almost every neural circuit in the brain. PMID- 23641211 TI - The Mesoscopic Modeling of Burst Suppression during Anesthesia. AB - The burst-suppression pattern is well recognized as a distinct feature of the mammalian electroencephalogram (EEG) waveform. Consisting of alternating periods of high amplitude oscillatory and isoelectric activity, it can be induced in health by deep anesthesia as well as being evoked by a range of pathophysiological processes that include coma and anoxia. While the electroencephalographic phenomenon and clinical implications of burst suppression have been studied extensively, the physiological mechanisms underlying its emergence remain unresolved and obscure. Because electroencephalographic bursting phenomenologically resembles the bursting observed in single neurons, it would be reasonable to assume that the theoretical insights developed to understand bursting at the cellular ("microscopic") level would enable insights into the dynamical genesis of bursting at the level of the whole brain ("macroscopic"). In general action potential bursting is the result of the interplay of two time scales: a fast time scale responsible for spiking, and a slow time scale that modulates such activity. We therefore hypothesize that such fast-slow systems dynamically underpin electroencephalographic bursting. Here we show that a well known mean field dynamical model of the electroencephalogram, the Liley model, while unable to produce burst suppression unmodified, is able to give rise to a wide variety of burst-like activity by the addition of one or more slow systems modulating model parameters speculated to be major "targets" for anesthetic action. The development of a physiologically plausible theoretical framework to account for burst suppression will lead to a more complete physiological understanding of the EEG and the mechanisms that serve to modify ongoing brain activity necessary for purposeful behavior and consciousness. PMID- 23641214 TI - Letters to the editor. PMID- 23641213 TI - Reward-based learning for virtual neurorobotics through emotional speech processing. AB - Reward-based learning can easily be applied to real life with a prevalence in children teaching methods. It also allows machines and software agents to automatically determine the ideal behavior from a simple reward feedback (e.g., encouragement) to maximize their performance. Advancements in affective computing, especially emotional speech processing (ESP) have allowed for more natural interaction between humans and robots. Our research focuses on integrating a novel ESP system in a relevant virtual neurorobotic (VNR) application. We created an emotional speech classifier that successfully distinguished happy and utterances. The accuracy of the system was 95.3 and 98.7% during the offline mode (using an emotional speech database) and the live mode (using live recordings), respectively. It was then integrated in a neurorobotic scenario, where a virtual neurorobot had to learn a simple exercise through reward-based learning. If the correct decision was made the robot received a spoken reward, which in turn stimulated synapses (in our simulated model) undergoing spike-timing dependent plasticity (STDP) and reinforced the corresponding neural pathways. Both our ESP and neurorobotic systems allowed our neurorobot to successfully and consistently learn the exercise. The integration of ESP in real-time computational neuroscience architecture is a first step toward the combination of human emotions and virtual neurorobotics. PMID- 23641212 TI - The neural origin of muscle synergies. AB - Muscle synergies are neural coordinative structures that function to alleviate the computational burden associated with the control of movement and posture. In this commentary, we address two critical questions: the explicit encoding of muscle synergies in the nervous system, and how muscle synergies simplify movement production. We argue that shared and task-specific muscle synergies are neurophysiological entities whose combination, orchestrated by the motor cortical areas and the afferent systems, facilitates motor control and motor learning. PMID- 23641215 TI - Effects of Urotensin II Receptor Antagonist, GSK1440115, in Asthma. AB - BACKGROUND: Urotensin II (U-II) is highly expressed in the human lung and has been implicated in regulating respiratory physiology in preclinical studies. Our objective was to test antagonism of the urotensin (UT) receptor by GSK1440115, a novel, competitive, and selective inhibitor of the UT receptor, as a therapeutic strategy for the treatment of asthma. METHODS: Safety, tolerability, and pharmacokinetics (PK) of single doses of GSK1440115 (1-750 mg) were assessed in a Phase I, placebo controlled study in 70 healthy subjects. In a Phase Ib study, 12 asthmatic patients were randomized into a two-period, single-blind crossover study and treated with single doses of 750 mg GSK1440115 or placebo and given a methacholine challenge. RESULTS: Administration of GSK1440115 was safe and well tolerated in healthy subjects and asthmatic patients. In both studies, there was a high degree of variability in the observed PK following oral dosing with GSK1440115 at all doses. There was a marked food effect in healthy subjects at the 50 mg dose. In the presence of food at the 750 mg dose, the time to maximal concentration was between 2 and 6 h and the terminal half-life was short at approximately 2 h. All asthmatic patients maintained greater than the predicted concentration levels necessary to achieve predicted 96% receptor occupancy for >=3 h (between 4 and 7 h post-dose). There were no apparent trends or relationships between the systemic plasma exposure of GSK1440115 and pharmacodynamic endpoints, PC20 after methacholine challenge and FEV1, in asthmatics. CONCLUSION: While GSK1440115 was safe and well-tolerated, it did not induce bronchodilation in asthmatics, or protect against methacholine-induced bronchospasm, suggesting that acute UT antagonism is not likely to provide benefit as an acute bronchodilator in this patient population. PMID- 23641216 TI - Mechanisms of resistance to chemotherapeutic and anti-angiogenic drugs as novel targets for pancreatic cancer therapy. AB - Pancreatic cancer remains one of the most lethal and poorly understood human malignancies and will continue to be a major unsolved health problem in the 21(st) century. Despite efforts over the past three decades to improve diagnosis and treatment, the prognosis for patients with pancreatic cancer is extremely poor with or without treatment, and incidence rates are virtually identical to mortality rates. Although advances have been made through the identification of relevant molecular pathways in pancreatic cancer, there is still a critical, unmet need for the translation of these findings into effective therapeutic strategies that could reduce the intrinsic drug resistance of this disease and for the integration of these molecularly targeted agents into established combination chemotherapy and radiotherapy regimens in order to improve patients' survival. Tumors are heterogeneous cellular entities whose growth and progression depend on reciprocal interactions between genetically altered neoplastic cells and a non-neoplastic microenvironment. To date, most of the mechanisms of resistance studied have been related to tumor cell-autonomous signaling pathways. However, recent data suggest a putative important role of tumor microenvironment in the development and maintenance of resistance to classic chemotherapeutic and targeted therapies. This present review is meant to describe and discuss some of the most important advances in the comprehension of the tumor cell-autonomous and tumor microenvironment-related molecular mechanisms responsible for the resistance of pancreatic cancer to the proapoptotic activity of the classic chemotherapeutic agents and to the most novel anti-angiogenic drugs. We present some of the emerging therapeutic targets for the modulation of this resistant phenotype. PMID- 23641217 TI - Practical aspects of estimating energy components in rodents. AB - Recently there has been an increasing interest in exploiting computational and statistical techniques for the purpose of component analysis of indirect calorimetry data. Using these methods it becomes possible to dissect daily energy expenditure into its components and to assess the dynamic response of the resting metabolic rate (RMR) to nutritional and pharmacological manipulations. To perform robust component analysis, however, is not straightforward and typically requires the tuning of parameters and the preprocessing of data. Moreover the degree of accuracy that can be attained by these methods depends on the configuration of the system, which must be properly taken into account when setting up experimental studies. Here, we review the methods of Kalman filtering, linear, and penalized spline regression, and minimal energy expenditure estimation in the context of component analysis and discuss their results on high resolution datasets from mice and rats. In addition, we investigate the effect of the sample time, the accuracy of the activity sensor, and the washout time of the chamber on the estimation accuracy. We found that on the high resolution data there was a strong correlation between the results of Kalman filtering and penalized spline (P-spline) regression, except for the activity respiratory quotient (RQ). For low resolution data the basal metabolic rate (BMR) and resting RQ could still be estimated accurately with P-spline regression, having a strong correlation with the high resolution estimate (R (2) > 0.997; sample time of 9 min). In contrast, the thermic effect of food (TEF) and activity related energy expenditure (AEE) were more sensitive to a reduction in the sample rate (R (2) > 0.97). In conclusion, for component analysis on data generated by single channel systems with continuous data acquisition both Kalman filtering and P-spline regression can be used, while for low resolution data from multichannel systems P-spline regression gives more robust results. PMID- 23641219 TI - The predictive brain and the "free will" illusion. PMID- 23641220 TI - Influences of rhythm- and timbre-related musical features on characteristics of music-induced movement. AB - Music makes us move. Several factors can affect the characteristics of such movements, including individual factors or musical features. For this study, we investigated the effect of rhythm- and timbre-related musical features as well as tempo on movement characteristics. Sixty participants were presented with 30 musical stimuli representing different styles of popular music, and instructed to move along with the music. Optical motion capture was used to record participants' movements. Subsequently, eight movement features and four rhythm- and timbre-related musical features were computationally extracted from the data, while the tempo was assessed in a perceptual experiment. A subsequent correlational analysis revealed that, for instance, clear pulses seemed to be embodied with the whole body, i.e., by using various movement types of different body parts, whereas spectral flux and percussiveness were found to be more distinctly related to certain body parts, such as head and hand movement. A series of ANOVAs with the stimuli being divided into three groups of five stimuli each based on the tempo revealed no significant differences between the groups, suggesting that the tempo of our stimuli set failed to have an effect on the movement features. In general, the results can be linked to the framework of embodied music cognition, as they show that body movements are used to reflect, imitate, and predict musical characteristics. PMID- 23641221 TI - How to Investigate Within-Subject Associations between Physical Activity and Momentary Affective States in Everyday Life: A Position Statement Based on a Literature Overview. AB - Several meta-analyses have investigated the association between physical activity and affective states and have found evidence suggesting that exercise exerts a positive effect on affective state. However, in this field of research, most studies have conducted between-subject analyses. Nonetheless, there is more and more interest in the within-subject associations between physical activity and momentary affective states in everyday life. This position statement pertains to this up-and-coming field of research and provides methodological recommendations for further studies. The paper is divided into three parts: first, we summarize and evaluate three methodological requirements necessary for the proper evaluation of within-subject associations between physical activity and momentary affective states in everyday life. We propose that the following issues should be considered: (a) to address the dynamic nature of such relationships, repeated assessments are necessary; (b) as activities performed in everyday life are mostly spontaneous and unconscious, an objective assessment of physical activity is useful; (c) given that recall of affective states is often affected by systematic distortions, real-time assessment is preferable. In sum, we suggest the use of ambulatory assessment techniques, and more specifically the combination of accelerometer-assessment of physical activity with an electronic diary assessment of the momentary affective state and additional context information. Second, we summarize 22 empirical studies published between 1980 and 2012 using ambulatory assessment to investigate within-subject associations between momentary affective states and physical activity in everyday life. Generally, the literature overview detects a positive association, which appears stronger among those studies that were of high methodological quality. Third, we propose the use of ambulatory assessment intervention (AAIs) strategies to change people's behavior and to enable people to be active as often as possible during the day (e.g., reducing sitting time, taking more steps per day). PMID- 23641218 TI - Neuronal nicotinic acetylcholine receptors: common molecular substrates of nicotine and alcohol dependence. AB - Alcohol and nicotine are often co-abused. As many as 80-95% of alcoholics are also smokers, suggesting that ethanol and nicotine, the primary addictive component of tobacco smoke, may functionally interact in the central nervous system and/or share a common mechanism of action. While nicotine initiates dependence by binding to and activating neuronal nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels normally activated by endogenous acetylcholine (ACh), ethanol is much less specific with the ability to modulate multiple gene products including those encoding voltage-gated ion channels, and excitatory/inhibitory neurotransmitter receptors. However, emerging data indicate that ethanol interacts with nAChRs, both directly and indirectly, in the mesocorticolimbic dopaminergic (DAergic) reward circuitry to affect brain reward systems. Like nicotine, ethanol activates DAergic neurons of the ventral tegmental area (VTA) which project to the nucleus accumbens (NAc). Blockade of VTA nAChRs reduces ethanol-mediated activation of DAergic neurons, NAc DA release, consumption, and operant responding for ethanol in rodents. Thus, ethanol may increase ACh release into the VTA driving activation of DAergic neurons through nAChRs. In addition, ethanol potentiates distinct nAChR subtype responses to ACh and nicotine in vitro and in DAergic neurons. The smoking cessation therapeutic and nAChR partial agonist, varenicline, reduces alcohol consumption in heavy drinking smokers and rodent models of alcohol consumption. Finally, single nucleotide polymorphisms in nAChR subunit genes are associated with alcohol dependence phenotypes and smoking behaviors in human populations. Together, results from pre-clinical, clinical, and genetic studies indicate that nAChRs may have an inherent role in the abusive properties of ethanol, as well as in nicotine and alcohol co-dependence. PMID- 23641222 TI - To be or Not to be Threatening, but What was the Question? Biased Face Evaluation in Social Anxiety and Depression Depends on How You Frame the Query. AB - Scientific evidence is equivocal on whether Social Anxiety Disorder (SAD) is characterized by a biased negative evaluation of facial expressions, even though it is assumed that such a bias plays a crucial role in the maintenance of the disorder. The way of framing the evaluation question may play an important role in the inconsistencies of earlier results. To investigate this issue, an unselected sample of 95 participants (11 males) with varying degrees of social anxiety and depressive symptoms rated facial crowds with different ratios of neutral-disgust, neutral-sad, neutral-happy, and neutral-surprised expressions in terms of friendliness, approval, difficulty to make contact, and threat. It appeared that the impact of social anxiety on ratings was highly dependent on the type of question that was asked, but not on the type of emotion that was shown: a high degree of social anxiety was related to a more positive evaluation of crowds when friendliness was assessed. When asking about the difficulty to make contact, social anxiety was related to more difficulty. When the threat evoked by a crowd had to be evaluated, higher degrees of social anxiety were tendentiously correlated with higher threat ratings. Degree of depression, on the other hand, was negatively correlated only to approval ratings. In addition, with an increasing degree of depression, the negative impact that any additional emotional face had on approval ratings increased as well. The theoretical and methodological implications of the results are discussed. PMID- 23641223 TI - Toward a neural chronometry for the aesthetic experience of music. AB - Music is often studied as a cognitive domain alongside language. The emotional aspects of music have also been shown to be important, but views on their nature diverge. For instance, the specific emotions that music induces and how they relate to emotional expression are still under debate. Here we propose a mental and neural chronometry of the aesthetic experience of music initiated and mediated by external and internal contexts such as intentionality, background mood, attention, and expertise. The initial stages necessary for an aesthetic experience of music are feature analysis, integration across modalities, and cognitive processing on the basis of long-term knowledge. These stages are common to individuals belonging to the same musical culture. The initial emotional reactions to music include the startle reflex, core "liking," and arousal. Subsequently, discrete emotions are perceived and induced. Presumably somatomotor processes synchronizing the body with the music also come into play here. The subsequent stages, in which cognitive, affective, and decisional processes intermingle, require controlled cross-modal neural processes to result in aesthetic emotions, aesthetic judgments, and conscious liking. These latter aesthetic stages often require attention, intentionality, and expertise for their full actualization. PMID- 23641224 TI - The embodied mind extended: using words as social tools. AB - The extended mind view and the embodied-grounded view of cognition and language are typically considered as rather independent perspectives. In this paper we propose a possible integration of the two views and support it proposing the idea of "Words As social Tools" (WAT). In this respect, we will propose that words, also due to their social and public character, can be conceived as quasi-external devices that extend our cognition. Moreover, words function like tools in that they enlarge the bodily space of action thus modifying our sense of body. To support our proposal, we review the relevant literature on tool-use and on words as tools and report recent evidence indicating that word use leads to an extension of space close to the body. In addition, we outline a model of the neural processes that may underpin bodily space extension via word use and may reflect possible effects on cognition of the use of words as external means. We also discuss how reconciling the two perspectives can help to overcome the limitations they encounter if considered independently. PMID- 23641225 TI - Music training, cognition, and personality. AB - Although most studies that examined associations between music training and cognitive abilities had correlational designs, the prevailing bias is that music training causes improvements in cognition. It is also possible, however, that high-functioning children are more likely than other children to take music lessons, and that they also differ in personality. We asked whether individual differences in cognition and personality predict who takes music lessons and for how long. The participants were 118 adults (Study 1) and 167 10- to 12-year-old children (Study 2). We collected demographic information and measured cognitive ability and the Big Five personality dimensions. As in previous research, cognitive ability was associated with musical involvement even when demographic variables were controlled statistically. Novel findings indicated that personality was associated with musical involvement when demographics and cognitive ability were held constant, and that openness-to-experience was the personality dimension with the best predictive power. These findings reveal that: (1) individual differences influence who takes music lessons and for how long, (2) personality variables are at least as good as cognitive variables at predicting music training, and (3) future correlational studies of links between music training and non-musical ability should account for individual differences in personality. PMID- 23641227 TI - Measuring individual differences in generic beliefs in conspiracy theories across cultures: conspiracy mentality questionnaire. AB - Conspiracy theories are ubiquitous when it comes to explaining political events and societal phenomena. Individuals differ not only in the degree to which they believe in specific conspiracy theories, but also in their general susceptibility to explanations based on such theories, that is, their conspiracy mentality. We present the Conspiracy Mentality Questionnaire (CMQ), an instrument designed to efficiently assess differences in the generic tendency to engage in conspiracist ideation within and across cultures. The CMQ is available in English, German, and Turkish. In four studies, we examined the CMQ's factorial structure, reliability, measurement equivalence across cultures, and its convergent, discriminant, and predictive validity. Analyses based on a cross-cultural sample (Study 1a; N = 7,766) supported the conceptualization of conspiracy mentality as a one dimensional construct across the three language versions of the CMQ that is stable across time (Study 1b; N = 141). Multi-group confirmatory factor analysis demonstrated cross-cultural measurement equivalence of the CMQ items. The instrument could therefore be used to examine differences in conspiracy mentality between European, North American, and Middle Eastern cultures. In Studies 2-4 (total N = 476), we report (re-)analyses of three datasets demonstrating the validity of the CMQ in student and working population samples in the UK and Germany. First, attesting to its convergent validity, the CMQ was highly correlated with another measure of generic conspiracy belief. Second, the CMQ showed patterns of meaningful associations with personality measures (e.g., Big Five dimensions, schizotypy), other generalized political attitudes (e.g., social dominance orientation and right-wing authoritarianism), and further individual differences (e.g., paranormal belief, lack of socio-political control). Finally, the CMQ predicted beliefs in specific conspiracy theories over and above other individual difference measures. PMID- 23641228 TI - On language production principles and the form of language: a mas como, menos por que. PMID- 23641226 TI - A review of embodiment in autism spectrum disorders. AB - In classical approaches to cognition, sensory, motor, and emotional experiences are stripped of domain-specific perceptual and sensorimotor information, and represented in a relatively abstract form. In contrast, the embodied cognition framework suggests that our representations retain the initial imprint of the manner in which information was acquired. In this paper, we argue that individuals with autism spectrum disorders (ASD) display impairments in the temporal coordination of motor and conceptual information (as shown in gesture research) and striking deficits in the interpersonal mimicry of motor behaviors (as shown in yawning research) - findings we believe are consistent with an embodied account of ASD that includes, but goes beyond, social experiences and is driven in part by significant but subtle motor deficits. In this paper, we review the research examining an embodied cognition account of ASD, and discuss its implications. PMID- 23641229 TI - A new perspective on the functioning of the brain and the mechanisms behind conscious processes. AB - An essential prerequisite for the development of a theory of consciousness is the clarification of the fundamental mechanisms underlying conscious processes. In this article I present an approach that sheds new light on these mechanisms. This approach builds on stochastic electrodynamics (SED), a promising theoretical framework that provides a deeper understanding of quantum systems and reveals the origin of quantum phenomena. I outline the most important concepts and findings of SED and interpret the neurophysiological body of evidence in the context of these findings, indicating that the functioning of the brain rests upon exactly the same principles that are characteristic for quantum systems. On this basis, I construct a new hypothesis on the mechanisms behind conscious processes and discuss the new perspectives this hypothesis opens up for consciousness research. In particular, it offers the possibility of elucidating the relationship between brain and consciousness, of specifying the connection between consciousness and information, and of answering the question of what distinguishes conscious processes from unconscious processes. PMID- 23641230 TI - Introduction to research topic: attention and consciousness in different senses. PMID- 23641231 TI - How does fingolimod (gilenya((r))) fit in the treatment algorithm for highly active relapsing-remitting multiple sclerosis? AB - Multiple sclerosis (MS) is a neurological disorder characterized by inflammatory demyelination and neurodegeneration in the central nervous system. Until recently, disease-modifying treatment was based on agents requiring parenteral delivery, thus limiting long-term compliance. Basic treatments such as beta interferon provide only moderate efficacy, and although therapies for second-line treatment and highly active MS are more effective, they are associated with potentially severe side effects. Fingolimod (Gilenya((r))) is the first oral treatment of MS and has recently been approved as single disease-modifying therapy in highly active relapsing-remitting multiple sclerosis (RRMS) for adult patients with high disease activity despite basic treatment (beta-interferon) and for treatment-naive patients with rapidly evolving severe RRMS. At a scientific meeting that took place in Vienna on November 18th, 2011, experts from ten Central and Eastern European countries discussed the clinical benefits and potential risks of fingolimod for MS, suggested how the new therapy fits within the current treatment algorithm and provided expert opinion for the selection and management of patients. PMID- 23641232 TI - Uncovering latent deficits due to mild traumatic brain injury by using normobaric hypoxia stress. AB - Memory deficits and other cognitive symptoms frequently associated with mTBI are commonly thought to resolve within 7-10 days. This generalization is based principally on observations made in individuals who are in the unstressed environmental conditions typical of a clinic and so does not consider the impact of physiologic, environmental, or psychological stress. Normobaric hypoxic stress can be generated with normal mean sea level (MSL) air, which is about 21% oxygen (O2) and 78% nitrogen (N), by reducing the percentage of O2 and increasing the percentage of N so that the resultant mixed-gas has a partial pressure of O2 approximating that of specified altitudes. This technique was used to generate normobaric hypoxic equivalents of 8,000, 12,000, and 14,000 feet above MSL in a group of 36 volunteers with a mTBI history and an equal number of controls matched on the basis of age, gender, tobacco smoking consumption, weight, height, and body mass index. Short-term visual memory was tested using the Matching to Sample (M2S) subtest of the BrainCheckers analog of the Automated Neuropsychological Assessment Metrics. Although there were no significant differences in M2S performance between the two groups of subjects at MSL, with increased altitude, the mTBI group performance was significantly worse than that of the control group. When the subjects were returned to MSL, the difference disappeared. This finding suggests that the "hypoxic challenge" paradigm developed here has potential clinical utility for assessing the effects of mTBI in individuals who appear asymptomatic under normal conditions. PMID- 23641233 TI - Local functional connectivity as a pre-surgical tool for seizure focus identification in non-lesion, focal epilepsy. AB - Successful resection of cortical tissue engendering seizure activity is efficacious for the treatment of refractory, focal epilepsy. The pre-operative localization of the seizure focus is therefore critical to yielding positive, post-operative outcomes. In a small proportion of focal epilepsy patients presenting with normal MRI, identification of the seizure focus is significantly more challenging. We examined the capacity of resting state functional MRI (rsfMRI) to identify the seizure focus in a group of four non-lesion, focal (NLF) epilepsy individuals. We predicted that computing patterns of local functional connectivity in and around the epileptogenic zone combined with a specific reference to the corresponding region within the contralateral hemisphere would reliably predict the location of the seizure focus. We first averaged voxel-wise regional homogeneity (ReHo) across regions of interest (ROIs) from a standardized, probabilistic atlas for each NLF subject as well as 16 age- and gender-matched controls. To examine contralateral effects, we computed a ratio of the mean pair-wise correlations of all voxels within a ROI with the corresponding contralateral region (IntraRegional Connectivity - IRC). For each subject, ROIs were ranked (from lowest to highest) on ReHo, IRC, and the mean of the two values. At the group level, we observed a significant decrease in the rank for ROI harboring the seizure focus for the ReHo rankings as well as for the mean rank. At the individual level, the seizure focus ReHo rank was within bottom 10% lowest ranked ROIs for all four NLF epilepsy patients and three out of the four for the IRC rankings. However, when the two ranks were combined (averaging across ReHo and IRC ranks and scalars), the seizure focus ROI was either the lowest or second lowest ranked ROI for three out of the four epilepsy subjects. This suggests that rsfMRI may serve as an adjunct pre-surgical tool, facilitating the identification of the seizure focus in focal epilepsy. PMID- 23641234 TI - Application of blood-based biomarkers in human mild traumatic brain injury. AB - Traumatic Brain Injury (TBI) is a global health concern. The majority of TBI's are mild, yet our ability to diagnose and treat mild traumatic brain injury (mTBI) is lacking. This deficiency results from a variety of issues including the difficulty in interpreting ambiguous clinically presented symptoms, and ineffective imaging techniques. Thus, researchers have begun to explore cellular and molecular based approaches to improve both diagnosis and prognosis. This has been met with a variety of challenges, including difficulty in relating biological markers to current clinical symptoms, and overcoming our lack of fundamental understanding of the pathophysiology of mTBI. However, recent adoption of high throughput technologies and a change in focus from the identification of single to multiple markers has given just optimism to mTBI research. The purpose of this review is to highlight a number of current experimental peripheral blood biomarkers of mTBI, as well as comment on the issues surrounding their clinical application and utility. PMID- 23641236 TI - Microbial community assembly, theory and rare functions. AB - Views of community assembly have traditionally been based on the contrasting perspectives of the deterministic niche paradigm and stochastic neutral models. This study sought to determine if we could use empirical interventions conceived from a niche and neutral perspective to change the diversity and evenness of the microbial community within a reactor treating wastewater and to see if there was any associated change in the removal of endocrine disrupting compounds (EDCs). The systematic removal of EDCs and micropollutants from biological treatment systems is a major challenge for environmental engineers. We manipulated pairs of bioreactors in an experiment in which "niche" (temporal variation in resource concentration and resource complexity) and "neutral" (community size and immigration) attributes were changed and the effect on the detectable diversity and the removal of steroidal estrogens was evaluated. The effects of manipulations on diversity suggested that both niche and neutral processes are important in community assembly. We found that temporal variation in environmental conditions increased diversity but resource complexity did not. Larger communities had greater diversity but attempting to increase immigration by adding soil had the opposite effect. The effects of the manipulations on EDC removal efficiency were complex. Decreases in diversity, which were associated with a decrease in evenness, were associated with an increase in EDC removal. A simple generalized neutral model (calibrated with parameters typical of wastewater treatment plants) showed that decreases in diversity should lead to the increase in abundance of some ostensibly taxa rare. We conclude that neither niche and neutral perspectives nor the effect of diversity on putative rare functions can be properly understood by naive qualitative observations. Instead, the relative importance of the key microbial mechanisms must be determined and, ideally, expressed mathematically. PMID- 23641237 TI - Changes in Fungal Community Composition in Response to Elevated Atmospheric CO2 and Nitrogen Fertilization Varies with Soil Horizon. AB - Increasing levels of atmospheric carbon dioxide (CO2) and rates of nitrogen (N) deposition to forest ecosystems are predicted to alter the structure and function of soil fungal communities, but the spatially heterogeneous distribution of soil fungi has hampered investigations aimed at understanding such impacts. We hypothesized that soil physical and chemical properties and fungal community composition would be differentially impacted by elevated atmospheric CO2 (eCO2) and N-fertilization in spatially separated field samples, in the forest floor, 0 2, 2-5, and 5-10 cm depth intervals in a loblolly pine Free-Air Carbon Dioxide Enrichment (FACE) experiment. In all soils, quantitative PCR-based estimates of fungal biomass were highest in the forest floor. Fungal richness, based on pyrosequencing of the fungal ribosomal large subunit gene, increased in response to N-fertilization in 0-2 cm and forest floor intervals. Composition shifted in forest floor, 0-2 and 2-5 cm intervals in response to N-fertilization, but the shift was most distinct in the 0-2 cm interval, in which the largest number of statistically significant changes in soil chemical parameters (i.e., phosphorus, organic matter, calcium, pH) was also observed. In the 0-2 cm interval, increased recovery of sequences from the Thelephoraceae, Tricholomataceae, Hypocreaceae, Clavicipitaceae, and Herpotrichiellaceae families and decreased recovery of sequences from the Amanitaceae correlated with N-fertilization. In this same depth interval, Amanitaceae, Tricholomataceae, and Herpotriciellaceae sequences were recovered less frequently from soils exposed to eCO2 relative to ambient conditions. These results demonstrated that vertical stratification should be taken into consideration in future efforts to elucidate environmental impacts on fungal communities and their feedbacks on ecosystem processes. PMID- 23641235 TI - Acting on Hormone Receptors with Minimal Side Effect on Cell Proliferation: A Timely Challenge Illustrated with GLP-1R and GPER. AB - G protein-coupled receptors (GPCRs) constitute a large family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and cellular responses. GPCR are involved in a wide variety of physiological processes, including in the neuroendocrine system. GPCR are also involved in many diseases and are the target of 30% of marketed medicinal drugs. Whereas the majority of the GPCR-targeting drugs have proved their therapeutic benefit, some of them were associated with undesired effects. We develop two examples of used drugs whose therapeutic benefits are tarnished by carcinogenesis risks. The chronic administration of glucagon-like peptide-1 (GLP-1) analogs widely used to treat type-2 diabetes was associated with an increased risk of pancreatic or thyroid cancers. The long-term treatment with the estrogen antagonist tamoxifen, developed to target breast cancer overexpressing estrogen receptors ER, presents agonist activity on the G protein-coupled estrogen receptor which is associated with an increased incidence of endometrial cancer and breast cancer resistance to hormonotherapy. We point out and discuss the need of pharmacological studies to understand and overcome the undesired effects associated with the chronic administration of GPCR ligands. In fact, biological effects triggered by GPCR often result from the activation of multiple intracellular signaling pathways. Deciphering which signaling networks are engaged following GPCR activation appears to be primordial to unveil their contribution in the physiological and physiopathological processes. The development of biased agonists to elucidate the role of the different signaling mechanisms mediated by GPCR activation will allow the generation of new therapeutic agents with improved efficacy and reduced side effects. In this regard, the identification of GLP-1R biased ligands promoting insulin secretion without inducing pro-tumoral effects would offer therapeutic benefit. PMID- 23641239 TI - Spatial variation of sediment mineralization supports differential CO2 emissions from a tropical hydroelectric reservoir. AB - Substantial amounts of organic matter (OM) from terrestrial ecosystems are buried as sediments in inland waters. It is still unclear to what extent this OM constitutes a sink of carbon, and how much of it is returned to the atmosphere upon mineralization to carbon dioxide (CO2). The construction of reservoirs affects the carbon cycle by increasing OM sedimentation at the regional scale. In this study we determine the OM mineralization in the sediment of three zones (river, transition, and dam) of a tropical hydroelectric reservoir in Brazil as well as identify the composition of the carbon pool available for mineralization. We measured sediment organic carbon mineralization rates and related them to the composition of the OM, bacterial abundance and pCO2 of the surface water of the reservoir. Terrestrial OM was an important substrate for the mineralization. In the river and transition zones most of the OM was allochthonous (56 and 48%, respectively) while the dam zone had the lowest allochthonous contribution (7%). The highest mineralization rates were found in the transition zone (154.80 +/- 33.50 mg C m(-) (2) d(-) (1)) and the lowest in the dam (51.60 +/- 26.80 mg C m( ) (2) d(-) (1)). Moreover, mineralization rates were significantly related to bacterial abundance (r (2) = 0.50, p < 0.001) and pCO2 in the surface water of the reservoir (r (2) = 0.73, p < 0.001). The results indicate that allochthonous OM has different contributions to sediment mineralization in the three zones of the reservoir. Further, the sediment mineralization, mediated by heterotrophic bacteria metabolism, significantly contributes to CO2 supersaturation in the water column, resulting in higher pCO2 in the river and transition zones in comparison with the dam zone, affecting greenhouse gas emission estimations from hydroelectric reservoirs. PMID- 23641238 TI - Mobile elements, zoonotic pathogens and commensal bacteria: conduits for the delivery of resistance genes into humans, production animals and soil microbiota. AB - Multiple antibiotic resistant pathogens represent a major clinical challenge in both human and veterinary context. It is now well-understood that the genes that encode resistance are context independent. That is, the same gene is commonly present in otherwise very disparate pathogens in both humans and production and companion animals, and among bacteria that proliferate in an agricultural context. This can be true even for pathogenic species or clonal types that are otherwise confined to a single host or ecological niche. It therefore follows that mechanisms of gene flow must exist to move genes from one part of the microbial biosphere to another. It is widely accepted that lateral (or horizontal) gene transfer (L(H)GT) drives this gene flow. LGT is relatively well understood mechanistically but much of this knowledge is derived from a reductionist perspective. We believe that this is impeding our ability to deal with the medical ramifications of LGT. Resistance genes and the genetic scaffolds that mobilize them in multiply drug resistant bacteria of clinical significance are likely to have their origins in completely unrelated parts of the microbial biosphere. Resistance genes are increasingly polluting the microbial biosphere by contaminating environmental niches where previously they were not detected. More attention needs to be paid to the way that humans have, through the widespread application of antibiotics, selected for combinations of mobile elements that enhance the flow of resistance genes between remotely linked parts of the microbial biosphere. Attention also needs to be paid to those bacteria that link human and animal ecosystems. We argue that multiply antibiotic resistant commensal bacteria are especially important in this regard. More generally, the post genomics era offers the opportunity for understanding how resistance genes are mobilized from a one health perspective. In the long term, this holistic approach offers the best opportunity to better manage what is an enormous problem to humans both in terms of health and food security. PMID- 23641240 TI - Who possesses drug resistance genes in the aquatic environment?: sulfamethoxazole (SMX) resistance genes among the bacterial community in water environment of Metro-Manila, Philippines. AB - Recent evidence has shown that antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) are ubiquitous in natural environments, including sites considered pristine. To understand the origin of ARGs and their dynamics, we must first define their actual presence in the natural bacterial assemblage. Here we found varying distribution profiles of sul genes in "colony forming bacterial assemblages" and "natural bacterial assemblages." Our monitoring for antibiotic contamination revealed that sulfamethoxazole (SMX) is a major contaminant in aquatic environments of Metro-Manila, which would have been derived from human and animal use, and subsequently decreased through the process of outflow from source to the sea. The SMX-resistant bacterial rate evaluated by the colony forming unit showed 10 to 86% of the total colony numbers showed higher rates from freshwater sites compared to marine sites. When sul genes were quantified by qPCR, colony-forming bacteria conveyed sul1 and sul2 genes in freshwater and seawater (10(-5)-10(-2) copy/16S) but not sul3. Among the natural bacterial assemblage, all sul1, sul2, and sul3 were detected (10(-5)-10(-3) copy/16S), whereas all sul genes were at an almost non-detectable level in the freshwater assemblage. This study suggests that sul1 and sul2 are main sul genes in culturable bacteria, whereas sul3 is conveyed by non-culturable bacteria in the sea. As a result marine bacteria possess sul1, sul2 and sul3 genes in the marine environment. PMID- 23641242 TI - Ca. Nitrososphaera and Bradyrhizobium are inversely correlated and related to agricultural practices in long-term field experiments. AB - Agricultural land management, such as fertilization, liming, and tillage affects soil properties, including pH, organic matter content, nitrification rates, and the microbial community. Three different study sites were used to identify microorganisms that correlate with agricultural land use and to determine which factors regulate the relative abundance of the microbial signatures of the agricultural land-use. The three sites included in this study are the Broadbalk Experiment at Rothamsted Research, UK, the Everglades Agricultural Area, Florida, USA, and the Kellogg Biological Station, Michigan, USA. The effects of agricultural management on the abundance and diversity of bacteria and archaea were determined using high throughput, barcoded 16S rRNA sequencing. In addition, the relative abundance of these organisms was correlated with soil features. Two groups of microorganisms involved in nitrogen cycle were highly correlated with land use at all three sites. The ammonia oxidizing-archaea, dominated by Ca. Nitrososphaera, were positively correlated with agriculture while a ubiquitous group of soil bacteria closely related to the diazotrophic symbiont, Bradyrhizobium, was negatively correlated with agricultural management. Analysis of successional plots showed that the abundance of ammonia oxidizing-archaea declined and the abundance of bradyrhizobia increased with time away from agriculture. This observation suggests that the effect of agriculture on the relative abundance of these genera is reversible. Soil pH and NH3 concentrations were positively correlated with archaeal abundance but negatively correlated with the abundance of Bradyrhizobium. The high correlations of Ca. Nitrososphaera and Bradyrhizobium abundances with agricultural management at three long-term experiments with different edaphoclimatic conditions allowed us to suggest these two genera as signature microorganisms for agricultural land use. PMID- 23641243 TI - Characterization and ex vivo Expansion of Human Placenta-Derived Natural Killer Cells for Cancer Immunotherapy. AB - Recent clinical studies suggest that adoptive transfer of donor-derived natural killer (NK) cells may improve clinical outcome in hematological malignancies and some solid tumors by direct anti-tumor effects as well as by reduction of graft versus host disease (GVHD). NK cells have also been shown to enhance transplant engraftment during allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies. The limited ex vivo expansion potential of NK cells from peripheral blood (PB) or umbilical cord blood (UCB) has however restricted their therapeutic potential. Here we define methods to efficiently generate NK cells from donor-matched, full-term human placenta perfusate (termed Human Placenta-Derived Stem Cell, HPDSC) and UCB. Following isolation from cryopreserved donor-matched HPDSC and UCB units, CD56+CD3- placenta-derived NK cells, termed pNK cells, were expanded in culture for up to 3 weeks to yield an average of 1.2 billion cells per donor that were >80% CD56+CD3-, comparable to doses previously utilized in clinical applications. Ex vivo-expanded pNK cells exhibited a marked increase in anti-tumor cytolytic activity coinciding with the significantly increased expression of NKG2D, NKp46, and NKp44 (p < 0.001, p < 0.001, and p < 0.05, respectively). Strong cytolytic activity was observed against a wide range of tumor cell lines in vitro. pNK cells display a distinct microRNA (miRNA) expression profile, immunophenotype, and greater anti-tumor capacity in vitro compared to PB NK cells used in recent clinical trials. With further development, pNK may represent a novel and effective cellular immunotherapy for patients with high clinical needs and few other therapeutic options. PMID- 23641241 TI - The intrinsic resistome of bacterial pathogens. AB - Intrinsically resistant bacteria have emerged as a relevant health problem in the last years. Those bacterial species, several of them with an environmental origin, present naturally low-level susceptibility to several drugs. It has been proposed that intrinsic resistance is mainly the consequence of the impermeability of cellular envelopes, the activity of multidrug efflux pumps or the lack of appropriate targets for a given family of drugs. However, recently published articles indicate that the characteristic phenotype of susceptibility to antibiotics of a given bacterial species depends on the concerted activity of several elements, what has been named as intrinsic resistome. These determinants comprise not just classical resistance genes. Other elements, several of them involved in basic bacterial metabolic processes, are of relevance for the intrinsic resistance of bacterial pathogens. In the present review we analyze recent publications on the intrinsic resistomes of Escherichia coli and Pseudomonas aeruginosa. We present as well information on the role that global regulators of bacterial metabolism, as Crc from P. aeruginosa, may have on modulating bacterial susceptibility to antibiotics. Finally, we discuss the possibility of searching inhibitors of the intrinsic resistome in the aim of improving the activity of drugs currently in use for clinical practice. PMID- 23641244 TI - Sugar metabolism and the plant target of rapamycin kinase: a sweet operaTOR? AB - In eukaryotes, the ubiquitous TOR (target of rapamycin) kinase complexes have emerged as central regulators of cell growth and metabolism. The plant TOR complex 1 (TORC1), that contains evolutionary conserved protein partners, has been shown to be implicated in various aspects of C metabolism. Indeed Arabidopsis lines affected in the expression of TORC1 components show profound perturbations in the metabolism of several sugars, including sucrose, starch, and raffinose. Metabolite profiling experiments coupled to transcriptomic analyses of lines affected in TORC1 expression also reveal a wider deregulation of primary metabolism. Moreover recent data suggest that the kinase activity of TORC1, which controls biological outputs like mRNA translation or autophagy, is directly regulated by soluble sugars. PMID- 23641245 TI - Cysteine-based redox regulation and signaling in plants. AB - Living organisms are subjected to oxidative stress conditions which are characterized by the production of reactive oxygen, nitrogen, and sulfur species. In plants as in other organisms, many of these compounds have a dual function as they damage different types of macromolecules but they also likely fulfil an important role as secondary messengers. Owing to the reactivity of their thiol groups, some protein cysteine residues are particularly prone to oxidation by these molecules. In the past years, besides their recognized catalytic and regulatory functions, the modification of cysteine thiol group was increasingly viewed as either protective or redox signaling mechanisms. The most physiologically relevant reversible redox post-translational modifications (PTMs) are disulfide bonds, sulfenic acids, S-glutathione adducts, S-nitrosothiols and to a lesser extent S-sulfenyl-amides, thiosulfinates and S-persulfides. These redox PTMs are mostly controlled by two oxidoreductase families, thioredoxins and glutaredoxins. This review focuses on recent advances highlighting the variety and physiological roles of these PTMs and the proteomic strategies used for their detection. PMID- 23641246 TI - Responses to flooding of plant water relations and leaf gas exchange in tropical tolerant trees of a black-water wetland. AB - This review summarizes the research on physiological responses to flooding of trees in the seasonal black-water wetland of the Mapire River in Venezuela. Inter annual variability was found during 8 years of sampling, in spite of which a general picture emerged of increased stomatal conductance (gs) and photosynthetic rate (PN) during the flooded period to values as high as or higher than in plants in drained wet soil. Models explaining the initial inhibitory responses and the acclimation to flooding are proposed. In the inhibitory phase of flooding, hypoxia generated by flooding causes a decrease in root water absorption and stomatal closure. An increase with flooding in xylem water potential (psi) suggests that flooding does not cause water deficit. The PN decreases due to changes in relative stomatal and non-stomatal limitations to photosynthesis; an increase in the latter is due to reduced chlorophyll and total soluble protein content. Total non-structural carbohydrates (TNC) accumulate in leaves but their content begins to decrease during the acclimatized phase at full flooding, coinciding with the resumption of high gs and PN. The reversal of the diminution in gs is associated, in some but not all species, to the growth of adventitious roots. The occurrence of morpho-anatomical and biochemical adaptations which improve oxygen supply would cause the acclimation, including increased water absorption by the roots, increased rubisco and chlorophyll contents and ultimately increased PN. Therefore, trees would perform as if flooding did not signify a stress to their physiology. PMID- 23641248 TI - Sub-cellular proteomics of Medicago truncatula. AB - Medicago truncatula is a leading model species and substantial molecular, genetic, genomics, proteomics, and metabolomics resources have been developed for this species to facilitate the study of legume biology. Currently, over 60 proteomics studies of M. truncatula have been published. Many of these have focused upon the unique symbiosis formed between legumes and nitrogen fixing rhizobia bacteria, while others have focused on seed development and the specialized proteomes of distinct tissues/organs. These include the characterization of sub-cellular organelle proteomes such as nuclei and mitochondria, as well as proteins distributed in plasma or microsomal membranes from various tissues. The isolation of sub-cellular proteins typically requires a series of steps that are labor-intensive. Thus, efficient protocols for sub cellular fractionation, purification, and enrichment are necessary for each cellular compartment. In addition, protein extraction, solubilization, separation, and digestion prior to mass spectral identification are important to enhance the detection of low abundance proteins and to increase the overall detectable proportion of the sub-cellular proteome. This review summarizes the sub-cellular proteomics studies in M. truncatula. PMID- 23641249 TI - Jasmonate-Mediated Induced Volatiles in the American Cranberry, Vaccinium macrocarpon: From Gene Expression to Organismal Interactions. AB - Jasmonates, i.e., jasmonic acid (JA) and methyl jasmonate (MeJA), are signaling hormones that regulate a large number of defense responses in plants which in turn affect the plants' interactions with herbivores and their natural enemies. Here, we investigated the effect of jasmonates on the emission of volatiles in the American cranberry, Vaccinium macrocarpon, at different levels of biological organization from gene expression to organismal interactions. At the molecular level, four genes (BCS, LLS, NER1, and TPS21) responded significantly to gypsy moth larval feeding, MeJA, and mechanical wounding, but to different degrees. The most dramatic changes in expression of BCS and TPS21 (genes in the sesquiterpenoid pathway) were when treated with MeJA. Gypsy moth-damaged and MeJA treated plants also had significantly elevated expression of LLS and NER1 (genes in the monoterpene and homoterpene biosynthesis pathways, respectively). At the biochemical level, MeJA induced a complex blend of monoterpene and sesquiterpene compounds that differed from gypsy moth and mechanical damage, and followed a diurnal pattern of emission. At the organismal level, numbers of Sparganothis sulfureana moths were lower while numbers of parasitic wasps were higher on sticky traps near MeJA-treated cranberry plants than those near untreated plants. Out of 11 leaf volatiles tested, (Z)-3-hexenyl acetate, linalool, and linalool oxide elicited strong antennal (EAG) responses from S. sulfureana, whereas sesquiterpenes elicited weak EAG responses. In addition, mortality of S. sulfureana larvae increased by about 43% in JA treated cranberry plants as compared with untreated plants, indicating a relationship among adult preference, antennal sensitivity to plant odors, and offspring performance. This study highlights the role of the jasmonate-dependent defensive pathway in the emissions of herbivore-induced volatiles in cranberries and its importance in multi-trophic level interactions. PMID- 23641247 TI - Plant cell wall proteomics: the leadership of Arabidopsis thaliana. AB - Plant cell wall proteins (CWPs) progressively emerged as crucial components of cell walls although present in minor amounts. Cell wall polysaccharides such as pectins, hemicelluloses, and cellulose represent more than 90% of primary cell wall mass, whereas hemicelluloses, cellulose, and lignins are the main components of lignified secondary walls. All these polymers provide mechanical properties to cell walls, participate in cell shape and prevent water loss in aerial organs. However, cell walls need to be modified and customized during plant development and in response to environmental cues, thus contributing to plant adaptation. CWPs play essential roles in all these physiological processes and particularly in the dynamics of cell walls, which requires organization and rearrangements of polysaccharides as well as cell-to-cell communication. In the last 10 years, plant cell wall proteomics has greatly contributed to a wider knowledge of CWPs. This update will deal with (i) a survey of plant cell wall proteomics studies with a focus on Arabidopsis thaliana; (ii) the main protein families identified and the still missing peptides; (iii) the persistent issue of the non-canonical CWPs; (iv) the present challenges to overcome technological bottlenecks; and (v) the perspectives beyond cell wall proteomics to understand CWP functions. PMID- 23641250 TI - Prospects for advancing defense to cereal rusts through genetical genomics. AB - Rusts are one of the most severe threats to cereal crops because new pathogen races emerge regularly, resulting in infestations that lead to large yield losses. In 1999, a new race of stem rust, Puccinia graminis f. sp. tritici (Pgt TTKSK or Ug99), was discovered in Uganda. Most of the wheat and barley cultivars grown currently worldwide are susceptible to this new race. Pgt TTKSK has already spread northward into Iran and will likely spread eastward throughout the Indian subcontinent in the near future. This scenario is not unique to stem rust; new races of leaf rust (Puccinia triticina) and stripe rust (Puccinia striiformis) have also emerged recently. One strategy for countering the persistent adaptability of these pathogens is to stack complete- and partial-resistance genes, which requires significant breeding efforts in order to reduce deleterious effects of linkage drag. These varied resistance combinations are typically more difficult for the pathogen to defeat, since they would be predicted to apply lower selection pressure. Genetical genomics or expression Quantitative Trait Locus (eQTL) analysis enables the identification of regulatory loci that control the expression of many to hundreds of genes. Integrated deployment of these technologies coupled with efficient phenotyping offers significant potential to elucidate the regulatory nodes in genetic networks that orchestrate host defense responses. The focus of this review will be to present advances in genetical genomic experimental designs and analysis, particularly as they apply to the prospects for discovering partial disease resistance alleles in cereals. PMID- 23641251 TI - Comparative genome analysis of Burkholderia phytofirmans PsJN reveals a wide spectrum of endophytic lifestyles based on interaction strategies with host plants. AB - Burkholderia phytofirmans PsJN is a naturally occurring plant-associated bacterial endophyte that effectively colonizes a wide range of plants and stimulates their growth and vitality. Here we analyze whole genomes, of PsJN and of eight other endophytic bacteria. This study illustrates that a wide spectrum of endophytic life styles exists. Although we postulate the existence of typical endophytic traits, no unique gene cluster could be exclusively linked to the endophytic lifestyle. Furthermore, our study revealed a high genetic diversity among bacterial endophytes as reflected in their genotypic and phenotypic features. B. phytofirmans PsJN is in many aspects outstanding among the selected endophytes. It has the biggest genome consisting of two chromosomes and one plasmid, well-equipped with genes for the degradation of complex organic compounds and detoxification, e.g., 24 glutathione-S-transferase (GST) genes. Furthermore, strain PsJN has a high number of cell surface signaling and secretion systems and harbors the 3-OH-PAME quorum-sensing system that coordinates the switch of free-living to the symbiotic lifestyle in the plant pathogen R. solanacearum. The ability of B. phytofirmans PsJN to successfully colonize such a wide variety of plant species might be based on its large genome harboring a broad range of physiological functions. PMID- 23641253 TI - The household contact study design for genetic epidemiological studies of infectious diseases. AB - MOST GENETIC EPIDEMIOLOGICAL STUDY DESIGNS FALL INTO ONE OF TWO CATEGORIES: family based and population-based (case-control). However, recent advances in statistical genetics call for study designs that combine these two approaches. We describe the household contact study design as we have applied it in our several years of study of the epidemiology of tuberculosis. Though we highlight its applicability for genetic epidemiological studies of infectious diseases, there are many facets of this design that are appealing for modern genetic studies, including the simultaneous enrollment of related and unrelated individuals, closely and distantly related individuals, collection of extensive epidemiologic and phenotypic data, and evaluation of effects of shared environment and gene by environment interaction. These study design characteristics are particularly appealing for current sequencing studies. PMID- 23641252 TI - Role of p97/VCP (Cdc48) in genome stability. AB - Ubiquitin-dependent molecular chaperone p97, also known as valosin-containing protein (VCP) or Cdc48, is an AAA ATPase involved in protein turnover and degradation. p97 converts its own ATPase hydrolysis into remodeling activity on a myriad of ubiquitinated substrates from different cellular locations and pathways. In this way, p97 mediates extraction of targeted protein from cellular compartments or protein complexes. p97-dependent protein extraction from various cellular environments maintains cellular protein homeostasis. In recent years, p97-dependent protein extraction from chromatin has emerged as an essential evolutionarily conserved process for maintaining genome stability. Inactivation of p97 segregase activity leads to accumulation of ubiquitinated substrates on chromatin, consequently leading to protein-induced chromatin stress (PICHROS). PICHROS directly and negatively affects multiple DNA metabolic processes, including replication, damage responses, mitosis, and transcription, leading to genotoxic stress and genome instability. By summarizing and critically evaluating recent data on p97 function in various chromatin-associated protein degradation processes, we propose establishing p97 as a genome caretaker. PMID- 23641254 TI - Asthma-snapshot or motion picture? PMID- 23641255 TI - Why does melanoma metastasize into the brain? Genes with pleiotropic effects might be the key. PMID- 23641256 TI - Antagonism of NF-kappaB-up-regulated micro RNAs (miRNAs) in sporadic Alzheimer's disease (AD)-anti-NF-kappaB vs. anti-miRNA strategies. PMID- 23641257 TI - Dual-energy X-ray absorptiometry versus quantitative ultrasonography in diagnosing osteoporosis in patients with refractory epilepsy and chronic antiepileptic drug use. AB - BACKGROUND: The aim of this study was to assess the feasibility of calcaneal quantitative ultrasonography (QUS) as a screening method for increased risk of osteoporosis in a unique population of people with chronic epilepsy, intellectual disability (ID), and chronic use of antiepileptic drugs. METHODS: A total of 205 patients from a long-stay care facility for people with epilepsy underwent dual energy X-ray absorptiometry (DXA) and QUS of the calcaneus. T-scores for both DXA and QUS were calculated and correlated. RESULTS: A total of 195 patients (95.1%) were successfully measured with DXA and 204 (99.5%) with QUS. High correlations were found between DXA and QUS T-scores: r = 0.666 (QUS versus T-score total femur), r = 0.631 (QUS versus T-score femur neck) and r = 0.485 (QUS versus T score lumbar spine). All correlations were statistically significant (p = 0.01). CONCLUSION: QUS showed a strong correlation with DXA and proved to be a feasible measuring method in a population with ID and epilepsy. Including osteopenia in the screening process increases the sensitivity of QUS to identify those patients at risk for the development of bone diseases. PMID- 23641258 TI - Personalized medicine for osteoarthritis: where are we now? AB - Personalized medicine is a much talked about subject that is a timely and important development to healthcare in general and also specifically for patients affected by osteoarthritis. This review uses biomarker examples pertinent to osteoarthritis to highlight the current status of the field, while also highlighting probable future developments. It is not meant to be an exhaustive account. The BIPED(s) [Burden of disease, Investigative, Prognosis, Efficacy, Diagnosis (safety)] classification system is used to organize the discussion of examples. Biomarkers pertaining to burden, investigation, prognosis, efficacy, diagnosis and safety are highlighted. The examples are followed by a discussion of issues related to interpretation and application of biomarker results and approaches to solve the challenges interpretation faces, including graphical, mathematical and synthetic representations. Through this review, it is hoped that a better appreciation can be gained of the potential and pitfalls of personal medicine in the care of patients with osteoarthritis. PMID- 23641260 TI - A primer to 'bio-objects': new challenges at the interface of science, technology and society. AB - Biotechnological and life science innovations do not only lead to immense progress in diverse fields of natural science and technical research and thereby drive economic development, they also fundamentally affect the relationship between nature, technology and society. Taken this seriously, the ethical and societal assessment of emerging biotechnologies as for example synthetic biology is challenged not only to constrain on questions of biosafety and biosecurity but also to face the societal questions within the different fields as an interface problem of science and society. In order to map this vague and stirring field, we propose the concept of bio-objects to explore the reciprocal interaction at the interface of science and society serious as well to have the opportunity to detect possible junctions of societal discontent and unease before their appearance. PMID- 23641261 TI - Atherosclerosis prevention in youth. AB - Atherosclerosis-associated circulatory disturbance is one of the most important global issues. In patients with atherosclerosis, eccentric intimal thickening and lipid deposition progress over a long period (at least 20 to 30 years). On the other hand, in patients with atherosclerosis-associated circulatory disturbance represented by myocardial infarction, the direct cause of death is thrombus formation rather than marked stenosis; wall destruction may lead to a fatal outcome. In the future, atherosclerosis susceptibility, that is, intrinsic genes, should be investigated. PMID- 23641262 TI - Recent advancement on surgical treatments for lymphedema. AB - Treatment for limb lymphedema is challenging. The recent development of the super microsurgical technique has made lymphaticovenular (LV) anastomosis an easier and more accurate surgical method for lymphedema. A summary of our experience as well as recent developments in surgical treatments for lymphedema are described. METHODS AND RESULTS: Ultra-microstructural analysis demonstrated that dysfunction of the lymphatics in lymphedema was caused by the degeneration and incomplete regeneration of smooth muscle cells and valve insufficiency in the lymphatic channel. ICG and infrared ray examinations have been proposed as new means of assessment of lymphatic function. LV anastomosis is suitable for genital edema, arm edema with severe phlegmone with leg edema, and early stage leg edema. Although pre- and postoperative compression therapy is generally required for limb edema, some cases do not require postoperative compression due to remaining or regenerated smooth muscle cells. As new methods of treatment, the vascularized lymphadiposal flap has been effective for progressive cases with LV anastomosis. LV anastomosis is also effective for congenital chyloabdomen. (*English Translation of J Jpn Coll Angiol 2008; 48: 173-178.). PMID- 23641259 TI - Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. AB - Osteoarthritis (OA) has traditionally been classified as a noninflammatory arthritis; however, the dichotomy between inflammatory and degenerative arthritis is becoming less clear with the recognition of a plethora of ongoing immune processes within the OA joint and synovium. Synovitis is defined as inflammation of the synovial membrane and is characteristic of classical inflammatory arthritidies. Increasingly recognized is the presence of synovitis in a significant proportion of patients with primary OA, and based on this observation, further studies have gone on to implicate joint inflammation and synovitis in the pathogenesis of OA. However, clinical OA is not one disease but a final common pathway secondary to many predisposing factors, most notably age, joint trauma, altered biomechanics, and obesity. How such biochemical and mechanical processes contribute to the progressive joint failure characteristic of OA is tightly linked to the interplay of joint damage, the immune response to perceived damage, and the subsequent state of chronic inflammation resulting in propagation and progression toward the phenotype recognized as clinical OA. This review will discuss a wide range of evolving data leading to our current hypotheses regarding the role of immune activation and inflammation in OA onset and progression. Although OA can affect any joint, most commonly the knee, hip, spine, and hands, this review will focus primarily on OA of the knee as this is the joint most well characterized by epidemiologic, imaging, and translational studies investigating the association of inflammation with OA. PMID- 23641263 TI - Compression therapy: clinical and experimental evidence. AB - AIM: A review is given on the different tools of compression therapy and their mode of action. METHODS: Interface pressure and stiffness of compression devices, alone or in combination can be measured in vivo. Hemodynamic effects have been demonstrated by measuring venous volume and flow velocity using MRI, Duplex and radioisotopes, venous reflux and venous pumping function using plethysmography and phlebodynamometry. Oedema reduction can be measured by limb volumetry. RESULTS: Compression stockings exerting a pressure of ~20 mmHg on the distal leg are able to increase venous blood flow velocity in the supine position and to prevent leg swelling after prolonged sitting and standing. In the upright position, an interface pressure of more than 50 mmHg is needed for intermittent occlusion of incompetent veins and for a reduction of ambulatory venous hypertension during walking. Such high intermittent interface pressure peaks exerting a "massaging effect" may rather be achieved by short stretch multilayer bandages than by elastic stockings. CONCLUSION: Compression is a cornerstone in the management of venous and lymphatic insufficiency. However, this treatment modality is still underestimated and deserves better understanding and improved educational programs, both for patients and medical staff. PMID- 23641264 TI - Endovascular training of vascular surgeons in the USA. AB - Current trends in vascular surgery in the USA are driven by increased demand for endovascular procedures. Traditionally-trained vascular surgeons have adapted to these trends by acquiring endovascular skills; vascular surgery fellowships were standardized to 2-years to incorporate endovascular training. However, the traditional "5 + 2" training paradigm appears to be less appealing to the current generation of surgical students, resulting in fellowship positions going unfilled, and potentially predicting a shortage of vascular surgeons. Recognition of this trend has led to the adoption of alternative training pathways, in particular the integrated "0 + 5" pathway, to supplement the traditional "5 + 2" independent pathway. The integrated pathway has several perceived advantages for vascular surgery trainees including early teaching of endovascular skills. However, it has challenges that include maintaining open operative skills and changing strategies to attract candidates from among the pool of medical students instead of the pool of general surgery residents. Simulators, both open and endovascular, are playing an increasingly important role in training programs as well as for outreach programs to medical students. Recruitment strategies for future generations of vascular surgeons in the USA may need to consider residents' lifestyle preferences as well as outreach to traditionally underrepresented groups such as women and minorities. PMID- 23641265 TI - Surgical treatment or conservative therapy for stanford type a acute aortic dissection with a thrombosed false lumen. AB - OBJECTIVES: Optimum treatment for acute aortic dissection (AAD) with a thrombosed false lumen (thrombosed AAD) remains controversial. We evaluated the outcome of thrombosed AAD according to treatment strategy. MATERIALS AND METHODS: We examined 280 patients with AAD, of which 30 had thrombosed AAD. We compared computed tomography findings, cardiac performance, and clinical course in 28 of these patients. Patients were divided into three groups for the comparison: Group E (emergency surgery), Group C (conservative therapy), and Group S (conservative therapy switched to emergency surgery). RESULTS: In Group E (n = 13), one patient died and 12 survived. In Group C (n = 10), all patients were discharged, of which two died of cancer and two of the remaining eight survivors underwent subsequent elective surgery. In Group S (n = 5), one patient died and four survived following surgery. CONCLUSIONS: It was hard to predict re-dissection or rupture following conservative treatment for thrombosed AAD. Basically, we should perform emergency surgery following the diagnosis of thrombosed AAD, particularly in complicated cases such as those with pericardial effusion, tamponade, and large aorta. Conservative therapy has a very limited application in patients with the initial stages of thrombosed AAD. PMID- 23641266 TI - Putting a Class I Stocking over a Class I Stocking Does Not Make a Class II Stocking. AB - OBJECTIVES: To evaluate the interface pressures (IP) obtained by double compression stockings. METHODS: Ten healthy volunteers with legs fitting size S stockings wore single and double class I stockings, sizes S to 4L. We measured IPs with the patient wearing each stocking standing and supine. RESULTS: IPs obtained wearing double S size stockings, standing and supine, were 1.7 times and 20 mmHg higher than those obtained by a single S size stocking (52.1 +/- 4.7 and 46.4 +/- 4.5 mmHg vs. 31.5 +/- 3.3 and 27.3 +/- 2.3 mmHg, respectively). Despite the decreasing IP with increased stocking sizes, all IPs obtained by double stockings, standing and supine, even with size 4L (43.2 +/- 5.1 and 37.3 +/- 5.5 mmHg respectively), were significantly higher than those obtained by a single S stocking. CONCLUSION: Significantly higher IPs were achieved standing and supine, by doubling stockings. We should rather be aware that double stockings in the supine position can result in excessively high IPs. PMID- 23641267 TI - Endovascular management of splenic arteriovenous fistula with giant venous aneurysmal dilatation. AB - Although splenic artery aneurysm is the commonest visceral and third most common intra abdominal aneurysm after aorta and iliac artery, aneurysm of splenic artery along with aneurysm of splenic vein and arteriovenous fistula is a rare entity. Most of them are <3 cm in diameter. Giant true splenic artery aneurysms are rare and very few lesions >10 cm have been reported. We report a case of 11 cm * 8 cm giant splenic vein aneurysm with splenic arteriovenous fistula as the 1st case of giant splenic venous aneurysm with arteriovenous fistula managed by endovascular treatment. PMID- 23641268 TI - A Case of Simultaneous Endovascular Aneurysmal Repair (EVAR) and Coronary Artery Bypass Grafting (CABG). AB - A male patient with abdominal aortic aneurysm (AAA) and coronary artery disease was referred to our hospital. Coronary angiography showed multiple coronary lesions including the left main trunk. Computed tomography revealed a large AAA measuring 78 mm. To prevent aneurysmal rupture after coronary artery bypass grafting or cardiac complications after AAA repair, we performed simultaneous endovascular aneurysmal repair and coronary artery bypass grafting. The postoperative course was uneventful. Endovascular therapy and beating coronary artery bypass grafting is less invasive and may offer another promising option for the treatment of complicated case of AAA with severe coronary artery disease. PMID- 23641269 TI - Acute remodeling of an adjoining aneurysm after endovascular treatment of a ruptured splanchnic arterial aneurysm: a case of clinically diagnosed segmental arterial mediolysis. AB - A 61-year-old woman with multiple splanchnic arterial aneurysms (SAAs) was transferred to our hospital in a state of shock. She underwent coil embolization under the diagnosis of ruptured pancreaticoduodenal artery aneurysm. Follow-up computed tomography performed 2 weeks later showed rapid enlargement of a gastric artery aneurysm, and she underwent an additional embolization. Atherosclerotic, inflammatory or hereditary causes were excluded, and the patient was clinically diagnosed with segmental arterial mediolysis accompanied by multiple SAAs, one of which showed acute remodeling after endovascular treatment. PMID- 23641271 TI - Acute Renal Failure due to Thrombotic Microangiopathy in Patient with Scleroderma: Autopsy Case Report. AB - This study presents a patient who died of acute renal failure (ARF) as a complication of scleroderma. The patient remained normotensive throughout the clinical course. Myeloperoxidase-anti-neutrophil cytoplasmic antibody was negative. Autopsy revealed fibrin thrombi in the glomerular capillaries and afferent arterioles, mesangiolysis, and double contour of the glomerular basement membrane. Contrarily, "onionskin lesions" of renal interlobular arteries, the histological hallmark of scleroderma renal crisis, were not discovered. These findings suggested that thrombotic microangiopathy (TMA) was the cause of ARF. Although the frequency is not high, close monitoring should be given to TMA in scleroderma because of possible mortality. PMID- 23641270 TI - Conversion to Open Repair from Emergency EVAR in a Patient with Ruptured AAA: Report of a Case. AB - A 77-year-old woman with a ruptured abdominal aortic aneurysm (AAA) was transferred to our hospital. Due to a severe comorbidity, endovascular aortic repair of the ruptured AAA was proposed. During the operation, although a Zenith((r)) AAA endovascular graft was deployed, digital subtracted angiography revealed an enhancement of the endoleak, and the patient became hemodynamically unstable. Therefore, we decided to convert to graft replacement of the abdominal aorta through a median laparotomy. During the postoperative period, the patient suffered from ischemic colitis, which resolved with conservative therapy. She was discharged after 33 postoperative days. PMID- 23641272 TI - Antibiotics and Drainage for Treating Stent-Graft Infection after EVAR. AB - The patient was a 64-year-old man. He developed fever and lumbago 6 months after the EVAR. Because CT showed an abscess in the aortic aneurysm surrounding the stent graft, stent-graft infection was diagnosed, and treatment with intravenous antibiotics was initiated. However, the fever and inflammatory markers persisted; therefore, CT-guided drainage catheter placement was performed. After all the pus had been discharged, the fever subsided, and the inflammatory reaction was also suppressed. One year has elapsed since the treatment, and the patient continues to visit with no complaints. We report that stent-graft infection was relieved with antibiotics and drainage. PMID- 23641273 TI - Circumferential dissection of the ascending aorta "intimo-intimal intussusception". AB - We describe a rare case of acute Stanford type A dissection with "intimo-intimal intussusception." A 38-year-old male with sudden back pain and unconsciousness was admitted to the hospital. A computed tomography (CT) scan revealed the presence of an intimal flap in the aortic root and the aortic arch, absence of an intimal flap in the ascending aorta along with dilatation and occlusion of the brachiocephalic artery. Surgical treatment consisted of ascending aorta replacement under circulatory arrest. During the operation, complete circumferential detachment of the intima at the level of the sinotubular junction with an inverted flap intruding into the brachiocephalic artery was visualized. The surgery was successful with an uneventful postoperative recovery. PMID- 23641275 TI - Asian society of vascular surgery in 2012-abstracts from Asia. PMID- 23641274 TI - Two cases of endovascular abdominal aortic aneurysm repair with iliac aneurysm using a zenith iliac bifurcation graft. AB - We report on treatment of an abdominal aortic aneurysm with common iliac artery aneurysm using an iliac branch device. We performed 2 cases because of a large common iliac artery aneurysm or a complication of an internal iliac artery aneurysm. Both cases had a good postoperative course and progressed without embolizing the iliac branch device during follow-up period. Though there is a drawback, it is not covered by the national insurance program in Japan and cannot be used in all applicable cases. However, use of a unilateral or bilateral iliac branch device allows us to maintain the bloodstream of the internal iliac artery, thus suggesting it to be effective in such cases. PMID- 23641276 TI - Commentary on "Surgical Treatment with or without Embolotherapy for Arteriovenous Malformations". PMID- 23641277 TI - Strategy of Infection Control in Immunosuppressive Therapy for ANCA-Associated Vasculitis. AB - Antineutrophil cytoplasmic antibodies (ANCA) are well known to be associated with small vessel vasculitic diseases such as microscopic polyangiitis (MPA), allergic granulomatous angiitis (AGA), and Granulomatosis with poly angiitis: GPA (Wegener's). Disease assessment by 1) vasculitic activity, 2) damage resulting from vasculitis, and 3) patient function, were the required endpoints for the therapeutic trials in ANCA-associated vasculitis (AAV). Harmonized steroids and cyclophosphamide or azathioprine are effective for active AAV. In evaluating tools for monitoring disease, titers of ANCA and the levels of CRP were found useful in AAV. However, it will be important for clinicians to observe AAV patients more closely and reduce immunosuppressive drug doses more cautiously, especially to prevent several infections (i.e., deep mycosis, pneumocystis jirovecii pneumonia and cytomegalovirus). We indicated that strategy of infection control in immunosuppressive therapy for AAV. (J Jpn Coll Angiol, 2009, 49: 93 99). PMID- 23641278 TI - Genomics of vasculitis: lessons from mouse models. AB - A genome analysis of mouse models may shed some light on the complex clinicopathological manifestations of systemic vasculitis. In the study of susceptibility loci to vasculitis in MRL mouse models, we found that systemic vasculitis developed through the cumulative effect of multiple gene loci, each of which by itself did not have a significant effect in inducing the related phenotype, thus indicating a polygenic system. The mice developed vasculitis in an additive manner with a hierarchical effect. Some of the susceptibility loci seemed to be common to those in other collagen diseases. Moreover, the loci controlling tissue specificity of vasculitis were present. One of the positional candidate genes for vasculitis showed an allelic polymorphism in the coding region, thus possibly causing a qualitative difference in its function. As a result, a particular combination of polygenes with such an allelic polymorphism may thus play a critical role in leading the cascade reaction to develop vasculitis, and also a regular variation of systemic vasculitis. This is designated as the polygene network in systemic vasculitis. (J Jpn Coll Angiol, 2009, 49: 11-16). PMID- 23641279 TI - Novel strategy for the treatment of refractory vasculitis syndrome. AB - The recent development of biologic therapies capable of selectively targeting components of the immune system has revolutionized the treatment of inflammatory arthritides. The increase in the use of biologic agents coupled with expansion in the knowledge of the pathogenesis of vascular inflammation has led to their application in the treatment of primary systemic vasculitis. Biological therapies appear to have a place in the therapeutic strategy for ANCA-associated systemic vasculitides, at least for patients whose disease is refractory to conventional therapy. The use of biologics as targeted therapies has also, in reverse, improved our understanding of the pathophysiology of vascular inflammation. However, the precise indications for TNF-alpha inhibitors or anti-CD20 monoclonal antibodies have not yet been defined. These biologics must be prescribed extremely cautiously and only in trial settings, especially in view of the adverse effects. (*English Translation of J Jpn Coll Angiol, 2009, 49: 75-79). PMID- 23641280 TI - Collective therapy and therapeutic strategy for critical limb ischemia. AB - OBJECTIVE: To determine a treatment strategy based on the outcomes of various previous interventions for critical limb ischemia in arteriosclerosis obliterans (ASO). MATERIAL AND METHODS: We examined outcomes of 292 ASO patients who had had critical limb ischemia between May 1995 and July 2009. Patients underwent the following procedures in 167 cases: aortofemoral bypass (n = 14), femorofemoral crossover bypass (n = 29), femoropopliteal bypass (n = 104) and femorotibial bypass (n = 40). Other procedures included bypass only (n = 147), bypass combined with thromboendarterectomy (n = 10), bypass combined with endovascular therapy (n = 6), bypass combined with lumbar sympathectomy (n = 2), endovascular therapy combined with thromboendarterectomy (n = 4), endovascular therapy (n = 19), lumbar sympathectomy (n = 6), conservative therapy (n = 65), and major amputation (n = 31). We also calculated P3 risk scores and measured transcutaneous oxygen pressure (tcPO2) and skin perfusion pressure (SPP) before and after therapy. RESULTS: The limb salvage rate was 87% at 2 years in the arterial reconstruction group. In the low-risk group (a P 3 risk score of 3), the 1-year amputation-free survival rate was 96%. In the medium-risk group (a P 3 risk score of 4-7), the 1 year amputation-free survival rate was 88%. In the high-risk group (a P 3 risk score of 8), the 1-year amputation-free survival rate was 66%. The hospital death rate in the arterial reconstruction group was 3.2%, all of whom were patients who underwent bypass. The survival rate at 5 years was 65% and 36% in the conservative therapy only group. Ulcers healed in 140 out of 144 patients. The 4 patients with unhealed infections had tcPO2 or SPP values of more than 30 mmHg after treatment. Major amputations were performed in 4 of 5 patients who had tcPO2 or SPP values from 20 to 30 mmHg after treatment. Major amputations were performed in all 6 patients who had tcPO2 or SPP values of less than 20 mmHg after treatment. CONCLUSION: In cases with tcPO2 or SPP values of more than 30 mmHg, an ulcer will probably heal, except in infected cases. We suggest that, if these values are less than 30 mmHg, complete revascularization should be performed. The P3 risk score was useful in predicting limb salvage in the current series. Hybrid therapy in bypass and endovascular therapy must be performed in cases where patients are in a generally poor condition. It is important to attempt amelioration in limb salvage and to control the operative mortality rate with sufficient perioperative control. (English Translation of Jpn J Vasc Surg 2011;20:905-911). PMID- 23641281 TI - Evaluation of the outcome of traumatic thoracic aortic rupture in patients in a trauma and critical care center. AB - OBJECTIVES: Multiple injuries may lead to traumatic thoracic aortic rupture (TTAR), which can be fatal. We evaluated the relationship between the clinical findings and outcomes of 26 patients with TTAR who were treated at our institution. METHODS: A total of 26 patients (men, 21; women, 5; average age, 45.8 +/- 19.6 years) with a diagnosis of TTAR received from 1999 to 2009 were studied. We categorized patients into groups based on the outcome (survival or death) and investigated the relationship between the outcome and the following factors: injury mechanism, vital signs, other combined injuries, injury severity score (ISS), revised trauma score, and probability of survival (Ps). RESULTS: Of the 26 TTAR patients, 7 underwent emergency operations, 5 underwent delayed operations, 1 received conservative treatment, and 13 suffered cardiopulmonary arrest immediately after consultation and died. Of the 13 patients who died, 11 died within 2 hours after injury because of bleeding. Two of the 7 patients who underwent emergency operations died within 1 day of consultation, whereas all those who underwent delayed operations survived. Patients who underwent TTAR repair had a relatively favorable outcome. Analysis of the relationship between the clinical data and outcome showed that a young age was significantly correlated with survival, and that the Glasgow coma scale (GCS), heart rate, respiratory rate, or occurrence of shock were not significantly related to the outcome. The abbreviated injury scale (AIS) was used to score the severity of multiple injuries, and ISS was calculated from the AIS score. ISS was significantly higher in the death group (P = 0.007). ISS did not significantly differ among body parts (P = 0.077), but ISS of the extremities was higher than those of other parts. Pelvic fractures were frequent in the death group. Our strategy, whereby the patient initially underwent pelvic external fixation followed by TTAR repair was found to be very effective. The P-values calculated by the trauma and injury severity score method were significantly higher in the survival group (both, P = 0.007). CONCLUSION: To treat TTAR, it is important to accurately evaluate the damage due to multiple injuries and apply an appropriate treatment strategy. Immediate repair of TTAR after bleeding due to combined injury improves the outcome. (English Translation of Jpn J Vasc Surg 2012; 21:5 9). PMID- 23641282 TI - A team approach to the management of intractable leg ulcers. AB - OBJECTIVES: The management of intractable leg ulcers requires a team approach which includes vascular surgeons and plastic surgeons. We retrospectively reviewed the results of the management of intractable leg ulcers by plastic surgeons. PATIENTS AND METHODS: A total of 73 patients with intractable leg ulcers, (79 limbs) were treated at the Department of Plastic Surgery at our institution. Skin perfusion pressure (SPP) around the ulcer on the limb was measured before and after arterial reconstructive procedures. Local ulcer management involved intra-wound continuous negative pressure and irrigation therapy or negative pressure wound therapy. We examined the rates of wound healing and associated prognostic factors. RESULTS: There were 21 limbs without ischemia (non-peripheral arterial disease [Non-PAD] group) and 58 limbs with ischemia (PAD group). The healing rates were 66% in the PAD group and 81% in the Non-PAD group, but the difference between the groups was not significant. A total of 41 limbs in the PAD group underwent revascularization, which involved bypass surgery in 18 limbs and endovascular therapy in 23 limbs. The salvage rate of the revascularized limbs was 83% at 1 year. The primary patency rates at 1 year were 87% for bypass surgery and 58% for endovascular therapy. The healing rate of the revascularized limbs was 66%, and the presence of concomitant hemodialysis, infected ulcers, and limbs without improved SPP were shown to be poor prognostic factors. Limbs treated with bypass surgery had a better healing rate than limbs treated with endovascular therapy, but the difference was not significant. CONCLUSION: Good ulcer-healing rates were achieved by effective revascularization and aggressive local management. These results suggest that a team approach is useful for the management of intractable leg ulcers. (English translation of Jpn J Vasc Surg 2011; 20: 913-920). PMID- 23641283 TI - Surgical Treatment with or without Embolotherapy for Arteriovenous Malformations. AB - OBJECTIVE: The management of arteriovenous malformations (AVMs) remains challenging due to the high rate of recurrence of these lesions. Surgical resection is the only potential cure; however, it is often difficult to perform and carries a risk of massive hemorrhage. The purpose of this study was to review our experience with AVMs treated by surgical resection. MATERIALS AND METHODS: We retrospectively reviewed the medical records of nine patients with AVM, treated with surgical resection. We treated these patients with excision surgery with or without embolotherapy. RESULTS: Eight were treated with surgical resection with embolotherapy and one was treated with a simple surgical resection. Five patients with AVMs were cured. However, two cases of AVM recurred after total excision, and AVMs remained in two cases of partial excisional surgery in which the lesions involved the joints. CONCLUSIONS: Total excision of AVMs leads to a cure; however, total excision is not adequate in cases of AVMs involving the joints. Multidisciplinary treatment may offer good results in reducing the morbidity. To minimize complications related to surgery, aggressive control of blood flow to the lesion, preoperatively, with appropriate embolotherapy is essential, and a complete resection with a chance of cure will be increased. PMID- 23641284 TI - Exercise-ankle brachial pressure index with one-minute treadmill walking in patients on maintenance hemodialysis. AB - BACKGROUND: The ankle-brachial pressure index (ABI) is widely used as a standard screening method for arterial occlusive lesion above the knee. However, the sensitivity of ABI is low in hemodialysis (HD) patients. Exercise stress (Ex-ABI) may reduce the false negative results. PATIENTS AND METHODS: After measuring resting ABI and toe-brachial pressure index (TBI), ankle pressure and ABI immediately after walking (Post-AP, Post-ABI) were measured using one-minute treadmill walking in 52 lower limbs of 26 HD patients. The definition of peripheral arterial occlusive disease (PAD) required an ABI value of less than 0.90, TBI value of less than 0.60, and decrease of more than 15% of the Post-ABI value and 20 mmHg of Post-AP in Ex-ABI. Computed tomographic angiography (CTA) was performed in 32 lower limbs of 16 HD patients. PAD is defined as presence of stenosis of more than 75% in the case of lesions from an iliac artery to knee on CTA. RESULTS: The accuracy of Ex-ABI (Sensitivity, 85.7%; Specificity, 77.7%) was higher than those of ABI (Sensitivity, 42.9%; Specificity, 83.3%) or TBI (Sensitivity, 78.6%; Specificity, 61.1%). CONCLUSION: Ex-ABI with one-minute treadmill walking is the most useful tool for the screening of arterial occlusive lesions above the knee in maintenance HD patients. PMID- 23641285 TI - Reliability of ultrasound duplex for detection of hemodynamically significant stenosis in hemodialysis access. AB - OBJECTIVE: This study aims to evaluate the accuracy of AVF and AVG duplex ultrasound (US) compared to angiographic findings in patients with suspected failing dialysis access. MATERIALS AND METHODS: From July 2008 to December 2010, US was performed on 35 hemodialysis patients with 51 vascular accesses having clinical feature or dialysis parameter suspicious of access problem. Peak systolic velocity ratio of >=2 was the criteria for diagnosing stenosis >=50%. Fistulogram was performed in all these patients. Results of US and fistulogram were compared using Kappa and Receiver Operator Characteristic (ROC) analyses. RESULTS: In 51 accesses (35 AVF, 16 AVG), US diagnosed significant stenosis in 45 accesses according to the criteria and angiogram confirmed 44 significant stenoses. In AVF lesions, Kappa was 0.533 with 93.3% sensitivity and 60% specificity for US whereas in AVG lesions, Kappa was 0.636 with 100% sensitivity and 50% specificity. Overall Kappa value of 0.56 meant fair to good agreement. ROC demonstrated area under the curve being 0.79 for all cases and was significant (p = 0.016). Using the >=50% criteria for stenosis diagnosed by US yielded the best sensitivity (95.5%) and specificity (57.1%). CONCLUSION: Duplex ultrasound study, using >=50% criteria, is a sensitive tool for stenosis detection in patients with suspected failing AVF and AVG. PMID- 23641286 TI - Study Design of PROCEDURE Study. A Randomized Comparison of the Dose-Dependent Effects of Pitavastatin in Patients with Abdominal Aortic Aneurysm with Massive Aortic Atheroma: Prevention of Cholesterol Embolization during Endovascular and Open Aneurysm Repair with Pitavastatin (PROCEDURE) Study. AB - Outcomes of abdominal aortic aneurysm (AAA) repair have improved in the 2 decades since the emergence of endovascular aneurysm repair (EVAR). However, EVAR is considered a contraindication for shaggy aorta because of the high risk of shower embolization. Recently, statins have been implicated in preventing embolization in patients with shaggy aorta via its pleiotropic effects, including atheroma reduction and coronary artery stabilization. We selected pitavastatin, a statin with potent effects, discovered and developed by a Japanese company because it has shown excellent pleiotropic effects on atheromatous arteries in the Japanese population. A randomized comparison study of dose-dependent effects of pitavastatin in patients with AAA with massive atheromatous aortic thrombus (PROCEDURE study) has begun. PROCEDURE has an enrollment goal of up to 80 patients with AAA with massive aortic atheroma (excluding intrasac atheroma), randomly allocated into 2 groups receiving pitavastatin at a dose of 1 or 4 mg/day. The endpoints of the PROCEDURE study include change in atheroma volume, major adverse events related to shower embolization after aneurysm repair, and lipid-lowering effects. When complete, results of the PROCEDURE study should provide objective evidence to use statins preoperatively for AAA with massive aortic atheroma. PMID- 23641287 TI - Development and physical characteristics of novel zero-porosity vascular graft "triplex((r))". AB - We developed a novel large-diameter graft "Triplex((r))" that uses a non biodegradable material as a coating material. This time, in order to demonstrate the physical properties of Triplex((r)) grafts, we conducted physical tests in accordance with the international guidelines, using the collagen coated vascular grafts (Hemashield, Boston Scientific, Natick, Massachusetts, USA) as the controls. The grafts were tested with regard to strength (burst strength, circumferential tensile strength, longitudinal tensile strength), suture retention strength, integral water permeability, water leakage (needle puncture, after using clamp), and change in luminal diameter following pacing stress according to ISO7198 and FDA guidance. As indicated by the results, we experimentally demonstrated that uniquely designed vascular graft Triplex((r)) led to less blood leakage from the vascular graft and less leakage from the needle puncture, although it has fundamental physical properties comparable to those of the vascular grafts using biodegradable material that has been utilized conventionally in clinical settings. Triplex ((r))is expected to play its role as a clinically beneficial next-generation vascular graft. PMID- 23641288 TI - Surgical management of vascular thoracic outlet syndrome: a teaching hospital experience. AB - OBJECTIVES: Thoracic outlet syndrome (TOS) consists of a group of distinct disorders that are caused by compression of the brachial plexus and/or subclavian artery and vein. The aim of this study was to highlight the different modalities of diagnosing and treating vascular TOS and evaluate outcomes. METHODS: We conducted a retrospective cohort study between 1999 and 2011 using the medical records database from a teaching hospital. RESULTS: During the study period, 54 cases with vascular TOS were identified in 38 patients. Bilateral TOS was in 16 patients. The median age of the patients was 33 years (range 12-49), and the majority (79%) were female. Arterial TOS represented forty-nine cases (90.7%). Preoperative information derived from plain x-ray, duplex scanning and in selected cases computed tomography (CT) and/or angiography. Decompression of the TOS was performed through a supraclavicular approach in all cases with scalenectomy coupled with either cervical rib excision (70%), 1st rib excision alone (15%) and excision of both cervical and 1st ribs (15%). Adjunctive vascular reconstructive procedures were done in 11 cases (20.3%); 9 arterial cases and 2 venous cases. There was no mortality; however, postoperative complications occurred in 7 cases (13%). CONCLUSION: The use of advanced radiological imaging and careful surgical planning for Vascular TOS in a high volume center resulted in good outcomes. PMID- 23641289 TI - Thoracic endovascular aortic repair in patients with prior open aortic surgery. AB - OBJECTIVE: To review our experience of thoracic endovascular aortic repair (TEVAR) in patients with prior open aortic repair (OAR). MATERIALS AND METHODS: Stent-grafts were deployed in the arch, descending thoracic and thoracoabdominal aortae of 39, 13 and 5 patients, respectively, and in a deteriorated extra anatomical prosthesis in one. The access route was the femoral artery in 10 of 23 patients with, and in 30 of 35 patients without a prior abdominal prosthesis. Prior prostheses and elephant trunks comprised 57 of 116 landing zones and 23 proximal landing zones, respectively. RESULTS: Three patients died before discharge. Type II endoleaks developed in six patients, and Types I and III developed in one patient each. Type I endoleaks were not found at landing zones comprising prosthetic grafts. The overall actuarial three-year survival rate including early mortality was 86.5%. CONCLUSION: The clinical outcomes of TEVAR were excellent, even in patients with prior OAR. Prosthetic grafts, including elephant trunks, provided good landing zones for TEVAR. Prostheses with larger caliber designs are recommended for iliac artery reconstruction in future TEVAR. PMID- 23641290 TI - A Case of Acute Aortic Dissection with Intimal Tear Found at 1 cm Above Previous Aortotomy. AB - Although it is rare, acute aortic dissection after cardiac surgery predisposes the patients to critical condition such as rupture, tamponade and death. Prompt diagnosis and treatment is mandatory for this fatal complication. We present our case in which acute aortic dissection occurred 7 years after aortic valve replacement. PMID- 23641291 TI - Mycotic Iliac Artery Aneurysm Caused by Clostridium difficile in a Patient with Axillobifemoral Bypass for Leriche Syndrome. AB - A 74-year old man on hemodialysis developed a mycotic aneurysm caused by Clostridium difficile. To the best of our knowledge, this is only the second case of such an aneurysm reported in the literature. He had previously undergone axillobifemoral bypass grafting because of symptomatic infrarenal aortic stenosis. Although no blood flow was detected in his occluded right common iliac artery, it expanded rapidly despite intensive antibiotic therapy. As the blood supply to the lower limbs was already secured, only resection of the infected arteries was performed. PMID- 23641293 TI - Late Lower Extremity Ischemia due to Thrombi in an Occluded Graft after Axillary Femoral Artery Bypass. AB - We experienced a rare case of acute ischemia of the lower extremity due to embolism caused by an occluded prosthetic graft late after axillary-femoral artery bypass. A 67-year-old woman developed acute right lower extremity ischemia 7 years after axillary-femoral artery bypass, which had been performed for lower limb ischemia as a complication of acute aortic dissection (Stanford B). The graft was occluded, and the native vessel had re-canalized by the time of the present admission. She was successfully treated by disconnection of the graft followed by revascularization. PMID- 23641292 TI - Massive hematuria and shock caused by ilio-ureteral fistula in a patient with an isolated internal iliac artery aneurysm. AB - An emergent operation was performed on a 73-year-old woman with massive hematuria and serious shock. A computed tomography (CT) revealed that the cause of the shock was hemorrhage from an aneurysm into the ureter, with resultant massive hematuria. During surgery, we observed that the ureter was encased into the wall of the aneurysm, with exposure of the pre-positioned ureteric stent inside the aneurysmal space. Reconstruction of the ureter was performed by wrapping the tissues with the ureteric stent inside. Postoperative recovery was uneventful, and CT angiography showed complete exclusion of the right internal iliac artery with the in situ ureteric stent. PMID- 23641294 TI - Inferior mesenteric artery aneurysm: case report and literature review. AB - An inferior mesenteric artery (IMA) aneurysm is the rarest among visceral artery aneurysms. A 69-year-old man was referred to our hospital with an asymptomatic IMA aneurysm associated with occlusion of the superior mesenteric artery (SMA) and celiac artery (CA). After revascularization of the SMA with an 8-mm expanded polytetrafluoroethylene (ePTFE) graft, the aneurysm was resected, and the IMA was reconstructed. The "jet disorder" phenomenon has been thought to cause an IMA aneurysm in the case of CA and SMA obstruction. We consider it better to revascularize not only an IMA but also an SMA or CA for preventing that phenomenon. PMID- 23641296 TI - Fourth Asian PAD Workshop. PMID- 23641295 TI - Intravenous Lobular Capillary Hemangioma Occurring after Needle Insertion during Routine Health Checkup. AB - Surgery was performed on a 53-year-old male patient with a painful mass in front of the elbow. The mass originally occurred after needle insertion during a routine health checkup and grew in size during a 1-year period. Intravenous tumor with arterio-venous fistula was diagnosed, and it was resected. Histopathological diagnosis of intravenous lobular capillary hemangioma was made. Occurrence of this tumor after a routine health checkup is rare. The etiology of this tumor occurring simultaneously with arteriovenous fistula is discussed. PMID- 23641297 TI - CASE REPORT Treatment of Otophyma: Case Report and Review of the Literature. AB - OBJECTIVES: Otophyma is a rare condition that can present as the end stage of any chronic inflammatory disease affecting the ear such as rosacea, eczema, or otitis externa. It can result in conductive hearing loss, low self-esteem, and social embarrassment. This report highlights a case of otophyma treated successfully using a full-thickness skin graft. METHODS: We present a case of a 41-year-old lady referred to our department with a 23-year history of bilateral otophyma. During this time, her hearing progressively diminished as the swelling occluded her external auditory meatus. She had been unsuccessfully managed for years with topical emollients, steroids, and regular ear toileting. RESULT: She was treated by excision of the phymatous tissue and full-thickness grafting, which resulted in a patent external auditory meatus and an improvement in her hearing. CONCLUSIONS: The use of a full-thickness skin graft is one of the many treatment options available for the treatment of otophyma. We present a literature review on this uncommon condition and a discussion on the various treatment options available to the patient. PMID- 23641298 TI - Anterolateral thigh flow-through flap in hand salvage. AB - OBJECTIVE: Hand salvage and reconstruction following trauma and oncologic resection often dictates the use of innovative reconstructive techniques. Preservation of functional anatomy is paramount to success in this clinical setting. Further constraints are placed on the reconstructive surgeon in the setting of the aging US population. We report a case of successful hand salvage in an elderly patient using a free anterolateral thigh flow-through flap. METHODS: A retrospective chart review was performed on prospectively entered data to examine the case in detail. Indications, radiographs, and follow-up visits were reviewed. A free anterolateral thigh flap was harvested and used to provide soft tissue coverage as well as reconstruction of the palmar arch. RESULTS: The free anterolateral thigh flap not only reconstructed the unique soft tissue envelope of the hand but also restored functional vascular anatomy by reconstituting the interrupted superficial palmar arch. The patient had an uneventful hospital course and was discharged without complications. CONCLUSIONS: The free anterolateral thigh flap is a versatile flap that can be used as an innovative solution for hand salvage where vascular anatomy and soft tissue need to be restored. PMID- 23641299 TI - CASE REPORT Complex Wound Closure of Partial Sacrectomy Defect With Human Acellular Dermal Matrix and Bilateral V to Y Gluteal Advancement Flaps in a Pediatric Patient. AB - OBJECTIVE: Sacrectomy creates a large, complex tissue defect that presents a reconstructive challenge for plastic surgeons. Several myocutaneous flaps have been described for reconstruction following sacral tumor extirpation; however, current publications focus on the reconstructive options applicable to adults. We present a method of reconstruction following sacral tumor extirpation in a pediatric patient. METHODS: The patient was 22 months old and in need of complex closure following low sacral amputation (S3-S4 osteotomy) and en bloc resection of a yolk sac tumor. Following tumor extirpation, the patient was left with a complex defect including extensive dead space, multiple exposed nerve roots, projection of the rectum into the wound, and inadequate soft tissue for primary closure. RESULTS: Reconstruction with human acellular dermal matrix to address the risk of posterior rectal herniation and bilateral gluteal V to Y advancement flaps for obliteration of the dead space allowed for durable closure of the surgical defect. CONCLUSIONS: This represents the first case report documenting sacral resection and reconstruction with bilateral V to Y gluteal advancement flaps in a pediatric patient. PMID- 23641301 TI - Does platelet-rich plasma enhance the survival of grafted fat? An update review. AB - Autologous fat grafting enables repair and augmentation of soft tissues and is increasingly used in plastic and reconstructive surgery. The main limitation of fat grafting is unpredictable graft resorption. To obviate this disadvantage, several studies have searched for new ways of increasing the viability of the transplanted tissue. One promising approach has been to mix the fat graft with Platelet-Rich Plasma (PRP) before transplantation. The purpose of this article is to review systematically the available comparative evidence about PRP-assisted fat grafting. PMID- 23641300 TI - The effect of vascular endothelial growth factor in the progression of bladder cancer and diabetic retinopathy. AB - Bladder cancer and diabetic retinopathy is a major public health and economical burden worldwide. Despite its high prevalence, the molecular mechanisms that induce or develop bladder carcinomas and diabetic retinopathy progression are poorly understood but it might be due to the disturbance in balance between angiogenic factors such as VEGF and antiangiogenic factors such as pigment epithelium derived growth factor. VEGF is one of the important survival factors for endothelial cells in the process of normal physiological and abnormal angiogenesis and induce the expression of antiapoptotic proteins in the endothelial cells. It is also the major initiator of angiogenesis in cancer and diabetic retinopathy, where it is up-regulated by oncogenic expression and different type of growth factors. The alteration in VEGF and VEGF receptors gene and overexpression, determines a diseases phenotype and ultimately the patient's clinical outcome. However, expressional and molecular studies were made on VEGF to understand the exact mechanism of action in the genesis and progression of bladder carcinoma and diabetic retinopathy , but still how VEGF mechanism involve in such type of disease progression are not well defined. Some other factors also play a significant role in the process of activation of VEGF pathways. Therefore, further detailed analysis via molecular and therapeutic is needed to know the exact mechanisms of VEGF in the angiogenesis pathway. The detection of these types of diseases at an early stage, predict how it will behave and act in response to treatment through regulation of VEGF pathways. The present review aimed to summarize the mechanism of alteration of VEGF gene pathways, which play a vital role in the development and progression of bladder cancer and diabetic retinopathy. PMID- 23641302 TI - Sodium alginate/heparin composites on PVC surfaces inhibit the thrombosis and platelet adhesion: applications in cardiac surgery. AB - Thrombosis and hemocyte damage are the main problems of applied non-coated biomaterials to cardiac surgery that remain unsolved. The present study is aimed at the chemical modification of polyvinyl chloride (PVC) for applications in cardiac surgery and the biological property assessment of modified PVC. Sodium alginate (SA)/heparin (HEP) composites were covalently immobilized onto the surface of the PVC pipeline. The surface grafting density and protein adsorption were determined by ultraviolet spectrophotometry. The surface contact angles were evaluated by contact-angle measurement, whereas the surface characteristics were evaluated by Fouriertransform infrared spectroscopy. Blood coagulation time and platelet adhesion were measured using an automated blood coagulation analyzer and a hemocytometer, respectively. Surface morphologies of the thrombus and platelets were evaluated by scanning electron microscopy. The immobilization of SA/HEP reduced the contact angles of the coated surface. Protein adsorption was reduced by the immobilization of SA. The activated partial thrombin time and thrombin time of the coated PVC were significantly prolonged as compared with the non coated PVC. Platelet adhesion and thrombus formation were all reduced by the immobilization of HEP. The results revealed that the SA/HEP coating can improve the antithrombogenicity of the PVC pipeline, as well as improve its biocompatibility and hemocompatibility, which are essential for cardiac pulmonary bypass surgery. PMID- 23641303 TI - Expression levels of microRNA machinery components Drosha, Dicer and DGCR8 in human (AGS, HepG2, and KEYSE-30) cancer cell lines. AB - MicroRNAs (miRNAs) have recently been shown to play fundamental roles in diverse cellular processes and linked to variety of cancers. Dicer and Drosha are two major enzymes in the miRNA maturation process. DGCR8 is the assistant of Drosha in the microprocessor complex. In this study, we evaluated the mRNA expression profiles of major miRNA processing machinery Drosha, Dicer, and DGCR8 in human gastrointestinal (AGS, KYSE30 and HepG2) cancer cell lines. MATERIALS AND METHODS: The cells were cultured and harvested, and total cellular RNA was isolated from cells. Then, first-strand cDNA was synthesized from the RNA of cells. Afterward, Quantitative analysis was performed by real-time RT-PCR using the PowerSYBR Green PCR Master Mix. RESULTS: Expression levels of Drosha in AGS and HepG2 cells were higher than the controls, whereas, Drosha's expression level in KYSE-30 cell line was lower. The Dicer expression levels in AGS and HepG2 cells were higher, while, its expression level in KYSE-30 cell was lower. The DGCR8 expression levels in all three cell lines were significantly higher than the control samples. CONCLUSION: Expression levels of the two most important enzymes of the miRNA machinery, Drosha and Dicer, and microprocessor complex component, DGCR8 were noticeably dysregulated when compared to healthy controls. PMID- 23641305 TI - ESR1 single nucleotide polymorphisms predict breast cancer susceptibility in the central European Caucasian population. AB - Estrogen and progesterone hormones are key regulators of a wide variety of biological processes. In addition to their influence on reproduction, cell differentiation and apoptosis, they affect inflammatory response, cell metabolism and most importantly, they regulate physiological breast tissue proliferation and differentiation as well as the development and progression of breast cancer. In order to assess whether genetic variants in the steroid hormone receptor gene ESR1 (estrogen receptor alpha) had an effect on sporadic breast cancer susceptibility, we assessed 7 ESR1 single nucleotide polymorphisms (SNPs) for associations with breast cancer susceptibility and clinical parameters in 221 breast cancer patients and 221 controls, respectively. We identified ESR1 intron SNP +2464 C/T (rs3020314) and ESR1 intron SNP -4576 A/C (rs1514348) to correlate with breast cancer susceptibility and progesterone receptor expression status. Patients genotyped CT for ESR1 intron SNP +2464 (rs3020314) (p <= 0.045) or genotyped AC for ESR1 intron SNP -4576 (rs1514348) (p <= 0.000026) were identified to carry a significant risk as to the development of breast cancer in the Central European Caucasian population (both together: p <= 0.000488). Our study could confirm previous associations and revealed new associations of SNP rs1514348 with susceptibility to breast cancer and clinical outcome, which might be used as new additional SNP markers. PMID- 23641304 TI - Screening for high risk human papilloma virus (HR-HPV) subtypes, among Sudanese patients with oral lesions. AB - HR-HPV subtypes are strongly linked to etiology of many human cancers including oral cancer. The epidemiology of infection with different HPV genotypes greatly varies in different countries. The aim of this study was to identify and genotype the HR-HPV subtypes in oral tissues obtained from Sudanese patients with oral lesions. In this retrospective study 200 patients with oral lesions were screened by molecular methods (PCR) for the presence of HR-HPV subtypes. Of the 200 patients, 100/200 were patients with oral cancer (ascertained as case group) and 100/200 were patients with non-neoplastic oral lesions (ascertained as control group). Out of the 200 patients, 12/200 (6%) were found with HR-HPV infection. Of the 12 positive patients, 8/12 (66.7%) were among cases and the remaining 4/12 (33.3%) were among control group. The distribution of different genotypes was: type HPV 16 6/12 (50%), HPV18 4/12 (34%), HPV 31 1/12 (8%) and HPV 33 1/12 (8%). In view of these findings, HPV particularly subtypes 16 and 18 play a role in the etiology of oral cancer in the Sudan. PMID- 23641306 TI - A point mutation in epsilon-sarcoglycan induces inherited myoclonus dystonia syndrome in a Chinese family. AB - Myoclonus dystonia syndrome is a rare movement disorder featured by myoclonic jerks and dystonia. We identified here a point mutation in epsilon-sarcoglycan gene exon 6 associating with inherited myoclonus dystonia syndrome in a Chinese Han family. The mutation identified induces a stop codon and terminates the transcription of epsilon-sarcoglycan mRNA. This in turn results in a large truncation of epsilon-sarcoglycan protein. The further investigation is required to understand physiological and pathological functions of epsilon-sarcoglycan. PMID- 23641307 TI - Alterations in prothrombin time and activated partial thromboplastin time in patients with acute myocardial infarction. AB - Prothrombin time (PT) and activated partial thromboplastin time (aPTT) respectively measures the extrinsic and intrinsic pathways of coagulation and are used to determine the bleeding or clotting tendency of blood. We compared PT and aPTT levels in acute myocardial infarction (AMI) patients and normal subjects. There were significant increases in PT levels in patients with STEMI (15.98 +/- 0.96 s), NSTEMI (16.03 +/- 0.97 s) and chest pain (15.02 +/- 0.54 s) as compared to control group (8.86 +/- 0.08 s). The level of aPTT in control subjects was 31.35 +/- 0.48 s. Patients with STEMI (40.79 +/- 1.83 s), NSTEMI (41.33 +/- 2.06) and chest pain (37.84 +/- 1.66 s) showed significantly higher levels of aPTT. There was a significant correlation between PT and aPTT levels. Both PT and aPTT were significantly correlated with age however there was no correlation between these coagulation markers and gender or body mass index. In conclusion, both PT and aPTT are significantly increased in AMI patients on anticoagulation therapy. The elevations in PT values were more than 2.5-fold greater than aPTT suggesting a high potential of PT for predicting blood clotting tendency in patients receiving anticoagulation therapy. PMID- 23641309 TI - The totally drug resistant tuberculosis (TDR-TB). PMID- 23641308 TI - Primary cervical and uterine corpus lymphoma; a case report and literature review. AB - Primary lymphoma of the uterine corpus and cervix is rare. We present a case of primary non-Hodgkin follicular lymphoma isolated to uterine corpus and parametria with focal spread to ovaries and fallopian tubes, incidentally found on the background of endometrial malignancy. A summary of the published cases focusing on the presentation and prognosis as well as a review of current management are discussed. The rising incidence of extra-nodal lymphoma and recent changes in classification and therapeutic approach, require clinical vigilance. In the absence of prospective studies assessing the value of the available therapeutic options, data from retrospective series and scattered case reports are presented in this review. PMID- 23641310 TI - Association between thrombelastography system and thromboembolic and bleeding events in Chinese aged people. AB - OBJECTIVES: This study was designed to obtain the knowledge about TEG indexes distribution in Chinese aged people, as well as to test the hypothesis that previous TEG indexes are associated with the subsequent thromboembolic and bleeding events in the aged population. METHODS: We conducted a two-year follow up study in Chinese PLA General Hospital, Beijing, China. 403 aged people were enrolled in our study. They received TEG measurements at least once when they entered this study. We collected their demographical characteristics, clinical examination information and their outcome during their observational period. Structural equation modeling (SEM) was used to analyze the relationship between the four indexes from TEG and the outcome via a pathway of indicator. RESULTS: We found that in the "model of bleeding" (adjusted by confounding of Anticoagulants), the model fit indices with chi-square/df = 9.555/7, CFI was 0.997, TLI was 0.994 and standardized root mean square residual (SRMR) was 0.034; while in the "model of thromboembolic events" (adjusted by confounding of Anticoagulants), the model fit indices with chi-square/df = 6.070/7, CFI was1.000, TLI was 1.002 and standardized root mean square residual (SRMR) was 0.000. The "model of thromboembolic events" showed that the four indexes (R, K, MA and ANGLE) were all significantly associated with thromboembolic events, while this significance was not found in the "model of bleeding". CONCLUSIONS: Previous TEG indexes are significantly associated with the subsequent thromboembolic events in the aged population. Future study can test this association and provide more information for the clinical use. PMID- 23641311 TI - From alpha4beta2 Nicotinic Ligands to the Discovery of sigma1 Receptor Ligands: Pharmacophore Analysis and Rational Design. AB - Comparative analyses of the pharmacophoric elements required for sigma1 and nicotinic ligands led to the identification of a potent and selective sigma1 ligand (15). Compound 15 displayed high selectivity for the sigma1 receptor (Ki, sigma1 = 4.1 nM, Ki, sigma2 = 1312 nM) with moderate binding affinity for the DAT (Ki = 373 nM) and NET (Ki = 203 nM) in the PDSP broad screening panel of common CNS neurotransmitter transporters and receptors. The key finding in this present work is that a subtle structural modifica tion could be used as a tool to switch a ligand's selectivity between nAChRs and sigma receptors. PMID- 23641312 TI - Modular Synthesis of the Pentacyclic Core of Batrachotoxin and Select Batrachotoxin Analogue Designs. AB - Pentacyclic analogues of the potent voltage-gated sodium ion channel agonist batrachotoxin can be accessed through an intermediate furan by exploiting Diels Alder cycloaddition reactions with ring-strained dienophiles. The use of 3 bromofuran as a 1,2-dianion equivalent, the application of carbamate reductive N alkylation for homomorpholine ring assembly, and the demonstration of CsF as an effective reagent for generating benzyne, cyclohexyne, and related dienophiles underscore this work. PMID- 23641313 TI - The role of viscosity on polymer ink transport in dip-pen nanolithography. AB - Understanding how ink transfers to a surface in dip-pen nanolithography (DPN) is crucial for designing new ink materials and developing the processes to pattern them. Herein, we investigate the transport of block copolymer inks with varying viscosities, from an atomic force microscope (AFM) tip to a substrate. The size of the patterned block copolymer features was determined to increase with dwell time and decrease with ink viscosity. A mass transfer model is proposed to describe this behaviour, which is fundamentally different from small molecule transport mechanisms due to entanglement of the polymeric chains. The fundamental understanding developed here provides mechanistic insight into the transport of large polymer molecules, and highlights the importance of ink viscosity in controlling the DPN process. Given the ubiquity of polymeric materials in semiconducting nanofabrication, organic electronics, and bioengineering applications, this study could provide an avenue for DPN to expand its role in these fields. PMID- 23641314 TI - High-Resolution Optical Imaging of Benign and Malignant Mucosa in the Upper Aerodigestive Tract: An Atlas for Image-Guided Surgery. AB - BACKGROUND: High-resolution optical imaging provides real-time visualization of mucosa in the upper aerodigestive tract (UADT) which allows non-invasive discrimination of benign and neoplastic epithelium. The high-resolution microendoscope (HRME) utilizes a fiberoptic probe in conjunction with a tissue contrast agent to display nuclei and cellular architecture. This technology has broad potential applications to intraoperative margin detection and early cancer detection. METHODS: Our group has created an extensive image collection of both neoplastic and normal epithelium of the UADT. Here, we present and describe imaging characteristics of benign, dysplastic, and malignant mucosa in the oral cavity, oropharynx, larynx, and esophagus. RESULTS: There are differences in the nuclear organization and overall tissue architecture of benign and malignant mucosa which correlate with histopathologic diagnosis. Different anatomic subsites also display unique imaging characteristics. CONCLUSION: HRME allows discrimination between benign and neoplastic mucosa, and familiarity with the characteristics of each subsite facilitates correct diagnosis. PMID- 23641315 TI - Yoga Empowers Seniors Study (YESS): Design and Asana Series. AB - The practice of yoga asanas (postures) may be an optimal method of preserving or enhancing physical function in older men and women. However, the physical demands, efficacy and safety of an asana practice for seniors have not been well studied. The Yoga Empowers Seniors Study (YESS) is an intervention development study that created two senior-adapted series of asanas targeted for an ambulatory older population. YESS is using biomechanics and physical performance tests to acquire information about the physical demands placed on the muscles and joints by the asanas and the functional performance adaptations resulting from the yoga practice. This manuscript details the standardized, senior-adapted, YESS asana series and the additional asana modifications provided when participants had physical limitations. This presentation will enable the yoga research and teaching communities to interpret the biomechanics, physical performance and side effects outcomes of YESS. PMID- 23641316 TI - Objective Assessment of Joint Stiffness: A Clinically Oriented Hardware and Software Device with an Application to the Shoulder Joint. AB - Examination of articular joints is largely based on subjective assessment of the "end-feel" of the joint in response to manually applied forces at different joint orientations. This technical report aims to describe the development of an objective method to examine joints in general, with specific application to the shoulder, and suitable for clinical use. We adapted existing hardware and developed laptop-based software to objectively record the force/displacement behavior of the glenohumeral joint during three common manual joint examination tests with the arm in six positions. An electromagnetic tracking system recorded three-dimensional positions of sensors attached to a clinician examiner and a patient. A hand-held force transducer recorded manually applied translational forces. The force and joint displacement were time-synchronized and the joint stiffness was calculated as a quantitative representation of the joint "end feel." A methodology and specific system checks were developed to enhance clinical testing reproducibility and precision. The device and testing protocol were tested on 31 subjects (15 with healthy shoulders, and 16 with a variety of shoulder impairments). Results describe the stiffness responses, and demonstrate the feasibility of using the device and methods in clinical settings. PMID- 23641317 TI - Assessment of Random Recruitment Assumption in Respondent-Driven Sampling in Egocentric Network Data. AB - BACKGROUND: One of the key assumptions in respondent-driven sampling (RDS) analysis, called "random selection assumption," is that respondents randomly recruit their peers from their personal networks. The objective of this study was to verify this assumption in the empirical data of egocentric networks. METHODS: We conducted an egocentric network study among young drug users in China, in which RDS was used to recruit this hard-to-reach population. If the random recruitment assumption holds, the RDS-estimated population proportions should be similar to the actual population proportions. Following this logic, we first calculated the population proportions of five visible variables (gender, age, education, marital status, and drug use mode) among the total drug-use alters from which the RDS sample was drawn, and then estimated the RDS-adjusted population proportions and their 95% confidence intervals in the RDS sample. Theoretically, if the random recruitment assumption holds, the 95% confidence intervals estimated in the RDS sample should include the population proportions calculated in the total drug-use alters. RESULTS: The evaluation of the RDS sample indicated its success in reaching the convergence of RDS compositions and including a broad cross-section of the hidden population. Findings demonstrate that the random selection assumption holds for three group traits, but not for two others. Specifically, egos randomly recruited subjects in different age groups, marital status, or drug use modes from their network alters, but not in gender and education levels. CONCLUSIONS: This study demonstrates the occurrence of non-random recruitment, indicating that the recruitment of subjects in this RDS study was not completely at random. Future studies are needed to assess the extent to which the population proportion estimates can be biased when the violation of the assumption occurs in some group traits in RDS samples. PMID- 23641318 TI - The role of quality control circles in sustained improvement of medical quality. AB - We used quality control circles (QCC) followed by the PDCA Deming cycle and analyzed the application of QCC to the sustained improvement of a medical institution in Zhejiang province. Analyses of the tangible and intangible achievements of QCC revealed that the achievement indices for reductions in internal errors, reductions in costs, improvements in the degree of patient satisfaction, improvements in work quality, and improvements in economic performance were 109.84% +/- 16.47%, 135.04% +/- 50.33%, 126.26% +/- 53.69%, 100.58% +/- 22.83%, and 104.07% +/- 5.45%, respectively. The improvements in these areas were 61.12% +/- 13.2%, 60.47% +/- 28.91%, 34.41% +/- 22.96%, 49.22% +/- 25.39%, and 73.70% +/- 5.24%, respectively. The intangible achievements were reflected as follows: 5% of QCC members showed an activity growth value of 1-2 points, 83% 1-2 points, 12% more than 2 points. As a result, QCC activity showed prominent results in fostering long-lasting improvement in the quality of medical institutions in terms of both tangible and intangible factors. In short, QCC can be used as an effective tool to improve medical quality. PMID- 23641319 TI - Interactive voice response - an automated follow-up technique for adolescents discharged from acute psychiatric inpatient care: a randomised controlled trial. AB - Follow-up methods must be easy for young people to handle. We examine Interactive Voice Response (IVR) as a method for collecting self-reported data. Sixty inpatients were recruited from a child and adolescent psychiatric emergency unit in Malmo, Sweden and called every second (N = 30) or every fourth (N = 30) day from discharge until first visit in outpatient care. A pre-recorded voice asked them to evaluate their current mood using their mobile phones. Average response rate was 91%, and 71% had a 100% response rate. Gender, age and length of inpatient treatment did not affect response rate, nor did randomisation. Boys estimated their current mood on average as 3.52 units higher than girls, CI = (2.65, 4.48). Automated IVR is a feasible method of collecting follow-up data among adolescents discharged from a psychiatric emergency unit. PMID- 23641320 TI - Physiological and morphological responses of Lead or Cadmium exposed Chlorella sorokiniana 211-8K (Chlorophyceae). AB - The heavy metal pollution in soils and aquatic environments is a serious ecological problem. In the green-microalga Chlorella sorokiniana 211-8K (Chlorophyceae) exposed to ions of lead (Pb) and cadmium (Cd) we studied the metabolic responses to the toxicity of these two heavy metals. Our data indicate that both the pollutants alter the alga cell ultrastructure and its physiological characteristics (growth, photosynthesis, respiration, enzyme activities). The toxic effects of the two metals resulted time-dependent to the exposure. After 24 h of treatment with 250 MUM Pb or Cd, photosynthesis was inhibited until to 77 and 86%, however respiration was strongly enhanced up to 300 and 350%, respectively. In the algal cells Pb or Cd exposure induced a reduction in the content of the total chlorophylls and a decrease of the soluble protein levels, significantly compromising the growth, particularly in cultures cadmium-treated. We report data on ultrastructural changes induced by the two heavy metals; they affected overall chloroplast ultrastructure of the alga. Most importantly, the O acetyl-L-serine(thiol)lyase (OASTL) activity was appreciably increased after only 2 h of Cd exposure, indicating the existence of a link between the metal contamination and cysteine synthesis. Then, Chlorella sorokiniana cells seem to better tolerate high concentrations of Pb while appear to be more sensitive to Cd ions. These results provide some additional information that can lead to better understand consequences of heavy metal poisoning in microalgae. PMID- 23641321 TI - Rare case of malignant transformation of recurrent respiratory papillomatosis associated with human papillomavirus type 6 infection and p53 overexpression. AB - Recurrent respiratory papillomatosis (RRP), a chronic upper respiratory condition characterized by diffuse multiple recurring papillomas, is thought to result from human papillomavirus (HPV) type 6 or 11 infection. Although RRP is an intractable disease, malignant transformation of RRP is rare. The underlying mechanism, however, has not been elucidated. We describe the clinical course of a patient who underwent more than 130 operations for RRP associated with HPV type 6 infection and subsequently suffered spontaneous malignant transformation to squamous cell carcinoma. Immunohistochemical analysis revealed that malignant transformation might result from a genomic defect, such as p53 inactivation, leading to stimulation of uncontrolled cell proliferation by HPV type 6 for an extended period, but not directly because of HPV itself. Our results could help in the development of novel therapeutic strategies for severe RRP, although further studies are required before clinical application of molecular targeted therapies. PMID- 23641322 TI - Effects of rocuronium and vecuronium on initial rundown of endplate potentials in the isolated phrenic nerve diaphragm preparation of rats. AB - Rocuronium and vecuronium, two non-depolarizing neuromuscular blockers, have been widely used in surgery procedures. However, their electrophysiological properties need to be more widely explored. We examined the effects of rocuronium and vecuronium on initial rundown of endplate potential amplitudes in the non-uniform stretched muscle preparation of the rat isolated phrenic nerve diaphragm. More specifically, the endplate potentials were recorded with one microelectrode from a single endplate. The effects of rocuronium or vecuronium each at 4 concentrations (0.5 *, l *, 2 *, 4 * EC95; EC95 = concentration of the drug required to produce the inhibitory effect by 95%) on the amplitude of endplate potentials and its rundown were observed. Treatment of the isolated rat phrenic nerve-diaphragm preparation with rocuronium (2.5-20 MUg/ml) or vecuronium (0.5-4 MUg/ml) decreased the amplitude of endplate potentials and inhibited its rundown in a concentration-dependent manner. At the concentration (2.5 MUg/ml for rocuronium and 0.5 MUg/ml for vecuronium) that did not alter the endplate potential amplitude, the onset of reduced endplate potential rundown was 3 and 5 min after administration of rocuronium or vecuronium, respectively. The results suggest that rocuronium and vecuronium block the neuromuscular junction presynaptically and that rocuronium does it faster than vecuronium. PMID- 23641323 TI - Natural radioactivity levels of some medicinal plants commonly used in Ghana. AB - Natural radioactivity levels in some selected medicinal plants commonly used in Ghana from the Centre for Scientific Research into Plant Medicine were investigated to determine the activity concentration and the annual committed effective dose due to naturally occurring radionuclides of (238)U, (232)Th and (40)K. The activity concentration was determined using gamma-ray spectrometry. The results of the analysis indicated an average activity concentration of (238)U, (232)Th and (40)K in the medicinal plants to be 31.8+/-2.8 Bq kg(-1), 56.2+/-2.3 Bq kg(-1) and 839.8+/-11.9 Bq kg(-1) respectively. Khaya ivorensis recorded the highest activity concentration of (238)U and (232)Th while Lippia multiflora recorded the highest activity concentrations of (40)K. The total annual committed effective doses ranged from 0.026+/-0.001 to 0.042+/-0.002 mSv a(-1) with an average value of 0.035+/-0.001 mSv a(-1). The average annual committed effective dose due to ingestion of the natural radionuclides in the medicinal plant samples were far below the world average annual committed effective dose of 0.3 mSv a(-1) for ingestion of natural radionuclides provided in UNSCEAR 2000 report. Therefore, the radiological hazard associated with intake of the natural radionuclides in the medicinal plants is insignificant. The results provide baseline values which may be useful in establishing rules and regulations relating to radiation protection as well as developing standards and guidelines for the use of medicinal or herbal plants to the appropriate authorities. PMID- 23641324 TI - Pharmacist-led medication-related needs assessment in rural Ghana. AB - Access to both essential and non-essential medications is increasing worldwide. While increased drug access is a positive development, many countries lack the infrastructure for appropriate distribution, administration, and monitoring of drug therapy. The objective of this study was to assess medication and pharmacy related needs in the rural Ashanti Region of Ghana and to determine barriers of achieving optimal health outcomes in this region. Qualitative domains and associated themes were identified by observations from integration into community culture and from conduction of semi-structured interviews with local community leaders, health workers, or those with knowledge of health-related issues. Eight semi-structured interviews were completed and four thematic domains were identified; access to care, resource shortages, medication safety, and education/training. Barriers and challenges identified under each thematic domain included (but were not limited to) availability of clean water sources, shortages of medications and diagnostic equipment, financial considerations, misunderstanding of medication indications and directions for use, and shortages of qualified pharmacy or dispensary staff. Most respondents also expressed a need for continuing education and training of healthcare personnel. It can be concluded that there is a need for development of health services related to medications. Locally supported interventions and future research should focus on barriers and challenges identified from the thematic domains. PMID- 23641326 TI - Anti-counterfeit technologies: a pharmaceutical industry perspective. AB - Growth of international free trade and inadequate drug regulation have led to the expansion of trade in counterfeit drugs worldwide. Technological protection is seen to be the best way to avoid this problem. Different technologies came into existence like overt, covert, and track and trace technologies. This review emphasises ideal technological characteristics, existing anti-counterfeit technologies, and their adoption in different countries. Developed countries like the USA have implemented RFID while the European trend is towards 2D barcodes. The Indian government is getting sensitised about the extent of the problem and has formulated rules mandating barcodes. Even the pharmaceutical companies have been employing these technologies in order to detain illegitimate drugs in their supply chain. PMID- 23641325 TI - Identification of plumbagin and sanguinarine as effective chemotherapeutic agents for treatment of schistosomiasis. AB - Schistosomiasis, a snail-borne parasitic disease, affects more than 200 million people worldwide. Currently the treatment of schistosomiasis relies on a single therapy of praziquantel, a drug developed over 30 years ago. Thus, there is an urgent need to develop alternative antischistosomal drugs. In the pursuit of novel antischistosomal drugs, we examined the antischistosomal activities of 45 compounds that had been reported to exhibit antimicrobial and/or antiparasitic activities. Two plant-derived compounds, plumbagin and sanguinarine, were found to possess potent antischistosomal activities in vitro. For both the compounds, a concentration of 10 MUM (equivalent to 1.88 MUg/ml for plumbagin and 3.68 MUg/ml for sanguinarine) resulted in 100% mortality at 48 h, which meets the World Health Organization's (WHO) criterion of "hit" compounds for the control of schistosomiasis. Morphological changes and tegumental alterations of the dead worms treated by the two compounds were quite different. The significant morphological changes of worms after treatment by the two compounds suggest the two compounds target different biological pathways, both of which result in parasite's death. This study provides evidence to suggest plumbagin and sanguinarine have real potential as effective alternative chemotherapeutic agents for the treatment of schistosomiasis. PMID- 23641327 TI - Design and Evaluation of Novel Antimicrobial and Anticancer Agents Among Tetrazolo[1,5-c]quinazoline-5-thione S-Derivatives. AB - The novel heterocyclization of 5-(2-aminophenyl)-1H-tetrazole with potassium ethylxanthogenate or carbon disulfide was proposed. The potassium salt of the tetrazolo[1,5-c]quinazoline-5-thione was subsequently modified by alkylation with proper halogen derivatives to (tetrazolo[1,5-c]quinazolin-5-ylthio)alkyls, N,N dialkylethylamines, 1-aryl-2-ethanones, 1-(alkyl)aryl-2-ethanols, carboxylic acids, and esters. The structures of all newly synthesized compounds were confirmed by FT-IR, UV-vis, LC-MS, (1)H, (13)C NMR, and elemental analysis data. The substances were screened for antibacterial and antifungal activities (100 MUg) against Escherichia coli, Staphylococcus aureus, Enterobacter aerogenes, Entrococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans. Preliminary bioluminescence inhibition tests against Photobacterium leiognathi Sh1 showed that substances 5.2-5.4, 6.1, 7.1 with ethanone or carboxylic acid substituents showed toxicity against bacteria cells. The substances chosen by the US National Cancer Institute (NCI) were screened for their ability to inhibit 60 different human tumor cell lines, where 2 (tetrazolo[1,5-c]quinazolin-5-ylthio)-1-(4-tolyl)ethanone (5.2), 3-(tetrazolo[1,5 c]quinazolin-5-ylthio)propanoic and related 3-metyl-butanoic acids (6.2, 6.3), and ethyl tetrazolo[1,5-c]quinazolin-5-ylthio)acetate (7.2) showed lethal antitumor activity (1.0 MUM) against the acute lymphoblastic leukemia cell line (CCRF-CEM), and substances 5.2 and 6.3 exhibited moderate anticancer properties inhibiting growth of the leukemia MOLT-4 and HL06-(TB) cell lines. The moderate antitumor activity was demonstrated in 1-(2,5-dimethoxyphenyl)-2-(tetrazolo[1,5 c]quinazolin-5-ylthio)ethanone (5.4) against the CNS cancer cell line SNB-75. Comparing the docking mode of the Gefitinib and synthesised substances on the ATP binding site of EGFR, it could be assumed that these compounds might act in the same way. The results of the investigation could be considered as a useful base for future development of potent antimicrobials and antitumor agents among tetrazolo[1,5-c]quinazoline-5-thione S-derivatives. PMID- 23641328 TI - In vitro antileishmanial, trypanocidal, and Mammalian cell activities of diverse n,n' -dihetaryl substituted diamines and related compounds. AB - The leishmaniasis and Chagas diseases constitute a serious public health problem worldwide with few and ineffective treatment options. The search for new antiparasitic candidates at the initial steps of drug discovery and development is still necessary. The synthesis of 22 de novo synthetized N,N'-dihetaryl alkyldiamine derivatives and in vitro antiparasitic activity were evaluated for the first time against intracellular and extracellular forms of Leishmania (Leishmania) infantum, L. (Viannia) panamensis, L. (Leishmania) amazonensis, and Trypanosoma cruzi. Additionally, the toxicity on mammalian cells was determined. Some of these substituted N,N'-diamines (25-35 % of the tested compounds) showed interesting results against free-living forms of parasites with activities at the inhibitory concentration (IC 50 ) level of 1.96 to 28.83 MUM for L. (L.) infantum promastigotes and IC50 of 0.02 to 5.31 MUM for T. cruzi epimastigotes. No activity at the IC50 level on intracellular amastigotes of T. cruzi was observed. However, N (1),N (2)-dibenzylethane-1,2-diamine 5a revealed an important activity against the intracellular amastigotes of L. infantum (IC50 25.42 MUM +/-0.33) and L. panamensis (IC50 58.20 MUM +/-3.23), while their analogue N(1),N(4) dibenzylbutane-1,4-diamine 5c resulted in activity only against L. panamensis (IC50 11.19 MUM +/-0.20) without toxicity on Vero and THP-1 mammalian cells. The active compounds against intracellular parasites with low toxicity in mammalian cells may be considered for future studies in experimental models. PMID- 23641329 TI - Predictive Modeling of Antioxidant Coumarin Derivatives Using Multiple Approaches: Descriptor-Based QSAR, 3D-Pharmacophore Mapping, and HQSAR. AB - The inability of the systemic antioxidants to alleviate the exacerbation of free radical formation from metabolic outputs and environmental pollutants claims an urgent demand for the identification and design of new chemical entities with potent antioxidant activity. In the present work, different QSAR approaches have been utilized for identifying the essential structural attributes imparting a potential antioxidant activity profile of the coumarin derivatives. The descriptor-based QSAR model provides a quantitative outline regarding the structural prerequisites of the molecules, while 3D pharmacophore and HQSAR models emphasize the favourable spatial arrangement of the various chemical features and the crucial molecular fragments, respectively. All the models infer that the fused benzene ring and the oxygen atom of the pyran ring constituting the parent coumarin nucleus capture the prime pharmacophoric features, imparting superior antioxidant activity to the molecules. The developed models may serve as indispensable query tools for screening untested molecules belonging to the class of coumarin derivatives. PMID- 23641330 TI - Chromatographic behaviour predicts the ability of potential nootropics to permeate the blood-brain barrier. AB - The log BB parameter is the logarithm of the ratio of a compound's equilibrium concentrations in the brain tissue versus the blood plasma. This parameter is a useful descriptor in assessing the ability of a compound to permeate the blood brain barrier. The aim of this study was to develop a Hansch-type linear regression QSAR model that correlates the parameter log BB and the retention time of drugs and other organic compounds on a reversed-phase HPLC containing an embedded amide moiety. The retention time was expressed by the capacity factor log k'. The second aim was to estimate the brain's absorption of 2 (azacycloalkyl)acetamidophenoxyacetic acids, which are analogues of piracetam, nefiracetam, and meclofenoxate. Notably, these acids may be novel nootropics. Two simple regression models that relate log BB and log k' were developed from an assay performed using a reversed-phase HPLC that contained an embedded amide moiety. Both the quadratic and linear models yielded statistical parameters comparable to previously published models of log BB dependence on various structural characteristics. The models predict that four members of the substituted phenoxyacetic acid series have a strong chance of permeating the barrier and being absorbed in the brain. The results of this study show that a reversed-phase HPLC system containing an embedded amide moiety is a functional in vitro surrogate of the blood-brain barrier. These results suggest that racetam type nootropic drugs containing a carboxylic moiety could be more poorly absorbed than analogues devoid of the carboxyl group, especially if the compounds penetrate the barrier by a simple diffusion mechanism. PMID- 23641331 TI - Stress Degradation Behavior of Atorvastatin Calcium and Development of a Suitable Stability-Indicating LC Method for the Determination of Atorvastatin, its Related Impurities, and its Degradation Products. AB - A rapid, reversed-phase liquid chromatographic method was developed for the quantitative determination of Atorvastatin calcium, its related substances (12 impurities), and degradation impurities in bulk drugs. The chromatographic separation was achieved on a Zorbax Bonus-RP column by employing a gradient elution with water-acetonitrile-trifluoroacetic acid as the mobile phase in a shorter run time of 25 min. The flow rate was 1.0 mL/min and the detection wavelength was 245 nm. The drug substance was subjected to stress studies such as hydrolysis, oxidation, photolysis, and thermal degradation, and considerable degradation was observed in acidic hydrolysis, oxidative, thermal, and photolytic stress conditions. The formed degradation products were reported and were well resolved from the Atorvastatin and its related substances. The stressed samples were quantified against a qualified reference standard and the mass balance was found to be close to 99.5% (w/w) when the response of the degradant was considered to be equal to the analyte (i.e. Atorvastatin), which demonstrates the stability-indicating capability of the method. The method was validated in agreement with ICH requirements. The method developed here was single and shorter (25 min method for the determination of all 12 related impurities of Atorvastatin and its degradation products), with clearly better resolution and higher sensitivity than the European (85 min method for the determination of six impurities) and United States pharmacopeia (115 min and 55 min, two different methods for the determination of six related substances). PMID- 23641332 TI - Method Development and Validation of a Stability-Indicating RP-HPLC Method for the Quantitative Analysis of Dronedarone Hydrochloride in Pharmaceutical Tablets. AB - A simple, precise, and accurate HPLC method has been developed and validated for the quantitative analysis of Dronedarone Hydrochloride in tablet form. An isocratic separation was achieved using a Waters Symmetry C8 (100 * 4.6 mm), 5 MUm particle size column with a flow rate of 1 ml/min and UV detector at 290 nm. The mobile phase consisted of buffer: methanol (40:60 v/v) (buffer: 50 mM KH2PO4 + 1 ml triethylamine in 1 liter water, pH=2.5 adjusted with ortho-phosphoric acid). The method was validated for specificity, linearity, precision, accuracy, robustness, and solution stability. The specificity of the method was determined by assessing interference from the placebo and by stress testing the drug (forced degradation). The method was linear over the concentration range 20-80 MUg/ml (r(2) = 0.999) with a Limit of Detection (LOD) and Limit of Quantitation (LOQ) of 0.1 and 0.3 MUg/ml respectively. The accuracy of the method was between 99.2 100.5%. The method was found to be robust and suitable for the quantitative analysis of Dronedarone Hydrochloride in a tablet formulation. Degradation products resulting from the stress studies did not interfere with the detection of Dronedarone Hydrochloride so the assay is thus stability-indicating. PMID- 23641333 TI - Development and Validation of a Precise, Single HPLC Method for the Determination of Tolperisone Impurities in API and Pharmaceutical Dosage Forms. AB - A novel, sensitive, stability-indicating HPLC method has been developed for the quantitative estimation of Tolperisone-related impurities in both bulk drugs and pharmaceutical dosage forms. Effective chromatographic separation was achieved on a C18 stationary phase with a simple mobile phase combination delivered in a simple gradient programme, and quantitation was by ultraviolet detection at 254 nm. The mobile phase consisted of a buffer and acetonitrile delivered at a flow rate 1.0 ml/min. The buffer consisted of 0.01 M potassium dihydrogen phosphate with the pH adjusted to 8.0 by using diethylamine. In the developed HPLC method, the resolution between Tolperisone and its four potential impurities was found to be greater than 2.0. Regression analysis showed an R value (correlation coefficient) of greater than 0.999 for the Tolperisone impurities. This method was capable of detecting all four impurities of Tolperisone at a level of 0.19 MUg/mL with respect to the test concentration of 1000 MUg/mL for a 10 ul injection volume. The tablets were subjected to the stress conditions of hydrolysis, oxidation, photolysis, and thermal degradation. Considerable degradation was found to occur in base hydrolysis, water hydrolysis, and oxidation. The stress samples were assayed against a qualified reference standard and the mass balance was found to be close to 100%. The established method was validated and found to be linear, accurate, precise, specific, robust, and rugged. PMID- 23641334 TI - Development and Validation of a Stability-Indicating LC-Method for the Simultaneous Estimation of Levodropropizine, Chloropheniramine, Methylparaben, Propylparaben, and Levodropropizine Impurities. AB - A simple, fast, and efficient RP-HPLC method has been developed and validated for the simultaneous estimation of Levodropropizine, Chloropheniramine, Methylparaben, Propylparaben, and the quantification of Levodropropizine impurities in the Reswas syrup dosage form. A gradient elution method was used for the separation of all the actives and Levodropropizine impurities by using the X-Bridge C18, 150 mm * 4.6 mm, 3.5 MUm column with a flow rate of 1.0 mL/min and detector wavelength at 223 nm. The mobile phase consisted of a potassium dihydrogen orthophosphate buffer and acetonitrile. All the peaks were symmetrical and well-resolved (resolution was greater than 2.5 for any pair of components) with a shorter run time. The limit of detection for Levodropropizine and its Impurity B was 0.07 MUg/ml & 0.05 MUg/ml, whereas the limit of quantification was 0.19 MUg/ml & 0.15 MUg/ml respectively. The method was validated in terms of precision, accuracy, linearity, robustness, and specificity. Degradation products resulting from the stress studies were well-resolved and did not interfere with the detection of Levodropropizine, Chloropheniramine, Methylparaben, Propylparaben, and Levodropropizine Impurity B, thus the test method is stability indicating. Validation of the method was carried out as per International Conference on Harmonization (ICH) guidelines. PMID- 23641335 TI - A Rapid, Validated RP-HPLC Method for the Simultaneous Determination of Cleaning Validation and Cross-Contamination of 12 Beta-Lactam Compounds. AB - The present work reports a rapid reversed-phase high-performance liquid chromatography (RP-HPLC) method for the simultaneous determination of 12 beta lactam components for cleaning validation and cross-contamination. A strategic experimental approach was implemented for the method development. The desired chromatographic separation was achieved on a Symmetry C18 (4.6 X 75 mm, 3.5 MUm) column using gradient elution. The optimized mobile phase consisted of the buffer tetrabutylammonium hydroxide pH-6.8 and acetonitrile. The eluted compounds were monitored at 215 nm and 254 nm wavelength using a photodiode array detector. The developed method separated 12-beta-lactam compounds from each other within a run time of 50 min. The method is effective for the determination of cross contamination of penicillin and cephalosporin production blocks. The present method is specific and a lower limit of quantification was determined on the basis of the signal-to-noise ratio method; it is 1 MUg/mL for all components. The developed RP-HPLC method was validated according to the International Conference on Harmonization (ICH) guidelines. PMID- 23641336 TI - Development and validation of a stability-indicating HPLC method for the simultaneous determination of sulfadiazine sodium and trimethoprim in injectable solution formulation. AB - A direct, precise, and stability-indicating HPLC method that is based on reversed phase liquid chromatography (RP-HPLC) coupled with a photodiode array detector (PDA) was developed, optimized, and validated for the simultaneous determination of sulfadiazine sodium (SDZS) and Trimethoprim (TMP) in Bactizine(r) forte injectable solution. The separation was achieved using a C18 column (250 mm*4.6 mm i.d., 5 MUm particle size) at room temperature, and an isocratic mobile phase that consisted of a trinary solvent mixture of water-acetonitrile-triethylamine (838:160:2, v/v) at pH 5.5 +/- 0.05. The mobile phase was delivered at 1.4 ml/min and the analytes were monitored at 254 nm. The effects of the operational chromatographic conditions on the peak's USP tailing factor, column efficiency, and resolution were systematically optimized. Forced degradation experiments were carried out by exposing SDZS, TMP standards, and their formulation to thermal, photolytic, oxidative, and acid-base hydrolytic stress conditions. The method was successfully validated in accordance to International Conference on Harmonization (ICH) and United States Pharmacopoeia (USP34/NF29) guidelines and found to be suitable for the quantitative determination and stability of SDZS and TMP in Bactizine(r) forte injectable solution. PMID- 23641338 TI - Comprehensive Assessment of Degradation Behavior of Aspirin and Atorvastatin Singly and in Combination by Using a Validated RP-HPLC Method. AB - A fixed-dose combination of atorvastatin and aspirin is widely used for the treatment of myocardial infarction. The present work describes a comprehensive study of the stress degradation behavior of atorvastatin and aspirin alone as well as in combination of 1:1 and 1:7.5 ratios, respectively, as per ICH guidelines. The degradation products of aspirin as well as atorvastatin were successfully separated by a developed simple, selective, and precise stability indicating reversed-phase HPLC method. Chromatographic separation was achieved on the Phenomenex Luna analytical column, 150 mm * 4.6 mm, 5MUm. The mobile phase consisted of 0.1% glacial acetic acid in water and acetonitrile in the ratio of 50:50 v/v at a flow rate of 1.0 ml/min. UV detection was performed at 246 nm. The extent of degradation was significantly influenced when both of the drugs were present in combination. Stress degradation behavior of atorvastatin was highly influenced by aspirin under acid hydrolysis, thermal degradation, and oxidative stress conditions. Similarly, the stress degradation behavior of aspirin was affected by atorvastatin especially under neutral hydrolysis, thermal degradation, and oxidative stress conditions. Additionally, the combination ratio of aspirin and atorvastatin also influenced the percentage degradation of each other. A mixture of aspirin and atorvastatin was also analyzed after a one-month stability study at 40 degrees C and 75% RH. All the results indicate chemical incompatibility of both aspirin and atorvastatin if present in combination. PMID- 23641337 TI - A Novel, Validated Stability-Indicating UPLC Method for the Estimation of Lansoprazole and its Impurities in Bulk Drug and Pharmaceutical Dosage Forms. AB - A novel, reversed-phase ultra-performance liquid chromatographic method was developed and validated for the determination of the assay and related substances of Lansoprazole (LAN) in bulk drug and capsule dosage forms. The related substances include degradation and process-related impurities. The method was developed using the Waters Acquity BEH C18 column and gradient program with mobile phase A as a pH 7.0 phosphate buffer and methanol in the ratio of 90: 10 (v/v), and mobile phase B as methanol and acetonitrile in the ratio of 50:50 (v/v). Lansoprazole and its impurities were monitored at 285 nm. Lansoprazole was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal, humidity, and photolytic degradation and found to degrade significantly under acid and oxidative stress conditions. The degradation products were well-resolved from the main peak and its impurities, proving the stability-indicating power of the method. The performance of the method was validated according to the present ICH guidelines for specificity, limit of detection, limit of quantification, linearity, accuracy, precision, ruggedness, and robustness. PMID- 23641339 TI - Antidepressant effect of aminophylline after ethanol exposure. AB - This work investigated the association of acute ethanol and aminophylline administration on behavioral models of depression and prefrontal monoamine levels (i.e. norepinephrine and dopamine) in mice. The animals received a single dose of ethanol (2 g/kg) or aminophylline (5 or 10 mg/kg) alone or in association. Thirty minutes after the last drug administration, the animals were assessed in behavioral models by the forced swimming and tail suspension tests. After these tests, the animals were sacrificed and the prefrontal cortices dissected to measure monoamine content. Results showed that ethanol presented depression-like activity in the forced swimming and tail suspension tests. These effects were reversed by the association with aminophylline in all tests. Norepinephrine and dopamine levels decreased, while an increase in the dopamine metabolite, (4 hydroxy-3-methoxyphenyl)acetic acid (DOPAC), after ethanol administration was observed. On the contrary, the association of ethanol and aminophylline increased the norepinephrine and dopamine content, while it decreased DOPAC when compared to the ethanol group, confirming the alterations observed in the behavioral tests. These data reinforce the involvement of the adenosinergic system on ethanol effects, highlighting the importance of the norepinephrine and dopamine pathways in the prefrontal cortex to the effects of ethanol. PMID- 23641340 TI - Inhibitions of several antineoplastic drugs on serum sialic Acid levels in mice bearing tumors. AB - Six murine tumors, including ascetic tumors HepA, EC, P388 leukemia, S180 and solid tumor S180, and Lewis lung carcinoma, were employed in this work. The free sialic acid concentrations in both blood and ascites were measured in tumor bearing mice. The results showed that the content of sialic acids in blood was increased in tumor growth and certain tumor types. Higher sialic acid content was observed in ascites than that present in blood. The influence of antineoplastic agents (vincristine, thiotepa, adriamycin, probimane, cisplatin, oxalysine, cortisone, nitrogen mustard, lycobetaine, Ara-C, harringtonine, and cyclophosphamide) on the content of sialic acids in mice blood bearing solid tumors of either S180 or Lewis lung carcinoma was observed. Different inhibitions of antineoplastic drugs on both tumor growth and serum sialic acid levels in mice bearing tumors were found. Among these antineoplastic drugs, probimane, cisplatin, nitrogen mustard, and lycobetaine were able to decrease the serum sialic acid levels in mice bearing tumors. Since these four antineoplastic drugs are all DNA chelating agents, it was proposed that the inhibition of tumor sialic acids by these drugs might be through the DNA template via two ways. Since we have found no effect of antineoplastic drugs on serum sialic acid levels in normal mice, this suggests that the inhibition of antineoplastic drugs on sialic acids is by tumor involvement. PMID- 23641341 TI - Inhibition of key digestive enzymes related to diabetes and hyperlipidemia and protection of liver-kidney functions by trigonelline in diabetic rats. AB - Diabetes is a serious health problem and a source of risk for numerous severe complications such as obesity and hypertension. Treatment of diabetes and its related diseases can be achieved by inhibiting key digestive enzymes related to starch and lipid digestion. The findings revealed that the administration of trigonelline to surviving diabetic rats helped to protect the pancreas beta-cells from death and damage. Additionally, the supplement of trigonelline to surviving diabetic rats significantly decreased intestinal alpha-amylase and maltase by 36 and 52%, respectively, which led to a significant decrease in the blood glucose rate by 46%. Moreover, the administration of trigonelline to surviving diabetic rats potentially inhibited key enzymes of lipid metabolism and absorption such as lipase activity in the small intestine by 56%, which led to a notable decrease in serum triglyceride (TG) and total cholesterol (TC) rates and an increase in the HDL cholesterol level. This treatment also improved glucose, maltase, starch, and lipid oral tolerance. Trigonelline was also observed to protect the liver-kidney functions efficiently, which was evidenced by the significant decrease in the serum aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), and lactate dehydrogenase (LDH) activities and creatinine, albumin, and urea rates. The histological analysis of the pancreas, liver, and kidney tissues further established the positive effect of trigonelline. Overall, the findings presented in this study demonstrate that the administration of trigonelline to diabetic rats can make it a potentially strong candidate for industrial application as a pharmacological agent for the treatment of hyperglycemia, hyperlipidemia, and liver-kidney dysfunctions. PMID- 23641342 TI - Stereochemistry of Consabatine from Convolvulus sabatius Viv. (Convolvulaceae). AB - The stereochemistry of consabatine, which was isolated from the roots of Convolvulus sabatius Viv. as a novel natural compound, has now been determined by the synthesis of its Mosher esters. Consabatine was found to be 1'R-configurated. PMID- 23641343 TI - Assessment of anti-quorum sensing activity for some ornamental and medicinal plants native to egypt. AB - This study investigated the effects of some plant extracts on the bacterial communication system, expressed as quorum sensing (QS) activity. Quorum sensing has a directly proportional effect on the amount of certain compounds, such as pigments, produced by the bacteria. Alcohol extracts of 23 ornamental and medicinal plants were tested for anti-QS activity by the Chromobacterium violaceum assay using the agar cup diffusion method. The screening revealed the anti-QS activity of six plants; namely the leaves of Adhatoda vasica Nees, Bauhinia purpurea L., Lantana camara L., Myoporum laetum G. Forst.; the fruits of Piper longum L.; and the aerial parts of Taraxacum officinale F.H. Wigg. PMID- 23641344 TI - An Improvement of the Efficacy of Moxifloxacin HCl for the Treatment of Bacterial Keratitis by the Formulation of Ocular Mucoadhesive Microspheres. AB - The aim of this study was to prepare novel ocular mucoadhesive microspheres of Moxifloxacin HCl to increase its residence time on the ocular surface and to enhance its therapeutic efficacy in ocular bacterial keratitis. Microspheres were fabricated with different grades of Methocel and Sodium CMC as polymers. Microspheres were evaluated for their particle size, morphology, encapsulation efficiency, mucoadhesion, antimicrobial efficacy, and in vitro drug release studies. In vivo studies were carried out for the promising formulation on eyes of albino rabbits by inducing bacterial keratitis. A sterile microspheres suspension in light mineral oil was applied to infected eyes twice a day. A marketed conventional eye drop was used as a positive control. Eyes were examined daily for improvement of clinical signs of bacterial keratitis by an ophthalmologist. The average particle size of microspheres was found to be less than 80 MUm. Methocel microspheres were found to have a smoother surface than Sodium CMC. Entrapment efficiency was enhanced with an increased polymer concentration and viscosity. The formulation containing Methocel K100M with a drug: polymer ratio of 1:2 exerted longer corneal and conjunctival mucoadhesion time of 8.45+/-0.15 h and 9.40+/-0.53 h respectively. In vitro release of Moxifloxacin HCl from microspheres was retarded with increased viscosity and concentration of polymers, and was controlled by diffusion as well as polymer relaxation. All formulations showed comparable antimicrobial activity in comparison with conventional marketed eye drops. The formulation containing Methocel K100M with a drug: polymer ratio of 1:2 was found to be a promising formulation and was used for the in vivo studies. The in vivo studies revealed that microspheres demonstrated significantly lower clinical scores and reduced the total duration of therapy than the marketed Moxifloxacin HCl eye drops. In vitro and in vivo studies showed that ocular mucoadhesive microspheres of Moxifloxacin HCl were found to have an improved efficacy in the treatment of ocular bacterial keratitis in comparison with the marketed formulation. PMID- 23641345 TI - Synthesis, characterization, and in vitro evaluation of new Ibuprofen polymeric prodrugs based on 2-hydroxypropyl methacrylate. AB - The present research work describes the synthesis and evaluation of new acrylic type polymeric systems having degradable ester bonds linked to ibuprofen as materials for drug delivery. Ibuprofen was linked to 2-hydroxy-propyl methacrylate by an activated ester methodology in a one-pot procedure with a high yield. The resulting material was copolymerized with either 2-hydroxyethyl methacrylate or methyl methacrylate (in 1:3 mole ratios) by the free radical polymerization method, utilizing azoisobutyronitrile at 65-70 degrees C. The characterization of the resulting products by FTIR, (1)H NMR, (13)C NMR, DSC, and elemental analysis confirmed their synthesis successfully. Ibuprofen release from the obtained polymers was preliminarily evaluated at different buffered solutions (pH 1, 7.4, and 10) into dialysis bags to show the capacity of prodrugs to release the drug under hydrolytic conditions. Detection of hydrolysis by UV spectroscopy at selected intervals showed that the drug can be released by selective hydrolysis of the ester bond at the side of the drug moiety. The release profiles indicated that the hydrolytic behavior of polymers is strongly based on the polymer hydrophilicity and the pH value of the hydrolysis solution. The results suggest that these polymers could be useful in controlled release systems. PMID- 23641346 TI - Scientia pharmaceutica, autorenhinweise 2013. PMID- 23641348 TI - The mechanism of white and brown adipocyte differentiation. AB - Obesity gives vent to many diseases such as type 2 diabetes, hypertension, and hyperlipidemia, being considered as the main causes of mortality and morbidity worldwide. The pathogenesis and pathophysiology of metabolic syndrome can well be understood by studying the molecular mechanisms that control the development and function of adipose tissue. In human body, exist two types of adipose tissue, the white and the brown one, which are reported to play various roles in energy homeostasis. The major and most efficient storage of energy occurs in the form of triglycerides in white adipose tissue while brown adipose tissue actively participates in both basal and inducible energy consumption in the form of thermogenesis. Recent years have observed a rapid and greater interest towards developmental plasticity and therapeutic potential of stromal cells those isolated from adipose tissue. The adipocyte differentiation involves a couple of regulators in the white or brown adipogenesis. Peroxisome proliferators-activated receptor-gamma actively participates in regulating carbohydrate and lipid metabolism, and also acts as main regulator of both white and brown adipogenesis. This review based on our recent research, seeks to highlight the adipocyte differentiation. PMID- 23641347 TI - Treatment of retinopathy of prematurity: a review of conventional and promising new therapeutic options. AB - Retinopathy of prematurity (ROP), a retinal vascular disease of premature infants, continues to be a major cause of preventable childhood blindness all over the world. The incidence of ROP varies among countries, being influenced by the quality of the level of neonatal intensive care. Here, we discuss the potential treatments that are now available or will soon or probably be available for ROP. Although ablation of the avascular retina with laser photocoagulation remains the current gold standard and well established therapy for ROP, some new therapeutic options including angiostatic therapies are being explored based on our knowledge of the pathophysiology of the ROP and complications and efficacy of laser treatment. However, prevention of the development of severe ROP and screening for ROP seem to be the best strategy in avoiding visual impairment caused by ROP in premature infants. New therapeutic interventions including vascular endothelial growth factor antibody administration, gene therapy and supplemental therapies should be supported with evidence-based data for the treatment of ROP. PMID- 23641349 TI - Cell therapy for diabetic neuropathy using adult stem or progenitor cells. AB - Diabetic neuropathy (DN) is the most common and disabling complication of diabetes that may lead to foot ulcers and limb amputations. Despite widespread awareness of DN, the only effective treatments are glucose control and pain management. A growing body of evidence suggests that DN is characterized by reduction of vascularity in peripheral nerves and deficiency in neurotrophic and angiogenic factors. Previous studies have tried to introduce neurotrophic or angiogenic factors in the form of protein or gene for therapy, but the effect was not significant. Recent studies have shown that bone marrow (BM)-derived stem or progenitor cells have favorable effects on the repair of cardiovascular diseases. Since these BM-derived stem or progenitor cells contain various angiogenic and neurotrophic factors, these cells have been attempted for treating experimental DN, and turned out to be effective for reversing various manifestations of experimental DN. These evidences suggest that cell therapy, affecting both vascular and neural components, can represent a novel therapeutic option for treatment of clinical DN. PMID- 23641350 TI - A systematic review of oxidative stress and safety of antioxidants in diabetes: focus on islets and their defense. AB - A growing body of evidence suggests that hyperglycemia-induced oxidative stress plays an important role in diabetic complications, especially beta-cell dysfunction and failure. Under physiological conditions, reactive oxygen species serve as second messengers that facilitate signal transduction and gene expression in pancreatic beta-cells. However, under pathological conditions, an imbalance in redox homeostasis leads to aberrant tissue damage and beta-cell death due to a lack of antioxidant defense systems. Taking into account the vulnerability of islets to oxidative damage, induction of endogenous antioxidant enzymes or exogenous antioxidant administration has been proposed as a way to protect beta-cells against diabetic insults. Here, we consider recent insights into how the redox response becomes deregulated under diabetic conditions, as well as the therapeutic benefits of antioxidants, which may provide clues for developing strategies aimed at the treatment or prevention of diabetes associated with beta-cell failure. PMID- 23641351 TI - Metformin and cancer in type 2 diabetes. PMID- 23641352 TI - Efficacy and safety of biphasic insulin aspart 30/70 in type 2 diabetes suboptimally controlled on oral antidiabetic therapy in Korea: a multicenter, open-label, single-arm study. AB - BACKGROUND: The purpose of this study was to evaluate change in glycosylated hemoglobin (HbA1c), side effects, and quality of life (QOL) after a 16-week treatment period with Biphasic insulin aspart 30/70 (BIasp30) in patients with type 2 diabetes mellitus (T2DM) who had been suboptimally controlled with oral antidiabetic drugs (OADs). METHODS: The study consisted of a 4-week titration period when concurrent OAD(s) were replaced with BIasp30 and followed by a 12 week maintenance period. All patients completed the Diabetes Treatment Satisfaction Questionnaire at the beginning and the end of the trial. Hypoglycemic episodes were recorded by the patient throughout the trial. RESULTS: Sixty patients were included, of whom 55 patients (92%) completed the full 16 week treatment period. Seven-point blood glucose was significantly improved as compared with the baseline, except for the postlunch blood glucose level. HbA1c at the end of period was significantly improved from 9.2% to 8.2% (P<0.001). Eleven percent (n=6) of patients achieved HbA1c values <=6.5% and 22% (n=12) of patients achieved <7.0%. There were 3.4 episodes/patients-year of minor hypoglycemia and 0.05 episodes/patients-year of major hypoglycemia. QOL showed significant changes only in the acceptability of high blood glucose category (P=0.003). CONCLUSION: Treatment with once or twice daily BIasp30 may be an option for the patients with T2DM suboptimally controlled with OADs in Korea. However, considering the low number of patients achieving the HbA1c target and the high postlunch blood glucose levels, additional management with another modality may be required for optimal control. PMID- 23641353 TI - The Relationship between Metformin and Cancer in Patients with Type 2 Diabetes. AB - BACKGROUND: Recently, several studies reported that the cancer incidence in type 2 diabetes patients is higher than in the general population. Although a number of risks are shared between cancer and diabetes patients, there have been few studies of its correlation. We evaluated the influences of several factors including low density lipoprotein cholesterol (LDL-C), albuminuria and use of metformin on the risk of cancer in patients with type 2 diabetes. METHODS: We enrolled 1,320 patients with at least 5 years of follow-up and 73 patients were diagnosed with cancer during this period. The associations of the risk factors with cancer incidence were evaluated by multiple regression analysis. The subjects were placed into two subgroups based on metformin dosage (<1,000 mg/day, >=1,000 mg/day) and we compared cancer incidence using analysis of covariance. RESULTS: LDL-C and albuminuria were not significantly correlated with cancer risk. In contrast, metformin showed a reverse correlation with cancer risk (P=0.006; relative risk, 0.574). In the metformin nonadministration group, smoking, male gender, and high triglyceride levels tended to be contributing factors without statistical significance. Cancer occurence was lower in the low dose metformin group (less than 1,000 mg/day) (P=0.00). CONCLUSION: These results suggest that the administration of low dose metformin in patients with type 2 diabetes may be associated with a reduced risk of cancer. PMID- 23641354 TI - Low levels of physical activity are associated with increased metabolic syndrome risk factors in korean adults. AB - BACKGROUND: Low levels of physical activity (PA) are strongly associated with the development of metabolic syndrome (MetS) and chronic diseases. However, few studies have examined this association in Koreans. The primary purpose of this study was to examine the associations between PA and MetS risks in Korean adults. METHODS: A total of 1,016 Korean adults (494 males and 522 females) participated in this study. PA levels were assessed using the International PA Questionnaire. MetS risk factors were determined using clinically established diagnostic criteria. RESULTS: Compared with the highest PA group, the group with the lowest level of PA was at greater risk of high triglyceride (TG) in males (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.07 to 3.24) and of hemoglobin A1c >=5.5% in females (OR, 1.75; 95% CI, 1.00 to 3.04) after adjusting for age and body mass index. Compared with subjects who met the PA guidelines, those who did not meet the guidelines were more likely to have low high density lipoprotein cholesterol in both males (OR, 1.69; 95% CI, 1.11 to 2.58), and females (OR, 1.82; 95% CI, 1.20 to 2.77). Furthermore, those who did not meet the PA guidelines were at increased risk of high TG levels in males (OR, 1.69; 95% CI, 1.23 to 2.86) and abnormal fasting glucose (OR, 1.93; 95% CI, 1.17 to 3.20) and MetS (OR, 2.10; 95% CI, 1.15 to 3.84) in females. CONCLUSION: Increased levels of PA are significantly associated with a decreased risk of abnormal MetS components. PMID- 23641356 TI - Is the indicator magnifying window for insulin pens helpful for elderly diabetic patients? AB - Patients with type 2 diabetes who require insulin therapy are commonly elderly and have poor visual acuity. In this study, we examined the clinical usefulness of the indicator magnifying window (IMW) for elderly patients with type 2 diabetes. We recruited 50 patients with type 2 diabetes over the age of 60 who had used insulin pens for glucose control. They were asked to set the insulin pen at randomly selected doses with or without an IMW. We assessed dosing accuracy, convenience, self-confidence, need for eyeglasses, preference, and willingness to recommend the IMW to other patients. Although the IMW did not improve the dosing accuracy or convenience, it significantly decreased the need for eyeglasses. Overall, the clinical usefulness of the IMW is quite limited in elderly patients with type 2 diabetes. PMID- 23641355 TI - Effects of high performance inulin supplementation on glycemic control and antioxidant status in women with type 2 diabetes. AB - BACKGROUND: The purpose of this study was to evaluate the effects of high performance inulin supplementation on blood glycemic control and antioxidant status in women with type 2 diabetes. METHODS: In a randomized, triple-blind controlled trial, 49 females (fiber intake <30 g/day, 25 80% of patients. Cardiac biomarkers were found to be elevated in >90% of our patients. CONCLUSIONS: TC is a worldwide problem and clinical presentation appears to be similar in North American, European, and Asian countries. However, fewer patients in our cohort presented with typical chest pain and electrocardiography (ECG) changes, which might suggest ethnic variations in the syndrome or perhaps a more aggressive diagnostic approach in North American countries. PMID- 23641367 TI - Quality in diagnostic microbiology: experiential note to emphasize value of internal control programs. AB - BACKGROUND: Quality control (QC) in diagnostic microbiology is a matter of effective, efficient, accurate reporting in the expected turnaround time. Major stages of the analytical "standard operational procedures" where QC could be easily affected include organism identification and antibacterial susceptibility testing. AIM: The objective of this experiential technical note is to provide an evidence base to highlight the value of internal QC program in evaluating the effectiveness and efficiency of a laboratory's standard operational procedures; and the competences of individual scientific/technical staff. MATERIALS AND METHODS: This report is based on four different scenarios requiring internal QC, including cases that are not reported within the turnaround time of standard operational procedures. Small-scale evaluations of (i) internal QC program, (ii) ciprofloxacin vs. moxifloxacin susceptibilities, and (iii) calibrated dichotomous susceptibility vs. directed susceptibility testing were performed. RESULTS: The internal QC program identified sources of discrepancies in laboratory results. Evidence base for decision on new methodology and antibiotic testing were developed. For instance, it is observed that calibrated dichotomous susceptibility gives greater annular radius than directed susceptibility (P < 0.01). CONCLUSIONS: Internal QC program continues to be valuable means of identifying discrepancies, and vetting new ideas. This report presents evidence base to reaffirm that the need for internal QC is ever present. PMID- 23641368 TI - Sonography of common carotid arteries' intima: media thickness in the normal adult population in Sudan. AB - BACKGROUND: Carotid ultrasonography is a useful diagnostic tool for assessing carotid disease. It is highly reliable, has no radiation risk, and has no risks when compared to conventional angiography. AIM: The study was to determine the common carotid artery (CCA) intima-media thickness (IMT) in the normal adult Sudanese so as to create standards for defining abnormalities. MATERIALS AND METHODS: In 440 participants, the intima-media thickness was obtained sonographically in the supine position at the point of 1 cm section distal to the carotid bulb. Due to ethnic variations, participants were divided into a five ethnic groups according to their geographic distribution in Sudan. RESULTS: The ranges of IMT found in the study were from 0.04 cm to 0.07 cm in carotids. Ethnically, males and females from West and East of Sudan show the highest IMT (0.070 +/- 0.00 cm and 0.065 +/- 0.01 cm) for CCA while males and females from the South of Sudan show the lowest IMT (0.055 +/- 0.01 cm and 0.058 +/- 0.004 cm). CONCLUSION: Mean carotids' IMT was slightly higher in females compared to males. No significant differences were found between IMT and different ethnics but significance was noted among participants' age and IMT of both sexes. PMID- 23641369 TI - Genetic Diversity of Plasmodium falciparum Field Isolates in Central Sudan Inferred by PCR Genotyping of Merozoite Surface Protein 1 and 2. AB - BACKGROUND: Characterization of Plasmodium falciparum diversity is commonly achieved by amplification of the polymorphic regions of the merozoite surface proteins 1 (MSP1) and 2 (MSP2) genes. AIMS: The present study aimed to determine the allelic variants distribution of MSP1 and MSP2 and multiplicity of infection in P. falciparum field isolates from Kosti, central Sudan, an area characterized by seasonal malaria transmission. MATERIALS AND METHODS: Total 121 samples (N = 121) were collected during a cross-sectional survey between March and April 2003. DNA was extracted and MSP1 and MSP2 polymorphic loci were genotyped. RESULTS: The total number of alleles identified in MSP1 block 2 was 11, while 16 alleles were observed in MSP2 block 3. In MSP1, RO33 was found to be the predominant allelic type, carried alone or in combination with MAD20 and K1 types, whereas FC27 family was the most prevalent in MSP2. Sixty two percent of isolates had multiple genotypes and the overall mean multiplicity of infection was 1.93 (CI 95% 1.66 2.20). Age correlated with parasite density (P = 0.017). In addition, a positive correlation was observed between parasite densities and the number of alleles (P = 0.022). CONCLUSION: Genetic diversity in P. falciparum field isolates in central Sudan was high and consisted of multiple clones. PMID- 23641370 TI - Gender Differences in Health Related Quality of Life of People Living with HIV/AIDS in the Era of Highly Active Antiretroviral Therapy. AB - BACKGROUND: Data about the health-related quality of life (HR-QOL) of people living with HIV/AIDS (PLHA) after the implementation of free antiretroviral treatment in India are scarce. AIM: The study was to describe the HR-QOL and gender differences of PLHA in rural India. MATERIALS AND METHODS: Cross sectional study of 120 PLHA who came to the outpatient department in a rural district hospital. Assessment of the HR-QOL was performed through interviews using a validated structured questionnaire from the Medical Outcome Study HIV Health Survey. Linear regression with robust standard errors was used for multivariable analysis. RESULTS: Domains related to social and daily activities such as cognitive, role and social functioning had lower HR-QOL scores than domains related to physical health. Men had higher scores of HR-QOL in health transition, perceived HR-QOL, health distress, social functioning and role functioning. In multivariable analysis, factors associated with poorer HR-QOL were female sex, lower levels of education and being widowed or separated in women. CONCLUSIONS: HR-QOL of PLHA in rural India is poor, especially in widowed or separated women and people with lower levels of education. There is an urgent need of implementing programmes for improving the HR-QOL of HIV infected women in rural India. PMID- 23641371 TI - Retrowalking as an adjunct to conventional treatment versus conventional treatment alone on pain and disability in patients with acute exacerbation of chronic knee osteoarthritis: a randomized clinical trial. AB - BACKGROUND: Increased external knee adduction moment during walking alters the joint biomechanics; which causes symptoms in chronic knee osteoarthritis patients. AIMS: To assess additional effects of Retro-walking over conventional treatment on pain and disability in patients with acute exacerbation of chronic knee osteoarthritis. MATERIALS AND METHODS: Thirty chronic knee osteoarthritis patients were randomly assigned into 2 groups. Group 'A' (7 men, 8 women) received conventional treatment. Group 'B' (8 men, 7 women) received conventional treatment and Retro-walking. Pain, assessed through visual analogue scale (VAS), and Western Ontario and McMaster Universities Arthritis Index (WOMAC) were the primary outcomes and knee range of motion (ROM), hip abductor and extensor strength were secondary outcomes; measured pre-intervention, after 1 week and after 3 weeks of intervention. RESULTS: Two factors analysis of variance for repeated measures was used for all outcomes. At the end of 3 weeks; WOMAC score showed highly significant difference within (P < 0.0001) and significant difference between groups (P = 0.040) also by Time * group interaction (P = 0.024), VAS showed highly significant difference within groups (P < 0.0001). Knee ROM showed significant difference within groups. Hip abductor and extensor strength showed significant difference by Time * group interaction (P < 0.05). CONCLUSION: Retrowalking is an effective adjunct to conventional treatment in decreasing disability in patients with knee osteoarthritis. PMID- 23641372 TI - Bacteriology of symptomatic adenoids in children. AB - BACKGROUND: Children with adenoid hypertrophy have been shown to harbor pathogenic bacteria in the nasopharynx despite antibiotics. Removal of the adenoid is associated with a reduction in the bacterial count. AIMS: The study was done to determine the bacteriology of the adenoid tissue in chronic adenotonsillitis and adenoid hypertrophy, and determine the antibiotic sensitivity of potential pathogens. MATERIALS AND METHODS: This is a descriptive study conducted on 100 patients aged between three and twelve years who underwent adenotonsillectomy/adenoidectomy. After adenoidectomy, the specimen along with the swab taken from the surface of the adenoid was sent for microbiological examination. After 48 and 96 hours, the microbial growth was identified and the antibiotic-sensitivity pattern of the isolate was studied. RESULTS: Aerobic organisms grew in 93% of the specimens and anaerobic organisms in 68%, whereas 7% had no growth. The surface was predominated by commensals and the pathogens were mainly found in the core. The predominant pathogens were Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus species. The organisms were resistant to penicillin but showed sensitivity to co-amoxiclav and ciprofloxacin. Co amoxiclav and ciprofloxacin should be considered as the first line of medical treatment for adenotonsillar diseases. CONCLUSIONS: Infection is the main cause of adenoid hypertrophy. Amoxicillin with potassium clavulanate and ciprofloxacin should be considered as the drugs of choice for all adenotonsillar diseases. Early and prompt treatment of adenoid hypertrophy with appropriate antibiotics will avoid unnecessary exposure to repeated antimicrobial therapy, thereby maintaining the beneficial effects of the normal adenoid flora. PMID- 23641373 TI - Knowledge About HIV/AIDS Among Secondary School Students. AB - BACKGROUND: HIV/AIDS has emerged as the single most formidable challenge to public health. School children of today are exposed to the risk of HIV/AIDS. AIMS: The study was conducted to determine the knowledge among secondary school students regarding HIV/AIDS and provide suggestions for HIV/AIDS education in schools. MATERIALS AND METHODS: A cross-sectional study was conducted among students of tenth to twelfth standard in the intermediate schools of Lucknow, India, from July to October 2011. A total of 215 students, both boys and girls, were enrolled in the study. RESULTS: In this study, for majority of the students (85%), the source of information about HIV/AIDS was the television. Regarding knowledge about modes of transmission of HIV/AIDS among girl students, 95.1% of them told that it is through unprotected sex. A total of 75.8% students said that it was transmitted from mother to child. CONCLUSION: It was observed that the knowledge of the school students was quite satisfactory for most of the variables like modes of transmission, including mother-to-child transmission of the disease. However, schools should come forward to design awareness campaigns for the benefit of the students. PMID- 23641374 TI - Morphological spectrum of pilar cysts. AB - BACKGROUND: Cysts of the skin are one of the commonly excised specimens in the surgical outpatient department. A majority of them being clinically diagnosed as sebaceous cysts, their true nature is only discernible on histopathological examination. Closer examination of the type of keratinization involved will throw light into the exact nature of the cyst. Trichilemmal or Pilar cyst is one such entity, which presents in both a non-neoplastic and neoplastic form. AIMS: The present retrospective observational study was undertaken to find out the incidence of these cysts in surgical pathology practice in a rural hospital and to enlist the various morphological forms that these cysts may take. MATERIALS AND METHODS: The histopathology files were reviewed for a period of 6 years for cases coded as pilar cyst. RESULTS: A total of eight cases (5.75%) were identified, which showed features of trichilemmal differentiation. A single case each of proliferating trichilemmal cyst and malignant proliferating trichilemmal tumors were noted. Most of the cases were seen among females on the scalp. CONCLUSIONS: Trichilemmal tumor is an uncommon histopathological entity. Many of these lesions may be mistakenly diagnosed due to lack of recognition of the unique type of keratinization. PMID- 23641375 TI - Anomalous origin and course of the suprascapular artery combined with absence of the suprascapular vein: case study and clinical implications. AB - BACKGROUND: Variations concerning the origin and course of the suprascapular artery are numerous and present important clinical implications. AIM: In the present study the origin and course of the suprascapular artery are investigated in a sample of Greek (Caucasian) origin. MATERIALS AND METHODS: The anatomy and course of the suprascapular artery were carefully examined in 31 adult human cadavers (16 male and 15 female). RESULTS: Anomalous origin of the suprascapular artery from the third segment of the subclavian artery was observed in the right side of only one female Caucasian specimen (1/62 = 1.6%). The suprascapular artery and the suprascapular nerve passed together under the superior transverse scapular ligament through the suprascapular notch, whereas the suprascapular vein was absent. CONCLUSION: According to the available literature, this type of variation in the origin of the suprascapular artery is considered rare. This variation is clinically important, since it is related to the creation mechanism of suprascapular neuropathy and has also obvious surgical implications. The variation is embryologically enlightened and has an interesting ontogenic aspect. PMID- 23641376 TI - Medical professional values and education: a survey on italian students of the medical doctor school in medicine and surgery. AB - BACKGROUND: The values such as participation/empathy, communication/sharing, self awareness, moral integrity, sensitivity/trustfulness, commitment to ongoing professional development, and sense of duty linked to the practice of the medical professionalism were defined by various professional oaths. AIMS: The aim of this study was to evaluate how these values are considered by the students of the degree course of medicine. MATERIALS AND METHODS: Four hundred twenty three students (254 females, 169 males) taking part of the first, fourth, and fifth years of the degree course in medicine were asked to answer seven questions. Pearson's Chi-square, Wilcoxon rank sum test, and Kruskal-Wallis test were used for the statistical analysis. RESULTS: The survey showed a high level of knowledge and self-awareness about the values and skills of medical profession. In particular, the respect, accountability, and the professional skills of competence were considered fundamental in clinical practice. However, the students considered that these values not sufficiently present in their educational experience. CONCLUSIONS: Teaching methods should be harmonized with the contents and with the educational needs to ensure a more complex patient based approach and the classical lectures of teachers should be more integrated with learning through experience methods. PMID- 23641377 TI - Vaginal birth after cesarean section. AB - BACKGROUND: The rate of primary cesarean section (CS) is on the rise. More and more women report with a history of a previous CS. A trial of vaginal delivery can save these women from the risk of repeat CS. AIMS: The study was conducted to assess the safety and success rate of vaginal birth after CS (VBAC) in selected cases of one previous lower segment CS (LSCS). MATERIALS AND METHODS: The prospective observational study was carried out in a tertiary care teaching hospital over a period of two years. One hundred pregnant women with a history of one previous LSCS were enrolled in the study. RESULTS: In the present study, 85% cases had a successful VBAC and 15% underwent a repeat emergency LSCS for failed trial of vaginal delivery. Cervical dilatation of more than 3 cm at the time of admission was a significant factor in favor of a successful VBAC. Birth weight of more than 3,000 g was associated with a lower success rate of VBAC. The incidence of scar dehiscence was 2% in the present study. There was no maternal or neonatal mortality. CONCLUSION: Trial of VBAC in selected cases has great importance in the present era of the rising rate of primary CS especially in rural areas. PMID- 23641378 TI - What is Our Development Progress for the Treatment Outcome of Newborn with Intestinal Atresia and Stenosis in a Period of 28 Years? PMID- 23641379 TI - Time Delay of Microdialysis in vitro. AB - BACKGROUND: Microdialysis is a specific and local sampling method to collect free molecules from the extracellular fluid, however, there are no reports on time delay issues of microdialysis applications. AIMS: This study was to check the time gap between the start of target molecule changes in detected fluid and corresponding stable concentration formation in the sampled dialysate. MATERIALS AND METHODS: A designated microdialysis system for free calcium ion was set up in vitro and perfused with saline. The dialysate was diluted synchronously, and collected in a vial every 10 min. The free calcium concentration [Ca++] of the sample was measured by an atomic absorption spectrophotometer. A signal-switching method was introduced to mimic the target molecule [Ca++] changes in the detected fluid, standard calcium solution and saline. RESULTS: There was a notable lag in dialysates [Ca++] for both uprising and down going course in spite of instant switching between the detected fluids. The recovery time (RT) of the microdialysis system was extrapolated to be 20 min for [Ca++] detection. CONCLUSIONS: With 10 min sampling interval, [Ca++] time delay of the microdialysis system existed, and could not be estimated precisely beforehand. The signal-switching method was applicable for RT calibration in vitro with a dedicated microdialysis system. PMID- 23641380 TI - Verrucous carcinoma on the helix of pinna. PMID- 23641381 TI - Cor triatrium presenting as mitral stenosis and severe anemia. PMID- 23641382 TI - Allergic myocardial infarction. PMID- 23641383 TI - Hymenoptera stings, anaphylactic shock and the kounis syndrome. PMID- 23641384 TI - Evidence-based health care, past deeds at a glance, challenges and the future prospects in iran. AB - BACKGROUND: Along with the global fervor over evidence based medicine (EBM), certain measures have been taken in Iran too. Many educational workshops and national and international seminars have been held. Multiple educational packages have been prepared and even included in the educational curriculum. In recent years, policies have been directed toward encouraging clinical guidelines, health technology assessment reports and policy briefs. Also, recently, the 'National Strategic Program in Evidence-Based Health Care in the Islamic Republic of Iran' has been defined by the Ministry of Health and Medical Education. In spite of all these efforts, studies that follow the uptake of evidence-based contents at the bedside show that EBM is not used in practice and at the bedside. The overall effect of the efforts mentioned is the knowledge promotion of the participants of the educational programs and or increasing their abilities in articles' critical appraisal; nothing has been added in the practice arena. It seems that, in Iran, EBM's current and future needs are to focus on its implementation, what is in other words called 'knowledge translation' or the application of scientific evidence. PMID- 23641385 TI - Under-5 mortality in Tanzania: a demographic scenario. AB - BACKGROUND: The government of the United Republic of Tanzania has initiated the Integrated Management of Childhood Illness program to improve the health and wellbeing of children. METHODS: Tanzania's under-five mortality rate is still 1.7 times higher than the world average and, in order to achieve its Millennium Development Goal 4 target, its annual reduction rate is quite low at 2.2. The main aim of the study is to examine under-five mortality combined with the Data from the Tanzania Demographic and Health Survey 2008 data was used. Odds ratios for infant and under-five mortality were estimated using logistic regression; crude and adjusting models were adopted. RESULTS: Mortality cases (18.3%) have been reported to children born with an interval of <24 months. Mothers with no education reported 14.6%, primary education mothers reported 11.1% and higher education reported only 5.3% (P<0.001). Therefore, maternal education plays is a major role on fertility and infant and under-five mortality behavior. CONCLUSION: Maternal education also influences a mother's behavior in her usage of available health services to improve the health of the children. Further in-depth analysis is immensely needed in this situation. PMID- 23641386 TI - Deaths rates in public hospitals of eastern cape province of South Africa. AB - BACKGROUND: South Africa (SA) is experiencing a rapid epidemiologic transition as a consequence of political, economic and social changes. In this study we described, based on hospital data, the mortality patterns of Non communicable Diseases (NCD), Communicable Diseases (CD), the NCD/CD ratios, and the trends of deaths. METHODS: We conducted a cross-sectional survey of all deaths occurring in several public hospitals in the Eastern Cape Province of SA between 2002 and 2006. Causes of deaths were coded according to the ICD 10 Edition. RESULTS: A total of 107380 admissions responded to the inclusion criteria between 2002 and 2006. The crude death rate was 4.3% (n=4566) with a mean age of 46+/-21 years and a sex ratio of 3.1 men (n=3453): 1 woman (n=1113). Out of all deaths, there were 62.9% NCD (n=2872) vs. 37.1% CD (n=1694) with NCD/CD ratio of 1.7. The ratio NCD/CD deaths in men was 1.3 (n=1951/1502) vs. NCD/CD deaths in women of 1.9 (n=735/378). The peak of deaths was observed in winter season. The majority of NCD deaths were at age of 30-64 years, whereas the highest rate of CD deaths was at age< 30 years. The trend of deaths including the majority of NCD, increased from 2002 to 2006. There was a tendency of increase in tuberculosis deaths, but a tendency of decrease in HIV/AIDS deaths was from 2002 to 2006. CONCLUSION: Non communicable diseases are the leading causes of deaths in rural Eastern Cape province of SA facing Post-epidemiologic transition stages. We recommend overarching priority actions for the response to the Non-communicable Diseases: policy change, prevention, treatment, international cooperation, research, monitoring, accountability, and re-orientation of health systems. PMID- 23641387 TI - Estimation of the Serial Interval for Pandemic Influenza (pH1N1) in the Most Southern Province of Argentina. AB - BACKGROUND: A retrospective cohort study, in the context of household transmission, to estimate the serial interval (SI) of pH1N1 influenza in the island of Tierra del Fuego was carried out. METHODS: We collected data from the epidemiological surveillance system during disease outbreak in Ushuaia and Rio Grande, the two main cities of the southernmost province of Argentina. Only the records of patients and households with a positive result of RT-PCR assay for pH1N1 virus were used. RESULTS: A total of 283 laboratory confirmed cases were detected, from 550 samples analyzed. Hospitalizations were necessary in 13.8% of patients, yet no deaths were reported. Complete data of household contacts were available in 13 patients. We calculated an SI of 2.0 days (95% CI = 1.5 - 2.6 days), fitting to a log-normal distribution, the one that presented the best adjustment. CONCLUSION: These results were consistent with estimates of SI calculated from Mexico, but lower than estimations from Canada, Germany and USA. We discuss these differences in relation to limitations of the current study design. PMID- 23641388 TI - Developing data elements for research information system in health; a starting point for systems integration. AB - BACKGROUND: This study defines necessary data elements required for the research information system in the domain of health, and its level of accountability to national health research indicators from the experts' perspective is being explored. METHODS: This qualitative study was conducted based on comparative approach using the focus group method. Data were collected through 6 semi structured group discussions held at the Undersecretary for Research and Technology, Ministry of Health and Medical Education, Tehran, Iran. For this study, 48 researchers were selected for the group discussions. All interviews and group discussions were recorded and transcribed. The Data analysis was performed simultaneously using Strauss and Corbin method. RESULTS: BASED ON CONTENT ANALYSIS, THE NECESSARY DATA ELEMENTS IDENTIFIED FOR THE NATIONAL HEALTH RESEARCH INFORMATION SYSTEM DESIGNED FOR ALL DATABASES WERE THE FOLLOWING: organizations, researchers, journals, articles, research projects and dissertations. Also, extracted from the focus group discussion were three main themes regarding data elements of these databases for the National Health Research Information System: 1) essential elements for each database 2) the system's data elements accountability to the national indicators in the domain of health research and 3) recommendations in the direction of optimizing the data. CONCLUSIONS: The results obtained from this study can serve as a valuable source in designing research information system in the domain of health within the country and in the region as well. PMID- 23641389 TI - Substance abuse in high school students in association with socio-demographic variables in northwest of iran. AB - BACKGROUND: Substance abuse in adolescents and its often tragic consequences, including addiction, is one of the preventable major public health problems. The aims of this paper were to estimate the prevalence of substance abuse and to evaluate its some associated factors in adolescents of Tabriz City (northwest of Iran). METHODS: A self-administered questionnaire was completed in 4903 randomly selected students with mean age of 15.7 years old. The aim of the questionnaire was obtaining information on substance abuse, socio-economical information, cigarette smoking behavior, general risk taking behavior, self-esteem, attitude towards smoking and self-injury as well as demographical characteristics. RESULTS: Prevalence of substance abuse was 1.4% (95% CI: 1.1-1.7) which was different statistically significant between boys (2.4%) and girls (0.6%) (P<0.001). Older age (OR=1.43), not living with parents (OR=2.34), having general risk taking behavior (OR=2.26), higher smoking stage (OR=2.39), lower self-esteem (OR=1.09) and positive attitude toward smoking (OR=1.08) were factors associated with student's ever use of substance. CONCLUSION: The result has shown low prevalence of substance abuse in Iranian adolescents. Our findings showed some associated factors such as lower self-esteem with adolescent's substance abuse. PMID- 23641391 TI - Introducing a quantitative method to calculate the rate of primary infertility. AB - BACKGROUND: In the previous studies, the rate of primary infertility was reported differently. It seems the main reasons are related to the different methods of data collection and information analysis. Therefore, introducing a precise method to determine the infertile couples and the population exposed to the risk of infertility is an important issue to study primary infertility. METHODS: The proposed methodology for assessing primary infertility rate has been designed and applied by Avicenna Research Institute in a national survey. Sampling was conducted based on probability proportional to size cluster method. In this survey, after reviewing the former studies, the reproductive history was used as a basis for data collection. Every reproductive event was recorded with a code and a date in the questionnaire. To introduce a precise method, all possible events were considered thoroughly and for each situation, it was determined whether these cases should be considered in numerator, denominator or it should be eliminated from the study. Also in some situations where the correct diagnosis of infertility was not possible, a sensitivity analysis was recommended to see the variability of results under different scenarios. CONCLUSION: The proposed methodology can precisely define the infertile women and the population exposed to the risk of infertility. So, this method is more accurate than other available data collection strategies. To avoid bias and make a consistent methodology, using this method is recommended in future prevalence studies. PMID- 23641392 TI - HIV, HSV2 and Syphilis Prevalence in Female Sex Workers in Kerman, South-East Iran; Using Respondent-Driven Sampling. AB - BACKGROUND: We estimated the prevalence of HIV, sexually transmitted infections (STIs), and risky behaviors among female sex workers (FSW) in Kerman City, Iran. METHODS: Women, 18 years or older, who reported selling sex for at least 6 months during their lifetime and had at least one sexual contact with a client in the recent 12 months were sampled using Responding Driven Sampling (RDS). Participants were interviewed about their sexual behaviors and provided whole blood for HIV, syphilis, and Herpes simplex type 2 (HSV2) testing. Data were analyzed using RDSAT Version 6.0 software. RESULTS: Among samples of 177 FSW, we did not find any HIV positive cases. The weighted prevalence of syphilis and HSV2 were 7.2% and 18.0%, respectively. The reported STI syndromes for the proceeding year of the survey were 36%. Unprotected sexual contact was about 17-22% and link to injecting drug users through injection was about 18%. CONCLUSION: While this survey found no HIV, there were findings of risky sexual behaviors and STI, markers for potential infection for HIV. The prevalence of STI and sexual risk behaviors for HIV is considerably high in this subpopulation that alarming for an urgent public health preventive measures and national control-plan to be developed and implemented. PMID- 23641390 TI - Serum levels of zinc, copper, vitamin B12, folate and immunoglobulins in individuals with giardiasis. AB - BACKGROUND: Giardia lamblia is one of the most important intestinal parasites. The aim of this study was to measure serum levels of IgA, IgE, zinc, copper, vitamin B12 and folate in individuals with giardiasis in comparison to normal subjects. METHODS: The study was carried out among 49 Giardia positive and 39 age and sex matched healthy volunteers. Examination of stool samples was done by direct wet smear and formol-ether concentration method. Serum samples were obtained for further laboratory examination. IgA levels were measured by Single Radial Immune Diffusion (SRID). IgE levels were measured by ELISA kit. Zinc and copper levels was measured by Ziestchem Diagnostics Kit and colorimetric endpoint method respectively. Vitamin B12 and folate levels were measured by DRG Diagnostics Kit and Enzyme Immunoassay method respectively. All data were analyzed using SPSS version 17. RESULTS: There was a statistically significant difference in IgA, IgE, copper and zinc levels between positive and negative groups (P<0.05). There was no significant difference between vitamin B12 and folate levels between the two groups. Mean values of Giardia positive and negative groups for IgA were 309.26 and 216.89 mg/dl, IgE 167.34 and 35.49 IU/ml, copper 309.74 and 253.61 MUg/dl and zinc 69.41 and 144.75 MUg/dl respectively. CONCLUSION: The results showed levels of IgA may correlate more closely with giardiasis than IgE. Regarding trace elements, giardiasis elevated serum copper levels, while it decreased serum zinc. Finally, there was no significant difference in serum levels of vitamin B12 and folic acid between the two groups. PMID- 23641393 TI - Pharmaceutical industry and trade liberalization using computable general equilibrium model. AB - BACKGROUND: Computable general equilibrium models are known as a powerful instrument in economic analyses and widely have been used in order to evaluate trade liberalization effects. The purpose of this study was to provide the impacts of trade openness on pharmaceutical industry using CGE model. METHODS: Using a computable general equilibrium model in this study, the effects of decrease in tariffs as a symbol of trade liberalization on key variables of Iranian pharmaceutical products were studied. Simulation was performed via two scenarios in this study. The first scenario was the effect of decrease in tariffs of pharmaceutical products as 10, 30, 50, and 100 on key drug variables, and the second was the effect of decrease in other sectors except pharmaceutical products on vital and economic variables of pharmaceutical products. The required data were obtained and the model parameters were calibrated according to the social accounting matrix of Iran in 2006. RESULTS: The results associated with simulation demonstrated that the first scenario has increased import, export, drug supply to markets and household consumption, while import, export, supply of product to market, and household consumption of pharmaceutical products would averagely decrease in the second scenario. Ultimately, society welfare would improve in all scenarios. CONCLUSION: We presents and synthesizes the CGE model which could be used to analyze trade liberalization policy issue in developing countries (like Iran), and thus provides information that policymakers can use to improve the pharmacy economics. PMID- 23641394 TI - The intermediary role of self-efficacy in relation with stress, glycosylated haemoglobin and health-related quality of life in patients with type2 diabetes. AB - BACKGROUND: Stress is not always a direct result of stressful conditions, but rather the way they are perceived. Thus individual variables that may be associated with perceived stress should be examined in stress studies. This study investigates the intermediary role of self-efficacy in relation with stress, glycosylated haemoglobin and health-related quality of life in patients with type2 diabetes. METHODS: All women with diabetes in Yazd Diabetes Research Centre, in 2012, were considered and 80 women were selected by random sampling. They completed Shirer's self-efficacy scale questionnaire, depression, anxiety and stress scale (DASS), and ADDQ0L19 questionnaire. Then they were introduced to the lab for blood test. Data were analysed by SPSS software and stepwise regression method. RESULTS: Pearson correlation test results showed that the hemoglobin A1c (r = 0.35) and Quality of Life (r = -0.22) are associated with stress (P <0.05). As so hemoglobin A1c (r = 0.83) and Quality of Life (r = 0.37) with variable of self efficacy are associated positively and significantly (P <0.05). Results of stepwise regression also showed that self efficacy and stress scales 0.697 of variance hemoglobin A1c and 0.140 of variance of Quality of life explaining to do. CONCLUSION: The impact of stress on blood sugar and patients' health-related quality of life can be influenced by their self-efficacy; therefore it is suggested that an educational intervention is done to increase patients' self-efficacy to better cope with stress in their life. PMID- 23641395 TI - Ophthalmic public health; the way ahead. AB - BACKGROUND: Visual sciences have been progressing quickly in recent decades through globalization phenomenon. An enormous change has taken place in ocular health issues, however, there are various problems facing ophthalmic public health worldwide. In the previous years, the World Health Organization and the International Agency for the Prevention of Blindness in partnership launched the global initiative to eradicate avoidable blindness by the year 2020, VISION 2020 the Right to Sight. It has concentrated on the prevention of blindness disability and recognized a health issue-sight as a human right. In view of challenges ahead of visual sciences, close collaboration between international agencies at the global level to implement new strategies and monitor the progress will be mandatory. In these circumstances non-governmental organizations should not be neglected. World Sight Day 2012 would be a great opportunity to be a focus on importance of visual impairment as an important public health issue and discovering new challenges ahead. PMID- 23641396 TI - Assessing the effect of highly cited papers on the impact factor of journals in the field of public health. AB - BACKGROUND: The aim of this study was to appraisal the effect of highly cited papers in the field of public health and find out whether the unusual citations affect the ranking order of the journals in this field or not. A total number of 142 journals titles were listed in Journal Citation Report (ISI Thomson) in the field of "Public, Environmental & Occupational Health". All but one of them had published papers at least for a year from 2009 to 2010. Journal title, number of citations and publication year of 45685 papers were collected from ISI web of knowledge database at December 25, 2011. About half of the papers (23226) had no citations and 89.4% (40835) had less than 6 citations. We concluded that the ranking of journals in the field of public health is not affected by the individual papers with unusual number of citations. PMID- 23641397 TI - Brucellosis-induced avascular necrosis of the hip in a middle-aged person. AB - BACKGROUND: Brucellosis is a zoonotic disease mostly transmitted to humans through consumption of unpasteurized dairy products and can lead to a systemic disease with any organ involvement. In this report, we describe a case of brucellosis-induced avascular necrosis of the hip. Brucellosis was diagnosed through serological tests, and avascular necrosis of the femoral head was confirmed by pelvic MRI. The patient was treated with a combination of antimicrobial treatments and referred to the orthopedic service for total hip arthroplasty. Brucellosis may present with unusual manifestations and should be always taken into consideration, particularly in endemic areas. PMID- 23641398 TI - New Constructed Tunnel: Is it Safe in the Incident? PMID- 23641399 TI - Prevalence and risk factors of type 2 diabetes in the adults in haikou city, hainan island, china. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) occurs around the world with high prevalence and causes serious physical harm and economic burden to the afflicted. Haikou City is China's southernmost tropical island city, which has not been previously studied for its T2DM prevalence. The objective of the study in employing a cross-sectional survey is to discuss the epidemiologic status of T2DM in Haikou City and to analyze the possible determinants. METHODS: A total of 12,000 community residents over 18 years old from four districts in Haikou City were stratified-randomly sampled. A questionnaire survey and physical examination were conducted. Data entry and statistical analysis were performed using SPSS17.0 software. RESULTS: The prevalence of T2DM in Haikou City was 5.3% (5.15% for males and 5.46% for females). According to the multivariate analysis, the positive factors mainly associated with T2DM in the city included family history, Waist-to-Hip Ratio (WHR), triglycerides, low high-density lipoproteins (HDL), and blood pressure. For both men and women, family history was the highest independent risk factor associated with T2DM (OR= 47.128). The T2DM risk increased with increasing metabolic aggregate. CONCLUSION: The prevalence of T2DM for the community population of Haikou City was low. The possible risk factors included age, occupation, BMI, waist circumference, WHR, overweight, systemic obesity, central obesity, systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, low-density lipoproteins, family history, and HDL. PMID- 23641400 TI - Road traffic accidents in Kazakhstan. AB - BACKGROUND: The article provides the analysis of death rates in road traffic accidents in Kazakhstan from 2004 to 2010 and explores the use of sanitary aviation. METHODS: Data of fatalities caused by road traffic accidents were collected and analysed. Descriptive and analytical methods of epidemiology and biomedical statistics were applied. RESULTS: Totaly 27,003 people died as a result of road traffic accidents in this period. The death rate for the total population due to road traffic accidents was 25.0+/-2.1(0)/0000. The death rate for men was (38.3+/-3.2(0)/0000), which was higher (P<0.05) than that for women (12.6+/-1.1(0)/0000). High death rates in the entire male population were identified among men of 30-39 years old, whereas the highest rates for women were attributed to the groups of 50-59 years old and 70-79 years old. In time dynamics, death rates tended to decrease: the total population (Tdec=-2.4%), men (Tdec=-2.3%) and women (Tdec=-1.4%). When researching territorial relevance, the rates were established as low (to 18.3(0)/0000), average (between 18.3 and 24.0(0)/0000) and high (from 24.0(0)/0000 and above). Thus, the regions with high rates included Akmola region (24.3(0)/0000), Mangistau region (25.9(0)/0000), Zhambyl region (27.3(0)/0000), Almaty region (29.3(0)/0000) and South Kazakhstan region (32.4(0)/0000). CONCLUSION: The identified epidemiological characteristics of the population deaths rates from road traffic accidents should be used in integrated and targeted interventions to enhance prevention of injuries in accidents. PMID- 23641401 TI - Anxiety Status and its Relationship with General Health Related Quality of Life among Prostate Cancer Patients in Two University Hospitals in Kuala Lumpur, Malaysia. AB - BACKGROUND: This study aimed to determine the prevalence of anxiety among prostate cancer patients, and to ascertain the association between stress status, socio-demographic, medical and surgical illness, current urinary problem and cancer status with general health-related quality of life (HRQOL) among these patients. METHODS: A hospital based, cross sectional study was conducted at Surgical Clinic, University Malaya Medical Centre (UMMC) and Universiti Kebangsaan Malaysia Medical Centre (UKMMC) using universal sampling. RESULT: A total of 193 patients were recruited. The prevalence of anxiety was 25.4% (95%CI: 19.2 - 31.6). The anxiety ratings were mild anxiety (10.4%), moderate anxiety (13.6%) and severe anxiety (1.6%). The total quality of life among stress group was 59.2 +/- 14.7 and among non-stress group was 73.9 +/- 12.7. There was a significant negative weak correlation between anxiety score and total quality of life (rs=-0.534, P<0.001). In multivariable analysis, there was a significant difference in the total quality of life (QOL) among anxiety status [adj. mean diff. = -9.1 (95%CI: -15.2, -4.7)]. The adjusted mean difference was associated by age category of the patients (P<0.001); living partner (P<0.001); intermittency (P=0.035) and problem of hematuria during micturition (P=0.005). CONCLUSION: The prevalence of anxiety among prostate cancer was moderately high. Treating the urination problem as well as encouraging living with spouse/family may improve the quality of life among anxiety condition of these patients. PMID- 23641402 TI - The importance of family relations for cannabis users: the case of serbian adolescents. AB - BACKGROUND: Adolescence is transitional stage of physical and mental human development occuring between childhood and adult life. Social interactions and environmental factors together are important predictors of adolescent cannabis use. This study aimed to examine the relationship between the social determinants and adolescents behavior with cannabis consumption. METHODS: A cross sectional study as part of the European School Survey Project on Alcohol and other Drugs was conducted among 6.150 adolescents aged 16 years in three regions of Serbia, and three types of schools (gymnasium, vocational - professional, and vocational handicraft) during May - June 2008. A multivariate logistic regression analysis was carried out to obtain adjusted odds ratios with 95% confidence intervals in which the dependent variable was cannabis consumption non-user and user. RESULTS: Among 6.7% of adolescents who had tried cannabis at least one in their lives, boys were more involved in cannabis use than girls, especially boys from gymnasium school. Well off family, lower education of mother, worse relations with parents were significantly associated with cannabis use (P < 0.05). Behaviors like skipping from schools, frequent evening outs, and playing on slot machines were also related to cannabis use (P < 0.05). CONCLUSIONS: The study confirmed the importance of family relationship development. Drug use preventive programmes should include building interpersonal trust in a family lifecycle and school culture. PMID- 23641403 TI - Organizational variables on nurses' job performance in Turkey: nursing assessments. AB - BACKGROUND: The purpose of this study was to describe the influence of organizational variables on hospital staff nurses' job performance as reported by staff nurses in two cities in Turkey. Hospital ownership status, employment status were examined for their effect on this influence. METHODS: The reported influence of organizational variables on job performance was measured by a questionnaire developed for this study. Nurses were asked to evaluate the influence of 28 organizational variables on their job performance using a five point Likert-type scale (1- Never effective, 5- Very effective). The study used comparative and descriptive study design. The staff nurses who were included in this study were 831 hospital staff nurses. Descriptive statistics, frequencies, t test, ANOVA and factor analysis were used for data analysis. RESULTS: The study showed the relative importance of the 28 organizational variables in influencing nurses' job performance. Nurses in this study reported that workload and technological support are the most influential organizational variables on their job performance. Factor analysis yielded a five-factor model that explained 53.99% of total variance. CONCLUSION: Administratively controllable influence job organizational variables influence job performance of nurses in different magnitude. PMID- 23641404 TI - Appraisal the potential of central iran, in the context of health tourism. AB - BACKGROUND: The aim of the present study was to appraisal the prose and cone of Shiraz City in terms of its potential in the context of health tourism. METHODS: The statistical sample included medical and health tourism sector in the city of Shiraz in the northwest of Fars Province, south of Iran. The efficient authorities on the topic were identified through the hospitals engaging in medical tourism. The research was based on theoretical sampling through which the experienced people of extensive knowledge on medical tourism were interviewed. RESULTS: Active hospitals on attraction foreign patients averagely admit 15 and 50 foreign patients monthly and annually, respectively. Arab countries in the Persian Gulf were detected as the main marketing for Shiraz medical tourism. Oman encompassed the highest rate with 20% of admitted patients. Eye treatments with 30% and orthopedic with 6% were demonstrated as the highest and lowest rates in terms of foreign patients' needs, respectively. Closeness of cultural and religious beliefs and familial relationships on one hand and trusting to Iranian physicians on the other hand were amongst the most reasons for selecting Iran as a destination for medical tourism by patients. CONCLUSION: Implementing 4 strategies on monitoring medical tourism would result into significant improvement of attracting more foreigner patients not only into Shiraz but all around Iran. These items have been discussed in the text. PMID- 23641405 TI - The effect of sociostructural and collaborative decision-making on diabetes self management. AB - BACKGROUND: Diabetic self-management is important for controlling the diabetes complications and promoting health-related quality of life in these patients. The objective of this study was to examine a hypothetical model regarding influences of sociostructural determinants, collaborative decision-making and patient's beliefs system on diabetes self-management. METHODS: In a cross-sectional descriptive study from Dec 2010 to Mar 2010, 500 patients of Iranian adult patients with type II diabetes attended the outpatient diabetic clinics of the Shariati Hospital in Tehran were selected by convenience sampling. Data were collected by The Demographical Information, Social- Economical Status and Diabetic History Questionnaire and eleven self-reported scales of this research. Structural equation modeling (SEM) with LIZREL software applied for data analysis. RESULTS: The modified model had a desirable fitness to the observed data. Patient's beliefs system directly influenced the diabetes self-management. Sociostructural determinants influenced diabetes self-management indirectly via collaborative decision-making and Patient's beliefs system. In addition, collaborative decision-making significantly influenced patient's beliefs system that thereby impacted diabetes self-management. CONCLUSIONS: Sociostructural determinants, collaborative decision-making and patient's beliefs system are integrated and cooperatively affect on diabetes self-management. Comprehensive intervention schedules required to improve these agents for encouragement the type II diabetes self-management. PMID- 23641406 TI - The Association between Completed Suicides and Season of the Year in an Iranian Population. AB - BACKGROUND: The main objective of the present study was to determine the association between completed suicides and season of the year in Iran during 2006 2010. METHODS: Data on completed suicides were collected by questionnaires field out by the family members of the victims in Legal Medicine Centers throughout the country over the period from 2006 to 2010. The maximum number of completed suicides (380) was observed in August, while the minimum number (231) was reported in February. RESULTS: Season-wise, completed suicides were most prevalent in summer (1040), whereas least prevalent in winter (726). Mean (SD) age of individuals having committed suicide was 31.5 (14.6) years. This value did not change significantly in different seasons (P=0.051); nor, was a statistically significant difference observed in the educational level and the reason for suicide across different seasons of the year. Self-immolation and toxic poisoning were found to be significantly less common in autumn and winter (P<0.05), respectively. The number of completed suicides was higher in warm seasons. CONCLUSION: Season of the year had significant relationships with gender as well the method of suicide, while no significant association was observed for age, level of education, and reason for suicide. PMID- 23641407 TI - Pneumocystis jirovecii Colonization in Non-HIV-Infected Patients Based on Nested PCR Detection in Bronchoalveolar Lavage Samples. AB - BACKGROUND: Pneumocystis jirovecii causes Pneumocystis pneumonia (PCP) in immunocompromised patients with a high rate of morbidity and mortality. Colonization with this fungus may stimulate pulmonary inflammation or lead to PCP in susceptible patients. The epidemiology of this infection and routs of its transmission has poorly studied in Iran. We examined Pneumosystis colonization in patients with various lung underlying diseases. METHODS: Bronchoalveolar lavage (BAL) fluids of 458 patients with different underlying diseases or pulmonary signs were collected between August 2010 and January 2012. Patients were divided into four groups: transplant recipients, malignant patients, immunosuppressive drug recipients and patients with other different lung diseases. A sensitive nested-PCR method targeted 18S ribosomal RNA gene was used for investigating P. jirovecii in the specimens. RESULTS: P. jirovecii DNA was detected in 57 out of 458 (12.5%) BAL samples by nested-PCR. Colonization rate in malignant patients, transplant recipients, immunosuppressive therapy recipients and patients with other various lung diseases was 21.7%, 20.3%, 12.7% and 7.3%, respectively. The enzyme BanI cuts all PCR products producing fragments with the size of 228 and 104 base pair. This finding as well as sequencing of four random positive samples validated and reconfirmed the PCR results. P. jirovecii cysts were found in 5 out of 57 PCR positive samples. CONCLUSION: A significant number of patients with pulmonary diseases were colonized by P. jirovecii that can develop to PCP in these patients or they may transmit the fungus to other susceptible patients. PMID- 23641408 TI - Patient safety in tehran university of medical sciences' general hospitals, iran. AB - BACKGROUND: It is important to focus on creating opportunities for patients' participation at all levels of health systems in order to promote their ability to improve patient safety and quality of services. The general aim of this study was to determine patient safety level in Tehran University of Medical Sciences' (TUMS) general hospitals, Tehran, Iran from patients' perspective and to determine the contributory factors on their perspective. METHODS: This was a cross-sectional study. In the spring 2011, the list of clinical departments of the six general hospitals affiliated to TUMS was obtained through the Website of TUMS. By using stratified random sampling, the sample size was calculated 300 patients. Data were collected by using a structured questionnaire and its validity and reliability were acceptable. Descriptive statistics, linear regression and logistic regression were used for analyzing the data. RESULTS: Totally, 60% of patients were female. Patient safety was evaluated high by 60% of respondents. The unmarried or educated or employed individuals tend to score lower than others. CONCLUSION: TUMS's general hospitals are enough safe from patients' perspective, patient safety should be improved. In clinical governance, contributing patients' perspective to the improvement of patient safety reforms is critical in generating new models of good practice. PMID- 23641409 TI - Investigation of low-pressure ultraviolet radiation on inactivation of rhabitidae nematode from water. AB - BACKGROUND: Rhabditidae is a family of free-living nematodes. Free living nematodes due to their active movement and resistance to chlorination, do not remove in conventional water treatment processes thus can be entered to distribution systems and cause adverse health effects. Ultraviolet radiation (UV) can be used as a method of inactivating for these organisms. This cross sectional study was done to investigate the efficiency of ultraviolet lamp in the inactivation of free living nematode in water. METHODS: The effects of radation time, turbidity, pH and temperature were invistigated in this study. Ultraviolet lamp used in this study was a 11 W lamp and intensity of this lamp was 24 MUw / cm(2). RESULTS: Radiation time required to achieve 100% efficiency for larvae nematode and adults was 9 and 10 minutes respectively. There was a significant correlation between the increase in radiation time, temperature rise and turbidity reduction with inactivation efficiency of lamp (P<0.001). Increase of turbidity up 25 NTU decreased inactivation efficiency of larvae and adult nematodes from 100% to 66% and 100% to 64% respectively. Change in pH range from 6 to 9 did not affect the efficiency of inactivation. With increasing temperature inactivation rate increased. Also the effect of the lamp on inactivation of larvae nematod was mor than adults. CONCLUSIONS: It seems that with requiring the favorable conditions low-pressure ultraviolet radiation systems can be used for disinfection of water containing Rhabitidae nematode. PMID- 23641410 TI - The Incidence of Onychomycosis Infection among Patients Referred to Hospitals in Kermanshah Province, Western Iran. AB - BACKGROUND: Onychomycosis is a nail disorder associated with aesthetic problems, discomfort, physical injury and loss of dexterity. The purpose of the present study was to isolate and identify the causative fungi of onychomycosis in 2402 patients in Kermanshah Province, western Iran in 1994 to 2010. METHODS: Mycologic assessment was carried out by standard methods including either microscopic or cultural procedures. RESULTS: Direct microscopy of the nail clips was positive in 1086 (45.2%) and fingernail and toenail onychomycoses were recognized in 773 (71.1%) and 313 (28.8%), respectively. Yeasts were detected in 853 (78.5%), dermatophytes in 201 (18.5%) and non-dermatophyte fungi in 32 (2.9%) patients. The results of fungal culture showed Candida albicans isolated in 384 (45.0%) and other Candida spp. isolated in 361 (54.0%) of the cases as the most common agents of onychomycosis while among dermatophytes, Trichophyton rubrum was found in 63 (37.0%) of the cases as the main dermatophytic agent followed by T. mentagrophytes 32 (15.9%) and Epidermophyton flocosum 30 (17.6%). Among the non dermatophyte moulds, Aspergillus flavus was the most prevalent species 12 (37.5%) followed by A. niger 8 (25.0%) and A. fumigatus 4 (12.5%). Moreover, 139 (12.8%) samples with positive direct microscopy yielded no growth. The highest rate of onychomycosis was found in patients between 30-40 years of age. CONCLUSION: In sum, the current results identified the aetiological agents and primary epidemiological aspects of onychomycosis in west Iran. PMID- 23641411 TI - Determination of Malaria Epidemiological Status in Iran's Malarious Areas as Baseline Information for Implementation of Malaria Elimination Program in Iran. AB - BACKGROUND: According to willingness of the Ministry of Health, Iran and presence of appropriate conditions for disease elimination, national malaria control program decided to conduct a research to clarify malaria status in 2007 and to provide required information to perform the elimination program. This review is comprised of the basis of national malaria elimination program in vision of 2025, which was started in 2010. METHODS: In this descriptive study, data were analyzed by applications of different variables at district level. All districts in the three south eastern provinces, in which malaria has local transmission, were considered. Malaria cases has been determined and studied based on the national malaria surveillance system. RESULTS: Since vivax malaria is predominant in Sistan & Baluchestan Province, number of vivax cases is equal to malaria positive cases approximately. The important point is that Nikshahr contains the maximum number of local vivax cases in this province and the maximum number of falciparum cases is reported from Sarbaz district. Among all districts of Hormozgan Province, no case of autochthonous falciparum was detected except in Bandar Jask and one case in Minab. There was no case of autochthonous falciparum in Kerman Province, except in Kahnoj and Ghale Ganj that each of them had one case in 2007. CONCLUSION: It appears that the report of locally transmitted cases in Iran is increasing over the past few years, before starting malaria elimination plan. Since the Afghan refugees started to return to their own country so the main source of reporting of imported malaria cases reduced and local cases would be demonstrated more clearly. PMID- 23641412 TI - Epigastric and umbilical hernia; work relatedness and return to work. AB - Abdominal wall hernia is common but reliable scientific data about its work relatedness is very limited and inconsistent. In this paper, a less common type of abdominal wall hernia in a 30 year old male worker is presented with recurrence after first surgery when he returned to work. In contrast with almost all kinds of hernia, a lifelong limitation for heavy lifting was recommended. It seems that contrary to popular belief, work relatedness of abdominal wall hernia is seriously doubtful, although conclusive evidences are not enough. It is preferable to make decisions cautiously for return to heavy duties of work after surgery of large umbilical, umbilical & epigastric or incisional hernia, while avoiding recommendations for long days off work after surgery of any hernia. PMID- 23641413 TI - World kidney day 2013: acute kidney injury; a public health aware. PMID- 23641414 TI - Poverty as a risk factor in human cancers. PMID- 23641415 TI - Sudden Cardiac Death and Its Prevention Ways among Athletes According to Iranian Traditional Medicine. AB - In the modern medical era sudden cardiac death and its causes among athletes have been described. Finding appropriate preventive ways from this tragic event is so important in sports medicine. According to different trials and observations, there are numerous reasons and some preventive strategies. Historically, sudden cardiac death among athletes had been described several hundred years ago by ancient physicians. The first physician who described this topic completely and recommended some preventive ways is Ibn Abi Sadiq al-Neishaburi. In this article, his opinion has been discussed. PMID- 23641416 TI - Prior authorizations and denials. PMID- 23641417 TI - A tree-bark and its pilgrimage through history. PMID- 23641418 TI - Testing, testing, testing--when will the madness stop? PMID- 23641419 TI - Showcasing bioscience in Rhode Island. AB - There are a number of well-recognized bioscience companies located in the greater Providence area. They represent a significant and growing source of jobs and future revenue, which promises to play a role in the revitalization and expansion of Rhode Island's economy. In an effort to support these companies and to showcase their research, the Rhode Island Medical Journal is highlighting five of these innovative enterprises in this issue. The companies selected are members of the Rhode Island BioScience Leaders organization, and their research spans a wide range of science, from biologics and informatics to innovative coatings for medical devices. They include ProThera Biologics, EpiVax, Tivorsan Pharmaceuticals, BioIntraface, and VeroScience. PMID- 23641420 TI - ProThera Biologics, Inc.: a novel immunomodulator and biomarker for life threatening diseases. AB - ProThera Biologics is a development stage bio-therapeutics company in East Providence, Rhode Island. The company was founded in 2002 to focus on the critical role and commercial potential of Inter-alpha Inhibitor Proteins (IAIP) for treating acute life-threatening inflammatory diseases. The discovery research originated in the basic research laboratories of the co-founders, Yow-Pin Lim, MD, PhD, and Douglas C. Hixson, PhD, at Rhode Island Hospital, a Lifespan partner. The company is backed by the Slater Technology Fund and has received research grants from the Rhode Island State Science and Technology Council (RI STAC) as well as continuous funding from the National Institutes of Health (NIH), with several Phase I and II Small Business Innovation Research (SBIR) grants over the past 10 years. ProThera has developed a novel process to purify Inter-alpha Inhibitor Proteins from source material, and has conducted groundbreaking research into the usage of IAIP to fight systemic inflammation. PMID- 23641421 TI - Building better biotherapeutics and vaccines by design: EpiVax, Inc., an immunology company. AB - EpiVax, Inc., is an early-stage informatics and immunology biotechnology company in Providence, Rhode Island. It applies computational tools to harness immunity in three major areas: immunomodulation, biotherapeutic immunogenicity risk assessment and de-risking, and vaccine development. Immunotherapy, bio-better and vaccine candidates under development at EpiVax promise to improve the health outcomes of millions of people affected by devastating immune-related diseases. PMID- 23641422 TI - On the path to a Duchenne muscular dystrophy therapy. AB - Duchenne Muscular Dystrophy (DMD) is a devastating inherited disease of children with no effective therapies. Here I discuss the landscape for new treatments and the history, current status and prospects for our work developing recombinant biglycan as DMD therapy. PMID- 23641423 TI - BioIntraface(r): the next quantum in medical devices. AB - BioIntraface(r), Inc., located in Riverside, Rhode Island, was formed in February of 2009 to commercialize its biomaterials surface treatment technologies. The platform technologies involve the creation of economical, multifunctional metal oxide and polymer materials and coatings to control the bioactivity and antimicrobial properties of medical devices and implants. Biointraface(r) has continued optimizing and validating coatings for promising applications in orthopaedics, dentistry, catheters, wound dressings, topical antimicrobial products, and cosmetics applications. It has also obtained third-party verification of ISO biocompatibility testing for eight coatings with increasing levels of antimicrobial agents, where no cytotoxicity was indicated and similar tests showing long lasting antimicrobial efficacy against multiple strains of bacteria. PMID- 23641424 TI - VeroScience: applying nature's genius to help improve the human condition. AB - VeroScience is a biotechnology company in Tiverton, Rhode Island, focused on the development of therapies and products to improve human health. The company has a strong pipeline of metabolic disease products and therapies for immunological disorders. A major platform technology of the company, Circadian Neuroendocrine Resetting Therapy, is utilized as a generator of multiple therapeutic strategies to treat a variety of disease states. The circadian timed daily (morning) administration of Cycloset(r), a quick release formulation of bromocriptine mesylate, a dopamine agonist, was developed for the treatment of type 2 diabetes using this platform technology. PMID- 23641425 TI - Barriers to completion of desired postpartum sterilization. AB - Tubal sterilization is a highly effective, permanent, and safe method of contraception. Many women who desire postpartum sterilization do not obtain the procedure due to barriers. We performed a retrospective cohort study examining patients from a single obstetrics practice who delivered between 1/1/07 and 6/30/07 at Women and Infants Hospital in Providence, RI. During the study period, 626 women in the practice delivered. Of these subjects, 87 (14%) desired postpartum sterilization. Of these 87, 45 (51.7%) underwent sterilization as planned. In multivariable analysis controlling for age, BMI, delivery mode and marital status, older age (OR 2.15, 95% CI 1.12, 4.12, p=0.02) and cesarean delivery (OR 19.65, 95% CI 3.75, 103.1, p < 0.001) were associated with completion of postpartum sterilization and being married (OR 0.10, 95% CI 0.02, 0.56, p=0.009) and having a higher BMI (OR 0.60, 95% CI 0.39, 0.91, p=0.02) were associated with incompletion. Only half of women who request postpartum sterilization antenatally end up obtaining the procedure. PMID- 23641426 TI - Decade of HIV in Rhode Island: demographic and clinical characteristics of patients diagnosed in 2001 and 2010. AB - This article provides an overview of the current epidemiology of HIV infection in Rhode Island, summarizes disease trends over the last decade, and describes circumstances surrounding patient diagnosis. METHODS: We performed a retrospective chart review of patients newly diagnosed with HIV who presented to the Immunology Clinic of The Miriam Hospital in 2001 and 2010. RESULTS: From 2001 to 2010 there was an increase in patients reporting MSM (men who have sex with men) as their primary risk factor, and in diagnosis occurring at outpatient sites (p=.03). CD4 count at diagnosis was highest when diagnosed at an HIV testing site and lowest in inpatients (p=.0003). Late presenters were more likely to be tested because of illness (p=.001), as inpatients (p=.000), and heterosexuals (p=.017)). CONCLUSIONS: MSM and minorities are overrepresented in the RI HIV population. Patients without traditional risk factors are more likely to present late and are poorly served by historic screening practices. PMID- 23641428 TI - Laughing at patients. PMID- 23641427 TI - Emerging global epidemiology of measles and public health response to confirmed case in Rhode Island. AB - Measles is a highly contagious viral disease and rapid identification and control of cases/outbreaks are important global health priorities. Measles was declared eliminated from the United States in March 2000. However, importations from endemic countries continued through out the last decade and in 2011, the United States reported its highest number of cases in 15 years. With a global snapshot of current measles epidemiology and the persistent risk of transnational spread based on population movement as the backdrop, this article describes the rare event of a measles case identification in the state of Rhode Island and the corresponding public health response. As the global effort for measles elimination continues to make significant progress, sensitive public health surveillance systems and strong routine immunization programs will be important to ensure we maintain local and regional control. PMID- 23641429 TI - In the dark winter of our discontent. PMID- 23641430 TI - Healthcare in Rhode Island: shooting for the moon. PMID- 23641431 TI - Arthroplasty of the lower extremities: a special monograph volume of the Rhode Island Medical Journal. PMID- 23641432 TI - Establishing a center of excellence: the Total Joint Center at the Miriam Hospital. AB - The Total Joint Center at The Miriam Hospital has been very successful and now serves as a model for other specialties. Key to this program's success is the cooperative relationship between various stakeholders. Leadership is required yet the input and participation of all is necessary to achieve the desired outcome. To achieve efficiencies, there must be a willingness to deeply integrate clinical services. Again, this requires input from sectors that in the past typically did not communicate with each other. Finally, surgeons and staff need to "pledge" and show their willingness to practice based on sound patient data and modify treatment based on this same data. We are extremely proud of the results achieved. Also impressive is how, in a very short period of time, we have been able to bring together an extremely dedicated team of professionals who work cooperatively in a seamless fashion. With this approach we are able to meet our strategic goal of providing state-of-the-art, high quality, patient-centric, efficient healthcare. PMID- 23641433 TI - Pathogenesis and epidemiology of osteoarthritis. AB - Osteoarthritis (OA) is a disease of high prevalence that produces substantial morbidity and is a leading cause of physical and psychological disability and expense, including time lost from work, medical care, and disability support. Until recently, the focus of research into the pathophysiology of OA has been on articular cartilage and has not resulted in either biomarkers of OA activity or effective targets for disease-modifying therapy. The contemporary paradigm of OA considers involvement of all joint tissues. It has been shown that, in later stage OA, bone blood flow and oxygen content are markedly reduced and have a deleterious effect on bone cells, inducing them to release proteins (cytokines) that contribute to the bone remodeling and cartilage breakdown seen in OA. PMID- 23641434 TI - Advanced blood management strategies for elective joint arthroplasty. AB - There is a high prevalence of anemia detected in the preoperative work-up of elective surgical patients preparing for total joint replacement. The impact of anemia in this population has significant implications due to elevations in postoperative morbidity and mortality. By using current clinical guidelines and medical evidence, clinicians can improve outcomes for these patients by employing a three-phase approach, focused on preoperative assessment, intraoperative hemostasis, and postoperative blood product management. Strategies to optimize preoperative hemoglobin levels, reduce intraoperative blood losses, and decrease postoperative transfusion rates can independently and collectively improve overall patient care and surgical outcomes following lower extremity total joint arthroplasty. PMID- 23641435 TI - Management of the 'young' patient with hip disease. AB - Although hip arthritis typically affects older patients, there is a rapidly growing population of "young" patients experiencing debilitating symptoms from hip disease. Most commonly, osteoarthritis and avascular necrosis affect this population, but a variety of other primary structural and metabolic causes can also occur. The expectations of these younger patients are often distinct from geriatric patients, and the challenges in optimizing their care are unique in this demanding population. Selection of the implant, bearing surface, and surgical technique can all impact the success and longevity of total hip replacement. A consideration for respecting the native bone stock is an important consideration that can potentially reduce some of the future challenges of revision arthroplasty in this young population. PMID- 23641436 TI - Current thoughts on ankle arthritis. AB - The ankle is the most commonly injured joint in athletic and work activities. In contrast, osteoarthritis of the ankle joint is relatively rare and is typically post-traumatic or inflammatory in nature. Common symptoms that prompt an orthopaedic consultation include pain, disability and altered gait mechanics. Non operative management has been the mainstay for previously undiagnosed patients. For those with advanced disease, ankle fusion or total ankle replacement may be the only surgical options. Though some recent studies have shown patients' preference for a well functioning ankle replacement, significant long- term follow-up data is lacking. PMID- 23641437 TI - Brief report: total knee arthroplasty performed with patient-specific, pre operative CT-guided navigation. AB - The clinical success and long-term outcomes of total knee arthroplasty (TKA) are dependent not only on the biomaterials within the prosthetic implant, but also on the surgeon's ability to correctly position the implants onto the bone. Intra operative computer navigation and robotic surgery have emerged as options to increase the accuracy of implant placement and enhance the outcomes of TKA, with mixed clinical results to date. Pre-operative CT-guided, patient-specific navigation is a unique method for planning TKA surgery to achieving consistent implant positioning, especially for patients with retained surgical hardware or unusual bony anatomy. This technology has been used in Rhode Island in a limited series of patients to assess the utility of the technique and represents an interesting advance for both orthopaedic surgeons and their patients. PMID- 23641438 TI - Psychotropics and sudden cardiac death. AB - Over the past two decades there has been a large increase in the number of patients prescribed psychotropic medications. Many of these agents are associated with QTc prolongation which is considered a marker for increased risk of sudden cardiac death due to malignant arrhythmias such as Torsades de pointes (TdP). Psychotropics rarely lead to sudden death in healthy individuals on a single QTc prolonging medication. However, factors such polypharmacy, recent initiation of a QTc prolonging medication, bradycardia, electrolyte abnormalities and preexisting arrhythmias increase the likelihood of psychotropic-induced sudden cardiac death. Therefore, clinicians must recognize which psychotropics and risk factors are associated with increased risk in order to minimize the risks of psychotropic QTc prolongation. PMID- 23641439 TI - Medical student-mothers. AB - Medical training is challenging and parenting is a full-time responsibility. Balancing a family with the significant demands of medical school is a daunting endeavor. Yet there is little research available to guide students, faculty, or administrators. Using one U.S. medical school as a case study, this article provides a comprehensive overview of the common personal and professional challenges that medical students who are also mothers face during their undergraduate medical education, and practical strategies and resources useful in navigating such challenges. This article is also a resource guide for the faculty and administrators who teach, advise, and mentor medical-student parents. For leaders in medical education, the article concludes with suggestions to better support the health and educational experience of medical student-parents: 1) a systematic network of career advisors, 2) scheduling flexibility, 3) formal breastfeeding policies and workplace support, 4) institutionally supported childcare, and 5) how student-parents may foster the educational health mission of medical schools. PMID- 23641440 TI - Veteran status of suicide victims in Rhode Island, 2005-2009. PMID- 23641441 TI - Joe's prior auth service. PMID- 23641442 TI - Seeking rest in a nation that never slumbers, never sleeps. PMID- 23641443 TI - Suboxone pharma foibles/FDA does its job well. PMID- 23641444 TI - The long and winding road Toward Alzheimer prevention FDA offers new guidance on developing drugs for early-stage AD; seeks input. PMID- 23641445 TI - The pulse of pediatrics in Rhode Island. PMID- 23641446 TI - Health care for gender variant or gender non-conforming children. AB - Most children explore various aspects of gender and sexuality as children. Youth with consistent, persistent, and insistent gender non-conformity or gender dysphoria are important to identify in the pre- and early-pubertal years as early intervention and support may be lifesaving. Those whose gender non-conformity persists into puberty and adolescence are most likely to identify as transgender. Blocking pubertal development at Tanner stage 2 for pre-pubertal, gender non conforming children is a relatively new but reversible and highly beneficial strategy to delay puberty, giving patients and families time to come up with a transition plan. Early identification, collaborative support from healthcare providers and mental health clinicians, and supportive interventions for both children and families grappling with gender variance may improve social and mental health outcomes for what has traditionally been considered a high-risk, vulnerable population. PMID- 23641447 TI - Preschool-aged wheezing. AB - Wheezing is a common physical finding in the pediatric age group 0-4 years and can have multiple diverse causes. Infectious causes are the most common culprit and lead to bronchiolitis or preschool asthma. The identification and understanding of these causes is fundamental in the appropriate treatment of our patients. The differentiation and underlying pathologies of these 2 conditions can be confusing and complicated. A systemic review of these conditions attempts to alleviate some of this confusion and tries to provide some clinical guidance for the treatment of these patients. PMID- 23641448 TI - Health care transition for adolescents with special health care needs: a report on the development and use of a clinical transition service. AB - BACKGROUND: A growing population of adolescents with special healthcare needs is aging into adulthood. These emerging adults face the transition challenges of their healthy peers but also potentially heightened risks and challenges related to their conditions. We describe the process of developing a pilot program to support healthcare services for emerging adults with chronic conditions and present preliminary data on utilization. RESULTS: An outpatient multidisciplinary consult model was developed based on patient, family and physician feedback. Patients with diverse conditions were equally referred from primary care, subspecialists and families and community agencies. Services provided included needs assessments (100%), referral to adult physicians (77%), care coordination (52%) and referrals to adult community services (10%). Clinical billing did not fully support the cost of providing services. CONCLUSION: The pilot program offered multidisciplinary transition services that were utilized by a diverse patient population. Local and national resources for health care transition are provided. PMID- 23641449 TI - Health screening of newly resettled refugees in a primary care setting. AB - Since October 2008, the Medicine/Pediatrics Primary Care Center (MPPCC) has been working with Rhode Island's refugee resettlement agency to coordinate medial care for newly resettled adults and adolescent refugees. The process includes obtaining extensive screening labs and providing immunizations. This review discusses the results of selected screening tests for latent TB, stool parasites, vitamin D, and vaccine-preventable diseases, such as hepatitis, performed as part of the initial intake exam during the first two years of operation of the MPPCC Refugee Clinic. PMID- 23641450 TI - Building international collaborations from the ground up: Brown University partnerships in Haiti and Ukraine. AB - The world is becoming more interconnected with a need for a global approach to healthcare. Brown University has remained a leader in global health through clinical service, education, cutting edge research and dedication to the development of sustainable global partnerships. We describe two programs from the ground up in Haiti and Ukraine, and the important lessons learned in their development. The path towards the development of global health programs in Ukraine and Haiti both illustrate that although circumstances may vary between global health programs, the recipe for successful collaboration is the same: identifying specific needs, developing strong and sustained partnerships, and addressing barriers by crafting effective solutions to ongoing challenges. PMID- 23641451 TI - Neurogenic detrusor overactivity: an update on management options. AB - Neurogenic detrusor overactivity (NDO) affects a variety of patients with storage and voiding dysfunction including those with multiple sclerosis, spinal cord injuries, Parkinson's disease, cerebral palsy, and myelomeningocele, and includes symptoms of urinary frequency, urgency, and incontinence. Primary treatment goals are 1) preventing renal injury, and 2) improving quality of life. First-line therapies include behavioral and anticholinergic agents, with onabotulinum toxin A as the only FDA- approved second-line therapy, and non-FDA approved second-line therapies including neuromodulation, and intravesical vanilloids. Surgical intervention is reserved for those at risk for upper-tract deterioration and with persistent incontinence. In select individuals an indwelling catheter may be necessary. PMID- 23641452 TI - Metachronous cancer. AB - Metachronous cancer (multiple primary tumors developing at intervals) will appear more commonly as cancer patients live longer lives. In this report, we use data from the Rhode Island Cancer Registry to look at commonly occurring metachronous cancers, their frequency over time, and the implications for cancer survivorship. Sequence two (refers to the chronologically second primary tumor diagnosed for a given patient) and higher primary malignant neoplasms were identified in cancer case reports made to the Rhode Island Cancer Registry, 1987-2009, and used to construct annual, age-adjusted, sequence-specific incidence rates for all cancers combined, and age-adjusted, site-specific incidence rates for common second and higher-order primary malignant neoplasms over the entire observational period. During the period of observation, the proportion of all cancers diagnosed as sequence two and higher primary tumors among males increased steadily from 11.5 to 20.3 percent, while the proportion of all cancers diagnosed as sequence two and higher primary tumors among females increased from 12.8 to 20.7 percent. A mere four cancer types--lung (and bronchus), colon (and rectum), breast, and prostate--account for over half of all sequence two and higher cancer diagnoses (54.3 percent). The average interval between first cancers and second cancers is 6.5 years for men and 4.8 years for women. Such is the "career" of a cancer survivor today that he or she has about a one in four chance of developing a second cancer. This statistic suggests the need for strong and lasting social support networks. Furthermore, the average interval between first and second cancers is substantial, and suggests opportunities for interventions (prevention and screening) that might reduce the burden of sequence two and higher cancers. PMID- 23641453 TI - Gestational diabetes in Rhode Island. PMID- 23641454 TI - Neurological novels. PMID- 23641455 TI - From so simple a beginning. PMID- 23641456 TI - International rotations during residency: spine deformity surgery in Ghana. AB - International elective rotations are becoming increasingly common in residency training programs. These experiences offer a tremendous opportunity to help patients in medically underserved nations, and can enhance training by exposing participants to pathology not often encountered in developed countries. Additionally, there is emerging evidence that international training exposure develops a broader appreciation of cultural diversity in patient care, offers personal and professional development, and teaches residents to use limited resources more efficiently, giving them a unique perspective on the ordering of tests and delivery of care when they return. This paper highlights the author's experience on a volunteer trip to Ghana that was focused on treating pediatric spinal deformity, and reviews notable international medical volunteers, and highlights the evidence supporting the benefits of international residency rotations. PMID- 23641457 TI - Introduction. Orthopedic conditions can lead to pain and disability. PMID- 23641458 TI - Rehabilitation for total joint arthroplasty. AB - Total hip and knee replacement are two of the most common and successful elective surgeries preformed in the United States each year. Preoperative medical preparation and postoperative rehabilitation are equally important to a successful outcome. Physical deconditioning, tobacco use, obesity and medical co morbidities can adversely affect outcomes and should be addressed before any elective procedure. Formal postoperative therapy is geared towards the specific surgery and is aimed at returning the patient to independent activity. PMID- 23641459 TI - Management of ankle fractures. AB - Ankle fractures are a common injury across all age groups. Management may be operative or nonoperative, depending on the severity of the injury and the patient's overall health and functional status. Although imaging defines the nature of the fracture, a careful history and physical also helps determine the patient's plan of care. Initial management is focused on adequate alignment and safe immobilization of the injury. Definitive management must provide anatomic alignment of the joint as well as consideration of the surrounding soft tissues. Rehabilitation after either operative or nonoperative treatment aims at restoring range of motion, strength, proprioception, and function. PMID- 23641460 TI - Essentials of anterior cruciate ligament rupture management. AB - Anterior cruciate ligament (ACL) rupture is a common knee injury and an understanding of current medical knowledge regarding its management is essential. Accurate and prompt diagnosis requires an awareness of injury mechanisms and risk factors, common symptoms and physical/radiologic findings. Early mobilization and physical therapy improves outcomes regardless of treatment modality. Many older patients regain sufficient stability and function after non-operative rehabilitation. Early ACL reconstruction is appropriate for younger patients and those who engage in activities requiring frequent pivoting and rapid direction changes. ACL surgery involves reconstruction of the torn ligament tissue with various replacement graft options, each with advantages and disadvantages. The guidance of a knowledgeable and experienced therapist is required throughout an intensive and prolonged rehabilitation course. Generally excellent outcomes and low complication rates are expected, but treatment does not prevent late osteoarthritis. PMID- 23641461 TI - Diagnosis and management of lisfranc injuries and metatarsal fractures. AB - Forefoot and midfoot injuries are relatively common and can lead to chronic disability, especially if they are not promptly diagnosed and appropriately treated. A focused history and physical examination must be coupled with a thorough review of imaging studies to identify the correct diagnosis. Subtle radiographic changes can represent significant ligamentous Lisfranc injury. Midfoot swelling in the presence of plantar ecchymosis should be considered to be a Lisfranc injury until proven otherwise. While most metatarsal fractures can be treated with some form of immobilization and protected weight-bearing, this article will distinguish these more common injuries from those requiring surgical intervention. We will review relevant anatomy and biomechanics, mechanisms of injury, clinical presentation, imaging studies, and diagnostic techniques and treatment. PMID- 23641462 TI - Nerve compression syndromes of the upper extremity: diagnosis, treatment, and rehabilitation. AB - Nerve compression syndromes of the upper extremity, including carpal tunnel syndrome, cubital tunnel syndrome, posterior interosseous syndrome and radial tunnel syndrome, are common in the general population. Diagnosis is made based on patient complaint and history as well as specific exam and study findings. Treatment options include various operative and nonoperative modalities, both of which include aspects of hand therapy and rehabilitation. PMID- 23641463 TI - Trouble from the tropics: challenges in managing malaria in Rhode Island. AB - The authors present a case of severe falciparum malaria diagnosed in a traveler after he returned to Rhode Island from a visit to the Dominican Republic. They then review aspects of the case pertinent to our local practice environment that make diagnosis and management especially challenging. PMID- 23641465 TI - Rhode island youth tobacco use: implications for pediatricians and family physicians. PMID- 23641464 TI - Resident physician preventive health behaviors and perspectives on primary care. AB - Little is known about lifestyle choices and preventive healthcare seeking behaviors among resident physicians. Residents function under unusual working conditions requiring extensive duty hours. This may significantly affect attentiveness to personal health and wellness. In this study, we surveyed residents across multiple training programs to compare lifestyle choices and access to preventive healthcare. METHODS: Resident physicians affiliated with Brown University, Providence, Rhode Island, were surveyed between February and April 2009 regarding lifestyle habits and experiences with primary care. We evaluated the relationships between training program and established primary care on health behaviors. RESULTS: Residents were in one of 5 programs: internal medicine, medicine/pediatrics, emergency medicine, surgery or pediatrics. Respondents slept an average of 6.7 hours per day and worked an average of 70 hours per week, with surgical residents sleeping the shortest and working the longest hours (p<0.001 for both). An average of 58.8% of residents indicated having a primary care physician. This rate was lowest among surgery residents at 37% (p=0.081). Rates of screening with regards to blood pressure, cholesterol and cervical cancer were significantly higher among residents maintaining primary care (p<0.001). A lack of time was the most common barrier to obtaining primary care. DISCUSSION: Surgical residents may have unique barriers to healthcare seeking behaviors, such as longer work hours. Residents with established primary care had significantly higher rates of adherence to preventive screening. Residency programs should address barriers to accessing healthcare for trainees, particularly among surgical programs. PMID- 23641466 TI - [A two-years challenge]. PMID- 23641467 TI - [Humanism, medical practice and technology]. PMID- 23641469 TI - Late right ventricular perforation: a rare complication of a pacemaker implantation. AB - Right ventricular perforation by a pacemaker lead is a rare complication of pacemaker implantation, with an incidence inferior to 1%. It usually occurs at the time of lead insertion or during the first 24 hours after the procedure (acute perforation).Late right ventricular perforation, defined as occurring at least 1 month after lead implantation, is even rarer. The clinical presentation varies widely and is mainly related to the stimulation of extracardiac structures and/or lead dysfunction.Its diagnosis may be difficult and must be complemented by appropriate imaging methods. The optimal management strategy remains controversial, varying from surgery to more conservative treatments. The authors present a case of late right ventricular myocardium lead perforation occurring in a 56-year-old-male patient, approached with open surgery. PMID- 23641468 TI - [Total anomalous pulmonary venous connection: a 17-years experience of a single pediatric cardiology center]. AB - OBJECTIVE: We reviewed our patients who underwent surgical repair for total anomalous pulmonary venous connection at our hospital. MATERIAL AND METHODS: All patients with total anomalous pulmonary venous connection who underwent correction from February 1995 to October 2012 were included in this retrospective analysis. Clinical data was collected on presentation,morphology, associated cardiac lesions, echocardiography and cardiac cathetherization results, surgical repair and postoperative course. RESULTS: There were 25 patients in the cohort, median age 19 days. The type of total anomalous venous connection was supracardiac in fifteen, cardiac in five, infracardiac in four, mixed-type in one patient. Six patients had single-ventricle anatomy with atrial isomerism in five. All patients with biventricular anatomy had cardiac defects associated: interauricular communication(17), patent arterial duct (9), tricuspid insufficiency (3), pulmonary stenosis (2), interventricular communication (1), mitral valve atresia (1), aortic arch hypoplasia (1). Nine patients (36%) presented with pulmonary venous obstruction. Respiratory distress was the most frequent symptom on presentation (80%), five patients were invasively ventilated. One patient was treated with extracorporeal membrane oxygenation prior to surgical correction. Twenty four cases were diagnosed with transthoracic echocardiography alone. Nine patients were evaluated with angiography that confirmed the echocardiographic diagnosis in eight patients; it allowed diagnosis of total anomalous pulmonary venous connection in one patient. Twenty four patients were submitted to surgery in the first six months of live (68% in neonatal period), one patient was operated at 27 years. Total anomalous pulmonary venous connection was corrected at first surgery in 22 patients. Two patients died after surgical correction,one with infracardiac total anomalous pulmonary venous connection with obstruction and another with supracardiac type with complex cardiac anomaly. There were no deaths in the last eleven years (14 patients). Postrepair pulmonary venous obstruction was diagnosed in one patient who was reoperated successfully. CONCLUSION: Echocardiography provides adequate diagnostic data on total anomalous pulmonary venous connection so that surgery can be performed without angiography in most cases. Early surgical correction of total anomalous pulmonary venous connection has acceptable mortality and good long-term postrepair outcome. PMID- 23641470 TI - Surgery for thoracic empyema: personal experience and current highlights. AB - Thoracic empyema remains challenging for thoracic surgeons. The principles of empyema treatment are early diagnosis and early treatment. Decision-making involves a triad consisting of the etiology of empyema, general condition of the patient and stage of disease. For acute empyema, early surgical intervention, such as video-assisted thoracoscopic debridement, is recommended when conventional chest tube drainage has failed. Radical treatments of chronic empyema include 1 removal of the empyema space (decortication with or without lung resection) and 2 obliteration of the pleural space with muscle flaps or omentum flaps, or by thoracoplasty. Decortication is the procedure of choice for patients with re-expandable underlying lung. For patients who are not eligible for the above-mentioned radical treatment, open-window thoracostomy can be considered. The current attitudes show that the present concepts are based mainly on expert opinion. No exclusive sequence of procedures leading to a uniformly predictable successful outcome is available. Individualized approaches can be recommended based on institutional practice and local protocols. PMID- 23641471 TI - [Denture impaction in the thoracic esophagus: surgical treatment - a case report]. AB - Esophageal foreign body impaction is mostly managed with endoscopic retrieval. However, in cases of large or irregularly shaped foreign bodies, or in cases of long standing impaction, this technique carries a high risk of perforation and a surgical approach is often mandatory.The authors report the case of a 55 year old woman, with a past history of mental retardation, presenting with dysphagia for solid food and regurgitation beginning one month earlier. After failed extraction by flexible esophagoscopy,the denture was removed by esophagotomy through a postero-lateral thoracotomy. In the postoperative period the patient developed a leakage of the suture line with resultant esophago-pleural fistula which was managed with double esophageal exclusion. She was discharged on the 40th postoperative day on semi-solid diet and is presently (eight months after the first surgery) symptom free. PMID- 23641472 TI - [The role of colour Doppler ultrasound in the creation, maturation and evaluation of arteriovenous fistula for hemodialysis]. AB - Chronic renal failure is a pathophysiologic process that can be lead to a loss of renal function and consequently to dialysis or transplantation. Currently, hemodialysis is dependent on the creation of arteriovenous fistulas, grafts and polytetrafluoroethylene double lumen catheters. However, fistulas have greater durability and lower rates of failure and infection. The Colour Doppler has assumed an important role in the arterial and venous mapping for the creation of fistulas as well at screening for complications. The aim of this study was to identify the sonographic criteria in the pre-operative period of maturation and evaluation throughout time of arteriovenous fistulas for hemodialysis. PMID- 23641473 TI - Ventricular lead dysfunction and subclavian vein stenosis: when problems come in pairs. AB - The widespread and increasing use of cardiac devices implantation naturally augments the number of device related complications. Lead failure is a known complication associated with increased morbidity, mortality and need for reintervention.Chronic stenosis or occlusions of coronary, cephalic or subclavian veins, especially at the site of previous device implantation,can limit lead passage through the target vein, imposing great technical difficulties, especially in patients needing follow-up procedures such as lead revisions and/or system upgrades. Venous balloon angioplasty can be a valuable and safe tool for successful implantation, helping to avoid more complex and hazardous procedures. The authors report the case of a 65 years old male presenting with a "Sprint Fidelis" defibrillator lead malfunction and severe asymptomatic left subclavian vein stenosis after cardiac resynchronization defibrillator therapy. The patient was submitted to a successful percutaneous balloon venoplasty in order to regain adequate venous access and enable reimplantation of the right ventricular lead. PMID- 23641474 TI - Tapered self expandable bare stent to treat acute superior mesenteric artery ischemia. AB - PURPOSE: This case demonstrates the use of carotid stents in off-label emergency condition where standard self-expandable stents doesn't fit to native artery and balloon-expandable stents could not be also recommended. CASE REPORT: 56 years old patient, EVAR therapy performed 2 months before, suffering acute severe abdominal pain; emergency angioCT showed oclusion of superior mesenteric artery (SMA) and no complications related to previous EVAR. A percutaneuos supraselective trombolysis was performed. After 24 hours control DSA showed partial recanalization and tight stenoses in distal SMA with poor run-off to terminal branches. A 6-8 x 40 mm Carotid Stent (Acculink(r), Abbot Vascular) was implanted with good inmediate technical result. After 6 months follow up both SMA and branches remain patent and no further treatment was required. CONCLUSIONS: tapered self expandable uncovered stents are a good treatment option to achieve better conformability to SMA,and bare metal stents do not compromise side branches of this artery. PMID- 23641475 TI - Paradoxical embolism and pulmonary embolism in a patient with patent foramen ovale: a case report. AB - Paradoxical embolism may occur in patients with acute pulmonary thromboembolism, when a patent foramen ovale(PFO) coexists with a right to left shunt associated to pulmonary hypertension. We presented the case of a 83 year old woman with paradoxical embolism to both legs, in the setting of pulmonary embolism. She was successfully treated with peripheral thrombectomy and anticoagulation. Patent foramen ovale closure wasn't performed because of its small size and right to left shunt absence after clinical stability. PMID- 23641476 TI - [Giant mediastinal abscess after closed chest trauma]. PMID- 23641477 TI - What we talk about when we talk about empathy. PMID- 23641478 TI - Is the Cochrane collaboration prepared for the era of patient-centred outcomes research? PMID- 23641479 TI - Cochrane reviews on neglected diseases: the case of cutaneous leishmaniasis. PMID- 23641481 TI - Emergency medicine: Long delay in receiving care in the ED may be violation of EMTALA. Scruggs v. Danville Regional Medical Center, No. 4:08CV00005 (W.D. Va. Sept. 5, 2008). PMID- 23641480 TI - Combination injectable contraceptives for contraception. AB - BACKGROUND: Combination injectable contraceptives (CICs) provide a highly effective, reversible method of preventing pregnancy, and they do not require daily administration or use at the time of coitus. Although they are used in many countries, their acceptability could be limited by method characteristics, such as the need to obtain a monthly injection or bleeding pattern changes. OBJECTIVES: To assess the contraceptive efficacy, bleeding patterns, discontinuation, user preferences, and side effects of CICs. SEARCH METHODS: In January and February 2013, we searched for randomized controlled trials (RCTs) of combination injectable contraceptives.Databases include MEDLINE, POPLINE, CENTRAL, EMBASE, and LILACS.We searched for current trials in ClinicalTrials.gov and ICTRP.Earlier searches also included AIM and IMEMR. For the initial review, we also assessed the references listed in review articles and in the eligible trial reports. SELECTION CRITERIA: RCTs were eligible if they compared a combination injectable contraceptive with any other contraceptive method (e.g., a second CIC,a progestin-only injectable contraceptive, another hormonal contraceptive or a barrier method) or a placebo. We limited the review to marketed CICs. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data on contraceptive efficacy, bleeding patterns, continuation, and side effects. We calculated the Peto odds ratio or mean difference with 95% confidence interval for dichotomous or continuous outcome, respectively. Survival analysis estimates for method discontinuation were presented where available. MAIN RESULTS: Twelve trials met the inclusion criteria. Combination injectable contraceptives include depot medroxyprogesterone acetate (DMPA)25 mg plus estradiol cypionate (E(2)C) 5 mg, as well as norethisterone enanthate (NET-EN) 50 mg plus estradiol valerate (E(2)V) 5mg. These contraceptives resulted in lower rates of early study discontinuation due to amenorrhea or other bleeding problems than progestin-only contraceptives. However, rates were higher for overall discontinuation and discontinuation due to other medical reasons.Acceptability results favored the CIC in one study and the progestin-only in another.Studies comparing two CICs found that NET-EN 50 mg plus E(2)V (5)mg resulted in less overall discontinuation and less discontinuation due to amenorrhea or prolonged bleeding than DMPA 25 mg plus E(2)C 5 mg. However, these differences were not detected in all trials.The NET-EN plus E (2) V group also had more regular bleeding and fewer prolonged bleeding reference periods than the DMPA plus E(2)C group. The groups did not differ in their amenorrhea rates. AUTHORS' CONCLUSIONS: While discontinuation rates can be viewed as a measure of method acceptability, the findings should be interpreted with caution since discontinuation depends on many factors. Future research should be directed toward improving the acceptability of combination injectable contraceptives, such as providing injections in settings more convenient than clinics, methods for women to administer their own injections, and counseling about possible bleeding pattern changes. PMID- 23641482 TI - Arbitration agreements: Arbitration agreement must be executed by properly authorized person to be effective. Hearn v. Quince Nursing and Rehabilitation Center, No.W2007-02563-COA-R3-CV (Ct. App. Tenn. Oct.16, 2008). PMID- 23641483 TI - Good Samaritans: Two cases highlight issues with Good Samaritans. Van Horn v. Watson, No. S152360 (Cal. Dec. 18, 2008); Lacy v. My Midwife, P.C., No. 1719/06 (Sup. Ct. NY Dec.17, 2008). PMID- 23641484 TI - Apparent agency: Hospitals must expressly disclaim agency to avoid liability. Knighten v. U.S., No. 06 C 1318 (N.D. Ill. Dec.16, 2008). PMID- 23641485 TI - Negligent supervision: Claim for sexual assault by unlicensed personnel sounds in ordinary negligence. Fairbanks Hospital v. Harrold, 895 N.E.2d 732 (Ct. App. Ind. Nov. 6, 2008). PMID- 23641486 TI - Response. PMID- 23641487 TI - First de novo mutation in RPS19 gene as the cause of hydrops fetalis in Diamond Blackfan anemia. PMID- 23641488 TI - Response. PMID- 23641489 TI - Response. PMID- 23641490 TI - Response. PMID- 23641491 TI - Response. PMID- 23641492 TI - Physician may be liable for failing to warn of side effects. Coombes v. Florio, 450 Mass. 182 (Mass. 2007). PMID- 23641493 TI - EMTALA may require stabilization of behavioral patient before incarceration. Bonnette v. Louisiana, 972 So. 2d 340 (Ct. App. La. 2007). PMID- 23641494 TI - Parents do not have the right to refuse to resuscitate normal newborn. Stewart Graves v. Vaughn, 162 Wn. 2d 115, 170 P. 3d 1151 (Wash. 2008). PMID- 23641495 TI - Withdrawal of life support impermissible without authorization. DeKalb Medical Center v. Hawkins, 288 Ga. App. 840 (Ct. App. Ga. 2007). PMID- 23641496 TI - EMTALA does not require medical screening of newborns. Preston v. Meriter Hospital, Inc., _____ Wis. _____, _____ N.W. 2d _____, No. 2006AP3013 (Ct. App. Wis. January 24, 2008). PMID- 23641497 TI - Smoking-related mortality in the United States. PMID- 23641498 TI - Abstracts of the American Transplant Congress 2013, the 13th Annual Meeting of the American Society of Transplant Surgeons. May 18-22, 2013. Seattle, Washington, USA. PMID- 23641499 TI - Abstracts of the British Maternal and Fetal Medicine Society 16th Annual Conference. April 25-26, 2013. Dublin, Ireland. PMID- 23641500 TI - Interference of hemoglobin (Hb) N-Baltimore on measurement of HbA(1c) using the HA-8160 HPLC method. PMID- 23641502 TI - Abstracts of the 2013 Vascular Annual Meeting. May 30-June 1, 2013. San Francisco, California, USA. PMID- 23641501 TI - An automated technique for the measurement of the plasma glutathione reductase activity and determination of reference limits for a healthy population. PMID- 23641503 TI - Abstracts of the Annual Scientific Sessions of the Asia Pacific Heart Association. Singapore. April, 19-21, 2013. PMID- 23641504 TI - Abstracts of the 58th Annual Meeting of the Plastic Surgery Research Council. May 2-4, 2013. Santa Monica, California, USA. PMID- 23641505 TI - How to perform ultrasound in labor: assessment of fetal occiput position. PMID- 23641506 TI - Inapplicability of FMBV to VOCAL indices and the amplitude origin of power Doppler. PMID- 23641507 TI - Re: Horizontal stomach as a new sonographic clue to antenatal diagnosis of right diaphragmatic hernia. PMID- 23641508 TI - Reply: To PMID 22903526. PMID- 23641509 TI - Ultrasound is the future diagnostic tool in active labor. PMID- 23641510 TI - Reflections: neurology and the humanities. Neuro kids. PMID- 23641511 TI - Author response. PMID- 23641512 TI - Vigna unguiculata modulates cholesterol induced cardiac markers, genotoxicity and gene expressions profile in an experimental rabbit model. AB - Vigna unguiculata (VU) leaves are edible and used as a leafy vegetable in cuisine from traditional times in India. This study was designed to investigate the cardioprotective effect of VU in cholesterol fed rabbits. The animals were randomly divided into 4 groups of 6 animals each and the experimental period was 3 months. Group I-ND [normal diet 40 g feed], Group II-ND + FVU [flavanoid fraction of Vigna unguiculata (150 mg kg (-1) per body weight)], Group III-ND + CH [cholesterol (400 mg)] and Group IV-ND + CH (400 mg) +FVU (150 mg kg(-1) per body weight). After the experimental period, animals were sacrificed and the various parameters, such as cardiac markers, toxicity parameters, genotoxicity and gene expression, were investigated. Cholesterol feeding causes a significant increase in the levels of cardiac marker enzymes, namely lactate dehydrogenase (LDH) and creatine phospokinase (CPK), atherogenic index, toxicity parameters like serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) were elevated. Antioxidant enzyme levels were decreased, lipid peroxidation products in heart tissue and inflammatory markers, namely cyclooxygenase (COX2) and lipooxygenase (LOX15) in peripheral blood monocytes (PBMCs), were significantly increased. A genotoxicity study using a Comet assay and gene expression by reverse transcriptase-polymerase chain reaction (RT-PCR) of transforming growth factor-b1 (TGF-b1) and heme oxygenase-1 (HO-1) from heart tissue showed an altered expression in the disease group. The supplementation of the flavonoid fraction of Vigna unguiculata leaves (FVU) in the CH + FVU group caused the reversal of the above parameters and cardiotoxicity to near normal when compared with the CH group and FVU. This study revealed the cardioprotective nature of Vigna unguiculata in preventing cardiovascular diseases and this effect is attributed to the presence of antioxidants and the antihyperlipidemic properties of the flavonoid fraction of Vigna unguiculata leaves. PMID- 23641513 TI - Can we improve quality under the ACO model? PMID- 23641514 TI - Faster procedures benefit patients and bottom line. PMID- 23641515 TI - Big rig: the Memphis Fire Department's bariatric ambulance. With increased demand, the department recently added a second bariatric unit. PMID- 23641516 TI - Even among the troubled. AB - I received a phone-call recently with some sad news. A patient with a complex psychiatric history who I had been seeing over the preceding 6 months had attempted suicide and was in intensive care. She died later that day. My experience of working with this patient was of a life filled with pain and chaos. She regularly missed clinic appointments and would then present to the emergency department in the evening intoxicated and suicidal, be admitted and discharge herself the next morning. Psychiatric reviews and medication changes were unsuccessful: she seemed to be on a rollercoaster of distress and no one seemed able to help her get off. PMID- 23641517 TI - Bronchiectasis. PMID- 23641518 TI - Bronchiectasis--reply. PMID- 23641519 TI - End-of-life decisions. PMID- 23641520 TI - Emergency management of anaphylaxis. PMID- 23641521 TI - Lady Windermere syndrome. PMID- 23641522 TI - Disclosure of child abuse. PMID- 23641523 TI - Disclosure of child abuse. Reply. PMID- 23641524 TI - Quality care plans. PMID- 23641525 TI - Non-adherence to prophylactic medication. PMID- 23641526 TI - Non-adherence to prophylactic medication. Reply. PMID- 23641527 TI - Rise in new HIV infections. PMID- 23641528 TI - On botany and gardening. PMID- 23641529 TI - The doctor-patient. PMID- 23641530 TI - Recruitment in general practice. PMID- 23641532 TI - Integrating simulation into student learning experiences. PMID- 23641531 TI - Telemedicine effective for perioperative orientation program. PMID- 23641533 TI - Simulation-based training for pediatric OR nurses. PMID- 23641535 TI - An institutionwide approach to redesigning management of cardiopulmonary resuscitation. AB - BACKGROUND: Despite widespread training in basic life support (BLS) and advanced cardiovascular life support (ACLS) among hospital personnel, the likelihood of survival from in-hospital cardiac arrests remains low. In 2006 a university affiliated tertiary medical center initiated a cardiopulmonary (CPR) resuscitation redesign project. REDESIGNING THE HOSPITAL'S RESUSCITATION SYSTEM: The CPR Committee developed the interventions on the basis of a large-scale view of the process of delivering BLS and ACLS, identification of key decision nodes and actions, and compartmentalization of specific functions. It was proposed that arrest management follow a steady progression in a two-layer scheme from BLS to ACLS. Handouts describing team structure and specific roles were given to all code team providers and house staff at the start of their month-long rotations. To further increase role clarity and team organization, daily morning and evening meetings of the arrest team were instituted. Site-specific BLS training, on-site ACLS refresher training, and defibrillator training were initiated. Project elements also included use of unannounced mock codes to provide system oversight; preparation and distribution of cognitive aids (printed algorithms, dosing guides, and other checklists to ensure compliance with ACLS protocols), identification of patients who may be unstable or a source of concern, event review and analysis of arrests and other critical events, and a CPR website. CONCLUSION: A mature hospital-based resuscitation system should include definition of arrest trends and resuscitation needs, development of local methods for approaching the arresting patient, an emphasis on prevention, establishment of training programs tailored to meet specific hospital needs, system examination and oversight, and administrative processes that maximize interaction between all components. PMID- 23641536 TI - Accelerating the use of best practices: the Mayo Clinic Model of Diffusion. PMID- 23641537 TI - Using a hospital quality improvement toolkit to improve performance on the AHRQ quality indicators. PMID- 23641534 TI - IBCD: development and testing of a checklist to improve quality of care for hospitalized general medical patients. AB - BACKGROUND: Several studies have demonstrated the usefulness of medical checklists to improve quality of care in surgery and the ICU. The feasibility, effectiveness, and sustainability of a checklist was explored. METHODS: Literature on checklists and adherence to quality indicators in general medicine was reviewed to develop evidence-based measures for the IBCD checklist: (I) pneumococcal immunization, (B) pressure ulcers (bedsores), (C) catheter associated urinary tract infections (CAUTIs), and (D) deep venous thrombosis (DVT) were considered conditions highly relevant to the quality of care in general medicine inpatients. The checklist was used by attending physicians during rounds to remind residents to perform four actions related to these measures. Charts were audited to document actions prompted by the checklist. RESULTS: The IBCD checklist was associated with significantly increased documentation of and adherence to care processes associated with these four quality indicators. Seventy percent (46/66) of general medicine teams during the intervention period of July 2010-March 2011 voluntarily used the IBCD checklist for 1,168 (54%) of 2,161 patients. During the intervention period, average adherence for all four checklist items increased from 68% on admission to 82% after checklist use (p < .001). Average adherence after checklist use was also higher when compared to a historical control group from one year before implementation (82% versus 50%, p < .0001). In the six weeks after the checklist was transitioned to the electronic medical record, IBCD was noted in documentation of 133 (59%) of 226 patients admitted to general medicine. CONCLUSION: A checklist is a useful and sustainable tool to improve adherence to, and documentation of, care processes specific to quality indicators in general medicine. PMID- 23641538 TI - Frontline hospital workers and the worker safety/patient safety nexus. PMID- 23641539 TI - National council: reflecting a field that is 'coming together'. PMID- 23641540 TI - The art of engagement. PMID- 23641541 TI - We can do that. PMID- 23641542 TI - Tulsa on track to end chronic homelessness. PMID- 23641543 TI - Medicaid expansion means more managed care. PMID- 23641544 TI - Time to advance the confidentiality conversation. PMID- 23641545 TI - Using the 'strengths bank' to build authentic community inclusion. PMID- 23641547 TI - Nurse Day at the Capitol 2013: successful and exhilarating. PMID- 23641546 TI - Inpatient facilities reflect specialized needs. PMID- 23641548 TI - A symphony in Lawton: OkMOM IV. PMID- 23641549 TI - Patient's page. Thinking about Invisalign? PMID- 23641550 TI - Changes at OUCOD: comprehensive care clinics. PMID- 23641551 TI - Oklahoma Heroes of Dentistry. PMID- 23641552 TI - Faculty spotlight. OU College of Dentistry Dr. Andrew Goldbeck. PMID- 23641553 TI - Qualifying for CMS electronic health record incentives for Oklahoma Medicaid providers. PMID- 23641554 TI - NIDCR grant will establish national dental practice-based research network. PMID- 23641555 TI - Top standards compliance issues for 2012. PMID- 23641556 TI - Published: accreditation manual updates. PMID- 23641557 TI - JCR Hospital Engagement Network completes successful first year. PMID- 23641558 TI - The Joint Commission and NQF honor 2012 Eisenberg Award Recipients. PMID- 23641559 TI - Clarifications and expectations. Preventing surgical fires. Making fire safety a top priority in the OR. PMID- 23641560 TI - New speak up video addresses pain. Video advises patients on how to describe their pain. PMID- 23641561 TI - Sentinel Event Alerts and the survey process. PMID- 23641562 TI - The hospital's role in treating the homeless. PMID- 23641563 TI - [Research, a simple question of semantics?]. PMID- 23641564 TI - [We must learn to speak more openly about death with our patients and their families]. PMID- 23641565 TI - [Making blood glucose monitoring easier for diabetics]. PMID- 23641566 TI - [The universalization of the nursing profession in France]. AB - Nurses who hold a doctorate in sciences do not have any defined function in France. Indeed, while there exists no specific doctoral programme in nursing sciences, the place and status of nurses with doctoral degrees are not recognised.To teach as a permanent trainer, a healthcare manager diploma issued by a healthcare manager training institute is required. Innovation in this respect therefore appears essential, for example by reconciling as from today, the demands of nursing practice, research and training. PMID- 23641567 TI - [Diab'a'table, a patient education program dedicated to eating behaviors]. AB - A long-lasting change in eating behaviour, essential when treating patients suffering from type 2 diabetes, can be difficult to put in practice. In order to achieve this objective, a therapeutic education programme was used with volunteer patients. Its encouraging results show the benefits it can offer for obese patients suffering from type 2 diabetes. PMID- 23641568 TI - [The language of care when meeting patients]. PMID- 23641569 TI - [Care as a language]. AB - Addressing the body, nursing practice involves caring for another and the possibility for this person to be in the world. It enables the person, in spite of illness, suffering or disability, to find his or her place in the community of people. Through language, care is hospitality. PMID- 23641570 TI - [The anthropological perspective in care]. AB - No culture is a symbolic straitjacket in itself. The anthropological perspective therefore helps nursing practice to perceive certain operating structures and to understand the other person, whether that person is a caregiver or a patient. PMID- 23641571 TI - [The interpersonal relationship with the patient and the notion of proper distance]. AB - Finding the right distance to establish when caring for a patient requires self knowledge on the part of the professional. The latter must develop the emotional intelligence and interpersonal skills needed to establish a warm, authentic and benevolent relationship with the patient. PMID- 23641573 TI - [Language in intensive care, the implications for the patient and the nurse]. AB - Adapted care in intensive care units requires nurses to be aware of and to take into account the challenges, the methods and the effects of language on patients. Words, communication and information represent the different methods to be used appropriately. Language must be used with care as it can be destructive as well as structuring. PMID- 23641572 TI - [Language, a unique care tool]. AB - It is important to take into account the mother tongue of migrant patients and their children in healthcare facilities. It is a tool for sharing information and expressing our emotions. Translators are therefore essential in these facilities. PMID- 23641574 TI - [The nurse-patient relationship in psychiatry]. AB - The psychiatric nurse implements strategies to favour the connection with the patient. Several areas exist in order to give meaning to the suffering expressed by the patient. Reporting and reflection as a team are essential in psychiatric care. PMID- 23641575 TI - [The body-mind approach in the helping relationship]. AB - The body-mind approach adds to and sometimes replaces verbal communication. It integrates into care sensorial, emotional and intuitive dimensions, as well as the bodily process. As a result, the act of care appears more beneficial, both from the patient's as well at the caregiver's point of view. PMID- 23641576 TI - [The "relational" touch in care?]. AB - Training in "relational" touch is offered by a nurse and a psychologist working in tandem, according to a theoretical-practical approach. This is based on nurses' experience, their impressions and interdisciplinarity. The carers are therefore supported in the (re)discovery of thisprecioussensewhichoffers a different way of communicating. PMID- 23641577 TI - [The language of touch in care]. AB - At the heart of the care relationship, the hands of the caregiver the body of the patient interact. The language of touch is therefore expressed in addition to the verbal and nonverbal elements of human communication. PMID- 23641578 TI - [Providing care despite impaired communication, student testimonies]. AB - During their work placements, nursing students sometimes witness situations where communication with the patient has been impaired due to a number of factors. After they have been analyzed and reflected upon, these experiences can enable students to position themselves differently, set out their choices and thereby perfect the process of their professionalization. PMID- 23641579 TI - [Using a telepresence robot for a new mode of communication]. PMID- 23641580 TI - [Bibliography. The language of care]. PMID- 23641581 TI - [Ethnonursing, combining culture, health and care]. AB - The life history of the patient, his or her intentions and normative system must be taken into account before any decisions are made with regard to health care. Ethnonursing thereby constitutes a qualitative research methodology exploring, from both an ethnographic and nursing perspective, the meaning, expression, regularities, function and structuring of health and care notions within a cultural group. PMID- 23641582 TI - [Standard care plans and clinical pathways]. PMID- 23641583 TI - Compiling evidence around chronic inflammation of upper airways in children. PMID- 23641584 TI - Noise exposure of care providers during otosurgical procedures. AB - OBJECTIVE: To monitor the noise exposure of care providers during otological surgery due to drilling and suction in the operating room. METHODS: A clinical study monitoring different standard otosurgical procedures was conducted; cochlear implantation (CI), mastotympanoplasty, and mastoidectomy alone. Noise exposure to the surgeon and assistant were monitored with wireless personal noise dosimetry and stationary sound monitoring. Both maximum peak level in dBC (Lpeak) and time-average sound pressure level in dBA (equivalent level or Leq) were measured during drilling episodes. Frequency analysis in one third octaves covering the frequency bands 6.3 Hz to 20 k Hz was performed using a sound analyzing program. RESULTS: When averaged over the entire procedure, the sound pressure level was highest for the surgeon and the assistant with values of 76.0 dBA and 72.5 dBA, respectively, during CI. Lpeak was 135.9 dBC. Leq for the stationary sound measurement was 74.2 dBA. During cortical bone work using a cutting burr, 84.6 dBA was measured. Mean values of L95% (estimation of the background noise) were between 55.8 dBA and 61.2 dBA. Frequency analysis showed the highest sound pressure level for all procedures was between 2.5 kHz and 3.15 kHz. CONCLUSION: This is the first study to use personal sound dosimetry to monitor noise exposure during otosurgical drilling. In accordance with other studies, the results presented show sound levels below international occupational noise level regulations. However, the measured noise exposure during drilling could have negative effects on care providers based on unfavorable acoustical comfort. PMID- 23641585 TI - Variation among pre-surgical CT assessments of chronic otitis media. AB - OBJECTIVE: To investigate the reliability of preoperative computed tomography (CT) in patients with chronic otitis media (COM) as assessed by otologist-ENT surgeons, compared with surgical findings and respective radiological assessments, and to identify areas of the middle ear that are difficult to evaluate reliably with preoperative CT. MATERIALS AND METHODS: Fifty patients with COM underwent preoperative temporal bone CT reported by a qualified radiologist. Each operating surgeon completed a standardized questionnaire regarding the status of 10 middle-ear structures after the operation. Two otologists blindly reviewed the scans. AC1-statistics between the radiology/otology report and the intra-operative findings were calculated. RESULTS: In the attic, malleus-incus complex, tympanic cavity, and round window niche, the otologists' assessments of CT scans corresponded better to intra operative findings than did the respective radiology report. In the lateral semicircular canal and sigmoid sinus, the otologists' assessments also outperformed those of the radiologists in cases of erosion. Radiological assessments outperformed those of otologists in only one of 10 studied areas: confirmation of an unexposed dura in the tegmen area. The scutum and oval window represent difficult areas for which to obtain a reliable preoperative CT scan report. CONCLUSION: Otologists' assessments regarding the pre-surgical status of the temporal bone in COM appear more reliable than those of radiologists. This finding has serious implications in current clinical practice, and should be considered when designing strategies for Radiology Head & Neck training. The inherent limitations of CT may necessitate modifications to imaging and operating strategies. PMID- 23641586 TI - Temporal bone erosion in patients with chronic suppurative otitis media. AB - OBJECTIVES: To analyse temporal bone erosion sites (including scutum, labyrinth, facial canal, mastoid tegmen, posterior fossa dural plate and sigmoid sinus plate) in patients with chronic suppurative otitis media (CSOM). METHODOLOGY: Retrospective case review in a tertiary referral centre. Medical records were reviewed from 905 patients (121 complicated; 784 non-complicated) who received a mastoidectomy as a minimum intervention for the treatment of CSOM. RESULTS: All types of temporal bone erosion were found to be more frequent in patients with complicated CSOM. Erosion in the scutum, mastoid tegmen, posterior fossa dural plate and labyrinth was observed significantly more frequently in complicated CSOM patients with a cholesteatoma. Granulation/polyp tissue invaded the sigmoid sinus and facial canal at a rate similar to cholesteatoma. CONCLUSIONS: Our study demonstrates that bone erosion is more frequent in complicated-CSOM patients. Temporal bone erosion can be seen in both cholesteatomatous and non cholesteatomatous CSOM patients. Granulation/polyp tissue was as important as cholesteatoma in the erosion of the facial canal and sigmoid sinus plate. PMID- 23641587 TI - Hearing aid compliance in the elderly. AB - OBJECTIVES: A decreasing but still substantial proportion of elderly persons with hearing aids use them only occasionally. Because the prevalence of age-related hearing loss is increasing, it is important for the hearing rehabilitation process to be effective. The aim of this study was to use a mailed questionnaire to evaluate the rate of hearing aid use and the reasons for minimal use or nonuse. METHODS: Questions about hearing aid use and associated problems were included in a survey of hearing mailed to 4,067 people in age cohorts of 70, 75, 80 and 85 years in an industrialized urban community in Finland. RESULTS: In this sample of 249 hearing aid users, 55.4% used their hearing aid daily, and 27.3% used it > 6 hours a day. The percentage of subjects who never used their hearing aid was 10.7%. Use of hearing aids tended to decline with advancing age. The most common reasons for minimal use were disturbing background noise, acoustic feedback problems, battery cost, and a lack of motivation to use the hearing aid. CONCLUSIONS: Compliance with hearing aid use by the elderly is increasing, but a significant proportion of hearing aids are still used only occasionally or never. We discuss methods to improve compliance in this patient group. Our results may be used to reexamine existing procedures for fitting hearing aids for counseling, which may increase patient compliance with hearing aids, leading to greater benefits from their use. PMID- 23641588 TI - Hearing preservation and tumour control after radiosurgery for NF2-related vestibular schwannomas. AB - OBJECTIVES: We analyzed the effects of stereotactic radiosurgery on tumour control and cranial nerve function in patients with vestibular schwannomas (VS) secondary to neurofibromatosis type 2 (NF2). Irradiation was performed with a Gamma Knife, model C equipped with a high-precision, robotized positioning system (APS). METHODOLOGY: This study included 18 patients with 25 VSs secondary to NF2 that were treated from 2001 to 2010 with radiosurgery at our Gamma Knife Center. The radiosurgical procedure included high-resolution conformational dose-planning with multiple, small-diameter isocenters, a single-fraction, low-dose irradiation prescription, and highly accurate gamma rays delivery to the target with the APS. RESULTS: The median follow-up time was 4.4 y. For 16 tumours in 12 patients with available follow-up data, we observed an actuarial tumour control of 87.5% at 2 y and 80.2% at 5 y, based on the Kaplan-Meier method. No patient developed facial weakness. Serviceable hearing was preserved in 78% of cases. Patients treated for bilateral and unilateral tumours had similar outcomes. CONCLUSIONS: Radiosurgery could control tumour growth and preserve hearing function and facial weakness in patients with VS secondary to NF2. The enhanced techniques of radiosurgical irradiation provided with the Gamma Knife model C have improved the results of this treatment alternative to microsurgery. PMID- 23641589 TI - Surgical treatment options for maxillary sinus fungus balls. AB - OBJECTIVE: 1) To evaluate the effectiveness and side-effects of endoscopic surgical treatment for maxillary sinus fungus balls, and to describe approaches to limiting recurrence of the disease and surgical complications. 2) To compare the results of this nasal endoscopic treatment with the results of treatment using a vestibular approach to the anterior wall of the maxillary sinus as described in the literature. PATIENTS AND METHODS: An institutional retrospective review was conducted for patients undergoing treatment for a maxillary sinus fungus ball using endonasal surgery alone from January 2005 to December 2010. RESULTS: A total of 100 patients were included in the study (58 women and 42 men, average age 54 years). The median follow-up time was 32 months. Three patients had a recurrence after our team performed endonasal surgery. No patients experienced complications. CONCLUSION: Our results are consistent with previous findings, indicating that the postoperative complication rate for endonasal surgery is low by comparison with the vestibular approach. Both techniques have similar outcomes. The nasal endoscopic route offers similar rates of success with a negligible complication rate. PMID- 23641590 TI - Pitfalls of CT for deep neck abscess imaging assessment: a retrospective review of 162 cases. AB - OBJECTIVES: To investigate the diagnostic value of contrast-enhanced computed tomography (CT) for the prediction of deep neck abscesses in different deep neck spaces and to evaluate the false-positive results. METHOD: We retrospectively analysed the clinical charts, CT examinations, surgical findings, bacteriology, pathological examinations and complications of hospitalised patients with a diagnosis of deep neck abscess from 2004 to 2010. The positive predictive values (PPV) for the prediction of abscesses by CT scan in different deep neck spaces were calculated individually on the basis of surgical findings. RESULTS: A total of 162 patients were included in this study. All patients received both intravenous antibiotics and surgical drainage. The parapharyngeal space was the most commonly involved space. The overall PPV for the prediction of deep neck abscess with contrast-enhanced CT was 79.6%. The PPV was 91.3% when more than one deep neck space was involved but only 50.0% in patients with isolated retropharyngeal abscesses. In the false-positive group, cellulitis was the most common final result, followed by cystic degeneration of cervical metastases. Five specimens taken intra-operatively revealed malignancy and four of these were not infected. CONCLUSIONS: There are some limitations affecting the differentiation of abscesses and cellulitis, particularly in the retropharyngeal space. A central necrotic cervical metastatic lymph node may sometimes also mimic a simple pyogenic deep neck abscess on both clinical pictures and CT images. Routine biopsy of the tissue must be performed during surgical drainage. PMID- 23641591 TI - Knowledge of primary care doctors about laryngopharyngeal reflux disease. AB - OBJECTIVES: Many patients with reflux disease present with atypical symptoms (globus pharyngeus, constant throat clearing, chronic cough, hoarseness, catarrh, dysphagia, halitosis, choking episodes, or asthma-like symptoms) due to laryngopharyngeal reflux (LPR). Because such patients can be easily misdiagnosed, doctors in primary care should be aware of LPR and its proper treatment. This study aimed to determine whether doctors working in the primary care setting are aware of the atypical manifestations of reflux and the differences in treatment between LPR and gastroesophageal reflux disease (GERD). METHODOLOGY: This study was conducted among primary care doctors referring to the Ear, Nose, and Throat department of Karditsa (Greece) General Hospital. A questionnaire regarding the clinical manifestation and treatment of GERD and LPR was supplied to 60 doctors working in the primary care setting of Karditsa prefecture. RESULTS: Fifty-one doctors returned the questionnaire. Twenty-three (45%) were acquainted with the entity of LPR and 8 (15.7%) were acquainted with the Reflux Symptom Index (RSI). The most common symptoms, for which proton pump inhibitors (PPIs) were prescribed, were: heartburn (76.5%), heartburn combined with other symptoms (17.6%), halitosis (1.96%), hoarseness (1.96%), and choking episodes (1.96%). Most of the surveyed doctors prescribed PPIs for fewer than 12 weeks (92%), once daily (70.6%), and preferably in the morning (50%). Forty-seven (92%) provided advice regarding lifestyle modifications. CONCLUSION: The majority of surveyed doctors were unaware of LPR or the RSI. More awareness is required in the primary care setting to recognize LPR early and treat it properly. PMID- 23641592 TI - A case of sudden hearing loss associated with ANCA. AB - A 46-year-old female patient presented to our clinic with complaints of aural fullness and hearing loss for two days. On audiometric examination, she had sensorineural hearing loss in the left ear. Mean pure tone audiometry (PTA) was 53dB. Her medical history was significant for oral medication-controlled diabetes mellitus and chronic thyroiditis. Laboratory studies showed an erythrocyte sedimentation rate (ESR) of 40 mm/h and an anti-neutrophil cytoplasmic antibody directed against myeloperoxidase (MPO-ANCA) level of 33.1 EU/ml. ANCA-associated vasculitis was considered. The patient was started on immunosuppressive treatment. Seven months after the initial episode, the patient suffered a relapse. At 17 month follow-up after the initial event, the patient is healthy with normal hearing. Serum MPO-ANCA is within normal limits. PMID- 23641593 TI - Necrotizing external otitis: a case series. AB - OBJECTIVES: Necrotizing (malignant) external otitis (NEO) is a life-threatening progressive infection of the external auditory canal, mastoid, and skull base. Here, we review the clinical findings for a series of NEO patients. METHODOLOGY: This case review study includes 18 patients with NEO (males: 11 (61.11%), females: 7 (38.88%), with a mean age of 65.11 years (range: 40-79)), hospitalized at Al-Zahra hospital in Isfahan province, Iran, during 2007-2011. RESULTS: The most common presentations were otalgia 18 (100%), otorrhea 15 (83.33%), edema and erythema of the external ear canal 14 (77.77%), and hearing loss 11 (61.11%). We found osteomyelitis of the skull base that involved cranial nerves (most commonly the facial nerve) in 8 patients (44.44%), which seemed to be a higher incidence than reported in previous studies. Pseudomonas aeruginosa was found in ear specimen cultures in only 7 cases (38.88%), which could be attributed to inappropriate topical and oral use of antipseudomonal agents before proper diagnosis. Nine patients underwent surgical debridement. All cases responded to systemic antipseudomonal antibiotics with no mortality. However, recurrence occurred during the follow-up period in two cases; yet, the patients responded to retreatment. CONCLUSION: The life expectancy is increasing for diabetic and immunocompromised patients; thus, it is necessary to identify those who have a high risk for NEO, especially older diabetic patients who complain of otalgia and otorrhea that are resistant to routine treatment. Immediate diagnosis and proper treatment is crucial to prevent complications and mortality. PMID- 23641594 TI - EMG-guided salpingopharyngeus Botox injection for palatal myoclonus. AB - Palatal myoclonus (PM) is a rare neurological disorder characterized by involuntary movements of the soft palate musculature causing objective clicking tinnitus. Two forms are recognized as distinct clinical entities, with poorly understood pathogenesis: essential and symptomatic PM. The intrusive nature of the tinnitus prompts patients to seek medical advice. Conventional medical treatments with anxiolytics, antidepressants, and anticonvulsants have limited efficacy in these patients. In this case report, electromyography-guided injection of botulinum toxin type A (Botox; Allergan, Irvine, CA, USA) to the involved salpingopharyngeus and tensor veli palatini yielded satisfactory results with minimal temporary adverse effects. PMID- 23641595 TI - Concomitant inverted papilloma and fungus ball in unilateral maxillary sinus. AB - PROBLEM: The concomitant appearance of an inverted papilloma and a fungus ball in unilateral maxillary sinus is rare. These disease entities may be difficult to distinguish before surgery. METHODOLOGY: A male patient presented with the characteristic symptoms of chronic rhinosinusitis. A preoperative sinus computed tomography scan revealed unilateral sinus opacification, hyperdense calcified spots, and bony erosion of the medial maxillary sinus wall. RESULTS: During the operation, a cheesy, clay-like fungus ball was removed. In addition, a papillary appearance of the sinus mucosa led to the suspicion of inverted papilloma behind the fungus ball and nasal polyps. The histopathology showed an inverted papilloma concomitant with a fungal ball and some inflammatory polyps. CONCLUSION: In addition to preoperative imaging, one should be aware of the potential etiology; careful intraoperative reevaluation is imperative for clinicians to avoid misdiagnosis and to provide adequate management of the underlying disease. PMID- 23641596 TI - Rhabdomyoma of the pyriform sinus: case report and review of the literature. AB - OBJECTIVE: Adult rhabdomyoma is a rare benign tumour that arises from skeletal muscle. It is mostly found in the head and neck region, and it should be included in the differential diagnosis of benign lesions. METHODS: A 62-year-old man presented with dysphagia, and flexible endoscopy revealed a submucosal mass obliterating the right pyriform sinus. Computed tomography imaging revealed that the mass was hyperattenuated and extended from the right pyriform sinus to the true vocal cord. The mass was excised transorally under general anesthesia with a carbon dioxide laser. Microscopically, the tumour demonstrated features of adult type rhabdomyoma. RESULTS: One year after surgery, the patient had no signs of recurrence. CONCLUSIONS: Rhabdomyoma is a rare neoplasm of the pyriform sinus. This entity should be considered in the differential diagnosis of tumours in this region. PMID- 23641597 TI - Great expectations and changing realities. PMID- 23641598 TI - Engaging with the data: the new imperative. PMID- 23641599 TI - Stepping up security. PMID- 23641600 TI - Relative risk. PMID- 23641601 TI - Choose your words wisely. PMID- 23641602 TI - The public's perception, the nurse's reality. PMID- 23641603 TI - The evolution of primary care in Alberta. PMID- 23641604 TI - Think you know perioperative nursing? PMID- 23641605 TI - Coming to terms with ECT. PMID- 23641606 TI - No place like home. PMID- 23641607 TI - The risky business of influenza. PMID- 23641608 TI - Diabetes prevention information in Japanese magazines with the largest print runs. Content analysis using clinical guidelines as a standard. AB - OBJECTIVES: To characterize information on diabetes prevention appearing in Japanese general health magazines and to examine the agreement of the content with that in clinical practice guidelines for the treatment of diabetes in Japan. METHODS: We used the Japanese magazines' databases provided by the Media Research Center and selected magazines with large print runs published in 2006. Two medical professionals independently conducted content analysis based on items in the diabetes prevention guidelines. The number of pages for each item and agreement with the information in the guidelines were determined. RESULTS: We found 63 issues of magazines amounting to 8,982 pages; 484 pages included diabetes prevention related content. For 23 items included in the diabetes prevention guidelines, overall agreement of information printed in the magazines with that in the guidelines was 64.5% (471 out of 730). The number of times these items were referred to in the magazines varied widely, from 247 times for food items to 0 times for items on screening for pregnancy-induced diabetes, dyslipidemia, and hypertension. Among the 20 items that were referred to at least once, 18 items showed more than 90% agreement with the guidelines. However, there was poor agreement for information on vegetable oil (2/14, 14%) and for specific foods (5/247, 2%). For the fatty acids category, "fat" was not mentioned in the guidelines; however, the term frequently appeared in magazines. "Uncertainty" was never mentioned in magazines for specific food items. CONCLUSION: The diabetes prevention related content in the health magazines differed from that defined in clinical practice guidelines. Most information in the magazines agreed with the guidelines, however some items were referred to inappropriately. To disseminate correct information to the public on diabetes prevention, health professionals and the media must collaborate. PMID- 23641609 TI - [Effectiveness of a community diagnosis workshop for the staff of a community comprehensive support center]. AB - OBJECTIVES: To examine the effectiveness of a community diagnosis workshop for the staff of a community comprehensive support center (CCSC). METHODS: The general instructional objective for the participants of the workshop was to experience the process of community diagnosis and obtain skills that are relevant to implementing community diagnosis. Specific behavioral objectives included the ability to explain necessary processes of community diagnosis and to implement community diagnosis in their daily work in the CCSC. The workshop included 6 sessions conducted for 19 staff of the CCSCs in Suginami ward, Tokyo from May to October, 2011. Workshops were developed based on the Community as Partner model. Group discussions were held among the participants during each session to promote the sharing of opinions. The participants completed 4 evaluations as follows: process evaluation (assessment of the participation rate in each session and content of the sessions), output evaluation (assessment of the dropout rate), quantitative outcome evaluation (comparison of perceptions and behaviors regarding performing community diagnosis at 3 time points; before, shortly after, and at 4 months after the workshop), and qualitative outcome evaluation (open ended feedback about the workshop). The quantitative outcome evaluation had 2 specific behavioral objectives: (1) evaluation of the concrete image of community diagnosis process and (2) the priority for performing community diagnosis in their daily CCSC work. In addition, we assessed self-efficacy for performing community diagnosis in the daily work. RESULTS: Participation rate was high in every session (83-100%). Almost all participants evaluated the contents of the workshop as understandable, interesting, appropriate, and useful. In total, 18 out of the 19 participants completed the workshop (dropout rate was 5%; 1 took a leave of absence). Thirteen attended the workshop perfectly, but 5 were absent once. Images of the 2 processes of community diagnosis ("the assessment of the problems in the community" and "the solution planning to the problems") were enhanced before and shortly after the workshop. These effects remained at 4 months after the workshop. The self-efficacy for implementing these 2 processes remained unchanged before and shortly after the workshop, but was improved at 4 months after the workshop. Comparing shortly after and 4 months after the workshop, planning solutions to the problems became a higher-priority task in the participants' daily work. From the open-ended feedback, the workshop could have had some spillover effect on other aspects of the CCSC. Participants indicated that they could understand the process and significance of community diagnosis. CONCLUSION: As demonstrated by the staff of a CCSC, the effectiveness of the community diagnosis workshop could have an effect on the individual participant's perceptions and behaviors as well as on the activities of the CCSC. PMID- 23641611 TI - [Dual-task gait performance among healthy elderly community dwellers]. PMID- 23641610 TI - [Difficulties and solutions related to the experience of developing a new project by Japanese municipal public health nurses according to their seniority]. AB - OBJECTIVES: Public health nurses (PHNs) have to regularly develop new projects that actively solve community health problems. The purpose of this study was to clarify the difficulties encountered by PHNs while developing a new project and their solutions for them. We also aimed to examine the effect of experience of Japanese PHNs in developing new projects, according to their seniority. METHODS: Using random sampling, we chose 374 of 1871 municipalities that could not be consolidated with neighbouring municipalities in 2005, and 305 municipalities responded to questionnaires. The self-administered questionnaires were mailed to 2306 Japanese PHNs working within the municipalities. The questionnaire included items on the following: (1) PHN-related variables; (2) whether the PHN had experience in project development; (3) open-ended description of the difficulties and solutions related to the development of new projects by the PHN; (4) the reasons why the PHN could not create new services. We used content analysis to categorize the descriptions based on commonalities. We divided PHNs into 4 groups according to their seniority: Novice, Lower middle-level, Upper middle-level, and Expert. We performed the chi2 test (Fisher's exact test) to examine the relationship between experience and parameters such as "the difficulties" and "the solutions" in each group. RESULTS: Among the 1270 respondents, 340 PHNs were in the Novice group, 347 in the Lower middle-level group, 329 in the Upper middle level group, and 254 in the Expert group. The chi2 test (Fisher's exact test) revealed that there was a significant difference between difficulties and having experience in all 4 groups: 'Facing a busy schedule.' In these 4 groups, the following 7 solutions were statistically related with experience: 'Deepening the understanding of the PHNs' work of supervisors and colleagues,' 'Explaining the need for creating a new system with evidence,' 'Sharing information for creating a new service on a daily basis, 'Organizing the evidence to demonstrate the need for developing a new project,' 'Making a practical project plan,' 'Cooperating with persons concerned and facilitating consensus-building among them,' 'Coping with the cost of a new program. CONCLUSION: In order to overcome difficulties encountered by PNHs while developing new projects, our findings suggest that the work done by PHNs' should be better understood by supervisors and colleagues. Further, evidence should be used to explain the need for creating a new system, and a consensus should be built at carefully. Moreover, the budget of the new program should be carefully managed. PMID- 23641612 TI - [Current status of practice of providing dietary advice to pregnant women by members of the Japanese Midwives' Association. Knowledge and utilization of the "Dietary Guidelines for Pregnant and Lactating Women"]. AB - OBJECTIVES: Midwives are actively involved in providing dietary advice to pregnant women. In order to describe the current status of prenatal dietary advice provided by midwives, we conducted a questionnaire survey inquiring about their knowledge and usage of the "Dietary Guidelines for Pregnant and Lactating Women" (Guidelines) issued by the Ministry of Health, Labour, and Welfare in 2006. METHODS: In total, 2000 members of the Japanese Midwives' Association were randomly selected for administration of the questionnaire. The recovery rate was 42.1%, and 785 responses were eligible for analyses. The questionnaire collected information on the respondent's age, years of work experience, current involvement in delivery practice, number of deliveries per year in the current affiliation, provision of dietary advice to pregnant women, and knowledge and usage of the Guidelines. RESULTS: The proportion of respondents in their 20 s was low (1.8%). About half of the respondents were practicing delivery. Further, 66.1% (519 midwives) reported they had knowledge of the Guidelines. Among those who had knowledge of the Guidelines and were currently providing dietary advice (426 midwives), 88.0% were using the Guidelines. The most frequently used item in the Guidelines was "Diet for preventing anemia" (75.8%). The least used item was "Shoku-iku (diet and nutrition education) for pregnant and lactating women" (58.5%). Midwives who were practicing delivery showed a significantly lower usage of the Guidelines than those who were not (84.9% vs. 92.6%, P = 0.02). Among midwives practicing delivery, the most common reason for not using the Guidelines was "using original educational material produced by oneself or the facility." CONCLUSION: Providing dietary advice to pregnant women constituted a large fraction of midwives' duties as well as delivery practice. About 90% of the midwives, who had knowledge of the Guidelines and provided dietary advice, were using the Guidelines. In order to increase the usage of individual items of the Guidelines, ready-to-use brochures should be developed for midwives. PMID- 23641613 TI - [Growing up too fast]. PMID- 23641614 TI - [Understanding the personal experience of parents of a premature infant]. PMID- 23641615 TI - [Feeding the premature infant, some specifics to take into account]. PMID- 23641616 TI - [Neonatal screening: a broadening of new illnesses?]. PMID- 23641617 TI - [Duration of breast feeding and immigrants]. PMID- 23641618 TI - [Mother-child relations. Building the relationship]. PMID- 23641619 TI - [The mother-child bond in transcultural situations]. AB - Mothering techniques vary significantly from one culture to another. These techniques are transformed as women migrate and come into contact with other ways of forging the mother-child bond. Being aware of and respecting mothers' cultural customs is a challenge for modern day child care workers. PMID- 23641620 TI - [Supporting the mother-child bond in the home]. AB - One of the missions of the professionals from the mother and child welfare service is to support the emergence of parent-child bonding. Observation of the interactions between parents and their baby bythe child care worker, in the home, is a fundamental tool.The professional then becomes a witness and player in this meetingand in the establishment of the initial bonds. PMID- 23641621 TI - [The parent-child bond tested by a placement]. AB - When a child is placed by a legal ruling into institutional care, his or her parents have correspondence, visiting and accommodation rights. The child welfare judge fixes the terms and can, if it is deemed to be in the child's interest, suspend the arrangement. He or she can also order that any visits are carried out in the presence of a third party nominated by the institution or the service to which the child has been entrusted. PMID- 23641622 TI - [Matching, the building of the parent-child bond with adoption]. AB - Matching is the culmination of an adoption project not without its difficulties as well as the start of a new life for the future parents and their new child. This first meeting between the adoptive parents and their child is submerged by emotions in proportion to the commitment which is at stake. This affiliation process can take place with the presence and the support of professionals. PMID- 23641623 TI - [The life course of a woman through motherhood and mourning]. PMID- 23641624 TI - [Bibliography. Mother-child relations]. PMID- 23641625 TI - [Consulting a child psychiatrist for sleep disorders]. AB - Sleep disorders in children and adolescents are frequent and can, in some cases, require psychiatric assessment and treatment.The consultation with a child psychiatrist assesses the characteristics of these problems in the newborn, infant and adolescent, to guide the practitioner towards suitable support. PMID- 23641626 TI - [The fight against school failure in children of migrants]. AB - The "Mastering the language" scheme focuses on the prevention of illiteracy in children of migrants in vocation-oriented high schools. According to interviews carried out with teachers, there seems to be a transformation in their conception of teaching within the scheme, which is in line with the change encouraged by the current reform of the whole public service sector. This reform offers hope with regard to the humanisation of institutions which are currently violent. PMID- 23641627 TI - [Disclosing birth defects to parents]. AB - A descriptive transversal study was carried out by the child psychiatry and neonatology team of Hedi-Chaker General Hospital in Sfax, Tunisia. Its aim was to study the methods and circumstances of the announcement of a disability confirmed during the infant's first days of life. The results of the study show that when the announcement is made by an experienced, trained team, and in favourable conditions, it leads to better acceptance of the disability by the parents. PMID- 23641628 TI - This post-Francis vision is blurred and misguided. PMID- 23641629 TI - Hunt's one-year work experience plan is 'unworkable', say academics. PMID- 23641630 TI - Ward sisters must be supervisory, ministers tell NHS trust boards. PMID- 23641631 TI - New chief inspector of hospitals could demand more NHS nurses. PMID- 23641632 TI - Can cash-strapped health boards afford to ignore safe staffing levels? PMID- 23641633 TI - When the patient is your mum. AB - Having a sick relative can be particularly stressful when you are a nurse, as the expectation that you will 'take charge' comes into conflict with the need to be reassured like any other relative. This article examines the tension between these roles, and provides advice for 'nurse family members' and the nursing teams who encounter them. PMID- 23641634 TI - A place to feel secure. AB - A new health and wellbeing centre has opened in Birmingham to address the health inequalities in the lesbian, gay, bisexual and trans (LGBT) community. Working alongside other service providers to target issues such as attempted suicide, depression, self-harm, smoking, drinking and sexual health, the centre will act as a'one-stop shop' providing ongoing support for LGBT people. PMID- 23641635 TI - 'Nursing charity gave me a lifeline'. AB - Cases of domestic abuse against members of the nursing profession are being highlighted in a campaign called Abuse at Home. Nurse Susan Hallam describes her experience of domestic violence and how she gained support from the Cavell Nurses' Trust. PMID- 23641636 TI - Cross-cultural communication barriers in health care. AB - AIM: To investigate healthcare professionals' perceptions of caring for people from ethnic minorities with poor or no English language skills when accessing health care. METHOD: Semi-structured interviews were carried out with 34 healthcare professionals to identify their perception of barriers encountered by those with poor or no English language skills. FINDINGS: Five main themes were identified in relation to barriers in accessing health care: language; low literacy; lack of understanding; attitudes, gender attitudes and health beliefs; and retention of information. CONCLUSION: It is essential that all individuals are able to interact effectively with healthcare services. New and innovative approaches are necessary to meet the needs of people from ethnic minorities accessing health care. PMID- 23641637 TI - Safe administration of intravenous iron therapy. AB - This article describes the process of setting up a community service to meet the needs of patients with chronic kidney disease who have iron-deficiency anaemia. The service provides a course of intravenous (IV) iron therapy, which is usually given initially weekly for five weeks. Collaboration between specialist anaemia services in secondary care and the community IV therapy team in Liverpool aimed to develop a safe, patient-centred service. This service and the development of new medications has made the delivery of IV iron therapy in the community possible. PMID- 23641639 TI - Prostate cancer. PMID- 23641638 TI - Providing constructive feedback to students during mentoring. AB - The need to provide students with regular feedback on their performance is integral to the assessment process, but not all mentors feel confident to do this. This article highlights the benefits of providing constructive feedback for both the mentor and the student. Five principles associated with giving constructive feedback are discussed. The importance of preparing for feedback, ensuring it is provided in a timely manner and being specific are emphasised. Development opportunities to enhance mentors' skills in giving feedback that is beneficial to the student are also discussed. PMID- 23641640 TI - Debate, discuss, develop. PMID- 23641641 TI - A traditional role in decline. PMID- 23641642 TI - Leading the next generation. PMID- 23641643 TI - Action needed to boost health visitor workforce. PMID- 23641644 TI - Evidence for intentional rounding said to be 'flimsy and questionable'. PMID- 23641645 TI - Lack of recognition for the RCN by councils leaves staff vulnerable. PMID- 23641646 TI - Number of health visitor recruits falls below government target. PMID- 23641647 TI - Further withdrawals from south west pay consortium welcomed. PMID- 23641648 TI - 'If we want caring nurses we must ensure time for good mentoring'. PMID- 23641649 TI - Nurses have their say on the regulator. AB - The Nursing and Midwifery Council has endured widespread criticism of its performance in recent years. Respondents to a Nursing Standard survey explain what they want from their regulator. Most do not want the NMC abolished but there is a strong desire for radical change. PMID- 23641650 TI - Camaraderie, tea... and laughter. AB - A project in Hull is going the extra mile to meet men's health needs. Men Need Sheds provides weekly meetings for older men with mild to moderate mental health needs at a shed on an allotment. Here they can socialise, relax and work together on practical projects. PMID- 23641651 TI - Strength in numbers. AB - Community matrons have complex caseloads and often work in isolation, supporting patients with chronic illness to stay out of hospital. In south London a community matrons network is helping senior nurses to establish links with one another, keep up to date and tackle variations in the quality of care they deliver to patients. PMID- 23641652 TI - Sexual health needs and the LGBT community. AB - Lesbian, gay, bisexual and trans (LGBT) individuals have particular vulnerabilities to sexually transmitted infections and HIV infection. Globally, reasons for this include physiological factors, discrimination and poor understanding of their sexual health needs. In many countries LGBT individuals are not able to exercise fully their rights to health care. This raises public health concerns for the LGBT community and the wider population. This article explores these issues, and makes recommendations for the healthcare profession to address health inequalities and promote improved health outcomes for LGBT populations. This article aims to promote an evidence-based approach that focuses on rights and public health issues. PMID- 23641653 TI - Acute stroke research: challenges and opportunities for nurses. AB - Clinical research in the early acute phase of stroke is inherently complex, but is crucial to improve diagnosis, treatment and care of patients. This article explores the challenges faced by nurses in determining the eligibility of patients who have experienced stroke and obtaining informed consent from patients for inclusion in a clinical research study. It highlights the role of clinical nurses in ensuring patients and their representatives are offered opportunities to participate in research and are supported.In addition, the article illustrates how clinical and research staff jointly assure the safety of patients and the integrity of the research data. Examples of how acute stroke studies provide an opportunity to embed research into everyday nursing practice, thereby enabling nurses to advocate for quality evidence-based patient care, are illustrated. PMID- 23641654 TI - Conclusion to the stroke series. PMID- 23641655 TI - Care of patients with a stoma. AB - Several diseases and operations may necessitate the formation of a stoma. Patients may be concerned about the effect of the stoma on their ability to carry out activities of daily living, as well as quality of life. Nurses who may be involved in the care of patients with a stoma should have an understanding of the reasons for stoma formation, and the types of stoma and appliances available, to educate and support patients, and allay any concerns. Issues related to diet, sexual relationships and self-image are also discussed briefly. PMID- 23641656 TI - Atrial fibrillation. PMID- 23641657 TI - Well-rounded nurses. PMID- 23641658 TI - Opening doors to job equality. PMID- 23641659 TI - The red jug revolution. PMID- 23641660 TI - The "virtual patient" in medicine and dentistry. PMID- 23641661 TI - Influence of scanning strategies on the accuracy of digital intraoral scanning systems. AB - The digital intraoral impression is a central part in today's CAD/CAM dentistry. With its possibilities, new treatment options for the patient is provided and the prosthetic workflow is accelerated. Nowadays, the major issue with intraoral scanning systems is to gain more accuracy especially for larger scan areas and to simplify clinical handling for the dentist. The aim of this study was to investigate different scanning strategies regardingtheir accuracy with full arch scans in an in-vitro study design. A reference master model was used for the digital impressions with the Lava COS, the Cerec Bluecam and a powderfree intraoral scanning system, Cadent iTero. The trueness and precision of each scanning protocol was measured. Lava COS provides the a trueness of 45.8 microm with the scanning protocol recommended from the manufacturer. A different scanning protocol shows significantly lower accuracy (trueness +/- 90.2 microm). Cerec Bluecam also benefits from an optimal scanning protocol with a trueness of +/- 23.3 microm compared to +/- 52.5 microm with a standard protocol. The powderfree impression system Cadent iTero shows also a high accurate full-arch scan with a trueness of +/- 35.0 microm and a precision of +/- 30.9 microm. With the current intraoral scanning systems, full arch dental impressions are possible with a high accuracy, if adequate scan strategies are used. The powderfree scanning system provides the same level of accuracy compared to scanning systems with surface pretreatment. PMID- 23641662 TI - 3D monitoring and quality control using intraoral optical camera systems. AB - The quality of intraoral scanning systems is steadily improving, and they are becoming easier and more reliable to operate. This opens up possibilities for routine clinical applications. A special aspect is that overlaying (superimposing) situations recorded at different times facilitates an accurate three-dimensional difference analysis. Such difference analyses can also be used to advantage in other areas of dentistry where target/actual comparisons are required. This article presents potential indications using a newly developed software, explaining the functionality of the evaluation process and the prerequisites and limitations of 3D monitoring. PMID- 23641663 TI - Surface EMG of the masticatory muscles (part 2): fatigue testing, mastication analysis and influence of different factors. AB - The second part of this review of the literature on the clinical significance of surface electromyography (EMG) of the masticatory muscles systematically examines the results of clinical studies in patients with temporomandibular disorders (TMD), preferably randomized controlled trials, investigating relevant aspects of EMG activity during prolonged chewing activity (fatigue effects), during the mastication process, and under the influence of different factors. Studies on the influence of factors such as gender, age, tooth status, orofacial morphology and (acute) pain, the significance of different occlusal relationships during static and dynamic occlusion, and the impact of changes in static occlusion on EMG activity of the masticatory muscles were included in the review. PMID- 23641664 TI - Cerec omnicam and the virtual articulator--a case report. AB - This case report demonstrates how two opposing teeth were restored with full crowns using Cerec software version 4.2 (pre-release version). In addition, an anterior tooth was provided with a veneer. The situation was scanned with the Cerec Omnicam. The new virtual articulator was used for the design to obtain correct dynamic contacts. The Cerec Omnicam can scan the entire situation prior to preparation without the help of an assistant, as no surface pretreatment is necessary. The locations of the occlusal contacts can be marked with articulating paper and are indicated on the virtual models. Selective deletion of individual areas allows the prepared teeth to be rescanned, considerably speeding up the workflow. A video demonstration is available of the acquisition and design procedure. PMID- 23641665 TI - A new, hybrid material for minimally invasive restorations in clinical use. AB - A new type of material consisting of a ceramic substructure infiltrated with a composite material--referred to as a hybrid ceramic--is currently being introduced for dental CAD/CAM use. The characteristic brittleness of ceramic is thus replaced by an elasticity resembling that of natural human dentin. The material features a high fracture load value of 2980 N, and is straightforward to process in CAD/CAM milling machines. This article presents a case example describing the manufacture of a veneer restoration. PMID- 23641666 TI - Design, synthesis, and characterization of heparin-binding peptoids. AB - A series of N-substituted glycine oligomers (peptoids) of varying length and side chains was synthesized with the aim of producing peptidomimetics that would bind with high affinity to heparin and thereby neutralize its anticoagulant activity. To this end, a library of 29 peptoids was synthesized using solid phase synthesis methodologies. The general design of the peptoids was the repeating trimer sequence N(cationic side chain)-N(alkyl or benzyl side chain)-N(alpha-chiral side chain), where the monomers are N-substituted glycine residues bearing the indicated side chains. The peptoids were designed to have a helical structure with positively charged ammonium or guanidinium groups on side chains that would interact electrostatically with negatively charged sites on heparin. Binding of the peptoids by heparin was characterized by isothermal titration calorimetry (ITC) and heparin affinity chromatography (HAC). The secondary structure of the peptoids was characterized by circular dichroism (CD) spectroscopy. The peptoid design was systematically modified to produce peptoids with high affinity binding to heparin as measured by the above methods, resulting in the synthesis of peptoids with micromolar and sub-micromolar heparin-binding affinity. The efficacy of selected peptoids as agents for neutralization of the anticoagulant activity of heparin was assayed by the Coatest method, which measures restoration of the activity of the serine protease factor Xa (FXa). The results indicate that peptoids show promise as potential therapeutic agents for neutralization of the anticoagulant activity of heparin. PMID- 23641667 TI - Dynamic kinetic asymmetric ring-opening/reductive amination sequence of racemic nitroepoxides with chiral amines: enantioselective synthesis of chiral vicinal diamines. AB - We report a highly diastereoselective synthesis of vicinal diamines by the treatment of nitroepoxides with primary amines and then a reducing agent. When using a chiral primary amine, racemic nitroepoxides are transformed into chiral diamines as a single enantiomers (>95:5 er) through a dynamic kinetic asymmetric transformation (DYKAT). The overall process is a one-pot procedure combining the exposure of nitroepoxides to chiral amines to afford diastereomeric mixtures of aminoimines and subsequent stereoselective imine reduction. PMID- 23641668 TI - Nutritional evaluation and health promoting activities of nuts and seeds cultivated in Greece. AB - Available data suggest that genetic as well as environmental factors may influence nuts and seeds nutrients content. In this context nuts and seeds cultivated in Greece were studied. Macronutrients content was in agreement with that from other areas. Total phenolics content was in the range of 43.0 +/- 2.1 1512.7 +/- 60.7 mg GAE/100 g for chestnut and walnut, respectively. Thirteen to 22 individual phenolics were identified in the studied species. Oleanolic acid was in the range of 0.10-9.03 mg/100 g. Pumpkin seeds contained the higher squalene content (71.6 mg/100 g). beta-Sitosterol predominated in all samples except pumpkin seeds. Tocopherols ranged from 8.9 mg/100 g (chestnut) to 29.3 mg/100 g (almond). Nuts and seeds hydrophilic extracts at quantities corresponding to the estimated daily consumption by the Greeks succeeded in inhibiting LDL oxidation in vitro by increasing lag time 1.1-14.1 times. One serving of nuts or seeds may cover a significant fraction of health promoting microconstituents daily intake. PMID- 23641670 TI - Implant-supported full-mouth restoration in a young patient with generalized aggressive periodontitis. PMID- 23641669 TI - A combination of transcriptomics and metabolomics uncovers enhanced bile acid biosynthesis in HepG2 cells expressing CCAAT/enhancer-binding protein beta (C/EBPbeta), hepatocyte nuclear factor 4alpha (HNF4alpha), and constitutive androstane receptor (CAR). AB - The development of hepatoma-based in vitro models to study hepatocyte physiology is an invaluable tool for both industry and academia. Here, we develop an in vitro model based on the HepG2 cell line that produces chenodeoxycholic acid, the main bile acid in humans, in amounts comparable to human hepatocytes. A combination of adenoviral transfections for CCAAT/enhancer-binding protein beta (C/EBPbeta), hepatocyte nuclear factor 4alpha (HNF4alpha), and constitutive androstane receptor (CAR) decreased intracellular glutamate, succinate, leucine, and valine levels in HepG2 cells, suggestive of a switch to catabolism to increase lipogenic acetyl CoA and increased anaplerosis to replenish the tricarboxylic acid cycle. Transcripts of key genes involved in bile acid synthesis were significantly induced by approximately 160-fold. Consistently, chenodeoxycholic acid production rate was increased by more than 20-fold. Comparison between mRNA and bile acid levels suggest that 12-alpha hydroxylation of 7-alpha-hydroxy-4-cholesten-3-one is the limiting step in cholic acid synthesis in HepG2 cells. These data reveal that introduction of three hepatocyte related transcription factors enhance anabolic reactions in HepG2 cells and provide a suitable model to study bile acid biosynthesis under pathophysiological conditions. PMID- 23641672 TI - Anatomical study of superior cluneal nerve entrapment. AB - OBJECT: Entrapment of the superior cluneal nerve (SCN) in an osteofibrous tunnel in the space surrounded by the iliac crest and the thoracolumbar fascia is a cause of low-back pain (LBP). Several anatomical and surgical reports describe SCN entrapment as a cause of LBP, and a recent clinical study reported that patients with suspected SCN disorder constitute approximately 10% of the patients suffering from LBP and/or leg symptoms. However, a detailed anatomical study of SCN entrapment is rare. The purpose of this study was to investigate the courses of SCN branches and to ascertain the frequency of SCN entrapment. METHODS: Branches of the SCN were dissected in 109 usable specimens (54 on the right side and 55 on the left side) obtained in 59 formalin-preserved cadavers (average age at death 84.8 years old). All branches were exposed at the points where they perforated the thoracolumbar fascia. The presence or absence of an osteofibrous tunnel was ascertained and, if present, the entrapment of the branches in the tunnel was determined. RESULTS: Of 109 specimens, 61 (56%) had at least 1 branch running through an osteofibrous tunnel. Forty-two medial (39%), 30 intermediate (28%), and 14 lateral (13%) SCN branches passed through such a tunnel. Of these, only 2 medial branches had obvious entrapment in an osteofibrous tunnel. There were several patterns for the SCN course through the tunnel: medial branch only (n = 25), intermediate branch only (n = 11), lateral branch only (n = 4), medial and intermediate branches (n = 11), medial and lateral branches (n = 2), intermediate and lateral branches (n = 4), and all branches (n = 4). CONCLUSIONS: Several anatomical variations of the running patterns of SCN branches were detected. Entrapment was seen only in the medial branches. Although obvious entrapment of the SCN is rare, it may cause LBP. PMID- 23641671 TI - Level of distress, somatisation and beliefs on health-disease in newly arrived immigrant patients attended in primary care centres in Catalonia and definition of professional competences for their most effective management: PROMISE Project. AB - BACKGROUND: Newly arrived immigrant patients who frequently use primary health care resources have difficulties in verbal communication. Also, they have a system of beliefs related to health and disease that makes difficult for health care professionals to comprehend their reasons for consultation, especially when consulting for somatic manifestations. Consequently, this is an important barrier to achieve optimum care to these groups. The current project has two main objectives: 1. To define the different stressors, the level of distress perceived, and its impact in terms of discomfort and somatisation affecting the main communities of immigrants in our area, and 2. To identify the characteristics of cross-cultural competence of primary health care professionals to best approach these reasons for consultation. METHODS/DESIGN: It will be a transversal, observational, multicentre, qualitative-quantitative study in a sample of 980 people from the five main non-European Union immigrant communities residing in Catalonia: Maghrebis, Sub-Saharans, Andean South Americans, Hindustanis, and Chinese. Sociodemographic data, level of distress, information on the different stressors and their somatic manifestations will be collected in specific questionnaires. Through a semi-structured interview and qualitative methodology, it will be studied the relation between somatic manifestations and particular beliefs of each group and how these are associated with the processes of disease and seeking for care. A qualitative methodology based on individual interviews centred on critical incidents, focal groups and in situ questionnaires will be used to study the cross-cultural competences of the professionals. DISCUSSION: It is expected a high level of chronic stress associated with the level of somatisations in the different non-European Union immigrant communities. The results will provide better knowledge of these populations and will improve the comprehension and the efficacy of the health care providers in prevention, communication, care management and management of resources. PMID- 23641673 TI - Upper facet joint en bloc resection for the treatment of thoracic myelopathy caused by ossification of the ligamentum flavum. AB - OBJECT: The authors introduce a novel technique to treat thoracic myelopathy caused by ossification of the ligamentum flavum (OLF): upper facet joint en bloc resection. This surgical procedure avoids surgery to the most heavily compressed cord surface, contact with the cord, and cord injury. The epidural venous plexus bleeding point can be directly seen and easily controlled during the decompression. METHODS: Between January 2007 and January 2009, thoracic myelopathy caused by OLF was diagnosed in 38 patients using plain radiography, CT, and MRI, and diagnoses were confirmed by postoperative pathological examination. All upper facet joint en bloc resection procedures were performed in 2 steps. First, the bony structures above the upper facet joint surfaces were resected and the upper facet joints were isolated. Second, en bloc resection of the upper facet joint was performed by dissection of the junction between the pedicle and upper facet joint. Intraoperative neurological monitoring was performed in all cases. The modified Japanese Orthopaedic Association (mJOA) scoring system was used to assess neurological status. The degree of postoperative expansion of the spinal cord was calculated on axial MR images. The pre- and postdecompression Cobb angle was applied to assess the magnitude of local kyphosis. RESULTS: Of the 38 cases of OLF, 6 were single level, 12 were double level, and 20 were multilevel. Of the 92 ossified segments in this study, 23 (25.0%) were located in the upper thoracic spine (T1-4), 13 (14.1%) were located in the midthoracic spine (T5-8), and 56 (60.9%) were located in the lower thoracic spine (T9-L1). The mean intraoperative blood loss was 340 +/- 54 ml. The neurological status improved during follow-up (mean 46.1 months) from a preoperative mean mJOA score of 5.39 +/- 1.52 to 8.97 +/- 1.22 points (t = 18.39, p < 0.05). The neurological function recovery rate ranged from 28.6% to 100%. The mean increase in pre- and postoperative kyphosis of the involved vertebrae was only 1.3 degrees +/- 1.6 degrees . The increase in the cross-sectional area of the dural sac at the level of maximum compression suggested that decompression was complete. CONCLUSIONS: Upper facet joint en bloc resection is effective and may be a reasonable alternative treatment choice for thoracic myelopathy caused by OLF. PMID- 23641674 TI - Spinal dural arteriovenous fistula presenting with paraplegia following lumbar puncture. AB - Spinal dural arteriovenous fistulas are rare lesions with an annual incidence of 1 per 100,000 population. In patients with this disease, an abnormal vascular dural shunt exists between a dural branch of a segmental artery and a subdural radicular vein that drains the perimedullary venous system, leading to venous hypertension and secondary congestive myelopathy. Generally, patients present with progressive paraparesis, urinary disturbances, and gait ataxia. In this report the authors describe a 61-year-old woman with a spinal dural arteriovenous fistula who developed an acute paraplegia after a nontraumatic lumbar puncture. The possible underlying mechanisms and treatment options are discussed. PMID- 23641675 TI - Neurological deficit due to cement extravasation following a vertebral augmentation procedure. AB - The authors endeavor to highlight the surgical management of severe neurological deficit resulting from cement leakage after percutaneous vertebroplasty and to systematically review the literature on the management of this complication. A patient presented after a vertebroplasty procedure for traumatic injury. A CT scan showed polymethylmethacrylate leakage into the right foramina at T-11 and L 1 and associated central stenosis at L-1. He underwent decompression and fusion for removal of cement and stabilization of the fracture segment. In the authors' systematic review, they searched Medline, Scopus, and Cochrane databases to determine the overall number of reported cases of neurological deficit after cement leakage, and they collected data on symptom onset, clinical presentation, surgical management, and outcome. After surgery, despite neurological recovery postoperatively, the patient developed pneumonia and died 16 days after surgery. The literature review showed 21 cases of cement extravasation with neurological deficit. Ultimately, 15 patients had resolution of the postoperative deficit, 5 had limited change in neurological status, and 2 had no improvement. Cement augmentation procedures are relatively safe, but certain precautions should be taken to avoid such complications including high-resolution biplanar fluoroscopy, considering the use of a local anesthetic, and controlling the location of cement spread in relationship to the posterior vertebral body. Immediate surgical intervention with removal of cement provides good results with complete recovery in most cases. PMID- 23641676 TI - Pharmacogenetic considerations for late life depression therapy. AB - INTRODUCTION: Geriatric depression is a heterogeneous disorder with a complex genetic background. Current first-line treatment of depression is associated with a lower therapeutic outcome in aged depressed patients, when compared to younger subjects. Research which has explored this inadequate response has highlighted several factors which have come into play with the pharmacogenetics of antidepressants in the elderly being a particular area of interest. AREAS COVERED: The authors perform a critical review of the English language articles from PubMed using search terms such as late-life/geriatric depression, antidepressants, pharmacogenetics, pharmacogenomics, pharmacokinetic, genetic, genotype, remission, therapy, treatment and polymorphism. EXPERT OPINION: The emerging clinical and pharmacogenetic data are slowly unveiling the importance of the genome - age interaction in antidepressant response. This data introduces a critical new parameter in personalized medicine. A profound analysis of the age factor in the pharmacogenetics of antidepressant response is imperative, in order to elucidate the clinical significance of these findings and thereby improve patient treatment in the elderly. PMID- 23641677 TI - [Microscopic colitis]. AB - Microscopic colitis is characterized by chronic or intermittent watery diarrhoea. Microscopic colitis is a common cause of chronic diarrhoea in predominantly older adults. The underlying mechanism in the pathogenesis of microscopic colitis remains unspecified. Microscopic colitis including colitis collagenous, lymphocytic, microscopic colitis with incomplete findings, minimal change colitis, eosinophilic colitis, Brainerd's diarrhoea, graft-versus-host disease, mastocytic enterocolitis and postinfectious irritable bowel syndrome. Careful consideration of the clinical features and colonic mucosal biopsies usually lead to correct diagnosis. Treatments of microscopic colitis were based primarily on case reports and personal experience. Many medications have been proposed that either offer symptomatic relief (loperamide, cholestyramine) or had anti inflammatory or immunosuppressive properties (aminosalicylates, steroids, adalimumab, azathioprine). PMID- 23641678 TI - [Irreversible electroporation: local, non-thermal, ablation therapy of malignant tumours]. AB - BACKGROUND: Irreversible electroporation (IRE) is a new method of local therapy of malign tumours based on bioelectric effect of electrical current. Short electric pulses with high voltage create nano size-pores in tumour cell membranes resulting in apoptosis of the exposed cells. The purpose of our study was to verify the IRE technique performed percutaneously under CT navigation and to assess effects of application of this method in early stages of primary and secondary hepatic, pancreatic, renal and pulmonary tumours. METHODS AND RESULTS: From November 2011 to October 2012 IRE was performed with NanoKnife (by AngioDynamics) in the population of 15 patients - 6 males and 9 females. IRE was performed under total anaesthesia with 2-5 needle electrodes introduced under CT navigation in the tumour base. The results of the treatment were assessed on the basis of modified RECIST criteria applied in 1-, 3- and 6-month intervals. A control CT or MRI examination 6 months post IRE was undertaken by 10 patients. One patient died one month post IRE of pulmonary embolism, two refused to visit for the control examination and another two are still to undergo the examination after 6 months. Out of the 10 examined patients success of IRE was demonstrated in 7 cases (70.0%) and IRE failure in 3 patients (30.0%). CONCLUSION: IRE is a new, mini-invasive therapeutic method applicable to local treatment of malignant tumours in cases where surgical approach is technically unfeasible or excessively risky. On the basis of first experience in a small cohort of patients IRE performed under CT navigation appears to be an effective and safe ablation method with a large therapeutic potential. Its results will however need to be assessed within a longer time horizon and in a larger cohort of population. PMID- 23641680 TI - [Long-term problem with addictive substances dependence and its solution: a case report]. AB - The recovery of a male health professional dependent on alcohol and other psychoactive substances was possible only after long-term cooperation with the organization Alcoholics Anonymous. This case report illustrates the principle that addiction is a chronic disease and its treatment is successful if it is treated as a chronic disease. PMID- 23641681 TI - [Joint Programming: a new instrument for intensive cooperation in biomedical research in Europe]. AB - The aim of the Joint Program-ming process is to pool national research efforts in order to make better use of European precious public research and development resources and to tackle common European challenges more effectively in a few key areas. Joint programming is a structured and strategic process whereby Member States agree, on a voluntary basis and in a partnership approach, on common visions and Strategic Research Agendas (SRA) to address major societal challenges. On a variable geometry basis, Member States commit to Joint Programming Initiatives (JPIs) where they implement together joint Strategic Research Agendas. PMID- 23641682 TI - [Marcus Tullius Cicero and medicine]. AB - The article deals with the selected parts of the writings of M. Tullius Cicero De natura deorum and Cato Maior De senectute dealing with medicine. It is an attempt to illustrate medical knowledge of educated people in ancient Rome. In its true sense, the above given writings have not a scientific character. However, the errors that the writings contain belong to the time when Marcus Tullius Cicero had lived. Ciceros knowledge in anatomy is given as an example. PMID- 23641683 TI - Self-terminating protocol for an interfacial complexation reaction in vacuo by metal-organic chemical vapor deposition. AB - The fabrication and control of coordination compounds or architectures at well defined interfaces is a thriving research domain with promise for various research areas, including single-site catalysis, molecular magnetism, light harvesting, and molecular rotors and machines. To date, such systems have been realized either by grafting or depositing prefabricated metal-organic complexes or by protocols combining molecular linkers and single metal atoms at the interface. Here we report a different pathway employing metal-organic chemical vapor deposition, as exemplified by the reaction of meso-tetraphenylporphyrin derivatives on atomistically clean Ag(111) with a metal carbonyl precursor (Ru3(CO)12) under vacuum conditions. Scanning tunneling microscopy and X-ray spectroscopy reveal the formation of a meso-tetraphenylporphyrin cyclodehydrogenation product that readily undergoes metalation after exposure to the Ru-carbonyl precursor vapor and thermal treatment. The self-terminating porphyrin metalation protocol proceeds without additional surface-bound byproducts, yielding a single and thermally robust layer of Ru metalloporphyrins. The introduced fabrication scheme presents a new approach toward the realization of complex metal-organic interfaces incorporating metal centers in unique coordination environments. PMID- 23641685 TI - Cavity ringdown spectroscopy of the hydroxy-methyl-peroxy radical. AB - We report vibrational and electronic spectra of the hydroxy-methyl-peroxy radical (HOCH2OO(*) or HMP), which was formed as the primary product of the reaction of the hydroperoxy radical, HO2(*), and formaldehyde, HCHO. The nu1 vibrational (OH stretch) spectrum and the A <- X electronic spectrum of HMP were detected by infrared cavity ringdown spectroscopy (IR-CRDS), and assignments were verified with density functional calculations. The HMP radical was generated in reactions of HCHO with HO2(*). Free radical reactions were initiated by pulsed laser photolysis (PLP) of Cl2 in the presence of HCHO and O2 in a flow reactor at 300 330 Torr and 295 K. IR-CRDS spectra were measured in mid-IR and near-IR regions over the ranges 3525-3700 cm(-1) (nu1) and 7250-7800 cm(-1) (A <- X) respectively, at a delay time 100 MUs after photolysis. The nu1 spectrum had an origin at 3622 cm(-1) and exhibited partially resolved P- and R-branch contours and a small Q-branch. At these short delay times, spectral interference from HOOH and HCOOH was minimal and could be subtracted. From B3LYP/6-31+G(d,p) calculations, we found that the anharmonic vibrational frequency and band contour predicted for the lowest energy conformer, HMP-A, were in good agreement with the observed spectrum. In the near-IR, we observed four well spaced vibronic bands, each with partially resolved rotational contours. We assigned the apparent origin of the A <- X electronic spectrum of HMP at 7389 cm(-1) and two bands to the blue to a progression in nu15', the lowest torsional mode of the A state (nu15' = 171 cm(-1)). The band furthest to the red was assigned as a hot band in nu15", leading to a ground state torsional frequency of (nu15" = 122 cm(-1)). We simulated the spectrum using second order vibrational perturbation theory (VPT2) with B3LYP/6-31+G(d,p) calculations at the minimum energy geometries of the HMP-A conformer on the X and A states. The predictions of the electronic origin frequency, torsional frequencies, anharmonicities, and rotational band contours matched the observed spectrum. We investigated the torsional modes more explicitly by computing potential energy surfaces of HMP as a function of the two dihedral angles tauHOCO and tauOOCO. Wave functions and energy levels were calculated on the basis of this potential surface; these results were used to calculate the Franck-Condon factors, which reproduced the vibronic band intensities in the observed electronic spectrum. The transitions that we observed all involved states with wave functions localized on the minimum energy conformer, HMP-A. Our calculations indicated that the observed near-IR spectrum was that of the lowest energy X state conformer HMP-A, but that this conformer is not the lowest energy conformer in the A state, which remains unobserved. We estimated that the energy of this lowest conformer (HMP-B) of the A state is E0 (A, HMP-B) ~ 7200 cm(-1), on the basis of the energy difference E0(HMP-B) - E0(HMP-A) on the A state computed at the B3LYP/6-31+G(d,p) level. PMID- 23641684 TI - Engineering cyanobacteria to improve photosynthetic production of alka(e)nes. AB - BACKGROUND: Cyanobacteria can utilize solar energy and convert carbon dioxide into biofuel molecules in one single biological system. Synechocystis sp. PCC 6803 is a model cyanobacterium for basic and applied research. Alkanes are the major constituents of gasoline, diesel and jet fuels. A two-step alkane biosynthetic pathway was identified in cyanobacteria recently. It opens a door to achieve photosynthetic production of alka(e)nes with high efficiency by genetically engineering cyanobacteria. RESULTS: A series of Synechocystis sp. PCC6803 mutant strains have been constructed and confirmed. Overexpression of both acyl-acyl carrier protein reductase and aldehyde-deformylating oxygenase from several cyanobacteria strains led to a doubled alka(e)ne production. Redirecting the carbon flux to acyl- ACP can provide larger precursor pool for further conversion to alka(e)nes. In combination with the overexpression of alkane biosynthetic genes, alka(e)ne production was significantly improved in these engineered strains. Alka(e)ne content in a Synechocystis mutant harboring alkane biosynthetic genes over-expressed in both slr0168 and slr1556 gene loci (LX56) was 1.3% of cell dry weight, which was enhanced by 8.3 times compared with wildtype strain (0.14% of cell dry weight) cultivated in shake flasks. Both LX56 mutant and the wildtype strain were cultivated in column photo-bioreactors, and the alka(e)ne production in LX56 mutant was 26 mg/L (1.1% of cell dry weight), which was enhanced by 8 times compared with wildtype strain (0.13% of cell dry weight). CONCLUSIONS: The extent of alka(e)ne production could correlate positively with the expression level of alkane biosynthetic genes. Redirecting the carbon flux to acyl-ACP and overexpressing alkane biosynthetic genes simultaneously can enhance alka(e)ne production in cyanobacteria effectively. PMID- 23641688 TI - Bioanalysis special focus issue on antibody-drug conjugates. PMID- 23641687 TI - An efficient flat-surface collar-free grafting method for Arabidopsis thaliana seedlings. AB - BACKGROUND: Grafting procedures are an excellent tool to study long range signalling processes within a plant. In the last decade, suitable flat-surface grafting procedures for young Arabidopsis seedlings using a collar to support the graft have been developed, allowing the study of long-range signals from a molecular perspective. RESULTS: In the modification presented here, scion and stock are put together on the medium without supporting elements, while cotyledons are removed from the scion, resulting in increased grafting success that can reach up to 100%. At the same time, the protocol enables to process as many as 36 seedlings per hour, which combined with the high success percentage represents increased efficiency per time unit. CONCLUSIONS: Growing cotyledons usually push the scion and the rootstock away in the absence of a supporting element. Removing them at the grafting step greatly improved success rate and reduced post-grafting manipulations. PMID- 23641686 TI - Dock3 interaction with a glutamate-receptor NR2D subunit protects neurons from excitotoxicity. AB - BACKGROUND: N-methyl-D-aspartate receptors (NMDARs) are critical for neuronal development and synaptic plasticity. Dysregulation of NMDARs is implicated in neuropsychiatric disorders. Native NMDARs are heteromultimeric protein complexes consisting of NR1 and NR2 subunits. NR2 subunits (NR2A-D) are the major determinants of the functional properties of NMDARs. Most research has focused on NR2A- and/or NR2B-containing receptors. A recent study demonstrated that NR2C- and/or NR2D-containing NMDARs are the primary targets of memantine, a drug that is widely prescribed to treat Alzheimer's disease. Our laboratory demonstrated that memantine prevents the loss of retinal ganglion cells (RGCs) in GLAST glutamate transporter knockout mice, a model of normal tension glaucoma (NTG), suggesting that NR2D-containing receptors may be involved in RGC loss in NTG. RESULTS: Here we demonstrate that NR2D deficiency attenuates RGC loss in GLAST deficient mice. Furthermore, Dock3, a guanine nucleotide exchange factor, binds to the NR2D C-terminal domain and reduces the surface expression of NR2D, thereby protecting RGCs from excitotoxicity. CONCLUSIONS: These results suggest that NR2D is involved in the degeneration of RGCs induced by excitotoxicity, and that the interaction between NR2D and Dock3 may have a neuroprotective effect. These findings raise the possibility that NR2D and Dock3 might be potential therapeutic targets for treating neurodegenerative diseases such as Alzheimer's disease and NTG. PMID- 23641689 TI - Insights into antibody-drug conjugates: bioanalysis and biomeasures in discovery. PMID- 23641691 TI - NanoString((r)) launches its first commercial diagnostic product. PMID- 23641690 TI - Key bioanalytical measurements for antibody-drug conjugate development: PK/PD modelers' perspective. PMID- 23641692 TI - Bioanalysis of antibody-drug conjugates: American Association of Pharmaceutical Scientists Antibody-Drug Conjugate Working Group position paper. AB - Antibody-drug conjugates (ADCs) typically consist of a cytotoxic drug covalently bound to an antibody by a linker. These conjugates have the potential to substantially improve efficacy and reduce toxicity compared with cytotoxic small molecule drugs. Since ADCs are generally complex heterogeneous mixtures of multiple species, these novel therapeutic products present unique bioanalytical challenges. The growing number of ADCs being developed across the industry suggests the need for alignment of the bioanalytical methods or approaches used to assess the multiple species and facilitate consistent interpretation of the bioanalytical data. With limited clinical data, the current strategies that can be used to provide insight into the relationship between the multiple species and the observed clinical safety and efficacy are still evolving. Considerations of the bioanalytical strategies for ADCs based on the current industry practices that take into account the complexity and heterogeneity of ADCs are discussed. PMID- 23641694 TI - PK assays for antibody-drug conjugates: case study with ado-trastuzumab emtansine. AB - BACKGROUND: Antibody-drug conjugates (ADCs) combine the characteristics of large molecule biologics and small-molecule drugs and are heterogeneous mixtures that can biotransform in vivo, resulting in additional complexity. ADC bioanalytical strategies require novel analytical methods, as well as existing large- and small molecule methods. Because ADCs in late-stage clinical development are relatively new, regulatory guidelines and standard industry best practices for developing strategies for bioanalytical PK assays are still being established. RESULTS: A PK assay strategy was developed that included comprehensive novel reagent and assay characterization approaches for the ADC ado-trastuzumab emtansine (T-DM1). CONCLUSION: The bioanalytical strategy was successfully applied to the drug development of T-DM1 and ensured that key analytes were accurately measured in support of nonclinical and clinical development. PMID- 23641693 TI - Immunogenicity assays for antibody-drug conjugates: case study with ado trastuzumab emtansine. AB - BACKGROUND: Antibody-drug conjugates (ADCs) such as KadcylaTM (ado-trastuzumab emtansine [T-DM1]) present covalently bound cytotoxic drugs, which may influence their immunogenicity potential compared with antibody therapies. Therefore, ADCs require assay strategies that allow measurement of responses to all the molecular components. RESULTS: The immunogenicity strategy for T-DM1 used a risk-based, tiered approach that included screening and titration to detect antitherapeutic antibodies; confirmation of positive responses; and characterization to assess whether the immune response is primarily to the antibody or to the linker-drug and/or new epitopes in trastuzumab resulting from conjugation. CONCLUSION: The tiered immunogenicity assay strategy for T-DM1 allowed detection of antitherapeutic antibodies to all components of the ADC in multiple nonclinical and clinical studies. Characterization strategies implemented in clinical studies provided additional insights into the specificity of the immune response. PMID- 23641695 TI - Immunogenicity testing strategy and bioanalytical assays for antibody-drug conjugates. AB - BACKGROUND: Immunogenicity testing is an important component of clinical development for large-molecule biotherapeutics. New complex types of large molecules, such as antibody-drug conjugates (ADCs), require careful evaluation of the testing strategy and bioanalytical assays used to monitor the development of antitherapeutic antibodies. RESULTS: An electrochemiluminescence-based immunoassay for the detection and epitope characterization of anti-ADC antibodies was validated. Using this assay format, antibodies directed against the monoclonal antibody and linker-drug components of the ADC were successfully detected in a multiple-dose rat toxicity study. CONCLUSION: Immunogenicity assays incorporating epitope determination may provide additional information about the characteristics of induced antitherapeutic antibodies, including the magnitude and timing of the various types of antibody responses. PMID- 23641696 TI - Characterization of the drug-to-antibody ratio distribution for antibody-drug conjugates in plasma/serum. AB - BACKGROUND: Antibody-drug conjugates (ADCs) are a new class of cancer therapeutics that deliver potent cytotoxins specifically to tumors to minimize systemic toxicity. However, undesirable release of covalently linked drugs in circulation can affect safety and efficacy. The objective of this manuscript was to propose and assess the assays that allow for the characterization of the drug deconjugation in plasma/serum. RESULTS: ADCs of three main drug conjugation platforms, linked via lysine, site-specific engineered cysteine or reduced interchain disulfide cysteine residues, were analyzed using affinity capture for sample enrichment coupled with LC-MS or hydrophobic interaction chromatography-UV for detection. These novel approaches enabled measurement of the relative abundance of individual ADC species with different drug-to-antibody ratios, while maintaining their structural integrity. CONCLUSION: The characterization data generated by affinity capture LC-MS or hydrophobic interaction chromatography-UV provided critical mechanistic insights into understanding the stability and bioactivity of ADCs in vivo, and also helped the development of appropriate quantitative ELISAs. PMID- 23641697 TI - Novel detection of DNA-alkylated adducts of antibody-drug conjugates with potentially unique preclinical and biomarker applications. AB - BACKGROUND: MDX-1203 is an antibody-drug conjugate (ADC) currently in clinical trials for the treatment of renal carcinoma. The active ingredient of MDX-1203 is a DNA minor groove-binding cytotoxic drug that forms a covalently linked adduct with an adenine base. Formation of this adenine adduct prevents DNA replication, thus triggering cell death. RESULTS: A method has been developed to successfully isolate, identify and quantitate the adenine adduct using LC-MS/MS. The method is highly useful to validate the mode of action of this class of ADCs. Additionally, we have demonstrated that this method could potentially be utilized to assess the efficacy of the ADC in in vitro studies by measuring the amount of adenine adduct in various cells expressing the antigen. CONCLUSION: Upon validation, this method could serve as an invaluable tool to evaluate compounds in preclinical in vivo models and in utilizing the DNA adduct as a potential biomarker. PMID- 23641698 TI - A personal perspective of the development and validation of a phase-specific antibody-drug conjugate cytotoxicity potency assay. AB - Antibody-drug conjugates are anticancer drugs in which a highly potent cytotoxin is linked to an antibody and used in targeted therapy. The cytotoxins are so potent that they themselves have limited therapeutic value, but the antibody provides targeted delivery and, once internalized, the inherent toxicity of the released toxin kills the cancer cells. Targeted delivery is achieved when a unique tumor-associated antigen is expressed on the cancer cell or where the antigen is overexpressed in the cancer relative to normal cells. Targeted therapy minimizes the associated side effects of conventional cancer drug therapy that is directed towards rapidly dividing cells. This paper seeks to discuss salient points in the development and validation of the cell-based potency assay, with particular reference to activities required for phase-specific validation, in the hope these considerations may lead to better data from their application. PMID- 23641700 TI - Strategies to address drug interaction potential for antibody-drug conjugates in clinical development. AB - Antibody-drug conjugates (ADCs) are a unique class of therapeutic proteins with both small and large molecular components. In vivo, ADCs are processed to multiple clinically relevant analytes, each with distinct PK properties. This increases the complexity for ADC drug interaction (DI) assessment. Furthermore, given the usually narrow therapeutic range for ADCs, a thorough risk assessment is essential to establish benefit/risk for patients. Therefore, an early understanding of the ADC catabolism and elimination pathways and cytochrome P450 reaction phenotyping, cytochrome P450 inhibition and induction potential, transporter interaction and inhibition potential for the cytotoxic drug catabolites assessed by in vitro and preclinical studies is essential. This information would be integrated with the clinical PK and PD properties of the ADC related analytes for a theoretical risk assessment of ADC DI in combination therapy. ADC DI assessment in clinical studies will further support the theoretical risk assessment and the conclusions for the labeling statement. PMID- 23641699 TI - Synthesis, bioanalysis and biodistribution of photosensitizer conjugates for photodynamic therapy. AB - Photodynamic therapy (PDT) was discovered in 1900 by Raab, and has since emerged as a promising tool for treating diseases characterized by unwanted cells or hyperproliferating tissue (e.g., cancer or infectious disease). PDT consists of the light excitation of a photosensitizer (PS) in the presence of O(2) to yield highly reactive oxygen species. In recent years, PDT has been improved by the synthesis of targeted bioconjugates between monoclonal antibodies and PS, and by investigating PS biodistribution and PD. Here, we provide a comprehensive review of major developments in PS-immunoconjugate-based PDT and the bioanalysis of these agents, with a specific emphasis on anticancer and antimicrobial PDT. PMID- 23641701 TI - A novel approach to capillary plasma microsampling for quantitative bioanalysis. AB - BACKGROUND: A novel device and procedure for the collection and isolation of microvolumes of plasma have been developed and two pilot rodent PK studies have been completed. RESULTS: This method involves collection of blood into a plastic wrapped, EDTA-coated capillary tube, containing a small amount of a thixotropic gel and a porous plug. Following blood collection, the capillary is placed into a secondary labeled container suitable for centrifugation and plasma is generated. During centrifugation, the thixotropic gel isolates the plasma from the red blood cells and creates a physical barrier between the two matrices. The plasma is then dispensed from the capillary tube into a separate container for storage or processing. CONCLUSION: A simple and robust novel approach for the collection of small plasma volumes from rodent TK studies has been demonstrated. PMID- 23641703 TI - Prevalence and factors associated with probable HIV dementia in an African population: a cross-sectional study of an HIV/AIDS clinic population. AB - BACKGROUND: The HIV/AIDS infection is common in sub-Saharan Africa and is associated with psychological and neuro- cognitive impairment. These conditions, however, remain largely unrecognized. In this study we aimed to determine the prevalence of probable HIV dementia (PHD) in an HIV clinic population in Uganda and to delineate the factors associated with such impairment in these HIV positive individuals. METHODS: Six hundred eighty HIV clinic attendees were surveyed in a cross sectional study. PHD was assessed using the International Dementia Scale (IHDS). Standardized measures were also used to assess clinical, psychological, social and demographic variables. Respondents were aged 18 years and above and did not have severe physical or mental health conditions. Multivariate analysis was conducted to identify associations between PHD and various factors. RESULTS: The prevalence of probable HIV dementia was 64.4%. PHD was significantly associated with increasing stress scores and psychosocial impairment but not with age, BMI, CD4 count, use of HAART, or a diagnosis of depression or alcohol dependence. CONCLUSION: The prevalence of probable HIV dementia in an ambulatory adult HIV positive population in Uganda was 64.4%. Increasing stress scores and psychosocial impairment were significant contributing factors. Clinicians need to be aware of this and to make efforts to identify neuro-cognitive impairment. Secondly there is need for more studies to better understand the relationship between PHD and stress in HIV populations so as to inform patient care. PMID- 23641705 TI - Analysing and recommending options for maintaining universal coverage with long lasting insecticidal nets: the case of Tanzania in 2011. AB - BACKGROUND: Tanzania achieved universal coverage with long-lasting insecticidal nets (LLINs) in October 2011, after three years of free mass net distribution campaigns and is now faced with the challenge of maintaining high coverage as nets wear out and the population grows. A process of exploring options for a continuous or "Keep-Up" distribution system was initiated in early 2011. This paper presents for the first time a comprehensive national process to review the major considerations, findings and recommendations for the implementation of a new strategy. METHODS: Stakeholder meetings and site visits were conducted in five locations in Tanzania to garner stakeholder input on the proposed distribution systems. Coverage levels for LLINs and their decline over time were modelled using NetCALC software, taking realistic net decay rates, current demographic profiles and other relevant parameters into consideration. Costs of the different distribution systems were estimated using local data. RESULTS: LLIN delivery was considered via mass campaigns, Antenatal Care-Expanded Programme on Immunization (ANC/EPI), community-based distribution, schools, the commercial sector and different combinations of the above. Most approaches appeared unlikely to maintain universal coverage when used alone. Mass campaigns, even when combined with a continuation of the Tanzania National Voucher Scheme (TNVS), would produce large temporal fluctuations in coverage levels; over 10 years this strategy would require 63.3 million LLINs and a total cost of $444 million USD. Community mechanisms, while able to deliver the required numbers of LLINs, would require a massive scale-up in monitoring, evaluation and supervision systems to ensure accurate application of identification criteria at the community level. School-based approaches combined with the existing TNVS would reach most Tanzanian households and deliver 65.4 million LLINs over 10 years at a total cost of $449 million USD and ensure continuous coverage. The cost of each strategy was largely driven by the number of LLINs delivered. CONCLUSIONS: The most cost efficient strategy to maintain universal coverage is one that best optimizes the numbers of LLINs needed over time. A school-based approach using vouchers targeting all students in Standards 1, 3, 5, 7 and Forms 1 and 2 in combination with the TNVS appears to meet best the criteria of effectiveness, equity and efficiency. PMID- 23641704 TI - A cross-sectional assessment of knowledge, attitude and practice among Hepatitis B patients in Quetta, Pakistan. AB - BACKGROUND: Hepatitis-B is a life threatening infection resulting in 0.6 million deaths annually. The prevalence of Hepatitis-B is rising in Pakistan and furthermore, there is paucity of information about Knowledge, Attitude and Practice among Hepatitis-B patients. Better disease related knowledge is important to have positive attitude and that will bring the good practices which will prevent the further spread of infection. This study aimed to evaluate knowledge, attitude and practice of Hepatitis-B Patients in Quetta city, Pakistan. METHODS: A cross-sectional, descriptive study was undertaken with 390 Hepatitis-B patients attending two public hospitals in Quetta city, Pakistan. Knowledge, attitude and practice regarding Hepatitis-B were assessed using a pre validated questionnaire containing 20, 7 and 8 questions for knowledge, attitude and practice, respectively. Descriptive statistics were used for elaborating patients' demographic characteristics and mean scores for knowledge, attitude and practice of Hepatitis-B patients. Inferential statistics (Mann-Whitney U test and Kruskal Wallis tests, p < 0.05) were used to establish association between study variables. Spearman's rho correlation was used to identify the association between the knowledge, attitude and practice scores. RESULTS: Out of 390 patients, 223 (57.2%) were males, with the majority (136, 34.9%) in the age group of 38-47 years. Mean age of the study cohort was 32.6 +/- 9.5 years. One hundred and four (26.7%) had primary level education, with 110 (28.2%) working in the private sector. The mean scores for knowledge, attitude and practice were 8.48 +/ 2.7, 3.87 +/- 1.2 and 2.37 +/- 1.0, respectively. Education, locality and occupation were significantly associated with knowledge, attitude and practice scores. Significant positive linear correlations between knowledge-attitude (r = 0.466, p < 0.01) knowledge-practice (r = 0.221, p < 0.01) and attitude-practice (r = 0.224, p < 0.01) were also observed from the study results. CONCLUSION: The findings of this study indicate that Hepatitis-B patients lack a basic understanding of infection control and management. This can result in the further spread of Hepatitis-B infection. Extensive health education campaigns should be provided to the patients in the hospital as well as in community settings for rational control and management of the disease. PMID- 23641707 TI - Assisted tandem catalytic cross metathesis-oxidation: in one flask from styrenes to 1,2-diketones and further to quinoxalines. AB - 1,2-Diketones were synthesized from styrenes by combining a cross metathesis and a Ru-catalyzed alkene oxidation to an assisted tandem catalytic sequence. The synthesis relies on the use of just one metathesis precatalyst, which was in situ converted to the oxidation catalyst by addition of an alkyl hydroperoxide as a chemical trigger and oxidant. The one-flask sequence can be extended beyond 1,2 diketones to quinoxalines, by condensation of the oxidation products with ortho phenylenediamine. PMID- 23641706 TI - Comparison study on statistical features of predicted secondary structures for protein structural class prediction: From content to position. AB - BACKGROUND: Many content-based statistical features of secondary structural elements (CBF-PSSEs) have been proposed and achieved promising results in protein structural class prediction, but until now position distribution of the successive occurrences of an element in predicted secondary structure sequences hasn't been used. It is necessary to extract some appropriate position-based features of the secondary structural elements for prediction task. RESULTS: We proposed some position-based features of predicted secondary structural elements (PBF-PSSEs) and assessed their intrinsic ability relative to the available CBF PSSEs, which not only offers a systematic and quantitative experimental assessment of these statistical features, but also naturally complements the available comparison of the CBF-PSSEs. We also analyzed the performance of the CBF-PSSEs combined with the PBF-PSSE and further constructed a new combined feature set, PBF11CBF-PSSE. Based on these experiments, novel valuable guidelines for the use of PBF-PSSEs and CBF-PSSEs were obtained. CONCLUSIONS: PBF-PSSEs and CBF-PSSEs have a compelling impact on protein structural class prediction. When combining with the PBF-PSSE, most of the CBF-PSSEs get a great improvement over the prediction accuracies, so the PBF-PSSEs and the CBF-PSSEs have to work closely so as to make significant and complementary contributions to protein structural class prediction. Besides, the proposed PBF-PSSE's performance is extremely sensitive to the choice of parameter k. In summary, our quantitative analysis verifies that exploring the position information of predicted secondary structural elements is a promising way to improve the abilities of protein structural class prediction. PMID- 23641708 TI - The lipid bilayer-inserted membrane protein BamA of Escherichia coli facilitates insertion and folding of outer membrane protein A from its complex with Skp. AB - Folding of beta-barrel membrane proteins, either from a urea-unfolded form or from chaperone-bound aqueous forms, has been characterized for pure lipid bilayers. The impact of preinserted integral proteins from biomembranes has not been examined in biophysical comparisons, but this knowledge is important for the characterization of protein assembly machinery in membranes to distinguish specific effects from unspecific effects. Here, folding was studied for a beta barrel membrane protein, outer membrane protein A (OmpA) from Escherichia coli, in the absence and presence of two other preinserted integral proteins, BamA of the beta-barrel assembly machinery complex (BAM) from E. coli and FomA from Fusobacterium nucleatum. Three different preformed lipid membranes of phosphatidylcholine were prepared to compare the folding kinetics of OmpA, namely, proteoliposomes containing either BamA or FomA and pure liposomes. Urea unfolded OmpA folded faster into phosphatidylcholine bilayers containing FomA than into pure lipid bilayers, but the kinetics of OmpA folding and insertion were fastest for bilayers containing BamA. Incorporation of BamA into lipid bilayers composed of phosphatidylcholine and phosphatidylethanolamine greatly weakened the inhibiting effect of phosphatidylethanolamine on the folding of OmpA. Folding of OmpA from its complex with the periplasmic chaperone Skp into bilayers composed of phosphatidylethanolamine and phosphatidylcholine was inhibited in the absence of BamA but facilitated when BamA was present, indicating an interaction of Skp-OmpA complexes with BamA. PMID- 23641709 TI - Limb girdle muscular dystrophy type 2B masquerading as inflammatory myopathy: case report. AB - Limb girdle muscular dystrophy type 2B is a rare subtype of muscular dystrophy, the predominant feature of which is muscle weakness. The disease is caused by an autosomal recessively inherited reduction/absence of muscle dysferlin due to a mutation in dysferlin gene at 2p12-14. We report a 10 year old boy who presented with severe non-transient right knee pain and swelling, which later became bilateral. His pain was worst in the morning and during rest. Blood tests revealed markedly raised creatine kinase values (highest 22, 297 U/l), raising the possibility of an inflammatory myositis. MRI showed bilateral asymmetrical muscle involvement of thighs and calves with oedematous changes mimicking the imaging appearances of inflammatory myositis. CRP and ESR levels were consistently within normal limits. Over several months his knee pain worsened and limited walking. Muscle biopsy revealed a severe reduction of dysferlin immunostaining, indicating the diagnosis, which was confirmed by 2 compound heterozygous pathogenic mutations in the dysferlin gene. It is not unusual for this subtype of the disease to mimic myositis: however, significant pain is a rare presenting symptom. Given the significant overlap between this form of muscular dystrophy and inflammatory myopathies, a high index of suspicion is needed to ensure an accurate and timely diagnosis. Furthermore, characteristic inflammatory-related morning pain should not rule out consideration of non inflammatory causes. PMID- 23641710 TI - [Cytopathology 2012: screening - education - diagnostics highlights of 37th European cytology congress, dubrovnik - cavtat, croatia 30.9. -3.10.2012]. AB - In Dubrovnik - Cavtat, Croatia more than 550 cytopathologists, representing 50 countries, met in the 37th European Cytology Congress. Three main topics dominated the programme: The cervical screening programmes focused on the optimal combination of HPV tests and screening cytology aimed at cost-effective and safe prolongation of the screening interval while still covering the target population. Regarding the mammary screening, the best organized "one day" diagnostic systems (French, Italian, Scandinavian) utilized sonography-guided fine needle diagnostics followed (only if needed) with a core biopsy.Great emphasis was placed on standardized European programmes of training and certification of cytotechnologists and pathologists. The role of cytotechnologists having a general education is increasing. The participation of clinical specialists will be limited to taking cytopathology samples.The strengthening role of cytodiagnostics was evident. Diagnostics is becoming a complex and multidisciplinary predictive process. Pathology lesions are regularly and routinely diagnosed with combined materials (smears, liquid based cytology, cytoblocks). ROSE (rapid on the spot evaluation) is performed - at minimum by a cytotechnician, but preferably by a pathologist with the rapid diagnosis made if possible. Cytotechnicians/cytopathologists are also responsible for optimal handling of these materials for molecular biology methods. The cooperation of the representatives of the Czech Society of Pathologists within working groups of EFCS (screening, education) represents an opportunity to improve the system of cytodiagnostics in the Czech Republic. PMID- 23641711 TI - Human papillomaviruses are not involved in the etiopathogenesis of salivary gland tumors. AB - BACKGROUND: Tumor-related high risk human papillomaviruses (HPV) 16 and 18 have been repeatedly detected in head and neck cancers, particularly, they are well known risk factors in squamous cell carcinoma of the oropharyngeal and tonsillar region. Little is known, however, about the possible role of HPV in salivary gland tumors. METHODS: Fifty-five cases of benign and malignant salivary gland tumors were tested using p16 immunohistochemistry followed by HPV DNA polymerase chain reaction (PCR) using SPF, CPSGB, GP5+/GP6+ primers, and type specific primers for HPV 16, 18, 31, 33, 35, 45 in the cases with strong immunohistochemical expression for p16 protein (score 3+). RESULTS: Only 5 tumors of 55 (9 %) were completely devoid of any p16 staining, and in 10 cases (18 %), less than 25 % of tumor cells stained (score 1+). In the majority of cases (35 of 55; 64 %) there was a patchy nuclear and cytoplasmic strong staining in 26 to 50 % of tumor cells (score 2+). In five cases (9 %), strong nuclear and cytoplasmic staining in more than 51% of tumor cells was detected (score 3+). However, none of the p16-positive cases showed any evidence of high-risk HPV by PCR. CONCLUSIONS: The results of the study indicate that HPV, in particular oncogenic types 16 and 18, are not involved in the etiology of benign and malignant epithelial tumors of salivary glands. Therefore, it is likely that salivary gland tumors belong to the category of tissues in which the p16 positive immunohistochemistry is not biologically relevant to the oncogenic role of HPV infection. PMID- 23641712 TI - Subependymal giant cell astrocytoma with atypical clinical and pathological features: a diagnostic pitfall. AB - Subependymal giant cell astrocytoma (SEGA) is benign, slowly growing tumor linked to the tuberous sclerosis complex. It almost always occurs near the foramen of Monro. Parenchymal extension and worrisome histological features, such as necrosis, mitoses, microvascular proliferation and pleomorphism are unusual in these tumors, but can occur rarely. A case of SEGA is presented, in a patient with no signs of tuberous sclerosis so far, with atypical imaging findings and areas of necrosis found microscopically. These worrisome features initially led to the false diagnosis of glioblastoma. The differential diagnosis of SEGA is discussed. PMID- 23641713 TI - [Primary large cell neuroendocrine carcinoma of the urinary bladder]. AB - Large cell neuroendocrine carcinoma of the urinary bladder is rare. In the last five years, we have had the opportunity to see this type of cancer in an 88-year old and in a 66-year-old males. In both cases, transurethral resection of carcinoma of the bladder was carried out. In the first case, urothelial carcinoma was detected and deeper in the bladder wall, large cell neuroendocrine carcinoma structures were found. In the second case, the bladder was only infiltrated with large cell neuroendocrine carcinoma. Both tumors expressed NSE, CD56 and synaptophysin. Other markers, such as those against calcitonin, chromogranin, PP, VIP, serotonin, gastrin, glucagon and somatostatin did not react with the tumor. In the first case, no tumor dissemination was found; in the second case, clinical methods confirmed dissemination into the liver, left adrenal gland, spleen and paracaval lymph nodes. Given his age, the first patient only received symptomatic therapy. The other patient underwent chemotherapy and his condition is stable. Paraneoplastic manifestations of the tumors were not clinically found. Histogenetic origin of neuroendocrine tumors is not fully clarified. In some cases, tumor development is thought to be associated with Brunns nests, cystitis cystica and urothelial carcinoma stem cells. PMID- 23641714 TI - Angiofibroma-like perineurioma. Report of a case. AB - We report an unusual perineurioma with numerous vessels, showing a strong similarity with angiofibroma. A 2,5 x 2 x 2 cm subcutaneous/dermal tumor occurred in 58-ys-old male in the left brachial region. Histologically, it was composed of haphazardly arranged bland spindle cells and it contained prominent vasculature. In rare foci, the tumor cells showed thin bipolar processes and an onion-like perivascular whorling pattern. Immunohistochemically, expression of perineural cell markers EMA, claudin-1 and CD34 was limited to perivascular foci and to rare cells among the vessels. In addition, the tumor expressed CD10 diffusely. Our finding indicates that diagnosis of perineurioma should be considered also by tumors with an "angiofibromatous" morphology. Especially soft tissue angiofibroma, which often express EMA (perineural cell marker), shows a strong resemblance to angiofibroma-like perineurioma. PMID- 23641715 TI - A novel germline mutation in the CYLD gene in a Slovak patient with Brooke Spiegler syndrome. AB - The authors report a 64-year-old female with Brooke-Spiegler syndrome who presented with multiple cutaneous nodules and tumors mostly involving the scalp. Histopathological examination of one of the lesions located in a periauricular area revealed a typical cylindroma. In some neoplastic nodules ductal differentiation and occasional bilayered glands composed of the dark abluminal basal/myoepithelial cells and luminal mucinous cells might be recognized. Apocrine secretion was focally noted. Molecular biologic study of the CYLD gene performed from the peripheral blood identified a novel splice site c.2041+1 G>T mutation. This new germline mutation in the CYLD gene of a Slovak patient with Brooke-Spiegler syndrome extends the catalogue of known CYLD germline mutations in this condition. PMID- 23641716 TI - [Undiagnosed Whipple's disease with a lethal outcome]. AB - Whipples disease is a rare multisystem disease caused by rod-shaped bacteria Tropheryma whipplei. Although it affects all age groups, the typical patient is a middle-aged white man. The clinical signs are very heterogeneous and depend on the stage of the disease. The most common is abdominal manifestation characterized by weight loss, disability, chronic diarrhea and abdominal pain. Untreated Whipples disease is almost always fatal. We describe probably the first published case of undiagnosed Whipples disease with a lethal outcome in Slovakia, occuring in a 33-year old white man with involvement of the gastrointestinal tract, abdominal lymphatic nodes and brain, who died of bronchopneumonia. PMID- 23641717 TI - Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: case report and review of literature. AB - Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is a rare condition affecting mostly women in the fifth and sixth decades of life. Here we present a case of its accidental finding in the lung parenchyma of a 56-year-old non-smoker female. In the periphery of the right middle lobe, linear and nodular proliferations were detected in the wall of the small bronchi and terminal and respiratory bronchioles. Under the pleura, several tumorlets were located. Immunohistologically, neuroendocrine cells were positive with antibodies against chromogranin A, synaptophysin, CD56, serotonin (weak positivity of some cells only), calcitonin, GRP/bombesin, cytokeratin 7 and TTF-1. PMID- 23641718 TI - An improved stable isotope N-terminal labeling approach with light/heavy TMPP to automate proteogenomics data validation: dN-TOP. AB - In silico gene prediction has proven to be prone to errors, especially regarding precise localization of start codons that spread in subsequent biological studies. Therefore, the high throughput characterization of protein N-termini is becoming an emerging challenge in the proteomics and especially proteogenomics fields. The trimethoxyphenyl phosphonium (TMPP) labeling approach (N-TOP) is an efficient N-terminomic approach that allows the characterization of both N terminal and internal peptides in a single experiment. Due to its permanent positive charge, TMPP labeling strongly affects MS/MS fragmentation resulting in unadapted scoring of TMPP-derivatized peptide spectra by classical search engines. This behavior has led to difficulties in validating TMPP-derivatized peptide identifications with usual score filtering and thus to low/underestimated numbers of identified N-termini. We present herein a new strategy (dN-TOP) that overwhelmed the previous limitation allowing a confident and automated N-terminal peptide validation thanks to a combined labeling with light and heavy TMPP reagents. We show how this double labeling allows increasing the number of validated N-terminal peptides. This strategy represents a considerable improvement to the well-established N-TOP method with an enhanced and accelerated data processing making it now fully compatible with high-throughput proteogenomics studies. PMID- 23641720 TI - Stereodivergent strategy for neurofuran synthesis via palladium-catalyzed asymmetric allylic cyclization: total synthesis of 7-epi-ST-Delta(8)-10 neurofuran. AB - Neurofurans are formed in vivo in the human brain as a consequence of an increased oxidative stress, and they could be valuable biomarkers of the neuronal oxidative stress. In this paper, an enantioselective stereodivergent approach to two key neurofuran precursors, belonging to the AC and ST classes, has been developed starting from a single achiral precursor, the meso-diol 11. The absolute configuration of the THF cores was secured by a Pd-catalyzed asymmetric allylic alkylation using (S,S)-L1 and (R,R)-L2 ligands, respectively. PMID- 23641719 TI - Simple method to enhance the photostability of the fluorescence reporter R6G for prolonged single-molecule studies. AB - For fluorescence-based single-molecule studies, photobleaching of the dye reporter often limits the time window over which individual molecules can be followed. As such, many strategies, for example, using a cocktail of chemical reagents, have been developed to decrease the rate of photobleaching. Herein, we introduce a new and highly effective method to enhance the photostability of one of the commonly used fluorescent dyes, rhodamine 6G (R6G). We show that micrometer-sized polydimethylsiloxane (PDMS) wells, when the PDMS surface is properly treated, not only provide a confined environment for single-molecule detection but can also significantly increase the survival time of individual R6G molecules before photobleaching. Moreover, our results suggest, consistent with several previous studies, that R6G photobleaching involves a radical state. PMID- 23641721 TI - Electron transfer reactions of candidate tumor suppressor 101F6 protein, a cytochrome b561 homologue, with ascorbate and monodehydroascorbate radical. AB - The candidate tumor suppressor 101F6 protein is a homologue of adrenal chromaffin granule cytochrome b561, which is involved in the electron transfer from cytosolic ascorbate to intravesicular monodehydroascorbate radical. Since the tumor suppressor activity of 101F6 was enhanced in the presence of ascorbate, it was suggested that 101F6 might utilize a similar transmembrane electron transfer reaction. Detailed kinetic analyses were conducted on the detergent-solubilized recombinant human 101F6 for its electron transfer reactions with ascorbate and monodehydroascorbate radical by stopped-flow and pulse radiolysis techniques. The reduction of oxidized 101F6 with ascorbate was found to be independent of pH in contrast to those observed for chromaffin granule and Zea mays cytochromes b561 in which both cytochromes exhibited very slow rates at pH 5.0 but faster at pH 6.0 and 7.0. The absence of the inhibition for the electron acceptance from ascorbate upon the treatment with diethyl pyrocarbonate suggested that 101F6 might not utilize a "concerted proton/electron transfer mechanism". The second order rate constant for the electron donation from the ascorbate-reduced 101F6 to the pulse-generated monodehydroascorbate radical was found to be 5.0 * 10(7) M(-1 )s(-1), about 2-fold faster than that of bovine chromaffin granule cytochrome b561 and about five times faster than that of Zea mays cytochrome b561, suggesting that human 101F6 is very effective for regenerating ascorbate from monodehydroascorbate radical in cells. Present observations suggest that 101F6 employs distinct electron transfer mechanisms on both sides of the membranes from those of other members of cytochrome b561 protein family. PMID- 23641722 TI - [Separation of sperm by micromanipulator from unusual forensic sample - case report]. AB - The aim of this study is to provide an information about the method of processing of unusual forensic sample that was submitted for the sexual assault case. We analyzed microscopic sample of vaginal swab stained using the hematoxylin-eosin mixture. After removing the covering glass we failed to collect the sperm cells to the micromanipulator capillary. The cells even started, due to the mechanical stress, to fall apart. We think that the main reason of the microdissection failure is the advanced cell lysis. Due to the negative results of the DNA analysis we defined a set of preventive and corrective actions that would (in case of application) increase the chance of positive identification in similar sexual assault cases. PMID- 23641723 TI - The use of trigonometry in bloodstain analysis. AB - Bloodstain pattern analysis (BPA) is a valid forensic method which belongs to the category of biological methods using trigonomic models. Despite its development through the years, the method has been re-formulated a standard one and globally used, recognized in standard sheets. This method permits exact analysis of the dynamic and characteristic properties of bloodstains after impact on surfaces such as floors, walls, and ceilings, various exterior and interior items, and clothes. It is also possible to determine the characteristics of blood from the outer part of the body. According to the presence of blood and its quantity, it is also possible to use this method for verification of reconstruction of criminal acts, while being tested for its validity with primary conditions of preserved and readable traces of blood. Even though this method is not considered as the major one or the only one information obtained in this way can be used for judicial. In our research, we tested the validity of this method in an experimental model using firearms. We compared measurements of the lengths of trajectory of impact and the height of the blood sprayed upwards from a distance of 1, 3, 5 and 10 meters. The experiment was based on two main presumptions. The first was the knowledge of the value of the distance and the angle of impact of the bloodstain, the second, the ability of the blood to reach a certain height and the angle of its impact. In accordance with trigonometric formulas, both the impact of the selected distance of drops of blood, and the height of the selected bloodstain could be determined without any verification of the flight trajectory and the distance of bloodstains. The results indicate that the method for these requirements differs from the real values, while increasing the measurements with the indicated spot of the shot. Aside from the unique values which were calculated, other results of the impact of the distance of drops of bloodstain were considered of lower value, and the values concerning the height of the bloods stains after the shot higher than real values. In spite of the lack of total accuracy, we recommend using this method widely and more often for investigation and verification of individual acts in criminal and forensic practice. PMID- 23641724 TI - Scuba diver deaths due to air embolism: two case reports. AB - Barotraumas and decompression sickness are the two most well-known complications of diving. First presented case was 32 year-old male with recreational diver, who was found floating prone position on the bottom of sea in a depth of 33 m. He had been carried to the surface in a controlled ascent. Second case was a 39 year-old male experienced dive instructor in a diving school, after following an uneventful duration of dive was found unconscious with a floating supine position in a depth of 30 m and there were no signs of life when they were transported to the hospital. Extensive subcutaneous emphysema of the extremities was detected by palpation of the skin. In the autopsy diffuse gas bubbles like beads were seen in the coronary arteries and in ventricles, basilar artery and all of the cerebral arteries. The cause of death was attributed due to gas embolism and drowning. PMID- 23641725 TI - An unusual case of penetrating intracranial injury due to scissors. AB - Craniocerebral penetrating non-missile injuries caused by metallic foreign bodies are uncommon events. Healthy 10 year-old boy applied to the hospital emergency service with his parents. Family members stated that the scissors have been stalled his head accidentally by his sister when they had played together. During physical examination the scissors located on left parietal region of the head was examined. There was no loss of consciousness and oriented with normal vital signs. Radiological investigation demonstrated a hyper dense foreign body (scissors) penetrating cranial cavity and ended before reaching posterior region of the left parietal lobe. To our knowledge, the presented was rare case of intracranial penetrating scissor, which was not removed until, injured, reached the hospital. Our goal was to discuss the rare case of penetrating non-missile foreign body cranial injury from medico legal aspect. PMID- 23641726 TI - An unusual case of firearm injury: bullet lodged in the tongue. AB - Firearm-related injuries are a major problem worldwide, in forensic medicine practice. and unusual presentation of bullet trajectory can create surgical or medico-legal diagnostic problems. A 23-year-old man suffered two gunshot wounds, was taken to emergency department immediately after the incident. Physical examination revealed two entrance gunshot wounds on the left lumbar region under the lower margin of left scapulae and right gluteal region. An exit wound was defined on the lateral side of the right gluteal region which was located 5 cm distance of entrance wound. Radiological investigation showed a bullet in the tongue without any life threatening impairment. A thoracic CT scan and abdominal USG were normal. Following the initial examinations he was hospitalized and the bullet removed from the tongue by a simple surgical operation. An interesting case of gunshot injury where the passage route of bullet extending along from upper posterior part of the left lumbar region to the tongue without vital organ injury or serious disability has been reported. PMID- 23641727 TI - Considering CYP1A2 phenotype and genotype for optimizing the dose of olanzapine in the management of schizophrenia. AB - INTRODUCTION: Schizophrenia, a mental disorder, is a debilitating condition which typically strikes young people in their early 20's. Antipsychotic medications are widely prescribed for the treatment of schizophrenia however a balancing act is necessary to provide the correct dose to each patient. It is suggested that a large number of patients discontinue antipsychotic pharmacotherapy because the treatments provided do not always reduce the positive symptoms of the disease, while many have adverse effects on the patients. This implies that neither the incorrect drug nor the optimal dosage for that patient is achieved. AREAS COVERED: The current review investigates variability in response to olanzapine with a specific focus on the common intrinsic and extrinsic factors that influence both olanzapine and CYP1A2 activity. Furthermore, the authors discuss the utilization of phenotyping and genotyping of CYP1A2 and their potential utility in clinical practice for olanzapine dosing regimens. The authors also consider the potential of pharmacometrics compared to pharmacogenomics as a tool to personalize medicine. EXPERT OPINION: Careful consideration must be given to the impact of a genetic variant on the disposition of a drug prior to implementing genetic 'tests' to determine response. CYP1A2 phenotypic assessment can yield important information regarding the disposition of olanzapine; however, it relies on the accuracy of the metric and the minimal impact of other metabolic pathways. The application of pharmacometrics provides an effective method to establish covariates that significantly influence olanzapine disposition which can incorporate phenotype and/or genotype. PMID- 23641728 TI - Modified edentulous ridge expansion technique and immediate implant placement: a 3-year follow-up. AB - Restoration of the edentulous alveolar ridge with implants often requires the ridge width to be augmented to allow its placement. The aim of this study was to evaluate the split-crest technique, with subepithelial connective tissue graft used as biological barrier, in patients with narrow ridges, focusing on the status of soft and hard tissues and on implant success rate, at 36 months after implant loading. Thirteen patients (6 males and 7 females), ages 32-68 years (mean 49.4 years) with an atrophic maxillary jaw underwent modified edentulous ridge expansion technique for implant placement. A total of 33 Laser-Lok tapered internal implant, were placed in the maxilla. The following parameters were evaluated: (1) initial ridge width (time t0); (2) ridge width at the time of abutment connection (time t1); four months after implants placement, healing abutments were connected and the prosthetic rehabilitation was initiated, and all patients were evaluated clinically and radiographically with periapical radiograph at intervals of 3-6 months for the first year and annually thereafter for 3 years. The ridge width was measured with a cone beam computed tomography. The initial ridge width ranged from 3.5 mm to 7 mm (mean: 4.67 mm), while at the end of the expansion procedure the width ranged from 6.3 mm to 11.0 mm (mean: 8.2 mm). The width gain of the edentulous ridge ranged from 1.45-4.9 mm (mean: 3.5 mm). Two implants became exposed 1 month after surgery. One implant was lost before loading (3%). The diameter of failed implant was 5.8 mm and length was 10.5 mm. The remaining 32 implants were stable and free of complications at the end of the study. Thus, the implant survival rate was 97%. Because no implant failed after loading, the cumulative survival rate of loaded implants was 100%. The minimally invasive regenerative technique presented here avoids the use of bone graft, secondary surgery for soft tissue augmentation, and mechanical expansion devices. However, the follow-up period for outcome evaluation and exiguous patient's number in this series was limited. PMID- 23641729 TI - The changing nature and scope of public health emergencies in response to annual flu. AB - The rapid spread of influenza during the 2012-13 season brought a series of public health challenges and corresponding response efforts. For decades, responses to annual flu have been undertaken routinely without extensive legal intervention. With the recent declaration of states of public health emergencies in Boston (January 9, 2013) and New York State (January 12, 2013), however, the legal baseline is changing. Propelled by a slate of state and local emergency declarations during the 2009-10 H1N1 pandemic, public officials are beginning to show cause for the issuance of formal emergency declarations in support of flu response efforts. The legal effects of these types of declarations are profound. Public and private actors are given significant, expedited public health powers. Scarce resources like vaccines can be more efficiently allocated. Laws relating to licensure, scope of practice, and liability can be effectively waived. Though originally conceptualized and once reserved for catastrophic, long-term health related or bioterrorism events, public health emergency declarations are evolving to address temporary impacts on health care and public health services arising annually from flu outbreaks. This commentary explores the changing nature of public health emergencies and their current and potential impact on the provision of healthcare services in response to national or regional threats to the public's health. PMID- 23641730 TI - Legal issues affecting children with preexisting conditions during public health emergencies. AB - Among the millions of children in the United States exposed to public health emergencies in recent years, those with preexisting health conditions face particular challenges. A public health emergency may, for example, disrupt treatment regimens or cause children to be separated from caregivers. Ongoing shortages of pediatricians and pediatric subspecialists may further exacerbate the risks that children with preexisting conditions face in disaster circumstances. The US Department of Homeland Security recently called for better integration of children's needs into all preparedness activities. To aid in this process, multiple legal concerns relevant to pediatricians and pediatric policymakers must be identified and addressed. Obtaining informed consent from children and parents may be particularly challenging during certain public health emergencies. States may need to invoke legal protections for children who are separated from caregivers during emergencies. Maintaining access to prescription medications may also require pediatricians to use specific legal mechanisms. In addition to practitioners, recommendations are given for policymakers to promote effective pediatric response to public health emergencies. PMID- 23641731 TI - Adapting urban water systems to a changing climate: lessons from the millennium drought in southeast Australia. PMID- 23641732 TI - Spin filtering and magneto-resistive effect at the graphene/h-BN ribbon interface. AB - Advances in the realization of hybrid graphene/h-BN materials open new ways to control the electronic properties of graphene nanostructures. In this paper, the structural, electronic, and transport properties of heterojunctions made of bare zigzag-shaped h-BN and graphene ribbons are investigated using first-principles techniques. Our results highlight the potential of graphene/h-BN junctions for applications in spintronic devices. At first, density functional theory is used to detail the role played by the edge states and dangling bonds in the electronic and magnetic behavior of h-BN and graphene ribbons. Then, the electronic conductance of the junction is computed in the framework of Green's function based scattering theory. In its high-spin configuration, the junction reveals a full spin polarization of the propagating carriers around the Fermi energy, and the magnitude of the transmission probability is predicted to be strongly dependent on the relative orientation of magnetic momenta in the leads. PMID- 23641734 TI - Molecular dynamics simulation and computational two-dimensional infrared spectroscopic study of model amyloid beta-peptide oligomers. AB - Molecular dynamics simulations were carried out to study the structure stability of model amyloid beta40 (Abeta40) peptide oligomers, from monomer to hexamer, in aqueous solution at room temperature. The initial oligomer models were built by using the parallel in-register beta-sheet fibril structure and then allowed to relax in the simulations. Our simulation results indicated that the stable Abeta40 monomer was a random coil, while the oligomer structures became more fibril-like with the increase of the peptide strands. Linear absorption and two dimensional infrared spectra of the isotope-labeled oligomers were calculated and analyzed in detail, which revealed the differential secondary structural features characteristic of Abeta40 aggregation. A quantitative relation was established to make connection between the calculated spectra and experimental ensemble measurements. PMID- 23641733 TI - Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors. AB - Small-molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a Ki value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer. PMID- 23641735 TI - The effect of a positioning index on the biomechanical stability of tapered implant-abutment connections. AB - The biomechanical stability of the implant-abutment connection is critical for the success of implant-supported restorations. This study investigated the effect of a positioning index on the abutment screw preload values of tapered connection implants. Twenty Morse taper implants presenting an internal locking hex received 10 solid and 10 straight screw retained abutments for cemented single-crown restorations. Ten abutments had a positioning index to fit the internal locking hex of the implant (straight), and 10 were locked only by the implant taper (solid). The preload values for each abutment screw after a tightening torque were registered by strain gauges. Prosthetic crowns were placed on each abutment and subjected to mechanical cycling. Detorque forces were applied to each abutment and compared with the initial torque values. Data were statistically analyzed using Kolmogorov-Smirnov and Student t tests. The nonindexed group presented higher initial preload (6.05 N +/- 0.95 N) compared with the indexed group (4.88 N +/- 0.92 N; P < .05). After cycling, the nonindexed group exhibited less reduction of preload (13.84% +/- 6.43%) compared with the indexed group (52.65% +/- 14.81%; P < .01). Indexed tapered abutments for single-crown restorations might represent greater biomechanical risk under function. PMID- 23641736 TI - A solitary hyperfunctioning thyroid nodule harboring thyroid carcinoma: review of the literature. AB - Hyperfunctioning nodules of the thyroid are thought to only rarely harbor thyroid cancer, and thus are infrequently biopsied. Here, we present the case of a patient with a hyperfunctioning thyroid nodule harboring thyroid carcinoma and, using MEDLINE literature searches, set out to determine the prevalence of and characteristics of malignant "hot" nodules as a group. Historical, biochemical and radiologic characteristics of the case subjects and their nodules were compared to those in cases of benign hyperfunctioning nodules. A literature review of surgical patients with solitary hyperfunctioning thyroid nodules managed by thyroid resection revealed an estimated 3.1% prevalence of malignancy. A separate literature search uncovered 76 cases of reported malignant hot thyroid nodules, besides the present case. Of these, 78% were female and mean age at time of diagnosis was 47 years. Mean nodule size was 4.13 +/- 1.68 cm. Laboratory assessment revealed T3 elevation in 76.5%, T4 elevation in 51.9%, and subclinical hyperthyroidism in 13% of patients. Histological diagnosis was papillary thyroid carcinoma (PTC) in 57.1%, follicular thyroid carcinoma (FTC) in 36.4%, and Hurthle cell carcinoma in 7.8% of patients. Thus, hot thyroid nodules harbor a low but non-trivial rate of malignancy. Compared to individuals with benign hyperfunctioning thyroid nodules, those with malignant hyperfunctioning nodules are younger and more predominantly female. Also, FTC and Hurthle cell carcinoma are found more frequently in hot nodules than in general. We were unable to find any specific characteristics that could be used to distinguish between malignant and benign hot nodules. PMID- 23641737 TI - Major adverse events, six months after endovascular revascularization for critical limb ischemia in diabetic patients. AB - BACKGROUND: This prospective study aimed to evaluate the detailed outcomes of diabetic patients with critical limb ischemia, six months after percutaneous transluminal angioplasty and appropriate multidisciplinary wound care. METHODS: Totally, 45 consecutive patients (50 limbs) were enrolled and then divided into two groups according to the healing of ulcers. The endpoints were ulcer healing and major adverse events including amputation, mortality, and cardiac or cerebral morbidities, during a six- month follow-up period. RESULTS: During six months follow-up, major amputation was performed for four of 50 limbs (8.0%). A total of nine (20%) patients died and the leading cause was cardiac death (13.3 %). Also, stroke and non-fatal myocardial infarction occurred in three (6.7 %) and one (2.2 %) of the patients, respectively. Among the 29 (59.2 %) healed wounds, 22 (44.9 %) were completely closed. The patients with nonhealing wounds had a higher rate of dialysis (40% vs. 0 %, P-value < 0.001) and more ulcers with stage of D3 according to the Texas Wound Classification (60% vs. 31 %, P-value = 0.016). Other demographic, clinical, ulcer characteristics and procedural characteristics such as number and level of the treated lesions did not differ significantly between the two groups. CONCLUSION: Based on our findings, it seems that along with current usual therapeutic routines which focus on wound healing and limb salvage, more attention should be paid to simultaneous diagnostic assessments and treatment of cardiovascular disease in this group of patients during short-term follow- up. PMID- 23641738 TI - The use of low- dose intrathecal fluorescein in endoscopic repair of cerebrospinal fluid rhinorrhea. AB - BACKGROUND: Intrathecal injection of fluorescein is a useful adjuvant method for localization of fistulas in endoscopic endonasal repair of cerebrospinal fluid (CSF) leakage. Although being neurotoxic in commercial doses, a low dose of diluted fluorescein seems to be safe on the basis the existing data in the literature. OBJECTIVES: The purpose of this study was to investigate the role of a low- dose intrathecal fluorescein injection in detection of CSF fistula and potential adverse effects of this technique. MATERIALS AND METHODS: CSF rhinorrhea was repaired in 20 patients with an endoscopic endonasal technique. Intraoperative intrathecal fluorescein injection was used for localization of the site of the CSF leak. The accuracy rate of leakage site identification and the incidence of complications and recurrences were recorded. RESULTS: Intrathecal administration of fluorescein demonstrated CSF leakage in 18 of the 20 patients (90%). There were no intraoperative complications. Definitive closure of the CSF leakage site was achieved in 16 patients (80%) after the initial reconstruction. Recurrence occurred in four cases and all patients were free of CSF leakage after the second surgical attempt. CONCLUSIONS: The present study suggested that a low dose of intraoperative intrathecal fluorescein administration is a safe and sensitive method for localization of CSF leakage sites. PMID- 23641739 TI - Chromosomal abnormalities in amenorrhea: a retrospective study and review of 637 patients in South India. AB - BACKGROUND: The aim of the present study was to investigate the chromosomal abnormalities and to identify the most prevalent or frequent type of chromosomal abnormalities in cases of amenorrhea from the southern region of India. METHODS: A total of 637 cases with amenorrhea were analyzed using G- banding, C-banding, Silver staining, and fluorescence in situ hybridization was done wherever necessary. RESULTS: Out of the 637 cases involved in our study, 132 abnormalities were detected. The incidence of chromosomal abnormalities in cases with primary and secondary amenorrhea was around 20.7 %. In addition to the numerical anomalies, various structural aberrations of the X chromosome like deletions, isochromosomes, duplications, ring chromosome, and also male karyotype were detected. CONCLUSION: Review of the literature and overall incidence of chromosomal abnormalities in patients with amenorrhea suggests the need for cytogenetic analysis to be performed in all the cases referred for amenorrhea with or without short stature. Precise identification of chromosomal abnormalities helps in confirming the provisional diagnosis; it helps the secondary amenorrhea patients in assisted reproduction and to understand the clinical heterogeneity involved and in efficient genetic counseling. PMID- 23641740 TI - The short- and long- term effects of estrogen deficiency on apoptosis in musculoskeletal tissues: an experimental animal model study. AB - BACKGROUND: Estrogen is the major sex steroid affecting the growth, remodeling, and homeostasis of the female skeleton. Estrogen loss in postmenopausal women leads to osteoporosis. The aim of this study was to evaluate the early and long- term effects of estrogen loss on bones, tendons, muscles, and menisci in ovariectomized rats. METHODS: Fifteen rats were randomized into three groups of five animals each. The first group was the control group with no additional surgical procedure, but the rest (groups 2 and 3) were bilaterally ovariectomized . All animals in the group 2 were sacrificed at 14th week to evaluate the short- term effect, and all of other animals in the groups 1 and 3 were sacrificed at 28th week to analyze the long- term effect of estrogen loss in the ovariectomized group and to control with the group 1. Quadriceps muscles, Achilles tendons, menisci, and femur cortical bones from both lower extremities were taken. The amount of apoptosis was measured. RESULTS: There was a significant increase in cell apoptosis in bones, muscles, and tendons with insignificant increase in cell apoptosis in menisci at early and late periods in rats with ovariectomies than the control. CONCLUSION: The results indicated that estrogen loss after ovariectomy does not only affect bones; it may also increase cell apoptosis in different tissues such as muscles, tendons, and menisci. PMID- 23641741 TI - State's pull-through for total colonic aganglionosis and GI dismotility. AB - BACKGROUND: Total colonic aganglionosis (TCA) is present in 4% - 5% of the patients with Hirschsprung's disease and has a high surgical mortality rate between 13% - 23%. Diagnosis and treatment of TCA is still a major challenge for pediatric surgeons. Many techniques with several advantages and disadvantages were established for its treatment. We have performed State's pull-through as total colectomy and ileo-proctostomy with long posterior rectal myotomy in TCA and severe dysmotility disorders. METHODS: In this retrospective study, 13 patients with TCA were evaluated from 1992 through 2012 in two pediatric surgery centers, which consisted of 10 TCA, one intestinal neuronal dysplasia (IND), and two chronic intestinal pseudo- obstruction syndrome (CIP). All patients underwent total colectomy, resection of part of the involved small intestine, and rectal anastomosis in one layer with 4/0 vicryl with long posterior rectal myotomy. All patients had preoperative barium enema and rectal biopsy for diagnosis. Leveling ileostomy was performed in 12 patients and mid-jejunostomy in one patient. In two of 13 children, proximal diverting loop ileostomy was established after definitive operation. In three patients, trans-rectal myotomy was needed two weeks after the initial operation. RESULTS: All patients were females with the age ranging from six months to six years. State's pull-through was carried out for all (the mean age of definitive procedure was 5.1 months). Rectal biopsy of 10 patients reported no ganglion cells of which one had extended aganglionosis to mid- jejunum, one had IND, and two had ganglionicbowel bowel with clinical presentation of CIP. The follow- up period was from six months to 10 years (the mean follow- up period was 10 months). There were no significant complications in 12 patients except episodes of diarrhea and severe dehydration which needed hospitalization. One patient with mid- jejunum aganglionosis had severe failure to thrive and needed repeated hospitalization for parenteral nutrition. All patients had acceptable bowel function following operation (two to six times a day). Now, five of the 13 patients are above the age of toilet training, having voluntary bowel movement with little or no medication (Leopromid). CONCLUSION: State's pull-through is recommended in all cases of TCA and severe dysmotility problems of the colon. This technique is less difficult to perform, and avoids the complications and disadvantages of removal of the rectum and has satisfactory results. PMID- 23641742 TI - Interaction between morphine and noradrenergic system of basolateral amygdala on anxiety and memory in the elevated plus-maze test based on a test-retest paradigm. AB - BACKGROUND: The amygdala is the key brain structure for anxiety and emotional memory storage. We examined the involvement of beta-adrenoreceptors in the basolateral amygdala (BLA) and their interaction with morphine in modulating these behaviors. METHODS: The elevated plus-maze has been employed for investigating anxiety and memory. Male Wistar rats were used for this test. We injected morphine (4, 5, and 6 mg/kg) intraperitoneally, while salbutamol (albuterol) (1, 2, and 4 MUg/rat) and propranolol (1, 2, and 4 MUg/rat) were injected into the BLA. Open- arms time percentage (%OAT), open- arms entry percentage (%OAE), and locomotor activity were determined by this behavioral test. Retention was tested 24 hours later. RESULTS: Intraperitoneal injection of morphine (6 mg/kg) had an anxiolytic-like effect and improvement of memory. The highest dose of salbutamol decreased the anxiety parameters in test session and improved the memory in retest session. Coadministration of salbutamol and ineffective dose of morphine presenting anxiolytic response. In this case, the memory was improved. Intra-BLA administration of propranolol (4 MUg/rat) decreased %OAT in the test session, while had no effect on memory formation. Coadministration of propranolol and morphine (6 mg/kg) showed an increase in %OAT. There was not any significant change in the above- mentioned parameter in the retest session. Coadministration of morphine and propranolol with the effective dose of salbutamol showed that propranolol could reverse anxiolytic like effect. CONCLUSION: We found that opioidergic and beta-adrenergic systems have the same effects on anxiety and memory in the BLA; but these effects are independent of each other. PMID- 23641743 TI - The role of mother's oral and vaginal yeasts in transmission of Helicobacter pylori to neonates. AB - BACKGROUND: Oral cavity has been proposed as an important reservoir of H.pylori, being implicated in bacterial transmission through oral-oral route. However, some investigators believe that the newborn acquires H.pylori from mother through vaginal delivery. In this study, oral and vaginal yeasts were examined for the intracellular occurrence of H.pylori and their possible role in bacterial transmission. METHODS: Sixty nine oral and vaginal yeasts from expecting mothers (39 oral and 30 vaginal) and seven oral yeasts from neonates(6/46 vaginal delivery, 1/43 cesarean) were identified and studied by light and fluorescent microscopy for observing the intracellular bacterium-like bodies(BLBs). Whole DNAs of yeasts were recruited for detection of H.pylori-specific genes. Urea breath test (UBT) was performed for detection of H.pylori infection in mothers. Stool antigen test (SAT) was used for detection of H.pylori antigens in infants' stool at birth and six months of age. RESULTS: Oral yeasts were isolated more frequently from normally-delivered neonates. The frequency of H.pylori genes in mothers' vaginal yeasts was significantly higher than in mothers' oral yeasts. A significant correlation was found between the occurrence of H.pylori genes in vaginal yeasts and that in neonates' oral yeasts, occurrence of H.pylori genes in mothers' vaginal yeasts or neonates' oral yeasts, and UBT+ results in mothers. CONCLUSION: C.albicans which colonizes the oral cavity of neonates through vaginal delivery or contact with environment or healthcare workers could be an important reservoir of H.pylori. Vaginal yeasts are more potent in accommodating H.pylori than oral yeasts. Accordingly, vaginal yeast is proposed as the primary reservoir of H.pylori which facilitates H.pylori transmission to neonates. PMID- 23641744 TI - Sample size calculation for epidemiologic studies: principles and methods. AB - This paper discusses the statistical principles, methods, and software programs used to calculate sample size. In addition, it reviews the practical challenges faced in calculating sample size. We show that because of such challenges, statistical calculations often do not provide us with a clear-cut number for the study sample size; rather they suggest a range of reasonable numbers. The paper also discusses several important nonstatistical considerations in determination of sample size, such as novelty of the study and availability of resources. PMID- 23641745 TI - Ulnar variance in scaphoid nonunion. AB - BACKGROUND: Negative ulnar variance can be a risk factor in Kienbock's disease, wrist instability, and scaphoid bone fracture. This study focused on the ulnar variance in wrists with scaphoid bone nonunion. METHODS: We retrospectively reviewed posteroanterior wrist radiographs of 65 patients who were diagnosed as established scaphoid nonunion and underwent open reduction and bone grafting between 2005 and 2010. We used reference radiographs from contralateral wrists of 65 consecutive skeletally- mature patients with distal radius fracture as the control group and then measured ulnar variance and compared it in both groups. RESULTS: Ulnar variance was measured in standard posteroanterior wrist X-rays of 65 scaphoid nonunion and 65 normal controls. Twenty five patients (38.5%) in the scaphoid nonunion group had negative ulnar variance, and the mean value was -0.26 (+/- 1.24) mm (range: -3, +2). In the control group, 15 subjects (23.1 %) had an ulnar minus wrist, and the mean ulnar variance was + 0.54 (+/- 1.47) mm (range: 3, +4) .The difference in ulnar variance was significant between the two groups (P-value = 0.001). CONCLUSION: Ulnar variance may influence developing of nonunion process in scaphoid bone fracture. PMID- 23641746 TI - Disseminated cryptococcosis with hepatic dysfuction as the initial manifestation in an immunocompetent adult. AB - Disseminated cryptococcosis is rare in immunocompetent hosts and hepatic manifestations as the presenting feature is further rare. We report a case of disseminated cryptococcosis with hepatic involvement as an initial manifestation in a previously healthy, immunocompetent adult. A young married female presented with progressive jaundice, anorexia, weightloss, cough with expectoration, and hepatosplenomegaly. Biochemical profile showed liver function derangement with increased transaminases, alkaline phosphatase, bilirubin with deranged coagulation assay, and decreased albumin. The patient was treated initially for disseminated tuberculosis with associated sepsis, but she succumbed on the third day. Diagnosis of cryptococcosis was made on the basis of sputum culture, serology, and liver histopathology. PMID- 23641747 TI - Congenital lens dislocation and fatal cerebral vein thrombosis in a patient with homocysteinemia: a lesson for urgent screening of pediatric population. AB - Congenital homocysteinemia is a genetic disease with various clinical manifestations such as thrombosis, lens dislocation and mental retardation and osteoporosis, so early diagnosis is important for decreasing the mortality and morbidity especially in pediatric populations. Here we describe a child with a presentation of coma with a past history of lens operation with unfortunate fatal clinical course, and a final diagnosis of congenital homocysteinemia. PMID- 23641748 TI - Cryptogenic myocardial infarction in young patients: which is the optimal diagnostic and therapeutic management? AB - A 31-year-old athlete was admitted to our hospital for previous inferior myocardial infarction (MI), diagnosed by transthoracic echocardiography, myocardial scintigraphy, and cardiac magnetic resonance, while coronary angiography revealed normal coronary arteries. Laboratory investigations excluded acquired or inherited thrombophilia, immunologic disorders, cardiotropic agents infection, and drug abuse. Antiplatelet therapy was started but, after 15 days, he was rehospitalized with diagnosis of multiple left renal infarctions. A transesophageal echocardiography (TEE) was so performed which excluded a right-to left shunt, suggestive of patent foramen ovale, or other cardioembolic sources in heart chambers and valve apparatus. Antiplatelet therapy was replaced with oral anticoagulants without any further embolic event at one-year follow-up. This case raises two important questions regarding young patients with cryptogenic MI. First, if TEE should be part of a complete diagnostic pathway; second, if oral anticoagulants should be preferred over antiplatelets for secondary prevention particularly when the cause of MI remains unknown. PMID- 23641749 TI - Acquired left coronary artery fistula draining to the right ventricle after myocardial infarction. AB - Coronary arteriography performed in a 42-year-old male patient showed communications from the left anterior descending artery to the right ventricle one month after a myocardial infarction. The area of communication did not correspond to the site of the infarction as established by electrocardiogram and previous angiography. Exactly how the fistula developed in our case remains unknown. Angiogenesis also suggests that myocardial infarction can lead to spontaneous formation of these coronary anomalies. PMID- 23641750 TI - Solitary huge intrahepatic mass (extramedullary hematopoiesis). PMID- 23641751 TI - Synthesis of differentially substituted 2-aminoimidazolidines via a microwave assisted tandem Staudinger/aza-Wittig cyclization. AB - A new route for the construction of 2-aminoimidazolidines including analogues of the alpha2 adrenergic agonist drug clonidine is elaborated. The key step is an intramolecular microwave-assisted Staudinger/aza-Wittig cyclization of an in situ generated urea intermediate (formed by the reaction of beta-amino azide and isocyanate) upon treatment with Bu3P or polymer-supported phosphine reagent, allowing the introduction of various substituents at the N1 and the 2-amino function. Furthermore, a useful one-pot Staudinger/aza-Wittig/Buchwald-Hartwig protocol leading to bicyclic guanidines has been elaborated. PMID- 23641752 TI - Itraconazole: an update on pharmacology and clinical use for treatment of invasive and allergic fungal infections. AB - INTRODUCTION: Fungal infections are a major source of global morbidity and mortality. Itraconazole is a triazole antifungal agent that is widely used for the prevention and treatment of fungal infection. While newer antifungal agents are now available, itraconazole is an orally bioavailable agent with broad spectrum antifungal activity. Itraconazole remains a useful drug for the management of allergic and invasive mycoses worldwide. AREAS COVERED: This article provides a summary of the pharmacokinetics, pharmacodynamics and clinical uses of itraconazole. Additionally, the authors summarise the safety and recently described toxicodynamics and discuss the value of therapeutic drug monitoring (TDM) with itraconazole. The following search criteria were constructed in order to identify relevant literature using PubMed and Ovid-MEDLINE: itraconazole, triazole, pharmacokinetics, pharmacodynamics, toxicodynamics and TDM. Relevant abstracts and articles identified from reviewing secondary citations were additionally retrieved and included if relevant. EXPERT OPINION: Itraconazole remains an important agent in the prevention and treatment of fungal infection. Itraconazole has a broad-spectrum of activity and is available in both an intravenous and oral form making long-term use in chronic mycoses practical. Itraconazole is widely used for the treatment of endemic fungal infections. Pharmacokinetic variability and clinically important drug interactions make TDM of itraconazole an important consideration. PMID- 23641753 TI - Continued non-compliance with the American College of Surgeons recommendations to decrease infectious exposure in the operating room: why? AB - BACKGROUND: The American College of Surgeons (ACS) Statement on Sharps Safety recommends the use of double gloving (DG), hands-free zone (HFZ), and blunt-tip suture needles (BTSN) in the operating room to decrease needlestick injuries. Despite this endorsement, compliance is low. This survey determined the perceptions, attitudes, and barriers to compliance with these guidelines. METHODS: A survey using a voluntary convenience sample of surgical staff members in which queries related to understanding of the ACS recommendations were posed. A total of 107 of the 324 surveys were completed and returned, for a response rate of 33%. Most respondents were residents (64%) or attending surgeons (29%). RESULTS: Respondents were most familiar with recommendations for DG (58% of residents and 68% of attendings) and HFZ (61% for both groups) but less so for BTSN (48% of residents and 52% of attendings). More than 50% of the staff believed that DG decreased the risk of needlesticks, yet fewer than half used DG more than 75% of the time. Half believed that HFZ protected from sticks, yet fewer than 10% used it at least 75% of the time. Fewer than 50% believed that BTSN minimizes the risk of injury, with fewer than 10% of respondents using them at least 75% of the time. Reasons for non-compliance included decreased tactile sensation with DG, lack of training with HFZ, and lack of availability of BTSN. CONCLUSIONS: To improve compliance with the ACS recommendations, institutions must improve awareness of the guidelines and the benefits associated with compliance and remove barriers to their incorporation into standard practice. PMID- 23641754 TI - Splenectomy for splenic abscess. PMID- 23641756 TI - Making graphene holey. Gold-nanoparticle-mediated hydroxyl radical attack on reduced graphene oxide. AB - Graphene oxide (GO) and reduced graphene oxide (RGO) have important applications in the development of new electrode and photocatalyst architectures. Gold nanoparticles (AuNPs) have now been employed as catalyst to generate OH(*) and oxidize RGO via hydroxyl radical attack. The oxidation of RGO is marked by pores and wrinkles within the 2-D network. Nanosecond laser flash photolysis was used in conjunction with competition kinetics to elucidate the oxidative mechanism and calculate rate constants for the AuNP-catalyzed and direct reaction between RGO and OH(*). The results highlight the use of the AuNP-mediated oxidation reaction to tune the properties of RGO through the degree of oxidation and/or functional group selectivity in addition to the nanoporous and wrinkle facets. The ability of AuNPs to catalyze the photolytic decomposition of H2O2 as well as the hydroxyl radical-induced oxidation of RGO raises new issues concerning graphene stability in energy conversion and storage (photocatalysis, fuel cells, Li-ion batteries, etc.). Understanding RGO oxidation by free radicals will aid in maintaining the long-term stability of RGO-based functional composites where intimate contact with radical species is inevitable. PMID- 23641755 TI - Characterization of the biofilm forming ability of Staphylococcus pseudintermedius from dogs. AB - BACKGROUND: Staphylococcus pseudintermedius is an opportunistic pathogen of dogs and has emerged as a leading cause of skin, wound and surgical site infections worldwide. Methicillin resistance is common and clinical infections as a result of methicillin-resistant S. pseudintermedius (MRSP) pose a clinical challenge. In other staphylococci, biofilm formation has been shown to be a virulence factor for infection, however, it has received little attention in S. pseudintermedius. The objectives of this study were to evaluate the biofilm forming ability of clinical isolates of S. pseudintermedius obtained from dogs using phenotypic and genotypic techniques. RESULTS: 96% (136/140) of S. pseudintermedius isolates were classified as strong or moderate biofilm producers, with the majority of isolates being able to produce biofilm. There was no difference in biofilm formation between MRSP and MSSP (p=0.8), amongst isolates from clinical infections compared with isolates obtained from colonized dogs (p=0.08), and between isolates from sequence type (ST) 71 and ST 68 (P=0.09). icaA was detected in 77.9% (109/140) of isolates and icaD was detected in 75.7% (106/140) of isolates. Scanning electron microscopic evaluation of S. pseudintermedius biofilm production revealed aggregates of cocci and irregularly produced extracellular polymeric matrix. CONCLUSION: The majority of S. pseudintermedius isolates evaluated in this study were able to produce biofilm and this may be an important virulence factor in the rapid emergence of this bacterium in veterinary hospitals worldwide. Further study into the mechanisms of biofilm formation by S. pseudintermedius is warranted. PMID- 23641758 TI - Gallery. Angiokeratomas and lymphangiomas on leg. PMID- 23641759 TI - Use of a mobile device app: a potential new tool for poster presentations and surgical education. AB - INTRODUCTION: Poster presentations are an important part of presenting scientific techniques and represent an integral part of conferences and meetings. Traditionally, paper format is used; however, in recent years electronic posters and other methods, such as incorporating a DVD player as part of a poster, have been successfully used. We describe and demonstrate the use of an augmented reality application for smartphones and tablets as a potential future addition to the presentation of scientific work and surgical techniques in poster format. This method allows the audience to view surgical techniques and research as 3D animation or video by using a trigger image in a poster/journal/text book via their smart device. METHOD: The author used the free Aurasma(c) application available on both iOS and Android 2.2 and higher platforms from iTunes App Store and Google Play. Once installed, any user with a 3G or WiFi connection via a smart phone or tablet can subscribe to the Medical Illustration channel for free. The user can then scan the trigger image placed on a poster with a mobile device to view videos, animations or 3D data. Further interaction can direct the user to a website for more content. RESULT: The author has trialled this method at a regional burns and plastic surgery centre and found it to be highly effective. CONCLUSION: The use of this novel method adds a new dimension to the presentation of scientific work at surgical and medical conferences and as part of journals and textbooks by permitting users to view scientific data and techniques on mobile devices as videos or as three dimensional environments at their own leisure. PMID- 23641760 TI - Creating pathology models from MRI data: a comparison of virtual 3D modelling and rapid prototyping techniques. AB - This paper discusses a pilot study in collaboration between the Centre for Anatomy and Human Identification and the Pathology Department at Ninewells Hospital, Dundee. Anonymised patient MRI data depicting renal cancer was used to create a virtual 3D model and two rapid prototype models of the kidneys and surrounding anatomy. A questionnaire was conducted to collect feedback from tutors and students in order to evaluate the models and determine user preference. It was found that the majority preferred the physical models to the virtual model. PMID- 23641761 TI - Photography of the histological and radiological analysis of the ligaments of the distal radioulnar joint. AB - This project was undertaken as part of the PhD research project of Paul Malone, Pricipal Investigator, Covance plc, Harrogate. Mr Malone approached the photography department for involvement in the study with the aim of settling the current debate on the anatomical and histological features of the distal radioulnar ligaments by capturing the anatomy photographically throughout the process of dissection via a microtome. The author was approached to lead on the photographic protocol as part of her post-graduate certificate training at Staffordshire University. High-resolution digital images of an entire human arm were required, the main area of interest being the distal radioulnar joint of the wrist. Images were to be taken at 40 MUm intervals as the specimen was sliced. When microtomy was undertaken through the ligaments images were made at 20 MUm intervals. A method of suspending a camera approximately 1 metre above the specimen was devised, together with the preparation for the capture, processing and storage of images. The resulting images were then to be subject to further analysis in the form of 3-Dimensional reconstruction, using computer modelling techniques and software. The possibility of merging the images with sequences obtained from both CT & MRI using image handling software is also an area of exploration, in collaboration with the University of Manchester's Visualisation Centre. PMID- 23641762 TI - Transillumination imaging of intraocular tumours. AB - The purpose of this paper is to discuss a recently described modification of a standard photo slit lamp system for ocular transillumination, with special emphasis on the light transmission through the eye wall and the photographic technique. Transillumination photography was carried out with the Haag-Streit Photo-Slit Lamp BX 900 (Haag-Streit AG, Koeniz, Switzerland). After having released the background lighting optic fibre cable from its holder, the patient was positioned at the slit lamp, and the fibre tip was gently pressed against the sclera or the cornea of the patient's eye. During about 1/1000 of a second, the eye was illuminated by the flash and the scleral shadow of the tumour was exposed to the camera sensor. The images were of good diagnostic quality, making it easy to outline the tumours and to evaluate the involvement of intraocular structures. None of the examined patients experienced discomfort or negative side effects. The method is recommended in cases where photographic transillumination documentation of intraocular pathologies is considered important. PMID- 23641763 TI - Serial photography and Wood's light examination as an aid to the clinical diagnosis of dermatitis artefacta. AB - A patient is described with dermatitis artefacta, which is a common psychocutaneous disorder whereby a fully-aware patient self-inflicts injury to their skin. The motives for their behaviour can vary and the patient always tries to hide the responsibilities for their actions. In this case report, serial use of standardised photography provided strong evidence to support the diagnosis of dermatitis artefacta. The fluorescent properties of Trimovate(r) Cream under Wood's light examination corroborated the diagnosis. Trimovate(r) Cream was applied to the skin surrounding the injuries and the limb was occluded with four layers of bandages. Traces of Trimovate(r) Cream were seen under Wood's light on the outer layers of the bandage. This suggested transfer of the cream from the occluded skin surface by the patient's fingers whilst tampering with the dressings. This case report shows how serial photography and imaging using ultraviolet (UV) fluorescence can provide evidence to support the diagnosis of dermatitis artefacta. PMID- 23641764 TI - Dermatomyositis--a case study. PMID- 23641765 TI - Preference for detail in medical illustrations amongst professionals and laypersons. AB - This study investigated the preferences of medical professionals and laypersons with respect to the level of detail shown in medical illustrations (i.e. graphic art shown in patient education materials) and the complexity of the subject being depicted (i.e. a visually simple versus a visually complex subject). Additionally, respondent's age, gender, and art background were recorded to yield further insight. The results showed that generally there was preference for high detail (complex) illustrations between the two groups, though the professionals group was somewhat more diverse in their choices. The other variables had no impact on illustration preference. PMID- 23641766 TI - Gallery. Medical illustrations. PMID- 23641770 TI - Current issues: consent for clinical photography. PMID- 23641773 TI - Professional development ?in medico-legal photography: understanding the ?importance of a clinical ?photographers role. PMID- 23641774 TI - Volatilization of trichloroethylene from trees and soil: measurement and scaling approaches. AB - Trichloroethylene (TCE) volatilization from leaves, trunk, and soil was measured to assess the significance of these pathways from phytoremediation sites at Travis and Fairchild Air Force Bases. Measurements were scaled temporally and spatially to estimate the annual volatilization of TCE at the Travis (0.82 +/- 0.51 kg/yr) and Fairchild sites (0.014 +/- 0.008 kg/yr). Volatilization was primarily through the leaf (0.34 +/- 0.16 kg/yr at Travis and 0.01 +/- 0.06 kg/yr at Fairchild) and soil (0.48 +/- 0.36 kg/yr at Travis, 0.003 +/- 0.002 kg/yr at Fairchild) pathways. The larger volatilization estimate at Travis was expected because of the site's higher TCE groundwater concentrations. Using groundwater data collected in 2004 and 2009, calculations show that over the 5 year period, 1.7 and 0.015 kg of TCE were removed each year at the Travis and Fairchild sites, respectively. On the basis of the scaled field measurements, volatilization from the leaves and soil may play a significant role in TCE removal at both sites. Daily and seasonal variations were not addressed during the limited daytime sampling events, but the methods described here provide a novel and practical framework for evaluating the potential importance of volatilization of TCE and similar compounds at phytoremediation sites. PMID- 23641776 TI - Rheumatic symptoms in childhood leukaemia and lymphoma-a ten-year retrospective study. AB - BACKGROUND: The initial symptoms of childhood leukaemia and lymphoma are often similar to those of juvenile idiopathic arthritis (JIA). In our study, we analyzed the frequency and characteristics of musculoskeletal complaints as the initial presenting symptoms of newly diagnosed leukaemia and lymphoma patients in the past 10 years in our clinic. METHODS: Using the Hungarian Tumour Register, we performed a retrospective analysis of the medical records of 166 new leukaemia and 95 new lymphoma pediatric patients treated from 1999 to 2009 at the 2nd. Dept. of Paediatrics of the Semmelweis University in Budapest. RESULTS: Twenty percent of the leukaemic (33 children) and 2% of the lymphoma patients (2 children) had musculoskeletal symptoms at first presentation. Two-thirds of both groups of patients had other general symptoms like fever and/or fatigue. The hip was the most frequently affected joint (7/33) in the leukaemic patients. Twenty four percent of all the children had been previously evaluated by an orthopaedist; 12% had visited another rheumatologist prior to diagnosis. Imaging had been done in an unexpectedly low number of patients prior to referral to our unit (radiographs: 16 or 48%, ultrasound: 5 patients or 15%). Radiographs of the affected joints were abnormal in only one case (1/16, 6%). The joint ultrasound was abnormal in only three children of 5 studied (3/5, 60%). Anaemia (26/32, 6%), thrombocytopenia (78%) and LDH elevation (3-4 times the normal count) were frequent in the leukaemic patients. Half of the cases had a normal leukocyte count. The lymphoma group had similar results. Two patients of the leukaemia group received steroid treatment before the final diagnosis. Severe pain out of proportion to physical findings is another clue. CONCLUSIONS: Haematologic malignancies must be excluded before initiation of therapy for childhood arthritis among children presenting with musculoskeletal signs and symptoms, particularly in atypical cases. Malignancies are to be suspected when pain is disproportionately severe compared to the physical examination findings, and when anaemia, thrombocytopenia, and an elevated LDH level are present. Diagnosing leukaemia early is important because the use of steroids and immunosuppressive medications may mask and delay its diagnosis. Additionally, pre-treatment of presumed JIA patients with these drugs who eventually are diagnosed to have a malignancy may lead to the malignancy being steroid-resistant and more difficult to treat. PMID- 23641775 TI - Sociodemographic and health-related predictors of self-reported mammogram, faecal occult blood test and prostate specific antigen test use in a large Australian study. AB - BACKGROUND: While several studies have examined factors that influence the use of breast screening mammography, faecal occult blood tests (FOBT) for bowel cancer screening and prostate specific antigen (PSA) tests for prostate disease in Australia, research directly comparing the use of these tests is sparse. We examined sociodemographic and health-related factors associated with the use of these tests in the previous two years either alone or in combination. METHODS: Cross-sectional analysis of self-reported questionnaire data from 96,711 women and 82,648 men aged 50 or over in The 45 and Up Study in NSW (2006-2010). RESULTS: 5.9% of men had a FOBT alone, 44.9% had a PSA test alone, 18.7% had both tests, and 30.6% had neither test. 3.2% of women had a FOBT alone, 56.0% had a mammogram alone, 16.2% had both and 24.7% had neither test. Among men, age and socioeconomic factors were largely associated with having both FOBT and PSA tests. PSA testing alone was largely associated with age, family history of prostate cancer, health insurance status and visiting a doctor. Among women, age, use of hormone replacement therapy (HRT), health insurance status, family history of breast cancer, being retired and not having a disability were associated with both FOBT and mammograms. Mammography use alone was largely associated with age, use of HRT and family history of breast cancer. FOBT use alone among men was associated with high income, living in regional areas and being fully-retired and among women, being fully-retired or sick/disabled. CONCLUSIONS: These results add to the literature on sociodemographic discrepancies related to cancer screening uptake and highlight the fact that many people are being screened for one cancer when they could be screened for two. PMID- 23641777 TI - Insecticide resistance status of Anopheles gambiae s.s population from M'Be: a WHOPES-labelled experimental hut station, 10 years after the political crisis in Cote d'Ivoire. AB - BACKGROUND: An experimental hut station built at M'Be in 1998 was used for many years for the evaluation of insecticidal product for public health until the civil war broke out in 2002. Breeding sites of mosquitoes and selection pressure in the area were maintained by local farming practices and the West African Rice Development Association (WARDA, actually AfricaRice) in a large rice growing area. Ten years after the crisis, bioassays, molecular and biochemical analyses were conducted to update the resistance status and study the evolution of resistance mechanisms of Anopheles gambiae s.s population. METHODS: Anopheles gambiae s.s larvae from M'Be were collected in breeding sites and reared until emergence. Resistance status of this population to conventional insecticides was assessed using WHO bioassay test kits for adult mosquitoes, with 10 insecticides belonging to pyrethroids, pseudo-pyrethroid, organochlorides, carbamates and organophosphates with and without the inhibitor piperonyl butoxyde (PBO). Molecular and biochemical assays were carried out to identify the L1014F kdr, L1014S kdr and ace-1(R) alleles in individual mosquitoes and to detect potential increase in mixed function oxidases (MFO) level, non-specific esterases (NSE) and glutathione S-transferases (GST) activities. RESULTS AND DISCUSSION: Anopheles gambiae s.s from M'Be exerted high resistance levels to organochlorides, pyrethroids, and carbamates. Mortalities ranged from 3% to 21% for organochlorides, from 50% to 75% for pyrethroids, 34% for etofenprox, the pseudo pyrethroid, and from 7% to 80% for carbamates. Tolerance to organophosphates was observed with mortalities ranging from 95% to 98%. Bioassays run with a pre exposition of mosquitoes to PBO induced very high levels of mortalities compared to the bioassays without PBO, suggesting that the resistance to pyrethroid and carbamate relied largely on detoxifying enzymes' activities. The L1014F kdr allelic frequency was 0.33 in 2012 compared to 0.05 before the crisis in 2002. Neither the L1014S kdr nor ace-1(R) mutations were detected. An increased activity of NSE and level of MFO was found relative to the reference strain Kisumu. This was the first evidence of metabolic resistance based resistance in An. gambiae s.s from M'Be. CONCLUSION: The An. gambiae s.s population showed very high resistance to organochlorides, pyrethroids and carbamates. This resistance level relied largely on two major types of resistance: metabolic and target-site mutation. This multifactorial resistance offers a unique opportunity to evaluate the impact of both mechanisms and their interaction with the vector control tools currently used or in development. PMID- 23641778 TI - Patient satisfaction in a Moroccan emergency department. AB - BACKGROUND: Measuring healthcare quality and improving patient satisfaction have become increasingly prevalent, especially among healthcare providers and purchasers of healthcare. Currently, research is interested to the satisfaction in several areas, and in various cultures. The aim of this study was; to confirm the reliability and validity of the Arabic version of the Emergency Department Quality Study (EDQS), to evaluate patient satisfaction with emergency care, and to determine associated factors with patient satisfaction. METHODS: A survey of socio demographic, visit and health characteristics of patients, conducted in emergency department (ED) of a Moroccan University Hospital during 1 week in February 2009. The EDQS was performed with patients who were discharged from ED. The psychometric properties of the EDQS were tested. Factors influencing patient satisfaction were identified using ordinal logistic regression. RESULTS: A total of 212 patients were enrolled. The Arabic version of the EDQS showed excellent reliability and validity. Sixty six percent of participants were satisfied with overall care, and 69.8% would return to our unit. The most patient-reported problems were about waiting time and test results. Variables associated with greater satisfaction with ED care were: emergent (OR: 0.15; 95% CI = 0.04-0.31; P < 0.001), or urgent patients (OR: 0.35; 95% CI = 0.15-0.86; P = 0.02) compared to non-urgent patients, and waiting time less than 15 min (OR: 0.41; 95% CI = 0.23 0.75; P = 0.003). Variables associated with lesser satisfaction were: distance patient's home hospital <=10Kilometers (OR: 2.64; 95% CI = 1.53-4.53; P < 0.001), weekday's admissions (OR: 2.66; 95% CI = 1.32 to 5.34; P < 0.006), and educational level; with secondary (OR: 5.19; 95% CI = 2.04-13.21; P < 0.001) primary (OR: 3.04; 95% CI = 1.10-8.04; P = 0.03) and illiterate patients (OR: 2.53; 95% CI = 1.02-6.30; P = 0.03) were less satisfied compared to those with high educational level. CONCLUSION: Medical staff needs to consider different interactions between those predictive factors in order to develop some supportive tools. PMID- 23641779 TI - "Effectiveness of interventions in reducing pain and maintaining physical activity in children and adolescents with calcaneal apophysitis (Sever's disease): a systematic review". AB - BACKGROUND: Calcaneal apophysitis, also commonly known as sever's disease, is a condition seen in children usually aged between 8-15 years. Conservative therapies, such as taping, heel lifts and orthotic intervention are accepted management practices for calcaneal apophysitis, though there is very little high quality research examining the efficacy of such treatment modalities. Previous narrative literature reviews and opinion pieces provide some evidence for the use of heel raises or orthoses. The aim of this manuscript was to complete a systemic review on the treatment options for calcaneal apophysitis as measured by pain reduction and maintenance of physical activity. METHODS: A search strategy completed by two reviewers examined nine databases from inception to May 2012. Search terms included heel pain, children, adolescent, calcaneal apophysitis, sever's disease, treatment, and management (full text publications, human studies). Systematic reviews, randomised control trials, case series, and case studies were included. The reference lists of the selected articles were also examined. The methodology, quality and risk of bias was examined and assessed using the PEDro scale. RESULTS: Nine articles were retrieved including three clinical trials involving randomisation, two case series, two retrospective case reviews, and two case reports. Effect size calculations and a meta analysis were unable to be completed due to the limited data reported within the literature. Numerous treatment options were reported throughout the literature, though few were examined against a control or alternate treatment option in well-designed trials. The limited evidence indicated that orthoses provided greater short-term pain relief than heel raises. Health practitioners should view these results with caution, as there were apparent methodological problems with the employed study design and limited follow-up of participants. CONCLUSION: There is limited evidence to support the use of heel raises and orthoses for children who have heel pain related to calcaneal apophysitis. Further research is needed to generate higher quality evidence with larger sample sizes, and validated measures of pain and function to establish effective treatment approaches for children with calcaneal apophysitis. PMID- 23641780 TI - Design, synthesis, and biological evaluation of pyridoquinazoline derivatives as potent epidermal growth factor receptor inhibitors. AB - Pyridoquinazolines have been synthesized, characterized, and tested for their in vitro epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory activity. The compounds were prepared from alkylideno/arylideno-bis-ureas. Their structures were elucidated on the basis of elemental analyses and spectral studies (infrared, nuclear magnetic resonance [1H NMR], fourier transform infrared spectroscopy [FTIR], and electron ionization mass spectrometry [EI-MS]). Three of the new compounds had IC50 values in the range of 4.5-11.0 nM. The cellular EGFR internalization response of selected compounds was evaluated using HeLa cells. Three halogenated derivatives had a pronounced effect in inhibiting EGFR internalization. PMID- 23641781 TI - Cell metabolism sets the differences between subpopulations of satellite cells (SCs). AB - BACKGROUND: We have recently characterized two distinct populations of Satellite Cells (SCs) that differ in proliferation, regenerative potential, and mitochondrial coupling efficiency and classified these in Low Proliferative Clones (LPC) and High Proliferative Clones (HPC). Herewith, we have investigated their cell metabolism and individuated features that remark an intrinsic difference in basal physiology but that are retrievable also at the initial phases of their cloning. RESULTS: Indeed, LPC and HPC can be distinguished for mitochondrial membrane potential (DeltaPsim) just after isolation from the fiber. This is matched by mitochondrial redox state measured via NAD+/NADH analysis and alternative respiratory CO2 production in cloned cells. All these parameters are accountable for metabolic differences reflected indeed by alternative expression of the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3). Also Ca2+ handling by mitochondria is different together with the sensitivity to apoptosis triggered via this pathway. Finally, according to the above, we were able to determine which one among the clones represents the suitable stem cell. CONCLUSIONS: These experimental observations report novel physiological features in the cell biology of SCs and refer to an intrinsic heterogeneity within which their stemness may reside. PMID- 23641782 TI - Effect of pre-operative neuromuscular training on functional outcome after total knee replacement: a randomized-controlled trial. AB - BACKGROUND: Total Knee Replacement (TKR) is the standard treatment for patients with severe knee osteoarthritis (OA). Significant improvement in pain and function are seen after TKR and approximately 80% of patients are very satisfied with the outcome. Functional status prior to TKR is a major predictor of outcome after the intervention. Thus, improving functional status prior to surgery through exercise may improve after surgery outcome. However, results from several previous trials testing the concept have been inconclusive after surgery. METHODS/DESIGN: In a randomized controlled trial (RCT) we will test the effect of a pre-operative neuromuscular training program versus an attention control program on lower extremity function - before and after surgery. We will enroll 80 participants, aged between 55-90 years, who are scheduled for TKR. In this single blinded RCT, the intervention group will receive a minimum of 8 and a maximum of 24 training sessions plus 3 educational sessions of the knee school. The control group will receive the 3 educational sessions only. Assessments are performed immediately before and after the intervention (before surgery), at 6 weeks, 3 months and 12 months (after surgery). The primary outcome will include the Chair Stand Test as a measure of leg strength and reaction time. Secondary outcomes are knee function and pain assessed with the self-reported Knee Injury and Osteoarthritis Outcome Score (KOOS). All measurements will be carried out by a specially trained physical therapist, blinded to group allocation. DISCUSSION: To our knowledge this is the first single-blinded RCT to test the effect of pre operative neuromuscular training plus knee school against knee school alone--on knee function and pain, assessed immediately after the interventions prior to surgery and repeatedly after surgery. TRIAL REGISTRATION: Clinical Trials NCT00913575. PMID- 23641783 TI - Antitumor activity of tumor-targeted RNA replicase-based plasmid that expresses interleukin-2 in a murine melanoma model. AB - Double-stranded RNA (dsRNA) has multiple antitumor mechanisms that may be used to control tumor growth. Previously we have shown that treatment of solid tumors with a plasmid that encodes Sindbis viral RNA replicase complex, pSIN-beta, significantly inhibited the growth of tumors in mice. In the present study, we evaluated the feasibility of further improving the antitumor activity of the pSIN beta plasmid by incorporating interleukin-2 (IL2) gene into the plasmid. The resultant pSIN-IL2 plasmid was delivered to mouse melanoma cells that overexpress the sigma receptor. Here we report that the pSIN-IL2 plasmid was more effective at controlling the growth of B16 melanoma in mice when complexed with sigma receptor-targeted liposomes than with the untargeted liposomes. Importantly, the pSIN-IL2 plasmid was more effective than pSIN-beta plasmid at controlling the growth of B16 melanoma in mice, and B16 tumor-bearing mice that were treated with pSIN-IL2 had an elevated number of activated CD4(+), CD8(+), and natural killer cells, as compared to those treated with pSIN-beta. The RNA replicase-based, IL2 expressing plasmid may have applications in melanoma gene therapy. PMID- 23641785 TI - Copper-catalyzed direct aryl quaternization of N-substituted imidazoles to form imidazolium salts. AB - Diaryliodonium salts are employed to directly quaternize N-substituted imidazoles by using a copper catalyst to construct aryl imidazolium salts in moderate to excellent yields. This transformation is tolerant to a broad range of functional groups and provides a straightforward, efficient, and versatile route to synthesize aryl imidazolium as well as triazolium salts, especially the unsymmetric version. PMID- 23641784 TI - Evidence of prescription of antidepressants for non-psychiatric conditions in primary care: an analysis of guidelines and systematic reviews. AB - BACKGROUND: Antidepressants (ADs) are commonly prescribed in primary care and are mostly indicated for depression. According to the literature, they are now more frequently prescribed for health conditions other than psychiatric ones. Due to their many indications in a wide range of medical fields, assessing the appropriateness of AD prescription seems to be a challenge for GPs. The aim of this study was to review evidence from guidelines for antidepressant prescription for non-psychiatric conditions in Primary Care (PC) settings. METHODS: Data were retrieved from French, English and US guideline databases. Guidelines or reviews were eligible if keywords regarding 44 non-psychiatric conditions related to GPs' prescription of ADs were encountered. After excluding psychiatric and non-primary care conditions, the guidelines were checked for keywords related to AD use. The latest updated version of the guidelines was kept. Recent data was searched in the Cochrane Database of Systematic Reviews and in PubMed for updated reviews and randomized control trials (RCTs). RESULTS: Seventy-eight documents were retrieved and were used to assess the level of evidence of a potential benefit to prescribing an AD. For 15 conditions, there was a consensus that prescribing an AD was beneficial. For 5 others, ADs were seen as potentially beneficial. No proof of benefit was found for 15 conditions and proof of no benefit was found for the last 9. There were higher levels of evidence for pain conditions, (neuropathic pain, diabetic painful neuropathy, central neuropathic pain, migraine, tension-type headaches, and fibromyalgia) incontinence and irritable bowel syndrome. There were difficulties in summarizing the data, due to a lack of information on the level of evidence, and due to variations in efficacy between and among the various classes of ADs. CONCLUSIONS: Prescription of ADs was found to be beneficial for many non-psychiatric health conditions regularly encountered in PC settings. On the whole, the guidelines were heterogeneous, seemingly due to a lack of trials assessing the role of ADs in treatment strategies. PMID- 23641786 TI - Increased serum interleukin-33 levels in patients with Graves' disease. AB - OBJECTIVE: Interleukin-33 (IL-33), a 30 kDa cytokine, is a member of IL-1 family. It is considered to be an autoimmune biomarker associated with T helper 2 (Th 2) response. gamma-interferon is also produced by T helper 1 (Th 1) cells to induce cellular responses. gamma-interferon is a 143-amino acid residue glycoprotein with several biological functions including potent anti-viral activity, stimulation of macrophage activity, modulation of Major Histocompatibilty Complex class I/class II expression, and regulation of a diversity of specific immune responses. The aim of this study was to investigate the serum levels of IL-33 and gamma-interferon in different thyroid disorders. METHODS: Twenty patients with Graves' disease, 21 patients with Hashimoto hypothyroidism, 21 euthyroid Hashimoto patients, and 27 control subjects were recruited to this study. Blood samples were drawn and IL-33 and gamma-interferon tests were analyzed from 89 participants. Serum IL-33 and gamma-interferon analyses were performed by enzyme linked immunosorbent assay. RESULTS: There was no statistically significant difference between groups for serum gamma-interferon levels. Serum IL-33 concentrations were significantly higher in Graves' disease group compared to the other groups (p<0.000) There was a positive correlation between serum IL-33 and free triiodothyronine (fT3) and thyroxine (fT4). Also, negative correlation between serum IL-33 and thyroid-stimulating hormone (TSH) was statistically significant (p<0.000). CONCLUSIONS: The correlation of serum IL-33 with thyroid hormone levels may be a useful indicator for Graves' disease. These findings may help to make evident the pathophysiologic processes of the autoimmune thyroid diseases and improve therapeutic methods. . PMID- 23641787 TI - Role of ionotropic glutamate receptors in the control of prolactin secretion by other neurotransmitters and neuropeptides at the level of the pituitary. AB - OBJECTIVE: Although prolactin (PRL) plays an important role in the milk production, it has also many other functions. PRL secretion can be inhibited by dopamine and stimulated by serotonin, thyrotropin releasing hormone (TRH), and vasoactive intestinal peptide (VIP). However, the exact mechanisms of PRL regulation are still not fully understood. Glutamate is also a potent elevator of PRL secretion. It has several receptors: ionotropic NMDA (N-methyl-D-aspartate) and non-NMDA as well as metabotropic receptors. Our interest was to find out whether endogenous glutamate may act at the hypophyseal level and affect the PRL regulating neurotransmitters (dopamine, serotonin, TRH, VIP). METHODS: MK-801 as NMDA blocker and GYKI52466 as a non-NMDA antagonist were used in this study. For dopamine and serotonin experiments intraperitoneal drug administration and blood sampling were applied. On the other hand, TRH and VIP effect on PRL secretion was studied in in vitro conditions by incubating them with a half 300*300nm choppered anterior pituitary gland of the adult male rats. RESULTS: The basal PRL levels were not influenced by the glutamate antagonists used either alone or combined in both in vivo and in vitro conditions. We failed to reveal interaction between dopamine-, serotonin-, and TRH-induced PRL rise and antagonists treatment. MK-801 had a significant inhibitory effect on VIP-induced PRL changes. CONCLUSIONS: Our data confirmed the regulatory role of dopamine, serotonin, and TRH on PRL secretion, however, the interaction between these and glutamatergic systems was not confirmed, at least not via the ionotropic receptors. On the other hand, the endogenous glutamate can through the NMDA receptor subtype contribute to the VIP induced PRL secretion at the level of the anterior pituitary. This regulation may be especially important during suckling and stress response when rapid release of PRL is required. PMID- 23641788 TI - G protein-coupled estrogen receptor1 (GPER1) may mediate Rho-kinase (ROCK-2) up regulation in coronary endothelial cells. AB - OBJECTIVE: Effect of estrogenic compounds and 17beta-estradiol (E2), which induces endothelial cell motility, was investigated on ROCK-2 expression in rat coronary vascular endothelial cells (CVEC). METHODS: The CVEC were isolated from the heart of Wistar rats by collagenase (0.04%) and incubated with E2 (1-100 nM), estrogen receptor alpha (ERalpha) agonist: propyl pyrazole triol (PPT, 10 nM); ERbeta agonists: (2,3-bis(4-hydroxyphenyl)-propionitrile, DPN, 10 nM) and E2 conjugate with bovine serum albumin (E2-BSA, 1 nM); and GPER1 agonist: G1 (100 nM). Furthermore, the effect of combination of E2 with estrogen receptors (ERs) antagonist and GPER1 agonist, ICI-182780 (10 uM), physiological estrogen antagonists: progesterone (P4, 10-100 nM) and testosterone (T, 10-100 nM); transcription inhibitor: actinomycin-D (1 ug/ml); GPER1 antagonist: G-15 (100 nM), superoxide dismutase, (SOD, 500 U/ml); Gi/o protein inhibitor: pertussis toxin (PTX, 100 ug/ml); and epidermal growth factor receptor (EGFR) blocker: AG 1478 (10 uM) was tested. After 24h incubation, ROCK-2 and GPER1 protein expressions were detected in the CVEC by Western-blotting. RESULTS: E2, ICI 182780, and G1 but not E2-BSA significantly up-regulated ROCK-2 expression, which was suppressed by actinomycin-D, PTX, AG-1478, and G-15. However, PPT and DPN had no effects on the ROCK-2 expression. ICI-182780, P4, T or SOD did not antagonize the E2 action. GPER1 expression was demonstrated in the CVEC. CONCLUSIONS: Estrogens could up-regulate ROCK-2 in the rat CVEC through GPER1 and EGFR transactivation. PMID- 23641789 TI - Long-term liquid nutrition intake and development of obesity: differences between young and adult rats. AB - OBJECTIVE: Obesity is particularly associated with an increased consumption of palatable fat and sugar dense food and beverages. Therefore, we examined the effect of a normocaloric liquid diet (Fresubin) with increased carbohydrate content (constituting 55% of calories) on development of obesity in different developmental periods in male Wistar rats. METHODS: Fresubin was provided to 3 groups of rats: the first group received Fresubin immediately after weaning (21st day of age) to the end of experiment (150th day of age) for 5 months; the second group was fed with Fresubin from weaning to adulthood (90th day of age) for 3 months; and the third group received Fresubin only in adulthood (from 90th to 150th day of age) for 2 months. The control group was fed with standard pellet chow from weaning to the end of the experiment. Body weight, food and water intake were periodically measured. After terminating the experiment, the adiposity index was determined. RESULTS: Rats fed with liquid nutrition showed increased energy intake and body weight in comparison with the control rats. Interestingly, while obesity in the juvenile rats developed as late as of 13 weeks after the Fresubin intake, the adult rats fed with liquid nutrition had significantly elevated the body weight already 2 weeks after starting the treatment. Increased adiposity index was observed in both groups of rats fed with Fresubin during the whole study as well as the adulthood. CONCLUSIONS: Our data indicate that feeding of male Wistar rats with a high carbohydrate normocaloric diet results in a substantial development of obesity. Moreover, exposure of juvenile individuals to obesogenic environment leads, after a certain "latent period", to the development of obesity that may reflect low protein content of used liquid diet or higher resistance of juvenile organism to the obesogenic factors. Finally, based on the data obtained we suggest that Fresubin, with respect to its properties, may serve as a diet for the development of obesity which may exemplify an "obesity model" applicable in small laboratory animals. PMID- 23641790 TI - Ependymal cells variations in the central canal of the rat spinal cord filum terminale: an ultrastructural investigation. AB - OBJECTIVE: The ependymal cells, considered today as an active participant in neuroendocrine functions, were investigated by electron microscopy in the central canal of the lowest spinal cord, the filum terminale (FT), in adult rats. In this area of the spinal cord, the central canal is covered by a heterogeneous population of ependymal cells. The aim of the present work was to compare the regional features of the ependymal cells in two different parts of the FT with a special regard to their ultrastructure. METHODS: Two parts of the FT were selected for the ultrastructural observations: the rostral (rFT) and the caudal (cFT) ones. The rTF was removed at the level of the immediate continuation of the conus medullaris, while the cFT 30 mm further caudally. After formaldehyde fixation, the spinal cord was removed and cut into small blocks for electron microscopic processing. The material was embedded into durcupan, contrasted with uranyl acetate, lead citrate as well as osmium tetroxide, and investigated under JEOL 1200 EX electron microscope. RESULTS: In the rFT, the ependymal lining is pseudostratified and one-layered in the cFT, whereas the shape of the ependymal cells may vary from cuboidal to flatten in the rostro-caudal direction. The basal membrane of many ependymal cells possesses deep invaginations, so called "filum terminale labyrinths". Many neuronal processes occur in the pericanalicular neuropil. In contrast to the rFT, the cFT is less rich in the neuropil particles. Some of the ependymal cells concurrently reach both the intracanalicular and extracanalicular cerebrospinal fluid (CSF), thus they may represent a new variant of the ependymal cells designated as "bridge cells of the FT". CONCLUSIONS: The present data indicate that the FT ependymal cells exhibit clear differences in anatomy as well as ultrastructure that may reflect their distinct functional activity. Therefore, observations presented here may serve for the better understanding of the physiological role of the individual ependymal areas in this special portion of the rat spinal cord. PMID- 23641791 TI - Significant pain alleviation, cease of hematuria, and renal stone removal after extracorporeal shock wave lithotripsy with adjuvant boron therapy - case report. AB - OBJECTIVE: Stone disease is an increasingly common form of renal disease. Therapy to prevent stones rests in lowering supersaturation uses both diet and medication. Environmental factors, especially diet, play an important role in the expression of the tendency to stone formation. Effective treatment decreases stone recurrence and need to use procedures to stone removal. Considering the nutrients, boron as an ultratrace element of the plant food is assumed to have an impact on the stone removal. METHOD: Female patient with a 10.0 mm stone in the lower pole underwent an extracorporeal shock wave lithotripsy (ESWL) and received 10 mg of boron supplement/day for two weeks. RESULTS: Ultrasonography assessment revealed complete stone removal or disposal without hydronephrosis with a significant pain alleviation and significant reduction in ureter bleeding or hematuria along with a little burning sensation in the genital region. The expulsion was confirmed by the collection of the lithiasic residues. CONCLUSIONS: Successful and comfortable kidney stone repulsion with a minor pain and bleeding indicates that the impact of boron in this issue deserves further study and clarification. PMID- 23641792 TI - Solution pH and oligoamine molecular weight dependence of the transition from monolayer to multilayer adsorption at the air-water interface from sodium dodecyl sulfate/oligoamine mixtures. AB - Neutron reflectivity and surface tension have been used to investigate the solution pH and oligoamine molecular weight dependence of the adsorption of sodium dodecyl sulfate (SDS)/oligoamine mixtures at the air-water interface. For diethylenetriamine, triamine, or triethylenetetramine, tetramine mixed with SDS, there is monolayer adsorption at pH 7 and 10, and multilayer adsorption at pH 3. For the slightly higher molecular weight tetraethylenepentamine, pentamine, and pentaethylenehexamine, hexamine, the adsorption is in the form of a monolayer at pH 3 and multilayers at pH 7 and 10. Hence, there is a pH driven transition from monolayer to multilayer adsorption, which shifts from low pH to higher pH as the oligoamine molecular weight increases from tetramine to pentamine. This results from the relative balance between the electrostatic attraction between the SDS and amine nitrogen group which decreases as the charge density decreases with increasing pH, the ion-dipole interaction between the amine nitrogen and SDS sulfate group which is dominant at higher pH, and the hydrophobic interalkyl chain interaction between bound SDS molecules which changes with oligoamine molecular weight. PMID- 23641793 TI - The effect of antibiotherapy on prostate-specific antigen levels and prostate biopsy results in patients with levels 2.5 to 10 ng/mL. AB - PURPOSE: This controlled prospective study aims to investigate the possible effects of antibiotic treatment on prostate-specific antigen (PSA) and its derivatives, and consequently on the transrectal biopsy rates, in the diagnosis of prostate cancer. PATIENTS AND METHODS: One hundred and forty patients aged 45 to 70 years old, with a PSA level between 2.5 and 10 ng/mL and normal digital rectal examinations (DRE), were included in this study between June 2009 and November 2010. The patients were randomly assigned into two groups. The first group received oral levofloxacin 500 mg 1*1 for 21 days; the second, the control group, was given no treatment. Initially, total PSA, free PSA, a DRE, urinary ultrasonography (including prostate volume, postvoiding residual urine), uroflowmetry, International Prostate Symptom Score, National Institutes of Health Chronic Prostatitis Symptom Index, and International Index of Erectile Function tests were performed. All of these were repeated at the end of 3 weeks of antibiotic treatment. An additional PSA measurement was also performed at day 10 of the treatment. All patients underwent transrectal ultrasonography (TRUS) guided prostate biopsy at day 21, just the day after the final (third) PSA sampling. RESULTS: The mean age of the patients was 59.6 years. Overall, in 23 patients, prostate cancer was detected, including those found in the rebiopsies. Statistically, there were significant changes in values of PSA and its derivatives in the treatment group (from 5.31 to 4.69 and 4.58 ng/mL, consecutively). Focusing on prostate cancer patients in both the treatment and control groups, however, we did not detect any significant change in the same parameters. CONCLUSION: Antibiotic treatment given to the patients with a PSA level between 2.5 and 10 ng/mL can be beneficial, before a decision for TRUS guided prostate biopsy, just in a limited subgroup, by reducing the PSA levels below the threshold value. Considering the large population of patients in the gray zone, however, it still does not provide clear solid evidence for avoiding unnecessary prostate biopsies. PMID- 23641794 TI - Visualizing osteogenesis in vivo within a cell-scaffold construct for bone tissue engineering using two-photon microscopy. AB - Tissue-engineering therapies have shown early success in the clinic, however, the cell-biomaterial interactions that result in successful outcomes are not yet well understood and are difficult to observe. Here we describe a method for visualizing bone formation within a tissue-engineered construct in vivo, at a single-cell resolution, and in situ in three dimensions using two-photon microscopy. First, two-photon microscopy and histological perspectives were spatially linked using fluorescent reporters for cells in the skeletal lineage. In the process, the tissue microenvironment that precedes a repair-focused study was described. The distribution and organization of type I collagen in the calvarial microenvironment was also described using its second harmonic signal. Second, this platform was used to observe in vivo, for the first time, host cells, donor cells, scaffold, and new bone formation within cell-seeded constructs in a bone defect. We examined constructs during bone repair 4 and 6 weeks after implantation. New bone formed on scaffolds, primarily by donor cells. Host cells formed a new periosteal layer that covered the implant. Scaffold resorption appeared to be site specific, where areas near the top were removed and deeper areas were completely embedded in new mineral. Visualizing the in vivo progression of the cell and scaffold microenvironment will contribute to our understanding of tissue-engineered regeneration and should lead to the development of more streamlined and therapeutically powerful approaches. PMID- 23641795 TI - Alcohol use and HIV serostatus of partner predict high-risk sexual behavior among patients receiving antiretroviral therapy in South Western Uganda. AB - BACKGROUND: Antiretroviral treatment restores the physical and immunological function for patients with HIV/AIDS and the return of sexual desire. The frequency and correlates of sexual activity among patients receiving ART have not been widely studied. There is concern that widespread availability of ART may result in sexual disinhibition including practice of high-risk sexual behavior. We determined the correlates of sexual activity and high-risk sexual behavior in an ART-treated population in rural and urban Uganda. METHODS: We conducted a cross-sectional study among 329 ART-treated adult patients at two hospitals, one located in rural and another in urban western Uganda. We collected data on sexual activity, frequency of condom use, pregnancy, viral load (VL) and CD4. Patients were considered sexually active if they had had sexual intercourse in the last 6 months. Any unprotected sex was considered high-risk sex. A two-stage logistic regression was performed to determine factors associated with sexual activity and high-risk sex among those sexually active. RESULTS: Overall, 222 (67%) patients were women, 138 (41.2%) had been on ART for at least one year, and 168 (51.4%) were sexually active of whom 127 (75.6%) used condoms at the last intercourse. Younger age (<=30 years) (Odds ratio; OR=2.3, 95% CI 1.2, 4.2), higher monthly income (OR=4.1, 95% CI 2.4, 7.4), and being married (OR=22.7, 95% CI 8.2, 62.9) were associated with being sexually active. Undetectable VL, CD4 count and treatment duration were not significantly associated with sexual activity. Among the sexually active, alcohol consumption (OR=3.3, 95% CI 1.2, 9.1) and unknown serostatus of partner (OR=5.8, 95% CI 1.5, 21.4) were significant predictors of high-risk sexual behavior. The frequency of unprotected sex at the last intercourse was 25.9% and 22.1% among the men and women respectively and was not significantly different (p value for chi square test =0.59). CONCLUSION: Younger persons receiving ART are more likely to be sexually active. ART clients are more likely to engage in unprotected sex when sero-status of partner is unknown or report use of alcohol. Counseling on alcohol use and disclosure of sero-status may be useful in reducing high risk sexual behavior. PMID- 23641797 TI - An optimized workflow for improved gene expression profiling for formalin-fixed, paraffin-embedded tumor samples. AB - BACKGROUND: Whole genome microarray gene expression profiling is the 'gold standard' for the discovery of prognostic and predictive genetic markers for human cancers. However, suitable research material is lacking as most diagnostic samples are preserved as formalin-fixed, paraffin-embedded tissue (FFPET). We tested a new workflow and data analysis method optimized for use with FFPET samples. METHODS: Sixteen breast tumor samples were split into matched pairs and preserved as FFPET or fresh-frozen (FF). Total RNA was extracted and tested for yield and purity. RNA from FFPET samples was amplified using three different commercially available kits in parallel, and hybridized to Affymetrix GeneChip(r) Human Genome U133 Plus 2.0 Arrays. The array probe set was optimized in silico to exclude misdesigned and misannotated probes. RESULTS: FFPET samples processed using the WT-OvationTM FFPE System V2 (NuGEN) provided 80% specificity and 97% sensitivity compared with FF samples (assuming values of 100%). In addition, in silico probe set redesign improved sequence detection sensitivity and, thus, may rescue potentially significant small-magnitude gene expression changes that could otherwise be diluted by the overall probe set background. CONCLUSION: In conclusion, our FFPET-optimized workflow enables the detection of more genes than previous, nonoptimized approaches, opening new possibilities for the discovery, validation, and clinical application of mRNA biomarkers in human diseases. PMID- 23641796 TI - The role of vascular endothelial growth factor and matrix metalloproteinases in canine lymphoma: in vivo and in vitro study. AB - BACKGROUND: Canine lymphoma represents the most frequent haematopoietic cancer and it shares some similarities with human non-Hodgkin lymphoma. Matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) play a coordinated role during invasion and proliferation of malignant cells; however, little is known about their role in canine haematologic malignancies. The aim of this study was to investigate the mRNA and protein expression of VEGF and the most relevant MMPs in canine lymphoma. Lymph node aspirates from 26 B-cell and 21 T-cell lymphomas were collected. The protein expression levels of MMP-9, MMP-2 and VEGF-A were evaluated by immunocytochemistry, and the mRNA levels of MMP-2, MMP-9, MT1-MMP, TIMP-1, TIMP-2, RECK, VEGF-A and VEGF-164 were measured using quantitative RT-PCR. RESULTS: MT1-MMP, TIMP-1 and RECK mRNA levels were significantly higher in T-cell lymphomas than in B-cell lymphomas. Higher mRNA and protein levels of MMP-9 and VEGF-A were observed in T-cell lymphomas than in B-cell lymphomas and healthy control lymph nodes. A positive correlation was found between MMP-9 and VEGF-A in T-cell lymphomas. Moreover, MMP-9, MT1-MMP, TIMP-1 and VEGF-A were expressed at the highest levels in high-grade T-cell lymphomas. CONCLUSIONS: This study provides new information on the expression of different MMPs and VEGF in canine lymphoma, suggesting a possible correlation between different MMPs and VEGF, immunophenotype and prognosis. PMID- 23641798 TI - Prediction of aluminum, uranium, and co-contaminants precipitation and adsorption during titration of acidic sediments. AB - Batch and column recirculation titration tests were performed with contaminated acidic sediments. A generic geochemical model was developed combining precipitation, cation exchange, and surface complexation reactions to describe the observed pH and metal ion concentrations in experiments with or without the presence of CO2. Experimental results showed a slow pH increase due to strong buffering by Al hydrolysis and precipitation and CO2 uptake. The cation concentrations generally decreased at higher pH than those observed in previous tests without CO2. Using amorphous Al(OH)3 and basaluminite precipitation reactions and a cation exchange selectivity coefficient K(Na?Al) of 0.3, the model approximately described the observed (1) pH titration curve, (2) Ca, Mg, and Mn concentration by cation exchange, and (3) U concentrations by surface complexation with Fe hydroxides at pH < 5 and with liebigite (Ca2UO2(CO3)3.10H2O) precipitation at pH > 5. The model indicated that the formation of aqueous carbonate complexes and competition with carbonate for surface sites could inhibit U and Ni adsorption and precipitation. Our results suggested that the uncertainty in basaluminite solubility is an important source of prediction uncertainty and ignoring labile solid phase Al underestimates the base requirement in titration of acidic sediments. PMID- 23641799 TI - Magnetic and photoresponsive theranosomes: translating cell-released vesicles into smart nanovectors for cancer therapy. AB - Cell-released vesicles are natural carriers that circulate in body fluids and transport biological agents to distal cells. As nature uses vesicles in cell communication to promote tumor progression, we propose to harness their unique properties and exploit these biogenic carriers as Trojan horses to deliver therapeutic payloads to cancer cells. In a theranostic approach, cell-released vesicles were engineered by a top-down procedure from precursor cells, previously loaded with a photosensitizer and magnetic nanoparticles. The double exogenous cargo provided vesicles with magnetic and optical responsiveness allowing therapeutic and imaging functions. This new class of cell-derived smart nanovectors was named "theranosomes". Theranosomes enabled efficient photodynamic tumor therapy in a murine cancer model in vivo. Moreover the distribution of this biogenic vector could be monitored by dual-mode imaging, combining fluorescence and MRI. This study reports the first success in translating a cell communication mediator into a smart theranostic nanovector. PMID- 23641800 TI - Upper Egypt experience in bladder preservation using concurrent chemoradiotherapy. AB - OBJECTIVE: To share our experience in bladder preservation in Upper Egypt, Assiut and Sohag Universities, using different treatment protocols. In Sohag study patients with operable muscle invasive bladder cancer were included and underwent transurethral resection followed by radiochemotherapy (5- fluorouracil and Cisplatin) for bladder preservation. In Assiut study after maximum safe resection of bladder tumor, patients received combined chemo-radiotherapy, 60 Gy of fractionated radiotherapy over 6 weeks, with Cisplatin and Gemcitabine. RESULTS: In Sohag study the age of patients ranged from 35-72ys with Median 56 years, 24 patients were male (80%) and 6 patients were female (20%). In Assiut study the mean of age was 57.30 years, median 58.5 years with peak incidence in 7th decade (9 cases) then in 6th decade 7 cases (23.33%). Performance status was represented as following, 23 patients (76.6%) were scale 1 and seven patients (23.3%) were scale 2. In Assiut study, 90% of patients were disease free at the time of cystoscopic reevaluation. Of concern is that within 18 months of follow up in Assiut study, 7 of 27 (74%) complete responding patients have had local recurrence and 66.7% of all cases. The recurrence free survival in Sohag study at the median follow up (17 months) was 84% and at the end of follow up (30 months) was 70%. The overall survival at the median follow up was 95%, and at the end of follow up was 84%. The disease free survival in Assiut study was 66.7% and the overall Survival in Assiut study was 76.7. CONCLUSION: Three significant prognostic factors were detected for overall survival, performance status, tumor size and residual of tumor and two significant prognostic factors were detected for disease free survival, tumor size and residual of tumor in Assiut study. And it was nearly similar to that reported by Sohag study as they found the completeness of TUR and early stage of the tumor had the strongest impact in response to treatment. PMID- 23641801 TI - Kin conflict in seed development: an interdependent but fractious collective. AB - Seeds are complex structures that unite diploid maternal tissues with filial tissues that may be haploid (gametophyte), diploid (embryo), or triploid (endosperm). Maternal tissues are predicted to favor smaller seeds than are favored by filial tissues, and filial genes of maternal origin are predicted to favor smaller seeds than are favored by filial genes of paternal origin. Consistent with these predictions, seed size is determined by an interplay between growth of maternal integuments, which limits seed size, and of filial endosperm, which promotes larger seeds. Within endosperm, genes of paternal origin favor delayed cellularization of endosperm and larger seeds, whereas genes of maternal origin favor early cellularization and smaller seeds. The ratio of maternal and paternal gene products in endosperm contributes to the failure of crosses between different ploidy levels of the same species and crosses between species. Maternally expressed small-interfering RNAs (siRNAs) are predicted to associate with growth-enhancing genes. PMID- 23641802 TI - Made in Europe: will artemisinin resistance emerge in French Guiana? AB - Resistance to artemisinin casts a shadow on the fight against malaria. The importance of illegal gold miners and of malaria in isolated regions of French Guiana constitutes a threat that endangers the fight against malaria in the Amazon. The hurdles of French laws and the remoteness of the territory from France make it impossible for the system to adapt to the problem of total inaccessibility of an important part of the malaria problem. Transmission is high in these areas and gold miners self-medicate with erratic regimens of artemisinin combinations, thus creating perfect conditions for the emergence of resistance. What needs to be done is being done, but within the limits of national law, with some results. However, facing the same difficult problem, Suriname shows more flexibility and is doing much better than French Guiana despite having lower resources. Local authorities in French Guiana cannot overrule the laws that block appropriate malaria care from reaching a third of malaria-exposed persons. Thus the health authorities in France should take immediate calibrated legislative and financial measures to avoid a predictable disaster. PMID- 23641804 TI - Migrant farm-workers and health. PMID- 23641803 TI - The study design and rationale of the randomized controlled trial: translating COPD guidelines into primary care practice. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating disease associated with significant clinical burden and is estimated to affect 15 million individuals in the US. Although a large number of individuals are diagnosed with COPD, many individuals still remain undiagnosed due to the slow progression of the disorder and lack of recognition of early symptoms. Not only is there under-diagnosis but there is also evidence of sub optimal evidence-based treatment of those who have COPD. Despite the development of international COPD guidelines, many primary care physicians who care for the majority of patients with COPD are not translating this evidence into effective clinical practice. METHOD/DESIGN: This paper describes the design and rationale for a randomized, cluster design trial (RCT) aimed at translating the COPD evidence-based guidelines into clinical care in primary care practices. During Phase 1, a needs assessment evaluated barriers and facilitators to implementation of COPD guidelines into clinical practice through focus groups of primary care patients and providers. Using formative evaluation and feedback from focus groups, three tools were developed. These include a computerized patient activation tool (an interactive iPad with wireless data transfer to the spirometer); a web-based COPD guideline tool to be used by primary care providers as a decision support tool; and a COPD patient education toolkit to be used by the practice team. During phase II, an RCT will be performed with one year of intervention within 30 primary care practices. The effectiveness of the materials developed in Phase I are being tested in Phase II regarding physician performance of COPD guideline implementation and the improvement in the clinically relevant outcomes (appropriate diagnosis and management of COPD) compared to usual care. We will also examine the use of a patient activation tool - 'MyLungAge' - to prompt patients at risk for or who have COPD to request spirometry confirmation and to request support for smoking cessation if a smoker. DISCUSSION: Using a multi-modal intervention of patient activation and a technology-supported health care provider team, we are testing the effectiveness of this intervention in activating patients and improving physician performance around COPD guideline implementation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01237561. PMID- 23641805 TI - Hexabothriids of devil rays (Mobulidae): new genus and species from gill of Mobula hypostoma in the Northern Gulf of Mexico and redescription of a congener from Mobula rochebrunei in the eastern Atlantic Ocean. AB - A new species of Hexabothriidae, Mobulicola enantiomorphica n. gen., n. sp., is described on the basis of specimens collected from the gill of a lesser devil ray, Mobula hypostoma (Bancroft, 1831) (Rajiformes: Mobulidae), captured in the northern Gulf of Mexico (30 degrees 13'49.22"N, 88 degrees 20'31.69"W) off Dauphin Island, Alabama. We also herein redescribe Mobulicola dubium (Euzet and Maillard, 1967) n. comb. on the basis of the holotype (36HG-69-1) and paratypes (36HG-69-2 and 36HG-69-3) collected from the gill of a lesser Guinean devil ray, Mobula rochebrunei (Vaillant, 1879), captured in the eastern Atlantic Ocean off the island of Goree (14 degrees 40'02.26"N, 17 degrees 23'4.96"W), Senegal. Mobulicola has the following combination of diagnostic features that differentiate it from other hexabothriid genera: haptor symmetrical; vasa efferentia narrow for entire length (not dilated distally), glandular-walled, joining medially immediately anterior to testicular field; vas deferens glandular for part or all of length and extensively convoluted; male copulatory organ massive, oblong, unarmed, dilated for entire length, lacking prostatic region; seminal receptacle present; ootype lacking longitudinal rows of large cells (ootype cotele); vaginae parallel, with well-differentiated proximal (narrow, tube-like) and distal (laterally expanded, musculoglandular) portions; uterine eggs with 2 elongate filaments. Mobulicola is morphologically most similar to Branchotenthes Bullard and Dippenaar, 2003 but differs from it by the combination of having short, delicate vasa efferentia that are narrow for their entire length and that each extends slightly anteriad from the testicular field before uniting medially, a vas deferens that is convoluted between the common vitelline duct and male copulatory organ, an ovate, compact seminal receptacle, an ovary that ascends, descends, then ascends, and a proximal uterus that is extensively convoluted posterior to the male copulatory organ. The new species differs from M. dubium by the combination of having a proportionally shorter sclerite hook (19 29% of sclerite shaft total length), a vas deferens that is glandular-walled and laterally expanded proximally and nonglandular and narrow distally, and a common vitelline duct with dextral and sinistral loops extending anteriad. This is only the second report of a hexabothriid from a mobulid and the first report of a monogenoid from Mobula hypostoma. PMID- 23641807 TI - Sulfur(IV)-mediated transformations: from ylide transfer to metal-free arylation of carbonyl compounds. AB - The development of a direct ylide transfer to carbonyl derivatives and of a sulfoxide-mediated arylation is presented from a unified perspective. Mechanistic studies (including density functional calculations) support a common reaction pathway and showcase how subtle changes in reactant properties can lead to disparate and seemingly unrelated reaction outcomes. PMID- 23641808 TI - Exposure to phthalic acid, phthalate diesters and phthalate monoesters from foodstuffs: UK total diet study results. AB - Phthalates are ubiquitous in the environment and thus exposure to these compounds can occur in various forms. Foods are one source of such exposure. There are only a limited number of studies that describe the levels of phthalates (diesters, monoesters and phthalic acid) in foods and assess the exposure from this source. In this study the levels of selected phthalate diesters, phthalate monoesters and phthalic acid in total diet study (TDS) samples are determined and the resulting exposure estimated. The methodology for the determination of phthalic acid and nine phthalate monoesters (mono-isopropyl phthalate, mono-n-butyl phthalate, mono isobutyl phthalate, mono-benzyl phthalate, mono-cyclohexyl phthalate, mono-n pentyl phthalate, mono-(2-ethylhexyl) phthalate, mono-n-octyl phthalate and mono isononyl phthalate) in foods is described. In this method phthalate monoesters and phthalic acid are extracted from the foodstuffs with a mixture of acidified acetonitrile and dichloromethane. The method uses isotope-labelled phthalic acid and phthalate monoester internal standards and is appropriate for quantitative determination in the concentration range of 5-100 ug kg-1. The method was validated in-house and its broad applicability demonstrated by the analysis of high-fat, high-carbohydrate and high-protein foodstuffs as well as combinations of all three major food constituents. The methodology used for 15 major phthalate diesters has been reported elsewhere. Phthalic acid was the most prevalent phthalate, being detected in 17 food groups. The highest concentration measured was di-(2-ethylhexyl) phthalate in fish (789 ug kg-1). Low levels of mono-n-butyl phthalate and mono-(2-ethylhexyl) phthalate were detected in several of the TDS animal-based food groups and the highest concentrations measured corresponded with the most abundant diesters (di-n-butyl phthalate and di-(2-ethylhexyl) phthalate). The UK Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) considered the levels found and concluded that they did not indicate a risk to human health from dietary exposure alone. PMID- 23641810 TI - Photocycloaddition of arenes and allenes. AB - In this work, we report on a new intramolecular para cycloaddition of arenes with allenes, yielding attractive rigid scaffolds bearing several reactive functionalities to build in further diversity. Bicyclo[2.2.2]octadiene-type products and benzoxepine acetals are formed in this reaction, in ratios and yields depending on the substitution pattern on the aromatic ring, the nature of the chromophore, and the tether. This unprecedented reaction has remarkable features that distinguish it from many other photochemical transformations: it is particularly robust with respect to substituents, it can be scaled up without a notable loss of efficiency, and it can lead to structures with a high degree of complexity in low to good yields. All photochemical precursors could be synthesized readily in three steps. We confirmed the compatibility of the nitrogen atom in the photocycloaddition step, which gives access to a bicyclo[2.2.2]octadiene scaffold with two points that allow further diversification. This reaction was scaled up to multigram quantities without erosion of the typically high yields in photocycloadducts. Sequential deprotection of the N- or C-terminus of bicyclic amino acids gave access to two conformationally constrained unnatural amino acids with different dispositions of the two anchor points. PMID- 23641809 TI - Budget impact of rosuvastatin initiation in high-risk hyperlipidemic patients from a US managed care perspective. AB - INTRODUCTION: Statins reduce low-density lipoprotein cholesterol (LDL-C) levels, which, when elevated, represent a significant risk factor for cardiovascular (CV) disease. Hyperlipidemic patients at risk of CV events initiated on simvastatin or atorvastatin may be less likely to meet LDL-C goals (defined in National Cholesterol Education Program guidelines) and more likely to experience CV events than patients initiated on rosuvastatin. A 3-year budget impact model was developed to estimate the clinical impact and cost to a US managed care organization (MCO) with 1 million members of initiating high-risk hyperlipidemic patients on rosuvastatin rather than simvastatin or atorvastatin. METHODS: A total of 1000 adult patients were assumed to initiate statins. The average baseline LDL-C level was 189 mg/dL. In scenario 1, all patients were initiated on simvastatin or atorvastatin and titrated to a higher dose, or switched to atorvastatin (if initiated on simvastatin) or rosuvastatin; in scenario 2, 50% of the 520 high-risk patients were initiated on rosuvastatin. Drug acquisition and administration costs were considered. Product labeling, clinical trial results, national prescription claims data, and published literature were used to populate the model. RESULTS: Over 3 years, 75 additional patients reached their LDL-C goal in scenario 2, compared with scenario 1 (633 vs 558, respectively), at an increased cost of $240,628 ($1,415,516 vs $1,174,888, respectively). The additional per member per month (PMPM) cost of scenario 2 was $0.007. LIMITATIONS: This analysis assumed that statin efficacy is the same in real life as in trials, and used titration and switching patterns not based on patients' goal attainment. However, sensitivity and scenario analyses showed that the model was less sensitive to these parameters than to cost-related parameters. CONCLUSIONS: Initiating high-risk hyperlipidemic patients on rosuvastatin may increase the number of patients reaching LDL-C goal at a relatively modest increase in PMPM cost to an MCO. PMID- 23641811 TI - Estimation of bovine leukemia virus (BLV) proviral load harbored by lymphocyte subpopulations in BLV-infected cattle at the subclinical stage of enzootic bovine leucosis using BLV-CoCoMo-qPCR. AB - BACKGROUND: Bovine leukemia virus (BLV) is associated with enzootic bovine leukosis (EBL), which is the most common neoplastic disease of cattle. BLV infection may remain clinically silent at the aleukemic (AL) stage, cause persistent lymphocytosis (PL), or, more rarely, B cell lymphoma. BLV has been identified in B cells, CD2+ T cells, CD3+ T cells, CD4+ T cells, CD8+ T cells, gamma/delta T cells, monocytes, and granulocytes in infected cattle that do not have tumors, although the most consistently infected cell is the CD5+ B cell. The mechanism by which BLV causes uncontrolled CD5+ B cell proliferation is unknown. Recently, we developed a new quantitative real-time polymerase chain reaction (PCR) method, BLV-CoCoMo-qPCR, which enabled us to demonstrate that the proviral load correlates not only with BLV infection, as assessed by syncytium formation, but also with BLV disease progression. The present study reports the distribution of BLV provirus in peripheral blood mononuclear cell subpopulations isolated from BLV-infected cows at the subclinical stage of EBL as examined by cell sorting and BLV-CoCoMo-qPCR. RESULTS: Phenotypic characterization of five BLV-infected but clinically normal cattle with a proviral load of > 100 copies per 1 * 105 cells identified a high percentage of CD5+ IgM+ cells (but not CD5- IgM+ B cells, CD4+ T cells, or CD8+T cells). These lymphocyte subpopulations were purified from three out of five cattle by cell sorting or using magnetic beads, and the BLV proviral load was estimated using BLV-CoCoMo-qPCR. The CD5+ IgM+ B cell population in all animals harbored a higher BLV proviral load than the other cell populations. The copy number of proviruses infecting CD5- IgM+ B cells, CD4+ cells, and CD8+ T cells (per 1 ml of blood) was 1/34 to 1/4, 1/22 to 1/3, and 1/31 to 1/3, respectively, compared with that in CD5+ IgM+ B cells. Moreover, the BLV provirus remained integrated into the genomic DNA of CD5+ IgM+ B cells, CD5- IgM+ B cells, CD4+ T cells, and CD8+ T cells, even in BLV-infected cattle with a proviral load of <100 copies per 105 cells. CONCLUSIONS: The results of the recent study showed that, although CD5+ IgM+ B cells were the main cell type targeted in BLV-infected but clinically normal cattle, CD5- IgM+ B cells, CD4+ cells, and CD8+ T cells were infected to a greater extent than previously thought. PMID- 23641812 TI - A de novo acute myeloid leukemia (AML-M4) case with a complex karyotype and yet unreported breakpoints. AB - BACKGROUND: Acute myelogeneous leukemia (AML) is a malignancy of the hematopoietic stem cells, for which cytogenetic analysis is still one of the most important diagnostic and prognostic tools. Still, we are far away from having seen and described all possible genetic changes associated with this kind of acquired disease. RESULTS: Bone marrow cells of a female patient with clinical diagnoses of AML and immunophenotypically confirmed AML-M4 were studied by GTG banding. The later was not able to resolve all karyotypic changes and the complex karyotype was characterized in more detail by fluorescence in situ hybridization (FISH) and array-proven multicolor banding (aMCB). To the best of our knowledge, the present case is the only one ever seen with a del(5)(q14q34), a der(17)t(4;17)(p13;p13), a del(2)(p23), a der(4)t(4;7)(p13;q11.23), a der(22)t(11;22)(q23;q11.2) and two complex rearranged chromosomes 11 involving chromosomes 7 and 22 as well as 2. CONCLUSIONS: The yet unreported breakpoints observed in this case seem to be correlated with an adverse prognosis. Overall, molecular cytogenetic studies are suited best for identification and characterization of chromosomal rearrangements in acute leukemia and single case reports as well as large scale studies are necessary to provide further insides in karyotypic changes taking place in human malignancies. PMID- 23641813 TI - Pain experience in children with juvenile idiopathic arthritis treated with anti TNF agents compared to non-biologic standard treatment. AB - BACKGROUND: Anti-TNF agents have proven efficacy in children with severe juvenile idiopathic arthritis (JIA) who are unresponsive to standard therapy. Therefore pain reduction or elimination could be expected. The aim of this study was to compare the pain experience in children with JIA treated with anti-TNF agents (n = 41) or non-biologic standard treatment (n = 50). METHODS: All children completed a 2-week pain diary and, for children treated with anti-TNF agents, measures of pain-coping and pain-specific beliefs. Parents rated the child's level of functional disability. Clinical data were collected from the pediatric rheumatologists. RESULTS: No significant differences were found between the anti TNF group and non-biologic standard treatment group for average pain score, number of children with daily pain reported in the pain diary, or level of functional disability. Significantly more children in the anti-TNF group reported no pain at all. Children undergoing standard treatment had significantly higher disease activity. Significant differences were found between the high pain patients treated with anti-TNF agents and the rest of the anti-TNF group in regards to their pain-specific beliefs of disability and harm, and the pain coping strategy of catastrophizing. CONCLUSION: These results indicate that a great proportion of children treated with anti-TNF agents respond well to the treatment in regards to disease activity and pain, but pain was still a problem for a subgroup of children though they were in remission with biological agents. More focus on pain management is needed. PMID- 23641814 TI - Effect of chloride on the dissolution rate of silver nanoparticles and toxicity to E. coli. AB - Pristine silver nanoparticles (AgNPs) are not chemically stable in the environment and react strongly with inorganic ligands such as sulfide and chloride once the silver is oxidized. Understanding the environmental transformations of AgNPs in the presence of specific inorganic ligands is crucial to determining their fate and toxicity in the environment. Chloride (Cl(-)) is a ubiquitous ligand with a strong affinity for oxidized silver and is often present in natural waters and in bacterial growth media. Though chloride can strongly affect toxicity results for AgNPs, their interaction is rarely considered and is challenging to study because of the numerous soluble and solid Ag-Cl species that can form depending on the Cl/Ag ratio. Consequently, little is known about the stability and dissolution kinetics of AgNPs in the presence of chloride ions. Our study focuses on the dissolution behavior of AgNPs in chloride-containing systems and also investigates the effect of chloride on the growth inhibition of E.coli (ATCC strain 33876) caused by Ag toxicity. Our results suggest that the kinetics of dissolution are strongly dependent on the Cl/Ag ratio and can be interpreted using the thermodynamically expected speciation of Ag in the presence of chloride. We also show that the toxicity of AgNPs to E.coli at various Cl(-) concentrations is governed by the amount of dissolved AgCl(x)((x-1)-) species suggesting an ion effect rather than a nanoparticle effect. PMID- 23641815 TI - Foamy virus for efficient gene transfer in regeneration studies. AB - BACKGROUND: Molecular studies of appendage regeneration have been hindered by the lack of a stable and efficient means of transferring exogenous genes. We therefore sought an efficient integrating virus system that could be used to study limb and tail regeneration in salamanders. RESULTS: We show that replication-deficient foamy virus (FV) vectors efficiently transduce cells in two different regeneration models in cell culture and in vivo. Injection of EGFP expressing FV but not lentivirus vector particles into regenerating limbs and tail resulted in widespread expression that persisted throughout regeneration and reamputation pointing to the utility of FV for analyzing adult phenotypes in non mammalian models. Furthermore, tissue specific transgene expression is achieved using FV vectors during limb regeneration. CONCLUSIONS: FV vectors are efficient mean of transferring genes into axolotl limb/tail and infection persists throughout regeneration and reamputation. This is a nontoxic method of delivering genes into axolotls in vivo/ in vitro and can potentially be applied to other salamander species. PMID- 23641816 TI - N-terminal truncation of an isolated human IgG1 CH2 domain significantly increases its stability and aggregation resistance. AB - Isolated human immunoglobulin G (IgG) CH2 domains are promising scaffolds for novel candidate therapeutics. Unlike other human IgG domains, CH2 is not involved in strong interchain interactions, and isolated CH2 is relatively stable. However, isolated single CH2 is prone to aggregation. In native IgG and Fc molecules, the N-terminal residues of CH2 from the two heavy chains interact with each other and form hinge regions. By contrast, the N-terminal residues are highly disordered in isolated CH2. We have hypothesized that the removal of the CH2 N-terminal residues may not only increase its stability but also its aggregation resistance. To test this hypothesis we constructed a shortened variant of IgG1 CH2 (CH2s) where the first seven residues of the N-terminus were deleted. We found that the thermal stability of CH2s was increased by 5 degrees C compared to CH2. Importantly, we demonstrated that CH2s is significantly less prone to aggregation than CH2 as measured by Thioflavin T (ThT) fluorescence, turbidity, and light scattering. We also found that the CH2s exhibited pH dependent binding to a soluble single-chain human neonatal Fc receptor (shFcRn) which was significantly stronger than the very weak binding of CH2 to shFcRn as measured by flow cytometry. Computer modeling suggested a possible mode of CH2 aggregation involving its N-terminal residues. Therefore, deletion of the N terminal residues could increase drugability of CH2-based therapeutic candidates. This strategy to increase stability and aggregation resistance could also be applicable to other Ig-related proteins. PMID- 23641817 TI - Effects of Lung Support Formula on respiratory symptoms among older adults: results of a three-month follow-up study in Shanghai, China. AB - BACKGROUND: With the acceleration of industrialization in low or middle-income nations, the prevalence of respiratory symptoms among older adults is even more significant now in China. Contemporary treatments using Western medicine, such as anti-inflammatory regimens, may be effective in relieving the symptoms, but may have unexpected side effects. Some natural products may be effective in improving respiratory functions, yet their efficacies remain to be examined in randomized, placebo-controlled studies. To evaluate the effects of Lung Support Formula, a nutritional supplement which contains naturally derived Chinese herbal medicines, we conducted a clinical study among older adults in Shanghai, China. METHODS: A total of 100 patients over 50 years old were recruited and blindly randomized into the treatment or control group. The subjects took either 1 Lung Support Formula capsule or a placebo capsule twice a day for 12 weeks. All subjects were followed-up every 4 weeks to perform investigative and clinical examinations. Repeated measure of analysis of variance was employed to compare the trend of respiratory symptoms scores between the 2 groups during 12 weeks of follow-up. RESULTS: Fifty patients from the treatment group and 49 patients in the control group completed the 3-month follow-up. No adverse events were reported in the treatment duration. The percentage of patients reported to have chronic cough, chronic expectoration and chronic bronchitis were significantly decreased in the treatment group when compared with baseline after a 3-month intervention (P < 0.05). The respiratory symptoms scores declined gradually with the lapse of time (P < 0.05) in the treatment group and there were no significant changes in the control group by repeated measure of analysis of variance (P > 0.05). CONCLUSIONS: The clinical research shows that use of Lung Support Formula shows significant improvements of respiratory symptoms and is well-tolerated in short term use among older adults. An additional study involving more subjects and longer-term follow-up would be needed to provide convincing evidence of the improvement of respiratory symptoms in the treatment group. PMID- 23641819 TI - Current pharmacological treatment options for male lower urinary tract symptoms. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) is a highly prevalent disease in the aging male and significantly impairs quality of life. Men with BPH present with lower urinary tract symptoms (LUTS), which include storage and voiding disorders. Medical therapy is the first option in patients with mild to moderate symptoms. AREAS COVERED: alpha1-adrenoceptor antagonists, 5alpha-reductase inhibitors or the combination of both have been considered gold standard for pharmacological treatment over the last decade in this patient cohort. Recently, a variety of novel substances have been tested which include Phosphodiesterase Typ 5 inhibitors (PDE5i), anti-cholinergic agents and beta-3-agonists. This article highlights the key studies with regard to each drug class and discusses current pharmacotherapy and possible future treatment options. EXPERT OPINION: In patients with small prostates, alpha1-adrenoceptor antagonists represent the gold standard in the medical treatment of mild LUTS. For men with large prostate glands and mild to moderate LUTS, recent data support the combination of alpha1 adrenoceptor antagonists and 5alpha-reductase inhibitors. PDE5i may be useful in men with LUTS and concomitant erectile dysfunction, while anti-cholinergics have been shown to be beneficial in patients with predominant storage disorders. Future studies have to elucidate the role of beta-3-agonists in men with BPH and LUTS. PMID- 23641818 TI - Anti-inflammatory and anti-oxidative effects of corilagin in a rat model of acute cholestasis. AB - BACKGROUND: Nowadays, treatments for cholestasis remain largely nonspecific and often ineffective. Recent studies showed that inflammatory injuries and oxidative stress occur in the liver with cholestasis. In this study, we would use corilagin to treat the animal model of acute cholestasis in order to define the activity to interfere with inflammation-related and oxidative stress pathway in cholestatic pathogenesis. METHODS: Rats were administrated with alpha-naphthylisothiocyanate to establish model of cholestasis and divided into corilagin, ursodeoxycholic acid, dexamethasone, model and normal groups with treatment of related agent. At 24h, 48h and 72h time points after administration, living condition, serum markers of liver damage, pathological changes of hepatic tissue, nuclear factor (NF)-kappaB, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO) were examined and observed. RESULTS: Compared to model group, corilagin had remarkable effect on living condition, pathological manifestation of liver tissue, total bilirubin, direct bilirubin, (P<0.01), but no effect on alanine aminotransferase (ALT) and aspartate aminotransferase (AST). With corilagin intervention, levels of MPO, MDA and translocation of NF-kappaB were notably decreased, and levels of SOD and NO were markedly increased (P<0.05 or P<0.01). CONCLUSIONS: It is shown that corilagin is a potential component to relieve cholestasis through inflammation-related and oxidation-related pathway. PMID- 23641820 TI - Contextualising migrants' health behaviour - a qualitative study of transnational ties and their implications for participation in mammography screening. AB - BACKGROUND: Lower participation rates in mammography screening are common among migrant women compared to native-born women. Explanations of these lower rates have mainly been based on behavioural theories investigating how lack of knowledge, access to services and culture influence the screening behaviour. The aim of the present study was to contextualise screening behaviour by exploring migrants' transnational ties and their influence on participation in mammography screening in Denmark. METHODS: The study is based on the analysis of qualitative interviews with 29 women residing in greater Copenhagen, Denmark and born in Somalia, Turkey, India, Iran, Pakistan and Arab-speaking countries. RESULTS: We found that while women had knowledge about breast cancer and mammography screening, it was not prioritised. All women were embedded in transnational ties, which they struggled to retain through emotional and financial obligations, and these current struggles in their everyday life seemed to leave little room for concerns about breast cancer and therefore seemed to contribute to their lower participation in screening. CONCLUSIONS: The study emphasises the need to take into account the multi-layered and multi-sided factors in migrants' everyday life in order to further understand their health behaviour. PMID- 23641821 TI - Risk of heart failure and edema associated with the use of pregabalin: a systematic review. AB - BACKGROUND: Pregabalin is used in the treatment of postherpetic neuralgia, diabetic neuropathic pain, partial seizures, anxiety disorders and fibromyalgia. Recognized adverse effects associated with its use include cognitive impairment, somnolence and dizziness. Heart failure associated with pregabalin has been described, however the strength of this association has not been well characterized. To examine this further, we will conduct a systematic review of the risk of heart failure and edema associated with use of pregabalin. METHODS/DESIGN: We will include all studies (experimental, quasi-experimental, observational, case series/reports, drug regulatory reports) that examine the use of pregabalin compared to placebo, gabapentin or conventional care. Our primary outcome is heart failure and the secondary outcomes include edema and weight gain. We will search electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials), and grey literature sources (trial registries, conference abstracts) to identify relevant studies. To ensure literature saturation, we will contact drug manufacturers, conduct forward citation searching, and scan the reference lists of key articles and included studies. We will not restrict inclusion by language or publication status.Two reviewers will screen citations (titles and abstracts) and full-text articles, conduct data abstraction, and appraise risk of bias. Random-effects meta-analysis will be conducted if the studies are deemed heterogeneous in terms of clinical, statistical and methodological factors but still suitable for meta-analysis. CONCLUSIONS: The results of this review will assist physicians to better appreciate pregabalin's risk for edema or congestive heart failure and will be pertinent to the thousands of patients worldwide who are administered this medication.Our protocol was registered in the PROSPERO database (CRD42012002948). PMID- 23641822 TI - Seizure outcome in surgically treated drug-resistant mesial temporal lobe epilepsy based on the recent histopathological classifications. AB - OBJECT: The study was performed to investigate the relation between seizure outcome after surgical treatment of mesial temporal lobe epilepsy (MTLE) and pathological findings, classified according to the recently proposed classifications of mesial temporal sclerosis (MTS), granule cell pathology (GCP), focal cortical dysplasia (FCD) and epilepsy-associated low-grade tumors (ELGT). METHODS: The authors analyzed data obtained in 120 consecutive cases involving patients presenting with drug-resistant MTLE, who underwent tailored anteromesial temporal lobe resection, and correlated seizure outcome with pathological findings. They identified 5 histopathological groups: Group 1-ELGT, alone or associated with other lesions (30 cases); Group 2-isolated FCD (17 cases); Group 3-MTS, with or without GCP (28 cases); Group 4-MTS associated with FCD, with or without GCP (37 cases); Group 5-other lesions (8 cases). RESULTS: Engel Class I outcome was observed in 83% of patients with ELGT (Class IA in 63%); in 59% of patients with isolated FCD, with FCD Type II showing a better prognosis than FCD Type I; in 82% of patients with isolated MTS (Class IA in 50%), with MTS Type 1a and MTS Type 1b showing a better prognosis than MTS Type 2 and patients with MTS and GCP having better postsurgical results than those with MTS without GCP. Engel Class I outcome was also achieved in 84% of patients with FCD associated with MTS (Engel Class IA in 62%); also in this group MTS 1a and MTS 1b associated with FCD showed a better prognosis than FCD associated with MTS 2. Finally, Engel Class I was also achieved in 2 patients with vascular malformation and in 1 with a temporal pole encephalocele. CONCLUSIONS: Patients with MTLE and ELGT, MTS, or MTS associated with FCD showed the best postsurgical seizure outcome (Engel Class I in more than 80% of cases), whereas only 63% of patients with isolated FCD achieved the same type of outcome. Interestingly, the analysis of seizure outcome in histopathological subtypes of FCD and of MTS showed different prognoses in the different pathological subgroups, with worse outcomes for atypical MTS, absence of GCP, and isolated FCD Type I. PMID- 23641823 TI - Dissociation of vasospasm-related morbidity and outcomes in patients with aneurysmal subarachnoid hemorrhage treated with clazosentan: a meta-analysis of randomized controlled trials. AB - OBJECT: Clazosentan therapy after aneurysmal subarachnoid hemorrhage (SAH) has been found to be effective in reducing the incidence of vasospasm in randomized controlled trials. However, while vasospasm-related morbidity, including delayed ischemic neurological deficits (DINDs) and delayed cerebral infarctions, was consistently decreased, statistical significance was not demonstrated and outcomes were not affected by clazosentan treatment. The objective of this meta analysis was to determine whether clazosentan treatment after aneurysmal SAH significantly reduced the incidence of DINDs and delayed cerebral infarctions and improved outcomes. METHODS: All randomized controlled trials investigating the effect of clazosentan were retrieved via searches with sensitive and specific terms. Six variables were abstracted after the assessment of the methodological quality of the trials. Analyses were performed following the method guidelines of the Cochrane Back Review Group. RESULTS: Four randomized, placebo-controlled trials met eligibility criteria, enrolling a total of 2181 patients. The meta analysis demonstrated a significant decrease in the incidence of DINDs (relative risk [RR] 0.76 [95% CI 0.62-0.92]) and delayed cerebral infarction (RR 0.79 [95% CI 0.63-1.00]) in patients treated with clazosentan after aneurysmal SAH. However, this treatment regimen was not shown to outcomes including functional outcomes measured by Glasgow Outcome Scale-Extended (RR 1.12 [95% CI 0.96-1.30]) or mortality (RR 1.02 [95%CI 0.70-1.49]). Adverse events, including pulmonary complications, anemia, and hypotension, were all significantly increased in patients who received clazosentan therapy. CONCLUSIONS: The results of the present meta-analysis show that treatment with clazosentan after aneurysmal SAH significantly reduced the incidence of the vasospasm-related DINDs and delayed cerebral infarctions, but did not improve poor neurological outcomes in patients with aneurysmal SAH. Further study is required to elucidate the dissociation between vasospasm-related morbidity and outcomes. PMID- 23641824 TI - Risk factor analysis of the development of new neurological deficits following supplementary motor area resection. AB - OBJECT: Supplementary motor area (SMA) resection often induces postoperative contralateral hemiparesis or speech disturbance. This study was performed to assess the neurological impairments that often follow SMA resection and to assess the risk factors associated with these postoperative deficits. METHODS: The records for patients who had undergone SMA resection for pharmacologically intractable epilepsy between 1994 and 2010 were gleaned from an epilepsy surgery database and retrospectively reviewed in this study. RESULTS: Forty-three patients with pharmacologically intractable epilepsy underwent SMA resection with intraoperative cortical stimulation and mapping while under awake anesthesia. The mean patient age was 31.7 years (range 15-63 years), and the mean duration and frequency of seizures were 10.4 years (range 0.1-30 years) and 14.6 per month (range 0.1-150 per month), respectively. Pathological examination of the brain revealed cortical dysplasia in 18 patients (41.9%), tumors in 16 patients (37.2%), and other lesions in 9 patients (20.9%). The mean duration of the follow up period was 84.0 months (range 24-169 months). After SMA resection, 23 patients (53.5%) experienced neurological deficits. Three patients (7.0%) experienced permanent deficits, and 20 (46.5%) experienced symptoms that were transient. All permanent deficits involved contralateral weakness, whereas the transient symptoms patients experienced were varied, including contralateral weaknesses in 15, apraxia in 1, sensory disturbances in 1, and dysphasia in 6. Thirteen patients recovered completely within 1 month. Univariate analysis revealed that resection of the SMA proper, a shorter lifetime seizure history (<10 years), and resection of the cingulate gyrus in addition to the SMA were associated with the development of neurological deficits (p=0.078, 0.069, and 0.023, respectively). Cingulate gyrus resection was the only risk factor identified on multivariate analysis (p=0.027, OR 6.530, 95% CI 1.234-34.562). CONCLUSIONS: Resection of the cingulate gyrus in addition to the SMA was significantly associated with the development of postoperative neurological impairment. PMID- 23641825 TI - Nonsurgical treatment of chronic subdural hematoma with tranexamic acid. AB - OBJECT: Chronic subdural hematoma (CSDH) is a common condition after head trauma. It can often be successfully treated surgically by inserting a bur hole and draining the liquefied hematoma. However, to the best of the authors' knowledge, for nonemergency cases not requiring surgery, no reports have indicated the best approach for preventing hematoma enlargement or resolving it completely. The authors hypothesized that hyperfibrinolysis plays a major role in liquefaction of the hematoma. Therefore, they evaluated the ability of an antifibrinolytic drug, tranexamic acid, to completely resolve CSDH compared with bur hole surgery alone. METHODS: From 2007 to 2011, a total of 21 patients with CSDH seen consecutively at Kuki General Hospital, Japan, were given 750 mg of tranexamic acid orally every day. Patients were identified by a retrospective records review, which collected data on the volume of the hematoma (based on radiographic measurements) and any complications. Follow-up for each patient consisted of CT or MRI every 21 days from diagnosis to resolution of the CSDH. RESULTS: Of the 21 patients, 3 with early stages of CSDH were treated by bur hole surgery before receiving medical therapy. The median duration of clinical and radiographic follow-up was 58 days (range 28-137 days). Before tranexamic acid therapy was initiated, the median hematoma volume for the 21 patients was 58.5 ml (range 7.5-223.2 ml); for the 18 patients who had not undergone surgery, the median hematoma volume was 55.6 ml (range 7.5-140.5 ml). After therapy, the median volume for all 21 patients was 3.7 ml (range 0-22.1 ml). No hematomas recurred or progressed. CONCLUSIONS: Chronic subdural hematoma can be treated with tranexamic acid without concomitant surgery. Tranexamic acid might simultaneously inhibit the fibrinolytic and inflammatory (kinin-kallikrein) systems, which might consequently resolve CSDH. This medical therapy could prevent the early stages of CSDH that can occur after head trauma and the recurrence of CSDH after surgery. PMID- 23641827 TI - Supplementary motor resections. PMID- 23641828 TI - Addendum: Evidence supports a "no-touch" approach to neuromuscular choristoma. PMID- 23641829 TI - Clinicopathological characteristics and treatment of rhabdoid glioblastoma. AB - OBJECT: Rhabdoid glioblastoma (GB) is an exceedingly rare tumor in which some of the tumor cells possess rhabdoid features such as eccentric nuclei, abundant eosinophilic cytoplasm, and pseudopapillary formations. These tumors are exceptionally aggressive, and leptomeningeal dissemination is common. In the 9 previously reported cases, the longest survival was only 9 months, with a median survival of 17.8 weeks. The authors report the clinicopathological characteristics of 4 cases of rhabdoid GB and demonstrate the utility of intensive temozolomide and adjuvant therapy in these tumors. The authors also review the literature to provide the most comprehensive understanding of these rare tumors to date. METHODS: A retrospective review was performed of patients treated for GB at the Duke University Medical Center between 2004 and 2012. One of two experienced neuropathologists identified 4 cases as being rhabdoid GBs. Immunohistochemistry and fluorescence in situ hybridization analyses were performed in all cases. Kaplan-Meier analysis was used to assess overall survival, with the log-rank test being used to evaluate differences between survival curves. An extensive review of the literature was also performed. RESULTS: The median age of patients with rhabdoid GB was 30 years. Clinical presentation varied with location, with headache being a presenting symptom in 90% of patients. All lesions were supratentorial, and 45.5% of the cases involved the temporal lobe. Leptomeningeal dissemination occurred in 63.6% of patients, with 1 patient having extracranial metastasis to the scalp and lungs. Fluorescence in situ hybridization revealed epidermal growth factor receptor gain or amplification in all study cases. The median survival in the authors' cohort was significantly higher than that of all previously reported cases (27.5 vs 4.5 months, p = 0.003). Postoperative treatment in the authors' cohort included radiotherapy with concurrent temozolomide, bevacizumab, interleukin 13, CCNU, and/or etoposide. CONCLUSIONS: Enhanced survival in the authors' 4 patients suggests that the current standard of care for the treatment of GB may be beneficial in rhabdoid GB cases, with postoperative radiotherapy and concomitant temozolomide treatment followed by adjuvant therapy. Due to the rapid tumor dissemination associated with these lesions, aggressive and timely therapy is warranted, with frequent surveillance and/or continued therapy despite stable disease. Additionally, patients should undergo full craniospinal imaging to monitor the development of distant metastatic disease. PMID- 23641830 TI - Social validation of vocabulary selection: ensuring stakeholder relevance. AB - The vocabulary needs of individuals who are unable to spell their messages continue to be of concern in the field of augmentative and alternative communication (AAC). Social validation of vocabulary selection has been suggested as one way to improve the effectiveness and relevance of service delivery in AAC. Despite increased emphasis on stakeholder accountability, social validation is not frequently used in AAC research. This paper describes an investigation of the social validity of a vocabulary set identified in earlier research. A previous study used stakeholder focus groups to identify vocabulary that could be used by South African adults who use AAC to disclose their experiences as victims of crime or abuse. Another study used this vocabulary to create communication boards for use by adults with complex communication needs. In this current project, 12 South African adults with complex communication needs who use AAC systems used a 5-point Likert scale to score the importance of each of the previously identified 57 vocabulary items. This two-step process of first using stakeholder focus groups to identify vocabulary, and then having literate persons who use AAC provide information on social validity of the vocabulary on behalf of their peers who are illiterate, appears to hold promise as a culturally relevant vocabulary selection approach for sensitive topics such as crime and abuse. PMID- 23641831 TI - Association of the sense of coherence with physical and psychosocial health in the rehabilitation of osteoarthritis of the hip and knee: a prospective cohort study. AB - BACKGROUND: According to Antonovsky's salutogenic concept, a strong sense of coherence is associated with physical and psychological health. The goal of this study was to analyze the association of Antonovsky's sense of coherence with physical and psychosocial health components in patients with hip and knee osteoarthritis before and after in- and outpatient rehabilitation. METHODS: Prospective cohort study with 335 patients, 136 (41%) with hip and 199 (59%) with knee osteoarthritis. The outcome was measured by Short Form-36 (SF-36), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Sense of Coherence (SOC-13). Baseline scores of the SF-36 and WOMAC scales and the observed effect sizes after rehabilitation were correlated with the baseline SOC 13. These correlations of the SF-36 scales were compared to the Factor Score Coefficients for the Mental Component Summary of SF-36, which quantify the factor load on the psychosocial dimension. Predictive impact of the baseline SOC-13 for the SF-36 and WOMAC scales (baseline scores and effect sizes) was then determined by multivariate linear regression controlled for possible confounders. RESULTS: At baseline, the SOC-13 correlated with the WOMAC scores between r = 0.18 (stiffness) and r = 0.25 (pain) and with the SF-36 scores between r = 0.10 (physical functioning) and r = 0.53 (mental health). The correlation of these SF 36 correlation coefficients to the Factor Score Coefficient of the SF-36 Mental Component Summary was r = 0.95. The correlations for the effect sizes (baseline > discharge) with the baseline SOC-13 global score were all negative and varied between r = 0.00 (physical functioning) and r = -0.19 (social functioning). In the multivariate linear regression model, the explained variance of the SF-36 scores by the baseline SOC-13 increased continuously from physical to psychosocial health dimensions (from 12.9% to 29.8%). This gradient was consistently observed for both the baseline scores and the effect sizes. The results of the WOMAC were consistent with the physical health scales of SF-36. CONCLUSIONS: The sense of coherence was associated with psychosocial health dimensions but hardly with physical health. The higher the load of a scale on the psychosocial dimension the higher was its correlation to the sense of coherence. This is in contrast to the idea of Antonovsky who predicted high associations with both mental and physical health. PMID- 23641832 TI - Serum microRNAs profile from genome-wide serves as a fingerprint for diagnosis of acute myocardial infarction and angina pectoris. AB - BACKGROUND: In order to identify miRNAs expression profiling from genome-wide screen for diagnosis of acute myocardial infarction (AMI) and angina pectoris (AP), we investigated the altered profile of serum microRNAs in AMI and AP patients at a relative early stage. METHODS: Serum samples were taken from 117 AMI patients, 182 AP patients and 100 age-and gender-matched controls. An initial screening of miRNAs expression was performed by Solexa sequencing. Differential expression was validated using RT-qPCR in individuals samples, the samples were arranged in a two-phase selection and validation. RESULTS: The Solexa sequencing results demonstrated marked upregulation of serum miRNAs in AMI patients compared with controls. RT-qPCR analysis identified a profile of six serum miRNAs (miR-1, miR-134, miR-186, miR-208, miR-223 and miR-499) as AMI biomarkers. MiR-208 and miR-499 were elevated higher in AP cases than in AMI cases. The ROC curves indicated a panel of six miRNAs has a great potential to offer sensitive and specific diagnostic tests for AMI. More especially, the panel of six miRNAs presents significantly differences between the AMI and AP cases. CONCLUSIONS: The six-miRNAs signature identified from genome-wide serum miRNA expression profiling may serves as a fingerprint for AMI and AP diagnosis. PMID- 23641833 TI - Acanthoparyphium sp. and other metazoan symbionts of the American oyster, Crassostrea virginica, from South Texas. AB - In this study, we investigated oysters, Crassostrea virginica , from Laguna Madre in South Texas, where a 45-yr old study recorded metacercarial infections of the echinostomatid trematode, Acanthoparyphium spinulosum , an Asian relative of which, Acanthoparyphium tyosenense, has been associated with human infections via the ingestion of raw mollusks. In an effort to examine the base-line infection parameters of Acanthoparyphium sp. in oysters, we examined the effect of distance from the shoreline, which is the habitat of the first intermediate host snail, Cerithidea pliculosa, as well as temporal changes in oyster infection levels, by conducting quarterly collections of oysters during a year. We found that almost all oysters (prevalence = 97.8-100%) were infected regardless of distance to the shoreline and season. However, the abundance of metacercariae was significantly higher close to the shoreline, while no significant temporal changes could be detected. In addition to the echinostomatid, we found a high abundance of the metacestode Tylocephalum sp. and the presence of 4 other metazoan parasites. None of the infections seemed to incur significant tissue damage to the oysters. Our study shows that at least locally, recreational harvesters of oysters may be exposed to Acanthoparyphium sp. Future studies should examine oysters from snail host habitats in the Gulf of Mexico, and the potential zoonotic risk of Acanthoparyphium sp. should be evaluated using experimental infections of animal models. PMID- 23641834 TI - The Oys of Yiddish. PMID- 23641835 TI - Nudging and informed consent. AB - Libertarian paternalism's notion of "nudging" refers to steering individual decision making so as to make choosers better off without breaching their free choice. If successful, this may offer an ideal synthesis between the duty to respect patient autonomy and that of beneficence, which at times favors paternalistic influence. A growing body of literature attempts to assess the merits of nudging in health care. However, this literature deals almost exclusively with health policy, while the question of the potential benefit of nudging for the practice of informed consent has escaped systematic analysis. This article focuses on this question. While it concedes that nudging could amount to improper exploitation of cognitive weaknesses, it defends the practice of nudging in a wide range of other conditions. The conclusion is that, when ethically legitimate, nudging offers an important new paradigm for informed consent, with a special potential to overcome the classical dilemma between paternalistic beneficence and respect for autonomy. PMID- 23641836 TI - Nudging, autonomy, and valid consent: context matters. PMID- 23641837 TI - Presumed consent models and health information exchanges: hard nudges and ambiguous benefits. PMID- 23641838 TI - Nudging and the complicated real life of "informed consent". PMID- 23641839 TI - Nudging without ethical fudging: clarifying physician obligations to avoid ethical compromise. PMID- 23641840 TI - Trust versus paternalism. PMID- 23641841 TI - Should we nudge informed consent? PMID- 23641842 TI - Context is all important in investigating attitudes: acceptability depends on the nature of the nudge, who nudges, and who is nudged. PMID- 23641843 TI - And as for the nudgees? PMID- 23641844 TI - Habits, nudges, and consent. PMID- 23641845 TI - "Nudging" and informed consent revisited: why "nudging" fails in the clinical context. PMID- 23641846 TI - On nudging and informed consent--four key undefended premises. PMID- 23641847 TI - Nudging in interpersonal contexts. PMID- 23641848 TI - Nudging the older person into care: an end to the dilemma? PMID- 23641849 TI - Autonomy support to foster individuals' flourishing. PMID- 23641850 TI - Toward a more stable blood supply: charitable incentives, donation rates, and the experience of September 11. AB - Although excess blood collection has characterized U.S. national disasters, most dramatically in the case of September 11, periodic shortages of blood have recurred for decades. In response, I propose a new model of medical philanthropy, one that specifically uses charitable contributions to health care as blood donation incentives. I explain how the surge in blood donations following 9/11 was both transient and disaster-specific, failing to foster a greater continuing commitment to donate blood. This underscores the importance of considering blood donation incentives. I defend charitable incentives as an alternative to financial incentives, which I contend would further extend neoliberal market values into health care. I explain my model's potential appeal to private foundations or public-private partnerships as a means for expanding both the pool of blood donors and the prosocial benefit of each act of blood donation. Finally I link my analysis to the empirical literature on blood donation incentives. PMID- 23641851 TI - A gift that some cannot give: the ethical significance of the ban on gay/bisexual men as blood donors. PMID- 23641852 TI - A Canadian perspective on Sass's proposal to initiate charitable incentives for blood donation. PMID- 23641853 TI - Access, entanglement, and prosociality. PMID- 23641854 TI - Charitable incentives for blood donation are promising, but require careful consideration. PMID- 23641855 TI - Medical philanthropy and blood supply in light of ethical documents and principles. PMID- 23641859 TI - Gold-catalyzed reactions between alkenyldiazo carbonyl species and acetals. AB - In the presence of catalyst IPrAuSbF6 catalyst (IPr = 1,3 bis(diisopropylphenyl)imidazol-2-ylidene), alkenyldiazo carbonyl species react with organic acetals to give E-configured alkyl 3,5-dimethoxy-5-pent-2-enoates stereoselectively. This reaction sequence comprises an initial Prins-type reaction, followed by gold carbene formation. PMID- 23641860 TI - The Housing First Model (HFM) fidelity index: designing and testing a tool for measuring integrity of housing programs that serve active substance users. AB - BACKGROUND: The Housing First Model (HFM) is an approach to serving formerly homeless individuals with dually diagnosed mental health and substance use disorders regardless of their choice to use substances or engage in other risky behaviors. The model has been widely diffused across the United States since 2000 as a result of positive findings related to consumer outcomes. However, a lack of clear fidelity guidelines has resulted in inconsistent implementation. The research team and their community partner collaborated to develop a HFM Fidelity Index. We describe the instrument development process and present results from its initial testing. METHODS: The HFM Fidelity Index was developed in two stages: (1) a qualitative case study of four HFM organizations and (2) interviews with 14 HFM "users". Reliability and validity of the index were then tested through phone interviews with staff members of permanent housing programs. The final sample consisted of 51 programs (39 Housing First and 12 abstinence-based) across 35 states. RESULTS: The results provided evidence for the overall reliability and validity of the index. CONCLUSIONS: The results demonstrate the index's ability to discriminate between housing programs that employ different service approaches. Regarding practice, the index offers a guide for organizations seeking to implement the HFM. PMID- 23641862 TI - Plasmon-mediated resonance energy transfer by metallic nanorods. AB - We investigate the enhancement of the resonance energy transfer rate between donor and acceptor associated by the surface plasmons of the Ag nanorods on a SiO2 substrate. Our results for a single nanorod with different cross sections reveal that the cylinder nanorod has the strongest ability to enhance the resonance energy transfer rate. Moreover, for donor and acceptor with nonparallel polarization directions, we propose simple V-shaped nanorod structures which lead to the remarkable resonance energy transfer enhancement that is ten times larger than that by the single nanorod structure. We demonstrate that these structures have good robustness and controllability. Our work provides a way to improve the resonance energy transfer efficiency in integrated photonic devices. PACS: 78.67.Qa, 73.20.Mf, 42.50.Ex. PMID- 23641861 TI - Protective role of DNJ-27/ERdj5 in Caenorhabditis elegans models of human neurodegenerative diseases. AB - AIMS: Cells have developed quality control systems for protection against proteotoxicity. Misfolded and aggregation-prone proteins, which are behind the initiation and progression of many neurodegenerative diseases (ND), are known to challenge the proteostasis network of the cells. We aimed to explore the role of DNJ-27/ERdj5, an endoplasmic reticulum (ER)-resident thioredoxin protein required as a disulfide reductase for the degradation of misfolded proteins, in well established Caenorhabditis elegans models of Alzheimer, Parkinson and Huntington diseases. RESULTS: We demonstrate that DNJ-27 is an ER luminal protein and that its expression is induced upon ER stress via IRE-1/XBP-1. When dnj-27 expression is downregulated by RNA interference we find an increase in the aggregation and associated pathological phenotypes (paralysis and motility impairment) caused by human beta-amyloid peptide (Abeta), alpha-synuclein (alpha-syn) and polyglutamine (polyQ) proteins. In turn, DNJ-27 overexpression ameliorates these deleterious phenotypes. Surprisingly, despite being an ER-resident protein, we show that dnj 27 downregulation alters cytoplasmic protein homeostasis and causes mitochondrial fragmentation. We further demonstrate that DNJ-27 overexpression substantially protects against the mitochondrial fragmentation caused by human Abeta and alpha syn peptides in these worm models. INNOVATION: We identify C. elegans dnj-27 as a novel protective gene for the toxicity associated with the expression of human Abeta, alpha-syn and polyQ proteins, implying a protective role of ERdj5 in Alzheimer, Parkinson and Huntington diseases. CONCLUSION: Our data support a scenario where the levels of DNJ-27/ERdj5 in the ER impact cytoplasmic protein homeostasis and the integrity of the mitochondrial network which might underlie its protective effects in models of proteotoxicity associated to human ND. PMID- 23641863 TI - Expression of phosphatase of regenerating liver family genes during embryogenesis: an evolutionary developmental analysis among Drosophila, amphioxus, and zebrafish. AB - BACKGROUND: Phosphatase of regenerating liver (PRL) family is classified as class IVa of protein tyrosine phosphatase (PTP4A) that removes phosphate groups from phosphorylated tyrosine residues on proteins. PRL phosphatases have been implicated in a number of tumorigenesis and metastasis processes and are highly conserved. However, the understanding of PRL expression profiles during embryonic development is very limited. RESULTS: In this study, we demonstrated and characterized the comprehensive expression pattern of Drosophila PRL, amphioxus PRL, and zebrafish PRLs during embryonic development by either whole mount immunostaining or in situ hybridization. Our results indicate that Drosophila PRL is mainly enriched in developing mid-guts and central nervous system (CNS) in embryogenesis. In amphioxus, initially PRL gene is expressed ubiquitously during early embryogenesis, but its expression become restricted to the anterior neural tube in the cerebral vesicle. In zebrafish, PRL-1 and PRL-2 share similar expression patterns, most of which are neuronal lineages. In contrast, the expression of zebrafish PRL-3 is more specific and preferential in muscle. CONCLUSIONS: This study, for the first time, elucidated the embryonic expression pattern of Drosophila, amphioxus, and zebrafish PRL genes. The shared PRL expression pattern in the developing CNS among diverse animals suggests that PRL may play conserved roles in these animals for CNS development. PMID- 23641864 TI - Imidafenacin for the treatment of overactive bladder. AB - INTRODUCTION: Imidafenacin (KRP-197/ONO-8025) is the latest antimuscarinic (AM) developed for the treatment of overactive bladder syndrome (OAB) and, at the moment, it is marketed only in Japan. This compound has been developed to improve the tolerability of AM therapy by binding specifically the M3 receptor subtype, thus limiting undesirable adverse events (AEs). AREAS COVERED: This systematic review offers a brief explanation of the mechanism of action and of the pharmacokinetics of imidafenacin and helps readers to understand the clinical efficacy, tolerability, and safety of the compound in the setting of OAB therapy. EXPERT OPINION: Imidafenacin is an AM drug with excellent efficacy, tolerability, and safety. It is indicated for patients with nocturia, nocturnal polyuria, and benign prostatic hyperplasia. This compound, due to its pharmacokinetic properties, gives the opportunity to be easily adjusted in its dosages. Further studies should assess the pharmacokinetics, clinical efficacy, safety, and tolerability of imidafenacin in Caucasian and African populations because this AM agent, at the moment, has been evaluated just in Asian populations. More studies should evaluate and compare efficacy, safety, and tolerability of imidafenacin also with other largely utilized AMs, such as oxybutynin, tolterodine, and fesoterodine, or with the other M3 selective compound, darifenacin. PMID- 23641866 TI - Preface: RECOMB systems biology, regulatory genomics, and DREAM 2012 special issue. PMID- 23641865 TI - Genetic analysis and epidemiology of Crimean Congo Hemorrhagic fever viruses in Baluchistan province of Pakistan. AB - BACKGROUND: Pakistan is considered as an endemic country for Crimean-Congo Hemorrhagic fever with numerous outbreaks and sporadic cases reported during the past two decades. Majority of cases are reported from Baluchistan province with subsequent transmissions to non-endemic regions mainly through infected animals directly or via infested ticks. We hereby describe the molecular investigations of CCHF cases reported during 2008 in Quetta city of Baluchistan province. METHODS: Serum Samples from 44 patients, with clinical signs of hemorrhagic fever attending a tertiary care hospital in Quetta city, were collected and tested for CCHF virus antigen and genomic RNA, using capture IgM EIA kit and standard RT-PCR assay, respectively. The partial S-gene fragments were directly sequenced to get information related to the prevailing CCHFV genotypes and their molecular epidemiology in Pakistan. RESULTS: Out of the total forty four, sixteen (36%) samples were found positive for CCHF IgM. Similarly, viral RNA was detected in six (16%) samples. Phylogenetic analysis revealed that all study viruses belong to genotype Asia-1 with closest similarity (99-100%) to the previously reported strains from Pakistan, Afghanistan and Iran. CONCLUSION: We conclude that CCHF virus remains endemic within Baluchistan and its neighboring regions of Afghanistan warranting a need of incessant surveillance activities. PMID- 23641867 TI - Optimal sparsity criteria for network inference. AB - Gene regulatory network inference (that is, determination of the regulatory interactions between a set of genes) provides mechanistic insights of central importance to research in systems biology. Most contemporary network inference methods rely on a sparsity/regularization coefficient, which we call zeta (zeta), to determine the degree of sparsity of the network estimates, that is, the total number of links between the nodes. However, they offer little or no advice on how to select this sparsity coefficient, in particular, for biological data with few samples. We show that an empty network is more accurate than estimates obtained for a poor choice of zeta. In order to avoid such poor choices, we propose a method for optimization of zeta, which maximizes the accuracy of the inferred network for any sparsity-dependent inference method and data set. Our procedure is based on leave-one-out cross-optimization and selection of the zeta value that minimizes the prediction error. We also illustrate the adverse effects of noise, few samples, and uninformative experiments on network inference as well as our method for optimization of zeta. We demonstrate that our zeta optimization method for two widely used inference algorithms--Glmnet and NIR--gives accurate and informative estimates of the network structure, given that the data is informative enough. PMID- 23641868 TI - Top-down network analysis to drive bottom-up modeling of physiological processes. AB - Top-down analyses in systems biology can automatically find correlations among genes and proteins in large-scale datasets. However, it is often difficult to design experiments from these results. In contrast, bottom-up approaches painstakingly craft detailed models that can be simulated computationally to suggest wet lab experiments. However, developing the models is a manual process that can take many years. These approaches have largely been developed independently. We present LINKER, an efficient and automated data-driven method that can analyze molecular interactomes to propose extensions to models that can be simulated. LINKER combines teleporting random walks and k-shortest path computations to discover connections from a source protein to a set of proteins collectively involved in a particular cellular process. We evaluate the efficacy of LINKER by applying it to a well-known dynamic model of the cell division cycle in Saccharomyces cerevisiae. Compared to other state-of-the-art methods, subnetworks computed by LINKER are heavily enriched in Gene Ontology (GO) terms relevant to the cell cycle. Finally, we highlight how networks computed by LINKER elucidate the role of a protein kinase (Cdc5) in the mitotic exit network of a dynamic model of the cell cycle. PMID- 23641869 TI - Variation in spatial and temporal incidence of the crustacean pathogen Hematodinium perezi in environmental samples from Atlantic Coastal Bays. AB - BACKGROUND: Hematodinium perezi, a parasitic dinoflagellate, infects and kills blue crabs, Callinectes sapidus, along the Atlantic and Gulf coasts of the United States. The parasite proliferates within host hemolymph and tissues, and also produces free-swimming biflagellated dinospores that emerge from infected crabs. Infections in C. sapidus recur annually, and it is not known if biotic or environmental reservoirs contribute to reinfection and outbreaks. To address this data gap, a quantitative PCR assay based on the internal transcribed spacer 2 (ITS2) region of H. perezi rRNA genes was developed to asses the temporal and spatial incidence of the parasite in Delaware and Maryland coastal bays. RESULTS: A previously-used PCR assay for H. perezi, based on the small subunit rRNA gene sequence, was found to lack adequate species specificity to discriminate non Hematodinium sp. dinoflagellate species in environmental samples. A new ITS2 targeted assay was developed and validated to detect H. perezi DNA in sediment and water samples using E. coli carrying the H. perezi rDNA genes. Application of the method to environmental samples identified potential hotspots in sediment in Indian River Inlet, DE and Chincoteague Bay, MD and VA. H. perezi DNA was not detected in co-occurring shrimp or snails, even during an outbreak of the parasite in C. sapidus. CONCLUSIONS: H. perezi is present in water and sediment samples in Maryland and Delaware coastal bays from April through November with a wide spatial and temporal variability in incidence. Sampling sites with high levels of H. perezi DNA in both bays share characteristics of silty, organic sediments and low tidal currents. The environmental detection of H. perezi in spring, ahead of peak prevalence in crabs, points to gaps in our understanding of the parasite's life history prior to infection in crabs as well as the mode of environmental transmission. To better understand the H. perezi life cycle will require further monitoring of the parasite in habitats as well as hosts. Improved understanding of potential environmental transmission to crabs will facilitate the development of disease forecasting. PMID- 23641870 TI - Differential specificity of HIV incidence assays in HIV subtypes A and D-infected individuals from Rakai, Uganda. AB - Assays to determine HIV incidence from cross-sectional surveys have exhibited a high rate of false-recent misclassification in Kenya and Uganda where HIV subtypes A and D predominate. Samples from individuals infected with HIV for at least 2 years with known infecting subtype (133 subtype A, 373 subtype D) were tested using the BED-CEIA and an avidity assay. Both assays had a higher rate of false-recent misclassification for subtype D compared to subtype A (13.7% vs. 6.0%, p=0.02 for BED-CEIA; 11.0% vs. 1.5%, p<0.001 for avidity). For subtype D samples, false-recent misclassification by the BED-CEIA was also more frequent in women than men (15.0% vs. 5.6%, p=0.002), and for samples where that had an amino acid other than lysine at position 12 in the BED-CEIA peptide coding region (p=0.002). Furthermore in subtype D-infected individuals, samples misclassified by one assay were 3.5 times more likely to be misclassified by the other assay. Differential misclassification by infecting subtype of long-term infected individuals as recently infected makes it difficult to use these assays individually to estimate population level incidence without precise knowledge of the distribution of these subtypes within populations where subtype A and D cocirculate. The association of misclassification of the BED-CEIA with the avidity assay in subtype D-infected individuals limits the utility of using these assays in combination within this population. PMID- 23641871 TI - The influence of maltotriose-modified poly(propylene imine) dendrimers on the chronic lymphocytic leukemia cells in vitro: dense shell G4 PPI. AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia in Europe and North America. For many years scientists and doctors have been working on introducing the most effective therapy into CLL as prognosis of survival time and the course of the disease differ among patients, which might pose a problem in treating. Nanotechnology is providing new insights into diagnosis and, compared with conventional treatments, more efficient treatments, which might improve patients' comfort by decreasing side effects. Among the various nanoparticles that are available, dendrimers are one of the most promising. The aim of this study was a preliminary assessment of the clinical value of treating CLL patients with fourth generation poly(propylene imine) (PPI) dendrimers-either unmodified (PPI-G4) or approximately 90% maltotriose-modified (PPI-G4-DS-Mal-III). PPI-G4-DS Mal-III dendrimers have, in contrast to the cationic PPI-G4, a neutral surface charge and are characterized by low cyto-, geno-, and hematotoxicity in vitro and in vivo. For the in vitro study we used blood mononuclear cells collected from both untreated CLL patients and from healthy donors. Apoptosis was measured by an annexin-V (Ann-V)/propidium iodide (IP) assay, and mitochondrial membrane potential was estimated with use of Mito Tracker Red CMXRos. Presented results confirm the influence of dendrimers PPI-G4 and PPI-G4-DS-Mal-III on apoptosis and CLL lymphocytes viability in in vitro cultures. Both tested dendrimers demonstrated higher cytotoxicity to CLL cells than to healthy donors cells, whereas unmodified dendrimers were more hematotoxic. The surface modification clearly makes glycodendrimers much more suitable for biomedical applications than unmodified PPI-G4; therefore further biological evaluations of these nanoparticles are conducted in our laboratories. PMID- 23641872 TI - Evaluating the place of 18-fluoro-2-deoxy-D-glucose positron emission tomography scanning in primary staging and beyond in patients with follicular lymphoma. PMID- 23641874 TI - Detection of glucose based on bimetallic PtCu nanochains modified electrodes. AB - A series of novel bimetallic PtCu nanochains have been synthesized through a water-based mild chemical route, and their compositions (Pt(x)Cu(1-x)) can be conveniently tuned at the mesoscopic scale by a facile dealloying process. These nanomaterials have been characterized by transmission electron microscope (TEM), high-resolution TEM (HRTEM), X-ray powder diffraction (XRD), and elemental analysis. They have different compositions (Pt88Cu12, Pt75Cu25, and Pt50Cu50) but have similar morphology. Electrochemical activity of these nanomaterials is compared to Pt and nanochains of Pt when they are chemically modified onto a glassy carbon electrode. Electrochemical measurements demonstrate that the sensors made by these PtCu nanomaterials are very sensitive and selective for glucose detection due to the wiring of dispersed crystals, porous nanostructure, clean surface, and synergetic electronic effects of the alloyed atoms. Among them, the modified electrode made of Pt75Cu25 shows the best performance. The superior catalytic activity and selectivity make nanomaterials, via the green synthesis, very promising for applications in direct biosensing of glucose. PMID- 23641873 TI - Particulate matter components and subclinical atherosclerosis: common approaches to estimating exposure in a Multi-Ethnic Study of Atherosclerosis cross-sectional study. AB - BACKGROUND: Concentrations of outdoor fine particulate matter (PM2.5) have been associated with cardiovascular disease. PM2.5 chemical composition may be responsible for effects of exposure to PM2.5. METHODS: Using data from the Multi Ethnic Study of Atherosclerosis (MESA) collected in 2000-2002 on 6,256 US adults without clinical cardiovascular disease in six U.S. metropolitan areas, we investigated cross-sectional associations of estimated long-term exposure to total PM2.5 mass and PM2.5 components (elemental carbon [EC], organic carbon [OC], silicon and sulfur) with measures of subclinical atherosclerosis (coronary artery calcium [CAC] and right common carotid intima-media thickness [CIMT]). Community monitors deployed for this study from 2007 to 2008 were used to estimate exposures at baseline addresses using three commonly-used approaches: (1) nearest monitor (the primary approach), (2) inverse-distance monitor weighting and (3) city-wide average. RESULTS: Using the exposure estimate based on nearest monitor, in single-pollutant models, increased OC (effect estimate [95% CI] per IQR: 35.1 MUm [26.8, 43.3]), EC (9.6 MUm [3.6,15.7]), sulfur (22.7 MUm [15.0,30.4]) and total PM2.5 (14.7 MUm [9.0,20.5]) but not silicon (5.2 MUm [ 9.8,20.1]), were associated with increased CIMT; in two-pollutant models, only the association with OC was robust to control for the other pollutants. Findings were generally consistent across the three exposure estimation approaches. None of the PM measures were positively associated with either the presence or extent of CAC. In sensitivity analyses, effect estimates for OC and silicon were particularly sensitive to control for metropolitan area. CONCLUSION: Employing commonly-used exposure estimation approaches, all of the PM2.5 components considered, except silicon, were associated with increased CIMT, with the evidence being strongest for OC; no component was associated with increased CAC. PM2.5 chemical components, or other features of the sources that produced them, may be important in determining the effect of PM exposure on atherosclerosis. These cross-sectional findings await confirmation in future work employing longitudinal outcome measures and using more sophisticated approaches to estimating exposure. PMID- 23641875 TI - The forgotten smoker: a qualitative study of attitudes towards smoking, quitting, and tobacco control policies among continuing smokers. AB - BACKGROUND: Although research suggests that the majority of smokers want to quit smoking, the uptake of Stop Smoking Services, designed to assist smokers with quitting, remains low. Little is known about continuing smokers who do not access these services, and opportunities to influence their motivation and encourage quit attempts through the uptake of services. Using PRIME theory, this study explored differences between continuing smokers who had varying levels of motivation to quit, in terms of their plans to quit, evaluative beliefs about smoking, cigarette dependence, and attitudes towards tobacco control policies and services. METHODS: Twenty-two current smokers, recruited from the community, were classified by motivation level to quit using a self-report questionnaire (two groups: high/low). Four focus groups (n=13) and individual interviews (n=9) were conducted with both groups using an interview guide incorporating aspects of PRIME theory. Discussion areas included motives for smoking, attitudes towards smoking and quitting, perceptions of dependence, motives for quitting, barriers to quitting, and attitudes towards existing and impending tobacco control policies and services. Verbatim transcripts were analysed using thematic framework analysis. RESULTS: All participants expressed low motivation to quit during discussions, despite some initially self-classifying as having high explicit levels of motivation to quit. Both groups reported similar attitudes towards smoking and quitting, including a perceived psychological addiction to smoking, positive evaluations about smoking which inhibited plans to quit, and similar suggested methods to increase motivation (simply wanting to, save money, improve health). Most felt that they 'ought' to quit as opposed to 'wanted' to. Little influence was ascribed towards tobacco control policies such as plain packaging and hidden sales displays, and participants felt that price increases of tobacco products needed to be considerable in order to influence motivation. Highly motivated smokers expressed more willingness to visit Stop Smoking Services, although none had done so. CONCLUSION: Continuing smokers' attitudes towards smoking and quitting suggests that research and policy need to focus on increasing smokers' implicit motivation to quit smoking, even for those who classified themselves as having high motivation to quit. Targeted information and further education about Stop Smoking Services is required to increase uptake. PMID- 23641876 TI - Ligand-free palladium-mediated site-specific protein labeling inside gram negative bacterial pathogens. AB - Palladium, a key transition metal in advancing modern organic synthesis, mediates diverse chemical conversions including many carbon-carbon bond formation reactions between organic compounds. However, expanding palladium chemistry for conjugation of biomolecules such as proteins, particularly within their native cellular context, is still in its infancy. Here we report the site-specific protein labeling inside pathogenic Gram-negative bacterial cells via a ligand free palladium-mediated cross-coupling reaction. Two rationally designed pyrrolysine analogues bearing an aliphatic alkyne or an iodophenyl handle were first encoded in different enteric bacteria, which offered two facial handles for palladium-mediated Sonogashira coupling reaction on proteins within these pathogens. A GFP-based bioorthogonal reaction screening system was then developed, allowing evaluation of both the efficiency and the biocompatibilty of various palladium reagents in promoting protein-small molecule conjugation. The identified simple compound-Pd(NO3)2 exhibited high efficiency and biocompatibility for site-specific labeling of proteins in vitro and inside living E. coli cells. This Pd-mediated protein coupling method was further utilized to label and visualize a Type-III Secretion (T3S) toxin-OspF in Shigella cells. Our strategy may be generally applicable for imaging and tracking various virulence proteins within Gram-negative bacterial pathogens. PMID- 23641877 TI - Detection of orally administered inositol stereoisomers in mouse blood plasma and their effects on translocation of glucose transporter 4 in skeletal muscle cells. AB - Simple pharmacological studies on inositol stereoisomers are presented in this study. Male ICR mice were orally administered 1 g/kg BW of three inositol stereoisomers, myo-inositol (MI), d-chiro-inositol (DCI), and scyllo-inositol (SI), and blood plasma samples and skeletal muscle fractions were prepared after an hour. The plasma samples were subjected to gas chromatography-coupled time-of flight mass spectrometry (GC-TOF-MS) analysis. None of the three stereoisomers was seen in untreated samples, but substantial amounts ranging from 2.5 to 6.5 mM were detected only after administration, indicating that orally administered inositol stereoisomers were readily absorbed and their levels elevated in the bloodstream. In addition, plasma of SI-administered animals contained substantial MI, suggesting a possible metabolic conversion of SI to MI. In the skeletal muscle fractions, glucose transporter type 4 (GLUT4) content in the plasma membrane increased, indicating that inositol stereoisomers stimulated GLUT4 translocation. PMID- 23641878 TI - TNA4OptFlux--a software tool for the analysis of strain optimization strategies. AB - BACKGROUND: Rational approaches for Metabolic Engineering (ME) deal with the identification of modifications that improve the microbes' production capabilities of target compounds. One of the major challenges created by strain optimization algorithms used in these ME problems is the interpretation of the changes that lead to a given overproduction. Often, a single gene knockout induces changes in the fluxes of several reactions, as compared with the wild type, and it is therefore difficult to evaluate the physiological differences of the in silico mutant. This is aggravated by the fact that genome-scale models per se are difficult to visualize, given the high number of reactions and metabolites involved. FINDINGS: We introduce a software tool, the Topological Network Analysis for OptFlux (TNA4OptFlux), a plug-in which adds to the open-source ME platform OptFlux the capability of creating and performing topological analysis over metabolic networks. One of the tool's major advantages is the possibility of using these tools in the analysis and comparison of simulated phenotypes, namely those coming from the results of strain optimization algorithms. We illustrate the capabilities of the tool by using it to aid the interpretation of two E. coli strains designed in OptFlux for the overproduction of succinate and glycine. CONCLUSIONS: Besides adding new functionalities to the OptFlux software tool regarding topological analysis, TNA4OptFlux methods greatly facilitate the interpretation of non-intuitive ME strategies by automating the comparison between perturbed and non-perturbed metabolic networks. The plug-in is available on the web site http://www.optflux.org, together with extensive documentation. PMID- 23641880 TI - Endocrine disorders in the neonatal period. AB - CME EDUCATIONAL OBJECTIVES: 1.Review common endocrine conditions that often present in the newborn and perinatal period.2.Determine the enzymes involved in steroidogenesis.3.Discuss the diagnostic evaluation of hypoglycemia. Many endocrine conditions are unique to the perinatal period. In this article, we review many such conditions, including disorders of the pituitary gland, disorders of sexual differentiation, disorders of glucose homeostasis, disorders of the thyroid gland, and disorders of calcium homeostasis. Rather than serving as a comprehensive resource, the article is meant to serve as a guide for general pediatricians and neonatologists caring for infants with endocrine disorders. Moreover, because the field of pediatric endocrinology continues to evolve, consultation with a pediatric endocrinologist for any child with an endocrinopathy is recommended. PMID- 23641879 TI - Multi-institutional comparison of treatment planning using stereotactic ablative body radiotherapy for hepatocellular carcinoma - benchmark for a prospective multi-institutional study. AB - INTRODUCTION: Several single institution phase I and phase II trials of stereotactic ablative body radiotherapy (SABR) for liver tumors have reported promising results and high local control rates of over 90%. However, there are wide variations in dose and fractionation due to different prescription policies and treatment methods across SABR series that have been published to date.This study aims to assess and minimize inter-institutional variations in treatment planning using SABR for hepatocellular carcinoma (HCC) in preparation for a prospective multi-institutional study. METHODS: Four institutions (A-D) participated in this study. Each institution was provided with data from four cases, including planning and diagnostic CT images and clinical information, and asked to implement three plans (a practice plan and protocol plans 1 and 2). Practice plans were established based on the current treatment protocols at each institution. In protocol plan 1, each institution was instructed to prescribe 40 Gy in five fractions within 95% of the planning target volume (PTV). After protocol plan 1 was evaluated, we made protocol plan 2, The additional regulation to protocol plan 1 was that 40 Gy in five fractions was prescribed to a 70% isodose line of the global maximum dose within the PTV. Planning methods and dose volume histograms (DVHs) including the median PTV D50 (Dm50) and the median normal liver volume that received 20 Gy or higher (Vm20) were compared. RESULTS: In the practice plan, Dm50 was 48.4 Gy (range, 43.6-51.2 Gy). Vm20 was 15.9% (range, 12.2-18.9%). In protocol plan 1, the Dm50 at institution A was higher (51.2 Gy) than the other institutions (42.0-42.2 Gy) due to differences in dose specifications. In protocol plan 2, variations in DVHs were reduced. The Dm50 was 51.9 Gy (range, 51.0-53.1 Gy), and the Vm20 was 12.3% (range, 10.4-13.2%). The homogeneity index was nearly equivalent at all institutions. CONCLUSIONS: There were notable inter-institutional differences in practice planning using SABR to treat HCC. The range of PTV and normal liver DVH values was reduced when the dose was prescribed to an isodose line within the PTV. In multi-institutional studies, detailed dose specifications based on collaboration are necessary. PMID- 23641881 TI - Failure to thrive, hyponatremia, and hyperkalemia in a neonate. AB - CME EDUCATIONAL OBJECTIVES: 1.Describe the varying clinical presentations of pseudohypoaldosteronism in the neonatal period.2.Review the physiology of aldosterone production and pathophysiology of pseudohypoaldosteronism.3.Identify treatment options for pseudohypoaldosteronism when identified in the neonatal period. Pseudohypoaldosteronism type I (PHA1) is a rare disease of mineralocorticoid resistance caused by defects in sodium transport in the distal tubule of the kidney. It presents in the neonate with life-threatening dehydration due to salt wasting, accompanied by hyperkalemia, acidosis, and, frequently, failure to thrive. Patients with PHA1 are often initially diagnosed with congenital adrenal hyperplasia, but their electrolyte abnormalities are resistant to treatment with glucocorticoids and mineralocorticoids. In these patients, an astute clinician will broaden his or her differential, resulting in life-saving treatment. PMID- 23641882 TI - Feeding extremely low birth weight infants. AB - CME EDUCATIONAL OBJECTIVES: 1.List the indications for parenteral nutrition in the preterm infant.2.Estimate protein and calories required by a preterm infant to support appropriate fetal weight gain.3.Discuss the calcium and phosphorus needs of preterm infants. The patient presented as a 5-week-old 26 week preterm infant, with a birth weight of 686 g. Her mother was 25 years old. The child's Apgar scores were 6 and 7 at 1 and 5 minutes. The infant was intubated after birth and placed on the high-frequency oscillator on day of life (DOL) 3 because of worsening respiratory failure. She was placed back on conventional mechanical ventilation on DOL 7, extubated on DOL 15, and placed on 40% oxygen via nasal cannula. She was discharged home on DOL 84 without mechanical ventilation. PMID- 23641883 TI - The risks and benefits of human donor breast milk. AB - CME EDUCATIONAL OBJECTIVES: 1.Review the advantages and disadvantages of donor banked milk over informal milk sharing.2.List disadvantages of proprietary infant formula for use as supplementation.3.Determine the primary ethical concerns when electing to use donor human milk versus propriety infant formula for supplementation. The benefits of breast-feeding, as well as the risks of some artificial formula, are well known. This growing recognition of the advantages of breast-feeding is reflected in the increased incidence of breast-feeding in recent years. However, one of the most common reasons for premature weaning is low milk supply, perceived or real, followed by nipple or breast pain. Given the increased awareness of the superiority of breast milk, however, more parents are turning to human donor milk to supplement their babies after they have been weaned. PMID- 23641884 TI - The opinion of millennials. PMID- 23641886 TI - Psychiatric polypharmacy monitoring in foster care. PMID- 23641887 TI - A 9-year-old girl with recurrent infections. PMID- 23641888 TI - The many faces of facial cellulitis. PMID- 23641889 TI - A 2-month-old female infant with failure to thrive. PMID- 23641890 TI - Issues in neonatology. PMID- 23641891 TI - Autoimmune polyendocrine syndrome: a case-based review. PMID- 23641892 TI - The 'five fingers' of the diagnostic evaluation for suspected immunodeficiency. PMID- 23641893 TI - A conversation with Sheldon L. Kaplan, MD. Interview by Stanford T Shulman. PMID- 23641895 TI - Editorial. Recommendations for quality maternity care: a function of cultural context. PMID- 23641896 TI - Men's perceptions of delivery care in rural Malawi: exploring community level barriers to improving maternal health. AB - In this cross-sectional survey with qualitative components (n = 389), we explored how husbands perceive delivery care in rural Malawi. Most husbands decide on maternal health care seeking, believe in antenatal care, and prefer institutional delivery. Men acknowledge that their unfaithfulness and violence can harm the pregnancy. Most husbands feel responsible for birth preparedness, but poor availability and unforeseeable transport costs hinder care seeking in pregnancy complications. Our findings suggest that innovative birth preparedness and transport interventions that involve men, as well as the extension of antenatal care (ANC) services to men, can help overcome obstacles to improving maternal health at the community level. PMID- 23641894 TI - Oxidative stress and autophagy in cardiovascular homeostasis. AB - SIGNIFICANCE: Autophagy is an evolutionarily ancient process of intracellular protein and organelle recycling required to maintain cellular homeostasis in the face of a wide variety of stresses. Dysregulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) leads to oxidative damage. Both autophagy and ROS/RNS serve pathological or adaptive roles within cardiomyocytes, depending on the context. RECENT ADVANCES: ROS/RNS and autophagy communicate with each other via both transcriptional and post-translational events. This cross talk, in turn, regulates the structural integrity of cardiomyocytes, promotes proteostasis, and reduces inflammation, events critical to disease pathogenesis. CRITICAL ISSUES: Dysregulation of either autophagy or redox state has been implicated in many cardiovascular diseases. Cardiomyocytes are rich in mitochondria, which make them particularly sensitive to oxidative damage. Maintenance of mitochondrial homeostasis and elimination of defective mitochondria are each critical to the maintenance of redox homeostasis. FUTURE DIRECTIONS: The complex interplay between autophagy and oxidative stress underlies a wide range of physiological and pathological events and its elucidation holds promise of potential clinical applicability. PMID- 23641897 TI - Lived experiences of Ghanaian women with obstetric fistula. AB - Obstetric fistula is a worldwide problem that is devastating for women. This qualitative descriptive study explores the experiences of Ghanaian women who sustained obstetric fistula during childbirth. In-depth interviews were conducted with 10 participants. The resultant themes include cultural beliefs and practices surrounding prolonged labor in childbirth, barriers to delivering at a health care facility, and the challenges of living with obstetric fistula, including psychosocial, socioeconomic, physical, and health care access issues. Recommendations include strategies to address this complex problem, including education of men and women on safe motherhood practices, training of traditional birth attendants (TBAs), and improving access to health care. PMID- 23641898 TI - Daily temperature fluctuations unpredictably influence developmental rate and morphology at a critical early larval stage in a frog. AB - BACKGROUND: Environmental temperature has profound consequences for early amphibian development and many field and laboratory studies have examined this. Most laboratory studies that have characterized the influence of temperature on development in amphibians have failed to incorporate the realities of diel temperature fluctuations (DTF), which can be considerable for pond-breeding amphibians. RESULTS: We evaluated the effects of different ecologically relevant ranges of DTF compared with effects of constant temperatures on development of embryos and larvae of the Korean fire-bellied toad (Bombina orientalis). We constructed thermal reaction norms for developmental stage, snout-vent length, and tail length by fitting a Gompertz-Gaussian function to measurements taken from embryos after 66 hours of development in 12 different constant temperature environments between 14 degrees C and 36 degrees C. We used these reaction norms as null models to test the hypothesis that developmental effects of DTF are more than the sum of average constant temperature effects over the distribution of temperatures experienced. We predicted from these models that growth and differentiation would be positively correlated with average temperature at low levels of DTF but not at higher levels of DTF. We tested our prediction in the laboratory by rearing B. orientalis embryos at three average temperatures (20 degrees C, 24 degrees C, and 28 degrees C) and four levels of thermal variation (0 degrees C, 6 degrees C, 13 degrees C, and 20 degrees C). Several of the observed responses to DTF were significantly different from both predictions of the model and from responses in constant temperature treatments at the same average temperatures. At an average temperature of 24 degrees C, only the highest level of DTF affected differentiation and growth rates, but at both cooler and warmer average temperatures, moderate DTF was enough to slow developmental and tail growth rates. CONCLUSIONS: These results demonstrate that both the magnitude of DTF range and thermal averages need to be considered simultaneously when parsing the effects of changing thermal environments on complex developmental responses, particularly when they have potential functional and adaptive significance. PMID- 23641899 TI - The expression and evolution of virulence in multiple infections: the role of specificity, relative virulence and relative dose. AB - BACKGROUND: Multiple infections of the same host by different strains of the same microparasite species are believed to play a crucial role during the evolution of parasite virulence. We investigated the role of specificity, relative virulence and relative dose in determining the competitive outcome of multiple infections in the Daphnia magna-Pasteuria ramosa host-parasite system. RESULTS: We found that infections by P. ramosa clones (single genotype) were less virulent and produced more spores than infections by P. ramosa isolates (possibly containing multiple genotypes). We also found that two similarly virulent isolates of P. ramosa differed considerably in their within-host competitiveness and their effects on host offspring production when faced with coinfecting P. ramosa isolates and clones. Although the relative virulence of a P. ramosa isolate/clone appears to be a good indicator of its competitiveness during multiple infections, the relative dose may alter the competitive outcome. Moreover, spore counts on day 20 post-infection indicate that the competitive outcome is largely decided early in the parasite's growth phase, possibly mediated by direct interference or apparent competition. CONCLUSIONS: Our results emphasize the importance of epidemiology as well as of various parasite traits in determining the outcome of within-host competition. Incorporating realistic epidemiological and ecological conditions when testing theoretical models of multiple infections, as well as using a wider range of host and parasite genotypes, will enable us to better understand the course of virulence evolution. PMID- 23641900 TI - Evaluation of a restriction fragment length enzyme assay for differentiation of Haemoproteus and Plasmodium across a standard region of the mitochondrial genome. AB - Avian hemosporidian parasites are a genetically diverse group of parasites with a near cosmopolitan distribution. Over the past 2 decades, several PCR protocols have been designed to detect these parasites. The majority of these protocols amplify part of or the entire mitochondrial cytochrome b gene. However, many of these protocols co-amplify 2 genera (Haemoproteus and Plasmodium), making it impossible to determine which genus is amplified without post-PCR analysis. A uniform database (MalAvi), containing sequences amplified with the primers HAEMF and HAEMR2, has been developed to increase comparability across studies. We analyzed sequences from the MalAvi database and new sequences and found that digestion with EcoRV could be used to distinguish Haemoproteus from the majority of Plasmodium sequences. In addition, we tested 220 wild birds from Costa Rica and the United States for avian hemosporidians and assessed the ability of EcoRV to distinguish these 2 genera. Thirty-six positive samples were sequenced to confirm the restriction profiles, and we also analyzed 63 new hemosporidian sequences from ongoing studies in the United States for the restriction site. Among these new samples, all of the 85 Haemoproteus (subgenus Parahaemoproteus) and 14 Plasmodium were distinguishable. Overall, 887 of 898 (98.8%) sequences from our studies and the MalAvi database were assigned to the correct genus. Of these samples, all Haemoproteus samples were correctly identified and all but 11 Plasmodium samples were correctly identified by the EcoRV assay. Overall, this restriction enzyme protocol is able to quickly and efficiently classify these 2 genera of avian malarial parasites and would be useful for researchers interested in identifying parasites to genus-level, studies focused on sequence analysis of only a single genus, or for detecting co-infections that would need cloning prior to sequence analysis. PMID- 23641901 TI - Barnacle cement as surface anchor for "clicking" of antifouling and antimicrobial polymer brushes on stainless steel. AB - Barnacle cement (BC) was utilized 'beneficially' as a surface anchor on stainless steel (SS) for coupling of functional polymer brushes via "click" reactions in both "grafting-to" and "grafting-from" processes. Ethylene sulfide (ES), propargyl carbonylimidazole (PPC) and azidoethyl carbonylimidazole (AEC) reacted with amine and/or hydroxyl groups in BC to introduce the corresponding thiol, alkyne, and azide groups on SS surfaces (SS-thiol, SS-alkyne, and SS-azide, respectively). Antifouling zwitterionic SS-PMPC surface was prepared by thiol-ene photopolymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) from the SS thiol surface. Protein-resistant SS-PPEGMA and protein-adsorbing SS-PPFS surfaces were prepared by coupling of the respective azide-functionalized poly(poly(ethylene glycol)methyl ether methacrylate) (azido-PPEGMA) and poly(2,3,4,5,6-pentafluorostyrene) (azido-PPFS) polymer brushes in azide-alkyne "click" reaction. Antifouling alkyne-functionalized poly(N-hydroxyethyl acrylamide) (alkynyl-PHEAA) and antibacterial alkyne-functionalized poly(2 (methacryloyloxy)ethyl trimethylammonium chloride) (alkynyl-PMETA) polymer brushes were clicked on the SS-azide surface. Adsorption of bovine serum albumin and bacteria fouling of Gram-negative Escherichia coli ( E. coli ) and Gram positive Staphylococcus epidermidis ( S. epidermidis ) were investigated on the polymer-functionalized SS surfaces. The versatile bioanchor and functional polymer brush coatings are stable in an abiotic aqueous environment for over a month. PMID- 23641902 TI - Campath, calcineurin inhibitor reduction and chronic allograft nephropathy (3C) study: background, rationale, and study protocol. AB - BACKGROUND: Kidney transplantation is the best treatment for patients with end stage renal failure, but uncertainty remains about the best immunosuppression strategy. Long-term graft survival has not improved substantially, and one possible explanation is calcineurin inhibitor (CNI) nephrotoxicity. CNI exposure could be minimized by using more potent induction therapy or alternative maintenance therapy to remove CNIs completely. However, the safety and efficacy of such strategies are unknown. METHODS/DESIGN: The Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy (3C) Study is a multicentre, open-label, randomized controlled trial with 852 participants which is addressing two important questions in kidney transplantation. The first question is whether a Campath (alemtuzumab)-based induction therapy strategy is superior to basiliximab-based therapy, and the second is whether, from 6 months after transplantation, a sirolimus-based maintenance therapy strategy is superior to tacrolimus-based therapy. Recruitment is complete, and follow-up will continue for around 5 years post-transplant. The primary endpoint for the induction therapy comparison is biopsy-proven acute rejection by 6 months, and the primary endpoint for the maintenance therapy comparison is change in estimated glomerular filtration rate from baseline to 2 years after transplantation. The study is sponsored by the University of Oxford and endorsed by the British Transplantation Society, and 18 centers for adult kidney transplant are participating. DISCUSSION: Late graft failure is a major issue for kidney-transplant recipients. If our hypothesis that minimizing CNI exposure with Campath-based induction therapy and/or an elective conversion to sirolimus-based maintenance therapy can improve long-term graft function and survival is correct, then patients should experience better graft function for longer. A positive outcome could change clinical practice in kidney transplantation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01120028 and ISRCTN88894088. PMID- 23641903 TI - Synapsable quadruplex-mediated fibers. AB - We have fabricated a DNA-based nanofiber created by self-assembly of guanine quadruplex (Hoogsteen base pairing) and double-stranded DNA (Watson-Crick base pairing). When duplexes containing a long stretch of contiguous guanines and single-stranded overhangs are incubated in potassium-containing buffer, the preformed duplexes create high molecular weight species that contain quadruplexes. In addition to observation of these larger species by gel electrophoresis, solutions were analyzed by atomic force microscopy to reveal nanofibers. Analysis of the atomic force microscopy images indicates that fibers form with lengths ranging from 250 to 2,000 nm and heights from 0.45 to 4.0 nm. This work is a first step toward the creation of new structurally heterogeneous (quadruplex/duplex), yet controllable, DNA-based materials exhibiting novel properties suitable for a diverse array of nanotechnology applications. PMID- 23641904 TI - Clinical and economic burden of invasive pneumococcal disease in adults: a multicenter hospital-based study. AB - BACKGROUND: Streptococcus pneumoniae causes a broad spectrum of illnesses ranging from mild upper respiratory tract infections to invasive pneumococcal disease (IPD). Quantitative data on the burden of pneumococcal disease, important for the establishment of appropriate vaccination strategies, is currently lacking in adults. METHODS: This multicenter, retrospective cohort study was designed to estimate the clinical and economic burden of IPD in adults over the last decade. Data were collected from patients with IPD at 10 university hospitals in South Korea. We estimated the proportion of IPD among all hospitalized patients, the case fatality rate, and the direct medical costs of IPD. Data were further analyzed according to age and risk groups. RESULTS: During the study period, 970 patients with IPD were identified. The mean age for all patients was 60.9 years; patients aged 50-64 years (33.0%) were most numerous, followed by those aged 65 74 years (27.4%). Overall, the proportion of IPD was 0.36 cases/1000 hospitalized patients and the case fatality rate was 30.9%, which increased significantly with age (p < 0.01). The mean direct medical costs were estimated to be US $7,452 without a difference between age and risk groups. On multivariate analysis, old age, advanced ECOG performance status, bacteremic pneumonia, and nosocomial infection were independent risk factors of 30-day case fatality. CONCLUSIONS: The clinical disease burden of IPD increased significantly with age and direct medical costs from IPD were substantial, regardless of age and co-morbid conditions. The current age-based vaccination strategy appears to be appropriate. PMID- 23641905 TI - Oxidative addition of a strained C-C bond onto electron-rich rhodium(I) at room temperature. AB - The C-C bond of cyclobutanones undergoes oxidative addition to a T-shape rhodium(I) complex possessing a PBP pincer ligand at room temperature. The remarkable propensity of the rhodium complex for oxidative addition is attributed to the highly electron-donating nature of the boron ligand as well as the unsaturation on the rhodium center. PMID- 23641906 TI - Correlation of the oxygen radical activity and antioxidants and severity in critically ill surgical patients - study protocol. AB - BACKGROUND: Surgical patients who require an emergent operation commonly have severe sepsis or septic shock, followed by high morbidity and mortality rates.Despite advances in treatment however, no predictable markers are available. In severe sepsis, many pathophysiologic mechanisms are involved in progression to organ failure, and oxygen free radical and antioxidants are known to contribute to this process. Oxygen free radical and antioxidants contribute to progression of organ failure in severe sepsis. In fact, oxygen radical activity has been reported to be correlated with disease severity and prognosis in patients with severe sepsis or septic shock. Accordingly, we aim to assess the usefulness of oxygen free radical and antioxidant concentrations to predict the disease severity and mortality in a cohort of critically ill surgical patients. METHODS/DESIGN: This is a prospective observation study including patient demographic characteristics, clinical information, blood sampling/serum oxygen radical activity, serum antioxidant activity, serum antioxidant concentrations (zinc, selenium and glutamate), disease severity scores, outcomes, lengths of stay in intensive care unit, hospital 30-day mortality. PMID- 23641907 TI - Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa. AB - BACKGROUND: Cytochrome P450 3A5 (CYP3A5) is an enzyme involved in the metabolism of many therapeutic drugs. CYP3A5 expression levels vary between individuals and populations, and this contributes to adverse clinical outcomes. Variable expression is largely attributed to four alleles, CYP3A5*1 (expresser allele); CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343) (low/non expresser alleles). Little is known about CYP3A5 variability in Africa, a region with considerable genetic diversity. Here we used a multi-disciplinary approach to characterize CYP3A5 variation in geographically and ethnically diverse populations from in and around Africa, and infer the evolutionary processes that have shaped patterns of diversity in this gene. We genotyped 2538 individuals from 36 diverse populations in and around Africa for common low/non-expresser CYP3A5 alleles, and re-sequenced the CYP3A5 gene in five Ethiopian ethnic groups. We estimated the ages of low/non-expresser CYP3A5 alleles using a linked microsatellite and assuming a step-wise mutation model of evolution. Finally, we examined a hypothesis that CYP3A5 is important in salt retention adaptation by performing correlations with ecological data relating to aridity for the present day, 10,000 and 50,000 years ago. RESULTS: We estimate that ~43% of individuals within our African dataset express CYP3A5, which is lower than previous independent estimates for the region. We found significant intra-African variability in CYP3A5 expression phenotypes. Within Africa the highest frequencies of high-activity alleles were observed in equatorial and Niger-Congo speaking populations. Ethiopian allele frequencies were intermediate between those of other sub-Saharan African and non-African groups. Re-sequencing of CYP3A5 identified few additional variants likely to affect CYP3A5 expression. We estimate the ages of CYP3A5*3 as ~76,400 years and CYP3A5*6 as ~218,400 years. Finally we report that global CYP3A5 expression levels correlated significantly with aridity measures for 10,000 [Spearmann's Rho= -0.465, p=0.004] and 50,000 years ago [Spearmann's Rho= -0.379, p=0.02]. CONCLUSIONS: Significant intra African diversity at the CYP3A5 gene is likely to contribute to multiple pharmacogenetic profiles across the continent. Significant correlations between CYP3A5 expression phenotypes and aridity data are consistent with a hypothesis that the enzyme is important in salt-retention adaptation. PMID- 23641908 TI - PM2.5, oxidant defence and cardiorespiratory health: a review. AB - Airborne fine particle mass concentrations (PM2.5) are used for ambient air quality management worldwide based in part on known cardiorespiratory health effects. While oxidative stress is generally thought to be an important mechanism in determining these effects, relatively few studies have specifically examined how oxidant defence may impact susceptibility to particulate air pollution. Here we review studies that explore the impact of polymorphisms in anti-oxidant related genes or anti-oxidant supplementation on PM2.5-induced cardiorespiratory outcomes in an effort to summarize existing evidence related to oxidative stress defence and the health effects of PM2.5. Recent studies of PM-oxidative burden were also examined. In total, nine studies were identified and reviewed and existing evidence generally suggests that oxidant defence may modify the impact of PM2.5 exposure on various health outcomes, particularly heart rate variability (a measure of autonomic function) which was the most common outcome examined in the studies reviewed. Few studies examined interactions between PM2.5 and oxidant defence for respiratory outcomes, and in general studies focused primarily on acute health effects. Therefore, further evaluation of the potential modifying role of oxidant defence in PM2.5-induced health effects is required, particularly for chronic outcomes. Similarly, while an exposure metric that captures the ability of PM2.5 to cause oxidative stress may offer advantages over traditional mass concentration measurements, little epidemiological evidence is currently available to evaluate the potential benefits of such an approach. Therefore, further evaluation is required to determine how this metric may be incorporated in ambient air quality management. PMID- 23641909 TI - Optimization of human corneal endothelial cell culture: density dependency of successful cultures in vitro. AB - BACKGROUND: Global shortage of donor corneas greatly restricts the numbers of corneal transplantations performed yearly. Limited ex vivo expansion of primary human corneal endothelial cells is possible, and a considerable clinical interest exists for development of tissue-engineered constructs using cultivated corneal endothelial cells. The objective of this study was to investigate the density dependent growth of human corneal endothelial cells isolated from paired donor corneas and to elucidate an optimal seeding density for their extended expansion in vitro whilst maintaining their unique cellular morphology. RESULTS: Established primary human corneal endothelial cells were propagated to the second passage (P2) before they were utilized for this study. Confluent P2 cells were dissociated and seeded at four seeding densities: 2,500 cells per cm2 ('LOW'); 5,000 cells per cm2 ('MID'); 10,000 cells per cm2 ('HIGH'); and 20,000 cells per cm2 ('HIGH(*2)'), and subsequently analyzed for their propensity to proliferate. They were also subjected to morphometric analyses comparing cell sizes, coefficient of variance, as well as cell circularity when each culture became confluent. At the two lower densities, proliferation rates were higher than cells seeded at higher densities, though not statistically significant. However, corneal endothelial cells seeded at lower densities were significantly larger in size, heterogeneous in shape and less circular (fibroblastic-like), and remained hypertrophic after one month in culture. Comparatively, cells seeded at higher densities were significantly homogeneous, compact and circular at confluence. Potentially, at an optimal seeding density of 10,000 cells per cm2, it is possible to obtain between 10 million to 25 million cells at the third passage. More importantly, these expanded human corneal endothelial cells retained their unique cellular morphology. CONCLUSIONS: Our results demonstrated a density dependency in the culture of primary human corneal endothelial cells. Sub-optimal seeding density results in a decrease in cell saturation density, as well as a loss in their proliferative potential. As such, we propose a seeding density of not less than 10,000 cells per cm2 for regular passage of primary human corneal endothelial cells. PMID- 23641910 TI - Laboratory degradation rates of 11 pyrethroids under aerobic and anaerobic conditions. AB - Degradation of 11 pyrethroids was measured over approximately 100 days in three sediment/water systems under aerobic and anaerobic conditions at 25 degrees C in the dark. The three California sediments represented a range of textures and organic matter. Test compounds were bifenthrin, cypermethrin, zeta-cypermethrin, cyfluthrin, beta-cyfluthrin, deltamethrin, esfenvalerate, fenpropathrin, gamma cyhalothrin, lambda-cyhalothrin, and permethrin. A non-standard design was employed to keep conditions essentially the same for all compounds. The test compounds were applied as two test mixtures (six active ingredients per mixture, with bifenthrin common to both) at approximately 50 MUg of test compound/kg of sediment (dry weight). Extracts of sediment/water were cleaned up by solid-phase extraction, concentrated, and analyzed by gas chromatography/mass spectrometry (except deltamethrin) against matrix-matched standards, with cyfluthrin-d6 as an internal standard. Deltamethrin was analyzed by liquid chromatography/tandem mass spectrometry using deltamethrin-phenoxy-(13)C6 as an internal standard. Similar degradation rates of bifenthrin and for related isomeric compounds (e.g., cyfluthrin and beta-cyfluthrin) were generally measured in both mixtures for each sediment. First-order half-lives under aerobic conditions ranged from 2.9 to greater than 200 days, with a median value of 18 days. Under anaerobic conditions, the range was from 20 to greater than 200 days, with a median value of 70 days. PMID- 23641912 TI - Pharmacogenetic angiogenesis profiling for first-line chemotherapy in patients with advanced gastric cancer. AB - We retrospectively investigated germline polymorphisms in angiogenesis pathway genes (14 SNPs) and their correlation to clinical outcome (progression free survival and overall survival) in 128 patients with unresectable-advanced gastric carcinoma (AGC) treated with first-line chemotherapy. Our analysis revealed that Endostatin +4349 G>A polymorphism exhibited a worse progression free survival (PFS) and overall survival (OS) compared with the GG genotype. Significant OS difference was also observed in the endothelial nitric oxide synthase (eNOS)-786 T>C polymorphism. Hence, common germline variants in Endostatin and eNOS genes have predictive significance for clinical outcome and survivality in AGC patients treated with first-line chemotherapy. PMID- 23641911 TI - A two-dimensional model for studying tumor angiogenesis inhibitors. AB - Inhibition of angiogenesis can attenuate tumor growth. Hence, mathematical modeling of tumor-induced angiogenesis can be a tool for predicting outcome of angiogenesis inhibitors. We have generated a two-dimensional cornea model of angiogenesis and have tested the effectiveness of the inhibitor through testing representative examples. The effects of thrombospondin and the way it interacts in the cornea with the endothelial cells and tumor angiogenic factors were examined. We were then able to define the inhibitor's role specific to our benchmark model. Finally, a thorough sensitivity analysis was performed to verify baseline values and determine the precise effects of the different parameters. Our findings can be used to design strategies involving manufacturing inhibitors to regulate the angiogenesis process. PMID- 23641913 TI - Association of CTLA-4 polymorphisms with improved overall survival in melanoma patients treated with CTLA-4 blockade: a pilot study. AB - CTLA-4 blockade with monoclonal antibodies can lead to cancer regression in patients with metastatic melanoma (MM). CTLA-4 gene polymorphisms may influence the response to anti-CTLA-4 antibodies although few data are available regarding this issue. We analyzed six CTLA-4 single nucleotide polymorphisms (-1661A > G, 1577G > A, -658C > T, -319C > T, +49A > G, and CT60G > A) in 14 Italian MM patients and 45 healthy subjects. We found a significant association between the 1577G/A and CT60G/A genotypes and improved overall survival (Pc < 0.006, Bonferroni corrected), further confirmed by the diplotype analysis (-1577 & CT60 GG-AA diplotype, p < 0.001). A positive trend toward an association between these genotypes and response to therapy was also observed. PMID- 23641914 TI - Copolymerization of 2-methylene-1,3-dioxepane and glycidyl methacrylate, a well defined and efficient process for achieving functionalized polyesters for covalent binding of bioactive molecules. AB - The understanding of cell-material interactions is important for creating personalized implants for tissue engineering. This has resulted in an interest in developing polymers with functional groups with the possibility of controlling the macromolecular surface. We have in a one-pot reaction synthesized a series of amorphous and degradable polyester-based copolymers with active functional groups by copolymerization of 2-methylene-1,3-dioxepane and glycidyl methacrylate. The properties of the final polymers were varied by varying the feed ratios of the monomers, and it was seen that it was possible to control the amount of active functional groups. The resulting epoxy-functionalized polyester was further modified by covalent immobilization of heparin. The heparinization was done in order, in a future aspect, to enhance the osteogenic differentiation of mesenchymal stem cells. Heparin binds directly with the growth factor bone morphogenetic protein-2 and helps to retain its activity. The molecular structure of the copolymers was characterized by nuclear magnetic resonance, size exclusion chromatography, and Fourier transform infrared spectroscopy. Differential scanning calorimetry and tensile testing showed that the monomer feed ratio had a great influence on the properties of the final polymer and that it thus was possible to control the mechanical properties to suit an intended application. The presence of heparin was verified by toluidine blue staining, and all of the films tested showed positive signals for heparin. PMID- 23641916 TI - Assessing tomorrow's learners: in competency-based education only a radically different holistic method of assessment will work. Six things we could forget. AB - In this paper we are challenging six traditional notions about assessment that are unhelpful when designing 'assessment for learning'-programmes for competency based education. We are arguing for the following: Reductionism is not the only way to assure rigour in high-stakes assessment; holistic judgements can be equally rigorous. Combining results of assessment parts only because they are of the same format (like different stations in an OSCE) is often not defensible; instead there must be a logically justifiable combination. Numbers describe the quality of the assessment. Therefore, manipulating the numbers is usually not the best way to improve its quality. Not every assessment moment needs to be a decision moment, disconnecting both makes combining summative and formative functions of assessment easier. Standardisation is not the only route to equity. Especially with diverse student groups tailoring is more equitable than standardisation. The most important element to standardise is the quality of the process and not the process itself. Finally, most assessment is too much focussed on detecting deficiencies and not on valuing individual student differences. In competency-based education--especially with a focus on learner orientation--this 'deficiency-model' is not as well aligned as a 'differences-model'. PMID- 23641917 TI - Utilizing visual art to enhance the clinical observation skills of medical students. AB - BACKGROUND: Clinical observation is fundamental in practicing medicine, but these skills are rarely taught. Currently no evidence-based exercises/courses exist for medical student training in observation skills. AIM: The goal was to develop and teach a visual arts-based exercise for medical students, and to evaluate its usefulness in enhancing observation skills in clinical diagnosis. METHODS: A pre- and posttest and evaluation survey were developed for a three-hour exercise presented to medical students just before starting clerkships. Students were provided with questions to guide discussion of both representational and non representational works of art. RESULTS: Quantitative analysis revealed that the mean number of observations between pre- and posttests was not significantly different (n=70: 8.63 vs. 9.13, p=0.22). Qualitative analysis of written responses identified four themes: (1) use of subjective terminology, (2) scope of interpretations, (3) speculative thinking, and (4) use of visual analogies. Evaluative comments indicated that students felt the exercise enhanced both mindfulness and skills. CONCLUSION: Using visual art images with guided questions can train medical students in observation skills. This exercise can be replicated without specially trained personnel or art museum partnerships. PMID- 23641915 TI - Drinking water disinfection byproduct iodoacetic acid induces tumorigenic transformation of NIH3T3 cells. AB - Iodoacetic acid (IAA) and iodoform (IF) are unregulated iodinated disinfection byproducts (DBPs) found in drinking water. Their presence in the drinking water of China has not been documented. Recently, the carcinogenic potential of IAA and IF has been a concern because of their mutagenicity in bacteria and genotoxicity in mammalian cells. Therefore, we measured their concentrations in Shanghai drinking water and assessed their cytotoxicity, genotoxicity, and ability to transform NIH3T3 cells to tumorigenic lines. The concentrations of IAA and IF in Shanghai drinking water varied between summer and winter with maximum winter levels of 2.18 MUg/L IAA and 0.86 MUg/L IF. IAA with a lethal concentration 50 (LC50) of 2.77 MUM exhibited more potent cytotoxicity in NIH3T3 cells than IF (LC50 = 83.37 MUM). IAA, but not IF, induced a concentration-dependent DNA damage measured by gamma-H2AX staining and increased tail moment in single-cell gel electrophoresis. Neither IAA nor IF increased micronucleus frequency. Prolonged exposure of NIH3T3 cells to IAA increased the frequencies of transformed cells with anchorage-independent growth and agglutination with concanavalin A. IAA transformed cells formed aggressive fibrosarcomas after inoculation into Balb/c nude mice. This study demonstrated that IAA has a biological activity that is consistent with a carcinogen and human exposure should be of concern. PMID- 23641918 TI - Beyond assessment of learning toward assessment for learning: educating tomorrow's physicians. AB - Beyond its importance in informing high-stakes decisions, the assessment process can also be designed to foster learning. To be effective, this requires developing a program in which curricular experiences, assessment practices and support activities are aligned to provide an educational culture that encourages self-regulated learning. We describe a program (based at Cleveland Clinic Lerner College of Medicine) in which explicit performance standards align these components and provide a roadmap for students to manage their learning. Information-rich assessment data, structured opportunities for reflection, and facilitated self-assessment using a portfolio approach are designed to support development of habits of reflective practice. Promotion depends on the achievement of competencies rather than grades. Preliminary evidence suggests that the program directs students towards learning, rather than on achieving a grade for grade's sake. PMID- 23641919 TI - The costs and utility of the mini-CEX. PMID- 23641920 TI - Identifying common learning outcomes for health: Celebrating diversity and maximising benefit from regulatory necessity. PMID- 23641921 TI - Supporting students in self-regulation: use of formative feedback and portfolios in a problem-based learning setting. AB - BACKGROUND: The widely recognized need for students to self-regulate their behavior and learning extends to the multiple dimensions of professionalism. AIM: This study examines the extent to which students self-regulate professionalism behaviors related to work habits and interpersonal skills in a PBL setting. METHODS: Formative feedback on works habits and interpersonal skills provided by peers and tutors to a Year 1 cohort (n = 32) over the course of a year-long PBL experience (5 blocks) was examined for comments on targeted areas for improvement (TAFIs) and observed improvements. We examined congruence between PBL feedback and students' self-reported TAFIs and behavioral improvements in their assessment portfolios. RESULTS: Both PBL peer and faculty feedback and portfolio self assessments targeted Interpersonal Skills TAFIs more frequently than Work Habit related issues. TAFIs were more frequently identified midway in PBL blocks versus the end. Students reported TAFIs in their portfolio essays, citing feedback from both peers and tutors, and provided evidence of improved performance over time. CONCLUSIONS: Students utilized external formative feedback to document their portfolio self-assessment in a system designed to support self-regulation of PBL professionalism-related behaviors. A decrease in TAFIs identified at the end of PBL blocks suggests students made use of mid-block feedback to self-regulate behaviors. PMID- 23641922 TI - Drug delivery across the blood-brain barrier. PMID- 23641923 TI - Use of folate-conjugated imaging agents to target alternatively activated macrophages in a murine model of asthma. AB - Pro-inflammatory macrophages play a prominent role in such autoimmune diseases as rheumatoid arthritis, Crohn's disease, psoriasis, sarcoidosis, and atherosclerosis. Because pro-inflammatory macrophages have also been shown to overexpress a receptor for the vitamin folic acid (i.e., folate receptor beta; FR beta), folate-linked drugs have been explored for use in imaging and treatment of these same diseases. To determine whether allergic inflammatory disorders might be similarly targeted with folate-linked drugs, we have examined the characteristics of macrophages that are prominent in the pathogenesis of asthma. We report here that macrophages from the lungs of mice with experimental allergic asthma express FR-beta. We further document that these FR-beta(+) macrophages coexpress markers of alternatively activated (M2-type) macrophages, including the mannose receptor and arginase-1. Finally, we demonstrate that folate-conjugated fluorescent dyes and radioimaging agents can be specifically targeted to these asthmatic lung macrophages, with little uptake by macrophages present in healthy lung tissue. These data suggest strategies for the development of novel diagnostic agents for the imaging of asthma and other diseases involving alternatively activated macrophages. PMID- 23641924 TI - The decision to extubate in the intensive care unit. AB - The day of extubation is a critical time during an intensive care unit (ICU) stay. Extubation is usually decided after a weaning readiness test involving spontaneous breathing on a T-piece or low levels of ventilatory assist. Extubation failure occurs in 10 to 20% of patients and is associated with extremely poor outcomes, including high mortality rates of 25 to 50%. There is some evidence that extubation failure can directly worsen patient outcomes independently of underlying illness severity. Understanding the pathophysiology of weaning tests is essential given their central role in extubation decisions, yet few studies have investigated this point. Because extubation failure is relatively uncommon, randomized controlled trials on weaning are underpowered to address this issue. Moreover, most studies evaluated patients at low risk for extubation failure, whose reintubation rates were about 10 to 15%, whereas several studies identified high-risk patients with extubation failure rates exceeding 25 or 30%. Strategies for identifying patients at high risk for extubation failure are essential to improve the management of weaning and extubation. Two preventive measures may prove beneficial, although their exact role needs confirmation: one is noninvasive ventilation after extubation in high risk or hypercapnic patients, and the other is steroid administration several hours before extubation. These measures might help to prevent postextubation respiratory distress in selected patient subgroups. PMID- 23641926 TI - Epithelial maturation pattern of dysplastic epithelium and normal oral epithelium exposed to tobacco and alcohol: a scanning electron microscopic study. AB - BACKGROUND: The detection of oral cancer at an early stage is an optimal strategy and is the most effective approach for preventing further progression. The rationale of the study was to evaluate the epithelial maturation pattern in oral mucosa exposed to tobacco/alcohol and on dysplastic oral mucosa using the scanning electron microscope. METHODS: Fifteen subjects were selected based on clinical examination and divided into three groups: group 1-patients with apparently normal oral mucosa; group 2-patients with oral mucosa exposed to tobacco/alcohol; group 3-patients with clinical diagnosis of leukoplakia. An incisional biopsy was performed from the buccal mucosa. One part of the specimen was prepared for light microscopy and the other part was prepared for scanning electron microscopy. RESULTS: Light microscopy revealed nonkeratinized stratified squamous epithelium in group 1, while group 2 demonstrated hyperparakeratinized stratified squamous epithelium with mild cytological atypia, and group 3 showed architectural and cytological changes. Scanning electron microscopy demonstrated flat-surfaced cells with equidistant parallel microridges in group 1, while group 2 showed irregular and widened microridges with numerous pits and absence of honeycomb pattern. Group 3 showed irregularly arranged broad and swollen cells with numerous pits and irregular microvilli projecting over the surface. CONCLUSION: The present study establishes the relationship of the surface abnormalities to the tendency of the cells to become malignant and thus serves as a tool in early detection of squamous cell carcinoma. It also emphasizes the need of routine follow-up in these high-risk patients for progression of carcinoma. PMID- 23641925 TI - S-nitrosylation of dynamin-related protein 1 mediates mutant huntingtin-induced mitochondrial fragmentation and neuronal injury in Huntington's disease. AB - AIMS: Dynamin-related protein1 (Drp1) is a large GTPase that mediates mitochondrial fission. We recently reported in Alzheimer's disease (AD) that S nitrosylation of Drp1 (forming S-nitroso [SNO]-Drp1) results in GTPase hyperactivity and mitochondrial fragmentation, thus impairing bioenergetics and inducing synaptic damage and neuronal loss. Here, since aberrant mitochondrial dynamics are also key features of Huntington's disease (HD), we investigated whether formation of SNO-Drp1 contributes to the pathogenesis of HD in cell-based and animal models. RESULTS: We found that expression of mutant huntingtin (mutHTT) protein in primary cultured neurons triggers significant production of nitric oxide (NO). Consistent with this result, increased levels of SNO-Drp1 were found in the striatum of a transgenic mouse model of HD as well as in human postmortem brains from HD patients. Using specific fluorescence markers, we found that formation of SNO-Drp1 induced excessive mitochondrial fragmentation followed by loss of dendritic spines, signifying synaptic damage. These neurotoxic events were significantly abrogated after transfection with non-nitrosylatable mutant Drp1(C644A), or by the blocking of NO production using an nitric oxide synthase inhibitor. These findings suggest that SNO-Drp1 is a key mediator of mutHTT toxicity, and, thus, may represent a novel drug target for HD. INNOVATION AND CONCLUSION: Our findings indicate that aberrant S-nitrosylation of Drp1 is a prominent pathological feature of neurodegenerative diseases such as AD and HD. Moreover, the SNO-Drp1 signaling pathway links mutHTT neurotoxicity to a malfunction in mitochondrial dynamics, resulting in neuronal synaptic damage in HD. PMID- 23641927 TI - Predictors of HIV serostatus disclosure to partners among HIV-positive pregnant women in Morogoro, Tanzania. AB - BACKGROUND: Prevention of mother to child transmission of HIV (PMTCT) has been scaled, to more than 90% of health facilities in Tanzania. Disclosure of HIV results to partners and their participation is encouraged in the program. This study aimed to determine the prevalence, patterns and predictors of HIV sero status disclosure to partners among HIV positive pregnant women in Morogoro municipality, Tanzania. METHODS: A cross sectional study was conducted in March to May 2010 among HIV-positive pregnant women who were attending for routine antenatal care in primary health care facilities of the municipality and had been tested for HIV at least one month prior to the study. Questionnaires were used to collect information on possible predictors of HIV disclosure to partners. RESULTS: A total of 250 HIV-positive pregnant women were enrolled. Forty one percent (102) had disclosed their HIV sero-status to their partners. HIV disclosure to partners was more likely among pregnant women who were < 25 years old [Adjusted odds ratio (AOR) = 2.2; 95% CI: 1.2-4.1], who knew their HIV status before the current pregnancy [AOR = 3.7; 95% CI: 1.7-8.3], and discussed with their partner before testing [AOR = 6.9; 95% CI: 2.4-20.1]. Dependency on the partner for food/rent/school fees, led to lower odds of disclosure to partners [AOR = 0.4; 95% CI: 0.1-0.7]. Nine out of ten women reported to have been counseled on importance of disclosure and partner participation. CONCLUSIONS: Six in ten HIV positive pregnant women in this setting had not disclosed their results of the HIV test to their partners. Empowering pregnant women to have an individualized HIV-disclosure plan, strengthening of the HIV provider initiated counseling and testing and addressing economic development, may be some of the strategies in improving HIV disclosure and partner involvement in this setting. PMID- 23641928 TI - Percutaneous coronary intervention with drug-eluting stents or coronary artery bypass surgery in subjects with type 2 diabetes. AB - There is a debate as to whether percutaneous coronary intervention (PCI) with drug-eluting stents or coronary artery bypass surgery (CABG) is the best procedure for subjects with type 2 diabetes and coronary artery disease requiring revascularization. There is some evidence that by following these procedures, there is less further revascularization with CABG than PCI in subjects with diabetes. Two recent studies, namely, the FREEDOM (Future Revascularization Evaluation in patients with Diabetes mellitus: Optimal Management of Multivessel Disease) trial and a trial using a real-world diabetic population from a Registry have shown that the benefits of CABG over PCI in subjects with type 2 diabetes extend to lower rates of death and myocardial infarction, in addition to lower rates of revascularization. However, the rates of stroke may be higher with CABG than PCI with drug-eluting stents in this population. Thus, if CABG is going to be preferred to PCI in subjects with type 2 diabetes and multivessel coronary disease, consideration should be given as to how to reduce the rates of stroke with CABG. PMID- 23641929 TI - Localization of putative binding sites for cyclic guanosine monophosphate and the anti-cancer drug 5-fluoro-2'-deoxyuridine-5'-monophosphate on ABCC11 in silico models. AB - BACKGROUND: The Multidrug Resistance Protein ABCC11/MRP8 is expressed in physiological barriers and tumor breast tissues in which it secretes various substrates including cGMP (cyclic guanosine monophosphate) and 5FdUMP (5-fluoro 2'-deoxyuridine-5'-monophosphate), the active metabolite of the anticancer drug 5 FluoroUracil (frequently included to anticancer therapy).Previously, we described that ABCC11 high levels are associated to the estrogen receptor (ER) expression level in breast tumors and in cell lines resistant to tamoxifen. Consequently, by lowering the intracellular concentration of anticancer drugs, ABCC11 likely promotes a multidrug resistance (MDR) phenotype and decreases efficiency of anticancer therapy of 5FdUMP. Since no experimental data about binding sites of ABCC11 substrate are available, we decided to in silico localize putative substrate interaction sites of the nucleotide derivatives. Taking advantage of molecular dynamics simulation, we also analysed their evolution under computational physiological conditions and during the time. RESULTS: Since ABCC11 crystal structure is not resolved yet, we used the X-ray structures of the mouse mdr3 (homologous to human ABCB1) and of the bacterial homolog Sav1866 to generate two independent ABCC11 homology models in inward- and outward-facing conformations. Based on docking analyses, two putative binding pockets, for cGMP and 5FdUMP, were localized in both inward- and outward-facing conformations. Furthermore, based on our 3D models, and available biochemical data from homologous transporters, we identified several residues, potentially critical in ABCC11 transport function. Additionally, molecular dynamics simulation on our inward-facing model revealed for the first time conformation changes assumed to occur during transport process. CONCLUSIONS: ABCC11 would present two binding sites for cGMP and for 5FdUMP. Substrates likely first bind at the intracellular side of the transmembrane segment while ABCC11 is open forward the cytoplasm (inward-facing conformation). Then, along with conformational changes, it would pass through ABCC11 and fix the second site (close to the extracellular side), until the protein open itself to the extracellular space and allow substrate release. PMID- 23641930 TI - End-of-life caregiving: challenges faced by older adult women. AB - In the United States, the number of people older than 60 is expected to triple over the next 50 years, and as the population ages so do family caregivers. Increased levels of depression and low ratings of subjective well-being in caregivers are consistently associated with older age, the spousal relationship, and female caregiver gender. Less well known is the effect care delivery models have on the older adult as his or her spouse approaches the end of life. The purpose of this study was to explore the challenges faced by older adult spousal caregivers providing end-of-life care across different life-limiting illness trajectories in distinctive care delivery models. An instrumental case study using purposive sampling identified the following themes for older spousal caregivers: balancing multiple morbidities; feeling overwhelmed and exhausted; dealing with personal health issues; feeling isolated; and coordinating care. Implications for health care providers are also examined. PMID- 23641931 TI - Rifampicin-warfarin interaction leading to macroscopic hematuria: a case report and review of the literature. AB - BACKGROUND: Rifampicin remains one of the first-line drugs used in tuberculosis therapy. This drug's potential to induce the hepatic cytochrome P450 oxidative enzyme system increases the risk of drug-drug interactions. Thus, although the presence of comorbidities typically necessitates the use of multiple drugs, the co-administration of rifampicin and warfarin may lead to adverse drug events. We report a bleeding episode after termination of the co-administration of rifampicin and warfarin and detail the challenges related to international normalized ratio (INR) monitoring. CASE PRESENTATION: A 59-year-old Brazilian woman chronically treated with warfarin for atrial fibrillation (therapeutic INR range: 2.0-3.0) was referred to a multidisciplinary anticoagulation clinic at a university hospital. She showed anticoagulation resistance at the beginning of rifampicin therapy, as demonstrated by repeated subtherapeutic INR values. Three months of sequential increases in the warfarin dosage were necessary to reach a therapeutic INR, and frequent visits to the anticoagulation clinic were needed to educate the patient about her pharmacotherapy and to perform the warfarin dosage adjustments. The warfarin dosage also had to be doubled at the beginning of rifampicin therapy. However, four weeks after rifampicin discontinuation, an excessively high INR was observed (7.22), with three-day macroscopic hematuria and the need for an immediate reduction in the warfarin dosage. A therapeutic and stable INR was eventually attained at 50% of the warfarin dosage used by the patient during tuberculosis therapy. CONCLUSIONS: The present case exemplifies the influence of rifampicin therapy on warfarin dosage requirements and the increased risk of bleeding after rifampicin discontinuation. Additionally, this case highlights the need for warfarin weekly monitoring after stopping rifampicin until the maintenance dose of warfarin has decreased to the amount administered before rifampicin use. In particular, patients with cardiovascular diseases and active tuberculosis represent a group with a substantial risk of drug-drug interactions. Learning how to predict and monitor drug-drug interactions may help reduce the incidence of clinically significant adverse drug events. PMID- 23641932 TI - The evolution of machining-induced surface of single-crystal FCC copper via nanoindentation. AB - The physical properties of the machining-induced new surface depend on the performance of the initial defect surface and deformed layer in the subsurface of the bulk material. In this paper, three-dimensional molecular dynamics simulations of nanoindentation are preformed on the single-point diamond turning surface of single-crystal copper comparing with that of pristine single-crystal face-centered cubic copper. The simulation results indicate that the nucleation of dislocations in the nanoindentation test on the machining-induced surface and pristine single-crystal copper is different. The dislocation embryos are gradually developed from the sites of homogeneous random nucleation around the indenter in the pristine single-crystal specimen, while the dislocation embryos derived from the vacancy-related defects are distributed in the damage layer of the subsurface beneath the machining-induced surface. The results show that the hardness of the machining-induced surface is softer than that of pristine single crystal copper. Then, the nanocutting simulations are performed along different crystal orientations on the same crystal surface. It is shown that the crystal orientation directly influences the dislocation formation and distribution of the machining-induced surface. The crystal orientation of nanocutting is further verified to affect both residual defect generations and their propagation directions which are important in assessing the change of mechanical properties, such as hardness and Young's modulus, after nanocutting process. PMID- 23641934 TI - Lead toxicity and endoscopic removal of ingested firearm cartridges. AB - CONTEXT: Lead toxicity from the ingestion of a lead foreign body has been described in several case reports. Management of ingested live ammunition presents its own challenges due to the risk of accidental discharge. A safe and effective method of retrieving a live cartridge must be considered. CASE DETAILS: We present two cases of lead toxicity due to intact firearm cartridge ingestion with the removal of the cartridges via endoscopy. The first case is of severe pediatric lead toxicity due to the ingestion of 30-mm rifle cartridges. The second case is an adult ingestion of .22 caliber cartridges resulting in mild lead toxicity. DISCUSSION: These cases illustrate a diagnostic dilemma in both the diagnosis of lead toxicity and the removal of live ammunition from the stomach. PMID- 23641935 TI - Contribution of serum ethanol concentration to the osmol gap: a prospective volunteer study. AB - BACKGROUND: The contribution of ethanol ([EtOH]) to the osmol gap (OG) is commonly described by the formula [EtOH (mg/dL)]/k, where k is assumed to be 4.6 (one-tenth of its molecular weight) if ethanol behaves ideally in solution. However, several studies on convenience samples of patients suggest that ethanol does not behave ideally and that k may be significantly different from this ideal constant. OBJECTIVES: To determine prospectively the relationship between serum ethanol concentration and total serum osmolality in a group of healthy volunteers. METHODS: Experimental subjects ingested 20 mL of 100% ethanol diluted in sugar-free soda at a rate of one drink every 10 min, up to a maximum of seven drinks. Control subjects ingested 20 mL of water diluted in sugar-free soda at the same rate. Blood samples were obtained at baseline and then at every 20 min for 180 min to measure serum [EtOH] concentration, electrolytes, glucose, and osmolality (via freezing-point depression). The OG was calculated by subtracting predicted osmolality from measured osmolality. The OG was then divided by [EtOH] to determine the coefficient of ethanol's contribution to total serum osmolality. RESULTS: A total of 10 volunteers (five men and five women; mean age, 38.8 years, and range, 28-49 years) participated in and completed the study. Eight (four male and four female) were in the experimental group, and two (one male and one female) were in the control group. Mean peak [EtOH] was 229 mg/dL (median, 223.5 mg/dL; IQR, 171-273 mg/dL) and a linear relationship between [EtOH] and OG (Pearson coefficient of 0.98) was found. Using covariate correction for each subject's baseline OG, k was calculated to be 4.25 (95% CI, 4.13-4.38) averaged over all participants. CONCLUSIONS: In this volunteer study, the coefficient describing the contribution of ethanol to serum osmolality (k) was found to be 4.25. This indicates that ethanol contributes more to total serum osmolality than would be predicted for an ideal solute. PMID- 23641933 TI - Plasma metabolomics identifies lipid abnormalities linked to markers of inflammation, microbial translocation, and hepatic function in HIV patients receiving protease inhibitors. AB - BACKGROUND: Metabolic abnormalities are common in HIV-infected individuals on antiretroviral therapy (ART), but the biochemical details and underlying mechanisms of these disorders have not been defined. METHODS: Untargeted metabolomic profiling of plasma was performed for 32 HIV patients with low nadir CD4 counts (<300 cells/ul) on protease inhibitor (PI)-based ART and 20 healthy controls using liquid or gas chromatography and mass spectrometry. Effects of Hepatitis C (HCV) co-infection and relationships between altered lipid metabolites and markers of inflammation, microbial translocation, and hepatic function were examined. Unsupervised hierarchical clustering, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), Random forest, pathway mapping, and metabolite set enrichment analysis (MSEA) were performed using dChip, Metaboanalyst, and MSEA software. RESULTS: A 35-metabolite signature mapping to lipid, amino acid, and nucleotide metabolism distinguished HIV patients with advanced disease on PI-based ART from controls regardless of HCV serostatus (p<0.05, false discovery rate (FDR)<0.1). Many altered lipids, including bile acids, sulfated steroids, polyunsaturated fatty acids, and eicosanoids, were ligands of nuclear receptors that regulate metabolism and inflammation. Distinct clusters of altered lipids correlated with markers of inflammation (interferon-alpha and interleukin-6), microbial translocation (lipopolysaccharide (LPS) and LPS-binding protein), and hepatic function (bilirubin) (p<0.05). Lipid alterations showed substantial overlap with those reported in non-alcoholic fatty liver disease (NALFD). Increased bile acids were associated with noninvasive markers of hepatic fibrosis (FIB-4, APRI, and YKL-40) and correlated with acylcarnitines, a marker of mitochondrial dysfunction. CONCLUSIONS: Lipid alterations in HIV patients receiving PI-based ART are linked to markers of inflammation, microbial translocation, and hepatic function, suggesting that therapeutic strategies attenuating dysregulated innate immune activation and hepatic dysfunction may be beneficial for prevention and treatment of metabolic disorders in HIV patients. PMID- 23641936 TI - Erythromelalgia associated with Clitocybe acromelalga intoxication. AB - CONTEXT: Erythromelalgia is a rare disorder characterized by reddening, severe burning pain, and swelling of the extremities. Food poisoning by Clitocybe acromelalga, a poisonous mushroom, is known to induce erythromelalgia; however, its treatment protocol remains unclear. We describe here three cases of erythromelalgia following the consumption of C. acromelalga with varying clinical courses. CASE DETAILS: Of the three patients, the first patient presented 22 days after the onset of erythromelalgia; although he was treated with aspirin, numbness in the limbs persisted as sequela. Patient 2 presented at 3 days after the symptomatic onset and was immediately treated with high-dose intravenous nicotinic acid, with a dramatic symptomatic improvement. Patient 3, who had milder symptoms, spontaneously recovered within a week without any treatment. DISCUSSION: The clinical manifestations and varying clinical courses associated with C. acromelalga toxicity are discussed here, with the pathogenesis of this mycotoxin and a potential treatment. Detailed interviews of such patients are important, particularly because of the remarkably slow course of this mycotoxin as compared with common food poisonings. Treatment with intravenous nicotinic acid was associated with improvement in one patient. We believe that this painful disorder might thus be treatable, although the mechanism underlying the treatment remains unclear. PMID- 23641938 TI - Bilateral staged thoracotomy for multiple lung hydatidosis. AB - BACKGROUND: Hydatid cyst disease is still a problem in many countries. Surgical removal is currently the generally accepted choice of treatment for lung hydatidosis. However, operating on bilateral widespread lung hydatidosis is still controversial. The aim of this retrospective study was to evaluate the results of surgical treatment in bilateral multiple hydatid disease of the lung. METHODS: In this study, we reviewed our experience in the surgical treatment of 17 (3.7%) patients with bilateral, and at least three, lung hydatid cysts. These 17 patients (8 male, 9 female), with an average age of 34.6 years (range 12-58 years), underwent bilateral staged thoracotomy. RESULTS: In total 105 lung cysts were removed from 17 patients who underwent staged thoracotomies. The mean count of cysts was 6.7 (range 3-20 cysts). Most of the cysts (38.2%) were located in the right lower lobe. The mean interval between thoracotomies was 4.2 (range 3-5) days. Two patients (11.7%) had cysts associated with hepatic hydatidosis and one (5.8%) had cysts associated with the spleen; they were treated via phrenotomy during thoracotomies. All cysts were removed without lung resection. We observed some complications such as prolonged air leaks (n = 2), atelectasis (n = 3) and empyema (n = 2). No further surgery was required for management of complications. The mean hospital stay was 9.3 days. (range 7-23 days). Oral albendazole was started on the 2nd post operative day after the first thoracotomy in the dose of 10-20 mg/kg and was continued for 3 months with a gap of 1 week after each 21 days. No recurrences or deaths occured during the follow-up period. CONCLUSIONS: Although staged thoracotomy applied in 3-5 days after the initial thoracotomy increases the total hospital stay, it decreases the chance of possible complications can occur in cysts in the other lung when long intervals are preferred between the first and the second thoracotomy. In our experience, bilateral staged thoracotomy is an appropriate surgical option because morbidity rates are minimal and the hospital stay is acceptable for the treatment of bilateral widespread lung hydatidosis, even in patients who had a total of 20 hydatid cysts. PMID- 23641937 TI - Quantum mechanics/molecular mechanics modeling of regioselectivity of drug metabolism in cytochrome P450 2C9. AB - Cytochrome P450 enzymes (P450s) are important in drug metabolism and have been linked to adverse drug reactions. P450s display broad substrate reactivity, and prediction of metabolites is complex. QM/MM studies of P450 reactivity have provided insight into important details of the reaction mechanisms and have the potential to make predictions of metabolite formation. Here we present a comprehensive study of the oxidation of three widely used pharmaceutical compounds (S-ibuprofen, diclofenac, and S-warfarin) by one of the major drug metabolizing P450 isoforms, CYP2C9. The reaction barriers to substrate oxidation by the iron-oxo species (Compound I) have been calculated at the B3LYP-D/CHARMM27 level for different possible metabolism sites for each drug, on multiple pathways. In the cases of ibuprofen and warfarin, the process with the lowest activation energy is consistent with the experimentally preferred metabolite. For diclofenac, the pathway leading to the experimentally observed metabolite is not the one with the lowest activation energy. This apparent inconsistency with experiment might be explained by the two very different binding modes involved in oxidation at the two competing positions. The carboxylate of diclofenac interacts strongly with the CYP2C9 Arg108 side chain in the transition state for formation of the observed metabolite-but not in that for the competing pathway. We compare reaction barriers calculated both in the presence and in the absence of the protein and observe a marked improvement in selectivity prediction ability upon inclusion of the protein for all of the substrates studied. The barriers calculated with the protein are generally higher than those calculated in the gas phase. This suggests that active-site residues surrounding the substrate play an important role in controlling selectivity in CYP2C9. The results show that inclusion of sampling (particularly) and dispersion effects is important in making accurate predictions of drug metabolism selectivity of P450s using QM/MM methods. PMID- 23641939 TI - Highly fluorinated 2,2'-biphenols and related compounds: relationship between substitution pattern and herbicidal activity. AB - A broad range of halogenated 2,2'-biphenols was tested for applicability as crop protection agents. The activity of these compounds toward four typical pest plants was observed after application by spraying of diluted solutions. Despite their rather simple structure, it was found that the studied compounds reveal a surprisingly high herbicidal impact. To gain a better understanding of the structure-activity relationship, specific sites of the molecule were chemically modified and the core structures thus gradually changed. The influence of the substitution pattern on the herbicidal properties is discussed, and conclusions on the active site of the biphenol structure are drawn. It was observed that type and position of the halogen substituents have a significant influence on the activity of the core structure. The hydroxy functionalities play a crucial role for the effectiveness of the tested compounds. Because the blocking of the hydroxy moiety leads to dramatically deteriorated performances, the presence of these functionalities on the aromatic ring seems to be indispensable. PMID- 23641940 TI - Rapid research response to the 2009 A(H1N1)pdm09 influenza pandemic (Revised). AB - BACKGROUND: When novel influenza viruses cause human infections, it is critical to characterize the illnesses, viruses, and immune responses to infection in order to develop diagnostics, treatments, and vaccines. The objective of the study was to collect samples from patients with suspected or confirmed A(H1N1)pdm09 infections that could be made available to the scientific community. Respiratory secretions, sera and peripheral blood mononuclear cells (PBMCs) were collected sequentially (when possible) from patients presenting with suspected or previously confirmed A(H1N1)pdm09 infections. Clinical manifestations and illness outcomes were assessed. Respiratory secretions were tested for the presence of A(H1N1)pdm09 virus by means of isolation in tissue culture and real time RT-PCR. Sera were tested for the presence and level of HAI and neutralizing antibodies against the A(H1N1)pdm09 virus. FINDINGS AND CONCLUSIONS: Thirty patients with confirmed A(H1N1)pdm09 infection were enrolled at Baylor College of Medicine (BCM). Clinical manifestations of illness were consistent with typical influenza. Twenty-eight of 30 had virological confirmation of illness; all recovered fully. Most patients had serum antibody responses or high levels of antibody in convalescent samples. Virus-positive samples were sent to J. Craig Venter Institute for sequencing and sequences were deposited in GenBank. Large volumes of sera collected from 2 convalescent adults were used to standardize antibody assays; aliquots of these sera are available from the repository. Aliquots of serum, PBMCs and stool collected from BCM subjects and subjects enrolled at other study sites are available for use by the scientific community, upon request. PMID- 23641941 TI - 3d element complexes of pentadentate bipyridine-pyridine-based ligand scaffolds: structures and photocatalytic activities. AB - The synthesis of the two penta-pyridyl type ligands pyridine-2,6 diylbis(dipyridin-2-ylmethanol) (PPy, 1) and bis-2,2''-bipyridine-6-yl(pyridine-2 yl)methanol (aPPy, 2) is described. Both ligands coordinate rapidly to the 3d element cations Mn(II), Fe(II), Co(II), Ni(II), Cu(II), and Zn(II), thereby yielding complexes of the general composition [MBr(1)](+) and [MBr(2)](+), respectively. Further, the X-ray structures of selected complexes with ligands 1 and 2 are described. They show metal center dependent structural features and complexes with 2 exhibiting distinctly distorted octahedral geometries. Moreover, photocatalytic water reduction with [Co(II)Br(PPy)]Br (1c) and [Co(II)Br(aPPy)]Br (2c) as water reducing catalysts (WRC) was investigated. Both complexes showed catalytic activity in water when in presence of ascorbic acid as sacrificial electron donor and [Re(py)(bpy)(CO)3](+) (3) as photosensitizer (PS). Turnover numbers, TONs (H2/Co), up to 11,000 were achieved. Complex 2c was more active than 1c, whereas none of the other complexes showed any activity. PMID- 23641943 TI - Nanotoxicology using the sea anemone Nematostella vectensis: from developmental toxicity to genotoxicology. AB - Concomitant with the fast-growing advances in the synthesis and engineering of colloidal nanocrystals, an urgent evaluation of their toxicity on human beings and environment is strongly encouraged by public health organisations. Despite the in vitro approaches employed for toxicological screening of hazardous compounds, the use of simple and cost-effective living organisms may enormously contribute to solve unanswered questions related to embryotoxic and teratogenic effects of nanomaterials. Here, the sea anemone Nematostella vectensis (Cnidaria, Anthozoa) is presented as a novel model organism to profile bio/non-bio interactions and to show a comprehensive toxicological analysis performed on embryos, larvae and adults treated with fluorescent cadmium-based nanocrystals. Spanning from in vivo biodistribution to molecular investigations, different behaviours and effects depending on the composition and surface coatings are showed. Rod-shaped cadmium selenide/cadmium sulfide (CdSe/CdS) nanocrystals resulted in excellent imaging probes to track N. vectensis development with negligible adverse effects, while spherical CdTe nanocrystals severely impaired embryogenesis, resulting in aberrant phenotypes and deregulation of developmental genes, which raise severe worries for a safe use of this type of nanoparticles for human purposes and environmental contamination. PMID- 23641942 TI - Influence of histidine incorporation on buffer capacity and gene transfection efficiency of HPMA-co-oligolysine brush polymers. AB - One of the major intracellular barriers to nonviral gene delivery is efficient endosomal escape. The incorporation of histidine residues into polymeric constructs has been found to increase endosomal escape via the proton sponge effect. Statistical and diblock copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA), oligolysine, and oligohistidine were synthesized via reversible-addition fragmentation chain transfer (RAFT) polymerization and tested for in vitro transfection efficiency, buffering ability, and polyplex uptake mechanism via the use of chemical endocytic inhibitors. Interestingly, histidine-containing statistical and diblock polymers exhibited increased buffer capacity in different endosomal pH ranges. Statistical copolymers transfected better than block copolymers that contained similar amounts of histidine. In addition, only the polymer containing the highest incorporation of oligohistidine residues led to increases in transfection efficiency over the HPMA-oligolysine base polymer. Thus, for these polymer architectures, high histidine incorporation may be required for efficient endosomal escape. Furthermore, inhibitor studies indicate that nonacidified caveolae-mediated endocytosis may be the primary route of transfection for these copolymers, suggesting that alternative approaches for increasing endosomal escape may be beneficial for enhancing transfection efficiency with these HPMA-oligolysine copolymers. PMID- 23641944 TI - Genetic background (DDD/Sgn versus C57BL/6J) strongly influences postnatal growth of male mice carrying the A(y) allele at the agouti locus: identification of quantitative trait loci associated with diabetes and body weight loss. AB - BACKGROUND: Mice carrying the A(y) allele at the agouti locus become obese and are heavier than their non-A(y) littermates. However, this does not hold true for the genetic background of the DDD mouse strain. At 22 weeks of age, DDD.Cg-A(y) females are heavier than DDD females, whereas DDD.Cg-A(y) males are lighter than DDD males. This study aimed to determine the possible cause and identify the genes responsible for the lower body weight of DDD.Cg-A(y) males. RESULTS: Growth curves of DDD.Cg-A(y) mice were analyzed and compared with those of B6.Cg-A(y) mice from 5 to 25 weeks. In DDD.Cg-A(y) males, body weight gain stopped between 16 and 17 weeks and the body weight gradually decreased; thus, the lower body weight was a consequence of body weight loss. Quantitative trait locus (QTL) mapping was performed in backcrossed (BC) males of DDD * (B6 * DDD.Cg-A(y)) F(1) A(y) mice. For the body weight at 25 weeks, significant QTLs were identified on chromosomes 1 and 4. The DDD allele was associated with a lower body weight at both loci. In particular, the QTL on chromosome 4 interacted with the A(y) allele. Furthermore, suggestive QTLs for plasma glucose and high molecular weight adiponectin levels were coincidentally mapped to chromosome 4. The DDD allele was associated with increased glucose and decreased adiponectin levels. When the body weight at 25 weeks and plasma glucose levels were considered as dependent and independent variables, respectively, BC A(y) males were classified into two groups according to statistical analysis using the partition method. Mice of one group had significantly higher glucose and lower adiponectin levels than those of the other group and exhibited body weight loss as observed with DDD-A(y) males. CONCLUSIONS: The lower body weight of DDD.Cg-A(y) male mice was a consequence of body weight loss. Diabetes mellitus has been suggested to be a possible contributory factor causing body weight loss. The QTL on distal chromosome 4 contained the major responsible genes. This QTL interacted with the Ay allele, implying the reason why body weight loss occurs in DDD.Cg-Ay but not in DDD males. PMID- 23641946 TI - Diaphragm dysfunction on admission to the intensive care unit. Prevalence, risk factors, and prognostic impact-a prospective study. AB - RATIONALE: Diaphragmatic insults occurring during intensive care unit (ICU) stays have become the focus of intense research. However, diaphragmatic abnormalities at the initial phase of critical illness remain poorly documented in humans. OBJECTIVES: To determine the incidence, risk factors, and prognostic impact of diaphragmatic impairment on ICU admission. METHODS: Prospective, 6-month, observational cohort study in two ICUs. Mechanically ventilated patients were studied within 24 hours after intubation (Day 1) and 48 hours later (Day 3). Seventeen anesthetized intubated control anesthesia patients were also studied. The diaphragm was assessed by twitch tracheal pressure in response to bilateral anterior magnetic phrenic nerve stimulation (Ptr,stim). MEASUREMENTS AND MAIN RESULTS: Eighty-five consecutive patients aged 62 (54-75) (median [interquartile range]) were evaluated (medical admission, 79%; Simplified Acute Physiology Score II, 54 [44-68]). On Day 1, Ptr,stim was 8.2 (5.9-12.3) cm H2O and 64% of patients had Ptr,stim less than 11 cm H2O. Independent predictors of low Ptr,stim were sepsis (linear regression coefficient, -3.74; standard error, 1.16; P = 0.002) and Simplified Acute Physiology Score II (linear regression coefficient, -0.07; standard error, 1.69; P = 0.03). Compared with nonsurvivors, ICU survivors had higher Ptr,stim (9.7 [6.3-13.8] vs. 7.3 [5.5-9.7] cm H2O; P = 0.004). This was also true for hospital survivors versus nonsurvivors (9.7 [6.3-13.5] vs. 7.8 [5.5 10.1] cm H2O; P = 0.004). Day 1 and Day 3 Ptr,stim were similar. CONCLUSIONS: A reduced capacity of the diaphragm to produce inspiratory pressure (diaphragm dysfunction) is frequent on ICU admission. It is associated with sepsis and disease severity, suggesting that it may represent another form of organ failure. It is associated with a poor prognosis. Clinical trial registered with www.clinicaltrials.gov (NCT 00786526). PMID- 23641945 TI - The use of the Cre/loxP system to study oxidative stress in tissue-specific manganese superoxide dismutase knockout models. AB - SIGNIFICANCE: Respiring mitochondria are a significant site for reactions involving reactive oxygen and nitrogen species that contribute to irreversible cellular, structural, and functional damage leading to multiple pathological conditions. Manganese superoxide dismutase (MnSOD) is a critical component of the antioxidant system tasked with protecting the oxidant-sensitive mitochondrial compartment from oxidative stress. Since global knockout of MnSOD results in significant cardiac and neuronal damage leading to early postnatal lethality, this approach has limited use for studying the mechanisms of oxidant stress and the development of disease in specific tissues lacking MnSOD. To circumvent this problem, a number of investigators have employed the Cre/loxP system to precisely knockout MnSOD in individual tissues. RECENT ADVANCES: Multiple tissue and organ specific Cre-expressing mice have been generated, which greatly enhance the specificity of MnSOD knockout in tissues and organ systems that were once difficult, if not impossible to study. CRITICAL ISSUES: Evaluating the contribution of MnSOD deficiency to oxidant-mediated mitochondrial damage requires careful consideration of the promoter system used for creating the tissue-specific knockout animal, in addition to the collection and interpretation of multiple indices of oxidative stress and damage. FUTURE DIRECTIONS: Expanded use of well-characterized tissue-specific promoter elements and inducible systems to drive the Cre/loxP recombinational events will lead to a spectrum of MnSOD tissue knockout models, and a clearer understanding of the role of MnSOD in preventing mitochondrial dysfunction in human disease. PMID- 23641947 TI - Evaluation of the inhibition of carbohydrate hydrolysing enzymes, antioxidant activity and polyphenolic content of extracts of ten African Ficus species (Moraceae) used traditionally to treat diabetes. AB - BACKGROUND: Some Ficus species have been used in traditional African medicine in the treatment of diabetes. The antidiabetic potential of certain species has been confirmed in vivo but the mechanism of activity remains uncertain. The aim of this study was to determine the activity and to investigate the mechanism of antidiabetic activity of ten selected Ficus species through inhibition of alpha amylase and alpha-glucosidase activity, and the possible relationship between these activities, the total polyphenolic content and the antioxidant activity. METHODS: Dried acetone leaf extracts were reconstituted with appropriate solvents and used to determine total polyphenolic content antioxidant activity, alpha amylase and alpha-glucosidase inhibitory activity. RESULTS: The crude acetone extract of F. lutea had the highest polyphenolic content (56.85 +/- 1.82 mg GAE/g of dry material) and the strongest antioxidant activity with a TEAC value of 4.80 +/- 0.90. The antioxidant activity of the acetone extracts of the Ficus species may not be ascribed to total polyphenolic content alone. The crude extract at a concentration of 0.5 mg/ml of F. lutea (64.3 +/- 3.6%) had the best alpha glucosidase (sucrase) inhibitory activity. The EC50 of F. lutea (290 +/- 111 MUg/ml) was not significantly different from that of F. sycomorus (217 +/- 69 MUg/ml). The alpha-amylase inhibitory activity of F. lutea (95.4 +/- 1.2%) at a concentration of 1 mg/ml was the highest among the Ficus species screened. The EC50 for F. lutea (9.42 +/- 2.01 MU g/ml), though the highest, was not significantly different (p < 0.05) from that of F. craterostoma and F. natalensis. It was apparent that the crude acetone extract of F. lutea is a partially non-competitive inhibitor of alpha-amylase and alpha-glucosidase. Based on correlation coefficients polyphenolics may be responsible for alpha glucosidase activity but probably not for alpha-amylase activity. CONCLUSION: Antidiabetic activity potential via inhibition of alpha-amylase and alpha glucosidase was discovered in Ficus lutea which has not been previously reported. The acetone extract of the leaves was high in total polyphenolic content and antioxidant activity, and was a potent inhibitor of alpha-amylase activity. Research is underway to isolate the active compound(s) responsible for the antidiabetic activity and to confirm the in vitro antidiabetic activity and to investigate in vitro toxicity. PMID- 23641948 TI - Expandable external support device to improve Saphenous Vein Graft Patency after CABG. AB - OBJECTIVES: Low patency rates of saphenous vein grafts remain a major predicament in surgical revascularization. We examined a novel expandable external support device designed to mitigate causative factors for early and late graft failure. METHODS: For this study, fourteen adult sheep underwent cardiac revascularization using two vein grafts for each; one to the LAD and the other to the obtuse marginal artery. One graft was supported with the device while the other served as a control. Target vessel was alternated between consecutive cases. The animals underwent immediate and late angiography and were then sacrificed for histopathologic evaluation. RESULTS: Of the fourteen animals studied, three died peri-operatively (unrelated to device implanted), and ten survived the follow-up period. Among surviving animals, three grafts were thrombosed and one was occluded, all in the control group (p = 0.043). Quantitative angiographic evaluation revealed no difference between groups in immediate level of graft uniformity, with a coefficient-of-variance (CV%) of 7.39 in control versus 5.07 in the supported grafts, p = 0.082. At 12 weeks, there was a significant non uniformity in the control grafts versus the supported grafts (CV = 22.12 versus 3.01, p < 0.002). In histopathologic evaluation, mean intimal area of the supported grafts was significantly lower than in the control grafts (11.2 mm^2 versus 23.1 mm^2 p < 0.02). CONCLUSIONS: The expandable SVG external support system was found to be efficacious in reducing SVG's non-uniform dilatation and neointimal formation in an animal model early after CABG. This novel technology may have the potential to improve SVG patency rates after surgical myocardial revascularization. PMID- 23641949 TI - T cell memory to evolutionarily conserved and shared hemagglutinin epitopes of H1N1 viruses: a pilot scale study. AB - BACKGROUND: The 2009 pandemic influenza was milder than expected. Based on the apparent lack of pre-existing cross-protective antibodies to the A (H1N1)pdm09 strain, it was hypothesized that pre-existing CD4+ T cellular immunity provided the crucial immunity that led to an attenuation of disease severity. We carried out a pilot scale study by conducting in silico and in vitro T cellular assays in healthy population, to evaluate the pre-existing immunity to A (H1N1)pdm09 strain. METHODS: Large-scale epitope prediction analysis was done by examining the NCBI available (H1N1) HA proteins. NetMHCIIpan, an eptiope prediction tool was used to identify the putative and shared CD4+ T cell epitopes between seasonal H1N1 and A (H1N1)pdm09 strains. To identify the immunogenicity of these putative epitopes, human IFN-gamma-ELISPOT assays were conducted using the peripheral blood mononuclear cells from fourteen healthy human donors. All donors were screened for the HLA-DRB1 alleles. RESULTS: Epitope-specific CD4+ T cellular memory responses (IFN-gamma) were generated to highly conserved HA epitopes from majority of the donors (93%). Higher magnitude of the CD4+ T cell responses was observed in the older adults. The study identified two HA2 immunodominant CD4+ T cell epitopes, of which one was found to be novel. CONCLUSIONS: The current study provides a compelling evidence of HA epitope specific CD4+ T cellular memory towards A (H1N1)pdm09 strain. These well-characterized epitopes could recruit alternative immunological pathways to overcome the challenge of annual seasonal flu vaccine escape. PMID- 23641951 TI - Autotaxin inhibitors: a patent review. AB - INTRODUCTION: Autotaxin (ATX) is a lysophospholipase D enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA) and choline. LPA is a bioactive lipid mediator that activates several transduction pathways, and is involved in migration, proliferation and survival of various cells. Thus, ATX is an attractive medicinal target. AREAS COVERED: The aim of this review is to summarize ATX inhibitors, reported in patents from 2006 up to now, describing their discovery and biological evaluation. EXPERT OPINION: ATX has been implicated in various pathological conditions, such as cancer, chronic inflammation, neuropathic pain, fibrotic diseases, etc. Although there is an intensive effort on the discovery of potent and selective ATX inhibitors in order to identify novel medicinal agents, up to now, no ATX inhibitor has reached clinical trials. However, the use of ATX inhibitors seems an attractive strategy for the development of novel medicinal agents, for example anticancer therapeutics. PMID- 23641950 TI - Impact of a multidimensional infection control approach on central line associated bloodstream infections rates in adult intensive care units of 8 cities of Turkey: findings of the International Nosocomial Infection Control Consortium (INICC). AB - BACKGROUND: Central line-associated bloodstream infections (CLABs) have long been associated with excess lengths of stay, increased hospital costs and mortality attributable to them. Different studies from developed countries have shown that practice bundles reduce the incidence of CLAB in intensive care units. However, the impact of the bundle strategy has not been systematically analyzed in the adult intensive care unit (ICU) setting in developing countries, such as Turkey. The aim of this study is to analyze the impact of the International Nosocomial Infection Control Consortium (INICC) multidimensional infection control approach to reduce the rates of CLAB in 13 ICUs of 13 INICC member hospitals from 8 cities of Turkey. METHODS: We conducted active, prospective surveillance before-after study to determine CLAB rates in a cohort of 4,017 adults hospitalized in ICUs. We applied the definitions of the CDC/NHSN and INICC surveillance methods. The study was divided into baseline and intervention periods. During baseline, active outcome surveillance of CLAB rates was performed. During intervention, the INICC multidimensional approach for CLAB reduction was implemented and included the following measures: 1- bundle of infection control interventions, 2- education, 3 outcome surveillance, 4- process surveillance, 5- feedback of CLAB rates, and 6- performance feedback on infection control practices. CLAB rates obtained in baseline were compared with CLAB rates obtained during intervention. RESULTS: During baseline, 3,129 central line (CL) days were recorded, and during intervention, we recorded 23,463 CL-days. We used random effects Poisson regression to account for clustering of CLAB rates within hospital across time periods. The baseline CLAB rate was 22.7 per 1000 CL days, which was decreased during the intervention period to 12.0 CLABs per 1000 CL days (IRR 0.613; 95% CI 0.43 - 0.87; P 0.007). This amounted to a 39% reduction in the incidence rate of CLAB. CONCLUSIONS: The implementation of multidimensional infection control approach was associated with a significant reduction in the CLAB rates in adult ICUs of Turkey, and thus should be widely implemented. PMID- 23641952 TI - Effect of multilayer structure on high-frequency properties of FeCo/(FeCo)0.63(SiO2)0.37 nanogranular films on flexible substrates. AB - The high-frequency properties of the FeCo-SiO2 monolayer nanogranular films and FeCo/(FeCo)0.63(SiO2)0.37 multilayer nanogranular films which were elaborated on flexible substrates by magnetron sputtering system were studied. Compared to the monolayer films with the same FeCo content, the multilayer structures comprised of FeCo/(FeCo)0.63(SiO2)0.37 exhibit more excellent properties that the real and imaginary parts of permeability, more than the double value of the monolayer, increase to 250 and 350, respectively. The variation was considered owing to the reduction of the anisotropy field. PMID- 23641953 TI - Dengue in peri-urban Pak-Ngum district, Vientiane capital of Laos: a community survey on knowledge, attitudes and practices. AB - BACKGROUND: Dengue remains an important cause of morbidity in Laos. Good knowledge, attitudes and practices (KAP) among the public regarding dengue prevention are required for the success of disease control. Very little is known about dengue KAP among the Lao general population. METHODS: This was a KAP household survey on dengue conducted in a peri-urban Pak-Ngum district of Vientiane capital, Laos. A two-stage cluster sampling method was used to select a sample of participants to represent the general community. Participants from 231 households were surveyed using an interviewer-administered questionnaire. RESULTS: Although 97% of the participants heard of dengue, there was a lack of depth of knowledge on dengue: 33% of them did not know that malaria and dengue were different diseases, 32% incorrectly believed that Aedes mosquito transmits malaria, 36% could not correctly report that Aedes mosquitoes bite most frequently at sunrise and sunset; and < 10% of them recognized that indoor water containers could be Aedes mosquito breeding sites. Attitude levels were moderately good with a high proportion (96%) of participants recognizing that dengue was a severe yet preventable disease. Self reported prevention methods were quite high yet observation of the participants' yards showed use of prevention methods to be only moderate. The majority (93%) of the interviewees did not believe that they had enough information on dengue. There was an association between good knowledge and better practices, but good knowledge was associated with worse attitudes. CONCLUSIONS: There is a lack of depth of knowledge regarding dengue in Pak-Ngum community and observation methods revealed that more needs to be done by community members themselves to prevent the spread of Aedes mosquitoes. PMID- 23641954 TI - 'Masterstroke: a pilot group stroke prevention program for community dwelling stroke survivors'. AB - OBJECTIVES: To explore whether a pilot secondary stroke prevention group program for community-dwelling chronic stroke survivors assisted participants in modifying their lifestyle to reduce their risk of secondary stroke. DESIGN: A mixed methods study (quantitative and qualitative). SETTING: Community. SUBJECTS: Twenty-two community dwelling, chronic stroke survivors. INTERVENTION: The Masterstroke program incorporated a secondary prevention stroke group program over a 9-week period with two 2-h sessions weekly (1 hour for education and 1 hour for exercise). The exercise component incorporated fitness, strength, mobility and balance and education focused on secondary stroke prevention whilst also providing chronic condition self-management support. MAIN MEASURES: Timed Up and Go (TUG), Six Minute Walk Test (6MWT), Fat and Fibre Barometer, The Stroke and Aphasia Quality of Life Scale (SaQoL-39), and questionnaires for salt intake and stroke knowledge. Qualitative outcomes were participants' perceptions. Data analysis involved an inductive thematic approach with constant comparison. RESULTS: There were insufficient participants for results to reach statistical significance in all categories, however, statistically significant results where achieved with regards to knowledge, TUG, salt intake and quality of life (QoL) scores. Qualitative responses explored participants' experience of the Masterstroke program; results confirmed increases in knowledge about stroke and exercise tolerance, successfulness of a group program and lifestyle modification post stroke. CONCLUSIONS: Participation in the Masterstroke program for community dwelling stroke survivors resulted in significant improvements in knowledge, functional balance, dietary behaviours and quality of life. Qualitative interviews support the participants' implementation of lifestyle changes essential for reducing risks of secondary stroke. Results support the utilisation of this model and warrants rigorous investigation regarding long-term impacts of an education and exercise program on community dwelling stroke survivors. IMPLICATIONS FOR REHABILITATION: * A program which incorporates exercise and education in a group setting may improve health-related quality of life and functional performance for community dwelling, chronic stroke survivors. * It is feasible for a multidisciplinary team to implement a secondary stroke prevention group program for community dwelling, chronic stroke survivors. PMID- 23641955 TI - Using human recombinant UDP-glucuronosyltransferase isoforms and a relative activity factor approach to model total body clearance of laropiprant (MK-0524) in humans. AB - A major pathway of elimination of the prostaglandin D2 receptor 1 antagonist laropiprant in humans is by uridine diphosphate-glucuronosyltransferase (UGT) mediated biotransformation. In this study, liver and kidney relative activity factors were developed for UGT1A1, 1A9 and 2B7 to allow for in vitro-in vivo extrapolation of intrinsic clearance data to whole organ clearance using recombinant human UGT isoforms applying this to laropiprant as a model substrate. The total body metabolic clearance of laropiprant determined using this approach (5.0 L/hr) agreed well with the value determined in vivo following intravenous administration to healthy human volunteers (5.1 L/hr). The results suggest that approximately 36%, 36% and 28% of the hepatic metabolic clearance of laropiprant was mediated by UGT1A1, 1A9 and 2B7, respectively. Likewise, 80% and 20% of the renal metabolic clearance was mediated by UGT1A9 and 2B7, respectively. Furthermore, the data suggested that the contribution of the kidney to the overall total metabolic clearance was minor relative to the liver (~ 12%). PMID- 23641956 TI - Direct detection of RDX vapor using a conjugated polymer network. AB - 1,3,5-Trinitroperhydro-1,3,5-triazine (RDX) is a principal component of plastic explosives used in acts of terrorism and within improvised explosive devices, among others. Approaches to detect RDX compatible with remote, "stand-off" sampling that do not require preconcentration strategies, such as the swabs commonly employed in airports, will benefit military and civilian security. Such detection remains a significant challenge because RDX is 10(3) less volatile than 1,3,5-trinitrotoluene (TNT), corresponding to a parts-per-trillion vapor pressure under ambient conditions. Therefore, while fluorescence quenching of conjugated polymers is sufficiently sensitive to detect TNT vapors, RDX vapor detection is undemonstrated. Here we report a cross-linked phenylene vinylene polymer network whose fluorescence is quenched by trace amounts of RDX introduced from solution or the vapor phase. Fluorescence quenching is reduced, but remains significant, when partially degraded RDX is employed, suggesting that the polymer responds to RDX itself. The polymer network also responds to TNT and PETN similarly introduced from solution or the vapor phase. Pure solvents, volatile amines, and the outgassed vapors from lipstick or sunscreen do not quench polymer fluorescence. The established success of TNT sensors based on fluorescence quenching makes this a material of interest for real-world explosive sensors and will motivate further interest in cross-linked polymers and framework materials for sensing applications. PMID- 23641957 TI - Structural determinants of drug partitioning in n-hexadecane/water system. AB - Surrogate phases have been widely used as correlates for modeling transport and partitioning of drugs in biological systems, taking advantage of chemical similarity between the surrogate and the phospholipid bilayer as the elementary unit of biological phases, which is responsible for most of the transport and partitioning. Solvation in strata of the phospholipid bilayer is an important drug characteristic because it affects the rates of absorption and distribution, as well as the interactions with the membrane proteins having the binding sites located inside the bilayer. The bilayer core can be emulated by n-hexadecane (C16), and the headgroup stratum is often considered a hydrophilic phase because of the high water content. Therefore, we tested the hypothesis that the C16/water partition coefficients (P) can predict the bilayer locations of drugs and other small molecules better than other surrogate systems. Altogether 514 PC16/W values for nonionizable (458) and completely ionized (56) compounds were collected from the literature or measured, when necessary. With the intent to create a fragment based prediction system, the PC16/W values were factorized into the fragment solvation parameters (f) and correction factors based on the ClogP fragmentation scheme. A script for the PC16/W prediction using the ClogP output is provided. To further expand the prediction system and reveal solvation differences, the fC16/W values were correlated with their more widely available counterparts for the 1 octanol/water system (O/W) using solvatochromic parameters. The analysis for 50 compounds with known bilayer location shows that the available and predicted PC16/W and PO/W values alone or the PC16/O values representing their ratio do not satisfactorily predict the preference for drug accumulation in bilayer strata. These observations indicate that the headgroups stratum, albeit well hydrated, does not have solvation characteristics similar to water and is also poorly described by the O/W partition characteristics. PMID- 23641958 TI - Analysis of risk factors for consecutive exotropia and review of the literature. AB - PURPOSE: To evaluate the possible risk factors in patients with consecutive exotropia following esotropia surgery. METHODS: Medical records of patients who had comitant esotropia surgery between June 1999 and April 2011 were reviewed. Those who developed consecutive exotropia composed the exotropia group; patients matched for age and duration of follow-up who did not develop consecutive exotropia composed the no exotropia group. The charts of the patients were reviewed and possible risk factors for development of consecutive exotropia were investigated. RESULTS: The average ages of 47 patients in the exotropia group and 54 patients in the no exotropia group were 10.8 +/- 8.7 years (range: 1 to 41 years) and 8.5 +/- 6.3 years (range: 1 to 30 years), respectively (P = .292). Amblyopia was detected in 31 (66%) and 12 (22.2%) patients in the exotropia and no exotropia groups, respectively (P = .004). Anisometropia was observed in 20 patients (42.6%) in the exotropia group and 5 patients (9.3%) in the no exotropia group (P = .003). Preoperative average esodeviation values were 42.5 +/- 8.3 prism diopters (PD) (range: 25 to 60 PD) in the exotropia group and 42 +/- 9.4 PD (range: 20 to 65 PD) in the no exotropia group (P = .673). Postoperative deviations were 32.8 +/- 23 PD exotropia (range: 10 to 90 PD exotropia) in the exotropia group and 4.4 +/- 4.2 PD esotropia (range: 0 to 10 PD esotropia) in the no exotropia group (P = .000). Asymmetric surgery had been performed in 61.7% of the exotropia group (n = 29) and 9.3% of the no exotropia group (n = 5) (P = .000). Limitation of adduction was detected in 14 patients (29.8%) in the exotropia group; none was noted in the no exotropia group (P = .000). The mean interval between the initial surgery and the onset of consecutive exotropia was 11.1 +/- 15.1 months (range: 0 to 126 months). CONCLUSIONS: Anisometropia, amblyopia, asymmetric surgery, and postoperative adduction deficit were associated with the development of consecutive exotropia. Long-term follow-up should be considered because consecutive exotropia can develop after months or years. PMID- 23641959 TI - Amygdalar neuromelanosis intractable epilepsy without leptomeningeal involvement. AB - Neurocutaneous melanosis (NCM) is a rare, congenital neuroectodermal dysplasia generally resulting in early death from neurological decline due to leptomeningeal involvement. Nonmeningeal CNS epileptogenic lesions presenting in later childhood in the absence of leptomeningeal disease are rare. This report summarizes a rare presentation and curative epilepsy surgery. The authors discuss the case of a 14-year-old girl with NCM who originally presented with intractable partial-onset seizures. The MRI, PET, and SPECT studies subsequently revealed a focal epileptogenic source in the right temporal lobe. Results of video electroencephalography monitoring concurred with the imaging findings, and a right temporal lobectomy was performed including the medial structures. Following surgery, histopathological features of the lesion included multiple scattered mononuclear cells with brown pigmentation in the amygdala specimen. The patient remains seizure free 2 years postresection, and no longer needs medication for seizure management. This patient presented with an atypical CNS manifestation of NCM that is curable by epilepsy surgery. Her intractable epilepsy developed secondary to amygdalar neuromelanosis, which had no associated leptomeningeal melanosis, an uncommon occurrence. As evidenced by the lack of seizure activity following resection, the patient's quality of life greatly improved after neurological surgery. PMID- 23641960 TI - Utility of STIR MRI in pediatric cervical spine clearance after trauma. AB - OBJECT: Although MRI with short-term T1 inversion recovery (STIR) sequencing has been widely adopted in the clearance of cervical spine in adults who have sustained trauma, its applicability for cervical spine clearance in pediatric trauma patients remains unclear. The authors sought to review a Level 1 trauma center's experience using MRI for posttraumatic evaluation of the cervical spine in pediatric patients. METHODS: A pediatric trauma database was retrospectively queried for patients who received an injury warranting radiographic imaging of the cervical spine and had a STIR-MRI sequence of the cervical spine performed within 48 hours of injury between 2002 and 2011. Demographic, radiographic, and outcome data were retrospectively collected through medical records. RESULTS: Seventy-three cases were included in the analysis. The mean duration of follow-up was 10 months (range 4 days-7 years). The mean age of the patients at the time of trauma evaluation was 8.3 +/- 5.8 years, and 65% were male. The majority of patients were involved in a motor vehicle accident. In 70 cases, the results of MRI studies were negative, and the patients were cleared prior to discharge with no clinical suggestion of instability on follow-up. In 3 cases, the MRI studies had abnormal findings; 2 of these 3 patients were cleared with dynamic radiographs during the same admission. Only 1 patient had an unstable injury and required surgical stabilization. The sensitivity of STIR MRI to detect cervical instability was 100% with a specificity of 97%. The positive predictive value was 33% and the negative predictive value was 100%. CONCLUSIONS: Although interpretation of our results are diminished by limitations of the study, in our series, STIR MRI in routine screening for pediatric cervical trauma had a high sensitivity and slightly lower specificity, but may have utility in future practices and should be considered for implementation into protocols. PMID- 23641961 TI - Role of barbiturate coma in the management of focally induced, severe cerebral edema in children. AB - Barbiturates are widely used in the management of high intracranial pressure (ICP) caused by diffuse brain swelling. The cardiovascular, renal, and immunological side effects of these drugs limit them to last-line therapy. There are few published data regarding the role of barbiturates in focal brain lesions causing refractory elevated ICP and intraoperative brain swelling in the pediatric population. The authors here present 3 cases of nontraumatic, focally induced, refractory intracranial hypertension due to 2 tumors and 1 arteriovenous malformation, in which barbiturate therapy was used successfully to control elevated ICP. They focus on cardiovascular, renal, and immune function during the course of pentobarbital therapy. They also discuss the role of pentobarbital induced hypothermia. From this short case series, they demonstrate that barbiturates in conjunction with standard medical therapy can be used to safely reduce postoperative refractory intracranial hypertension and intraoperative brain swelling in children with focal brain lesions. PMID- 23641962 TI - Delayed germinal matrix hemorrhage induced by ventriculoperitoneal shunt insertion for congenital hydrocephalus. AB - Germinal matrix hemorrhages (GMHs) are typically seen in preterm neonates during the first 4 days of life. The authors encountered 2 children with late-onset GMH subsequent to ventriculoperitoneal (VP) shunt insertion for congenital hydrocephalus. Both children were delivered at full term with normal body weight, although they were compromised with the preceding hypoxic events prior to shunt insertion. The first case involved a female infant with severe craniofacial deformities. Because of aspiration pneumonia related to the comorbid upper airway stenosis, endotracheal intubation with intermittent mechanical ventilation was necessary. The associated congenital hydrocephalus was treated with VP shunt insertion when she was 35 days of age, and GMH was confirmed 1 week after shunt placement. During a period of conservative observation, the hemorrhage resolved without any neurological deterioration. The second case involved a male infant with a large intraparenchymal cyst on the left parietal portion. He was intubated for pneumonia at 1 month of age. He had associated congenital hydrocephalus that was progressive, and he was treated with VP shunting at 69 days of age, after his pneumonia had resolved. Postoperative GMH was confirmed, although hydrocephalus was well controlled by VP shunt insertion. Observed conservatively, he fared well and the GMH resolved. These 2 cases had unique features in common; both had congenital anomalies in the CNS and respiratory problems before shunting. The hypoxic insults on the residual germinal matrix layer and sudden decrease in CSF pressure may relate to the occurrence of these late-onset GMHs. PMID- 23641963 TI - Ossified choroid plexus papilloma of the fourth ventricle: elucidation of the mechanism of osteogenesis in benign brain tumors. AB - True ossification within benign brain tumors is rare, and the molecular mechanism for this process is poorly understood. The authors report a case of ossified choroid plexus papilloma (CPP) and analyze it to help elucidate the underlying molecular basis of osteogenesis in benign brain tumors. A 21-year-old man presented with headache and depression that progressed over years. Computed tomography, MRI, and angiography demonstrated a large heavily calcified fourth ventricular tumor with a vascular blush and no hydrocephalus. The tumor was resected and was found to be an ossified CPP. Immunohistochemical staining for VEGF, Sox2, BMP-2, osterix, osteopontin, and osteocalcin was performed in an attempt to elucidate the mechanism of bone formation. The tumor was extensively ossified with mature bone trabeculae. Immunostaining for VEGF was positive. Additional staining showed the presence of osteocalcin in this ossified tumor but not in samples of nonossified CPPs collected from other patients. Staining for osterix and osteopontin was equivocally positive in the ossified CPP but also in the nonossified CPPs examined. The presence of osteocalcin in the ossified CPP demonstrates that there is true bone formation rather than simple calcification. Its appearance within cells around the trabeculae suggests the presence of osteoblasts. The presence of osterix suggests that a pluripotent cell, or one that is already partially differentiated, may be differentiated into an osteoblast through this pathway. This represents the first systematic immunohistochemical analysis of osteogenesis within choroid plexus tumors. PMID- 23641964 TI - Structural and magnetic characterization of a tetranuclear copper(II) cubane stabilized by intramolecular metal cation-pi interactions. AB - A novel tetranuclear copper(II) complex (1) was synthesized from the self assembly of copper(II) perchlorate and the ligand N-benzyl-1-(2 pyridyl)methaneimine (L(1)). Single-crystal X-ray diffraction studies revealed that complex 1 consists of a Cu4(OH)4 cubane core, where the four copper(II) centers are linked by MU3-hydroxo bridges. Each copper(II) ion is in a distorted square-pyramidal geometry. X-ray analysis also evidenced an unusual metal cation pi interaction between the copper ions and phenyl substituents of the ligand. Calculations based on the density functional theory method were used to quantify the strength of this metal-pi interaction, which appears as an important stabilizing parameter of the cubane core, possibly acting as a driving parameter in the self-aggregation process. In contrast, using the ligand N-phenethyl-1-(2 pyridyl)methaneimine (L(2)), which only differs from L(1) by one methylene group, the same synthetic procedure led to a binuclear bis(MU-hydroxo)copper(II) complex (2) displaying intermolecular pi-pi interactions or, by a slight variation of the experimental conditions, to a mononuclear complex (3). These complexes were studied by X-ray diffraction techniques. The magnetic properties of complexes 1 and 2 are reported and discussed. PMID- 23641965 TI - Body packing by rectal insertion of cocaine packets: a case report. AB - BACKGROUND: Body packing is used for international drug transport, immediate drug concealment during a police searching or introducing drugs inside prisons. Despite the high level of specialization of dealers who have started to manufacture more complex packs, up to 5% of patients could develop intoxication due to pack rupture. Bowel obstruction is another acute complication. CASE PRESENTATION: A 27-year-old black male patient was sent to the hospital by court order for clinical evaluation and toxicological examination. The patient was conscious, oriented, had good color, normal arterial pressure and heart rate, and no signs of acute intoxication. Abdominal examination revealed discrete pain upon deep palpation and a small mass in the left iliac fossa. A plain abdominal radiograph revealed several oval structures located in the rectum and sigmoid. Fasting and a 50 g dose of activated charcoal every six hours were prescribed. After three days, the patient spontaneously evacuated 28 cocaine packs. CONCLUSION: Adequate clinical management and prompt identification of potential complications are of fundamental importance in dealing with body packing. PMID- 23641966 TI - Selective 351 nm photodissociation of cysteine-containing peptides for discrimination of antigen-binding regions of IgG fragments in bottom-up liquid chromatography-tandem mass spectrometry workflows. AB - Despite tremendous inroads in the development of more sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) strategies for mass spectrometry-based proteomics, there remains a significant need for enhancing the selectivity of MS/MS-based workflows for streamlined analysis of complex biological mixtures. Here, a novel LC-MS/MS platform based on 351 nm ultraviolet photodissociation (UVPD) is presented for the selective analysis of cysteine peptide subsets in complex protein digests. Cysteine-selective UVPD is mediated through the site-specific conjugation of reduced cysteine residues with a 351 nm active chromogenic Alexa Fluor 350 (AF350) maleimide tag. Only peptides containing the AF350 chromophore undergo photodissociation into extensive arrays of b- and y-type fragment ions, thus providing a facile means for differentiating cysteine-peptide targets from convoluting peptide backgrounds. With the use of this approach in addition to strategic proteolysis, the selective analysis of diagnostic heavy-chain complementarity determining regions (CDRs) of single-chain antibody (scAb) fragments is demonstrated. PMID- 23641967 TI - Concern-driven integrated approaches to nanomaterial testing and assessment- report of the NanoSafety Cluster Working Group 10. AB - Bringing together topic-related European Union (EU)-funded projects, the so called "NanoSafety Cluster" aims at identifying key areas for further research on risk assessment procedures for nanomaterials (NM). The outcome of NanoSafety Cluster Working Group 10, this commentary presents a vision for concern-driven integrated approaches for the (eco-)toxicological testing and assessment (IATA) of NM. Such approaches should start out by determining concerns, i.e., specific information needs for a given NM based on realistic exposure scenarios. Recognised concerns can be addressed in a set of tiers using standardised protocols for NM preparation and testing. Tier 1 includes determining physico chemical properties, non-testing (e.g., structure-activity relationships) and evaluating existing data. In tier 2, a limited set of in vitro and in vivo tests are performed that can either indicate that the risk of the specific concern is sufficiently known or indicate the need for further testing, including details for such testing. Ecotoxicological testing begins with representative test organisms followed by complex test systems. After each tier, it is evaluated whether the information gained permits assessing the safety of the NM so that further testing can be waived. By effectively exploiting all available information, IATA allow accelerating the risk assessment process and reducing testing costs and animal use (in line with the 3Rs principle implemented in EU Directive 2010/63/EU). Combining material properties, exposure, biokinetics and hazard data, information gained with IATA can be used to recognise groups of NM based upon similar modes of action. Grouping of substances in return should form integral part of the IATA themselves. PMID- 23641968 TI - Functional genomic analysis of bile salt resistance in Enterococcus faecium. AB - BACKGROUND: Enterococcus faecium is a Gram-positive commensal bacterium of the mammalian intestinal tract. In the last two decades it has also emerged as a multi-resistant nosocomial pathogen. In order to survive in and colonize the human intestinal tract E. faecium must resist the deleterious actions of bile. The molecular mechanisms exploited by this bacterium to tolerate bile are as yet unexplored. RESULTS: In this study we used a high-throughput quantitative screening approach of transposon mutant library, termed Microarray-based Transposon Mapping (M-TraM), to identify the genetic determinants required for resistance to bile salts in E. faecium E1162. The gene gltK, which is predicted to encode a glutamate/aspartate transport system permease protein, was identified by M-TraM to be involved in bile resistance. The role of GltK in bile salt resistance was confirmed by the subsequent observation that the deletion of gltK significantly sensitized E. faecium E1162 to bile salts. To further characterize the response of E. faecium E1162 to bile salts, we performed a transcriptome analysis to identify genes that are regulated by exposure to 0.02% bile salts. Exposure to bile salts resulted in major transcriptional rearrangements, predominantly in genes involved in carbohydrate, nucleotide and coenzyme transport and metabolism. CONCLUSION: These findings add to a better understanding of the molecular mechanisms by which E. faecium responds and resists the antimicrobial action of bile salts. PMID- 23641969 TI - Pilot educational program to enhance empowering patient education of school-age children with diabetes. AB - BACKGROUND: Nurses have a crucial role in patient education of children with type 1 diabetes, but they often exhibit lack of knowledge of the patient education process. This study aimed to describe an educational program to enhance empowering patient education process for the blood glucose monitoring education of school-age children and nurses' perceptions of using empowering techniques. METHODS: An empowering patient education process for the diabetes education of school-age children was developed. The researcher collected nurse's perceptions of managing the educational program by semi-structured interviews. Ten nurses carried out the diabetes education, and 8 of them participated in the interview. Three nurses implemented the diabetes education twice and were interviewed twice. The data consisted of 11 descriptions of the blood glucose monitoring education. The interviewer analyzed the data deductively and inductively by content analysis. RESULTS: Nurses described successful managing of the empowering patient education process. The need assessment consisted of using multiple methods and clarifying the capabilities and challenges of children and their parents. Planning manifested itself in adequate preparation and multiple objectives stated together with the family. Implementation comprised the relevant content, and the use of suitable teaching materials and methods. Evaluation was performed with various methods and documented accurately. Nurses also faced some challenges related to management and leadership, ambivalence with traditional and empowering patient education, and families' overall situation. CONCLUSION: An example of developing evidence-based patient education program is presented, but besides education other factors supporting changes in work practices should be considered in further development. PMID- 23641970 TI - Discovery and development of heat shock protein 90 inhibitors as anticancer agents: a review of patented potent geldanamycin derivatives. AB - INTRODUCTION: There has been research on anticancer strategies which focus on disrupting a single malignant protein. One of the strategies is the inhibition of one protein, heat shock protein 90 (Hsp90). There are many reasons why Hsp90 protein is targeted by anticancer agents: maintenance of cellular homeostasis in organisms involves Hsp90 and its client proteins; moreover, Hsp90 complex is involved in regulating several signal transduction pathways and plays an important role in the maturation of lots of tumor-promoting client proteins. Geldanamycin (GM), the first benzoquinone ansamycin, has shown anticancer activity by binding to Hsp90. Currently, several GM derivatives such as 17-AAG, 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin, IPI-493, and IPI-504 are being progressively developed toward clinical application. AREAS COVERED: Several research groups have studied GM and its derivatives to develop novel and potent Hsp90 inhibitors for the treatment of cancer. The crystal structure of Hsp90 was utilized to undergo structural optimization of GM derivatives. A wide variety of structural modifications were performed and some of the derivatives are now in clinical studies. The aim of this review was to summarize and analyze the structure-activity relationships of GM derivatives and the focus is on patented novel and pharmaceutically efficacious derivatives published from 1971 to 2012. EXPERT OPINION: Hsp90 inhibitors offer an effective therapeutic approach for treatment of cancer. To date, the clinical results of 17-AAG, IPI-493, and IPI 504 suggest that these GM derivatives could be used either alone or in combination with other marketed medications for the treatment of cancer patients. As there are not any marketed Hsp90 inhibitors, inhibiting Hsp90 chaperone function remains as a promising strategy that still requires further research. PMID- 23641971 TI - Development and specification of cerebellar stem and progenitor cells in zebrafish: from embryo to adult. AB - BACKGROUND: Teleost fish display widespread post-embryonic neurogenesis originating from many different proliferative niches that are distributed along the brain axis. During the development of the central nervous system (CNS) different cell types are produced in a strict temporal order from increasingly committed progenitors. However, it is not known whether diverse neural stem and progenitor cell types with restricted potential or stem cells with broad potential are maintained in the teleost fish brain. RESULTS: To study the diversity and output of neural stem and progenitor cell populations in the zebrafish brain the cerebellum was used as a model brain region, because of its well-known architecture and development. Transgenic zebrafish lines, in vivo imaging and molecular markers were used to follow and quantify how the proliferative activity and output of cerebellar progenitor populations progress. This analysis revealed that the proliferative activity and progenitor marker expression declines in juvenile zebrafish before they reach sexual maturity. Furthermore, this correlated with the diminished repertoire of cell types produced in the adult. The stem and progenitor cells derived from the upper rhombic lip were maintained into adulthood and they actively produced granule cells. Ventricular zone derived progenitor cells were largely quiescent in the adult cerebellum and produced a very limited number of glia and inhibitory inter neurons. No Purkinje or Eurydendroid cells were produced in fish older than 3 months. This suggests that cerebellar cell types are produced in a strict temporal order from distinct pools of increasingly committed stem and progenitor cells. CONCLUSIONS: Our results in the zebrafish cerebellum show that neural stem and progenitor cell types are specified and they produce distinct cell lineages and sub-types of brain cells. We propose that only specific subtypes of brain cells are continuously produced throughout life in the teleost fish brain. This implies that the post-embryonic neurogenesis in fish is linked to the production of particular neurons involved in specific brain functions, rather than to general, indeterminate growth of the CNS and all of its cell types. PMID- 23641972 TI - In vitro and in vivo antidermatophytic activity of the dichloromethane-methanol (1:1 v/v) extract from the stem bark of Polyscias fulva Hiern (Araliaceae). AB - BACKGROUND: During the last decades, the number of people suffering from dermatophytoses has seriously increased, mainly due to the development of resistant strains of microorganisms to a range of formally efficient antibiotics. Polyscias fulva, a medium size tree which grows in the West Region of Cameroon is traditionally used for local application against dermatoses and orally against venereal infections. The dichloromethane-methanol (1:1 v/v) extract from the stem bark of Polyscias fulva was evaluated for its in vitro and in vivo antifungal activities. METHODS: The plant extract was prepared by maceration of its stem bark powder in CH(2)Cl(2)-MeOH (1:1 v/v). The extract obtained was successively partitioned in hexane, ethyl acetate and n-butanol. Phytochemical screening was performed using standard methods. In vitro antidermatophytic activity was assayed by the well diffusion and broth microdilution methods. The degree of dermal irritation of the crude extract was determined in guinea pigs using the occluded dermal irritation test method. The in vivo antidermatophytic activity of the extract-oil formulation (1.25, 2.5 and 5% w/w concentrations) was evaluated using Trichophyton mentagrophytes-induced dermatophytosis in a guinea pigs model. RESULTS: Phytochemical screening indicated that, the crude extract, ethyl acetate, n-butanol and residue fractions contain in general saponins, tannins, alkaloids, anthraquinones and phenols while the hexane fraction contains only alkaloids. The ethyl-acetate, n-butanol and residue fractions displayed higher antifungal activities (MIC = 0.125-0.5 mg.mL(-1)) against eight dermatophytes as compared to the crude extract (MIC = 0.5-1 mg.mL(-1)). This latter appeared to have slight perceptible erythema effects on guinea pigs as the primary irritation index (PII) was calculated to be 0.54. In vivo, the antidermatophytic activities of the extract-oil formulations were dose-dependent. Griseofulvin-oil 5% at 0.01 g/kg and formulated extract-oil (5%) at 0.1 g/kg eradicated the microbial infection after thirteen and fourteen days of daily treatment respectively. CONCLUSIONS: The results of preclinical in vitro and in vivo evaluations indicate that the extract-oil formulation at 5% may constitute an alternative means to alleviate fungal infections caused by dermatophytes. PMID- 23641973 TI - Pseudomonas aeruginosa ventilator-associated pneumonia. predictive factors of treatment failure. AB - RATIONALE: The predictive factors of treatment failure for ventilator-associated pneumonia (VAP) caused by Pseudomonas aeruginosa (PA) remain uncertain. OBJECTIVES: To describe PA-VAP recurrence prognosis and to identify associated risk factors in a large cohort of intensive care unit patients with PA-VAP. METHODS: From the multicenter OUTCOMEREA database (1997-2011), PA-VAP onset and recurrence were recorded. All suspected cases of VAP were confirmed by a positive quantitative culture of a respiratory sample. Multidrug-resistant PA strains were defined by the resistance to two antibiotics among piperacillin, ceftazidime, imipenem, colistine, and fluoroquinolones (FQ). An extensively resistant PA was defined by resistance to piperacillin, ceftazidime, imipenem, and FQ. A treatment failure was defined as a PA-VAP recurrence or by the death occurrence. MEASUREMENTS AND MAIN RESULTS: A total of 314 patients presented 393 PA-VAP. Failure occurred for 112 of them, including 79 recurrences. Susceptible, multidrug resistant, and extensively resistant PA represented 53.7%, 32%, and 14.3% of the samples, respectively. Factors associated with treatment failure were age (P = 0.02); presence of at least one chronic illness (P = 0.02); limitation of life support (P = 0.0004); a high Sepsis-Related Organ Failure Assessment score (P < 0.0001); PA bacteremia (P = 0.003); and previous use of FQ before the first PA-VAP (P = 0.0007). The failure risk was not influenced by the strain resistance profile or by the biantibiotic treatment, but decreased in case of VAP treatment that includes FQ (subdistribution hazard ratio, 0.5 [0.3-0.7]; P = 0.0006). However, the strain resistance profile slowed down the intensive care unit discharge hazard (subdistribution hazard ratio, 0.6 [0.4-1.0]; P = 0.048). CONCLUSIONS: Neither resistance profile nor biantibiotic therapy decreased the risk of PA-VAP treatment failure. However, the profile of PA resistance prolonged the length of stay. Better evaluation of the potential benefit of an initial treatment containing FQ requires further randomized trials. PMID- 23641975 TI - Are catalase -844A/G polymorphism and activity associated with childhood obesity? AB - Catalase (CAT) is a peroxisomal antioxidant enzyme that is up-regulated upon oxidative stress. Previous studies have found associations between some single nucleotide polymorphisms (SNPs) located in the CAT promoter region in a variety of metabolic diseases. This is the first study that analyzes the association between erythrocyte CAT activity and candidate CAT SNPs with childhood obesity. The association study showed a significant positive association of the promoter variant -844A/G with childhood obesity and biomarkers of obesity such as weight, body mass index (BMI), BMI Z-Score, and adipocyte fatty acid-binding protein, along with a tendency toward significance with insulin resistance biomarkers. In addition, CAT erythrocyte activity was found to be significantly lower in obese children, and it was significantly correlated with obesity and insulin resistance biomarkers. No association was found between erythrocyte CAT activity and the SNP -844A/G. However, further in vitro and in vivo studies are needed to fully understand the role of CAT activity and SNPs in the development of insulin resistance in the setting of obesity. We hypothesize that CAT plays a role in early metabolic complications of obesity. PMID- 23641974 TI - Transmission of methicillin-resistant Staphylococcus aureus in the long term care facilities in Hong Kong. AB - BACKGROUND: The relative contribution of long term care facilities (LTCFs) and hospitals in the transmission of methicillin-resistant Staphylococcus aureus (MRSA) is unknown. METHODS: Concurrent MRSA screening and spa type analysis was performed in LTCFs and their network hospitals to estimate the rate of MRSA acquisition among residents during their stay in LTCFs and hospitals, by colonization pressure and MRSA transmission calculations. RESULTS: In 40 LTCFs, 436 (21.6%) of 2020 residents were identified as 'MRSA-positive'. The incidence of MRSA transmission per 1000-colonization-days among the residents during their stay in LTCFs and hospitals were 309 and 113 respectively, while the colonization pressure in LTCFs and hospitals were 210 and 185 per 1000-patient-days respectively. MRSA spa type t1081 was the most commonly isolated linage in both LTCF residents (76/121, 62.8%) and hospitalized patients (51/87, 58.6%), while type t4677 was significantly associated with LTCF residents (24/121, 19.8%) compared with hospitalized patients (3/87, 3.4%) (p<0.001). This suggested continuous transmission of MRSA t4677 among LTCF residents. Also, an inverse linear relationship between MRSA prevalence in LTCFs and the average living area per LTCF resident was observed (Pearson correlation -0.443, p=0.004), with the odds of patients acquiring MRSA reduced by a factor of 0.90 for each 10 square feet increase in living area. CONCLUSIONS: Our data suggest that MRSA transmission was more serious in LTCFs than in hospitals. Infection control should be focused on LTCFs in order to reduce the burden of MRSA carriers in healthcare settings. PMID- 23641977 TI - Public reporting of surgeons' performance. PMID- 23641976 TI - In pursuit of surgical success. PMID- 23641978 TI - Providing non-technical skills for surgeons. PMID- 23641981 TI - Smoothing out the ride for surgical patients. PMID- 23641982 TI - Deciding when quality and safety improvement interventions warrant widespread adoption. PMID- 23641983 TI - Apology laws and open disclosure. PMID- 23641984 TI - Emergency surgery model improves outcomes for patients with acute cholecystitis. PMID- 23641985 TI - A cluster randomised controlled trial of vascular risk factor management in general practice. PMID- 23641986 TI - A cluster randomised controlled trial of vascular risk factor management in general practice--author's reply. PMID- 23641987 TI - Toxicity from bodybuilding supplements and recreational use of products containing 1,3-dimethylamylamine. PMID- 23641988 TI - The effectiveness of helmets in reducing head injuries and hospital treatment costs: a multicentre study. PMID- 23641989 TI - Injuries to the head and face sustained while surfboard riding. PMID- 23641990 TI - J-curve revisited: cardiovascular benefits of moderate alcohol use cannot be dismissed. AB - While the Australian National Health and Medical Research Council guideline document of 2009 on reducing health risks from drinking alcohol provided sensible advice for public policy on alcohol, it appeared to dismiss the cardiovascular benefits of low to moderate consumption. Undue prominence was given to a hypothesis from a single research group that the well documented J-curve relationship of lower risk of ischaemic heart disease events with low to moderate intake alcohol consumption may have been due to a misclassification of drinking patterns. The misclassification hypothesis suggested that the higher risks among abstainers may have been due to the inclusion of high-risk subjects who had become abstainers later in life. Recent studies have separated recent abstainers from lifetime abstainers and the misclassification hypothesis has not been confirmed as an explanation for the J-shaped curve. The J-shaped relationship between alcohol consumption and cardiovascular risk has been studied and confirmed in multiple studies; while it complicates the formulation of public policy on alcohol consumption, it cannot be dismissed. PMID- 23641991 TI - Supply and demand mismatch for flexible (part-time) surgical training in Australasia. AB - OBJECTIVES: To define current patterns of flexible (part-time) surgical training in Australasia, determine supply and demand for part-time positions, and identify work-related factors motivating interest in flexible training. DESIGN, SETTING AND PARTICIPANTS: All Royal Australasian College of Surgeons trainees (n = 1191) were surveyed in 2010. Questions assessed demographic characteristics and working patterns, interest in flexible training, work-related fatigue and work-life balance preferences. MAIN OUTCOME MEASURES: Interest in part-time training, and work-related factors motivating this interest. RESULTS: Of the 1191 trainees, 659 responded (response rate, 55.3%). Respondents were representative of all trainees in terms of specialty and sex. The median age of respondents was 32 2013s, and 187 (28.4%) were female. Most of the 659 respondents (627, 95.1%) were in full time clinical training; only two (0.3%) were in part-time clinical training, and 30 (4.6%) were not in active clinical training. An interest in part-time training was reported by 208 respondents (31.6%; 54.3% of women v 25.9% of men; P < 0.001). Trainees expressing an interest in part-time training were more likely to report that fatigue impaired their performance at work and limited their social or family life, and that they had insufficient time in life for things outside surgical training, including study or research (P < 0.05). CONCLUSIONS: There is a striking mismatch between demand for flexible surgical training and the number of trainees currently in part-time training positions in Australia and New Zealand. Efforts are needed to facilitate part-time surgical training. PMID- 23641992 TI - Flexible surgical training in Australasia. PMID- 23641993 TI - Increasing incidence of hospitalisation for sport-related concussion in Victoria, Australia. AB - OBJECTIVE: To describe trends in hospitalisation for sport-related concussion. DESIGN, SETTING AND PATIENTS: Analysis of routinely collected hospital admissions data from all Victorian hospitals (public and private) over the 2002-03 to 2010 11 financial 2013s for patients aged >= 15 2013s with a diagnosis of concussion and an ICD-10-AM external cause activity code indicating sport. MAIN OUTCOME MEASURES: Number and cost of hospitalisations; rate of hospitalisation per 100 000 participants overall and for specific sports; and percentage change in frequency and hospitalisation rate per 100 000 participants over 9 2013s. RESULTS: There were 4745 hospitalisations of people aged >= 15 2013s for sport related concussion, with a total hospital treatment cost of $17 944 799. The frequency of hospitalisation increased by 60.5% (95% CI, 41.7%-77.3%) over the 9 2013s, but could only partially be explained by increases in sports participation, as the rate per 100 000 participants also increased significantly, by 38.9% (95% CI, 17.5%-61.7%). After adjustment for participation, rates were highest for motor sports, equestrian activities, Australian football, rugby and roller sports. The greatest significant increases in rates were seen in roller sports, rugby, soccer and cycling. CONCLUSIONS: The frequency and participation adjusted rate of hospitalisation for sport-related concussion, both overall and across several sports, increased significantly over the 9 2013s. These findings, along with high levels of public concern, make prevention of head injury in sport a population health priority in Australia. PMID- 23641994 TI - Frequency of sunburn in Queensland adults: still a burning issue. AB - OBJECTIVE: To assess the current frequency of sunburn, a preventable risk factor for skin cancer, among Queensland adults. DESIGN AND SETTING: Cross-sectional population-based surveys of 16 473 residents aged >= 18 2013s across Queensland in 2009 and 2010. MAIN OUTCOME MEASURES: Proportion of the adult population reporting sunburn (skin reddening lasting 12 hours or more) during the previous weekend, by age, sex and other risk factors. RESULTS: One in eight men and one in 12 women in Queensland reported being sunburnt on the previous weekend. Age up to 65 2013s was the strongest predictor of sunburn: eg, people aged 18-24 2013s were seven times more likely (adjusted odds ratio [OR], 7.35; 95% CI, 5.09-10.62) and those aged 35-44 2013s were five times more likely (adjusted OR, 5.22) to report sunburn compared with those aged >= 65 2013s. Not having a tertiary education and being in the workforce were also significantly associated with sunburn. Those who had undertaken any physical activity the previous week were more likely to be sunburnt than those who were physically inactive. Sunburn was significantly less likely among people who generally took sun-protective measures in summer. Sunburn was not related to location of residence, socioeconomic disadvantage, skin colour, body weight or current smoking status. CONCLUSIONS: Sunburn remains a public health problem among Queensland residents, especially those under 45 2013s of age. Sun-safe habits reduce sunburn risk, but advice must be integrated with health promotion messages regarding physical activity to reduce the skin cancer burden while maintaining active wellbeing. PMID- 23641995 TI - Risk factors for recurrent Mycobacterium ulcerans disease after exclusive surgical treatment in an Australian cohort. AB - OBJECTIVE: To describe risk factors for recurrence after exclusive surgical treatment of Mycobacterium ulcerans infection. DESIGN, SETTING AND PARTICIPANTS: Prospective observational cohort study of all M. ulcerans cases managed with surgery alone at Barwon Health, a tertiary referral hospital, from 1 January 1998 to 31 December 2011. A random-effects Poisson regression model was used to assess rates and associations of treatment failure. MAIN OUTCOME MEASURES: Rates of treatment failure and rate ratios (RRs) for factors associated with treatment failure. RESULTS: Of 192 patients with M. ulcerans infection, 50 (26%) had exclusive surgical treatment. Median age was 65.0 2013s (interquartile range [IQR], 45.5-77.7 2013s), and median duration of symptoms was 46 days (IQR, 26-90 days). There were 20 recurrences in 16 patients. For first lesions, the recurrence incidence rate was 41.8 (95% CI, 25.6-68.2) per 100 person-2013s, and median time to recurrence was 50 days (IQR, 30-171 days). Recurrence occurred <= 3 cm from the original lesion in 13 cases, and > 3 cm in nine. On univariable analysis, age >= 60 2013s (RR 13.84; 95% CI, 2.21-86.68; P < 0.01), distal lesions (RR, 20.43; 95% CI, 1.97-212.22; P < 0.01), positive histological margins (RR, 21.02; 95% CI, 5.51-80.26; P < 0.001), immunosuppression (RR, 17.97; 95% CI, 4.17-77.47; P < 0.01) and duration of symptoms > 75 days (RR, 10.13; 95% CI, 1.76 58.23; P = 0.02) were associated with treatment failure. On multivariable analysis, positive margins (RR, 7.72; 95% CI, 2.71-22.01; P < 0.001) and immunosuppression (RR, 6.45; 95% CI, 2.42-17.20; P = 0.01) remained associated with treatment failure. CONCLUSIONS: Recurrence rates after exclusive surgical treatment of M. ulcerans disease in an Australian cohort are high, with increased rates associated with immunosuppression or positive histological margins. PMID- 23641996 TI - Angiostrongylus meningoencephalitis: survival from minimally conscious state to rehabilitation. PMID- 23641997 TI - Steroids control paradoxical worsening of Mycobacterium ulcerans infection following initiation of antibiotic therapy. PMID- 23641998 TI - Open disclosure: ethical, professional and legal obligations, and the way forward for regulation. AB - Open disclosure (OD) after adverse health care events is the subject of a national standard that has been implemented in state health policy documents, and is included in the Medical Board of Australia's code of conduct for doctors. Nevertheless, doctors have been slow to embrace the practice of OD. There is a strong ethical case for implementing OD in the primary interests of patients, and additionally from a medicolegal risk management point of view. There are no statutory requirements in relation to OD, but common law judgments have imposed a duty of OD in tort and contract. There are a number of barriers to the better uptake and implementation of OD, including perceptions of legal risk, lack of education and training, reluctance to admit error, uncertainty concerning what and how much to disclose, and the variations in state and territory "apology laws". The implementation of OD could be improved by making apology laws consistent across jurisdictions, including providing "blanket" cover for admissions of fault; by preventing insurers voiding contracts when apologies are made, either through self-regulation or legislation; and by inserting OD obligations into different structures within the health system. PMID- 23641999 TI - Early obstetric simulators in Australia. PMID- 23642000 TI - Cation size mismatch and charge interactions drive dopant segregation at the surfaces of manganite perovskites. AB - Cation segregation on perovskite oxide surfaces affects vastly the oxygen reduction activity and stability of solid oxide fuel cell (SOFC) cathodes. A unified theory that explains the physical origins of this phenomenon is therefore needed for designing cathode materials with optimal surface chemistry. We quantitatively assessed the elastic and electrostatic interactions of the dopant with the surrounding lattice as the key driving forces for segregation on model perovskite compounds, LnMnO3 (host cation Ln = La, Sm). Our approach combines surface chemical analysis with X-ray photoelectron and Auger electron spectroscopy on model dense thin films and computational analysis with density functional theory (DFT) calculations and analytical models. Elastic energy differences were systematically induced in the system by varying the radius of the selected dopants (Ca, Sr, Ba) with respect to the host cations (La, Sm) while retaining the same charge state. Electrostatic energy differences were introduced by varying the distribution of charged oxygen and cation vacancies in our models. Varying the oxygen chemical potential in our experiments induced changes in both the elastic energy and electrostatic interactions. Our results quantitatively demonstrate that the mechanism of dopant segregation on perovskite oxides includes both the elastic and electrostatic energy contributions. A smaller size mismatch between the host and dopant cations and a chemically expanded lattice were found to reduce the segregation level of the dopant and to enable more stable cathode surfaces. Ca-doped LaMnO3 was found to have the most stable surface composition with the least cation segregation among the compositions surveyed. The diffusion kinetics of the larger dopants, Ba and Sr, was found to be slower and can kinetically trap the segregation at reduced temperatures despite the larger elastic energy driving force. Lastly, scanning probe image contrast showed that the surface chemical heterogeneities made of dopant oxides upon segregation were electronically insulating. The consistency between the results obtained from experiments, DFT calculations, and analytical theory in this work provides a predictive capability to tailor the cathode surface compositions for high-performance SOFCs. PMID- 23642002 TI - Biology, epidemiology, and control of Heterobasidion species worldwide. AB - Heterobasidion annosum sensu lato is a species complex comprising five species that are widely distributed in coniferous forests of the Northern Hemisphere and are each characterized by a distinct host preference. More than 1,700 papers have been published on these fungi in the past four decades, making them perhaps the most widely studied forest fungi. Heterobasidion species are at different levels on the saprotroph-necrotroph gradient, and the same individual can switch from one mode to the other. This offers a unique opportunity to study how genomic structure, gene expression, and genetic trade-offs may all interact with environmental factors to determine the life mode of the organism. The abilities of Heterobasidion spp. to infect stumps as saprotrophs and to spread to neighboring trees as pathogens have resulted in significant damages to timber production in managed forests. This review focuses on the current knowledge of the biology, ecology, evolution, and management of these species and is based on classical and modern studies. PMID- 23642001 TI - Defining neighborhood boundaries in studies of spatial dependence in child behavior problems. AB - BACKGROUND: The purpose of this study was to extend the analysis of neighborhood effects on child behavioral outcomes in two ways: (1) by examining the geographic extent of the relationship between child behavior and neighborhood physical conditions independent of standard administrative boundaries such as census tracts or block groups and (2) by examining the relationship and geographic extent of geographic peers' behavior and individual child behavior. METHODS: The study neighborhood was a low income, ethnic minority neighborhood of approximately 20,000 residents in a large city in the southwestern United States. Observational data were collected for 11,552 parcels and 1,778 face blocks in the neighborhood over a five week period. Data on child behavior problems were collected from the parents of 261 school-age children (81% African American, 14% Latino) living in the neighborhood. Spatial analysis methods were used to examine the spatial dependence of child behavior problems in relation to physical conditions in the neighborhood for areas surrounding the child's home ranging from a radius of 50 meters to a radius of 1000 meters. Likewise, the spatial dependence of child behavior problems in relation to the behavior problems of neighborhood peers was examined for areas ranging from a radius 255 meters to a radius of 600 meters around the child's home. Finally, we examined the joint influence of neighborhood physical conditions and geographic peers. RESULTS: Poor conditions of the physical environment of the neighborhood were related to more behavioral problems, and the geographic extent of the physical environment that mattered was an area with a radius between 400 and 800 meters surrounding the child's home. In addition, the average level of behavior problems of neighborhood peers within 255 meters of the child's home was also positively associated with child behavior problems. Furthermore, these effects were independent of one another. CONCLUSIONS: These findings demonstrate that using flexible geographies in the study of neighborhood effects can provide important insights into spatial influences on health outcomes. With regards to child behavioral outcomes, specifically, these findings support the importance of addressing the physical and social environment when planning community-level interventions to reduce child behavior problems. PMID- 23642003 TI - Harmonic analysis of Boolean networks: determinative power and perturbations. AB - : Consider a large Boolean network with a feed forward structure. Given a probability distribution on the inputs, can one find, possibly small, collections of input nodes that determine the states of most other nodes in the network? To answer this question, a notion that quantifies the determinative power of an input over the states of the nodes in the network is needed. We argue that the mutual information (MI) between a given subset of the inputs X={X1,...,Xn} of some node i and its associated function fi(X) quantifies the determinative power of this set of inputs over node i. We compare the determinative power of a set of inputs to the sensitivity to perturbations to these inputs, and find that, maybe surprisingly, an input that has large sensitivity to perturbations does not necessarily have large determinative power. However, for unate functions, which play an important role in genetic regulatory networks, we find a direct relation between MI and sensitivity to perturbations. As an application of our results, we analyze the large-scale regulatory network of Escherichia coli. We identify the most determinative nodes and show that a small subset of those reduces the overall uncertainty of the network state significantly. Furthermore, the network is found to be tolerant to perturbations of its inputs. PMID- 23642004 TI - Revisiting the mechanism of neutral hydrolysis of esters: water autoionization mechanisms with acid or base initiation pathways. AB - The mechanism of neutral hydrolysis of ester has long been explored by theoretical studies. However, reliable theoretical calculations show that the usual bifunctional catalysis mechanism reported by different authors cannot explain the experimental kinetics. An important advance was recently reported by Gunaydin and Houk, suggesting that ions are involved in the mechanism and the process initiates by water autoionization followed by protonation of the ester (W(AI)A mechanism). However, this mechanism does not explain the hydrolysis of activated esters. In this work, we have used ab initio calculations, continuum solvation models, and intrinsic reaction coordinate method to support the W(AI)A mechanism for normal ester. In the case of activated esters, the process can also be viewed as water autoionization with formation of hydroxide ion aided by a second water molecule acting as a general base (W(AI)B mechanism). This is the mechanism that was proposed by Jencks and Carriuolo 50 years ago. Our analysis point out that the usual method for exploring mechanisms, searching for saddle points, may not work for problems like the present one, since there are no saddle points on the reaction pathway. Rather, the formation of a pair of ions from a neutral species may have an asymptotic barrier. The approach used in this paper allows the calculation of the free energy profile and enable us to explain the mechanism and kinetics of the neutral hydrolysis of normal (methyl acetate) and activated (methyl trifluoroacetate) esters. In addition, the present study suggests that formation of a pair of ions should always be considered in reactions in aqueous solution. PMID- 23642005 TI - Meropenem and piperacillin/tazobactam prescribing in critically ill patients: does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used? AB - BACKGROUND: Correct antibiotic dosing remains a challenge for the clinician. The aim of this study was to assess the influence of augmented renal clearance on pharmacokinetic/pharmacodynamic target attainment in critically ill patients receiving meropenem or piperacillin/tazobactam, administered as an extended infusion. METHODS: This was a prospective, observational, pharmacokinetic study executed at the medical and surgical intensive care unit at a large academic medical center. Elegible patients were adult patients without renal dysfunction receiving meropenem or piperacillin/tazobactam as an extended infusion. Serial blood samples were collected to describe the antibiotic pharmacokinetics. Urine samples were taken from a 24-hour collection to measure creatinine clearance. Relevant data were drawn from the electronic patient file and the intensive care information system. RESULTS: We obtained data from 61 patients and observed extensive pharmacokinetic variability. Forty-eight percent of the patients did not achieve the desired pharmacokinetic/pharmacodynamic target (100% fT>MIC), of which almost 80% had a measured creatinine clearance>130 mL/min. Multivariate logistic regression demonstrated that high creatinine clearance was an independent predictor of not achieving the pharmacokinetic/pharmacodynamic target. Seven out of nineteen patients (37%) displaying a creatinine clearance>130 mL/min did not achieve the minimum pharmacokinetic/pharmacodynamic target of 50% fT>MIC. CONCLUSIONS: In this large patient cohort, we observed significant variability in pharmacokinetic/pharmacodynamic target attainment in critically ill patients. A large proportion of the patients without renal dysfunction, most of whom displayed a creatinine clearance>130 mL/min, did not achieve the desired pharmacokinetic/pharmacodynamic target, even with the use of alternative administration methods. Consequently, these patients may be at risk for treatment failure without dose up-titration. PMID- 23642006 TI - Evaluation of femtosecond laser clear corneal incision: an experimental study. AB - PURPOSE: To evaluate the changes of corneal topography following femtosecond laser and manual clear corneal incision (CCI). METHODS: Inflation testing was performed in 14 human eye globes to evaluate the topographic response of the cornea to CCIs. In seven samples (femtosecond laser group), a 2.75-mm three-plane CCI was created using the iFS femtosecond laser (Abbott Medical Optics, Inc., Santa Ana, CA); the remaining seven samples (control group) received a 2.75-mm manual CCI using disposable angled knives. Topographic maps of the anterior and posterior cornea were acquired using a Scheimpflug topographer Pentacam HR (Oculus Optikgerate GmbH, Wetzlar, Germany). Keratometric data were used to analyze the curvature changes of the cornea. The changes of corneal astigmatism were analyzed by vector analysis. RESULTS: After CCI, the mean change of the anterior keratometric power was 0.04 +/- 0.39 and 0.05 +/- 0.51 diopters (D) (analysis of variance, P > .05) in the femtosecond laser and control groups, respectively. The mean change (P > .05) of the posterior corneal keratometric power was 0.16 +/- 0.19 and 0.15 +/- 0.18 D, respectively. The average change of the anterior and posterior corneal astigmatism vector magnitude was 0.17 D or less in both groups (P > .05). A slight against-the-rule astigmatic change of the anterior and posterior corneal interfaces was found after both CCI techniques. CONCLUSION: The 2.75-mm three-plane CCI created with femtosecond laser showed minimal changes of the anterior and posterior corneal topography, comparable with those of single-plane angled manual incision. PMID- 23642007 TI - Phosphodiesterase-4 inhibitors: a review of current developments (2010 - 2012). AB - INTRODUCTION: At last, after many years of research, roflumilast has become the first oral phosphodiesterase-4 inhibitor to be approved by the medical agencies as an add-on therapy for chronic obstructive pulmonary disease. A second compound, apremilast is targeted for submission of new drug application for the treatment of psoriasis in the second half of 2013. These compounds represent a breakthrough and a reward in the field after the many failures to date in clinical development. AREAS COVERED: This review summarizes the clinical development of PDE4 inhibitors from 2010 - 2012 and the associated patent literature with a focus on strategies to overcome the common pitfalls of oral PDE4 inhibitors. EXPERT OPINION: In the last few years, influenced by the body of published clinical data, many companies have lost interest in PDE4 as a target. Many of those that have persevered have opted to realign their research programs either toward compounds specifically designed for inhaled delivery or in search of an increase in clinical efficacy by combining two mechanisms in a single compound. This change is reflected by the continued disclosure of novel and chemically diverse molecules, indicating for some in the pharmaceutical industry that all is not yet lost. PMID- 23642008 TI - Gold-nanobeacons for gene therapy: evaluation of genotoxicity, cell toxicity and proteome profiling analysis. AB - Antisense therapy is a powerful tool for post-transcriptional gene silencing suitable for down-regulating target genes associated to disease. Gold nanoparticles have been described as effective intracellular delivery vehicles for antisense oligonucleotides providing increased protection against nucleases and targeting capability via simple surface modification. We constructed an antisense gold-nanobeacon consisting of a stem-looped oligonucleotide double labelled with 3'-Cy3 and 5'-Thiol-C6 and tested for the effective blocking of gene expression in colorectal cancer cells. Due to the beacon conformation, gene silencing was directly detected as fluorescence increases with hybridisation to target, which can be used to assess the level of silencing. Moreover, this system was extensively evaluated for the genotoxic, cytotoxic and proteomic effects of gold-nanobeacon exposure to cancer cells. The exposure was evaluated by two dimensional protein electrophoresis followed by mass spectrometry to perform a proteomic profile and 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay, glutathione-S-transferase assay, micronucleus test and comet assay to assess the genotoxicity. This integrated toxicology evaluation showed that the proposed nanotheranostics strategy does not exhibit significant toxicity, which is extremely relevant when translating into in vivo systems. PMID- 23642009 TI - What Google Maps can do for biomedical data dissemination: examples and a design study. AB - BACKGROUND: Biologists often need to assess whether unfamiliar datasets warrant the time investment required for more detailed exploration. Basing such assessments on brief descriptions provided by data publishers is unwieldy for large datasets that contain insights dependent on specific scientific questions. Alternatively, using complex software systems for a preliminary analysis may be deemed as too time consuming in itself, especially for unfamiliar data types and formats. This may lead to wasted analysis time and discarding of potentially useful data. RESULTS: We present an exploration of design opportunities that the Google Maps interface offers to biomedical data visualization. In particular, we focus on synergies between visualization techniques and Google Maps that facilitate the development of biological visualizations which have both low overhead and sufficient expressivity to support the exploration of data at multiple scales. The methods we explore rely on displaying pre-rendered visualizations of biological data in browsers, with sparse yet powerful interactions, by using the Google Maps API. We structure our discussion around five visualizations: a gene co-regulation visualization, a heatmap viewer, a genome browser, a protein interaction network, and a planar visualization of white matter in the brain. Feedback from collaborative work with domain experts suggests that our Google Maps visualizations offer multiple, scale-dependent perspectives and can be particularly helpful for unfamiliar datasets due to their accessibility. We also find that users, particularly those less experienced with computer use, are attracted by the familiarity of the Google Maps API. Our five implementations introduce design elements that can benefit visualization developers. CONCLUSIONS: We describe a low-overhead approach that lets biologists access readily analyzed views of unfamiliar scientific datasets. We rely on pre computed visualizations prepared by data experts, accompanied by sparse and intuitive interactions, and distributed via the familiar Google Maps framework. Our contributions are an evaluation demonstrating the validity and opportunities of this approach, a set of design guidelines benefiting those wanting to create such visualizations, and five concrete example visualizations. PMID- 23642010 TI - WALK 2.0 - using Web 2.0 applications to promote health-related physical activity: a randomised controlled trial protocol. AB - BACKGROUND: Physical inactivity is one of the leading modifiable causes of death and disease in Australia. National surveys indicate less than half of the Australian adult population are sufficiently active to obtain health benefits. The Internet is a potentially important medium for successfully communicating health messages to the general population and enabling individual behaviour change. Internet-based interventions have proven efficacy; however, intervention studies describing website usage objectively have reported a strong decline in usage, and high attrition rate, over the course of the interventions. Web 2.0 applications give users control over web content generated and present innovative possibilities to improve user engagement. There is, however, a need to assess the effectiveness of these applications in the general population. The Walk 2.0 project is a 3-arm randomised controlled trial investigating the effects of "next generation" web-based applications on engagement, retention, and subsequent physical activity behaviour change. METHODS/DESIGN: 504 individuals will be recruited from two sites in Australia, randomly allocated to one of two web-based interventions (Web 1.0 or Web 2.0) or a control group, and provided with a pedometer to monitor physical activity. The Web 1.0 intervention will provide participants with access to an existing physical activity website with limited interactivity. The Web 2.0 intervention will provide access to a website featuring Web 2.0 content, including social networking, blogs, and virtual walking groups. Control participants will receive a logbook to record their steps. All groups will receive similar educational material on setting goals and increasing physical activity. The primary outcomes are objectively measured physical activity and website engagement and retention. Other outcomes measured include quality of life, psychosocial correlates, and anthropometric measurements. Outcomes will be measured at baseline, 3, 12 and 18 months. DISCUSSION: The findings of this study will provide increased understanding of the benefit of new web-based technologies and applications in engaging and retaining participants on web-based intervention sites, with the aim of improved health behaviour change outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12611000157976. PMID- 23642012 TI - Effect of cinacalcet availability and formulary listing on parathyroidectomy rate trends. AB - BACKGROUND: Recent trends in parathyroidectomy rates are not known. Our objective was to investigate the trend in parathyroidectomy rates between 2001 and 2010, and to evaluate if the availability and reimbursement of cinacalcet modified that trend. METHODS: Using a provincial administrative database, we included all adult patients receiving chronic dialysis treatments between 2001 and 2010 (incident and prevalent) in a time series analysis. The effect of cinacalcet availability on parathyroidectomy bimonthly rates was modeled using an ARIMA intervention model using different cut-off dates: September 2004 (Health Canada cinacalcet approval), January 2005, June 2005, January 2006, June 2006 (date of cinacalcet provincial reimbursement), and January 2007. RESULTS: A total of 12 795 chronic dialysis patients (mean age 64 years, 39% female, 82% hemodialysis) were followed for a mean follow-up of 3.3 years. During follow-up, 267 parathyroidectomies were identified, translating to an average rate of 7.0 per 1000 person-years. The average parathyroidectomy rate before cinacalcet availability was 11.4 /1000 person-years, and 3.6 /1000 person-years after cinacalcet public formulary listing. Only January 2006 as an intervention date in the ARIMA model was associated with a change in parathyroidectomy rates (estimate: -5.58, p = 0.03). Other intervention dates were not associated with lower parathyroidectomy rates. CONCLUSIONS: A reduction in rates of parathyroidectomy was found after January 2006, corresponding to cinacalcet availability. However, decreased rates may be due to other factors occurring simultaneously with cinacalcet introduction and further studies are needed to confirm these findings. PMID- 23642013 TI - Directed surface assembly of 4-(chloromethyl)phenyltrichlorosilane: self polymerization within spatially confined sites of Si(111) viewed by atomic force microscopy. AB - The self-polymerization of 4-chloromethylphenyltrichlorosilane (CMPS) was studied within spatially confined nanoholes on Si(111) using atomic force microscopy (AFM). Surface platforms of nanoholes were fabricated within a film of octadecyltrichlorosilane using immersion particle lithography. A heating step was developed to temporarily solder the silica mesospheres to the surface, to enable sustained immersion of mesoparticle masks in solvent solutions for the particle lithography protocol. Substrates with a film of mesospheres were heated briefly to anneal the particles to the surface, followed by a rinsing step with sonication to remove the silica beads to generate nanopores within an octadecyltrichlorosilane (OTS) film. Nanopatterned surface templates were immersed in CMPS solutions and removed at different time points to monitor the successive growth of nanostructures over time. Analysis of AFM images after progressive exposure of the nanoholes to solutions of CMPS provided quantitative information and details of the surface self-assembly reaction. Pillar nanostructures of CMPS with different heights and diameters were produced exclusively within the exposed areas of the substrates. Throughout the reaction, the surrounding matrix of OTS-passivated substrate did not evidence growth of CMPS; the surface assembly of CMPS was strictly confined within the nanopores. The diameter of the CMPS nanostructures grew to match the initial sizes of the confined areas of Si(111) but did not spread out beyond the edges of the OTS nanocontainers. However, the vertical growth of columns was affected by the initial size of the sites of uncovered substrate, evidencing a direct correspondence; larger sites produced taller structures, and correspondingly the growth of shorter structures was observed within smaller nanoholes. The heights of CMPS nanostructures indicate that multilayers were formed, with taller columns generated after longer immersion times. These experiments offer intriguing possibilities for using particle lithography as a general approach for nanoscale studies of molecular self-assembly. PMID- 23642011 TI - Novel therapeutic agents in clinical development for systemic lupus erythematosus. AB - Conventional immunosuppressive therapies have radically transformed patient survival in systemic lupus erythematosus (SLE), but their use is associated with considerable toxicity and a substantial proportion of patients remain refractory to treatment. A more comprehensive understanding of the complexity of SLE immunopathogenesis has evolved over the past decade and has led to the testing of several biologic agents in clinical trials. There is a clear need for new therapeutic agents that overcome these issues, and biologic agents offer exciting prospects as future SLE therapies.An array of promising new therapies are currently emerging or are under development including B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and anti-cytokine therapies, such as monoclonal antibodies against interleukin-6 and interferon-alpha. PMID- 23642016 TI - Analytical condition setting a crucial step in the quantification of unstable polyphenols in acidic conditions: analyzing prenylflavanoids in biological samples by liquid chromatography-electrospray ionization triple quadruple mass spectrometry. AB - The interest in studying hops and beer prenylflavanoids, isoxanthohumol, xanthohumol, and 8-prenylnaringenin, has increased in recent years due to their biological activity as strong phytoestrogens and potent cancer chemopreventive agents. However, prenylflavanoids behave differently from most polyphenols, since they are unstable at acidic pH. To our knowledge, no published studies to date have considered the degradation of these compounds during analytical processes. In the present work, a new sensitive and specific method based on solid phase extraction and liquid chromatography coupled to electrospray ionization triple quadruple mass spectrometry (LC-ESI-MS/MS) was developed and validated. The new method was optimized to avoid degradation of the selected analytes, isoxanthohumol, xanthohumol, and 8-prenylnaringenin, throughout the analytical process and to reduce the urine matrix effect in LC-ESI-MS/MS assays. It was concluded that a neutral pH (pH 7.0) is necessary for the analysis of prenylflavanoids, in order to maintain the stability of compounds for at least 24 h. The addition of ascorbic acid to the media improved stability, calibration curves, coefficients of correlation, accuracy, and precision parameters. Mix-mode cation exchange sorbent yielded the best matrix effect factors and recoveries. Method validation results showed appropriate intraday and interday accuracy and precision (<15%). Recovery of isoxanthohumol, xanthohumol, and 8-prenylnaringenin was 97.1% +/- 0.03, 105.8% +/- 0.05, and 105.4% +/- 0.04, respectively, and matrix effect factors were nearly 100%. The stability assay showed that analytes were stable for at least 24 h. The method was applied to quantify 10 human samples of urine and was able to quantify prenylflavanoids in urine after the consumption of a single dose of beer (330 mL). PMID- 23642014 TI - Regulation where autophagy intersects the inflammasome. AB - SIGNIFICANCE: The autophagy and inflammasome pathways are ancient innate immune mechanisms for controlling invading pathogens that are linked by mutual regulation. In addition to controlling the metabolic homeostasis of the cell through nutrient recycling, the "self-eating" process of autophagy is also responsible for the degradation of damaged organelles, cells, and pathogens to protect the integrity of the organism. As a cytosolic pathogen recognition receptor (PRR) complex, the inflammasome both induces and is induced by autophagy through direct interactions with autophagy proteins or through the effects of secondary molecules, such as mitochondrial reactive oxygen species and mitochondrial DNA. RECENT ADVANCES: While the molecular mechanisms of inflammasome activation and regulation are largely unknown, much of the current knowledge has been established through investigation of the role of autophagy in innate immunity. Likewise, regulatory proteins in the NOD-like receptor family, which includes inflammasome PRRs, are able to stimulate autophagy in response to the presence of a pathogen. CRITICAL ISSUES: Many of the newly uncovered links between autophagy and inflammasomes have raised new questions about the mechanisms controlling inflammasome function, which are highlighted in this review. FUTURE DIRECTIONS: Our basic understanding of the mutual regulation of inflammasomes and autophagy will be essential for designing therapeutics for chronic inflammatory diseases, especially those for which autophagy and inflammasome genes have already been linked. PMID- 23642015 TI - Bacillus subtilis genome vector-based complete manipulation and reconstruction of genomic DNA for mouse transgenesis. AB - BACKGROUND: The Bacillus subtilis genome (BGM) vector is a novel cloning system for large DNA fragments, in which the entire 4.2 Mb genome of B. subtilis functions as a vector. The BGM vector system has several attractive properties, such as a large cloning capacity of over 3 Mb, stable propagation of cloned DNA and various modification strategies using RecA-mediated homologous recombination. However, genetic modifications using the BGM vector system have not been fully established, and this system has not been applied to transgenesis. In this study, we developed important additions to the genetic modification methods of the BGM vector system. To explore the potential of the BGM vector, we focused on the fish like odorant receptor (class I OR) gene family, which consists of 158 genes and forms a single gene cluster. Although a cis-acting locus control region is expected to regulate transcription, this has not yet been determined experimentally. RESULTS: Using two contiguous bacterial artificial chromosome clones containing several class I OR genes, we constructed two transgenes in the BGM vector by inserting a reporter gene cassette into one class I OR gene. Because they were oriented in opposite directions, we performed an inversion modification to align their orientation and then fused them to enlarge the genomic structure. DNA sequencing revealed that no mutations occurred during gene manipulations with the BGM vector. We further demonstrated that the modified, reconstructed genomic DNA fragments could be used to generate transgenic mice. Transgenic mice carrying the enlarged transgene recapitulated the expression and axonal projection patterns of the target class I OR gene in the main olfactory system. CONCLUSION: We offer a complete genetic modification method for the BGM vector system, including insertion, deletion, inversion and fusion, to engineer genomic DNA fragments without any trace of modifications. In addition, we demonstrate that this system can be used for mouse transgenesis. Thus, the BGM vector system can be an alternative platform for engineering large DNA fragments in addition to conventional systems such as bacterial and yeast artificial chromosomes. Using this system, we provide the first experimental evidence of a cis-acting element for a class I OR gene. PMID- 23642017 TI - Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice. AB - Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in various biological functions, including cell survival, proliferation, migration, and adhesion. FAK is an essential factor for transforming growth factor beta to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors, including platelet-derived growth factor and insulin-like growth factor I, in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of alpha-smooth muscle actin induced by transforming growth factor beta, indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis and that it can become a promising target for therapeutic approaches to pulmonary fibrosis. PMID- 23642019 TI - Coulomb fission in dielectric dication clusters: experiment and theory on steps that may underpin the electrospray mechanism. AB - A series of five molecular dication clusters, (H2O)n(2+), (NH3)n(2+), (CH3CN)n(2+), (C5H5N)n(2+), and (C6H6)n(2+), have been studied for the purpose of identifying patterns of behavior close to the Rayleigh instability limit where the clusters might be expected to exhibit Coulomb fission. Experiments show that the instability limit for each dication covers a range of sizes and that on a time scale of 10(-4) s ions close to the limit can undergo either Coulomb fission or neutral evaporation. The observed fission pathways exhibit considerable asymmetry in the sizes of the charged fragments, and are associated with kinetic (ejection) energies of ~0.9 eV. Coulomb fission has been modeled using a theory recently formulated to describe how charged particles of dielectric materials interact with one another (Bichoutskaia et al. J. Chem. Phys. 2010, 133, 024105). The calculated electrostatic interaction energy between separating fragments accounts for the observed asymmetric fragmentation and for the magnitudes of the measured ejection energies. The close match between theory and experiment suggests that a significant fraction of excess charge resides on the surfaces of the fragment ions. The experiments provided support for a fundamental step in the electrospray ionization (ESI) mechanism, namely the ejection from droplets of small solvated charge carriers. At the same time, the theory shows how water and acetonitrile may behave slightly differently as ESI solvents. However, the theory also reveals deficiencies in the point-charge image-charge model that has previously been used to quantify Coulomb fission in the electrospray process. PMID- 23642020 TI - Sr3BeB6O13: a new borate in the SrO/BeO/B2O3 system with novel tri-six-membered ring (BeB6O15)10- building block. AB - A new polyborate Sr3BeB6O13 has been synthesized and grown by the traditional solid-state reaction method and spontaneous crystallization flux method. It crystallizes in orthorhombic space group Pnma (No. 62) with the following unit cell dimensions: a = 12.775(3) A, b = 10.029(2) A, c = 8.0453(16) A, and Z = 4. The crystal is characterized by an infinite two-dimensional network with a tri six-membered ring (BeB5O13)(9-) anionic group, which was first found in beryllium borates. Ultraviolet (UV)-visible-near-infrared diffuse reflectance spectroscopy demonstrates that its UV cutoff edge is below 200 nm, and the first-principles electronic structure calculations reveal its energy band gap of 7.03 eV (~175 nm). Thermal analysis exposes its incongruent feature at 1043 degrees C. IR spectroscopy measurements are consistent with the crystallographic study. These data reveal that this crystal would be applied as a deep-ultraviolet optical material. PMID- 23642021 TI - p-Stilbazole moieties as artificial base pairs for photo-cross-linking of DNA duplex. AB - In this study, we report a photo-cross-linking reaction between p-stilbazole moieties. p-Stilbazoles were introduced into base-paring positions of complementary DNA strands. The [2 + 2] photocycloaddition reaction occurred rapidly upon light irradiation at 340 nm. Consequently, duplex was cross-linked and highly stabilized after 3 min irradiation. The CD spectrum of the cross linked duplex indicated that the B-form double-helical structure was not severely distorted. NMR analysis revealed only one conformation of the duplex prior to UV irradiation, whereas two diastereomers were detected after the photo-cross linking reaction. Before UV irradiation, p-stilbazole can adopt two different stacking modes because of rotation around the single bond between the phenyl and vinyl groups; these conformations cannot be discriminated on the NMR time scale due to rapid interconversion. However, photo-cross-linking fixed the conformation and enabled discrimination both by NMR and HPLC. The artificial base pair of p methylstilbazolium showed almost the same reactivity as p-stilbazole, indicating that positive charge does not affect the reactivity. When a natural nucleobase was present in the complementary strand opposite p-stilbazole, the duplex was significantly destabilized relative to the duplex with paired p-stilbazole moieties and no photoreaction occurred between p-stilbazole and the nucleobase. The p-stilbazole pair has potential as a "third base pair" for nanomaterials due to its high stability and superb orthogonality. PMID- 23642018 TI - Time course changes of anti- and pro-apoptotic proteins in apigenin-induced genotoxicity. AB - BACKGROUND: Apigenin (4',5,7-trihydroxyflavone, AP), an active component of many medicinal Chinese herbs, exhibits anticancer properties in vitro and in vivo. This study aims to investigate the genotoxic, cytostatic, and cytotoxic effects of AP and time course changes in the levels of anti- and pro-apoptotic proteins involved in the DNA damage response in HepG2 cells. METHODS: The genotoxic potential of AP was determined by sister chromatid exchanges (SCEs) and chromosomal aberrations (CAs) analysis. The levels of cytostaticity and cytotoxicity were evaluated by the proliferation rate and mitotic indices, respectively. MTT was used to study cytotoxicity, while the induction of apoptosis and the expression of apoptosis-related proteins were determined by ELISA. RESULTS: At concentrations greater than 10 MUM, AP decreased cell survival in a dose- (48 h: 10 vs. 20 MUMU, P < 0.001 and 20 vs. 50 MUMU, P = 0.005; 72 h: 10 vs. 20 MUMU, P < 0.001 and 20 vs. 50 MUMU, P = 0.001) and time-dependent manner (20 MUMU: 24 vs. 48 h, P < 0.001 and 48 vs. 72 h, P = 0.003; 50 MUMU: 24 vs. 48 h, P < 0.001 and 48 vs. 72 h, P < 0.001; 100 MUMU: 24 vs. 48 h, P < 0.001 and 48 vs. 72 h, P < 0.001). SCEs rates, cell proliferation, and mitotic divisions were also affected in a dose-dependent manner (P < 0.001). There was no change in the frequency of aberrant cells (1 MUMU AlphaP: P = 0.554; 10 MUM AP: P = 0.337; 20 MUMU AP: P = 0.239). Bcl-2 levels were reduced 3 h after AP administration (P = 0.003) and remained reduced throughout the 48 h observation period (6 h, P = 0.044; 12 h, P = 0.001; 24 h, P = 0.042; 48 h, P = 0.012). Bax and soluble Fas exhibited a transient upregulation 24 h after AP treatment. The Bax/Bcl-2 ratio was also increased at 12 h and remained increased throughout the 48 h observation period. CONCLUSION: AP exhibited dose-dependent genotoxic potential in HepG2 cells. The protein levels of sFas, Bcl-2, and Bax were affected by AP to promote cell survival and cell death, respectively. PMID- 23642022 TI - Antioxidant and relaxant activity of fractions of crude methanol extract and essential oil of Artemisia macrocephala Jacquem. AB - BACKGROUND: The current work is an attempt to know about additional chemical profile of Artemisia macrocephala. Antioxidant activity is performed as the plant is reported to contain flavonoids, which have antioxidant activity in general. Relaxant activity of fractions of crude methanol extract is performed to know in which fraction(s) the relaxant constituents concentrate as we have already reported that its crude methanol has relaxant activity. Antispasmodic activity of essential oil is also performed as the plant is rich with essential oil. METHODS: Phytochemical profile of the plant is performed. Free radical scavenging activity was performed using 2, 2-diphenyl-1-picrylhydrazyl (DPPH). Relaxation activity tests of fractions and essential oil of Artemisia macrocephala were performed on sections of rabbits' jejunum. Calcium chloride curves were constructed to investigate the mode of action of plant extracts and its essential oil. RESULTS: We detected carbohydrates, flavonoids and saponins in A. macrocephala. At concentration 0.005 mg/ml, free radical scavenging activity of ethyl acetate fraction was 121.5 +/- 2.02% of ascorbic acid.n- hexane fraction relaxed spontaneous activity with EC50 0.74 +/- 0.04 mg/ml. Essential oil relaxed spontaneous activity with EC50 0.8 +/- 0.034 mg/ml. Chloroform and ethylacetate fractions relaxed both spontaneous and KCl-induced contractions suggesting its possible mode through calcium channels. Constructing calcium chloride curves, the test fractions showed a right shift in the EC50. Essential oil at concentration 0.1 mg/ml produced right shift with EC50 (log [Ca++]M) -2.08 +/- 0.08 vs. control with EC50 -2.47 +/- 0.07. The curve resembled the curves of verapamil, which caused a right shift at 0.1 MUM, with EC50 -1.7 +/-0.07 vs. control EC50 (log [Ca++]M) -2.45 +/- 0.06. CONCLUSIONS: Crude methanol and its fractions (ethyl acetate, chloroform and butanol) are rich sources of antioxidant constituents. The relaxing constituents following calcium channel blocking mechanisms are more concentrated in n-hexane, chloroform and ethyl acetate fractions that warrant isolation. PMID- 23642023 TI - Corticotropin-releasing factor 1 receptor antagonists: a patent review. AB - INTRODUCTION: Corticotropin-releasing factor (CRF) is a 41 amino acid peptide hypothalamic factor that plays a key role in the body's response to stress. The receptors for CRF (CRF1 and CRF2) are members of the class B G-protein coupled receptor family and several small molecule antagonists have been evaluated clinically in stress-related disorders. AREAS COVERED: The present review covers the disclosures of non-peptide CRF1 antagonists in the patent literature since 2006. EXPERT OPINION: Antagonists of the CRF1 receptor have failed to demonstrate clinical utility. All of the compounds evaluated are similar structures and are allosteric inhibitors of the CRF1 receptor. Further clinical evaluation of new compounds appears unlikely unless novel structures are identified that interact with the receptor distinct to the first-generation antagonists. PMID- 23642024 TI - Wave intensity analysis in the human coronary circulation in health and disease. AB - Coronary artery hemodynamics are very different to that of the systemic arteries; unlike the systemic circulation, in the coronary circulation pressure is generated from both the proximal and distal end of the artery - due to the effect of contraction and relaxation of the myocardium on the microvasculature. As a result, the systemic artery hemodynamic model cannot be used to explain the pressure-flow relationship in the coronaries. Wave intensity analysis is an investigative tool that is able to distinguish simultaneous proximal and distal influences on coronary blood flow and is therefore uniquely suitable for the study of coronary haemodynamics. This review discusses the concept behind wave intensity analysis and evaluates how it has been used to characterise and provide new insights on coronary haemodynamics in health and disease. PMID- 23642025 TI - Takotsubo cardiomyopathy a short review. AB - Takotsubo cardiomyopathy (TCM), otherwise cardiomyopathy,apical ballooning syndrome or broken heart syndrome is a reversible cardiomyopathy, predominantly occurs in post-menopausal women and commonly due to emotional or physical stress. Typically, patients present with chest pain and ST elevation or T wave inversion on their electrocardiogram mimicking acute coronary syndrome, but with normal or non-flow limiting coronary artery disease. Acute dyspnoea, hypotension and even cardiogenic shock may be the presenting feature of this condition. The wall motion abnormalities typically involve akinesia of the apex of the left ventricle with hyperkinesia of the base of the heart. Atypical forms of TCM have also recently been described. An urgent left ventriculogram or echocardiogram is the key investigation to identify this syndrome. Characteristically, there is only a limited release of cardiac enzymes disproportionate to the extent of regional wall motion abnormality. Transient right ventricular dysfunction may occur and is associated with more complications, longer hospitalisation and worse left ventricular systolic dysfunction. Recently, cardiac MRI has been increasingly used to diagnose this condition and to differentiate from acute coronary syndrome in those who have abnormal coronary arteries. Treatment is often supportive, however beta-blocker and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocking agent are being used in routine clinical practice. The syndrome is usually spontaneously reversible and cardiovascular function returns to normal after a few weeks. This review article will elaborate on the pathophysiology, clinical features including the variant forms, latest diagnostic tools, management and prognosis of this condition. PMID- 23642026 TI - Molecular mechanism of misfolding and aggregation of Abeta(13-23). AB - The misfolding and self-assembly of the amyloid-beta (Abeta) peptide into aggregates is a molecular signature of the development of Alzheimer's disease, but molecular mechanisms of the peptide aggregation remain unknown. Here, we combined Atomic Force Microscopy (AFM) and Molecular Dynamics (MD) simulations to characterize the misfolding process of an Abeta peptide. Dynamic force spectroscopy AFM analysis showed that the peptide forms stable dimers with a lifetime of ~1 s. During MD simulations, isolated monomers gradually adopt essentially similar nonstructured conformations independent from the initial structure. However, when two monomers approach their structure changes dramatically, and the conformational space for the two monomers become restricted. The arrangement of monomers in antiparallel orientation leads to the cooperative formation of beta-sheet conformation. Interactions, including hydrogen bonds, salt bridges, and weakly polar interactions of side chains stabilize the structure of the dimer. Under the applied force, the dimer, as during the AFM experiments, dissociates in a cooperative manner. Thus, misfolding of the Abeta peptide proceeds via the loss of conformational flexibility and formation of stable dimers suggesting their key role in the subsequent Abeta aggregation process. PMID- 23642027 TI - Gene expression profiling of chronic myeloid leukemia with variant t(9;22) reveals a different signature from cases with classic translocation. AB - BACKGROUND: The t(9;22)(q34;q11) generating the BCR/ABL1 fusion gene represents the cytogenetic hallmark of chronic myeloid leukemia (CML). About 5-10% of CML cases show variant translocations with the involvement of other chromosomes in addition to chromosomes 9 and 22. The molecular bases of biological differences between CML patients with classic and variant t(9;22) have never been clarified. FINDINGS: In this study, we performed gene expression microarray analysis to compare CML patients bearing variant rearrangements and those with classic t(9;22)(q34;q11). We identified 59 differentially expressed genes significantly associated with the two analyzed groups. The role of specific candidate genes such as TRIB1 (tribbles homolog 1), PTK2B (protein tyrosine kinase 2 beta), and C5AR1 (complement component 5a receptor 1) is discussed. CONCLUSIONS: Our results reveal that in CML cases with variant t(9;22) there is an enhancement of the MAPK pathway deregulation and show that kinases are a common target of molecular alterations in hematological disorders. PMID- 23642028 TI - Structure-based drug design for hypoxia-inducible factor prolyl-hydroxylase inhibitors and its therapeutic potential for the treatment of erythropoiesis stimulating agent-resistant anemia: raising expectations for exploratory clinical trials. AB - INTRODUCTION: Anemia occurs in various chronic diseases and its treatment is dramatically improved after the appearance of erythropoiesis-stimulating agents (ESA). However, there are several problems regarding the use of ESA including: i) invasiveness, ii) high cost and iii) ESA resistance. Therefore, there is a need to develop small molecule drugs which can improve these problems. Hypoxia inducible factor (HIF) plays a key role in regulating erythropoietin production. HIF stabilizers, particularly, prolyl hydroxylase domain-containing protein (PHD) inhibitors, have emerged as small molecule-based anti-anemia medicine. AREAS COVERED: This article discusses the current status of PHD inhibitors and the pros and cons of currently tested methods. Specifically, the article reviews the advantages of structure-based drug design in the development of PHD inhibitors and looks at future perspectives within the field. EXPERT OPINION: Despite the fact that structure-based drug design has dramatically improved drug discovery, testing on humans is still one of the most time-consuming parts of drug discovery and one that is not accelerated by structural approaches. Exploratory clinical trials, first-in-man studies have emerged as a new strategy for preclinical and clinical development of drugs. Exploratory clinical trials will not only reduce the time and cost in preclinical trials but also provide important information on candidate drug's pharmacological effects in humans. Exploratory clinical trials may be a potential alternative strategy for the drug discovery in the future. PMID- 23642029 TI - Semisynthesis of radiolabeled amino acid and lipid brevetoxin metabolites and their blood elimination kinetics in C57BL/6 mice. AB - Brevetoxin B (BTX-B), produced by dinoflagellates of the species Karenia, is a highly reactive molecule, due in part to an alpha,beta-unsaturated aldehyde group at the terminal side chain, leading to the production of metabolites in shellfish by reduction, oxidation, and conjugation. We have investigated in mice the blood elimination of three common bioactive brevetoxin metabolites found in shellfish, which have been semisynthesized from BTX-B in radioactive forms. BTX-B was reduced at C42 to yield [(3)H] dihydro-BTX-B. [(3)H] S-desoxy-BTX-B2 (cysteine brevetoxin B) was semisynthesized from BTX-B by the conjugation of cysteine at the C50 olefinic group then [(3)H] radiolabeled by C42 aldehyde reduction. [(14)C] N-Palmitoyl-S-desoxy-BTX-B2 was prepared using S-desoxy-BTX-B2 as the starting material with addition of the [(14)C] radiolabeled fatty acid via cysteine-amide linkage. The elimination of intravenously administered [(3)H] S desoxy-BTX-B2, [(14)C] N-palmitoyl-S-desoxy-BTX-B2, or [(3)H] dihydro-BTX-B was measured in blood collected from C57BL/6 mice over a 48 h period. Each brevetoxin metabolite tested exhibited biexponential elimination kinetics and fit a two compartment model of elimination that was applied to generate toxicokinetic parameters. The rate of transfer between the central compartment (i.e., blood) and the peripheral compartment (e.g., tissue) for each brevetoxin differed substantially, with dihydro-BTX-B exchanging rapidly with the peripheral compartment, S-desoxy-BTX-B2 eliminating rapidly from the central compartment, and N-palmitoyl-S-desoxy-BTX-B2 eliminating slowly from the central compartment. Toxicokinetic parameters were analyzed in the context of the unique structure of each brevetoxin metabolite resulting from a reduction, amino acid conjugation, or fatty acid addition to BTX-B. PMID- 23642030 TI - Seroprevalence of Streptococcal Inhibitor of Complement (SIC) suggests association of streptococcal infection with chronic kidney disease. AB - BACKGROUND: Group A streptococcus (GAS) is an etiological agent for the immune mediated sequela post streptococcal glomerulonephritis (PSGN). In some populations PSGN is recognized as a risk factor for chronic kidney disease (CKD) and end-stage renal disease (ESRD). It was found that a significantly greater proportion of subjects with past history of PSGN than without the history exhibited seroreactions to streptococcal antigens called streptococcal inhibitor of complement (SIC) and to distantly related SIC (DRS). These antigens are expressed by major PSGN-associated GAS types. We therefore predicted that in populations such as India, which is endemic for streptococcal diseases and which has high prevalence of CKD and ESRD, greater proportions of CKD and ESRD patients exhibit seroreaction to SIC and DRS than healthy controls. METHODS: To test this we conducted a SIC and DRS seroprevalence study in subjects from Mumbai area. We recruited 100 CKD, 70 ESRD and 70 healthy individuals. RESULTS: Nineteen and 35.7% of CKD and ESRD subjects respectively were SIC antibody-positive, whereas only 7% of healthy cohort was seropositive to SIC. Furthermore, significantly greater proportion of the ESRD patients than the CKD patients is seropositive to SIC (p=0.02; odds ratio 2.37). No association was found between the renal diseases and DRS-antibody-positivity. CONCLUSIONS: Past infection with SIC positive GAS is a risk factor for CKD and ESRD in Mumbai population. Furthermore, SIC seropositivity is predictive of poor prognosis of CKD patients. PMID- 23642032 TI - Challenges in the control of human African trypanosomiasis in the Mpika district of Zambia. AB - BACKGROUND: Human African Trypanosomiasis is one of the Neglected Tropical Diseases that is targeted for elimination by the World Health Organization. Strong health delivery system in endemic countries is required for a control program to eliminate this disease. In Zambia, Human African Trypanosomiasis is lowly endemic in the northeastern part of the country. FINDINGS: We conducted a cross-sectional survey of health institutions in Mpika district in Northern Province of Zambia from 9th to 23rd November 2011. The aim of this study was to assess current health delivery system in the management of Human African Trypanosomiasis cases in Mpika district, Northern Province of Zambia. Ten health institutions were covered in the survey. Two structured questionnaires targeting health workers were used to collect the data on general knowledge on HAT and state of health care facilities in relation to HAT management from the surveyed health institution.Only 46% of the 28 respondents scored more than 50% from the questionnaire on general knowledge about Human African Trypanosomiasis disease. None of the respondents knew how to differentiate the two clinical stages of Human African Trypanosomiasis disease. There were only three medical doctors to attend to all Human African Trypanosomiasis cases and other diseases at the only diagnostic and treatment hospital in Mpika district. The supply of antitrypanosomal drugs to the only treatment centre was erratic. Only one refresher course on Human African Trypanosomiasis case diagnosis and management for health staff in the district had been organized by the Ministry of Health in conjunction with the World Health Organization in the district in 2009. The referral system for suspected Human African Trypanosomiasis cases from Rural Health Centres (RHCs) to the diagnostic/treatment centre was inefficient. CONCLUSIONS: There are a number of challenges that have been identified and need to be addressed if Human African Trypanosomiasis is to be eliminated in a lowly endemic country such as Zambia. These include shortage of trained health workers, inadequate diagnostic and treatment centres, lack of more sensitive laboratory diagnostic techniques, shortage of trypanosomicides among others discussed in detail here. PMID- 23642031 TI - Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer's disease mice. AB - BACKGROUND: Recent evidence suggests that the inducible kinin B1 receptor (B1R) contributes to pathogenic neuroinflammation induced by amyloid-beta (Abeta) peptide. The present study aims at identifying the cellular distribution and potentially detrimental role of B1R on cognitive and cerebrovascular functions in a mouse model of Alzheimer's disease (AD). METHODS: Transgenic mice overexpressing a mutated form of the human amyloid precursor protein (APPSwe,Ind, line J20) were treated with a selective and brain penetrant B1R antagonist (SSR240612, 10 mg/kg/day for 5 or 10 weeks) or vehicle. The impact of B1R blockade was measured on i) spatial learning and memory performance in the Morris water maze, ii) cerebral blood flow (CBF) responses to sensory stimulation using laser Doppler flowmetry, and iii) reactivity of isolated cerebral arteries using online videomicroscopy. Abeta burden was quantified by ELISA and immunostaining, while other AD landmarks were measured by western blot and immunohistochemistry. RESULTS: B1R protein levels were increased in APP mouse hippocampus and, prominently, in reactive astrocytes surrounding Abeta plaques. In APP mice, B1R antagonism with SSR240612 improved spatial learning, memory and normalized protein levels of the memory-related early gene Egr-1 in the dentate gyrus of the hippocampus. B1R antagonism restored sensory-evoked CBF responses, endothelium dependent dilations, and normalized cerebrovascular protein levels of endothelial nitric oxide synthase and B2R. In addition, SSR240612 reduced (approximately 50%) microglial, but not astroglial, activation, brain levels of soluble Abeta1-42, diffuse and dense-core Abeta plaques, and it increased protein levels of the Abeta brain efflux transporter lipoprotein receptor-related protein-1 in cerebral microvessels. CONCLUSION: These findings show a selective upregulation of astroglial B1R in the APP mouse brain, and the capacity of the B1R antagonist to abrogate amyloidosis, cerebrovascular and memory deficits. Collectively, these findings provide convincing evidence for a role of B1R in AD pathogenesis. PMID- 23642033 TI - Nanoscale patterning of membrane-bound proteins formed through curvature-induced partitioning of phase-specific receptor lipids. AB - This work describes a technique for forming high-density arrays and patterns of membrane-bound proteins through binding to a curvature-organized compositional pattern of metal-chelating lipids (Cu(2+)-DOIDA or Cu(2+)-DSIDA). In this bottom up approach, the underlying support is an e-beam formed, square lattice pattern of hemispheres. This curvature pattern sorts Cu(2+)-DOIDA to the 200 nm hemispherical lattice sites of a 600 nm * 600 nm unit cell in Ld - Lo phase separated lipid multibilayers. Binding of histidine-tagged green fluorescent protein (His-GFP) creates a high density array of His-GFP-bound pixels localized to the square lattice sites. In comparison, the negative pixel pattern is created by sorting Cu(2+)-DSIDA in Ld - Lbeta' phase separated lipid multibilayers to the flat grid between the lattice sites followed by binding to His-GFP. Lattice defects in the His-GFP pattern lead to interesting features such as pattern circularity. We also observe defect-free arrays of His-GFP that demonstrate perfect arrays can be formed by this method suggesting the possibility of using this approach for the localization of various active molecules to form protein, DNA, or optically active molecular arrays. PMID- 23642035 TI - Easier said than done: challenges of applying the Ecohealth approach to the study on heavy metals exposure among indigenous communities of the Peruvian Amazon. AB - BACKGROUND: The renewed interest in community participation in health research is linked to its potential for bridging gaps between research and practice. Its main attributes are the generation of knowledge that can lead to socially robust, long lasting solutions and the creation of a co-learner relationship between researchers and research users. Following this philosophy, Ecohealth has evolved into a specialized framework for participatory research on the impact of pollution on ecosystems and human health. However, its principles pose considerable challenges. Its outcomes are strongly influenced by contextual factors that are impossible to control for ahead of time.This paper describes how the Ecohealth principles were applied to an epidemiological study of heavy metals exposure among indigenous communities of the Peruvian Amazon. It illustrates how knowledge generated from participatory research does not necessarily imply solving a public health problem. This study aimed to contribute to the understanding of the benefits and barriers of following the basic principles of the Ecohealth approach, and assist researchers working in similar contexts. RESEARCH PROCESS: Based upon their personal experience as participant observers, the authors describe the research process; then, they discuss the most important challenges faced, their implications, and the attempted strategies for resolution. CHALLENGES: Challenges were grouped into four themes: (1) building trust; (2) one partnership, many stakeholders, multiple agendas; (3) being a researcher; and (4) communicating complex and unexpected findings. CONCLUSIONS: Integrating the principles of transdisciplinarity and participation posed a series of challenges to the research process that were difficult, and sometimes impossible to overcome. However, positive outcomes from this experience were the lessons learned by the different actors. Despite the lack of immediate action, it is expected that useful interventions to prevent and control lead exposure in the Corrientes population will be implemented in the medium term. PMID- 23642034 TI - Autophagy in kidney health and disease. AB - SIGNIFICANCE: Autophagy is emerging as an important pathway in many biological processes and diseases. This review summarizes the current progress on the role of autophagy in renal physiology and pathology. RECENT ADVANCES: Studies from renal cells in culture, human kidney tissues, and experimental animal models implicate that autophagy regulates many critical aspects of normal and disease conditions in the kidney, such as diabetic nephropathy and other glomerular diseases, tubular injuries, kidney development and aging, cancer, and genetic diseases associated with the kidney. CRITICAL ISSUES: The importance of autophagy in the kidney has just started to be elucidated. How the process of autophagy is altered in the pathogenesis of kidney diseases and how this alteration is beneficial or detrimental to kidney functions still need to be fully understood. FUTURE DIRECTIONS: Investigations that uncover the precise mechanism and regulation of autophagy in various kidney diseases may lead to new strategies for therapeutic modulation. PMID- 23642036 TI - New approach to electrode kinetic measurements in square-wave voltammetry: amplitude-based quasireversible maximum. AB - The influence of the potential pulse height of square-wave voltammetry (SWV) (i.e., the SW amplitude) is studied for a variety of quasireversible electrode mechanisms, including a simple solution-phase electrode reaction at a planar or spherical electrode, a solution phase electrode reaction coupled with a reversible follow-up chemical reaction, and a diffusionless surface confined electrode reaction. The electrode kinetics of all the electrode mechanisms depends critically on the SW amplitude, and the quasireversible kinetic region is a function of both frequency-related electrode kinetic parameters and the SW amplitude. Thus, a novel methodology for electrode kinetics measurements is proposed by altering the SW amplitude only, at a fixed frequency of the SW potential modulation, that is, at a constant scan rate of the voltammetric experiment. Electrode kinetic measurements at a constant SW frequency are of exceptional importance especially when complex electrode mechanisms are studied, which depend on several frequency-related kinetic parameters. The electrode kinetic measurements are based on a novel feature termed the "amplitude-based quasireversible maximum", manifested as a parabolic dependence of the amplitude normalized net SW peak current versus the SW amplitude. The position of the amplitude-based quasireversible maximum depends on the standard rate constant of the electrode reaction, enabling estimation of this important kinetic parameter in a simple and fast procedure. The novel quasireversible maximum is attributed to all studied electrode mechanisms, implying that it is a general feature of most electrode mechanisms under conditions of SWV. PMID- 23642037 TI - Surface-sensitive two-dimensional magneto-fingerprint in mesoscopic Bi2Se3 channels. AB - Periodic Aharonov-Bohm and Altshuler-Aronov-Spivak oscillations have traditionally been observed in lateral transport through patterned mesoscopic loops of diffusive conductors. However, our studies of perpendicular-to-plane magnetotransport in straight-channel, diffusive devices of epitaxial Bi2Se3 surprisingly reveal signatures of Aharonov-Bohm orbits, periodic conductance fluctuation magneto-fingerprints, even though the devices are not explicitly patterned into loops. We show that the length scale of these orbits corresponds to the typical perimeter of triangular terraces found on the surface of these thin film devices, strongly suggesting that the periodic magneto-fingerprint arises from coherent scattering of electron waves from the step-edges. Our interpretation is bolstered by control measurements in devices without such surface morphology that only show a conventional, aperiodic magneto-fingerprint. These results show that lithographically patterned Bi2Se3 devices provide a novel class of mesoscopic physical systems for systematic studies of coherent surface sensitive transport. PMID- 23642039 TI - Conference report from the 2012 AHA scientific sessions in Los Angeles. AB - The 2012 Scientific Sessions of the American Heart Association was held on November 3 - 7 in Los Angels, California. It covered up-to-date research on both basic- and clinical-cardiovascular science. We describe the highlights of the meeting focusing on basic science and clinical cardiology. More specifically we will discuss new insights on arrhythmias, cardiac cell death/survival and clinical studies involving novel and unique treatment paradigms. PMID- 23642040 TI - Delivery and use of individualised feedback in large class medical teaching. AB - BACKGROUND: Formative feedback that encourages self-directed learning in large class medical teaching is difficult to deliver. This study describes a new method, blueprinted feedback, and explores learner's responses to assess its appropriate use within medical science teaching. METHODS: Mapping summative assessment items to their relevant learning objectives creates a blueprint which can be used on completion of the assessment to automatically create a list of objectives ranked by the attainment of the individual student. Two surveys targeted medical students in years 1, 2 and 3. The behaviour-based survey was released online several times, with 215 and 22 responses from year 2, and 187, 180 and 21 responses from year 3. The attitude-based survey was interviewer administered and released once, with 22 responses from year 2 and 3, and 20 responses from year 1. RESULTS: 88-96% of learners viewed the blueprinted feedback report, whilst 39% used the learning objectives to guide further learning. Females were significantly more likely to revisit learning objectives than males (p = 0.012). The most common reason for not continuing learning was a 'hurdle mentality' of focusing learning elsewhere once a module had been assessed. CONCLUSIONS: Blueprinted feedback contains the key characteristics required for effective feedback so that with further education and support concerning its use, it could become a highly useful tool for the individual and teacher. PMID- 23642041 TI - Genome wide analysis of the complete GlnR nitrogen-response regulon in Mycobacterium smegmatis. AB - BACKGROUND: Nitrogen is an essential element for bacterial growth and an important component of biological macromolecules. Consequently, responding to nitrogen limitation is critical for bacterial survival and involves the interplay of signalling pathways and transcriptional regulation of nitrogen assimilation and scavenging genes. In the soil dwelling saprophyte Mycobacterium smegmatis the OmpR-type response regulator GlnR is thought to mediate the transcriptomic response to nitrogen limitation. However, to date only ten genes have been shown to be in the GlnR regulon, a vastly reduced number compared to other organisms. RESULTS: We investigated the role of GlnR in the nitrogen limitation response and determined the entire GlnR regulon, by combining expression profiling of M. smegmatis wild type and glnR deletion mutant, with GlnR-specific chromatin immunoprecipitation and high throughput sequencing. We identify 53 GlnR binding sites during nitrogen limitation that control the expression of over 100 genes, demonstrating that GlnR is the regulator controlling the assimilation and utilisation of nitrogen. We also determine a consensus GlnR binding motif and identify key residues within the motif that are required for specific GlnR binding. CONCLUSIONS: We have demonstrated that GlnR is the global nitrogen response regulator in M. smegmatis, directly regulating the expression of more than 100 genes. GlnR controls key nitrogen stress survival processes including primary nitrogen metabolism pathways, the ability to utilise nitrate and urea as alternative nitrogen sources, and the potential to use cellular components to provide a source of ammonium. These studies further our understanding of how mycobacteria survive nutrient limiting conditions. PMID- 23642042 TI - Lupus enteritis: from clinical findings to therapeutic management. AB - Lupus enteritis is a rare and poorly understood cause of abdominal pain in patients with systemic lupus erythematosus (SLE). In this study, we report a series of 7 new patients with this rare condition who were referred to French tertiary care centers and perform a systematic literature review of SLE cases fulfilling the revised ACR criteria, with evidence for small bowel involvement, excluding those with infectious enteritis. We describe the characteristics of 143 previously published and 7 new cases. Clinical symptoms mostly included abdominal pain (97%), vomiting (42%), diarrhea (32%) and fever (20%). Laboratory features mostly reflected lupus activity: low complement levels (88%), anemia (52%), leukocytopenia or lymphocytopenia (40%) and thrombocytopenia (21%). Median CRP level was 2.0 mg/dL (range 0-8.2 mg/dL). Proteinuria was present in 47% of cases. Imaging studies revealed bowel wall edema (95%), ascites (78%), the characteristic target sign (71%), mesenteric abnormalities (71%) and bowel dilatation (24%). Only 9 patients (6%) had histologically confirmed vasculitis. All patients received corticosteroids as a first-line therapy, with additional immunosuppressants administered either from the initial episode or only in case of relapse (recurrence rate: 25%). Seven percent developed intestinal necrosis or perforation, yielding a mortality rate of 2.7%. Altogether, lupus enteritis is a poorly known cause of abdominal pain in SLE patients, with distinct clinical and therapeutic features. The disease may evolve to intestinal necrosis and perforation if untreated. Adding with this an excellent steroid responsiveness, timely diagnosis becomes primordial for the adequate management of this rare entity. PMID- 23642044 TI - Assessing cellular DNA damage from a helium plasma needle. AB - The aim of the present study is to determine the deoxyribonucleic acid (DNA) damage by cells exposed to atmospheric pressure non-thermal plasma (APNTP). Mouse leukocytes embedded in agarose were exposed to the plasma at two different distances from a helium plasma needle outlet and during three different exposure periods. Damage was assessed by the single cell gel electrophoresis assay. The results indicate that, at 0.1 cm from the plasma needle, the exposure caused complete DNA fragmentation determined by the presence of so called "clouds". Samples exposed at 0.5 cm from the slide sample surface presented damage proportional to the exposure periods in terms of tail intensity, tail moment and "clouds" frequency. Studies performed with alkaline single cell gel electrophoresis assay to determine DNA breaks and alkali-labile sites, indicates that DNA damage produced by exposure to APNTP was caused mainly by oxidative radicals, rather than by UV light which causes cyclobutane pyrimidine dimers. These results allow us to conclude that plasma needle induced DNA breaks in mice leukocytes proportionally to exposure time. PMID- 23642043 TI - Effects of dimethylarginine dimethylaminohydrolase-1 overexpression on the response of the pulmonary vasculature to hypoxia. AB - Acute and sustained hypoxic pulmonary vasoconstriction (HPV), as well as chronic pulmonary hypertension (PH), is modulated by nitric oxide (NO). NO synthesis can be decreased by asymmetric dimethylarginine (ADMA), which is degraded by dimethylarginine dimethylaminohydrolase-1 (DDAH1). We investigated the effects of DDAH1 overexpression (DDAH1(tg)) on HPV and chronic hypoxia-induced PH. HPV was measured during acute (10 min) and sustained (3 h) hypoxia in isolated mouse lungs. Chronic PH was induced by the exposure of mice to 4 weeks of hypoxia. ADMA and cyclic 3',5'-guanosine monophosphate (cGMP) were determined by ELISA, and NO generation was determined by chemiluminescence. DDAH1 overexpression exerted no effects on acute HPV. However, DDAH1(tg) mice showed decreased sustained HPV compared with wild-type (WT) mice. Concomitantly, ADMA was decreased, and concentrations of NO and cGMP were significantly increased in DDAH1(tg). The administration of either Nomega-nitro-l-arginine or 1H-[1,2,4]oxadiazolo [4,3 a]quinoxalin-1-one potentiated sustained HPV and partly abolished the differences in sustained HPV between WT and DDAH1(tg) mice. The overexpression of DDAH1 exerted no effect on the development of chronic hypoxia-induced PH. DDAH1 overexpression selectively decreased the sustained phase of HPV, partly via activation of the NO-cGMP pathway. Thus, increased ADMA concentrations modulate sustained HPV, but not acute HPV or chronic hypoxia-induced PH. PMID- 23642045 TI - Functional proteomics analysis to study ATM dependent signaling in response to ionizing radiation. AB - Ataxia telangiectasia (AT) is a human genetic disease characterized by radiation sensitivity, impaired neuronal development and predisposition to cancer. Using a genetically defined model cell system consisting of cells expressing a kinase dead or a kinase proficient ATM gene product, we previously reported systemic alterations in major metabolic pathways that translate at the gene expression, protein and small molecule metabolite levels. Here, we report ionizing radiation induced stress response signaling arising from perturbations in the ATM gene, by employing a functional proteomics approach. Functional pathway analysis shows robust translational and post-translational responses under ATM proficient conditions, which include enrichment of proteins in the Ephrin receptor and axonal guidance signaling pathways. These molecular networks offer a hypothesis generating function for further investigations of cellular stress responses. PMID- 23642046 TI - DNA branch migration reactions through photocontrollable toehold formation. AB - Strand displacement cascades are commonly used to make dynamically assembled structures. Particularly, the concept of "toehold-mediated DNA branch migration reactions" has attracted considerable attention in relation to dynamic DNA nanostructures. However, it is a challenge to obtain and control the formation of pure 1:1 ratio DNA duplexes with toehold structures. Here, for the first time, we report a photocontrolled toehold formation method, which is based on the photocleavage of 2-nitrobenzyl linker-embedded DNA hairpin precursor structures. UV light irradiation (lambda ~ 365 nm) of solutions containing these DNA hairpin structures causes the complete cleavage of the nitrobenzyl linker, and pure 1:1 DNA duplexes with toehold structures are easily formed. Our experimental results indicate that the amount of toehold can be controlled by simply changing the dose of UV irradiation and that the resulting toehold structures can be used for subsequent toehold-mediated DNA branch migration reactions, e.g., DNA hybridization chain reactions. This newly established method will find broad application in the construction of light-powered, controllable, and dynamic DNA nanostructures or large-scale DNA circuits. PMID- 23642049 TI - A terthiophene-containing alkynylplatinum terpyridine Pacman complex: controllable folding/unfolding modulated by weak intermolecular interactions. AB - Folded and unfolded solid-state structures of a bimetallic alkynylplatinum terpyridine complex with a flexible terthiophene linker have been obtained. Weak intermolecular interactions including pi-pi stacking and C-H...O and C-H...Cl interactions as well as Cl-pi interactions stabilize the folded structure. In solution, folding is studied by electronic absorption spectroscopy and (1)H and NOESY NMR experiments. PMID- 23642048 TI - Molecular changes induced by the curcumin analogue D6 in human melanoma cells. AB - BACKGROUND: In a previous report, we described the in vitro and in vivo antiproliferative and proapoptotic activity of a hydroxylated biphenyl (D6), a structural analogue of curcumin, on malignant melanoma and neuroblastoma tumours. In this paper, we investigated the molecular changes induced by such a compound, underlying cell growth arrest and apoptosis in melanoma cells. RESULTS: To shed light on the mechanisms of action of D6, we firstly demonstrated its quick cellular uptake and subsequent block of cell cycle in G2/M phase transition. A gene expression profile analysis of D6-treated melanoma cells and fibroblasts was then carried out on high density microarrays, to assess gene expression changes induced by this compound. The expression profile study evidenced both an induction of stress response pathways and a modulation of cell growth regulation mechanisms. In particular, our data suggest that the antiproliferative and proapoptotic activities of D6 in melanoma could be partially driven by up regulation of the p53 signalling pathways as well as by down-regulation of the PI3K/Akt and NF-kB pathways. Modulation of gene expression due to D6 treatment was verified by western blot analysis for single proteins of interest, confirming the results from the gene expression profile analysis. CONCLUSIONS: Our findings contribute to the understanding of the mechanisms of action of D6, through a comprehensive description of the molecular changes induced by this compound at the gene expression level, in agreement with the previously reported anti-tumour effects on melanoma cells. PMID- 23642050 TI - Rapid-developed primary malignant myoepithelioma in the cavernous sinus: a case report. AB - BACKGROUND: Malignant myoepithelioma is a relatively rare malignant tumor occurring most frequently in the salivary glands. A few isolated cases have been described in other locations, including soft tissue, bone, lung, bronchus, oral cavity, nasopharynx, larynx, and maxillary sinus. Malignant myoepithelioma, however, is uncommonly involved within the cavernous sinus. To the best of our knowledge, this is the first report of malignant myoepithelioma arising from within the cavernous sinus. CASE PRESENTATION: Herein, we report a case of a 48 year-old woman who presented a 1-month history of diplopia and blepharoptosis as well as radiological evidence of a rapidly developing cavernous sinus tumor. The patient underwent a trans-sphenoidal biopsy and a histological diagnosis indicated a malignant myoepithelioma. After diagnosis, the tumor grew rapidly and her clinical condition deteriorated progressively. Therefore, a pterional craniotomy with partial tumor removal was performed. The patient's clinical state was worsened, and she died two months after the initial operation. Because the malignant myoepithelioma could not be traced to an organ of origin, other than the cavernous sinus, this case was diagnosed as a primary intracranial malignant myoepithelioma. CONCLUSION: The purpose of presenting this case report is to raise awareness among clinicians to consider malignant myoepithelioma as a differential diagnosis when a cavernous sinus mass is identified. Furthermore, an ideal management strategy for malignant myoepithelioma is not known and the prognosis seems to be unfavorable; therefore, more cases are needed to enhance our knowledge of the diagnosis, treatment, and prognosis of this rare intracranial lesion. PMID- 23642051 TI - The many facets of PEDF in drug discovery and disease: a diamond in the rough or split personality disorder? AB - INTRODUCTION: Pigment epithelium-derived factor (PEDF) was discovered as a neurotrophic factor secreted by retinal pigment epithelial cells. A decade later, it re-emerged as a powerful angiogenesis inhibitor guarding ocular function. Since then, significant advances were made identifying PEDF's mechanisms, targets and biomedical applications. AREAS COVERED: The authors review several methodologies that have generated significant new information about the potential of PEDF as a drug. Furthermore, the authors review and discuss mechanistic and structure-function analyses combined with the functional mapping of active fragments, which have yielded several short bioactive PEDF peptides. Additionally, the authors present functional studies in knockout animals and human correlates that have provided important information about conditions amenable to PEDF-based therapies. EXPERT OPINION: Through its four known receptors, PEDF causes a wide range of cellular events vitally important for the organism, which include survival and differentiation, migration and invasion, lipid metabolism and stem cell maintenance. These processes are deregulated in multiple pathological conditions, including cancer, metabolic and cardiovascular disease. PEDF has been successfully used in countless preclinical models of these conditions and human correlates suggest a wide utility of PEDF-based drugs. The most significant clinical application of PEDF, to date, is its potential therapeutic use for age-related macular degeneration. Moreover, PEDF-based gene therapy has advanced to early stage clinical trials. PEDF active fragments have been mapped and used to design short peptide mimetics conferring distinct functions of PEDF, which may address specific clinical problems and become prototype drugs. PMID- 23642052 TI - Editorial (hot topic:human pluripotent stem cells in regenerative and personalized medicine). PMID- 23642053 TI - Pluripotent stem cell-derived somatic stem cells as tool to study the role of microRNAs in early human neural development. AB - The in vitro differentiation of human pluripotent stem cells represents a convenient approach to generate large numbers of neural cells for basic and translational research. We recently described the derivation of homogeneous populations of long-term self-renewing neuroepithelial-like stem cells from human pluripotent stem cells (lt-NES(r) cells). These cells constitute a suitable source of neural stem cells for in vitro modelling of early human neural development. Recent evidence demonstrates that microRNAs are important regulators of stem cells and nervous system development. Studies in several model organisms suggest that microRNAs contribute to different stages of neurogenesis - from progenitor self-renewal to survival and function of differentiated neurons. However, the understanding of the impact of microRNA-based regulation in human neural development is still at its dawn. Here, we give an overview on the current state of microRNA biology in stem cells and neural development and examine the role of the neural-associated miR-124, miR- 125b and miR-9/9* in human lt-NES(r) cells. We show that overexpression of miR-124, as well as overexpression of miR 125b, impair lt-NES(r) cell self-renewal and induce differentiation into neurons. Overexpression of the miR-9/9* locus also impairs self-renewal of lt-NES(r) cells and supports their commitment to neuronal differentiation. A detailed examination revealed that overexpression of miR-9 promotes differentiation, while overexpression of miR-9* affects both proliferation and differentiation of lt NES(r) cells. This work provides insights into the regulation of early human neuroepithelial cells by microRNAs and highlights the potential of controlling differentiation of human stem cells by modulating the expression of selected microRNAs. PMID- 23642047 TI - Oxygen saturation and outcomes in preterm infants. AB - BACKGROUND: The clinically appropriate range for oxygen saturation in preterm infants is unknown. Previous studies have shown that infants had reduced rates of retinopathy of prematurity when lower targets of oxygen saturation were used. METHODS: In three international randomized, controlled trials, we evaluated the effects of targeting an oxygen saturation of 85 to 89%, as compared with a range of 91 to 95%, on disability-free survival at 2 years in infants born before 28 weeks' gestation. Halfway through the trials, the oximeter-calibration algorithm was revised. Recruitment was stopped early when an interim analysis showed an increased rate of death at 36 weeks in the group with a lower oxygen saturation. We analyzed pooled data from patients and now report hospital-discharge outcomes. RESULTS: A total of 2448 infants were recruited. Among the 1187 infants whose treatment used the revised oximeter-calibration algorithm, the rate of death was significantly higher in the lower-target group than in the higher-target group (23.1% vs. 15.9%; relative risk in the lower-target group, 1.45; 95% confidence interval [CI], 1.15 to 1.84; P=0.002). There was heterogeneity for mortality between the original algorithm and the revised algorithm (P=0.006) but not for other outcomes. In all 2448 infants, those in the lower-target group for oxygen saturation had a reduced rate of retinopathy of prematurity (10.6% vs. 13.5%; relative risk, 0.79; 95% CI, 0.63 to 1.00; P=0.045) and an increased rate of necrotizing enterocolitis (10.4% vs. 8.0%; relative risk, 1.31; 95% CI, 1.02 to 1.68; P=0.04). There were no significant between-group differences in rates of other outcomes or adverse events. CONCLUSIONS: Targeting an oxygen saturation below 90% with the use of current oximeters in extremely preterm infants was associated with an increased risk of death. (Funded by the Australian National Health and Medical Research Council and others; BOOST II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry numbers, ACTRN12605000055606 and ACTRN12605000253606.). PMID- 23642054 TI - Human progenitor cells for bone engineering applications. AB - In this report, the authors review the human skeleton and the increasing burden of bone deficiencies, the limitations encountered with the current treatments and the opportunities provided by the emerging field of cell-based bone engineering. Special emphasis is placed on different sources of human progenitor cells, as well as their pros and cons in relation to their utilization for the large-scale construction of functional bone-engineered substitutes for clinical applications. It is concluded that, human pluripotent stem cells represent a valuable source for the derivation of progenitor cells, which combine the advantages of both embryonic and adult stem cells, and indeed display high potential for the construction of functional substitutes for bone replacement therapies. PMID- 23642055 TI - The dark side of stem cells: triggering cancer progression by cell fusion. AB - The phenomenon of cell fusion plays a crucial role in a plethora of physiological processes, including fertilization, wound healing, and tissue regeneration. In addition to this, cell fusion also takes place during pathophysiological processes such as virus entry into host cells and cancer. Particularly in cancer, cell fusion has been linked to a number of properties being associated with the progression of the disease including an increased proliferation rate, an enhanced metastatogenic behavior, an increased drug resistance and an increased resistance towards apoptosis. Although the process of cell fusion including the molecules to be involved-in is not completely understood in higher organisms, recent data revealed that chronic inflammation seems to be strong mediator. Since tumor tissue resembles chronically inflamed tissue, it can be concluded that cell fusion between recruited macrophages, bone marrow-derived cells (BMDCs), and tumor (stem) cells should be a common phenomenon in cancer. In the present review, we will summarize how a chronic inflamed microenvironment could originate in cancerous tissues, the role of M2-polarized tumor associated macrophages (M2 TAMs) within this process and how fusion between macrophages and BMDCs will trigger cancer progression. A particular emphasis will be drawn on recurrence cancer stem cells (rCSCs), which will play a pivotal role in "oncogenic resistance" and which might originate from fusion events between tumor (stem) cells and BMDCs. PMID- 23642056 TI - MicroRNAs and cancer: towards a personalized medicine. AB - MicroRNAs (miRNAs) are de-regulated in cancer versus the normal tissue counterpart and actively participate in human carcinogenesis. Among the genes whose expression is under their control there are both oncogenes and tumor suppressor genes, revealing that it is not only limiting but simply wrong to assign them a function just as oncogenes or as tumor suppressor genes. In addition to primary tumors, miRNAs can be detected in almost all human body fluids and effectively help to diagnose cancer and to prognosticate clinical outcome and response to treatment of tumors. The advent of miRNA mimic and miRNA silencing molecules has allowed to modulate miRNA expression in tumors, showing that miRNAs can be effectively used as therapeutic agents. This review will focus on those findings that have provided the rationale for the use of miRNAs as patient "tailored" anti-cancer agents. PMID- 23642058 TI - Improved generation of patient-specific induced pluripotent stem cells using a chemically-defined and matrigel-based approach. AB - Reprogramming of somatic cells into patient-specific pluripotent analogues of human embryonic stem cells (ESCs) emerges as a prospective therapeutic angle in molecular medicine and a tool for basic stem cell biology. However, the combination of relative inefficiency and high variability of non-defined culture conditions precluded the use of this technique in a clinical setting and impeded comparability between laboratories. To overcome these obstacles, we sequentially devised a reprogramming protocol using one lentiviral-based polycistronic reprogramming construct, optimized for high co-expression of OCT4, SOX2, KLF4 and MYC in conjunction with small molecule inhibitors of non-permissive signaling cascades, such as transforming growth factor beta (SB431542), MEK/ERK (PD0325901) and Rho-kinase signaling (Thiazovivin), in a defined extracellular environment. Based on human fetal liver fibroblasts we could efficiently derive induced pluripotent stem cells (iPSCs) within 14 days. We attained efficiencies of up to 10.97+/-1.71% resulting in 79.5- fold increase compared to non-defined reprogramming using four singular vectors. We show that the overall increase of efficiency and temporal kinetics is a combinatorial effect of improved lentiviral vector design, signaling inhibition and definition of extracellular matrix (Matrigel(r)) and culture medium (mTESR(r)1). Using this protocol, we could derive iPSCs from patient fibroblasts, which were impermissive to classical reprogramming efforts, and from a patient suffering from familial platelet disorder. Thus, our defined protocol for highly efficient reprogramming to generate patient-specific iPSCs, reflects a big step towards therapeutic and broad scientific application of iPSCs, even in previously unfeasible settings. PMID- 23642059 TI - Differences between Parkinson's and Huntington's diseases and their role for prioritization of stem cell-based treatments. AB - The problems of allocation of scarce resources and priority setting in health care have so far not been much studied in the context of stem cell-based therapeutic applications. If and when competitive cost effective stem cell-based therapies are available, the problem of priority setting - to whom should stem cellbased therapies be offered and on what grounds - is discussed in this article using the examples of Parkinson's Disease (PD) and Huntington's Disease (HD). The aim of this paper is to examine the presently known differences between PD and HD and analyze the role of these differences for setting priorities of stem cell based therapeutic applications to treat these diseases. To achieve this aim, we (1) present the theoretical framework used in the analysis; (2) compare PD and HD in terms of health related and non-health related consequences of these diseases for patients, their relatives and third parties; (3) analyze the ethical relevance of observed differences for priority setting given different values and variables; (4) compare PD and HD in terms of social justice related consequences of stem cell-based therapies; and (5) analyze the ethical relevance of these differences for priority setting given different values and variables. We argue that the steps of analysis applied in this paper could be helpful when setting priorities among treatments of other diseases with similar differences as those between PD and HD. PMID- 23642057 TI - MicroRNA regulation and role in stem cell maintenance, cardiac differentiation and hypertrophy. AB - There are currently 1527 known microRNAs (miRNAs) in human, each of which may regulate hundreds or thousands of target genes. miRNA expression levels vary between cell types; for example, miR- 302 and miR-290 families are highly enriched in embryonic stem cells, while miR-1 is a muscle specific miRNA. miRNA biosynthesis and function are highly regulated and this regulation may be cell type specific. The processing enzymes and factors that recognize features in sequence and secondary structure of the miRNA play key roles in regulating the production of mature miRNA. Mature miRNA enriched in stem cells control stem cell self-renewal as well as their differentiation. Though specific miRNAs have been shown to control differentiation towards various lineages such as neural or skin cells, some of the most well characterized miRNAs have been found in promoting the formation of cardiac cells. In addition, miRNAs also play a critical role in cardiomyocyte hypertrophy, especially in a pathological context. Such miRNAs are predicted to be therapeutic targets for treating cardiovascular diseases. In this review we will discuss how miRNAs act to maintain the stem cell state and also explore the current knowledge of the mechanisms that regulate miRNAs. Furthermore, we will discuss the emerging roles of miRNAs using cardiomyocyte differentiation and maturation as a paradigm. Emphasis will also be given on some of the less ventured areas such as the role of miRNAs in the physiological maturation of cardiomyocytes. These potentially beneficial miRNAs are likely to improve cardiac function in both in vivo and in vitro settings and thus provide additional strategy to treat heart diseases and more importantly serve as a good model for understanding cardiomyocyte maturation in vitro. PMID- 23642060 TI - Induced pluripotent stem cells (iPSCs) derived from different cell sources and their potential for regenerative and personalized medicine. AB - Human induced pluripotent stem cells (hiPSCs) have great potential as a robust source of progenitors for regenerative medicine. The novel technology also enables the derivation of patient-specific cells for applications to personalized medicine, such as for personal drug screening and toxicology. However, the biological characteristics of iPSCs are not yet fully understood and their similarity to human embryonic stem cells (hESCs) is still unresolved. Variations among iPSCs, resulting from their original tissue or cell source, and from the experimental protocols used for their derivation, significantly affect epigenetic properties and differentiation potential. Here we review the potential of iPSCs for regenerative and personalized medicine, and assess their expression pattern, epigenetic memory and differentiation capabilities in relation to their parental tissue source. We also summarize the patient-specific iPSCs that have been derived for applications in biological research and drug discovery; and review risks that must be overcome in order to use iPSC technology for clinical applications. PMID- 23642061 TI - What makes a pluripotency reprogramming factor? AB - Resetting differentiated cells to a pluripotent state is now a widely applied technology and a key step towards personalized cell replacement therapies. Conventionally, combinations of transcription factor proteins are introduced into a differentiated cell to convert gene expression programs and to change cell fates. Yet, the molecular mechanism of nuclear reprogramming is only superficially understood. Specifically, it is unclear what sets pluripotency reprogramming factors (PRFs) molecularly apart from other transcription factor molecules that induce, for example, lineage commitment in embryonic development. Ultimately, PRFs must scan the genome of a differentiated cell, target enhancers of pluripotency factors and initiate gene expression. This requires biochemical properties to selectively recognize DNA sequences, either alone or by cooperating with other PRFs. In this review, we will discuss the molecular make-up of the prominent PRFs Sox2, Oct4, Klf4, Esrrb, Nr5a2 and Nanog and attempt to identify unique features distinguishing them from highly homologous yet functionally contrasting family members. Except for Klf4, the consensus DNA binding motifs are highly conserved for PRFs when compared to non-pluripotency inducing family members, suggesting that the individual DNA sequence preference may not be the distinguishing factor. By contrast, variant composite DNA motifs were found in pluripotency enhancers that lead to a differential assembly of various Sox and Oct family members due selective protein-protein interaction platform. As a consequence, the cooperation of PRFs on distinctly configured DNA motifs may underlie the reprogramming process. Indeed, it has been demonstrated that Sox17 can be rationally engineered into a PRF by modulating its cooperation with Oct4. An in deep understanding of this phenomenon would allow rational engineering and optimization of PRFs. This way, the reprogramming efficiency can be enhanced and fine-tuned to generate optimal synthetic reagents for regenerative medicine. PMID- 23642062 TI - Development of patient-specific hematopoietic stem and progenitor cell grafts from pluripotent stem cells, in vitro. AB - Pluripotent stem cells hold great promise for future applications in many areas of regenerative medicine. Their defining property of differentiation towards any of the three germ layers and all derivatives thereof, including somatic stem cells, explains the special interest of the biomedical community in this cell type. In this review, we focus on the current state of directed differentiation of pluripotent stem cells towards hematopoietic stem cells (HSCs). HSCs are especially interesting because they are the longest known and, thus, most intensively investigated somatic stem cells. They were the first stem cells successfully used for regenerative purposes in clinical human medicine, namely in bone marrow transplantation, and also the first stem cells to be genetically altered for the first successful gene therapy trial in humans. However, because of the technical difficulties associated with this rare type of cell, such as the current incapability of prospective isolation, in vitro expansion and gene repair by homologous recombination, there is great interest in using pluripotent stem cells, such as Embryonic Stem (ES-) cells, as a source for generating and genetically altering HSCs, ex vivo. This has been hampered by ethical concerns associated with the use of human ES-cells. However, since Shinya Yamanaka's successful attempts to reprogram somatic cells of mice and men to an ES-cell like state, so-called induced pluripotent stem (iPS) cells, this field of research has experienced a huge boost. In this brief review, we will reflect on the status quo of directed hematopoietic differentiation of human and mouse pluripotent stem cells. PMID- 23642063 TI - The multiple aspects of stroke and stem cell therapy. AB - Cumulative evidence shows that transplantation of stem cells (SC) derivatives can reduce the functional deficits induced by cerebral ischemia or hemorrhage in animals. Most SC sources have been applied to stroke models, with varying degrees of differentiation into neural derivatives and in varying number, timing and route of administration, with similar benefits on functional outcome. Pioneering clinical trials developed in parallel, and currently outnumber other applications of SC in neurological disorders. These trials reflect a paradigm shift from cell replacement therapy to disease-modeling effects, with increased used of non neural SC. This shift stems in experimental demonstration of paracrine effects of SC that attenuate inflammation, limit cell death through neurotrophic effects, and enhance endogenous recovery processes. Due to its pathogenic characteristics, stroke can uniquely benefit from this variety of actions. PMID- 23642064 TI - Disease-specific iPS cell models in neuroscience. AB - Neurodegenerative diseases are a heterogeneous group of sporadic or familial disorders of the nervous system that mostly lead to a progressive loss of neural cells. A major challenge in studying the molecular pathomechanisms underlying these disorders is the limited experimental access to disease-affected human nervous system tissue. In addition, considering that the molecular disease initiation occurs years or decades before the symptomatic onset of a medical condition, these tissues mostly reflect only the final phase of the disease. To overcome these limitations, various model systems have been established based on gain and loss-of-function studies in transformed cell lines or transgenic animal models. Although these approaches provide valuable insights into disease mechanisms and development they often lack physiological protein expression levels and a humanized context of molecular interaction partners. The generation of human induced pluripotent stem (hiPS) cells from somatic cells provides access to virtually unlimited numbers of patient-specific cells for modeling neurological disorders in vitro. In this review, we focus on the current progress made in hiPS cell-based modeling of neurodegenerative diseases and discuss recent advances in the quality assessment of hiPS cell lines. PMID- 23642065 TI - Improved hepatic differentiation strategies for human induced pluripotent stem cells. AB - Based on their almost unlimited self-renewal capacity and their ability to differentiate into derivatives of all three germ layers, human induced pluripotent stem cells (hiPSCs) might serve as a preferable source for hepatic transplants in metabolic liver disorders or acute liver failure. Furthermore, the generation of patient specific hiPSCs might facilitate the development of innovative therapeutic strategies by accurately modelling disease in vitro. In our study, we aimed for an efficient hepatic differentiation protocol that is applicable for both human embryonic stem cells (hESCs) and hiPSCs. We attempted to accomplish this goal by using a cytokine and small molecule-based protocol for direct differentiation of hESCs and hiPSCs into hepatic cells. Selecting differentiated hepatic cells was possible using an albumin promoter-driven G418 resistance system. Due to IRES-dependent dTomato reporter expression, we were able to track hepatic differentiated cells and we evaluated the most efficient time frame for G418 selection. The status of hepatic differentiation was determined by qRT-PCR comparing the expression of hepatic markers such as AFP, ALB, SOX17, and HNF4 to standard hepatic cells. Functional analysis of the hepatic phenotype was obtained by measuring secreted albumin levels and by analysis of cytochrome P450 type 1A1 activity (EROD). The percentage of differentiated cells was quantified by FACS analysis. In conclusion, our improved protocol demonstrates that both pluripotent cell sources (hESC and hiPSC) can efficiently be differentiated into mature hepatic cells with functional characteristics similar to those of standard hepatic cell lines such as HepG2. PMID- 23642066 TI - Mechanisms of immune modulation by mesenchymal stromal cells and clinical translation. AB - Cell therapy with mesenchymal stromal cells (MSCs) is the focus of intensive investigation. Several clinical trials, including large-scale placebo-controlled phase III clinical trials, are currently underway evaluating the therapeutic potential of autologous and allogeneic MSCs for treatment of catastrophic inflammatory diseases, including steroid-refractory graft-versus-host disease (GvHD), multiple sclerosis (MS) and Crohn's disease. MSCs are also being investigated as carriers of anti-cancer biotherapeutics. We here review recent developments in our understanding of the immunosuppressive properties of MSCs. We firstly discuss the effects of ex vivo culture conditions on the phenotype and functions of MSCs. Secondly, we summarize the immune functions suppressed by MSCs with a focus on T cell, B cell, natural killer cell and dendritic cell functions. Thirdly, we discuss newly identified pathways responsible for the immunosuppressive activity of MSCs, including the expression of heme-oxygenase (HO)-1, the secretion of galectins, CCL2 antagonism, T regulatory cell (Treg) cross-talk and production of TNF-alpha stimulated gene/protein-6 (TSG-6). Finally, we review the literature on the molecular pathways governing MSC homing and discuss recent clinical data on the use of MSCs for treatment of GvHD, MS and Crohn's disease. PMID- 23642067 TI - Roadmap to cellular reprogramming--manipulating transcriptional networks with DNA, RNA, proteins and small molecules. AB - Recent reports demonstrate that the plasticity of mammalian somatic cells is much higher than previously assumed and that ectopic expression of transcription factors may have the potential to induce the conversion of any cell type into another. Fibroblast cells can be converted into embryonic stem cell-like cells, neural cells, cardiomyocytes, macrophage-like cells as well as blood progenitors. Additionally, the conversion of astrocytes into neurons or neural stem cells into monocytes has been demonstrated. Nowadays, in the era of systems biology, continuously growing holistic data sets are providing increasing insights into core transcriptional networks and cellular signaling pathways. This knowledge enables cell biologists to understand how cellular fate is determined and how it could be manipulated. As a consequence for biomedical applications, it might be soon possible to convert patient specific somatic cells directly into desired transplantable other cell types. The clinical value, however, of such reprogrammed cells is currently limited due to the invasiveness of methods applied to induce reprogramming factor activity. This review will focus on experimental strategies to ectopically induce cell fate modulators. We will emphasize those strategies that enable efficient and robust overexpression of transcription factors by minimal genetic alterations of the host genome. Furthermore, we will discuss procedures devoid of any genomic manipulation, such as the direct delivery of mRNA, proteins, or the use of small molecules. By this, we aim to give a comprehensive overview on state of the art techniques that harbor the potential to generate safe reprogrammed cells for clinical applications. PMID- 23642068 TI - A comment on pluripotent stem cells in next-generation biomedical theranostics. AB - New developments in DNA sequencing platforms and the advancements in GWAS studies (genome-wide association studies) are changing the understanding of human pathologies. Such developments will ultimately result in a deeper understanding of how genomic variations contribute to diseases. Induced pluripotent stem cells (iPSCs) are currently entering clinical research phases, allowing the investigation of disease pathways and the identification of new targets and potentially druggable biomarkers. IPSCs can serve as a model for studying human diseases as they retain all the genetic information from a patient; iPSC-derived cells can be used as a tool for drug screening or discovery. In combination with next generation sequencing (NGS)-based and GWAS technologies, iPSCs have the potential to become a novel platform technology to predict adverse drug and off target effects, and using such cell models to predict toxicity. In view of the arising concepts of regenerative theranostics, iPSCs and NGS technologies provide a powerful means to analyze the complexity of diseases on the molecular level and to better understand the processes that lead to pathobiology. To promote the widespread use of iPSC-based approaches in drug development it has to be shown that the cells can be reliably produced in the quantity, consistency and purity needed to meet pharmaceutical standards. Integrative genomics and genetic approaches have shown to be a useful tool in elucidating the complexity found in gene regulatory pathways. In this review, the application of pluripotent stem cells for the generation of next-generation theranostics and newer perspectives on iPSCs in modeling clinical diseases, are discussed. PMID- 23642069 TI - Pluripotency-regulating networks provide basis for reprogramming. AB - The reprogramming of somatic cells into induced pluripotent stem cells or iPS cells can be achieved by the ectopic expression of defined factors. Patient specific iPS cell lines can be derived and used for disease modeling, drug and toxicology screening, cellular replacement therapies and basic research. However, reprogramming is slow and inefficient and numerous methods have been described aiming to improve this process. These methods include screening for new genetic factors and chemical compounds, and the engineering of new synthetic factors. Here, we review recent progress made in this field and show how a better understanding of the ES (embryonic stem) cell transcriptional network is important for efficient reprogramming. PMID- 23642070 TI - Ascorbic acid and sodium-dependent vitamin C transporters in the peripheral nervous system: from basic science to clinical trials. AB - SIGNIFICANCE: Ascorbic acid and sodium-dependent vitamin C transporters (SVCT) have been shown to have important functions in the peripheral nervous system (PNS). Ascorbic acid is known to promote myelination in vitro in Schwann cell/dorsal root ganglion co-cultures by the formation of a collagen- and laminin containing extracellular matrix. RECENT ADVANCES: Recently, the function of ascorbic acid and SVCT2 in the PNS has been shown in vivo as well. Several studies on ascorbic acid treatment of Charcot-Marie-Tooth neuropathy 1A (CMT1A) have been completed and showed no clinical benefit. CRITICAL ISSUES: Possible reasons for the failure of ascorbic acid in CMT1A treatment are discussed in this review. More preclinical trials, ideally using different animal models, should be considered before the initiation of clinical trials in humans. More knowledge about ascorbic acid transport kinetics and inter-individual differences in humans is necessary for future studies. FUTURE DIRECTIONS: Further research into ascorbic acid transport mechanisms in the PNS is warranted. Especially the effects of transgenic or pharmacologic SVCT2 up-regulation on PNS myelination and remyelination will be an interesting area of research in the future. Furthermore, the potential use of ascorbic acid for peripheral neuropathies other than CMT1A would be a possible future research direction. PMID- 23642071 TI - Presentation of systemic lupus erythematosus (SLE) in emergency department: a case report. AB - BACKGROUND: Abrupt and life-threatening presentations in connective tissue diseases (CTD) are rarely reported. Their early recognition and specific management could change course disease. SLE is a multisystem inflammatory disease that is often difficult to diagnose in the emergency department (ED). CASE PRESENTATION: A 26-year-old woman presented to the ED with a 48 hour history of progressive dispnea, generalized edema and left lower chest pain with non productive cough. On examination, patient was feeling very ill, afebrile, tachycardic, tachypneic and a peripheral oxygen saturation of 94% on 40% supplemented oxygen with raised jugular venous pressure was noted. Intermittently, she presented an obtunded state of consciousness. A large pericardial, pleural and abdominal effusion was confirmed and a broad differential diagnosis was made. The patient had a 6 months history of inflammatory polyarthralgias involving initially interphalangeal joints, evolving, sometime later, the knees and elbows bilaterally and she was started glucocorticoids. 12 days before admission, she had had symptoms of a urethritis episode. In the context of an immunosupressed patient, with initial focal urologic complains, evidence of multiorgan dysfunction and a picture resembling a distributive shock, dictated a low threshold for sepsis. CONCLUSIONS: Separating an acute episode of SLE from sepsis, on emergency grounds, can even be the most challenging decision. In the ED, acute life-threatening and multisystemic conditions should arise the suspicion of autoimmune diseases, particularly SLE. PMID- 23642072 TI - Factors associated with cervical cancer screening uptake among Inuit women in Nunavik, Quebec, Canada. AB - BACKGROUND: The Canadian circumpolar Inuit population has a higher incidence rate of cervical cancer than the general population and the majority of cases occur among underscreened women. The objectives of this study were to determine Pap smear utilization rates and to determine factors associated with time inappropriate use of cervical cancer screening among a cohort of Inuit women from Nunavik, Quebec, Canada. METHODS: This study utilizes baseline information collected from a cohort formed between January 2002 and December 2007 to study the natural history of HPV among Inuit women aged 21-69 years in Nunavik, Quebec. Cervical cancer screening history and other variables were obtained from a baseline questionnaire and medical chart review. Unconditional logistic regression was used to estimate the odds ratios and 95% confidence intervals for potential predictors of not having a Pap smear within the previous 3 years prior to cohort entry. RESULTS: A total of 403 Inuit women who had a baseline questionnaire and chart review were included. The mean age of the study population was 34.2 years. In the three years prior to study entry, 25% of women did not have a Pap smear. Older age and never giving birth were significant predictors of time-inappropriate Pap smear use. CONCLUSIONS: Our results suggest that older women and women who are not accessing reproductive care have a lower compliance with time-appropriate cervical cancer screening and future research should address potential strategies to increase screening coverage among this group. PMID- 23642073 TI - Parallel on-chip analysis of single vesicle neurotransmitter release. AB - Real-time investigations of neurotransmitter release provide a direct insight on the mechanisms involved in synaptic communication. Carbon fiber microelectrodes are state-of-the-art tools for electrochemical measurements of single vesicle neurotransmitter release. Yet, they lack high-throughput capabilities that are required for collecting robust statistically significant data across multiple samples. Here, we present a chip-based recording system enabling parallel in vitro measurements of individual neurotransmitter release events from cells, cultured directly on planar multielectrode arrays. The applicability of this cell based platform to pharmacological screening is demonstrated by resolving minute concentration-dependent effects of the dopamine reuptake inhibitor nomifensine on recorded single-vesicle release events from PC12 cells. The experimental results, showing an increased half-time of the recorded events, are complemented by an analytical model for the verification of drug action. PMID- 23642075 TI - Metal-controlled cycloaddition of 2-alkynyl-1,4-benzoquinones and styrenyl systems: Lewis acid versus pi acid. AB - Metal-controlled cycloaddition of 2-alkynyl-1,4-benzoquinones and electron-rich styrenyl systems were investigated. The density functional theory (DFT) calculations revealed that the regioselectivity of the cycloaddition results from the different activation modes of Bi(OTf)3 and AuCl. PMID- 23642074 TI - Microglial activation decreases retention of the protease inhibitor saquinavir: implications for HIV treatment. AB - BACKGROUND: Active HIV infection within the central nervous system (CNS) is confined primarily to microglia. The glial cell compartment acts as a viral reservoir behind the blood-brain barrier. It provides an additional roadblock to effective pharmacological treatment via expression of multiple drug efflux transporters, including P-glycoprotein. HIV/AIDS patients frequently suffer bacterial and viral co-infections, leading to deregulation of glial cell function and release of pro-inflammatory mediators including cytokines, chemokines, and nitric oxide. METHODS: To better define the role of inflammation in decreased HIV drug accumulation into CNS targets, accumulation of the antiretroviral saquinavir was examined in purified cultures of rodent microglia exposed to the prototypical inflammatory mediator lipopolysaccharide (LPS). RESULTS: [(3)H]-Saquinavir accumulation by microglia was rapid, and was increased up to two-fold in the presence of the specific P-glycoprotein inhibitor, PSC833. After six or 24 hours of exposure to 10 ng/ml LPS, saquinavir accumulation was decreased by up to 45%. LPS did not directly inhibit saquinavir transport, and did not affect P glycoprotein protein expression. LPS exposure did not alter RNA and/or protein expression of other transporters including multidrug resistance-associated protein 1 and several solute carrier uptake transporters. CONCLUSIONS: The decrease in saquinavir accumulation in microglia following treatment with LPS is likely multi-factorial, since drug accumulation was attenuated by inhibitors of NF-kappabeta and the MEK1/2 pathway in the microglia cell line HAPI, and in primary microglia cultures from toll-like receptor 4 deficient mice. These data provide new pharmacological insights into why microglia act as a difficult-to treat viral sanctuary site. PMID- 23642076 TI - Factors that influence midwifery students in Ghana when deciding where to practice: a discrete choice experiment. AB - BACKGROUND: Mal-distribution of the health workforce with a strong bias for urban living is a major constraint to expanding midwifery services in Ghana. According to the UN Millennium Development Goals (MDG) report, the high risk of dying in pregnancy or childbirth continues in Africa. Maternal death is currently estimated at 350 per 100,000, partially a reflection of the low rates of professional support during birth. Many women in rural areas of Ghana give birth alone or with a non-skilled attendant. Midwives are key healthcare providers in achieving the MDGs, specifically in reducing maternal mortality by three-quarters and reducing by two-thirds the under 5 child mortality rate by 2015. METHODS: This quantitative research study used a computerized structured survey containing a discrete choice experiment (DCE) to quantify the importance of different incentives and policies to encourage service to deprived, rural and remote areas by upper-year midwifery students following graduation. Using a hierarchical Bayes procedure we estimated individual and mean utility parameters for two hundred and ninety eight third year midwifery students from two of the largest midwifery training schools in Ghana. RESULTS: Midwifery students in our sample identified: 1) study leave after two years of rural service; 2) an advanced work environment with reliable electricity, appropriate technology and a constant drug supply; and 3) superior housing (2 bedroom, 1 bathroom, kitchen, living room, not shared) as the top three motivating factors to accept a rural posting. CONCLUSION: Addressing the motivating factors for rural postings among midwifery students who are about to graduate and enter the workforce could significantly contribute to the current mal-distribution of the health workforce. PMID- 23642077 TI - Identification of somatic mutations in cancer through Bayesian-based analysis of sequenced genome pairs. AB - BACKGROUND: The field of cancer genomics has rapidly adopted next-generation sequencing (NGS) in order to study and characterize malignant tumors with unprecedented resolution. In particular for cancer, one is often trying to identify somatic mutations--changes specific to a tumor and not within an individual's germline. However, false positive and false negative detections often result from lack of sufficient variant evidence, contamination of the biopsy by stromal tissue, sequencing errors, and the erroneous classification of germline variation as tumor-specific. RESULTS: We have developed a generalized Bayesian analysis framework for matched tumor/normal samples with the purpose of identifying tumor-specific alterations such as single nucleotide mutations, small insertions/deletions, and structural variation. We describe our methodology, and discuss its application to other types of paired-tissue analysis such as the detection of loss of heterozygosity as well as allelic imbalance. We also demonstrate the high level of sensitivity and specificity in discovering simulated somatic mutations, for various combinations of a) genomic coverage and b) emulated heterogeneity. CONCLUSION: We present a Java-based implementation of our methods named Seurat, which is made available for free academic use. We have demonstrated and reported on the discovery of different types of somatic change by applying Seurat to an experimentally-derived cancer dataset using our methods; and have discussed considerations and practices regarding the accurate detection of somatic events in cancer genomes. Seurat is available at https://sites.google.com/site/seuratsomatic. PMID- 23642078 TI - Multinuclear solid state nuclear magnetic resonance investigation of water penetration in proton exchange membrane Nafion-117 by mechanical spinning. AB - (1)H, (17)O, and (19)F solid state NMR spectroscopies have been used to investigate water penetration in Nafion-117 under mechanical spinning. It is found that both (1)H and (17)O spectra depend on the orientation of the membrane with respect to the magnetic field. The intensities of the side chain (19)F spectra depend slightly on the orientation of membrane with respect to the magnetic field, but the backbone (19)F spectra do not exhibit orientation dependence. By analyzing the orientation dependent (1)H and (17)O spectra and time-resolved (1)H spectra, we show that the water loaded in Nafion-117, under high spinning speed, may penetrate into regions that are normally inaccessible by water. Water penetration is enhanced as the spinning speed is increased or the spinning time is increased. In the meantime, mechanical spinning accelerates water exchange. It is also found that water penetration by mechanical spinning is persistent; i.e., after spinning, water remains in those newly found regions. While water penetration changes the pores and channels in Nafion, (19)F spectra indicate that the chemical environments of the polymer backbone do not show change. These results provide new insights about the structure and dynamics of Nafion-117 and related materials. They are relevant to proton exchange membrane aging and offer enlightening points of view on antiaging and modification of this material for better proton conductivity. It is also interesting to view this phenomenon in the perspective of forced nanofiltration. PMID- 23642079 TI - Simulations of droplet coalescence in simple shear flow. AB - Simulating droplet coalescence is challenging because small-scale (tens of nanometers) phenomena determine the behavior of much larger (micrometer- to millimeter-scale) droplets. In general, liquid droplets colliding in a liquid medium coalesce when the capillary number is less than a critical value. We present simulations of droplet collisions and coalescence in simple shear flow using the free-energy binary-liquid lattice Boltzmann method. In previous simulations of low-speed collisions, droplets coalesced at unrealistically high capillary numbers. Simulations of noncoalescing droplets have not been reported, and therefore, the critical capillary number for simulated collisions was unknown. By simulating droplets with radii up to 100 lattice nodes, we determine the critical capillary number for coalescence and quantify the effects of several numerical and geometric parameters. The simulations were performed with a well resolved interface, a Reynolds number of one, and capillary numbers from 0.01 to 0.2. The ratio of the droplet radius and interface thickness has the greatest effect on the critical capillary number. As in experiments, the critical capillary number decreases with increasing droplet size. A second numerical parameter, the interface diffusivity (Peclet number) also influences the conditions for coalescence: coalescence occurs at higher capillary numbers with lower Peclet numbers (higher diffusivity). The effects of the vertical offset between the droplets and the confinement of the droplets were also studied. Physically reasonable results were obtained and provide insight into the conditions for coalescence. Simulations that match the conditions of experiments reported in the literature remain computationally impractical. However, the scale of the simulations is now sufficiently large that a comparison with experiments involving smaller droplets (~10 MUm) and lower viscosities (~10(-6) m(2)/s, the viscosity of water) may be possible. Experiments at these conditions are therefore needed to determine the interface thickness and Peclet number that should be used for predictive simulations of coalescence phenomena. PMID- 23642080 TI - Assessment of internal exposure doses in Fukushima by a whole body counter within one month after the nuclear power plant accident. AB - Information on early internal radiation doses in Fukushima after the nuclear power plant accident on March 11, 2011, is quite limited due to initial organizational difficulties, high background radiation and contamination of radiation measuring devices. In Nagasaki, approximately 1,200 km away from Fukushima, the internal radioactivity in evacuees and short-term visitors to Fukushima has been measured by a whole body counter (WBC) since March 15, 2011. A horizontal bed-type scanning WBC equipped with two NaI(Tl) scintillation detectors was used for 173 people who stayed in the Fukushima prefecture between March 11 and April 10, 2011. The average length of stay was 4.8 days. The internal radioactivity was converted to an estimated amount of intake according to the scenario of acute inhalation, and then the committed effective dose and the thyroid dose were evaluated. (131)I, (134)Cs and (137)Cs were detected in more than 30% of examined individuals. In subjects who stayed in Fukushima from March 12 to March 18, the detection rate was approximately 50% higher for each radionuclide and 44% higher for all three nuclides. The maximum committed effective dose and thyroid equivalent dose were 1 mSv and 20 mSv, respectively. Although the number of subjects and settlements in the study are limited, the results suggest that the internal radiation exposure in Fukushima due to the intake of radioactive materials shortly after the accident will probably not result in any deterministic or stochastic health effects. PMID- 23642081 TI - 3,4-Dimethoxyphenyl bis-benzimidazole derivative, mitigates radiation-induced DNA damage. AB - Radiation-induced DNA damage initiates a series of overlapping responses that include DNA damage recognition and repair, induction of cell cycle checkpoints, senescence and/or apoptosis. This study assessed the DNA damage response and whole genome expression profile in two mammalian cell lines (HEK and U87) in response to (5-{4-methylpiperazin-1-yl}-2-[2'-(3,4-dimethoxyphenyl)-5' benzimidazolyl] benzimidazole) DMA and ionizing radiation. DMA has been shown to act as a potent radiation protector, yielding significant levels of protection, i.e., 20.9% in HEK cells and 21.2% in U87 cells. Our findings revealed treatment with DMA significantly reduced gamma-H2AX, 53BP1 and Rad51 foci formation after irradiation. MAP kinase, WNT signaling and p53 pathways were found to be activated in DMA-treated cells. In addition, the DNA damage response genes, HSP70, HSPD1, PRDX1, PRX, CALR, NPM, UBC, and SET showed differential regulation in DMA, DMA + radiation and radiation-treated cells. The data suggest that DMA influenced repertoire of repair proteins, which are an indispensable part of the cell, interplay with each other to reduce DNA damage and maintain the genomic integrity of the cell. PMID- 23642082 TI - Oxygen-saturation targets in preterm infants. PMID- 23642083 TI - Brittle cornea syndrome: recognition, molecular diagnosis and management. AB - Brittle cornea syndrome (BCS) is an autosomal recessive disorder characterised by extreme corneal thinning and fragility. Corneal rupture can therefore occur either spontaneously or following minimal trauma in affected patients. Two genes, ZNF469 and PRDM5, have now been identified, in which causative pathogenic mutations collectively account for the condition in nearly all patients with BCS ascertained to date. Therefore, effective molecular diagnosis is now available for affected patients, and those at risk of being heterozygous carriers for BCS. We have previously identified mutations in ZNF469 in 14 families (in addition to 6 reported by others in the literature), and in PRDM5 in 8 families (with 1 further family now published by others). Clinical features include extreme corneal thinning with rupture, high myopia, blue sclerae, deafness of mixed aetiology with hypercompliant tympanic membranes, and variable skeletal manifestations. Corneal rupture may be the presenting feature of BCS, and it is possible that this may be incorrectly attributed to non-accidental injury. Mainstays of management include the prevention of ocular rupture by provision of protective polycarbonate spectacles, careful monitoring of visual and auditory function, and assessment for skeletal complications such as developmental dysplasia of the hip. Effective management depends upon appropriate identification of affected individuals, which may be challenging given the phenotypic overlap of BCS with other connective tissue disorders. PMID- 23642084 TI - Predictors of the timing of initiation of antenatal care in an ethnically diverse urban cohort in the UK. AB - BACKGROUND: In the UK, women are recommended to engage with maternity services and establish a plan of care prior to the 12th completed week of pregnancy. The aim of this study was to identify predictors for late initiation of antenatal care within an ethnically diverse cohort in East London. METHODS: Cross-sectional analysis of routinely collected electronic patient record data from Newham University Hospital NHS Trust (NUHT). All women who attended their antenatal booking appointment within NUHT between 1st January 2008 and 24th January 2011 were included in this study. The main outcome measure was late antenatal booking, defined as attendance at the antenatal booking appointment after 12 weeks (+6 days) gestation. Data were analysed using multivariable logistic regression with robust standard errors. RESULTS: Late initiation of antenatal care was independently associated with non-British (White) ethnicity, inability to speak English, and non-UK maternal birthplace in the multivariable model. However, among those women who both spoke English and were born in the UK, the only ethnic group at increased risk of late booking were women who identified as African/Caribbean (aOR: 1.40: 95% CI: 1.11, 1.76) relative to British (White). Other predictors identified include maternal age younger than 20 years (aOR: 1.32; 95% CI: 1.13-1.54), high parity (aOR: 2.09; 95% CI: 1.77-2.46) and living in temporary accommodation (aOR: 1.71; 95% CI: 1.35-2.16). CONCLUSIONS: Socio cultural factors in addition to poor English ability or assimilation may play an important role in determining early initiation of antenatal care. Future research should focus on effective interventions to encourage and enable these minority groups to engage with the maternity services. PMID- 23642085 TI - Automated docking for novel drug discovery. AB - INTRODUCTION: The volume of three-dimensional structural information of macromolecules and the number of computational tools to predict binding modes and affinities of molecular complexes are increasing daily. Molecular docking is a rational structural approach employed to predict thermodynamic parameters based on molecular recognition between two or more molecules. In addition, docking studies have become very important for therapeutic applications in modern structure-based drug design because this computational tool uses few economic resources. However, they omit many biological conditions that critically influence small and macromolecular structural motions. To mimic physiological conditions, it is necessary to consider other environmental factors, such as the presence of water molecules and the flexibility of ligands and side chain residues of proteins. Furthermore, molecular dynamics simulations have been coupled with docking procedures to expand the boundaries and obtain more reliable information. AREAS COVERED: In this article, we review current advances in protein-small molecule docking and possible future directions. EXPERT OPINION: Docking studies include many conformations to predict binding free energies (scoring functions) and to search (scoring sampling) for the most representative binding conformations. Therefore, several biological properties, from side chain residues to complete protein motions, have been included in docking studies to improve theoretical predictions. PMID- 23642087 TI - Ice-phobic coatings based on silicon-oil-infused polydimethylsiloxane. AB - A simple and low-cost technique for the preparation of silicon-oil-infused polydimethylsiloxane (PDMS) coatings with different silicon oil contents have been developed and studied. This material is designed for ice-phobic applications, and thus a high hydrophobic property of PDMS is maintained by avoiding any polar groups such as C?O and OH in the structure. Therefore, the polymer main chain was attached with vinyl and Si-H groups to obtain a cross linking capability, meanwhile to ensure a nonpolar chemical structure. Its ice phobic property has been investigated in terms of ice adhesion strength (tensile and shear), water contact angle, icing dynamics using high-speed photography and morphology using TEM, SEM and AFM. The prepared coating surface shows a low surface energy and very low ice adhesion strength of 50 kPa, only about 3% of the value on a bare aluminum (Al) surface. In the silicon oil infused PDMS coatings, the low surface energy of the silicon oil and PDMS, and the high mobility of silicon oil played an important role on the ice-phobic property. Both of these factors offer the surface a large water contact angle and hence a small contact area, leading to the formation of a loose ice layer. In addition, the oil infused polymer structure significantly reduces the contact area of the ice with solid substrate since the ice mostly contacts with the mobile oil. This leads to a very weak interaction between the substrate and ice, consequently significantly reduces the ice adhesion strength on the surface. Therefore, such material could be a good candidate for ice-phobic coatings on which the accumulated ice may be easily removed by a nature force, such as wind, gravity, and vibration. PMID- 23642086 TI - Relationship between serum levels of triglycerides and vascular inflammation, measured as COX-2, in arteries from diabetic patients: a translational study. AB - BACKGROUND: Inflammation is a common feature in the majority of cardiovascular disease, including Diabetes Mellitus (DM). Levels of pro-inflammatory markers have been found in increasing levels in serum from diabetic patients (DP). Moreover, levels of Cyclooxygenase-2 (COX-2) are increased in coronary arteries from DP. METHODS: Through a cross-sectional design, patients who underwent CABG were recruited. Vascular smooth muscle cells (VSMC) were cultured and COX-2 was measured by western blot. Biochemical and clinical data were collected from the medical record and by blood testing. COX-2 expression was analyzed in internal mammary artery cross-sections by confocal microscopy. Eventually, PGI2 and PGE2 were assessed from VSMC conditioned media by ELISA. RESULTS: Only a high glucose concentration, but a physiological concentration of triglycerides exposure of cultured human VSMC derived from non-diabetic patients increased COX-2 expression .Diabetic patients showed increasing serum levels of glucose, Hb1ac and triglycerides. The bivariate analysis of the variables showed that triglycerides was positively correlated with the expression of COX-2 in internal mammary arteries from patients (r(2) = 0.214, P < 0.04). CONCLUSIONS: We conclude that is not the glucose blood levels but the triglycerides levels what increases the expression of COX-2 in arteries from DP. PMID- 23642088 TI - Role of the electronically excited-state hydrogen bonding and water clusters in the luminescent metal-organic framework. AB - The electronically excited state and luminescence property of metal-organic framework Zn(3-tzba)(2,2'-bipy)(H2O).nH2O have been investigated using the density functional theory (DFT) and time-dependent DFT (TDDFT). The calculated geometry and infrared spectra in the ground state are consistent with the experimental results. The frontier molecular orbitals and electronic configuration indicated that the origin of luminescence is attributed to a ligand to-ligand charge transfer (LLCT). We theoretically demonstrated that the hydrogen bond H47...O5?C is weakened in the excited state S1; the weakening of the excited state hydrogen bonding should be beneficial to the luminescence. To explore the effect of the water clusters on the luminescence, we studied four complexes Zn(3 tzba)(2,2'-bipy)(H2O).3H2O, Zn(3-tzba)(2,2'-bipy)(H2O).2H2O, Zn(3-tzba)(2,2' bipy)(H2O).H2O, and Zn(3-tzba)(2,2'-bipy)(H2O). The results reveal that the presence of water should play an important role in the emission characteristics of the MOF. Also, the UV-vis absorption and emission spectra of Zn(3-tzba)(2,2' bipy)(H2O).3H2O are in good agreement with the experimental results. PMID- 23642089 TI - A minimal transcriptional controlling network of regulatory T cell development. AB - Regulatory T cells (Treg) are a subpopulation of T cells that are central to immune homeostasis and develop under the control of a complex regulatory network consisting of FoxP3 and its partner factors. A central question about this network is how does it enable T cells to robustly specify and stably maintain their states despite intrinsic and environmental fluctuations. Inspired by recent experimental advances, we propose here a minimal transcriptional controlling network and use it to illustrate the robustness and dynamic features of Treg development. Our study shows that the controlling network may exhibit distinct dynamics depending on its parameter regimes and that the maintenance of multistability requires the orchestration of both its positive and negative feedback loops. In addition, system volume contributes monotonically to the increase in the network's robustness. We further show that the dynamics of our model varies with the alteration of FoxP3-DNA binding affinity, consistent with recent experimental findings. This minimal model thereby offers new insights into the dynamics and robustness of Treg development and may serve as a platform for future exploration toward a more quantitative and systematic understanding of the immune system. PMID- 23642090 TI - Adenosine signaling pathways as potential therapeutic targets in respiratory disease. AB - INTRODUCTION: Adenosine receptors (ARs) and their differential pattern of expression modulate a series of pleiotropic activities that are known to contribute to the control of inflammation, remodeling, and tissue repair. Consequently, pharmacological manipulation of adenosine signaling pathway is of great interest and is currently exploited as a therapeutic target for a number of respiratory diseases with several molecules with agonist and antagonist activities against known ARs being developed for the treatment of different conditions of the respiratory system. AREAS COVERED: Herein, we will review the rational basis leading to the development of novel therapies for asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and cystic fibrosis. Their most recent clinical development will be also discussed. EXPERT OPINION: Advances in our understanding of the pathogenetic role of adenosine in respiratory diseases may be soon translated into effective treatment options. In consideration of the complex interplay driven by the different pattern of receptor distribution and/or affinity of the four known AR subtypes in specific cell types at different stages of the disease, it is likely that combination of selective antagonist/agonists for different AR subtypes will be required to obtain reasonable clinical efficacy. Alternatively, controlling the factors involved in driving adenosine concentrations in the tissue may be also of great significance. PMID- 23642091 TI - Organocatalytic asymmetric Michael addition of 5H-oxazol-4-ones to nitroolefins. AB - The first organocatalytic asymmetric Michael addition of 5H-oxazol-4-ones to nitroolefins has been developed. In the presence of easily prepared L-tert leucine-derived tertiary amine/thiourea catalyst, the Michael addition of 5H oxazol-4-ones to nitroolefins proceeded in an excellent diastereo- and enantioselective manner (up to 99% ee and >19:1 dr). The Michael adducts obtained are valuable precursors for the synthesis of chiral alpha-alkyl-alpha-hydroxy carboxylic acid derivatives, which represent a series of versatile building blocks in many biologically active compounds. PMID- 23642092 TI - How to interpret the transmissibility of novel influenza A(H7N9): an analysis of initial epidemiological data of human cases from China. AB - BACKGROUND: As the human infections with novel influenza A(H7N9) virus have been reported from several different provinces in China, the pandemic potential of the virus has been questioned. The presence of human-to-human transmission has not been demonstrated, but the absence of demonstration does not guarantee that there is no such transmission. METHODS: A mathematical model of cluster size distribution is devised without imposing an assumption of subcriticality of the reproduction number and accounting for right censoring of new clusters. The proportion of cases with a history of bird contact is analytically derived, permitting us to fit the model to the observed data of confirmed cases. Using contact history with bird among confirmed cases (n = 129), we estimate the reproduction number of the novel influenza A(H7N9) from human to human. RESULTS: Analysing twenty confirmed cases with known exposure, the reproduction number for human-to-human transmission was estimated at 0.28 (95% CI: 0.11, 0.45). Sensitivity analysis indicated that the reproduction number is substantially below unity. CONCLUSIONS: It is unlikely to observe an immediate pandemic of novel influenza A(H7N9) virus with human to human transmission. Continued monitoring of cases and animals would be the key to elucidate additional epidemiological characteristics of the virus. PMID- 23642093 TI - Does vitamin C deficiency increase lifestyle-associated vascular disease progression? Evidence based on experimental and clinical studies. AB - SIGNIFICANCE: Despite continuous advances in the prevention of cardiovascular disease (CVD), critical issues associated with an unhealthy lifestyle remain an increasing cause of morbidity and mortality in industrialized countries. RECENT ADVANCES: A growing body of literature supports a specific role for vitamin C in a number of reactions that are associated with vascular function and control including, for example, nitric oxide bioavailability, lipid metabolism, and vascular integrity. CRITICAL ISSUES: A large body of epidemiological evidence supports a relationship between poor vitamin C status and increased risk of developing CVD, and the prevalence of deficiency continues to be around 10%-20% of the general Western population although this problem could easily and cheaply be solved by supplementation. However, large intervention studies using vitamin C have not found a beneficial effect of supplementation. This review outlines the proposed mechanism by which vitamin C deficiency worsens CVD progression. In addition, it discusses problems with the currently available literature, including the discrepancies between the large intervention studies and the experimental and epidemiological literature. FUTURE DIRECTIONS: Increased insights into vitamin C deficiency-mediated CVD progression will enable the design of future randomized controlled trials that are better suited to test the efficacy of vitamin C in disease prevention as well as the identification of high risk individuals which could possibly benefit from supplementation. PMID- 23642094 TI - Self-assembly of amphiphilic plasmonic micelle-like nanoparticles in selective solvents. AB - Amphiphilic plasmonic micelle-like nanoparticles (APMNs) composed of gold nanoparticles (AuNPs) and amphiphilic block copolymers (BCPs) structurally resemble polymer micelles with well-defined architectures and chemistry. The APMNs can be potentially considered as a prototype for modeling a higher-level self-assembly of micelles. The understanding of such secondary self-assembly is of particular importance for the bottom-up design of new hierarchical nanostructures. This article describes the self-assembly, modeling, and applications of APMN assemblies in selective solvents. In a mixture of water/tetrahydrofuran, APMNs assembled into various superstructures, including unimolecular micelles, clusters with controlled number of APMNs, and vesicles, depending on the lengths of polymer tethers and the sizes of AuNP cores. The delicate interplay of entropy and enthalpy contributions to the overall free energy associated with the assembly process, which is strongly dependent on the spherical architecture of APMNs, yields an assembly diagram that is different from the assembly of linear BCPs. Our experimental and computational studies suggested that the morphologies of assemblies were largely determined by the deformability of the effective nanoparticles (that is, nanoparticles together with tethered chains as a whole). The assemblies of APMNs resulted in strong absorption in near-infrared range due to the remarkable plasmonic coupling of Au cores, thus facilitating their biomedical applications in bioimaging and photothermal therapy of cancer. PMID- 23642095 TI - Temporal changes of cytochrome P450 (Cyp) and eicosanoid-related gene expression in the rat brain after traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) induces arachidonic acid (ArA) release from cell membranes. ArA metabolites form a class of over 50 bioactive eicosanoids that can induce both adaptive and/or maladaptive brain responses. The dynamic metabolism of ArA to eicosanoids, and how they affect the injured brain, is poorly understood due to their diverse activities, trace levels, and short half-lives. The eicosanoids produced in the brain postinjury depend upon the enzymes present locally at any given time. Eicosanoids are synthesized by heme containing enzymes, including cyclooxygenases, lipoxygenases, and arachidonate monoxygenases. The latter comprise a subset of the cytochrome P450 "Cyp" gene family that metabolize fatty acids, steroids, as well as endogenous and exogenous toxicants. However, for many of these genes neither baseline neuroanatomical nor injury-related temporal expression have been studied in the brain.In a rat model of parietal cortex TBI, Cyp and eicosanoid-related mRNA levels were determined at 6 h, 24 h, 3d, and 7d postinjury in parietal cortex and hippocampus, where dynamic changes in eicosanoids have been observed. Quantitative real-time polymerase chain reaction with low density arrays were used to assay 62 rat Cyps, 37 of which metabolize ArA or other unsaturated fatty acids; 16 eicosanoid related enzymes that metabolize ArA or its metabolites; 8 eicosanoid receptors; 5 other inflammatory- and recovery-related genes, plus 2 mouse Cyps as negative controls and 3 highly expressed "housekeeping" genes. RESULTS: Sixteen arachidonate monoxygenases, 17 eicosanoid-related genes, and 12 other Cyps were regulated in the brain postinjury (p < 0.05, Tukey HSD). Discrete tissue levels and distinct postinjury temporal patterns of gene expression were observed in hippocampus and parietal cortex. CONCLUSIONS: The results suggest complex regulation of ArA and other lipid metabolism after TBI. Due to the temporal nature of brain injury-induced Cyp gene induction, manipulation of each gene (or its products) at a given time after TBI will be required to assess their contributions to secondary injury and/or recovery. Moreover, a better understanding of brain region localization and cell type-specific expression may be necessary to deduce the role of these eicosanoid-related genes in the healthy and injured brain. PMID- 23642096 TI - Role of cyclooxygenase-2 in exacerbation of allergen-induced airway remodeling by multiwalled carbon nanotubes. AB - The emergence of nanotechnology has produced a multitude of engineered nanomaterials such as carbon nanotubes (CNTs), and concerns have been raised about their effects on human health, especially for susceptible populations such as individuals with asthma. Multiwalled CNTs (MWCNTs) have been shown to exacerbate ovalbumin (OVA)-induced airway remodeling in mice. Moreover, cyclooxygenase-2 (COX-2) has been described as a protective factor in asthma. We postulated that COX-2-deficient (COX-2(-/-)) mice would be susceptible to MWCNT induced exacerbations of allergen-induced airway remodeling, including airway inflammation, fibrosis, and mucus-cell metaplasia (i.e., the formation of goblet cells). Wild-type (WT) or COX-2(-/-) mice were sensitized to OVA to induce allergic airway inflammation before a single dose of MWCNTs (4 mg/kg) delivered to the lungs by oropharyngeal aspiration. MWCNTs significantly increased OVA induced lung inflammation and mucus-cell metaplasia in COX-2(-/-) mice compared with WT mice. However, airway fibrosis after exposure to allergen and MWCNTs was no different between WT and COX-2(-/-) mice. Concentrations of certain prostanoids (prostaglandin D2 and thromboxane B2) were enhanced by OVA or MWCNTs in COX-2(-/-) mice. No differences in COX-1 mRNA concentrations were evident between WT and COX-2(-/-) mice treated with OVA and MWCNTs. Interestingly, MWCNTs significantly enhanced allergen-induced cytokines involved in Th2 (IL-13 and IL 5), Th1 (CXCL10), and Th17 (IL-17A) inflammatory responses in COX-2(-/-) mice, but not in WT mice. We conclude that exacerbations of allergen-induced airway inflammation and mucus-cell metaplasia by MWCNTs are enhanced by deficiencies in COX-2, and are associated with the activation of a mixed Th1/Th2/Th17 immune response. PMID- 23642097 TI - Antilock braking system effectiveness in prevention of road traffic crashes in Iran. AB - BACKGROUND: Anti-lock Brake System (ABS) helps the equipped vehicles to stop under heavy braking, in a shorter distance and with a better control of direction. It was expected that this technology will reduce the rate of fatal road traffic crashes (RTC); however, the outcome is controversial in the real world. The aim of this study is to compare the claimed annual incidence rate and financial losses due to RTCs in ABS vs. non-ABS personal vehicles in Iran. METHODS: A telephone survey among drivers of two similar models of personal vehicles was arranged. The studied vehicles were of the same brand and type; but only one of them was equipped with ABS. The number of RTCs, subsequent financial loss, and drivers' knowledge and perception about ABS were sought. The sample consisted of drivers of 1232 ABS and 3123 non-ABS vehicles. RESULTS: The annual incidence rate of RTC involving another vehicle was 145.1 (134.8-155.9) per 1000 vehicle-years and there was not a statistically significant difference between study groups.The incidence of RTC with another vehicle due to brake failure was 50.3 (42.9-58.5) for 1000 non ABS vehicle-years and 30.0 (21.2-41.2) for 1000 ABS equipped vehicle-years. The difference was statistically significant after adjustment for the driver and vehicle's age and the daily driving time. The attributable risk of RTC for non-ABS vehicles was 20/1000 vehicles and the excess fraction was 39.8%. The mean financial loss due to reported RTCs was $987.9 +/- $1547.3 US Dollars and there was not a statistically significant difference between study groups. While 61.1% of ABS vehicle drivers reported situations in which they believed the ABS had prevented a crash, 44.1% of them however, they did not know how to use ABS efficiently. CONCLUSIONS: Law enforcement to maintain safe distance and adhere to speed limit while driving, is needed to raise the effectiveness of ABS. This is as necessary as considering mandatory outfitting of ABS. Safety authorities should first consider the global experience and local evidence, before adopting any specific policy in this regard. The drivers need to learn the right way to use ABS for maximum effectiveness. PMID- 23642098 TI - HPV prevalence and genetic predisposition to cervical cancer in Saudi Arabia. AB - BACKGROUND: Cervical cancer incidence is low in Saudi Arabian women, suggesting low prevalence to HPV infection due to environmental, cultural and genetic differences. Therefore, we investigated HPV prevalence and genotype distribution in cervical cancer as well as the association with 9 genetic single nucleotide polymorphisms (SNPs): CDKN1A (p21) C31A, TP53 C72G, ATM G1853A, HDM2 promoter T309G, HDM2 A110G, LIG4 A591G, XRCC1 G399A, XRCC3 C241T and TGFbeta1 T10C, presumed to predispose to cancer. METHODS: One hundred cervical cancer patients (90 squamous cell carcinoma and 10 adenocarcinoma) and 100 age/sex-matched controls were enrolled. SNPs were genotyped by direct sequencing and HPV was detected and typed in tumors using the HPV Linear Array Test. RESULTS: Eighty-two cases (82%) were positive for HPV sequences. Seven HPV genotypes were present as single infections (16, 18, 31, 45, 56, 59, 73) and five double infections (16/18, 16/39, 16/70, 35/52, 45/59) were detected. Most common genotypes were HPV-16 (71%), 31 (7%), and 18, 45, 73 (4% each). Only XRCC1 SNP was significantly associated with cervical cancer (P=0.02, OD=1.69; 95% CI= 1.06-2.66). However, nested analysis revealed a preponderance of HPV-positivity in patients harboring the presumed risk allele TP53 G (P=0.06). Both XRCC1 and TP53 SNPs tended to deviate from Hardy-Weinberg equilibrium (HWE; P=0.03-0.07). CONCLUSIONS: HPV prevalence (82%) in cervical cancer is at the lower range of the worldwide estimation (85 - 99%). While XRCC1 G399A was significantly associated with cervical cancer, TP53 G72C showed borderline association only in HPV-positive patients. Deviation from HWE in HPV-positive patients indicates co-selection, hence implicating the combination of HPV and SNPs in cancer predisposition. Thus, SNPs could be more relevant biomarkers of susceptibility to cervical cancer when associated with HPV infection. PMID- 23642099 TI - Sleep for preserving and transforming episodic memory. AB - Sleep is known to support memory consolidation. Here we review evidence for an active system consolidation occurring during sleep. At the beginning of this process is sleep's ability to preserve episodic experiences preferentially encoded in hippocampal networks. Repeated neuronal reactivation of these representations during slow-wave sleep transforms episodic representations into long-term memories, redistributes them toward extrahippocampal networks, and qualitatively changes them to decontextualized schema-like representations. Electroencephalographic (EEG) oscillations regulate the underlying communication: Hippocampal sharp-wave ripples coalescing with thalamic spindles mediate the bottom-up transfer of reactivated memory information to extrahippocampal regions. Neocortical slow oscillations exert a supraordinate top-down control to synchronize hippocampal reactivations of specific memories to their excitable up phase, thus allowing plastic changes in extrahippocampal regions. We propose that reactivations during sleep are a general mechanism underlying the abstraction of temporally stable invariants from a flow of input that is solely structured in time, thus representing a basic mechanism of memory formation. PMID- 23642100 TI - An electronic portfolio for quantitative assessment of surgical skills in undergraduate medical education. AB - BACKGROUND: We evaluated a newly designed electronic portfolio (e-Portfolio) that provided quantitative evaluation of surgical skills. Medical students at the University of Seville used the e-Portfolio on a voluntary basis for evaluation of their performance in undergraduate surgical subjects. METHODS: Our new web-based e-Portfolio was designed to evaluate surgical practical knowledge and skills targets. Students recorded each activity on a form, attached evidence, and added their reflections. Students self-assessed their practical knowledge using qualitative criteria (yes/no), and graded their skills according to complexity (basic/advanced) and participation (observer/assistant/independent). A numerical value was assigned to each activity, and the values of all activities were summated to obtain the total score. The application automatically displayed quantitative feedback. We performed qualitative evaluation of the perceived usefulness of the e-Portfolio and quantitative evaluation of the targets achieved. RESULTS: Thirty-seven of 112 students (33%) used the e-Portfolio, of which 87% reported that they understood the methodology of the portfolio. All students reported an improved understanding of their learning objectives resulting from the numerical visualization of progress, all students reported that the quantitative feedback encouraged their learning, and 79% of students felt that their teachers were more available because they were using the e Portfolio. Only 51.3% of students reported that the reflective aspects of learning were useful. Individual students achieved a maximum of 65% of the total targets and 87% of the skills targets. The mean total score was 345 +/- 38 points. For basic skills, 92% of students achieved the maximum score for participation as an independent operator, and all achieved the maximum scores for participation as an observer and assistant. For complex skills, 62% of students achieved the maximum score for participation as an independent operator, and 98% achieved the maximum scores for participation as an observer or assistant. CONCLUSIONS: Medical students reported that use of an electronic portfolio that provided quantitative feedback on their progress was useful when the number and complexity of targets were appropriate, but not when the portfolio offered only formative evaluations based on reflection. Students felt that use of the e Portfolio guided their learning process by indicating knowledge gaps to themselves and teachers. PMID- 23642101 TI - Utility of geriatric assessment to predict mortality in the oldest old: the Octabaix study 3-year follow-up. AB - OBJECTIVE: Few studies have prospectively evaluated the utility of geriatric assessment tools as predictors of mortality in the oldest population. We investigated predictors of death in an oldest-old cohort after 3 years of follow up. METHODS: The Octabaix study is a prospective, community-based study with a follow-up period of 3 years involving 328 subjects aged 85 at baseline. Data were collected on functional and cognitive status, co-morbidity, nutritional and falls risk, quality of life, social risk, and long-term drug prescription. Vital status for the total cohort was evaluated after 3 years of follow-up. RESULTS: Mortality after 3 years was 17.3%. Patients who did not survive had significantly poorer baseline functional status for basic and instrumental activities of daily living (Barthel and Lawton Index), higher co-morbidity (Charlson), higher nutritional risk (Mini Nutritional Assessment), higher risk of falls (Tinetti Gait Scale), poor quality of life (visual analog scale of the Quality of Life Test), and higher number of chronic drugs prescribed. Cox regression analysis identified the Lawton Index (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.73-0.89) and the number of chronic drugs prescribed (HR 1.09, 95% CI 1.01-1.18) as independent predictors of mortality at 3 years. CONCLUSIONS: Among the variables studied, the ability to perform instrumental activities of daily living and using few drugs on a chronic basis at baseline are the best predictors of which oldest-old community dwelling subjects survive after a 3-year follow-up period. PMID- 23642102 TI - Luminescent carbon dot-gated nanovehicles for pH-triggered intracellular controlled release and imaging. AB - In this paper, the use of biocompatible carbon dots (C-Dots) as caps on the surface of mesoporous silica nanoparticles (MSPs) for the design of intelligent on-demand molecular delivery and cell imaging system is described. These C-Dots attached MSPs exhibited low cytotoxicity toward the cells and strong luminescence both in vitro and in vivo. A further loading of anticancer drug (DOX) endowed the fluorescent material with therapeutic functions. It was found that changing the pH to mildly acidic condition at physiological temperature caused the dissociation of the C-Dots@MSPs complex and release of a large number of DOX from the nanospheres. Moreover, the DOX-loaded nanocomposites exhibited a remarkably enhanced efficiency in killing cancer cells. The endocytosis and the efficient drug release properties of the system were confirmed by luminescence microscopy. Overall, we believe that the well-designed C-Dots@MSPs nanocomposites are promising for a simultaneous bioimaging and drug delivery system, which show more potential for clinical application. PMID- 23642103 TI - Anti-allergic drug discovery in China for eczema: current methods and future strategies. AB - INTRODUCTION: Eczema is a common childhood atopic disease associated with chronicity and impaired quality of life. As there is no cure for this disease, treatment relies on topical and systemic anti-allergic or immunomodulating therapies. Topical corticosteroids, macrolide immunosuppressants and oral immunomodulating drugs have been the mainstay for the treatment of recalcitrant disease. However, in China as well as throughout Asia, the use of traditional and proprietary topical and herbal medicines is also popular. AREAS COVERED: This article reviews the evidence for the anti-allergic effects of topical and oral forms of these medicinal. The authors also present and discuss the current methods of preparation and evaluation for these traditional and proprietary medications. Additionally, the authors present the novel delivery method of employing nanotechnology to deliver these herbal therapies. EXPERT OPINION: Many herbal concoctions have had trials which have claimed therapeutic benefits for eczema. However, the scientific methods in these trials are often flawed and often not objective. In fact, the majority of these trials do not provide proof of objective efficacy for the anti-allergic effects claimed. It is felt that the delivery of herbal medication by nanotechnology has several crucial challenges that certainly need to be overcome for the optimal design of therapies for eczema, through optimizing material properties, methods of delivery and understanding the mechanisms of action. PMID- 23642104 TI - Efficacy of indoxacarb applied to cats against the adult cat flea, Ctenocephalides felis, flea eggs and adult flea emergence. AB - BACKGROUND: A study was conducted to evaluate the effect of indoxacarb applied to cats on adult cat fleas, Ctenocephalides felis, flea egg production and adult flea emergence. METHODS: Sixteen cats were selected for the study and allocated to two treatment groups. Eight cats were treated with a 19.5% w/v topical spot-on solution of indoxacarb on day 0 and eight cats served as untreated controls. Each cat was infested with 50 fleas on Days -2, 7, 14, 21, 28, 35 and 42. On Days 1, 2, and 3, and at 2 and 3 days after each post treatment reinfestation flea eggs were collected from the pan under each cat cage. Eggs were counted and viability assessed by evaluating adult flea emergence 28 days after egg collection. Three days after treatment or infestation, each cat was combed to remove and count live fleas. RESULTS: Treatment with indoxacarb provided 100% efficacy following infestations on day -2, 7, 14, 21 and 28 and efficacy was 99.6% following infestations on days 35 and 42. Egg production from indoxacarb treated cats was reduced by 99.9% within 72 hours of treatment. For subsequent infestations no eggs were produced from treated cats from day 8 through day 30. Egg production was still reduced by >=95.8% through day 45. Indoxacarb treatment also reduced adult flea emergence from eggs for 5 weeks after treatment. The combination of reduction in egg numbers and egg viability from indoxacarb treated cats reduced predicted flea emergence by 100% from days 2 - 31 and 99.9%, 100%, 96.4% and 99.0% on days 37, 38, 44 and 45, respectively. CONCLUSIONS: A topical spot-on formulation of indoxacarb provided >=99.6% efficacy against flea infestations on cats for 6 weeks following a single treatment. Indoxacarb also eliminated or markedly reduced egg production for the entire evaluation period and reduced the viability of the few eggs that were produced from Day 1 through Day 38. Given indoxacarb's effect on adult fleas, egg production and egg viability; this formulation can interrupt flea reproduction on treated cats for at least 6 weeks after treatment. PMID- 23642105 TI - Underreporting of conflicts of interest in clinical practice guidelines: cross sectional study. AB - BACKGROUND: Conflicts of interest affect recommendations in clinical guidelines and disclosure of such conflicts is important. However, not all conflicts of interest are disclosed. Using a public available disclosure list we determined the prevalence and underreporting of conflicts of interest among authors of clinical guidelines on drug treatments. METHODS: We included up to five guidelines published from July 2010 to March 2012 from each Danish clinical specialty society. Using the disclosure list of the Danish Health and Medicines Authority, we identified author conflicts of interest and compared them with the disclosures in the guidelines. For each guideline we extracted methodological characteristics of guideline development. RESULTS: Forty-five guidelines from 14 specialty societies were included. Of 254 authors, 135 (53%) had conflicts of interest, corresponding to 43 of the 45 guidelines (96%) having one or more authors with a conflict of interest. Only one of the 45 guidelines (2%) disclosed author conflicts of interest. The most common type of conflict of interest (83 of the 135) was being a consultant, an advisory board member or a company employee. Only 10 guidelines (22%) described the methods used for guideline development, 27 (60%) used references in the text and 11 (24%) graded the types of evidence. CONCLUSIONS: Conflicts of interest were common, but disclosures were very rare. Most guidelines did not describe how they were developed and many did not describe the evidence behind specific recommendations. Publicly available disclosure lists may assist guideline issuing bodies in ensuring that all conflicts are disclosed. PMID- 23642106 TI - Upregulation of triglyceride synthesis in skeletal muscle overexpressing DGAT1. AB - The gene encoding diacylglycerol acyltransferase (DGAT1) is a functional and positional candidate gene for milk and intramuscular fat content. A bovine DGAT1 overexpression vector was constructed containing mouse MCK promoter and bovine DGAT1 cDNA. MCK-DGAT1 transgene in FVB mice was researched in present study. The transgene DGAT1 had a high level of expression in contrast to the endogenous DGAT1 in posterior tibial muscle of the transgenic mice, but a low expression level in the cardiac muscle. Compared with wild-type mice, triglyceride and DGAT1 content were approximately fourfold and 50% increased in posterior tibial muscle of the transgenic mice, respectively, while a little increase in cardiac muscle. PMID- 23642108 TI - Orientation resolving dipolar high-field EPR spectroscopy on disordered solids: II. Structure of spin-correlated radical pairs in photosystem I. AB - The distance and relative orientation of functional groups within protein domains and their changes during chemical reactions determine the efficiency of biological processes. In this work on electron transfer proteins, we report the results of orientation resolving dipolar high-field EPR spectroscopy on the charge-separated state P700*+ A1*- (P700, primary electron donor; A1, phylloquinone electron acceptor) in Photosystem I (PS I). Pulsed high-field EPR spectroscopy at W-band (95 GHz, 3.4 T) with extensions to PELDOR (pulsed electron electron double resonance) and RIDME (relaxation-induced dipolar modulation enhancement) was utilized to obtain the parameters describing the three dimensional structure of the laser-flash-induced transient radical pair P700*+ A1*- in a frozen solution of deuterated PS I from the cyanobacterium Synechocystis sp. PCC 6803, which is performing oxygenic photosynthesis. The measured distances and relative orientations of the weakly coupled radical ions in the radical pair P700*+ A1*- are compared with previously reported geometries and with those of the precursor cofactors P700 and A1 known from X-ray crystallography. Cyclic electron transfer was found to proceed exclusively via the A-branch of the cofactor chain of PS I at cryogenic temperature. The position and orientation of the reduced phylloquinone coincide with those of the precursor, revealing that no substantial orientational changes of the phylloquinone molecule upon charge separation occur. Several distinct orientations of the P700*+ g-tensor axes with respect to the molecular frame of the primary donor were found experimentally, which we explain by several conformational substates of the P700*+ radical structure having slightly different electron spin density distributions. PMID- 23642107 TI - The associations of perceived neighborhood disorder and physical activity with obesity among African American adolescents. AB - BACKGROUND: According to recent research studies, the built and socioeconomic contexts of neighborhoods are associated with African American adolescents' participation in physical activity and obesity status. However, few research efforts have been devoted to understand how African American adolescents' perceptions of their neighborhood environments may affect physical activity behaviors and obesity status. The objective of the current study was to use a perceived neighborhood disorder conceptual framework to examine whether physical activity mediated the relationship between perceived neighborhood disorder and obesity status among African American adolescents. METHODS: The data were obtained from a cross-sectional study that examined social and cultural barriers and facilitators of physical activity among African American adolescents. The study included a sample of 101 African American adolescents age 12 to 16 years and their parents who were recruited from the Birmingham, Alabama metropolitan area. The primary outcome measure was obesity status which was classified using the International Obesity Task Force cut off points. Moderate-to-vigorous physical activity was assessed via accelerometry. Perceived neighborhood disorder was assessed using the Perceived Neighborhood Disorder Scale. Mediation models were used to examine whether the relationship between neighborhood disorder and obesity status was mediated by physical activity. RESULTS: Perceived neighborhood disorder was significantly and positively related to obesity status and moderate to-vigorous physical activity was inversely associated with obesity status. However, there was no evidence to support a significant mediating effect of moderate-to-vigorous physical activity on the relationship between neighborhood disorder and obesity status. CONCLUSION: Future studies should longitudinally assess perceived neighborhood disorder characteristics and childhood adiposity to examine the timing, extent, and the mechanisms by which perceived neighborhood disorder characteristics increase the risk of obesity. PMID- 23642109 TI - Computational study of the initial stage of diborane pyrolysis. AB - The rate constants for the association of two boranes to form diborane are investigated using several methods. The most sophisticated method is the variable reaction coordinate-variational transition state theory (VRC-VTST) which has been developed to handle reactions with no enthalpic barriers. The calculated rate constant of 8.2 * 10(-11) cm(3).molecule(-1).s(-1) at 545 K is in good agreement with experiment. The rate constant was also computed using conventional VTST with the G4 composite method. Two variations of the multistep mechanisms for diborane pyrolysis are presented. One is initiated by the step B2H6 ? 2 BH3 while the other begins with 2 B2H6 ? B3H9 + BH3 as the initial elementary step. Both variations are 3/2 order in diborane and have the same activation energy (G4, 28.65 kcal/mol at 420 K). In contrast, the traditional mechanism involving a B3H9 intermediate with C3v symmetry has a higher activation energy (33.37 kcal/mol). The two variations involve a C2-symmetry penta-coordinate B3H9 structure that, while an electronic minimum, is not a stationary point on the free energy path between B2H6 + BH3 -> B3H7 + H2. While the calculated activation barrier is higher than the recently determined experimental barrier, the variation in reported values is large (22.0-29.0 kcal/mol). We discuss possible sources of disagreement between experiment and theory. PMID- 23642111 TI - A humanized model of microvascular infection. PMID- 23642112 TI - Does host cholesterol metabolism impact the gut microbiota and why does it matter? PMID- 23642114 TI - Regulation of pathogenicity by noncoding RNAs in bacteria. AB - Regulatory noncoding RNAs (ncRNAs) play important roles in bacterial gene regulation, primarily at the post-transcriptional level. There are four broad categories of regulatory ncRNAs including trans-encoded ncRNAs, cis-encoded ncRNAs, RNA thermometers and riboswitches, and they can influence the translation and/or stability of mRNAs by binding to the base-pairing sites in their target transcripts. In pathogenic bacteria, numerous ncRNAs are involved in the coordinated expression of virulence determinants to facilitate the pathogenicity in a concerted manner. This review discusses the modes of action of different regulatory ncRNAs and, furthermore, exemplifies their roles in regulating bacterial pathogenicity. PMID- 23642110 TI - Dysregulation of corticostriatal ascorbate release and glutamate uptake in transgenic models of Huntington's disease. AB - SIGNIFICANCE: Dysregulation of cortical and striatal neuronal processing plays a critical role in Huntington's disease (HD), a dominantly inherited condition that includes a progressive deterioration of cognitive and motor control. Growing evidence indicates that ascorbate (AA), an antioxidant vitamin, is released into striatal extracellular fluid when glutamate is cleared after its release from cortical afferents. Both AA release and glutamate uptake are impaired in the striatum of transgenic mouse models of HD owing to a downregulation of glutamate transporter 1 (GLT1), the protein primarily found on astrocytes and responsible for removing most extracellular glutamate. Improved understanding of an AA glutamate interaction could lead to new therapeutic strategies for HD. RECENT ADVANCES: Increased expression of GLT1 following treatment with ceftriaxone, a beta-lactam antibiotic, increases striatal glutamate uptake and AA release and also improves the HD behavioral phenotype. In fact, treatment with AA alone restores striatal extracellular AA to wild-type levels in HD mice and not only improves behavior but also improves the firing pattern of neurons in HD striatum. CRITICAL ISSUES: Although evidence is growing for an AA-glutamate interaction, several key issues require clarification: the site of action of AA on striatal neurons; the precise role of GLT1 in striatal AA release; and the mechanism by which HD interferes with this role. FUTURE DIRECTIONS: Further assessment of how the HD mutation alters corticostriatal signaling is an important next step. A critical focus is the role of astrocytes, which express GLT1 and may be the primary source of extracellular AA. PMID- 23642115 TI - Bacterial behaviors associated with the quorum-sensing peptide pheromone ('alarmone') in streptococci. AB - Streptococci are among the predominant bacterial species living in the human body. They are normally harmless bacteria, but have the ability to cause diverse infections, ranging from mild (e.g., tooth decay and sore throat) to life threatening (e.g., endocarditis and meningitis). Streptococci have evolved various means of coping with the deleterious effects of environmental stressors and avoiding the host immune system. Recently, several studies have shown that streptococci colonizing the mouth and upper respiratory tract are able to mount complex stress responses in order to persist and successfully survive competition in their ecological niche. Using a small quorum-sensing peptide pheromone acting as a stress-inducible 'alarmone', oral streptococci synchronize the gene expression of a specific group of cells to coordinate important biological activities. PMID- 23642117 TI - Proteases in Mycobacterium tuberculosis pathogenesis: potential as drug targets. AB - TB is still a major global health problem causing over 1 million deaths per year. An increasing problem of drug resistance in the causative agent, Mycobacterium tuberculosis, as well as problems with the current lengthy and complex treatment regimens, lends urgency to the need to develop new antitubercular agents. Proteases have been targeted for therapy in other infections, most notably these have been successful as antiviral agents in the treatment of HIV infection. M. tuberculosis has a number of proteases with good potential as novel drug targets and developing drugs against these should result in agents that are effective against drug-resistant and drug-sensitive strains. In this review, the authors summarize the current status of proteases with potential as drug targets in this pathogen, particularly focusing on proteases involved in protein secretion (signal peptidases LepB and LspA), protein degradation and turnover (ClpP and the proteasome) and virulence (mycosins and HtrA). PMID- 23642118 TI - Pneumonia pathogen detection and microbial interactions in polymicrobial episodes. AB - Recent reports show that microbial communities associated with respiratory infections, such as pneumonia and cystic fibrosis, are more complex than expected. Most of these communities are polymicrobial and might comprise microorganisms originating from several diverse biological and ecological sources. Moreover, unexpected bacteria in the etiology of these respiratory infections have been increasingly identified. These findings were established with the use of efficient microbiological diagnostic tools, particularly molecular tools based on common gene amplification, followed by cloning and sequencing approaches, which facilitated the identification of the polymicrobial flora. Similarly, recent investigations reported that microbial interactions might exist between species in polymicrobial communities, including typical pneumonia pathogens, such as Pseudomonas aeruginosa and Candida albicans. Here, we review recent tools for microbial diagnosis, in particular, of intensive care unit pneumonia and the reported interactions between microbial species that have primarily been identified in the etiology of these infections. PMID- 23642116 TI - Genetic diversity in the oral pathogen Porphyromonas gingivalis: molecular mechanisms and biological consequences. AB - Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that colonizes the human oral cavity. It is implicated in the development of periodontitis, a chronic periodontal disease affecting half of the adult population in the USA. To survive in the oral cavity, these bacteria must colonize dental plaque biofilms in competition with other bacterial species. Long-term survival requires P. gingivalis to evade host immune responses, while simultaneously adapting to the changing physiology of the host and to alterations in the plaque biofilm. In reflection of this highly variable niche, P. gingivalis is a genetically diverse species and in this review the authors summarize genetic diversity as it relates to pathogenicity in P. gingivalis. Recent studies revealing a variety of mechanisms by which adaptive changes in genetic content can occur are also reviewed. Understanding the genetic plasticity of P. gingivalis will provide a better framework for understanding the host-microbe interactions associated with periodontal disease. PMID- 23642119 TI - Bacterial genome evolution within a clonal population: from in vitro investigations to in vivo observations. AB - Bacteria are faced with a diversity of environmental stresses that include high salt concentrations, heavy metals and pH fluctuations. Adaptation to resist such stresses is a complex phenomenon that involves global pathways and simultaneous acquisition of multiple unrelated properties. During the last 3 years, the development of new technologies in the field of molecular biology has led to numerous fundamental and quantitative in vitro and in vivo evolutionary studies that have improved our understanding of the principles underlying bacterial adaptations, and helped us develop strategies to cope with the health burden of bacterial virulence. In this review, the authors discuss the evolution of bacteria in the laboratory and in human patients. PMID- 23642120 TI - Evaluation of fosfomycin activity against uropathogens in a fosfomycin-naive population in South India: a prospective study. AB - AIM: The aim was to evaluate the in vitro activity of fosfomycin against common uropathogens in a fosfomycin-naive population in India. METHODS: The authors prospectively collected and tested all consecutive isolates of Escherichia coli and Enterococcus spp. from urine samples between December 2009 and April 2010. RESULTS: A total of 3141 isolates were included in the study, 2416 E. coli and 725 Enterococcus spp. Fosfomycin was the most active antibiotic against both pathogens with an overall susceptibility of 83 and 99% for E. coli and Enterococcus spp, respectively. Among E. coli, 47.6% of the isolates were extended-spectrum beta-lactamase producing, of which 81% were susceptible to fosfomycin, while 51.5% were multidrug resistant, with 75.7% of this portion being susceptible to fosfomycin. CONCLUSION: Fosfomycin exhibits good in vitro activity against both the uropathogens tested. Therefore, it might be considered as a treatment option for urinary tract infections in India; however, clinical trials should first reinforce the in vitro findings. PMID- 23642121 TI - Opportunistic bacteria in dental unit waterlines: assessment and characteristics. AB - AIM: The study aimed to determine qualitative and quantitative contamination of dental unit reservoir water with aerobic and facultative anaerobic bacteria, with regards to health risk to dental staff and patients. MATERIALS & METHODS: The study material included water samples from 107 unit reservoirs. Conventional microbiological methods were used. The isolated bacteria were divided into three groups according to pathogenic mechanisms. RESULTS: Dental unit water contamination was widespread. The isolated bacteria average concentration was 1.1 * 10(5) CFU/ml, with Ralstonia pickettii as the prevailing species (49.33%). The total potentially pathogenic bacteria were 54.54% of all the isolated bacteria. Bacteria causing infectious and invasive diseases constituted over one-half of this group, while allergizing and immunotoxic bacteria occurred in smaller quantities. CONCLUSION: The presence of over 50% potentially pathogenic microorganisms among the isolated bacteria and their very high concentrations call for the daily use of effective methods to reduce dental unit water contamination and health risk. PMID- 23642124 TI - Synthesis of hollow Ag-Au bimetallic nanoparticles in polyelectrolyte multilayers. AB - Ag nanoparticles of ~20 nm size and rather uniform size distribution were synthesized in polyelectrolyte multilayers (PEMs) via an ion-exchange/reduction process in two stages (seeding and growth), which were used as sacrificial templates to fabricate Ag-Au bimetallic hollow nanoparticles via galvanic replacement reaction. The reaction process was monitored by UV-vis spectroscopy. The morphology and structure of the nanoparticles were characterized by transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy, which confirmed the formation of hollow Ag-Au bimetallic nanoparticles. UV-vis absorbance spectroscopy and TEM results indicated that both size and optical properties of the Ag nanoparticles in the PEM can be controlled by manipulating ion content in the PEM and the number of the ion-exchange/reduction cycle, whereas that of Ag-Au bimetallic nanoparticles were dependent on size of the Ag templates and the replacement reaction kinetics. The hollow Ag-Au bimetallic nanoparticles exhibited a significant red shift in the surface plasmon resonance to the near-infrared region. The strategy enables facile preparation of hollow bimetallic nanoparticles in situ in polymer matrixes. PMID- 23642123 TI - Functional transcriptomic analysis of the role of MAB-5/Hox in Q neuroblast migration in Caenorhabditis elegans. AB - BACKGROUND: Directed cell migration is a fundamental process in normal development and in tumor metastasis. In C. elegans the MAB-5/Hox transcription factor is a determinant of posterior migration of the Q neuroblast descendants. In this work, mab-5 transcriptional targets that control Q descendant migration are identified by comparing RNA-seq profiles in wild type and mab-5 mutant backgrounds. RESULTS: Transcriptome profiling is a widely-used and potent tool to identify genes involved in developmental and pathological processes, and is most informative when RNA can be isolated from individual cell or tissue types. Cell specific RNA samples can be difficult to obtain from invertebrate model organisms such as Drosophila and C. elegans. Here we test the utility of combining a whole organism RNA-seq approach with mab-5 loss and gain-of-function mutants and functional validation using RNAi to identify genes regulated by MAB-5 to control Q descendant migration. We identified 22 genes whose expression was controlled by mab-5 and that controlled Q descendant migration. Genes regulated by mab-5 were enriched for secreted and transmembrane molecules involved in basement membrane interaction and modification, and some affected Q descendant migration. CONCLUSIONS: Our results indicate that a whole-organism RNA-seq approach, when combined with mutant analysis and functional validation, can be a powerful method to identify genes involved in a specific developmental process, in this case Q descendant posterior migration. These genes could act either autonomously in the Q cells, or non-autonomously in other cells that express MAB-5. The identities of the genes regulated by MAB-5 indicate that MAB-5 acts by modifying interactions with the basement membrane, resulting in posterior versus anterior migration. PMID- 23642125 TI - Australasian randomised trial to evaluate the role of maternal intramuscular dexamethasone versus betamethasone prior to preterm birth to increase survival free of childhood neurosensory disability (A*STEROID): study protocol. AB - BACKGROUND: Both dexamethasone and betamethasone, given to women at risk of preterm birth, substantially improve short-term neonatal health, increase the chance of the baby being discharged home alive, and reduce childhood neurosensory disability, remaining safe into adulthood. However, it is unclear which corticosteroid is of greater benefit to mother and child.This study aims to determine whether giving dexamethasone to women at risk of preterm birth at less than 34 weeks' gestation increases the chance of their children surviving free of neurosensory disability at two years' corrected age, compared with betamethasone. METHODS/DESIGN: Design randomised, multicentre, placebo controlled trial.Inclusion criteria women at risk of preterm birth at less than 34 weeks' gestation with a singleton or twin pregnancy and no contraindications to the use of antenatal corticosteroids and who give informed consent.Trial entry & randomisation at telephone randomisation eligible women will be randomly allocated to either the dexamethasone group or the betamethasone group, allocated a study number and corresponding treatment pack.Study groups women in the dexamethasone group will be administered two syringes of 12 mg dexamethasone (dexamethasone sodium phosphate) and women in the betamethasone group will be administered two syringes of 11.4 mg betamethasone (Celestone Chronodose). Both study groups consist of intramuscular treatments 24 hours apart.Primary study outcome death or any neurosensory disability measured in children at two years' corrected age.Sample size a sample size of 1449 children is required to detect either a decrease in death or any neurosensory disability from 27.0% to 20.1% with dexamethasone compared with betamethasone, or an increase from 27.0% to 34.5% (two-sided alpha 0.05, 80% power, 5% loss to follow up, design effect 1.2). DISCUSSION: This study will provide high-level evidence of direct relevance for clinical practice. If one drug clearly results in significantly fewer deaths and fewer disabled children then it should be used consistently in women at risk of preterm birth and would be of great importance to women at risk of preterm birth, their children, health services and communities. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: ACTRN12608000631303. PMID- 23642126 TI - The sexual quality of life-female (SQOL-F) questionnaire: translation and psychometric properties of the Iranian version. AB - BACKGROUND: Female sexual dysfunction is a common condition that extremely affects reproductive health and quality of life. To assess this health condition, a valid and reliable questionnaire is required. The aim of this study was to translate and validate the Sexual Quality of Life-Female (SQOL-F) questionnaire in Iran. METHOD: Forward-backward procedure was applied to translate the questionnaire from English into Persian. After linguistic validation and pilot examination, a cross-sectional study was carried out and psychometric properties of the Iranian version of questionnaire were tested. One hundred reproductive aged, married, healthy and sexually active women completed the questionnaire. Reliability was assessed by internal consistency (Cronbach's alpha), and test retest (intraclass correlation coefficient) analyses. In addition, content, and face validity were assessed and the factor structure of the questionnaire was extracted by performing exploratory factor analysis. RESULTS: The mean age of participants was 33 (SD = 8.07) years, and the mean quality of sexual life score was 86.4 (SD = 1.78) ranging from 36 to 108. Most women were housewife (n = 92). Reliability evaluation revealed high internal consistency and good test-retest reliability. The Cronbach's alpha coefficient was 0.73 and intraclass correlation coefficient (ICC) was 0.88. The mean scores for the content validity index (CVI) and the content validity ratio (CVR) were 0.91 and 0.84, respectively. The results of exploratory factor analysis (EFA) indicated a four-factor solution for the questionnaire that jointly accounted for 60.8% of variance observed. CONCLUSION: The findings from this study suggest that the Iranian version of SQOL F questionnaire has good psychometric properties and it will be useful to assess the female sexual quality of life in reproductive health care settings. PMID- 23642127 TI - Design and synthesis of small-molecule fluorescent photoprobes targeted to aminopeptdase N (APN/CD13) for optical imaging of angiogenesis. AB - We report here the synthesis of a nonpeptide, small-molecule fluorescent imaging agent with high affinity to aminopeptidase N (APN/CD13), a key player in a variety of pathophysiological angiogenic processes. On the basis of a recently described lead structure, we synthesized three putative precursor compounds by introducing polyethylene glycol (PEG) spacers comprising amino groups for dye labeling. Different attachment sites resulted in substantial differences in target affinity, cell toxicity, and target imaging performance. In comparison to bestatin, a natural inhibitor of many aminopeptidases, two of our compounds (22, 23) exhibit comparable inhibition potency, while a third (21) does not show any inhibiting effect. Cell binding assays with APN-positive BT-549 and APN-negative BT-20 cells and the final fluorescent probes Cy 5.5-21 and Cy 5.5-23 confirm these findings. The favorable characteristics of Cy 5.5-23 will now be proven in in vivo experiments with murine models of high APN expression and may serve as a tool to better understand APN pathophysiology. PMID- 23642129 TI - Granzyme B deficiency exacerbates lung inflammation in mice after acute lung injury. AB - Granzyme B (GzmB) is a serine protease with intracellular and extracellular activities capable of regulating inflammation through cytokine processing and the apoptosis of effector cells. We tested the hypothesis that GzmB expression in T regulatory cells (Tregs) is required for the control of inflammatory responses and pathology during acute lung injury. To substantiate the clinical relevance of GzmB during lung injury, we performed GzmB immunohistochemistry on lung tissue from patients with acute respiratory distress syndrome (ARDS) and healthy control subjects. We also performed in vivo experiments with wild-type (WT) C57BL/6 and GzmB(-/-) mice exposed to a single intranasal instillation of bleomycin to model lung injury. Our results demonstrate that the expression of GzmB was elevated in ARDS lung sections, relative to healthy control samples. Bleomycin-exposed GzmB( /-) mice exhibited greater morbidity and mortality, which was associated with increased numbers of lung lymphocytes. Bleomycin induced an equal increase in CD4(+)/CD25(+)/FoxP3(+) Treg populations in WT and GzmB(-/-) mice. GzmB expression was not significant in Tregs, with the majority of the expression localized to natural killer (NK)-1.1(+) cells. The expression of GzmB in NK cells of bleomycin-exposed WT mice was associated with greater lymphocyte apoptosis, reduced total lymphocyte numbers, and reduced pathology relative to GzmB(-/-) mice. Our data demonstrate that GzmB deficiency results in the exacerbation of lymphocytic inflammation during bleomycin-induced acute lung injury, which is associated with pathology, morbidity, and mortality. PMID- 23642130 TI - Infections and cancer: debate about using vaccines as a cancer control tool. AB - In 2012, Infectious Agents and Cancer commissioned a thematic series collection of articles on Prevention of HPV related cancer. The articles have attracted wide interest and stimulated debate, including about the utility of vaccines in cancer control. The application of vaccines to cancer control fulfills a promise envisioned at the turn of the 20th century when remarkable experiments showed that some cancers were caused by infections. This suggested the possibility of applying infection-control strategies to cancer control. Vaccines represent the most practical cost-effective technology to prevent wide human suffering and death from many acute infectious diseases, such as small pox or polio. Hitherto applied to control of acute fatal infections, vaccines, if developed, might provide a potent way to control cancer. The articles in the HPV thematic series show success in developing and applying a vaccine against human papilloma virus (HPV). A vaccine is also available against hepatitis B virus (HBV), which causes liver cancer. These vaccines augment the tools available to control the associated cancers. Scientific endeavor continues for six other cancer-associated infections, mostly viruses. Not surprisingly, debate about the safety of vaccines targeting cancer has been triggered in the scientific community. Questions about safety have been raised for those populations where other means to control these cancers may be available. Although it is difficult to quantify risk from vaccines in individuals where other cancer control services exist, it is likely to be low. Vaccines are much safer today than before. Technological advancement in vaccine development and manufacture and improved regulatory review and efficient distribution have minimized substantially the risk for harm from vaccines. Formal and informal debate about the pros and cons of applying vaccines as a cancer control tools is ongoing in scientific journals and on the web. Infectious Agents and Cancer encourages evidence-based discussion to clarify understanding of the role of vaccines in cancer control. In a similar vein, the journal will not consider anecdotal reports and rhetorical arguments because they are unlikely to inform policy, regulation, or the public. PMID- 23642131 TI - Comprehensive computational study of decamethyldizincocene formation. 1. Reaction of ZnR2 reagents with decamethylzincocene. AB - Computational methods were used to study the surprising 2004 synthesis of decamethyldizincocene, Zn2(eta(5)-C5Me5)2, which was the first molecule to have a direct, unbridged bond between two first-row transition metals. The computational results show that the methyl groups of decamethylzincocene, Zn(eta(5) C5Me5)(eta(1)-C5Me5), affect the transition-state stability of its reaction with ZnEt2 (or ZnPh2) through steric hindrance, and this could possibly allow a counter-reaction, the homolytic dissociation of Zn(eta(5)-C5Me5)(eta(1)-C5Me5) into Zn(eta(5)-C5Me5)(*) and (eta(1)-C5Me5)(*), to occur, and because no such steric hindrance occurs when zincocene, Zn(eta(5)-C5H5)(eta(1)-C5H5), is used as a reactant, its dissociation never occurs regardless of what ZnR2 reagent is used. PMID- 23642132 TI - Developmental mechanisms of topographic map formation and alignment. AB - Brain connections are organized into topographic maps that are precisely aligned both within and across modalities. This alignment facilitates coherent integration of different categories of sensory inputs and allows for proper sensorimotor transformations. Topographic maps are established and aligned by multistep processes during development, including interactions of molecular guidance cues expressed in gradients; spontaneous activity-dependent axonal and dendritic remodeling; and sensory-evoked plasticity driven by experience. By focusing on the superior colliculus, a major site of topographic map alignment for different sensory modalities, this review summarizes current understanding of topographic map development in the mammalian visual system and highlights recent advances in map alignment studies. A major goal looking forward is to reveal the molecular and synaptic mechanisms underlying map alignment and to understand the physiological and behavioral consequences when these mechanisms are disrupted at various scales. PMID- 23642133 TI - The evolution of Drosophila melanogaster as a model for alcohol research. AB - Animal models have been widely used to gain insight into the mechanisms underlying the acute and long-term effects of alcohol exposure. The fruit fly Drosophila melanogaster encounters ethanol in its natural habitat and possesses many adaptations that allow it to survive and thrive in ethanol-rich environments. Several assays to study ethanol-related behaviors in flies, ranging from acute intoxication to self-administration and reward, have been developed in the past 20 years. These assays have provided the basis for studying the physiological and behavioral effects of ethanol and for identifying genes mediating these effects. In this review we describe the ecological relationship between flies and ethanol, the effects of ethanol on fly development and behavior, the use of flies as a model for alcohol addiction, and the interaction between ethanol and social behavior. We discuss these advances in the context of their utility to help decipher the mechanisms underlying the diverse effects of ethanol, including those that mediate ethanol dependence and addiction in humans. PMID- 23642134 TI - Episodic neurologic disorders: syndromes, genes, and mechanisms. AB - Many neurologic diseases cause discrete episodic impairment in contrast with progressive deterioration. The symptoms of these episodic disorders exhibit striking variety. Herein we review what is known of the phenotypes, genetics, and pathophysiology of episodic neurologic disorders. Of these, most are genetically complex, with unknown or polygenic inheritance. In contrast, a fascinating panoply of episodic disorders exhibit Mendelian inheritance. We classify episodic Mendelian disorders according to the primary neuroanatomical location affected: skeletal muscle, cardiac muscle, neuromuscular junction, peripheral nerve, or central nervous system (CNS). Most known Mendelian mutations alter genes that encode membrane-bound ion channels. These mutations cause ion channel dysfunction, which ultimately leads to altered membrane excitability as manifested by episodic disease. Other Mendelian disease genes encode proteins essential for ion channel trafficking or stability. These observations have cemented the channelopathy paradigm, in which episodic disorders are conceptualized as disorders of ion channels. However, we expand on this paradigm to propose that dysfunction at the synaptic and neuronal circuit levels may underlie some episodic neurologic entities. PMID- 23642135 TI - Pauson-Khand reactions in a photochemical flow microreactor. AB - Pauson-Khand reactions were achieved at ambient temperature without any additive using a photochemical flow microreactor. The efficiency of the reaction was better than that in a conventional batch reactor, and the reaction could be operated continuously for 1 h. PMID- 23642136 TI - Circulating markers for prognosis of hepatocellular carcinoma. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) is a lethal liver malignancy with an exceptionally high incidence in Asia and Africa. The number of new cases in America and Europe is rapidly increasing, making HCC a worldwide health problem. Patients with early HCC can be treated by potentially curative interventions such as tumor resection, liver transplantation, and radiofrequency ablation, but unfortunately a considerable portion of them would develop tumor recurrence, which in many cases cannot be detected early. As such, it remains imperative to develop accurate, noninvasive blood tests, which can be applied in most clinical laboratories, for the measurement of treatment responses and the surveillance for tumor recurrence. AREAS COVERED: This review article focuses on the recent discoveries of circulating proteins, DNA, microRNAs, cancer cells, and regulatory T cells as serological prognostic biomarkers for patients with HCC. These biomarkers not only have prognostic implications, but also hold promises to help physicians stratify patients for different interventions. EXPERT OPINIONS: Biomarkers will certainly serve as accurate tools in disease prognostication, changing the ways physicians stratify patients for specific therapy and monitor patients' responses toward treatment. PMID- 23642137 TI - Development of metal-organic nanotubes exhibiting low-temperature, reversible exchange of confined "ice channels". AB - Nanotubular materials have unique water transport and storage properties that have the potential to advance separations, catalysis, drug delivery, and environmental remediation technologies. The development of novel hybrid materials, such as metal-organic nanotubes (MONs), is of particular interest, as these materials are amenable to structural engineering strategies and may exhibit tunable properties based upon the presence of inorganic components. A novel metal organic nanotube, (C4H12N2)(0.5)[(UO2)(Hida)(H2ida)].2H2O (UMON) (ida = iminodiacetate), that demonstrates the possibilities of these types of hybrid compounds has been synthesized via a supramolecular approach. Single-crystal X ray diffraction of the compound revealed stacked macrocyclic arrays that contain highly ordered water molecules with structural similarities to the "ice channels" observed in single-walled carbon nanotubes. Nanoconfinement of the water molecules may be the cause of the unusual exchange properties observed for UMON, including selectivity to water and reversible exchange at low temperature (37 degrees C). Similar properties have not been reported for other inorganic or hybrid compounds and indicate the potential of MONs as advanced materials. PMID- 23642139 TI - Study of whole genome linkage disequilibrium in Nellore cattle. AB - BACKGROUND: Knowledge of the linkage disequilibrium (LD) between markers is important to establish the number of markers necessary for association studies and genomic selection. The objective of this study was to evaluate the extent of LD in Nellore cattle using a high density SNP panel and 795 genotyped steers. RESULTS: After data editing, 446,986 SNPs were used for the estimation of LD, comprising 2508.4 Mb of the genome. The mean distance between adjacent markers was 4.90 +/- 2.89 kb. The minor allele frequency (MAF) was less than 0.20 in a considerable proportion of SNPs. The overall mean LD between marker pairs measured by r(2) and |D'| was 0.17 and 0.52, respectively. The LD (r(2)) decreased with increasing physical distance between markers from 0.34 (1 kb) to 0.11 (100 kb). In contrast to this clear decrease of LD measured by r(2), the changes in |D'| indicated a less pronounced decline of LD. Chromosomes BTA1, BTA27, BTA28 and BTA29 showed lower levels of LD at any distance between markers. Except for these four chromosomes, the level of LD (r(2)) was higher than 0.20 for markers separated by less than 20 kb. At distances < 3 kb, the level of LD was higher than 0.30. The LD (r(2)) between markers was higher when the MAF threshold was high (0.15), especially when the distance between markers was short. CONCLUSIONS: The level of LD estimated for markers separated by less than 30 kb indicates that the High Density Bovine SNP BeadChip will likely be a suitable tool for prediction of genomic breeding values in Nellore cattle. PMID- 23642140 TI - Non invasive evaluation of cardiomechanics in patients undergoing MitrClip procedure. AB - BACKGROUND: In the last recent years a new percutaneous procedure, the MitraClip, has been validated for the treatment of mitral regurgitation. MitraClip procedure is a promising alternative for patients unsuitable for surgery as it reduces the risk of death related to surgery ensuring a similar result. Few data are present in literature about the variation of hemodynamic parameters and ventricular coupling after Mitraclip implantation. METHODS: Hemodynamic data of 18 patients enrolled for MitraClip procedure were retrospectively reviewed and analyzed. Echocardiographic measurements were obtained the day before the procedure (T0) and 21 +/- 3 days after the procedure (T1), including evaluation of Ejection Fraction, mitral valve regurgitation severity and mechanism, forward Stroke Volume, left atrial volume, estimated systolic pulmonary pressure, non invasive echocardiographic estimation of single beat ventricular elastance (Es(sb)), arterial elastance (Ea) measured as systolic pressure * 0.9/ Stroke Volume, ventricular arterial coupling (Ea/Es(sb) ratio). Data were expressed as median and interquartile range. Measures obtained before and after the procedure were compared using Wilcoxon non parametric test for paired samples. RESULTS: Mitraclip procedure was effective in reducing regurgitation. We observed an amelioration of echocardiographic parameters with a reduction of estimated systolic pulmonary pressure (45 to 37,5 p = 0,0002) and left atrial volume (110 to 93 p = 0,0001). Despite a few cases decreasing in ejection fraction (37 to 35 p = 0,035), the maintained ventricular arterial coupling after the procedure (P = 0,67) was associated with an increasing in forward stroke volume (60,3 to 78 p = 0,05). CONCLUSION: MitraClip is effective in reducing mitral valve regurgitation and determines an amelioration of hemodynamic parameters with preservation of ventricular arterial coupling. PMID- 23642138 TI - Taxis assays measure directional movement of mosquitoes to olfactory cues. AB - BACKGROUND: Malaria control methods targeting indoor-biting mosquitoes have limited impact on vectors that feed and rest outdoors. Exploiting mosquito olfactory behaviour to reduce blood-feeding outdoors might be a sustainable approach to complement existing control strategies. Methodologies that can objectively quantify responses to odour under realistic field conditions and allow high-throughput screening of many compounds are required for development of effective odour-based control strategies. METHODS: The olfactory responses of laboratory-reared Anopheles gambiae in a semi-field tunnel and A. arabiensis females in an outdoor field setting to three stimuli, namely whole human odour, a synthetic blend of carboxylic acids plus carbon dioxide and CO(2) alone at four distances up to 100 metres were measured in two experiments using three-chambered taxis boxes that allow mosquito responses to natural or experimentally-introduced odour cues to be quantified. RESULTS: Taxis box assays could detect both activation of flight and directional mosquito movement. Significantly more (6 18%) A. arabiensis mosquitoes were attracted to natural human odour in the field up to 30 metres compared to controls, and blended synthetic human odours attracted 20% more A. gambiae in the semi-field tunnel up to 70 metres. Whereas CO(2) elicited no response in A. arabiensis in the open field, it was attractive to A. gambiae up to 50 metres (65% attraction compared to 36% in controls). CONCLUSIONS: We have developed a simple reproducible system to allow for the comparison of compounds that are active over medium- to long-ranges in semi-field or full-field environments. Knowing the natural range of attraction of anopheline mosquitoes to potential blood sources has substantial implications for the design of malaria control strategies, and adds to the understanding of olfactory behaviour in mosquitoes. This experimental strategy could also be extended from malaria vectors to other motile arthropods of medical, veterinary and agricultural significance. PMID- 23642142 TI - Interaction between platinum complexes and the C-terminal motif of human copper transporter 1. AB - Human copper transporter 1 (hCTR1) facilitates the cellular uptake of cisplatin, and the extracellular N-terminal domain has been proven to coordinate to platinum drugs. It has been reported that the intracellular C-terminal motif is crucial for the function of hCTR1 in cisplatin influx. In this work, we conduct reactions of the intracellular motif with platinum drugs. The octapeptide from the C terminal domain of hCTR1 is used, and the reactions are investigated using ultraviolet, high-performance liquid chromatography, electrospray ionization mass spectrometry, and nuclear magnetic resonance spectroscopy. Results show that the C8 peptide is highly reactive to cisplatin and oxaliplatin, and the -HCH sequence is the most favorable binding site of platinum agents. Cisplatin first binds to the cysteine residues in the reaction with the C8 peptide. The ammine ligand, even trans to a thiol ligand, can remain coordinated in platination adducts for a >12 h reaction. Intramolecular platinum migration was observed in the C8 peptide, and the ammine ligands remain coordinated to platinum during this process. This result indicates that hCTR1 can transfer cisplatin in the active form through a trans chelation process. These findings provide insight into the mechanism of the C-terminus of hCTR1 in the transfer of platinum drugs from the trimeric pore of hCTR1 to the cytoplasm. PMID- 23642141 TI - Structural and functional characterization of ScsC, a periplasmic thioredoxin like protein from Salmonella enterica serovar Typhimurium. AB - AIMS: The prototypical protein disulfide bond (Dsb) formation and protein refolding pathways in the bacterial periplasm involving Dsb proteins have been most comprehensively defined in Escherichia coli. However, genomic analysis has revealed several distinct Dsb-like systems in bacteria, including the pathogen Salmonella enterica serovar Typhimurium. This includes the scsABCD locus, which encodes a system that has been shown via genetic analysis to confer copper tolerance, but whose biochemical properties at the protein level are not defined. The aim of this study was to provide functional insights into the soluble ScsC protein through structural, biochemical, and genetic analyses. RESULTS: Here we describe the structural and biochemical characterization of ScsC, the soluble DsbA-like component of this system. Our crystal structure of ScsC reveals a similar overall fold to DsbA, although the topology of beta-sheets and alpha helices in the thioredoxin domains differ. The midpoint reduction potential of the CXXC active site in ScsC was determined to be -132 mV versus normal hydrogen electrode. The reactive site cysteine has a low pKa, typical of the nucleophilic cysteines found in DsbA-like proteins. Deletion of scsC from S. Typhimurium elicits sensitivity to copper (II) ions, suggesting a potential involvement for ScsC in disulfide folding under conditions of copper stress. INNOVATION AND CONCLUSION: ScsC is a novel disulfide oxidoreductase involved in protection against copper ion toxicity. PMID- 23642143 TI - Bone marrow T cells from the femur are similar to iliac crest derived cells in old age and represent a useful tool for studying the aged immune system. AB - BACKGROUND: CD4+ and CD8+ T cells reside in the human bone marrow (BM) and show a heightened activation state. However, only small sample sizes are available from sources such as the iliac crest. Larger samples can be obtained from the femur in the course of hip replacement surgery. It was therefore the goal of the present study to compare the phenotype and function of BM T cells from different sources from elderly persons and to investigate how femur derived bone marrow T cells can serve as a tool to gain a better understanding of the role of adaptive immune cells in the BM in old age. RESULTS: Bone marrow mononuclear cells (BMMC) were isolated from either the iliac crest or the femur shaft. As expected the yield of mononuclear cells was higher from femur than from iliac crest samples. There were no phenotypic differences between BMMC from the two sources. Compared to PBMC, both BM sample types contained fewer naive and more antigen experienced CD4+ as well as CD8+ T cells, which, in contrast to peripheral cells, expressed CD69. Cytokine production was also similar in T cells from both BM types. Larger sample sizes allowed the generation of T cell lines from femur derived bone marrow using non-specific as well as specific stimulation. The phenotype of T cell lines generated by stimulation with OKT-3 and IL-2 for two weeks was very similar to the one of ex vivo BM derived T cells. Such lines can be used for studies on the interaction of different types of BM cells as shown by co-culture experiments with BM derived stromal cells. Using CMVNLV specific T cell lines we additionally demonstrated that BM samples from the femur are suitable for the generation of antigen specific T cell lines, which can be used in studies on the clonal composition of antigen specific BM T cells. CONCLUSION: In conclusion, our results demonstrate that BMMC from the femur shaft are a useful tool for studies on the role of T cells in the BM in old age. PMID- 23642144 TI - Structural and bioactive studies of terpenes and cyclopeptides from the Genus Rubia. AB - Genus Rubia fell into about 70 species distributed widely around the world, a total of 36 species and 2 varieties were reported from China. The extracts and phytochemicals of Rubia plants had drawn considerable attention due to their potent bioactivities. As the two major ingredients from these plants, pentacyclic triterpenes and cyclopeptides were becoming a hot topic over the past twenty years for their remarkable anticancer, antioxidant and other effects. This paper compiled all 65 terpenes and 44 cyclopeptides with their distributions, physiological activities and melting points (or optical rotations) as reported in 85 references; besides, structure-activity relationships of these derivatives were briefly discussed. The information involved in this paper was expected to be meaningful for the further studies of the Genus Rubia. PMID- 23642145 TI - Implementation and effectiveness of 'care navigation', coordinated management for people with complex chronic illness: rationale and methods of a randomised controlled trial. AB - BACKGROUND: Chronic illness is a significant driver of the global burden of disease and associated health care costs. People living with severe chronic illness are heavy users of acute hospital services; better coordination of their care could potentially improve health outcomes while reducing hospital use. The Care Navigation trial will evaluate an in-hospital coordinated care intervention on health service use and quality of life in chronically ill patients. METHODS/DESIGN: A randomised controlled trial in 500 chronically ill patients presenting to the emergency department of a hospital in Western Sydney, Australia. Participants have three or more hospital admissions within a previous 12 month period and either aged >=70 years; or aged >=45 years and of Aboriginal or Torres Strait Islander descent; or aged >= 16 with a diagnosis of a respiratory or cardiology related illness. Patients are randomised to either the coordinated care program (Care Navigation), or to usual care. The Care Navigation program consists of dedicated nurses who conduct patient risk assessments, oversee patient nursing while in hospital, and guide development of a care plan for the management of chronic illness after being discharged from hospital. These nurses also book community appointments and liaise with general practitioners. The main outcome variables are the number of emergency department re presentations and hospital readmissions, and quality of life during a 24 month follow-up. Secondary outcomes are length of hospital stay, mortality, time to first hospital re-admission, time to first emergency department re-presentation, patient satisfaction, adherence to prescribed medications, amount and type of in hospital referrals made for consultations and diagnostic testing, and the number and type of community health referrals. A process evaluation and economic analysis will be conducted alongside the randomised trial. DISCUSSION: A trial of in-hospital care coordination may support recent evidence that engaging primary health services in care plans linked to multidisciplinary team support improves patient outcomes and reduces costs to the health system. This will inform local, national and international health policy. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12609000554268. PMID- 23642148 TI - Ab initio QM/MM calculations show an intersystem crossing in the hydrogen abstraction step in dealkylation catalyzed by AlkB. AB - AlkB is a bacterial enzyme that catalyzes the dealkylation of alkylated DNA bases. The rate-limiting step is known to be the abstraction of an H atom from the alkyl group on the damaged base by a Fe(IV)-oxo species in the active site. We have used hybrid ab initio quantum mechanical/molecular mechanical methods to study this step in AlkB. Instead of forming an Fe(III)-oxyl radical from Fe(IV) oxo near the C-H activation transition state, the reactant is found to be an Fe(III)-oxyl with an intermediate-spin Fe (S = 3/2) ferromagnetically coupled to the oxyl radical, which we explore in detail using molecular orbital and quantum topological analyses. The minimum energy pathway remains on the quintet surface, but there is a transition between (IS)Fe(III)-oxyl and the state with a high-spin Fe (S = 5/2) antiferromagnetically coupled to the oxyl radical. These findings provide clarity for the evolution of the well-known pi and sigma channels on the quintet surface in the enzyme environment. Additionally, an energy decomposition analysis reveals nine catalytically important residues for the C-H activation step, some of which are conserved in two human homologues. These conserved residues are proposed as targets for experimental mutagenesis studies. PMID- 23642147 TI - Impact on caesarean section rates following injections of sterile water (ICARIS): a multicentre randomised controlled trial. AB - BACKGROUND: Sterile water injections have been used as an effective intervention for the management of back pain during labour. The objective of the current research is to determine if sterile water injections, as an intervention for back pain in labour, will reduce the intrapartum caesarean section rate. METHODS/DESIGN: DESIGN: A double blind randomised placebo controlled trialSetting: Maternity hospitals in AustraliaParticipants: 1866 women in labour, >=18 years of age who have a singleton pregnancy with a fetus in a cephalic presentation at term (between 37 + 0 and 41 + 6 weeks gestation), who assess their back pain as equal to or greater than seven on a visual analogue scale when requesting analgesia and able to provide informed consent. INTERVENTION: Participants will be randomised to receive either 0.1 to 0.3 millilitres of sterile water or a normal saline placebo via four intradermal injections into four anatomical points surrounding the Michaelis' rhomboid over the sacral area. Two injections will be administered over the posterior superior iliac spine (PSIS) and the remaining two at two centimetres posterior, and one centimetre medial to the PSIS respectively. MAIN OUTCOME MEASURE: Proportion of women who have a caesarean section in labour.Randomisation: Permuted blocks stratified by research site.Blinding (masking):Double-blind trial in which participants, clinicians and research staff blinded to group assignment. FUNDING: Funded by the National Health and Medical Research CouncilTrial registration:Australian New Zealand Clinical Trials Registry (No ACTRN12611000221954). DISCUSSION: Sterile water injections, which may have a positive effect on reducing the CS rate, have been shown to be a safe and simple analgesic suitable for most maternity settings. A procedure that could reduce intervention rates without adversely affecting safety for mother and baby would benefit Australian families and taxpayers and would reduce requirements for maternal operating theatre time. Results will have external validity, as the technique may be easily applied to maternity populations outside Australia. In summary, the results of this trial will contribute High level evidence on the impact of SWI on intrapartum CS rates and provide evidence of the analgesic effect of SWI on back pain. PMID- 23642149 TI - Pd-catalyzed one-pot synthesis of polysubstituted acrylamidines from isocyanides, diazo compounds, and imines. AB - A novel and efficient Pd-catalyzed one-pot reaction of ethyl diazoacetate, isocyanides, and imines for the synthesis of acrylamidines was developed. The multicomponent reaction may have occurred through an unpredicted ring-opening process of the ketenimine-imine [2 + 2] intermediate to form the acrylamidine products. PMID- 23642150 TI - Aggregation behavior of 1-dodecyl-3-methylimidazolium bromide in aqueous solution: effect of ionic liquids with aromatic anions. AB - The effects of ionic liquids (ILs), 1-butyl-3-methylimidazolium methylsulfonate (bmimMsa), 1-butyl-3-methylimidazolium benzenesulfonate (bmimBsa), and 1-butyl-3 methylimidazolium 2-naphthalenesulfonate (bmimNsa), on the aggregation behavior of 1-dodecyl-3-methylimidazolium bromide (C12mimBr) in aqueous solution were investigated by surface tension, dynamic light scattering measurements, and (1)H NMR spectroscopy. The ability to promote the surfactant aggregation is in the order bmimNsa > bmimBsa > bmimMsa. Nevertheless, only bmimNsa distinctly reduces both the CMC value and the surface tension at CMC. Due to the penetration of C10H7SO3(-)anions into the surfactant aggregate, bmimNsa is found to induce a phase transition from micelles to vesicles, whereas the other ILs only slightly increase the sizes of micelles. The combined effect of intermolecular interactions, such as hydrophobic effect, electrostatic attractions, and pi-pi stacking interactions, is supposed to be responsible for this structural transformation, in which pi-pi stacking plays an important role. PMID- 23642151 TI - Safety issues around misuse of antiepileptics. AB - INTRODUCTION: Drug misuse is a deliberate or accidental (by omission) nonadherence to medical recommendations, which may range from inappropriate use (missed, increased, or lowered doses or even complete discontinuation of therapy) to compulsive overdosing. Currently, this phenomenon affects as many as 20 - 80% of epileptic patients. AREAS COVERED: Long-standing research has enabled the identification and understanding of factors behind the phenomenon of nonadherence to medical recommendations. An inappropriate use of antiepileptic drugs usually has serious health implications for both children and adults. These involve increased frequency of seizures in patients who lower their doses or discontinue therapy, which may often lead to pathologies. On the other hand, patients who increase or take extra doses expose themselves to toxic effects of antiepileptic drugs. In both cases, there is an increased need for hospitalization, which further implies extra healthcare costs. The most misused antiepileptic drug is gabapentin (53%), whereas the least misused are lamotrigine, levetiracetam, and phenytoin (all drugs at 32%). EXPERT OPINION: The prevalence of misuse of antiepileptic drugs among epileptic patients is comparable to that observed in other chronically ill individuals. Preventive strategies have to be based on the reasons leading to nonadherence. PMID- 23642152 TI - Early time excited-state structural evolution of pyranine in methanol revealed by femtosecond stimulated Raman spectroscopy. AB - To understand chemical reactivity of molecules in condensed phase in real time, a structural dynamics technique capable of monitoring molecular conformational motions on their intrinsic time scales, typically on femtoseconds to picoseconds, is needed. We have studied a strong photoacid pyranine (8-hydroxypyrene-1,3,6 trisulfonic acid, HPTS, pK(a)* ~ 0) in pure methanol and observed that excited state proton transfer (ESPT) is absent, in sharp contrast with our previous work on HPTS in aqueous solutions wherein ESPT prevails following photoexcitation. Two transient vibrational marker bands at ~1477 (1454) and 1532 (1528) cm(-1) appear in CH3OH (CD3OD), respectively, rising within the instrument response time of ~140 fs and decaying with 390-470 (490-1400) fs and ~200 ps time constants in CH3OH (CD3OD). We attribute the mode onset to small-scale coherent proton motion along the pre-existing H-bonding chain between HPTS and methanol, and the two decay stages to the low-frequency skeletal motion-modulated Franck-Condon relaxation within ~1 ps and subsequent rotational diffusion of H-bonding partners in solution before fluorescence. The early time kinetic isotope effect (KIE) of ~3 upon methanol deuteration argues active proton motions particularly within the first few picoseconds when coherent skeletal motions are underdamped. Pronounced quantum beats are observed for high-frequency modes consisting of strong phenolic COH rocking (1532 cm(-1)) or H-out-of-plane wagging motions (952 cm(-1)) due to anharmonic coupling to coherent low-frequency modes impulsively excited at ca. 96, 120, and 168 cm(-1). The vivid illustration of atomic motions of HPTS in varying H-bonding geometry with neighboring methanol molecules unravels the multidimensional energy relaxation pathways immediately following photoexcitation, and provides compelling evidence that, in lieu of ESPT, the photoacidity of HPTS promptly activates characteristic low-frequency skeletal motions to search phase space mainly concerning the phenolic end and to efficiently dissipate vibrational energy via skeletal deformation and proton shuttling motions within the intermediate, relatively confined excited-state HPTS methanol complex on a solvent-dependent dynamic potential energy surface. PMID- 23642153 TI - Using VIPT-jump to distinguish between different folding mechanisms: application to BBL and a Trpzip. AB - Protein folding involves a large number of sequential molecular steps or conformational substates. Thus, experimental characterization of the underlying folding energy landscape for any given protein is difficult. Herein, we present a new method that can be used to determine the major characteristics of the folding energy landscape in question, e.g., to distinguish between activated and barrierless downhill folding scenarios. This method is based on the idea that the conformational relaxation kinetics of different folding mechanisms at a given final condition will show different dependences on the initial condition. We show, using both simulation and experiment, that it is possible to differentiate between disparate kinetic folding models by comparing temperature jump (T-jump) relaxation traces obtained with a fixed final temperature and varied initial temperatures, which effectively varies the initial potential (VIP) of the system of interest. We apply this method (hereafter refer to as VIPT-jump) to two model systems, tryptophan zipper (Trpzip)-2c and BBL, and our results show that BBL exhibits characteristics of barrierless downhill folding, whereas Trpzip-2c folding encounters a free energy barrier. In addition, using the T-jump data of BBL we are able to provide, via Langevin dynamics simulations, a realistic estimate of its conformational diffusion coefficient. PMID- 23642154 TI - Development of tumor-targeted near infrared probes for fluorescence guided surgery. AB - Complete surgical resection of malignant disease is the only reliable method to cure cancer. Unfortunately, quantitative tumor resection is often limited by a surgeon's ability to locate all malignant disease and distinguish it from healthy tissue. Fluorescence-guided surgery has emerged as a tool to aid surgeons in the identification and removal of malignant lesions. While nontargeted fluorescent dyes have been shown to passively accumulate in some tumors, the resulting tumor to-background ratios are often poor, and the boundaries between malignant and healthy tissues can be difficult to define. To circumvent these problems, our laboratory has developed high affinity tumor targeting ligands that bind to receptors that are overexpressed on cancer cells and deliver attached molecules selectively into these cells. In this study, we explore the use of two tumor specific targeting ligands (i.e., folic acid that targets the folate receptor (FR) and DUPA that targets prostate specific membrane antigen (PSMA)) to deliver near-infrared (NIR) fluorescent dyes specifically to FR and PSMA expressing cancers, thereby rendering only the malignant cells highly fluorescent. We report here that all FR- and PSMA-targeted NIR probes examined bind cultured cancer cells in the low nanomolar range. Moreover, upon intravenous injection into tumor bearing mice with metastatic disease, these same ligand-NIR dye conjugates render receptor-expressing tumor tissues fluorescent, enabling their facile resection with minimal contamination from healthy tissues. PMID- 23642155 TI - Trend and geographic analysis for traumatic brain injury mortality and cost based on MarketScan database. AB - The objective of the current research was to examine the current epidemiology of traumatic brain injury (TBI); to determine the effects of geographic region, co morbidities, year of injury, injury severity, and demographics on hospital costs, length of stay (LOS), and mortality. All subjects were drawn from the Thomason Reuters MarketScan((r)) database. Statistical methods used included descriptive analysis, bivariate analysis, logistic regression, and the Geographic Information System (GIS) software, ArcMap. We studied 76,313 patients with TBI from 2004 to 2009 (52,721 with commercial insurance and 23,592 with Medicare) from the MarketScan database. As age increased, mortality rate and median LOS increased. The median hospital costs for adults were the highest ($13,000 for ages 18-64) compared with children ($8000 for age 0-14) and elderly persons ($9000 for age >= 65). The mortality rate for the elderly population has decreased slightly (11.1% in 2004 to 9.9% in 2009 for men, and 7.0% to 6.9% for women); however, their hospital costs have increased significantly ($6899 in 2004 to $11,567 in 2009 for men; $6784 to $9782 for women). Concerning the impact of geography, the western United States (e.g., Washington and California) had lower mortality rates and higher median costs while the southeast United States had the highest mortality and mixed median costs. Both overall mortality and median LOS have remained relatively stable over the years. Hospital cost, however, has increased for the elderly population even after accounting for the inflation. There is significant geographic variation for both mortality and hospital costs. PMID- 23642156 TI - Mortality following unemployment in Canada, 1991-2001. AB - BACKGROUND: This study describes the association between unemployment and cause specific mortality for a cohort of working-age Canadians. METHODS: We conducted a cohort study over an 11-year period among a broadly representative 15% sample of the non-institutionalized population of Canada aged 30-69 at cohort inception in 1991 (888,000 men and 711,600 women who were occupationally active). We used cox proportional hazard models, for six cause of death categories, two consecutive multi-year periods and four age groups, to estimate mortality hazard ratios comparing unemployed to employed men and women. RESULTS: For persons unemployed at cohort inception, the age-adjusted hazard ratio for all-cause mortality was 1.37 for men (95% confidence interval (CI): 1.32-1.41) and 1.27 for women (95% CI: 1.20-1.35). The age-adjusted hazard ratio for unemployed men and women was elevated for all six causes of death: malignant neoplasms, circulatory diseases, respiratory diseases, alcohol-related diseases, accidents and violence, and all other causes. For unemployed men and women, hazard ratios for all-cause mortality were equivalently elevated in 1991-1996 and 1997-2001. For both men and women, the mortality hazard ratio associated with unemployment attenuated with age. CONCLUSIONS: Consistent with results reported from other long-duration cohort studies, unemployed men and women in this cohort had an elevated risk of mortality for accidents and violence, as well as for chronic diseases. The persistence of elevated mortality risks over two consecutive multi-year periods suggests that exposure to unemployment in 1991 may have marked persons at risk of cumulative socioeconomic hardship. PMID- 23642157 TI - A functional VipA-VipB interaction is required for the type VI secretion system activity of Vibrio cholerae O1 strain A1552. AB - BACKGROUND: Many Gram-negative bacteria rely on a type VI secretion system (T6SS) to infect eukaryotic cells or to compete against other microbes. Common to these systems is the presence of two conserved proteins, in Vibrio cholerae denoted VipA and VipB, which have been shown to interact in many clinically relevant pathogens. In this study, mutagenesis of a defined region within the VipA protein was used to identify residues important for VipB binding in V. cholerae O1 strain A1552. RESULTS: A dramatically diminished interaction was shown to correlate with a decrease in VipB stability and a loss of hemolysin co-regulated protein (Hcp) secretion and rendered the bacterium unable to compete with Escherichia coli in a competition assay. CONCLUSIONS: This confirms the biological relevance of the VipA-VipB interaction, which is essential for the T6SS activity of many important human pathogens. PMID- 23642159 TI - Unique coordination-based heterometallic approach for the stoichiometric inclusion of high-valent metal ions in a porous metal-organic framework. AB - A heterometallic metal-organic framework incorporating Zn(2+) and Ti(4+) is successfully synthesized. The unique coordination mode of each metal ion to 2 oxido-1,4-benzenedicarboxylate leads to Zn6Ti2 building blocks, which extend to form a double-walled primitive cubic net. This material possesses a permanent porosity and long-term stability. PMID- 23642160 TI - Synthesis of thiophene-based TAK-779 analogues by C-H arylation. AB - A rapid synthesis of thiophene-based TAK-779 analogues 1 is reported using a late stage diversification strategy. At the end of the synthesis, the key building block 2, which was prepared in six steps from thiophene, was arylated regioselectively at the alpha-position directly with iodoarenes. Since 2 offers several reactive positions, various established catalyst systems were tested. It was found that Crabtree catalyst (an Ir catalyst) converted efficiently and selectively the thiophene system 2 into 2-aryl-substituted compounds 9. The direct C-H arylation of 2 with electron-rich iodoarenes led to high yields, whereas electron-deficient iodoarenes required longer reaction times for complete conversion. A small set of diverse amides 1 was synthesized by hydrolysis of 9 and subsequent HATU coupling with primary amines 4. PMID- 23642158 TI - Updating the mitochondrial free radical theory of aging: an integrated view, key aspects, and confounding concepts. AB - An updated version of the mitochondrial free radical theory of aging (MFRTA) and longevity is reviewed. Key aspects of the theory are emphasized. Another main focus concerns common misconceptions that can mislead investigators from other specialties, even to wrongly discard the theory. Those different issues include (i) the main reactive oxygen species (ROS)-generating site in the respiratory chain in relation to aging and longevity: complex I; (ii) the close vicinity or even contact between that site and the mitochondrial DNA, in relation to the lack of local efficacy of antioxidants and to sub-cellular compartmentation; (iii) the relationship between mitochondrial ROS production and oxygen consumption; (iv) recent criticisms on the MFRTA; (v) the widespread assumption that ROS are simple "by-products" of the mitochondrial respiratory chain; (vi) the unnecessary postulation of "vicious cycle" hypotheses of mitochondrial ROS generation which are not central to the free radical theory of aging; and (vii) the role of DNA repair concerning endogenous versus exogenous damage. After considering the large body of data already available, two general characteristics responsible for the high maintenance degree of long-lived animals emerge: (i) a low generation rate of endogenous damage: and (ii) the possession of tissue macromolecules that are highly resistant to oxidative modification. PMID- 23642161 TI - Redescription of Cercopithifilaria bainae Almeida & Vicente, 1984 (Spirurida, Onchocercidae) from a dog in Sardinia, Italy. AB - BACKGROUND: Three species of the genus Cercopithifilaria have been morphologically and molecularly characterized in dog populations in southern Europe: Cercopithifilaria grassii (Noe, 1907), Cercopithifilaria sp. sensu Otranto et al., 2011 (reported as Cercopithifilaria sp. I), and Cercopithifilaria sp. II sensu Otranto et al., 2012. The adults of Cercopithifilaria sp. I have remained unknown until the present study. METHODS: The material originated from a dog from Sardinia (Italy) diagnosed with dermal microfilariae of Cercopithifilaria sp. I. The holotype and three paratypes of Cercopithifilaria bainae Almeida & Vicente, 1984, described from dogs in Brazil, were studied as comparative material. A cox1 (~689 bp) and 12S (~330 bp) gene fragments were amplified and phylogenetic analysis carried out. RESULTS: The highest numbers of adult nematodes (82%) were collected in the sediment of the subcutaneous tissues of the trunk (n = 37) and forelimbs (n = 36). The morphology of the adult nematodes and microfilariae collected from the dog in Sardinia corresponded to those of C. bainae. All cox1 and 12S gene sequences showed a high homology (99 100%) with sequences from microfilariae of Cercopithifilaria sp. I CONCLUSIONS: The morphological and molecular identity of the microfilariae of C. bainae overlap those described previously as Cercopithifilaria sp. sensu Otranto et al., 2011 (=Cercopithifilaria sp. I). Therefore, the present study reports the occurrence of C. bainae in Europe, for the first time after its description and the single record in Brazil. C. bainae appears to be highly diffused in dog populations in southern Europe. The phylogenetic analyses based on cox1 and 12S do not reveal the three species of Cercopithifilaria parasitizing dogs as a monophyletic group, which suggests that they have derived independently by host switching. PMID- 23642162 TI - Comparing children's self-report instruments for health-related quality of life using the International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY). AB - Children with chronic conditions often experience a long treatment which can be complex and negatively impacts the child's well-being. In planning treatment and interventions for children with chronic conditions, it is important to measure health-related quality of life (HrQoL). HrQoL instruments are considered to be a patient-reported outcome measure (PROM) and should be used in routine practice. PURPOSE: The aim of this study was to compare the content dimensions of HrQoL instruments for children's self-reports using the framework of ICF-CY. METHOD: The sample consist of six instruments for health-related quality of life for children 5 to 18 years of age, which was used in the Swedish national quality registries for children and adolescents with chronic conditions. The following instruments were included: CHQ-CF, DCGM-37, EQ-5D-Y, KIDSCREEN-52, Kid-KINDL and PedsQL 4.0. The framework of the ICF-CY was used as the basis for the comparison. RESULTS: There were 290 meaningful concepts identified and linked to 88 categories in the classification ICF-CY with 29 categories of the component body functions, 48 categories of the component activities and participation and 11 categories of the component environmental factors. No concept were linked to the component body structures. The comparison revealed that the items in the HrQoL instruments corresponded primarily with the domains of activities and less with environmental factors. CONCLUSIONS: In conclusion, the results confirm that ICF CY provide a good framework for content comparisons that evaluate similarities and differences to ICF-CY categories. The results of this study revealed the need for greater consensus of content across different HrQoL instruments. To obtain a detailed description of children's HrQoL, DCGM-37 and KIDSCREEN-52 may be appropriate instruments to use that can increase the understanding of young patients' needs. PMID- 23642163 TI - Loss of gastric interstitial cells of Cajal in patients with hereditary transthyretin amyloidosis. AB - BACKGROUND: Hereditary transthyretin (TTR) amyloidosis is a systemic neuropathic disorder caused by TTR gene mutations. Gastrointestinal complications are common and the underlying mechanisms remain unclear. The interstitial cells of Cajal (ICC) function as pacemaker cells in the gastrointestinal tract and are important for gastrointestinal motility. The aim of this study was to investigate the densities of gastric ICC and nerves in patients with TTR amyloidosis compared to non-amyloidosis controls. METHODS: Antral wall autopsy specimens from 11 Japanese ATTR V30M patients and 10 controls were analyzed with immunohistochemistry and computerized analysis. Antibodies to c-Kit and TMEM16A were used to assess ICC and an antibody to PGP 9.5 was used to assess nervous tissue. The study was approved by a Japanese ethical committee. RESULTS: The densities of c-Kit immunoreactive (IR) ICC were significantly lower in the circular and longitudinal muscle layers of patients compared to controls (p = 0.004 for both). Equivalent results were found for TMEM16A-IR ICC. There were no significant differences in PGP 9.5-IR cells in the circular or longitudinal muscle layers between patients and controls (p = 0.173 and 0.099, respectively). CONCLUSIONS: A loss of gastrointestinal ICC may be an important factor for the digestive disturbances in hereditary TTR amyloidosis. PMID- 23642164 TI - The effect of hydration state and energy balance on innate immunity of a desert reptile. AB - INTRODUCTION: Immune function is a vital physiological process that is often suppressed during times of resource scarcity due to investments in other physiological systems. While energy is the typical currency that has been examined in such trade-offs, limitations of other resources may similarly lead to trade-offs that affect immune function. Specifically, water is a critical resource with profound implications for organismal ecology, yet its availability can fluctuate at local, regional, and even global levels. Despite this, the effect of osmotic state on immune function has received little attention. RESULTS: Using agglutination and lysis assays as measures of an organism's plasma concentration of natural antibodies and capacity for foreign cell destruction, respectively, we tested the independent effects of osmotic state, digestive state, and energy balance on innate immune function in free-ranging and laboratory populations of the Gila monster, Heloderma suspectum. This desert dwelling lizard experiences dehydration and energy resource fluctuations on a seasonal basis. Dehydration was expected to decrease innate immune function, yet we found that dehydration increased lysis and agglutination abilities in both lab and field studies, a relationship that was not simply an effect of an increased concentration of immune molecules. Laboratory-based differences in digestive state were not associated with lysis or agglutination metrics, although in our field population, a loss of fat stores was correlated with an increase in lysis. CONCLUSIONS: Depending on the life history of an organism, osmotic state may have a greater influence on immune function than energy availability. Thus, consideration of osmotic state as a factor influencing immune function will likely improve our understanding of ecoimmunology and the disease dynamics of a wide range of species. PMID- 23642167 TI - The cysteine 34 residue of A1M/alpha1-microglobulin is essential for protection of irradiated cell cultures and reduction of carbonyl groups. AB - alpha1-microglobulin (A1M) is a 26 kDa plasma and a tissue protein belonging to the lipocalin family. The reductase and free radical scavenger A1M has been shown to protect cells and extracellular matrix against oxidative and irradiation induced damage. The reductase activity was previously shown to depend upon an unpaired cysteinyl side-chain, C34, and three lysyl side-chains, K92, 118, and 130, located around the open end of the lipocalin pocket. The aim of this work was to investigate whether the cell and matrix protection by A1M is a result of its reductase activity by using A1M-variants with site-directed mutations of the C34, K92, K118, and K130 positions. The results show that the C34 side-chain is an absolute requirement for protection of HepG2 cell cultures against alpha particle irradiation-induced cell death, upregulation of stress response and cell cycle regulation genes. Mutation of C34 also resulted in loss of the reduction capacity toward heme- and hydrogen peroxide-oxidized collagen, and the radical species 2,2'-azino-bis (3-ethyl-benzo-thiazoline-6-sulphonic acid) (ABTS). Furthermore, mutation of C34 significantly suppressed the cell-uptake of A1M. The K92, K118, and K130 side-chains were of minor importance in cell protection and reduction of oxidized collagen but strongly influenced the reduction of the ABTS radical. It is concluded that antioxidative protection of cells and collagen by A1M is totally dependent on its C34 amino acid residue. A model of the cell protection mechanism of A1M should be based on the redox activity of the free thiolyl group of the C34 side-chain and a regulatory role of the K92, K118, and K130 residues. PMID- 23642168 TI - Adsorption of the compounds encountered in monosaccharide dehydration in zeolite beta. AB - A comprehensive study of the adsorption of the compounds involved in the reaction of dehydration of fructose to 5-hydroxymethyl furfural (HMF) on the zeolite H-BEA with SiO2/Al2O3 = 18 has been carried out. Furthermore, a method for the estimation of the real adsorption loading from the experimentally measured excess adsorption is developed and applied to calculate the adsorption isotherms both in the case of single-solute and multisolute mixtures. It was found that zeolite H BEA adsorbs HMF and levulinic acid from water mixtures to greater extent than sugars and formic acid, which prefer to partition in the aqueous phase. HMF and levulinic acid adsorption isotherms could be fitted in a Redlich-Peterson isotherm model, while the adsorption of formic acid is better fitted using the Freundlich model and sugars via the Henry model. Adsorption loadings decreased with increasing temperature (0, 25, and 40 degrees C), which is characteristic of an exothermic process. From the temperature dependence of the isotherms, the limiting heat of adsorption at zero coverage was determined using van't Hoff equation. Given the importance and the complexity of multicomponent systems, several experiments of adsorption of multisolute solutions have been carried out. In most of the cases, the ideal adsorbed solution theory (IAST) has been proven to satisfactorily predict adsorption from multisolute mixtures using as input the single-solute isotherms. PMID- 23642165 TI - High CRP values predict poor survival in patients with penile cancer. AB - BACKGROUND: High levels of circulating C-reactive protein (CRP) have recently been linked to poor clinical outcome in various malignancies. The aim of this study was to evaluate the prognostic significance of the preoperative serum CRP level in patients with squamous cell carcinoma (SCC) of the penis. METHODS: This retrospective analysis included 79 penile cancer patients with information about their serum CRP value prior to surgery who underwent either radical or partial penectomy at two German high-volume centers (Ulm University Medical Center and Hannover Medical School) between 1990 and 2010. They had a median (mean) follow up of 23 (32) months. RESULTS: A significantly elevated CRP level (>15 vs. <= 15 mg/l) was found more often in patients with an advanced tumor stage (>=pT2) (38.9 vs. 11.6%, p=0.007) and in those with nodal disease at diagnosis (50.0 vs. 14.6%, p=0.007). However, high CRP levels were not associated with tumor differentiation (p=0.53). The Kaplan-Meier 5-year cancer-specific survival (CSS) rate was 38.9% for patients with preoperative CRP levels above 15 mg/l and 84.3% for those with lower levels (p=0.001). Applying multivariate analysis and focusing on the subgroup of patients without metastasis at the time of penile surgery, both advanced local tumor stage (>=pT2; HR 8.8, p=0.041) and an elevated CRP value (>15 mg/l; HR 3.3, p=0.043) were identified as independent predictors of poor clinical outcome in patients with penile cancer. CONCLUSIONS: A high preoperative serum CRP level was associated with poor survival in patients with penile cancer. If larger patient populations confirm its prognostic value, its routine use could enable better risk stratification and risk-adjusted follow-up of patients with SCC of the penis. PMID- 23642169 TI - Photosensitized generation of singlet oxygen from Re(I) complexes: a photophysical study using LIOAS and luminescence techniques. AB - Quantum yields and efficiencies of (1)O2 ((1)Deltag) production along with photophysical properties for a number of Re(I) complexes in acetonitrile solutions are reported. Two different classes of Re(I) complexes, L(S)-CO2 Re(CO)3(bpy) (L(S) = 2-pyrazine, 2-naphthalene, 9-anthracene, 1-pyrene, 2 anthraquinone) and XRe(CO)3L (X = CF3SO3, py; L = bpy, phen), were probed as photosensitizers for (1)O2 ((1)Deltag) production in air-saturated acetonitrile solutions. Depending on the nature of the Re(I) complex, the excited state responsible for the generation of (1)O2 ((1)Deltag) is either a metal-to-ligand charge transfer ((3)MLCT) or a ligand centered ((3)LC) state. With L(S)-CO2 Re(CO)3(bpy) complexes, (1)O2 ((1)Deltag) is produced by oxygen quenching of (3)LC states of anthracene and pyrene with high quantum yields (PhiDelta between 0.8 and 1.0), while the complexes bearing the ligands L(S) = 2-anthraquinone, 2 pyrazine, and 2-naphthalene did not yield (1)O2. XRe(CO)3L complexes generate (1)O2 ((1)Deltag) mainly by oxygen quenching of their (3)MLCT luminescence with an efficiency of (1)O2 ((1)Deltag) formation close to unity. Bimolecular rate constants for the quenching of the XRe(CO)3L complexes' emission by molecular oxygen range between 1 * 10(9) and 2 * 10(9) M(-1) s(-1), and they are all <= (1/9)kd, in good agreement with the predominance of the singlet channel in the mechanism of (1)O2 ((1)Deltag) generation using these Re(I) complexes as photosensitizers. All the experimental singlet oxygen efficiencies are consistent with calorimetric and luminescence data for the studied complexes. With L(S)-CO2 Re(CO)3(bpy) complexes, calorimetric experiments were utilized in the calculation of the quantum yields of triplet formation; namely phiT = 0.76 and 0.83 for the triplet states of anthracene and pyrene, respectively. PMID- 23642170 TI - Amide formation in one pot from carboxylic acids and amines via carboxyl and sulfinyl mixed anhydrides. AB - An efficient method has been developed for the preparation of yet unknown acyclic mixed anhydrides of carboxylic and sulfinic acids. Sterically hindered 2 methylbut-3-ene-2-sulfinyl carboxylates add primary and secondary amines preferentially onto the carbonyl moieties realizing a new method for the one-pot preparation of carboxamides. It uses 1:1 mixtures of carboxylic acids and amines without a base, requires no excess of reagents, and liberates only volatile coproducts. Protected di- and tripeptides have been prepared in solution without epimerization by application of this method. PMID- 23642171 TI - Optimization of transplastomic production of hemicellulases in tobacco: effects of expression cassette configuration and tobacco cultivar used as production platform on recombinant protein yields. AB - BACKGROUND: Chloroplast transformation in tobacco has been used extensively to produce recombinant proteins and enzymes. Chloroplast expression cassettes can be designed with different configurations of the cis-acting elements that govern foreign gene expression. With the aim to optimize production of recombinant hemicellulases in transplastomic tobacco, we developed a set of cassettes that incorporate elements known to facilitate protein expression in chloroplasts and examined expression and accumulation of a bacterial xylanase XynA. Biomass production is another important factor in achieving sustainable and high-volume production of cellulolytic enzymes. Therefore, we compared productivity of two tobacco cultivars - a low-alkaloid and a high-biomass - as transplastomic expression platforms. RESULTS: Four different cassettes expressing XynA produced various mutant phenotypes of the transplastomic plants, affected their growth rate and resulted in different accumulation levels of the XynA enzyme. The most productive cassette was identified and used further to express XynA and two additional fungal xylanases, Xyn10A and Xyn11B, in a high-biomass tobacco cultivar. The high biomass cultivar allowed for a 60% increase in XynA production per plant. Accumulation of the fungal enzymes reached more than 10-fold higher levels than the bacterial enzyme, constituting up to 6% of the total soluble protein in the leaf tissue. Use of a well-characterized translational enhancer with the selected expression cassette revealed inconsistent effects on accumulation of the recombinant xylanases. Additionally, differences in the enzymatic activity of crude plant extracts measured in leaves of different age suggest presence of a specific xylanase inhibitor in the green leaf tissue. CONCLUSION: Our results demonstrate the pivotal importance of the expression cassette design and appropriate tobacco cultivar for high-level transplastomic production of recombinant proteins. PMID- 23642172 TI - Cerebral perfusion changes in chronic subdural hematoma. PMID- 23642173 TI - Factors associated with evidence-based practice among registered nurses in Sweden: a national cross-sectional study. AB - BACKGROUND: Evidence-based practice (EBP) is emphasized to increase the quality of care and patient safety. EBP is often described as a process consisting of distinct activities including, formulating questions, searching for information, compiling the appraised information, implementing evidence, and evaluating the resulting practice. To increase registered nurses' (RNs') practice of EBP, variables associated with such activities need to be explored. The aim of the study was to examine individual and organizational factors associated with EBP activities among RNs 2 years post graduation. METHODS: A cross-sectional design based on a national sample of RNs was used. Data were collected in 2007 from a cohort of RNs, included in the Swedish Longitudinal Analyses of Nursing Education/Employment study. The sample consisted of 1256 RNs (response rate 76%). Of these 987 RNs worked in healthcare at the time of the data collection. Data was self-reported and collected through annual postal surveys. EBP activities were measured using six single items along with instruments measuring individual and work-related variables. Data were analyzed using logistic regression models. RESULTS: Associated factors were identified for all six EBP activities. Capability beliefs regarding EBP was a significant factor for all six activities (OR = 2.6-7.3). Working in the care of older people was associated with a high extent of practicing four activities (OR = 1.7-2.2). Supportive leadership and high collective efficacy were associated with practicing three activities (OR = 1.4-2.0). CONCLUSIONS: To be successful in enhancing EBP among newly graduated RNs, strategies need to incorporate both individually and organizationally directed factors. PMID- 23642174 TI - Computationally efficient methodology for atomic-level characterization of dendrimer-drug complexes: a comparison of amine- and acetyl-terminated PAMAM. AB - PAMAM dendrimers have been widely studied as a novel means for controlled drug delivery; however, computational study of dendrimer-drug complexation is made difficult by the conformational flexibility of dendrimers and the nonspecific nature of the dendrimer-drug interactions. Conventional protocols for studying drug binding have been designed primarily for protein substrates, and, therefore, there is a need to establish new protocols to deal with the unique aspects of dendrimers. In this work, we generate cavities in generation-5 polyamidoamine (PAMAM) dendrimers at selected distances from the center of mass of the dendrimer for the insertion of the model drug: dexamethasone 21-phosphate or Dp21. The complexes are then allowed to equilibrate with distance between centers of mass of the drug and dendrimers confined to selected ranges; the free energy of complexation is estimated by the MM-GBSA (MM, molecular mechanics; GB, generalized Born; SA, surface area) method. For both amine- and modified acetyl terminated PAMAM at both low and neutral pH, the most favorable free energy of complexation is associated with Dp21 at distance of 15-20 A from the center of mass of the dendrimer and that smaller or larger distances yield considerably weaker affinity. In agreement with experimental results, we find acetyl terminated PAMAM at neutral pH to form the least stable complex with Dp21. The greatest affinity is seen in the case of acetyl-terminated PAMAM at low pH, which appears to be due a complex balance of different contributions, which cannot be attributed to electrostatics, van der Waals interactions, hydrogen bonds, or charge-charge interactions alone. PMID- 23642175 TI - Site preference and ordering induced by Au substitution in the gamma-brass related complex Au-Cr-Zn phases. AB - The crystal chemistry of the ternary Au-Cr-Zn alloy was studied by means of synthesis, single crystal X-ray diffraction, and electron structure calculations. While the compound CrZn(~17) represents the binary end-point of the homogeneity range, the inclusion of Au proves to be very site specific, and at the limiting composition Au10Cr4Zn89 the structure is completely ordered. The crystallographic site occupancy pattern calculated by the Local Density Approximation (LDA) Density Functional Theory (DFT) parametrized extended Huckel (eH) Mulliken charge populations in Au10Cr4Zn89 agrees very well with the experimentally found site occupancy pattern. PMID- 23642176 TI - Mechanistic details for cobalt catalyzed photochemical hydrogen production in aqueous solution: efficiencies of the photochemical and non-photochemical steps. AB - A detailed examination of each step of the reaction sequence in the photochemical sacrificial hydrogen generation system consisting of [Ru(bpy)3](2+)/ascorbate/[Co(DPA-bpy)OH2](3+) was conducted. By clearly defining quenching, charge separation, and back electron transfer in the [Ru(bpy)3](2+)/ascorbate system, the details necessary for evaluation of the efficiency of water reduction with various catalysts are provided. In the particular Co(III) catalyst investigated, it is clear that the light induced catalytic process is considerably less efficient than the electrocatalytic process. A potential source of catalyst inefficiency in this system is reduction of the products formed in oxidation of the sacrificial electron donor. The data provided for excited state quenching and charge separation in this particular aqueous system are meant to be used by others for thorough investigation of the quantum efficiencies of other aqueous homogeneous and nanoheterogeneous catalysts for water reduction. PMID- 23642177 TI - BaFe9LiO15: a new layered antiferromagnetic ferrite. AB - The new Fe(3+) oxide BaFe9LiO15 is isostructural with the magnetically frustrated material BaV10O15, adopting a structure based on the stacking of close-packed pure oxide and BaO7 layers. Neutron diffraction and Mossbauer spectroscopy shows that BaFe9LiO15 is long-range antiferromagnetically ordered with a Neel temperature of 460 K. The magnetic ordering of antiferromagnetically coupled ferromagnetic planes is stabilized by 90 degrees and 180 degrees superexchange interactions between the Fe(3+) cations that supersede the frustrated in-plane direct exchange observed in t(2g)-only systems. PMID- 23642178 TI - Metal atom lability in polynuclear complexes. AB - The asymmetric oxidation product [((Ph)L)Fe3(MU-Cl)]2 [(Ph)LH6 = MeC(CH2NHPh-o NHPh)3], where each trinuclear core is comprised of an oxidized diiron unit [Fe2](5+) and an isolated trigonal pyramidal ferrous site, reacts with MCl2 salts to afford heptanuclear bridged structures of the type ((Ph)L)2Fe6M(MU-Cl)4(thf)2, where M = Fe or Co. Zero-field, (57)Fe Mossbauer analysis revealed the Co resides within the trinuclear core subunits, not at the octahedral, halide-bridged MCl4(thf)2 position indicating Co migration into the trinuclear subunits has occurred. Reaction of [((Ph)L)Fe3(MU-Cl)]2 with CoCl2 (2 or 5 equivalents) followed by precipitation via addition of acetonitrile afforded trinuclear products where one or two irons, respectively, can be substituted within the trinuclear core. Metal atom substitution was verified by (1)H NMR, (57)Fe Mossbauer, single crystal X-ray diffraction, X-ray fluorescence, and magnetometry analysis. Spectroscopic analysis revealed that the Co atom(s) substitute(s) into the oxidized dimetal unit ([M2](5+)), while the M(2+) site remains iron substituted. Magnetic data acquired for the series are consistent with this analysis revealing the oxidized dimetal unit comprises a strongly coupled S = 1 unit ([FeCo](5+)) or S = 1/2 ([Co2](5+)) that is weakly antiferromagnetically coupled to the high spin (S = 2) ferrous site. The kinetic pathway for metal substitution was probed via reaction of [((Ph)L)Fe3(MU-Cl)]2 with isotopically enriched (57)FeCl2(thf)2, the results of which suggest rapid equilibration of (57)Fe into both the M(2+) site and oxidized diiron site, achieving a 1:1 mixture. PMID- 23642179 TI - Tetrathiafulvalene-1,3,5-triazines as (multi)donor-acceptor systems with tunable charge transfer: structural, photophysical, and theoretical investigations. AB - Palladium-catalyzed cross-coupling reactions between chlorinated 1,3,5-triazines (TZ) and tetrathiafulvalene (TTF) trimethyltin derivatives afford mono- and C3 symmetric tris(TTF)-triazines as donor-acceptor compounds in which the intramolecular charge transfer (ICT) is modulated by the substitution scheme on TTF and TZ and by chemical or electrochemical oxidation. The TTF-TZ-Cl2 and (SMe)2TTF-TZ-Cl2 derivatives show fully planar structures in the solid state as a consequence of the conjugation between the two units. Electrochemical and photophysical investigations, supported by theoretical calculations, clearly demonstrate that the lowest excited state can be ascribed to the intramolecular charge transfer (ICT) pi(TTF)->pi*(TZ) transition. The tris(TTF) compound [(SMe)2TTF]3-TZ shows fluorescence when excited in the ICT band, and the emission is quenched upon oxidation. The radical cations TTF(+*) are easily observed in all of the cases through chemical and electrochemical oxidation by steady-state absorption experiments. In the case of [(SMe)2TTF]3-TZ, a low energy band at 5000 cm(-1), corresponding to a coupling between TTF(+*) and TTF units, is observed. A crystalline radical cation salt with the TTF-TZ-Cl2 donor and PF6(-) anion, prepared by electrocrystallization, is described. PMID- 23642180 TI - New aqua N-heterocyclic carbene Ru(II) complexes with two-electron process as selective epoxidation catalysts: an evaluation of geometrical and electronic effects. AB - New ruthenium complexes with general formula [Ru(II)(T)(CN-Me)X](n+) (X = Cl(-) or H2O; T = 2,2':6',2"-terpyridine, trpy, or N,N-bis(2-pyridyl)ethylamine, bpea; CN-Me = N-methyl-N'-2-pyridylimidazolium) have been prepared. The complexes obtained have been characterized in solution by spectroscopic (1D- and 2D-NMR and UV-vis) techniques, mass spectrometry, and elemental analysis. The chloro complexes have also been characterized by X-ray diffraction analysis. The redox properties of all the compounds were studied by CV revealing, for the reported Ru OH2 complexes, bielectronic Ru(IV/II) redox processes throughout a wide pH range. The catalytic activity of aquo complexes was evaluated in the epoxidation of olefins using PhIO as oxidant, displaying in general good yields and high selectivities for the epoxide product. The influence of electronic and geometrical factors on the spectroscopic and electrochemical properties as well as on the catalytic activity is discussed. PMID- 23642181 TI - Synthesis, steady-state, and femtosecond transient absorption studies of resorcinol bound ruthenium(II)- and osmium(II)-polypyridyl complexes on nano-TiO2 surface in water. AB - The synthesis of two new ruthenium(II)- and osmium(II)-polypyridyl complexes 3 and 4, respectively, with resorcinol as the enediol anchoring moiety, is described. Steady-state photochemical and electrochemical studies of the two sensitizer dyes confirm strong binding of the dyes to TiO2 in water. Femtosecond transient absorption studies have been carried out on the dye-TiO2 systems in water to reveal <120 fs and 1.5 ps electron injection times along with 30% slower back electron transfer time for the ruthenium complex 3. However, the corresponding osmium complex 4 shows strikingly different behavior for which only a <120 fs ultrafast injection is observed. Most remarkably, the back electron transfer is faster as compared to the corresponding catechol analogue of the dye. The origin and the consequences of such profound effects on the ultrafast interfacial dynamics are discussed. This Article on the electron transfer dynamics of the aforesaid systems reinforces the possibility of resorcinol being explored and developed as an extremely efficient binding moiety for use in dye sensitized solar cells. PMID- 23642183 TI - Natural polyphenols in the management of major depression. AB - INTRODUCTION: Natural polyphenols, the non-essential micronutrients, found in array of plant products, are known to affect various physiological and biochemical functions in the body. Studies have shown the protective effect of these polyphenols in different neurological and mental disorders. These polyphenols modulate monoaminergic neurotransmission in the brain and thus possess antidepressant-like activity at least in animal models of depression. AREAS COVERED: The present review discusses the use of these natural polyphenols in the treatment of major depression. The review article discusses the antidepressant potential of some important polyphenols such as amentoflavone, apigenin, chlorogenic acid, curcumin, ferulic acid, hesperidin, rutin, quercetin, naringenin, resveratrol, ellagic acid, nobiletin and proanthocyanidins. The mechanism of action of these polyphenols in the treatment of major depression is also discussed in detail. EXPERT OPINION: There is an exciting prospect in the discovery of natural polyphenols as therapeutic agents in the treatment of major depression. PMID- 23642182 TI - Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of the literature. AB - We report a rare case of lymphoepithelioma-like hepatocellular carcinoma. A 79 year-old Japanese man had undergone curative resection of extrahepatic bile ducts because of bile duct cancer 9 years prior. The bile duct cancer was diagnosed as mucosal adenocarcinoma, and the patient had been followed up every 6 months for the last 9 years. A recent computed tomography examination revealed a tumor, 4.2 cm in size, in the lateral segment of the liver. Based on the imaging findings, the tumor was diagnosed as hepatocellular carcinoma. Serology tests were negative for hepatitis B and C viruses. Chest and abdominal image analyses showed no evidence of metastasis, but a swollen lymph node was noted around the abdominal aorta. The patient subsequently underwent extended lateral segmentectomy and resection of the swollen lymph node. Microscopically, the tumor had the characteristic appearance of poorly differentiated hepatocellular carcinoma. Moreover, an abundant infiltration of inflammatory cells was observed in the tumor. Therefore, we diagnosed the tumor as lymphoepithelioma-like hepatocellular carcinoma. The resected para-aortic lymph node also had a carcinoma with features similar to those of the main tumor. The patient has been alive for 20 months since performance of the surgery. Since the first report of lymphoepithelioma like hepatocellular carcinoma in 2000, only nine cases have been reported in the medical literature, and the clinicopathological features of the disease have not been well documented. Herein, we describe the clinicopathological features of this case for further understanding of the disease and review past cases in the literature. PMID- 23642184 TI - Understanding cervical cancer screening among lesbians: a national survey. AB - BACKGROUND: Lesbians have low rates of cervical cancer screening, even though they are at risk of developing the disease. The aim of this study was to examine cervical cancer screening behaviors in a national sample of lesbians. METHODS: A standardized internet survey was sent to 3,000 self-identified lesbians to assess cervical cancer screening behaviors and barriers to screening. The sample consisted of 1,006 respondents. RESULTS: Sixty-two percent of the weighted sample of respondents were routine screeners. Lack of a physician referral (17.5%) and lack of a physician (17.3%) were the most commonly-cited top reasons for lack of screening. Adjusting for age, education, relationship status, employments status, and insurance status, women who had disclosed their sexual orientation to their primary care physician (adjusted odds ratio [OR] 2.84 [95% confidence interval 1.82-4.45]) or gynecologist (OR 2.30 [1.33-3.96]) had greater odds of routine screening than those who did not. Those who knew that lack of Pap testing is a risk factor for cervical cancer were also more likely to be routine screeners (OR 1.95 [1.30-2.91]), although no association with screening was apparent for women who had more knowledge of general cervical cancer risk factors. Physician recommendation appeared to be a potent determinant of regular screening behavior. Routine screeners perceived more benefits and fewer barriers to screening, as well as higher susceptibility to cervical cancer. CONCLUSIONS: Some women who identify as lesbian are at a potentially elevated risk of cervical cancer because they are not routinely screened. Evidence-based interventions should be developed to address critical health beliefs that undermine participation in screening. Given the value placed on physician recommendation, patient-provider communication may serve as the optimal focus of effective intervention. PMID- 23642185 TI - Imatinib mesylate inhibits cell growth of malignant peripheral nerve sheath tumors in vitro and in vivo through suppression of PDGFR-beta. AB - BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive and associated with poor prognosis. Basic research to develop new treatment regimens is critically needed. METHODS: The effects of imatinib mesylate on MPNSTs were examined in six human MPNST cell lines and in a xenograft mouse model. RESULTS: The results showed expression of platelet-derived growth factor receptor-beta and suppression of its phosphorylation by imatinib mesylate in all six cell lines. Imatinib mesylate effectively suppressed MPNST cell growth in vitro at concentrations similar to those used clinically (1.46 - 4.6 MUM) in three of six cell lines. Knockdown of PDGFR-beta by transfection with a specific siRNA also caused significant reduction in cell proliferation in the sensitive cell lines, but not in the resistant cell lines. Furthermore, imatinib mesylate also significantly suppressed colony formation within soft agar and tumor growth in xenograft models using two of the three sensitive MPNST cell lines. There was excellent agreement between in vitro and in vivo sensitivity to imatinib mesylate, suggesting possible selection of imatinib-sensitive tumors by in vitro analysis. CONCLUSIONS: The results suggest that imatinib mesylate may be useful in the treatment of MPNST patients and in vitro studies may help select cells that are sensitive to imatinib mesylate in vivo. PMID- 23642186 TI - Phenotypic and genotypic properties of Microbacterium yannicii, a recently described multidrug resistant bacterium isolated from a lung transplanted patient with cystic fibrosis in France. AB - BACKGROUND: Cystic fibrosis (CF) lung microbiota consists of diverse species which are pathogens or opportunists or have unknown pathogenicity. Here we report the full characterization of a recently described multidrug resistant bacterium, Microbacterium yannicii, isolated from a CF patient who previously underwent lung transplantation. RESULTS: Our strain PS01 (CSUR-P191) is an aerobic, rod shaped, non-motile, yellow pigmented, gram positive, oxidase negative and catalase positive bacterial isolate. Full length 16S rRNA gene sequence showed 98.8% similarity with Microbacterium yannicii G72T type strain, which was previously isolated from Arabidopsis thaliana. The genome size is 3.95Mb, with an average G+C content of 69.5%. In silico DNA-DNA hybridization analysis between our Microbacterium yannicii PS01isolate in comparison with Microbacterium testaceum StLB037 and Microbacterium laevaniformans OR221 genomes revealed very weak relationship with only 28% and 25% genome coverage, respectively. Our strain, as compared to the type strain, was resistant to erythromycin because of the presence of a new erm 43 gene encoding a 23S rRNA N-6-methyltransferase in its genome which was not detected in the reference strain. Interestingly, our patient received azithromycin 250 mg daily for bronchiolitis obliterans syndrome for more than one year before the isolation of this bacterium. CONCLUSIONS: Although significance of isolating this bacterium remains uncertain in terms of clinical evolution, this bacterium could be considered as an opportunistic human pathogen as previously reported for other species in this genus, especially in immunocompromised patients. PMID- 23642187 TI - Cu(OTf)2-catalyzed asymmetric Friedel-Crafts alkylation reaction of indoles with arylidene malonates using bis(sulfonamide)-diamine ligands. AB - A highly efficient Cu-catalyzed asymmetric Friedel-Crafts alkylation reaction of indoles with arylidene malonates using simple, stable, and easily prepared bis sulfonamide diamine ligands was developed. The desired products were obtained in up to 99% yield with 96% ee. PMID- 23642189 TI - Excited state intramolecular charge transfer suppressed proton transfer process in 4-(diethylamino)-2-hydroxybenzaldehyde. AB - In this work, we report intramolecular charge transfer (ICT) suppressed excited state intramolecular proton transfer (ESIPT) process in 4-(diethylamino)-2 hydroxybenzaldehyde (DEAHB). Photophysical properties of DEAHB have been extensively studied in different solvents with varying pH, polarity, and hydrogen bonding capability of the solvent using steady state and time-resolved spectroscopy. To establish the competition between the ICT and ESIPT processes in DEAHB, we have synthesized and studied the photophysical properties of 4 (diethylamino)-2-methoxybenzaldehyde (DEAMB) molecule where only the charge transfer process has been observed. Recently, we have reported simple Schiff base molecules (J. Phys. Chem. A 2012, 116, 10948) formed by condensation of DEAHB and hydrazine (5-(diethylamino)-2-[(4 (diethylamino)benzylidene)hydrazonomethyl]phenol (DDBHP) and N,N'-bis(4-N,N (diethylamino)salisalidene)hydrazine (DEASH)), where charge transfer is assisted by the proton transfer process. In the present case, the DEAHB molecule shows the reverse phenomenon; i.e., charge transfer is suppressed by the proton transfer process. Comparing the photophysical properties of DEAHB with DEAMB it is also found that ICT process in DEAHB is suppressed by the ESIPT process. PMID- 23642190 TI - Transcriptional analysis of Clostridium beijerinckii NCIMB 8052 to elucidate role of furfural stress during acetone butanol ethanol fermentation. AB - BACKGROUND: Furfural is the prevalent microbial inhibitor generated during pretreatment and hydrolysis of lignocellulose biomass to monomeric sugars, but the response of acetone butanol ethanol (ABE) producing Clostridium beijerinckii NCIMB 8052 to this compound at the molecular level is unknown. To discern the effect of furfural on C. beijerinckii and to gain insight into molecular mechanisms of action and detoxification, physiological changes of furfural stressed cultures during acetone butanol ethanol (ABE) fermentation were studied, and differentially expressed genes were profiled by genome-wide transcriptional analysis. RESULTS: A total of 5,003 C. beijerinckii NCIMB 8052 genes capturing about 99.7% of the genome were examined. About 111 genes were differentially expressed (up- or down-regulated) by C. beijerinckii when it was challenged with furfural at acidogenic growth phase compared with 721 genes that were differentially expressed (up- or down-regulated) when C. beijerinckii was challenged with furfural at solventogenic growth phase. The differentially expressed genes include genes related to redox and cofactors, membrane transporters, carbohydrate, amino sugar and nucleotide sugar metabolisms, heat shock proteins, DNA repair, and two-component signal transduction system. While C. beijerinckii exposed to furfural stress during the acidogenic growth phase produced 13% more ABE than the unstressed control, ABE production by C. beijerinckii ceased following exposure to furfural stress during the solventogenic growth phase. CONCLUSION: Genome-wide transcriptional response of C. beijerinckii to furfural stress was investigated for the first time using microarray analysis. Stresses emanating from ABE accumulation in the fermentation medium; redox balance perturbations; and repression of genes that code for the phosphotransferase system, cell motility and flagellar proteins (and combinations thereof) may have caused the premature termination of C. beijerinckii 8052 growth and ABE production following furfural challenge at the solventogenic phase.This study provides insights into basis for metabolic engineering of C. beijerinckii NCIMB 8052 for enhanced tolerance of lignocellulose-derived microbial inhibitory compounds, thereby improving bioconversion of lignocellulose biomass hydrolysates to biofuels and chemicals. Indeed, two enzymes encoded by Cbei_3974 and Cbei_3904 belonging to aldo/keto reductase (AKR) and short-chain dehydrogenase/reductase (SDR) families have been identified to be involved in furfural detoxification and tolerance. PMID- 23642191 TI - Asperterpenols A and B, new sesterterpenoids isolated from a mangrove endophytic fungus Aspergillus sp. 085242. AB - Asperterpenol A (1) and asperterpenol B (2), two novel sesterterpenoids with an unusual 5/8/6/6 tetracyclic ring skeleton, were isolated from a mangrove endophytic fungus Aspergillus sp. 085242. The structures were elucidated on the basis of spectroscopic methods and the absolute configurations determined by single-crystal X-ray diffraction analysis. Compounds 1 and 2 inhibit acetylcholinesterase with IC50 values of 2.3 and 3.0 MUM, respectively. PMID- 23642192 TI - Anatomy and development of the larval nervous system in Echinococcus multilocularis. AB - BACKGROUND: The metacestode larva of Echinococcus multilocularis (Cestoda: Taeniidae) develops in the liver of intermediate hosts (typically rodents, or accidentally in humans) as a labyrinth of interconnected cysts that infiltrate the host tissue, causing the disease alveolar echinococcosis. Within the cysts, protoscoleces (the infective stage for the definitive canid host) arise by asexual multiplication. These consist of a scolex similar to that of the adult, invaginated within a small posterior body. Despite the importance of alveolar echinococcosis for human health, relatively little is known about the basic biology, anatomy and development of E. multilocularis larvae, particularly with regard to their nervous system. RESULTS: We describe the existence of a subtegumental nerve net in the metacestode cysts, which is immunoreactive for acetylated tubulin-alpha and contains small populations of nerve cells that are labeled by antibodies raised against several invertebrate neuropeptides. However, no evidence was found for the existence of cholinergic or serotoninergic elements in the cyst wall. Muscle fibers occur without any specific arrangement in the subtegumental layer, and accumulate during the invaginations of the cyst wall that form brood capsules, where protoscoleces develop. The nervous system of the protoscolex develops independently of that of the metacestode cyst, with an antero-posterior developmental gradient. The combination of antibodies against several nervous system markers resulted in a detailed description of the protoscolex nervous system, which is remarkably complex and already similar to that of the adult worm. CONCLUSIONS: We provide evidence for the first time of the existence of a nervous system in the metacestode cyst wall, which is remarkable given the lack of motility of this larval stage, and the lack of serotoninergic and cholinergic elements. We propose that it could function as a neuroendocrine system, derived from the nervous system present in the bladder tissue of other taeniids. The detailed description of the development and anatomy of the protoscolex neuromuscular system is a necessary first step toward the understanding of the developmental mechanisms operating in these peculiar larval stages. PMID- 23642193 TI - Drug-loaded fluorescent cubosomes: versatile nanoparticles for potential theranostic applications. AB - In this work, monoolein-based cubosomes were doped with two fluorescent probes, namely, fluorescein and dansyl, properly modified with a hydrocarbon chain to increase their encapsulation efficiency within the monoolein palisade. The same nanocarriers were also loaded with quercetin, a hydrophobic molecule with potential anticancer activity. Particularly, the cubosomes doped with the modified fluorescein probe were successfully exploited for single living cell imaging. The physicochemical and photophysical characterizations reported here, along with the well-known ability of cubosomes in hosting molecules with pharmaceutical interest, strongly encourage the use of these innovative fluorescent nanocarriers for theranostic purposes. PMID- 23642194 TI - Novel aspects of dietary nitrate and human health. AB - The circulation of nitrogen in nature is a prerequisite for life on earth. In the nitrogen cycle atmospheric nitrogen is fixated by bacteria into forms that can be utilized by plants and mammals. Nitrate and nitrite are obligate intermediates in this cycle, and for more than half a century these anions have interested nutritional scientists, mostly in relation to cancer, because of their ability to form nitrosamines. However, after the discovery of mammalian endogenous nitric oxide (NO) generation and later that its oxidation products nitrate and nitrite can be recycled back to bioactive NO, a novel field of research has emerged that explores a potentially beneficial role of these anions in physiology, nutrition, and therapeutics. In our diet, vegetables are the major source of nitrate that can fuel a nitrate-nitrite-NO pathway. Herein we discuss the nutritional aspects of this pathway and what is presently known about the implications for human health. PMID- 23642195 TI - O-GlcNAc cycling: a link between metabolism and chronic disease. AB - To maintain homeostasis under variable nutrient conditions, cells rapidly and robustly respond to fluctuations through adaptable signaling networks. Evidence suggests that the O-linked N-acetylglucosamine (O-GlcNAc) posttranslational modification of serine and threonine residues functions as a critical regulator of intracellular signaling cascades in response to nutrient changes. O-GlcNAc is a highly regulated, reversible modification poised to integrate metabolic signals and acts to influence many cellular processes, including cellular signaling, protein stability, and transcription. This review describes the role O-GlcNAc plays in governing both integrated cellular processes and the activity of individual proteins in response to nutrient levels. Moreover, we discuss the ways in which cellular changes in O-GlcNAc status may be linked to chronic diseases such as type 2 diabetes, neurodegeneration, and cancers, providing a unique window through which to identify and treat disease conditions. PMID- 23642196 TI - Vitamin E trafficking in neurologic health and disease. AB - Vitamin E was identified almost a century ago as a botanical compound necessary for rodent reproduction. Decades of research since then established that of all members of the vitamin E family, alpha-tocopherol is selectively enriched in human tissues, and it is essential for human health. The major function of alpha tocopherol is thought to be that of a lipid-soluble antioxidant that prevents oxidative damage to biological components. As such, alpha-tocopherol is necessary for numerous physiological processes such as permeability of lipid bilayers, cell adhesion, and gene expression. Inadequate levels of alpha-tocopherol interfere with cellular function and precipitate diseases, notably ones that affect the central nervous system. The extreme hydrophobicity of alpha-tocopherol poses a serious thermodynamic barrier for proper distribution of the vitamin to target tissues and cells. Although transport of the vitamin shares some steps with that of other lipids, selected tissues evolved dedicated transport mechanisms involving the alpha-tocopherol transfer protein (alphaTTP). The critical roles of this protein and its ligand are underscored by the debilitating pathologies that characterize human carriers of mutations in the TTPA gene. PMID- 23642197 TI - Nutrient deficiencies after gastric bypass surgery. AB - Bariatric surgery, and in particular, gastric bypass, is an increasingly utilized and successful approach for long-term treatment of obesity and amelioration of comorbidities. Nutrient deficiencies after surgery are common and have multiple causes. Preoperative factors include obesity, which appears to be associated with risk for several nutrient deficiencies, and preoperative weight loss. Postoperatively, reduced food intake, suboptimal dietary quality, altered digestion and absorption, and nonadherence with supplementation regimens contribute to risk of deficiency. The most common clinically relevant micronutrient deficiencies after gastric bypass include thiamine, vitamin B12, vitamin D, iron, and copper. Reports of deficiencies of many other nutrients, some with severe clinical manifestations, are relatively sporadic. Diet and multivitamin use are unlikely to consistently prevent deficiency, thus supplementation with additional specific nutrients is often needed. Though optimal supplement regimens are not yet defined, most micronutrient deficiencies after gastric bypass currently can be prevented or treated by appropriate supplementation. PMID- 23642199 TI - Cocoa and human health. AB - Cocoa is a dry, powdered, nonfat component product prepared from the seeds of the Theobroma cacao L. tree and is a common ingredient of many food products, particularly chocolate. Nutritionally, cocoa contains biologically active substances that may affect human health: flavonoids (epicatechin and oligomeric procyanidins), theobromine, and magnesium. Theobromine and epicatechin are absorbed efficiently in the small intestine, and the nature of their conjugates and metabolites are now known. Oligomeric procyanidins are poorly absorbed in the small intestine, but catabolites are very efficiently absorbed after microbial biotransformation in the colon. A significant number of studies, using in vitro and in vivo approaches, on the effects of cocoa and its constituent flavonoids have been conducted. Most human intervention studies have been performed on cocoa as an ingredient, whereas many in vitro studies have been performed on individual components. Approximately 70 human intervention studies have been carried out on cocoa and cocoa-containing products over the past 12 years, with a variety of endpoints. These studies indicate that the most robust biomarkers affected are endothelial function, blood pressure, and cholesterol level. Mechanistically, supporting evidence shows that epicatechin affects nitric oxide synthesis and breakdown (via inhibition of nicotinamide adenine di-nucleotide phosphate oxidase) and the substrate arginine (via inhibition of arginase), among other targets. Evidence further supports cocoa as a biologically active ingredient with potential benefits on biomarkers related to cardiovascular disease. However, the calorie and sugar content of chocolate and its contribution to the total diet should be taken into account in intervention studies. PMID- 23642198 TI - Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function. AB - New evidence for the regulation of vitamin C homeostasis has emerged from several studies of human genetic variation. Polymorphisms in the genes encoding sodium dependent vitamin C transport proteins are strongly associated with plasma ascorbate levels and likely impact tissue cellular vitamin C status. Furthermore, genetic variants of proteins that suppress oxidative stress or detoxify oxidatively damaged biomolecules, i.e., haptoglobin, glutathione-S-transferases, and possibly manganese superoxide dismutase, affect ascorbate levels in the human body. There also is limited evidence for a role of glucose transport proteins. In this review, we examine the extent of the variation in these genes, their impact on vitamin C status, and their potential role in altering chronic disease risk. We conclude that future epidemiological studies should take into account genetic variation in order to successfully determine the role of vitamin C nutriture or supplementation in human vitamin C status and chronic disease risk. PMID- 23642201 TI - Extrarenal vitamin D activation and interactions between vitamin D2, vitamin D3, and vitamin D analogs. AB - Our understanding of the mechanism of action of vitamin D has been broadened by the discovery of the extrarenal 1alpha-hydroxylase (CYP27B1) in various vitamin D target tissues around the body and the implications of this for the putative paracrine actions of 1alpha,25-dihydroxyvitamin D3. This review updates our current knowledge of the cytochrome P450-mediated steps of vitamin D activation (CYP2R1, CYP27B1) and inactivation (CYP24A1, CYP3A4) and the newest physiological roles of vitamin D. The review goes on to examine how well exogenously supplied vitamin D compounds, whether dietary vitamin D2 supplements or prescribed vitamin D analogs, substitute for their natural counterparts; how in some cases vitamin D can be used in conjunction with vitamin D analogs; and the overall impact of these supplements and drugs on the components of the vitamin D signal transduction machinery. PMID- 23642200 TI - Quantifying diet for nutrigenomic studies. AB - The field of nutrigenomics shows tremendous promise for improved understanding of the effects of dietary intake on health. The knowledge that metabolic pathways may be altered in individuals with genetic variants in the presence of certain dietary exposures offers great potential for personalized nutrition advice. However, although considerable resources have gone into improving technology for measurement of the genome and biological systems, dietary intake assessment remains inadequate. Each of the methods currently used has limitations that may be exaggerated in the context of gene * nutrient interaction in large multiethnic studies. Because of the specificity of most gene * nutrient interactions, valid data are needed for nutrient intakes at the individual level. Most statistical adjustment efforts are designed to improve estimates of nutrient intake distributions in populations and are unlikely to solve this problem. An improved method of direct measurement of individual usual dietary intake that is unbiased across populations is urgently needed. PMID- 23642203 TI - Prevention of chronic diseases by tea: possible mechanisms and human relevance. AB - Tea, made from leaves of the plant Camellia sinensis, Theaceae, has been used by humans for thousands of years, first as a medicinal herb and then as a beverage that is consumed widely. For the past 25 years, tea has been studied extensively for its beneficial health effects, including prevention of cancer, reduction of body weight, alleviation of metabolic syndrome, prevention of cardiovascular diseases, and protection against neurodegenerative diseases. Whether these effects can be produced by tea at the levels commonly consumed by humans is an open question. This review examines these topics and elucidates the common mechanisms for these beneficial health effects. It also discusses other health effects and possible side effects of tea consumption. This article provides a critical assessment of the health effects of tea consumption and suggests new directions for research in this area. PMID- 23642204 TI - Iron nutrition and premenopausal women: effects of poor iron status on physical and neuropsychological performance. AB - Iron is a nutritionally essential trace element that functions through incorporation into proteins and enzymes, many of which contribute to physical and neuropsychological performance. Poor iron status, including iron deficiency (ID; diminished iron stores) and iron deficiency anemia (IDA; poor iron stores and diminished hemoglobin), affects billions of people worldwide. This review focuses on physical and neuropsychological outcomes associated with ID and IDA in premenopausal women, as the prevalence of ID and IDA is often greater in premenopausal women than other population demographics. Recent studies addressing the physiological effects of poor iron status on physical performance, including work productivity, voluntary activity, and athletic performance, are addressed. Similarly, the effects of iron status on neurological performance, including cognition, affect, and behavior, are summarized. Nutritional countermeasures for the prevention of poor iron status and the restoration of decrements in performance outcomes are described. PMID- 23642205 TI - The role of cost-effectiveness analysis in developing nutrition policy. AB - Concern about the overconsumption of unhealthy foods is growing worldwide. With high global rates of noncommunicable diseases related to poor nutrition and projections of more rapid increases of rates in low- and middle-income countries, it is vital to identify effective but low-cost interventions. Cost-effectiveness studies show that individually targeted dietary interventions can be effective and cost-effective, but a growing number of modeling studies suggest that population-wide approaches may bring larger and more sustained benefits for population health at a lower cost to society. Mandatory regulation of salt in processed foods, in particular, is highly recommended. Future research should focus on lacunae in the current evidence base: effectiveness of interventions addressing the marketing, availability, and price of healthy and unhealthy foods; modeling health impacts of complex dietary changes and multi-intervention strategies; and modeling health implications in diverse subpopulations to identify interventions that will most efficiently and effectively reduce health inequalities. PMID- 23642202 TI - Functional organization of neuronal and humoral signals regulating feeding behavior. AB - Energy homeostasis--ensuring that energy availability matches energy requirements -is essential for survival. One way that energy balance is achieved is through coordinated action of neural and neuroendocrine feeding circuits, which promote energy intake when energy supply is limited. Feeding behavior engages multiple somatic and visceral tissues distributed throughout the body--contraction of skeletal and smooth muscles in the head and along the upper digestive tract required to consume and digest food, as well as stimulation of endocrine and exocrine secretions from a wide range of organs. Accordingly, neurons that contribute to feeding behaviors are localized to central, peripheral, and enteric nervous systems. To promote energy balance, feeding circuits must be able to identify and respond to energy requirements, as well as the amount of energy available from internal and external sources, and then direct appropriate coordinated responses throughout the body. PMID- 23642206 TI - Vitamin D biology revealed through the study of knockout and transgenic mouse models. AB - Early studies identifying vitamin D as an antirachitic factor led to studies in vitamin D-deficient models that resulted in a basic understanding of the mechanism of action of vitamin D. Recent studies using genetically modified mice have provided important new insight into the physiological role of vitamin D at target tissues and the functional significance of vitamin D target proteins, as well as the functional significance of proteins involved in the transport and metabolism of vitamin D. Studies using these mice have played an increasingly important role in elucidating the mechanisms involved in the control of calcium homeostasis and have provided evidence for a role of vitamin D in extraskeletal health. PMID- 23642207 TI - Endothelin-1 and -3 induce choleresis in the rat through ETB receptors coupled to nitric oxide and vagovagal reflexes. AB - We have reported previously that centrally applied ET (endothelin)-1 and ET-3 induce either choleresis or cholestasis depending on the dose. In the present study, we sought to establish the role of these endothelins in the short-term peripheral regulation of bile secretion in the rat. Intravenously infused endothelins induced significant choleresis in a dose-dependent fashion, ET-1 being more potent than ET-3. Endothelins (with the exception of a higher dose of ET-1) did not affect BP (blood pressure), portal venous pressure or portal blood flow. ET-1 and ET-3 augmented the biliary excretion of bile salts, glutathione and electrolytes, suggesting enhanced bile acid-dependent and -independent bile flows. ET-induced choleresis was mediated by ET(B) receptors coupled to NO and inhibited by truncal vagotomy, atropine administration and capsaicin perivagal application, supporting the participation of vagovagal reflexes. RT (reverse transcription)-PCR and Western blot analysis revealed ETA and ET(B) receptor expression in the vagus nerve. Endothelins, through ET(B) receptors, augmented the hepatocyte plasma membrane expression of Ntcp (Na+/taurocholate co transporting polypeptide; Slc10a1), Bsep (bile-salt export pump; Abcb11), Mrp2 (multidrug resistance protein-2; Abcc2) and Aqp8 (aquaporin 8). Endothelins also increased the mRNAs of these transporters. ET-1 and ET-3 induced choleresis mediated by ET(B) receptors coupled to NO release and vagovagal reflexes without involving haemodynamic changes. Endothelin-induced choleresis seems to be caused by increased plasma membrane translocation and transcriptional expression of key bile transporters. These findings indicate that endothelins are able to elicit haemodynamic-independent biological effects in the liver and suggest that these peptides may play a beneficial role in pathophysiological situations where bile secretion is impaired. PMID- 23642208 TI - Transmission of AA amyloidosis may cause outbreaks of amyloid A amyloidosis in chickens. PMID- 23642209 TI - Phonation after cervical spinal cord injury (CSCI): prospective case examinations of the acute and sub-acute stages of recovery. AB - The aim of the investigation was to examine the changes in phonation and related quality-of-life in the acute and sub-acute stages of recovery post-cervical spinal cord injury (CSCI). A prospective examination of phonation was conducted using perceptual and instrumental measures of respiratory and laryngeal functioning alongside a quality-of-life rating scale. Change was present across measures for both cases at each time point. Overall, a general pattern of recovery was seen, although some areas deteriorated between 6-12 months. Severity of impairments, extent of change, and impact on quality-of-life differed between the cases. Measures varied in sensitivity to change in function. Phonation can be impaired following both complete and incomplete CSCI, with type and severity of impairment/s undergoing change throughout the acute and sub-acute period post injury. Spontaneous physiological recovery does not necessarily result in improved phonation and/ or quality-of-life. Potential exists for targeted speech language therapy in this population, throughout recovery, to best capitalize on the physical changes that are occurring and to maximize functional application of skills to improve quality- of-life. Further research is warranted to examine this recovery period on a larger scale. PMID- 23642210 TI - The implementation of evidence-based practice in the management of adults with functional voice disorders: a national survey of speech-language pathologists. AB - This study examined Australian speech-language pathologists' (SLPs) use of evidence-based practice (E(3)BP) when treating adults with functional voice disorders (FVDs). It was hypothesized that SLPs would report using the available evidence to care for their clients but may be limited by time and skills. Fifty eight SLPs completed a 26-item survey. A combination of indirect and direct voice therapy was most frequently reported, with hum and nasal consonants, pitch extension, elimination of glottal attack, and diaphragmatic breathing being the most frequently used techniques. In the absence of higher levels of evidence, 98% of respondents reported they relied on clinical experience to guide their clinical decision-making. Despite a lack of research evidence supporting this decision, SLPs also reported simultaneously using a combination of direct voice therapies to cater to the needs of their individual clients. Barriers to EBP were lack of time, specialty training and high quality evidence. To improve SLPs' management of adults with FVDs, it is suggested that SLPs need both greater access to voice training and to use practice-based evidence by actively collecting and reporting clinical data. PMID- 23642211 TI - Enlarging the panoply of site-directed spin labeling electron paramagnetic resonance (SDSL-EPR): sensitive and selective spin-labeling of tyrosine using an isoindoline-based nitroxide. AB - Site-directed spin labeling (SDSL) combined with electron paramagnetic resonance (EPR) spectroscopy has emerged as a powerful approach to study structure and dynamics in proteins. One limitation of this approach is the fact that classical spin labels are functionalized to be grafted on natural or site-directed mutagenesis generated cysteine residues. Despite the widespread success of cysteine-based modification strategies, the technique becomes unsuitable when cysteine residues play a functional or structural role in the protein under study. To overcome this limitation, we propose an isoindoline-based nitroxide to selectively target tyrosine residues using a Mannich type reaction, the feasibility of which has been demonstrated in a previous study. This nitroxide has been synthesized and successfully grafted successively on p-cresol, a small tetrapeptide and a model protein: a small chloroplastic protein CP12 having functional cysteines and a single tyrosine. Studying the association of the labeled CP12 with its partner protein, we showed that the isoindoline-based nitroxide is a good reporter to reveal changes in its local environment contrary to the previous study where the label was poorly sensitive to probe structural changes. The successful targeting of tyrosine residues with the isoindoline-based nitroxide thus offers a highly promising approach, complementary to the classical cysteine-SDSL one, which significantly enlarges the field of applications of the technique for probing protein dynamics. PMID- 23642212 TI - Robust prototypical anti-icing coatings with a self-lubricating liquid water layer between ice and substrate. AB - A robust prototypical anti-icing coating with a self-lubricating liquid water layer (SLWL) is fabricated via grafting cross-linked hygroscopic polymers inside the micropores of silicon wafer surfaces. The ice adhesion on the surface with SLWL is 1 order of magnitude lower than that on the superhydrophobic surfaces and the ice formed atop of it can be blown off by an action of strong breeze. The surface with self-lubricating liquid water layer exhibits excellent capability of self-healing and abrasion resistance. The SLWL surface should also find applications in antifogging and self-cleaning by rainfall, in addition to anti icing and antifrosting. PMID- 23642213 TI - Insecticide-impregnated netting as a potential tool for long-lasting control of the leishmaniasis vector Lutzomyia longipalpis in animal shelters. AB - BACKGROUND: Leishmaniasis remains a serious neglected disease, with more than 350 million people potentially at risk worldwide. Control strategies often rely on spraying residual insecticides to target populations of the sand fly vectors that transmit Leishmania parasites when blood-feeding. These programmes are often difficult to sustain effectively, as sand fly resting sites must be resprayed on a regular basis. Here, we investigate whether application of insecticide impregnated netting to a surface could act as an alternative to residual spraying for controlling the American visceral leishmaniasis vector Lutzomyia longipalpis. METHODS: Female L. longipalpis from our laboratory colony were exposed for 1 h to three treatments applied to plywood surfaces: 2% permethrin-impregnated netting (Olyset(r)), 20 mg a.i.m-2 micro-encapsulated lambda-cyhalothrin (Demand CS(r)) and a no-treatment control. We compared the speed at which these treatments acted, by measuring the percentage of sand flies killed both immediately after exposure to the treatment for 1 hour, as well as the number that had died 24 h after the 1 hour exposure. We repeated the experiment at 6 and 12 months following application to test the effectiveness of each treatment over time. RESULTS: When first applied, the lambda-cyhalothrin killed more sand flies in the first hour than the permethrin-impregnated netting. However, the effectiveness of the lambda-cyhalothrin diminished over time, so that there was no difference between the two treatments at 12 months. Both killed more sand flies than the control. When measured 24 h following exposure, both test treatments had killed close to 100% of sand flies when first applied, but while the lethal effect of the netting was maintained at close to 100% over 12 months, the effectiveness of the residual insecticide diminished to approximately 80% after 6 months. CONCLUSIONS: The results of these initial laboratory experiments indicate that covering surfaces with insecticide impregnated netting material may provide a longer-lasting solution for killing sand flies than residual spraying. Field trials are needed to identify the feasibility of treating surfaces with netting or similar impregnated materials as part of a control program. In targeting L. longipalpis, the greatest benefits may be seen in treating animal sheds with netting, where these sand flies aggregate in large numbers, and which can be difficult to treat repeatedly by conventional spraying. PMID- 23642214 TI - Tissue culture-induced genetic and epigenetic alterations in rice pure-lines, F1 hybrids and polyploids. AB - BACKGROUND: Genetic and epigenetic alterations can be invoked by plant tissue culture, which may result in heritable changes in phenotypes, a phenomenon collectively termed somaclonal variation. Although extensive studies have been conducted on the molecular nature and spectrum of tissue culture-induced genomic alterations, the issue of whether and to what extent distinct plant genotypes, e.g., pure-lines, hybrids and polyploids, may respond differentially to the tissue culture condition remains poorly understood. RESULTS: We investigated tissue culture-induced genetic and epigenetic alterations in a set of rice genotypes including two pure-lines (different subspecies), a pair of reciprocal F1 hybrids parented by the two pure-lines, and a pair of reciprocal tetraploids resulted from the hybrids. Using two molecular markers, amplified fragment length polymorphism (AFLP) and methylation-sensitive amplified polymorphism (MSAP), both genetic and DNA methylation alterations were detected in calli and regenerants from all six genotypes, but genetic alteration is more prominent than epigenetic alteration. While significant genotypic difference was observed in frequencies of both types of alterations, only genetic alteration showed distinctive features among the three types of genomes, with one hybrid (N/9) being exceptionally labile. Surprisingly, difference in genetic alteration frequencies between the pair of reciprocal F1 hybrids is much greater than that between the two pure-line subspecies. Difference also exists in the pair of reciprocal tetraploids, but is to a less extent than that between the hybrids. The steady-state transcript abundance of genes involved in DNA repair and DNA methylation was significantly altered in both calli and regenerants, and some of which were correlated with the genetic and/or epigenetic alterations. CONCLUSIONS: Our results, based on molecular marker analysis of ca. 1,000 genomic loci, document that genetic alteration is the major cause of somaclonal variation in rice, which is concomitant with epigenetic alterations. Perturbed expression by tissue culture of a set of 41 genes encoding for enzymes involved in DNA repair and DNA methylation is associated with both genetic and epigenetic alterations. There exist fundamental differences among distinct genotypes, pure-lines, hybrids and tetraploids, in propensities of generating both genetic and epigenetic alterations under the tissue culture condition. Parent-of-origin has a conspicuous effect on the alteration frequencies. PMID- 23642216 TI - Pitfall in quantum mechanical/molecular mechanical molecular dynamics simulation of small solutes in solution. AB - Developments in computing hardware and algorithms have made direct molecular dynamics simulation with the combined quantum mechanical/molecular mechanical methods affordable for small solute molecules in solution, in which much improved accuracy can be obtained via the quantum mechanical treatment of the solute molecule and even sometimes water molecules in the first solvation shell. However, unlike the conventional molecular mechanical simulations of large molecules, e.g., proteins, in solutions, special care must be taken in the technical details of the simulation, including the thermostat of the solute/solvent system, so that the conformational space of the solute molecules can be properly sampled. We show here that the common setup for classical molecular mechanical molecular dynamics simulations, such as the Berendsen or single Nose-Hoover thermostat, and/or rigid water models could lead to pathological sampling of the solutes' conformation. In the extreme example of a methanol molecule in aqueous solution, improper and sluggish setups could generate two peaks in the distribution of the O-H bond length. We discuss the factors responsible for this somewhat unexpected result and evoke a simple and ancient technical fix-up to resolve this problem. PMID- 23642215 TI - Mortality risk of black women and white women with invasive breast cancer by hormone receptors, HER2, and p53 status. AB - BACKGROUND: Black women are more likely than white women to have an aggressive subtype of breast cancer that is associated with higher mortality and this may contribute to the observed black-white difference in mortality. However, few studies have investigated the black-white disparity in mortality risk stratified by breast cancer subtype, defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. Furthermore, it is not known whether additional consideration of p53 protein status influences black-white differences in mortality risk observed when considering subtypes defined by ER, PR and HER2 status. METHODS: Four biomarkers were assessed by immunohistochemistry in paraffin-embedded breast tumor tissue from 1,204 (523 black, 681 white) women with invasive breast cancer, aged 35-64 years at diagnosis, who accrued a median of 10 years' follow-up. Multivariable Cox proportional hazards regression models were fit to assess subtype-specific black-white differences in mortality risk. RESULTS: No black-white differences in mortality risk were observed for women with triple negative (ER-negative [ER-], PR-, and HER2-) subtype. However, older (50-64 years) black women had greater overall mortality risk than older white women if they had been diagnosed with luminal A (ER-positive [ER+] or PR+ plus HER2-) breast cancer (all-cause hazard ratio, HR, 1.88; 95% confidence interval, CI, 1.18 to 2.99; breast cancer specific HR, 1.51; 95% CI, 0.83 to 2.74). This black-white difference among older women was further confined to those with luminal A/p53- tumors (all-cause HR, 2.22; 95% CI, 1.30 to 3.79; breast cancer-specific HR, 1.89; 95% CI, 0.93 to 3.86). Tests for homogeneity of race-specific HRs comparing luminal A to triple negative subtype and luminal A/p53- to luminal A/p53+ subtype did not achieve statistical significance, although statistical power was limited. CONCLUSIONS: Our findings suggest that the subtype-specific black-white difference in mortality risk occurs mainly among older women diagnosed with luminal A/p53- breast cancer, which is most likely treatable. These results further suggest that factors other than subtype may be relatively more important in explaining the increased mortality risk seen in older black women. PMID- 23642217 TI - Antenatal and obstetric care in Afghanistan--a qualitative study among health care receivers and health care providers. AB - BACKGROUND: Despite attempts from the government to improve ante- and perinatal care, Afghanistan has once again been labeled "the worst country in which to be a mom" in Save the Children's World's Mothers' Report. This study investigated how pregnant women and health care providers experience the existing antenatal and obstetric health care situation in Afghanistan. METHODS: Data were obtained through one-to-one semi-structured interviews of 27 individuals, including 12 women who were pregnant or had recently given birth, seven doctors, five midwives, and three traditional birth attendants. The interviews were carried out in Kabul and the village of Ramak in Ghazni Province. Interviews were taped, transcribed, and analyzed according to the principles of Giorgi's phenomenological analysis. RESULTS: Antenatal care was reported to be underused, even when available. Several obstacles were identified, including a lack of knowledge regarding the importance of antenatal care among the women and their families, financial difficulties, and transportation problems. The women also reported significant dissatisfaction with the attitudes and behavior of health personnel, which included instances of verbal and physical abuse. According to the health professionals, poor working conditions, low salaries, and high stress levels contributed to this matter. Personal contacts inside the hospital were considered necessary for receiving high quality care, and bribery was customary. Despite these serious concerns, the women expressed gratitude for having even limited access to health care, especially treatment provided by a female doctor. Health professionals were proud of their work and enjoyed the opportunity to help their community. CONCLUSION: This study identified several obstacles which must be addressed to improve reproductive health in Afghanistan. There was limited understanding of the importance of antenatal care and a lack of family support. Financial and transportation problems led to underuse of available care, especially by poorly educated rural women. Patients frequently complained of being treated disrespectfully, and health care providers correspondingly complained about poor working conditions leading to exhaustion and a lack of compassion. Widespread corruption, including the necessity of personal contacts inside hospitals, was also emphasized as an obstacle to equitable antenatal and obstetric health care. PMID- 23642218 TI - Tandem synthesis of pyrroloacridones via [3 + 2] alkyne annulation/ring-opening with concomitant intramolecular aldol condensation. AB - An efficient cascade strategy for the direct synthesis of pyrrolo[3,2,1 de]acridones 4a-v, 5a-h from iodo-pyranoquinolines 2a-i by the palladium catalyzed regioselective [3 + 2] alkyne annulation/ring-opening followed by intramolecular aldol condensation under microwave irradiation is described. The chemistry involves the in situ formation of pyrroloquinolines Y, via palladium catalyzed selective [3 + 2] annulation of iodopyranoquinolines and internal akynes with ring-opening and successive intramolecular cross-aldol condensation. Both the symmetrical and unsymmetrical internal alkynes were reacted smoothly to provide the desired pyrroloacridones in good yields. This methodology provides the facile conversion of easily accessble iodopyranoquinoline into highly functionalized biologically important pyrroloacridones in a single process. PMID- 23642219 TI - Analytical technologies for influenza virus-like particle candidate vaccines: challenges and emerging approaches. AB - Influenza virus-like particle vaccines are one of the most promising ways to respond to the threat of future influenza pandemics. VLPs are composed of viral antigens but lack nucleic acids making them non-infectious which limit the risk of recombination with wild-type strains. By taking advantage of the advancements in cell culture technologies, the process from strain identification to manufacturing has the potential to be completed rapidly and easily at large scales. After closely reviewing the current research done on influenza VLPs, it is evident that the development of quantification methods has been consistently overlooked. VLP quantification at all stages of the production process has been left to rely on current influenza quantification methods (i.e. Hemagglutination assay (HA), Single Radial Immunodiffusion assay (SRID), NA enzymatic activity assays, Western blot, Electron Microscopy). These are analytical methods developed decades ago for influenza virions and final bulk influenza vaccines. Although these methods are time-consuming and cumbersome they have been sufficient for the characterization of final purified material. Nevertheless, these analytical methods are impractical for in-line process monitoring because VLP concentration in crude samples generally falls out of the range of detection for these methods. This consequently impedes the development of robust influenza VLP production and purification processes. Thus, development of functional process analytical techniques, applicable at every stage during production, that are compatible with different production platforms is in great need to assess, optimize and exploit the full potential of novel manufacturing platforms. PMID- 23642220 TI - Molecular and cellular mechanisms of neutral lipid accumulation in diatom following nitrogen deprivation. AB - BACKGROUND: Nitrogen limitation can induce neutral lipid accumulation in microalgae, as well as inhibiting their growth. Therefore, to obtain cultures with both high biomass and high lipid contents, and explore the lipid accumulation mechanisms, we implemented nitrogen deprivation in a model diatom Phaeodactylum tricornutum at late exponential phase. RESULTS: Neutral lipid contents per cell subsequently increased 2.4-fold, both the number and total volume of oil bodies increased markedly, and cell density rose slightly. Transcriptional profile analyzed by RNA-Seq showed that expression levels of 1213 genes (including key carbon fixation, TCA cycle, glycerolipid metabolism and nitrogen assimilation genes) increased, with a false discovery rate cut-off of 0.001, under N deprivation. However, most light harvesting complex genes were down-regulated, extensive degradation of chloroplast membranes was observed under an electron microscope, and photosynthetic efficiency declined. Further identification of lipid classes showed that levels of MGDG and DGDG, the main lipid components of chloroplast membranes, dramatically decreased and triacylglycerol (TAG) levels significantly rose, indicating that intracellular membrane remodeling substantially contributed to the neutral lipid accumulation. CONCLUSIONS: Our findings shed light on the molecular mechanisms of neutral lipid accumulation and the key genes involved in lipid metabolism in diatoms. They also provide indications of possible strategies for improving microalgal biodiesel production. PMID- 23642221 TI - alpha-Diazo-beta-ketonitriles: uniquely reactive substrates for arene and alkene cyclopropanation. AB - An investigation of the intramolecular cyclopropanation reactions of alpha-diazo beta-ketonitriles is reported. These studies reveal that alpha-diazo-beta ketonitriles exhibit unique reactivity in their ability to undergo arene cyclopropanation reactions; other similar acceptor-acceptor-substituted diazo substrates instead produce mixtures of C-H insertion and dimerization products. alpha-Diazo-beta-ketonitriles also undergo highly efficient intramolecular cyclopropanation of tri- and tetrasubstituted alkenes. In addition, the alpha cyano-alpha-ketocyclopropane products are demonstrated to serve as substrates for SN2, SN2', and aldehyde cycloaddition reactions. PMID- 23642222 TI - Trifluoromethanesulfonic acid catalyzed friedel-Crafts alkylations of 1,2,4 trimethoxybenzene with aldehydes or benzylic alcohols. AB - Trifluoromethanesulfonic acid in acetonitrile was found to efficiently catalyze Friedel-Crafts alkylations of 1,2,4-trimethoxybenzene with a variety of simple or functionalized aldehydes to provide di- or triarylmethanes in high yields. The operationally simple protocol allowed a short synthesis of the phenylpropanoid natural product (-)-tatarinoid C establishing its absolute configuration. Under the developed reaction conditions a benzylic alcohol instead of an aldehyde also underwent reactions with 1,2,4-trimethoxybenzene and other nucleophiles to afford unsymmetrically substituted compounds. PMID- 23642223 TI - Quantitative analysis of organizational culture in occupational health research: a theory-based validation in 30 workplaces of the organizational culture profile instrument. AB - BACKGROUND: This study advances a measurement approach for the study of organizational culture in population-based occupational health research, and tests how different organizational culture types are associated with psychological distress, depression, emotional exhaustion, and well-being. METHODS: Data were collected over a sample of 1,164 employees nested in 30 workplaces. Employees completed the 26-item OCP instrument. Psychological distress was measured with the General Health Questionnaire (12-item); depression with the Beck Depression Inventory (21-item); and emotional exhaustion with five items from the Maslach Burnout Inventory general survey. Exploratory factor analysis evaluated the dimensionality of the OCP scale. Multilevel regression models estimated workplace-level variations, and the contribution of organizational culture factors to mental health and well-being after controlling for gender, age, and living with a partner. RESULTS: Exploratory factor analysis of OCP items revealed four factors explaining about 75% of the variance, and supported the structure of the Competing Values Framework. Factors were labeled Group, Hierarchical, Rational and Developmental. Cronbach's alphas were high (0.82-0.89). Multilevel regression analysis suggested that the four culture types varied significantly between workplaces, and correlated with mental health and well-being outcomes. The Group culture type best distinguished between workplaces and had the strongest associations with the outcomes. CONCLUSIONS: This study provides strong support for the use of the OCP scale for measuring organizational culture in population-based occupational health research in a way that is consistent with the Competing Values Framework. The Group organizational culture needs to be considered as a relevant factor in occupational health studies. PMID- 23642224 TI - Longitudinal study of rural health workforce in five counties in China: research design and baseline description. AB - BACKGROUND: The village doctors have served rural residents for many decades in China, and their role in rural health system has been highly praised in the world; unfortunately, less attention has been paid to the health workforce during the ambitious healthcare reform in recent years. Therefore, we conducted a longitudinal study to explore the current situation and track the future evolution of the rural healthcare workforce. METHODS: The self-administered structured Village Clinic Questionnaire and Village Doctor Questionnaire, which were modified from the official questionnaires of the Ministry of Health, were constructed after three focus groups, in-depth interviews in Hebei Province, and a pilot survey in Sichuan Province. Using a stratified multistage cluster sampling process, we gathered baseline data for a longitudinal survey of village doctors, village clinics from Changshu County, Liyang County, Yongchuan District, Mianzhu County, and Jingning County in China in 2011. Well-trained interviewers and strict procedures were employed to ensure the quality of this survey. Descriptive and correlation analyses were performed with Stata 12.0. RESULTS: After four months of surveying, 1,982 Village Doctor Questionnaires were collected, and the response rate was 88.1%. There were 1,507 (76.0%) male and 475 (24.0%) female doctors, with an average age of 51.3 years. The majority of village doctors (58.5%) practiced both western medicine and Traditional Chinese Medicine, and 91.2% of the doctors received their education below college level. Their practice methods were not correlated with education level (P = 0.43), but closely related to the way they obtained their highest degree (that is, prior to starting work or as on-the-job training) (P < 0.01). The mean income of the village doctors was 1,817 (95% CI 1,733 to 1,900) RMB per month in 2011; only 757 (41.3%) doctors had pensions, and the self-reported expected pension was 1,965 RMB per month. CONCLUSIONS: Village doctors in rural China are facing critical challenges, including aging, gender imbalance, low education, and a lack of social protection. This study may be beneficial for making better policies for the development of the health workforce and China's healthcare reform. PMID- 23642225 TI - Phase I/II RAF kinase inhibitors in cancer therapy. AB - INTRODUCTION: Aberrant activation of RAF signalling is a frequent finding in human cancers. BRAF is the only RAF family member that is commonly mutated, whilst CRAF and ARAF play important roles in the signal transduction from mutant RAS. BRAF-specific inhibitors have been more effective in the treatment of BRAF mutant melanoma than BRAF-mutant thyroid and colorectal cancers. AREAS COVERED: The review summarises the experience with RAF kinase inhibitors, including efficacy, modes of acquired resistance, and the mechanism behind the progression of pre-malignant RAS-mutant lesions observed with RAF kinase inhibitors. The authors review all the completed and ongoing Phase I or II clinical trials of RAF kinase inhibitors and discuss in detail the rationale behind the combinatorial approaches. EXPERT OPINION: The success of RAF kinase inhibitors has demonstrated the necessity of genotype-driven treatment selection for cancer patients. The spectrum of responses in different tumour types is explained by feedback events that are determined by cell lineage. Dissection of these events and the mechanisms of acquired resistance will determine the appropriate combination therapies. Ongoing characterisation of RAS-MAPK regulation in malignant cells may aid the development of novel agents that have greater potency for the inhibition of activated RAF kinase, and lesser propensity for promotion of RAS-mutant tumours. PMID- 23642226 TI - Vibrational perturbations of W(CO)6 trapped in a molecular lattice probed by linear and nonlinear spectroscopy. AB - Vibrational dynamics of the T1u CO stretching mode of tungsten hexacarbonyl is explored when the molecule is embedded in a nitrogen matrix at low temperature. Experiments combined infrared (IR) absorption spectroscopy and IR stimulated photon echoes at the femtosecond time scale. W(CO)6 is found to be trapped in two main families of sites differing by their symmetry (called hereafter Oh and D2h sites). In Oh sites, the vibrational coherence is strongly temperature dependent, exhibiting a coupling with librational phonons of the nitrogen lattice. Perturbation in D2h sites results in the splitting of the T1u band in three components. Each component is inhomogeneously broadened, with dephasing times in the tens of picoseconds, and is weakly coupled to the lattice phonons. Experiments in solid krypton are performed to compare the effect of atomic and diatomic host lattices. Dephasing time in Kr does not depend on temperature and remains in the hundreds of picoseconds, highlighting the molecular origin of the dephasing process in N2. Additionally, nonlinear signals show oscillations due to quantum beats and polarization interferences between different frequency components of the induced third order polarization, giving information, in particular, on the overtone vibrational transition. PMID- 23642227 TI - Perturbations in skeletal muscle sarcomere structure in patients with heart failure and type 2 diabetes: restorative effects of (-)-epicatechin-rich cocoa. AB - HF (heart failure) and T2D (Type 2 diabetes) associate with detrimental alterations in SkM (skeletal muscle) structure/function. We have demonstrated recently that (-)-ERC (epicatechin-rich cocoa) improves SkM mitochondrial structure [Taub, Ramirez-Sanchez, Ciaraldi, Perkins, Murphy, Naviaux, Hogan, Ceballos, Maisel, Henry et al. (2012) Clin. Trans. Sci. 5, 43-47]. We hypothesized that an improved mitochondrial structure may facilitate the reversal of detrimental alterations in sarcomeric microstructure. In a pilot study, five patients with HF and T2D consumed ERC for 3 months; treadmill testing [VO2max (maximum oxygen consumption)] and SkM biopsies were performed. Western blot analysis, immunohistochemistry and electron microscopy were used. We report severe perturbations in components of the DAPC (dystrophin-associated protein complex) as well as sarcomeric microstructure at baseline. ERC induced recovery/enhancement of DAPC protein levels, sarcomeric microstructure and, in a co-ordinated fashion, alterations in markers of SkM growth/differentiation consistent with myofibre regeneration. VO2max increased (~24%) but did not reach statistical significance. These initial results warrant further rigorous investigation, since the use of ERC (or pure epicatechin) may represent a safe and novel means of improving muscle function. PMID- 23642228 TI - Imaging cell surface glycosylation in vivo using "double click" chemistry. AB - Dynamic alterations in cell surface glycosylation occur in numerous biological processes that involve cell-cell communication and cell migration. We report here imaging of cell surface glycosylation in live mice using double click chemistry. Cell surface glycans were metabolically labeled using peracetylated azido-labeled N-acetylgalactosamine and then reacted, in the first click reaction, with either a cyclooctyne, in a Huisgen [3 + 2] cycloaddition, or with a Staudinger phosphine, via Staudinger ligation. The second click reaction was a [4 + 2] inverse electron demand Diels-Alder reaction between a trans-cyclooctene and a tetrazine, where the latter reagent had been fluorescently labeled with a far-red fluorophore. After administration of the fluorescent tetrazine, the bifunctional cyclooctyne-cyclooctene produced significant azido sugar-dependent fluorescence labeling of tumor, kidney, liver, spleen, and small intestine in vivo, where the kidney and tumor could be imaged noninvasively in the live mouse. PMID- 23642230 TI - Effect of transglutaminase on the mechanical and barrier properties of whey protein/pectin films prepared at complexation pH. AB - The behavior of pectin and thermally denatured whey proteins at both different protein/polysaccharide ratios and different pH values was investigated. Our findings suggest the formation at pH 5.1 (complexation pH) of transglutaminase catalyzed cross-links among soluble ionic whey protein/pectin complexes, which could be responsible for the observed increase of both tensile strength (2-fold) and elongation to break (10-fold) of films obtained in the presence of enzyme. Conversely, a significant reduction of elasticity, probably due to the formation of covalent bonds among single whey protein molecules, was observed when the films were prepared in the presence of the enzyme at pH 6.0. In addition, the presence of the enzyme at complexation pH significantly reduced film permeability. Atomic force and scanning electron microscopy revealed significant changes in the microstructure of the films prepared in the presence of TGase as well as in the morphology of their surface. PMID- 23642229 TI - Readout of epigenetic modifications. AB - This review focuses on a structure-based analysis of histone posttranslational modification (PTM) readout, where the PTMs serve as docking sites for reader modules as part of larger complexes displaying chromatin modifier and remodeling activities, with the capacity to alter chromatin architecture and templated processes. Individual topics addressed include the diversity of reader-binding pocket architectures and common principles underlying readout of methyl-lysine and methyl-arginine marks, their unmodified counterparts, as well as acetyl lysine and phosphoserine marks. The review also discusses the impact of multivalent readout of combinations of PTMs localized at specific genomic sites by linked binding modules on processes ranging from gene transcription to repair. Additional topics include cross talk between histone PTMs, histone mimics, epigenetic-based diseases, and drug-based therapeutic intervention. The review ends by highlighting new initiatives and advances, as well as future challenges, toward the promise of enhancing our structural and mechanistic understanding of the readout of histone PTMs at the nucleosomal level. PMID- 23642231 TI - Malaria infection does not affect the sensitivity of peripheral receptor neurons in Anopheles stephensi. AB - BACKGROUND: Mosquitoes transmit many important diseases including malaria, dengue and yellow fever. Disease transmission from one vertebrate host to another depends on repeated blood feedings by single mosquitoes. In order for the mosquito to acquire the blood that it needs to complete oogenesis, the insect must locate a suitable host. Olfactory cues (including carbon dioxide) released by the host and detected by the mosquito are the primary signals that vector insects use for host location. Previous studies have suggested that the physiological status - including bacterial, fungal, viral and Plasmodium infections - can modulate aspects of behavior in haematophagous insects. METHODS: Standard electrophysiological techniques were used to record extracellular responses from the receptor neurons located in sensilla found on the maxillary palps of the insects. The recording microelectrode was inserted through the cuticle at the base of an individual sensillum and the extracellular electrical signals obtained from the three neurons within the sensillum were recorded. Stimulations consisted of 2 s pulses of the desired concentrations of CO(2) or dosages of 1-octen-3-ol. RESULTS: Accordingly, we were interested in determining whether Plasmodium infection affects the sensitivity of those peripheral olfactory sensors that are involved in host-seeking in mosquitoes. Our studies indicate that infection of female Anopheles stephensi with Plasmodium berghei does not alter the response characteristics of the neurons innervating the maxillary palp sensilla that respond to the attractants carbon dioxide and 1 octen-3-ol. Although the response characteristics of the peripheral sensory neurons are not affected by infection status, we found that the age of the mosquito alone does affect the threshold of sensitivity of these neurons to carbon dioxide. The proportion of older insects (21-30 d post-emergence) that responds to 150 ppm carbon dioxide is higher than the proportion that responds among younger insects (1-10 d post-emergence). CONCLUSIONS: Anopheles stephensi infected with Plasmodium berghei exhibit sensitivities to stimulation with carbon dioxide and 1-octen-3-ol similar to those of uninfected mosquitoes. However, the age of the infected or uninfected mosquito does affect the threshold of sensitivity of these neurons to carbon dioxide. PMID- 23642232 TI - Expression of matrix metalloproteinase-12 in aortic dissection. AB - BACKGROUND: Aortic dissection(AD) is an acute process of large blood vessels characterized by dangerous pathogenic conditions and high disability and high mortality. The pathogenesis of AD remains debated. Matrix metalloproteinase-12 (MMP-12) participates in many pathological processes such as abdominal aortic aneurysm, atherosclerosis, emphysema and cancer. However, this elastase has rarely been assessed in the presence of AD. The aim of the present study was to investigate the expression of MMP-12 in aortic tissue so as to offer a better understanding of the possible mechanisms of AD. METHODS: The protein expression levels of MMP-12 were analyzed and compared in aorta tissue and the blood serum samples by reverse transcription polymerase chain reaction(RT-PCR), Western blotting, immuno-histochemistry, fluorescence resonance energy transfer ( FRET ) activity assay and enzyme-linked immuno sorbent assay ( ELISA ), respectively. Ascending aorta tissue specimens were obtained from 12 patients with an acute Stanford A-dissection at the time of aortic replacement, and from 4 patients with coronary artery disease (CAD) undergoing coronary artery bypass surgery. Meanwhile, serum samples were harvested from 15 patients with an acute Stanford A dissection and 10 healthy individuals who served as the control group. RESULTS: MMP-12 activity could be detected in both AD and CAD groups, but the level in the AD group was higher than those in the CAD group (P < 0.05). MMP-12 proteolysis existed in both serum samples of the AD and healthy groups, and the activity level in the AD group was clearly higher than in the healthy group (P < 0.05). For AD patients, MMP-12 activity in serum was higher than in the aorta wall (P < 0.05). MMP-12 activity in the aortic wall tissue can be inhibited by MMP inhibitor v (P < 0.05). CONCLUSION: The present study directly demonstrates that MMP-12 proteolytic activity exists within the aorta specimens and blood samples from aortic dissection patients. MMP-12 might be of potential relevance as a clinically diagnostic tool and therapeutic target in vascular injury and repair. PMID- 23642233 TI - Zwitterionic phenyl layers: finally, stable, anti-biofouling coatings that do not passivate electrodes. AB - Organic coatings on electrodes that limit biofouling by proteins but are of sufficiently low impedance to still allow Faradaic electrochemistry to proceed at the underlying electrode are described for the first time. These organic coatings formed using simple aryl diazonium salts present a zwitterionic surface and exhibit good electrochemical stability. The layers represent a low impedance alternative to the oligo (ethylene glycol) (OEG)-based anti-biofouling coatings and are expected to find applications in electrochemical biosensors and implantable electrodes. Two different zwitterionic layers grafted to glassy carbon surfaces are presented and compared to a number of better-known surfaces, including OEG-based phenyl-layer-grafted glassy carbon surfaces and OEG alkanethiol SAMs coated on gold, to allow the performance of these new layers to be compared to the body of work on other anti-biofouling surfaces. The results suggest that phenyl-based zwitterionic coatings are as effective as the OEG SAMs at resisting the nonspecific adsorption of bovine serum albumin and cytochrome c, as representative anionic and cationic proteins at physiological pH, whereas the impedance of the zwitterionic phenyl layers are two orders of magnitude lower than OEG SAMs. PMID- 23642234 TI - Influence of gender and age on the survival of patients with nasopharyngeal carcinoma. AB - BACKGROUND: The prognostic value of gender and age in the survival of nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT) is unclear. Several studies have suggested a female advantage in the prognosis of solid tumors. We investigated the relationship between gender differences and disease outcome in NPC patients treated with IMRT in South China. METHODS: A total of 299 patients with non-disseminated NPC were analyzed retrospectively. IMRT was delivered with a simultaneous modulated, accelerated radiotherapy boost technique at prescribed doses of 70 Gy/30 fractions/6 weeks to the primary tumor (GTVp) and positive neck nodes (GTVn), 60Gy (2.0 Gy/day) to the clinical target volume (CTV) and upper neck region and 54 Gy (1.8 Gy/day) to the clinically negative low neck. A median boost dose of 9.2 Gy (4-20 Gy) was administered to patients with persistent disease at the primary site. RESULTS: With a median follow-up of 52 months, the male patients had a significantly unfavorable 5-year OS (70.7% compared to 94.1%, P < 0.001), DPFS (71.5% compared to 87.3%, P = 0.029) and DMFS (77.2% compared to 89.7%, P = 0.036) than the female patients. In patients younger than 45, the male patients had a poorer 5 year OS (66.8% compared to 91.2%, P = 0.008), DPFS (59.9% compared to 91.2%, P = 0.005) and DMFS (66.4% compared to 94.0%, P = 0.004) than the female patients. For patients older than 45, only the 5-year OS (72.2% compared to 96.0%, P = 0.001) was significantly different. CONCLUSIONS: Gender and age are strong independent prognostic factors for NPC in this study. We are the first to report that younger male patients were more likely to have distant metastases and exhibited inferior overall survival and disease progression-free survival rates compared to other patients. PMID- 23642235 TI - Baclofen into the lateral parabrachial nucleus induces hypertonic sodium chloride intake during cell dehydration. AB - BACKGROUND: Activation of GABA(B) receptors with baclofen into the lateral parabrachial nucleus (LPBN) induces ingestion of water and 0.3 M NaCl in fluid replete rats. However, up to now, no study has investigated the effects of baclofen injected alone or combined with GABA(B) receptor antagonist into the LPBN on water and 0.3 M NaCl intake in rats with increased plasma osmolarity (rats treated with an intragastric load of 2 M NaCl). Male Wistar rats with stainless steel cannulas implanted bilaterally into the LPBN were used. RESULTS: In fluid replete rats, baclofen (0.5 nmol/0.2 MUl), bilaterally injected into the LPBN, induced ingestion of 0.3 M NaCl (14.3 +/- 4.1 vs. saline: 0.2 +/- 0.2 ml/210 min) and water (7.1 +/- 2.9 vs. saline: 0.6 +/- 0.5 ml/210 min). In cell dehydrated rats, bilateral injections of baclofen (0.5 and 1.0 nmol/0.2 MUl) into the LPBN induced an increase of 0.3 M NaCl intake (15.6 +/- 5.7 and 21.5 +/- 3.5 ml/210 min, respectively, vs. saline: 1.7 +/- 0.8 ml/210 min) and an early inhibition of water intake (3.5 +/- 1.4 and 6.7 +/- 2.1 ml/150 min, respectively, vs. saline: 9.2 +/- 1.4 ml/150 min). The pretreatment of the LPBN with 2 hydroxysaclofen (GABA(B) antagonist, 5 nmol/0.2 MUl) potentiated the effect of baclofen on 0.3 M NaCl intake in the first 90 min of test and did not modify the inhibition of water intake induced by baclofen in cell-dehydrated rats. Baclofen injected into the LPBN did not affect blood pressure and heart rate. CONCLUSIONS: Thus, injection of baclofen into the LPBN in cell-dehydrated rats induced ingestion of 0.3 M NaCl and inhibition of water intake, suggesting that even in a hyperosmotic situation, the blockade of LPBN inhibitory mechanisms with baclofen is enough to drive rats to drink hypertonic NaCl, an effect independent of changes in blood pressure. PMID- 23642236 TI - A novel pathway to produce butanol and isobutanol in Saccharomyces cerevisiae. AB - BACKGROUND: The sustainable production of biofuels remains one of the major issues of the upcoming years. Among the number of most desirable molecules to be produced, butanol and isobutanol deserve a prominent place. They have superior liquid-fuel features in respect to ethanol. Particularly, butanol has similar properties to gasoline and thus it has the potential to be used as a substitute for gasoline in currently running engines. Clostridia are recognized as natural and good butanol producers and are employed in the industrial-scale production of solvents. Due to their complex metabolic characteristics and to the difficulty of performing genetic manipulations, in recent years the Clostridia butanol pathway was expressed in other microorganisms such as Escherichia coli and Saccharomyces cerevisiae, but in yeast the obtained results were not so promising. An alternative way for producing fusel alcohol is to exploit the degradation pathway of aminoacids released from protein hydrolysis, where proteins derive from exhausted microbial biomasses at the end of the fermentation processes. RESULTS: It is known that wine yeasts can, at the end of the fermentation process, accumulate fusel alcohols, and butanol is among them. Despite it was quite obvious to correlate said production with aminoacid degradation, a putative native pathway was never proposed. Starting from literature data and combining information about different organisms, here we demonstrate how glycine can be the substrate for butanol and isobutanol production, individuating at least one gene encoding for the necessary activities leading to butanol accumulation. During a kinetic of growth using glycine as substrate, butanol and isobutanol accumulate in the medium up to 92 and 58 mg/L, respectively. CONCLUSIONS: Here for the first time we demonstrate an alternative metabolic pathway for butanol and isobutanol production in the yeast S. cerevisiae, using glycine as a substrate. Doors are now opened for a number of optimizations, also considering that starting from an aminoacid mixture as a side stream process, a fusel alcohol blend can be generated. PMID- 23642237 TI - Polymorphism in cisplatin anticancer drug. AB - This study reports a combined experimental and theoretical study of the solid state polymorphism of the anticancer agent cisplatin. A complete assignment was performed for the inelastic neutron scattering (INS) and Raman spectra collected simultaneously for cisplatin, at different temperatures, with a view to obtain reliable and definitive evidence of the relative thermal stability of its alpha and beta polymorphic species. A marked temperature-dependent hysteresis was observed, as previously reported in the literature. Theoretical calculations were carried out at the density functional theory level, using a plane-wave basis set approach and pseudopotentials. A detailed comparison with the experimental Raman and INS data showed that the alpha polymorph is present at the lowest temperatures, whereas the beta form occurs near room temperature. Furthermore, regions of coexistence of both forms are identified, which depend on the working mode (heating or cooling). These findings imply that Raman spectroscopy allows clear identification of the alpha and beta polymorphs at a given temperature and can unambiguously discriminate between them. Elucidation of the polymorphic equilibrium of this widely used anticancer drug is paramount for its pharmaceutical preparation and storage conditions. PMID- 23642238 TI - The delivery of preventive care to clients of community health services. AB - BACKGROUND: Smoking, poor nutrition, risky alcohol use, and physical inactivity are the primary behavioral risks for common causes of mortality and morbidity. Evidence and guidelines support routine clinician delivery of preventive care. Limited evidence describes the level delivered in community health settings. The objective was to determine the: prevalence of preventive care provided by community health clinicians; association between client and service characteristics and receipt of care; and acceptability of care. This will assist in informing interventions that facilitate adoption of opportunistic preventive care delivery to all clients. METHODS: In 2009 and 2010 a telephone survey was undertaken of 1284 clients across a network of 56 public community health facilities in one health district in New South Wales, Australia. The survey assessed receipt of preventive care (assessment, brief advice, and referral/follow-up) regarding smoking, inadequate fruit and vegetable consumption, alcohol overconsumption, and physical inactivity; and acceptability of care. RESULTS: Care was most frequently reported for smoking (assessment: 59.9%, brief advice: 61.7%, and offer of referral to a telephone service: 4.5%) and least frequently for inadequate fruit or vegetable consumption (27.0%, 20.0% and 0.9% respectively). Sixteen percent reported assessment for all risks, 16.2% received brief advice for all risks, and 0.6% were offered a specific referral for all risks. The following were associated with increased care: diabetes services, number of appointments, being male, Aboriginal, unemployed, and socio economically disadvantaged. Acceptability of preventive care was high (76.0% 95.3%). CONCLUSIONS: Despite strong client support, preventive care was not provided opportunistically to all, and was preferentially provided to select groups. This suggests a need for practice change strategies to enhance preventive care provision to achieve adherence to clinical guidelines. PMID- 23642239 TI - Granulocyte-macrophage colony-stimulating factor-armed oncolytic measles virus is an effective therapeutic cancer vaccine. AB - Oncolytic measles viruses (MV) derived from the live attenuated vaccine strain have been engineered for increased antitumor activity, and are currently under investigation in clinical phase 1 trials. Approaches with other viral vectors have shown that insertion of immunomodulatory transgenes enhances the therapeutic potency. In this study, we engineered MV for expression of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). For the first time, therapeutic efficacy and adaptive immune response in the context of MV oncolysis could be evaluated in the previously established immunocompetent murine colon adenocarcinoma model MC38cea. MC38cea cells express the human carcinoembryonic antigen (CEA), allowing for infection with retargeted MV. Intratumoral application of MV-GMCSF significantly delayed tumor progression and prolonged median overall survival compared with control virus-treated mice. Importantly, more than one-third of mice treated with MV-GMCSF showed complete tumor remission and rejected successive tumor reengraftment, demonstrating robust long-term protection. An enhanced cell-mediated tumor-specific immune response could be detected by lactate dehydrogenase assay and interferon-gamma enzyme-linked immunospot assay. Furthermore, MV-GMCSF treatment correlated with increased abundance of tumor-infiltrating CD3(+) lymphocytes analyzed by quantitative microscopy of tumor sections. These findings underline the potential of oncolytic, GM-CSF-expressing MV as an effective therapeutic cancer vaccine actively recruiting adaptive immune responses for enhanced therapeutic impact and tumor elimination. Thus, the treatment benefit of this combined immunovirotherapy approach has direct implications for future clinical trials. PMID- 23642240 TI - Respiratory illness healthcare-seeking behavior assessment in the Lao People's Democratic Republic (Laos). AB - BACKGROUND: Respiratory illness (RI) remains a public health problem in Laos, but little is known about the overall burden and people's healthcare-seeking behavior for RI. Understanding the burden of RI and community patterns of healthcare seeking behavior would provide better guidance for Lao public health program and policy planners to improve RI public health practice, surveillance systems, and prevention strategies. METHODS: A quantitative and qualitative survey was conducted in 14 randomly selected villages of two purposively selected peri-urban and two rural provinces in Laos. A pre-designed and pre-tested questionnaire was used to collect information on RI in household members (defined as new fever with cough and/or sore-throat in the absence of other diagnoses during the preceding 30 days) from all heads of household in each village. Sixteen focus group discussions were conducted to obtain more information to support the quantitative survey. RESULTS: Among 1,751 households (9,114 people) studied, 3.5% (317/9,114) had experienced RI (fever, cough, and/or sore-throat) in the 30 days before the survey [6.2% in rural and 2.4% in peri-urban areas (p<0.001)]. The percentage of RI among persons aged>=15 years was 2.7%, 3.7% for those aged 5-14 years, and 8.2% for children<5 years (p<0.001). Of all sick persons, 71% sought treatment [94% in peri-urban and 48% in rural areas (p<0.001)] and 31.5% of them self medicated [55.5% in peri-urban and 29% in rural areas (p<0.001)]. Sick people in peri-urban areas preferred to chose private clinics and pharmacies as their first treatment option while in rural areas they frequently consulted with village health volunteers and visited health centres as their first choice. The qualitative study suggests that distance, costs of care, and service availability are the most important determinants of seeking healthcare. CONCLUSIONS: The RI burden and healthcare-seeking behavior are different between rural and peri-urban areas of Laos and this is probably due to the differences in environmental and hygienic conditions, health service availability and socio-economic status between the two areas. Therefore strategies for healthcare service improvement may also need to differ between the two areas. PMID- 23642242 TI - Mechanics in neuronal development and repair. AB - Biological cells are well known to respond to a multitude of chemical signals. In the nervous system, chemical signaling has been shown to be crucially involved in development, normal functioning, and disorders of neurons and glial cells. However, there are an increasing number of studies showing that these cells also respond to mechanical cues. Here, we summarize current knowledge about the mechanical properties of nervous tissue and its building blocks, review recent progress in methodology and understanding of cellular mechanosensitivity in the nervous system, and provide an outlook on the implications of neuromechanics for future developments in biomedical engineering to aid overcoming some of the most devastating and currently incurable CNS pathologies such as spinal cord injuries and multiple sclerosis. PMID- 23642241 TI - Microfluidics and coagulation biology. AB - The study of blood ex vivo can occur in closed or open systems, with or without flow. Microfluidic devices, which constrain fluids to a small (typically submillimeter) scale, facilitate analysis of platelet function, coagulation biology, cellular biorheology, adhesion dynamics, and pharmacology and, as a result, can be an invaluable tool for clinical diagnostics. An experimental session can accommodate hundreds to thousands of unique clotting, or thrombotic, events. Using microfluidics, thrombotic events can be studied on defined surfaces of biopolymers, matrix proteins, and tissue factor, under constant flow rate or constant pressure drop conditions. Distinct shear rates can be generated on a device using a single perfusion pump. Microfluidics facilitated both the determination of intraluminal thrombus permeability and the discovery that platelet contractility can be activated by a sudden decrease in flow. Microfluidic devices are ideal for multicolor imaging of platelets, fibrin, and phosphatidylserine and provide a human blood analog to mouse injury models. Overall, microfluidic advances offer many opportunities for research, drug testing under relevant hemodynamic conditions, and clinical diagnostics. PMID- 23642245 TI - The pivotal role of vascularization in tissue engineering. AB - Vascularization is one of the great challenges that tissue engineering faces in order to achieve sizeable tissue and organ substitutes that contain living cells. There are instances, such as skin replacement, in which a tissue-engineered substitute does not absolutely need a preexisting vascularization. However, tissue or organ substitutes in which any dimension, such as thickness, exceeds 400 MUm need to be vascularized to ensure cellular survival. Consistent with the wide spectrum of approaches to tissue engineering itself, which vary from acellular synthetic biomaterials to purely biological living constructs, approaches to tissue-engineered vascularization cover numerous techniques. Those techniques range from micropatterns engineered in biomaterials to microvascular networks created by endothelial cells. In this review, we strive to provide a critical overview of the elements that must be considered in the pursuit of this goal and the major approaches that are investigated in hopes of achieving it. PMID- 23642243 TI - Multifunctional nanoparticles for drug delivery and molecular imaging. AB - Recent advances in nanotechnology and growing needs in biomedical applications have driven the development of multifunctional nanoparticles. These nanoparticles, through nanocrystalline synthesis, advanced polymer processing, and coating and functionalization strategies, have the potential to integrate various functionalities, simultaneously providing (a) contrast for different imaging modalities, (b) targeted delivery of drug/gene, and (c) thermal therapies. Although still in its infancy, the field of multifunctional nanoparticles has shown great promise in emerging medical fields such as multimodal imaging, theranostics, and image-guided therapies. In this review, we summarize the techniques used in the synthesis of complex nanostructures, review the major forms of multifunctional nanoparticles that have emerged over the past few years, and provide a perceptual vision of this important field of nanomedicine. PMID- 23642244 TI - Functional attachment of soft tissues to bone: development, healing, and tissue engineering. AB - Connective tissues such as tendons or ligaments attach to bone across a multitissue interface with spatial gradients in composition, structure, and mechanical properties. These gradients minimize stress concentrations and mediate load transfer between the soft and hard tissues. Given the high incidence of tendon and ligament injuries and the lack of integrative solutions for their repair, interface regeneration remains a significant clinical challenge. This review begins with a description of the developmental processes and the resultant structure-function relationships that translate into the functional grading necessary for stress transfer between soft tissue and bone. It then discusses the interface healing response, with a focus on the influence of mechanical loading and the role of cell-cell interactions. The review continues with a description of current efforts in interface tissue engineering, highlighting key strategies for the regeneration of the soft tissue-to-bone interface, and concludes with a summary of challenges and future directions. PMID- 23642248 TI - Replacing antibodies: engineering new binding proteins. AB - Nature's reliance on proteins to carry out nearly all biological processes has led to the evolution of biomolecules that exhibit a seemingly endless range of functions. Much research has been devoted toward advancing this process in the laboratory in order to create new proteins with improved or unique capabilities. The protein-engineering field has rapidly evolved from pioneering studies in engineering protein stability and activity to an application-driven powerhouse on the forefront of emerging technologies in biomedical engineering and biotechnology. A classic protein-engineering technique in the medical field has focused on manipulating antibodies and antibody fragments for various applications. New classes of alternative scaffolds have recently challenged this paradigm, and these structures have been successfully engineered for applications including targeted cancer therapy, regulated drug delivery, in vivo imaging, and a host of others. This review aims to capture recent advances in the engineering of nonimmunoglobulin scaffolds as well as some of the applications for these molecular recognition elements in the biomedical field. PMID- 23642246 TI - Atlas-based neuroinformatics via MRI: harnessing information from past clinical cases and quantitative image analysis for patient care. AB - With the ever-increasing amount of anatomical information radiologists have to evaluate for routine diagnoses, computational support that facilitates more efficient education and clinical decision making is highly desired. Despite the rapid progress of image analysis technologies for magnetic resonance imaging of the human brain, these methods have not been widely adopted for clinical diagnoses. To bring computational support into the clinical arena, we need to understand the decision-making process employed by well-trained clinicians and develop tools to simulate that process. In this review, we discuss the potential of atlas-based clinical neuroinformatics, which consists of annotated databases of anatomical measurements grouped according to their morphometric phenotypes and coupled with the clinical informatics upon which their diagnostic groupings are based. As these are indexed via parametric representations, we can use image retrieval tools to search for phenotypes along with their clinical metadata. The review covers the current technology, preliminary data, and future directions of this field. PMID- 23642249 TI - Engineered culture models for studies of tumor-microenvironment interactions. AB - Heterogeneous microenvironmental conditions play critical roles in cancer pathogenesis and therapy resistance and arise from changes in tissue dimensionality, cell-extracellular matrix (ECM) interactions, soluble factor signaling, oxygen as well as metabolic gradients, and exogeneous biomechanical cues. Traditional cell culture approaches are restricted in their ability to mimic this complexity with physiological relevance, offering only partial explanation as to why novel therapeutic compounds are frequently efficacious in vitro but disappoint in preclinical and clinical studies. In an effort to overcome these limitations, physical sciences-based strategies have been employed to model specific aspects of the cancer microenvironment. Although these strategies offer promise to reveal the contributions of microenvironmental parameters on tumor initiation, progression, and therapy resistance, they, too, frequently suffer from limitations. This review highlights physicochemical and biological key features of the tumor microenvironment, critically discusses advantages and limitations of current engineering strategies, and provides a perspective on future opportunities for engineered tumor models. PMID- 23642247 TI - Multiscale computational models of complex biological systems. AB - Integration of data across spatial, temporal, and functional scales is a primary focus of biomedical engineering efforts. The advent of powerful computing platforms, coupled with quantitative data from high-throughput experimental methodologies, has allowed multiscale modeling to expand as a means to more comprehensively investigate biological phenomena in experimentally relevant ways. This review aims to highlight recently published multiscale models of biological systems, using their successes to propose the best practices for future model development. We demonstrate that coupling continuous and discrete systems best captures biological information across spatial scales by selecting modeling techniques that are suited to the task. Further, we suggest how to leverage these multiscale models to gain insight into biological systems using quantitative biomedical engineering methods to analyze data in nonintuitive ways. These topics are discussed with a focus on the future of the field, current challenges encountered, and opportunities yet to be realized. PMID- 23642250 TI - Impact of combined oral contraceptives containing ethinylestradiol on the liver microsomal metabolism. AB - OBJECTIVES: To check whether currently used combined oral contraceptives (COCs) containing ethinylestradiol (EE) affect the liver microsomal metabolism. METHODS: (13)C-methacetin breath test ((13)C-MBT) - a sensitive non-invasive probe of cytochrome P-450 1A2 activity - was performed in 15 women on day 14, 15, 16, 17 or 18 of intake of their COC (containing EE), and between day 1 and 5 during the withdrawal bleeding, as well as in nine women not using hormonal contraception during the luteal phase of their cycle (between the 17th and the 23rd day), and between day 1 and 5 during menstruation. RESULTS: The maximum breath (13)C elimination was significantly lower during the phase of intake of contraceptive pills than during withdrawal bleeding: 31.5 +/- 2.2 %/h vs. 38.2 +/- 1.9 %/h (p = 0.0045), whereas the time to reach it was similar on the two study days: 21.2 +/- 1.2 min vs. 21.0 +/- 1.1 min. Between the 27th and the 180th min of observation the cumulative breath (13)C elimination was statistically significantly lower during intake of the pill than during withdrawal bleeding. No significant menstrual cycle phase-dependent fluctuations in the results of the (13)C- methacetin breath test were observed in the control group. CONCLUSION: COCs containing EE markedly inhibit hepatic microsomal function. This phenomenon must be taken into consideration when interpreting results of (13)C-MBT. PMID- 23642251 TI - Improved benchmark-multiplier method to estimate the prevalence of ever-injecting drug use in Belgium, 2000-10. AB - BACKGROUND: Accurate estimates of the size of the drug-using populations are essential for evidence-based policy making. However, drug users form a 'hidden' population, necessitating the use of indirect methods to estimate population sizes. METHODS: The benchmark-multiplier method was applied to estimate the population size of ever injecting drug users (ever-IDUs), aged 18-64 years, in Belgium using data from the national HIV/AIDS register and from a sero-behavioral study among injecting drug users. However, missing risk factor information and absence of follow-up of the HIV+/AIDS- cases, limits the usefulness of the Belgian HIV/AIDS register as benchmark. To overcome these limitations, statistical corrections were required. In particular, Imputation by Chained Equations was used to correct for the missing risk factor information whereas stochastic mortality modelling was applied to account for the mortality among the HIV+/AIDS- cases. Monte Carlo simulation was used to obtain confidence intervals, properly reflecting the uncertainty due to random error as well as the uncertainty associated with the two statistical corrections mentioned above. RESULTS: In 2010, the prevalence (/1000) of ever-IDUs was estimated to be 3.5 with 95% confidence interval [2.5;4.8]. No significant time trends were observed for the period 2000-2010. CONCLUSIONS: To be able to estimate the ever-IDU population size using the Belgian HIV/AIDS register as benchmark, statistical corrections were required without which seriously biased estimates would result. By developing the improved methodology, Belgium is again able to provide ever-IDU population estimates, which are essential to assess the coverage of treatment and to forecast health care needs and costs. PMID- 23642252 TI - A photoresponsive supramolecular G-quadruplex. AB - Photoirradiation of a hexadecameric supramolecular G-quadruplex leads to a diastereoselective [2 + 2] cyclodimerization of half of its constituent subunits, which in turn shifts the equilibrium toward the formation of a precise heteromeric octamer. PMID- 23642253 TI - Graphical identification of cancer-associated gene subnetworks based on small proteomics data sets. AB - Proteomics is a rapidly emerging frontier in post-genomics medicine and biology, but the quantitative analysis and validation of proteomic data are in need of further improvements. Before selecting potential candidate proteomic biomarkers, it is important to understand the broader context of how biological processes are regulated under different conditions or in different phenotypes. The enrichment of proteomic data consists of extracting as much biological meaning as possible from curated, pathway-based, functional protein interaction networks. Currently, most of the enrichment tools are intended for microarray data and require parametric data, whereas proteomic data are often nonparametric. In this study, we aimed to select a suite of interactive tools that can enrich proteomic results with a graphical overview. This facilitated diagnosis and interpretation prior to further analysis. From a list of proteins, a network was constructed using a map of the most severely disrupted biological process, and the disease entity was then identified on the basis of clinical data. Taken together, this graphical and interactive method ranks potential proteins via functional analysis in order to improve the choice of biomarkers for validation with the following advantages: 1) It adds neighbor proteins that are not selected by mass spectrometry analysis, but could in fact be key proteins; 2) pinpoints the biological process most often involved; and 3) predicts the most likely disease on the basis of clinical data. PMID- 23642254 TI - End of life care for frail older patients in family practice (ELFOP)--protocol of a longitudinal qualitative study on needs, appropriateness and utilisation of services. AB - BACKGROUND: Frail elderly people represent a major patient group in family practice. Little is known about the patients' needs, and how their needs evolve over time with increasing frailty towards the end of life. This study will address end-of-life care needs, service utilisation, and experiences of frail elderly patients and their informal caregivers, with regard to family practice. This paper aims to introduce the research protocol. METHODS/DESIGN: The study uses a multiple perspective approach qualitative design. The first study part consists of serial six-monthly in-depth interviews with 30 community-dwelling elderly patients (>=70 years) with moderate to severe frailty and their key informal caregivers, over a period of 18 months. Additionally, semi-structured interviews with the patients' family physician will be conducted. The serial interviews will be analysed with grounded theory and narrative approaches. Special attention will be paid to the comparison of distinct views of the patients', informal caregivers', and family physicians' as well as on chronological aspects. In the second study part, five focus groups with experts in family medicine, geriatrics, palliative medicine, and nursing will be conducted. Finally, the implications for family practice and health care policy will be discussed in an expert workshop. DISCUSSION: To our knowledge, this is the first prospective, longitudinal qualitative study on the needs of elderly patients with advanced frailty towards the end of life in German family practice, which integrates the perspectives of patients, informal caregivers, family physicians and other health professionals. The study will contribute to the understanding of the clinical, psychosocial and information needs of patients and their caregivers, and of respective changes of experiences and needs along the illness/frailty trajectory including the last phase of life. It will provide an empirical basis for improving patient-centred care for this increasingly relevant target group. PMID- 23642255 TI - Motor regulation problems and pain in adults diagnosed with ADHD. AB - BACKGROUND: Most children who are diagnosed with attention deficit-hyperactivity disorder (ADHD) have moderate-to-severe motor problems using the Motor Function Neurological Assessment battery (MFNU). The MFNU focuses on specific muscle adjustment problems associated with ADHD, especially motor inhibition problems and high muscle tone. Here we investigated whether adults with ADHD/hyperkinetic disorder (HKD) have similar motor problems. In our clinical experience, adults with ADHD often complain about back, shoulder, hip, and leg pain. We also investigate reported pain in adults with ADHD. METHODS: Twenty-five adult outpatients diagnosed with ADHD/HKD who were responders to methylphenidate (MPH) were compared to 23 non-ADHD controls on 16 MFNU subtests and using a 'total score' ('TS') parameter. The MFNU test leader was blinded to group identity. The two groups were also compared using the Pain Drawing and Numerical Pain Rating Scale. RESULTS: The adult ADHD group had significantly (p < .001) more motor problems (higher TS) than controls. On the muscle regulation subtests, 36-96% of the ADHD group showed 'moderate' to 'severe' problems compared to 13-52% of the control group, and 80% of the ADHD group reported widespread pain. Highly significant differences were found between the ADHD and control groups for the variables 'pain level' (p < .001) and 'pain location' (p < .001). Significant correlations were found between TS and 'pain location' and between TS and 'pain level'. CONCLUSIONS: These findings suggest that similar to children with ADHD, adults diagnosed with ADHD also have motor inhibition problems and heightened muscle tone. The presence of significantly higher pain levels and more widespread pain in the ADHD group compared to non-ADHD controls might indicate that pain is a long-term secondary effect of heightened muscle tone and restricted movement that can be demonstrated in children and adults by the MFNU battery. PMID- 23642256 TI - Rhodium(III)-catalyzed indazole synthesis by C-H bond functionalization and cyclative capture. AB - An efficient, one-step, and highly functional group-compatible synthesis of substituted N-aryl-2H-indazoles is reported via the rhodium(III)-catalyzed C-H bond addition of azobenzenes to aldehydes. The regioselective coupling of unsymmetrical azobenzenes was further demonstrated and led to the development of a new removable aryl group that allows for the preparation of indazoles without N substitution. The 2-aryl-2H-indazole products also represent a new class of readily prepared fluorophores for which initial spectroscopic characterization has been performed. PMID- 23642257 TI - Quality of neonatal healthcare in Kilimanjaro region, northeast Tanzania: learning from mothers' experiences. AB - BACKGROUND: With a decline of infant mortality rates, neonatal mortality rates are striking high in development countries particularly sub Saharan Africa. The toolkit for high quality neonatal services describes the principle of patient satisfaction, which we translate as mother's involvement in neonatal care and so better outcomes. The aim of the study was to assess mothers' experiences, perception and satisfaction of neonatal care in the hospitals of Kilimanjaro region of Tanzania. METHODS: A cross sectional study using qualitative and quantitative approaches in 112 semi structured interviews from 14 health facilities. Open ended questions for detection of illness, care given to the baby and time spent by the health worker for care and treatment were studied. Probing of the responses was used to extract and describe findings by a mix of in-depth interview skills. Closed ended questions for the quantitative variables were used to quantify findings for statistical use. Narratives from open ended questions were coded by colours in excel sheet and themes were manually counted. RESULTS: 80 mothers were interviewed from 13 peripheral facilities and 32 mothers were interviewed at a zonal referral hospital of Kilimanjaro region. 59 mothers (73.8%) in the peripheral hospitals of the region noted neonatal problems and they assisted for attaining diagnosis after a showing a concern for a request for further investigations. 11 mothers (13.8%) were able to identify the baby's diagnosis directly without any assistance, followed by 7 mothers (8.7%) who were told by a relative, and 3 mothers (3.7%) who were told of the problem by the doctor that their babies needed medical attention. 24 times mothers in the peripheral hospitals reported bad language like "I don't have time to listen to you every day and every time." 77 mothers in the periphery (90.6%) were not satisfied with the amount of time spent by the doctors in seeing their babies. CONCLUSION: Mothers of the neonates play great roles in identifying the illness of the newborn. Mother's awareness of what might be needed during neonatal support strategies to improve neonatal care in both health facilities and the communities. PMID- 23642258 TI - Physical activity and sedentary behavior during the early years in Canada: a cross-sectional study. AB - BACKGROUND: Physical activity and sedentary behavior habits are established during early childhood, yet only recently has objectively measured data been available on children aged 5 years and younger. This study presents data on the physical activity and sedentary behaviors of Canadian children aged 3-5 years. METHODS: Data were collected as part of the Canadian Health Measures Survey between 2009 and 2011. A nationally-representative sample (n = 459) of children aged 3-5 years wore Actical accelerometers during their waking hours for 7 consecutive days. Data were collected in 60-sec epochs and respondents with >=4 valid days were retained for analysis. Parents reported their child's physical activity and screen time habits in a questionnaire. RESULTS: Eighty-four percent of 3-4 year old children met the physical activity guideline of 180 minutes of total physical activity every day while 18% met the screen time target of <1 hour per day. Fourteen percent of 5 year old children met the physical activity guideline of 60 minutes of daily moderate-to-vigorous physical activity (MVPA) while 81% met the screen time target of <2 hours per day. Children aged 3-4 years accumulated an average of 352 min/d of total physical activity and 66 minutes of MVPA while 5 year old children accumulated an average of 342 min/d of total physical activity and 68 minutes of MVPA. Children were sedentary for approximately half of their waking hours and spent an average of 2 hours per day in front of screens. Only 15% of 3-4 year olds and 5% of 5 year olds are meeting both the physical activity and sedentary behavior guidelines. CONCLUSIONS: Promoting physical activity while reducing sedentary behavior is important at all stages of life. The findings of the present study indicate that there remains significant room for improvement in these behaviors among young Canadian children. PMID- 23642259 TI - Hepatic stellate cells increase in Toxoplasma gondii infection in mice. AB - BACKGROUND: Toxoplasma gondii is a ubiquitous protozoan parasite that can infect humans and animals. The severity of toxoplasmosis varies according to the immune status of the individual, parasite strain, and host species. In mammalian species, it has been observed that severe lesions of acute toxoplasmosis form in visceral organs such as the liver, lung, and spleen. Some epidemiological studies have reported an association of T. gondii infection with liver cirrhosis. METHODS: Acute infection was induced in fifteen 30-day-old normal Swiss albino mice. The mice were infected by intraperitoneal inoculation of 5000 T. gondii RH strain tachyzoites. The mice were sacrificed in groups of 5 at 2, 4, and 6 days after inoculation. Another group of 5 mice were used as the controls. Anti-glial fibrillary acidic protein (GFAP) and anti-T. gondii antibodies were used to compare GFAP-immunoreactive cells and anti-T. gondii-immunopositive areas in the liver between the T. gondii-infected groups and the healthy controls, respectively. RESULTS: There was a significant correlation between the numbers of GFAP-positive hepatic stellate cells (HSCs) when they were compared with T. gondii antigen immunostaining (p < 0.05). The amount of T. gondii immunostaining increased significantly with the increase in the number of HSCs. CONCLUSIONS: There is a significant relationship between the number of HSCs and T. gondii antigens, which may represent an active role of HSCs in liver pathology and the pathobiology of T. gondii-related hepatitis. PMID- 23642260 TI - Composition and quantification of major polyphenolic compounds, antioxidant activity and colour properties of quince and mixed quince jams. AB - AIMS: The aim of the study was to establish whether the addition of some berries and fruits during quince jam processing, improves its colour and enriches it in polyphenol compounds, other than those found in quince fruits. METHODS: Phenolic compounds were identified and quantified by LC-MS Q/TOF and HPLC. Antioxidant activity was measured by ABTS, DPPH and FRAP methods. The colour of jams was expressed as L, a*, b* value. RESULTS: The total content of polyphenolic compounds in quince jam was 484.5 mg/100 g. The highest level of phenolic compounds and antioxidant activity (p < 0.05) was observed in samples with the addition of chokeberry > black currant > flowering quince. The colour of examined jams could be due to the type of fruit addition, the nature of the pigments in these fruits. CONCLUSION: Overall, the results indicated that some mixed jams can represent a good source of antioxidant compounds and can have an attractive colour for the consumer. PMID- 23642262 TI - Base-specific ionization of deprotonated nucleotides by resonance enhanced two photon detachment. AB - The intrinsic ionization energy of a base in DNA plays a critical role in determining the energies at which damage mechanisms may emerge. Here, a two photon resonance-enhanced ionization scheme is presented that utilizes the (1)pipi* transition, localized on the DNA base, to elucidate the base-specific ionization in a deprotonated nucleotide. In contrast to previous reports, the scheme is insensitive to competing ionization channels arising from the sugar phosphate backbone. Using this approach, we demonstrate that for all bases except guanine, the lowest electron detachment energy corresponds to detachment from the sugar-phosphate backbone and allows us to determine the lowest adiabatic ionization energy for the other three bases for the first time in an isolated nucleotide. PMID- 23642261 TI - Parallel evolution of circulating FABP4 and NT-proBNP in heart failure patients. AB - BACKGROUND: Circulating adipocyte fatty acid-binding protein (FABP4) levels are considered to be a link between obesity, insulin resistance, diabetes, and cardiovascular (CV) diseases. In vitro, FABP4 has exhibited cardiodepressant activity by suppressing cardiomyocyte contraction. We have explored the relationship between FABP4 and the N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) as a clinical parameter of heart failure (HF). METHODS: We included 179 stable HF patients who were referred to a specialized HF unit, 108 of whom were prospectively followed for up to 6 months. A group of 163 non-HF patients attending a CV risk unit was used as the non-HF control group for the FABP4 comparisons. RESULTS: In the HF patients, FABP4 and NT-proBNP were assayed, along with a clinical and functional assessment of the heart at baseline and after 6 months of specialized monitoring. The FABP4 levels were higher in the patients with HF than in the non-HF high CV risk control group (p<0.001). The FABP4 levels were associated with the NT-proBNP levels in patients with HF (r=0.601, p<0.001), and this association was stronger in the diabetic patients. FABP4 was also associated with heart rate and the results of the 6-minute walk test. After the follow-up period, FABP4 decreased in parallel to NT-proBNP and to the clinical parameters of HF. CONCLUSIONS: FABP4 is associated with the clinical manifestations and biomarkers of HF. It exhibits a parallel evolution with the circulating levels of NT-proBNP in HF patients. PMID- 23642263 TI - Mass spectrometry-based proteomics identifies UPF1 as a critical gene expression regulator in MonoMac 6 cells. AB - 5-Lipoxygenase (5-LO) catalyzes the two initial steps in the biosynthesis of leukotrienes, a group of inflammatory lipid mediators derived from arachidonic acid. Recently, we have demonstrated that 5-LO mRNA expression is regulated by alternative splicing and nonsense-mediated mRNA decay (NMD). In addition to this, 5-LO protein expression was reduced on translational level in UPF1 knockdown cells, suggesting that UPF1 has a positive influence on 5-LO translation. Therefore, a mass spectrometry-based proteomics study was performed to identify compartment-specific protein expression changes upon UPF1 knockdown in differentiated and undifferentiated MM6 cells. The proteomics analysis revealed that the knockdown of UPF1 results in numerous protein changes in the microsomal fraction (~21%) but not in the cytosolic fraction (<1%). The results suggest that UPF1 is a critical gene expression regulator in a compartment-specific way. During differentiation by TGFbeta and calcitriol, the majority of UPF1 regulated proteins were adjusted to normal level. This indicates that the translational regulation by UPF1 can potentially be cell differentiation-dependent. PMID- 23642267 TI - Suitability of the adenosine antagonist istradefylline for the treatment of Parkinson's disease: pharmacokinetic and clinical considerations. AB - INTRODUCTION: Recent experimental and clinical research has shown that A2A adenosine receptor antagonism can bring about an improvement in the motor behavior of patients with Parkinson's disease. Istradefylline , a xanthine derivative, has the longest half-life of all the currently available A2A adenosine receptor antagonists; it can successfully permeate through the blood brain barrier and has a high human A2A adenosine receptor affinity. AREAS COVERED: In this article, the author discusses the potential role of A2A adenosine receptor antagonists in the treatment of Parkinson's disease through the evaluation of istradefylline. Specifically, the article reviews the clinical and pharmacokinetic information available to elucidate its therapeutic potential. EXPERT OPINION: A2A adenosine receptor antagonists are efficacious in combination with l-dopa. l-dopa has a complex pharmacokinetic behavior and causes long-term behavioral and metabolic side effects. Future research on A2A adenosine receptor antagonism should consider compounds like istradefylline as l-dopa and/or dopamine agonist-sparing treatment alternatives, since their clinical handling, safety and side-effect profile are superior to l-dopa and/or dopamine agonists. The current focus to demonstrate a specific dyskinesia-ameliorating efficacy of A2A adenosine receptor antagonism in clinical trials is risky, since the presentation of dyskinesia varies on a day-to-day basis and is considerably influenced by peripheral l-dopa metabolism. The demonstration of an antidyskinetic effect may convince authorities, but this is far less relevant in clinical practice as patients generally better tolerate dyskinesia than other phenomena and dopaminergic side effects. PMID- 23642269 TI - Resuscitation. Foreword. PMID- 23642268 TI - Proteomic analyses and identification of arginine methylated proteins differentially recognized by autosera from anti-Sm positive SLE patients. AB - BACKGROUND: Antibodies against spliceosome Sm proteins (anti-Sm autoantibodies) are specific to the autoimmune disease systemic lupus erythematosus (SLE). Anti Sm autosera have been reported to specifically recognize Sm D1 and D3 with symmetric di-methylarginines (sDMA). We investigated if anti-Sm sera from local SLE patients can differentially recognize Sm proteins or any other proteins due to their methylation states. RESULTS: We prepared HeLa cell proteins at normal or hypomethylation states (treated with an indirect methyltransferase inhibitor adenosine dialdehyde, AdOx). A few signals detected by the anti-Sm positive sera from typical SLE patients decreased consistently in the immunoblots of hypomethylated cell extracts. The differentially detected signals by one serum (Sm1) were pinpointed by two-dimensional electrophoresis and identified by mass spectrometry. Three identified proteins: splicing factor, proline- and glutamine rich (SFPQ), heterogeneous nuclear ribonucleoprotein D-like (hnRNP DL) and cellular nucleic acid binding protein (CNBP) are known to contain methylarginines in their glycine and arginine rich (GAR) sequences. We showed that recombinant hnRNP DL and CNBP expressed in Escherichia coli can be detected by all anti-Sm positive sera we tested. As CNBP appeared to be differentially detected by the SLE sera in the pilot study, differential recognition of arginine methylated CNBP protein by the anti-Sm positive sera were further examined. Hypomethylated FLAG CNBP protein immunopurified from AdOx-treated HeLa cells was less recognized by Sm1 compared to the CNBP protein expressed in untreated cells. Two of 20 other anti-Sm positive sera specifically differentiated the FLAG-CNBP protein expressed in HeLa cells due to the methylation. We also observed deferential recognition of methylated recombinant CNBP proteins expressed from E. coli by some of the autosera. CONCLUSION: Our study showed that hnRNP DL and CNBP are novel antigens for SLE patients and the recognition of CNBP might be differentiated dependent on the level of arginine methylation. PMID- 23642270 TI - A review of cardiopulmonary resuscitation and its history. PMID- 23642271 TI - Adult resuscitation summary. PMID- 23642272 TI - Pediatric resuscitation guidelines. PMID- 23642273 TI - Neonatal resuscitation guidelines. PMID- 23642274 TI - Acute coronary syndromes. PMID- 23642275 TI - Adult stroke summary. PMID- 23642276 TI - Ethical considerations in resuscitation. PMID- 23642277 TI - When the group practice breaks up: a qualitative study. AB - BACKGROUND: Group practices are increasingly common for primary care physicians worldwide. Although breakups are likely to happen frequently within group practices, their process has not been studied to date. The aims of this study were therefore to explore the reasons for breakups of group practices of general practitioners and to describe the associated feelings. METHODS: We conducted a qualitative study consisting of in-depth interviews of 21 general practitioners and one secretary from past group practices in the Rhone-Alpes region, France, who experienced a breakup. RESULTS: When getting started in group practice for the first time, young doctors did not feel ready and supported, and did not necessarily share the same expectations as their partners. The reasons for the breakups involved imbalances within the groups, contrasting working and management styles, and breakdowns in communication. The breakup process often generated long-persistent feelings of suffering and failure for almost every partner who experienced a breakup, particularly for the partner who was leaving. CONCLUSIONS: Weakening factors exist from the very beginning of a partnership, and problems are likely to increase at every change or event occurring in the group. We provide several recommendations, including fair management, a shared project based on a precise contract, the consultation of third parties as necessary and, in the worst case scenario, leaving the group practice in time. PMID- 23642278 TI - SATB1 is overexpressed in metastatic prostate cancer and promotes prostate cancer cell growth and invasion. AB - BACKGROUND: Special AT-rich sequence binding protein 1 (SATB1) is a nuclear factor that functions as the global chromatin organizer to regulate chromatin structure and gene expression gene expression. SATB1 has been shown to be abnormally expressed in various types of cancer. However, the expression and role of SATB1 in prostate cancer remain unclear. METHODS: 120 cases of prostatic carcinoma and 60 cases of benign prostate hyperplasia were analyzed for SATB1 expression by immunohistochemistry. LNCaP, DU-145, and PC3 prostate cancer cells were examined for SATB1 expression by Western blot analysis. Cell proliferation and invasion was evaluated by CCK8 and transwell invasion assay, respectively. RESULTS: SATB1 staining was stronger in prostatic carcinomas with metastasis than in those without metastasis, but was absent in benign prostate hyperplasia. Furthermore, SATB1 expression was positively correlated with bone metastasis and the Gleason score. SATB1 overexpression promoted the proliferation and invasion of LNCaP cells while SATB1 knockdown inhibited the proliferation and invasion of DU-145 cells. CONCLUSIONS: These findings provide novel insight into oncogenic role of SATB1 in prostate cancer, suggesting that SATB1 is a promising biomarker and therapeutic target for prostate cancer. PMID- 23642279 TI - Anopheles species associations in Southeast Asia: indicator species and environmental influences. AB - BACKGROUND: Southeast Asia presents a high diversity of Anopheles. Environmental requirements differ for each species and should be clarified because of their influence on malaria transmission potential. Monitoring projects collect vast quantities of entomological data over the whole region and could bring valuable information to malaria control staff but collections are not always standardized and are thus difficult to analyze. In this context studying species associations and their relation to the environment offer some opportunities as they are less subject to sampling error than individual species. METHODS: Using asymmetrical similarity coefficients, indirect clustering and the search of indicator species, this paper identified species associations. Environmental influences were then analysed through canonical and discriminant analysis using climatic and topographic data, land cover in a 3 km buffer around villages and vegetation indices. RESULTS: Six groups of sites characterized the structure of the species assemblage. Temperature, rainfall and vegetation factors all play a role. Four out of the six groups of sites based on species similarities could be discriminated using environmental information only. CONCLUSIONS: Vegetation indices derived from satellite imagery proved very valuable with one variable explaining more variance of the species dataset than any other variable. The analysis could be improved by integrating seasonality in the sampling and collecting at least 4 consecutive days. PMID- 23642280 TI - [Skin and soft tissues infection in a non-human immunodeficiency virus immunosuppressed patient]. PMID- 23642281 TI - Combined effect of linezolid and N-acetylcysteine against Staphylococcus epidermidis biofilms. AB - INTRODUCTION: Staphylococcus epidermidis is an organism commonly associated with infections caused by biofilms. Biofilms are less sensible to antibiotics and therefore are more difficult to eradicate. Linezolid and N-acetylcysteine (NAC), have demonstrated to be active against gram-positive microorganisms. Therefore and since linezolid and NAC have different modes of action, the main objective of this work was to investigate the single and synergistic effect of linezolid and NAC against S. epidermidis biofilms. METHODS: This work reports the in vitro effect of linezolid and NAC against S. epidermidis biofilms, treated with MIC (4mgml(-1)) and 10*MIC of NAC, and MIC (1MUgml(-1)) and peak serum concentration (PS=18MUgml(-1)) of linezolid alone and in combination. After exposure of S. epidermidis biofilms to linezolid and/or NAC for 24h, several biofilm parameters were evaluated, namely the number of cultivable cells [colony forming unit (CFU) enumeration], total biofilm biomass and cellular activity. RESULTS: When tested alone, NAC at 10*MIC was the most effective agent against S. epidermidis biofilms. However, the combination linezolid (MIC)+NAC (10*MIC) showed a synergistic effect and was the most biocidal treatment tested, promoting a 5log reduction in the number of biofilm viable cells. CONCLUSION: This combination seems to be a potential candidate to combat infections caused by S. epidermidis biofilms, namely as a catheter lock solution therapy. PMID- 23642282 TI - [Acute, chronic and fulminant hepatitisE: seven years of experience (2004-2011)]. AB - OBJECTIVE: To study the clinical and epidemiological profiles of in 43cases of acute hepatitis, 5cases of fulminant hepatitis, and one of chronic hepatitis due to hepatitis E virus (HEV), detected over a 7-year period. PATIENTS: Forty-nine individuals (33male and 10female) treated between 2004 and 2011 in the Hospital Ramon y Cajal (Comunidad de Madrid, Spain). The diagnosis was made by the detection of IgG and IgM anti-HEV and RNA HEV in serum samples. Acute hepatitisE was defined by the presence of IgM anti-HEV and/or RNA HEV in serum, and chronic hepatitisE if the ARN was detectable more than 6months. Fulminant hepatitisE was diagnosed if encephalopathy was observed in addition to IgM anti-HEV and/or RNA HEV in serum. RESULTS: The median age was 46.67 and 49.6years in acute hepatitisE and fulminant hepatitisE, respectively. The risk factors recorded were travel to endemic areas in 13patients, 4were in contact with animals, 4suffered from hepatic steatosis due to alcohol consumption, 3consumed uncontrolled foods, and 2drank water from streams. DISCUSSION: HEV is the cause of acute self-limited hepatitis, although 36.73% of the studied cases had to be hospitalised. However a small number of patients, 10.2%, had fulminant hepatitis requiring liver transplant. Chronic hepatitisE is very infrequent in immunocompetent individuals. The increase in incidence of hepatitisE is due to the introduction of better diagnostic tests in recent years. PMID- 23642283 TI - [Consensus statement on the clinical management of human immunodeficiency virus associated neurocognitive disorders]. AB - OBJECTIVE: To develop a consensus document containing clinical recommendations for the management of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND). METHODS: We assembled a panel of experts appointed by GeSIDA and the Secretariat of the National AIDS Plan (PNS), including internal medicine physicians with expertise in the field of HIV, neuropsychologists, neurologists and neuroradiologists. Scientific information was reviewed to October 2012 in publications and conference papers. In support of the recommendations using two levels of evidence: the strength of the recommendation in the opinion of the experts (A, B, C) and the level of empirical evidence (I, II, III), two levels based on the criteria of the Infectious Disease Society of America, already used in previous documents GeSIDA/SPNS. RESULTS: Multiple recommendations for the clinical management of these disorders are provided, including two graphics algorithms, considering both the diagnostic and possible therapeutic strategies. CONCLUSIONS: Neurocognitive disorders associated with HIV infection is currently highly prevalent, are associated with a decreased quality of life and daily activities, and given the possibility of occurrence of an increase in the coming years, there is a need to adequately manage these disorders, from a diagnostic as well as therapeutic point of view, and always from a multidisciplinary perspective. PMID- 23642284 TI - [Evaluation of the Sysmex UF-1000i flow cytometer for screening of urinary tract infection]. AB - INTRODUCTION: The urine culture is a huge workload in the Microbiology Laboratory and remains the gold standard for the diagnosis of urinary tract infections. Considering the high prevalence of negative results, the implementation of a reliable screening method could lead to cost saving in the workload, and speed up reporting of negative results. METHODS: We evaluated the usefulness of the flow cytometer UF-1000i in the screening for negative samples than could be excluded from culture. We divided the samples into two groups, Group 1, males and women of childbearing age who were considered positive with a growth >= 104 CFU/ml, and Group 2, considered positive with >= 105 CFU/ml growth. RESULTS: On comparing the culture and screening data in the ROC curve, the best sensitivity and specificity points were 53.1 bact/MUl for Group 1, and 128.3 bact/MUl for Group 2. In Group 1, the sensitivity was 92.2% and a specificity of 60%, a reduction in urine cultures of 46%, with 2.1% false negative (42 samples). In Group 2, the sensitivity was 86%, with a specificity of 87.7%, a culture reduction of 57.5%, and 5.1% false negatives (74 samples). CONCLUSION: The incorporating of the UF 1000i cytometer to the screening of urine samples depends on the characteristics of the patients and the definition of positive urine culture. In our case, with only studying bacteriuria, the data on the reduction of workload and the false negatives seriously question this incorporation. PMID- 23642285 TI - Traditional use of medicinal plants in south-central Zimbabwe: review and perspectives. AB - BACKGROUND: Traditional medicine has remained as the most affordable and easily accessible source of treatment in the primary healthcare system of resource poor communities in Zimbabwe. The local people have a long history of traditional plant usage for medicinal purposes. Despite the increasing acceptance of traditional medicine in Zimbabwe, this rich indigenous knowledge is not adequately documented. Documentation of plants used as traditional medicines is needed so that the knowledge can be preserved and the utilized plants conserved and used sustainably. The primary objective of this paper is to summarize information on traditional uses of medicinal plants in south-central Zimbabwe, identifying research gaps and suggesting perspectives for future research. METHODS: This study is based on a review of the literature published in scientific journals, books, reports from national, regional and international organizations, theses, conference papers and other grey materials. RESULTS: A total of 93 medicinal plant species representing 41 families and 77 genera are used in south-central Zimbabwe. These plant species are used to treat 18 diseases and disorder categories, with the highest number of species used for gastro intestinal disorders, followed by sexually transmitted infections, cold, cough and sore throat and gynaecological problems. Shrubs and trees (38% each) were the primary sources of medicinal plants, followed by herbs (21%) and climbers (3%). The therapeutic claims made on medicinal plants documented in south-central Zimbabwe are well supported by literature, with 82.8% of the plant species having similar applications in other regions of Zimbabwe as well as other parts of the world and 89.2% having documented biological and pharmacological properties. CONCLUSION: This study illustrates the importance of traditional medicines in the treatment and management of human diseases and ailments in south-central Zimbabwe. Traditional medicines still play an important role in meeting basic health care of local communities in Zimbabwe. PMID- 23642286 TI - [Usefulness of autoantibodies for the diagnosis of autoimmune myopathies]. AB - INTRODUCTION: Idiopathic myopathies are a group of acquired muscular diseases considered as autoimmune disorders. Characteristic histopathologic features allow the classification into myositis (polymyositis, dermatomyositis, and inclusion body myositis) and immune-mediated necrotizing myopathies. But overlapping histological features may be observed between different idiopathic myopathies and even between acquired and genetic muscular diseases. In the group of idiopathic myopathies important discrepancies can be observed concerning extra-muscular involvement and prognosis. STATE OF ART: The discovery of myositis-specific antibodies and myositis-associated antibodies has led to a serologic approach complementary to histological classification, because striking associations of myositis-specific antibodies with clinical features and survival were observed. Here we reviewed the myositis-specific antibodies including autoantibodies directed against the aminoacyl tRNA-synthetase enzymes, the Mi-2 protein and the signal recognition particle, and the main myositis-associated autoantibodies, that can be tested in clinical practice. PERSPECTIVES: We will also focus on newly described dermatomyositis-associated antibodies (directed against: transcription intermediary factor 1 family proteins, small ubiquitin-like modifier activating enzyme, and melanoma differentiation-associated gene 5), and immune-mediated necrotizing myopathy-associated antibodies (directed against HMGcoA-reductase). CONCLUSION: Myositis-specific antibodies and myositis associated antibodies are useful for the diagnosis of forms of autoimmune myopathies with distinct clinical features. They may help to define patients into clinical syndromes with specific outcomes and thus influence treatment strategies. PMID- 23642287 TI - Pyrimidyn compounds: dual-action small molecule pyrimidine-based dynamin inhibitors. AB - Dynamin is required for clathrin-mediated endocytosis (CME). Its GTPase activity is stimulated by phospholipid binding to its PH domain, which induces helical oligomerization. We have designed a series of novel pyrimidine-based "Pyrimidyn" compounds that inhibit the lipid-stimulated GTPase activity of full length dynamin I and II with similar potency. The most potent analogue, Pyrimidyn 7, has an IC50 of 1.1 MUM for dynamin I and 1.8 MUM for dynamin II, making it among the most potent dynamin inhibitors identified to date. We investigated the mechanism of action of the Pyrimidyn compounds in detail by examining the kinetics of Pyrimidyn 7 inhibition of dynamin. The compound competitively inhibits both GTP and phospholipid interactions with dynamin I. While both mechanisms of action have been previously observed separately, this is the first inhibitor series to incorporate both and thereby to target two distinct domains of dynamin. Pyrimidyn 6 and 7 reversibly inhibit CME of both transferrin and EGF in a number of non neuronal cell lines as well as inhibiting synaptic vesicle endocytosis (SVE) in nerve terminals. Therefore, Pyrimidyn compounds block endocytosis by directly competing with GTP and lipid binding to dynamin, limiting both the recruitment of dynamin to membranes and its activation. This dual mode of action provides an important new tool for molecular dissection of dynamin's role in endocytosis. PMID- 23642289 TI - Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. AB - BACKGROUND: In recent years, 2 new syndromes of mast cell activation have been described in patients with episodes of mast cell mediator release that range from flushing and abdominal cramping to anaphylaxis: monoclonal mast cell activation syndrome (MMAS) and idiopathic mast cell activation syndrome (MCAS). OBJECTIVE: This review will discuss these 2 new syndromes in the larger context of mast cell activation disorders as well as the diagnostic and treatment approaches for these conditions. METHODS: PubMed was searched using the following terms: mast cell activation disorder, mast cell activation syndrome, and clonal mast cell. Only English-language articles published up until February 27, 2013, were considered. RESULTS: MMAS has been diagnosed in patients with systemic reactions to hymenoptera stings and elevated baseline serum tryptase as well as in patients with unexplained episodes of anaphylaxis. A bone marrow biopsy establishes the diagnosis by revealing the presence of monoclonal mast cells that carry the D816V KIT mutation and/or express CD25 while the diagnostic requirements for systemic mastocytosis are not met. MCAS affects predominantly women in whom no mast cell abnormality or external triggers account for their episodes of mast cell activation. MCAS is a diagnosis of exclusion, and primary and secondary mast cell activation disorders as well as idiopathic anaphylaxis have to be ruled out before making the diagnosis. Patients with MCAS and MMAS are treated in a stepwise fashion with drugs that block the effects of mediators released by mast cells on activation. One third of MCAS patients experience complete resolution of symptoms with treatment, while one third have a major response and one third a minor response to treatment. A combination of drugs is usually necessary to achieve symptom control. No drug trial has been performed in patients with MMAS and MCAS. CONCLUSIONS: MMAS and MCAS are 2 newly described, rare syndromes of mast cell activation. Further studies will be necessary to better understand the cause of these conditions and their natural evolution and to validate and improve the treatment approach. Research should also focus on developing drugs with the potential to cure these debilitating disorders. To achieve these goals, centers with expertise in mast cell activation disorders are essential as they allow for a critical mass of these patients to be enrolled in studies while providing those patients with the most up-to-date diagnostic procedures and treatment strategies. PMID- 23642288 TI - Effects of 24-week treatment with acarbose on glucagon-like peptide 1 in newly diagnosed type 2 diabetic patients: a preliminary report. AB - BACKGROUND: Treatment with the alpha-glucosidase inhibitor (AGI) acarbose is associated with a significant reduction the risk of cardiovascular events. However, the underlying mechanisms of this effect are unclear. AGIs were recently suggested to participate in stimulating glucagon-like peptide 1 (GLP-1) secretion. We therefore examined the effects of a 24-week treatment of acarbose on endogenous GLP-1, nitric oxide (NO) levels, nitric oxide synthase (NOS) activity, and carotid intima-media thickness (CIMT) in newly diagnosed patients with type 2 diabetes (T2D). METHODS: Blood was drawn from 24 subjects (14 male, 10 female, age: 50.7 +/- 7.36 years, BMI: 26.64 +/- 3.38 kg/m2, GHbA1c: 7.00 +/- 0.74%) with drug-naive T2D at 0 and 120 min following a standard mixed meal for the measurements of active GLP-1, NO and NOS. The CIMT was measured prior to and following 24 weeks of acarbose monotherapy (mean dose: 268 mg daily). RESULTS: Following 24 weeks of acarbose treatment, both fasting and postprandial plasma GLP-1 levels were increased. In patients with increased postprandial GLP-1 levels, serum NO levels and NOS activities were also significantly increased and were positively related to GLP-1 levels. Although the CIMT was not significantly altered following treatment with acarbose, a decreased CIMT was negatively correlated with increased GLP-1 levels. CONCLUSIONS: Twenty-four weeks of acarbose monotherapy in newly diagnosed patients with T2D is associated with significantly increased levels of both fasting and postprandial GLP-1 as well as significantly increased NO levels and NOS activity for those patients in whom postprandial GLP-1 levels were increased. Therefore, the benefits of acarbose on cardiovascular risk may be related to its stimulation of GLP-1 secretion. PMID- 23642290 TI - Retrospective real-world adherence in patients with type 2 diabetes initiating once-daily liraglutide 1.8 mg or twice-daily exenatide 10 MUg. AB - BACKGROUND: The effectiveness of a drug is significantly influenced by a patient's adherence to the required regimen. OBJECTIVE: The goal of this retrospective database analysis was to determine the factors affecting adherence over a 12-month follow-up period in adults with type 2 diabetes mellitus (DM) initiating once-daily liraglutide (1.8 mg) or twice-daily exenatide (10 MUg). METHODS: A patient-centric claims database was used, covering the period January 2009 to December 2011. Patients were included if they had >=1 claim of once-daily liraglutide 1.8 mg or twice-daily exenatide 10 MUg from January to December 2010 (index date [ID]), >=2 diagnoses of type 2 DM before ID, continuous enrollment for 12 months before and after ID, and age >=18 years at ID. Patients were required to be glucagon-like peptide-1 receptor agonist treatment-naive in the 12 months preceding ID and have a second prescription for once-daily liraglutide 1.8 mg or twice-daily exenatide 10 MUg during the 12 months after ID. The medication possession ratio (MPR) was used as a continuous variable and to categorize patients as high-adherent (MPR >=80%) or low-adherent (MPR <80%). Regression analyses were conducted to determine the predictors for nonadherence in the type 2 DM population, with bivariate testing of the MPR categories conducted initially to determine the predictors to be included in the final regression model. RESULTS: A total of 3623 patients (once-daily liraglutide 1.8 mg, n = 2036; twice daily exenatide 10 MUg, n = 1587) were identified. Variables found to reduce adherence were younger age, female sex, Southern geographic region, twice-daily exenatide treatment, and higher percentage of copayment from the claimant. After adjusting for confounding factors, patients receiving once-daily liraglutide 1.8 mg were ~11% more adherent than patients receiving twice-daily exenatide 10 MUg (95% CI, 7-14; P < 0.0001). The odds ratio for "poor" adherence (MPR <80%) with twice-daily exenatide 10 MUg therapy compared with liraglutide 1.8 mg once-daily was 1.33 (95% CI, 1.16-1.53; P < 0.0001). CONCLUSIONS: This study found that adherence to once-daily liraglutide 1.8 mg treatment was superior to twice-daily exenatide 10 MUg over a 12-month follow-up period. Nonadherence has important implications to the health care system, both in terms of clinical effectiveness and economic burden (eg, hospitalization, productivity losses). Using strategies to increase adherence is vital to reduce the future clinical and economic burden of diabetes. PMID- 23642291 TI - Chemical sensitivity: pathophysiology or pathopsychology? AB - BACKGROUND: Escalating numbers of people throughout the world are presenting to primary care physicians, allergists, and immunologists with myriad clinical symptoms after low-level exposure to assorted everyday chemicals such as smoke, perfumes, air fresheners, paints, glues, and other products. This clinical state is referred to by various diagnostic labels, including multiple chemical sensitivity disorder, environmental intolerance, chemical sensitivity (CS), and sensitivity-related illness, and has been the subject of much controversy within the health care community. OBJECTIVE: The goal of this study was to provide a brief overview of the etiology, pathogenesis, clinical presentation, and management of CS. An evaluation of the medical community's response to this emerging diagnosis was also explored. METHODS: This review was prepared by assessing available medical and scientific literature from MEDLINE, as well as by reviewing numerous books, toxicology journals, conference proceedings, government publications, and environmental health periodicals. A primary observation, however, is that there is limited scientific literature available on the issue of CS. The format of a traditional integrated review was chosen because such reviews play a pivotal role in scientific research and professional practice in medical issues with limited primary study and uncharted clinical territory. RESULTS: The sensitization state of CS seems to be initiated by a significant toxic exposure, occurring as a 1-time event, or on surpassing a threshold of toxicity after toxicant accrual from repeated lower-level exposures. Once sensitized through a toxicant-induced loss of tolerance, individuals exposed to inciting triggers such as minute amounts of diverse everyday chemicals may experience various clinical and immune sequelae, sometimes involving lymphocyte, antibody, or cytokine responses. Precautionary avoidance of inciting triggers will prevent symptoms, and desensitization immunotherapy or immune suppression may improve symptoms in some cases. Sustained resolution of the CS state occurs after successful elimination of the accrued body burden of toxicants through natural mechanisms of toxicant bioelimination and/or interventions of clinical detoxification. Despite extensive clinical evidence to support the veracity of this clinical state, many members of the medical community are reluctant to accept this condition as a pathophysiologic disorder. CONCLUSIONS: The emerging problem of ubiquitous adverse toxicant exposures in modern society has resulted in escalating numbers of individuals developing a CS disorder. As usual in medical history, iconoclastic ideas and emerging evidence regarding novel disease mechanisms, such as the pathogenesis of CS, have been met with controversy, resistance, and sluggish knowledge translation. PMID- 23642292 TI - Atopic conditions in search of pathogenesis and therapy. PMID- 23642293 TI - Bioresources in the pharmacotherapy and healing of burns: A mini-review. AB - The present mini-review actualizes the pharmacy of botanical, animal, and fungal sources of potential value in the management of burns wounds. It also highlights the importance of applying contemporary imaged-based sciences such as radiology in the assessment and prognosis of wounds and burns. PMID- 23642294 TI - Have the 2010 national maternity reforms delivered choice, control and continuity to Australian women? PMID- 23642295 TI - Meal frequencies in early adolescence predict meal frequencies in late adolescence and early adulthood. AB - BACKGROUND: Health and risk behaviours tend to be maintained from adolescence into adulthood. There is little knowledge on whether meal frequencies in adolescence are maintained into adulthood. We investigated whether breakfast, lunch and evening meal frequencies in early adolescence predicted meal frequencies in late adolescence and in early adulthood. Further, the modifying effect of gender and adolescent family structure were investigated. METHODS: National representative sample of 15-year-olds in Denmark with 4 and 12 year follow-up studies with measurement of breakfast, lunch and evening meal frequencies. A total of 561 persons completed questionnaires at age 15 years (baseline 1990, n=847, response rate 84.6%), age 19 years (n=729, response rate 73.2%) and age 27 years (n=614, response rate 61.6%). RESULTS: Low meal frequencies at age 15 years was a significant predictor for having low meal frequencies at age 19 years (odds ratio (OR, 95% CI)) varying between 2.11, 1.33 3.34 and 7.48, 3.64-15.41). Also, low meal frequencies at age 19 years predicted low meal frequencies at age 27 years (OR varying between 2.26, 1.30-3.91 and 4.38, 2.36-8.13). Significant predictions over the full study period were seen for low breakfast frequency and low lunch frequency (OR varying between 1.78, 1.13-2.81 and 2.58, 1.31-5.07). Analyses stratified by gender showed the same patterns (OR varying between 1.88, 1.13-3.14 and 8.30, 2.85-24.16). However, the observed predictions were not statistical significant among men between age 15 and 27 years. Analyses stratified by adolescent family structure revealed different lunch predictions in strata. CONCLUSIONS: Having low meal frequencies in early adolescence predicted low meal frequencies in late adolescence and early adulthood. We propose that promotion of regular meals become a prioritised issue within health education. PMID- 23642297 TI - [Cardiovascular clearance for competitive sport in aging people]. AB - The regular sport practice slows the physiological deleterious effects of aging. However, during intense exercise, the hazard of acute cardiovascular event is significantly increased. Whatever their cardiovascular risk factors are, aging people are more prone to coronary acute event during intense exertion than a young one. Cardiovascular exam, with resting ECG and maximal exercise test, is needed to give clearance for competitive sport in aging people (>65 y.o.). The limited value to evaluate the individual risk of acute cardiac event during intense exercise must be clearly explained to Master athletes. They must be aware to the necessity to consult their physician in case of abnormal symptom during exercise. PMID- 23642298 TI - [Place for "Chest Pain Unit" in France. Emergency physicians point of view]. AB - The concept of "Chest Pain Unit" was born in the United States in the 1980s. The interest of the transposition, in France, of this American concept is not obvious. Radical difference in cardiovascular risk factors, coronary heart disease prevalence and in emergency care organization are the first limits. The medico-economic analysis of "Chest Pain Unit" does not seem to be favorable. The only published French experience provides no convincing arguments. In consequence, in the French system, early call to the SAMU-Centre 15, prehospital medical management and direct access to the cath lab or cardiologic ICU must remain the rule. This strategy is associated with time saved and reduced morbidity and mortality. To educate the patient at vascular (cardiologic and neurologic) risk in this sense should be encouraged. PMID- 23642296 TI - Evaluation and optimization of mass spectrometric settings during data-dependent acquisition mode: focus on LTQ-Orbitrap mass analyzers. AB - Mass-spectrometry-based proteomics has evolved as the preferred method for the analysis of complex proteomes. Undoubtedly, recent advances in mass spectrometry instrumentation have greatly enhanced proteomic analysis. A popular instrument platform in proteomics research is the LTQ-Orbitrap mass analyzer. In this tutorial, we discuss the significance of evaluating and optimizing mass spectrometric settings on the LTQ-Orbitrap during CID data-dependent acquisition (DDA) mode to improve protein and peptide identification rates. We focus on those MS and MS/MS parameters that have been systematically examined and evaluated by several researchers and are commonly used during DDA. More specifically, we discuss the effect of mass resolving power, preview mode for FTMS scan, monoisotopic precursor selection, signal threshold for triggering MS/MS events, number of microscans per MS/MS scan, number of MS/MS events, automatic gain control target value (ion population) for MS and MS/MS, maximum ion injection time for MS/MS, rapid and normal scan rate, and prediction of ion injection time. We furthermore present data from the latest generation LTQ-Orbitrap system, the Orbitrap Elite, along with recommended MS and MS/MS parameters. The Orbitrap Elite outperforms the Orbitrap Classic in terms of scan speed, sensitivity, dynamic range, and resolving power and results in higher identification rates. Several of the optimized MS parameters determined on the LTQ-Orbitrap Classic and XL were easily transferable to the Orbitrap Elite, whereas others needed to be reevaluated. Finally, the Q Exactive and HCD are briefly discussed, as well as sample preparation, LC-optimization, and bioinformatics analysis. We hope this tutorial will serve as guidance for researchers new to the field of proteomics and assist in achieving optimal results. PMID- 23642299 TI - Pathophysiology of autoimmune polyneuropathies. AB - The most common autoimmune neuropathies include the acute inflammatory polyneuropathy [the Guillain-Barre Syndrome(s)]; chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN) and IgM anti-MAG-antibody mediated paraproteinemic neuropathy. These neuropathies occur when immunologic tolerance to peripheral nerve components (myelin, Schwann cell, axon, and motor or ganglionic neurons) is lost. Based on the immunopathologic similarities with experimental allergic neuritis induced after immunization with nerve proteins, disease transfer experiments with the patients' serum or with intraneural injections, and immunocytochemical studies on the patients' nerves, it appears that both cellular and humoral factors, either independently or in concert with each other, play a role in the cause of these neuropathies. Although in some of them there is direct evidence for autoimmune reactivity mediated by specific antibodies or autoreactive T lymphocytes, in others the underlying immune-mediated mechanisms have not been fully elucidated, in spite of good response to immunotherapies. The review highlights the factors associated with breaking the T-cell tolerance, the T-cell activation and costimulatory molecules, the immunoregulatory T-cells and relevant cytokines and the antibodies against peripheral nerve glycolipids or glycoproteins that seem to be of pathogenic relevance. Antigens in the nodal, paranodal and juxtaparanodal regions are discussed as potentially critical targets in explaining conduction failure and rapid recovery. Based on the immunopathologic network believed to play a fundamental role in the pathogenesis of these neuropathies, future therapeutic directions are highlighted using new biological agents against T-cells, cytokines, B-cells, transmigration and transduction molecules. PMID- 23642300 TI - The effect of the target-organ geometric complexity on the choice of delivery between RapidArc and sliding-window IMRT for nasopharyngeal carcinoma. AB - We attempted to assess the effect of target-organ geometric complexity on the plan quality of sliding-window intensity-modulated radiotherapy (IMRT), double arc (RA2), and triple-arc (RA3) RapidArc volumetric-modulated arc radiotherapy for nasopharyngeal carcinoma (NPC). Plans for 9-field sliding-window IMRT, RA2, and RA3 were optimized for 36 patients with NPC ranging from T1 to T4 tumors. Initially the patients were divided into 2 groups, with group A representing the most simple early stage (T1 and T2) cases, whereas group B represented the more complex advanced cases (T3 and T4). Evaluation was performed based on target conformity, target dose homogeneity, organ-sparing capability, and delivery efficiency. Based on the plan quality results, a subgroup of advanced cases, group B2, representing the most demanding task was distinguished and reported separately from the rest of the group B cases, B1. Detailed analysis was performed on the anatomic features for each group of cases, so that planners can easily identify the differences between B1 and B2. For the group A cases, RA3 plans were superior to the IMRT plans in terms of organ sparing, whereas target conformity and dose homogeneity were similar. For the group B1 cases, the RA3 plans produced almost equivalent plan quality as the IMRT plans. For the group B2 cases, for most of which large target volumes were adjacent to (5mm or less) and wrapping around the brain stem, RA2 and RA3 were inferior to the IMRT regarding both target dose homogeneity and conformity. RA2 plans were slightly inferior to IMRT and RA3 plans for most cases. The plan comparison results depend on the target to brain stem distances and the target sizes. The plan quality results together with the anatomic information may allow the evaluation of the 3 treatment options before actual planning. PMID- 23642302 TI - Key issues and challenges in developing a pedagogical intervention in the simulation skills center--an action research study. AB - Simulation skills centers (SSC) are considered important learning arenas for preparing and qualifying nursing students. Limited clinical placements and claims of diminished learning opportunities raise concerns that newly educated nurses lack proficiency in many psychomotor skills. Accordingly, there is an increased focus on learning in the SSC. However, it has been questioned if the pedagogical underpinning of teaching and learning in the SSC is missing or unclear. At a bachelor nursing education in Norway, there was a desire to change practice and enhance learning in the SSC by systematic use of The Model of Practical Skill Performance (Bjork and Kirkevold, 2000). A participatory action research design was chosen. A pedagogical intervention was developed and implemented in 2010 in a cohort of eighty-seven first year bachelor nursing students during their basic nursing skill course. The intervention is shortly described. This article reports key issues and challenges that emerged during development of the new intervention. Data to inform the study were collected via thorough meeting minutes and the project leader's logbook, and analyzed using fieldnotes analysis. Six key issues and challenges were identified. These are presented and discussed consecutively in light of their importance for development and implementation of the new intervention. PMID- 23642303 TI - The effect of anti-reflux treatment on subjective voice measurements of patients with laryngopharyngeal reflux. AB - OBJECTIVE: To assess the impact of anti-reflux treatment and speech therapy on subjective voice measurements of patients with laryngopharyngeal reflux. METHODS: This paper reports a prospective study of patients seen in a voice clinic over a three-year period who were being treated for laryngopharyngeal reflux. Patients were assessed at presentation using the reflux symptom index and voice symptom scale, and were reassessed at three months and six months post-treatment. Treatment entailed twice daily proton pump inhibitor therapy and speech therapy. RESULTS: The study comprised 74 patients. The reflux symptom index and voice symptom scale scores significantly improved following treatment at both three and six months. There was a correlation between improved reflux symptom index scores and improved voice symptom scale scores. CONCLUSION: Treatment of laryngopharyngeal reflux with twice daily proton pump inhibitors and speech therapy resulted in improved subjective voice measurements for patients. PMID- 23642304 TI - Eosinophils affect functions of in vitro-activated human CD3-CD4+ T cells. AB - BACKGROUND: The recent development of eosinophil-targeting agents has raised enthusiasm for management of patients with hypereosinophilic syndromes. Roughly half of anti-IL-5-treated patients with corticosteroid-responsive lymphocytic (L HES) and idiopathic disease variants can be tapered off corticosteroids. Potential consequences of corticosteroid-withdrawal on clonal expansion of pre malignant CD3-CD4+ T-cells associated with L-HES are a subject of concern. Indeed, corticosteroid treatment inhibits T-cell activation and may lower blood CD3-CD4+ cell counts. On the other hand, previous studies have shown that eosinophils support CD4 T-cell activation, suggesting that targeted eosinophil depletion may negatively regulate these cells. OBJECTIVES: Effects of eosinophils on CD4 T-cell activation in vitro were investigated as an indirect means of exploring whether treatment-induced eosinophil depletion may affect pathogenic T cells driving L-HES. METHODS: Helper (CD4) T-cells and CD3-CD4+ cells from healthy controls and L-HES patients, respectively, were cultured in vitro in presence of anti-CD3/CD28 or dendritic cells. Effects of eosinophils on T-cell proliferation and cytokine production were investigated. RESULTS: Eosinophils enhanced CD3-driven proliferation of CD4 T-cells from healthy subjects in vitro, while inhibiting TCR-independent proliferation and IL-5 production by CD3-CD4+ T cells. CONCLUSIONS: While this study confirms previous work showing that eosinophils support activation of normal helper T-cells, our in vitro findings with CD3-CD4+ T-cells suggest that eosinophil-depletion may favor activation and expansion of this pathogenic lymphocyte subset. With the ongoing development of eosinophil-targeted therapy for various eosinophilic conditions, the indirect consequences of treatment on the underlying immune mechanisms of disease should be investigated in detail in the setting of translational research programs. PMID- 23642305 TI - Transgenic mice expressing human glucocerebrosidase variants: utility for the study of Gaucher disease. AB - Gaucher disease is an autosomal recessively inherited storage disorder caused by deficiency of the lysosomal hydrolase, acid beta-glucosidase. The disease manifestations seen in Gaucher patients are highly heterogeneous as is the responsiveness to therapy. The elucidation of the precise factors responsible for this heterogeneity has been challenging as the development of clinically relevant animal models of Gaucher disease has been problematic. Although numerous murine models for Gaucher disease have been described each has limitations in their specific utility. We describe here, transgenic murine models of Gaucher disease that will be particularly useful for the study of pharmacological chaperones. We have produced stable transgenic mouse strains that individually express wild type, N370S and L444P containing human acid beta-glucosidase and show that each of these transgenic lines rescues the lethal phenotype characteristic of acid beta-glucosidase null mice. Both the N370S and L444P transgenic models show early and progressive elevations of tissue sphingolipids with L444P mice developing progressive splenic Gaucher cell infiltration. We demonstrate the potential utility of these new transgenic models for the study of Gaucher disease pathogenesis. In addition, since these mice produce only human enzyme, they are particularly relevant for the study of pharmacological chaperones that are specifically targeted to human acid beta-glucosidase and the common mutations underlying Gaucher disease. PMID- 23642307 TI - Traffic conflicts on bicycle paths: a systematic observation of behaviour from video. AB - In The Netherlands, on bicycle paths, single-bicycle accidents, bicycle-bicycle and bicycle-moped accidents constitute a considerable share of all bicyclist injuries. Over three quarters of all hospitalised bicyclist victims in the Netherlands cannot be directly related to a crash with motorised traffic. As the usage of bicycle paths steadily increases, it is to be expected that safety on bicycle paths will become a major issue in the coming years in The Netherlands. A study was conducted into the behaviour of bicyclists and moped riders to improve traffic safety on bicycle paths. By behavioural observations with video, mutual conflicts and bicyclist behaviour on bicycle paths were recorded and analysed, among other things by means of the conflict observation method DOCTOR (Dutch Objective Conflict Technique for Operation and Research). The explorative phase of the study (phase 1), included two research locations, one in the city of Amsterdam and one in Eindhoven. The results gave guidance for a better understanding of the behaviour between different users of separate two directional bicycle paths. An example includes the relationship between bicyclist moped rider behaviour and the width of the bicycle path. For a condition with busy bicycle traffic in both directions the width of the bicycle path in Amsterdam (effectively 3.55m) is relatively narrow, whereas the bicycle path width in Eindhoven (>4.94m) appears to be sufficient to accommodate large flows of bicyclists. Because of a large flow of crossing pedestrians resulting in (severe) conflicts with bicyclists in Amsterdam, additional countermeasures to better control these interactions are needed. The DOCTOR conflict observation method from video appears to be applicable for conflicts between intersecting road users and for head-on conflicts on the bicycle path. Conflict situations between bicyclists in the same direction (constituting an important share of injury accidents on bicycle paths) require an additional and more general systematic observation of specific behaviour. Therefore, phase 2 of the project will focus in particular on interactions between bicycle path users in the same direction and underlying processes. PMID- 23642306 TI - Using a new odour-baited device to explore options for luring and killing outdoor biting malaria vectors: a report on design and field evaluation of the Mosquito Landing Box. AB - BACKGROUND: Mosquitoes that bite people outdoors can sustain malaria transmission even where effective indoor interventions such as bednets or indoor residual spraying are already widely used. Outdoor tools may therefore complement current indoor measures and improve control. We developed and evaluated a prototype mosquito control device, the 'Mosquito Landing Box' (MLB), which is baited with human odours and treated with mosquitocidal agents. The findings are used to explore technical options and challenges relevant to luring and killing outdoor biting malaria vectors in endemic settings. METHODS: Field experiments were conducted in Tanzania to assess if wild host-seeking mosquitoes 1) visited the MLBs, 2) stayed long or left shortly after arrival at the device, 3) visited the devices at times when humans were also outdoors, and 4) could be killed by contaminants applied on the devices. Odours suctioned from volunteer-occupied tents were also evaluated as a potential low-cost bait, by comparing baited and unbaited MLBs. RESULTS: There were significantly more Anopheles arabiensis, An. funestus, Culex and Mansonia mosquitoes visiting baited MLB than unbaited controls (P<=0.028). Increasing sampling frequency from every 120 min to 60 and 30 min led to an increase in vector catches of up to 3.6 fold (P<=0.002), indicating that many mosquitoes visited the device but left shortly afterwards. Outdoor host-seeking activity of malaria vectors peaked between 7:30 and 10:30 pm, and between 4:30 and 6:00 am, matching durations when locals were also outdoors. Maximum mortality of mosquitoes visiting MLBs sprayed or painted with formulations of candidate mosquitocidal agent (pirimiphos-methyl) was 51%. Odours from volunteer occupied tents attracted significantly more mosquitoes to MLBs than controls (P<0.001). CONCLUSION: While odour-baited devices such as the MLBs clearly have potential against outdoor-biting mosquitoes in communities where LLINs are used, candidate contaminants must be those that are effective at ultra low doses even after short contact periods, since important vector species such as An. arabiensis make only brief visits to such devices. Natural human odours suctioned from occupied dwellings could constitute affordable sources of attractants to supplement odour baits for the devices. The killing agents used should be environmentally safe, long lasting, and have different modes of action (other than pyrethroids as used on LLINs), to curb the risk of physiological insecticide resistance. PMID- 23642308 TI - Mycoplasma hominis prosthetic valve endocarditis: the value of molecular sequencing in cardiac surgery. PMID- 23642309 TI - Major controlling factors and predictions for cadmium transfer from the soil into spinach plants. AB - Predicting the mobility, bioavailability and transfer of cadmium (Cd) in the soil plant system is of great importance with regards to food safety and environmental management. In this study, the transfer characteristics of Cd (exogenous salts) from a wide range of Chinese soils to spinach (Spinacia oleracea L.) were investigated. The major controlling factors and prediction equations for Cd transfer in the soil-plant system were also investigated. The results showed that plant Cd concentration was positively correlated with soil Cd concentration. The maximum transfer factor (ratio of the Cd concentration in the plant to that in the soil) was found in acid soils. The extended Freundlich-type function was able to describe the Cd transfer from soil to spinach plants. Combining soil total Cd, pH and organic carbon (OC) content in the prediction equation greatly improved the correlation performance compared with predictions based on total Cd only. A slight protection effect of OC on Cd uptake was observed at low soil Cd concentrations. The results are a useful tool that can be used to predict Cd transfer from soil to plant. PMID- 23642311 TI - Ab initio molecular dynamics of Na+ and Mg2+ countercations at the backbone of RNA in water solution. AB - The interactions between sodium or magnesium ions and phosphate groups of the RNA backbone represented as dinucleotide fragments in water solution have been studied using ab initio Born-Oppenheimer molecular dynamics. All systems have been simulated at 300 and 320 K. Sodium ions have mobility higher than that of the magnesium ions and readily change their position with respect to the phosphate groups, from directly bonded to completely solvated state, with a rough estimate of the lifetime of bonded Na(+) of about 20-30 ps. The coordination number of the sodium ions frequently changes in irregular intervals ranging from several femtoseconds to about 10 ps with the most frequently encountered coordination number five, followed by six. The magnesium ion is stable both as directly bonded to an oxygen atom from the phosphate group and completely solvated by water. In both states the Mg(2+) ion has exactly six oxygen atoms in the first coordination shell; moreover, during the whole simulation of more than 100 ps no exchange of ligand in the first coordination shells has been observed. Solvation of the terminal phosphate oxygen atoms by water molecules forming hydrogen bonds in different locations of the ions is also discussed. The stability of the system containing sodium ions essentially does not depend on the position of the ions with respect to the phosphate groups. PMID- 23642310 TI - Lactic acid fermentation as a tool to enhance the functional features of Echinacea spp. AB - BACKGROUND: Extracts and products (roots and/or aerial parts) from Echinacea ssp. represent a profitable market sector for herbal medicines thanks to different functional features. Alkamides and polyacetylenes, phenols like caffeic acid and its derivatives, polysaccharides and glycoproteins are the main bioactive compounds of Echinacea spp. This study aimed at investigating the capacity of selected lactic acid bacteria to enhance the antimicrobial, antioxidant and immune-modulatory features of E. purpurea with the prospect of its application as functional food, dietary supplement or pharmaceutical preparation. RESULTS: Echinacea purpurea suspension (5%, wt/vol) in distilled water, containing 0.4% (wt/vol) yeast extract, was fermented with Lactobacillus plantarum POM1, 1MR20 or C2, previously selected from plant materials. Chemically acidified suspension, without bacterial inoculum, was used as the control to investigate functional features. Echinacea suspension fermented with Lb. plantarum C2 exhibited a marked antimicrobial activity towards Gram-positive and -negative bacteria. Compared to control, the water-soluble extract from Echinacea suspension fermented with Lactobacillus plantarum 1MR20 showed twice time higher radical scavenging activity on DPPH. Almost the same was found for the inhibition of oleic acid peroxidation. The methanol extract from Echinacea suspension had inherent antioxidant features but the activity of extract from the sample fermented with strain 1MR20 was the highest. The antioxidant activities were confirmed on Balb 3T3 mouse fibroblasts. Lactobacillus plantarum C2 and 1MR20 were used in association to ferment Echinacea suspension, and the water-soluble extract was subjected to ultra-filtration and purification through RP-FPLC. The antioxidant activity was distributed in a large number of fractions and proportional to the peptide concentration. The antimicrobial activity was detected only in one fraction, further subjected to nano-LC-ESI-MS/MS. A mixture of eight peptides was identified, corresponding to fragments of plantaricins PlnH or PlnG. Treatments with fermented Echinacea suspension exerted immune-modulatory effects on Caco-2 cells. The fermentation with Lb. plantarum 1MR20 or with the association between strains C2 and 1MR20 had the highest effect on the expression of TNF-alpha gene. CONCLUSIONS: E. purpurea subjected to lactic acid fermentation could be suitable for novel applications as functional food dietary supplements or pharmaceutical preparations. PMID- 23642312 TI - Subhealth: definition, criteria for diagnosis and potential prevalence in the central region of China. AB - BACKGROUND: A full evaluation of health conditions is necessary for the effective implementation of public health interventions. However, terms to address the intermediate state between health and disease are lacking, leading the public to overlook this state and thus increasing the risks of developing disease. METHODS: A cross-sectional health survey of 1,473 randomly recruited Chinese Han adults of both sexes living in the central region of China. The criteria for diagnosis of subhealth was defined as the presence of >= 1 of the following abnormalities: body mass index >= 25 kg/m2 or waist circumference >= 102 cm in men and 88 cm in women; systolic pressure 120-139 mmHg and/or diastolic pressure 80-89 mmHg; serum triglyceride level >= 150 mg/dL and/or total cholesterol level >= 200 mg/dL and/or high-density lipoprotein cholesterol level < 40 mg/dL in men and 50 mg/dL in women; serum glucose level 110-125 mg/dL; estimated glomerular filtration rate 60-89 ml/min/1.73 m2; levels of liver enzymes in liver function tests between 41 59 U/L, or with fatty liver disease but < 33% of affected hepatocytes; levels of oxidative stress biomarkers beyond the reference range of 95%; or problems with both sleep quality and psychological state. RESULTS: The prevalences of subhealth and disease in the central region of China were 36.6% and 43.1%, respectively. The prevalence of disease increased from 26.3% in participants aged 20-39 years, to 47.6% and 78.9% for participants aged 40-59 years and those aged 60 years or older, respectively. Compared with participants aged 20-39, the prevalences of health and subhealth in participants aged 60 years or older decreased by 86.7% and 60.3%, respectively. The prevalence of subhealth was increased in association with increases in lifestyle risk scores, while the prevalences of both health and disease were reduced. CONCLUSION: The prevalences of subhealth and disease are high in central China. Subhealth is associated with high lifestyle risk scores. Both the health care sector and the public should pay more attention to subhealth. Lifestyle modifications and/or psychological interventions are needed to ameliorate these conditions. PMID- 23642313 TI - Malignant head and neck paragangliomas: treatment efficacy and prognostic indicators. AB - PURPOSE: Malignant head and neck paragangliomas (MHNPs) are rare and occur in 6% 19% of all HNPs. We sought to identify predictors of survival and compare efficacy of treatment modalities to inform management of this rare disease. MATERIALS AND METHODS: We performed a retrospective cohort study of MHNP cases in the National Cancer Institute Surveillance Epidemiology and End Results database (SEER) from 1973 to 2009. We identified 86 patients with MHNP who had documented regional or distant tumor spread with a median follow-up of 74 months. We used Cox proportional hazard models to assess the significance of demographic factors and treatment on five-year overall survival. RESULTS: The most common treatment was surgery alone (36.0 %), followed by surgery with adjuvant radiation (33.7%). Five-year overall survival was 88.1% for surgery alone and 66.5% for adjuvant radiation (p = 0.2251). In univariate analysis, regional (vs. distant) spread (HR 0.23, p < 0.0001), surgery alone (HR 0.29, p < 0.0001) and primary site in the carotid body (HR 0.32, p = 0.006) conferred significant survival advantage whereas age > 50 (HR 4.04, p < 0.0001) worsened survival. Regional (vs. distant) spread (HR 0.42, p = 0.046) and age > 50 (HR 2.98, p = 0.005) remained significant in multivariate analysis. In patients with regional-only disease, five-year overall survival was 95.4% for surgery alone compared to 75.6% for surgery with radiation (p = 0.1055). CONCLUSIONS: This is the largest and most contemporary series of MHNP patients. Age and tumor stage are significant factors in predicting survival. Surgical resection significantly improves survival outcomes. From this analysis, the value of adjuvant radiation is not clear. PMID- 23642314 TI - Moderate/heavy alcohol use and HCV infection among injection drug users in two Russian cities. AB - BACKGROUND: In Russia, injection drug use and transmission of blood-borne pathogens such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are inextricably linked, however the burden of alcohol use remains unexplored among injection drug users (IDUs). METHODS: Individuals who were 18 years of age and older and had injected drugs in the previous 30 days were recruited in the cities of Novosibirsk and Ivanovo by respondent driven sampling. Consenting individuals were administered a quantitative survey instrument and provided blood samples for serological testing. RESULTS: In Novosibirsk and Ivanovo, 29% and 35% of respondents were categorized as moderate/heavy drinkers, respectively. Individuals reported problems related to alcohol use that affected their physical health (23%), family (55%), and induced financial hardships (43%). In the multivariate analysis, we found that methamphetamine injection in the past 12 months was a strong and significant correlate of moderate/heavy drinking in Novosibirsk (aOR=5.63 95% CI: [1.01-31.47]) and Ivanovo (aOR=3.81 95% CI: [2.20 6.62]). There was poor agreement between self-reported HCV status and HCV test results (kappa=-0.05 and 0.26 in Novosibirsk and Ivanovo, respectively). IDUs who correctly knew their HCV seropositive status in Novosibirsk and IDUs who correctly knew their HCV seronegative status in Ivanovo were significantly more likely to be moderate/heavy drinkers. CONCLUSION: Alcohol use is problematic among IDUs who are at high risk for HCV. Future interventions should target IDUs who are moderate/heavy drinkers in order to prevent liver complications resulting from HCV infection. PMID- 23642315 TI - Patterns of injection drug use cessation during an expansion of syringe exchange services in a Canadian setting. AB - BACKGROUND: Needle and syringe programmes (NSPs) have been shown to reduce HIV risk among people who inject drugs (IDUs). However, concerns remain that NSPs delay injecting cessation. METHODS: Individuals reporting injection drug use in the past six months in the greater Vancouver area were enrolled in the Vancouver Injection Drug Users Study (VIDUS). Annual estimates of the proportion of IDU reporting injecting cessation were generated. Generalized estimating equation (GEE) analysis was used to assess factors associated with injecting cessation during a period of NSP expansion. RESULTS: Between May 1996 and December 2010, the number of NSP sites in Vancouver increased from 1 to 29 (P<0.001). The estimated proportion of participants (n=2710) reporting cessation increased from 2.4% (95% confidence interval [CI]: 0.0-7.0%) in 1996 to 47.9% (95% CI: 46.8 48.9%) in 2010 (P<0.001). In a multivariate GEE analysis, the authors observed an association between increasing calendar year and increased likelihood of injecting cessation (Adjusted Odds Ratio=1.17, 95% CI: 1.15, 1.19, P<0.001). CONCLUSION: The proportion of IDU reporting injecting cessation increased during a period of NSP expansion, implying that increased NSP availability did not delay injection cessation. These results should help inform community decisions on whether to implement NSPs. PMID- 23642317 TI - A coupled SAFE-2.5D BEM approach for the dispersion analysis of damped leaky guided waves in embedded waveguides of arbitrary cross-section. AB - The paper presents a Semi-Analytical Finite Element (SAFE) formulation coupled with a 2.5D Boundary Element Method (BEM) for the computation of the dispersion properties of viscoelastic waveguides with arbitrary cross-section and embedded in unbounded isotropic viscoelastic media. Attenuation of guided modes is described through the imaginary component of the axial wavenumber, which accounts for material damping, introduced via linear viscoelastic constitutive relations, as well as energy loss due to radiation of bulk waves in the surrounding media. Energy radiation is accounted in the SAFE model by introducing an equivalent dynamic stiffness matrix for the surrounding medium, which is derived from a regularized 2.5D boundary element formulation. The resulting dispersive wave equation is configured as a nonlinear eigenvalue problem in the complex axial wavenumber. The eigenvalue problem is reduced to a linear one inside a chosen contour in the complex plane of the axial wavenumber by using a contour integral method. Poles of leaky and evanescent modes are obtained by choosing appropriately the phase of the wavenumbers normal to the interface in compliance with the nature of the waves in the surrounding medium. Finally, the obtained eigensolutions are post-processed to compute the energy velocity and the radiated wavefield in the surrounding domain. The reliability of the method is first validated on existing results for waveguides of circular cross sections embedded in elastic and viscoelastic media. Next, the potential of the proposed numerical framework is shown by computing the dispersion properties for a square steel bar embedded in grout and for an H-shaped steel pile embedded in soil. PMID- 23642316 TI - Crosswalk between DSM-IV dependence and DSM-5 substance use disorders for opioids, cannabis, cocaine and alcohol. AB - BACKGROUND: Ascertaining agreement between DSM-IV and DSM-5 is important to determine the applicability of treatments for DSM-IV conditions to persons diagnosed according to the proposed DSM-5. METHODS: Data from a nationally representative sample of US adults were used to compare concordance of past-year DSM-IV opioid, cannabis, cocaine and alcohol dependence with past-year DSM-5 disorders at thresholds of 3+, 4+, 5+ and 6+ positive DSM-5 criteria among past year users of opioids (n=264), cannabis (n=1622), cocaine (n=271) and alcohol (n=23,013). Substance-specific 2 * 2 tables yielded overall concordance (kappa), sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV). RESULTS: For DSM-IV alcohol, cocaine and opioid dependence, optimal concordance occurred when 4+ DSM-5 criteria were endorsed, corresponding to the threshold for moderate DSM-5 alcohol, cocaine and opioid use disorders. Maximal concordance of DSM-IV cannabis dependence and DSM-5 cannabis use disorder occurred when 6+ criteria were endorsed, corresponding to the threshold for severe DSM-5 cannabis use disorder. At these optimal thresholds, sensitivity, specificity, PPV and NPV generally exceeded 85% (>75% for cannabis). CONCLUSIONS: Overall, excellent correspondence of DSM-IV dependence with DSM-5 substance use disorders was documented in this general population sample of alcohol, cannabis, cocaine and opioid users. Applicability of treatments tested for DSM-IV dependence is supported by these results for those with a DSM-5 alcohol, cocaine or opioid use disorder of at least moderate severity or severe cannabis use disorder. Further research is needed to provide evidence for applicability of treatments for persons with milder substance use disorders. PMID- 23642318 TI - Reprint of: B cell elimination in systemic lupus erythematosus. Clin. Immunol. 146(2) 90-103. AB - Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution, potentially life-threatening with considerable morbidity. The elimination of pathogenic B cells has emerged as a rational therapeutic option. Many open label studies have reported encouraging results in which clinical and serological remission have invariably been described, often enabling the reduction of steroid and immunosuppressive treatment. However, the results from randomized controlled studies have been disappointing and several questions remain to be answered. In this review we will focus on results of B cell direct depletion in the treatment of patients with systemic lupus erythematosus. PMID- 23642319 TI - Pharmacotherapy of impulsive aggression: a quality comparison of controlled studies. AB - The present study assessed the quality of pharmacotherapy trials to treat impulsive aggressive behavior. While a search of the literature found 55 peer reviewed published studies on the pharmacotherapy of aggression, only 23 met criteria for inclusion in the quality analysis. To be included in this review, the study must have had at least one comparison group to control for placebo effects. The study must have also adequately defined and diagnosed the presence of impulsive aggression or intermittent explosive disorder. The primary reason studies were excluded from the quality analysis was that impulsive aggression was not specifically defined as the behavior being treated (25 of 32, 78%). The results of the quality analysis found that higher quality studies (n=10; 45%) were characterized by a clear definition of impulsive aggression; specific criteria for what constitutes an impulsive aggressive act; the exclusion of participants with neurological disorders, serious mental disorders, and/or low IQ; and information concerning the serum levels of the medication being investigated. A significant weakness found in the literature is the paucity of high quality studies accessing the efficacy of pharmacological agents other than anticonvulsants for the treatment of impulsive aggression. PMID- 23642320 TI - Is there a recognizable post-incarceration syndrome among released "lifers"? AB - It has been suggested that released prisoners experience a unique set of mental health symptoms related to, but not limited to, post-traumatic stress disorder. We sought to empirically assess whether there is a recognizable post incarceration syndrome that captures the unique effects of incarceration on mental health. We conducted in-depth life interviews with 25 released "lifers" (individuals serving a life sentence), who served an average of 19 years in a state correctional institution. We assessed to what extent the symptoms described by the participants overlapped with other mental disorders, most notably PTSD. The narratives indicate a specific cluster of mental health symptoms: In addition to PTSD, this cluster was characterized by institutionalized personality traits, social-sensory disorientation, and alienation. Our findings suggest that post incarceration syndrome constitutes a discrete subtype of PTSD that results from long-term imprisonment. Recognizing Post-Incarceration Syndrome may allow for more adequate recognition of the effects of incarceration and treatment among ex inmates and ultimately, successful re-entry into society. PMID- 23642321 TI - Prevalence of mental disorders among detained asylum seekers in deportation arrest in Switzerland and validation of the Brief Jail Mental Health Screen BJMHS. AB - BACKGROUND: Though slowly growing, knowledge about prisoners detained for having violated an Alien Act is still marginal and most studies involve detained asylum seekers in the USA and Australia. Little is known about prevalence rates of mental health disorders in such a population. The Brief Jail Mental Health Screening BJMHS has been demonstrated in other prison populations as a valid screening for serious mental illness. AIM: The aims of this study were to describe prevalence rates for mental disorders according to ICD-10 and to validate the BJMHS for this population. METHODS: 80 inmates at a detention center for prisoners having violated the Swiss Aliens Act were surveyed using the BJMHS at their admission. The results were cross validated with the WHO Composite International Diagnostic Interview (CIDI). RESULTS: When omitting disorders caused by smoking tobacco, 76% of the prisoners suffered from at least one mental disorder according to CIDI. Whereas the rates for disorders due to psychoactive substance use as well as schizophrenic and affective disorders were comparable with other prison populations, we found a specific increased reporting of phobic (14%) and post-traumatic stress disorders (23%). The BJMHS detected serious mental illness defined as schizophrenic or affective disorders with a sensitivity of 81.0% and a specificity of 74.6%. DISCUSSION: As in other prison populations prevalence rates for mental disorders were markedly above the general population. The specific pattern with high rates of phobic as well as post-traumatic stress disorders may reflect the very often traumatic backgrounds of this population. Whereas the results for the validation of the BJMHS were even better than in other similar studies and the instrument proved to be practicable and helpful to detect serious mental illness, sensitivity for a screening tool of around 80% is still too low. Additionally the fact that other serious mental disorders are not covered emphasizes the importance of other elements in the screening process, including the need to have well-trained staff, and to have a low threshold for psychiatric examination. PMID- 23642322 TI - Emerging LDL therapies: Using human genetics to discover new therapeutic targets for plasma lipids. AB - In humans, genetic variation occurs through different types of alleles that vary in frequency and severity of effect. Mendelian mutations, such as those in the low-density lipoprotein (LDL) receptor (LDLR) that result in familial hypercholesterolemia, are rare and have powerful phenotypic effects. Conversely, alleles that are common in the population (such that homozygotes for the minor allele are present even in modest sample sizes) typically have very modest phenotypic effects. In the middle of the spectrum are "Goldilocks" alleles such as mutations in the gene for proprotein convertase subtilisin/kexin type 9 (PCSK9). Loss-of-function mutations in PCSK9 result in significantly decreased LDL-cholesterol levels and a disproportionately large reduction in coronary heart disease risk by reducing the exposure to LDL-cholesterol throughout life. Several agents to inhibit PCSK9 are currently in development, demonstrating the potential utility of translating genetics into clinical therapeutics. To date, most investigations aimed at identifying the genes responsible for hypercholesterolemia have used linkage analysis, which requires samples collected from multiple families with defects in the same gene, or common variant analysis which requires thousands of samples from the population. However, case studies have shown that with advances in whole genome sequencing or exome sequencing (targeted exome capture), the process of discovering causal genetic mutations can be significantly streamlined. Astute clinical observation of individual patients and their families with atypical lipid profiles, followed by sequencing of the affected individual, has the potential to lead to important findings regarding the genetic mutations that cause lipid abnormalities. PMID- 23642323 TI - Emerging low-density lipoprotein therapies: Targeting PCSK9 for low-density lipoprotein reduction. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein secreted by the hepatocyte that regulates the surface expression of low-density lipoprotein (LDL) receptors by targeting them for lysosomal degradation. Statins enhance PCSK9 synthesis, an effect that blunts the LDL-cholesterol (-C)-lowering effectiveness of statins. Loss-of-function mutations in the PCSK9 gene produce life-long low levels of LDL-C and reduce cardiovascular risk. Monoclonal antibodies to PCSK9, which mimic the effects of genetic mutations by inhibiting PCSK9, are in clinical trial development. Two different commercial development programs have demonstrated significant success in lowering LDL-C in phase 1 and 2 trials with similar agents: REGN727/SAR236553 (REGN727) and, more recently, AMG 145. When administered subcutaneously at doses ranging from 50 to 150 mg every 2 weeks or 200 to 400 mg every 4 weeks, these agents produced similar dose responses in LDL-C lowering. In hypercholesterolemic patients, LDL-C reductions ranged up to 60%, and, as would be expected, an even greater response was reported for statin-treated hypercholesterolemic patients-up to 70% decrease. LDL C has typically shown a gradual increase after the nadir as monoclonal antibodies are cleared from the circulation. Results to date indicate that the PCSK9 monoclonal antibody approach appears safe, well-tolerated, and profoundly lowers LDL-C levels while also favorably altering apolipoprotein B, triglycerides, lipoprotein (a), and high-density lipoprotein-C. It is expected to meet an important clinical need for patients unable to achieve adequate LDL-C-lowering with currently available therapies. PMID- 23642324 TI - Emerging low-density lipoprotein therapies: Microsomal triglyceride transfer protein inhibitors. AB - Microsomal triglyceride transfer protein, which is localized in the endoplasmic reticulum of enterocytes and hepatocytes, is necessary for the formation of chylomicron and very low-density lipoprotein particles. Lomitapide is a small molecule microsomal triglyceride transfer protein inhibitor that was recently approved by the Food and Drug Administration as an adjunct to a low-fat diet and other lipid-lowering therapies for reducing low-density lipoprotein cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia (FH). Results from clinical trials of lomitapide have demonstrated its ability to reduce atherogenic lipoprotein concentrations in this population. Most recently, in a phase 3 clinical trial of 29 men and women with homozygous FH (mean baseline LDL C, 336 mg/dL) who were on stable doses of concomitant lipid therapies and a low fat diet, lomitapide was gradually titrated over 26 weeks (from 5 to 60 mg/d), followed by 52 weeks at the maximum tolerated dose. LDL-C decreased from baseline by 50% at 26 weeks, and reductions were maintained through the end of the study. Gastrointestinal disorders were the most frequent side effects and the most common reason for failure to tolerate lomitapide dose escalation. Few patients had elevated aspartate or alanine aminotransferases; bilirubin and alkaline phosphatase levels were unaffected; and hepatic fat increased by ~ 10 g/100 g. In conclusion, recent data support the LDL-C-lowering efficacy of low-dose titrated lomitapide in patients with homozygous FH; however, concerns regarding increased hepatic fat will need to be addressed in long-term safety studies. PMID- 23642325 TI - Emerging low-density lipoprotein (LDL) therapies: Management of severely elevated LDL cholesterol--the role of LDL-apheresis. AB - Low-density lipoprotein (LDL)-apheresis is a Food and Drug Administration approved treatment for patients with homozygous familial hypercholesterolemia (FH) or severe heterozygous FH. Based on electrochemical principles, it selectively removes apolipoprotein B-containing lipoproteins through extracorporeal precipitation with either heparin (Heparin-induced Extracorporeal LDL Precipitation, ie, HELP) or dextran sulfate (Liposorber). LDL-apheresis can lead to an acute decrease in LDL cholesterol (LDL-C) of 70%-80%, but there is a rapid rebound to baseline levels within approximately 2 weeks. LDL-apheresis is typically performed once-a-week in patients with homozygous FH and every other week in those with heterozygous FH to produce time-average LDL-C reductions of ~ 40%. Side effects associated with LDL-apheresis include hypotension (later found to be due to concomitant use of angiotensin-converting enzyme inhibitors), nausea/vomiting, flushing, angina, and fainting. Posttreatment bleeding can occur secondary to heparin used during the procedure. Challenges associated with LDL apheresis include vascular access often requiring an arteriovenous fistula (fistulas may clot and require revision over time), the time associated with each treatment session (2-4 hours), the frequency of treatment, and the scarcity of medical centers which perform LDL-apheresis. Given the nature of LDL-apheresis, randomized placebo controlled trials are nearly impossible, and virtually all studies of clinical benefit have been non-randomized investigations of small numbers of subjects. Nonetheless, results from those studies support the benefits of LDL-C reduction for reducing coronary atherosclerosis and cardiovascular events. PMID- 23642326 TI - Emerging LDL therapies: Mipomersen-antisense oligonucleotide therapy in the management of hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is characterized by severe elevations in low density lipoprotein cholesterol (LDL-C) and poses considerable treatment challenges. Substantive LDL-C reductions are difficult to achieve with standard therapies, and many patients with FH do not tolerate currently available lipid lowering medications. Mipomersen is an antisense oligonucleotide injectable drug that was recently approved by the Food and Drug Administration for the treatment of homozygous FH. It is complementary in sequence to a segment of the human apolipoprotein (Apo) B-100 messenger RNA and specifically binds to it, blocking translation of the gene product. Reducing the production of Apo B-100 reduces hepatic production of very low-density lipoprotein, consequently decreasing circulating levels of atherogenic very low-density lipoprotein remnants, intermediate-density lipoproteins, LDL, and lipoprotein(a) particles. Results from a pivotal trial conducted in patients with homozygous FH, and supporting trials in patients with heterozygous FH with coronary artery disease (CAD) (LDL-C >= 100 mg/dL, triglycerides < 200 mg/dL), severe hypercholesterolemia (LDL-C >= 300 mg/dL or >= 200 mg/dL with CAD), and individuals at high risk for CAD (LDL-C >= 100 mg/dL, triglycerides <= 200 mg/dL), have indicated that mipomersen reduces all Apo B-containing atherogenic lipoproteins. The average LDL-C reduction was >100 mg/dL in homozygous FH and severe hypercholesterolemia populations. The main on-treatment adverse events were mild-to-moderate injection site reactions and flu-like symptoms. Available data regarding the efficacy, safety and tolerability of mipomersen, including results at up to 104 weeks of therapy, support the use of mipomersen for the treatment of FH. PMID- 23642327 TI - Improving outcomes in colorectal cancer: where do we go from here? AB - Colorectal cancer (CRC) places a considerable burden on individuals and society in Europe, being the second most common cause of cancer-related death in the region. While earlier diagnosis and advances in treatment have considerably improved survival in recent years, further progress is needed. One of the greatest challenges associated with the treatment of CRC is the fact that current therapies for advanced disease are not curative, necessitating treatment for many years and placing a significant healthcare burden on society. To reduce the burden of CRC, care delivery must be more efficient and cost-effective. In particular, development of adequate screening programmes is needed, along with chemo-preventative strategies and newer, more active therapies. Further challenges include the lack of optimal selection of patients for adjuvant therapy, identification of the most appropriate target populations for current treatments and the optimum sequence for new molecular targeted agents. This article outlines current developments and unmet needs in CRC, and provides a detailed vision for improvements in the management of the disease. Implementation of some of these strategies will go some way to improving outcomes for patients with CRC. PMID- 23642328 TI - Improvement in survival of metastatic colorectal cancer: are the benefits of clinical trials reproduced in population-based studies? AB - AIM OF THE STUDY: To describe trends in survival of non-resectable metastatic colorectal cancer (MCRC) over a 34-year period in a French population-based registry taking into account major advances in medical therapy. PATIENTS AND METHODS: 3804 patients with non-resectable metastatic colorectal cancer diagnosed between 1976 and 2009 were included. Three periods (1976-96, 1997-2004 and 2005 09) were considered. RESULTS: The proportion of patients receiving chemotherapy dramatically increased from 19% to 57% between the first two periods, then increased steadily thereafter reaching 59% during the last period (p<0.001). Median relative survival increased from 5.9 months during the 1976-96 period to 10.2 months during the 1997-2004 period but, despite the availability of targeted therapies, remained at 9.5 months during the 2005-09 period. During the last study period, less than 10% of elderly patients received targeted therapies compared to more than 40% for younger patients. Their median relative survival was 5.0 months compared to 15.6 months in younger patients. CONCLUSION: There was an improvement in survival in relation with the increased use of more effective medical treatment. However, at a population-based level, patients are not all treated equally and most of them, especially the elderly, do not benefit from the most up-to-date treatment options. PMID- 23642329 TI - Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. AB - BACKGROUND: This phase III study investigated the addition of aflibercept to gemcitabine, in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Patients with metastatic pancreatic cancer were randomly assigned to receive either intravenous (i.v.) aflibercept, 4 mg/kg every 2 weeks, or matching placebo combined with gemcitabine, 1000 mg/m(2) i.v. weekly for 7 weeks out of 8, then weekly for 3 weeks out of 4 until progressive disease, unacceptable toxicity or withdrawal of consent. The primary objective was to demonstrate an improvement in overall survival (OS) between the treatment arms. RESULTS: The study was stopped for futility following a planned interim analysis of OS in 427 randomised patients. With a median follow-up of 7.9 months, based on the 546 patients at study termination, median OS was 7.8 months in the gemcitabine plus placebo arm (n=275) versus 6.5 months in the gemcitabine plus aflibercept arm (n=271), which was not significant (hazard ratio 1.165, 95% confidence interval (CI) 0.921 1.473, p=0.2034). Median progression-free survival was 3.7 months in both arms. Treatment discontinuations due to adverse events were more frequent in the aflibercept than in the placebo-containing arm (23% versus 12%). CONCLUSION: Adding aflibercept to gemcitabine did not improve OS in patients with metastatic pancreatic cancer. PMID- 23642330 TI - Treating severe and enduring anorexia nervosa: a randomized controlled trial. AB - BACKGROUND: There are no evidence-based treatments for severe and enduring anorexia nervosa (SE-AN). This study evaluated the relative efficacy of cognitive behavioral therapy (CBT-AN) and specialist supportive clinical management (SSCM) for adults with SE-AN. METHOD: Sixty-three participants with a diagnosis of AN, who had at least a 7-year illness history, were treated in a multi-site randomized controlled trial (RCT). During 30 out-patient visits spread over 8 months, they received either CBT-AN or SSCM, both modified for SE-AN. Participants were assessed at baseline, end of treatment (EOT), and at 6- and 12 month post-treatment follow-ups. The main outcome measures were quality of life, mood disorder symptoms and social adjustment. Weight, eating disorder (ED) psychopathology, motivation for change and health-care burden were secondary outcomes. RESULTS: Thirty-one participants were randomized to CBT-AN and 32 to SSCM with a retention rate of 85% achieved at the end of the study. At EOT and follow-up, both groups showed significant improvement. There were no differences between treatment groups at EOT. At the 6-month follow-up, CBT-AN participants had higher scores on the Weissman Social Adjustment Scale (WSAS; p = 0.038) and at 12 months they had lower Eating Disorder Examination (EDE) global scores (p = 0.004) and higher readiness for recovery (p = 0.013) compared to SSCM. CONCLUSIONS: Patients with SE-AN can make meaningful improvements with both therapies. Both treatments were acceptable and high retention rates at follow-up were achieved. Between-group differences at follow-up were consistent with the nature of the treatments given. PMID- 23642331 TI - Improved myocardial strain measured by strain-encoded magnetic resonance imaging in a patient with cardiac sarcoidosis. AB - A woman aged 64 years with cardiac sarcoidosis responded favourably to corticosteroid therapy in terms of recovered longitudinal myocardial strain, as evaluated by strain-encoded magnetic resonance imaging (SENC-MRI). In contrast, circumferential myocardial strain and late gadolinium enhancement demonstrated minimal improvement, suggesting relatively advanced pathology of the myocardial middle layer. We propose SENC-MRI as a marker of disease at an early stage of cardiac sarcoidosis. PMID- 23642332 TI - Nothing refractory about cardiac cell therapy. PMID- 23642333 TI - Antiplatelet therapy and cardiac surgery: review of recent evidence and clinical implications. AB - Since the publication of the 2009 Canadian Cardiovascular Society position paper on antiplatelet therapy and cardiac surgery, new antiplatelet strategies with either double-dose clopidogrel or with new and more potent agents (prasugrel and ticagrelor) have become accepted practice. For the patient requiring coronary artery bypass surgery who has recently received either double-dose clopidogrel or one of the new P2Y12 platelet inhibitors, increased perioperative bleeding can be anticipated. For patients who are stable and can wait, surgery should be delayed for 5 days after the last dose of clopidogrel (standard or double-dose), and for 7 days after the last dose of prasugrel. Patients who have received ticagrelor should wait 5 days after the last dose before surgery, although it is likely that surgery can be safely performed 3 days after discontinuing ticagrelor. For patients who require emergency surgery despite recently receiving double-dose clopidogrel, prasugrel, or ticagrelor, the measures to limit perioperative bleeding discussed in the 2009 Canadian Cardiovascular Society position paper remain applicable, but have not yet been rigourously tested. Recent studies have suggested the value of preoperative in vitro platelet aggregometry to determine perioperative bleeding risk. PMID- 23642334 TI - Electrophysiologic considerations in congenital heart disease and their relationship to heart failure. AB - Current survival rates for complex forms of congenital heart disease (CHD) are excellent, allowing for an ever-growing population of adult survivors. Previous interventions and complex physiology, including the systemic right ventricle and single ventricle circulations, predispose these patients to heart failure and arrhythmias. The relationship between arrhythmias and heart failure in CHD is complex: cause and effect are not always readily separated. Therefore, the assessment and management of these patients requires an understanding of the relationship between the 2, with careful review of risk factors and arrhythmia substrates. Several forms of CHD predispose to arrhythmias even in the absence of surgical intervention because of abnormalities of the conduction system and intrinsic structural malformations. Surgical interventions might result in sinus node dysfunction and propensity for supraventricular and ventricular arrhythmias. Arrhythmias are important risk factors for sudden death in the CHD population. Device therapies directed at maintaining chronotropic competence, cardiac resynchronization, and preventing sudden death are increasingly used. These challenges unique to CHD underscore recommendations for such complex patients to be referred to specialized centres with expertise in managing CHD and its complications. In this review, we explore the complex interplay between arrhythmogenesis, CHD, and heart failure. PMID- 23642335 TI - PEP-1-CAT protects hypoxia/reoxygenation-induced cardiomyocyte apoptosis through multiple sigaling pathways. AB - BACKGROUND: Catalase (CAT) breaks down H2O2 into H2O and O2 to protects cells from oxidative damage. However, its translational potential is limited because exogenous CAT cannot enter living cells automatically. This study is aimed to investigate if PEP-1-CAT fusion protein can effectively protect cardiomyocytes from oxidative stress due to hypoxia/reoxygenation (H/R)-induced injury. METHODS: H9c2 cardomyocytes were pretreated with catalase (CAT) or PEP-1-CAT fusion protein followed by culturing in a hypoxia and re-oxygenation condition. Cell apoptosis were measured by Annexin V and PI double staining and Flow cytometry. Intracellular superoxide anion level was determined, and mitochondrial membrane potential was measured. Expression of apoptosis-related proteins including Bcl-2, Bax, Caspase-3, PARP, p38 and phospho-p38 was analyzed by western blotting. RESULTS: PEP-1-CAT protected H9c2 from H/R-induced morphological alteration and reduced the release of lactate dehydrogenase (LDH) and malondialdehyde content. Superoxide anion production was also decreased. In addition, PEP-1-CAT inhibited H9c2 apoptosis and blocked the expression of apoptosis stimulator Bax while increased the expression of Bcl-2, leading to an increased mitochondrial membrane potential. Mechanistically, PEP-1-CAT inhibited p38 MAPK while activating PI3K/Akt and Erk1/2 signaling pathways, resulting in blockade of Bcl2/Bax/mitochondrial apoptotic pathway. CONCLUSION: Our study has revealed a novel mechanism by which PEP-1-CAT protects cardiomyocyte from H/R-induced injury. PEP-1-CAT blocks Bcl2/Bax/mitochondrial apoptotic pathway by inhibiting p38 MAPK while activating PI3K/Akt and Erk1/2 signaling pathways. PMID- 23642336 TI - Graphene-based materials: fabrication, characterization and application for the decontamination of wastewater and wastegas and hydrogen storage/generation. AB - Graphene, as an ideal two-dimensional material and single-atom layer of graphite, has attracted exploding interests in multidisciplinary research because of its unique structure and exceptional physicochemical properties. Especially, graphene based materials offer a wide range of potentialities for environmental remediation and energy applications. This review shows an extensive overview of the main principles and the recent synthetic technologies about designing and fabricating various innovative graphene-based materials. Furthermore, an extensive list of graphene-based sorbents and catalysts from vast literature has been compiled. The adsorptive and catalytic properties of graphene-based materials for the removal of various pollutants and hydrogen storage/production as available in the literature are presented. Tremendous adsorption capacity, excellent catalytic performance and abundant availability are the significant factors making these materials suitable alternatives for environmental pollutant control and energy-related system, especially in terms of the removal of pollutants in water, gas cleanup and purification, and hydrogen generation and storage. Meanwhile, a brief discussion is also included on the influence of graphene materials on the environment, and its toxicological effects. Lastly, some unsolved subjects together with major challenges in this germinating area of research are highlighted and discussed. Conclusively, the expanding of graphene based materials in the field of adsorption and catalysis science represents a viable and powerful tool, resulting in the superior improvement of environmental pollution control and energy development. PMID- 23642338 TI - Psychometric and neurobiological assessment of resilience in a non-clinical sample of adults. AB - BACKGROUND: Resilient individuals are capable of adjusting and coping successfully in the face of adversity. Efforts to assess resilience and its biomarkers have focused on individuals with a history of trauma and related disorders. OBJECTIVE: To psychologically assess resilience in a non-clinical community population through questionnaires, and analyse the associations between the psychological parameters and salivary cortisol and dehydroepiandrosterone sulphate (DHEA-S) as putative biomarkers of resilience. METHOD: An opportunistic sample (n=196) completed a cross-sectional survey assessing resilience, self reported depressive symptoms and anxiety, and possible correlates. A sub-sample (n=32) selected in order to maximise variation of mental health, provided saliva samples for enzyme-linked immunoassay (ELISA) detection of cortisol and DHEA-S. RESULTS: Resilience correlated negatively with depressive symptoms, trait anxiety and early life stress, and positively with self-efficacy, optimism, social support and wellbeing (all r>0.40; all p-values <=0.001 except for early life stress: r=-0.20; p<=0.05). Resilience and DHEA-S concentrations correlated significantly (r=0.35; p<=0.05); this relationship remained stable after adjustment for demographics. Gender differences were observed for DHEA-S and cortisol (p<=0.05). CONCLUSION: Resilience is associated with positive aspects of psychological health and salivary DHEA-S, suggesting the latter can be treated as a biomarker of resilience in a non-clinical sample of adults. PMID- 23642337 TI - Anesthesia and incident dementia: a population-based, nested, case-control study. AB - OBJECTIVE: To test the hypothesis that exposure to procedures requiring general anesthesia during adulthood is not significantly associated with incident dementia using a retrospective, population-based, nested, case-control study design. PARTICIPANTS AND METHODS: Using the Rochester Epidemiology Project and the Mayo Clinic Alzheimer's Disease Patient Registry, residents of Olmsted County, Minnesota, diagnosed as having dementia between January 1, 1985, and December 31, 1994, were identified. For each incident case, a sex- and age matched control was randomly selected from the general pool of Olmsted County residents who were dementia free in the index year of dementia diagnosis. Medical records were reviewed to determine exposures to procedures requiring anesthesia after age 45 years and before the index year. Data were analyzed using logistic regression. RESULTS: We analyzed 877 cases of dementia, each with a corresponding control. Of the dementia cases, 615 (70%) underwent 1681 procedures requiring general anesthesia; of the controls, 636 (73%) underwent 1638 procedures. When assessed as a dichotomous variable, anesthetic exposure was not significantly associated with dementia (odds ratio, 0.89; 95% CI, 0.73-1.10; P=.27). In addition, no significant association was found when exposure was quantified as number of procedures (odds ratios, 0.87, 0.86, and 1.0 for 1, 2-3, and >=4 exposures, respectively, compared with none; P=.51). CONCLUSION: This study found no significant association between exposure to procedures requiring general anesthesia after age 45 years and incident dementia. PMID- 23642339 TI - Women prisoners, mental health, violence and abuse. AB - This article examines the specific experiences of women in prison, focusing on previous (and continuing) physical and mental abuse, the consequent health care requirements of women prisoners, the policy response and the availability of suitable health care in prisons across the EU. It draws from an extensive review of the literature on women prisoners across Europe that was part of an on-going European Project funded by the DAPHNE programme of the European Commission, entitled 'DAPHNE Strong'. It also uses the field research from the project collected via surveys and in-depth interviews with key personnel in organisations that work with women prisoners or ex-prisoners and staff with a strategic overview of activity from the ministries of justice, police, prison service and women's support organisations. There are probably many more women prisoners with a history of domestic abuse than is officially recognised. Many of the women prison population who have experienced violence and abuse mask this by problematic drug or alcohol use as well as self-injury. These are key areas that training for prison staff needs to address. The availability of services for this group of women is inconsistent within and between countries of the EU. The political will to address the situation of women in prison, as distinct from the norms applied to men, is variable and it seems to take the determined efforts of active lobby groups to make inroads into an area of latent inertia. PMID- 23642340 TI - Exploring the acquisition of entry-to-practice competencies by second-degree nursing students during a preceptorship experience. AB - BACKGROUND: Nursing programs across Canada have begun to implement at an unprecedented rate second-degree nursing programs in response to consumer demands and a nursing shortage. While these types of programs are enjoying considerable popularity among prospective students and employers, it is imperative that nursing programs assess their graduates' ability to meet Registered Nursing entry to-practice competencies (ETCs). OBJECTIVES: This study sought to determine if second-degree undergraduate nursing students achieved the entry-to-practice competencies established by the provincial regulatory body for registered nurses of Alberta, Canada. SETTING: The study took place in southern Alberta, Canada as the first cohort of second-degree undergraduate nursing students were completing the final practice course for the program. DESIGN: In this exploratory study, quantitative and qualitative data generation approaches were used. Quantitative data were collected using the nursing program's standardized Clinical Evaluation Tool which is mapped to the 119 ETCs established by the regulatory body. Qualitative data were generated by conducting focus group interviews with students, faculty advisors, and preceptors. PARTICIPANTS: A convenience sample consisting of both male and female students (n=14) submitted their mid-term and final clinical evaluations for inclusion in the dataset. Thirteen preceptors submitted mid-term and final clinical evaluations. Three students, three faculty advisors, and two preceptors participated in focus group interviews. RESULTS: At mid-term, statistically significant differences were noted on 31% of the indicators within the clinical evaluation tool between students and preceptors with preceptors consistently ranking students higher than the students' ratings of their performance. Student and preceptor ratings of students' clinical performance were more consistent on the final evaluation. However, where there were differences, preceptors rated students higher than student ratings. Qualitative data analysis suggests that the concept of competence is complex and multifaceted and understood differently by students, preceptors, and advisors. CONCLUSIONS: The findings of this study suggest that there is ambiguity among second-degree students, preceptors and faculty advisors surrounding the concept of competence. In order to develop an understanding of competence, nursing program administrators must encourage faculty advisors, preceptors and students to engage in a discussion at the outset of the preceptored practice experience in regard to what is meant by competence within various practice setting. Further, we suggest nursing programs in collaboration with their clinical partners and re examine their practice evaluation tools to determine the degree to which they are sensitive to the clinical practice context. PMID- 23642341 TI - Seizure prediction and documentation--two important problems. PMID- 23642342 TI - Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-resistant epilepsy: a first-in-man study. AB - BACKGROUND: Seizure prediction would be clinically useful in patients with epilepsy and could improve safety, increase independence, and allow acute treatment. We did a multicentre clinical feasibility study to assess the safety and efficacy of a long-term implanted seizure advisory system designed to predict seizure likelihood and quantify seizures in adults with drug-resistant focal seizures. METHODS: We enrolled patients at three centres in Melbourne, Australia, between March 24, 2010, and June 21, 2011. Eligible patients had between two and 12 disabling partial-onset seizures per month, a lateralised epileptogenic zone, and no history of psychogenic seizures. After devices were surgically implanted, patients entered a data collection phase, during which an algorithm for identification of periods of high, moderate, and low seizure likelihood was established. If the algorithm met performance criteria (ie, sensitivity of high likelihood warnings greater than 65% and performance better than expected through chance prediction of randomly occurring events), patients then entered an advisory phase and received information about seizure likelihood. The primary endpoint was the number of device-related adverse events at 4 months after implantation. Our secondary endpoints were algorithm performance at the end of the data collection phase, clinical effectiveness (measures of anxiety, depression, seizure severity, and quality of life) 4 months after initiation of the advisory phase, and longer-term adverse events. This trial is registered with ClinicalTrials.gov, number NCT01043406. FINDINGS: We implanted 15 patients with the advisory system. 11 device-related adverse events were noted within four months of implantation, two of which were serious (device migration, seroma); an additional two serious adverse events occurred during the first year after implantation (device-related infection, device site reaction), but were resolved without further complication. The device met enabling criteria in 11 patients upon completion of the data collection phase, with high likelihood performance estimate sensitivities ranging from 65% to 100%. Three patients' algorithms did not meet performance criteria and one patient required device removal because of an adverse event before sufficient training data were acquired. We detected no significant changes in clinical effectiveness measures between baseline and 4 months after implantation. INTERPRETATION: This study showed that intracranial electroencephalographic monitoring is feasible in ambulatory patients with drug resistant epilepsy. If these findings are replicated in larger, longer studies, accurate definition of preictal electrical activity might improve understanding of seizure generation and eventually lead to new management strategies. FUNDING: NeuroVista. PMID- 23642344 TI - Anticoagulant therapy in acute brain ischaemia. PMID- 23642343 TI - Targeted use of heparin, heparinoids, or low-molecular-weight heparin to improve outcome after acute ischaemic stroke: an individual patient data meta-analysis of randomised controlled trials. AB - BACKGROUND: Many international guidelines on the prevention of venous thromboembolism recommend targeting heparin treatment at patients with stroke who have a high risk of venous thrombotic events or a low risk of haemorrhagic events. We sought to identify reliable methods to target anticoagulant treatment and so improve the chance of avoiding death or dependence after stroke. METHODS: We obtained individual patient data from the five largest randomised controlled trials in acute ischaemic stroke that compared heparins (unfractionated heparin, heparinoids, or low-molecular-weight heparin) with aspirin or placebo. We developed and evaluated statistical models for the prediction of thrombotic events (myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism) and haemorrhagic events (symptomatic intracranial or significant extracranial) in the first 14 days after stroke. We calculated the absolute risk difference for the outcome "dead or dependent" in patients grouped by quartiles of predicted risk of thrombotic and haemorrhagic events with random effect meta analysis. FINDINGS: Patients with ischaemic stroke who were of advanced age, had increased neurological impairment, or had atrial fibrillation had a high risk of both thrombotic and haemorrhagic events after stroke. Additionally, patients with CT-visible evidence of recent cerebral ischaemia were at increased risk of thrombotic events. In evaluation datasets, the area under a receiver operating curve for prediction models for thrombotic events was 0.63 (95% CI 0.59-0.67) and for haemorrhagic events was 0.60 (0.55-0.64). We found no evidence that the net benefit from heparins increased with either increasing risk of thrombotic events or decreasing risk of haemorrhagic events. INTERPRETATION: There was no evidence that patients with ischaemic stroke who were at higher risk of thrombotic events or lower risk of haemorrhagic events benefited from heparins. We were therefore unable to define a targeted approach to select the patients who would benefit from treatment with early anticoagulant therapy. We recommend that guidelines for routine or selective use of heparin in stroke should be revised. FUNDING: MRC. PMID- 23642345 TI - A past Haff disease outbreak associated with eating freshwater pomfret in South China. AB - BACKGROUND: Haff disease is unexplained rhabdomyolysis caused by consumption of fishery products in the previous 24 h. It was first identified in Europe in 1924 but the condition is extremely rare in China. Here we describe a past outbreak of acute food borne muscle poisoning that occurred in Guangdong Province (South China) in 2009. METHODS: The first full outbreak of Haff disease reported in Jiangsu Province (East China) in 2010, indicated that the incidence of the disease may be increasing in China. We, therefore first retrospectively reviewed epidemiologic, trace-back, environmental studies, and laboratory analyses, including oral toxicity testing to ascertain risk and chemical analysis to identify toxin(s), from the 2009 Guangdong outbreak. Then we compared data from the 2009 outbreak with data from all other Haff disease outbreaks that were available. RESULTS: Clinical symptoms and laboratory findings indicated that the 2009 Guangdong outbreak disease was consistent with rhabdomyolysis. Epidemiologic, trace-back, environmental studies and laboratory analyses implied that the disease was caused by freshwater Pomfrets consumed prior to the onset of symptoms. We also identified common factors between the 2009 Guangdong outbreak and previous Haff disease outbreaks reported around the world, while as with other similar outbreaks, the exact etiological factor(s) of the disease remains unknown. CONCLUSIONS: The 2009 Guangdong outbreak of 'muscle poisoning' was retrospectively identified as an outbreak of Haff disease. This comprised the highest number of cases reported in China thus far. Food borne diseases emerging in this unusual form and the irregular pattern of outbreaks present an ongoing public health risk, highlighting the need for improved surveillance and diagnostic methodology. PMID- 23642346 TI - Schizophrenia, antipsychotics and risk of hip fracture: a population-based analysis. AB - In a nationwide study using linkage of Danish hospital registers we examined predictors of hip fracture (ICD-10: S72) in 15,431 patients with schizophrenia (ICD-10: F20 or ICD-8: 295) and 3,807,597 population controls. Shorter education, disability pension, lifetime alcohol abuse, somatic co-morbidity, antipsychotics (IRR=1.19; 95% CI 1.15-1.24), antidepressant (IRR=1.18; 95% CI 1.16-1.20), anticholinergics (IRR=1.29; 95% CI 1.22-1.36), benzodiazepines (IRR=1.06; 95% CI 1.04-1.08) and corticosteroids (IRR=1.44; 95% CI 1.36-1.53) were significant predictors. In 556 persons with schizophrenia and hip fracture (matched to 1:3 to schizophrenia controls without hip fracture), antipsychotic polypharmacy predicted hip fracture. Analyses among antipsychotic monotherapy patients showed no differential effect of individual antipsychotics. A dose-response relationship of hip fracture and lifetime antipsychotics consumption was found (IRR=1.13 95% CI 1.07-1.19) and both prolactin-increasing and non-prolactin-increasing antipsychotics contributed to the effect. In conclusion, several factors, including complex psychopharmacological treatment, contribute in the prediction of hip fracture in large populations. Preventive strategies should focus attention to severely ill patients with high likelihood of a receiving complex psychopharmacologic treatment and high doses of antipsychotics. PMID- 23642347 TI - Animal assisted interventions in neurorehabilitation: a review of the most recent literature. AB - INTRODUCTION: While conventional wisdom has always affirmed the value of animals in promoting human health and well-being, only recently has their therapeutic role in medicine become a topic for dedicated research. Animal assisted interventions (AAI) can be classified as animal-assisted activities, animal assisted therapy, and service animal programs. OBJECTIVE: The aim of this review is to analyse original papers addressing AAI and neurological diseases and published in the most influential medical journals between 2001 and 2012, and discuss their findings in the light of what may be of interest in the field of neurology. DISCUSSION: We selected a total of 23 articles on neurorehabilitation in cerebral palsy, pervasive developmental disorders, multiple sclerosis, spinal cord injury, stroke, and mental disorders. The main therapeutic results were improvement on the Gross Motor Function Classification Scale and in upper limb dexterity (cerebral palsy); improvement in social functioning and interaction; reductions in stress, anxiety, and loneliness (pervasive developmental disorders and mental disorders); and decreased spasticity with improved balance (multiple sclerosis, spinal cord injury, stroke). CONCLUSION: These interventions, performed with highly specialised animals in very specific neurological populations, deliver an increasing body of scientific evidence suggesting that they are an effective complement to other existing therapies. In these diseases, further high-quality studies are warranted in order to define the most appropriate programmes for therapy. PMID- 23642348 TI - A comparative analysis of fatty infiltration and muscle atrophy in patients with chronic rotator cuff tears and suprascapular neuropathy. AB - BACKGROUND: Little is known of the mechanisms that lead to the muscle changes associated with rotator cuff disorders. We have observed that the magnetic resonance imaging (MRI) appearance of fatty infiltration (FI) and muscle atrophy (MA) differ between chronic cuff tears and suprascapular neuropathy, suggesting different pathophysiology. This study compares the different MRI changes that occur in chronic cuff tears and suprascapular neuropathy. METHODS: Two groups were retrospectively identified: (1) RCT group (20 shoulders): patients with chronic tears of the supraspinatus and/or infraspinatus without electromyographic (EMG) evidence of suprascapular neuropathy; (2) neuro group (17 shoulders): patients with EMG documented suprascapular nerve dysfunction and absence of a rotator cuff tear. Magnetic resonance arthrograms were analyzed for the degree of FI and MA, and the morphology of the muscle was assessed, in particular the muscle border, pattern of FI, and extent of involvement. RESULTS: The muscle changes that occur following chronic cuff tears differ from that following denervation secondary to suprascapular neuropathy, especially with respect to the muscle border, degree of perineural fat, and overall distribution of FI. Highly specific and characteristic morphological patterns of FI exist for both chronic cuff tears and suprascapular neuropathy. CONCLUSION: Chronic rotator cuff tendon tears and suprascapular neuropathy are both associated with FI and MA of the rotator cuff muscles. The pattern of FI is markedly different in the 2 situations. These findings have diagnostic potential and may serve as a basis for further research concerning type, severity, and evolution of FI under different conditions and after treatment. PMID- 23642349 TI - Untreated obstructive sleep apnea and the risk for serious long-term adverse outcomes: a systematic review. AB - BACKGROUND: Reports on the association between obstructive sleep apnea (OSA) and risk of death, cardiovascular (CV) events, diabetes and depression have been inconsistent. METHODS: We conducted a systematic review of the prognostic value of clinical and polysomnographic (PSG) characteristics of OSA for adverse long term outcomes of untreated OSA in adult patients. A comprehensive search strategy for prognosis studies, OSA, CV events, mortality, depression and diabetes was developed in collaboration with a medical information specialist. All English language studies, from Jan 1999 to Dec 2011, with longitudinal design in adults with OSA diagnosed by PSG recording, found through Medline, Embase and bibliographies of identified articles, were considered eligible. Quality was assessed using published guidelines. RESULTS: Among 26 articles, ten evaluated the association of OSA with mortality, 9 with a composite CV outcome, 4 with stroke, 2 with diabetes and 1 with depression. Significant relationships between the apnea-hypopnea index (AHI) and outcomes of interest were reported in 18 studies: seven for all-cause mortality, six for composite CV events, three for stroke, one for diabetes and one for depression. The effect of AHI was attenuated by female gender, older age, absence of daytime sleepiness and higher body mass index. Due to clinical heterogeneity between studies, meta-analyses were not performed. CONCLUSION: Evidence exists in men for a relationship between OSA and all-cause mortality and a composite CV outcome. Associations between OSA and other outcomes remain uncertain. Among OSA-specific markers, only AHI was a consistent predictor. Other consistent predictors were traditional CV risk factors. Research is required to identify effect modifiers and the predictive ability of various AHI threshold values and hypopnea definitions. An enhanced set of OSA-specific predictors will allow better risk stratification to guide OSA treatment. PMID- 23642350 TI - Quality indicator development and implementation in maternity units. AB - Measuring the quality of inpatient obstetrical care has generated considerable interest in recent years. Numerous quality measures have been proposed by national and international programmes and by obstetrics societies; however, no agreement has been reached on which measures should be used. Differences in opinions across healthcare professionals complicate the development of a standardised set of quality indicators. The use of structured methods, particularly consensus methods such as Delphi techniques, can help to choose indicators according to quality goals. Once relevant indicators are identified, maternity units should consider using a dashboard to plan and improve their services. Statistical process control is a statistical method designed to monitor and control processes. This method seems particularly promising for monitoring quality indicators in maternity units. Among statistical process control techniques, cumulative sum charts that monitor pre-selected quality indicators can be easily designed for obstetrics and gynaecology units. Cumulative sum charts provide clinicians with a picture of current practices, and rapidly detect unwanted changes in quality indicator rates. PMID- 23642351 TI - Reflections on the Canadian MORE(OB) obstetrical risk management programme. AB - In, 2001, the Patient Safety Division of the Society of Obstetricians and Gynaecologists of Canada initiated and championed a new program to improve patient safety performance in Canadian hospital obstetric units. This new program was developed under the banner of Managing Obstetrical Risk Efficiently and called the MORE(OB) Programme The MORE(OB) Programme was first piloted in Canadian hospitals at the beginning of May 2002 and, by mid 2004, 33 pilot sites had been implemented. In autumn 2004, this program embarked on a national launch. In 2007, the Society of Obstetricians and Gynaecologists of Canada collaborated with the Healthcare Insurance Reciprocal of Canada to form Salus Global Corporation. The birth of this corporate entity embraced the support of rapid expansion of the program within and outside of Canada. This collaboration also enabled innovation and implementation of safety programs beyond the obstetric discipline. PMID- 23642352 TI - Protecting patient safety in resource-poor settings. AB - A crucial element in the delivery of high-quality health care is patient safety. The rate of adverse events among hospital patients is an indication of patient safety. A systematic review of in-hospital adverse events revealed the median incidence of adverse events as 9.2%; 7.4% were lethal and 43.5% preventable. All the studies in the systemic review were from developed countries, as research is lacking from developing countries. In 2012, data from 10 developing countries reported adverse events ranging from 2.5 to 18.4% per country; 30% were lethal and 83% preventable. This study places patient safety as one of the major concerns of the health policy agenda in developing countries. Human resources for health deficits in developing countries constitute a major structural constraint for ensuring patient safety. The key to reducing adverse events in health care is system-based interventions rather than clinical interventions or technologies. Patient safety skills training, effective communication, and good team work are essential in improving patient safety in developing countries. Research on patient safety is needed to address the knowledge gap in developing countries. PMID- 23642353 TI - Gamma interferon-inducible lysosomal thioreductase (GILT) ablation renders mouse fibroblasts sensitive to dengue virus replication. AB - Dengue viruses (DENV), members of mosquito-borne Flaviviruses, are human pathogens of global significance. The virus enters the host cell through endocytosis and uncoating subsequent to a low pH-triggered conformational change of E protein in endosomes. The endosomes are active in antigen processing and the key enzyme involved is the gamma interferon-inducible lysosomal thiol reductase (GILT). Here, we sought to address the role of GILT in DENV2 entry using fibroblasts from wild type (WT) and GILT knockout (GILT(-/-)) mice (MFs) with defective antigen processing. Our results obtained using DENV2 infectious and Renilla luciferase reporter replicon RNAs show that WT MFs are relatively resistant and GILT(-/-) MFs are susceptible to DENV2 translation and replication. We show that DENV2 infection of WT MEFs induced autophagy based on an increased LC3-II/LC3-I ratio that is further enhanced in GILT(-/-) cells. The increased susceptibility of DENV2 infection in the GILT(-/-)MFs strongly correlates with increased autophagy. PMID- 23642354 TI - Health, body image, gender, and migration status: their relationship to sexuality in old age. AB - BACKGROUND: The aim of this study was to assess the relationships between gender, migration status, perceived health, body image, and sexual activity and satisfaction among older adults. It was hypothesized that men and those who are long-standing residents in Israel will report better perceived health, a positive body image, and these will be associated with greater sexuality, compared with women, new immigrants with poorer perceived health and a negative body image. METHODS: The sample included 200 respondents who were 60 years and older, functionally independent and living with a spouse or a partner for at least one year, heterosexual, and living in the community in Israel. Respondents were recruited through community-based services for older persons and snowballing. Multivariate analyses were performed to examine differences by groups of respondents and to identify the best predictors of the outcome variables. RESULTS: The majority had some kind of sexual activity. No significant differences were found between men and women with regard to perceived health, body image, sexual activity and satisfaction, but significant differences were found between new immigrants from former Soviet Union countries and long-standing residents in Israel. Mental health, age, and migration status were significant in explaining sexual activity, while age, education, and sexual activity were significant in explaining sexual satisfaction. CONCLUSIONS: A variety of factors play a role with regard to sexuality in old age, in particular immigration status. Appropriate interventions can help older adults cope with the determinants that negatively affect their mental health and sexual life. PMID- 23642355 TI - Human cortical interneurons take their time. AB - In this issue, Maroof et al. (2013) and Nicholas et al. (2013) describe strategies for deriving cortical interneurons from human pluripotent stem cells. Functional maturation of these neurons occurs over a protracted period, which resembles normal human development, and suggests these cells may be useful for modeling brain development and disease. PMID- 23642356 TI - miR-34a sets the "sweet spot" for notch in colorectal cancer stem cells. AB - Mechanisms underlying alternative modes of symmetric versus asymmetric stem cell fates are not well understood. In this issue of Cell Stem Cell, Bu et al. (2013) find that miR-34a acts as a toggle switch for Notch signaling that dictates binary symmetric and asymmetric fates in colon cancer stem cells. PMID- 23642357 TI - Same function, different origins: multipotent stromal precursors in lymphoid tissues. AB - The evolutionary and lineage relationships between various stromal cell types that support the immune system are not well understood. Recently, in Immunity, Castagnaro et al. (2013) identified multipotent mesenchymal precursors that specifically give rise to stromal cell types in the spleen, but not other lymphoid tissue, and support injury-induced regeneration. PMID- 23642358 TI - iOPs: a new tool for studying myelin pathologies? AB - Generating patient-specific oligodendrocyte progenitors capable of repairing myelination defects observed in multiple neurological afflictions holds great therapeutic potential. Recently in Nature Biotechnology, Najm et al. (2013) and Yang et al. (2013) generated these progenitors by direct reprogramming, bringing us closer to their use in disease analysis and autologous transplantation strategies. PMID- 23642359 TI - Therapeutic hope, spiritual distress, and the problem of stem cell tourism. AB - Managing patients' therapeutic hope and spiritual distress-in addition to tighter regulation of commercial therapies and improved patient understanding-may offer a more comprehensive approach to reducing the overall incidence of stem cell tourism. Such patient support must occur early in the clinical relationship after appropriate assessment and discussion. PMID- 23642360 TI - Patents and misplaced angst: lessons for translational stem cell research from genomics. AB - Realizing the therapeutic potential of both stem cell and genomics research requires harnessing the respective strengths of academic, biotechnology, and pharmaceutical sectors, supported by policies and legal incentives for multisectorial collaboration. Here, we discuss issues facing these fields and lessons from the genomics sector that apply to stem cell research. PMID- 23642361 TI - Whole-genome analysis, stem cell research, and the future of biobanks. AB - The convergence of the genomic revolution and biobanking with rapid progress in stem cell research holds vast potential for personalized medicine and novel therapies. In this Forum, we explore social and ethical considerations emerging from strategies to realize the promise of these remarkable technologies. PMID- 23642362 TI - Hopes and fears for professional movement in the stem cell community. AB - We examine here how the issue of professional migration in stem cell research has been explored in news media, government documents, and the peer-reviewed literature. The results shed light on how patterns of and forces that motivate these movements are depicted and highlight issues of significance to the stem cell community. PMID- 23642363 TI - Next-generation regenerative medicine: organogenesis from stem cells in 3D culture. AB - The behavior of stem cells, when they work collectively, can be much more sophisticated than one might expect from their individual programming. This Perspective covers recent discoveries about the dynamic patterning and structural self-formation of complex organ buds in 3D stem cell culture, including the generation of various neuroectodermal and endodermal tissues. For some tissues, epithelial-mesenchymal interactions can also be manipulated in coculture to guide organogenesis. This new area of stem cell research-the spatiotemporal control of dynamic cellular interactions-will open a new avenue for next-generation regenerative medicine. PMID- 23642364 TI - Reduced Oct4 expression directs a robust pluripotent state with distinct signaling activity and increased enhancer occupancy by Oct4 and Nanog. AB - Embryonic stem cell (ESC) pluripotency is governed by a gene regulatory network centered on the transcription factors Oct4 and Nanog. To date, robust self renewing ESC states have only been obtained through the chemical inhibition of signaling pathways or enforced transgene expression. Here, we show that ESCs with reduced Oct4 expression resulting from heterozygosity also exhibit a stabilized pluripotent state. Despite having reduced Oct4 expression, Oct4(+/-) ESCs show increased genome-wide binding of Oct4, particularly at pluripotency-associated enhancers, homogeneous expression of pluripotency transcription factors, enhanced self-renewal efficiency, and delayed differentiation kinetics. Cells also exhibit increased Wnt expression, enhanced leukemia inhibitory factor (LIF) sensitivity, and reduced responsiveness to fibroblast growth factor. Although they are able to maintain pluripotency in the absence of bone morphogenetic protein, removal of LIF destabilizes pluripotency. Our findings suggest that cells with a reduced Oct4 concentration range are maintained in a robust pluripotent state and that the wild-type Oct4 concentration range enables effective differentiation. PMID- 23642365 TI - Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. AB - Human pluripotent stem cells are a powerful tool for modeling brain development and disease. The human cortex is composed of two major neuronal populations: projection neurons and local interneurons. Cortical interneurons comprise a diverse class of cell types expressing the neurotransmitter GABA. Dysfunction of cortical interneurons has been implicated in neuropsychiatric diseases, including schizophrenia, autism, and epilepsy. Here, we demonstrate the highly efficient derivation of human cortical interneurons in an NKX2.1::GFP human embryonic stem cell reporter line. Manipulating the timing of SHH activation yields three distinct GFP+ populations with specific transcriptional profiles, neurotransmitter phenotypes, and migratory behaviors. Further differentiation in a murine cortical environment yields parvalbumin- and somatostatin-expressing neurons that exhibit synaptic inputs and electrophysiological properties of cortical interneurons. Our study defines the signals sufficient for modeling human ventral forebrain development in vitro and lays the foundation for studying cortical interneuron involvement in human disease pathology. PMID- 23642366 TI - Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. AB - Directed differentiation from human pluripotent stem cells (hPSCs) has seen significant progress in recent years. However, most differentiated populations exhibit immature properties of an early embryonic stage, raising concerns about their ability to model and treat disease. Here, we report the directed differentiation of hPSCs into medial ganglionic eminence (MGE)-like progenitors and their maturation into forebrain type interneurons. We find that early-stage progenitors progress via a radial glial-like stem cell enriched in the human fetal brain. Both in vitro and posttransplantation into the rodent cortex, the MGE-like cells develop into GABAergic interneuron subtypes with mature physiological properties along a prolonged intrinsic timeline of up to 7 months, mimicking endogenous human neural development. MGE-derived cortical interneuron deficiencies are implicated in a broad range of neurodevelopmental and degenerative disorders, highlighting the importance of these results for modeling human neural development and disease. PMID- 23642369 TI - Physical exercise: potential candidate as coping strategy for people with epilepsy. PMID- 23642367 TI - Mesp1 patterns mesoderm into cardiac, hematopoietic, or skeletal myogenic progenitors in a context-dependent manner. AB - Mesp1 is regarded as the master regulator of cardiovascular development, initiating the cardiac transcription factor cascade to direct the generation of cardiac mesoderm. To define the early embryonic cell population that responds to Mesp1, we performed pulse inductions of gene expression over tight temporal windows following embryonic stem cell differentiation. Remarkably, instead of promoting cardiac differentiation in the initial wave of mesoderm, Mesp1 binds to the Tal1 (Scl) +40 kb enhancer and generates Flk-1+ precursors expressing Etv2 (ER71) and Tal1 that undergo hematopoietic differentiation. The second wave of mesoderm responds to Mesp1 by differentiating into PDGFRalpha+ precursors that undergo cardiac differentiation. Furthermore, in the absence of serum-derived factors, Mesp1 promotes skeletal myogenic differentiation. Lineage tracing revealed that the majority of yolk sac and many adult hematopoietic cells derive from Mesp1+ precursors. Thus, Mesp1 is a context-dependent determination factor, integrating the stage of differentiation and the signaling environment to specify different lineage outcomes. PMID- 23642368 TI - A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. AB - microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs. PMID- 23642371 TI - Corneal hysteresis as a risk factor for glaucoma progression: a prospective longitudinal study. AB - PURPOSE: To evaluate the role of corneal hysteresis (CH) as a risk factor for the rate of visual field progression in a cohort of patients with glaucoma followed prospectively over time. DESIGN: Prospective observational cohort study. PARTICIPANTS: The study group included 114 eyes of 68 patients with glaucoma followed for an average of 4.0 +/- 1.1 years. Visual fields were obtained with standard automated perimetry. Included eyes had a median number of 7 (range, 5 12) tests during follow-up. METHODS: The CH measurements were acquired at baseline using the Ocular Response Analyzer (Reichert Instruments, Depew, NY). Evaluation of rates of visual field change during follow-up was performed using the visual field index (VFI). Linear mixed models were used to investigate the relationship between rates of visual field loss and baseline CH, baseline intraocular pressure (IOP), and central corneal thickness (CCT), while adjusting for potentially confounding factors. An interaction term between IOP and CH was included in the model to investigate whether the effect of IOP on rates of progression depended on the level of CH. MAIN OUTCOME MEASURES: Effects of CH, IOP, and CCT on rates of VFI loss over time. RESULTS: The CH had a significant effect on rates of visual field progression over time. In the univariable model including only CH as a predictive factor along with time and their interaction, each 1 mmHg lower CH was associated with a 0.25%/year faster rate of VFI decline over time (P<0.001). The multivariable model showed that the effect of IOP on rates of progression depended on CH. Eyes with high IOP and low CH were at increased risk for having fast rates of disease progression. The CH explained a larger proportion of the variation in slopes of VFI change than CCT (17.4% vs. 5.2%, respectively). CONCLUSIONS: The CH measurements were significantly associated with risk of glaucoma progression. Eyes with lower CH had faster rates of visual field loss than those with higher CH. The prospective longitudinal design of this study supports the role of CH as an important factor to be considered in the assessment of the risk of progression in patients with glaucoma. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23642372 TI - Cost-effectiveness of various interventions for newly diagnosed diabetic macular edema. AB - OBJECTIVE: Anti-vascular endothelial growth factor therapies have revolutionized the treatment of clinically significant diabetic macular edema (CSDME); yet these agents are expensive, and whether they are cost-effective is unclear. The purpose of this study is to determine the most cost-effective treatment option for patients with newly diagnosed CSDME: focal laser photocoagulation alone (L), focal laser plus intravitreal ranibizumab (L+R), focal laser plus intravitreal bevacizumab (L+B), or focal laser plus intravitreal triamcinolone (L+T) injections. DESIGN: Cost-effectiveness analysis. PARTICIPANTS: Hypothetical cohort of 57-year-old patients with newly diagnosed CSDME. METHODS: By using a Markov model with a 25-year time horizon, we compared the incremental cost effectiveness of treating patients with newly diagnosed CSDME using L, L+R, L+B, or L+T. Data came from the DRCRnet randomized controlled trial, the Medicare fee schedule, and the medical literature. MAIN OUTCOME MEASURES: Costs, quality adjusted life years (QALYs), and incremental costs per QALY gained. RESULTS: Compared with L, the incremental cost-effectiveness of L+R and L+B was $89903/QALY and $11138/QALY, respectively. L+T was dominated by L. A probabilistic sensitivity analysis demonstrated that, at a willingness to pay (WTP) of $50000/QALY, L was approximately 70% likely to be the preferred therapy over L+R and L+T. However, at a WTP of $100000/QALY, more than 90% of the time, L+R therapy was the preferred therapy compared with L and L+T. In the probabilistic sensitivity analysis, L+B was found to be the preferred therapy over L and L+T for any WTP value >$10000/QALY. Sensitivity analyses revealed that the annual risk of cerebrovascular accident would have to be at least 1.5% higher with L+B than with L+R for L+R to be the preferred treatment. In another sensitivity analysis, if patients require <8 injections per year over the remainder of the 25-year time horizon, L+B would cost <$100000/QALY, whereas L+R would be cost-effective at a WTP of $100000/QALY if patients require fewer than 0.45 injections per year after year 2. CONCLUSIONS: With bevacizumab and ranibizumab assumed to have equivalent effectiveness and similar safety profiles when used in the management of CSDME, bevacizumab therapy confers the greatest value among the different treatment options for CSDME. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23642373 TI - Ostium shrinkage after endoscopic dacryocystorhinostomy. AB - OBJECTIVE: Ostium closure after endoscopic dacryocystorhinostomy (DCR) is the commonest cause for anatomic failure. We aimed to determine the changes in size of the DCR ostium over time and investigate the correlation of ostium size and surgical outcomes. DESIGN: A single surgeon, prospective, nonrandomized, noncomparative, interventional case series. PARTICIPANTS: We included a consecutive series of patients who underwent powered endonasal DCR. All patients had radiologically confirmed nasolacrimal duct or canalicular obstruction. METHODS: Patients were operated on by 1 surgeon (D.S.) and follow-up was at 4 weeks and 12 months. Ostium sizes were measured at the end of surgery and at 4 weeks and 12 months after surgery. MAIN OUTCOME MEASURES: Intraoperative and postoperative ostium size, correlation of ostium size, and surgical outcome. RESULTS: We included 161 patients who fulfilled the inclusion criteria. Three patients were lost to follow-up. The ostium measured 8.6 (95% confidence interval [CI], 5.0-12.2) by 13.4 (95% CI, 10.3-16.5) at the time of surgery and 5.7 (95% CI, 2.3-9.0) by 9.5 (95% CI, 6.0-13.0) at 4 weeks, and 4.8 (95% CI, 1.9-7.7) by 8.2 (95% CI, 4.5-11.9) at 12 months. There was significant ostial shrinkage from surgery to 4 weeks (mean shrinkage of 50%) and from 4 weeks to 12 months (mean shrinkage of a further 15%). The intraoperative ostium size and postoperative size were positively correlated. Ostial size was not predictive of final ostial patency and symptomatic resolution of epiphora. CONCLUSIONS: After endoscopic DCR, the final ostium size on average is 35% of the original at 12 months postoperatively. The majority of the ostium shrinkage occurs within 4 weeks postoperatively with a lesser degree of shrinkage between 1 and 12 months postoperatively. Ostium size was not predictive of overall surgical outcome. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article. PMID- 23642374 TI - Molecular diagnosis and ocular imaging of West Nile virus retinitis and neuroretinitis. AB - PURPOSE: To describe the ocular features of West Nile virus (WNV) infection proven by serology and molecular diagnostic techniques. DESIGN: Prospective case series. PARTICIPANTS: Fifty-two patients who presented to the uveitis clinic with ocular inflammatory signs and history of fever preceding ocular symptoms between January 2010 and January 2012 were enrolled for laboratory diagnosis. Serum samples were collected from 30 healthy controls from the same geographic area. METHODS: Patients were tested for all endemic infectious diseases that can cause ocular inflammation by serology or molecular diagnostics. When patients had positive antibodies for WNV, serum/plasma samples were tested by real-time reverse transcription (RT) polymerase chain reaction (PCR) and RT loop-mediated isothermal gene amplification assays. The PCR product was subjected to nucleotide sequencing. Fundus fluorescence angiography (FFA), optical coherence tomography (OCT), and indocyanine green angiography were performed. Visual prognosis was analyzed. MAIN OUTCOME MEASURES: Clinical signs (retinitis, neuroretinitis, and choroiditis) and ocular complications (decrease in vision). RESULTS: A total of 37 of 52 patients (71%) showed positive results for at least 2 laboratory tests for WNV. Fundus examination revealed discrete, superficial, white retinitis; arteritis; phlebitis; and retinal hemorrhages with or without macular star. The FFA revealed areas of retinal inflammation with indistinct borders, vascular and optic disc leakage, vessel wall staining, or capillary nonperfusion. Indocyanine green angiography confirmed choroidal inflammation in 1 of the patients who was diabetic. The OCT scan of the macula revealed inner retinal layer edema in active inflammation and retinal atrophy in late stage. At the final visit, 43% of patients had visual acuity better than 6/12. CONCLUSIONS: In addition to previously reported clinical signs, retinitis, neuroretinitis, and retinal vasculitis were seen in this population. Atrophy of the inner retinal layer was seen on OCT after resolution of inflammation. Visual prognosis was good in patients with focal retinitis and poor in patients with occlusive vasculitis. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23642375 TI - Short-term consumption of oral omega-3 and dry eye syndrome. AB - PURPOSE: To assess the effect of oral omega-3 fatty acids on tear break-up time (TBUT), Schirmer's score, and Ocular Surface Disease Index (OSDI) through a double-blind clinical trial. DESIGN: Randomized, double-blind clinical trial. PARTICIPANTS: Sixty-four patients with dry eye symptoms between the ages of 45 and 90 years were randomized into 2 groups: 33 persons in the treatment group and 31 persons in the placebo group. METHODS: The treatment group received 2 capsules of omega-3 (each containing 180 mg eicosapentaenoic acid [EPA] and 120 mg docosahexaenoic acid [DHA]) daily for 30 days, and the placebo group received 2 medium-chain triglyceride oil capsules daily for 1 month. The outcomes were measured 1 month after the intervention. MAIN OUTCOME MEASURES: The primary outcome measure was an increase from baseline in TBUT at day 30. Secondary outcome measures were a decrease from baseline in the OSDI score and an increase in the Schirmer's score at day 30. RESULTS: In the placebo group, before the intervention, the mean TBUT, OSDI, and Schirmer's scores were 4.5 +/- 2.1 seconds, 36.4 +/- 13.8, and 6.0 +/- 2.6 mm, respectively, and 1 month later were 4.7 +/- 2.6 seconds, 37.6 +/- 13.5, and 6.2 +/- 2.5 mm, respectively. In the treatment group, these values were 3.9 +/- 1.7 seconds, 38.7 +/- 16.5, and 5.8 +/ 2.5 mm before the intervention and 5.67 +/- 2.6 seconds, 29.3 +/- 15.9, and 6.8 +/- 2.8 mm after the intervention, respectively. Repeated-measures analysis of variance showed that improvements in TBUT, OSDI, and Schirmer's scores were significantly better in the treatment group than in the placebo group. The changes in the treatment and placebo groups were 71% and 3.3% for TBUT (P < 0.001), 26% and 4% (P=0.004) for dry eye symptoms, and 22.3% and 5.1% for Schirmer's score (P=0.033), respectively. CONCLUSIONS: This study demonstrated that oral consumption of omega-3 fatty acids (180 mg EPA and 120 mg DHA twice daily for 30 days) is associated with a decrease in the rate of tear evaporation, an improvement in dry eye symptoms, and an increase in tear secretion. PMID- 23642376 TI - Incidence of canalicular closure with endonasal dacryocystorhinostomy without intubation in primary nasolacrimal duct obstruction. AB - PURPOSE: To describe the incidence of canalicular closure with powered endonasal dacryocystorhinostomy (DCR) without canalicular intubation in primary acquired nasolacrimal duct obstruction (PANDO). DESIGN: A single-surgeon, prospective, nonrandomized, noncomparative, interventional case series. PARTICIPANTS: Consecutive patients attending a specialist clinic of an oculoplastic surgeon (DS) with radiologically confirmed diagnosis of PANDO. Cases of canalicular disease were excluded. METHODS: Patients with radiologically confirmed PANDO without canalicular involvement underwent endonasal DCR without intubation. The operation was performed by 1 surgeon (DS) and follow-up was at 4 weeks and 12 months. MAIN OUTCOME MEASURES: Outcomes were recorded as subjective symptomatic relief at 12 months and endoscopic evidence of ostium patency and canalicular patency. RESULTS: There were 132 cases that fulfilled the inclusion criteria. Three cases were lost to follow-up. Preoperatively, 96.3% of cases had Munk scores of >2. Of the 129 cases, 127 (98.5%) had endoscopic evidence of a patent ostium with a positive endoscopic dye test at the 12-month follow-up. All cases had a patent canalicular system as demonstrated by syringing and probing. Of the 129 cases, 117 (90.7%) had subjective improvement of epiphora at 12 months with 88.4% of cases reporting Munk scores of <=1. CONCLUSIONS: In this prospective series of nonintubation for PANDO, there were no cases of canalicular closure or stenosis at 12 months. Anatomic and functional success was similar to reported outcomes for DCR with intubation for PANDO. We advocate that routine intubation for the purpose of maintaining canalicular patency is not necessary when performing endonasal DCR in PANDO. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23642378 TI - Improving function in age-related macular degeneration: a randomized clinical trial. AB - PURPOSE: To compare the efficacy of problem-solving therapy (PST) with supportive therapy (ST) to improve targeted vision function (TVF) in age-related macular degeneration (AMD). DESIGN: Single-masked, attention-controlled, randomized clinical trial with outcome assessments at 3 months (main trial endpoint) and 6 months (maintenance effects). PARTICIPANTS: Patients with AMD (n = 241) attending retina practices. INTERVENTIONS: Whereas PST uses a structured problem-solving approach to reduce vision-related task difficulty, ST is a standardized attention control treatment. MAIN OUTCOME MEASURES: We assessed TVF, the 25-item National Eye Institute Vision Function Questionnaire plus Supplement (NEI VFQ), the Activities Inventory (AI), and vision-related quality of life (QoL). RESULTS: There were no between-group differences in TVF scores at 3 (P = 0.47) or 6 (P = 0.62) months. For PST subjects, mean +/- standard deviation TVF scores improved from 2.71+/-0.52 at baseline to 2.18+/-0.88 at 3 months (P = 0.001) and were 2.18+/-0.95 at 6 months (change from 3 to 6 months, P = 0.74). For ST subjects, TVF scores improved from 2.73+/-0.52 at baseline to 2.14+/-0.96 at 3 months (P = 0.001) and were 2.15+/-0.96 at 6 months (change from 3 to 6 months, P = 0.85). Similar proportions of PST and ST subjects had less difficulty performing a TVF goal at 3 months (77.4% vs 78.6%, respectively; P = 0.83) and 6 months (76.2% vs 79.1%, respectively; P = 0.61). There were no changes in the NEI VFQ or AI. Vision-related QoL improved for PST relative to ST subjects at 3 months (F(4, 192) = 2.46; P = 0.05) and at 6 months (F(4, 178) = 2.55; P = 0.05). The PST subjects also developed more adaptive coping strategies than ST subjects. CONCLUSIONS: We found that PST was not superior to ST at improving vision function in patients with AMD, but that PST improved their vision-related QoL. Despite the benefits of anti-vascular endothelial growth factor treatments, AMD remains associated with disability, depression, and diminished QoL. This clinical reality necessitates new rehabilitative interventions to improve the vision function and QoL of older persons with AMD. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article. PMID- 23642379 TI - Intravenous leiomyomatosis with intracardiac extension - a review of diagnosis and management with an illustrative case. AB - Intravenous leiomyomatosis with intracardiac extension is an uncommon pathologic progression of uterine leiomyomata. It is a histologically benign condition, however due to interfence with right sided cardiac function patients may present with marked cardiovascular compromise and present a diagnostic dilemma to clinicians who are unfamiliar with this condition. Given the rarity of this condition, experience in individual institutions is usually limited to a few cases. We present an illustrative case and provide a review of the clinical presentation, preoperative assessment, operative approach, pathology and postoperative issues. The importance of a multidisciplinary approach to diagnosis and management is highlighted. Operative management aims to completely resect all tumour in the safest manner for the patient, most commonly via single or two stage operation. Where complete resection is achieved, recurrence appears to be a rare event. PMID- 23642380 TI - Meta-analysis of rivaroxaban and bleeding risk. AB - Rivaroxaban, a factor Xa inhibitor, is a new oral anticoagulant that has been developed as an alternative to vitamin K antagonists. However, its safety remains unclear. Reported randomized controlled trials comparing the safety of rivaroxaban with that of vitamin K antagonists (warfarin, acenocoumarol, phenprocoumon, and fluindione) were systematically searched. Inclusion was restricted to studies of >=30 days' treatment duration. Safety end points examined included major and clinically relevant nonmajor bleeding, as well as mortality. Data were pooled across randomized controlled trials using random effects meta-analysis models. Five randomized controlled trials including 23,063 patients that met the inclusion criteria were identified. Patients received treatment for nonvalvular atrial fibrillation (n = 14,264), deep vein thrombosis (n = 3,967), or acute symptomatic pulmonary embolism (n = 4,832). Overall, rivaroxaban was not associated with the risk of a composite end point of major or clinically relevant nonmajor bleeding (relative risk 0.99, 95% confidence interval 0.93 to 1.06). However, rivaroxaban was associated with a significant decrease in fatal bleeding (relative risk 0.48, 95% confidence interval 0.31 to 0.74). In 2 studies reporting intracranial bleeding events, rivaroxaban was associated with decreased risk compared with vitamin K antagonists. It was not associated with decreased risk for all-cause mortality (relative risk 0.89, 95% confidence interval 0.73 to 1.09). In conclusion, with a decrease in fatal bleeding and no suggestion of an increase in all-cause mortality, rivaroxaban has a favorable safety profile with respect to bleeding. PMID- 23642381 TI - Comparison by meta-analysis of mortality after isolated coronary artery bypass grafting in women versus men. AB - Short- and long-term mortality in women who undergo coronary artery bypass grafting (CABG) has been evaluated in multiple studies with conflicting results. The investigators conducted a meta-analysis of all existing studies to evaluate the impact of female gender on mortality in patients who undergo isolated CABG. A comprehensive search of studies published through May 31, 2012 identified 20 studies comparing men and women who underwent isolated CABG. All-cause mortality was evaluated at short-term (postoperative period and/or at 30 days), midterm (1 year), and long-term (5-year) follow-up. Odds ratios (ORs) and 95% confidence interval (CIs) were calculated using a random-effects model. A total of 966,492 patients (688,709 men [71%], 277,783 women [29%]) were included in this meta analysis. Women were more likely to be older; had significantly greater co morbidities, including hypertension, diabetes mellitus, hyperlipidemia, unstable angina, congestive heart failure, and peripheral vascular disease; and were more likely to undergo urgent CABG (51% vs 44%, p <0.01). Short-term mortality (OR 1.77, 95% CI 1.67 to 1.88) was significantly higher in women. At midterm and long term follow-up, mortality remained high in women compared with men. Women remained at increased risk for short-term mortality in 2 subgroup analyses including prospective studies (n = 41,500, OR 1.83, 95% CI 1.59 to 2.12) and propensity score-matched studies (n = 11,522, OR 1.36, 95% CI 1.04 to 1.78). In conclusion, women who underwent isolated CABG experienced higher mortality at short-term, midterm, and long-term follow-up compared with men. Mortality remained independently associated with female gender despite propensity score matched analysis of outcomes. PMID- 23642382 TI - Comparison of inferolateral early repolarization and its electrocardiographic phenotypes in pre- and postadolescent populations. AB - Inferolateral early repolarization (ER) patterns on standard electrocardiogram (ECG) are associated with increased risk for cardiac and arrhythmic death in general adult population cohorts. We sought to determine the prevalence of inferolateral ER on surface ECG in multiracial pre- and postadolescent populations and to analyze its association with age, race, gender, and ST-segment patterns. A retrospective review was conducted of all ECGs recorded from preadolescent (aged 8-12 years, n = 719) and postadolescent (aged 21-25 years, n = 755) patients seen at a large academic medical center between January 1, 2009, and December 31, 2010. The overall prevalence of inferolateral ER was similar in the preadolescent and postadolescent populations (17% vs 16%, NS). The prevalence of ER increased after puberty in male patients (16% to 25%, p <0.001) and decreased in female patients (18% to 9%, p <0.001). Prevalence of ascending early repolarization (benign variant) also increased in males after puberty (15% to 23%, p <0.004) and decreased in females (11% to 4%, p <0.001). There were no differences in the prevalence of the risk-associated horizontal/descending pattern (3% in both groups). Subgroup analysis was performed on ECGs from the cohort of outpatients without cardiac disease, and the statistical trends remained the same. In conclusion, the overall prevalence of inferolateral ER was higher in pre- and postadolescent populations than in adult populations. However, the prevalence of the risk-associated horizontal/descending ST-segment pattern was only 3%, comparable to prevalence rates in the adult population. The variations in prevalence by gender and age suggest a possible influence of reproductive hormones. PMID- 23642383 TI - Frequency and implication of ST-T abnormalities on hospital admission electrocardiograms in patients with type A acute aortic dissection. AB - Although patients with Stanford type A acute aortic dissection often show ST-T abnormalities at presentation, the frequency and implication of such findings remain unclear. To clarify these points, admission electrocardiograms from 233 patients admitted <=6 hours after symptom onset who underwent emergency surgery for type A acute aortic dissection were studied. The prevalence of electrocardiographic (ECG) patterns was 51% for ST-T abnormalities (4% for ST segment elevation and 47% for ST-segment depression and/or negative T waves), 30% for normal ECG findings or no significant ST-T changes, and 19% for ECG confounders such as bundle branch block or left ventricular hypertrophy. Patients with ST-T abnormalities had higher prevalence of pericardial effusion (48% vs 9% and 38%), cardiac tamponade (28% vs 3% and 18%), moderate or severe aortic regurgitation (28% vs 7% and 18%), shock on admission (34% vs 3% and 13%), coronary ostial involvement (14% vs 1% and 2%), concomitant coronary artery bypass surgery (9% vs 1% and 0%), and in-hospital mortality (11% vs 1% and 4%) compared with patients with normal ECG findings or no significant ST-T changes and those who had ECG confounders (p <0.05 for all). On multivariate analysis, ST T abnormalities were the only independent predictor of in-hospital mortality (odds ratio 3.87, 95% confidence interval 1.02 to 14.7, p = 0.035). In conclusion, about 50% of patients who underwent emergency surgery for type A acute aortic dissection had ST-T abnormalities, characterized predominantly by ST segment depression or negative T waves, in the acute phase. ST-T abnormalities were associated with more complicated features and independently predicted in hospital death. PMID- 23642384 TI - Prevalence and prognosis of aortic valve disease in subjects older than 85 years of age. AB - Although degenerative aortic valve disease is common with increasing age, limited data exist regarding prevalence and prognosis of aortic valve disease among the oldest old. Subjects were recruited from the Jerusalem Longitudinal Cohort Study. Echocardiography was performed at home in 498 randomly selected subjects. Subjects were divided into 3 groups; normal subjects, subjects with valve calcium but without stenosis (AVC), and subjects with aortic stenosis (AS). Survival status at 5-year follow-up was assessed via the centralized population registry. AVC was noted in 55% of the study subjects and AS was seen in 8.2%. There were no significant differences between the 3 groups in any of the clinical parameters examined including risk factors for atherosclerotic heart disease. Of the 498 subjects, 107 (21%) had died at the time of 5-year follow-up. Five-year mortality was similar among the normal (17%) and AVC (20%) subjects but was significantly higher among the subjects with AS (46%; p <0.0001). AS was associated with a nearly fourfold increased likelihood of mortality (hazard ratio 3.7, 95% confidence interval 1.4 to 9.3). In conclusion, among subjects >=85 years of age, the prevalence of AS is higher than previously reported and not associated with traditional vascular risk factors. AS but not AVC alone was independently predictive of 5-year mortality. PMID- 23642385 TI - Reports on the distribution of aromatic cyanogenic glycosides in Australian tropical rainforest tree species of the Lauraceae and Sapindaceae. AB - The aromatic cyanogenic glycosides taxiphyllin [(R)-4-hydroxymandelonitrile beta D-glucoside] and prunasin [(R)-mandelonitrile beta-D-glucoside] were identified as the main cyanogenic compounds in tissues of Australian endemic tropical rainforest tree taxa in the Lauraceae and Sapindaceae families, respectively. The tyrosine-derived taxiphyllin was the main cyanogenic glycoside in foliage of Beilschmiedia collina. This is the first reported cyanogenic compound from the Lauraceae. In addition, substantial quantitative variation in the capacity for cyanogenesis was detected in leaves from 40 individuals, with taxiphyllin concentrations ranging from 23 to 1263 MUg CN g(-1) dry wt. No acyanogenic individuals were detected. Concentrations of taxiphyllin were, on average, 2.2 fold greater in young leaves than in old leaves. Prunasin was the dominant cyanogenic compound in tissues of Mischocarpus grandissimus (leaves) and Mischocarpus exangulatus (leaves and seed capsule). Better known for cyanolipids in seed oils, this is the first time a phenylalanine-derived cyanogenic glycoside has been reported in the Sapindaceae. The concentrations of prunasin varied widely, over an order of magnitude, among individuals and different tissue types in these species, with the higher concentrations found in seed capsules and young leaves. PMID- 23642386 TI - 2-O-beta-D-Glucopyranosyl-carboxyatractyligenin from Coffea L. inhibits adenine nucleotide translocase in isolated mitochondria but is quantitatively degraded during coffee roasting. AB - Atractyloside (1) and carboxyatractyloside (2) are well-known inhibitors of the adenine nucleotide translocase (ANT) in mitochondria, thus effectively blocking oxidative phosphorylation. Structurally related derivatives atractyligenin (3), 2 O-beta-D-glucopyranosyl-atractyligenin (4), 3'-O-beta-D-glucopyranosyl-2'-O isovaleryl-2beta-(2-desoxy-atractyligenin)-beta-D-glucopyranoside (5), and 2-O beta-D-glucopyranosyl-carboxyatractyligenin (6) were isolated from raw beans of Coffea L. and the impact of 1-6 on ANT activity was evaluated in isolated mitochondria. Among the coffee components, 6 significantly inhibited ANT activity leading to reduced respiration. Quantitative analysis in commercial coffees, experimental roastings of coffee, and model experiments using purified compound 6 consistently revealed a complete degradation during thermal treatment. In comparison, raw coffee extracts were found to contain high levels of 6, which are therefore expected to be present in food products enriched with raw coffee extracts. This implies the necessity of analytically controlling the levels of 6 in raw coffee extracts when used as additives for food products. PMID- 23642387 TI - Structural analysis and profiling of phenolic secondary metabolites of Mexican lupine species using LC-MS techniques. AB - Flavonoid glycoconjugates from roots and leaves of eight North America lupine species (Lupinus elegans, Lupinus exaltatus, Lupinus hintonii, Lupinus mexicanus, Lupinus montanus, Lupinus rotundiflorus, Lupinus stipulatus, Lupinus sp.), three Mediterranean species (Lupinus albus, Lupinus angustifolius, Lupinus luteus) and one species from South America domesticated in Europe (Lupinus mutabilis) were analyzed using two LC/MS systems: low-resolution ion trap instrument and high resolution quadrupole-time-of-flight spectrometer. As a result of the LC/MS profiling using the CID/MS(n) experiments structures of 175 flavonoid glycoconjugates found in 12 lupine species were identified at three confidence levels according to the Metabolomic Standard Initiative, mainly at level 2 and 3, some of them were classified to the level 1. Among the flavonoid derivatives recognized in the plant extracts were isomeric or isobaric compounds, differing in the degree of hydroxylation of the aglycones and the presence of glycosidic, acyl or alkyl groups in the molecules. The elemental composition of the glycoconjugate molecules was established from the exact m/z values of the protonated/deprotonated molecules ([M+H](+)/[M-H](-)) measured with the accuracy better than 5 ppm. Information concerning structures of the aglycones, the type of sugar moieties (hexose, deoxyhexose or pentose) and, in some cases, their placement on the aglycones as well as the acyl substituents of the flavonoid glycoconjugates was achieved in experiments, in which collision-induced dissociation was applied. Flavonoid aglycones present in the studied O glycoconjugates were unambiguously identified after the comparison of the pseudo MS(3) spectra with the spectra registered for the standards. Isomers of flavonoid glycoconjugates, in which one or two sugar moieties were attached to 4'- or 7 hydroxyl groups or directly to the C-6 or C-8 of the aglycones, could be distinguished on the basis of the MS(2) spectra. However, the collision energy applied in the CID experiments had to be optimized for each group of the compounds and there were no universal settings that allowed the acquisition of structural information for all the compounds present in the sample. Information obtained from the flavonoid conjugate profiling was used for the chemotaxonomic comparison of the studied lupine species. A clear-cut discrimination of the Mediterranean and North American lupines was obtained as a result of this analysis. PMID- 23642388 TI - Malonyl-ginsenoside content of a cell-suspension culture of Panax japonicus var. repens. AB - The presence of large amounts of ginsenosides malonyl-Rb1, -Rc, -Rb2, and -Rd in a suspension culture of Panax japonicus var. repens cells was demonstrated for the first time. Identification of ginsenoside malonyl-Rb1 was based on chromatographic, chemical, and spectroscopic evidence. Ginsenosides malonyl-Rc, Rb2, and -Rd were identified on the basis of chromatographic and chemical data. Content and composition of the individual ginsenosides (Rg1, R0, malonyl-Rb1, Rb1, Rc, Rb2, and Rd) were monitored in the suspension culture over 4 years. The RP-HPLC-UV analysis showed that Rg1, R0, and malonyl-Rb1 accounted for more than 75% of the total pool of ginsenosides. In accordance with this result, and data analysis reported in the literature, we propose that ginsenoside formation in the cells of P. japonicus var. repens in vitro is closely related to the cellular compartmentation of these substances. In particular, the accumulation of the 20(S)-protopanaxadiol ginsenosides (especially Rb1) is strongly dependent on their pattern of malonylation, which likely targets them for transport into the vacuole. PMID- 23642389 TI - Classification of flavonoid compounds by using entropy of information theory. AB - A total of 74 flavonoid compounds are classified into a periodic table by using an algorithm based on the entropy of information theory. Seven features in hierarchical order are used to classify structurally the flavonoids. From these features, the first three mark the group or column, while the last four are used to indicate the row or period in a table of periodic classification. Those flavonoids in the same group and period are suggested to show maximum similarity in properties. Furthermore, those with only the same group will present moderate similarity. In this report, the flavonoid compounds in the table, whose experimental data in bioactivity and antioxidant properties have been previously published, are related. PMID- 23642390 TI - Cadinane sesquiterpenes from the mushroom Lyophyllum transforme. AB - Two rare cadinane-type sesquiterpenes, lyophyllone A (1) and lyophyllanetriol A (2), were isolated from the mushroom Lyophyllum transforme. The structures were elucidated on the basis of exhaustive NMR techniques, together with MS, UV-Vis and molecular modelling. The absolute configuration of lyophyllone A was determined by ab initio theoretical CD calculation performed by Density Functional Theory (DFT) using the B3PW91/6-31G(d,p) basis set. The experimental CD were found to be in good agreement with the corresponding population-weighted theoretical CD spectra, allowing for the determination of the absolute stereochemistry of the compound. PMID- 23642391 TI - Kaurane diterpenes from Sideritis spp. exert a cytoprotective effect against oxidative injury that is associated with modulation of the Nrf2 system. AB - Kaurane diterpenes have been shown to possess antioxidant properties. As a part of our ongoing studies on the identification of biologically active diterpenes from Sideritis spp., we have previously isolated and structurally elucidated the major kaurane diterpenes foliol, linearol and sidol, in a previous study from the aerial parts of Sideritis linearifolia and Sideritis leucantha. We have now examined the ability of these compounds to protect PC12 cells in an H2O2-induced oxidative stress model. Linearol and sidol (5 and 10 MUM, 24 h) significantly attenuated loss of mitochondrial function (MTT assay) and membrane integrity (LDH assay) and morphological changes associated with H2O2-mediated cytotoxicity. Moreover, pretreatments with linearol and sidol effectively reduced intracellular ROS production, decreased MDA levels (lipid peroxidation product) and restored GSH/GSSG ratio. Furthermore, analysis of the effect of diterpenes on antioxidant enzymes showed that linearol and sidol induced the upregulation and protein expression of the main antioxidant enzymes CAT, SOD, GPx, GR and HO-1. Considering molecular mechanisms for maintaining cellular redox homeostasis by linearol and sidol, it would appear that the Nrf2 transcription factor seems to be involved. These results indicate that linearol and sidol are potential cytoprotective compounds, through antioxidant mechanisms, under H2O2-induced oxidative stress. PMID- 23642392 TI - Chemical constituents from Tribulus terrestris and screening of their antioxidant activity. AB - Two oligosaccharides (1,2) and a stereoisomer of di-p-coumaroylquinic acid (3) were isolated from the aerial parts of Tribulus terrestris along with five known compounds (4-8). The structures of the compounds were established as O-beta-D fructofuranosyl-(2->6)-alpha-D-glucopyranosyl-(1->6)-beta-D-fructofuranosyl-(2 >6)-beta-D-fructofuranosyl-(2->1)-alpha-D-glucopyranosyl-(6->2)-beta-D fructofuranoside (1), O-alpha-D-glucopyranosyl-(1->4)-alpha-D-glucopyranosyl-(1 >4)-alpha-D-glucopyranosyl-(1->2)-beta-D-fructofuranoside (2), 4,5-di-p-cis coumaroylquinic acid (3) by different spectroscopic methods including 1D NMR ((1)H, (13)C and DEPT) and 2D NMR (COSY, TOCSY, HMQC and HMBC) experiments as well as ESI-MS analysis. This is the first report for the complete NMR spectral data of the known 4,5-di-p-trans-coumaroylquinic acid (4). The antioxidant activity represented as DPPH free radical scavenging activity was investigated revealing that the di-p-coumaroylquinic acid derivatives possess potent antioxidant activity so considered the major constituents contributing to the antioxidant effect of the plant. PMID- 23642394 TI - Is Helicobacter pylori the usual suspect behind gastroesophageal reflux disease and dacryostenosis? PMID- 23642393 TI - Carbohydrate intake in relation to BMI, HbA1c and lipid profile in children and adolescents with type 1 diabetes. AB - BACKGROUND & AIMS: To compare reported and recommended carbohydrate intake in children and adolescents with type 1 diabetes (T1D) and to explore associations with BMI, HbA1c and lipid profile. METHODS: A cross-sectional observational study of reported carbohydrate intake in 46,010 patients with T1D aged 1-18 years from 332 diabetes centres in Germany and Austria in comparison to age-matched healthy children and adolescents. RESULTS: The median reported carbohydrate intake in T1D patients was markedly lower than in healthy children. It varied between 56% and 90% of recommended amounts across the paediatric age range with younger patients showing levels closer to recommend. Lower carbohydrate intake was associated with higher BMI-SDS (p < 0.001), particularly during adolescence, higher total cholesterol (p < 0.001), higher LDL-cholesterol (p = 0.005) and lower HbA1c (p < 0.001). CONCLUSIONS: The methodologically simple measure of reported carbohydrate intake may be a valuable addition to the information gathered on paediatric patients with T1D in an outpatient setting. Children and adolescents with T1D appear to restrict their consumption of carbohydrates, which may have adverse effects on BMI and the lipid profile, particularly if there is a compensatory increased fat intake. Health care providers should therefore advise patients and parents of the recommended age-dependent levels of carbohydrate intake. PMID- 23642395 TI - Redefining lumbosacral transitional vertebrae (LSTV) classification: integrating the full spectrum of morphological alterations in a biomechanical continuum. AB - In light of advancements in imaging techniques and basic science studies, this study proposes modifications in the existing Castellvi's classification for better clinical and biomechanical correlation of LSTV subtypes. LSTVs are commonly occurring variations of the lower spine. The current system does not include functionally important structural variations of the neural arch components and sacral auricular surfaces induced by LSTV afflictions within the classification. This study is an attempt to integrate vital biomechanical correlates into the proposed modification. Emerging diagnostic and clinical evidence also point out the need of understating subdivisions within LSTV anomalies as distinctly stratified entities to get a better correlation with the biomechanical continuum involved with LSTV associated low back pain. Important neural arch element and sacral auricular surface alterations associated with each LSTV subtypes were studied from a large number of osseous samples and data available from published LSTV related clinical and morphological studies. Sacralisation and lumbarisation were designated separate stratifications in the proposed revision, with arrangement of the LSTV subtypes as members of a LSTV anatomical 'array' extending cranio-caudally at the lumbo-sacral junction. The proposed modification is capable of identifying LSTV associated structural defects (in anterior and posterior elements), their exact level of occurrence and status of facet and auricular surface morphologies. Coding for the inclusion of biomechanically important alterations associated with LSTV types within the proposed new classification would probably be helpful in better clinical correlation of LSTV. PMID- 23642396 TI - Stimulation of the pedunculopontine tegmental nucleus may affect renal function by melanocortinergic signaling. AB - Deep brain stimulation of the pedunculopontine tegmental nucleus (PPTg) has been reported to improve gait disturbance in animal models of Parkinsonism and among patients with Parkinson's disease. Evidence suggests that neurons in the PPTg are involved in the control of the sympathetic outflow to the kidneys, and sympathetic regulation is a major component of central melanocortin action. Our recent studies using transneuronal labeling pseudorabies virus (PRV)-614 and melanocortin-4 receptor (MC4R)-green fluorescent protein (GFP) transgenic mice supported the melanocortinergic nature of the middle and caudal PPTg (mPPTg and cPPTg). Because PRV-614/MC4R-GFP double-labeled neurons in the mPPTg and cPPTg were detected, we propose a hypothesis that deep brain stimulation of the PPTg may influence renal function by the melanocortinergic pathway. PMID- 23642397 TI - Transformation of keloids is determined by stress occurrence patterns on peri keloid regions in response to body movement. AB - Keloids gradually change their shapes as they grow. We hypothesize that the change of keloid morphology reflects the incremental change of the stress patterns occurring in peri-keloid regions due to movement of the keloid-carrying body part. To examine the validity of this hypothesis, we used three-dimensional finite element analysis to calculate the stresses occurring in the peri-keloid regions of keloids on the chest in response to respiratory movement. The stresses concentrate at the peri-keloid regions close to the bilateral ends of the keloids. By reviewing this result in reference to our hypothesis, we can explain why keloids on the chest are likely to present crab or butterfly shapes. Although we know that keloids grow in response to mechanical stresses, our hypothesis differs from existing ones in that it focuses on morphological transformation. Our hypothesis is helpful for physicians in performing treatment for keloids, because they can predict what part of a keloid is likely to grow and perform preventive treatment in reference to the hypothesis. PMID- 23642398 TI - The dangers of ambidexterity: the origins of handedness. AB - Handedness remains an enigmatic phenomenon. There is no definitive explanation as to why man should have single rather than dual handedness. Intuitively it would seem advantageous in almost every context to have the benefit of equally dextrous hands. Either in context of warfare or hunting, using two hands equally as effectively would appear to be a favourable adaptation over single dexterity. No satisfactory explanation has been offered as to why and how single-handedness evolved. PMID- 23642399 TI - The possible roles of vitamin D and curcumin in treating gonorrhea. AB - Drug-resistant gonorrhea, Neisseria gonorrhoeae (N. gonorrhoeae), is an emerging concern, especially because the risk of bladder cancer is associated with this infection. N. gonorrhoeae suppresses T-helper 1(Th1) and Th2 responses and enhances Th17 responses via a mechanism involving transforming growth factor-beta (TGF-beta) and regulatory T cells. Blockade of TGF-beta alleviates the suppression of specific anti-gonococcal responses and allows Th1 and Th2 responses to emerge with concomitant boosting of immune memory and protective immunity. Gonorrhea activates nuclear factor kappaB (NF-kappaB), which plays a critical role in signal-transduction pathways involved in inflammation. The innate immune system can eventually clear gonorrhea. Vitamin D is emerging as a potential, powerful, anti-microbial agent with these effects: it supports the innate immune system in combating bacterial infections; it decreases levels of TGF-beta and NF-kappaB activation; and it induces production of LL-37 (cathelicidin), which has antimicrobial and antiendotoxin properties. In addition, via an independent vitamin D receptor pathway, curcumin also induces LL 37 production, inhibiting N. gonorrhoeae-induced NF-kappaB signaling and inducing autophagy. Therefore, vitamin D and curcumin taken together may be useful in combating both normal and drug-resistant gonorrhea. Moreover, the possible synergy between these two agents in improving outcomes is worthy of additional investigation. PMID- 23642400 TI - Tight calorie control in geriatric patients following hip fracture decreases complications: a randomized, controlled study. AB - BACKGROUND & AIMS: Optimizing nutritional intake has been recommended for geriatric patients undergoing hip-fracture surgery. Whether nutritional support guided by repeated measurements of resting energy requirements (REE) improves outcomes in these patients is not known. METHODS: A randomized, controlled, unblinded, prospective, cohort study comparing provision of energy with a goal determined by repeated REE measurements using indirect calorimetry, with no intervention. Oral nutritional supplements were started 24 h after surgery and the amount adjusted to make up the difference between energy received from hospital food and measured energy expenditure. RESULTS: 50 Geriatric patients were included in the study. Patients in the intervention group (n = 22) received significantly higher daily energy intake than the control group (n = 28) (1121.3 +/- 299.0 vs. 777.1 +/- 301.2 kcal, p = 0.001). This was associated with a significantly less negative cumulative energy balance (-1229.9 +/- 1763 vs. 4975.5 +/- 4368 kcal, p = 0.001). A significant negative correlation was found between the cumulative energy balance and total complication rate (r = -0.417, p = 0.003) as well as for length of hospital stay (r = -0.282, p = 0.049). CONCLUSION: We have demonstrated that nutritional support actively supervised by a dietician and guided by repeated measurements of REE was achievable and improved outcomes in geriatric patients following surgery for hip fractures. Clinicaltrials.gov Identifier: NCT017354435. PMID- 23642401 TI - Dry stacking of wastewater treatment sludges. AB - Drying pans are used during wastewater treatment (WWT) to store, stabilise and dry residual solids. The pans are filled with sludge that dries via exposure to sunshine and wind. We propose that drying pans be operated based on dry stacking principles, a technique with proven success in the mineral processing industry. The implementation of the dry stacking technique requires very little in the way of additional engineering beyond a conventional drying pan. By applying the sludge in thin layers, the sludge naturally forms its own stack with an angle that is dependent on the consistency of the material. The benefits of dry stacking are that the slope allows instantaneous run-off of rainfall and supernatant, allowing operation throughout the year rather than seasonally. The layering approach also maximises the evaporation achieved in the available deposition area compared to filling the pans sequentially. A series of laboratory tests were carried out on samples from Melbourne Water's Western Treatment Plant in Werribee, Australia, to provide validation of the dry stacking concept for WWT sludges. Rheological tests showed that samples had appropriate flow properties to form stacks. Drying and re-wetting tests on the samples indicated that a sloped, partially dry sludge sheds rainfall, depending on the slope, cake dryness and amount of rainfall. Local rainfall data was used to estimate a potential increase in pan throughput of 65%-140% due to dry stacking. The greatest improvements were predicted to occur during wetter years. In combination, the results indicated that dry stacking has the potential to dramatically improve the performance of WWT sludge drying pans. PMID- 23642402 TI - Secular changes in the relation between social factors and depression: a study of two birth cohorts of Swedish septuagenarians followed for 5 years. AB - BACKGROUND: Rapid societal changes occurred in the Western world during the 20(th) century. It is not clear whether this has changed the relation between social factors and depression in older people. METHODS: Representative samples of 70-year-olds from Gothenburg, Sweden, were examined with identical psychiatric examinations in 1971-72 (N=392; 226 women and 166 men) and 2000-01 (N=499; 270 women and 229 men). Follow-up studies were conducted after five years. Social factors were obtained by self-report and depression was diagnosed according to DSM-IV-TR. RESULTS: Feelings of loneliness were related to both concurrent depression at baseline and new depression at follow-up in both birth cohorts. Visits with others than children and neighbours once per month or less, compared to having more visits, and the perception of having too little contact with others, were related to both concurrent and new depression in 70-year-olds examined 1971-72, but not in those examined 30 years later. LIMITATIONS: The response rate declined from 85.2% in 1971-72 to 65.8% in 2000-01. Participation bias may have resulted in an underestimation of depression in the later-born cohort. CONCLUSIONS: Social contacts with others were related to depression in 70 year-olds examined in the 1970s, but not in those examined in the 2000s. This may reflect period changes in the ways of socialising, communicating and entertaining, e.g. due to technological development and expansion of mass media. Findings may be useful when developing modern and effective programs for the prevention of mental ill-health in older people. PMID- 23642403 TI - Alarming predictions for obesity and non-communicable diseases in the Middle East. AB - OBJECTIVE: The present study aimed to model obesity trends and future obesity related disease for nine countries in the Middle East; in addition, to explore how hypothetical reductions in population obesity levels could ameliorate anticipated disease burdens. DESIGN: A regression analysis of cross-sectional data v. BMI showed age- and sex-specific BMI trends, which fed into a micro simulation with a million Monte Carlo trials for each country. We also examined two alternative scenarios where population BMI was reduced by 1 % and 5 %. SETTING: Statistical modelling of obesity trends was carried out in nine Middle East countries (Bahrain, Egypt, Iran, Jordan, Kuwait, Lebanon, Oman, Saudi Arabia and Turkey). SUBJECTS: BMI data along with disease incidence, mortality and survival data from national and sub-national data sets were used for the modelling process. RESULTS: High rates of overweight and obesity increased in both men and women in most countries. The burden of incident type 2 diabetes, CHD and stroke would be moderated with even small reductions in obesity levels. CONCLUSIONS: Obesity is a growing problem in the Middle East which requires government action on the primary prevention of obesity. The present results are important for policy makers to know the effectiveness of obesity interventions on future disease burden. PMID- 23642406 TI - Are the epilepsy representative groups truly representative? PMID- 23642405 TI - Encephalopathy with hemi-status epilepticus during sleep or hemi-continuous spikes and waves during slow sleep syndrome: a study of 21 patients. AB - PURPOSE: To retrospectively analyze the electroclinical features, etiology, treatment, and prognosis of 21 patients with encephalopathy with hemi-status epilepticus during sleep (ESES) or hemi-continuous spikes and waves during slow sleep (CSWSS) syndrome. METHODS: Charts of 21 patients with hemi-ESES/CSWSS syndrome followed between 1997 and 2012 were analyzed. Inclusion criteria were: (1) Focal seizures or apparently generalized seizures and focal EEG epileptiform discharges; (2) Further occurrence of atypical absences, and myoclonic, atonic, and/or generalized seizures; (3) Cognitive impairment and/or behavioral disturbances; (4) Hemi-continuous spike-and-wave discharges during slow sleep in more than 85% of non-REM sleep at onset and throughout the ESES/CSWSS period. RESULTS: Mean follow-up from onset of hemi-ESES/CSWSS was 8 years (range, 2-15 years). Idiopathic cases were not identified. Unilateral polymicrogyria was found in 11, shunted hydrocephalus in four, a porencephalic cyst associated with polymicrogyria in three, and a thalamic lesion in three children. All started with focal seizures with or without secondary generalization. During the hemi ESES/CSWSS period, all children developed new types of seizure, such as negative and positive myoclonus, absences, motor deterioration, cognitive impairment, and behavioral disturbances. All AED responders returned to baseline cognitive development. Seven patients were refractory to AEDs. CONCLUSION: Our study suggests that the hemi-ESES/CSWSS syndrome has electroclinical features compatible with an epileptic encephalopathy. The most commonly used treatments were clobazam, ethosuximide, and sulthiame, alone or in combination. In refractory cases, high-dose corticosteroids were administered. Although the number of patients in this study is too low to draw definite conclusions, we consider that in children with hemi-ESES/CSWSS secondary to a unilateral lesion, surgery should be considered. PMID- 23642407 TI - Comparison between febrile and afebrile seizures associated with mild rotavirus gastroenteritis. AB - PURPOSE: We aimed on identifying the differences of febrile and afebrile seizures associated with mild rotavirus gastroenteritis (RVGE) in the pediatric population. METHOD: Medical charts of pediatric patients who had been admitted between July 1999 and June 2011 due to RVGE were retrospectively reviewed. Subjects were ultimately divided into three groups; 'no seizure' (NS: patients without seizure), 'febrile seizure' (FS: patients with fever during seizure), 'afebrile seizure' (AFS: patients without fever during seizure). Comparisons between groups were carried out on demographic and clinical characteristics, laboratory test results, electroencephalogram findings, brain magnetic resonance imaging findings, antiepileptic treatment, and prognosis. RESULTS: Among the 755 subjects who had been admitted due to mild rotavirus enteritis, 696 (90.3%) did not have any seizures, 17 (2.2%) had febrile seizures, 42 (5.5%) had afebrile seizures. The duration of gastrointestinal symptoms before the onset of seizures were significantly shorter in the FS group compared to the AFS group (1.3+/-0.8 vs. 2.8+/-1.0 days; p<0.0001). A single seizure attack was significantly higher in the AFS group (3.0+/-1.6 vs. 1.7+/-1.0 episodes; p=0.0003), and the frequency of seizures that were of focal type with or without secondary generalization were significantly higher in the AFS group (33.3% vs. 6.0%; p=0.0139). All patients among the FS and AFS group had not received further antiepileptic treatment after discharge, and none developed epilepsy during follow up period. CONCLUSION: Despite some differences in seizure characteristics, both febrile and afebrile seizures associated with mild RVGE were mostly benign with a favorable prognosis. PMID- 23642408 TI - Protein kinase B/Akt is required for complete Freund's adjuvant-induced upregulation of Nav1.7 and Nav1.8 in primary sensory neurons. AB - Voltage-gated sodium channels (Nav) are essential for the generation and conduction of action potentials. Peripheral inflammation increases the expression of Nav1.7 and Nav1.8 in dorsal root ganglion (DRG) neurons, suggesting that they participate in the induction and maintenance of chronic inflammatory pain. However, how Nav1.7 and Nav1.8 are regulated in the DRG under inflammatory pain conditions remains unclear. Using a complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model and Western blot analysis, we found that phosphorylated Akt (p-Akt) was significantly increased in the ipsilateral L4/5 DRGs of rats on days 3 and 7 after intraplantar CFA injection. Immunohistochemistry showed that the percentage of p-Akt-positive neurons in the DRG was also significantly increased in the ipsilateral L4/5 DRGs at these time points. Moreover, CFA injection increased the colocalization of p-Akt with Nav1.7 and Nav1.8 in L4/5 DRG neurons. Pretreatment of rats with an intrathecal injection of Akt inhibitor IV blocked CFA-induced thermal hyperalgesia and CFA induced increases in Nav1.7 and Nav1.8 in the L4/5 DRGs on day 7 after CFA injection. Our findings suggest that the Akt pathway participates in inflammation induced upregulation of Nav1.7 and Nav1.8 expression in DRG neurons. This participation might contribute to the maintenance of chronic inflammatory pain. PERSPECTIVE: This article presents that inhibition of Akt blocks CFA-induced thermal hyperalgesia and CFA-induced increases in dorsal root ganglion Nav1.7 and Nav1.8. These findings have potential implications for use of Akt inhibitors to prevent and/or treat persistent inflammatory pain. PMID- 23642377 TI - Macular morphology and visual acuity in the comparison of age-related macular degeneration treatments trials. AB - OBJECTIVE: To describe the effects of treatment for 1 year with ranibizumab or bevacizumab on macular morphology and the association of macular morphology with visual acuity (VA) in eyes with neovascular age-related macular degeneration (AMD). DESIGN: Prospective cohort study within a randomized clinical trial. PARTICIPANTS: Participants in the Comparison of Age-related Macular Degeneration Treatments Trials. METHODS: Participants were assigned randomly to treatment with ranibizumab or bevacizumab on a monthly or as-needed schedule. Optical coherence tomography (OCT), fluorescein angiography (FA), color fundus photography (FP), and VA testing were performed periodically throughout 52 weeks. Masked readers graded images. General linear models were applied to evaluate effects of time and treatment on outcomes. MAIN OUTCOME MEASURES: Fluid type and location and thickness by OCT, size, and lesion composition on FP, FA, and VA. RESULTS: Intraretinal fluid (IRF), subretinal fluid (SRF), subretinal pigment epithelium fluid, and retinal, subretinal, and subretinal tissue complex thickness decreased in all treatment groups. A higher proportion of eyes treated monthly with ranibizumab had fluid resolution at 4 weeks, and the difference persisted through 52 weeks. At 52 weeks, there was little association between the presence of fluid of any type (without regard to fluid location) and the mean VA. However, at all time points, eyes with residual IRF, especially foveal IRF, had worse mean VA (9 letters) than those without IRF. Eyes with abnormally thin (<120 MUm) or thick (>212 MUm) retinas had worse VA than those with normal thickness (120-212 MUm). At week 52, eyes with larger neovascular lesions or with foveal scar had worse VA than eyes without these features. CONCLUSIONS: Anti-vascular endothelial growth factor (VEGF) therapy reduced lesion activity and improved VA in all treatment groups. At all time points, eyes with residual IRF had worse VA than those without. Eyes with abnormally thin or thick retinas, residual large lesions, and scar also had worse VA. Monthly ranibizumab dosing yielded more eyes with no fluid and an abnormally thin retina, although the long-term significance is unknown. These results have important treatment implications in eyes undergoing anti-VEGF therapy for neovascular AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23642409 TI - Factor structure of the children's depression inventory in a multisite sample of children and adolescents with chronic pain. AB - This study examined the factor structure of the Children's Depression Inventory (CDI) among children and adolescents with chronic pain using exploratory and confirmatory factor analysis in a large, multisite sample of treatment-seeking youth. Participants included 1,043 children and adolescents (ages 8-18) with a range of chronic pain complaints who presented for initial evaluation at 1 of 3 tertiary care pediatric chronic pain clinics across the United States. They completed the CDI and reported on pain intensity and functional disability. Factor analysis was conducted using a 2-step (exploratory and confirmatory) approach. Results supported a 5-factor model for the CDI with good fit to the data. The distribution and item-total correlations of the somatic items (eg, pain complaints, fatigue) were explored in this sample. Results indicate that the CDI is a useful tool for assessing depressive symptoms in youth with chronic pain, but some caution is warranted in interpreting the clinical significance of scores in light of the overlap of specific symptoms common to both pain and depression. PERSPECTIVE: The CDI can be considered a valid tool for assessing mood symptoms in children with chronic pain. Caution is encouraged when interpreting the clinical significance of scores due to symptom overlap between chronic pain and depression. PMID- 23642410 TI - Histamine produces opposing effects to serotonin in the knee joint of rats. AB - Formalin injected in the knee joint of rats produces concentration-dependent nociception, edema, and plasma leakage (PL). Herein, we investigated the effect of histamine H1 receptor (H1R) antagonists in this model. Articular nociception was inferred from the paw elevation time (PET; seconds) during 1-minute periods of stimulated walking, determined every 5 minutes, throughout a 60-minute experimental session. Edema was evaluated by the increase in articular diameter (AD; mm), and PL was measured by the amount of Evans blue dye in the synovial fluid (PL; MUg/mL). Loratadine and cetirizine, given systemically, both increased the PET. None of the treatments changed the AD and PL. Loratadine given locally with formalin increased the PET but was without effect when given in the contralateral knee. Systemic loratadine was also without effect when formalin was coinjected with sodium cromoglycate. Histamine and the selective H1R agonist 2 pyridylethylamine decreased the PET and potentiated morphine spinal analgesia, but did not affect the AD and PL. Cetirizine prevented the antinociceptive effect of the H1R agonist. The N-methyl-D-aspartate/histamine-site agonist tele methylhistamine coinjected with formalin only increased PET. Serotonin alone had no effect on the PET and increased the AD, and the highest dose increased the PL. When coinjected with formalin, serotonin only caused hypernociception, and the highest dose also increased AD. NAN 190, cyproheptadine, and ondansetron (respectively, 5-HT1, 5-HT2, and 5-HT3 receptor antagonists) decreased the PET without changing the AD or PL. Collectively, these results suggest that in rats, the H1R plays an antinociceptive role within the knee joint, while serotonin receptors play a pronociceptive role. PERSPECTIVE: The present study revealed an antinociceptive mechanism that has previously not been detected by traditional nociceptive tests. Our observations may help to improve the development of new pharmacological strategies for the treatment of clinically relevant pains that generally originate in deep structures. PMID- 23642411 TI - Modality-specific nociceptor sensitization following UV-B irradiation of human skin. AB - Ultraviolet-B (UV-B) irradiation is a well-established inflammatory pain model inducing mechanical and thermal hyperalgesia, presumably mediated by released mediators that sensitize sensory nerve endings. Here, we used additional electrical stimulation to investigate axonal hyperexcitability. The lower leg of 13 volunteers was irradiated with 3-fold the minimum erythema UV-B dose and sensitization was recorded at days 1, 3, 7, and 14. Maximum heat pain (47 degrees C, 5 seconds) developed at day 1 (visual analog scale [VAS: 0-100]; 59), was reduced at day 3 (VAS 43, P < .002), and was back to normal at day 7 (VAS 18). Mechanical impact pain (8 m/s), pinprick (150 mN), and pressure (100 kPa) hyperalgesia were maximum throughout days 1 to 3 (VAS 16, 8, and 12, respectively, P < .001) and back to normal at day 7. Suprathreshold transcutaneous electrical stimuli (1.5-fold pain threshold) were delivered in trains of 10 pulses at frequencies of 5 to 100 Hz. Electrical pain thresholds (determined at 2 Hz) decreased significantly (P < .002) and suprathreshold electrical pain increased by about 70% at days 1 to 3 after irradiation (VAS 36, P < .002). Electrical hyperalgesia did not correlate with mechanical sensitization but with reduced heat pain threshold and increased tonic heat pain (r = -.46 and .53; P < .05 and < .01), indicating that axonal hyperexcitability might contribute to heat hyperalgesia. Released inflammatory mediators (eg, prostaglandins) might sensitize both heat transducer molecules and axonal ion channels and receptors, which would explain the simultaneous development and close correlation between heat hyperalgesia and axonal hyperexcitability. PERSPECTIVE: Local inflammation by UV-B irradiation sensitizes not only sensory endings, but also axons. Increased axonal excitability could contribute to inflammatory hyperalgesia by facilitating spike generation and increasing peak discharge frequencies of nociceptors. Thus, axonal channels and receptors crucial for this sensitization need to be identified to provide new therapeutic targets. PMID- 23642412 TI - Staphylococcus pseudintermedius heterogeneously expresses the mecA gene. PMID- 23642413 TI - Clostridium difficile infection in horses: a review. AB - Clostridium difficile is considered one of the most important causes of diarrhea and enterocolitis in horses. Foals and adult horses are equally susceptible to the infection. The highly resistant spore of C. difficile is the infectious unit of transmission, which occurs primarily via the fecal-oral route, with sources of infection including equine feces, contaminated soil, animal hospitals, and feces of other animals. Two major risk factors for the development of C. difficile associated disease (CDAD) in adult horses are hospitalization and antimicrobial treatment, although sporadically, cases of CDAD can occur in horses that have not received antimicrobials or been hospitalized. The most common antibiotics associated with CDAD in horses are erythromycin, trimethoprim/sulfonamides, beta lactam antimicrobials, clindamycin, rifampicin, and gentamicin. Clinical signs and intestinal lesions of CDAD infection are not specific and they cannot be used to distinguish infections by C. difficile from infections by other agents, such as Clostridium perfringens or Salmonella sp. The distribution of lesions throughout the intestinal tract seems to be age-dependent. Small intestine is invariably affected, and colon and cecum may or may not have lesions in foals<1 month old. Naturally acquired disease in older foals and adult horses has a more aboral distribution, affecting colon and sometimes cecum, but rarely the small intestine. Detection of toxin A, toxin B or both in intestinal contents or feces is considered the most reliable diagnostic criterion for CDAD in horses. Isolation of toxigenic strains of C. difficile from horses with intestinal disease is highly suggestive of CDAD. A better understanding of pathogenesis, reservoirs of infection, and vaccines and other methods of control is needed. Also further studies are recommended to investigate other possible predisposing factors and/or etiological agents of enteric diseases of horses. PMID- 23642415 TI - High-impact animal health research conducted at the USDA's National Animal Disease Center. AB - Commissioned by President Dwight Eisenhower in 1958 and opened with a dedication ceremony in December 1961, the USDA, Agricultural Research Service (ARS), National Animal Disease Center (NADC) celebrated its 50-year anniversary in November 2011. Over these 50 years, the NADC established itself among the world's premier animal health research centers. Its historic mission has been to conduct basic and applied research on selected endemic diseases of economic importance to the U.S. livestock and poultry industries. Research from NADC has impacted control or management efforts on nearly every major animal disease in the United States since 1961. For example, diagnostic tests and vaccines developed by NADC scientists to detect and prevent hog cholera were integral in the ultimate eradication of this costly swine disease from the U.S. Most major veterinary vaccines for critical diseases such as brucellosis and leptospirosis in cattle, porcine respiratory and reproductive syndrome (PRRS), porcine parvovirus and influenza in swine had their research origins or were developed and tested at the NADC. Additional discoveries made by NADC scientists have also resulted in the development of a nutritional approach and feed additives to prevent milk fever in transition dairy cattle. More recently, NADC's archive of historic swine influenza viruses combined with an established critical mass of influenza research expertise enabled NADC researchers to lead an effective national research response to the pandemic associated with the novel 2009 H1N1 influenza virus. This review commemorates some of the key animal health contributions in NADC's first 50 years, recaps the newly completed modernization of the center into new facilities, and offers highlights of the ongoing research that will define NADC's mission going forward. PMID- 23642414 TI - Strangles: taking steps towards eradication. AB - Strangles, caused by the host adapted Lancefield group C bacterium Streptococcus equi sub-species equi (S. equi), is one of the oldest recognised infectious diseases of horses and continues to cause significant welfare and economic cost throughout the world. The ability of S. equi to establish sub-clinical persistent infections primarily in the guttural pouches of convalescent horses has been instrumental to its success. However, the implementation of simple control measures that permit the identification and treatment of persistently infected carriers can prevent further outbreaks of disease at a local level. This review summarises some of the molecular mechanisms exploited by S. equi to cause disease. New qPCR and iELISA diagnostic tests replace culture methodologies as the gold standard for the detection of infected animals. A strategy to maximise the effective application of these tests to direct management methods for the eradication of S. equi infection is presented and the role of preventative vaccines is discussed. In contrast to current understanding, emerging data illustrates the dynamism of the global S. equi population and potential consequences for the effectiveness of currently available vaccines. The ability to use modern vaccines alongside conventional biosecurity and screening procedures will be critical to the large-scale prevention and even eradication of strangles, providing an opportunity to finally break the stranglehold that this disease has on the world's equine industry. PMID- 23642416 TI - Intestinal invasion of Salmonella enterica serovar Typhimurium in the avian host is dose dependent and does not depend on motility and chemotaxis. AB - Salmonella enterica serotype Typhimurium (S. Typhimurium) can invade in the intestine of the avian host, and knowledge on the mechanisms that govern this is potentially important for prevention of disease. This study investigated the invasion of S. Typhimurium in the avian host and to which extent it depended on motility and chemotaxis. Wild type and previously well-characterized transposon mutants in flagella genes fliC and fljB and in chemotaxis genes cheA, cheB and cheR were used as challenge strains in intestinal loop experiments. Invasion was shown to be dose dependent, but did not require functional flagella or chemotaxis genes. In support of the results from intestinal loop experiments, flagella and chemotaxis genes were not significantly important to the outcome of an oral infection. The results showed that S. Typhimurium invasion in the avian host was dose dependent and was not affected by the loss of flagella and chemotaxis genes. PMID- 23642417 TI - Analysis of glutamate, GABA, noradrenaline, dopamine, serotonin, and metabolites using microbore UHPLC with electrochemical detection. AB - The applicability of microbore ultrahigh performance liquid chromatography (UHPLC) with electrochemical detection for offline analysis of a number of well known neurotransmitters in less than 10 MUL microdialysis fractions is described. Two methods are presented for the analysis of monoamine or amino acid neurotransmitters, using the same UHPLC instrument. Speed of analysis of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and the metabolites homovanillic acid (HVA), 5-hydroxyindole aceticacid (5-HIAA), and 3,4 dihydroxyphenylacetic acid (DOPAC) was predominated by the retention behavior of NA, the nonideal behavior of matrix components, and the loss in signal of 5-HT. This method was optimized to meet the requirements for detection sensitivity and minimizing the size of collected fractions, which determines temporal resolution in microdialysis. The amino acid neurotransmitters glutamate (Glu) and gamma aminobutyric acid (GABA) were analyzed after an automated derivatization procedure. Under optimized conditions, Glu was resolved from a number of early eluting system peaks, while the total runtime was decreased to 15 min by a 4-fold increase of the flow rate under UHPLC conditions. The detection limit for Glu and GABA was 10 nmol/L (15 fmol in 1.5 MUL); the monoamine neurotransmitters had a detection limit between 32 and 83 pmol/L (0.16-0.42 fmol in 5 MUL) in standard solutions. Using UHPLC, the analysis times varied from 15 min to less than 2 min depending on the complexity of the samples and the substances to be analyzed. PMID- 23642418 TI - Breastfeeding in the first hour of life protects against neonatal mortality. PMID- 23642419 TI - Advancing and prioritizing research on oral clefts in Brazil. PMID- 23642420 TI - Influence of family environment on children's oral health: a systematic review. AB - OBJECTIVE: To review current models and scientific evidence on the influence of parents' oral health behaviors on their children's dental caries. SOURCES: MEDLINE articles published between 1980 and June, 2012. Original research articles on parents' oral health behavior were reviewed. A total of 218 citations were retrieved, and 13 articles were included in the analysis. The studies were eligible for review if they matched the following inclusion criteria: (1) they evaluated a possible association between dental caries and parents' oral-health related behaviors, and (2) the study methodology included oral clinical examination. The main search terms were "oral health", "parental attitudes", "parental knowledge", and "dental caries". SUMMARY OF THE FINDINGS: : 13 experimental studies contributed data to the synthesis. Original articles, reviews, and chapters in textbooks were also considered. CONCLUSION: Parents' dental health habits influence their children's oral health. Oral health education programs aimed at preventive actions are needed to provide children not only with adequate oral health, but better quality of life. Special attention should be given to the entire family, concerning their lifestyle and oral health habits. PMID- 23642421 TI - Attention deficit-hyperactivity disorder, comorbidities, and risk situations. AB - OBJECTIVE: Attention deficit/hyperactivity disorder (ADHD) is highly prevalent, and its symptoms often represent a significant public health problem; thus, the aim of this study was to verify emergency situations caused by certain comorbidities, or by exposing the patient to a higher risk of accidents. DATA SOURCE: A literature search was carried out in the PubMed database between the years 1992 and 2012, using the key words "adhd", "urgency", "comorbidity", "substance disorder", "alcohol", "eating disorder", "suicide", "trauma", "abuse", "crime", "internet", "videogame", "bullying", and their combinations. The selection considered the most relevant articles according to the scope of the proposed topic, performed in a non-systematic way. DATA SYNTHESIS: Several situations were observed in which ADHD is the most relevant psychiatric diagnosis in relation to its urgency, such as the risk of accidents, suicide risk and addition, exposure to violence, or risk of internet abuse or sexual abuse; or when ADHD is the most prevalent comorbidity and is also correlated with emergency situations, such as in bipolar and eating disorders. CONCLUSIONS: The results show several comorbidities and risk situations involving the diagnosis of ADHD, thus reinforcing the importance of their identification for the adequate treatment of this disorder. PMID- 23642422 TI - Breastfeeding during the first hour of life and neonatal mortality. AB - OBJECTIVE: To analyze the correlation between breastfeeding in the first hour of life with neonatal mortality rates. METHODS: The present study used secondary data from 67 countries, obtained from the Demographic and Health Surveys. Initially, for data analysis, Spearman Correlation (95% CI) and Kernel graphical analysis were employed, followed by a Negative Binomial Pois- son regression model, adjusted for potential confounders. RESULTS: Breastfeeding within the first hour of life was negatively correlated with neo- natal mortality (Spearman's Rho = -0.245, p = 0.046), and this correlation was stronger among countries with more than 29 neonatal deaths per 1000 newborns (Spearman's Rho = 0.327, p = 0.048). According to the statistical model, countries with the lowest breastfeeding tertiles had 24% higher neonatal mortality rates (Rate ratio = 1.24, 95% CI = 1.07-1.44, p < 0.05), even when adjusted for potential confounders. CONCLUSION: The protective effect of breastfeeding during the first hour of life on neo- natal mortality in this ecological study is consistent with findings from previous observa- tional studies, indicating the importance of adopting breastfeeding within the first hour as a routine neonatal care practice. PMID- 23642423 TI - Clinical and epidemiological study of orofacial clefts. AB - OBJECTIVE: Cleft lip with or without cleft palate (CL+/-P) or cleft palate (CP) are groups of malformations named orofacial clefts (OC), which are the second leading cause of birth defects. This study aimed to analyze clinical and epidemiological features of Brazilian patients with OC, studying cases treated in the reference center of the state of Parana (PR). METHODS: 2,356 charts were reviewed and 1,838 were evaluated by the same clinical geneticist. Data were collected in the reference center, and compared with those of the Health Department of the state of Parana. Clinical characteristics, presence of other anomalies, and birth prevalence were evaluated. RESULTS: 389 (21.2%) patients had CP, 437 (23.8%) had cleft lip (CL), and 1,012 (55%) had cleft lip and palate (CLP). Syndromic OC were identified in 15.3% of patients, 10.4% of patients with CL+/-P, and 33.9% of patients with CP. Common additional anomalies were: central nervous system, limbs, cardiovascular, and musculoskeletal defects. The number of syndromic cases was lower when clinical evaluation was performed by other medical specialists when compared to that of the clinical geneticist. Birth prevalence was 1/1,010 live births. Lack of notification with the national birth registry was observed in 49.9% of CL+/-P. The present data suggests a decrease of 18.52% in the prevalence of non-syndromic OC after folic acid fortification in Brazil. CONCLUSION: Better understanding of clinical and epidemiological aspects of OC is crucial to improve the understanding of pathogenesis, promote preventive strategies, and guide clinical care, including the presence of clinical geneticists in the multidisciplinary team for OC treatment. PMID- 23642424 TI - Association between family structure, maternal education level, and maternal employment with sedentary lifestyle in primary school-age children. AB - OBJECTIVE: To determine the association between family structure, maternal education level, and maternal employment with sedentary lifestyle in primary school-age children. METHOD: Data were obtained from 897 children aged 6 to 12 years. A questionnaire was used to collect information. Body mass index (BMI) was determined using the age- and gender-specific Centers for Disease Control and Prevention definition. Children were categorized as: normal weight (5(th) percentile<=BMI<85(th) percentile), at risk for overweight (85(th)<=BMI<95(th) percentile), overweight (>= 95(th) percentile). For the analysis, overweight was defined as BMI at or above the 85(th) percentile for each gender. Adjusted odds ratios (adjusted ORs) for physical inactivity were determined using a logistic regression model. RESULTS: The prevalence of overweight was 40.7%, and of sedentary lifestyle, 57.2%. The percentage of non-intact families was 23.5%. Approximately 48.7% of the mothers had a non-acceptable educational level, and 38.8% of the mothers worked outside of the home. The logistic regression model showed that living in a non-intact family household (adjusted OR=1.67; 95% CI=1.04-2.66) is associated with sedentary lifestyle in overweight children. In the group of normal weight children, logistic regression analysis show that living in a non-intact family, having a mother with a non-acceptable education level, and having a mother who works outside of the home were not associated with sedentary lifestyle. CONCLUSION: Living in a non-intact family, more than low maternal educational level and having a working mother, appears to be associated with sedentary lifestyle in overweight primary school-age children. PMID- 23642425 TI - Bone mineral density, pulmonary function, chronological age, and age at diagnosis in children and adolescents with cystic fibrosis. AB - OBJECTIVE: To assess bone mineral density in patients with cystic fibrosis (CF), and to correlate it with possible intervening variables. METHODS: Children and adolescents diagnosed with CF, aged 6 to 18 years, followed at the outpatient clinic were included in the study. First, demographic data were collected and, subsequently, patients underwent a spirometric test. All patients answered the Cystic Fibrosis Quality of Life Questionnaire (CFQ) and underwent the six-minute walk test (6MWT) and bone densitometry (DXA). RESULTS: A total of 25 CF patients were included, of which 56% were males. The mean age was 12.3+/-3.4 years; mean height was 149.2+/-14.4 cm; and mean weight was 44.4+/-13.9 kg. Most results on pulmonary function and bone mineral density (BMD) were within normal limits. The mean forced expiratory volume in one second (FEV) was 92.5+/-23.6 (% of predicted), mean forced vital capacity (FVC) was 104.4+/-21.3 (% of predicted), and1 mean BMD z-score was 0.1+/-1.0. BMD was moderately correlated with FEV (r = 0.43, p = 0.03) and FVC (r = 0.57, p = 0.003). Regarding chronological age and age at diagnosis, a moderate and inverse correlation was also found (r = -0.55, p = 0.004; r = -0.57, p = 0.003, respectively). However, no significant correlations were found with the data from CFQ, 6MWT, and body mass index. CONCLUSION: Most patients had BMD within normal limits and presented a positive correlation with pulmonary function, as well as a negative correlation with chronological age and age at diagnosis. PMID- 23642426 TI - Respiratory function in children of asthmatic mothers. AB - OBJECTIVE: To evaluate lung function and clinical manifestations suggestive of asthma in children of mothers with a reported medical diagnosis of asthma. METHODS: An observational cross-sectional analytical study nested in a cohort of 4,757 pregnant women. A total of 86 six-year-old children were evaluated, born to mothers with a medical diagnosis of asthma before pregnancy. Information was collected regarding clinical symptoms of atopy and respiratory diseases, as well as socioeconomic and exposure variables; the children were submitted to spirometry. RESULTS: Spirometric alterations were observed in 30.3% of cases, with a prevalence of asthma in those who had an obstructive pattern. 9.3% of the children had a previous medical diagnosis of asthma; however, the established diagnosis based on the presence and frequency of asthma symptoms was 18.6%. Of the 86 participating children, 37.2% had a score of five or more points in the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, which was associated with spirometry alterations (p=0.002). After multiple logistic regression analysis, higher paternal education, higher number of bedrooms in the family's home, and mother who did not have "wheezing" episodes during pregnancy were statistically significant as protective factors for the presence of respiratory disorder detected by spirometry. CONCLUSIONS: The frequency of spirometry alterations in children of asthmatic mothers was high; the restrictive pattern was more often observed that the obstructive. There was a higher incidence of obstructive test results in those who presented clinical symptoms of asthma, with a higher frequency of clinical diagnosis of asthma than that found in the literature. PMID- 23642427 TI - Prevalence and characteristics of victims and perpetrators of bullying. AB - OBJECTIVE: To determine the prevalence of bullying (victims and perpetrators) in a representative sample of sixth graders from schools located in the city of Caxias do Sul, RS, Brazil and to determine possible associations with maternal education, socioeconomic level, sedentary habits, nutritional status, dissatisfaction with body image, gender, and age. METHODS: This was a school based epidemiological study. The target population consisted of sixth graders (11 14 years). A self-administered questionnaire and anthropometric measurements of weight and height were used for the assessment of nutritional status. Bullying was assessed through the Kidscape questionnaire, and body image through the Body Shape Questionnaire. Descriptive statistics and bivariate and multivariate analyses were used. RESULTS: 1,230 schoolchildren were evaluated, and the prevalences of victims and perpetrators of bullying were 10.2% and 7.1%, respectively. Those dissatisfied with their body image were three times more likely to be victims of bullying (PR=3.24; CI=1.99- 5.28), and almost twice as likely to be aggressors (PR=1.98; CI=1.53-3.73) than those who were satisfied. Schoolchildren with sedentary habits (more than three hours a day) were 55% more likely to be victims of bullying (PR=1.55; CI=1.01- 2.36) and more than twice as likely (PR=2.42; CI=1.47-3.97) to be aggressors. Boys were more than twice as likely (PR=2.45; CI=1.42-4.24) to be aggressors. CONCLUSIONS: Body image and sedentary habits were associated with victims and perpetrators, and male gender was more prevalent among the perpetrators of bullying. PMID- 23642428 TI - A critical comparison between the World Health Organization list of essential medicines for children and the Brazilian list of essential medicines (Rename). AB - OBJECTIVE: To perform a critical comparison between the Brazilian national essential medicines list (Rename, 2012) with the list of essential medicines for children (LEMC, 2011) of the World Health Organization (WHO), regarding the differences among drugs and formulations listed for children. METHODS: The LEMC drugs were classified into four categories: 1) absent in Rename; 2) included in Rename but without any formulation suitable for children; 3) listed in Rename only in some formulations; 4) present in Rename in all formulations. The missing formulations were analyzed by therapeutic group. Alternatives present in Rename were searched. RESULTS: From the 261 drugs of interest on the LEMC, 30.3% are absent from Rename, 11.1% are in Rename but without any pediatric formulation, and 32.2% are present in some but not all formulations listed in LEMC. Considering all formulations items listed in the LEMC (n = 577), 349 are missing from Rename, of these 19.6% due to their strength, and 18.5% due to the the dosage form. Useful formulations specific for neonatal care, respiratory tract, central nervous system, and anti-infectives, among other groups, are missing. CONCLUSION: The lack of age-appropriate formulations of essential medicines for children in Brazil includes important therapeutic groups and indispensable drugs for severe clinical conditions. Some of these products exist in the Brazilian pharmaceutical market, but not in public facilities; others could be produced by national laboratories with commercial interest or stimulated by a specific governmental policy, as in other countries. PMID- 23642429 TI - Excess weight in preschoolers: prevalence and associated factors. AB - OBJECTIVE: To study the prevalence and factors associated with excess weight in children enrolled in public schools in the states of Rio Grande do Sul (RS) and Santa Catarina (SC). METHODS: This was a cross-sectional study, carried out with children aged 4 to 6 years. The studied outcome was excess weight, defined by z score > two standard deviations for body mass index (BMI)/age, compared with the World Health Organization (WHO) reference population of 2006/2007. Anthropometric measurements of body mass and height were measured in duplicate using standard techniques, in accordance with the WHO. Data were double entered using EPI-INFO software, release 6.04. Absolute and relative frequencies were calculated, as well as mean values and standard deviations. Associations between excess weight and other variables were assessed by using Poisson model with robust variance. STATA software release 12.0 was used (p < 0.05). RESULTS: A total of 4,914 children were evaluated (2,578 in RS and 2,336 in SC). In RS, the incidence of excess weight was 14.4% (95% CI = 13.1% to 15.8%) and in SC, 7.5% (95% CI = 6.5% to 8.7%). The variables associated with excess weight were number of household members, maternal education, marital status, number of children, mother's age at birth of first child, gestational age, and birth weight. CONCLUSION: Children enrolled in public preschools in RS had a two-fold higher excess weight prevalence than that identified in SC, demonstrating a significant difference in the magnitude of childhood obesity in two Brazilian states located in the same region. PMID- 23642430 TI - Risk factors and lethality of laboratory-confirmed bloodstream infection caused by non-skin contaminant pathogens in neonates. AB - OBJECTIVE: To evaluate risk factors and lethality of late onset laboratory confirmed bloodstream infection (LCBI) in a Brazilian neonatal unit for progressive care (NUPC). METHODS: This was a case-control study, performed from 2008 to 2012. Cases were defined as all newborns with late onset LCBI, excluding patients with isolated common skin contaminants. Controls were newborns who showed no evidence of late onset LCBI, matched by weight and time of permanence in the NUPC. Variables were obtained in the Hospital Infection Control Committee (HICC) database. Analysis was performed using the Statistical Package for the Social Sciences (SPSS). The chi-squared test was used, and statistical significance was defined as p < 0.05, followed by multivariate analysis. RESULTS: 50 patients with late onset LCBI were matched with 100 patients without late onset LCBI. In the group of patients with late onset LCBI, a significant higher proportion of patients who underwent surgical procedures (p = 0.001) and who used central venous catheter (CVC) (p = 0.012) and mechanical ventilation (p = 0.001) was identified. In multivariate analysis, previous surgery and the use of CVC remained significantly associated with infection (p = 0.006 and p = 0.047; OR: 4.47 and 8.99, respectively). Enterobacteriacea was identified in 14 cases, with three (21.4%) deaths, and Staphylococcus aureus was identified in 20 cases, with three (15%) deaths. CONCLUSIONS: Surgical procedures and CVC usage were significant risk factors for LCBI. Therefore, prevention practices for safe surgery and CVC insertion and manipulation are essential to reduce these infections, in addition to training and continuing education to surgical and assistance teams. PMID- 23642431 TI - Clinical manifestations, treatment, and outcomes of children and adolescents with eosinophilic esophagitis. AB - OBJECTIVE: This study aimed to describe the clinical, endoscopic, and histologic characteristics, as well as the response to conventional treatment of pediatric patients with the classical form of eosinophilic esophagitis (EoE). METHODS: Study of clinical, laboratory, endoscopic, and histologic data and response to conventional treatment of 43 previously followed pediatric patients with the classical form of EoE. RESULTS: A total of 43 patients diagnosed with EoE were included in the study, of which 37 were males (86%), with a mean age of 8.4 years. The most common symptoms were: nausea, vomiting, and abdominal pain (100%) in children younger than 7 years, and loss of appetite (60%), heartburn (52%), and food impaction (48%) in children older than 7 years and adolescents. Regarding the endoscopic findings, 12 (28%) patients had whitish plaques on the esophageal lining, 8 (18.5%) had longitudinal grooves, 2 (4.5%) had concentric rings, 3 (7%) had longitudinal grooves and whitish plaques, and the remaining 18 (42%) had esophageal mucosa with normal appearance. Despite the initial favorable response, 76.7% of patients required more than one course of corticosteroid therapy (systemic or aerosol) and diet (exclusion or elimination of food or elementary allergens). Persistence of eosinophil infiltration was found in some patients despite favorable clinical response. CONCLUSIONS: The classic form of EoE typically shows different symptoms according age range. A significant number of patients required more than one treatment cycle to show clinical remission. Endoscopic and histologic improvement was observed; however, eosinophilic infiltration persisted in some patients. PMID- 23642432 TI - Role of wireless capsule endoscopy in reclassifying inflammatory bowel disease in children. AB - OBJECTIVE: To evaluate the role of wireless capsule endoscopy in identifying small bowel lesions in pediatric patients with newly diagnosed colonic inflammatory bowel disease (IBD) type unclassified (IBDU), and to assess whether capsule endoscopy findings result in altered patient management. METHODS: Ten pediatric patients recently diagnosed with IBDU through standard investigations were recruited from the pediatric gastroenterology clinic at McMaster Children's Hospital to undergo capsule endoscopy using the Pillcam SB(TM) (Given Imaging) capsule. Findings consistent with a diagnosis of Crohn's disease required the identification of at least three ulcerations. RESULTS: Three out of ten patients had newly identified findings on capsule endoscopy that met criteria for Crohn's disease. Three more patients had findings suspicious for Crohn's disease, but failed to meet the diagnostic criteria. Three additional patients had findings most consistent with ulcerative colitis, and one had possible gastritis with a normal intestine. Findings from capsule endoscopy allowed for changes in the medical management of three patients. In all ten cases, capsule endoscopy allowed for a better characterization of the type and extent of disease. No adverse outcomes occurred in the present cohort. CONCLUSION: This prospective study reveals that wireless capsule endoscopy is feasible, valuable, and non-invasive, offering the ability to potentially better characterize newly diagnosed pediatric IBDU cases by identifying lesions in the small bowel and reclassifying these as Crohn's disease. PMID- 23642434 TI - Risk factors for early postoperative complications after pneumonectomy for benign lung disease. AB - BACKGROUND: Pneumonectomy is associated with a significant incidence of postoperative complications. The purpose of this study is to identify the risk factors associated with adverse outcomes. METHODS: One hundred thirty-six patients with benign lung disease who underwent pneumonectomy were included in this retrospective analysis. Postoperative complications were observed during the 30-day follow-up. Univariate and multivariate analysis was performed to investigate the risk factors of pneumonectomy among the patients. RESULTS: Postoperative complications were observed in 33 patients (24.26%). The rate of bronchopleural fistula was 6.1% (9 of 136). Five perioperative deaths (3.68%) were noted. Univariate analysis and multivariate analysis indicated that type of disease (hazard ratio [HR], 3.158; 95% confidence interval [CI], 1.248 to 7.992; p = 0.015) and operation duration (HR, 2.508; 95% CI, 1.035 to 6.080; p = 0.042) were independent risk factors of postoperative complications, and that type of disease (HR, 6.409; 95% CI, 1.669 to 6.021; p = 0.011) and pulmonary function (HR, 6.159; 95% CI, 0.018 to 0.625; p = 0.013) were independent risk factors of bronchopleural fistula for patients with benign lung disease after pneumonectomy. CONCLUSIONS: A high incidence of complications was reported among patients with benign lung disease after pneumonectomy. The type of disease and operation duration were the best independent predictors of morbidity after this surgery. With careful patient selection and operative technique, morbidity and mortality rates could be comparable to those for pneumonectomy in cancer patients. Pneumonectomy is still a satisfactory treatment method for benign lung disease. PMID- 23642433 TI - Central sensitization and MAPKs are involved in occlusal interference-induced facial pain in rats. AB - We previously developed a rat dental occlusal interference model of facial pain that was produced by bonding a crown onto the right maxillary first molar and was reflected in sustained facial hypersensitivity that was suggestive of the involvement of central sensitization mechanisms. The aim of the present study was to investigate potential central mechanisms involved in the occlusal interference induced facial hypersensitivity. A combination of behavioral, immunohistochemical, Western blot, and electrophysiological recording procedures was used in 98 male adult Sprague Dawley rats that either received the occlusal interference or were sham-operated or naive rats. Immunohistochemically labeled astrocytes and microglia in trigeminal subnucleus caudalis (Vc) showed morphological changes indicative of astrocyte and microglial activation after the occlusal interference. Prolonged upregulation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) was also documented in Vc after placement of the occlusal interference and was expressed in both neurons and glial cells at time points when rats showed peak mechanical facial hypersensitivity. The intrathecal administration of the p38 MAPK inhibitor SB203580 to the medulla significantly inhibited the occlusal interference-induced hypersensitivity, and the ERK inhibitor PD98059 produced an even stronger effect. Central sensitization of functionally identified Vc nociceptive neurons following placement of the occlusal interference was also documented by extracellular electrophysiological recordings, and intrathecal administration of PD98059 could reverse the neuronal central sensitization. These novel findings suggest that central mechanisms including central sensitization of trigeminal nociceptive neurons and non-neuronal processes involving MAPKs play significant roles in the production of occlusal interference-induced facial pain. PERSPECTIVE: Central mechanisms including trigeminal nociceptive neuronal sensitization, non-neuronal processes involving glial activation, and MAPKs play significant roles in occlusal interference-induced facial pain. These mechanisms may be involved in clinical manifestations of facial pain that have been reported in patients with an occlusal interference. PMID- 23642435 TI - Favorable outcomes for multidrug and extensively drug resistant tuberculosis patients undergoing surgery. AB - BACKGROUND: New approaches are needed in the treatment of multidrug-resistant and extensively drug-resistant pulmonary tuberculosis (M/XDR-PTB). We evaluated the role of adjunctive surgical therapy in the treatment of M/XDR-PTB in the setting of directly observed treatment strategy (DOTS)-Plus implementation. METHODS: We conducted an observational cohort study consisting of M/XDR-PTB patients who underwent thoracic surgery at the National Tuberculosis Center in Tbilisi, Georgia between October 2008 and February 2011. Indications for surgery included presence of M/XDR-PTB, localized pulmonary disease, fit to undergo surgery, and either medical treatment failure or such extensive drug resistance that failure was likely. Second-line anti-tuberculosis medical therapy was administered per World Health Organization (WHO) recommendations. RESULTS: Seventy-five patients (51 MDR, 24 XDR) with PTB underwent adjunctive thoracic surgery. Median age was 30 years and average duration of preoperative M/XDR-PTB medical therapy was 342 days. The following surgical procedures were performed: pneumonectomy (11%), lobectomy (54%), and segmentectomy (35%). Mean postoperative follow-up time was 372 days. Of 72 patients with evaluable outcomes, 59 (82%) had favorable outcomes including 90% of MDR and 67% of XDR-TB patients. There was no postoperative mortality; postoperative complications occurred in 7 patients (9%). Risk factors for poor treatment outcomes in univariate analysis included bilateral disease, XDR, increasing effective drugs received, positive preoperative sputum culture, and major postoperative surgical complication. CONCLUSIONS: Patients with M/XDR PTB undergoing adjunctive thoracic surgery had high rates of favorable outcomes, no surgical-related mortality, and low rates of complications. Adjunctive surgery appears to play an important role in the treatment of select patients with M/XDR PTB. PMID- 23642436 TI - Cardioprotective mechanism of diazoxide involves the inhibition of succinate dehydrogenase. AB - BACKGROUND: The adenosine triphosphate-sensitive potassium (KATP) channel opener, diazoxide, preserves myocyte volume homeostasis and contractility during stress via an unknown mechanism. Pharmacologic overlap has been suggested between succinate dehydrogenase (SDH) activity and KATP channel modulators. Diazoxide may be cardioprotective due to the inhibition of SDH which may form a portion of the mitochondrial KATP channel. To determine the role of inhibition of SDH in diazoxide's cardioprotection, this study utilized glutathione to prevent the inhibition of SDH. METHODS: SDH activity was measured in isolated mitochondria exposed to succinate (control), malonate (inhibitor of succinate dehydrogenase), diazoxide, and varying concentrations of glutathione alone or in combination with diazoxide. Enzyme activity was measured by spectrophotometric analysis. To evaluate myocyte volume and contractility, cardiac myocytes were superfused with Tyrode's physiologic solution (Tyrode's) (20 minutes), followed by test solution (20 minutes), including Tyrode's, hyperkalemic cardioplegia (stress), cardioplegia + diazoxide, cardioplegia + diazoxide + glutathione, or glutathione alone; followed by Tyrode's (20 minutes). Myocyte volume and contractility were recorded using image grabbing software. RESULTS: Both malonate and diazoxide inhibited succinate dehydrogenase. Glutathione prevented the inhibition of succinate dehydrogenase by diazoxide in a dose-dependent manner. The addition of diazoxide prevented the detrimental myocyte swelling due to cardioplegia alone and this benefit was lost with the addition of glutathione. However, glutathione elicited an independent cardioprotective effect on myocyte contractility. CONCLUSIONS: The ability of diazoxide to provide beneficial myocyte homeostasis during stress involves the inhibition of succinate dehydrogenase, which may also involve the opening of a purported mitochondrial adenosine triphosphate sensitive potassium channel. PMID- 23642437 TI - A strategy for supraclavicular lymph node dissection using recurrent laryngeal nerve lymph node status in thoracic esophageal squamous cell carcinoma. AB - BACKGROUND: The desirability of supraclavicular lymph node (LN) dissection, which is the cervical part of three-field LN dissection, has been discussed for a long time. In this study, we examine the pattern of supraclavicular LN metastasis in esophageal cancer, with a particular focus on the correlation between recurrent laryngeal nerve (RLN) LN and supraclavicular LN metastasis. METHODS: In all, 220 cases of R0 resected T1 to T3 squamous cell carcinomas were retrospectively examined. All of these patients underwent bilateral RLN LNs dissection; none received cancer treatment before surgery. RESULTS: Of 21 upper esophageal cancer cases, 33.3% of the patients had metastasis in the supraclavicular LN. Every patient in whom supraclavicular LN metastasis developed had metastasis in the RLN LN. Of 141 cases of middle esophageal cancer, 19.1% had metastasis in the supraclavicular LN. Among the patients whose RLN LN metastasized, 38.3% had metastasis in the supraclavicular LN. A similar correlation between RLN LN and supraclavicular LN metastasis was observed in lower esophageal cancer cases, especially in T3 cases. When considering cancers of the esophagus and patients who had metastasis in the supraclavicular LN, our data demonstrated that RLN LN metastasis did not always lead to metastasis on the same side of the supraclavicular LN. CONCLUSIONS: The status of the RLN LN can be an indicator of supraclavicular LN dissection in upper esophageal cancer patients and advanced cases of middle and lower esophageal cancer patients. Bilateral supraclavicular LN dissection should be recommended even when only unilateral RLN LN metastasis occurs. PMID- 23642438 TI - Production of aromatic hydrocarbons by catalytic pyrolysis of microalgae with zeolites: catalyst screening in a pyroprobe. AB - Catalytic pyrolysis of microalgae and egg whites was investigated to evaluate the performance of different zeolites for the production of aromatic hydrocarbons. Three zeolites with different structures (H-Y, H-Beta and H-ZSM5) were used to study the effect of catalyst type on the aromatic yield. All three catalysts significantly increased the aromatic yields from pyrolysis of microalgae and egg whites compared with non-catalytic runs, and H-ZSM5 was most effective with a yield of 18.13%. Three H-ZSM5 with silica-to-alumina ratios of 30, 80 and 280 were used to study the effect of Si/Al ratio on the aromatic yield. The maximum yield was achieved at the Si/Al ratio of 80, which provides moderate acidity to achieve high aromatic production and reduce coke formation simultaneously. Aromatic production increased with the incorporation of copper or gallium to HZSM 5. However, other studied metals either had no significant influence or led to a lower aromatic yield. PMID- 23642439 TI - Stress-induced lipids are unsuitable as a direct biodiesel feedstock: a case study with Chlorella pyrenoidosa. AB - The effects of various stresses on the suitability of lipid synthesized by Chlorella pyrenoidosa for biodiesel production were investigated. Lipids were characterized for detailed fatty acid methyl ester profiling and biodiesel properties like cetane number (CN), iodine value, cold filter plugging point (CFPP). Maximum biomass productivity (106.63 mgL(-1)d(-1)) and lipid content (29.68%) were obtained at indoor cultivation (nitrate sufficient, pH 8-10, 24h illumination). However, compared to this condition, other nitrate sufficient cultures [pH 6-8 and 10-12 (24h illumination), and at ambient CO2 and 16:8h light:dark photoperiod (pH unadjusted)] showed ~12-14% lower lipid productivity. Upon 50% nitrate depletion (at indoor and outdoor; pH unadjusted) lipid content has increased by 7.62% and 17%, respectively. Though stress conditions helped enhancing lipid accumulation, there was two-fold increase in PUFA content compared to that observed at pH 8-10. This resulted in fuel properties which did not comply with the biodiesel standards. PMID- 23642440 TI - Course of depression, mental health service utilization and treatment preferences in women receiving chemotherapy for breast cancer. AB - OBJECTIVE: This prospective study aimed to estimate the prevalence and course of depression during chemotherapy in women with Stage I-III breast cancer, identify potential risk factors for depression and determine which treatments for depression were being used and which were most preferred. METHOD: Thirty-two women were followed over consecutive chemotherapy infusions, with 289 assessments conducted altogether (mean, 9.0 assessments/subject). Current depression, anxiety, physical symptoms and mental health service use were recorded during each assessment. A linear mixed effects model was used to identify factors associated with depression. Patients also ranked depression treatment preferences. We referred patients with more severe depression for treatment. RESULTS: Clinically significant depression was identified in 37.5% of patients. Depression severity tended to peak at 12-14 weeks and 32 or more weeks of chemotherapy. Depression severity was associated with anxiety severity, physical symptom burden, non-White race, receiving one's first chemotherapy regimen, Adriamycin-Cytoxan chemotherapy and chemotherapy duration. Most (65.5%) patients preferred evidence-based treatments for depression, and 66.7% of depressed patients were using such treatments. CONCLUSIONS: Depression is common in women receiving chemotherapy for breast cancer. Most patients prefer evidence-based depression treatments. We recommend regular screening for depression during chemotherapy to ensure adequate detection and patient-centered treatment. PMID- 23642444 TI - [Ulcerated lipoma of the ileocecal valve presenting as acute abdomen]. PMID- 23642445 TI - Polymorphonuclear cell count on frozen section is not an absolute index of reimplantation in infected total knee arthroplasty. AB - We evaluated the outcomes in 15 patients with infected total knee arthroplasty (TKA) who underwent reimplantation following excision arthroplasty in the presence of five to twenty polymorphonuclear cells per high power field (hpf) on intraoperative frozen section. At a minimum of two years of follow-up, we achieved 100% infection eradication rate with normalization of C-reactive protein levels, no radiolucency on plain radiographs and no clinical evidence of recurred infection. Successful reimplantation for infected TKA is possible despite of the presence of five to twenty polymorphonuclear cells per hpf in intraoperative frozen section with clear appearance of the tissues in the operative field. Clinical and serological confirmations of infection eradication before reimplantation as well as healthy operative findings are equally important factors for a successful reimplantation. PMID- 23642446 TI - Porous tantalum tibial component prevents periprosthetic loss of bone mineral density after total knee arthroplasty for five years-a matched cohort study. AB - In 21 knees receiving porous tantalum tibial component and 21 knees receiving a cemented cobalt-chromium tibial component, dual x-ray absorptiometry scans were performed for five years post-operatively. The postoperative decrease in the bone mineral density in the lateral aspect of the tibia was significantly less in knees with porous tantalum tibial components (11.6%) than in knees with cemented cobalt-chromium tibial components (29.6%) at five years (p < 0.05). No prosthetic migration or periprosthetic fracture was detected in either group. The present study is one of the studies with the longest follow-up period on bone mineral density after total knee arthroplasty. Porous tantalum tibial component has a favorable effect on the bone mineral density of the proximal tibia after total knee arthroplasty up to five years. PMID- 23642447 TI - The patterns of limb length, height, weight and body mass index changes after total knee arthroplasty. AB - The objective of this retrospective review of 466 patients was to document changes in limb length, leg length discrepancy (LLD), height, weight, and body mass index (BMI) 1 year after TKA and the patterns of height, weight, and BMI during 5 years. To determine change patterns over 5 years, the data of 291 patients were analyzed and compared with those of age and gender-matched normal subjects. Limb length, height, and weight increased, BMI remained unchanged, and LLD decreased 1 year after TKA. The bilateral group had a greater height increase and lower rate of LLD. Preoperative mechanical tibiofemoral angle was related to limb length increase, and patients with a smaller preoperative BMI showed more weight gain. During the 5 years, weight and BMI at 1 year were maintained, but height diminished, while the healthy population showed a decreasing trend in weight. PMID- 23642448 TI - Simultaneous bilateral computer assisted total knee arthroplasty: the effect of intravenous or intraarticular tranexamic acid. AB - The use of tranexamic acid (TA) in total knee arthroplasty is well documented. However, there is limited evidence to suggest the use of TA in simultaneous bilateral computer assisted total knee arthroplasty (CATKA). We, therefore, studied the effect of TA, in simultaneous bilateral computer assisted total knee arthroplasty, in terms of blood transfusion, routes of administration and complications. We divided 90 patients into three groups. Group I patients received intravenous normal saline alone (IVNS group). Group II received intravenous TA alone (IVTA group). Group III received intraarticular TA alone (IATA group). Our study confirms that there is significant benefit of using TA but no difference between the intravenous or intraarticular routes of administration. PMID- 23642449 TI - The effect of fracture stability on the performance of locking plate fixation in periprosthetic femoral fractures. AB - Periprosthetic femoral fracture (PFF) fixation failures are still occurring. The effect of fracture stability and loading on PFF fixation has not been investigated and this is crucial for optimum management of PFF. Models of stable and unstable PPFs were developed and used to quantify the effect of fracture stability and loading in a single locking plate fixation. Stress on the plate was higher in the unstable compared to the stable fixation. In the case of unstable fractures, it is possible for a single locking plate fixation to provide the required mechanical environment for callus formation without significant risk of plate fracture, provided partial weight bearing is followed. In cases where partial weight bearing is unlikely, additional biological fixation could be considered. PMID- 23642451 TI - Extraskeletal osteosarcoma: a very rare case report of primary tumor of the colon rectum and review of the literature. AB - Extraskeletal osteosarcoma (ESOS) is a malignant mesenchymal tumor in which neoplastic cells produce bone osteoid in variable amounts. An 81-year-old woman presented with severe abdominal pain, tenesmus, constipation and rectal bleeding. The digital rectal exploration showed a large lesion of hard consistency, occupying the lumen, with the presence of splinters that "pierced" the endoscopist's glove. Endoscopic examination and CTscan revealed an ulcerative exophytic neoplasia of the lower rectum in which multiple calcified areas were found. The lesion showed no bone involvement. An abdominal perineal resection sec Miles was performed. The histological examination revealed a highly cellular mesenchymal lesion, with spindle and epithelioid cells with moderate nuclear pleomorphism. The calcified component consisted of widespread osteoid deposition. The immunohistochemical investigations of neoplastic cells showed strong positivity for vimentin and osteonectin. The definitive histological diagnosis of primary extraskeletal osteosarcoma arising from the colon-rectum was made. To our knowledge, only one previous case of colonic osteosarcoma was published in the literature in 2001, reported by Shimazu and other authors. The extreme rarity of the tumor at this location, also confirmed by morphological and immunohistochemical data, prompted us to present this case report and to review the literature. PMID- 23642450 TI - Outcomes of primary total joint arthroplasty after lung transplantation. AB - Lung transplantation is increasingly common with improving survival rates. Post transplant patients can be expected to seek total hip (THA) and knee arthroplasty (TKA) to improve their quality of life. Outcomes of 20 primary total joint arthroplasties (15 THA, 5 TKA) in 14 patients with lung transplantation were reviewed. Clinical follow-up time averaged 27.5 and 42.8 months for THA and TKA respectively. Arthroplasty indications included osteonecrosis, osteoarthritis, and fracture. All patients subjectively reported good or excellent outcomes with a final average Harris Hip Score of 88.7, Knee Society objective and functional score of 92.0. There were 4 minor and 1 major acute perioperative complications. 1 late TKA infection was successfully treated with two-stage revision. The mortality rate was 28.5% (4/14 patients) at an average 20.6 months following but unrelated to arthroplasty. Overall, total joint arthroplasty can be safely performed and provide good functional outcomes in lung transplant recipients. PMID- 23642452 TI - Positivity of serum "classical" onconeural antibodies in a series of 2063 consecutive patients with suspicion of paraneoplastic neurological syndrome. AB - This study determined the prevalence of classical onconeural Ab in a series of 2063 consecutive patients that were investigated because of suspicion of PNS as well as evaluated individual onconeural Ab in relationship to the clinical spectrum of associated neurological syndromes and tumor types detected in 70 patients finally diagnosed with PNS. We conclude that detectability of onconeural Ab is low among patients suspected with PNS. Specification of Ab is helpful in defining a neurological syndrome as paraneoplastic as well as in searching of underlying tumor. The success in tumor screening depends on the type of onconeural Ab. PMID- 23642453 TI - Hyperandrogenism during puberty in the development of polycystic ovary syndrome. AB - The hormonal events of puberty, from adrenarche to menarche and beyond, include the secretion of androgens as well as estrogen and P. This normal pubertal process is briefly reviewed and a physiologic role for pubertal androgens proposed. It is further suggested that the hyperandrogenic state we call polycystic ovary syndrome is a maladaptation of the advantageous role of normal pubertal androgens. PMID- 23642454 TI - Cryptosporioptide: a bioactive polyketide produced by an endophytic fungus Cryptosporiopsis sp. AB - An antibiotic polyketide, Cryptosporioptide (1) was isolated from the culture extract of the endophytic fungus Cryptosporiopsis sp. The structure of Cryptosporioptide has been established with the help of 1D ((1)H, (13)C), 2D NMR (HSQC, HMBC, COSY, NOESY) techniques and mass spectrometry (FABMS, HRFABMS). The absolute configuration was established by means of electronic circular dichroism (ECD). Cryptosporioptide exhibited both lipoxygenase inhibitory and anti-Bacillus megaterium activities. PMID- 23642455 TI - Harpagoside: from Kalahari Desert to pharmacy shelf. AB - Harpagoside is an iridoid glycoside that was first isolated from Harpagophytum procumbens (devil's claw, Pedaliaceae), a medicinal plant in which it is the major constituent of the iridoid pool. Both the pure compound and devil's claw extracts have potent anti-rheumatic, anti-inflammatory and analgesic effects. According to the European Pharmacopoeia commercial devil's claw products should contain at least 1.2% harpagoside. However, the compound has also been isolated from several other plant species and in vitro plant culture systems. Recent advances in knowledge of harpagoside distribution, biosynthesis/accumulation and pharmacology are summarized in this review. We also discuss the possible synergism and/or antagonism between major constituents in harpagoside-containing phytopharmaceutical products. Finally, future perspectives for its potential application are highlighted. PMID- 23642456 TI - Terpenes and polyacetylenes from cultivated Artemisia granatensis boiss (Royal chamomile) and their defensive properties. AB - Artemisia granatensis, an endemic endangered plant species from Sierra Nevada (Spain) has been successfully cultivated in artificial systems (plants in artificial soil and transformed in vitro roots) to generate enough plant biomass (aerial and root) to allow for its chemical and biological study and at the same time to provide with methods for the sustainable production of the plant and its metabolites. A eudesmanolide (17) along with six sesquiterpenes (11-16), nine monoterpenes (2-10), one nor-monoterpene (1), three acetylenic spiroacetal enoleters (18-20) and one coumarin (21) have been identified from the aerial plant ethanolic extract. Acetylenic spiroacetal enoleters 18-19 and coumarins 21 23 have been isolated from the transformed root ethanolic extract. These extracts and some isolated compounds or mixtures of them have been tested for their insect antifeedant effects against Spodoptera littoralis, Myzus persicae and Rhopalosiphum padi. Significant antifeedant properties were determined for the aerial plant extract, spiroacetals 19-20 and secoguaianolides 13+14 and 16. PMID- 23642457 TI - Monosaccharide analysis of succulent leaf tissue in Aloe. AB - INTRODUCTION: The succulent leaf mesophyll in Aloe species supports a burgeoning natural products industry, particularly in Africa. Comparative data necessary to prioritise species with economic potential have been lacking. OBJECTIVE: To survey leaf mesophyll monosaccharide composition in the genus Aloe using a predictive phylogenetic approach. METHODOLOGY: Monosaccharide composition was assessed in 31 species, representing the morphological and taxonomic diversity of Aloe sensu stricto. Leaf mesophyll polysaccharides were partially hydrolysed in a trifluoroacetic acid (TFA)-SilA assay. Oximes and trimethylsilyl ether products were detected by GC-MS. Constituent monosaccharides accounting for the greatest variation among species were identified by principal component analysis. Two plant DNA barcoding regions were sequenced in 28 of the sampled species and the resulting maximum likelihood tree was used to evaluate phylogenetic signal in monosaccharide composition throughout the genus. RESULTS: Nineteen peaks (Rt=16.76-23.67 min) were identified in the GC-MS spectra. All samples were dominated by one constituent; glucose was the major monosaccharide in 19 species, mannose in eight species, and xylose in one species (Aloidendron pillansii). Three monosaccharides therefore account for 90% of the variation in leaf mesophyll in Aloe. Species which do not share this typical monosaccharide profile appear to group outside the core Aloe clade in the phylogeny. CONCLUSION: Preliminary findings suggest that leaf mesophyll monosaccharide composition is conservative in Aloe. Characterisation of within-species variation and quantitative differences between species will be necessary to authenticate leaf mesophyll products, whereas unusual monosaccharide profiles could be diagnostic in some species. The common glucose-mannose-xylose profile identified in commercially important species is shared by many other Aloe species. PMID- 23642458 TI - Triterpene saponins of Genista ulicina Spach. AB - From the n-BuOH extract of the aerial parts of Genista ulicina, six triterpene saponins, 3-O-beta-D-glucopyranosyl-olean-12-ene-3beta,27,28,30-tetraol, 3-O-beta D-glucopyranosyl-olean-12-ene-3beta,27,28,29-tetraol, 3,29-di-O-beta-D glucopyranosyl-olean-12-ene-3beta,27,28,29-tetraol, 3-O-beta-D-glucopyranosyl olean-12-ene-3beta,28,29-triol-27-oic acid, 3-O-beta-D-glucopyranosyl-olean-12 ene-3beta,27,28-triol-29-oic acid, and 3-O-beta-D-glucopyranosyl-14-H-27-nor olean-12-ene-3beta,28,29-triol, were isolated together with eight known triterpene saponins and six flavonoids. Their structures were established mainly by means of spectroscopic methods (1D and 2D-NMR as well as HR-ESI-MS). The n BuOH extract, investigated for its antitumor growth inhibition of human colon cancer HT-29 cells, presented no significant activity (IC50>100 MUg). PMID- 23642459 TI - Biodiesel from dewatered wastewater sludge: a two-step process for a more advantageous production. AB - Alternative approaches for obtaining biodiesel from municipal sludge have been successfully investigated. In order to avoid the expensive conventional preliminary step of sludge drying, dewatered sludge (TSS: 15wt%) was used as starting material. The best performance in terms of yield of fatty acid methyl esters (18wt%) with the lowest energy demand (17MJkgFAME(-1)) was obtained by a new two-step approach based on hexane extraction carried out directly on dewatered acidified (H2SO4) sludge followed by methanolysis of extracted lipids. It was found that sulphuric acid plays a key role in the whole process not only for the transesterification of glycerides but also for the production of new free fatty acids from soaps and their esterification with methanol. In addition to biodiesel production, the investigated process allows valorization of primary sludge as it turns it into a valuable source of chemicals, namely sterols (2.5wt%), aliphatic alcohols (0.8wt%) and waxes (2.3wt%). PMID- 23642460 TI - Effects of attachment quality on caregiving of a parent with dementia. AB - OBJECTIVES: The purpose of the current study was to examine the moderating role of attachment quality on the relationship between dementia-specific stressors and: (a) caregiver distress and (b) caregiver satisfaction. METHOD: Caregivers (N = 91) of a parent with dementia completed questionnaires that assessed caregiving stressors (parental cognitive impairment and behavioral problems), attachment (early and present-day attachment) and measures of caregiver distress and satisfaction. A series of regression analyses were conducted to test the hypothesis that better attachment quality may buffer the effects of cognitive impairment and behavioral problems on the caregiver's experience of distress and enhance caregiver satisfaction. RESULTS: Results did suggest that present-day attachment moderates the effects of both cognitive impairment and behavioral problems on global distress but, contrary to our hypotheses, attachment security did not buffer the negative impact associated with these demands. Instead, secure present-day attachment was positively associated with an increased risk for emotional distress at mild levels of care-recipient cognitive impairment. Most analyses indicated no significant relationship between caregiving stressors and caregiver distress or satisfaction and few interactions based on attachment quality were found. CONCLUSIONS: Our study indicates that attachment security does not always have a protective or stress-buffering function but may amplify the effect of stressors under certain conditions. Different ways of understanding the obtained pattern of findings are discussed and additional work is required to test if secure attachment may be associated with increased resilience when the disease is more advanced. Clinical implications of the present findings are discussed. PMID- 23642461 TI - An observational study of the health benefits of yoga or tai chi compared with aerobic exercise in community-dwelling middle-aged and older adults. PMID- 23642463 TI - Effects of management practices as risk factors for juvenile osteochondral conditions in 259 French yearlings. AB - Several studies have demonstrated a statistical association between management practices and juvenile osteochondral conditions (JOCC) in foals from birth to 6months of age, but this association has not been investigated in yearlings. The purpose of the current study was to determine the adjusted effects of management practices on the onset and evolution of JOCC in French yearlings. The study sample consisted of 259 yearlings born on 20 stud farms in Normandy. The breeding conditions of these horses were monitored from 6 to 17months. They were radiographed at 6 and 17months to determine their radiographic score (RS) and its evolution. Potential risk factors were investigated using univariate and multivariate analyses. The prevalence of JOCC was 48% at 6months and 42% at 17months. Between 6 and 17months, the RS changed (for better or worse) in 52% of yearlings. The main risk factors leading to deterioration in the RS were traumatic. 'Mixed housing' during winter, pastures with rough ground and a bad RS at 6months were significantly associated with deterioration in RS between 6 and 17months. In the multivariate analysis, the breed was not significantly associated with any evolution in the yearlings' RS. This study provides some indications on protective measures to prevent the worsening of JOCC lesions between 6 and 17months, a crucial period since it precedes the sale of yearlings and the beginning of training. PMID- 23642462 TI - Effect of sertraline on risk of falling in older adults with psychotic depression on olanzapine: results of a randomized placebo-controlled trial. AB - OBJECTIVE: Observational studies report that selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with an increased risk of falls in the elderly, but these studies may overestimate drug-specific risk because of confounding. A randomized controlled trial (RCT) is the optimal way to assess the causal relationship between use of an SSRI and falls. We therefore analyzed data from a RCT of the treatment of psychotic depression, to examine whether combined olanzapine and sertraline interacted with older age to increase the risk of falling compared with olanzapine plus placebo. DESIGN: Double-blind placebo controlled RCT. SETTING: Four academic medical centers. PARTICIPANTS: Two hundred fifty-nine patients with major depressive disorder with psychotic features (N = 117 aged 18-59 years and N = 142 aged 60 years or older). INTERVENTION: Twelve weeks of randomized double-blind treatment with olanzapine plus sertraline or olanzapine plus placebo. MEASUREMENTS: Proportion of participants who fell at least once. RESULTS: Older participants were significantly more likely than younger participants to fall. Among older participants, the odds ratio of falling with olanzapine plus sertraline versus olanzapine plus placebo was 1.56 (95% confidence interval: 0.63-3.83). There was not a statistically significant treatment effect or treatment * age interaction with respect to the proportion of participants falling. These negative results may have been due to low statistical power. CONCLUSION: Evaluating the association between SSRIs and falls in a RCT is limited by the large sample size that is required. An alternative approach is to examine the effect of an SSRI on measures of postural stability and gait that are valid markers of risk of falling. PMID- 23642464 TI - Study design for the investigation of likely aetiological factors of juvenile osteochondral conditions (JOCC) in foals and yearlings. AB - The possible aetiology of osteochondrosis and, to a lesser extent, other developmental orthopaedic diseases or juvenile osteochondral conditions (JOCC), has been intensively investigated. However, most studies have focused on single factors of this multi-factorial disorder, or have been conducted under experimental conditions. This paper aims to present and discuss the scientific background of the BOSAC (Breeding, Osteochondral Status and Athletic Career) research program, a multi-factorial investigation on JOCC risk factors in field conditions. The epidemiology of JOCC in horses born in Normandy between 2002 and 2004 was studied. Horses were subjected to repeated body measurements, blood sampling and locomotion evaluation from birth until yearling sales. A radiographic examination, including 10 views of the limbs, was performed on each subject at approximately 6 and 17months of age. Information on nutrition and management programmes was collected by specialists from visits to the farms and the use of questionnaires. A total of 393 foals of three French breeds were monitored from birth to weaning, and 321 of these remained available for further follow-up, making the study unique as regards both the number of subjects and the variety of information collected. The study was designed to describe the evolution of JOCC, and determine possible early markers, risk factors and prognostic factors with respect to performance. Relevant data, suitable for epidemiological analyses, were collected under various field conditions that reflect current management practices in Normandy, France's main horse breeding region. PMID- 23642465 TI - Cobalamin deficiency states: a fine example of the One Medicine concept. PMID- 23642466 TI - Heat and ultraviolet light treatment of colostrum and hospital milk: effects on colostrum and hospital milk characteristics and calf health and growth parameters. AB - The aim of this study was to evaluate the effects of different physical treatments of bovine colostrum and hospital milk on milk bacteriology, immunoglobulin G (IgG) and lactoferrin concentrations, calf serum IgG concentrations and calf health, growth and survivability. Pooled colostrum samples (n=297) were heat treated (HTC; 63 degrees C for 60 min), exposed to ultraviolet light (UVC; 45 J/cm(2)) or untreated ('raw', RC). Hospital milk (n=712) was subjected to high temperature short time pasteurization (HTST; 72 degrees C for 15s), ultraviolet light irradiation (UVH; 45 J/cm(2)) or was untreated. Neonatal Holstein heifer calves (n=875) were randomly enrolled (309 HTC, 285 UVC, 281 RC) and block randomized (by colostrum treatment) into hospital milk treatments HTST (n=449) or UVH (n=426). HTC was more effective than UVC and HTST was more effective than UVH in reducing bacterial counts. IgG and lactoferrin concentrations were significantly lower in HTC and UVC than in RC. Lactoferrin concentrations were significantly lower in HTST than in UVH or untreated hospital milk. There were no significant differences in serum IgG concentrations among calves fed HTC, UVC or RC. Colostrum and hospital milk treatments did not have any significant effect on calf body weight gain, survivability, or frequency of diarrhea or pneumonia. PMID- 23642467 TI - Adjuvant effect of Escherichia coli heat labile enterotoxin B subunit against internal egg contamination in domestic fowl immunised with a live Salmonella enterica serovar Enteritidis vaccine. AB - This study evaluated the effect of Salmonella enterica serovar Enteritidis (SE) secreting Escherichia coli heat labile enterotoxin B subunit (LTB) protein as an adjuvant for a live SE vaccine (JOL919) against virulent SE challenge in hens. The eltB gene encoding LTB was inserted into the Asd+ beta-lactamase signal plasmid pJHL65. This plasmid was transformed into DeltalonDeltacpxRDeltaasd SE to generate the LTB strain JOL1228. One-hundred female domestic fowl were divided into five groups and hens in immunised groups were primed and subsequently boosted with either JOL919 or a JOL919-JOL1228 mixture. Humoral and cellular immune responses were significantly higher in the immunised groups than the control group. On challenge with virulent SE, egg protection was 89.3% in immunised hens in group B (primed and boosted twice with JOL919 only), 89.3% in group C (primed with JOL919-JOL1228 mixture and boosted twice with JOL919), 100% in group D (primed and first booster with JOL919-JOL1228 mixture, then subsequently boosted with JOL919), 90.5% in group E (primed and boosted twice with JOL919-JOL1228 mixture) and 60.7% in group A (control group of non-immunised hens inoculated with phosphate buffered saline). The challenge strain was detected significantly less in all organs examined from hens in group D than those of the control group. These results indicate that vaccination with JOL1228, especially when added to priming and first booster immunisations, may reduce egg contamination with SE. PMID- 23642468 TI - An application of item response theory to fMRI data: prospects and pitfalls. AB - When using functional brain imaging to study neuropsychiatric patients an important challenge is determining whether the imaging task assesses individual differences with equal precision in healthy control and impaired patient groups. Classical test theory (CTT) requires separate reliability studies of patients and controls to determine equivalent measurement precision with additional studies to determine measurement precision for different levels of disease severity. Unlike CTT, item response theory (IRT) provides estimates of measurement error for different levels of ability, without the need for separate studies, and can determine if different tests are equivalently difficult when investigating differential deficits between groups. To determine the potential value of IRT in functional brain imaging, IRT was applied to behavioral data obtained during a multi-center functional MRI (fMRI) study of working memory (WM). Average item difficulty was approximately one standard deviation below the ability scale mean, supporting the task's sensitivity to individual differences within the ability range of patients with WM impairment, but not within the range of most controls. The correlation of IRT estimated ability with fMRI activation during the task recognition period supported the linkage of the latent IRT scale to brain activation data. IRT can meaningfully contribute to the design of fMRI tasks. PMID- 23642469 TI - Social perception in schizophrenia: evidence of temporo-occipital and prefrontal dysfunction. AB - Individuals with schizophrenia evidence deficits in social functioning such as difficulties in communication, maintaining employment, and functioning as a member of the community. Impairment in such functions has been linked with higher order social cognitive deficits, which, in turn, have been associated with abnormal brain function. However, it is unclear whether brain abnormalities are found specifically for higher order social cognitive functioning, or whether "lower order" social processing, such as perceiving social stimuli, might demonstrate abnormalities at the neural level. The current study used functional magnetic resonance imaging to explore the neural correlates of social perception in schizophrenia. Individuals with schizophrenia (n=14) and healthy comparison participants (n=14) viewed social (i.e., faces, people) and nonsocial (i.e., scenes, objects) images that varied in affective content (emotional, neutral). Schizophrenia patients showed decreased brain activation, compared to controls, in occipital and temporal regions associated with early visual processing, as well as increased cingulate activity, in response to emotional social relative to nonsocial images. Results indicate aberrant neural response during early stages of visual processing of social information, which may contribute to higher order social cognitive deficits characteristic of this population. PMID- 23642471 TI - Adverse skin effects of imatinib, a tyrosine kinase inhibitor. AB - Imatinib mesylate is a tyrosine kinase inhibitor that targets the BCR-ABL, c-kit, and PDGF (platelet-derived growth factor) receptors. Imatinib is mainly indicated for chronic myeloid leukemia and gastrointestinal stromal tumors but is also prescribed by dermatologists for dermatofibrosarcoma protuberans, systemic sclerosis, and systemic mastocytosis, among other conditions. Most adverse effects are mild or moderate and therapy is generally well tolerated. Adverse skin effects are very common and include nonspecific manifestations such as edema and maculopapular rashes or eruptions of diverse types (lichenoid or psoriasiform lesions, acute generalized exanthematic pustulosis, Stevens-Johnson syndrome, and more). Identifying and properly treating these reactions can help optimize adherence to treatment and improve the prognosis of the underlying disease. PMID- 23642473 TI - Human factors/ergonomics as a systems discipline? "The human use of human beings" revisited. AB - Discussions of the possible future of Human factors/ergonomics (HFE) usually take the past for granted in the sense that the future of HFE is assumed to be more of the same. This paper argues that the nature of work in the early 2010s is so different from the nature of work when HFE was formulated 60-70 years ago that a critical reassessment of the basis for HFE is needed. If HFE should be a systems discipline, it should be a soft systems rather than a hard systems discipline. It is not enough for HFE to seek to improve performance and well-being through systems design, since any change to the work environment in principle alters the very basis for the change. Instead HFE should try to anticipate how the nature of work will change so that it can both foresee what work will be and propose what work should be. PMID- 23642472 TI - Probing the ability of presynaptic tyrosine kinase receptors to regulate striatal dopamine dynamics. AB - Brain-derived neurotrophic factor (BDNF) modulates the synaptic transmission of several monoaminergic neuronal systems. Molecular techniques using synapatosomes in previous studies have suggested that BDNF's receptor, tyrosine kinases (Trk), can quickly regulate dopamine release and transporter dynamics. Our main objective in this study is to determine whether slice fast scan cyclic voltammetry can be used to investigate the role of the TrkB receptor on dopamine release and uptake processes in the caudate-putamen. Fast scan cyclic voltammetry measured dopamine release and uptake rates in the presence of BDNF, or its agonist 7,8-dihydroxyflavone, or a TrkB inhibitor K252a. Superfusion of BDNF led to partial recovery of the electrically stimulated dopamine release response in BDNF(+/-) mice which is blunted compared to wildtype mice, with no effect in wildtype mice. Conversely, infusion of 7,8-dihydroxyflavone increased electrically stimulated dopamine release in wildtype mice with no difference in BDNF(+/-) mice. Overall, BDNF and 7,8-dihydroxyflavone had no effect on dopamine uptake rates. Concentrations greater than 3 MUM 7,8-dihydroxyflavone affected dopamine uptake rates in BDNF(+/-) mice only. To demonstrate that BDNF and 7,8 dihydroxyflavone modulate dopamine release by activating the TrkB receptor, both genotypes were pretreated with K252a. K252a was able to block BDNF and 7,8-DHF induced increases during stimulated dopamine release in BDNF(+/-) and wildtype mice, respectively. Fast scan cyclic voltammetry demonstrates that acute TrkB activation potentiates dopamine release in both genotypes. PMID- 23642474 TI - Effect of coating over the handle of a drill machine on vibration transmissibility. AB - This study was to see the effect of different coatings on the handle of hand-held drilling machines. Out of five different handles chosen for this study, including one handle uncoated. Root mean square (rms) values of the vibration levels (acceleration) were recorded at the surface of handle and wrist of the operators. Results showed that maximum vibrations were reduced by coating of handle coated with rubber sheet and Rexene (H4) followed by handle coated with cotton sandwiched between jeans cloth (H5). Equivalent vibrations transmitted through coating of handles coated with sponge and velvet (H2) and jute and cotton (H3) were of almost same magnitude and these two coated handles were able to reduce least vibration transmitted. Transmissibility of vibrations along dominant (Z) direction was analyzed using ANOVA. Results showed that coating on handles significantly affected vibration transmitted in Z direction. Vibration transmissibility ratios were found to be 0.354, 0.571, 0.408, 0.4326, and 0.3555 for handles H1, H2, H3, H4 and H5 respectively. PMID- 23642475 TI - An analysis of specialist and non-specialist user requirements for geographic climate change information. AB - The EU EuroClim project developed a system to monitor and record climate change indicator data based on satellite observations of snow cover, sea ice and glaciers in Northern Europe and the Arctic. It also contained projection data for temperature, rainfall and average wind speed for Europe. These were all stored as data sets in a GIS database for users to download. The process of gathering requirements for a user population including scientists, researchers, policy makers, educationalists and the general public is described. Using an iterative design methodology, a user survey was administered to obtain initial feedback on the system concept followed by panel sessions where users were presented with the system concept and a demonstrator to interact with it. The requirements of both specialist and non-specialist users is summarised together with strategies for the effective communication of geographic climate change information. PMID- 23642476 TI - Extensively hydrolyzed protein formula reduces acid gastro-esophageal reflux in symptomatic preterm infants. AB - BACKGROUND: Gastro-esophageal reflux (GER) is diagnosed frequently in preterm infants. Pharmacological treatment of GER has some potential side effects. Conservative treatment of GER should be the first-line approach and should include body positioning and diet modifications. Formula-fed preterm infants experience frequently symptoms of feeding intolerance. Hydrolyzed protein formula (HPF) is often used in these infants due to their effects on gastrointestinal motility. AIMS: To investigate the role of an extensively HPF (eHPF) on GER indexes in formula-fed preterm infants with symptoms of both GER and feeding intolerance. STUDY DESIGN: Randomized crossover trial. SUBJECTS: Preterm infants (gestational age <=33 weeks) with symptoms of feeding intolerance (large gastric residuals, abdominal distension and constipation) and GER (frequent regurgitations and/or postprandial desaturations). OUTCOME MEASURES: GER indexes detected by 24-h combined multichannel intraluminal impedance and pH monitoring. GER indexes detected after 4 feeds of an eHPF were compared to those detected after 4 feeds of a standard preterm formula (SPF) by Wilcoxon signed ranks test. A p<0.05 was considered statistically significant. RESULTS: eHPF significantly reduced the number of GERs detected by pH monitoring (p=0.036) and also the reflux index (p=0.044) compared to SPF. No differences in impedance bolus exposure indexes nor in GER height were detected. CONCLUSIONS: The use of an eHPF should be evaluated for reducing esophageal acid exposure in preterm infants with feeding intolerance and symptoms of GER. Future research should focus on the evaluation of an eHPF adequate for preterm infants in improving clinical symptoms of GER. PMID- 23642477 TI - Hypophosphatemia on the intensive care unit: individualized phosphate replacement based on serum levels and distribution volume. AB - BACKGROUND: Hypophosphatemia occurs in about 25% of patients admitted to the intensive care unit. To date, a safe and validated phosphate replacement protocol is not available. OBJECTIVE: To evaluate an individualized phosphate replacement regimen. DESIGN: Fifty consecutive intensive care unit patients with a serum phosphate level<0.6 mmol/L were treated with sodium-potassium-phosphate intravenously at a rate of 10 mmol/h. The dose was calculated according to the following equation: Phosphate dose in mmol=0.5*Body Weight*(1.25-[serum Phosphate]). Phosphate levels were measured immediately upon completion of the infusion, as well as the next morning at 8 am. RESULTS: Post-infusion phosphate levels were >0.6 mmol/L in 98% of the patients. Hyperphosphatemia, hyperkalemia or a decrease in serum calcium were not observed. In about a third of patients serum phosphate decreased to <0.6 mmol/L within the next 24 hours after infusion. The phosphate distribution volume calculated from the results of infusion and corrected for renal phosphate loss during the infusion period was 0.51 L/kg (95% CI 0.42-0.61 L/kg). CONCLUSION: This study shows that phosphate replacement with dose calculation based on serum phosphate levels and a Vd of 0.5 L/kg is effective and safe. PMID- 23642478 TI - Carbonic anhydrase inhibitors. Benzenesulfonamides incorporating cyanoacrylamide moieties strongly inhibit Saccharomyces cerevisiae beta-carbonic anhydrase. AB - A series of benzenesulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogs) were assayed as inhibitors of the beta-carbonic anhydrase (CA, EC 4.2.1.1) from Saccharomyces cerevisiae, ScCA. Some of these compounds were low nanomolar or subnanomolar ScCA inhibitors and showed selectivity ratios in the range of 4.91-69.86 for inhibiting the yeast enzyme over the offtarget human (h) isoforms hCA I and of 6.46-13.52 for inhibiting ScCA over hCA II. The model organism S. cerevisiae and this particular enzyme may be useful for detecting antifungals with a novel mechanism of action compared to the classical azole drugs to which significant drug resistance emerged. Indeed, some of these sulfonamides inhibited the growth of the yeast with CC50-s in the range of 0.73 6.54 MUM. PMID- 23642480 TI - Synthesis of new conjugated coumarin-benzimidazole hybrids and their anticancer activity. AB - A series of novel coumarin-benzimidazole hybrids, 3-(1H-benzo[d]imidazol-2-yl)-7 (substituted amino)-2H-chromen-2-one derivatives of biological interest were synthesized. Six out of the newly synthesized compounds were screened for in vitro antitumor activity against preliminary 60 tumor cell lines panel assay. A significant inhibition for cancer cells was observed with compound 8 (more than 50% inhibition) compared with other compounds and active known drug 5 fluorouracil (in some cell lines) as positive control. Compound 8 displayed appreciable anticancer activities against leukemia, colon cancer and breast cancer cell lines. PMID- 23642479 TI - Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: development of chemical probe ML315. AB - Substituted pyrimidine inhibitors of the Clk and Dyrk kinases have been developed, exploring structure-activity relationships around four different chemotypes. The most potent compounds have low-nanomolar inhibitory activity against Clk1, Clk2, Clk4, Dyrk1A and Dyrk1B. Kinome scans with 442 kinases using agents representing three of the chemotypes show these inhibitors to be highly selective for the Clk and Dyrk families. Further off-target pharmacological evaluation with ML315, the most selective agent, supports this conclusion. PMID- 23642481 TI - Chemical constituents from Nelumbo nucifera leaves and their anti-obesity effects. AB - Nelumbo nucifera Gaertn. (Nymphaeaceae), commonly called lotus, is widely distributed throughout Eastern Asia. It has been used for food and medicine for a long time. A phytochemical investigation of N. nucifera leaves led to the isolation of 13 megastigmanes (1-13), including a new megastigmane, nelumnucifoside A (1), and a new eudesmane sesquiterpene, nelumnucifoside B (14), eight alkaloids (15-22), and 11 flavonoids (23-33). Their chemical structures were determined based on spectroscopic methods including 1D, 2D NMR and MS spectrometry. The relative and absolute stereochemistry of the compounds was determined by NOESY and CD spectrometry, respectively. Compounds 19 and 22 significantly inhibited pancreatic lipase, whereas compounds 15 and 16 showed a strong inhibitory effect on adipocyte differentiation. Therefore, the leaves of N. nucifera have potential as an anti-obesity agent by inhibiting pancreatic lipase and adipocyte differentiation. PMID- 23642482 TI - Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1. AB - The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan JAK inhibitor (tofacitinib). PMID- 23642483 TI - Gene expression profiling of thymus in beef cattle treated with prednisolone. AB - Glucocorticoids (GCs) are extensively used in livestock production, not only for their anti-inflammatory properties but also to improve the quality and quantity of meat in veal and beef production. In Italy, an increase in GC-positive cases has been observed in cattle since 2008, particularly prednisolone (PDN). Recent studies clearly demonstrate that both histopathological analysis and high performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) were unable to detect PDN treatments. The aim of this study was to identify transcriptomic signatures of PDN administration in the thymus of experimentally treated animals by comparison with untreated controls, in order to identify gene expression changes or pathways alteration induced by the corticosteroid treatment. Microarray data analysis showed substantial modifications in thymus gene expression profiles after PDN treatment. Several of the 388 differentially expressed genes encoded pro-inflammatory and anti-inflammatory mediators or immune regulators which showed that PDN might have a role in the regulation of immunologic homeostasis, act on both innate and acquired components of the immunity and mainly induce the activation of immune tolerance and anti inflammatory pathways. Thus, this study allowed to deepen the effects of PDN on the immune system and showed the potentiality of gene expression profiling by DNA microarray as a powerful tool to complement the existing methods against the illegal use of growth promoting hormones, especially when working on samples collected after slaughtering. PMID- 23642485 TI - Echocardiographic evaluation of the cardiovascular effects of medetomidine, acepromazine and their combination in healthy dogs. AB - The aim of this study was to compare the cardiovascular effects of medetomidine, acepromazine and their combination administered intravenously in healthy dogs. Ten dogs were included in this study and randomly assigned to the three different sedative protocols: medetomidine (2 MUg/kg, protocol M), acepromazine (20 MUg/kg, protocol A) and acepromazine followed by medetomidine with the same doses as above (protocol AM), in three different times. In all subjects before (Tbase) and 15 (T15), 50 (T50) and 80 (T80) minutes after the administration of the drugs, the following non-invasive measurements were obtained: blood pressure with oscillometric method, ECG, and echocardiography. Blood pressure and echocardiography evidenced decrease in left ventricular afterload secondary to acepromazine and an increase in right ventricular afterload due to medetomidine. The combination of the two drugs mitigated the effects expected by the single drugs used alone, and prevented the onset of atrioventricular blocks, such as seen in protocol M. The three protocols were eligible for sedation and premedication in healthy dogs. Moreover they had little impact on the echocardiographic variables evaluated in this study. PMID- 23642484 TI - Use of infrared thermography to assess the influence of high environmental temperature on rabbits. AB - The aim of this work was to ascertain if infrared thermography (IRT) can be used on rabbits to assess differences in surface body temperature when they are subjected to two different environmental temperatures outside the comfort zone. Rabbits housed in room A were maintained at a temperature of below 30 degrees C and rabbits in room B at a temperature of above 32 degrees C for a year. Faeces were collected six times during the year to assess stress by means of faecal cortisol metabolites (FCM). The assessment of IRT was carried out to assess maximum and minimum temperatures on the eyes, nose and ears. FCM concentration was higher in room B than A, to confirm that stress conditions were higher in room B. Significant differences in IRT were found between the animals housed in both rooms. It was observed that it was more difficult for animals from room B to maintain a regular heat loss. Although all the body zones used to assess temperature with IRT gave statistical differences, the correlations found between the eyes, nose and ears were moderate, suggesting that they were giving different information. In addition, differences up to 3.36 degrees C were found in the eye temperature of rabbits housed in the same room, with a clear effect of their position in relation to extractors and heating equipments. Therefore, IRT could be a good tool to assess heat stress in animals housed on typical rabbit farm buildings, giving a measure of how the animal is perceiving a combination of humidity, temperature and ventilation. Some face areas were better for analysing images. Minimum temperature on eyes and temperatures on nose are suggested to assess heat losses and critical areas of the farm for heat stress in rabbits. PMID- 23642486 TI - Transit of micro-bubbles through the pulmonary circulation of Thoroughbred horses during exercise. AB - It has been observed that microbubbles may pass through the pulmonary circulation of dogs and humans during exercise. In humans, this phenomenon has been associated with lower pulmonary artery pressures, enhanced right ventricular function and greater exercise capacity. In the exercising Thoroughbred horse, extraordinarily high cardiac outputs exert significant pulmonary vascular stresses. The aim of this study was to determine, using contrast echocardiography, whether Thoroughbred horses performing strenuous exercise developed pulmonary transit of agitated contrast microbubbles (PTAC). At rest, agitated contrast was observed in the right ventricle, but not in the left ventricle. However, post-exercise microbubbles were observed in the left ventricle, confirming the occurrence of PTAC with exercise but not at rest. Further investigation is warranted to investigate whether this phenomenon may be associated with superior physiology and performance measures as has been implicated in other species. PMID- 23642487 TI - Auditory risk of hyperbilirubinemia in term newborns: a systematic review. AB - OBJECTIVES: High levels of unconjugated bilirubin have been associated with neuronal damage. The auditory brain nuclei and the inferior colliculi are often the first part of the brainstem to be involved, often leading to hearing abnormalities. A systematic review of clinical studies was conducted to evaluate the effect of hyperbilirubinemia on hearing in term newborns, to show the relationship between hearing function and bilirubin levels as well as the effect of treatment. METHODS: Eligible studies were identified through searches of electronic databases Ovid MEDLINE, Ovid MEDLINE In-Process, Embase, PubMed and The Cochrane Library. Articles obtained were independently reviewed by 2 authors using inclusion criteria to identify eligible studies. The search was restricted to articles written in English, French and Spanish and published between 1970 and 2010. Data extracted included study type, number of patients, bilirubin levels, hyperbilirubinemia criteria, hearing assessment methods, time of hearing assessment and outcome measures. RESULTS: The nineteen articles included showed heterogeneity regarding the time of hearing test and hyperbilirubinemia criteria. The incidence of hearing loss at initial testing ranged between 13.2-83.3% and 6.7-14.3% at 3 months follow-up. Five studies showed a rising incidence of hearing loss with increasing levels of serum bilirubin. CONCLUSIONS: Hyperbilirubinemia resulted in abnormal hearing assessment in up to 83.3% of term newborns. Greater hearing abnormalities were observed with rising serum bilirubin levels. Treatment of hyperbilirubinemia led to a considerable decrease in the incidence of hearing loss. PMID- 23642488 TI - Age of diagnosis and evaluation of consequences of submucous cleft palate. AB - OBJECTIVES: To evaluate the frequency of submucous cleft palate (SMCP) in a group of children with clefts. The reason for suspecting submucous cleft, age of diagnosis, effect of age on speech development, problems in speech, hearing and swallowing were compared with previous literature. METHODS: Retrospective chart review: Out of 33 patients with SMCP, registered by the Groninger cleft team over approximately 20 years (1990 until July 2012), 28 non-syndromic patients with a proven diagnosis of SMCP were included: 17 males and 11 females. Speech and hearing were examined and the number of patients with SMCP and age at time of diagnosis were evaluated. The percentages of problems in resonance, articulation and hearing, present at time of diagnosis, were compared with the percentages of problems found after surgery. RESULTS: Out of 800 patients with clefts, 28 patients (3,5%) were diagnosed with SMCP at a mean age of 3;9 years. All patients presented one or more symptomatic complaints at time of diagnosis: hypernasality (65%), problems in articulation (46%), conductive hearing loss (39%) and/or swallowing problems (32%). A bifid uvula was found in 92%. Following surgery, hypernasal speech and swallowing problems were no longer observed. The articulation problems remained after surgery. Age of diagnosis seems no predictor of articulation problems. An improvement in hearing was observed but normal hearing was not achieved. Pharyngoplasty appeared to be a successful and save treatment of hypernasality. CONCLUSIONS: SMCP is a rare cleft palate which is, despite the presence of a bifid uvula and symptoms of velopharyngeal insufficiency, often diagnosed late. In children with a bifid uvula and mild problems in speech, hearing and swallowing, it is important to be alert to SMCP because SMCP may account for these persistent mild complaints. Therefore, early detecting of SMCP can yield profits. PMID- 23642489 TI - Microbiologic analysis of peri-pancreatic fluid collected during EUS in patients with pancreatitis: impact on antibiotic therapy. AB - BACKGROUND: Pancreatitis is a potentially life-threatening condition frequently accompanied by peri-pancreatic fluid collections (PPFC), such as pseudocysts or pancreatic necrosis. Aspiration of PPFCs during EUS interventions for microbiologic analysis is still rarely performed in clinical routine. OBJECTIVE: To evaluate the role of routine microbiologic analysis of PPFCs and its impact on antibiotic therapy in patients with pancreatitis. DESIGN: Prospective, observational, multicenter study. SETTING: Four treatment centers. PATIENTS: A total of 44 consecutive patients who presented for endoscopic treatment of PPFCs were included. INTERVENTION: Concomitantly, PPFC during intervention and concomitant blood cultures were obtained. MAIN OUTCOME MEASUREMENTS: Microbiologic examination of PPFCs and blood samples. RESULTS: Colonization of PPFCs was found in 59% of PPFC cultures, whereas all but 2 concomitant blood cultures showed no microbial growth. Risk factors for a colonization were the presence of necrosis (P = .006), acute pancreatitis (P = .033), leukocytosis (P = .001), elevated C-reactive protein levels (P = .003), fever (P = .02), turbid material (P = .031), and longer hospital stay (P = .003). In 23 patients with fluid colonization despite empiric antibiotic therapy, the treatment had to be adjusted in 18 patients (78%) according to the observed antibiotic susceptibility profile. LIMITATIONS: Contamination cannot be totally excluded. CONCLUSION: The microbiologic colonization of PPFCs in patients with pancreatitis is common. Only the direct microbiologic analysis of PPFCs, but not of blood cultures, is useful to optimize an effective antibiotic therapy in patients with pancreatitis. PMID- 23642490 TI - Utility of contrast-enhanced harmonic EUS in the diagnosis of malignant gallbladder polyps (with videos). AB - BACKGROUND: The differential diagnosis between benign and malignant polyps of the gallbladder (GB) is often challenging. OBJECTIVES: To evaluate whether contrast enhanced harmonic EUS (CEH-EUS) might be an accurate method for discriminating malignant GB polyps from benign polyps. DESIGN: Observational study. SETTING: Tertiary care medical center. PATIENTS: Ninety-three patients with GB polyps larger than 10 mm in diameter that were detected by conventional EUS underwent CEH-EUS for evaluation of microvasculature. INTERVENTION: CEH-EUS was performed using a radial echoendoscope and the extended pure harmonic detection mode. MAIN OUTCOME MEASUREMENTS: The abilities of conventional EUS and CEH-EUS to diagnose malignant polyp were compared. Two blinded reviewers classified the perfusion images into 3 categories: diffuse enhancement, perfusion defect, or nonenhancement. The vessel images were categorized as having a regular spotty vessel, an irregular vessel, or no vessels. RESULTS: An irregular vessel pattern determined by CEH-EUS aided in the diagnosis of malignant polyps with a sensitivity and specificity of 90.3% and 96.6%, respectively. The presence of perfusion defects, determined by CEH-EUS, was calculated to diagnose malignant polyps with a sensitivity and specificity of 90.3% and 94.9%, respectively. Based on the definitely determined diagnosis, sensitivity and specificity for CEH-EUS were 93.5% and 93.2% versus 90.0% and 91.1% for conventional EUS. In 8 cases, management changed after CEH-EUS. LIMITATIONS: A tertiary medical center with a limited number of patients. CONCLUSIONS: The presence of irregular intratumoral vessels or perfusion defects seen on CEH-EUS may be sensitive and accurate predictors of malignant GB polyps. CEH-EUS offers slightly improved diagnostic accuracy compared with EUS. PMID- 23642491 TI - The impact of fair colonoscopy preparation on colonoscopy use and adenoma miss rates in patients undergoing outpatient colonoscopy. AB - BACKGROUND: The impact of fair bowel preparation on endoscopists' recommendations and adenoma miss rates in average-risk patients undergoing colonoscopy is unknown. OBJECTIVE: To assess the impact of fair bowel preparation on endoscopists' interval colonoscopy recommendations and miss rates in colonoscopies performed within 3 years of the index colonoscopy in average-risk patients undergoing colorectal cancer screening. DESIGN: Retrospective chart review. SETTING: Tertiary-care center. PATIENTS: Average-risk patients undergoing index colonoscopy for colorectal cancer screening between 2004 and 2006. INTERVENTION: Colonoscopy. MAIN OUTCOME MEASUREMENTS: Endoscopists' interval recommendations, adenoma miss rates. RESULTS: A total of 16,251 colonoscopy records were reviewed over a 2-year period. Of these cases, 1943 colonoscopies were performed for the sole indication of average risk or screening. Of these, fair bowel preparation was reported in 619 patients (31.9%). A repeat colonoscopy within 5 years was recommended in 70.4% of patients. The follow-up colonoscopy compliance rate within 3 years was 55.9%. Adenoma detection rates at index and follow-up colonoscopy were 20.5% and 28.2%, respectively. Of the 39 patients with follow-up colonoscopy within 3 years, the overall adenoma miss rate was 28%. Of the patients with an adenoma identified on follow-up colonoscopy, 13.6% had normal colonoscopy results on index examination. LIMITATIONS: Retrospective design. CONCLUSION: Fair bowel preparation led to a deviation from national guidelines with early repeat colonoscopy follow-up recommendations in nearly 60% of average-risk patients with normal colonoscopy results. In patients who returned for repeat colonoscopy within 3 years, the overall adenoma miss rate was 28%. Further guidelines on timing for repeat colonoscopy for fair bowel preparation are needed. PMID- 23642492 TI - Levetiracetam vs. sulthiame in benign epilepsy with centrotemporal spikes in childhood: a double-blinded, randomized, controlled trial (German HEAD Study). AB - OBJECTIVE: To show non-inferiority of levetiracetam to sulthiame with respect to efficacy, tolerability and safety in benign epilepsy with centrotemporal spikes in a prospective, double-blinded randomized controlled trial. METHODS: A sample size of 60 subjects (treatment group) was calculated to show reliable statistical results for non-inferiority. A total of 44 patients could be randomly allocated to either (LEV or STM) treatment group. Explorative data analysis was performed to investigate differences in the number of treatment failure events (occurrence of a seizure during the observation period of 6 months) and total dropouts. In addition, information of the occurrence of adverse events was collected. RESULTS: 43 patients were analyzed. One patient had to be excluded due to protocol violation. Treatment failure events occurred in four patients (19.0%) in the LEV treatment group and in two patients (9.1%) in the STM treatment group, respectively, (p = 0.412). The number of dropouts due to adverse reactions was five in the LEV treatment group and one in STM treatment group (23.8% vs. 4.5%, respectively, p = 0.095). Severe adverse events occurred in patients treated with LEV (n = 2, 9.5%). The total number of dropouts due to either seizure recurrence or adverse events was significantly higher in the LEV group (n = 9, 42.9%) compared to the STM group (n = 3, 13.6%, p = 0.03). INTERPRETATION: The study results concerning non-inferiority were not conclusive, as the calculated sample size was not reached to support sufficient statistical power due to limited recruitment in a 26 months period. The rates of seizure free patients were [relatively] high in both groups. However, the results indicate that termination of drug treatment due to seizure recurrence or adverse events occurred more frequently in the LEV group compared to STM. Behavioral disturbances were the most common adverse event causing study termination. PMID- 23642493 TI - Clinical outcomes of the Realize Adjustable Gastric Band-C at 2 years in a United States population. AB - BACKGROUND: In 2008, the Realize Band (RB) adopted a precurved design (RB-C). We present 2-year outcomes data from the first multiinstitutional study of RB-C. The objective of this study was to analyze weight loss and safety data from bariatric practices in the United States, including academic, nonacademic, public, and private. METHODS: The study included adult RB-C patients with a preoperative body mass index (BMI)>=40 kg/m(2) or >35 kg/m(2) with co-morbidity. Exclusions included RB-C's label contraindications for use. Outcomes parameters were percent excess weight loss (%EWL), BMI change, number and volume of band adjustments, and adverse events. RESULTS: A total of 231 patients met inclusion/exclusion criteria. Of these, 161 had 24-month data available. Mean %EWL was 44.4%+/-26.9% (P<.0001). BMI decreased from 44.1+/-5.7 kg/m(2) to 35.3+/-6.9 kg/m(2) (P<.0001). Percent EWL varied by preoperative BMI (P = .0002), bariatric practice (P<.0001), aftercare frequency (P = .0004), and band fill frequency (P = .0271), but %EWL was not influenced by gender, race, or age (P>.20 each). Adverse events were dysphagia (21.2%), gastroesophageal reflux (21.6%), and vomiting (30.7%). Incidence of pouch dilation, esophageal dilation, and slippage was <=1%. Revisions (2.2%) were for unbuckled band, tube kinking, slippage, and suspected band leak (1 each). No erosions, explants, or mortality were reported. CONCLUSION: RB-C appears to be as well tolerated and effective as the first generation RB for weight loss. The near 45% EWL at 2 years is consistent with other high-quality publications on the RB. Preoperative BMI and frequency of postoperative care, including frequency of band fills, influence %EWL. Significant weight loss is achievable with RB-C despite variable postoperative management practices. The low morbidity and the absence of mortality at 24 months reflect positively on the RB-C characteristics. PMID- 23642495 TI - High-throughput measurement of ionic conductivity in composition-spread thin films. AB - This paper demonstrates the feasibility of high-throughput investigation of ionic conductivity in oxygen-ion conductors. Yttria stabilized zirconia (YSZ) composition-spread thin films with nanometer-size grains were prepared by 90 degrees off-axis reactive RF cosputtering. We compare results for two electrode configurations, namely, out-of-plane (parallel plate) and in-plane (planar interdigitated electrode) and find that the contribution from the intragrain conductivity in YSZ thin films (150 nm) is more explicit in the latter configuration because it greatly diminishes electrode effects. The intragrain oxygen ion conductivity of thin film YSZ was systematically measured as a function of yttria concentration over the range 2 mol % to 12 mol %. The results show that the measured conductivity of the YSZ thin films is close to that of corresponding bulk materials with a peak value around 3 * 10-4 S cm-1 at 440 degrees C at the optimum Y2O3 concentration of 8 mol %. Validation of this technique means that it can be applied to novel chemical systems for which systematic bulk measurements have not been attempted. PMID- 23642494 TI - 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) enhances placental inflammation. AB - Preterm birth is a leading cause of perinatal morbidity and mortality that is often associated with ascending infections from the lower genital tract. Recent studies with animal models have suggested that developmental exposure to the environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can increase the risk of preterm birth in the offspring. How TCDD may modify placental immunity to ascending infections is unclear. Therefore, we studied the effects of TCDD treatment on basal and Escherichia coli-stimulated cytokine production by placental explants. Cultures of second-trimester placentas were treated with up to 40 nM TCDD for 72 h and then stimulated with 10(7)CFU/ml E. coli for an additional 24h. Concentrations of cytokines and PGE2 were measured in conditioned medium by immunoassay. TCDD exposure increased mRNA levels of IL-1beta by unstimulated cultures, but no effects on protein levels of this cytokine were detected. TNF-alpha production was unaffected by TCDD for unstimulated cultures, but pre-treatment with 40 nM TCDD significantly increased E. coli-stimulated TNF alpha production. Both basal and bacteria-stimulated PGE2 and COX-2 gene expression were enhanced by TCDD pretreatment. In contrast, production of the anti-inflammatory cytokine, IL-10, was reduced by TCDD pretreatment for both unstimulated and E. coli-stimulated cultures. No effect of TCDD on the viability of the cultures was detected. These results suggest that TCDD exposure may shift immunity to enhance a proinflammatory phenotype at the maternal-fetal interface that could increase the risk of infection-mediated preterm birth. PMID- 23642496 TI - Size distribution of microbubbles as a function of shell composition. AB - The effect of modifying the shell composition of a population of microbubbles on their size demonstrated through experiment. Specifically, these variations include altering both the mole fraction and molecular weight of functionalized polymer, polyethylene glycol (PEG) in the microbubble phospholipid monolayer shell (1-15 mol% PEG, and 1000-5000 g/mole, respectively). The size distribution is measured with an unbiased image segmentation program written in MATLAB which identifies and sizes bubbles from micrographs. For a population of microbubbles with a shell composition of 5 mol% PEG2000, the mean diameter is 1.42 MUm with a variance of 0.244 MUm. For the remainder of the shell compositions studied herein, we find that the size distributions do not show a statistically significant correlation to either PEG molecular weight or mole fraction. All the measured distributions are nearly Gaussian in shape and have a monomodal peak. PMID- 23642497 TI - Maternal mental health is associated with child undernutrition and illness in Bangladesh, Vietnam and Ethiopia. AB - OBJECTIVE: We assessed associations of maternal common mental disorders (CMD) with undernutrition and two common illnesses in children aged 0-5 years. DESIGN: Cross-sectional survey. Maternal CMD was measured using the WHO Self-Reporting Questionnaire-20. Child undernutrition was defined as stunting, underweight or wasting. Child illnesses included diarrhoea and acute respiratory infections (ARI). Multivariate logistic regression was used to test these associations adjusting for confounders at child, maternal and household levels. SETTING: Bangladesh, Vietnam and Ethiopia. SUBJECTS: Mothers with children aged 0-5 years from 4400 households in Bangladesh, 4029 households in Vietnam and 3000 households in Ethiopia. RESULTS: The prevalence of maternal CMD was high, ranging from 31 % in Vietnam to 49 % in Bangladesh. Child undernutrition was more prevalent in Bangladesh and Ethiopia than in Vietnam. Symptoms of ARI and diarrhoea were also prevalent. In multivariate analysis, maternal CMD was associated with child stunting in Bangladesh (OR = 1.21; 95 % CI 1.03, 1.41) and with child underweight in Vietnam (OR = 1.27; 95 % CI 1.01, 1.61); no association was found with wasting. Maternal CMD was strongly associated with diarrhoea and ARI in all three countries. CONCLUSIONS: Maternal CMD, which affected nearly half of women in Bangladesh and one-third in Vietnam, was an important determinant of child stunting and underweight, respectively. No such association was found in Ethiopia, although CMD affected 39 % of women. Maternal CMD was strongly associated with childhood illnesses in all three countries. Interventions to support maternal mental health are important for women's own well-being and could make important contributions to improving child health and nutrition. PMID- 23642498 TI - Expression of estradiol receptor, GPR30, in bovine anterior pituitary and effects of GPR30 agonist on GnRH-induced LH secretion. AB - G-protein - coupled receptor 30 (GPR30) is an estradiol receptor located on the plasma membrane, and it initiates several rapid, non-genomic signaling events. GPR30 has recently been identified in rat anterior pituitary (AP); however, little is known about the role of GPR30 in controlling luteinizing hormone (LH) secretion from gonadotropes in animals. To fill this research gap, we hypothesized that GPR30 is expressed in bovine AP and mediates estradiol inhibition of gonadotropin-releasing hormone (GnRH)-induced LH release. We confirmed the expressions of GPR30 mRNA and protein by RT-PCR, western blotting, and immunohistochemistry. We cultured bovine AP cells (n=8) for 3 days in steroid free conditions and then treated them with increasing concentrations (0.001nM, 0.01nM, 0.1nM, 1nM, and 10nM) of estradiol or a GPR30-specific agonist, G1, for 5min before GnRH stimulation. As expected, estradiol at 0.001-0.1nM inhibited the GnRH-stimulated LH secretion. However, we found also that G1 at 0.001nM was able to inhibit this secretion (P<0.05). In contrast, both estradiol and G1 at higher doses were less efficient in suppressing the GnRH-stimulated LH secretion. Neither estradiol nor G1 suppressed GnRH-stimulated follicle-stimulating hormone secretion. In separate experiments, fluorescent immunohistochemistry and immunocytochemistry revealed that approximately 50% of GPR30-positive cells express LH, and about 30% of LH-positive cells express GPR30. In conclusion, GPR30 is expressed in bovine gonadotropes and other AP cells and may partially contribute to rapid negative estradiol feedback of GnRH-induced LH secretion. PMID- 23642499 TI - A comparative study of sperm morphometric subpopulations in cattle, goat, sheep and pigs using a computer-assisted fluorescence method (CASMA-F). AB - This study was designed to compare the sperm nuclear morphometric subpopulations of four species of domestic artiodactyls (cattle, sheep, goat and pigs). Samples from 20 males of each species were collected. After semen collection, sperm concentration and motility were measured and samples prepared for morphometric determinations. Smears were fixed with 2% glutaraldehyde, stained with Hoechst 33342 and photographed. At least 200 spermatozoa per sample were processed using the Image J analysis open software. Clustering procedures were performed to identify sperm subpopulations using the morphometric data obtained from each species. Results of the present study show that, applying the computer-assisted sperm morphometry analyisis-fluorescence (CASMA-F) technology and multivariate cluster analyses, it was possible to determine the subpopulations of spermatozoa with different morphometric characteristics in the four species studied. Bulls and boars had two clearly differentiated size categories: large and small. However, the final sperm subpopulations were four in the bull (large-round, large elongated, small-round, and small-elongated) and only three in the boar (large, small-elongated and small-round). In small ruminant species, three sperm nuclei size categories were established: large, average sized and small. Two of these subpopulations were also elongated in goat bucks, with three subpopulations (large-round, small-elongated and average size-elongated). In the ram three morphometric subpopulations were also obtained (large, small and average size round), but none was elongated. When comparing among species, sperm subpopulations were smaller in the buck and less elliptical and elongated in the ram than those in the other species studied. Male variability was identified in the distribution of sperm subpopulations described in the four species studied. It was concluded that the combination of CASMA-F technology with multivariate cluster analyses allow the study of morphometric sperm subpopulations and that there are important variations in the subpopulations among the four species studied. PMID- 23642500 TI - Ultrastructure of spermatozoa of the Atlantic cod Gadus morhua L. observed by scanning and transmission electron microscopy. AB - The present study on wild caught Atlantic cod Gadus morhua provides a detailed description of the spermatozoa ultrastructure. The spermatozoa of G. morhua are composed of a head (nucleus) with no acrosome, a midpiece and a single flagellum. The total length is 67.69+/-6.33MUm with a lanceolate sperm head that is 2.34+/ 0.26MUm long and 1.32+/-0.26MUm wide. The nucleus presents homogeneous condensation of chromatin with few lacunae of decondensed chromatin. The nuclear fossa penetrates over three third of the nuclear axis and is tubiform. The axoneme is composed of a typical 9+2 microtubular doublet structure and is enclosed by the plasma membrane. Central microtubules are absent from the proximal portion of the anterior end of nuclear notch and a distal centriole complex is perpendicular to the axoneme. A group of mitochondria and vesicles is present in the midpiece. The ultrastructure of the Gadidae G. morhua spermatozoon differs from the structures described earlier for other Gadiformes. The unique features may be synapomorphic for marine Gadidae, and may contribute to the study of phylogenetic relationships in teleost fishes, and be a reference for future studies on spermatozoon quality and morphology in fish. PMID- 23642501 TI - Sex differentiation with regard to coronary artery disease. AB - Coronary artery disease was considered a male disease for many years. However, nowadays, coronary artery disease constitutes the leading cause of death in women, although there are a lot of gender-related differences regarding the presentation of acute myocardial infarction, its diagnosis, its treatment, short- and long-term mortality rates, and post-acute myocardial infarction complications. Generally, women have smaller and stiffer hearts and cardiac vessels, suffering a greater extent of atherosclerosis and endothelial and smooth muscle dysfunction. They are usually older than men and they have more comorbidities such as hypertension, renal impairment, and diabetes mellitus. Moreover, female coronary artery disease, the diagnosis of which is more complicated due to more false negative results of some diagnostic methods in women, is more often presented with atypical symptoms and women's symptoms of typical or atypical angina are more severe. Furthermore, women delay significantly more in seeking care and they are more frequently undertreated. Finally, women are associated with generally poorer in-hospital and long-term prognosis having almost two-fold higher early mortality and they are more prone to complications such as bleeding complications, shock, and heart failure, as well as to post-myocardial infarction depression and poorer physical function and mental health. In this review, we discuss these sex-related differences according to current literature. PMID- 23642502 TI - Clinical outcomes after treating acute coronary syndrome patients with a drug eluting stent: results from REWARDS-EMI (Endeavor for Myocardial Infarction Registry). AB - BACKGROUND: Drug-eluting stents have shown promising clinical results in the treatment of acute coronary syndrome (ACS) patients. We aimed to evaluate the long-term outcome of Endeavor zotarolimus-eluting stent (EZES) implantation in an ACS population and to compare these results with those obtained in patients treated with sirolimus-eluting (SES) and paclitaxel-eluting stents (PES). METHODS: This prospective study included 1481 consecutive ACS patients (72% myocardial infarction, age 65 +/- 13 years, 62% male) treated with a drug-eluting stent: (SES, n=925; PES, n=417; EZES, n=139). The primary end point was major adverse cardiac events (MACE) at 2 years, defined as the composite of death, myocardial infarction, and target vessel revascularization. Two-year follow-up was obtained in all patients. RESULTS: Baseline clinical and angiographic characteristics were mostly similar. Unadjusted 2-year MACE and death rates were lower in the EZES group than in the SES and PES groups (MACE: 18.7% vs. 25.3% vs. 30.2%, p=0.02; death: 10.1% vs. 16.4% vs. 22.2%, p=0.002, respectively). The rate of definite stent thrombosis at 2 years was lower in the EZES group without statistically significant difference (0.7% vs. 2.9% SES vs. 1.7% PES, p=0.16). After adjusting for differences in baseline characteristics, EZES use was an independent correlate for 2-year MACE (vs. SES, hazard ratio 0.65, p=0.049; vs. PES, hazard ratio 0.57, p=0.01). CONCLUSION: In an ACS patient population, a lower long-term MACE rate was observed in patients treated with an EZES when compared to treatment with first-generation drug-eluting stents. The use of EZES in contemporary practice has excellent long-term outcome in terms of low rates of revascularization and clinical events. PMID- 23642503 TI - [DVT and combined oral contraceptives: update of the pluridisciplinary CNGOF FNCGM-GEHT-SFMV group]. AB - Thrombotic risk among combined oral contraceptives (COC) users has recently been debated following a court action initiated by a patient. Recent epidemiological data, as well as accumulating biological data underlying these data, have led French Health authorities to modify COC prescription and reimbursement modalities. A short synthesis is proposed by a multidisciplinary group of experts from four French societies (CGOF, FNCGM, GHT, and SFMV). PMID- 23642504 TI - RAPPER: the radiogenomics of radiation toxicity. PMID- 23642505 TI - Comparison of functional recovery following percutaneous coronary intervention for ST elevation myocardial infarction in three age groups (<70, 70 to 79, and >=80 years). AB - Functional outcomes of elderly patients >=80 years who undergo percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI) are unknown. Registry data indicate that up to 55% of elderly patients with STEMI do not receive reperfusion therapy despite a suggested mortality benefit, and only limited data are available regarding outcomes in elderly patients treated with primary PCI. Therefore, prospective data from a regional STEMI transfer program were analyzed to determine major adverse cardiac events, length of stay, and discharge status of consecutive patients with STEMI >=80 years from March 2003 to November 2006. Of the 1,323 consecutive patients with STEMI treated in this regional STEMI system from March 2003 to November 2006, 199 (15.0%) were >=80 years old. In-hospital mortality in elderly patients was 11.6%, with a 1-year mortality rate of 25.6%. Of the 166 patients with age >=80 who lived independently or in assisted living before hospital admission and survived, 150 (90.4%) were discharged to a similar living situation or projected to such a living situation after temporary nursing home care. The median length of hospital stay was 4 days for these patients. In conclusion, elderly patients with age >=80 receiving PCI for STEMI in a regional STEMI program have short hospital stays and excellent functional recovery on the basis of a very high rate of return to a similar previous living situation. PMID- 23642506 TI - Comparison of lipid deposition at coronary bifurcations versus at nonbifurcation portions of coronary arteries as determined by near-infrared spectroscopy. AB - Atherosclerosis has been shown to develop preferentially at sites of coronary bifurcation, yet culprit lesions resulting in ST-elevation myocardial infarction do not occur more frequently at these sites. We hypothesized that these findings can be explained by similarities in intracoronary lipid and that lipid and lipid core plaque would be found with similar frequency in coronary bifurcation and nonbifurcation segments. One hundred seventy bifurcations were identified, 156 of which had comparative nonbifurcation segments proximal and/or distal to the bifurcation. We compared lipid deposition at bifurcation and nonbifurcation segments in coronary arteries using near-infrared spectroscopy (NIRS), a novel method for the in vivo detection of coronary lipid. Any NIRS signal for the presence of lipid was found with similar frequency in bifurcation and nonbifurcation segments (79% vs 74%, p = NS). Lipid core burden index, a measure of total lipid quantity indexed to segment length, was similar across bifurcation segments as well as their proximal and distal controls (lipid core burden index 66.3 +/- 106, 67.1 +/- 116, and 66.6 +/- 104, p = NS). Lipid core plaque, identified as a high-intensity focal NIRS signal, was found in 21% of bifurcation segments, and 20% of distal nonbifurcation segments (p = NS). In conclusion, coronary bifurcations do not appear to have higher levels of intracoronary lipid or lipid core plaque than their comparative nonbifurcation regions. PMID- 23642507 TI - Risk factors for profuse systemic-to-pulmonary artery collateral burden in hypoplastic left heart syndrome. AB - Risk factors for developing systemic-to-pulmonary artery collaterals (SPCs) in hypoplastic left heart syndrome (HLHS) are unknown. We performed a retrospective case-control study to identify risk factors for developing a profuse SPC burden in HLHS. Angiograms of 439 patients with HLHS (performed <2 years of age) were reviewed using a previously published angiographic grading scale to identify cases (profuse SPC burden, n = 20) and controls (no or minimal SPC burden, n = 35). In univariate analyses, profuse SPC burden was associated with mitral atresia and aortic atresia subtype (MA/AA) (65% vs 14%, p <0.0001), use of a Sano shunt (70% vs 37%, p = 0.03), longer log-transformed durations of intensive care unit stay (p = 0.02), hospital stay (p = 0.002), pleural drainage (p = 0.008) after stage 1 palliation, lower oxygen saturation at discharge after stage 1 palliation (82 +/- 4 vs 85 +/- 4%, p = 0.03), and a history of severe shunt obstruction (37% vs 11%, p = 0.04). In a multivariate logistic regression model, profuse SPC burden was associated with MA/AA subtype (odds ratio 6.6), Sano shunt type (odds ratio 8.6), and log-transformed duration of hospital stay after stage 1 (odds ratio 7.9, model p <0.0001, area under the curve 0.88). Nonassociated parameters included fetal aortic valve dilation, severe cyanotic episodes, number of days with open sternum or number of additional exploratory thoracotomies after stage 1 palliation, pulmonary vein stenosis, and restrictive atrial septal defect. In conclusion, in the present case-control study of patients with HLHS, the development of a profuse SPC burden was associated with MA/AA subtype, Sano shunt type, and longer duration of hospital stay after stage 1 palliation. PMID- 23642508 TI - EuroSCORE II versus additive and logistic EuroSCORE in patients undergoing percutaneous coronary intervention. AB - The aim of the present study was to externally validate the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II (ESII) in patients undergoing percutaneous coronary intervention (PCI) and to compare its performance with that of its previously released versions, named additive (addES) and logistic EuroSCORE (logES). A total of 537 patients undergoing PCI were analyzed by different measurements of discrimination, calibration, and global accuracy. A significant gradient in all-cause mortality was seen with all the models at 30 days, 1 year, and 5 years, with the exception of the ESII at 30 days. The ESII had the lowest area under the receiver operating characteristic curve at all time points compared with its previous version, being 0.83 (vs 0.90 for both addES and logES) at 30 days, 0.75 (vs 0.82 for both addES and logES) at 1 year, and 0.69 (vs 0.77 for addES and 0.76 for logES) at 5 years. However, the ESII displayed a better calibration than the logES at 30 days, whereas both scores were miscalibrated at 1 and 5 years. The Brier score displayed similar global accuracy between the ESII and logES. In conclusion, the ESII is better calibrated than the logES at 30 days but does not represent a step forward in discrimination and global accuracy compared with its previous versions for predicting early- and long-term mortality of patients undergoing PCI. PMID- 23642510 TI - Usefulness of QRS axis change to predict mortality in patients with left bundle branch block. AB - QRS duration correlates with poor prognosis in patients with left bundle branch block (LBBB), but the importance of left-axis deviation (LAD) is not well established. To determine if LAD confers a mortality risk in patients with LBBB, a single-center, retrospective, population-based cohort study was conducted. Included were all patients at 1 hospital with LBBB on electrocardiography from 1995 to 2005 over a 17-year follow-up period (n = 2,794, median follow-up duration 20 months, interquartile range 6 to 64). Half of all patients with LBBB had LAD. The all-cause mortality rate in the entire cohort was 15%. LAD was not associated with mortality, either as a single outcome (odds ratio [OR] 1.1, 95% confidence interval [CI] 0.88 to 1.3, p = 0.50) or in time-to-event analysis (p = 0.40). Significant risk factors for mortality included high creatinine (OR 1.2, 95% CI 1.1 to 1.3), low hemoglobin (OR 1.2, 95% CI 1.1 to 1.3), history of atrial fibrillation (OR 1.6, 95% CI 1.3 to 2.1), electrocardiographic evidence of previous infarct (OR 1.5, 95% CI 1.2 to 1.9), and history of ventricular tachycardia (OR 1.4, 95% CI 1.0 to 1.9). On bivariate analysis, LAD was associated with atrial fibrillation, ventricular tachycardia, age, and congestive heart failure. Patients with LBBB who converted from normal axis to LAD had significantly higher mortality in time-to-event analysis (p = 0.02). In conclusion, in patients with LBBB, LAD does not confer significant mortality risk. However, those with normal axis who developed LAD during the study period had significantly higher mortality. Perhaps when LBBB and LAD develop concurrently, there is no increased risk over baseline LBBB development, but it may herald a worse prognosis if LAD develops against the background of previous LBBB, from an unknown mechanism. PMID- 23642509 TI - Relation of outbursts of anger and risk of acute myocardial infarction. AB - The aim of the present study was to explore the association between outbursts of anger and acute myocardial infarction (AMI) risk. Outbursts of anger are associated with an abrupt increase in cardiovascular events; however, it remains unknown whether greater levels of anger intensity are associated with greater levels of AMI risk or whether potentially modifiable factors can mitigate the short-term risk of AMI. We conducted a case-crossover analysis of 3,886 participants from the multicenter Determinants of Myocardial Infarction Onset Study, who were interviewed during the index hospitalization for AMI from 1989 to 1996. We compared the observed number and intensity of anger outbursts in the 2 hours preceding AMI symptom onset with its expected frequency according to each patient's control information, defined as the number of anger outbursts in the previous year. Of the 3,886 participants in the Determinants of Myocardial Infarction Onset Study, 1,484 (38%) reported outbursts of anger in the previous year. The incidence rate of AMI onset was elevated 2.43-fold (95% confidence interval 2.01 to 2.90) within 2 hours of an outburst of anger. The association was consistently stronger with increasing anger intensities (p trend <0.001). In conclusion, the risk of experiencing AMI was more than twofold greater after outbursts of anger compared with at other times, and greater intensities of anger were associated with greater relative risks. Compared with nonusers, regular beta blocker users had a lower susceptibility to heart attacks triggered by anger, suggesting that some drugs might lower the risk from each anger episode. PMID- 23642511 TI - Left ventricular function by echocardiography, tissue Doppler imaging, and carotid intima-media thickness in obese adolescents with nonalcoholic fatty liver disease. AB - The aims of this study were to evaluate left ventricular (LV) systolic and diastolic function in obese adolescents with nonalcoholic fatty liver disease (NAFLD) using conventional echocardiography and pulsed-wave tissue Doppler imaging and to investigate the relations between LV function and carotid intima media thickness (CIMT). LV remodeling, tissue Doppler-derived LV velocities, and cardiovascular risk profiles in obese adolescents with NAFLD were also studied. One hundred eighty obese adolescents and 68 healthy controls were enrolled in the study. LV end-diastolic and end-systolic and left atrial diameters and LV mass were higher in the 2 obese groups compared with controls. By pulsed-wave Doppler echocardiography and pulsed-wave tissue Doppler imaging, the NAFLD group had normal LV systolic function, impaired diastolic function, and altered global systolic and diastolic myocardial performance. In patients with NAFLD, LV mass was positively correlated with homeostasis model assessment of insulin resistance and serum alanine aminotransferase. CIMT was positively correlated with homeostasis model assessment of insulin resistance, alanine aminotransferase, and LV mass. By multiple stepwise regression analysis, alanine aminotransferase (beta = 0.124, p = 0.026), homeostasis model assessment of insulin resistance (beta = 0.243, p = 0.0001), LV mass (beta = 0.874, p = 0.0001) were independent parameters associated with increased CIMT. In conclusion, insulin resistance has a significant independent impact on CIMT and LV remodeling in the absence of diabetes in patients with NAFLD. Pulsed-wave tissue Doppler imaging is suggested to detect LV dysfunction at an earlier stage in obese adolescents with NAFLD for careful monitoring of cardiovascular risk. PMID- 23642512 TI - Comparison of first- and second-generation drug-eluting stents in saphenous vein grafts used as aorto-coronary conduits. AB - Saphenous vein grafts (SVGs) are prone to an aggressive atherosclerotic process, and the efficacy of drug-eluting stents (DES) in treating this is still debated. In recent years, second-generation DES have been increasingly used in SVG intervention. The main objective of this study was to compare midterm clinical outcomes between first- and second-generation DES in SVGs because data regarding the use of second-generation DES in SVG are lacking. Patients treated with first generation DES (127 patients with 143 lesions) and those treated with second generation DES (84 patients with 100 lesions) were included in the study. Major adverse cardiac events, defined as the composite of all-cause death, myocardial infarction, and target vessel revascularization, as well as target vessel revascularization and target lesion revascularization separately, were evaluated at 30-day, 12-month, and 18-month follow-up. Baseline characteristics were similar between the 2 groups. Older grafts were treated with second-generation DES (11.6 +/- 5.3 vs 14.3 +/- 6.0 years, p = 0.001). Stent length was longer in the first-generation group (34.1 +/- 25.1 vs 30.5 +/- 19.4 mm, p = 0.006), and maximum balloon diameter was smaller in the second-generation group (3.42 +/- 0.42 vs 3.30 +/- 0.41 mm, p = 0.003). Embolic protection device use was higher in the second-generation DES group (55.2% vs 72.0%, p = 0.012). At 18-month follow up, rates of major adverse cardiac events, target vessel revascularization, and target lesion revascularization for the first- and second-generation groups were 24.4% versus 20.2% (p = 0.479), 18.1% versus 14.2% (p = 0.465), and 15.0% versus 10.7% (p = 0.373), respectively. In conclusion, second-generation DES are at least comparable with first-generation DES with regard to clinical outcomes at midterm follow-up. PMID- 23642513 TI - Residual dyslipidemia among United States adults treated with lipid modifying therapy (data from National Health and Nutrition Examination Survey 2009-2010). AB - Despite available medications for dyslipidemia, many treated patients still have suboptimal lipid levels. The aim of this study was to examine the extent of residual dyslipidemia in United States adults. Of 2509 United States adults aged >=18 years from the National Health and Nutrition Examination Survey (NHANES) 2009-2010, 1,129 (41.8% weighted) had hyperlipidemia on the basis of modified treatment guidelines for low-density lipoprotein (LDL) cholesterol according to risk category or pharmacologic treatment. Of these, 484 (42.4%) were treated with lipid-modifying therapy, and the proportions of subjects who still had LDL cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, or non HDL cholesterol not at recommended levels were examined. In this cohort treated for hyperlipidemia, the mean age was 60.1 +/- 14.9 years, and 52% were men. Only 36.5% of subjects receiving treatment for hyperlipidemia were at goal or normal levels for all 3 lipids (LDL cholesterol, HDL cholesterol, and triglycerides). LDL cholesterol remained higher than goal for 37.5% of subjects, 28.9% had low HDL cholesterol, and 36.3% had elevated triglycerides. One, 2, and 3 lipid parameters were at abnormal levels in 32.4%, 23.0%, and 8.2% of subjects, respectively; 36.5% had no lipid disorder. In addition, 38.6% of treated subjects were above non-HDL cholesterol goal, and even in those at LDL cholesterol goal, 12.9% were not at non-HDL cholesterol goal. Those with cardiovascular disease conditions had poorer goal attainment of LDL cholesterol, HDL cholesterol, and composite all lipids than those without cardiovascular disease. In conclusion, despite widely available treatments for dyslipidemia, many patients remain at suboptimal lipid levels, indicating need for greater adherence to lifestyle and medical therapies to address these gaps in the management of dyslipidemia. PMID- 23642514 TI - Pathophysiology of proliferative vitreoretinopathy in retinal detachment. AB - Because proliferative vitreoretinopathy cannot be effectively treated, its prevention is indispensable for the success of surgery for retinal detachment. The elaboration of preventive and therapeutic strategies depends upon the identification of patients who are genetically predisposed to develop the disease, as well as upon an understanding of the biological process involved and the role of local factors, such as the status of the uveovascular barrier. Detachment of the retina or vitreous activates glia to release cytokines and ATP, which not only protect the neuroretina but also promote inflammation, retinal ischemia, cell proliferation, and tissue remodeling. The vitreal microenvironment favors cellular de-differentiation and proliferation of cells with nonspecific nutritional requirements. This may render a pharmacological inhibition of their growth difficult without causing damage to the pharmacologically vulnerable neuroretina. Moreover, reattachment of the retina relies upon the local induction of a controlled wound-healing response involving macrophages and proliferating glia. Hence, the functional outcome of proliferative vitreoretinopathy will be determined by the equilibrium established between protective and destructive repair mechanisms, which will be influenced by the location and the degree of damage to the photoreceptor cells that is induced by peri-retinal gliosis. PMID- 23642515 TI - Fatigue of the hip abductors results in increased medial-lateral center of pressure excursion and altered peroneus longus activation during a unipedal landing task. AB - BACKGROUND: Previous studies have reported that diminished hip abductor muscle strength is associated with a loss of frontal plane postural stability and increased risk for ankle sprain. The purpose of this study was to determine whether hip abductor fatigue results in compensatory changes in neuromuscular activation of the peroneus longus (an important lateral stabilizer of the ankle) during a unipedal landing task. METHODS: Thirty healthy females performed a unipedal landing task before and after completing a hip abductor fatigue protocol. Paired t-tests were used to assess changes in medial-lateral center of pressure displacement, and EMG (electromyographic) amplitude of the peroneus longus following hip abductor fatigue. Changes in peroneus longus onset timing also were assessed. FINDINGS: Following the hip abductor fatigue protocol, participants exhibited increased mean center of pressure displacement (7.7 (1.5) vs. 9.2 (2.0) cm, P<0.01), and increased EMG amplitude of peroneus longus (0.75 (0.18) vs. 0.86 (0.21), P<0.01) during the deceleration phase of landing. Post fatigue, significantly earlier peroneus longus onset timing prior to landing was observed (88.9 (24.9) vs. 121.9 (25.7) ms, P<0.01). INTERPRETATION: The increased EMG amplitude and earlier onset of the peroneus longus appears to be a protective compensatory adaptation to stabilize the ankle in response to frontal plane postural instability induced by hip abductor fatigue. PMID- 23642519 TI - Re. "Great saphenous vein diameter at the saphenofemoral junction and proximal thigh as parameters of venous disease class". PMID- 23642520 TI - Re. 'Re. 'Cost-effectiveness of vascular access for haemodialyis: arteriovenous fistulas versus arteriovenous grafts". PMID- 23642522 TI - Re. 'Cost-effectiveness of vascular access for haemodialyis: arteriovenous fistulas versus arteriovenous grafts'. PMID- 23642521 TI - Outcome of ischemic foot ulcer in diabetic patients who had no invasive vascular intervention. AB - OBJECTIVE/BACKGROUND: There is limited information regarding outcome in patients not available for revascularisation. Our aim was to identify factors related to ulcer healing in diabetic patients with severe peripheral arterial disease who were not available for revascularisation. METHODS: Diabetic patients with a foot ulcer, consecutively presenting at a multidisciplinary foot centre with systolic toe pressure <45 mmHg or an ankle pressure <80 mmHg were prospectively included. Patients who received revascularisation were excluded. All patients had continuous follow-up until healing or death. RESULTS: Out of 602 patients (median age: 76 years) included in this study, 50% healed either primarily (76%) or with a minor amputation (24%). Seventeen percent of patients healed after major amputation and 33% died unhealed. By regression analysis, rest pain, impaired renal function, ischemic heart disease, cerebral vascular disease, extent of tissue destruction, and ankle pressure >50 mmHg affected the outcome of the ulcers. CONCLUSION: Diabetic patients with ischemic foot ulcers not available for revascularisations are not excluded from healing without major amputation. Factors strongly related to outcome were co-morbidity, severity of peripheral arterial disease, and extent of tissue destruction. Our findings reinforce the need for a classification system considering these factors at decision-making for vascular intervention. PMID- 23642523 TI - Fenestrated stent-grafts for salvage of prior endovascular abdominal aortic aneurysm repair. AB - OBJECTIVES: To review our experience with fenestrated endovascular aneurysm repair (F-EVAR) to treat complications after previous standard infrarenal endovascular aneurysm repair (EVAR). METHODS: A prospectively maintained database including all consecutive patients with juxtarenal abdominal aortic aneurysm that were treated with F-EVAR after failed previous EVAR within the period March 2002 to November 2012 at the University Medical Center of Groningen, Netherlands (up to October 2009), and the Klinikum Nurnberg Sud, Germany (from November 2009) was analyzed. Evaluated outcomes included initial technical success, operative mortality and morbidity, and late procedure-related events with regard to survival, target vessel patency, endoleak, renal function, and reintervention. RESULTS: A total of 26 patients (24 male, mean age 73.2 +/- 6.5 years) were treated. All patients had proximal anatomies precluding endovascular reintervention with standard techniques. In 23 patients a fenestrated proximal cuff was used, and in three patients a bifurcated fenestrated stent graft. Technical success was achieved in 24 (92.3%) patients. One patient required on table open conversion because of impossibility to retrieve the top cap as a result of twist of the ipsilateral limb. In the second patient the right kidney was lost due to inadvertent stenting in a smaller branch of the renal artery. Catheterization difficulties, all related to the passage through the limbs or struts of the previous stent graft, were encountered in 11 (42.3%) cases, including five (19.2%) patients with iliac access problems and six (23.1%) with challenging renal catheterization. Operative target vessel perfusion success rate was 94.6% (70/74). Operative mortality was 0%. Mean follow-up was 26.8 +/- 28.5 months. No proximal type I endoleak was present on first postoperative CTA. The mean aneurysm maximal diameter decreased from 73 +/- 20 mm to 66.7 +/- 21 mm (p < .05). There were six late deaths, one of them aneurysm related. Estimated survival rates at 1 and 2 years were 94.1 +/- 5.7% and 87.4 +/- 8.4%, respectively. Patency during follow-up for the target vessels treated successfully with a fenestrated stent graft was 100% (70/70). Reintervention was required in four cases, including one acute conversion due to rupture, one for iliac limb occlusion and two for type Ib and II endoleak. Renal function deterioration was observed solely in the two cases of primary technical failure. CONCLUSIONS: F-EVAR represents a feasible option for the repair of juxtarenal abdominal aortic aneurysm after prior EVAR failure. It is advantageous in terms of mortality and less morbid than open surgery, but is associated with increased technical challenges because of the previously placed stent graft. Outcome seems related to initial technical success. PMID- 23642524 TI - Evaluation of automated 2D-3D image overlay system utilizing subtraction of bone marrow image for EVAR: feasibility study. AB - OBJECTIVE: To evaluate the automated 2D-3D image overlay system ("3D Roadmap") for use during endovascular aneurysm repair (EVAR) in the hybrid operating theater. METHODS: Datasets of preoperative CT images were modified to subtract dense bone marrow to improve the visualization of vasculature on the overlaid image, and allow for accurate navigation of the endovascular devices. The 3D-CT overlay image was registered on the 2D fluoroscopy image to mark the iliac crest and lumbar vertebrae on both images as landmarks. RESULTS: Arteriography was performed only twice to confirm the precision of the position of renal artery and the final evaluation. Twenty patients underwent EVAR with Medtronic Endurant, Gore Excluder, or COOK Zenith using "3D Roadmap". The origin of the renal artery and iliac bifurcation were registered with complete accuracy in 10 patients (50%). The lower renal artery deviated toward the cranial side less than 3 mm in six patients. In all cases, EVAR was successful, and completed with the volume of contrast material limited to 43.8 +/- 3.1 mL. CONCLUSION: "3D Roadmap" was confirmed to be valuable for visualization of vessel origin in a fused image and for reduction of contrast material during EVAR. PMID- 23642525 TI - The long arm of parental addictions: the association with adult children's depression in a population-based study. AB - Parental addictions have been associated with adult children's depression in several clinical and population-based studies. However, these studies have not examined if gender differences exist nor have they controlled for a range of potential explanatory factors. Using a regionally representative sample of 6268 adults from the 2005 Canadian Community Health Survey (response rate=83%), we investigated the association between parental addictions and adulthood depression controlling for four clusters of variables: adverse childhood experiences, adult health behaviors, adult socioeconomic status and other stressors. After controlling for all factors, adults exposed to parental addiction had 69% higher odds of depression compared to their peers with non-addicted parents (OR=1.69; 95% CI, 1.25-2.28). The relationship between parental addictions and depression did not vary by gender. These findings underscore the intergenerational consequences of drug and alcohol addiction and reinforce the need to develop interventions that support healthy childhood development. PMID- 23642526 TI - Phase II open-label study of bevacizumab combined with neoadjuvant anthracycline and taxane therapy for locally advanced breast cancer. AB - BACKGROUND: Neoadjuvant anthracycline- and taxane-based chemotherapy is frequently administered in breast cancer. Pathological complete response (pCR) rates vary according to clinical disease stage and biology of breast cancer. The critical role of angiogenesis in the progression of breast cancer, together with significantly improved efficacy when bevacizumab is combined with chemotherapy in the metastatic setting, provides a strong rationale for evaluating the integration of bevacizumab into neoadjuvant chemotherapy regimens. METHODS: A single-arm, multicentre, phase II, open-label study evaluated four 3-weekly cycles of FEC (5-fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2)) followed by 12 cycles of weekly paclitaxel (80 mg/m(2)) in combination with bevacizumab 10 mg/kg every 2 weeks as neoadjuvant therapy for HER2-negative stage III locally advanced or inflammatory breast carcinoma. The primary endpoint was pCR rate. RESULTS: Planned treatment was completed in 49 of the 56 enrolled patients. In the intent-to-treat population, the pCR rate was 21% and the clinical response rate was 59%. Breast-conserving surgery was achieved in 34% of patients. In the subgroup of 15 patients with triple-negative disease, the pCR rate was 47%. Grade 3 adverse events in >=5% of patients were neutropenia, leucopenia, asthenia, and rash. One case each of hypertensive retinopathy and post-operative wound complication, both after treatment completion, were considered probably related to bevacizumab. There were no treatment-related deaths and no cardiac function abnormalities. CONCLUSIONS: This study indicates that FEC followed by weekly paclitaxel with bevacizumab is an active neoadjuvant regimen for locally advanced breast cancer, with no major safety concerns. CLINICAL TRIAL REGISTRATION: NCT00559845. PMID- 23642527 TI - Are bilateral breast cancers different from breast cancers coexisting with ovarian cancer? An immunohistochemical analysis aimed at intrinsic tumor phenotype. AB - RATIONALE: Bilateral breast cancers (BBC) and breast cancers coexisting with ovarian cancer (BOCS) are associated with genetic predisposition more frequently than sporadic cases. We compared the phenotypes of these tumors to better understand their pathomechanisms and aid the guiding of their clinical management. MATERIALS AND METHODS: Tumor morphology and expression of ER, PgR, HER2, Ki67, CK5/6, E-cadherin, vimentin and EGFR were assessed in a tissue microarray containing cores from 174 BBC, 23 BOCS and 2 BBC + BOCS. RESULTS: BOCS tumors were characterized by higher incidence of EGFR expression, HER2 negativity and lower incidence of intraductal component. HER2-positive phenotypes were marginally more frequent in the BBC group and triple negative tumors - in BOCS. CONCLUSION: Breast cancers from BOCS patients are characterized by more aggressive phenotype, most probably related to their more frequent association with BRCA1 mutation. PMID- 23642528 TI - "The Infinite Maze" of breast cancer, signaling pathways and radioresistance. AB - The parallel growth in our understanding of tumor biology and genetics might be the key to understanding local recurrence after optimal treatment is applied. Data suggest that genetic alterations and breast cancer molecular subtypes have an effect on radiotherapy efficacy and that the HER2, EGFR/PI3K/Akt signaling pathways play a pivotal role in modulation of post-irradiation survival. These pathways have been found to be involved in radiosensitivity and/or radioresistance, tumor cell proliferation, and hypoxia. Therefore, affecting the functional activity of key players combined with radiotherapy might be the future of breast irradiation. PMID- 23642529 TI - Locoregional recurrence in patients with HER2 positive breast cancer. AB - Literature shows that HER2/neu positive breast cancer cells are more sensitive to radiation-induced apoptosis by targeting the epidermal growth factor receptor family tyrosine kinase. We selected 466 patients with pT1-2 HER2/neu positive tumors who received adjuvant trastuzumab for primary invasive breast cancer. Patients were divided into three groups [Quadrantectomy followed by conventional radiotherapy vs Quadrantectomy followed by Intra-operative radiotherapy with electrons vs Mastectomy without radiotherapy]. After a median follow-up of 52 months, the 5-year cumulative incidence of locoregional recurrence (LRR) was 1.9%, 11.5% and 5.0% respectively (p < 0.01). At the multivariate analysis, extensive perivascular invasion, Luminal B HER2/Progesterone Receptor (PgR) negative status and Quadrantectomy followed by Intra-operative radiotherapy with electrons have significantly increased the risk of LRR. Our results suggest that HER2/neu positive breast cancer might have better outcomes when treated simultaneously with external radiotherapy and trastuzumab. Moreover, we underline the importance of PgR and further new stratification of risk among luminal subtypes. PMID- 23642530 TI - Percutaneous temporary aortic valve: a hemodynamic support system for acute aortic insufficiency. AB - A percutaneous temporary aortic valve hemodynamic support catheter is a device that can conceptually maintain stable hemodynamics when significant structural damage occurs to the native aortic valve ensuing acute severe aortic insufficiency. Applications may include a bridge to surgery in active aortic valve endocarditis and an option to allow for diseased valve resection prior to transcatheter aortic valve replacement. An early prototype has undergone successful fundamental mathematical, bench and animal proof-of-concept studies. Design, concept and early data are presented and discussed. PMID- 23642532 TI - The effects of crosslinking of scaffolds engineered from cartilage ECM on the chondrogenic differentiation of MSCs. AB - Scaffolds fabricated from cartilage extracellular matrix provide a chondroinductive environment that stimulates cartilaginous matrix synthesis in a variety of cell types. A limitation of these cartilage-derived matrix (CDM) scaffolds is that they contract during in vitro culture, which unpredictably alters their shape. The current study examined the hypothesis that collagen crosslinking techniques could inhibit cell-mediated contraction of CDM scaffolds. We analyzed the effects of dehydrothermal (DHT) treatment, ultraviolet light irradiation (UV), and the chemical crosslinker carbodiimide (CAR) on scaffold contraction and chondrogenic differentiation of adult human bone marrow-derived stem cells (MSCs). Both physical and chemical crosslinking treatments retained the original scaffold dimensions. DHT and UV treatments produced significantly higher glycosaminoglycan and collagen contents than CAR crosslinked and non crosslinked constructs. Crosslinking treatments influenced the composition of newly synthesized matrix, and DHT treatment best matched the composition of native cartilage. DHT, UV, and non-crosslinked CDM films supported cell attachment, while CAR crosslinking inhibited cell adhesion. These results affirm that collagen crosslinking treatments can prevent cell-mediated contraction of CDM scaffolds. Interestingly, crosslinking treatments influence chondrogenic differentiation. These effects seem to be mediated by modifications to cell matrix interactions between MSCs and the CDM; however, further work is necessary to elucidate the specific mechanisms involved in this process. PMID- 23642533 TI - Multiscale analysis of collagen microstructure with generalized image correlation spectroscopy and the detection of tissue prestress. AB - Prestress in tissue is currently detected through destructive methods which obviate both in vivo and longitudinal assessment. We hypothesized that prestress could be detected and quantified by analyzing the microstructure of the extracellular matrix at different spatial scales using non-invasive and non destructive optical imaging. A simple model of tissue prestress was created using fibroblast-mediated contraction of collagen gels around a central mandrel. Using a quantitative, multiscale, image processing technique, termed generalized image correlation spectroscopy (GICS) of second harmonic images, collagen fiber number and alignment at three different length scales characteristic of the collagen fibril, collagen fiber, and cell were analyzed. GICS fiber alignment (sigma(maj/min)) was significantly different across load state, level of prestress, and length scale. The largest fiber ratio, and thus highest alignment, was seen in prestressed, externally loaded gels at a length scale equivalent to the size of the fibroblast cells. Alignment at both fiber and cell scale correlated with prestress in this model. We conclude that GICS of second harmonic images of collagen can predict prestress, and that microstructural organization at the collagen fiber and cell scale are the primary determinants of prestress in cellularized collagen gels. PMID- 23642534 TI - The margination propensity of ellipsoidal micro/nanoparticles to the endothelium in human blood flow. AB - Particle shape is becoming increasingly recognized as an important parameter for the development of vascular-targeted carriers (VTCs) for disease treatment and diagnosis. However, limited research exists that investigates how particle shape coupled with hemodynamics affects VTC margination (localization and adhesion). In this study, we investigate the effects of particle shape parameters (volume, aspect ratio, axis length) on the margination efficacy of targeted spheres and prolate ellipsoids (rods) to an inflamed endothelial wall from human blood flow in an in vitro model of human vasculature. Overall, particles with 2 MUm equivalent spherical diameters (ESD) display higher margination than particles with either 1 MUm or 500 nm ESDs. Interestingly, rod-shaped microparticles (1 MUm or 2 MUm ESD) with high aspect ratios display significantly improved margination compared to spheres of equal volume, particularly under high shear rates and disturbed flow profiles. Nanorods (500 nm ESD), even with high aspect ratio, do not display enhanced margination compared to that of equivalent spheres, which suggests that nanorods, like nanospheres, display minimal margination due to their inability to effectively localize to the vessel wall in the presence of RBCs. PMID- 23642535 TI - Tissue-engineered cardiac patch for advanced functional maturation of human ESC derived cardiomyocytes. AB - Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) provide a promising source for cell therapy and drug screening. Several high-yield protocols exist for hESC-CM production; however, methods to significantly advance hESC-CM maturation are still lacking. Building on our previous experience with mouse ESC CMs, we investigated the effects of 3-dimensional (3D) tissue-engineered culture environment and cardiomyocyte purity on structural and functional maturation of hESC-CMs. 2D monolayer and 3D fibrin-based cardiac patch cultures were generated using dissociated cells from differentiated Hes2 embryoid bodies containing varying percentage (48-90%) of CD172a (SIRPA)-positive cardiomyocytes. hESC-CMs within the patch were aligned uniformly by locally controlling the direction of passive tension. Compared to hESC-CMs in age (2 weeks) and purity (48-65%) matched 2D monolayers, hESC-CMs in 3D patches exhibited significantly higher conduction velocities (CVs), longer sarcomeres (2.09 +/- 0.02 vs. 1.77 +/- 0.01 MUm), and enhanced expression of genes involved in cardiac contractile function, including cTnT, alphaMHC, CASQ2 and SERCA2. The CVs in cardiac patches increased with cardiomyocyte purity, reaching 25.1 cm/s in patches constructed with 90% hESC-CMs. Maximum contractile force amplitudes and active stresses of cardiac patches averaged to 3.0 +/- 1.1 mN and 11.8 +/- 4.5 mN/mm(2), respectively. Moreover, contractile force per input cardiomyocyte averaged to 5.7 +/- 1.1 nN/cell and showed a negative correlation with hESC-CM purity. Finally, patches exhibited significant positive inotropy with isoproterenol administration (1.7 +/ 0.3-fold force increase, EC50 = 95.1 nm). These results demonstrate highly advanced levels of hESC-CM maturation after 2 weeks of 3D cardiac patch culture and carry important implications for future drug development and cell therapy studies. PMID- 23642536 TI - The role of exendin-4-conjugated superparamagnetic iron oxide nanoparticles in beta-cell-targeted MRI. AB - Noninvasive targeted visualization of pancreatic beta cells or islets is becoming the focus of molecular imaging application in diabetes and islet transplantation studies, but it is currently unsuccessful due to the lack of specific beta cell biomarkers. Glucagon-like peptide 1 receptor (GLP-1R) is highly expressed in beta cells and considered as a promising target. We here developed a targeted superparamagnetic iron oxide (SPIO) nanoparticle using GLP-1 analog-exendin-4 which is conjugated to polyethylene glycol coated SPIO (PEG-SPIO). The results demonstrated that exendin-4 functionalized SPIO was able to specifically bind to and internalized by GLP-1R-expressing INS-1 cells, with the higher labeling efficiency than non-targeted nanoparticles. Notably, SPIO-exendin4 could differentially label islets in pancreatic slices or beta cell grafts in vitro. Systemic delivery of SPIO-exendin4 into nude mice bearing s.c. insulinomas (derived from INS-1 cells) leads to the accumulation of the nanoparticles in tumors, generating a strong magnetic resonance imaging contrast detectable by a clinical MRI scanner at field strength of 3.0 T, and the iron deposition in tumors was further confirmed by Prussian blue staining. Furthermore, preliminary biodistribution study indicated that SPIO-exendin4 had a tendency to accumulate in pancreas. Toxicity assessments demonstrated good biocompatibility in vivo. These results suggest that SPIO-exendin4 has potential as molecularly targeted imaging agents for in vivo imaging of insulinoma, and possibly for future beta cell imaging. PMID- 23642537 TI - Biologic properties of surgical scaffold materials derived from dermal ECM. AB - Surgical scaffold materials manufactured from donor human or animal tissue are increasingly being used to promote soft tissue repair and regeneration. The clinical product consists of the residual extracellular matrix remaining after a rigorous decellularization process. Optimally, the material provides both structural support during the repair period and cell guidance cues for effective incorporation into the regenerating tissue. Surgical scaffold materials are available from several companies and are unique products manufactured by proprietary methodology. A significant need exists for a more thorough understanding of scaffold properties that impact the early steps of host cell recruitment and infiltration. In this study, a panel of in vitro assays was used to make direct comparisons of several similar, commercially-available materials: Alloderm, Medeor Matrix, Permacol, and Strattice. Differences in the materials were detected for both cell signaling and scaffold architecture-dependent cell invasion. Material-conditioned media studies found Medeor Matrix to have the greatest positive effect upon cell proliferation and induction of migration. Strattice provided the greatest chemotaxis signaling and best suppressed apoptotic induction. Among assays measuring structure-dependent properties, Medeor Matrix was superior for cell attachment, followed by Permacol. Only Alloderm and Medeor Matrix supported chemotaxis-driven cell invasion beyond the most superficial zone. Medeor Matrix was the only material in the chorioallantoic membrane assay to support substantial cell invasion. These results indicate that both biologic and structural properties need to be carefully assessed in the considerable ongoing efforts to develop new uses and products in this important class of biomaterials. PMID- 23642538 TI - The generation of pancreatic beta-cell spheroids in a simulated microgravity culture system. AB - Islet transplantation can induce a substantial improvement in the treatment of type 1 diabetes mellitus. However, the clinical application of islet transplantation is severely limited by the shortage of donor organs. It is thus essential to improve the engraftment rate to achieve the expected outcome in the treatment of diabetes mellitus using a limited amount of donor islets. In this manuscript, we describe the generation of beta-cell spheroids using mouse insulinoma cells (MIN6) as a model of beta-cells. We established a 3D culture system that simulates microgravity using a 3D clinostat. Using this method, we were able to produce 100 spheroids per mL of culture media. The optimization of the culture conditions in the clinostat produced spheroids with a size of approximately 250 MUm, which is a size that is known to induce good graft survival after islet transplantation. The spheroids produced in the clinostat expressed several beta-cell signature genes at higher levels than the levels that were found in MIN6 cells that were cultured in a standard 2D culture dish (MIN6 2D). The transplantation of the spheroids into the portal vein of streptozotocin induced diabetic mice ameliorates hyperglycemia, whereas the transplantation of the equivalent number of 2D-cultured cells failed to cure diabetes. These results indicate that the clinostat culture provides a new method for the reconstitution of a large number of functional beta-cell spheroids for diabetes treatment. PMID- 23642540 TI - Small RNA populations for two unrelated viruses exhibit different biases in strand polarity and proximity to terminal sequences in the insect host Homalodisca vitripennis. AB - Next generation sequence analyses were used to assess virus-derived small RNA (vsRNA) profiles for Homalodisca coagulata virus-1 (HoCV-1), family Dicistroviridae, and Homalodisca vitripennis reovirus (HoVRV), family Reoviridae, from virus-infected H. vitripennis, the glassy-winged sharpshooter. The vsRNA reads were mapped against the monopartite genome of HoCV-1 and all 12 genome segments of HoVRV, and 21nt vsRNAs were most common. However, strikingly contrasting patterns for the HoCV-1 and HoVRV genomic RNAs were observed. The majority of HoCV-1 vsRNAs mapped to the genomic positive-strand RNA and, although minor hotspots were observed, vsRNAs mapped across the entire genomic RNA. In contrast, HoVRV vsRNAs mapped to both positive and negative-sense strands for all genome segments, but different genomic segments showed distinct hotspots. The HoVRV vsRNAs were more common for 5' and 3' regions of HoVRV regions of all segments. These data suggest that taxonomically different viruses in the same host offer different targets for RNA-antiviral defense. PMID- 23642539 TI - The stability of BMP loaded polyelectrolyte multilayer coatings on titanium. AB - Immobilization of bone morphogenetic proteins (BMP) onto material surfaces is a promising, but still challenging, strategy for achieving dependable and consistent osseointegration of long-term metal implants. In the present study, we have developed an osteoinductive coating of a porous titanium implant using biomimetic polyelectrolyte multilayer (PEM) films loaded with BMP-2. The amount of BMP-2 loaded in these films was tuned - over a large range - depending on the cross-linking extent of the film and of the BMP-2 initial concentration. The air dried PEM films were stable for at least one year of storage at 4 degrees C. In addition, they resisted exposure to gamma-irradiation at clinically approved doses. The preservation of the growth factor bioactivity upon long-term storage and sterilization were evaluated both in vitro (using C2C12 cells) and in vivo (in a rat ectopic model) for the perspective of industrial and clinical development. BMP-2 loaded in dried PEM films exhibited shelf-life stability over one year. However, their bioactivity in vitro decreased from 50 to 80% after irradiation depending on the gamma-irradiation dose. Remarkably, the in vivo studies showed that the osteoinductive potential of BMP-2 contained in PEM-coated Ti implants was fully preserved after air-drying of the implants and sterilization at 25 kGy. Film drying or irradiation did not affect the amount of new bone tissue formation. This "off-the-shelf" novel technology of functionalized implants opens promising applications in prosthetic and tissue engineering fields. PMID- 23642542 TI - Gain and coherence estimates between respiration and heart-rate: differences between inspiration and expiration. AB - The interaction of respiration and heart-rate variability (HRV), leading to respiratory sinus arrhythmia (RSA) and, in the inverse direction, cardioventilatory coupling has been subject of much study and controversy. A parametric linear feedback model can be used to study these interactions. In order to investigate differences between inspiratory and expiratory periods, we propose that models are estimated separately for each period, by finding least mean square estimates only over the desired signal segments. This approach was tested in simulated data and heart-rate and respiratory air flow signals recorded from 25 young healthy adults (13 men and 12 women), at rest, breathing spontaneously through a face mask for 5 min. The results show significant differences (p<0.05) between the estimates of coherence obtained from the whole recording, and the inspiration and expiration periods. Simple and causal coherence from respiration to HRV was higher during inspiration than expiration. The estimates of gain also differed significantly in the high frequency (HF) band (0.15-0.5Hz) between those obtained from the whole recording, and the inspiratory and expiratory periods. These results indicate that a single linear model fitted to the whole recording neglects potentially important differences between inspiration and expiration, and the current paper shows how such differences can be estimated, without the need to control breathing. PMID- 23642543 TI - Supplementary values of the dosimetric parameters kNR and Em for various types of detectors in 6 and 15 MV photon fields. AB - The present communication broadens the data base for determinations of the non reference condition correction factor kNR needed in high-energy photon dosimetry to accomplish the use of various detectors under non-reference conditions. Following our previous strategy of calculating semiempirical values of kNR and correlating them with the mean photon energy Em at the point of measurement in a large water phantom, the values of Em are now stated for 6 and 15 MV photon radiations of accelerators with and without flattening filters, square field sizes from 1 to 30 cm side length and depths from 0 to 28 cm. The unambiguity of the kNR-Em correlation is again confirmed and is quantified by fitting formulae for air-filled ionization chambers, TLD detectors and Si diodes. This survey provides a practicable access to the kNR values, particularly for the non-water equivalent detectors to be used in small-field dosimetry. PMID- 23642541 TI - Age at natural menopause in relation to all-cause and cause-specific mortality in a follow-up study of US black women. AB - OBJECTIVES: Early age at natural menopause has been associated with increased all cause mortality in several studies, although the literature is not consistent. This relation has not been examined among African American women. STUDY DESIGN: Data were from the Black Women's Health Study, a follow-up study of African American women enrolled in 1995. Among 11,212 women who were naturally menopausal at entry to the study or during follow-up through 2008, we assessed the relation of age at natural menopause to all-cause and cause-specific mortality. At baseline and biennially, participants reported on reproductive and medical history, including gynecologic surgeries and exogenous hormone use. Mortality data were obtained from the National Death Index. Multivariable Cox proportional hazard models were used to estimate mortality rate ratios (MRR) and 95% confidence intervals (CI) for categories of age at menopause. RESULTS: Of 692 deaths identified during 91,829 person years of follow-up, 261 were due to cancer, 199 to cardiovascular diseases and 232 to other causes. Natural menopause before age 40 was associated with increased all-cause mortality (MRR=1.34, 95% CI 0.96-1.84, relative to menopause at 50-54 years; P-trend=0.04) and with the subcategories of death considered - cancer, cardiovascular disease, and all other causes. The associations were present among never and ever users of postmenopausal female hormones and among never and ever smokers. CONCLUSIONS: In this large prospective cohort of African-American women, natural menopause before age 40 was associated with a higher rate of all-cause and cause-specific mortality. These findings provide support for the theory that natural menopause before age 40 may be a marker of accelerated somatic aging. PMID- 23642544 TI - Computational fluid dynamic analysis of the posterior airway space after maxillomandibular advancement for obstructive sleep apnea syndrome. AB - PURPOSE: This study evaluated the soft tissue change of the upper airway after maxillomandibular advancement (MMA) using computational fluid dynamics. MATERIALS AND METHODS: Eight patients with obstructive sleep apnea syndrome who required MMA were recruited into this study. All participants underwent pre- and postoperative computed tomography and then MMA by a single oral and maxillofacial surgeon. Upper airway computed tomographic datasets for these 8 patients were created with high-fidelity 3-dimensional numerical models for computational fluid dynamics. The 3-dimensional models were simulated and analyzed to study how changes in airway anatomy affect the pressure effort required for normal breathing. Airway dimensions, skeletal changes, apnea-hypopnea index, and pressure effort of pre- and postoperative 3-dimensional models were compared and correlations were interpreted. RESULTS: After MMA, laminar and turbulent air flows were significantly decreased at every level of the airway. The cross sectional areas at the soft palate and tongue base were significantly increased. CONCLUSIONS: This study showed that MMA increased airway dimensions by increasing the distance from the occipital base to the pogonion. An increase of this distance showed a significant correlation with an improvement in the apnea hypopnea index and a decreased pressure effort of the upper airway. Decreasing the pressure effort will decrease the breathing workload. This improves the condition of obstructive sleep apnea syndrome. PMID- 23642546 TI - 3-dimensional facial simulation in orthognathic surgery: is it accurate? AB - PURPOSE: The purpose of this study was to measure the accuracy of 3D computer simulation of soft tissue changes after orthognathic surgery. MATERIALS AND METHODS: Consecutive patients who underwent orthognathic surgery were studied by photogrammetric facial scanning and cone-beam computed tomography before and after surgery. The photogrammetric scan was then fused to the cone-beam computed tomogram, creating a patient-specific image. The surgery was simulated in 3D form and the simulated soft tissue face was compared with the actual facial scan obtained 6 months postoperatively. Absolute millimeter differences between the simulated and actual postoperative changes in selected cephalometric skin markings were computed. RESULTS: The study was composed of 23 subjects (mean age, 31 yr; 13 women and 10 men). Eighteen different cephalometric landmarks were measured (total, 28). For 15 landmarks, the difference between actual and simulated measurements was smaller than 0.5 mm. Only 3 landmarks had a difference of 0.5 mm, and these were in the region of the labial landmarks. CONCLUSION: Based on the present study, 3-dimensional computer surgical simulation of the soft tissue of the face for routine orthognathic surgery is accurate enough for routine clinical use. PMID- 23642545 TI - Combination of zoledronic Acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma. AB - PURPOSE: To investigate the efficacy and safety of zoledronic acid (ZA) combined with targeted therapy (TT). MATERIALS AND METHODS: A retrospective study was performed in patients with metastatic renal cell carcinoma treated with ZA and TT. RESULTS: Twenty-one patients received ZA and TT to prevent skeletal-related events and no pretherapy oral and maxillofacial (OM) examination (cohort A). Six patients (29%) developed osteonecrosis of the jaw (ONJ), which was observed only in patients receiving sunitinib and ZA. Sixteen patients received TT and ZA for hypercalcemia and no pretherapy OM examination (cohort B). In these patients, no ONJ was observed. Nine patients received ZA and TT and pretherapy OM examination (cohort C). One patient (11%) developed ONJ during sunitinib and ZA treatment. Mean skeletal morbidity rates were 0.8 for cohort A and 1.2 for cohort C. In the combined cohort (A plus C; n = 30), 47% developed skeletal-related events, 7% pathologic fracture, 7% medullary compression, and 37% progression of bone metastases. Patients who developed ONJ had a significantly improved median survival of 31.6 months compared with 14.5 months in patients without ONJ (P = .039). CONCLUSION: The combination of ZA and TT resulted in high, clinically meaningful activity. ONJ may be exacerbated by concomitant ZA and sunitinib. Regular OM examinations before and during treatment are recommended. PMID- 23642547 TI - Lower concentrations of B-vitamin subgroups in the serum and amniotic fluid correlate to cleft lip and palate appearance in the offspring of A/WySn mice. AB - PURPOSE: The pathogenesis and prevention of cleft lip and palate (CL/P) have been studied mainly in clinical and animal experiments. A prophylactic poly-B-vitamin substitution during the first months of pregnancy has provided the most encouraging results for the prevention of CL/P recurrence in families at risk. In vitro studies of the palatal organ in an A/WySn mouse model have confirmed the positive influence of B-vitamins on palatal development. The present animal study was performed to analyze different B-vitamin concentrations in the serum and amniotic fluid of A/WySn mice according to the appearance of CL/P in their offspring. MATERIAL AND METHODS: Concentrations of different B-vitamins (B1, B2, B3, B5, B6, and folic acid) in serum and amniotic fluid were analyzed by high performance liquid chromatographic detection. Immunohistochemical staining against thiamin-1 receptor was performed on histologic midface sections of A/WySn fetuses with (n = 12) and without (n = 14) CL/P. RESULTS: Vitamin B5 (P < .001) and folic acid (P < .004) concentrations in the amniotic fluid of dams with CL/P were significantly lower than in dams without CL/P. Serum concentrations of folic acid (P = .5) and B5 (P = .4) showed no difference between the 2 groups. Dams with CL/P had significantly lower thiamine concentrations in serum (P = .01) and amniotic fluid (P < .001). Histologic midface sections presented high thiamin-1 receptor expression in the palatal shelf of fetuses with CL/P. CONCLUSION: A decreased use or uptake of some B-vitamin subgroups (B1, B5, and folic acid) in amniotic fluid and serum (vitamin B1) was correlated to an increased cleft appearance in A/WySn mice. The high thiamin-1 receptor expression in the palatal tissue of mouse fetuses with CL/P may be caused by a decreased availability of vitamin B1. PMID- 23642548 TI - Functional effects of local administration of thyroid hormone combined with chitosan conduit after sciatic nerve transection in rats. AB - PURPOSE: To assess the local effect of triiodothyronine (T3) on peripheral nerve regeneration in a rat model of sciatic nerve transection. MATERIALS AND METHODS: Forty-five male healthy white Wistar rats were divided randomly into 3 experimental groups (n = 15): sham operation, control (CHIT), and T3 treatment (CHIT/T3). In the sham-operated group, the left sciatic nerve was exposed under anesthesia through a gluteal muscle incision and the muscle was sutured after homeostasis. In the CHIT group, the left sciatic nerve was exposed the same way and transected proximal to the tibioperoneal bifurcation, leaving a 10-mm gap. Each proximal and distal stump was inserted into a chitosan conduit, which was filled with phosphate buffered solution 10 MUL. In the CHIT/T3 group, the defect was bridged using a chitosan conduit filled with T3 10 MUL. Each group was subdivided into 3 subgroups of 5 animals each and studied 4, 8, and 12 weeks after surgery. Data were analyzed statistically by factorial analysis of variance and the Bonferroni test for pairwise comparisons. RESULTS: Behavioral testing and sciatic nerve function study confirmed a faster and better recovery of regenerated axons in the CHIT/T3 group than in the CHIT group (P < .05). Gastrocnemius muscle mass was significantly larger in the CHIT/T3 group than in the CHIT group. Morphometric indices of regenerated fibers showed that the number and diameter of the myelinated fibers were significantly larger in the CHIT/T3 group than in the CHIT group. Immunohistochemistry showed that the locations of reaction to S-100 were clearly more positive in the CHIT/T3 group than in the CHIT group. CONCLUSIONS: The response to local treatment showed that thyroid hormone influenced and improved the functional recovery of peripheral nerve regeneration. PMID- 23642549 TI - p16 immunohistochemistry can be used to detect human papillomavirus in oral cavity squamous cell carcinoma. AB - PURPOSE: Human papillomavirus (HPV) is of etiologic significance in the development of oral squamous carcinoma and is noted to result in p16 overexpression. Identification of HPV is clinically important because the presence of HPV has prognostic and epidemiologic associations. Detection of HPV by polymerase chain reaction (PCR) is expensive and not widely accessible. The authors examined p16 immunohistochemistry (IHC) as a surrogate marker for high risk HPV and its use as an alternative test to PCR. PATIENTS AND METHODS: A retrospective cohort of patients with oral squamous cell carcinoma underwent surgery and then analysis with p16 IHC and HPV PCR. The p16 IHC staining intensity was graded from 0 to 3+, and these results were compared with PCR. Descriptive and frequency statistics were performed by comparing HPV PCR results with p16 IHC, patient age, gender, and outcome. RESULTS: Eighty-one cases were included in the study. Forty-four study patients were men and 37 were women (mean age, 63.9 yr). Forty-five cases (55.6%) had 0 staining, 22 cases (27.2%) had 1+ staining, and 7 cases (8.6%) had 2+ staining. Seven cases (8.6%) had 3+ staining, all of which were positive for HPV serotype 16 by PCR. Three of 7 HPV PCR positive cases had keratinization typical of an oral cavity location and not the basaloid growth of HPV oropharyngeal tumors. There was a statistical correlation (P < .001) among HPV PCR positivity, 3+ staining, and younger age. CONCLUSION: p16 3+ staining correlates with HPV PCR positivity. p16 IHC is a technically simple and widely available test, and this study establishes the use of p16 IHC as an alternative test to HPV PCR. Given the clinical significance of HPV in oral squamous carcinoma, p16 IHC should be performed in all cases and included in the pathology report. PMID- 23642550 TI - Sudden hearing loss after dental treatment. AB - A 66-year-old man presented with impaired balance, tinnitus, sensation of blockage, and hearing loss in his left ear, which developed after dental treatment for dental pain 4 days previously. Treatment of the carious left upper second molar tooth had included pulp extirpation, canal expansion, and tooth filling under local anesthesia with articaine and epinephrine. Impaired balance decreased spontaneously within 3 days of dental treatment, but tinnitus and hearing loss persisted. Pure tone audiogram showed profound sensorineural hearing loss in the left ear, with a downslope from 40 to 100 dB, and an abnormal speech discrimination score (50%). Treatment included intravenous prednisolone, intratympanic dexamethasone, and oral betahistine and trimetazidine. The patient had improved hearing and resolution of tinnitus. Sudden hearing loss is rare after dental treatment, and awareness of this complication may prompt early referral for treatment and may improve recovery and prognosis. PMID- 23642551 TI - Brain tumors: a multimodality approach with diffusion-weighted imaging, diffusion tensor imaging, magnetic resonance spectroscopy, dynamic susceptibility contrast and dynamic contrast-enhanced magnetic resonance imaging. AB - This article focuses on advanced magnetic resonance (MR) imaging techniques and how they can be used to help diagnose a specific tumor, suggest tumor grade and prognosis, follow tumor progression, evaluate tumor extension, suggest the ideal site for biopsy, and assess therapeutic response. Advanced MR imaging techniques may also help to distinguish between lesions that simulate brain tumors on conventional MR imaging studies. PMID- 23642552 TI - Posttreatment evaluation of central nervous system gliomas. AB - Although conventional contrast-enhanced MR imaging remains the standard-of-care imaging method in the posttreatment evaluation of gliomas, recent developments in therapeutic options such as chemoradiation and antiangiogenic agents have caused the neuro-oncology community to rethink traditional imaging criteria. This article highlights the latest recommendations. These recommendations should be viewed as works in progress. As more is learned about the pathophysiology of glioma treatment response, quantitative imaging biomarkers will be validated within this context. There will likely be further refinements to glioma response criteria, although the lack of technical standardization in image acquisition, postprocessing, and interpretation also need to be addressed. PMID- 23642554 TI - Clinical applications of diffusion tensor imaging. AB - The potential utility of diffusion tensor (DT) imaging in clinical practice is broad, and new applications continue to evolve as technology advances. Clinical applications of DT imaging and tractography include tissue characterization, lesion localization, and mapping of white matter tracts. DT imaging metrics are sensitive to microstructural changes associated with central nervous system disease; however, further research is needed to enhance specificity so as to facilitate more widespread clinical application. Preoperative tract mapping, with either directionally encoded color maps or tractography, provides useful information to the neurosurgeon and has been shown to improve clinical outcomes. PMID- 23642553 TI - Clinical applications of functional MR imaging. AB - Functional magnetic resonance (fMR) imaging for neurosurgical planning has become the standard of care in centers where it is available. Although paradigms to measure eloquent cortices are not yet standardized, simple tasks elicit reliable maps for planning neurosurgical procedures. A patient-specific paradigm design will refine the usability of fMR imaging for prognostication and recovery of function. Certain pathologic conditions and technical issues limit the interpretation of fMR imaging maps in clinical use and should be considered carefully. However, fMR imaging for neurosurgical planning continues to provide insights into how the brain works and how it responds to pathologic insults. PMID- 23642555 TI - Clinical applications of diffusion imaging in the spine. AB - As in the brain, the sensitivity of diffusion-weighted imaging (DWI) to ischemic damage in the spinal cord may provide early identification of infarction. Diffusion anisotropy may enhance the detection and understanding of damage to the long fiber tracts with clinical implications for diseases such as multiple sclerosis and amyotrophic lateral sclerosis and may also yield insight into damage that occurs with spondylotic and traumatic myelopathy. This article reviews the basis for DWI for the evaluation of the spinal cord, osseous, and soft tissues of the spine and reviews the imaging appearance of a variety of disease states. PMID- 23642556 TI - Breast magnetic resonance imaging: diffusion-weighted imaging. AB - More imaging centers are incorporating diffusion-weighted imaging (DWI) into the clinical breast magnetic resonance (MR) examination, with the potential of increasing the specificity of breast MR imaging. This article reviews the role of DWI in the evaluation of breast lesions. The principles, technique, and protocol of DWI are discussed, including the importance of the chosen b value. The interpretation strategy, including quantitative and qualitative analysis is described. Clinical applications of breast DWI are evaluated, such as distinguishing malignant from benign lesions, tumor characterization and monitoring treatment planning, and potential pitfalls such as false-negative and false-positive findings are discussed. PMID- 23642557 TI - Modern imaging evaluation of the liver: emerging MR imaging techniques and indications. AB - Modern MR imaging evaluation of the liver allows for a comprehensive morphologic and functional assessment of the liver parenchyma, hepatic vessels, and biliary tree, thus aiding in the diagnosis of both focal and diffuse liver diseases. PMID- 23642558 TI - MR enterography for the assessment of small bowel diseases. AB - This article focuses on MR enterography in the evaluation of small bowel diseases, including the protocol, enteric contrast agents, imaging timing and sequence selection. It is becoming the first-line radiological investigation to evaluate the small bowel in patients diagnosed with Crohn disease, particularly in young adults, in whom ionizing radiation is a concern. A key question in the management of such patients is the assessment of disease activity. Knowledge of the location, severity, and presence of complications may assist in providing patients with appropriate treatment options. Other small bowel diseases beyond Crohn disease will also be discussed. PMID- 23642559 TI - Magnetic resonance imaging of rectal cancer. AB - Optimal treatment decisions for patients with rectal cancer are based on knowledge of tumor characteristics and prognostic features and any initial treatment must aim to reduce the risk of both local and distant recurrence. The radiologist has become an increasingly important part of multidisciplinary team managing rectal cancer. The primary goal of MRI staging of rectal tumors is to identify prognostic factors in order to offer patients a tailored treatment based on individual risks. Restaging of rectal tumors using MRI after chemoradiation therapy is becoming more relevant issue, since further tailoring of treatment is increasingly being considered after the treatment. PMID- 23642560 TI - Multiparametric magnetic resonance imaging of the prostate. AB - The multiparametric approach expanded the clinical applications for prostate magnetic resonance (MR) imaging to include not only staging but also a correlation with tumor aggressiveness. It can also help to guide biopsies, to achieve a higher tumor detection rate, and to better reflect the true Gleason grade. The improved accuracy provided by multiparametric MR imaging and a better understanding of the clinical significance of the imaging findings can pave the way to a more direct role of MR imaging in patient management. PMID- 23642561 TI - MR imaging of the pelvic floor: defecography. AB - Defecography by magnetic resonance (MR) imaging makes it possible to view the multiple compartments of the pelvic floor at one examination, with high resolution images at rest and dynamic images, providing accurate evaluation of the morphology and function of the anorectal and pelvic organs and muscles, involved in pelvic floor dynamics. MR imaging of the pelvic floor identifies the diseases affecting the evacuation mechanism, providing information essential for surgical planning and choice of treatment approach. This article focuses on the MR details of the pelvic floor anatomy and the most commonly observed anatomic and functional abnormalities. PMID- 23642562 TI - Diseases of the female pelvis: advances in imaging evaluation. AB - Magnetic resonance (MR) imaging has been widely accepted as a powerful imaging modality for the evaluation of the pelvis because of its intrinsic superior soft tissue contrast compared with that of computed tomography. In certain cases, however, the morphologic study provided by MR imaging may not be enough. Functional evaluation with perfusion and diffusion, which allow estimation of the microvascular characteristics and cellularity of the lesions, favors the differentiation of benign from malignant lesions. This article focuses on new magnetic resonance techniques and their contribution to the differentiation and characterization of pelvic pathologies. PMID- 23642563 TI - Magnetic Resonance Imaging Clinics of North America. Modern imaging evaluation of the brain, body and spine. Foreword. PMID- 23642564 TI - Magnetic Resonance Imaging Clinics of North America. Modern imaging evaluation of the brain, body and spine. Preface. PMID- 23642565 TI - Perchlorate content of plant foliage reflects a wide range of species-dependent accumulation but not ozone-induced biosynthesis. AB - Perchlorate (ClO4(-)) interferes with uptake of iodide in humans. Emission inventories do not explain observed distributions. Ozone (O3) is implicated in the natural origin of ClO4(-), and has increased since pre-industrial times. O3 produces ClO4(-)in vitro from Cl(-), and plant tissues contain Cl(-) and redox reactions. We hypothesize that O3 exposure may induce plant synthesis of ClO4(-). We exposed contrasting crop species to environmentally relevant O3 concentrations. In the absence of O3 exposure, species exhibited a large range of ClO4(-) accumulation but there was no relationship between leaf ClO4(-) and O3, whether expressed as exposure or cumulative flux (dose). Older, senescing leaves accumulated more ClO4(-) than younger leaves. O3 exposed vegetation is not a source of environmental ClO4(-). There was evidence of enhanced ClO4(-) content in the soil surface at the highest O3 exposure, which could be a significant contributor to environmental ClO4(-). PMID- 23642566 TI - The increase in cholesterol levels at early stages after dengue virus infection correlates with an augment in LDL particle uptake and HMG-CoA reductase activity. AB - Several cellular molecules and components, specifically, cholesterol and lipid rafts have been described as necessary elements for dengue virus entry and signaling in several human cells. Thus, changes in lipid rafts formation and cholesterol levels were evaluated. Here we report that the amount of total cholesterol and lipid rafts formation increase early after infection of Huh-7 cells. This augment correlates with an increase in the amount of low density lipoprotein receptor (LDLr) on the surface of infected cells and also with a lower phosphorylation level of the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). None of the changes were observed in Huh 7 cells infected with VSV used as a control. These results suggest that dengue virus infection increases intracellular cholesterol levels at early times post infection by triggering the modulation of LDL particles uptake and the increase in the enzymatic activity of HMG-CoA reductase. PMID- 23642567 TI - Prevalence of intestinal protozoa in communities along the Lake Victoria region of Uganda. AB - The objective of this study was to assess water-borne parasite point prevalence in communities in close proximity to Lake Victoria in Uganda prior to the implementation of a clean water intervention, and to investigate possible associations of water source and latrine access with protozoan prevalence. Utilizing a rapid antigen test, parasite prevalence for Giardia lamblia and Entamoeba histolytica/dispar was determined from stool samples of individuals living in six Ugandan communities. Stool sample test results were stratified by the independent variables of gender, age, community, water source (improved or lake), and presence of a latrine. The impact of the independent variables on parasite prevalence was investigated with bivariable and multivariable analyses. The prevalence of Giardia (12%) was influenced by age and community of residence. The prevalence of Entamoeba (10%) did not significantly vary by the independent variables. The prevalence of intestinal protozoan parasites is significant in Ugandan communities bordering Lake Victoria. Interventions to continue to improve water sources remain a high priority. Rapid antigen testing is likely to be useful in the monitoring of water-borne parasite prevalence. PMID- 23642569 TI - Malignant diseases and mortality in blood donors infected with human T lymphotropic virus type 1 in Israel. AB - OBJECTIVES: The natural history of blood donors infected with human T lymphotropic virus type 1 (HTLV-1) in Israel has never been assessed. The aim of this study was to evaluate the prevalence of malignant disorders and mortality among a cohort of Israelis diagnosed as HTLV-1 carriers during routine blood unit screening. METHODS: This was an observational retrospective cohort study. All HTLV-1 cases among Israeli blood donors between 1995 and 2009 were included. Data regarding malignant diseases were extracted from the Israel National Cancer Registry. Mortality data were extracted from the Israel Population Registry. RESULTS: Between January 9, 1995 and December 31, 2009, 1574497 blood donors were screened for HTLV-1 in the central blood bank services. Of these, 90 were found to be HTLV-1 carriers. This cohort of HTLV-1-infected blood donors was followed for an average of 9.2 +/- 6 years. Among them six (6.7%) were diagnosed as having malignant diseases, four of them with adult T-cell leukemia/lymphoma (ATLL). The incidence of ATLL was 0.37 (95% confidence interval 0.13-1.08)/100 HTLV-1 carrier years. CONCLUSIONS: We found a high rate of malignant diseases among HTLV-1 infected blood donors. PMID- 23642570 TI - Straw management effects on CO2 efflux and C storage in different Mediterranean agricultural soils. AB - The crop residues buried in semiarid soils as a carbon sink are evaluated. Both C CO2 evolved and C sequestered from agricultural soils amended with barley straw were measured seasonally over 2 farming seasons in a semiarid environment (NE Spain). Six experimental soils with low organic matter content and contrasted properties were selected. The CO2 efflux, as a result of soil microbial activity, showed a significant seasonal variation according to changes in both soil moisture and temperature being the spring and early summer when respiration rates get higher. On annual average, more organic, calcareous soils, evolved higher carbon dioxide efflux (up to 53 mg CO2/kg and day) than soils with high levels of gypsum or more soluble salts (up to 25 mg CO2/kg and day), which have a lower percentage of organic carbon. Straw residue incorporation increases these CO2 emissions significantly for each soil type. Although CO2 emissions are significantly and negatively correlated with the C storage, straw addition increases soil organic C content, at the end of the period of study. In calcareous soils were stored up to 550 kgC/ha and year, gypseous soils up to 1135 kgC/ha and year and saline soils up to 1450 kgC/ha and year. According to the amount of stored C in the different soil types, the isohumic coefficient of barley straw ranges from 0.087 to 0.259 (kg of humus formed from 1 kg of dry straw). PMID- 23642571 TI - Concurrent photolytic degradation of aqueous methylmercury and dissolved organic matter. AB - Monomethyl mercury (MeHg) is a potent neurotoxin that threatens ecosystem viability and human health. In aquatic systems, the photolytic degradation of MeHg (photodemethylation) is an important component of the MeHg cycle. Dissolved organic matter (DOM) is also affected by exposure to solar radiation (light exposure) leading to changes in DOM composition that can affect its role in overall mercury (Hg) cycling. This study investigated changes in MeHg concentration, DOM concentration, and the optical signature of DOM caused by light exposure in a controlled field-based experiment using water samples collected from wetlands and rice fields. Filtered water from all sites showed a marked loss in MeHg concentration after light exposure. The rate of photodemethylation was 7.5*10(-3)m(2)mol(-1) (s.d. 3.5*10(-3)) across all sites despite marked differences in DOM concentration and composition. Light exposure also caused changes in the optical signature of the DOM despite there being no change in DOM concentration, indicating specific structures within the DOM were affected by light exposure at different rates. MeHg concentrations were related to optical signatures of labile DOM whereas the percent loss of MeHg was related to optical signatures of less labile, humic DOM. Relationships between the loss of MeHg and specific areas of the DOM optical signature indicated that aromatic and quinoid structures within the DOM were the likely contributors to MeHg degradation, perhaps within the sphere of the Hg-DOM bond. Because MeHg photodegradation rates are relatively constant across freshwater habitats with natural Hg-DOM ratios, physical characteristics such as shading and hydrologic residence time largely determine the relative importance of photolytic processes on the MeHg budget in these mixed vegetated and open-water systems. PMID- 23642572 TI - Cognitive decline in Dravet syndrome: is there a cerebellar role? AB - PURPOSE: The aim of the study was to perform a detailed assessment of cognitive abilities and behaviour in a series of epileptic patients with Dravet syndrome (DS) in order to establish a possible cerebellar-like pattern. METHODS: Nine children with DS without major behavioural disturbances and with cognitive abilities compatible with the assessment of specific cognitive skills (IQ>45) were enrolled in the study, in parallel with another group of nine epileptic patients (cryptogenic or symptomatic with minor brain injuries) consecutively admitted into the hospital matched for chronological age and IQ. All cases underwent neurological examination, long term EEG monitoring, neuroimaging and genetic analysis as well as a neuropsychological assessment including specific cognitive skills. RESULTS: On neurological examination 8 of the 9 DS patients had cerebellar signs, which were mild in six and more severe in the other two cases. DS patients had a constant discrepancy between verbal and performance items scales (verbal better than visual-spatial) that was not found in the control group. As to specific cognitive competence, the DS patients differ from the control group in the pattern of cognitive defects involving four main areas of cognitive abilities (a) expressive language with relatively spared comprehension, (b) visual-spatial organization, (c) executive function defects, (d) behavioural disorders. CUNCLUSIONS: The pattern of cognitive difficulties found in DS patients is consistent with what is reported in literature as cerebellar cognitive syndrome and may account for a possible cerebellar origin (at least as co-factor) of the cognitive decline observed in DS patients, as suggested by other clinical and experimental studies. PMID- 23642573 TI - TMS-EEG reveals impaired intracortical interactions and coherence in Unverricht Lundborg type progressive myoclonus epilepsy (EPM1). AB - Unverricht-Lundborg disease (EPM1) is an inherited neurodegenerative disorder, and the most common form of progressive myoclonus epilepsies. Its main symptoms, epileptic seizures and drug-resistant myoclonus, may be associated with neurophysiological evidence of abnormal cortical excitability or reduced inhibition. The aim of the present study was to utilize transcranial magnetic stimulation (TMS) to induce cortical responses measured with electroencephalography (EEG) in order to observe prevailing cortical excitability/inhibition changes, as well as power and coherence of the cortical oscillations in EPM1. We studied 7 genetically verified EPM1 patients (4 female; age 36+/-6 years) and 6 healthy control subjects (1 female; age 34+/-12 years). Navigated TMS was focused on the left primary motor cortex at the representation area of the right thumb. TMS-EEG responses were measured at 90% of the resting motor threshold intensity in 110-150 trials. We observed that P30 waveform following the TMS was significantly (p<0.05) increased in EPM1 patients suggesting increased cortico-cortical excitability, while the later N100/P180 waveform was significantly (p<0.05) decreased indicating reduced inhibition. In the event-related spectral perturbation (ERSP), we found that alpha, beta and gamma band oscillations following the TMS were significantly lower in power in the EPM1 patients compared to controls. In the alpha and beta bands, the inter trial coherence (ITC) representing the degree of synchronization was also decreased in EPM1. Our results suggest abnormal reactivity in EPM1, and may indicate impaired cortico-cortical inhibition and attenuation of subsequent cortical circuits or the thalamic or subcortical nuclei. PMID- 23642574 TI - Postictal psychosis in temporal lobe epilepsy: risk factors and postsurgical outcome? AB - PURPOSE: Postictal psychosis (PIP) occurs in ~7% of patients with temporal lobe epilepsy (TLE). The aims of this study were to identify risk factors that may predispose patients to developing PIP and determine whether the severity of PIP predicts postsurgical outcome. METHODS: We compared 20 patients with a history of TLE+PIP to 60 age-matched TLE patients without any psychiatric history (TLE only), with respect to pre-surgical clinical and neuropsychological variables. Group differences in postsurgical psychiatric, histopathological, cognitive and seizure outcomes were also examined. KEY FINDINGS: TLE+PIP patients were significantly less likely to have localised ictal epileptiform activity than the TLE controls (p=0.05) and were significantly more likely to have a positive family psychiatric history than TLE controls (p=0.04). Other pre-surgical clinical and neuropsychological variables did not distinguish between the groups. Patients with two or more PIP episodes had significantly increased odds of developing de novo psychopathology within 4 years of surgery, after controlling for comorbid pre-surgical psychiatric status and a history of SGTCS (OR: 9.11, 95% CI: 1.53-54.10, p=0.02). A history of PIP did not significantly predict other postsurgical outcomes (seizure freedom (ILAE=1) or cognitive outcome). SIGNIFICANCE: Our results suggest that more widespread or diffuse brain abnormalities as reflected by pre-surgical EEG findings and positive genetic determinants may contribute to the development of PIP. Furthermore, patients with recurrent PIP episodes who undergo TLE surgery are at increased risk of developing de novo psychiatric disorders, particularly mood disorders. This has implications for pre-operative counselling and highlights a need for postsurgical psychiatric monitoring for these patients. PMID- 23642575 TI - International Work Group criteria for the diagnosis of Alzheimer disease. AB - Alzheimer-type biomarker changes are identifiable in asymptomatic and mildly symptomatic predementia phases of Alzheimer disease (AD) and AD dementia. The International Work Group (IWG) guidelines for diagnosis identify a unified spectrum of 3 phases. The classic clinical feature that indicates AD is an episodic memory defect of the amnestic type. IWG criteria require biomarker support for the diagnoses of AD at any clinical stage. Pathophysiologic and topographic biomarkers are recognized. These criteria are proposed to allow highly specific diagnosis of AD and assist in identifying patients for clinical trials of AD-related treatments and other types of AD research. PMID- 23642576 TI - The application of cerebrospinal fluid biomarkers in early diagnosis of Alzheimer disease. AB - This article gives an updated account of the clinical application of cerebrospinal fluid (CSF) biomarkers for Alzheimer disease (AD). The clinically most relevant biomarkers, total tau, phospho-tau and Abeta42 are discussed, and how they may be used, together with other diagnostic investigations, to make a predementia diagnosis of AD. Recent findings in sporadic and genetic preclinical AD are also discussed and, more specifically, what the biomarkers have taught us on the sequence of events in the pathogenic process underlying AD. PMID- 23642577 TI - Amyloid imaging with PET in early Alzheimer disease diagnosis. AB - In vivo imaging of amyloid-beta (Abeta) with positron emission tomography has moved from the research arena into clinical practice. Clinicians working with cognitive decline and dementia must become familiar with its benefits and limitations. Amyloid imaging allows earlier diagnosis of Alzheimer disease and better differential diagnosis of dementia and provides prognostic information for mild cognitive impairment. It also has an increasingly important role in therapeutic trial recruitment and for evaluation of anti-Abeta treatments. Longitudinal observations are required to elucidate the role of Abeta deposition in the course of Alzheimer disease and provide information needed to fully use the prognostic power of this investigation. PMID- 23642578 TI - Relevance of magnetic resonance imaging for early detection and diagnosis of Alzheimer disease. AB - Hippocampus volumetry currently is the best-established imaging biomarker for AD. However, the effect of multicenter acquisition on measurements of hippocampus volume needs to be explicitly considered when it is applied in large clinical trials, for example by using mixed-effects models to take the clustering of data within centers into account. The marker needs further validation in respect of the underlying neurobiological substrate and potential confounds such as vascular disease, inflammation, hydrocephalus, and alcoholism, and with regard to clinical outcomes such as cognition but also to demographic and socioeconomic outcomes such as mortality and institutionalization. The use of hippocampus volumetry for risk stratification of predementia study samples will further increase with the availability of automated measurement approaches. An important step in this respect will be the development of a standard hippocampus tracing protocol that harmonizes the large range of presently available manual protocols. In the near future, regionally differentiated automated methods will become available together with an appropriate statistical model, such as multivariate analysis of deformation fields, or techniques such as cortical-thickness measurements that yield a meaningful metrics for the detection of treatment effects. More advanced imaging protocols, including DTI, DSI, and functional MRI, are presently being used in monocenter and first multicenter studies. In the future these techniques will be relevant for the risk stratification in phase IIa type studies (small proof-of-concept trials). By contrast, the application of the broader established structural imaging biomarkers, such as hippocampus volume, for risk stratification and as surrogate end point is already today part of many clinical trial protocols. However, clinical care will also be affected by these new technologies. Radiologic expert centers already offer "dementia screening" for well-off middle-aged people who undergo an MRI scan with subsequent automated, typically VBM-based analysis, and determination of z-score deviation from a matched control cohort. Next-generation scanner software will likely include radiologic expert systems for automated segmentation, deformation-based morphometry, and multivariate analysis of anatomic MRI scans for the detection of a typical AD pattern. As these developments will start to change medical practice, first for selected subject groups that can afford this type of screening but later eventually also for other cohorts, clinicians must become aware of the potentials and limitations of these technologies. It is decidedly unclear to date how a middle-aged cognitively intact subject with a seemingly AD positive MRI scan should be clinically advised. There is no evidence for individual risk prediction and even less for specific treatments. Thus, the development of preclinical diagnostic imaging poses not only technical but also ethical problems that must be critically discussed on the basis of profound knowledge. From a neurobiological point of view, the main determinants of cognitive impairment in AD are the density of synapses and neurons in distributed cortical and subcortical networks. MRI-based measures of regional gray matter volume and associated multivariate analysis techniques of regional interactions of gray matter densities provide insight into the onset and temporal dynamics of cortical atrophy as a close proxy for regional neuronal loss and a basis of functional impairment in specific neuronal networks. From the clinical point of view, clinicians must bear in mind that patients do not suffer from hippocampus atrophy or disconnection but from memory impairment, and that dementia screening in asymptomatic subjects should not be used outside of clinical studies. PMID- 23642579 TI - Cognitive approaches to early Alzheimer's disease diagnosis. AB - In this article, cognitive measures in the screening of individuals at risk for Alzheimer disease (AD) are reviewed. Use of cognitive tasks in identifying clinical cases of AD is considered, as well as methods for detecting those in the prodromal stages of the disease, including cognitive screening instruments. Traditional assessments, such as the mini-mental state examination, as well as contemporary computerized screening instruments, are examined. Areas of cognition for investigation in the detection of prodromal AD are recommended. The prospects for general cognitive screening are reviewed, and more engaging technologies to tests individuals at risk for developing AD are recommended. PMID- 23642580 TI - Clinical trials in predementia stages of Alzheimer disease. AB - Effective treatments of Alzheimer disease (AD) dementia are an urgent necessity. There is a growing consensus that effective disease-modifying treatment before the onset of clinical dementia and slowing the progression of mild symptoms are needed after recent setbacks in AD therapeutics. The identification of at-risk and preclinical AD populations is becoming important for targeting primary and secondary prevention clinical trials in AD. This article reviews the strategies and challenges in targeting at-risk and preclinical AD populations for a new generation of AD clinical trials. Design, outcome measures, and complexities in successfully completing a clinical trial targeting this population are reviewed. PMID- 23642581 TI - Emotional and psychological implications of early AD diagnosis. AB - This article reviews the current recommendations in early diagnosis and the desires of the patients and their relatives, put in perspective with the reality of the clinical practices. More specific situations covered are: (1) the issue of young diseased patients, taking into account the psychological implications of the early occurrence of the disease in life and of the longer delay for these patients between the first observable signs and the diagnosis and (2) the issue of genetic testing, taking into account the implications of this extremely early form of bad news on the individual's existence and on the family structure. PMID- 23642582 TI - Applying the IWG research criteria in clinical practice: feasibility and ethical issues. AB - One of the strengths of the IWG criteria was to reconceptualize the diagnosis of AD, from a clinical-pathologic diagnosis to a clinical-biologic one, which can be performed in vivo. The diagnosis should, therefore, be implemented in the clinical stage of the disease, relying on the essence of the new IWG diagnostic criteria in the recognition of this dual aspect of AD: a specific clinical presentation that is related to a well-defined underlying pathology. Biomarkers measured by PET or CSF correlate with high sensitivity and specificity with AD pathologic features; episodic memory properly measured also presents high specificity to detect patients who develop AD dementia, and clinical studies have demonstrated that these criteria applied in a clinical setting present good specificity, making feasible a diagnosis in the prodromal stage of the disease. From an ethical perspective, the governing principle for early prodromal diagnosis should be autonomy, because the decision of wishing to know or not to know should be performed individually by a competent individual. Furthermore, the potential benefit of an early diagnosis may be mediated through an autonomous decision. PMID- 23642583 TI - FDG-PET in early AD diagnosis. AB - FDG-PET is a valuable tool that will continue to aid in identifying AD in its prodromal and early dementia stages, distinguishing it from other causes of dementia, and tracking progression of the disease. As brain FDG-PET scans and well-trained readers of these scans are becoming more widely available to clinicians who are becoming more informed about the role FDG-PET can play in early AD diagnosis, its use is expected to increase. PMID- 23642584 TI - Medical Clinics of North America. Early diagnosis and intervention in predementia Alzheimer's disease. Preface. PMID- 23642585 TI - Universal screening of newborns to detect hearing impairment--is it necessary? AB - BACKGROUND: In contrast to the recommendations of the Joint Committee on Infant Hearing, neonatal hearing screening programs are still not universally available. OBJECTIVES: To prospectively evaluate the presence of hearing loss in all newborn babies delivered in our hospital during study period using the transient evoked otoactoustic emission as the primary screening tool followed by confirmation with brainstem evoked response audiometry before six months of age and to determine risk factors responsible for hearing loss. DESIGN: A prospective study of nonrandomized cohort. SETTING: Nursery, Postnatal ward and NICU of Tertiary care center. PARTICIPANTS: 500 neonates (439: not at risk; 61: at risk) from a total of 610 neonates born in between 2009 and 2010. MEASUREMENTS: Incidence of hearing impairment in the "at risk" and "no risk" group was compared, using proportion test. MAIN OUTCOME MEASURE(S): Incidence of hearing loss in newborns both "at risk" and in "no risk" group, risk factors responsible for hearing loss, importance of universal newborn hearing screening. RESULTS: The overall incidence of hearing impairment was 8 per 1000 screened. The incidence in "no risk" and "at risk" group was 2.27 per 1000 screened and 49.18 per 1000 screened respectively. Statistically significant difference in the incidence of hearing impairment between the two groups. (P<0.05; Proportion Test) was seen. Common risk factors identified were culture positive postnatal infections, birth asphyxia, low birth weight, and prematurity. CONCLUSIONS: A high incidence of hearing impairment warrants the implementation of universal newborn hearing screening. Considering the economic limitations of our country we may employ screening of "at risk" groups initially. PMID- 23642586 TI - Allergy history as a predictor of early onset adenoids/adenotonsillar hypertrophy among Nigerian children. AB - BACKGROUND: Previous reports have established the association of allergy with adenoidal and tonsillar hypertrophy, and adenotonsillar hypertrophy is a well known co-morbid factor in patients with allergic rhinitis. Very little is known about the association of history of allergy with timing of first presentation in adenotonsillitis patients. SETTING: Tertiary care urban referral hospital. STUDY DESIGN: Descriptive analysis of prospectively collected data. METHODS: All cases which had adenotonsillectomy carried out between September 2005 and September 2012 at National Hospital Abuja that met the selection criteria were recruited and analyzed on the basis of family history of allergy in first degree relatives, clinical history of allergic rhinitis, asthma and atopic dermatitis. RESULT: Total of 434 cases were recruited. Mean age was 5 years (range 9 months-15 years, std. dev. 3.535). 56% of participants were aged 3 years and below. 22, 15, and 16% of participants aged 3 years and below had family history of allergy, allergic rhinitis and atopic dermatitis respectively compared to 6, 4 and 4% for participants aged above 3 years. The mean age at onset of symptoms is 7.59, 10.32, and 13.62 months for participants with family history of allergy, clinical allergic rhinitis and atopic dermatitis respectively and 23.890 months for participants with no history of atopy or allergy. Family history of allergy significantly predicts onset of symptoms before age 6 months (OR 7.59, 95% CI 4.74-12.12, P<0.0001). CONCLUSIONS: Family history of allergy and presence of clinical allergic or atopic dermatitis are related to early onset of symptoms in Nigerian children with adenoids/adenotonsillar hypertrophy. PMID- 23642589 TI - Device lead screw tip induced pericarditis--a subtle complication in need of wider recognition. PMID- 23642587 TI - Exploring a neurogenic basis of velopharyngeal dysfunction in Tbx1 mutant mice: no difference in volumes of the nucleus ambiguus. AB - OBJECTIVE: Velopharyngeal hypotonia seems to be an important factor in velopharyngeal dysfunction in 22q11.2 deletion syndrome, but the etiology is not understood. Because TBX1 maps within the typical 22q11.2 deletion and Tbx1 deficient mice phenocopy many findings in patients with the 22q11.2 deletion syndrome, TBX1 is considered the major candidate gene in the etiology of these defects. Tbx1 heterozygosity in mice results in abnormal vocalization 7 days postnatally, suggestive of velopharyngeal dysfunction. Previous case-control studies on muscle specimens from patients and mice revealed no evidence for a myogenic cause of velopharyngeal dysfunction. Velopharyngeal muscles are innervated by cranial nerves that receive signals from the nucleus ambiguus in the brainstem. In this study, a possible neurogenic cause underlying velopharyngeal dysfunction in Tbx1 heterozygous mice was explored by determining the size of the nucleus ambiguus in Tbx1 heterozygous and wild type mice. METHODS: The cranial motor nuclei in the brainstems of postnatal day 7 wild type (n=4) and Tbx1 heterozygous (n=4) mice were visualized by in situ hybridization on transverse sections to detect Islet-1 mRNA, a transcription factor known to be expressed in motor neurons. The volumes of the nucleus ambiguus were calculated. RESULTS: No substantial histological differences were noted between the nucleus ambiguus of the two groups. Tbx1 mutant mice had mean nucleus ambiguus volumes of 4.6 million MUm(3) (standard error of the mean 0.9 million MUm(3)) and wild type mice had mean volumes of 3.4 million MUm(3) (standard error of the mean 0.6 million MUm(3)). Neither the difference nor the variance between the means were statistically significant (t-test p=0.30, Levene's test p=0.47, respectively). CONCLUSIONS: Based on the histology, there is no difference or variability between the volumes of the nucleus ambiguus of Tbx1 heterozygous and wild type mice. The etiology of velopharyngeal hypotonia and variable speech in children with 22q11.2 deletion syndrome warrants further investigation. PMID- 23642590 TI - Quality of life benefits after percutaneous coronary intervention in the elderly. PMID- 23642591 TI - Outcomes of weekend versus weekday admission for acute aortic dissection or rupture: a retrospective study on the Italian National Hospital Database. PMID- 23642592 TI - Thrombus aspiration in elderly STEMI patients: a single center experience. PMID- 23642593 TI - Critical role of systemic inflammation in patients with ST-segment elevation myocardial infarction complicated with renal dysfunction. PMID- 23642594 TI - Ticagrelor immediately prior to stenting is associated with smaller residual thrombus in patients with acute coronary syndrome. PMID- 23642595 TI - Culture negative prosthetic valve endocarditis in chronic Q fever: an under recognized entity. PMID- 23642596 TI - Prognosis of patients with chronic systolic heart failure: Chagas disease versus systemic arterial hypertension. PMID- 23642597 TI - Is there any correlation between serum uric acid levels and right ventricular function parameters in patients with cardiovascular risk factors? PMID- 23642598 TI - Cerebral damage in cardiac surgery assessed by serum S100 proteins. PMID- 23642599 TI - Treatment failure of low molecular weight heparin bridging therapy. PMID- 23642600 TI - Contribution of arterial excess pressure and arterial stiffness to central augmentation pressure in healthy subjects. PMID- 23642601 TI - Prognosis after tilt training in patients with recurrent vasovagal syncope. PMID- 23642602 TI - Routine cardiac catheterization and angioplasty in anticoagulated patients: does warfarin need to be discontinued? PMID- 23642603 TI - Relationship between serum 25-hydroxyvitamin D status and cardiorespiratory fitness: findings from the National Health and Nutrition Examination Survey. PMID- 23642604 TI - Cardiac myosin-binding protein C gene mutation expressed as hypertrophic cardiomyopathy and left ventricular noncompaction within two families: insights from cardiac magnetic resonance in clinical screening: Camuglia MYBPC3 gene mutation and MRI. PMID- 23642605 TI - Obesity paradox: clinical benefits not observed in obese patients with ST-segment elevation myocardial infarction: a multicenter, prospective, cohort study of the northern region of China. PMID- 23642606 TI - From treatment to diagnosis of Kounis syndrome in the catherization laboratory: the resolution of vasospastic angina after intracoronary tirofiban and nitrate therapy. PMID- 23642607 TI - Utilities of 320-slice computed-tomography for evaluation of tricuspid valve annular diameter before tricuspid-valve-plasty compared with the direct measurement of tricuspid valve annular diameter during open heart-surgery. PMID- 23642608 TI - Self-declared ethnicity associated with risk factors of cardiovascular diseases in an urban sample of the Brazilian population: the role of educational status in the association. PMID- 23642609 TI - Glucagon-like peptide-1 and related agents: novel anti-arrhythmic agents during myocardial ischemia and reperfusion. PMID- 23642610 TI - Gender similarities and differences in the presentation of symptoms in acute myocardial infarction. PMID- 23642611 TI - Shared and non-shared familial susceptibility of coronary heart disease, ischemic stroke, peripheral artery disease and aortic disease. AB - BACKGROUND: Little is known about whether the four main manifestations of arterial vascular disease (coronary heart disease = CHD, ischemic stroke, peripheral artery disease = PAD, and aortic (i.e. atherosclerosis/aneurysm) disease = AD) share familial susceptibility. The aim of this nationwide study was to determine the familial risks of concordant (same disease in proband and exposed relative) and discordant (different disease in proband and exposed relative) cardiovascular disease (CVD). METHODS: Data from the Swedish Multigeneration Register on individuals aged 0-76 years were linked to Swedish Hospital Discharge Register data for the period 1964-2008. Standardized incidence ratios (SIRs) for CHD (n = 140,708 cases), ischemic stroke (n = 73,771), PAD (n = 18,982) and AD (n = 7879) were calculated for siblings of individuals hospitalized due to CHD, stroke, PAD or AD compared to those of unaffected siblings. The procedure was repeated for parent-offspring and spouses. RESULTS: All concordant and discordant sibling risks were increased for both males and females. Concordant risks were generally higher than discordant risks. The highest sibling risks were observed for premature concordant disease (<55 years for males and <65 years for females): SIR for CHD = 1.93 (95% CI: 1.90-1.96), SIR for ischemic stroke = 1.45 (1.39-1.50), SIR for PAD = 2.76 (2.54-3.00), and SIR for AD = 6.36 (5.28-7.59). Premature parent-offspring transmission followed the same pattern. The disease risk was modestly increased in spouses, highest for AD (SIR = 1.48 (1.28-1.69)) and PAD (SIR = 1.27 (1.21-1.32)). CONCLUSIONS: The four main manifestations of CVD share familial susceptibility, but unique site specific familial factors may exist. PMID- 23642612 TI - Off-label use of prasugrel in stable coronary artery disease is associated with greater degree of platelet inhibition compared with use after acute coronary syndrome. PMID- 23642613 TI - Platelet inhibition by IV glyceryl trinitrate in patients with stable coronary artery disease on dual antiplatelet therapy subjected to PCI. PMID- 23642614 TI - Serum neuregulin-1beta levels are positively correlated with VEGF and angiopoietin-1 levels in patients with diabetes and unstable angina pectoris. PMID- 23642615 TI - Meta-analysis of everolimus-eluting stents versus first-generation drug-eluting stents in patients with left main coronary artery undergoing percutaneous coronary intervention. PMID- 23642616 TI - Wolff-Parkinson-White syndrome in Duchenne muscular dystrophy. PMID- 23642617 TI - Chronic renal disease is associated with stroke and thromboembolism in atrial fibrillation independently from gender. PMID- 23642618 TI - In regard to Yu et al. PMID- 23642619 TI - In reply to Gates and Salem. PMID- 23642620 TI - In regard to Jakobsen et al. PMID- 23642621 TI - In reply to Fekete. PMID- 23642622 TI - Research funding for radiation oncology: an unfortunately small sliver of an inadequate pie. PMID- 23642623 TI - The Red Journal's most downloaded physics articles of 2012. PMID- 23642624 TI - Health-related quality of life in elderly patients with newly diagnosed glioblastoma treated with short-course radiation therapy plus concomitant and adjuvant temozolomide. AB - PURPOSE: To describe the quality of life (QOL) in elderly patients with glioblastoma (GBM) treated with an abbreviated course of radiation therapy (RT; 40 Gy in 15 fractions) plus concomitant and adjuvant temozolomide (TMZ). METHODS AND MATERIALS: Health-related QOL (HRQOL) was assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30, version 3) and EORTC Quality of Life Questionnaire Brain Cancer Module (QLQ-BN20). Changes from baseline in the score of 9 preselected domains (global QLQ, social functioning, cognitive functioning, emotional functioning, physical functioning, motor dysfunction, communication deficit, fatigue, insomnia) were determined 4 weeks after RT and thereafter every 8 weeks during the treatment until disease progression. The proportion of patients with improved HRQOL scores, defined as a change of 10 points or more, and duration of changes were recorded. RESULTS: Sixty-five patients completed the questionnaires at baseline. The treatment was consistently associated with improvement or stability in most of the preselected HRQOL domains. Global health improved over time; mean score differed by 9.6 points between baseline and 6-month follow-up (P=.03). For social functioning and cognitive functioning, mean scores improved over time, with a maximum difference of 10.4 points and 9.5 points between baseline and 6 month follow-up (P=.01 and P=.02), respectively. By contrast, fatigue worsened over time, with a difference in mean score of 5.6 points between baseline and 4 month follow-up (P=.02). CONCLUSIONS: A short course of RT in combination with TMZ in elderly patients with GBM was associated with survival benefit without a negative effect on HRQOL until the time of disease progression. PMID- 23642625 TI - Chemoradiation with paclitaxel and carboplatin in high-risk cervical cancer patients after radical hysterectomy: a Korean Gynecologic Oncology Group study. AB - PURPOSE: To evaluate the efficacy and toxicity of concurrent chemoradiation with paclitaxel and carboplatin in patients with high-risk cervical cancer. METHODS AND MATERIALS: Patients after radical hysterectomy for cervical cancer, with at least 1 high-risk characteristic, were administered paclitaxel 135 mg/m(2), carboplatin area under the curve = 5 every 3 weeks for 3 cycles concomitant with radiation therapy as adjuvant treatment. RESULTS: This prospective study enrolled 71 consecutive patients. Sixty-six patients (93%) completed the planned treatment. The majority of grade 3/4 neutropenia or nonhematologic toxicities were usually self-limited. Diarrhea grades 3/4 were observed in 4 patients (5.6%). One patient developed anaphylactic shock after infusion of paclitaxel. With a median follow-up of 57 months, recurrences occurred in 16 patients. Multivariable analysis indicated that common iliac lymph node involvement is an independent risk factor for disease recurrence (odds ratio 13.48; 95% confidence interval 2.93-62.03). In the intent-to-treat population (n=71), the estimated 5 year disease-free survival and overall survival rates were 77.3% and 80.3% respectively. In the per-protocol population (n=62), disease-free survival was 78.9% and overall survival was 83.9%. CONCLUSIONS: Concurrent chemoradiation with paclitaxel/carboplatin is well tolerated and seems to be effective for patients who undergo radical hysterectomy. Therefore, a prospective, randomized controlled study should be designed to evaluate efficacy of this approach for patients with high-risk cervical cancer. PMID- 23642626 TI - A simple technique of suture loop for acute acromioclavicular joint dislocation. PMID- 23642627 TI - Rapid sciatic nerve regeneration of rats by a surface modified collagen-chitosan scaffold. AB - In the previous study, we attempted to use a collagen-chitosan (CCH) scaffold to mimic the bio-functional peripheral nerve and to bridge sciatic nerve defects in rats. The results demonstrated that it could support and guide the nerve regeneration after three months. In the current study, a type of peptide which carried RGD sequences was connected to the CCH surface by a chemical method. After this process, the microtubule structure of the scaffold was not changed. Then the coated scaffolds were used to repair a 15mm sciatic nerve defect in rats. Four weeks after implantation, linear growth of axons in the longitudinal structure was observed, and the number of regenerated axons remarkably increased. Two months later, the scaffold was partly absorbed and replaced by large quantity of regenerated axons. Importantly, the functional examinations also support the morphological results. Compared with the CCH group, all of the achievements revealed the superior function of RGD-CCH in the rapid regeneration of injured sciatic nerve. PMID- 23642628 TI - Brain CT perfusion provides additional useful information in severe traumatic brain injury. AB - BACKGROUND: The role of brain CT perfusion (CTP) imaging in severe traumatic brain injury (STBI) is unclear. We hypothesised that in STBI early CTP may provide additional information beyond the non contrast CT (NCCT). METHODS: Subset analysis of an ongoing prospective observational study on trauma patients with STBI who did not require craniectomy and deteriorated or failed to improve neurologically during the first 48h from trauma. Subsequently to follow-up NCCT, a CTP was obtained. Additional findings were defined as an area of altered perfusion on CTP larger than the abnormal area detected by the simultaneous NCCT. Patients who had additional finding (A-CTP) were compared with patients who did not have additional findings (NA-CTP). RESULTS: Study population was 30 patients [male: 90%, mean age: 38.6 (SD 16.9), blunt trauma: 100%; prehospital intubation: 6 (20%); lowest GCS before intubation: 5.1 (SD 2.0); mean ISS: 30.5 (SD 8.3); mean head and neck AIS: 4.4 (SD 0.8). Days in ICU: 10.2 (SD 6.3). Intracranial pressure (ICP) monitored in 12 (40%). Mean highest ICP in mmHg: 30.1 (SD14.1). There were five (17%) deaths. Findings of NCCT: primarily diffuse axonal injury (DAI) pattern in seven (23%), primarily haematoma in ten (33%), and primarily intracerebral contusion in nine (30%). CTP was performed 24.9 (SD 13) hours from trauma. There were 18 (60%) patients in the A-CTP group and 12 (40.0%) in NA-CTP. The A-CTP group was older (41.7 (SD16.9) vs 27.7 (SD 12.8): P<0.02) and showed on admission NCCT presence of cerebral contusion and absence of DAI. The degree of hypoperfusion was found to be severe enough to be in the ischaemic range in eight patients (27%). CTP altered clinical management in three patients (10%), who were diagnosed with massive and unsurvivable strokes despite minimal changes on NCCT. CONCLUSION: When compared to NCCT, CTP provided additional diagnostic information in 60% of patients with STBI. CTP altered clinical management in 10% of patients. PMID- 23642629 TI - Soleus fascicle length changes are conserved between young and old adults at their preferred walking speed. AB - Older adults have been shown to naturally select a walking speed approximately 20% slower than younger adults. We explored the possibility that a reduction in preferred speed in older adults represents a strategy to preserve the mechanical function of the leg muscles. We examined this question in the soleus muscle in eight healthy young (25.8+/-3.5 years) and eight healthy older adults (66.1+/-2.3 years) who were paired so that their preferred speed differed by ~20%. Soleus muscle fascicle lengths were recorded dynamically using ultrasound, together with simultaneous measurements of soleus EMG activity and ankle joint kinematics while (a) older adults walked on a treadmill at a speed 20% above their preferred speed (speeds matched to the preferred speed of young adults), and (b) young and older adults walked at their preferred treadmill speeds. Analyses of mean muscle fascicle length changes revealed that, at matched speeds, older adults had a statistically different soleus fascicle length pattern compared to young adults, where the muscle's stretch-shorten cycle during stance was diminished. However, older adults walking at their preferred speed exhibited a more pronounced stretch shorten cycle that was not statistically different from young adults. Conserving muscle length patterns through a reduction in speed in older adults may represent a physiologically relevant modulation of muscle function that permits greater force and power production. Our findings offer a novel mechanical explanation for the slower walking speed in older adults, whereby a reduction in speed may permit muscles to function in a mechanically similar manner to that of younger adults. PMID- 23642630 TI - Pretreatment outcome indicators in an eating disorder outpatient group: the effects of self-esteem, personality disorders and dissociation. AB - OBJECTIVE: The prognosis for eating disorders (ED) is unsatisfactory, and the literature about outcome indicators is controversial. The present study evaluates the roles of self-esteem, personality disorders (PD), and dissociation as outcome predictors. METHOD: Fifty-seven ED outpatients were recruited from a population beginning a Cognitive Behavioral Therapy-Enhanced (CBT-E) treatment. All patients received the Structured Clinical Interview for DSM-IV Axis I (SCID-I), the Structured Clinical Interview for DSM-IV Axis II (SCID-II), and completed the Eating Disorder Examination Questionnaire (EDE-Q), the Dissociation Questionnaire (DIS-Q), and the Rosenberg Self-Esteem Scale (RSES). One month after the end of treatment, recovery was evaluated as meeting the DSM-IV criteria for EDs. RESULTS: A small group of patients recovered (42.2%). Low self-esteem and dissociation results correlated with a negative outcome. DISCUSSION: Dissociation may be an important moderator of psychotherapy and treatment success, as already suggested by previous studies on non-eating-related disorders. PMID- 23642631 TI - Psychometric properties of the Korean version of the Interpersonal Sensitivity Measure (IPSM-K). AB - The aim of this study was to investigate the psychometric properties of a Korean version of Interpersonal Sensitivity Measure (IPSM). A Korean version of the IPSM (IPSM-K) was produced through forward translation, reconciliation, and back translation. A total of 338 healthy, non-clinical participants were selected through screening and clinical interview, and they each were given a set of questionnaires including IPSM-K. All subscales, as well as a full-scale IPSM-K showed satisfactory internal consistency (Cronbach's alpha=0.73-0.83 and 0.94, respectively). Test-retest reliability at 2-week intervals was significant, with coefficient r ranging between .80 and .94. In terms of convergent validity, IPSM K showed the significant positive correlation with sociotropy and autonomy subscale of Personal Style Inventory-II, as well as with neuroticism subscale of Neuroticism Extraversion Openness-Personality Inventory. IPSM-K had no correlation with Social Desirability Scale, thus demonstrated divergent validity with social desirability. A factor analysis of the scale was conducted and five factors emerged (low self-confidence, interpersonal awareness, lack of assertiveness/separation anxiety, interpersonal vulnerability, and need for approval). This study demonstrated that IPSM-K could be useful in assessing interpersonal sensitivity in Korean population. PMID- 23642632 TI - The Norwegian Junior Temperament and Character Inventory (JTCI): an assessment of its psychometric properties. AB - The role of adolescent personality concerning mental health, well-being, self development, and academic performance is an interesting aspect that needs more attention. The use of the JTCI (Junior Temperament and Character Inventory) can contribute to more knowledge and a better understanding of a possible influence of personality in this context. The aim of this study was to assess the psychometric properties of the Norwegian version of the JTCI among an adolescent sample in terms of factor analysis, reliability and validity. The sample included 2075 subjects in the age from 15-18years. We analyzed the factor structure, internal consistency, and validity of the measure. The Norwegian version of the JTCI was found to have good psychometric properties in terms of internal consistency, a reasonable factor structure and significant correlations with depression, self-esteem, and self-efficacy. However, further research on its differentiation of Harm Avoidance and Self-directedness is needed. The JTCI appears as a useful tool in addressing issues ranging from scholastic performance to developmental issues, mental health and well-being. PMID- 23642633 TI - A family history of alcoholism relates to alexithymia in substance use disorder patients. AB - OBJECTIVES: Previous research identified alexithymia as a potential risk factor for substance use disorders (SUD). More insight into the relation between alexithymia and SUD is needed in order to treat SUD effectively. Therefore, we investigated whether a familial vulnerability to alcoholism relates to the presence and severity of alexithymia in SUD patients. METHOD: Hospitalized, abstinent SUD-patients (n=187), were assessed with the Toronto Alexithymia Scale (TAS-20) and Addiction Severity Index (EuropASI). A maternal, paternal, and total continuous measure of the Family History of Alcohol (FHA) was developed. Kruskal Wallis tests and Spearman correlations were used to relate the composite scores of FHA to alexithymia as a categorical and continuous measure. Multivariate regression models were performed to control for the effects of confounders on the relation between FHA and alexithymia. RESULTS: Compared to moderate (33%) and low (17%) alexithymic SUD-patients, high alexithymic (50%) patients were more likely to have fathers with alcohol problems (P=0.004). Such a difference was not found for mothers with alcohol problems. The composite FHA-score was significantly associated with alexithymia (Rs=.19, P=0.01). However, only a paternal FHA, independent from disturbed family functioning, related to the degree of alexithymia (beta=.13, P=0.06), especially to the Difficulty Identifying Feelings as measured by the TAS-20 (beta=.16, P=0.02). CONCLUSIONS: The relation between a paternal FHA and a higher degree of alexithymia in SUD-patients suggests that alexithymia could mediate the familiality of alcoholism or SUD in the paternal line. PMID- 23642635 TI - Craving Typology Questionnaire (CTQ): a scale for alcohol craving in normal controls and alcoholics. AB - INTRODUCTION: Craving is commonly thought to play a crucial role both in the transition from controlled drinking to alcohol dependence and in the mechanism underlying relapse. However there is no consensus on its definition, and on its correct assessment. Another significant hindrance is that craving is almost certainly a multi-faceted construct. To this respect a three pathway psychobiological model able to differentiate craving into a reward, relief, and obsessive component has been suggested. METHODS: CTQ was administered to 547 control subjects and to 100 alcohol dependent patients. The dimensional structure of the questionnaire, through the principal component analysis, the reliability and the threshold values were evaluated in both the control and clinical sample. RESULTS: The results showed and confirmed that the CTQ is composed of three dimensions. Cronbach's alpha coefficients suggest that the questionnaire is reliable. Alcohol-dependent subjects had a significantly higher mean score as compared to the normative sample in both Reward, Relief, Obsessive craving. Younger age correlated with higher scores on Reward craving (r=0.38; p<0.001) and males reported significantly higher scores than women on Reward craving (t=4.36; p<0.001). DISCUSSION: CTQ showed to be a reliable and valid questionnaire to distinguish a normative sample from pathological individuals. The average scores obtained represent the first normative data available for this questionnaire. Identifying a craving type may represent an important predicting or matching variable for anti-craving psychotropics. More research is needed with respect to CTQ's external validity, i.e. correlations with phenotypic, endophenotypic and genetic indicators of relief, reward and obsessive drinking. PMID- 23642634 TI - A clinically useful social anxiety disorder outcome scale. AB - Increasingly, emphasis is being placed on measurement-based care to improve the quality of treatment. Although much of the focus has been on depression, measurement-based care may be particularly applicable to social anxiety disorder (SAD) given its high prevalence, high comorbidity with other disorders, and association with significant functional impairment. Many self-report scales for SAD currently exist, but these scales possess limitations related to length and/or accessibility that may serve as barriers to their use in monitoring outcome in routine clinical practice. Therefore, the aim of the current study was to develop and validate the Clinically Useful Social Anxiety Disorder Outcome Scale (CUSADOS), a self-report measure of SAD. The CUSADOS was designed to be reliable, valid, sensitive to change, brief, easy to score, and easily accessible, to facilitate its use in routine clinical settings. The psychometric properties of the CUSADOS were examined in 2415 psychiatric outpatients who were presenting for treatment and had completed a semi-structured diagnostic interview. The CUSADOS demonstrated excellent internal consistency, and high item total correlations and test-retest reliability. Within a sub-sample of 381 patients, the CUSADOS possessed good discriminant and convergent validity as it was more highly correlated with other measures of SAD than with other psychiatric disorders. Furthermore, scores were higher in outpatients with a current diagnosis of SAD compared to those without a SAD diagnosis. Preliminary support also was obtained for the sensitivity to change of the CUSADOS in a sample of 15 outpatients receiving treatment for comorbid SAD and depression. Results from this validation study in a large psychiatric sample show that the CUSADOS possesses good psychometric properties. Its brevity and ease of scoring also suggest that it is feasible to incorporate into routine clinical practice. PMID- 23642636 TI - Alcohol use disorders and drinking among survivors of the 9/11 attacks on the World Trade Center in New York City. AB - Research on the relationship of alcohol and disasters has yielded mixed conclusions. Some studies investigate alcohol consumption but others examine alcohol use disorders in relation to disaster. Alcohol consumption and alcohol use disorders have not be studied concurrently in relation to specific disaster trauma exposures. A volunteer sample of 379 individuals from New York City agencies affected by the September 11, 2001 (9/11) attacks on World Trade Center were assessed approximately 3years postdisaster for alcohol consumption and alcohol use disorders relative to specific disaster exposures. Increases in alcohol consumption were relatively small, eventually returning to pre-9/11 levels, with few cases of new alcohol use disorders or alcohol relapse. The findings suggest that postdisaster alcohol use has negligible clinical relevance for most of the population. Scarce disaster resources should be focused on those at identified risk of excessive alcohol use, that is, those with pre-existing alcohol or other psychiatric disorders. PMID- 23642637 TI - Differential effects of the chronic and acute zinc exposure on carnitine composition, kinetics of carnitine palmitoyltransferases I (CPT I) and mRNA levels of CPT I isoforms in yellow catfish Pelteobagrus fulvidraco. AB - The present study is conducted to determine the effect of acute and chronic zinc (Zn) exposure on carnitine concentration, carnitine palmitoyltransferases I (CPT I) kinetics, and expression levels of CPT I isoforms in liver, muscle and heart of yellow catfish Pelteobagrus fulvidraco. To this end, yellow catfish are subjected to chronic waterborne Zn exposure (0.05 mg Zn L(-1), 0.35 mg Zn L(-1) and 0.86 mg Zn L(-1), respectively) for 8 weeks and acute Zn exposure (0.05 mg Zn L(-1) and 4.71 mg L(-1)Zn, respectively) for 96 h, respectively. Reduced Michaelis-Menten constants (Km) and maximal reaction rates (Vmax) values in liver and muscle are observed in fish exposed to chronic Zn concentration. In contrast, Vmax and Km values in heart increase with increasing Zn concentration. Chronic Zn exposure also significantly influences the contents of free carnitine (FC), total carnitine (TC) and acylcarnitine (AC) in liver and heart, but not in muscle. The acute Zn exposure significantly increases FC, AC, TC contents in liver and muscle, but reduces their contents in heart. The chronic and acute Zn exposure influences the mRNA levels of four CPT I isoforms (CPT Ialpha1b, CPT Ibeta, CPT Ialpha2a and CPT Ialpha1a) in liver, muscle and heart. Furthermore, correlations are observed in the mRNA levels between CPT I isoforms and Km, and between isoforms expression and activity of CPT I. Thus, chronic and acute Zn exposure shows differential effects on carnitine content, CPT I kinetics and mRNA levels of four CPT I isoforms in yellow catfish, which provides new mechanism for Zn exposure on lipid metabolism and also novel insights into Zn toxicity in fish. PMID- 23642638 TI - Use of fly ash for remediation of metals polluted sediment--green remediation. AB - The aim of this study was to determine the possibility of using fly ash and combination of kaolinite and fly ash for the solidification/stabilization (S/S) of Ni and Zn contaminated sediment from the Krivaja river basin (Serbia), which represents an extraordinary risk to the environment and belongs to the last quality class in the Serbian sediment classification. Fly ash was used as a stabilising agent because it occurs as a secondary industrial product, so in this way two types of waste are immobilized. Microwave assisted BCR sequential extraction procedure was employed to assess potential of Ni and Zn mobility and risk to the aquatic environment. In order to determine the long-term behavior of the S/S mixture, the semi-dynamic ANS 16.1 leaching test was performed. The existing leaching method was modified and acetic acid and humic acid were also used as leachants instead of deionised water, in order to simulate possible "worst case" leaching conditions for S/S waste being disposed of in a landfill environment (acid rain, floods, etc.). S/S effectiveness was evaluated by measuring the cumulative fractions of metals leached, effective diffusion coefficients - De and leachability indices - LX. X-ray diffraction (XRD), scanning electron microscope (SEM) and energy dispersive X-ray analyzer (EDS) along with leaching tests were implemented to elucidate the mechanisms responsible for immobilization of the Ni and Zn. The controlling leaching mechanism was found to be diffusion, in all treated samples. Overall, the test results indicated that S/S treatment was effective for immobilization of these two types of waste, and can be considered acceptable for "controlled utilization". PMID- 23642639 TI - Quantum chemistry study on the destruction mechanism of 2,3,7,8-TCDD by OH and O(3) radicals. AB - Due to its fundamental importance, the destruction mechanism of the dioxins, as exemplified by 2,3,7,8-TCDD, by OH and O3 radicals was investigated in detail employing Quantum Chemical Calculations in this paper. Theoretical results showed that, OH radical degraded 2,3,7,8-TCDD via substituting chlorine at the 2,3,7,8 positions, while O3 radical degraded 2,3,7,8-TCDD via destructing CC bonds and aromatic ring. Based on the mechanism study, the kinetic parameters of the reactions were also calculated by Transition State Theory. By comparing, the rate constant of the 2,3,7,8-TCDD destruction by OH was found to be much higher than that by O3, which indicated that OH radical have much stronger ability to degrade 2,3,7,8-TCDD than O3 radical. This finding was consistent with the standard electrode potential of OH and O3 radical. The theoretical results in this paper can be believed to supply important theory basis for the further investigation on dioxins removal by using the catalytic oxidation technology. PMID- 23642640 TI - Gross patterns of umbilical cord coiling: correlations with placental histology and stillbirth. AB - INTRODUCTION: The purpose of this study was to define gross patterns of umbilical cord hypercoiling and determine correlations with histological features in the placenta and/or perinatal outcomes such as stillbirth. METHODS: Gross images of placentas with hypercoiled umbilical cords (>3 coils/10 cm) were assigned a major umbilical coiling pattern and the direction (right or left) of the coiling. Definitions of 4 gross coiling patterns were established: undulating, rope, segmented, and linked, each with progressively deeper indentations in cord diameter. Outcome variables obtained from placental pathology reports and maternal medical records included histological abnormalities indicative of significant chronic fetal vascular obstruction, such as fetal vascular thrombi, avascular villi, villous stromal-vascular karyorrhexis, and fetal thrombotic vasculopathy, and stillbirth. RESULTS: 318 placentas/umbilical cords met inclusion criteria. The rope pattern was the most common (52%), followed by the undulating (26%), segmented (19%) and linked (3%) patterns. The segmented and linked gross coiling patterns were significantly correlated with histologic evidence of chronic fetal vascular obstruction and stillbirth, when compared with the ropeand undulating patterns. Cords with right twists were also significantly correlated with histologic evidence of chronic fetal vascular obstruction and stillbirth when compared with cords with left twists. The number of cord coils per 10 cm did not correlate with any of the outcome variables. CONCLUSIONS: Among hypercoiled umbilical cords, specific gross patterns of coiling can be recognized, and patterns with the most significant indentation or pinching of the cord diameter are associated with histological evidence of chronic fetal vascular obstruction and stillbirth. PMID- 23642641 TI - Effects of tactile massage on metabolic biomarkers in patients with type 2 diabetes. AB - AIM: Tactile massage (TM) is a gentle and superficial form of massage. A pilot study of patients with type 2 diabetes in primary care reported a reduction of 0.8% in glycosylated haemoglobin (HbA1c), whereas a randomized study comparing the effects of 10 weeks of TM once per week with relaxation exercises performed once per week as per instructions on a CD found no effects of TM on HbA(1c) in an intention-to-treat analysis. However, a significant reduction in waist circumference (WC) was found between the groups. METHODS: This was a secondary per-protocol analysis of the effect of TM (n=21) compared with relaxation (n=25) on other metabolic biomarkers. Anthropometrics (BMI and WC) and metabolic factors (B HbA(1c), S IGF, fS insulin, S adiponectin, S leptin and fP ghrelin) were assessed, insulin resistance (IR) was determined by modified homoeostasis model assessment (HOMA2-IR) using fP glucose and fS insulin, and ratios of adiponectin to-leptin, adiponectin-to-HOMA-IR, adiponectin-to-WC and adiponectin-to-HbA1c were calculated at baseline, and at 10 weeks and 6 months after the intervention. RESULTS: Significant results adjusted for age, gender and changes in lifestyle and medical factors were shown for WC in women (-6.2 cm [95% CI: -10.4, -1.9]), but not in men. In addition, improvements in the TM group were found for adiponectin and ratios of adiponectin-to-leptin and adiponectin-to-HbA1c levels. CONCLUSION: Our data indicate that TM therapy may affect metabolic markers in type 2 diabetes despite the lack of significant effects on HbA(1c). The clinical implications of our findings need to be evaluated in further studies. PMID- 23642642 TI - Treatment of diabetic ketoacidosis with subcutaneous insulin lispro: a review of the current evidence from clinical studies. AB - AIM: Low-dose intravenous infusions of regular insulin, usually initiated in the emergency department and continued in the intensive care unit (ICU), are the standard care for patients with diabetic ketoacidosis (DKA) to ensure rapid resolution of hyperglycaemia and ketoacidosis. Several studies have evaluated whether subcutaneous injections of the rapid-acting analogue insulin lispro may be an alternative to intravenous insulin infusion for avoiding ICU admissions of uncomplicated DKA cases. METHODS: This review summarizes the current clinical evidence for the effectiveness and safety of subcutaneous insulin lispro injections in non-severe DKA patients. Relevant studies were identified by a systematic literature search through the PubMed database. RESULTS: To date, four small randomized studies (156 patients overall; three studies in adults and one in paediatric patients with diabetes) have directly compared subcutaneous insulin lispro injections every 1-2h vs continuous intravenous infusions of regular insulin. Patients with severe complications were excluded. In all studies, the mean time to resolution of DKA was similar in both treatment groups [range (three studies): lispro 10-14.8h; regular insulin 11-13.2h]. The mean time to resolution of hyperglycaemia, total insulin doses required, number of hospitalization days and number of hypoglycaemic episodes were similar in both treatment groups; no severe complications or DKA recurrences were reported, and one study showed a 39% cost reduction for the insulin lispro group. CONCLUSION: In patients with mild-to moderate DKA, subcutaneous injections of insulin lispro every 1-2h offer a feasible alternative to continuous intravenous infusions of regular insulin, and should now be evaluated in larger, more appropriately powered studies. PMID- 23642643 TI - Prevalence of treatment for diabetes during 1997-2007, and trends in cardiovascular risk factors between 2001 and 2007 according to diabetic treatment, in the IPC (Investigations Preventives et Cliniques; Preventive and Clinical Investigations) cohort. AB - AIM: This study aimed to evaluate changes in the prevalence of glucose-lowering agents in a large, unselected general French population from 1997 to 2007, with specific focus on changes in other cardiovascular risk factors in relation to diabetic status during 2001-2002 and 2006-2007. METHODS: The prevalence of treated diabetes was assessed in a large population who had a health check-up at the "Investigations Preventives et Cliniques" Center between 1997-2007. Baseline characteristics and risk profiles of individuals with and without treatment for diabetes were assessed and compared with data for 2001-2002 and 2006-2007. RESULTS: From 1997 to 2007, the prevalence of treatment for diabetes increased from 0.75% to 1.73% in men and from 0.7% to 2.28% in women. In 2006-2007 compared with 2001-2002, the odds ratios for receiving glucose-lowering agents, adjusted for age, body mass index (BMI) and educational level, were 1.54 (95% CI: 1.28 1.86) in men and 1.59 (95% CI: 1.26-2.03) in women. In those treated for diabetes compared with untreated subjects, greater decreases in blood pressure, cholesterol and glycaemia were found, stress and depression scores improved, and a greater increase in BMI was found. Smoking decreased in both treated and untreated individuals. Physical activity decreased in treated individuals, but remained unchanged in the general population. CONCLUSION: The prevalence of people treated with diabetes increased in the Paris area. Although most concomitant risk factors decreased more in treated individuals than in the general population, physical activity and BMI worsened, thus, emphasizing the need for improving patient education. PMID- 23642644 TI - Extensive diversification is a common feature of Pseudomonas aeruginosa populations during respiratory infections in cystic fibrosis. AB - BACKGROUND: Populations of the Liverpool Epidemic Strain (LES) of Pseudomonas aeruginosa undergo extensive diversification in the cystic fibrosis (CF) lung during long-term chronic infections. METHODS: We analyzed sets of 40 isolates from the sputa of five CF patients, each chronically infected with a different non-LES strain of P. aeruginosa. For each sample (two per patient), diversity was assessed by characterizing nine phenotypic traits. RESULTS: All P. aeruginosa populations were highly diverse, with the majority of phenotypic variation being due to within-sample diversity. CONCLUSIONS: Maintenance of diverse populations in the CF lung is a common feature of P. aeruginosa infections. PMID- 23642645 TI - Antitumor activity of caffeic acid 3,4-dihydroxyphenethyl ester and its pharmacokinetic and metabolic properties. AB - Caffeic acid 3,4-dihydroxyphenethyl ester (CADPE), a natural polyphenol from Sarcandra glabra, has potent in vitro anticancer activity through multiple targets. This study investigated its in vivo anticancer efficacy and its pharmacokinetic and metabolic characteristics. CADPE at any of the dosage regimes (ip 2.5 mg/kg at an interval of 7 h, 12 h, or 24 h for eight days) significantly decreased tumor growth in hepatoma H22 and sarcoma S180 tumor-bearing mice. CADPE also significantly inhibited H22-induced acute ascites development. The in vivo anticancer efficacies of CADPE in these tumor models were equivalent to those of 5-fluorouracil (10 mg/kg, ip) and cyclophosphamide (10 mg/kg, ip), and CADPE did not show any toxicity. A high performance liquid chromatography method with the aid of liquid chromatography/mass spectrometry was established and validated for the pharmacokinetic and metabolic studies of CADPE. CADPE was detected in blood and the organs including liver, kidney, heart, spleen, and brain 1 min after tail intravenous administration, indicating that CADPE was able to quickly distribute to these organs. CADPE was quickly hydrolyzed both in mice and in vitro mice plasma, but was much stable in vitro human plasma, suggesting a better bioavailability of CADPE in human than in mice. The major metabolites of CADPE in mice were caffeic acid, hydroxytyrosol, and a CADPE glucuronide. This was the first time to reveal the pharmacokinetic and metabolic characteristics of CADPE. Taken together, CADPE had potent in vivo antitumor activity and was able to rapidly reach the body organs and to be hydrolyzed in blood to anticancer agents of caffeic acid and hydroxytyrosol. This study suggested that CADPE has the potential for the treatment of cancers and is worthy of further study. PMID- 23642647 TI - Review of group A rotavirus strains reported in swine and cattle. AB - Group A rotavirus (RVA) infections cause severe economic losses in intensively reared livestock animals, particularly in herds of swine and cattle. RVA strains are antigenically heterogeneous, and are classified in multiple G and P types defined by the two outer capsid proteins, VP7 and VP4, respectively. This study summarizes published literature on the genetic and antigenic diversity of porcine and bovine RVA strains published over the last 3 decades. The single most prevalent genotype combination among porcine RVA strains was G5P[7], whereas the predominant genotype combination among bovine RVA strains was G6P[5], although spatiotemporal differences in RVA strain distribution were observed. These data provide important baseline data on epidemiologically important RVA strains in swine and cattle and may guide the development of more effective vaccines for veterinary use. PMID- 23642646 TI - Disentangling neighborhood contextual associations with child body mass index, diet, and physical activity: the role of built, socioeconomic, and social environments. AB - Obesity prevalence among US children and adolescents has tripled in the past three decades. Consequently, dramatic increases in chronic disease incidence are expected, particularly among populations already experiencing health disparities. Recent evidence identifies characteristics of "obesogenic" neighborhood environments that affect weight and weight-related behaviors. This study aimed to examine associations between built, socioeconomic, and social characteristics of a child's residential environment on body mass index (BMI), diet, and physical activity. We focused on pre-adolescent children living in New Haven, Connecticut to better understand neighborhood environments' contribution to persistent health disparities. Participants were 1048 fifth and sixth grade students who completed school-based health surveys and physical measures in fall 2009. Student data were linked to US Census, parks, retailer, and crime data. Analyses were conducted using multilevel modeling. Property crimes and living further from a grocery store were associated with higher BMI. Students living within a 5-min walk of a fast food outlet had higher BMI, and those living in a tract with higher density of fast food outlets reported less frequent healthy eating and more frequent unhealthy eating. Students' reported perceptions of access to parks, playgrounds, and gyms were associated with more frequent healthy eating and exercise. Students living in more affluent neighborhoods reported more frequent healthy eating, less unhealthy eating, and less screen time. Neighborhood social ties were positively associated with frequency of exercise. In conclusion, distinct domains of neighborhood environment characteristics were independently related to children's BMI and health behaviors. Findings link healthy behaviors with built, social, and socioeconomic environment assets (access to parks, social ties, affluence), and unhealthy behaviors with built environment inhibitors (access to fast food outlets), suggesting neighborhood environments are an important level at which to intervene to prevent childhood obesity and its adverse consequences. PMID- 23642648 TI - Hypermutable Staphylococcus aureus strains present at high frequency in subclinical bovine mastitis isolates are associated with the development of antibiotic resistance. AB - Hypermutable bacterial strains with greatly elevated spontaneous mutation rates have been described at high frequencies in various clinically important species, particularly in cystic fibrosis (CF) patients. It has been suggested that such strains can play a major role in the development of chronic respiratory infections. Nevertheless, little information is available regarding the potential association between hypermutation and other chronic infection settings. Here, we investigated the mutation frequencies of 261 Staphylococcus aureus isolates from bovine mastitis cases. The comparative analysis revealed that the subclinical mastitis (SM) isolates harbored significantly more hypermutators than the clinical mastitis (CM) isolates (26/141 versus 0/120, P<0.001, Fisher's exact test). Analysis of mutS and mutL genes, which are major components of the methyl mismatch repair (MMR) system, revealed that 13 of the 14 genetically unrelated hypermutators showed alterations in their deduced MutS and/or MutL amino acid sequences. The hypermutators were much more frequently found to be resistant to all of the 7 antibiotics tested (except sulfafurazole) than the nonmutators. Moreover, the proportion of hypermutators harboring multi-drug resistance was significantly higher than that of the nonmutators as well (P<0.001). Taken together, this work provides evidence that hypermutability plays an important role in antibiotic resistance development during long-term persistence of S. aureus, and reveals that the link between hypermutation and chronic infections appears not to be restricted to respiratory infections alone. PMID- 23642649 TI - Genetic variation and phylogenetic analysis of hemagglutinin genes of H9 avian influenza viruses isolated in China during 2010-2012. AB - Genetic variation and phylogenetic relationships of H9 avian influenza viruses (AIVs) were analyzed based on hemagglutinin (HA) gene sequences of 84 Chinese H9 reference viruses recently available in GenBank, 3 widely used vaccine strains and 29 novel isolates. The novel isolates were obtained from vaccinated poultry flocks in 11 provinces of China during 2010 to 2012. The nucleotide homologies of HA genes of these isolates ranged from 87.8-99.8%, and from 89.8-93.2% as compared with the vaccine strains. Among the 29 novel isolates and the 84 reference viruses, 69.9% of the them belonged to the lineage h9.4.2.5 and had the dominant PSRSSR?GLF motifs in the HA cleavage sites, while 27.4% of the them belonged to the newly emerging lineage h9.4.2.6 and had the dominant PARSSR?GLF motifs, no consecutive basic amino acids insertion, showing the characteristic feature of low-pathogenic AIV. All the lineage h9.4.2.5 viruses and 75% of the lineage h9.4.2.6 viruses had the substitution Q226L (in H3 numbering). Additional potential glycosylation site at residues 313-315 (NCS) were found merely in all the lineage h9.4.2.5 viruses. Our results demonstrated that lineage h9.4.2.5 was more dominant than other lineages as it harbored more viruses that widely distributed in China in recent years. New lineage h9.4.2.6 previously existed mainly in South China had emerged in North China. Updated vaccine and increased veterinary biosecurity on poultry farms and trade markets are needed to prevent and control avian influenza. PMID- 23642650 TI - Short-term outcomes of laparoscopic versus open total gastrectomy: a matched cohort study. AB - BACKGROUND: This study was designed to compare short-term laparoscopic total gastrectomy (LTG) with open total gastrectomy (OTG) outcomes in gastric cancer. METHODS: Seventy patients who underwent total gastrectomy via LTG or OTG were included. All cases were matched for stage, age, and sex by means of statistically generated selection of all gastrectomies performed during the same period. RESULTS: Although the operation time was not longer for LTG, the time required for esophagojejunostomy was significantly longer in LTG than in OTG (43 vs 14 min, P < .05). The incidence of anastomotic complications was higher in the LTG group as well. CONCLUSIONS: Postoperative complications such as anastomotic leakage and stenosis were observed more frequently in LTG. To improve the safety of esophagojejunostomy in LTG, technical innovations should be pursued. PMID- 23642651 TI - Surgical adverse events: a systematic review. AB - BACKGROUND: The aim of this systematic review is to quantify potentially preventable patient harm from the frequency, severity, and preventability of the consequences and causes of surgical adverse events to help target patient safety improvement efforts. DATA SOURCES: Two authors independently reviewed articles retrieved from systematic searches of the Cochrane library, MEDLINE, Embase, PsycINFO, and Cumulative Index to Nursing & Allied Health Literature databases for inclusion and exclusion criteria, methodology, and end points. All retrospective record review studies of adverse events were included. The primary end point was the frequency of general surgery adverse events. The secondary end points were the severity and preventability of consequences and causes. CONCLUSIONS: Fourteen record review studies incorporating 16,424 surgical patients were included. Adverse events occurred in 14.4% of patients (interquartile range [IQR], 12.5% to 20.1%), and potentially preventable adverse events occurred in 5.2% (IQR, 4.2% to 7.0%). The consequences of 3.6% of adverse events (IQR, 3.1% to 4.4%) were fatal, those of 10.4% (IQR, 8.5% to 12.3%) were severe, those of 34.2% (IQR, 29.2% to 39.2%) were moderate, and those of 52.5% (IQR, 49.8% to 55.3%) were minor. Errors in nonoperative management caused more frequent adverse events than errors in surgical technique. PMID- 23642652 TI - Biodegradability enhancement of a leachate after biological lagooning using a solar driven photo-Fenton reaction, and further combination with an activated sludge biological process, at pre-industrial scale. AB - This work proposes an integrated leachate treatment strategy, combining a solar photo-Fenton reaction, to enhance the biodegradability of the leachate from an aerated lagoon, with an activated sludge process, under aerobic and anoxic conditions, to achieve COD target values and nitrogen content according to the legislation. The efficiency and performance of the photo-Fenton reaction, concerning a sludge removal step after acidification, defining the optimum phototreatment time to reach a biodegradable wastewater that can be further oxidized in a biological reactor and, activation sludge biological process, defining the nitrification and denitrification reaction rates, alkalinity balance and methanol dose necessary as external carbon source, was evaluated in the integrated system at a scale close to industrial. The pre-industrial plant presents a photocatalytic system with 39.52 m(2) of compound parabolic collectors (CPCs) and 2 m(3) recirculation tank and, an activated sludge biological reactor with 3 m(3) capacity. Leachate biodegradability enhancement by means of a solar driven photo-Fenton process was evaluated using direct biodegradability tests, as Zahn-Wellens method, and indirect measure according to average oxidation state (AOS), low molecular carboxylic acids content (fast biodegradable character) and humic substances (recalcitrant character) concentration. Due to high variability of leachate composition, UV absorbance on-line measurement was established as a useful parameter for photo-Fenton reaction control. PMID- 23642653 TI - Nitrogen-removal performance and community structure of nitrifying bacteria under different aeration modes in an oxidation ditch. AB - Oxidation-ditch operation modes were simulated using sequencing batch reactors (SBRs) with alternate stirring and aerating. The nitrogen-removal efficiencies and nitrifying characteristics of two aeration modes, point aeration and step aeration, were investigated. Under the same air-supply capacity, oxygen dissolved more efficiently in the system with point aeration, forming a larger aerobic zone. The nitrifying effects were similar in point aeration and step aeration, where the average removal efficiencies of NH4(+) N were 98% and 96%, respectively. When the proportion of anoxic and oxic zones was 1, the average removal efficiencies of total nitrogen (TN) were 45% and 66% under point aeration and step aeration, respectively. Step aeration was more beneficial to both anoxic denitrification and simultaneous nitrification and denitrification (SND). The maximum specific ammonia-uptake rates (AUR) of point aeration and step aeration were 4.7 and 4.9 mg NH4(+)/(gMLVSS h), respectively, while the maximum specific nitrite-uptake rates (NUR) of the two systems were 7.4 and 5.3 mg NO2(-) N/(gMLVSS h), respectively. The proportions of ammonia-oxidizing bacteria (AOB) to all bacteria were 5.1% under point aeration and 7.0% under step aeration, and the proportions of nitrite-oxidizing bacteria (NOB) reached 6.5% and 9.0% under point and step aeration, respectively. The dominant genera of AOB and NOB were Nitrosococcus and Nitrospira, which accounted for 90% and 91%, respectively, under point aeration, and the diversity of nitrifying bacteria was lower than under step aeration. Point aeration was selective of nitrifying bacteria. The abundance of NOB was greater than that of AOB in both of the operation modes, and complete transformation of NH4(+) N to NO3(-)-N was observed without NO2(-)-N accumulation. PMID- 23642655 TI - Does plexin-B1, a semaphorin 4D receptor, play a role in thrombosis? PMID- 23642654 TI - Hydrodynamic characterization of recombinant human fibrinogen species. AB - INTRODUCTION: Fibrinogen is a key component of the blood coagulation system and plays important, diverse roles in several relevant pathologies such as thrombosis, hemorrhage, and cancer. It is a large glycoprotein whose three dimensional molecular structure is not fully known. Furthermore, circulating fibrinogen is highly heterogeneous, mainly due to proteolytic degradation and alternative mRNA processing. Recombinant production of human fibrinogen allows investigating the impact on the three-dimensional structure of specific changes in the primary structure. METHODS: We performed analytical ultracentrifugation analyses of a full-length recombinant human fibrinogen, its counterpart purified from human plasma, and a recombinant human fibrinogen with both Aalpha chains truncated at amino acid 251, thus missing their last 359 amino acid residues. RESULTS: We have accurately determined the translational diffusion and sedimentation coefficients (Dt(20,w)(0), s(20,w)(0)) of all three species. This was confirmed by derived molecular weights within 1% for the full length species, and 5% for the truncated species, as assessed by comparison with SDS-PAGE/Western blot analyses and primary structure data. No significant differences in the values of Dt(20,w)(0) and s(20,w)(0) were found between the recombinant and purified full length human fibrinogens, while slightly lower and higher values, respectively, resulted for the recombinant truncated human fibrinogen compared to a previously characterized purified human fibrinogen fragment X obtained by plasmin digestion. CONCLUSIONS: Full-length recombinant fibrinogen is less polydisperse but hydrodynamically indistinguishable from its counterpart purified from human plasma. Recombinant Aalpha251-truncated human fibrinogen instead behaves differently from fragment X, suggesting a role for the Bbeta residues 1 52 in inter-molecular interactions. Overall, these new hydrodynamic data will constitute a reliable benchmark against which models of fibrinogen species could be compared. PMID- 23642656 TI - Fox baiting against Echinococcus multilocularis: contrasted achievements among two medium size cities. AB - In Europe, most cities are currently colonized by red foxes (Vulpes vulpes), which are considered to be the main definitive host of the zoonotic cestode Echinococcus multilocularis. The risk of transmission to humans is of particular concern where high fox populations overlap with high human populations. The distribution of baits containing praziquantel has successfully reduced the infection pressure in rural areas and in small plots within large cities. The purpose of this study was to assess its efficiency in two medium size cities (less than 100,000 inhabitants) in areas of high human alveolar echinococcosis incidence. From August 2006 to March 2009, 14 baiting campaigns of praziquantel treatment were run in Annemasse and Pontarlier (Eastern France), each of which encompassed 33 km(2), with a density of 40 baits/km(2). The bait consumption appeared to be lower in strictly urban context compared to suburban areas (78.9% vs. 93.4%) and lower in Annemasse than in Pontarlier (82.2% vs. 89.5%). During our study, the prevalence of E. multilocularis, as assessed by EM-ELISA on fox faeces collected in the field in Annemasse, was lower within the treated area than in the rural control area. A "before/during" treatment comparison revealed a significant decrease of spring prevalence from 13.3% to 2.2%. No significant change in prevalence was detected in Pontarlier (stable prevalence: 9.1%) where the contamination of the treated area followed the temporal trend observed in the control area. There, a greater resilience of the parasite's life cycle, probably due to a strong pressure of recontamination from outside the treated area, may have counteracted the prophylaxis treatment. These contrasted outcomes suggest that the frequency of fox anthelmintic treatment should be adapted to the local situation. PMID- 23642657 TI - An interview with Barry Halliwell. PMID- 23642658 TI - The diverse therapeutic actions of pregabalin: is a single mechanism responsible for several pharmacological activities? AB - Pregabalin is a specific ligand of the alpha2-delta (alpha2-delta) auxiliary subunit of voltage-gated calcium channels. A growing body of evidence from studies of anxiety and pain indicate that the observed responses with pregabalin may result from activity at the alpha2-delta auxiliary protein expressed presynaptically, in several different circuits of the central nervous system (CNS). The disorders that appear to be effectively treated with pregabalin are thematically linked by neuronal dysregulation or hyperexcitation within the CNS. This review proposes how binding to the alpha2-delta protein target in different regions of the CNS may contribute to the observed clinical activity of pregabalin, as well as to the adverse event profile of the compound. Whether this compound regulates synaptic function via alpha2-delta in additional conditions is yet to be discovered. The potential of pregabalin to regulate neuronal hyperactivity involving other CNS circuits will require further exploration. PMID- 23642659 TI - Asymmetric perturbation of pLGICs: action! PMID- 23642660 TI - Effect of wheelchair mass, tire type and tire pressure on physical strain and wheelchair propulsion technique. AB - The purpose of this study was to evaluate the effect of wheelchair mass, solid vs. pneumatic tires and tire pressure on physical strain and wheelchair propulsion technique. 11 Able-bodied participants performed 14 submaximal exercise blocks on a treadmill with a fixed speed (1.11 m/s) within 3 weeks to determine the effect of tire pressure (100%, 75%, 50%, 25% of the recommended value), wheelchair mass (0 kg, 5 kg, or 10 kg extra) and tire type (pneumatic vs. solid). All test conditions (except pneumatic vs. solid) were performed with and without instrumented measurement wheels. Outcome measures were power output (PO), physical strain (heart rate (HR), oxygen uptake (VO2), gross mechanical efficiency (ME)) and propulsion technique (timing, force application). At 25% tire pressure PO and subsequently VO2 were higher compared to 100% tire pressure. Furthermore, a higher tire pressure led to a longer cycle time and contact angle and subsequently lower push frequency. Extra mass did not lead to an increase in PO, physical strain or propulsion technique. Solid tires led to a higher PO and physical strain. The solid tire effect was amplified by increased mass (tire * mass interaction). In contrast to extra mass, tire pressure and tire type have an effect on PO, physical strain or propulsion technique of steady-state wheelchair propulsion. As expected, it is important to optimize tire pressure and tire type. PMID- 23642661 TI - Single-stage cartilage repair in the knee with microfracture covered with a resorbable polymer-based matrix and autologous bone marrow concentrate. AB - BACKGROUND: Different single-stage surgical approaches are currently under evaluation to repair focal cartilage lesions. This study aims to analyze the clinical and histological results after treatment of focal condylar articular lesions of the knee with microfracture and subsequent covering with a resorbable polyglycolic acid/hyaluronan (PGA -HA) matrix augmented with autologous bone marrow concentrate (BMC). METHODS: Nine patients with focal lesions of the condylar articular cartilage were consecutively treated with arthroscopic PGA -HA covered microfracture and bone marrow concentrate (PGA -HA-CMBMC). Patients were retrospectively assessed using standardized assessment tools and magnetic resonance imaging (MRI). Five patients consented to undergo second look arthroscopy and 2 consented biopsy harvest. RESULTS: All the patients but one showed improvement in clinical scoring from the pre-operative situation to the latest follow-up (average 22+/-2months). The mean IKDC subjective score, Lysholm score, VAS and the median Tegner score significantly increased from baseline to the latest follow-up. Cartilage macroscopic assessment at 12months revealed that one repair appeared normal, three almost normal and one appeared abnormal. Histological analysis proofed hyaline-like cartilage repair tissue formation in one case. MRI at 8 to 12months follow-up showed complete defect filling. CONCLUSIONS: The first clinical experience with single-stage treatment of focal cartilage defects of the knee with microfracture and covering with the PGA -HA matrix augmented with autologous BMC (PGA -HA-CMBMC) suggests that it is safe, it improves knee function and has the potential to regenerate hyaline-like cartilage. LEVEL OF EVIDENCE: IV, case series. PMID- 23642662 TI - Recently discovered human polyomaviruses in lesional and non-lesional skin of patients with primary cutaneous T-cell lymphomas. PMID- 23642663 TI - Emerging role for the killer-cell immunoglobulin-like receptors genotype, in the susceptibility of skin diseases. AB - NK cells are a major group of immune cells responsible for the phenomenon of natural, innate cytotoxicity. One of the better studied receptors of human NK cells are killer cell immunoglobulin-like receptors (KIR) responsible for checking the presence of MHC class I molecules, which serve as their ligands. Although previously treated as specific for NK cells, nowadays these receptors are known to also occur on T cells. Genetics of KIR molecules is very complicated, what create a great variability of haplotypes in various populations world-wide. In addition, some KIR are known to recognize HLA-C (epitopes C1 or C2), HLA-B (Bw4) or HLA-A (A3 and/or A11) molecules. Therefore, this makes a huge diversity of reactions among individuals, depending on the presence or absence of given KIR and their ligands, hence differential susceptibility to several diseases, including various dermatoses. This paper underlines the important role of both KIR genotypes and HLA class I genes with reference to the various skin diseases. PMID- 23642664 TI - The epidermal Integrin beta-1 and p75NTR positive cells proliferating and migrating during wound healing produce various growth factors, while the expression of p75NTR is decreased in patients with chronic skin ulcers. AB - BACKGROUND: More effective treatment strategies are needed for the chronic skin ulcers. Recently, it has been reported that clinical application of stem cells improve wound healing. OBJECTIVE: We aimed to determine the dynamic time-course movement of epidermal stem cell markers especially p75 neurotrophin receptor (p75NTR) and Integrin beta-1 in wound healing process. Furthermore, we also investigated the presence of these markers in human. METHODS: Epidermal Integrin beta-1(+) and p75NTR(+) cells were counted in wound healing process in mice. Both cells were also counted in human skin specimen obtained from chronic skin ulcers and healthy controls. Growth factor gene expression levels by purified mouse epidermal p75NTR(+) cells were also analyzed using real-time RT-PCR. RESULTS: Integrin beta-1(+) and p75NTR(+) cells were proliferated from 3 days after wounding. Reepithelization was completed 7 days after wounding, and the numbers of cells were returned to the baseline levels by 14 days after wounding. Integrin beta-1(+) cells were proliferated in the basal layer, and p75NTR(+) cells were proliferated in the upper layer of epidermis. In human skin, Integrin beta-1(+) and p75NTR(+) cells were 81%+/-12% and 36%+/-15% of the basal cells, respectively. In patients with chronic skin ulcers, the percentage of Integrin beta-1(+) cells in the epidermis was identical to healthy controls. Surprisingly, p75NTR(+) cells were significantly decreased in chronic skin ulcer patients (1.2%+/-2.6%; p<0.0005) compared to healthy controls. Purified mouse epidermal p75NTR(+) cells expressed higher transforming growth factor-beta2 and vascular endothelial growth factor-alpha transcripts and lower epidermal growth factor transcripts than p75NTR(-) cells. CONCLUSION: These results suggest that Integrin beta-1(+) and p75NTR(+) cells play an important role in wound healing process, and that p75NTR may be a key molecule and a candidate for new therapeutic target besides preexisting molecules for chronic skin ulcer patients. PMID- 23642665 TI - The potential of materials analysis by electron rutherford backscattering as illustrated by a case study of mouse bones and related compounds. AB - Electron Rutherford backscattering (ERBS) is a new technique that could be developed into a tool for materials analysis. Here we try to establish a methodology for the use of ERBS for materials analysis of more complex samples using bone minerals as a test case. For this purpose, we also studied several reference samples containing Ca: calcium carbonate (CaCO(3)) and hydroxyapatite and mouse bone powder. A very good understanding of the spectra of CaCO(3) and hydroxyapatite was obtained. Quantitative interpretation of the bone spectrum is more challenging. A good fit of these spectra is only obtained with the same peak widths as used for the hydroxyapatite sample, if one allows for the presence of impurity atoms with a mass close to that of Na and Mg. Our conclusion is that a meaningful interpretation of spectra of more complex samples in terms of composition is indeed possible, but only if widths of the peaks contributing to the spectra are known. Knowledge of the peak widths can either be developed by the study of reference samples (as was done here) or potentially be derived from theory. PMID- 23642666 TI - Reconstruction of the scalp, calvarium, and frontal sinus. AB - Scalp and cranial deformities are common after trauma or ablative surgery. Local flaps and free flaps may be used in reconstruction of soft tissue defects, and autogenous bone or alloplastic bone substitutes may be used for cranioplasty procedures. Injuries to the frontal sinus, particularly when complicated by leak of cerebrospinal fluid or obstruction of the nasofrontal outflow tract, represent special challenges. Further studies are recommended to improve the multidisciplinary management of these complex, debilitating conditions, in anticipation of enhanced function and cosmesis, reduced donor site morbidity, and improved surgical outcomes. PMID- 23642667 TI - Acquired defects of the nose and naso-orbitoethmoid (NOE) region. AB - Nasal injuries coupled with midface fractures of the orbit and ethmoids constitute a nasoorbitoethmoid (NOE) fracture pattern, which is typically the most challenging facial fracture to repair. Hard and soft tissue defects of this region may require advanced reconstruction techniques, including local rotational flaps, free tissue transfer, and even prosthetics. The restoration of form and function dictates treatment, and the success of primary repair is paramount, because secondary correction is challenging in this area of the midface. Because of the complex nature of this region, this discussion is divided into hard tissue defects, with a focus on trauma, and soft tissue defects, with a focus on oncology. PMID- 23642668 TI - Zygoma reconstruction. AB - Ideal reconstruction of the zygoma position is essential in restoring facial width, projection, and symmetry. Reconstruction should be focused on the zygoma's 4 articulations and restoring the vertical and horizontal pillars of the facial skeleton. This article describes the applied surgical anatomy as it relates to zygomatic deformities, surgical approaches, and reconstruction. The basis for diagnosing and classifying zygoma deformities as they relate to severity of injury and associated displacement, comminution, and comorbidities is also discussed. Traditional and contemporary concepts in posttraumatic, postablative, and esthetic reconstruction are also described. PMID- 23642669 TI - Maxillary reconstruction. AB - Postablative maxillary defects present a wide range of functional and esthetic challenges. Several classification schemes have added clarity to the subject, but the surgeon must maintain a clear vision of the defect and appreciate its reconstructive implications. Local tissue flaps remain valuable tools in the reconstruction of small isolated defects of the posterior maxilla and palate; however, microvascular free flaps have eclipsed prosthetic obturators as the mainstay of therapy in advanced postablative defects of the maxilla. Many excellent microvascular options exist and the overall objectives remain to preserve oral function in accordance with the needs of the patient. PMID- 23642670 TI - Zygoma implant reconstruction of acquired maxillary bony defects. AB - The reconstruction of acquired maxillary bony defects after pathologic ablation, infectious debridement, avulsive trauma, or previously failed reconstructions with zygoma implants represents a treatment alternative that is safe, predictable, and cost-effective. Still the single most important factor for treatment success of these complex reconstructions is the implementation of a team approach between the surgeon and the restorative dentist. The focus of this article is to review the surgical and prosthetic nuances to successfully reconstruct acquired maxillary defects with zygoma implants. PMID- 23642671 TI - Reconstruction of acquired oromandibular defects. AB - Acquired defects of the mandible resulting from trauma, infection, osteoradionecrosis, and ablative surgery of the oral cavity and lower face are particularly debilitating. Familiarity with mandibular and cervical anatomy is crucial in achieving mandibular reconstruction. The surgeon must evaluate which components of the hard and soft tissue are missing in selecting a method of reconstruction. Complexity of mandibular reconstruction ranges from simple rigid internal fixation to microvascular free tissue transfer, depending on defect- and patient-related factors. Modern techniques for microvascular tissue transfer provide a wide array of reconstructive options that can be tailored to patients' specific needs. PMID- 23642672 TI - Reconstruction of acquired temporomandibular joint defects. AB - Various conditions are responsible for the development of acquired temporomandibular joint (TMJ) defects, the reconstruction of which represents a unique challenge, as the TMJ plays an important role in the functioning of the jaw including mastication, deglutition, and phonation. Autogenous reconstructions such as costochondral or sternoclavicular joint graft continue to be the best option in children, owing to their ability to transfer a growth center. In adults, alloplastic reconstructions are a safe and predictable option. Vascularized tissue transfers have also become a popular and reliable way to restore these defects. PMID- 23642673 TI - Static and dynamic repairs of facial nerve injuries. AB - The patient with facial paralysis presents a daunting challenge to the reconstructive surgeon. A thorough evaluation is key in directing the surgeon to the appropriate treatment methods. Aggressive and immediate exploration with primary repair of the facial nerve continues to be the standard of care for traumatic transection of the facial nerve. Secondary repair using dynamic techniques is preferred over static procedures, because the outcomes have proved to be superior. However, patients should be counseled that facial movement and symmetry are difficult to mimic and none of the procedures described is able to restore all of the complex vectors and overall balance of facial movement and expression. PMID- 23642674 TI - Surgical navigation in reconstruction. AB - Navigational systems are paramount in solving today's traffic dilemmas, and have important applications in the human body. Current imaging must be diagnostic and is often dictated by the radiologist, but it is up to the surgeon to consider surgical procedures and to decide in which case surgical navigation (SN) has advantages. Knowledge of the surgical capabilities of SN is indispensable. The aims of this article are to support real-time image-guided SN, present routine and advanced cases with precise preoperative planning, and show the scientific capabilities of SN. PMID- 23642675 TI - Fallopian tube invasive molar disease. PMID- 23642676 TI - Vitamin K treatment of brodifacoum poisoning in a pregnant woman. PMID- 23642677 TI - Cadmium exposure induces hematuria in Korean adults. AB - INTRODUCTION: Toxic heavy metals have adverse effects on human health. However, the risk of hematuria caused by heavy metal exposure has not been evaluated. METHODS: Data from 4701 Korean adults were obtained in the Korean National Health and Nutritional Examination Survey (2008-2010). Blood levels of the toxic heavy metals cadmium, lead, and mercury were measured. Hematuria was defined as a result of >=+1 on a urine dipstick test. The odds ratios (ORs) for hematuria were measured according to the blood heavy metal levels after adjusting for multiple variables. RESULTS: Individuals with blood cadmium levels in the 3rd and 4th quartiles had a greater OR for hematuria than those in the 1st quartile group: 3rd quartile, 1.35 (1.019-1.777; P=0.037); 4th quartile, 1.52 (1.140-2.017; P=0.004). When blood cadmium was considered as a log-transformed continuous variable, the correlation between blood cadmium and hematuria was significant: OR, 1.97 (1.224-3.160; Ptrend=0.005). In contrast, no significant correlations between hematuria and blood lead or mercury were found in the multivariate analyses. DISCUSSION: The present study shows that high cadmium exposure is associated with a risk of hematuria. PMID- 23642680 TI - Perilipin and adipophilin expression in sebaceous carcinoma and mimics. AB - Although adipophilin has been reported to be a sensitive marker for sebaceous carcinoma, others have noted its expression in squamous cell carcinoma and a variety of noncutaneous tumors, suggesting that lipid droplet accumulation is a frequent feature of neoplastic cells. We investigated the expression of adipophilin and perilipin in 101 cutaneous carcinomas. They included 30 cases of sebaceous carcinoma, 28 squamous cell carcinoma with clear cell change (18 invasive and 10 in situ tumors), 8 hidradenocarcinomas, 1 spiradenocarcinoma, 10 porocarcinomas, 4 malignant chondroid syringomas, 1 malignant cylindroma, 7 apocrine carcinomas, 6 eccrine carcinomas, 5 aggressive digital papillary adenocarcinomas, and 1 pilomatrical carcinoma. Adipophilin stained the rim of cytoplasmic lipid droplets in various tumor types, including sebaceous carcinomas (30/30, 100%), squamous cell carcinoma with clear cell change (21/28, 75%), and eccrine-apocrine carcinomas (25/43, 58%). On the other hand, perilipin expression was seen in 13 (43%) of 30 sebaceous carcinoma and only 1 hidradenocarcinoma. The remaining 28 squamous cell carcinomas with clear cell change and 42 eccrine apocrine carcinomas were negative. Although specific for invasive sebaceous carcinoma, perilipin expression was not helpful in distinguishing sebaceous carcinoma in situ from squamous cell carcinoma in situ with clear cell change. The expression of adipophilin seen in variety of cutaneous tumors suggests that the biosynthesis of lipid is altered in these neoplasms. PMID- 23642683 TI - Tobacco control--political will needed. PMID- 23642684 TI - HIV: population-based approaches to a pandemic. PMID- 23642681 TI - Predictors and risk of pacemaker implantation after the Cox-maze IV procedure. AB - BACKGROUND: The incidence of and causes for permanent pacemaker implantation (PPM) after surgical arrhythmia procedures remain poorly understood because of the varied lesion patterns and energy sources reported in small series. This study characterized the incidence, indications, and risk factors for PPM after the Cox-maze IV (CMIV) procedure when performed as either a lone or a concomitant procedure. METHODS: A retrospective analysis of 340 patients undergoing a CMIV as either a lone (n = 112) or a concomitant (n = 228) procedure was conducted. The incidence, indication, and variables associated with PPM implantation within 1 year of the operation were assessed. Follow-up was conducted at 30 days and 1 year and was 90% complete. RESULTS: The incidence of PPM after a lone CMIV procedure was 5%. Patients with concomitant cardiac operations had a nonsignificant increase in PPM insertion at 30 days (11% vs 5%, p = 0.14) and 1 year (15% vs 6%, p = 0.06) when compared with lone CMIV patients. Of patients who required pacemakers, sinus node dysfunction was present in 79% (35/44) of patients in the entire series and in 88% (8/9) after lone CMIV. After PPM, 84% (37/44) of patients remained paced at last follow-up. Multivariate analysis identified age (odds ratio = 1.10 [1.06-1.14], p < 0.001) as the only variable associated with higher risk of a PPM after any CMIV procedure. CONCLUSIONS: The risk of PPM implantation after a lone CMIV is 5% and increases with age. The need for a PPM after a CMIV is largely due to SA node dysfunction, which appears unlikely to recover. These data should help physicians counsel patients regarding the perioperative risks associated with the CMIV. PMID- 23642682 TI - Analyzing "failure to rescue": is this an opportunity for outcome improvement in cardiac surgery? AB - BACKGROUND: In the setting of a statewide quality collaborative approach to the review of cardiac surgical mortalities in intensive care units (ICUs), variations in complication-related outcomes became apparent. Utilizing "failure to rescue" methodology (FTR; the probability of death after a complication), we compared FTR rates after adult cardiac surgery in low, medium, and high mortality centers from a voluntary, 33-center quality collaborative. METHODS: We identified 45,904 patients with a Society of Thoracic Surgeons predicted risk of mortality who underwent cardiac surgery between 2006 and 2010. The 33 centers were ranked according to observed-to-expected ratios for mortality and were categorized into 3 equal groups. We then compared rates of complications and FTR. RESULTS: Overall unadjusted mortality was 2.6%, ranging from 1.5% in the low-mortality group to 3.6% in the high group. The rate of 17 complications ranged from 19.1% in the low group to 22.9% in the high group while FTR rates were 6.6% in the low group, 10.4% in the medium group, and 13.5% in the high group (p < 0.001). The FTR rate was significantly better in the low mortality group for the majority of complications (11 of 17) with the most significant findings for cardiac arrest, dialysis, prolonged ventilation, and pneumonia. CONCLUSIONS: Low mortality hospitals have superior ability to rescue patients from complications after cardiac surgery procedures. Outcomes review incorporating a collaborative multi hospital approach can provide an ideal opportunity to review processes that anticipate and manage complications in the ICU and help recognize and share "differentiators" in care. PMID- 23642685 TI - Guantanamo: hunger strikes and a doctor's duty. PMID- 23642686 TI - Saving lives with the US Tobacco Control Act. PMID- 23642687 TI - Linking child survival and child development for health, equity, and sustainable development. PMID- 23642688 TI - Tocilizumab versus adalimumab for rheumatoid arthritis. PMID- 23642690 TI - Judith MacKay: self-made scourge of the tobacco industry. PMID- 23642691 TI - Assessing catheter-associated urinary tract infection. PMID- 23642692 TI - Assessing catheter-associated urinary tract infection. PMID- 23642693 TI - Regorafenib for metastatic colorectal cancer. PMID- 23642694 TI - Assessing catheter-associated urinary tract infection - Authors' reply. PMID- 23642695 TI - Regorafenib for metastatic colorectal cancer. PMID- 23642696 TI - Regorafenib for metastatic colorectal cancer. PMID- 23642697 TI - Regorafenib for metastatic colorectal cancer - Authors' reply. PMID- 23642698 TI - Understanding the Tobacco Control Act: efforts by the US Food and Drug Administration to make tobacco-related morbidity and mortality part of the USA's past, not its future. AB - The USA has a rich history of public health efforts to reduce morbidity and mortality from tobacco use. Comprehensive tobacco-prevention programmes, when robustly implemented, reduce the prevalence of youth and adult smoking, decrease cigarette consumption, accelerate declines in tobacco-related deaths, and diminish health-care costs from tobacco-related diseases. Effective public health interventions include raising the price of tobacco products, smoke-free policies, counter-marketing campaigns, advertising restrictions, augmenting access to treatment for tobacco use through insurance coverage and telephone help lines, and comprehensive approaches to prevent children and adolescents from accessing tobacco products. The US Food and Drug Administration (FDA) has six major areas of regulatory authority: regulation of tobacco products; regulation of the advertising, marketing, and promotion of tobacco products; regulation of the distribution and sales of tobacco products; enforcement of the provisions of the Tobacco Control Act and tobacco regulations; regulatory science to support FDA authorities and activities; and public education about the harms of tobacco products and to support FDA regulatory actions. With passing of the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) in June, 2009, important new regulatory approaches were added to the tobacco prevention and control arsenal. PMID- 23642699 TI - Tobacco control in Asia. AB - For the purpose of this article, Asia refers to WHO's combined South-East Asia and Western Pacific regions and thus includes Australia and New Zealand. Asia has the highest number of tobacco users and is the prime target of transnational tobacco companies. The future of global tobacco control rests in this region and the challenges are clear. China, India, and Indonesia are key markets and Asia is a frontrunner in tobacco control measures, such as plain packaging of cigarettes. Some countries in Asia have a long history of tobacco control activities beginning in the 1970s, and WHO's Western Pacific Region is still the only region where all countries have ratified WHO's Framework Convention on Tobacco Control. We reviewed the history, research, epidemiology, tobacco control action, obstacles, and potential responses and solutions to the tobacco epidemic in this region. Levels of development, systems of government, and population size are very different between countries, with population size ranging from 1500 to 1.3 billion, but similarities exist in aspects of the tobacco epidemic, harms caused, obstacles faced, and tobacco control actions needed. PMID- 23642700 TI - Tobacco control efforts in Europe. AB - Smoking is prevalent across Europe, but the severity and stage of the smoking epidemic, and policy responses to it, vary substantially between countries. Much progress is now being made in prohibition of paid-for advertising and in promotion of smoke-free policies, but mass media campaigns are widely underused, provision of services for smokers trying to quit is generally poor, and price policies are undermined by licit and illicit cheap supplies. Monitoring of prevalence is inadequate in many countries, as is investment in research and capacity to address this largest avoidable cause of death and disability across Europe. However, grounds for optimism are provided by progress in implementation of the WHO Framework Convention on Tobacco Control, and in the development of a new generation of nicotine-containing devices that could enable more widespread adoption of harm-reduction strategies. The effect of commercial vested interests has been and remains a major barrier to progress. PMID- 23642701 TI - Pachymeningitis after meningococcal infection. PMID- 23642702 TI - Environmental toxicological fate prediction of diverse organic chemicals based on steady-state compartmental chemical mass ratio using quantitative structure-fate relationship (QSFR) models. AB - Four quantitative prediction models for steady-state compartmental chemical mass concentrations (Wn,g) were obtained from structural information, physiochemical properties, degradation rate and transport coefficients of 455 diverse organic chemicals using chemometric tools in a quantitative structure-fate relationship (QSFR) study. The mass ratio assessment of environmentally prevalent organic chemicals may be helpful to predict their toxicological fate in the ecosystems. Four sets of mass ratios [(1) log(Wair) from water emissions (water to air compartment), (2) log(Wair) from air emissions (within different zones of the air compartment), (3) log(Wwater) from water emissions (within different zones of the water compartment) and (4) log(Wwater) from air emissions (air to water compartment)] have been used. The developed models using genetic function approximation followed by multiple linear regression (GFA-MLR) and subsequent partial least squares (PLS) treatment identify only four descriptors for log(Wair) from water emission, six descriptors for log(Wair) from air emission, five descriptors for log(Wwater) from water emission and seven descriptors for log(Wwater) from air emission for predicting efficiently a large number of test set chemicals (ntest=182). The conclusive models suggest that descriptors such as partition coefficients (Kaw, Kow and Ksw), degradation parameters (Ksoil,Kwater and Kair), vapor pressure (Pv), diffusivity (Dwater), spatial descriptors (Jurs WNSA-1, Jurs-WNSA-2, Jurs-WPSA-3, Jurs-FNSA-3 and Density), thermodynamic descriptors (MolRef and AlogP98), electrotopological state indices (S_dsN, S_ssNH and S_dsCH) are important for predicting the chemical mass ratios. The developed models may be applicable in toxicological fate prediction of diverse chemicals in the ecosystems. PMID- 23642704 TI - Upper-limb motor control in patients after stroke: attentional demands and the potential beneficial effects of arm support. AB - The goal of this study was to investigate the attentional load of using the upper limb in moderately and mildly affected patients after stroke, with and without arm support. Ten patients with stroke (4 mild and 6 moderate paresis) and ten healthy, gender- and age-matched control subjects performed a dual-task experiment that consisted of a circle drawing task and an auditive Stroop task. Complexity of the motor task was manipulated by supporting the arm against gravity. Individual motor (area*speed) and cognitive (accuracy/reaction time) scores during the dual-task conditions were converted into percentage scores relative to the respective single-task scores and then combined in a single measure of net dual-task performance. Without arm support, only moderately affected patients showed significantly greater side differences in dual-task performance to the detriment of the affected upper limb. With arm support, no side differences were found for any of the three groups. Thus, the hypothesis that patients with moderate upper-limb paresis suffer from a lack of automaticity of motor control was substantiated by the dual-task condition. Furthermore, supporting the arm reduced the attentional load of using the affected side. PMID- 23642703 TI - Contribution of endoplasmic reticulum Ca2+ regulatory mechanisms to the inflammation-induced increase in the evoked Ca2+ transient in rat cutaneous dorsal root ganglion neurons. AB - Persistent inflammation results in an increase in the magnitude and duration of high K(+)-evoked Ca(2+) transients in putative nociceptive cutaneous dorsal root ganglion (DRG) neurons. The purpose of the present study was to determine whether recruitment of Ca(2+)-induced Ca(2+) release (CICR) contributes to these inflammation-induced changes. Acutely dissociated, retrogradely labeled cutaneous DRG neurons from naive and complete Freund's adjuvant inflamed adult male Sprague Dawley rats were studied with ratiometric microfluorimetry. Ryanodine only attenuated the duration but not magnitude of the high K(+)-evoked Ca(2+) transient in neurons from inflamed rats. However, there was no significant impact of inflammation on the potency or efficacy of ryanodine-induced block of the caffeine-evoked Ca(2+) transient, or the impact of sarco-endoplasmic reticulum ATPase (SERCA) inhibition on the high K(+)-evoked Ca(2+) transient. Furthermore, while there was no change in the magnitude, an inflammation-induced increase in the duration of the caffeine-evoked Ca(2+) transient was only observed with a prolonged caffeine application. In contrast to the high K(+)-evoked Ca(2+) transient, there was no evidence of direct mitochondrial involvement or that of the Ca(2+) extrusion mechanism, the Na(+)/Ca(2+) exchanger, on the caffeine evoked Ca(2+) transient, and block of SERCA only increased the duration of this transient. These results indicate the presence of Ca(2+) regulatory domains in cutaneous nociceptive DRG neurons within which cytosolic Ca(2+) increased via influx and release are highly segregated. Furthermore, our results suggest that changes in neither CICR machinery nor the coupling between Ca(2+) influx and CICR are primarily responsible for the inflammation-induced changes in the evoked Ca(2+) transient. PMID- 23642705 TI - [Finger bone and joint trauma of the hand in children]. AB - The hand is the most commonly injured location of a child. Fractures of the digits are the most frequent lesions with two specific locations: 1) in the young child, the fracture is usually a crush injury, such as occurs when a hand gets caught in a door, with lesion of the distal phalanx; soft tissue associated injuries are the main problem in this location; 2) in the older child, the fracture is usually secondary to recreational sports, with lesion on the proximal phalanx of the second and fifth digits. Dislocations or sprains are less common. Most interphalangeal joint injuries occur at the proximal interphalangeal joint and are secondary to hyperextension with as results a volar plate injury. Most fingers injuries in children are treated non operatively with a favorable outcome. The treating physician should however identify those clinical situations that require surgery, as complications are most commonly due to a failure to identify and treat an injury requiring an operation acutely. These injuries include intra-articular fractures, displaced phalangeal neck fractures, and malrotated fractures. Malrotation or intra-articular malunion have no remodeling capacity. Non-union and stiff digits are uncommon but a significant trauma or a high-energy mechanism with severe soft tissues injuries appears to be a factor of risk. PMID- 23642706 TI - Commentary on: Anticholinergic therapy vs onabotulinumtoxinA for urgency urinary incontinence. PMID- 23642708 TI - Obesity and asthma: a coincidence or a causal relationship? A systematic review. AB - BACKGROUND AND AIM: Epidemiological data has established increasing adiposity as a risk factor for incident asthma. However, the mechanisms underlying the association between obesity and asthma are incompletely understood. In the present paper, we review current knowledge of possible mechanisms mediating the observed association between obesity and asthma. METHODS: Systematic literature review. RESULTS: Obesity and asthma share some etiological factors, such as a common genetic predisposition and effects of in utero conditions, and may also have common predisposing factors such as physical activity and diet. Obesity results in important changes in the mechanical properties of the respiratory system which could explain the occurrence of asthma. However, there are also plausible biological mechanisms whereby obesity could be expected to either cause or worsen asthma. These include co-morbidities such as gastro-oesophageal reflux, complications from sleep-disordered breathing, breathing at low lung volumes, chronic systemic inflammation, and endocrine factors, including adipokines and reproductive hormones. Obesity related asthma is in general not associated with eosinophilic airway inflammation, and adipokines are likely to play important roles in the inflammatory pathogenesis of asthma in obese individuals. CONCLUSION: The association between obesity and asthma is not straightforward, and further knowledge is clearly needed, as understanding the underlying mechanisms may lead to new therapeutic options for this high-risk part of the asthma population. PMID- 23642707 TI - Where no synapses go: gatekeepers of circuit remodeling and synaptic strength. AB - Growth inhibitory molecules in the adult mammalian central nervous system (CNS) have been implicated in the blocking of axonal sprouting and regeneration following injury. Prominent CNS regeneration inhibitors include Nogo-A, oligodendrocyte myelin glycoprotein (OMgp), and chondroitin sulfate proteoglycans (CSPGs), and a key question concerns their physiological role in the naive CNS. Emerging evidence suggests novel functions in dendrites and at synapses of glutamatergic neurons. CNS regeneration inhibitors target the neuronal actin cytoskeleton to regulate dendritic spine maturation, long-term synapse stability, and Hebbian forms of synaptic plasticity. This is accomplished in part by antagonizing plasticity-promoting signaling pathways activated by neurotrophic factors. Altered function of CNS regeneration inhibitors is associated with mental illness and loss of long-lasting memory, suggesting unexpected and novel physiological roles for these molecules in brain health. PMID- 23642712 TI - Levodopa changes the severity of freezing in Parkinson's disease. AB - Oral levodopa has been proposed to be one of the more effective medications to alleviate freezing of gait, but there is limited data on its efficacy. We evaluated the gait phenomenology of 20 Parkinson's disease patients with freezing of gait before and 60 min after a standardized levodopa dose using a rating scale based on the assumption that festination and akinetic freezing share a common pathophysiology. Levodopa abolished festination and freezing in 20% of patients (p < 0.0001), and reduced the freezing sum score from a median of 15 (IQR 6.75 27.5) to 3.5 (1-11.25), p < 0.001) in all but one of the remainder. Pre-dose ratings correlated with post-dose ratings, in that those patients with lower pre dose item-scores also showed lower post-dose outcome scores. Levodopa's effect on both festination and akinetic freezing was linear, thereby supporting the concept that festination and freezing are variants on a continuity of episodic gait disorders in PD. PMID- 23642711 TI - Multiple activating and repressive cis-promoter regions regulate TNFSF15 expression in human primary mononuclear cells. AB - TL1A/TNFSF15 has been associated with IBD (inflammatory bowel disease) in GWAS (genome-wide association study) and plays a role mediating mucosal inflammation in IBD. Higher TL1A expression is associated with disease severity in both patients and mouse models. Although TL1A has been studied extensively for IBD associated SNPs, the cis/trans-regulatory regions are poorly defined. Herein we identify response elements regulating TNFSF15 in primary human myeloid cells. Peripheral mononuclear cells transfected with TNFSF15 promoter constructs displayed 30-fold enhanced promoter activity in a minimal -74 bp region. Transactivation was mediated partly by AP-1, since mutation of the AP-1 site resulting in loss of promoter activity. Monocytes transfected with c-Jun siRNA or treated with TAT-TI-JIP (JNK Inhibitor VII TAT-TI-JIP) demonstrated reduced TL1A mRNA and protein levels. Surprisingly, constructs larger than -74 bp did not increase promoter expression (expression of -1275 bp construct was 25% of -74 bp activity), suggesting the presence of both activating and repressing TL1A promoter elements. In fact, mutation of the -210 bp NFkappaB site enhanced promoter activity (60-fold) suggesting a repressive role for this site. DNA protein binding to the TL1A AP-1 and NFkappaB elements was inhibited by excess consensus or TL1A oligonucleotides and binding and confirmed by chromatin immuno precipitation analysis. Yet, despite the fact that the -210 bp NFkappaB site acts as a suppressor element, overall mRNA and protein expression were inhibited in monocytes treated with MG132 (NFkappaB/proteasome inhibitor) or SN50 (NFkappaB p50 blocking peptide), suggesting that NFkappaB acts as both an activator and silencer of TL1A expression. These data suggest that modulation of TL1A expression involves a complex interplay between positive and negative signals, binding to distinct regulatory regions. PMID- 23642714 TI - Laboratory evaluation of peripheral neuropathy. AB - The question of how to evaluate peripheral neuropathies is complicated by there being hundreds of potential causes, both acquired and inherited. This article focuses on a targeted and thoughtful approach to the laboratory evaluation of patients with peripheral neuropathy, designed to allow the identification of treatable neuropathies without undue expense and risk to patients. After determining which clinical patterns are present, the patterns are used to define a discrete manageable subset of diseases underlying these neuropathies. Thinking in terms of such patterns is often more helpful than relying on electrodiagnostic studies, leading to a more accurate, cost-effective laboratory evaluation. PMID- 23642713 TI - Pattern-recognition approach to neuropathy and neuronopathy. AB - Neuropathic disorders encompass those that affect the neuron's cell body or neuronopathies, those affecting the peripheral process, or peripheral neuropathies. The peripheral neuropathies can be broadly subdivided into the myelinopathies and axonopathies, conditions which can be hereditary or acquired. Each of these disorders has distinct clinical features that enable neurologists to recognize the various patterns of presentation. Once a particular pattern is established, further laboratory studies can be performed to support the clinical impression. PMID- 23642715 TI - Treatment of painful peripheral neuropathy. AB - Neuropathic pain management is an important aspect in the management of painful peripheral neuropathy. Anticonvulsants and antidepressants have been studied extensively and are often used as first-line agents in the management of neuropathic pain. In this article, data from multiple randomized controlled studies on painful peripheral neuropathies are summarized to guide physicians in treating neuropathic pain. Treatment is a challenge given the diverse mechanisms of pain and variable responses in individuals. However, most patients derive pain relief from a well-chosen monotherapy or well-designed polypharmacy that combines agents with different mechanisms of action. PMID- 23642716 TI - Entrapment neuropathies. AB - Compression neuropathy includes a heterogeneous group of focal neuropathy syndromes related to peripheral nerve compression. Although acute or chronic compression-related injury may occur in essentially any peripheral nerve, certain anatomic considerations may predispose certain nerves to intrinsic or extrinsic compression-related injury. The clinical presentations of specific compression or entrapment syndromes depend on factors such as chronicity, location, severity, and mechanism of involvement of a particular nerve. In this article the diagnosis and management strategies of the more common and well-established entrapment and compression-related neuropathy syndromes are addressed. PMID- 23642717 TI - Diabetic neuropathy part 1: overview and symmetric phenotypes. AB - Diabetes is the most common cause of neuropathy in United States and neuropathies are the most common complication of diabetes mellitus, affecting up to 50% of patients with type 1 and type 2 diabetes mellitus. Symptoms usually include numbness, tingling, pain, and weakness. Dizziness with postural changes can be seen with autonomic neuropathy. Metabolic, vascular, and immune theories have been proposed for the pathogenesis of diabetic neuropathy. Axonal damage and segmental demyelination can be seen with diabetic neuropathies. Management of diabetic neuropathy should begin at the initial diagnosis of diabetes and mainly requires tight and stable glycemic control. PMID- 23642718 TI - Diabetic neuropathy part 2: proximal and asymmetric phenotypes. AB - Diabetic neuropathies consist of a variety of syndromes resulting from different types of damage to peripheral or cranial nerves. Although distal symmetric polyneuropathy is the most common type of diabetic neuropathy, many other subtypes have been defined since the 1800s, including proximal diabetic, truncal, cranial, median, and ulnar neuropathies. Various theories have been proposed for the pathogenesis of these neuropathies. The treatment of most requires tight and stable glycemic control. Spontaneous recovery is seen in most of these conditions with diabetic control. Immunotherapies have been tried in some of these conditions however are controversial. PMID- 23642720 TI - Nutritional neuropathies. AB - Neuropathies due to nutritional problems can affect certain patient populations and have a varied presentation because of multiple coexistent nutritional deficiencies. Clinicians should consider nutritional neuropathies in patients presenting with neuropathies. Clinicians should be alert for signs and symptoms of neuropathy in patients who have had bariatric surgery. PMID- 23642719 TI - Cryptogenic sensory polyneuropathy. AB - Chronic sensory or sensorimotor polyneuropathy is a common cause for referral to neurologists. Despite extensive diagnostic testing, up to one-third of these patients remain without a known cause, and are referred to as having cryptogenic sensory peripheral neuropathy. Symptoms progress slowly. On examination, there may be additional mild toe flexion and extension weakness. Electrophysiologic testing and histology reveals axonal neuropathy. Prognosis is usually favorable, as most patients maintain independent ambulation. Besides patient education and reassurance, management is focused on pharmacotherapy for neuropathic pain and physical therapy for balance training, and, occasionally, assistive devices. PMID- 23642722 TI - Chronic inflammatory demyelinating polyneuropathy. AB - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune disorder of the peripheral nervous system. This article highlights our current understanding of the condition along with its phenotypic variants that are encountered in clinical practice. The diagnostic evaluation of CIDP includes laboratory studies to detect associated medical conditions and electrodiagnostic studies to assess for demyelination. Current treatment options include corticosteroids, plasma exchange, and intravenous immune globulin, along with alternative therapies that may be used as corticosteroid-sparing agents or for treatment-refractory cases. Approximately 85% to 90% of patients eventually improve or stabilize with treatment, and the long-term prognosis of CIDP is favorable. PMID- 23642721 TI - Guillain-Barre syndrome and variants. AB - Guillain-Barre syndrome (GBS) is characterized by rapidly evolving ascending weakness, mild sensory loss, and hyporeflexia or areflexia. Acute inflammatory demyelinating polyneuropathy was the first to be recognized over a century ago and is the most common form of GBS. Axonal motor and sensorimotor variants have been described in the last three decades and are mediated by molecular mimicry targeting peripheral nerve motor axons. Other rare phenotypic variants have been recently described with pure sensory variant, restricted autonomic manifestations, and the pharyngeal-cervical-brachial pattern. It is important to recognize GBS and its variants because of the availability of equally effective therapies in the form of plasmapheresis and intravenous immunoglobulins. PMID- 23642724 TI - The neuropathies of vasculitis. AB - Vasculitic neuropathy can occur as an isolated entity (nonsystemic vasculitic neuropathy) but more commonly evolves in the setting of primary systemic vasculitides or secondary vasculitides related to infections, drugs, or connective tissue disorders. Vasculitic neuropathies are usually but not always painful and tend to produce sensory motor or sensory symptoms. Patients with purely motor or small-fiber dysfunction are unlikely to have vasculitis. Deficits are typically multifocal or asymmetric, but distal symmetric polyneuropathy occurs uncommonly. Evaluation requires laboratory tests, electrodiagnostic studies, and nerve or nerve/muscle biopsy. This article reviews classification, clinical presentation, diagnostic evaluation, and management of peripheral nerve vasculitis. PMID- 23642726 TI - Peripheral neuropathies. Preface. PMID- 23642723 TI - Multifocal motor neuropathy, multifocal acquired demyelinating sensory and motor neuropathy, and other chronic acquired demyelinating polyneuropathy variants. AB - Chronic acquired demyelinating neuropathies (CADP) constitute an important group of immune neuromuscular disorders affecting myelin. This article discusses CADP with emphasis on multifocal motor neuropathy, multifocal acquired demyelinating sensory and motor neuropathy, distal acquired demyelinating symmetric neuropathy, and less common variants. Although each of these entities has distinctive laboratory and electrodiagnostic features that aid in their diagnosis, clinical characteristics are of paramount importance in diagnosing specific conditions and determining the most appropriate therapies. Knowledge regarding pathogenesis, diagnosis, and management of these disorders continues to expand, resulting in improved opportunities for identification and treatment. PMID- 23642727 TI - Positive identification of a burned body using an implanted orthopedic plate. AB - Human identification is usually obtained by comparing fingerprints, antemortem and postmortem radiographs, dental records and also by DNA profiling. Sometimes forensic investigators come across some medical appliances such as orthopedic devices. These medical devices may be useful to achieve positive human identification. This paper aims to present a positive identification of a burned human body by tracking batch numbers engraved in an implanted orthopedic device found in the decedent's left ulna bone. The examiners also collected and analyzed other valuable hints related to the case. Forensic examination can provide reliable positive human identification, even if few, but precise information can be obtained from antemortem and postmortem records. The present report illustrates a set of valuable techniques and how identifying numbers in orthopedic devices are helpful to determine positive human identification in cases of carbonization. As seen in this case, the forensic experts used low-cost identification procedures with accurate results, avoiding DNA profiling method that would be of higher cost and time consuming. Considering social and legal aspects, it is quite important that physicians and dentists understand that correct and accurate records of surgeries they perform, such as fixation of orthopedic devices and dental implants, are utterly relevant and helpful in cases of human identification. PMID- 23642725 TI - Inherited peripheral neuropathies. AB - Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral neuropathies in which the neuropathy is the sole or primary component of the disorder, as opposed to diseases in which the neuropathy is part of a more generalized neurologic or multisystem syndrome. Because of the great genetic heterogeneity of this condition, it can be challenging for the general neurologist to diagnose patients with specific types of CMT. This article reviews the biology of the inherited peripheral neuropathies, delineates major phenotypic features of the CMT subtypes, and suggest strategies for focusing genetic testing. PMID- 23642728 TI - Estimation of sex from the lower limb measurements of Sudanese adults. AB - The sex estimation from mutilated and amputated limbs or body parts is one of the most vital steps in person identification in medical-legal autopsies. Sex estimation from lower limb anthropometric measurements has demonstrated a high degree of expected accuracy in a limited range of the global population. The aims of this study were to assess the degree of the sexual dimorphism in lower limb measurements and the accuracy of utilization of these measurements for estimation of sex in a contemporary adult Sudanese population. The tibial length, bimalleolar breadth, foot length, and foot breadth of 240 right-handed Sudanese Arab subjects (120 males and 120 females) aged between 25 and 30 years were measured following international anthropometric standards. Demarking points, sexual dimorphism indices and discriminant functions were developed from 200 subjects (100 males and 100 females) who comprised the study group. All variables were sexually dimorphic. The bimalleolar breadth and foot breadth significantly contributed to sex estimation. Leg dimensions showed a higher accuracy for sex estimation than foot dimensions. Cross-validated sex classification accuracy ranged between 78% and 89.5%. The reliability of these standards was assessed in a test sample of 20 males and 20 females, and the results showed accuracy between 75% and 90%. This study provides new forensic standards for sex estimation from lower limb measurements of Sudanese adults. PMID- 23642729 TI - Risk factors for imipenem-nonsusceptible Acinetobacter nosocomialis bloodstream infection. AB - BACKGROUND: The emergence of imipenem-nonsusceptible (INS) Acinetobacter baumannii complex has had a great impact on healthcare systems worldwide. Understanding the risk factors related to INS infection is useful for infection control. The risk factors for INS A. baumannii have been well documented; however, the risk factors related to INS Acinetobacter nosocomialis infection lack documentation. The purpose of this study was to identify the risk factors associated with INS A. nosocomialis bacteremia. METHODS: This retrospective 9 year study included 329 adults with A. nosocomialis bacteremia in a tertiary medical center in Taiwan. Acinetobacter nosocomialis was identified using a multiplex polymerase chain reaction method and sequence analysis of a 16S-23S intergenic spacer. RESULTS: Among 329 patients with A. nosocomialis bacteremia, 67 had INS isolates (20.4%). Patients with INS isolates tended to have a more severe form of the diseases [with ICU admission and a higher APACHE (Acute Physiology and Chronic Health Evaluation) II score], specific underlying diseases (associated with chronic lung diseases and end-stage renal diseases, but less commonly alcoholism and chemotherapy), multiple invasive procedures, pneumonia as a primary focus of infection, and prior antimicrobial use (sulbactam, antipseudomonal penicillins, aminoglycosides, and carbapenems). Multivariable analysis showed that ICU admission, chronic lung diseases, arterial line catheterization, total parenteral nutrition, and prior use of carbapenems were independent risk factors; prior use of carbapenems was found to be the most influential (odds ratio 6.36, 95% confidence interval 2.00-20.21; p = 0.002). CONCLUSION: To our knowledge, this is the first study describing the risk factors associated with INS A. nosocomialis bacteremia. Regulated antibiotic control policy, especially for carbapenem, and infection control measures targeting patients hospitalized in ICU, with chronic lung diseases and multiple invasive procedures, may be helpful in reducing INS A. nosocomialis infection. PMID- 23642730 TI - Automatic crystallographic characterization in a transmission electron microscope: applications to twinning induced plasticity steels and Al thin films. AB - A new automated crystallographic orientation mapping tool in a transmission electron microscope technique, which is based on pattern matching between every acquired electron diffraction pattern and precalculated templates, has been used for the microstructural characterization of nondeformed and deformed aluminum thin films and twinning-induced plasticity steels. The increased spatial resolution and the use of electron diffraction patterns rather than Kikuchi lines make this tool very appropriate to characterize fine grained and deformed microstructures. PMID- 23642731 TI - Food sources of sodium, saturated fat and added sugar in the Spanish hypertensive and diabetic population. AB - OBJECTIVES: Previous research has shown that the diet of hypertensive and diabetic patients has a low accordance with the main nutritional recommendations, mostly due to the high intake of sodium, saturated fat and added sugars. This is the first study to identify the main food sources of these nutrients in these patients. METHODS: Cross-sectional study conducted in 2008-2010 in a representative sample of the Spanish adult population, including 2323 patients with hypertension and 635 with diabetes. The habitual diet was assessed using a validated diet history. The intake of sodium, saturated fat and added sugars was estimated with Spanish food composition tables. RESULTS: The hypertensive and diabetic population showed, respectively, an intake of 2.9 and 3.1 g/day of sodium, 26 and 26 g/day of saturated fat, and 33 and 24 g/day of added sugar. In hypertensive and diabetic patients, respectively, most sodium intake came from bread (35%, 34%), raw-cured sausages (15%, 15%), cooked sausages (6%, 7%), and soup (5%, 6%). The main sources of saturated fat were cured cheese (13%, 13%), bakery products (12%, 11%), red meat (10%, 11%), raw-cured sausages (8%, 9%) and whole milk (4%, 4%). The food groups that most contributed to added sugar intake were sugar directly added to coffee and other beverages (27%, 19%), bakery products (15%, 19%), sugary soft drinks (10%, 13%), and whole yogurt (9%, 12%). The main food sources of nutrients were similar in all sex and age groups. CONCLUSIONS: In patients with hypertension and diabetes, the intake of sodium, saturated fat and added sugar can be substantially reduced by prioritizing low salt varieties of bread, reducing the consumption of bakery products and sausages, replacing cured cheese and other whole dairy products by low-fat products, using non-sugary sweeteners, and substituting sugar-free soft drinks, or plain water, for sugary sodas. PMID- 23642733 TI - The effect of aerobic exercise intensity on attenuation of postprandial lipemia is dependent on apolipoprotein E genotype. AB - OBJECTIVE: To investigate the effect of aerobic exercise intensity on postprandial lipemia according to allelic variants of the apolipoprotein E gene. METHODS: Three groups of 10 healthy men each were formed based genotyping of the APOE gene, rested or performed 500 Kcal tests in a random sequence separated by a minimum 48 h interval, as follows: (a) no exercise (control), (b) intense intermittent exercise, (c) moderate continuous exercise. Each test series was completed 30-min before ingestion of a high-fat meal (1 g fat/kg). Venous blood was collected before and at 1, 2, 3 and 4 h after the high-fat meal. Postprandial lipemia was assessed using the area under the curve approach as well as the kinetic profile of mean lipid variables. Statistical significance was adopted at P <= 0.05 level. RESULTS: The main results show that, in the moderate continuous exercise, total postprandial cholesterolemia was higher in E4 than in E2 carriers, whereas under intense intermittent exercise, total and LDL cholesterolemia were higher in E4 than in E2 and E3 carriers. There was no difference in the lipemic profile of the subjects across APOE genotypes at baseline. CONCLUSION: Moderate and intense exercise were effective in attenuating PPL in both E2 and E3 subjects, with E2 subjects being more susceptible to the lipid lowering effect of moderate training than E3 subjects. Carriers of the E4 allele, however, showed no attenuation of postprandial lipemia. PMID- 23642732 TI - Association of SNPs in the UGT1A gene cluster with total bilirubin and mortality in the Diabetes Heart Study. AB - OBJECTIVE: A negative relationship between total bilirubin concentration (TBili) and CVD risk has been documented in a series of epidemiological studies. In addition, TBili is thought to be under strong genetic regulation via the UGT1A gene family, suggesting it may be a heritable CVD risk factor. However, few studies directly relate TBili-associated UGT1A variants to CVD severity or outcome. This study replicated the genetic association for TBili in the Diabetes Heart Study (DHS), and examined the relationships of TBili-associated SNPs with measures of subclinical CVD and mortality. METHODS: This investigation included 1220 self-described European American (EA) individuals from the DHS, a family based study examining risk for macrovascular complications in type 2 diabetes (T2D). Genetic associations with TBili were examined using the Affymetrix Genome wide Human SNP Array 5.0 and the Illumina Infinium Human Exome beadchip v1.0. Subsequent analyses assessed the relationships of the top TBili-associated SNPs with measures of vascular calcified plaque and mortality. RESULTS: A genome-wide association study detected 18 SNPs within the UGT1A gene family associated with TBili at p < 5 * 10(-8). The top hit was rs887829 (p = 8.67 * 10(-20)). There was no compelling evidence of association between the top TBili-associated SNPs and vascular calcified plaque (p = 0.05-0.88). There was, however, evidence of association with all-cause mortality (p = 0.0004-0.06), the top hit being rs2741034. CONCLUSION: These findings support a potential role for UGT1A genetic variants in risk for mortality in T2D. Further quantification of the extent of CVD risk conferred by UGT1A gene family variants in a high risk cohort with T2D is still required. PMID- 23642734 TI - Up-regulation of vitamin B1 homeostasis genes in breast cancer. AB - An increased carbon flux and exploitation of metabolic pathways for the rapid generation of biosynthetic precursors is a common phenotype observed in breast cancer. To support this metabolic phenotype, cancer cells adaptively regulate the expression of glycolytic enzymes and nutrient transporters. However, activity of several enzymes involved in glucose metabolism requires an adequate supply of cofactors. In particular, vitamin B1 (thiamine) is utilized as an essential cofactor for metabolic enzymes that intersect at critical junctions within the glycolytic network. Intracellular availability of thiamine is facilitated by the activity of thiamine transporters and thiamine pyrophosphokinase-1 (TPK-1). Therefore, the objective of this study was to establish if the cellular determinants regulating thiamine homeostasis differ between breast cancer and normal breast epithelia. Employing cDNA arrays of breast cancer and normal breast epithelial tissues, SLC19A2, SLC25A19 and TPK-1 were found to be significantly up regulated. Similarly, up-regulation was also observed in breast cancer cell lines compared to human mammary epithelial cells. Thiamine transport assays and quantitation of intracellular thiamine and thiamine pyrophosphate established a significantly greater extent of thiamine transport and free thiamine levels in breast cancer cell lines compared to human mammary epithelial cells. Overall, these findings demonstrate an adaptive response by breast cancer cells to increase cellular availability of thiamine. PMID- 23642735 TI - Ethyl-eicosapentaenoic acid ameliorates the clinical course of experimental allergic encephalomyelitis induced in dark agouti rats. AB - Eicosapentaenoic acid (EPA), a fatty acid present in high amount in fish, modulates immune response and stimulates myelin gene expression. In the present paper, we investigated the effects of EPA in an established animal model for multiple sclerosis (MS): experimental autoimmune encephalomyelitis (EAE) induced in dark agouti rats. Diets supplemented either with 0.2% or 0.4% of EPA were administrated daily from the day of induction until the end of experiment. One group of rats received diet supplemented with 0.2% of EPA 10 days before induction. The control group (immunized rats) was fed with chow diet. The animals were analyzed at two different stages of the disease: during the acute phase (14 d.p.i.) and during the recovery phase (32 d.p.i.). We showed a delayed onset of clinical severity of disease in all groups of rats fed EPA-supplemented diets. This effect was associated to an increased expression of myelin proteins and an improved integrity of the myelin sheath as well as an up-regulation of FoxP3 expression in the central nervous system during the acute phase of EAE. No significant changes in T cell subsets were noted at the periphery. On the contrary, during the recovery phase of EAE, in animals assuming EPA-supplemented diet, an increase of CD4(+)CD25(+) and CD4(+)CD25(+)FoxP3(+) in peripheral lymphocytes was noted. Our results indicate that EPA-supplemented diets may provide benefits to MS patients. PMID- 23642736 TI - CD47 is expressed abnormally on hematopoietic cells in myelodysplastic syndrome. AB - The increased LSC in MDS has correlation with the progression to AML, which the mechanism of immune evasion is unclear. Our study showed the expression of CD47 on LSC of the patients in high-risk MDS based on IPSS/WPSS score was higher than that of in low-risk MDS and controls. The level of CD47 on erythroblast of MDS patients had a significant positive correlation with their peripheral RBC count. It suggested that the proportion of CD34(+)CD38(-)CD47(+) cells increased in high risk MDS which might protect LSC from avoiding phagocytosis, and low-expression of CD47 on erythroblast in MDS might be correlated to anemia. PMID- 23642737 TI - The BCL2 E17 and SP66 antibodies discriminate 2 immunophenotypically and genetically distinct subgroups of conventionally BCL2-"negative" grade 1/2 follicular lymphomas. AB - Follicular lymphoma (FL) is characterized by the translocation t(14;18)(q32;q21) resulting in constitutive overexpression of BCL2. However, in 10% to 15% of FL grade 1/2, immunohistochemical staining for BCL2 remains negative. To analyze the incidence of BCL2 negativity and the underlying molecular mechanisms in FL grade 1/2, BCL2 expression was investigated with 3 antibodies (clones 100D5, E17, SP66). The presence of a break in the BCL2 locus was determined by fluorescence in situ hybridization. The region of the BCL2 gene where the epitope of the standard BCL2 antibody resides was sequenced. Twenty-two (9.2%) of 240 identified cases of FL grade 1/2 were negative with the standard BCL2 antibody. Of these, 12 cases (55%) carried a break in the BCL2 gene locus, which, in all but one case, correlated with BCL2 expression using the alternative antibodies E17 and SP66 and with missense mutations of BCL2. Ten (45%) of the 22 cases had an intact BCL2 gene locus; 2 cases carried a BCL6/IGH translocation. All 10 cases were negative for the E17/SP66 antibodies and showed a wild-type sequence of BCL2. Six of these showed an aberrant phenotype, with CD10 negativity (30%) or CD23 expression (30%). In summary, the alternative E17/SP66 antibodies identify 2 immunohistochemically and genetically distinct subgroups of BCL2-"negative" FL grade 1/2. PMID- 23642738 TI - Histologic changes in type A chronic atrophic gastritis indicating increased risk of neuroendocrine tumor development: the predictive role of dysplastic and severely hyperplastic enterochromaffin-like cell lesions. AB - The role of putative preneoplastic enterochromaffin-like cell lesions, either hyperplastic or dysplastic, in the genesis of type 1 enterochromaffin-like cell neuroendocrine tumors associated with type A chronic atrophic gastritis, their actual neoplastic risk, and their precise histogenetic mechanism deserve further clarification by specific histopathologic studies coupled with patient follow-up. A total of 100 patients with severe type A chronic atrophic gastritis, enterochromaffin-like cell hyperplasia, and antral G-cell hyperplasia were endoscopically and histologically followed up for a median of 90.1 months (total of 9118 person-months). Preneoplastic enterochromaffin-like cell lesions and newly developed neuroendocrine tumors were investigated histologically and histochemically, in parallel with enterochromaffin-like cell lesions found in nontumor mucosa of another 32 well-characterized and previously reported type 1 neuroendocrine tumors. Both neuroendocrine and nonneuroendocrine mucosa changes were analyzed and statistically evaluated. During follow-up, 7 of 100 patients developed neuroendocrine tumors: 5 were in a group of 20 cases with previous enterochromaffin-like cell dysplasia and 2 were among 80 cases showing only enterochromaffin-like cell hyperplasia throughout the study (hazard ratio, 20.7; P < .001). The severity of enterochromaffin-like cell hyperplasia at first biopsy, with special reference to linear hyperplasia with 6 chains or more per linear millimeter, also increased the risk of neuroendocrine tumor development during follow-up (hazard ratio, 13.0; P < .001). Enterochromaffin-like cell microinvasive dysplastic lesions arising at the epithelial renewal zone level, in connection with immature proliferating mucous-neck cells, were found to be linked to early intramucosal neuroendocrine tumor histogenesis. Both enterochromaffin like cell dysplasia and severe hyperplasia indicate increased risk of neuroendocrine tumor development in type A chronic atrophic gastritis with hypergastrinemia/G-cell hyperplasia. PMID- 23642740 TI - In praise of ignorance (seriously!), epistemology (sort of ...), and the circle of least confusion. PMID- 23642739 TI - Overexpression of the chromatin remodeler death-domain-associated protein in prostate cancer is an independent predictor of early prostate-specific antigen recurrence. AB - Molecular markers reliably predicting the aggressiveness of prostate cancer are currently lacking. Death-domain-associated protein (DAXX) has been implicated in the regulation of chromatin remodeling, transcription, and apoptosis that are integral to oncogenesis and cancer progression. DAXX expression was analyzed by immunohistochemistry on a tissue microarray containing 7478 prostate cancer specimens. Results were compared with tumor phenotype, biochemical recurrence, and v-ets erythroblastosis virus E26 oncogene homolog (ERG) status. DAXX expression was predominantly seen in the nucleus. DAXX expression was detectable in 4609 (80.6%) of 5718 interpretable cancers and considered strong in 5.9%, moderate in 45.8%, and weak in 28.9%. Strong DAXX expression was associated with both transmembrane protease, serine 2 (TMPRSS2)/ERG rearrangement and ERG expression (P < .0001 each). Strong DAXX expression was tightly linked to high Gleason grade, advanced pT stage, increased cell proliferation index, and early prostate-specific antigen recurrence (P < .0001 each). The prognostic role of DAXX expression was independent of Gleason grade, pT stage, and pN stage. Our study establishes DAXX as a novel independent prognosticator in prostate cancer and suggests an important role of DAXX expression for both prostate cancer development and progression. Furthermore, DAXX appears to exert biologically different effects in ERG-positive and ERG-negative prostate cancers. PMID- 23642741 TI - C-reactive protein levels and tear function parameters. PMID- 23642742 TI - Aflibercept-related sterile inflammation. PMID- 23642743 TI - Transiency of Fleischer's rings in Forme-Fruste keratoconus. PMID- 23642744 TI - Internal limiting membrane peeling for primary rhegmatogenous retinal detachment repair. PMID- 23642745 TI - Tuberculosis of eyelid presenting as a chalazion. PMID- 23642746 TI - Author reply: To PMID 22584020. PMID- 23642747 TI - Author reply: To PMID 22627119. PMID- 23642748 TI - Axial length and diabetic retinopathy. PMID- 23642749 TI - Cognitive impairment in AMD. PMID- 23642750 TI - Author reply: To PMID 22705343. PMID- 23642751 TI - Caregiver burden in ocular disease. PMID- 23642752 TI - Author reply: To PMID 22035578. PMID- 23642753 TI - Gene expression profiling versus TNM classification. PMID- 23642754 TI - Erlotinib-related corneal melting. PMID- 23642755 TI - Knowledge of transient ischemic attack among the Japanese. AB - Stroke is often preceded by a transient ischemic attack (TIA). To properly recognize TIA and take prompt initial action, all citizens should be fully educated about TIA. Our objective is to evaluate how much knowledge of TIA has spread among Japanese citizens. As a preliminary study with this goal, we conducted an Internet-based questionnaire survey of 30,000 Japanese citizens aged 20 years or more, excluding health care professionals, from across Japan to investigate their awareness and knowledge of stroke and TIA. Valid responses were obtained from 11,121 Japanese citizens, aged 44.8 +/- 13.1 (mean +/- SD) years. The most frequent response pertaining to initial action at TIA onset was "visit the family doctor" (41.8%), followed by "immediately call an ambulance" (22.4%). Tokushima, Kagawa, and Kumamoto were the top 3 prefectures with the highest ambulance request rates. Factors contributing to immediately calling an ambulance were respondents' confidence about the involvement of stroke (odds ratio [OR] 2.290, 95% confidence interval [CI] 1.250-4.318, P = .009) and knowledge of the importance of initiating treatment within 3 hours of symptom onset (OR 2.273, 95% CI 1.923-2.825, P = .000). Although television was the primary source of information about stroke for all groups of age, older respondents obtained more information from newspapers than younger respondents. The results showed that many Japanese citizens would fail to call an ambulance in response to TIA, and diagnosis by a primary care physician appears to be the main triage system for the treatment of TIA. Rather than instituting a nationally uniform strategy of education for the promotion of TIA awareness among Japanese citizens, education programs should account for age-specific and regional differences among citizens. PMID- 23642756 TI - Methylenetetrahydrofolate reductase (C677T and A1298C) polymorphisms, hyperhomocysteinemia, and ischemic stroke in Tunisian patients. AB - OBJECTIVE: The present study evaluated the role of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C gene polymorphisms and correlated these results with plasma homocysteine (Hcy) levels in Tunisian ischemic stroke (IS) patients. METHODS: Overall, 84 patients with IS were included and compared with 100 healthy controls. The most common stroke risk factors were investigated. Fasting plasma Hcy levels were measured. Genotyping of the MTHFR C677T and A1298 polymorphisms was studied by polymerase chain reaction. RESULTS: Aside from tobacco and alcohol use, the other studied factors were significant risk factors for IS. Mean plasma Hcy levels were significantly higher in IS patients than in controls (16.1 +/- 8.28 MUmol/L versus 8.76 +/- 3.48 MUmol/L, P < 10(-3)). Significant associations were found with both the MTHFR 677(CT + TT) and 1298 (AC + CC) genotypes in comparison with controls (P < 10(-3)). A significant synergistic interaction was also found with the double heterozygote MTHFR 677CT/1298AC (P < 10(-3)). Homocysteine levels were significantly higher in IS patients with the MTHFR C677T variant (CT and TT genotypes) (P < 10(-3)); however, the difference was not significant with the MTHFR A1298C variant (AC and CC genotypes) (P = .31). CONCLUSION: The MTHFR C677T and A1298 polymorphisms (individually or in concert) and hyperhomocysteinemia represent important risk factors for IS. Elevated Hcy levels were found to be associated with the MTHFR C677T variant; however, no significant association was found with the MTHFR A1298C variant. PMID- 23642757 TI - Targeting telestroke: benchmarking time performance in telestroke consultations. AB - OBJECTIVE: To describe the length of time physicians spend completing telestroke consultations and examine factors associated with that period. METHODS: This is a retrospective review of data from telestroke software. Clinical data obtained between July 2010 and February 2011 from 8 hub and 24 spoke hospitals were abstracted for 235 consecutive consultations and linked to time metadata generated by software interaction. Consult length was defined as the time logged on to the robot and was exclusive of any telephone interaction or documentation time. Response time was defined as patient arrival to physician log-on. RESULTS: Mean consult length for 203 complete, time-stamped cases was 14.5 minutes. There was no independent association between consult length and age, diagnosis, time of arrival from symptom onset, neurological exam findings, known recombinant tissue plasminogen activator (r-tPA) contraindications, and absence of vascular risk factors. Mean consult length was statistically longer in r-tPA-recommended cases (20.0 versus 15.3 minutes; P = .04). Mean response time was 76.3 minutes. CONCLUSIONS: The relatively short consult length suggests a workflow model in which acute stroke care is largely completed before telestroke consultation with a specialist rendering an expert opinion on previously gathered data performed off-line. The findings for prolonged response times indicate an area for improvement. Future workflow models for telestroke consultation will need to be reconsidered to optimize quality of care and clinical efficiency. PMID- 23642758 TI - The cancer stem cell hypothesis applied to oral carcinoma. AB - It has been proposed that the development of tumors is based exclusively on the activity of cancer stem cells (CSCs) leading to a new model of carcinogenesis, the CSC hypothesis, in opposition to the conventional model of clonal evolution. The new model may help to explain the high mortality of oral cancer, unchanged over the past decades, the low response to treatment and the tendency of oral squamous cell carcinoma (OSCC) patients to develop multiple tumors. However, a more profound understanding of the molecular pathways involved in maintaining the stem cell (SC) state and of their alterations is required to elucidate the mechanisms underlying the development of tumors and metastatic spread, but research into SC biopathology is hampered by the lack of specific markers for identifying SCs and CSCs in tissues and for establishing topographic relationships with their lineage. We review current knowledge on stem cells in relation to oral cancer, including their possible origins, focusing on the CSC hypothesis of oral tumorigenesis and attempts being made to identify oral stem cells. PMID- 23642759 TI - Effects of restrictive clothing on lumbar range of motion and trunk muscle activity in young adult worker manual material handling. AB - The objective of this study was to examine the effect of wearing restrictive trousers on lumbar spine movement, trunk muscle activity and low back discomfort (LBD) in simulations of manual material handling (MMH) tasks. Twenty-eight young adults participated in the study performing box lifting, liquid container handling while squatting, and forward reaching while sitting on a task chair when wearing tight pants (sizes too small for the wearer) vs. fit pants (correct size according to anthropometry). Each task was repeated three times and video recordings were used as a basis for measuring lumbar range of motion (LRoM). The response was normalized in terms on baseline hip mobility. Trunk muscle activity of rectus abdominis (RA) and erector spinae (ES) muscles were also measured in each trial and normalized. At the close of each trial, participants rated LBD using a visual analog scale. Results revealed significant effects of both pants and task types on the normalized LRoM, trunk muscle activity and subjective ratings of LBD. The LRoM was higher and trunk muscle (ES) activity was lower for participants when wearing tight pants, as compared to fit pants. Discomfort ratings were significantly higher for tight pants than fit. These results provide guidance for recommendations on work clothing fit in specific types of MMH activities in order to reduce the potential of low-back pain among younger workers in industrial companies. PMID- 23642761 TI - Assessing drivers of N2O production in California tomato cropping systems. AB - Environmental conditions and agricultural management events affect the availability of substrates and microbial habitat required for the production and consumption of nitrous oxide (N2O), influencing the temporal and spatial variability of N2O fluxes from soil. In this study, we monitored for diurnal and event-related patterns in N2O emissions in the field, evaluated how substrate availability influenced denitrification, and assessed N2O reduction potential following major events in two tomato (Lycopersicon esculentum) management systems on clay loam soils: 1) conventional (sidedress fertilizer injection, furrow irrigation, and standard tillage) and 2) integrated (fertigation, subsurface drip irrigation, and reduced tillage). Potential denitrification activity, substrate limitation, and reduction to N2 were measured with an anaerobic slurry technique. In the field, we found no consistent diurnal patterns. This suggests that controlling factors that vary on an event-basis overrode effects of diurnally variable controls on N2O emissions. The lack of consistent diurnal patterns also indicates that measuring N2O emissions once per day following major events is sufficient to adequately assess annual N2O emissions in those systems. Nitrous oxide emissions varied per event and across functional locations in both systems. This illustrates that mechanisms underlying N2O emissions vary at relatively small temporal and spatial scales and demonstrates the importance of studying N2O emissions in the context of events and functional locations. In the conventional system, N2O fluxes were high [74.2+/-43.9-390.5+/-90.1 MUg N2O-N m(-2) h(-1)] and N2O reduction potential was significant. Both management systems exhibited carbon limitation on denitrification rates; and rates were N limited in the third fertigation event in the integrated system. Our findings suggest that denitrification is strongly contributing to high N2O emissions in conventional tomato cropping systems in California. Hence, management practices that reduce the conditions that favor denitrification, such as subsurface drip irrigation, are promising strategies for N2O reduction. PMID- 23642760 TI - Treatment of smoking in smokers with chronic obstructive pulmonary disease. Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR). PMID- 23642762 TI - Can discoblock replace discography for identifying painful degenerated discs? AB - OBJECTIVES: The aim of the present study was to intra-individually compare provocative discography and discoblock (disc analgesia) of idiopathic degenerated discs (IDD) results to each other, to clinical parameters, and to MRI findings. By this the value of both diagnostic features should be critically reevaluated. METHODS: 31 intervertebral IDD (Pfirrmann III degrees -IV degrees ) of 26 patients were analyzed for surgery decision making by combined discoblock/discography procedure in an open MRI at 1T. A correlation analysis was performed between the Dallas Discogram Scale, pain discrimination score (PDS: concordant/discordant/no pain), positive discoblock (Numerical Rating Scale [NRS] reduction by >= 3, 60 min after intervention), presence of Modic changes or high intensity zones (HIZ), patient sex and age, intervention level, injection pressure and discography endpoint analysis (pain/pressure/anatomic/volume). RESULTS: Concordant pain could be evoked in 35% of the IDDs whereas discoblock was positive in 64%. Patients' age, sex, Dallas I, Dallas II, and Pfirrmann scores, as well as the presence of HIZ did not correlate to PDS or discoblock results. Discoblock correlated positively to concordant pain. Further positive correlation was found between PDS and intervention level/pressure, between discoblock and Modic changes/discography endpoint as well as between HIZ and discography endpoint. CONCLUSIONS: We suggest discoblock to be an additional tool for surgery decision making in patients with IDD because it correlates to concordant pain evoked by provocative discography as well as to presence of Modic changes. Additionally, assessment of a release instead of provocation of pain can be of advantage. PMID- 23642763 TI - Comment on "repetitive transarterial chemoembolization (TACE) of liver metastases from gastric cancer: local control and survival results": will there be clinical implications in the future? PMID- 23642764 TI - Response to comment on "repetitive transarterial chemoembolization (TACE) of liver metastases from gastric cancer: local control and survival results": will there be clinical implications in the future? PMID- 23642765 TI - Rapid detection of blaVIM-1-37 and blaKPC1/2-12 alleles from clinical samples by multiplex PCR-based assays. AB - VIM and KPC are two major families of carbapenemases involved in nosocomial outbreaks of multidrug-resistant Gram-negative bacilli. To rapidly detect bla(VIM)- and bla(KPC)-encoding strains, three multiplex PCR-based methods were designed and validated: (i) a real-time PCR to detect all reported VIM alleles, namely bla(VIM-1-19, 23-37); (ii) a real-time PCR to identify bla(VIM)-type and bla(KPC) carbapenemases in an ultrarapid single reaction; and (iii) a standard PCR to amplify and sequence all VIM alleles. All three methods detected 33 VIM positive samples among 107 Gram-negative isolates with imipenem and meropenem minimum inhibitory concentrations >=1 mg/L. The three methods displayed 100% sensitivity, specificity and concordance. Sequencing of the bla(VIM) amplicons revealed that 30 samples encoded bla(VIM-1) and 3 samples encoded bla(VIM-2). The real-time assay, optimised for the simultaneous detection of bla(VIM) and bla(KPC), identified 3 and 12 isolates positive for both bla(VIM)/bla(KPC) and for bla(KPC), respectively. The analytical sensitivity of the real-time assays was linear over 6 log dilutions, with a reproducible detection limit of 1 CFU. No cross-reactivity was detected. The developed assays provide powerful tools for rapid identification of VIM and KPC carbapenemase producers, therefore contributing to the prevention and containment of resistance dissemination. PMID- 23642766 TI - Capnocytophaga spp. involvement in bone infections: a review. AB - Capnocytophaga are commensal gliding bacteria that are isolated from human and animal oral flora and are responsible for infections both in immunocompromised and immunocompetent hosts. Accumulation of microbial plaque, loss of collagen attachment, and alveolar bone resorption around the tooth can lead to local Capnocytophaga spp. bone infections. These capnophilic bacteria, from oral sources or following domestic animal bites, are also causative agents of bacteraemia and systemic infections as well as osteomyelitis, septic arthritis, and infections on implants and devices. The present literature review describes the main aetiologies of bone infections due to Capnocytophaga spp., the cellular mechanisms involved, methods used for diagnosis, antimicrobial susceptibility, and effective treatments. PMID- 23642767 TI - Magnetic microsphere-confined graphene for the extraction of polycyclic aromatic hydrocarbons from environmental water samples coupled with high performance liquid chromatography-fluorescence analysis. AB - In this paper, a magnetic microsphere-confined graphene adsorbent (Fe3O4@SiO2-G) was fabricated and used for the extraction of five polycyclic aromatic hydrocarbons (fluorene, anthracene, phenanthrene, fluoranthene and pyrene) from environmental water samples prior to high performance liquid chromatography with fluorescence detection. The Fe3O4@SiO2-G was characterized by various instrumental methods. Various experimental parameters that could affect the extraction efficiencies, such as the amount of Fe3O4@SiO2-G, the pH and ionic strength of sample solution, the extraction time and the desorption conditions, were investigated. Due to the high surface area and excellent adsorption capacity of the Fe3O4@SiO2-G, satisfactory extraction can be achieved with only 15mg of the adsorbent per 250mL solution and 5min extraction. Under the optimum conditions, a linear response was observed in the concentration range of 5 1500ngL(-1) for fluorene, 2.5-1500ngL(-1) for anthracene and 15-1500ngL(-1) for phenanthrene, fluoranthene and pyrene, with the correlation coefficients (r) ranging from 0.9897 to 0.9961. The limits of detection (S/N=3) of the method were between 0.5 and 5.0ngL(-1). The relative standard deviations (RSDs) were less than 5.6%. The recoveries of the method were in the range between 83.2% and 108.2%. The results indicated that this graphene-based magnetic nanocomposite had a great adsorptive ability toward the five polycyclic aromatic hydrocarbons from environmental water samples. PMID- 23642768 TI - Characterization of cerebrospinal fluid by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry. AB - Comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC*GC-TOFMS) was applied in the quantification and identification of organic compounds in patient-matched human cerebrospinal fluid (CSF) and serum samples. Concentrations of 21 amino and hydroxyl acids varied from 0.04 to 77ng/MUl in CSF and from 0.1 to 84ng/MUl in serum. In total, 91 metabolites out of over 1200 detected were identified based on mass spectra and retention indices. The other metabolites were identified at the functional group level. The main metabolites detected in CSF were sugar and amino acid derivatives. The CSF and serum had clearly distinct metabolic profiles, with larger biological variation in the serum than in CSF. The GC*GC-TOFMS allowed detection and identification of several metabolites that have not been previously detected in CSF. PMID- 23642769 TI - Self-interaction chromatography in pre-packed columns: a critical evaluation of self-interaction chromatography methodology to determine the second virial coefficient. AB - The characterization of protein-protein interactions is commonly conducted via self-interaction chromatography to describe magnitude and direction of the interactions with the resulting osmotic second virial coefficient (B22). However, the method is invasive and protein immobilization on the adsorber surface can influence the results obtained. In order to replace batch immobilization procedures followed by a column packing, direct on-column preparation was optimized in terms of protein immobilization under a continuous flow. Surface load was measured applying a novel method based on partial least squares analysis of spectral scans to reduce analytical error when determining the amount of immobilized protein. Subsequently influencing parameters such as the effects of absolute surface load, injected protein concentration and distribution of protein orientation were analyzed and system performance evaluated. The results disprove the consistency of the SIC method regarding the non-random orientation of proteins on adsorber particles. Thus the determined B22-values differ quantitatively from those determined with static light scattering. Furthermore, variations in immobilization conditions influence the results obtained. These results make clear that SIC does not fulfill the theoretical framework of B22 analysis. It is rather a qualitative measure of protein-protein interactions in the respective system used for experimentation. PMID- 23642770 TI - Models for estimating the biological age of five organs using clinical biomarkers that are commonly measured in clinical practice settings. AB - OBJECTIVES: To date, no worldwide studies have been conducted to estimate the biological age of five organs using clinical biomarkers that are associated with the aging status. Therefore, we conducted this study to develop the models for estimating the biological age of five organs (heart, lung, liver, pancreas, and kidney) using clinical biomarkers which are commonly measured in clinical practice. DESIGN: A cross sectional study. METHODS: Subjects were recruited from the routine health check-up centers in Korea from 2004 through 2010. Data obtained from 121,189 subjects (66,168 men and 55,021 women) were used for clinical evaluation and statistical analysis. We examined the relations between clinical biomarkers associated with five organs and the chronological age and proposed a model for estimating the biological age of five organs. RESULTS: In the models for predicting the biological ages of the heart, lung, liver, pancreas and kidney in men, 12, 2, 8, 3, and 5 parameters were respectively included (R(2)=0.652, 0.427, 0.107, 0.245, and 0.651). In contrast to men, 10, 2, 8, 3, and 5 parameters in women were respectively included (R(2)=0.780, 0.435, 0.140, 0.384, and 0.501). CONCLUSION: We first proposed the models for predicting the biological age of five organs in the current study. We developed those using clinical parameters that can be easily obtained in clinical practice settings. Our biological age prediction models may be used as supplementary tools to assess the aging status of five organs in clinical practice settings. PMID- 23642771 TI - Improved femoral neck BMD in older Finnish women between 2002 and 2010. AB - PURPOSE: The number of hip fractures among Finns over 50-years of age rose constantly between 1970 and 1997, but since then, there has been a nationwide decline in incidence of hip fractures. One possible explanation, although not the only one, for the declining fracture rates, could be improved bone mineral density (BMD). The aim of this study was to evaluate differences in femoral neck BMD between older Finnish women born about a decade apart. METHODS: We compared the baseline data of two population-based samples of home-dwelling 70-80-year-old women who were initially recruited in exercise intervention studies (N=216 in Cohort1, and N=389 in Cohort 2). Femoral neck BMD was measured with DXA. Between cohort differences were evaluated with analysis of covariance using age, height, weight, and use of hormone therapy as covariates. RESULTS: The later-born Cohort 2 was somewhat older and taller than Cohort 1. Adjusted mean difference (95% CI) in femoral neck BMD between the cohorts was 0.043g/cm(2) (0.023-0.064) corresponding the mean difference of 0.36 (0.19-0.53) in T-score in favor of Cohort 2. CONCLUSIONS: Despite several factors that basically could have indicated lower mean BMD in Cohort 2, the finding was the opposite. This suggests that the mean femoral neck BMD has increased substantially among older Finnish women within a decade, but primary reason for this improvement remains unclear, but improved social and economic resources may have at least partly accounted for this favorable phenomenon. PMID- 23642772 TI - The conserved tetrameric subunit stoichiometry of Slc26 proteins. AB - The Slc26 family proteins, with one possible exception, transport anions across membranes in a wide variety of tissues in vertebrates, invertebrates, and plants. Mutations in human members of the family are a significant cause of disease. Slc26 family proteins are thought to be oligomers, but their stoichiometry of association is in dispute. A recent study, using sequential bleaching of single fluorophore-coupled molecules in membrane fragments, demonstrated that mammalian Slc26a5 (prestin) is a tetramer. In this article, the stoichiometry of two nonmammalian prestins and three human SLC26 proteins has been analyzed by the same method, including the evolutionarily-distant SLC26A11. The analysis showed that tetramerization is common and likely to be ubiquitous among Slc26 proteins, at least in vertebrates. The implication of the findings is that tetramerization is present for functional reasons. PMID- 23642773 TI - An alternative explanation for the inverse relationship between atopy and myocardial infarction. PMID- 23642774 TI - Reply: To PMID 22921873. PMID- 23642775 TI - Pretreatment of defatted wheat germ proteins (by-products of flour mill industry) using ultrasonic horn and bath reactors: effect on structure and preparation of ACE-inhibitory peptides. AB - The ultrasonic horn and bath reactors were compared based on production of angiotensin-converting-enzyme (ACE) inhibitory peptides from defatted wheat germ proteins (DWGP). The DWGP was sonicated before hydrolysis by Alcalase. Degree of hydrolysis, ACE-inhibitory activity, surface hydrophobicity, fluorescence intensity, free sulfhydryl (SH), and disulfide bond (SS) were determined. The highest ACE-inhibitory activity of DWGP hydrolysate was obtained at power intensity of 191.1 W/cm(2) for 10 min in the ultrasonic horn reactor. The fixed frequency of 33 kHz and the sweep frequency of 40+/-2 kHz resulted in the maximum ACE-inhibitory activity. The combined irradiation of dual fixed frequency (24/68 kHz) produced significant increase in ACE-inhibitory activity compared with single frequency (33 kHz). The ultrasonic probe resulted in significant higher ACE-inhibitory activity compared with ultrasonic bath operating at single or dual fixed and sweep frequencies. The changes in conformation of the DWGP due to sonication were confirmed by the changes in fluorescence intensity, surface hydrophobicity, SHf and SS contents and they were found in conformity with the ACE-inhibitory activity in case of the ultrasonic horn reactor but not in bath reactor. PMID- 23642776 TI - Extra virgin olive oil (EVOO) consumption and antioxidant status in healthy institutionalized elderly humans. AB - Recent studies show that the elderly have increased oxidative stress and impaired antioxidant defense systems. Our study aims to evaluate the effects of daily consumption of EVOO in the healthy institutionalized elderly. We studied anthropometric, biochemical and antioxidant parameters in 62 subjects aged 65-96 years after a 6-week daily intake of polyphenol-rich EVOO with high oleuropein derivative contents. Subjects were divided into a control group (CG) who maintained their dietary habits (n=39) and an olive group (OG) who consumed EVOO as the only added fat, plus a daily dose of 50ml (n=23). We found a significant reduction of total cholesterol (TC), HDL, LDL and TGs in OG subjects and a significant increase of HDL levels. There was no significant variation in the CG parameters. In OG the total antioxidant capacity (TAC) in plasma increased with significant differences over CG. Plasma hydroxytyrosol (OH-Tyr) concentration showed a significant increase after EVOO intervention. Daily consumption of EVOO was found to have positive effects on lipid profiles, OH-Tyr levels and TAC. The results also show a significant increase of catalase (CAT) in erythrocytes and a decrease (p<0.05) in superoxide dismutase (SOD) and glutathione peroxidase (GH PX) activity after EVOO intake. To our knowledge, no other study has examined the effects of EVOO consumption on biochemical parameters, antioxidant capacity and antioxidant enzyme activity in healthy elderly subjects. In conclusion, our results show that nutritional intervention with EVOO improves antioxidant status in healthy elderly people. PMID- 23642778 TI - Assessment of heavy metals in tilapia fish (Oreochromis niloticus) from the Langat River and Engineering Lake in Bangi, Malaysia, and evaluation of the health risk from tilapia consumption. AB - Concentrations of the heavy metals copper (Cu), cadmium (Cd), zinc (Zn), lead (Pb) and nickel (Ni) were determined in the liver, gills and muscles of tilapia fish from the Langat River and Engineering Lake, Bangi, Selangor, Malaysia. There were differences in the concentrations of the studied heavy metals between different organs and between sites. In the liver samples, Cu>Zn>Ni>Pb>Cd, and in the gills and muscle, Zn>Ni>Cu>Pb>Cd. Levels of Cu, Cd, Zn and Pb in the liver samples from Engineering Lake were higher than in those from the Langat River, whereas the Ni levels in the liver samples from the Langat River were greater than in those from Engineering Lake. Cd levels in the fish muscle from Engineering Lake were lower than in that from the Langat River. Meanwhile, the Cd, Zn and Pb levels in the fish muscle from the Langat River were lower than in that from Engineering Lake, and the Ni levels were almost the same in the fish muscle samples from the two sites. The health risks associated with Cu, Cd, Zn, Pb and Ni were assessed based on the target hazard quotients. In the Langat River, the risk from Cu is minimal compared to the other studied elements, and the concentrations of Pb and Ni were determined to pose the greatest risk. The maximum allowable fish consumption rates (kg/d) based on Cu in Engineering Lake and the Langat River were 2.27 and 1.51 in December and 2.53 and 1.75 in February, respectively. The Cu concentrations resulted in the highest maximum allowable fish consumption rates compared with the other studied heavy metals, whereas those based on Pb were the lowest. A health risk analysis of the heavy metals measured in the fish muscle samples indicated that the fish can be classified at one of the safest levels for the general population and that there are no possible risks pertaining to tilapia fish consumption. PMID- 23642779 TI - Assessment of the toxicity of organochlorine pesticide endosulfan in clams Ruditapes philippinarum. AB - This study is aimed at evaluating the effects of endosulfan in clams (Ruditapes philippinarum). For this purpose, a study was performed on clams exposed to 0.005, 0.05 and 0.5MUg/L endosulfan for 15 days. S ubsequently, the level of ethoxyresorufin-O-deethylase (EROD) activity, glutathione-S-transferase (GST) activity, glutathione (GSH) content, superoxide dismutase (SOD) activity, lipid peroxidation (LPO) and DNA strand break was determined in gills and digestive glands. Among the parameters, endosulfan caused significant changes in induction of EROD activity and oxidative stress in clams R. philippinarum. The exposure to endosulfan increased the concentration of EROD, GST, GSH, MDA and decreased the concentration of SOD. Moreover, according to the correlation analysis results, the EROD activity and GSH content in digestive gland as well as GST activity, LPO and DNA damage in both tissues had excellent correlation with endosulfan concentration. These results provided information on potential biomarkers that could be effectively applied to the biomonitoring of aquatic ecosystem in areas susceptible to persistent organochlorine compounds contamination, and also information on toxic effects. PMID- 23642780 TI - Introduction: Neovascular age-related macular degeneration: approaches for improving visual acuity and reducing the burden of care. PMID- 23642781 TI - Emerging therapies for neovascular age-related macular degeneration: drugs in the pipeline. AB - TOPIC: Discuss the emerging therapies that could improve the treatment of neovascular age-related macular degeneration (AMD). CLINICAL RELEVANCE: Current antiangiogenic therapies require frequent injections, and not all patients respond to these therapies. Thus, there is a need to identify additional therapies that could improve the treatment of neovascular AMD. METHODS: Review of medical literature and ongoing clinical trials as well as their results in the area of neovascular AMD treatment. RESULTS: There are numerous areas of investigation into new treatment for AMD, including the newly approved aflibercept eye; sustained-release compounds that may allow for fewer injections, combination therapy with anti-vascular endothelial growth factor (VEGF) therapy and ionizing radiation, and investigational drugs that address different targets along the angiogenic signaling cascade, or other pathways related to the pathophysiology of neovascular AMD altogether. CONCLUSIONS: Despite the outstanding advances made in the treatment of neovascular AMD with anti-VEGF therapies, patients still require numerous injections and office visits. Future therapies, however, have the potential not only to reduce patient visits and injections, but also to improve outcomes by targeting additional pathways, increasing target affinity, and lengthening treatment durability. PMID- 23642782 TI - Putting theories and results into practice: managing cases. AB - The following are highlights from a case discussion, which was moderated by the Course Director, Quan Dong Nguyen, MD, MSc. The faculty reviewed 3 case studies and discussed their different approaches to managing the treatment of each patient. They also fielded questions from audience members about their management suggestions and the potential US Food and Drug Administration approval of aflibercept, which was not approved at the time of this discussion. In addition, the 2-year CATT (Comparison of Age-Related Macular Degeneration Treatments Trials) results and 1-year IVAN (Inhibit Vascular Endothelial Growth Factor in Age-Related Choroidal Neovascularization) results were not released at the time this discussion took place. PMID- 23642783 TI - Neovascular age-related macular degeneration: individualizing therapy in the era of anti-angiogenic treatments. AB - The treatment of neovascular age-related macular degeneration (AMD) had been revolutionized by the use of anti-vascular endothelial growth factor (VEGF) drugs: bevacizumab and ranibizumab. With the introduction of a third anti-VEGF drug, aflibercept, ophthalmologists have several options to choose from, as well as various treatment regimens they can follow. In this Interview, Jeffrey S. Heier, MD, of Ophthalmic Consultants of Boston, Massachusetts, discusses his approaches to managing the treatment of patients with AMD and providing them with individualized care. PMID- 23642784 TI - Current anti-vascular endothelial growth factor dosing regimens: benefits and burden. AB - TOPIC: To examine the outcomes of clinical trials and case studies that investigated the different dosing regimens used for the 3 intravitreal anti vascular endothelial growth factor (VEGF) inhibitors that are available currently. The Comparisons of Age-Related Macular Degeneration (AMD) Treatments Trial (CATT) data are discussed briefly here and are reviewed in greater detail in a separate accompanying article. CLINICAL RELEVANCE: Sustained improvement with the 2 most widely used anti-VEGF drugs, bevacizumab and ranibizumab, requires monthly visits, posing a difficulty for patients. Thus, there is a need to evaluate whether individualized treatment regimens may reduce patient burden and improve patient outcomes. METHODS: Review of clinical trials and case studies presented at recent medical conferences and published in peer-reviewed literature. RESULTS: Numerous trials, including the Efficacy and Safety of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization (CNV) Secondary to AMD, Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intraocular Ranibizumab, Study of Ranibizumab in Patients with Subfoveal CNV Secondary to AMD, Extension Study to Evaluate the Safety and Tolerability of Ranibizumab in Subjects with CNV Secondary to AMD or Macular Edema Secondary to Retinal Vein Occlusion, Safety Assessment of Intravitreal Lucentis for AMD, and CATT, have evaluated alternatives to monthly dosing. Evidence suggests that either a treat-as-needed or, possibly, a treat-and extend regimen provides a reasonable approach to monthly injections recommended for bevacizumab and ranibizumab, with the caveat that as yet, careful and ongoing surveillance remains a key feature of optical management. CONCLUSIONS: Individualization of antiangiogenic treatment using data from clinical trials evaluating various dosing regimens against the patient's disease, lifestyle, and economic restrictions continues to evolve. PMID- 23642785 TI - Implications of the comparisons of age-related macular degeneration treatments trials on clinical practice: what have we learned? AB - TOPIC: Discussion of Comparisons of Age-Related Macular Degeneration (AMD) Treatments Trials (CATT) results and the potential impact on neovascular AMD treatment. CLINICAL RELEVANCE: Ranibizumab and bevacizumab are most commonly used for treatment of neovascular AMD. Although bevacizumab costs less, its use primarily has been based on retrospective studies without level 1 medical evidence. Thus, there was an unmet need to determine whether there is any difference in efficacy and safety between the 2 agents when used monthly or as needed (pro re nata [PRN]). METHODS: Review of CATT (focusing on 1-year data because 2-year data were not released at the time of this symposium), a randomized clinical trial evaluating the efficacy and safety of monthly and PRN dosing of ranibizumab and bevacizumab. RESULTS: At the 1-year primary end point, eyes that received monthly ranibizumab gained an average of 8.5 letters; those that received monthly bevacizumab gained a mean of 8 letters. Eyes randomized to PRN ranibizumab gained an average of 6.8 letters; those randomized to PRN bevacizumab gained a mean of 5.9 letters. In the pairwise comparisons, PRN bevacizumab compared with monthly bevacizumab and PRN bevacizumab compared with monthly ranibizumab both were found to be inconclusive. At the 2-year end point, eyes that received monthly ranibizumab gained an average of 8.8 letters; those that received monthly bevacizumab gained a mean of 7.8 letters; those randomized to PRN ranibizumab gained an average of 6.7 letters; those randomized to PRN bevacizumab gained a mean of 5 letters. A higher rate of serious systemic adverse events also was detected among bevacizumab-treated subjects. CONCLUSIONS: The CATT demonstrated that PRN ranibizumab is equivalent to monthly ranibizumab at the 1-year primary outcome. Monthly bevacizumab also is equivalent to monthly ranibizumab at the 1-year end point. The 2-year data showed less visual acuity gain with PRN dosing of either drug than monthly dosing. PMID- 23642786 TI - Environmental biotechnology. PMID- 23642787 TI - Systems-integration of plant metabolism: means, motive and opportunity. AB - System integration of metabolism is considered in analogy to the investigation of corporate misdemeanour. Motive, or goal-oriented explanation, provides hypotheses that can guide the investigation of network structure. Opportunity can be established by correlative analysis using large-scale omics resources. However, correlative approaches on their own remain inconclusive and seldom identify all the links in a network. Establishment of means, or the ability to act on other network components and contribute to a phenotype, is therefore crucial. This requires functional information. Integration of quantitative data in the context of pathway models provides a powerful approach to establish 'means'. This is illustrated by discussing: first, how protein abundance is regulated by a network including transcript abundance, translation and protein degradation and second, how a combination of experimentation and modelling provides information about pathway flux, an emergent network property that integrates changes in proteins and metabolites and determines composition and biomass. PMID- 23642788 TI - The role of anti-smoking legislation on cigarette and alcohol consumption habits in Italy. AB - The short-term effects of public smoking bans on individual smoking and drinking habits were investigated in this paper. In 2005, a smoking ban was introduced in Italy, and we exploited this exogenous variation to measure the effect on both smoking participation and intensity and the indirect effect on alcohol consumption. Using data from the Everyday Life Aspects survey, for the period 2001-2007, we show that the introduction of smoke-free legislation in Italy significantly affected smoking behavior. We also document significant indirect effects on alcohol consumption for the main alcoholic beverage categories. A robustness analysis is also performed, to test the extent to which unobservable variables may bias our estimated parameters. Our results are then used to perform a cost-effectiveness analysis of the anti-smoking legislation in Italy. PMID- 23642789 TI - Academic Collaborative Centre Limburg: a platform for knowledge transfer and exchange in public health policy, research and practice? AB - Research findings often fail to find their way into policy and practice, which is assumed to limit the effectiveness of public health policies and programmes. We evaluated to what extent the Academic Collaborative Centre Limburg (ACCL), a Dutch boundary organization linking policy, research and practice, has improved knowledge transfer and exchange between the three domains. We used a mixed methods approach. First, stakeholders jointly defined the ACCL's programme theory, showing how the ACCL was supposed to achieve its intended effects. Second, we assessed the achievements of the ACCL in terms of knowledge transfer and exchange on the basis of the programme theory. The ACCL was found to provide a platform for interaction between actors from the policy, research and practice domains, facilitated by integrated network structures. The number of collaborative projects and actors involved in the ACCL increased, but actual cross-domain interaction patterns did not really change. Cross-domain knowledge transfer and exchange still require major boundary-spanning efforts by the ACCL programme leader. Boundary organizations do not automatically produce cross domain interactions. In addition to infrastructural arrangements, cross-domain knowledge transfer and exchange could benefit from additional cultural changes, like adopting a deliberative approach to policy making and applying constructivist research designs. PMID- 23642790 TI - "Underwater" EMR of sporadic laterally spreading nonampullary duodenal adenomas (with video). AB - BACKGROUND: EMR for the treatment of duodenal adenomas is challenging due to a thin wall and rich vascularity. OBJECTIVE: To evaluate a novel technique of "underwater" EMR without prior submucosal injection for the removal of large (>=2 cm) laterally spreading nonampullary duodenal adenomas. DESIGN: Prospective, observational study. SETTING: Tertiary academic referral center. PATIENTS: Twelve patients (median age, 60 years) meeting the inclusion criteria. INTERVENTIONS: Piecemeal EMR technique after sterile water submersion when using a double channel endoscope. MAIN OUTCOME MEASUREMENTS: Technical success, adverse events, completeness of resection on follow-up endoscopy. RESULTS: Median adenoma size was 35 mm (25% greater than one-half circumference, 50% equal to one-third to one half circumference, and 25% less than one-third circumference). Median procedure time was 65 minutes (range, 32-151). Final histology was tubular adenoma (7), tubulovillous adenoma (1), villous adenoma (3), and high-grade dysplasia (1). Eleven patients (92%) met the primary endpoint (technical success) and all patients met the secondary endpoint (completeness of resection). Median interval until follow-up endoscopy was 16 weeks (range, 11-56). Adverse events were as follows: delayed bleeding (3 patients, of whom 2 required transfusions), water intoxication syndrome manifested by altered mental status and hyponatremia (1), and stricture formation (1) that responded to balloon dilation. No perforation or postresection abdominal pain was found. LIMITATIONS: Single operator, single center, small sample size, limited follow-up. CONCLUSION: Underwater EMR for large sessile duodenal adenomas has high success rates for complete removal. The risk of delayed bleeding is significant, and precautions are needed when infusing a large volume of fluid into the GI tract. PMID- 23642791 TI - An overview of fecal microbiota transplantation: techniques, indications, and outcomes. PMID- 23642792 TI - Male mastectomy: an oncoplastic solution to improve aesthetic appearance. AB - Mastectomy for breast cancer in men typically results in an unsatisfactory aesthetic appearance due to loss of the normal male chest contour. In this article we present two case studies and a new oncoplastic surgical technique that has given excellent aesthetic results for this challenging problem. PMID- 23642793 TI - A reliable anatomic approach for identification of the masseteric nerve. PMID- 23642794 TI - Autologous fat grafting for treatment of facial atrophy in Behcet's disease: a case report. AB - Behcet's disease (BD) is an autoimmune & autoinflammatory disease of unclear etiology characterized by recurrent oral & genital ulcers as well as other systemic manifestations. A key pathogenesis is excessive inflammatory wound healing response. While descriptions of the cutaneous manifestations of disease are limited to short-term consequences such as extensive pustule and papule formation in response to minor tissue injury, the long-term consequences are significant fibrosis and scarring of epithelial tissue. We describe the case of a patient with Behcet's disease who presented with unilateral facial atrophy secondary to minor trauma to the oral mucosa. She was treated with autologous fat grafting. Though a rare disease, plastic surgeons should be aware of the entity of Behcet's disease and its complications of tissue atrophy that may require reconstructive surgery. PMID- 23642795 TI - Improving outcomes in microsurgical breast reconstruction: lessons learnt from 406 consecutive DIEP/TRAM flaps performed by a single surgeon. AB - BACKGROUND: Multiple preoperative, intraoperative and postoperative decisions can influence the outcome of microsurgical breast reconstruction. We have simplified the decision-making process by incorporating a number of algorithms into our microsurgical breast reconstruction practice and critically review our results in this study. METHODS: Prospectively maintained databases for all microsurgical breast reconstructions performed by a single surgeon over a nine-year period were examined to determine: patient demographics; operative details including flap choice, donor and recipient vessel selection; and, details of intraoperative and early postoperative (=0-letter gain) compared with ANCHOR or MARINA baseline measurements, whereas 34% declined by 15 letters or more, with overall a mean decline of 8.6 letters (P<0.005). Since exit from the HORIZON study, study eyes had received a mean of 6.8 anti-vascular endothelial growth factor (VEGF) injections during the mean 3.4-year interval; a subgroup of patients who received 11 or more anti-VEGF injections had a significantly better mean gain in letter score since HORIZON exit (P<0.05). Active exudative disease was detected by spectral-domain OCT in 68% of study eyes, and 46% were receiving ongoing ocular anti-VEGF treatments. Macular atrophy was detected by FAF in 98% of eyes, with a mean area of 9.4 mm(2); the area of atrophy correlated significantly with poor visual outcome (P<0.0001). CONCLUSIONS: Approximately 7 years after ranibizumab therapy in the ANCHOR or MARINA trials, one third of patients demonstrated good visual outcomes, whereas another third had poor outcomes. Compared with baseline, almost half of eyes were stable, whereas one third declined by 15 letters or more. Even at this late stage in the therapeutic course, exudative AMD patients remain at risk for substantial visual decline. PMID- 23642855 TI - The incidence, co-occurrence, and predictors of dysphagia, dysarthria, and aphasia after first-ever acute ischemic stroke. AB - Dysphagia, dysarthria and aphasia occur frequently following stroke. Our purpose was to identify the incidence, co-occurrence, and predictors of these impairments after first-ever ischemic stroke. We used the Registry of the Canadian Stroke Network's database (2003-2008) from one stroke center to identify a random sample of 250 patients with acute ischemic stroke confirmed by MR imaging. We further conducted a retrospective medical chart review. We established reliable data capture and identified the presence of the three impairments. We derived incidence and co-occurrence estimates along with 95% confidence intervals (CI) for dysphagia, dysarthria, and aphasia. We then computed odds ratios (OR) through logistic regression to identify predictors. Twenty-nine patient charts were not available for review. Estimates of the incidence of dysphagia, dysarthria, and aphasia were 44% (95% CI, 38-51), 42% (95% CI, 35-48) and 30% (95% CI, 25-37), respectively. The highest co-occurrence of any two impairments was 28% (95% CI, 23-34) for the presence of both dysphagia and dysarthria. Ten percent of all 221 patients had all three impairments. The highest predictors were non-alert level of consciousness for dysphagia (OR 2.6, CI 1.03-6.5), symptoms of weakness for dysarthria (OR 5.3, CI 2.4-12.0), and right-sided symptoms for aphasia (OR 7.1, CI 3.1-16.6). These findings are a first step toward identifying the incidence and predictors of multiple co-occurring impairments in a homogenous stroke sample. LEARNING OUTCOMES: Learning outcomes: Readers will be able to (1) RECOGNIZE the need for research in stroke, whereby outcomes are reported according to stroke etiology and recurrence patterns, (2) identify the incidence and co-occurrence of dysphagia, dysarthria, and aphasia after a first-ever acute ischemic stroke, and (3) describe clinical precursors of these impairments in the acute stage of stroke. PMID- 23642857 TI - Modelling spatio-temporal patterns of long-distance Culicoides dispersal into northern Australia. AB - Novel arboviruses, including new serotypes of bluetongue virus, are isolated intermittently from cattle and insects in northern Australia. These viruses are thought to be introduced via windborne dispersal of Culicoides from neighbouring land masses to the north. We used the HYSPLIT particle dispersal model to simulate the spatio-temporal patterns of Culicoides dispersal into northern Australia from nine putative source sites across Indonesia, Timor-Leste and Papua New Guinea. Simulated dispersal was found to be possible from each site, with the islands of Timor and Sumba highlighted as the likely principal sources and February the predominant month of dispersal. The results of this study define the likely spatial extent of the source and arrival regions, the relative frequency of dispersal from the putative sources and the temporal nature of seasonal winds from source sites into arrival regions. Importantly, the methodology and results may be applicable to other insect and pathogen incursions into northern Australia. PMID- 23642858 TI - Short sleep and obesity: other factors to be considered. PMID- 23642861 TI - P21-activated kinase 4--not just one of the PAK. AB - P21-activated kinase 4 (PAK4) is a member of the p21-activated kinase (PAK) family. Historically much of the attention has been directed towards founding family member PAK1 but the focus is now shifting towards PAK4. It is a pluripotent serine/threonine kinase traditionally recognised as a downstream effector of the Rho-family GTPases. However, emerging research over the last few years has revealed that this kinase is much more than that. New findings have shed light on the molecular mechanism of PAK4 activation and how this kinase is critical for early development. Moreover, the number of PAK4 substrates and binding partners is rapidly expanding highlighting the increasing amount of cellular functions controlled by PAK4. We propose that PAK4 should be considered a signalling integrator regulating numerous fundamental cellular processes, including actin cytoskeletal dynamics, cell morphology and motility, cell survival, embryonic development, immune defence and oncogenic transformation. This review will outline our current understanding of PAK4 biology. PMID- 23642862 TI - Selected emerging infectious diseases of ornamental fish. AB - Several emerging infectious diseases have serious implications for the trade and husbandry of ornamental fish. Although many of these diseases have been well studied and described in certain species, there are still many diseases that are not well understood. The following discussion focuses on select important emerging infectious diseases that affect ornamental fish in the aquarium and aquaculture industries: goldfish herpesvirus, koi herpesvirus, Ranavirus, Megalocytivirus, Betanodavirus, Francisella, Cryptobia iubilans, and Exophiala. When possible, the known species affected, clinical signs, diagnosis, treatment, disinfection, and prevention modalities for each disease are discussed. PMID- 23642859 TI - Optogenetics in psychiatric diseases. AB - Optogenetic tools have revolutionized the field of neuroscience, and brought the study of neural circuits to a higher level. Optogenetics has significantly improved our understanding not only of the neuronal connections and function of the healthy brain, but also of the neuronal changes that lead to psychiatric disorders. In this review, we summarize recent optogenetic studies that explored different brain circuits involved in natural behaviors, such as sleep and arousal, reward, fear, and social and aggressive behavior. In addition, we describe how alterations in these circuits may lead to psychiatric disorders such as addiction, anxiety, depression, or schizophrenia. PMID- 23642863 TI - Selected emerging diseases of amphibia. AB - This review summarizes the most recent updates on emerging infectious diseases of amphibia. A brief summary of Batrachochytrium dendrobatidis history, epidemiology, pathogenesis, life cycle, diagnosis, treatment, and biosecurity is provided. Ambystoma tigrinum virus, common midwife toad virus, frog virus 3, Rana grylio virus, Rana catesbeiana ranavirus, Mahaffey Road virus, Rana esculenta virus, Bohle iridovirus, and tiger frog virus ranaviruses are extensively reviewed. Emerging bacterial pathogens are discussed, including Flavobacter sp, Aeromonas sp, Citrobacter freundii, Chlamydophila sp, Mycobacterium liflandii, Elizabethkingia meningoseptica, and Ochrobactrum anthropi. Rhabdias sp, Ribeiroia sp, and Spirometra erinacei are among several of the parasitic infections overviewed in this article. PMID- 23642864 TI - Emerging infectious diseases of chelonians. AB - Various new diseases have emerged in captive and wild populations of turtles and tortoises. Several of these seem to be on the rise and have the potential to cause widespread disease. This article reviews the current literature and authors' experience with intranuclear coccidiosis, cryptosporidium, iridovirus, and adenovirus. The biology, epidemiology, clinical signs, diagnosis, treatment, and pathologic changes are described for each disease. PMID- 23642865 TI - Selected emerging infectious diseases of squamata. AB - It is important that reptile clinicians have an appreciation for the epidemiology, clinical signs, pathology, diagnostic options, and prognostic parameters for novel and emerging infectious diseases in squamates. This article provides an update on emerging squamate diseases reported in the primary literature within the past decade. Updates on adenovirus, iridovirus, rhabdovirus, arenavirus, and paramyxovirus epidemiology, divergence, and host fidelity are presented. A new emerging bacterial disease of Uromastyx species, Devriesea agamarum, is reviewed. Chrysosporium ophiodiicola-associated mortality in North American snakes is discussed. Cryptosporidium and pentastomid infections in squamates are highlighted among emerging parasitic infections. PMID- 23642866 TI - Avian bornavirus and proventricular dilatation disease: diagnostics, pathology, prevalence, and control. AB - Avian bornavirus (ABV) has been shown the cause of proventricular dilatation disease (PDD) in psittacines. Many healthy birds are infected with ABV, and the development of PDD in such cases is unpredictable. As a result, the detection of ABV in a sick bird is not confirmation that it is suffering from PDD. Treatment studies are in their infancy. ABV is not restricted to psittacines. It has been found to cause PDD-like disease in canaries. It is also present at a high prevalence in North American geese, swans, and ducks. It is not believed that these waterfowl genotypes can cause disease in psittacines. PMID- 23642867 TI - Emerging and reemerging diseases of avian wildlife. AB - Of the many important avian wildlife diseases, aspergillosis, West Nile virus, avipoxvirus, Wellfleet Bay virus, avian influenza, and inclusion body disease of cranes are covered in this article. Wellfleet Bay virus, first identified in 2010, is considered an emerging disease. Avian influenza and West Nile virus have recently been in the public eye because of their zoonotic potential and links to wildlife. Several diseases labeled as reemerging are included because of recent outbreaks or, more importantly, recent research in areas such as genomics, which shed light on the mechanisms whereby these adaptable, persistent pathogens continue to spread and thrive. PMID- 23642868 TI - Update on diseases of chinchillas. AB - Chinchillas have been successfully maintained in captivity for almost a century. They have only recently been recognized as excellent, long-lived, and robust pets. Most of the literature on diseases of chinchillas comes from farmed chinchillas, whereas reports of pet chinchilla diseases continue to be sparse. This review aims to provide information on current, poorly reported disorders of pet chinchillas, such as penile problems, urolithiasis, periodontal disease, otitis media, cardiac disease, pseudomonadal infections, and giardiasis. This review is intended to serve as a complement to current veterinary literature while providing valuable and clinically relevant information for veterinarians treating chinchillas. PMID- 23642869 TI - Hyperthyroidism and hyperparathyroidism in guinea pigs (Cavia porcellus). AB - Abnormal conditions of the thyroid and parathyroid in the guinea pig appear in the English-language scientific literature on an emerging basis. Although true descriptions of abnormal thyroid and parathyroid anatomy or morphology are not new findings, the clinical condition of abnormal thyroid or parathyroid function seems to be a more common observation by clinicians in recent years. This article is an overview of general clinical conditions and adequate diagnosis, and offers treatment options. PMID- 23642870 TI - Gastrointestinal disease in guinea pigs and rabbits. AB - This article reviews diagnosis and management of gastrointestinal diseases in guinea pigs and rabbits. The review includes established causes of gastrointestinal disease in these species. The authors highlight syndromes that may be considered emerging or less-recognized causes of gastrointestinal stasis, including gastric dilation and volvulus in guinea pigs and lead toxicity, colonic entrapment, and liver torsion in rabbits. Practitioners should recommend initial diagnostics, including radiographs and blood work on guinea pigs and rabbits presenting with nonspecific signs of gastrointestinal stasis, to better determine possible cause and make the best treatment recommendations. PMID- 23642871 TI - Viral infections of rabbits. AB - Viral diseases of rabbits have been used historically to study oncogenesis (e.g. rabbit fibroma virus, cottontail rabbit papillomavirus) and biologically to control feral rabbit populations (e.g. myxoma virus). However, clinicians seeing pet rabbits in North America infrequently encounter viral diseases although myxomatosis may be seen occasionally. The situation is different in Europe and Australia, where myxomatosis and rabbit hemorrhagic disease are endemic. Advances in epidemiology and virology have led to detection of other lapine viruses that are now recognized as agents of emerging infectious diseases. Rabbit caliciviruses, related to rabbit hemorrhagic disease, are generally avirulent, but lethal variants are being identified in Europe and North America. Enteric viruses including lapine rotavirus, rabbit enteric coronavirus and rabbit astrovirus are being acknowledged as contributors to the multifactorial enteritis complex of juvenile rabbits. Three avirulent leporid herpesviruses are found in domestic rabbits. A fourth highly pathogenic virus designated leporid herpesvirus 4 has been described in Canada and Alaska. This review considers viruses affecting rabbits by their clinical significance. Viruses of major and minor clinical significance are described, and viruses of laboratory significance are mentioned. PMID- 23642872 TI - Selected emerging diseases in ferrets. AB - Since their introduction as pets several decades ago, ferrets have become an increasingly popular household pet. Great strides have been made in improving their diet and understanding common diseases (eg, insulinoma, hyperadrenocorticism, lymphoma) that affect them. With the frequency with which these conditions are seen, it sometimes is easy to forget that ferrets can be affected by other diseases. Some of these diseases, such as cryptococcosis, are known, but may be increasing in incidence and range, whereas others, such as hypothyroidism and pure red cell aplasia, may be underrecognized or underreported. This review highlights new and emerging diseases not already well reviewed in the literature. PMID- 23642873 TI - New and emerging diseases. PMID- 23642874 TI - New place-of-service rules. PMID- 23642875 TI - Eight questions to enhance lecturing. PMID- 23642876 TI - Retirement issues for radiologists, part 2: Consensus statement on retirement and preretirement issues by the Commission on Human Resources of the ACR. AB - There are many retirement and preretirement issues facing individual radiology groups and practices. The discussion of the numerous options available for radiologists contemplating retirement sometimes becomes contentious within a practice and may pit younger radiologists against the more senior members of the group. The potential exists for the process to degenerate into personality clashes. The purpose of this article is to offer some objective guidance on retirement issues. PMID- 23642878 TI - An evaluation of the impact of clinically embedded reading rooms on radiologist referring clinician communication. AB - The aim of this study was to investigate whether locating reading rooms in clinical areas at a large tertiary care, academic hospital in the United States corresponds with increased rates of direct communication between radiologists and clinicians. Data recorded included the frequency, form, duration, and general purpose of communications. Two-tailed Fisher's exact tests were used to determine the statistical significance of differences between the frequencies of communication methods for the reading rooms included in the study. During the observation period, there were a total of 175 episodes of communication between radiologists and referring providers in the 4 study reading rooms. There was a highly significant difference (P < .0001) in the percentage of visits and critical test result management messages sent between embedded and nonembedded reading rooms, while the differences in the proportion of calls both to and from referring providers was not significant (P = .4468). Although the purpose of this study was to assess the impact of reading room location on radiologists' communications with referring providers, several alternative hypotheses could also explain the results. The value of this study emerges from the documentation of the high degree of variability among institutions in communication practices among different kinds of radiologists and referring physicians. The extent of these different practices among the 4 reading rooms has important implications for future studies of communication patterns between radiologists and referring providers as well as for designing effective interventions to enhance the role of radiologists as consultants. PMID- 23642877 TI - The next level of radiology peer review: enterprise-wide education and improvement. AB - It is essential to the future of radiology that our profession own and embrace the objectives and methodology of peer review. The authors describe a natural evolution of peer review away from measurement and error identification toward the goal of performance improvement for the entire profession by allowing everyone to learn from the mistakes of everyone else. This can be accomplished by a comprehensive program of reviewer education, cross-platform anonymous prospective data collection, third-party expert arbitration, and meaningful sharing of results with the entire body of radiologists and residency programs. Such a system would require robust informatics and leadership from provincial and state as well as national radiologist associations. In so doing, apprehension and risk for the individual radiologist could be minimized, while ensuring that everyone benefits from others' mistakes, thereby measurably reducing errors across the entire enterprise. Seldom, and only in cases of significant and immediate patient risk, would an individual's identity and performance ever need to be made visible, even to the administrators of the program. PMID- 23642879 TI - Make sure your loved ones get it when you're gone: the need for estate planning. PMID- 23642880 TI - Can health IT tools enable improved documentation of quality, safety measures, and regulatory requirements in radiology reports? PMID- 23642881 TI - Dual-energy CT: is it ready for prime time? PMID- 23642882 TI - Martin Donner. PMID- 23642883 TI - Authors' response. PMID- 23642884 TI - Re: "Recent measures to improve radiology reporting: perspectives from primary care physicians". PMID- 23642885 TI - Re: "Recent measures to improve radiology reporting: perspectives from primary care physicians". PMID- 23642886 TI - Re: "The ACR/Society of Breast Imaging resident and fellowship training curriculum for breast imaging, updated". PMID- 23642887 TI - Heparin-induced thrombocytopenia during extracorporeal membrane oxygenation. PMID- 23642888 TI - Transesophageal echocardiography during orthotopic liver transplantation: maximizing information without the distraction. PMID- 23642889 TI - Clinical significance of the cross-sectional area of the internal jugular vein. AB - OBJECTIVES: The aim of this study was to compare the cross-sectional area (CSA) of the right internal jugular vein (IJV) with that of the left IJV and to evaluate the anatomic location of the IJV in relation to the common carotid artery, utilizing computed tomography scans of the neck. DESIGN: Retrospective observational study. SETTING: A tertiary care hospital. PARTICIPANTS: Eighty patients with neck computed tomography scans scheduled for thyroid surgery. INTERVENTION: No. MEASUREMENTS AND MAIN RESULTS: Mean CSA of the right and left IJV were 165+/-81 and 119+/-57 mm(2), respectively (p<0.01). A relatively larger CSA of the right IJV, compared with that of the left , was seen in 63 (79%) patients. A larger CSA of the right IJV was shown in more right-handed subjects than left-handed subjects (82 v 43%, p<0.05). Small CSA (<50 mm(2)) of the right or left IJV were seen in 4 patients. Both IJVs were located commonly either laterally or anterolaterally to their common carotid arteries. A posterolateral position of the IJV was seen in 4 patients. CONCLUSIONS: This study suggested one advantage of using the right IJV compared with the left for central venous cannulation. However, anatomic variations of the IJV, such as a small CSA and a medial or posterior position, are not associated with demographic data. Although right-handedness was well-correlated with a larger ipsilateral IJV, a possibility of a larger contralateral IJV should be considered. Therefore, central venous cannulation with ultrasonography is recommended to avoid complications and repeated needling. PMID- 23642890 TI - Characteristics associated with postoperative diagnosis of adenomyosis or combined adenomyosis with fibroids. AB - OBJECTIVE: To identify clinical characteristics associated with combined adenomyosis and fibroids and to determine whether preoperative diagnosis by ultrasonography correlates with postoperative diagnosis by pathology. METHODS: A retrospective chart review was conducted of 206 women who attended Nassau University Medical Center, East Meadow, USA, between July 1, 2007, and June 30, 2010. The patients were stratified into 3 groups-fibroids only (n=148); adenomyosis only (n=21); or combined adenomyosis and fibroids (n=37)-according to postoperative pathology findings and variables known to be associated with adenomyosis and fibroids. Significant variables were included in a multinomial regression analysis. RESULTS: Dysmenorrhea was the only variable significantly associated with a diagnosis of adenomyosis. The odds ratio (OR) was 3.34 (95% confidence interval [CI], 1.14-9.80). Variables significantly associated with combined adenomyosis and fibroids were age (OR, 1.08; 95% CI, 1.01-1.15), black ethnicity (OR, 2.72; 95% CI, 1.11-6.68), and parity (OR, 1.44; 95% CI, 1.08 1.92). Preoperative diagnosis by ultrasonography did not correlate with the postoperative pathology report. CONCLUSION: Including the identified variables in the preoperative evaluation of patients with suspicion of fibroids might improve the counseling process and aid the choice of surgical procedure, especially among patients desiring a conservative approach. PMID- 23642891 TI - Let there be light! PMID- 23642892 TI - Donor site morbidity of an islanded inferior gluteal artery myocutaneous flap with vascularized fascia lata. AB - The perineal defect following extended abdominoperineal resection (APR) is commonly reconstructed with a pedicled vertical rectus abdominus muscle (VRAM) flap. To avoid unnecessary insult to the abdominal wall the authors have preferred an islanded inferior gluteal artery myocutaneous (IGAM) flap with vascularized fascia lata. The gluteal region is not without its own documented morbidity concerns which in this patient demographic is further complicated by nearby irradiated tissue and oncological surgery. This prospective review examines the donor site morbidity of patients following modified IGAM flaps. MATERIAL & METHODS: The records of all APR patients who had IGAM flap reconstruction performed by the senior author (August 2008-August 2012) were retrospectively reviewed for outcomes and complications, and then prospectively followed-up using a purpose-specific assessment tool. Outcome measures included (i) wound healing, (ii) posterior cutaneous nerve of the thigh (PCNT) and sciatic nerve function, (iii) gluteus maximus (GM) and tensor fascia lata (TFL) strength, and (iv) post-operative functional levels assessed using the 'Timed-Up-and-Go' (TUG) test and Oswestry Disability Index. RESULTS: Of the 35 patients who satisfied the inclusion criteria 32/35 (91%) patients completed the prescribed follow-up. The average age was 62 years (range 22-82) and mean follow-up period was 10.5 (range 3-32) months. All patients had rectal cancer and received neoadjuvant chemoradiotherapy, and all except two reconstructions were performed primarily. There were 3 cases (9%) of wound dehiscence none of which were attributed to wound infection or haematoma. Scar tenderness in 5 patients (16%) was the most common post-operative complaint. PCNT hypoesthesia affected 10/32 (31%) patients while there was no significant GM or TFL weakness. Mean TUG time was 9.6 (range 3.2-15) seconds, while mean ODI score was 6.6 (range 0-40). CONCLUSIONS: In spite of challenging circumstances the IGAM flap can provide appropriate wound coverage with surprisingly little donor site morbidity contrary to previous reports. PMID- 23642893 TI - Combination cosmetic surgery: an individual surgeon's experience in non post massive weight loss patients. PMID- 23642894 TI - A reflective practice intervention for professional development, reduced stress and improved patient care--a qualitative developmental evaluation. AB - OBJECTIVE: Professional capabilities, such as empathy and patient-centeredness, decline during medical education. Reflective practice is advocated for teaching these capabilities. The Clinical Reflection Training (CRT) is a reflective practice intervention using the professional dilemmas faced by medical students during clinical practice. The aim of this study was to evaluate students' perceptions of the helpfulness of the CRT and its effects on their medical education. METHODS: Eighteen semi-structured interviews were conducted with medical students who had participated in the CRT. Content analysis was used to analyze the interview data. RESULTS: Medical students did not feel adequately prepared to manage the difficult personal and interpersonal problems frequently encountered in clinical practice. They reported that the CRT reduces stress, improves patient care and serves as a tool for professional development. CONCLUSION: The CRT may be a useful tool for developing professionalism during medical education, reducing stress and enhancing the quality of patient care. PRACTICE IMPLICATIONS: Providing students with reflective practice training that draws on their current personal clinical problems in order to improve their clinical work may be a productive investment in personal professional development, physician health, and quality improvement. PMID- 23642895 TI - [Goiter: a rare cause of childhood dyspnea]. AB - We report the case of a patient who presented dyspnea due to a large intrathoracic goiter. This patient had congenital hypothyroidism due to thyroid enzyme deficiency. He came to a pediatric emergency department for dyspnea. At home, he had inspiratory and expiratory dyspnea with a stridor. No signs of respiratory distress were observed. The neck was deformed by a large goiter. The patient indicated that he did not follow the recommended L-thyroxine treatment. Chest and neck radiography showed tracheal compression. A cervical CT scan showed a 60% reduction of the tracheal caliber. To our knowledge, only one case report of goiter with tracheal compression due to congenital hypothyroidism has been reported in the literature. In the case of retrosternal goiter, dyspnea is more common than respiratory distress. Absence of tachypnea or use of accessory muscles does not exclude an anatomic compression. In the case of dyspnea, the search for a goiter is recommended. PMID- 23642896 TI - [Respiratory syncytial virus brainstem encephalitis in a 7-year-old boy]. AB - The literature reports that neurological complications of childhood respiratory diseases due to respiratory syncytial virus (RSV) fluctuate between 1 and 40% of cases. They mostly involve central apnea - often the first symptom of infection - anoxia, and ischemic brain damage due to severe sudden weakness in infants, and seizures and consciousness disorders more or less associated with focalized neurological deficiency proving an encephalitis lesion. We report the case of brainstem encephalitis in a 7-year-old boy with RSV A nasopharyngitis, with meningitis, positive polymerase chain reaction in cerebrospinal fluid and magnetic resonance imaging (MRI) abnormalities, which was explained by viral replication encephalitis. Based on a literature review, we discuss the main aspects of epidemiology and physiopathology of the main neurological complication of RSV. Most of them have not been fully investigated and only a few articles report encephalitis. As far as central apnea is concerned, an animal experimental hypothesis surprisingly suggests a peripheral mechanism. PMID- 23642897 TI - [A paediatrician's play kit: example and basic tool for an approach of the infant's global development between 0 and 4 years of age]. AB - The South and West Francilien Pediatric Network (Reseau Pediatrique du Sud et Ouest Francilien [RPSOF]) has established a protocol for the developmental follow up of infants inspired by the existing developmental scales adapted to the current practice of out patient consultation. The consultation described here collects a set of very simple objects and trade toys that are a support for a qualitative exploration of the development for the infants of less than 4 years of age. Different fields are taken into account: global motor skills, hand-eye coordination, manipulation and construction, communication and language, attentional capacity, relational and social behaviour. The time of exchange and play between the paediatrician and the infant allows a first detection of possible problems: the orientation towards a specialized professional for a consultation, a standard check-up or even a therapeutic care becomes easier and clearer. This playful environment also offers a space for the parents, and supports their participation as primary role players in the development of their child. This time, integral part of the consultation, is completed by the somatic examination and sensory screening tests. At present reserved for children identified as being at risk, this type of consultation could be universalised for all infants. PMID- 23642898 TI - [Relationship between glomerular filtration rate, uric acid, and parathyroid hormone in children]. AB - INTRODUCTION: Parathyroid hormone (PTH) and uric acid (UA) levels increase early during chronic kidney disease (CKD). The objective of this study was to evaluate the relationship between these two parameters at different stages of pediatric CKD. PATIENTS AND METHODS: One hundred patients (range, 5-18 years) were included in this retrospective study: they had undergone renal exploration with a direct measurement of the glomerular filtration rate (GFR) using the reference standard (i.e., inulin clearance, Cin) and presented with increased circulating levels of PTH and/or UA. RESULTS: GFR was normal in 39% of patients, with UA increased in 44% and PTH in 75% of them. Interestingly, 29% of the children with increased PTH levels had a strictly normal GFR (i.e., above 90 mL/min/1.73 m(2)). An inverse association was found between UA and GFR (r=-0.452, P <= 0.0001) as well as between PTH and GFR (r=-0.226, P=0.024). The same negative relationships were found between UA and PTH (r=-0.266, P=0.007), and between UA and the phosphate reabsorption rate (r=-0.415, P<0.001). DISCUSSION: Since hyperuricemia was found at all stages of CKD, an early silent tubular impairment can be discussed to explain these findings. The early increase in PTH levels during CKD has not been described by all authors, with North American studies describing rather late increased PTH levels during CKD. Prospective studies are required to confirm these data and evaluate the role of UA in the pathophysiology of the mineral disorders observed during CKD. PMID- 23642899 TI - [Seroprevalence of infectious markers among blood donors in Niamey (Niger)]. AB - BACKGROUND: The study aimed to determine the seroprevalence of transfusion transmitted infectious (TTI) markers for human immunodeficiency virus (HIV), hepatitis B and C viruses (HBV, HCV) and syphilis among blood donors in Niamey (Niger). The association between seroprevalence of ITT markers and sociodemographic characteristics of blood donors was investigated. METHODS: A cross-sectional study was conducted in 2010 among 3213 blood donors. Data were collected from a pre-donation questionnaire and from laboratory tests results. RESULTS: The male/female ratio was 4/1. Up to 18.1% of donations had at least one positive marker, in which 2.7% presented a positive test for two or more agents. A seroprevalence of 1.62% (95%CI: 1.21-2.12) was associated with HIV, 15.4% (13.9 16.7) with HBV, 1.18% (0.84-1.62) with HCV, and 0.47% (0.26-0.77) for blood samples reacted with RPR test for syphilis. The HIV seroprevalence was two-fold higher in family than in volunteer donors (OR=2.15, 95%CI: 1.24-3.73). It was also higher in Rhesus D negative donors (OR=2.40, 95%CI: 1.11-5.17). The hepatitis B surface antigen seroprevalence was significantly higher in males than females (OR=1.85, 95%CI: 1.39-2.45) and in first time than in regular donors (P<0.0001). The HCV seroprevalence was significantly higher in male donors (OR=4.41, 95%CI: 1.06-18.4) and in donors from rural areas (OR=4.09, 95%CI: 1.42 11.8). Syphilis marker was significantly associated with the marital status (higher seroprevalence in divorced donors, P=0.0085). CONCLUSION: Prevalence of TTI markers is high and national strategies for safe blood transfusion have to be strengthened. It is essential to recruit and maintain more volunteer donors, while females should be encouraged to donate blood. PMID- 23642900 TI - [Adaptation of a peer pressure scale in French and German: the Peer Pressure Inventory]. AB - BACKGROUND: Peer pressure is regarded as an important determinant of substance use, sexual behavior and juvenile delinquency. However, few peer pressure scales are validated, especially in French or German. Little is known about the factor structure of such scales or the kind of scale needed: some scales takes into account both peer pressure to do and peer pressure not to do, while others consider only peer pressure to do. The aim of the present study was to adapt French and German versions of the Peer Pressure Inventory, which is one of the most widely used scales in this field. We considered its factor structure and concurrent validity. METHODS: Five thousand eight hundred and sixty-seven young Swiss men filled in a questionnaire on peer pressure, substance use, and other variables (conformity, involvement) in a cohort study. RESULTS: We identified a four-factor structure, with the three factors of the initial Peer Pressure Inventory (involvement, conformity, misconduct) and adding a new one (relationship with girls). A non-valued scale (from no peer pressure to peer pressure to do only) showed stronger psychometric qualities than a valued scale (from peer pressure not to do to peer pressure to do). Concurrent validity was also good. Each behavior or attitude was significantly associated with peer pressure. CONCLUSION: Peer pressure seems to be a multidimensional concept. In this study, peer pressure to do showed the strongest influence on participants. Indeed, peer pressure not to do did not add anything useful. Only peer pressure to do affected young Swiss men's behaviors and attitudes and was reliable. PMID- 23642901 TI - Azimuthal projections: data rotation and projection switching in real time. AB - Pole figures are often used to present crystal orientation data. The huge number of single orientation measurements acquired by electron backscatter diffraction (EBSD) poses a challenge for pole figure representation due to the large number of calculations required. This significantly reduces the speed at which the data may be rotated and affects the ability to switch between different projection types. In the present work, it will be shown that satisfactory representation of orientation data in different projection types can generally be achieved by an imaging of a spherical projection. With this approach, explicit calculation of the projections is no longer required, allowing for both real-time dataset rotation and real-time switching between all projection types relevant to materials science. The technique can be applied to any other directional property distribution, for example, not only for EBSD orientation presentation. PMID- 23642902 TI - Measurement decisions in nursing and midwifery research. PMID- 23642903 TI - Fluorescence in situ hybridization (FISH) for rapid identification of Salmonella spp. from agar and blood culture broth--an option for the tropics? AB - BACKGROUND: Salmonella enterica is an important cause of diarrhea with the potential to cause systemic infection including sepsis, particularly in the tropics. Sepsis in particular requires quick and reliable identification to allow a rapid optimization of antibiotic therapy. We describe the establishment and evaluation of fluorescence in situ hybridization (FISH) as a rapid and easy-to perform molecular identification procedure from agar and blood culture broths. METHODS: Two newly developed FISH probes with specificity for Salmonella spp. were evaluated with 10 reference strains, 448 clinical isolates of Gram-negative bacteria from Germany and Ghana including 316 Salmonella spp. strains, and 39 environmental Salmonella spp. isolates from rivers and streams in Ghana. One FISH probe was further tested with 207 pre-incubated blood culture broths from Germany with Gram-negative rod-shaped bacteria in Gram stain. RESULTS: Evaluation of the newly designed FISH probes demonstrated sensitivity of 99.2% and specificity of 98.4% for clinical isolates, sensitivity of 97.4% for environmental Salmonella spp. isolates, and sensitivity of 100% and specificity of 99.5% for blood culture materials. CONCLUSIONS: FISH proved to be highly reliable for a rapid identification of Salmonella spp. directly from pre-incubated blood culture broths as well as after growth on agar. The inexpensive and easy-to-perform procedure is particularly suitable for resource-limited areas where more sophisticated procedures are not available. PMID- 23642904 TI - Unique preferential conduction within the isolated septal substrate in a patient with ventricular tachycardia complicated with non-ischemic dilated cardiomyopathy. AB - We describe the case of a 67-year-old woman with non-ischemic dilated cardiomyopathy who underwent successful radiofrequency catheter ablation for ventricular tachycardia (VT) originated from the isolated ventricular septal substrate. Pacemapping exhibited either left, identical to clinical VT, or right bundle branch block like wide QRS morphology. Time interval from the stimulus to QRS onset (St-QRS) was prolonged at the center of the substrate, while St-QRS at the border was shortened. Difference in the morphology of pacemapping was dependent on whether or not the pacing stimulus could propagate directly into the right ventricle due to the possible intramural conduction disturbance. PMID- 23642906 TI - Molecular targeted agents--where we are and where we are going. AB - A total of 23 new cancer medicines or indication expansions were approved by the U. S. Food and Drug Administration in 2012. Among these, 12 are new molecular entities (NMEs)--new chemical or biological drugs approved for the first time for oncologic use--and 10 of these NMEs are molecular targeted agents. Among the 10 targeted agents, 4 are anti-angiogenesis agents and 2 are Bcr-Abl pathway inhibitors, targeting well established targets validated by previously approved agents such as bevacizumab (Avastin) or imatinib (Gleevec). Despite this progress, several questions remain: Do these newly approved agents provide sufficient treatment options to manage the broad spectrum of cancers we deal with in the clinic? Where will the next wave of new cancer drugs come from? Where should R&D efforts be invested to continue improve cancer treatment and management, especially for tumor types uniquely prevalent in China? This editorial and the review articles in this special issue of Chinese Journal of Cancer provide an in depth review of the progress and challenges in developing targeted cancer therapies, as well as an outlook of new research areas where near term breakthroughs are expected to overcome some of these challenges. PMID- 23642905 TI - Protein production from the structural genomics perspective: achievements and future needs. AB - Despite a multitude of recent technical breakthroughs speeding high-resolution structural analysis of biological macromolecules, production of sufficient quantities of well-behaved, active protein continues to represent the rate limiting step in many structure determination efforts. These challenges are only amplified when considered in the context of ongoing structural genomics efforts, which are now contending with multi-domain eukaryotic proteins, secreted proteins, and ever-larger macromolecular assemblies. Exciting new developments in eukaryotic expression platforms, including insect and mammalian-based systems, promise enhanced opportunities for structural approaches to some of the most important biological problems. Development and implementation of automated eukaryotic expression techniques promises to significantly improve production of materials for structural, functional, and biomedical research applications. PMID- 23642907 TI - Targeting the PI3K-AKT-mTOR signaling network in cancer. AB - The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR, a vital substrate along this pathway, led to the approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers. However, the suboptimal duration of response in unselected patients remains an unresolved issue. Numerous novel therapies against critical nodes of this pathway are therefore being actively investigated in the clinic in multiple tumor types. In this review, we focus on the progress of these agents in clinical development along with their biological rationale, the need of predictive biomarkers and various combination strategies, which will be useful in counteracting the mechanisms of resistance to this class of drugs. PMID- 23642908 TI - Critical care management of verapamil and diltiazem overdose with a focus on vasopressors: a 25-year experience at a single center. AB - STUDY OBJECTIVE: Verapamil or diltiazem overdose can cause severe morbidity and death, and there exist limited human data describing management and outcome of a large number of such patients. This article describes the management and outcome of patients with nondihydropyridine calcium-channel blocker overdose, with an emphasis on vasopressor dosing, at a single center. METHODS: This study is a retrospective chart review of patients older than 14 years and admitted to the inpatient toxicology service of a single tertiary care medical center for treatment of verapamil or diltiazem overdose from 1987 through 2012, and who had the presence of either drug confirmed by urine drug screening. Patients were identified by review of patient encounter logs. Data abstracted from medical records included demographics, laboratory results, drugs used to support blood pressure, complications, and outcomes. A second group included patients with a reported calcium channel blocker ingestion but for whom results of the urine drug testing were no longer available. In an effort to assess selection bias, this group was included to determine whether patients who were excluded from the primary group only because of unavailability of urine drug screen results had different outcomes. RESULTS: During the study period, 48 patients met inclusion criteria. The median age was 45 years, with a range of 15 to 76 years, and 52% were male patients. Verapamil accounted for 24 of 48 (50%) ingestions. Vasopressors were administered to 33 of 48 (69%) patients. Maximal vasopressor infusion doses were epinephrine 150 MUg/minute, dopamine 100 MUg/kg per minute, dobutamine 245 MUg/kg per minute, isoproterenol 60 MUg/minute, phenylephrine 250 MUg/minute, and norepinephrine 100 MUg/minute. The use of multiple vasopressors was common. Hyperinsulinemic euglycemia was used in 3 patients who also received multiple vasopressors. Eight probable or possible ischemic complications were noted in 5 of 48 (10%) patients. Gastrointestinal bleeding occurred in 3 of 48 (6%) patients; a brain magnetic resonance imaging in 1 patient suggested mild ischemia, without clinical evidence of infarction; 1 patient had ischemic bowel; and 3 patients developed renal failure from acute tubular necrosis, which resolved in each case. Six of the 8 ischemic complications were evident before use of vasopressor therapy. Three patients sustained inhospital cardiac arrest before admission and were successfully resuscitated. Each of these arrests occurred before instituting vasopressor infusions. One patient experienced a late cardiac arrest from primary respiratory arrest from administration of sedatives, and multiple organ system failure followed resuscitation, with death occurring during manipulation of a pulmonary artery catheter. The remaining 47 patients recovered. There were 12 patients in the group of additional poisoned patients for whom results of urine drug screening were unavailable. Four patients were treated with vasopressors, 2 experienced acute tubular necrosis that was present before vasopressor use, and all recovered. CONCLUSION: In our series of patients admitted with verapamil or diltiazem overdose, hypotension was common and managed with the use of multiple vasopressors and without hyperinsulinemic euglycemia in all but 3 cases. Despite high doses of vasopressors, ischemic complications were the exception and were usually present before use of vasopressors. Death occurred in a single patient whose death was not attributed directly to calcium-channel blocker toxicity. Vasopressor use after verapamil or diltiazem overdose was associated with good clinical outcomes without permanent sequelae. PMID- 23642909 TI - Successful treatment of acute uncomplicated appendicitis in pregnancy with intravenous antibiotics. PMID- 23642911 TI - Intravascular papillary endothelial hyperplasia (Masson's tumour) in the vulva. PMID- 23642910 TI - Endometriosis, dysmenorrhoea and diet. AB - OBJECTIVE: To review the literature on the effects of diet on endometriosis and dysmenorrhoea. STUDY DESIGN: A systematic search for trials investigating a relationship between diet and endometriosis/dysmenorrhoea was undertaken, and 23 studies were included in this review. RESULTS: Data on the relationship between diet and endometriosis were limited to 12 trials, three of which were animal studies, resulting in a total of 74,708 women. One large study (n=70,709) found a relatively strong association between endometriosis and trans-fatty acid consumption, and a lower risk of endometriosis with increased consumption of long chain omega-3 fatty acids. The latter finding was also supported by smaller studies. No further dietary recommendations for reducing the risk of endometriosis were possible, and results for intake of vegetable, fibre and fruit were equivocal. The relationship between diet and dysmenorrhoea was investigated in 11 trials with different designs, including a total of 1433 women. Intake of fish oil seemed to reduce dysmenorrhoea. CONCLUSION: The literature on endometriosis and dysmenorrhoea in relation to diet is sparse, yielding equivocal results on specific elements. Overall, however, the literature suggests that specific types of dietary fats are associated with endometriosis and/or dysmenorrhoea, thereby indicating that there may be modifiable risk factors. Further research is recommended on both subjects. PMID- 23642912 TI - The relationship between job type and development of cerebral stroke in a large, longitudinal cohort study of workers in a railway company in Japan. AB - BACKGROUND AND PURPOSE: The aim of this study was to clarify the relationship between occupational factors and the development of cerebral stroke in a large cohort working at a railway company in Japan. METHODS: A 10-year prospective cohort study was conducted in 32,441 male workers who received annual health check-ups at a Japanese railway company. Diagnosis of cerebral stroke was based on the results of the annual health check-ups and individual medical histories. Cerebral stroke included cerebral hemorrhage, cerebral infarction, and subarachnoid hemorrhage. The relationship between job type and the development of cerebral stroke was investigated using a proportional hazards regression with time-dependent covariates adjusted for age, body mass index, mean arterial pressure, family history of cerebral stroke, tobacco and alcohol consumption, and habitual exercise. RESULTS: A negative relationship between job type and the development of cerebral stroke was observed in train crew members, with a significantly lower hazard ratio (HR) seen in train drivers (HR 0.63, 95% confidence interval (CI), 0.42-0.95) and conductors (HR 0.41, 95% CI, 0.24-0.71) in comparison to clerical workers. CONCLUSIONS: Since the present results were adjusted for various behavioral and biological factors, they suggest that train crew work itself is associated with a decreased risk of cerebral stroke. These results suggest that further studies on the effect of driving on health may provide information useful for the future prevention of cerebral stroke. PMID- 23642914 TI - Transfusion-related acute lung injury: a clinical review. AB - Three decades ago, transfusion-related acute lung injury (TRALI) was considered a rare complication of transfusion medicine. Nowadays, the US Food and Drug Administration acknowledge the syndrome as the leading cause of transfusion related mortality. Understanding of the pathogenesis of TRALI has resulted in the design of preventive strategies from a blood-bank perspective. A major breakthrough in efforts to reduce the incidence of TRALI has been to exclude female donors of products with high plasma volume, resulting in a decrease of roughly two-thirds in incidence. However, this strategy has not completely eradicated the complication. In the past few years, research has identified patient-related risk factors for the onset of TRALI, which have empowered physicians to take an individualised approach to patients who need transfusion. PMID- 23642913 TI - The effect of HIV infection on atherosclerosis and lipoprotein metabolism: a one year prospective study. AB - OBJECTIVES: HIV infection is associated with dyslipidaemia and increased risk of cardiovascular disease. The effects of HIV infection and antiretroviral treatment on surrogate markers of atherosclerosis, and lipoprotein metabolism were evaluated in a 12 month prospective study. METHODS AND RESULTS: Treatment-naive HIV patients were recruited into one of three groups: untreated HIV infection not likely to require initiation of antiretroviral therapy (ART) for at least 12 months; initiating treatment with non nucleoside reverse transcriptase inhibitor containing ART regimen and initiating treatment with protease inhibitor containing ART regimen. The patients underwent assessment of carotid intima-media thickness (cIMT), pulse wave velocity (PWV), brachial flow-mediated dilation (FMD) and variables of plasma lipoprotein metabolism at baseline and 12 months. The findings were compared with published values for age and sex matched HIV negative healthy subjects in a cross-sectional fashion. cIMT and FMD were lower while PWV was higher in HIV-patients compared with HIV-negative individuals; none of the markers changed significantly during 12 months follow up. HIV patients had hypoalphalipoproteinemia and elevated plasma levels of lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein. The only significant changes in lipid-related variables were elevation of total cholesterol and triglycerides in patients treated with PI-containing regimen and elevation of plasma LCAT levels in patients treated with NNRTI-containing regimen. The ability of whole and apoB-depleted plasma to effect cholesterol efflux was not impaired in all three groups. CONCLUSIONS: This study did not find evidence for rapid progression of subclinical atherosclerosis and deterioration of dyslipidaemia in HIV patients within 1 year. PMID- 23642916 TI - Open repair of intact thoracoabdominal aortic aneurysms in the American College of Surgeons National Surgical Quality Improvement Program. AB - OBJECTIVE: Open surgical repair of thoracoabdominal aortic aneurysms (TAAAs) is uncommon. Mortality rates of 20% are reported in studies using national data and are 5% to 8% in single-institution studies. Clinical trials are currently evaluating branched and fenestrated endografts. The purpose of this study is to establish a benchmark for future comparisons with endovascular trials using open repair of TAAAs in the National Surgical Quality Improvement Program (NSQIP) database. METHODS: We identified all patients undergoing open elective and emergency surgical repair of intact TAAAs in NSQIP (2005 to 2010) using Current Procedural Terminology (American Medical Association, Chicago, Ill) and International Classification of Diseases, 9th Edition codes. We analyzed demographics, comorbidities, 30-day mortality, postoperative complications, and length of stay. Multivariable logistic regression was used to identify predictors of mortality. RESULTS: We identified 450 patients who underwent open surgical repair (418 elective, 32 emergent) of an intact TAAA. Mean age was 69.4 years, 60.7% were male, and 85.6% were white. Comorbidities included hypertension (87.1%), chronic obstructive pulmonary disease (27.3%), prior stroke or transient ischemic attack (16.7%), diabetes (11.6%), and peripheral vascular disease (9.6%). Thirty-day mortality was 10.0%. Pulmonary complications were the most common: failure to wean from ventilator (39.1%), pneumonia (23.1%), and reintubation (13.8%). Acute renal failure requiring dialysis occurred in 10.7% of patients. Multivariable analysis (odds ratio [95% confidence interval]) showed predictors of mortality were emergent repair (3.3 [1.03-10.83]; P = .04), age >70 years (3.5 [1.03-7.56], P = .001), preoperative dialysis (8.4 [1.90-37.29], P = .005), cardiac complication (2.9 [1.05-8.21], P = .04), and renal complications (8.4 [3.41-20.56], P < .001). CONCLUSIONS: In this study of NSQIP hospitals, the first to analyze open surgical repair of TAAAs, the 30-day mortality rate of 10.0% is similar to single-institution reports. However, morbidity and mortality after open TAAA repair remain high, confirming the need for less invasive procedures. PMID- 23642917 TI - Histologic analysis of stent graft oversizing in the thoracic aorta. AB - OBJECTIVE: To elucidate the histologic changes after stent graft oversizing in nonatherosclerotic aortas using an experimental porcine model. We previously reported that the diameter and angulation of the aorta in this model are similar to those in young individuals who undergo stent graft repair for blunt aortic injuries. The lack of commercially available stent grafts specific for repairing blunt aortic injuries, particularly for small and angulated aortas, may be related to the high rate of endograft complications in this population. METHODS: Twenty-five pigs were randomized into one control group (without stent graft implantation) and four oversized groups (A: 10%-19%, B: 20%-29%, C: 30%-39%, and D: >40%). Three circumferential fragments were collected from the aorta for histologic and immunohistochemical studies. Morphometric analyzes were performed using an inflow system and image analysis software (Quantimet 500; Leica Cambridge Ltd, Cambridge, UK). RESULTS: Collagen expression in the aortic wall was not significantly different among the five groups (P = .5604). There were significantly fewer muscle fibers in the aortic wall in the oversized groups compared with the control group (P = .000198). The proportion of elastic fibers in the aortic wall was significantly smaller in the oversized groups compared with the control group (P = .0000001). Immunohistochemical analysis showed that alpha-actin expression in the aortic wall was significantly decreased in the oversized groups compared with the control group (P = .002031). There were no significant differences in either the number of muscle fibers or alpha-actin expression among the four oversized groups. CONCLUSIONS: Histologic and immunohistochemical studies confirmed the structural disarrangement of the aortic wall after insertion of an endoprosthesis, including reduced number of muscle and elastic fibers. PMID- 23642918 TI - Hemiaortic arch debranching using native supra-aortic vessels. AB - Endovascular treatment of aortic arch aneurysms with a proximal landing zone in zone I requires carotid-carotid bypass. We report two patients with aortic arch aneurysms in whom we used a new hybrid approach by transposing the left common carotid artery and left subclavian artery to the right common carotid artery. This innovative technique uses a native vessel instead of prosthetic material and a shunt to maintain cerebral perfusion, thereby avoiding bilateral carotid clamping. PMID- 23642919 TI - Vasculitis resulting from a superficial femoral artery angioplasty with a paclitaxel-eluting balloon. AB - Drug-eluting balloons (DEBs) coated with the antiproliferative agent paclitaxel may improve primary patency by reducing recurrent luminal stenosis. A proportion of the active drug and excipient coating are known to embolize distally, but until now, there have been no reports of adverse events resulting from their use. We report an unusual case of a painful nodular, biopsy specimen-proven vasculitic rash that afflicted the ipsilateral lower limb of a patient after superficial femoral artery treatment with a DEB. This adverse event may have implications for the use of DEB in this and other vascular territories. PMID- 23642920 TI - Endovascular repair of bilateral common iliac artery aneurysms following open abdominal aortic aneurysm repair with preservation of both hypogastric arteries using commercially available stent grafts. AB - Endovascular treatment of aneurysmal disease has become the predominant form of repair for all aneurysms. Some areas continue to pose specific challenges to stay within the general tenets of successful repair, mainly achieving adequate seal without sacrificing other arterial pathways. Following aortic aneurysm repair, the common iliac arteries can continue to have aneurysmal degeneration. We present a case of bilateral common iliac artery aneurysms that presented 9 years after open repair of an infrarenal abdominal aortic aneurysm in conjunction with an extensive aortic dissection. These were repaired using endovascular techniques with preservation of both hypogastric arteries. PMID- 23642921 TI - Direct sonographic-guided superior gluteal artery access for treatment of a previously treated expanding internal iliac artery aneurysm. AB - Isolated internal iliac artery aneurysms are relatively uncommon compared with all aortoiliac aneurysms. Transcatheter treatment with coil embolization is an attractive noninvasive alternative to surgical resection. However, if the aneurysm is insufficiently treated with only proximal coil embolization without concurrent embolization of distal runoff vessels, there is a risk of aneurysm expansion from retrograde collateral flow. We present a case of previously treated internal iliac aneurysm that underwent late rapid expansion. Due to occlusion of the internal iliac artery, direct sonographic-guided puncture of the superior gluteal artery was made in order to access the aneurysm. We believe this is the first reported case of such treatment. PMID- 23642922 TI - A new technique for reconstruction of the aortic bifurcation with saphenous vein panel graft. AB - A 60-year-old male patient presented with a false aneurysm of the common iliac artery and methicillin-resistant Staphylococcus aureus septicemia complicating previously placed kissing covered stents of the aortic bifurcation. We removed the prosthetic material and repaired the aortic bifurcation with a composite saphenous vein panel graft. To our knowledge, this technique is presented for the first time in the literature. PMID- 23642923 TI - Re-entry into the true lumen from the subintimal space. AB - Endovascular reconstruction of the femoral and popliteal arteries is replacing femoral-popliteal bypass. This is made possible by subintimal recanalization to manage long chronic total occlusions. Re-entry into the true lumen is the most challenging step in this process. This article summarizes the techniques for re entry into the true lumen in the superficial femoral and above- and below-the knee popliteal arteries. PMID- 23642924 TI - The United States StuDy for EvalUating EndovasculaR TreAtments of Lesions in the Superficial Femoral Artery and Proximal Popliteal By usIng the Protege EverfLex NitInol STent SYstem II (DURABILITY II). AB - OBJECTIVE: Angioplasty and stenting are options for revascularization of symptomatic femoral popliteal disease. Although angioplasty alone is effective in short lesions, longer lesions are often treated with stents. Multiple overlapping stents are expensive and may be associated with stent fracture. This trial evaluated the safety and efficacy of a single self-expanding stent up to 20 cm in length in patients with atherosclerotic disease of the superficial femoral artery (SFA) and proximal popliteal artery. METHODS: Patients with lesions >4 cm and <18 cm were enrolled in this nonrandomized, prospective, multicenter trial that evaluated the Protege EverFlex Self-Expanding Peripheral Stent System (Covidien, Plymouth, Minn). The study's primary end points were the 30-day major adverse event rate and duplex ultrasound-assessed patency at 1 year. These were compared with published performance goals. A preplanned analysis was conducted for the primary effectiveness end points at 1 year. Follow-up, including history, ankle brachial index, patient-reported outcomes, duplex ultrasound assessment, and radiographs, is planned through 3 years. There was core laboratory review of angiograms, ultrasound scans, and plain radiographs. A subgroup of patients was studied with graded treadmill testing. RESULTS: The study enrolled 287 patients (66% male; mean age, 68 years) with stenotic, restenotic, or occluded lesions of the SFA at 44 investigational sites in the United States and Europe. Systemic comorbidities included hypertension (88%), hyperlipidemia (86%), diabetes (43%), and prior SFA intervention (41%). The mean lesion length measured by the core laboratory was 89 mm. The mean normal-to-normal lesion length measured by sites was 110 mm. A total of 303 stents were implanted, and 95% of patients received a single stent. No major adverse events occurred at 30 days. At 1 year, primary outcome of duplex ultrasound stent patency was 67.7% in evaluable patients, and among 1-year secondary outcomes, the mean ankle-brachial index increased by 0.25. Walking Improvement Questionnaire scores improved in pain by 33.7, distance by 37.1, speed by 18.6, and stair climbing by 24.7. The Kaplan-Meier estimate of primary patency was 77.2%, primary assisted patency was 86.9%, and secondary patency was 87.3%. Rutherford clinical category improved in 83.5% of patients. Stent fracture rate was 0.4%. Matched absolute claudication distance was 412 feet greater and was not statistically different in this subgroup of 29 individuals. CONCLUSIONS: The results of DURABILITY II (StuDy for EvalUating EndovasculaR TreAtments of Lesions in the Superficial Femoral Artery and Proximal Popliteal By usIng the Protege EverfLex NitInol Stent SYstem II) suggest that a new single stent strategy is safe and effective for the treatment of long lesions of the SFA and proximal popliteal arteries at 1 year. PMID- 23642925 TI - Veno-venous perfusion to cool and rewarm in thoracic and thoracoabdominal aortic aneurysm repair. AB - BACKGROUND: Femoro-femoral veno-arterial perfusion is an established circulatory support and cooling method for thoracic- and/or thoracoabdominal aortic aneurysm repair. However, retrograde perfusion through femoral arteries can lead to retrograde cerebral embolization and neurologic dysfunction after surgery. To avoid these complications, we have established a femoro-femoral veno-venous perfusion technique and evaluated its safety and effectiveness in elective and nonelective patients. METHODS: Common femoral veins were cannulated bilaterally percutaneously following systemic low-dose heparinization (100 IU/kg body weight). Venous blood was drained from drainage of the inferior vena cava, and venous return followed through the superior vena cava. After proximal aortic cross-clamping, veno-venous perfusion was switched to veno-arterial antegrade perfusion through the distal descending thoracic aorta to achieve spinal and visceral perfusion or through iliac arteries for distal perfusion combined with selective renovisceral blood perfusion. After completion of aortic repair, the arterial cannula was removed and the patient rewarmed just by switching back to veno-venous perfusion. Gas and temperature exchange as well as relevant hemodynamic parameters were recorded prospectively and analyzed retrospectively in 25 consecutive patients including 15 nonelective cases. RESULTS: Percutaneous insertion of outflow (28F cannula) and inflow (18F cannula) venous cannulae was complication-free and allowed unrestricted perfusion in all 25 patients. Veno venous perfusion allowed effective cooling (mean body temperature 36.6 +/- 0.6 degrees C to 31.6 +/- 2.1 degrees C, P = .001 compared with start of cooling) and re-warming (mean body temperature 30.5 +/- 3 degrees C to 36.3 +/- 0.8 degrees C, P = .03 compared with start of re-warming). Hemodynamic as well as pulmonary parameters remained remarkably stable during surgical dissection and single lung ventilation even in nonelective cases. There was no complication associated with the perfusion technique during surgery. CONCLUSIONS: Transfemoral veno-venous cooling and re-warming results in remarkable hemodynamic stability during open repair of thoracic- and/or thoracoabdominal aortic aneurysms and eliminates the need for retrograde arterial perfusion and its inherent risks. PMID- 23642926 TI - Modifiable risk factor burden and the prevalence of peripheral artery disease in different vascular territories. AB - BACKGROUND: The precise relationship between risk factor burden and prevalence of peripheral artery disease (PAD) in different vascular territories (PAD, carotid artery stenosis [CAS], and abdominal aortic aneurysms [AAAs]) is unclear. METHODS: We investigated the association of modifiable risk factors (hypertension, hypercholesterolemia, smoking, diabetes, and sedentary lifestyle) with any and type-specific peripheral vascular disease (PVD) among 3.3 million patients in the U.S., aged 40 to 99, who underwent screening bilateral ankle brachial indices, carotid duplex ultrasound, and abdominal aortic ultrasound in the Life Line Screening program between 2004 and 2008. Multivariate logistic regression analysis was used to estimate the odds of disease in different risk factor categories. Population-attributable risk was calculated to estimate the proportion of disease that could be potentially ascribed to modifiable risk factors. RESULTS: Among 3,319,993 participants, prevalence of any PVD was 7.51% (95% confidence interval [CI], 7.50%-7.53%). PAD was present in 3.56% (95% CI, 3.54%-3.58%), CAS in 3.94% (95% CI, 3.92%-3.96%), and AAAs in 0.88% (95% CI, 0.86%-0.89%). The multivariate-adjusted prevalence with the presence of 0, 1, 2, 3, 4, and 5 modifiable risk factors was 2.76, 4.63, 7.12, 10.73, 16.00, and 22.08 (P < .0001 for trend) for any PVD; 1.18, 2.09, 3.28, 5.14, 8.32, and 12.43 (P < .0001 for trend) for PAD; 1.41, 2.36, 3.72, 5.73, 8.48, and 11.58 (P < .0001 for trend) for CAS; and 0.31, 0.54, 0.85, 1.28, 1.82, and 2.39 (P < .0001 for trend) for AAAs, respectively. These associations were similar for men and women. For every additional modifiable risk factor that was present, the multivariate adjusted odds of having vascular disease increased significantly (any PVD [odds ratio (OR), 1.58; 95% CI, 1.58-1.59]; PAD [OR, 1.62; 95% CI, 1.62-1.63]; CAS [OR, 1.57; 95% CI, 1.56-1.57]; and AAA [OR, 1.51; 95% CI, 1.50-1.53]). CONCLUSIONS: This very large contemporary database demonstrates that risk factor burden is associated with an increased prevalence of PVD, and there is a graded association between the number of risk factors present and the prevalence of PAD, CAS, and AAAs. PMID- 23642928 TI - The use of dextran and carbon dioxide for optical coherence tomography in the superficial femoral artery. AB - The following case report describes using carbon dioxide (CO2) as contrast media for intravascular optical coherence tomography (OCT) imaging in the superficial femoral artery. For initial OCT imaging, 20 mL of iodinated contrast was used during automated pullback. This was followed by 20 mL of hand-injected dextran 40 in normal saline, and finally hand-injected 50 mL of CO2. CO2 gave comparable erythrocyte clearance and imaging quality compared with dextran and iodinated contrast. To our knowledge, this is the first reported case using both dextran and CO2 with OCT imaging of the superficial femoral artery. Using CO2 is a viable option in patients with contraindications to contrast or dextran use. PMID- 23642927 TI - Optimal selection of patients for elective abdominal aortic aneurysm repair based on life expectancy. AB - OBJECTIVE: Elective abdominal aortic aneurysm (AAA) repair is beneficial when rupture is likely during a patient's expected lifetime. The purpose of this study was to identify predictors of long-term mortality after elective AAA repair for moderately sized AAAs (<6.5-cm diameter) to identify patients unlikely to benefit from surgery. METHODS: We analyzed 2367 elective infrarenal AAA (<6.5 cm) repairs across 21 centers in New England from 2003 to 2011. Our main outcome measure was 5-year life-table survival. Cox proportional hazards analysis was used to describe associations between patient characteristics and 5-year survival. RESULTS: During the study period, 1653 endovascular AAA repairs and 714 open AAA repairs were performed. Overall, 5-year survival rates were similar by procedure type (75% endovascular repair, 80% open repair; P = .14). Advanced age >=75 years (hazard ratio [HR], 2.0; P < .01) and age >80 years (HR, 2.6; P < .01), coronary artery disease (HR, 1.4; P < .04), unstable angina or recent myocardial infarction (HR, 4.6; P < .01), oxygen-dependent chronic obstructive pulmonary disease (HR, 2.7; P < .01), and estimated glomerular filtration rate <30 mL/min/1.73 m(2) (HR, 2.8; P < .01) were associated with poor survival. Aspirin (HR, 0.8; P < .03) and statin (HR, 0.7; P < .01) use were associated with improved survival. We used these risk factors to develop risk strata for low risk, medium-risk, and high-risk groups with survival, respectively, of 85%, 69%, and 43% at 5 years (P < .001). CONCLUSIONS: More than 75% of patients with moderately sized AAAs who underwent elective repair in our region survived 5 years, but 4% were at high risk for 5-year mortality. Patients with multiple risk factors, especially age >80 years, unstable angina, oxygen-dependent chronic obstructive pulmonary disease, and estimated glomerular filtration rate <30 mL/min/1.73 m(2), are unlikely to achieve sufficient long-term survival to benefit from surgery, unless their AAA rupture risk is very high. PMID- 23642929 TI - Methylglyoxal chronic administration promotes diabetes-like cardiac ischaemia disease in Wistar normal rats. AB - BACKGROUND AND AIMS: The influence of lifestyle is well documented, especially the diet regime, in the development of type 2 diabetes (T2D) and associated cardiovascular diseases. Diabetic patients have increased risk of suffering cardiac ischemia and impaired response to such accidents. Methylglyoxal (MG) circulates at high concentration in diabetics' blood and is linked to the development of diabetes chronic complications. We propose that besides promoting the cardiovascular disease, MG may also negatively regulate the endogenous cardioprotection pathways after ischemia. METHODS AND RESULTS: We performed a comparative study between three animal groups: normal Wistar (W), type 2 diabetic non-obese Goto-Kakizaki (GK) and normal rats submitted to MG chronic administration (3 months) with gradually enhanced concentration, up to 75 mg/Kg (WMG). Hearts were submitted to different experimental conditions: control, ischemia and ischemia-reperfusion. Levels of oxidative stress markers, advanced glycation end-products (AGEs) and their receptors (RAGEs) were evaluated. The serine/threonine protein kinase Akt (Akt), crucial for cardiomyocytes recovery after ischemia, and apoptosis markers were also assessed. Levels of MG, systemic and cardiac oxidative stress markers, AGEs and RAGEs were similar in GK and WMG groups. Akt protein was negatively regulated by MG, leading to impaired apoptotic markers. CONCLUSION: Chronic MG administration to normal rodents mimicked most diabetic alterations, being associated with the development of cardiovascular disease and the impairment of survival pathways. Our results demonstrate the negative effect of MG rich diet in healthy animals and suggest the potential of methylglyoxal as a therapeutic target in diabetes. PMID- 23642931 TI - Editorial comment. PMID- 23642930 TI - Moderate alcohol use and health: a consensus document. AB - AIMS: The aim of this consensus paper is to review the available evidence on the association between moderate alcohol use, health and disease and to provide a working document to the scientific and health professional communities. DATA SYNTHESIS: In healthy adults and in the elderly, spontaneous consumption of alcoholic beverages within 30 g ethanol/d for men and 15 g/d for women is to be considered acceptable and do not deserve intervention by the primary care physician or the health professional in charge. Patients with increased risk for specific diseases, for example, women with familiar history of breast cancer, or subjects with familiar history of early cardiovascular disease, or cardiovascular patients should discuss with their physician their drinking habits. No abstainer should be advised to drink for health reasons. Alcohol use must be discouraged in specific physiological or personal situations or in selected age classes (children and adolescents, pregnant and lactating women and recovering alcoholics). Moreover, the possible interactions between alcohol and acute or chronic drug use must be discussed with the primary care physician. CONCLUSIONS: The choice to consume alcohol should be based on individual considerations, taking into account the influence on health and diet, the risk of alcoholism and abuse, the effect on behaviour and other factors that may vary with age and lifestyle. Moderation in drinking and development of an associated lifestyle culture should be fostered. PMID- 23642933 TI - Outcomes of distal ureteral reconstruction through reimplantation with psoas hitch, Boari flap, or ureteroneocystostomy for benign or malignant ureteral obstruction or injury. AB - OBJECTIVE: To assess functional outcomes and complications of ureteroneocystotomies (UNCs) with or without psoas hitch or Boari flap in the reconstruction and repair of the ureter. METHODS: We reviewed a consecutive series of patients that underwent open ureteral reconstruction for ureteral obstruction or injury. Underlying ureteral disorder, preoperative and postoperative estimated glomerular filtration rate (eGFR), and imaging studies regarding resolution of hydronephrosis were assessed. RESULTS: A total of 100 ureteral reimplantations performed at our institution from November 1986 to August 2012 were identified: 24 primary ureteroneocystotomies, 58 with psoas hitch, and 18 with Boari flap. Median follow-up was 48.7 months (range 12.3-253 months). The most common underlying disorder was ureteral transitional cell cancer (TCC). Men were found to have more frequent underlying chronic ureteral disorders with chronic renal failure when compared to women. Ureteral stents were placed in 81% and were removed after a median of 33 days (range 2-161 days). Resolution of hydronephrosis was noted in 81% of the patients. The eGFR deteriorated significantly over time only in male patients (P = .001). Postoperative complications included stent-related dysuria, urinary tract infection, and contrast-extravasation on cystogram necessitating prolonged urethral and ureteral catheter drainage. CONCLUSION: Excellent functional outcome without significant morbidity associated with ureteral reimplantation/reconstruction was achieved. Despite resolution of hydronephrosis in the vast majority of patients, those with chronic underlying ureteral disorder and renal failure did not show improvement of their eGFR. PMID- 23642934 TI - Quest for the missing kidney in the "treasure chest": report of a thoracic kidney in a child with recurrent diaphragmatic hernia. AB - The thoracic cavity is the rarest location of all the renal ectopic sites. We report a rare case of an acquired thoracic kidney associated with a previous congenital diaphragmatic hernia in a child with nephrotic syndrome. Although only 13 cases of the thoracic kidney in the pediatric age group have been described in worldwide reports during the past 25 years, we present the first to be associated with a recurrent diaphragmatic hernia. The classification, differential diagnosis, and management options of this rare form of ectopia are discussed. PMID- 23642935 TI - Laparoendoscopic single-site nephrectomy and heminephroureterectomy in children using standard laparoscopic setup versus conventional laparoscopy. AB - OBJECTIVE: To investigate the safety and effectiveness of laparoendoscopic single site surgery (LESS) using standard laparoscopic setup in pediatric nephrectomy/heminephroureterectomy (HN) by comparing with conventional laparoscopy (CL). METHODS: Twelve consecutive children who underwent LESS (nephrectomy = 8, HN = 4) from 2009 to 2012 were compared with a matched cohort of 18 children who underwent CL (nephrectomy = 12, HN = 6) at the same institution. Data were reviewed retrospectively. RESULTS: There was no difference between the 2 groups in the age of patients, body weight, gender distribution, laterality of pathology, postoperative analgesic requirement, and hospital stay. Eleven of the 12 children in the LESS group underwent the procedure successfully without additional trocar placement. The only open conversion happened in the case of LESS of the lower moiety HN. LESS nephrectomy took longer operative time than CL (mean 156 +/- 45 vs 99 +/- 35 minutes, median 155 vs 90 minutes, P <.01). Wound infection occurred in 1 patient after CL nephrectomy. No postoperative complication or access site hernia was noted in the children in the LESS group at follow-up. CONCLUSION: LESS nephrectomy and HN in the pediatric population is safe and effective with a minimally invasive nature comparable to CL. Learning curve factors may contribute to the reported longer operative time in LESS. Further studies are required to investigate the implication of patient selection and the cosmetic benefits of LESS, which may potentially require longer operative time. PMID- 23642936 TI - Testicular teratoma, mimicking a simple testicular cyst, in an infant. AB - Prepubertal testicular tumors are rare, and teratoma is the second most frequent histologic type. Its typical features are those of a hard and painless scrotal mass at clinical examination, and nonhomogeneous, echoic, often with calcifications at ultrasonography. Rare but reported is the atypical presentation as a transilluminating scrotal mass, due to the presence of some internal cystic areas, detectable at ultrasonography. We report the case of an infant with a transilluminating scrotal mass, mimicking at ultrasonography and surgery a simple, fully liquid cyst, which the pathologic examination revealed to be mature cystic testicular teratoma. PMID- 23642937 TI - Correlation between overactive bladder symptoms and quality of life in Japanese male patients: focus on nocturia. AB - OBJECTIVE: To elucidate the effects of nocturia, one of the most bothersome of symptoms, on health-related quality of life (QOL), we examined the correlation between nocturia-specific QOL and other lower urinary tract symptoms (LUTS). METHODS: Patients who visited our hospital complaining of LUTS were assessed retrospectively. A total of 259 men with LUTS answered the following questionnaires: International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), Nocturia QOL questionnaire (NQOL), and the Benign Prostatic Hyperplasia Impact Index (BII). The Spearman rank correlation coefficient was used to examine the correlation between NQOL total score and NQOL subdomain scores of sleep/energy and bother/concern and scores of other questionnaires. We then compared NQOL score in patients with or without OAB symptoms. RESULTS: The NQOL total score correlated significantly not only with IPSS total, IPSS storage symptoms, IPSS voiding symptoms, and QOL index but also with the OABSS and BII scores. The NQOL total score was significantly higher in the non-OAB vs OAB patients, indicating that OAB may deteriorate QOL as it relates to nocturia. In nocturia subgroups 0 to 2 (mild nocturia), NQOL score was significantly higher in non-OAB than in OAB patients, whereas in the nocturia subgroups 3 to 5 (severe nocturia), NQOL score was not significantly different between non-OAB and OAB patients. CONCLUSION: The NQOL total score correlated significantly with IPSS, OABSS, and BII scores. Symptoms of OAB and bother due to benign prostatic hyperplasia might affect QOL in patients with nocturia. PMID- 23642939 TI - Editorial comment. PMID- 23642940 TI - Lower ureteral stones revisited: expanding the horizons of robotics. AB - OBJECTIVE: To study the feasibility of robot-assisted laparoscopic ureterolithotomy for large (>2 cm) or impacted lower ureteral stones and the immediate outcome measures such as the stone-free rate and occurrence of intra- and postoperative complications. MATERIALS AND METHODS: From April 2010 to August 2012, 52 robotic stone surgeries were performed in our department. Robot-assisted laparoscopic ureterolithotomy was performed in 16 patients for large (>2 cm) or impacted lower ureteral stones. RESULTS: The stone was most commonly located in the juxtavesical position in all 16 patients. The average stone size was 2.2 cm, and all stones were impacted. The mean operative time was 45.3 minutes (range, 38 63), including stent placement time, and the mean blood loss was 10 mL. The mean console time was 20.3 minutes. No conversion to an open procedure was required. CONCLUSION: Robot-assisted laparoscopic ureterolithotomy for large, impacted, lower ureteral stones is an acceptable alternative. The ease of surgery and shorter operative times are significant advantages compared with the laparoscopic approach. PMID- 23642941 TI - Commentary on: everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. PMID- 23642942 TI - The effects of Panax notoginseng on delayed onset muscle soreness and muscle damage in well-trained males: a double blind randomised controlled trial. AB - OBJECTIVES: The aim of the study was to determine if Panax notoginseng is effective in reducing pain, indicators of inflammation and muscle damage, and in turn improve performance in well trained males who underwent a bout of eccentric exercise designed to induce delayed onset muscle soreness (DOMS). DESIGN: A double blind randomised placebo controlled trial. SETTING: Twenty well trained male volunteers, matched by maximum aerobic capacity were randomly assigned to consume a regime of 4000 mg of P. notoginseng capsules or an indistinguishable placebo before and after a downhill treadmill running episode designed to induce DOMS. MAIN OUTCOME MEASURES: Performance measures (Kin-Com, counter movement and squat jump), pain assessments (visual analogue scale (VAS), algometer) and blood analyses (interleukin-1, interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF alpha), C-reactive protein, myoglobin, creatine kinase) were assessed at 7 time points over 5 days (pre, post, 4, 24, 48, 72 and 96 h after the downhill run). RESULTS: The placebo group demonstrated a significant decrease in squat jump performance immediately post the downhill run, with a mean change +/- 95% confidence interval (CI) of 0.8 cm (-3.53 to 1.93). The placebo group also experienced increased pain in the quadriceps 96 h after the downhill run, with a mean VAS change +/- 95% CI of -0.32 cm (-0.34 to 0.98).The serum concentration of IL-6 and TNF-alpha were significantly lower in the placebo group 24h after the downhill run. Mean IL-6 change +/- 95% CI of 0.50 pg/mL (-1.59 to 0.59), and mean TNF-alpha change +/- 95% CI was 0.98 pg/mL (-2.04 to 0.09). No other significant differences were identified between the groups for any other outcome measure. CONCLUSION: Considering all data from this study, P. notoginseng did not convincingly have an effect on performance, muscular pain or assessed blood markers in well-trained males after an intense bout of eccentric exercise that induced DOMS. PMID- 23642943 TI - Evaluation of the effect of omega-3 fatty acids in the treatment of premenstrual syndrome: "a pilot trial". AB - INTRODUCTION: Premenstrual syndrome (PMS) refers to a cyclic appearance of somatic and psychiatric symptoms that affect some women. Finding an effective and safe method for the treatment of PMS has always been a serious concern, because approximately 40% of women report PMS, and in 2-10% of cases it is severe enough to affect their life style and job. OBJECTIVE: The purpose of the present study is to evaluate the effect of omega-3 fatty acids on the treatment of PMS. METHOD: A randomized double blind controlled trial was performed on 184 eligible women. The eligible women were randomly assigned into two groups. The number of women who have finalized the study with us was 124. In the case group (omega-3 group = group A, n = 70), omega-3 in an amount of 2 g was prescribed for a one per day basis on a single dosage (two 1 g pearls), and in the control group (placebo group = group B, n = 69) 2 placebo soft gel, which were completely similar to omega-3 soft gels, were prescribed. The severity and duration of each of the symptoms were compared in both groups 1.5 and 3 months after the beginning of treatment. RESULTS: There were no significant differences between the two groups according to age, BMI, level of education, and the severity and duration of primary symptoms. After 45 days from starting omega-3, the mean severity of depression (P = 0.03), anxiety (P = 0.02), lack of concentration (P = 0.03) and bloating (P = 0.02) in the case group, were all significantly lower than in the control group. The duration of depression (P = 0.04) and bloating (P = 0.031) in the case group were less than in the control group. After 90 days from starting the treatment, the mean severity of depression (P = 0.007), anxiety (P = 0.004), lack of concentration (P = 0.009), bloating (P = 0.004), nervousness (P = 0.01) and the duration of depression (P = 0.01), nervousness (P = 0.02), anxiety (P = 0.03), lack of concentration (P = 0.02), bloating (P = 0.004), headache (P = 0.04) and breast tenderness (P = 0.02) were all lower in the case group. CONCLUSION: It appears that omega-3 fatty acids may reduce the psychiatric symptoms of PMS including depression, nervousness, anxiety, and lack of concentration and may also reduce the somatic symptoms of PMS including bloating, headache and breast tenderness. These effects increased by longer duration of treatment. PMID- 23642944 TI - Effect of Turkish classical music on blood pressure: a randomized controlled trial in hypertensive elderly patients. AB - BACKGROUND: Existing studies suggest that music therapy can have favorable effects on hypertension and anxiety. We therefore set out to investigate the effect of Turkish classical music. OBJECTIVES: To investigate whether Turkish classical music has positive effects on blood pressures and anxiety levels in elderly patients. DESIGN, SETTING AND SUBJECTS: This was a randomized controlled trial performed on 60 hypertensive patients living in a local elderly home in Adana, Turkey. METHODS: Following the completion of a socio-demographic form for each patient, Hamilton anxiety scale was applied. Thereafter, the subjects were randomly divided into two equal-size groups and were allowed to either listen to Turkish classical music (music therapy group) or have a resting period (control group) for 25 min. OUTCOME MEASURES: The primary and secondary outcome measures were blood pressure and Hamilton anxiety scale scores, respectively. RESULTS: The mean reduction in systolic blood pressure was 13.00 mmHg in the music therapy group and 6.50 mmHg in the control group. The baseline adjusted between treatment group difference was not statistically significant (95% CI 6.80-9.36). The median reductions in diastolic blood pressures were 10 mmHg both in the music therapy and control groups. The between treatment group difference was not statistically significant (Mann-Whitney U test, P = 0.839). The mean reduction in HAMA-A was 1.63 in the music therapy group and 0.77 in the control group. The baseline adjusted between treatment group difference was not statistically significant (95% CI 0.82-1.92). CONCLUSION: The study demonstrated that both Turkish classical music and resting alone have positive effects on blood pressure in patients with hypertension. PMID- 23642945 TI - Bee venom acupuncture point injection for central post stroke pain: a preliminary single-blind randomized controlled trial. AB - OBJECTIVE: We investigated apipuncture, or acupuncture point injection with diluted bee venom, as a promising new treatment for central post stroke pain (CPSP). METHODS: Bee venom, diluted to 0.005% in normal saline, was administered to the treatment group, and normal saline given to control group as twice-weekly injections for three weeks. The points were LI15, GB21, LI11, GB31, ST36 and GB39 of the affected side and the amount of injection was 0.05 ml at each point. RESULTS: Eight patients in each group were included in the analysis. After three weeks there were significant decreases in visual analogue pain scores compared with baseline in both groups and the treatment group improved more significantly than the control group (p = 0.009). CONCLUSION: Apipuncture significantly improved CPSP in this pilot trial. Further studies of its mechanisms and a larger and long-term follow-up trial will be needed to determine more definitely the efficacy of apipuncture and to elucidate duration of improvement. PMID- 23642946 TI - The effect of aromatherapy massage on the psychological symptoms of postmenopausal Iranian women. AB - BACKGROUND: Menopausal symptoms experienced by women vary widely, and while many women transition through menopause with manageable symptoms, others experience severe symptoms, which may impair their quality of life. OBJECTIVES: A randomized clinical trial was conducted to determine the effect of aromatherapy massage on psychological symptoms during menopause. METHODS: The study population comprised 90 women. Each subject in the aromatherapy massage group received 30 min aromatherapy sessions with aroma oil, twice a week, for four weeks; each subject in the massage therapy group received the same treatment with odorless oil, while no treatment was provided to subjects in the control group. The outcome measures were psychological symptoms, as obtained through the psychological subscale of the Menopause Rating Scale. RESULTS: A total of 87 women were evaluated. A statistically significant difference was found between the participants' pre- and post-application psychological score in intervention groups, whereas the score in the control group did not differ significantly. Aromatherapy massage decreased the psychological score MD: -3.49 (95% Confidence Interval of Difference: -4.52 to -2.47). Massage therapy also decreased the psychological score MD: -1.20 (95% Confidence Interval of Difference: -2.19 to -0.08). To distinguish the effect of aromatherapy from massage separately, we compared the reduction in the psychological score. Aromatherapy massage decreased the psychological score more than massage therapy MD: -2.29 (95% Confidence Interval of Difference: -3.01 to 0.47). CONCLUSION: Both aromatherapy massage and massage were effective in reducing psychological symptoms, but, the effect of aromatherapy massage was higher than massage. PMID- 23642947 TI - The clinical efficacy of a bovine lactoferrin/whey protein Ig-rich fraction (Lf/IgF) for the common cold: a double blind randomized study. AB - OBJECTIVE: The aim of the study was to determine if a bovine lactoferrin/whey protein Ig-rich fraction (Lf/IgF) combination was effective in reducing the number of colds and in turn improving symptom recovery in a cohort of males and females that reported frequently contracting a cold. DESIGN: A double blind randomized placebo-controlled clinical trial. SETTING: One-hundred and twenty-six participants matched by age, BMI, dietary and physical parameters with self reported frequent upper respiratory tract symptoms and infections were randomly assigned to receive 600 mg of Lf/IgF or a placebo daily for 90 days. MAIN OUTCOME MEASURES AND RESULTS: A total of 90 participants (47 receiving the active and 43 placebo) completed the 90 day trial and 15 completed 45 days participation (6 in the active and 9 in the placebo group). The total number of colds recorded over the study period was 48 for the treatment group versus 112 for the placebo group (p < 0.001). The significant trend was retained when the data was corrected for medications returned (p < 0.001) and for guessing treatment allocations (p < 0.001). Non-parametric analysis demonstrated that the total number of cold associated symptoms reported by participants that received Lf/IgF was significantly less than those in the placebo group (p < 0.05). Also, total days sick with a cold and cold severity were reduced over the clinical trial period for Lf/IgF over placebo, but the trend was not significant. CONCLUSIONS: These findings demonstrate that the Lf/IgF combination significantly decreased the incidence of colds and the cumulative number of cold-related symptoms over placebo. This therapeutic combination may be indicated for the prevention of colds and its most common symptoms in the general population when administered as a preventative supplement. PMID- 23642948 TI - A phase II randomised double-blind placebo-controlled clinical trial investigating the efficacy and safety of ProstateEZE Max: a herbal medicine preparation for the management of symptoms of benign prostatic hypertrophy. AB - OBJECTIVE: The aim of the clinical trial was to evaluate the efficacy and safety of ProstateEZE Max, an orally dosed herbal preparation containing Cucurbita pepo, Epilobium parviflorum, lycopene, Pygeum africanum and Serenoa repens in the management of symptoms of medically diagnosed benign prostate hypertrophy (BPH). DESIGN: This was a short-term phase II randomized double-blind placebo controlled clinical trial. SETTING: The trial was conducted on 57 otherwise healthy males aged 40-80 years that presented with medically diagnosed BPH. INTERVENTION: The trial participants were assigned to receive 3 months of treatment (1 capsule per day) with either the herbal preparation (n = 32) or a matched placebo capsule (n = 25). OUTCOME MEASURES: The primary outcome measure was the international prostate specific score (IPSS) measured at baseline, 1, 2 and 3 months. The secondary outcomes were the specific questions of the IPSS and day-time and night time urinary frequency. RESULTS: There was a significant reduction in IPSS total median score in the active group of 36% as compared to 8% for the placebo group, during the 3-months intervention (p < 0.05). The day-time urinary frequency in the active group also showed a significant reduction over the 3-months intervention (7.0-5.9 times per day, a reduction of 15.6% compared to no significant reduction change for the placebo group (6.2-6.3 times per day) (p < 0.03). The night-time urinary frequency was also significantly reduced in the active group (2.9-1.8, 39.3% compared to placebo (2.8-2.6 times, 7%) (p < 0.004). CONCLUSION: The herbal preparation (ProstateEZE Max) was shown to be well tolerated and have a significant positive effect on physical symptoms of BPH when taken over 3 months, a clinically significant outcome in otherwise healthy men. PMID- 23642949 TI - A pilot study investigating the effect of Caralluma fimbriata extract on the risk factors of metabolic syndrome in overweight and obese subjects: a randomised controlled clinical trial. AB - OBJECTIVES: Central obesity is a key component of metabolic syndrome and it is often associated with other risk factors such as dyslipidemia, elevated plasma glucose levels and elevated blood pressure (BP). In this pilot study, the effect of Caralluma fimbriata (an edible succulent) extract in combination with controlled dietary intake and physical activity on these risk factors was assessed in overweight and obese Australian subjects. DESIGN: This was a randomised, double blind placebo controlled clinical trial. Forty-three adults aged 29-59 years were recruited. The eligibility criteria included a Body Mass Index (BMI) >25 kg/m(2), or a waist circumference >94 cm (male), >80 cm (female). Thirty-three participants completed the 12-week study at Victoria University Nutritional Therapy Clinic. Participants were randomly assigned into two groups. C. fimbriata extract and placebo were orally administered as 500 mg capsules twice daily (1 g/day) and dietary intake and exercise were monitored weekly. RESULTS: The results of thirty-three participants (experimental group, n = 17; placebo group n = 16) were analysed. The primary outcome measure was the decline in waist circumference. By week 9, the experimental group had lost 5.7 cm, compared to only 2.8 cm loss in the placebo group (Difference: -2.890; 95% CI; 5.802 to 0.023). Post intervention, the experimental group had lost 6.5 cm compared to 2.6 cm loss in the placebo group (Difference: -3.847; 95% CI; -7.466 to 0.228). Waist to hip ratio (WHR) also improved significantly after 12 weeks intervention in the experimental group, with a total reduction of 0.03 being recorded compared to 0.01 increase in the placebo group (Difference: -0.033; 95% CI; -0.064 to -0.002). There was also a significant decline in the palatability (visual appeal, smell, taste) of the test meal and sodium intake in the experimental group at week 12 (p < 0.05). In addition a significant reduction in body weight, BMI, hip circumference, systolic BP, HR, triglyceride levels, total fat and saturated fat intake within both groups was observed following the intervention period (p < 0.05). CONCLUSION: Supplementation with C. fimbriata extract whilst controlling overall dietary intake and physical activity may potentially play a role in curbing central obesity, the key component of metabolic syndrome. Controlling dietary intake and exercise improved body weight and favourably influenced the metabolic risk profile. PMID- 23642950 TI - N-of-1 trials in China. AB - CONTEXT: The N-of-1 trial design (randomized and blinded single-patient trials) has been popular abroad for 25 years or more. Many papers using the N-of-1 trials have been published in international medical journals. However, little is known about this methodology in China. Our purpose is to describe the current status of N-of-1 trials in China, to explain why they have not been more widely used, and to suggest a roadmap for the development of N-of-1 trials, especially for the study of Traditional Chinese Medicine (TCM). METHODS: An electronic search was conducted using the Chinese Biological Medicine Database (CBM) and China National Knowledge Infrastructure (CNKI) with the keywords "N-of-1 trial, single case OR individual patient AND randomized". We also searched PubMed. The Chinese Science Citation Database (CSCD) as a citation was searched at last. RESULTS: 23 studies were retrieved from CBM and 34 from CNKI. There were 13 papers about N-of-1 trials in CBM and 17 in CNKI. Only 3 studies were rigorously designed (i.e., using randomization, control periods and blinding). The other 8 papers were descriptive and review articles, most of which were in TCM. One review was published in SCI-E and one in MEDLINE. Three papers were found in CSCD as citations. Only one of the retrieved studies was funded. CONCLUSIONS: While N-of 1 trials may offer a good tool to individualize clinical care and enrich TCM clinical research, they have not been widely used to date. To spur the development of this method, we would like to suggest three points. First, the Chinese government should endorse and sponsor N-of-1 studies. Second, researchers and physicians should be systematically trained in the method. Third, thorough considerations on trials allow better research and focus on the patients' needs. PMID- 23642951 TI - A randomised double-blind comparability study of a placebo for Individualised Western Herbal Medicine. AB - OBJECTIVES: To determine the non-inferiority of placebo Individualised Western Herbal Medicine (IWHM) tinctures compared with true IWHM tinctures. DESIGN: Randomised double blind comparability study. SETTING: Pharmacy department of an NHS integrated medicine hospital. INTERVENTIONS: The IWHM intervention consisted of mixed tinctures of five herbs from a list of eleven herbs for which chronic knee pain is an established indication. Placebo IWHM tinctures contained food and colouring extracts, designed to mimic as closely as possible the taste, smell and appearance of true IWHM. MAIN OUTCOME MEASURES: The primary outcome of the study was the proportion of patients who indicated that they believed they were taking true IWHM. Secondary outcomes included the palatability of the true and placebo tinctures. RESULTS: 64% of the placebo group indicated that they believed they had consumed true IWHM, compared with 60% of the true IWHM group. The palatability of the placebo IWHM was also acceptable to participants, and similar to the palatability of true IWHM. CONCLUSIONS: The findings from the present study indicate that the placebo tinctures were non-inferior to the true IWHM tinctures in terms of participants' ability to correctly identify them as herbal tinctures by their taste, smell and appearance. The placebo tinctures could be utilised in future double blind, placebo controlled randomised trials of IWHM. PMID- 23642952 TI - Inpatient treatment for severe atopic dermatitis in a Traditional Korean Medicine hospital: introduction and retrospective chart review. AB - OBJECTIVES: Patients with atopic dermatitis increasingly seek complementary and alternative medical treatment. A number of studies have demonstrated the efficacy of herbs and acupuncture in the treatment of atopic dermatitis. Some patients with extensive disease, outpatient treatment failure, acute deterioration or highly impaired everyday functioning require inpatient care. The aim of this study was to introduce and evaluate inpatient treatments for severe atopic dermatitis patients at a Traditional Korean Medicine hospital. DESIGN AND SUBJECTS: We performed a retrospective chart review of inpatients with severe atopic dermatitis between March 2008 and October 2011. Eligibility criteria for inclusion were: (1) a diagnosis of atopic dermatitis according to the criteria established by Hanifin and Rajka and (2) hospitalisation because of severe atopic dermatitis (objective scoring atopic dermatitis (SCORAD) score >= 40). MAIN OUTCOME MEASUREMENT: The SCORAD score was assessed by trained investigators at admission and discharge. RESULTS: Among 37 inpatients, there were 29 patients who met the criteria. Patients received treatments including acupuncture, herbal medicine and herbal wet wrap dressings. The mean total scoring SCORAD decreased from 60.63 to 37.37 during hospitalisation. Despite the relatively small sample size, these findings were statistically significant. CONCLUSION: In atopic dermatitis, Traditional Korean Medicine effectively decreased clinical disease severity. This study's weaknesses include the relatively small number of patients, some aspects of the study design, lack of follow-up assessment and lack of second measurement. PMID- 23642953 TI - Does the effect of acupuncture depend on needling sensation and manipulation? AB - BACKGROUND: Acupuncture sensation and manipulation have been considered to be an important component of acupuncture in traditional Asian medicine. However, there has been limited research as to whether acupuncture sensation is associated with therapeutic benefit. This study investigated the relationship between acupuncture sensation and analgesic effect according to acupuncture manipulation. METHOD: Fifty-three healthy volunteers received three different forms of acupuncture in a single-blinded crossover design: superficial needling (0.3 cm), deep needling (2 cm) and needling with bi-directional rotation. The effects of acupuncture were evaluated by using the pressure pain threshold. Acupuncture sensation measurement was done in two ways. RESULTS: Both total acupuncture sensation and increase of the pressure pain threshold were maximum in needling with rotation, followed by deep needling and superficial needling. Repeated-measure analysis of variance (ANOVA) analysis was carried out to assess whether there was a significant difference; both showed significant difference (p = 0.000, 0.003). A paired sample t-test was carried out, which revealed that needling with rotation showed significant difference from both superficial needling and deep needling. Further, the correlation between the total acupuncture sensation and changes in pressure pain threshold were calculated using Pearson correlation; there was a significant correlation (p = 0.002, p = 0.013). CONCLUSION: Acupuncture sensation and pressure pain threshold increase according to the depth and rotation of acupuncture. Especially, both display significant increase with needle rotation. Further, there is a significant correlation between acupuncture needling sensation and increase in pressure pain threshold. It seems that needle rotation and acupuncture sensation play an important role in verifying the effect of acupuncture. PMID- 23642954 TI - Utilization of traditional Chinese medicine in patients treated for depression: a population-based study in Taiwan. AB - OBJECTIVES: Traditional Chinese medicine (TCM) has been used to treat depression like symptoms in Taiwan. We aim to examine factors associated with utilization of TCM in patients with depression and to test whether the use of TCM would impact the use of psychiatric services with a subsequent impact on healthcare costs. METHODS: Adult patients (n = 216,557) who received antidepressant treatment for depression in 2003 was identified in the National Health Insurance Research Database in Taiwan. A Two-Part model was conducted. A multivariate logistic regression was employed to explore factors associated with the use of TCM, with a particular focus on baseline comorbidities, painful physical symptoms (PPS), and frequency of psychiatric service contacts over the ensuing 12-month study period. Multivariate generalized linear modeling was then applied to examine factors associated with healthcare costs for TCM users. RESULTS: More than 40% of individuals prescribed with antidepressant treatments for depression used TCM services. Younger age, female gender, the presence of certain comorbid mental/physical illnesses or PPS, as well as having fewer psychiatric service contacts were found to be associated with the use of TCM services. These factors also affected TCM costs for users; the TCM costs equaled to 30% of costs of psychiatric out-patient services for TCM users. CONCLUSIONS: The current study suggested a set of significant factors which could influence use and cost of TCM services for patients with depression. Utilization of TCM services could have a substantial impact on use of psychiatric services and healthcare costs for patients with depression. PMID- 23642955 TI - Prevalence of complementary and alternative medicine (CAM)-use in UK paediatric patients: a systematic review of surveys. AB - AIM: This systematic review is aimed at estimating the prevalence of complementary and alternative medicine (CAM)-use by paediatric populations in the United Kingdom (UK). METHOD: AMED, CINAHL, COCHRANE, EMBASE and MEDLINE were searched for English language peer-reviewed surveys published between 01 January 2000 and September 2011. Additionally, relevant book chapters and our own departmental files were searched manually. RESULTS: Eleven surveys were included with a total of 17,631 paediatric patients. The majority were of poor methodological quality. Due to significant heterogeneity of the data, a formal meta-analysis was deemed inappropriate. Ten surveys related to CAM in general, while one was specifically on homeopathy. Across all surveys on CAM in general, the average one-year prevalence rate was 34% and the average lifetime prevalence was 42%. In surveys with a sample size of more than 500, the prevalence rates were considerably lower than in surveys with the sample size of lower than 500. Herbal medicine was the most popular CAM modality, followed by homeopathy and aromatherapy. CONCLUSIONS: Many paediatric patients in the UK seem to use CAM. Paediatricians should therefore have sufficient knowledge about CAM to issue responsible advice. PMID- 23642956 TI - Syzygium cumini (L.) Skeels., a novel therapeutic agent for diabetes: folk medicinal and pharmacological evidences. AB - OBJECTIVES: During the past few decades numerous folk medicinal and scientific investigations on the antidiabetic effects of jambolan (Syzygium cumini (L.) Skeels) have been reported. However no comprehensive evidence-based review is available. Hence this review was aimed to summarize the antidiabetic effects of different parts and active principles of jambolan. METHODS: The review is based on the available electronic literature indexed in the PubMed. The search terms were: Syzygium cumini, Eugenia jambolana, jambolan, jamun, and java plum with and without antidiabetic effect. RESULTS: Based on experimental studies and folk medicinal evidences, we summarized an up to date and comprehensive report on the antidiabetic activity of jambolan. The mode of action of some of the parts and active principles is also included. Preclinical and clinical studies suggest that, different parts of this plant especially fruits, seeds and stem bark were reported for promising activity against diabetes. CONCLUSIONS: Till date no review is available for the evidence based preclinical/clinical study of jambolan with its antidiabetic effect. There is an immediate attention need for detailed analysis to identify its active principles. It could be used to produce safer drugs to treat diabetes. PMID- 23642958 TI - Systems biology approach opens door to essence of acupuncture. AB - For World Health Organization proposed 'Health for All', we should be to promote the use of traditional medicine. Traditional Chinese acupuncture has a history over 3000 years and is effective in the treatment of many conditions with few side effects. Acupuncture, an intrinsic part of traditional Chinese medicine (TCM), which utilizes fine needles to pierce through specific anatomical points (called "acupoints"), has been extensively used and has emerged as an important modality of complementary and alternative therapy to Western medicine. It is vital and necessary to explore the underlying biological mechanisms of acupuncture. Systems biology has become practically available and resembles acupuncture in many aspects and is current key technology that serves as the major driving force for translation of acupuncture medicine revolution into practice, will advance acupuncture therapy into healthcare for individuals. High throughput genomics, proteomics and metabolomics in the context of systems biology have been able to identify potential candidates for the effects of acupuncture and provide valuable information toward understanding mechanisms of the therapy. To realize the full potential of TCM acupuncture, we describe the current status of principles and practice of acupuncture integrated with systems biology platform in the post-genomic era. Some characteristic examples are presented to highlight the application of this platform in omics and systems biology approaches to acupuncture research and some of the necessary milestones for moving acupuncture into mainstream health care. PMID- 23642957 TI - A narrative review of yoga and mindfulness as complementary therapies for addiction. AB - This paper reviews the philosophical origins, current scientific evidence, and clinical promise of yoga and mindfulness as complementary therapies for addiction. Historically, there are eight elements of yoga that, together, comprise ethical principles and practices for living a meaningful, purposeful, moral and self-disciplined life. Traditional yoga practices, including postures and meditation, direct attention toward one's health, while acknowledging the spiritual aspects of one's nature. Mindfulness derives from ancient Buddhist philosophy, and mindfulness meditation practices, such as gentle Hatha yoga and mindful breathing, are increasingly integrated into secular health care settings. Current theoretical models suggest that the skills, insights, and self-awareness learned through yoga and mindfulness practice can target multiple psychological, neural, physiological, and behavioral processes implicated in addiction and relapse. A small but growing number of well-designed clinical trials and experimental laboratory studies on smoking, alcohol dependence, and illicit substance use support the clinical effectiveness and hypothesized mechanisms of action underlying mindfulness-based interventions for treating addiction. Because very few studies have been conducted on the specific role of yoga in treating or preventing addiction, we propose a conceptual model to inform future studies on outcomes and possible mechanisms. Additional research is also needed to better understand what types of yoga and mindfulness-based interventions work best for what types of addiction, what types of patients, and under what conditions. Overall, current findings increasingly support yoga and mindfulness as promising complementary therapies for treating and preventing addictive behaviors. PMID- 23642959 TI - Prevalence of complementary and alternative medicine use in a community-based population in South Korea: a systematic review. AB - OBJECTIVES: To examine the prevalence of the use of complementary and alternative medicine (CAM) in the Republic of Korea and identify the factors responsible for variations in the reported prevalence, the socio-demographic factors associated with CAM use, and the relationship between CAM use and study methodological quality. DESIGN: Two international and 6 representative Korean medical databases were searched to identify cross-sectional studies that had surveyed the general Korean population in community settings to determine prevalence of CAM use. Data collection and assessment of the methodological quality of the studies were conducted by 3 independent reviewers. RESULTS: The prevalence of CAM use reported by the 11 studies that met the selection criteria ranged from 29% to 83%. Inclusion of Korean medicine within the definition of CAM was not found to be a significant factor in the heterogeneity, but several factors that may have contributed to it, namely, inconsistency in CAM taxonomies, recall bias, use of unrepresentative sampling strategies, and lack of pilot testing, were identified. Higher CAM use was found to be associated with female sex, high level of education, and advanced age. CONCLUSIONS: The inclusion of Korean medicine within the definition of CAM does not explain the heterogeneity in the reported prevalence of CAM use among the South Korean population. A standard questionnaire appropriate for the Korean context should be developed to define and classify the common CAM modalities and control for confounding factors. PMID- 23642960 TI - Filling the gap between traditional Chinese medicine and modern medicine, are we heading to the right direction? AB - Traditional Chinese medicine (TCM), the ancient medicine popular in China and surrounding areas, has been recognized as a typical representative of complementary and alternative medicine. Over long period in clinical practice, especially the progress in basic research, data on the effectiveness and beneficial contribution of TCM herbs to public health and disease control have been accumulated while the quality of the evidence is generally poor. The most common clinical practice of TCM herbs is herb combination called formula which consists of several types of medicinal herbs or minerals, which is quite different from modern medicine. Definitely, tens of hundreds of compounds could be identified in even a small formula. With the regained enthusiasm on natural products based new drug R&D, the proposed multi-target drug discovery strategy, the booming of -omics technologies, and the implementation of ambitious plan of TCM modernization in China, attempts have been made to fill the gap between TCM herbs and modern drugs. However, are we heading to the right direction? PMID- 23642961 TI - The effects of preferred and non-preferred running strike patterns on tissue vibration properties. AB - OBJECTIVES: To characterize soft tissue vibrations during running with a preferred and a non-preferred strike pattern in shoes and barefoot. DESIGN: Cross sectional study. METHODS: Participants ran at 3.5 m s(-1) on a treadmill in shoes and barefoot using a rearfoot and a forefoot strike for each footwear condition. The preferred strike patterns for the subjects were a rearfoot strike and a forefoot strike for shod and barefoot running, respectively. Vibrations were recorded with an accelerometer overlying the belly of the medial gastrocnemius. Thirteen non-linearly scaled wavelets were used for the analysis. Damping was calculated as the overall decay of power in the acceleration signal post ground contact. A higher damping coefficient indicates higher damping capacities of the soft tissue. RESULTS: The shod rearfoot strike showed a 93% lower damping coefficient than the shod forefoot strike (p<0.001). A lower damping coefficient indicates less damping of the vibrations. The barefoot forefoot strike showed a trend toward a lower damping coefficient compared to a barefoot rearfoot strike. Running barefoot with a forefoot strike resulted in a significantly lower damping coefficient than a forefoot strike when wearing shoes (p<0.001). The shod rearfoot strike showed lower damping compared to a barefoot rearfoot strike (p<0.001). While rearfoot striking showed lower vibration frequencies in shod and barefoot running, it did not consistently result in lower damping coefficients. CONCLUSIONS: This study showed that the use of a preferred movement resulted in lower damping coefficients of running related soft tissue vibrations. PMID- 23642962 TI - Psychosensorial assessment of skin damage caused by a sliding on artificial turf: the development and validation of a skin damage area and severity index. AB - OBJECTIVES: Injury prevention is an important reason for the development of performance standards in football. Currently, there is no objective method available to classify sliding induced skin injuries, which includes the perceived sliding friendliness of football pitches. The purpose of this study was to develop a non-invasive method for quantification of the observed sliding induced skin damage and evaluate whether there is a correlation between the subjective perceived skin irritation and sliding friendliness. STUDY DESIGN: Randomized controlled trial. METHODS: Previously obtained clinical images of sliding induced skin lesions where rated by a dermatologist on the degree of abrasion, erythema and type of exudation. To test the practical feasibility of a proposed Skin Damage and Severity Index (SDASI) to characterize sliding induced skin lesions, a randomized user trial with nine amateur football players was performed. The sliding friendliness of three different grades of infill materials was tested. RESULTS: The Skin Damage and Severity Index correlates both with the perceived skin irritation (r=-0.53, P=0.02) and sliding friendliness (r=-0.58, P=0.01). Statistical analysis of the individual clinical scores showed that perception of skin irritation and sliding friendliness correlate very well with the degree of erythema and abrasion. However, these scores are independent of the size of the lesion and type of exudation. There was no statistical significant difference found between the three evaluated types of infill and their sliding performance. CONCLUSIONS: This study demonstrated that the Skin Damage and Severity Index, which is a tool for quantification of a sliding induced skin lesion, correlates very well with the perceived skin irritation and the sliding friendliness. PMID- 23642963 TI - The effect of exercise repetition on the frequency characteristics of motor output force: implications for Achilles tendinopathy rehabilitation. AB - OBJECTIVES: To investigate the frequency characteristics of the ground reaction force (GRF) recorded throughout the eccentric Achilles tendon rehabilitation programme described by Alfredson. DESIGN: Controlled laboratory study, longitudinal. METHODS: Nine healthy adult males performed six sets (15 repetitions per set) of eccentric ankle exercise. Ground reaction force was recorded throughout the exercise protocol. For each exercise repetition the frequency power spectrum of the resultant ground reaction force was calculated and normalised to total power. The magnitude of peak relative power within the 8 12 Hz bandwidth and the frequency at which this peak occurred was determined. RESULTS: The magnitude of peak relative power within the 8-12 Hz bandwidth increased with each successive exercise set and following the 4th set (60 repetitions) of exercise the frequency at which peak relative power occurred shifted from 9 to 10 Hz. CONCLUSIONS: The increase in magnitude and frequency of ground reaction force vibrations with an increasing number of exercise repetitions is likely connected to changes in muscle activation with fatigue and tendon conditioning. This research illustrates the potential for the number of exercise repetitions performed to influence the tendons' mechanical environment, with implications for tendon remodelling and the clinical efficacy of eccentric rehabilitation programmes for Achilles tendinopathy. PMID- 23642964 TI - Influence of playing standard on the physical demands of junior rugby league tournament match-play. AB - OBJECTIVES: To investigate the physical demands on junior rugby league players competing at three different standards of tournament match-play. DESIGN: Cross sectional study. METHODS: Sixty junior rugby league players (mean +/- SD age, 16.7 +/- 0.7 years) participated in this study. Players were either competing in Division 1, Division 2, or Division 3 teams of the Confraternity carnival. Global positioning system (GPS) analysis was completed during 17 matches (totalling 139 appearances). RESULTS: Division 1 and 2 players covered significantly (p=0.001) greater distance per minute of match play than Division 3 players (83.0 +/- 12.3m/min and 81.5 +/- 6.9 m/min vs. 73.3 +/- 9.8m/min). The greater total distance at the higher competitive standard was achieved through greater (p=0.001) distances at low speeds, with Division 1 players also covering more (p=0.038) high speed running than Division 3 players. Expressed relative to playing time, the number of total collisions was lower (p=0.001) in Division 3 players. Division 2 players engaged in more (p=0.034) repeated high-intensity effort bouts than Division 3 players. Significant decrements in total (p=0.005) and low speed distances (p=0.006) were found, with Division 3 players showing the largest reductions in performance. CONCLUSIONS: These findings demonstrate that both the average intensity and the repeated high-intensity effort demands of junior rugby league tournament match-play are greater at higher playing standards. Sport scientists and conditioning staff can use these data to plan appropriate training sessions to allow players to tolerate match-play demands, and recover from the demands of competition. PMID- 23642965 TI - Synthesis of 7-oxabicyclo[2.2.1]hept-5-en-2-yl derivatives and their screening for antimicrobial and antioxidant properties. AB - Novel 7-oxabicyclo[2.2.1]hept-5-en-2-yl derivatives have been synthesized using boron trifluoride diethyl etherate catalyzed Diels-Alder reaction. This method presents considerable synthetic advantages in terms of high atom economy, mild reaction condition and good yields. The synthesized compounds have been screened for their antibacterial and antioxidant activities. PMID- 23642966 TI - Discovery of pyrido[2,3-d]pyrimidine-based inhibitors of HCV NS5A. AB - Efforts to improve the genotype 1a potency and pharmacokinetics of earlier naphthyridine-based HCV NS5A inhibitors resulted in the discovery of a novel series of pyrido[2,3-d]pyrimidine compounds, which displayed potent inhibition of HCV genotypes 1a and 1b in the replicon assay. SAR in this system revealed that the introduction of amides bearing an additional 'E' ring provided compounds with improved potency and pharmacokinetics. Introduction of a chiral center on the amide portion resulted in the observation of a stereochemical dependence for replicon potency and provided a site for the attachment of functional groups useful for improving the solubility of the series. Compound 21 was selected for administration in an HCV-infected chimpanzee. Observation of a robust viral load decline provided positive proof of concept for inhibition of HCV replication in vivo for the compound series. PMID- 23642967 TI - Racial disparities in screening for diabetic retinopathy in youth with type 1 diabetes. AB - Of 1112 children with type 1 diabetes, dilated eye exams were performed in 717 (64%). Children were less likely to be screened for diabetic retinopathy (DR) if they were black (OR=1.6; p=0.005) or had poorer diabetes control (p=0.002). Those at greatest risk for DR were least likely to be screened. PMID- 23642968 TI - Gestational diabetes mellitus: including serum pregnancy-associated plasma protein-A testing in the clinical management of primiparous women? A case-control study. AB - AIMS: To assess pregnancy-associated plasma protein A (PAPP-A) correlation with GDM and its usefulness in predicting GDM in primiparous women. METHODS: First trimester data related to 307 pregnant women affected by GDM and 366 control pregnant women were retrieved from a computer data base and integrated with ad hoc data. Clinical data were recorded at delivery. A logistic model was used to analyze the association between first trimester data and subsequent clinical outcomes. We derived a risk score using both classical risk factors for GDM and PAPP-A. RESULTS: Diabetic and control women were significantly different in terms of age (p<0.001), BMI (p<0.001), weight (p<0.001), family history of diabetes (p<0.001), PAPP-A concentration and PAPP-A corrected multiple of the median (MoM) (p<0.001). The ROC-AUC of the clinical risk score was 0.60 (95%CI 0.56-0.64), the adjusted score including PAPP-A MoM was 0.70 (95%CI 0.66-0.74). CONCLUSIONS: Low PAPP-A was strongly associated with GDM and lower values were found in diabetic women needing insulin therapy. Adding PAPP-A to first trimester screening could improve the prediction of women at high risk who will develop GDM. Further studies are needed to validate the applicability of our findings in different populations and settings. PMID- 23642969 TI - Diabetes in the Middle East and North Africa. AB - AIMS: Even though the Middle East and North Africa (MENA) region had the highest comparative prevalence of diabetes in 2012, little is known about the nuances of diabetes risk and capacity to address the burdens. To provide a comprehensive overview, we reviewed the literature on diabetes in the MENA region. METHODS: We conducted a systematic search in PubMed between January 1990 and January 2012 for studies on diabetes in the MENA region without language restriction. RESULTS: There was a paucity of country-specific epidemiology data in the region. Diabetes prevalence varied widely across studies, from 2.5% in 1982 to 31.6% in 2011. Older age and higher body mass index were the most strongly associated risk factors for diabetes. Among people with diabetes, over half did not meet recommended care targets. In addition, macrovascular and microvascular complications were observed in 9-12% and 15-54% of diabetes population, respectively. CONCLUSIONS: This review suggests a need for more representative surveillance data in this noteworthy focal point of the global diabetes epidemic. Such actions will not only help to understand the actual burden of diabetes but also motivate actions on design and implementation of diabetes prevention and control programs. PMID- 23642970 TI - More than just bad sex: sexual dysfunction and distress in patients with endometriosis. AB - OBJECTIVES: The aim of the current study was to evaluate the prevalence and the impact of sexual dysfunction, sexual distress and interpersonal relationships in patients with endometriosis. STUDY DESIGN: A questionnaire-based multicentre cohort study was conducted in eight tertiary referral centres in Austria and Germany. One hundred and twenty-five patients with histologically proven endometriosis and dyspareunia were included. The Female Sexual Function Index and the Female Sexual Distress Scale were used to screen women's sexuality. Additionally, we evaluated psychological parameters and pain intensity during/after sexual intercourse via a self-administered questionnaire. RESULTS: Female sexual distress and sexual dysfunction were observed in 97/125 and 40/125 patients. Statistically significant correlations were found between sexual dysfunction and pain intensity during/after sexual intercourse (p<0.01/p<0.01), a lower number of episodes of sexual intercourse per month (p<0.01), greater feelings of guilt towards the partner (p<0.01) and fewer feelings of femininity (p<0.01). Thirty-eight out of 125 women agreed that the primary motivation for sexual intercourse was to conceive and nearly half of women (46%) included stated that satisfying the partner acted as primary motivation for sexual contact. CONCLUSION: Overall, our findings demonstrate that dyspareunia as a common complaint in patients with endometriosis causes a severe impairment of sexual function, relationship and psychological wellbeing. PMID- 23642971 TI - Health-related quality of life and perception of anxiety in women with abnormal cervical cytology referred for colposcopy: an observational study. AB - OBJECTIVE: To evaluate health-related quality of Life (HRQoL) in patients with abnormal cervical cytology referred for colposcopy. STUDY DESIGN: An observational study with prospective and retrospective cohorts. In the prospective arm 240 women referred for colposcopy filled in the 15D HRQoL and the State Anxiety Inventory (STAI) questionnaires and were followed up for 12 months. In the retrospective arm 208 patients who had been treated for cervical dysplasia eight years earlier filled in the 15D HRQoL questionnaire. Results were compared with the age- and sex-standardized general population. RESULTS: In the prospective part of the study, the mean 15D score of the patients did not differ from that of the general population. On the dimensions of sleeping, distress and sexual activity, however, the patients scored lower than the general population (p<0.001). Patients with higher levels of anxiety at baseline, according to the STAI questionnaire, had lower HRQoL during the whole 12-month observation period (p<0.001). The overall HRQoL score of the patients treated for cervical dysplasia eight years earlier did not differ from that of the general population. CONCLUSIONS: Abnormal cytology and referral for colposcopy were associated with anxiety and slightly impaired psychosocial components of HRQoL but did not reduce the overall HRQoL. High anxiety levels at baseline were associated with impaired HRQoL. Previous treatment for cervical dysplasia was not associated with impaired overall HRQoL. PMID- 23642972 TI - Variance of melatonin and cortisol rhythm in patients with allergic rhinitis. AB - OBJECTIVE: Allergic rhinitis is an IgE-mediated inflammatory disease which effects 10%-50% of the normal population. The mechanism of its formation and the circadian rhythm of cortisol and melatonin in allergic rhinitis have not been investigated. STUDY DESIGN: Salivary levels of melatonin and cortisol were measured by radioimmunoassay in 35 newly diagnosed allergic rhinitis patients and in 23 control subjects matched for age and gender. RESULTS: In the study group; amplitude, baseline and peak levels of salivary melatonin were significantly decreased compared with healty controls (p<0.001). No differences were found in the acrophase and the peak duration of salivary melatonin between the study and control groups (p>0.05). In the study subjects, the circadian rhythm of cortisol was flattened when compared with the control group. The amplitude and the 24h mean levels of salivary cortisol in the study group were significantly lower than in the control group and the acrophase was delayed in patients compared with control subjects (p<0.001). CONCLUSION: The circadian rhythms of salivary melatonin and cortisol were found to be disrupted in patients with allergic rhinitis. These results may also be contributive data to explain the pathogenesis of allergic rhinitis and also they can be applicable as adjunctive therapeutic tools in the future and melatonin drugs might be an alternative in the therapy of resistant allergic rhinitis patients or allergic rhinitis patients who cannot use cortisol drugs. PMID- 23642974 TI - Classification of psychotic disorders: need to move toward a neuroscience informed nosology. PMID- 23642973 TI - Patterns of physical activity, sedentary behavior, and diet in U.S. adolescents. AB - OBJECTIVE: To identify patterns in adolescents' obesogenic behaviors and their relations to physical and psychological health. METHODS: A nationally representative sample of 9,174 U.S. adolescents ages 11 to 16 years was surveyed on physical activity (PA), screen-based sedentary behavior (SB), frequency of consumption of healthy and unhealthy food items, weight status, weight control behavior, depression, physical symptoms, body dissatisfaction, overall health, and life satisfaction. Latent class analysis was used to identify patterns of PA, SB, and diet. RESULTS: A model with three latent classes best fit the data: Class 1 with high PA and high fruit and vegetable intake and low SB and intake of sweets, soft drinks, chips, and fries; Class 2 with high SB and high intake of sweets, soft drinks, chips, and fries; and Class 3 with low PA, low fruit and vegetable intake, and low intake of sweets, chips, and fries. Membership in the three classes was related to age, gender, race/ethnicity, and socioeconomic status. In addition, members of Class 1 (26.5%) were more likely to be of normal weight status and to fare well on most of the other health indices; of Class 2 (26.4%) were less likely to be trying to lose weight but scored poorly on the mental health indices; and of Class 3 (47.2%) were less likely to be underweight and reported greater body dissatisfaction. CONCLUSIONS: Three prevalent patterns of adolescent obesogenic behaviors were identified and these patterns related to weight status, depression, and other indicators of physical and psychological health. PMID- 23642975 TI - Music as a therapy: role in psychiatry. AB - Music is popularly believed to usher in bliss and serenity, and healing is considered its natural quality. It has an emotionally charging charisma of its own, that we all as listeners might have experienced at times. Music has been there with mankind since the beginning of history, but where does it stand as a therapy? Is there any evidence base? How this therapy came into being and how it has evolved, and what the old and current research says about its role in psychiatric disorders. This review tries to explore these questions and arrives at a conclusion that music certainly promises more than just entertainment, and evidence so far suggests music therapy can be beneficial in the treatment of psychiatric disorders, as a cost effective noninvasive adjunct to standard therapy in a variety of settings and patient groups, yet more validated scientific research is still required to establish it as a sole quantified therapy. PMID- 23642976 TI - Efficacy and tolerability of clozapine in Japanese patients with treatment resistant schizophrenia: results from a 12-week, flexible dose study using raters masked to antipsychotic choice. AB - Japan approved clozapine for treatment-resistant schizophrenia in June 2009. The aim of this study was to evaluate clozapine's efficacy and tolerability in Japanese patients. A twelve-week, single-arm clinical trial of clozapine in treatment-resistant schizophrenia inpatients, was conducted under real-world conditions using raters masked for type of antipsychotic. Thirty-eight patients were recruited, with 33 (86.8%) completing the trial. At week 12, clozapine was associated with significant improvement in the Positive and Negative Syndrome Scale (PANSS) total (p < 0.0001), PANSS positive (p < 0.0001), negative (p = 0.0055) and general subscale scores (p < 0.0001). Significant improvements occurred in all PANSS scores by week 4, the first post-baseline psychopathology rating. Altogether, 50.0% of patients showed >=20% reduction in PANSS total score, 20.6% had >=30% reduction and 14.7% had >40% reduction. Eighteen patients (47.4%) were discharged before week 12. However, all patients experienced >=1 adverse event. Two of 38 patients (5.2%) dropped out due to moderate leucopenia and one of them developed agranulocytosis after stopping clozapine. However, both patients recovered. Eight adverse events (hypersalivation, fatigue, sedation, constipation, insomnia, nausea/vomiting, chest pain and leucopenia) were observed in 34-79% of patients. These findings suggest that clozapine is beneficial in Japanese treatment-resistant schizophrenia patients. However, attention should be paid to patients' adverse events. PMID- 23642977 TI - The impact of a simple individual psycho-education program on quality of life, rate of relapse and medication adherence in bipolar disorder patients. AB - INTRODUCTION: Bipolar disorder is one of ten most debilitating diseases in the world, leading to a lessened quality of life amongst its sufferers. This randomised control trial demonstrates the effectiveness of psycho-education intervention along with a patient support system in the management of this disorder. METHODOLOGY: In this trial, 108 patients, divided equally into two groups, were randomly assigned to receive either pharmacotherapy alone (control group) or psycho-education along with pharmacotherapy treatment (intervention group) for a two year period. Each individual patient in the "intervention" group received eight, fifty-minute sessions of psychological education, followed by monthly telephone follow-up care and psychological support in the subsequent 18 months. Each group was evaluated, once every 6 months for a period of 18 months, in the areas of "quality of life", "symptoms of relapse", "pharmacotherapy compliance" and "number of hospital admission for recurrence of bipolar disorder". RESULT: The result of this study indicates that patients in the "intervention" group had a statistically significant enhancement in medication compliance (P = 0.008). Regarding every aspect of life quality, this group was at a better position than the "control" group (P = 0.000). As to relapse and hospital admission, the "intervention" group reported much lower cases compared with the "control" group at a significance level of P = 0.000. CONCLUSION AND DISCUSSION: This research has demonstrated that in the psycho-education intervention group, there was a more significant improvement in all areas of quality of life, number of relapses, and hospitalization due to recurrence of bipolar disorder and medication compliance than it was evident in the control groups. PMID- 23642978 TI - The 'Operationalized Predicaments of Suicide' (OPS) applied to Northern Territory coroners' reports. AB - OBJECTIVE: To apply the "Operationalized Predicaments of Suicide" (OPS) to coroners' reports with a view to classifying the drivers/triggers of suicide in the Northern Territory (Australia) for the years July 2000-December 2010, with attention to the total population, and to a comparison of suicide triggers for the Indigenous and non-Indigenous communities. METHODS: A total of 411 reports (Indigenous, 198; non-Indigenous, 213) were obtained from the National Coroners Information System (NCIS). A research officer thematically analysed each case report and classified each according to the four categories of the OPS. Calculations were performed for the entire sample and comparisons were made between Indigenous and non-Indigenous groups. RESULTS: For the total sample, 20% of suicides were triggered by mental illness, and 58% were triggered by social/environmental events. In 9% there were both mental illness and social/environmental factors, and in 14% no triggers could be identified. There were group differences; the non-Indigenous group was over represented in the mental illness category and the Indigenous group was over represented in the social/environmental category (chi(2) (3) = 41.5, p = 0.000). CONCLUSIONS: Social/environmental stressors are important triggers of suicide in the Northern Territory. Social/environmental stressors were more often the suicide trigger in Indigenous community suicide compared to non-Indigenous community suicide. PMID- 23642979 TI - High prevalence of anxiety disorders among adolescent Tibetan refugees. AB - INTRODUCTION: Psychiatric disturbance has been shown to result from stress associated with events related to being a refugee. Children of refugees also experience significant stress but little is known about the prevalence of psychiatric disorders in this group. This survey explores the prevalence of psychiatric disorders in a Tibetan refugee enclave in rural North India. METHODS: A prevalence survey was conducted using the Beck Anxiety Inventory (BAI) to determine the prevalence of anxiety amongst the Tibetan community. Three hundred fifty forms were distributed amongst the students; 335 were completed of which 300 were considered suitable to be collated and analysed. RESULTS: The results revealed that 21% of the study population had significant levels of anxiety classed as moderate or severe using the BAI. Late adolescents had higher levels of significant moderate and severe anxiety than early and middle adolescents x(2) = 92.95 (P < 0.0001). Female participants had higher levels of moderate and severe anxiety but this was not statistically significant (x(2) = 1.286, P = 0.2568). CONCLUSION: There were high rates of anxiety in this study of Tibetan school aged children. School based anxiety prevention programmes and other interventions should be considered in such vulnerable populations especially amongst females and late adolescents who are disproportionately affected. These findings indicate a need for further evaluation of young Tibetan refugees for definitive diagnosis of anxiety disorders, specific phobias, social anxiety, post traumatic stress disorders and other anxiety disorders. PMID- 23642980 TI - Health status assessment tool for the family member caregiver of patients with bipolar disorder: development and psychometric testing. AB - INTRODUCTION: The caregivers' health assessment requires the application of a valid instrument that provided based on their experiences about the health concept. The purpose of this study was to develop and test the psychometric properties of the health assessment tool for family member caregivers' of patients with bipolar disorder. METHODS: This study utilized mixed research. The specific validation processes used were: content and face validity, construct validity using factor analysis, reliability and internal consistency using test retest reliability and Cronbach's alpha correlation coefficient. RESULTS: The exploratory factor analysis revealed ten factors: safe life with peace, maintaining physical health, painful emotions, psychological tolerance, maintaining physical-psychological potency, families and relatives support, health care system support, moral-financial support, maintaining social relationships, and worry over the label. The internal consistency (Cronbach's alpha) was 95. Test-retest reliability of the questionnaire with interval time of two weeks was 0.93 (p < 0.001). CONCLUSION: Family caregivers' health assessment questionnaire with 75 items helped to determine family caregivers' health in different settings such as clinical settings, homes and research environments by health care providers. PMID- 23642981 TI - A randomized controlled trial of brief psychoanalytic psychotherapy in patients with functional dyspepsia. AB - Functional dyspepsia (FD) is a common cause of upper gastrointestinal symptoms and discomfort. The present study aimed to assess the effectiveness of brief core conflictual relationship theme (CCRT) psychoanalytic psychotherapy on changing gastrointestinal symptoms, alexithymia, and defense mechanisms in patients with FD. In a randomized controlled trial study, 49 patients with FD were randomly assigned to medical treatment with brief psychodynamic therapy (24 subjects) or medical treatment alone (25 subjects). Gastrointestinal symptoms, defense mechanisms, and alexithymia were assessed before the trial, after treatment, and at 1- and 12-month follow-ups. The results showed that brief psychodynamic therapy improved all of the gastrointestinal symptoms, including heartburn, nausea, fullness, bloating, upper abdominal pain, and lower abdominal pain, after treatment and at two follow-ups. The CCRT therapy significantly improved many psychological symptoms, including mature defenses, neurotic defenses, immature defenses, difficulties in identifying feelings, difficulties in describing feelings, and total alexithymia score. In conclusion, brief psychodynamic therapy is a reliable method to improve gastrointestinal symptoms, mature defenses, and alexithymia scores in patients with functional dyspepsia. PMID- 23642982 TI - Comorbidity of attention-deficit/hyperactivity disorder and bipolar disorder in North Indian clinic children and adolescents. AB - OBJECTIVE: This study examined comorbidity between attention deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) in children attending child and adolescent psychiatry (CAP) services in a Medical University in North India. METHODS: Children attending CAP services, old or new, were assessed using unstructured clinical interview, kiddie-Schedule for Affective Disorders and Schizophrenia for School-age Children-Present and Lifetime Version (K-SADS-PL), Mental State Examination (MSE) for ADHD, Child Mania Rating Scale (CMRS) Parent Version and Children's Global Assessment Scale (C-GAS). Information was collected from both children and parents. All children were clinically evaluated, and prospectively followed up. The diagnosis was made by consensus. Subjects with DSM-IV-TR diagnosis of ADHD, BPD, and ADHD+BPD were compared with each other. Research criteria for broad phenotype BPD were applied in ADHD subjects without DSM-IV-TR diagnosis of BPD. RESULTS: 45 subjects had ADHD; 21, BPD and; 7 had lifetime DSM-IV-TR diagnosis of ADHD+BPD. 13.5% of ADHD subjects had comorbid BPD and 25% of BPD subjects had comorbid ADHD. ADHD-CT was the most common subtype of ADHD. Nearly two third of BPD subjects had their first mood episode before 13 years of age. ADHD+BPD subjects were more likely to be mentally retarded and have longer duration of mood episode compared to BPD subjects. Three subjects with DSM-IV-TR diagnosis of ADHD without BPD were additionally diagnosed with broad phenotype of BPD. CONCLUSIONS: Variable comorbidity rates of ADHD+BPD in different studies are most likely due to differences in study setting, study sample, conceptualization of BPD and assessment methods. PMID- 23642983 TI - Battery for ECT Related Cognitive Deficits (B4ECT-ReCoDe): development and validation. AB - BACKGROUND: The use of electroconvulsive therapy (ECT) in treatment of psychiatric disorders is associated with adverse cognitive effects. There is a need to develop a short assessment tool of cognitive functions during the course of ECT. OBJECTIVE: This study aimed at developing and validating a short, sensitive battery to assess cognitive deficits associated with ECT in India. METHODS: Battery for ECT Related Cognitive Deficits (B4ECT-ReCoDe), a brief cognitive battery (20-30 min) to assess verbal, visual, working and autobiographic memory, sustained attention, psychomotor speed and subjective memory impairment, was administered to 30 in-patients receiving bilateral ECT, one day after the 1st, 3rd and 6th ECT. Data was analysed using repeated measures analysis of variance and Pearson's correlation. RESULTS: Significant deficits were found in verbal, visual and autobiographic memory, psychomotor speed. Subjective experience of memory loss correlated positively with verbal memory impairment. CONCLUSIONS: B4ECT-ReCoDe, a brief, sensitive measure of cognitive impairments associated with ECT can be used in routine clinical practice. PMID- 23642984 TI - Prevalence of depression among HIV patients on antiretro viral therapy: a study from India. PMID- 23642985 TI - Depression in patients with pulmonary tuberculosis in a tertiary care general hospital. PMID- 23642986 TI - Does clinical posting in psychiatry contribute to changing medical interns' attitude towards psychiatry? PMID- 23642987 TI - Adjuvant raloxifene treatment for negative symptoms of schizophrenia. PMID- 23642988 TI - The effect of escitalopram on metabolic parameters in patients with major depressive disorder, generalised anxiety disorder, and panic disorder: a prospective 6-month follow-up study. PMID- 23642989 TI - Psychosis education on a monthly Chinese newspaper to target Chinese American immigrants. PMID- 23642991 TI - Psychotic disorders in ICD-11. AB - In the process of revising ICD-10, the World Health Organization (WHO) has appointed a Working Group on the Classification of Psychotic Disorders (WGPD). Several changes to the classification criteria of schizophrenia and other primary psychotic disorders have been proposed with the aim of increasing the clinical utility, reliability and validity of the diagnostic classification. These proposals will be tested in field trials and subsequently revised according to the needs of clinical practice before final publication in 2015. The main proposals include the following: change of the chapter title, the replacement of the present schizophrenia subtypes with symptom specifiers, a revision of course specifiers, the inclusion of stricter diagnostic criteria for schizoaffective disorder, and a reorganization of acute and transient psychotic disorders and delusional disorders. The proposals for ICD-11 are compared with those for the corresponding DSM-5 chapter. PMID- 23642992 TI - Psychotic disorders in DSM-5: summary of changes. AB - Key issues related to the diagnosis of schizophrenia and other psychotic disorders addressed in DSM-5 were more precisely defining diagnostic boundaries between different psychotic disorders, reducing spurious comorbidity, improving coherence across the diagnostic manual, and enhancing validity without loss of reliability. New information about the nature of these disorders generated since DSM-IV was incorporated into their definition. Resulting changes in DSM-5 include elimination of the classic subtypes of schizophrenia, elimination of special treatment of Schneiderian 'first-rank symptoms', more precise delineation of schizoaffective disorder from schizophrenia and psychotic mood disorders, and clarification of the nosologic status of catatonia and its consistent treatment across the manual. Changes in section 3 of the manual include addition of a new category of "attenuated psychosis syndrome" as a condition for further study and addition of unique psychopathological dimensions (that represent treatment targets across disorders). The specific nature of these revisions in the DSM-5 criteria for schizophrenia and other psychotic disorders along with their rationale are summarized in this article. PMID- 23642993 TI - ICD11 and DSM5: the Indian dilemma. PMID- 23642994 TI - Mohan Agashe, M.D. eminent psychiatrist and veteran actor. PMID- 23642995 TI - Country in focus: Qatar. PMID- 23642996 TI - Platinum nanoparticles for the photothermal treatment of Neuro 2A cancer cells. AB - This study demonstrates the effective synthesis of five different sized/shaped Pt NPs, within a narrow size regime of 1-21 nm using a modified methodology and the toxicity/biocompatibility of Pt NPs on Neuro 2A cancer cells was investigated elaborately by using light microscopic observations, tryphan blue exclusion assay, MTT assay and ICP-MS. The Pt NPs-C with sizes 5-6 nm showed superior non cytotoxic property compared to the other four Pt NPs. These non-cytotoxic Pt NPs were employed for successful photothermal treatment of Neuro 2A cell lines using near-IR 1064 nm of laser irradiation. The Pt NPs-C could generate a 9 degrees C increase in temperature leading to effective photothermal killing of cancer cells. The MALDI-MS was used to prove the possibility of apoptosis related triggering of cell death in the presence of the Pt NPs. The results confirm that the current approach is an effective platform for in vivo treatment of neuro cancer cells. PMID- 23642997 TI - Relationship between levels of angiogenic and lymphangiogenic factors and the endoscopic, histological and clinical activity, and acute-phase reactants in patients with inflammatory bowel disease. AB - BACKGROUND: Angiogenic and lymphangiogenic factors (ALFs) may play an important role in inflammatory bowel disease (IBD). Our aims were to evaluate levels of ALFs in serum and the colonic mucosa culture supernatant (MCS) of patients with active and quiescent IBD and healthy subjects and to correlate them with the endoscopic, clinical and histological activity and with acute-phase reactants. METHODS: This is a prospective study of 28 controls and 72 IBD patients. Serum and MCS concentration of VEGFA, VEGFC, VEGFD, VEGFR1, VEGFR2, VEGFR3, PlGF, Ang1, Ang2 and Tie2 were measured by ELISA. Activity was established by specific indexes (CDAI, Mayo score, SES-CD, D'Haens scale and Riley index). Acute-phase reactants were routinely measured. RESULTS: MCS levels of all ALFs except VEGFR3 were higher in patients with endoscopic (p<0.05), clinical (p<0.05) and histological (p<0.01) activity than in those without it. In serum, VEGFA, VEGFC and Ang1 and VEGFA and Ang1 levels were lower in patients in remission than in patients with clinical and histological activity, respectively (p<0.05). There was a correlation between serum and MCS concentrations for VEGFD, VEGFR3, PlGF and Tie2 (r=0.25, r=0.48, r=-0.45 and r=0.36; p<0.05). Ang2 in MCS was the best predictor for the diagnosis of endoscopic, histological and clinical activity (area under ROC curve>0.8). CONCLUSIONS: MCS determination suggests a local increase in ALFs that correlates with IBD activity. Although the correlation between ALFs in serum and MCS was not good, the study of some of these factors as possible targets of new drugs for IBD constitutes a key new line of research. PMID- 23642998 TI - [T2 mapping and knee thickness measurement in healthy young adults using quantitative 3.0T magnetic resonance imaging]. AB - OBJECTIVE: To investigate the T2 values and knee thickness in healthy young adults using 3.0 T magnetic resonance imaging(MRI) . METHODS: Totally 40 volunteers(18-30 years old) with body mass index between 18.5-24.0 kg/m(2) were divided into two groups(22 men and 18 women) according to their gender. Also in addition, each group was divided into two subgroups(right knee and left knee) . The T2 values and the thickness of the areas on the medial condyle of femur, the lateral condyle of femur, the medial tibial plateau, the lateral tibial plateau, and the patella of the knee cartilage were measured. RESULTS: The T2 values and the thickness of the right and left knee cartilages showed no significant differences between men and women (P>0.05) . Also, the T2 values in the five parts of the knee cartilage also were not significantly different between men and women (P>0.05) . However, the thickness of the 5 parts of the knee cartilage significantly differed between men and women(P<0.05) . CONCLUSIONS: The thickness of the knee cartilage may different between male and female young adults. The T2 values of the cartilage may be not affected by the gender. PMID- 23642999 TI - [CT findings of tuberous sclerosis associated with hepatic and renal angiomyolipomas]. AB - OBJECTIVE: To summarize the clinical and computed tomographic(CT) findings of tuberous sclerosis(TS) associated with hepatic and renal angiomyolipomas. METHOD: We retrospectively analyzed the clinical and CT findings of 7 TS patients with hepatic and renal angiomyolipomas. RESULTS: Brain CT showed calcified nodules and/or the uncalcified nodule in the lateral ventricle subependymal in 7 patients. Abdominal CT showed bilateral renal angiomyolipomas in 7 cases and hepatic angiomyolipomas in 2 cases. Chest CT showed lymphangioleiomyomatosis in one case. CONCLUSIONS: TS associated with merger hepatic and/or renal angiomyolipomas have typical CT findings. Liver angiomyolipomas shows certain correlation with bilateral renal angiomyolipomas. PMID- 23643000 TI - [Sonographic features of lymphoma in the abdominal lymph nodes]. AB - OBJECTIVE: To summarize the sonographic features of the lymphoma in the abdominal lymph nodes. METHOD: The clinical data and sonographic findings of 41 lymphoma patients with original appearance of abdominal mass or lymphadenectasis were retrospectively analyzed. RESULTS: Among these 41 cases, the retroperitoneal and mesenteric lymph nodes were most commonly involved.These patients were divided into two types according to sonographic appearances:solitary mass(n=14) and multiple nodules(n=27) .Solitary hypoechoic mass in abdomen was found in the former type, mostly with irregular or lobular shape, and the inner echo was often heterogenous.The typical appearances of the latter type were multiple enlarged lymph nodes, mostly round or oval, with homogeneous inner echo and clear margins.Some other sonographic characteristics were also helpful for the diagnosis of lymphoma, such as cobblestone sign, intranodular reticulation, vessels-embedded sign, and hilar vascularity. CONCLUSION: Ultrasonography can provide useful information in the diagnosis of the lymphoma in the abdominal lymph nodes. PMID- 23643001 TI - [Influence of different tranexamic acid administration methods during and after cardiac surgery on coagulation function and postoperative blood loss]. AB - OBJECTIVE: To evaluate the influence of different tranexamic acid administration methods during and after cardiac surgery with cardiopulmonary bypass(CPB) on coagulation function and postoperative bleeding. METHODS: Patients undergoing elective cardiac surgery with use of CPB (n=60) were randomized in a double-blind fashion to one of two treatment groups:group A(n=30) , administered with tranexamic acid 10 mg/kg (intravenous injection slowly before skin incision) , followed by infusion of normal saline until postoperative 12 hours;and group B(n=30) , administered with tranexamic acid 10 mg/kg(intravenous injection slowly before skin incision) , followed by infusion of tranexamic acid 1 mg/(kg.h) until postoperative 12 hours. Hemoglobin, platelet count, and coagulation function were assessed before anesthesia induction, after surgery, 8am next day and 24 hours after surgery. Bleeding, allogeneic blood transfusion, and fluid infusion during the postoperative 24 hours were recorded. RESULT: No differences were found between groups in terms of coagulant function, postoperative bleeding, allogeneic blood transfusion, and fluid infusion(P>0.05) . CONCLUSION: Compared with intraoperative administration alone, prolonged treatment with tranexamic acid after cardiac surgery shows no advantage because it can not further improve coagulant function, reduce bleeding, or reduce allogeneic blood transfusion. PMID- 23643002 TI - [Application of carbon nanoparticles in the laparoscopic sentinel lymph node detection in patients with cervical cancer]. AB - OBJECTIVE: To explore the role of laparoscopic sentinel lymph node(SLN) detection with carbon nanoparticles tracer in cervical carcinoma. METHODS: Totally 21 patients with confirmed early cervical cancer were enrolled in this study.Before laparoscopic extended hysterectomy and pelvic lymphadenoetomy(and para-aortic lymphadenoectomy) , they were injected with carbon nanoparticles suspension injection tracer from cervical neck before surgery. The black-staining lymph nodes were cut as SLN under the laparoscope for routine pathological examination. RESULTS: Of these 21 patients, at least one SLN was successfully detected in 20 patients(95.24%) , and a total of 158 SLNs were detected.The conventional pathology results suggested that 5 patients(23.81%) had positive lymph nodes(n=16, including 14 in 4 patients) . The new approach showed a sensitivity of 80.0%(4/5) , accuracy of 100.0%(20/20) , and negative predictive value of 100.0%(16/16) for SLN detection. CONCLUSION: Laparoscopic SLN detection with carbon nanoparticles tracer is a relative safe and sensitive method for in cervical carcinoma. PMID- 23643003 TI - [Changes of lymphocyte subsets before and after chemotherapy in colorectal carcinoma patients]. AB - OBJECTIVE: To investigate the change of lymphocyte subsets before and after chemotherapy in colorectal carcinoma patients. METHODS: Twenty-one peripheral blood lymphocyte subsets from 62 colorectal carcinoma patients before and after FOLFOX4(including oxaliplatin, 5-fluorouracil and leucovorin) , FOLFRI(including irinotecan, 5-fluorouracil and leucovorin) , or XELOX(including oxaliplatin and capecitabine) regimen chemotherapy were examined by flow cytometry.The differences of these lymphocyte subsets were analyzed. RESULTS: After chemotherapy, the percentages of CD3(+), CD3(+)CD8(+), CD29(+), CD4(+)CD29(+), and CD4(+)CD25(+) cells in peripheral blood of colorectal carcinoma patients increased significantly, while the percentages of CD19(+) and human leukocyte antigen(locus) DR(HLA-DR) (+) cells decreased significantly(P<0.05) .The results of subgroup analysis showed that the patients' CD3(+)CD8(+) and CD4(+)CD25(+) cells increased significantly, CD19(+) and HLA-DR(+) cells decreased significantly after FOLFOX4 regimen chemotherapy(P<0.05) ;CD3(+)CD8(+) cells increased significantly and CD19(+) cells decreased significantly after XELOX regimen chemotherapy(P<0.05) ;while after FOLFRI regimen chemotherapy, there were no significant changes in all 21 lymphocyte subsets(P>0.05) . CD3(+), CD3(+)CD8(+), memory T lymphoctye(45RO(+)) , and CD4(+)CD45RO(+) cells increased significantly(P<0.05) in patients who received no more than 4 cycles of chemotherapy. However, in patients that received 5 to 8 cycles and more than 9 cycles chemotherapy, we only found significant decrease of HLADR(+) cells and significant increase of CD29(+) cells, respectively(P<0.05) . CONCLUSIONS: The humoral immunity is attenuated after chemotherapy in colorectal carcinoma patients. FOLFOX4 may suppress the cellular immunity.Chemotherapy that is less than 4 cycles will strengthens the cellular immunity by modulating body immunity arrangement;however, along with the increase of chemotherapy cycles, the cellular immunity gradually declines in these patients. PMID- 23643004 TI - [Diagnosis and treatment of adipsic diabetes insipidus accompanied with intracranial calcification]. AB - OBJECTIVE: To summarize our experience in the management of adipsic central diabetes insipidus(ADI) accompanied with intracranial calcification. METHOD: The clinical data of one ADI patient accompanied with intracranial calcification who was treated in our hospital since December 2011 were retrospectively summarized. RESULTS: The 24-hour urine volume was 800 ml. She didn't feel thirsty even with increased plasma sodium concentration(153 mmol/L) and blood osmotic pressure(333 mmol/L) . Combined water deprivation and vasopressin test revealed the diagnosis of central diabetes insipidus. The high intensity signal(on T1-weighted magnetic resonance imaging) in the posterior lobe of pituitary gland was found. Computed tomography showed calcifications in the bilateral basal ganglia.Serum cytomegalovirus IgG was positive. She was treated with desmopressin and asked for regular water intake regardless of the adipsia. The plasma sodium concentration was still below 150 mmol/L during the 4-month follow-up. CONCLUSIONS: Routine adipsia evaluation and combined water deprivation and vasopressin test are critical for the diagnosis and treatment of ADI. Past insidious intracranial cytomegalovirus infection may explain the cause of ADI and calcification. PMID- 23643005 TI - [Efficacy of iodine-131 in treating hyperthyroid heart disease]. AB - OBJECTIVE: To investigate the value of iodine-131 therapy for hyperthyroidism complicated hyperthyroid heart disease(HHD) induced by Graves' disease or Plummer disease. METHODS: Totally 40 HHD cases who were confirmed in our department from 2009 to 2010 were enrolled in this study. All patients received serum thyroid hormones and associated antibodies tests, 12-lead electrocardiogram, and/or thyroid imaging before and after iodine-131 therapy to access the treatment effectiveness. RESULTS: Among 31 patients with HHD due to Graves' disease and 9 due to Plummer disease, iodine-131 treatment resulted in euthyroidism in 15 and 5 patients and hypothyroid in 7 and 2 patients, while 9 and 2 remain hyperthyroid, respectively.Serum free triiodothyronine, free thyroxine, and thyroid-stimulating hormone were statistically significant(P<0.05) before and after iodine-131 therapy, while no significant difference for serum thyrotrophin receptor antibody, antithyroid peroxidase autoantibody, and anti-thyroglobulin antibody.Atrial fibrillation was the most common cardiac complication of hyperthyroidism(n=25, 62.5%) .The remission rate after iodine-131 treatment was 76.0%. CONCLUSION: Iodine-131 therapy can effectively and timely control hyperthyroid in HHD patients. PMID- 23643006 TI - [Expression of breast cancer resistance protein and p-glycoprotein in residual breast cancer tissue after chemotherapy and its correlation with cancer stem cells]. AB - OBJECTIVE: To compare the expression differences of breast cancer resistance protein(BCRP/ABCG2) and P-glycoprotein(P-gp) in breast cancer tissue before chemotherapy and in residual breast cancer tissue, and to explore its correlation with breast cancer stem cells. METHODS: Immunohistochemistry was used to detect the expression of ABCG2, P-gp, and breast cancer stem cells(BCSCs) markers(CD44 and CD24) in breast cancer tissue before chemotherapy and residual breast cancer tissue after chemotherapy. Immunofluorescence was applied for determination of the CD44 and CD24 protein expressions of BCSCs microspheres cells. The monoclone forming ability of BCSCs microspheres cells was detected by limited dilution assay. The expressions of ABCG2, P-gp, CD44, and CD24 proteins were detected by Western blot. RESULTS: Compared with those in breast cancer tissue before chemotherapy, the expression levels of ABCG2 and P-gp were positively correlated with the expression level of CD44 protein(Chi(2)=41.34, r=0.83;Chi(2)=22.81, r=0.61) in residual breast cancer tissue after chemotherapy;meanwhile, they were negatively correlated with the expression of CD24 protein(Chi(2)=-21.25, r=0.72;Chi(2)=-17.26, r=0.65) (all P<0.05) .The diameter of BCSCs microspheres were increased significantly after chemotherapy.The content of BCSCs increased by about 2.5 times after chemotherapy.The expressions of ABCG2, P-gp and CD44 proteins significantly increased and that of CD24 protein significantly declined(P<0.05) . CONCLUSION: Chemotherapy endows residual breast cancer tissue with cancer stem cells-like features, leading to multidrug resistance of breast cancer. PMID- 23643007 TI - [Effect of LMO2 overexpression in hemangioblast on its proliferation and hematopoietic differentiation]. AB - OBJECTIVE: To investigate function of the Lim-only protein(LMO2) in hemangioblast generated from murine embryonic stem cells differentiation to hematopoietic cells. METHODS: The hemangioblast-specific expression vector with lmo2 or green fluorescence protein gene was constructed, respectively. The murine embryonic stem cells were transfected by the hemangioblast-specific expression vectors. The neomycin-resistance ES cell clones were obtained after having been screened by G418. The cell clones were spontaneously differentiated into embryo bodies(EB) containing hemangioblast.Expression of the hematopoietic genes was investigated by real-time reverse transcription-ploymerase chain reaction during EB differentiation.For the EB cells, blast-cloning forming cells analysis and blood colony forming unit analysis were then performed, respectively. The numbers of the blasts were counted during hematopoietic differentiation. RESULTS: The hemangioblast-specific expression vector with lmo2 or green fluorescence protein was transfected into ES cells.The neomycin-resistance ES cells generated EBs from 2.5 days to 10 days.Real time reverse transcription-ploymerase chain reaction analysis indicated that overexpression of lmo2 increased the expression of hematopoietic genes(gata1, tal1, Beta-h1, and Beta-major globin) during EB formation.Blast-cloning forming cells analysis showed that the numbers of the blasts generated by ES/lmo2 was 2-or 3-fold than those in the controls.The total numbers of the blood-colony forming unit or the numbers of the erythrocyte colony forming unit generated by ES/lmo2 were 2.5 times or 3 times, respectively, when compared with the controls. CONCLUSION: LMO2 enhances the proliferation and differentiation of hemangioblasts. PMID- 23643008 TI - [Expressions of p-c-jun and cyclinD1 between vascular smooth muscle cells and endothelial cells exposured to cigarette smoke extract]. AB - OBJECTIVE: To investigate the cell viabilities of vascular smooth muscle cells and vascular endothelial cells stimulated by cigarette smoke extract(CSE) . METHODS: The CSE was prepared by smoke-bubbled phosphate buffered saline(PBS) generation.After culturing cells with different concentrations of CSE, we used the cell counting kit-8 to determine the cell viability.The expression levels of c-jun and cyclinD1 were analyzed through Western blot.The c-jun plasmid was transfected to detect the change of cyclinD1 expression. RESULTS: The smooth muscle cell viability increased when the CSE concentration ranged 0.625%-10%, whereas the endothelial cells viability decreased when exposed to the CSE concentration. After exposure to CSE for 48 hours, there was no difference in c jun expression between toxin group and PBS group;however, the expression of p-c jun in the smooth muscle cells significantly increased in the toxin groups than in the PBS group(P<0.05) and the expression of p-c-jun in the vascular endothelial cells significantly decreased(P<0.05) . The level of cyclinD1 significantly increased after exposed to CSE, and its expression level also increased in respond to the c-jun overexpression. CONCLUSION: CSE can enhance the proliferation of vascular smooth muscle cells and decrease in the activity of endothelial cells proliferation, which may be explained by the phosphorylation of c-jun and the expression of cyclinD1. PMID- 23643009 TI - [Influence of hepatocyte cell adhesion molecule on gene expression profile of human bladder transitional cell carcinoma cell line]. AB - OBJECTIVE: To investigate the changes of gene expression file in transitional cell carcinoma of bladder after hepatocyte cell adhesion molecule(hepaCAM) overexpression. METHODS: Affymetrix Human Genome U133 Plus 2.0 Array was used to investigate the changes of gene expression profile between adenovirus-green fluorescent protein(GFP) -hepaCAM group and GFP group in transitional cell carcinoma of bladder EJ cells.Significant Analysis of Microarray(SAM) was used to screen the differentially expressed genes, DAVID software was used to conduct gene ontology analysis and wikiPathway analysis based on the differentially expressed genes. Reverse transcription-polymerase chain reaction and Western blot were applied to verify microarray data. RESULTS: Compared with the GFP group, a total of 2469 genes were up-regulated or down-regulated by more than 2 times in the GFP-hepaCAM group. Among these genes, 1602 genes were up-regulated and 867 were down-regulated.Most of the differentially expressed genes were involved in the function of cell proliferation and cell cycle regulation. The mRNA expressions of nibrin, liver kinase B1, and cyclin D1 detected by reverse transcription-polymerase chain reaction in three different bladder cancer cell lines were consistent with the microarray data.The protein expressions of nibrin and liver kinase B1 in these three cell lines measured by Western blot were consistent with the mRNA expression. CONCLUSIONS: HepaCAM can alter the gene expression profile of bladder cancer EJ cells. The well-known anti-tumor effect of hepaCAM may be mediated by regulating the gene expression via multiple pathways. PMID- 23643010 TI - [Prognostic value of T lymphocytes infiltration in breast cancer]. AB - OBJECTIVE: To assess and compare the prognostic role of tumor-infiltrating T lymphocytes in stage 1-3 breast cancer. METHODS: Paraffin sections were retrospectively collected from 130 cases of stage 1-3 breast cancer patients who received surgery between January 2000 and December 2002 in General Hospital of the People's Liberation Army. Immunohistochemistry was used to assess the density of tumor-infiltrating lymphocytes(TILs) that were positive of CD4 and CD8. These variables were evaluated for their association with histopathologic features along with overall survival(OS) , distant disease-free survival(DDFS) and disease free survival(DFS) . RESULTS: Intraepithelial CD4+lymphocytes infiltration was an independent prognostic factor for DFS(HR=0.248, 95%CI=0.113-0.543, P=0.000) , DDFS(HR=0.361, 95%CI=0.157-0.830, P=0.017) , and OS(HR=0.297, 95%CI=0.119-0.741, P=0.009) in multifactor COX regression model. In hormone receptor negative group, mesenchymal CD8+lymphocytes and intraepithelial CD8+lymphocytes were independent prognostic factors for OS(HR=0.286, 95%CI=0.101-0.807, P=0.018) and DDFS(HR=0.293, 95%CI=0.104-0.825, P=0.020) , respectively. In hormone receptor positive group, mesenchymal CD8+lymphocytes and intraepithelial CD8+lymphocytes were independent prognostic factors for OS(HR=4.854, 95%CI=1.435-16.415, P=0.011) and DDFS(HR=10.493, 95%CI=1.226-89.795, P=0.032) respectively. Further analysis found that OS of hormone receptor positive patients with lower mesenchymal CD8+TILs was significantly proved by adjuvant endocrine therapy. CONCLUSIONS: In the current investigation, intraepithelial CD4+TILs demonstrated independent prognostic significance for survival. CD8+TILs were associated with better survival in hormone receptor negative patients but associated with worse survival in hormone receptor positive patients. The long-term clinical effects of adjuvant endocrine therapy is related with density of mesenchymal CD8+TILs and in turn affected prognostic value of mesenchymal CD8+TILs. PMID- 23643012 TI - [An individualized approach combining local flaps with radiotherapy for the treatment of auricle keloid]. AB - OBJECTIVE: To investigate an individualized approach to the treatment of auricle keloid to maintain the normal appearance of external ear and meanwhile reduce the recurrence. METHODS: Different local flaps were performed according to the location of the keloid in our approach. The auricle was divided into different anatomical regions and all the patients received local postoperative radiotherapy. RESULTS: Of 68 patients with auricle keloid received the individualized approach, 3 cases suffered delayed healing due to partial flap necrosis. The remaining patients were followed up for 8-21 months(mean:11.5 months) . Recurrence occurred in one patient(1.47%) . CONCLUSION: The individualized approach combining local flaps with radiotherapy in treating auricle keloid can effectively maintain the normal ear appearance with low recurrence rate. PMID- 23643011 TI - [Roles of Cookgas and Fastrach intubating laryngeal mask airway for anticipated difficult tracheal intubation]. AB - OBJECTIVE: To compare the clinical effectiveness of blind intubation through the Cookgas intubating laryngeal airway(CILA) or Fastrach intubating laryngeal mask airway(FT-LMA) for anticipated difficult tracheal intubation. METHODS: Eighty-six patients with anticipated difficult tracheal intubation who were undergoing elective plastic surgery under general anesthesia were randomly allocated into CILA group(n=43) and FT-LMA group(n=43) . After general anesthesia being induced and CILA or FT-LMA being inserted, the patients were treated with blind intubation through CILA or FT-LMA. In each case, the number and the time of intubating laryngeal airway(ILA) insertion and blind intubation attempts and ILA removal were recorded. The view of glottis under fiberoptic bronchoscope(FOB) via CILA or FT-LMA was recorded. In addition, noninvasive blood pressure and heart rate were recorded before and after intravenous anesthetic induction, at ILA insertion, at intubation, at ILA removal and every minute thereafter for 5 minutes. RESULTS: CILA or FT-LMA was inserted successfully in all 86 patients. The rate of the first successful insertion was not significantly different between two groups(P>0.05) . In CILA group, the first intubation attempt succeeded in 35 patients;5 and 2 cases were intubated blindly at the second and the third attempt, one patient failed who was intubated successfully by FOB via CILA. In FT-LMA group, 32 patients were intubated successfully at the first attempt, 4 at the second attempt, 3 at the third attempt, and 4 cases failed, three of them were intubated smoothly with FOB through FT-LMA, one failed patient was intubated by FOB. The time of FT-LMA insertion(34.2?13.9) s was significantly longer when compared with CILA(22.4?18.9) s (P<0.05) . However, the time of blind intubation through CILA and FT-LMA [(46.0?26.7) s vs.(51.8?41.1) s]and the time of ILA removal[(39.3?11.9) s vs.(35.3?10.4) s] were not significantly different between groups(P>0.05) . Hemodynamic changes during blind intubation in the two groups showed no significant differences(P>0.05) . CONCLUSIONS: Blind intubation via CILA or FT-LMA is safe and effective for anticipated difficult tracheal intubation. Nevertheless, CILA is easier to be inserted, with relatively higher success rate of blind intubation. PMID- 23643013 TI - [Liver stiffness measured by acoustic radiation force impulse imaging in assessing hepatic functional reserve in patients with space-occupying lesions in the liver]. AB - OBJECTIVE: To investigate the value of liver stiffness measured by acoustic radiation force impulse imaging(ARFI) in assessing hepatic functional reserve in patients with space-occupying lesions in the liver. METHODS: Sixty-three patients with space-occupying lesions in the liver were enrolled. Liver stiffness (LS) measurements with ARFI and indocyanine green(ICG) retention test were performed in the same day, and plasma clearance rate of indocyanine green(ICG-K), ICG retention at 15 minutes(ICGR15) as well as 10 effective values of LS were recorded. The correlation between Child-Pugh score, ICGR15, ICG-K, and LS were evaluated. RESULTS: The LS measurements with ARFI failed in one patient. A strong correlation between LS and ICGR15(r=0.789, P<0.01) and an inverse correlation between LS and ICG-K(r=-0.738, P<0.01) were observed. Besides, there was a significant correlation between LS measurements and Child-Pugh score(r=0.929, P<0.01) . The LS significantly differed among patients with Child-Pugh class A, B, and C(P<0.01) . CONCLUSION: ARFI is a simple, feasible and non-invasive method for assessing hepatic functional reserve in patients with space-occupying lesions in the liver. PMID- 23643014 TI - [Effects of phosphatidylinositol-3 kinase/protein kinase b/bone morphogenetic protein-15 pathway on the follicular development in the mammalian ovary]. AB - In mammals, ovarian follicle is made of an oocyte with its surrounding granulosa cells and theca cells. Follicular growth and development is a highly coordinated programmable process, which guarantees the normal oocyte maturation and makes it having the fertilizing capacity. The paracrine and autocrine between oocytes and granulosa cells are essential for the follicular development to provide a suitable microenvironment. Phosphatidylinositol-3 kinase /protein kinase B is one of these important regulatory signaling pathways during this developmental process, and bone morphogenetic protein-15 an oocyte-specific secreted signal molecule, which regulates the follicular development by paracrine in the mammalian ovary. The present article overviewed the role of phosphatidylinositol 3 kinase / protein kinase B signaling during the follicular development based on our previous investigation about protein kinase B /forkhead transcription factor forkhead family of transcription factors -3a, and then focused on the regulatory effects of bone morphogenetic protein-15, as a downstream signal molecule of phosphatidylinositol-3 kinase / forkhead family of transcription factors -3a pathway, on ovarian follicular development, which helped to further understand the molecular mechanism regulating the follicular development and to treat ovarian diseases like infertility. PMID- 23643015 TI - [Research progress of mechanisms through which dipeptidyl peptidase-4 inhibitors regulate glycemia]. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors are promising new antidiabetic drugs. It had been proposed that DPP-4 inhibitors exert their antidiabetic effect by inhibiting the degradation of glucagon-like peptide 1(GLP-1) . However, new evidence has shown that the increase of GLP-1 is not notable after the use of these drugs in patients with type 2 diabetes. Therefore, the specific mechanisms via which DPP-4 inhibitors in controlling blood glucose has became questionable. In recent years, studies have revealed many possible mechanisms through which DPP 4 inhibitors regulate glycemia: DPP-4 inhibitors may selectively reduce DPP-4 activity in the intestine, causing the increase of portal plasma GLP-1 level and thus promoting the release of insulin via nerve reflex;also, they may decrease the cleavage product of GLP-1 and reduce the degradation of other bioactive peptides. PMID- 23643016 TI - Standard of care in North American small animal dental service. AB - Veterinary standard of care is peer-regulated, measured as the level of care provided and acceptable among most veterinarians in a given geographic area. This article proposes that today it should be the responsibility of the guiding organization of each medical discipline, such as the American Veterinary Dental College for the veterinary dental profession, to provide guidance to ruling Medical Boards regarding a recommended standard of care, rather than being defined by geographic boundaries. Within each medical discipline, specialists should be held to a higher standard than generalists, with both operating to a standard of care commensurate with their training. PMID- 23643017 TI - Therapeutic decision making and planning in veterinary dentistry and oral surgery. AB - Veterinary dentistry is an exacting science, in which decisions are made not only for an individual patient, but also for individual teeth, which may vary in severity of disease. Multiple therapeutic decisions and treatment plans may be necessary for a single patient. Veterinary dental patients must be anesthetized to receive thorough treatment, which results in additional decisions that may not be necessary for human dental patients. This article discusses considerations and approaches toward therapeutic decision making and treatment planning in veterinary dentistry and oral surgery. PMID- 23643018 TI - Oral and dental imaging equipment and techniques for small animals. AB - In the diagnosis and treatment of oral and dental diseases in dogs and cats, digital intraoral radiography offers many advantages over the use of standard dental radiographic film, including rapid image generation, easier exposure correction, enhancement, and paperless storage. Digital image receptors can be divided into 2 main types, direct digital systems using charged coupled devices and complementary metal oxide semiconductor sensors, and indirect digital systems using phosphor plates with a computerized scanner. Each system is paired with a computer software system to allow handling, visualization, enhancement, sharing, and archiving of the images. PMID- 23643019 TI - Clinical canine dental radiography. AB - The purpose of this article is to provide small animal veterinarians in private practice a guideline for interpretation of the most common findings in canine intraoral radiology. Normal oral and dental anatomy is presented. A brief review of variations of normal, common periodontal and endodontic pathology findings and developmental anomalies is provided. PMID- 23643020 TI - Clinical feline dental radiography. AB - Dental radiography is a necessary diagnostic modality in small animal practice. It is not possible to accurately assess and diagnose tooth resorption, periodontal disease, endodontic disease, neoplasia and injury without it. Dental radiography is also necessary for treatment and assessment of the patient postoperatively. PMID- 23643021 TI - Oral inflammation in small animals. AB - The oral cavity can be affected by a wide variety of disorders characterized by inflammation of the gingiva and/or oral mucosa. In dogs and cats, differential diagnoses for generalized oral inflammatory disorders include plaque-reactive mucositis, chronic gingivostomatitis, eosinophilic granuloma complex, pemphigus and pemphigoid disorders, erythema multiforme, and systemic lupus erythematosus. In addition, endodontic or periodontal abscesses, infectious conditions, reactive lesions, and neoplastic conditions may initially present with localized or generalized inflammation of the oral mucosa. Determination of the underlying cause of an oral inflammatory condition relies on a thorough history, complete physical and oral examination, and incisional biopsy and histopathologic examination of lesions. PMID- 23643022 TI - Exodontics: extraction of teeth in the dog and cat. AB - Dental disease can have a profound effect on the comfort and well-being of pets. Oral disease can be difficult to detect. Patients often hide their discomfort. The identification and treatment or removal of diseased teeth are the responsibility of the veterinarian. When diseased teeth cannot be saved by specialized care, extraction of teeth is necessary. Proper extraction of teeth in dogs and cats can be challenging and frustrating, but with review of the oral anatomy, proper instrumentation, and gentle tissue-handling techniques, this can be a rewarding part of clinical practice. PMID- 23643023 TI - Equipment for oral surgery in small animals. AB - This article provides an overview of equipment used for oral surgery. Specific instruments and materials used when performing relevant operative procedures are also mentioned in other articles in this issue. PMID- 23643024 TI - Oral and maxillofacial surgery in dogs and cats. AB - Advancements in diagnostic and treatment modalities for oral and maxillofacial surgery have allowed veterinarians to offer clients a range of alternatives for their pets. Categories of oral and maxillofacial surgery reviewed in this article include jaw fracture management, management of palatal/oronasal defects, recognition and treatment of oral masses, and management of several miscellaneous pathologic conditions. Miscellaneous oral lesions discussed in this article include odontogenic cysts, osteonecrosis and osteomyelitis, and lesions of the tongue and lips. PMID- 23643025 TI - Laser and radiosurgery in veterinary dentistry. AB - Lasers and radiosurgery frequently used in human dentistry are rapidly entering veterinary dental use. The carbon dioxide, diode, and low-level therapy lasers have features including hemostasis control, access to difficult to reach areas, and decreased pain, that make them useful for oral surgery. Periodontal pocket surgery, gingivectomy, gingivoplasty, gingival hyperplasia, operculectomy, tongue surgery, oropharyngeal inflammation therapy, oral mass surgery, crown, and frenectomy laser surgeries are described, including images. PMID- 23643026 TI - Anesthesia and pain management for small animals. AB - Anesthesia for oral surgery in dogs and cats requires special consideration and thorough planning to maximize patient safety. Well-trained technical staff capable of providing expedient delivery of quality dental radiographs and precision anesthesia monitoring are essential. Doctors need to be well versed in dental radiographic interpretation and competent and experienced in oral surgical techniques, particularly in surgical extractions. The work flow from patient induction to recovery involves estimate generation and client communication with multiple staff members. Knowledge of anesthetic and analgesic agents from premedication to postoperative pain management play an equally important role in patient safety. PMID- 23643027 TI - Clinical veterinary dentistry. PMID- 23643028 TI - Compressive properties of fibrous repair tissue compared to nucleus and annulus. AB - The wound healing process includes filling the void between implant and tissue edges by collagenous connective repair tissue. This fibrous repair tissue may load share or stabilize implants such as spinal disc replacements. The objective of this study was the biomechanical characterization of human fibrous tissue compared to annulus fibrosus and nucleus pulposus. Human lumbar discs (10 nucleus and annulus) and 10 lumbar deep wound fibrous tissue specimens were sectioned into 12mm diameter*6mm high cylindrical samples. Confined compression testing, after 2h swelling at 0.11MPa, was performed at 5%, 10% and 15% strain over 3.5h. Unconfined dynamic testing (2-0.001Hz) was performed at 5-15% strain. Semi quantitative histology estimated the proportion of proteoglycan to collagen. Fibrous tissue exhibited a decrease in height during the swelling period whereas annulus and nucleus tissues did not. The aggregate modulus was significantly less for fibrous tissue (p<0.002). Percent stress relaxation was greatest for the fibrous tissue and similar for annulus and nucleus. Dynamic testing found the storage modulus (E') was greater than the loss modulus (E") for all tissues. Annulus were found to have greater E' and E" than nucleus, whereas E' and E" were similar between annulus and fibrous tissue. Fibrous tissue had the greatest increase in both moduli at greater frequencies, but had the lowest hydration and proteoglycan content. Fibrous tissue would not be a substitute for native tissue within the disc space but if adjacent to a disc prosthesis may impart some degree of intersegmental stability during acute loading activities. PMID- 23643029 TI - CT two-dimensional reformation versus three-dimensional volume rendering with regard to surgical findings in the preoperative assessment of the ossicular chain in chronic suppurative otitis media. AB - PURPOSE: To assess the role of three-dimensional volume rendering (3DVR) in the preoperative assessment of the ossicular chain in chronic suppurative otitis media (CSOM). MATERIALS AND METHODS: Sixty-six patients with CSOM were included in this prospective study. Temporal bone was scanned with a 128-channel multidetector row CT and the axial data was transferred to the workstation for multiplanar reformation (MPR) and 3DVR reconstructions. Evaluation of the ossicular chain according to a three-point scoring system on two-dimensional reformation (2D) and 3DVR was performed independently by two radiologists. The evaluation results were compared with surgical findings. RESULTS: 2D showed over 89% accuracy in the assessment of segmental absence of the ossicular chain in CSOM, no matter how small the segmental size was. 3DVR was as accurate as 2D for the assessment of segmental absence. However, 3DVR was found to be more accurate than 2D in the evaluation of partial erosion of segments. CONCLUSION: Both 3DVR and 2D are accurate and reliable for the assessment of the ossicular chain in CSOM. The inclusion of 3DVR images in the imaging protocol improves the accuracy of 2D in detecting ossicular erosion from CSOM. PMID- 23643030 TI - Real time elastography endoscopic ultrasound (RTE-EUS), a comprehensive review. AB - Real-time elastography (RTE) performed during endoscopic ultrasound (EUS) is a relatively new technique which allows the evaluation of tissue stiffness, with the intent of better characterising lesions during EUS examinations. The aim of this comprehensive review was to describe the technique of RTE-EUS, as well as the clinical applications, including the study of pancreatic lesions, but also hepatobiliary, gastrointestinal (GI) tract pathology (including anal canal), lymph nodes, adrenal glands, lung and mediastinum, as well as urogenital applications. One of the advantages of the RTE-EUS technique is especially the possibility to be used in various locations accessible from the GI tract. Future developments are also briefly discussed, as elastography is a tissue characterising technique that will certainly not replace biopsy, but will rather be an adjunct during EUS examinations, due to its ease of use and low cost. PMID- 23643031 TI - Five- to ten-year outcomes for modular metal-on-metal total hip arthroplasty. AB - In recent years, metal-on-metal (MOM) arthroplasty has come under fire with reported adverse outcomes of metal hypersensitivity, adverse local tissue reaction (ALTR), and the carcinogenicity concern from systemic metal ions. We present a retrospective analysis of 354 primary total hip arthroplasties from 2 independent centers. Revision data, predicted survival and Harris Hip Scores (HHS) are reported. Nine hips (2.5%) underwent component revision, and 9 year predicted survival was 95.8%. One revision had elevated metal ions but no histological evidence of ALTR. Average HHS at a minimum 5 year follow up (range 5 10 years) improved significantly from 52 pre-operatively to 93 post-operatively. While a 2.5% revision rate and improved clinical outcomes are reported in this study, longer term follow-up is warranted to monitor for late complications. PMID- 23643032 TI - Advancing the adoption, integration and testing of technological advancements within existing care systems. AB - OBJECTIVE: This manuscript reviews the work on uptake and dissemination of health information technologies in mental health populations and settings, with the goal of informing the future research agenda. METHODS: We reviewed both the formal and "grey" literature describing the rates and correlates of uptake for electronic health records (EHRs) and personal health records (PHRs) for general and specialty mental health settings. RESULTS: Rates of uptake and use of EHRs and PHRs are low in general medical settings, and the limited evidence suggests even lower rates for specialty mental health settings. Many of the patient, provider and system-level characteristics associated with lower rates of use in general populations would be expected to be exacerbated in mental health settings. CONCLUSIONS: The findings suggest a need to better understand both the causes and strategies for overcoming barriers to uptake of health information technology (HIT) in mental health settings. Observational studies could help to better elucidate the barriers to adoption of HIT that are unique or disproportionate in mental health populations. Implementation science studies are needed to better identify strategies for addressing these barriers and optimizing uptake of mental health HIT interventions. PMID- 23643033 TI - Suicide attempts and clinical risk factors in patients with bipolar and unipolar affective disorders. AB - BACKGROUND: Suicide is an important clinical problem in psychiatric patients. The highest risk of suicide attempts is noted in affective disorders. OBJECTIVE: The aim of the study was to look for suicide risk factors among sociodemographic and clinical factors, family history and stressful life events in patients with diagnosis of unipolar and bipolar affective disorder (597 patients, 563 controls). METHOD: In the study, the Structured Clinical Interview for DSM-IV Axis I Disorders and the Operational Criteria Diagnostic Checklist questionnaires, a questionnaire of family history, and a questionnaire of personality disorders and life events were used. RESULTS: In the bipolar and unipolar affective disorders sample, we observed an association between suicidal attempts and the following: family history of psychiatric disorders, affective disorders and psychoactive substance abuse/dependence; inappropriate guilt in depression; chronic insomnia and early onset of unipolar disorder. The risk of suicide attempt differs in separate age brackets (it is greater in patients under 45 years old). No difference in family history of suicide and suicide attempts; marital status; offspring; living with family; psychotic symptoms and irritability; and coexistence of personality disorder, anxiety disorder or substance abuse/dependence with affective disorder was observed in the groups of patients with and without suicide attempt in lifetime history. PMID- 23643034 TI - Mental health consequences of intimate partner violence in Vhembe district, South Africa. AB - OBJECTIVE: The aim of this study was to assess the contributions of different forms of intimate partner violence (physical violence, sexual violence, psychological abuse, and stalking) on symptoms of posttraumatic stress disorder (PTSD) and depression. METHODS: In all 268 women (18 years and older) consecutively receiving a protection order in the Vhembe district in South Africa were assessed by an external interviewer. Hierarchical regressions tested the unique effects of different types of intimate partner violence on PTSD and depression. RESULTS: In terms of PTSD symptom severity, more than half (51.9%) of the sample reported severe PTSD and 66.4% reported severe depression symptoms. Two types of intimate partner violence (physical and sexual) were significantly associated with PTSD symptoms, while only psychological violence was moderately correlated with depression symptoms. Physical abuse contributed to the prediction of PTSD and psychological abuse to depression. CONCLUSIONS: A significant number of women with protection orders suffer from PTSD and depression. The results confirm a relationship between severity of intimate partner violence and mental health problems (PTSD and depression). Assessment of intimate partner violence should incorporate the multiple dimensions that have been identified as contributing to poor mental health. PMID- 23643035 TI - Dorsal and ventral pathways in language development. AB - The dorsal and ventral information streams between inferior frontal and temporal language regions in the human brain are implemented by two fiber connections that consist of separable tracts. We compared the maturation of the two connections including their subcomponents in three different age groups: newborn infants, 7 year-old children, and adults. Our results reveal a maturational primacy of the ventral connection in the language network associating the temporal areas to the inferior frontal gyrus during early development, which is already in place at birth. Likewise, a dorsal pathway from the temporal cortex to the premotor cortex is observable at this early age. This is in contrast to the dorsal pathway to the inferior frontal gyrus which matures at later stages in development and might play a role in more complex language functions. PMID- 23643036 TI - On the exploitation of mid-infrared iridescence of plumage for remote classification of nocturnal migrating birds. AB - A challenging task in ornithology lies in identifying high-altitude nocturnal migrating bird species and genders. While the current approaches including radar, lunar obscuration, and single-band thermal imaging provide means of detection, a more detailed spectral or polarimetric analysis of light has the potential for retrieval of additional information whereby the species and sex could be determined. In this paper, we explore remote classification opportunities provided by iridescent features within feathers in the mid-infrared region. Our approach first involves characterizing the microstructural features of the feather by using rotation and straining, and a scheme for their remote detection is proposed by correlating these microstructural changes to spectral and polarimetric effects. Furthermore, we simulate the spectral signature of the entire bird by using a model that demonstrates how classification would be achieved. Finally, we apply infrared hyperspectral polarization imaging, showing that the net iridescent effect persists for the bird as a whole. PMID- 23643037 TI - Interaction of melamine molecules with silver nanoparticles explored by surface enhanced Raman scattering and density functional theory calculations. AB - Recently, unethical manufacturers illegally adulterated foods to increase the nitrogen content of protein through the use of melamine. Although surface enhanced Raman scattering (SERS) methods have been widely used to detect melamine, the details of the interaction mechanism between a melamine molecule and silver colloids are still unclear. In this paper, we present the adsorption behavior of melamine on the surface of silver nanoparticles, which we explored by using SERS and density functional theory calculation methods. The calculated results demonstrate that the melamine molecule interacts with the silver surface mainly via the heterocyclic nitrogen. When comparing the predicted spectra of the complexes of melamine-Ag(+) and melamine-Ag(0), we found that the spectrum of the former agrees better with the experimental spectra than that of the latter. In the structure of the melamine-Ag(+) complex, we found that the melamine molecule "stands" on the surface of nanoparticles, with a small tilt angle. The concentration-dependent SERS spectra reveal that the melamine molecule stands on the silver surface with a small tilt angle in high concentration, and the tilt angle becomes larger when the concentrations are diluted. PMID- 23643038 TI - In situ-monitoring of biofilm formation by using surface-enhanced Raman scattering. AB - A biofilm is a complex biochemical structure composed of microorganisms and extracellular polymeric substances used by microorganisms to adhere to each other and to surfaces. The monitoring of molecular changes during biofilm formation in situ can provide valuable insights in medicine, microbiology, and industrial processes. In this study, we investigated the characterization of biofilm produced by two model bacteria by using surface-enhanced Raman scattering (SERS) with the use of core silver (AgNPs)-shell chitosan nanoparticles (c-AgNPs), which are prepared by coating citrate-reduced AgNPs with a thin layer of chitosan averaging 10 nm. The chitosan thin film acts as porous layer and prevents the excess interactions of biological media secreted by bacteria. The two model bacteria, Escherichia coli and Staphylococcus cohnii, gram positive and gram negative, respectively, were chosen for the study. The SERS spectra were acquired directly from the growth culture by simply placing c-AgNPs substrate on the biofilm formed during the growth of the bacteria for in situ monitoring. It was found that c-AgNPs are effective SERS substrates to monitor molecular changes in the biofilm during the biofilm formation. PMID- 23643039 TI - Carrier recombination-incited substrate vibrations after pulsed UV-laser photolysis of TiO2 thin single-crystal plate and nanoparticle films. AB - Photo-induced carrier generation and recombination have been regarded as important steps in understanding the photocatalytic reactions on the surfaces of semiconductors such as TiO2. During the investigation of a photocatalytic water splitting reaction on the surface of semiconductor TiO2 (rutile) single-crystal plate and sintered-nanoparticle (anatase) films coated on a CaF2 plate, a pulsed 355 nm laser was used for band-gap excitation and a continuous-working, mid infrared laser as the probe to trace the kinetics of the photogenerated electrons. Fast oscillations with periods of 10-50 MUs were observed. We demonstrated experimentally that these oscillations are neither from the nonlinear carrier recombination dynamics nor surface chemical reactions; instead, they are caused by the thermal-induced flexural vibrations initiated by the fast carrier recombination in the light-absorbing area. The observed oscillations can be well accounted for by thermal stress-induced flexural vibrations of the substrates due to rapid charge recombination, and the observed oscillation frequencies match the flexural vibration frequencies predicted by the Kirchhoff Love thin-plate theory. Light-interference effect caused by the beam reflecting off the surfaces of the substrate and windows, which can amplify the oscillation signals, is also discussed. Several approaches are proposed to minimize or eliminate the interference from the substrate vibration in the transient kinetic measurement when a coherent laser is used as the probe beam. PMID- 23643040 TI - Short-range demonstrations of monocular passive ranging using O2 (X3Sigmag- -> b1Sigmag+) absorption spectra. AB - The depth of absorption bands in observed spectra of distant, bright sources can be used to estimate range to the source. Experimental results are presented based on observations of the O2 X(v" = 0) -> b(v' = 0) absorption band centered around 762 nm and the O2 X(v" = 0) -> b(v' = 1) band around 689 nm. Range is estimated by comparing observed values of band-average absorption against predicted curves derived from either historical data or model predictions. Accuracy of better than 0.5% was verified in short-range (up to 3 km), static experiments using a high resolution (1 cm(-1)) spectroradiometer. This method was also tested against the exhaust plume of a Falcon 9 rocket launched from Cape Canaveral, Florida. The rocket was launched from an initial range of 13 km and tracked for 90 s after ignition. Range error was below 2% for the first 30 s and consistent with predicted error throughout the track. PMID- 23643041 TI - Spectral study and protein labeling of inclusion complex between dye and calixarene sulfonate. AB - The host-guest inclusion complex of calix[6]arene sulfonate (SCA6) with thiazole orange (TO) formed in aqueous solution was studied. Absorption and fluorescence techniques were used for the analysis of this inclusion complex. The addition of calixarene sulfonate leads to a decrease in both absorption and fluorescence intensity of the dye, indicating that the inclusion complex was formed. Simultaneously, the inclusion phenomenon of another cyanine dye, Cy3, with calixarene sulfonate was investigated. The stability constant of the two complexes was determined, and the results were compared. The water solubility of TO dye was increased in the presence of calixarene sulfonate, and further protein labeling experiments suggested that this TO-SCA6 complex can act as a fluorescent probe for labeling of biomolecules. PMID- 23643042 TI - Pre-concentration procedure based on chitosan combined with ionic liquid for the determination of cobalt, nickel, and copper in water samples. AB - An environmentally friendly analytical procedure of pre-concentration of cobalt, nickel, and copper according to the rules of green chemistry has been developed. The proposed method is based on using chitosan for sorption of trace elements from water samples. The novel modification of the sorption process is the combination of an ionic liquid (1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6]) with chitosan. Ionic liquid partly decreases the crystallinity of the chitosan. The crystalline regions of the polymer are not accessible to metal ions. Although the ionic liquid cannot completely disrupt the crystalline domains of chitosan, it may gain in the reactive groups of the chitosan, even at the center of the particle. Consequently, the sorption of metal ions by chitosan is significantly improved. In this paper, adsorption characteristics of cobalt, nickel, and copper using newly developed sorption are studied. The effect of pH and time of chitosan activation, as well as sorption, salt concentration, some metals ion concentrations, and the amount of adsorbent on the extent of adsorption, are investigated. Chitosan with adsorbed metal ions was dissolved in acetic acid. After evaporation a solvent film formed and was then analyzed using X-ray fluorescence spectrometry (XRF). As it meets the criterion of thin samples for XRF analysis, the matrix effects can be neglected. With the proposed procedure we obtained detection limits of 7 ng mL(-1) for cobalt, 5 ng mL(-1) for nickel, and 4 ng mL(-1) for copper. PMID- 23643043 TI - Abnormal behavior of longitudinal optical phonon in silicon dioxide films on 4H SiC bulk epitaxial substrate using Fourier transform infrared (FT-IR) spectroscopy. AB - We report the abnormal behavior of longitudinal optical (LO) phonon in a silicon dioxide (SiO2) film on a 4H-SiC bulk epitaxial substrate using an attenuated total reflection (ATR) technique. The peak frequency of the LO phonon in the ATR spectrum was observed at around 1165 cm(-1) and red-shifted by approximately 92 cm(-1) relative to that at the grazing incidence (40 degrees ), whereas the peak frequency of the transverse optical (TO) phonon in the ATR spectrum agreed well with that at the grazing incidence. Furthermore, the peak frequency of the TO phonon hardly depends on change in the incident angle and thickness, suggesting that the microstructure of the sample is homogeneous within a thickness of 100 nm. On the other hand, we found that the microstructure of the sample was inhomogeneous within a thickness less than 5 nm. Fourier transform infrared (FT IR) spectroscopy provides us with a large amount of data on microstructures in the SiO2 films on a 4H-SiC substrate. PMID- 23643045 TI - A new method to quantitatively evaluate the chemical composition of waterlogged wood by means of attenuated total reflectance Fourier transform infrared (ATR FT IR) measurements carried out on wet material. AB - Wood degradation in waterlogged conditions, although slow, is relevant in some specific contexts, such as in the case of cultural heritage preservation (e.g., ancient shipwrecks found under the water table). This decay process induces the selective depletion of the biopolymers constituting wood cell walls and mainly of their structural polysaccharides (both cellulose and hemicelluloses). Assessment of residual composition of cell walls is normally carried out using conventional chemical analyses, which, however, require elevated amounts of material. The present work reports on a new approach to quantitatively determine the residual chemical composition of wood (in terms of amount of lignin and holocellulose) and therefore its extent of degradation. This was accomplished by acquiring attenuated total reflectance Fourier transform infrared (ATR FT-IR) spectra on material still in waterlogged conditions, which was simply placed in optical contact with the ATR crystal. Data for the calibration set were obtained by means of wet analyses, and the calibration model was based on multivariate statistical analysis through partial least square regression. Acquired spectra showed signals higher and better resolved than for dry wood. Calibration was selected after comparing two different normalization procedures and after processing signals of two different spectral ranges. Furthermore, the exclusion of some outliers led to a substantial improvement in the error parameters (R(2) and root mean square error of cross validation) associated with the calibration model, thus allowing for the selection of the best model. The stability of this best model was also established by means of the leave-more-out method. Finally, a procedure of external validation confirmed that the proposed model also could be applied to similar (for instance, belonging to Pinaceae) wood remains from other excavations. PMID- 23643044 TI - Recovery of absorption spectra from Fourier transform infrared (FT-IR) microspectroscopic measurements of intact spheres. AB - An infrared spectrum recorded from a microscopic sample depends on spectral properties of the constituent material as well as on morphology. Many samples or domains within heterogeneous materials can be idealized as spheres, in which both scattering and absorption from the three-dimensional shape affect the recorded spectrum. Spectra recorded from such objects may be altered to such an extent that they bear little resemblance to spectra recorded from the bulk material; there are no methods, however, to reconcile the two from first principles. Here we provide the mathematical description of the optical physics underlying light spherical sample interaction within an instrument. We use the developed analytical expressions to predict recorded data from spheres using Fourier transform infrared (FT-IR) spectroscopic imaging. Recorded spectra are shown to depend strongly on the size of the sphere as well as the optical arrangement of the instrument. Next, we present theory and experiments demonstrating the recovery of the complex refractive index of the material using data recorded from a sphere. The effects of the sample morphology on the measured spectra can be removed, and using the imaginary part of the index, the shape-independent IR absorption spectrum of the material is recovered. PMID- 23643046 TI - SERS mapping in Langmuir-Blodgett films and single-molecule detection. AB - Plasmon-enhanced spectroscopic techniques have expanded single-molecule detection (SMD) and are revolutionizing areas such as bio-imaging and single-cell manipulation. Surface-enhanced (resonance) Raman scattering (SERS or SERRS) combines high sensitivity with molecular-fingerprint information at the single molecule level. Spectra originating from single-molecule SERS experiments are rare events, which occur only if a single molecule is located in a hot-spot zone. In this spot, the molecule is selectively exposed to a significant enhancement associated with a high, local electromagnetic field in the plasmonic substrate. Here, we report an SMD study with an electrostatic approach in which a Langmuir film of a phospholipid with anionic polar head groups (PO4(-)) was doped with cationic methylene blue (MB), creating a homogeneous, two-dimensional distribution of dyes in the monolayer. The number of dyes in the probed area of the Langmuir-Blodgett (LB) film coating the Ag nanostructures established a regime in which single-molecule events were observed, with the identification based on direct matching of the observed spectrum at each point of the mapping with a reference spectrum for the MB molecule. In addition, advanced fitting techniques were tested with the data obtained from micro-Raman mapping, thus achieving real-time processing to extract the MB single-molecule spectra. PMID- 23643047 TI - An in-depth study linking the infrared spectroscopy and photoluminescence of porous silicon during ambient hydrogen peroxide oxidation. AB - We carefully tailored a porous silicon (pSi) surface by oxidation with hydrogen peroxide (H2O2) to determine the time-dependent changes in nanocrystallite surface chemistries (e.g., Si-O-Si, SiH(x) [x = 1, 2], OySiH [y = 2, 3], and SiOH/H2O) and their influence on the pSi photoluminescence (PL). The relationship between infrared band amplitudes and PL intensity were evaluated under H2O2 and O3 (previously studied) oxidation. The pSi surface composition under O3 and H2O2 oxidation conditions tended to, save the O(y)SiH (y = 2, 3) species, approach similar values at the longest oxidation times studied, but they took very different paths in reaching these end points. Furthermore, the pSi surface compositions that exhibit maximum/minimum PL under each oxidant are very different. PMID- 23643048 TI - Progressive resistance, whole body long-axis rotational training improves kicking motion motor performance. AB - OBJECTIVES: To evaluate lower extremity muscle activation, peak resultant ground reaction force (GRF) production and quickness during performance of a kicking motion following progressive resistance, whole body long-axis rotational training. DESIGN: Randomized, controlled study. SETTING: Kinesiological research laboratory. PARTICIPANTS: Thirty-six healthy subjects were assigned to a training (Group 1) or to a control (Group 2) group. MAIN OUTCOME MEASURES: Time synchronized EMG (1000 Hz), peak resultant GRF (1000 Hz) and two-dimensional kinematic (60 Hz) data were collected as subjects responded to an audio cue by kicking a cone. Group mean change differences (MCD) were compared using independent sample t-tests. Fisher's exact tests were used to determine group differences in the proportion of subjects that displayed earlier activation responses post-training. RESULTS: Group 1 MCD revealed earlier gluteus maximus, gluteus medius, rectus femoris, medial hamstrings, and biceps femoris activation timing than Group 2 (P <= 0.006) and more Group 1 subjects displayed earlier activation of these muscles post-training (P <= 0.041). Group 1 MCD also revealed earlier peak resultant GRF timing and improved "kick quickness" than Group 2 (P <= 0.014) and more Group 1 subjects displayed earlier response timing for these variables post-training (P = 0.035). CONCLUSION: Progressive resistance, whole body long-axis rotational training may improve performance during sports movements that require quick, integrated trunk-lower extremity function. PMID- 23643049 TI - High-precision alignment of electron tomography tilt series using markers formed in helium-ion microscope. AB - Tungsten nanodots formed in a helium-ion microscope (HIM) provide a practical means of aligning markers of electron tomography tilt series with a high degree of precision. The nanodots were formed using a HIM equipped with a W(CO)6 gas injection system, enabling the precise placement of the nanodots at desired locations of a sample. Template matching was applied to the markers formed in the HIM to detect the positions automatically. The relation between the positions of the markers and the accuracy of the alignment was also determined in order to achieve precise alignment. The method was applied to the markers in order to reconstruct three-dimensional (3D) images of a rod-shaped specimen that contained a 65-nm-diameter via structure in a Cu/Low-k interconnect. PMID- 23643050 TI - Determination of the interfacial rheological properties of a poly(DL-lactic acid) encapsulated contrast agent using in vitro attenuation and scattering. AB - The stabilizing encapsulation of a microbubble-based ultrasound contrast agent (UCA) critically affects its acoustic properties. Polymers, which behave differently from materials commonly used (i.e., lipids or proteins) for monolayer encapsulation, have the potential for better stability and improved control of encapsulation properties. Air-filled microbubbles coated with poly(DL-lactic acid) (PLA) are characterized here using in vitro acoustic experiments and several models of encapsulation. The interfacial rheological properties of the encapsulation are determined according to each model using attenuation of ultrasound through a suspension of microbubbles. Then the model predictions are compared with scattered non-linear (sub- and second harmonic) responses. For this microbubble population (average diameter, 1.9 MUm), the peak in attenuation measurement indicates a weighted-average resonance frequency of 2.5-3 MHz, which, in contrast to other encapsulated microbubbles, is lower than the resonance frequency of a free bubble of similar size (diameter, 1.9 MUm). This apparently contradictory result stems from the extremely low surface dilational elasticity (around 0.01-0.07 N/m) and the reduced surface tension of the poly(DL-lactic acid) encapsulation, as well as the polydispersity of the bubble population. All models considered here are shown to behave similarly even in the non-linear regime because of the low surface dilational elasticity value. Pressure-dependent scattering measurements at two different excitation frequencies (2.25 and 3 MHz) revealed strongly non-linear behavior with 25-30 dB and 5-20 dB enhancements in fundamental and second-harmonic responses, respectively, for a contrast agent concentration of 1.33 MUg/mL in the suspension. Sub-harmonic responses are registered above a relatively low generation threshold of 100-150 kPa, with up to 20 dB enhancement beyond that pressure. Numerical predictions from all models show good agreement with the experimentally measured fundamental response, but not with the experimental second-harmonic response. The characteristic features of sub-harmonic responses and the steady response beyond the threshold are matched well by model predictions. However, prediction of the threshold value depends on estimated properties and size distribution. The variation in size distribution from sample to sample leads to variation in estimates of encapsulation properties: the lowest estimated value for surface dilational viscosity better predicts the sub-harmonic threshold. PMID- 23643051 TI - Impaired fasting blood glucose is associated with increased endothelin-1 vasoconstrictor tone. AB - AIM/HYPOTHESIS: The experimental aim of this study was to determine whether ET-1 mediated vasoconstrictor tone is elevated in adult humans with impaired fasting blood glucose concentrations, independent of other cardiovascular risk factors. METHODS: Forearm blood flow (FBF: plethysmography) responses to intra-arterial infusion of selective ETA receptor blockade (BQ-123: 100 nmol/min for 60 min) and non-selective ETA/B blockade (BQ-123 + BQ-788: 50 nmol/min for 60 min) were determined in 28 middle-aged, sedentary adults (17 M/11 F): 14 with normal fasting blood glucose (age: 57 +/- 2 yr; 6 F/8 M; BMI: 29.2 +/- 0.9 kg/m(2); glucose: 4.9 +/- 0.1 mmol/L) and 14 impaired fasting blood glucose (58 +/- 1 yr; 5 F/9 M; 29.6 +/- 1.1 kg/m(2); 5.8 +/- 0.1 mmol/L) concentrations. RESULTS: Selective ETA receptor blockade elicited a significantly greater (~20%) increase in FBF in the impaired fasting glucose adults compared with the normoglycemia controls. ETA/B blockade resulted in a further 2-fold increase (P < 0.05) in FBF above that elicited by ETA receptor antagonism in the impaired fasting glucose but not normal fasting glucose adults. There was a positive correlation between fasting blood glucose levels and the peak vascular responses to ETA (r = 0.44; P < 0.05) and ETA/B (r = 0.62; P < 0.05) blockade. No other anthropometric, hemodynamic or metabolic variable was correlated with the blood flow responses to ET-1 receptor blockade. CONCLUSIONS/INTERPRETATION: ET-1-mediated vasoconstrictor tone is elevated in adults with impaired fasting blood glucose concentrations, independent of other cardiometabolic risk factors. Enhanced ET-1 system activity may underlie endothelial vasomotor dysfunction and increased cardiovascular risk in adults with impaired fasting blood glucose concentrations. PMID- 23643052 TI - Dipeptidyl peptidase-4 inhibition and vascular repair by mobilization of endogenous stem cells in diabetes and beyond. AB - Endothelial integrity is maintained by local neighboring cells, but studies in the field of regenerative medicine have highlighted that circulating bone marrow derived endothelial progenitor cells (EPCs) contribute to endothelial homeostasis in health and disease. In addition, bone-marrow derived smooth muscle precursors may be recruited to the diseased vasculature. Therefore, modulation of vascular stem/progenitor cells holds promises to tackle the development and progression of vascular disease. The dipeptidyl peptidase-4 (DPP-4) ectopeptidase cleaves several proteins, including the incretin hormones that regulate meal-induced insulin release. Another attractive DPP-4 natural substrate is the highly conserved chemokine SDF-1alpha, a major regulator of stem/progenitor cell trafficking in the bone marrow and tissues. DPP-4 might also broadly affect bone marrow function, by acting on hematopoietic growth factors. Emerging data indicate that diabetes is associated with impaired bone marrow structure and function, which translates into pauperization of vascular regenerative cells and contributes to vascular disease. DPP-4 inhibition has potentials to tackle these alteration and promote vascular repair. Currently, millions of diabetic patients around the world are being treated with DPP-4 inhibitors and the study of ancillary effects is gaining an increasing interest for the possible cardiovascular benefit of these drugs beyond glucose control. As DPP-4 inhibitors show favorable safety profiles and do not cause hypoglycemia, they are attractive drugs also for non-diabetic patients and may become part of a vascular regenerative pharmacotherapy. PMID- 23643053 TI - Egg consumption and risk of cardiovascular diseases and diabetes: a meta analysis. AB - OBJECTIVES: To assess the dose-response relationship between egg consumption and the risk of cardiovascular diseases (CVD) and diabetes. METHODS: We systematically searched MEDLINE database through December 2012. Fixed- or random effects model was used to pool the relative risks (RRs) and their 95% confidence intervals (CIs). Subgroup analyses was performed to explore the potential sources of heterogeneity. Weighted linear regression model was used to estimate the dose response relationship. RESULTS: Fourteen studies involving 320,778 subjects were included. The pooled RRs of the risk of CVD, CVD for separated diabetes patients, and diabetes for the highest vs lowest egg intake were 1.19 (95% CI 1.02-1.38), 1.83 (95% CI 1.42-2.37), 1.68 (95% CI 1.41-2.00), respectively. For each 4/week increment in egg intake, the RRs of the risk for CVD, CVD for separated diabetes patients, diabetes was 1.06 (95% CI 1.03-1.10), 1.40 (95% CI 1.25-1.57), 1.29 (95% CI 1.21-1.37), respectively. Subgroup analyses showed that population in other western countries have increased CVD than ones in USA (RR 2.00, 95% CI 1.14 to 3.51 vs 1.13, 95% CI 0.98 to 1.30, P = 0.02 for subgroup difference). CONCLUSIONS: Our study suggests that there is a dose-response positive association between egg consumption and the risk of CVD and diabetes. PMID- 23643054 TI - Ultrasound improves the uptake and distribution of liposomal Doxorubicin in prostate cancer xenografts. AB - Combining liposomally encapsulated cytotoxic drugs with ultrasound exposure has improved the therapeutic response to cancer in animal models; however, little is known about the underlying mechanisms. This study focused on investigating the effect of ultrasound exposures (1 MHz and 300 kHz) on the delivery and distribution of liposomal doxorubicin in mice with prostate cancer xenografts. The mice were exposed to ultrasound 24 h after liposome administration to study the effect on release of doxorubicin and its penetration through the extracellular matrix. Optical imaging methods were used to examine the effects at both microscopic subcellular and macroscopic tissue levels. Confocal laser scanning microscopy revealed that ultrasound-exposed tumors had increased levels of released doxorubicin compared with unexposed control tumors and that the distribution of liposomes and doxorubicin through the tumor tissue was improved. Whole-animal optical imaging revealed that liposomes were taken up by both abdominal organs and tumors. PMID- 23643055 TI - Electronic beam steering used with a toroidal HIFU transducer substantially increases the coagulated volume. AB - Treatment with high-intensity focused ultrasound is well established but requires extended treatment time. A device composed of 256 elements arranged on a toroidal transducer was developed to increase the coagulated volume. When all the elements are working in phase for 40 s, a volume of 6-8 cm(3) can be ablated. However, the mechanical juxtaposition of single lesions is still necessary for treating one tumor with a diameter of 2 cm. The objective of this study was to combine this toroidal transducer geometry with electronic beam steering to ablate tumors with adequate normal tissue margins and without any mechanical displacement of the high-intensity focused ultrasound device. In vitro tests demonstrated that the coagulated volume obtained from 130 s of total exposure has an average diameter of 41.4 +/- 4.0 mm and an average length of 53.3 +/- 6.1 mm. This single lesion can be used to treat various size of metastasis, located at depths in the liver ranging 5-45 mm. PMID- 23643057 TI - Quantitative contrast-enhanced ultrasound comparison between inflammatory and fibrotic lesions in patients with Crohn's disease. AB - The aim of this study was to determine whether there are differences in absolute blood flow between patients with Crohn's disease with inflammation or fibrosis using contrast-enhanced ultrasound. Eighteen patients with fibrotic disease and 19 patients with inflammation were examined. Video sequences of contrast data were analyzed using a pharmacokinetic model to extract the arterial input and tissue residue functions with a custom software, enabling calculation of the absolute values for mean transit time, blood volume and flow. Feasibility of the examination was 89%. The fibrosis group had lower blood volume (0.9 vs. 3.4 mL per 100 mL tissue; p = 0.001) and flow (22.6 vs. 45.3 mL/min per 100 mL tissue; p = 0.003) compared with the inflammation group. There was no significant difference in mean transit time (3.9 vs. 5.5 s). In conclusion, absolute perfusion measurement in the gastrointestinal wall using contrast-enhanced ultrasound is feasible. There seems to be reduced blood volume and blood flow in patients with fibrotic disease. PMID- 23643058 TI - Left ventricular longitudinal strain measured by speckle tracking as a predictor of the decrease in left ventricular deformation in children with congenital stenosis of the aorta or coarctation of the aorta. AB - Children born with a left ventricular outflow tract obstruction (LVOTO) can present with symptoms of left ventricular (LV) failure while ejection fraction (EF) is normal. A more sensitive parameter of systolic function might be obtained with speckle tracking echocardiography, which describes ventricular longitudinal deformation in strain values. It is presumed that despite a normal or only slight decrease in ejection fraction, patients with a LVOTO demonstrate aberrations in the longitudinal deformation of the left ventricle. In addition, it is expected that after a successful intervention, longitudinal deformation returns to normal values. Standard trans-thoracic echocardiography was performed on 33 consecutive patients with a LVOTO, either an isolated aortic coarctation (AoCo) or an isolated aortic stenosis (AoSt). Before intervention a significant decrease in strain values was observed compared with the control group (N = 40), with an additional decrease in strain values in the first week after intervention (N = 16). Strain values recovered after a mean follow-up period of 42 wk (N = 9), though normal values were never reached. In addition, patients with an AoCo had a smaller decrease in strain values compared with patients with AoSt. All strain values were measured with a concomitant ejection fraction between normal limits. It is concluded that patients with a congenital LVOTO have decreased ventricular systolic function measured as strain values, whereas their ejection fraction is within the normal range. Therefore, as ejection fraction may not be an accurate measure, speckle tracking-based strain may be significant in the identification of subtle changes in longitudinal deformation and may create opportunities for patients to benefit from early treatment for heart failure. PMID- 23643059 TI - Assessment of the fundamental flexural guided wave in cortical bone by an ultrasonic axial-transmission array transducer. AB - The fundamental flexural guided wave (FFGW), as modeled, for example, by the A0 Lamb mode, is a clinically useful indicator of cortical bone thickness. In the work described in this article, we tested so-called multiridge-based analysis, based on the crazy climber algorithm and short-time Fourier transform, for assessment of the FFGW component recorded by a clinical array transducer featuring a limited number of elements. Methods included numerical finite-element simulations and experiments in bone phantoms and human radius specimens (n = 41). The proposed approach enabled extraction of the FFGW component and determination of its group velocity. This group velocity was in good agreement with theoretical predictions and possessed reasonable sensitivity to cortical width (r(2) = 0.51, p < 0.001) in the in vitro experiments. It is expected that the proposed approach enables related clinical application. Further work is still needed to analyze in more detail the challenges related to the impact of the overlying soft tissue. PMID- 23643060 TI - Ultrasound elastographic evaluation in the diagnosis of carpal tunnel syndrome: initial findings. AB - The purpose of this study was to investigate ultrasound (US)- and US elastography detected changes in the median nerve of patients with carpal tunnel syndrome (CTS). Seventy-four wrists of 41 female patients with CTS (mean age, 47.73 +/- 11.45 y) and 45 wrists of 24 asymptomatic female controls (mean age, 42.83 +/- 10.66 y) were examined with US and US elastography. Electromyography results confirmed the diagnosis of CTS in the patients. The mean median nerve perimeter (MN-P = 15.26 +/- 2.18 mm) and median nerve cross-sectional area (MN-CSA = 11.81 +/- 4.05 mm2) of patients with CTS were higher than those of controls (12.08 +/- 1.54 mm and 7.76 +/- 1.40 mm2, respectively) (p < 0.05). Mean tissue strain was lower in the patients with CTS (0.094 +/- 0.045 than in the controls (0.145 +/- 0.068) (p < 0.05). The most sensitive cut-off value for tissue strain was 0.0635, and the most specific was 0.19. US and US elastography, in addition to electromyography, proved to be beneficial in the diagnosis of CTS. US elastography is a new technique that may well find a place in the diagnosis of nerve entrapment syndromes. PMID- 23643056 TI - Acoustic waves in medical imaging and diagnostics. AB - Up until about two decades ago acoustic imaging and ultrasound imaging were synonymous. The term ultrasonography, or its abbreviated version sonography, meant an imaging modality based on the use of ultrasonic compressional bulk waves. Beginning in the 1990s, there started to emerge numerous acoustic imaging modalities based on the use of a different mode of acoustic wave: shear waves. Imaging with these waves was shown to provide very useful and very different information about the biological tissue being examined. We discuss the physical basis for the differences between these two basic modes of acoustic waves used in medical imaging and analyze the advantages associated with shear acoustic imaging. A comprehensive analysis of the range of acoustic wavelengths, velocities and frequencies that have been used in different imaging applications is presented. We discuss the potential for future shear wave imaging applications. PMID- 23643061 TI - Effects of biophysical parameters in enhancing radiation responses of prostate tumors with ultrasound-stimulated microbubbles. AB - We show here that ultrasound-stimulated microbubbles can enhance cell death within tumors when combined with radiation. The aim of this study was to investigate how different ultrasound parameters, different microbubble concentrations and different radiation doses interact to enhance cell death. Prostate xenograft tumors (PC-3) in severe combined immunodeficiency mice were subjected to ultrasound treatment at various peak negative pressures (250, 570 and 750 kPa) at a center frequency of 500 kHz, different microbubble concentrations (8, 80 and 1000 MUL/kg) and different radiation doses (0, 2 and 8 Gy). Twenty-four hours after treatment, tumors were excised and assessed for cell death. Histologic analyses revealed that increases in radiation dose, microbubble concentration and ultrasound pressure promoted apoptotic cell death and disruption within tumors by as much as 21%, 30% and 43%, respectively. Comparable increases in ceramide, a cell death mediator, were identified using immunohistochemistry. We also show here that even clinically used microbubble concentrations combined with ultrasound can induce significant enhancement of cell death. PMID- 23643063 TI - Elopement - missing in action. PMID- 23643062 TI - Enhanced intracellular delivery of a model drug using microbubbles produced by a microfluidic device. AB - Focal drug delivery to a vessel wall facilitated by intravascular ultrasound and microbubbles holds promise as a potential therapy for atherosclerosis. Conventional methods of microbubble administration result in rapid clearance from the bloodstream and significant drug loss. To address these limitations, we evaluated whether drug delivery could be achieved with transiently stable microbubbles produced in real time and in close proximity to the therapeutic site. Rat aortic smooth muscle cells were placed in a flow chamber designed to simulate physiological flow conditions. A flow-focusing microfluidic device produced 8 MUm diameter monodisperse microbubbles within the flow chamber, and ultrasound was applied to enhance uptake of a surrogate drug (calcein). Acoustic pressures up to 300 kPa and flow rates up to 18 mL/s were investigated. Microbubbles generated by the flow-focusing microfluidic device were stabilized with a polyethylene glycol-40 stearate shell and had either a perfluorobutane (PFB) or nitrogen gas core. The gas core composition affected stability, with PFB and nitrogen microbubbles exhibiting half-lives of 40.7 and 18.2 s, respectively. Calcein uptake was observed at lower acoustic pressures with nitrogen microbubbles (100 kPa) than with PFB microbubbles (200 kPa) (p < 0.05, n > 3). In addition, delivery was observed at all flow rates, with maximal delivery (>70% of cells) occurring at a flow rate of 9 mL/s. These results demonstrate the potential of transiently stable microbubbles produced in real time and in close proximity to the intended therapeutic site for enhancing localized drug delivery. PMID- 23643064 TI - The patient experience of musculoskeletal therapy. PMID- 23643065 TI - Editors' response. PMID- 23643066 TI - Faecalibacterium prausnitzii upregulates regulatory T cells and anti-inflammatory cytokines in treating TNBS-induced colitis. AB - BACKGROUND AND AIMS: Faecalibacterium prausnitzii (F. prausnitzii) is a common anaerobic bacteria colonized in the human gut and inflammatory bowel disease (IBD) patients are usually lack of F. prausnitzii. The aims of this study were to evaluate the anti-inflammatory and immunomodulatory capacity of F. prausnitzii by comparing it with Bifidobacterium longum (B. longum) in both cellular and animal experiments. METHODS: Human peripheral blood mononuclear cells (PBMCs) and 2, 4, 6-trinitrobenzenesulphonic acid (TNBS)-induced colitis rat models were treated with F. prausnitzii, B. longum, F. prausnitzii supernatant or F. prausnitzii medium, respectively. Interleukin (IL)-10, TGF-beta1 and IL-12p70 in human PBMCs culture supernatant and rat blood serum were detected. The frequency of CD25(+)Foxp3(+)Treg in human PBMCs, rat PBMCs and rat splenocytes were investigated. Besides, the T-bet, GATA-3, ROR-gammat and Foxp3 mRNA in human PBMCs, histopathologic characteristics of the intestinal mucosal and weight loss in the rat models were examined. RESULTS: F. prausnitzii, B. longum and F. prausnitzii supernatant clearly facilitated the induction of IL-10 and TGF-beta1, while induced relatively mild production of IL-12p70 in both cellular and animal models. The F. prausnitzii, B. longum and supernatant differed in their capacity to induce T-bet, GATA-3 and ROR-gammat mRNA expression in human PBMCs (both bacterial strains inhibited the expression of ROR-gammat while supernatant inhibited the T-bet and GATA-3). However, all of them induced the Foxp3 and Treg production and ameliorated the TNBS-induced colitis. In addition, F. prausnitzii supernatant exhibited the supreme anti-inflammatory capacity. CONCLUSIONS: F. prausnitzii and its unidentified metabolites in the supernatant are promising candidates in treating IBD, and further research remains necessary to elucidate the safety, efficacy, optimum and mechanism of this bacterium in the clinical practice. PMID- 23643067 TI - Parenteral vs oral iron in patients with inflammatory bowel disease: quantifying information size by trial sequential analysis. PMID- 23643068 TI - A new form of rodent placentation in the relict species, Laonastes aenigmamus (Rodentia: Diatomyidae). AB - INTRODUCTION: The Laotian rock rat is a relict species in a sister group relationship to hystricognath rodents (Hystricognathi). We asked whether there were similarities in placentation that might reflect this relationship or differences that might cast light on the evolution of Hystricognathi. METHODS: We examined the reproductive tract of nonpregnant (n = 5), early (n = 3) and mid to late gestation (n = 2) females. Selected characters were mapped to a phylogenetic tree to examine their evolution in rodents. RESULTS: The chorionic placenta was discoid and labyrinthine with a spongy zone but without internal lobes. The interhemal region was hemodichorial with syncytiotrophoblast lining maternal blood spaces and an inner layer of vacuolated cytotrophoblast. There was no subplacenta. The yolk sac was well developed with a villous portion that faced the placental disk but no fibrovascular ring. There was a single fetus that very likely would be precocial at birth. DISCUSSION: A lobulated labyrinth and the presence of a subplacenta and a fibrovascular ring emerged as synapomorphies for Hystricognathi. Laonastes, Ctenodactylus and stem Hystricognathi all had precocial young, whereas altriciality was the plesiomorphic condition for rodents. A hemomonochorial interhemal region was plesiomorphic for rodents and Hystricognathi, and the hemodichorial condition found in Laonastes, and possibly in Ctenodactylus, was unlike that of any rodent studied to date. CONCLUSION: Similar to Hystricognathi, Laonastes bears precocial young, but this species lacks placental adaptations such as the subplacenta, suggesting they were evolved subsequent to a change in reproductive strategy in the common ancestor of Laonastes and Hystricognathi. PMID- 23643070 TI - Mission impossible: how HPV-associated head and neck cancers escape a primed immune response. PMID- 23643069 TI - Enrichment in c-Kit+ enhances mesodermal and neural differentiation of human chorionic placental cells. AB - OBJECTIVE: Human term placenta (HTP) has attracted increasing attention as an alternative source of stem cells for regenerative medicine since the amniochorionic membrane harbors stem cells populations that are easily accessible, abundantly available without ethical objections. In the chorionic side of HTP we found a progenitor perivascular "niche" in which rare cells co express Oct-4 and c-Kit. We investigated the stem cell characteristics and differentiation potential of a chorionic derived population enriched in c-Kit(+) cells and compared this to the unenriched population. STUDY DESIGN: Cells, isolated from the chorion of HTP, were expanded and enriched in c-Kit(+) cells (Chorionic Stem Cells-CSC). Histological staining, immunofluorescence, Western blot and flow cytometry were used to verify the stem cells characteristics of the populations and to compare the differentiation capability towards mesodermal and neural lineages in vitro. RESULTS: The expression of the pluripotent marker Oct-4 was greater in the CSCs compared to the unselected cells (Chorionic Cell-CC) but both Oct-4 and c-Kit expression decreased during passages. After differentiation, CSC displayed stronger chondrogenic and osteogenic potential and a greater adipogenic forming capacity compared to unselected ones. CSC differentiated better into immature oligodendrocytes while CC showed a neuronal progenitor differentiation potential. Moreover, both populations were able to differentiate in hepatogenic lineage. CONCLUSION: CSC display improved Oct-4 expression and a high differentiation potential into mesodermal lineages and oligodendrocytes. PMID- 23643071 TI - Vitamin E attenuates homocysteine and cholesterol induced damage in rat aorta. AB - BACKGROUND: The aim of this study was to investigate the effect of vitamin E on homocysteine and cholesterol-induced damage of rat aorta. METHODS: Wistar rats (all fed with a vitamin E poor diet) were divided into five groups. Control group was fed with the diet only, the second group received 1 mg kg(-1) day(-1) L methionine in drinking water, the third group was fed with 2% cholesterol containing diet, the fourth group received L-methionine and cholesterol together, and the fifth group was fed with L-methionine and cholesterol and received intramuscular injections of vitamin E. After 4 weeks serum homocysteine, cholesterol and vitamin E levels were measured; aortas were removed; collagen and elastin and the major extracellular matrix components were evaluated microscopically as indicators of aortic degeneration. Aortic collagen content was measured by a colorimetric hydroxyproline assay. RESULTS: Four-week diet supplementation with methionine and cholesterol caused a twofold increase in serum homocysteine and 22% increase in serum cholesterol levels; endothelial damage and degenerative alterations in the aortic media were observed, as indicated by the dissociation of elastic fibers and accumulation of collagen. Vitamin E completely prevented the accumulation of collagen and largely prevented aorta damage as shown by the morphological data. CONCLUSION: The results indicate that, even moderate increases in homocysteine and cholesterol levels are sufficient to induce vascular degeneration that may be prevented by vitamin E supplementation. PMID- 23643072 TI - Prospects for research and clinical medicine in sleep bruxism. PMID- 23643074 TI - [Inhibitory effect of NaV1.9 gene silencing on proliferation, phagocytosis and migration in RAW264.7 cells]. AB - OBJECTIVE: To establish the cell line with stable voltage-gated sodium channels (VGSCs/NaVs) alpha subunit NaV1.9 gene silencing through RNA interference (RNAi) in murine RAW264.7 macrophages, and to investigate proliferation, phagocytosis and migration in this cell line. METHODS: The stable NaV1.9-deficient cell line was generated by selection in G418 after the transfection of short hairpin (shRNA) plasmid with Lipofectamine TM2000. RNAi efficiency was qualified by RT PCR; proliferation ability was measured by CCK-8 assay; cell cycle and phagocytic ability were analyzed by flow cytometry; and migrating ability was detected by Transwell migration assay. RESULTS: Stable NaV1.9-deficient cell line was established and the expression of NaV1.9 was reduced by 80%. CCK-8 assay and flow cytometry showed that the proliferation of the NaV1.9-deficient cell line was inhibited (P<0.05). Flow cytometry revealed that phagocytic ability was reduced in the cell line (P<0.05). Transwell migration assay demonstrated that migrating ability was depressed in the cell line (P<0.05). CONCLUSION: In the stable NaV1.9 deficient cells we successfully constructed, proliferation, phagocytosis and migration were obviously inhibited. PMID- 23643075 TI - [Secretion of Th1-type cytokines and production of HBV-specific cytotoxic T lymphocytes in C57BL/6 mice induced by cytoplasmic transduction peptide-HBcAg18 27-Tapasin]. AB - OBJECTIVE: To observe whether the fusion protein of cytoplasmic transduction peptide (CTP)-HBcAg18-27;-Tapasin could induce Th1-type cytokine secretion and expression of hepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTL) in C57BL/6 mice. METHODS: C57BL/6 mice were randomly divided into 4 groups, with 5 mice in each group. The mice of 4 groups were intramuscularly injected with the fusion protein CTP-HBcAg18-27;-Tapasin, CTP-HBcAg18-27;, HBcAg18-27;-Tapasin (50 MUg) and normal saline, respectively. The levels of cytokines secreted by T lymphocytes were detected by ELISA and intracellular cytokine of proliferative T cells by flow cytometry. The proliferation of T lymphocytes was observed using CCK-8 assay. RESULTS: CTP-HBcAg18-27;-Tapasin not only induced significantly T lymphocyte proliferation, but also increased the production of cytokines (IFN gamma, IL-2) compared with CTP-HBcAg18-27; or HBcAg18-27;-Tapasin alone or normal saline. Moreover, CTP-HBcAg18-27;-Tapasin fusion protein increased significantly the percentages of IFN-gamma(+);CD8(+); T cells. CONCLUSION: The CTP-HBcAg18-27; Tapasin fusion protein can effectively stimulate the secretion of Th1-type cytokines, induce T lymphocyte proliferation and increase the expression of HBV specific CTLs in C57BL/6 mice. PMID- 23643073 TI - Age at onset and clinical correlates in body dysmorphic disorder. AB - OBJECTIVE: Age at onset is an important clinical feature of all disorders. However, no prior studies have focused on this important construct in body dysmorphic disorder (BDD). In addition, across a number of psychiatric disorders, early age at disorder onset is associated with greater illness severity and greater comorbidity with other disorders. However, clinical correlates of age at onset have not been previously studied in BDD. METHODS: Age at onset and other variables of interest were assessed in two samples of adults with DSM-IV BDD; sample 1 consisted of 184 adult participants in a study of the course of BDD, and sample 2 consisted of 244 adults seeking consultation or treatment for BDD. Reliable and valid measures were used. Subjects with early-onset BDD (age 17 or younger) were compared to those with late-onset BDD. RESULTS: BDD had a mean age at onset of 16.7 (SD=7.3) in sample 1 and 16.7 (SD=7.2) in sample 2. 66.3% of subjects in sample 1 and 67.2% in sample 2 had BDD onset before age 18. A higher proportion of females had early-onset BDD in sample 1 but not in sample 2. On one of three measures in sample 1, those with early-onset BDD currently had more severe BDD symptoms. Individuals with early-onset BDD were more likely to have attempted suicide in both samples and to have attempted suicide due to BDD in sample 2. Early age at BDD onset was associated with a history of physical violence due to BDD and psychiatric hospitalization in sample 2. Those with early onset BDD were more likely to report a gradual onset of BDD than those with late onset in both samples. Participants with early-onset BDD had a greater number of lifetime comorbid disorders on both Axis I and Axis II in sample 1 but not in sample 2. More specifically, those with early-onset BDD were more likely to have a lifetime eating disorder (anorexia nervosa or bulimia nervosa) in both samples, a lifetime substance use disorder (both alcohol and non-alcohol) and borderline personality disorder in sample 1, and a lifetime anxiety disorder and social phobia in sample 2. CONCLUSIONS: BDD usually began during childhood or adolescence. Early onset was associated with gradual onset, a lifetime history of attempted suicide, and greater comorbidity in both samples. Other clinical features reflecting greater morbidity were also more common in the early-onset group, although these findings were not consistent across the two samples. PMID- 23643076 TI - [Mechanism of hematopoietic stem/progenitor cell aging induced by radiation damage]. AB - OBJECTIVE: To explore the mechanism underlying the aging of hematopoietic stem/progenitor cells (HSC/HPC) induced by radiation stress. METHODS: Male C57BL/6J mice were divided randomly into radiation group and control group. The radiation group were treated with total 6.5 Gy X-ray radiation for 24 h; the control group received the same treatment except radiation. Thereafter, Sca 1(+);HSC/HPC were isolated by magnetic-activated cell sorting (MACS) from bone marrow of all the mice. The distributions of cell cycle were tested by flow cytometry. The percentage of aging cells was detected by SA-beta-Gal staining. The potentials of self-renewal and multi-differentiation were measured by CFU-Mix assay. DNA damages of Sca-1(+);HSC/HPC were analyzed by single cell gel electrophoresis technique (SCGE). The expressions of senescence-associated genes p16(INK4a);, p19(Arf);, p53, p21(Cip1/Waf1); mRNA were detected by RT-PCR. Western blotting was performed to analyze the expressions of p16(INK4a); and p21(Cip1/Waf1); proteins. RESULTS: The purity of Sca-1(+);HSC/HPC reached 94% after MACS. Compared with control group cells, after radiation, the number of Sca 1(+);HSC/HPC per femur and CFU-Mix sharply decreased (P<0.05), Sca-1(+);HSC/HPC apparently showed G1 arrest and elevated percentage of SA-beta-Gal positive cells (P<0.05), cell trailing had a prolonged time, and the expressions of senescence associated genes (p16(INK4a);, p19(Arf);, p53, p21(Cip1/Waf1);) and relevant proteins (p16(INK4a);, p21(Cip1/Waf1);) were up-regulated significantly (P<0.05). CONCLUSION: DNA damage and senescence-associated biological changes of Sca 1(+);HSC/HPC can be achieved by X-ray radiation, which may be involved in p16(INK4a);-Rb and p19(Arf);-p53-p21(Cip1/Waf1); signal pathways. PMID- 23643077 TI - [Inhibitory effect of Sirt3 on proliferation of vascular smooth muscle cells induced by angiotensin II]. AB - OBJECTIVE: To detect the expression of Sirtuin3 (Sirt3) in mice vascular smooth muscle cells (VSMCs) and explore the effect of Sirt3 on VSMCs proliferation induced by angiotensin II (AngII). METHODS: The mRNA and protein expressions of Sirt3 in wild C57 mice VSMCs were assessed by RT-PCR and Western blotting, respectively. After the cells were exposed to various concentrations of AngII (10(-7);, 10(-6);, 10(-5); mol/L), the mRNA and protein expressions of Sirt3 were assessed again in the same way. The effect of Sirt3 on cell proliferation was observed with Edu (5-ethynyl -2'-deoxyuridine) kit after Sirt3 silencing by small interference RNA. RESULTS: Sirt3 was stably expressed in C57 mice VSMCs as revealed by Western blotting and RT-PCR, respectively. A significant increase was found in the mRNA and protein expressions of Sirt3 (P<0.01) after the stimulation of all the three different concentrations of AngII, particularly the 10(-6); mol/L group with the highest increase of Sirt3 expression, and there was a significant difference between the 10(-6); mol/L group and the other groups (P<0.05). The rate of cell proliferation in Sirt3 SiRNA group increased obviously compared to the control group (P<0.01), and the rate in the Sirt3 SiRNA+AngII group was also elevated significantly compared to the AngII group (P<0.01). CONCLUSION: The expression of Sirt3 is stable in VSMCs; AngII can elevate the mRNA and protein expression of Sirt3 and promote the cell proliferation, what's more, Sirt3 silencing would further increase the cell proliferation. PMID- 23643078 TI - [Preparation and knockdown efficiency evaluation of shRNA expressing lentiviral vector targeting B7-H1]. AB - OBJECTIVE: To design and package shRNA expressing lentiviral particles targeting B7-H1, and evaluate their inhibitory effect on B7-H1 expression in U251 cells. METHODS: Three shRNAs targeting B7-H1 was designed and the sense and antisense primers were produced by chemical synthesis. After annealing, they were linked into restriction enzyme digested pLKO.1 vector. Confirmed by DNA sequencing, the lentiviral particles were packaged and applied to infect U251 cells. qRT-PCR and Western blotting were used to detect the B7-H1 mRNA and protein levels respectively. RESULTS: qRT-PCR and Western blotting showed that two of the three shRNAs effectively knocked-down B7-H1 expression in U251 cells. CONCLUSION: The packaged lentiviral particles can specifically inhibit B7-H1 expression, which will be helpful for further functional study on B7-H1. PMID- 23643079 TI - [Myocardial regeneration was promoted by injected Oct4 adenovirus eukaryotic expression vector]. AB - OBJECTIVE: To construct octamer-binding transcription factor-4 (Oct4) adenoviruse eukaryotic expression vector pAV.Ex1d.-CMV>mOCT4/IRES/eGFP, and study its effect on myocardial regeneration in mice. METHODS: We constructed eukaryotic expression vector pAV.Ex1d.-CMV>mOCT4/IRES/eGFP using Gateway(R);technology and then packaged the vector with adenoviruses. After adenovirus packaging, the vector was injected into the mouse myocardium by microsyringe. The expression of Oct4 was determined by the methods of immunofluorescence and RT-PCR, and hematoxylin-eosin (HE) staining was used to detect whether the myocardial tissue was changed after the expression of Oct4. We also constructed mouse myocardial infarction model and identified the infarct area using HE staining for injecting the Oct4 adenovirus vector into the area surrounding the infarct area, Four weeks later, we detected the expression of cardiac troponin T in the infact area by Western blotting. RESULTS: Immunofluorescence showed red fluorescence indicating that Oct4 was expressed in the myocardial cell nucleus, but it could not be detected in the control group and the the control virus group. RT-PCR also proved the expression of Oct4 in Oct4 adenovirus vector group but not in the control virus group and the control group. There was no pathological changes in the myocardial tissues after Oct4 was expressed in vivo. Four weeks after the adenovirus vector was injected around the infarct area, the expression level of cardiac troponin T in Oct4 group was significantly different from that in the control group or the control empty virus group (P<0.5). CONCLUSION: Exogenous Oct4 can be expressed in the mature myocardial tissues in vivo and promote myocardial regeneration. PMID- 23643080 TI - [The reduced pulmonary function is related to the decreased expression of Treg and Foxp3 in adjuvant-induced arthritis rats]. AB - OBJECTIVE: To observe changes of pulmonary function, regulatory T cells (Treg), forkhead transcription factor protein 3 (Foxp3) in adjuvant-induced arthritis (AA) rats, and explore the roles of Treg and Foxp3 expression in immunological mechanisms of AA. METHODS: Thirty rats were randomly divided into normal control (NC) group and model control (MC) group, with 15 in each. The rats of MC group were induced by intracutaneous injection of 0.1 mL complete Freund's adjuvant in the right posterior paw. After 30 d, we observed the changes of the toe swelling degree, arthritis index. Pulmonary function was detected by animal spirometry, Treg in the peripheral blood by flow cytometry, and Foxp3 mRNA and protein by RT PCR, immunohistochemistry, Western blotting, respectively. RESULTS Compared with the NC group, the toe swelling degree and arthritis index significantly increased, and the parameters of pulmonary function, CD4(+);CD25(+); Treg, CD4(+);CD25(+);FoxP3(+); Treg, Foxp3 mRNA and protein levels decreased in the MC group (P<0.01 or P<0.05). CONCLUSION: AA rats suffer from reduced pulmonary function and immune dysfunction, which may be related to the decreased expressions of Treg and Foxp3. PMID- 23643081 TI - [Establishment of hepatic stem cell line stably expressing HBx protein and the effect of HBx on cell proliferation]. AB - OBJECTIVE: To establish HP14.5 cell line stably expressing hepatitis B virus X (HBx) and detect the effect of HBx on cell proliferation, cell cycle and the wnt/beta-catenin signal pathway of hepatic progenitor cells. METHODS: The plasmid of pSEB-Flag-HBx and the packaging plasmid pAmpho were co-transfected into HEK 293T cells to construct the recombinant retrovirus carrying HBx gene. The recombinant retrovirus wan then transfected into mouse hepatic progenitor cells HP14.5. The blasticidin-resistant clones of HBx cells (HP14.5/HBx) were selected out and cultured as the experimental group, paralleled with the vector control HP14.5/Rv (HP14.5/pSEEB-Flag) and HP14.5 cell as negative control. The cell proliferation was tested by MTS assay, the cell cycle was measured by flow cytometry, the expression levels of cyclin D1 and c-myc mRNA were tested by real time PCR, and the expression leveIs of HBx, cyclin D1, c-myc, GSK3beta, p GSK3beta (ser-9), beta-catenin proteins were examined by Western blotting. RESULTS: The expression of HBx at both mRNA and protein levels was positive in HP14.5/HBx cell line as confirmed by RT-PCR and Western blotting. Compared with the control groups, the proliferation of HP14.5/HBx cells increased significantly (P<0.05), and the expression level of cyclin D1 and c-myc mRNA rose significantly(P<0.05). G1-phase cell proportion was reduced while the proportion in S and G2 phases went up significantly (P<0.05). The expression levels of cyclin D1, c-myc, beta-catenin and p-GSK3beta (ser-9) proteins increased significantly (P<0.05)except GSK3beta (P>0.05). CONCLUSION: The hepatic stem cell line stably expressing HBx has been constructed successfully. HBx can promote the proliferation and malignant transformation of hepatic stem cells via the activation of Wnt/beta-catenin signal pathway. PMID- 23643082 TI - [Construction and identification of mouse BTLA lentiviral expression vector]. AB - OBJECTIVE: To construct and identify a lentiviral vector for mBTLA (mouse B and T lymphocyte attenuator) expression. METHODS: The entire coding sequence of mBTLA gene was amplified from pET-28a-mBTLA plasmid, and then mBTLA gene was transferred into pMD18-T plasmid before cloning into a lentiviral transfer vector. Liposome was used to package lentiviral particles in 293T cells. After lentiviral particles packaging, morphological changes of 293T cells were observed by fluorescence microscope. The recombinant plasmid was identified using RT-PCR and sequencing. Lentiviral titer was detected by 50% tissue culture infectious dose (TCID50;) assay. RT-PCR and Western blotting were used to detect mBTLA mRNA and protein expression. RESULTS: pMD18-T-mBTLA and pSL6-mBTLA plasmids were successfully constructed and digested for electrophoresis appearing a near 1 kb strip which matched the size of mBTLA coding sequence. Gene sequencing and alignment analysis further confirmed mBTLA coding sequence to be successfully integrated into the plasmid vector. Morphological observation and supernatant PCR amplification of 293T cells confirmed that Lenti-mBTLA lentiviral packaging was successful, and the Lenti-mBTLA lentiviral titer was 1.3*10(8); pfu/mL. RT-PCR and Western blotting demonstrated that the Lenti-mBTLA vector could effectively express mBTLA mRNA and protein. CONCLUSION: The lentiviral vector which can effectively express mBTLA mRNA and protein has been successfully constructed. PMID- 23643083 TI - [The roles of C5a and C5aR antagonist in TNF-alpha secretion and CD88 expression of BV2 microglial cells treated with Abeta1-42 oligomer]. AB - OBJECTIVE: To investigate the role of C5a in the release of TNF-alpha from microglial cells and its related mechanism, and identify the intervention effect of C5aR antagonist (C5aRA) in the pathological change of Alzheimer's disease (AD). METHODS: Soluble Abeta1-42 oligomer was prepared, identified by atomic force microscopy. Then Abeta1-42 oligomer alone, or in a combination with different levels of C5a, C5aRA, or C5a+C5aRA was used to treat cultured BV2 cells. The non-treated BV2 cells served as controls. ELISA was used to detect the concentration of TNF-alpha, and flow cytometry to analyze the expression of C5a receptor (CD88). RESULTS: Abeta1-42 oligomer significantly stimulated BV2 cells to release TNF-alpha and CD88, compared to the control group (P<0.05 and P<0.01, respectively). C5a further increased the release of TNF-alpha (P<0.05 vs Abeta1 42 group). In contrast, C5aRA inhibited remarkably the release of TNF-alpha stimulated by Abeta1-42 (P<0.01). Nevertheless, C5a or C5aRA didn't show a significant effect on the expression of CD88 in BV2 cells that was elevated by Abeta1-42 treatment (P>0.05). CONCLUSION: C5a promotes the release of TNF-alpha from microglial cells; Abeta1-42 can further boost the release and C5aRA can inhibite TNF-alpha secretion of microglial cells significantly. PMID- 23643084 TI - [Prokaryotic expression, purification and antigenicity identification of human renal cell carcinoma-associated antigen G250]. AB - OBJECTIVE: To amplify human renal cell carcinoma (RCC)-associated antigen G250 gene and construct a recombinant plasmid pET-42a-hG250, express and purify human G250 protein and identify its antigenicity. METHODS: The gene of human G250 was amplified from pGEM-T-G250 by PCR. After sequencing, the PCR product (112-1242 bp) was cloned into pET-42a prokaryotic expression vector to construct the recombinant plasmid pET-42a-hG250. The plasmid was transformed into BL21 (DE3) and human G250 protein was expressed under the induction of IPTG. The fusion protein was purified and identified by SDS-PAGE, Western blotting and ELISA sequentially. RESULTS: The human G250 prokaryotic expression vector pET-42a-hG250 was successfully constructed as confirmed by enzyme digestion and DNA sequencing. After transformation into BL21 (DE3), the target protein was successfully induced to express and purified as expected. Western blotting and ELISA demonstrated that the purified human G250 protein had a desirable immunogenicity. CONCLUSION: The recombinant prokaryotic expression vector pET-42a-hG250 has been constructed successfully. The purified human G250 protein has a good antigenicity. PMID- 23643085 TI - [Effect of AKR1A1 knock-down on H2;O2; and 4-hydroxynonenal-induced cytotoxicity in human 1321N1 astrocytoma cells]. AB - OBJECTIVE: To investigate the role of human aldo-keto reductase 1A1 (AKR1A1) in the resistance to oxidative stress and the metabolism of toxic aldehyde in astrocytoma cells. METHODS: The siRNA was transfected into 1321N1 astrocytoma cells using Lipofectamine(TM); RNAiMax. Western blotting and qRT-PCR were applied to evaluate the knock-down efficiency of AKR1A1. MTT assay was used to examine the cell viability after H2;O2; and 4-hydroxynonenal treatment in AKR1A1 knock down cells. In addition, the effect of knocking down AKR1A1 on cellular reactive oxygen species (ROS) level in the presence of H2;O2; was measured using 2', 7' dichlorofluorescein (DCFH-DA). RESULTS: Western blotting and qRT-PCR showed that the AKR1A1-specific siRNA inhibited AKR1A1 gene expression by about 70% in 1321N1 cells. Cells with knock-down of AKR1A1 were more sensitive to H2;O2; and 4 hydroxynonenal-induced cytotoxicity. Furthermore, cellular ROS level in the cells with knock-down of AKR1A1 was much higher than that in the control cells in the presence of H2;O2;. CONCLUSION: The specific siRNA could efficiently inhibit AKR1A1 expression in 1321N1 cells. AKR1A1 could be involved in the metabolism of 4-hydroxynonenal and play a role in the resistance to oxidative stress. PMID- 23643086 TI - [Identification of the epitope of von Willebrand factor recognized by monoclonal antibody SZ-125 with immune-affinity mass spectrometry]. AB - OBJECTIVE: To identify the epitope of von Willebrand factor (vWF) recognized by monoclonal antibody SZ-125 (mAb SZ-125) using immune-affinity matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) assay in combination with peptide synthesis and amino acid site-mutagenesis technology. METHODS: Recombinant vWF A3 domain (rVWF A3) was directly affinity bound to SZ 125 antibody beads and proselytized by trypsin. The digested peptide fragments were then measured using MALDI-TOF-MS. The detected peptide sequence by MALDI-TOF MS was synthesized and several amino-acids in it were mutated to test its affinity with mAb SZ-125. RESULTS: The epitope of rVWF A3 recognized by SZ-125 was identified to be the peptide fragment(1001);EGGPSQIGDALGFAVR(1016);. Synthesized peptide NH2;-EGGPSQIGDALGFAVR-COOH could bind to mAb SZ125. RESULTS: of site-directed mutagenesis revealed that amino acids E1001, F1013, V1015 and R1016 played critical roles in the binding between mAb SZ-125 and rVWF A3. CONCLUSION: The epitope of rVWF A3 recognized by mAb SZ-125 has been accurately confirmed using immune-affinity mass spectrometry in combination with peptide synthesis and site-directed mutagenesis of special amino acids. PMID- 23643087 TI - [Comparison of three detection methods for neutralizing antibodies induced by Coxsackievirus A16 vaccine]. AB - OBJECTIVE: To develop a comprehensive detection platform for immunoprotection of inactivated coxsackievirus A16(CA16) vaccine based on the neutralizing antibodies tested through competitive inhibition ELISA, micro-cytopathic effect neutralization test and neonatal mice challenge protection test. METHODS: The female BALB/c mice, SD rats and Hartley guinea pigs were inoculated intraperitoneally at 0, 4, 6, 8 weeks with the three vaccine candidates which were made from 3726, 4430 and 4432 virus absorbed on aluminium adjuvant. Immune sera were taken at 0, 4, 6, 8, 10 weeks and serum neutralizing antibodies were evaluated by competitive inhibition-ELISA, micro-cytopathic effect neutralization test and neonatal mice challenge protection test, respectively. The relationships of the three methods were analyzed by SPSS16.0 statistical software. RESULTS: The level of neutralizing antibodies reached the peak after the second booster. The correlation coefficient was 0.861 between competitive inhibition-ELISA and micro cytopathic effect neutralization test, 0.8 between competitive inhibition-ELISA and neonatal mice challenge protection test and 0.89 between micro-cytopathic effect neutralization test and neonatal mice challenge protection test. CONCLUSION: A comprehensive detection system through competitive inhibition ELISA, micro-cytopathic effect neutralization test and neonatal mice challenge protection test measuring the neutralizing antibodies in immune sera has been constructed. The competitive inhibition-ELISA is superior to "golden standards" in speed, sensitivity, throughput and price, which may have great application prospect. PMID- 23643088 TI - [Effect of GFP-containing lentivirus infection on the expression of octamer transcription factor 4 in human umbilical cord mesenchymal stem cells]. AB - OBJECTIVE: To infect human umbilical cord mesenchymal stem cells (hUCMSCs) with lentivirus carrying green fluorescence protein (GFP) and observe its effect on octamer binding transcription factor 4 (Oct4) expression. METHODS: Mesenchymal stem cells isolated from human umbilical cord by tissue adherence method were cultured and detected for the the surface markers by flow cytometry. HUCMSCs were infected with lentivirus carrying GFP at different multiplicity of infection (MOI). GFP expression efficiency was observed using the fluorescence microscope and flow cytometry to obtain optimal MOI value. The experiment included non transfection group and the GFP transfection group. The effect of GFP lentivirus on cell proliferation was evaluated by MTT. Oct4 expression in hUCMSCs cultured in vitro continuously for 2 and 8 weeks was measured by quantitative reverse transcriptase PCR (qRT-PCR) and immunofluorescence staining. RESULTS: HUCMSCs displayed fusiform shape as fibroblasts in vitro. Flow cytometry revealed that the third-passage cells highly expressed CD29, CD105 and CD90, and lowly expressed CD34 and CD45. At 96 h after infection with GFP lentivirus (MOI=20), GFP positive rate of hUCMSCs was more than 75%, the highest level. MTT showed nearly no change in cell proliferation in the transfected group in comparison with the non-transfection group (P>0.05). The relative expression of Oct4 detected by qRT-PCR in cells cultured for 2 and 8 weeks were 0.9075+/-0.0124 and 0.8600+/-0.0135, respectively. Immunofluorescence staining showed that Oct4 expression was localized in the nucleus of cells. CONCLUSION: Lentivirus-mediated GFP gene can be expressed in hUCMSCs and has no significant effect on the expression of Oct4. PMID- 23643089 TI - [Expression of PCAF in hepatocellular carcinoma and its clinical significance]. AB - OBJECTIVE: To investigate the expression of P300/CBP-associated factor (PCAF) in hepatocellular carcinoma (HCC) and its clinical significance. METHODS: Immunohistochemistry was performed to evaluate the expression of PCAF in HCC tissues and adjacent normal liver tissues of 35 HCC patients. We analyzed the correlation between the expression of PCAF and clinical data using chi-square test, and then anaylzed the factors which affected survival by Kaplan-Meier Log rank test and multivariate Cox regression model. RESULTS: The expression of PCAF in the HCC tissues was significantly different from that in the adjacent liver tissues (P<0.05) and it was correlated with tumor TNM staging and tumor metastasis (P<0.05). Multivariate COX regression analysis showed that the independent factors predicting poor long-term HCC survival after radical liver resection included low PCAF expression, advanced TNM stage and tumor metastasis. CONCLUSION: PCAF expression is down-regulated in HCC and constitutes a promising biomarker for the prognosis after curative liver resection. PMID- 23643090 TI - [Establishment of recombinant Lac Z reporter gene-transformed yeast cells for bioassay of androgen-like compounds in environment]. AB - OBJECTIVE: To establish the yeast-based bioassay system for the androgenic endocrine disruptors in the environment. METHODS: The recombinant gene transformed yeast cells were constructed based on two episomal vectors. In the expression vector, the expression of androgen receptor (AR) gene was driven by 3 glyceraldehydephosphate dehydrogenase (GPD) promoter and the gene was fused to V5 epitope; in the reporter vector, the expression of the Lac Z gene as a report gene was under the control of the androgen response element (ARE). The vectors were transformed into yeast cells (W303-1A) to construct the yeast-based bioassay system. The sensitivity of this assay system was evaluated by the androgenic compounds (dihydrotestosterone, DHT and testosterone propionate, TP)and the specificity of this system by the estrogenic compounds (17beta-estradiol, estriol, estrone, diethylstilbestrol and ethinyl estradiol). RESULTS: Both DHT and TP yielded a significant dose-effect model with the recombinant gene transformed yeast cells, indicating that this yeast bioassay system has a high sensitivity. Moreover, the assay also exhibited a high specificity in that the yeast cells had no dose-effect relationship with the different concentrations of five estrogens (17beta-estradiol, estriol, estrone, diethylstilbestrol and ethinyl estradiol). CONCLUSION: The recombinant yeast cells could be applied to screen for the androgen-like compounds in the environment. PMID- 23643091 TI - Previously unclassified bacteria dominate during thermophilic and mesophilic anaerobic pre-treatment of primary sludge. AB - Thermophilic biological pre-treatment enables enhanced anaerobic digestion for treatment of wastewater sludges but, at present, there is limited understanding of the hydrolytic-acidogenic microbial composition and its contribution to this process. In this study, the process was assessed by comparing the microbiology of thermophilic (50-65 degrees C) and mesophilic (35 degrees C) pre-treatment reactors treating primary sludge. A full-cycle approach for the 16S rRNA genes was applied in order to monitor the diversity of bacteria and their abundance in a thermophilic pre-treatment reactor treating primary sludge. For the thermophilic pre-treatment (TP), over 90% of the sequences were previously undetected and these had less than 97% sequence similarity to cultured organisms. During the first 83 days, members of the Betaproteobacteria dominated the community sequences and a newly designed probe was used to monitor a previously unknown bacterium affiliated with the genus Brachymonas. Between days 85 and 183, three phylotypes that affiliated with the genera Comamonas, Clostridium and Lysobacter were persistently dominant in the TP community, as revealed by terminal-restriction fragment length polymorphism (T-RFLP). Hydrolytic and fermentative functions have been speculated for these bacteria. Mesophilic pre treatment (MP) and TP communities were different but they were both relatively dynamic. Statistical correlation analysis and the function of closely allied reference organisms indicated that previously unclassified bacteria dominated the TP community and may have been functionally involved in the enhanced hydrolytic performance of thermophilic anaerobic pre-treatment. This study is the first to reveal the diversity and dynamics of bacteria during anaerobic digestion of primary sludge. PMID- 23643093 TI - Apoptosis inducing activity of benzophenanthridine-type alkaloids and 2 arylbenzofuran neolignans in HCT116 colon carcinoma cells. AB - Thirteen compounds belonging to different classes of alkaloids (1-9) and lignans (10-13), isolated from the methanol extract of roots of the African medicinal plant Zanthoxylum capense, were assayed for their ability as apoptosis inducers in HCT116 colon carcinoma cells. The cytotoxicity of these compounds was evaluated in HCT116 colon carcinoma cells by the MTS assay. Out of the tested compounds, three benzophenanthridine alkaloids (1, 4, and 7), a dibenzyl butyrolactone lignan (10), and two 2-arylbenzofuran neolignans (12 and 13) displayed significant cytotoxicity to HCT116 cells, confirmed by the Guava ViaCount viability assay. The selected compounds (1, 4, 7, 10, 12, and 13) were further tested for apoptosis induction activity in HCT116 cells, by evaluation of nuclear morphology following Hoechst staining, and by caspase-3 like activity assays. Morphologic evaluation of HCT116 nuclei following Hoechst staining and fluorescence microscopy revealed that compounds 1, 4, 7, 10, 12, and 13 induced apoptosis in HCT116 colon carcinoma cells, producing similar, or higher, apoptosis levels when compared with 5-fluorouracil (5-FU), the cornerstone cytotoxic used in colon cancer treatment for several decades. In fact, HCT116 cells developed morphological changes characteristic of apoptosis, including chromatin condensation, nuclear fragmentation and formation of apoptotic bodies. Importantly, compounds 4 and 13 at 20 MUM were the most promising in this study, inducing respectively ~11- and 7-fold increases in apoptotic cells as compared to vehicle control, whereas 5-FU increased apoptosis by ~2-fold. Apoptosis induction for compounds 4 and 13 was further confirmed by caspase-3-like activity assays, which showed respectively ~2- and 1.5-fold increases in caspase-3-like activity compared to vehicle control. These results suggested that specific benzophenanthridine alkaloids and 2-arylbenzofuran neolignans isolated from Zanthoxylum capense show strong anticancer activity in HCT116 colon carcinoma cells. PMID- 23643094 TI - Nordihydroguaiaretic acid induces Nrf2 nuclear translocation in vivo and attenuates renal damage and apoptosis in the ischemia and reperfusion model. AB - It has been shown that the pretreatment with nordihydroguaiaretic acid (NDGA), a lignan with direct and indirect antioxidant properties, protects against the ischemia-reperfusion (I/R)-induced renal oxidant damage. Although it has been shown that NDGA induces Nrf2 nuclear translocation in renal epithelial LLC-PK1 cells in culture, it is unknown if NDGA may induce Nrf2 translocation in vivo. In this work was explored if NDGA is able to induce in vivo Nrf2 nuclear translocation in kidneys of rats submitted to uni-nephrectomy (U-NX) or I/R injury. Four groups of male Wistar rats were used: U-NX, NDGA, I/R, and I/R+NDGA. NDGA was injected i.p. (10mg/kg/day) starting 48 h before I/R. Kidney samples were obtained at 3 h of reperfusion after to measure Nrf2 translocation. Additional groups of rats were studied at 24 h of reperfusion to measure histological damage and apoptosis. NDGA was able to induce Nrf2 translocation in vivo in kidneys of rats submitted to both U-NX and I/R injury and to protect against renal histological damage and apoptosis. It is concluded that the pretreatment of NDGA is able to induce in vivo nuclear Nrf2 translocation in kidney of rats suggesting that this may be involved in the renoprotection against I/R. PMID- 23643095 TI - Microbial influence on tolerance and opportunities for intervention with prebiotics/probiotics and bacterial lysates. AB - Epidemiologic studies indicate that microbes and microbial components are associated with protection against chronic inflammatory disease. Consequently, a plethora of clinical approaches have been used to investigate the benefits of a range of microbial products on inflammatory conditions in human trials. Centered particularly on the use of prebiotics, probiotic bacteria, and bacterial lysates in early life, this review provides an overview on clinical approaches aimed at reducing the global burden of allergic disease through primary prevention. Microbial interventions beginning before birth and in early infancy are discussed in the context of underlying mechanisms of oral tolerance and the establishment of gut colonization as a critical early homeostatic influence. We explore both the findings and challenges faced in existing studies with a view toward improving future clinical studies of the application of microbial compounds for the prevention of allergic disease and other inflammatory diseases. PMID- 23643092 TI - Phylogenetic diversity of Rhizobium strains nodulating diverse legume species growing in Ethiopia. AB - The taxonomic diversity of thirty-seven Rhizobium strains, isolated from nodules of leguminous trees and herbs growing in Ethiopia, was studied using multilocus sequence analyses (MLSA) of six core and two symbiosis-related genes. Phylogenetic analysis based on the 16S rRNA gene grouped them into five clusters related to nine Rhizobium reference species (99-100% sequence similarity). In addition, two test strains occupied their own independent branches on the phylogenetic tree (AC86a2 along with R. tibeticum; 99.1% similarity and AC100b along with R. multihospitium; 99.5% similarity). One strain from Milletia ferruginea was closely related (>99%) to the genus Shinella, further corroborating earlier findings that nitrogen-fixing bacteria are distributed among phylogenetically unrelated taxa. Sequence analyses of five housekeeping genes also separated the strains into five well-supported clusters, three of which grouped with previously studied Ethiopian common bean rhizobia. Three of the five clusters could potentially be described into new species. Based on the nifH genes, most of the test strains from crop legumes were closely related to several strains of Ethiopian common bean rhizobia and other symbionts of bean plants (R. etli and R. gallicum sv. phaseoli). The grouping of the test strains based on the symbiosis-related genes was not in agreement with the housekeeping genes, signifying differences in their evolutionary history. Our earlier studies revealing a large diversity of Mesorhizobium and Ensifer microsymbionts isolated from Ethiopian legumes, together with the results from the present analysis of Rhizobium strains, suggest that this region might be a potential hotspot for rhizobial biodiversity. PMID- 23643097 TI - Reply: To PMID 23040367. PMID- 23643096 TI - Serum tryptase determination in patients with acute allergic reactions. PMID- 23643098 TI - Fast and multiresidue determination of twenty glucocorticoids in bovine milk using ultra high performance liquid chromatography-tandem mass spectrometry. AB - Glucocorticoids constitute a class of molecules widely used in animal husbandry. Some of these compounds are licensed for veterinary practices while their use for growth promoting purposes is prohibited within the European Union. In order to ensure the respect of the legislation and consumers safety, several methodologies have been proposed to monitor these substances in various products, including edible matrices for which a regulatory limit has been set up (MRL). An extended range of targeted analytes together with reduced time of analysis and cost are however still current challenges regularly revisited according to the continuous technological improvements. In this context, the aim of the present study was to develop and implement a new fast and multi-residue method based on UHPLC-MS/MS for the determination of twenty glucocorticoids in bovine milk, included the screening of the three regulated MRL compounds (dexamethasone, betamethasone and prednisolone). This validated method authorises such multi-analyte measurement within a 10min runtime while the signal specificity is ensured through the SRM acquisition mode. Decision limits and detection capabilities were calculated in the range of 0.001-0.363MUgL(-1), which allows a very efficient control at low trace level for a potential illegal use of these substances. The performances obtained in terms of application range, selectivity and sensitivity were found to be significantly improved in comparison to other reported approaches either for screening or confirmation purposes: regarding linearity, correlation coefficients were above 0.98 within the range of 0.01-5.0MUgL(-1), repeatability and reproducibility parameters ranged from 1 to 30% with the maximum relative standard deviation (RSD) observed for cortisone (30.1%). Stability of the stock solutions and minor changes in the standard operating procedure have been included for the determination of ruggedness of the method. Identification was systematically ensured according to 4 identification points, RSD of transitions ratio (T2/T1) ranged from 3.2% and 19.3% and the RSD of the retention time was lower than 0.25%. PMID- 23643099 TI - Controlling detrimental effects of metal cations in the quantification of energy metabolites via ultrahigh pressure-liquid chromatography-electrospray-tandem mass spectrometry by employing acetylacetone as a volatile eluent modifier. AB - The majority of energy metabolites involved in glycolysis, the citric acid cycle and the phosphate pentose pathway shows a high affinity for metal cations. In this paper, we demonstrate the negative effect of metal cations on the UHPLC-ESI MS/MS analysis of energy metabolites and suggest acetylacetone (acac) as a volatile, metal-chelating eluent modifier with the potential to remediate these negative effects. For the 52 analytes considered, eluent modification with acac led to significant improvements of almost all analytical figures of merit. Using aqueous standards, peak intensities were increased 2.5-fold on average. In biological matrices (yeast, murine tissue), a 5-fold increase was observed, whereas the number of detectable analytes was increased by 26% from 31 to 39 on average. Limits of detection were improved 4-fold on average (equaling two 1:1 dilution steps), with the most significant improvements seen for efficient metal chelators like citrate (256-fold), salicylate or coenzyme A and acetyl-coenzyme A (16-fold each). The beneficial effect of acac resulted mainly from an increase in averaged column efficiency (number of theoretical plates, N) of 57%. To determine the metal species scavenged by acac, we quantified the metal-acetylacetonate complexes in the UHPLC eluent by ESI-MS/MS. Our results indicate that Al(3+) (342+/-34pM/min leakage into the column effluent) and Fe(3+) (22+/-1pM/min leakage into the column effluent), presumably due to mild corrosion inside the analytical column, are responsible for the detrimental effects alleviated by acac. PMID- 23643100 TI - Derivatization of hydroxyl functional groups for liquid chromatography and capillary electroseparation. AB - The derivatization reactions commonly used to enhance the analytical signal in the HPLC and CE determination of compounds with hydroxyl functional groups are revised. Focus is placed on the determination of compounds having aliphatic alcohols and phenols while lacking other reactive functional groups. The derivatization with acyl chlorides, organic anhydrides, isocyanates and a variety of other approaches, including oxidation of primary and secondary alcohols, sulfonation, esterification with carboxylic acids, and the use of azides, sulfonyl chlorides and other reagents having miscellaneous leaving groups, is covered. Reactions mainly addressed to introduce a chromophore or a fluorophore in the analyte molecule, or to introduce a charge to enhance sensitivity in MS detection, or to enable CE separation are included. Applications related to the industrial quality control of raw materials and manufactured products, and to the evaluation of their environmental impact are emphasized. The problem of the different response factors of the derivatives when complex mixtures of oligomers are derivatized, as occurs with non-ionic surfactants (mainly fatty alcohol ethoxylates) and soluble synthetic polymers, is discussed. Other applications related to the biochemical, biomedical, pharmaceutical, nutritional and toxicological fields are also reviewed. The reactions, the criteria to be applied to select the reagent, and the characteristics of the derivatives in relation to separation and detection, are discussed. PMID- 23643101 TI - Implementing clinical guidelines in stroke: a qualitative study of perceived facilitators and barriers. AB - BACKGROUND: Clinical guidelines are frequently used as a mechanism for implementing evidence-based practice. However research indicates that health professionals vary in the extent to which they adhere to these guidelines. This study aimed to study the perceptions of stakeholders and health professionals on the facilitators and barriers to implementing national stroke guidelines in Ireland. METHODS: Qualitative interviews using focus groups were conducted with stakeholders (n=3) and multidisciplinary team members from hospitals involved in stroke care (n=7). All focus group interviews were semi-structured, using open ended questions. Data was managed and analysed using NVivo 9 software. RESULTS: The main themes to emerge from the focus groups with stakeholders and hospital multidisciplinary teams were very similar in terms of topics discussed. These were resources, national stroke guidelines as a tool for change, characteristics of national stroke guidelines, advocacy at local level and community stroke care challenges. Facilitators perceived by stakeholders and health professionals included having dedicated resources, user-friendly guidelines relevant at local level and having supportive advocates on the ground. Barriers were inadequate resources, poor guideline characteristics and insufficient training and education. CONCLUSIONS: This study highlights health professionals' perspectives regarding many key concepts which may affect the implementation of stroke care guidelines. The introduction of stroke clinical guidelines at a national level is not sufficient to improve health care quality as they should be incorporated in a quality assurance cycle with education programmes and feedback from surveys of clinical practice. PMID- 23643103 TI - Amygdala activation and its functional connectivity during perception of emotional faces in social phobia and panic disorder. AB - Social phobia (SP) and panic disorder (PD) have been associated with aberrant amygdala responses to threat-related stimuli. The aim of the present study was to examine amygdala function and its connectivity with medial prefrontal cortex (mPFC) during emotional face perception in PD and SP, and the role of illness severity. Blood oxygen level dependent responses while perceiving emotional facial expressions were compared in 14 patients with PD, 17 patients with SP, 8 patients with comorbid PD and SP, and 16 healthy controls. We found that PD, but not SP, was associated with amygdala and lingual gyrus hypoactivation during perception of angry, fearful, happy and neutral faces, compared to healthy participants. No significant effect of PD and SP diagnoses was found on amygdala mPFC connectivity. A positive correlation of anxiety symptom severity was found on amygdala-dorsal anterior cingulate and dorsal mPFC connectivity during perception of fearful faces. Amygdala hypoactivation suggests reduced responsiveness to positive and negative emotional faces in PD. Symptom severity, but not the presence of PD and SP diagnosis per se, explains most of the abnormalities in amygdala-mPFC connectivity during perception of fearful faces. PMID- 23643104 TI - Higher risk of developing mood disorders among adolescents with comorbidity of attention deficit hyperactivity disorder and disruptive behavior disorder: a nationwide prospective study. AB - Attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD) are frequently comorbid. Previous studies suggested that the comorbidity of CD and ODD in ADHD may increase the risk of a further development of mood disorder, but most studies had a small sample size. Using a population-based prospective study design, a large sample composed of 1277 adolescents with ADHD-alone, 46 with ADHD + ODD, 87 with ADHD + CD, and 5640 age/gender-matched controls were enrolled in 2003. These cases were followed to 2010 to identify the cases developing unipolar depressive disorder and bipolar disorder. ADHD + CD groups exhibited a higher prevalence of unipolar depressive disorder (23.0% vs. 13.0% vs. 8.7% vs. 0.7%, p < 0.001) and bipolar disorder (3.4% vs. 2.2% vs. 1.3% vs. 0.2%, p < 0.001) than ADHD + ODD group, ADHD-alone group, and control group. Adolescents with ADHD + CD, those with ADHD + ODD, and those with ADHD-alone had a higher likelihood of developing unipolar depressive disorder (hazard ratio [HR]: 44.34, 95% confidence interval [CI]: 23.95-71.36; HR: 18.76, 95%CI: 7.87-44.71; HR: 13.01, 95%CI: 8.99-18.82) and bipolar disorder (HR: 14.39, 95%CI: 4.00-51.80; HR: 8.32, 95%CI: 1.06-65.32; HR: 5.24, 95%CI: 2.44 11.24) than the controls. Adolescents with ADHD had elevated risks of unipolar depression and bipolar disorder in their later life, and especially, those with ADHD and comorbidity of CD or ODD exhibited the highest risk. Further study would be required to evaluate whether prompt intervention for ADHD and disruptive behavior problems would decrease the risk of developing mood disorder. PMID- 23643102 TI - Perceived weight, not obesity, increases risk for major depression among adolescents. AB - This study examined the association between major depression, obesity and body image among adolescents. METHODS: Participants were 4175 youths 11-17 years of age sampled from the community who were interviewed using the Diagnostic Interview Schedule for Children and Adolescents, Version IV, completed a self report questionnaire, and had their weight and height measured. There were 2 measures of body image: perceived weight and body satisfaction. Obesity was associated with increased risk of depression, with no controls for covariates. However, when the association was examined in models which included weight, major depression, and body image measures and covariates, there was no association between major depression and body weight, nor between body satisfaction and major depression. Perceived overweight was strongly and independently associated with body weight (O.R. = 2.62). We found no independent association between major depression and body weight. If there is an etiologic link between major depression and body weight among adolescents, it most likely operates through processes involving components of body image. Future research should focus on the role of depression and body image in the etiology of obesity. PMID- 23643105 TI - Dietary zinc intake and the risk of depression in middle-aged men: a 20-year prospective follow-up study. AB - BACKGROUND: Zinc is an immunomodulatory trace element suggested to be beneficial in the augmentation of antidepressant therapy. Cross-sectional studies have also suggested an association between low dietary zinc and depression. This study examined the association between dietary zinc intake and depression in a prospective setting in initially depression-free men during a 20-year follow-up. METHODS: The study formed a part of the population-based Kuopio Ischemic Heart Disease Risk Factor (KIHD) Study, and comprised 2317 Finnish men aged 42-61 years. Zinc intake was assessed at baseline by a 4-d food record. Baseline depression severity was recorded with the Human Population Laboratory Depression Scale. In the prospective setting, depression was defined as having received a hospital discharge diagnosis of unipolar depressive disorder. Individuals who at baseline had elevated depressive symptoms were excluded (n=283). RESULTS: Altogether, 60 (2.7%) individuals received a hospital discharge diagnosis of depression during the 20-year follow-up. In Cox regression analysis adjusted for age, baseline depression severity, smoking, alcohol use, physical exercise and the use of dietary supplements, belonging to the lowest tertile of energy adjusted zinc intake was not associated with an increased depression risk (RR 1.06, 95% CI 0.59-1.90). LIMITATIONS: These observations may not be generalizable to women, or to individuals with a depression level not warranting hospitalization. CONCLUSIONS: Our findings suggest that a low dietary zinc intake may not longitudinally precede depression in men. Dietary zinc intake may not have relevance for the prevention of depression in middle-aged men with a sufficient dietary zinc intake. PMID- 23643106 TI - Modulation of amygdala response and connectivity in depression by serotonin transporter polymorphism and diagnosis. AB - BACKGROUND: Polymorphisms in the serotonin transporter gene (5-HTTLPR) modulate amygdala activity in healthy individuals. Increased responses to negative stimuli in carriers of low transcription alleles have been proposed to contribute to the pathogenesis of depression. We sought to investigate the effects of genotype as well as diagnosis in patients with depression. METHODS: Subjects with recurrent depression (n=67) and matched healthy controls (n=49) participated in a fMRI task of implicit processing of sad facial stimuli. Effects of biallelic (short (S) and long (L) alleles) and triallelic (including rs25531 A/G single nucleotide variation) models of 5-HTTLPR polymorphisms on amygdala activity and connectivity were investigated. RESULTS: Significant effects were observed of both genotype and diagnosis on amygdala activity. Increased amygdala activity was associated with 5-HTTLPR genotype in low transcription allele carriers as well as with a diagnosis of depression. The connectivity analysis revealed a main effect of genotype with reduced connectivity to the subgenual region of the anterior cingulate in carriers of the low transcription alleles. There was also a main effect of diagnosis with reduced connectivity to the dorsal region of the anterior cingulate and to the dorsolateral prefrontal cortex in depression. There were no interaction effects between genotype and diagnosis in amygdala activity or connectivity. CONCLUSIONS: Significant independent effects of genotype and diagnosis on amygdala responsivity were revealed. The effects of genotype and diagnosis on amygdala connectivity showed a regional segregation, suggesting that 5-HTTLPR polymorphisms bias frontal-limbic connectivity while the development of depression involves more extensive neural disturbances. These findings point to the potential of connectivity maps as a diagnostic biomarker for depression. PMID- 23643107 TI - Two-dimensional and three-dimensional cup coverage in total hip arthroplasty with developmental dysplasia of the hip. AB - We analyzed the mean difference and correlation between 2D cup coverage measured from different projections and three-dimensional (3D) cup coverage to investigate their precise relationship in total hip arthroplasty (THA) among patients with developmental dysplasia of the hip (DDH). We created DDH-THA models on six foam pelvic models. 3D cup coverage was measured using a motion capture system and imaging software. Digitally reconstructed radiographs with predetermined pelvic rotations were simulated using image processing software at three different angles of rotation around the long body axis (0 degrees , 25 degrees and 45 degrees ). 2D cup coverage was then measured on these reconstructed radiographs. The 3D technique showed excellent intra-observer (kappa>0.98) and inter-observer (kappa>0.99) reliability. The 2D technique tended to overestimate the real cup coverage by about 15%. The smallest difference between 2D and 3D cup coverage occurred when 2D measurement was performed on the radiographs with 45 degrees of pelvic rotation toward the operated side (14.50%, P<0.0001), meanwhile, the highest correlation coefficient between 2D and 3D cup coverage was also observed when the 2D measurement was performed on the radiographs at this same pelvic rotation (r=0.67, P=0.0003). Published recommendations regarding the minimum cup coverage based on 2D measurement should be interpreted cautiously. The minimal cup coverage, as an intra-operative 3D parameter related to the long term fixation of the cup component, should be more accurately determined with intra operative measurement. PMID- 23643108 TI - Reducing depression in nursing homes: so little, so late. PMID- 23643109 TI - Exercise for late-life depression? It depends. PMID- 23643110 TI - A structural multidisciplinary approach to depression management in nursing-home residents: a multicentre, stepped-wedge cluster-randomised trial. AB - BACKGROUND: Depression in nursing-home residents is often under-recognised. We aimed to establish the effectiveness of a structural approach to its management. METHODS: Between May 15, 2009, and April 30, 2011, we undertook a multicentre, stepped-wedge cluster-randomised trial in four provinces of the Netherlands. A network of nursing homes was invited to enrol one dementia and one somatic unit per nursing home. In enrolled units, nursing-home staff recruited residents, who were eligible as long as we had received written informed consent. Units were randomly allocated to one of five groups with computer-generated random numbers. A multidisciplinary care programme, Act in Case of Depression (AiD), was implemented at different timepoints in each group: at baseline, no groups were implenting the programme (usual care); the first group implemented it shortly after baseline; and other groups sequentially began implementation after assessments at intervals of roughly 4 months. Residents did not know when the intervention was being implemented or what the programme elements were; research staff were masked to intervention implementation, depression treatment, and results of previous assessments; and data analysts were masked to intervention implementation. The primary endpoint was depression prevalence in units, which was the proportion of residents per unit with a score of more than seven on the proxy-based Cornell scale for depression in dementia. Analyses were by intention to treat. This trial is registered with the Netherlands National Trial Register, number NTR1477. FINDINGS: 16 dementia units (403 residents) and 17 somatic units (390 residents) were enrolled in the course of the study. In somatic units, AiD reduced prevalence of depression (adjusted effect size -7.3%, 95% CI -13.7 to 0.9). The effect was not significant in dementia units (0.6, -5.6 to 6.8) and differed significantly from that in somatic units (p=0.031). Adherence to depression assessment procedures was lower in dementia units (69% [SD 19%]) than in somatic units (82% [15%]; p=0.045). Adherence to treatment pathways did not differ between dementia units (43% [SD 33%]) and somatic units (38% [40%]; p=0.745). INTERPRETATION: A structural approach to management of depression in nursing homes that includes assessment procedures can reduce depression prevalence in somatic units. Improvements are needed in depression screening in dementia units and in implementation of nursing-home treatment protocols generally. FUNDING: The Netherlands Organization for Health Research and Development. PMID- 23643111 TI - Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses. AB - BACKGROUND: On March 30, 2013, a novel avian influenza A H7N9 virus that infects human beings was identified. This virus had been detected in six provinces and municipal cities in China as of April 18, 2013. We correlated genomic sequences from avian influenza viruses with ecological information and did phylogenetic and coalescent analyses to extrapolate the potential origins of the virus and possible routes of reassortment events. METHODS: We downloaded H7N9 virus genome sequences from the Global Initiative on Sharing Avian Influenza Data (GISAID) database and public sequences used from the Influenza Virus Resource. We constructed phylogenetic trees and did 1000 bootstrap replicates for each tree. Two rounds of phylogenetic analyses were done. We used at least 100 closely related sequences for each gene to infer the overall topology, removed suspicious sequences from the trees, and focused on the closest clades to the novel H7N9 viruses. We compared our tree topologies with those from a bayesian evolutionary analysis by sampling trees (BEAST) analysis. We used the bayesian Markov chain Monte Carlo method to jointly estimate phylogenies, divergence times, and other evolutionary parameters for all eight gene fragments. We used sequence alignment and homology-modelling methods to study specific mutations regarding phenotypes, specifically addressing the human receptor binding properties. FINDINGS: The novel avian influenza A H7N9 virus originated from multiple reassortment events. The HA gene might have originated from avian influenza viruses of duck origin, and the NA gene might have transferred from migratory birds infected with avian influenza viruses along the east Asian flyway. The six internal genes of this virus probably originated from two different groups of H9N2 avian influenza viruses, which were isolated from chickens. Detailed analyses also showed that ducks and chickens probably acted as the intermediate hosts leading to the emergence of this virulent H7N9 virus. Genotypic and potential phenotypic differences imply that the isolates causing this outbreak form two separate subclades. INTERPRETATION: The novel avian influenza A H7N9 virus might have evolved from at least four origins. Diversity among isolates implies that the H7N9 virus has evolved into at least two different lineages. Unknown intermediate hosts involved might be implicated, extensive global surveillance is needed, and domestic-poultry-to-person transmission should be closely watched in the future. FUNDING: China Ministry of Science and Technology Project 973, National Natural Science Foundation of China, China Health and Family Planning Commission, Chinese Academy of Sciences. PMID- 23643112 TI - Exercise for depression in elderly residents of care homes: a cluster-randomised controlled trial. AB - BACKGROUND: Depression is common and is associated with poor outcomes among elderly care-home residents. Exercise is a promising low-risk intervention for depression in this population. We tested the hypothesis that a moderate intensity exercise programme would reduce the burden of depressive symptoms in residents of care homes. METHODS: We did a cluster-randomised controlled trial in care homes in two regions in England; northeast London, and Coventry and Warwickshire. Residents aged 65 years or older were eligible for inclusion. A statistician independent of the study randomised each home (1 to 1.5 ratio, stratified by location, minimised by type of home provider [local authority, voluntary, private and care home, private and nursing home] and size of home [<32 or >=32 residents]) into intervention and control groups. The intervention package included depression awareness training for care-home staff, 45 min physiotherapist-led group exercise sessions for residents (delivered twice weekly), and a whole home component designed to encourage more physical activity in daily life. The control consisted of only the depression awareness training. Researchers collecting follow-up data from individual participants and the participants themselves were inevitably aware of home randomisation because of the physiotherapists' activities within the home. A researcher masked to study allocation coded NHS routine data. The primary outcome was number of depressive symptoms on the geriatric depression scale-15 (GDS-15). Follow-up was for 12 months. This trial is registered with ISRCTN Register, number ISRCTN43769277. FINDINGS: Care homes were randomised between Dec 15, 2008, and April 9, 2010. At randomisation, 891 individuals in 78 care homes (35 intervention, 43 control) had provided baseline data. We delivered 3191 group exercise sessions attended on average by five study participants and five non-study residents. Of residents with a GDS-15 score, 374 of 765 (49%) were depressed at baseline; 484 of 765 (63%) provided 12 month follow-up scores. Overall the GDS-15 score was 0.13 (95% CI -0.33 to 0.60) points higher (worse) at 12 months for the intervention group compared with the control group. Among residents depressed at baseline, GDS-15 score was 0.22 (95% CI -0.52 to 0.95) points higher at 6 months in the intervention group than in the control group. In an end of study cross-sectional analysis, including 132 additional residents joining after randomisation, the odds of being depressed were 0.76 (95% CI 0.53 to 1.09) for the intervention group compared with the control group. INTERPRETATION: This moderately intense exercise programme did not reduce depressive symptoms in residents of care homes. In this frail population, alternative strategies to manage psychological symptoms are required. FUNDING: National Institute for Health Research Health Technology Assessment. PMID- 23643113 TI - Investigation of the areas of high radon concentration in Gyeongju. AB - The aim of this study was to survey the radon concentrations at 21 elementary schools in Gyeongju, Republic of Korea, to identify those schools with high radon concentrations. Considering their geological characteristics and the preliminary survey results, three schools were finally placed under close scrutiny. For these three schools, continuous measurements over 48 h were taken at the principal's and administration office. The radon concentrations at one school, Naenam, exceeded the action level (148 Bq/m(3)) established by the U.S. EPA, while those at the other two schools were below that level. PMID- 23643114 TI - Sharing milk but not messages: campylobacteriosis associated with consumption of raw milk from a cow-share program in Alaska, 2011. AB - Alaska public and environmental health authorities investigated a cluster of campylobacteriosis cases among people who had consumed raw, unpasteurized milk obtained from a cow-share program in Alaska. Although raw milk is not permitted by law to be offered commercially, consumers can enter into cow-share agreements whereby they contribute funds for the upkeep of cows and in turn receive a share of the milk for their personal use. Laboratory testing of stool specimens collected from ill persons and from cows on the farm revealed an indistinguishable strain of Campylobacter. In this outbreak, numerous confirmed and suspected cases were not among cow shareholders; therefore, these individuals had not been advised of the potential health hazards associated with consumption of raw milk nor were they informed of the outbreak developments. PMID- 23643115 TI - Simple, rapid, and reliable detection of Escherichia coli O26 using immunochromatography. AB - Shiga toxin-producing Escherichia coli (STEC) O26 has been increasingly associated with diarrheal disease all over the world. We developed an immunochromatographic (ic) strip for the rapid detection of E. coli O26 in food samples. To determine the specificity of the IC strip, pure cultures of 67 E. coli and 22 non-E. coli strains were tested with the IC strip. The IC strip could detect all (18 of 18) E. coli O26 strains tested and did not react with strains of any other E. coli serogroup or non-E. coli strains tested (0 of 71). The minimum detection limits for E. coli O26 were 2.2 * 10(3) to 1.0 * 10(5) cfu/ml. To evaluate the ability of the IC strip to detect E. coli O26 in food, 25-g food samples (ground beef, beef liver, ground chicken, alfalfa sprout, radish sprout, spinach, natural cheese, and apple juice) were spiked with E. coli O26. The IC strip was able to detect E. coli O26 at very low levels (approximately 1 cfu/25 g of food samples) after an 18-h enrichment, and the IC strip results were in 100% agreement with the results of the culture method and pcr assay. When 115 meat samples purchased from supermarkets were tested, 5 were positive for E. coli O26 with the IC strip; these results were confirmed with a pcr assay. These results suggest that the IC strip is a useful tool for detecting E. coli O26 in food samples. PMID- 23643116 TI - Potential rapid and simple lateral flow assay for Escherichia coli O111. AB - We developed and evaluated a lateral flow assay (LFA) as a simple and rapid method for direct detection of Escherichia coli O111 in food after enrichment. When cell suspensions of 8 E. coli O111 strains and 77 non-E. coli O111 strains were tested with the LFA, the former all yielded positive results and the latter all yielded negative results. The minimum detection limits for the E. coli O111 strains were 1.8 * 10(3) to 5.6 * 10(5) CFU/ml of cell suspension, and the LFA was able to detect live cultures or those killed by autoclaving at nearly the same level of sensitivity. To evaluate the ability of LFA to detect its target in food, enrichment cultures of meat samples inoculated with 10-fold serial dilutions of E. coli O111 were tested with the LFA and PCR. Even when there were very few E. coli O111 cells in the meat samples (1.6 * 10(0) to 1.6 * 10(1) CFU/25 g of food), when they were cultured in modified E. coli broth with novobiocin for 22 h at 42 degrees C, the LFA yielded positive results that corresponded to the PCR results. Although the LFA requires further evaluation and field study, these results suggest that this assay has sufficient sensitivity and specificity. This procedure can be completed with a one-step incubation after the test strip has been inserted into the sample after 22 h of culture, whereas the standard culture method requires multiple cultures, skilled personnel, a well equipped laboratory, and 4 or 5 days. The speed and simplicity of this LFA make it suitable for use as part of routine screening assays in the food industry. PMID- 23643117 TI - Use of global trade item numbers in the investigation of a salmonella newport outbreak associated with blueberries in Minnesota, 2010. AB - In August 2010, the Minnesota Department of Agriculture and Minnesota Department of Health investigated an outbreak of six cases of Salmonella Newport infection occurring in northwestern Minnesota, which identified fresh blueberries as the cause. Initially, traditional traceback methods involving the review of invoices and bills of lading were used to attempt to identify the source of the outbreak. When these methods failed, novel traceback methods were used. Specifically, supplier-specific 12-digit Global Trade Item Numbers (GTINs) and shopper-card information were used to identify a single blueberry grower linked to cases, corroborating the results of a case-control study in which consuming fresh blueberries was statistically associated with illness (5 of 5 cases versus 8 of 19 controls, matched odds ratio [MOR] undefined, P = 0.02). Consuming fresh blueberries from retailer A was also statistically associated with illness (3 of 3 cases versus 3 of 18 controls, MOR undefined, P = 0.03). Based on initially incomplete evidence in this investigation, the invoices pointed to wholesaler A and grower A, based on first-in-first-out product rotation. However, when point of-sale data were analyzed and linked to shopper-card information, a common GTIN was identified. This information led to an on-site record evaluation at retailer A, and the discovery of additional records at this location documented the supply chain from grower B to wholesaler C to retailer A, shifting the focus of the investigation from grower A to grower B. This investigation demonstrates the emerging concepts of Critical Tracking Events (CTEs) and Key Data Elements (KDE) related to food product tracing. The use of these shopper-cased data and the event data that were queried by investigators demonstrates the potential utility of consciously designed CTEs and KDEs at critical points in the supply chain to better facilitate product tracing. PMID- 23643118 TI - Efficacy of sanitizers in reducing Salmonella on pecan nutmeats during cracking and shelling. AB - Studies were done to evaluate the efficacy of chlorine (200 to 1,000 MUg/ml), lactic acid (0.5 to 2%), levulinic acid (0.5 to 2%), sodium dodecyl sulfate (SDS, 0.05%), lactic acid plus SDS, levulinic acid plus SDS, and a mixed peroxyacid sanitizer (Tsunami 200, 40 and 80 MUg/ml) in killing Salmonella on or in immersion- and on surface-inoculated pecan nutmeats (U.S. Department of Agriculture medium pieces and mammoth halves). The addition of SDS to treatment solutions containing lactic acid or levulinic acid resulted in generally higher reductions of Salmonella, but differences in these reductions were not always significant. Lactic and levulinic acids (2%) containing SDS (0.05%) were equivalent in killing Salmonella on immersion-inoculated nutmeats. Tsunami 200 (40 MUg/ml) was less lethal or equivalent to 1 or 2% lactic and levulinic acids, with or without 0.05% SDS. Reductions did not exceed 1.1 log CFU/g of immersion inoculated pieces and halves, regardless of sanitizer concentration or treatment time (up to 20 min). Reductions on surface-inoculated pieces and halves were 0.7 to 2.6 log CFU/g and 1.2 to 3.0 log CFU/g, respectively. Treatment with 2% lactic acid plus SDS (0.05%) and Tsunami (80 MUg/ml) was most effective in killing Salmonella on surface-inoculated pieces; treatment of halves with chlorine (1,000 MUg/ml) or lactic acid (1 or 2%), with or without SDS, was most efficacious. Exposure of immersion-inoculated pecan pieces to chlorine (200 MUg/ml), lactic acid (2%) and levulinic acid (2%) with or without SDS, and Tsunami (80 MUg/ml) during intermittent vacuum (18 +/- 2 mbar) and ambient atmospheric pressure treatments for up to 20 min reduced Salmonella by only 0.1 to 1.0 log CFU/g. These studies emphasize the importance of preventing contamination of pecan nutmeats with Salmonella. Once nuts are contaminated, the lethality of sanitizers tested in this study is minimal. PMID- 23643119 TI - Development of antimicrobial coatings for improving the microbiological safety and quality of shell eggs. AB - This study was conducted to develop antimicrobial coatings to decontaminate and prevent cross-contamination of shell eggs. Egg shells were inoculated with nalidixic acid-resistant Salmonella enterica Enteritidis strains OB030832, OB040159, and C405 and treated with antimicrobial coatings. Polylactic acid served as a nonedible polymer, and chitosan served as an edible polymer carrier of natural antimicrobials, including nisin, allyl isothiocyanate (AIT), lauric arginate ester (LAE), and organic acids. Increases of AIT concentrations or addition of nisin to AIT in either the polylactic acid or chitosan coating solutions resulted in greater reductions of Salmonella. Chitosan coatings with 0.1, 0.5, and 1.0% LAE reduced Salmonella by 1.7, 2.5, and 5.2 log CFU/cm(2), respectively. Shell eggs treated with 1.0 and 0.5% LAE in chitosan coatings had nondetectable Salmonella cells (< 0.5 log CFU/cm(2)) after 3 and 7 days of storage at 7 degrees C, respectively, and no outgrowth was observed up to 28 days. Coating treatments significantly reduced weight loss of shell eggs during 12 weeks of storage at 7 or 4 degrees C. This study demonstrates an alternative and effective intervention technology for decontaminating shell eggs and provides an alternative approach to reduce possible recalls and outbreaks associated with pathogen contamination on shell eggs and in egg products. PMID- 23643120 TI - Salmonella and Escherichia coli O157:H7 prevalence in cattle and on carcasses in a vertically integrated feedlot and harvest plant in Mexico. AB - To determine the prevalence of Salmonella and Escherichia coli O157:H7 in cattle feedlots and the impact of subsequent contamination on carcasses in a Mexican Federal Inspection Type Standards harvest facility, 250 animals were tagged and sampled in each step of the slaughter process. Samples were taken from hides and fecal grabs, and composite samples were taken from three anatomical carcass sites (hindshank, foreshank, and inside round) during the slaughter process, at preevisceration (PE), prior to entering the hot box (PHB), and after 24 h of dry chilling (DC). Additionally, 250 fecal samples were collected from the feedlot (FL), holding pens (HP), and intestinal feces (IF), and water samples were taken from the HP area. E. coli O157:H7 and Salmonella detection were carried out with the BAX System, immunomagnetic separation, and conventional methods. Overall Salmonella prevalence was 52.5%. The highest prevalence (92.4%) was found on hides, followed by feces from the HP (91.0%), FL (55.56%), PE (49.0%), IF (46.8%), and PHB (24.8%), for all sampling periods combined. The lowest prevalence of 6.0% was found after DC. The overall prevalence of E. coli O157:H7 was as follows: 11.7% for hides, 5.2% for IF, 2.7% for FL, 2.0% for HP, 0.8% for PE, 0.4% for PHB, and 0.4% for the cooler. High prevalence of Salmonella in IF and on hides present a significant risk factor for contamination by Salmonella at the different processing steps. These results serve as a warning as to the risks of contamination in meats for these pathogens and the importance of following good manufacturing practices during beef production processes. PMID- 23643121 TI - Implementation of statistical tools to support identification and management of persistent Listeria monocytogenes contamination in smoked fish processing plants. AB - Listeria monocytogenes persistence in food processing plants is a key source of postprocessing contamination of ready-to-eat foods. Thus, identification and elimination of sites where L. monocytogenes persists (niches) is critical. Two smoked fish processing plants were used as models to develop and implement environmental sampling plans (i) to identify persistent L. monocytogenes subtypes (EcoRI ribotypes) using two statistical approaches and (ii) to identify and eliminate likely L. monocytogenes niches. The first statistic, a binomial test based on ribotype frequencies, was used to evaluate L. monocytogenes ribotype recurrences relative to reference distributions extracted from a public database; the second statistic, a binomial test based on previous positives, was used to measure ribotype occurrences as a risk factor for subsequent isolation of the same ribotype. Both statistics revealed persistent ribotypes in both plants based on data from the initial 4 months of sampling. The statistic based on ribotype frequencies revealed persistence of particular ribotypes at specific sampling sites. Two adaptive sampling strategies guided plant interventions during the study: sampling multiple times before and during processing and vector swabbing (i.e., sampling of additional sites in different directions [vectors] relative to a given site). Among sites sampled for 12 months, a Poisson model regression revealed borderline significant monthly decreases in L. monocytogenes isolates at both plants (P = 0.026 and 0.076). Our data indicate elimination of an L. monocytogenes niche on a food contact surface; niches on nonfood contact surfaces were not eliminated. Although our data illustrate the challenge of identifying and eliminating L. monocytogenes niches, particularly at nonfood contact sites in small and medium plants, the methods for identification of persistence we describe here should broadly facilitate science-based identification of microbial persistence. PMID- 23643122 TI - Refined liquid smoke: a potential antilisterial additive to cold-smoked sockeye salmon (Oncorhynchus nerka). AB - Cold-smoked salmon (CSS) is a potentially hazardous ready-to-eat food product due to the high risk of contamination with Listeria monocytogenes and lack of a listericidal step. We investigated the antilisterial property of liquid smokes (LS) against Listeria innocua ATCC 33090 (surrogate to L. monocytogenes) as a potential supplement to vacuum-packaged CSS. A full-strength LS (Code 10-Poly), and three commercially refined fractions (AM-3, AM-10, and 1291) having less color and flavor (lower content of phenols and carbonyl-containing compounds) were tested. In vitro assays showed strong inhibition for all LS except for 1291. The CSS strips were surface coated with AM-3 and AM-10 at 1% LS (vol/wt) with an L-shaped glass rod and then inoculated with L. innocua at 3.5 log CFU/g, vacuum packaged, and stored at 4 degrees C. The LS did not completely eliminate L. innocua but provided a 2-log reduction by day 14, with no growth up to 35 days of refrigerated storage. A simple difference sensory test by 180 untrained panelists showed the application of AM-3 did not significantly influence the overall sensorial quality of CSS. In essence, the application of the refined LS as an antilisterial additive to CSS is recommended. PMID- 23643123 TI - Interaction between Bacillus cereus and cultured human enterocytes: effect of calcium, cell differentiation, and bacterial extracellular factors. AB - Bacillus cereus interaction with cultured human enterocytes and the signaling pathways responsible for the biological effects of the infection were investigated. Results demonstrate that calcium depletion increases the ability of strains T1 and 2 to invade cells. Bacteria associated in greater extent to undifferentiated enterocytes and extracellular factors from strain 2 increased its own association and invasion. Inhibitors of signaling pathways related to phosphorylated lipids (U73122 and wortmannin) were able to significantly reduce cytoskeleton disruption induced by B. cereus infection. Adhesion of strain T1 decreased in the presence of U73122 and of wortmannin, as well as when those inhibitors were used together. In contrast, invasion values were diminished only by U73122. Results show that different factors are involved in the interaction between B. cereus and cultured human enterocytes. Following infection, disruption of the cytoskeleton could facilitate invasion of the eukaryotic cells. PMID- 23643124 TI - Native microflora in fresh-cut produce processing plants and their potentials for biofilm formation. AB - Representative food contact and nonfood contact surfaces in two mid-sized, fresh cut processing facilities were sampled for microbiological analyses after routine daily sanitization. Mesophilic and psychrotrophic bacteria on the sampled surfaces were isolated by plating on nonselective bacterial media. Alternatively, bacteria were isolated after an incubation period that allowed the formation of heterogeneous biofilms on stainless steel beads. Of over 1,000 tested isolates, most were capable of forming biofilms, with approximately 30 % being strong or moderate biofilm formers. Selected isolates (117) were subjected to species identification by using the Biolog Gen III microbial identification system. They distributed among 23 genera, which included soil bacteria, plant-related bacteria, coliforms, and opportunistic plant- or human-pathogenic bacteria. The most commonly identified bacteria species were Pseudomonas fluorescens, Rahnella aquatilis, and Ralstonia insidiosa. The high prevalence of R. insidiosa, a strong biofilm former, and P. fluorescens, a moderate biofilm former, suggests that they were established residents in the sampled plants. These results suggest that native microflora capable of forming biofilms are widely distributed in fresh produce processing environments. PMID- 23643125 TI - Effect of the temperature of the dipping solution on the antimicrobial effectiveness of various chemical decontaminants against pathogenic and spoilage bacteria on poultry. AB - The influence of the temperature of the dipping solution on the antimicrobial effectiveness of several chemical poultry decontaminants was assessed. A total of 765 poultry legs were inoculated with gram-positive bacteria (Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus, or Brochothrix thermosphacta) or gram-negative bacteria (Salmonella enterica serotype Enteritidis, Escherichia coli, Yersinia enterocolitica, or Pseudomonas fluorescens). Samples were dipped for 15 min in solutions (wt/vol) of trisodium phosphate (12%), acidified sodium chlorite (1,200 ppm), citric acid (2%), peroxyacids (220 ppm), chlorine dioxide (50 ppm), or tap water or were left untreated (control). The temperatures of the dipping solutions were 4, 20, or 50 degrees C. Microbiological analyses and pH determinations were carried out after 0, 1, 3, and 5 days of storage at 4 degrees C. In comparison with the control samples, all chemical solutions were effective for reducing microbial loads. The temperature of treatment affected the microbial reductions caused by all chemicals (P < 0.001). The lowest average bacterial reductions caused by trisodium phosphate, acidified sodium chlorite, citric acid, and peroxyacids were observed at 4 degrees C, all sampling days and microbial groups being considered simultaneously. The highest and the lowest effectiveness for chlorine dioxide were observed at 4 and 50 degrees C, respectively. These results may be of use to meat processors for selecting the best conditions for decontamination treatments and may help the European Regulatory Authorities make their decisions for authorization of poultry decontamination treatments. PMID- 23643126 TI - Microbiological quality of retail spices in Tehran, Iran. AB - The microbiological quality of 351 samples of nine types of spices including black pepper, caraway, cinnamon, cow parsnip, curry powder, garlic powder, red pepper, sumac, and turmeric, collected from retail shops in Tehran during 2007, was determined. The numbers of aerobic mesophilic bacteria, Escherichia coli, and molds exceeded Iran's National Standard limits, at 63.2% (>5 * 10(5) CFU/g), 23.4% (>0.3 MPN/g), and 21.9% (>5 * 10(3) CFU/g) of the studied samples, respectively. Coliform contamination was more than 10(3) MPN/g in 24.8% of samples. High contamination of retail spices is considered an indication of environmental or fecal contamination due to unhygienic practices in their production. Use of spices with high microbial content could increase the chance of food spoilage and transmission of foodborne pathogens. Accordingly, application of food safety measurements to reduce microbial counts in spices is strongly recommended. PMID- 23643127 TI - Aflatoxin m1 in milk products in china and dietary risk assessment. AB - This study was conducted to investigate the occurrence of aflatoxin M1 (AFM1) in milk products in China using the competitive enzyme-linked immunosorbent assay method and to estimate the dietary exposure to this toxin through a probabilistic approach. Based on the exposure assessment results, a quantitative cancer potency formula developed by the Joint Food and Agriculture Organization and World Health Organization Expert Committee on Food Additives was applied to assess the cancer risk. AFM1 was detected in 48.07% of the milk samples and 4.49% of the yoghurt samples. No samples contained AFM1 above the current regulatory limit in China. The simulated AFM1 intake (90% confidence interval) in various sex-age groups ranged from 0.023 (0.021 to 0.023) ng/kg of body weight per day for 30- to 45 year-old men to 0.382 (0.354 to 0.386) ng/kg of body weight per day for 2- to 4 year-old girls at the 99th percentile. The cancer risk of AFM1 to the general population of China was assessed to be 0.129 cancer cases per year per 10(8) persons at the 99th percentile. These results indicate that the health risk associated with AFM1 in milk in China is relatively low. PMID- 23643128 TI - Production of tyramine by Enterococcus faecalis strains in water-boiled salted duck. AB - The potential to produce biogenic amines was investigated with 15 Lactococcus lactis and 15 Enterococcus faecalis strains isolated from water-boiled salted duck. The production of biogenic amines from the isolated strains grown in de Man Rogosa Sharpe broth containing precursor amino acids was determined by thin-layer chromatography and high-performance liquid chromatography. None of the L. lactis strains produced any biogenic amines, whereas 12 strains of E. faecalis produced tyramine and b -phenylethylamine. PCR assays were used to detect the presence of tyrosine decarboxylase genes in all of the isolated strains. Only the 12 biogenic amine-producing Enterococcus strains had a 924-bp fragment characteristic for the tyrosine decarboxylase gene. The comparison of the amplified partial tyrDC gene sequences of the 12 positive Enterococcus strains revealed 99% similarity within the same species. The tyramine production of the sterilized water-boiled salted duck inoculated with E. faecalis R612Z1 increased significantly during storage. This study reveals that the isolated E. faecalis strains can produce tyramine and beta-phenylethylamine in the medium; however, they can only produce tyramine in water-boiled salted duck. PMID- 23643129 TI - Determination and frying loss of histamine in striped marlin fillets implicated in a foodborne poisoning. AB - An incident of foodborne poisoning causing illness in 67 victims due to ingestion of fried fish fillets occurred in June 2011, in southern Taiwan. Of the five suspected fish fillets, one fried sample contained 62.0 mg/100 g and one raw sample contained 89.6 mg/100 g histamine, levels which are greater than the potential hazard action level (50 mg/100 g) in most illness cases. Given the allergy-like symptoms of the victims and the high histamine content in the suspected fish samples, this foodborne poisoning was strongly suspected to be caused by histamine intoxication. Five histamine-producing bacterial strains capable of producing 59 to 562 ppm of histamine in Trypticase soy broth supplemented with 1.0% L-histidine were identified as Enterobacter aerogenes (two strains), Raoultella ornithinolytica (two strains), and Morganella morganii (one strain). The degradation loss of histamine in suspected raw fillets was 28% after they were fried at 170 degrees C for 5 min. PMID- 23643130 TI - Multilaboratory validation of a luminex microbead-based suspension array for the identification of the 11 most clinically relevant Shiga toxin-producing Escherichia coli O serogroups. AB - Rapid and high-throughput identification and serotyping of Shiga toxin-producing Escherichia coli (STEC) O serogroups is important for detecting, investigating, and controlling STEC infection outbreaks and removing hazardous products from commerce. A Luminex microbead-based suspension array has been developed to identify the 11 most clinically relevant STEC serogroups: O26, O45, O91, O103, O104, O111, O113, O121, O128, O145, and O157. Here we present results of a blinded multilaboratory collaborative study involving 10 participants from nine laboratories using 55 unknown strains. From the total 495 analyses, two false positive and three false-negative results were obtained, indicating the assay to be a rapid, high-throughput, and robust method for identifying clinically relevant STEC serogroups. PMID- 23643131 TI - Evaluation of seven different commercially available real-time PCR assays for detection of shiga toxin 1 and 2 gene subtypes. AB - Following the recent outbreak of Shiga toxin-producing Escherichia coli (STEC) O104:H4 infection in Germany, the demand for fast detection of STEC has again increased. Various real-time PCR-based methods enabling detection of Shiga toxin genes (stx) have been developed and can be used for applications in food microbiology. The present study was conducted to evaluate the reliability of seven commercially available real-time PCR systems for detection of stx1 and stx2 subtypes. For this purpose, pure cultures of 18 STEC strains harboring all known stx1 and/or stx2 subtypes were tested. Only one of the seven real-time PCR systems detected all known stx1 and stx2 subtypes. Six systems failed to detect the stx2f subtype. One system missed stx2 subtypes reported in association with severe human disease. Because the presence of certain stx genes (subtypes) is considered an important indicator of STEC virulence, systems differentiating between the stx1 and stx2 gene groups provide added value. Reliable and fast detection of stx genes is of major importance for both diagnostic laboratories and the food industry. PMID- 23643132 TI - Validation of the 3M molecular detection system for the detection of listeria in meat, seafood, dairy, and retail environments. AB - There is a continued need to develop improved rapid methods for detection of foodborne pathogens. The aim of this project was to evaluate the 3M Molecular Detection System (3M MDS), which uses isothermal DNA amplification, and the 3M Molecular Detection Assay Listeria using environmental samples obtained from retail delicatessens and meat, seafood, and dairy processing plants. Environmental sponge samples were tested for Listeria with the 3M MDS after 22 and 48 h of enrichment in 3M Modified Listeria Recovery Broth (3M mLRB); enrichments were also used for cultural detection of Listeria spp. Among 391 samples tested for Listeria, 74 were positive by both the 3M MDS and the cultural method, 310 were negative by both methods, 2 were positive by the 3M MDS and negative by the cultural method, and one sample was negative by the 3M MDS and positive by the cultural method. Four samples were removed from the sample set, prior to statistical analyses, due to potential cross-contamination during testing. Listeria isolates from positive samples represented L. monocytogenes, L. innocua, L. welshimeri, and L. seeligeri. Overall, the 3M MDS and culture-based detection after enrichment in 3M mLRB did not differ significantly (P < 0.05) with regard to the number of positive samples, when chi-square analyses were performed for (i) number of positive samples after 22 h, (ii) number of positive samples after 48 h, and (iii) number of positive samples after 22 and/or 48 h of enrichment in 3M mLRB. Among 288 sampling sites that were tested with duplicate sponges, 67 each tested positive with the 3M MDS and the traditional U.S. Food and Drug Administration Bacteriological Analytical Manual method, further supporting that the 3M MDS performs equivalently to traditional methods when used with environmental sponge samples. PMID- 23643133 TI - Isolation and identification of zoonotic species of genus arcobacter from chicken viscera obtained from retail distributors of the metropolitan area of San Jose, Costa Rica. AB - Arcobacter is a genus of growing importance worldwide; some of its species are considered emerging enteropathogens and potential zoonotic agents. In Costa Rica, as well as in other countries, its isolation has been reported, so the objective of this project was to evaluate and identify the presence of Arcobacter in chicken viscera sold in the metropolitan area of San Jose, Costa Rica, as well as to determine the antimicrobial resistance patterns associated with it. One hundred fifty samples of chicken viscera including heart, liver, and other gastrointestinal organs were purchased from 15 supermarkets and 15 local retailers. De Boer and Houf broths were used as enrichment media; isolation was done with Arcobacter-selective medium and with membrane filtration with blood agar. Typical colonies were identified with genus-specific PCR, and species identification was made with multiplex PCR. Susceptibility to ampicillin, ciprofloxacin, chloramphenicol, erythromycin, gentamicin, and tetracycline was done with the Epsilometer test. The isolation frequency of Arcobacter genus obtained in this study was of 17.3%. A total of 33 isolates were obtained from the poultry samples, and according to the multiplex PCR methodology, 22 (66.7%) isolates were identified as Arcobacter butzleri, 8 (24.2%) as Arcobacter cryaerophilus, and 1 (3.1%) as Arcobacter skirrowii. Two strains were not identified. No statistical significant difference was found when the source of samples was compared. Resistance toward chloramphenicol was 68.75%, followed by ampicillin (43.75%) and ciprofloxacin (18.75%); all strains were susceptible to tetracycline. PMID- 23643134 TI - Genetic diversity of Cronobacter sakazakii isolates collected from a Swiss infant formula production facility. AB - In this study, 141 Cronobacter isolates that were collected based on a hygienic monitoring program performed in a powdered infant formula production facility in Switzerland between September 2011 and October 2012 were further characterized. Isolates were identified to the species level by molecular methods, and strains of Cronobacter sakazakii were further subtyped by applying PCR-based O-antigen serotyping, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). C. sakazakii was the most prevalent species identified (93.6%). Among this collection of isolates, representatives of all but one O antigen serotype (serotype O5) were recognized. MLST analysis of 19 selected isolates revealed that most of the typeable isolates belonged to sequence type (ST) 4. Correlations between ST4 and serotype O2 and between ST83 and serotype O7 were observed. PFGE analysis revealed clusters with multiple isolates, including strains from samples collected at different time points and sampling sources. Generally, the observed heterogeneity among strains collected over the 13 months of the monitoring program was high, suggesting a constant flux among strains rather than a selection for persisting organisms. PMID- 23643135 TI - Growth potential of Salmonella and Listeria monocytogenes in ready-to-eat lettuce and collard greens packaged under modified atmosphere and in perforated film. AB - This study was aimed at determining the effects of different storage scenarios on the growth potential of Salmonella strains and Listeria monocytogenes in ready-to eat (RTE) mixes of iceberg and crisp lettuces (Lactuca sativa) and collard greens (Brassica oleracea). Vegetables were submitted to minimal processing, experimentally contaminated to achieve 10(1) and 10(2) CFU/g, packed under modified atmosphere and in perforated film, and submitted to the following storage scenarios: I = 100 % of the shelf life (6 days) at 7 degrees C; II = 70 % of shelf life at 7 degrees C and 30 % at 15 degrees C; III = 30 % at 7 degrees C and 70 % at 15 degrees C; IV = 100 % at 15 degrees C. Higher populations of Salmonella were observed in lettuce mixes than in collard greens; the opposite occurred with L. monocytogenes. Keeping the RTE vegetables at 15 degrees C during the whole shelf life (scenario IV) or part of it (scenarios II and III) markedly influenced the growth of both pathogens in most of the scenarios studied (P < 0.05). Growth potentials of strains of Salmonella and L. monocytogenes were significantly different depending on the scenarios in samples packed with perforated film in comparison to those stored under modified atmosphere (P < 0.05). The findings indicate that even contamination as low as 10(1) CFU/g can lead to high populations if there is temperature abuse during storage (15 degrees C). This study of the behavior of Salmonella and L. monocytogenes in RTE vegetables provides insights that may be useful in the development of strategies to control pathogen growth in these products. PMID- 23643136 TI - Fluorometric detection of active alkaline phosphatase and gamma-glutamyl transferase in fluid dairy products from multiple species. AB - Over the past 80 years, a variety of methods have been developed to detect underpasteurized or improperly pasteurized milks used in dairy products. Existing methods are hampered by duration of analysis, poor reproducibility, and in some cases the use of hazardous chemicals. To overcome these issues, two new methods have been developed using fluorogenic substrates for two marker enzymes, alkaline phosphatase and gamma-glutamyl transferase. In 30 min, up to 18 samples can be analyzed in triplicate by both methods on two separate 96-well plates. Sample preparation is not necessary for liquid milks when using these methods. The relative standard deviation for each assay is less than 9%, and the correlation coefficient for results of the two methods is greater than 0.98. Using the new methods, milks from four species and nine commercially available liquid milk products were tested. The new methods were also tested directly against an existing phosphatase method (Fluorophos) in spiked whole milk samples. PMID- 23643137 TI - Role of slaughtering in Salmonella spreading and control in pork production. AB - Salmonella is one of the major foodborne pathogens worldwide. Pork products are among the main sources of Salmonella infection in humans, and several countries have established Salmonella surveillance and control programs. The role of slaughtering in carcass contamination has been indicated by studies focused on the slaughterhouse environment. In this review, we examine and discuss the information available regarding the influence that farm status, pig transport, and lairage have on the carriage of Salmonella by pigs entering the slaughter line. The evolution of carcass contamination throughout the slaughtering process, the main sources of contamination in the dirty and clean zones of the slaughter line, and previously reported prevalence of Salmonella on carcasses and factors affecting this prevalence also are discussed. The importance of implementing interventions at the slaughter level is discussed briefly. Consistent with the information available, pigs from infected farms and newly acquired or recrudescent infections in pigs at the subsequent stages of transport and lairage are important sources of Salmonella at the slaughtering plant. The continuous introduction of Salmonella into the slaughterhouse and the potential for resident flora constitute a risk for carcass contamination. At the slaughterhouse, some dressing activities can reduce carcass contamination, but others are critical control points that jeopardize carcass hygiene. This information indicates the importance of considering slaughter and previous stages in the pork production chain for controlling Salmonella in swine production. PMID- 23643138 TI - Review of the characteristics of food-derived and endogenous ne carboxymethyllysine. AB - Ne-Carboxymethyllysine (CML), a representative of advanced glycation end products (AGEs), is commonly found in food and is considered a potential hazard to human health. Food scientists have begun to investigate the formation of CML in food processes. As the understanding of CML is mainly based on that of endogenous CML from the fields of biology and medicine, this review summarizes the different characteristics of food-derived CML and endogenous CML with respect to food safety, detection methods, formation environment, formation mechanism, and methods for inhibiting the formation of CML. Additionally, future research directions for the study of food-derived CML are proposed, including understanding its digestion, absorption, and metabolism in human health, developing rapid, reliable, and inexpensive detection methods, revealing its relationship with food components and production processes, and controlling the formation of CML through the addition of inhibitors and/or modification of food processing conditions, so as to contribute to the methods for controlling food derived AGEs. PMID- 23643139 TI - Pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy for pancreatic or periampullary tumours: a multicentre randomised trial. AB - BACKGROUND: Postoperative pancreatic fistula is the leading cause of death and morbidity after pancreaticoduodenectomy. However, the best reconstruction method to reduce occurrence of fistula is debated. We did a multicentre, randomised superiority trial to compare the outcomes of different reconstructive techniques in patients undergoing pancreaticoduodenectomy for pancreatic or periampullary tumours. METHODS: Patients aged 18-85 years with confirmed or suspected neoplasms of the pancreas, distal bile duct, ampulla vateri, duodenum, or periampullary tumours were eligible for inclusion. An internet-based platform was used to randomly assign patients to either pancreaticojejunostomy or pancreaticogastrostomy as reconstruction after pancreaticoduodenectomy, using permuted blocks with six patients per block. Within each centre the randomisation was stratified on the pancreatic duct diameter (<=3 mm vs >3 mm) measured at the time of surgery. The primary endpoint was the occurrence of clinical postoperative pancreatic fistula (grade B or C) as defined by the International Study Group on Pancreatic Fistula. The study was not masked and analyses were done by intention to treat. Patient follow-up was closed 2 months after discharge from the hospital. This study is registered with ClinicalTrials.gov, number NCT00830778. FINDINGS: Between June, 2009, and August, 2012, we randomly allocated 167 patients to receive pancreaticojejunostomy and 162 to receive pancreaticogastrostomy. 33 (19.8%) patients in the pancreaticojejunostomy group and 13 (8.0%) in the pancreaticogastrostomy group had clinical postoperative pancreatic fistula (OR 2.86, 95% CI 1.38-6.17; p=0.002). The overall incidence of postoperative complications did not differ significantly between the groups (99 in the pancreaticojejunostomy group vs 100 in the pancreaticogastrostomy group), although more events in the pancreaticojejunostomy group were of grade >=3a than in the pancreaticogastrostomy group (39 vs 35). INTERPRETATION: In patients undergoing pancreaticoduodenectomy for pancreatic head or periampullary tumours, pancreaticogastrostomy is more efficient than pancreaticojejunostomy in reducing the incidence of postoperative pancreatic fistula. FUNDING: Funding Johnson & Johnson Medical Devices, Belgium. PMID- 23643140 TI - Pancreaticoduodenectomy: time to change our approach? PMID- 23643141 TI - Month of birth and risk of multiple sclerosis in a Portuguese population. AB - BACKGROUND: Several studies analyzing the month of birth (MOB) of multiple sclerosis (MS) patients and the risk of the disease have been published; as a whole, MS patients were found to be predominantly born in spring months, leading to the current assumption that MOB is somewhat related to the risk of MS. OBJECTIVE: Estimate the risk of MS by MOB in a Portuguese population. METHODS: MS patients sample was obtained from the database of patients attended at our MS clinic and born in the districts of Porto, Braga and Viana do Castelo. The control sample was composed of the live births records in the same time period and geographical area. We applied the Hewitt test for seasonality. RESULTS: We found 421 patients that satisfied the conditions to enter the study. The rank sums for successive 6-month segments indicate the July-December period as of higher incidence; however, the corresponding rank-sum (48) was not statistically significant according to the Hewitt test (p>0.05). CONCLUSION: Our data does not support the seasonality hypothesis of MOB as risk factor for MS in Portugal. However we are aware that the analysis of a larger MS sample could shed more light in this issue. PMID- 23643142 TI - Laughing gas abuse is no joke. An overview of the implications for psychiatric practice. AB - Abuse of nitrous oxide--also known as laughing gas--can lead to a number of well known neurological symptoms but also to less documented psychiatric symptoms. Studies show abuse prevalence rates ranging from 12% to 20% among youngsters and thereby classify nitrous oxide as one of the five most frequently used inhalants. Its abuse still remains unrecognized in psychiatric settings, however. Since treatment is straightforward, it is important to raise the awareness of clinicians with respect to typical signs and symptoms. This paper presents a case report and gives an overview of the existing literature on psychiatric symptoms and therapy. PMID- 23643143 TI - Intracerebral metastases of malignant melanoma and their recurrences--a clinical analysis. AB - INTRODUCTION: Brain metastases (BM) commonly occur in patients with metastatic malignant melanoma (MM). Prognosis is poor even with maximal therapy. The aim of the current study was to retrospectively evaluate patients with BM of MM who were treated neurosurgically with respect to clinical presentation, recurrent disease, survival and factors affecting survival. PATIENTS AND METHODS: Thirty-four patients (19f/15m) with BM of MM were treated in our hospital between 2000 and 2010. Patient data were analysed, survival was examined using Kaplan-Meier estimates and factors affecting prognosis were evaluated using uni- and multivariate analysis. RESULTS: Twenty-two patients (64.7%) had a single BM, whereas twelve patients (35.3%) revealed two or more lesions. Median survival for patients with a single BM was 13.0 months (95%-CI 9.3-16.7 months), this was significantly (p=0.014) better than for patients with two or more BM (median 5.0, 95%-CI 3.4-14.6 months). Nineteen patients (55.9%) developed an intracranial relapse after microsurgical resection of a first lesion. Patients with an isolated intracerebral relapse survived significantly (p=0.003) longer than those with systemic progression (median 6.0, 95%-CI 0.0-15.3 months vs median 3.0, 95% CI 1.7-4.3 months). Similarly, patients with a high performance status showed significantly (p=0.001) prolonged survival (median 7.0, 95%-CI 0.0-19.9 months vs median 1.0, 95%-CI 0.0-2.2 months). Eleven out of nineteen patients (57.9%) underwent either another microsurgical resection (n=6) or stereotactic radiosurgery (n=5). These patients remained on a high performance status even after aggressive therapy. DISCUSSION: Even though the prognosis for patients with BM of MM is generally poor, patients with a single BM can benefit from microsurgical resection. However, there is a high risk of intracranial relapse. In selected patients with a good performance status and recurrent intracranial disease, recurrent local therapy can be justified and useful. PMID- 23643144 TI - Preoperative functional MRI of number processing in left trigonal meningioma. PMID- 23643145 TI - Ictal sign of cross-does it have any religious annotations at all? PMID- 23643146 TI - Altered synapses and gliotransmission in Alzheimer's disease and AD model mice. AB - Amyloid-beta (Abeta) plaque accumulation in Alzheimer's disease (AD) is associated with glutamatergic synapse loss, but less is known about its effect on inhibitory synapses. Here, we demonstrate that vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) presynaptic bouton density is unaffected in human preclinical and end-stage AD and in APP/PS1 transgenic (TG) mice. Conversely, excitatory vesicular glutamate transporter 1 (VGlut1) boutons are significantly reduced in end-stage AD cases and less reduced in preclinical AD cases and TGs. Aged TGs also show reduced protein levels of VGlut1 and synaptophysin but not VGAT or glutamate decarboxylase (GAD). These findings indicate that GABAergic synapses are preserved in human AD and mouse TGs. Synaptosomes isolated from plaque-rich TG cortex had significantly higher GAD activity than those from plaque-free cerebellum or the cortex of wild-type littermates. Using tissue fractionation, this increased activity was localized to glial synaptosomes, suggesting that Abeta plaques stimulate increased astrocyte GABA synthesis. PMID- 23643147 TI - Bootstrapping a de-identification system for narrative patient records: cost performance tradeoffs. AB - PURPOSE: We describe an experiment to build a de-identification system for clinical records using the open source MITRE Identification Scrubber Toolkit (MIST). We quantify the human annotation effort needed to produce a system that de-identifies at high accuracy. METHODS: Using two types of clinical records (history and physical notes, and social work notes), we iteratively built statistical de-identification models by annotating 10 notes, training a model, applying the model to another 10 notes, correcting the model's output, and training from the resulting larger set of annotated notes. This was repeated for 20 rounds of 10 notes each, and then an additional 6 rounds of 20 notes each, and a final round of 40 notes. At each stage, we measured precision, recall, and F score, and compared these to the amount of annotation time needed to complete the round. RESULTS: After the initial 10-note round (33min of annotation time) we achieved an F-score of 0.89. After just over 8h of annotation time (round 21) we achieved an F-score of 0.95. Number of annotation actions needed, as well as time needed, decreased in later rounds as model performance improved. Accuracy on history and physical notes exceeded that of social work notes, suggesting that the wider variety and contexts for protected health information (PHI) in social work notes is more difficult to model. CONCLUSIONS: It is possible, with modest effort, to build a functioning de-identification system de novo using the MIST framework. The resulting system achieved performance comparable to other high performing de-identification systems. PMID- 23643148 TI - Evaluation of medication dose alerts in pediatric inpatients. AB - OBJECTIVE: This study evaluates the impact of 12,093 consecutive dose alerts generated by a computerized provider order entry system on pediatric medication ordering. PATIENTS AND METHODS: All medication orders entered and all resulting medication dose alerts at the Johns Hopkins Children's Medical and Surgical Center in 2010, were retrospectively evaluated. Inclusion criteria were hospitalized patients less than 21 years old. There were no exclusion criteria. RESULTS: During 2010, there were 7738 admissions for 5553 unique patients. A total of 182,308 medication orders for 1092 unique medications were submitted by providers. Six percent (11,155) of orders or order attempts generated alerts for 2046 patients and 524 medications. Two categories of alerts were analyzed: dose range alerts and informational alerts. 73.4% (8187) of all alerts were dose range alerts, with a compliance rate of 8.5% (694); 26.6% (2968) were informational alerts, with a compliance rate of 5.5% (163). CONCLUSIONS: We found that underdosing alerts provide less value to providers than overdosing alerts. However, the low compliance with the alerts should trigger the evaluation of clinical practice behavior and the existing alert thresholds. Informational alerts noting the absence of established dosing guidelines had little effect on provider behavior and should be avoided when building a dose range alert system. PMID- 23643149 TI - Aplastic Anemia & MDS International Foundation (AA&MDSIF): bone marrow failure disease scientific symposium 2012. AB - Aplastic anemia (AA), myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria (PNH) are rare disorders of bone marrow failure. Once considered distinct entities, these three diseases are now believed to have overlapping pathophysiologies. The Aplastic Anemia and MDS International Foundation, a nonprofit organization that supports patients and families living with bone marrow failure disorders, sponsored a scientific symposium in Bethesda, MD, in March 2012. This report summarizes the symposium presentations by 30 of the world's leading AA, MDS, and PNH researchers on recent findings, current areas of controversy, and recommendations for basic and clinical research to advance the field. PMID- 23643150 TI - Ectodomain shedding of CD200 from the B-CLL cell surface is regulated by ADAM28 expression. AB - CD200, a membrane glycoprotein of the immunoglobulin superfamily, is overexpressed in CLL. Soluble in serum CD200 (sCD200) is correlated with poor prognosis in CLL. ADAM (a disintegrin and metalloproteinase) enzymes are implicated in membrane protein shedding. ADAM28 mRNA expression in CLL was correlated with plasma sCD200 levels, and release into culture from CLL cells. siRNA for ADAM28 decreased release of sCD200 from cultures and transfection of a cloned ADAM28 gene into CD200(+) cells enhanced release of sCD200. Our data support the hypothesis that ADAM28 plays a role in the shedding of CD200 from B cell CLL cells. PMID- 23643153 TI - A 4-year surveillance of device-associated nosocomial infections in a neonatal intensive care unit. AB - BACKGROUND: The aim of this study was to determine the rate of health care associated infection (HC-AI) and device-associated health care-associated infections (DA-HAIs), and distribution of causative microorganisms and etiologic factors responsible for these infections in a neonatal intensive care unit (NICU) of a state hospital in southeastern Turkey. METHODS: A laboratory-based, active, prospective nosocomial infection surveillance study was performed in NICUs from January 2008 to December 2011. The rates of HC-AIs were determined on a daily basis. The findings were evaluated by applying the definitions of the Centers for Disease Control and Prevention National Healthcare Safety Network. RESULTS: In a 4-year period, 580 HC-AIs, 81 of which were DA-HAIs, were detected among 6932 patients. The rate of hospital acquired infection was 8.3% and 7.69/1000 patient days. Ventilator-associated pneumonia (VAP) was the second most frequent (13.1%) HC-AI and the most frequent was DA-HAI. The VAP rate was 6.4 per 1000 ventilator days. Mechanical ventilation was the most frequently used invasive device. Median time to diagnosis of VAP was 32.11 +/- 29.3 days from the time of admission. Acinetobacter baumannii (48%) and Pseudomonas aeruginosa (32%) were the most frequent microorganisms. Colistin was the most effective antibiotic by in vitro test. The antibiotic resistance ratios of A. baumannii were >=54% for carbapenems, aminoglycosides, and cefoperazone-sulbactam; >=88% for quinolones; and >=92% for ceftazidime, ceftriaxone, and piperacillin-tazobactam. CONCLUSIONS: Device-associated nosocomial infections was a particularly important problem in NICU. Close monitoring will decrease the rates of device-related nosocomial infections. PMID- 23643154 TI - Group versus individual family planning counseling in Ghana: a randomized, noninferiority trial. AB - BACKGROUND: Group, rather than individual, family planning counseling has the potential to increase family planning knowledge and use through more efficient use of limited human resources. STUDY DESIGN: A randomized, noninferiority study design was utilized to identify whether group family planning counseling is as effective as individual family planning counseling in Ghana. Female gynecology patients were enrolled from two teaching hospitals in Ghana in June and July 2008. Patients were randomized to receive either group or individual family planning counseling. The primary outcome in this study was change in modern contraceptive method knowledge. Changes in family planning use intention before and after the intervention and intended method type were also explored. RESULTS: Comparisons between the two study arms suggest that randomization was successful. The difference in change in modern contraceptive methods known from baseline to follow-up between the two study arms (group-individual), adjusted for study site, was -0.21, (95% confidence interval: -0.53 to 0.12) suggesting no difference between the two arms. CONCLUSIONS: Group family planning counseling was as effective as individual family planning counseling in increasing modern contraceptive knowledge among female gynecology patients in Ghana. PMID- 23643155 TI - Practice of and attitudes towards family planning among South Asian American immigrants. AB - BACKGROUND: Previous studies performed outside of the US that examined contraceptive knowledge and beliefs in South Asian women identified significant barriers. Our study aimed to further understand these practices in this population residing in the US. METHODS: This cross-sectional study surveyed women of all ethnicities receiving health care from either of two ambulatory practices in New Jersey from October 2011 to November 2012. Using chi-squared testing, the frequencies of contraceptive outcomes between South Asians and non-South Asians were compared. STUDY DESIGN: There were 42 South Asian respondents and 143 non South Asian respondents. Our results show that South Asians are statistically significantly less likely to routinely use contraception and that gaps in contraceptive knowledge appear to stem from multiple barriers, including family opposition and pressure from spouse or in-laws to have children, cultural prohibitions, fear of side effects and misinformation, lack of education/knowledge about contraceptives and difficulty in accessing contraception. These gaps in contraceptive knowledge were also found to be multigenerational, despite higher levels of education generally seen in the South Asian population. CONCLUSIONS: Clinicians caring for South Asian women should acknowledge both the barriers and the lack of contraceptive knowledge in this population and provide culturally competent family planning information to them during all women's health encounters. PMID- 23643156 TI - Pathways to unsafe abortion in Ghana: the role of male partners, women and health care providers. AB - BACKGROUND: Despite abortion being legal, complications from induced abortion are the second leading cause of maternal mortality in Ghana. The objective of this study was to understand the decision-making process associated with induced abortion in Ghana. STUDY DESIGN: Data were collected from female postabortion patients, male partners, family planning nurses and obstetricians/gynecologists at two teaching hospitals in Ghana using in-depth interviews and focus group discussions. RESULTS: While experiences differ for married and single women, men are involved in abortion decision making directly, through "orders" to abort, or indirectly, through denying responsibility for the pregnancy. Health care providers can be barriers to seeking safe abortions in this setting. CONCLUSIONS: Women who choose to terminate a pregnancy without their male partners' knowledge should have the means (both financial and social) to do so safely. Interventions with health care providers should discourage judgemental attitudes and emphasize individually focused patient care. PMID- 23643157 TI - Tissue gadolinium deposition in renally impaired rats exposed to different gadolinium-based MRI contrast agents: evaluation with inductively coupled plasma mass spectrometry (ICP-MS). AB - OBJECTIVES: To quantify tissue gadolinium (Gd) deposition in renally impaired rats exposed to Gd-EOB-DTPA and other Gd-based MRI contrast agents by means of inductively coupled plasma mass spectrometry (ICP-MS), and to compare the differences in distribution among major organs as possible triggers for nephrogenic systemic fibrosis (NSF). METHODS: A total of 15 renally impaired rats were injected with Gd-EOB-DTPA, Gd-DTPA-BMA and Gd-HP-DO3A. Gd contents of skin, liver, kidney, lung, heart, spleen, diaphragm and femoral muscle were measured by inductively coupled plasma mass spectrometry (ICP-MS). Histological assessment was also conducted. RESULTS: Tissue Gd deposition in all organs was significantly higher (P=0.005~0.009) in the Gd-DTPA-BMA group than in the Gd-HP-DO3A and Gd-EOB DTPA groups. In the Gd-DTPA-BMA group, Gd was predominantly deposited in kidney (1306+/-605.7MUg/g), followed by skin, liver, lung, spleen, femoral muscle, diaphragm and heart. Comparing Gd-HP-DO3A and Gd-EOB-DTPA groups, Gd depositions in the kidney, liver and lung were significantly lower (P=0.009~0.011) in the Gd EOB-DTPA group than in the Gd-HP-DO3A group although no significant differences were seen for any other organs. CONCLUSIONS: Gd-EOB-DTPA is a stable and safe Gd based contrast agent (GBCA) showing lower Gd deposition in major organs in renally impaired rats, compared with other GBCAs. This fact suggests that the risk of NSF onset would be low in the use of Gd-EOB-DTPA. PMID- 23643158 TI - RF-related heating assessment of extracranial neurosurgical implants at 7T. AB - PURPOSE: The purpose was to evaluate radiofrequency (RF)-related heating of commonly used extracranial neurosurgical implants in 7-T magnetic resonance imaging (MRI). MATERIALS AND METHODS: Experiments were performed using a 7-T MR system equipped with a transmit/receive RF head coil. Four commonly used titanium neurosurgical implants were studied using a test procedure adapted from the American Society for Testing and Materials Standard F2182-11a. Implants (n=4) were tested with an MRI turbo spin echo pulse sequence designed to achieve maximum RF exposure [specific absorption rate (SAR) level=9.9W/kg], which was further validated by performing calorimetry. Maximum temperature increases near each implant's surface were measured using fiberoptic temperature probes in a gelled-saline-filled phantom that mimicked the conductive properties of soft tissue. Measurement results were compared to literature data for patient safety. RESULTS: The highest achievable phantom averaged SAR was determined by calorimetry to be 2.0+/-0.1W/kg due to the highly conservative SAR estimation model used by this 7-T MR system. The maximum temperature increase at this SAR level was below 1.0 degrees C for all extracranial neurosurgical implants that underwent testing. CONCLUSION: The findings indicated that RF-related heating under the conditions used in this investigation is not a significant safety concern for patients with the particular extracranial neurosurgical implants evaluated in this study. PMID- 23643159 TI - Probing of susceptibility structures through the distant dipolar field effect. AB - In this paper, the utilization of the distant dipolar field (DDF) signal to extract the properties of susceptibility structures over a subvoxel length scale is investigated. Numerical simulations are performed to study a system of randomly distributed blood vessels with a susceptibility offset inside a voxel. It is shown that the DDF signal of the system as a function of the strength of the correlation gradient field manifests a peak that depends on the volume ratio, size, and susceptibility offset of the blood vessels. In particular, the location of the signal peak is found to vary as powers of these parameters. As a result, by varying the strength of the correlation gradient field, the characteristic properties of the blood vessels can be extracted from the peak position of the DDF signal. It is also found that, for a given volume ratio of the blood vessels, a smaller size of the blood vessels can be probed when the susceptibility offset is increased. Nevertheless, it is demonstrated that, owing to the broad width of the signal peak, the DDF effect generally cannot be used for the preferential selection of the signal arising from the blood vessels on the length scale determined by the correlation length. PMID- 23643160 TI - [Effect of pulsed electrical stimulation on the proliferation and differentiation of H9c2 cells]. AB - OBJECTIVE: To observe the inhibition of pulsed electric stimulation on the proliferation of H9c2 cells and the induction on the differentiation of the cells. METHODS: We applied a set of pulse electrical stimulations of different frequencies (0, 1, 5, 10, 50, 100 Hz), different voltage (0, 5, 10, 20, 40, 50 V) and different time (0, 1, 2, 4, 6, 8 h/d) on H9c2 cells in rats. 5-azacytidine was used as an intervention factor control. We detected the proliferation rate of H9c2 cells through MTT assay, the expressions of cardiac troponin T (cTNT) and Oct4 through immunofluorescence cytochemical staining, and the expressions of cTNT and alpha-MHC mRNA using RT-PCR method. RESULTS: Pulsed electric stimulation inhibited the proliferation of H9c2 cells (P<0.05). The pulsed electric stimulation of 1 Hz, 4 h/d and 10 V was proved optimized in inhibiting the growth of H9c2 cells to the greatest extent but not inducing the death of cells. Two weeks after the optimized pulsed elctric stimulation on H9c2 cells, the expression of Oct4 was reduced (P<0.05), while the expressions of cTNT and alpha MHC were still strong. CONCLUSION: Pulsed electric stimulation can not only inhibit the reproduction of myoblast cell line H9c2 in heart tissue of rat embryo, but also induce the differentiation of H9c2 cells. During it, the expressions of cTNT and alpha-MHC are enhanced but Oct4 is weakened. PMID- 23643161 TI - [Effect of Kruppel like factor 4 gene silencing on apoptosis and phagocytosis of murine RAW264.7 macrophages]. AB - OBJECTIVE: To investigate the effect of down-regulation of Kruppel like factor 4 (KLF4) by RNA interference on proliferation, apoptosis and phagocytosis in murine RAW264.7 macrophage cell line. METHODS: Stable KLF4 silencing in RAW264.7 cells was achieved by recombinant shRNA plasmid targeting murine KLF4 gene via liposome mediated transfection, followed by G418 selection. The efficacy of KLF4 silencing in G418 resistant cells was verified by fluorescent microcopy and Western blotting, respectively. Proliferative activity was analyzed by CCK-8 assay. Apoptosis and phagocytosis were evaluated by annexinV-FITC/PI staining and flow cytometry with assistant use of fluorescein-labeled E.coli K-12 particles, respectively. RESULTS: KLF4 protein expression was significantly down-regulated by the recombinant shRNA plasmid as compared with negative control (NC) plasmid transfection, inhibition rate being over 76%. From the third day, KLF4-silencing cells exhibited lower proliferative activity as compared with NC RAW264.7 cells (P<0.05). In resting state, apoptosis rate in wide type, NC and KLF4-silencing cells were 1.73%, 6.85% and 12.76%, respectively, and KLF4-silencing resulted in a statistical difference in apoptosis as compared with NC cells (P<0.05). Finally, phagocytic capability in wide type, NC and KLF4-silencing cells revealed by the mean fluorescence intensity of engulfed FITC-labeled E.coli particles were 122.0 +/- 2.80, 48.97 +/- 5.69 and 80.10 +/- 4.61, respectively, and compared with NC cells, KLF4-silencing cells had a significant increase in phagocytosis (P<0.05). CONCLUSION: KLF4 gene silencing inhibits RAW264.7 macrophage proliferation, increase apoptosis and enhance phagocytic function in resting state, which provides a novel tool for revealing the role of KLF4 in macrophage immunity. PMID- 23643162 TI - [Immunostimulator CH2a bearing thiazolidin-4-one promotes the function of human iNKT cells in vitro]. AB - OBJECTIVE: To explore the immunostimulatory effect of immunostimulant CH2a bearing thiazolidin-4-one on human invariant natural killer T (iNKT) cell function in vitro. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from healthy adults, and then amplified with alpha-Galcer and IL-2 in vitro. The iNKT cells were isolated from these proliferating cells by magnetic activated cell sorting (MACS) method. The purified iNKT cells were labled with 5 (and 6)-carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) and then incubated with CH2a for functional analysis, including cell proliferation, expressions of IFN-gamma and IL-4 by flow cytometry, proliferation rate and cytotoxicity by MTT assay. In additon, ELISA was performed to determine the levels of IFN-gamma and IL-4 in cell culture media. RESULTS: CH2a significantly promoted the proliferation of iNKT cells induced by IL-2 in vitro, stimulated the release of both IFN-r and IL-4, and led to the increase in IFN-gamma/IL-4 ratio. More importantly, the cytotoxicity of iNKT was also markedly elevated under the stimulation of CH2a. CONCLUSION: Immunostimulant CH2a probably promote the production of Th1-like cytokines and the differentiation of Th0 to Th1, so as to improve cellular immune function. In addition, CH2a could significantly enhance the cytotoxicity of iNKT cells. PMID- 23643163 TI - [Construction and identification of recombinant adenovirus of muramidase-released protein gene fragment from Streptococcus suis type 2]. AB - OBJECTIVE: To construct and identify the recombinant adenovirus of muramidase released protein (MRP) gene fragment from Streptococcus suis type 2 (SS2). METHODS: The specific primers were designed based on the sequence of MRP gene fragment. The MRP gene fragment (467-1351 bp) was amplified by PCR method with genomic DNA of SS2 as a template. PCR products were cloned in pMD18-T vector. Then MRP gene fragment was linked into the adenovirus shuttle plasmid (pShuttle CMV) to construct recombinant shuttle plasmid (pShuttle-CMV-MRP). After PmeI digestion, it was transformed into BJ5183-AD-1 competent cells containing adenoviral backbone plasmid pAdEasy-1 to construct homogeneous recombinant adenovirus plasmid (pAdeno-CMV-MRP). Then the recombinant adenovirus plasmid was linearized by PmeI and then transfected into AD-293 cells for viral packaging. Finally, the virus liquid was tested by PCR and Western blotting. RESULTS: Cytopathic effect (CPE) was observed at 8 d after transfection of linear pAdeno CMV-MRP in AD-293 cells. MRP gene fragment and protein expression were also detected in the virus liquid. CONCLUSION: The recombinant adenovirus of MRP gene fragment (rAdeno-MRP) from SS2 was constructed successfully. PMID- 23643164 TI - [Expressions of reactive oxygen species and fibronectin are regulated by transcriptional co-activator p300 in human mesangial cells exposed to high glucose and methylglyoxal advanced glycation end products]. AB - OBJECTIVE: To study the roles and interrelationship of transcriptional co activator p300 and protein kinase Cbeta2(PKCbeta2) in the production of reactive oxygen species (ROS) and the expression of fibronectin in human mesangial cells (HMCs) under the stimulation of high glucose and methylglyoxal-derived advanced glycation end products (AGEs). METHODS: The HMCs were divided into the following groups: 1 normal glucose group (NG), high glucose group (HG), osmotic control group (LG), normal glucose+bovine serum albumin group (BSA), normal glucose+AGEs group (AGEs); 2 high glucose+empty vector group (HN), high glucose+PKCbeta2 group (PO), high glucose+PKCbeta2 inhibitor CGP53353 group (PI), AGEs+empty vector group (AN), AGEs+PKCbeta2 group (APO), AGEs+PKCbeta2 inhibitor CGP53353 group (API); 3 normal glucose+p300 inhibitor garcinol group (NG+Gar), high glucose+garcinol group (HG+Gar), BSA+garcinol group (BSA+Gar), and AGEs+garcinol group (AGEs+Gar). All cells in each group were cultured for 2 d. ROS levels were measured by fluorescence microscope and fluorescence microplate reader. The protein expressions of p300, PKCbeta2 and fibronectin were detected by Western blotting. RESULTS: Levels of p300, PKCbeta2 and ROS in HG and AGEs groups were elevated by 1.04, 1.26, 0.78 and 1.45, 1.07, 0.71 folds of those in NG group and BSA control group, respectively (P<0.05). However, ROS levels in HG+Gar and AGEs+Gar groups decreased significantly to 0.43 and 0.39 folds of those in HG and AGEs groups, respectively (P<0.05). p300 and PKCbeta2 protein expressions in PO and APO groups were up-regulated by 1.19, 1.73 and 1.23, 1.69 folds compared with HG and AGEs groups, respectively (P<0.05). However, in the present of CGP53353, both p300 and PKCbeta2 decreased significantly (P<0.05); the two factors stayed stable in HN and AN groups as compared with HG and AGEs groups. Expressions of p300 and FN proteins decreased in HG+Gar and AGEs+Gar groups, being 31%, 43% and 37%, 29% of those in HG and AGEs groups, respectively (P<0.05). CONCLUSION: High glucose and AGEs can up-regulate the expressions of ROS and fibronectin in human mesangial cells by activating transcriptional co-activator p300. PMID- 23643165 TI - [Changes of protein expression in HepG2 cells with CDK2 RNA interference]. AB - OBJECTIVE: To investigate the effects of stable transfection of CDK2 siRNA on biological activities and nuclear proteins of human hepatocellular carcinoma HepG2 cells. METHODS: HepG2 cells were transfected with the eukaryotic expression vector of P(Genesil-1-CDK2); via RNA interference and selected for the ones with stable transfection. We observed the changes in the cell growth curve and cell cycle. The mRNA contents of CDK2 and differentially expressed nucleoproteins were detected and analyzed by RT-PCR and two-dimensional (2D) electrophoresis-mass spectrum (MS)-database, respectively. Western blotting were used to confirm the differential protein expressions. RESULTS: Compared with P(HK-siRNA);-HepG2 and untransfected groups, the proliferation of HepG2 cells in P(CDK2-siRNA);-HepG2 group was significantly inhibited (P<0.01), and the expression of CDK2 mRNA significantly decreased in P(CDK2-siRNA);-HepG2 group. Four proteins not expressed in P(CDK2-siRNA);-HepG2 cells were detected by 2D electrophoresis-MS, and they were further confirmed by Western blotting. CONCLUSION: CDK2 siRNA significantly suppressed CDK2 mRNA expression and the proliferation of HepG2 cells, four proteins not expressed in p(CDK2-siRNA);-HepG2 cells are similar to ribosomal protein S12, beta-actin, zine finger 276 and chaperonin 10 related protein. PMID- 23643166 TI - [Effect of electrical stimulation on the differentiation of induced pluripotent stem cells into cardiomyocytes induced by vitamin C in vitro]. AB - OBJECTIVE: To investigate the effect of electrical stimulation on the differentiation of induced pluripotent stem cells (iPSCs) into cardiomyocytes in vitro. METHODS: Classical hanging-drop method was used to induce iPSCs from mice to form embryoid bodies (EBs) and vitamin C was contained in the medium through the induction period. According to whether or not electrical stimulation was used in the whole induction period, iPSCs were divided to electrical stimulation group and non-stimulation group. During the induction, dynamic morphological changes of the EBs were observed and photographed, the time point when beating EBs in each group appeared was recorded and the number of them was counted. The percentage of beating ones in all EBs was calculated as the differentiation rate of cardiomyocytes induced from iPSCs. Furthermore, expression of cardiac troponin T (cTnT) was observed by immunofluorescent staining under a confocal laser scanning microscope (CLSM), and mRNA expression levels of the related genes Oct-4, GATA-4 and alpha-MHC were analyzed by RT-PCR. RESULTS: Compared with the non-stimulation group, beating cells in electrical stimulation group appeared in a shorter time, and the differentiation rate of cardiomyocytes was higher [(68.89 +/- 5.09)% vs (52.22 +/- 3.85)%, P<0.05]. c-TnT was expressed in the beating area of both groups, but the cells in the electrical stimulation group showed a more clear cytoskeleton. The mRNA level of Oct-4 decreased in a time-dependent manner in the whole period of induction and in the electrical stimulated group it decreased faster than the non-stimulation group (P<0.05). In addition, more GATA4 and alpha MHC mRNA in electrical stimulation group were expressed than the non-stimulated group at the same point-in-time (P<0.05). CONCLUSION: The electrical stimulation which simulates cardiac electrical microenvironment to some extent improved the differentiation of iPSCs into functional cardiomyocytes induced by vitamin C in vitro. PMID- 23643167 TI - [Effect of recombinant human growth hormone on the secretion of TNF-alpha and IL 6 by THP-1 cells and its correlation with the NF-kappaB pathway]. AB - OBJECTIVE: To investigate the effect of recombinant human growth hormone (rhGH) on the secretion of TNF-alpha and IL-6 in THP-1 cells and analyze the correlation between the secretion and NF-kappaB signaling pathway. METHODS: The concentrations of TNF-alpha and IL-6 in the supernatants of THP-1 induced by rhGH were measured with ELISA. The effects of LPS and an NF-kappaB inhibitor, BAY11 7082 on the secretion of TNF-alpha and IL-6 were also observed. The activity of NF-kappaB was detected by luciferase reporter and electrophoretic mobility shift assay (EMSA) in THP-1 cells induced by rhGH. RESULTS: rhGH alone promoted the secretion of TNF-alpha and IL-6 in THP-1 cells while inhibited the secretion of TNF-alpha and IL-6 in THP-1 stimulated by LPS. BAY11-7082 inhibited the secretion of TNF-alpha and IL-6 in THP-1 stimulated by LPS and rhGH. The activity of NF kappaB was significantly correlated with the secretion of TNF-alpha and IL-6. CONCLUSION: rhGH played a bidirectional role in the regulation on the secretion of TNF-alpha and IL-6 via NF-kappaB signaling pathway in THP-1 cells. PMID- 23643168 TI - [Inhibiting effect of IL-10 in tumor microenvironment on anti-tumor activity of SOCS1-silenced DC vaccine]. AB - OBJECTIVE: To observe the anti-tumor effect of suppressors of cytokine signaling 1(SOCS1)-silenced dentritic cell (DC) vaccines in melanoma-bearing mice, and the influence of IL-10 in the tumor microenvironment on DC vaccine action. METHODS: To obtain SOCS1-silenced DCs, DCs derived from mouse bone marrow cells ex vivo were induced to differentiation in the presence of granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-4, and then transduced with Len-SOCS1-shRNA or control Len-GFP lentiviruses. The SOCS1-silenced DCs were loaded by TRP2 peptide to prepare the DC vaccine, which was induced to mature by LPS. The DCs were analyzed by flow cytometry (FCM) for surface expressions of MHCII and CD86 and by real-time PCR for the expressions of SOCS1, IL-10 as well as IL-12p40. B16 or IL 10-silenced B16 (IL-10(-/-);) cells were inoculated into C57BL/6 mice. Five days later, the mice were randomly divided into 3 groups (PBS-DC, Len-DC and SOCS1 shRNA-DC groups) and injected with 1*106;/100 MUL per mouse of the transduced DCs or PBS-DCs. We observed the tumor growth and the survival of the tumor-bearing mice. Tumor-infiltrating leukocytes (TIL) were isolated from tumor tissues using the discontinuous gradient centrifugation and the distribution of CD8+;T was analyzed by FCM; IFN-gamma secretion and CTL activity were detected by the ELISpot and the standard microcytotoxicity assay, respectively. RESULTS: SOCS1 expression in DCs was down-regulated by 80% after Len-SOCS1-shRNA lentivirus infection. In the DCs with down-regulated SOCS1 expression, the expressions of MHCII and CD86 increased a little, which did not differ significantly from the control DCs, and IL-10 level dropped and IL-12p40 went up significantly compared with the control DCs. There was no any effect of SOCS1-silenced DCs on the survival of melanoma-bearing mice, however, the survival of B16-IL-10(-/-); bearing mice was promoted(P<0.05). The further investigation showed that SOCS1 shRNA DCs raised the number of CD8+;T lymphocytes, promoted the TRP2-specific IFN gamma production and CTL responses in B16-IL-10(-/-);-bearing mice. CONCLUSION: The activity of the DC vaccine could be enhanced by silencing SOCS1 expression; however, the anti-tumor activity of SOCS1-silenced DC vaccine could be inhibited by IL-10 in tumor microenvironment. PMID- 23643169 TI - [Optimization of bacterial display technology based on antigen-antibody co expression]. AB - OBJECTIVE: To co-express antigen and antibody in E.coli periplasm in which the antigen and antibody will fold correctly and bind to each other. METHODS: Human IL-1beta gene and mouse anti-human IL-1beta single chain variable fragment (anti hIL-1beta scFv) were inserted into the down stream from the NlpA and pelB leading peptides of pBFD vector respectively. The recombinant plasmid was named pBFD-Ab Ag. The E.coli DH5alpha transformed with pBFD-Ab-Ag was induced by IPTG to co express antigen and antibody. After the outer membrane of E.coli DH5alpha was broken (spheroplast formation), the bacteria were incubated with mouse anti-hIL 1beta antibody labeled by FITC. The co-expression and interaction of antigen and antibody was analyzed by flow cytometry (FCM) based on fluorescence signal intensity. RESULTS: The FCM detection showed the strong signal in E.coli DH5alpha transformed with pBFD-Ab-Ag and the positive rate was significantly improved. CONCLUSION: The results showed that the antigen and antibody can fold and bind to each other efficiently in E.coli periplasm. The system can make antibody screening process easier and also provide a novel method for protein-protein interaction. PMID- 23643170 TI - [Preparation and characterization of monoclonal antibodies against viral hemorrhagic septicemia virus]. AB - OBJECTIVE: To prepare the monoclonal antibody (mAb) against viral hemorrhagic septicemia virus (VHSV) and analyze the biological properties. METHODS: The BALB/c mice were immunized with the VHSV which was purified by differential centrifugation. Spleen cells of the immune mice were collected and fused with Sp2/0 myeloma cells by hybridoma technology. The indirect ELISA was used to screen hyridoma cells and identify the specificity of mAb. The Western blotting was used to identify antigen site. RESULTS: After three cycle of subcloning with limited dilution method, we obtained a cell strain that secreted mAb against VHSV and was named 4A5. The indirect ELISA showed that the titer of mAb ascites was 10 4;. It belonged to IgG3 subclass kappa chain and couldn't react with other fish viruses or fish cell lines in the ELISA except VHSV. Western blotting revealed that mAb 4A5 bound to a 70 kDa of protein band of VHSV as antigen. CONCLUSION: The obtained mAb has a high specificity, which could be used for rapid diagnosis and detection of VHSV in aquaculture. PMID- 23643171 TI - [Immunoregulation of autologous peripheral blood stem cell transplantation in patients with hepatitis B-related end-stage liver disease]. AB - OBJECTIVE: To investigate the immunoregulatory effect of autologous peripheral blood stem cells (PBSCs) transplantation on T lymphocytes and cytokines in patients with HBV-related end-stage liver disease. METHODS: Flow cytometry was used to measure the percentages of Th1, Th2 and regulatory T cells (Treg) in peripheral blood. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the levels of serum IFN-gamma, IL-6 and IL-10. RESULTS: Patients with HBV related end-stage liver disease displayed significantly improved liver function after PBSCs transplantation. Statistically, after PBSCs transplantation, the percentages of Th2 and Treg in peripheral blood markedly increased, but serum IL 6 and IL-10 declined significantly. No significant differences were observed in the changes of Th1 and its cytokine, IFN-gamma after transplantation. CONCLUSION: Autologous PBSCs transplantation can depress inflammation in liver by regulating immune microenvironment, which at least in part delineates the mechanism of stem cells-mediated therapeutic benefit on end-stage liver disease. PMID- 23643172 TI - [Detection of serum autoantibodies against premelanosome protein 17 increases in the vitiligo patients]. AB - OBJECTIVE: To detect the distribution of autoantibodies against premelanosome protein 17 (Pmel 17) in the sera of vitiligo patients with the recombinant Pmel 17 protein. METHODS: The cDNA encoding human Pmel 17 was amplified by RT-PCR from the primary melanocytes and was cloned into vector pMD19-T and subsequently the expression vector pGEX-4T-1. After being induced by IPTG, the recombinant Pmel 17 protein was purified by high-performance affinity chromatography. The presence of autoantibodies against Pmel 17 in the sera of vitiligo patients was determined by indirect ELISA coated with recombinant Pmel 17 protein. RESULTS: The recombinant Pmel 17 plasmids were right as we expected by DNA sequencing. The recombinant Pmel 17 protein was successfully expressed and purified. The indirect ELISA revealed that, as compared with healthy control group (0/100, 0%), positive rate of the serum autoantibodies in the progress vitiligo patients was 22% and positive rate of stable vitiligo patients was only 2%(2/100). The difference of positive rate between patients with progress and stable vitiligo was statistically significant. CONCLUSION: The recombinant Pmel 17 protein was successfully expressed. The autoantibodies against Pmel 17 is closely related to the severity of vitiligo. PMID- 23643173 TI - [Cloning and expression of Neisserial surface protein A gene and its applicalion in detection of serum specific antibody]. AB - OBJECTIVE: To construct recombinant protein of Neisserial surface protein A (NspA) and determine the anti-NspA antibody levels using it as antigen in patients at the recovery stage of Neisseria meningitides, so as to explore the possibility of using NspA protein as the antigen for designing a novel vaccine for epidemic Neisseria meningitides. METHODS: NspA gene was cloned from the isolated pathogen of patients with Neisseria meningitides to construct the prokaryotic expression vector. NspA protein was expressed in the form of soluble protein in E.coli and purified by GSTrap FF affinity chromatography. The antibody titers of recovery-stage patients with Neisseria meningitides were determined using the purified recombinant NspA. RESULTS: Functional NspA was successfully expressed with Mr; being 44 000. The purified NspA had a good biological function. Antibodies against NspA could be detected in the sera of patients at the recovery stage of Neisseria meningitides using NspA protein. Positive rate reached 90% when titer was 1:40. CONCLUSION: Recombinant NspA protein was expressed successfully and it could be used to detect the anti-NspA antibodies in the sera of patients with Neisseria meningitides at recovery stage. PMID- 23643174 TI - [Establishment of an intrahepatic xenograft tumor model in nude mice and its detection by in vivo fluorescence imaging system]. AB - OBJECTIVE: To establish an intrahepatic xenograft tumor model in nude mice and dynamically monitor the tumor growth by in vivo fluorescence imaging system. METHODS: We first transfected the recombinant plasmid pcDNA3.1-Luc to constructe the PLC/PRF/5 cell line which stably expressed luciferase, and then injected the cell line into the liver of nude mice. Tumor growth was monitored dynamically using in vivo fluorescence imaging system. The fluorescence-positive mouse was dissected to observe the tumor. Immunofluoresence histochemistry was used to detect the expression of HBsAg in Xenografe. RESULTS: In the nude mouse model bearing intrahepatic xenograft tumor, robust fluorescence was detected where the PLC/PRF/5 cells were injected. Xenograft was observed in the liver by dissecting the fluorescence-positive mouse. The expression of HBsAg in xenograft tissues was confirmed. CONCLUSION: Intrahepatic xenograft tumor model in nude mice has been established successfully, which offers a tool for therapeutic development and evaluation of anti-hepatocelluar carcinoma drugs. PMID- 23643175 TI - [Establishment and preliminary application of a quantitative real-time PCR method for detecting the transcriptions of Th1/Th2 cytokines in RAW264.7 cells]. AB - OBJECTIVE: To establish a quantitative real-time PCR method to detect the transcriptions of Th1/Th2 cytokines in RAW264.7 cells. METHODS: The specific primers were designed according to the sequences of TNF-alpha, IFN-gamma, IL-2, IL-4, IL-6, IL-10 and beta-actin in GenBank database. Total RNA was extracted from RAW264.7 cells, and then was reverse-transcriped into cDNA, which was established as a positive standard template of the quantitative real-time PCR method. The established method was used to detect the cytokine transcriptions in RAW264.7 cells infected with Brucella abortus S2308. RESULTS: Cytokine genes above had a good linear relationship (R(2);>= 0.982) with the detection limit of 10(2); copies/MUL standard samples. The established quantitative real-time PCR method showed high specificity, sensitivity, and single melting peak for every cytokine. CONCLUSION: The quantitative real-time PCR method for detecting the transcription levels of cytokine Th1 and Th2 of macrophage RAW264.7 cells was established successfully. PMID- 23643176 TI - Randomized phase II trial of uracil/tegafur and cisplatin versus vinorelbine and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage III non-small-cell lung cancer: NJLCG 0601. AB - INTRODUCTION: The optimal chemotherapy with thoracic radiotherapy (TRT) for locally advanced non-small-cell lung cancer (NSCLC) remains to be established. This randomized phase II study of concurrent chemoradiotherapy was conducted to compare uracil/tegafur (UFT) and cisplatin with vinorelbine and cisplatin for stage III NSCLC. PATIENTS AND METHODS: Patients with unresectable stage III NSCLC were randomized to receive UP (400 mg/m(2) UFT on days 1-14 and 29-42 and 80 mg/m(2) cisplatin on days 8 and 36) or NP (20 mg/m(2) vinorelbine on days 1, 8, 29, and 36 and 80 mg/m(2) cisplatin on days 1 and 29). TRT began on day 1 (total 60 Gy in 30 fractions). RESULTS: Of 70 enrolled patients, 66 were evaluable for efficacy and safety. The overall response rates were 80% (95% CI: 67-93%) and 71% (95% CI: 55-87%) for the UP arm and the NP arm. With a median follow-up of 20.2 months, the progression-free survival and median survival time were 8.8 and 26.9 months in the UP arm, and 6.8 and 21.7 months in the NP arm. The 2-/3-year survival rates were 51.0/34.3% and 46.9/33.4% for the UP arm and the NP arm, respectively. Grade 3/4 neutropenia occurred in 20% and 58% of patients in the UP and NP arms, respectively. CONCLUSION: Combined with concurrent TRT, the UP arm achieved better efficacy and safety compared with the NP arm, suggesting it to be a promising candidate as a standard regimen for locally advanced NSCLC. Further evaluation of the UP arm is warranted. PMID- 23643177 TI - Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study. AB - Platinum-based chemotherapy is the standard treatment for patients with advanced non-small cell lung cancer (NSCLC), but the evidence of its efficacy among ECOG performance status (PS)2 patients is weak because these patients are usually excluded from clinical trials; concern exists about tolerability and feasibility of standard chemotherapy in these patients. No prospective randomized trial has tested the addition of cisplatin to single-agent chemotherapy in patients with advanced NSCLC and PS2. CAPPA-2 was a multicenter, randomized phase 3 study for first-line treatment of PS2 patients with advanced NSCLC. Patients, aged 18-70, were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes (TNM VI edition) and adequate organ function. Patients in standard arm received gemcitabine 1200 mg/m(2) days 1 and 8. Patients in experimental arm received cisplatin 60 mg/m(2) day 1 plus gemcitabine 1000 mg/m(2) days 1 and 8. All treatments were repeated every 3 weeks, up to 4 cycles, unless disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). To have 80% power of detecting hazard ratio (HR) 0.71, corresponding to an increase in median OS from 4.8 to 6.8 months, 285 deaths were required. The study was stopped in June 2012 after the enrolment of 57 patients, due to the slow accrual and the report of positive results from a similar study. Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin plus gemcitabine (HR 0.52, 95% CI 0.28-0.98, p = 0.039). Combination chemotherapy produced longer PFS (median 1.7 vs. 3.3 months, HR 0.49, 95% CI 0.27 0.89, p = 0.017) and higher response rate (4% vs. 18%, p = 0.19), without substantial increase in toxicity. The addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC. PMID- 23643178 TI - Osteogenic induction protects rat bone marrow-derived mesenchymal stem cells against hypoxia-induced apoptosis in vitro. AB - BACKGROUND: Bone marrow-derived mesenchymal stem cells (BMSCs) undergo hypoxia induced apoptosis when cells are transplanted from a normoxic to a hypoxic microenvironment in vivo. The effect of the osteogenic microenvironment on BMSCs under hypoxic conditions has not yet been revealed. MATERIALS AND METHODS: In the current study, we investigated the effects on BMSCs of hypoxia and osteogenic induction (OI) individually and in combination. We isolated BMSCs from rat bone marrow and confirmed them by recognition of surface antigens using cytometry. After passaging the BMSCs to the third generation, we treated them with the following conditions: 1% oxygen and OI, normoxia and OI, and 1% oxygen without OI; normoxia without OI was the control condition. On days 3, 7, 14, and 21, we detected the expression levels of hypoxia inducible factor-1alpha and alkaline phosphate via Western blotting. Cellular apoptosis was detected by Hoechst staining and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine, 5' triphosphate nick end labeling; caspase activity was also detected. RESULTS: The expression of hypoxia inducible factor-1alpha was induced and up-regulated when BMSCs were grown under 1% oxygen. The incidence of terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine, 5'-triphosphatenick end labeling-positive cells in the hypoxia plus OI group was much lower than that in the hypoxia group without OI. Caspase activity increased on days 3, 7, 14, and 21. The absolute value of caspase was statistically higher in the BMSC hypoxia group than in the other three groups, whose values were similar to each other. CONCLUSIONS: Osteogenic induction could protect BMSCs against hypoxia-induced apoptosis. Bone marrow-derived mesenchymal stem cells may be appropriate candidate cells for cytotherapy for skeletal diseases. PMID- 23643179 TI - Intravenous rt-PA in patients with ischaemic stroke and renal dysfunction. AB - OBJECTIVE: Renal dysfunction (RD) increases risk for ischaemic stroke (IS). The impact of RD on the effects of iv-thrombolysis in the Caucasian population has not been fully determined. AIMS: To evaluate the associations between RD and the outcome of iv-thrombolysis in Caucasian patients with IS. METHODS: The observational, multicentre study included 404 patients with IS who were treated with iv-thrombolysis. RD was defined as estimated glomerular filtration rate <= 60 ml/min/1.73 m(2). Outcome was assessed with modified Rankin Score at 3 months after the stroke onset. RESULTS: Medians baseline NIHSS score did not differ between groups of patients with and without RD (12.0 vs. 11.0 pts, p=0.33). Unfavourable outcome was found in 52.1% of patients with and in 41.2% of patients without RD (p=0.05), mortality was higher in patients with RD (29.9% vs. 14.3%, p<0.001), and the presence of haemorrhagic transformation (HT) did not differ between the groups (17.1% vs. 17.1% respectively, p=0.996). A multivariate analysis showed no impact of RD on the unfavourable outcome (OR 0.98; 95%CI 0.88 1.10), mortality (OR 0.92; 95%CI 0.81-1.05) or presence of HT (OR 1.03; 95%CI 0.90-1.18). CONCLUSIONS: We found no impact of RD on the safety and efficacy of iv-thrombolysis in Caucasian patients with IS. PMID- 23643180 TI - Clinical presentation, etiology, and survival in adult acute encephalitis syndrome in rural Central India. AB - BACKGROUND: Acute encephalitis syndrome (AES) is a constellation of symptoms that includes fever and altered mental status. Most cases are attributed to viral encephalitis (VE), occurring either in outbreaks or sporadically. We conducted hospital-based surveillance for sporadic adult-AES in rural Central India in order to describe its incidence, spatial and temporal distribution, clinical profile, etiology and predictors of mortality. METHODS: All consecutive hospital admissions during the study period were screened to identify adult-AES cases and were followed until 30-days of hospitalization. We estimated incidence by administrative sub-division of residence and described the temporal distribution of cases. We performed viral diagnostic studies on cerebrospinal fluid (CSF) samples to determine the etiology of AES. The diagnostic tests included RT-PCR (for enteroviruses, HSV 1 and 2), conventional PCR (for flaviviruses), CSF IgM capture ELISA (for Japanese encephalitis virus, dengue, West Nile virus, Varicella zoster virus, measles, and mumps). We compared demographic and clinical variables across etiologic subtypes and estimated predictors of 30-day mortality. RESULTS: A total of 183 AES cases were identified between January and October 2007, representing 2.38% of all admissions. The incidence of adult AES in the administrative subdivisions closest to the hospital was 16 per 100,000. Of the 183 cases, a non-viral etiology was confirmed in 31 (16.9%) and the remaining 152 were considered as VE suspects. Of the VE suspects, we could confirm a viral etiology in 31 cases: 17 (11.2%) enterovirus; 8 (5.2%) flavivirus; 3 (1.9%) Varicella zoster; 1 (0.6%) herpesvirus; and 2 (1.3%) mixed etiology); the etiology remained unknown in remaining 121 (79.6%) cases. 53 (36%) of the AES patients died; the case fatality proportion was similar in patients with a confirmed and unknown viral etiology (45.1 and 33.6% respectively). A requirement for assisted ventilation significantly increased mortality (HR 2.14 (95% CI 1.0 4.77)), while a high Glasgow coma score (HR 0.76 (95% CI 0.69-0.83)), and longer duration of hospitalization (HR 0.88 (95% CI 0.83-0.94)) were protective. CONCLUSION: This study is the first description of the etiology of adult-AES in India, and provides a framework for future surveillance programs in India. PMID- 23643181 TI - Ictal bradycardia and asystole in an adult with a focal left insular lesion. PMID- 23643182 TI - Factors affecting the structure and maturation of human tissue engineered skeletal muscle. AB - Tissue engineered skeletal muscle has great utility in experimental studies of physiology, clinical testing and its potential for transplantation to replace damaged tissue. Despite recent work in rodent tissue or cell lines, there is a paucity of literature concerned with the culture of human muscle derived cells (MDCs) in engineered constructs. Here we aimed to tissue engineer for the first time in the literature human skeletal muscle in self-assembling fibrin hydrogels and determine the effect of MDC seeding density and myogenic proportion on the structure and maturation of the constructs. Constructs seeded with 4 * 10(5) MDCs assembled to a greater extent than those at 1 * 10(5) or 2 * 10(5), and immunostaining revealed a higher fusion index and a higher density of myotubes within the constructs, showing greater structural semblance to in vivo tissue. These constructs primarily expressed perinatal and slow type I myosin heavy chain mRNA after 21 days in culture. In subsequent experiments MACS((r)) technology was used to separate myogenic and non-myogenic cells from their heterogeneous parent population and these cells were seeded at varying myogenic (desmin +) proportions in fibrin based constructs. Only in the constructs seeded with 75% desmin + cells was there evidence of striations when immunostained for slow myosin heavy chain compared with constructs seeded with 10 or 50% desmin + cells. Overall, this work reveals the importance of cell number and myogenic proportions in tissue engineering human skeletal muscle with structural resemblance to in vivo tissue. PMID- 23643183 TI - Analysis of giant electrorheological fluids. AB - The yield stress dependence on electric field strength for giant electrorheological (GER) fluids over the full range of electric fields was examined using Seo's scaling function which incorporated both the polarization and the conductivity models. If a proper scaling was applied to the yield stress data to collapse them onto a single curve, the Seo's scaling function could correctly fit the yield stress behavior of GER suspensions, even at very high electric field strengths. The model predictions were also compared with recently proposed Choi et al.'s model to allow a consideration of the universal framework of ER fluids. PMID- 23643184 TI - One-pot hydrothermal synthesis of Co(OH)2 nanoflakes on graphene sheets and their fast catalytic oxidation of phenol in liquid phase. AB - A cobalt hydroxide (Co(OH)2) nanoflake-reduced graphene oxide (rGO) hybrid was synthesized by a one-pot hydrothermal method using glucose as a reducing agent for graphene oxide (GO) reduction. The structural and surface properties of the material were investigated by scanning and transmission electron microscopies, energy-dispersive X-ray spectrometry, powder X-ray diffraction, Fourier transform infrared spectroscopy, and thermogravimetric analysis. Catalytic activities of GO, rGO, Co(OH)2 and Co(OH)2-rGO in aqueous phenol degradation using peroxymonosulfate as an oxidant were compared. A synergetic effect on the catalytic activity was found on the Co(OH)2-rGO hybrid. Although rGO has weak catalytic activity, Co(OH)2-rGO hybrid showed a higher catalytic activity than Co(OH)2. The phenol degradation on Co(OH)2-rGO was extremely fast and took around 10 min for 100% phenol removal. The degradation was found to follow the first order kinetics and a mechanism for phenol degradation was presented. PMID- 23643185 TI - Recruitment of Th1 effector cells in human tuberculosis: hierarchy of chemokine receptor(s) and their ligands. AB - Selective recruitment of IFN-gamma biased Th1 effector cells at the pathologic site(s) determines the local immunity of tuberculosis (TB). We observed the enrichment of CXCR3, CCR5 and CD11a(high) T cells in the peripheral blood, pleural fluid and bronchoalveolar lavage of TB pleural effusion (TB-PE) and miliary tuberculosis (MTB) patients respectively. CXCR3(+)CCR5(+) T cells were significantly high at the local disease site(s) in both the forms of TB and their frequency was highest among activated lymphocytes in TB-PE. Interestingly, all CCR5(+) cells were invariably positive for CXCR3 but all CXCR3(+) cells did not co-express CCR5 in pleural fluid whereas the situation was reverse in bronchoalveolar lavage. These CXCR3(+)CCR5(+) cells dominantly produced IFN-gamma in response to Mycobacterium tuberculosis antigen. In vitro chemotaxis assay indicates dominant role of RANTES and IP-10 in the selective recruitment of CXCR3(+)CCR5(+)cells at the tubercular pathologic sites. PMID- 23643186 TI - A versatile polydopamine platform for facile preparation of protein stationary phase for chip-based open tubular capillary electrochromatography enantioseparation. AB - A novel, simple, and economical method for the preparation of chiral stationary phases for chip-based enantioselective open tubular capillary electrochromatography (OT-CEC) using polydopamine (PDA) coating as an adhesive layer was reported for the first time. After the poly(dimethylsiloxane) (PDMS) microfluidic chip was filled with dopamine (DA) solution, PDA film was gradually formed and deposited on the inner wall of microchannel as permanent coating via the oxidation of DA by the oxygen dissolved in the solution. Due to possessing plentiful catechol and amine functional groups, PDA coating can serve as a versatile multifunctional platform for further secondary reactions, leading to tailoring of the coatings for protein bioconjugation by the thiols and amines via Michael addition or Schiff base reactions. Bovine serum albumin (BSA), acting as a target protein, was then stably and homogeneously immobilized in the PDA-coated PDMS microchannel to fabricate a novel protein stationary phase. Compared with the native PDMS microchannels, the modified surfaces exhibited much better wettability, more stable and enhanced electroosmotic mobility, and less nonspecific adsorption. The water contact angle and electroosmotic flow of PDA/BSA-coated PDMS substrate were measured to be 44 degrees and 2.83*10( 4)cm(2)V(-1)s(-1), compared to those of 112 degrees and 2.10*10(-4)cm(2)V(-1)s( 1) from the untreated one, respectively. Under a mild condition, d- and l tryptophan were efficiently separated with a resolution of 1.68 within 130s utilizing a separation length of 37mm coupled with in-column amperometric detection on the PDA/BSA-coated PDMS microchips. This present versatile platform, facile conjugation of biomolecules onto microchip surfaces via mussel adhesive protein inspired coatings, may offer new processing strategies to prepare a biomimetic surface design on microfluidic chips, which is promising in high throughput and complex biological analysis. PMID- 23643187 TI - Anger as a predictor of psychological distress and self-harm ideation in inmates: a structured self-assessment diary study. AB - Suicidal ideation and behaviour are common among inmates. Anger is found at exaggerated levels and has been associated with suicidal ideation and behaviour in inmate samples suggesting its possible salience in the prediction of suicide. The study investigated relationships between anger, psychological distress, and self-harm/suicidal ideation among inmates. The principles of Ecological Momentary Assessment were considered and a structured self-assessment diary was utilised to examine relationships between the variables of interest. Participants completed a structured self-assessment diary for six consecutive days which included momentary ratings of items describing psychological states of concurrent affects, thoughts, and appraisals related to anger, psychological distress, and self harm/suicidal ideation. Psychometric assessment measures were also conducted. Temporal associations between predictors and outcomes were investigated. Multilevel modelling analyses were performed. Increased anger was significantly associated with concurrent high levels of self-harm ideation in inmates, when controlling for depression and hopelessness. Temporal analyses also revealed that anger at one time point did not predict suicidal ideation at the next time point. Elucidating the temporal nature of the relationship between anger, psychological distress, and self-harm/suicidal ideation has advanced understanding of the mechanisms of suicidal behaviour, by demonstrating an increased risk of suicide when a male inmate is angry. PMID- 23643189 TI - Reliability of clinical judgements of insight in patients with psychoses. AB - We evaluated the reliability of scaled and binary clinical judgements of insight. Twelve clinicians rated 30 DVD interview recordings of patients diagnosed with a psychotic disorder. Scaled ratings produced an ICC of 0.62. Reliability of categorical (binary) ratings was 0.37 (k). While ordinal ratings are more reliable than binary ratings, reliability across both methods is too low for important decision-making. Clinical judgements of insight are impaired by a lack of standardised diagnostic criteria. PMID- 23643190 TI - Possible conflicts of interest in medical publishing. PMID- 23643188 TI - Everyday functional ability across different phases of bipolar disorder. AB - Bipolar Disorder (BD) is a chronic illness characterized by significant neurocognitive impairment and functional deficits. Functional status is typically assessed with self-report or observer ratings restricted by poor participant insight and subjective judgment, while application of performance-based measures has been limited. We assessed functional ability in manic, depressed, and euthymic BD individuals using the UCSD Performance-Based Skills Assessment (UPSA 2), which simulates real-world tasks such as medication management. UPSA-2 was administered to 17 manic or hypomanic BD, 14 depressed BD, 23 euthymic BD, and 28 healthy comparison (HC) participants matched for age, education, and IQ. Psychopathology was quantified with the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), and the Positive and Negative Syndrome Scale (PANSS); executive functioning was assessed with the Wisconsin Card Sorting Task (WCST). All BD groups exhibited functional ability deficits on the UPSA-2 and impaired performance on the WCST compared to HC. UPSA-2 scores were lower in manic/hypomanic subjects relative to other BD participants and mania symptoms correlated with functional impairment. Poor WCST performance was also associated with worse UPSA-2 function. In summary, BD functional deficits occur across different phases of the disorder and may be impacted by symptom severity and associated with executive dysfunction. PMID- 23643191 TI - Can we really predict risk of cancer? AB - BACKGROUND: Growing awareness of the potential to predict a person's future risk of cancer has resulted in the development of numerous algorithms. Such algorithms aim to improve the ability of policy makers, doctors and patients to make rational decisions about behaviour modification or surveillance, with the expectation that this activity will lead to overall benefit. There remains debate however, about whether accurate risk prediction is achievable for most cancers. METHODS: We conducted a brief narrative review of the literature regarding the history and challenges of risk prediction, highlighting our own recent experiences in developing tools for oesophageal adenocarcinoma. RESULTS AND CONCLUSIONS: While tools for predicting future risk of cardiovascular outcomes have been translated successfully to clinical practice, the experience with cancer risk prediction has been mixed. Models have now been developed and validated for predicting risk of melanoma and cancers of the breast, colo-rectum, lung, liver, oesophagus and prostate, and while several of these have adequate performance at the population-level, none to date have adequate discrimination for predicting risk in individual patients. Challenges of individual risk prediction for cancer are many, and include long latency, multiple risk factors of mostly small effect, and incomplete knowledge of the causal pathways. PMID- 23643192 TI - Risk of adult acute and chronic myeloid leukemia with cigarette smoking and cessation. AB - BACKGROUND: Cigarette smoking is an established risk factor for adult myeloid leukemia, particularly acute myeloid leukemia (AML), but less is known about the nature of this association and effects of smoking cessation on risk. METHODS: In a large population-based case-control study of myeloid leukemia that included 414 AML and 185 chronic myeloid leukemia (CML) cases and 692 controls ages 20-79 years, we evaluated risk associated with cigarette smoking and smoking cessation using unconditional logistic regression methods and cubic spline modeling. RESULTS: AML and CML risk increased with increasing cigarette smoking intensity in men and women. A monotonic decrease in AML risk was observed with increasing time since quitting, whereas for CML, the risk reduction was more gradual. For both AML and CML, among long-term quitters (>=30 years), risk was comparable to non-smokers. CONCLUSIONS: Our study confirms the increased risk of myeloid leukemia with cigarette smoking and provides encouraging evidence of risk attenuation following cessation. PMID- 23643193 TI - Joining the dots on the emergence of pandemic influenza. AB - Extensive research in the last 20 years has unveiled some of the factors associated with the emergence of pandemic influenza A viruses. Nonetheless, numerous extrinsic and virological factors are yet to be fully understood, especially with reference to their interconnection and interdependence. Knowledge gathered so far has motivated the scientific community to embrace the One Health One Flu concept and to explore new scientific approaches in the field of influenza infections in order to make educated decisions when it comes to pandemic preparedness. As a result of this awareness, risk assessment methodology is currently being explored as a new tool to estimate the pandemic potential of influenza viruses circulating in animals, underlining the urgency for interdisciplinary collaboration and the need to share updated and high quality scientific and surveillance data. PMID- 23643194 TI - Cytokine targets in airway inflammation. AB - Asthma is an inflammatory disease of the airway wall that leads to bronchial hyper-reactivity and airway obstruction, caused by inflammation, mucus hyper production and airway wall remodelling. Central to pathogenesis, Th2 and Th17 lymphocytes of the adaptive immune system control many aspects of the disease by producing cytokines such as IL-4, IL-5, IL-13, and IL-17. In addition, many cells of the innate immune system such as mast cells, basophils, neutrophils, eosinophils, dendritic cells (DCs), and innate lymphoid cells (ILCs) play an important role in the initiation or maintenance of disease. Epithelial cells are ever more implicated in disease pathogenesis, as they are able to sense exposure to pathogens via pattern recognition receptors (PRRs) and can activate DCs. This review article will deal with the role of cytokines that are considered essential controllers of the inflammatory, immune and regenerative response to allergens, viruses and environmental pollutants. Emerging Th2 cytokines such as thymic stromal lymphopoietin, GM-CSF, IL-1, IL-33, IL-25 mediate the crosstalk between epithelial cells, DCs, and ILCs. Understanding the crosstalk between structural cells, innate and adaptive immune cells that is mediated by cytokines provides important mechanistic insights into how asthma develops and perpetuates itself. It could also provide the framework on which we will select new therapeutic strategies that prevent exacerbations and alter the natural course of the disease. PMID- 23643195 TI - Burden of cancer in Korea during 2000-2020. AB - BACKGROUND: This study estimates the burden of cancer in Korea during 2000-2020, ameliorating the Global Burden of Disease Study Group (GBD) method with the Incidence-Prevalence-Mortality (IPM) Model. METHODS: Besides using the GBD approach to calculate the Years of Life Lost in Korea during 2000-2020, this research calculates the Years Lived with Disability (YLDs) of major cancers based on the combination of the GBD method and the IPM Model. RESULTS: Colon, breast and thyroid cancers became more significant in terms of Disability Adjusted Life Years during 2000-2010 and this will continue during 2010-2020, colon cancer leading the pack instead of stomach cancer in 2020. The rise of colon cancer is more evident for the older age group and the opposite is true for breast and thyroid cancers. Indeed, stomach and liver cancers were resilient in terms of DALYs during 2000-2010 and this will continue during 2010-2020. Overall, the burden of cancer in Korea is characterized by an increasing centrality of YLDs (chronic components) as in other advanced nations. CONCLUSIONS: Korea's convergence with other advanced nations in cancer burden might reflect their convergence in living standards, the age structure, health behavior and medical technology during the past four decades. These transitions have been reflected in the Second 10-Year Plan for Cancer Control in Korea during 2006-2015, government policy consisting of four main programs, i.e., primary prevention, early detection, diagnosis/treatment and palliative care. PMID- 23643196 TI - The study of DNA methylation in urological cancer: present and future. AB - OBJECTIVES: We have synthesized the principal advances in the field of the study of epigenetics and specifically DNA methylation regarding the diagnosis of urological neoplasms. ACQUISITION OF EVIDENCE: Review of the literature (PubMed, MEDLINE and Cochrane) on the study of DNA methylation in urological neoplasms (prostate cancer, bladder cancer, renal cancer and testicular cancer), considering all the studies published up to January 2013. SYNTHESIS OF EVIDENCE: It was possible to determine the state of methylation of many genes in our tumor samples. When these were compared with healthy tissue samples, it was possible to define the specific aberrant methylation patterns for each type of tumor. The study and definition of specific abnormal methylation patterns of each type of tumor is a tool having potential utility for diagnosis, evaluation, prediction of prognosis and treatment of the different forms of genitourinary cancer. The analysis of gene methylation in urine after micturition or post-prostatic massage urine, semen, in the wash plasma or fluid from prostatic biopsies may allow early detection of bladder, prostate, renal and testicular cancer. In each one of the neoplasms, an epigenetic signature that may be detected in the DNA has been identified, obtained from very scarce or not at all invasive specimens, with potential in the diagnosis and evaluation of prognosis. Validation of these studies will confirm the accuracy, effectiveness and reproducibility of the results available up to now. Criteria have still not been developed that determine if a gene panel provides sufficient information in the health care practice to guide an unequivocal diagnosis or therapeutic conduct. More studies are needed to compare sensitivity, specificity, positive and negative predictive value of the test in each case. Multicenter studies analyzing the real reproducibility of these results in a clinical setting also do not exist. CONCLUSIONS: The study of aberrant DNA methylation in biological specimens of patients has an enormous potential for the early diagnosis and screening of genitourinary neoplasms. A larger number of studies is needed to be able to define the series of genes that would mean unequivocal signatures of malignancy. This methodology also has potential when defining prognostic groups and potential of response to different therapies. PMID- 23643197 TI - Sonochemical synthesis of solar-light-driven Ag degrees -PbMoO4 photocatalyst. AB - Ag degrees -PbMoO4 photocatalysts were synthesized by facile sonochemical method with different mol.% of Ag nanoparticles dispersed on the surface of PbMoO4. The synthesized powders were characterized by X-ray Diffraction (XRD) Spectroscopy, X Ray Photoelectron Spectroscopy (XPS), Transmission Electron Microscopy (TEM), and Diffuse Reflectance Spectroscopy (UV-vis DRS) to investigate the crystal structure, morphology, chemical composition, and optical properties of the photocatalyst. Photocatalytic activities of the Ag degrees -PbMoO4 samples were evaluated by the degradation of Indigo Carmine (IC) dye under simulated solar light irradiation. It has been observed that the sample containing 0.3 mol.% of Ag showed the best photocatalytic activity as compared to other samples. The results suggest that the dispersion of Ag nanoparticles on the surface of PbMoO4 significantly enhances the photocatalytic activity of PbMoO4. Increase in photocatalytic activity of Ag degrees -PbMoO4 photocatalyst has been explained on the basis of surface plasmon resonance (SPR) effect caused by the silver nanoparticles present in the photocatalyst. PMID- 23643199 TI - Influence of body size on Cu bioaccumulation in zebra mussels Dreissena polymorpha exposed to different sources of particle-associated Cu. AB - Size of organisms is critical in controlling metal bioavailability and bioaccumulation, while mechanisms of size-related metal bioaccumulation are not fully understood. To investigate the influences of different sources of particle associated Cu on body size-related Cu bioavailability and bioaccumulation, zebra mussels (Dreissena polymorpha) of different sizes were exposed to stable Cu isotope ((65)Cu) spiked algae (Chlorella vulgaris) or sediments in the laboratory and the Cu tissue concentration-size relationships were compared with that in unexposed mussels. Copper tissue concentrations decreased with mussel size (tissue or shell dry weight) in both unexposed and algal-exposed mussels with similar decreasing patterns, but were independent of size in sediment-exposed mussels. Furthermore, the relative contribution of Cu uptake from algae (65-91%) to Cu bioaccumulation is always higher than that from sediments (9-35%), possibly due to the higher bioavailability of algal-Cu. Therefore, the size-related ingestion of algae could be more important in influencing the size-related variations in Cu bioaccumulation. However, the relative contribution of sediment Cu to Cu bioaccumulation increased with body size and thus sediment ingestion may also affect the size-related Cu variations in larger mussels (tissue weight >7.5mg). This study highlights the importance of considering exposure pathways in normalization of metal concentration variation when using bivalves as biomonitors. PMID- 23643198 TI - Arsenic in groundwater and its influence on exposure risks through traditionally cooked rice in Prey Veng Province, Cambodia. AB - Arsenic (As) contamination of communal tubewells in Prey Veng, Cambodia, has been observed since 2000. Many of these wells exceed the WHO As in drinking water standard of 10 MUg/L by a factor of 100. The aim of this study was to assess how cooking water source impacts dietary As intake in a rural community in Prey Veng. This aim was fulfilled by (1) using geostatistical analysis techniques to examine the extent of As contaminated groundwater in Prey Veng and identify a suitable study site, (2) conducting an on-site study in two villages to measure As content in cooked rice prepared with water collected from tubewells and locally harvested rainwater, and (3) determining the dietary intake of As from consuming this rice. Geostatistical analysis indicated that high risk tubewells (>50 MUg As/L) are concentrated along the Mekong River's east bank. Participants using high risk tubewells are consuming up to 24 times more inorganic As daily than recommended by the previous FAO/WHO provisional tolerable daily intake value (2.1 MUg/kg BW/day). However, As content in rice cooked in rainwater was significantly reduced, therefore, it is considered to be a safer and more sustainable option for this region. PMID- 23643200 TI - Surgical treatment of chronic achilles tendinopathy: long-term results of the endoscopic technique. AB - Surgery has long been established as a valid alternative for chronic Achilles tendinopathies that have failed conservative treatment. Endoscopic procedures have shown satisfactory preliminary results for managing such injuries. The aim of the present study was to evaluate the long-term clinical outcomes of endoscopic surgery in patients with chronic midportion Achilles tendinopathy. We evaluated 27 endoscopic procedures in 24 patients (mean age 45.5 +/- 8.9 years; 12 males and 12 females) with chronic Achilles tendinopathy and at least 5 (mean 7.7, range 5 to 14) years of follow-up. All ambulatory procedures consisted of paratenon debridement and longitudinal tenotomies. The clinical evaluation included 2 specific functional rating systems (the Achilles Tendon Scoring System and the Victorian Institute Sport Assessment-Achilles questionnaire) and a pain visual analog scale. Patient satisfaction with the procedure was assessed using a patient global assessment response to therapy Likert scale score. All patients had an improved clinical outcome at the final follow-up visit. Both scoring systems showed significant improvement in all clinical outcomes at the last follow-up visit. The Victorian Institute Sport Assessment-Achilles questionnaire score had improved from 37.0 +/- 4.9 points preoperatively to 97.5 +/- 12.1 points postoperatively (p = .0006). The Achilles Tendon Scoring System score had improved from 32.6 +/- 13.1 points preoperatively to 97.2 +/- 12.3 points postoperatively (p = .000006). The pain visual analog scale score averaged 0.2 +/ 1.1, and the patient global assessment response to therapy score was 0.25 +/- 0.71. The percentage of patients with an excellent patient global assessment response to therapy score was 85.1%. Two postoperative problems were reported (7.4%): a delayed keloid lesion and a seroma with chronic fistula. The infection rate and systemic complication rate were 0%. In conclusion, endoscopic surgery provided a high rate of excellent long-term results in patients with chronic midportion Achilles tendinopathy. Debridement of the paratenon and crural fascia, along with longitudinal tenotomies, using a minimally invasive procedure provided completely resolution of symptoms at 7 years postoperatively in 96% of patients in the present consecutive series. PMID- 23643201 TI - Child sexual abuse in China: a meta-analysis of 27 studies. AB - OBJECTIVE: To examine whether Chinese studies of child sexual abuse (CSA) in the general population show lower prevalence rates than other international studies, and whether certain features of these studies may help to account for variation in estimates. METHODS: A meta-analysis and meta-regression were conducted on 27 studies found in the English and Chinese language peer reviewed journals that involved general populations of students or residents, estimated CSA prior to age 18, and specified rates for males or females individually. RESULTS: Estimates for Chinese females were lower than the international composites. For total CSA for females, the Chinese pooled estimate was 15.3% (95% CI=12.6-18.0) based on the meta-analysis of 24 studies, lower than the international estimate (Stoltenborgh, van IJzendoorn, Euser, & Bakermans-Kranenburg, 2011) but not significantly. For contact CSA for females, the pooled estimate was 9.5% (95% CI=7.5-11.5), based on 16 studies, significantly lower than the international prevalence. For penetrative CSA for females, the pooled estimate was 1% (95% CI=0.7-1.3), based on 15 studies, significantly lower than the international estimate of 15.1%. Chinese men reported significantly less penetrative CSA but significantly more total CSA than international estimates; while contact CSA reported by Chinese and international males appeared to be roughly equivalent. Chinese CSA prevalence estimates were lower in studies from urban areas and non-mainland areas (Hong Kong and Taiwan), and in surveys with larger and probability samples, multiple sites, face-to-face interview method and when using less widely used instruments. CONCLUSIONS: The findings to date justify further research into possible cultural and sociological reasons for lower risk of contact and penetrative sexual abuse of girls and less penetrative abuse of boys in China. Future research should examine sociological explanations, including patterns of supervision, sexual socialization and attitudes related to male sexual prowess. PRACTICE IMPLICATIONS: The findings suggest that future general population studies in China should use well validated instruments, avoid face-to-face interview formats and be careful to maintain methodological standards when sampling large populations over multiple sites. PMID- 23643202 TI - What's in a name? PMID- 23643203 TI - Depression as a culture-bound syndrome: implications for primary care. PMID- 23643204 TI - Management of opioid addiction in primary care: a pragmatic approach prioritising wellbeing not ideology. PMID- 23643205 TI - Managing malnutrition in the community: we will all gain from finding and feeding the frail. PMID- 23643206 TI - Diagnosing type 2 diabetes and identifying high-risk individuals using the new glycated haemoglobin (HbA1c) criteria. PMID- 23643207 TI - Diabetes is on the rise, so why are we not bothered? PMID- 23643208 TI - Inter-arm blood pressure differences compare with ambulatory monitoring: a manifestation of the 'white-coat' effect? PMID- 23643209 TI - The numbers needed to inform consent? PMID- 23643210 TI - Sharing control of appointment length with patients in general practice. PMID- 23643211 TI - Use of email for consulting with patients in general practice. PMID- 23643212 TI - Frostbite developing secondary to cryotherapy for viral warts. PMID- 23643213 TI - Family medicine in Africa. PMID- 23643214 TI - From South Wigston to South Luangwa. PMID- 23643215 TI - First do no harm: preparing for failure by practising failing safely. PMID- 23643216 TI - One scale too far? PMID- 23643217 TI - Caution required with total disc replacement for chronic back pain. PMID- 23643218 TI - The Euthyphro dilemma. PMID- 23643223 TI - I'm just a sense-making analyst. PMID- 23643224 TI - Global health: time for full integration into GP education. PMID- 23643225 TI - Low mood and depression in adolescence: clinical update. PMID- 23643226 TI - A hidden problem: consequences of the misdiagnosis of perinatal obsessive compulsive disorder. PMID- 23643227 TI - Depressive disorder in the last phase of life in patients with cardiovascular disease, cancer, and COPD: data from a 20-year follow-up period in general practice. AB - BACKGROUND: Depression is assumed to be common in chronically ill patients during their last phase of life and is associated with poorer outcomes. The prevalence of depression is widely varying in previous studies due to the use of different terminology, classification, and assessment methods. AIM: To explore the reported incidence of depressive disorder, as registered in the last phase of life of patients who died from cardiovascular disease, cancer or COPD, in a sample of primary care patients. DESIGN AND SETTING: A historic cohort study, using a 20 year period registration database of medical records in four Dutch general practices (a dynamic population based on the Continuous Morbidity Registration database). METHOD: Medical history of the sample cohort was analysed for the diagnosis of a new episode of depressive disorder and descriptive statistics were used. RESULTS: In total 982 patients were included, and 19 patients (1.9%) were diagnosed with a new depressive disorder in the last year of their life. The lifetime prevalence of depressive disorder in this sample was 8.2%. CONCLUSION: The incidence of depressive disorder in the last phase of life is remarkably low in this study. These data were derived from actual patient care in general practice. Psychiatric diagnoses were made by GPs in the context of both patient needs and delivered care. A broader concept of depression in general practice is recommended to improve the diagnosis and treatment of mood disorders in patients in the last phase of life. PMID- 23643228 TI - Assessing depression severity using the UK Quality and Outcomes Framework depression indicators: a systematic review. AB - BACKGROUND: Depression is a major cause of chronic ill-health and is managed in primary care. Indicators on depression severity assessment were introduced into the UK Quality and Outcomes Framework (QOF) in 2006 and 2009. QOF is a pay-for performance scheme and indicators should have evidence to support their use; potential unintended consequences should also have been considered. AIM: To review the effectiveness of routine assessment of depression severity using structured tools in primary care, and to determine the views of GPs and patients regarding their use. DESIGN: Systematic review. METHOD: Studies were identified by searching electronic databases; study selection, data abstraction, and quality assessment were carried out by one reviewer, with checks from other authors and GRADE (grading of recommendations, assessment, development and evaluation) tables completed for included effectiveness studies. RESULTS: Eight studies met the eligibility criteria. There was very low-quality evidence that assessing severity in a structured way at diagnosis using a validated tool led to interventions that were appropriate to the severity of depression. Patients and GPs had different perceptions of the assessment of depression at diagnosis, with patients being more positive. GPs highlighted unintended consequences. There was low-quality evidence that structured assessment at follow-up led to increased rates of remission and response, but changes to management were not seen. Patients used this assessment to measure their own response to treatment. CONCLUSION: Any estimate of the effect of structured assessment of depression severity in UK general practice is uncertain. GPs consider routine use of questionnaires as incentivised by the QOF has unintended consequences, which could adversely affect patient care. PMID- 23643230 TI - Antibiotic prescribing and C-reactive protein testing for pulmonary infections in patients with intellectual disabilities. AB - BACKGROUND: Excessive prescribing of antibiotics in patients with lower respiratory tract infections (LRTIs) is common in the general population. Due to communication difficulties, it is hypothesised that prescriptions are even more commonplace in the primary care of individuals with intellectual disabilities. Point-of-care C-reactive protein (POC-CRP) testing might lead to more efficient prescribing of antibiotics. AIM: To evaluate the effect of POC-CRP testing on antibiotic prescriptions for LRTIs by physicians specialising in the care of individuals with intellectual disabilities. DESIGN AND SETTING: A prospective case-control study in four care centres for individuals with intellectual disabilities in The Netherlands. METHOD: Between 27 October 2010 and 27 October 2011, a prospective efficiency study was performed with a base population of 1472 individuals. This population consisted of 882 individuals in whom POC-CRP tests were used and a control group (n = 590) in whom no POC-CRP test was performed. RESULTS: Of the 48 patients in the control group who were diagnosed as having an LRTI, 43 (90%) received antibiotics, compared with 59 out of the 144 patients (41%) in the case group (OR = 12.0; 95% CI = 4.1-35.3). No significant differences in outcome were found between both groups during a follow-up period of 1 month. CONCLUSION: This study shows that the use of POC-CRP testing in patients with intellectual disabilities and LRTIs can lead to a significant reduction in antibiotic prescriptions, with no significant differences in outcome during follow-up. PMID- 23643229 TI - GP consultations for medically unexplained physical symptoms in parents and their children: a systematic review. AB - BACKGROUND: There is evidence of an association of medically unexplained physical symptoms (MUPS) between parents and children, but it is unclear whether this association is also present for GP consultations. AIM: To review the literature investigating the association of GP consultations for MUPS between parents and children. DESIGN OF STUDY: Systematic review. METHOD: Systematic search of MEDLINE((r)), Embase, CINAHL, and PsycINFO databases from their inception to October 2012. Observational studies examining the association of GP consultations for MUPS between parents and children were included. RESULTS: Eight studies were included in the review. Three studies found significant associations between GP consultations for multiple MUPS between parents and children. Two studies reported significant associations between irritable bowel syndrome diagnosis in parents and multiple MUPS in children. One study showed no significant associations between multiple MUPS in mothers and functional abdominal pain in children. Two studies investigated the association of non-specific low back pain in parents and children; one study showed a significant association, whereas the other study found no significant association. Formal pooling of the results was not performed owing to a high degree of study heterogeneity. CONCLUSION: This review provides evidence of an association between GP consultations for MUPS in parents and children, although the evidence is limited by some potential biases and study heterogeneity. GPs need to be aware of this association, which has implications for management of children presenting with MUPS. More longitudinal research focusing on all common MUPS in children, which relies on more precise sources of data, is needed to further investigate this association. PMID- 23643231 TI - A new competency model for general practice: implications for selection, training, and careers. AB - BACKGROUND: Recent structural and policy changes in the UK health service have significantly changed the job responsibilities for the GP role. AIM: To replicate a previous job analysis study to examine the relevance of current competency domains and selection criteria for doctors entering training. DESIGN AND METHOD: A multisource, multimethod approach comprising three phases: (1) stakeholder consultation (n = 205) using interviews, focus groups and behavioural observation of practising GPs; (2) a validation questionnaire based on results from phase 1 (n = 1082); followed by (3) an expert panel (n = 6) to review and confirm the final competency domains. RESULTS: Eleven competency domains were identified, which extends previous research findings. A new domain was identified called Leading for Continuing Improvement. Results show that, Empathy and Perspective Taking, Communication Skills, Clinical Knowledge and Expertise, and Professional Integrity are currently rated the most important domains. Results indicate a significant increase in ratings of importance for each domain in the future (P<0.001), except for Communication Skills and Empathy and Perspective Taking, which consistently remain high. CONCLUSION: The breadth of competencies required for GPs has increased significantly. GPs are now required to resolve competing tensions to be effective in their role, such as maintaining a patient focus while overseeing commissioning, with a potential ethical conflict between these aspects. Selection criteria remain largely unchanged but with increased priority in some domains (for example, Effective Teamworking). However, there is an urgent need to review the training provision arrangements to reflect the greater breadth of competencies now required. PMID- 23643232 TI - Are there enough GPs in England to detect hypertension and maintain access? A cross-sectional study. AB - BACKGROUND: Fewer patients are recorded by practices as having hypertension than are identified in systematic population surveys. However, as more patients are recorded on practice hypertension registers, mortality from coronary heart disease and stroke declines. AIM: To determine whether the number of GPs per 1000 practice population is associated with the number of patients recorded by practices as having hypertension, and whether patients' reports of being able to get an appointment with a GP are associated with the number of GPs and the number of patients recorded as having hypertension. DESIGN AND SETTING: Cross-sectional study of available data for all general practices in England for 2008 to 2009. METHOD: A model was developed to describe the hypothesised relationships between population (deprivation, ethnicity, age, poor health) and practice characteristics (list size, number of GPs per 1000 patients, management of hypertension) and the number of patients with hypertension and patient-reported ability to get an appointment fairly quickly. Two regression analyses were undertaken. RESULTS: Practices recorded only 13.3% of patients as having hypertension. Deprivation, age, poor health, white ethnicity, hypertension management, and the number of GPs per 1000 patients predicted the number of patients recorded with hypertension. Being able to get an appointment fairly quickly was associated with the number of patients recorded with hypertension, age, deprivation, practice list size, and the number of GPs per 1000 patients. CONCLUSION: In order to improve detection of hypertension as part of a strategy to lower mortality from coronary heart disease, the capacity of practices to detect hypertension while maintaining access needs to be improved. Increasing the supply of GPs may be necessary, as well as improvements in efficiency. PMID- 23643233 TI - Using the 7-point checklist as a diagnostic aid for pigmented skin lesions in general practice: a diagnostic validation study. AB - BACKGROUND: GPs need to recognise significant pigmented skin lesions, given rising UK incidence rates for malignant melanoma. The 7-point checklist (7PCL) has been recommended by NICE (2005) for routine use in UK general practice to identify clinically significant lesions which require urgent referral. AIM: To validate the Original and Weighted versions of the 7PCL in the primary care setting. DESIGN AND SETTING: Diagnostic validation study, using data from a SIAscopic diagnostic aid randomised controlled trial in eastern England. METHOD: Adults presenting in general practice with a pigmented skin lesion that could not be immediately diagnosed as benign were recruited into the trial. Reference standard diagnoses were histology or dermatology expert opinion; 7PCL scores were calculated blinded to the reference diagnosis. A case was defined as a clinically significant lesion for primary care referral to secondary care (total 1436 lesions: 225 cases, 1211 controls); or melanoma (36). RESULTS: For diagnosing clinically significant lesions there was a difference between the performance of the Original and Weighted 7PCLs (respectively, area under curve: 0.66, 0.69, difference = 0.03, P<0.001). For the identification of melanoma, similar differences were found. Increasing the Weighted 7PCL's cut-off score from recommended 3 to 4 improved detection of clinically significant lesions in primary care: sensitivity 73.3%, specificity 57.1%, positive predictive value 24.1%, negative predictive value 92.0%, while maintaining high sensitivity of 91.7% and moderate specificity of 53.4% for melanoma. CONCLUSION: The Original and Weighted 7PCLs both performed well in a primary care setting to identify clinically significant lesions as well as melanoma. The Weighted 7PCL, with a revised cut-off score of 4 from 3, performs slightly better and could be applied in general practice to support the recognition of clinically significant lesions and therefore the early identification of melanoma. PMID- 23643234 TI - Factors affecting the physician-patient relationship of older veterans with inadequate health literacy: an observational study. AB - BACKGROUND: In Taiwan, older veterans typically match the characteristics of a high prevalence of inadequate health literacy, which is a major barrier to effective communication in delivering proper health care. A good physician patient relationship increases patients' trust and willingness to communicate, so an awareness of the factors that influence this relationship could improve it over time and enhance patients' health. AIM: To explore factors related to the physician-patient relationship among older veterans with inadequate health literacy in Taiwan. DESIGN AND SETTING: Observational study in veterans' homes. METHOD: Data were collected using self-report questionnaires in face-to-face interviews. Patients with a Test of Functional Health Literacy in Adults score <60 (defined as inadequate health literacy) were recruited. Demographic characteristics, the Geriatric Depression Scale-Short Form, Multidimensional Health Locus of Control, and Perceived Involvement in Care Scales were used to identify related factors. Multiple regression and bootstrapping were used for data analyses. RESULTS: A total of 256 older individuals were defined as having inadequate health literacy. Patients' perceived involvement in health care partially mediated the relationship between Health Locus of Control and the physician-patient relationship. Perceived Involvement in Care, depression score, and Health Locus of Control were predictors of the physician-patient relationship. CONCLUSION: Older patients with inadequate health literacy had difficulty becoming actively involved in health care. The GP is in an ideal position to become a key person in helping such patients become involved in health care, and appropriately treating their depression may improve the physician-patient relationship. PMID- 23643236 TI - Medical generalism in a modern NHS: preparing for a turbulent future. PMID- 23643237 TI - Is emergency department cardioversion of recent-onset atrial fibrillation safe and effective? AB - BACKGROUND: Atrial fibrillation (AF) is a very common dysrhythmia presenting to Emergency Departments (EDs). Controversy exists regarding the optimal clinical therapy for these patients, which typically focuses on rhythm rate-control and admission or cardioversion and discharge home. CLINICAL QUESTION: Is ED cardioversion of recent-onset atrial fibrillation safe, effective, and does it result in positive meaningful patient outcomes? EVIDENCE REVIEW: Five observation studies with nearly 1600 ED patients with atrial fibrillation treated with either rate-control or cardioversion were reviewed and results compiled. RESULTS: Overall, ED cardioversion for recent-onset AF seems safe and effective, with success rates ranging from 85.5% to 97% in these studies. Although further research should seek to identify patients at low risk for thromboembolic complication, more rigorously assess patient satisfaction, and show cost savings, emergency physicians should feel comfortable using this approach in select patients. CONCLUSION: ED cardioversion for recent-onset AF seems safe and effective. PMID- 23643235 TI - Polymyalgia rheumatica: diagnosis, prescribing, and monitoring in general practice. AB - BACKGROUND: Polymyalgia rheumatica (PMR) is a common rheumatological disorder of older patients. The majority of UK patients are diagnosed and managed exclusively in general practice. In primary care, it has been shown that there is wide variation in practice, and established diagnostic criteria are infrequently used. AIM: This study aims to investigate the diagnostic processes, management, and monitoring of patients with PMR in UK primary care. DESIGN AND SETTING: This is a retrospective cohort study set in primary care. METHOD: Data were extracted from two interlinked primary care databases from north Staffordshire. Patients with PMR were identified using Read Codes and the relevant investigation, prescription, and consultation data were extracted and reviewed. RESULTS: Three hundred and four patients' records were analysed. Documentation of symptoms leading to a diagnosis of PMR was found in 248 records (81.6%). A documented process of exclusion of relevant differential diagnoses was demonstrated in 68 (22.4%) patients. The mean initial dose of prednisolone was 21.5 mg. Referral to specialist care was made for 135 (44.4%) patients. Gastric prophylaxis was prescribed in 85 (28.0%) cases. Osteoporosis prophylaxis was prescribed to 183 patients (60.2%); 12 patients (3.9%) developed osteoporosis and 56 (18.4%) developed gastric symptoms that led to GP consultation. CONCLUSION: The management of PMR in general practice could be optimised. Identified areas for improvement include clear documentation of a process of exclusion of other diagnoses, and prophylaxis for potential treatment complications, including osteoporosis and gastric symptoms. PMID- 23643239 TI - Behavioral problems of seniors in an emergency department. AB - BACKGROUND: Behavioral disorders are frequent in seniors with cognitive impairments. The ailment responsible for presentation to the Emergency Department (ED), in combination with preexisting conditions, can bring about a temporary cognitive disturbance or worsen an existing cognitive disturbance, thus increasing the frequency of behavioral disorders. STUDY OBJECTIVES: The purpose of this research was to investigate whether there is any connection between pain, cognitive impairment, time in the ED, presence or absence of a supportive escort, and behavioral disorders exhibited by a senior. METHODS: The study sample consisted of 140 seniors aged 69 years and older who visited the ED. Data collected included personal data, presence or absence of an escort, length of stay in the ED, and formal reproducible evaluation of cognition, behavior, and pain. RESULTS: Behavioral disorders were found to be present in 18% of the total sample and in 25% of the group of seniors who suffered from cognitive impairment. The presence of cognitive impairment was found to increase by almost sevenfold the risk of a behavioral disorder. Presence of severe pain increased the risk of a behavioral disorder even more (odds ratio 63). Seniors with cognitive impairment who spent a longer-than-average time period in the ED exhibited behavioral disorders that were more severe than disorders in seniors without cognitive impairment. There was no moderating effect on behavioral disturbances by the presence of a supportive escort observed. CONCLUSIONS: The findings of this study suggest that the risk of behavioral disorders in seniors attending the ED may be predicted by screening them for cognitive impairment and pain, and by monitoring the time period they are in the ED. PMID- 23643238 TI - Acquired hemophilia presenting as profound hematuria: evaluation, diagnosis, and management of elusive cause of bleeding in the emergency department setting. AB - BACKGROUND: There are numerous causes of bleeding that may present to the Emergency Department (ED). Although rare, acquired hemophilia is a potentially life-threatening bleeding disorder, with reported mortality rates ranging from 6% to 8% among patients who received proper diagnosis and treatment. Approximately two thirds of patients with this condition will present with major bleeding, the magnitude of which may necessitate urgent evaluation and care. OBJECTIVES: The aim of this article is to provide an overview of the evaluation, differential diagnosis, and management of acquired hemophilia for the emergency physician. CASE REPORT: A case report of a patient who presented to the ED with gross hematuria secondary to undiagnosed acquired hemophilia is described to facilitate a review of the laboratory evaluation, differential diagnosis, and treatment of acquired hemophilia. CONCLUSION: Patients with acquired hemophilia-related bleeding may present to the ED for care, given the often serious nature of their bleeding. Delayed diagnosis may postpone the initiation of targeted, effective treatments for achieving hemostasis, with potentially catastrophic consequences, particularly in patients who require emergent invasive procedures. Recognition of the potential for an underlying bleeding disorder and subsequent consultation with a hematologist are critical first steps in effectively identifying and managing a patient with acquired hemophilia who presents with bleeding. PMID- 23643240 TI - Customizing anaphylaxis guidelines for emergency medicine. AB - BACKGROUND: Most episodes of anaphylaxis are managed in emergency medical settings, where the cardinal signs and symptoms often differ from those observed in the allergy clinic. Data suggest that low recognition of anaphylaxis in the emergency setting may relate to inaccurate coding and lack of a standard, practical definition. OBJECTIVE: Develop a simple, consistent definition of anaphylaxis for emergency medicine providers, supported by clinically relevant consensus statements. DISCUSSION: Definitions of anaphylaxis and criteria for diagnosis from current anaphylaxis guidelines were reviewed with regard to their utilization in emergency medical settings. The agreed-upon working definition is: Anaphylaxis is a serious reaction causing a combination of characteristic findings, and which is rapid in onset and may cause death. It is usually due to an allergic reaction but can be non-allergic. The definition is supported by Consensus Statements, each with referenced discussion. For a positive outcome, quick diagnosis and treatment of anaphylaxis are critical. However, even in the emergency setting, the patient may not present with life-threatening symptoms. Because mild initial symptoms can quickly progress to a severe, even fatal, reaction, the first-line treatment for any anaphylaxis episode--regardless of severity--is intramuscular injection of epinephrine into the anterolateral thigh; delaying its administration increases the potential for morbidity and mortality. When a reaction appears as "possible anaphylaxis," it is generally better to err on the side of caution and administer epinephrine. CONCLUSION: We believe that this working definition and the supporting Consensus Statements are a first step to better management of anaphylaxis in the emergency medical setting. PMID- 23643241 TI - Oropharyngeal airway obstruction after the accidental ingestion of Arisaema amurense. AB - BACKGROUND: Arisaema amurense is widely known in Korean folklore as a poisonous plant, and its lethal toxicity has long been recognized. The toxicity of Arisaema amurense is due to its content of calcium oxalate, which causes painful oropharyngeal edema, hypersalivation, aphonia, oral ulceration, esophageal erosion, and hypocalcemia. OBJECTIVE: We report a case of accidental poisoning after ingestion of the rhizome of Arisaema amurense, resulting in airway obstruction that required endotracheal intubation. CASE REPORT: A 60-year-old man developed oral pain and swelling after accidentally ingesting a rhizome from the Arisaema amurense plant as a medicinal herb. His symptoms worsened upon his arrival in the Emergency Department, and he was unable to speak due to oral swelling and hypersalivation. The patient underwent endotracheal intubation to protect his airway and was treated with antihistamines and corticosteroids. Three days after treatment, he had improved and was extubated. CONCLUSION: We describe an emergent treatment course for a patient with acute airway obstruction resulting from the ingestion of Arisaema amurense. PMID- 23643242 TI - Bilateral subdural hematomas after lumboperitoneal shunt placement. AB - BACKGROUND: Lumboperitoneal shunts are commonly placed as treatment for a variety of conditions, and complications can be significant. OBJECTIVES: We discuss a rare complication of these shunts, namely bilateral non-traumatic subdural hematoma formation. CASE REPORT: A patient with a normal neurologic examination but severe nausea, weight loss, and dehydration presented 2 weeks after lumboperitoneal shunt placement for cryptococcal meningitis, and was found to have bilateral subdural hematomas. CONCLUSIONS: Physicians should be aware of this potentially devastating complication of shunt placement so that prompt and appropriate treatment can be initiated. PMID- 23643244 TI - Hemispheric dissociation of reward processing in humans: insights from deep brain stimulation. AB - Rewards have various effects on human behavior and multiple representations in the human brain. Behaviorally, rewards notably enhance response vigor in incentive motivation paradigms and bias subsequent choices in instrumental learning paradigms. Neurally, rewards affect activity in different fronto striatal regions attached to different motor effectors, for instance in left and right hemispheres for the two hands. Here we address the question of whether manipulating reward-related brain activity has local or general effects, with respect to behavioral paradigms and motor effectors. Neuronal activity was manipulated in a single hemisphere using unilateral deep brain stimulation (DBS) in patients with Parkinson's disease. Results suggest that DBS amplifies the representation of reward magnitude within the targeted hemisphere, so as to affect the behavior of the contralateral hand specifically. These unilateral DBS effects on behavior include both boosting incentive motivation and biasing instrumental choices. Furthermore, using computational modeling we show that DBS effects on incentive motivation can predict DBS effects on instrumental learning (or vice versa). Thus, we demonstrate the feasibility of causally manipulating reward-related neuronal activity in humans, in a manner that is specific to a class of motor effectors but that generalizes to different computational processes. As these findings proved independent from therapeutic effects on parkinsonian motor symptoms, they might provide insight into DBS impact on non motor disorders, such as apathy or hypomania. PMID- 23643245 TI - Right-sided representational neglect after left brain damage in a case without visuospatial working memory deficits. AB - Brain damaged patients suffering from representational neglect (RN) fail to report, orient to, or verbally describe contra-lesional elements of imagined environments or objects. So far this disorder has only been reported after right brain damage, leading to the idea that only the right hemisphere is involved in this deficit. A widely accepted account attributes RN to a lateralized impairment in the visuospatial component of working memory. So far, however, this hypothesis has not been tested in detail. In the present paper, we describe, for the first time, the case of a left brain damaged patient suffering from right-sided RN while imagining both known and new environments and objects. An in-depth evaluation of her visuospatial working memory abilities, with special focus on the presence of a lateralized deficit, did not reveal any abnormality. In sharp contrast, her ability to memorize visual information was severely compromised. The implications of these results are discussed in the light of recent insights in the neglect syndrome. PMID- 23643243 TI - One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas mediated genome engineering. AB - Mice carrying mutations in multiple genes are traditionally generated by sequential recombination in embryonic stem cells and/or time-consuming intercrossing of mice with a single mutation. The CRISPR/Cas system has been adapted as an efficient gene-targeting technology with the potential for multiplexed genome editing. We demonstrate that CRISPR/Cas-mediated gene editing allows the simultaneous disruption of five genes (Tet1, 2, 3, Sry, Uty--8 alleles) in mouse embryonic stem (ES) cells with high efficiency. Coinjection of Cas9 mRNA and single-guide RNAs (sgRNAs) targeting Tet1 and Tet2 into zygotes generated mice with biallelic mutations in both genes with an efficiency of 80%. Finally, we show that coinjection of Cas9 mRNA/sgRNAs with mutant oligos generated precise point mutations simultaneously in two target genes. Thus, the CRISPR/Cas system allows the one-step generation of animals carrying mutations in multiple genes, an approach that will greatly accelerate the in vivo study of functionally redundant genes and of epistatic gene interactions. PMID- 23643246 TI - Schemas reveal spatial relations to a patient with simultanagnosia. AB - Maps, graphs, and diagrams use simplified graphic forms, like lines and blobs, to represent basic spatial relations, like boundaries and enclosures. A schema is an iconic representation where perceptual detail has been abstracted away from reality in order to provide a more flexible structure for cognition. Unlike truly symbolic representations of spatial relations (i.e., prepositions) a schema preserves some analog spatial qualities of the relation it stands in for. We tested the efficacy of schemas in facilitating the perception and comprehension of spatial relations in a patient with bilateral occipitoparietal damage and resulting simultanagnosia. Patient E.E. performed six matching tasks involving WORDS (in, on, above, below), photographic PICTURES of objects, and/or SCHEMAS depicting the same spatial relations. E.E. was instructed to match a single spatial relation to a corresponding image from an array of four choices. On the two tasks that did not include matching to or from schemas, E.E. performed at chance levels. On tasks with schemas, performance was significantly better, indicating that schematic representations make spatial relations visible in a manner that symbols and complex images do not. The results provide general insight as to how schemas facilitate spatial reasoning when used in graphic depictions, and how such theoretically intermediate representational structures could serve to link perceptual and verbal representations of spatial relations in the brain. PMID- 23643247 TI - Experience of head and neck theatre staff and attitudes to human factors using an aviation-based analysis and classification system--a pilot survey. AB - The role that human factors have in contributing to air crashes is well known and is included as an essential part of training. Awareness of human factors in surgery is increasingly being recognised but surprisingly few papers have come from head and neck specialties. We circulated a questionnaire on human factors based on an aviation model to 140 head and neck medical and ancillary staff who work in operating theatres in 3 large UK hospitals. Most positive responses were found in the consultant group followed by trainee doctors and support staff. A significant difference was found in the subcategories of Unsafe Supervision (p=0.002) and Preconditions to Unsafe Acts (p=0.001). This work will help to identify multi-system deficiencies that can be corrected, and highlights aspects that may yield the greatest reduction in surgical errors. PMID- 23643248 TI - Analysis methods and reference concentrations of 12 minor and trace elements in fish blood plasma. AB - A comprehensive review of the analytical literature revealed substantial under representation of trace element concentrations in fish blood, particularly for marine species. We describe a simple dilution procedure to measure Li, Mg, K, Ca, Mn, Cu, Zn, Se, Rb, Sr, Ba and Pb concentrations in low volumes of blood plasma of adult plaice (Pleuronectes platessa) using high resolution-inductively coupled plasma-mass spectrometry (HR-ICP-MS). Captive male and female plaice (n = 18) were serially sampled for one year and samples collected outside of the spawning season (n = 157) used to estimate reference ranges for this species. Method accuracy was deemed satisfactory, based on its application to the analysis of a certified reference material. Precision was generally <3%, with the most conservative measure of precision being <=10% for all elements except Pb (~20%). This is the first study to analyse fish blood plasma by ICP-MS and includes some of the first reference ranges for trace element concentrations in fish blood. PMID- 23643249 TI - Preparation and characterization of nanodispersions of yttria, yttrium aluminium garnet and lutetium aluminium garnet. AB - Refractory and chemically inert nanoparticulate solids like yttria, yttrium aluminium garnet or lutetium aluminium garnet are notoriously difficult to disperse in aqueous solution, although such dispersions might prove useful for 2D and 3D-printing, deposition of films or other shaping procedures for ceramic green bodies. This work reports on experiments to prepare such dispersions from nanopowders, using a range of selected carboxylic acids as ligands for electrostatic charging and stabilization of the various nanomaterials. The assessment of the system properties achieved combines zeta-potential and viscosity (flow curve) measurements in the resulting colloidal systems. Calculations of the molecular electrostatic potential of the ligands were used to correlate the molecular structure of the ligands and their capability to dock to the surface of the solid particles. The colloid chemical data received have then been interpreted on this background; citric acid and polyacrylic acid have been identified as the most attractive dispersants. PMID- 23643250 TI - Probing the amphiphile micellar to hexagonal phase transition using Positron Annihilation Lifetime Spectroscopy. AB - Positron Annihilation Lifetime Spectroscopy (PALS) has been utilised only sparingly for structural characterisation in self assembled materials. Inconsistencies in approaches to experimental configuration and data analysis between studies has complicated comparisons between studies, meaning that the technique has not provided a cohesive data set across the study of different self assembled systems that advance the technique towards an important tool in soft matter research. In the current work a systematic study was conducted using ionic and non-ionic micellar systems with increasing surfactant concentration to probe positron behaviour on changes between micellar phase structures, and data analysed using contemporary approaches to fit four component spectra. A characteristic orthopositronium lifetime (in the organic regions) of 3.5+/-0.2 ns was obtained for the hexagonal phase for surfactants with C12 alkyl chains. Chemical quenching of the positron species was also observed for systems with ionic amphiphiles. The application of PALS has also highlighted an inconsistency in the published phase diagram for the octa(ethylene oxide) monododecyl ether (C12EO8) system. These results provide new insight into how the physical properties of micellar systems can be related to PALS parameters and means that the PALS technique can be applied to other more complex self-assembled amphiphile systems. PMID- 23643251 TI - Carboxymethyl cellulose binding to mineral substrates: characterization by atomic force microscopy-based force spectroscopy and quartz-crystal microbalance with dissipation monitoring. AB - The attachment of the sodium salt of carboxymethyl cellulose (CMC) onto iron oxide and various silicate substrates in aqueous solution as a function of salt concentration and pH was studied by atomic force microscopy-based force spectroscopy (AFM) and quartz-crystal microbalance with dissipation monitoring (QCM-D). Both ionic strength and cation valency were found to influence substrate binding. Notably, QCM-D experiments strongly suggested that the solubility of CMC is directly impacted by the presence of CaCl2. Such data are critical for the design of new molecules for stabilizing mineral floc dispersions and for assessing the mobility of CMC-coated particles in the subsurface. Modeling of AFM data with an extended Ohshima theory showed that van der Waals and steric forces played a major role in the interactions between CMC and mineral substrates, and that hydration forces were also important. PMID- 23643252 TI - Predictions of the maximum energy extracted from salinity exchange inside porous electrodes. AB - Capacitive energy extraction based on double layer expansion (CDLE) is the name of a new method devised for extracting energy from the exchange of fresh and salty water in porous electrodes. It is based on the change of the capacitance of electrical double layers (EDLs) at the electrode/solution interface when the concentration of the bulk electrolyte solution is modified. The use of porous electrodes provides huge amounts of surface area, but given the typically small pore size, the curvature of the interface and EDL overlap should affect the final result. This is the first aspect dealt with in this contribution: we envisage the electrode as a swarm of spherical particles, and from the knowledge of their EDL structure, we evaluate the stored charge, the differential capacitance and the extracted energy per CDLE cycle. In all cases, different pore radii and particle sizes and possible EDL overlap are taken into account. The second aspect is the consideration of finite ion size instead of the usual point-like ion model: given the size of the pores and the relatively high potentials that can be applied to the electrode, excluded volume effects can have a significant role. We find an extremely strong effect: the double layer capacitance is maximum for a certain value of the surface potential. This is a consequence of the limited ionic concentration at the particle-solution interface imposed by the finite size of ions, and leads to the presence of two potential ranges: for low electric potentials the capacitance increases with the ionic strength, while for large potentials we find the opposite trend. The consequences of these facts on the possibility of net energy extraction from porous electrodes, upon changing the solution in contact with them, are evaluated. PMID- 23643253 TI - Thermal unbinding and ordering of amphiphile bilayers in the presence of salt. AB - We have studied the effect of KBr on the electrostatically stabilized fluid lamellar phase of the ionic surfactant, C12-alkenylsuccinic acid (ASA). Three distinct regimes are found in the temperature - salt phase diagram of this system at a fixed ASA concentration of 20 wt.%. A collapsed lamellar phase is formed in the low-salt regime, which exhibits an unbinding transition into uncorrelated bilayers on heating. In the intermediate salt regime the opposite trend is observed, with the uncorrelated bilayers present at low temperatures ordering into a lamellar phase at higher temperatures. As far as we are aware, this is the first report of such an ordering transition of uncorrelated bilayers. In the high salt regime, the topology of the bilayer changes, resulting in a lamellar-sponge transition. All the three transitions are reversible and the corresponding transition temperatures decrease with increasing salt concentration. The occurrence of these transitions in a single amphiphile system demonstrates the strong influence of salt on the bilayer elastic moduli as well as on the inter bilayer interactions in the present system. PMID- 23643254 TI - Production of W/O/W (water-in-oil-in-water) multiple emulsions: droplet breakup and release of water. AB - We investigate breakup of W/O/W double emulsion droplets at high viscosity ratios and coalescence of inner water droplets dependent on the dispersed phase content (DPC) of the inner emulsion. The rheological analyses of the inner emulsions confirm the behavior expected from literature - increasing viscosity with increasing DPC and elastic behavior for high DPC. The resulting droplet sizes seem to be influenced only by the viscosity ratio calculated using the viscosity of the inner emulsion. An influence of the elastic properties of the inner emulsions could not be observed. Moreover, breakup of double emulsion droplets seems to follow the same rules as breakup of Newtonian droplets. In the second part of the paper we focus on the release of water from double emulsions by coalescence. A direct correlation between resulting double emulsion droplet sizes and encapsulation efficiency was found for each system. The initial inner dispersed phase content has a big influence on the release rate. This can partly be explained by the influence of the dispersed phase content on collision rate. Moreover, it was found that for high internal phase concentrations inner droplets coalesce with each other. The so formed bigger inner droplets seem to increase the overall release rate. PMID- 23643255 TI - Migraine, triptans, and the risk of developing rosacea: a population-based study within the United Kingdom. AB - BACKGROUND: Rosacea is a common skin disease, involving neurogenic inflammation and neurovascular dysregulation. Migraine has been associated with vascular changes and sterile inflammation. The 2 diseases have been associated over decades, but evidence is scarce. Triptans have vasoconstricting and antiinflammatory properties, but a potential impact of this drug class on rosacea remains uninvestigated. OBJECTIVE: We sought to analyze the association between migraine or triptan exposure and the risk of developing rosacea within the United Kingdom. METHODS: We conducted a case-control study using the United Kingdom based General Practice Research Database. We identified patients with incident rosacea between 1995 and 2009 (cases), and matched 1 rosacea-free control subject to each case. We compared the prevalence of diagnosed migraine and exposure to triptans before the first-time rosacea diagnosis between cases and controls using multivariate conditional logistic regression. RESULTS: Among 53,927 cases and 53,927 controls, we observed a small overall association between rosacea and migraine in women (adjusted odds ratio 1.22, 95% confidence interval 1.16-1.29), but not in men. This effect was somewhat more distinct in female migraineurs aged 50 to 59 years (odds ratio 1.36, 95% confidence interval 1.21-1.53). Female triptan users also revealed slightly increasing risk estimates with increasing age, with the highest odds ratio of 1.66 (95% confidence interval 1.30-2.10) in women aged 60 years or older. LIMITATIONS: This is a retrospective case-control study, for which a certain degree of bias and confounding cannot be ruled out. CONCLUSIONS: We observed a slightly increased risk for female migraineurs to develop rosacea, particularly in women with severe migraine aged 50 years or older. PMID- 23643257 TI - Increased levels of microRNA-424 are associated with the pathogenesis of fetal growth restriction. AB - Studies show a number of miRNAs are expressed in the placenta including miRNA 424, a hypoxia-regulated miRNA, suggesting miRNA-424 may have a potential regulatory role in fetal growth restriction (FGR). The levels of miRNA-424 and its target gene, mitogen-activated protein kinase 1 (MEK1), and fibroblast growth factor receptor 1 (FGFR1) were examined. The levels of miRNA-424 were significantly increased in placentae from women with FGR. Both mRNA levels and protein levels of MEK1 and FGFR1 were significantly reduced in placentae complicated with FGR. Furthermore, the increased levels of miRNA-424 were negatively correlated with the mRNA levels of MEK1 in placentae complicated with FGR. Our study suggests upregulated miRNA-424 may be associated with the pathogenesis of FGR. PMID- 23643256 TI - A randomized study to evaluate the efficacy and safety of adding topical therapy to etanercept in patients with moderate to severe plaque psoriasis. AB - BACKGROUND: Few clinical trials have evaluated the combination of topical corticosteroids plus systemic therapies for psoriasis. OBJECTIVE: We sought to evaluate efficacy and safety of etanercept plus topical clobetasol propionate (CP) foam versus etanercept monotherapy for treatment of moderate to severe plaque psoriasis. METHODS: Adults with Psoriasis Area and Severity Index (PASI) score greater than or equal to 10 and psoriasis-affected body surface area greater than or equal to 10% were randomized to etanercept with CP as needed to clear (2 up-to-2-week courses, weeks 11-12 and 23-24) or etanercept alone (each arm at 50 mg twice weekly for 12 weeks followed by 50 mg once weekly for 12 weeks). RESULTS: A total of 592 patients enrolled (295 etanercept + CP arm; 297 etanercept arm). At week 12, significant differences were observed for response of 75% improvement in PASI score (primary end point, 65.2% vs 48.3% in the etanercept + CP vs etanercept arms, respectively; P < .001), response of 90% improvement in PASI score (29.7% vs 19.4%; P = .009), percentage PASI score improvement (76.5% vs 68.2%; P < .001), static physician global assessment of clear/almost clear (63.1% vs 47.3%; P < .001), and patient satisfaction with treatment (P = .006). Response of 75% improvement in PASI score and static physician global assessment of clear/almost clear were not significantly different between arms at week 24. Patient satisfaction with treatment (P = .001) and percentage improvement in PASI score (P = .031) were also greater in the etanercept + CP arm compared with etanercept only at week 24. Comparable numbers of adverse events occurred in each arm. LIMITATIONS: No placebo for CP foam was provided in the etanercept arm. CONCLUSIONS: Addition of CP to etanercept yielded increased efficacy compared with etanercept alone at week 12 without an increase in treatment-related adverse events. PMID- 23643258 TI - [Proportion and characteristics of gammadeltaT cells in different tissues and organs of C57BL/6 mice]. AB - OBJECTIVE: To compare the percentages of gammadeltaT cells in the lymphocytes and CD3+; T cells isolated from the livers, lungs, spleen and mesenteric lymph nodes of C57BL/6 mice and the phonotype and function of gammadeltaT cells in different tissues or organs. METHODS: Lymphocytes were isolated from livers, lungs, spleen and mesenteric lymph nodes of normal C57BL/6 mice, respectively. Then, percentages of gammadeltaT cells in lymphocytes and CD3+; T cells, and phenotypic characteristics of gammadeltaT cells were examined by flow cytometry. Moreover, IFN-gamma, IL-4, IL-9 and IL-17 secreted by gammadeltaT cells were detected by means of intracellular cytokine staining after stimulation with PMA plus ionomycin. RESULTS: The percentage of gammadeltaT in lymphocyte cells of the livers was significantly higher than that of the lungs, spleen and mesenteric lymph nodes (P<0.05), and the percentage in CD3+; T cells of the mesenteric lymph nodes was the lowest (P<0.05). CD4-; CD8-; gammadeltaT cells were the main subpopulation in these tissues and organs and there was also a small proportion of CD8+; gammadeltaT cells. The proportion of CD4+; gammadeltaT cells in the mesenteric lymph nodes was significantly higher than that in the others (P<0.05), and a group of CD4+; CD8+; gammadeltaT cells existed obviously. The percentage of IL-17+; cells in gammadeltaT cells was significantly higher than IFN-gamma+; and IL-4+; cells, and almost no IL-9 gammadeltaT cells were found. The ability of secreting cytokines of gammadeltaT cells in the lungs was the strongest and the percentage of IL-17+; gammadeltaT was (26.6 +/- 12.1) %. In addition, the proportion of IFN-gamma+-; gammadeltaT cells in the livers and lungs were (1.36 +/- 0.37)% and (1.6 +/- 0.7)%, respectively. CONCLUSION: The proportion, phenotype and function of gammadeltaT cells had significant difference in the livers, lungs, spleen, mesenteric lymph nodes of C57BL/6 mice. PMID- 23643259 TI - [Transgenic expression of T cell receptors on HBV-specific cytotoxic T lymphocytes]. AB - OBJECTIVE: To express T lymphocyte receptors (TCRs) on hepatitis B virus (HBV) specific cytotoxic T lymphocytes (CTLs) mediated by retrovirus and investigate their binding affinity. METHODS: Peripheral blood mononuclear cells were isolated from acute hepatitis B patients with HLA-A2+; phenotype, and after induced, HBV specific CTLs were sorted out followed by cloning and proliferating. Cell RNAs were extracted. The sequences of TCR's alpha and beta chains were obtained by means of RT-PCR, 5'RACE and OVER-LAP PCR, for constructing TCR retrovirus vectors. Through retrovirus-mediated transduction, HBV-specific TCRs were expressed on Jurkat cells and CD8+; T cells from HLA-A+; healthy subjects. RESULTS: Two paired TCR Valpha and Vbeta, respectively named alpha21beta13 and alpha15beta13, were obtained from one patient with acute hepatitis B and HLA A2+;. The titers of packaged recombinant retroviruses were 1.5*10;-5.0*105; IU/mL. Immunofluorescence staining by anti-Vbeta13 TCR-PE targeting the specific TCR and HLA-A2 restricted epitope-specific pentamer showed a positive expression of reconstructed TCR on T cells. The positive cells accounted for 1.06%-2.25% for Vbeta13 on Jurkat cells, 1.03%-2.06% for Vbeta13 chain and 1.05%-1.12% for the epitope-specific pentamer on T cells from healthy HLA-A2+; subjects respectively. By contrast, only less than 0.05% cells from healthy HLA-A2- ;subjects were positive for either Vbeta13 or the pentamer. CONCLUSION: TCRs on HBV-specific CTLs could be expressed by TCR gene transfer mediated by retrovirus, and they were proved with binding affinity to HLA-A2-restricted epitope. PMID- 23643260 TI - [Inhibitive effect of celecoxib combined with tegafur gimeracil oteracil potassium on the growth of xenograft tumor of gastric cancer in nude mice]. AB - OBJECTIVE: To investigate the anti-tumor effect of celecoxib combined with tegafur gimeracil oteracil potassium on subcutaneous xenograft tumor of gastric cancer in nude mice and analyze the possible mechanism. METHODS: A xenograft tumor model of gastric cancer was established subcutaneously in nude mice. After the largest diameter of tumor reached about 5 mm, the nude mice were randomly divided into 4 groups: the control group, the celecoxib group, the tegafur gimeracil oteracil potassium group, and the combination group; the drug was administered respectively for 21 days. Thereafter, tumor tissues were collected, tumor volume was measured, and tumor inhibition rate was calculated. Apoptosis was determined by TUNEL assay and the expression levels of PCNA, Bcl-2 and caspase-3 by immunohistochemistry. RESULTS: The tumor inhibition rates of the celecoxib group, the tegafur gimeracil oteracil potassium group, the combination group were 30.8%, 50.1%, 78.8%, respectively. The apoptosis index in treatment groups was higher than that in the control group (P<0.01), and the combination group was higher than single drug group (P<0.01). The expressions of PCNA, Bcl-2 in treatment groups were lower than those in the control group (P<0.01), and the combination group was lower than single drug group (P<0.05). The expression of caspase-3 in treatment groups was higher than that in the control group (P<0.05), and the combination group was higher than single drug group (P<0.01). CONCLUSION: Both celecoxib and tegafur gimeracil oteracil potassium showed obvious anti-tumor effect, and the combination of the two acted synergistically. The possible mechanism was that they inhibited tumor growth through inhibiting proliferation and promoting apoptosis of the tumor cells. PMID- 23643261 TI - [Effect of cell cycle-related novel gene CACUL1 on the apoptosis of colorectal cancer cells in vitro]. AB - OBJECTIVE: To investigate the role of the cell cycle-related novel gene CDK2 associated, culin clomain 1(CACUL1) in tumor cell apopotosis and explore the relationship between CACUL1 and apoptosis regulation. METHODS: We induced the cell cycle arrest by ultraviolet radiation and chemotherapeutic drugs and then studied the expression of CACUL1 in cell DNA damage state. Meanwhile, Western blotting, Northern blotting and other methods were applied to detect the expression of the CACUL1 at both protein and mRNA levels and analyze their relationships with p53 in p53 wild-type and knock-out colorectal cancer cells. RESULTS: The CACUL1 was proved related to the regulation of apoptosis. In the case of DNA damage induced by ultraviolet radiation and chemotherapeutic drugs, the expression of CACUL1 protein peaked at 2 h, and with time went by, the expression of CACUL1 gradually decreased. The increase of CACUL1 expression was independent of p53. Northern blotting revealed that the increased expression of CACUL1 was post-transcriptional regulation. It was also found that the high expression of CACUL1 inhibited cell apoptosis induced by ultraviolet radiation and chemotherapeutic drugs. CONCLUSION: The role of CACUL1 in cell apoptosis is to help cells cross the G1/S checkpoints in a posttranscriptional regulation of p53-independent manner, thus facilitating cell survival. PMID- 23643262 TI - [Cloning and eukaryotic expression of human TRAF3IP3 gene]. AB - OBJECTIVE: To construct an eukaryotic expression plasmid of human TNF receptor associated factor 3 in teracting protein 3(TRAF3IP3) gene and identify its expression in HEK293 cells. METHODS: Human TRAF3IP3 cDNA was amplified by RT-PCR from bone marrow mononuclear cells. After digested by restriction enzymes XhoI and SalI, the complete open reading frame of TRAF3IP3 gene was inserted into pIRES2-EGFP eukaryotic expression vector with a Flag tag at the N-terminus. The recombinant plasmid was identified by double restriction enzyme digestion and sequencing analysis. The constructed TRAF3IP3 eukaryotic expression plasmid was transfected into HEK293 cells by calcium phosphate precipitation method. The expression of green fluorescence protein was observed by fluorescence microscopy. Real-time PCR and Western blotting were performed to detect the expression of Flag-TRAF3IP3 fusion protein. RESULTS: Double restriction enzyme digestion and sequencing analysis revealed that TRAF3IP3 eukaryotic expression plasmid was constructed successfully. Green fluorescence was detected in transfected HEK293 cells. Real-time PCR showed TRAF3IP3 mRNA was expressed at a high level. The approximate 62 kD Flag-TRAF3IP3 fusion protein was found by Western blotting. CONCLUSION: Human TRAF3IP3 eukaryotic expression plasmid pIRES2-EGFP-TRAF3IP3 has been constructed successfully, which provides a foundation for the gene function research of TRAF3IP3. PMID- 23643263 TI - [Construction and expression of eukaryotic expression plasmid pIRES-neo-HBAg carrying HBV fusion antigen gene]. AB - OBJECTIVE: To construct a eukaryotic expression plasmid harboring HBV fusion antigen gene, and to express it in 293T cells. METHODS: The HBV fusion gene fragment was amplified by PCR from the plasmid pVAX1-HBV containing HBV fusion gene. After purified, the product was cloned into pMD18-T vector. The recombinant plasmid was confirmed by endonuclease digestion and sequencing analysis, and then subcloned into eukaryotic expression vector pIRES-neo. Then the recombinant expression plasmid pIRES-neo-HBAg was transfered into 293T cells by Lipofectamine(TM); 2000. The expression of HBV fusion antigen was identified by Western blotting, flow cytometry and immunofluorescence cytochemistry. RESULTS: The eukaryotic expression vector pIRES-neo-HBAg was constructed successfully. The expression of fusion antigen could be detected in the pIRES-neo-HBAg transfected 293T cells by Western blotting, immunofluorescence cytochemistry and flow cytometry. CONCLUSION: The eukaryotic expression plasmid pIRES-neo-HBAg is successfully constructed and the fusion antigen is expressed in 293T cells. PMID- 23643264 TI - [Comparison between lentivirus and plasmid as shRNA vector targeting RhoA gene of ovary cancer cell line HO8910]. AB - OBJECTIVE: To compare the different effects of lentivirus and plasmid as shRNA vector targeting RAS homologue gene-family member A (RhoA) of ovary cancer cell line HO8910. METHODS: Lentivirus and plasmid vectors carrying siRNA targeting RhoA gene were respectively transferred into HO8910 cells. The transferred cells were screened with puromycin for the ones stably silencing RhoA gene. As passaging went on, the two types of vectors were compared in the ability of silencing RhoA gene expression by means of fluorescence microscopy, real-time quantitative PCR and Western blotting, and in the inhibitory effects on the invasion and metastasis of cells by scratch wound migration assay and tube formation assay. RESULTS: Two groups of stable RhoA-knockdown cell lines were established with lentivirus and plasmid as RNAi vectors, respectively. Detected by fluorescence microscopy, the expression rate of GFP decreased in the plasmid group as the culture generation increased; it was 70% and 45% at the 15th and 25th generations respectively. The expression rate of GFP in the lentivirus group maintained above 95%. Both real-time quantitative PCR and Western blotting indicated that the expression of RhoA mRNA and protein had no significant difference in the two groups at the 3rd generation; but as the culture generation increased, the expression of RhoA mRNA and protein in the lentivirus group kept at the lower level, while it increased in the plasmid group. The scratch wound migration assay and tube formation assay revealed that lentivirus as RNAi vector suppressed more stably and persistently the invasion and metastasis of ovary cancer cell line HO8910 as compared with the plasmid group (P<0.05). CONCLUSION: Lentivirus as RNAi vector can suppress the RhoA gene expression more stably as compared with the plasmid; the plasmid is more suitable for transient transfection studies. PMID- 23643265 TI - [Conivaptan inhibites cell proliferation and collagen production of cardiac fibroblasts induced by arginine vasopressin]. AB - OBJECTIVE: To investigate the effects of arginine vasopressin (AVP) and its receptor antagonist conivaptan (CON) on the proliferation of cardiac fibroblasts (CFs) and the production of collagen I and III. METHODS: CFs were isolated by collagenase II method and purified with differential attachment and detachment methods. The cell viability of CFs after AVP and/or CON administration was assessed by cell counting kit-8 (CCK-8). The expressions of COL1A1 and COL3A1 mRNA were detected by RT-PCR, and the protein levels of (collagen type 1, alpha 1, COL1A1) and COL3A1 were assessed by Western blotting. RESULTS: At 24 h after intervention, 10(-7); mol/L AVP promoted the proliferation of CFs in comparison with that in control group (P<0.01), and 10(-7); mol/L CON inhibited the effect significantly (P<0.01). At 12 h after intervention, 10(-7); mol/L AVP significantly enhanced the expressions of COL1A1 and COL3A1 at both mRNA and protein levels, and 10(-7); mol/L CON inhibited the effect again. CONCLUSION: AVP promoted the proliferation of CFs and enhanced the COL1A1 and COL3A1 expressions at both mRNA and protein levels, while CON could restrain the AVP effects partially. PMID- 23643266 TI - [The expression, purification and characterization of beta-hCG protein in E.coli]. AB - OBJECTIVE: To obtain beta-chain human chorionic gonadotropin (beta-hCG) fusion protein (beta-hCG/GST) and identify its antigenicity. METHODS: The full-length gene of beta-hCG was amplified by PCR. The PCR product was cloned into pET-42a prokaryotic expression vector to construct the recombinant plasmid pET-42a-beta hCG, and then it was transformed into BL21 (DE3) for beta-hCG/GST fusion protein expression under IPTG induction. After SDS-PAGE assay, the fusion protein was purified by affinity chromatography and identified by Western blotting. The antigenicity of the purified fusion protein was characterized by ELISA. RESULTS: The beta-hCG gene we obtained had an identical sequence to that retrieved in GenBank. The prokaryotic expression vector pET-42a-beta-hCG was successfully constructed as confirmed by enzyme digestion and DNA sequencing. Both Western blotting and ELISA demonstrated that the purified beta-hCG fusion protein had satisfactory antigenicity. CONCLUSION: The purified beta-hCG/GST fusion protein with satisfactory antigenicity has been obtained, which will facilitate further study on active anti-tumor immunotherapy targeting beta-hCG. PMID- 23643267 TI - [Screening of atherosclerosis related polypeptide from phage display peptide library]. AB - OBJECTIVE: To screen atherosclerosis (AS) related polypeptide from phage display 12-peptide library, and verify the binding activity of selected positive phages and synthetic protein fragment. METHODS: We collected plasma from AS patients as target for biopanning against phage-displayed 12-peptide library. After 3 rounds of screening, 10 positive phages were picked up and the binding activity was proved by ELISA. Single-stranded DNA of the phages were purified and sequenced, and a similar polypeptide was synthesized to test the binding activity to AS patients plasma. RESULTS: Selected phages significantly bound to AS patients' plasma. Five of ten phages had GPRPPSAPNMPL sequence. Corresponding synthetic polypeptide also showed a high binding activity to AS patient plasma. CONCLUSION: AS-related polypeptide can be obtained by phage display, which facilitates the research into the immune mechanism of AS. PMID- 23643268 TI - [Effect of Staphylococcus aureus on the expressions of TLR2, IL-1beta, TNF-alpha and NF-kappaB in Bcap-37 cells]. AB - OBJECTIVE: To observe the effects of Staphylococcus aureus (S.aureus) on the expressions of Toll-like receptor 2 (TLR2), proinflammatory cytokines (IL-1beta, TNF-alpha) and nuclear factor kappaB(NF-kappaB) in human breast cancer Bcap-37 cells in vitro. METHODS: At the different time points after Bcap-37 cells were challenged with S.aureus, the expressions of TLR2 mRNA and protein were respectively detected using RT-PCR and flow cytometry, the concentrations of IL 1beta and TNF-alpha were examined by ELISA and NF-kappaB level by Western blotting. RESULTS: The mRNA and protein levels of TLR2 gradually increased in Bcap-37 cells since the stimulations of S.aureus and then dropped after the levels peaked at 4 and 6 hours, respectively (P<0.05). Meanwhile, the expressions of IL-1beta and TNF-alpha was significantly elevated when Bcap-37 cells were exposed to S.aureus, and reached the maximal levels at 12 and 16 hours, respectively (P<0.05), and then IL-1beta went down. Expression of NF-kappaB rose in a time-dependent manner after stimulated by S.aureus up to the maximum at 12 hours, and declined after 14 hours. CONCLUSION: In Bcap-37 cells, S.aureus exposure could up-regulate the expression of TLR2 at both mRNA and protein levels, increase the production of IL-1beta and TNF-alpha, and stimulate the expression of NF-kappaB. PMID- 23643269 TI - [Effect of lumican gene over-expression on proliferation of lung adenocarcinoma cell A549 and its mechanism]. AB - OBJECTIVE: To investigate the effect of the lumican gene on the proliferation of lung adenocarcinoma cell A549 and the possible mechanism. METHODS: The lung adenocarcinoma cell line A549 was infected with the recombinant lentivirus carrying the human lumican gene and a stable cell line was obtained via puromycin selection. The expression of lumican mRNA and protein was confirmed by fluorescence quantitative PCR(FQ-PCR) and Western blotting. We examined the cell growth curve, doubling time, proliferation index using MTT assay and flow cytometry and observed the status of the tumor in the experimental animals. Meanwhile, Western blotting was used to detect the expressions of RhoC and p-Akt proteins. RESULTS: The A549 cell line with the lumican gene over-expression was successfully built. Compared with the control group and the empty vector group, the cells in the experimental group grew faster (P<0.05), the doubling time was shortened (P<0.05), the proliferation index went up (P<0.05), subcutaneous tumors in volume and mass increased and cells of the mitotic figures became more (P<0.05), and the expressions of RhoC and p-Akt proteins were raised (P<0.05). However, there was no obvious difference between the control group and the empty vecor group (P>0.05). CONCLUSION: Lumican gene can promote the proliferation of lung adenocarcinoma cell A549, and its mechanism may be related to increased RhoC and p-Akt protein expressions. PMID- 23643270 TI - [Preparation of monoclonal antibody against phosphinothricin acetyltransferase]. AB - OBJECTIVE: To express phosphinothricin acetyltransferase (PAT) with biological activity and prepare monoclonal antibodies against PAT. METHODS: The full length bar gene was cloned by PCR and inserted into prokaryotic expression vector pET28a+. The recombinant plasmid pET28-bar was transformed into E.coli BL21(DE3), and under the induction of IPTG, PAT was expressed. The expressed protein was purified by Ni+; affinity chromatography to analyze its activity. The purified PAT was used to immunize BALB/c mice, and then the spleen cells from the immunized mice were fused with Sp2/0 cells. The hybridoma clones secreting antibodies against PAT were isolated by indirect ELISA and then subcloned. RESULTS: Soluble PAT was expressed in E.coli. The purified PAT had the activity of acetyltransferase. We totally prepared 9 hybridoma cell lines which secreted specific anti-PAT monoclonal antibodies. CONCLUSION: The expressed recombinant PAT can be used for biological reagent to prevent and relieve herbicide damage. Monoclonal antibodies against PAT may be used to detect the transgenic products. PMID- 23643271 TI - [Clonning and expression of procalcitonin and preparation of its polyclonal antibody]. AB - OBJECTIVE: To clone, express the procalcitonin (PCT) and prepare its polyclonal antibody. METHODS: We designed 10 DNA primers according to the encoding sequence of human PCT gene from GenBank, amplified PCT gene by PCR and constructed the recombinant vector pGEX-KG-PCT. Then the fusion protein, PCT-GST, was expressed in E.coli and purified by affinity chromatography. The corresponding polyclonal antibody was produced in the New Zealand white rabbits immunized with the fusion protein, and its biological activity was detected by Western blotting. The specificity and titer of the polyclonal antibody was identified by agar gel immunodiffusion test. RESULTS: We successfully obtained the full-length PCT gene and expressed the fusion PCT-GST in E.coli. SDS-PAGE showed that relative molecular mass (Mr;) was about 36 000. Agar gel immunodiffusion test revealed that the prepared polyclonal antibody could specially recognized PCT and its titer was 1:4. CONCLUSION: The PCT is successfully cloned, expressed and purified. The high specific polyclonal antibody of PCT is prepared. PMID- 23643272 TI - [The expression of humam sperm actin-like protein 7a and preparation of its polyclonal antibody]. AB - OBJECTIVE: To express and purify the recombinant human sperm actin-like protein 7a (ACTL7a) N terminal (1-70) in E.coli, and prepare the corresponding rabbit anti-ACTL7a polyclonal antibodies. METHODS: We constructed the recombinant expression plasmid pGEX-6p-1-ACTL7a (1-70), transformed the plasmid into E.coli BL21 (DE3), and selected positive recombinant strain. The target protein was induced to express by IPTG and purified by nickel ions-chelating resin and glutathione sepharose 4B resin, and finally obtained by molecular sieve chromatography. The purified ACTL7a (1-70) protein were used to immunize New Zealand rabbits to prepare anti-ACTL7a polyclonal antibodies. The antibody titers were detected by ELISA, the antibody specificity by Western blotting, and the localization of ACTL7a in the spermatogenic cells of seminiferous tubule epithelium by immunofluorescence histochemistry. RESULTS: The target protein ACTL7a (1-70) was successfully expressed by IPTG in E.coli, and the corresponding antiserum was obtained in the rabbits immunized with it. The titer of the antiserum reached 1:160 000 and it was proved with a good specificity. CONCLUSION: ACTL7a was expressed in the constructed prokaryotic expression vector. After purification and immunization, high titer and specific anti-ACTL7a antibody was prepared in rabbits. PMID- 23643273 TI - [The expression and purification of TRPM2 protein in E.coli and preparation of its polyclonal antibody]. AB - OBJECTIVE: To purify the prokaryotically expressed GST-TRPM2N fusion protein and prepare specific polyclonal antibody against human transient receptor potential melastatin 2(TRPM2) protein. METHODS: The DNA fragment encoding evolutionarily conserved N-terminus (1-334 amino acids) of TRPM2 was amplified by PCR. The amplicon was then subcloned into prokaryotic expression plasmid pGEX-4T-3 and the recombinant plasmid was transformed into BL21 (DE3) cells. The expression of GST TRPM2N fusion protein with a molecular weight about 70 000 Da was induced with 1 mmol/L IPTG and purified by GST affinity chromatography. The purified protein was mixed with complete Freund's adjuvant and used to immunize the New Zealand white rabbits with classical 4-injection protocol to generate specific anti-TRPM2 polyclonal antibody. The specificity and titer of the anti-TRPM2 antibody was analyzed by Western blotting. RESULTS: The cDNA fragment encoding N-terminus of human TRPM2 was amplified by PCR and directionally subcloned into pGEX-4T3 plasmid. Under the induction of IPTG, we observed the expression of GST-TRPM2N fusion protein. Polyclonal antibody against human TRPM2 protein was successfully prepared in the rabbits immunized with the purified GST-TRPM2N fusion protein. And the preliminary analysis showed that the anti-TRPM2 antibody could specifically identify transiently expressed TRPM2-EE in HEK293 cells. CONCLUSION: The specific polyclonal antibody against human TRPM2 protein has been successfully prepared, which facilitates our future research on the function of TRPM2 channel. PMID- 23643274 TI - [Peripheral blood CD4+;CXCR5+; follicular helper T cells are related to hyperglobulinemia of patients with chronic hepatitis B]. AB - OBJECTIVE: To detect cell frequency and surface markers of peripheral blood CD4+;CXCR5+;follicular helper T cells (Tfh cells) and analyze the correlation between CD4+;CXCR5+;Tfh cells and hyperglobulinemia of patients with chronic hepatitis B. METHODS: We collected blood samples of 20 HBV infected patients with hyperglobulinemia, 10 chronic HBV infected patients and 10 health volunteers and isolated plasma and peripheral blood mononuclear cells (PBMCs). The percentage of CD4+;CXCR5+;Tfh cells and the expressions of PD-1, ICOS and CD40L on CD4+;CXCR5+;Tfh cells were detected by flow cytometry. The levels of CXCL13, IFN gamma and IL-21 in plasma were measured by ELISA. RESULTS: Compared with the percentage of CD4+;CXCR5+;Tfh cells in chronic HBV infected patients (11.9 +/- 3.9) and health controls (6.8 +/- 3.9), it was higher in HBV infected patients with hyperglobulinemia (22.6 +/- 4.7, P<0.05). And in the hyperglobulinemia patients, the expressions of PD-1 and CD40L on CD4+;CXCR5+;Tfh cells and the levels of CXCL13 and IL-21 in plasma increased, whereas the level of IFN-gamma significantly declined (P<0.05). CONCLUSION: The results suggest that CD4+;CXCR5+;Tfh cells may participate in the pathogenesis of hyperglobulinemia during HBV infection. PMID- 23643275 TI - [Correlations between miRNAs and TGF-beta1 in tumor microenvironment of esophageal squamous cell cancer]. AB - OBJECTIVE: To detect the levels of mir-18a-5p, mir-23a-3p, mir-24-3p, mir-25-3p and TGF-beta1 in tumor microenvironment of esophageal squamous cell cancer (ESCC) patients and explore their clinical significances and correlations. METHODS: The mRNA expressions of mir-18a-5p, mir-23a-3p, mir-24-3p, mir-25-3p and TGF-beta1 were measured by real-time quantitative RT-PCR in ESCC cell lines ECA-109 and TE 1, normal esophageal squamous epithelial cells, tumor tissues and tumor-adjacent normal tissues from 52 ESCC patients. The expression of TGF-beta1 protein in the three types of cells, tumor tissues and tumor-adjacent normal tissues from 52 ESCC patients was detected by Western blotting. RESULTS: The expressions of mir 18a-5p, mir-24-3p, mir-25-3p and mir-23a-3p in ECA-109 were significantly higher than those in normal esophageal squamous epithelial cells (P<0.05); that is also true of the first three miRNAs in TE-1 (P<0.05). Compared with the normal esophageal squamous epithelial cells, the expression of TGF-beta1 was reduced in ECA-109 and TE-1 (P<0.05). Compared with the normal tissues, ESCC tumor tissues were characterized by significant overexpressions of mir-18a-5p, mir-23a-3p, mir 24-3p and mir-25-3p with the rates being 86.5% (45/52), 63.5% (33/52), 78.8% (41/52), 86.5% (45/52), respectively (all P<0.05), and by significantly decreased expression of TGF-beta1 (P<0.05). The up-regulation of mir-18a-5p, mir-23a-3p, mir-24-3p, mir-25-3p and the down-regulation of TGF-beta1 were not correlated with sex, age, tumor size and tumor site in ESCC patients, but the overexpressions of mir-18a-5p, mir-23a-3p, mir-25-3p were significantly related to tumor differentiation (P<0.05), and a significant variation of mir-25-3p was found in different T stages (P<0.05). TGF-beta1 level was lower in tumor tissues compared to normal tissues from the 52 ESCC patients, and higher in stage TIII/IV; than stage TI/II;(P<0.05), and a significant variation was found in histological differentiation (P<0.05). There was no correlation between mir-18a 5p, mir-23a-3p and TGF-beta1, but mir-24-3p and mir-25-3p had an inverse correlation with TGF-beta1 in tumor microenvironment of ESCC. CONCLUSION: Mir-18a 5p, mir-23a-3p, mir-24-3p, mir-25-3p and TGF-beta1 might play important roles in the carcinogenic process of ESCC. PMID- 23643276 TI - Identification of accurate reference genes for RT-qPCR analysis of formalin-fixed paraffin-embedded tissue from primary non-small cell lung cancers and brain and lymph node metastases. AB - Lung cancer is the most common cause of cancer-related deaths worldwide, and metastatic spread of the cancer rather than the primary tumor is the main cause of death. However, the molecular alterations of cancer cells leading to the formation of metastasis are poorly understood. This is partly a result of most solid tumor samples available for retrospective studies being archived as formalin-fixed paraffin-embedded (FFPE) specimens causing the nucleic acids to be highly degraded. Furthermore, stably expressed reference genes for normalization of gene expression data using reverse transcriptase quantitative PCR (RT-qPCR) have not been identified for combined analysis of primary lung tumors and the tissues where to the cancer metastasize. Using an optimized RT-qPCR workflow we have analyzed the expression of 23 candidate reference genes in a total of 54 FFPE specimens derived from primary Non-Small Cell Lung Cancer tumors, brain metastases, and lymph node metastases as well as normal lung, lymph node, and brain tissues. We show that every aspect of the workflow is highly reproducible, and the PUM1, TBP, and IPO8 genes were identified as the most stably expressed reference genes among the candidates, by using the GeNorm and NormFinder software programs. Furthermore, we demonstrate that commonly used reference genes such as ACTB (beta-actin), GAPDH, and rRNA18S are less stably expressed in the studied samples. The presented workflow and the identified reference genes may facilitate more reliable gene expression studies in lung cancer using RNA from FFPE tissues. PMID- 23643277 TI - The largest UK single centre series using hypofractionated radical radiotherapy for NSCLC in the very elderly. PMID- 23643278 TI - [Oxidative stress in Crohn's disease]. AB - Crohn's disease (CD) is characterized by transmural inflammation that is most frequently located in the region of the terminal ileum. Although the physiopathological mechanisms of the disease are not yet well defined, the unregulated immune response is associated with high production of reactive oxygen species (ROS). These elements are associated with complex systems known as antioxidant defenses, whose function is ROS regulation, thereby preventing the harmful effects of these elements. However, the presence of an imbalance between ROS production and ROS elimination by antioxidants has been widely described and leads to oxidative stress. In this article, we describe the most significant findings on oxidative stress in the intestinal mucosa and peripheral blood. PMID- 23643279 TI - Hypoxia-inducible factor pathway and diseases of the vascular wall. AB - BACKGROUND: Hypoxia may contribute to the pathogenesis of various diseases of the vascular wall. Hypoxia-inducible factors (HIFs) are nuclear transcriptional factors that regulate the transcription of genes that mediate cellular and tissue homeostatic responses to altered oxygenation. This article reviews the published literature on and discusses the role of the HIF pathway in diseases involving the vascular wall, including atherosclerosis, arterial aneurysms, pulmonary hypertension, vascular graft failure, chronic venous diseases, and vascular malformation. METHODS: PubMed was searched with the terms "hypoxia-inducible factor" or "HIF" and "atherosclerosis," "carotid stenosis," "aneurysm," "pulmonary artery hypertension," "varicose veins," "venous thrombosis," "graft thrombosis," and "vascular malformation." RESULTS: In atherosclerotic plaque, HIF 1alpha was localized in macrophages and smooth muscle cells bordering the necrotic core. Increased HIF-1alpha may contribute to atherosclerosis through alteration of smooth muscle cell proliferation and migration, angiogenesis, and lipid metabolism. The expression of HIF-1alpha is significantly elevated in aortic aneurysms compared with nonaneurysmal arteries. In pulmonary hypertension, HIF-1alpha contributes to the increase of intracellular K(+) and Ca(2+) leading to vasoconstriction of pulmonary smooth muscle cells. Alteration of the HIF pathway may contribute to vascular graft failure through the formation of intimal hyperplasia. In chronic venous disease, HIF pathway dysregulation contributes to formation of varicose veins and venous thromboembolism. However, whether the activation of the HIF pathway is protective or destructive to the venous wall is unclear. Increased activation of the HIF pathway causes aberrant expression of angiogenic factors contributing to the formation and maintenance of vascular malformations. CONCLUSIONS: Pathologic vascular wall remodelling of many common diseases of the blood vessels has been found to be associated with altered activity of the HIF pathway. Therefore, understanding the role of the HIF pathway in diseases of the vascular wall is important to identify novel therapeutic strategies in the management of these pathologies. PMID- 23643280 TI - Endovascular repair of descending thoracic aortic aneurysm in patient with Wiskott-Aldrich syndrome. AB - An association has been reported between Wiskott-Aldrich syndrome and necrotizing vasculitis and aneurysmal arterial dilatation. We present here the first endovascular repair of descending thoracic aortic aneurysm in a 35-year-old male patient with the classical Wiskott-Aldrich syndrome phenotype. He had a successful endovascular repair with early discharge from hospital with no postoperative complications. His 1-year follow-up computed tomography scan confirmed appropriate stent position, aneurysm sac resolution with no evidence of endoleak, and no further aneurysm formation. PMID- 23643281 TI - The use of a learning community and online evaluation of utilization for SPECT myocardial perfusion imaging. AB - Resource-sensitive and quality-centered imaging begins with the selection of the appropriate patient and test. Appropriate use criteria have been developed to aid clinicians but are often not available in an easily accessible format. FOCUS (Formation of Optimal Cardiovascular Utilization Strategies), a Web-based community and quality improvement instrument, was developed to increase the feasibility of measuring and improving practice patterns based on the appropriate use criteria. The FOCUS instrument proposed to reduce inappropriate imaging by 15% in 1 year and by 50% within 3 years. Between April 2010 and December 2011, data were voluntarily collected through the FOCUS radionuclide imaging performance improvement module (PIM). Appropriateness rates were compared between phases of the PIM. For the 55 participating sites that had completed the PIM by December 2011, the proportion of inappropriate cases decreased from 10% to 5% (p < 0.0001). These preliminary data from initial participating sites suggest that through the use of a self-directed, quality improvement software and an interactive community, physicians may be able to significantly decrease the proportion of tests not meeting appropriate use criteria. PMID- 23643282 TI - OCT analysis in patients with very late stent thrombosis. AB - OBJECTIVES: We report optical coherence tomography (OCT) findings in 33 patients who presented with very late stent thrombosis (VLST) after either drug-eluting stent (DES) or bare-metal stent (BMS) implantation. BACKGROUND: VLST is a potentially life-threatening complication, but the underlying mechanisms remain unclear. METHODS: In 33 patients (27 DES- and 6 BMS-treated lesions) with definite VLST, OCT images were acquired before either thrombus aspiration or intravascular ultrasonography (IVUS) imaging. RESULTS: The median duration from implantation was 61.5 months in the DES group and 109.1 months in the BMS group. In the overall cohort, combining DES and BMS, 94% showed intraluminal thrombi. VLST was associated with in-stent neointimal rupture in 23 patients (70%); 22 had thrombi near the site of neointimal rupture. Stent malapposition was observed in 14 (42%) lesions, but only 9 of them showed thrombi at the site of stent malapposition; moreover, 6 (18%) stented segments with malapposition also had neointimal rupture. Only 2 (6%) lesions had no evidence of neointimal rupture or malapposition. Stent fracture was detected in 3 DES-treated lesions, all with concomitant neointimal rupture. Compared with lesions without neointimal rupture, lesions with neointimal rupture showed a higher frequency of ST-segment elevation myocardial infarction (65% vs. 20%, respectively, p = 0.040) as well as a higher peak creatine kinase-myocardial band level (163.1 ng/ml vs. 15.7 ng/ml, respectively, p = 0.017). CONCLUSIONS: OCT imaging indicated that advanced neoatherosclerosis with neointimal rupture and thrombosis was the most common mechanism of definite VLST and was associated with a high frequency of ST-segment elevation myocardial infarction. PMID- 23643283 TI - Myocardial extracellular volume fraction from T1 measurements in healthy volunteers and mice: relationship to aging and cardiac dimensions. AB - OBJECTIVES: This study aimed to test the characteristics of the myocardial extracellular volume fraction (ECV) derived from pre- and post-contrast T1 measurements among healthy volunteers. BACKGROUND: Cardiac magnetic resonance (CMR) T1 measurements of myocardium and blood before and after contrast allow quantification of the ECV, a tissue parameter that has been shown to change in proportion to the connective tissue fraction. METHODS: Healthy volunteers underwent standard CMR imaging with administration of gadolinium. T1 measurements were performed with a Look-Locker sequence followed by gradient-echo acquisition. We tested the segmental, interslice, inter-, intra-, and test-retest characteristics of the ECV, as well as the association of the ECV with other variables. Juvenile and aged mice underwent a similar protocol, and cardiac sections were harvested for measurement of fibrosis. RESULTS: In healthy volunteers (N = 32, 56% female; age 21 to 72 years), the ECV averaged 0.28 +/- 0.03 (range 0.23 to 0.33). The intraclass coefficients for the intraobserver, interobserver, and test-retest absolute agreements of the ECV were 0.94 (95% confidence interval: 0.84 to 0.98), 0.93 (95% confidence interval: 0.80 to 0.98), and 0.95 (95% confidence interval: 0.52 to 0.99), respectively. In volunteers, the ECV was associated with age (r = 0.74, p < 0.001), maximal left atrial volume index (r = 0.67, p < 0.001), and indexed left ventricular mass. There were no differences in the ECV between segments in a slice or between slices. In mice (N = 12), the myocardial ECV ranged from 0.20 to 0.32 and increased with age (0.22 +/- 0.02 vs. 0.30 +/- 0.02, juvenile vs. aged mice, p < 0.001). In mice, the ECV correlated with the extent of myocardial fibrosis (r = 0.94, p < 0.001). CONCLUSIONS: In healthy volunteers, the myocardial ECV ranges from 0.23 to 0.33, has acceptable test characteristics, and is associated with age, left atrial volume, and left ventricular mass. In mice, the ECV also increases with age and strongly correlates with the extent of myocardial fibrosis. PMID- 23643284 TI - Noninvasive monitoring of oxidative stress in transplanted mesenchymal stromal cells. AB - OBJECTIVES: The goal of this study was to validate a pathway-specific reporter gene that could be used to noninvasively image the oxidative status of progenitor cells. BACKGROUND: In cell therapy studies, reporter gene imaging plays a valuable role in the assessment of cell fate in living subjects. After myocardial injury, noxious stimuli in the host tissue confer oxidative stress to transplanted cells that may influence their survival and reparative function. METHODS: Rat mesenchymal stromal cells (MSCs) were studied for phenotypic evidence of increased oxidative stress under in vitro stress. On the basis of their up-regulation of the pro-oxidant enzyme p67(phox) subunit of nicotinamide adenine dinucleotide phosphate (NAD[P]H oxidase p67(phox)), an oxidative stress sensor was constructed, comprising the firefly luciferase (Fluc) reporter gene driven by the NAD(P)H p67(phox) promoter. MSCs cotransfected with NAD(P)H p67(phox)-Fluc and a cell viability reporter gene (cytomegalovirus-Renilla luciferase) were studied under in vitro and in vivo pro-oxidant conditions. RESULTS: After in vitro validation of the sensor during low-serum culture, transfected MSCs were transplanted into a rat model of myocardial ischemia/reperfusion (IR) and monitored by using bioluminescence imaging. Compared with sham controls (no IR), cardiac Fluc intensity was significantly higher in IR rats (3.5-fold at 6 h, 2.6-fold at 24 h, 5.4-fold at 48 h; p < 0.01), indicating increased cellular oxidative stress. This finding was corroborated by ex vivo luminometry after correcting for Renilla luciferase activity as a measure of viable MSC number (Fluc:Renilla luciferase ratio 0.011 +/- 0.003 for sham vs. 0.026 +/- 0.004 for IR at 48 h; p < 0.05). Furthermore, in IR animals that received MSCs preconditioned with an antioxidant agent (tempol), Fluc signal was strongly attenuated, substantiating the specificity of the oxidative stress sensor. CONCLUSIONS: Pathway-specific reporter gene imaging allows assessment of changes in the oxidative status of MSCs after delivery to ischemic myocardium, providing a template to monitor key biological interactions between transplanted cells and their host environment in living subjects. PMID- 23643286 TI - Inflammation and microvascular dysfunction in cardiac syndrome X patients without conventional risk factors for coronary artery disease. AB - OBJECTIVES: The aim of this study was to ascertain whether coronary microvascular dysfunction (CMD) and inflammation are related in cardiac syndrome X (CSX). BACKGROUND: CMD can lead to CSX, defined as typical angina and transient myocardial ischemia despite normal coronary arteriograms. Inflammation has been suggested to play a role in the pathogenesis of myocardial ischemia in CSX. METHODS: We assessed 21 CSX patients (age 52 +/- 10 years; 17 women) without traditional cardiovascular risk factors and 21 matched apparently healthy control subjects. Positron emission tomography was used to measure myocardial blood flow (MBF) and coronary flow reserve (CFR) in response to intravenous adenosine, whereas high-sensitivity C-reactive protein (CRP) was measured to assess inflammation. Patients were subdivided a priori into 2 groups according to CRP concentrations at study entry (i.e., <=3 or >3 mg/l). RESULTS: There were no differences in resting (1.20 +/- 0.23 ml/min/g vs. 1.14 +/- 0.20 ml/min/g; p = 0.32) or hyperemic MBF (3.28 +/- 1.02 ml/min/g vs. 3.68 +/- 0.89 ml/min/g; p = 0.18) between CSX patients and the control group, whereas CFR was mildly reduced in CSX patients compared with the control group (2.77 +/- 0.80 vs. 3.38 +/- 0.80; p = 0.02). Patients with CRP >3 mg/l had more severe impairment of CFR (2.14 +/- 0.33 vs. 3.16 +/- 0.76; p = 0.001) and more ischemic electrocardiographic changes during adenosine administration than patients with lower CRP, and a negative correlation between CRP levels and CFR (r = -0.49, p = 0.02) was found in CSX patients. CONCLUSIONS: CSX patients with elevated CRP levels had a significantly reduced CFR compared with the control group, which is indicative of CMD. Our study thus suggests a role for inflammation in the modulation of coronary microvascular responses in patients with CSX. PMID- 23643285 TI - Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease. AB - OBJECTIVES: The goal of this study was to determine if low to moderate doses of anthracycline-based chemotherapy (Anth-bC) are associated with subclinical cardiovascular (CV) injury. BACKGROUND: Cancer survivors who receive Anth-bC experience premature CV events. It is unknown whether low to moderate doses of anthracyclines promote early subclinical CV disease manifested by deteriorations in left ventricular ejection fraction (LVEF) or increases in aortic stiffness, or if these doses are associated with changes in quality of life (QOL). METHODS: In 53 men and women with breast cancer, leukemia, or lymphoma, we assessed left ventricular volumes, LVEF, circumferential strain, aortic pulse wave velocity, late gadolinium enhancement, serum B-type natriuretic peptide, troponin I, and the impact of treatment on QOL before and 1, 3, and 6 months after receipt of Anth-bC. RESULTS: Participants averaged 50 +/- 2 (range 19 to 80) years in age, 58% were women, 17% were black, and they each received a range of 50 to 375 mg/m(2) of doxorubicin-equivalent chemotherapy. Left ventricular end-systolic volume (48 +/- 3 ml to 54 +/- 3 ml; p = 0.02), left ventricular strain (-17.7 +/- 0.4 to -15.1 +/- 0.4; p = 0.0003), pulse wave velocity (6.7 +/- 0.5 m/s to 10.1 +/- 1 m/s; p = 0.0006), and QOL deterioration (15.4 +/- 3.3 to 28.5 +/- 3.9; p = 0.008) increased, whereas LVEF (58 +/- 1% to 53 +/- 1%; p = 0.0002) decreased within 6 months after low to moderate doses of Anth-bC. All findings persisted after accounting for age, gender, race (white/black), doxorubicin-equivalent dose, doxorubicin administration technique, comorbidities associated with CV events, and cancer diagnosis (p = 0.02 to 0.0001 for all). There were no new late gadolinium enhancement findings after 6 months. CONCLUSIONS: In these study patients, low to moderate doses of Anth-bC were associated with the early development of subclinical abnormalities of cardiac and vascular function that in other populations are associated with the future occurrence of CV events. PMID- 23643287 TI - Immune response and serum bactericidal activity against Brucella ovis elicited using a short immunization schedule with the polymeric antigen BLSOmp31 in rams. AB - Brucella ovis is the etiologic agent of ovine brucellosis. The control measures for this disease are periodical diagnosis by serological tests and/or bacteriological culture and culling of positive animals. Vaccination with Brucella melitensis Rev 1 is recommended when prevalence is high. This attenuated strain vaccine gives protection against B. ovis but it has important disadvantages associated with the development of antibodies interfering with serodiagnosis, virulence for humans and the prohibition of its use in countries considered free of B. melitensis. Consequently, there is a need for new safe and effective brucellosis vaccines to be developed. We have previously reported that the polymeric subcellular vaccine BLSOmp31 confers protection against experimental challenge with B. ovis when rams are immunized three times. In the present work we evaluated and characterized, along 56 weeks after the first immunization of adult rams, the evolution of the immune response elicited by BLSOmp31 using a short immunization schedule. PMID- 23643288 TI - Tumor marker levels in patients aged 85 years and older with chronic heart failure. AB - BACKGROUND: Recent studies have suggested that carbohydrate antigen 125 (CA 125) serum levels are remarkably elevated in patients with heart failure. We hypothesized that there was a relationship between serum levels of tumor markers and the four stages of chronic heart failure (CHF) in patients aged 85 years and older with CHF. METHODS: The retrospective study enrolled 2115 patients aged 85 years and older suffering from CHF between January 2004 and January 2011. The levels of various tumor markers, N-terminal proB-type natriuretic peptide (NT proBNP) in the different stages of CHF, and clinical risk factors were analyzed. All patients were followed for 180 days, and major cardiovascular events were recorded. RESULTS: Only the CA 125 level increased as the stage of CHF increased (p<0.05) among the tumor markers. Significantly higher CA 125 serum levels were found in patients with pleural fluids or peripheral edema, compared with patients without pericardial effusion or peripheral edema (p<0.01). During 180 days of follow-up, CA 125 values were significantly higher in patients who died or were rehospitalized, compared with those who remained alive or did not undergo rehospitalization. Linear regression analysis between CA 125 and NT-proBNP serum levels showed a statistically significant relation (r=0.5103, p<0.05). CONCLUSIONS: Among the tumor markers evaluated, only CA 125 appeared to be related to the severity of CHF and NT-proBNP, along with the presence of pleural fluid or peripheral edema in patients aged 85 years and older with CHF. PMID- 23643290 TI - In vivo hip joint loads during three methods of walking with forearm crutches. AB - BACKGROUND: Patients with osteoarthritis, joint implants or fractures use crutches in order to reduce lower limb loading. However, insufficient information exists on how much the loading is then in fact reduced. This situation was studied by using seven patients who had instrumented hip implants. METHODS: Part I: To investigate the effectiveness of forearm crutches, crutch and hip joint contact forces were measured in seven patients with instrumented hip prostheses. Additionally, the bending moments in the implant neck and torsion around its stem were determined. Reductions of peak loads during 3, 4, and 2-point gaits were compared with loads present when walking without crutches. Part II: This examines joint load reduction during a 4-point gait from one to 12 weeks post-operatively. FINDINGS: Part I: During a 3, 4, and 2-point gait, the joint force was 17, 12, and 13% lower than it was while walking without crutches. The corresponding reductions of the bending moment were 16, 11, and 12%, while the maximum torque decreased by 19, 21, and 10%. Part II: The reductions of contact forces in comparison with walking without crutches were highest during the first 4 weeks after surgery. One and 4 weeks post-operatively, the force maximum was 21 and 8% lower than it was after 3 months. When compared with the initial values of the 1st week, crutch forces decreased by 28% in the 4th week and by 38% in the 3rd month. INTERPRETATION: Average reductions of the joint load by more than 20% are achieved only during the first 4 post-operative weeks. Because fractures are in most cases relatively stable after 6 weeks, and bone ingrowth into implant interfaces is nearly finished after this time, a single crutch and a 2-point gait can be prescribed during the 5th and 6th post-operative week. PMID- 23643289 TI - Load response of the medial longitudinal arch in patients with flatfoot deformity: in vivo 3D study. AB - BACKGROUND: The acquisition of flatfoot by an adult is thought to primarily be caused by posterior tibial tendon dysfunction, although some other causes, such as congenital flexible flatfoot or an accessory navicular, may also be responsible. The objective of this study was to evaluate the bone rotation of each joint in the medial longitudinal arch (MLA) and compare the response in healthy feet with that in flat feet by analyzing the reconstructive three dimensional (3D) CT image data during weightbearing. METHODS: CT scans of 20 healthy feet and 24 feet with flatfoot deformity were taken in non-load condition followed by full-body weightbearing condition. Images of the tibia and MLA bones (first metatarsal bone, cuneiforms, navicular, talus, and calcaneus) were reconstructed into 3D models. The volume merge method in three planes was used to calculate the bone-to-bone relative rotations. FINDINGS: Under loading conditions, the flatfoot dorsiflexed more in the first tarsometatarsal joint, and everted more in the talonavicular and talocalcaneal joints compared with the healthy foot. The total relative rotation was larger in the flatfoot compared with the healthy foot only in the first tarsometatarsal joint. INTERPRETATION: Supporting the MLA in the sagittal direction and the subtalar joint in the coronal direction may be useful for treating flatfoot deformity. The first tarsometatarsal joint may play an important role in diagnosing or treating flatfoot deformity. PMID- 23643291 TI - Quality of life after management of advanced osteoradionecrosis of the mandible. AB - Osteoradionecrosis (ORN) of the mandible is a severe complication of radiation therapy for head and neck cancer. In this case series, the authors analyzed their treatment and quality of life outcomes over the past 6 years. A retrospective chart review of 42 patients treated surgically for advanced ORN was conducted. A telephone survey was conducted and quality of life (QOL) questionnaires were completed in a subset of patients. 30 patients responded to the telephone survey assessing QOL for speech, swallowing and overall functioning correlated with oral nutrition and performance status. Surgery for ORN can result in an improved QOL. Functional outcomes of oral intake, speech intelligibility, and eating in public correlated with patient rated QOL measures. A lack of improvement in QOL, despite the restoration of an intact mandible, relates to the persistent effects of chemoradiotherapy. PMID- 23643292 TI - Ambient temperature and emergency department visits for heat-related illness in North Carolina, 2007-2008. AB - PURPOSE: To estimate the association between environmental temperatures and the occurrence of emergency department visits for heat-related illness in North Carolina, a large Southern state with 85 rural and 15 urban counties; approximately half the state's population resides in urban counties. METHODS: County-level daily emergency department visit counts and daily mean temperatures for the period 1/1/2007-12/31/2008 were merged to form a time-series data structure. Incidence rates were calculated by sex, age group, region, day of week, and month. Incidence rate ratios were estimated using categorical and linear spline Poisson regression models and heterogeneity of the temperature emergency department visit association was assessed using product interaction terms in the Poisson models. RESULTS: In 2007-2008, there were 2539 emergency department visits with heat-related illness as the primary diagnosis. Incidence rates were highest among young adult males (19-44 year age group), in rural counties, and in the Sandhills region. Incidence rates increased exponentially with temperatures over 15.6 degrees C (60 degrees F). The overall incidence rate ratio for each 1 degrees C increase over 15.6 degrees C in daily mean temperature was 1.43 (95%CI: 1.41, 1.45); temperature effects were greater for males than females, for 45-64 year olds, and for residents of rural counties than residents of urban counties. CONCLUSIONS: As heat response plans are developed, they should incorporate findings on climate effects for both mortality and morbidity. While forecast-triggered heat health warning systems are essential to mitigate the effects of extreme heat events, public health preparedness plans should not ignore the effects of more persistently observed high environmental temperatures like those that occur throughout the warm season in North Carolina. PMID- 23643293 TI - Prevalence of hospital-associated infections can be decreased effectively in developing countries. AB - BACKGROUND: Hospital-acquired infections (HAI) are an important public health problem worldwide. Little information is available from African countries, but published data show that the burden of HAI is greater in Africa than in developed countries. In 2002, the World Health Organization (WHO) published guidelines for preventing HAI. AIM: To evaluate the impact of a hospital infection control programme on the prevalence of HAI among patients in a large Ugandan hospital. METHODS: A one-day cross-sectional prevalence survey and a ward procedure survey were performed in Lacor Hospital in March 2010 using standardized questionnaires. All patients admitted to hospital not less than two days before the survey were eligible to participate in the prevalence survey. Modified WHO criteria for HAI were used. The ward procedure survey examined the procedures to prevent HAI. Several hospital infection control measures were subsequently implemented, in accordance with WHO infection control guidelines, starting in October 2010. The prevalence survey and ward procedure survey were repeated in October 2011. FINDINGS: The prevalence of HAI was 34% in 2010 and 17% in 2011. The prevalence of infected patients reduced from 28% to 14%. The prevalence of HAI was lower in all age groups and for all types of HAI except urinary tract infections following the implementation of infection control activities. CONCLUSION: This study showed that HAI is an important problem in this large African hospital, and that the prevalence of HAI can be reduced effectively following the adoption of basic infection control procedures. PMID- 23643294 TI - Ca2+ homeostasis in the endoplasmic reticulum measured with a new low-Ca2+ affinity targeted aequorin. AB - We use here a new very low-Ca(2+)-affinity targeted aequorin to measure the [Ca(2+)] in the endoplasmic reticulum ([Ca(2+)]ER). The new aequorin chimera has the right Ca(2+)-affinity to make long-lasting measurements of [Ca(2+)]ER in the millimolar range. Moreover, previous Ca(2+)-depletion of the ER is no longer required. The steady-state [Ca(2+)]ER obtained is 1-2 mM, higher than previously reported. In addition, we find evidence that there is significant heterogeneity in [Ca(2+)]ER among different regions of the ER. About half of the ER had a [Ca(2+)]ER of 1 mM or below, and the rest had [Ca(2+)]ER values above 1mM and in some parts even above 2 mM. About 5% of the ER was also found to have high [Ca(2+)]ER levels but to be thapsigargin-insensitive and inositol trisphosphate insensitive. The rate of refilling with Ca(2+) of the ER was almost linearly dependent on the extracellular [Ca(2+)] between 0.1 and 3 mM, and was only partially affected by mitochondrial membrane depolarization. Instead, it was significantly reduced by loading cells with chelators, and the fast chelator BAPTA was much more effective than the slow chelator EGTA. This suggests that local [Ca(2+)] microdomains connecting the store operated Ca(2+) channels with the ER Ca(2+) pumps may be important during refilling. PMID- 23643295 TI - FcgammaRI is required for TGFbeta2-treated macrophage-induced tolerance. AB - Macrophages treated with TGFbeta2 (TGFbeta2-Mphi) and antigen are highly tolerogenic in vivo, and induce antigen-specific and long-lasting tolerance in both naive and primed mice via induction of suppressor/regulatory T cells. In this study, we examined the molecular pathways, including the requirements for Smad-dependent signaling, that are involved in the induction and function of tolerogenic TGFbeta2-Mphi. Treatment of murine macrophages with TGFbeta2 induced translocation of Smad2/3 to the nucleus, and impairment of Smad3-, but not Smad2 , dependent signaling inhibited the tolerogenic function of a TGFbeta2-treated murine macrophage cell line. Gene expression in murine macrophages treated with TGFbeta2 was evaluated by microarray analysis. The FcgammaRI gene was one of a number of immune-related genes differentially expressed in TGFbeta2-Mphi, and appeared to be critical for tolerance in this system, since TGFbeta2-Mphi from FcgammaRI deficient mice were unable to induce tolerance. The role that FcgammaRI plays in TGFbeta2-Mphi-mediated tolerance is currently unclear. The results of this study provide important information about the factors that are critical for the induction of TGFbeta2-Mphi-mediated tolerance, and a better understanding of these mechanisms could lead to the development of more effective tolerance inducing strategies for the treatment of autoimmune/inflammatory diseases. PMID- 23643297 TI - Global health education: a pilot in trans-disciplinary, digital instruction. AB - BACKGROUND: The development of new global health academic programs provides unique opportunities to create innovative educational approaches within and across universities. Recent evidence suggests that digital media technologies may provide feasible and cost-effective alternatives to traditional classroom instruction; yet, many emerging global health academic programs lag behind in the utilization of modern technologies. OBJECTIVE: We created an inter-departmental University of Southern California (USC) collaboration to develop and implement a course focused on digital media and global health. DESIGN: Course curriculum was based on core tenants of modern education: multi-disciplinary, technologically advanced, learner-centered, and professional application of knowledge. Student and university evaluations were reviewed to qualitatively assess course satisfaction and educational outcomes. RESULTS: 'New Media for Global Health' ran for 18 weeks in the Spring 2012 semester with N=41 students (56.1% global health and 43.9% digital studies students). The course resulted in a number of high quality global health-related digital media products available at http://iml420.wordpress.com/. Challenges confronted at USC included administrative challenges related to co-teaching and frustration from students conditioned to a rigid system of teacher-led learning within a specific discipline. Quantitative and qualitative course evaluations reflected positive feedback for the course instructors and mixed reviews for the organization of the course. CONCLUSION: The development of innovative educational programs in global health requires on-going experimentation and information sharing across departments and universities. Digital media technologies may have implications for future efforts to improve global health education. PMID- 23643298 TI - Surgery for metastatic neuroendocrine tumors with occult primaries. AB - INTRODUCTION: Neuroendocrine tumors (NETs) frequently metastasize prior to diagnosis. Although metastases are often identifiable on conventional imaging studies, primary tumors, particularly those in the midgut, are frequently difficult to localize preoperatively. MATERIALS AND METHODS: Patients with metastatic NETs with intact primaries were identified. Clinical and pathologic data were extracted from medical records. Primary tumors were classified as localized or occult based on preoperative imaging. The sensitivities and specificities of preoperative imaging modalities for identifying the primary tumors were calculated. Patient characteristics, tumor features, and survival in localized and occult cases were compared. RESULTS: Sixty-one patients with an intact primary tumor and metastatic disease were identified. In 28 of these patients (46%), the primary tumor could not be localized preoperatively. A median of three different preoperative imaging studies were utilized. Patients with occult primaries were more likely to have a delay (>6 mo) in surgical referral from time of onset of symptoms (57% versus 27%, P = 0.02). Among the 28 patients with occult primary tumors, 18 (64%) were found to have radiographic evidence of mesenteric lymphadenopathy corresponding, in all but one case, to a small bowel primary. In all but three patients (89%), the primary tumor could be identified intraoperatively. CONCLUSION: The primary tumor can be identified intraoperatively in a majority of patients with metastatic NETs, irrespective of preoperative localization status. Referral for surgical management should not, therefore, be influenced by the inability to localize the primary tumor. PMID- 23643299 TI - A meta-analysis of the effectiveness and safety of using tranexamic acid in primary unilateral total knee arthroplasty. AB - BACKGROUND: To evaluate the effectiveness and safety of tranexamic acid (TEA) treatment in reducing perioperative blood loss and transfusion for patients receiving primary unilateral total knee arthroplasty (TKA) and to explore the most effective and safe protocol. MATERIALS AND METHODS: This study was based on Cochrane methodology for conducting meta-analyses. Only randomized controlled trials were eligible for this study. The participants were adults who had undergone primary unilateral TKA. The Review Manager Database (RevMan version 5.0, The Cochrane Collaboration, 2008) was used to analyze selected studies. RESULTS: Nineteen randomized controlled trials involving 1114 patients were included. The use of TEA reduced postoperative drainage by a mean of 290 mL (95% confidence interval [CI] -385 to -196], total blood loss by a mean of 570 mL (95% CI -663 to -478), the number of blood transfusions per patient by 0.96 units (95% CI -1.32 to -0.59), and the volumes of blood transfusions per patient -440 mL (95% CI -518 to -362). TEA led to a significant reduction in the proportion of patients requiring blood transfusion (relative risk 0.39). There were no significant differences in venous thromboembolism or other adverse events among the study groups. CONCLUSIONS: Intravenous TEA could significantly reduce perioperative blood loss and blood transfusion requirements following primary unilateral TKA. Its application is not associated with increased risk of venous thromboembolisms or other adverse events. PMID- 23643300 TI - Viscoelastic creep induced by repetitive spine flexion and its relationship to dynamic spine stability. AB - Repetitive trunk flexion elicits passive tissue creep, which has been hypothesized to compromise spine stability. The current investigation determined if increased spine flexion angle at the onset of flexion relaxation (FR) in the lumbar extensor musculature was associated with altered dynamic stability of spine kinematics. Twelve male participants performed 125 consecutive cycles of full forward trunk flexion. Spine kinematics and lumbar erector spinae (LES) electromyographic (EMG) activity were obtained throughout the repetitive trunk flexion trial. Dynamic stability was evaluated with maximum finite-time Lyapunov exponents over five sequential blocks of 25cycles. Spine flexion angle at FR onset, and peak LES EMG activity were determined at baseline and every 25th cycle. Spine flexion angle at FR increased on average by 1.7 degrees after baseline with significant increases of 1.7 degrees and 2.4 degrees at the 50th and 100th cycles. Maximum finite-time Lyapunov exponents demonstrated a transient, non-statistically significant, increase between cycles 26 and 50 followed by a recovery to baseline over the remainder of the repetitive trunk flexion cycles. Recovery of dynamic stability may be the consequence of increased active spine stiffness demonstrated by the non-significant increase in peak LES EMG that occurred as the repetitive trunk flexion progressed. PMID- 23643301 TI - Circulating antipodocyte antibodies in membranous nephropathy: new findings. PMID- 23643302 TI - Babesiosis-induced acute kidney injury with prominent urinary macrophages. AB - Babesia is an obligate intracellular erythrocyte parasite that can infect humans. Severe symptomatic disease from massive hemolysis and multiorgan system failure, including acute kidney injury (AKI), occurs. Acute tubular injury from a combination of volume depletion and heme pigment toxicity from profound hemolysis is the most common cause of AKI. We present a case of severe babesiosis complicated by dialysis-requiring AKI with the unique finding of large macrophages containing engulfed erythrocyte fragments in urine sediment. This urinary finding raised the possibility of another diagnosis distinct from acute tubular injury. Subsequent kidney biopsy demonstrated infection-associated acute interstitial nephritis. PMID- 23643303 TI - Circulating antipodocyte antibodies in membranous nephropathy: pathophysiologic and clinical relevance. PMID- 23643305 TI - Silencing of the glucocorticoid-induced leucine zipper improves the immunogenicity of clinical-grade dendritic cells. AB - BACKGROUND: The maturation cocktail composed of interleukin (IL)-6, IL-1beta, tumor necrosis factor-alpha and prostaglandin E2 is considered the "gold standard" for inducing the maturation of dendritic cells (DCs) for use in cancer immunotherapy. Nevertheless, although this maturation cocktail induces increased expression of several activation markers, such as CD83, the co-stimulation molecules CD80, CD86 and CD40 and the chemokine receptor involved in DC homing in lymph nodes CCR7, the DC immune stimulatory function in vivo contrasts with this mature phenotype, and good clinical outcomes in patients with cancer treated with DC-based vaccines remain rare. METHODS: Phenotypic characterization of the immunosuppressive status of DCs differentiated from peripheral blood mononuclear cells of healthy volunteers and matured with the "gold standard" cocktail was performed. Glucocorticoid-induced leucine zipper (GILZ) targeting small interfering RNA (siRNA) was electroporated into DCs after maturation to increase their immunogenicity. RESULTS: The mature phenotype of DCs treated for 48 h with this cocktail was associated with the expression of several immunosuppressive regulators, including programmed cell death 1 ligand 1 (PD-L1), IL-10 and GILZ. Electroporation is a very efficient and safe way to deliver siRNA into DCs (80% of DCs receive at least one molecule of siRNA). Silencing GILZ in clinical-grade DCs by siRNA leads to a decrease of the PD-L1 expression associated with an increase in their IL-12 secretion and T-cell induction capability. CONCLUSIONS: GILZ silencing is a promising approach to achieving complete clinical-grade DC maturation and avoiding the immunosuppressive effects of the maturation cocktail on DCs intended for clinical use. PMID- 23643304 TI - Multipotent mesenchymal stromal cells protect against kidney injury. PMID- 23643306 TI - The promoter of the carotenoid cleavage dioxygenase 4a-5 gene of Chrysanthemum morifolium (CmCCD4a-5) drives petal-specific transcription of a conjugated gene in the developing flower. AB - Carotenoids comprise one of the major groups of pigments in flowers. Because carotenoids are physiologically indispensable pigments for all photosynthetic plants, their catabolism must be discretely regulated in photosynthetic organs and non-photosynthetic organs such as petals or fruits. In the chrysanthemum, carotenoid cleavage dioxygenase 4a (CmCCD4a), which is dominantly expressed in petals, cleaves carotenoid, leading to a white flower. CmCCD4a-5 was recently identified as a new member of the CmCCD4a family, but its detailed expression profile in plant tissues has not yet been established. In this study, we sequenced a 1094-bp region upstream of CmCCD4a-5 and assessed its petal-specific promoter activity. To evaluate the activity of this gene, we constructed two types of transgenic Arabidopsis thaliana that possessed, respectively, a fusion gene of a 1090-bp or 505-bp segment of the upstream region plus the beta-d glucuronidase (GUS) gene (1090bUR::GUS and 505bUR::GUS). GUS activity in the 505bUR::GUS strain was observed mainly in the anthers/pollen in flower buds, whereas GUS activity of the 1090bUR::GUS strain was observed in immature petals of the flower buds. Among the cis-acting elements located between positions -505 and -1090, no elements that have previously been reported to enhance the expression in petals or to suppress it in anthers/pollen were detected by PLACE analysis, indicating the existence of unknown cis-element(s). A semiquantitative reverse transcription-polymerase chain reaction analysis revealed that CmCCD4a-5 transcription was prominent in petals but was undetectable in roots, stems and leaves. PMID- 23643307 TI - [Interhospital transfer of ECMO-assisted patients in Martinique]. AB - OBJECTIVE: The transportation of critically ill patients in the French West Indies represents a real challenge; in order to ensure territorial continuity of health care provision, the cardiac surgical department of the Fort-de-France Hospital created a mobile ECMO/ECLS unit. The aim of our work is to describe the logistical, technical and financial aspects of the interhospital transfer of ECMO/ECLS-assisted patients in the French Caribbean. PATIENTS AND METHODS: All ECMO/ECLS-assisted patients in the French Antilles-Guyane area subsequently repatriated towards the Fort-de-France Hospital were included from December 29th, 2009 to September 30th, 2011. Indication and type of the extracorporeal assistance used, location of departure, type of transport vehicle, complications during transfer, survival after hospital discharge and direct costs were collected. RESULTS: Nineteen patients were supported by our mobile unit far away from our centre (sex-ratio 0.63, median age 34years old [16-64]). Twelve were assisted by ECMO for a refractory ARDS, and seven were assisted by ECLS for a refractory cardiogenic shock. Four patients were transferred by ambulance (7 29km), seven by helicopter (190-440km), and eight by plane (440-1430km). No patient died during transfer. No major adverse event occurred during these transfers. Fifteen patients survived. An economic assessment was conducted. CONCLUSION: Interhospital transfer of ECMO/ECLS-assisted patients by land or air is technically feasible under perfectly secure conditions in our area. Prior coordination of this activity has helped to make it affordable. PMID- 23643308 TI - Sphingosine-1-phosphate exhibits anti-proliferative and anti-inflammatory effects in mouse models of psoriasis. AB - BACKGROUND: It has been indicated that the sphingolipid sphingosine-1-phosphate (S1P) restrains the ability of dendritic cells to migrate to lymph nodes. Furthermore S1P has been demonstrated to inhibit cell growth in human keratinocytes. However, only little is known about the effect of S1P in hyperproliferative and inflammatory in vivo models. OBJECTIVE: In this study, locally acting S1P was explored in different experimental mouse models of psoriasis vulgaris. METHODS: S1P and FTY720 were tested in the imiquimod-induced psoriasis mouse model, the mouse tail assay and a pilot study of the severe combined immunodeficiency mice (SCID). RESULTS: In the imiquimod model the positive control diflorasone diacetate and S1P, but not FTY720 reduced the imiquimod-induced epidermal hyperproliferation of the ear skin. This effect was confirmed in the SCID model, where S1P treated skin from patients suffering from psoriasis showed a decrease in epidermal thickness compared to vehicle. In the imiquimod model, there was also significant inhibition of ear swelling and a moderate reduction of inflammatory cell influx and oedema formation in ear skin by S1P treatment. The inflammatory response on the back skin was, however, only reduced by diflorasone diacetate. In the mouse tail assay, the influence of S1P and FTY720 in stratum granulosum formation was tested compared to the positive control calcipotriol. Whereas topical administration of calcipotriol led to a low but significant increase of stratum granulosum, S1P and FTY720 lacked such an effect. CONCLUSION: Taken together, these results imply that topical administration of S1P might be a new option for the treatment of mild to moderate psoriasis lesions. PMID- 23643309 TI - Prominent fatigue in spinal muscular atrophy and spinal and bulbar muscular atrophy: evidence of activity-dependent conduction block. AB - OBJECTIVES: To clarify whether patients with spinal muscular atrophy (SMA) or spinal and bulbar muscular atrophy (SBMA) suffer disabling muscle fatigue, and whether activity-dependent conduction block (ADCB) contributes to their fatigue. ADCB is usually caused by reduced safety factor for impulse transmission in demyelinating diseases, whereas markedly increased axonal branching associated with collateral sprouting may reduce the safety factor in chronic lower motor neuron disorders. METHODS: We assessed the fatigue severity scale (FSS) in 22 patients with SMA/SBMA, and in 100 disease controls (multiple sclerosis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy (CIDP), and axonal neuropathy). We then performed stimulated-single fibre electromyography (s SFEMG) in the extensor digitorum communis (EDC) muscle of 21 SMA/SBMA patients, 6 CIDP patients, and 10 normal subjects. RESULTS: The FSS score was the highest in SMA/SBMA patients [4.9 +/- 1.1 (mean +/- SD)], with 81% of them complaining of disabling fatigue, compared with normal controls (3.5 +/- 1.0), whereas patients with multiple sclerosis (4.3 +/- 1.6), myasthenia gravis (4.0 +/- 1.6) or CIDP (4.3 +/- 1.4) also showed higher FSS score. When 2000 stimuli were delivered at 20 Hz in s-SFEMG, conduction block of single motor axons developed in 46% of patients with SMA/SBMA, and 40% of CIDP patients, but in none of the normal controls. CONCLUSION: SMA/SBMA patients frequently suffer from disabling fatigue presumably caused by ADCB induced by voluntary activity. SIGNIFICANCE: ADCB could be the mechanism for muscle fatigue in chronic lower motor neuron diseases. PMID- 23643310 TI - Can task-related gamma activity guide the neurosurgeon in epilepsy surgery? PMID- 23643311 TI - EEG segmentation for improving automatic CAP detection. AB - OBJECTIVE: The aim of this study is to provide an improved method for the automatic classification of the Cyclic Alternating Pattern (CAP) sleep by applying a segmentation technique to the computation of descriptors from the EEG. METHODS: A dataset of 16 polysomnographic recordings from healthy subjects was employed, and the EEG traces underwent first an automatic isolation of NREM sleep portions by means of an Artificial Neural Network and then a segmentation process based on the Spectral Error Measure. The information content of the descriptors was evaluated by means of ROC curves and compared with that of descriptors obtained without the use of segmentation. Finally, the descriptors were used to train a discriminant function for the automatic classification of CAP phases A. RESULTS: A significant improvement with respect to previous scoring methods in terms of both information content carried by the descriptors and accuracy of the classification was obtained. CONCLUSIONS: EEG segmentation proves to be a useful step in the computation of descriptors for CAP scoring. SIGNIFICANCE: This study provides a complete method for CAP analysis, which is entirely automatic and allows the recognition of A phases with a high accuracy thanks to EEG segmentation. PMID- 23643312 TI - Nerve excitabitability and fasciculations. PMID- 23643313 TI - Asymmetry of balance responses to monaural galvanic vestibular stimulation in subjects with vestibular schwannoma. AB - OBJECTIVE: We investigated the potential of galvanic vestibular stimulation (GVS) to quantify lateralised asymmetry of the vestibulospinal pathways by measuring balance responses to monaural GVS in 10 subjects with vestibular schwannoma and 22 healthy control subjects. METHODS: Subjects standing without vision were stimulated with 3 s, 1 mA direct current stimuli delivered monaurally. The mean magnitude and direction of the evoked balance responses in the horizontal plane were measured from ground-reaction forces and from displacement and velocity of the trunk. Vestibular-evoked myogenic potentials (VEMPs) to 500 Hz air and bone conducted tones were also recorded. RESULTS: In healthy subjects, the magnitudes of the force, velocity and displacement responses were not significantly different for left compared to right ear stimulation. Their individual asymmetry ratios were always < 30%. Subjects with vestibular schwannoma had significantly smaller force, velocity and displacement responses to stimulation of the affected compared with non-affected ear. Their mean asymmetry ratios were significantly elevated for all three measures (41.2 +/- 10.3%, 40.3 +/- 15.1% and 21.9 +/- 14.6%). CONCLUSIONS: Asymmetry ratios of balance responses to monaural GVS provide a quantitative and clinically applicable lateralising test of the vestibulospinal pathways. SIGNIFICANCE: This method offers a more clinically relevant measure of standing balance than existing vestibular function tests which assess only vestibuloocular and vestibulocollic pathways. PMID- 23643314 TI - Reply to "Higher response time increases theta energy, conflict increases response time". PMID- 23643315 TI - Clinical-neurophysiological correlations in a series of patients with IgM-related neuropathy. AB - OBJECTIVE: We aim to draw clinical-neurophysiological correlations in our cohort of patients affected by IgM-related neuropathy to investigate whether neurophysiological parameters may help differentiate the classical phenotype from atypical forms. METHODS: We retrospectively evaluated patients with IgM-related neuropathy referred to our Institute from 1990 to 2011. All patients underwent extensive laboratory, clinical and neurophysiological evaluation. RESULTS: A classic sensory-ataxic form was observed in 20 of 34 patients, while an atypical phenotype (multiple mononeuropathy, polyneuropathy with predominant motor impairment, painful small-fibre neuropathy) was identified in the remaining 14 cases. Nerve conduction studies revealed in almost all cases a pattern typical of demyelination. A reduced terminal latency index and a prolonged distal motor latency of median nerve, as well as a prolonged distal motor latency and a reduced motor conduction velocity of peroneal nerve when recorded from extensor digitorum brevis, were significantly associated with classic sensory-ataxic phenotype. Conversely, a compound muscle action potential amplitude reduction of peroneal nerve from the tibialis anterior, was mostly associated with atypical forms. CONCLUSIONS: No clear electrophysiological differences between classical forms and atypical cases can be identified in IgM-related neuropathy. Still, we demonstrated that demyelinating abnormalities are more often associated with classical phenotypes, while axonal impairment occurs more often in atypical clinical patterns. SIGNIFICANCE: Performing correlations between clinical and neurophysiological findings in IgM-related neuropathy may help to better understand different disease mechanisms in this heterogeneous form of inflammatory neuropathy. PMID- 23643316 TI - Harms of unintentional leaks during volume targeted pressure support ventilation. AB - BACKGROUND: Volume targeted pressure support ventilation (VT-PSV) is a hybrid mode increasingly used to maintain a minimal tidal volume (VT) by automatically adjusting the level of inspiratory pressure. The objective of the study was to determine the ability of home ventilators to maintain the preset minimal VT during unintentional leaks in a VT-PSV mode. METHODS: Seven ventilators were tested on a lung bench with different circuit configurations and with different levels of unintentional leaks. Unintentional leaks were generated using calibrated holes. RESULTS: All the studied ventilators with a single-limb circuit with intentional leak (n = 5) were able to maintain the minimal preset VT during unintentional leaks. One ventilator overcompensated VT during unintentional leaks of high intensity. In contrast, all studied ventilators with a single circuit with an expiratory valve (n = 2) or a double-circuit (n = 3) but one failed to maintain the minimal VT during unintentional leaks. Unintentional leaks generated a decrease in inspiratory pressure, which was responsible for the fall in VT. CONCLUSIONS: Most of the studied ventilators with a single-limb circuit with intentional leak correctly estimate the expiratory VT and therefore successfully maintain the preset minimal VT during unintentional leaks, in contrast to most of the studied ventilators with a double-circuit, which paradoxically are not able to directly measure expiratory VT. Importantly, the VT-PSV mode, when used with most ventilators with expiratory valve or double-circuit, can paradoxically exacerbate the VT drop during unintentional leaks. PMID- 23643317 TI - Non-steroidal anti-inflammatory drug hypersensitivity in adults and the factors associated with asthma. AB - BACKGROUND: Characteristics of non-steroidal anti-inflammatory drug (NSAID) hypersensitivity (NH) associated with underlying/accompanying diseases has not been studied in Turkey. In addition, the factors associated with asthma in NH patients are not well known. The present study aimed to investigate the relationship between NH and chronic urticaria, rhinitis/rhinosinusitis, and asthma in an effort to identify NH phenotypes. The study's secondary aim was to identify the factors associated with asthma in NH patients and the NSAID reaction pattern in asthmatics. METHODS: Data for 1137 NH patients in our hospital's allergy clinic database were retrospectively analyzed. Patients were divided into 5 groups based on their accompanying diseases (chronic urticaria, asthma, rhinitis/rhinosinusitis). Asthmatic patients were compared to non-asthmatic patients to identify the factors associated with asthma. RESULTS: Reaction patterns and patient characteristics in each group differed from those in the reference group (NH only group). Asthma in patients with NH was associated with female gender, sinonasal polyposis/polyp surgery, rhinitis/rhinosinusitis, NSAID induced rhinitis/asthma or a blended reaction pattern, immediate reaction following NSAID intake, self-reported history of food allergy, and family history of asthma; the odds ratios and 95% CIs were 1.35 (1.02-1.78), 13.52 (8.74 20.9)/10.94 (6.73-17.77), 12.06 (9-16.17), 15.28 (10.45-22.36)/2.43 (1.70-3.45), 1.76 (1.31-2.35), 1.49 (1.04-2.14), and 3.1 (2.35-4.08), respectively. The characteristics of the asthmatic patients that had urticaria/angioedema-type reactions to NSAID intake (pseudo Samter's syndrome) differed from those in the asthmatics with rhinitis/asthma-type reactions. CONCLUSIONS: Chronic urticaria, rhinitis, and asthma commonly accompany NH. NSAID response patterns in NH patients may help differentiate groups of patients. The present study identified factors associated with asthma in NH patients and observed that there seems to be different phenotypes of Samter's syndrome, for which a new classification scheme was proposed. PMID- 23643318 TI - Sclerosing odontogenic carcinoma: a morphologic pattern or pathologic entity? PMID- 23643319 TI - Sclerosing odontogenic carcinoma--an enigma. PMID- 23643320 TI - Ten-year retrospective study of head and neck carcinoma in situ: incidence, treatment, and clinical outcome. AB - OBJECTIVES: To examine the management and clinical outcome for patients with primary head and neck carcinoma in situ (CIS) and to estimate the incidence in the referral population. STUDY DESIGN: A retrospective study from 2000-2009 of patients with head and neck CIS referred for treatment at Rigshospitalet. The referral area was East Denmark and Greenland with a population of 2.4 million. RESULTS: Fifty-five patients with primary CIS were identified: 21 oral cavity, 7 pharynx, 25 larynx, 2 nasal cavity/paranasal sinuses. The median annual incidence was 0.24/100,000. Eleven patients (20%) had T-site recurrence. The 5-year disease specific survival rate and 5-year recurrence-free survival rate were 98% and 74% respectively. CONCLUSIONS: The annual incidence of primary head and neck CIS was low and in accordance with previous findings reported in the literature. We recommend that CIS lesions should be treated on T-site and surveilled as T1/T2 head and neck carcinomas. PMID- 23643321 TI - Orofacial pain and sensory characteristics of chronic patients compared with controls. AB - OBJECTIVES: To investigate orofacial and sensorial characteristics of patients with orofacial pain and healthy controls. STUDY DESIGN: Case-control. Seventy five patients (61 women) who had chronic orofacial pain for more than 6 months (i.e., idiopathic trigeminal neuralgia, burning mouth syndrome, persistent idiopathic facial pain, nonidiopathic neuropathic pain, fibromyalgia or temporomandibular disorders were compared with 41 healthy subjects (19 women). They were evaluated with a quantitative sensory testing protocol involving a combination of gustative, olfactory, thermal, mechanical and pain stimuli. Mean pain duration in this population was 6.27 +/- 6.06 years. Orofacial characteristics (masticatory and articular abnormalities), oral health and sensitivity to muscular palpation were assessed. RESULTS: The majority of patients (73.3%) had pain upon craniofacial muscle palpation and 46.7% had numbness. High cold thresholds were observed with burning mouth syndrome and nonidiopathic neuropathic pain (P = .017), while high tactile thresholds were observed in persistent idiopathic facial pain patients (P = .048). Persistent idiopathic facial pain and temporomandibular disorders were associated with a low threshold for pain perception (P < .002). Several of these sensorial alterations were associated with positive musculoskeletal findings. CONCLUSIONS: Sensorial abnormalities were observed in neuropathic and somatic pain patients. The masticatory system is associated with and may be a secondary cause of pain in such patients. PMID- 23643322 TI - Complex regional pain syndrome following trigeminal nerve injury: report of 2 cases. PMID- 23643323 TI - Differential diagnosis of the complex regional pain syndrome. PMID- 23643324 TI - CD13 expression is an independent adverse prognostic factor in adults with Philadelphia chromosome negative B cell acute lymphoblastic leukemia. AB - In adults with precursor-B lymphoblastic leukemia (BCP-ALL) there remain a majority of patients who fall in an intermediate cytogenetics risk category with a heterogenous outcome. We analyzed immunophenotypic and cytogenetic factors retrospectively in 126 consecutive adults with BCR-ABL negative BCP-ALL who were treated with a pediatric-based protocol at a single institution over a 10 year period. In addition to age, WBC and cytogenetic findings, CD13 positivity was an independent poor prognostic indicator for overall survival (OS, p=0.049), event free survival (EFS, p=0.013), and relapse-free survival (RFS, p<0.001). The prognostic value of CD13 was primarily seen in patients with normal or intermediate risk cytogenetics. A risk model that includes age>60 years, WBC>30*10(9)/L, SWOG high/very high risk cytogenetics and CD13 positivity, performs better than a risk model of cytogenetics alone for stratifying patients by OS (p=0.001), EFS (p=7*10(-4)) and RFS (p=8*10(-4)). Incorporating CD13 into a scoring system provides high discrimination for relapse risk and survival. PMID- 23643325 TI - High frequency of NAD(P)H:quinone oxidoreductase 1 (NQO1) C(609)T germline polymorphism in MDS/AML with trisomy 8. AB - The NQO1 C(609)T germline polymorphism resulting in a lowering of enzyme activity may confer susceptibility to MDS. To assess this association, we performed a case control study including 330 Greek patients with de novo MDS and 416 healthy donors, using a Real-Time PCR genotyping method. Focusing on cytogenetic aberrations most commonly found in MDS, we retrospectively genotyped 566 MDS/AML patients carrying -5/del(5q), -7/del(7q), +8, del(20q) and -Y. The case-control analysis revealed no differences in NQO1 genotype distribution. Interestingly, a 6-fold increased frequency of the homozygous variant genotype was observed among patients with isolated trisomy 8 (p<0.0001), suggesting that null NQO1 activity may influence the occurrence of +8 in MDS/AML. PMID- 23643326 TI - Predictive factors for all-trans retinoic acid-related differentiation syndrome in patients with acute promyelocytic leukemia. AB - All-trans retinoic acid (ATRA) used for the treatment of APL can lead to the development of differentiation syndrome (DS), a potentially life threatening complication. Since ATRA is metabolized by cytochrome P450 (CYP) enzymes, we sought to identify drug interactions that might be associated with a higher risk for the development of DS in addition to other predictive factors related to the incidence of DS. We identified 60 consecutive patients with APL treated at our institution with ATRA from May 2004 until January 2010. Of the 60 patients identified, 29 (48%) developed DS within a median of 5 days (range 1-31) of ATRA initiation. We did not find any difference in overall incidence of DS whether patients were on concurrent CYP 2C8, 2C9 or 3A4 inhibitors, inducers or substrates. In multivariable analysis, higher peripheral blood blast counts on admission (p=0.04) as well as higher body mass index (p=0.003) were associated with developing DS. Out of the 29 patients with DS, there were 4 early deaths of which 2 were attributed to DS compared to no early deaths in the patients who did not develop DS (p=0.05). Regarding disease-related outcomes, only CR rate was different between patients developing DS versus those who did not develop DS. PMID- 23643328 TI - Aripiprazole, Ziprasidone and Quetiapine in the treatment of first-episode nonaffective psychosis: a 12-week randomized, flexible-dose, open-label trial. AB - BACKGROUND: Differences among antipsychotics in terms of effectiveness have turned out to be a topic of increasing research interest, although comparisons between the different second generation antipsychotics (SGAs) are scarce. We aimed to compare the clinical effectiveness in the short-term of Aripiprazole, Ziprasidone and Quetiapine in the treatment of first-episode schizophrenia spectrum disorders. METHOD: From October 2005 to January 2011, a prospective, randomized, open-label study was undertaken. 202 first-episode drug-naive patients were randomly assigned to Aripiprazole (N = 78), Ziprasidone (N = 62), or Quetiapine (N = 62) and followed-up for 3 months. The primary effectiveness measure was all-cause of treatment discontinuation. In addition, an analysis based on intention-to-treat populations was conducted in the analysis for clinical efficacy. RESULTS: The overall dropout rate at 3 months was small (13.86%). The treatment discontinuation rate differed significantly between treatment groups (Aripiprazole = 23.1%, Ziprasidone = 37.1% and Quetiapine = 61.3%) (chi(2) = 21.334; p < 0.001). Insufficient efficacy in the group of Quetiapine is the main reason for discontinuation rate differences (chi(2) = 20.223; p < 0.001). The mean time to all-cause discontinuation was significantly different between groups (LogRank = 23.467 p < 0.001). Aripiprazole and Quetiapine were associated with a greater depressive symptoms improvement (p = 0.043). The profile of side-effects varies between treatments. Patients on Quetiapine were less likely to be prescribed hypnotics. CONCLUSIONS: Patients treated with Quetiapine had a higher risk of treatment discontinuation in the short-term after a first episode due to insufficient efficacy. Establishing differences between SGAs may help clinicians in prescribing decisions for the treatment of individuals presenting with first-episode schizophrenia. PMID- 23643327 TI - Rates and predictors of remission in first-episode schizophrenia within 1 year of antipsychotic maintenance treatment. Results of a randomized controlled trial within the German Research Network on Schizophrenia. AB - OBJECTIVE: Full and sustained symptom remission is a major treatment objective after a first-episode in schizophrenia. Findings regarding differences in remission between first- and second-generation antipsychotics are inconclusive. This study aimed to provide rates and predictors of remission in first-episode schizophrenia and to identify symptoms that prevent remission. METHODS: Prevalence rates of "symptomatic remission" (symptom criteria only) and "enduring remission" (symptom and 6-month time criteria), defined according to Andreasen et al. (2005), were determined in first-episode patients participating in a RCT by the German Research Network on Schizophrenia (GRNS) that compared post-acute, 1 year maintenance treatment with risperidone or haloperidol. Respective predictors at baseline were identified by logistic and Cox regression analysis. RESULTS: Prevalence rates were 91.5% for symptomatic remission (n=152/166 eligible patients) and 58.6% for enduring remission (n=65 of 111 patients who continued for at least 6 months; 39.2% of all 166 patients included), with no significant differences between risperidone and haloperidol in either type of remission. Enduring remission often was not reached because of negative symptoms: After 6 months, 40.5% of the patients had at least 1 negative symptom, whereas only 10.8% of the patients had "persisting" positive symptoms. Of the different predictors identified in univariate analyses, (lower) negative symptoms and participating in standardized psychological treatment remained significant in multivariate (stepwise forward) analyses for enduring remission. CONCLUSIONS: By far most of the first-episode patients reached a temporary state of full symptomatic remission within 1 year of antipsychotic treatment. However, only about 50% achieved sustained, enduring remission. Negative symptoms are still a major treatment obstacle to enduring remission in schizophrenia. PMID- 23643329 TI - International challenges of self-sufficiency in blood products. AB - To face known and emerging threats to public health, all countries have to overcome the challenges of providing sufficient supplies of blood and blood products of the highest quality and safety. Unfortunately, self-sufficiency is not yet a reality in many countries. In 2011, experts from WHO addressed the urgent need to establish strategies and mechanisms for achieving this goal. A summary of these recommendations is further discussed. PMID- 23643330 TI - [HSP70, an erythropoiesis regulator that determines the fate of erythroblasts between death and differentiation]. AB - Erythropoiesis is finely regulated by two major cytokines, stem cell factor (SCF) and erythropoietin (Epo). Decrease levels of Epo result in caspase activation and erythroid progenitors apoptosis. However, normal erythroid cell maturation requests caspase activation and cleavage of various caspase substrates, except the erythroid transcription factor GATA-1, that is protected by interaction with the chaperone HSP70 in the nucleus. Therefore, molecular abnormalities associated with decrease of HSP70 expression in the nucleus may result in ineffective erythropoiesis characterized by apoptosis and impaired maturation of erythroid precursors. These findings open new potential targeted therapies for erythroid disorders. PMID- 23643331 TI - New pieces for the substance P puzzle. PMID- 23643332 TI - The prevelance of psichiatric symptoms in preschool children with adenotonsillar hypertrophy. AB - OBJECTIVES: The aim of this study was to determine the prevalence of psychiatric disorders and symptoms in preschool-age children who are indicated for operation due to adenotonsillar hypertrophy. MATERIALS AND METHODS: Forty-eight patients between the ages of three and five years with indication for adenotonsillectomy were included in the study, as well as 40 control patients. Cases underwent routine ear nose throat (ENT) examination, flexible nasopharyngoscopy and tympanometry. The Early Childhood Inventory-4 (ECI-4) parent form and Strengths and Difficulties Questionnaire (SDQ) parent form were completed by the parent caring for the child. The SPSS for Windows 16.0 program was used for statistical analysis. RESULTS: Groups were compared according to they received at least one psychiatric diagnosis measured by ECI-4, the group of adenotonsillar hypertrophy was diagnosed more than the control group. Attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and sleep disorders were detected at a higher rate in patients with adenotonsillar hypertrophy. It also was established that in the comparison of the severity of psychiatric symptoms determined by ECI-4, symptom severity of ADHD, ODD, anxiety disorders, and sleep disorders was higher in the adenotonsillar hypertrophy group than in the control group. In the evaluation of the SDQ parent form, it was determined that attention deficit, hyperactivity, behavioral, and peer relations problems occurred more frequently in the adenotonsillar hypertrophy group. CONCLUSIONS: In addition to oral respiration, snoring, and disordered breathing during sleep, adenotonsillar hypertrophy may also associated with psychiatric disorders and symptoms. PMID- 23643333 TI - Tissue fatty acid composition in obstructive sleep apnea and recurrent tonsillitis. AB - OBJECTIVE: Tonsillar hypertrophy cells appear to have an altered lipid metabolism as evidenced by modulated inflammatory cytokines that affect tissue lipid metabolism. The aim of this study was to investigate differences in tissue fat composition between obstructive sleep apnea (OSA) and recurrent infective tonsillitis (RT) in children. METHODS: Tonsillar tissues were collected from 114 patients with OSA and 92 patients with RT, aged 4-10 years, during tonsillectomy. The tissue lipid extracts were analyzed by gas liquid chromatography for a comprehensive fatty acid profile. RESULTS: In the tonsillitis tissue, the levels of palmitoleic acid (16:1n-7; P=0.002) and oleic acid (18:1n-9; P=0.003) were higher, and the level of stearic acid (18:0; P=0.004) was lower than that in the hyperplastic tonsillar tissue. Overall, tonsillar tissue of patients with RT had a significant increase in the total monounsaturated fatty acids (+9.9%; P<0.001) and the fatty acid desaturation index (+20.5%; P<0.001). Furthermore, oleic acid content of tonsillar tissue was positively correlated with BMI (r=0.20, P=0.004), snoring (r=0.16, P=0.022) and hypertrophy grade (r=0.18, P=0.023), which remain significant in the subgroup analysis by hypertrophy type. CONCLUSIONS: The change in the fatty acid composition may be regarded as an indicator of altered lipid metabolism occurring in vivo during human tonsillar hypertrophy, which might be linked to the severity or type of the tissue damage. PMID- 23643335 TI - The protective effects of parent-college student communication on dietary and physical activity behaviors. AB - PURPOSE: Recent studies suggest that parents maintain influence as their adolescents transition into college. Advances in communication technology make frequent communication between parents and college students easy and affordable. This study examines the protective effect of parent-college student communication on student eating and physical activity behaviors. METHODS: Participants were 746 first-year, first-time, full-time students at a large university in the United States who completed a baseline and 14 daily web-based surveys. RESULTS: On days when students communicated with their parents for 30 minutes or more, they consumed fruits and vegetables, an additional 14%, more times and were 50% more likely to engage in 30 minutes or more of physical activity, consistent with a protective within-person effect. CONCLUSIONS: Encouraging parents to communicate with their college-aged children could improve these students' daily eating and physical activity behaviors and should be explored as a relatively easy and affordable component of a student preventive intervention. PMID- 23643336 TI - Effective health interventions for adolescents that could be integrated with human papillomavirus vaccination programs. AB - PURPOSE: We reviewed published data to identify health interventions for 9-15 year-old girls and boys that could to be usefully integrated with programs of human papillomavirus (HPV) vaccination in low- and middle-income countries (LMICs). METHODS: Relevant literature reviews, bibliographic databases, and journals were searched to identify health-related interventions, other than immunizations, that had been found to have beneficial outcomes among adolescent girls and/or boys. An intervention was excluded if there was no evidence of its effective delivery in LMICs or no demonstrated potential for its adaptation for delivery in such countries, and/or if there was, apparently, no feasible way in which it could be delivered during a course of HPV vaccinations. RESULTS: Overall, 33 different interventions were found to have had beneficial outcomes among adolescents living in LMICs. Of these, 19 were excluded because they were deemed too expensive or too difficult to deliver within the calendar of a HPV vaccination program. The remaining 14 health-related interventions, in the fields of screening (for schistosomiasis and defects in vision), health education (on mosquito-borne diseases, the benefits of exercise, accessing health care, and sexual and reproductive health), skills building (improving condom usage) and delivery of commodities (anthelminthic drugs, vitamin A supplements, soap and/or bed nets) were deemed potential candidates for delivery in conjunction with the HPV vaccine. CONCLUSIONS: The potential benefits and selection of other health related interventions that are delivered in conjunction with HPV vaccine will be influenced by a range of factors, including the ease of delivery, the epidemiology of the priority health problems affecting adolescents, the vaccine delivery schedule, and various environmental, economic, and social factors. However, there appear to be several interventions that could usefully be integrated in many, if not all, HPV vaccination programs. The ability to deliver multiple interventions along with HPV vaccine could not only offer important efficiencies but also serve as an entry point to increase adolescents' access to health care and services. PMID- 23643334 TI - Benefits and barriers among volunteer teaching faculty: comparison between those who precept and those who do not in the core pediatrics clerkship. AB - BACKGROUND: Community-based outpatient experiences are a core component of the clinical years in medical school. Central to the success of this experience is the recruitment and retention of volunteer faculty from the community. Prior studies have identified reasons why some preceptors volunteer their time however, there is a paucity of data comparing those who volunteer from those who do not. METHODS: A survey was developed following a review of previous studies addressing perceptions of community-based preceptors. A non-parametric, Mann-Whitney U test was used to compare active preceptors (APs) and inactive preceptors (IPs) and all data were analyzed in SPSS 20.0. RESULTS: There was a 28% response rate. Preceptors showed similar demographic characteristics, valued intrinsic over extrinsic benefits, and appreciated Continuing Medical Education (CME)/Maintenance of Certification (MOC) opportunities as the highest extrinsic reward. APs were more likely to also precept at the M1/M2 level and value recognition and faculty development opportunities (p<0.05). IPs denoted time as the most significant barrier and, in comparison to APs, rated financial compensation as more important (p<0.05). CONCLUSIONS: Community preceptors are motivated by intrinsic benefits of teaching. Efforts to recruit should initially focus on promoting awareness of teaching opportunities and offering CME/MOC opportunities. Increasing the pool of preceptors may require financial compensation. PMID- 23643337 TI - Interventions in pediatric chronic fatigue syndrome/myalgic encephalomyelitis: a systematic review. AB - PURPOSE: A range of interventions have been used for the management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) in children and adolescents. Currently, debate exists as to the effectiveness of these different management strategies. The objective of this review was to synthesize and critically appraise the literature on interventions for pediatric CFS/ME. METHOD: CINAHL, PsycINFO and Medline databases were searched to retrieve relevant studies of intervention outcomes in children and/or adolescents diagnosed with CFS/ME. Two reviewers independently selected articles and appraised the quality on the basis of predefined criteria. RESULTS: A total of 24 articles based on 21 studies met the inclusion criteria. Methodological design and quality were variable. The majority assessed behavioral interventions (10 multidisciplinary rehabilitation; 9 psychological interventions; 1 exercise intervention; 1 immunological intervention). There was marked heterogeneity in participant and intervention characteristics, and outcome measures used across studies. The strongest evidence was for Cognitive Behavioral Therapy (CBT)-based interventions, with weaker evidence for multidisciplinary rehabilitation. Limited information exists on the maintenance of intervention effects. CONCLUSIONS: Evidence for the effectiveness of interventions for children and adolescents with CFS/ME is still emerging. Methodological inadequacies and inconsistent approaches limit interpretation of findings. There is some evidence that children and adolescents with CFS/ME benefit from particular interventions; however, there remain gaps in the current evidence base. PMID- 23643338 TI - The impact of a middle school program to reduce aggression, victimization, and sexual violence. AB - PURPOSE: To evaluate the impact of the Second Step: Student Success Through Prevention (SS-SSTP) Middle School Program on reducing youth violence including peer aggression, peer victimization, homophobic name calling, and sexual violence perpetration and victimization among middle school sixth-grade students. METHODS: The study design was a nested cohort (sixth graders) longitudinal study. We randomly assigned 18 matched pairs of 36 middle schools to the SS-SSTP or control condition. Teachers implemented 15 weekly lessons of the sixth-grade curriculum that focused on social emotional learning skills, including empathy, communication, bully prevention, and problem-solving skills. All sixth graders (n = 3,616) in intervention and control conditions completed self-report measures assessing verbal/relational bullying, physical aggression, homophobic name calling, and sexual violence victimization and perpetration before and after the implementation of the sixth-grade curriculum. RESULTS: Multilevel analyses revealed significant intervention effects with regard to physical aggression. The adjusted odds ratio indicated that the intervention effect was substantial; individuals in intervention schools were 42% less likely to self-report physical aggression than students in control schools. We found no significant intervention effects for verbal/relational bully perpetration, peer victimization, homophobic teasing, and sexual violence. CONCLUSIONS: Within a 1-year period, we noted significant reductions in self-reported physical aggression in the intervention schools. Results suggest that SS-SSTP holds promise as an efficacious prevention program to reduce physical aggression in adolescent youth. PMID- 23643339 TI - Youths' health-related social problems: concerns often overlooked during the medical visit. AB - OBJECTIVE: The objectives of this study were to (1) measure the prevalence of health-related social problems among adolescent and young adult primary care patients; (2) estimate previous screening and referral experiences; and (3) examine participant attitudes toward screening and referral. METHODS: Data were collected as part of a cross-sectional study conducted in an urban young adult clinic. Patients aged 15 to 25 years completed a computerized questionnaire screening for health-related social problems in nine social domains. In addition, participants answered questions about their previous screening experiences, need for referrals, and their experience using the system. RESULTS: Seventy-six percent (304/401) of youth screened positive for at least one major problem, including healthcare access (37%), housing (34%), and food security (29%). Forty seven percent (190/401) experienced major problems in two or more social domains. The prevalence of screening in the past year for each domain averaged 26%; 3% were screened in all nine domains in the previous 12 months and 33% were not screened in any domain. Overall, 75% needed a referral within the previous year, and 42% identified at least one unmet referral need. The majority (84%) of participants reported that it was acceptable to screen for these problems. CONCLUSION: Prevalence of health-related social problems among youth is high. The majority needed at least one referral for a social need in the previous year. Primary care physicians would benefit from improved systems for screening and referral of health-related social problems in order to create a comprehensive medical home for their patients. PMID- 23643340 TI - The effects of mercury on the dynamics of the peracarida community in a temperate coastal lagoon (Ria de Aveiro, Portugal). AB - This study focuses on the impact of mercury on the dynamics and bioaccumulation patterns of suprabenthic peracarida community along a mercury gradient. Suprabenthic peracarida was negatively affected in terms of biomass, diversity and productivity. Mysids including Mesopodopsis slabberi dominated the community, presenting a regular distribution along the Hg gradient, so are considered tolerant species to mercury. Then, isopods, the second most abundant group, dominated in the most contaminated areas being considered also a tolerant group. Contrarily, amphipods were negatively correlated with higher Hg concentrations, dominating in the intermediate areas, thus are considered more sensitive species. In addition, isopods and amphipods were the taxa with higher mercury body burden, followed by mysids. This paper highlights the importance of suprabenthic peracarida as a vehicle of mercury transference through the estuarine trophic web since it is a main link between benthic and pelagic levels and an essential food resource for numerous fish species. PMID- 23643341 TI - Kinetics and equilibrium models for the sorption of tributyltin to nZnO, activated carbon and nZnO/activated carbon composite in artificial seawater. AB - The removal of tributyltin (TBT) from artificial seawater using nZnO, activated carbon and nZnO/activated carbon composite was systematically studied. The equilibrium and kinetics of adsorption were investigated in a batch adsorption system. Equilibrium adsorption data were analyzed using Langmuir, Freundlich, Temkin and Dubinin-Radushkevich (D-R) isotherm models. Pseudo first- and second order, Elovich, fractional power and intraparticle diffusion models were applied to test the kinetic data. Thermodynamic parameters such as DeltaG degrees , DeltaS degrees and DeltaH degrees were also calculated to understand the mechanisms of adsorption. Optimal conditions for the adsorption of TBT from artificial seawater were then applied to TBT removal from natural seawater. A higher removal efficiency of TBT (>99%) was obtained for the nZnO/activated carbon composite material and for activated carbon but not for nZnO. PMID- 23643342 TI - Research agenda consensus conference. PMID- 23643343 TI - Vitamin D effects in atopic dermatitis. AB - BACKGROUND: Because vitamin D has immunomodulatory properties and immunologic mechanisms play a role in the pathogenesis of atopic dermatitis (AD), it is possible that vitamin D may influence the activity of AD. OBJECTIVE: The aim of the study was to correlate vitamin D concentrations in patients who had AD with clinical, immunologic, constitutional, and environmental factors, and to determine if vitamin D supplementation affects the clinical manifestations of AD. METHODS: Clinical and laboratory parameters of 95 patients with AD and 58 control subjects were measured. Severity of AD was assessed with the SCORAD index. RESULTS: The mean serum concentration of 25(OH)D3 in patients with AD was not statistically different from control subjects. The frequency of bacterial skin infections was higher in patients with AD who had lower 25(OH)D3 levels. No statistical associations between vitamin D levels and other multiple laboratory and clinical parameters were found. After supplementation both mean objective SCORAD and SCORAD index were significantly lower (P < .05). LIMITATIONS: All study patients were Caucasians and only one supplemental vitamin D dose and treatment duration were assessed. CONCLUSION: The results from this study indicate that vitamin D supplementation may help ameliorate clinical signs of the disease and can be considered as a safe and well-tolerated form of therapy. PMID- 23643344 TI - The increasing burden of mental and neurological disorders. PMID- 23643345 TI - Metabolic engineering of a novel Klebsiella oxytoca strain for enhanced 2,3 butanediol production. AB - Fermentative 2,3-butanediol (2,3-BD) production has been receiving increasing interest for its potential as a platform chemical intended for the production of synthetic rubbers, plastics, and solvents. In this study, Klebsiella oxytoca GSC 12206, a 2,3-BD native hyper-producing and nonpathogenic bacterium, was isolated from a cattle farm. Since this isolate produced a significant amount of lactic acid along with 2,3-BD, its mutant deficient in lactic acid formation was constructed by disrupting the ldhA gene which encodes lactate dehydrogenase. The ldhA gene was deleted precisely by using the pKGS plasmid. When compared to the wild-type strain, the mutant deleted with the ldhA gene in glucose fermentation resulted in an increase of 54%, 13%, 60%, and 78% of 2,3-BD titer, productivity, yield, and selectivity, respectively. A fed-batch fermentation by this mutant with intermittent glucose feeding produced 115 g/L of 2,3-BD with an yield and productivity of 0.41 g 2,3-BD per g glucose and 2.27 g/L h, respectively, indicating the usefulness for the industrial production of 2,3-BD. PMID- 23643346 TI - Psychometric properties concerning four instruments measuring job satisfaction, strain, and stress of conscience in a residential care context. AB - There are many instruments assessing the wellbeing of staff, but far from all have been psychometrically investigated. When evaluating supportive interventions directed toward nurse assistants in residential care, valid and reliable instruments are needed in order to detect possible changes. The aim of the study was to investigate validity in terms of data quality, construct validity, convergent and divergent validity and reliability in terms of the internal consistency and stability of the Job Satisfaction Questionnaire, the Psychosocial Aspects of Job Satisfaction, the Strain in Dementia Care Scale (SDCS), and the Stress of Conscience Questionnaire (SCQ) in a residential care context. The psychometric properties of the instruments were investigated in terms of data quality, construct validity, convergent and divergent validity and reliability, including test-retest reliability, in a residential care context with a sample consisting of nurse assistants (n=114). The four instruments responded with different psychometric-related problems such as internal missing data, floor and ceiling effects, problems with construct validity and low test-retest reliability, especially when assessed on the item level. These problems were however reduced or disappeared completely when assessed for total and factor scores. From a psychometric perspective, the SDCS seemed to stand out as the best instrument. However, it should be modified in order to reduce floor effects on item level and thereby gain sensitivity. The Job Satisfaction Questionnaire seemed to have problems both with the construct validity and test-retest reliability. The final choice of instrument must, however, be made dependent on what one intends to measure. PMID- 23643347 TI - Skin autofluorescence is associated with past glycaemic control and complications in type 1 diabetes mellitus. AB - As skin autofluorescence (AF) can assess subcutaneous accumulation of fluorescent advanced glycation end-products (AGEs), this study aimed to investigate whether it was linked to glycaemic control and complications in patients with type 1 diabetes mellitus (T1DM). Using the AGE ReaderTM, AF was measured in T1DM patients referred to Haut-Leveque Hospital (Bordeaux, France); data on their HbA1c levels measured every 6months as far back as the last 5years were also collected. The association of AF with the patients' past glucose control, based on their latest HbA1c values, and the means of the last five and 10 HbA1c values, and with diabetic complications was also examined by linear regression analysis. The sample included 300 patients: 58% were male; the mean age was 49 (SD 17) years and the mean diabetes duration was 21 (SD 13) years. The median skin AF measurement was 2.0 [25th-75th percentiles: 1.7-2.4] arbitrary units (AU), and this was associated with age (beta=0.15 per 10years, P<0.001) and diabetes duration (beta=0.17 per 10years, P<0.001). After adjusting for age and estimated glomerular filtration rate (eGFR), the skin AF measurement was also related to the means of the last five and 10 HbA1c values (beta=0.10 per 1% of HbA1c, P=0.005, and beta=0.13 per 1% of HbA1c, P=0.001, respectively). In addition, the skin AF was associated with retinopathy (P<0.001), albuminuria (P<0.001) and decreased eGFR (P<0.001). In conclusion, the skin AF is related to the long-term glucose control and diabetic complications. PMID- 23643348 TI - Prediction of macrosomia by serial sonographic measurements of fetal soft-tissues and the liver in women with pregestational diabetes. AB - OBJECTIVES: This study aimed to determine whether antenatal ultrasound measurements of fetal soft-tissues and liver can predict macrosomia in women with pregestational diabetes. METHODS: Fetal biometry, soft-tissue thickness (anterior abdominal wall [STAW], thigh [STT], upper arm [STA], scapular [STS]) and liver size were measured sonographically at 23, 28, 31 and 34 weeks of gestation. Large for gestational age (LGA) was defined as a birth weight greater than 90th percentile for gestational age on standard curves adjusted for maternal height and weight, parity and fetal gender. The area (+/-standard error) under receiver operating characteristic (AUROC) curves were also calculated. RESULTS: A total of 29 pregnant women with pregestational diabetes were included, and a total of 663 measurements taken. Fifteen neonates were LGA. There was no significant difference in fetal soft-tissue thickness at 23, 28 and 31 weeks between the LGA and non-LGA neonates. In contrast, at 34 weeks, fetal soft-tissues were significantly thicker in LGA neonates (P<0.05), but with no difference in liver surface area between the two groups. The specificity and sensitivity of 34-week ultrasonography to detect macrosomia was 78.6% and 66.7%, respectively, for abdominal circumference (AC), 71.4% and 93.3% for STT, 85.7% and 80.0% for STA, and 71.4% and 86.7% for STAW. No parameter was more powerful than the others. The best AUROC curves were found for AC (0.807), STT (0.821), STA (0.855) and STAW (0.821). CONCLUSION: Third-trimester sonographic measurements of fetal soft tissue may help to detect macrosomia in pregnancies complicated by pregestational diabetes. PMID- 23643349 TI - Incretin dysfunction in type 2 diabetes: clinical impact and future perspectives. AB - The incretin effect refers to the augmentation of insulin secretion after oral administration of glucose compared with intravenous glucose administration at matched glucose levels. The incretin effect is largely due to the release and action on beta-cells of the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). This system has in recent years had considerable interest due to the success of incretin therapy as a glucose-lowering strategy in type 2 diabetes. In non-diabetic subjects, the incretin effect is responsible for 50-70% of insulin release during oral glucose administration. In type 2 diabetes patients, the incretin effect is impaired and contributes to only 20-35% of the insulin response to oral glucose. The reason for the defective incretin effect in type 2 diabetes has been the subject of many studies. Although the reports in the literature are mixed, most studies of GIP and GLP-1 secretory responses to oral glucose or a mixed meal have shown fairly normal results in type 2 diabetes. In contrast, the insulinotropic effects of both GIP and GLP-1 are impaired in type 2 diabetes with greater suppression of insulin secretion augmentation with GIP than with GLP-1. The suggested causes of these defects are a defective beta-cell receptor expression or post-receptor defects secondary to the diabetes milieu, defective beta-cell function in general resulting in defective incretin effect and genetic factors initiating incretin hormone resistance. Identifying the mechanisms in greater detail would be important for understanding the strengths, weaknesses and efficacy of incretin therapy in individual patients to more specifically target this glucose-lowering therapy. PMID- 23643350 TI - Impaired endothelial function is not associated with arterial stiffness in adults with type 1 diabetes. AB - AIM: This study investigated the relationship between endothelial dysfunction (ED) and arterial stiffness (AS) in adults with type 1 diabetes and no clinical cardiovascular (CV) disease. METHODS: A total of 68 patients with type 1 diabetes and 68 age- and gender-matched healthy (non-diabetic) subjects were evaluated. ED was assessed by reactive hyperaemia peripheral arterial tonometry (RH-PAT) and by serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and E-selectin. AS was assessed by aortic pulse wave velocity (aPWV). All statistical analyses were stratified by gender. RESULTS: Adults with type 1 diabetes had RH-PAT index scores similar to those of their matching controls [men: 1.55 (1.38-1.98)% versus 1.61 (1.40-2.17)%, P=0.556; women: 2.07 (1.55-2.31)% versus 2.08 (1.79-2.49)%; P=0.215]. However, after adjusting for potential confounders, type 1 diabetes emerged as the main determinant of the RH-PAT index in women. Also, differences between genders in both the controls and type 1 diabetes patients disappeared. Men with diabetes had higher serum concentrations of E-selectin, and women had higher serum concentrations of sICAM-1, sVCAM-1 and E-selectin than their respective controls. However, after adjusting for potential confounders, only the differences in sICAM-1 (women) and E-selectin (both genders) remained significant. No association was found between aPWV and the RH-PAT index and ED markers after adjusting for CV risk factors. CONCLUSION: ED was increased in adults with type 1 diabetes compared with age-matched non-diabetic subjects. Also, gender differences in ED were lost in type 1 diabetes. However, ED was not associated with AS after adjusting for potential confounders. These findings suggest that ED occurs earlier than AS in type 1 diabetes. PMID- 23643351 TI - Physical activity and type 2 diabetes. Recommandations of the SFD (Francophone Diabetes Society) diabetes and physical activity working group. AB - Although regular physical activity is an integral part of T2D management, few diabetic patients have a sufficient level of physical activity. However over the past decade or so, the beneficial effects of regular physical activity have been well demonstrated, both in T2D prevention (50% reduction in the incidence of T2D in subjects with high metabolic risk) as well as T2D management for the improvement of glycaemic control (mean 0.7% improvement of HbA1c) and the reduction of T2D-related comorbidities (improvement in blood pressure values and lipid profile, decrease in insulin resistance). Physical activity has both acute effects (effects of one exercise session) and more prolonged effects of exercise when it is repeated on a regular basis (training effect). In addition, the physical activity recommendations have been extended to a wide range of physical activities (by combining both endurance and muscle strengthening exercises), thus varying the physical activity practiced according to the patient's available time, practice sites, preferences and interests. Following a pathophysiology review, the effects of physical activity will be discussed and presented in terms of evidence-based medicine. The recommendations will be defined and practical prescribing information will be suggested, while taking into account that clinicians are concerned with answering questions regarding how, where and with whom: how can patients be motivated to practice a physical activity over the long term? And how can qualified exercise trainers and appropriate practice settings be found? PMID- 23643352 TI - Relationship between blood pressure, cognitive function and education level in elderly patients with diabetes: a preliminary study. AB - AIMS: This study aimed to assess the relationship between blood pressure and cognitive function in elderly patients with diabetes mellitus (DM). METHODS: A total of 32 patients with DM aged >= 65 years (seven women and 25 men; mean +/- SD age: 74.3 +/- 6.4 years) were included in this cross-sectional study. Relationships between blood pressure and neuropsychological tests were determined using Spearman's rank correlations (rho) and multivariable linear regression models. RESULTS: Lower diastolic blood pressure was associated with lower scores on the Frontal Assessment Battery (rho=0.32, P=0.02), longer times to complete the Trail Making Test Part B (rho=0.51, P=0.003), lower scores for the Finger Tapping Test (rho=0.36, P=0.046) and less verbal fluency (rho=0.36, P=0.047). In multivariable models, these relationships were attenuated after adjusting for levels of education. CONCLUSION: There was an association between lower diastolic blood pressure and poorer executive function in this cohort of elderly DM patients. These results underline the importance of systematic cognitive evaluation in elderly patients with DM, and suggest that a too-low diastolic blood pressure may have deleterious effects on mental function. Larger studies in the future are required to confirm these preliminary results. PMID- 23643353 TI - Glycogen storage disease type 1 and diabetes: learning by comparing and contrasting the two disorders. AB - Glycogen storage disease type 1 (GSD1) and diabetes may look at first like totally opposite disorders, as diabetes is characterized by uncontrolled hyperglycaemia, whereas GSD1 is characterized by severe fasting hypoglycaemia. Diabetes is due to a failure to suppress endogenous glucose production (EGP) in the postprandial state because of either a lack of insulin or insulin resistance. In contrast, GSD1 is characterized by a lack of EGP. However, both diseases share remarkably similar patterns in terms of pathophysiology such as the long-term progression of renal dysfunction and hepatic steatosis leading to renal failure and the development of hepatic tumours, respectively. Thus, much may be learned from considering the similarities between GSD1 and diabetes, especially in the metabolic pathways underlying nephropathy and fatty liver, and perhaps even more from their differences. In this review, the differences between diabetes and GSD1 are first highlighted, as both are characterized by alterations in EGP. The molecular pathways involved in liver pathologies, including steatosis, hepatomegaly (glycogenic hepatopathy) and the development of liver tumours are also compared. These pathologies are mainly due to the accumulation of lipids and/or glycogen in hepatocytes. Finally, the similar pathways leading to nephropathy in both diabetic and GSD1 patients are described. In conclusion, comparisons of these pathologies should lead to a better understanding of the crucial role of EGP in the control of glucose and energy homoeostasis. Moreover, it may highlight similar therapeutic targets for the two disorders. Thus, this review suggests that the treatment of adult patients with either GSD1 or diabetes could be carried out by the same specialists-diabetologists. PMID- 23643354 TI - GLP-1 agonists in type 1 diabetes. AB - Despite years of research in the field of type 1 diabetes, patients with the disease remain without a therapeutic agent that can alter the underlying immune response in a clinically beneficial way. Glucagon-like peptide 1 agonist therapies have shown some promising effects in terms of positively affecting overall beta cell health and increasing beta cell mass, primarily in mouse models. The three agents of this class currently available for patients with type 2 diabetes have shown beneficial clinical effects on glucose control in this patient population. The purpose of this article is to review the preclinical and clinical data of these agents to date with a focus on the potential immunological and clinical benefits these drugs may have on patients with type 1 diabetes. PMID- 23643355 TI - Targeted therapies of metastatic breast cancer: relationships with cancer stem cells. AB - In the last years, many targeted agents have been developed for metastatic breast cancer (MBC) treatment and are being tested in clinical trials. In spite of this, apart from epidermal growth factor receptor 2 (HER2) positive subset, no significant increase in the median overall survival (OS) has been reported. Similarly to conventional chemo- and radiotherapy, the cancer stem cell theory has been evoked to explain the frustrating results often obtained with this emerging category of drugs. This review examines the results in MBC of the approved targeted therapies or those currently under evaluation in experimental studies or in clinical trials, in the light of their relationships with breast CSCs and of the efforts to circumvent the development of resistance. In the next, there is the principal need to investigate if the effects on CSCs may be used to overcome cancer resistance and it will be opportune to consider whether molecular targeted therapies should be used alone or combined with conventional therapy, or with a different target drug specific for CSCs. PMID- 23643356 TI - MicroRNA-21 activates hepatic stellate cells via PTEN/Akt signaling. AB - Activation of hepatic stellate cells is the key event in the liver fibrosis. miRs have been shown to play fundamental role in diverse biological and pathological processes. In the present study, we investigated the fibrogenic role of miR-21 in human hepatic stellate LX-2 cells and explored underlying mechanisms. The results showed that treatment of LX-2 cells with platelet-derived growth factor (PDGF)-BB significantly stimulated alpha1(I) collagen mRNA synthesis and the protein expression of alpha-SMA, which are characteristics of activation of hepatic stellate cells and simultaneously increased miR-21 expression. Downregulation of miR-21 expression by transfection of anti-miR-21 into LX-2 cells prevented PDGF BB-induced LX-2 cell activation. Overexpression of miR-21 expression alone also stimulated LX-2 cell activation, while downregulation of miR-21 expression suppressed LX-2 cell activation. miR-21 also played a role in mRNA expression and activity of matrix metalloproteinase 2 (MMP2) in LX-2 cells. Moreover, overexpression of miR-21 decreased protein expression of PTEN in LX-2 cells, resulting in activation of the Akt. Inhibition of Akt signaling by specific inhibitor LY 294002 blocked miR-21-induced fibrogenic effects in LX-2 cells. In summary, miR-21 is an important mediator in LX-2 cell activation. The fibrogenic effects of miR-21 on LX-2 cell activation are mediated through PTEN/Akt pathway. miR-21 may be a potential novel molecular target for the liver fibrosis. PMID- 23643357 TI - Eco-epidemiological factors contributing to the low risk of human exposure to ixodid tick-borne borreliae in southern California, USA. AB - Little is known about the eco-epidemiology of Lyme disease in southern California, a region where the incidence is much lower than it is in northern California. Here, we sought to discover the previously unknown microhabitats of nymphs of the primary vector, the western black-legged tick (Ixodes pacificus), in 3 moderately to heavily-utilized state parks in the Santa Monica Mountains in Los Angeles County; to elucidate the seasonal distribution and abundance of adults of I. pacificus and another human-biter, the Pacific Coast tick (Dermacentor occidentalis); and to determine what Lyme-disease or relapsing-fever group borreliae are present in questing nymphs or adult ticks. I. pacificus nymphs were collected infrequently at various times of day in 2 chaparral or 7 woodland litter areas by dragging (combined mean=0.4 nymphs per hour). The western fence lizard (Sceloporus occidentalis) was a choice sentinel animal for detecting the presence of I. pacificus nymphs (and larvae) in diverse biotopes even when dragging litter in them was fruitless. The abundance and seasonality of I. pacificus and D. occidentalis adults resembled what had been documented previously for these ticks in northern California. Overall, zero of 27 free living and 118 lizard-infesting I. pacificus nymphs, 7 (0.29%) of 2392 I. pacificus adults and 2 (0.22%) of 896 D. occidentalis adults were infected with Borrelia burgdorferi sensu lato (Bb sl), but none of them harbored B. miyamotoi, a relapsing-fever group spirochete implicated recently as a zoonotic pathogen in Russia. Borrelia americana and the human pathogen B. burgdorferi sensu stricto were each detected in one (0.04%), and uncharacterized Bb sl in 5 adult I. pacificus (0.21%) that clustered with B. americana. Both PCR-positive D. occidentalis adults contained B. burgdorferi sensu stricto. We conclude that the acarologic risk of being bitten by a B. burgdorferi sensu lato-infected ixodid tick in the habitats studied is slight, which offers a plausible explanation for the low reported incidence of Lyme disease in south coastal California. PMID- 23643358 TI - Distribution, seasonality and risk factors for tick paralysis in Australian dogs and cats. AB - Tick paralysis is a serious and potentially fatal condition of Australian companion animals induced by the paralysis ticks, Ixodes holocyclus and Ixodes cornuatus. Limited published information is available on the distribution, seasonality and risk factors for tick paralysis mortality in dogs and cats. This study describes 3479 cases of canine and feline tick paralysis in Australia using data extracted from a real-time disease surveillance program. Risk factors for mortality were identified, and maps of the distribution of cases were generated. Cluster analysis was performed using a space-time permutation scan statistic. Tick paralysis was found to be distinctly seasonal, with most cases reported during spring. Most cases were located on the eastern coast of Australia with New South Wales and Queensland accounting for the majority of reported cases. A cluster of cases was identified on the south coast of New South Wales. Dogs were found to be at significantly higher risk (P<0.05) of death if less than 6 months of age or if a toy breed. No significant risk factors for mortality were identified for cats. Some animals receiving chemoprophylactic treatment for tick infestation experienced tick paralysis during the products' period of effectiveness. There is a high risk of tick paralysis in dogs and cats on the eastern coast of Australia during the spring months. The risk factors for mortality identified can be used by veterinarians to determine prognosis in cases of canine tick paralysis and potentially to improve the treatment of cases. Daily tick searches of pets - particularly in high risk areas and during high risk periods - are recommended since the prevention of tick paralysis via chemoprophylaxis is not 100% guaranteed across the whole population. PMID- 23643359 TI - Fatal multi-organ Clonorchis sinensis infection in dog: a case report. AB - We describe here a fatal case of a dog with extensive Clonorchis sinensis (C. sinensis) infection. C. sinensis were detected in organs including the abdomen, bladder and heart. The infection was very heavy with a total number of 155,183 worms. These worms were in different developmental stages, but the majority of them were adult. PMID- 23643360 TI - Structured interviews and "ancillary" restless legs syndrome. PMID- 23643361 TI - [Tolerance and efficacy of preoperative radiation therapy for elderly patients treated for rectal cancer]. AB - PURPOSE: To retrospectively assess the impact of age on tolerance and oncologic outcomes treated by neoadjuvant treatment for patients of 70 years old or above with locally advanced rectal cancer. PATIENTS AND METHODS: Ninety-one consecutive patients were divided into three groups: group 1 from 70 to 75 years (n=31); group 2: 76 to 79 years (n=31) and group 3, patients aged 80 years or above (n=29). Radiation therapy was delivered according two schemes: 25Gy in five fractions (short scheme) or 45 to 50Gy with a classical fractionation (long scheme). Long scheme patients received a concomitant chemotherapy with 5-fluoro uracile alone or associated with oxaliplatin. RESULTS: The three groups were comparable for performance status, Charlson's score and T staging. Long scheme radiation therapy and chemotherapy were performed in 77.5, 74.5 and 48.3% of patients (P=0.03) and 77.4, 71 and 41.4% (P=0.006) in the groups 1, 2 and 3, respectively. All patients treated with the short scheme irradiation received the treatment without any acute toxicity. In the long scheme group, 65% of patients received the treatment on time and grade 3 or above toxicity was observed in 12% of patients who did not receive oxaliplatin and in 48% of patients who received oxaliplatin. The overall survival rate at 3 and 5 years was 66.9% and 60.8% in the group 1, 90.5% and 75.9% in the group 2 and 80.5% and 73.8% in the group 3 (P=0.15). CONCLUSION: Neoadjuvant treatment is feasible with encouraging survival rates for patients aged 70 years and older. Short scheme radiation therapy seems to be an interesting option in this population. PMID- 23643364 TI - Inference based on diagnostic measures from studies of new imaging devices. AB - RATIONALE AND OBJECTIVES: Before using a new diagnostic imaging device regularly in a clinic, it should be studied using patients and radiologists. Often such studies report diagnostic performance in terms of sensitivity, specificity, area under the receiver operating characteristic curve (AUC), or differences thereof. In this report we look at how these studies differ from actual future clinical practice and how those differences may affect reported performance measures. MATERIALS AND METHODS: We review signal detection (receiver operating characteristic) theory and decision theory. We compare diagnostic measures from several published studies in medical imaging and examine how they relate to theory and each other. RESULTS: We see that clinical decisions can be modeled using signal detection and decision theories. Sensitivity and specificity are inextricably linked with clinical factors, such as prevalence and costs. Imaging devices are used in many different ways in clinical practice, so that sensitivities, specificities, and AUCs measured in studies of new diagnostic imaging devices will differ from those in actual future clinical use. CONCLUSIONS: Measured sensitivities, specificities, and the directions of changes thereof are not necessarily consistent or reproducible across studies of new diagnostic devices. A change in the AUC, which should be independent of clinical costs or prevalence, is a consistent measure across similar studies, and a positive change in AUC is indicative of additional diagnostic information that will be available to radiologists in a future clinical environment. PMID- 23643363 TI - Chromatin regulation by BAF170 controls cerebral cortical size and thickness. AB - Increased cortical size is essential to the enhanced intellectual capacity of primates during mammalian evolution. The mechanisms that control cortical size are largely unknown. Here, we show that mammalian BAF170, a subunit of the chromatin remodeling complex mSWI/SNF, is an intrinsic factor that controls cortical size. We find that conditional deletion of BAF170 promotes indirect neurogenesis by increasing the pool of intermediate progenitors (IPs) and results in an enlarged cortex, whereas cortex-specific BAF170 overexpression results in the opposite phenotype. Mechanistically, BAF170 competes with BAF155 subunit in the BAF complex, affecting euchromatin structure and thereby modulating the binding efficiency of the Pax6/REST-corepressor complex to Pax6 target genes that regulate the generation of IPs and late cortical progenitors. Our findings reveal a molecular mechanism mediated by the mSWI/SNF chromatin-remodeling complex that controls cortical architecture. PMID- 23643362 TI - EGF-induced centrosome separation promotes mitotic progression and cell survival. AB - Timely and accurate assembly of the mitotic spindle is critical for the faithful segregation of chromosomes, and centrosome separation is a key step in this process. The timing of centrosome separation varies dramatically between cell types; however, the mechanisms responsible for these differences and its significance are unclear. Here, we show that activation of epidermal growth factor receptor (EGFR) signaling determines the timing of centrosome separation. Premature separation of centrosomes decreases the requirement for the major mitotic kinesin Eg5 for spindle assembly, accelerates mitosis, and decreases the rate of chromosome missegregation. Importantly, EGF stimulation impacts upon centrosome separation and mitotic progression to different degrees in different cell lines. Cells with high EGFR levels fail to arrest in mitosis upon Eg5 inhibition. This has important implications for cancer therapy because cells with high centrosomal response to EGF are more susceptible to combinatorial inhibition of EGFR and Eg5. PMID- 23643365 TI - The royal touch: a look at healing in times past. PMID- 23643366 TI - Bravenet launches patient-reported outcomes registry. PMID- 23643367 TI - False equivalencies and the mediocrity of nonlocal consciousness research criticism. PMID- 23643368 TI - On mind wandering, attention, brain networks, and meditation. AB - Human attention selectively focuses on aspects of experience that are threatening, pleasant, or novel. The physical threats of the ancient times have largely been replaced by chronic psychological worries and hurts. The mind gets drawn to these worries and hurts, mostly in the domain of the past and future, leading to mind wandering. In the brain, a network of neurons called the default mode network has been associated with mind wandering. Abnormal activity in the default mode network may predispose to depression, anxiety, attention deficit, and posttraumatic stress disorder. Several studies show that meditation can reverse some of these abnormalities, producing salutary functional and structural changes in the brain. This narrative review presents a mechanistic understanding of meditation in the context of recent advances in neurosciences about mind wandering, attention, and the brain networks. PMID- 23643370 TI - Religious features of curanderismo training and practice. AB - The purpose of this study is to investigate religious features of curanderismo, specifically the role of ostensibly Roman Catholic beliefs and practices in the training and work of curandero/as. The integration of religious beliefs and practices within the rituals of curanderismo and how this potential clash of worldviews negatively and positively impacts clients and practitioners are examined. Interviews were conducted with practicing curandero/as and clients who had sought their services. Factors observed to have potential to facilitate healing include psychological reassurance gained through incorporating familiar religious beliefs and paraphernalia and the therapeutic healing property of features of curanderismo practice, such as herbs used in many remedies. Negative effects may result from feelings of distrust, fear, and embarrassment engendered by seeking care from a curandero/a. Future research targeting the complexities of the relationship between Roman Catholicism and curanderismo might focus specifically on how negotiating this conflict of worldviews may affect health. PMID- 23643369 TI - Qigong as a novel intervention for service members with mild traumatic brain injury. AB - PURPOSE: To describe the experience of internal qigong practice in service members diagnosed with mild traumatic brain injury (mTBI). THEORETICAL FRAMEWORK: The study used qualitative descriptive phenomenological methods originally described by Husserl and later refined by Giorgi. METHODOLOGY: Participants were interviewed about their experiences while learning qigong to determine their level of interest, benefits, and/or adverse effects; ease of learning/performing the routine; and any barriers to practice. SAMPLE: Six service members with mTBI receiving outpatient neurorehabilitation at the Defense and Veterans Brain Injury Center-Charlottesville Rehabilitation Center. INTERVENTION: Participants learned Reflective Exercise Qigong, a form of qigong developed specifically to require less complex movement and balance than most forms of qigong, making it ideal for those with potential coordination and balance issues. DATA COLLECTION: Semistructured interviews took place after four weeks of formal qigong instruction, then again after the subjects completed eight weeks. Interview data were analyzed with phenomenological methods described by Giorgi. RESULTS: Four themes emerged from the interview data: "the physical experience of qigong," "regaining control," "no pain, a lot of gain," and "barriers to qigong practice." Participants offered examples of how qigong enabled them to control refractory symptoms after mTBI while decreasing reliance on pharmacotherapy. All agreed that qigong was uniquely conducive to the disciplined mindset of military service members and that the simplicity of Reflective Exercise qigong, compared with similar modalities such as tai chi and yoga, was well suited to individuals with decreased balance, cognition, and memory related to mTBI. PMID- 23643371 TI - Taking spiritual history in clinical practice: a systematic review of instruments. AB - BACKGROUND: To facilitate the addressing of spirituality in clinical practice, several authors have created instruments for obtaining a spiritual history. However, in only a few studies have authors compared these instruments. The aim of this study was to compare the most commonly used instruments for taking a spiritual history in a clinical setting. METHODS: A systematic review of spiritual history assessment was conducted in five stages: identification of instruments used in the literature (databases searching); relevant articles from title and initial abstract review; exclusion and Inclusion criteria; full text retrieval and final analysis of each instrument. RESULTS: A total of 2,641 articles were retrieved and after the analysis, 25 instruments were included. The authors independently evaluated each instrument on 16 different aspects. The instruments with the greatest scores in the final analysis were FICA, SPIRITual History, FAITH, HOPE, and the Royal College of Psychiatrists. Concerning all 25 instruments, 20 of 25 inquire about the influence of spirituality on a person's life and 17 address religious coping. Nevertheless, only four inquire about medical practices not allowed, six deal with terminal events, nine have mnemonics to facilitate their use, and five were validated. CONCLUSIONS: FICA, SPIRITual History, FAITH, HOPE, and Royal College of Psychiatrists scored higher in our analysis. The use of each instrument must be individualized, according to the professional reality, time available, patient profile, and settings. PMID- 23643372 TI - Qualitative evaluation of a high school yoga program: feasibility and perceived benefits. AB - This is the first published qualitative assessment of a yoga program applied in a high school setting. This qualitative interview study was nested in a randomized, controlled trial studying the effects of a yoga program offered in place of a semester of physical education classes at a rural public high school. Student interviews were conducted after taking part in a semester of the yoga program. A formal passive consent with information about the qualitative study was sent home to parents/guardians of all students in the parent study before the interviews. Most students enjoyed the yoga classes and felt benefits. Negative reports of yoga practice were associated with gender as most males sensed peer pressure against practicing yoga. Despite this finding, most students wanted to continue yoga and would continue if it were offered in school. Positive reports include a greater kinesthetic awareness, which some students associated with a greater respect for the body and improved self-image. Among students reporting psychological benefits, many cited stress reduction; many used yoga to manage negative emotions; and some propagated more optimism. Most thought yoga could reduce interest in the use of drugs and alcohol and increase social cohesion with family and peers. We found that a yoga program is feasible in this sample of 9th and 10th graders, especially after benefits are perceived. We also found evidence that yoga may lead to emergent positive benefits in health behaviors not directly prescribed by the program. These results suggest that school-based yoga programs may be appropriate for promoting healthy behaviors at a societal level by focusing on the prevention of negative patterns during the adolescent transition. PMID- 23643373 TI - Acupuncture and migraine prophylaxis, probiotics and C. Difficile-associated diarrhea, preventive group counseling and postpartum depression, black cohosh and menopausal symptoms, deep needling electroacupuncture and trigeminal neuralgia. PMID- 23643374 TI - Nutritional deficiency in healthcare education. PMID- 23643375 TI - Oncology scan - gynecological cancers: new treatments, old treatments, imaging, and meta-analyses. PMID- 23643376 TI - The Red Journal's most downloaded articles of 2012. PMID- 23643377 TI - eXclusion: toward integrating the X chromosome in genome-wide association analyses. AB - The X chromosome lags behind autosomal chromosomes in genome-wide association study (GWAS) findings. Indeed, the X chromosome is commonly excluded from GWAS analyses despite being assayed on all current GWAS microarray platforms. This raises the question: why are so few hits reported on the X chromosome? This commentary aims to examine this question through review of the current X chromosome results in the National Human Genome Research Institute Catalog of Published Genome-Wide Association Studies (NHGRI GWAS Catalog). It will also investigate commonly cited reasons for exclusion of the X chromosome from GWAS and review the tools currently available for X chromosome analysis. It will conclude with recommendations for incorporating X chromosome analyses in future studies. PMID- 23643378 TI - Incidental variants are critical for genomics. AB - The topic of incidental variants detected through exome and genome sequencing is controversial, both in clinical practice and in research. The arguments for and against the deliberate analysis and return of incidental variants focus on issues of clinical validity, clinical utility, autonomy, clinical and research infrastructure and costs, and, in the research arena, therapeutic misconception. These topics are briefly reviewed and an argument is made that these variants are the future of genomic medicine. As a field, we should take full advantage of all opportunities to study these variants by searching them out, returning them to patients and research participants, and studying their utility for predictive medicine. PMID- 23643379 TI - MASTOR: mixed-model association mapping of quantitative traits in samples with related individuals. AB - Genetic association studies often sample individuals with known familial relationships in addition to unrelated individuals, and it is common for some individuals to have missing data (phenotypes, genotypes, or covariates). When some individuals in a sample are related, power can be gained by incorporating all individuals in the analysis, including individuals with partially missing data, while properly accounting for the dependence among them. We propose MASTOR, a mixed-model, retrospective score test for genetic association with a quantitative trait. MASTOR achieves high power in samples that contain related individuals by making full use of the relationship information to incorporate partially missing data in the analysis while correcting for dependence. Individuals with available phenotype and covariate information who are not genotyped but have genotyped relatives in the sample can still contribute to the association analysis because of the dependence among genotypes. Similarly, individuals who are genotyped but are missing covariate or phenotype information can contribute to the analysis. MASTOR is valid even when the phenotype model is misspecified and with either random or phenotype-based ascertainment. In simulations, we demonstrate the correct type 1 error of MASTOR, the increase in power that comes from making full use of the relationship information, the robustness to misspecification of the phenotype model, and the improvement in power that comes from modeling the heritability. We show that MASTOR is computationally feasible and practical in genome-wide association studies. We apply MASTOR to data on high-density lipoprotein cholesterol from the Framingham Heart study. PMID- 23643380 TI - Sherlock: detecting gene-disease associations by matching patterns of expression QTL and GWAS. AB - Genetic mapping of complex diseases to date depends on variations inside or close to the genes that perturb their activities. A strong body of evidence suggests that changes in gene expression play a key role in complex diseases and that numerous loci perturb gene expression in trans. The information in trans variants, however, has largely been ignored in the current analysis paradigm. Here we present a statistical framework for genetic mapping by utilizing collective information in both cis and trans variants. We reason that for a disease-associated gene, any genetic variation that perturbs its expression is also likely to influence the disease risk. Thus, the expression quantitative trait loci (eQTL) of the gene, which constitute a unique "genetic signature," should overlap significantly with the set of loci associated with the disease. We translate this idea into a computational algorithm (named Sherlock) to search for gene-disease associations from GWASs, taking advantage of independent eQTL data. Application of this strategy to Crohn disease and type 2 diabetes predicts a number of genes with possible disease roles, including several predictions supported by solid experimental evidence. Importantly, predicted genes are often implicated by multiple trans eQTL with moderate associations. These genes are far from any GWAS association signals and thus cannot be identified from the GWAS alone. Our approach allows analysis of association data from a new perspective and is applicable to any complex phenotype. It is readily generalizable to molecular traits other than gene expression, such as metabolites, noncoding RNAs, and epigenetic modifications. PMID- 23643381 TI - Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. AB - Transcription factor SOX10 plays a role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation and is a major actor in the development of the neural crest. It has been implicated in Waardenburg syndrome (WS), a rare disorder characterized by the association between pigmentation abnormalities and deafness, but SOX10 mutations cause a variable phenotype that spreads over the initial limits of the syndrome definition. On the basis of recent findings of olfactory-bulb agenesis in WS individuals, we suspected SOX10 was also involved in Kallmann syndrome (KS). KS is defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Mutations in any of the nine genes identified to date account for only 30% of the KS cases. KS can be either isolated or associated with a variety of other symptoms, including deafness. This study reports SOX10 loss-of-function mutations in approximately one-third of KS individuals with deafness, indicating a substantial involvement in this clinical condition. Study of SOX10-null mutant mice revealed a developmental role of SOX10 in a subpopulation of glial cells called olfactory ensheathing cells. These mice indeed showed an almost complete absence of these cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs. PMID- 23643383 TI - Genome-wide association analysis for multiple continuous secondary phenotypes. AB - There is increasing interest in the joint analysis of multiple phenotypes in genome-wide association studies (GWASs), especially for the analysis of multiple secondary phenotypes in case-control studies and in detecting pleiotropic effects. Multiple phenotypes often measure the same underlying trait. By taking advantage of similarity across phenotypes, one could potentially gain statistical power in association analysis. Because continuous phenotypes are likely to be measured on different scales, we propose a scaled marginal model for testing and estimating the common effect of single-nucleotide polymorphism (SNP) on multiple secondary phenotypes in case-control studies. This approach improves power in comparison to individual phenotype analysis and traditional multivariate analysis when phenotypes are positively correlated and measure an underlying trait in the same direction (after transformation) by borrowing strength across outcomes with a one degree of freedom (1-DF) test and jointly estimating outcome-specific scales along with the SNP and covariate effects. To account for case-control ascertainment bias for the analysis of multiple secondary phenotypes, we propose weighted estimating equations for fitting scaled marginal models. This weighted estimating equation approach is robust to departures from normality of continuous multiple phenotypes and the misspecification of within-individual correlation among multiple phenotypes. Statistical power improves when the within-individual correlation is correctly specified. We perform simulation studies to show the proposed 1-DF common effect test outperforms several alternative methods. We apply the proposed method to investigate SNP associations with smoking behavior measured with multiple secondary smoking phenotypes in a lung cancer case-control GWAS and identify several SNPs of biological interest. PMID- 23643382 TI - Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. AB - Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ~12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH. PMID- 23643384 TI - Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. AB - Inherited white-matter disorders are a broad class of diseases for which treatment and classification are both challenging. Indeed, nearly half of the children presenting with a leukoencephalopathy remain without a specific diagnosis. Here, we report on the application of high-throughput genome and exome sequencing to a cohort of ten individuals with a leukoencephalopathy of unknown etiology and clinically characterized by hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL), as well as the identification of compound-heterozygous and homozygous mutations in cytoplasmic aspartyl-tRNA synthetase (DARS). These mutations cause nonsynonymous changes to seven highly conserved amino acids, five of which are unchanged between yeast and man, in the DARS C-terminal lobe adjacent to, or within, the active-site pocket. Intriguingly, HBSL bears a striking resemblance to leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate (LBSL), which is caused by mutations in the mitochondria-specific DARS2, suggesting that these two diseases might share a common underlying molecular pathology. These findings add to the growing body of evidence that mutations in tRNA synthetases can cause a broad range of neurologic disorders. PMID- 23643387 TI - Cumulative trauma and symptom complexity in children: a path analysis. AB - Multiple trauma exposures during childhood are associated with a range of psychological symptoms later in life. In this study, we examined whether the total number of different types of trauma experienced by children (cumulative trauma) is associated with the complexity of their subsequent symptomatology, where complexity is defined as the number of different symptom clusters simultaneously elevated into the clinical range. Children's symptoms in six different trauma-related areas (e.g., depression, anger, posttraumatic stress) were reported both by child clients and their caretakers in a clinical sample of 318 children. Path analysis revealed that accumulated exposure to multiple different trauma types predicts symptom complexity as reported by both children and their caretakers. PMID- 23643386 TI - Weight loss after gastric bypass is associated with a variant at 15q26.1. AB - The amount of weight loss attained after Roux-en-Y gastric bypass (RYGB) surgery follows a wide and normal distribution, and recent evidence indicates that this weight loss is due to physiological, rather than mechanical, mechanisms. To identify potential genetic factors associated with weight loss after RYGB, we performed a genome-wide association study (GWAS) of 693 individuals undergoing RYGB and then replicated this analysis in an independent population of 327 individuals undergoing RYGB. We found that a 15q26.1 locus near ST8SIA2 and SLCO3A1 was significantly associated with weight loss after RYGB. Expression of ST8SIA2 in omental fat of these individuals at baseline was significantly associated with weight loss after RYGB. Gene expression analysis in RYGB and weight-matched, sham-operated (WMS) mice revealed that expression of St8sia2 and Slco3a1 was significantly altered in metabolically active tissues in RYGB-treated compared to WMS mice. These findings provide strong evidence for specific genetic influences on weight loss after RYGB and underscore the biological nature of the response to RYGB. PMID- 23643385 TI - Mutations in SCO2 are associated with autosomal-dominant high-grade myopia. AB - Myopia, or near-sightedness, is an ocular refractive error of unfocused image quality in front of the retinal plane. Individuals with high-grade myopia (dioptric power greater than -6.00) are predisposed to ocular morbidities such as glaucoma, retinal detachment, and myopic maculopathy. Nonsyndromic, high-grade myopia is highly heritable, and to date multiple gene loci have been reported. We performed exome sequencing in 4 individuals from an 11-member family of European descent from the United States. Affected individuals had a mean dioptric spherical equivalent of -22.00 sphere. A premature stop codon mutation c.157C>T (p.Gln53*) cosegregating with disease was discovered within SCO2 that maps to chromosome 22q13.33. Subsequent analyses identified three additional mutations in three highly myopic unrelated individuals (c.341G>A, c.418G>A, and c.776C>T). To determine differential gene expression in a developmental mouse model, we induced myopia by applying a -15.00D lens over one eye. Messenger RNA levels of SCO2 were significantly downregulated in myopic mouse retinae. Immunohistochemistry in mouse eyes confirmed SCO2 protein localization in retina, retinal pigment epithelium, and sclera. SCO2 encodes for a copper homeostasis protein influential in mitochondrial cytochrome c oxidase activity. Copper deficiencies have been linked with photoreceptor loss and myopia with increased scleral wall elasticity. Retinal thinning has been reported with an SC02 variant. Human mutation identification with support from an induced myopic animal provides biological insights of myopic development. PMID- 23643388 TI - Role of emotion dysregulation in the relationship between childhood abuse and probable PTSD in a sample of substance abusers. AB - This study examined associations among childhood abuse, emotion dysregulation, and probable posttraumatic stress disorder (PTSD) within a sample of 93 substance use disorder (SUD) patients in residential treatment. SUD patients with probable PTSD (vs. non-PTSD) reported (a) greater severity of childhood sexual, physical, and emotional abuse and (b) significantly higher levels of overall emotion dysregulation and the specific dimensions of difficulties engaging in goal directed behavior when upset, difficulties controlling impulsive behaviors when distressed, limited access to effective emotion regulation strategies, and lack of emotional clarity. Additionally, significant positive associations were found between both childhood physical and emotional (but not sexual) abuse on the one hand and dimensions of emotion dysregulation on the other. Further analyses indicated that difficulties controlling impulsive behaviors when distressed accounted for the associations of both childhood physical and emotional abuse with probable PTSD status. Findings of the present study highlight a potential mechanism underlying the relationships between both childhood emotional and physical abuse and PTSD in SUD patients. PMID- 23643390 TI - Moving into the future: electronic surveillance for healthcare-associated infections. PMID- 23643389 TI - Gain of interaction with IRS1 by p110alpha-helical domain mutants is crucial for their oncogenic functions. AB - PIK3CA, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3 kinase alpha, is frequently mutated in human cancers. Most of these mutations occur at two hot-spots: E545K and H1047R located in the helical domain and the kinase domain, respectively. Here, we report that p110alpha E545K, but not p110alpha H1047R, gains the ability to associate with IRS1 independent of the p85 regulatory subunit, thereby rewiring this oncogenic signaling pathway. Disruption of the IRS1-p110alpha E545K interaction destabilizes the p110alpha protein, reduces AKT phosphorylation, and slows xenograft tumor growth of a cancer cell line expressing p110alpha E545K. Moreover, a hydrocarbon-stapled peptide that disrupts this interaction inhibits the growth of tumors expressing p110alpha E545K. PMID- 23643391 TI - On the difficulties of isolating Clostridium difficile from hospital environments. AB - Spores of Clostridium difficile were deposited on to a stainless steel surface and subsequently exposed to a chlorine-releasing disinfectant (dichloroisocyanurate). Recovery of the spores was carried out using RODAC plates containing a variety of selective and non-selective agars. The non-selective agar media yielded higher recoveries of both control and chlorine-stressed spores. Our results show that the antibiotics used in selective media imposed an additional stress on both disinfectant-treated and untreated spores resulting in considerably reduced recoveries. This could lead to a serious underestimate of the extent of environmental contamination by this organism. PMID- 23643393 TI - Quinolones for mycobacterial infections. AB - The fluoroquinolones (FQs) are important agents for the treatment of mycobacterial infections. In leprosy, the use of FQs has enabled a dramatic shortening of formerly long and complicated therapy. Both animal and human studies support the inclusion of certain FQs as a cornerstone of leprosy therapy. In tuberculosis (TB), particularly in multidrug-resistant (MDR) infections, the place of the major antimycobacterial FQs is less clear as there is widespread resistance to these agents in areas of the world in which MDR-TB and extensively drug-resistant (XDR)-TB are prevalent, particularly in Southeast Asia. The place of the newly developed FQ-related diarylquinoline compound known as bedaquiline in the treatment of drug-resistant TB is unclear; however, human studies suggest that it might be effective for this indication. PMID- 23643392 TI - Accumulation of mutations in DNA gyrase and topoisomerase IV genes contributes to fluoroquinolone resistance in Vibrio cholerae O139 strains. AB - High resistance rates to nalidixic acid (NAL) in Vibrio cholerae serogroup O139 strains have been found, and ciprofloxacin (CIP) resistance is also observed. In this study, mutations within the quinolone-resistance determining regions (QRDRs) of DNA gyrase and topoisomerase IV from NAL-resistant O139 strains were analysed. The predominant mutation profile was S83I in GyrA in combination with S85L in ParC. In addition, the combination substitutions of D87N in GyrA and D420N in ParE in combination with S83I in GyrA and S85L in ParC as well as D87N in GyrA and P439S in ParE in combination with S83I in GyrA and S85L in ParC were found in the CIP-resistant strains. A series of site-directed mutants comprising D87 in GyrA, D420 in ParE and P439 in ParE were constructed from a wild-type V. cholerae O139 strain carrying the common mutations S83I in GyrA and S85L in ParC. Introduction of the mutation D87N in GyrA increased the CIP minimum inhibitory concentration (MIC) of the mutant strain by nearly 4-fold compared with the initial strain. The second introduction of D420N in ParE further significantly increased the CIP MIC to ca. 23-fold compared with the initial strain. A second introduction of P439S in ParE also increased the CIP MIC by 17-fold. Therefore, it is concluded that the emergence of D87N in GyrA and D420N or P439S in ParE dramatically induces resistance to fluoroquinolones in V. cholerae O139, and the accumulation of multiple mutations in the QRDRs confers significant resistance to fluoroquinolones in V. cholerae. PMID- 23643394 TI - Inheritance studies of SSR and ISSR molecular markers and phylogenetic relationship of rice genotypes resistant to tungro virus. AB - Multivariate analyses were performed using 13 morphological traits and 13 molecular markers (10 SSRs and three ISSRs) to assess the phylogenetic relationship among tungro resistant genotypes. For morphological traits, the genotypes were grouped into six clusters, according to D(2) statistic and Canonical vector analysis. Plant height, days to flowering, days to maturity, panicle length, number of spikelet per panicle, number of unfilled grain per panicle and yield were important contributors to genetic divergence in 14 rice genotypes. Based on Nei's genetic distance for molecular studies, seven clusters were formed among the tungro resistant and susceptible genotypes. Mantel's test revealed a significant correlation (r = 0.834*) between the morphological and molecular data. To develop high yielding tungro resistant varieties based on both morphological and molecular analyses, crosses could be made with susceptible (BR10 and BR11) genotypes with low yielding but highly resistant genotypes, Sonahidemota, Kumragoir, Nakuchimota, Khaiyamota, Khairymota and Kachamota. The chi-square analysis for seven alleles (RM11, RM17, RM20, RM23, RM80, RM108 and RM531) of SSR and five loci (RY1, MR1, MR2, MR4 and GF5) of three ISSR markers in F2 population of cross, BR11*Sonahidemota, showed a good fit to the expected segregation ratio (1:2:1) for a single gene model. PMID- 23643395 TI - Middle ferritin genes from the icefish Chionodraco rastrospinosus: comparative analysis and evolution of fish ferritins. AB - Ferritin is a major intracellular iron storage protein in higher vertebrates and plays an important role in iron metabolism. This study reports the identification from the Antarctic icefish Chionodraco rastrospinosus of a complete mRNA sequence and four partial mRNA sequences, all encoding the ferritin M subunit and sharing a clear homology with the ferritin M-chain of other fish species. The open reading frame of the complete ferritin M transcript is of 528 base pairs and encodes a protein of 176 amino acids that retains the residues involved in the ferroxidase diiron center and in the ferrihydrite nucleation center. Despite the absence of hemoglobin and of any appreciable amount of iron in the icefish blood, RT-PCR analysis shows that H and M ferritin subunits are expressed both in blood and in other tissues, such as spleen, head kidney, liver and kidney. Phylogenetic analysis shows that the H and M subunits form two well separated clusters. Basal to these two clusters emerges a heterogeneous cluster, formed by two Danio rerio M, a Salmo salar M and an Orechromis niloticus H isoforms; these forms maybe represent the heritage of ancestral forms from which arose the two major H and M subunits of the fishes. PMID- 23643396 TI - Autonomic nervous system dysfunction: implication in sickle cell disease. AB - Sickle cell disease is an inherited hemoglobinopathy caused by a single amino acid substitution in the beta chain of hemoglobin that causes the hemoglobin to polymerize in the deoxy state. The resulting rigid, sickle-shaped red cells obstruct blood flow causing hemolytic anemia, tissue damage, and premature death. Hemolysis is continual. However, acute exacerbations of sickling called vaso occlusive crises (VOC) resulting in severe pain occur, often requiring hospitalization. Blood rheology, adhesion of cellular elements of blood to vascular endothelium, inflammation, and activation of coagulation decrease microvascular flow and increase likelihood of VOC. What triggers the transition from steady state to VOC is unknown. This review discusses the interaction of blood rheological factors and the role that autonomic nervous system (ANS) induced vasoconstriction may have in triggering crisis as well as the mechanism of ANS dysfunction in SCD. PMID- 23643397 TI - Hematopoietic stem cell transplantation in SCD. AB - Hematopoietic stem cell transplantation (HSCT) is the one and only curative therapy available for patient with severe sickle cell disease (SCD). Until today, several hundreds of patients have undergone geno-identical HSCT. More than 200 patients were transplanted in France. The first indication was cerebral vasculopathy. Among both malignant and non-malignant diseases treated with HSCT, the success rate obtained in SCD patients appears as the best one. From the year 2000, more than 95% of transplanted patients survived the HSCT procedure and more than 90% are completely cured and experience a very satisfying health condition post-transplantation. However, the current standard procedure includes a myeloablative conditioning regimen for warranting engraftment. Such regime is linked to severe long-term side effects such as hypofertility. Due to the excellent obtained results, we have to think about a possible widening of indications, a decrease of conditioning intensity and toxicity, and about HSCT from alternative stem cell sources, such as mismatch family donor, unrelated volunteer donor or unrelated cord blood. PMID- 23643398 TI - Relevance of blood groups in transfusion of sickle cell disease patients. AB - Blood groups are clinically significant in sickle cell disease (SCD) as transfusion remains a key treatment in this pathology. The occurrence of a delayed haemolytic transfusion reaction (DHTR) is not rare and is a life threatening event. The main cause of DHTR is the production of alloantibodies against red blood cell antigens. The high rate of alloimmunization in SCD patients is mainly due to the differences of red blood groups between patients of African descent, and the frequently Caucasian donors. From an immuno haematological point of view, DHTR in SCD patients has specific features: classical antibodies known to be haemolytic can be encountered, but otherwise non significant antibodies, autoantibodies and antibodies related to partial and rare blood groups are also frequently found in individuals of African descent. In some cases, there are no detectable antibodies. As alloimmunization remains the main cause of DHTR, it is extremely important to promote blood donation by individuals of African ancestry to make appropriate blood available. PMID- 23643399 TI - Nutrition and sickle cell disease. AB - A common observation in sickle cell disease is growth retardation, in particular, wasting. Wasting is associated with increased hospitalization and possibly poorer clinical outcomes. Therefore understanding the mechanism of wasting is crucial and reducing the degree of wasting by improving the nutritional status, holds the potential for modifying the course of the disease. PMID- 23643401 TI - Natural antiband 3 antibodies in patients with sickle cell disease. AB - Band 3 oligomers, precociously formed in the membrane of sickle red blood cells (SS RBC) as a result of oxidative damage, induce two significant changes: (1) contribution to the adhesive nature of these cells to endothelial cells; (2) production of recognition sites for natural antiband 3 antibodies (antiband 3 Nabs). The inhibition of the adhesion of SS RBC to endothelial cells by band 3 peptides suggests a participation of antiband 3 Nabs in the etiology and prevention of vaso-occlusive crises (VOC). To address this question, we measured the levels of antiband 3 Nabs in sickle cell anaemia (SCA) patients (45 in steady state, 35 in VOC) and in controls (27 sickle trait, 30 normal AA subjects). A significant decreased of antiband 3 Nabs in the VOC group was demonstrated as compared with the steady state group, the sickle trait and healthy controls. This study provides data suggesting that Antiband 3 Nabs are likely to play a role in the SCA VOC. PMID- 23643400 TI - Post-transfusional iron overload in the haemoglobinopathies. AB - In this report, we review the recent advances in evaluation and treatment of transfusional iron overload (IO). Results of the French thalassaemia registry are described. According to the disease, thalassaemia major or sickle cell anaemia, mechanisms and toxicity of iron overload, knowledge about IO long-term outcome and chelation treatment results, respective value of IO markers, differ. The recent tools evaluating organ specific IO and the diversification of iron chelator agents make possible to individualize chelation therapy in clinical practice. The severity of IO and the level of transfusional iron intake, the preferential localization of IO (heart/liver) as well as the tolerance and adherence profiles of the patient can now be taken into account. Introduction of cardiac magnetic resonance imaging for the quantification of myocardial iron and use of oral chelators have already been reported as decreasing the cardiac mortality rate related to IO in thalassaemia major patients. Long-term observation of patients under oral chelators will show if morbidity is also improving via a more continuous control of toxic iron and/or a better accessibility to cellular iron pools. PMID- 23643403 TI - EAFS 2012 6th European Academy of Forensic Science Conference The Hague, 20-24 August 2012. Introduction. PMID- 23643402 TI - Hydroxycarbamide: clinical aspects. AB - Due to its oral route of administration and mild toxicity profile, as well as its potent laboratory and clinical effects, hydroxyurea (or hydroxycarbamide) has been the primary focus of fetal hemoglobin (HbF) induction strategies for the treatment of children with sickle cell anemia (SCA). When administered orally once a day, hydroxyurea treatment is very well tolerated with little short-term toxicity. Hydroxyurea has documented laboratory efficacy with increases in Hb and HbF; treatment also significantly reduces the number of painful episodes, acute chest syndrome, transfusions, and hospitalizations. Most young patients reach a maximum tolerated dose of hydroxyurea at 25-30 mg/kg/d, where they will achieve key laboratory thresholds (Hb >= 9 g/dL and HbF >= 20%) without excessive myelosuppression. Potential long-term toxicities continue to be of great concern and should be monitored in all patients with SCA who receive hydroxyurea therapy. To date, however, no increases in stroke, myelodysplasia, or carcinogenicity have been detected in SCA patient cohorts, with drug exposure now reaching 15 years for some treated children. Taken together, available evidence suggests that hydroxyurea represents an inexpensive and effective treatment option that should be offered to most, if not all, patients with SCA. As countries in Africa develop newborn screening programs to identify SCA, the widespread use of hydroxyurea may prove to be a useful treatment to help ameliorate the disease in resource-limited settings. Hydroxyurea is the only currently available disease-modifying therapy for SCA, and is emerging as a safe and effective treatment for all patients with SCA, in both developed and developing countries. PMID- 23643404 TI - Liver enzymes and vitamin D levels in metabolically healthy but obese individuals: Korean National Health and Nutrition Examination Survey. AB - OBJECTIVE: Increased liver enzymes and decreased vitamin D levels are associated with insulin resistance and type 2 diabetes. We examined liver enzymes and vitamin D levels in metabolically healthy but obese (MHO) individuals and compared the values with those of other body size phenotypes in the Korean population. MATERIALS/METHODS: A total of 16,190 people over the age of 18years were analyzed using data from the Fourth Korean National Health and Nutrition Examination Survey, which is a nationally representative survey. Body size phenotypes were classified into four groups by body mass index (BMI) and number of metabolic syndrome components. RESULTS: The prevalence of MHO was 14.9% in the entire population and 47.7% in the obese population. In a correlation analysis adjusted for age, sex, and BMI, AST and ALT levels were positively correlated with insulin resistance and cardiometabolic risk factors of the metabolic syndrome, whereas vitamin D level was negatively correlated with these variables. MHO individuals had significantly lower concentrations of AST and ALT compared to metabolically abnormal obese (MAO) subjects, although vitamin D levels were not significantly different. Furthermore, a multiple logistic regression analysis revealed that MHO individuals had lower risk of liver enzyme abnormality compared to MAO after adjusting for potential confounding factors. However, the risk of vitamin D deficiency was not significantly different among groups with different body size phenotypes. CONCLUSIONS: Although both liver enzymes and vitamin D levels are related to insulin resistance and metabolic syndrome, only liver enzymes were independently associated with MHO phenotype. PMID- 23643405 TI - Bombs away! PMID- 23643406 TI - Can stormwater be detected by algae in an urban reef in Hawai'i? AB - Nitrogen (N) enrichment of tropical reefs can result in the dominance of invasive algae. The invasive alga Acanthophora spicifera and the native alga Laurencia nidifica are part of a diverse reef assemblage in 'Ewa Beach, O'ahu. Their N contents and delta(15)N values were investigated to determine if N was enriched and to evaluate potential nitrogenous sources near and removed from storm-drain outlets. delta(15)N values of algae (3.8-17.70/00) were within and above the range for algae around the island (1.9-11.90/00). Elevated algae N isotope values (delta(15)N>+70/00, [N]>1.6%) and seawater nitrate+nitrite levels (0.59-7.93 MUM) indicated a mixed, high nutrient environment. The overlap in delta(15)N values with multiple nitrogenous sources precluded identification. However, spatial and temporal patterns did not support stormwater as the dominant, nitrogenous source. Patterns were congruent with algal incorporation of terrestrial derived N, subjected to a high degree of biogeochemical cycling. PMID- 23643408 TI - Emerging contaminants in Belgian marine waters: single toxicant and mixture risks of pharmaceuticals. AB - Knowledge on the effects of pharmaceuticals on aquatic marine ecosystems is limited. The aim of this study was therefore to establish the effect thresholds of pharmaceutical compounds occurring in the Belgian marine environment for the marine diatom Phaeodactylum tricornutum, and subsequently perform an environmental risk assessment for these substances. Additionally, a screening level risk assessment was performed for the pharmaceutical mixtures. No immediate risk for acute toxic effects of these compounds on P. tricornutum were apparent at the concentrations observed in the Belgian marine environment. In two Belgian coastal harbours however, a potential chronic risk was observed for the beta blocker propranolol. No additional risks arising from the exposure to mixtures of pharmaceuticals present in the sampling area could be detected. However, as risk characterization ratios for mixtures of up to 0.5 were observed, mixture effects could emerge should more compounds be taken into account. PMID- 23643409 TI - Efficient tools for marine operational forecast and oil spill tracking. AB - Ocean forecasting and oil spill modelling and tracking are complex activities requiring specialised institutions. In this work we present a lighter solution based on the Operational Ocean Forecast Python Engine (OOFepsilon) and the oil spill model General NOAA Operational Modelling Environment (GNOME). These two are robust relocatable and simple to implement and maintain. Implementations of the operational engine in three different regions with distinct oceanic systems, using the ocean model Regional Ocean Modelling System (ROMS), are described, namely the Galician region, the southeastern Brazilian waters and the Texas Louisiana shelf. GNOME was able to simulate the fate of the Prestige oil spill (Galicia) and compared well with observations of the Krimsk accident (Texas). Scenarios of hypothetical spills in Campos Basin (Brazil) are illustrated, evidencing the sensitiveness to the dynamical system. OOFepsilon and GNOME are proved to be valuable, efficient and low cost tools and can be seen as an intermediate stage towards more complex operational implementations of ocean forecasting and oil spill modelling strategies. PMID- 23643407 TI - Critical research needs for identifying future changes in Gulf coral reef ecosystems. AB - Expert opinion was assessed to identify current knowledge gaps in determining future changes in Arabian/Persian Gulf (thereafter 'Gulf') coral reefs. Thirty one participants submitted 71 research questions that were peer-assessed in terms of scientific importance (i.e., filled a knowledge gap and was a research priority) and efficiency in resource use (i.e., was highly feasible and ecologically broad). Ten research questions, in six major research areas, were highly important for both understanding Gulf coral reef ecosystems and also an efficient use of limited research resources. These questions mirrored global evaluations of the importance of understanding and evaluating biodiversity, determining the potential impacts of climate change, the role of anthropogenic impacts in structuring coral reef communities, and economically evaluating coral reef communities. These questions provide guidance for future research on coral reef ecosystems within the Gulf, and enhance the potential for assessment and management of future changes in this globally significant region. PMID- 23643410 TI - Surviving sepsis: are new technologies the answer or should we do it old-school? PMID- 23643412 TI - American Association of Heart Failure Nurses position paper on the Certified Heart Failure Nurse (CHFN) certification. PMID- 23643413 TI - Re. 'Provision of vascular surgery in England in 2012'. PMID- 23643411 TI - Defining sedation-related adverse events in the pediatric intensive care unit. AB - BACKGROUND: Clinical trials exploring optimal sedation management in critically ill pediatric patients are urgently needed to improve both short- and long-term outcomes. Concise operational definitions that define and provide best-available estimates of sedation-related adverse events (AE) in the pediatric population are fundamental to this line of inquiry. OBJECTIVES: To perform a multiphase systematic review of the literature to identify, define, and provide estimates of sedation-related AEs in the pediatric ICU setting for use in a multicenter clinical trial. METHODS: In Phase One, we identified and operationally defined the AE. OVID-MEDLINE and CINAHL databases were searched from January 1998 to January 2012. Key terms included sedation, intensive and critical care. We limited our search to data-based clinical trials from neonatal to adult age. In Phase Two, we replicated the search strategy for all AEs and identified pediatric specific AE rates. RESULTS: We reviewed 20 articles identifying sedation-related adverse events and 64 articles on the pediatric-specific sedation-related AE. A total of eleven sedation-related AEs were identified, operationally defined and estimated pediatric event rates were derived. AEs included: inadequate sedation management, inadequate pain management, clinically significant iatrogenic withdrawal, unplanned endotracheal tube extubation, post-extubation stridor with chest-wall retractions at rest, extubation failure, unplanned removal of invasive tubes, ventilator-associated pneumonia, catheter-associated bloodstream infection, Stage II+ pressure ulcers and new tracheostomy. CONCLUSIONS: Concise operational definitions that defined and provided best-available event rates of sedation-related AEs in the pediatric population are presented. Uniform reporting of adverse events will improve subject and patient safety. PMID- 23643414 TI - Commentary on 'An optimal combination for EVAR: low profile endograft body and continuous spiral stent limbs'. PMID- 23643415 TI - Kinetic sonication effects in aqueous acetonitrile solutions. Reaction rate levelling by ultrasound. AB - The kinetics of the pH-independent hydrolysis of 4-methoxyphenyl dichloroacetate were investigated with and without ultrasonic irradiation in acetonitrile-water binary mixtures containing 0.008 to 35 wt.% of acetonitrile and the kinetic sonication effects (kson/knon) were calculated. Molecular dynamics (MD) simulations of the structure of the solutions were performed with ethyl acetate as the model ester. The ester is preferentially solvated by acetonitrile. The excess of acetonitrile over water in the solvation shell grows fast with an increase in the co-solvent content in the bulk solution. In parallel, the formation of a second solvation shell rich in acetonitrile takes place. Significant kinetic sonication effects for the hydrolysis were explained with facile destruction of the diffuse second solvation shell followed by a rearrangement of the remaining solvent layer under sonication. The rate levelling effect of ultrasound was discussed. In an aqueous-organic binary solvent, independent of the solvent composition, the ultrasonic irradiation evokes changes in the reaction medium which result in an almost identical solvation state of the reagent thus leading to the reaction rate levelling. PMID- 23643416 TI - Human amnion epithelial cells modulate hyperoxia-induced neonatal lung injury in mice. AB - BACKGROUND AIMS: Human amnion epithelial cells (hAECs) prevent pulmonary inflammation and injury in fetal sheep exposed to intrauterine lipopolysaccharide. We hypothesized that hAECs would similarly mitigate hyperoxia induced neonatal lung injury. METHODS: Newborn mouse pups were randomized to either normoxia (inspired O2 content (FiO2) = 0.21, n = 60) or hyperoxia (FiO2 = 0.85, n = 57). On postnatal days (PND) 5, 6 and 7, hAECs or sterile saline (control) was administered intraperitoneally. All animals were assessed at PND 14. RESULTS: Hyperoxia was associated with lung inflammation, alveolar simplification and reduced postnatal growth. Administration of hAECs to hyperoxia exposed mice normalized body weight and significantly attenuated some aspects of hyperoxia-induced lung injury (mean linear intercept and septal crest density) and inflammation (interleukin-1alpha, interleukin-6, transforming growth factor beta and platelet-derived growth factor-beta). However, hAECs did not significantly alter changes to alveolar airspace volume, septal tissue volume, tissue-to-airspace ratio, collagen content or leukocyte infiltration induced by hyperoxia. CONCLUSIONS: Intraperitoneal administration of hAECs to neonatal mice partially reduced hyperoxia-induced lung inflammation and structural lung damage. These observations suggest that hAECs may be a potential therapy for neonatal lung disease. PMID- 23643417 TI - Chromosomal aberrations and deoxyribonucleic acid single-strand breaks in adipose derived stem cells during long-term expansion in vitro. AB - BACKGROUND AIMS: Adipose-derived stem cells (ASCs) are a promising mesenchymal cell source for tissue engineering approaches. To obtain an adequate cell amount, in vitro expansion of the cells may be required in some cases. To monitor potential contraindications for therapeutic applications in humans, DNA strand breaks and chromosomal aberrations in ASCs during in vitro expansion were examined. METHODS: After isolation of ASC from human lipoaspirates of seven patients, in vitro expansion over 10 passages was performed. Cells from passages 1, 2, 3, 5 and 10 were used for the alkaline single-cell microgel electrophoresis (comet) assay to detect DNA single-strand breaks and alkali labile as well as incomplete excision repair sites. Chromosomal changes were examined by means of the chromosomal aberration test. RESULTS: During in vitro expansion, ASC showed no DNA single-strand breaks in the comet assay. With the chromosomal aberration test, however, a significant increase in chromosomal aberrations were detected. CONCLUSIONS: The study showed that although no DNA fragmentation could be determined, the safety of ASC cannot be ensured with respect to chromosome stability during in vitro expansion. Thus, reliable analyses for detecting ASC populations, which accumulate chromosomal aberrations or even undergo malignant transformation during extensive in vitro expansion, must be implemented as part of the safety evaluation of these cells for stem cell-based therapy. PMID- 23643418 TI - Complications of pacemaker therapy in adults with congenital heart disease: a multicenter study. AB - BACKGROUND: This study aims to investigate indications and complications of permanent cardiac pacing in adults with congenital heart disease (CHD). METHODS AND RESULTS: Two-hundred and seventy-four CHD patients were identified who underwent permanent pacemaker implantation between 1972 and 2009. The indication for pacing was acquired sinus node or AV node conduction disease (63%), sinus node or AV node conduction disease after cardiac surgery (28%), and drug/arrhythmia-related indications (9%). Patients with complex CHD received a pacemaker at younger age (23 versus 31 years, p<0.0001) and more often received an epicardial pacing system (51% versus 23%, p<0.0001) compared to those with simple or moderate CHD. Twenty-nine patients (10.6%) had a periprocedural complication during the primary pacemaker implantation (general population: 5.2%). The most common acute complications were lead dysfunction (4.0%), bleeding (2.6%), pocket infection (1.5%) and pneumothorax (1.5%). During a median follow up of 12 years, pacemaker-related complications requiring intervention occurred in 95 patients (34.6%). The most common late pacemaker-related complications included lead failure (24.8%), pacemaker dysfunction/early battery depletion (5.1%), pacemaker migration (4.7%) and erosion (4.7%). Pacemaker implantation at younger age (<18 years) was an independent predictor of late pacemaker-related complication (adjusted hazard ratio 1.68, 95% confidence interval 1.07 to 2.63, p=0.023). CONCLUSIONS: The risk of periprocedural complications seems higher in the CHD population compared to the general population and more than one-third of CHD patients encountered a pacemaker-related complication during long-term follow up. This risk increases for those who receive a pacemaker at younger age. PMID- 23643419 TI - Sensitivity and specificity of commonly used EKG criterion to assess left ventricular hypertrophy in centenarians. PMID- 23643420 TI - Natural angioplasty as a mechanical effect of exercise. PMID- 23643421 TI - Avicenna's view on the prevention of thrombosis. PMID- 23643422 TI - Newly identified synergy between clopidogrel and calcium-channel blockers for blood pressure regulation possibly involves CYP2C19 rs4244285. PMID- 23643423 TI - The prediction of one-year mortality in elderly congestive heart failure patients: a clinical score. PMID- 23643424 TI - Drug-eluting balloons for coronary artery disease: an updated meta-analysis of randomized controlled trials. PMID- 23643425 TI - Exercise-resembling effects of periodic somatosensory stimulation in heart failure. AB - BACKGROUND: The mechanism of the beneficial effects of exercise training on autonomic derangement and neurohumoral activation in chronic heart failure (CHF) is largely unexplained. In our here-presented hypothesis-generating study we propose that part of these effects is mediated by the exercise-accompanying somatosensory nerve traffic. To demonstrate this, we compared the effects of periodic electrical somatosensory stimulation in patients with CHF with the effects of exercise training and with usual care. METHODS: In a randomized controlled study we measured, in CHF patients, changes in blood pressure, baroreflex sensitivity (BRS), neurohormones, exercise capacity and quality of life (QOL) in response to periodic somatosensory stimulation in the form of 2 Hz transcutaneous electrical nerve stimulation (TENS) at both feet, in response to conventional exercise training (EXTR) and, as control (CTRL), in patients with usual care only. RESULTS: Group sizes were N=31 (TENS group), N=25 (EXTR group) and N=30 (CTRL group), respectively. Practically all improvements in BRS, neurohormone concentrations, exercise capacity and QOL in the TENS group were comparable to, or sometimes even better than in the EXTR group. These improvements were not observed in the CTRL group. CONCLUSIONS: This study demonstrates that periodic electrical somatosensory stimulation is as effective as exercise training in improving BRS, neurohormone concentrations, exercise capacity and QOL in CHF patients. These results encourage exploration of exercise modalities that concentrate on rhythm rather than on effort, with the purpose to normalize autonomic derangement and neurohumoral activation in CHF. PMID- 23643426 TI - Primary angioplasty limited to the culprit vessel in patients with multivessel disease: impact on clinical outcomes. PMID- 23643428 TI - Avicenna's description of Willis circle. PMID- 23643427 TI - Right atrial area and right ventricular outflow tract akinetic length predict sustained tachyarrhythmia in repaired tetralogy of Fallot. AB - AIMS: Repaired tetralogy of Fallot (rtoF) patients are at risk of atrial or ventricular tachyarrhythmia and sudden cardiac death. Risk stratification for arrhythmia remains difficult. We investigated whether cardiac anatomy and function predict arrhythmia. METHODS: One-hundred-and-fifty-four adults with rtoF, median age 30.8 (21.9-40.2) years, were studied with a standardised protocol including cardiovascular magnetic resonance (CMR) and prospectively followed up over median 5.6 (4.6-7.0) years for the pre-specified endpoints of new-onset atrial or ventricular tachyarrhythmia (sustained ventricular tachycardia/ventricular fibrillation). RESULTS: Atrial tachyarrhythmia (n=11) was predicted by maximal right atrial area indexed to body surface area (RAAi) on four-chamber cine-CMR (Hazard ratio 1.17, 95% Confidence Interval 1.07-1.28 per cm(2)/m(2); p=0.0005, survival receiver operating curve; ROC analysis, area under curve; AUC 0.74 [0.66-0.81]; cut-off value 16 cm(2)/m(2)). Atrial arrhythmia-free survival was reduced in patients with RAAi >=16 cm(2)/m(2) (logrank p=0.0001). Right ventricular (RV) restrictive physiology on echocardiography (n=38) related to higher RAAi (p=0.02) and had similar RV dilatation compared with remaining patients. Ventricular arrhythmia (n=9) was predicted by CMR RV outflow tract (RVOT) akinetic area length (Hazard ratio 1.05, 95% Confidence Interval 1.01-1.09 per mm; p=0.003, survival ROC analysis, AUC 0.77 [0.83-0.61]; cut-off value 30 mm) and decreased RV ejection fraction (Hazard ratio 0.93, 95% Confidence Interval 0.87-0.99 per %; p=0.03). Ventricular arrhythmia-free survival was reduced in patients with RVOT akinetic region length >30 mm (logrank p=0.02). CONCLUSION: RAAi predicts atrial arrhythmia and RVOT akinetic region length predicts ventricular arrhythmia in late follow-up of rtoF. These are simple, feasible measurements for inclusion in serial surveillance and risk stratification of rtoF patients. PMID- 23643429 TI - STEMI and NSTEMI: a mono versus a multivessel disease? PMID- 23643430 TI - Temporal change of leukocytes and chemokines in aortic dissection patient: relationship to regional lesion on aorta. PMID- 23643431 TI - Acute effect of isometric resistance exercise on blood pressure of normotensive healthy subjects. PMID- 23643432 TI - Sex hormone changes and its relationship with cardiovascular risk factors and major adverse cardiac events in old patients with castrated prostatic cancer. PMID- 23643433 TI - Conscious sedation and analgesia for cardiac device implantation: anesthesiologist or not? PMID- 23643435 TI - Electron microscopy in patients with clinically suspected of cardiac amyloidosis who underwent endomyocardial biopsy and negative Congo red staining. PMID- 23643434 TI - Incidental diagnosis of cor triatriatum and ventricular septal defect in the elderly. PMID- 23643436 TI - A missense mutation G109R in the PROC gene associated with type I protein C deficiency in a young Polish man with acute myocardial infarction. PMID- 23643437 TI - Cardiovascular readmissions and excess costs following percutaneous coronary intervention in patients with chronic kidney disease: data from a large multi centre Australian registry. AB - BACKGROUND: Chronic kidney disease (CKD) is a well-established risk factor for adverse events in patients undergoing percutaneous coronary intervention (PCI). However, few data exists on the subsequent healthcare resource use and related incremental costs in this patient subgroup. The present study compares the rates of cardiac-related hospitalisations and the associated direct costs, post-PCI in patients with and without CKD. METHODS: Healthcare costs were estimated for 12,998 PCI patient-procedures from the Melbourne Interventional Group (MIG) registry, collected between February 2004 and October 2010. Information collected included the use of cardiovascular drugs and cardiac-related hospitalisations from those that completed 12-month follow-up. Individual patients were assigned unit costs based on published data from the National Hospital Cost Data Collection for Admissions in Victoria (2008-2009) and the Pharmaceutical Benefit Scheme (PBS) schedule (2011-2012). Bootstrap multiple linear regression was used to estimate the direct excess healthcare costs, adjusting for age and gender and relevant comorbidities. RESULTS: Excess cardiac-related readmissions occurred among patients with "severe CKD or dialysis" (estimated glomerular filtration rate (eGFR): <30 ml/min/1.73 m(2); n = 330; 35%), compared to "moderate CKD" (eGFR: 30-60 ml/min/1.73 m(2); n = 2648; 28%), or the "referent CKD status" (eGFR: >= 60 ml/min/1.73 m(2); n = 10,020; 24%). On average, excess (95%CI) overall direct costs were significantly higher in patients with severe CKD or dialysis compared to those with referent CKD status [$AUD 2206 ($AUD 1148 to 3688)]. CONCLUSIONS: From the healthcare payer's perspective, PCI patients with severe CKD compared to no-CKD imposed significantly higher burden on subsequent healthcare resources. Hospitalisations accounted for the majority of these expenditures. PMID- 23643438 TI - Clinical use of microvolt T-wave alternans in patients with depressed left ventricular function eligible for ICD implantation: mortality outcomes after long term follow-up. PMID- 23643439 TI - Shortest door-to-balloon time in primary percutaneous coronary intervention for a young resident physician suffering from in-hospital inferior ST-segment elevation myocardial infarction. PMID- 23643440 TI - Diagnostic value of portable electrocardiogram (Cardiophone) in patients complaining of palpitation. PMID- 23643441 TI - The effectiveness of footwear as an intervention to prevent or to reduce biomechanical risk factors associated with diabetic foot ulceration: a systematic review. AB - AIM: Footwear interventions are used within clinical practice in an effort to reduce ulcerations however the effectiveness of these interventions is unclear. The aim of this paper was to conduct a systematic review which examined the effectiveness of footwear as an intervention for prevention of diabetic foot ulcers or the reduction of biomechanical risk factors for ulceration and to discuss the quality and interpret the findings of research to date. METHODS: The CINAHL, Medline and Cochrane Register of Controlled Trials databases were searched with 12 articles identified for review. RESULTS: The majority of these studies were cross sectional and examined the effect of different footwear conditions on plantar pressure measurements. Factors which influenced study findings such as participant selection, measurement and analysis techniques, footwear design and compliance are discussed and recommendations for future studies are provided. CONCLUSIONS: No research to date has examined the effectiveness of footwear in preventing ulceration. Conflicting findings are reported on the effective of footwear interventions to prevent reulceration. While the use of rocker sole footwear and custom orthoses in plantar pressure reduction are supported in cross sectional studies, longitudinal studies are required to confirm their benefit. PMID- 23643446 TI - Economic models for evaluating plastic surgery ideas. PMID- 23643445 TI - Different patterns of cerebellar abnormality and hypomyelination between POLR3A and POLR3B mutations. AB - BACKGROUND: Mutations of POLR3A and POLR3B have been reported to cause several allelic hypomyelinating disorders, including hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome). PATIENTS AND METHODS: To clarify the difference in MRI between the two genotypes, we reviewed MRI in three patients with POLR3B mutations, and three with POLR3A mutations. RESULTS: Though small cerebellar hemispheres and vermis are common MRI findings with both types of mutations, MRI in patients with POLR3B mutations revealed smaller cerebellar structures, especially vermis, than those in POLR3A mutations. MRI also showed milder hypomyelination in patients with POLR3B mutations than those with POLR3A mutations, which might explain milder clinical manifestations. CONCLUSIONS: MRI findings are distinct between patients with POLR3A and 3B mutations, and can provide important clues for the diagnosis, as these patients sometimes have no clinical symptoms suggesting 4H syndrome. PMID- 23643443 TI - Tract-specific white matter correlates of fatigue and cognitive impairment in benign multiple sclerosis. AB - BACKGROUND: Although benign multiple sclerosis (BMS) is traditionally defined by the presence of mild motor involvement decades after disease onset, symptoms of fatigue and cognitive impairment are very common. OBJECTIVE: To investigate the association between micro-structural damage in the anterior thalamic (AT) tracts and in the corpus callosum (CC), as measured by diffusion tensor imaging (DTI) tractography, and fatigue and cognitive deficits. METHODS: DTI data were acquired from 26 BMS patients and 24 sex- and age-matched healthy controls. RESULTS: General and mental fatigue scores were significantly impaired in patients compared with controls (p<=0.05 for both) and 38% of patients resulted cognitively impaired. Mean diffusivity (MD) of the AT and CC tracts was significantly higher and fractional anisotropy (FA) was lower in patients compared with controls (p<0.001 for all). Fatigue was associated with increased MD (p=0.01) of the AT tracts whereas deficit of executive functions and verbal learning were associated with decreased FA in the body (p=0.004) and genu (p=0.008) of the CC. Deficits in processing speed and attention were associated with the T2 lesion volume of the AT tracts (p<0.01 for all). DISCUSSION: These findings suggest that fatigue and cognitive impairment are quite frequent in BMS patients and are, at least in part, related to micro-structural damage and T2LV of WM tracts connecting the brain cortical and sub-cortical regions of the two hemispheres. PMID- 23643444 TI - Effector and memory T cell responses to commensal bacteria. AB - Barrier surfaces are home to a vast population of commensal organisms that together encode millions of proteins; each of them possessing several potential foreign antigens. Regulation of immune responses to this enormous antigenic load represents a tremendous challenge for the immune system. Tissues exposed to commensals have developed elaborate systems of regulation including specialized populations of resident lymphocytes that maintain barrier function and limit potential responses to commensal antigens. However, in settings of infection and inflammation these regulatory mechanisms are compromised and specific effector responses against commensal bacteria can develop. This review discusses the circumstances controlling the fate of commensal specific T cells and how dysregulation of these responses could lead to severe pathological outcomes. PMID- 23643447 TI - Evolutionary activism: Stephen Jay Gould, the New Left and sociobiology. PMID- 23643448 TI - Enhancing skills of critical reflection to evidence learning in professional practice. AB - Professional organisations and regulatory bodies are making critical reflection a mandatory component of professional practice. Reflection is a vital part of learning from experience and is central to developing and maintaining competency across a practitioner's lifetime. This paper will discuss key educational theories to illustrate why reflection is important. Kolb's and Gibbs' reflective cycles are used to structure the process of critical reflection. Elements of the educational tradition of Bildung are discussed and integrated to enrich the understanding of self and to facilitate the reader's ability to enhance their professional practice. PMID- 23643449 TI - Genesis of avian-origin H7N9 influenza A viruses. PMID- 23643450 TI - Cleaning assessment of disinfectant cleaning wipes on an external surface of a medical device contaminated with artificial blood or Streptococcus pneumoniae. AB - BACKGROUND: Improperly cleaned, disinfected, or sterilized reusable medical devices are a critical cause of health care-associated infections. More effective studies are required to address the improvement of cleaning and disinfection instructions, as well as selection of cleaning and disinfecting agents, for surfaces of reusable devices and equipment. METHODS: Six commercially available disinfectant cleaning wipes were evaluated for their effectiveness to remove a coagulated blood test soil or Streptococcus pneumoniae bacteria from the surface of a reusable medical device. Liquid aliquots of the coagulated blood or bacteria were dried onto the surface of the device and removed with the wipes. Effectiveness of the wipes was assessed by 3 methods: residual protein debris by o-phthaldialdehyde analysis, bacterial survival by adenosine triphosphate measurement, and force required to remove the dried debris by force measurement. RESULTS: A sodium hypochlorite wipe was most effective in removing protein debris from the device surface. All tested wipes were equivalent in disinfecting bacterial contamination from the device surface. CONCLUSION: The active ingredient, wipe design, and wipe wetness are important factors to consider when selecting a disinfectant cleaning wipe. Additionally, achieving conditions that effectively clean, disinfect, and/or inactivate surface bacterial contamination is critical to preventing the spread of health care-associated infections. PMID- 23643451 TI - Improving hand hygiene compliance in health care workers: Strategies and impact on patient outcomes. AB - BACKGROUND: We described a systematic process for improving hand hygiene (HH) compliance in health care providers and assessed the impact of HH on patient outcomes. METHODS: This retrospective cohort study was conducted between July 2008 and September 2011 in a children's hospital. We employed failure mode effectiveness analysis to identify barriers for complying with HH requirements and instituted improvement measures. We conducted a subanalysis using methicillin resistant Staphylococcus aureus (MRSA) acquisition data and HH compliance data collected in the neonatal intensive care unit (NICU) to demonstrate the impact of HH on patient outcomes. RESULTS: The overall HH compliance rate increased from 50.3% preintervention (July 2008-September 2008) to 84.0% postintervention (January 2009-September 2011) (relative risk [RR], 1.7; 95% confidence interval [CI]: 1.6-1.9). Compliance among physicians and nurses increased from 48.6% to 87.0% (RR, 1.4; 95% CI: 1.3-1.6) and from 46.5% to 77.9% (RR, 1.3; 95% CI: 1.2 1.4), respectively. Sustaining HH at 80% or higher was associated with a 48% further reduction of MRSA acquisition (incident rate ratio, -0.52; 95% CI: -0.31 to -0.90) in a unit that had comprehensive MRSA prevention measures. This reduction represents the prevention of 1.3 MRSA acquisitions per month, resulting in a saving of 11.6 NICU-days and $66,397 hospital charges. CONCLUSION: This study demonstrated the utility of failure mode effectiveness analysis to improve staff HH and suggested HH as a potential cost-effective means for preventing MRSA in hospitals. PMID- 23643452 TI - InPouchTM TF-Feline medium is not specific for Tritrichomonas foetus. AB - Trichomonads are a group of anaerobic flagellates. Two species of intestinal trichomonads have been described in cats - pathogenic Tritrichomonas foetus and probably harmless Pentatrichomonas hominis. InPouchTM TF-Feline medium (Bio-Med Diagnostics, White City, Oregon, USA) is considered the gold standard for diagnosis of T. foetus infection in cats. It is commercially available, relatively cheap and easy-to-use. The medium is intended to be highly specific to T. foetus as morphologically similar Pentatrichomonas hominis and Giardia sp. do not survive here longer than 24h. In this study we successfully cultivated P. hominis in InPouchTM TF-Feline medium for 3 days after inoculation with cat faeces. The identity of the organism was assessed by sequencing of SSU rDNA and ITS region. Possible coinfection with T. foetus was ruled out using Tritrichomonas-specific PCR. Our results suggest possible misdiagnosis of tritrichomonosis in cats using InPouchTM TF-Feline medium. PCR-based verification of culture-positive samples prior the potentially neurotoxic ronidazole treatment is recommended. PMID- 23643453 TI - Effects of Mimosa tenuiflora on larval establishment of Haemonchus contortus in sheep. AB - Anthelmintic resistance has limited the ability to control the gastrointestinal nematodes of small ruminants and has therefore awakened an interest in the study of tanniferous plants as a source of anthelmintics. This study was carried out to evaluate the effect of Mimosa tenuiflora intake, a tanniferous plant that is fed to small ruminants in northeastern Brazil, on the larval establishment of Haemonchus contortus in sheep. In this experiment, 18 nematode-free sheep were divided into three groups (n=6) according to live weight. Group 1 was fed M. tenuiflora leaves; Group 2 was fed M. tenuiflora stems; Group 3 served as the control group and was fed Cynodon dactylon, a plant with low levels of tannins. The animals consumed the plants for 13 days (Day -7 to Day 5). On Day 0, the sheep were experimentally infected with 4500 third-stage H. contortus each. Five days after infection (Day 5), the sheep were slaughtered to count the worm burden and perform a histological analysis of the abomasum. The daily plant intake and the live weight gain of the animals were recorded. The groups that ingested M. tenuiflora leaves and stems consumed less dry matter than did those that ingested C. dactylon (P<0.05). The consumption of M. tenuiflora leaves did not reduce the L3 establishment of H. contortus compared to the control (P>0.05). The intake of M. tenuiflora stems tended toward decreasing larval establishment, but the reduction was not significant (P>0.05). No significant differences were observed in the mucosal cellular response and live weight gain among the groups. These data demonstrated that, with the protocol used, M. tenuiflora has no effect on larval establishment of H. contortus in sheep. PMID- 23643454 TI - Presence of Cryptosporidium scrofarum, C. suis and C. parvum subtypes IIaA16G2R1 and IIaA13G1R1 in Eurasian wild boars (Sus scrofa). AB - The aim of the present study was to identify the species of Cryptosporidium infecting Eurasian wild boars (Sus scrofa) in Galicia (NW, Spain). A sampling of 209 wild boars shot in different game preserves was carried out during the hunting season in 2009-2010. All samples were examined for Cryptosporidium infection, using both immunological and molecular tools. Cryptosporidium oocysts in faecal samples were identified using a direct immunofluorescence technique with monoclonal antibodies (DFA). The presence of Cryptosporidium DNA was determined using nested PCR involving amplification of a fragment of the small subunit (SSU) ribosomal RNA gene (SSU rRNA). A total of 35 (16.7%) samples tested positive with both techniques. However, sequencing was only possible in 27 samples. Cryptosporidium scrofarum, Cryptosporidium suis and Cryptosporidium parvum oocysts were identified in 19, 5 and 3 of the samples, respectively. Moreover, C. scrofarum was detected as a dominant species infecting all age groups (juveniles, sub adults and adults). Sequence analyses of the glycoprotein (GP60) gene revealed the presence of C. parvum subtypes IIaA16G2R1 in 2 juveniles and IIaA13G1R1 in 1 sub adult wild boar. These species and subtypes have previously been described in human patients, indicating that isolates from asymptomatic wild boars might have zoonotic potential. This is the first report of the presence of C. scrofarum, C. suis and C. parvum subtypes IIaA16G2R1 and IIaA13G1R1 in wild boars (S. scrofa) in Spain. PMID- 23643455 TI - Endogenous morphogens and fibrin bioscaffolds for stem cell therapeutics. AB - Clinical translation of mesenchymal stem cells (MSCs) is leading to optimization of procedures for ex vivo expansion. Endogenous growth factors and fibrin scaffolds can be used to support MSC expansion and transplantation. Cell growth on a fibrin scaffold mimics the 3D environment of tissue and facilitates handling and subsequent transplantation. This approach is presented as an essential toolbox in the substitution of fetal bovine serum in all large-scale ex vivo processes, providing quick and safe expansion of MSCs. This paper reviews the state of the art of platelet-rich plasma technology applied to clinical use of stem cells, focusing on current technology and methods, new challenges, and controversies. PMID- 23643457 TI - Implications of early treatment among Medicaid patients with Alzheimer's disease. AB - OBJECTIVE: The objective of this study was to examine the effect of treatment timing on risk of institutionalization of Medicaid patients with Alzheimer's disease (AD) and to estimate the economic implications of earlier diagnosis and treatment initiation. METHODS: New Jersey Medicaid claims data (1997-2009) were used retrospectively to study the effect of treatment on time to institutionalization. Observed Medicaid payments were used to calculate savings from delayed institutionalization, adjusting for cost offsets resulting from concurrent changes in use of other medical services. RESULTS: Initiation of existing therapies at earliest symptomatic onset is predicted to delay institutionalization by 91 days, reducing Medicaid costs by $19,108/institutionalized patient. Incorporating an 18.5% cost offset from increased use of other medical services as well as drug costs associated with earlier treatment results in net savings of $12,687/patient. Projected annual Medicaid savings exceed $1 billion. CONCLUSION: Earlier treatment leads to a small delay in institutionalization among AD patients, resulting in significant costs savings to Medicaid. PMID- 23643456 TI - Risk factors for mild cognitive impairment among Mexican Americans. AB - BACKGROUND: Although a great deal of literature has focused on risk factors for mild cognitive impairment (MCI), little published work examines risk for MCI among Mexican Americans. METHODS: Data from 1628 participants (non-Hispanic n = 1002; Mexican American n = 626) were analyzed from two ongoing studies of cognitive aging and Alzheimer's disease, Project FRONTIER (Facing Rural Obstacles to health Now Through Intervention, Education & Research) and TARCC (Texas Alzheimer's Research & Care Consortium). RESULTS: When looking at the full cohorts (non-Hispanic and Mexican American), age, education, Apolipoprotein E (APOE) epsilon4 status and gender were consistently related to MCI diagnosis across the two cohorts. However, when split by ethnicity, advancing age was the only significant risk factor for MCI among Mexican Americans across both cohorts. CONCLUSIONS: The current data suggest that many of the previously established risk factors for MCI among non-Hispanic cohorts may not be predictive of MCI among Mexican Americans and point to the need for additional work aimed at understanding factors related to cognitive aging among this underserved segment of the population. PMID- 23643458 TI - Evaluation of memory endophenotypes for association with CLU, CR1, and PICALM variants in black and white subjects. AB - BACKGROUND: Genetic variants at the CLU, CR1, and PICALM loci associate with risk for late-onset Alzheimer's disease (LOAD) in genomewide association studies. In this study, our aim was to determine whether the LOAD risk variants at these three loci influence memory endophenotypes in black and white subjects. METHODS: We pursued an association study between single nucleotide polymorphism genotypes at the CLU, CR1, and PICALM loci and memory endophenotypes. We assessed black subjects (AA series: 44 with LOAD and 224 control subjects) recruited at Mayo Clinic Florida and whites recruited at Mayo Clinic Minnesota (RS series: 372 with LOAD and 1690 control subjects) and Florida (JS series: 60 with LOAD and 529 control subjects). Single nucleotide polymorphisms at the LOAD risk loci CLU (rs11136000), CR1 (rs6656401, rs3818361), and PICALM (rs3851179) were genotyped and tested for association with Logical Memory immediate recall, Logical Memory delayed recall, Logical Memory percent retention, Visual Reproduction immediate recall, Visual Reproduction delayed recall, and Visual Reproduction percent retention scores from the Wechsler Memory Scale-Revised using multivariable linear regression analysis, adjusting for age at exam, sex, education, and apolipoprotein E epsilon4 dosage. RESULTS: We identified nominally significant or suggestive associations between the LOAD-risky CR1 variants and worse Logical Memory immediate recall scores in blacks (P = .068-.046, beta = -2.7 to -1.2). The LOAD-protective CLU variant is associated with better logical memory endophenotypes in white subjects (P = .099-.027, beta = 0.31-0.93). The CR1 associations persisted when the control subjects from the AA series were assessed separately. The CLU associations appeared to be driven by one of the white series (RS) and were also observed when the control subset from RS was analyzed. CONCLUSION: These results suggest for the first time that LOAD risk variants at CR1 may influence memory endophenotypes in blacks. In addition, the CLU LOAD protective variant may confer enhanced memory in whites. Although these results would not remain significant after stringent corrections for multiple testing, they need to be considered in the context of the LOAD associations with which they have biological consistency. They also provide estimates for effect sizes on memory endophenotypes that could guide future studies. The detection of memory effects for these variants in clinically normal subjects, implies that these LOAD risk loci might modify memory prior to clinical diagnosis of AD. PMID- 23643461 TI - Hybridisation between the two major African schistosome species of humans. AB - It is generally accepted that Schistosoma mansoni and Schistosoma haematobium, causing intestinal and urinary schistosomiasis, respectively, are not able to hybridise, due to the high phylogenetic distance between them. Cloning of nuclear internal transcribed spacer rDNA and partial mitochondrial cytochrome c oxidase 1 fragments revealed two internal transcribed spacer rDNA genotypes within single eggs and miracidia, one identical to S. mansoni and the other identical to S. haematobium, suggesting hybrid ancestry. The cytochrome c oxidase 1 clones always belonged to only one of the parental species. This demonstrates that offspring of heterologous pairing between these two species is not (always) parthenogenetic. PMID- 23643459 TI - Differences in rate of functional decline across three dementia types. AB - BACKGROUND: The purpose of this study was to estimate differences in rates of functional decline in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular dementia (VaD) and whether differences vary by age or sex. METHODS: Data came from 32 U.S. Alzheimer's Disease Centers. The cohort of participants (n = 5848) were >=60 years of age and had clinical dementia with a primary etiologic diagnosis of probable AD, DLB, or probable VaD; a Clinical Dementia Rating-Sum of Boxes score <16; and a duration of symptoms <=10 years. Dementia diagnoses were assigned using standard criteria. Annual mean rate of change of the Functional Activities Questionnaire (FAQ) score was modeled using multiple linear regression with generalized estimating equations adjusted for demographics, comorbidities, years since onset, and cognitive status (mean follow-up = 2.0 years). RESULTS: FAQ declined more slowly over time in those with VaD compared with AD (difference in mean annual rate of change: -0.91; 95% confidence interval [CI]: -1.68, 0.14). VaD participants also declined at a slower rate than DLB participants, but this difference was not statistically significant (-0.61; 95% CI: -1.45, 0.24). There was no significant difference between DLB and AD. Within each group, rate of decline was more rapid for the youngest participants. CONCLUSIONS: In this sample, findings suggested that VaD patients declined in their functional abilities at a slower rate compared with AD patients and that there were no significant differences in rate of functional decline between patients with DLB compared with those with either AD or VaD. These results may provide guidance to clinicians about average expected rates of functional decline in three common dementia types. PMID- 23643463 TI - Neuroimaging and electroencephalographic changes after vagus nerve stimulation in a boy with medically intractable myoclonic astatic epilepsy. AB - Myoclonic astatic epilepsy (MAE) is characterized by multiple seizure types, which are often refractory. Although vagus nerve stimulation (VNS) is an alternative treatment for medically intractable seizures, its exact mechanism of action remains unclear. Herein, we report the case of a 4-year-old boy with intractable MAE who has been in a seizure-free status for 2 years and 3 months since 6 months after the implantation of a vagus nerve stimulator (Model 103, Cyberonics, Inc., Houston, TX). Various test results 6 months after VNS were compared with those before VNS. Results of an electroencephalograph revealed disappearance of epileptiform discharges and an increased beta-gamma spectrum rhythm. The brain diffusion-tensor imaging showed an increased ratio of fraction anisotropy in the right fimbria-fornix, indicating improved diffusion of the white matter tract, and (18)F-fluorodeoxyglucose positron emission tomography revealed globally improved cerebral glucose metabolism. His cognitive and social emotional performances also improved at 2 years after VNS. To the best of our knowledge, this is the first report to describe the effects of VNS on fimbria fornix and glucose metabolism in MAE. PMID- 23643464 TI - Role of the supplementary motor area in the automatic activation of motor plans in de novo Parkinson's disease patients. AB - The role of the basal ganglia-cortical motor loop in automatic and unconscious motor processes is poorly understood. Here, we used event-related functional magnetic resonance imaging in 11 de novo Parkinson's disease patients as they performed a visuomotor masked priming task. The stronger subliminal priming effect for the non-dominant side of motor symptoms than for the dominant side was paralleled by stronger supplementary motor area proper activity in response to lateralized visual stimuli presented below the threshold of awareness. This novel result supports the prediction that this area is involved in the automatic activation of motor plans as a function of striatal dopamine levels. PMID- 23643466 TI - Effects of aging in postural strategies during a seated auto-stabilization task. AB - Impaired sensory, motor and central processing systems combining with biomechanical changes are risk of fall factors in the elderly population. The aim of this study was to assess the auto-adaptation and the regulation of the dynamic control of equilibrium in age-related adaptive strategies, by using a seated position on a seesaw. 15 young adults and 12 healthy middle-aged adults were asked to actively maintain a sitting posture as stable as possible during 12.8s, on a 1-degree of freedom seesaw (auto-stabilization paradigm), with and without vision. The seesaw was placed in order to allow roll or pitch oscillations. We determine length and surfaces CoP shifts, mean positions and variability, a Postural Performance Index (PI) and a Strategy Organization Ratio (SOR). Our results shows that adopted strategies are plane-dependant during auto stabilization (parallel and perpendicular axes control is impacted) and age dependant. PIx during roll seated auto-stabilization tasks appears as the most relevant parameter of aged-related instability. The visual effect, during pitch auto-stabilization, characterizes the postural sensory-motor human behavior. The quantitative and qualitative postural assessment, thanks to seated auto stabilization task, need to be promoted for long-term health care and probably for the rehabilitation of various disorders. PMID- 23643467 TI - Influence of the knee flexion on muscle activation and transmissibility during whole body vibration. AB - The influence of the knee flexion on muscle activation and transmissibility during whole body vibration is controversially discussed in the literature. In this study, 34 individuals had electromyography activity (EMG) of the vastus lateralis and the acceleration assessed while squatting with 60 degrees and 90 degrees of knee flexion either with or without whole-body vibration (WBV). The conditions were maintained for 10s with 1min of rest between each condition. The main findings were (1) the larger the angle of knee flexion (90 degrees vs. 60 degrees ), the greater the EMG (p<0.001), with no difference on acceleration transmissibility; (2) for both angles of knee flexion, the addition of WBV produced no significant difference in EMG and higher acceleration compared to without WBV (p<0.001). These results suggest that the larger the knee flexion angle (60 degrees vs. 90 degrees ), the greater the muscle activation without acceleration modification. However, the addition of WBV increases the transmissibility of acceleration in the lower limbs without modification in EMG of vastus lateralis. PMID- 23643465 TI - The apical ES-BTB-BM functional axis is an emerging target for toxicant-induced infertility. AB - Testes are sensitive to toxicants, such as cadmium and phthalates, which disrupt a local functional axis in the seminiferous epithelium known as the 'apical ectoplasmic specialization (apical ES)-blood-testis barrier (BTB)-basement membrane (BM)'. Following exposure, toxicants contact the basement membrane and activate the Sertoli cell, which perturbs its signaling function. Thus, toxicants can modulate signaling and/or cellular events at the apical ES-BTB-BM axis, perturbing spermatogenesis without entering the epithelium. Toxicants also enter the epithelium via drug transporters to potentiate their damaging effects, and downregulation of efflux transporters by toxicants impedes BTB function such that toxicants remain in the epithelium and efficiently disrupt spermatogenesis. These findings support a novel model of toxicant-induced disruption of spermatogenesis that could be interfered with using small molecules. PMID- 23643469 TI - Combined dementia-risk biomarkers in Parkinson's disease: a prospective longitudinal study. AB - Neuropsychological (mostly posterior-cortical) deficits, quantitative magnetic resonance imaging (MRI) atrophy patterns, and low cerebrospinal fluid (CSF) levels of amyloid-beta have been separately related to worsening cognition in Parkinson's disease (PD). However, these biomarkers have not been longitudinally assessed in combination as PD-dementia predictors. In this prospective longitudinal study, 27 non-demented PD patients underwent CSF, neuropsychological and 3-T brain-MRI studies at baseline and were re-assessed 18 months later in terms of progression to dementia (primary outcome) and longitudinal neuropsychological and cortical thickness changes (secondary outcomes). At follow up 11 patients (41%) had progressed to dementia. Lower CSF amyloid-beta, worse verbal learning, semantic fluency and visuoperceptual scores, and thinner superior-frontal/anterior cingulate and precentral regions were significant baseline dementia predictors in binary logistic regressions as quantitative and/or dichotomised traits. All participants without baseline biomarker abnormalities remained non-demented whereas all with abnormalities in each biomarker type progressed to dementia, with intermediate risk for those showing abnormalities in a single to two biomarker types (p = 0.006). Both the dementia outcome and low baseline CSF amyloid-beta were prospectively associated with limbic and posterior-cortical neuropsychological decline and frontal, limbic and posterior-cortical thinning from baseline to follow-up. These findings suggest that the combination of CSF amyloid-beta, neuropsychological and cortical thickness biomarkers might provide a basis for dementia-risk stratification and progression monitoring in PD. PMID- 23643468 TI - [Mycotic aneurysm of the superior mesenteric artery: should it have been operated earlier?]. PMID- 23643471 TI - Health beneficial long chain omega-3 fatty acid levels in Australian lamb managed under extensive finishing systems. AB - The variation in levels of the health claimable long chain omega-3 fatty acids, eicosapentaenoic acid (EPA, 20:5n-3) plus docosahexaenoic acid (DHA, 22:6n-3) across production regions of Australia was studied in 5726 lambs over 3 years completed in 87 slaughter groups. The median level of EPA plus DHA differed dramatically between locations and sometimes between slaughters from the same location. The ratio of EPA plus DHA from lambs with high values (97.5% quantile) to lambs with low values (2.5% quantile) also differed dramatically between locations, and between slaughters from the same location. Consistency between years, at a location, was less for the high to low value ratio of EPA plus DHA than for the median value of EPA plus DHA. To consistently obtain high levels of omega-3 fatty acids in Australian lamb, there must be a focus on lamb finishing diets which are likely to need a supply of alpha-linolenic acid (18:3n-3), the precursor for EPA and DHA. PMID- 23643470 TI - Induced pluripotent stem cells as a new strategy for cardiac regeneration and disease modeling. AB - The possibility to induce pluripotency in somatic cells or, even further, to induce cell transdifferentiation through the forced expression of reprogramming factors has offered new, attractive options for cardiovascular regenerative medicine. In fact, recent discoveries have demonstrated that induced pluripotent stem (iPS) cells can be differentiated into cardiomyocytes, suggesting that iPS cells have the potential to significantly advance future cardiac regenerative therapies. Herein, we provide an overview of the characteristics and differentiation potential associated with iPS cells. In addition, we discuss current methods for inducing their specification towards a cardiovascular phenotype as well as in vivo evidence supporting the therapeutic benefit of iPS derived cardiac cells. Finally, we describe recent findings regarding the use of iPS-derived cells for modeling several genetic cardiac disorders, which have indicated that these pluripotent cells represent an ideal tool for drug testing and might contribute to the development of future personalized regenerative cell therapies. PMID- 23643472 TI - Exotic protein sources to meet all needs. AB - Venison from farmed deer has by now become common on the market. This follows the application of animal husbandry techniques to ensure a controlled supply of quality meat. Numerous studies discussed in this presentation have elucidated some of the factors that influence the meat composition and quality derived from various deer species. On the other hand, meat from wild, free-roaming animals has not yet reached a similar position in the industry and in the mind of the consumer. Yet these species show great potential, especially as pertaining to their meat production when discussed under the global warming scenario. In particular, the rodent species that are currently utilized in the bushmeat trade show potential for meat production. This presentation will endeavor to discuss the positive and negative aspects of these species as potential meat sources. PMID- 23643474 TI - Scotblood 2012: transfusion/transplant medicine in the 2nd decade of the 21st century. AB - Transfusion medicine is a technology-based discipline, undergoing continual changes for improvement. It requires staff at all levels to be continually educated and trained in appropriate multidisciplinary skills, in line with the rapid developments in all areas of transfusion practice: from blood/organ collection, through processing and storage to the more advanced cellular and hospital-based transfusion/transplantation therapies. Whilst the majority of the challenges to improve hospital and general transfusion practice can be overcome through team work, education, timely objectives and perseverance, it is important to envisage opportunities for implementing digital technologies to reduce all of the applicable hazards associated with transfusion. These can vary widely from new and emerging pathogens to limitations of supply due to growing demographic changes in populations. In the first decade of 21st century we have already witnessed unprecedented advances in haematopoietic stem cell transplantation to minimise the toxicities of graft versus host disease (GvHD), and in cell therapy to explore immunotherapy against cancer and other malignant disorders. Today there are 1000 genome project hapmaps that only the extreme cost of their implementation to routine practices may limit. Transfusion medicine, like all disciplines of medicine, nevertheless, will face difficult choices between increasing healthcare technology and increasing worldwide health. Drs. Colligan and McGowan, the new lead organisers of this wonderful yearly educational programme have agreed to follow the previous organisers' strategy to make a summary report of their meeting to become available, through TRASCI to broader interested groups, with the sprit that "sharing is caring". The main highlights of the 2012 conference were: targeting transfusion practices in hospital, a continuing journey; emerging infections and the potential causes and possible remedial actions; building for the future; the challenging issues of donor recruitment/retention; and finally; the application of Information Technology as a decision making tool, utilising clinical audit monitoring to evaluate good practice. This year's conference also coincided with the retirement of Martin Bruce OBE, after his 41years distinguished career, who gave the most delightful and humorous talk of a" life time of learning" which delighted all the participants. Finally, 2012 also marked the retirements of the previous lead Scotblood organisers Prof. Robin Fraser and Dr. Hagop Bessos after over thirty years service to SNBTS, and to whom we would like to dedicate this meeting report and wish them a happy and healthy retirement. This commentary comprises summaries of the presentations, based in part on the abstracts provided by the speakers. PMID- 23643473 TI - Feasibility of applying the 2day deferral for repeat plateletpheresis: Indian perspective. AB - As the use of single donor apheresis platelets and plateletpheresis procedures done steadily increases in India, the plateletpheresis donors are at an increased risk of postpheresis anemia and thrombocytopenia. This study was planned in order to evaluate the effect of plateletpheresis on the hematological parameters in the local donor population and to evaluate the possibility of following the 2day deferral for repeat plateletpheresis. A total of 60 plateletpheresis procedures performed over a period of 1year with CS 3000 Plus Baxter Fenwal were evaluated. All the post-donation hematological parameters showed a significant decrease from the pre-donation values (p<0.001). Post-donation hemoglobin <12g, which is defined by WHO as anemia irrespective of the gender occurred in 25% (n=15) of the donors. The post-donation platelet count was less than 100*10(9)/L in 16.6% (n=10) of the procedure. The ability of these donors to serve as repeat plateletpheresis donor after 2days as recommended by AABB needs to be evaluated by further studies done post donation. Keeping in view the hematological profile of our donor population we recommend that donors who already have a low or borderline pre-donation platelet count and hemoglobin should be assessed and monitored post-donation for decrements in these parameters. While serving as repeat donors, their pre donation hemoglobin and platelet counts should be tested again. PMID- 23643475 TI - Which regimen is better for stem cell mobilization of lymphoma patients? AB - Although chemotherapy combined with G-CSF is an effective method for hematopoietic stem cell mobilization, standard chemotherapy protocol leading to best stem cell yield is not defined. In our study, we aimed to assess the impact of chemotherapy choice on mobilization outcome in lymphoma patients. Patients were mobilized with cyclophosphamide (n:15), ASHAP (n:11) or VGEPP (n:12) protocols. Groups were similar according to collected CD34+ cell count, total nucleated cell count and median apheresis days. Five out of fifteen (33%) patients could not be mobilized in Cy group but there was only one failed mobilization attempt in both salvage groups (9% with ASHAP vs 8% with VGEPP). In conclusion, we showed that VGEPP and ASHAP are safe protocols in terms of stem cell mobilization and have similar mobilization capacity as cyclophosphamide alone. PMID- 23643476 TI - Effect of different substrata on rhizome growth, leaf biometry and shoot density of Posidonia oceanica. AB - The effects of different substratum typologies on Posidonia oceanica growth and morphology were estimated in four Sicilian meadows using Generalized and Linear Mixed Models combined with retrodating and biometric analyses. Substratum exerted a multiple effect, resulting in different biometric features for P. oceanica shoots settled on rock from those growing on sand and matte. On rock, values for growth rate, leaf length and shoot surface were lower than those on other substrata, with 42%, 23% and 32% the highest degree of difference respectively. The present study may have interesting methodological consequences for the comprehensive understanding of the causative variables potentially affecting meadows features and their health status. The importance of substratum in the prediction of likely biometry changes in P. oceanica meadows, means that knowledge of substratum type should receive due attention in the future to derive reliable estimates of meadow status. PMID- 23643477 TI - Strategies to improve recruitment and retention of older stroke survivors to a randomized clinical exercise trial. AB - BACKGROUND: Relatively few exercise randomized clinical trials (RCTs) among stroke survivors have reported the effectiveness of recruitment and retention strategies, despite its central importance to study integrity. OBJECTIVE: Our objective is to examine recruitment and retention strategies used among a group of older community-dwelling stroke survivors for an exercise RCT. METHODS: Recruitment strategies were multidimensional using both paid (ie, newspaper, radio and, television) and unpaid advertisements (ie, staff visits, flyers, and brochures placed at outpatient rehabilitation centers, physician offices, and community facilities working with older adults; free media coverage of the study, presentations at stroke support groups, relatives/friends, and study Web site) to obtain referrals. Retention strategies centered on excellent communication, the study participants' needs, and having dedicated study staff. Attrition rates and adherence to the intervention were used to examine the effectiveness of these retention strategies. RESULTS: A total of 393 referrals were received, 233 persons were screened, and 145 stroke survivors enrolled in the study. During 3 years of study recruitment, we achieved 97% of our enrollment target. We enrolled 62% of those screened. Study enrollment from paid advertising was 21.4% (n = 31), whereas unpaid advertisements resulted in 78.6% (n = 114) of our participants. Attrition was 10% (n = 14 dropouts), and adherence to the intervention was 85%. CONCLUSIONS: Recruitment and retention of participants in an exercise RCT are time and labor intensive. Multiple recruitment and retention strategies are required to ensure an adequate sample of community-dwelling stroke survivors. Many of these strategies are also relevant for exercise RCTs among adults with other chronic illnesses. PMID- 23643478 TI - Nonaneurysmal subarachnoid hemorrhage after udenafil intake. AB - We report a 67-year-old man who presented with severe headache after taking 50 mg of udenafil, a new phosphodiesterase 5 inhibitor. Computed tomographic imaging of the brain revealed a small amount of acute subarachnoid hemorrhage localized around basal cisterns (anterior to midbrain and pons). There were no aneurysms in the cerebral arteries, although vein of Galen stenosis was suspected after magnetic resonance venography. This case anecdotally suggests that phosphodiesterase 5 inhibition might trigger perimesencephalic subarachnoid hemorrhage with venous hypertension possibly associated with vein of Galen stenosis. PMID- 23643480 TI - Test system for evaluating the influence of polymer properties on primary human keratinocytes and fibroblasts in mono- and coculture. AB - Interactions of cells with polymer-based biomaterials are influenced by properties of the substrate. Polymers, which are able to induce cell specific effects, gain increasing importance for biotechnology and regenerative therapies. A test system was developed, which allows studying primary human keratinocytes and fibroblasts in mono- and cocultures to analyze and operate the effect of polymer properties. This system offers to identify polymers for keratinocyte cultivation or wound dressings, since adherence, viability and functionality can be analyzed. Especially the coculture system enables the characterization of potential cell specific effects of polymer-based biomaterials. To establish a coculture test system, it is challenging to find a suitable culture medium, to identify initial seeding densities for comparable cell growth and to develop methods to distinguish and characterize both cell types. Poly(n-butyl acrylate) networks (cPnBAs) as model biomaterials were used to demonstrate the applicability of our newly developed coculture screening system for differential cell growth. The apparent Young's modulus of the cPnBAs differentially regulated fibroblasts and keratinocytes. Particularly, cPnBA73 with an apparent Young's modulus of 930+/-140 kPa measured in phosphate buffered saline (PBS) solution at ambient temperature seemed to have favoring properties for keratinocyte adhesion, while fibroblast adhesion was not affected. For keratinocytes the concentration of some pro-inflammatory cytokines was lower on cPnBA73 and a decreased deposition of collagen, elastin and fibronectin was observed in the coculture. PMID- 23643479 TI - Chloroplast-targeted expression of recombinant crystal-protein gene in cotton: an unconventional combat with resistant pests. AB - Plants transformed with single Bt gene are liable to develop insect resistance and this has already been reported in a number of studies carried out around the world where Bt cotton was cultivated on commercial scale. Later, it was envisaged to transform plants with more than one Bt genes in order to combat with resistant larvae. This approach seems valid as various Bt genes possess different binding domains which could delay the likely hazards of insect resistance against a particular Bt toxin. But it is difficult under field conditions to develop homozygous plants expressing all Bt genes equally after many generations without undergoing recombination effects. A number of researches claiming to transform plants from three to seven transgenes in a single plant were reported during the last decade but none has yet applied for patent of homozygous transgenic lines. A better strategy might be to use hybrid-Bt gene(s) modified for improved lectin binding domains to boost Bt receptor sites in insect midgut. These recombinant-Bt gene(s) would express different lectin domains in a single polypeptide and it is relatively easy to develop homozygous transgenic lines under field conditions. Enhanced chloroplast-localized expression of hybrid-Bt gene would leave no room for insects to develop resistance. We devised and successfully applied this strategy in cotton (Gossypium hirsutum) and data up to T3 generation showed that our transgenic cotton plants were displaying enhanced chloroplast-targeted Cry1Ac RB expression. Laboratory and field bioassays gave promising results against American bollworm (Heliothis armigera), pink bollworm (Pictinophora scutigera) and fall armyworm (Spodoptera frugiperda) that otherwise, were reported to have evolved resistance against Cry1Ac toxin. Elevated levels of hybrid-Bt toxin were confirmed by ELISA of chloroplast-enriched protein samples extracted from leaves of transgenic cotton lines. While, localization of recombinant Cry1Ac-RB protein in chloroplast was established through confocal laser scanning microscopy. PMID- 23643481 TI - [Penaly ordered care in France: principles of procedures and caregiver's role]. AB - BACKGROUND: Penaly ordered care constitutes a type of legal penalty and a form of special care, linking health and legal environments, and as such is a difficult exercise for the various parties involved. METHODS: This article is based on a comprehensive study of medical and legal literature on the subject. RESULTS: Each of the measures presented has a legal basis, procedures for implementation and different application fields. According to the measure, the caregiver has a defined role in the organization of care and flexibility in dealing with specific legal authorities. Doctors are often uncertain of their rights and duties in this type of care. CONCLUSION: Penaly ordered care requires cooperation between two professional bodies with different ethical and professional requirements. Beyond this first difficulty, it appears that these measures are also complicated by the many pieces of legislation published recently, stressing the political will of the ever-expanding scope of ordered care, despite the lack of means downstream, sometimes to the detriment of their effectiveness. PMID- 23643482 TI - Applying principles of self-management to facilitate workers to return to or remain at work with a chronic musculoskeletal condition. AB - It is incumbent on health care professionals to support patients with chronic musculoskeletal conditions to manage the impact of the condition on their life. Work is a positive health behaviour for which self-management skills are essential. In this paper, self-management is defined and the role of clinicians in promoting self-management for return to work is outlined with examples and tips on how the clinician can incorporate self-management into practice. The clinician is ideally placed to assist individuals with chronic musculoskeletal conditions manage to remain at work or return to work. This can be achieved through such activities as the promotion of the core self-management skills of problem-solving, decision making, resource utilisation, developing a cooperative partnership between clinician and patient and making an action plan. PMID- 23643483 TI - Interactive effects of smoking and glutathione S-transferase polymorphisms on the development of non-alcoholic fatty liver disease. AB - Glutathione S-transferases (GSTs) protect cells against exogenous and endogenous oxidative stress. GST polymorphisms are associated with the development of cardiovascular disease (CVD) and diabetes mellitus (DM), especially in current smokers. Non-alcoholic fatty liver disease (NAFLD) is a predictor of future CVD or DM, because oxidative stress contributes to their pathogenesis. This study investigated whether the combination of smoking status and GST genotypes could affect the risk for NAFLD. A cross-sectional analysis was conducted among 713 Japanese participants (458 males and 255 females) during a health screening program. The GSTM1 null, GSTT1 null, GSTP1 A/B or B/B and GSTA1 A/B or B/B genotypes were determined and deemed to be high-risk genotypes. The prevalence of NAFLD was 18.7%. Among never-smokers, carriers of one, and those of two or more high-risk GSTM1, GSTP1 or GSTA1 genotypes were at a higher risk for NAFLD than those who were not carriers [odds ratio (95% confidence interval): 2.6 (1.1-5.9) and 3.3 (1.3-8.1), respectively], and the risk was further increased among current-smokers [4.6 (1.6-13.0) and 5.4 (1.2-23.7), respectively]. This is the first report to show that the combination of current-smoking and harboring high risk GSTM1, GSTP1 and/or GSTA1 genotypes is interactively associated with the risk of NAFLD. PMID- 23643485 TI - Impact of ApoB-100 expression on cognition and brain pathology in wild-type and hAPPsl mice. AB - During their lifetime, people are commonly exposed to several vascular risk factors that may affect brain ageing and cognitive function. In the last few years, increasing evidence suggests that pathological plasma lipid profiles contribute to the pathogenesis of late-onset Alzheimer's disease. Importantly, hypercholesterolemia, especially elevated low-density lipoprotein cholesterol values, that is, increased apolipoprotein B-100 (ApoB-100) levels, represents an independent risk factor. In this study, the effects of ApoB-100 overexpression, either alone or in combination with cerebral expression of human amyloid precursor protein (hAPP), on cognitive functions and brain pathology were assessed. Our results show that ApoB-100 overexpression induces memory decline and increases cerebral lipid peroxidation and amyloid beta levels compared to those in wild-type animals. Although double-transgenic ApoBxAPP animals did not develop more distinct behavioral deficits than single-transgenic hAPP littermates, hApoB-100 expression caused additional pathophysiological features, such as high LDL and low HDL-cholesterol levels, increased lipid peroxidation, and pronounced ApoB-100 accumulation in cerebral vessels. Thus, our results indicate that ApoBxAPP mice might better reflect the situation of elderly humans than hAPPsl overexpression alone. PMID- 23643484 TI - Critical ages in the life course of the adult brain: nonlinear subcortical aging. AB - Age-related changes in brain structure result from a complex interplay among various neurobiological processes, which may contribute to more complex trajectories than what can be described by simple linear or quadratic models. We used a nonparametric smoothing spline approach to delineate cross-sectionally estimated age trajectories of the volume of 17 neuroanatomic structures in 1100 healthy adults (18-94 years). Accelerated estimated decline in advanced age characterized some structures, for example hippocampus, but was not the norm. For most areas, 1 or 2 critical ages were identified, characterized by changes in the estimated rate of change. One-year follow-up data from 142 healthy older adults (60-91 years) confirmed the existence of estimated change from the cross sectional analyses for all areas except 1 (caudate). The cross-sectional and the longitudinal analyses agreed well on the rank order of age effects on specific brain structures (Spearman rho = 0.91). The main conclusions are that most brain structures do not follow a simple path throughout adult life and that accelerated decline in high age is not the norm of healthy brain aging. PMID- 23643486 TI - Real-life comparison of beclometasone dipropionate as an extrafine- or larger particle formulation for asthma. AB - BACKGROUND: Beclometasone dipropionate is an inhaled corticosteroid (ICS) available in both extrafine and larger-particle hydrofluoroalkane formulations. Extrafine beclometasone has greater small airway distribution and inhalation technique tolerance than larger-particle beclometasone; therefore, its use may be associated with improved asthma outcomes at population levels. The study objective was to compare real-life effectiveness of extrafine and larger-particle beclometasone. METHODS: Retrospective matched cohort study including primary care patients with asthma (ages 12-60 and non-smokers 61-80 years) prescribed extrafine or larger-particle beclometasone by metered-dose inhaler. We studied patients receiving their first ICS (initiation population, n = 11,289) or switched from another ICS without dose change (switch population, n = 19,065). The extrafine and larger-particle beclometasone cohorts were matched in each population for demographic and database measures of asthma control during a baseline year; and endpoints assessed during 1 outcome year were adjusted for residual confounding factors. RESULTS: The odds of no loss of asthma control (no asthma-related hospital attendance, consultation for lower respiratory tract infection, or oral corticosteroids) were significantly higher in the extrafine beclometasone cohorts of both initiation population (adjusted odds ratio [aOR] 1.12; 95% CI 1.02-1.23) and switch population (aOR 1.10; 95% CI 1.01-1.19). The odds of better adherence to ICS therapy were also significantly higher in both extrafine beclometasone cohorts (initiation population, aOR 1.64; 95% CI 1.52 1.75 and switch population, aOR 1.35; 95% CI 1.27-1.43). CONCLUSIONS: These findings are consistent with the hypothesis that delivery of beclometasone in extrafine particle size produces real-life asthma treatment benefits. Clinical trials no. NCT01400217. PMID- 23643487 TI - Adherence to inhaled therapies, health outcomes and costs in patients with asthma and COPD. AB - Suboptimal adherence to pharmacological treatment of asthma and chronic obstructive pulmonary disease (COPD) has adverse effects on disease control and treatment costs. The reasons behind non-adherence revolve around patient knowledge/education, inhaler device convenience and satisfaction, age, adverse effects and medication costs. Age is of particular concern given the increasing prevalence of asthma in the young and increased rates of non-adherence in adolescents compared with children and adults. The correlation between adherence to inhaled pharmacological therapies for asthma and COPD and clinical efficacy is positive, with improved symptom control and lung function shown in most studies of adults, adolescents and children. Satisfaction with inhaler devices is also positively correlated with improved adherence and clinical outcomes, and reduced costs. Reductions in healthcare utilisation are consistently observed with good adherence; however, costs associated with general healthcare and lost productivity tend to be offset only in more adherent patients with severe disease, versus those with milder forms of asthma or COPD. Non-adherence is associated with higher healthcare utilisation and costs, and reductions in health related quality of life, and remains problematic on an individual, societal and economic level. Further development of measures to improve adherence is needed to fully address these issues. PMID- 23643488 TI - Time trends in 30 day case-fatality following hospitalisation for asthma in adults in Scotland: a retrospective cohort study from 1981 to 2009. AB - BACKGROUND: The risk of case-fatality following hospitalisation for asthma has not been well characterised. We describe trends in 30 day case-fatality following hospitalisation for asthma in adults in Scotland from 1981 to 2009. METHODS: Using the Scottish Morbidity Record Scheme (SMR01) with all asthma hospitalisations for adults (>=18 years) with ICD9 493 and ICD10 J45-J46 in the principal diagnostic position at discharge (1981-2009). These data were linked to mortality data from the General Register Office for Scotland (GROS), with asthma case-fatality defined as death within 30 days of asthma admission (in or out of hospital). Logistic regression was used to explore the impact of age, sex, previous asthma admission (in the 12 months prior to hospitalisation), socioeconomic deprivation, year of admission and co-morbidity on 30-day case fatality. RESULTS: There were a total of 116,457 asthma hospitalisations; a total of 1000 (0.9%) hospitalisations resulted in a post-admission death (within 30 days of admission). Odds ratios for unadjusted and adjusted case-fatality showed a decreased risk of case-fatality from the mid-1990s onwards when compared to case-fatality in 1981. Advancing age and co-morbid diagnoses of respiratory failure, cancer, renal failure, cor pulmonale, coronary heart disease and respiratory infection were associated with increased likelihood of death. CONCLUSIONS: 30 day case-fatality has declined over the last three decades, comparable to case-fatality reported in other parts of the U.K. This decline may be in part due to improved guidelines, protocols and disease management for asthma over the last 30 years. The likelihood of death 30 days following an asthma admission increased with age group and was associated with respiratory failure, renal failure and cancer. PMID- 23643489 TI - How to design a drug for the disordered proteins? AB - Structural disorders of proteins make drug design a difficult task. The gel-like state of intrinsically disordered protein (IDP) or intrinsically disordered regions (IDRs) remains a big puzzle for drug designers. Here, we propose a novel concept for drug design by understanding protein disintegration and protein protein interaction (PPI) using molecular dynamics (MD) simulation and propose a possible approach for overcoming current obstacles in IDP drug design. PMID- 23643490 TI - Replication stress-induced genome instability: the dark side of replication maintenance by homologous recombination. AB - Homologous recombination (HR) is an evolutionary-conserved mechanism involved in a subtle balance between genome stability and diversity. HR is a faithful DNA repair pathway and has been largely characterized in the context of double-strand break (DSB) repair. Recently, multiple functions for the HR machinery have been identified at arrested forks. These are evident across different organisms and include replication fork-stabilization and fork-restart functions. Interestingly, a DSB appears not to be a prerequisite for HR-mediated replication maintenance. HR has the ability to rebuild a replisome at inactivated forks, but perhaps surprisingly, the resulting replisome is liable to intrastrand and interstrand switches leading to replication errors. Here, we review our current understanding of the replication maintenance function of HR. The error proneness of these pathways leads us to suggest that the origin of replication-associated genome instability should be re-evaluated. PMID- 23643491 TI - The retrovirus MA and PreTM proteins follow immature MLV cores. AB - We have used mild detergent to analyze the core of Moloney Murine Leukemia Virus (MoMLV) and core-like complexes in infected cells. The immature core consists of the Gag polyprotein (PrGag) and viral RNA (vRNA). It is known to be detergent resistant, in contrast to the mature Gag core. The core matures by cleavage of PrGag into MA (matrix), p12, CA (capsid) and NC (nucleocapsid) protein. We found that mature Gag proteins were bound to the PrGag cores. The degree of binding differed widely. No (<0.1%) p12 bound, low amount of CA (3-5%), and higher amount of MA (13-20%) bound. Varying NC was bound (5-15%). NC could be released by RNase A in agreement with its binding to viral RNA. The TM (transmembrane) protein was also examined. A low amount of TM was bound to the PrGag core (approximately 5%), whereas a very high amount (65%) of the PreTM (TM with the cytoplasmic R peptide tail) bound. The binding in the PrGag core appears to occur by direct protein protein interactions as only minute amounts of lipids including raft lipids were observed after detergent treatment. PMID- 23643492 TI - E-cadherin supports steady-state Rho signaling at the epithelial zonula adherens. AB - In simple polarized epithelial cells, the Rho GTPase commonly localizes to E cadherin-based cell-cell junctions, such as the zonula adherens (ZA), where it regulates the actomyosin cytoskeleton to support junctional integrity and tension. An important question is how E-cadherin contributes to Rho signaling, notably whether junctional Rho may depend on cadherin adhesion. We sought to investigate this by assessing Rho localization and activity in epithelial monolayers depleted of E-cadherin by RNAi. We report that E-cadherin depletion reduced both Rho and Rho-GTP at the ZA, an effect that was rescued by expressing a RNAi-resistant full-length E-cadherin transgene. This impact on Rho signaling was accompanied by reduced junctional localization of the Rho GEF ECT2 and the centralspindlin complex that recruits ECT2. Further, the Rho signaling pathway contributes to the selective stabilization of E-cadherin molecules in the apical zone of the cells compared with E-cadherin at the lateral surface, thereby creating a more defined and restricted pool of E-cadherin that forms the ZA. Thus, E-cadherin and Rho signaling cooperate to ensure proper ZA architecture and function. PMID- 23643493 TI - EMG and tibial shock upon the first attempt at barefoot running. AB - As a potential means to decrease their risk of injury, many runners are transitioning into barefoot running. Habitually shod runners tend to heel-strike (SHS), landing on their heel first, while barefoot runners tend to mid-foot or toe-strike (BTS), landing flat-footed or on the ball of their foot before bringing down the rest of the foot including the heel. This study compared muscle activity, tibial shock, and knee flexion angle in subjects between shod and barefoot conditions. Eighteen habitually SHS recreational runners ran for 3 separate 7-minute trials, including SHS, barefoot heel-strike (BHS), and BTS conditions. EMG, tibial shock, and knee flexion angle were monitored using bipolar surface electrodes, an accelerometer, and an electrogoniometer, respectively. A one-way MANOVA for repeated measures was conducted and several significant changes were noted between SHS and BTS, including significant increases in average EMG of the medial gastrocnemius (p=.05), average and peak tibial shock (p<.01), and the minimum knee flexion angle (p<.01). Based on our data, the initial change in mechanics may have detrimental effects on the runner. While it has been argued that BTS running may ultimately be less injurious, these data indicate that habitually SHS runners who choose to transition into a BTS technique must undertake the process cautiously. PMID- 23643494 TI - Independence and control of the fingers depend on direction and contraction mode. AB - Both biomechanical and neural factors are suggested to contribute to the limited independence of finger movement and involuntary force production. The purpose of this study was to evaluate finger independence by examining the activity of the four compartments of extensor digitorum (ED) and flexor digitorum superficialis (FDS) and involuntary force production in the non-task fingers using the "enslaving effect" (EE). Twelve male participants performed a series of 5s sub maximal exertions at 5%, 25%, 50% and 75% of maximum using isometric isotonic and ramp flexion and extension exertions. Ramp exertions were performed from 0% to 85% of each finger's maximum force with ascending and descending phases taking 4.5s. EE was lower in flexion exertions likely due to the higher activity of the antagonist ED compartments counterbalancing the involuntary activation of the non task FDS compartments. Minimal FDS activity was seen during extension exertions. At forces up to and including 50%, both EE and muscle activity of the non-task compartments were significantly higher in descending exertions than isotonic or ascending exertions. Up to mid-level forces, both finger proximity and contraction mode affect involuntary force production and muscle activation while only finger proximity contributed to finger independence at higher forces. PMID- 23643495 TI - The NMDA receptor 30 years on. Foreword. PMID- 23643496 TI - Intestinal acyl-CoA:diacylglycerol acyltransferase 2 overexpression enhances postprandial triglyceridemic response and exacerbates high fat diet-induced hepatic triacylglycerol storage. AB - Intestinal acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2) is important in the cellular and physiological responses to dietary fat. To determine the effect of increased intestinal DGAT2 on cellular and physiological responses to acute and chronic dietary fat challenges, we generated mice with intestine-specific overexpression of DGAT2 and compared them with intestine-specific overexpression of DGAT1 and wild-type (WT) mice. We found that when intestinal DGAT2 is present in excess, triacylglycerol (TG) secretion from enterocytes is enhanced compared to WT mice; however, TG storage within enterocytes is similar compared to WT mice. We found that when intestinal DGAT2 is present in excess, mRNA levels of genes involved in fatty acid oxidation were reduced. This result suggests that reduced fatty acid oxidation may contribute to increased TG secretion by overexpression of DGAT2 in intestine. Furthermore, this enhanced supply of TG for secretion in Dgat2(Int) mice may be a significant contributing factor to the elevated fasting plasma TG and exacerbated hepatic TG storage in response to a chronic HFD. These results highlight that altering fatty acid and TG metabolism within enterocytes has the capacity to alter systemic delivery of dietary fat and may serve as an effective target for preventing and treating metabolic diseases such as hepatic steatosis. PMID- 23643498 TI - Reply: To PMID 23428213. PMID- 23643497 TI - Socioeconomic disparities in the use of cardioprotective medications among patients with peripheral artery disease: an analysis of the American College of Cardiology's NCDR PINNACLE Registry. AB - OBJECTIVES: The aim of this paper was to examine disparities in the use of cardioprotective medications in the treatment of peripheral artery disease (PAD) by socioeconomic status (SES). BACKGROUND: PAD is associated with increased cardiovascular risk and is more prevalent among those of lower SES. However, the use of guideline-recommended secondary preventive measures for the treatment of PAD across diverse income subgroups and the influence of practice site on potential treatment disparities by SES are unknown. METHODS: Within the National Cardiovascular Disease Registry (NCDR) PINNACLE Registry, 62,690 patients with PAD were categorized into quintiles of SES, as defined by the median income of each patient's zip code. The association between SES and secondary preventive treatment with antiplatelet and statin medications was evaluated using sequential hierarchical modified Poison models, adjusting first for practice site and then for clinical variables. RESULTS: Compared with the highest SES quintile (median income: >$60,868), PAD patients in the lowest SES quintile (median income: <$34,486) were treated less often with statins (72.5% vs. 85.8%; RR: 0.84; 95% CI: 0.83 to 0.86; p < 0.001) and antiplatelet therapy (79.0% vs. 84.6%; RR: 0.93; 95% CI: 0.91 to 0.94; p < 0.001). These differences were markedly attenuated after controlling for practice site variation: statins (adjusted RR: 0.97; 95% CI: 0.95 to 0.99; p = 0.003) and antiplatelet therapy (adjusted RR: 0.98; 95% CI: 0.97 to 1.00; p = 0.012). Additional adjustment for patients' clinical characteristics had minimal impact, with slight further attenuation with statins (adjusted RR: 1.00: 95% CI: 0.99 to 1.01; p = 0.772) and antiplatelet therapy (adjusted RR: 1.00; 95% CI: 0.99 to 1.01; p = 0.878). CONCLUSIONS: Among PAD patients, the practice site at which patients received care largely explained the observed SES differences in treatment with guideline-recommended secondary preventive medications. Future efforts to reduce treatment disparities in these vulnerable populations should target systems improvement at practices serving high proportions of patients with low SES. PMID- 23643499 TI - Reply: Types of sleep apnea in patients with heart failure: a spectrum of disease severity or separate entities. PMID- 23643500 TI - Types of sleep apnea in patients with heart failure: a spectrum of disease severity or separate entities. PMID- 23643502 TI - Ventricular arrhythmias and implantable cardioverter-defibrillator therapy in patients with continuous-flow left ventricular assist devices: need for primary prevention? AB - OBJECTIVES: This study sought to evaluate the prevalence and significance of ventricular arrhythmia (VA) and the role of an implantable cardioverter defibrillator (ICD) in patients supported by a continuous-flow left ventricular assist device (CF-LVAD). BACKGROUND: VAs are common in patients supported by CF LVADs but prospective data to support the routine use of ICDs in these patients are lacking. METHODS: All patients supported by long-term CF-LVAD receiving care at our institution were enrolled. The ICDs were interrogated at baseline and throughout prospective follow-up. The VA was defined as ventricular tachycardia/fibrillation lasting >30 s or effectively terminated by appropriate ICD tachytherapy. The primary outcome was the occurrence of VA >30 days after CF LVAD implantation. RESULTS: Ninety-four patients were enrolled; 77 had an ICD and 17 did not. Five patients with an ICD had it deactivated or a depleted battery not replaced during the study. Twenty-two patients had a VA >30 days after LVAD implantation. Pre-operative VA was the major predictor of post-operative arrhythmia. Absence of pre-operative VA conferred a low risk of post-operative VA (4.0% vs. 45.5%; p < 0.001). No patients discharged from the hospital without an ICD after CF-LVAD implantation died during 276.2 months of follow-up (mean time without ICD, 12.7 +/- 12.3 months). CONCLUSIONS: Patients with pre-operative VA are at risk of recurrent VA while on CF-LVAD support and should have active ICD therapy to minimize sustained VA. Patients without pre-operative VA are at low risk and may not need active ICD therapy. PMID- 23643501 TI - Patient outcome following 2 different stress imaging approaches: a prospective randomized comparison. AB - OBJECTIVES: The study sought to prospectively compare patient outcome after stress real-time myocardial contrast echocardiography (RTMCE) versus conventional stress echo (CSE), where contrast is used to optimize wall motion (WM) analysis. BACKGROUND: Myocardial perfusion imaging with RTMCE may improve the detection of coronary artery disease (CAD), and predict patient outcome. METHODS: Patients with intermediate to high pre-test probability referred for dobutamine or exercise stress echocardiography were prospectively randomized to either RTMCE or CSE. Definity contrast was used for CSE only when endocardial border delineation was inadequate (63% of studies). Studies were interpreted by either an experienced contrast reviewer (R1; n = 1257), or 4 Level 3 echocardiographers (R2) with basic contrast training (n = 806). Death, nonfatal myocardial infarction (MI), and revascularizations were recorded at follow-up. RESULTS: Follow-up was available in 2,014 patients (median 2.6 years). Mean age was 59 +/- 13 years (53% women). An abnormal RTMCE was more frequently observed than an abnormal CSE (p < 0.001), and more frequently resulted in revascularization (p = 0.004). Resting WM abnormalities were also more frequently seen with RTMCE (p < 0.01), and were an independent predictor of death/nonfatal MI (p = 0.005) for RTMCE, but not CSE. The predictive value of a positive study, whether with CSE or RTMCE, was significant for both R1 and R2 reviewers in predicting the combined endpoint, but R1 was better than R2 at predicting patients at risk for death or nonfatal MI. CONCLUSIONS: Perfusion imaging with RTMCE improves the detection of CAD during stress echocardiography, and identifies those more likely to undergo revascularization following an abnormal study. PMID- 23643503 TI - Choosing troponin immunoassays in a world of limited resources. PMID- 23643504 TI - Refugee cardiologists and the coexistence of the American Heart Association and the American College of Cardiology. PMID- 23643505 TI - Reply: To PMID 23395074. PMID- 23643506 TI - The challenge of obesity: can we look to the moon instead of the finger? PMID- 23643507 TI - Evaluation of the new CE-IVD marked BD MAX Cdiff Assay for the detection of toxigenic Clostridium difficile harboring the tcdB gene from clinical stool samples. AB - The evaluation of the fully automated BD MAX Cdiff assay on a panel of 100 stool samples characterized by the Xpert C. difficile assay reported a high concordance between the two molecular assays (kappa coefficient of 0.96), which makes this new assay suitable for routine detection of toxigenic Clostridium difficile. PMID- 23643508 TI - Anti-major histocompatibility complex-induced obliterative airway disease: selective role for CD4 and CD8 T cells in inducing immune responses to self antigens. AB - BACKGROUND: The goal of this study was to define the role of T-cell sub-sets in the pathogenesis of autoimmunity-induced obliterative airway disease by passive transfer of CD8+ or CD4+ T cells. METHODS: Antibodies to major histocompatibility complex (MHC) class I were administered intrabronchially into C57BL/6 animals. Lungs were analyzed by histopathology and immunohistochemistry. The CD8+ and CD4+ T-cell sub-sets were purified from the lung-infiltrating cells and intrabronchially transferred. Frequency of cells secreting interleukin-17, interferon-gamma, or interleukin-10 to self-antigens was enumerated by enzyme linked immunospot assay. Myeloperoxidase and antibodies to self-antigens were determined by enzyme-linked immunosorbent assay. Cytokine and growth factor expression was determined by quantitative reverse-transcription polymerase chain reaction. RESULTS: Passive transfer of lung-infiltrating CD8 T cells isolated after anti-MHC class I administration, along with sub-optimal dose, induced significantly higher cellular infiltration (89.3% +/- 7.9% vs 62.8% +/- 10.1%, p < 0.05) vs the CD4 transfer group. Further, passive transfer of CD8 cells resulted in infiltration of neutrophils and macrophages, suggesting early injury response. In contrast, passive transfer of CD4+ T cells induced a significantly higher degree of luminal occlusion (29.3% +/- 5.6% vs 8.6 +/- 2.5%, p < 0.05) and fibrosis (54.4% +/- 9.3% vs 10.2% +/- 2.4%, p < 0.05) vs the CD8 group and B-cell infiltration, leading to immune responses to lung-associated self-antigens and fibrosis. CONCLUSION: Ligation of MHC molecules by its specific antibodies induced early injury with neutrophils, macrophages, and CD8 T cells, which leads to exposure of cryptic self-antigens and their presentation by the infiltrating CD4+ T cells and B cells, leading to the development of immune responses to self antigens and culminating in obliterative airway disease. PMID- 23643509 TI - Carrier-free combination for dry powder inhalation of antibiotics in the treatment of lung infections in cystic fibrosis. AB - The aim of the study was to develop an efficient combination antibiotic formulation containing tobramycin and clarithromycin as a dry powder for inhalation. A carrier-free formulation of the two drugs was produced by spray drying and characterised for its aerodynamic behaviour by impaction tests with an NGI and release profiles. The particle size distribution, morphological evaluation and crystallinity state were determined by laser diffraction, scanning electron microscopy and powder X-ray diffraction, respectively. Drug deposition profiles were similar for the two antibiotics, which has a synergistic effect, allowing them to reach the target simultaneously at the expected dose. The release profiles show that tobramycin and clarithromycin should probably dissolve without any difficulties in vivo in the lung as 95% of tobramycin and 57% of clarithromycin mass dissolved in 10min for the spray-dried formulation. The FPF increased from 35% and 31% for the physical blend for tobramycin and clarithromycin, respectively, to 65% and 63% for the spray-dried formulation. The spray-dried formulation shows particularly high deposition results, even at sub optimal inspiratory flow rates, and therefore, represents an attractive alternative in the local treatment of lung infection such as in cystic fibrosis. PMID- 23643510 TI - Efficacy of edelfosine lipid nanoparticles in breast cancer cells. AB - Breast cancer is a heterogeneous group of neoplasms predominantly originating in the terminal duct lobular units. It represents the leading cause of cancer death in women and the survival frequencies for patients at advanced stages of the disease remain low. New treatment options need to be researched to improve these rates. The anti-tumor ether lipid edelfosine (ET) is the prototype of a novel generation of promising anticancer drugs. However, it presents several drawbacks for its use in cancer therapy, including gastrointestinal and hemolytic toxicity and low oral bioavailability. To overcome these obstacles, ET was encapsulated in Precirol ATO 5 lipid nanoparticles (ET-LN), and its anti-tumor potential was in vitro tested in breast cancer. The formulated ET-LN were more effective in inhibiting cell proliferation and notably decreased cell viability, showing that the cytotoxic effect of ET was considerably enhanced when ET was encapsulated. In addition, ET and ET-LN were able to promote cell cycle arrest at G1 phase. Moreover, although both treatments provoked an apoptotic effect in a time dependent manner, such anti-tumor effects were noticeably improved with ET-LN treatment. Therefore, our results indicate that encapsulating ET in LN played an essential role in improving the efficacy of the drug. PMID- 23643511 TI - Instability of repolarization in LQTS mutation carriers compared to healthy control subjects assessed by vectorcardiography. AB - BACKGROUND: Potassium channel dysfunction in congenital and acquired forms of long QT syndrome types 1 and 2 (LQT1 and LQT2) increases the beat-to-beat variability of the QT interval. OBJECTIVE: To study about the little known variability (instability) of other aspects of ventricular repolarization (VR) in humans by using vectorcardiography. METHODS: Beat-to-beat analysis was performed regarding vectorcardiography derived RR, QRS, and QT intervals, as well as T vector- and T vector loop-based parameters during 1-minute recordings of uninterrupted sinus rhythm at rest in 41 adult LQT1 (n = 31) and LQT2 (n = 10) mutation carriers and 41 age- and sex-matched control subjects. The short-term variability for each parameter, describing the mean orthogonal distance to the line of identity on the Poincare plot, was calculated. RESULTS: Mutation carriers showed significantly larger (by a factor 2) instability in most VR parameters compared to controls despite higher instantaneous heart rate variability (STVRR) in the control group. The longer the QT interval, the greater was its instability, and the instability of VR dispersion measures. CONCLUSIONS: A greater instability of most aspects of VR already at rest seems to be a salient feature in both LQT1 and LQT2, which might pave the way for early afterdepolarizations and torsades de pointes ventricular tachycardia. In contrast, no signs of increased VR dispersion per se were observed in mutation carriers. PMID- 23643512 TI - Bidomain simulations of defibrillation: 20 years of progress. PMID- 23643513 TI - Cardiac magnetic resonance T1 mapping of left atrial myocardium. AB - BACKGROUND: Cardiac magnetic resonance (CMR) T1 mapping is an emerging tool for objective quantification of myocardial fibrosis. OBJECTIVES: To (a) establish the feasibility of left atrial (LA) T1 measurements, (b) determine the range of LA T1 values in patients with atrial fibrillation (AF) vs healthy volunteers, and (c) validate T1 mapping vs LA intracardiac electrogram voltage amplitude measures. METHODS: CMR imaging at 1.5 T was performed in 51 consecutive patients before AF ablation and in 16 healthy volunteers. T1 measurements were obtained from the posterior LA myocardium by using the modified Look-Locker inversion-recovery sequence. Given the established association of reduced electrogram amplitude with fibrosis, intracardiac point-by-point bipolar LA voltage measures were recorded for the validation of T1 measurements. RESULTS: The median LA T1 relaxation time was shorter in patients with AF (387 [interquartile range 364-428] ms) compared to healthy volunteers (459 [interquartile range 418-532] ms; P < .001) and was shorter in patients with AF with prior ablation compared to patients without prior ablation (P = .035). In a generalized estimating equations model, adjusting for data clusters per participant, age, rhythm during CMR, prior ablation, AF type, hypertension, and diabetes, each 100-ms increase in T1 relaxation time was associated with 0.1 mV increase in intracardiac bipolar LA voltage (P = .025). CONCLUSIONS: Measurement of the LA myocardium T1 relaxation time is feasible and strongly associated with invasive voltage measures. This methodology may improve the quantification of fibrotic changes in thin-walled myocardial tissues. PMID- 23643514 TI - Identification and characterisation of functional expressed sequence tags-derived simple sequence repeat (eSSR) markers for genetic linkage mapping of Schistosoma mansoni juvenile resistance and susceptibility loci in Biomphalaria glabrata. AB - Biomphalaria glabrata susceptibility to Schistosoma mansoni has a strong genetic component, offering the possibility for investigating host-parasite interactions at the molecular level, perhaps leading to novel control approaches. The identification, mapping and molecular characterisation of genes that influence the outcome of parasitic infection in the intermediate snail host is, therefore, seen as fundamental to the control of schistosomiasis. To better understand the evolutionary processes driving disease resistance/susceptibility phenotypes, we previously identified polymorphic random amplification of polymorphic DNA and genomic simple sequence repeats from B. glabrata. In the present study we identified and characterised polymorphic expressed simple sequence repeats markers (Bg-eSSR) from existing B. glabrata expressed sequence tags. Using these markers, and with previously identified genomic simple sequence repeats, genetic linkage mapping for parasite refractory and susceptibility phenotypes, the first known for B. glabrata, was initiated. Data mining of 54,309 expressed sequence tag, produced 660 expressed simple sequence repeats of which dinucleotide motifs (TA)n were the most common (37.88%), followed by trinucleotide (29.55%), mononucleotide (18.64%) and tetranucleotide (10.15%). Penta- and hexanucleotide motifs represented <3% of the Bg-eSSRs identified. While the majority (71%) of Bg eSSRs were monomorphic between resistant and susceptible snails, several were, however, useful for the construction of a genetic linkage map based on their inheritance in segregating F2 progeny snails derived from crossing juvenile BS-90 and NMRI snails. Polymorphic Bg-eSSRs assorted into six linkage groups at a logarithm of odds score of 3. Interestingly, the heritability of four markers (Prim1_910, Prim1_771, Prim6_1024 and Prim7_823) with juvenile snail resistance were, by t-test, significant (P<0.05) while an allelic marker, Prim24_524, showed linkage with the juvenile snail susceptibility phenotype. On the basis of our results it is possible that the gene(s) controlling juvenile resistance and susceptibility to S. mansoni infection in B. glabrata are not only on the same linkage group but lie within a short distance (42cM) of each other. PMID- 23643515 TI - Dangerous liaisons between interleukin-6 cytokine and toll-like receptor families: a potent combination in inflammation and cancer. AB - The potent pro-inflammatory actions of members of the interleukin (IL)-6 cytokine and toll-like receptor (TLR) families have been implicated in numerous inflammatory disorders, as well as inflammation-associated cancers. It is fast becoming apparent that a hallmark of many such inflammatory-related diseases is the overlapping deregulated expression of members of each family, and the consequent augmented activation of shared signaling pathways. Here, we review the molecular basis by which the IL-6 cytokine and TLR family signaling networks are regulated, and integrate recent advances exploring the intimate cross-regulation of these two families which may provide the foundation for the future development of therapeutics to target chronic inflammation-associated diseases, including cancer. PMID- 23643516 TI - Decreased functional connectivity of the amygdala in Alzheimer's disease revealed by resting-state fMRI. AB - Alzheimer's disease (AD), the most common cause of dementia, is thought to be a progressive neurodegenerative disease that is clinically characterised by a decline of memory and other cognitive functions. Mild cognitive impairment (MCI) is considered to be the prodromal stage of AD. However, the relationship between AD and MCI and the development process remains unclear. The amygdala is one of the most vulnerable structures in the early stages of AD. To our knowledge, this is the first report on the alteration of the functional connectivity of the amygdala in AD and MCI subjects. We hypothesised that the amygdala-cortical loop is impaired in AD and that these alterations relate to the disease severity. In our study, we used resting-state functional MRIs to investigate the altered amygdala connectivity patterns in 35 AD patients, 27 MCI patients and 27 age- and gender-matched normal controls (NC). Compared with the NC, the decreased functional connectivity found in the AD patients was mainly located between the amygdala and the regions that are included in the default mode, context conditioning and extinction networks. Importantly, the decreased functional connectivity between the amygdala and some of the identified regions was positively correlated with MMSE, which indicated that the cognitive function impairment is related to an altered functional connectivity pattern. PMID- 23643517 TI - Pharmacokinetics and in vivo chemosuppressive activity studies on cryptolepine hydrochloride and cryptolepine hydrochloride-loaded gelatine nanoformulation designed for parenteral administration for the treatment of malaria. AB - The main objective of this investigation was to establish the pharmacokinetics profile and in vivo chemosuppressive activities of cryptolepine hydrochloride loaded gelatine nanoparticles (CHN) designed for parenteral administration for the treatment of malaria in comparison to the drug free in solution (CHS). Single dose pharmacokinetics was investigated in Wistar rats by administering CHN or CHS (equivalent to 10 mg/kg of drug) by IV bolus injection via the lateral tail vein. The drug concentration in plasma was monitored over a 24-h period following administration. Chemosuppressive activity was investigated in Wistar rats challenged with P berghei parasites. Animals were given a daily dose of either CHN or CHS, equivalent to 2.5-100 mg/kg by intraperitoneal injection. The level of parasitaemia was determined by light microscopy by examining Giemsa-stained thin blood smears prepared from the tail end on day four of infection. It was found that CHN attained a higher (4.5-folds) area under the curve (AUC (0-24)) compared to CHS. CHS however produced a higher volume of distribution (4-folds). Distribution and elimination rates were higher with CHS which resulted in a lower (11.7 h) elimination half-life compared to that of CHN (21.85 h). The superior pharmacokinetic profile of CHN translated into superior chemosuppressive activity at all dose levels relative to CHS. As a conclusion, loading cryptolepine hydrochloride into gelatine nanoparticles improved both pharmacokinetics and in vivo antiplasmodial activity of the compound with the highest chemosuppression (97.89 +/- 3.10) produced by 100 mg/kg of CHN. PMID- 23643518 TI - Chagas disease (American trypanosomiasis) in Mexico: an update. AB - Chagas disease is a parasitic infection caused by the protozoan Trypanosoma cruzi, a flagellated organism that is transmitted mainly to humans through the infected feces of triatomine kissing bugs (vector transmission in endemic areas) or by transfusion of infected blood, donations of infected organ, or transmission from an infected mother to her child at birth. Chagas disease was first described in 1909 by the Brazilian physician Carlos Chagas, and due to the parasite's distribution throughout North, Central and South America, the disease is commonly known as American trypanosomiasis. However, this disease is now present in non endemic countries such as Canada, the United States of America, and several countries in Europe (principally Spain). Moreover, Chagas disease was recently designated by the World Health Organization as one of the main neglected tropical diseases. The aim of this review is to summarize the research efforts recently described in studies conducted in Mexico on Chagas disease. In this country, there are no existing vector control programs. In addition, there is no consensus on the diagnostic methods for acute and chronic Chagas disease in maternity wards and blood banks, and trypanocidal therapy is not administered to chronic patients. The actual prevalence of the disease is unknown because no official reporting of cases is performed. Therefore, the number of people infected by different routes of transmission (vector, congenital, blood transfusion, organ transplantation, or oral) is unknown. We believe that by promoting education about Chagas disease in schools starting at the basic elementary level and including reinforcement at higher education levels will ensure that the Mexican population would be aware of this health problem and that the control measures adopted will have more acceptance and success. We hope that this review sensitizes the relevant authorities and that the appropriate measures to reduce the risk of infection by T. cruzi are undertaken to provide the Mexican people a better quality of life. PMID- 23643519 TI - Insecticidal and repellence activity of the essential oil of Pogostemon cablin against urban ants species. AB - Ants are highly abundant in neotropical regions, with certain species adapted to the urban environment, where they can cause damage to human health. The main method for controlling ants consists of using organosynthetic insecticides, which are potentially toxic to the environment. Essential plant oils are considered a viable alternative to the use of conventional insecticides. In this study, we analyze the bioinsecticidal activity and repellence of patchouli essential oil (Pogostemon cablin) against three species of urban ants: Camponotus melanoticus, Camponotus novograndensis, and Dorymyrmex thoracicus. The chemical composition of the essential oil was analyzed by GC-MS and GC-FID. The major compounds were patchoulol (36.6%) followed by alpha-bulnesene (13.95%), and alpha-guaiene (11.96%). Toxicity and repellency bioassays were performed using the essential oil over the ants, and mortality evaluations were performed at 4, 24, and 48 h after performing the bioassays. Mortality percentage of the ants on 7 MUg/mg was on average 84%. The essential oil of P. cablin displayed toxicity against all three species of urban ants, with the lowest LD50 being observed for D. thoracicus (2.02 MUg oil/mg insect) after 48 h of exposure compared to C. melanoticus (2.34 MUg oil/mg insect) and C. novogranadensis (2.95 MUg oil/mg insect). The essential oil of P. cablin was strongly repellent to the three species of ants in all concentrations tested (0.01% and 1% v/v). Considering the potential toxicity and repellency of the P. cablin essential oil to the urban ants, future studies could investigate the practical application of this oil to control of this insects. PMID- 23643520 TI - Adequate but not supplemental folic acid combined with soy isoflavones during early life improves bone health at adulthood in male mice. AB - Previous investigations from our laboratory have demonstrated that neonatal exposure to soy isoflavones (ISO) improves bone outcomes in CD-1 mice at adulthood with greater benefits in females than males. This study determined whether early-life exposure to supplemental folic acid (FA) - that may enhance DNA methylation of target genes - in combination with ISO provides greater benefits to male bone development than ISO alone. CD-1 dams were randomized to a low (0 mg/kg diet), adequate (2 mg/kg diet) or supplemental (8 mg/kg diet) level of FA during pregnancy and lactation. Offspring received corn oil or ISO (7 mg/kg of body weight per day) from postnatal day 1-10. From weaning, males were fed adequate FA and studied to age 4 months. Offspring exposed to adequate FA+ISO had multiple benefits to bone health: higher (P<.05) bone mineral density (BMD) and greater (P<.05) resistance to fracture at the femur and lumbar spine than mice exposed to adequate FA alone. Exposure to supplemental FA+ISO resulted in higher (P<.05) serum osteoprotegerin (OPG), and a higher ratio of OPG to receptor activator for nuclear factor kappabeta ligand (RANKL) but did not result in greater BMD or strength at the femur or lumbar spine than supplemental FA alone. In conclusion, early-life exposure to adequate FA+ISO provided functional benefits to male bone development, while improvements induced by supplemental FA+ISO were limited to a higher level of serum OPG. Mechanistic studies are needed to better understand how FA and ISO improve bone development in male offspring. PMID- 23643521 TI - Effects of excess dietary iron and fat on glucose and lipid metabolism. AB - PURPOSE: Diets rich in fat and energy are associated with metabolic syndrome (MS). Increased body iron stores have been recognized as a feature of MS. High fat diets (HFs), excess iron loading and MS are closely associated, but the mechanism linking them has not been clearly defined. We investigated the interaction between dietary fat and dietary Fe in the context of glucose and lipid metabolism in the body. METHODS: C57BL6/J mice were divided into four groups and fed the modified AIN-93G low-fat diet (LF) and HF with adequate or excess Fe for 7 weeks. The Fe contents were increased by adding carbonyl iron (2% of diet weight) (LF+Fe and HF+Fe). RESULTS: High iron levels increased blood glucose levels but decreased high-density lipoprotein cholesterol levels. The HF group showed increases in plasma levels of glucose and insulin and insulin resistance. HF+Fe mice showed greater changes. Representative indices of iron status, such hepatic and plasma Fe levels, were not altered further by the HF. However, both the HF and excess iron loading changed the hepatic expression of hepcidin and ferroportin. The LF+Fe, HF and HF+Fe groups showed greater hepatic fat accumulation compared with the LF group. These changes were paralleled by alterations in the levels of enzymes related to hepatic gluconeogenesis and lipid synthesis, which could be due to increases in mitochondrial dysfunction and oxidative stress. CONCLUSIONS: High-fat diets and iron overload are associated with insulin resistance, modified hepatic lipid and iron metabolism and increased mitochondrial dysfunction and oxidative stress. PMID- 23643522 TI - Inflammation markers predict zinc transporter gene expression in women with type 2 diabetes mellitus. AB - The pathology of type 2 diabetes mellitus (DM) often is associated with underlying states of conditioned zinc deficiency and chronic inflammation. Zinc and omega-3 polyunsaturated fatty acids each exhibit anti-inflammatory effects and may be of therapeutic benefit in the disease. The present randomized, double blind, placebo-controlled, 12-week trial was designed to investigate the effects of zinc (40 mg/day) and alpha-linolenic acid (ALA; 2 g/day flaxseed oil) supplementation on markers of inflammation [interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, C-reactive protein (CRP)] and zinc transporter and metallothionein gene expression in 48 postmenopausal women with type 2 DM. No significant effects of zinc or ALA supplementation were observed on inflammatory marker concentrations or fold change in zinc transporter and metallothionein gene expression. Significant increases in plasma zinc concentrations were observed over time in the groups supplemented with zinc alone or combined with ALA (P=.007 and P=.009, respectively). An impact of zinc treatment on zinc transporter gene expression was found; ZnT5 was positively correlated with Zip3 mRNA (P<.001) only in participants receiving zinc, while zinc supplementation abolished the relationship between ZnT5 and Zip10. IL-6 predicted the expression levels and CRP predicted the fold change of the ZnT5, ZnT7, Zip1, Zip7 and Zip10 mRNA cluster (P<.001 and P=.031, respectively). Fold change in the expression of metallothionein mRNA was predicted by TNF-alpha (P=.022). Associations among inflammatory cytokines and zinc transporter and metallothionein gene expression support an interrelationship between zinc homeostasis and inflammation in type 2 DM. PMID- 23643523 TI - Fructose during pregnancy affects maternal and fetal leptin signaling. AB - Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome and cardiovascular diseases. Fructose intake also causes features of metabolic syndrome in laboratory animals. Therefore, we have investigated whether fructose modifies lipidemia in pregnant rats and produces changes in their fetuses. Thus, fructose administration (10% wt/vol.) in the drinking water of rats throughout gestation leads to maternal hypertriglyceridemia. This change was not observed in glucose-fed rats, although both carbohydrates produced similar changes in liver triglycerides and in the expression of transcription factors and enzymes involved in lipogenesis. After fasting overnight, mothers fed with carbohydrates were found to be hyperleptinemic. However, after a bolus of glucose, leptinemia in fructose-fed mothers showed no response, whereas it increased in parallel in glucose-fed and control mothers. Fetuses from fructose-fed mothers showed hypotriglyceridemia and a higher hepatic triglyceride content than fetuses from control or glucose-fed mothers. A higher expression of genes related to lipogenesis and a lower expression of fatty acid catabolism genes were also found in fetuses from fructose-fed mothers. Moreover, although hyperleptinemic, these fetuses exhibited increased tyrosine phosphorylation of the signal transducer and activator of transcription-3 (STAT-3) protein, without a parallel increase in the serine phosphorylation of STAT-3 nor in the suppressor of cytokine signaling-3 protein levels whose expression is regulated by leptin through STAT-3 activation. Thus, fructose intake during gestation provoked a diminished maternal leptin response to fasting and refeeding and an impairment in the transduction of the leptin signal in the fetuses, which could be responsible for their hepatic steatosis. PMID- 23643524 TI - Modulation of colonic inflammation in Mdr1a(-/-) mice by green tea polyphenols and their effects on the colon transcriptome and proteome. AB - Animal models are an important tool to understand the complex pathogenesis of inflammatory bowel diseases (IBDs). This study tested the anti-inflammatory potential of a green tea extract rich in polyphenols (GrTP) in the colon of the multidrug resistance targeted mutation (Mdr1a(-/-)) mouse model of IBD. Insights into mechanisms responsible for this reduction in inflammation were gained using transcriptome and proteome analyses. Mice were randomly assigned to an AIN-76A (control) or GrTP-enriched diet. At 21 or 24 weeks of age, a colonic histological injury score was determined for each mouse, colon mRNA transcript levels were assessed using microarrays, and colon protein expression was measured using two dimensional gel electrophoresis and liquid chromatography-mass spectrometry protein identification. Mean colonic histological injury score of GrTP-fed Mdr1a( /-) mice was significantly lower compared to those fed the control diet. Microarray and proteomics analyses showed reduced abundance of transcripts and proteins associated with immune and inflammatory response and fibrinogenesis pathways, and increased abundance of those associated with xenobiotic metabolism pathways in response to GrTP, suggesting that its anti-inflammatory activity is mediated by multiple molecular pathways. Peroxisome proliferator-activated receptor-alpha and signal transducer and activator of transcription 1 appear to be two key molecules which regulate these effects. These results support the view that dietary intake of polyphenols derived from green tea can ameliorate intestinal inflammation in the colon of a mouse model of IBD, and are in agreement with studies suggesting that consumption of green tea may reduce IBD symptoms and therefore play a part in an overall IBD treatment regimen. PMID- 23643525 TI - Characterization of the GufA subfamily member SLC39A11/Zip11 as a zinc transporter. AB - Cellular zinc influx and efflux are maintained by two major transporter families, the ZIP (SLC39A) and ZnT (SLC30A or CDF) molecules. The functions of one molecule in this class, ZIP11/SLC39A11, remain unclear. Bioinformatics analysis of the distribution and evolutionary relationships of different ZIP members in eukaryotes and prokaryotes indicated that Zip11, the sole member of gufA subfamily, is an ancient ZIP family member that might have originated in early eukaryotic ancestors. Murine Zip11 mRNA is abundantly expressed in testes and the digestive system including stomach, ileum and cecum. Analysis of cellular zinc content, metallothionein levels, and cell viability under high or low zinc conditions in cells transfected with a murine Zip11 expression plasmid, suggest that Zip11 is a zinc importer. Further, cellular zinc concentrations and metallothionein levels decreased when Zip11 was knocked down. In mice supplemented with zinc, both mRNA and protein levels of Zip11 were slightly up regulated in several tissues. The metal response element sequences (MREs) upstream of the first exon of Zip11 responded to elevated extracellular zinc concentrations, as assessed by luciferase reporter assays. Mutagenic analysis showed that several of the MREs could regulate Zip11 promoter activity, and metal responsive transcription factor-1 (MTF-1) was shown to be involved in this process. Collectively, these data suggest that Zip11 has unique protein sequence and structure features, it functions as a cellular zinc transporter, and its expression is at least partially regulated by zinc via hMTF-1 binding to MREs of the Zip11 promoter. PMID- 23643526 TI - Smad7 foci are present in micronuclei induced by heavy particle radiation. AB - DNA damage and reactive oxygen species (ROS) generated by ionizing radiation (IR) activate DNA damage response (DDR) and cytokine signaling pathways, including double strand break (DSB) repair and TGFbeta/Smad signaling pathway. Proteins assembled at IR-induced DSB sites can be visualized as foci, including gammaH2AX, 53BP1, ATM and ATF2. Unrepaired DSBs are thought to be one origin of micronuclei (MN), an indicator of genotoxic stress and chromosomal instability. Studies have detected gammaH2AX in IR-induced MN, indicating the presence of DSB in MN. Previously we reported that TGFbeta downstream proteins Smad7 and phospho-Smad2 (pSmad2) co-localized with DDR proteins following radiation. Here we studied the status of Smad7 and pSmad2 in MN post high linear energy transfer (LET) radiation in human normal and cancerous cells. We observed gammaH2AX foci in IR-induced MN, whereas 53BP1 and ATF2 were absent. Interestingly, Smad7 foci, but not pSmad2, were detectable in both spontaneous and IR-induced MN. We compared the effect of particle track structures on the yield of MN using 5.6MeV/u boron (B) and 600MeV/u iron (Fe) particles with similar LET (200 and 180keV/MUm, respectively) in human fibroblasts. The frequency of MN induced by B was lower than that by Fe particles, albeit the proportion of Smad7-positive to Smad7-negative MN remained constant. An increased frequency of spontaneous MN, with slightly higher ratio of Smad7 or gammaH2AX positive, was found in human prostate cancer cells (PC3) compared to normal cells. 24h after 1Gy of Fe particles exposure, the yield of MN increased, and the majority (~70%) carried gammaH2AX and Smad7. Phospho-ATM (Ser1981) foci were found in both spontaneous and IR-induced MN in PC3 cells, displaying a much lower frequency compared to gammaH2AX and Smad7. Our data suggest a unique role of Smad7 in IR-induced MN formation, which may associate with DNA repair, apoptosis and genomic instability. PMID- 23643527 TI - Genotoxic effects induced by zearalenone in a human embryonic kidney cell line. AB - Mycotoxins are considered to be significant contaminants of food and animal feed. Zearalenone (ZEA) is a hepatotoxic mycotoxin with estrogenic and anabolic activity found in cereal grains worldwide. ZEA affects hematological and immunological parameters in humans and rodents. The compound can induce cell death, cause lipid peroxidation, inhibit protein and DNA synthesis, and exert genotoxic effects. ZEA may cause increased phagolysosomal fragility in the kidney. Our research showed that exposure of human embryonic kidney (HEK293) cells to ZEA (10 or 20MUM) resulted in a concentration-dependent increase in DNA strand breaks measured with the comet assay. Damage was reduced in cells pretreated with NH4Cl, pepstatin A, or desipramine for 1h. Production of reactive oxygen species (ROS) was increased in cells exposed to ZEA, but DNA strand break induction could not be inhibited by the antioxidant hydroxytyrosol (HT). These results suggest that oxidative stress does not play a key role in DNA strand breaks induced by ZEA, that lysosomal injury precedes DNA strand breaks, and that the lysosome may be a primary target for ZEA in HEK293 cells. PMID- 23643529 TI - Photoactivation of gold nanoparticles for glioma treatment. AB - Radiosensitization efficacy of gold nanoparticles (AuNPs) with low energy radiations (88 keV) was evaluated in vitro and in vivo on rats bearing glioma. In vitro, a significant dose-enhancement factor was measured by clonogenic assays after irradiation with synchrotron radiation of F98 glioma cells in presence of AuNPs (1.9 and 15 nm in diameter). In vivo, 1.9 nm nanoparticles were found to be toxic following intracerebral delivery in rats bearing glioma, whether no toxicity was observed using 15 nm nanoparticles at the same concentration (50 mg/mL). The therapeutic efficacy of gold photoactivation was determined by irradiating the animals after intracerebral infusion of AuNPs. Survival of rats that had received the combination of treatments (AuNPs: 50 mg/mL, 15 Gy) was significantly increased in comparison with the survival of rats that had received irradiation alone. In conclusion, this experimental approach is promising and further studies are foreseen for improving its therapeutic efficacy. FROM THE CLINICAL EDITOR: These investigators report that gold nanoparticles of the correct size can be used to enhance the effects of irradiation in the context of a glioma model. Since many of the glioma varieties are currently incurable, this or similar approaches may find their way to clinical trials in the near future. PMID- 23643528 TI - Cross-protection by co-immunization with influenza hemagglutinin DNA and inactivated virus vaccine using coated microneedles. AB - The need for annual revaccination against influenza is a burden on the healthcare system, leads to low vaccination rates and makes timely vaccination difficult against pandemic strains, such as during the 2009 H1N1 influenza pandemic. In an effort toward achieving a broadly protective vaccine that provides cross protection against multiple strains of influenza, this study developed a microneedle patch to co-immunize with A/PR8 influenza hemagglutinin DNA and A/PR8 inactivated virus vaccine. We hypothesize that this dual component vaccination strategy administered to the skin using microneedles will provide cross protection against other strains of influenza. To test this hypothesis, we developed a novel coating formulation that did not require additional excipients to increase coating solution viscosity by using the DNA vaccine itself to increase viscosity and thereby enable thick coatings of DNA vaccine and inactivated virus vaccine on metal microneedles. Co-immunization in this way not only generated robust antibody responses against A/PR8 influenza but also generated robust heterologous antibody responses against pandemic 2009 H1N1 influenza in mice. Challenge studies showed complete cross-protection against lethal challenge with live pandemic 2009 H1N1 virus. Control experiments using A/PR8 inactivated influenza virus vaccine with placebo DNA coated onto microneedles produced lower antibody titers and provided incomplete protection against challenge. Overall, this is the first study showing DNA solution as a microneedle coating agent and demonstrating cross-protection by co-immunization with inactivated virus and DNA vaccine using coated microneedles. PMID- 23643530 TI - The role of the bacterial mismatch repair system in SOS-induced mutagenesis: a theoretical background. AB - A theoretical study is performed of the possible role of the methyl-directed mismatch repair system in the ultraviolet-induced mutagenesis of Escherichia coli bacterial cells. For this purpose, mathematical models of the SOS network, translesion synthesis and mismatch repair are developed. Within the proposed models, the key pathways of these repair systems were simulated on the basis of modern experimental data related to their mechanisms. Our model approach shows a possible mechanistic explanation of the hypothesis that the bacterial mismatch repair system is responsible for attenuation of mutation frequency during ultraviolet-induced SOS response via removal of the nucleotides misincorporated by DNA polymerase V (the UmuD'2C complex). PMID- 23643531 TI - Modelling adipocytes size distribution. AB - Adipocytes are cells whose task is to store excess energy as lipid droplets in their cytoplasm. Adipocytes can adapt their size according to the lipid amount to be stored. Adipocyte size variation can reach one order of magnitude inside the same organism which is unique among cells. A striking feature in adipocytes size distribution is the lack of characteristic size since typical size distributions are bimodal. Since energy can be stored and retrieved and adipocytes are responsible for these lipid fluxes, we propose a simple model of size-dependent lipid fluxes that is able to predict typical adipocytes size distribution. PMID- 23643532 TI - Hebbian plasticity guides maturation of glutamate receptor fields in vivo. AB - Synaptic plasticity shapes the development of functional neural circuits and provides a basis for cellular models of learning and memory. Hebbian plasticity describes an activity-dependent change in synaptic strength that is input specific and depends on correlated pre- and postsynaptic activity. Although it is recognized that synaptic activity and synapse development are intimately linked, our mechanistic understanding of the coupling is far from complete. Using Channelrhodopsin-2 to evoke activity in vivo, we investigated synaptic plasticity at the glutamatergic Drosophila neuromuscular junction. Remarkably, correlated pre- and postsynaptic stimulation increased postsynaptic sensitivity by promoting synapse-specific recruitment of GluR-IIA-type glutamate receptor subunits into postsynaptic receptor fields. Conversely, GluR-IIA was rapidly removed from synapses whose activity failed to evoke substantial postsynaptic depolarization. Uniting these results with developmental GluR-IIA dynamics provides a comprehensive physiological concept of how Hebbian plasticity guides synaptic maturation and sparse transmitter release controls the stabilization of the molecular composition of individual synapses. PMID- 23643533 TI - Generation of integration-free and region-specific neural progenitors from primate fibroblasts. AB - Postnatal and adult human and monkey fibroblasts were infected with Sendai virus containing the Yamanaka factors for 24 hr, then they were cultured in a chemically defined medium containing leukemia inhibitory factor (LIF), transforming growth factor (TGF)-beta inhibitor SB431542, and glycogen synthase kinase (GSK)-3beta inhibitor CHIR99021 at 39 degrees C for inactivation of the virus. Induced neural progenitor (iNP) colonies appeared as early as day 13 and can be expanded for >20 passages. Under the same defined condition, no induced pluripotent stem cell (iPSC) colonies formed at either 37 degrees C or 39 degrees C. The iNPs predominantly express hindbrain genes and differentiate into hindbrain neurons, and when caudalized, they produced an enriched population of spinal motor neurons. Following transplantation into the forebrain, the iNP derived cells retained the hindbrain identity. The ability to generate defined, integration-free iNPs from adult primate fibroblasts under a defined condition with predictable fate choices will facilitate disease modeling and therapeutic development. PMID- 23643535 TI - Morphological and molecular characterization of adult midgut compartmentalization in Drosophila. AB - Although the gut is a central organ of Eumetazoans and is essential for organismal health, our understanding of its morphological and molecular determinants remains rudimentary. Here, we provide a comprehensive atlas of Drosophila adult midgut. Specifically, we uncover a fine-grained regional organization consisting of 14 subregions with distinct morphological, histological, and genetic properties. We also show that Drosophila intestinal regionalization is defined after adult emergence, remains stable throughout life, and reestablishes following acute tissue damage. Additionally, we show that this midgut compartmentalization is achieved through the interplay between pan-midgut and regionalized transcription factors, in concert with spatial activities of morphogens. Interestingly, disruption of the midgut compartmentalization leads to a loss of intestinal homeostasis characterized by an increase in stem cell proliferation and aberrant immune responses. Our integrative analysis of Drosophila midgut compartmentalization provides insights into the conserved mechanisms underlying intestinal regionalization in metazoans. PMID- 23643536 TI - Chromosomal instability triggered by Rrm2b loss leads to IL-6 secretion and plasmacytic neoplasms. AB - Chronic inflammation has a tight cause-and-effect relationship with DNA damage by inflicting tissue damage and increasing cancer risk. Rrm2b, a key enzyme in de novo deoxyribonucleotide synthesis, is involved in DNA damage repair, but its role in cancer development has yet to be demonstrated. In this work, Rrm2b gene loss led to severe numerical and structural chromosome abnormalities that caused ATM activation, inducing p-Ser85 IKKgamma/NEMO and IkappaB kinase (IKK). NF kappaB consequently induced by IKK triggered sustained IL-6 expression that constitutively activated STAT3 in Rrm2b-deficient cells. High plasma interleukin 6 (IL-6) and associated hematologic disorders were observed in Rrm2b-/- mice, and 30%-40% of aged Rrm2b heterozygous knockout mice developed plasma cell neoplasms and suffered from progressive splenomegaly and ascites. The genetic ablation of IL-6 suppressed STAT3 induction and delayed disease onset in Rrm2b-/- mice, extending their lifespan. Thus, Rrm2b plays a crucial role in maintaining chromosomal stability and preventing chronic-inflammation-associated tumorigenesis. PMID- 23643534 TI - Cdc45 is a critical effector of myc-dependent DNA replication stress. AB - c-Myc oncogenic activity is thought to be mediated in part by its ability to generate DNA replication stress and subsequent genomic instability when deregulated. Previous studies have demonstrated a nontranscriptional role for c Myc in regulating DNA replication. Here, we analyze the mechanisms by which c-Myc deregulation generates DNA replication stress. We find that overexpression of c Myc alters the spatiotemporal program of replication initiation by increasing the density of early-replicating origins. We further show that c-Myc deregulation results in elevated replication-fork stalling or collapse and subsequent DNA damage. Notably, these phenotypes are independent of RNA transcription. Finally, we demonstrate that overexpression of Cdc45 recapitulates all c-Myc-induced replication and damage phenotypes and that Cdc45 and GINS function downstream of Myc. PMID- 23643537 TI - Inositol pyrophosphates regulate cell growth and the environmental stress response by activating the HDAC Rpd3L. AB - Cells respond to stress and starvation by adjusting their growth rate and enacting stress defense programs. In eukaryotes this involves inactivation of TORC1, which in turn triggers downregulation of ribosome and protein synthesis genes and upregulation of stress response genes. Here we report that the highly conserved inositol pyrophosphate (PP-IP) second messengers (including 1-PP-IP5, 5 PP-IP4, and 5-PP-IP5) are also critical regulators of cell growth and the general stress response, acting in parallel with the TORC1 pathway to control the activity of the class I histone deacetylase Rpd3L. In fact, yeast cells that cannot synthesize any of the PP-IPs mount little to no transcriptional response to osmotic, heat, or oxidative stress. Furthermore, PP-IP-dependent regulation of Rpd3L occurs independently of the role individual PP-IPs (such as 5-PP-IP5) play in activating specialized stress/starvation response pathways. Thus, the PP-IP second messengers simultaneously activate and tune the global response to stress and starvation signals. PMID- 23643538 TI - SNARE proteins synaptobrevin, SNAP-25, and syntaxin are involved in rapid and slow endocytosis at synapses. AB - Rapid endocytosis, which takes only a few seconds, is widely observed in secretory cells. Although it is more efficient in recycling vesicles than in slow clathrin-mediated endocytosis, its underlying mechanism, thought to be clathrin independent, is largely unclear. Here, we report that cleavage of three SNARE proteins essential for exocytosis, including synaptobrevin, SNAP-25, and syntaxin, inhibited rapid endocytosis at the calyx of Held nerve terminal, suggesting the involvement of the three SNARE proteins in rapid endocytosis. These SNARE proteins were also involved in slow endocytosis. In addition, SNAP-25 and syntaxin facilitated vesicle mobilization to the readily releasable pool, most likely via their roles in endocytosis and/or exocytosis. We conclude that both rapid and slow endocytosis share the involvement of SNARE proteins. The dual role of three SNARE proteins in exo- and endocytosis suggests that SNARE proteins may be molecular substrates contributing to the exocytosis-endocytosis coupling, which maintains exocytosis in secretory cells. PMID- 23643541 TI - Displaced nasal silicone implant: an unusual cause of nasotracheal tube obstruction. PMID- 23643539 TI - A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia. AB - The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1 deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target. PMID- 23643542 TI - Water extract of licorice had anti-viral activity against human respiratory syncytial virus in human respiratory tract cell lines. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Licorice (Glycyrrhiza uralensis Fisch., Leguminosae) has been used in herbal medicine and food supplement worldwide for centuries. Licorice is a common ingredient of several prescriptions of traditional Chinese medicine which have been proved to inhibit infection of human respiratory syncytial virus (HRSV). There are two preparations of licorice, Radix Glycyrrhizae and Radix Glycyrrhizae Preparata. However, it is unknown whether licorice or which preparation of licorice is effective against HRSV, nor is its active constituent. AIM OF THE STUDY: We tested the hypothesis that Radix Glycyrrhizae can effectively decrease HRSV-induced plaque formation in respiratory mucosal cell lines. We also tried to find out the active constituent. MATERIALS AND METHODS: Anti-HRSV activities of hot water extracts of preparations of licorice, glycyrrhizin and 18beta-glycyrrhetinic acid (18beta-GA), the active constituents of licorice, were examined by plaque reduction assay in both human upper (HEp-2) and low (A549) respiratory tract cell lines. Abilities of crude licorice to inhibit viral replication and to stimulate IFN-beta were evaluated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. RESULTS: Radix Glycyrrhizae and Radix Glycyrrhizae Preparata dose-dependently inhibited HRSV-induced plaque formation in both HEp-2 and A549 cell lines (p<0.0001). The effect of Radix Glycyrrhizae was better than that of Radix Glycyrrhizae Preparata on HEp-2 cells. However, there was no difference of their anti-HRSV effects on A549 cells. Besides, glycyrrhizin was ineffective at all. Nevertheless, 18beta-GA showed a potent anti HRSV activity. Radix Glycyrrhizae was more effective when given before viral inoculation (p<0.0001) which may be due to its inhibition of viral attachment on (p<0.0001) and penetration (p<0.0001) into the host cells. The anti-HRSV activity of Radix Glycyrrhizae was further confirmed by RT-PCR and qRT-PCR. 300 MUg/ml Radix Glycyrrhizae markedly decreased the viral amounts within the cells and in the suspension. Radix Glycyrrhizae might further stimulate mucosal cells to secrete IFN-beta to counteract viral infection. CONCLUSIONS: Both Radix Glycyrrhizae and Radix Glycyrrhizae Preparata are effective against HRSV infection on airway epithelial cells. Radix Glycyrrhizae inhibited HRSV mainly by preventing viral attachment, internalization, and by stimulating IFN secretion. 18beta-GA may be one of its active constituents. PMID- 23643540 TI - Socioeconomic position and adolescent trajectories in smoking, drinking, and psychiatric distress. AB - PURPOSE: Smoking, drinking, and psychiatric distress are inter-related and may also be associated with socioeconomic position (SEP). This paper investigates the role of SEP in adolescent development across all three of these outcomes. METHODS: Data were self-reported by adolescents in the Twenty-07 Study (N = 1,515) at ages 15, 17, and 18 years. Latent class analysis was used to identify homogeneous subgroups of adolescents with distinct developmental patterns. Associations between developmental patterns and a range of socioeconomic indicators were then tested. RESULTS: Five classes were identified. A Low Risk class had low levels for all outcomes. A High Distress class had persistently high levels of distress, but was otherwise similar to the Low Risk group. A High Drinking class drank alcohol earlier and more heavily but also had higher levels of distress than the Low Risk group. Smokers were grouped in two classes, Early Smokers and Late Smokers, and both also had raised levels of drinking and distress. Early Smokers tended to begin earlier and smoke more heavily than Late Smokers. Relative to the Low Risk class, adolescents in a disadvantaged SEP were more likely to be Early Smokers and somewhat less likely to be in the High Drinking class. SEP was not consistently associated with membership in the High Distress or Late Smokers classes. CONCLUSIONS: Associations with SEP are evident in opposing directions or absent depending on the combination and timing of outcomes, suggesting that a disadvantaged SEP is not a simple common cause for all three outcomes. PMID- 23643543 TI - Pharmacokinetic study of four flavones of Glycyrrhiza in rat plasma using HPLC MS. AB - AIM OF THE STUDY: This study aimed to develop a specific HPLC-MS method for simultaneous quantification of four flavones of Glycyrrhiza in rat plasma after oral administration and to describe the pharmacokinetics of four flavones in rat plasma. MATERIALS AND METHODS: A simple, sensitive and selective method for simultaneous determination of four flavones of Glycyrrhiza in rat plasma, i.e., liquiritin, isoliquiritin, liquiritigenin, and isoliquiritigenin, by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS) with negative electrospray ionization mode, was developed and validated. The method was applied to investigate the pharmacokinetics of four flavones in rat plasma after oral administration of Glycyrrhiza flavones. Chromatographic separation was accomplished on an Agilent TC-C18 column (4.6mm*250mm, and 5MUm), with gradient elution by using a mixture of methanoic acid (A) and acetonitrile (B) as the mobile phase at a flow rate of 0.8mL/min. RESULTS: The calibration curves for four flavones had good linearity higher than 0.997 in the measured range. Relative standard deviations (RSDs) of the intra- and inter-day precision at different levels were all less than 4.8%. The pharmacokinetic profile of four flavones in rat plasma was fitted with a two-compartment model detected by a simple, rapid and accurate HPLC-MS method. Time (h) to reach peak concentration (MUg/mL) of liquiritin (2.69+/-0.04), isoliquiritin (10.16+/-0.02), liquiritigenin (2.83+/-0.02), and isoliquiritigenin (0.28+/-0.01) was 2.02+/ 0.23, 1.97+/-0.20, 0.48+/-0.02, and 1.93+/-0.36, respectively. The distribution and elimination half-life (h) and area under the concentration-time curve (MUg/mL h) from t=0 to last time of liquiritin, isoliquiritin, liquiritigenin, and isoliquiritigenin were 1.02+/-0.48/2.27+/-0.53/16.97+/-0.43, 2.04+/-1.01/2.38+/ 0.80/69.20+/-5.24, 0.35+/-0.10/4.26+/-0.16/14.83+/-0.11, and 1.18+/-0.32/3.04+/ 0.22/2.10+/-0.09, respectively. Isoliquiritin presented the phenomenon of double peaks and the others appeared together in a single and plateau absorption phase. Isoliquiritigenin had the lowest oral bioavailability because of Cmax and AUC0 infinity. Liquiritigenin had the fastest absorption and distribution rate and the lowest elimination rate according to Tmax, t1/2alpha, and t1/2beta. CONCLUSIONS: This paper first reported on identification and determination of four flavones of Glycyrrhiza in rat plasma and their respective pharmacokinetic characteristics. The results provided a meaningful basis for better understanding the absorption mechanism of Glycyrrhiza and evaluating the clinical application of this medicine. PMID- 23643544 TI - Herbalists and wild medicinal plants in M'Sila (North Algeria): an ethnopharmacology survey. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The main aim of this study was to identify, catalogue and document the large number of wild medicinal plants used in the M'Sila region (northern Algeria) for the treatment of several human pathologies. Another more ambitious aim is to contribute to overcoming the limits of an orally transmitted pharmacopoeia, attempting to exploit the large ethnopharmacology patrimony of the region for further pharmacological purposes. MATERIALS AND METHODS: Our field study was carried out over a period of three years (2008 2010). During this period, herbalists were interviewed using semi-structured questionnaires investigating the herbalist as a holder of information (gender, age and educational level) and about wild medicinal plants (local name, uses and part used). In addition, the relative importance value of the species was determined and informant consensus factor (ICF) was calculated for the medicinal plants included in the study. RESULTS: A total of 83 herbalists were interviewed; men dominate the practice of traditional medicine in the region. About 41% of them are between 31 and 40 years, and about a third (34%) are illiterate. The traditional herbal knowledge is passed from generation to generation in the verbal form, a writing tradition being almost totally absent. The interviewed herbalists identified and recorded 58 plants species and 50 genera belonging to 27 plant families. Lamiaceae and Asteraceae were the most represented plant families. The aerial parts were the most commonly used plant part, while infusion and decoction were the most common method of traditional drug preparation. CONCLUSIONS: The survey provides a veritable source of information on the herbalists and wild medicinal plants. Plants which are used in different parts of the world for the treatment of similar diseases may be deemed to be effective in pharmacological terms. These medicinal plants may be incorporated into the healthcare delivery system of the country. PMID- 23643545 TI - Aortic valve disease in pulmonary atresia and major aortopulmonary collaterals. AB - BACKGROUND: Aortic valve disease in association with pulmonary atresia, ventricular septal defect, and major aortopulmonary collaterals (PA/VSD/MAPCAs) is an extremely rare combination of congenital heart defects. The presence of aortic stenosis or insufficiency or both imposes an additional physiologic burden that complicates the management of PA/VSD/MAPCAs. This report summarizes our experience with 7 patients who underwent surgical repair of this rare combination of defects. METHODS: This was a retrospective review of patients who had both aortic valve disease and PA/VSD/MAPCAs. Four patients had predominantly aortic stenosis, 2 patients had aortic insufficiency, and 1 had mixed stenosis and insufficiency. Anatomically, this corresponded to a dysplastic trileaflet valve in 4, bicuspid valve in 2, and quadricuspid valve in 1. RESULTS: Four of the 7 patients underwent aortic valve surgery at the time of their first operation for PA/VSD/MAPCAs. The remaining 3 patients had aortic valve surgery at subsequent operations. All 7 patients are alive, with a median duration of follow-up of 3 years. One patient has required aortic valve replacement 2 years after repair of an insufficient bicuspid valve. CONCLUSIONS: This manuscript summarizes our experience with 7 patients who had the rare combination of aortic valve disease and PA/VSD/MAPCAs. Although aortic valve disease has been reported for other conotruncal defects, we believe this is the first report of its presence in association with PA/VSD/MAPCAs. PMID- 23643546 TI - Biventricular finite element modeling of the Acorn CorCap Cardiac Support Device on a failing heart. AB - BACKGROUND: The Acorn CorCap Cardiac Support Device (CSD; Acorn Cardiovascular Inc, St. Paul, MN) is a woven polyester jacket that is placed around the heart and designed to reverse the progressive remodeling associated with dilated cardiomyopathy. However, the effects of the Acorn CSD on myofiber stress and ventricular function remain unknown. We tested the hypothesis that the Acorn CSD reduces end-diastolic (ED) myofiber stress. METHODS: A previously described weakly coupled biventricular finite element (FE) model and circulatory model based on magnetic resonance images of a dog with dilated cardiomyopathy was used. Virtual applications of the CSD alone (Acorn), CSD with rotated fabric fiber orientation (rotated), CSD with 5% prestretch (tight), and CSD wrapped only around the left ventricle (LV; LV-only) were performed, and the effect on myofiber stress at ED and pump function was calculated. RESULTS: The Acorn CSD has a large effect on ED myofiber stress in the LV free wall, with reductions of 55%, 79%, 92%, and 40% in the Acorn, rotated, tight, and LV-only cases, respectively. However, there is a tradeoff in which the Acorn CSD reduces stroke volume at LV end-diastolic pressure of 8 mm Hg by 23%, 25%, 30%, and 7%, respectively, in the Acorn, rotated, tight, and LV-only cases. CONCLUSIONS: The Acorn CSD significantly reduces ED myofiber stress. However, CSD wrapped only around the LV was the only case with minimal negative effect on pump function. Findings suggest that LV-only CSD and Acorn fabric orientation should be optimized to allow maximal myofiber stress reduction with minimal reduction in pump function. PMID- 23643548 TI - Fate of newly detected lesions during postoperative surveillance for non-small cell lung cancer. AB - BACKGROUND: Chest computed tomography (CT) is the mainstay of postoperative surveillance for non-small cell lung cancer (NSCLC). However, there is no clear consensus about the optimal management of newly detected lesions on follow-up CT. Our goals were (1) to determine the eventual outcome of newly detected lesions on follow-up CT in patients with previously resected NSCLC and (2) to determine the characteristics of the detected lesions that suggest recurrence. METHODS: In this retrospective study, we investigated 116 patients with NSCLC who underwent operations between February 2004 and December 2011 and had newly detected lesions on postoperative surveillance CT at least once during the follow-up period (median, 29 months). We investigated lesion size, growth, laterality, multiplicity, and recurrence patterns, as well as demographic data. RESULTS: One hundred fifty-seven new lesions were detected during the follow-up period. Of the 157 lesions, 139 were intrathoracic (lung, 83; lymph node, 34; pleura, 14; others, 8) and 18 were extrathoracic. Further investigation or follow-up confirmed that 78 lesions (49.7% [78 of 157]) were recurrences. Extrathoracic lesions showed a higher correlation with recurrence compared with intrathoracic ones (83.3% versus 45.3%; p = 0.002). Regarding lung lesions, solid nodules (p = 0.003; hazard ratio, 13.190) and lesions in patients with stage III disease (p = 0.043; hazard ratio, 6.464), were much more likely to reflect recurrence. CONCLUSIONS: In patients with newly detected lesions on follow-up chest CT after resection of NSCLC, special attention should be paid to lesions with the following characteristics: extrathoracic lesions, solid lung nodules, and lung lesions in patients with stage III disease. It is necessary to investigate these lesions more aggressively because they suggest the presence of recurrent disease. PMID- 23643547 TI - Visceral pleural invasion is not predictive of survival in patients with lung cancer and smaller tumor size. AB - BACKGROUND: Visceral pleural invasion (VPI) is used as an indicator of adverse prognosis in non-small cell lung cancer (NSCLC). The purpose of this retrospective study was to evaluate the impact of VPI on disease-free survival (DFS) and overall survival (OS) in patients with node-negative NSCLC. METHODS: Between 1998 and 2009, 1,166 patients with pathologic N0M0 NSCLC underwent surgical resection by lobectomy. Two hundred fourteen patients with VPI were compared with 952 patients without VPI. RESULTS: Median follow-up was 59 months. In multivariate analysis, VPI, larger tumor size, older age, female sex, and poor performance status were significantly associated with decreased OS. In contrast, larger tumor size, female sex, and poor performance, but notably not VPI, were associated with decreased DFS. After examining interactive effects of VPI and T stage subgroups, we found that VPI did not significantly affect either OS or DFS in the subgroups of patients with smaller tumor sizes-stage T1a, stage T1b, or stage T2a. In contrast, a deleterious effect of VPI on DFS was seen for tumors larger than 5 cm-stages T2b and T3-with the VPI-stage T3 interaction effect being statistically significant for DFS but not for OS. CONCLUSIONS: The effect of VPI on survival in NSCLC varies greatly with tumor size, with VPI not strongly associated with OS or DFS in tumors smaller than 5 cm, but showing large negative effects on DFS for stage T2b and stage T3 tumors. Using VPI to upstage T1 tumors to a higher T stage is not warranted because it would misrepresent these VPI-T stage subgroup effects. PMID- 23643549 TI - Coarctation-associated aneurysms: a localized disease or diffuse aortopathy. AB - BACKGROUND: We evaluated the occurrence and treatment of aortic aneurysms in coarctation patients. METHODS: During 1962 to 2011, 943 cases of coarctation were repaired. Aortic aneurysms were identified in 55 patients (5.8%). Forty-eight had prior coarctation repair (median 23 years earlier, interquartile range 18 to 26 years). Forty-two aneurysms were found in the descending thoracic aorta (76.4%), 18 in the ascending aorta (32.7%), 8 in the left subclavian artery (14.5%), and 1 each (1.8%) in the abdominal aorta, iliac artery, and innominate artery. Twenty three patients (41.8%) had multiple aneurysms. Twenty-five patients (45.4%) had a bicuspid aortic valve. RESULTS: Fifty-three patients' aneurysms were treated surgically. Thirty-five (66.0%) had descending thoracic aortic repair, of whom 11 had aorto-left subclavian bypass. Aortic cross-clamping alone was used in 23 patients, left heart bypass in 4, and circulatory arrest in 8. Eleven patients underwent endovascular repair (20.8%). Proximal aortic aneurysms were repaired in 7 patients (13.2%); 1 had simultaneous antegrade endostent delivery. Four patients had ascending-to-descending aortic bypass (7.3%). Concomitant valve sparing root repair was performed in 2 patients, Bentall in 4, aortic valve replacement in 3, and coronary artery bypass in 1. One 30-day death occurred (1.9%). Three patients (5.7%) had transient neurologic deficits, 2 (3.8%) required tracheostomy, and 11 (20.8%) had vocal cord paralysis. CONCLUSIONS: Coarctation is a marker for aortic aneurysm formation in adults and merits long term surveillance. Anatomic complexity and associated conditions can complicate the surgical repair. Various open, extra-anatomic, and endovascular techniques may be used. PMID- 23643550 TI - Systematic review of adrenalectomy and lymph node dissection in locally advanced renal cell carcinoma. AB - CONTEXT: Controversy remains over whether adrenalectomy and lymph node dissection (LND) should be performed concomitantly with radical nephrectomy (RN) for locally advanced renal cell carcinoma (RCC) cT3-T4N0M0. OBJECTIVE: To systematically review all relevant literature comparing oncologic, perioperative, and quality-of life (QoL) outcomes for locally advanced RCC managed with RN with or without concomitant adrenalectomy or LND. EVIDENCE ACQUISITION: Relevant databases were searched up to August 2012. Randomised controlled trials (RCTs) and comparative studies were included. Outcome measures were overall survival, QoL, and perioperative adverse effects. Risks of bias (RoB) were assessed using Cochrane RoB tools. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. EVIDENCE SYNTHESIS: A total of 3658 abstracts and 252 full-text articles were screened. Eight studies met the inclusion criteria: six LNDs (one RCT and five nonrandomised studies [NRSs]) and two adrenalectomies (two NRSs). RoB was high across the evidence base, and the quality of evidence from outcomes ranged from moderate to very low. Meta-analyses were not undertaken because of diverse study designs and data heterogeneity. There was no significant difference in survival between the groups, even though 5 yr overall survival appears better for the RN plus LND group compared with the no LND group in one randomised study. There was no evidence of a difference in adverse events between the RN plus LND and no-LND groups. No studies reported QoL outcomes. There was no evidence of an oncologic difference between the RN with adrenalectomy and RN without adrenalectomy groups. No studies reported adverse events or QoL outcomes. CONCLUSIONS: There is insufficient evidence to draw any conclusions on oncologic outcomes for patients having concomitant LND or ipsilateral adrenalectomy compared with patients having RN alone for cT3-T4N0M0 RCC. The quality of evidence is generally low and the results potentially biased. Further research in adequately powered trials is needed to answer these questions. PMID- 23643552 TI - What does it take to become 'best friends'? Evolutionary changes in canine social competence. AB - The traditional and relatively narrow-focused research on ape-human comparisons has recently been significantly extended by investigations of different clades of animals, including the domestic dog (Canis familiaris). Here, we provide a short overview of how the comparative investigation of canine social behaviour advances our understanding of the evolution of social skills and argue that a system-level approach to dog social cognition provides a broader view on the 'human-likeness' of canine social competence. We introduce the concept of evolutionary social competence as a collateral notion of developmental social competence. We argue that such an extended perspective on social competence provides a useful tool for conceptualising wolf-dog differences in socio-cognitive functioning, as well as for considering specific social skills not in isolation, but as a part of a system. PMID- 23643551 TI - Conidial acquisition and survivorship of adult Asian longhorned beetles exposed to flat versus shaggy agar fungal bands. AB - Fungal bands can deliver lethal conidial doses to adult Asian longhorned beetles. Because higher doses result in shorter survival times, developing a method to deliver more conidia to beetles walking across the fungal bands is desirable. We compared fungal bands made using standard flat material to bands made using a shaggy, textured material. The median survival time of adult beetles exposed to shaggy bands was reduced to 10 d versus 18 d for beetles exposed to flat bands. Beetles climbing across shaggy bands acquired 1.83*10(6) conidia per beetle, which was 14.6 times greater than beetles exposed to flat bands. PMID- 23643553 TI - Prevalence and types of extended spectrum beta-lactamases among urinary Escherichia coli isolates in Moroccan community. AB - This study was designed to characterize extended-spectrum-beta-lactamases (ESBL) produced by Escherichia coli isolates causing community urinary tract infections over a 2-year period (2010 and 2011) in a Moroccan large geographical region. Molecular characterization was done by using PCR and sequencing of the beta lactamases genes and plasmid-mediated quinolone resistance determinants. Among 1174 isolates, 49 (4.1%) were ESBL producers. The blaCTx-M-15 (n = 31) was the most frequent ESBL gene detected, followed by blaCTx-M-1 (n = 5), blaSHV-12 (n = 6), blaPER-2 (n = 3), then blaTEM-3, blaTEM-20, blaTEM-158, blaSHV-27, blaSHV-28, blaSHV-36, blaSHV-125, blaCTx-M-14 and blaCTx-M-27 with one isolate for each. The non-ESBL genes detected were blaTEM-70 (n = 1), blaTEM-176 (n = 1), blaTEM-104 (n = 6), blaTEM-1 (n = 15) and blaOxA-1 (n = 12). Plasmid mediated AmpC beta lactamases genes; blaACT-5 (n = 1), blaDHA-1(n = 2) and blaCMY-2 (n = 4) were detected in seven isolates (14.2%). The blaOxA-48 (n = 1) and blaIMP-1 (n = 1) carbapenemases genes were detected among five carbapenem-resistant E. coli. Five isolates (10.2%) harboured qnr genes, qnrB1 (n = 3), qnrB2 (n = 1) and qnrS1 (n = 1) type were detected. Thirty isolates (61.2%) were positive for aac(6')-Ib-cr gene. The class 1 integron was detected in twenty two (44.8%) isolates. Phylogenetic grouping revealed that 22 (44.8%) isolates belonged to group A, while 15 (30.6%), 11 (22.4%) and 1 (2%) belonged to B2, D and B1. Results of conjugation experiments indicated that blaCTx-M-15, blaTEM-1, blaOxA-1, aac(6') Ib-cr and qnrB1 genes were co-transferred and that these genes were carried by a conjugative plasmid of high molecular weight. The results of this work reports the genetic diversity of ESBL genes, with the CTX-M-15 enzyme being the most common among ESBL-producing E. coli in Moroccan community. PMID- 23643554 TI - Dopaminergic contributions to distance estimation in Parkinson's disease: a sensory-perceptual deficit? AB - Recent research has found that perceptual deficits exist in Parkinson's disease (PD), yet the link between perception and movement impairments is not well understood. Inaccurate estimation of distance has the potential to be an underlying cause of movement impairments. Alternatively, those with PD may not be able to perceive their own movements accurately. The main objectives of these studies were to evaluate (1) whether distance estimation is influenced by static perception compared to perception during movement in PD, (2) how visual motion processing contributes to distance estimation during movement, and (3) how dopaminergic medication contributes to these distance estimation deficits. Thirty seven participants (19 individuals with PD, 18 age-matched healthy control (HC) participants) estimated distance to a remembered target in a total of 48 trials, in 4 randomized blocks. Estimation conditions included: (i) static perception (laser): participants pointed with a laser, (ii) active dynamic perception (walk): participants walked to the estimated position, (iii) passive dynamic perception (wheelchair): participants were pushed in a wheelchair while they gave their estimate. PD patients completed this protocol twice; once OFF and once ON dopaminergic medication. Participants with PD and HC did not differ in judgment accuracy during the static perception (laser) condition. However, those with PD had greater amounts of error compared to HC participants while estimating distance during active dynamic perception (walk). Interestingly, those with PD significantly underestimated the target position compared to healthy control participants across all conditions. Individuals with PD also demonstrated greater variability in their judgments overall. There was no significant influence of dopaminergic medication in any of the conditions. Individuals with PD demonstrated distance estimation deficits only when required to actively move through their environment. In contrast to estimations made with movement, neither static perception (laser) nor passive dynamic perceptions (wheelchair) revealed significant differences in the magnitude of error between the two groups. Thus perceptual estimation deficits appear to be amplified during movement, which may be suggestive of an underlying sensory processing deficit which leads to a problem integrating vision and self-motion information. PMID- 23643555 TI - Emergence of a novel lineage genetically divergent from the predominant Ind2001 lineage of serotype O foot-and-mouth disease virus in India. AB - In India, emergence of Ind2001 lineage of foot-and-mouth disease virus (FMDV) serotype O was recorded in the year 2001. After causing sporadic incidences, the Ind2001 lineage that re-surged in 2008 out-competed PanAsia from the field during 2009 and continued its dominance during 2010 and 2011 as well. The lineage has diversified in due course of time, leading to two sub-lineages (Ind2001a and Ind2001b). The sub-lineage Ind2001a include isolates collected during 2001-2002 and sub-lineage Ind2001b is constituted largely by isolates collected during 2008 2012. The nucleotide substitution rate of sub-lineage Ind2001b was estimated at 6.58*10-3 substitutions/site/year. The most stable PanAsia lineage is restricted only to few outbreaks. During 2011, emergence of a new genetic group with >9% nucleotide divergence from rest of the lineages circulating in the country was detected and named as lineage Ind2011. Two specific amino acid substitutions at positions VP1-36 (F) and VP2-133 (T) were observed in the Ind2011 lineage. The new lineage at present is restricted only to southern states of the country. It is uncertain whether the emergence was triggered by immune pressure or due to a bottleneck in transmission or selected for higher fitness value. Six sites (4, 68, 83, 135, 138 and 209) in VP1 protein were identified to undergo episodic diversifying selection in serotype O field isolates. Both emerging and re emerging lineages had appropriate antigenic match with currently used vaccine strain, INDR2/1975. Irrespective of genetic variability, the field isolates showed remarkable conservation at antigenically critical residues that might contribute to the observed antigenic stability. With the emergence of a new genetic group after a span of 10 years, the overall epidemiological scenario in the region is expected to change in the coming years. PMID- 23643556 TI - The best of times, the worst of times... PMID- 23643557 TI - Outcomes in the emergency endovascular repair of blunt thoracic aortic injuries. AB - Thoracic aorta blunt injury (BAI) is a highly lethal lesion. A large number of victims die before obtaining emergency care. Thoracic endovascular aneurysm repair (TEVAR) is a less invasive method compared with open surgery and may change protocols for BAI treatment. This retrospective study was developed to evaluate the potential issues about thoracic endografting in the management of these patients. Twenty-seven patients with a BAI underwent aortic stent grafting. Intervention was preceded by the treatment of more urgent associated lesions in nine cases. In-hospital mortality was 7.4%. No paraplegia or ischemic complications developed because of the coverage of the left subclavian artery. In one case (3.2%), a type I endoleak was detected, proximal endograft infolding in two cases (7.4%) and endograft distal migration in further two cases were detected during follow-up (6-110 months). Thoracic endovascular aneurysm repair of BAI showed encouraging results in terms of perioperative mortality and morbidity. Concerns still remain about the potential mid- and long-term complications in younger patients. PMID- 23643558 TI - Discussion. PMID- 23643559 TI - Plasma total homocysteine is associated with abdominal aortic aneurysm and aortic diameter in older men. AB - OBJECTIVE: This study was conducted to determine whether plasma total homocysteine (tHcy) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism are associated with abdominal aortic aneurysm (AAA) and aortic diameter. METHODS: This was a cross-sectional study set in Western Australia of 4248 community-dwelling men aged 70 to 88 years. Infrarenal aortic diameter was measured using ultrasound scan, tHcy was measured by immunoassay, and MTHFR 677T polymorphism was detected by polymerase chain reaction. RESULTS: Adjusted multinomial logistic regression analysis showed the odds of having an AAA (aortic diameter >= 30 mm) for men with high tHcy (>= 15 MUmol/L) compared with those with normal tHcy (<15 MUmol/L) was 1.45 (95% confidence interval [CI], 1.10 1.91). Every 5-MUmol/L increment in tHcy was associated with 0.15-mm (95% CI, 0.01-0.28 mm) increase in mean aortic diameter. The tHcy concentration was higher in MTHFR TT homozygote individuals than in wild-type CC individuals. There was, however, no apparent association between MTHFR C677T polymorphism with AAA (TT vs CC genotype: odds ratio, 0.97; 95% CI, 0.72-1.31) or aortic diameter (TT vs CC genotype: mean increment of 0.01 mm; 95% CI, -0.63 to 0.65 mm). CONCLUSIONS: Elevated tHcy is associated with the presence of AAA in older men. There is also a positive dose-response relationship between tHcy and abdominal aortic diameter. Longitudinal studies and clinical trials of lowering tHcy are required to assess whether these relationships are causal. PMID- 23643560 TI - Early report from an investigator-initiated investigational device exemption clinical trial on physician-modified endovascular grafts. AB - OBJECTIVE: To determine whether a physician-modified endovascular graft (PMEG) is a safe and effective method for treating patients with juxtarenal aortic aneurysms who are deemed unsuitable for open repair. METHODS: A nonrandomized, prospective, consecutively enrolling investigational device exemption clinical trial was used. Data collected on patients treated with PMEG between April 2011 and August 2012 were analyzed. Subjects were followed with computed tomography, visceral duplex, and four-view X-ray at 30 days, 6 months, and 1 year. The protocol was designed to include follow-up to 5 years. The primary safety end point was the proportion of subjects who experienced a major adverse event (MAE) within 30 days of the procedure. The primary efficacy end point was the proportion of subjects experiencing treatment success. RESULTS: During the 16 month study period, 28 patients were consented and 26 underwent endovascular repair using PMEGs. Anatomic, operative details, and length of stay were recorded and included aneurysm diameter (mean, 62.5 mm), proximal neck length (mean, 4.4 mm), graft manufacture time (mean, 59.7 minutes), procedure time (mean, 169 minutes), fluoroscopy time (mean, 42.8 minutes), total contrast usage (mean, 63 mL), estimated blood loss (mean, 221 mL), and length of hospital stay (mean, 4.9 days). There were 63 fenestrations created for 48 renal arteries and 15 superior mesenteric arteries. Renal artery fenestrations were stented whenever possible (96%) and superior mesenteric artery fenestrations were all left unstented. There were no unanticipated adverse device events, no MAEs, and only a single minor adverse device event treated with a successful reintervention. At 30 days, there were no type I or III endoleaks and only four type II endoleaks (15.4%). Two patients died during the study period, one at day 23 from respiratory failure (in hospital and 30-day mortality = 3.8%) and one at day 210 from urosepsis and congestive heart failure. MAEs occurred in 11.5% of patients at 30 days. The primary efficacy end point was achieved in 87.5% of patients (technical success 100%, freedom from migration, rupture or conversion, type I or III endoleaks, or sac enlargement = 100%, 100%, 87.5%, and 87.5%, respectively). CONCLUSIONS: These preliminary data suggest that endovascular repair with PMEG is safe and effective for managing patients with juxtarenal aortic aneurysms. Endovascular repair with PMEG has acceptable early rates of morbidity, mortality, and endoleak. This endovascular aortic strategy is particularly appealing for those patients presenting with symptomatic or ruptured aortic aneurysms until reliable off-the shelf solutions become widely available. PMID- 23643561 TI - Sex differences in 30-day and 5-year outcomes after endovascular repair of abdominal aortic aneurysms in the EUROSTAR study. AB - OBJECTIVE: The purpose of this study was to determine the effect of sex on 30-day and long-term outcomes after elective endovascular aneurysm repair. METHODS: Patients entered into the European collaborators on stent graft techniques for abdominal aortic aneurysm repair (EUROSTAR) study formed the basis of our study. Data were analyzed by means of multivariable logistic regression for 30-day mortality and composite outcome of mortality, systemic complication, or conversion. Kaplan-Meier survival analyses were used to compare long-term survival and long-term event-free survival times between women and men. The log rank test was used to test for differences. Cox proportional hazards regression was used to analyze survival and event-free survival (with end point mortality or reintervention). Multivariable analyses were adjusted for age, comorbidities, aneurysm characteristics, and treatment characteristics. RESULTS: There were 623 women and 8604 men available for analysis. No difference in 30-day mortality was demonstrated for women compared with men (odds ratio, 0.89; 95% confidence interval [CI], 0.48-1.67), but women did have a significantly higher cumulative incidence of the composite end point (odds ratio, 1.32; 95% CI, 1.05-1.66). The Kaplan-Meier curves demonstrated worse outcomes for both long-term survival (P = .05) and long-term event-free survival (P =.005). Survival analyses adjusting for covariates demonstrated a higher albeit nonsignificant difference in long-term mortality for women compared to men (hazard rate ratio, 1.21; 95% CI, 0.96-1.53) and a significant higher rate of the composite end point mortality or reintervention (hazard rate ratio, 1.28; 95% CI, 1.07-1.54). CONCLUSIONS: Women undergoing endovascular aortic repair have higher complication and reintervention rates compared with men, implying that the role of elective endovascular aneurysm repair in women needs to be examined more closely. PMID- 23643562 TI - Prestimulus alpha and beta determinants of ERP responses in the Go/NoGo task. AB - The nature of the relationships between the level of immediately-prestimulus EEG activity and auditory ERP components remains unclear. Particularly, both inverse and direct relationships have been reported for the alpha band. Here we aim to clarify the pattern of prestimulus EEG contributions in alpha (8-13 Hz), and investigate those in beta (14-24 Hz), for five ERP components (P1, N1, P2, N2, P3) in an auditory equiprobable Go/NoGo paradigm. Separate FFTs were applied to the prestimulus Cz data of each accepted trial. The alpha and beta bands were independently assessed. The mean prestimulus spectral band amplitude was computed and used to sort the trials at nine central sites, and the upper and lower sorted trial thirds were averaged to form ERPs for Go and NoGo responses. Prestimulus EEG level effects (High vs. Low) were examined in each component's latency and amplitude, and Go reaction time was also assessed. Prestimulus alpha directly modulated the amplitude of the positive components (P1, P2, P3), while prestimulus beta directly modulated the positivity of the exogenous component amplitudes (P1, N1, P2); each amplitude effect occurred independently of the Go/NoGo stimulus conditions. Prestimulus beta also inversely modulated Go N1 latency; no reaction time effects were found for either band. The pattern of findings is intriguing and the various modulations are discussed in relation to attention and arousal. Together, these results confirm the importance of the EEG brain state immediately prestimulus, and indicate the considerable influence that these states have on event-related response processing. PMID- 23643563 TI - EEG alpha and cortical inhibition in affective attention. AB - Recent progress in cognitive neuroscience suggests that alpha activity may reflect selective cortical inhibition involved in signal amplification, rather than neural idling. Unfortunately, these theoretical advances remain largely ignored in affective neuroscience. To address this limitation the present paper proposes a novel research avenue aimed at using alpha to elucidate cortical inhibitory mechanisms involved in affective processes. The proposal is illustrated by developing inhibitory accounts of affective attention and affective tuning phenomena. The emergent predictions were tested using event related perturbations from 73 students evaluating affective and nonaffective aspects of five types of emotional images. The results revealed that upper alpha power was increased by affective content in general and aversive stimuli in particular from 350 ms at posterior and from 575 ms at central sites. The evaluation task interacted with affective content only at a liberal statistical significance level in late posterior alpha. These results are generally in line with the proposed inhibitory accounts of affective attention and tuning, although the evidence is preliminary rather than conclusive. As confirmation of functional origins of alpha in affect remains beyond the scope of a single study, this paper aims to inspire further extrapolation of the inhibitory account of alpha within affective neuroscience. PMID- 23643564 TI - The late positive potential (LPP) in response to varying types of emotional and cigarette stimuli in smokers: a content comparison. AB - Identifying neural mechanisms associated with addiction has substantially improved the overall understanding of addictive processes. Indeed, research suggests that drug-associated cues may take advantage of neural mechanisms originally intended for emotional processing of stimuli relevant to survival. In this study, we investigated cortical responses to several categories of emotional cues (erotic, romance, pleasant objects, mutilation, sadness, and unpleasant objects) as well as two types of smoking-related cues (people smoking and cigarette-related objects). We recorded ERPs from 180 smokers prior to their participation in a smoking cessation clinical trial and assessed emotional salience by measuring the amplitude of the late positive potential (LPP; 400 to 600 ms after picture onset). As expected, emotional and cigarette-related pictures prompted a significantly larger LPP than neutral pictures. The amplitude of the LPP increased as a function of picture arousal level, with high-arousing erotic and mutilation pictures showing the largest response in contrast to low arousing pleasant and unpleasant objects, which showed the smallest response (other than neutral). Compared to females, male participants showed larger LPPs for high-arousing erotic and mutilation pictures. However, unlike emotional pictures, no difference was noted for the LPP between cigarette stimuli containing people versus those containing only objects, suggesting that in contrast to emotional objects, cigarette-related objects are highly relevant for smokers. We also compared the smokers to a small (N=40), convenience sample of never-smokers. We found that never-smokers had significantly smaller LPPs in response to erotic and cigarette stimuli containing only objects compared to smokers. PMID- 23643565 TI - In vitro differentiation into insulin-producing beta-cells of stem cells isolated from human amniotic fluid and dental pulp. AB - AIM: To investigate the ability of human amniotic fluid stem cells and human dental pulp stem cells to differentiate into insulin-producing cells. METHODS: Human amniotic fluid stem cells and human dental pulp stem cells were induced to differentiate into pancreatic beta-cells by a multistep protocol. Islet-like structures were assessed in differentiated human amniotic fluid stem cells and human dental pulp stem cells after 21 days of culture by dithizone staining. Pancreatic and duodenal homebox-1, insulin and Glut-2 expression were detected by immunofluorescence and confocal microscopy. Insulin secreted from differentiated cells was tested with SELDI-TOF MS and by enzyme-linked immunosorbent assay. RESULTS: Human amniotic fluid stem cells and human dental pulp stem cells, after 7 days of differentiation started to form islet-like structures that became evident after 14 days of induction. SELDI-TOF MS analysis, revealed the presence of insulin in the media of differentiated cells at day 14, further confirmed by enzyme-linked immunosorbent assay after 7, 14 and 21 days. Both stem cell types expressed, after differentiation, pancreatic and duodenal homebox-1, insulin and Glut-2 and were positively stained by dithizone. Either the cytosol to nucleus translocation of pancreatic and duodenal homebox-1, either the expression of insulin, are regulated by glucose concentration changes. Day 21 islet-like structures derived from both human amniotic fluid stem cells and human dental pulp stem cell release insulin in a glucose-dependent manner. CONCLUSION: The present study demonstrates the ability of human amniotic fluid stem cells and human dental pulp stem cell to differentiate into insulin-producing cells, offering a non-pancreatic, low-invasive source of cells for islet regeneration. PMID- 23643566 TI - "Primum Non Nocere": are we getting carried away? PMID- 23643567 TI - Adverse events of computed tomography colonography: an Italian National Survey. AB - AIM: To retrospectively study the frequency and magnitude of complications associated with computed tomography (CT) colonography in clinical practice. METHODS: A questionnaire on complications of CT colonography was sent to Italian public radiology departments identified as practicing CT colonography with a reasonable level of training. The frequency of complications and possible risk factors were retrospectively determined. Responses were collated and row frequencies determined. A multivariate analysis of the factors causing adverse events was also performed. RESULTS: 40,121 examinations were performed in13 centers during the study period. No deaths were reported. Bowel perforations occurred in 0.02% (7 exams). All perforations were asymptomatic and occurred in patients undergoing manual insufflation. Five perforations (71%) occurred in procedures performed following a recent colonoscopy. There was no significant difference between perforations associated with rectal balloon (0.017%) and those that were not (0.02%). Complications related to vasovagal reaction (either with or without spasmolytic) occurred in 0.16% (63 exams). All vasovagal reactions resolved in less than 3h, without any sequelae. CONCLUSIONS: Perforation rate at CT colonography in Italy is comparable with elsewhere in the world, occurring regardless of the experience of radiology centers. Although the risk is very small, it may not be negligible when compared with the risk of diagnostic colonoscopy. PMID- 23643568 TI - Individual determinants of fish choosing in open-air street markets from Santo Andre, SP/Brazil. AB - The objective of this study was to identify the determinants of fish consumption in the population that attends open-air street markets in the city of Santo Andre, SP, Brazil.We performed a survey, covering approximately 482 people in 49 street markets.It consisted of free-answer questions, half open choice and half multiple-choice options, for the identification and evaluation of socioeconomic factors that facilitate and hinder fish consumption.A descriptive analysis of the data and further tests were used to determine the association between variables and linearity with consumption, with a significance level of 5%. The most commonly cited types of fish consumed were hake, sardine and dogfish. The factors that facilitate the purchase and consumption of fish are listed as follows: a preference for purchasing fish at street markets, appearance, firmness, fresh presentation, frozen presentation, as well as the respondent's education and individual monthly income. Limiting factors were identified as the price and the presence of spines. Perishability, odour, ethnicity, proximity to points of sale of residence and work, gender, age, number of people in the household, presence of children and acquisition supermarket were not characteristics that influenced decisions about fish consumption. PMID- 23643569 TI - Observation of parental functioning at mealtime using a sibling design. AB - This study investigates whether parental feeding practices are part of the shared environment or responsive to characteristics of different children from the same family. Thirty-six mothers with two children (4-12 y) of which 10 sibling-pairs were discordant for weight status (healthy weight-overweight), were invited to the lab for a standard meal. Maternal responsive and controlling behaviour was observed and coded. Children's weight status and eating behaviour was assessed. Results indicated that in general, mothers show similar levels of responsiveness and controlling behaviour within families. However, the use of mothers' authoritarian and permissive behaviour and her expressions of involvement at mealtime were consequently related to children's amount of food eaten and their restraining eating style. Thus, the amount of food children eat, both observed and assessed by questionnaire, seems related to more maladaptive parenting practices in mothers. This pleads for more tailor-made guidelines when advising parents of children with eating- and weight problems. PMID- 23643570 TI - Laparoscopic lumbar-aortic lymphadenectomy in residual post-chemotherapy tumours in testicular cancer. AB - INTRODUCTION: Open lumbar-aortic lymphadenectomy (OLAL) is the gold standard for treating post-chemotherapy retroperitoneal masses. Laparoscopic OLAL (L-OLAL) has emerged in recent years as an alternative for the handling of patients with these masses, with the additional potential benefits of minimal invasion. OBJECTIVE: To present our experience with the laparoscopic handling (L-OLAL) of residual post chemotherapy masses in patients with advanced testicular cancer. MATERIAL AND METHODS: Between 1993 and 2009, 43 patients underwent post-chemotherapy L-OLAL. A transperitoneal technique was employed in all patients. We assessed demographic, perioperational and pathological variables, as well as complications and follow up. RESULTS: A unilateral dissection was performed in 17 patients, while 26 patients underwent a bilateral retroperitoneal dissection. In the first group, 4 patients relapsed. In the second group, there were no relapses. After an average follow-up of 21 months, the overall survival rate reached 95%. We recorded a rate of perioperative complications of only 9.3%. CONCLUSIONS: In experienced hands, L OLAL is a technically feasible surgical alternative for the treatment of patients who are carriers of advanced testicular cancer with residual post-chemotherapy masses. The dissection performed should be bilateral to avoid tumour relapses and increase the survival rate of these patients. PMID- 23643571 TI - Reply: To PMID 23453884. PMID- 23643572 TI - Compounded hydroxyprogesterone caproate. PMID- 23643574 TI - Grip force control during simple manipulation tasks in non-neuropathic diabetic individuals. AB - OBJECTIVE: To assess hand function and grip force (GF) control in non-neuropathic diabetic individuals using traditional hand function tests and instrumented handles that provide information about the underlying neural mechanisms controlling simple manipulation tasks. METHODS: Twelve diabetic individuals (31 60 years-old) without neuropathy and 12 controls performed traditional functional tests (i.e., nine hole peg test, Jebsen-Taylor test, and maximum grip strength test) and were tested for GF control in two situations: holding a free moving instrumented handle and isometrically pulling fixed handles. Task performance in the tests and safety margin (SM - percentage of GF above the minimum needed to hold the handle) were the main dependent variables assessed. RESULTS: There was no difference between diabetics and controls in any functional test and in SM in isometric pulling task. However, diabetics presented around twice lower SM than controls in the free holding task. CONCLUSIONS: Diabetics showed no impairment in functional manipulation tasks. However, they presented a lower SM than healthy controls. SIGNIFICANCE: This lower SM suggests that diabetics may present sensory impairment that could put them at risk of losing objects during its manipulation. Also, it suggests that the applied experimental procedure is sensitive to detect mild sensory impairment in diabetics. PMID- 23643573 TI - Maternal engineered nanomaterial exposure and fetal microvascular function: does the Barker hypothesis apply? AB - OBJECTIVE: The continued development and use of engineered nanomaterials (ENM) has given rise to concerns over the potential for human health effects. Although the understanding of cardiovascular ENM toxicity is improving, one of the most complex and acutely demanding "special" circulations is the enhanced maternal system to support fetal development. The Barker hypothesis proposes that fetal development within a hostile gestational environment may predispose/program future sensitivity. Therefore, the objective of this study was 2-fold: (1) to determine whether maternal ENM exposure alters uterine and/or fetal microvascular function and (2) test the Barker hypothesis at the microvascular level. STUDY DESIGN: Pregnant (gestation day 10) Sprague-Dawley rats were exposed to nano titanium dioxide aerosols (11.3 +/- 0.039 mg/m(3)/hr, 5 hr/d, 8.2 +/- 0.85 days) to evaluate the maternal and fetal microvascular consequences of maternal exposure. Microvascular tissue isolation (gestation day 20) and arteriolar reactivity studies (<150 MUm passive diameter) of the uterine premyometrial and fetal tail arteries were conducted. RESULTS: ENM exposures led to significant maternal and fetal microvascular dysfunction, which was seen as robustly compromised endothelium-dependent and -independent reactivity to pharmacologic and mechanical stimuli. Isolated maternal uterine arteriolar reactivity was consistent with a metabolically impaired profile and hostile gestational environment that impacted fetal weight. The fetal microvessels that were isolated from exposed dams demonstrated significant impairments to signals of vasodilation specific to mechanistic signaling and shear stress. CONCLUSION: To our knowledge, this is the first report to provide evidence that maternal ENM inhalation is capable of influencing fetal health and that the Barker hypothesis is applicable at the microvascular level. PMID- 23643575 TI - Myopathic EMG findings and type II muscle fiber atrophy in patients with Lambert Eaton myasthenic syndrome. AB - OBJECTIVE: Lambert-Eaton myasthenic syndrome (LEMS) is a rare condition, which may mimic myopathy. A few reports have described that EMG in LEMS may show changes compatible with myopathy, and muscle biopsies have been described with type II as well as type I atrophy. The EMG results were, however, based on qualitative EMG examination and the histopathological methods were not always clear. The objective of this study was to investigate if the previous EMG findings could be confirmed with quantitative EMG (QEMG) and to describe muscle histology in LEMS. METHODS: QEMG, nerve conduction studies and muscle biopsy were performed in four consecutive LEMS patients. RESULTS: QEMG showed significantly decreased mean MUP duration and muscle biopsy showed marked type II fiber atrophy. CONCLUSION: EMG and biopsy abnormalities mimicking myopathy may often be found in patients with LEMS. SIGNIFICANCE: LEMS is a debilitating, but treatable disease, which often precedes detection of a malignancy and it is therefore of obvious importance to diagnose these patients with speed and certainty. Hence it is important that neurophysiologists and neurologists are aware that EMG and histological abnormalities mimicking myopathy may be found in LEMS patients so that these findings do not prolong or misdirect the diagnostic process in these patients. PMID- 23643577 TI - Seizure prediction in patients with mesial temporal lobe epilepsy using EEG measures of state similarity. AB - OBJECTIVES: In patients with intractable epilepsy, predicting seizures above chance and with clinically acceptable performance has yet to be demonstrated. In this study, an intracranial EEG-based seizure prediction method using measures of similarity with a reference state is proposed. METHODS: 1565 h of continuous intracranial EEG data from 17 patients with mesial temporal lobe epilepsy were investigated. The recordings included 175 seizures. In each patient the data was split into a training set and a testing set. EEG segments were analyzed using continuous wavelet transform. During training, a reference state was defined in the immediate preictal data and used to derive three features quantifying the discrimination between preictal and interictal states. A classifier was then trained in the feature space. Its performance was assessed using testing set and compared with a random predictor for statistical validation. RESULTS: Better than random prediction performance was achieved in 7 patients. The sensitivity was higher than 85%, the warning rate was less than 0.35/h and the proportion of time under warning was less than 30%. CONCLUSION: Seizures are predicted above chance in 41% of patients using measures of state similarity. SIGNIFICANCE: Sensitivity and specificity levels are potentially interesting for closed-loop seizure control applications. PMID- 23643576 TI - The effects of antihistamines with varying anticholinergic properties on voluntary and involuntary movement. AB - OBJECTIVE: Recent evidence indicates that antihistamines can affect movement, which is most likely due to altered neurotransmission in cholinergic and histaminergic pathways. The purpose of this study was to determine if antihistamines with varying anticholinergic properties differentially affect voluntary and involuntary movement control. METHODS: Eleven healthy subjects were enlisted into a human double blind, placebo-controlled, five-way crossover study. Drowsiness, reaction time, and physiological tremor were examined 1-, 2-, and 3 hr post-ingestion of antihistamines with known anticholinergic profiles. These were the first-generation promethazine, and second-generation loratadine, desloratadine, and fexofenadine. Hyoscine butylbromide was used in an additional experiment to determine how a peripheral antimuscarinic drug influenced neuromotor function. RESULTS: Promethazine, desloratadine and fexofenadine increased drowsiness. Promethazine increased simple and choice reaction time and reduced tremor. Desloratadine increased choice reaction time and tremor, while loratadine slowed simple and choice reaction time. CONCLUSION: Central anticholinergic and antihistaminergic properties of antihistamines potentially contribute to movement dysfunction. SIGNIFICANCE: Second-generation antihistamines have provided the consumer with a safer alternative to the first generation sedating antihistamine. However, the results of this study suggest that loratadine and desloratadine have the potential to affect movement control, and further research is warranted to understand the clinical relevance of these findings. PMID- 23643578 TI - Daily training with realistic visual feedback improves reproducibility of event related desynchronisation following hand motor imagery. AB - OBJECTIVE: Few brain-computer interface (BCI) studies have addressed learning mechanisms by exposure to visual feedback that elicits scalp electroencephalogram. We examined the effect of realistic visual feedback of hand movement associated with sensorimotor rhythm. METHODS: Thirty-two healthy participants performed in five daily training in which they were shown motor imagery of their dominant hand. Participants were randomly assigned to 1 of 4 experimental groups receiving different types of visual feedback on event-related desynchronisation (ERD) derived over the contralateral sensorimotor cortex: no feedback as a control, bar feedback with changing bar length, anatomically incongruent feedback in which the hand open/grasp picture on screen was animated at eye level, and anatomically congruent feedback in which the same hand open/grasp picture was animated on the screen overlaying the participant's hand. RESULTS: Daily training with all types of visual feedback induced more robust ERD than the no feedback condition (p < 0.05). The anatomically congruent feedback produced the highest reproducibility of ERD with the smallest inter-trial variance (p < 0.05). CONCLUSION: Realistic feedback training is a suitable method to acquire the skill to control a BCI system. SIGNIFICANCE: This finding highlights the possibility of improvement of reproducibility of ERD and can help to use BCI techniques. PMID- 23643579 TI - Cost-effectiveness landscape analysis of treatments addressing xerostomia in patients receiving head and neck radiation therapy. AB - Head and neck (H&N) radiation therapy (RT) can induce irreversible damage to the salivary glands thereby causing long-term xerostomia or dry mouth in 68%-85% of the patients. Not only does xerostomia significantly impair patients' quality-of life (QOL) but it also has important medical sequelae, incurring high medical and dental costs. In this article, we review various measures to assess xerostomia and evaluate current and emerging solutions to address this condition in H&N cancer patients. These solutions typically seek to accomplish 1 of the 4 objectives: (1) to protect the salivary glands during RT, (2) to stimulate the remaining gland function, (3) to treat the symptoms of xerostomia, or (4) to regenerate the salivary glands. For each treatment, we assess its mechanisms of action, efficacy, safety, clinical utilization, and cost. We conclude that intensity-modulated radiation therapy is both the most widely used prevention approach and the most cost-effective existing solution and we highlight novel and promising techniques on the cost-effectiveness landscape. PMID- 23643580 TI - Solid variant of keratocystic odontogenic tumor of the mandible: report of a case with a clear cell component and review of the literature. AB - This is a case report on a solid variant of keratocystic odontogenic tumor arising in the mandible, which aggressively infiltrated into the cancelous spaces and involved the periosteal connective tissue of the mandible. The patient was a 57-year-old woman with an ill-defined radiolucent lesion having a moth-eaten pattern in the left molar region of the mandible. Computed tomography scans revealed that the tumor penetrated the buccal cortical plate of the mandible. Histologically, the lesion was characterized by multicystic spaces lined with a thin layer of keratinizing squamous epithelium, which contained basal cells with palisaded hyperchromatic nuclei. Lumina were filled with concentric layers of parakeratin. An additional feature was the appearance of a conspicuous clear cell component showing intraluminal papillary proliferation or forming small cord-like nests in the fibrous stroma. The patient underwent segmental mandibulectomy followed by reconstruction using a titanium plate. A 20-year follow-up revealed no recurrence of the tumor. PMID- 23643581 TI - Long-term dental and skeletal changes following surgically assisted rapid palatal expansion. PMID- 23643582 TI - Long-term dental and skeletal changes following SARPE. PMID- 23643583 TI - Biocompatibility of gold and stainless steel chains used for forced eruption of impacted teeth - an in vitro investigation. AB - OBJECTIVE: Surgical approaches for the mobilization of impacted teeth involve the use of gold chains to connect the impacted tooth with the orthodontic appliance. In this study we have compared the local effects gold plated stainless steel with stainless steel specimen using an in vitro model of the gingival mucosa and monolayer cultures of cells of the alveolus. STUDY DESIGN: Local effects on differentiation, proliferation, and apoptosis and inflammatory response were tested using organotypic cultures of gingival cells. Cytotoxicity was measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays with monolayer cultures of human periodontal cells. RESULTS: The data obtained in this study could not reveal any differences in favor of using gold plated chains during the mobilization of impacted teeth. CONCLUSION: For patients not suffering from allergies against nickel there might be no rationale to favor gold plated chains, as there are no functional aspects to favor gold plated chains over stainless steel chains. PMID- 23643584 TI - Oral ulcers in patients with advanced breast cancer receiving everolimus: a case series report on clinical presentation and management. AB - OBJECTIVE: We report the clinical features and management outcomes in 7 patients with everolimus-related stomatitis. STUDY DESIGN: Fifteen women with hormone receptor-positive advanced breast cancer receiving everolimus combined with exemestane were prospectively evaluated to assess the development of stomatitis. Oral ulcers were diagnosed based on established criteria. RESULTS: Seven patients developed stomatitis (46.6%). All patients were treated with topical dexamethasone solution, while everolimus was temporarily discontinued in 4 patients. Stomatitis resolved within 1-2 weeks. Two of the 4 patients, who had interrupted everolimus, developed recurrent stomatitis following drug resume and everolimus was again discontinued and restarted after 2 weeks. To date, 5 patients receive everolimus in full dose. The 2 patients, who developed recurrent stomatitis, received a reduced dose. CONCLUSIONS: Everolimus-related oral ulcers were frequent and led to dose modifications. Controlled trials, endorsing a consensus in terminology, are needed to evaluate measures on prevention and management of this unique toxicity. PMID- 23643585 TI - The bicipital tuberosity and distal radius are unreliable landmarks for radial head implant alignment. AB - BACKGROUND: As more anatomic asymmetric radial head implants emerge, it is necessary to determine the optimal landmarks to ensure correct rotational orientation. The bicipital tuberosity and distal radius are possible bony landmarks that can be used for rotational alignment of asymmetric prostheses; however, they have not been validated. The purpose of this study was to evaluate the reliability of the bicipital tuberosity and distal radius as rotational landmarks for orientation of asymmetric radial head prostheses. METHODS: Measurements were made from computer tomography scans of 50 elbows in order to determine the rotational relationships between the radial head, bicipital tuberosity, biceps tendon footprint, and distal radius. RESULTS: The maximum radial head diameter was oriented 65 degrees +/- 28 degrees from the bicipital tuberosity, 119 degrees +/- 38 degrees from the biceps tendon footprint, 82 degrees +/- 29 degrees from the radial styloid, and 76 degrees +/- 28 degrees from the volar surface of the distal radius. All of these landmarks had a significantly greater variance than a proposed acceptable clinical tolerance of 10 degrees (P < .001). CONCLUSION: The results demonstrate that the measured landmarks show no consistent rotational relationship with the maximum diameter of the radial head. In order to maximize the utility of more anatomic asymmetric radial head implant systems, further studies are necessary to identify more reliable rotational landmarks to ensure optimal implant positioning. PMID- 23643586 TI - Male isolation: a behavioral representation of the pheromonal 'female effect' in donkey (Equus asinus). AB - The appearance of a decisive component of the sexual response to chemosexual signals in the male donkey was investigated through a comparison of the variations in the time-span of the behavioral classes and units for the natural versus induced breeding seasons. The results demonstrate that there are significant variations in the length of the appetitive sexual behavior (ASB) and consummatory sexual behavior (CSB) under these two reproductive conditions. These differences are analyzed for the ASB, which is adaptable, compared with the stereotyped CSB. For the ASB, male isolation is the most represented behavior of both the natural and induced breeding seasons. This is the key that allows the passage from courtship, which consists of appetitive behaviors, to copula, the consummatory behavior. This isolation appears to provide the time required to activate the hypothalamic-pituitary-gonadal axis through the chemosexual pathway of pheromone stimuli. This isolation is lengthened with induced breeding, supporting the hypothesis of the activation of the neuroendocrine system, which is not 'primed' outside the natural breeding season, and which is necessary to release the stereotyped CSB. PMID- 23643588 TI - Anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal NOS phosphorylation. AB - RATIONALE: Stimulation of beta3-adrenoreceptors (beta3-AR) blunts contractility and improves chronic left ventricular function in hypertrophied and failing hearts in a neuronal nitric oxide synthase (nNOS) dependent manner. nNOS can be regulated by post-translational modification of stimulatory phosphorylation residue Ser1412 and inhibitory residue Ser847. However, the role of phosphorylation of these residues in cardiomyocytes and beta3-AR protective signaling has yet to be explored. OBJECTIVE: We tested the hypothesis that beta3 AR regulation of myocyte stress requires changes in nNOS activation mediated by differential nNOS phosphorylation. METHODS AND RESULTS: Endothelin (ET-1) or norepinephrine induced hypertrophy in rat neonatal ventricular cardiomyocytes (NRVMs) was accompanied by increased beta3-AR gene expression. Co-administration of the beta3-AR agonist BRL-37433 (BRL) reduced cell size and reactive oxygen species (ROS) generation, while augmenting NOS activity. BRL-dependent augmentation of NOS activity and ROS suppression due to NE were blocked by inhibiting nNOS (L-VNIO). BRL augmented nNOS phosphorylation at Ser1412 and dephosphorylation at Ser847. Cells expressing constitutively dephosphorylated Ser1412A or phosphorylated Ser847D nNOS mutants displayed reduced nNOS activity and a lack of BRL modulation. BRL also failed to depress ROS from NE in cells with nNOS-Ser847D. Inhibiting Akt decreased BRL-induced nNOS-Ser1412 phosphorylation and NOS activation, whereas Gi/o blockade blocked BRL-regulation of both post-translational modifications, preventing enhancement of NOS activity and ROS reduction. BRL resulted in near complete dephosphorylation of Ser847 and a moderate rise in Ser1412 phosphorylation in mouse myocardium exposed to chronic pressure-overload. CONCLUSION: beta3-AR regulates myocardial NOS activity and ROS via activation of nNOS involving reciprocal changes in phosphorylation at two regulatory sites. These data identify a novel and potent anti-oxidant and anti hypertrophic pathway due to nNOS post-translational modification that is coupled to beta3-AR receptor stimulation. PMID- 23643590 TI - Oxygen pre-conditioning prevents contrast-induced nephropathy (OPtion CIN Study). PMID- 23643591 TI - Development and progression of coronary artery calcification in long-term smokers: adverse effects of continued smoking. PMID- 23643589 TI - Oxidative stress in atrial fibrillation: an emerging role of NADPH oxidase. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia. Patients with AF have up to seven-fold higher risk of suffering from ischemic stroke. Better understanding of etiologies of AF and its thromboembolic complications are required for improved patient care, as current anti-arrhythmic therapies have limited efficacy and off target effects. Accumulating evidence has implicated a potential role of oxidative stress in the pathogenesis of AF. Excessive production of reactive oxygen species (ROS) is likely involved in the structural and electrical remodeling of the heart, contributing to fibrosis and thrombosis. In particular, NADPH oxidase (NOX) has emerged as a potential enzymatic source for ROS production in AF based on growing evidence from clinical and animal studies. Indeed, NOX can be activated by known upstream triggers of AF such as angiotensin II and atrial stretch. In addition, treatments such as statins, antioxidants, ACEI or AT1RB have been shown to prevent post-operative AF; among which ACEI/AT1RB and statins can attenuate NOX activity. On the other hand, detailed molecular mechanisms by which specific NOX isoform(s) are involved in the pathogenesis of AF and the extent to which activation of NOX plays a causal role in AF development remains to be determined. The current review discusses causes and consequences of oxidative stress in AF with a special focus on the emerging role of NOX pathways. PMID- 23643592 TI - Another piece to the Troponin Puzzle: better confirmed, and with a path forward. PMID- 23643593 TI - Obesity and its association to phenotype and clinical course in hypertrophic cardiomyopathy. AB - OBJECTIVES: This study sought to assess the impact of body mass index (BMI) on cardiac phenotypic and clinical course in a multicenter hypertrophic cardiomyopathy (HCM) cohort. BACKGROUND: It is unresolved whether clinical variables promoting left ventricular (LV) hypertrophy in the general population, such as obesity, may influence cardiac phenotypic and clinical course in patients with HCM. METHODS: In 275 adult HCM patients (age 48 +/- 14 years; 70% male), we assessed the relation of BMI to LV mass, determined by cardiovascular magnetic resonance (CMR) and heart failure progression. RESULTS: At multivariate analysis, BMI proved independently associated with the magnitude of hypertrophy: pre-obese and obese HCM patients (BMI 25 to 30 kg/m(2) and >30 kg/m(2), respectively) showed a 65% and 310% increased likelihood of an LV mass in the highest quartile (>120 g/m(2)), compared with normal weight patients (BMI <25 kg/m(2); hazard ratio [HR]: 1.65; 95% confidence interval [CI]: 0.73 to 3.74, p = 0.22 and 3.1; 95% CI: 1.42 to 6.86, p = 0.004, respectively). Other features associated with LV mass >120 g/m(2) were LV outflow obstruction (HR: 4.9; 95% CI: 2.4 to 9.8; p < 0.001), systemic hypertension (HR: 2.2; 95% CI: 1.1 to 4.5; p = 0.026), and male sex (HR: 2.1; 95% CI: 0.9 to 4.7; p = 0.083). During a median follow-up of 3.7 years (interquartile range: 2.5 to 5.3), obese patients showed an HR of 3.6 (95% CI: 1.2 to 10.7, p = 0.02) for developing New York Heart Association (NYHA) functional class III to IV symptoms compared to nonobese patients, independent of outflow obstruction. Noticeably, the proportion of patients in NYHA functional class III at the end of follow-up was 13% among obese patients, compared with 6% among those of normal weight (p = 0.03). CONCLUSIONS: In HCM patients, extrinsic factors such as obesity are independently associated with increase in LV mass and may dictate progression of heart failure symptoms. PMID- 23643594 TI - Obesity and hypertrophic cardiomyopathy: chickens, eggs, and causality: clinical skills remain the key to caring for patients. PMID- 23643595 TI - Copeptin helps in the early detection of patients with acute myocardial infarction: primary results of the CHOPIN trial (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction). AB - OBJECTIVES: The goal of this study was to demonstrate that copeptin levels <14 pmol/L allow ruling out acute myocardial infarction (AMI) when used in combination with cardiac troponin I (cTnI) <99 th percentile and a nondiagnostic electrocardiogram at the time of presentation to the emergency department (ED). BACKGROUND: Copeptin is secreted from the pituitary early in the course of AMI. METHODS: This was a 16-site study in 1,967 patients with chest pain presenting to an ED within 6 hours of pain onset. Baseline demographic characteristics and clinical data were collected prospectively. Copeptin levels and a contemporary sensitive cTnI (99 th percentile 40 ng/l; 10% coefficient of variation 0.03 MUg/l) were measured in a core laboratory. Patients were followed up for 180 days. The primary outcome was diagnosis of AMI. Final diagnoses were adjudicated by 2 independent cardiologists blinded to copeptin results. RESULTS: AMI was the final diagnosis in 156 patients (7.9%). A negative copeptin and cTnI at baseline ruled out AMI for 58% of patients, with a negative predictive value of 99.2% (95% confidence interval: 98.5 to 99.6). AMIs not detected by the initial cTnI alone were picked up with copeptin >14 pmol/l in 23 (72%) of 32 patients. Non-ST segment elevation myocardial infarctions undetected by cTnI at 0 h were detected with copeptin >14 pmol/l in 10 (53%) of 19 patients. Projected average time-to decision could be reduced by 43% (from 3.0 h to 1.8 h) by the early rule out of 58% of patients. Both abnormal copeptin and cTnI were predictors of death at 180 days (p < 0.0001 for both; c index 0.784 and 0.800, respectively). Both were independent of age and each other and provided additional predictive value (all p < 0.0001). CONCLUSIONS: Adding copeptin to cTnI allowed safe rule out of AMI with a negative predictive value >99% in patients presenting with suspected acute coronary syndromes. This combination has the potential to rule out AMI in 58% of patients without serial blood draws. PMID- 23643596 TI - Dimensions of sensation assessed in urinary urgency: a systematic review. AB - PURPOSE: Urinary urgency is an adverse sensory experience. Confirmation of the multidimensional nature of other adverse sensory experiences such as pain and dyspnea has improved the understanding of neurophysiological and perceptual mechanisms leading to innovations in assessment and treatment. It has been suggested that the sensation of urgency may include multiple dimensions such as intensity, suddenness and unpleasantness. In this systematic review we determine which dimensions of sensation have been assessed by instruments used to measure urinary urgency. MATERIALS AND METHODS: A systematic search was undertaken of MEDLINE, Embase, AMED, CINAHL, Ageline, Web of Science, InformIT Health and Scopus databases to identify studies that included assessments of urinary urge or urgency. Articles were included in the analysis if they were primary studies that described the method used to measure urge/urgency in adults and published in English in peer reviewed publications since January 1, 2000. Articles were excluded from study if urgency was measured only in conjunction with other symptoms (eg frequency or incontinence) or if there was no English version of the instrument. Secondary analyses and systematic reviews were retained to hand search references for additional primary studies. Data were extracted for the instruments used to measure urge/urgency. For each instrument the items specific to urinary urgency were reviewed using a prospectively developed categorization process for the sensory dimension and the measurement metric. Items used to assess urinary urgency were collated in a matrix (sensory dimensions vs assessment metric). The most frequently used dimensions, metrics and combinations were descriptively analyzed. RESULTS: After removal of duplicate articles 1,048 full text articles were screened and 411 were excluded, leaving 637 eligible articles from which data were extracted. A total of 216 instruments were identified which were 1 of 6 types, namely 1) wider symptom questionnaires, 2) urgency specific questionnaires, 3) ordinal scales, 4) visual analog scales, 5) event records or 6) body maps. These 216 instruments contained a total of 309 urgency specific items. Of the instruments 51% did not define a dimension of sensation and 26% did not define the metric used. From the remaining instruments 8 dimensions of sensation and 5 types of metrics were identified. From most common to least common, the sensory dimensions assessed were behavioral response, intensity, suddenness, bother, affective response, unpleasantness, quality (descriptors) and problems associated with sensation. Metrics were magnitude, frequency, presence, time frame or location. The most common sensory dimension/metric combinations were frequency of a behavioral response (14% of items) and magnitude of bother caused by the sensation (8% of items). CONCLUSIONS: The hypothesis that urinary urgency is multidimensional is supported by the range of dimensions assessed with available instruments. To clarify the nature of urinary urgency compared with the normal desire to void, prospective studies are required to determine whether sensory dimensions are distinct, and which may delineate between normal and pathological sensation. PMID- 23643597 TI - Optimization of near infrared fluorescence tumor localization during robotic partial nephrectomy. AB - PURPOSE: Near infrared fluorescence allows the differentiation of tumors and normal parenchyma during robotic partial nephrectomy. This may facilitate tumor excision but requires proper dosing of indocyanine green. Under dosing causes inadequate fluorescence of peritumor parenchyma. Overdosing causes tumors to fluoresce inappropriately. Currently there are no described dosing strategies to our knowledge to optimize near infrared fluorescence and reported doses vary widely. We devised a dosing strategy and assessed the reliability of near infrared fluorescence for differential fluorescence. MATERIALS AND METHODS: Robotic partial nephrectomy with near infrared fluorescence was performed for 79 tumors. Dosing strategy involved at minimum 2 indocyanine green doses, including the test dose and the calibrated dose before resection. The test dose was deliberately low to avoid confounding over-fluorescence. The second dose was calibrated depending on the extent of differential fluorescence achieved with the test doses. Intraoperative assessment of tumor fluorescence was recorded before pathological assessment. RESULTS: Mean tumor size was 3.5 cm (range 1.1 to 9.8) with a mean R.E.N.A.L. score of 8 (range 4 to 12). Median indocyanine green test dose and re-dose before clamping were 1.25 mg (range 0.625 to 2.5) and 1.875 mg (range 0.625 to 5), respectively. Differential fluorescence was achieved in 65 of 79 tumors (82%) that did not fluoresce. After 3 exclusions for the inability to assess fluorescence or indeterminate histology, 60 of 76 tumors were renal cell carcinoma. Of 60 renal cell carcinomas 55 behaved appropriately and did not fluoresce (92%). Overall 65 of 76 tumors behaved appropriately for an 86% agreement between histology and near infrared fluorescence behavior. CONCLUSIONS: With our dosing regimen near infrared fluorescence was highly reliable in achieving differential fluorescence of kidney and renal cell carcinomas. Standardized dosing is needed before deciding whether near infrared fluorescence improves robotic partial nephrectomy outcomes and additional studies may further improve reliability. PMID- 23643598 TI - Improving patient knowledge about sacral nerve stimulation using a patient based educational video. AB - PURPOSE: We developed a patient based educational video to address the information needs of women considering sacral nerve stimulation for overactive bladder. MATERIALS AND METHODS: Five semistructured focus groups were used to identify patient knowledge gaps, information needs, patient acceptable terminology and video content preferences for a patient based sacral nerve stimulation educational video. Each session was transcribed, independently coded by 2 coders and examined using an iterative method. A 16-minute educational video was created to address previously identified knowledge gaps and information needs using patient footage, 3-dimensional animation and peer reviewed literature. We developed a questionnaire to evaluate participant sacral nerve stimulation knowledge and therapy attitudes. We then performed a randomized trial to assess the effect of the educational video vs the manufacturer video on patient knowledge and attitudes using our questionnaire. RESULTS: We identified 10 patient important domains, including 1) anatomy, 2) expectations, 3) sacral nerve stimulation device efficacy, 4) surgical procedure, 5) surgical/device complications, 6) post-procedure recovery, 7) sacral nerve stimulation side effects, 8) postoperative restrictions, 9) device maintenance and 10) general sacral nerve stimulation information. A total of 40 women with overactive bladder were randomized to watch the educational (20) or manufacturer (20) video. Knowledge scores improved in each group but the educational video group had a greater score improvement (76.6 vs 24.2 points, p <0.0001). Women who watched the educational video reported more favorable attitudes and expectations about sacral nerve stimulation therapy. CONCLUSIONS: Women with overactive bladder considering sacral nerve stimulation therapy have specific information needs. The video that we developed to address these needs was associated with improved short-term patient knowledge. PMID- 23643599 TI - National trends in augmentation cystoplasty in the 2000s and factors associated with patient outcomes. AB - PURPOSE: Augmentation cystoplasty is a major surgery performed by pediatric urologists. We evaluated national estimates of children undergoing augmentation cystoplasty in the United States for trends during the 2000s, and analyzed patient and hospital factors associated with outcomes. MATERIALS AND METHODS: Patients who underwent augmentation cystoplasty registered in the 2000 to 2009 Kids' Inpatient Database were included. Estimates of total number of augmentation cystoplasties performed and patient and hospital characteristics were evaluated for trends. Hierarchical models were created to evaluate patient and hospital factors associated with length of stay, total hospital charges and odds of having a postoperative complication. RESULTS: An estimated 792 augmentation cystoplasties were performed in 2000, which decreased to 595 in 2009 (p = 0.02). Length of stay decreased from 10.5 days in 2000 to 9.2 days in 2009 (p = 0.04). A total of 1,622 augmentation cystoplasties were included in the hierarchical models and 30% of patients had a complication identified. Patient factors associated with increased length of stay and increased odds of any complication included bladder exstrophy-epispadias complex diagnosis and older age. Pediatric hospitals had 31% greater total hospital charges (95% CI 7-55). CONCLUSIONS: The estimated number of augmentation cystoplasties performed in children in the United States decreased by 25% in the 2000s, and mean length of stay decreased by 1 day. The cause of the decrease is multifactorial but could represent changing practice patterns in the United States. Of the patients 30% had a potential complication during hospitalization after augmentation cystoplasty. Older age and bladder exstrophy-epispadias complex diagnosis were associated with greater length of stay and increased odds of having any complication. PMID- 23643600 TI - Predictive factors of oncologic outcomes in patients who do not achieve undetectable prostate specific antigen after radical prostatectomy. AB - PURPOSE: We identified factors predicting oncologic outcomes in cases of persistently detectable prostate specific antigen. MATERIALS AND METHODS: We reviewed the charts of patients treated with radical prostatectomy between 1998 and 2011 at a total of 14 centers. Study inclusion criteria were radical prostatectomy for presumed localized prostate cancer, absent positive nodes and detectable prostate specific antigen, defined as prostate specific antigen 0.1 ng/ml or greater 6 weeks postoperatively. Of the 9,735 radical prostatectomy cases reviewed 496 (5.1%) were eligible for analysis. Predictive factors for oncologic outcomes were assessed in time dependent analyses using the Kaplan Meier method and Cox regression models. RESULTS: At 6 weeks prostate specific antigen was 0.1 to 6.8 ng/ml. Biochemical progression was noted in 74.4% of patients and clinical metastasis was noted in 5%. The 2 most powerful predictors of general salvage treatment (vs radiotherapy) were postoperative prostate specific antigen greater than 1 ng/ml (OR 3.46, p=0.032) and prostate specific antigen velocity greater than 0.2 ng/ml per year (HR 6.01, p=0.001). Positive prostate specific antigen velocity was the single factor that independently correlated with the risk of failed salvage therapy (HR 2.6, p=0.001). The 5-year disease-free survival rate was 81.0% in patients with stable or negative prostate specific antigen velocity compared with 58.4% in those with positive prostate specific antigen velocity (p<0.001). CONCLUSIONS: Patients with detectable prostate specific antigen after radical prostatectomy have a poor biochemical outcome. We identified postoperative prostate specific antigen and prostate specific antigen velocity as independent predictors of progression and failed salvage treatment. In addition to pathological prognostic factors, these factors should be considered early to better stratify patients for adjuvant therapy. PMID- 23643604 TI - Microstructural characterization of vocal folds toward a strain-energy model of collagen remodeling. AB - Collagen fibrils are believed to control the immediate deformation of soft tissues under mechanical load. Most extracellular matrix proteins remain intact during frozen sectioning, which allows them to be scanned using atomic force microscopy (AFM). Collagen fibrils are distinguishable because of their periodic roughness wavelength. In the present study, the shape and organization of collagen fibrils in dissected porcine vocal folds were quantified using nonlinear laser scanning microscopy data at the micrometer scale and AFM data at the nanometer scale. Rope-shaped collagen fibrils were observed. The geometric characteristics for the fibrils were fed into a hyperelastic model to predict the biomechanical response of the tissue. The model simulates the micrometer-scale unlocking behavior of collagen bundles when extended from their unloaded configuration. Force spectroscopy using AFM was used to estimate the stiffness of collagen fibrils (1+/-0.5MPa). The presence of rope-shaped fibrils is postulated to change the slope of the force-deflection response near the onset of nonlinearity. The proposed model could ultimately be used to evaluate changes in elasticity of soft tissues that result from the collagen remodeling. PMID- 23643606 TI - Effect of bioactive borate glass microstructure on bone regeneration, angiogenesis, and hydroxyapatite conversion in a rat calvarial defect model. AB - Borate bioactive glasses are biocompatible and enhance new bone formation, but the effect of their microstructure on bone regeneration has received little attention. In this study scaffolds of borate bioactive glass (1393B3) with three different microstructures (trabecular, fibrous, and oriented) were compared for their capacity to regenerate bone in a rat calvarial defect model. 12weeks post implantation the amount of new bone, mineralization, and blood vessel area in the scaffolds were evaluated using histomorphometric analysis and scanning electron microscopy. The amount of new bone formed was 33%, 23%, and 15%, respectively, of the total defect area for the trabecular, oriented, and fibrous microstructures. In comparison, the percent new bone formed in implants composed of silicate 45S5 bioactive glass particles (250-300MUm) was 19%. Doping the borate glass with copper (0.4 wt.% CuO) had little effect on bone regeneration in the trabecular and oriented scaffolds, but significantly enhanced bone regeneration in the fibrous scaffolds (from 15 to 33%). The scaffolds were completely converted to hydroxyapatite within the 12week implantation. The amount of hydroxyapatite formed, 22%, 35%, and 48%, respectively, for the trabecular, oriented, and fibrous scaffolds, increased with increasing volume fraction of glass in the as fabricated scaffold. Blood vessels infiltrated into all the scaffolds, but the trabecular scaffolds had a higher average blood vessel area compared with the oriented and fibrous scaffolds. While all three scaffold microstructures were effective in supporting bone regeneration, the trabecular scaffolds supported more bone formation and may be more promising in bone repair. PMID- 23643605 TI - Human mesenchymal stem cell culture on heparin-based hydrogels and the modulation of interactions by gel elasticity and heparin amount. AB - Human adipose-derived stem cells (hADSCs) are a promising cell source for tissue engineering and regenerative medicine with no ethnical issue and easy access of large quantities. Conventional surfaces for hADSC culture, such as tissue culture plates (TCPs), do not provide optimal environmental cues, leading to limited expansion, loss of pluripotency and undesirable differentiation of stem cells. The present study demonstrated that heparin-based hydrogels without additional modification provided an excellent surface for adhesion and proliferation of hADSCs, which were further tunable by both the amount of heparin (in a positive way) and the elasticity of hydrogel (in a negative way). The optimized heparin based hydrogel could selectively modulate the adhesion of hADSCs and human bone marrow stem cells (but not all kinds of cells), and resulted in a significant increase in cell proliferation compared to TCP. Furthermore, in terms of the maintenance of pluripotency and specific differentiation, heparin-based hydrogel was much superior to TCP. The selective binding and proliferation of human mesenchymal stem cells on heparin-based hydrogel over other hydrogels were largely mediated by integrin beta1 and selectin, and these superior characteristics were observed regardless of the presence of serum proteins in the culture medium. Consequently, heparin-based hydrogel could be a powerful platform for cultivation of mesenchymal stem cells in various applications. PMID- 23643603 TI - Pathological outcomes in men with low risk and very low risk prostate cancer: implications on the practice of active surveillance. AB - PURPOSE: We assessed oncologic outcomes at surgery in men with low risk and very low risk prostate cancer who were candidates for active surveillance. MATERIALS AND METHODS: In a prospectively collected institutional database, we identified 7,486 subjects eligible for active surveillance who underwent radical retropubic prostatectomy. Candidates were designated as being at low risk (stage T1c/T2a, prostate specific antigen 10 ng/ml or less, and Gleason score 6 or less) or very low risk (stage T1c, prostate specific antigen density 0.15 or less, Gleason score 6 or less, 2 or fewer positive biopsy cores, 50% or less cancer involvement per core) based on preoperative data. Adverse findings were Gleason score upgrade (score 7 or greater) and nonorgan confined cancer on surgical pathology. The relative risk of adverse findings in men at low risk with very low risk disease was evaluated in a multivariate model using Poisson regression. RESULTS: A total of 7,333 subjects met the criteria for low risk disease and 153 had very low risk disease. The proportion of subjects at low risk found to have Gleason score upgrade or nonorgan confined cancer on final pathology was 21.8% and 23.1%, respectively. Corresponding values in those at very low risk were 13.1% and 8.5%, respectively. After adjusting for age, race, year of surgery, body mass index, and prostate specific antigen at diagnosis, the relative risk of Gleason score upgrade in men with low risk vs very low risk disease was 1.89 (95% CI 1.21 2.95). The relative risk of nonorgan confined cancer was 2.06 (95% CI 1.19-3.57). CONCLUSIONS: Men with very low risk prostate cancer were at significantly lower risk for adverse findings at surgery compared to those with low risk disease. These data support the stratification of low risk cancer when selecting and counseling men who may be appropriate for active surveillance. PMID- 23643607 TI - Nanostructural control of the release of macromolecules from silica sol-gels. AB - The therapeutic use of biological molecules such as growth factors and monoclonal antibodies is challenging in view of their limited half-life in vivo. This has elicited the interest in delivery materials that can protect these molecules until released over extended periods of time. Although previous studies have shown controlled release of biologically functional BMP-2 and TGF-beta from silica sol-gels, more versatile release conditions are desirable. This study focuses on the relationship between room temperature processed silica sol-gel synthesis conditions and the nanopore size and size distribution of the sol-gels. Furthermore, the effect on release of large molecules with a size up to 70kDa is determined. Dextran, a hydrophilic polysaccharide, was selected as a large model molecule at molecular sizes of 10, 40 and 70kDa, as it enabled us to determine a size effect uniquely without possible confounding chemical effects arising from the various molecules used. Previously, acid catalysis was performed at a pH value of 1.8 below the isoelectric point of silica. Herein the silica synthesis was pursued using acid catalysis at either pH 1.8 or 3.05 first, followed by catalysis at higher values by adding base. This results in a mesoporous structure with an abundance of pores around 3.5nm. The data show that all molecular sizes can be released in a controlled manner. The data also reveal a unique in vivo approach to enable release of large biological molecules: the use more labile sol gel structures by acid catalyzing above the pH value of the isoelectric point of silica; upon immersion in a physiological fluid the pores expand to reach an average size of 3.5nm, thereby facilitating molecular out-diffusion. PMID- 23643608 TI - Wear and abrasion resistance selection maps of biological materials. AB - The mechanical design of biological materials has generated widespread interest in recent years, providing many insights into their intriguing structure-property relationships. A critical characteristic of load-bearing materials, which is central to the survival of many species, is their wear and abrasion tolerance. In order to be fully functional, protective armors, dentitious structures and dynamic appendages must be able to tolerate repetitive contact loads without significant loss of materials or internal damage. However, very little is known about this tribological performance. Using a contact mechanics framework, we have constructed materials selection charts that provide general predictions about the wear performance of biological materials as a function of their fundamental mechanical properties. One key assumption in constructing these selection charts is that abrasion tolerance is governed by the first irreversible damage at the contact point. The maps were generated using comprehensive data from the literature and encompass a wide range of materials, from heavily mineralized to fully organic materials. Our analysis shows that the tolerance of biological materials against abrasion depends on contact geometry, which is ultimately correlated to environmental and selective pressures. Comparisons with experimental data from nanoindentation experiments are also drawn in order to verify our predictions. With the increasing amount of data available for biological materials also comes the challenge of selecting relevant model systems for bioinspired materials engineering. We suggest that these maps will be able to guide this selection by providing an overview of biological materials that are predicted to exhibit the best abrasion tolerance, which is of fundamental interest for a wide range of applications, for instance in restorative implants and protective devices. PMID- 23643609 TI - Interleukin-10 gene promoter polymorphisms are associated with cyclosporin A induced gingival overgrowth in renal transplant patients. AB - OBJECTIVE: Interleukin-10 (IL-10) is an anti-inflammatory cytokine whose genetic polymorphisms are associated with the production of IL-10 and the susceptibility to periodontal diseases. The aim of this study was to investigate the possible association of IL-10 single nucleotide polymorphisms (SNPs) and cyclosporin A (CsA)-induced gingival overgrowth (GO) in renal transplant patients in a Chinese population, taking into account subgingival microbiota as additional variables. MATERIAL AND METHODS: A total of 202 patients were dichotomized into two groups: 122 with GO and 80 without GO. The IL-10-1082 SNP, -819 SNP and -592 SNP were measured using an allele-specific PCR method. The levels of subgingival bacteria were measured by real-time PCR. Genotype and allele frequencies were analyzed using the Chi-square test and logistic regression analysis. RESULTS: The frequency of IL-10-819TT (-592AA) genotype was statistically higher in patients with GO than that in patients without GO (P<0.05). Multiple logistic regression analysis demonstrated that the prevalence of GO is not dependent on age, gender, and pharmacological variables, being significantly associated with the carriers of ATA haplotype (OR=2.425, 95%CI=1.214-4.845, P=0.012). Moreover, ATA positive carriers in the GO group presented significantly higher levels of Porphyromonas gingivalis and Treponema denticola than those negative carriers. CONCLUSIONS: Our results show that IL-10-819TT (-592AA) genotype and ATA halpotype are associated with susceptibility to CsA-induced GO. Meanwhile, ATA haplotype is associated with a higher detection of P. gingivalis and T. denticola in GO patients, and may increase the risk of developing GO. PMID- 23643611 TI - [Management of type 2 diabetes: new drugs, new recommendations]. PMID- 23643610 TI - Sleep-disordered breathing: effects on brain structure and function. AB - Sleep-disordered breathing is accompanied by neural injury that affects a wide range of physiological systems which include processes for sensing chemoreception and airflow, driving respiratory musculature, timing circuitry for coordination of breathing patterning, and integration of blood pressure mechanisms with respiration. The damage also occurs in regions mediating emotion and mood, as well as areas regulating memory and cognitive functioning, and appears in structures that serve significant glycemic control processes. The injured structures include brain areas involved in hormone release and action of major neurotransmitters, including those playing a role in depression. The injury is reflected in a range of structural magnetic resonance procedures, and also appears as functional distortions of evoked activity in brain areas mediating vital autonomic and breathing functions. The damage is preferentially unilateral, and includes axonal projections; the asymmetry of the injury poses unique concerns for sympathetic discharge and potential consequences for arrhythmia. Sleep-disordered breathing should be viewed as a condition that includes central nervous system injury and impaired function; the processes underlying injury remain unclear. PMID- 23643612 TI - [Right atrial myxoma complicated by pulmonary embolism and revealed by right heart failure]. PMID- 23643613 TI - [Management of type 2 diabetes: new or previous agents, how to choose?]. AB - Once lifestyle measures implemented, if hyperglycemia persists, above individual HbA1c targets, a medication should be started in type 2 diabetic patients (T2DM). First, unless exception, an oral antidiabetic drug. Except in case of intolerance, the initial monotherapy, metformin remains the strengthening treatment. Latter, combination of two oral drugs, now offers several options, mainly the choice to associate a "conventional insulin-secretor", sulfonylureas, glinide, or a "new one" belonging the class of "incretin", more readily a gliptine (DPP-4 inhibitors) rather than injectable GLP-1 analogue which can also be sometimes chosen at this stage. These options are mostly new and have the advantage a neutral or favourable (for GLP-1) effect on body weight in obese type 2 DM patient and the absence of any hypoglycaemic risk in both classes of incretins. But this risk varies depending on the patient profile, much higher if the target HbA1c is low (6 to 6.5 or 7%), or in the elderly, fragile and/or in case of renal insufficiency. These two different situations with a high risk of hypoglycaemia, define best indications of this new class. If dual oral therapy does not achieve the goals we are faced with three options: triple oral therapy: metformin-sulfonylurea-gliptine or one of two approaches with injections, insulin or GLP-1 analogues. The use of GLP-1 analogues is often delayed today and put wrongly in balance with the transition to insulin, a use already delayed in France and insufficient. The use of incretins is new and needs to be validated by studies of sustainability on glycemic control, prevention of microvascular and macrovascular complications and after years on the market security of use, primarily on the exocrine pancreas. In short, individualization of strategies and HbA1c targets are required, the new molecules can help us in this process. This individualization can easily be done through the handy guide proposed by the experts ADA EASD statement, endorsed by the SFD, abandoning the complex algorithm recently again proposed by HAS and ANSM in 2013. A recommendation that prioritizes the costs of the strategies. An absolutely critical issue, while admitting not to have the tools to measure them in all their dimensions. Finally, we must reconsider every treatment after a maximum of 6 months of use, if the results are deemed inadequate substitute rather than adding drugs. PMID- 23643614 TI - Application of S-thanatin, an antimicrobial peptide derived from thanatin, in mouse model of Klebsiella pneumoniae infection. AB - Thanatin was first discovered from the hemipteran insect Podisus maculiventris and showed a promising antimicrobial activity. Multidrug-resistant (MDR) clinical isolates of Klebsiella pneumoniae have developed resistance to current therapies. As an attempt to resolve this problem, the efficacy of thanatin and its analogues against clinical isolates of K. pneumoniae was studied in vitro and in vivo. S thanatin showed an improved antimicrobial activity with the tested MIC values was 2-8-fold lower than those of other thanatin analogs. Antimicrobial assay indicated a high activity of S-thanatin against K. pneumoniae in vitro with MIC between 4 and 8 MUg/ml. Its in vivo activity was evaluated using a K. pneumoniae infected mice model. Adult male ICR mice were randomly grouped and given an intraperitoneal (i.p.) administration of 2 * 10(10)colony-forming units of K. pneumoniae (CI 120204205). Afterwards, mouse groups were subjected to i.p. administration of saline or S-thanatin (5, 10, or 15 mg/kg). After an inspection of 72 h, the mice were finally sacrificed for analysis of in vivo bacterial growth and plasma endotoxin level. The results showed that S-thanatin administration apparently improved the survival rate and reduced the bacterial CFU from intra-abdominal fluid in mice. The plasma endotoxin level was improved as well. All above implied that S-thanatin, as an alternative, may provide a novel strategy for treating K. pneumoniae infection and other infections due to multidrug-resistant bacteria. PMID- 23643615 TI - [Advance care planning and severe chronic diseases]. AB - INTRODUCTION: Advanced care planning (ACP) helps in make decisions on the health problems of people who have lost the capacity for informed consent. It has proven particularly useful in addressing the end of life. The aim of this study was to determine the prevalence of ACP in patients with severe chronic diseases. MATERIAL AND METHODS: Review of medical records of patients with dementia, amyotrophic lateral sclerosis, Parkinson's disease, chronic obstructive pulmonary disease or interstitial lung disease, heart failure, chronic kidney disease on dialysis and cancer, all in advanced stages. We collected data on living wills or registered prior decisions by the physician according to clinical planned. RESULTS: A total of 135 patients were studied. There was a record of ACP in 22 patients (16.3%). In most of them it was planned not to start any vital treatment in the event of high risk of imminent death and lacking the ability to make decisions. Only two patients were had a legal living will. CONCLUSION: The registration of ACP is relatively low, and this can affect decision-making in accordance with the personal values of patients when they do not have the capacity to exercise informed consent. PMID- 23643617 TI - An in vitro approach for production of non-scar minicircle DNA vectors. AB - Minicircle (MC) DNA vectors have shown prolonged expression in gene transfection studies. Here we have developed a facile approach based on enzyme-catalyzed reactions to produce the MC DNA in vitro. eGFP plasmid was inserted by two mirror symmetry pairs of EcoRV and HindIII restriction enzyme sites at both sides of the expression cassette. The highly purified eGFP MC DNA vector was obtained through a dephosphorylating/re-exposing process, followed by a selective ligation of MC DNA and selective removal of the bacterial backbone fragment. The GFP expression study showed a significant improvement by using MC vectors. This method mimics the recombination process in vitro, avoids the need for specific bacterial strains, strict inducing strategy and complex purification approach, which provides potential for manufacturing the high-quality minicircle DNA vectors for vaccination and gene therapy applications. PMID- 23643616 TI - Intrachromosomal homologous recombination between inverted amplicons on opposing Y-chromosome arms. AB - Amplicons--large, nearly identical repeats in direct or inverted orientation--are abundant in the male-specific region of the human Y chromosome (MSY) and provide targets for intrachromosomal non-allelic homologous recombination (NAHR). Thus far, NAHR events resulting in deletions, duplications, inversions, or isodicentric chromosomes have been reported only for amplicon pairs located exclusively on the short arm (Yp) or the long arm (Yq). Here we report our finding of four men with Y chromosomes that evidently formed by intrachromosomal NAHR between inverted repeat pairs comprising one amplicon on Yp and one amplicon on Yq. In two men with spermatogenic failure, sister-chromatid crossing-over resulted in pseudoisoYp chromosome formation and loss of distal Yq. In two men with normal spermatogenesis, intrachromatid crossing-over generated pericentric inversions. These findings highlight the recombinogenic nature of the MSY, as intrachromosomal NAHR occurs for nearly all Y-chromosome amplicon pairs, even those located on opposing chromosome arms. PMID- 23643618 TI - Nanoneedle insertion into the cell nucleus does not induce double-strand breaks in chromosomal DNA. AB - An atomic force microscope probe can be formed into an ultra-sharp cylindrical shape (a nanoneedle) using micro-fabrication techniques such as focused ion beam etching. This nanoneedle can be effectively inserted through the plasma membrane of a living cell to not only access the cytosol, but also to penetrate through the nuclear membrane. This technique shows great potential as a tool for performing intranuclear measurements and manipulations. Repeated insertions of a nanoneedle into a live cell were previously shown not to affect cell viability. However, the effect of nanoneedle insertion on the nucleus and nuclear components is still unknown. DNA is the most crucial component of the nucleus for proper cell function and may be physically damaged by a nanoneedle. To investigate the integrity of DNA following nanoneedle insertion, the occurrence of DNA double strand breaks (DSBs) was assessed. The results showed that there was no chromosomal DNA damage due to nanoneedle insertion into the nucleus, as indicated by the expression level of gamma-H2AX, a molecular marker of DSBs. PMID- 23643619 TI - Effect of the nanostructure of porous alumina on growth behavior of MG63 osteoblast-like cells. AB - It is well known that cellular responses to materials, in terms of adhesion, migration and proliferation, are highly affected by the surface characteristics of the materials. The investigation of the effect of material surface topography on cell behaviors is of great importance for the development of implanted biomaterials in tissue engineering. Alumina is one of the most popular implant materials used in orthopedics, but few data are available concerning the potential cellular responses of MG63 to nanoporous alumina. The present study investigated the size effect of nanoporous alumina substrates on MG63 cell behaviors in terms of cell viability, expression of integrin beta1, alkaline phosphatase (ALP) activity and changes of cell morphology, respectively. Cell viability was measured by means of MTT assay and integrin beta1 expression was detected by immunofluorescence staining and real-time PCR. Scanning electron microscopy (SEM) was used to observe cell morphology. Cell function was evaluated by detecting the ALP activity and mineralization. Results showed that cell viability and expression of integrin beta1 were decreased with the increasing pore size, however, the increasing pore size of the alumina resulted in elongated cell morphology, enhanced ALP activity and mineralization. This study showed that the surface topography of nanoporous alumina plays an important role in regulating the behaviors of MG63 osteoblast-like cells and porous alumina can be regarded as useful substrate in tissue engineering. PMID- 23643620 TI - Effect of length of molecular recognition moiety on enzymatic activity switching. AB - We site-specifically conjugated biotin-PEG derivatives with spacer arms of different lengths to mutant P450cam (3mD) and evaluated the activity of and structural changes in the conjugates as a first step toward clarifying the mechanism whereby the activity of the 3mD conjugate is inhibited. 3mD was prepared by site-specific mutation to inhibit its enzymatic activity artificially, after which the derivative compounds were conjugated to the enzyme. 3mD has one cysteine on its surface with a reactive thiol group that can react with compounds near the active site, where a conformational change will be induced after conjugation. The activity of 3mD was retained in the biotin-PEG2 3mD conjugate, but was dramatically reduced in the biotin-PEG11-3mD conjugate. To investigate the effect of poly(ethylene glycol) (PEG) length on the enzymatic activity after conjugation, PEGs of different lengths, exceeding that in biotin PEG11, and whose termini were not biotin, were conjugated to 3mD. The activity of 3mD decreased in all these conjugates. This indicates that the activity of 3mD in these conjugates decreased after its conjugation with PEG molecules that exceeded a certain length. The biotin-PEG2-3mD, which retains enzymatic activity after conjugation, showed avidin responsiveness; the enzymatic activity decreased after avidin binding. PMID- 23643621 TI - Quantitative MUC5AC and MUC6 mucin estimations in gastric mucus by a least squares minimization method. AB - We have determined the molar proportions of the MUC5AC and MUC6 mucus glycoproteins (mucins) in mucus from the normal and pathological human gastric antrum using a least-squares minimization analysis applied to amino acid compositions. We noted that the content of MUC5AC mucin in mucus from individuals without gastroduodenal disease was very high, suggesting that the integrity and barrier properties of the adherent gastric mucus layer are normally maintained by building-block structures formed from this mucin alone. We observed that the molar content of MUC6 mucin doubled (without significance) in mucus from patients with duodenal ulcer, and increased five times (with high significance) in mucus from patients with gastric ulcer, when compared with that in mucus from individuals without gastroduodenal disease. PMID- 23643622 TI - Laser capture microdissection: should an ultraviolet or infrared laser be used? AB - Laser capture microdissection (LCM) is a well-established cell separation technique. It combines microscopy with laser beam technology and allows targeting of specific cells or tissue regions that need to be separated from others. Consequently, this biological material can be used for genome or transcriptome analyses. Appropriate methods of sample preparation, however, are crucial for the success of downstream molecular analysis. The aim of this study was to objectively compare the two main LCM systems, one based on an ultraviolet (UV) laser and the other based on an infrared (IR) laser, on different criteria ranging from user-friendliness to sample quality. The comparison was performed on two types of samples: peripheral blood mononuclear cells and blastocysts. The UV laser LCM system had several advantages over the IR laser LCM system. Not only does the UV system allow faster and more precise sample collection, but also the obtained samples-even single cell samples-can be used for DNA extraction and downstream polymerase chain reaction (PCR) applications. RNA-based applications are more challenging for both LCM systems. Although sufficient RNA can be extracted from as few as 10 cells for reverse transcription quantitative PCR (RT qPCR) analysis, the low RNA quality should be taken into account when designing the RT-qPCR assays. PMID- 23643623 TI - Comparative kinetics of serological and coproantigen ELISA and faecal egg count in cattle experimentally infected with Fasciola hepatica and following treatment with triclabendazole. AB - Three methods of diagnosing Fasciola hepatica (F. hepatica) infection (a coproantigen ELISA, Bio-X Diagnostics, Belgium, Faecal Egg Count (FEC), and a serum IgG ELISA,Bio-X Diagnostics, Belgium) were evaluated in artificially infected cattle, with and without drug treatment. Specifically, the potential value of the coproantigen ELISA in the quantitation of F. hepatica infection was sought. Twelve steers were each infected with 100, 200 or 500 metacercariae (n=4 cattle/group). On day 84, post infection (PI), 2 animals from each group were treated orally with triclabendazole (TCBZ). Faecal and blood samples were collected weekly after infection from all animals, as well as over 5 consecutive days (days 105-109 PI) for the six animals remaining infected to determine the repeatability of these assays. Cattle were killed 126 days PI and the coproantigen, FEC and IgG levels were compared with the number of fluke recovered. Animals first tested positive for infection with the serum ELISA, with 11/12 animals positive on day 28, and IgG responses increased to day 42 PI. The coproantigen ELISA was first positive on day 42 (3/12 animals), with all animals positive by day 56 PI. The first F. hepatica egg was detected on day 49 from an animal infected with 500 metacercariae; however only on one occasion (day 84) did all animals return positive FEC. Within one week of treatment with TCBZ, all six treated animals had returned to negative status by coproantigen ELISA and FEC whereas IgG levels persisted. Weekly variation in both coproantigen level and FEC was evident throughout the trial. Results from the consecutive daily collections varied greatly between days for both methods, with 2-6-fold differences in coproantigen levels and 2-4-fold variation in FEC. Strong correlations were observed between fluke burdens (day 126) and day 125 coproantigen levels (R(2)=0.8718) and FEC (R(2)=0.8368). The coproantigen ELISA was more sensitive than FEC (FEC displayed false negatives) and detected infection earlier. This ELISA showed good correlation to fluke burdens in these cattle and has promise as a test for detecting low fluke burdens. PMID- 23643624 TI - Everolimus immunosuppression in de novo heart transplant recipients: what does the evidence tell us now? AB - The efficacy of everolimus with reduced cyclosporine in de novo heart transplant patients has been demonstrated convincingly in randomized studies. Moreover, everolimus-based immunosuppression in de novo heart transplant recipients has been shown in two randomized trials to reduce the increase in maximal intimal thickness based on intravascular ultrasound, indicating attenuation of cardiac allograft vasculopathy (CAV). Randomized trials of everolimus in de novo heart transplantation have also consistently shown reduced cytomegalovirus infection versus antimetabolite therapy. In maintenance heart transplantation, conversion from calcineurin inhibitors to everolimus has demonstrated a sustained improvement in renal function. In de novo patients, a renal benefit may only be achieved if there is an adequate reduction in exposure to calcineurin inhibitor therapy. Delayed introduction of everolimus may be appropriate in patients at high risk of wound healing complications, e.g. diabetic patients or patients with ventricular assist device. The current evidence base suggests that the most convincing reasons for use of everolimus from the time of heart transplantation are to slow the progression of CAV and to lower the risk of cytomegalovirus infection. A regimen of everolimus with reduced-exposure calcineurin inhibitor and steroids in de novo heart transplant patients represents a welcome addition to the therapeutic armamentarium. PMID- 23643625 TI - Clinical spectrum and treatment outcome of West Syndrome in children from Northern India. AB - PURPOSE: This study was intended to document the clinical profile and treatment outcome of West syndrome in children attending a tertiary care center in Northern India. METHOD: Data were collected by a retrospective chart review of children diagnosed with West syndrome between January 2008 and January 2012. Information was recorded pertaining to the age at onset and presentation, etiology, and associated co-morbidities; results of electroencephalography (EEG) and neuroimaging; treatment given; and final outcome. The following drugs were used for treatment: pyridoxine, prednisolone, vigabatrin, sodium valproate, nitrazepam, topiramate, and levetiracetam. The response was categorized as spasm cessation, partial improvement (>50% improvement), or no improvement. The final outcome was considered favorable when there was a complete cessation of spasms; with absence of relapse and no progression to other seizure types for at least 6 months. RESULTS: Records of 148 children (120 boys) were analyzed. The mean (SD) age at onset and presentation was 5.3 (4.6) months, and 13.1 (7.3) months, respectively. Perinatal asphyxia (61.4%), neonatal sepsis/meningitis (10.6%), and postnatal meningitis (11.4%) were the predominant causes. The etiology could not be ascertained in 16.6% of children. Favorable outcome was observed in 45 (30.4%) children with spasm cessation rate of 25.4% with prednisolone. Age at onset, gender, time lag to treatment, presence of perinatal asphyxia, or co-morbid cerebral palsy did not affect the final outcome. CONCLUSION: This study highlights the developing country perspective of children with West syndrome, including delayed presentation, adverse perinatal events as the predominant etiology, and modest response to oral steroids. PMID- 23643626 TI - Febrile infection-related epilepsy syndrome: a study of 12 patients. AB - PURPOSE: To analyze the electroclinical features, neuroimaging findings, treatment, and outcome of 12 patients with febrile infection-related epilepsy syndrome (FIRES). METHODS: This is a retrospective study of 12 children with FIRES with a mean time of follow-up of 6.5 years carried out at the Garrahan Hospital of Buenos Aires between 1997 and 2012. RESULTS: Eight males and four females had focal status epilepticus preceded by febrile infection with a mean age at presentation of 8.5 years. In the acute period, the treatment included antiepileptic drugs (AEDs) in all cases, immunotherapy in 10 cases, and burst suppression coma in eight. The ketogenic diet was tried in two, plasmapheresis in one, and rituximab in one. Two patients treated with IVIG and one patient given steroids had a good response, but in this phase only three patients had a prolonged good response to IVIG and a ketogenic diet. No patients died in this period. In the chronic epilepsy phase, all children had seizures arising from neocortical regions. All patients had refractory epilepsy, and most mental retardation, and behavioral disturbances. All received different AEDs and in this phase a third patient was put on a ketogenic diet. One patient was operated without good results. Only two cases had a good outcome after 2 and 10 years of follow-up. CONCLUSION: FIRES is a well-defined severe epileptic syndrome, probably in the group of epileptic encephalopathies, characterized by focal or multifocal seizures arising from the neocortical regions with an unknown etiology. Immunoglobulin and the ketogenic diet may be considered a potentially efficacious treatment. PMID- 23643627 TI - Peroxynitrite induced structural changes result in the generation of neo-epitopes on human serum albumin. AB - Human serum albumin (HSA), the most abundant plasma protein, is quite vulnerable to oxidizing and nitrating agents. In this study, peroxynitrite induced nitration and oxidation of HSA was assessed by various physicochemical techniques. Cross linking of HSA was evident on polyacrylamide gel electrophoresis. The carbonyl content was markedly elevated in peroxynitrite-modified HSA as compared to the native protein. Dityrosine and 3-nitrotyrosine were present only in peroxynitrite modified HSA. The peroxynitrite-modified HSA induced high titre antibodies in experimental animals showing high specificity towards the immunogen. Spectroscopic studies showed structural alterations in the HSA molecule upon peroxynitrite treatment which result in the generation of neo-epitopes and enhanced immunogenicity. The possible role of damaged HSA in various diseases has been suggested. PMID- 23643628 TI - Chaperonin GroEL: a novel phylogenetically conserved protein with strong immunoreactivity of Avian Pathogenic Escherichia coli isolates from duck identified by immunoproteomics. AB - Avian Pathogenic Escherichia coli (APEC) is one of the most important bacterial pathogens of poultry. The lack of suitable vaccines and the emergence of multi resistant strains have hampered the control of avian colibacillosis. To identify immunogenic proteins of APEC as vaccine candidates, immunoproteomics and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) were applied. Proteins from total cell lysates of APEC DE205B isolated from the brain of a duck with septicemia and neurological symptom in China were separated by two-dimensional electrophoresis (2-DE) and reacted with hyperimmune duck serum against DE205B. Fourteen immunoreactive spots were found, representing 11 distinct proteins. These included two predominant immunogenic components, outer membrane protein A (OmpA) and flagellin (FliC). GroEL, which is a member of the molecular chaperone family and identical structurally to eukaryotic heat shock protein 60 (Hsp60), and the other eight antigens are reported here as immunoreactive proteins of APEC for the first time. Subsequently, nine genes encoding the identified proteins were successfully cloned and expressed in E. coli BL21 (DE3). Seven of the recombinant proteins were able to react with hyperimmune duck serum and three of them, GroEL, OmpA and FliC, showed stronger immunoreactivity. Challenge studies revealed that, just like OmpA and FliC, recombinant GroEL stimulated a strong antibody response and supported protective efficacy against APEC infection in ducks. With high phylogenetic conservation, it is considered that GroEL would be an ideal immunogen of APEC for vaccine development. PMID- 23643629 TI - Factors associated with human papillomavirus vaccination among young adult women in the United States. AB - BACKGROUND: Human papillomavirus (HPV) vaccination is recommended to protect against HPV-related diseases. OBJECTIVE: To estimate HPV vaccine coverage and assess factors associated with vaccine awareness, initiation and receipt of 3 doses among women age 18-30 years. METHODS: Data from the 2010 National Health Interview Survey were analyzed to assess associations of HPV vaccination among women age 18-26 (n=1866) and 27-30 years (n=1028) with previous HPV exposure, cervical cancer screening and selected demographic, health care and behavioral characteristics using bivariate analysis and multivariable logistic regression. RESULTS: Overall, 23.2% of women age 18-26 and 6.7% of women age 27-30 years reported receiving at least 1 dose of HPV vaccine. In multivariable analyses among women age 18-26 years, not being married, having a regular physician, seeing a physician or obstetrician/gynecologist in the past year, influenza vaccination in the past year, and receipt of other recommended vaccines were associated with HPV vaccination. One-third of unvaccinated women age 18-26 years (n=490) were interested in receiving HPV vaccine. Among women who were not interested in receiving HPV vaccine (n=920), the main reasons reported included: not needing the vaccine (41.3%); concerns about safety of the vaccine (12.5%); not knowing enough about the vaccine (11.9%); not being sexually active (8.2%); a doctor not recommending the vaccine (7.6%); and already having HPV (2.7%). Among women with health insurance, 10 or more physician contacts within the past year and no contraindications, 74.5% reported not receiving HPV vaccine. CONCLUSIONS: HPV vaccination coverage among women age 18-26 years remains low. Opportunities to vaccinate are missed. Healthcare providers can play an important role in educating young women about HPV and encouraging vaccination. Successful public health and educational interventions will need to address physician attitudes and practice patterns and other factors that influence vaccination behaviors. PMID- 23643630 TI - Tradeoffs between the strength of conformity and number of conformists in variable environments. AB - Organisms often respond to environmental change phenotypically, through learning strategies that enhance fitness in variable and changing conditions. But which strategies should we expect in population exposed to those conditions? We address this question by developing a mathematical model that specifies the consequences of different mixtures of individual and social learning strategies on the frequencies of different cultural variants in temporally and spatially changing environments. Assuming that alternative cultural variants are differently well adapted to diverse environmental conditions, we are able to evaluate which mixture of learning strategies maximises the mean fitness of the population. We find that, even in rapidly changing environments, a high proportion of the population will always engage in social learning. In those environments, the highest adaptation levels are achieved through relatively high fractions of individual learning and a strong conformist bias. We establish a negative relationship between the proportion of the population learning socially and the strength of conformity operating in a population: strong conformity requires fewer conformists (i.e. larger proportion of individual learning), while many conformists can only be found when conformist transmission is weak. Investigations of cultural diversity show that in frequently changing environments high levels of adaptation require high level of cultural diversity. Finally, we demonstrate how the developed mathematical framework can be applied to time series of usage or occurrence data of cultural traits. Using Approximate Bayesian Computation we are able to infer information about the underlying learning processes that could have produced observed patterns of variation in the dataset. PMID- 23643631 TI - Melamine activates NFkappaB/COX-2/PGE2 pathway and increases NADPH oxidase dependent ROS production in macrophages and human embryonic kidney cells. AB - Melamine is a wildly used compound in manufactures of plastics and resins. A variety of toxic effects from melamine, including nephrolithiasis, chronic kidney inflammation, and bladder carcinoma, have been mentioned. Oxidative stress is considered to be an important pathogenic mechanism of kidney disease which may develop from an increasing free radical production through inflammation. The aim of this study is to investigate melamine-induced oxidative stress and inflammation in macrophage-like cell line RAW 264.7 and human embryonic kidney cell line HEK293. Results indicated melamine activated nuclear factor (NF)-kappaB through increasing IkappaB-alpha degradation and NF-kappaB p65/p50 DNA-binding activity. In addition, melamine significantly increased COX-2 expression and prostaglandin E2 (PGE2) production. Moreover, melamine activated NADPH oxidase (NOX), including NOX1, NOX2 and NOX4, accompanied with an increase in reactive oxygen species (ROS) production. Furthermore, melamine-induced ROS production could be attenuated by apocynin, a NOX inhibitor. In conclusion, our findings suggest melamine increased inflammation and oxidative stress via activation of NF kappaB/COX-2 and NOX/ROS pathway, and first revealed the critical role of NOX in melamine-induced ROS production, suggesting the potential of NOX inhibitor against melamine toxicity. PMID- 23643632 TI - Macelignan attenuated allergic lung inflammation and airway hyper-responsiveness in murine experimental asthma. AB - AIMS: Macelignan isolated from Myristica fragrans Houtt. is widely used for spice and flavoring for foods, and has been reported to have anti-inflammatory activity. The aim of this study was to investigate the effects of macelignan on allergic lung inflammation with a murine model of experimental asthma. MAIN METHODS: Fungal protease mixed with chicken egg ovalbumin allergen was used as a challenge to induce murine experimental asthma. To determine its effects on allergy and inflammation, macelignan was administered orally during allergen challenge, and the symptoms of allergic asthma and its underlined mechanisms were examined. KEY FINDINGS: Treatment with macelignan attenuated eosinophilic airway inflammation and airway hyper-responsiveness. With the administration of macelignan, interleukin-4 (IL-4) producing cells, but not interferon-gamma (IFN gamma) or IL-17 producing cells, were diminished in the lungs. Additionally, activation of the T helper type 2 (Th2) cell-specific master transcription factor, GATA3 was decreased with macelignan treatment. Finally, production of IL 4 but not IFN-gamma or IL-17, by CD4(+) T cells was reduced with stimulation when combined with the administration of macelignan. SIGNIFICANCE: Our data show that macelignan has anti-inflammatory effects on Th2 cell-mediated allergic lung inflammation and could potentially provide a novel preventative and/or therapy for the treatment of allergic diseases. PMID- 23643633 TI - Sulodexide improves renal function through reduction of vascular endothelial growth factor in type 2 diabetic rats. AB - AIMS: Sulodexide is a promising therapeutic drug for the management of diabetic nephropathy. Although sulodexide has demonstrated a renoprotective effect through its ability to restore glomerular ionic permselectivity, the exact mechanism is still not clear. We investigated the effects of long-term sulodexide treatment on diabetic nephropathy in Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats. MAIN METHODS: Diabetic rats were treated with or without sulodexide at 10mg/kg/day in the drinking water for nine months. Renal morphology and changes in VEGF and p38 mitogen-activated protein kinase (p38 MAPK), urinary levels of albumin (UAE) and urinary VEGF excretion were determined. To define the direct effects of sulodexide, we performed an in vitro experiment using podocytes. KEY FINDINGS: UAE was significantly higher in OLETF rats than in control LETO rats, and the sulodexide group showed significantly decreased UAE after six months of treatment. Interestingly, urinary VEGF levels were also significantly decreased in the sulodexide-treated group. In accordance with UAE and urinary VEGF changes, the renal expression of profibrotic molecules was significantly decreased after sulodexide treatment. In addition, the activation of p38 MAPK, assessed by measuring the level of phospho-specific p38 MAPK, increased in diabetic renal tissues and was markedly suppressed by sulodexide treatment. In cultured podocytes, sulodexide treatment significantly decreased high glucose-induced p38 MAPK activation and VEGF synthesis. SIGNIFICANCE: Sulodexide directly suppresses VEGF synthesis through the p38 MAPK pathway in podocytes, and these results suggest that sulodexide may provide renoprotection via suppression of renal VEGF synthesis independently of glomerular basement membrane ionic permselectivity in type 2 diabetic rats. PMID- 23643634 TI - Oxidative damage of rat liver mitochondria during exposure to t-butyl hydroperoxide. Role of Ca2+ ions in oxidative processes. AB - AIMS: The present study was designed for further evaluation of the biochemical mechanism of hepatic mitochondrial dysfunction under oxidative damages induced by organic hydroperoxide, tert-butyl hydroperoxide (tBHP), for estimation of the molecular targets impaired during oxidative stress, and for investigation of the role of Ca(2+) ions in mitochondrial oxidative reactions and of the protective effect of melatonin during mitochondrial peroxidative damage. MAIN METHODS: Mitochondria were isolated by differential centrifugation from the rat liver. The effects of tBHP exposure, EDTA, Ca(2+) ions and melatonin on mitochondrial respiratory activity, mitochondrial enzyme activities and redox status were measured. KEY FINDINGS: The present study provides evidence that tBHP (at low concentrations of 0.02-0.065mM, in EDTA-free medium) induced uncoupling of the oxidation and phosphorylation processes and decreased the efficiency of the phosphorylation reaction. This effect depended on the respiratory substrate used. The presence of EDTA prevented oxidative impairment of mitochondrial respiration, but Ca(2+) ions in the medium enhanced oxidant-induced mitochondrial damage considerably. In the presence of 0.5mM EDTA, tBHP (at high concentrations, 0.5 2mM) considerably oxidized mitochondrial reduced glutathione, enhanced accumulation of membrane lipid peroxidation products and mixed protein glutathione disulfides and led to an inhibition of oxoglutarate dehydrogenase and succinate dehydrogenase. SIGNIFICANCE: Direct oxidative modification of enzymatic complexes of the respiratory chain and mitochondrial matrix, mitochondrial reduced glutathione depletion, protein glutathionylation, membrane lipid peroxidation and Ca(2+) overload are the main events of mitochondrial peroxidative damages. Experiments in vitro demonstrated that melatonin inhibited the mitochondrial peroxidative damage, preventing redox-balance changes and succinate dehydrogenase inactivation. PMID- 23643636 TI - Analysis of the human gut microbiome and association with disease. PMID- 23643635 TI - Upregulation of CXCR3 expression on CD8+ T cells due to the pervasive influence of chronic hepatitis B and C virus infection. AB - Chronic systemic 'latent' viral infections such as Cytomegalovirus infection (CMV) are known to leave a fingerprint in the total T-cell population. We investigated whether chronic infections with a 'persistent' viremia, such as chronic hepatitis B and C (CHB, CHC), characterized by local organ-specific inflammation, also impact the total peripheral T-cell population or other virus specific T-cells that do not target hepatitis viruses. No phenotypic or functional differences were found between CD8(+) T-cells or CMV- or Epstein-Barr virus specific T-cells in viral hepatitis and healthy controls (HC). However, expression of chemokine-receptor CXCR3 was significantly higher on total peripheral CD8(+) T-cells of CHB or CHC patients compared to HC (p<0.005) which may reflect the pervasive influence of a persistent viral infection, even when restricted to the liver. In CHB higher CXCR3 expression was associated with positive HBeAg-status and correlated with the percentage of HBsAg expressing hepatocytes found in liver biopsies, both pointing to a relation between CXCR3 expression and disease activity. In fact chemokine-receptors such as CXCR3 are important for T-cell recruitment to the liver and chemokine-ligands specific for CXCR3 are upregulated in chronic hepatitis. Modulating chemokine(receptor) expression could be a potential target for future therapy to optimize the anti viral immunologic environment in the liver. PMID- 23643637 TI - A cross sectional assessment of allergic rhinitis and asthma control at an immunoallergology outpatient hospital setting using CARAT10 questionnaire. AB - INTRODUCTION: The most recent guidelines on asthma and rhinitis management recommend the optimal control of both diseases as the primary goal of treatment. CARAT10 is a recently developed and validated Portuguese questionnaire, which permits the simultaneous assessment of allergic rhinitis and asthma (ARA) control. There is no published data about the use of this tool. AIMS: To assess ARA control using CARAT10 in an Immunoallergology hospital setting; METHODS: Patients with diagnosis of allergic rhinitis with or without asthma (positive aeroallergens prick-tests and/or positive specific IgE) were sequentially enrolled and asked to fill in CARAT10 questionnaire at their first appointment. RESULTS: Two hundred patients were included, mostly female (n=142) with an average age of 33.6+/-12.3 years. ARA was present in 86 patients while 114 had isolated allergic rhinitis. In ARA group, 86% scored CARATtotal <= 24, meaning poor control. Subscores revealed that 83% had poorly controlled rhinitis (CARATr <= 8) and 74% had poorly controlled asthma (CARATa < 16). There were no age or gender related differences in ARA control. In allergic rhinitis group (n=114), 89% were poorly controlled. CONCLUSIONS: Only 14% of patients presenting rhinitis and asthma had both diseases controlled. PMID- 23643639 TI - Mycobacterium tuberculosis, how long did you walk? PMID- 23643638 TI - Cross-cultural adaptation and validation of the Portuguese version of the Living with Asthma Questionnaire. AB - OBJECTIVE: To translate and culturally adapt the Living with Asthma Questionnaire (LWAQ) to the Portuguese language and to test its reliability and validity. METHODS: The Portuguese version of this disease-specific health-related quality of life measure was obtained with forward/backward translations, consensus panels and a pre-test. The Portuguese LWAQ and Medical Outcomes Study - 36 item Short Form (SF-36) questionnaires, and a form for the characteristics of the patients were administered to 61 subjects with asthma. RESULTS: Reliability of LWAQ scores was good with Cronbach's alpha coefficients ranging from 0.70 to 0.97 [with the exception of "preoccupation" (0.62) construct, and "sleep" (0.67) and "effects on others" (0.47) domains] and intraclass correlation coefficients between 0.86 and 0.99. Construct validity was supported by the confirmation of predefined hypotheses involving expected significant correlations between LWAQ total, constructs and domains, and SF-36 dimensions with similar content. CONCLUSION: The Portuguese LWAQ exhibited suitable psychometric properties, in terms of internal consistency, reproducibility and construct validity. PMID- 23643640 TI - Osteoimmunology, osteorheumatology or rheumatology alone? PMID- 23643641 TI - Transient osteoporosis of both hips in pregnancy. PMID- 23643642 TI - Anal intraepithelial neoplasia--is treatment better than observation? AB - Anal Intraepithelial Neoplasia (AIN) is an increasingly common condition for which the best treatment has not been well established. Traditional management was based on a 'watch and wait' strategy, but as the natural history of AIN and its progression to anal cancer is becoming better understood, more active treatment strategies are warranted. A best evidence topic in surgery was written according to a structured protocol to address the question whether treatment is indicated in patients with AIN. A total of 169 papers were identified using the defined search criteria. This included only one randomised controlled trial. Case series were therefore also included to help answer the question. The details of the papers were tabulated including relevant outcomes and study weaknesses. We conclude that treatment of high grade AIN, particularly in high risk groups is recommended to try to avoid progression to anal cancer. Treatment options that have shown some benefit include topical use of imiquimod cream or ablation directed by high resolution anoscopy. PMID- 23643643 TI - A primer on thermodynamic-based models for deciphering transcriptional regulatory logic. AB - A rigorous analysis of transcriptional regulation at the DNA level is crucial to the understanding of many biological systems. Mathematical modeling has offered researchers a new approach to understanding this central process. In particular, thermodynamic-based modeling represents the most biophysically informed approach aimed at connecting DNA level regulatory sequences to the expression of specific genes. The goal of this review is to give biologists a thorough description of the steps involved in building, analyzing, and implementing a thermodynamic-based model of transcriptional regulation. The data requirements for this modeling approach are described, the derivation for a specific regulatory region is shown, and the challenges and future directions for the quantitative modeling of gene regulation are discussed. PMID- 23643644 TI - Emerging roles of Cdk8 in cell cycle control. AB - Cyclin dependent kinase 8 (Cdk8) is a component of Mediator, an evolutionary conserved multiprotein complex that regulates RNA polymerase II-dependent transcription. Cdk8 has been implicated as a regulator of multiple steps in cell cycle progression. We here discuss recent advances in our understanding of Cdk8 function and a possible role for Mediator as a hub for integrating transcription regulation with cell cycle progression. PMID- 23643645 TI - [Assessment of the impact of the use single-dose medications in 2 primary care centres]. AB - OBJECTIVE: To evaluate the economical impact of using medications packaged in a single dose non-reusable container (Onedose((r))), compared to prescribing preparations in the usual multidose containers. DESIGN: We performed a cost minimization analysis from a prescribing center's perspective. The observational study design is retrospective and analyzes 23 products in prescriptions made between January and April 2012. SETTING: Two Spanish Primary Care Centers located in the province of Barcelona. The first covered an urban area with a population of 24.500 people, and the second a semi-urban area with 10.000 people. PRIMARY OUTCOME MEASURES: Each examined product was measured between January and April 2012 and extrapolated annually, based on the defined substitution scenarios results of total Euro savings in non-prescribed doses and price differences. RESULTS: The Savings related to the substitution of the prescribed packaging presentations with Onedose((r)) were 45.000 Euros (24%) in the months of analysis and 133.000 Euros annually, avoiding the use of 212.000 doses (14%) in the period analyzed and 669.000 doses annually. CONCLUSIONS: The use of single dose non reusable container packaging (Onedose((r))) in the analyzed health centers reduced prescription-related expenses without increasing dispensing costs, thus reducing the household stock of those medicines which are not objectively suitable to be used without a previous diagnosis. PMID- 23643646 TI - Maternal immune stimulation during pregnancy shapes the immunological phenotype of offspring. AB - Epidemiological studies have associated infection during pregnancy with increased risk of neurodevelopmental disorders in children, which is modeled in rodents by stimulating the immune system of pregnant dams with microorganisms or their mimics, such as poly(I:C) or LPS. In two prenatal mouse models, we show that in utero exposure of the fetus to cytokines/inflammatory mediators elicited by maternal immune stimulation with poly(I:C) yields offspring that exhibit a proinflammatory phenotype due to alterations in developmental programming of their immune system. Changes in the innate and adaptive immune elements of these pro-inflammatory offspring result in more robust responses following exposure to immune stimuli than those observed in control offspring from PBS-injected pregnant dams. In the first model, offspring from poly(I:C)-injected immunologically naive dams showed heightened cellular and cytokine responses 4 h after injection of zymosan, a TLR2 agonist. In the second model, using dams with immunological memory, poly(I:C) injection during pregnancy produced offspring that showed preferential differentiation toward Th17 cell development, earlier onset of clinical symptoms of EAE, and more severe neurological deficits following immunization with MOG35-55. Such "fetal programming" in offspring from poly(I:C)-injected dams not only persists into neonatal and adult life, but also can have profound consequences on health and disease. PMID- 23643647 TI - Association between weekend catch-up sleep duration and hypertension in Korean adults. AB - OBJECTIVE: Our objective was to investigate if weekend catch-up sleep is independently related to a decrease in the risk for hypertension in Korean adults. METHODS: The subjects included 2782 Korean adults ages 19 years and older. Data on demographic variables, sleep duration (weekday and weekend), and hypertension were obtained using questionnaires. Logistic regression analyses were performed to test the association between hypertension and sleep duration (weekday and weekend catch-up sleep duration); we also adjusted for possible covariates. RESULTS: After adjustment for confounding variables, we found that individuals who slept less than 6 hours a night had an increased odds ratio (OR) for hypertension (OR, 1.73; 95% confidence interval [CI], 1.13-2.64) compared to individuals who slept 7 to <8 hours a night. Furthermore, one hour of weekend catch-up sleep was significantly associated with decreased risk for hypertension (OR, 0.83; 95% CI, 0.72-0.95). There were significant differences for groups with and without subjective sleep insufficiency in the association between weekend catch-up sleep duration and the prevalence of hypertension; in addition, the effect of an extra hour of weekend catch-up sleep per night on hypertension was stronger in those subjects who experienced subjective sleep insufficiency (OR, 0.61; 95% CI, 0.46-0.82). CONCLUSIONS: Sleeping more on the weekend to compensate for weekday sleep deficit could lower the risk for hypertension in Korean adults, especially in Korean adults who have the subjective symptom of sleep insufficiency. PMID- 23643648 TI - Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. AB - BACKGROUND: Individuals affected with narcolepsy represent a vulnerable segment of the population. However, we only have a partial understanding of this vulnerability. Our study aims to examine psychiatric disorders and medical conditions associated with narcolepsy. METHODS: A total of 320 narcoleptic participants were interviewed regarding sleeping habits, health, medication consumption, medical conditions (International Statistical Classification of Diseases and Related Health Problems, 10th edition), sleep disorders (International Classification of Sleep Disorders, second edition [ICSD-2]) and mental disorders (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision [DSM-IV-TR]) using Sleep-EVAL. A general population comparison sample (N=1464) matched for age, sex, and body mass index (BMI) and interviewed with the same instrument was used to estimate odds ratios (OR). RESULTS: Five diseases were more frequently observed among narcoleptic participants, including hypercholesterolemia (OR, 1.51), diseases of the digestive system (OR, 3.27), heart diseases (OR, 2.07), upper respiratory tract diseases (OR, 2.52), and hypertension (OR, 1.32). Most frequent psychiatric disorders among the narcolepsy group were major depressive disorder (MDD) (OR, 2.67) and social anxiety disorder (OR, 2.43), both affecting nearly 20% of narcoleptic individuals. However, most mood and anxiety disorders were more prevalent among the narcoleptic group. Alcohol abuse or alcohol dependence was comparable between groups. CONCLUSIONS: Narcolepsy is associated with a high comorbidity of both medical conditions and psychiatric disorders that need to be addressed when developing a treatment plan. PMID- 23643649 TI - Obstructive sleep apnea in children is associated with severity-dependent deterioration in overnight endothelial function. AB - BACKGROUND: Restorative sleep is expected to promote improved endothelial function (EF) in the morning compared to the evening. However, in adults with obstructive sleep apnea (OSA) EF is not only adversely affected, but it worsens during the night. Data in pediatric OSA are scarce, and overnight changes have not been explored. Therefore, we sought to examine potential associations between pediatric OSA and overnight changes in EF. METHODS: 59 habitually snoring children with various degrees of sleep-disordered breathing (age range, 4-16 years) underwent EF assessment (reactive hyperemia test by EndoPAT, Itamar Medical, Israel) in the evening before and the morning after an overnight polysomnography (PSG). Two brachial occlusion periods (1 min and 5 min) also were tested. Potential associations between evening-to-morning changes in EF and polysomnographic parameters were explored. RESULTS: Evening-to-morning changes in children with OSA displayed severity-dependent deterioration of EF, and occlusions lasting 1 or 5 min during the reactive hyperemia test yielded similar findings. CONCLUSIONS: In children deterioration in EF during the night significantly correlated with the severity of OSA. Furthermore, the reactive hyperemia test can be reliably performed with only 60 seconds of arterial flow occlusion in children. These findings support our hypothesis that similarly to adults, sleep apnea in children results in endothelial dysfunction (ED). We speculate that pediatric OSA is less commonly associated with cardiovascular complications possibly due to the shorter duration of the syndrome. PMID- 23643650 TI - Sleep and daytime function in adults with attention-deficit/hyperactivity disorder: subtype differences. AB - OBJECTIVES: Although sleep disorders have been reported to affect more than half of adults with attention-deficit/hyperactivity disorder (ADHD), the association between sleep and ADHD is poorly understood. The aims of our study were to investigate sleep-related variables in adults with ADHD and to assess if any differences exist between ADHD of the predominantly inattentive (ADHD-I) and combined (ADHD-C) subtypes. METHODS: We used the Epworth sleepiness scale (ESS), the Pittsburgh Sleep Quality Index (PSQI), and the fatigue severity scale (FSS) to collect data on daytime sleepiness, sleep quality, and fatigue in 126 subjects (45 ADHD-I and 81 ADHD-C subjects). RESULTS: Approximately 85% of subjects reported excessive daytime sleepiness or poor sleep quality. The most common sleep concerns were initial insomnia, interrupted sleep, and feeling too hot. When examining ADHD subtype differences, ADHD-I subtypes reported poorer sleep quality and more fatigue than ADHD-C subtypes. Partial correlation analyses revealed that interrelationships between sleep quality, daytime sleepiness, and fatigue differ between ADHD subtypes; in ADHD-I subtypes fatigue was associated with sleep quality, while in the ADHD-C subtypes fatigue was associated with both sleep quality and daytime sleepiness. There also appears to be a subtype*gender interaction that affects the perception of fatigue, as subjective fatigue was markedly higher in ADHD-I women than in ADHD-C women. CONCLUSION: Altogether our data indicate that the interplay of variables associated with daytime function and sleep varies between ADHD subtypes. This finding may have considerable relevance in the management and pathophysiologic understanding of ADHD, and thus lead to tailored treatments for ADHD subtypes. PMID- 23643651 TI - Hypocretin (orexin) neuropeptide precursor gene, HCRT, polymorphisms in early onset narcolepsy with cataplexy. AB - BACKGROUND: To test if the hypocretin (orexin) neuropeptide precursor (HCRT) gene, HCRT, mutations are implicated in the development of narcolepsy with cataplexy deficiency in young children. METHODS: The entire HCRT gene and ~2000 bp promoter region was first sequenced in 181 patients and 153 controls, and rare polymorphisms including three nonsynonymous amino acid changes were identified. Next the 557 bp region of exon 2 harboring the three nonsynonymous changes was sequenced in an additional 298 early-onset subjects and in 148 control samples. RESULTS: A previously known common polymorphism (rs760282) and nine rare novel polymorphisms were identified in subjects and controls without significant differences. Two nonsynonymous exon 2 substitutions (+977 H54A, +979 G55R) were detected in two subjects with early onset at 7 and 6 years, respectively, but were not found in any controls. These substitutions are not likely to vastly change peptide binding to hypocretin receptors. One additional exon 2 substitution (+1019, K68R) was found in two patients and one control. Additional sequencing that focused on exon 2 showed additional subjects and controls with the +1019 K68R polymorphism and without significant differences between the subjects and the control. Segregation of two of these three nonsynonymous single nucleotide polymorphisms (SNPs) were observed from unaffected parents to offspring. CONCLUSIONS: Sequencing of a large number of early-onset narcolepsy subjects revealed three novel nonsynonymous substitutions within the preprohypocretin protein, two of which were only found in patients with early onset narcolepsy but are not likely to be functionally significant, especially in heterozygote subjects. PMID- 23643652 TI - Sleep bruxism, snoring, and headaches in adolescents: short-term effects of a mandibular advancement appliance. AB - OBJECTIVES: Sleep bruxism (SB) frequently is associated with other sleep disorders and pain concerns. Our study assesses the efficacy of a mandibular advancement appliance (MAA) for SB management in adolescents reporting snoring and headache (HA). METHODS: Sixteen adolescents (mean age, 14.9+/-0.5) reporting SB, HA (>1d/wk), or snoring underwent four ambulatory polysomnographies for baseline (BSL) and while wearing MAA during sleep. MAA was worn in three positions (free splints [FS], neutral position [NP], and advanced to 50% of maximum protrusion [A50]) for 1 week each in random order (FS-NP-A50 or NP-A50 FS; titration order, NP-A50). Reports of HA were assessed with pain questionnaires. RESULTS: Overall, sleep variables did not differ across the four nights. SB index decreased up to 60% with MAA in A50 (P=.004; analysis of variance). Snoring was measured as the percentage of sleep time spent snoring. The subgroup of snorers (n=8) showed significant improvement with MAA (-93%; P=.002). Initial HA intensity was reported at 42.7+/-5/100 mm, showing a decreasing trend with MAA (-21% to -51%; P=.07). CONCLUSION: Short-term use of an MAA appears to reduce SB, snoring, and reports of HA. However, interactions between SB, breathing during sleep, and HA as well as the long-term effectiveness and safety of MAA in adolescents need further investigation. PMID- 23643653 TI - Nurses working on fast rotating shifts overestimate cognitive function and the capacity of maintaining wakefulness during the daytime after a rotating shift. AB - OBJECTIVES: The objective of our study was to explore changes in cognitive functions, sleep propensity, and sleep-related hormones (growth hormone [GH], cortisol, prolactin [PRL], thyrotropin [TSH]) in the daytime of nurses working on fast rotating shifts. METHODS: Twenty nurses who worked two consecutive night shifts and 23 off-duty nurses were recruited from an acute psychiatric ward. The maintenance of wakefulness test (MWT), Stanford sleepiness scale (SSS), visual attention tasks, Wisconsin card sorting test (WCST), multiple sleep latency test (MSLT), and measuring hormones were administered four times throughout the daytime at 2-hour intervals. RESULTS: The subjects in the off-duty group were more able to maintain wakefulness than those in the night-shift group; however, there were no differences in self-reported total sleep time or sleep latency on the MSLT and SSS scores between the two groups. The subjects in the night-shift group had poorer performances on visual attentive tasks and higher levels of TSH than those in the off-duty group, and this resulted in a lack of a learning effect on the tasks that required a high attentive load. CONCLUSIONS: Nurses working on fast rotating shifts overestimate the cognitive functions and capacity of maintaining wakefulness following daytime sleep restriction. Attention performance depended on the attentive load requirement and was possibly related to TSH level. PMID- 23643654 TI - Disorders of arousal and sleep-related bruxism among Japanese adolescents: a nationwide representative survey. AB - OBJECTIVE: The main objective of our study was to clarify the prevalence of disorders of arousal (confusional arousals, sleepwalking, sleep terrors) and sleep-related bruxism (teeth grinding) and their associated factors among Japanese adolescents. METHODS: Our study was designed as a cross-sectional sampling survey. The targets were students attending junior and senior high schools throughout Japan. The questionnaire asked for personal data and information on lifestyle, depressive state, and sleep status including the frequency of experiencing disorders of arousal and sleep-related bruxism. RESULTS: A total of 99,416 adolescents responded. The overall response rate was 63.7%, and 98,411 questionnaires were subjected to analysis. The prevalence of disorders of arousal was 7.1% (95% confidence interval [CI], 6.9-7.3%) among boys and 7.7% (95% CI, 7.5-7.9%) among girls. The prevalence of sleep-related bruxism was 2.3% (95% CI, 2.2-2.4%) among boys and 3.0% (95% CI, 2.8-3.2%) among girls. The factors associated with disorders of arousal were the grade in school, smoking habit, alcohol consumption, naptime (min), breakfast habit, participation in club activities, sleep duration, difficulty initiating sleep, nocturnal awakening, early morning awakening, subjective sleep assessment, snoring, decrease in positive feelings, and depression (all p<.001). The factors associated with sleep-related bruxism were gender, smoking habit, nocturnal awakening, snoring, early morning awakening, decrease in positive feelings, and depressive feelings (all p<.001). CONCLUSIONS: If disorders of arousal or sleep related bruxism are observed in an adolescent, his or her smoking habit, alcohol consumption, sleep status, and depressive state should be considered. PMID- 23643655 TI - Blood pressure changes associated with periodic leg movements during sleep in healthy subjects. AB - BACKGROUND AND OBJECTIVES: Periodic leg movements during sleep (PLMS) are associated with important blood pressure (BP) increases in restless legs syndrome (RLS) patients. These movements also are highly prevalent in the healthy elderly population. The aims of our study were to evaluate if heart rate (HR) and BP changes associated with PLMS are present in healthy subjects with no report of health concerns and to compare the amplitude of cardiovascular changes in healthy subjects to that of RLS subjects. METHODS: Fourteen healthy subjects (six men, eight women; 46.6+/-9.7 y) and 14 RLS subjects (six men, eight women; 47.6+/-11.8 y) matched for age and gender participated in our study. Beat-to-beat noninvasive BP was continuously recorded during one night of polysomnography. HR, systolic BP (SBP) and diastolic BP (DBP) were measured for 10 beats before and 15 beats after onset of PLMS with and without microarousals (MA). RESULTS: PLMS were associated with sudden and significant increases of HR, SBP and DBP in both groups; however, cardiovascular increases were more pronounced in RLS subjects than in healthy subjects. CONCLUSIONS: Because PLMS index increases with age in healthy subjects and aging is associated with higher cardiovascular risk, further studies should investigate the impact of PLMS-related BP changes on the development of cardiovascular diseases in healthy elderly populations. PMID- 23643656 TI - Response. PMID- 23643657 TI - When restless legs syndrome turns malignant. AB - Usually symptoms of restless legs syndrome (RLS) respond well to treatment with dopaminergic drugs, opiates, or anticonvulsant medications. Yet sometimes symptoms can be severe and become refractory, even to high-dose combination therapy. Here we present two cases of familial RLS with rigorous and unusual motor and sensory symptoms in the form of episodes of myoclonic hyperkinesias and painful sensations in addition to more characteristic features of RLS. Stepwise reduction of all RLS-and antidepressant medication down to opiate monotherapy-and subsequent opiate rotation led to an improvement of symptoms. Yet in both cases, reintroduction of low-dose dopaminergic drugs was necessary to achieve satisfactory treatment effect. We have termed this form of RLS refractory to multiple combinations of all classes of commonly used drugs malignant RLS. Therapeutically simplification and reduction of the drug scheme and opiate rotation should be considered in malignant RLS. PMID- 23643658 TI - Subjectively impaired bed mobility in Parkinson disease affects sleep efficiency. AB - BACKGROUND: Impaired bed mobility (IBM) may be an important reason for the high prevalence of sleep insomnia in Parkinson disease (PD). Here we assessed the influence of subjectively IBM on both subjective and objective sleep parameters in insomnia PD patients with (PD+IBM) and without (PD-IBM) concerns of IBM and controls with primary insomnia. METHODS: We included 44 PD patients with sleep initiation or maintenance concerns and 44 control subjects with primary insomnia. Sleep questionnaires, polysomnographic sleep parameters, activity data, and the number of body position changes were compared between PD patients and controls as well as within the PD group between PD+IBM vs PD-IBM subjects. RESULTS: There were 54.5% of PD subjects who reported having IBM. In the PD+IBM group, the number of body position changes was significantly lower than in PD-IBM (0.4/h [0.0-1.8] vs 1.4/h [0.0-4.6], P=.015). Sleep efficiency (SE) was lower in PD+IBM patients (63.5; 26.2-85.6) compared to PD-IBM patients (78.4; 54.8-92.6; P<.001). CONCLUSION: PD patients who report IBM have fewer sleep-related body position changes (i.e., nocturnal hypokinesia) than PD patients without such concerns. Furthermore, objective SE is significantly diminished in these patients. PMID- 23643659 TI - Solute transport across the articular surface of injured cartilage. AB - Solute transport through extracellular matrix (ECM) is important to physiology and contrast agent-based clinical imaging of articular cartilage. Mechanical injury is likely to have important effects on solute transport since it involves alteration of ECM structure. Therefore it is of interest to characterize effects of mechanical injury on solute transport in cartilage. Using cartilage explants injured by an established mechanical compression protocol, effective partition coefficients and diffusivities of solutes for transport across the articular surface were measured. A range of fluorescent solutes (fluorescein isothiocyanate, 4 and 40kDa dextrans, insulin, and chondroitin sulfate) and an X ray contrast agent (sodium iodide) were used. Mechanical injury was associated with a significant increase in effective diffusivity versus uninjured explants for all solutes studied. On the other hand, mechanical injury had no effects on effective partition coefficients for most solutes tested, except for 40kDa dextran and chondroitin sulfate where small but significant changes in effective partition coefficient were observed in injured explants. Findings highlight enhanced diffusive transport across the articular surface of injured cartilage, which may have important implications for injury and repair situations. Results also support development of non-equilibrium methods for identification of focal cartilage lesions by contrast agent-based clinical imaging. PMID- 23643660 TI - Hepatic encephalopathy: clinical aspects and pathogenetic concept. PMID- 23643661 TI - Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer. AB - Alterations of signal transduction pathways leading to uncontrolled cellular proliferation, survival, invasion, and metastases are hallmarks of the carcinogenic process. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and the Raf/mitogen-activated and extracellular signal regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways are critical for normal human physiology, and also commonly dysregulated in several human cancers, including breast cancer (BC). In vitro and in vivo data suggest that the PI3K/AKT/mTOR and Raf/MEK/ERK cascades are interconnected with multiple points of convergence, cross-talk, and feedback loops. Raf/MEK/ERK and PI3K/AKT/mTOR pathway mutations may co-exist. Inhibition of one pathway can still result in the maintenance of signaling via the other (reciprocal) pathway. The existence of such "escape" mechanisms implies that dual targeting of these pathways may lead to superior efficacy and better clinical outcome in selected patients. Several clinical trials targeting one or both pathways are already underway in BC patients. The toxicity profile of this novel approach of dual pathway inhibition needs to be closely monitored, given the important physiological role of PI3K/AKT/mTOR and Raf/MEK/ERK signaling. In this article, we present a review of the current relevant pre-clinical and clinical data and discuss the rationale for dual inhibition of these pathways in the treatment of BC patients. PMID- 23643663 TI - Analysis of the autoimmune regulator gene in patients with autoimmune non-APECED polyendocrinopathies. AB - The pathogenesis of autoimmunity was derived from a complex interaction of genetic and environmental factors. Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy is a rare autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE gene variants and, in particular, heterozygous loss-of-function mutations were also discovered in organ-specific autoimmune disorders, possibly contributing to their etiopathogenesis. It was suggested that even predisposition to develop certain autoimmune conditions may be derived from AIRE gene polymorphisms including S278R and intronic IVS9+6 G>A. In this study we unravel the hypothesis on whether AIRE gene variants may predispose individuals to associated autoimmune conditions in 41 Italian patients affected by non-APECED autoimmune polyendocrinopathies. We could not detect any heterozygous mutations of the AIRE gene. Although a trend of association was observed, heterozygous polymorphisms S278R and IVS9+6 G>A were detected in patients without statistically significant prevalence than in controls. Their putative contribution to autoimmune polyendocrinopathies and their predictive value in clinical strategies of disease development could be unravelled by analysing a larger sample of diseased patients and healthy individuals. PMID- 23643665 TI - Arthroscopic bone grafting of talar bone cyst using posterior ankle arthroscopy. AB - A subchondral cyst of the talus frequently occurs with an osteochondral lesion of the talar dome. Debridement, curettage, and bone grafting through the articular defect was frequently the recommended treatment in reported studies for a massive cyst. We report a case of a massive cyst of the talar body with a small osteochondral lesion of the talar dome. Our patient was successfully treated by curettage and bone grafting of the cyst using posterior ankle arthroscopy, with minimal disruption of the articular surface of the talar dome. PMID- 23643664 TI - Sustained resistance to acute MPTP toxicity by hypothalamic dopamine neurons following chronic neurotoxicant exposure is associated with sustained up regulation of parkin protein. AB - Hypothalamic tuberoinfundibular dopamine (TIDA) neurons remain unaffected in Parkinson disease (PD) while there is significant degeneration of midbrain nigrostriatal dopamine (NSDA) neurons. A similar pattern of susceptibility is observed following acute exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), and the resistance of TIDA neurons to MPTP is associated with increased expression of parkin and ubiquitin carboxy-terminal hydrolase L-1 (UCHL-1). In the present study, the response of TIDA and NSDA neurons to acute MPTP administration following chronic MPTP exposure was examined. Mice were treated with ten injections of either MPTP (20mg/kg; s.c.; every 3.5 days) or saline vehicle (10 ml/kg; s.c.; every 3.5 days). Following a 21 day recovery period, chronic saline- and MPTP-treated mice received an additional injection of either saline (10 ml/kg; s.c.) or MPTP (20mg/kg; s.c.) and were sacrificed 24h later. NSDA neurons displayed significant axon terminal degeneration (as reflected by decreases in DA, tyrosine hydroxylase (TH) and DA transporter concentrations in the striatum) as well as loss of TH-immunoreactive (IR) neurons in the substantia nigra (SN) following MPTP, whereas TIDA neurons revealed no overt axon terminal pathology or loss of TH-IR cell bodies. NSDA neuronal pathology was associated with transient decreases in concentrations of parkin and UCHL-1 protein in the SN, which returned to normal levels by 21 days following cessation of chronic neurotoxicant exposure. Resistance of TIDA neurons to MPTP toxicity was correlated with a transient increase in UCHL-1 and a sustained elevation in parkin in the arcuate nucleus. TIDA neurons represent a DA neuron population with a unique and inherent ability to adapt to acute and chronic toxicant administration with a sustained elevation of the neuroprotective protein parkin. The correlation between the ability to increase parkin and UCHL-1 expression and the resistance of DA neurons to neurotoxicant exposure is consistent with a functional link between these features and an underlying differential susceptibility to toxicant-associated neurodegeneration. PMID- 23643662 TI - Topical delivery of anti-TNFalpha siRNA and capsaicin via novel lipid-polymer hybrid nanoparticles efficiently inhibits skin inflammation in vivo. AB - The barrier properties of the skin pose a significant but not insurmountable obstacle for development of new effective anti-inflammatory therapies. The objective of this study was to design and evaluate therapeutic efficacy of anti nociception agent Capsaicin (Cap) and anti-TNFalpha siRNA (siTNFalpha) encapsulated cyclic cationic head lipid-polymer hybrid nanocarriers (CyLiPns) against chronic skin inflammatory diseases. Physico-chemical characterizations including hydrodynamic size, surface potential and entrapment efficacies of CyLiPns were found to be 163+/-9nm, 35.14+/-8.23mV and 92% for Cap, respectively. In vitro skin distribution studies revealed that CyLiPns could effectively deliver FITC-siRNA up to 360MUm skin depth. Further, enhanced (p<0.001) Cap permeation from CyLiPns was observed compared to Capsaicin-Solution and Capzasin HP. Therapeutic efficacies of CyLiPns were assessed using imiquamod-induced psoriatic plaque like model. CyLiPns carrying both Cap and siTNFalpha showed significant reduced expression of TNFalpha, NF-kappaB, IL-17, IL-23 and Ki-67 genes compared to either drugs alone (p<0.05) and were in close comparison with Topgraf(r). Collectively these findings support our notion that novel cationic lipid-polymer hybrid nanoparticles can efficiently carry siTNFalpha and Cap into deeper dermal milieu and Cap with a combination of siTNFalpha shows synergism in treating skin inflammation. PMID- 23643666 TI - Modification of side-locking loop suture technique using an antislip knot for repair of Achilles tendon rupture. AB - The 2-strand side-locking loop suture technique provides high tensile strength and stiffness immediately after surgery, and good clinical results have been reported in the treatment of Achilles tendon rupture. However, it is assumed that major differences exist among surgeons with regard to the optimal tension of the side-locking loop suture. We report a detailed technique to ensure application of a standard tension with the use of the side-locking loop suture in the clinical setting. PMID- 23643667 TI - A large extraskeletal osteochondroma of the foot. AB - Osteochondromas are very common benign tumors composed of cartilage and bone. They are usually found at the end of the growth plate of long bones, most often at the area of the joints, and are contiguous with the medullary cavity. Extraskeletal osteochondromas, the same as their namesake, are composed of cartilage and bone. However, unlike typical osteochondromas, extraskeletal osteochondromas are not contiguous with bone, as their name implies. They usually arise from the synovial tissue and tendon sheaths. Although rare, extraskeletal osteochondromas have been reported to occur within the knee and around the hip; however, they are more commonly reported to occur in the hands and feet. When found in the hands or feet, these new growths are often very small and only occasionally symptomatic. We present the case of a 49-year-old female who had a slow-growing mass of 4 years' duration, located on the plantar aspect of her left foot. The mass was slowly becoming more palpable as it increased in size and was progressively causing pain and discomfort during ambulation. Imaging studies revealed an ossified mass bearing no connection to any other structure on the plantar aspect of her foot. An excision biopsy was performed, and the easily dissectible mass, although much larger than its usual presentation, proved to be an extraskeletal osteochondroma. PMID- 23643668 TI - Ewing sarcoma in a diabetic male with history of foot ulceration. AB - Ewing sarcoma is a rare diagnosis, with as few as 225 new cases diagnosed in North America annually, and only 3% occurring in the foot. They generally present in the second decade of life and are very infrequently found in patients older than 40 years. The diagnosis of Ewing sarcoma can be difficult, especially in older patients with diabetes and a history of ulceration, because it can have an appearance on radiography similar to that of osteomyelitis. We present a case of Ewing sarcoma of the foot in a patient with type 2 diabetes in his sixth decade of life. PMID- 23643669 TI - Progesterone is not the same as 17alpha-hydroxyprogesterone caproate: implications for obstetrical practice. PMID- 23643671 TI - Evolution of World Cup soccer final games 1966-2010: game structure, speed and play patterns. AB - OBJECTIVES: There are relatively few performance analysis studies on field sports investigating how they evolve from a structural or tactical viewpoint. Field sports like soccer involve complex, non-linear dynamical systems yet consistent patterns of play are recognisable over time and among different sports. This study on soccer trends helps build a framework of potential causative mechanisms for these patterns. DESIGN: Retrospective correlational study. METHODS: Broadcast footage of World Cup finals between 1966 and 2010 was used to assess patterns of play and stop periods, type and duration of game stoppages, ball speed, player density (congestion) and passing rates. This involved computer-based ball tracking and other notational analyses. These results were analysed using linear regression to track changes across time. RESULTS: Almost every variable assessed changed significantly over time. Play duration decreased while stoppage duration increased, both affecting the work: recovery ratios. Ball (game) speed increased by 15% over the 44-year period. Play structure changed towards a higher player density with a 35% greater passing rate. CONCLUSIONS: Increases in soccer ball speed and player density show similarities with other field sports and suggest common evolutionary pressures may be driving play structures. The increased intensity of play is paralleled by longer stoppage breaks which allow greater player recovery and subsequently more intense play. Defensive strategies dominate over time as demonstrated by increased player density and congestion. The long term pattern formations demonstrate successful coordinated states within team structures are predictable and may have universal causative mechanisms. PMID- 23643672 TI - Suppression of murine collagen-induced arthritis by vaccination of synovial vascular endothelial cells. AB - AIMS: Endothelial cells (ECs) lining the lumina of blood vessels are involved in leukocyte extravasation underlying inflammatory states, such as rheumatoid arthritis (RA). The rheumatoid pannus, the site of inflammation and joint destruction in the rheumatoid synovium, relies on the development of neovascular vessels to sustain its growth. We studied a method to selectively target and destroy new synovial blood vessels by vaccination with synovial EC. MAIN METHODS: Collagen-induced arthritis (CIA) mice were vaccinated with tumor necrosis factor (TNF)-alpha-stimulated EC (TNF-EC) antigen with an incomplete adjuvant. TNF-EC was used as a model of EC in synovial tissue on RA. KEY FINDINGS: Arthritis was significantly decreased in TNF-EC vaccinated mice compared with non-vaccinated mice based on the arthritis score. Moreover, the TNF-EC vaccine suppressed bone erosion, hyperplasia of the synovium and expression of neovascular vessel as shown by hematoxylin-eosin staining, X-ray analysis and immunohistochemical. SIGNIFICANCE: Vaccine therapy against vascular EC in synovial tissue may provide a novel approach to the treatment of RA. PMID- 23643670 TI - Acidic tumor microenvironment downregulates hMLH1 but does not diminish 5 fluorouracil chemosensitivity. AB - Human DNA mismatch repair (MMR) recognizes and binds 5-fluorouracil (5FU) incorporated into DNA and triggers a MMR-dependent cell death. Absence of MMR in a patient's colorectal tumor abrogates 5FU's beneficial effects on survival. Changes in the tumor microenvironment like low extracellular pH (pHe) may diminish DNA repair, increasing genomic instability. Here, we explored if low pHe modifies MMR recognition of 5FU, as 5FU can exist in ionized and non-ionized forms depending on pH. We demonstrate that MMR-proficient cells at low pHe show downregulation of hMLH1, whereas expression of TDG and MBD4, known DNA glycosylases for base excision repair (BER) that can remove 5FU from DNA, were unchanged. We show in vitro that 5FU within DNA pairs with adenine (A) at high and low pH (in absence of MMR and BER). Surprisingly, 5FdU:G was repaired to C:G in hMLH1-deficient cells cultured at both low and normal pHe, similar to MMR proficient cells. Moreover, both hMSH6 and hMSH3, components of hMutSalpha and hMutSbeta, respectively, bound 5FU within DNA (hMSH6>hMSH3) but is influenced by hMLH1. We conclude that an acidic tumor microenvironment triggers downregulation of hMLH1, potentially removing the execution component of MMR for 5FU cytotoxicity, whereas other mechanisms remain stable to implement overall 5FU sensitivity. PMID- 23643673 TI - Angiotensin II Type 1 receptor blockade protects endothelium-derived hyperpolarising factor-mediated relaxation in a rat model of monoarthritis. AB - AIMS: Rheumatoid arthritis (RA) is associated with high cardiovascular mortality. Impaired endothelial cell (EC) function and elevated angiotensin II levels may be central to the link between vascular dysfunction and RA. Here we investigated the action of angiotensin type 1 receptor (AT1R) blockade on endothelium-dependent relaxation of the isolated saphenous artery in a rat model of monoarthritis. MAIN METHODS: Adjuvant arthritis was induced in rats with and without prophylactic losartan (AT1R antagonist) treatment. Vehicle-treated rats were used as controls. Wire myography was employed to investigate EC function of isolated rings of saphenous artery. KEY FINDINGS: EC-dependent relaxation in arteries from non inflamed control rats was mediated by both nitric oxide (NO) and endothelium derived hyperpolarising factor (EDHF) with the EDHF response dependent principally on functional myoendothelial gap junctions. While NO-dependent relaxation remained unaffected, the EDHF-mediated response was abolished in arteries from arthritic rats (P<0.001), however, substantial protection (approximately 50%) of the EDHF-relaxation was found in arthritic rats treated with losartan (P<0.01). Thus, the attenuated EDHF response found in the saphenous artery of arthritic rats was significantly reversed by AT1R blockade. SIGNIFICANCE: These results suggest a key role for the angiotensin system in the EC dysfunction found in chronic joint inflammation and highlights AT1R as a potential therapeutic target to redress the vascular impairment and mortality associated with RA. PMID- 23643675 TI - Meta-analysis: aerobic exercise for the treatment of anxiety disorders. AB - BACKGROUND: This meta-analysis investigates the efficacy of exercise as a treatment for DSM-IV diagnosed anxiety disorders. METHODS: We searched PubMED and PsycINFO for randomized, controlled trials comparing the anxiolytic effects of aerobic exercise to other treatment conditions for DSM-IV defined anxiety disorders. Seven trials were included in the final analysis, totaling 407 subjects. The control conditions included non-aerobic exercise, waitlist/placebo, cognitive-behavioral therapy, psychoeducation and meditation. A fixed-effects model was used to calculate the standardized mean difference of change in anxiety rating scale scores of aerobic exercise compared to control conditions. Subgroup analyses were performed to examine the effects of (1) comparison condition; (2) whether comparison condition controlled for time spent exercising and (3) diagnostic indication. RESULTS: Aerobic exercise demonstrated no significant effect for the treatment of anxiety disorders (SMD=0.02 (95%CI: -0.20-0.24), z = 0.2, p = 0.85). There was significant heterogeneity between trials (chi(2) test for heterogeneity = 22.7, df = 6, p = 0.001). The reported effect size of aerobic exercise was highly influenced by the type of control condition. Trials utilizing waitlist/placebo controls and trials that did not control for exercise time reported large effects of aerobic exercise while other trials report no effect of aerobic exercise. CONCLUSIONS: Current evidence does not support the use of aerobic exercise as an effective treatment for anxiety disorders as compared to the control conditions. This remains true when controlling for length of exercise sessions and type of anxiety disorder. Future studies evaluating the efficacy of aerobic exercise should employ larger sample sizes and utilize comparison interventions that control for exercise time. PMID- 23643674 TI - Pharmacological blockade of GluN2B-containing NMDA receptors induces antidepressant-like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain. AB - NMDA receptor (NMDAR) antagonists like ketamine and MK-801 possess remarkable antidepressant effects with fast onset. However, they over-stimulate the retrosplenial cortex, evoking psychosis-like effects and neuronal injury, revealed by de novo induction of the heat shock protein 70 (Hsp70). Moreover, early in the development MK-801 triggers widespread cortical apoptosis, inducing extensive caspase-3 expression. Altogether these data raise strong concerns on the clinical applicability of NMDAR antagonist therapies. Therefore, the development of novel therapeutics targeting more specifically NMDAR to avoid psychotomimetic effects is necessary. Here we investigated a GluN2B (NR2B) antagonist in behavioral and neurotoxicity paradigms in rats to assess its potential as possible alternative to unspecific NMDA receptor antagonists. We found that treatment with the GluN2B specific antagonist Ro 25-6981 evoked robust antidepressant-like effects. Moreover, Ro 25-6981 did not cause hyperactivity as displayed after treatment with unspecific NMDAR antagonists, a correlate of psychosis-like effects in rodents. Additionally, Ro 25-6981, unlike MK-801, did not induce caspase-3 and HSP70 expression, markers of neurotoxicity in the perinatal and adult brain, respectively. Moreover, unexpectedly, in the adult retrosplenial cortex Ro 25-6981 pretreatment significantly reduced MK-801 triggered neurotoxicity. Our results suggest that GluN2B antagonists may represent valuable alternatives to unspecific NMDAR antagonists with robust antidepressant efficacy and a more favorable side-effect profile. PMID- 23643677 TI - Lung tumor growth-promoting function of peroxiredoxin 6. AB - This study compared lung tumor growth in PRDX6-overexpressing transgenic (Tg) mice and normal mice. These mice expressed elevated levels of PRDX6 mRNA and protein in multiple tissues. In vivo, Tg mice displayed a greater increase in the growth of lung tumor compared with normal mice. Glutathione peroxidase and calcium-independent phospholipase 2 (iPLA2) activities in tumor tissues of Tg mice were much higher than in tumor tissues of normal mice. Higher tumor growth in PRDX6-overexpressing Tg mice was associated with an increase in activating protein-1 (AP-1) DNA-binding activity. Moreover, expression of proliferating cell nuclear antigen, Ki67, vascular endothelial growth factor, c-Jun, c-Fos, metalloproteinase-9, cyclin-dependent kinases, and cyclins was much higher in the tumor tissues of PRDX6-overexpressing Tg mice than in tumor tissues of normal mice. However, the expression of apoptotic regulatory proteins including caspase 3 and Bax was slightly less in the tumor tissues of normal mice. In tumor tissues of PRDX6-overexpressing Tg mice, activation of mitogen-activated protein kinases (MAPKs) was much higher than in normal mice. In cultured lung cancer cells, PRDX6 siRNA suppressed glutathione peroxidase and iPLA2 activities and cancer cell growth, but the enforced overexpression of PRDX6 increased cancer cell growth associated with their increased activities. In vitro, among the tested MAPK inhibitors, c-Jun NH2-terminal kinase (JNK) inhibitor clearly suppressed the growth of lung cancer cells and AP-1 DNA binding, glutathione peroxidase activity, and iPLA2 activity in normal and PRDX6-overexpressing lung cancer cells. These data indicate that overexpression of PRDX6 promotes lung tumor growth via increased glutathione peroxidase and iPLA2 activities through the upregulation of the AP-1 and JNK pathways. PMID- 23643676 TI - Foetal presentation of cartilage hair hypoplasia with extensive granulomatous inflammation. AB - Cartilage-hair-hypoplasia is a rare autosomal recessive metaphyseal dysplasia due to RMRP (the RNA component of the RNase MRP ribonuclease mitochondrial RNA processing complex) gene mutations. So far, about 100 mutations have been reported in the promoter and the transcribed regions. Clinical characteristics include short-limbed short stature, sparse hair and defective cell-mediated immunity. We report herein the antenatal presentation of a female foetus, in whom CHH was suspected from 23 weeks' gestation, leading to a medical termination of the pregnancy at 34 weeks gestation, and thereafter confirmed by morphological and molecular studies. Post-mortem examination confirmed short stature and limbs, and revealed thymic hypoplasia associated with severe CD4 T-cell immunodeficiency along with extensive non caseating epithelioid granulomas in almost all organs, which to our knowledge has been described only in five cases. Molecular studies evidenced on one allele the most frequently reported founder mutation NR_003051: g.70A>G, which is present in 92% of Finnish patients with Cartilage Hair Hypoplasia. On the second allele, a novel mutation consisting of a 10 nucleotide insertion at position -18 of the promoter region of the RMRP gene (M29916.1:g.726_727insCTCACTACTC) was detected. The founder mutation was inherited from the father, and the novel mutation from the mother. To our knowledge, this case report represents the first detailed foetal analysis described in the literature. PMID- 23643678 TI - Percutaneous interventricular septal access in a patient with aortic and mitral mechanical valves: a novel technique for catheter ablation of ventricular tachycardia. PMID- 23643679 TI - Epidemiology of Paget's disease of bone: a systematic review and meta-analysis of secular changes. AB - CONTEXT: Several studies have suggested that the prevalence and severity of PDB have fallen in recent years. The magnitude of this trend and its globalization have not been well established. OBJECTIVE: The objective of this study is to estimate the pooled magnitude of the changes in the prevalence of PDB and as a secondary objective, to make up a world atlas of PDB prevalence. METHODS: A systematic review of English and non-English articles using MEDLINE (1946 to 2013) and EMBASE (1980 to 2013) was the method used. Search terms included epidemiology, incidence, prevalence, cohort studies, osteitis deformans or Paget's disease of bone. Studies with incidence and/or prevalence rate for PDB were included. Two authors independently extracted the data using predefined data fields and quality assessment. A pooled analysis based on random-effects models was carried out for secular trends. RESULTS: Twenty-eight articles documented the prevalence of PDB; four articles the incidence and two articles the rate of new referrals. The prevalence of PDB varied greatly between the different countries, from 0.00028% in Japan to 5.4% in the UK. There were available data on changes in prevalence from two different surveys over two different time frames in Europe and New Zealand. In all but one city (Turin), a drop in the prevalence of PDB was recorded (pooled OR 0.64; 95% CI 0.45-0.91). CONCLUSION: The incidence and prevalence rates of PDB vary widely between populations but both have decreased in most regions over recent years. The changes are heterogeneous however and within countries, the largest changes have been in areas that previously had a high prevalence. The reasons for these changes remain unclear at present but are likely to be due to an interaction between genetic factors and environmental triggers which may differ in different regions. PMID- 23643680 TI - Parathyroid hormone reverses radiation induced hypovascularity in a murine model of distraction osteogenesis. AB - BACKGROUND: Radiation treatment results in a severe diminution of osseous vascularity. Intermittent parathyroid hormone (PTH) has been shown to have an anabolic effect on osteogenesis, though its impact on angiogenesis remains unknown. In this murine model of distraction osteogenesis, we hypothesize that radiation treatment will result in a diminution of vascularity in the distracted regenerate and that delivery of intermittent systemic PTH will promote angiogenesis and reverse radiation induced hypovascularity. MATERIALS AND METHODS: Nineteen Lewis rats were divided into three groups. All groups underwent distraction of the left mandible. Two groups received radiation treatment to the left mandible prior to distraction, and one of these groups was treated with intermittent subcutaneous PTH (60 MUg/kg, once daily) beginning on the first day of distraction for a total duration of 21 days. One group underwent mandibular distraction alone, without radiation. After consolidation, the rats were perfused and imaged with micro-CT angiography and quantitative vascular analysis was performed. RESULTS: Radiation treatment resulted in a severe diminution of osseous vascularity in the distracted regenerate. In irradiated mandibles undergoing distraction osteogenesis, treatment with intermittent PTH resulted in significant increases in vessel volume fraction, vessel thickness, vessel number, degree of anisotropy, and a significant decrease in vessel separation (p < 0.05). No significant difference in quantitative vascularity existed between the group that was irradiated, distracted and treated with PTH and the group that underwent distraction osteogenesis without radiation treatment. CONCLUSIONS: We quantitatively demonstrate that radiation treatment results in a significant depletion of osseous vascularity, and that intermittent administration of PTH reverses radiation induced hypovascularity in the murine mandible undergoing distraction osteogenesis. While the precise mechanism of PTH-induced angiogenesis remains to be elucidated, this report adds a key component to the pleotropic effect of intermittent PTH on bone formation and further supports the potential use of PTH to enhance osseous regeneration in the irradiated mandible. PMID- 23643681 TI - Diminished response to in vivo mechanical loading in trabecular and not cortical bone in adulthood of female C57Bl/6 mice coincides with a reduction in deformation to load. AB - Bone loss occurs during adulthood in both women and men and affects trabecular bone more than cortical bone. The mechanism responsible for trabecular bone loss during adulthood remains unexplained, but may be due at least in part to a reduced mechanoresponsiveness. We hypothesized that trabecular and cortical bone would respond anabolically to loading and that the bone response to mechanical loading would be reduced and the onset delayed in adult compared to postpubescent mice. We evaluated the longitudinal adaptive response of trabecular and cortical bone in postpubescent, young (10 week old) and adult (26 week old) female C57Bl/6J mice to axial tibial compression using in vivo microCT (days 0, 5, 10, and 15) and dynamic histomorphometry (day 15). Loading elicited an anabolic response in both trabecular and cortical bone in young and adult mice. As hypothesized, trabecular bone in adult mice exhibited a reduced and delayed response to loading compared to the young mice, apparent in trabecular bone volume fraction and architecture after 10 days. No difference in mechanoresponsiveness of the cortical bone was observed between young and adult mice. Finite element analysis showed that load-induced strain was reduced with age. Our results suggest that trabecular bone loss that occurs in adulthood may in part be due to a reduced mechanoresponsiveness in this tissue and/or a reduction in the induced tissue deformation which occurs during habitual loading. Therapeutic approaches that address the mechanoresponsiveness of the bone tissue may be a promising and alternate strategy to maintain trabecular bone mass during aging. PMID- 23643683 TI - Consensus Statement on medication use in multiple sclerosis by the Spanish Society of Neurology's study group for demyelinating diseases. AB - Treatments for multiple sclerosis therapy are rapidly evolving. It is believed that new drugs will be approved in the near future, thereby changing current indications for treatment. In this context, the Spanish Society of Neurology's study group on demyelinating diseases, which evaluates medication use in MS, has decided to draw up a consensus statement on the current indications and guidelines for multiple sclerosis treatment. PMID- 23643684 TI - Quantitative phase-contrast MRI study of cerebrospinal fluid flow: a method for identifying patients with normal-pressure hydrocephalus. AB - OBJECTIVES: The aim of this study is to evaluate the use of phase-contrast MR imaging to diagnose normal pressure hydrocephalus (NPH) and differentiate it from other neurological disorders with similar clinical symptoms. METHODS: The study included 108 subjects, of whom 61 were healthy controls and 47, patients; in the patient group, 19 had cerebrovascular disease (CVD) and 28 had NPH. All patients underwent a phase-contrast MRI study and several CSF flow and velocity parameters were measured at the aqueduct of Sylvius. Discriminant analyses were performed to evaluate the classification capacity of both individual parameters and the combination of different parameters. RESULTS: Maximum diastolic velocity, mean flow, and stroke volume showed statistically significant differences that could be used to distinguish between NPH and CVD patients (P<.001). Stroke volume and mean flow showed no false positive results and successful classification rates of 86% and 79%, respectively. No other parameters or combination produced better results. CONCLUSIONS: Phase-contrast MR imaging is a useful tool for the early diagnosis of patients with NPH. CSF flow quantitative parameters, along with morphological features in a conventional MR study, enable us to differentiate between NPH and CVD patients. PMID- 23643682 TI - Genetic polymorphism at Val80 (rs700518) of the CYP19A1 gene is associated with aromatase inhibitor associated bone loss in women with ER + breast cancer. AB - PURPOSE: Polymorphisms in the CYP19A1 (aromatase) gene have been reported to influence disease-free survival and the incidence of musculoskeletal complaints in patients taking aromatase inhibitors (AIs) for estrogen receptor positive (ER+) breast cancer. Bone loss and fractures are well-recognized complications from AI therapy. The objective of this study is to determine the influence of polymorphisms in the CYP19A1 gene on bone loss among patients taking aromatase inhibitors for ER+ breast cancer. PATIENTS AND METHODS: The subjects consisted of 97 postmenopausal women with ER+ breast cancer who were initiated on third generation AIs. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry at baseline and at 6 and 12 months. Twenty-four hour urine N telopeptide (NTX) was measured by Elisa and serum estradiol was measured by ultrasensitive radioimmunoassay at baseline, and at 6 months. Genotyping was done by Taqman SNP allelic discrimination assay. RESULTS: Women with the AA genotype for the rs700518 (G/A at Val(80)) developed significant bone loss at the lumbar spine and the total hip at 12 months relative to patients carrying the G allele (GA/GG); both p = 0.03. There was a borderline greater increase in urinary NTX in those with the AA genotype compared to patients with the G allele, p = 0.05; but no significant difference in changes in estradiol levels among the genotypes. CONCLUSION: Patients with the AA genotype for the rs700518 polymorphism in the CYP19A1 gene are at risk for AI-associated bone loss and deserve close follow-up during long-term AI therapy. PMID- 23643685 TI - Dichotomy of CCL21 and CXCR3 in nerve injury-evoked and autoimmunity-evoked hyperalgesia. AB - The chemokine CCL21 is released from injured neurons and acts as a ligand of the chemokine receptor, CXCR3, which likely contributes to pro-inflammatory adaptations and secondary neuronal damage. CCL21-CXCR3 signalling may therefore impact on the development of neuropathic pain. By using the respective knockout mice we show that deficiency of CCL19/21 in plt/plt mice attenuates nerve injury evoked pain but not the hyperalgesia evoked by autoimmune encephalomyelitis (EAE). Oppositely, CXCR3-deficiency had no protective effect after traumatic nerve injury but reduced EAE-evoked hyperalgesia and was associated with reduced clinical EAE scores, a reduction of the pro-inflammatory cell infiltration and reduced upregulation of interferon gamma and interleukin-17 in the spinal cord. In contrast, microglia activation in the spinal cord after traumatic sciatic nerve injury was neither attenuated in CXCR3(-/-) nor plt/plt mice, nor in double knockouts. However, the severity of EAE, but not the hyperalgesia, was also reduced in plt/plt mice, which was associated with reduced infiltration of the spinal cord with CCR7+ T-cells, an increase of CD25+ T-cells and reduced upregulation of CXCL9 and 10, CCL11 and 12. The data show that CCL21 and CXCR3 have dichotomous functions in traumatic and EAE-evoked neuropathic pain suggesting diverse mechanisms likely requiring diverse treatments although both types of neuropathic pain are mediated in part through the immune activation. PMID- 23643686 TI - Systematic framework to classify the status of research on spinal cord injury and physical activity. AB - OBJECTIVES: To systematically classify the physical activity research for individuals with a spinal cord injury by using the behavioral epidemiologic framework; and to identify where the physical activity research for individuals with a spinal cord injury has focused between 2000 and 2012. DESIGN: Relevant research was identified and then categorized into 1 of 5 phases by following the coding rules of the behavioral epidemiology framework. Phase 1 studies link physical activity and health outcomes, phase 2 studies validate or develop measures of physical activity, phase 3 studies identify factors that influence behavior or examine explanatory theories of behavior, phase 4 studies evaluate interventions, and phase 5 studies disseminate health promotion programs or policies and translate research into practice. SETTING: Specific keywords were identified and then searched through EBSCOhost, PubMed, and Google Scholar. PARTICIPANTS: Not applicable. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Not applicable. RESULTS: One hundred and thirteen articles met the criteria. Of the articles, 55% were categorized as phase 1, 12% as phase 2, 24% as phase 3, 5% as phase 4, and 4% as phase 5. CONCLUSIONS: Most studies were categorized as phase 1, 2, or 3, which implies that this field is still in the early stages of development and research should focus on intervention development and dissemination. PMID- 23643687 TI - Dual-task effect on gait balance control in adolescents with concussion. AB - OBJECTIVE: To prospectively and longitudinally examine how concussion affects gait balance control in adolescents during single- and dual-task walking. DESIGN: Cohort, prospective, repeated-measures design. SETTING: Motion analysis laboratory. PARTICIPANTS: Adolescents (N=20) identified as suffering a concussion were matched with healthy control subjects (N=20) and tested 5 times across a 2 month period after injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Gait temporal-distance parameters included average walking speed, step length, and step width; whole body center of mass (COM) parameters included medial/lateral displacement and peak COM medial/lateral and anterior velocities; dual-task cost, which was defined as percent change from single- to dual-task conditions; and Stroop test accuracy. RESULTS: No between-group differences were observed for step length and step width. The dual-task cost for average walking speed for subjects with concussion was greater than control subjects across the 2 month testing period (main effect of group P=.019), as was the dual-task costs for peak anterior COM velocity (main effect of group P=.017) and total COM medial/lateral displacement (main effect of group P=.013). The total COM medial/lateral displacement (group * task interaction P=.006) and peak COM medial/lateral velocity (main effect of group P=.027; main effect of task P=.01) were significantly greater in subjects with concussion compared with control subjects during dual-task walking. Subjects with concussion were significantly less accurate than controls on the Stroop test (main effect of group P=.004). CONCLUSIONS: The findings suggest that concussion affects the ability of adolescents to control body posture during gait up to 2 months after injury. Furthermore, dual-task paradigms may provide additional useful information in the clinical assessment and recovery of concussion. PMID- 23643688 TI - Assessing gait impairment after permanent middle cerebral artery occlusion in rats using an automated computer-aided control system. AB - Systematic gait analyses have been widely used in clinical settings as a reliable means of evaluating stroke severity and the efficacy of rehabilitation on people. However, the extent of gait changes post-stroke in experimental quadrupeds remains to be explored. To date, gait studies in cerebral ischemia have been limited to the mild ischemia-reperfusion model. However, studies on pathophysiology and therapy of experimental stroke suggest that permanent middle cerebral artery occlusion (pMCAO) is more similar to naturally occurring cerebral ischemia in humans. This is the first preclinical study to demonstrate that pMCAO rats can be used to assess long-term functional deficits related to gait by a computer-assisted method. Our gait analysis results demonstrate obvious gait deficits in the acute phase of the disease. During recovery, gait function gradually improved, but deficits were still detectable 42 days post-pMCAO. Objective and accurate photogrammetric parameters were used to illuminate laws of impairment and compensation in rats at different stages of cerebral ischemia in injured and uninjured limbs during walking. Compared to previous gait studies involving transient (t) MCAO rats, gait changes observed in pMCAO rats were more similar to changes following naturally occurring cerebral ischemia in humans. Importantly, the average body rotation and propulsion index, not previously used, are specific parameters for accurately assessing gait function during the acute phase of post-pMCAO. Furthermore, the gait test results revealed significant correlations between the final infarction volume and earlier behavioral outcomes. In conclusion, the gait analysis is a promising tool for assessing cerebral ischemia severity, and that it may provide a new means of investigating mechanisms of cerebral ischemia and evaluating potential therapies. PMID- 23643689 TI - Optogenetic investigation of the role of the superior colliculus in orienting movements. AB - In vivo studies have demonstrated that the superior colliculus (SC) integrates sensory information and plays a role in controlling orienting motor output. However, how the complex microcircuitry within the SC, as documented by slice studies, subserves these functions is unclear. Optogenetics affords the potential to examine, in behaving animals, the functional roles of specific neuron types that comprise heterogeneous nuclei. As a first step toward understanding how SC microcircuitry underlies motor output, we applied optogenetics to mice performing an odor discrimination task in which sensory decisions are reported by either a leftward or rightward SC-dependent orienting movement. We unilaterally expressed either channelrhodopsin-2 or halorhodopsin in the SC and delivered light in order to excite or inhibit motor-related SC activity as the movement was planned. We found that manipulating SC activity predictably affected the direction of the selected movement in a manner that depended on the difficulty of the odor discrimination. This study demonstrates that the SC plays a similar role in directional orienting movements in mice as it does in other species, and provides a framework for future investigations into how specific SC cell types contribute to motor control. PMID- 23643690 TI - Stress and decision making: a few minutes make all the difference. AB - Stress has been shown to impair decision making. However the temporal development of this phenomenon remains poorly understood. We speculated that the rapid stress induced increase in norepinephrine and the delayed increase in cortisol might exert opposing effects on decision making under risk. Therefore, three different experimental groups underwent the Trier Social Stress Test (TSST) and performed the Game of Dice Task (GDT) at different time points in relation to the stressor, which lasted approximately 18min. The first group performed the GDT 5min after stress onset, the second and third group performed the GDT either 18 or 28min after TSST onset. Decision-making performance of the control group was measured after a respective resting time. Results confirmed a rapid activation of the sympathetic nervous system and a somewhat slower response of the hypothalamic pituitary adrenal axis. In the GDT an improvement of decision-making performance in the 5 and 18min stress groups compared to controls and the 28min stress group occurred. Descriptively, decision making of the 28min after stress group was more risky than decision making of the control group. Our findings are in line with the idea that a moderate increase in catecholamines enhances decision-making performance, while elevated cortisol concentrations may negatively affect decision making presumably via rapid nongenomic mechanisms. PMID- 23643691 TI - Long-term home cage activity scans reveal lowered exploratory behaviour in symptomatic female Rett mice. AB - Numerous experimental models have been developed to reiterate endophenotypes of Rett syndrome, a neurodevelopmental disorder with a multitude of motor, cognitive and vegetative symptoms. Here, female Mecp2(Stop) mice [1] were characterised at mild symptomatic conditions in tests for anxiety (open field, elevated plus maze) and home cage observation systems for food intake, locomotor activity and circadian rhythms. Aged 8-9 months, Mecp2(Stop) mice presented with heightened body weight, lower overall activity in the open field, but no anxiety phenotype. Although home cage activity scans conducted in two different observation systems, PhenoMaster and PhenoTyper, confirmed normal circadian activity, they revealed severely compromised habituation to a novel environment in all parameters registered including those derived from a non-linear decay model such as initial exploration maximum, decay half-life of activity and span, as well as plateau. Furthermore, overall activity was significantly reduced in nocturnal periods due to reductions in both fast ambulatory movements, but also a slow lingering. In contrast, light-period activity profiles during which the amount of sleep was highest remained normal in Mecp2(Stop) mice. These data confirm the slow and progressive development of Rett-like symptoms in female Mecp2(Stop) mice resulting in a prominent reduction of overall locomotor activity, while circadian rhythms are maintained. Alterations in the time-course of habituation may indicate deficiencies in cognitive processing. PMID- 23643692 TI - Alterations in the endocannabinoid system in the rat valproic acid model of autism. AB - The endocannabinoid system plays a crucial role in regulating emotionality and social behaviour, however it is unknown whether this system plays a role in symptoms associated with autism spectrum disorders. The current study evaluated if alterations in the endocannabinoid system accompany behavioural changes in the valproic acid (VPA) rat model of autism. Adolescent rats prenatally exposed to VPA exhibited impaired social investigatory behaviour, hypoalgesia and reduced lococmotor activity on exposure to a novel aversive arena. Levels of the endocananbinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG) in the hippocampus, frontal cortex or cerebellum were not altered in VPA- versus saline exposed animals. However, the expression of mRNA for diacylglycerol lipase alpha, the enzyme primarily responsible for the synthesis of 2-AG, was reduced in the cerebellum of VPA-exposed rats. Furthermore, while the expression of mRNA for the 2-AG-catabolising enzyme monoacylglycerol lipase was reduced, the activity of this enzyme was increased, in the hippocampus of VPA-exposed animals. CB1 or CB2 receptor expression was not altered in any of the regions examined, however VPA exposed rats exhibited reduced PPARalpha and GPR55 expression in the frontal cortex and PPARgamma and GPR55 expression in the hippocampus, additional receptor targets of the endocannabinoids. Furthermore, tissue levels of the fatty acid amide hydrolase substrates, AEA, oleoylethanolamide and palmitoylethanolamide, were higher in the hippocampus of VPA-exposed rats immediately following social exposure. These data indicate that prenatal VPA exposure is associated with alterations in the brain's endocannabinoid system and support the hypothesis that endocannabinoid dysfunction may underlie behavioural abnormalities observed in autism spectrum disorders. PMID- 23643693 TI - Infusion of cannabidiol into infralimbic cortex facilitates fear extinction via CB1 receptors. AB - Previous studies have implicated cannabinoids in extinction of conditioned fear. We have recently showed that intraventricular infusion of the phytocannabinoid cannabidiol (CBD) facilitates fear extinction, but the brain regions underlying this effect remained unknown. Here we demonstrate that repeated microinjections of CBD into the infralimbic cortex (IL) facilitated fear extinction, as indicated by reduced levels of freezing during extinction test. Systemic administration of the CB1 receptor antagonist rimonabant blocked the effects of intra-IL CBD, suggesting that CBD acts through CB1 receptors to facilitate fear extinction. Our findings suggest a potential therapeutic use of CBD for extinction-based therapies of aversive memories in humans. PMID- 23643694 TI - Late recurrence in melanoma: clinical implications of lost dormancy. AB - BACKGROUND: For patients with melanoma, if there has been no recurrence of disease 10 years after initial treatment, additional disease is believed to be very unlikely. However, such late recurrences are known to occur. The frequency of this phenomenon and its clinical significance are not well characterized due to the difficulty in obtaining relevant data. We examined a large, mature, institutional database to evaluate late recurrence. STUDY DESIGN: The late recurrence cohort was defined as having a disease-free interval of 10 or more years after potentially curative treatment and was compared with an early recurrence cohort recurring within 3 years. Actuarial late recurrence frequency and factors associated with late recurrence were examined. Post-recurrence overall and melanoma-specific survival and prognostic variables were analyzed. RESULTS: Among all patients, 408 exhibited late recurrence (mean disease-free interval 15.7 years). For patients who received primary treatment at our institution with 10 or more years follow-up, 327 of 4,731 (6.9%) showed late recurrence. On an actuarial basis, late recurrence rates were 6.8% and 11.3% at 15 and 20 years, respectively, for those with no recurrence at 10 years. Late recurrence was associated with both tumor (thin, non-ulcerated, non-head/neck, node negative) and patient (younger age, less male predominant) characteristics. Multivariate analysis confirmed younger age, thinner and node negative tumors in the late recurrence group. Late recurrences were more likely to be distant, but were associated with better post-recurrence survival on univariate and multivariate analyses. CONCLUSIONS: Late melanoma recurrence is not rare. It occurs more frequently in certain clinical groups and is associated with improved post-recurrence survival. PMID- 23643696 TI - Shedding light on women's help seeking behaviour for self discovered breast symptoms. AB - PURPOSE: To describe women's help seeking behaviour (HSB) and the associated influencing factors on self-discovery of a breast symptom. METHODS: A descriptive, correlational survey design was used. Following ethical approval, survey data were collected from women (n = 449) attending the breast clinics of two large urban hospitals within the Republic of Ireland. RESULTS: The majority of women (69.9%; n = 314) sought help (by visiting their General practitioner, GP) within one month, 30.1% (n = 135) delayed help seeking for more than one month following symptom discovery and 16.7% (n = 75) delayed for three months or more. The factors most significantly associated with delayed HSB were knowledge around symptom identity (Odds Ratio (OR) = 4.80, p = 0.005); ignoring the symptom and hoping it would go away (OR = 10.72, p < 0.001) and women's belief that the symptom would persist for a long time (OR = 1.18, p = 0.023). Being afraid on symptom discovery (OR = 0.37, p = 0.005) was associated with reduced risk of delayed HSB. CONCLUSIONS: It is encouraging to see that the majority of women who find a breast symptom seek help promptly. However, a small cohort of women delay seeking help from their GP. HSB is influenced by multiple factors which can impact on patient outcomes. Findings are important for oncology nurses who have a key role to play in promoting breast awareness, prompt help seeking and early detection and treatment of breast cancer, amongst women. PMID- 23643695 TI - Epigenetic mechanisms of drug addiction. AB - Drug addiction involves potentially life-long behavioral abnormalities that are caused in vulnerable individuals by repeated exposure to a drug of abuse. The persistence of these behavioral changes suggests that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. Work over the past decade has demonstrated a crucial role for epigenetic mechanisms in driving lasting changes in gene expression in diverse tissues, including brain. This has prompted recent research aimed at characterizing the influence of epigenetic regulatory events in mediating the lasting effects of drugs of abuse on the brain in animal models of drug addiction. This review provides a progress report of this still early work in the field. As will be seen, there is robust evidence that repeated exposure to drugs of abuse induces changes within the brain's reward regions in three major modes of epigenetic regulation-histone modifications such as acetylation and methylation, DNA methylation, and non-coding RNAs. In several instances, it has been possible to demonstrate directly the contribution of such epigenetic changes to addiction-related behavioral abnormalities. Studies of epigenetic mechanisms of addiction are also providing an unprecedented view of the range of genes and non-genic regions that are affected by repeated drug exposure and the precise molecular basis of that regulation. Work is now needed to validate key aspects of this work in human addiction and evaluate the possibility of mining this information to develop new diagnostic tests and more effective treatments for addiction syndromes. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23643697 TI - Differences in self-reported outcomes of open prostatectomy patients and robotic prostatectomy patients in an international web-based survey. AB - OBJECTIVES: To compare patient reported outcomes between robotic assisted surgery and non-robotic assisted surgery. METHODS: This was an international web-based survey based on a qualitative research and literature review, an internet-based questionnaire was developed with approximately 70 items. The questionnaire included both closed and open-ended questions. RESULTS: Responses were received from 193 men of whom 86 had received either open (OP) or robotic (RALP) surgery. A statistically significant (p=0.027), ranked analysis of covariance was found demonstrating higher recent distress in the robotic (RALP) surgery group. Although not statistically significant, there was a pattern of men having robotic (RALP) surgery reporting fewer urinary and bowel problems, but having a greater rate of sexual dysfunction. CONCLUSIONS: Men who opt for robotic surgery may have higher expectations for robotic (RALP) surgery, when these expectations are not fully met they may be less likely to accept the consequences of this major cancer surgery. Information regarding surgical choice needs to be tailored to ensure that men diagnosed with prostate cancer are fully informed of not only short term surgical and physical outcomes such as erectile dysfunction and incontinence, but also of potential issues with regards to masculinity, lifestyle and sexual health. PMID- 23643699 TI - Evaluation of genotoxicity of nitrile fragrance ingredients using in vitro and in vivo assays. AB - Genotoxicity studies were conducted on a group of 8 fragrance ingredients that belong to the nitrile family. These nitriles are widely used in consumer products however there is very limited data in the literature regarding the genotoxicity of these nitriles. The 8 nitriles were assessed for genotoxicity using an Ames test, in vitro chromosome aberration test or in vitro micronucleus test. The positive results observed in the in vitro tests were further investigated using an in vivo micronucleus test. The results from these different tests were compared and these 8 nitriles are not considered to be genotoxic. Dodecanitrile and 2,2,3-trimethylcyclopent-3-enylacetonitrile were negative in the in vitro chromosome aberration test and in vitro micronucleus test, respectively. While citronellyl nitrile, 3-methyl-5-phenylpentanenitrile, cinnamyl nitrile, and 3 methyl-5-phenylpent-2-enenitrile revealed positive results in the in vitro tests, but confirmatory in vivo tests determined these nitriles to be negative in the in vivo micronucleus assay. The remaining two nitriles (benzonitrile and alpha cyclohexylidene benzeneacetonitrile) were negative in the in vivo micronucleus test. This study aims to evaluate the genotoxicity potential of these nitriles as well as enrich the literature with genotoxicity data on fragrance ingredients. PMID- 23643698 TI - Laparoscopic versus open surgery for colon cancer: a meta-analysis of 5-year follow-up outcomes. AB - BACKGROUND: Colon cancer is one of the most common malignant tumors of digestive tract with a rather high incidence rate. Currently, surgery is the only radical therapy for colon cancer, while Laparoscopic colectomy (LAC) has become another focus since studies reported LAC could improve the short-time outcomes and quick recovery of patients compared with open colectomy (OC). However, it's still unclear whether LAC can better improve patients' long-time survival than OC. OBJECTIVE: We aimed to perform a meta-analysis to answer whether the 5-year recurrence and survival rate after LAC are comparable to those reported after OC in patient with colon cancer. METHODS: We searched Cochrane Library, PubMed, Embase, CBM, VIP, and CNKI for relevant studies. The time searched was from the establishment time of the databases to September 15, 2011. At the same time, we searched Google, Medical Martix and Baidu for more studies as well as a hand search. We limited the language to English and Chinese. Two reviewers independently screened articles to identify randomized controlled trials (RCTs) according to the inclusion and exclusion criteria and assessed the methodological quality of included trials, and then extracted data. Meta-analysis was performed using RevMan5.0. RESULTS: Five RCTs involving 2695 patients reported long-term outcomes based on 5-year data and were included in the analysis. No significant differences between LAC and OC were found in the overall mortality (RR = 0.94; 95% CI (0.82, 1.09); P = 0.23, I(2) = 21%), total recurrence rate (RR = 0.94; 95% CI (0.81, 1.10); P = 0.24, I(2) = 27%), 5-year tumor free survival rate (RR = 1.00, 95% CI (0.94, 1.06); P = 0.96, I(2) = 0%). and overall 5-year survival (RR = 1.02; 95% CI (0.97, 1.07); P = 0.55, I(2) = 0%). CONCLUSIONS: This meta analysis suggests that LAC was as effective and safe as OC for colon cancer. PMID- 23643701 TI - Effects of red wine intake on human salivary antiradical capacity and total polyphenol content. AB - The protective effects of grape polyphenols have been reported on oral health, though unreasonable alcohol consumption represents a risk factor for developing oral cancer. The possible effects of red wine consumption on salivary antiradical activity were investigated in healthy volunteers for the first time, to the best of our knowledge. Time-course (from 0 min to 240 min) changes of salivary radical scavenging capacity were measured by the 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonic acid) (ABTS(+)) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays, in twelve healthy volunteers, after the intake of red wine (125 mL), a capsule of red wine extract (300 mg) or water (125 mL). Furthermore, time-course of salivary total polyphenol levels, detected by the Folin-Ciocalteu colorimetric method, was also determined. Both ABTS and DPPH tests showed that red wine consumption did not increase salivary antiradical activity in volunteers. Conversely, red wine extract administration caused a marked rise in salivary ABTS radical-scavenging capacity within 30 min, followed by a plateau up to 240 min. The same treatment also raised salivary DPPH radical-scavenging activity at any time point, though to a minor extent. The highest salivary polyphenol concentration was reached 30 min after wine drinking, followed by a steady decrease up to 240 min. Wine drinking was not associated to a reduced salivary antiradical capacity. However, wine extract greatly improved the salivary antioxidant status. PMID- 23643700 TI - Vitamin C and lifespan in model organisms. AB - The process of ageing has been repeatedly associated with increasing oxidative damage which has led to the hypothesis that reducing oxidative stress through antioxidant dietary factors may prolong lifespan. Ascorbic acid is an essential antioxidant in human diets and is widely used for supplementation. However, it is rather unclear if and to what extent ascorbic acid may affect lifespan in humans and model organisms. In our review of literature on vitamin C supplementation and its effect on lifespan in different model organisms we found that some studies suggest an increase in lifespan, other studies failed to observe any beneficial effect of vitamin C on longevity and some studies even reported a decrease in lifespan following vitamin C supplementation. Of the 14 studies included in our analysis, three were carried out in worms, four in flies and seven in rodents. The discrepancies between the studies may be related to species-specific differences, the concentration of vitamin C administered, the duration of supplementation and whether vitamin C was used alone or as part of a combined antioxidant diet. Potential underlying mechanisms through which vitamin C may influence lifespan and differences amongst species regarding the capacity to produce vitamin C endogenously are discussed. PMID- 23643702 TI - Hydroxytyrosyl alkyl ether derivatives inhibit platelet activation after oral administration to rats. AB - The low lipophilicity of hydroxytyrosol (HT) has motivated efforts to synthesize homologous series with better lipid solubility, such as the ethers, which are more lipophilic than HT. Because HT inhibits platelet aggregation, the aim of the study was to assess the possible anti-platelet effect of five HT ether derivatives (ethyl, butyl, hexyl, octyl and dodecyl) after oral administration to rats. Whole blood collagen-induced platelet aggregation and calcium-induced thromboxane B2 (TxB2), aortic 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) and nitrites+nitrates, plasma concentration of lipid peroxides (TBARS) and red blood cell content of reduced glutathione (GSH) were measured. The administration of 20 mg/kg/day inhibited platelet aggregation, TxB2 and TBARS in a non-linear manner related to the length of the carbon chain, with a cut-off effect in the hexyl derivative. Aortic nitrite and red blood cell GSH production were also increased. The aortic production of 6-keto-PGF1alpha was unaltered except in the group treated with the dodecyl derivative. The administration of 50 mg/kg/day showed a similar pharmacodynamic profile but without the non-linear effect. In conclusion, HT ethers, especially the hexyl derivative, are a potential alternative to hydroxytyrosol, and their effect merits additional research to determine their role in the prophylaxis of vascular disease. PMID- 23643703 TI - Hyperthermia-induced genotoxic effects in human A549 cells. AB - Genotoxic effects of hyperthermia in vitro and in vivo have repeatedly been reported. Short-duration heat shocks and elevated temperature over longer time periods have been shown to induce DNA damage, chromosomal damage and to inhibit DNA repair. Using the comet assay and the micronucleus test, we now investigated temperature- and time-related effects on DNA damage and chromosomal effects of hyperthermia on the A549 human lung cell line. We also related the genotoxic effects to cytotoxic effects and the induction of apoptosis. Our results indicate that exposure to hyperthermia (42-48 degrees C for 30-120min) induced genotoxic effects in a temperature- and time-related manner. Interestingly, hyperthermia induced DNA damage measured by the comet assay was not rapidly removed by post incubation at 37 degrees C but even increased after exposure to 48 degrees C for 60min. Cytotoxic effects occurred in parallel to the genotoxic effects but apoptosis was not significantly induced under these experimental conditions. PMID- 23643705 TI - Different chemical reaction times between normal and solid cancer cells. AB - Entropy generation approach has been developed in order to use it for the analysis of complex systems with particular regards to biological systems in order to evaluate their stationary states. The entropy generation is related to the transport processes related to energy flows. Moreover, cancer can be described as an open complex dynamic and self-organizing system. Using the entropy generation approach it is possible to point out different chemical reaction time between normal and solid cancer cells. PMID- 23643706 TI - Mirror neuron system activation for conscious states assessment: for patients in vegetative and minimally conscious states. AB - Mirror neuron system (MNS) represents the direct pathway to consciousness. Measuring MNS activation provides an accurate and reliable assessment of conscious status in vegetative and minimally conscious states (VS and MCS) patients. It will be further interesting to design MNS activation-based procedure to "recall" the consciousness in such patients. PMID- 23643704 TI - The p53-microRNA-34a axis regulates cellular entry receptors for tumor-associated human herpes viruses. AB - A growing number of reports indicate the frequent presence of DNA sequences and gene products of human cytomegalovirus in various tumors as compared to adjacent normal tissues, the brain tumors being studied most intensely. The mechanisms underlying the tropism of human cytomegalovirus to the tumor cells or to the cells of tumor origin, as well as the role of the host's genetic background in virus-associated oncogenesis are not well understood. It is also not clear why cytomegalovirus can be detected in many but not in all tumor specimens. Our in silico prediction results indicate that microRNA-34a may be involved in replication of some human DNA viruses by targeting and downregulating the genes encoding a diverse group of proteins, such as platelet-derived growth factor receptor-alpha, complement component receptor 2, herpes simplex virus entry mediators A, B, and C, and CD46. Notably, while their functions vary, these surface molecules have one feature in common: they serve as cellular entry receptors for human DNA viruses (cytomegalovirus, Epstein-Barr virus, human herpes virus 6, herpes simplex viruses 1 and 2, and adenoviruses) that are either proven or suspected to be linked with malignancies. MicroRNA-34a is strictly dependent on its transcriptional activator tumor suppressor protein p53, and both p53 and microRNA-34a are frequently mutated or downregulated in various cancers. We hypothesize that p53-microRNA-34a axis may alter susceptibility of cells to infection with some viruses that are detected in tumors and either proven or suspected to be associated with tumor initiation and progression. PMID- 23643707 TI - Is primary hyperparathyroidism a pathogenic factor in some conditions mediated by B lymphocytes hyperactivity? AB - Several clinical cases have shown the association of primary hyperparathyroidism and immune conditions related to B-cell hyperactivity. In some of these cases the treatment of hyperparathyroidism led to the resolution of the autoimmune phenomena. Thus, this paper hypothesizes that high levels of parathyroid hormone (PTH) may modify B lymphocytes function and induce the development of autoimmunity mediated by B-cell hyperactivity. PMID- 23643708 TI - Can anti-speeding messages based on protection motivation theory influence reported speeding intentions? AB - The study investigated the effects of anti-speeding messages based on protection motivation theory (PMT) components: severity, vulnerability, rewards, self efficacy, response efficacy, and response cost, on reported speeding intentions. Eighty-three participants aged 18-25 years holding a current Australian driver's license completed a questionnaire measuring their reported typical and recent speeding behaviors. Comparisons were made between 18 anti-speeding messages used on Australian roads and 18 new anti-speeding messages developed from the PMT model. Participants reported their reactions to the 36 messages on the perceived effectiveness of the message for themselves and for the general population of drivers, and also the likelihood of themselves and other drivers driving within the speed limit after viewing each message. Overall the PMT model-derived anti speeding messages were better than jurisdiction-use anti-speeding messages in influencing participants' reported intention to drive within the speed limit. Severity and vulnerability were the most effective PMT components for developing anti-speeding messages. Male participants reported significantly lower intention to drive within the speed limit than did female participants. However, males reported significantly higher intention to drive within the speed limit for PMT derived messages compared with jurisdiction-based messages. Third-person effects were that males reported anti-speeding messages to be more effective for the general driving population than for themselves. Females reported the opposite effect - that all messages would be more effective for themselves than for the general driving population. Findings provided support for using a sound conceptual basis as an effective foundation for anti-speeding message development as well as for evaluating proposed anti-speeding messages on the target driver population. PMID- 23643709 TI - Antioxidant effect of human adult adipose-derived stromal stem cells in alveolar epithelial cells undergoing stretch. AB - INTRODUCTION: Alveolar epithelial cells undergo stretching during mechanical ventilation. Stretch can modify the oxidative balance in the alveolar epithelium. The aim of the present study was to evaluate the antioxidant role of human adult adipose tissue-derived stromal cells (hADSCs) when human alveolar epithelial cells were subjected to injurious cyclic overstretching. METHODS: A549 cells were subjected to biaxial stretch (0-15% change in surface area for 24h, 0.2Hz) with and without hADSCs. At the end of the experiments, oxidative stress was measured as superoxide generation using positive nuclear dihydroethidium (DHE) staining, superoxide dismutase (SOD) activity in cell lysates, 8-isoprostane concentrations in supernatant, and 3-nitrotyrosine by indirect immunofluorescence in fixed cells. RESULTS: Cyclically stretching of AECs induced a significant decrease in SOD activity, and an increase in 8-isoprostane concentrations, DHE staining and 3 nitrotyrosine staining compared with non-stretched cells. Treatment with hADSCs significantly attenuated stretch-induced changes in SOD activity, 8-isoprostane concentrations, DHE and 3-nitrotyrosine staining. CONCLUSION: These data suggest that hADSCs have an anti-oxidative effect in human alveolar epithelial cells undergoing cyclic stretch. PMID- 23643710 TI - Disruption of the CREBBP gene and decreased expression of CREB, NFkappaB p65, c JUN, c-FOS, BCL2 and c-MYC suggest immune dysregulation. AB - Genomic aberrations in the CREBBP (CREB-binding protein - CREBBP or CBP) gene such as point mutations, small insertions or exonic copy number changes are usually associated with Rubinstein-Taybi syndrome (RTs). In this study, the disruption of the CREBBP gene on chromosome 16p13.3, as revealed by CGH-array and FISH, suggests immune dysregulation in a patient with the Rubinstein Taybi syndrome (RTs) phenotype. Further investigation with Western blot techniques demonstrated decreased expression of CREB, NFkappaB, c-Jun, c-Fos, BCL2 and cMyc in peripheral blood mononuclear cells, thus indicating that the CREBBP gene is essential for the normal expression of these proteins and the regulation of immune responses. PMID- 23643712 TI - Inhibition of N-acetylglutamate synthase by various monocarboxylic and dicarboxylic short-chain coenzyme A esters and the production of alternative glutamate esters. AB - Hyperammonemia is a frequent finding in various organic acidemias. One possible mechanism involves the inhibition of the enzyme N-acetylglutamate synthase (NAGS), by short-chain acyl-CoAs which accumulate due to defective catabolism of amino acids and/or fatty acids in the cell. The aim of this study was to investigate the effect of various acyl-CoAs on the activity of NAGS in conjunction with the formation of glutamate esters. NAGS activity was measured in vitro using a sensitive enzyme assay with ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) product analysis. Propionyl-CoA and butyryl CoA proved to be the most powerful inhibitors of N-acetylglutamate (NAG) formation. Branched-chain amino acid related CoAs (isovaleryl-CoA, 3 methylcrotonyl-CoA, isobutyryl-CoA) showed less pronounced inhibition of NAGS whereas the dicarboxylic short-chain acyl-CoAs (methylmalonyl-CoA, succinyl-CoA, glutaryl-CoA) had the least inhibitory effect. Subsequent work showed that the most powerful inhibitors also proved to be the best substrates in the formation of N-acylglutamates. Furthermore, we identified N-isovalerylglutamate, N-3 methylcrotonylglutamate and N-isobutyrylglutamate (the latter two in trace amounts), in the urines of patients with different organic acidemias. Collectively, these findings explain one of the contributing factors to secondary hyperammonemia, which lead to the reduced in vivo flux through the urea cycle in organic acidemias and result in the inadequate elimination of ammonia. PMID- 23643713 TI - High short-term loosening rates with the Wagner Standard Cup. AB - The stability of prosthetic fixation is to a large extent dependent on component design. The purpose of this study is to analyze the short-term radiological results obtained with the Wagner Standard Cup in primary hip arthroplasty. An assessment was made of one hundred primary hip arthroplasties. The radiological evaluation revealed bone ingrowth in 37 of cases, fibrous integration in 49 and loosening in 14. In summary, osseointegration of the Wagner Standard Cup was unsuccessful in a high percentage of cases. This finding, which was unrelated to the type of stem or bearing surface used, bore a statistically significant relation (P<0.05) with an observed poor bone coverage of the acetabular component. Although insufficient bone coverage could arguably be attributable to a poor surgical technique, we would tend to agree with other authors that it is rather likely to result from a flawed implant design that impedes osseointegration. PMID- 23643711 TI - Hydrogen peroxide production regulates the mitochondrial function in insulin resistant muscle cells: effect of catalase overexpression. AB - The mitochondrial redox state plays a central role in the link between mitochondrial overloading and insulin resistance. However, the mechanism by which the ROS induce insulin resistance in skeletal muscle cells is not completely understood. We examined the association between mitochondrial function and H2O2 production in insulin resistant cells. Our hypothesis is that the low mitochondrial oxygen consumption leads to elevated ROS production by a mechanism associated with reduced PGC1alpha transcription and low content of phosphorylated CREB. The cells were transfected with either the encoded sequence for catalase overexpression or the specific siRNA for catalase inhibition. After transfection, myotubes were incubated with palmitic acid (500MUM) and the insulin response, as well as mitochondrial function and fatty acid metabolism, was determined. The low mitochondrial oxygen consumption led to elevated ROS production by a mechanism associated with beta-oxidation of fatty acids. Rotenone was observed to reduce the ratio of ROS production. The elevated H2O2 production markedly decreased the PGC1alpha transcription, an effect that was accompanied by a reduced phosphorylation of Akt and CREB. The catalase transfection prevented the reduction in the phosphorylated level of Akt and upregulated the levels of phosphorylated CREB. The mitochondrial function was elevated and H2O2 production reduced, thus increasing the insulin sensitivity. The catalase overexpression improved mitochondrial respiration protecting the cells from fatty acid-induced, insulin resistance. This effect indicates that control of hydrogen peroxide production regulates the mitochondrial respiration preventing the insulin resistance in skeletal muscle cells by a mechanism associated with CREB phosphorylation and beta-oxidation of fatty acids. PMID- 23643715 TI - What elements of the informational, management, and relational continuity are associated with patient satisfaction with rehabilitation care and global rating change? AB - OBJECTIVE: To describe the quality of patients' continuity experiences in a population of outpatients receiving postacute rehabilitation care, and to check which elements and types of continuity most strongly determine their satisfaction with care and functional changes. DESIGN: Cross-sectional self-report survey. SETTING: Three postacute ambulatory centers in metropolitan areas. PARTICIPANTS: Outpatients (N=218; mean age +/- SD, 38.5+/-11.7y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The questionnaire included experiences regarding aspects of informational (transference of information, accumulated knowledge), management (consistency and flexibility of care), and relational (established relation and consistency of provider) continuity, as well as questions concerning patients' sociodemographic characteristics, satisfaction with care, and global rating change. RESULTS: Respondents indicated more problems in terms of management and relational continuity than in informational continuity. For all patient groups, experiences regarding elements of management continuity (R(2)=15.3%-22.4%), followed by relational continuity (R(2)=14.3% 25.2%), explained most of the variance of satisfaction. Consistency and flexibility of care, together with an established relation, were the most determining elements of satisfaction. Experiences regarding elements of management continuity explained most of the variance of change (18.5%), and flexibility was the most decisive element. CONCLUSIONS: Patient satisfaction and functional changes are related with experiences in aspects of management continuity, where there is room for improvement. Measures of management continuity may be promising as indicators of continuity, and they should be prioritized. PMID- 23643714 TI - Posterior sliding of the femur during stair ascending and descending in a high flex posterior stabilized total knee arthroplasty. AB - This study investigated the anteroposterior stability of the femur during stair motions. We examined 18 knees with a clinically successful high-flexion posterior stabilized total knee arthroplasty to evaluate the in vivo kinematics of stair ascending and descending using two- to three-dimensional registration. Posterior sliding of the femur was observed while shifting weight to the leg during stair ascending and descending in almost all knees. Anterior tibial post impingement was observed in 10 knees when the knee was extended in stair ascending, whereas in stair descending, the impingement was observed in 14 knees when posterior sliding of the femur occurred. The impingement contributed to the stabilization of the knee during stair motion; however, impingement may result in additional polyethylene wear and tibial post failure. PMID- 23643716 TI - Physiotherapy for sleep disturbance in people with chronic low back pain: results of a feasibility randomized controlled trial. AB - OBJECTIVE: To determine the feasibility of a randomized controlled trial investigating the effectiveness of physiotherapy for sleep disturbance in chronic low back pain (CLBP) (>=12wks). DESIGN: Randomized controlled trial with evaluations at baseline, 3 months, and 6 months. SETTING: Outpatient physiotherapy department in an academic teaching hospital. PARTICIPANTS: Participants with CLBP were randomly assigned to a walking program (n=20; mean age +/- SD, 46.4+/-13.8y), supervised exercise class (n=20; mean age +/- SD, 41.3+/-11.9y), or usual physiotherapy (n=20; mean age +/- SD, 47.1+/-14.3y). The 3-month evaluation was completed by 44 participants (73%), and 42 (70%) participants completed the 6-month evaluation. INTERVENTIONS: Participants received a physiotherapy-delivered 8-week walking program, an 8-week group supervised exercise class (1 class/wk), or 1-to-1 usual physiotherapy (advice, manual therapy, and exercise). MAIN OUTCOME MEASURES: Sleep was assessed by the self-reported Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Pittsburgh Sleep Diary, and objective actigraphy. RESULTS: Groups were comparable at baseline. Most (95%, n=57) of the participants had sleep disturbance. The acceptability of actigraphy was excellent at baseline (58 of 60 participants), but dropped at 3 months (26 of 44 participants). There were improvements on the PSQI and ISI in all groups at 3 and 6 months, with predominantly medium effect sizes (Cohen d=0.2-0.5). CONCLUSIONS: The high prevalence of sleep disturbance indicated the feasibility of good recruitment in future trials. The PSQI would be a suitable screening tool and outcome measure alongside an objective nonobtrusive sleep outcome measure. The effectiveness of physiotherapy for sleep disturbance in CLBP warrants investigation in a fully powered randomized controlled trial. PMID- 23643717 TI - Intimate partner violence in Europe: design and methods of a multinational study. AB - OBJECTIVE: To describe the design, methods, procedures and characteristics of the population involved in a study designed to compare Intimate Partner Violence (IPV) in eight European countries. METHODS: Women and men aged 18-65, living in Ghent-Belgium (n = 245), Stuttgart-Germany (n = 546), Athens-Greece (n = 548), Budapest-Hungary (n = 604), Porto-Portugal (n = 635), Granada-Spain (n = 138), Ostersund-Sweden (n = 592), London-United Kingdom (n = 571), were sampled and administered a common questionnaire. Chi-square goodness of fit and five-age strata population fractions ratios for sex and education were computed to evaluate samples' representativeness. RESULTS: Differences in the age distributions were found among women from Sweden and Portugal and among men from Belgium, Hungary, Portugal and Sweden. Over-recruitment of more educated respondents was noted in all sites. CONCLUSION: The use of a common research protocol with the same structured questionnaire is likely to provide accurate estimates of the general population IPV frequency, despite limitations in probabilistic sampling and restrictions in methods of administration. PMID- 23643718 TI - [The incidence of lues in a Zaragoza hospital over a period of 13 years]. PMID- 23643719 TI - Socioeconomic inequalities in the incidence and prevalence of type 2 diabetes mellitus in Europe. AB - OBJECTIVE: The aim of this study was to analyze socioeconomic position (SEP) inequalities in the prevalence and incidence of type 2 diabetes mellitus (T2DM) in people aged 50 years and over in Europe and to describe the contribution of body mass index (BMI) and other possible mediators. METHODS: This was a cross sectional and longitudinal study including men and women >= 50 years old in 11 European countries in 2004 and 2006 (n = 21,323). The prevalence and cumulative incidence of T2DM were calculated with self-reported T2DM or when the individual took drugs for diabetes. Prevalence ratio (PR) and relative risk (RR) of prevalent and incident T2DM were calculated according to educational level and adjusted by BMI and other possible mediators. RESULTS: The age-adjusted and country-adjusted prevalence of T2DM in 2004 was 10.2% in men and 8.5% in women. Compared to those with higher education, men and women with lower education had a PR [95% CI] of T2DM of 1.29 [1.12-1.50] and 1.61 [1.39-1.86], respectively. SEP related inequalities in incidence (RR [95%CI]) were 1.88 [1.35-2.62] in women and 1.04 [0.78-1.40] in men. Adjusting for potential mediators reduced inequalities in the prevalence and incidence of T2DM among women by 26.2% and 21.6%, respectively, and inequalities in prevalence among men by 44.8%. CONCLUSIONS: We observed significant inequalities in the prevalence and incidence (women only) of T2DM as a function of socioeconomic position. These inequalities were mediated by BMI. PMID- 23643720 TI - Introducing enteral feeds in the high-risk preterm infant. AB - Establishing enteral feeding in high-risk, very preterm infants is difficult: they are born at a time of rapid growth and development, yet immaturity of gut and metabolic function makes it difficult to accumulate adequate nutrients. Parenteral nutrition will provide the bulk of nutrients in the first few weeks while the preterm infant gut adapts. Intestinal function, nutritional substrate and microbial environment all interact to enable this to happen, and imbalance of these components may result in the serious condition of necrotising enterocolitis. Mother's breast milk is the safest feed and there is no evidence that delaying the introduction of small volumes is of benefit. Volumes can gradually be increased as tolerated and nutrient intakes optimised with addition of supplements or breast-milk fortifier to minimise the extent of extrauterine growth restriction. PMID- 23643721 TI - Comparative bioenergetic study of neuronal and muscle mitochondria during aging. AB - Mitochondrial respiratory chain defects have been associated with various diseases and with normal aging, particularly in tissues with high energy demands, including brain and skeletal muscle. Tissue-specific manifestation of mitochondrial DNA (mtDNA) mutations and mitochondrial dysfunction are hallmarks of mitochondrial diseases although the underlying mechanisms are largely unclear. Previously, we and others have established approaches for transferring mtDNA from muscle and synaptosomes of mice at various ages to cell cultures. In this study, we carried out a comprehensive bioenergetic analysis of cells bearing mitochondria derived from young, middle-aged, and old mouse skeletal muscles and synaptosomes. Significant age-associated alterations in oxidative phosphorylation and regulation during aging were observed in cybrids carrying mitochondria from both skeletal muscle and synaptosomes. Our results also revealed that loss of oxidative phosphorylation capacity may occur at various ages in muscle and brain. These findings indicate the existence of a tissue-specific regulatory mechanism for oxidative phosphorylation. PMID- 23643723 TI - Combined use of native and caged mussels to assess biological effects of pollution through the integrative biomarker approach. AB - Native and caged mussels were used in combination for the monitoring of pollution biological effects through an integrative biomarker approach. Mussels (Mytilus galloprovincialis) were deployed in cages in two well-known model localities with different pollution levels in the Basque coast. After 3 weeks caged and native mussels were collected from each site and a suite of effect and exposure biomarkers (from molecular/cellular to organism level) was applied and chemical contaminants (metals, PAHs, PCBs, phthalates and nonylphenol ethoxylates) were analytically determined. Integrative biomarker indices and pollutant indices of tissues were calculated. Several biomarkers used herein responded similarly in native and caged mussels, whereas others exhibited significant differences. Overall, biomarkers in-a-suite depicted site-specific profiles useful for the diagnostic of mussel health status and therefore for ecosystem health assessment in marine pollution biomonitoring. On the other hand, biomarkers and bioaccumulation exhibited different response times, which was especially evident when comparing biomarker and pollutant indices of tissues. The suite of biomarkers was more sensitive after caging (short-term response), whereas tissue pollutant concentrations were more sensitive in native mussels (long-term response). Thus, the combination of native and caged mussels is highly recommended to monitor biological effects of pollution in mussels through the integrative biomarker approach, especially in chronically polluted sites. PMID- 23643722 TI - A truncated splice-variant of the FcepsilonRIbeta receptor subunit is critical for microtubule formation and degranulation in mast cells. AB - Human linkage analyses have implicated the MS4A2-containing gene locus (encoding FcepsilonRIbeta) as a candidate for allergy susceptibility. We have identified a truncation of FcepsilonRIbeta (t-FcepsilonRIbeta) in humans that contains a putative calmodulin-binding domain and thus, we sought to identify the role of this variant in mast cell function. We determined that t-FcepsilonRIbeta is critical for microtubule formation and degranulation and that it may perform this function by trafficking adaptor molecules and kinases to the pericentrosomal and Golgi region in response to Ca2+ signals. Mutagenesis studies suggest that calmodulin binding to t-FcepsilonRIbeta in the presence of Ca2+ could be critical for t-FcepsilonRIbeta function. In addition, gene targeting of t-FcepsilonRIbeta attenuated microtubule formation, degranulation, and IL-8 production downstream of Ca2+ signals. Therefore, t-FcepsilonRIbeta mediates Ca2+ -dependent microtubule formation, which promotes degranulation and cytokine release. Because t-FcepsilonRIbeta has this critical function, it represents a therapeutic target for the downregulation of allergic inflammation. PMID- 23643724 TI - Acute ZnO nanoparticles exposure induces developmental toxicity, oxidative stress and DNA damage in embryo-larval zebrafish. AB - Nano-scale zinc oxide (nano-ZnO) is widely used in various industrial and commercial applications. However, the available toxicological information was inadequate to assess the potential ecological risk of nano-ZnO to aquatic organisms and the publics. In this study, the developmental toxicity, oxidative stress and DNA damage of nano-ZnO embryos were investigated in the embryo-larval zebrafish, the toxicity of Zn(2+) releasing from nano-ZnO were also investigated to ascertain the relationship between the nano-ZnO and corresponding Zn(2+). Zebrafish embryos were exposed to 1, 5, 10, 20, 50, and 100mg/L nano-ZnO and 0.59, 2.15, 3.63, 4.07, 5.31, and 6.04 mg/L Zn(2+) for 144 h post-fertilisation (hpf), respectively. Up to 144 hpf, activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and malondialdehyde (MDA) contents, the genes related to oxidative damage, reactive oxygen species (ROS) generation and DNA damage in zebrafish embryos were measured. The nano-ZnO was found to exert a dose-dependent toxicity to zebrafish embryos and larvae, reducing the hatching rate and inducing malformation and the acute toxicity to zebrafish embryos was greater than that of the Zn(2+) solution. The generation of ROS was significantly increased at 50 and 100mg/L nano-ZnO. DNA damage of zebrafish embryo was evaluated by single-cell gel electrophoresis and was enhanced with increasing nano-ZnO concentration. Moreover, the transcriptional expression of mitochondrial inner membrane genes related to ROS production, such as Bcl-2, in response to oxidative damage, such as Nqo1, and related to antioxidant response element such as Gstp2 were significantly down-regulated in the nano-ZnO treatment groups. However, the nano-ZnO up-regulated the transcriptional expression of Ucp2-related to ROS production. In conclusion, nano ZnO induces developmental toxicity, oxidative stress and DNA damage on zebrafish embryos and the dissolved Zn(2+) only partially contributed to the toxicity of nano-ZnO. The adverse effects of nano-ZnO may be the important mechanisms of its toxicity to zebrafish embryos. PMID- 23643725 TI - The use of antioxidant enzymes in freshwater biofilms: temporal variability vs. toxicological responses. AB - This study aims to investigate the potential of antioxidant enzyme activities (AEA) as biomarkers of oxidative stress in freshwater biofilms. Therefore, biofilms were grown in channels for 38 days and then exposed to different concentrations (0-150 MUg L(-1)) of the herbicide oxyfluorfen for 5 more weeks. Under control conditions, the AEA of biofilms were found to change throughout time with a significant increase in ascorbate peroxidase (APX) activity during the exponential growth and a more important role of catalase (CAT) and glutathione reductase (GR) activities during the slow growth phase. Chronic exposure to oxyfluorfen led to slight variations in AEA, however, the ranges of variability of AEA in controls and exposed communities were similar, highlighting the difficulty of a direct interpretation of AEA values. After 5 weeks of exposure to oxyfluorfen, no clear effects were observed on chl-a concentration or on the composition of other pigments suggesting that algal group composition was not affected. Eukaryotic communities were structured clearly by toxicant concentration and both eukaryotic and bacterial richness were reduced in communities exposed to the highest concentration. In addition, during acute exposure tests performed at the end of the chronic exposure, biofilms chronically exposed to 75 and 150 MUg L(-1) oxyfluorfen showed a higher CAT activity than controls. Chronic exposure to oxyfluorfen provoked then structural changes but also functional changes in the capacity of biofilm CAT activity to respond to a sudden increase in concentration, suggesting a selection of species with higher antioxidant capacity. This study highlighted the difficulty of interpretation of AEA values due to their temporal variation and to the absence of absolute threshold value indicative of oxidative stress induced by contaminants. Nevertheless, the determination of AEA pattern throughout acute exposure test is of high interest to compare oxidative stress levels undergone by different biofilm communities and thus determine their antioxidant capacity. PMID- 23643726 TI - Thermodynamically accurate modeling of the catalytic cycle of photosynthetic oxygen evolution: a mathematical solution to asymmetric Markov chains. AB - Forty-three years ago, Kok and coworkers introduced a phenomenological model describing period-four oscillations in O2 flash yields during photosynthetic water oxidation (WOC), which had been first reported by Joliot and coworkers. The original two-parameter Kok model was subsequently extended in its level of complexity to better simulate diverse data sets, including intact cells and isolated PSII-WOCs, but at the expense of introducing physically unrealistic assumptions necessary to enable numerical solutions. To date, analytical solutions have been found only for symmetric Kok models (inefficiencies are equally probable for all intermediates, called "S-states"). However, it is widely accepted that S-state reaction steps are not identical and some are not reversible (by thermodynamic restraints) thereby causing asymmetric cycles. We have developed a mathematically more rigorous foundation that eliminates unphysical assumptions known to be in conflict with experiments and adopts a new experimental constraint on solutions. This new algorithm termed STEAMM for S state Transition Eigenvalues of Asymmetric Markov Models enables solutions to models having fewer adjustable parameters and uses automated fitting to experimental data sets, yielding higher accuracy and precision than the classic Kok or extended Kok models. This new tool provides a general mathematical framework for analyzing damped oscillations arising from any cycle period using any appropriate Markov model, regardless of symmetry. We illustrate applications of STEAMM that better describe the intrinsic inefficiencies for photon-to-charge conversion within PSII-WOCs that are responsible for damped period-four and period-two oscillations of flash O2 yields across diverse species, while using simpler Markov models free from unrealistic assumptions. PMID- 23643727 TI - Intermediates generated during the reaction of reduced Rhodobacter sphaeroides cytochrome c oxidase with dioxygen. AB - Cytochrome oxidase is one of the functionally most intriguing redox-driven proton pumps. During the last decade our increased understanding of the system has greatly benefited from theoretical calculations and modeling in the framework of three-dimensional structures of cytochrome c oxidases from different species. Because these studies are based on results from experiments, it is important that any ambiguities in the conclusions extracted from these experiments are discussed and elucidated. In a recent study Szundi et al. (Szundi et al. Biochemistry 2012, 51, 9302) investigated the reaction of the reduced Rhodobacter sphaeroides cytochrome c oxidase with O2 and arrived at conclusions different from those derived from earlier investigations. In this short communication we compare these very recent data to those obtained from earlier studies and discuss the origin of the differences. PMID- 23643728 TI - Electrophysiological correlates of tactile remapping. AB - Orienting our gaze or attention to the location of tactile events in the skin feels natural and effortless. However, this process requires combining somatosensory and proprioceptive information in a non-trivial, time consuming, fashion. Here we address the time course of tactile remapping, from somatotopically-based representations, to a spatiotopic reference frame. We compared electrical responses at the scalp evoked by touch at one finger as participants held their arms straight or else, crossed about the body midline. This postural manipulation creates a conflict between frames of reference, which can be used to reveal the consequences of spatial remapping. Behavioural performance was gauged online for crossed and uncrossed postures using bimanual temporal order judgment (TOJ) trials occurring occasionally during the recording session. The first electrophysiological signs of tactile remapping were observed around 70 ms after the tactile event, overlapping in time with the somatosensory component N80. This electrophysiological effect was strongly lateralized to the left scalp and independent of the hand being stimulated. Moreover, participants who manifested a stronger behavioural conflict between frames of reference in the TOJ task displayed a larger electrophysiological effect. Based on these findings, and the known properties of the somatosensory network, we argue that remapping of tactile space depends on fast feedback projections from association areas of the parietal cortex, and encompasses a left-lateralized fronto-parietal network supporting the selection of guided actions. PMID- 23643729 TI - Saliency affects feedforward more than feedback processing in early visual cortex. AB - Early visual cortex activity is influenced by both bottom-up and top-down factors. To investigate the influences of bottom-up (saliency) and top-down (task) factors on different stages of visual processing, we used transcranial magnetic stimulation (TMS) of areas V1/V2 to induce visual suppression at varying temporal intervals. Subjects were asked to detect and discriminate the color or the orientation of briefly-presented small lines that varied on color saliency based on color contrast with the surround. Regardless of task, color saliency modulated the magnitude of TMS-induced visual suppression, especially at earlier temporal processing intervals that reflect the feedforward stage of visual processing in V1/V2. In a second experiment we found that our color saliency effects were also influenced by an inherent advantage of the color red relative to other hues and that color discrimination difficulty did not affect visual suppression. These results support the notion that early visual processing is stimulus driven and that feedforward and feedback processing encode different types of information about visual scenes. They further suggest that certain hues can be prioritized over others within our visual systems by being more robustly represented during early temporal processing intervals. PMID- 23643730 TI - Juglone, isolated from Juglans mandshurica Maxim, induces apoptosis via down regulation of AR expression in human prostate cancer LNCaP cells. AB - Juglone is a natural compound which has been isolated from Juglans mandshurica Maxim. Recent studies have shown that juglone had various pharmacological effects such as anti-viral, anti-bacterial and anti-cancer. However, its anti-cancer activity on human prostate cancer LNCaP cell has not been examined. Thus, the current study was designed to elucidate the molecular mechanism of apoptosis induced by juglone in androgen-sensitive prostate cancer LNCaP cells. MTT assay was performed to examine the anti-proliferative effect of juglone. Occurrence of apoptosis was detected by Hoechst 33342 staining and flow cytometry in LNCaP cells treated with juglone for 24h. The result shown that juglone inhibited the growth of LNCaP cells in a dose-dependent manner. Morphological changes of apoptotic body formation after juglone treatment were observed by Hoechst 33342 staining. This apoptotic induction was associated with loss of mitochondrial membrane potential, and caspase-3, -9 activation. Moreover, we found that juglone significantly inhibited the expression levels of androgen receptor (AR) and prostate-specific antigen (PSA) in a dose-dependent manner, as well as abrogated up-regulation of AR and PSA genes with and/or without dihydrotestosterone (DHT). Take together, our results demonstrated that juglone might induce the apoptosis in LNCaP cell via down-regulation of AR expression. Therefore, our results indicated that juglone may be a potential candidate of drug for androgen sensitive prostate cancer. PMID- 23643732 TI - Nutritional strategies to modulate inflammation and oxidative stress pathways via activation of the master antioxidant switch Nrf2. AB - The nuclear factor E2-related factor 2 (Nrf2) plays an important role in cellular protection against cancer, renal, pulmonary, cardiovascular and neurodegenerative diseases where oxidative stress and inflammation are common conditions. The Nrf2 regulates the expression of detoxifying enzymes by recognizing the human Antioxidant Response Element (ARE) binding site and it can regulate antioxidant and anti-inflammatory cellular responses, playing an important protective role on the development of the diseases. Studies designed to investigate how effective Nrf2 activators or modulators are need to be initiated. Several recent studies have shown that nutritional compounds can modulate the activation of Nrf2-Keap1 system. This review aims to discuss some of the key nutritional compounds that promote the activation of Nrf2, which may have impact on the human health. PMID- 23643731 TI - Induction of mitochondrial biogenesis protects against caspase-dependent and caspase-independent apoptosis in L6 myoblasts. AB - Apoptotic signaling plays an important role in skeletal muscle degradation, atrophy, and dysfunction. Mitochondria are central executers of apoptosis by directly participating in caspase-dependent and caspase-independent cell death signaling. Given the important apoptotic role of mitochondria, altering mitochondrial content could influence apoptosis. Therefore, we examined the direct effect of modest, but physiological increases in mitochondrial biogenesis and content on skeletal muscle apoptosis using a cell culture approach. Treatment of L6 myoblasts with SNAP or AICAR (5h/day for 5days) significantly increased PGC 1, AIF, cytochrome c, and MnSOD protein content as well as MitoTracker staining. Following induction of mitochondrial biogenesis, L6 myoblasts displayed decreased sensitivity to apoptotic cell death as well as reduced caspase-3 and caspase-9 activation following exposure to staurosporine (STS) and C2-ceramide. L6 myoblasts with higher mitochondrial content also exhibited reduced apoptosis and AIF release following exposure to hydrogen peroxide (H2O2). Analysis of several key apoptosis regulatory proteins (ARC, Bax, Bcl-2, XIAP), antioxidant proteins (catalase, MnSOD, CuZnSOD), and reactive oxygen species (ROS) measures (DCF and MitoSOX fluorescence) revealed that these mechanisms were not responsible for the observed cellular protection. However, myoblasts with higher mitochondrial content were less sensitive to Ca(2+)-induced mitochondrial permeability transition pore formation (mPTP) and mitochondrial membrane depolarization. Collectively, these data demonstrate that increased mitochondrial content at physiological levels provides protection against apoptotic cell death by decreasing caspase-dependent and caspase-independent signaling through influencing mitochondrial Ca(2+)-mediated apoptotic events. Therefore, increasing mitochondrial biogenesis/content may represent a potential therapeutic approach in skeletal muscle disorders displaying increased apoptosis. PMID- 23643733 TI - A new perspective on muscarinic receptor antagonism in obstructive airways diseases. AB - Acetylcholine has traditionally only been regarded as a neurotransmitter of the parasympathetic nervous system, causing bronchoconstriction and mucus secretion in asthma and COPD by muscarinic receptor activation on airway smooth muscle and mucus-producing cells. Recent studies in experimental models indicate that muscarinic receptor stimulation in the airways also induces pro-inflammatory, pro proliferative and pro-fibrotic effects, which may involve activation of airway structural and inflammatory cells by neuronal as well as non-neuronal acetylcholine. In addition, mechanical changes caused by muscarinic agonist induced bronchoconstriction may be involved in airway remodeling. Crosstalk between muscarinic receptors and beta2-adrenoceptors on airway smooth muscle causes a reduced bronchodilator response to beta2-agonists, and a similar mechanism could possibly apply to the poor inhibition of inflammatory and remodeling processes by these drugs. Collectively, these findings provide novel perspectives for muscarinic receptor antagonists in asthma and COPD, since these drugs may not only acutely affect cholinergic airways obstruction, but also have important beneficial effects on beta2-agonist responsiveness, airway inflammation and remodeling. The clinical relevance of these findings is presently under investigation and starting to emerge. PMID- 23643734 TI - Early stage epithelial ovarian cancers: a study of morphologic prognostic factors. AB - We intended to reevaluate the morphologic prognostic factors for early-stage ovarian carcinomas. We reviewed 111 patients diagnosed with early-stage ovarian cancer who had undergone primary surgery at Hacettepe Hospital between 1984 and 2001, using diagnostic criteria from the WHO-2003 classification. We applied the Universal grading system suggested by Shimizu/Silverberg and noted FIGO-stage, histotype, tumor size, bilaterality, and endometriosis. These features were compared with each other and survival. The survival analysis was carried out by Kaplan-Meier curves. Of the cases, 52 were reclassified as 'borderline tumor' or 'cystadenoma with borderline foci' and 59 as 'invasive carcinoma'. FIGO-stage and mitotic count were significant for survivals of 59 patients with cancer. Mitotic index was also significant for the probability of metastasis. The patients with stage-II cancer had 5.65 times more risk of recurrence than stage-I cancer. The 5 year overall and disease-free survivals rates were 90.6% and 87.5% for stage-I, 54.7% and 39.3% for stage-II, respectively. Universal grade did not reach statistical significance for survivals but it was related to FIGO-stage significantly. In conclusion, FIGO-stage is the most reliable prognosticator. Although prognostic value of universal grade is not significant, mitotic count may provide important prognostic information for early-stage ovarian carcinomas. PMID- 23643736 TI - Lecithin based lamellar liquid crystals as a physiologically acceptable dermal delivery system for ascorbyl palmitate. AB - Liquid crystalline systems with a lamellar structure have been extensively studied as dermal delivery systems. Ascorbyl palmitate (AP) is one of the most studied and used ascorbic acid derivatives and is employed as an antioxidant to prevent skin aging. The aim of this study was to develop and characterize skin compliant dermal delivery systems with a liquid crystalline structure for AP. First, a pseudoternary phase diagram was constructed using Tween 80/lecithin/isopropyl myristate/water at a Tween 80/lecithin mass ratio of 1/1, and the region of lamellar liquid crystals was identified. Second, selected unloaded and AP-loaded lamellar liquid crystal systems were physicochemically characterized with polarizing optical microscopy, small-angle X-ray scattering, differential scanning calorimetry, and rheology techniques. The interlayer spacing and rheological parameters differ regarding quantitative composition, whereas the microstructure of the lamellar phase was affected by the AP incorporation, resulting either in additional micellar structures (at 25 and 32 degrees C) or being completely destroyed at higher temperature (37 degrees C). After this, the study was oriented towards in vitro cytotoxicity evaluation of lamellar liquid crystal systems on a keratinocyte cell line. The results suggest that the lamellar liquid crystals that were developed could be used as a physiologically acceptable dermal delivery system. PMID- 23643735 TI - Ion-pair strategy for enabling amifostine oral absorption: rat in situ and in vivo experiments. AB - This study shows the effect of ion pair formation on intestinal absorption and oral bioavailability of amifostine. Amifostine is a prodrug used as a highly potent and selective radiotherapy and chemotherapy protectant but due to its low lipophilicity and charge at physiological pH range, its trans epithelial transport and its potential for oral drug delivery is very low. Ion pair formation with negatively charged counter ions was evaluated by in situ rat perfusion studies as a possible strategy to enhance intestinal absorption of amifostine. Succinic acid, phthalic acid and benzoic acid were used as counter ions. Rat intestinal perfusion studies confirmed a statistically significant increase in amifostine permeability in the presence of the counter ions in the order of succinic>phthalic>benzoic. Rat pharmacokinetic studies in vivo were performed to calculate oral absolute bioavailability of amifostine alone and with ion pairs in order to confirm the in situ perfusion results and the applicability of the ion pair approach. Intravenous and intraduodenal administrations were done in rats using a permanent jugular vein cannulation technique and a duodenal cannulation method to avoid drug degradation in stomach. In vivo oral bioavailability studies demonstrated a 20-30-fold increase in amifostine bioavailability with succinic acid depending on counter ion ratio and 10-fold increase with phthalic acid as ion pair. In summary ion pair strategy with succinic acid could enable amifostine oral administration on enteric coated formulations. PMID- 23643737 TI - 1,4-Substituted 4-(1H)-pyridylene-hydrazone-type inhibitors of AChE, BuChE, and amyloid-beta aggregation crossing the blood-brain barrier. AB - Given the fundamentally multifactorial character of Alzheimer's disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid beta fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC50=90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction. PMID- 23643738 TI - Monitoring of imatinib targeted delivery in human leukocytes. AB - The success of imatinib therapy in chronic myeloid leukemia is highly influenced by its active transport into target cells. However, the methodology for analytical evaluation of intracellular drug concentration is rare and usually reliant upon the use of radioactively labeled drugs. More specifically, there is no published method available in the literature for the determination of imatinib concentration in granulocytes. To gain further insight into the intracellular drug uptake a very reliable two-stage sample concentration procedure was devised and coupled with a sensitive ultra-high performance liquid chromatography tandem mass spectrometry. The reliability of this sample preparation and sensitivity of the analysis was confirmed by a successful validation of all necessary method parameters to an impressive lower limit of quantification of 0.5 ng imatinib per 10(6) cells still at the signal to noise ratio of 670. The usefulness of the method is further improved with only 6 mL of blood being necessary for patient analysis. The method has been applied to blood samples of 13 CML patients treated with imatinib and all the measured intracellular drug concentrations were within the validated range. These and further measurements will enable the research of factors which may, besides blood plasma concentration, influence the individual's response to imatinib therapy. Furthermore, individualisation of dosing based on the directly measured targeted drug delivery could be possible. PMID- 23643739 TI - Glycerol and urea can be used to increase skin permeability in reduced hydration conditions. AB - The natural moisturizing factor (NMF) is a group of hygroscopic molecules that is naturally present in skin and protects from severe drying. Glycerol and urea are two examples of NMF components that are also used in skin care applications. In the present study, we investigate the influence of glycerol and urea on the permeability of a model drug (metronidazole, Mz) across excised pig skin membranes at different hydrating conditions. The degree of skin hydration is regulated by the gradient in water activity across the membrane, which in turn depends on the water activity of the formulation in contact with the skin membrane. Here, we determine the water activity of all formulations employed using an isothermal calorimetric method. Thus, the gradient in water activity is controlled by a novel experimental set-up with well-defined boundary conditions on both sides of the skin membrane. The results demonstrate that glycerol and urea can retain high steady state flux of Mz across skin membranes at dehydrating conditions, which otherwise would decrease the permeability due to dehydration. X ray diffraction measurements are performed to give insight into the effects of glycerol and urea on SC molecular organization. The novel steady state flux results can be related to the observation that water, glycerol, and urea all affect the structural features of the SC molecular components in a similar manner. PMID- 23643740 TI - Medicines combinations options and regulatory hurdles. PMID- 23643741 TI - Triptolide induces suppressor of cytokine signaling-3 expression and promotes lamina propria mononuclear cells apoptosis in Crohn's colitis. AB - BACKGROUND: IL-6/STAT3/SOCS3 signaling pathway plays an important role in the pathogenesis of Crohn's disease by induction of the antiapoptotic factors Bcl-2 and Bcl-xl in lamina propria mononuclear cells (LPMCs). We previously reported that triptolide showed therapeutic activity in mouse colitis by mechanisms involving suppression of IL-6 trans-signaling. IL-10 gene-deficient mice with established colitis were used for the experiments with triptolide administration. METHODS: This study further investigates the mechanism by which triptolide attenuates Crohn's colitis. IL-10 gene-deficient mice (IL-10(-)/(-)) of 10 12weeks with established colitis were used for the experiments with chronic triptolide administration. Apoptosis of lamina propria mononuclear cells (LPMCs) were measured by flow cytometry. SOCS, Bcl-2, Bcl-xl and Bax were determined by Western blot. Furthermore, an in vitro study was performed by using cultured intestine from CD patients to observe the direct effects of triptolide. RESULTS: Our data indicated triptolide promoted apoptosis in LPMCs in vivo. Interestingly, triptolide significantly induced the apoptosis of LP-CD4-positive but not LP-CD4 negative cells. Triptolide significantly induced SOCS3 protein and reduced STAT3 target anti-apoptotic genes Bcl-2 and Bcl-xl in LPMCs. The results were confirmed by an in vitro study using colonic explants cultured with triptolide. CONCLUSIONS: Our results indicated that triptolide therapy may restore the homeostatic balance of LP-T cell apoptosis within the gut, and demonstrate a novel mechanism of action of triptolide therapy mediated through regulation IL 6/STAT3/SOCS3 signaling pathway. PMID- 23643742 TI - How does hemoglobin generate such diverse functionality of physiological relevance? AB - The absolute values of the O2-affinities (P50, Klow, and Khigh) of hemoglobin (Hb) are regulated neither by changes in the static T-/R-quaternary and associated tertiary structures nor the ligation states. They are pre-determined and regulated by the extrinsic environmental factors such as pH, buffers, and heterotropic effectors. The effect and role of O2 on Hb are reversibly to drive the structural allosteric equilibrium between the T(deoxy)- and R(oxy)-Hb toward R(oxy)-Hb (the structural allostery). R(oxy)-Hb has a higher O2-affinity (Khigh) relative to that (Klow) of the T(deoxy)-Hb (Khigh>Klow) under any fixed environmental conditions. The apparent O2-affinity of Hb is high, as the globin matrix interferes with the dissociation process of O2, forcing the dissociated O2 geminately to re-bind to the heme Fe. This artificially increases [oxy-Hb] and concomitantly decreases [deoxy-Hb], leading to the apparent increases of the O2 affinity of Hb. The effector-linked high-frequency thermal fluctuations of the globin matrix act as a gating mechanism to modulate such physical, energetic, and kinetic barriers to enhance the dissociation process of O2, resulted in increases in [deoxy-Hb] and concomitant decrease in [oxy-Hb], leading to apparent reductions of the O2-affinity of Hb (the entropic allostery). The heme in Hb is simply a low-affinity O2-trap, the coordination structure of which is not altered by static T-/R-quaternary and associated tertiary structural changes of Hb. Thus, heterotrophic effectors are the signal molecule, which acts as a functional link between these two allosteries and generates the diverse functionality of Hb of physiological relevance. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. PMID- 23643743 TI - Cyclooxygenase activity contributes to the monoaminergic damage caused by serial exposure to stress and methamphetamine. AB - Methamphetamine (Meth) is a widely abused psychostimulant that causes long-term dopamine (DA) and serotonin (5-HT) depletions. Stress and Meth abuse are comorbid events in society and stress exacerbates Meth-induced monoaminergic terminal damage. Stress is also known to produce neuroinflammation. This study examined the role of the neuroinflammatory mediator, cyclooxygenase (COX), in the depletions of monoamines caused by serial exposure to chronic unpredictable stress (CUS) and Meth. CUS produced an increase in COX-2 protein expression and enhanced Meth-induced monoaminergic depletions in the striatum and hippocampus. The enhanced DA and 5-HT depletions in the striatum, but not the hippocampus, were prevented by pretreatment with COX inhibitor, ketoprofen, during stress or during Meth; however, ketoprofen did not attenuate the monoaminergic damage caused by Meth alone. The COX-dependent enhancement by stress of Meth-induced monoaminergic depletions was independent of hyperthermia, as ketoprofen did not attenuate Meth-induced hyperthermia. In addition, the EP1 receptor antagonist, SC 51089, did not attenuate DA or 5-HT depletions caused by stress and Meth. These findings illustrate that COX activity, but not activation of the EP1 receptor, is responsible for the potentiation of Meth-induced damage to striatal monoamine terminals by stress and suggests the use of anti-inflammatory drugs for mitigating the neurotoxic effects associated with the combination of stress and Meth. PMID- 23643744 TI - Repeated potentiation of the metabotropic glutamate receptor 5 and the alpha 7 nicotinic acetylcholine receptor modulates behavioural and GABAergic deficits induced by early postnatal phencyclidine (PCP) treatment. AB - The underlying mechanism of the GABAergic deficits observed in schizophrenia has been proposed to involve NMDA receptor hypofunction. An emerging treatment strategy therefore aims at enhancing GABAergic signalling by increasing the excitatory transmission onto interneurons. We wanted to determine whether behavioural and GABAergic functional deficits induced by the NMDA receptor channel blocker, phencyclidine (PCP), could be reversed by repeated administration of two drugs known to enhance GABAergic transmission: the positive allosteric modulator (PAM) of the metabotropic glutamate receptor 5 (mGluR5), ADX47273, and the partial agonist of the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR), SSR180711. Adolescent rats (4-5 weeks) subjected to PCP treatment during the second postnatal week displayed a consistent deficit in prepulse inhibition (PPI), which was reversed by a one-week treatment with ADX47273 or SSR180711. We examined GABAergic transmission by whole cell patch-clamp recordings of miniature inhibitory postsynaptic currents (mIPSC) in pyramidal neurons in layer II/III of prefrontal cortex (PFC) and by activation of extrasynaptic delta-containing GABAA receptors by THIP. Following PCP treatment, pyramidal neurons displayed a reduced mIPSC frequency and up-regulation of extrasynaptic THIP-induced current. ADX47273 treatment restored this up regulation of THIP-induced current. Reduced receptor function seems to be the underlying cause of the reported changes, since repeated treatment with ADX47273 and SSR180711 decreased the induction of spontaneous inhibitory current caused by acute and direct agonism of mGluR5s and alpha7 nAChRs in slices. These results show that repeated administration of ADX47273 or SSR180711 reverses certain behavioural and functional deficits induced by PCP, likely through down regulation or desensitisation of mGluR5s and alpha7 nAChRs, respectively. PMID- 23643745 TI - Pharmacological and genetic evidence for pre- and postsynaptic D2 receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands. AB - A combined pharmacological and genetic approach was undertaken to investigate the contribution of endogenous dopamine to the motor actions of nociceptin/orphanin FQ (N/OFQ) receptor (NOP receptor) ligands. Motor activity was evaluated by a battery of behavioural tests in mice. The involvement of the various DA receptor subtypes in the motor effects of N/OFQ and NOP receptor antagonists was evaluated pharmacologically, using D1/D5 (SCH23390), D2/D3 (raclopride, amisulpride) and D3 (S33084) receptor antagonists, and by using D2 receptor knockout mice. Low doses of N/OFQ and NOP receptor antagonists promoted movement whereas higher doses inhibited it. Motor facilitation was selectively prevented by raclopride while motor inhibition was prevented by amisulpride. Amisulpride also attenuated the hypolocomotion induced by the D2/D3 receptor agonist pramipexole and dopamine precursor l-3,4-dihydroxyphenylalanine, whereas raclopride (and S33084) worsened it. To dissect out the contribution of pre- and postsynaptic D2 receptors, mice lacking the D2 receptor (D2R(-/-)) or its long isoform (D2L(-/-)) were used. Motor facilitation induced by N/OFQ and NOP receptor antagonists was lost in D2R( /-) and D2L(-/-) mice whereas motor inhibition induced by NOP receptor antagonists (and pramipexole) was lost in D2R(-/-) but preserved in D2L(-/-) mice. N/OFQ-induced hypolocomotion was observed in both genotypes. We demonstrate that motor actions of NOP receptor ligands rely on the modulation of endogenous dopamine. Motor facilitation induced by NOP receptor antagonists as well as low dose N/OFQ is mediated through D2L postsynaptic receptors whereas motor inhibition observed with higher doses of N/OFQ occurs by direct inhibition of mesencephalic DA neurons. Motor inhibition seen with high doses of NOP receptor antagonists appears to be mediated through the D2 presynaptic autoreceptors. These data confirm that endogenous N/OFQ is a powerful modulator of dopamine transmission in vivo and that the effects of NOP receptor antagonists on motor function reflect the blockade of this endogenous N/OFQ tone. PMID- 23643746 TI - Enhanced excitability in the infralimbic cortex produces anxiety-like behaviors. AB - The medial prefrontal cortex (mPFC) has been implicated in modulating anxiety. However, it is unknown whether excitatory or inhibitory neurotransmission in the infralimbic (IL) subregion of the mPFC underlies the pathology of anxiety-related behavior. To address this issue, we infused the GABAA receptor (GABAAR) antagonist bicuculline to temporarily activate the IL cortex. IL cortex activation decreased the time spent in the center area in the open field test, decreased exploration of the open-arms in the elevated plus maze test, and increased the latency to bite food in the novelty-suppressed feeding test. These findings substantiate the GABAergic system's role in anxiety-related behaviors. IL cortex inactivation with the AMPA receptor (AMPAR) antagonist CNQX produced opposite, anxiolytic effects. However, infusion of the NMDA receptor (NMDAR) antagonist AP5 into the IL cortex had no significant effect. Additionally, we did not observe motor activity deficits or appetite deficits following inhibition of GABAergic or glutamatergic neurotransmission. Interestingly, we found parallel and corresponding electrophysiological changes in anxious mice; compared to mice with relatively low anxiety, the relatively high anxiety mice exhibited smaller evoked inhibitory postsynaptic currents (eIPSCs) and larger AMPA-mediated evoked excitatory postsynaptic currents (eEPSCs) in pyramidal neurons in the IL cortex. The changes of eIPSCs and eEPSCs were due to presynaptic mechanisms. Our results suggest that imbalances of neurotransmission in the IL cortex may cause a net increase in excitatory inputs onto pyramidal neurons, which may underlie the pathogenic mechanism of anxiety disorders. PMID- 23643747 TI - Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. AB - The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. We found that administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which preferentially express dopamine D2 receptors (D2Rs). This effect was abolished by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. PMID- 23643749 TI - Dopamine D(3) receptor deletion or blockade attenuates cocaine-induced conditioned place preference in mice. AB - The dopamine (DA) D3 receptor (D3R) has received much attention in medication development for treatment of addiction. However, the functional role of the D3R in drug reward and addiction has been a matter of debate. We recently reported that D3 receptor-knockout (D3(-/-)) mice display increased vulnerability to cocaine self-administration, which we interpret as a compensatory response to attenuated cocaine reward after D3R deletion. Here we report that D3(-/-) mice displayed attenuated cocaine-induced conditioned place response (CPP) compared to wild-type mice. Similarly, blockade of brain D3Rs by YQA-14, a novel DA D3 receptor antagonist, significantly and dose-dependently inhibits acquisition and expression of cocaine-induced CPP in WT mice, but not in D3(-/-) mice. These findings suggest that: 1) D3Rs play an important role in mediating cocaine's rewarding effects; and 2) YQA-14 is a highly potent and selective D3R antagonist in vivo, which deserves further study as a candidate for treatment of cocaine addiction. PMID- 23643748 TI - Prosocial effects of oxytocin in two mouse models of autism spectrum disorders. AB - Clinical evidence suggests that oxytocin treatment improves social deficits and repetitive behavior in autism spectrum disorders (ASDs). However, the neuropeptide has a short plasma half-life and poor ability to penetrate the blood brain barrier. In order to facilitate the development of more bioavailable oxytocinergic compounds as therapeutics to treat core ASD symptoms, small animal models must be validated for preclinical screens. This study examined the preclinical utility of two inbred mouse strains, BALB/cByJ and C58/J, that exhibit phenotypes relevant to core ASD symptoms. Mice from both strains were intraperitoneally administered oxytocin, using either acute or sub-chronic regimens. Acute oxytocin did not increase sociability in BALB/cByJ; however, sub chronic oxytocin had significant prosocial effects in both BALB/cByJ and C58/J. Increased sociability was observed 24 h following the final oxytocin dose in BALB/cByJ, while prosocial effects of oxytocin emerged 1-2 weeks post-treatment in C58/J. Furthermore, acute oxytocin decreased motor stereotypy in C58/J and did not induce hypoactivity or anxiolytic-like effects in an open field test. This study demonstrates that oxytocin administration can attenuate social deficits and repetitive behavior in mouse models of ASD, dependent on dose regimen and genotype. These findings provide validation of the BALB/cByJ and C58/J models as useful platforms for screening novel drugs for intervention in ASDs and for elucidating the mechanisms contributing to the prosocial effects of oxytocin. PMID- 23643751 TI - Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death. AB - We investigated the ability of 19 recently synthesized arylpiperazine compounds to protect human SH-SY5Y neuroblastoma cells from the neurotoxin 6 hydroxydopamine (6-OHDA). The compound with the most potent neuroprotective action was N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide (6b), which reduced 6-OHDA-induced apoptotic death through stabilization of mitochondrial membrane and subsequent prevention of superoxide production, caspase activation and DNA fragmentation. 6-OHDA-triggered autophagic response was also reduced by 6b, which prevented inactivation of the main autophagy repressor mTOR, upregulation of proautophagic beclin-1, conversion of microtubule associated protein 1 light chain 3 (LC3)-I to autophagosome-associated LC3-II, as well as intracytoplasmic acidification induced by 6-OHDA. The inhibition of autophagy using LC3beta gene silencing or pharmacological autophagy blockers 3 methyladenine or bafilomycin A1, mimicked the cytoprotective effect of 6b. While the treatment with 6b had no effect on the phosphorylation of proapoptotic MAP kinases ERK and JNK, it markedly increased the phosphorylation of the prosurvival kinase Akt in 6-OHDA-treated cells. Akt inhibitor DEBC or RNA interference mediated Akt silencing reduced the ability of 6b to block 6-OHDA-triggered apoptotic and autophagic responses, thus confirming their dependency on Akt activation. The cytoprotective effect of 6b was also observed in 6-OHDA-treated neuronal PC12 cells, but not in SH-SY5Y or PC12 cells exposed to 1-methyl-4 phenylpyridinium, indicating that the observed neuroprotection was dependent on the cytotoxic stimulus. Because of the ability to prevent 6-OHDA induced apoptotic/autophagic cell death through activation of Akt, the investigated arylpiperazines could be potential candidates for treatment of neurodegenerative diseases. PMID- 23643750 TI - Transient increase in alcohol self-administration following a period of chronic exposure to corticosterone. AB - Stressful life events and chronic stressors have been associated with escalations in alcohol drinking. Stress exposure leads to the secretion of glucocorticoids (cortisol in the human; corticosterone (CORT) in the rodent). To model a period of heightened elevations in CORT, the present work assessed the effects of chronic exposure to the stress hormone CORT on alcohol self-administration. Male Long Evans rats were trained to self-administer a sweetened alcohol solution (2% sucrose/15% alcohol) resulting in moderate levels of daily alcohol intake (0.5 0.7 g/kg). Following stable baseline operant self-administration, rats received CORT in the drinking water for 7 days. A transient increase in alcohol self administration was observed on the first self-administration session following CORT exposure, and behavior returned to control levels by the second session. Control experiments determined that this increase in alcohol self-administration was specific to alcohol, unrelated to general motor activation, and functionally dissociated from decreased CORT levels at the time of testing. These results indicate that repeated exposure to heightened levels of stress hormone (e.g., as may be experienced during stressful episodes) has the potential to lead to exacerbated alcohol intake in low to moderate drinkers. Given that maladaptive drinking patterns, such as escalated alcohol drinking following stressful episodes, have the potential to put an individual at risk for future drinking disorders, utilization of this model will be important for examination of neuroadaptations that occur as a consequence of CORT exposure in order to better understand escalated drinking following stressful episodes in nondependent individuals. PMID- 23643752 TI - The fatty acid amide hydrolase inhibitor, URB597, promotes retinal ganglion cell neuroprotection in a rat model of optic nerve axotomy. AB - The endocannabinoid, N-arachidonoylethanolamine (AEA), is degraded by the enzyme fatty acid amide hydrolase (FAAH). This study examined whether the FAAH inhibitor, URB597, increases retinal ganglion cell (RGC) survival following optic nerve axotomy in young and aged animals. URB597 alone, or together with either a CB1 or CB2 receptor antagonist, was administered daily for 1 or 2 weeks post axotomy. Histological assessment of retinas indicated that URB597 increased RGC survival in young retina at 1 and 2 weeks post-axotomy. The increase in RGC survival at 2 weeks was accompanied by a reduction in phagocytic microglia. The CB1 antagonist, AM281, but not the CB2 antagonist, AM630, ablated URB597-mediated RGC neuroprotection. CB1 or CB2 antagonism increased phagocytic microglia in URB597 and vehicle-treated animals. In aged animals, URB597 increased RGC survival at 1 week, but not at 2 weeks post-axotomy and had no effect on microglia. Retinal Iba-1 positive microglia were also decreased in URB597-treated axotomized young animals and this decrease was mitigated by CB1 but not CB2 antagonism. As seen with phagocytotic microglia, the CB2 antagonist, AM630, increased Iba-1 positive microglia in the absence of URB597 treatment. Measurement of retinal endocannabinoid levels in URB597-treated animals at 2 weeks post-axotomy revealed a significant increase in AEA levels, accompanied by a decrease in the AEA metabolite, N-arachidonoyl glycine, in young animals but not aged animals. 2-arachidonoylglycerol levels were similar across all experimental groups. These data demonstrate that URB597-mediated retinal neuroprotective effects are mediated primarily through CB1 receptors and that URB597 neuroprotective efficacy declines with age. PMID- 23643753 TI - Opposite motor responses elicited by ethanol in the posterior VTA: the role of acetaldehyde and the non-metabolized fraction of ethanol. AB - Recent electrophysiological evidence suggests that ethanol simultaneously exerts opposite effects on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) through two parallel mechanisms, one promoting and the other reducing the GABA release onto VTA DA neurons. Here we explore the possible behavioural implications of these findings by investigating the role displayed by acetaldehyde (the main metabolite of ethanol) and the non-metabolized fraction of ethanol in motor activity of rats. We analyse the appearance of motor activation or depression after intra-VTA administration of ethanol in rats subjected to different pharmacological pre-treatments designed to preferentially test either the effects of acetaldehyde or the non-metabolized ethanol. Motor activity was evaluated after intra-VTA administration of 35 nmol of ethanol, an apparently ineffective dose that does not modify the motor activity of animals. Pharmacological pre-treatments were used in order to either increase (cyanamide, 10 mg/kg, ip) or decrease (D-penicillamine, 50 mg/kg, ip and sodium azide, 7 mg/kg, ip) acetaldehyde levels in the VTA. Pre-treatments aimed to augment acetaldehyde, increased motor activity of rats. Otherwise, pre-treatments intended to decrease local acetaldehyde levels evoked significant reductions in motor activity that were prevented by the local blockade (bicuculline, 17.5 pmol) of the GABAA receptors. Our findings suggest that the brain-generated acetaldehyde is involved in the stimulant effects of ethanol, whereas the non biotransformed fraction of ethanol, acting through the GABAA receptors, would account for the depressant effects. The present behavioural findings suggest that ethanol dually modulates the activity of DA neurons. PMID- 23643754 TI - Upregulation of the dorsal raphe nucleus-prefrontal cortex serotonin system by chronic treatment with escitalopram in hyposerotonergic Wistar-Kyoto rats. AB - Wistar-Kyoto (WKY) rats are sensitive to chronic stressors and exhibit depression like behavior. Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons projecting to the prefrontal cortex (PFC) comprise the important neurocircuitry underlying the pathophysiology of depression. To evaluate the DRN-PFC 5-HT system in WKY rats, we examined the effects of escitalopram (ESCIT) on the extracellular 5-HT level in comparison with Wistar rats using dual-probe microdialysis. The basal levels of 5-HT in the DRN, but not in the PFC, in WKY rats was reduced as low as 30% of Wistar rats. Responses of 5-HT in the DRN and PFC to ESCIT administered systemically and locally were attenuated in WKY rats. Feedback inhibition of DRN 5-HT release induced by ESCIT into the PFC was also attenuated in WKY rats. Chronic ESCIT induced upregulation of the DRN-PFC 5-HT system in WKY rats, with increases in basal 5-HT in the DRN, responsiveness to ESCIT in the DRN and PFC, and feedback inhibition, whereas downregulation of these effects was induced in Wistar rats. Thus, the WKY rat is an animal model of depression with low activity of the DRN-PFC 5HT system. The finding that chronic ESCIT upregulates the 5-HT system in hyposerotonergic WKY rats may contribute to improved understanding of mechanisms of action of antidepressants, especially in depression with 5-HT deficiency. PMID- 23643755 TI - Differential effects of cholinergic and noradrenergic neuromodulation on spontaneous cortical network dynamics. AB - Cholinergic and noradrenergic neuromodulation play a key role in determining overall behavioral state by shaping the underlying cortical network dynamics. The effects of these systems on synaptic and intrinsic cellular targets are quite diverse and a comprehensive understanding of how these neuromodulators regulate (spontaneous) cortical network activity has remained elusive. Here, we used multielectrode electrophysiology in vitro to investigate the effect of these neuromodulators on spontaneous network dynamics in acute slices of mouse visual cortex. We found that application of Carbachol (CCh) and Norepinephrine (NE) both enhanced the spontaneous network dynamics by increasing (1) the activity levels, (2) the temporal complexity of the network activity, and (3) the spatial complexity by decorrelating the network activity over a wide range of neuromodulator concentrations (1 MUM, 10 MUM, 50 MUM, and 100 MUM). Interestingly, we found that cholinergic neuromodulation was limited to the presence of CCh in the bath whereas the effects of NE, in particular for higher concentrations, induced plasticity that caused outlasting effects most prominently in the deep cortical layers. Together, these results provide a comprehensive network-level understanding of the similarities and differences of cholinergic and noradrenergic modulation of spontaneous network dynamics. PMID- 23643756 TI - Assessment of subjective cognitive and emotional effects of antipsychotic drugs. Effect by defect? AB - Antipsychotic medication represents the first-line treatment for schizophrenia. While it is undisputed that antipsychotics ameliorate positive symptoms, the exact cognitive and emotional pathways through which the effect is exerted has remained unclear. The present study investigated the subjective effects of antipsychotics across various domains of cognition and emotion in both patients with psychotic symptoms and patients with other psychiatric diagnoses. A total of 69 patients with a probable history of psychosis or psychotic symptoms and 26 patients with psychiatric diagnoses other than psychosis participated in a survey conducted over the Internet. Multiple control measures aimed to secure response validity. All patients were currently or had previously been treated with antipsychotic agents. A questionnaire comprising 49 items and measuring possible effects of antipsychotics on cognition and emotion was administered. For 30 out of 49 items a clear response pattern emerged, which was similar for patients with psychotic disorders and patients with other diagnoses. Factor analysis of these items revealed three main effects of antipsychotic medication related to doubt and self-doubt, cognitive and emotional numbing, and social withdrawal. Antipsychotic treatment appears to be connected to a number of negative subjective effects on cognition and emotion. Further studies are warranted to assess how these effects impact on the patients' subjective well-being and quality of life, as well as their association with antipsychotic efficacy on one hand, and adherence rates on the other. Induction of doubt and dampening of emotion may be one reason why antipsychotics work and at the same time offer an explanation why they are experienced as rather unpleasant and are eventually discontinued by many patients. PMID- 23643757 TI - [100 essential drugs. An internal medicine approach]. AB - PURPOSE: Up to 4600 drugs in about 15,000 pharmaceutical forms are available in France which may be a source of misuse with increased occurrence of side effects and costs. While the World Health Organization is encouraging each developed country to work out its own list of essential drugs. The list provided in 2008 by the French Office for the safety of health products has had so far limited impact on practice, so it became obvious to a group of internists to work out a "wise list" of 100 essential medicines covering 95% of the disorders observed in France. METHODS: In June 2011, 10 internists agreed to each provide a list of 100 essential medicines, according to individual experience. In December 2011, a meeting of the participants provided a list as initial consensus and mandated five among them to make proposals for those areas neglected by too many participants or in which needless dispersion of medicines was stated. After internet-facilitated exchanges, an additional list was validated in mild-January 2012. RESULTS: Fifty-four drugs were included in the list of initial consensus (including nine selected by all 10 participants), and 46 in the additional list. So the final "wise list" included 100 drugs. In June 2012, 56 of these drugs were available as generics. This list was compared to those lists set out by five countries in the European Union. CONCLUSION: Generating such a list is feasible. Undoubtedly still non-comprehensive, this list will benefit from the expertise of 14 general practitioners who are currently working out a similar list across France. The final list will be submitted for validation by the French associations of generalist teachers and Internists. PMID- 23643758 TI - Intracerebroventricular administration of ouabain, a Na/K-ATPase inhibitor, activates mTOR signal pathways and protein translation in the rat frontal cortex. AB - Intracerebroventricular (ICV) injection of ouabain, a specific Na/K-ATPase inhibitor, induces behavioral changes in rats in a putative animal model of mania. The binding of ouabain to Na/K-ATPase affects signaling molecules in vitro, including ERK1/2 and Akt, which promote protein translation. We have also reported that ERK1/2 and Akt in the brain are involved in the ouabain-induced hyperactivity of rats. In this study, rats were given an ICV injection of ouabain, and then their frontal cortices were examined to determine the effects of ouabain on the mTOR/p70S6K/S6 signaling pathway and protein translation, which are important in modifications of neural circuits and behavior. Rats showed ouabain-induced hyperactivity up to 8h following injection, and increased phosphorylation levels of mTOR, p70S6K, S6, eIF4B, and 4E-BP at 1, 2, 4, and 8h following ouabain injection. Immunohistochemical analyses revealed that increased p-S6 immunoreactivity in the cytoplasm of neurons by ouabain was evident in the prefrontal, cingulate, and orbital cortex. These findings suggested increased translation initiation in response to ouabain. The rate of protein synthesis was measured as the amount of [(3)H]-leucine incorporation in the cell-free extracts of frontal cortical tissues, and showed a significant increase at 8h after ouabain injection. These results suggest that ICV injection of ouabain induced activation of the protein translation initiation pathway regulated by ERK1/2 and Akt, and prolonged hyperactivity in rats. In conclusion, protein translation pathway could play an important role in ouabain-induced hyperactivity in a rodent model of mania. PMID- 23643759 TI - Huntingtin disrupts lipid bilayers in a polyQ-length dependent manner. AB - Huntington's Disease (HD) is a neurodegenerative disorder that is defined by the accumulation of nanoscale aggregates comprised of the huntingtin (htt) protein. Aggregation is directly caused by an expanded polyglutamine (polyQ) domain in htt, leading to a diverse population of aggregate species, such as oligomers, fibrils, and annular aggregates. Furthermore, the length of this polyQ domain is directly related to onset and severity of disease. The first 17 N-terminal amino acids of htt have been shown to further modulate aggregation. Additionally, these 17 amino acids appear to have lipid binding properties as htt interacts with a variety of membrane-containing structures present in cells, such as organelles, and interactions with these membrane surfaces may further modulate htt aggregation. To investigate the interaction between htt exon1 and lipid bilayers, in situ atomic force microscopy (AFM) was used to directly monitor the aggregation of htt exon1 constructs with varying Q-lengths (35Q, 46Q, 51Q, and myc-53Q) on supported lipid membranes comprised of total brain lipid extract. The exon1 fragments accumulated on the lipid membranes, causing disruption of the membrane, in a polyQ dependent manner. Furthermore, the addition of an N-terminal myc-tag to the htt exon1 fragments impeded the interaction of htt with the bilayer. PMID- 23643760 TI - Differences on morphological and phonological processing between typically developing children and children with Down syndrome. AB - It is widely acknowledged that people with Down syndrome (Ds) have less highly developed morphosyntactic abilities than typically developing (TD) children. However, little is known about the morphological processing of this population. In this paper we carry out two experiments in which the morphological Base Frequency (BF) effect is explored in both groups. The aim of the experiments is to carry out an in-depth exploration of morphological processing in children with Ds and TD children. In the first experiment children performed a definition task; in the second children had to provide a plural form for singular words. The results show a significant BF effect in only the first experiment. In the second experiment this morphological variable does not reach significance, but the variable we called Ending phoneme (a phonological variable that refers to the last phoneme of the bases prior to the addition of plural morphemes) does. The results also show that children with Ds score significantly below the two control groups in both experiments, with no significant differences between control groups. We go on to discuss morphological processing in children with and without Ds, the role of the two tasks carried out (paying special attention to the role played by working memory), and the possible relationship between our results and morphosyntactic deficits described in the literature. PMID- 23643761 TI - Reliability and validity of the Trunk Impairment Scale in children and adolescents with cerebral palsy. AB - Standardized clinical tools are useful for treatment planning and evaluation, however clinical tools to assess quality in trunk movements in children with cerebral palsy (CP) are sparse. We have recently reported good intra- and inter observer reliability of the Trunk Impairment Scale (TIS) in 5-12 year old children with CP. The aim of this study was to assess reliability in adolescents (13-19 years old), and to assess the construct validity in children and adolescents in the whole age spectrum from 5 to 19 years. Video recordings of 17 children with CP with Gross Motor Function Classification (GMFCS) level I-IV were analyzed by three observers on two occasions. For construct validity the TIS was compared with Gross Motor Function Measure (GMFM), in 37 children with GMFCS levels I-IV. Intraclass correlation coefficients varied between 0.82 and 0.98, and 86% of the kappa values varied between 0.61 and 1.00, suggesting high inter- and intra-observer reliability. The smallest detectable difference (SDD) of the TIS (scale range 0-23) varied between 2.55 and 3.82 for intra- and 4.07-8.23 for inter-observer observations. The high inter-observer SDD was partly due to consistently lower TIS scores by one observer. The correlation between the TIS total score and the dimension scores of the GMFM was high (Spearman's rho: 0.80 0.87), while decreasing GMFCS levels were associated with increasing total TIS score; both findings indicating good construct validity of the TIS. This study suggests that the TIS is a reliable and valid measure of trunk control for both children and adolescents with cerebral palsy. PMID- 23643762 TI - Assessing independency in daily activities in very preterm children at preschool age. AB - This study investigates whether very low birth weight (VLBW) preschoolers experience disability in daily activities and what the risk factors for disability in daily activities are. The Dutch Pediatric Evaluation of Disability Inventory (PEDI-NL) was used to detect disability in daily activities in 143 VLBW children without cerebral palsy (CP) at 44 months of corrected age (CA). Data from the psychomotor-developmental index (PDI) and the mental developmental index (MDI) of the Bayley Scales of Infant Development II (BSID II) at 24 months CA, and data relating to perinatal and socio-economic status were available. Disability in daily activities was found in 27 (19%) VLBW children without CP. High frequencies of disability were found in 19 (13%) children on the mobility domain and in 12 (8%) children on the social functioning domain. The multiple logistic regression analyses showed that low BSID II outcomes (<2 SD) were risk factors for disability in the mobility domain, but not for disability in the social functioning domain. The predictive value of the BSID II outcomes is moderate, 46% of the VLBW children with a low PDI and 44% with a low MDI developed a disability in the mobility domain. This study showed a higher frequency of disability in daily activities in VLBW preschoolers compared to term born peers. Therefore, it is suggested to assess VLBW children's performance of daily activities before they start school. PMID- 23643763 TI - Catechol-O-methyltransferase Val158Met polymorphism and hyperactivity symptoms in Egyptian children with autism spectrum disorder. AB - Catechol-O-methyltransferase (COMT) plays an important role in the catabolism of brain dopamine and norepinephrine, which have been implicated in the pathogenesis of Autism spectrum disorder (ASD) as well as in other neuropsychatric disorders. We aimed to investigate the association of COMT Val158Met gene polymorphism with ASD and to examine the influence of such genotypes on hyperactivity symptoms in ASD patients. Eighty ASD patients (mean age 9 +/- 1.9 years) and 100 control children (mean age 8.9 +/- 1.9 years) were examined. COMT Val58Met polymorphism was genotyped using Tetra-primer ARMS-PCR method. The clinical diagnosis of ASD and ADHD were confirmed according to the DSM-IV criteria for research. We found no significant difference in genotypes or alleles' frequencies of COMT Val158Met polymorphism between ASD patients and control group. There was a significant association between COMT (Val/Val) genotype and both increasing CARS (p=0.001) and hyperactivity scores (p=0.006). Regarding Conner's Score, the DSM-IV hyperactive impulsive were significantly higher in Val/Val genotype than both Met/Val and Met/Met genotypes (p=0.03). Our data suggested an association between COMT Val58Met polymorphism and hyperactivity symptoms in Egyptian children with ASD. PMID- 23643765 TI - Cerebellar vermis abnormalities and cognitive functions in individuals with Williams syndrome. AB - In Williams syndrome (WS) cerebellar measures were only indirectly related to behavioral outcomes. T1-weighted magnetic resonance images and neuropsychological data were acquired to investigate whether cerebellar vermis differences were present in 12 WS individuals compared with 13 chronological age-matched controls and whether WS cerebellar vermis measures were related to cognitive scores. In WS participants, we observed a significant increase in the volume of the posterior superior cerebellar vermis (lobules VI-VII) and an atypical ratio between width and height of the cerebellar vermis. Furthermore, we found an inverse correlation between cerebellar posterior vermis volume and scores on implicit learning, phonological fluency and the verbal short-term memory tasks. The present study supported a role for the posterior cerebellar vermis in higher cognitive processes and indicated that the cerebellar vermis abnormalities (enlargement) in WS individuals have an effect in worsening the cognitive performance in specific domains. PMID- 23643764 TI - A comparison of the oxygen cost and physiological responses to running in children with and without Developmental Coordination Disorder. AB - The aim of this study was to compare the oxygen cost of running in boys with and without Developmental Coordination Disorder (DCD). Fourteen boys with DCD (9.1 +/ 1.4 yr) and 16 typically developing (TD) controls (9.4 +/- 1.3 yr) were tested on two separate occasions at least a week apart. On the first visit, motor proficiency, body composition and maximal aerobic capacity were established. On the second visit, oxygen consumption was determined via indirect calorimetry while participants ran at three submaximal speeds (7.2 km/h, 8.0 km/h and 8.8 km/h) on a motorised treadmill for 4 min each. Additional physiological responses such as blood lactate, respiratory exchange ratio (RER), heart rate, salivary alpha amylase and pain threshold were monitored at baseline and after each submaximal effort. Although there were no differences in the oxygen cost of running at all three speeds, the boys with DCD had higher blood lactate concentration (7.2 km/h, p=0.05; 8.0 km/h p=0.019), heart rate (p <= 0.001), RER (8.0 km/h, p=0.019; 8.8 km/h, p=0.001), salivary alpha amylase (8.0 km/h, p=0.023; 8.8 km/h, p=0.020) and a lower pain threshold (p<0.01). The higher overall metabolic cost of running in boys with DCD as indicated by the higher RER, heart rate and blood lactate concentrations, together with the higher levels of sympathoadrenal medullary activity and sensitivity to pain, may be deterring factors for participation in physical activity in this population. PMID- 23643766 TI - Outpatient rehabilitation utilization and medical expenses in children aged 0-7 years with ADHD: analyses of population-based national health insurance data. AB - Medical costs of attention-deficit/hyperactivity disorder (ADHD) are substantial and have a large impact on the public health system. The present study presents information regarding outpatient rehabilitation care usage and medical expenditure for children with ADHD. A cross-sectional study was conducted by analyzing data from the Taiwan National Health Insurance claims database for the year 2009. A total of 6643 children aged 0-7 years with ADHD (ICD-9-CM codes 314.0x: attention deficit disorder, 314.00: attention deficit disorder without hyperactivity, or 314.01: attention-deficit disorder with hyperactivity) who had used outpatient rehabilitation care were included in the analyses. Results showed that the mean annual rehabilitation care was 22.24 visits. Among the care users, 76% of patients were male, and 24% were female. More than half of the children with ADHD had comorbid mental illnesses as well. A logistic regression analysis of outpatient rehabilitation expenditure (low vs. high) showed that of those children with ADHD, those aged 0-2 years tended to incur more medical costs than those aged 6-7 years. Other factors such as frequency of rehabilitation visits, hospital medical setting and ownership, location of medical care setting, and types of rehabilitation were also significantly correlated with medical expenditure. The results from this study suggest that health care systems should ensure accurate diagnosis and measurement of impairment to maintain appropriate and successful management of rehabilitation needs for children with ADHD. PMID- 23643767 TI - Effects of conducting peer behavioral observations on the observer's correct use of discrete trial teaching procedures. AB - A procedure consisting of peer observation and evaluation termed behavioral observations was used to improve educational staff's correct use of discrete trial teaching procedures (DTT). All participants had been previously trained and proficient in using DTT procedures; however, during baseline, showed a low level of correct demonstration of DTT procedures (mean scores: 38.3%, 43.3%, and 35.0%). Participants were then taught use a checklist to observe and score a peer's performance during DTT sessions in a classroom setting. After conducting behavioral observations, staff increased their correct usage of DTT procedures to 85.1%, 88.3%, and 81.1% respectively. These data indicate that conducting behavioral observations can lead to large and rapid improvements in educational staff's correct use of DTT procedures with a large effect size (d=4.19). PMID- 23643769 TI - Short term memory and working memory in blind versus sighted children. AB - There is evidence that blind people may strengthen their memory skills to compensate for absence of vision. However, which aspects of memory are involved is open to debate and a developmental perspective is generally lacking. In the present study, we compared the short term memory (STM) and working memory (WM) of 10-year-old blind children and sighted children. STM was measured using digit span forward, name learning, and word span tasks; WM was measured using listening span and digit span backward tasks. The blind children outperformed their sighted peers on both STM and WM tasks. The enhanced capacity of the blind children on digit span and other STM tasks confirms the results of earlier research; the significantly better performance of the blind children relative to their sighted peers on verbal WM tasks is a new interesting finding. Task characteristics, including the verbal nature of the WM tasks and strategies used to perform these tasks, are discussed. PMID- 23643768 TI - Goal perspectives and sport participation motivation of Special Olympians and typically developing athletes. AB - Based on social-learning and self-determination motivational theories, the purpose of this study was to determine the sources of motivation in youth and young adults with intellectual disability (ID) who participate in Special Olympics (SO) competitions and those of typically developed (TD) age- and activity-matched athletes. A convenience sample of 63 SO (25 females and 38 males) and 59 TD (16 females and 43 males) athletes was retrieved through communication with local club coaches. Three sub-groups of SO athletes were identified based on disability, including non specified intellectual disability (NSID=39), Down syndrome (DS=17), and Autism (Aut=7). Mean SO and TD athlete ages were 20.35 (SD=7) and 18.8 (SD=8), respectively. For analysis purposes four age groups were created (<15, 15-17, 18-20, >20 years). Participants completed the 13 item, two-factor Task and Ego Orientation in Sport Questionnaire (TEOSQ) and a 16 item four-factor abridged version of the Sport Motivation Scale (SMS). SO and TD athletes were active in swimming (54 and 48, respectively) and basketball (9 and 11, respectively). Groups with and without ID were compared by means of t-tests in the dichotomized variables gender and activity, as well as by 1-way ANOVA with Tukey HSD post hoc comparisons across disability and age groups. Gender distribution was the same in both groups. Participants with DS and NSID scored significantly higher than TD athletes in most motivational scales. Participants with ID increased their external motivation with increasing age, while a reversed pattern was observed in TD. In summary, significant differences between motivational patterns of SO athletes with ID and TD athletes can be observed. These differences should be considered when developing training and competition programs. PMID- 23643770 TI - When the body is time: spatial and temporal deixis in children with visual impairments and sighted children. AB - While there is mounting evidence explaining how concrete concepts are processed, the evidence demonstrating how abstract concepts are processed is rather scant. Most research illustrating how concrete and abstract concepts are processed has been obtained from adult populations. Consequently, not much is known about how these concepts are processed by children, especially those with sensorimotor impairments. This paper reports a study in which groups of children who were either visual-motor impaired (VMG), blind (BG), or sighted (CG) were requested to perform deictic gestures for temporal and spatial concepts. The results showed that: (i) spatial pointing was performed faster than temporal pointing across all groups of children; (ii) such difference in pointing times occurred also within groups; and (iii) the slowest pointing times were those of the blind children followed by the VMG and the CG children, respectively. Additionally, while CG children correctly performed the pointing tasks, VMG and, particularly, BG children relied on a form of deixis known as autotopological (or personal) deixis. The results thus suggest that deprivation or lack of sensorimotor experience with the environment affects the processing of abstract concepts and that a compensatory mechanism may be to rely on the body as a reference frame. PMID- 23643771 TI - Effects of treadmill inclination on the gait of children with Down syndrome. AB - The goal of this study was to analyze the effects of upward treadmill inclination on the gait of children with Down syndrome (DS). Sixteen children with a mean age 8.43 +/- 2.25 years, classified at level I of the Gross Motor Function Classification System (GMFCS) and able to walk without personal assistance and/or assistive devices/orthosis were evaluated. Spatial-temporal variables were observed as well as the angular variation of hip, knee and ankle in the sagittal plane, while children walked on the treadmill carried out on 0% and 10% upward inclination. The results showed that children with DS presented changes in spatio temporal variables (reduced cadence and increased cycle time and swing time) and in angular variables (increased hip, knee and ankle angles at initial contact; increased maximum hip flexion and maximum stance dorsiflexion; and reduced plantarflexion at pre-swing). Treadmill inclination seemed to act positively on the angular and spatio-temporal characteristics of gait in children with DS, demonstrating a possible benefit from the use of this type of surface in the gait rehabilitation of this population. PMID- 23643773 TI - The SWedish Eating Assessment for Autism spectrum disorders (SWEAA)-Validation of a self-report questionnaire targeting eating disturbances within the autism spectrum. AB - The aim was to design and validate a questionnaire pertaining to eating problems in individuals with normal intelligence, within the autism spectrum. The questionnaire was based on literature search and clinical experience. The validation focused on psychometric properties of reliability and validity using a clinical group of individuals with autism spectrum disorders (ASD) (n=57) and a matched, healthy comparison group (n=31). The instrument showed high levels of reliability, convergent and discriminant validity and scaling properties. Logistic regression analyses discerned the single item Simultaneous capacity and the subscale Social situation at mealtime as the best predictors of ASD. In conclusion, the questionnaire is valid and reliable to detect disturbed eating behaviours in individuals with ASD and normal intelligence. PMID- 23643772 TI - Walker devices and microswitch technology to enhance assisted indoor ambulation by persons with multiple disabilities: three single-case studies. AB - These three single-case studies assessed the use of walker devices and microswitch technology for promoting ambulation behavior among persons with multiple disabilities. The walker devices were equipped with support and weight lifting features. The microswitch technology ensured that brief stimulation followed the participants' ambulation responses. The participants were two children (i.e., Study I and Study II) and one man (i.e., Study III) with poor ambulation performance. The ambulation efforts of the child in Study I involved regular steps, while those of the child in Study II involved pushing responses (i.e., he pushed himself forward with both feet while sitting on the walker's saddle). The man involved in Study III combined his poor ambulation performance with problem behavior, such as shouting or slapping his face. The results were positive for all three participants. The first two participants had a large increase in the number of steps/pushes performed during the ambulation events provided and in the percentages of those events that they completed independently. The third participant improved his ambulation performance as well as his general behavior (i.e., had a decline in problem behavior and an increase in indices of happiness). The wide-ranging implications of the results are discussed. PMID- 23643775 TI - A secondary craniosynostosis associated with juvenile hyperthyroidism. PMID- 23643774 TI - Relationship between brain structure on magnetic resonance imaging and motor outcomes in children with cerebral palsy: a systematic review. AB - Magnetic resonance imaging (MRI) is recommended in all children with cerebral palsy (CP) where the aetiology has not been established, and the major presenting problem in CP is reduced motor capacity. A systematic review of the literature was performed to investigate the relationship between brain structure on MRI and motor outcomes in children with CP. A total of 37 studies met inclusion criteria, and were analysed in terms of (a) population characteristics, (b) MRI data, (c) motor outcome data, and (d) the relationship between MRI data and motor outcomes. All studies used a qualitative system to classify brain lesions; however, few reported information about the location and extent of lesions. Valid and reliable classifications of motor abilities were not always used, and three studies did not link motor findings to MRI features. There was, however, a relationship between the type of brain lesion on MRI and two specific motor outcomes, namely gross motor functional classification (using GMFCS) and motor type. This relationship could aid in the prediction and optimisation of early interventions for children with CP. There is also need for a quantitative MRI classification measure which includes detailed information about the location and severity of lesions. PMID- 23643776 TI - The humeral origin of the brachioradialis muscle: an unusual site of high radial nerve compression. AB - Radial nerve compression is seldom encountered in the upper arm, and most commonly described compression syndromes have their anatomical cause in the forearm. The teres major, the triceps muscle, the intermuscular septum region and the space between the brachialis and brachioradialis muscles have all been identified as radial nerve compression sites above the elbow. We describe the case of a 38-year-old male patient who presented with dorso-lateral forearm pain and paraesthesias without neurological deficit. Surgical exploration revealed radial nerve compression at the humeral origin of the brachioradialis muscle. Liberation of the nerve at this site was successful at relieving the symptoms. To our knowledge, this compression site has not been described in the literature. PMID- 23643777 TI - Zygomatic dysmorphology in unicoronal synostosis. AB - INTRODUCTION: Unicoronal synostosis (UCS) imparts a fronto-facial deformity, the hallmark feature being orbital and forehead dysmorphology. The facial and malar regions also consistently display asymmetry, however, zygomatic structural characteristics have not been investigated. The purpose of this study is to objectively analyze the zygomata of UCS patients compared to normal controls. METHODS: Three dimensional-computed tomographic images and demographic information were obtained from normal control and UCS patients. Volumetric and morphometric analyses were performed and results statistically analyzed. P values<0.05 were considered statistically significant. RESULTS: A total of 68 zygomatic sides were analyzed: twelve control (6 females; mean age: 6.6 months) and 22 UCS patients (10 females; mean age: 5.1 months). The affected side was right in 55% (n=12) and left in 45% (n=10) of UCS patients. The affected zygomata were volumetrically deficient compared to unaffected and normal control zygomata. Unaffected zygomata demonstrated diminished volume compared to norms. Morphometrically, affected zygomata differed, while both the unaffected and control zygomata were similar. Age stratification revealed marked differences in zygomatic volume and morphometry between the affected and unaffected zygomata was greatest at an early age interval. CONCLUSION: The affected UCS zygomata are on average smaller compared to unaffected and normal control zygomata. Moreover, distinct morphometric differences exist on the affected zygomata versus both unaffected and control zygomata. These differences are not addressed by commonly employed treatment approaches. Further studies evaluating the growth effect of UCS zygomatic morphology should be entertained. PMID- 23643778 TI - Lymphoedema caused by idiopathic lymphatic thrombus. AB - Primary lymphoedema includes some diseases whose genetic anomaly is detected and others whose pathology is unknown. In this article, we report a lymphatic thrombus found in a limb with lymphoedema during lymphatico-venous anastomosis (LVA). A 32-year-old man was aware of oedema in his left calcar pedis 3 years previously, which appeared without any trigger. Indocyanine green lymphography indicated lymphatic stasis in the left calf and thigh region, and we performed LVA for the patient. During the operation, we found yellow vessels, which were thought to be lymphatic vessels filled with a yellow solid substance, just beneath the superficial fascia at the left ankle. Pathological examination of the thrombi revealed hyaline material mixed with cell components. The cells were categorised as lymphatic endothelial cells, as they were positive for podoplanin. There was no evidence of malignancy. Causes of idiopathic lymphatic thrombus such as this may be one of the causes of so-called primary lymphoedema, and evaluation of such cases may be the first step towards elucidating the mechanisms involved in the development of primary lymphoedema. PMID- 23643779 TI - Neo-vascularisation of musculocutaneous and muscle flaps after division of the major vascular supply: an experimental study. AB - BACKGROUND AND AIM: Experimental studies have shown that musculocutaneous flaps are not dependent on a major pedicle for survival after 7-8 days, as revascularisation occurs from surrounding well-nourished tissue. However, muscle component loss in myocutaneous flaps after pedicle division has been reported. No study that examines the nature of the vascular ingrowth from underlying beds by blocking the peripheral cutaneous beds has been conducted in musculocutaneous and skin-covered muscle flaps. This study was designed to investigate the origin of the dominant source of neo-vascularisation after interruption of the major vascular supply in island musculocutaneous and island skin-covered muscle flaps by blocking neo-vascularisation from wound edges and the recipient bed. METHOD: Twenty-eight rats were divided into four experimental groups. In group I, a cutaneous maximus musculocutaneous island flap (MCIF) was raised, and the wound edges of the flap were blocked with a silastic sheet. In group II, an MCIF was raised, and the recipient bed was blocked with silastic. In group III, an island cutaneous maximus muscle flap (IMF) was raised as an island flap covered by a full-thickness skin graft (FTSG), and the wound margins were blocked with silastic. In group IV, an IMF was raised as an island flap covered by an FTSG, and the recipient bed was blocked with a silastic sheet. On the seventh postoperative day, vessel ligation was performed in each animal. Microangiographic studies and histopathological evaluations were performed 14 days after the first operation. RESULTS: In microangiographic studies, neo vascularisation was more prominent in groups II and IV (the groups in which the recipient beds were blocked) than in groups I and III (the groups in which the wound edges were blocked). Upon histopathological examination, the number of vessels was significantly lower in group I and group III than in group II and group IV (p<0.001). CONCLUSIONS: Our findings revealed that neo-vascularisation from either the recipient bed or the wound edges was sufficient to ensure full flap survival in musculocutaneous flaps, and skin-grafted muscle flaps do not need major axial vessels 7 days after flap elevation in rats if the recipient bed or wound edges are well-vascularised. The results also indicated that revascularisation mainly comes from the peripheral wound edges and is independent of flap type. PMID- 23643780 TI - Predictive value of electrocardiogram in diagnosing acute coronary artery lesions among patients with out-of-hospital-cardiac-arrest. AB - AIMS: Acute coronary lesions are known to be the most common trigger of out of hospital cardiac arrest (OHCA). Aim of the present study was to assess the predictive value of ST-segment changes in diagnosing the presence of acute coronary lesions among OHCA patients METHODS: Findings of coronary angiography (CA) performed in patients resuscitated from OCHA were retrospectively reviewed and related to ST-segment changes on post-ROSC electrocardiogram (ECG) RESULTS: Ninety-one patients underwent CA after OHCA; 44% of patients had ST-segment elevation and 56% of patients had other ECG patterns on post-ROSC ECG. Significant coronary artery disease (CAD) was found in 86% of patients; CAD was observed in 98% of patients with ST-segment elevation and in 77% of patients with other ECG patterns on post-ROSC ECG (p=0.004). Acute or presumed recent coronary artery lesions were diagnosed in 56% of patients, respectively in 85% of patients with ST-segment elevation and in 33% of patients with other ECG patterns (p<0.001). ST-segment analysis on post-ROSC ECG has a good positive predictive value but a low negative predictive value in diagnosing the presence of acute or presumed recent coronary artery lesions (85% and 67%, respectively) CONCLUSIONS: Electrocardiographic findings after OHCA should not be considered as strict selection criteria for performing emergent CA in patients resuscitated from OHCA without obvious extra-cardiac cause; even in the absence of ST-segment elevation on post-ROSC ECG, acute culprit coronary lesions may be present and considered the trigger of cardiac arrest. PMID- 23643781 TI - Bleeding events in refractory cardiac arrest treated with extracorporeal membrane oxygenation--a single centre experience. PMID- 23643782 TI - Arterial carbon dioxide tension after cardiac arrest: too little, too much, or just right? PMID- 23643783 TI - Reply to letter: association of serum lactate and survival outcomes after cardiac arrest. PMID- 23643784 TI - Controlling the physical form of mannitol in freeze-dried systems. AB - A potential drawback with the use of mannitol as a bulking agent is its existence as mannitol hemihydrate (MHH; C6H14O6.0.5H2O) in the lyophile. Once formed during freeze-drying, MHH dehydration may require secondary drying under aggressive conditions which can be detrimental to the stability of thermolabile components. If MHH is retained in the lyophile, the water released by MHH dehydration during storage has the potential to cause product instability. We systematically identified the conditions under which anhydrous mannitol and MHH crystallized in frozen systems with the goal of preventing MHH formation during freeze-drying. When mannitol solutions were cooled, the temperature of solute crystallization was the determinant of the physical form of mannitol. Based on low temperature X ray diffractometry (using both laboratory and synchrotron sources), MHH formation was observed when solute crystallization occurred at temperatures <= -20 degrees C, while anhydrous mannitol crystallized at temperatures <= -10 degrees C. The transition temperature (anhydrate - MHH) appears to be ~-15 degrees C. The use of a freeze-dryer with controlled ice nucleation technology enabled anhydrous mannitol crystallization at ~-5 degrees C. Thus, ice crystallization followed by annealing at temperatures <= -10 degrees C can be an effective strategy to prevent MHH formation. PMID- 23643785 TI - Molecular aspects of androgenic signaling and possible targets for therapeutic intervention in prostate cancer. AB - The androgen axis is of crucial importance in the development of novel therapeutic approaches for non-organ-confined prostate cancer. Recent studies revealed that tumor cells have the ability to synthesize androgenic hormones in an intracrine manner. This recognition opened the way for the development of a novel drug, abiraterone acetate, which shows benefits in clinical trials. A novel anti-androgen enzalutamide that inhibits androgen receptor (AR) nuclear translocation has also been developed and tested in the clinic. AR coactivators exert specific cellular regulatory functions, however it is difficult to improve the treatment because of a large number of coregulators overexpressed in prostate cancer. AR itself is a target of several miRNAs which may cause its increased degradation, inhibition of proliferation, and increased apoptosis. Truncated AR occur in prostate cancer as a consequence of alternative splicing. They exhibit ligand-independent transcriptional activity. Although there has been an improvement of endocrine therapy in prostate cancer, increased intracrine ligand synthesis and appearance of variant receptors may facilitate the development of resistance. PMID- 23643786 TI - Localization of the regulatory particle subunit Sem1 in the 26S proteasome. AB - The ubiquitin-proteasome system is responsible for regulated protein degradation in the cell with the 26S proteasome acting as its executive arm. The molecular architecture of this 2.5 MDa complex has been established recently, with the notable exception of the small acidic subunit Sem1. Here, we localize the C terminal helix of Sem1 binding to the PCI domain of the subunit Rpn7 using cryo electron microscopy single particle reconstruction of proteasomes purified from yeast cells with sem1 deletion. The approximate position of the N-terminal region of Sem1 bridging the cleft between Rpn7 and Rpn3 was inferred based on site specific cross-linking data of the 26S proteasome. Our structural studies indicate that Sem1 can assume different conformations in different contexts, which supports the idea that Sem1 functions as a molecular glue stabilizing the Rpn3/Rpn7 heterodimer. PMID- 23643787 TI - Crystal structure of Mycobacterium tuberculosis Rv2606c: a pyridoxal biosynthesis lyase. AB - Tuberculosis is a lethal infectious disease caused by Mycobacterium tuberculosis. We determined the crystal structure of Rv2606c, a potential pyridoxal biosynthesis lyase (PdxS), from M. tuberculosis H37Rv at 1.8 A resolution. The overall structure of the protein, composed of a (beta/alpha)8-barrel and two small 310-helices, was quite similar to those of other PdxS proteins. A glycerol molecule was observed to be bound at the active site of the Rv2606c structure through interactions with the conserved residues of Asp29 and Lys86, providing information regarding the potential active site and the substrate-binding environment of the protein. The interface for Rv2606c dodecamerization, which is primarily mediated by salt bridges and hydrophobic interactions, was quite different from those of other PdxS proteins. Furthermore, we observed that the Rv2606c and Rv2604c form a stable complex, suggesting that these proteins might function as PdxS and PdxT in M. tuberculosis. PMID- 23643788 TI - Mixtures of receiver operating characteristic curves. AB - RATIONALE AND OBJECTIVES: Receiver operating characteristic (ROC) curves are ubiquitous in the analysis of imaging metrics as markers of both diagnosis and prognosis. While empirical estimation of ROC curves remains the most popular method, there are several reasons to consider smooth estimates based on a parametric model. MATERIALS AND METHODS: A mixture model is considered for modeling the distribution of the marker in the diseased population motivated by the biological observation that there is more heterogeneity in the diseased population than there is in the normal one. It is shown that this model results in an analytically tractable ROC curve which is itself a mixture of ROC curves. RESULTS: The use of creatine kinase-BB isoenzyme in diagnosis of severe head trauma is used as an example. ROC curves are fit using the direct binormal method, ROCKIT software, and the Box-Cox transformation as well as the proposed mixture model. The mixture model generates an ROC curve that is much closer to the empirical one than the other methods considered. CONCLUSIONS: Mixtures of ROC curves can be helpful in fitting smooth ROC curves in datasets where the diseased population has higher variability than can be explained by a single distribution. PMID- 23643789 TI - Transfusion and blood donation in comic strips. AB - The representation of blood transfusion and donation of blood in the comic strip has never been studied. The comic strip, which is a relatively recent art, emerged in the 19th century before becoming a mass medium during the 20th century. We have sought, by calling on collectors and using the resources of Internet, comic strips devoted, wholly or in part, to the themes of transfusion and blood donation. We present some of them here in chronologic order, indicating the title, country of origin, year of publication, and names of authors. The theme of the superhero using transfusion to transmit his virtues or his powers is repeated throughout the 20th century in North American comic strips. More recently, comic strips have been conceived from the outset with a promotional aim. They perpetuate positive images and are directed toward a young readership, wielding humor to reduce the fear of venipuncture. Few comic strips denounce the abuse of the commercialization of products derived from the human body. The image of transfusion and blood donation given by the comic strips is not to be underestimated because their readership is primarily children, some of whom will become blood donors. Furthermore, if some readers are transfused during their lives, the impact of a memory more or less conscious of these childhood readings may resurface, both in hopes and in fears. PMID- 23643791 TI - A novel approach for copy number variation analysis by combining multiplex PCR with matrix-assisted laser desorption ionization time-of-flight mass spectrometry. AB - With the increasing interest in copy number variation as it pertains to human genomic variation, common phenotypes, and disease susceptibility, there is a pressing need for methods to accurately identify copy number. In this study, we developed a simple approach that combines multiplex PCR with matrix-assisted laser desorption ionization time-of-flight mass spectrometry for submicroscopic copy number variation detection. Two pairs of primers were used to simultaneously amplify query and endogenous control regions in the same reaction. Using a base extension reaction, the two amplicons were then distinguished and quantified in a mass spectrometry map. The peak ratio between the test region and the endogenous control region was manually calculated. The relative copy number could be determined by comparing the peak ratio between the test and control samples. This method generated a copy number measurement comparable to those produced by two other commonly used methods - multiplex ligation-dependent probe amplification and quantitative real-time PCR. Furthermore, it can discriminate a wide range of copy numbers. With a typical 384-format SpectroCHIP, at least six loci on 384 samples can be analyzed simultaneously in a hexaplex assay, making this assay adaptable for high throughput, and potentially applicable for large-scale association studies. PMID- 23643790 TI - Epigenetics of the antibody response. AB - Epigenetic marks, such as DNA methylation, histone post-translational modifications and miRNAs, are induced in B cells by the same stimuli that drive the antibody response. They play major roles in regulating somatic hypermutation (SHM), class switch DNA recombination (CSR), and differentiation to plasma cells or long-lived memory B cells. Histone modifications target the CSR and, possibly, SHM machinery to the immunoglobulin locus; they together with DNA methylation and miRNAs modulate the expression of critical elements of that machinery, such as activation-induced cytidine deaminase (AID), as well as factors central to plasma cell differentiation, such as B lymphocyte-induced maturation protein-1 (Blimp 1). These inducible B cell-intrinsic epigenetic marks instruct the maturation of antibody responses. Their dysregulation plays an important role in aberrant antibody responses to foreign antigens, such as those of microbial pathogens, and self-antigens, such as those targeted in autoimmunity, and B cell neoplasia. PMID- 23643792 TI - In vivo toxicological evaluation of polymeric nanocapsules after intradermal administration. AB - Polymeric nanocarriers have shown great promise as delivery systems. An alternative strategy has been to explore new delivery routes, such as intradermal (i.d.), that can be used for vaccines and patch-based drug delivery. Despite their many advantages, there are few toxicity studies, especially in vivo. We report a safety assessment of biodegradable poly(E-caprolactone) lipid-core nanocapsules (LNC) with a mean size of 245+/-10nm following single and repeated intradermal injections to Wistar rats. Suspensions were prepared by interfacial deposition of polymer. The animals (n=6/group) received a single-dose of saline solution (1.2ml/kg) or LNC (7.2*10(12)LNC/kg), or repeated-doses of two controls, saline solution or Tween 80 (0.9ml/kg), or three different concentrations of LNC (1.8, 3.6, and 5.4*10(12)LNC/kg) for 28 consecutive days. Clinical and physiological signs and mortality were observed. Samples of urine, blood, and tissue were used to perform toxicological evaluation. There were no clinical signs of toxicity or mortality, but there was a slight decrease in the relative body weights in the Tween 80-treated group (p<0.01) after repeated administration. No histopathological alterations were observed in tissues or significant changes in blood and urinary biomarkers for tissue damage. Mild alterations in white blood cells count with increases in granulocytes in the Tween-80 group (p<0.05) were found. Genotoxicity was evaluated through the comet assay, and no statistical difference was observed among the groups. Therefore, we conclude that, under the conditions of these experiments, biodegradable LNC did not present appreciable toxicity after 28 consecutive days of intradermal administration and is promising for its future application in vaccines and patch based devices for enhancing the delivery of drugs. PMID- 23643793 TI - Controlled ice nucleation in the field of freeze-drying: fundamentals and technology review. AB - In the scientific community as well as in commercial freeze-drying, controlled ice nucleation has received a lot of attention because increasing the ice nucleation temperature can significantly reduce primary drying duration. Furthermore, controlled ice nucleation enables to reduce the randomness of the ice nucleation temperature, which can be a serious scale-up issue during process development. In this review, fundamentals of ice nucleation in the field of freeze-drying are presented. Furthermore, the impact of controlled ice nucleation on product qualities is discussed, and methods to achieve controlled ice nucleation are presented. PMID- 23643794 TI - Research supervision without style. PMID- 23643795 TI - Percutaneous trigger finger release. PMID- 23643796 TI - An electrophysiological index of changes in risk decision-making strategies. AB - Human decision-making is significantly modulated by previously experienced outcomes. Using event-related potentials (ERPs), we examined whether ERP components evoked by outcome feedbacks could serve as biomarkers to signal the influence of current outcome evaluation on subsequent decision-making. In this study, 18 adult volunteers participated in a simple monetary gambling task, in which they were asked to choose between two options that differed in risk. Their decisions were immediately followed by outcome presentation. Temporospatial principle component analysis (PCA) was applied to the outcome-onset locked ERPs in the 200-1000 ms time window. The PCA factors that approximated classical ERP components (P2, feedback-related negativity, P3a, and P3b) in terms of time course and scalp distribution were tested for their association with subsequent decision-making strategies. Our results revealed that a fronto-central PCA factor approximating the classical P3a was related to changes of decision-making strategies on subsequent trials. The decision to switch between high- and low risk options resulted in a larger P3a relative to the decision to retain the same choice. According to the results, we suggest that the amplitude of the fronto central P3a is an electrophysiological index of the influence of current outcome on subsequent risk decision-making. Furthermore, the ERP source analysis indicated that the activations of the frontopolar cortex and sensorimotor cortex were involved in subsequent changes of strategies, which enriches our understanding of the neural mechanisms of adjusting decision-making strategies based on previous experience. PMID- 23643798 TI - Investigation on the interaction of the toxicant, gentian violet, with bovine hemoglobin. AB - Gentian violet (GV) is a well-known triarylmethane dye that is used in aquacultural, industrial and medicinal fields. But concerns in growing number have been paid to its potential health problems to human beings and its hazardous effects to environment. Herein, the toxic interaction of GV with bovine hemoglobin (BHb) was investigated by a series of spectroscopic methods and molecular modeling method. The fluorescence emission profile exhibited a remarkable quenching upon addition of GV to the buffered aqueous solution of BHb and the analysis of results revealed the dominant role of static quenching mechanism in GV-BHb interaction. The negative DeltaH and positive DeltaS values demonstrated that the electrostatic interactions mainly stabilized this toxicantprotein complex. Synchronous fluorescence, UV-Vis absorption and CD spectroscopic studies proved that the conformational change of BHb was induced by GV's combination. Molecular modeling studies exhibited the binding mode of GV-BHb complex and the detailed information of related driving forces. During the (1)H nuclear magnetic resonance spectra ((1)H NMR) study, the chemical shift perturbation and spin-lattice relaxation times of different protons were further used to investigate the interaction of GV with BHb and the results indicated that GV bound orientationally to BHb. PMID- 23643797 TI - Electrophysiological correlates of visual adaptation and sensory competition. AB - The face-sensitive evoked N170 component of the event related potential (ERP) is reduced if another face is presented before when compared to the previous presentation of a low-level control stimulus (phase-scrambled face). This effect is thought to reflect category-specific adaptation processes. Similarly, presenting two faces concurrently also reduces the N170, suggesting that stimuli compete for neural representations in the occipito-temporal cortex as early as 170 ms. Here we compared the ERPs obtained for two faces or for a face and a phase-scrambled face in three different conditions: (1) a first stimulus (S1) followed by a second one (S2), similarly to previous adaptation paradigms; (2) S1 remaining on screen when S2 appeared, as previously used in studies of competition; (3) or S1 and S2 having simultaneous onset and offset as well. We found a significant and stimulus specific reduction of the N170 in both conditions where the onset of S1 preceded the onset of S2. In contrast, simultaneous presentation of the two stimuli had no specific effect on the ERPs at least until 200 ms post-stimulus onset. This suggests either that competition does not lead to early repetition suppression or that the absence of a larger N170 response to two simultaneously presented face stimuli compared to a single stimulus reflects competition between overlapping representations. Overall, our results show that the asynchronous presentation of S1 and S2 is critical to observe stimulus specific reduction of the N170, presumably reflecting adaptation related processes. PMID- 23643799 TI - Bioconcentration of chromium in edible mushrooms: influence of environmental and genetic factors. AB - Chromium concentrations were determined in 167 samples of wild edible mushrooms, collected from three different sites (urban, traffic and pastureland areas) in Lugo (NW Spain). The hymenophore (H) and the rest of the fruiting body (RFB) were analysed separately. The analyses were performed using inductively coupled plasma optical emission spectrometry (ICP-OES). The highest mean chromium levels (mg/kg dry weight) of 3.5 and 8.0, 4.5 and 6.2, and 6.2 and 4.3 were found in Lycoperdon utriforme, Coprinus comatus and Agaricus campestris in H and RFB, respectively. The highest concentrations of chromium were observed in terrestrial saprophytic species in relation to mycorrhizal species. With respect to the underlying substrates, chromium concentration was lowest in the pastureland area (24.6 mg/kg dw). All mushroom species were bioexclusors of chromium (BCF<1) with statistically significant differences (p<0.001). The consumption of mushrooms harvested from the areas investigated poses no toxicological risk to human health due to chromium. PMID- 23643802 TI - Prospective multi-center study for quantification of chemotherapies and CTX related direct medication costs avoided by use of biomarkers uPA and PAI-1 in primary breast cancer. AB - Biomarkers uPA/PAI-1 as recommended by ASCO and AGO are used in primary breast cancer to avoid unnecessary CTX in medium risk-recurrence patients. This study verified how many CTX cycles and CTX-related direct medication costs can be avoided by uPA/PAI-1 testing. A prospective, non-interventional, multi-center study was performed among six Certified Breast Centers to analyze application of uPA/PAI-1 and consecutive decision-making. CTX avoided were identified and direct costs for CTX, CTX-related concomitant medication and febrile neutropenia (FN) prophylaxis with G-CSF calculated. In n = 93 breast cancers n = 35 CTX (37.6%) with 210 CTX cycles were avoided according to uPA/PAI-1 test result. uPA/PAI-1 testing saved direct medication costs for CTX of 177,453 ?, CTX-related concomitant medication of 27,482 ? and FN prophylaxis of 20,599 ?, overall 225,534 ?. At test costs at 287.50 ? uPA/PAI-1 testing resulted in additional costs of 26,737.50 ?. uPA/PAI-1 has proven to be cost-effective at a return-on investment ratio of 8.4:1. Indirect cost savings further increase this ROI. These results support decision-making for cost-effective diagnostics and therapy in breast cancer. PMID- 23643803 TI - Potential impact of the 70-gene signature in the choice of adjuvant systemic treatment for ER positive, HER2 negative tumors: a single institution experience. AB - PURPOSE: We investigated in a single institution series of 124 women with operable breast cancer whether tumor clinicopathological features could predict the 70-gene signature (Mammaprint, MP) results, and whether MP results could help to make decisions for the use of chemotherapy (CT) in patients (pts) with ER positive breast cancer beyond recommendations of international guidelines. RESULTS: Among the 68 ER/PgR positive, HER2 negative tumors, Ki-67 >= 20% was the only significant predictor of a high risk-MP among standard clinicopathological features. In candidates for endocrine therapy with undetermined benefit from CT according to international guidelines, MP results would have led to different treatment decisions in 13/46 (28%) and in 20/68 (29%) pts according to NCCN and St. Gallen recommendations, respectively. CONCLUSIONS: Ki-67 independently predicted high risk-MP in ER/PgR positive, HER2 negative tumors. MP results would have led to discordant treatment recommendations in about 30% of cases, generally increasing indication rate for CT. The results of large randomized trials are warranted in order to understand whether we should rely on multigene assays rather than on standard clinicopathological features for treatment decisions. PMID- 23643804 TI - Nutritional factors, physical activity, and breast cancer by hormonal receptor status. AB - PURPOSE: To investigate the association between food and nutrient intake, occupational and leisure-time physical activity, and body mass index and breast cancer risk by estrogen receptor (ER) and progesterone receptor (PR) status. METHODS: We analyzed data from a hospital-based case-control study conducted between 1991 and 1994 in Italy, including 1075 women with incident breast cancer and 1477 controls. RESULTS: The associations with breast cancer risk were similar according to ER status for all risk factors considered. In particular, significant reduced risk of ER- and ER+ breast cancers were observed for raw vegetables (multivariate odds ratio, OR, for high vs low consumption: 0.6 and 0.7, respectively) and for polyunsaturated fats (OR: 0.6 and 0.7, respectively). No significant heterogeneous risk estimates were observed for combinations of ER and PR status. CONCLUSIONS: Our study does not suggest major differences risk for various dietary and lifestyle factors according to ER and PR breast cancer subtypes. PMID- 23643801 TI - Epithelial to mesenchymal transition in arsenic-transformed cells promotes angiogenesis through activating beta-catenin-vascular endothelial growth factor pathway. AB - Arsenic exposure represents a major health concern increasing cancer risks, yet the mechanism of arsenic carcinogenesis has not been elucidated. We and others recently reported that cell malignant transformation by arsenic is accompanied by epithelial to mesenchymal transition (EMT). However, the role of EMT in arsenic carcinogenesis is not well understood. Although previous studies showed that short term exposure of endothelial cells to arsenic stimulated angiogenesis, it remains to be determined whether cells that were malignantly transformed by long term arsenic exposure have a pro-angiogenic effect. The objective of this study was to investigate the effect of arsenic-transformed human bronchial epithelial cells that underwent EMT on angiogenesis and the underlying mechanism. It was found that the conditioned medium from arsenic-transformed cells strongly stimulated tube formation by human umbilical vein endothelial cells (HUVECs). Moreover, enhanced angiogenesis was detected in mouse xenograft tumor tissues resulting from inoculation of arsenic-transformed cells. Mechanistic studies revealed that beta-catenin was activated in arsenic-transformed cells up regulating its target gene expression including angiogenic-stimulating vascular endothelial growth factor (VEGF). Stably expressing microRNA-200b in arsenic transformed cells that reversed EMT inhibited beta-catenin activation, decreased VEGF expression and reduced tube formation by HUVECs. SiRNA knockdown beta catenin decreased VEGF expression. Adding a VEGF neutralizing antibody into the conditioned medium from arsenic-transformed cells impaired tube formation by HUVECs. Reverse transcriptase-PCR analysis revealed that the mRNA levels of canonical Wnt ligands were not increased in arsenic-transformed cells. These findings suggest that EMT in arsenic-transformed cells promotes angiogenesis through activating beta-catenin-VEGF pathway. PMID- 23643805 TI - HER-2 overexpression is not associated with increased ipsilateral breast tumor recurrence in DCIS treated with breast-conserving surgery followed by radiotherapy. AB - BACKGROUND: We evaluated the clinical implications of human epidermal growth factor receptor (HER)-2 overexpression after adjuvant radiotherapy (RT) for ductal carcinoma in situ (DCIS). METHODS: We reviewed 215 patients with DCIS who underwent breast-conserving surgery followed by RT. The association between HER-2 overexpression and ipsilateral breast tumor recurrence (IBTR) was evaluated. RESULTS: HER-2 overexpression was associated with comedo-type architecture, high nuclear grade, and negative hormonal receptors. The median follow-up duration was 75 months. Sixteen patients experienced IBTR; seven as DCIS recurrence and nine as invasive recurrence. The IBTR rate was 11.4% at 10 years. There was no significant difference in IBTR according to HER-2 expression (P = 0.1764), neither in invasive nor DCIS recurrence. Time to recurrence was shorter in HER-2 positive tumors (P = 0.0697). CONCLUSION: Adjuvant RT seems to counteract the negative effect of HER-2 overexpression in DCIS, while time to recurrence was relatively shorter. PMID- 23643800 TI - Mitochondrial dysfunction and oxidative stress in Parkinson's disease. AB - Parkinson's disease (PD) is a movement disorder that is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta resulting in dopamine deficiency in the striatum. Although majority of the PD cases are sporadic several genetic mutations have also been linked to the disease thus providing new opportunities to study the pathology of the illness. Studies in humans and various animal models of PD reveal that mitochondrial dysfunction might be a defect that occurs early in PD pathogenesis and appears to be a widespread feature in both sporadic and monogenic forms of PD. The general mitochondrial abnormalities linked with the disease include mitochondrial electron transport chain impairment, alterations in mitochondrial morphology and dynamics, mitochondrial DNA mutations and anomaly in calcium homeostasis. Mitochondria are vital organelles with multiple functions and their dysfunction can lead to a decline in energy production, generation of reactive oxygen species and induction of stress-induced apoptosis. In this review, we give an outline of mitochondrial functions that are affected in the pathogenesis of sporadic and familial PD, and hence provide insights that might be valuable for focused future research to exploit possible mitochondrial targets for neuroprotective interventions in PD. PMID- 23643806 TI - Prediction of Oncotype DX and TAILORx risk categories using histopathological and immunohistochemical markers by classification and regression tree (CART) analysis. AB - Oncotype DX is an RT-PCR assay used to predict which patients with ER-positive node-negative (NN) disease will benefit from chemotherapy. Each patient is stratified into a risk category based on a recurrence score (RS) and the TAILORx trial is determining the benefit of chemotherapy for patients with mid-range RSs. We tested if Oncotype DX and TAILORx risk categories could be predicted by standard pathological features and protein markers corresponding to 10 genes in the assay (ER, PR, Ki67, HER2, BCL2, CD68, Aurora A kinase, survivin, cyclin B1 and BAG1) on 52 patients who enrolled on TAILORx. Immunohistochemistry for the protein markers was performed on whole tissue sections. Classification and regression tree (CART) analysis correctly classified 69% of cases into Oncotype DX risk categories based on the expression of PR, survivin and nuclear pleomorphism. All tumours with PR staining (Allred score >= 2) and marked nuclear pleomorphism were in the high-risk category. No case with PR <2, low survivin (<= 15.5%) and nuclear pleomorphism <3 was high-risk. Similarly, 77% of cases were correctly classified into TAILORx categories based on nuclear pleomorphism, survivin, BAG1 and cyclin B1. Ki67 was the only variable that predicted the absolute RS with a cut-off for positivity of 15% (p = 0.003). In conclusion, CART revealed key predictors including proliferation markers, PR and nuclear pleomorphism that correctly classified over two thirds of ER-positive NN cancers into Oncotype DX and TAILORx risk categories. These variables could be used as an alternative to the RT-PCR assay to reduce the number of patients requiring Oncotype DX testing. PMID- 23643807 TI - DCIS and LCIS are confusing and outdated terms. They should be abandoned in favor of ductal intraepithelial neoplasia (DIN) and lobular intraepithelial neoplasia (LIN). AB - The terms ductal and lobular intraepithelial neoplasia (DIN and LIN) were introduced by Tavossoli 15 years ago, who proposed they should replace, respectively, ductal and lobular carcinoma in situ (DCIS and LCIS). This proposal has been slowly gaining ground. We argue that DCIS and LCIS should now be definitively abandoned. Bringing together 'in situ' and other entities into the simpler and more logical DIN/LIN framework--as has been done with intraepithelial neoplasias of cervix, vagina, vulva, prostate, and pancreas--would eliminate the artificial and illogical distinctions between 'not cancers' (e.g. flat epithelial atypia, atypical ductal hyperplasia--now classified as low grade DIN) and 'cancers' (e.g. DCIS--now considered medium-high grade DIN). Elimination of the term 'carcinoma' from entities that cannot metastasize will reduce confusion among health professionals and patients, and contribute to reducing the risk of overtreatment, as well as reducing adverse psychological reactions in patients. PMID- 23643808 TI - Alteration of prolyl oligopeptidase and activated alpha-2-macroglobulin in multiple sclerosis subtypes and in the clinically isolated syndrome. AB - Prolyl oligopeptidase (PREP) has been considered as a drug target for the treatment of neurodegenerative diseases. In plasma, PREP has been found altered in several disorders of the central nervous system including multiple sclerosis (MS). Oxidative stress and the levels of an endogenous plasma PREP inhibitor have been proposed to decrease PREP activity in MS. In this work, we measured the circulating levels of PREP in patients suffering of relapsing remitting (RR), secondary progressive (SP), primary progressive (PP) MS, and in subjects with clinically isolated syndrome (CIS). We found a significantly lower PREP activity in plasma of RRMS as well as in PPMS patients and a trend to reduced activity in subjects diagnosed with CIS, compared to controls. No signs of oxidative inactivation of PREP, and no correlation with the endogenous PREP inhibitor, identified as activated alpha-2-macroglobulin (alpha2M*), were observed in any of the patients studied. However, a significant decrease of alpha2M* was recorded in MS. In cell cultures, we found that PREP specifically stimulates immune active cells possibly by modifying the levels of fibrinogen beta, thymosin beta4, and collagen. Our results open new lines of research on the role of PREP and alpha2M* in MS, aiming to relate them to the diagnosis and prognosis of this devastating disease. PMID- 23643810 TI - iNOS promotes HBx-induced hepatocellular carcinoma via upregulation of JNK activation. AB - Inducible nitric oxide (iNOS) is closely correlated with chronic inflammation in hepatitis B virus X protein (HBx)-induced hepatocellular carcinoma (HCC). However, the molecular mechanisms through which iNOS contribute to hepatocarcinogenesis remain poorly understood. Therefore, we investigated the role of iNOS in signaling pathways underlying HBx-induced liver tumorigenesis. iNOS deletion showed a marked decrease in the hepatic tumor size and stage of HBx transgenic (Tg) mice, indicating a strong contribution of iNOS signaling pathways to hepatocarcinogenesis. In addition, we found that nitric oxide (NO) increased HBx mRNA by recruiting CREB to the CRE site of HBV enhancer in HepG2 cells, suggesting a positive feedback loop between HBx and iNOS signaling pathway. Moreover, iNOS-modulated JNK activation was associated with sustained upregulation of Cyclin D1 in HBxTg mice and HepG2-HBx cells. These results imply that iNOS may play a key role in HBx-associated HCC development. Taken together, our findings demonstrate that iNOS aligns with HBx to promote tumor progression. These findings provide a better understating of the mechanism involving HBx mediated hepatic tumorigenesis and selective inhibition of iNOS may have therapeutic applications in HBx-associated HCC. PMID- 23643809 TI - Biomechanical characterization of ascending aortic aneurysm with concomitant bicuspid aortic valve and bovine aortic arch. AB - Studies have shown that patients harboring bicuspid aortic valve (BAV) or bovine aortic arch (BAA) are more likely than the general population to develop ascending aortic aneurysm (AsAA). A thorough quantification of the AsAA tissue properties for these patient groups may offer insights into the underlying mechanisms of AsAA development. Thus, the objective of this study was to investigate and compare the mechanical and microstructural properties of aortic tissues from AsAA patients with and without concomitant BAV or BAA. AsAA (n=20), BAV (n=20) and BAA (n=15) human tissues were obtained from patients who underwent elective AsAA surgery. Planar biaxial and uniaxial failure tests were used to characterize the mechanical and failure properties of the tissues, respectively. Histological analysis was performed to detect medial degenerative characteristics of aortic aneurysm. Individual layer thickness and composition were quantified for each patient group. The circumferential stress-strain response of the BAV samples was stiffer than both AsAA (p=0.473) and BAA (p=0.152) tissues at a low load. The BAV samples were nearly isotropic, while AsAA and BAA samples were anisotropic. The areal strain of BAV samples was significantly less than that of AsAA (p=0.041) and BAA (p=0.004) samples at a low load. The BAA samples were similar to the AsAA samples in both mechanical and failure properties. On the microstructural level, all samples displayed moderate medial degeneration, characterized by elastin fragmentation, cell loss, mucoid accumulation and fibrosis. The ultimate tensile strength of BAV and BAA sampleswere also found to decrease with age. Overall, the BAV samples were stiffer than both AsAA and BAA samples, and the BAA samples were similar to the AsAA samples. The BAV samples were thinnest, with less elastin than AsAA and BAA samples, which may be attributed to the loss of extensibility of these tissues at a low load. No apparent difference in failure mechanics among the tissue groups suggests that each of the patient groups may have a similar risk of rupture. PMID- 23643811 TI - APC/C(Cdh1)-dependent degradation of Cdc20 requires a phosphorylation on CRY-box by Polo-like kinase-1 during somatic cell cycle. AB - Cdc20 is an activator of the anaphase-promoting complex (APC/C), and APC/C(Cdc20) is essential for metaphase-anaphase transition. To allow progression beyond mitosis, Cdc20 is degraded through KEN-box-dependent APC/C(Cdh1) activity. Mammalian Cdc20 contains the CRY box, a second APC/C(Cdh1)-dependent degron, but the molecular mechanism in degradation process remains undefined. Polo-like kinase-1 (Plk1) is an essential mitotic kinase regulating various targets in kinetochore, centrosome, and midbody for proper mitotic progression. Plk1 directly bound to Cdc20 and phosphorylates it on serine-170 located in CRY-box. Whereas wild-type Cdc20 was degraded according to progress cell cycle beyond mitosis, the phosphorylation-defective mutant, which serine-170 was changed into alanine, was not destroyed in early G1 phase. The phosphorylation on serine-170 by Plk1 was important for ubiquitination and Cdh1-dependent proteolysis. However, this modification by Plk1 on CRY box had no effect on the subcellular localization of Cdc20 and the formation of APC/C-inhibitory checkpoint complexes under spindle assembly checkpoint. This mechanism will be the first finding of inhibitory phosphorylation related to Cdc20 instability. PMID- 23643812 TI - Aberrant methylation and loss of CADM2 tumor suppressor expression is associated with human renal cell carcinoma tumor progression. AB - Cell adhesion molecules (CADMs) comprise a protein family whose functions include maintenance of cell polarity and tumor suppression. In this report, we show that the CADM2 gene is repressed in human clear renal cell carcinoma by DNA promoter hypermethylation and/or loss of heterozygosity. Moreover, the loss of CADM2 expression is associated with a higher tumor pathology stage (p<0.05). The re expression of CADM2 in the renal cancer cell line 786-O significantly suppressed tumor cell growth in vitro and in mouse xenografts by a G1 phase cell cycle arrest and the induction of apoptosis. Lentivirus-mediated CADM2 expression also significantly suppressed cancer cell anchorage-independent growth and invasion. Furthermore, the inhibition of endogenous CADM2 expression using siRNAs induced a tumorigenic phenotype in polarized non-tumorigenic MDCK cells. Thus, we conclude that CADM2 functions as a novel tumor suppressor and may serve as a potential therapeutic target for human renal cell carcinoma. PMID- 23643813 TI - F-box only protein 9 is required for adipocyte differentiation. AB - The objective of this study is to investigate whether F-box only protein 9 (FBXO9), an ubiquitination E3 ligase, has a functional role in adipocyte differentiation. Expression of FBXO9 was compared between obese mice and control lean mice using real-time PCR. Also, expression pattern of FBXO9 was monitored during 3T3-L1 adipocyte differentiation. FBXO9 was highly expressed in obese mice, and increased in the early stages of adipogenesis. To verify a functional role of FBXO9 in adipogenesis, FBXO9 was knocked down using transfection of siRNAs against FBXO9 into 3T3-L1 cells during the induction of adipogenesis. Knockdown of FBXO9 in early stage of adipogenesis almost completely inhibited adipogenesis, and CCAAT/enhancer binding protein beta (C/EBPbeta) levels were significantly reduced. However, the cells stably expressing C/EBPbeta were fairly differentiated into adipocytes in the FBXO9 knockdown condition. These results suggest that FBXO9 is required for adipocyte differentiation, and C/EBPbeta plays a role in the effect of FBXO9 on adipogenesis. PMID- 23643814 TI - Acoustical sensing of cardiomyocyte cluster beating. AB - Spontaneously beating human pluripotent stem cell-derived cardiomyocytes clusters (CMCs) represent an excellent in vitro tool for studies of human cardiomyocyte function and for pharmacological cardiac safety assessment. Such testing typically requires highly trained operators, precision plating, or large cell quantities, and there is a demand for real-time, label-free monitoring of small cell quantities, especially rare cells and tissue-like structures. Array formats based on sensing of electrical or optical properties of cells are being developed and in use by the pharmaceutical industry. A potential alternative to these techniques is represented by the quartz crystal microbalance with dissipation monitoring (QCM-D) technique, which is an acoustic surface sensitive technique that measures changes in mass and viscoelastic properties close to the sensor surface (from nm to MUm). There is an increasing number of studies where QCM-D has successfully been applied to monitor properties of cells and cellular processes. In the present study, we show that spontaneous beating of CMCs on QCM D sensors can be clearly detected, both in the frequency and the dissipation signals. Beating rates in the range of 66-168 bpm for CMCs were detected and confirmed by simultaneous light microscopy. The QCM-D beating profile was found to provide individual fingerprints of the hPS-CMCs. The presented results point towards acoustical assays for evaluation cardiotoxicity. PMID- 23643815 TI - Characterization of Tudor-sn-containing granules in the silkworm, Bombyx mori. AB - The Tudor-sn protein, which contains four staphylococcal nuclease domains and a Tudor domain, is a ubiquitous protein found in almost all organisms. It has been reported that Tudor-sn in mammals participates in various cellular pathways involved in gene regulation, cell growth, and development. In insects, we have previously identified a Tudor-sn ortholog in the silkworm, Bombyx mori, and detected its interactions between with Argonaute proteins. The role of Tudor-sn in silkworm, however, still remains largely unknown. In this study, we demonstrated that silkworm Tudor-sn is a stress granule (SG) protein, and determined its interactions with other SG proteins using Bimolecular Fluorescence Complementation assay and Insect Two-Hybrid method. Depletions of Argonaute proteins and SG-marker protein Tia1 by RNAi impaired the involvement of Tudor-sn in the SG formation. Protein domain deletion analysis of Tudor-sn demonstrated that SN2 is the key domain required for the aggregation of Tudor-sn in SGs. PMID- 23643816 TI - Comparison of the efficacy of KOB03, ketotifen, and montelukast in an experimental mouse model of allergic rhinitis. AB - KOB03 is a polyherbal medicine derived from an oriental prescription traditionally used to treat allergic diseases. In the present study, we compared the efficacy of KOB03 with modern drugs such as ketotifen and montelukast in an experimental mouse model of allergic rhinitis (AR). Ketotifen is a H1 receptor antagonist and montelukast is a leukotriene receptor antagonist. Mice were treated with KOB03, ketotifen or montelukast in an established AR mouse model using ovalbumin (OVA)-sensitized/challenged BALB/c mice. The treatment of KOB03 had inhibitory effects on symptom scores, serum levels of OVA-specific IgE, histamine, leukotriene C4, IL-4, TNF-alpha, and IL-1beta in AR mice, and the histolopathological changes of nasal mucosa with mucin release and inflammation. AR mice treated with KOB03 had significantly lower serum levels of OVA-specific IgE, LTC4, IL-4, and IL-1beta than mice treated with ketotifen, whereas they only had significantly lower serum levels of OVA-specific IgE and IL-4 than those treated with montelukast. In addition, the histolopathological changes of nasal mucosa with eosinophil infiltration were significantly lower in the KOB03-treated mice than those in the ketotifen and montelukast-treated group. These results suggest that KOB03 has therapeutic potential for treating AR like other modern medicines. PMID- 23643817 TI - An echocardiographic study of healthy Border Collies with normal reference ranges for the breed. AB - OBJECTIVES: The objectives of this study were to obtain standard echocardiographic measurements from healthy Border Collies and to compare these measurements to those previously reported for a general population of dogs. ANIMALS: Standard echocardiographic data were obtained from twenty apparently healthy Border Collie dogs. These data (n = 20) were compared to data obtained from a general population of healthy dogs (n = 69). METHODS: Border Collies were deemed healthy based on normal history, physical examination, complete blood count, serum biochemical profile, electrocardiogram, and blood pressure, with no evidence of congenital or acquired heart disease on echocardiographic examination. Standard two dimensional, M-mode, and Doppler echocardiographic measurements were obtained and normal ranges determined. The data were compared to data previously obtained at our hospital from a general population of normal dogs. RESULTS: Two dimensional, M-mode, and Doppler reference ranges for healthy Border Collies are presented in tabular form. Comparison of the weight adjusted M mode echocardiographic means from Border Collies to those from the general population of dogs showed Border Collies to have larger left ventricular systolic and diastolic dimensions, smaller interventricular septal thickness, and lower fractional shortening. CONCLUSIONS: There are differences in some echocardiographic parameters between healthy Border Collies and the general dog population, and the echocardiographic reference ranges provided in this study should be used as breed specific reference values for Border Collies. PMID- 23643818 TI - Common two-dimensional echocardiographic estimates of aortic linear dimensions are interchangeable. AB - OBJECTIVE: To compare two echocardiographic methods of measuring aortic diameter in short-axis projections. METHODS: Right-parasternal short-axis 2-dimensional projections of the left atrium and aorta were obtained from dogs and cats undergoing routine cardiac evaluation. Two investigators measured the aortic valve linear dimension using 2 methods: along the commissure between the non coronary and right-coronary cusps and along the commissure between the non coronary and left-coronary cusps. Inter-observer and intra-observer variability and agreement were assessed by comparing blinded measurements with each method by 4 trained observers on a standardized set of images. Measurements were compared for agreement using the limits of agreement analysis. Variability between observers was compared by examining residuals and intraclass correlation. RESULTS: 274 canine and 100 feline aortic valve images were measured in the first part of the study. One observer demonstrated slight proportional bias, while the other observer showed more variability (less agreement). When results were pooled for both investigators, no bias was identified, and 95% limits of agreement were +/-10% of the mean measurement for both species. In the second part of the study, 106 images were measured. Intraobserver variability was <4% for all observers. Inter-observer agreement was very high. Individual bias was identified in some observers, but was considered clinically inconsequential. Normalized differences between the 2 methods of measurement were below +/-15% of the measured value for all observers. CONCLUSIONS: Our results show sufficient agreement between two common methods used to measure aortic linear dimensions to suggest that these methods are interchangeable. PMID- 23643819 TI - Influence of heart rate on myocardial function using two-dimensional speckle tracking echocardiography in healthy dogs. AB - OBJECTIVE: The objective of this study was to evaluate the influence of heart rate (HR) on myocardial function assessed by two-dimensional speckle-tracking echocardiography (2D-STE) in healthy dogs. ANIMALS: Thirteen healthy beagle dogs. METHODS: Animals were anesthetized and HR was controlled with right atrial pacing. Myocardial function of each dog was assessed using 2D-STE at pacing rates of 120, 140, 160, and 180 bpm. RESULTS: All strain and strain rate variables in the longitudinal, circumferential, and radial directions were not significantly different between pacing rates. Peak early diastolic torsion rate at 180 bpm was significantly increased compared with that at 120 bpm (P = 0.003). CONCLUSION: Torsion rate in early diastole was elevated at 180 bpm, which may reflect improved myocardial relaxation with higher HR. Changes in left ventricular torsion during tachycardia may play an important role in preserving stroke volume in the presence of shortened ejection and filling times. PMID- 23643820 TI - Cowper gland syringocele. PMID- 23643821 TI - Service user involvement: inspiring student nurses to make a difference to patient care. AB - UK policy directives have placed service users/carers at the centre of health care provision and education. Underlying these policy directives is the anticipation that this involvement will produce practitioners capable of delivering enhanced care. This paper reports on the evaluation of an innovation around the introduction of a student nurse pledge to enhance patient care. Following exposure to the service user stories in the classroom students documented a pledge, within their practice assessment documents, to improve one aspect of patient care. Of the 284 pledges evaluated, 219 were successfully achieved with, 171 relating to compassion, communication and nutrition. These aspects of care are often cited as causing the most distress to patients.65 students were unable to fulfil their pledge, citing reasons such as poor resources, lack of time. Disappointingly, mentors validated the students' inability to fulfil their pledge with little guidance as to how to succeed with their pledge. The impact of this innovation on student practice learning and patient care are discussed. The paper concludes that service user involvement can result in enhanced patient care and that educators can support students to narrow the theory/practice gap by making connections between theory and real life experiences. PMID- 23643822 TI - The use of blended learning to create a module about ill-health during childbirth for pre-registration midwifery students. AB - Reforms in the way higher education is delivered in order to address the needs of learners in the 21st century are increasingly being considered by university departments. This has led academics to combine e-learning with more traditional classroom based methods of teaching when designing new modules of study, a method commonly called blended learning. This paper will describe the different teaching and learning methods which were blended together to create a module for second year pre-registration midwifery students in England, which focused upon ill health during pregnancy and childbearing. It is imperative that at the point of registration midwifery students possess the skills to identify deviations from normal, initiate immediate actions and make appropriate referrals. The health of women all over the world is of concern to health care professionals. Midwives are increasingly being upon to provide expert care. Midwives need a sound education to allow them to carry out their roles effectively. The International Confederation of Midwives global standards for midwifery education (2010) attempts to address the need for competent caring midwives to help women and families in every corner of the world. The paper will also cover the pedagogical issues considered when blending together the different elements of learning namely: traditional discursive lectures, small group work, e-learning, formative presentations and the use of simulation during a skills and drills day. PMID- 23643823 TI - Supporting the novice nurse to fly: a literature review. AB - The evolution from a newly graduated or novice nurse to a competent nurse can be challenging and difficult. This transition involves a tidal wave of emotions along with time needed to develop critical thinking skills, in order to apply their knowledge to patient situations, make decisions and respond with appropriate actions. The purpose of this paper was to explore the existing literature in the area of supports for novice nurses; by determining who is a novice nurse, what can plague a novice's transition, and how to support their successful transition. These results have been compared with the role of Clinical Nurse Expert at The Ottawa Hospital and overall, the findings suggest that a one year coaching program for novices is an effective strategy for supporting their transition, subsequently increasing their retention rates, as well as having a positive influence on the nursing profession, our patients and the healthcare system. PMID- 23643824 TI - Therapeutic cell encapsulation: ten steps towards clinical translation. AB - Since the conception of cell microencapsulation, many scientists bet on this biotechnology as they saw in it a promising alternative to protect transplanted cells from host immunoresponse. Some decades later, this initial enthusiasm is giving rise to a phase of certain conformism and lack of novel advances in the field. This perspective critically discusses current challenges needed to help this approach become a realistic clinical proposal. Alginate seems to be well established as the biomaterial of choice, but additional efforts are needed regarding current cross-linkers and coatings. Biofunctionalization of the matrices may provide the necessary biomimetic microenvironment to control cell behavior. Different alginate degradation rates would allow widening the applications of this biotechnology from drug delivery to cell delivery. In this sense, stem cells from stromal tissues could be the most suitable cell source due to their intrinsic hypoimmunogenicity, their immunomodulatory effects and their capacity to cell homing. The incorporation of suicide and reporter genes in the genome of enclosed cells may overcome some of the existing biosafety concerns. Administration and extraction by means of less invasive procedures also need to be developed to succeed in clinical translation. Finally, improving cost effectiveness for the scale-up, together with establishing and fulfilling a series of strict regulatory aspects will be indispensable to make the final step to the clinic. PMID- 23643826 TI - Sleep duration, sleep quality and body weight: parallel developments. AB - The increase in obesity, including childhood obesity, has developed over the same time period as the progressive decrease in self-reported sleep duration. Since epidemiological studies showed an inverse relationship between short or disturbed sleep and obesity, the question arose, how sleep duration and sleep quality are associated with the development of obesity. In this review, the current literature on these topics has been evaluated. During puberty, changes in body mass index (BMI) are inversely correlated to changes in sleep duration. During adulthood, this relationship remains and at the same time unfavorable metabolic and neuro-endocrinological changes develop, that promote a positive energy balance, coinciding with sleep disturbance. Furthermore, during excessive weight loss BMI and fat mass decrease, in parallel, and related with an increase in sleep duration. In order to shed light on the association between sleep duration, sleep quality and obesity, until now it only has been shown that diet-induced body-weight loss and successive body-weight maintenance contribute to sleep improvement. It remains to be demonstrated whether body-weight management and body composition improve during an intervention concomitantly with spontaneous sleep improvement compared with the same intervention without spontaneous sleep improvement. PMID- 23643827 TI - Melatonin reduces body weight gain and increases nocturnal activity in male Wistar rats. AB - AIM: This study evaluated the effect of the administration of melatonin, the chief secretory product of the pineal gland, on the body weight in male Wistar rats. MAIN METHODS: The animals were housed for 4months in cages equipped to log horizontal activity within a thermostatically-controlled chamber, under a 12h/12h light/dark photoperiod (lights on at 08:00h). After acclimatization, the animals were divided into two groups: (1) control animals, and (2) melatonin-treated animals. Melatonin was administered in tap water (20MUg/ml), and fresh drinking fluid was changed twice weekly. Rats were fed a standard diet ad libitum. KEY FINDINGS: Food and water intake, body weight, the amplitude of the activity/rest rhythm (motor activity), and blood melatonin and glucose concentrations were measured. The administration of melatonin did not influence either food or water intake or glucose levels relative to those found in the control animals. However, melatonin administration reduced body weight gain and increased nocturnal locomotor activity. The peak concentration of melatonin was found at night coinciding with the increase in nocturnal activity. SIGNIFICANCE: The results show that exogenous melatonin reduces body weight gain without having marked effects on metabolism. This may be due in part to the increased nocturnal activity shown by the animals treated with the indoleamine. PMID- 23643825 TI - Manganese-enhanced magnetic resonance imaging (MEMRI) reveals brain circuitry involved in responding to an acute novel stress in rats with a history of repeated social stress. AB - Responses to acute stressors are determined in part by stress history. For example, a history of chronic stress results in facilitated responses to a novel stressor and this facilitation is considered to be adaptive. We previously demonstrated that repeated exposure of rats to the resident-intruder model of social stress results in the emergence of two subpopulations that are characterized by different coping responses to stress. The submissive subpopulation failed to show facilitation to a novel stressor and developed a passive strategy in the Porsolt forced swim test. Because a passive stress coping response has been implicated in the propensity to develop certain psychiatric disorders, understanding the unique circuitry engaged by exposure to a novel stressor in these subpopulations would advance our understanding of the etiology of stress-related pathology. An ex vivo functional imaging technique, manganese enhanced magnetic resonance imaging (MEMRI), was used to identify and distinguish brain regions that are differentially activated by an acute swim stress (15 min) in rats with a history of social stress compared to controls. Specifically, Mn(2+) was administered intracerebroventricularly prior to swim stress and brains were later imaged ex vivo to reveal activated structures. When compared to controls, all rats with a history of social stress showed greater activation in specific striatal, hippocampal, hypothalamic, and midbrain regions. The submissive subpopulation of rats was further distinguished by significantly greater activation in amygdala, bed nucleus of the stria terminalis, and septum, suggesting that these regions may form a circuit mediating responses to novel stress in individuals that adopt passive coping strategies. The finding that different circuits are engaged by a novel stressor in the two subpopulations of rats exposed to social stress implicates a role for these circuits in determining individual strategies for responding to stressors. Finally, these data underscore the utility of ex vivo MEMRI to identify and distinguish circuits engaged in behavioral responses. PMID- 23643828 TI - The C1 domain-targeted isophthalate derivative HMI-1b11 promotes neurite outgrowth and GAP-43 expression through PKCalpha activation in SH-SY5Y cells. AB - Protein kinase C (PKC) is a family of serine/threonine phosphotransferases ubiquitously expressed and involved in multiple cellular functions, such as proliferation, apoptosis and differentiation. The C1 domain of PKC represents an attractive drug target, especially for developing PKC activators. Dialkyl 5 (hydroxymethyl)isophthalates are a novel group of synthetic C1 domain ligands that exhibit antiproliferative effect in HeLa cervical carcinoma cells. Here we selected two isophthalates, HMI-1a3 and HMI-1b11, and characterized their effects in the human neuroblastoma cell line SH-SY5Y. Both of the active isophthalates exhibited significant antiproliferative and differentiation-inducing effects. Since HMI-1b11 did not impair cell survival even at the highest concentration tested (20MUM), and supported neurite growth and differentiation of SH-SY5Y cells, we focused on studying its downstream signaling cascades and effects on gene expression. Consistently, genome-wide gene expression microarray and gene set enrichment analysis indicated that HMI-1b11 (10MUM) induced changes in genes mainly related to cell differentiation. In particular, further studies revealed that HMI-1b11 exposure induced up-regulation of GAP-43, a marker for neurite sprouting and neuronal differentiation. These effects were induced by a 7-min HMI 1b11 treatment and specifically depended on PKCalpha activation, since pretreatment with the selective inhibitor Go6976 abolished the up-regulation of GAP-43 protein observed at 12h. In parallel, we found that a 7-min exposure to HMI-1b11 induced PKCalpha accumulation to the cytoskeleton, an effect that was again prevented by pretreatment with Go6976. Despite similar binding affinities to PKC, the isophthalates had different effects on PKC-dependent ERK1/2 signaling: HMI-1a3-induced ERK1/2 phosphorylation was transient, while HMI-1b11 induced a rapid but prolonged ERK1/2 phosphorylation. Overall our data are in accordance with previous studies showing that activation of the PKCalpha and ERK1/2 pathways participate in regulating neuronal differentiation. Furthermore, since PKC has been classified as one of the cognitive kinases, and activation of PKC is considered a potential therapeutic strategy for the treatment of cognitive disorders, our findings suggest that HMI-1b11 represents a promising lead compound in research aimed to prevent or counteract memory impairment. PMID- 23643829 TI - [A case of hydatid cyst caused by Echinococcus granulosus in Puebla, Mexico, that resulted in successful surgical treatment]. AB - We present herein the case of a 16-year-old female from the southern portion of the State of Puebla, Mexico. When gathering her past medical history, it was revealed that she had grown up with pet dogs and that her family raised sheep. Because the patient presented with few symptoms, a benign lesion was suspected, and after laparoscopic exploration, the possibility of surgical management for a non-parasitic cyst was considered. A dull pain in the right hypochondrium persisted and open surgical exploration was performed in which a 6cm young, active, uncomplicated hydatid cyst was discovered. Its surgical removal was successful and the pathologist provided the definitive diagnosis. The three layers characteristic of a parasitic cyst were present and it was histologically consistent with Echinococcus granulosus. Postoperative progression was unremarkable and the control ultrasound study revealed complete restitution of the hepatic parenchyma. PMID- 23643830 TI - Administration of PTH and ibandronate increases ovariectomized rat compact bone viscoelasticity. AB - In this study, the bone mineral density (BMD), geometry, macroscopic viscoelastic properties and mechanical strength in five different groups of Sprague-Dawley rats (sham operated, ovariectomized with vehicle, parathyroid hormone and/or ibandronate administration) were examined by peripheral quantitative computed tomography (pQCT), dynamic mechanical analysis (DMA) and three-point bending test. At the end of the study, storage modulus (E'), loss tangent (tandelta), ultimate force (Fu) and stiffness (S) had greatly decreased in vehicle-treated ovariectomized group as compared to sham group (p<0.05). The concurrent administration of parathyroid hormone and ibandronate group exhibited the largest cortical area (Ct.Ar) and thickness (Ct.Th), E', tandelta (0.3Hz) and subsequently highest Fu as compared to the mono-therapy groups (p<0.05). However, significant changes were not observed in the BMD values of different groups (p>0.05). The relationships between these potential predictors of bone strength (E', tandelta, BMD and Ct.Ar) and bone mechanical strength parameters (Fu, S and ultimate stress sigmau) were also examined. Interestingly, during normal daily activity frequency range (0.9-6Hz), tandelta and Fu were positively correlated. Taken together, these data suggest that DMA can serve as an effective tool to assess bone strength which would be ignored under the normal clinical screenings due to an unchanged BMD. DMA can therefore be used as a better tool to assess the osteoporotic drug efficacy. PMID- 23643831 TI - Discovery of highly potent triazole antifungal derivatives by heterocycle-benzene bioisosteric replacement. AB - On the basis of our previously discovered triazole antifungal lead compounds, heterocycle-benzene bioisosteric replacement was used to improve their pharmacokinetic profile. The designed new triazole derivatives have good antifungal activity toward a wide range of pathogenic fungi. Their binding mode with the target enzyme was clarified by molecular docking. The MIC value of the highly potent compound 8f against Candida albicans, Candida tropicalis, and Cryptococcus neoformans is 0.016 MUg/mL, 0.004 MUg/mL, and 0.016 MUg/mL, respectively. Moreover, preliminary pharmacokinetic studies revealed that it showed improved oral absorption as compared to the lead compound iodiconazole and deserved for further evaluations. PMID- 23643832 TI - Color reproduction for advanced manufacture of soft tissue prostheses. AB - OBJECTIVES: The objectives of this study were to develop a color reproduction system in advanced manufacture technology for accurate and automatic processing of soft tissue prostheses. METHODS: The manufacturing protocol was defined to effectively and consistently produce soft tissue prostheses using a 3D printing system. Within this protocol printer color profiles were developed using a number of mathematical models for the proposed 3D color printing system based on 240 training colors. On this basis, the color reproduction system was established and their system errors including accuracy of color reproduction, performance of color repeatability and color gamut were evaluated using 14 known human skin shades. RESULTS: The printer color profile developed using the third-order polynomial regression based on least-square fitting provided the best model performance. The results demonstrated that by using the proposed color reproduction system, 14 different skin colors could be reproduced and excellent color reproduction performance achieved. Evaluation of the system's color repeatability revealed a demonstrable system error and this highlighted the need for regular evaluation. The color gamut for the proposed 3D printing system was simulated and it was demonstrated that the vast majority of skin colors can be reproduced with the exception of extreme dark or light skin color shades. CONCLUSIONS: This study demonstrated that the proposed color reproduction system can be effectively used to reproduce a range of human skin colors for application in advanced manufacture of soft tissue prostheses. PMID- 23643833 TI - New complete structure of Hafnia alvei clinical isolate strain PCM 2670 semi rough lipopolysaccharide. AB - Hafnia alvei strain PCM 2670 is a clinical isolate from a patient with chronic reproductive tract infection. The novel structure of the semi-rough lipopolysaccharide was established with the use of NMR spectroscopy and mass spectrometry as well as immunochemical techniques. According to the mass spectrometry data, heptose in the oligosaccharide is partially substituted by glycine. H. alvei PCM 2670 core structure encompasses the common core of H. alvei which is modified with two additional galactose units. [structure: see text]. The 6-substituted galactose is the O-antigen repeating unit substitution residue. The repeating unit consists of five monosaccharide residues and has the following structure: ->2)-beta-Galp-(1->6)-alpha-Glcp-(1->6)-alphaGlcpNAc3OAc-(1->4)-alpha GalpA-(1->3)-beta-GlcpNAc6OAc-(1->6)-core. PMID- 23643834 TI - Synthetic tools for the characterization of galactofuranosyl transferases: glycosylations via acylated glycosyl iodides. AB - With the aim of developing synthetic tools for the characterization of galactofuranosyltransferases, the synthesis of 9-decenyl glycosides of D-Manp, D Galf, and beta-D-Galf-(1->3)-D-Manp was targeted. The interest in the alkenyl aglycone arises via potential conjugation reactions, once the terminal double bond has been conveniently functionalized. The glycosylation of beta-D-Galf-(1 >3)-D-Manp was attempted by two different approaches: the trichloroacetimidate method and the glycosylation via the glycosyl iodide. The conditions for the latter were established on the basis of glycosylation assays of per-O acetylmannose. On the other hand, the study of glycosylation reactions via per-O benzoylated galactofuranosyl iodide confirms the versatility of glycosyl iodides as donors. PMID- 23643836 TI - Association of callous traits with reduced neural response to others' pain in children with conduct problems. AB - Children with conduct problems (CP) persistently violate others' rights and represent a considerable societal cost. These children also display atypical empathic responses to others' distress, which may partly account for their violent and antisocial behavior. Callous traits index lack of empathy in these children and confer risk for adult psychopathy. Investigating neural responses to others' pain is an ecologically valid method to probe empathic processing, but studies in children with CP have been inconclusive. Using functional magnetic resonance imaging (fMRI), we measured neural responses to pictures of others in pain (versus no pain) in a large sample of children with CP and matched controls. Relative to controls, children with CP showed reduced blood oxygen level dependent responses to others' pain in bilateral anterior insula (AI), anterior cingulate cortex (ACC), and inferior frontal gyrus, regions associated with empathy for pain in previous studies. In the CP group, callous traits were negatively associated with responses to others' pain in AI and ACC. We conclude that children with CP have atypical neural responses to others' pain. The negative association between callous traits and AI/ACC response could reflect an early neurobiological marker indexing risk for empathic deficits seen in adult psychopathy. PMID- 23643835 TI - Myelodysplastic syndrome: an inability to appropriately respond to damaged DNA? AB - Myelodysplastic syndrome (MDS) is considered a hematopoietic stem cell disease that is characterized by abnormal hematopoietic differentiation and a high propensity to develop acute myeloid leukemia. It is mostly associated with advanced age, but also with prior cancer therapy and inherited syndromes related to abnormalities in DNA repair. Recent technologic advances have led to the identification of a myriad of frequently occurring genomic perturbations associated with MDS. These observations suggest that MDS and its progression to acute myeloid leukemia is a genomic instability disorder, resulting from a stepwise accumulation of genetic abnormalities. The notion is now emerging that the underlying mechanism of this disease could be a defect in one or more pathways that are involved in responding to or repairing damaged DNA. In this review, we discuss these pathways in relationship to a large number of studies performed with MDS patient samples and MDS mouse models. Moreover, in view of our current understanding of how DNA damage response and repair pathways are affected by age in hematopoietic stem cells, we also explore how this might relate to MDS development. PMID- 23643837 TI - Metabolic regulation of brain response to food cues. AB - Identification of energy sources depends upon the ability to form associations between food cues and nutritional value. As such, cues previously paired with calories elicit neuronal activation in the nucleus accumbens (NAcc), which reflects the reinforcing value of food. The identity of the physiological signals regulating this response remains elusive. Using fMRI, we examined brain response to noncaloric versions of flavors that had been consumed in previous days with either 0 or 112.5 calories from undetected maltodextrin. We report a small but perceptually meaningful increase in liking for the flavor that had been paired with calories and find that change in liking was associated with changes in insular responses to this beverage. In contrast, NAcc and hypothalamic response to the calorie-paired flavor was unrelated to liking but was strongly associated with the changes in plasma glucose levels produced by ingestion of the beverage when consumed previously with calories. Importantly, because each participant ingested the same caloric dose, the change in plasma glucose depended upon individual differences in glucose metabolism. We conclude that glucose metabolism is a critical signal regulating NAcc and hypothalamic response to food cues, and that this process operates independently from the ability of calories to condition liking. PMID- 23643839 TI - Activator or inhibitor? GSK-3 as a new drug target. AB - Glycogen synthase kinase-3 (GSK-3) is a cytoplasmic serine/threonine protein kinase that phosphorylates and inhibits glycogen synthase, thereby inhibiting glycogen synthesis from glucose. However, this serine/threonine kinase is now known to regulate numerous cellular processes through a number of signaling pathways important for cell proliferation, stem cell renewal, apoptosis and development. Because of these diverse roles, malfunction of this kinase is also known to be involved in the pathogenesis of human diseases, such as nervous system disorders, diabetes, bone formation, inflammation, cancer and heart failure. Therefore, GSK-3 is recognized as an attractive target for the development of new drugs. The present review summarizes the roles of GSK-3 in the insulin, Wnt/beta-catenin and hedgehog signaling pathways including the regulation of their activities. The roles of GSK-3 in the development of human diseases within the context of its participation in various signaling pathways are also summarized. Finally, the possibility of new drug development targeting this kinase is discussed with recent information about inhibitors and activators of GSK-3. PMID- 23643838 TI - The impact of hemodynamic stress on sensory signal processing in the rodent lateral geniculate nucleus. AB - Hemodynamic stress via hypotensive challenge has been shown previously to cause a corticotropin-releasing factor (CRF)-mediated increase in tonic locus coeruleus (LC) activity and consequent release of norepinephrine (NE) in noradrenergic terminal fields. Although alterations in LC-NE can modulate the responsiveness of signal processing neurons along sensory pathways, little is understood regarding how continuous CRF-mediated activation of LC-NE output due to physiologically relevant stressor affects downstream target cell physiology. The goal of the present study was to investigate the effects of a physiological stressor [hemodynamic stress via sodium nitroprusside (SNP) i.v.] on stimulus evoked responses of sensory processing neurons that receive LC inputs. In rat, the dorsal lateral geniculate nucleus (dLGN) of the thalamus is the primary relay for visual information and is a major target of the LC-NE system. We used extracellular recording techniques in the anesthetized rat monitor single dLGN neuron activity during repeated presentation of light stimuli before and during hemodynamic stress. A significant decrease in magnitude occurred, as well as an increase in latency of dLGN stimulus-evoked responses were observed during hemodynamic stress. In another group of animals the CRF antagonist DpheCRF12-41 was infused onto the ipsilateral LC prior to SNP administration. This infusion blocked the hypotension-induced changes in dLGN stimulus-evoked discharge. These results show that CRF-mediated increases in LC-NE due to hemodynamic stress disrupts the transmission of information along thalamic-sensory pathways by: (1) initially reducing signal transmission during onset of the stressor and (2) decreasing the speed of stimulus evoked sensory transmission. PMID- 23643840 TI - Epidural lipomatosis as a cause for high impedance values during a spinal cord stimulator trial. PMID- 23643841 TI - A novel alpha-synuclein-GFP mouse model displays progressive motor impairment, olfactory dysfunction and accumulation of alpha-synuclein-GFP. AB - Compelling evidence suggests that accumulation and aggregation of alpha-synuclein (alpha-syn) contribute to the pathogenesis of Parkinson's disease (PD). Here, we describe a novel Bacterial Artificial Chromosome (BAC) transgenic model, in which we have expressed wild-type human alpha-syn fused to green fluorescent protein (GFP), under control of the mouse alpha-syn promoter. We observed a widespread and high expression of alpha-syn-GFP in multiple brain regions, including the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the ventral tegmental area, the olfactory bulb as well as in neocortical neurons. With increasing age, transgenic mice exhibited reductions in amphetamine-induced locomotor activity in the open field, impaired rotarod performance and a reduced striatal dopamine release, as measured by amperometry. In addition, they progressively developed deficits in an odor discrimination test. Western blot analysis revealed that alpha-syn-GFP and phospho-alpha-syn levels increased in multiple brain regions, as the mice grew older. Further, we observed, by immunohistochemical staining for phospho-alpha-syn and in vivo by two-photon microscopy, the formation of alpha-syn aggregates as the mice aged. The latter illustrates that the model can be used to track alpha-syn aggregation in vivo. In summary, this novel BAC alpha-syn-GFP model mimics a unique set of aspects of PD progression combined with the possibility of tracking alpha-syn aggregation in neocortex of living mice. Therefore, this alpha-syn-GFP-mouse model can provide a powerful tool that will facilitate the study of alpha-syn biology and its involvement in PD pathogenesis. PMID- 23643843 TI - Psychophysical contrast calibration. AB - Electronic displays and computer systems offer numerous advantages for clinical vision testing. Laboratory and clinical measurements of various functions and in particular of (letter) contrast sensitivity require accurately calibrated display contrast. In the laboratory this is achieved using expensive light meters. We developed and evaluated a novel method that uses only psychophysical responses of a person with normal vision to calibrate the luminance contrast of displays for experimental and clinical applications. Our method combines psychophysical techniques (1) for detection (and thus elimination or reduction) of display saturating non-linearities; (2) for luminance (gamma function) estimation and linearization without use of a photometer; and (3) to measure without a photometer the luminance ratios of the display's three color channels that are used in a bit-stealing procedure to expand the luminance resolution of the display. Using a photometer we verified that the calibration achieved with this procedure is accurate for both LCD and CRT displays enabling testing of letter contrast sensitivity to 0.5%. Our visual calibration procedure enables clinical, internet and home implementation and calibration verification of electronic contrast testing. PMID- 23643844 TI - Ulcerative colitis in a child with partial trisomy 16. PMID- 23643845 TI - Synthetic pathway to 22,23-dioxocholestanic chain derivatives and their usefulness for obtaining brassinosteroid analogues. AB - Recognizing the functionality of the pentacyclic steroidal derivative 7a as important synthon to obtain new brassinosteroid analogs, we have accomplished the derivatization of hecogenin, a sapogenin from the 25R serie containing a carbonyl group at C-12, to a 22,23-dioxocholestanic chain derivative. Starting from hecogenin acetate (5a) or hecogenin tosylate (5b), we obtained two pentacyclic derivatives (7a and 7b) which were subjected to an oxidation reaction on the double bond at C-12(23) to obtain a 22,23-dioxocholestanic chain, with the regeneration of the carbonyl group at C-12. Reduction of the carbonyl groups lead to the 20-epi-12,23-dihydroxy-22-oxo system 11a-b. The absolute configuration of compound 11a was established by X-ray diffraction analysis. PMID- 23643842 TI - Maternal choline supplementation improves spatial learning and adult hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome. AB - In addition to intellectual disability, individuals with Down syndrome (DS) exhibit dementia by the third or fourth decade of life, due to the early onset of neuropathological changes typical of Alzheimer's disease (AD). Deficient ontogenetic neurogenesis contributes to the brain hypoplasia and hypocellularity evident in fetuses and children with DS. A murine model of DS and AD (the Ts65Dn mouse) exhibits key features of these disorders, notably deficient ontogenetic neurogenesis, degeneration of basal forebrain cholinergic neurons (BFCNs), and cognitive deficits. Adult hippocampal (HP) neurogenesis is also deficient in Ts65Dn mice and may contribute to the observed cognitive dysfunction. Herein, we demonstrate that supplementing the maternal diet with additional choline (approximately 4.5 times the amount in normal rodent chow) dramatically improved the performance of the adult trisomic offspring in a radial arm water maze task. Ts65Dn offspring of choline-supplemented dams performed significantly better than unsupplemented Ts65Dn mice. Furthermore, adult hippocampal neurogenesis was partially normalized in the maternal choline supplemented (MCS) trisomic offspring relative to their unsupplemented counterparts. A significant correlation was observed between adult hippocampal neurogenesis and performance in the water maze, suggesting that the increased neurogenesis seen in the supplemented trisomic mice contributed functionally to their improved spatial cognition. These findings suggest that supplementing the maternal diet with additional choline has significant translational potential for DS. PMID- 23643846 TI - Introduction to the special issue: 2012 AE-PCOS meeting. PMID- 23643847 TI - In vivo bisphenol-a release from dental pit and fissure sealants: a systematic review. AB - OBJECTIVE: To search the literature and assess the short- and long-term release of bisphenol-A (BPA) in human tissues after treatment with dental sealants. DATA: Two review authors performed data extraction independently and in duplicate using data collection forms. Disagreements were resolved by discussion with an arbiter. SOURCES: Electronic database searches of published and unpublished literature were performed. The following electronic databases with no language and publication date restrictions were searched: MEDLINE (via Ovid and Pubmed), EMBASE (via ovid), Cochrane Trials Register and CENTRAL. The reference lists of all eligible studies were hand-searched. STUDY SELECTION: In the absence of RCTs, six interventional and two observational studies, examining in vivo BPA release in human salivary, blood and urinary samples, were included. Due to the heterogeneity in methodology and reporting, the main synthesis of the results was qualitative. The quantitative synthesis based on the weighted Z-test could only include two studies. BPA levels identified in saliva ranged from traces below the method's detection limit to 30 MUg/ml. In urine, BPA quantities spanned from 0.17 mg/g to 45.4 mg/g. BPA was not traced in any blood sample at any point of time in the relevant studies. The quantitative analysis showed evidence of BPA release one hour after sealant placement compared to the amount traced before restoration (Stouffer's z trend: <0.001). CONCLUSIONS: The available evidence on this topic derived from studies that represent a moderate level of evidence. Nevertheless, the available evidence supports that BPA is released in saliva after sealant placement. CLINICAL SIGNIFICANCE: From the qualititative and quantitative synthesis of studies, it is reasonable to conclude that BPA is released after placement of some dental pit and fissure sealants in the oral cavity. The biggest quantities are detected in saliva immediately after or one hour after their placement. PMID- 23643848 TI - Effect of desensitising paste containing 8% arginine and calcium carbonate on biofilm formation of Streptococcus mutans in vitro. AB - OBJECTIVES: To evaluate the influence of desensitising paste containing 8% arginine and calcium carbonate (Ar-Ca) on biofilm formation on dentine. METHODS: Dentine discs were cut from extracted third molars and divided into the following three groups: no treatment, pumice treatment and Ar-Ca treatment. Surface topography and roughness were examined using scanning electron microscopy (SEM) and non-contact 3D surface profiler. After sterilisation, samples were incubated with Streptococcus mutans (S. mutans) for 4 h, 24 h and 72 h. Bacterial adhesion and biofilm formation were analysed using SEM, whereas MTT and lactic acid production assays were used to analyse the metabolic activity of S. mutans. RESULTS: After polishing with either pumice or Ar-Ca, the surfaces of the samples became smoother than in the control group. The Ra values of the three experimental groups decreased significantly to 0.43 MUm, 0.3 MUm and 0.26 MUm, respectively. Compared to the control group, fewer bacteria adhered to the dentine surface in the Ar-Ca group, while biofilm thickness decreased significantly for both groups after incubating for 24 h and 72 h. MTT and lactic acid production levers also showed a significant reduction in the Ar-Ca group. CONCLUSIONS: Ar-Ca appears to present antibiofilm efficacy and may provide a promising approach to combat bacterial infection in hypersensitive dentinal lesions. CLINICAL SIGNIFICANCE: As a clinical application of desensitising polishing paste, the paste containing 8% arginine and calcium carbonate could also inhibit the biofilm formation effectively. PMID- 23643849 TI - Identification of the monocyte activating motif in Mycobacterium tuberculosis chaperonin 60.1. AB - Evidence is emerging that moonlighting proteins, defined as proteins with more than one biological function, play important roles in bacterial virulence. The Mycobacterium tuberculosis chaperone, chaperonin 60.1, is a potent stimulator of human monocyte cytokine synthesis and modulator of giant cell and osteoclast formation. Previously, we had shown that these moonlighting activities resided in the equatorial domain of this protein. In this study, through the generation of chaperonin 60.1 amino acid sequence-deletion mutants and synthetic peptides, we have identified the minimal moonlighting site in this molecular chaperone responsible for monocyte activation as peptide sequence DGSVVVNKVSELPAGHGLNVNTLSYGDLAAD, residues 461-491, in the equatorial domain, Modelling of this biologically active sequence in the M. tuberculosis chaperonin 60.1 protein reveals a surface-exposed motif with significant alpha-helical structure. PMID- 23643850 TI - Regional difference of microcirculation in patients with asymmetric hypertrophic cardiomyopathy: transthoracic Doppler coronary flow velocity reserve analysis. AB - OBJECTIVE: To evaluate, by noninvasive coronary flow velocity reserve (CFVR), whether patients with asymmetric hypertrophic cardiomyopathy (HC), with or without left ventricular outflow tract obstruction, demonstrate significant regional differences of CFVR. METHODS: We evaluated 61 patients with HC (27 men; mean age 49 +/- 16 years), including 20 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 41 patients without obstruction (HCM). The control group included 20 age- and sex-matched subjects. Transthoracic Doppler echocardiography CFVR of the left anterior descending coronary artery (LAD) and the posterior descending coronary artery (PD) were performed, including calculation of relative CFVR as the ratio between CFVR LAD and CFVR PD. RESULTS: Compared with the controls, all the patients with HC had lower CFVR LAD (2.12 +/- 0.53 vs 3.34 +/- 0.67; P < .001) and CFVR PD (2.29 +/- 0.49 vs 3.21 +/- 0.65; P < .001). CFVR LAD in HOCM group in comparison with the HCM group was significantly lower (1.93 +/- 0.42 vs 2.22 +/- 0.55; P = .047), due to higher basal diastolic coronary flow velocities (0.40 +/- 0.09 vs 0.33 +/- 0.07 m/sec; P = .002), with similar hyperemic diastolic flow velocities (0.71 +/- 0.16 vs 0.76 +/- 0.19 m/sec; P = .330), respectively. There was no significant difference in CFVR PD between patients with HOCM and those with HCM (2.33 +/- 0.46 vs 2.27 +/- 0.50; P = .636), respectively. Relative CFVR was lower in the HOCM group compared with the HCM group (0.84 +/- 0.16 vs 0.98 +/- 0.14; P = .001). By multivariable regression analysis, left ventricular outflow tract gradient was the independent predictor of CFVR LAD (B = -0.24; P = .008) and relative CFVR (B = -0.34; P = .016). CONCLUSIONS: CFVR LAD and relative CFVR were significantly lower in patients with HOCM compared with patients with HCM. Regional differences of CFVR are present only in patients with significant left ventricular outflow tract obstruction, which suggests that obstruction per se, by increasing wall stress in basal conditions, leads to higher basal diastolic coronary flow velocities and results in lower CFVR in LAD compared with PD. PMID- 23643851 TI - Methods for detection and analysis of apoptosis signaling in the C. elegans germline. AB - This review assesses current and emerging methods for the detection, and analysis of apoptosis in the Caenorhabditis elegans germline. The nematode worm C. elegans is highly tractable to genetic manipulation, making it an excellent model for elucidating mechanisms of apoptosis signaling in a multicellular setting. Here we profile the most efficacious fluorescent tools to visualize and quantify germline apoptosis. We focus specifically on the application of fluorescent markers to screen by RNAi for genes and pathways that regulate germline apoptosis under normal conditions or in response to genotoxic stress. We also present the limitations of these methods, and suggest complimentary techniques in order that researchers new to the field can comprehensively assess apoptosis phenotypes in the C. elegans germline. PMID- 23643852 TI - Environmental lead exposure risks associated with children's outdoor playgrounds. AB - This study examines exposure risks associated with lead smelter emissions at children's public playgrounds in Port Pirie, South Australia. Lead and other metal values were measured in air, soil, surface dust and on pre- and post-play hand wipes. Playgrounds closest to the smelter were significantly more lead contaminated compared to those further away (t(27.545) = 3.76; p = .001). Port Pirie post-play hand wipes contained significantly higher lead loadings (maximum hand lead value of 49,432 MUg/m(2)) than pre-play hand wipes (t(27) = 3.57, p = .001). A 1% increase in air lead (MUg/m(3)) was related to a 0.713% increase in lead dust on play surfaces (95% CI, 0.253-1.174), and a 0.612% increase in post play wipe lead (95% CI, 0.257-0.970). Contaminated dust from smelter emissions is determined as the source and cause of childhood lead poisoning at a rate of approximately one child every third day. PMID- 23643853 TI - Serum adhesion molecules, outcome and neuro-psychological function in acute traumatic brain injury patients. AB - BACKGROUND: Serum concentrations of adhesion molecules may be associated with secondary brain injury after acute traumatic brain injury (TBI). METHODS: Blood samples of 68 patients admitted within 24h after TBI were obtained on admission and on Days 4 and 7 after TBI. Patients received neuro-psychological testing on discharge and at 3 months after TBI. RESULTS: Compared to controls, patients with acute TBI had markedly increased sICAM-1 and sVCAM-1 on presentation (p=0.002 and p=0.021, respectively), but markedly decreased sL-selectin and sE-selectin (p=0.009 and p<=0.001, respectively). Outcome was assessed upon discharge using the Glasgow Outcome Scale (GOS). Good outcome was defined as GOS >=4 and poor outcome as GOS <=3. Motor deficits on admission (p<=0.001), Glasgow Coma Scale score on admission (p=0.002), Injury Severity Score on admission (p=0.009), neuro surgical intervention (p=0.004), post-traumatic seizure (p=0.04), and sVCAM-1 level on admission (p=0.033) were significant risk factors of outcome. A sVCAM-1 cut-off value of 752.5ng/ml on admission had 80.0% sensitivity and 68.1% specificity for predicting outcome. CONCLUSION: Serum adhesion molecules are not specific for predicting outcome in patients with TBI. However, higher mean levels of these molecules on admission may imply more severe inflammatory response causing secondary brain injury and worse neuro-psychological function. These molecules may be added as evaluation markers in clinical practice. PMID- 23643854 TI - Hepcidin-25: Measurement by LC-MS/MS in serum and urine, reference ranges and urinary fractional excretion. AB - A liquid chromatography tandem-mass spectrometry (LC-MS/MS) method was developed for reliably quantifying hepcidin-25 in human urine and serum. A 95% reference range was established for serum hepcidin-25 levels by standardizing the sampling time between 8:00am and 11:00am in 90 apparently healthy volunteers. The association between hepcidin-25 concentration and other biological parameters was studied using multivariable analysis and the coefficient of renal excretion of hepcidin-25 was calculated. Preanalytical variables were also investigated. The LC-MS/MS method was validated using a recent validation strategy based on accuracy profiles. Good results were obtained in terms of trueness, precision, and linearity in the following dosing ranges: from 0.77 to 200nmol/L for urine and from 0.48 to 100nmol/L for serum. The 95% reference range of serum hepcidin 25 concentration established after excluding known conditions that affect hepcidin-25 expression was 1.5 to 15.2nmol/L. A difference between genders was demonstrated with a median concentration of 5.5 versus 7.2nmol/L for women and men, respectively. Serum hepcidin-25 concentrations were strongly correlated with ferritin and, to a lesser extent, with iron levels. The coefficient of renal excretion ranged from 0.1 to 16.4%. Higher values of hepcidin-25 concentrations were observed on ethylene diamine tetraacetate tubes compared to serum or lithium heparin devices. PMID- 23643855 TI - Visual thalamocortical circuits in parvalbumin-deficient mice. AB - The dorsal lateral geniculate nucleus (dLGN) is considered as the visual gateway to the visual cortex (VC) and sends collaterals to the thalamic reticular nucleus (RTN) that in turn receives collaterals of the corticofugal feedback projections. At all levels of this thalamocortical circuit there are GABAergic neurons expressing the calcium-buffer parvalbumin (PV). The present study reports for the first time the analysis of in vivo extracellular electrophysiological recordings performed simultaneously in dLGN, RTN and VC of anesthetized wild-type (WT) and parvalbumin-deficient (PVKO) mice. The firing rates of VC and RTN cells were increased in PVKO during spontaneous activity as well as in the presence of a photic stimulation (strobe flash at 2.5Hz). Interestingly, dLGN cells in PVKO did not show significant changes in the rate of firing in comparison to WT. dLGN responses to the light flashes were characterized by ripples of inhibition and phasic excitation/rebound. We have analyzed the pattern of functional interactions between pairs of neighboring cells in VC, dLGN and RTN and across these areas in simultaneously recorded thalamocortical triplets, with one neuron from each area. We found that in PVKO the strength of the interactions tended to decrease locally, between neighboring cells, but tended to increase across the areas. The combination of these analyses provides new evidence on the important role played by PV-expression in regulating information processing in the central visual pathway suggesting that the ability to process information along parallel channels is decreased in the thalamocortical pathway of PV-deficient mice. This article is part of a Special Issue entitled Neural Coding 2012. PMID- 23643856 TI - Food restriction-induced autophagy modulates degradation of mutant SOD1 in an amyotrophic lateral sclerosis mouse model. AB - Autophagy dysregulation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). The expression of LC3II and sequestosome 1 (P62) was progressively increased in the lumbar spinal cord of ALS mice. However, whether autophagy is activated or inhibited is still unclear. By treating mice with food restriction, a well-recognized way to induce autophagy, we found that 48 h of food restriction significantly reduced p62 and mutated SOD1 expressions at onset stage but not at pre-end stage in the spinal cord of SOD1-G93A mice. These data indicate that activating autophagy at a certain disease stage may have potential protective effects on ALS. PMID- 23643857 TI - The effect of native-language experience on the sensory-obligatory components, the P1-N1-P2 and the T-complex. AB - The influence of native-language experience on sensory-obligatory auditory-evoked potentials (AEPs) was investigated in native-English and native-Polish listeners. AEPs were recorded to the first word in nonsense word pairs, while participants performed a syllable identification task to the second word in the pairs. Nonsense words contained phoneme sequence onsets (i.e., /pt/, /pet/, /st/ and /set/) that occur in the Polish and English languages, with the exception that /pt/ at syllable onset is an illegal phonotactic form in English. P1-N1-P2 waveforms from fronto-central electrode sites were comparable in English and Polish listeners, even though, these same English participants were unable to distinguish the nonsense words having /pt/ and /pet/ onsets. The P1-N1-P2 complex indexed the temporal characteristics of the word stimuli in the same manner for both language groups. Taken together, these findings suggest that the fronto central P1-N1-P2 complex reflects acoustic feature processing of speech and is not significantly influenced by exposure to the phoneme sequences of the native language. In contrast, the T-complex from bilateral posterior temporal sites was found to index phonological as well as acoustic feature processing to the nonsense word stimuli. An enhanced negativity for the /pt/ cluster relative to its contrast sequence (i.e., /pet/) occurred only for the Polish listeners, suggesting that neural networks within non-primary auditory cortex may be involved in early cortical phonological processing. PMID- 23643859 TI - Therapeutic impact of eicosapentaenoic acid on ischemic brain damage following transient focal cerebral ischemia in rats. AB - Long-chain n-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), have been shown to reduce ischemic neuronal injury. We investigated the effects of ethyl-EPA (EPA-E) on ischemic brain damage using a rat transient focal cerebral ischemia model. Male Sprague-Dawley rats (n=105) were subjected to 90 min of focal cerebral ischemia. EPA-E (100mg/kg/day) or vehicle was administered once a day for 3, 5 or 7 days prior to ischemia. Different withdrawal intervals of 3, 5, and 7 days prior to ischemia following 7-day pretreatment with EPA-E or vehicle were also examined. In addition, post-ischemic administration of EPA-E was investigated. Pretreatment with EPA-E for 7 and 5 days, but not 3 days, showed significant infarct volume reduction and neurological improvements when compared with vehicle pretreatment. In addition, withdrawal of EPA-E administration for 3 days, but not 5 and 7 days, also demonstrated significant infarct volume reduction and neurological improvements when compared with vehicle treatment. Post-ischemic treatment of EPA-E did not show any neuroprotection. Immunohistochemistry revealed that 7-day pretreatment with EPA-E significantly reduced cortical expression of 8-hydroxydeoxyguanosine (maker for oxidative DNA damage), 4-hydroxy-2-nonenal (maker for lipid peroxidation), phosphorylated adducin (marker for Rho-kinase activation) and von Willebrand factor (endothelial marker) when compared with vehicle pretreatment. In addition, phosphorylated adducin expression co-localized with von Willebrand factor immunoreactivity. The present study established the neuroprotective effect of EPA-E on ischemic brain damage following transient focal cerebral ischemia in rats, which may be involved in the suppression of oxidative stress and endothelial Rho-kinase activation. PMID- 23643858 TI - AMPA and GABA(A/B) receptor subunit expression in the cortex of adult squirrel monkeys during peripheral nerve regeneration. AB - The primate somatosensory neuroaxis provides a highly translational model system with which to investigate adult neural plasticity. Here, we report immunohistochemical staining data for AMPA and GABAA/B receptor subunits in the area 3b cortex of adult squirrel monkeys one and five months after median nerve compression. This method of nerve injury was selected because it allows unique insight into how receptor expression changes during the regeneration of the peripheral nerve. One month after nerve compression, the pattern of subunit staining provides evidence that the cortex enters a state of reorganization. GABA alpha1 receptor subunits are significantly down-regulated in layer IV, V, and VI. Glur2/3 AMPA receptor subunits and postsynaptic GABABR1b receptor subunits are up and down regulated respectively across all layers of cortex. After five months of recovery from nerve compression, the pattern of AMPA and GABAA/B receptor subunits remain significantly altered in a layer specific manner. In layer II/III, GluR1, GluR2/3, and GABA alpha1 subunit expression is significantly up regulated while post synaptic GABABR1b receptor subunits are significantly down regulated. In layer VI, V, and VI the GluR2/3 and presynaptic GABABR1a receptor subunits are significantly up-regulated, while the postsynaptic GABABR1b receptor subunits remain significantly down-regulated. Taken together, these results suggest that following nerve injury the cortex enters a state of reorganization that has persistent effects on cortical plasticity even after partial or total reinnervation of the peripheral nerve. PMID- 23643860 TI - Cytotoxicity, genotoxicity, and mutagenicity of 1-chloro-2-hydroxy-3-butene and 1 chloro-3-buten-2-one, two alternative metabolites of 1,3-butadiene. AB - The cytotoxicity, genotoxicity, and mutagenicity of 1-chloro-2-hydroxy-3-butene (CHB), a known in vitro metabolite of the human carcinogen 1,3-butadiene, have not previously been investigated. Because CHB can be bioactivated by alcohol dehydrogenases to yield 1-chloro-3-buten-2-one (CBO), a bifunctional alkylating agent that caused globin-chain cross-links in erythrocytes, in the present study we investigated the cytotoxic and genotoxic potential of CHB and CBO in human normal hepatocyte L02 cells using the MTT assay, the relative cloning efficiency assay and the comet assay. We also investigated the mutagenic potential of these compounds with the Ames test using Salmonella strains TA1535 and TA1537. The results provide clear evidence for CHB and CBO being both cytotoxic and genotoxic with CBO being approximately 100-fold more potent than CHB. Interestingly, CHB generated both single-strand breaks and alkali-labile sites on DNA, whereas CBO produced only alkali-labile sites. CHB did not directly result in DNA breaks, whereas CBO was capable of directly generating breaks on DNA. Interestingly, both compounds did not induce DNA cross-links as examined by the comet assay. The Ames test results showed that CHB induced point mutation but not frameshift mutation, whereas the toxic effects of CBO made it difficult to reliably assess the mutagenic potential of CBO in the two strains. Collectively, the results suggest that CHB and CBO may play a role in the mutagenicity and carcinogenicity of 1,3 butadiene. PMID- 23643862 TI - Architecture of cortical bone determines in part its remodelling and structural decay. AB - Bone remodelling accelerates and becomes unbalanced after menopause; less bone is deposited than resorbed from the surface of canals traversing the cortex. The canals enlarge so the intracortical surface area enlarges. We hypothesized that cortical bone with a larger internal surface area, due to more or larger canals, is more liable to being remodelled, further enlarging the internal surface area and facilitating more remodelling and structural deterioration. For 95 monozygotic twin pairs aged 40-61 years, we measured internal cortical surface areas and structure of the distal tibia using high resolution peripheral computed tomography, and three circulating bone remodelling markers. Using principal component (PC) analyses, we identified one summary measure of intracortical and endocortical bone surface areas, cortical porosity and volumetric bone mineral density (structure PC), and one summary measure of bone remodelling markers (remodelling PC). We applied a twin regression analysis (Inference on Causation by Examination of Familial Confounding; ICE FALCON) to assess consistency with a causal component in the association between a predictor (X) and an outcome (Y) by testing if the regression coefficient for the X value of the co-twin decreases after adjusting for the X value of the twin herself. With Y = remodelling PC, the regression coefficient for structure PC in the co-twin was 0.29 (p < 0.001) before, and 0.18 (p = 0.03) after, adjusting for her own structure PC (40% lower; p = 0.06). With Y = structure PC, the regression coefficient for remodelling PC in the co-twin was 0.17 (p = 0.01) before, and 0.20 (p < 0.001) after, adjusting for her own remodelling PC (22% higher; p = 0.7). The structure of bone, its surface area to bone matrix volume configuration, might contribute in part to its own remodelling and deterioration, but not vice versa. PMID- 23643861 TI - Cloning and characterization of a novel human BRMS1 transcript variant in hepatocellular carcinoma cells. AB - Breast cancer metastasis suppressor 1 (BRMS1) is able to suppress tumor metastasis without affecting primary tumor growth in various cancers. Here, we report a novel transcript variant of human BRMS1, termed BRMS1.vh. BRMS1.vh is identical to the major BRMS1 variant (BRMS1.v1) except for missing base pairs 683 775, encoding a 215-amino acid protein lacking a functional nuclear localization sequence. Expression of BRMS1.vh in hepatocellular carcinoma (HCC) cells suppressed NF-kappaB signaling pathway, sensitized cells to apoptotic stimuli, leading to suppressed tumor growth. Taken together, our results suggest a potential role for BRMS1.vh in regulating cell apoptosis and tumor growth in HCC. PMID- 23643863 TI - Load-bearing capacity of soldered and subsequently veneered 4-unit zirconia FDPs. AB - OBJECTIVES: This study evaluated and compared the impact of soldering on fracture resistance of veneered 4-unit fixed dental prostheses (FDPs). MATERIALS AND METHODS: Forty-eight 4-unit zirconia frameworks were milled and randomly divided in four groups (n=12). Untreated frameworks served as control, one group underwent thermal treatment, one group was sectioned and soldered in the connector between both pontics and one group was sectioned and soldered centrally in the mesial pontic. All frameworks were veneered with glass-ceramic material in powder build-up technique. The fracture load was determined on two different failure types, namely on chipping of the veneering ceramic and on total fracture of the FDP. Data were analysed using descriptive statistics, one-way ANOVA together with the Scheffe post-hoc test and Weibull statistics (p<0.05). RESULTS: The mean range of fracture load of chipped FDPs was determined between 655 N and 789 N; no differences between the tested groups were found (p=0.587). The mean fracture load until total fracture ranged in all tested groups from 768 N to 1261 N. Sound FDPs and soldered FDPs in the connector area presented lower mean total fracture load compared to soldered FDPs in the pontic (p<0.001). CONCLUSIONS: Soldered zirconia frameworks showed similar in-vitro performance compared to sound frameworks. PMID- 23643864 TI - Brownian nanoimaging of interface dynamics and ligand-receptor binding at cell surfaces in 3-D. AB - We describe a method for nanoimaging interfacial dynamics and ligand-receptor binding at surfaces of live cells in 3-D. The imaging probe is a 1-MUm diameter glass bead confined by a soft laser trap to create a "cloud" of fluctuating states. Using a facile on-line method of video image analysis, the probe displacements are reported at ~10 ms intervals with bare precisions (+/-SD) of 4 6 nm along the optical axis (elevation) and 2 nm in the transverse directions. We demonstrate how the Brownian distributions are analyzed to characterize the free energy potential of each small probe in 3-D taking into account the blur effect of its motions during CCD image capture. Then, using the approach to image interactions of a labeled probe with lamellae of leukocytic cells spreading on cover-glass substrates, we show that deformations of the soft distribution in probe elevations provide both a sensitive long-range sensor for defining the steric topography of a cell lamella and a fast telemetry for reporting rare events of probe binding with its surface receptors. Invoking established principles of Brownian physics and statistical thermodynamics, we describe an off line method of super resolution that improves precision of probe separations from a non-reactive steric boundary to ~1 nm. PMID- 23643865 TI - A guide to design and optimization of reporter assays for 3' untranslated region mediated regulation of mammalian messenger RNAs. AB - Post-transcriptional regulatory mechanisms are pervasive in the control of gene expression. Regulatory sequences within transcripts can control RNA processing, localization, translation efficiency, and stability of the RNA. Regulation is mediated by a diverse set of RNA binding regulators, including proteins and RNAs, which interact with specific mRNA sequences that are often found in untranslated regions. The potential for vast post-transcriptional control exists: mammalian mRNAs contain extensive untranslated regions and their genomes encode many hundreds of RNA binding proteins and non-coding RNAs. Facile quantitative methods are necessary to study the activities and mechanisms of regulatory sequences and the RNA binding factors that recognize them. Here we discuss the design and implementation of luciferase-based reporter assays to measure the effect of regulatory RNA sequences on protein and RNA expression. Protocols are described for transfection of the reporter into cells, measurement of protein expression levels with luciferase activity assays, RNA purification, and measurement of mRNA levels by reverse-transcription and quantitative polymerase chain reaction. For each assay, troubleshooting of common problems and critical controls are discussed. We present our optimized techniques and data from studies that measure specific and direct repression (i.e. negative regulation) of mRNAs by members of the PUF family of RNA binding proteins in cultured human cells. PMID- 23643866 TI - A proteomics workflow for quantitative and time-resolved analysis of adaptation reactions of internalized bacteria. AB - The development of a mass spectrometric workflow for the sensitive identification and quantitation of the kinetics of changes in metaproteomes, or in particular bacterial pathogens after internalization by host cells, is described. This procedure employs three essential stages: (i) SILAC pulse-chase labeling and infection assay; (ii) isolation of bacteria by GFP-assisted cell sorting; (iii) mass spectrometry-based proteome analysis. This approach displays greater sensitivity than techniques relying on conventional cell sorting and protein separation, due to an efficient combination of a filtration-based purification and an on-membrane digestion. We exemplary describe the use of the workflow for the identification and quantitation of the proteome of 106 cells of Staphylococcus aureus after internalization by S9 human bronchial epithelial cells. With minor modifications, the workflow described can be applied for the characterization of other host-pathogen pairs, permitting identification and quantitation of hundreds of bacterial proteins over a time range of several hours post infection. PMID- 23643868 TI - Radiographic findings of juvenile osteochondral conditions detected in 392 foals using a field radiographic protocol. AB - Radiographic examination in young horses is commonly used to detect juvenile osteochondral conditions (JOCC). The aim of this study is to present the radiographic findings (RF) detected at the age of 6months in the joints of 392 foals from three breeds: French Trotter Standardbreds (FT), Selle-Francais Warmbloods (SF) and Thoroughbreds (TB). Radiographic examination included lateromedial views of the fore and hind digits, tarsi and stifles, and dorsopalmar projections of both carpi. In all areas RF indicative of JOCC were classified according to a four-grade severity scoring system. Distribution and severity of the RF varied according to breed with the SF most affected. The most frequently affected site was the hind fetlock (28.3% of foals). The second most affected site was the fore fetlock in TB and SF, while the carpus and proximal tarsus were the second and third affected sites in FT. The radiographic protocol and grading system used can serve as a basis for field research and further studies on the evolution of RF, risk factors for JOCC or the correlation between RF and the subsequent athletic career of horses. PMID- 23643869 TI - Impact of maedi-visna in intensively managed dairy sheep. AB - Maedi-visna (MV) is a slow lentiviral disease of sheep that has a significant economic impact in many sheep-producing regions although there remains a paucity of data relating to actual production losses resulting from this disease. The objective of this study was to evaluate direct losses, through death or culling, from two dairy sheep flocks with high seroprevalences of infection over a 2 year period. Maedi-visna was found, either alone or in combination with other diseases, to be the most common disease diagnosed in these sheep, and the major cause of direct animal losses in the two flocks. Moderate to severe lesions associated with MV were found in 52% and 80% of the sheep, respectively, affecting the lungs, brain and/or mammary glands. Despite the similarity of the two flocks under study in terms of breed, number of animals, geographical proximity, and inter-change of rams, a striking difference was observed regarding the clinical presentation of the disease: in one flock the respiratory form was dominant while in the other 70% of animals died or were culled because of neurological signs. PMID- 23643867 TI - Methods of effective conjugation of antigens to nanoparticles as non-inflammatory vaccine carriers. AB - It has recently become clear that nanoparticle size is a major determinant for how antigen presenting cells (APCs), and specifically dendritic cells (DC) recognize and handle particles, and hence a critical parameter for the formulation of particulate vaccines that aim to induce immunity by targeting DC. Our previous studies in mice and sheep have shown polystyrene nanoparticles of 40 50 nm (PSNPs) with covalently bound antigen offer a new class of vaccines, which contain only 2 elements, antigen and particle, and no added inflammatory stimuli, but evoke very potent combined CD8 T cell and antibody responses. Herein we have optimized the methods for antigen conjugation to PSNPs to controllably promote a single antigen (protein or peptide) layer coating on the nanoparticle. Surprisingly, these nanovaccines not only continued to induce high levels of CD8 T cells in vivo, but were further more potent antibody inducers than nanoparticles containing multiple antigen layers. Addressing the issue of antigen loading on PSNPs, we found an optimal range, above or below which immunogenicity is changed either for antibodies or CD8 T cells. The mechanism behind the induction of high levels of CD8 T cells was further explored by assessing the DC subset that takes up the PSNPs in vivo, and these were found to be preferentially CD8(+) CD11c(+) DC in the lymph node draining the injection site. Since the levels of induced antibodies were highly elevated, and CD8(+) DC do not traditionally induce antibodies, we further sought to find if, despite no detectable inflammation at the injection site, the PSNPs may perhaps induce inflammatory cytokines locally in the lymph node after injection, or systemically in sera, resulting in an adjuvant effect. The initial findings presented herein show no detectable induction of the key inflammatory cytokines such as TNF-alpha, IL-1 or IL-6, suggesting a novel "non-inflammatory" adjuvant mechanism. PMID- 23643870 TI - Physico-chemical properties of R140G and K141Q mutants of human small heat shock protein HspB1 associated with hereditary peripheral neuropathies. AB - Some physico-chemical properties of R140G and K141Q mutants of human small heat shock protein HspB1 associated with hereditary peripheral neuropathy were analyzed. Mutation K141Q did not affect intrinsic Trp fluorescence and interaction with hydrophobic probe bis-ANS, whereas mutation R140G decreased both intrinsic fluorescence and fluorescence of bis-ANS bound to HspB1. Both mutations decreased thermal stability of HspB1. Mutation R140G increased, whereas mutation K141Q decreased the rate of trypsinolysis of the central part (residues 5-188) of HspB1. Both the wild type HspB1 and its K141Q mutant formed large oligomers with apparent molecular weight ~560 kDa. The R140G mutant formed two types of oligomers, i.e. large oligomers tending to aggregate and small oligomers with apparent molecular weight ~70 kDa. The wild type HspB1 formed mixed homooligomers with R140G mutant with apparent molecular weight ~610 kDa. The R140G mutant was unable to form high molecular weight heterooligomers with HspB6, whereas the K141Q mutant formed two types of heterooligomers with HspB6. In vitro measured chaperone-like activity of the wild type HspB1 was comparable with that of K141Q mutant and was much higher than that of R140G mutant. Mutations of homologous hot spot Arg (R140G of HspB1 and R120G of alphaB-crystallin) induced similar changes in the properties of two small heat shock proteins, whereas mutations of two neighboring residues (R140 and K141) induced different changes in the properties of HspB1. PMID- 23643871 TI - Galectin-7 levels predict radiation response in squamous cell carcinoma of the cervix. AB - OBJECTIVE: We previously found that galectin-7 was upregulated in patients with cervical cancer who remained recurrence-free after chemoradiation. We hypothesized that pretreatment levels of galectin-7 predict radiation response in patients with squamous cell carcinoma (SCC) of the cervix. METHODS: Galectin-7 expression was assessed by immunohistochemical staining of a tissue microarray of paraffin-embedded specimens from 161 patients with cervical SCC treated with definitive radiation therapy in 1980-1999. Galectin-7 expression was scored as absent or present. Distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) were computed using the Kaplan-Meier method and log-rank tests. RESULTS: The median age at diagnosis was 45 years (range 21-85) and median follow-up interval was 71 months (range 0-285). Of the 161 patients, 105 (65%) had FIGO stage IB disease, 18 (11%) stage IIA, and 38 (24%) stage IIB. Median tumor diameter was 5.5 cm (range 3.5-8). Seven patients (4%) received concurrent chemotherapy; 139 patients (86%) had galectin-7-positive tumors and 22 (14%) galectin-7-negative tumors. Five-year DMFS rates for patients with galectin-7-positive versus -negative tumors were 73% and 55% (p=0.05); DSS, 65% and 36% (p=0.004); and OS, 64% and 36% (p=0.005). In multivariate analysis adjusting for age, stage, and tumor diameter, galectin-7 expression remained a significant predictor of DMFS (hazard ratio [HR]=0.43, p=0.03), DSS (HR=0.34, p=0.001), and OS (HR=0.34, p=0.001). CONCLUSIONS: Elevated galectin-7 expression is associated with improved outcomes after radiation therapy for cervical cancer. Further studies are required to validate these findings and clarify the role of galectin-7 in disease progression and radiation response. PMID- 23643872 TI - A complementary LC-ESI-MS and MALDI-TOF approach for screening antibacterial proteomic signature of farmed European sea bass mucus. AB - Antibacterial protection in the mucus is provided by antimicrobial compounds and till now few numbers of AMP and proteins were identified. Herein, mass spectral profiling of fresh mucus from farmed sea bass (Dicentrarchus labrax) using Matrix assisted laser desorption/ionization-time-of-flight mass spectrometer (MALDI-TOF) and liquid chromatography mass spectrometry is investigated in order to survey the infective/healthy status of the mucus. We identify AMP peptides of 2891.7, 2919.45 and 2286.6 Da molecular weight respectively and characterize Chrysophsins in the mucus of Dicentrarchus labrax. These peptides display broad-spectrum bactericidal activity against Gram-negative (Minimum Inhibitory Concentrations namely MICs < 0.5 MUM) and Gram-positive bacteria (MICs < 0.5 MUM) including Escherichia coli and Bacillus subtilis. Furthermore, sensitivity to yeast Candida albicans is reported for the first time and shows interesting MICs of less than 2 MUM. We also demonstrate that the fish pathogen Aeromonas salmonoicida is sensitive to Chrysophsins (MICs ranging between 5 and 14 MUM). Our mucus molecular mass mapping developed approach allows for fast exploration of immune status. Our data provides evidence that Chrysophsins are secreted by immune cells and are released in mucus of non-challenged farmed European sea bass. These results suggest that Chrysophsins, secreted by gills of red sea bream, are an important widespread component of Teleostei defense against disease. PMID- 23643873 TI - Cloning and expression analysis of grouper (Epinephelus coioides) M-CSFR gene post Cryptocaryon irritans infection and distribution of M-CSFR(+) cells. AB - The M-CSF/M-CSFR system plays a central role in the cell survival, proliferation, differentiation and maturation of the monocyte/macrophage lineage. In present study, we cloned the sequence of the M-CSFR cDNA from the orange-spotted grouper (Epinephelus coioides). Sequence analysis reveals that ten cysteines in the extracellular immunoglobulin-like (Ig-like) domains of EcM-CSFR are conserved in fish and mammals, its nine possible N-glycosylation sites are conserved in fish but not mammals, 7 of 8 identified mammal M-CSFR intracellular autophosphorylation tyrosine sites was found in EcM-CSFR. Real-time PCR showed that the constitutive expression level of EcM-CSFR was the highest in the spleen, less in the gill, kidney, head kidney and liver, least in the blood, skin, gut and thymus. A rabbit anti-EcM-CSFR polyclonal antibody against the recombinant EcM-CSFR extracellular domain was developed and it was efficient in labeling the monocytes and macrophages isolated from the head kidney. Immunochemistry analysis showed that M-CSFR(+) cells located in all tested paraffin-embedded tissues and M CSFR(+) cell centres with the characteristic of melano-macrophage centres(MMCs) was found in the spleen, head kidney, kidney, gut and liver. All these results indicate the widespread distribution of macrophages in grouper tissues and its importance in fish immune system. In Crytocaryon irritans infected grouper, EcM CSFR was transient up-regulated and rapidly down-regulated in skin, gill, head kidney and spleen. The possible activation mechanism of macrophage via EcM-CSFR signal transduction in the fish anti-C. irritans infection was discussed. PMID- 23643874 TI - Immunological responses of customised probiotics-fed marron, Cherax tenuimanus, (Smith 1912) when challenged with Vibrio mimicus. AB - A two-phased experiment was conducted to investigate the effects of dietary supplementation of customised probiotics on marron physiology. During the first phase marron were fed probiotic supplemented feed for 70 days, while in phase two the same marron were challenged with Vibrio mimicus and their physiological responses were investigated for 4 days post-challenged. The experiment was carried out in a purpose-built room, designed for aquaculture research, using 18 of 250 L cylindrical plastic tanks. Five species of isolated probiotic bacteria from commercial probiotic products and marron's intestine were tested in this experiment. The probiotic bacteria were (Bacillus sp.); A10 (Bacillus mycoides); A12 (Shewanella sp.); PM3 (Bacillus subtilis); and PM4 (Bacillus sp.), which were added to the formulated basal marron diet (34% crude protein, 8% crude lipid, 6% ash) at a concentration of 10(8) cfu/g of feed. Immune responses of marron fed probiotics were evaluated by investigating organosomatic indices, growth rate, survival, intermoult period, total haemocytes counts (THC), proportion of granular cells (GC), bacteraemia, bacteria load in the intestine and water quality. The results showed that dietary supplementation of probiotics in marron had no significant impact on growth, intermoult period and survival of the marron. However, their supplementation improved the physiological condition of marron in terms of significantly higher tail muscle indices, THC and proportion of granular cells (GC) and reduced bacterial load in the haemolymph. The addition of probiotics in marron diets also increased the bacteria load in the marron intestine. In addition, dietary supplementation of the customised probiotics was effective in improving the resistance of marron against V. mimicus as they had higher THC, higher proportion of GC and lower presence of bacteria in their haemolymph, after marron were challenged with V. mimicus. The results also showed that probiotic Bacillus mycoides (A10) and PM4 are the most beneficial dietary probiotics for marron health. PMID- 23643875 TI - Conserved structural complement component C3 in miiuy croaker Miichthys miiuy and their involvement in pathogenic bacteria induced immunity. AB - Complement component C3 is a key protein in the complement system whose activation is essential for all the important functions performed by this system. In this study, the complete C3 cDNA sequence was isolated from the miiuy croaker (Miichthys miiuy), which was high similarity to other complement C3. In this study, we report the primary sequence, the tissue expression profile, the polypeptide domain architecture and the phylogenetic analysis of miiuy croaker C3 gene. Rapid amplification of the cDNA ends (RACE) yielded the full open reading frame of this protein (4974 bp), and subsequent analysis indicated that the M. miiuy C3 gene encoded a protein of 1657 amino acids. The deduced amino acid sequence showed that M. miiuy C3 has conserved residues and domains known to be critical for C3 function. Phylogenetic analysis showed that miiuy croaker was most closely related to Epinephelus coioides. Expression analysis showed that C3 was expressed differentially in miiuy croaker tissues, while liver was the main source of C3 expression. Infection of miiuy croaker with Vibrio anguillarum resulted in significant changes expression of C3 gene in the immune-related tissues. These results showed that C3 gene might play an important role in immune mechanisms. PMID- 23643876 TI - Immune effects of a bivalent expressed outer membrane protein to American eels (Anguilla rostrota). AB - The specific and non-specific immune parameters and protection of American eels (Anguilla rostrata) were evaluated after immunized eels with a bivalent expressed out membrane protein (OMP) of porin II of Aeromonas hydrophila and ompS2 of Edwardsiella tarda. One hundred eighty eels were distributed into 3 equal groups and intraperitoneal (i.p) injection with phosphate-buffered saline (PBS group), formalin-killed-whole-cell (FKC) of A. hydrophila and E. tarda (FKC group) or the bivalent OMP (OMP group). The lymphocytes and red blood cells collected on 14, 21 and 42 days post-vaccination were used to evaluate the stimulation index (SI) and the sera collected on 14, 21, 28 and 42 days were used to assize the titers of specific antibody as well as lysozyme activity. Lysozyme activities in skin mucus, suspension of liver and kidney were also recorded on 14, 21 and 28 days. On 28 d post-vaccination, eels from all three groups were challenged by i.p injection of live A. hydrophila or E. tarda. The results show that, compared with the PBS group, proliferation of lymphocytes in OMP group was significantly (P < 0.05) enhanced on 21 days, and the serum titers of anti-A. hydrophila and anti- E. tarda antibody in eels of FKC and OMP group were significant increased (P < 0.05 or P < 0.01) on 14, 21 and 28 days. Activity of the lysozyme in serum, skin mucus, liver and kidney were significant changed (P < 0.05 or P < 0.01) between the three groups. Relative Percent Survival (RPS) after challenged with A. hydrophila on 28 days post immunization in two vaccinated groups vs. PBS group were 50%, and the RPS challenge E. tarda in FKC and OMP vs. PBS group were 50% and 37.5% respectively. These results suggest that American eels immunized with the bivalent OMP would positively affect specific as well as non-specific immune parameters and protect against infection by the two pathogens in freshwater farming. PMID- 23643878 TI - An outbreak of lethal adenovirus infection among different otariid species. AB - An outbreak of fatal fulminant hepatitis at a Japanese aquarium involved 3 otariids: a California sea lion (Zalophus californianus), a South African fur seal (Arctocephalus pusillus) and a South American sea lion (Otaria flavescens). In a span of about a week in February 2012, 3 otariids showed diarrhea and were acutely low-spirited; subsequently, all three animals died within a period of 3 days. Markedly increased aspartate amino transferase and alanine amino transferase activities were observed. Necrotic hepatitis and eosinophilic intranuclear inclusion bodies in liver hepatocytes and intestinal epithelial cells were observed in the South American sea lion on histological examination. Otarine adenovirus DNA was detected from the livers of all three animals by polymerase chain reaction and determination of the sequences showed that all were identical. These results suggest that a single otarine adenovirus strain may have been the etiological agent of this outbreak of fatal fulminant hepatitis among the different otariid species, and it may be a lethal threat to wild and captive otariids. This is the first evidence of an outbreak of lethal adenovirus infection among different otariid species. PMID- 23643879 TI - Effect of gait speed changes on foot loading characteristics in children. AB - Gait speed has been shown to influence foot loading patterns in adults but the mechanism has not been investigated in children. The present study investigated the effects of changes in gait speed on foot loading characteristics in 20 typically developing children who participated in plantar pressure measurements at normal, slow and fast walking speeds. In spite of shorter contact times in the fast walking speed condition, significantly increased foot loading was seen in the hindfoot, medial and central forefoot and toes while it slightly decreased in the lateral midfoot and forefoot. The results generally confirm the findings in adults that gait speed does not uniformly affect foot loading characteristics and that these effects should be kept in mind when comparing different subject groups or children at repeated measurement occasions. PMID- 23643880 TI - Validity of the Microsoft Kinect for providing lateral trunk lean feedback during gait retraining. AB - Gait retraining programs are prescribed to assist in the rehabilitation process of many clinical conditions. Using lateral trunk lean modification as the model, the aim of this study was to assess the concurrent validity of kinematic data recorded using a marker-based 3D motion analysis (3DMA) system and a low-cost alternative, the Microsoft KinectTM (Kinect), during a gait retraining session. Twenty healthy adults were trained to modify their gait to obtain a lateral trunk lean angle of 10 degrees . Real-time biofeedback of the lateral trunk lean angle was provided on a computer screen in front of the subject using data extracted from the Kinect skeletal tracking algorithm. Marker coordinate data were concurrently recorded using the 3DMA system, and the similarity and equivalency of the trunk lean angle data from each system were compared. The lateral trunk lean angle data obtained from the Kinect system without any form of calibration resulted in errors of a high (>2 degrees ) magnitude (mean error=3.2+/-2.2 degrees ). Performing global and individualized calibration significantly (P<0.001) improved this error to 1.7+/-1.5 degrees and 0.8+/-0.8 degrees respectively. With the addition of a simple calibration the anatomical position coordinates of the Kinect can be used to create a real-time biofeedback system for gait retraining. Given that this system is low-cost, portable and does not require any sensors to be attached to the body, it could provide numerous advantages when compared to laboratory-based gait retraining systems. PMID- 23643881 TI - Inhibition of porcine liver carboxylesterase by phosphorylated flavonoids. AB - We have recently synthesized a series of phosphorylated flavonoids and identified some of them as potent inhibitors of pancreatic cholesterol esterase (CEase) with excellent selectivity for CEase over acetylcholinesterase (AChE). In the present paper, we investigated the inhibitory activities of these compounds against porcine liver carboxylesterase (CE) since carboxylesterases (CEs) are another family of serine esterases responsible for the metabolism and detoxification of many ester-containing xenobiotics and clinical esterified drugs, and there exists much structural similarity between CEase and CEs. The results indicated that phosphorylated flavonoids exhibited significantly improved inhibition potency toward CE than their parent compounds, and six of them had IC50 values less than 5.0nM. Among all compounds tested, compounds 3d and 3e are the two most potent inhibitors of CE, giving IC50 values of 1.79nM and 1.58nM, respectively. Interestingly, these compounds inhibited CEase and CE with similar structure activity correlations, and those with high inhibitory activities toward CEase could also inhibit CE efficiently. The presences of a free hydroxyl group at position 5 and a phosphate group at position 7 of the phosphorylated flavonoids are favorable to the inhibition of CE. The inhibition mechanism and kinetic characterization studies of the most potent inhibitors revealed that they are irreversible competitive inhibitors. PMID- 23643882 TI - Social [and health] relevance of psychotropic substances monitoring in air. AB - Drug abuse assessment methods based on measuring illicit substances in waste waters are consolidated. The approach of ambient air monitoring looks questionable, nonetheless it can be explored if the variables determining the drug burdens are accounted for, or suitable co-contaminants are adopted to normalize concentrations to environmental and human contours. The general approach linking the airborne drug concentrations to consumption is presented and the case of cocaine is discussed according to measurements conducted in Italy. The cocaine/nicotine concentration ratio, identified as the most suitable tool, fitted well with anti-drug Police operations and people noticed for drug-related crimes, and with the abuse prevalence estimated in the cities investigated. According to that, the conversion factors of drug concentrations into prevalence estimates seem assessable, provided sufficient databases over space and time are collected. Further investigations are necessary to understand if airborne drugs cause adverse sanitary effects. PMID- 23643883 TI - Streptococcus pneumoniae ClpP protease induces apoptosis via caspase-independent pathway in human neuroblastoma cells: cytoplasmic relocalization of p53. AB - Streptococcus pneumoniae causes the most severe form of the bacterial meningitis which is the major cause of bacterial meningitis. Virulence factors produced by S. pneumoniae have been known to contribute significantly to the disease process. ClpP protease (ClpP) which is essential for virulence and survival under stress conditions in S. pneumoniae was examined for the ability to induce apoptosis and the mechanism of the induction of apoptosis in human neuron-like cells, SK-N-SH neuroblastoma cells. ClpP inhibited cell growth and induced apoptosis in SK-N-SH cells. Treatment with ClpP resulted in hypodiploid DNA contents, increased Bax/Bcl-2 ratio and induction of reactive oxygen species (ROS) production. The release of cytochrome c from mitochondria into the cytosol, which is an initiator of the activation of caspase cascades, was not observed in ClpP-treated cells. In addition, pretreatment with Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk), a broad spectrum caspase inhibitor, could not rescue apoptotic cells from ClpP toxicity. Coincidently, caspase-3 and -8 activation and cleavage of PARP were not detected. Moreover, caspase independent apoptosis-inducing factor (AIF) was released from mitochondria and translocated to the nucleus in response to ClpP. We also found that ClpP treatment resulted in the increase of p53 activity and cytoplasmic p53 levels were increased by ClpP, suggesting that functional activation of p53 is intact despite increased cytoplasmic accumulation. Taken together, these data suggest that ClpP contributes to neuronal damage in meningitis and provide further insight into the mechanisms underlying action of pneumococcal virulence factors during bacterial pathogenesis. PMID- 23643884 TI - Analytical performance of three point of care methods for pleural fluid pH analysis. AB - OBJECTIVE: The performance of three point of care methods for pleural fluid pH analysis was compared to a currently validated blood gas analyzer. DESIGN AND METHODS: An ABL 725 (Radiometer America, Westlake, OH) was used as the reference method to evaluate three cartridge-based assays: ABL 90 FLEX (Radiometer), and i STAT 1 (Abbott Point of Care, Abbott Park, IL) CG4+ and G3+ cartridges for pleural fluid pH analysis. Pooled residual pleural fluid samples and quality control material were analyzed to determine intra- and inter-assay precision. Method comparison was performed with spiked (n=40) and clinically-ordered (n=10) pleural fluid samples across the analytical measuring range. RESULTS: All methods demonstrated inter-assay CVs<0.1% at pH values of 7.1 and 7.6, and intra-assay CVs<0.3% at pH values of 7.2 and 7.7. Bland-Altman plots demonstrated clinically significant bias between ABL 725 and each cartridge-based method only at pH>7.6. For samples with pH<7.6 mean bias vs. ABL 725 was -0.01 for ABL 90 FLEX and 0.03 for i-STAT 1 CG4+ and G3+ cartridges. Clinical concordance using a decision limit of pH7.2 was 96-98% for the three methods. CONCLUSIONS: Analytical and clinical performance of the three cartridge-based methods was comparable to a validated blood gas analyzer for pleural fluid pH analysis. Cartridge-based pH methods offer the advantage of easier troubleshooting for clots and clogs as they use disposable electrodes. However cartridge-based methods are not currently FDA approved for pleural fluid samples, such that additional validation would be required for this specimen type. PMID- 23643885 TI - The potential clinical utility of serial plasma albumin mRNA monitoring for the post-liver transplantation management. AB - OBJECTIVES: Elevated albumin (ALB) mRNA concentration has been reported in the plasma of patients with liver diseases. The plasma ALB mRNA measurement was shown to be an effective indicator of liver pathologies with superior diagnostic sensitivity and specificity when compared with alanine transaminase (ALT). We hypothesized that serial plasma ALB mRNA analysis would be helpful in the early detection and monitoring of post-liver transplantation complications. DESIGN AND METHODS: One hundred and five blood specimens were collected from 24 post transplant recipients. Biochemical liver function test profiles and plasma ALB mRNA concentrations were assessed. RESULTS: Over the study period, the health status of 14 recipients (58%) remained stable (Stable group). Their plasma ALB mRNA concentrations remained within a low-concentration range. In contrast, 10 recipients (42%) developed 14 episodes of hepatic complications (Unstable group). The median plasma ALB mRNA concentration of the Unstable group was 6.5-times higher than that of the Stable group. Plasma ALB mRNA concentration was elevated on 13/14 (93%) episodes of the hepatic complications while ALT was elevated only on 8/14 (57%) episodes. CONCLUSIONS: The elevation of plasma ALB mRNA may allow sensitive detection of hepatic complications and monitoring of the clinical course in a dynamic fashion. Serial plasma ALB mRNA measurement is potentially useful for post-liver transplantation management. PMID- 23643886 TI - Optimizing blood collection, transport and storage conditions for cell free DNA increases access to prenatal testing. AB - OBJECTIVES: Fetal mutations and fetal chromosomal abnormalities can be detected by molecular analysis of circulating cell free fetal DNA (ccffDNA) from maternal plasma. This comprehensive study was aimed to investigate and verify blood collection and blood shipping conditions that enable Noninvasive Prenatal Testing. Specifically, the impact of shipping and storage on the stability and concentration of circulating cell-free DNA (ccfDNA) in Streck(r) Cell-Free DNATM Blood Collection Tubes (Streck BCTs, Streck, Omaha NE). These BCTs were designed to minimize cellular degradation, and thus effectively prevent dilution of fetal ccf DNA by maternal genomic DNA, was evaluated. DESIGN AND METHODS: Peripheral venous maternal blood was collected into Streck BCTs to investigate four aspects of handling and processing conditions: (1) time from blood draw to plasma processing; (2) storage temperature; (3) mechanical stress; and (4) lot-to-lot tube variations. RESULTS: Maternal blood stored in Streck BCTs for up to 7 days at ambient temperature provides stable concentrations of ccffDNA. The amount of fetal DNA did not change over a broad range of storage temperatures (4 degrees C, 23 degrees C, 37 degrees C, 40 degrees C), but the amount of total (largely maternal) DNA increased in samples stored at 23 degrees C and above, indicating maternal cell degradation and genomic DNA release at elevated temperatures. Shipping maternal blood in Streck BCTs, did not affect sample quality. CONCLUSIONS: Maternal plasma DNA stabilized for 0 to 7 days in Streck BCTs can be used for non-invasive prenatal molecular applications, when temperatures are maintained within the broad parameters assessed in this study. PMID- 23643887 TI - A new and simplified approach to target the suprascapular nerve with ultrasound. PMID- 23643888 TI - Isolation of (-)-olivil-9'-O-beta-d-glucopyranoside from Sambucus williamsii and its antifungal effects with membrane-disruptive action. AB - In this study, we isolated (-)-olivil-9'-O-beta-d-glucopyranoside (OLI9G), a phytochemical from the stem bark of Sambucus williamsii, and investigated the antifungal mechanism of OLI9G against Candida albicans. First of all, the antifungal susceptibility testing and hemolysis assay showed that OLI9G exerted a potent activity without hemolysis compared to the activity of amphotericin B. To investigate the mechanism of action of OLI9G, we first examined membrane depolarization using cyanine dye, 3,3'-dipropylthiacarbocyanine iodide (diSC35). The results showed that OLI9G significantly changed the fungal membrane potential. To further understand this activity on the membrane, we did the propidium iodide (PI) influx assay. From the results, OLI9G caused membrane permeabilization in the fungal membrane, and the three dimensional (3D) flow cytometric contour plot from the PI influx assay further showed that the cells had shrunk due to the membrane damage. Finally, the membrane-active mechanism of OLI9G was confirmed by synthesizing a model membrane, calcein-encapsulating large unilamellar vesicles (LUVs). The calcein leakage showed the membrane-disruptive effects caused by direct action of OLI9G. In conclusion, the current study suggests that OLI9G exerts its antifungal activity through a membrane-disruptive action. PMID- 23643890 TI - A bacterial monorhamnolipid alters the biophysical properties of phosphatidylethanolamine model membranes. AB - This work presents a biophysical study on the interactions of a monorhamnolipid (monoRL) produced by Pseudomonas aeruginosa MA01 with model dielaidoylphosphatidylethanolamine (DEPE) membranes. Incorporation of monoRL into DEPE shifts the onset temperature of the Lbeta-to-Lalpha and the Lalpha-to-HII phase transitions toward lower values. Incorporation of monoRL into DEPE indicates the coexistence of lamellar and hexagonal-HII phases in rhamnolipid containing samples at 60 degrees C, at which pure DEPE is lamellar. Thus, both techniques show that monoRL facilitates formation of the hexagonal-HII phase in DEPE, i.e. it destabilizes the bilayer organization. The phase diagram for the phospholipid component indicates a near-ideal behavior, with better miscibility of monoRL into DEPE in the fluid phase than in the gel phase. The various vibrational mode bands of the acyl chains of DEPE were studied by FTIR spectroscopy, focusing on the CH2 symmetric stretching mode. Incorporation of monoRL into DEPE shifts the frequency of this band to higher wavenumbers, at temperatures both below and above the main gel to liquid-crystalline phase transition. Examination of the CO stretching band of DEPE indicates that monoRL/DEPE interactions result in an overall dehydration effect on the polar headgroup of DEPE. These results are discussed in light of the possible role of rhamnolipids as bilayer stabilizers/destabilizers during cell membrane fluctuation events. PMID- 23643889 TI - Cord factor (trehalose 6,6'-dimycolate) forms fully stable and non-permeable lipid bilayers required for a functional outer membrane. AB - Cord factor (trehalose 6,6'-dimycolate, TDM) is the major lipid in the outer membrane of Corynebacteria and Mycobacteria. Although its role is well recognized in the immune response phenomena, its membrane biophysical properties remained largely unexplored and TDM has often been described as a detergent. We purified the main components of the outer membrane from Corynebacterium glutamicum and analyzed their membrane forming properties. In mixture with endogenous cardiolipin, but not alone, the spontaneous hydration of TDM produces liposomes. As a pure component, TDM formed vesicles only by the detergent dialysis method. Perdeuterated cardiolipin-TDM mixtures were shown by deuterium nuclear magnetic resonance (NMR) to exhibit a gel to liquid crystalline phase transition over a 273-295K temperature range, for cells grown at 303K, and thus to be in a liquid crystalline state at physiological temperature. Molecular dynamics simulations of hydrated TDM bilayers provided the trehalose average orientation and conformation, the chain order parameters, the area per lipid and the bilayer thickness which was confirmed by electron microscopy. Finally the Porin A-Porin H ion channel from the Corynebacterial outer membrane was reconstituted in TDM liposomes. With properly mycoloylated proteins, it manifested the typical voltage dependent ion channel properties of an outer membrane porin. PMID- 23643891 TI - Insertion of TAT peptide and perturbation of negatively charged model phospholipid bilayer revealed by neutron diffraction. AB - TAT peptide is one of the best-characterized cell penetrating peptides derived from the transactivator of transcription protein from the human immunodeficiency virus 1. The aim of this study was to investigate the interaction between TAT peptide and partially negatively-charged phospholipid bilayer by using lamellar neutron diffraction. The main findings are the existence of a contiguous water channel across the bilayer in the presence of TAT peptide. Taken in combination with other observations, including thinning of the lipid bilayer, this unambiguously locates the peptide within the lipid bilayer. The interaction of TAT peptide with anionic lipid bilayer, composed of an 80:20 mixture of DOPC and DOPS, takes place at two locations. One is in the peripheral aqueous phase between adjacent bilayers and the second is below the glycerol backbone region of bilayer. A membrane thinning above a peptide concentration threshold (1mol%) was found, as was a contiguous transbilayer water channel at the highest peptide concentration (10mol%). This evidence leads to the suggestion that the toroidal pore model might be involved in the transmembrane of TAT peptide. We interpret the surface peptide distribution in the peripheral aqueous phase to be a massive exclusion of TAT peptide from its intrinsic location below the glycerol backbone region of the bilayer, due to the electrostatic attraction between the negatively charged headgroups of phospholipids and the positively charged TAT peptides. Finally, we propose that the role that negatively-charged headgroups of DOPS lipids play in the transmembrane of TAT peptide is less important than previously thought. PMID- 23643892 TI - The calibrated, unidimensional anxiety item bank for cardiovascular patients provided the basis for anxiety assessment in cardiovascular rehabilitation patients. AB - OBJECTIVE: Computer adaptive tests (CATs) offer a flexible, test fair, and economic opportunity for accurate measurement of anxiety in patients with cardiovascular diseases (CVDs). The objective of this study was to develop and calibrate an item bank [anxiety item bank for cardiovascular patients (AIB cardio)] as a prerequisite for an anxiety-CAT in CVD patients. STUDY DESIGN AND SETTING: After pretesting for relevance and comprehension, a pool of 155 anxiety items was answered on a five-point Likert scale. Sample consisted of 715 CVD patients, who were recruited in 14 German cardiac rehabilitation centers. A confirmatory factor analysis (CFA), Mokken analysis, and Rasch analysis were conducted. RESULTS: The results of CFA and Mokken analysis confirmed one factor structure and double monotonicity. In Rasch analysis, merging response categories and removing items with misfit, differential item functioning or local response dependency reduced the AIB-cardio to 37 items. The AIB-cardio fitted to the Rasch model with a nonsignificant item-trait interaction (chi-square, 133.89; degrees of freedom, 111; P = 0.07). Person separation reliability was 0.85, and unidimensionality could be verified. CONCLUSION: The calibrated, unidimensional AIB-cardio provides the basis for a CAT to assess anxiety in rehabilitation patients with CVD with good psychometric properties. Further testing in other cardiovascular patients is needed to increase generalizability. PMID- 23643893 TI - Police AED programs: a systematic review and meta-analysis. AB - BACKGROUND: Approximately 359,400 out-of-hospital cardiac arrests occur in the United States every year, and around 60% of them are treated by emergency medical services (EMS) personnel. In order to alleviate the impact of this public health burden, some communities have trained police officers as first responders so that they can provide cardiopulmonary resuscitation and defibrillation to cardiac arrest patients. This paper is a review of the current literature on the impact of police automated external defibrillators (AEDs) programs in these communities. METHODS AND RESULTS: A literature search of electronic journal databases was conducted to identify articles that evaluated police AED programs and quantified survival rates. The 10 articles that met the inclusion criteria were very heterogeneous in terms of study design, controlling for confounders, outcome definitions, and comparison groups. Two communities found a statistically significant difference in survival and 6 studies reported a statistically significant difference in time to defibrillation after the implementation of these programs. The weighted mean survival rate of the study groups was higher than that of the control groups (p<0.001), as was the weighted mean survival rate of the group first shocked by police compared to those first shocked by EMS (39.4% vs. 28.6%, p<0.001). The pooled relative risk of survival was 1.4 (95% CI: 1.3-1.6). CONCLUSIONS: Though there are many challenges in initiating these programs, this literature review shows that time to defibrillation decreased and survival from out-of-hospital cardiac arrests increased with the implementation of police AED programs. PMID- 23643894 TI - Identification and characterization of OmpL as a potential vaccine candidate for immune-protection against salmonellosis in mice. AB - Salmonella is gram-negative flagellated bacteria that can cause food and waterborne gastroenteritis and typhoid fever in humans. Despite the importance of Salmonella infections in human and animal health, the target antigens of Salmonella-specific immunity remain poorly defined, the effectiveness of the currently available vaccines is also limited. Outer membrane proteins (OMPs) of Salmonella have been considered possible candidates for conferring protection against salmonellosis. OMPs interface the cell with the environment, thus representing important potential vaccine candidate for pathogen infection. We showed that the outer membrane porin L (OmpL) is a transmembrane beta barrel (TMBB) protein, which forms 12 transmembrane beta-strands. OmpL of S. Typhimurium is highly immunogenic, OmpL could evoke humoral and cell-mediated immune responses, and confer 100% protection to immunized mice against challenge with very high doses of S. Typhimurium. Besides, very efficient clearance of bacteria from the reticuloendothelial systems of immunized mice was seen. The homology search further revealed that OmpL is widely distributed and conserved, homologous proteins were identified in S. Typhi and Paratyphi by RT-PCR and western blot. We also found that anti-rOmpL serum harber a high bactericidal activity for Salmonella serovars tested in this study. Therefore, OmpL provide a promising target for the development of a candidate vaccine against Salmonella infection. PMID- 23643896 TI - Stimulatory effect of gonadal hormones on fetal rat hippocampal neural proliferation requires neurotrophin receptor activation in vitro. AB - To determine the effects of gonadal hormones on proliferation of the hippocampal neural cells, which are of importance in learning and memory function. 17beta Estradiol or testosterone was added to the culture at various concentrations. Their proliferation and protective effects on the neural cell were determined with BrdU, flow cytometry and MTT assay. Effects of the gonadal hormones on brain derived neurotrophic factor (BDNF) expression were determined using ELISA and RT PCR respectively. 17beta-Estradiol and testosterone at 20nM or higher concentrations significantly increased the neural cell proliferation and viability, and induced increasing in the S phase arrest which is essential for cell proliferation. Both estradiol and testosterone significantly increased the neural cell expression of cellular mature BDNF and BDNF mRNA. Effect of testosterone on hippocampal neural proliferation was blocked by Trk neurotrophin receptor inhibitor. 17beta-Estradiol and testosterone promoted hippocampal neural proliferation and improved cell viability in vitro. The effect of testosterone on hippocampal neural cell proliferation required neurotrophin receptor activation. PMID- 23643895 TI - Cholesterol affects gene expression of the Jun family in colon carcinoma cells using different signaling pathways. AB - Hyperlipidemia and hypercholesterolemia have been found to be important factors in cancer development and metastasis. However, the metabolic mechanism and downstream cellular processes following cholesterol stimulation are still unknown. Here we tested the effect of cholesterol on MC-38 colon cancer cells. Using Illumina gene array technology we found a number of genes that were differentially expressed following short term (20-40 min) and longer term (between 2 and 5h) cholesterol stimulation. Three genes were consistently increased at these time points; c-Jun, Jun-B and the chemokine CXCL-1. We have previously shown that cholesterol stimulation leads to PI3K/Akt phosphorylation, and now demonstrated that cholesterol inhibits ERK1/2 phosphorylation; both effects reversed when cholesterol is depleted from lipid rafts using methyl-beta cyclodextrin (MBCD). In addition, vanadate, an inhibitor of phosphatases, reversed the cholesterol inhibition of ERK1/2 phosphorylation. Specific inhibition of p-Akt by wortmannin did not affect cholesterol's stimulation of the expression of c-Jun and Jun-B, however the vanadate effect of increasing p ERK1/2, inhibited c-Jun expression, specifically, and the MBCD effect of increasing p-ERK and inhibiting p-Akt reduced c-Jun expression. In contrast MBCD and vanadate both enhanced Jun-B gene expression in the presence of cholesterol and elevation of ERK phosphorylation. Thus there is apparently, a differential signaling pathway whereby cholesterol enhances gene expression of the Jun family members. PMID- 23643897 TI - Brain nitric oxide metabolites in rats preselected for nicotine preference and intake. AB - Nicotine addiction is a serious health problem resulting in millions of preventable deaths worldwide. The gas messenger molecule nitric oxide (NO) plays a critical role in addiction, and nicotine increases nitric oxide metabolites (NOx) in the brain. Understanding the factors which underlie individual differences in nicotine preference and intake is important for developing effective therapeutic strategies for smoking cessation. The present study aimed to assess NO activity, by measuring its stable metabolites, in three brain regions that express high levels of nicotinic acetylcholine receptors in rats preselected for nicotine preference. Rats (n=88) were exposed to two-bottle, free choice of oral nicotine/water starting either as adolescents or adults; control animals received only water under identical conditions. Following 12 or six weeks of exposure, levels of NOx (nitrite+nitrate), were determined in the hippocampus, frontal cortex, and amygdala. Since the rats were singly housed during oral nicotine treatment, naive rats were also included in the study to evaluate the effect of isolation stress. Isolation stress increased NOx in the hippocampus. Nicotine preference did not have a significant effect on NO activity, but rats with adolescent exposure had higher NOx levels in the frontal cortex compared to adult-onset rats. Our findings suggest that nicotine exposure during adolescence, regardless of the amount of nicotine consumed, results in higher NO activity in the frontal cortex of rats, which persists through adulthood. PMID- 23643899 TI - Modified silaffin R5 peptides enable encapsulation and release of cargo molecules from biomimetic silica particles. AB - Biomimetic silica formation has attracted increasing interest over the last decade for numerous biotechnological applications due to the favorable mild reaction conditions. Inspired from silica biogenesis in diatoms, peptide variants derived from native silaffins have been used for silica formation in vitro. Here a generally applicable route for covalently linking a cargo molecule to the R5 silaffin peptide via a disulfide linkage is established. The peptide CG12AB, a peptide ligand of the epidermal growth factor receptor, was chosen as model. The ability of such silaffin-cargo conjugates to encapsulate the cargo molecule during silaffin-mediated silica precipitation is demonstrated. Cargo release from silica material under different conditions was analyzed. The results obtained here provide a rational basis for developing engineered R5 silaffin peptides into efficient tools for silica precipitation as well as for entrapment and release of cargo molecules under physiological conditions. PMID- 23643898 TI - Structural requirements for inhibitory effects of bisphenols on the activity of the sarco/endoplasmic reticulum calcium ATPase. AB - Bisphenols (BPs) are a class of small organic compounds with widespread industrial applications. Previous studies have identified several BPs that interfere with the activity of the ion-translocating enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA). In order to define the molecular determinants of BP-mediated SERCA inhibition, we conducted enzyme activity assays with rabbit SERCA to determine the inhibitory potencies of 27 commercially available BPs, which were the basis for structure-activity relationships. The most potent BPs inhibited SERCA at low micromolar concentrations and carried at their two phenyl rings multiple non-polar substituents, such as small alkyl groups or halides. Furthermore, the presence of methyl groups or a cyclohexyl group at the central carbon atom connecting the two phenyl moieties correlated with good potencies. For a characterization and visualization of enzyme/inhibitor interactions, molecular docking was performed, which suggested that hydrogen bonding with Asp254 and hydrophobic interactions were the major driving forces for BP binding to SERCA. Calcium imaging studies with a selection of BPs showed that these inhibitors were able to increase intracellular calcium levels in living human cells, a behavior consistent with that of a SERCA inhibitor. PMID- 23643900 TI - Structure-activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template. AB - In an effort to design inhibitors of human glutaminyl cyclase (QC), we have synthesized a library of N-aryl N-(5-methyl-1H-imidazol-1-yl)propyl thioureas and investigated the contribution of the aryl region of these compounds to their structure-activity relationships as cyclase inhibitors. Our design was guided by the proposed binding mode of the preferred substrate for the cyclase. In this series, compound 52 was identified as the most potent QC inhibitor with an IC50 value of 58 nM, which was two-fold more potent than the previously reported lead 2. Compound 52 is a most promising candidate for future evaluation to monitor its ability to reduce the formation of pGlu-Abeta and Abeta plaques in cells and transgenic animals. PMID- 23643901 TI - Curcumin-I Knoevenagel's condensates and their Schiff's bases as anticancer agents: synthesis, pharmacological and simulation studies. AB - Pyrazolealdehydes (4a-d), Knoevenagel's condensates (5a-d) and Schiff's bases (6a d) of curcumin-I were synthesized, purified and characterized. Hemolysis assays, cell line activities, DNA bindings and docking studies were carried out. These compounds were lesser hemolytic than standard drug doxorubicin. Minimum cell viability (MCF-7; wild) observed was 59% (1.0 MUg/mL) whereas the DNA binding constants ranged from 1.4*10(3) to 8.1*10(5) M(-1). The docking energies varied from -7.30 to -13.4 kcal/mol. It has been observed that DNA-compound adducts were stabilized by three governing forces (Van der Wall's, H-bonding and electrostatic attractions). It has also been observed that compounds 4a-d preferred to enter minor groove while 5a-d and 6a-d interacted with major grooves of DNA. The anticancer activities of the reported compounds might be due to their interactions with DNA. These results indicated the bright future of the reported compounds as anticancer agents. PMID- 23643902 TI - Synthesis and application of cNGR-containing imaging agents for detection of angiogenesis. AB - Angiogenesis is a multi-step process regulated by pro- and anti-angiogenic factors. Inhibition of angiogenesis is a potential anti cancer treatment strategy that is now investigated clinically. In addition, advances in the understanding of the angiogenic process have led to the development of new angiogenesis therapies for ischemic heart disease. Currently, researchers search for objective measures that indicate pharmacological responses to pro- and anti-angiogenic drugs and therefore, there is a great interest in techniques to visualize angiogenesis noninvasively. As CD13 is selectively expressed in angiogenic blood vessels, it can serve as a target for molecular imaging tracers to noninvasively visualize angiogenic processes in animal models and patients. Here, an overview on the currently used CD13 targeted molecular imaging probes for noninvasive visualization of angiogenesis is given. PMID- 23643903 TI - Editorial comment. PMID- 23643904 TI - Editorial comment. PMID- 23643906 TI - The effect of spatial frequency on perceptual learning of inverted faces. AB - We investigated the efficacy of training adults to recognize full spectrum inverted faces presented with different viewpoints. To examine the role of different spatial frequencies in any learning, we also used high-pass filtered faces that preserved featural information and low-pass filtered faces that severely reduced that featural information. Although all groups got faster over the 2 days of training, there was more improvement in accuracy for the group exposed to full spectrum faces than in the two groups exposed to filtered faces, both of which improved more modestly and only when the same faces were shown on the 2 days of training. For the group exposed to the full spectrum range and, to a lesser extent, for those exposed to high frequency faces, training generalized to a new set of full spectrum faces of a different size in a different task, but did not lead to evidence of holistic processing or improved sensitivity to feature shape or spacing in inverted faces. Overall these results demonstrate that only 2h of practice in recognizing full-spectrum inverted faces presented from multiple points of view is sufficient to improve recognition of the trained faces and to generalize to novel instances. Perceptual learning also occurred for low and high frequency faces but to a smaller extent. PMID- 23643905 TI - Measuring contrast sensitivity. AB - Contrast sensitivity defines the threshold between the visible and invisible, which has obvious significance for basic and clinical vision science. Fechner's 1860 review reported that threshold contrast is 1% for a remarkably wide range of targets and conditions. While printed charts are still in use, computer testing is becoming more popular because it offers efficient adaptive measurement of threshold for a wide range of stimuli. Both basic and clinical studies usually want to know fundamental visual capability, regardless of the observer's subjective criterion. Criterion effects are minimized by the use of an objective task: multiple-alternative forced-choice detection or identification. Having many alternatives reduces the guessing rate, which makes each trial more informative, so fewer trials are needed. Finally, populations who may experience crowding or target confusion should be tested with one target at a time. PMID- 23643907 TI - Food search through the eyes of a monkey: a functional substitution approach for assessing the ecology of primate color vision. AB - Efficient detection and selection of reddish fruits against green foliage has long been thought to be a major selective pressure favoring the evolution of primate trichromatic color vision. This has recently been questioned by studies of free-ranging primates that fail to show predicted differences in foraging efficiency between dichromats and trichromats. In the present study, we use a unique approach to evaluate the adaptive significance of trichromacy for fruit detection by undertaking a functional substitution model. The color vision phenotypes of neotropical monkeys are simulated for human observers, who use a touch-sensitive computer interface to search for monkey food items in digital images taken under natural conditions. We find an advantage to trichromatic phenotypes - especially the variant with the most spectrally separated visual pigments - for red, yellow and greenish fruits, but not for dark (purple or black) fruits. These results indicate that trichromat advantage is task-specific, and that shape, size and achromatic contrast variation between ripe and unripe fruits cannot completely mitigate the advantage of color vision. Similarities in fruit foraging performance between primates with different phenotypes in the wild likely reflect the behavioral flexibility of dichromats in overcoming a chromatic disadvantage. PMID- 23643908 TI - On the function of chitin synthase extracellular domains in biomineralization. AB - Molluscs with various shell architectures evolved around 542-525 million years ago, as part of a larger phenomenon related to the diversification of metazoan phyla. Molluscs deposit minerals in a chitin matrix. The mollusc chitin is synthesized by transmembrane enzymes that contain several unique extracellular domains. Here we investigate the assembly mechanism of the chitin synthase Ar-CS1 via its extracellular domain ArCS1_E22. The corresponding transmembrane protein ArCS1_E22TM accumulates in membrane fractions of the expression host Dictyostelium discoideum. Soluble recombinant ArCS1_E22 proteins can be purified as monomers only at basic pH. According to confocal fluorescence microscopy experiments, immunolabeled ArCS1_E22 proteins adsorb preferably to aragonitic nacre platelets at pH 7.75. At pH 8.2 or pH 9.0 the fluorescence signal is less intense, indicating that protein-mineral interaction is reduced with increasing pH. Furthermore, ArCS1_E22 forms regular nanostructures on cationic substrates as revealed by atomic force microscopy (AFM) experiments on modified mica cleavage planes. These experiments suggest that the extracellular domain ArCS1_E22 is involved in regulating the multiple enzyme activities of Ar-CS1 such as chitin synthesis and myosin movements by interaction with mineral surfaces and eventually by protein assembly. The protein complexes could locally probe the status of mineralization according to pH unless ions and pCO2 are balanced with suitable buffer substances. Taking into account that the intact enzyme could act as a force sensor, the results presented here provide further evidence that shell formation is coordinated physiologically with precise adjustment of cellular activities to the structure, topography and stiffness at the mineralizing interface. PMID- 23643909 TI - Unremodeled endochondral bone is a major architectural component of the cortical bone of the rat (Rattus norvegicus). AB - The laboratory rat is one of the most frequently-used animal models for studying bone biology and skeletal diseases. Here we show that a substantial portion of the cortical bone of mature rats is primary endochondral bone, consisting of a disorganized arrangement of mineralized collagen fibers. We characterize the structure and mechanical properties of the cortical bone of the rat. We show that the cortical bone consists of two architecturally distinct regions. One region, consisting of well-organized circumferential lamellae (CLB), is located in the endosteal and/or the periosteal regions while another, disorganized region, is located in the more central region of the cortex. Unexpectedly, we found that the disorganized region contains many islands of highly mineralized cartilage. Micro tomography showed different structural and compositional properties of the two primary structural elements; the CLB region has lower mineral density, lower porosity, larger but fewer blood vessels and fewer lacunae. However, no difference was found in the average lacunar volume. Additionally the mean indentation modulus of the CLB region was lower than that of the disorganized region. The islands of calcified cartilage were found to be extremely stiff, with an indentation modulus of 33.4 +/- 3.5GPa. We conclude that though the cortical bone of rats is in part lamellar, its architecture is markedly different from that of the cortical bone of humans, a fact that must be borne in mind when using the rat as a model animal for studies of human bone biology and disease. PMID- 23643910 TI - Loss of ELF3 immunoexpression is useful for detecting oral squamous cell carcinoma but not for distinguishing between grades of epithelial dysplasia. AB - Early diagnosis and targeted therapy are crucial to mitigating the morbidity and mortality of oral squamous cell carcinoma. Among the potentially malignant oral disorders, epithelial dysplasia has known association with malignant transformation, but defensible gradation of dysplasia severity presents unmet challenges. Published microarray data has denoted dysregulation of CLSP, ELF3, IFI44, USP18, and CXCL13 genes in potentially malignant oral disorders. The present study investigated the diagnostic potential of these gene products to grade oral epithelial dysplasia severity. Archived biopsies from independent patient cohorts comprised "training" (n=107) and "test" (n=278) sample sets. Immunoreactivity for candidate markers was determined in the "training" set of normal oral mucosa (NOM), mild dysplasia (MD), moderate to severe dysplasia, and oral squamous cell carcinoma (OSCC). The diagnostic potential of ELF3 immunoscoring to improve detection and severity gradation of epithelial dysplasia was assessed with the "test" set. A reciprocal relationship between disease severity and immunoreactivity score for CLSP and ELF3 was observed (MD/NOM to OSCC: P<.08, Mann-Whitney U test), whereas elevated IFI44 immunostaining was present for OSCC compared to MD/NOM (P<.08, Mann-Whitney U test). Loss of ELF3 immunostaining effectively distinguished OSCC from non-malignant tissues (sensitivity=0.81; specificity=0.56; area under the curve [AUC]=0.68) but did not distinguish dysplasia from NOM (sensitivity=0.55; specificity=0.40; AUC=0.47) or moderate to severe dysplasia from MD (sensitivity=0.63; specificity=0.51; AUC=0.57). The results confirm via immunohistochemistry the relevance of published CLSP, ELF3, and IFI44 (but not USP18 or CXCL13) gene expression data to potentially malignant oral lesion severity. Loss of ELF3 immunostaining discriminated OSCC from dysplasia but was unreliable for grading dysplasia severity. PMID- 23643913 TI - Bioinspired surface modification of poly(2-hydroxyethyl methacrylate) based microbeads via oxidative polymerization of dopamine. AB - Surface modification of support materials is crucial for improving their selectivities and biocompatibilities in bioaffinity applications. However, conventional modification techniques including chemical or physical conjugations mostly suffer from limitations of their multistep and complicated procedures, surface denaturations, batch-to-batch inconsistencies, and insufficient surface conjugations. In this study, we demonstrate a simple yet effective bioinspired approach for the surface modification of poly(2-hydroxyethyl methacrylate) [PHEMA] based bioaffinity adsorbents through oxidative polymerization of dopamine. The magnetic (mPHEMA) and non-magnetic (PHEMA) polymeric microbeads were fabricated by suspension polymerization technique. Surface modification of obtained microbeads was then carried out by using dopamine molecules under alkaline conditions. The polydopamine (PDOPA) coated microbeads were further employed as a bioaffinity absorbent targeted for immunoglobulin G (IgG) molecules. The effects of pH, temperature, protein concentration and ionic strength on the IgG adsorption process have been investigated. We found that PDOPA coated microbeads display dramatically higher IgG adsorption capacities when compared with their un-modified forms. Adsorption capacities also increased with increasing temperature. Monolayer Langmuir adsorption model can be thought more applicable for these adsorbent systems. PMID- 23643911 TI - Soft-binding ligand-capped fluorescent CdSe/ZnS quantum dots for the facile labeling of polysaccharide-based self-assemblies. AB - In this research, soft-binding aminopropanol (APP) was employed as an efficient ligand, for the transfer of as-prepared hydrophobic CdSe/ZnS quantum dots (QDs) into polar solvents. It was found that the ligands at the surface of the original QDs could be completely replaced by APP after a phase-transferring process which successfully maintained fluorescence properties and original morphology of the QDs. The resulting intermediate QDs were soluble in common polar organic solvents, such as dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) and tetrahydrofuran (THF), and the soft-binding ligand could be easily removed by exposure to water. Taking advantage of the excellent solubility of the APP-capped QDs and the soft-binding characteristics of APP, a novel reaction-free method was investigated for the fluorescent labeling of polysaccharide-based micelles via encapsulation of the intermediate QDs. The incorporation of QDs had little effect on the size of the micelles and did not elevate their cytotoxicity. A photo induced fluorescence enhancement effect was observed for the incorporated QDs, and the QD-labeled micelles could be used for cell imaging. The concept of soft binding ligand capped QDs and the reaction-free fluorescent labeling method can be applied to a wide range of QD studies. PMID- 23643912 TI - Incorporation of camptothecin into reduction-degradable supramolecular micelles for enhancing its stability. AB - In this research, a reduction-degradable supramolecular micelle delivery system of camptothecin (CPT) was developed to enhance the stability of CPT in aqueous media. Firstly, Michael addition polymerization occurred between N, N' bis(acryloyl) cystamine (BAC) and mono(6-(2-aminoethyl)amino-6-deoxy)-beta cyclodextrin (CDen) to produce the reduction-degradable polymer of BAC-CDen. And adamantyl-modified polyethylene glycol monomethyl ether (mPEG-Ad) was further encapsulated into it to gain supramolecular micelles of mPEG-Ad@BAC-CDen. Then mPEG-Ad@BAC-CDen/CPT supramolecular micelles could be easily obtained by incorporation of CPT into mPEG-Ad@BAC-CDen via dialysis method. The particle size of supramolecular micelles increased from 106 nm (bare micelles) to 142 nm (CPT loaded micelles), suggesting their passive targeting potential to tumor tissue. Owing to the reduction degradability of disulfide linker in main chain of BAC CDen, the CPT could be sustainably released from the above micelles with the gradual cleavage of polymer in the presence of dithiothreitol (DTT) at the concentration of simulating the intracellular condition. It was noted that the stability of CPT in aqueous media was remarkably improved in the mPEG-Ad@BAC-CDen supramolecular micelles, which effectively protected the active lactone ring of CPT from hydrolysis under physiological condition. Besides, compared with free CPT, the CPT-loaded supramolecular micelles showed much lower cytotoxicity against L929 cell line. All these results suggested the potential utilization of the mPEG-Ad@BAC-CDen supramolecular micelles as the carriers of hydrophobic drugs with better stability and lower cytotoxicity. And the resulted anti-tumor CPT supramolecular micelles can be delivered to tumor cells with a high selectivity. PMID- 23643914 TI - Novel 'Si-C' carbosilane dendrimers as carriers for anti-HIV nucleic acids: studies on complexation and interaction with blood cells. AB - Treatment of HIV infection by gene therapy is a promising tool for combating AIDS. One of the primary limitations of gene therapy is the effective delivery of nucleic acids to the target cells. Dendrimers are nanoparticles that are increasingly being used as nucleic acid vehicles. We have synthesized "Si-C" amino-terminated carbosilane dendrimers [GnO3(NMe3)m](m+) functionalized with quaternary ammonium (NMe3(+)) terminal groups via hydrosilylation of allyl dimethylamine with the corresponding GnO3(SiH)m dendrimers and further addition of MeI. These dendrimers are soluble in water. Initially, complexation between these "Si-C" dendrimers and anti-HIV nucleic acids (oligodeoxynucleotides ANTITAR and GEM91, siRNA siP24) was studied and molar ratios for complete complexation were determined. Then the charge and size of the dendriplexes (complexes of "Si C" dendrimers with nucleic acids) were analyzed and it was found that they possessed charges of +5 to +40 mV and sizes of 60-600 nm (zeta-size) or 50-100 nm (atomic force microscopy) suitable for cell transfection. Stability studies showed that the dendriplexes were stable over time and were resistant to degradation by serum albumin. The effects of dendrimers and their dendriplexes on erythrocytes (isolated and in whole blood) revealed that the dendriplexes were significantly less cytotoxic than the pure dendrimers. The effects of dendrimers and their dendriplexes on peripheral blood mononuclear cells (the main target of HIV) were analyzed and it was found that the dendriplexes were 10 times less cytotoxic than the pure dendrimers. Finally, transfection experiments revealed that "Si-C"-carbosilane dendrimers had a restricted ability to deliver long-chain double-stranded nucleic acids. The results indicate that these cationic carbosilane dendrimers are good candidates for delivering short-chain siRNA and oligodeoxynucleotide to HIV-infected peripheral blood mononuclear cells or lymphocytes. PMID- 23643915 TI - A comparative study of fine polished stainless steel, TiN and TiN/Ag surfaces: adhesion and attachment strength of Listeria monocytogenes as well as anti listerial effect. AB - Magnetron sputtering was used to produce nanocomposite TiN and TiN/Ag coatings on stainless steel surfaces. The surface chemistry (EDX), physicochemical properties (contact angles), topography and roughness parameters (WLP and AFM) of the fine polished stainless steel (FPSS), TiN and TiN/8.6 at.% Ag surfaces were examined. Real-time initial adhesion of two Listeria monocytogenes strains (EGDe and 64) to the three surfaces was determined under flow conditions, and their attachment strength after adhesion was measured using atomic force microscopy (AFM). The anti-listerial properties of the surfaces were determined using LIVE/DEAD staining. Our results demonstrate that FPSS, TiN and TiN/8.6 at.% Ag possessed different surface properties, which may influence both attachment strength and anti-listerial properties. There were no significant (p>0.05) differences in the initial adhesion of the two L. monocytogenes strains to the three different surfaces. Attachment studies showed that the two L. monocytogenes strains did not attach to FPSS under wetted conditions. However, both strains attached to TiN and TiN/8.6 at.% Ag surfaces, although with less strength to TiN/8.6 at.% Ag than to TiN surfaces. The TiN/8.6 at.% Ag surface showed marked anti-listerial properties as compared with FPSS and TiN. Initial adhesion, attachment strength and anti listerial properties were found to be strain dependent. PMID- 23643916 TI - Synthesis and characterization of N-ethyl-N'-(3-dimethylaminopropyl)-guanidinyl polyethylenimine polymers and investigation of their capability to deliver DNA and siRNA in mammalian cells. AB - Recent advancements in polymeric gene delivery have raised the potential of gene therapy as treatment for various acquired and inherited diseases. Here, we report on the synthesis and characterization of N-ethyl-N'-(3-dimethylaminopropyl) guanidinyl-polyethylenimine (sGP) polymers and investigation of their capability to carry DNA and siRNA in vitro. Zinc triflate-mediated activation of primary amines of branched polyethylenimine (bPEI) followed by reaction with varying amounts of N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide (EDAC) resulted in the generation of a small series of trisubstituted guanidinyl-modified polyethylenimine polymers. Determination of primary amines on modified polymers by TNBS assay revealed 62-84% of the attempted conjugation of EDAC onto bPEI. These modified polymers were shown to condense plasmid DNA and retard its mobility on 0.8% agarose gel. Further, these polymers were evaluated for their capability to carry pDNA into the cells by performing transfection assay on various mammalian cells. All the modified polymer/pDNA complexes exhibited significantly higher levels of gene expression with one of the complexes, sGP3/pDNA complex, displayed ~1.45 to 3.0 orders of magnitude higher transfection efficiency than that observed in the native bPEI and the commercial transfection reagent, LipofectamineTM. The efficacy of sGP3 polymer was further assessed by siRNA delivery, which resulted in ~81% suppression of the target gene. In conclusion, these studies demonstrate the potential of these substituted guanidinyl-modified PEIs as efficient gene delivery vectors. PMID- 23643917 TI - Conjugation of succinic acid to non-ionogenic amphiphilic polymers modulates their interaction with cell plasma membrane and reduces cytotoxic activity. AB - Pluronic block copolymers L61 and L121 were reacted with succinic anhydride to produce, respectively, their mono- and bisderivatives with succinic acid. The critical micelle concentration of Pluronics decreased after modification. The modification of Pluronic L61 promoted its association with the plasma membrane of human cells and increased membrane damage, while the membranotropic activity of modified Pluronic L121 reduced compared to the initial copolymer. Modified Pluronics interfered with the viability, apoptosis induction and metabolism of A549 cells and skin fibroblasts to a much lesser extent presumably due to the introduction of succinic acid residue inhibited intracellular penetration of copolymers. Modified Pluronic L121 promoted the cellular uptake of doxorubicin and rhodamine 123 in A549 cells attributed to the inhibition of membrane P glycoprotein. Our study provides an approach to assessing the mechanism of interaction of amphiphilic polymers with living cells and demonstrates that Pluronic-succinic acid conjugates can be used as safe and efficient modulators of intracellular drug delivery. PMID- 23643918 TI - Hard corona composition and cellular toxicities of the graphene sheets. AB - Graphene nanomaterials are recognized as one of the most promising nanomaterials because of their unique and highly attractive physicochemical properties (e.g., thermal conductivity, superlative mechanical strength, and ultrahigh surface-to volume ratios). It is well established that when nanomaterials interact with biological medium, biomolecules and in particular proteins attach to their surfaces, which form a complex between surface of nanoparticles and proteins called corona. Thus, the interaction of the biological system with the nanomaterials depends on the composition of the protein layer, rather than the surface characteristics of the nanomaterials itself. Although there is a significant increase of interest in the application of graphene in medical science, there has been a little attention to the nanotoxicological aspects of these newly developed materials. For this reason, we aimed to investigate whether the effect of the interactions between graphene-sheets with various human plasma concentrations (i.e. both in vitro (cells/tissues) and in vivo simulating states) is toxic. The results showed that by increasing the human plasma concentration, the affinity of proteins with low molecular weights to graphene-sheets surface is significantly increased. Fluorescence microscopy of Hela and Panc-1 cell lines showed a reduction of nuclei number and an increase of reactive oxygen species (ROS) production respectively after a longer incubation of graphene-sheets with plasma proteins. ROS production was higher in Panc-1 cell line, when used as protein source for graphene-sheets than HeLa cell line. PMID- 23643919 TI - The effect of cavitation bubbles on the removal of juvenile barnacles. AB - The effect of cavitation bubbles on the removal of juvenile barnacles was documented using high speed photography. Using spark generated bubbles, the interaction between barnacle and cavitation bubble was examined in detail. The liquid jet generated by the bubble collapse was observed to be directed towards barnacle at different impact intensities, which is related to the dimensionless distance H' (H'=H/Rm), where H is the distance between bubble formation point and the top of barnacle, and Rm is the maximum bubble radius. At lower values of H', higher speed liquid jet was produced; consequently a larger impact pressure was generated. In general, barnacles are more easily removed at a younger stage. In older barnacles, the liquid jet impact was only able to remove the barnacle shells, leaving the base plate attached to the surface. This study indicates that cavitation can be used to remove attached barnacles, and it would be more efficient if it is applied during early stages of fouling, before the formation of hard calcareous structures. PMID- 23643920 TI - Prevalence of lactose malabsorption in Mexican children: importance of measuring methane in expired air. AB - BACKGROUND AND AIMS: To compare the prevalence of lactose malabsorption (LM) in children by analyzing hydrogen content in expired air vs. the inclusion of methane excretion. METHODS: A total of 138 children (4-17 years old) attending different boarding schools in Mexico were included in this study. To measure H2 and CH4 in expired air, breath samples were collected before administering whole milk (240 mL for 4- to 6-year-old children and 360 mL for 7- to 17-year-old children) and at 60, 120, 180, and 240 min afterward. A coprological examination was also carried out. RESULTS: Methane production prevalence was 47.8% (29.7% of the children produced methane and hydrogen, whereas 18.1% produced methane only). When measuring only exhaled hydrogen in expired air (H2 >=20 ppm), prevalence of LM was 31%; however, when methane concentration was considered (H2 + (CH4 x 2)) >=18 ppm, prevalence increased significantly to 44%. Among children with LM, 51.6% presented intestinal parasites. CONCLUSIONS: Methane should be measured in exhaled air to improve diagnosis of LM in populations with a high prevalence of methane production. PMID- 23643921 TI - Functional interactions between intrinsic brain activity and behavior. AB - The brain continuously maintains a remarkably high level of intrinsic activity. This activity is non-stationary and its dynamics reveal highly structured patterns across several spatial scales, from fine-grained functional architecture in sensory cortices to large-scale networks. The mechanistic function of this activity is only poorly understood. The central goal of the current review is to provide an integrated summary of recent studies on structure, dynamics and behavioral consequences of spontaneous brain activity. In light of these empirical observations we propose that the structure of ongoing activity and its itinerant nature can be understood as an indispensible memory system modeling the statistical structure of the world. We review the dynamic properties of ongoing activity, and how they are malleable over short to long temporal scales that permit adapting over a range of short- to long-term cognitive challenges. We conclude by reviewing how the functional significance of ongoing activity manifests in its impact on human action, perception, and higher cognitive function. PMID- 23643922 TI - Somatotopic mapping of natural upper- and lower-extremity movements and speech production with high gamma electrocorticography. AB - Precise delineation of pathological and eloquent cortices is essential in pre neurosurgical diagnostics of epilepsy. A limitation of existing experimental procedures, however, is that they critically require active cooperation of the patient, which is not always achievable, particularly in infants and in patients with insufficient cognitive abilities. In the present study, we evaluated the potential of electrocorticographic recordings of high gamma activity during natural, non-experimental behavior of epilepsy patients to localize upper- and lower-extremity motor and language functions, and compared the results with those obtained using electrocortical stimulation. The observed effects were highly significant and functionally specific, and agreed well with the somatotopic organization of the motor cortex, both on the lateral convexity and in the supplementary motor area. Our approach showed a similar specificity and sensitivity for extremity movements as previously obtained from experimental data. We were able to quantify, for the first time, sensitivity and specificity of high gamma underlying non-experimental lower-extremity movements in four patients, and observed values in the same range as for upper extremities (analyzed in six patients). Speech-related responses in the three investigated patients, however, exhibited only a very low sensitivity. The present findings indicate that localization of not only upper- but also lower-extremity movements congruent with electrocortical stimulation mapping is possible based on event related high gamma responses that can be observed during natural behavior. Thus, non-experimental mapping may be usefully applied as adjunct to established clinical procedures for identification of both upper- and lower-extremity motor functions. PMID- 23643923 TI - Prefrontal activation in response to emotional words in patients with bipolar disorder and major depressive disorder. AB - Abnormal emotional processing is involved in the pathophysiology of bipolar disorder (BD) and major depressive disorder (MDD). However, whether the neural mechanism underlying this deficit is a trait characteristic of BD and MDD is unclear. The aim of this study was to elucidate the similarities and differences in processing of emotional stimuli between patients with BD and MDD in remission, using functional near-infrared spectroscopy (fNIRS). Thirty-two patients (16 with BD and 16 with MDD) and 20 healthy control subjects matched for age, sex, handedness, and years of education were included. An emotional Stroop task, including happy, sad, and threat words, was used. The relative oxygenated and deoxygenated hemoglobin concentration ([oxy-Hb] and [deoxy-Hb]) changes in the frontal region were measured using 52-channels of NIRS. During the threat task, compared to healthy control subjects, patients with BD showed significantly increased [oxy-Hb] in the left inferior frontal region whereas patients with MDD showed significantly increased [oxy-Hb] in the left middle frontal region. During the happy task, compared to healthy control subjects, patients with BD showed significantly decreased [oxy-Hb] in the middle frontal region in both hemispheres. Moreover, patients with BD exhibited decreased [oxy-Hb] and increased [deoxy-Hb] in the superior frontal and middle frontal regions compared to MDD in response to the happy stimulus. No significant differences in [oxy-Hb] or [deoxy-Hb] were seen between the groups during the sad task. These results suggest that abnormal neural responses to emotional stimuli in patients with mood disorders in remission may be a trait characteristic, that negative emotional stimuli are associated with similar prefrontal responses, and that positive emotional stimuli are associated with different prefrontal responses in patients with BD and MDD. These findings indicate that different neural circuits play a role in emotional processing in BD and MDD; this may aid the elucidation of the pathophysiology of these two disorders. PMID- 23643924 TI - Spatio-temporal Granger causality: a new framework. AB - That physiological oscillations of various frequencies are present in fMRI signals is the rule, not the exception. Herein, we propose a novel theoretical framework, spatio-temporal Granger causality, which allows us to more reliably and precisely estimate the Granger causality from experimental datasets possessing time-varying properties caused by physiological oscillations. Within this framework, Granger causality is redefined as a global index measuring the directed information flow between two time series with time-varying properties. Both theoretical analyses and numerical examples demonstrate that Granger causality is a monotonically increasing function of the temporal resolution used in the estimation. This is consistent with the general principle of coarse graining, which causes information loss by smoothing out very fine-scale details in time and space. Our results confirm that the Granger causality at the finer spatio-temporal scales considerably outperforms the traditional approach in terms of an improved consistency between two resting-state scans of the same subject. To optimally estimate the Granger causality, the proposed theoretical framework is implemented through a combination of several approaches, such as dividing the optimal time window and estimating the parameters at the fine temporal and spatial scales. Taken together, our approach provides a novel and robust framework for estimating the Granger causality from fMRI, EEG, and other related data. PMID- 23643926 TI - Real-time fMRI brain computer interfaces: self-regulation of single brain regions to networks. AB - With the advent of brain computer interfaces based on real-time fMRI (rtfMRI BCI), the possibility of performing neurofeedback based on brain hemodynamics has become a reality. In the early stage of the development of this field, studies have focused on the volitional control of activity in circumscribed brain regions. However, based on the understanding that the brain functions by coordinated activity of spatially distributed regions, there have recently been further developments to incorporate real-time feedback of functional connectivity and spatio-temporal patterns of brain activity. The present article reviews the principles of rtfMRI neurofeedback, its applications, benefits and limitations. A special emphasis is given to the discussion of novel developments that have enabled the use of this methodology to achieve self-regulation of the functional connectivity between different brain areas and of distributed brain networks, anticipating new and exciting applications for cognitive neuroscience and for the potential alleviation of neuropsychiatric disorders. PMID- 23643927 TI - Worried sleep: 24-h monitoring in high and low worriers. AB - BACKGROUND: Commonly used trait measures might not accurately capture the relationship between worry and sleep difficulties in real life. METHODS: In a 24 h ambulatory monitoring study, high and low trait worriers maintained a log of worry and sleep characteristics while actigraphy, heart rates (HR), skin conductance (SC), and ambient temperature were recorded. RESULTS: Worrying in bed on the night of the recording was associated with longer self-reported and actigraphic nocturnal awakenings, lower actigraphic sleep efficiency, higher HR, lower HR variability, elevated SC level, and more non-specific SC fluctuations compared to not worrying in bed. High trait worriers had higher HR during waking and sleep, and reported shorter total sleep time and poorer sleep quality. CONCLUSIONS: While trait worry is mainly associated with subjective sleep difficulties, worrying in bed impairs sleep according to both subjective and objective sleep parameters, including heightened sympathetic and reduced parasympathetic activation. PMID- 23643925 TI - Disrupted directed connectivity along the cingulate cortex determines vigilance after sleep deprivation. AB - The cingulate cortex is regarded as the backbone of structural and functional connectivity of the brain. While its functional connectivity has been intensively studied, little is known about its effective connectivity, its modulation by behavioral states, and its involvement in cognitive performance. Given the previously reported effects on cingulate functional connectivity, we investigated how eye-closure and sleep deprivation changed cingulate effective connectivity, estimated from resting-state high-density electroencephalography (EEG) using a novel method to calculate Granger Causality directly in source space. Effective connectivity along the cingulate cortex was dominant in the forward direction. Eyes-open connectivity in the forward direction was greater compared to eyes closed, in well-rested participants. The difference between eyes-open and eyes closed connectivity was attenuated and no longer significant after sleep deprivation. Individual variability in the forward connectivity after sleep deprivation predicted subsequent task performance, such that those subjects who showed a greater increase in forward connectivity between the eyes-open and the eyes-closed periods also performed better on a sustained attention task. Effective connectivity in the opposite, backward, direction was not affected by whether the eyes were open or closed or by sleep deprivation. These findings indicate that the effective connectivity from posterior to anterior cingulate regions is enhanced when a well-rested subject has his eyes open compared to when they are closed. Sleep deprivation impairs this directed information flow, proportional to its deleterious effect on vigilance. Therefore, sleep may play a role in the maintenance of waking effective connectivity. PMID- 23643928 TI - Using bound fatty acids to disclose the functional structure of serum albumin. AB - BACKGROUND: Serum albumin is a major transport protein in mammals and is known to have at least seven binding sites for long-chain fatty acids (FAs). SCOPE OF REVIEW: We have devised a new electron paramagnetic resonance (EPR) spectroscopic approach to gain information on the functional structure of serum albumin in solution in a "coarse-grained" manner from the ligands' point of view. Our approach is based on using spin labeled (paramagnetic) stearic acids self assembled with albumin and subsequent nanoscale distance measurements between the FAs using double electron-electron resonance spectroscopy (DEER). Simple continuous wave (CW) EPR spectroscopy, which allows for quantification of bound ligands, complements our studies. MAJOR CONCLUSIONS: Based on DEER nanoscale distance measurements, the functional solution structure of human serum albumin (HSA) has remarkably been found to have a much more symmetric distribution of entry points to the FA binding sites than expected from the crystal structure, indicating increased surface flexibility and plasticity for HSA in solution. In contrast, for bovine serum albumin (BSA), the entry point topology is in good agreement with that expected from the crystal structure of HSA. Changes in the solution structures between albumins can hence be revealed and extended to more albumins to detect functional differences at the nanoscale. Going beyond fundamental structural studies, our research platform is also excellently suited for general studies of protein-solvent interactions, temperature effects and ligand binding. GENERAL SIGNIFICANCE: We discuss how our research platform helps illuminate protein dynamics and function and can be used to characterize albumin based hybrid materials. This article is part of a Special Issue entitled Serum Albumin. PMID- 23643929 TI - Glutathione metabolism modeling: a mechanism for liver drug-robustness and a new biomarker strategy. AB - BACKGROUND: Glutathione metabolism can determine an individual's ability to detoxify drugs. To increase understanding of the dynamics of cellular glutathione homeostasis, we have developed an experiment-based mathematical model of the kinetics of the glutathione network. This model was used to simulate perturbations observed when human liver derived THLE cells, transfected with human cytochrome P452E1 (THLE-2E1 cells), were exposed to paracetamol (acetaminophen). METHODS: Human liver derived cells containing extra human cytochrome P4502E1 were treated with paracetamol at various levels of methionine and in the presence and absence of an inhibitor of glutamyl-cysteine synthetase (GCS). GCS activity was also measured in extracts. Intracellular and extracellular concentrations of substances involved in glutathione metabolism were measured as was damage to mitochondria and proteins. A bottom up mathematical model was made of the metabolic pathways around and including glutathione. RESULTS: Our initial model described some, but not all the metabolite-concentration and flux data obtained when THLE-2E1 cells were exposed to paracetamol at concentrations high enough to affect glutathione metabolism. We hypothesized that the lack of correspondence could be due to upregulation of expression of glutamyl cysteine synthetase, one of the enzymes controlling glutathione synthesis, and confirmed this experimentally. A modified model which incorporated this adaptive response adequately described the observed changes in the glutathione pathway. Use of the adaptive model to analyze the functioning of the glutathione network revealed that a threshold input concentration of methionine may be required for effective detoxification of reactive metabolites by glutathione conjugation. The analysis also provided evidence that 5-oxoproline and ophthalmic acid are more useful biomarkers of glutathione status when analyzed together than when analyzed in isolation, especially in a new, model assisted integrated biomarker strategy. CONCLUSION: A robust mathematical model of the dynamics of cellular changes in glutathione homeostasis in cells has been developed and tested in vitro. GENERAL SIGNIFICANCE: Mathematical models of the glutathione pathway that help examine mechanisms of cellular protection against xenobiotic toxicity and the monitoring thereof, can now be made. PMID- 23643930 TI - Relationship between serum TGF-beta1, OPG levels and osteoporotic risk in native Chinese women. AB - BACKGROUND: Cytokines including transforming growth factor beta 1 (TGF-beta1) and osteoprotegerin (OPG) are closely related to bone metabolism. However, the relationships between TGF-beta1, OPG and risk of osteoporosis in native Chinese women are unknown. Our research indicated that there is a positive correlation between TGF-beta1 and bone mineral density (BMD) T-score, and a negative correlation between OPG and T-score. The risk of osteoporosis is reduced as TGF beta1 increases and increases as OPG was raised. We investigated correlations of BMD T-scores with circulating TGF-beta1 and BMD T-scores with circulating OPG in healthy native Chinese women, and to study the effects of changes in TGF-beta1 and OPG on osteoporosis. METHODS: This was a cross-sectional study of 691 healthy native Chinese women aged 20-80 years. Concentrations of serum TGF-beta1 and OPG were determined. BMD T-scores at the posteroanterior spine, left hip, and forearm were measured by dual-energy X-ray absorptiometry. RESULTS: There were positive correlations between serum TGF-beta1 and T-scores at the various skeletal sites (r=0.167-0.285, all P=0.000) and negative correlations between serum OPG and T scores (r=-0.179 to -0.270, all P=0.007-0.000). After adjusting for age and BMI, correlations between TGF-beta1 and T-score at the lumbar vertebrae and ultradistal forearm, and between OPG and T-score at the ultradistal forearm in premenopausal subjects, remained statistically significant. Multivariate linear stepwise analysis showed that TGF-beta1 could explain 1.9-8.3% of T-score variation at each skeletal site. OPG could explain 2.4-4.4% of T-score variation. When TGF-beta1 and OPG concentrations were grouped according to quartile intervals, T-score and the prevalence and risk of osteoporosis varied with changes in the cytokines. CONCLUSIONS: The risk of osteoporosis in native Chinese women increased as circulating TGF-beta1 was reduced and OPG was raised. PMID- 23643931 TI - Non-transference of biological reference interval of TSH by electrochemiluminescence immunoassay: an Indian population perspective. AB - INTRODUCTION: Although TSH measurement by electrochemiluminescence immunoassay has become commonplace in India, significant discrepancy has been observed on interpretation of the test results when the manufacturer supplied biological reference interval (BRI) criteria were applied. This report determined whether the manufacturer's BRI (Roche Cobas) is transferable to the Indian population. METHODS: Three hundred seventy-eight age- and sex-matched healthy subjects were selected from an urban Indian population. TSH reference measurements were acquired, and the reference data were statistically analysed. RESULTS: BRI of the Indian urban reference population was determined by non-parametric means. BRI was found to be 1.134 to 7.280MUIU/ml. CONCLUSION: BRI thus calculated was found to be significantly different from that mentioned by the manufacturer (0.27 to 4.20MUIU/ml), which, needless to mention, has profound clinical implications in this part of the globe. PMID- 23643932 TI - Heterologously expressed formyl peptide receptor 2 (FPR2/ALX) does not respond to lipoxin A4. AB - Lipoxin A4 (LXA4) has been described as an anti-inflammatory mediator, which exerts its effects through the formyl peptide receptor FPR2, also known as ALX. However, there has been a controversy whether or not cells expressing FPR2/ALX, such as neutrophils, respond to LXA4. We, therefore, systematically examined the ability of the human and murine forms of the receptor to respond to LXA4. We show that both receptor orthologues responded to the FPR2/ALX peptide agonist WKYMVM when expressed heterologously. In contrast, LXA4 from different sources neither increased [Ca2+](i) and extracellular-signal-regulated kinase (ERK) phosphorylation, nor did it induce a decrease in cAMP levels or a translocation of beta-arrestin. Also, several LXA4 analogs were found to be unable to signal through FPR2/ALX. We conclude that FPR2/ALX is not activated by LXA4 and that the molecular mechanism by which LXA4 functions still needs to be identified. PMID- 23643933 TI - Induction of the liver cancer-down-regulated long noncoding RNA uc002mbe.2 mediates trichostatin-induced apoptosis of liver cancer cells. AB - Differential expression of long non-coding RNAs (lncRNAs) plays critical roles in hepatocarcinogenesis. Considerable attention has focused on the antitumor effect of histone deacetylase inhibitor (Trichostatin A, TSA) as well as the coding gene expression-induced apoptosis of cancer cells. However, it is not known whether lncRNA has a role in TSA-induced apoptosis of human hepatocellular carcinoma (HCC) cells. The global expression of lncRNAs and coding genes was analyzed with the Human LncRNA Array V2.0 after 24 h treatment. Expression was verified in cell lines and tissues by quantitative real-time PCR. The data showed that 4.8% (959) of lncRNA and 6.1% (1849) of protein coding gene were significantly differentially expressed. The differential expressions of lncRNA and protein coding genes had distinguishable hierarchical clustering expression profiling pattern. Among these differentially expressed lncRNAs, the greatest change was noted for uc002mbe.2, which had more than 300 folds induction upon TSA treatment. TSA selectively induced uc002mbe.2 in four studied HCC cell lines. Compared with normal human hepatocytes and adjacent noncancerous tissues, uc002mbe.2 expression level was significantly lower in the HCC cell lines and liver cancer tissues. The TSA-induced uc002mbe.2 expression was positively correlated with the apoptotic effect of TSA in HCC cells. In addition, knockdown the expression of uc002mbe.2 significantly reduced TSA-induced apoptosis of Huh7cells. Therefore, TSA-induced apoptosis of HCC cells is uc002mbe.2 dependent and reduced expression of uc002mbe.2 may be associated with liver carcinogenesis. PMID- 23643934 TI - The impact on children's bone health of a school-based physical education program and participation in leisure time sports: the Childhood Health, Activity and Motor Performance School (the CHAMPS) study, Denmark. AB - OBJECTIVE: To evaluate the effect of a school based physical education (PE) program and the amount of leisure time sport (LTS) on children's bone health and to examine if LTS influences the impact of school type on children's bone health. METHODS: Children attending "sports" schools (6 * 45 min PE lessons per week) were compared to children at "traditional" schools (2 * 45 min of PE lessons per week) in Svendborg, Denmark. Whole-body DXA scans were performed at baseline (2008) and at a two-year follow-up (2010). Bone mineral content (BMC), bone mineral density (BMD), and bone area (BA) were measured. Multilevel regression analyses examined the impact of school type and LTS participation on bone. RESULTS: 742/800 (93%) invited children accepted to participate. 682/742 (92%) participated at two-year follow-up. Mean (SD) age was 9.5 years (0.9) at baseline. A positive association between LTS and BMC, BMD (p<0.001) and for BA (p<0.05) (total body less head (TBLH) and lower limb (LL)) was found. All effects regarding school type were insignificant. CONCLUSION: A positive impact of attending LTS on bone traits was found. There was no effect on BMC, BMD and BA (TBLH, and LL) for children attending sports schools compared to traditional schools. PMID- 23643935 TI - Climbing fiber input shapes reciprocity of Purkinje cell firing. AB - The cerebellum fine-tunes motor activity via its Purkinje cell output. Purkinje cells produce two different types of spikes, complex spikes and simple spikes, which often show reciprocal activity: a periodical increase in complex spikes is associated with a decrease in simple spikes, and vice versa. This reciprocal firing is thought to be essential for coordinated motor behavior, yet how it is accomplished is debated. Here, we show in Ptf1a::cre;Robo3(lox/lox) mice that selectively rerouting the climbing fibers from a contralateral to an ipsilateral projection reversed the complex-spike modulation during sensory stimulation. Strikingly, modulation of simple spikes, which is supposed to be controlled by mossy fibers, reversed as well. Climbing fibers enforce this reciprocity in part by influencing activity of inhibitory interneurons, because the phase of their activity was also converted. Ptf1a::cre;Robo3(lox/lox) mice showed severe ataxia highlighting that climbing fiber input and its impact on reciprocity of Purkinje cell firing play an important role in motor coordination. PMID- 23643937 TI - Route familiarity breeds inattention: a driving simulator study. AB - Inattention is a major cause of traffic accidents. Here, we show that, contrary to common-sense expectation, familiarity with a route is itself a source of driving impairment. This effect may be attributed to increased mind-wandering along familiar routes. In the present work, participants followed a vehicle along a route with which they were either familiar or unfamiliar. During the experimental session, the lead-vehicle braked at random locations, forcing participants to brake to avoid a collision. Participants were also required to respond with a button press when they noticed pedestrians heading toward the road from a sidewalk. In Experiment 1 we found that familiar drivers follow the lead vehicle more closely and are slower to notice approaching pedestrians. In Experiment 2, with following distance held constant, reaction times to central and peripheral events were longer for familiar drivers. Consistent with the mind wandering hypothesis, all these effects were eliminated in Experiment 3 when drivers were made to focus on the driving task. PMID- 23643936 TI - The ventral hippocampus is the embryonic origin for adult neural stem cells in the dentate gyrus. AB - Adult neurogenesis represents a unique form of plasticity in the dentate gyrus requiring the presence of long-lived neural stem cells (LL-NSCs). However, the embryonic origin of these LL-NSCs remains unclear. The prevailing model assumes that the dentate neuroepithelium throughout the longitudinal axis of the hippocampus generates both the LL-NSCs and embryonically produced granule neurons. Here we show that the NSCs initially originate from the ventral hippocampus during late gestation and then relocate into the dorsal hippocampus. The descendants of these cells are the source for the LL-NSCs in the subgranular zone (SGZ). Furthermore, we show that the origin of these cells and their maintenance in the dentate are controlled by distinct sources of Sonic Hedgehog (Shh). The revelation of the complexity of both the embryonic origin of hippocampal LL-NSCs and the sources of Shh has important implications for the functions of LL-NSCs in the adult hippocampus. PMID- 23643938 TI - Bicycling safety and distracted behavior in The Hague, the Netherlands. AB - As planners and public health officials in many cities around the world seek to increase bicycle ridership, bicyclists who are performing a secondary task (such as listening to a portable music device) may pose a risk to public safety. This study examines bicycling safety and potentially distracted behavior in The Hague, the Netherlands, a place where bicycling is a common, everyday travel mode among all walks of life and where bicycling infrastructure is well developed. Based on 1360 observations of bicycling behavior, this study shows that bicyclists who were using a cell phone, listening to a portable music device, or talking with other bicyclists exhibited more unsafe behaviors than those bicyclists who were not performing a secondary task. Furthermore, bicyclists who were performing a secondary task also more frequently created situations where other people had to evade them to avoid an accident. As with distracted car driving, the performance of a secondary task while bicycling may be unsafe for the person engaging in the behavior as well as for other people around them. PMID- 23643941 TI - IFN-gamma selectively exerts pro-apoptotic effects on tumor-initiating label retaining colon cancer cells. AB - Label-retaining cancer cells (LRCCs) represent a novel population of stem-like cancer cells exhibiting slow cycling, chemoresistance and tumor-initiating capacities; however, their properties remain unclear, and approaches to eradicate LRCCs remain elusive. Here, we report that colon cancer cells with high fluorescent intensity, referred to as LRCCs, have the greatest cancer stem cell (CSC)-like capacities and that they preferentially express CSC markers and stemness-related genes. Moreover, we found that Lgr5, which has been reported to be a marker of rapid cycling CSCs, is almost negatively expressed in LRCCs but that its expression is gradually increased in the differentiation process of LRCCs. Interestingly, we found that LRCCs are especially sensitive to the pro apoptotic effect of IFN-gamma treatment both in vitro and in vivo because LRCCs possess higher IFN-gammaR levels compared with non-LRCCs, which results in the upregulation of the apoptosis pathway after IFN-gamma treatment. Furthermore, we found that IFN-gamma shows synergistic effects with the conventional anticancer drug Oxaliplatin to eliminate both LRCCs and non-LRCCs. In conclusion, this is the first study to suggest that LRCCs, as a distinct tumor-initiating population, can be selectively eradicated by IFN-gamma, which may provide a novel therapeutic strategy for colon cancer treatment. PMID- 23643940 TI - OXER1, a G protein-coupled oxoeicosatetraenoid receptor, mediates the survival promoting effects of arachidonate 5-lipoxygenase in prostate cancer cells. AB - Inhibition of 5-Lox induces apoptosis in prostate cancer cells by inactivating PKCepsilon which is prevented by 5-oxoETE, and activators of PKCepsilon prevent 5 Lox inhibition-induced apoptosis, suggesting that 5-Lox metabolites exert survival signaling via PKCepsilon. However, mechanisms by which 5-Lox metabolites activate PKCepsilon are not understood yet. We found that prostate cancer cells express high levels of OXER1, a G protein-coupled 5-oxoETE receptor, which delivers signal by generating diacyl-glycerol through phospholipase C-beta. Interestingly, we found that U73122, an inhibitor of PLC-beta, interrupts the apoptosis-preventing effect of 5-oxoETE, and exogenous diacyl-glycerol effectively prevents 5-Lox inhibition-induced apoptosis, suggesting that 5-oxoETE signals via OXER1 to promote prostate cancer cell survival. PMID- 23643939 TI - Differential BMP signaling controls formation and differentiation of multipotent preplacodal ectoderm progenitors from human embryonic stem cells. AB - Sensory and endoneurocrine tissues as diverse as the lens, the olfactory epithelium, the inner ear, the cranial sensory ganglia, and the anterior pituitary arise from a common pool of progenitors in the preplacodal ectoderm (PPE). Around late gastrulation, the PPE forms at the border surrounding the anterior neural plate, and expresses a unique set of evolutionarily conserved transcription regulators including Six1, Eya 1 and Eya2. Here, we describe the first report to generate and characterize the SIX1(+) PPE cells from human embryonic stem (ES) cells by adherent differentiation. Before forming PPE cells, differentiating cultures first expressed the non-neural ectoderm specific transcriptional factors TFAP2A, GATA2, GATA3, DLX3, and DLX5, which are crucial in establishing the PPE competence. We demonstrated that bone morphogenetic protein (BMP) activity plays a transient but essential role in inducing expression of these PPE competence factors and eventually the PPE cells. Interestingly, we found that attenuating BMP signaling after establishing the competence state induces anterior placode precursors. By manipulating BMP and hedgehog signaling pathways, we further differentiate these precursors into restricted lineages including the lens placode and the oral ectoderm (pituitary precursor) cells. Finally, we also show that sensory neurons can be generated from human PPE cells, demonstrating the multipotency of the human ES-derived PPE cells. PMID- 23643942 TI - Angiopoietin2 enhances doxorubin resistance in HepG2 cells by upregulating survivin and Ref-1 via MSK1 activation. AB - Angiopoietin2 (Ang2) and its Tie2 receptor have extensive effects on tumor malignancy including angiogenesis and metastasis. In this study, we evaluated the protective effect of Ang2 on doxorubicin-induced apoptosis in HepG2 cells. Ang2 (400 ng/ml) attenuated doxorubicin-mediated cytotoxicity by upregulating the expression of Survivin and Ref-1, which was reversed by a soluble extracellular domain of Tie2. Mechanistic study showed Ang2 activated ERK-MSK cascade to induce histone H3 phosphorylation and inducible gene expression. The stimulatory effect of Ang2 on anti-apoptotic genes was attenuated by either MSK inhibitor (H89) or by overexpression of a kinase-deficient MSK1. Activated MSK1 phosphorylated the CREB at Ser133 and phosho-CREB was recruited to Ref-1 promoter rapidly to initiate the gene expression. Moreover, knockdown of MSK1 by specific siRNA also attenuated the pro-survival activity of Ang2 and CREB phosphorylation. Hence, our study suggests the existence of an Ang2-ERK-MSK signaling axis mediating survival responses and drug resistance of tumor cells. PMID- 23643944 TI - Naked-eye detection of nucleic acids through rolling circle amplification and magnetic particle mediated aggregation. AB - We are presenting a new method for sequence-specific and naked-eye detection of nucleic acids (NAs) through isothermal amplification and magnetic particle mediated aggregation. A padlock probe was designed to hybridize to specific sequence on target genes followed by ligation and rolling circle amplification (RCA). Magnetic particles (MPs) were then added into RCA products solution. MPs would physically combine with long linear DNA coils (such as products of RCA reaction) and form visible intertwined aggregates, while no aggregate was observed in the absence of high molecular weight NAs (>1kb). As little as 0.62amol (124fM) of target DNA molecules was detected by the naked eye. It was further applied to detect human papillomavirus type 18 gene in genomic DNA isolated from HeLa cells. This assay is sensitive and low-cost with minimal instrumentation, revealing great potential for molecular diagnostics in developing countries and regions with limited settings. PMID- 23643945 TI - Highly sensitive recognition of Pb(2+) using Pb(2+) triggered exonuclease aided DNA recycling. AB - Here, we have demonstrated an ultra-high sensitive detection platform with the detection limit of 5pM for an environmental toxin-Pb(2+). We designed a Pb(2+) triggered exonuclease aided DNA recycling system to improve the detection sensitivity. In our system, a Pb(2+) dependent 8-17 DNAzyme and its substrate were used to form hybridization duplex. In the presence of Pb(2+), the substrate was cleaved and disassociated from the duplex. Then, the released 8-17 DNAzyme was used as a target of the exonuclease aided DNA recycling system which can amplify the fluorescence signal by recycling the 8-17 DNAzyme continuously. Then, the sensitive Pb(2+) detection are accomplished and the detection limit of Pb(2+) was down to 5pM which is about 1000 times lower than the traditional detection method based on the 8-17 DNAzyme. PMID- 23643943 TI - Base excision repair in the mammalian brain: implication for age related neurodegeneration. AB - The repair of damaged DNA is essential to maintain longevity of an organism. The brain is a matrix of different neural cell types including proliferative astrocytes and post-mitotic neurons. Post-mitotic DNA repair is a version of proliferative DNA repair, with a reduced number of available pathways and most of these attenuated. Base excision repair (BER) is one pathway that remains robust in neurons; it is this pathway that resolves the damage due to oxidative stress. This oxidative damage is an unavoidable byproduct of respiration, and considering the high metabolic activity of neurons this type of damage is particularly pertinent in the brain. The accumulation of oxidative DNA damage over time is a central aspect of the theory of aging and repair of such chronic damage is of the highest importance. We review research conducted in BER mouse models to clarify the role of this pathway in the neural system. The requirement for BER in proliferating cells also correlates with high levels of many of the BER enzymes in neurogenesis after DNA damage. However, the pathway is also necessary for normal neural maintenance as larger infarct volumes after ischemic stroke are seen in some glycosylase deficient animals. Further, the requirement for DNA polymerase beta in post-mitotic BER is potentially more important than in proliferating cells due to reduced levels of replicative polymerases. The BER response may have particular relevance for the onset and progression of many neurodegenerative diseases associated with an increase in oxidative stress including Alzheimer's. PMID- 23643946 TI - Supersandwich-type electrochemiluminescenct aptasensor based on Ru(phen)3(2+) functionalized hollow gold nanoparticles as signal-amplifying tags. AB - An electrochemiluminescent (ECL) aptasensor was fabricated and used for the amplified detection of thrombin (TB) based on DNA supersandwich structure. Herein, hollow gold nanospheres (HGNPs) were firstly employed as effective tag carriers for the immobilization of detection aptamer (TBA 2) to form the HGNPs labeled TBA 2 (HGNPs-TBA 2). Subsequently, streptavidin (SA) was used to block the non-specific binding sites of HGNPs-TBA 2 as well as to supply binding sites, which could further introduce numerous initiator DNA strands (bio-S1) via biotin streptavidin specific interaction. Next, bio-S1 could in situ trigger hybridization chain reaction (HCR) to create a long nicked double helices analogous (dsDNA) in the present of ssDNA S2 and ssDNA S3 (S3 is partially complementary to the S2) to obtain the DNA supersandwich structure. Furthermore, Ru(phen)3(2+), a well-known ECL luminophore, could be intercalated into the grooves of dsDNA (Ru-dsDNA) to form the Ru-dsDNA-SA-HGNPs-TBA 2 bioconjugate. As a result, the target of TB was sandwiched between Ru-dsDNA-SA-HGNPs-TBA 2 and TBA 1. In this strategy, numerous Ru(phen)3(2+) could be immobilized on the electrode based on the supersandwich structure, resulting in an increased ECL signal output. A supersandwich ECL assay for TB detection was developed with excellent sensitivity of a large concentration variation from 5fM to 50pM and a detection limit of 1.6fM. PMID- 23643947 TI - The response profiles of HSPA12A and TCTP from Mytilus galloprovincialis to pathogen and cadmium challenge. AB - Heat shock 70 kDa protein 12A (HSPA12A) is an atypical member of HSP70 family, and the translationally controlled tumor protein (TCTP) is a novel HSP with chaperone-like activity. They are both involved in protecting organisms against various stressors. In the present study, the cDNAs of HSPA12A and TCTP (called MgHSPA12A and MgTCTP) were identified from Mytilus galloprovincialis by RACE approaches. The full-length cDNA of MgHSPA12A and MgTCTP encoded a peptide of 491 and 171 amino acids, respectively. Real-time PCR was employed to analyze the tissue distribution and temporal expression of these two genes after bacterial challenge and cadmium (Cd) exposure. It was found that the transcripts of MgHSPA12A and MgTCTP were dominantly expressed in gonad and muscle, respectively. The expression level of MgTCTP at 48 h post Vibrio anguillarum challenge was detected to be significantly up-regulated in hepatopancreas (P < 0.05). As concerned to Cd exposure, 2.0-fold increase of MgHSPA12A expression compared to that of the control was observed at 48 h in 5 MUg/L Cd(2+)-treated group, while the expression levels of MgTCTP were significantly decreased after exposed to both 5 and 50 MUg/L Cd(2+) for 24 h and 96 h. These results suggested the potential involvement of MgHSPA12A and MgTCTP in the mediation of the immune responses and environmental stress in mussels. PMID- 23643948 TI - MgATP regulates allostery and fiber formation in IMPDHs. AB - Inosine-5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in nucleotide biosynthesis studied as an important therapeutic target and its complex functioning in vivo is still puzzling and debated. Here, we highlight the structural basis for the regulation of IMPDHs by MgATP. Our results demonstrate the essential role of the CBS tandem, conserved among almost all IMPDHs. We found that Pseudomonas aeruginosa IMPDH is an octameric enzyme allosterically regulated by MgATP and showed that this octameric organization is widely conserved in the crystal structures of other IMPDHs. We also demonstrated that human IMPDH1 adopts two types of complementary octamers that can pile up into isolated fibers in the presence of MgATP. The aggregation of such fibers in the autosomal dominant mutant, D226N, could explain the onset of the retinopathy adRP10. Thus, the regulatory CBS modules in IMPDHs are functional and they can either modulate catalysis or macromolecular assembly. PMID- 23643949 TI - Three-dimensional protein fold determination from backbone amide pseudocontact shifts generated by lanthanide tags at multiple sites. AB - Site-specific attachment of paramagnetic lanthanide ions to a protein generates pseudocontact shifts (PCS) in the nuclear magnetic resonance (NMR) spectra of the protein that are easily measured as changes in chemical shifts. By labeling the protein with lanthanide tags at four different sites, PCSs are observed for most amide protons and accurate information is obtained about their coordinates in three-dimensional space. The approach is demonstrated with the chaperone ERp29, for which large differences have been reported between X-ray and NMR structures of the C-terminal domain, ERp29-C. The results unambiguously show that the structure of rat ERp29-C in solution is similar to the crystal structure of human ERp29-C. PCSs of backbone amides were the only structural restraints required. Because these can be measured for more dilute protein solutions than other NMR restraints, the approach greatly widens the range of proteins amenable to structural studies in solution. PMID- 23643951 TI - Structural insights into the intrinsic self-assembly of Par-3 N-terminal domain. AB - Par-3, the central organizer of the Par-3/Par-6/atypical protein kinase C complex, is a multimodular scaffold protein that is essential for cell polarity establishment and maintenance. The N-terminal domain (NTD) of Par-3 is capable of self-association to form filament-like structures, although the underlying mechanism is poorly understood. Here, we determined the crystal structure of Par 3 NTD and solved the filament structure by cryoelectron microscopy. We found that an intrinsic "front-to-back" interaction mode is important for Par-3 NTD self association and that both the lateral and longitudinal packing within the filament are mediated by electrostatic interactions. Disruptions of the lateral or longitudinal packing significantly impaired Par-3 NTD self-association and thereby impacted the Par-3-mediated epithelial polarization. We finally demonstrated that a Par-3 NTD-like domain from histidine ammonia-lyase also harbors a similar self-association capacity. This work unequivocally provides the structural basis for Par-3 NTD self-association and characterizes one type of protein domain that can self-assemble via electrostatic interactions. PMID- 23643950 TI - Crystal structures of the viral protease Npro imply distinct roles for the catalytic water in catalysis. AB - Npro is a key effector protein of pestiviruses such as bovine viral diarrhea virus and abolishes host cell antiviral defense mechanisms. Synthesized as the N terminal part of the viral polyprotein, Npro releases itself via an autoproteolytic cleavage, triggering its immunological functions. However, the mechanisms of its proteolytic action and its immune escape were unclear. Here, we present the crystal structures of Npro to 1.25 A resolution. Structures of pre- and postcleavage intermediates identify three catalytically relevant elements. The trapping of the putative catalytic water reveals its distinct roles as a base, acid, and nucleophile. The presentation of the substrate further explains the enigmatic latency of the protease, ensuring a single in cis cleavage. Additionally, we identified a zinc-free, disulfide-linked conformation of the TRASH motif, an interaction hub of immune factors. The structure opens additional opportunities in utilizing Npro as an autocleaving fusion protein and as a pharmaceutical target. PMID- 23643952 TI - The role of pentraxin 3 as diagnostic value in classification of patients with heart failure. AB - OBJECTIVE: Pentraxin 3 (PTX3) is a new inflammatory marker that is the prototype of the long pentraxin group, while C-reactive protein (CRP) is the short pentraxin group. The aim of the present study was to investigate the clinical significance of plasma PTX3 and CRP levels in heart failure (HF). MATERIALS AND METHODS: The study included 22 male and 37 female patients with HF, and 23 healthy volunteers as the control group. Patients were divided into 4 groups (class I, II, III and IV) according to New York Heart Association functional class. RESULTS: Plasma PTX3 and CRP levels were significantly elevated in HF patients compared to healthy controls. Comparing PTX3 levels in patient groups, statistically significant difference was found between class-I and class-II, class-III and class-IV patients (p=0.009, p=0.001, p<0.001, respectively). There was a positive correlation between PTX3 and CRP levels (r=0.369, p=0.004). In receiver-operating characteristic (ROC) curves, area under the curve (AUC) values for PTX3 and CRP were 0.928 (p=0.001) and 0.834 (p=0.001), respectively. CONCLUSIONS: Plasma PTX3 levels are elevated in HF and might be used as diagnostic value in classification of patients with HF. It is still debated whether inflammation may be just a cause or a consequence of the disease. Therefore further work is needed to better understand in large populations of patients with HF. PMID- 23643953 TI - Derivative mechanisms of organic acids in microwave oxidation of landfill leachate. AB - This study compared formation and degradation behaviors of organic acids in landfill leachate under microwave oxidation process (MOP) and under conventional heating oxidation (CHO) and explored derivative mechanisms of organic acids in MOP. The results showed that formation and degradation behaviors of oxalic acid were very similar under CHO and MOP, in which its concentrations decreased in the temperature-raising period, then increased due to decomposition of TOC from 10 to 70 min, decreased due to persulfate oxidation from 70 to 130 min, and stayed the same afterwards. The pH values of the leachate solution dropped 0.51 and 0.65 pH units after MOP and CHO treatment, respectively. Oxalic acid was the dominant organic acid formed in MOP. The derivative mechanisms of organic acids were developed using the experimental results. Lactic acid was generated from decomposition of malic acid, and oxalic acid was formed from oxidation of its precursors. Acetic acid was formed and soon decomposed. Lactic acid had its maximum concentration with a persulfate dose of 0.5M, while lower or higher persulfate doses yielded few or no lactic acid in MOP. PMID- 23643954 TI - The optimization of As(V) removal over mesoporous alumina by using response surface methodology and adsorption mechanism. AB - The Box-Behnken Design of the response surface methodology was employed to optimize four most important adsorption parameters (initial arsenic concentration, pH, adsorption temperature and time) and to investigate the interactive effects of these variables on arsenic(V) adsorption capacity of mesoporous alumina (MA). According to analysis of variance (ANOVA) and response surface analyses, the experiment data were excellent fitted to the quadratic model, and the interactive influence of initial concentration and pH on As(V) adsorption capacity was highly significant. The predicted maximum adsorption capacity was about 39.06 mg/g, and the corresponding optimal parameters of adsorption process were listed as below: time 720 min, temperature 52.8 degrees C, initial pH 3.9 and initial concentration 130 mg/L. Based on the results of arsenate species definition, FT-IR and pH change, As(V) adsorption mechanisms were proposed as follows: (1) at pH 2.0, H3AsO4 and H2AsO4(-) were adsorbed via hydrogen bond and electrostatic interaction, respectively; (2) at pH 6.6, arsenic species (H2AsO4(-) and HAsO4(2-)) were removed via adsorption and ion exchange, (3) at pH 10.0, HAsO4(2-) was adsorbed by MA via ion exchange together with adsorption, while AsO4(3-) was removed by ion exchange. PMID- 23643955 TI - A mechanistic study of arsenate removal from artificially contaminated clay soils by electrokinetic remediation. AB - Batch desorption experiments and bench-scale electrokinetic experiments were performed to elucidate the electrokinetic remediation mechanisms of arsenate from artificially contaminated kaolinite. The electrokinetic experiments in which a constant voltage was applied demonstrated that high soil pH favored arsenate remediation with respect to both the remediation time and electricity consumption. It was also demonstrated that applying a pulse voltage (1 h ON, 1 h OFF) significantly improved the electricity consumption efficiency when the soil pH was maintained at the initial value during the experiments; this trend was not observed when the soil pH was gradually increased from the cathode side. These electrokinetic experimental results, with the support of arsenate desorption data obtained from batch experiments, indicate that the remediation rate-limiting step varied with soil pH. When the soil pH was maintained at the initial value of 7.2 during the experiments, arsenate desorption was the remediation rate-limiting step rather than the migration of dissolved arsenate toward the anode. Conversely, when the cathode pH was not controlled and the soil pH was correspondingly increased gradually from the cathode side, the migration of hydroxyl and desorbed arsenate ions toward the anode played a more important role in the control of the overall remediation efficiency. PMID- 23643956 TI - A high efficiency microreactor with Pt/ZnO nanorod arrays on the inner wall for photodegradation of phenol. AB - A high efficiency microreactor with Pt coated ZnO (Pt/ZnO) nanorod arrays on the inner wall was successfully fabricated by pumping a Pt sol into the microchannel containing preformed ZnO nanorod arrays. Phenol was selected as a persistent organic pollutant to evaluate the photocatalytic performance of the microreactors. The microreactor which was coated by Pt sol for 5 min showed the best photocatalytic performance compared with other Pt/ZnO nanorod array-modified microreactors. The presence of Pt nanoparticles on the surfaces of ZnO nanorods promoted the separation of photoinduced electron-hole pairs and thus enhanced the photocatalytic activity. In addition, the recyclable property of the microcreator was investigated. It was found that the microreactor displayed higher durability during the continuous photocatalytic process. PMID- 23643957 TI - Comparison of chlorine and ammonia concentration field trial data with calculated results from a Gaussian atmospheric transport and dispersion model. AB - The Jack Rabbit Test Program was sponsored in April and May 2010 by the Department of Homeland Security Transportation Security Administration to generate source data for large releases of chlorine and ammonia from transport tanks. In addition to a variety of data types measured at the release location, concentration versus time data was measured using sensors at distances up to 500 m from the tank. Release data were used to create accurate representations of the vapor flux versus time for the ten releases. This study was conducted to determine the importance of source terms and meteorological conditions in predicting downwind concentrations and the accuracy that can be obtained in those predictions. Each source representation was entered into an atmospheric transport and dispersion model using simplifying assumptions regarding the source characterization and meteorological conditions, and statistics for cloud duration and concentration at the sensor locations were calculated. A detailed characterization for one of the chlorine releases predicted 37% of concentration values within a factor of two, but cannot be considered representative of all the trials. Predictions of toxic effects at 200 m are relevant to incidents involving 1-ton chlorine tanks commonly used in parts of the United States and internationally. PMID- 23643958 TI - Adsorption of pharmaceuticals onto trimethylsilylated mesoporous SBA-15. AB - The adsorption of a complex mixture of 12 selected pharmaceuticals to trimethylsilylated mesoporous SBA-15 (TMS-SBA-15) has been investigated by batch adsorption experiments. The adsorption of pharmaceuticals to TMS-SBA-15 was highly dependent on the solution pH and pharmaceutical properties (i.e., hydrophobicity (logKow) and acidity (pKa)). Good log-log linear relationships between the adsorption (Kd) and pH-dependent octanol-water coefficients (Kow(pH)) were then established among the neutral, anionic, and cationic compounds, suggesting hydrophobic interaction as a primary driving force in the adsorption. In addition, the neutral species of each compound accounted for a major contribution to the overall compound adsorption onto TMS-SBA-15. The adsorption kinetics of pharmaceuticals was evaluated by the nonlinear first-order and pseudo second-order models. The first-order model gave a better fit for five pharmaceuticals with lower adsorption capacity, whereas the pseudo-second-order model fitted better for seven pharmaceuticals having higher adsorption capacity. In the same group of properties, pharmaceuticals having higher adsorption capacity exhibited faster adsorption rates. The rate-limiting steps for adsorption of pharmaceuticals onto TMS-SBA-15 are boundary layer diffusion and intraparticle diffusion including diffusion in mesopores and micropores. In addition, the adsorption of pharmaceuticals to TMS-SBA-15 was not influenced by the change of initial pharmaceutical concentration (10-100MUgL(-1)) and the presence of natural organic matter. PMID- 23643959 TI - Photocatalytic conversion of gaseous ethylbenzene on lanthanum-doped titanium dioxide nanotubes. AB - The photocatalytic properties of titanium dioxide (TiO2) make it an attractive material for environmental remediation. In the present study, lanthanum (La(3+)) doped TiO2 nanotubes with excellent photocatalytic activity were fabricated by a combination of sol-gel method and hydrothermal technique. The optimal preparation parameters were determined by the structural characterization using a range of methods and the photocatalytic degradation of gaseous ethylbenzene (EB). Compared with pure TiO2 nanoparticles, 1.2%-La(3+)-doped - titania nanotubes (1.2%-La(3+) TNTs) exhibited higher activity under 254 nm UV for conversion of EB. The initial EB concentrations and relative humidity (RH) obviously influenced the photocatalytic activity of 1.2%-La(3+)-TNTs. Kinetic analysis showed that surface adsorption and surface reaction controlled the rate-determining step for RH of 40 50% and >80%, respectively. Gas chromatography and mass spectrometry were used to analyze the intermediates generated in the conversion of EB, allowing a tentative decomposition pathway to be proposed. The prepared photocatalyst exhibited enhanced EB conversion compared with undoped TiO2, and showed a promise for the decomposition of recalcitrant compounds before subsequent biopurification. PMID- 23643961 TI - Defining what evidence is, linking it to patient outcomes, and making it relevant to practice: insight from clinical nurses. AB - BACKGROUND/RATIONALE: Factors that impede or enable successful evidence based practice for nurses in their daily work is well documented. Less known is how nurses define evidence in their daily clinical practice and how this knowledge can inform strategies to enhance evidence based patient care and outcomes. AIMS/METHODS: A qualitative study was undertaken to explore nurses' perceptions of what constitutes evidence as part of EBP and how applicable evidence is to their daily practice. A qualitative design using semi-structured interviews was employed for this study. Data were analyzed using directed content analysis. RESULTS: The following four key themes emerged: viewing evidence as research based and a proven practice; linking evidence to patient outcomes; basing evidence on experience; and making evidence relevant to practice. IMPLICATIONS: Study findings point to having accessible, practical tools to make evidence credible and relevant for nurses tailored to their clinical contexts. PMID- 23643960 TI - Removal of carbon, nitrogen and phosphorus from the separated liquid phase of hog manure by the multi-zone BioCAST technology. AB - The removal of chemical oxygen demand (COD), total nitrogen (TN) and total phosphorus (TP) at concentrations of 960 +/- 38 to 2400 +/- 96 mg/L, 143 +/- 9 to 235 +/- 15 mg/L and 25 +/- 2 to 57 +/- 4 mg/L, respectively, from the separated liquid phase of hog manure by the multi-zone BioCAST technology is discussed. Despite the inhibitory effect of hog waste toward microbial activities, removal efficiencies up to 89.2% for COD, 69.2% for TN and 47.6% for TP were obtained during 185 d of continuous operation. The free ammonia inhibition was postulated to be responsible for the steady reduction of COD and TP removal with the increase of TN/TP ratio from 3.6 to 5.8. On the contrary, the increase of COD/TN ratio from 4.8 to 14.1 improved the removal of all contaminants. Nitrogen removal did not show any dependence on the COD/TP ratio, despite the steady increase of COD and TP removal with this ratio in the range of 19.3-50.6. The removal efficiencies of organic and inorganic contaminants increased progressively owing to the adaptation of microbial biomass, resulting from the presence of suspended biomass in the mixed liquor that circulated continuously between the three zones of aerobic, microaerophilic and anoxic, as well as the attached biomass immobilized inside the aerobic zone. PMID- 23643962 TI - Relationship between adiponectin and nitrite in healthy and preeclampsia pregnancies. AB - BACKGROUND: Controversial results have been reported regarding plasma adiponectin levels in preeclampsia (PE) compared to healthy pregnancies (HP). Adiponectin activates eNOS, increasing the levels of the vasodilator nitric oxide (NO). PE reduces the levels of nitrite (an NO marker) and induces higher levels of ADMA (an endogenous eNOS inhibitor) compared to HP. No previous study has examined whether a positive correlation exists between adiponectin and nitrite in HP and PE and how ADMA may interfere with this correlation. METHODS: We measured plasma nitrite concentrations using an ozone-based chemiluminescence assay, and plasma ADMA and adiponectin levels using enzyme immunoassays in 117 pregnant women (70 healthy and 47 preeclamptic). RESULTS: We found higher adiponectin levels (23.6+/ 13.0 vs. 17.8+/-5.6ug/ml; P<0.05) and lower plasma nitrite levels (104.5+/-84.3 vs. 177.2+/-151.3 nM; P<0.05) in PE compared to HP. We found a significant positive correlation between these markers in HP (r=0.3; P<0.05), but no correlation in PE. However, when we grouped PE women regarding ADMA levels (low and high levels), a strong positive correlation was found in the group with lower ADMA levels (r=0.67; P<0.05), suggesting that high ADMA concentrations may interfere with the physiological activation of eNOS by adiponectin in PE. CONCLUSIONS: Our findings showed higher levels of adiponectin and lower nitrite levels in PE compared to HP, and these levels were positively correlated in HP and in PE presenting lower concentrations of ADMA. PMID- 23643963 TI - Reevaluation of glypican-3 as a serological marker for hepatocellular carcinoma. AB - BACKGROUND: Glypican-3 (GPC3) is a novel histochemical marker of hepatocellular carcinoma (HCC). However, its utility as a serologic marker for HCC is not conclusive. METHODS: A total of 1037 subjects, including 155 patients with HCC, 180 with chronic hepatitis, 124 with liver cirrhosis, 442 with non-HCC cancer and 136 healthy controls, were analyzed for serum GPC3 (sGPC3) by an ELISA constructed with 2 monoclonal antibodies. RESULTS: The average level of sGPC3 in HCC patients was 99.94+/-267.2ng/ml, which was significantly higher than in patients with chronic hepatitis (10.45+/-46.02ng/ml, P<0.0001), liver cirrhosis (19.44+/-50.88ng/ml, P=0.0013), non-HCC cancer (20.50+/-98.33ng/ml, P<0.0001) and healthy controls (4.14+/-31.65ng/ml, P<0.0001). The sensitivity of sGPC3 in HCC diagnosis was 40.0%, whereas the specificity was 98.5%, 94.4% and 87.1% in healthy controls, chronic hepatitis patients and liver cirrhosis patients, respectively. In addition, 13.5% (28/207) of lung cancer patients and 13.2% (9/68) of thyroid cancer patients had positive results with sGPC3. CONCLUSION: Serum GPC3 is a potential marker for HCC. However, the presence of sGPC3 in patients with lung cancer and thyroid cancer might limit its application as a single marker in the diagnosis of HCC. PMID- 23643964 TI - Comparative genomic and phylogenetic analyses of the intelectin gene family: implications for their origin and evolution. AB - Intelectin is a newly characterized gene family involved in early embryogenesis, host-pathogen interactions and iron metabolism. In this study, we searched the genomes of metazoans by extensive BLAST survey and found no intelectin homologs in invertebrate metazoans but 12 in amphioxus Branchiostoma floridae and 21 in ascidians Ciona intestinalis. Some ascidians oocyte cortical granule lectins (CGLs) have unknown insertion sequences between fibrinogen-related domain (FReD) and Intelectin Domain, the boundaries of which are equivalent to exon structures. In addition to ascidians intelectins/CGLs located in the base, phylogenetic tree comprises four main clades representing mammal, frog, fish, and amphioxus, indicating that intelectin genes undergo extensive lineage-specific duplication or gene conversion. However, genomic neighborhood surrounding analysis shows that clear proto-orthologies are difficult to be established among these counterparts. In addition, sequence comparison and phylogenetic analysis of FReDs from intelectins and other fibrinogen-like proteins from choanoflagellate, anemone, frog and human indicate FReDs of intelectins are unique. Likewise, these choanoflagellate and anemone genes may be close to intelectin gene. PMID- 23643965 TI - Inorganic phosphate uptake in Trypanosoma cruzi is coupled to K(+) cycling and to active Na(+) extrusion. AB - BACKGROUND: Orthophosphate (Pi) is a central compound in the metabolism of all organisms, including parasites. There are no reports regarding the mechanisms of Pi acquisition by Trypanosoma cruzi. METHODS: (32)Pi influx was measured in T. cruzi epimastigotes. The expression of Pi transporter genes and the coupling of the uptake to Na(+), H(+) and K(+) fluxes were also investigated. The transport capacities of different evolutive forms were compared. RESULTS: Epimastigotes grew significantly more slowly in 2mM than in 50mM Pi. Influx of Pi into parasites grown under low Pi conditions took place in the absence and presence of Na(+). We found that the parasites express TcPho84, a H(+):Pi-symporter, and TcPho89, a Na(+):Pi-symporter. Both Pi influx mechanisms showed Michaelis-Menten kinetics, with a one-order of magnitude higher affinity for the Na(+)-dependent system. Collapsing the membrane potential with carbonylcyanide-p trifluoromethoxyphenylhydrazone strongly impaired the influx of Pi. Valinomycin (K(+) ionophore) or SCH28028 (inhibitor of (H(+)+K(+))ATPase) significantly inhibited Pi uptake, indicating that an inwardly-directed H(+) gradient energizes uphill Pi entry and that K(+) recycling plays a key role in Pi influx. Furosemide, an inhibitor of the ouabain-insensitive Na(+)-ATPase, decreased only the Na(+)-dependent Pi uptake, indicating that this Na(+) pump generates the Na(+) gradient utilized by the symporter. Trypomastigote forms take up Pi inefficiently. CONCLUSIONS: Pi starvation stimulates membrane potential-sensitive Pi uptake through different pathways coupled to Na(+) or H(+)/K(+) fluxes. GENERAL SIGNIFICANCE: This study unravels the mechanisms of Pi acquisition by T. cruzi, a key process in epimastigote development and differentiation to trypomastigote forms. PMID- 23643966 TI - Photochemical internalization of CD133-targeting immunotoxins efficiently depletes sarcoma cells with stem-like properties and reduces tumorigenicity. AB - BACKGROUND: The normal stem cell marker CD133 is also a putative marker of cancer stem cells (CSCs) in different types of cancers. Hence, a major challenge when targeting CD133-expressing CSCs is to prevent depletion of the normal stem cell pool. We hypothesized that the site-specific and light-controlled drug delivery method photochemical internalization (PCI) may have the potential to enhance selectivity and endosomal escape of CD133-targeting immunotoxins in stem-like sarcoma cells. METHODS: We have used a sarcoma model, SW872 cells isolated from xenografts harboring CSCs within a ~2% CD133(high) subpopulation to investigate the potential of PCI of CD133-targeting toxin as a novel strategy to kill CSCs. Model immunotoxins were generated by binding the ribosome-inactivating protein toxin saporin to each of the monoclonal antibodies CD133/1 (AC133) or CD133/2 (293C), specific for individual CD133-epitopes. Cellular targeting, intracellular co-localization with the PCI photosensitizer, disulfonated meso tetraphenylchlorin (TPCS2a), and cytotoxic efficacy of PCI of the CD133-targeting toxins were evaluated. RESULTS: PCI of CD133-saporin efficiently targets CD133 expressing SW872 and HT1080 sarcoma cells and results in loss of cell viability. Following sub-toxic treatment, surviving SW872 cells, depleted of the CD133 expressing population, display reduced proliferative capacity and attenuated CSC properties, such as reduced colony-forming ability and tumorigenicity. CONCLUSION: Here we present a proof-of-concept study, where PCI enables light triggered delivery of CD133-targeting antibody-drug conjugates, resulting in decreased sarcoma tumor-initiating capacity. GENERAL SIGNIFICANCE: PCI of CD133 targeting toxins may be used as a minimal invasive strategy in the treatment of sarcomas, and potentially as a therapeutic for other solid tumors expressing CD133. PMID- 23643967 TI - Fibrin nanoparticles as Possible vehicles for drug delivery. AB - BACKGROUND: Several issues have been raised emphasizing the harmful toxic effects of metal nanoparticles towards biological systems. Search of biological nanoparticles with excellent biocompatibility and bioavailability could address this problem. METHODS: Fibrin nanoparticles (FNP) were prepared using a novel technique and characterized for their physico-chemical properties. In vitro studies were performed to examine cytotoxicity and cellular uptake of FNP. Innate immune response to FNP was studied by (i) estimating in vitro generation of complement split products, C3a and C4d and (ii) in vivo expression of pro inflammatory cytokines, TNF-alpha, IL-1 and IL-6. In vivo biodistribution study was carried out by intravenous administration of FITC-labelled FNP in mice. RESULTS: FNP were spherical with size ranging from 25 to 28nm. In vitro studies proved the biocompatibility of the nanoparticles, with their distribution across the cytoplasm and nucleus of treated cells. Complement activation studies showed insignificant increase in the level of C3a when compared with positive control. RT-PCR results revealed significant upregulation of TNF-alpha and downregulation of IL-6 cytokines after 6h of FNP administration. In vivo biodistribution studies showed moderate blood circulation time, with predominant distribution of nanoparticles in the liver followed by the lungs, kidney and spleen. Haematology, serum biochemistry, and histopathology analyses demonstrated that FNP were non toxic. CONCLUSION: Owing to their small size, low cost, ease of preparation and excellent biocompatibility, FNP might be a promising novel material for drug delivery applications. GENERAL SIGNIFICANCE: Our results demonstrate the safe and promising use of FNP for biomedical applications. PMID- 23643968 TI - Dual-energy X-ray absorptiometry measured regional body composition least significant change: effect of region of interest and gender in athletes. AB - Dual-energy X-ray absorptiometry (DXA) is widely used to evaluate body composition in athletes. Knowledge of measurement precision is essential for monitoring body composition changes over time. This study begins characterizing DXA body composition precision in 60 (30 males and 30 females) Division 1 athletes focusing on gender, regional, and tissue type differences. Two total body scans with repositioning between were performed on the same day. Least significant change (LSC) for the root-mean-square deviation (LSCRMSD) and the percent coefficient of variation (LSC%CV) for total, lean, and fat mass was calculated for 6 regions of interest. The effect of gender, region, tissue type, and mass on the standard deviation (SD) and percent coefficient of variation (%CV) between the 2 scans was evaluated using repeated measures regression analysis. Statistically significant effects of gender, region, tissue type, and mass on SD and %CV were noted. To generalize, a nonlinear positive relationship between LSCRMSD and mass and a nonlinear negative relationship between LSC%CV and mass were observed. In conclusion, DXA body composition LSC varies among genders, regions, tissues, and mass. As such, when evaluating serial body composition in athletes, especially if assessing regional change, knowledge of precision in individuals of similar body size and gender to the population of interest is needed. PMID- 23643969 TI - Biodegradable hollow zein nanoparticles for removal of reactive dyes from wastewater. AB - In this study, biodegradable hollow zein nanoparticles with diameters less than 100 nm were developed to remove reactive dyes from simulated post-dyeing wastewater with remarkably high efficiency. Reactive dyes are widely used to color cellulosic materials, such as cotton and rayon. Wastewater from reactive dyeing process contains up to 50% dye and electrolytes with concentrations up to 100 g L(-1). Current methods to remove reactive dyes from wastewater are suffering from low adsorption capacities or low biodegradability of the sorbents. In this research, biodegradable zein nanoparticles showed high adsorption capacities for dyes. Hollow zein nanoparticles showed higher adsorption for Reactive Blue 19 than solid structures, and the adsorption amount increased as temperature decreased, pH decreased or initial dye concentration increased. At pH 6.5 and pH 9.0, increasing electrolyte concentration could improve dye adsorption significantly. Under simulated post-dyeing condition with 50.0 g L(-1) salt and pH 9.0, maximum adsorption of 1016.0 mg dye per gram zein nanoparticles could be obtained. The adsorption capacity was much higher than that of various biodegradable adsorbents developed to remove reactive dye. It is suggested that the hollow zein nanoparticles are good candidates to remove reactive dye immediately after dyeing process. PMID- 23643970 TI - Cryptic patterns of diversification of a widespread Amazonian woodcreeper species complex (Aves: Dendrocolaptidae) inferred from multilocus phylogenetic analysis: implications for historical biogeography and taxonomy. AB - Inferring evolutionary relationships between recently diverged taxa is still challenging, especially taking into account the likely occurrence of incomplete lineage sorting and/or introgression. The Xiphorhynchus pardalotus/ocellatus species complex includes between two to three polytypic species and eight to nine subspecies distributed throughout most of lowland Amazonia and the foothills of the eastern Andes. To understand its historical diversification and address the main unsettled issues of phylogenetic relationships and taxonomy, we apply several approaches using data from two mitochondrial (Cyt b and ND2) and three nuclear genes (beta-fibint7, CPZint3 and CRYAAint1) for all described species and most subspecies of this complex. We compared single gene trees with a multilocus concatenated tree and Bayesian species tree inferred under a coalescent framework ((*)BEAST). Our results showed a general pattern of incongruence among gene trees and multilocus trees. Despite of this, the coalescent-based species tree analysis supports the sister-taxa relationship of X. ocellatus and X. chunchotambo, while X. pardalotus comes out as the basal taxon. With exception of the last, our results revealed within both X. ocellatus and X. chunchotambo high levels of genetic differentiation (p-distances 0.5-5.5%) with well-supported lineages. Our phylogenetic analyses showed several incongruences with current subspecies taxonomy, revealing that X. o. ocellatus is paraphyletic relative to X. o. perplexus, and the currently recognized subspecies X. c. napensis corresponds to two distinct evolutionary lineages, which are not supported as sister-lineages. In addition, the deep level of genetic divergence between X. o. beauperthuysii and the extant subspecies of X. ocellatus is more consistent with species-level differences found in this complex. Divergence time estimates were consistent with a historical scenario of intense population subdivision and speciation during the Early-mid Pleistocene. The spatial pattern and timing of diversification overlap broadly with that reported for other Amazonian vertebrate lineages. PMID- 23643971 TI - Regional population expansion in Eucalyptus globulus. AB - Foundation tree species define the structure of forest habitat and influence their ecosystem dynamics. However, there is limited understanding of both the patterns and timing of population fluctuations in foundation trees and how they vary among geographical regions. We have reconstructed the demographic history of five genetically distinct populations of the Tasmanian blue gum (Eucalyptus globulus ssp. globulus) at the species and regional levels, using three nuclear loci sequenced from 104 individuals. Analysis using a Bayesian skyline plot indicated that the species experienced two periods of expansion, commencing in the Pliocene. Regional analyses showed that island populations expanded earlier, but that the rate of expansion was relatively slow when compared to that of the mainland group. This highlights the need for local demographic history to be taken into account when inferring local adaptation for candidate genes. Population growth throughout the Quaternary signals the ability of the species to persist and thrive under the predominantly harsh conditions of this period. PMID- 23643972 TI - Evolution of Manduca sexta hornworms and relatives: biogeographical analysis reveals an ancestral diversification in Central America. AB - The hawkmoth genus Manduca is a diverse group of very large, conspicuous moths that has served as an important model across many biological disciplines. Two species in particular, the tobacco hornworm (Manduca sexta) and the tomato hornworm (Manduca quinquemaculatus) have been researched extensively. Studies across biological fields have referred to these two species as being closely related or even sister species, but the extent to which these two model organisms are related remains largely unknown. We conducted a comprehensive multi-gene phylogenetic analysis of Manduca, based on both an ML and Bayesian framework, which resulted in a monophyletic Manduca but only when two other genera, Dolba and Euryglottis are included. We tentatively conclude that the sister group to Manduca sexta comprises the Caribbean M. afflicta and M. johanni, and the sister lineage to this clade includes M. quinquemaculatus and the Hawaiian M. blackburni. Thus, M. sexta and M. quinquemaculatus are closely related, but are not sister species. Biogeographical analyses reveal an ancestral center of diversification in Central America, and Manduca appears to have subsequently colonized North and South America. Our phylogeny provides an important foundation for comparative studies of two model organisms and their relatives. PMID- 23643973 TI - In intro antioxidant activities of different sulfated polysaccharides from chlorophytan seaweeds Ulva fasciata. AB - Four different molecular weight sulfated polysaccharides (UFP1, UFP2, UFP3 and UFP4) were extracted and separated from Ulva fasciata by hot water extraction and ultrafiltration. Their chemical and physical characteristics were determined and antioxidant activities were investigated on the basis of superoxide radical assay, hydroxyl radical assay, ABTS radical assay, and reducing power assay. The results showed that four polysaccharides exhibited antioxidant properties, and UFP2 and UFP3, which have lower content of sulfate showed higher antioxidant activities than UFP1 and UFP4, which have higher content of sulfate. Besides, the content of protein, uronic acid and molecular weights of polysaccharides also influence their antioxidant activities. The antioxidant activities of UFP were not a function of a single factor but a combination of several factors. PMID- 23643974 TI - In vitro antioxidant activities of sulfated polysaccharide ascophyllan isolated from Ascophyllum nodosum. AB - Antioxidant activities of sulfated polysaccharide ascophyllan from Ascophyllum nodosum was investigated in vitro by various assays, and compared with those of fucoidan. A chemiluminescence (CL) analysis using a luminol analog, L-012, showed that ascophyllan scavenges superoxide, and the activity is greater than fucoidan. However, in the presence of 10MUg/ml of ascophyllan or 10MUg/ml and 100MUg/ml of fucoidan, slightly enhanced CL-responses were observed. Since EDTA-treatment resulted in disappearance of the enhancement effects, it was suggested that metal ions especially iron ions in the polysaccharides might be involved in this phenomenon. In fact, metal element analysis revealed that ascophyllan and fucoidan inherently contain iron and other metal elements. EDTA-treatment resulted in significant increase in Fe(2+)-chelating activities of these polysaccharides. In an electron spin resonance (ESR)-spin trapping analysis in which direct UV-radiation to hydrogen peroxide was used as a source of hydroxyl radical, ascophyllan and fucoidan showed potent hydroxyl radical scavenging activity with similar extent. Reducing power of ascophyllan was stronger than that of fucoidan. Our results indicate that ascophyllan can exhibit direct and potent antioxidant activity. PMID- 23643975 TI - Chitin based polyurethanes using hydroxyl terminated polybutadiene. Part I: molecular engineering. AB - Chitin based polyurethanes (PUs) using hydroxyl terminated polybutadiene (HTPB) as soft segment were prepared and the structure of the proposed PU was confirmed using FTIR spectrometer. PU prepolymer was prepared using HTPB and toluene-2,4 diisocyanate (TDI), and the chain was extended with different proportions of 1,4 butane diol (BDO) and chitin. During the detailed FTIR study, it was observed that tri-functional character of chitin results in the formation of network structure due to crosslinking of the material, whereas bi-functional aliphatic diol based polyurethane produced linear PU. Hydrogen bonding between the hard segments was identified by the IR spectroscopy. The scanning electron microscope (SEM) analysis also confirmed the cross-linked structure. PMID- 23643976 TI - The Pandora's box of neonatal analgesia. PMID- 23643977 TI - Neural mechanisms mediating association of sympathetic activity and exploration in decision-making. AB - The somatic marker hypothesis asserts that decision-making can be guided by feedback of bodily states to the brain. In line with this hypothesis, the present study tested whether sympathetic activity shows an association with a tonic dimension of decision-making, exploratory tendency represented by entropy in information theory, and further examined the neural mechanisms of the association. Twenty participants performed a stochastic reversal learning task that required decision-making in an unstable and uncertain situation. Regional cerebral blood flow was evaluated using (15)O-water positron emission tomography (PET), and cardiovascular indices and concentrations of catecholamine in peripheral blood were also measured, during the task. In reversal learning, increased epinephrine during the task positively correlated with larger entropy, indicating a greater tendency for exploration in decision-making. The increase of epinephrine also correlated with brain activity revealed by PET in the somatosensory cortices, anterior insula, dorsal anterior cingulate cortex, and the dorsal pons. This result is consistent with previously reported brain matrixes of representation of bodily states and interoception. In addition, activity of the anterior insula specifically correlated with entropy, suggesting possible mediation of this brain region between peripheral sympathetic arousal and exploration in decision-making. These findings shed a new light about a role of bodily states in decision-making and underlying neural mechanisms. PMID- 23643979 TI - Prediction for human intelligence using morphometric characteristics of cortical surface: partial least square analysis. AB - A number of imaging studies have reported neuroanatomical correlates of human intelligence with various morphological characteristics of the cerebral cortex. However, it is not yet clear whether these morphological properties of the cerebral cortex account for human intelligence. We assumed that the complex structure of the cerebral cortex could be explained effectively considering cortical thickness, surface area, sulcal depth and absolute mean curvature together. In 78 young healthy adults (age range: 17-27, male/female: 39/39), we used the full-scale intelligence quotient (FSIQ) and the cortical measurements calculated in native space from each subject to determine how much combining various cortical measures explained human intelligence. Since each cortical measure is thought to be not independent but highly inter-related, we applied partial least square (PLS) regression, which is one of the most promising multivariate analysis approaches, to overcome multicollinearity among cortical measures. Our results showed that 30% of FSIQ was explained by the first latent variable extracted from PLS regression analysis. Although it is difficult to relate the first derived latent variable with specific anatomy, we found that cortical thickness measures had a substantial impact on the PLS model supporting the most significant factor accounting for FSIQ. Our results presented here strongly suggest that the new predictor combining different morphometric properties of complex cortical structure is well suited for predicting human intelligence. PMID- 23643978 TI - Posterior hypothalamic modulation of light-evoked trigeminal neural activity and lacrimation. AB - Enhanced light sensitivity is a common feature of many neuro-ophthalmic conditions and some chronic headaches. Previously we reported that the bright light-evoked increases in trigeminal brainstem neural activity and lacrimation depended on a neurovascular link within the eye (Okamoto et al., 2012). However, the supraspinal pathways necessary for these light-evoked responses are not well defined. To assess the contribution of the posterior hypothalamic area (PH), a brain region closely associated with control of autonomic outflow, we injected bicuculline methiodide (BMI), a GABAa receptor antagonist, into the PH and determined its effect on the encoding properties of ocular neurons at the ventrolateral trigeminal interpolaris/caudalis transition (Vi/Vc) and caudalis/upper cervical cord junction (Vc/C1) regions and on reflex lacrimation in male rats under isoflurane anesthesia. BMI markedly reduced light-evoked (>80%) responses of Vi/Vc and Vc/C1 neurons at 10 min with partial recovery by 50 min after injection. BMI also reduced (>35%) the convergent cutaneous receptive field area of Vi/Vc and Vc/C1 ocular neurons indicating that both intra-ocular and periorbital cutaneous inputs were affected by changes in PH outflow. Light evoked lacrimation was reduced by >35% at 10 min after BMI, while resting mean arterial pressure increased promptly and remained elevated (>20 mmHg) throughout the 50-min post-injection period. These results suggested that PH stimulation, acting in part through increased sympathetic activity, significantly inhibited light- and facial skin-evoked activity of ocular neurons at the Vi/Vc and Vc/C1 region. These data provide further support for the hypothesis that autonomic outflow plays a critical role in mediating light-evoked trigeminal brainstem neural activity and reflex lacrimation. PMID- 23643980 TI - Effects of UCMS-induced depression on nociceptive behaviors induced by electrical stimulation of the dura mater. AB - The comorbidity between migraine and depression not only provides a major treatment challenge, but also represents a heavy burden on society. However, the relationship between depression and migraine and their molecular biological mechanisms remain unclear. This study investigated the effects of depression elicited by unpredictable chronic mild stress (UCMS) on trigeminovascular nociception in conscious rats and detected a concentration of calcitonin gene related peptide (CGRP) and substance P (SP) in the external jugular vein. We divided the rats into four groups: control-stimulated (C/S), control nonstimulated (C/NS), UCMS-stimulated (U/S), and UCMS-nonstimulated (U/NS). We stimulated the dura mater adjacent to the superior sagittal sinus of rats in the C/S and U/S groups and observed their nociceptive behaviors. We found significant differences between the UCMS and control groups in weight, sucrose preference, and locomotor behavior. Nociceptive behaviors (number of head flicks and head turning time) were significantly increased in the U/S compared with the C/S group, and head-turning time correlated with depressive-like behaviors. The plasma level of SP was increased significantly in the U/NS compared with the C/NS group. However, no significant differences involving the other groups were observed. UCMS-induced depression can exacerbate trigeminovascular nociception, making rats more sensitive to pain. PMID- 23643981 TI - Mitochondrial impairment induced by 3-nitropropionic acid is enhanced by endogenous metalloprotease activity inhibition in cultured rat striatal neurons. AB - Metalloproteases from the metzincin family mediate molecule processing at the cell membrane termed ectodomain shedding (ES). This mechanism enables the generation of intracellular and extracellular fragments from cell membrane molecules that exert additional functions involved in cell processes including cell death, beyond those of full length molecules. Micotoxin 3-nitropropionic acid (3-NP) induces striatal neuronal degeneration in vivo and in vitro through mitochondrial complex II inhibition. In this study, we hypothesized that metalloproteases regulate mitochondrial activity in cultured rat striatal neurons undergoing degeneration. To test this idea, striatal neuronal cultures characterized by NeuN and GAD-67 expression were treated with 3-NP together with the metalloprotease inhibitor GM6001 and their mitochondrial activity was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Our results showed that metalloprotease inhibition potentiated mitochondrial activity impairment induced by 3-NP whereas the inhibitor alone had no effect. These results indicate that metalloproteases regulate and promote mitochondrial functionality in striatal neurons undergoing degeneration induced by 3-NP. Since NMDA receptor is involved in the excitotoxic neuronal death triggered by 3-NP and is known to undergo ES, we analyzed NMDAR subunit NR1 phenotypic distribution by immunofluorescence. 3-NP and GM6001 induced abnormal perinuclear NR1 accumulation that was not observed with 3-NP or GM6001 alone. This observation suggests that metalloproteases are involved in NR1 cellular reorganization induced by 3-NP, and that their inhibition results in abnormal NR1 distribution. Together results indicate that endogenous metalloproteases are activated during striatal neurodegeneration induced by 3-NP eliciting an adaptative or compensatory response that protects mitochondrial functionality. PMID- 23643982 TI - Pro-inflammatory cytokine network in peripheral inflammation response to cerebral ischemia. AB - The key circulating pro-inflammatory cytokines and their interaction in peripheral inflammation after acute cerebral ischemia are poorly understood. CD40L, IFN-gamma, IL-1alpha, IL-1beta, IL-6, IL-8, IL-17 and TNF-alpha were determined using multi-ELISA kit in stroke patients within 72 h of an acute ischemic attack. Leukocyte mRNAs were determined using real-time polymerase chain reactions (PCR). Stroke severity and clinical outcomes were evaluated by National Institutes of Health Stroke Scores (NIHSS) and modified Rankin Scale (mRS). Plasma/mRNA cytokine interactions were analyzed using the Bayesian network learning procedure. Compared to controls, stroke patients had higher IL-6, IL-8 and TNFalpha protein in plasma and lower IL-6, IL-8, TNFalpha, IL-1alpha, and IL 1beta mRNA in leukocyte within 72 h after stroke. However, only the elevation of IL-6 correlated with the severity and prognosis of their stroke. This was associated with a decreased IL-6 mRNA in leukocyte. Further study showed that Bayesian network analysis revealed that changes in the other cytokines were subsequent to IL-6 leukocyte cytokine RNA. The change of other cytokines in plasma proteins after ischemic brain injury appeared secondary to IL-6. Pro inflammatory cytokines up-regulation in plasma and compensatory immunity depression in leukocyte involve in peripheral inflammation response to cerebral ischemia. IL-6 appears to be the key mediator of circulating pro-inflammatory cytokines network. PMID- 23643983 TI - Identifying Ki-67 specific miRNA-mRNA interactions in malignant astrocytomas. AB - BACKGROUND: Ki-67 is an excellent indicator of glioma cell growth. However, limited information is available regarding the mechanisms underlying abnormal expression of Ki-67 in glioma tissue. The aim of this study is to identify Ki-67 specific miRNA-mRNA interactions on basis of miRNA and mRNA expression profilings. METHODS: We performed a large-scale miRNA (n=829) and mRNA (n=29,421) expression profiling in primary glioblastoma multiforme (pGBM) and anaplastic astrocytoma (AA) tissues (with an aim to investigate Ki-67 related miRNAs and mRNAs). From target prediction databases, the targeting relationships between Ki 67 specific miRNAs and mRNAs were established, and functions of these mRNAs were analyzed by DAVID. The functional verifications of the candidate miRNA were also performed in LN229 cell line. RESULTS: High expression level of Ki-67 protein predicted a shorter survival time for patients with AA. Integrated analysis of profiling data from pGBM and AA revealed 4 Ki-67 positively and 5 negatively correlated miRNAs, along with the top 12 Ki-67 positively and 2 negatively correlated mRNAs. By means of target prediction, we found that the target mRNAs employed by miR-218 were the most significant among Ki-67 specific mRNAs. Up regulation of miR-218 was further demonstrated to reduce Ki-67 expression, promote apoptosis, and induce G0/G1 phase cell cycle arrest in LN229 cells. CONCLUSIONS: Ki-67 protein may be regulated by specific miRNA-mRNA interactions which may contribute to the proliferation of glioma cells. PMID- 23643984 TI - Antiepileptic effect of dimethyl sulfoxide in a rat model of temporal lobe epilepsy. AB - Dimethyl sulfoxide (DMSO) is an amphipathic molecule widely used to solubilize water-insoluble compounds. In many studies it was reported that DMSO is capable of affecting several biological processes, thus resulting in a potential cause for the misinterpretation of experimental data. Recent papers showed that DMSO modified the brain bioelectric activity in animal models of epilepsy. In an in vivo model of temporal lobe epilepsy in the rat, we examined the effects of different doses (10%, 50% and 100%) of DMSO on the maximal dentate activation (MDA). The results show that DMSO induced a dose-dependent significant reduction of the electrically induced paroxysmal activity. PMID- 23643985 TI - Neuroglobin expression in neurogenesis. AB - Neuroglobin is a hypoxia-inducible, neuroprotective protein related to myoglobin and hemoglobin, but little is known about its neurodevelopmental expression or function. To begin to explore these issues, we measured neuroglobin protein expression during neuronal differentiation of human embryonic stem cells in vitro and in the neurogenic subventricular zone of adult rats in vivo. Neuroglobin protein expression was barely detectable by western blotting in human embryonic stem cells, but was readily demonstrable in neural stem cells, and was further induced upon differentiation to neurons. In the adult subventricular zone, neuroglobin expression coincided with that of the neuronal lineage marker doublecortin, but not with vimentin or glial fibrillary acidic protein. These findings suggest that neuroglobin is expressed early in the course of neuronal differentiation and may, therefore, have a role in neurodevelopment. PMID- 23643986 TI - Farnesyltransferase inhibitor attenuates methamphetamine toxicity-induced Ras proteins activation and cell death in neuroblastoma SH-SY5Y cells. AB - Several lines of evidence support that methamphetamine (METH) toxicity plays a pivotal role in neurodegenerative diseases. However, the molecular mechanisms underlying METH-induced neurotoxicity are still unclear. In addition, Ras modulated death signaling has been continually reported in several cell types. In this study, intracellular Ras-dependent death signaling cascade activation was proposed to contribute to METH-induced neuronal cell degeneration in dopaminergic SH-SY5Y cultured cells. Exposure to a toxic dose of METH significantly decreased cell viability, and tyrosine hydroxylase phosphorylation, but increased c-Jun phosphorylation and active, GTP-bound Ras in cultured SH-SY5Y cells. Farnesyltransferase inhibitor, FTI-277, an inhibitor of the enzyme catalyzed the farnesylation of Ras proteins was able to diminish the toxic effects of METH on induction in cell degeneration, activation in c-Jun-N-terminal kinase cascades, and Ras activation in SH-SY5Y cells. The results of this study show that activation in Ras signaling cascade may be implicated in the METH-induced death signaling pathway in neuroblastoma SH-SY5Y cells. PMID- 23643987 TI - Event-related potentials indicating impaired emotional attention in cerebellar stroke--a case study. AB - The cerebellum has been implicated in affective and attentional processes, but little is known about corresponding neural signatures. We investigated early and late components of event-related potentials (ERPs) to emotionally arousing pictures, with and without competing attentional tasks, in a patient with an ischemic right posterior cerebellar infarction, at two months post infarct and two year follow-up. The early posterior negativity (EPN) response to highly arousing emotional cues in the competing visual attention condition revealed that the augmentation over occipital areas, as typically seen in normals, was absent post-infarct but was restored after two years. The late positive potentials (LPP) response to highly arousing emotional cues showed augmentation over frontal areas post-infarct, and over centro-parietal regions after two years. These ERP findings suggest a specific pattern of disruption of neural function associated with emotional-behavioral disturbances following cerebellar lesions, which can revert to normal with long term recovery. PMID- 23643988 TI - Novel ascorbic acid-resistive nitroxide in a lipid emulsion: an efficient brain imaging contrast agent for MRI of small rodents. AB - Nitroxides have recently been used as redox-sensitive contrast agents for both MRI and EPR imaging. However, the rapid in vivo reduction in paramagnetism of nitroxides due to reductants such as ascorbic acid (AsA) has limited their use as contrast agents. This study developed a formulation of a newly synthesized AsA resistive nitroxide (2,2,6,6-tetraethylpiperidine-4-one-1-oxyl (TEEPONE)) with a lipid emulsion system and examined the in vivo stability of TEEPONE by magnetic resonance imaging (MRI). MRI of mouse heads after administration of TEEPONE clearly indicated that TEEPONE has a remarkable in vivo stability and is a blood brain barrier (BBB) permeable nitroxide. MRI also showed that TEEPONE is preferentially localized in the mouse brain. The distribution of TEEPONE in the mouse head can be controlled by the lipid content in the emulsion system used to solubilize TEEPONE. PMID- 23643989 TI - Hippocampal levels of ChAT, PKA, phospho-PKA and phospho-CaMKIIalpha but not CaMKIIalpha positively correlate with spatial learning skills in rats. AB - Despite very extensive investigations on molecular processes underlying memory formation, there are very few studies examining potential differences in the brain biochemistry between "good" and "poor" learners belonging to a random population of young animals. In the present study, an attempt was made to correlate individual variation in spatial learning in young-adult Long-Evans rats with hippocampal levels of protein kinase A (PKA), calcium/calmodulin-dependent protein kinase II alpha (CaMKIIalpha), and choline acetyltransferase (ChAT). Additionally, in order to indirectly estimate the activity of CaMKIIalpha and PKA, hippocampal levels of their phosphorylated forms (pCaMKIIalpha and pPKA) were assessed using Western blot technique. Rats were classified as "good" and "poor" learners on the basis of their performance in a partially baited 12-arm radial maze. The biochemical assays did not reveal a significant difference in the basal hippocampal levels of the CaMKIIalpha, however, the level of pCaMKIIalpha, was significantly higher in "good" learners. Also, hippocampal levels of both PKA and pPKA, as well as that of ChAT, were significantly higher in "good" as compared to "poor" learners. Our results suggest that the differences in the expression level of PKA and ChAT (but not of CaMKIIalpha), as well as the differences in the activation of both PKA and CaMKIIalpha, may contribute to the individual variation in learning skills and episodic-like memory in a random population of young-adult subjects. PMID- 23643990 TI - Effects of mechanical vibration of the foot sole and ankle tendons on cutaneomuscular responses in man. AB - The modulation of cutaneomuscular responses in response to mechanical vibration applied to the foot sole and to the ankle tendons was established in ten healthy subjects. The effects of mechanical vibration applied to the skin adjacent to the tibialis anterior (TA) and Achilles tendons were examined in two subjects. With the subjects seated, mechanical vibration applied to the TA and/or Achilles tendons significantly depressed the cutaneomuscular responses in all subjects, regardless of the frequency (50, 150, 250 Hz) of vibration. Mechanical vibration applied either to the foot sole or to the skin adjacent to the tendons induced no significant effects. The demonstration that mechanical vibration applied to muscle tendons exerts an inhibitory effect on cutaneomuscular responses supports the hypothesis that receptors that mediate body kinesthesia can be used as a vehicle to alter the spinal excitability state. The data suggests that tendon vibration could be utilized in neurological disorders to induce exogenous mediated potentiation of presynaptic inhibition. PMID- 23643991 TI - Lack of association between brain-derived neurotrophic factor Val66Met polymorphism and body mass index change over time in healthy adults. AB - Obesity is becoming the epidemic health problem worldwide with a very complex etiology. The interaction between diverse genetic and environmental factors contributes to development of obesity. Among myriad of functions in central and peripheral tissues, brain-derived neurotrophic factor (BDNF) also regulates energy homeostasis, food intake and feeding behavior, and has a role in obesity and increased body mass index (BMI). BDNF Val66Met (rs6265) polymorphism is associated with BMI gain, but both positive associations and non-replications are reported. Since BMI changes over time and since genetic influences on BMI vary with age, the aim of the study was to evaluate association between BDNF Val66Met polymorphism and BMI gain in healthy subjects with middle or old age. The study included a cohort of 339 adult healthy Caucasians of Croatian origin, free of eating and metabolic disorders, evaluated in three time periods in the year 1972, 1982 and 2006, when the subjects were around 40, 50 and 70 years old, respectively. The results revealed a significant effect of smoking on BMI, but a lack of significant association between BDNF Val66Met polymorphism and overweight or obesity, and no significant association between BDNF Val66Met and BMI changes over time. These results did not confirm the major role of BDNF Val66Met in the regulation of BMI changes in adult and old healthy subjects. PMID- 23643992 TI - iNOS participates in apoptosis of spinal cord neurons via p-BAD dephosphorylation following ischemia/reperfusion (I/R) injury in rat spinal cord. AB - The pro-apoptotic effect of nitric oxide (NO) has been reported both in vivo and in vitro. Previous studies have revealed that NO, especially which produced by inducible nitric oxide synthase (iNOS), has an important effect on apoptosis of neurons in spinal cord ischemia/reperfusion (I/R) injury. To investigate the role of iNOS in this process, a randomized, controlled study was designed using a classical rat model of ischemic spinal cord injury. Fifty-four male Sprague Dawley rats were randomly divided into three different groups: a sham-operated group (n=6), a vehicle group (I/R, n=24), and an iNOS inhibitor (aminoguanidine: AG) group (I/R+AG, n=24). Rats were sacrificed 6, 12, 24 and 72 h after reperfusion. We examined neurological motor function evaluated by 'Tarlov's score', assessed alterations in the morphology of spinal cord neurons by transmission electron microscopy (TEM), analyzed expression of iNOS at the levels of mRNA and protein, evaluated local concentrations and cellular locations of other key regulatory proteins, and investigated protein-protein interactions. In the vehicle group, iNOS expression, dephosphorylation of p-BAD (Ser 136), disassociation of BAD from p-BAD/14-3-3 dimers, and release of cytochrome c were all increased compared with the sham group. But in the AG group, all the performances above were decreased compared with the vehicle group. Similarly, rats in the sham group got a maximum score of 5 by Tarlov's motor scores evaluation. While the scores were higher in the AG group compared to the vehicle group because iNOS was inhibited. These results indicate that the activity of iNOS plays a critical role in the apoptosis of spinal cord neurons by influencing the dephosphorylation of p-BAD (Ser 136) and the interaction between BAD and 14-3 3. PMID- 23643994 TI - Injury of the corticoreticular pathway in patients with proximal weakness following cerebral infarct: diffusion tensor tractography study. AB - The corticoreticular pathway (CRP) innervates mainly the proximal muscles of extremities. Identification of the CRP by diffusion tensor tractography (DTT) in the human brain has recently become possible. However, little is known about the relation between proximal weakness and injury of the CRP in stroke patients. In this study, we attempted to investigate the usefulness of DTT for elucidation of the relation between proximal motor weakness and injury of the CRP in patients with cerebral infarct. Among 247 consecutive patients with cerebral infarct, four hemiparetic patients who showed more severe weakness in proximal joints (shoulder and hip) than distal joints (finger and ankle) of the affected extremities were recruited for this study. Evaluation of motor function, DTT, and transcranial magnetic stimulation (TMS) for evaluation of the corticospinal tract state by analysis of the characteristics of the motor-evoked potential were performed at the early stage of cerebral infarct (mean: 17.0 days; range: 11-29). The integrity of the CST on DTT findings in the affected hemisphere was preserved in all four patients and TMS findings in terms of latency and amplitude showed within normal range (one patient) and partial injuries (three patients) of the corticospinal tract. By contrast, on DTT of the CRP in the affected hemispheres, we observed Wallerian degeneration in two patients and discontinuations at infarct level in two patients. The injury of the CRP appeared to attribute the proximal weakness of the shoulder and hip observed in these four patients. Therefore, DTT of the CRP would be useful for elucidating the relation between proximal weakness and injury of the CRP in patients with cerebral infarct. PMID- 23643995 TI - Spontaneous brain activity in combat related PTSD. AB - Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder, especially in combat veterans. Existing functional neuroimaging studies have provided important insights into the neural mechanisms of PTSD using various experimental paradigms involving trauma recollection or other forms of emotion provocation. However it is not clear whether the abnormal brain activity is specific to the mental processes related to the experimental tasks or reflects general patterns across different brain states. Thus, studying intrinsic spontaneous brain activity without the influence of external tasks may provide valuable alternative perspectives to further understand the neural characteristics of PTSD. The present study evaluated the magnitudes of spontaneous brain activity of male US veterans with or without PTSD, with the two groups matched on age, gender, and ethnicity. Amplitudes of low frequency fluctuation (ALFF), a data driven analysis method, were calculated on each voxel of the resting state fMRI data to measure the magnitudes of spontaneous brain activity. Results revealed that PTSD subjects showed increased spontaneous activity in the amygdala, ventral anterior cingulate cortex, insula, and orbital frontal cortex, as well as decreased spontaneous activity in the precuneus, dorsal lateral prefrontal cortex and thalamus. Within the PTSD group, larger magnitudes of spontaneous activity in the thalamus, precuneus and dorsal lateral prefrontal cortex were associated with lower re-experiencing symptoms. Comparing our results with previous functional neuroimaging findings, increased activity of the amygdala and anterior insula and decreased activity of the thalamus are consistent patterns across emotion provocation states and the resting state. PMID- 23643993 TI - Behavioral deficits, abnormal corticosterone, and reduced prefrontal metabolites of adolescent rats subject to early life stress. AB - The present study investigated the effect of early life stress in adolescent rats on brain metabolites, serum corticosterone, and depressive-like behavior. A group of rats was subject to early life stress from postnatal day (PND) 1 to 14. A matched control group was studied. Behavioral tests, serum corticosterone and high-resolution proton magnetic resonance spectroscopy were conducted between PND 30 and 40. In this study, adolescent rats exposed to early life stress demonstrated depressive-like behavior and increased serum corticosterone during adolescence. They also showed reduced glutamate, glutamine, and N-acetylaspartate (NAA) levels in the prefrontal cortex. A reduced myo-inositol level, consistent with astroglial deficits, was observed but was not statistically significant. Together, these findings characterize the effect of early life stress on adolescent animals and underscore the long-lasting and detrimental effects of childhood adversities. PMID- 23643996 TI - Does increasing the ratio of AMPA-to-NMDA receptor mediated neurotransmission engender antidepressant action? Studies in the mouse forced swim and tail suspension tests. AB - Monoamine-based antidepressant drugs increase alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor (AMPAR) function and decrease N-methyl-d aspartate receptor (NMDAR) function. The NMDAR antagonist ketamine shows potent antidepressant action in humans and the antidepressant-like effects of ketamine and monoamine-based antidepressants in rodents depend on increased AMPAR throughput. Further, the antidepressant-like effects of monoamine-based antidepressants are enhanced by AMPAR potentiation and by NMDAR antagonism. This has led to a hypothesis that antidepressant efficacy involves an increases ratio of AMPAR-to-NMDAR-mediated neurotransmission. To further elucidate the interaction of AMPAR, NMDAR and monoamine transmission we tested combinations of the AMPAR positive allosteric modulator (AMPA potentiator), (R,R)-N,N-(2,20 [biphenyl-4-40-diyl]bis[propane-2,1-diyl])dimethanesulfonamide (PIMSD), with: the uncompetitive NMDAR antagonist MK-801; nicotine, which has potent glutamate releasing properties; and the selective serotonin reuptake inhibitor escitalopram using the mouse forced swim (mFST) and tail suspension tests (mTST). MK-801, nicotine or escitalopram did not induce antidepressant-like effects in either of the two tests. PIMSD enhanced the effect of MK-801 in the mFST, supporting the hypothesis that increasing AMPAR-to-NMDAR-mediated neurotransmission conveys antidepressant action. Nicotine-induced glutamate release simultaneously activates NMDARs and AMPARs and showed no net effect in the mFST when given alone. However, increasing the ratio of AMPAR-to-NMDA-R transmission by favouring AMPAR throughput with PIMSD revealed an antidepressant-like action of nicotine in the mFST. PIMSD also enhanced the effect of escitalopram treatment in the mFST and mTST, supporting existing evidence and suggesting a synergistic effect of simultaneously facilitating monoamine transmission and increasing the ratio of AMPAR-to-NMDAR throughput. No synergistic effects of the PIMSD+MK-801 or PIMSD+nicotine were found in the mTST, indicating a differential sensitivity of mFST and mTST when investigating glutamate-based antidepressant mechanisms. This study corroborates existing evidence that there may be an unexploited therapeutic potential in treating depression by directly increasing the ratio of AMPAR-to NMDAR neurotransmission, possibly in combination with monoamine-based mechanisms. PMID- 23643997 TI - Altered nucleolar morphology in substantia nigra dopamine neurons following 6 hydroxydopamine lesion in rats. AB - The nucleolus, the site of ribosomal ribonucleic acid (rRNA) transcription and assembly, is an important player in the cellular response to stress. Altered nucleolar function and morphology, including decreased nucleolar volume, has been observed in Parkinson's disease; thus the nucleolus represents a potential indicator of neurodegeneration in the disease. This study determined the effects of a partial unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesion, which models the dopaminergic loss found in Parkinson's disease, on the nucleoli of dopaminergic cells in the substantia nigra pars compacta (SNpc). Adult male Long Evans rats underwent unilateral intrastriatal infusion of 6-OHDA (12.5MUg). Lesions were verified by amphetamine-stimulated rotation 7 days later, and rats were euthanized 14 days after infusion. Coronal sections (50MUm) were stained for tyrosine hydroxylase-silver nucleolar (TH-AgNOR) stain using MultiBrain Technology (NeuroScience Associates), which resulted in clearly defined nucleoli and neuronal outlines. Stereological methods were used to compare dopaminergic morphology between lesioned and intact hemispheres in each rat. In cells exhibiting a definable nucleolus, nucleolar volume was decreased by 16% on the ipsilateral side. The ipsilateral SNpc also exhibited an 18% decrease in SNpc planimetric volume, a 46% decrease in total TH-positive neuron number, and an 11% decrease in neuronal body volume (all P<0.05 by paired t-test). These findings suggest that the 6-OHDA lesion alters nucleolar morphology and that these changes are similar to those occurring in Parkinson's disease. PMID- 23643999 TI - Graph analysis of the human connectome: promise, progress, and pitfalls. AB - The human brain is a complex, interconnected network par excellence. Accurate and informative mapping of this human connectome has become a central goal of neuroscience. At the heart of this endeavor is the notion that brain connectivity can be abstracted to a graph of nodes, representing neural elements (e.g., neurons, brain regions), linked by edges, representing some measure of structural, functional or causal interaction between nodes. Such a representation brings connectomic data into the realm of graph theory, affording a rich repertoire of mathematical tools and concepts that can be used to characterize diverse anatomical and dynamical properties of brain networks. Although this approach has tremendous potential - and has seen rapid uptake in the neuroimaging community - it also has a number of pitfalls and unresolved challenges which can, if not approached with due caution, undermine the explanatory potential of the endeavor. We review these pitfalls, the prevailing solutions to overcome them, and the challenges at the forefront of the field. PMID- 23643998 TI - Functional BK channels facilitate the beta3-adrenoceptor agonist-mediated relaxation of nerve-evoked contractions in rat urinary bladder smooth muscle isolated strips. AB - The large-conductance voltage- and Ca(2+)-activated K(+) (BK) channel is a major regulator of detrusor smooth muscle (DSM) contractility thus facilitating urinary bladder function. Recent findings suggest that activation of beta3-adrenoceptors causes DSM relaxation. However, it is unknown whether the beta3-adrenoceptor mediated DSM relaxation is BK channel-dependent during nerve-evoked contractions. To test this hypothesis, we induced nerve-evoked contractions in rat DSM isolated strips by using a tissue bath system equipped with platinum electrodes for electrical field stimulation (EFS). (+/-)-(R(*),R(*))-[4-[2-[[2-(3-chlorophenyl) 2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL37344), a beta3-adrenoceptor agonist, significantly decreased the amplitude and muscle force of the 20 Hz EFS-induced DSM contractions in a concentration-dependent manner. The BRL37344 inhibitory effect was significantly antagonized by 1-(2 ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol hydrochloride (SR59230A), a beta3-adrenoceptor antagonist. We further isolated the cholinergic from the purinergic component of the 0.5-50 Hz EFS-induced DSM contractions by using selective inhibitors, atropine as well as suramin and alpha,beta-methylene-ATP. We found that BRL37344 inhibited both the purinergic and cholinergic components of the nerve-evoked contractions in rat DSM isolated strips. The pharmacological blockade of the BK channels with iberiotoxin, a selective BK channel inhibitor, increased the amplitude and muscle force of the 20 Hz EFS-induced contractions in rat DSM isolated strips. In the presence of iberiotoxin, there was a significant reduction in the BRL37344-induced inhibition of the 20 Hz EFS-induced contractions in rat DSM isolated strips. These latter findings suggest that BK channels play a critical role in the beta3-adrenoceptor mediated inhibition of rat DSM nerve-evoked contractions. PMID- 23644000 TI - Physiological observations validate finite element models for estimating subject specific electric field distributions induced by transcranial magnetic stimulation of the human motor cortex. AB - Recent evidence indicates subject-specific gyral folding patterns and white matter anisotropy uniquely shape electric fields generated by TMS. Current methods for predicting the brain regions influenced by TMS involve projecting the TMS coil position or center of gravity onto realistic head models derived from structural and functional imaging data. Similarly, spherical models have been used to estimate electric field distributions generated by TMS pulses delivered from a particular coil location and position. In the present paper we inspect differences between electric field computations estimated using the finite element method (FEM) and projection-based approaches described above. We then more specifically examined an approach for estimating cortical excitation volumes based on individualistic FEM simulations of electric fields. We evaluated this approach by performing neurophysiological recordings during MR-navigated motormapping experiments. We recorded motor evoked potentials (MEPs) in response to single pulse TMS using two different coil orientations (45 degrees and 90 degrees to midline) at 25 different locations (5*5 grid, 1cm spacing) centered on the hotspot of the right first dorsal interosseous (FDI) muscle in left motor cortex. We observed that motor excitability maps varied within and between subjects as a function of TMS coil position and orientation. For each coil position and orientation tested, simulations of the TMS-induced electric field were computed using individualistic FEM models and compared to MEP amplitudes obtained during our motormapping experiments. We found FEM simulations of electric field strength, which take into account subject-specific gyral geometry and tissue conductivity anisotropy, significantly correlated with physiologically observed MEP amplitudes (rmax=0.91, p=1.8*10(-5) rmean=0.81, p=0.01). These observations validate the implementation of individualistic FEM models to account for variations in gyral folding patterns and tissue conductivity anisotropy, which should help improve the targeting accuracy of TMS in the mapping or modulation of human brain circuits. PMID- 23644001 TI - Local mechanical properties of white matter structures in the human brain. AB - The noninvasive measurement of the mechanical properties of brain tissue using magnetic resonance elastography (MRE) has emerged as a promising method for investigating neurological disorders. To date, brain MRE investigations have been limited to reporting global mechanical properties, though quantification of the stiffness of specific structures in the white matter architecture may be valuable in assessing the localized effects of disease. This paper reports the mechanical properties of the corpus callosum and corona radiata measured in healthy volunteers using MRE and atlas-based segmentation. Both structures were found to be significantly stiffer than overall white matter, with the corpus callosum exhibiting greater stiffness and less viscous damping than the corona radiata. Reliability of both local and global measures was assessed through repeated experiments, and the coefficient of variation for each measure was less than 10%. Mechanical properties within the corpus callosum and corona radiata demonstrated correlations with measures from diffusion tensor imaging pertaining to axonal microstructure. PMID- 23644002 TI - Coalescence of dominance motivation and responses to facial anger in resting state and event-related electrophysiology. AB - People vary in their proneness to dominate as a function of their motivation to fulfill their need for reward and social status. Recent research suggests that in humans dominant individuals respond vigilantly to angry faces, whereas non dominant individuals rapidly signal submission. Dominance motivation has been suggested to reside in asymmetrical patterns of cortical and subcortical processing. The ratio between delta and beta band oscillations has been proposed as a proxy for this asymmetry, which we here aimed to map onto individual patterns of the event-related potentials (N170) as well as behavioral responses to facial anger in the context of dominance motivation. Results show that dominance motivation indeed predicts increased delta in the delta/beta asymmetry; a pattern that further translates into behavioral vigilance as well as attenuation of the event-related response to angry faces. The present data are interpreted to suggest that dominance motivation is related to increased subcortical and decreased cortical processing, and that this translates into increased vigilance in dominance challenges. This motivational state is further characterized by less detailed processing of facial information as reflected in the attenuation of N170 amplitude. PMID- 23644004 TI - Developmental changes of functional and directed resting-state connectivities associated with neuronal oscillations in EEG. AB - Several studies demonstrated that resting-state EEG power differs tremendously between school-aged children and adults. Low-frequency oscillations (delta and theta, <7 Hz) are dominant in children but become less prominent in the adult brain, where higher-frequency alpha oscillations (8-12 Hz) dominate the mature brain rhythm. However, this assessment of developmental effects with EEG power mapping is restricted to the scalp level and blind to the information flow between brain regions, thus limiting insights about brain development. In contrast dynamic source synchronization provides a tool to study inter-regional directionality on the cortical and sub-cortical source level. In this study we investigated functional and directed connectivities (information flow) with renormalized partial directed coherence during resting state EEG (eyes open and eyes closed) recordings in 17 school-aged children and 17 young adults. First, we found higher spectral mean source power in children relative to adults, irrespective of the examined frequency band and resting state. We further found that coherence values were stronger in adults compared to children in all frequency bands. The directed within-group coherence analysis indicated information flow from frontal to parietal sources in children, while information flow from parietal to frontal was observed in adults. In addition, significant thalamocortical connectivity was unidirectional (i.e., outflow to cortical regions) in adults, but bidirectional in children. Group comparison confirmed the results of the single subject analyses for both functional and directed connectivities. Our results suggest that both functional and directed connectivities are sensitive to brain maturation as the distribution and directionality of functional connections differ between the developing and adult brains. PMID- 23644005 TI - Fluorosurfactant-capped gold nanoparticles-based label-free colorimetric assay for Au3+ with tunable dynamic range via a redox strategy. AB - Gold nanoparticles-based colorimetric assay possesses several unique advantages, and has been applied for a wide range of targets, varying from nucleic acids to different metal ions. However, due to the lack of proper coordinating ligand, gold nanoparticles-based colorimetric sensing system for Au3+ has not been developed so far. It is well-known that Au3+ could induce the oxidation transition of thiol compounds to disulfide compounds. In this article, for the first time we converted such thiol masking reaction into colorimetric sensing system for label-free detection of Au3+ via a target-controlled aggregation of nanoparticles strategy. In the new proposed sensing system, fluorosurfactant capped gold nanoparticles were chosen as signal reporter units, while an Au3+ triggered oxidation of cysteine (Cys), which inhibited the aggregation of gold nanoparticles, acted as the recognition unit. By varying the amount of Cys, a tunable response range accompanied with different windows of color change could be obtained for Au3+, illustrating the universality of the sensing system for Au3+ samples with different sensitivity requirements. Under optimized condition, the proposed sensing system exhibits a high sensitivity towards Au3+ with a detection limit of 50 nM, which is lower than previously reported spectroscopic methods. It has also been applied for detection of Au3+ in practical water samples with satisfactory result. PMID- 23644003 TI - Neurovascular factors in resting-state functional MRI. AB - There has been growing interest in the use of resting-state functional magnetic resonance imaging (rsfMRI) for the assessment of disease and treatment, and a number of studies have reported significant disease-related changes in resting state blood oxygenation level dependent (BOLD) signal amplitude and functional connectivity. rsfMRI is particularly suitable for clinical applications because the approach does not require the patient to perform a task and scans can be obtained in a relatively short amount of time. However, the mechanisms underlying resting-state BOLD activity are not well understood and thus the interpretation of changes in resting state activity is not always straightforward. The BOLD signal represents the hemodynamic response to neural activity, and changes in resting-state activity can reflect a complex combination of neural, vascular, and metabolic factors. This paper examines the role of neurovascular factors in rsfMRI and reviews approaches for the interpretation and analysis of resting state measures in the presence of confounding factors. PMID- 23644006 TI - LSI-based amperometric sensor for real-time monitoring of embryoid bodies. AB - A large scale integration (LSI)-based amperometric sensor is used for electrochemical evaluation and real-time monitoring of the alkaline phosphatase (ALP) activity of mouse embryoid bodies (EBs). EBs were prepared by the hanging drop culture of embryonic stem (ES) cells. The ALP activity of EBs with various sizes was electrochemically detected at 400 measurement points on a Bio-LSI chip. The electrochemical measurements revealed that the relative ALP activity was low for large EBs and decreased with progress of the differentiation level of the ES cells. The ALP activity of the EBs was successfully monitored in real time for 3.5h, and their ALP activity in a glucose-free buffer decreased after 2h. To the best of our knowledge, this is the first report on the application of an LSI based amperometric sensor for real-time cell monitoring over 3h. The chip is expected to be useful for the evaluation of cell activities. PMID- 23644007 TI - Vasovagal reflex emergency caused by Riedel's thyroiditis: A case report and review of the literature. AB - Riedel's thyroiditis is a rare type of chronic thyroiditis, associated with fibroinflammatory process and invasion into surrounding tissues, leading to compressive symptoms. A 45-year-old man had a left thyroid mass, presenting with hypotension and bradycardia many times. He was diagnosed with vasovagal reflex caused by cervical vessel compression due to a thyroid lesion. We performed the emergency operation, and most of the left thyroid was removed to relieve the compression on cervical vessels. The result of pathology proved to be Riedel's thyroiditis. The vasovagal reflex did not occur any more during the 28-month follow up, except on the 3(rd) day after the surgery. Six months after the thyroidectomy, the patient was found to have retroperitoneal fibrosis, diagnosed by biopsy during a laparotomy for biliary disease. Riedel's thyroiditis can lead to a vasovagal episode and might not be a primary thyroid disease but rather a manifestation of the systemic disorder, multifocal fibrosclerosis. PMID- 23644008 TI - Parenteral nutrition mixtures prepared at home by trained parents are as safe as pharmacy-made mixtures: a 3-y prospective study. AB - OBJECTIVES: Home parenteral nutrition (HPN) prevents malnutrition in children with intestinal failure improving chances for the best possible physical development and quality of life. For organizational reasons, in Poland the majority of children on HPN receive nutrition mixtures prepared at home by their parents. The aim of this study was to evaluate whether this method influences the frequency of catheter-related bloodstream infections (CRBSIs). METHODS: The aim of this prospective study was to assess the incidence of CRBSIs from January 2008 to December 2010 in 181 children on HPN and to compare the incidence in two subgroups of these children: group Ph (pharmacy) consisting of 43 patients receiving mixtures prepared in the hospital pharmacy weekly, and group H (home) 138 patients receiving nutrition mixtures prepared daily at home by their caregivers. Central venous CRBSIs were diagnosed by the presence of clinical signs (such as fever, chills, malaise, vomiting) associated with positive blood culture from the central catheter. RESULTS: From 2008 to 2010 parenteral nutrition was administrated during 128 905 catheter-days in 181 patients, and CRBSIs occurred 129 times (1 episode per 1000 catheter-days) in 65 patients. There were 42 bloodstream infections in group Ph during 29 225 catheter-days (i.e., 1.43 per 1000 catheter-days), whereas 87 bloodstream infections occurred in group H during 100 775 catheter-days (i.e., 0.86 per 1000 catheter-days; P = 0.0516). CONCLUSIONS: Preparing parenteral nutrition mixtures at home by trained parents is a safe method of HPN with a slightly (however insignificantly) lower incidence of CRBSIs compared with hospital pharmacy-prepared parenteral nutrition mixtures. PMID- 23644009 TI - Psychosocial factors influencing the frequency of fast-food consumption among urban and rural Costa Rican adolescents. AB - OBJECTIVE: The aim of this study was to identify psychosocial factors that influence fast-food consumption in urban and rural Costa Rican adolescents. METHODS: A self-administered questionnaire designed for the study asked about sociodemographic information, frequency of fast-food consumption, meaning of "fast food," location of purchase, and psychosocial correlates. Five psychosocial factors were extracted by using principal components analysis with Varimax rotation method and eigenvalues. Descriptive statistics and a hierarchical linear regression model were used to predict the frequency of fast-food consumption. RESULTS: Responses from 400 adolescents (ages 12-17 y) reveal that daily consumption of fast food was 1.8 times more frequently mentioned by rural adolescents compared with urban youth. Urban and rural differences were found in the way adolescents classified fast foods (rural adolescents included more traditional foods like chips, sandwiches, and Casado-a dish consisting of rice, black beans, plantains, salad, and a meat), and in purchasing locations (rural adolescents identified neighborhood convenience stores as fast-food restaurants). Living in rural areas, convenience and availability of foods, and the presence of external loci of control were predictors of a higher frequency of fast-food consumption, whereas health awareness predicted a lower frequency. CONCLUSIONS: The development of interventions to reduce fast-food consumption in Costa Rican adolescents should consider not only convenience, but also the availability of these foods where adolescents are more exposed, particularly in rural areas. Interventions such as improving the convenience of healthy fast foods available in school canteens and neighborhood stores, policies to increase the price of unhealthy fast food, and activities to provide adolescents with the skills to increase self-efficacy and reduce the effect of external loci of control are recommended. PMID- 23644010 TI - Analyzing weight loss intervention studies with missing data: which methods should be used? AB - OBJECTIVE: Missing data due to study dropout is common in weight loss trials and several statistical methods exist to account for it. The aim of this study was to identify methods in the literature and to compare the effects of methods of analysis using simulated data sets. METHODS: Literature was obtained for a 1-y period to identify analytical methods used in reporting weight loss trials. A comparison of methods with large or small between-group weight loss, and missing data that was, or was not, missing randomly was conducted in simulated data sets based on previous research. RESULTS: Twenty-seven studies, some with multiple analyses, were retrieved. Complete case analysis (n = 17), last observation carried forward (n = 6), baseline carried forward (n = 4), maximum likelihood (n = 6), and multiple imputation (n = 2) were the common methods of accounting for missing data. When comparing methods on simulated data, all demonstrated a significant effect when the between-group weight loss was large (P < 0.001, interaction term) regardless of whether the data was missing completely at random. When the weight loss interaction was small, the method used for analysis gave considerably different results with mixed models (P = 0.180) and multiple imputations (P = 0.125) closest to the full data model (P = 0.033). CONCLUSION: The simulation analysis showed that when data were not missing at random, treatment effects were small, and the amount of missing data was substantial, the analysis method had an effect on the significance of the outcome. Careful attention must be paid when analyzing or appraising studies with missing data and small effects to ensure appropriate conclusions are drawn. PMID- 23644011 TI - Ability of different screening tools to predict positive effect on nutritional intervention among the elderly in primary health care. AB - OBJECTIVE: Routine identification of nutritional risk screening is paramount as the first stage in nutritional treatment of the elderly. The major focus of former validation studies of screening tools has been on the ability to predict undernutrition. The aim of this study was to validate Mini Nutritional Assessment Short Form (MNA-SF), the Malnutrition Universal Screening Tool (MUST), the Nutritional Risk Screening 2002 (NRS-2002), Body Mass Index (BMI) <24, and the Eating Validation Scheme (EVS), using published randomized controlled trials of nutritional intervention among old people in primary health care, in order to evaluate whether they were capable of distinguishing those with a positive benefit from those that showed no benefit of nutritional intervention. METHODS: The methods used were a literature search; classification of participants with respect to nutritional risk according to the different nutritional screening tools; and validation (i.e., evaluation of whether the different tools were capable of distinguishing those with a positive benefit from those that showed no benefit of nutritional intervention by assessing the positive [PPV] and negative [NPV] predictive values). RESULTS: MNA-SF, NRS-2002, BMI <24 and EVS had the highest PPV (0.75) and EVS the highest NPV (0.74) with regard to function-the primary clinical outcome. CONCLUSION: Overall EVS seemed most capable of distinguishing those clients and residents with a positive benefit from those that showed no benefit of nutritional intervention. The findings should be confirmed in further validation and intervention studies. PMID- 23644012 TI - Effects of a meal rich in medium-chain saturated fat on postprandial lipemia in relatives of type 2 diabetics. AB - OBJECTIVE: Patients with type 2 diabetes and their relatives (REL) have increased risk for cardiovascular disease (CVD). Postprandial triglyceridemia (PPL), which is influenced by diet, is an independent risk factor for CVD. Little is known about the effects of medium-chain saturated fatty acids (medium-chain SFA) on PPL and gene expression in REL. The objective of this study was to test the hypothesis that medium-chain SFA cause larger PPL response in REL compared with controls (CON) and have a differential effect on circulating incretins and ghrelin and gene expression in muscle and adipose tissue in REL and CON. METHODS: Seventeen REL and 17 CON received a fat-rich meal (79 energy percent from fat) based on medium-chain SFA (coconut oil). Plasma concentrations of triglycerides (TG), free-fatty acids, insulin, glucose, glucagon-like peptide-1, glucose dependent insulintropic peptide, and ghrelin were measured before and during 240 min postprandially. Muscle and adipose tissue biopsies were taken at baseline and after the test meal. RESULTS: After the test meal, REL had a higher plasma TG response (P = 0.002) and a tendency toward higher insulin response (P = 0.100). A number of genes were upregulated in response to the meal rich in medium-chain SFA in CON, but not in REL. CONCLUSION: A meal high in medium-chain SFA resulted in larger PPL response in REL than in CON. It remains to be clarified whether this can be reproduced by a pure medium-chain fat (MCT) load. The meal exerted a differential effect on gene expression in muscle, but not adipose tissue, of REL compared with CON. PMID- 23644013 TI - Quality and patient safety in the diagnosis of breast cancer. AB - The media, medical legal, and safety science perspectives of a laboratory medical error differ and assign variable levels of responsibility on individuals and systems. We examine how the media identifies, communicates, and interprets information related to anatomic pathology breast diagnostic errors compared to groups using a safety science Lean-based quality improvement perspective. The media approach focuses on the outcome of error from the patient perspective and some errors have catastrophic consequences. The medical safety science perspective does not ignore the importance of patient outcome, but focuses on causes including the active events and latent factors that contribute to the error. Lean improvement methods deconstruct work into individual steps consisting of tasks, communications, and flow in order to understand the affect of system design on current state levels of quality. In the Lean model, system redesign to reduce errors depends on front-line staff knowledge and engagement to change the components of active work to develop best practices. In addition, Lean improvement methods require organizational and environmental alignment with the front-line change in order to improve the latent conditions affecting components such as regulation, education, and safety culture. Although we examine instances of laboratory error for a specific test in surgical pathology, the same model of change applies to all areas of the laboratory. PMID- 23644014 TI - Avian host defense peptides. AB - Host defense peptides (HDPs) are important effector molecules of the innate immune system of vertebrates. These antimicrobial peptides are also present in invertebrates, plants and fungi. HDPs display broad-spectrum antimicrobial activities and fulfill an important role in the first line of defense of many organisms. It is becoming increasingly clear that in the animal kingdom the functions of HDPs are not confined to direct antimicrobial actions. Research in mammals has indicated that HDPs have many immunomodulatory functions and are also involved in other physiological processes ranging from development to wound healing. During the past five years our knowledge about avian HDPs has increased considerably. This review addresses our current knowledge on the evolution, regulation and biological functions of HDPs of birds. PMID- 23644015 TI - Innate and adaptive immune mechanisms are effectively induced in ileal Peyer's patches of Salmonella typhimurium infected pigs. AB - In this report we employed laser-capture microdissection (LCM) coupled to qPCR technology and bioinformatic analysis to characterize, for the first time, the response of Peyer's patches (PP) from orally infected animals to Salmonella typhimurium, in a model of non-typhoidal salmonellosis. Pathogen was highly found in the cytoplasm of phagocytes in PP and differential gene expression analysis indicated an up-regulation of proinflammatory molecules, establishment of a Th1 driven response and triggering of DC and T-cell activity. Furthermore, predictions by bioinformatic analysis pointed to an activation of processes regarding stimulation and maturation of DC, influx of leukocytes in tissue and T lymphocytes priming and differentiation. In short, the approach used in this study proved to be a promising strategy to explore infectious processes. Indeed, it revealed an effective induction of innate and adaptive immune mechanisms in swine PP which appear to be distinct from those observed in mesenteric lymph nodes and closely related to response of gut mucosa. PMID- 23644016 TI - Analysis of supercooling activity of tannin-related polyphenols. AB - Based on the discovery of novel supercooling-promoting hydrolyzable gallotannins from deep supercooling xylem parenchyma cells (XPCs) in Katsura tree (see Wang et al. (2012) [38]), supercooling capability of a wide variety of tannin-related polyphenols (TRPs) was examined in order to find more effective supercooling promoting substances for their applications. The TRPs examined were single compounds including six kinds of hydrolyzable tannins, 11 kinds of catechin derivatives, two kinds of structural analogs of catechin and six kinds of phenolcarboxylic acid derivatives, 11 kinds of polyphenol mixtures and five kinds of crude plant tannin extracts. The effects of these TRPs on freezing were examined by droplet freezing assays using various solutions containing different kinds of identified ice nucleators such as the ice nucleation bacterium (INB) Erwinia ananas, the INB Xanthomonas campestris, silver iodide and phloroglucinol as well as a solution containing only unintentionally included unidentified airborne ice nucleators. Among the 41 kinds of TRPs examined, all of the hydrolyzable tannins, catechin derivatives, polyphenol mixtures and crude plant tannin extracts as well as a few structural analogs of catechin and phenolcarboxylic acid derivatives exhibited supercooling-promoting activity (SCA) with significant differences (p>0.05) from at least one of the solutions containing different kinds of ice nucleators. It should be noted that there were no TRPs exhibiting ice nucleation-enhancing activity (INA) in all solutions containing identified ice nucleators, whereas there were many TRPs exhibiting INA with significant differences in solutions containing unidentified ice nucleators alone. An emulsion freezing assay confirmed that these TRPs did not essentially affect homogeneous ice nucleation temperatures. It is thought that not only SCA but also INA in the TRPs are produced by interactions with heterogeneous ice nucleators, not by direct interaction with water molecules. In the present study, several TRPs that might be useful for applications due to their high SCA in many solutions were identified. PMID- 23644017 TI - Raffinose and hypotaurine improve the post-thawed Merino ram sperm parameters. AB - The aim of this study was to determine the effects of raffinose and hypotaurine on sperm parameters after the freeze-thawing of Merino ram sperm. Totally 40 ejaculates of five Merino ram were used in the study. Semen samples, which were diluted with a Tris-based extender containing 10mM raffinose, 5mM hypotaurine, 5mM raffinose +2.5mM hypotaurine (H+R) and no antioxidant (control), were cooled to 5 degrees C and frozen in 0.25 ml French straws and stored in liquid nitrogen. Frozen straws were then thawed individually at 37 degrees C for 25s in a water bath for evaluation. The addition of raffinose led to higher percentages of subjective and CASA motilities (47.5 +/- 12.2%, 46.3 +/- 13.6%) compared to controls (38.8 +/- 13.8%, 30.5 +/- 11.7%, P<0.05). For the CASA progressive motility, 5mM raffinose (20.12 +/- 8.82%) had increasing effect in comparison to control (10 +/- 7.94%, P<0.05) following the freeze-thawing process. Raffinose and hypotaurine led to higher viability (40.8 +/- 4.68%, 40.8 +/- 4.7%), high sperm mitochondrial activity (29.5 +/- 5.4%, 27.3 +/- 4.9%) and acrosome integrity (50.8 +/- 8.1, 50.7 +/- 4.4) percentages, compared to control groups (31.5 +/- 3.5%, 9.5 +/- 8.2%, 42.8 +/- 7.3%, P<0.05). H+R group only led to high sperm mitochondrial activity when compared to control group. In the comet test, raffinose and hypotaurine resulted in lower sperm with damaged DNA (6.2% and 3.9%) than that of control (9.1%), reducing the DNA damage. For TUNEL assay, The TUNEL-positive cell was distinguished by distinct nuclear staining. Raffinose and H+R groups resulted in lower sperm with TUNEL-positive cell (1.5 +/- 1.2% and 2.1 +/- 0.9%) than that of control (4.9 +/- 2.5%) (P<0.05). In conclusion, findings of this study showed that raffinose and hypotaurine supplementation in semen extenders provided a better protection of sperm parameters against cryopreservation injury, in comparison to the control groups. PMID- 23644018 TI - Ubc9 sumoylation controls SUMO chain formation and meiotic synapsis in Saccharomyces cerevisiae. AB - Posttranslational modification with the small ubiquitin-related modifier SUMO depends on the sequential activities of E1, E2, and E3 enzymes. While regulation by E3 ligases and SUMO proteases is well understood, current knowledge of E2 regulation is very limited. Here, we describe modification of the budding yeast E2 enzyme Ubc9 by sumoylation (Ubc9(*)SUMO). Although less than 1% of Ubc9 is sumoylated at Lys153 at steady state, a sumoylation-deficient mutant showed significantly reduced meiotic SUMO conjugates and abrogates synaptonemal complex formation. Biochemical analysis revealed that Ubc9(*)SUMO is severely impaired in its classical activity but promoted SUMO chain assembly in the presence of Ubc9. Ubc9(*)SUMO cooperates with charged Ubc9 (Ubc9~SUMO) by noncovalent backside SUMO binding and by positioning the donor SUMO for optimal transfer. Thus, sumoylation of Ubc9 converts an active enzyme into a cofactor and reveals a mechanism for E2 regulation that orchestrates catalytic (Ubc9~SUMO) and noncatalytic (Ubc9(*)SUMO) functions of Ubc9. PMID- 23644019 TI - A review on zinc and nickel adsorption on natural and modified zeolite, bentonite and vermiculite: examination of process parameters, kinetics and isotherms. AB - Adsorption and ion exchange can be effectively employed for the treatment of metal-contaminated wastewater streams. The use of low-cost materials as sorbents increases the competitive advantage of the process. Natural and modified minerals have been extensively employed for the removal of nickel and zinc from water and wastewater. This work critically reviews existing knowledge and research on the uptake of nickel and zinc by natural and modified zeolite, bentonite and vermiculite. It focuses on the examination of different parameters affecting the process, system kinetics and equilibrium conditions. The process parameters under investigation are the initial metal concentration, ionic strength, solution pH, adsorbent type, grain size and concentration, temperature, agitation speed, presence of competing ions in the solution and type of adsorbate. The system's performance is evaluated with respect to the overall metal removal and the adsorption capacity. Furthermore, research works comparing the process kinetics with existing reaction kinetic and diffusion models are reviewed as well as works examining the performance of isotherm models against the experimental equilibrium data. PMID- 23644020 TI - Association between fibromyalgia syndrome and polymorphism of the IL-4 gene in a Turkish population. AB - PURPOSE: Fibromyalgia (FM) syndrome is a form of non-articular rheumatism characterized by long term and widespread musculoskeletal pain, morning stiffness, sleep disturbance, paresthesia, and pressure hyperalgesia at characteristic sites, called soft tissue tender points. The etiology of FM is still obscure. Genetic factors may predispose individuals to FM. Cytokines may play a role in the pathophysiology of FM. The aim of this study was to investigate the interleukin-4 (IL-4) 70 bp VNTR variations in Turkish patients with FM and evaluate if there was an association with clinical features, especially between these polymorphisms. METHODS: The study included 300 patients with FM and 270 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) for the IL-4 gene 70 bp VNTR polymorphisms. RESULTS: There was statistically significant difference between the groups with respect to IL-4 genotype distribution and allele frequencies (p<0.0001). The homozygous P1P1 genotype and P1 allele were significantly higher in FM patients than in healthy controls (p=0.04; OR: 3.25, 95% CI: 1-10, p<0.0001; OR:4.84, 95% CI:3-7.7). There was not any difference between the groups respect to IL-4 genotype distribution and allele frequencies (p>0.05) and clinical characteristics. CONCLUSION: Our findings suggest that there is an association of IL-4 gene 70 bp VNTR polymorphism with susceptibility of a person for development of FM. As a result, further studies are necessary to determine whether IL-4 may be a genetic marker for FM in the Turkish population. PMID- 23644021 TI - De novo sequencing and assembly of Centella asiatica leaf transcriptome for mapping of structural, functional and regulatory genes with special reference to secondary metabolism. AB - Centella asiatica (L.) Urban is an important medicinal plant and has been used since ancient times in traditional systems of medicine. C. asiatica mainly contains ursane skeleton based triterpenoid sapogenins and saponins predominantly in its leaves. This investigation employed Illumina next generation sequencing (NGS) strategy on a pool of three cDNAs from expanding leaf of C. asiatica and developed an assembled transcriptome sequence resource of the plant. The short transcript reads (STRs) generated and assembled into contigs and singletons, representing majority of the genes expressed in C. asiatica, were termed as 'tentative unique transcripts' (TUTs). The TUT dataset was analyzed with the objectives of (i) development of a transcriptome assembly of C. asiatica, and (ii) classification/characterization of the genes into categories like structural, functional, regulatory etc. based on their function. Overall, 68.49% of the 46,171,131 reads generated in the NGS process could be assembled into a total of 79,041 contigs. Gene ontology and functional annotation of sequences resulted into the identification of genes related to different sets of cellular functions including identification of genes related to primary and secondary metabolism. The wet lab validation of seventeen assembled gene sequences identified to be involved in secondary metabolic pathways and control of reactive oxygen species (ROS) was established by semi-quantitative and real time PCR (qRT PCR). The validation also included sequencing/size matching of a set of semi quantitative PCR amplicons with their in silico assembled contig/gene. This confirmed the appropriateness of assembling the reads and contigs. Thus, the present study constitutes the largest report to date on C. asiatica transcriptome based gene resource that may contribute substantially to the understanding of the basal biological functions and biochemical pathways of secondary metabolites as well as the transcriptional regulatory elements and genetic markers. This work sets the stage for multi-faceted future improvement of the plant, through discovery of new genes, marker-assisted breeding or genetic engineering, on this species as well as for other species of Apiaceae and triterpene producing medicinal plants. PMID- 23644022 TI - Identification and gene expression analyses of natriuretic peptide system in the ovary of goat (Capra hircus). AB - Natriuretic peptides (NPs) are involved in maintaining cardiovascular and fluid homeostasis, regulating reproductive processes and bone growth, and other numerous functions. To better understand the role of NPs in goat (Capra hircus), in the present study, full-length cDNAs of goat Nppa (natriuretic peptide precursor A), Nppb (natriuretic peptide precursor B) and Nppc (natriuretic peptide precursor C), respectively encoding ANP, BNP and CNP, were cloned from adult goat heart and ovary. The putative prepropeptide ANP (prepro-ANP) and prepro-CNP share a high amino acid sequence identity with other species. Real time PCR showed that Nppa, Nppb and Nppc were widely expressed in adult goat tissues. The mRNA expression of Nppa and Nppb in the heart was extremely higher compared with other tissues. Nppc mRNA expression in the lung and uterus was also higher than in other tissues. The expression of Nppa, Nppb and Nppc genes was examined at different ovarian follicle stages using RT-PCR. The mRNAs of Nppa and Nppb were detected in secondary follicles as well as in COCs (cumulus-oocyte complexes) and granulosa cells of antral follicles. However, the mRNA expression of Nppc was observed throughout ovarian follicle development, and it was especially higher in granulosa cells of antral follicles. In vitro, stimulating goat granulosa cells with FSH led to an increase in the expression of Nppc by dose- and time-dependent manners and a rapid decline was induced by LH stimulation, but the expression of Nppa and Nppb did not change after FSH or LH treatment. These results suggest that Nppc is a gonadotropin-induced gene in granulosa cells of goat ovary and CNP may be involved in the regulation of ovarian follicle development and oocyte maturation. PMID- 23644023 TI - Relationship of polymorphisms within ZBED6 gene and growth traits in beef cattle. AB - ZBED6 is a novel transcription factor that was identified and shown to act as a repressor of IGF2 transcription in skeletal muscle. The aim of this study was to examine the association of the ZBED6 polymorphism with growth traits in beef cattle breed. Three single nucleotide polymorphisms (SNPs) were identified in the bovine ZBED6 by sequencing pooled DNA samples (Pool-Seq) and forced polymerase chain reaction-restriction fragment length polymorphism (Forced PCR-RFLP) methods. Overall, we reported one mutation (SNP1) in the promoter region and two missense mutations (SNP2 and 3) in the coding region (single exon) within the bovine ZBED6 gene, and the haplotype variability and extent of linkage disequilibrium (LD) in 1522 individuals representing four main cattle breeds from China (Nanyang, NY; Qinchuan, QC; Jiaxian, JX; and Chinese Holstein, CH). We also investigated haplotype frequencies and linkage disequilibrium coefficients for three SNPs in all study populations. LD and haplotype structure of ZBED6 were different between breeds. The result of haplotype analysis of three SNPs showed that eight different haplotypes were identified in all breeds. The wild-type haplotype (Hap 1: GCA) and mutant-type haplotype (Hap 8: AGG) shared by all four populations accounted for 15.1, 29.8, 21.7, 57.5% and 9.5, 8.6, 16.7, 0% of all haplotypes were observed in NY, QC, JX and CH, respectively. The statistical analyses indicated that three SNPs were significantly associated with growth traits in NY cattle population (P<0.05 or P<0.01) at five different ages. The results of this study suggest that the ZBED6 gene possibly is a strong candidate gene that affects growth traits in beef cattle breeding program. PMID- 23644024 TI - Natural Killer Cell Immunoglobulin-like Receptor (KIR) genotypes in Follicular Lymphoma patients: results of a pilot study. AB - AIMS: The Natural Killer Cell Immunoglobulin-like Receptor (KIR) genotype profiling in Follicular Lymphoma has not been reported before in the literature. MATERIALS AND METHODS: DNA extracted from 20 Follicular Lymphoma patients and 62 healthy controls was analyzed for KIR genotyping using a polymerase chain reaction/sequence specific primers technique (PCR/SSP) for the presence of 16 KIR gene and pseudogene loci. RESULTS: The AA, AB, and BB genotype frequencies were, respectively, 20%, 60% and 20% with an A:B ratio of 1:1. KIR 2DL4, KIR 3DL2, KIR 3DL3, and KIR 3DP1*003 were presented in all individuals. No significant difference between patients and controls was detected. CONCLUSION: KIR genotyping profile does not seem to be associated with Follicular Lymphoma. The results presented in this pilot research represent the first international report about this important clinical entity. PMID- 23644025 TI - Molecular karyotyping of an isolated partial trisomy 11q patient with additional findings. AB - Isolated partial duplication of the long arm of chromosome 11 is very rare. The main features are dysmorphic facial features, pre/postnatal growth retardation, speech delay, mental retardation, hypotonia, microcephaly, and cardiac, vertebral, limb and genital anomalies. In this case, we report a patient with partial trisomy of 11q13.5->qter due to a de novo rearrangement consisting of the whole X chromosome and part of chromosome 11; 46,X,der(X)(Xqter->Xp22.33::11q13.5 >11qter). Additional findings were a separated clavicle, lacrimal duct stenosis and prenatally detected renal hypoplasia. SNP array results revealed a duplication between 11q13.5 and 11qter, measuring 58 Mb, from nucleotide 76,601,607 to 134,926,021. As a result, molecular karyotyping could be performed in such cases in order to establish a definite phenotype-genotype correlation using conventional or molecular cytogenetics techniques. PMID- 23644026 TI - Multiple bursts of pancreatic ribonuclease gene duplication in insect-eating bats. AB - Pancreatic ribonuclease gene (RNASE1) was previously shown to have undergone duplication and adaptive evolution related to digestive efficiency in several mammalian groups that have evolved foregut fermentation, including ruminants and some primates. RNASE1 gene duplications thought to be linked to diet have also been recorded in some carnivores. Of all mammals, bats have evolved the most diverse dietary specializations, mainly including frugivory and insectivory. Here we cloned, sequenced and analyzed RNASE1 gene sequences from a range of bat species to determine whether their dietary adaptation is mirrored by molecular adaptation. We found that seven insect-eating members of the families Vespertilionidae and Molossidae possessed two or more duplicates, and we also detected three pseudogenes. Reconstructed RNASE1 gene trees based on both Bayesian and maximum likelihood methods supported independent duplication events in these two families. Selection tests revealed that RNASE1 gene duplicates have undergone episodes of positive selection indicative of functional modification, and lineage-specific tests revealed strong adaptive evolution in the Tadarida beta clade. However, unlike the RNASE1 duplicates that function in digestion in some mammals, the bat RNASE1 sequences were found to be characterized by relatively high isoelectric points, a feature previously suggested to promote defense against viruses via the breakdown of double-stranded RNA. Taken together, our findings point to an adaptive diversification of RNASE1 in these two bat families, although we find no clear evidence that this was driven by diet. Future experimental assays are needed to resolve the functions of these enzymes in bats. PMID- 23644027 TI - Two novel and functional DNA sequence variants within an upstream enhancer of the human NKX2-5 gene in ventricular septal defects. AB - Mortality in patients with congenital heart disease (CHD) is significantly increased even with successful surgeries. The main causes are late cardiac complications, such as heart failure and arrhythmia, probably due to genetic defects. To date, genetic causes for CHD remain largely unknown. NKX2-5 gene encodes a highly conserved homeobox transcription factor, which is essential to the heart development in embryos and cardiac function in adults. Mutations in NKX2-5 gene have been implicated in diverse types of CHD, including ventricular septal defect (VSD). As NKX2-5 is a dosage-sensitive regulator, we have speculated that changed NKX2-5 levels may mediate CHD development by influencing cardiac gene regulatory network. In previous studies, we have analyzed the NKX2-5 gene promoter and a proximal enhancer in VSD patients. In the present study, we further genetically and functionally analyzed an upstream enhancer of the NKX2-5 gene in large cohorts of VSD patients (n=340) and controls (n=347). Two novel heterozygous DNA sequence variants (DSVs), g.17483576C>G and g.17483564C>T, were identified in three VSD patients, but none in controls. Functionally, these two DSVs significantly decreased the activity of the enhancer (P<0.01). Another novel heterozygous DSV, g.17483557Ins, was found in both VSD patients and controls with similar frequencies (P>0.05). Taken together, our data suggested that the DSVs within the upstream enhancer of the NKX2-5 gene may contribute to a small number of VSD. Therefore, genetic studies of CHD may provide insight into designing novel therapies for adult CHD patients. PMID- 23644028 TI - Pathway analysis of a genome-wide association study in schizophrenia. AB - OBJECTIVE: The aim of this study was to identify the candidate single nucleotide polymorphisms (SNPs) and candidate mechanisms that contribute to schizophrenia susceptibility and to generate a SNP to gene to pathway hypothesis using an analytical pathway-based approach. METHODS: We used schizophrenia GWAS data of the genotypes of 660,259 SNPs in 1378 controls and 1351 cases of European descent after quality control filtering. ICSNPathway (Identify candidate Causal SNPs and Pathways) analysis was applied to the schizophrenia GWAS dataset. The first stage involved the pre-selection of candidate SNPs by linkage disequilibrium analysis and the functional SNP annotation of the most significant SNPs found. The second stage involved the annotation of biological mechanisms for the pre-selected candidate SNPs using improved-gene set enrichment analysis. RESULTS: ICSNPathway analysis identified fifteen candidate SNPs, ten candidate pathways, and nine hypothetical biological mechanisms. The most strongly associated potential pathways were as follows. First, rs1644731 and rs1644730 to RDH8 to estrogen biosynthetic process (p<0.001, FDR<0.001). The genes involved in this pathway are RDH8 and HSD3B1 (p<0.05). All-trans-retinol dehydrogenase (RDH8) is a visual cycle enzyme that reduces all-trans-retinal to all-trans-retinol in the presence of NADPH. The chemical reactions and pathways involved result in the formation of estrogens, which are C18 steroid hormones that can stimulate the development of female sexual characteristics. Second, rs1146031 to ACVR1 to mesoderm formation and activin binding (p<0.001, FDR=0.032, 0.034). Two of 15 candidate genes are known genes associated with schizophrenia: KCNQ2 and APOL2. One of the 10 candidate pathways, estrogen biosynthetic process, is known to be associated with schizophrenia (p<0.001, FDR<0.001). However, 13 of candidate genes (RDH8, ACVR1, PSMD9, KCNAB1, SLC17A3, ARCN1, COG7, STAB2, LRPAP1, STAB1, CXCL16, COL4A4, EXOSC3) and 9 of candidate pathways were novel. CONCLUSION: By applying ICSNPathway analysis to schizophrenia GWAS data, we identified candidate SNPs, genes like KCNQ2 and APOL2 and pathways involving the estrogen biosynthetic process may contribute to schizophrenia susceptibility. Further analyses are needed to validate the results of this analysis. PMID- 23644029 TI - Systematic review, structural analysis, and new theoretical perspectives on the role of serotonin and associated genes in the etiology of psychopathy and sociopathy. AB - Since its theoretical inception, psychopathy has been considered by philosophers, clinicians, theorists, and empirical researchers to be substantially and critically explained by genetic factors. In this systematic review and structural analysis, new hypotheses will be introduced regarding gene-gene and gene environment interactions in the etiology of psychopathy and sociopathy. Theory and research from neurobiological and behavioral sciences will be integrated in order to place this work in a broader conceptual framework and promote synergy across fields. First, a between groups comparison between psychopathy and sociopathy is made based on their specific dysfunctions in emotional processing, behavioral profiles, etiological pathways, HPA-axis functioning, and serotonergic profiles. Next, it is examined how various polymorphisms in serotonergic genes (e.g., TPH, 5HTT, HTR1A, HTR2A, HTR2C, and HTR3) might contribute either individually or interactively to the development of these disorders and through which specific biological and behavioral endophenotypes this effect could be mediated. A short introduction is made into mediating variables such as GABAergic functioning and testosterone which could potentially alter the decisive effect of serotonergic genotypes on behavior and physiology. Finally, critical commentary is presented on how to interpret the hypotheses put forward in this review. PMID- 23644030 TI - Os acromiale, a cause of shoulder pain, not to be overlooked. AB - INTRODUCTION: Os acromiale is a failure of fusion of the acromial process. It is usually asymptomatic and discovered by chance. When it is painful a differential diagnosis must be made in relation to the subacromial impingement syndrome. HYPOTHESIS: Unstable os acromiale is the cause of atypical scapulalgias. Stabilization by tension band wiring and an embedded slot shaped graft achieves union and relieves pain. PATIENTS ET METHODS: This series includes 10 patients mean age 43 years old presenting with shoulder pain resistant to a mean 15 months of conservative treatment. Pain followed trauma in three cases. Three patients had a history of acromioplasty, which had not relieved pain. All had pain during palpation of the superior aspect of the acromion. The diagnosis was confirmed in eight patients by positive results to local injection of the os acromiale. The mean preoperative Constant score was 53.4. The procedure included open reduction and fixation of the acromion by tension band wiring and pinning associated with an embedded iliac crest graft without acromioplasty. RESULTS: The mean follow-up was 48 months. Pain was relieved in seven cases and all patients had improved and were satisfied. Union of os acromiale was confirmed on CT scan in all patients. The mean Constant score was 82.2. DISCUSSION: The role of os acromiale in the origination of pain is confirmed by the efficacy of preoperative injection of the os acromiale and pain relief after achieving union. Moreover, our technique is reliable and always resulted in union of the os acromiale. Internal fixation by tension banding favors minimal upward migration of the os acromiale and union. In case of subacromial impingement syndrome an os acromiale should be looked for, as this condition could deteriorate with simple acromioplasty. LEVEL OF EVIDENCE: Level IV retrospective observational study. PMID- 23644031 TI - Survival analysis of total knee arthroplasty at a minimum 10 years' follow-up: a multicenter French nationwide study including 846 cases. AB - INTRODUCTION: Survivorship for modern total knee arthroplasties (TKA) is not precisely known from large series, other than registries. The present retrospective study therefore analyzed 846 TKAs at a minimum 10 years' follow-up. HYPOTHESIS: Ten-year survivorship for TKAs in a multicenter study exceeds 90%, independently of design and level of prosthetic constraint. MATERIALS AND METHODS: Eight hundred and twenty-eight patients (846 TKAs) were assessed on the Knee Society score. Mean age was 71 years (range, 41-93 years); 274 males and 554 females (67%); 496 patients (60%) were active; diagnosis was principally osteoarthritis (n=752 [89%]). Most TKAs were cemented (n=704 [83%]), replacing the patella (n=668 [79%]) and sacrificed the posterior cruciate ligament (PCL) (n=707 [84%]), 65% being posterior-stabilized and 35% ultracongruent, with fixed (39%) or mobile bearing (61%). RESULTS: At a minimum 10 years' follow-up, mean knee score rose from 35 (15-55) to 83 points (74-95), and functional score from 24 (5-45) to 74 points (60-90); mean flexion rose from 105 degrees (25-125 degrees ) to 112 degrees (25-125 degrees ). Mean hip-knee-ankle angle was 179.5 degrees (169-189 degrees ). Sixty-three (7.5%) revision surgeries were required, mainly for loosening (n=18 [2%]) or infection (n=18 [1.8%]). Overall 10-year survivorship was 92% (95% CI: 0.90-0.94). There was no significant difference in survivorship according to implant design or PCL retention. Activity level correlated with revision rate; mechanical complications were more frequent in active and infectious complications in sedentary subjects. Revision was not more frequent in TKA aligned outside the 177-183 degrees range. DISCUSSION: Ten-year TKA survivorship was 92%, independently of design and level of mechanical stress. Revision was mainly for infection or loosening, and not for greater than 3 degrees axis misalignment. Mechanical complications were more frequent in younger and more active subjects, for whom therefore other treatment options or technical improvements should be sought. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 23644032 TI - Comments on: "fixation of split anterior tibialis tendon transfer by anchorage to the base of the 5th metatarsal bone" by N. Gasse, T. Luth, F. Loisel, A. Serre, L. Obert, B. Parratte, D. Lepage published in Orthopaedics & Traumatology: Surgery & Research 2012;98(7):829-33. PMID- 23644033 TI - Pronociceptive changes in the activity of rostroventromedial medulla (RVM) pain modulatory cells in the streptozotocin-diabetic rat. AB - Neuropathic pain is one of the most frequent complications of diabetes. The increased neuronal activity of primary afferents and spinal cord neurons in streptozotocin (STZ)-diabetic rats increases the recruitment of the nociceptive ascending pathways, which may affect the activity of pain control circuits in the brain. This study aimed to characterize the electrophysiological responses of neurons of the rostroventromedial medulla (RVM), a key brainstem area involved in descending modulation of nociceptive neurotransmission at the spinal cord, in STZ diabetic rats. Spontaneous and noxious-evoked activity of ON-like cells (pain facilitatory cells) and OFF-like cells (pain inhibitory cells) in the RVM were analyzed by single cell extracellular electrophysiological recordings in STZ diabetic rats with behavioral signs of diabetic neuropathic pain 4 weeks after diabetes induction and in age-matched non-diabetic controls (CTRL). The electrophysiological analysis revealed an increase in the spontaneous activity of RVM pronociceptive ON-like cells in STZ-diabetic rats when compared to CTRL. On the contrary, the number of active antinociceptive OFF-like cells was significantly lower in the STZ-diabetic rats and their spontaneous activity was decreased when compared with CTRL. Overall, the changes in the activity of RVM pain modulatory cells in STZ-diabetic rats point to enhancement of descending pain facilitation. Based on similar results obtained at the RVM in traumatic neuropathic pain models, the changes in the electrophysiological responses of RVM in STZ-diabetic rats may account for exacerbated pain-like behaviors in diabetic neuropathy. PMID- 23644034 TI - Effect of hospital disinfectants on spores of clinical Brazilian Clostridium difficile strains. AB - The aim of this study was to evaluate the sporicidal activity of hospital disinfectants against spores of two Brazilian Clostridium difficile ribotypes and the BI/NAP1/027. Our results showed that CloroRio((r)) and Cidex Opa((r)) were the most efficient agents for eliminating spores of C difficile. PMID- 23644036 TI - Human serum albumin from recombinant DNA technology: challenges and strategies. AB - BACKGROUND: As the most abundant protein in the blood, human serum albumin (HSA) plays an important role in maintaining plasma oncotic pressure and fluid balance between the body's compartments. HSA is thus widely used in the clinic to treat diseases. However, the shortage of and safety issues arising from using plasma HSA (pHSA) underscore the importance of recombinant HSA (rHSA) as a promising substitute for pHSA. SCOPE OF REVIEW: Here, we review the production of rHSA, from expression to downstream processing, and highlight the scalability and cost effectiveness of the two main expression platforms. We also discuss the biosafety of commercially available pharmaceutical rHSA with respect to impurities and contaminants, followed by an analysis of recent progress in preclinical and clinical trials. We emphasise the challenges of producing pharmaceutical-grade rHSA. MAJOR CONCLUSIONS: rHSA can be highly expressed in various hosts and seems to be identical to pHSA. rHSA generated from yeast appears to be as efficient and safe as pHSA in a series of preclinical and clinical trials, whereas rHSA from rice seeds exhibits great potential for more cost-effective production. Cost effective products with no adverse effects will likely play a vital role in future human therapeutics. GENERAL SIGNIFICANCE: Our understanding of pharmaceutical-grade rHSA production has improved with respect to expression hosts, biochemical properties, downstream processing, and the detection and removal of impurities. However, due to the large dosages required for clinical applications, the production of sufficient quantities of rHSA still presents challenges. This article is part of a Special Issue entitled Serum Albumin. PMID- 23644037 TI - Redox properties of serum albumin. AB - BACKGROUND: Oxidative damage results in protein modification, and is observed in numerous diseases. Human serum albumin (HSA), the most abundant circulating protein in the plasma, exerts important antioxidant activities against oxidative damage. SCOPE OF REVIEW: The present review focuses on the characterization of chemical changes in HSA that are induced by oxidative damage, their relevance to human pathology and the most recent advances in clinical applications. MAJOR CONCLUSIONS: The antioxidant properties of HSA are largely dependent on Cys34 and its contribution to the maintenance of intravascular homeostasis, including protecting the vascular endothelium under disease conditions related to oxidative stress. Recent studies also evaluated the susceptibility of other important amino acid residues to free radicals. The findings suggest that a redox change in HSA is related to the oxidation of several amino acid residues by different oxidants. Further, Cys34 adducts, such as S-nitrosylated and S-guanylated forms also play an important role in clinical applications. On the other hand, the ratio of the oxidized form to the normal form of albumin (HMA/HNA), which is a function of the redox states of Cys34, could serve as a useful marker for evaluating systemic redox states, which would be useful for the evaluation of disease progression and therapeutic efficacy. GENERAL SIGNIFICANCE: This review provides new insights into our current understanding of the mechanism of HSA oxidation, based on in vitro and in vivo studies. This article is part of a Special Issue entitled Serum Albumin. PMID- 23644035 TI - Immuno-spin trapping from biochemistry to medicine: advances, challenges, and pitfalls. Focus on protein-centered radicals. AB - BACKGROUND: Immuno-spin trapping (IST) is based on the reaction of a spin trap with a free radical to form a stable nitrone adduct, followed by the use of antibodies, rather than traditional electron paramagnetic resonance spectroscopy, to detect the nitrone adduct. IST has been successfully applied to mechanistic in vitro studies, and recently, macromolecule-centered radicals have been detected in models of drug-induced agranulocytosis, hepatotoxicity, cardiotoxicity, and ischemia/reperfusion, as well as in models of neurological, metabolic and immunological diseases. SCOPE OF THE REVIEW: To critically evaluate advances, challenges, and pitfalls as well as the scientific opportunities of IST as applied to the study of protein-centered free radicals generated in stressed organelles, cells, tissues and animal models of disease and exposure. MAJOR CONCLUSIONS: Because the spin trap has to be present at high enough concentrations in the microenvironment where the radical is formed, the possible effects of the spin trap on gene expression, metabolism and cell physiology have to be considered in the use of IST and in the interpretation of results. These factors have not yet been thoroughly dealt with in the literature. GENERAL SIGNIFICANCE: The identification of radicalized proteins during cell/tissue response to stressors will help define their role in the complex cellular response to stressors and pathogenesis; however, the fidelity of spin trapping/immuno-detection and the effects of the spin trap on the biological system should be considered. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. PMID- 23644039 TI - Acute stress does not impair long-term memory retrieval in older people. AB - Previous studies have shown that stress-induced cortisol increases impair memory retrieval in young people. This effect has not been studied in older people; however, some findings suggest that age-related changes in the brain can affect the relationships between acute stress, cortisol and memory in older people. Our aim was to investigate the effects of acute stress on long-term memory retrieval in healthy older people. To this end, 76 participants from 56 to 76 years old (38 men and 38 women) were exposed to an acute psychosocial stressor or a control task. After the stress/control task, the recall of pictures, words and stories learned the previous day was assessed. There were no differences in memory retrieval between the stress and control groups on any of the memory tasks. In addition, stress-induced cortisol response was not associated with memory retrieval. An age-related decrease in cortisol receptors and functional changes in the amygdala and hippocampus could underlie the differences observed between the results from this study and those found in studies performed with young people. PMID- 23644038 TI - Differential change in specific depressive symptoms during antidepressant medication or cognitive therapy. AB - Cognitive therapy and antidepressant medications are effective treatments for depression, but little is known about their relative efficacy in reducing individual depressive symptoms. Using data from a recent clinical trial comparing cognitive therapy, antidepressant medication, and placebo in the treatment of moderate-to-severe depression, we examined whether there was a relative advantage of any treatment in reducing the severity of specific depressive symptom clusters. The sample consisted of 231 depressed outpatients randomly assigned to: cognitive therapy for 16 weeks (n = 58); paroxetine treatment for 16 weeks (n = 116); or pill placebo for 8 weeks (n = 57). Differential change in five subsets of depressive symptoms was examined: mood, cognitive/suicide, anxiety, typical vegetative, and atypical-vegetative symptoms. Medication led to a greater reduction in cognitive/suicide symptoms relative to placebo by 4 weeks, and both active treatments reduced these symptoms more than did placebo by 8 weeks. Cognitive therapy reduced the atypical-vegetative symptoms more than placebo by 8 weeks and more than medications throughout the trial. These findings suggest that medications and cognitive therapy led to different patterns of response to specific symptoms of depression and that the general efficacy of these two well validated treatments may be driven in large part by changes in cognitive or atypical-vegetative symptoms. PMID- 23644040 TI - Digital replacement of the distorted dentition acquired by cone beam computed tomography (CBCT): a pilot study. AB - During cone beam computed tomography (CBCT) scanning, intra-oral metallic objects may produce streak artefacts, which impair the occlusal surface of the teeth. This study aimed to determine the accuracy of replacement of the CBCT dentition with a more accurate dentition and to determine the clinical feasibility of the method. Impressions of the teeth of six cadaveric skulls with unrestored dentitions were taken and acrylic base plates constructed incorporating radiopaque registration markers. Each appliance was fitted to the skull and a CBCT performed. Impressions were taken of the dentition with the devices in situ and dental models were produced. These were CBCT-scanned and the images of the skulls and models imported into computer-aided design/computer-aided manufacturing (CAD/CAM) software and aligned on the registration markers. The occlusal surfaces of each dentition were then replaced with the occlusal image of the corresponding model. The absolute mean distance between the registration markers in the skulls and the dental models was 0.09+/-0.02mm, and for the dentition was 0.24+/-0.09mm. When the method was applied to patients, the distance between markers was 0.12+/-0.04mm for the maxilla and 0.16+/-0.02mm for the mandible. It is possible to replace the inaccurate dentition on a CBCT scan using this method and to create a composite skull which is clinically acceptable. PMID- 23644041 TI - How to coexist with fire ants: the roles of behaviour and cuticular compounds. AB - Because territoriality is energetically costly, territorial animals frequently respond less aggressively to neighbours than to strangers, a reaction known as the "dear enemy phenomenon" (DEP). The contrary, the "nasty neighbour effect" (NNE), occurs mainly for group-living species defending resource-based territories. We studied the relationships between supercolonies of the pest fire ant Solenopsis saevissima and eight ant species able to live in the vicinity of its nests plus Eciton burchellii, an army ant predator of other ants. The workers from all of the eight ant species behaved submissively when confronted with S. saevissima (dominant) individuals, whereas the contrary was never true. Yet, S. saevissima were submissive towards E. burchellii workers. Both DEP and NNE were observed for the eight ant species, with submissive behaviours less frequent in the case of DEP. To distinguish what is due to chemical cues from what can be attributed to behaviour, we extracted cuticular compounds from all of the nine ant species compared and transferred them onto a number of S. saevissima workers that were then confronted with untreated conspecifics. The cuticular compounds from three species, particularly E. burchellii, triggered greater aggressiveness by S. saevissima workers, while those from the other species did not. PMID- 23644042 TI - Tetramethylpyrazine reduces cellular inflammatory response following permanent focal cerebral ischemia in rats. AB - Tetramethylpyrazine (TMP) has been used to treat ischemic stroke. However, scientific evidence related to its effectiveness or precise modes of neuroprotective action is largely unclear. This study provides evidence of an alternative target for TMP and sheds light on the mechanism of its physiological benefits. We report a global inhibitory effect of TMP on intracerebral cellular inflammatory response in a rat model of permanent cerebral ischemia. TMP exhibited a neuroprotective effect against ischemic deficits by reduction of behavioral disturbance, brain infarction, and edema. The results of immunohistochemistry, enzymatic assay, Western blot, real-time reverse transcriptase-polymerase chain reaction (RT-PCR), and flow cytometric analysis revealed that TMP reduced the percentages of activated macrophages/microglia and infiltrative lymphocytes, neutrophils, and macrophages and pro-inflammatory cytokine expression after cerebral ischemia. In parallel with these immunosuppressive phenomena, TMP also attenuated the activities of ischemia induced inflammation-associated signaling molecules and transcription factors. Another finding in this study was that the anti-inflammatory and neuroprotective effects of TMP were accompanied by a further elevated expression of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in ipsilateral neurons and macrophages/microglia after cerebral ischemia. Taken together, our results suggest that both the promotion of endogenous defense capacity and the attenuation of the extent and composition percentage of the major cellular inflammatory responses via targeting of macrophages/microglia by elevating Nrf2/HO-1 expression might actively contribute to TMP-mediated neuroprotection against cerebral ischemia. PMID- 23644043 TI - Hydrogel-forming microneedle arrays exhibit antimicrobial properties: potential for enhanced patient safety. AB - We describe, for the first time, the microbial characterisation of hydrogel forming polymeric microneedle arrays and the potential for passage of microorganisms into skin following microneedle penetration. Uniquely, we also present insights into the storage stability of these hydroscopic formulations, from physical and microbiological viewpoints, and examine clinical performance and safety in human volunteers. Experiments employing excised porcine skin and radiolabelled microorganisms showed that microorganisms can penetrate skin beyond the stratum corneum following microneedle puncture. Indeed, the numbers of microorganisms crossing the stratum corneum following microneedle puncture were greater than 105 cfu in each case. However, no microorganisms crossed the epidermal skin. When using a 21G hypodermic needle, more than 104 microorganisms penetrated into the viable tissue and 106 cfu of Candida albicans and Staphylococcus epidermidis completely crossed the epidermal skin in 24 h. The hydrogel-forming materials contained no microorganisms following de-moulding and exhibited no microbial growth during storage, while also maintaining their mechanical strength, apart from when stored at relative humidities of 86%. No microbial penetration through the swelling microneedles was detectable, while human volunteer studies confirmed that skin or systemic infection is highly unlikely when polymeric microneedles are used for transdermal drug delivery. Since no pharmacopoeial standards currently exist for microneedle-based products, the exact requirements for a proprietary product based on hydrogel-forming microneedles are at present unclear. However, we are currently working towards a comprehensive specification set for this microneedle system that may inform future developments in this regard. PMID- 23644044 TI - "He who sees things grow from the beginning will have the finest view of them" a systematic review of genetic studies on psychological traits in infancy. AB - This paper reviews the studies that have aimed to identify genes influencing psychological traits in infancy (from birth to age 12 months). The review also addresses why genetic research in infancy is worthwhile and what genetic approaches such as genome-wide association studies and next generation sequencing could offer infant genetics. The results revealed that: (a) all studies (N=26) have employed a candidate gene association design; (b) existing studies have most commonly focused on the Dopamine receptor D4 (DRD4) and the Serotonin transporter promoter (5-HTTLPR) gene polymorphisms; (c) phenotypes that have been assessed are temperament, attachment, and attention. Two further studies included both temperament and electrophysiological markers; (d) among many unreplicated findings, the most promising result appeared to be an association between the long DRD4 polymorphism and several "positive" temperament characteristics from birth to 4-months of age and at 12-months of age. It is concluded that, to date, there are limited, and mixed, findings regarding the possible association of genes with psychological phenotypes in infancy. PMID- 23644045 TI - Molecular monitoring of minimal residual disease in the peripheral blood of patients with multiple myeloma. AB - The prognostic relevance of minimal residual disease (MRD) in patients with multiple myeloma is still an open question. In bone marrow, the level of residual myeloma cells is associated with treatment outcome, but the role of clonotypic cells in the peripheral blood (PB) for the prognosis of patients is not identified yet. In this study, we retrospectively analyzed MRD by quantitative real-time IgH-PCR (IgH-qPCR) in the PB of 42 patients undergoing high-dose therapy followed by autologous PB stem cell transplantation as first-line therapy for multiple myeloma. The MRD level of PB samples was in median 40-fold lower than in bone marrow samples, collected on the same day, with a wide intra- and interindividual variation (range, .4- to 4628-fold). The presence or absence of detectable MRD levels in PB did not correlate with the serological remission status. Still, patients with negative PCR results in PB 3 months after high-dose therapy and PB stem cell transplantation had lower International Staging System stage (P = .01), lower levels of beta2-microglobulin (P = .02), higher hemoglobin levels (P = .01), and a prolonged event-free (median, 15 versus 4 months; P = .004) and overall (median, 52 versus 17 months; P = .03) survival. Importantly, by sequential monitoring of clonotypic cells in PB, in 19 of 29 patients (66%) with progressive disease, an increase of the 2IgH/beta-actin ratio of at least 1 log step could be detected in median 4 months (range, .8 to 13 months) before the relapse was diagnosed on the basis of the European Group for Blood and Marrow Transplantation criteria. These patients with a molecular relapse in PB before a serological relapse had a significantly shorter overall survival than other patients (median, 17 months versus median not reached, P = .02). In conclusion, IgH-qPCR is a sensitive technique for the detection of clonotypic cells in PB, which precede clinical relapse. Future studies are needed to evaluate whether these circulating tumor cells play a role in promoting disease recurrence. PMID- 23644047 TI - Effect of phosvitin on lipid and protein oxidation in ground beef treated with high hydrostatic pressure. AB - In this study, we aimed to examine the effect of phosvitin on lipid and protein oxidation of raw and cooked ground beef treated with high hydrostatic pressure (HHP). Ground beef patty with 0, 500, or 1000 mg phosvitin/kg meat was treated with HHP at 0.1, 300, or 600 MPa. Half of the patties were used in a raw meat analysis, and the other half were used in a cooked meat analysis. Phosvitin and HHP treatment at 300 MPa synergistically reduced microbial growth, and HHP treatment at 600 MPa reduced microbial counts to undetectable levels (<1 log CFU/g) throughout the length of the study in all samples. Phosvitin delayed lipid and protein oxidation in HHP-treated cooked and raw ground beef, respectively. However, phosvitin had no effect on the color changes of raw ground beef attributable to HHP. The results indicated that phosvitin could enhance the stability of lipids and proteins but not color changes of raw ground beef caused by HHP. PMID- 23644046 TI - Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against cancers. AB - p300 is one of several acetyltransferases that regulate FOXP3 acetylation and functions. Our recent studies have defined a complex set of histone acetyltransferase interactions which can lead to enhanced or repressed changes in FOXP3 function. We have explored the use of a natural p300 inhibitor, Garcinol, as a tool to understand mechanisms by which p300 regulates FOXP3 acetylation. In the presence of Garcinol, p300 appears to become disassociated from the FOXP3 complex and undergoes lysosome-dependent degradation. As a consequence of p300's physical absence, FOXP3 becomes less acetylated and eventually degraded, a process that cannot be rescued by the proteasome inhibitor MG132. p300 plays a complex role in FOXP3 acetylation, as it could also acetylate a subset of four Lys residues that repressively regulate total FOXP3 acetylation. Garcinol acts as a degradation device to reduce the suppressive activity of regulatory T cells (Treg) and to enhance the in vivo anti-tumor activity of a targeted therapeutic anti-p185(her2/neu) (ERBB2) antibody in MMTV-neu transgenics implanted with neu transformed breast tumor cells. Our studies provide the rationale for molecules that disrupt p300 stability to limit Treg functions in targeted therapies for cancers. PMID- 23644048 TI - Spanish, French and British consumers' acceptability of Uruguayan beef, and consumers' beef choice associated with country of origin, finishing diet and meat price. AB - The effect of country of origin (local, Switzerland, Argentina, Uruguay), finishing diet (grass, grass plus concentrate, concentrate), and price (low, medium, high) on consumer's beef choice and segmentation was evaluated in Spain, France and United Kingdom. Sensory acceptability of Uruguayan beef from different production systems was also evaluated and contrasted with consumers' beef choices. Origin was the most important characteristic for the choice of beef with preference for meat produced locally. The second most important factor was animal feed followed by price with preference for beef from grass-fed animals and lowest price. The least preferred product was beef from Uruguay, concentrate-fed animals and highest price. Sensory data showed higher acceptability scores for Uruguayan beef from grass-fed animals with or without concentrate supplementation than animals fed concentrate only. Consumer segments with distinct preferences were identified. Foreign country promotion seems to be fundamental for marketing beef in Europe, as well as the development of different marketing strategies to satisfy each consumer segment. PMID- 23644049 TI - Effect of high pressure processing on the gel properties of salt-soluble meat protein containing CaCl2 and kappa-carrageenan. AB - The effects of high pressure processing (HPP) on the water-binding capacity and texture profile (TPA) of salt-soluble meat protein (SSMP) containing 0.2% CaCl2 and 0.6% kappa-carrageenan (SSMP-CK) gels were investigated. The results showed that 300-400 MPa improved water-binding capacity and decreased TPA parameters of SSMP-CK gels (P<0.05), while 100 MPa could increase hardness and chewiness of the gels. The thermal transition temperature peak for the myosin head (Tpeak1) of SSMP disappeared on addition of CaCl2 and kappa-carrageenan. 300 MPa produced a new peak, and caused a shift of the NH-stretching left peak and amide I and the disappearance of NH-stretching right peak. The destruction of network structure and the weakening of molecular interaction within the pressurized gels could result in the decrease of TPA parameters. Thus gelling properties could be modified by HPP, kappa-carrageenan and Ca(2+). It is of interest to develop low fat and sodium-reduced meat products. PMID- 23644050 TI - Sensory and consumer evaluation of pork loins from crossbreeds between Danish Landrace, Yorkshire, Duroc, Iberian and Mangalitza. AB - Iberian (I) and Mangalitza (M) boars were crossed with Duroc (D) and Landrace/Yorkshire (LY) sows and compared with the traditional crossbreed DLY. The sensory attributes were analysed, and consumers evaluated the fried loins. Gas chromatography (GC) aroma analysis was performed on the fried meat, and fatty acid composition was determined on the loin and the subcutaneous fat, respectively. No marked differences were found in odour, appearance or flavour/taste between the alternative crossbreeds and DLY; however, the alternative crossbreeds had improved textural properties. Consumer evaluation revealed that the alternative crossbreeds obtained positive associations compared with DLY, and MD was ranked best or second best by almost 60% of the consumers. No pronounced differences were found in the aroma compounds between the different crossbreeds. Correlations were found between the fatty acid composition and sensory attributes. In conclusion, by crossing the alternative breeds Iberian and Mangalitza with traditional Danish pig breeds it is possible to produce pork with attractive sensory attributes. PMID- 23644051 TI - Alternative pre-rigor foreshank positioning can improve beef shoulder muscle tenderness. AB - Thirty beef carcasses were harvested and the foreshank of each side was independently positioned (cranial, natural, parallel, or caudal) 1h post-mortem to determine the effect of foreshank angle at rigor mortis on the sarcomere length and tenderness of six beef shoulder muscles. The infraspinatus (IS), pectoralis profundus (PP), serratus ventralis (SV), supraspinatus (SS), teres major (TM) and triceps brachii (TB) were excised 48 h post-mortem for Warner Bratzler shear force (WBSF) and sarcomere length evaluations. All muscles except the SS had altered (P<0.05) sarcomere lengths between positions; the cranial position resulted in the longest sarcomeres for the SV and TB muscles whilst the natural position had longer sarcomeres for the PP and TM muscles. The SV from the cranial position had lower (P<0.05) shear than the caudal position and TB from the natural position had lower (P<0.05) shear than the parallel or caudal positions. Sarcomere length was moderately correlated (r=-0.63; P<0.01) to shear force. PMID- 23644054 TI - Individual differences in the effects of chronic stress on memory: behavioral and neurochemical correlates of resiliency. AB - Chronic stress has been shown to impair memory, however, the extent to which memory can be impaired is often variable across individuals. Predisposed differences in particular traits, such as anxiety, may reveal underlying neurobiological mechanisms that could be driving individual differences in sensitivity to stress and, thus, stress resiliency. Such pre-morbid characteristics may serve as early indicators of susceptibility to stress. Neuropeptide Y (NPY) and enkephalin (ENK) are neurochemical messengers of interest implicated in modulating anxiety and motivation circuitry; however, little is known about how these neuropeptides interact with stress resiliency and memory. In this experiment, adult male rats were appetitively trained to locate sugar rewards in a motivation-based spatial memory task before undergoing repeated immobilization stress and then being tested for memory retention. Anxiety-related behaviors, among other characteristics, were monitored longitudinally. Results indicated that stressed animals which showed little to no impairments in memory post-stress (i.e., the more stress-resilient individuals) exhibited lower anxiety levels prior to stress when compared to stressed animals that showed large deficits in memory (i.e., the more stress-susceptible individuals). Interestingly, all stressed animals, regardless of memory change, showed reduced body weight gain as well as thymic involution, suggesting that the effects of stress on metabolism and the immune system were dissociated from the effects of stress on higher cognition, and that stress resiliency seems to be domain-specific rather than a global characteristic within an individual. Neurochemical analyses revealed that NPY in the hypothalamus and amygdala and ENK in the nucleus accumbens were modulated differentially between stress-resilient and stress-susceptible individuals, with elevated expression of these neuropeptides fostering anxiolytic and pro-motivation function, thus driving cognitive resiliency in a domain-specific manner. Findings suggest that such neurochemical markers may be novel targets for pharmacological interventions that can serve to prevent or ameliorate the negative effects of stress on memory. PMID- 23644053 TI - Differential regulation of locomotor activity to acute and chronic cocaine administration by acid-sensing ion channel 1a and 2 in adult mice. AB - Acid-sensing ion channels (ASICs) are densely expressed in the brain with ASIC1a and ASIC2 channels being the predominant subtypes. These channels are enriched at synaptic sites and are central for the regulation of normal synaptic transmission. Moreover, increasing evidence links ASICs to the pathogenesis of various neurological and neuropsychiatric disorders. In this study, we explore the putative role of ASIC1a and ASIC2 in the regulation of behavioral sensitivity to the psychostimulant cocaine by utilizing ASIC1a or ASIC2 knockout mice. Acute cocaine injection induced a typical dose-dependent increase in locomotor activities in wild-type (WT) mice. However, in ASIC1a and ASIC2 mutant mice, different motor responses to cocaine were observed. In ASIC1a(-/-) mice, cocaine induced a significantly less motor response at all doses (5, 10, 20, and 30 mg/kg), while in ASIC2(-/-) mice, cocaine (5-20 mg/kg) stimulated locomotor activity to an extent comparable to WT mice. Only at 30 mg/kg, the cocaine stimulated motor activity was reduced in ASIC2(-/-) mice. In a chronic cocaine administration model (20mg/kg, once daily for 5 days), a challenge injection of cocaine (10mg/kg, after 2-week withdrawal) caused an evident behavioral sensitization in the cocaine-pretreated WT mice. This behavioral sensitization to challenge cocaine was also displayed in ASIC1a(-/-) and ASIC2(-/-) mice. However, ASIC2(-/-) mice showed less sensitization to challenge cocaine when compared to WT and ASIC1a(-/-) mice. Our results demonstrate the important role of ASIC1a and ASIC2 channels in the modulation of behavioral sensitivity to cocaine. The two synapse-enriched ASIC subtypes are believed to play distinguishable roles in the regulation of behavioral responses to acute and chronic cocaine administration. PMID- 23644055 TI - Psychological stress, cocaine and natural reward each induce endoplasmic reticulum stress genes in rat brain. AB - Our prior research has shown that the transcription of endoplasmic reticulum (ER) stress transcription factors activating transcription factor 3 (ATF3) and ATF4 are induced by amphetamine and restraint stress in rat striatum. However, presently the full extent of ER stress responses to psychological stress or cocaine, and which of the three ER stress pathways is activated is unknown. The current study examines transcriptional responses of key ER stress target genes subsequent to psychological stress or cocaine. Rats were subjected to acute or repeated restraint stress or cocaine treatment and mRNA was isolated from dorsal striatum, medial prefrontal cortex and nucleus accumbens brain tissue. ER stress gene mRNA expression was measured using quantitative polymerase chain reaction (PCR) and RNA sequencing. Restraint stress and cocaine-induced transcription of the classic ER stress-induced genes (BIP, CHOP, ATF3 and GADD34) and of two other ER stress components x-box binding protein 1 (XBP1) and ATF6. In addition, rats living in an enriched environment (large group cage with novel toys changed daily) exhibited rapid induction of GADD34 and ATF3 after 30 min of exploring novel toys, suggesting these genes are also involved in normal non-pathological signaling. However, environmental enrichment, a paradigm that produces protective addiction and depression phenotypes in rats, attenuated the rapid induction of ATF3 and GADD34 after restraint stress. These experiments provide a sensitive measure of ER stress and, more importantly, these results offer good evidence of the activation of ER stress mechanisms from psychological stress, cocaine and natural reward. Thus, ER stress genes may be targets for novel therapeutic targets for depression and addiction. PMID- 23644056 TI - Propofol prevents cerebral ischemia-triggered autophagy activation and cell death in the rat hippocampus through the NF-kappaB/p53 signaling pathway. AB - Propofol (2,6-diisopropylphenol) has been shown to attenuate neuronal injury under a number of experimental conditions; however, the mechanisms involved in its neuroprotective effects remain unclear. We therefore investigated whether inhibition of p53 induction by propofol contributes to the neuroprotection of cerebral ischemic cell death through both autophagic and apoptotic mechanisms. A transient global cerebral ischemia-reperfusion (I/R) model was produced with a 10 min, 2-vessel occlusion. The change in target genes including damage-regulated autophagy modulator (DRAM), microtubule-associated protein 1 light chain 3 (LC3), Beclin 1, cathepsin D, cathepsin B, p53-upregulated modulator of apoptosis (PUMA), Bax and Bcl-2 upon p53 inhibition was assessed with the co-administration of the intravenous anesthetic propofol and 3-methyladenine (3-MA), Pifithrin alpha (PFT-alpha) or SN50. The I/R-induced increases of protein levels of p53 and LC3-II were significantly inhibited by treatment with propofol, 3-MA or PFT alpha. The I/R-induced increases of protein levels of DRAM, Beclin 1, active cathepsin D and cathepsin B were significantly inhibited by treatment with propofol, PFT-alpha or SN50. The negative effects of the I/R-induced up regulation of PUMA and Bax and the down-regulation of Bcl-2 in the rat hippocampus were all blocked by treatment with propofol, PFT-alpha or SN50. Our results suggest that cerebral I/R can induce nuclear factor-kappa B-dependent expression of p53. The autophagic and apoptotic mechanisms participate in programed cell death by regulating the p53-mediated pathway. Our results are the first to show that propofol, at clinically relevant concentrations, attenuated cell death through both autophagic and apoptotic mechanisms in the rat hippocampus after a cerebral I/R insult. PMID- 23644057 TI - Responses of primate LGN cells to moving stimuli involve a constant background modulation by feedback from area MT. AB - The feedback connections from the cortical middle temporal (MT) motion area, to layer 6 of the primary visual cortex (V1), have the capacity to drive a cascaded feedback influence from the layer 6 cortico-geniculate cells back to the lateral geniculate nucleus (LGN) relay cells. This introduces the possibility of a re entrant motion signal affecting the relay of the retinal input through the LGN to the visual cortex. The question is whether the response of LGN cells to moving stimuli involves a component derived from this feedback. By producing a reversible focal pharmacological block of the activity of an MT direction column we show the presence of such an influence from MT on the responses of magno, parvo and koniocellular cells in the macaque LGN. The pattern of effect in the LGN reflects the direction bias of the MT location inactivated. This suggests a moving stimulus is captured by iterative interactions in the circuit formed by visual cortical areas and visual thalamus. PMID- 23644058 TI - Nickel nanoparticle-chitosan-reduced graphene oxide-modified screen-printed electrodes for enzyme-free glucose sensing in portable microfluidic devices. AB - A facile one-step strategy is reported to synthesize nanocomposites of chitosan reduced graphene oxide-nickel nanoparticles (CS-RGO-NiNPs) onto a screen-printed electrode (SPE). The synthesis is initiated by electrostatic and hydrophobic interactions and formation of self-assembled nanocomposite precursors of negatively charged graphene oxide (GO) and positively charged CS and nickel cations (Ni(2+)). The intrinsic mechanism of co-depositions from the nanocomposite precursor solution under cathodic potentials is based on simultaneous depositions of CS at high localized pH and in situ reduced hydrophobic RGO from GO as well as cathodically reduced metal precursors into nanoparticles. There is no need for any pre- or post-reduction of GO due to the in situ electrochemical reduction and the removal of oxygenated functionalities, which lead to an increase in hydrophobicity of RGO and successive deposition on the electrode surface. The as-prepared CS-RGO-NiNPs-modified SPE sensor exhibited outstanding performance for enzymeless glucose (Glc) sensing in alkaline media with high sensitivity (318.4uAmM(-1)cm(-2)), wide linear range (up to 9mM), low detection limit (4.1uM), acceptable selectivity against common interferents in physiological fluids, and excellent stability. A microfluidic device was fabricated incorporating the SPE sensor for real-time Glc detection in human urine samples; the results obtained were comparable to those obtained using a high-performance liquid chromatography (HPLC) coupled with an electrochemical detector. The excellent sensing performance, operational characteristics, ease of fabrication, and low cost bode well for this electrochemical microfluidic device to be developed as a point-of-care healthcare monitoring unit. PMID- 23644060 TI - Colorimetric surface plasmon resonance imaging (SPRI) biosensor array based on polarization orientation. AB - A colorimetric surface plasmon resonance (SPR) imaging biosensor array based on polarization orientation rotation is presented in this paper. It measures the spectral characteristic variations caused by the steep phase difference between the p- and s-polarization occurring at surface plasmon excitation. It provides one-order of magnitude sensor resolution improvement comparing to existing phase sensitive SPR imaging sensors and the two-dimensional (2D) sensing capability of the imaging sensor enables multiplex, high throughput array based simultaneous detection for a range of different bio-molecular interactions. Experiments on the binding interactions detection between anti-bovine serum albumin (anti-BSA) and BSA antigen have been performed. All binding interactions occurred at 5*4 protein array were real-time monitored simultaneously. A sensor resolution of 8.26ng/ml (125pM) has been demonstrated, which is one-order of magnitude (12 times) better than the detection limit reported by existing phase-sensitive SPR imaging sensors in the literature, while no time-consuming phase modulation and phase extraction processes are required. Furthermore, the optical colorimetric image read-out of the sensor is easy to be identified by the end users comparing to conventional intensity or phase information. The colorimetric SPR imaging biosensor array can find promising potential applications in high throughput clinical disease diagnosis, protein biomarkers screening and drug screening. PMID- 23644059 TI - Miniaturized flow system based on enzyme modified PMMA microreactor for amperometric determination of glucose. AB - This paper describes the development of a microfluidic system having as main component an enzymatic reactor constituted by a microchannel assembled in poly(methyl methacrylate) (PMMA) substrate connected to an amperometric detector. A CO2 laser engraving machine was used to make the channels, which in sequence were thermally sealed. The internal surfaces of the microchannels were chemically modified with polyethyleneimine (PEI), which showed good effectiveness for the immobilization of the glucose oxidase enzyme using glutaraldehyde as crosslinking agent, producing a very effective microreactor for the detection of glucose. The hydrogen peroxide generated by the enzymatic reaction was detected in an electrochemical flow cell localized outside of the reactor using a platinum disk as the working electrode. The proposed system was applied to the differential amperometric determination of glucose content in soft drinks showing good repeatability (DPR=1.72%, n=50), low detection limit (1.40*10(-6)molL(-1)), high sampling frequency (calculated as 345 samples h(-1)), and relatively good stability for long-term use. The results were in close agreement with those obtained by the classical spectrophotometric method utilized to quantify glucose in biological fluids. PMID- 23644061 TI - Electrochemical cholesterol sensor based on carbon nanotube@molecularly imprinted polymer modified ceramic carbon electrode. AB - A monolithic molecular imprinting sensor based on ceramic carbon electrode (CCE) has been reported. The sensor can be renewed simply by smoothing. It was fabricated by thoroughly mixing multiwalled carbon nanotube@molecularly imprinted polymer (MWCNT@MIP), graphite powder, and silicon alkoxide, and then packing the resulting complex mixture of components firmly into the electrode cavity of a Teflon sleeve. The incorporated MWCNT@MIP in CCEs functioned as a recognition element for cholesterol determination. The MWCNT@MIP-CCEs were tested in the presence or absence of cholesterol by cyclic voltammetry and linear sweep voltammetry. The cholesterol sensor has excellent sensitivity with a linear range of 10-300nM and a detection limit of 1nM (S/N=3). The monolithic molecular imprinting sensor exhibits good stability, high sensitivity, and user-friendly reusability for cholesterol determination. This study shows that CCE is a promising matrix for MIP sensors. PMID- 23644052 TI - Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. AB - Mounting evidence indicates that inflammatory cytokines contribute to the development of depression in both medically ill and medically healthy individuals. Cytokines are important for development and normal brain function, and have the ability to influence neurocircuitry and neurotransmitter systems to produce behavioral alterations. Acutely, inflammatory cytokine administration or activation of the innate immune system produces adaptive behavioral responses that promote conservation of energy to combat infection or recovery from injury. However, chronic exposure to elevated inflammatory cytokines and persistent alterations in neurotransmitter systems can lead to neuropsychiatric disorders and depression. Mechanisms of cytokine behavioral effects involve activation of inflammatory signaling pathways in the brain that results in changes in monoamine, glutamate, and neuropeptide systems, and decreases in growth factors, such as brain-derived neurotrophic factor. Furthermore, inflammatory cytokines may serve as mediators of both environmental (e.g. childhood trauma, obesity, stress, and poor sleep) and genetic (functional gene polymorphisms) factors that contribute to depression's development. This review explores the idea that specific gene polymorphisms and neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensions of cytokine-related depression. Additionally, potential therapeutic strategies that target inflammatory cytokine signaling or the consequences of cytokines on neurotransmitter systems in the brain to prevent or reverse cytokine effects on behavior are discussed. PMID- 23644062 TI - Mouse limbs expressing only the Gli3 repressor resemble those of Sonic hedgehog mutants. AB - Anterioposterior vertebrate limb patterning is controlled by opposing action between Sonic Hedgehog (Shh) and the Gli3 transcriptional repressor. Unexpectedly, Gli3(Delta699) mutant mice, which are thought to express only a Gli3 repressor and not the full-length activator, exhibit limb phenotypes inconsistent with those of Shh mutant mice. Therefore, it remains debatable whether Shh patterns the anterioposterior limb primarily by inhibiting generation of the Gli3 repressor. However, one caveat is that Gli3(Delta699) may not be as potent as the natural form of Gli3 repressor because of the nature of the mutant allele. In the present study, we created a conditional Gli3 mutant allele that exclusively expresses Gli3 repressor in the presence of Cre recombinase. Using this mutant, we show that the phenotypes of mouse limbs expressing only the Gli3 repressor exhibit no or single digit, resembling those of Shh mutant limbs. Consistent with the limb phenotypes, the expression of genes dependent on Shh signaling is also inhibited in both mutants. This inhibition by the Gli3 repressor is independent of Shh. Thus, our study clarifies the current controversy and provides important genetic evidence to support the hypothesis that Shh patterns the anterioposterior limb primarily through the inhibition of Gli3 repressor formation. PMID- 23644063 TI - The role of SOX10 during enteric nervous system development. AB - The SOX10 transcription factor is a characteristic marker for migratory multipotent neural crest (NC) progenitors as well as several of their differentiated derivatives. The involvement of SOX10 in Waardenburg-Hirschsprung disease (pigmentation defects, deafness and intestinal aganglionosis) and studies of mutant animal models have contributed significantly to the understanding of its function in neural crest cells (NCC) in general and in the melanocytes and enteric nervous system (ENS) in particular. Cell-based studies have further demonstrated the important roles of this transcription factor in maintaining the NC progenitor cell number and in determining glial cell fate. Phenotypic variability observed among patients presenting with SOX10 mutations is in agreement with molecular genetics and animal model studies, which revealed that SOX10 cooperates with different partner factors; a number of genetic modifiers of SOX10 have been identified. This study reviews the expression, regulation, and function of SOX10 in normal development of the ENS and in disease conditions, as well as the genetic and molecular interactions of SOX10 with other ENS genes/factors. We also discuss future research areas. Further understanding of SOX10 function will benefit from genomic and cell biological studies that integrate the cell-intrinsic molecular mechanisms and the interactions of the enteric NCC with the niche environment. PMID- 23644064 TI - Biomass proximate analysis using thermogravimetry. AB - This work proposes a 25 min-last thermogravimetric method as a tool to determine biomass sample's proximate analysis data (moisture, ash, volatile matter and fixed carbon contents) just by direct measure of weight changes on each sample's TG chart. Compared with international standards commonly used to that aim, TG is a faster and easier to develop technique. Obtained results were satisfactory, with AEE under 6% for moisture and volatile matter, close to 10% for fixed carbon determination and AAD of 1.6 points for ash content. PMID- 23644065 TI - Production of polyols via direct hydrolysis of kraft lignin: effect of process parameters. AB - Kraft lignin (KL) was successfully depolymerized into polyols of moderately high hydroxyl number and yield with moderately low weight-average molecular weight (Mw) via direct hydrolysis using NaOH as a catalyst, without any organic solvent/capping agent. The effects of process parameters including reaction temperature, reaction time, NaOH/lignin ratio (w/w) and substrate concentration were investigated and the polyols/depolymerized lignins (DLs) obtained were characterized with GPC-UV, FTIR-ATR, (1)H NMR, Elemental & TOC analyzer. The best operating conditions appeared to be at 250 degrees C, 1h, and NaOH/lignin ratio ~0.28 with 20 wt.% substrate concentration, leading to <0.5% solid residues and ~92% yield of DL (aliphatic-hydroxyl number ~352 mg KOH/mg and Mw~3310 g/mole), suitable for replacement of polyols in polyurethane foam synthesis. The overall % carbon recovery under the above best conditions was ~90%. A higher temperature favored reduced Mw of the polyols while a longer reaction time promoted dehydration/condensation reactions. PMID- 23644066 TI - Engineered Enterobacter aerogenes for efficient utilization of sugarcane molasses in 2,3-butanediol production. AB - Sugarcane molasses is considered to be a good carbon source for biorefinery due to its high sugar content and low price. Sucrose occupies more than half of the sugar in the molasses. Enterobacter aerogenes is a good host strain for 2,3 butanediol production, but its utilization of sucrose is not very efficient. To improve sucrose utilization in E. aerogenes, a sucrose regulator (ScrR) was disrupted from the genomic DNA. The deletion mutation increased the sucrose consumption rate significantly when sucrose or sugarcane molasses was used as a carbon source. The 2,3-butanediol production from sugarcane molasses by the mutant was enhanced by 60% in batch fermentation compared to that by the wild type strain. In fed-batch fermentation, 98.69 g/L of 2,3-butanediol production was achieved at 36 h. PMID- 23644067 TI - Characterization of bacterial consortium and its application in an ectopic fermentation system. AB - This study aimed to develop an ectopic fermentation system (EFS) to reduce the pollution of cow wastewater and to provide a basis for the production of biofertilizer with fermentation residues. Six thermophilic strains, three of which have efficient cellulose-degrading abilities and the other have good ammonia-N utilizing abilities, were chosen as the microbial inocula. The results showed that EFS inoculated with microbial consortium brought higher temperature and more wastewater was needed to ensure continuous fermentation. The pH values decreased in the early stage of fermentation, and then increased during the process. It caused increases in total Kjeldahl nitrogen, total phosphorous, and total potassium content. Decreases in organic matter content and C/N ratio were also observed. The high level of nutrients indicated the suitability of the paddings after fermentation for agronomic uses. It firstly attempted to combine cow wastewater treatment and bio-organic fertilizer production by EFS with mixed microbial culture. PMID- 23644068 TI - Effect of filter media size, mass flow rate and filtration stage number in a moving-bed granular filter on the yield and properties of bio-oil from fast pyrolysis of biomass. AB - Fast pyrolysis of cassava rhizome was performed in a bench-scale fluidised-bed reactor unit incorporated with a cross-flow moving-bed granular filter. The objective of this research was to examine several process parameters including the granular size (425-1160 MUm) and mass flow rate (0-12 g/min) as well as the number of the filtration stages (1-2 stages) on yields and properties of bio-oil. The results showed that the bio-oil yield decreased from 57.7 wt.% to 42.0-49.2 wt.% when increasing the filter media size, the mass flow rate and the filtration stage number. The effect of the process parameters on various properties of bio oil is thoroughly discussed. In general, the bio-oil quality in terms of the solids content, ash content, initial viscosity, viscosity change and ageing rate could be enhanced by the hot vapour granular filtration. Therefore, bio-oil of high stability could be produced by the pyrolysis reactor configuration designed in this work. PMID- 23644069 TI - The effect of a buffer function on the semi-continuous anaerobic digestion. AB - The characteristics of the long term (90 d) anaerobic semi-continuous digestion of food wastes/animal slurry wastewater with different C/N ratio were investigated. The research demonstrates that, in the semi-continuous digestion process, different C/N ratios of substrate led to a significant effect to the characteristic of anaerobic digestion (AD). It is undoubtedly that the semi continuous AD is efficient within a wide range of C/N ratios, and the lower C/N substrate promoted the activity of the methanogen in a long time, which maintained a stable high CH4 concentration and total organic carbon (TOC) utilization. During the whole AD process, an active buffer system was formed from NH4(+) and VFAs (by-products of TOC): this buffer system provided high concentrations of VFAs, thus increasing both the CH4 yield and TOC utilization; and also maintained a high tolerance to NH4(+) and VFAs in the system, which defusing the impact of NH4(+). PMID- 23644071 TI - Manufacture of dissolving pulps from cornstalk by novel method coupling steam explosion and mechanical carding fractionation. AB - In order to solve the inhomogeneity of cornstalk as fiber material to manufacture dissolving pulp, a novel method of steam explosion coupling mechanical carding was put forward to fractionate cornstalk long fiber for the production of cornstalk dissolving pulp. The fractionated long fiber had homogeneous structure and low hemicellulose and ash content. The fiber cell content was up to 85% in area, and the hemicellulose and ash content was 8.34% and 1.10% respectively. The alpha-cellulose content of cornstalk dissolving pulps was up to 93.10-97.10%, the viscosity was 14.37-23.96 mPas, and the yields of cornstalk dissolving pulps were from 10.11% to 12.44%. In addition, the fractionated short fiber was to be hydrolyzed by enzyme to build sugar platform. The constructed method of steam explosion coupling mechanical carding achieved the fractionation of cornstalk into long fiber and short fiber cleanly and effectively, and provided a new way for cornstalk integrated refinery. PMID- 23644070 TI - Carbon and nutrient removal from centrates and domestic wastewater using algal bacterial biofilm bioreactors. AB - The mechanisms of carbon and nutrient removal in an open algal-bacterial biofilm reactor and an open bacterial biofilm reactor were comparatively evaluated during the treatment of centrates and domestic wastewater. Comparable carbon removals (>80%) were recorded in both bioreactors, despite the algal-bacterial biofilm supported twice higher nutrient removals than the bacterial biofilm. The main carbon and nitrogen removal mechanisms in the algal-bacterial photobioreactor were assimilation into algal biomass and stripping, while stripping accounted for most carbon and nitrogen removal in the bacterial biofilm. Phosphorus was removed by assimilation into algal-bacterial biomass while no effective phosphorous removal was observed in the bacterial biofilm. Carbon, nitrogen and phosphorus removals of 91 +/- 3%, 70 +/- 8% and 85 +/- 9%, respectively, were recorded in the algal-bacterial bioreactor at 10d of hydraulic retention time when treating domestic wastewater. However, the high water footprint recorded (0.5-6.7 Lm(-2)d( 1)) could eventually compromise the environmental sustainability of this microalgae-based technology. PMID- 23644072 TI - Thermogravimetric and decomposition kinetic studies of Mesua ferrea L. deoiled cake. AB - The present study aims to explore the physico-chemical properties of Mesua ferrea L. (Iron wood tree) deoiled cake (MFDC) and decomposition parameters for thermochemical methods of conversion. The physico-chemical characteristics of MFDC were investigated by bomb calorimetry, TG/DTA (10, 20 and 40 degrees C min( 1)), elemental analysis (CHN) and FTIR spectroscopy. The proximate composition was calculated using standard ASTM methodology. The temperature profile, activation energy (E), pre-exponential factor (A) and reaction order (n) for the active pyrolysis zone of the species under investigation have been provided for the respective heating rates using Arrhenius, Coats-Redfern, Flynn-Wall-Ozawa (FWO) and Global independent reactions model. The current investigation suggests that within the realm of existing biomass conversion technologies, MFDC can be used as a feedstock for thermochemical conversion. PMID- 23644074 TI - Biodegradation of tetrahydrofuran by Pseudomonas oleovorans DT4 immobilized in calcium alginate beads impregnated with activated carbon fiber: mass transfer effect and continuous treatment. AB - A novel entrapment matrix, calcium alginate (CA) coupled with activated carbon fiber (ACF), was prepared to immobilize Pseudomonas oleovorans DT4 for degrading tetrahydrofuran (THF). The addition of 1.5% ACF increased the adsorption capacity of the immobilized bead, thus resulting in an enhanced average removal rate of 30.3mg/(Lh). The synergism between adsorption and biodegradation was observed in the hybrid CA-ACF beads instead of in the system comprising CA beads and freely suspended ACF. The effective diffusion coefficient of the CA-ACF bead was not significantly affected by bead size, but the bead's value of 1.14*10(-6)cm(2)/s (for the bead diameter of 0.4 cm) was larger than that of the CA bead by almost one order of magnitude based on the intraparticle diffusion-reaction kinetics analysis. Continuous treatment of the THF-containing wastewater was succeeded by CA-ACF immobilized cells in a packed-bed reactor for 54 d with a >90% removal efficiency. PMID- 23644073 TI - Heterotrophic nitrification and aerobic denitrification at low temperature by a newly isolated bacterium, Acinetobacter sp. HA2. AB - A psychrotrophic heterotrophic nitrifying-aerobic denitrifying bacterium was newly isolated and identified as Acinetobacter sp. with phenotypic and phylogenetic analysis. The strain possessed excellent tolerance to low temperature with 20 degrees C as its optimum and 4 degrees C as viable. Moreover, ammonium, nitrite and nitrate could be removed efficiently under low-temperature, solely aerobic conditions with little accumulation of intermediates. The average removal rate at 10 degrees C reached as high as 3.03, 2.51 and 1.88 mg NL(-1)h( 1) for ammonium, nitrite and nitrate respectively. N2 was produced through heterotrophic nitrification and aerobic denitrification via nitrite but N2O was never detected in the whole process. Nitrogen balance analysis indicated that N2 and intracellular nitrogen were two major fates of the initial ammonium, accounting for 32.4 and 49.2%, respectively. Further aerated batch test demonstrated efficient removal of COD and TN from synthetic wastewater, which implied promising practical application of the present strain. PMID- 23644075 TI - Evaluation of immunogenicity and protective efficacy of orally delivered Shigella type III secretion system proteins IpaB and IpaD. AB - Shigella spp. are food- and water-borne pathogens that cause shigellosis, a severe diarrheal and dysenteric disease that is associated with a high morbidity and mortality in resource-poor countries. No licensed vaccine is available to prevent shigellosis. We have recently demonstrated that Shigella invasion plasmid antigens (Ipas), IpaB and IpaD, which are components of the bacterial type III secretion system (TTSS), can prevent infection in a mouse model of intranasal immunization and lethal pulmonary challenge. Because they are conserved across Shigella spp. and highly immunogenic, these proteins are excellent candidates for a cross-protective vaccine. Ideally, such a vaccine could be administered to humans orally to induce mucosal and systemic immunity. In this study, we investigated the immunogenicity and protective efficacy of Shigella IpaB and IpaD administered orally with a double mutant of the Escherichia coli heat labile toxin (dmLT) as a mucosal adjuvant. We characterized the immune responses induced by oral vs. intranasal immunization and the protective efficacy using a mouse pulmonary infection model. Serum IgG and fecal IgA against IpaB were induced after oral immunization. These responses, however, were lower than those obtained after intranasal immunization despite a 100-fold dosage increase. The level of protection induced by oral immunization with IpaB and IpaD was 40%, while intranasal immunization resulted in 90% protective efficacy. IpaB- and IpaD specific IgA antibody-secreting cells in the lungs and spleen and T-cell-derived IL-2, IL-5, IL-17 and IL-10 were associated with protection. These results demonstrate the immunogenicity of orally administered IpaB and IpaD and support further studies in humans. PMID- 23644077 TI - Outcomes of adults with acute lymphoblastic leukemia relapsing after allogeneic hematopoietic stem cell transplantation. AB - For patients with acute lymphoblastic leukemia (ALL) who relapse after allogeneic hematopoietic stem cell transplantation (HSCT), treatment options are limited, and the clinical course and prognostic factors affecting outcome have not been well characterized. We retrospectively analyzed outcomes of 123 adult patients with ALL who relapsed after a first HSCT performed at our center between 1993 and 2011. First-line salvage included second HSCT (n = 19), donor lymphocyte infusion with or without prior chemotherapy (n = 11), radiation therapy (n = 6), cytoreductive chemotherapy (n = 30), mild chemotherapy (n = 27), or palliative care (n = 23), with median postrelapse overall survival (OS) of 10 months, 6.5 months, 3 months, 4 months, 4 months, and 1 month, respectively. Despite a complete remission rate of 38% after first-line salvage in the treated patients, the OS rate remained limited with 1- and 2- year OS rates of 17% (95% confidence interval, 13 to 29) and 10% (95% confidence interval, 6 to 20), respectively. On univariate analysis, adverse factors for OS included active disease at the time of first HSCT and short time to progression from first HSCT (<6 months). There was no difference in the 6-month survival postrelapse in patients with isolated extramedullary relapse (44%) compared with combined extramedullary and bone marrow relapse (29%) or those with isolated bone marrow relapse (34%) (P = .8). Our data provide more insight into the disease behavior and treatment outcomes of ALL at relapse after HSCT against which future trials may be compared. PMID- 23644078 TI - Report from the multinational irritable bowel syndrome initiative 2012. AB - In 2012, a group of 29 internationally recognized experts in the pathophysiology, diagnosis, and treatment of irritable bowel syndrome (IBS) convened to audit the current state of IBS research. The meeting was preceded by a comprehensive online survey that focused on research needs for IBS diagnosis (particularly the strengths and shortcomings of current criteria), definitions used in clinical trials for IBS patients and "healthy controls," potential biomarkers for IBS, and outcome measures in drug trials. While the purpose of the meeting was not to make binding recommendations, participants developed a framework for future questions and research needs in IBS. First, participants indicated the need for revised criteria for the diagnosis of IBS; in particular, inclusion of bloating and de emphasis of pain as criteria were considered critical needs. Second, participants noted that definitions of normal, healthy controls varied widely among clinical trials; these definitions need to be standardized not only to improve the reliability of results, but also to better facilitate inter-trial comparisons and data synthesis. Third, participants highlighted the need for accurate biomarkers of disease. Fourth and finally, participants noted that further defining outcome measures, so that they are functionally relevant and reflect normalization of bowel function, is a critical need. Together, the discussions held at this workshop form a framework to address future research in IBS. PMID- 23644080 TI - Patent foramen ovale science: keeping the horse in front of the cart. PMID- 23644079 TI - Early administration of azathioprine vs conventional management of Crohn's Disease: a randomized controlled trial. AB - BACKGROUND & AIMS: Immunomodulator therapy is effective for patients with Crohn's disease (CD) but has not been shown to affect disease progression, presumably because it is given too late after diagnosis. We compared the efficacy of early treatment (within 6 months after diagnosis) with azathioprine versus conventional management of patients at high risk for disabling disease. METHODS: We performed an open-label trial of adults with a diagnosis of CD for less than 6 months who were at risk for disabling disease. From July 2005 to November 2010, patients at 24 French centers were randomly assigned to treatment with azathioprine (2.5 mg ? kg(-1) ? day(-1), n = 65) or conventional management (azathioprine only in cases of corticosteroid dependency, chronic active disease with frequent flares, poor response to corticosteroids, or development of severe perianal disease) (n = 67). The primary end point was the proportion of trimesters spent in corticosteroid free and anti-tumor necrosis factor (TNF)-free remission during the first 3 years after inclusion. RESULTS: During the 3-year follow-up period, 16 patients in the azathioprine group were switched to mercaptopurine or methotrexate therapy because of intolerance or poor efficacy. Forty-one patients in the conventional management group required immunosuppressant therapy (61%; median time to first prescription, 11 months). In the azathioprine group, a median 67% of trimesters were spent in remission (interquartile range, 11%-85%) compared with 56% in the conventional management group (interquartile range, 29%-73%) (P = .69). Among secondary outcomes, a higher cumulative proportion of patients in the azathioprine group were free of perianal surgery than in the conventional management group (96% +/- 3% and 82% +/- 6% at month 36, respectively; P = .036). The cumulative proportion of patients free of intestinal surgery and anti-TNF therapy did not differ between groups. CONCLUSIONS: Based on results from a clinical trial, administration of azathioprine within 6 months of diagnosis of CD was no more effective than conventional management in increasing time of clinical remission. Clinicaltrials.gov, Number NCT00546546. PMID- 23644076 TI - Microglia during development and aging. AB - Microglia are critical nervous system-specific cells influencing brain development, maintenance of the neural environment, response to injury, and repair. They contribute to neuronal proliferation and differentiation, pruning of dying neurons, synaptic remodeling and clearance of debris and aberrant proteins. Colonization of the brain occurs during gestation with an expansion following birth with localization stimulated by programmed neuronal death, synaptic pruning, and axonal degeneration. Changes in microglia phenotype relate to cellular processes including specific neurotransmitter, pattern recognition, or immune-related receptor activation. Upon activation, microglia cells have the capacity to release a number of substances, e.g., cytokines, chemokines, nitric oxide, and reactive oxygen species, which could be detrimental or beneficial to the surrounding cells. With aging, microglia shift their morphology and may display diminished capacity for normal functions related to migration, clearance, and the ability to shift from a pro-inflammatory to an anti-inflammatory state to regulate injury and repair. This shift in microglia potentially contributes to increased susceptibility and neurodegeneration as a function of age. In the current review, information is provided on the colonization of the brain by microglia, the expression of various pattern recognition receptors to regulate migration and phagocytosis, and the shift in related functions that occur in normal aging. PMID- 23644081 TI - Evaluation and management of paravalvular aortic regurgitation after transcatheter aortic valve replacement. AB - Paravalvular aortic regurgitation (PAR) negatively affects the prognosis after transcatheter aortic valve replacement (TAVR) with dramatically increased morbidity and mortality in patients with more than mild PAR. Because transcatheter heart valves are implanted in a sutureless fashion using oversizing to anchor the prosthesis stent frame at the level of the virtual aortic annulus, stent frame underexpansion due to heavily calcified cusps, suboptimal placement of the prosthesis, and/or annulus-prosthesis-size mismatch due to malsizing can contribute to paravalvular leakage. In contrast to open heart surgery, TAVR does not offer the opportunity to measure the aortic annulus under direct vision during the procedure. Therefore, the dilemma before each TAVR procedure is the appropriate sizing of the dimensions of the aortic annulus and to choose not only the size but also the transcatheter heart valve type (self-expanding vs. balloon expandable) that fits the given anatomy best. Because precise echocardiographic quantification of PAR in patients with TAVR remains challenging especially in the acute implantation situation, a multimodal approach for the evaluation of PAR with the use of hemodynamic measurements and imaging modalities is imperative to precisely quantify the severity of aortic regurgitation immediately after valve implantation and to identify patients who will benefit from corrective measures such as post-dilation or valve-in-valve implantation. Every measure has to be taken to prevent or reduce PAR to provide a satisfying long-term clinical outcome. PMID- 23644082 TI - The STS-ACC transcatheter valve therapy national registry: a new partnership and infrastructure for the introduction and surveillance of medical devices and therapies. AB - The Society of Thoracic Surgeons (STS) and American College of Cardiology (ACC) transcatheter valve therapy (TVT) registry is a novel, national registry for all new TVT devices created through a partnership of the STS and the ACC in close collaboration with the Food and Drug Administration, the Center for Medicare and Medicaid Services, and the Duke Clinical Research Institute. The registry will serve as an objective, comprehensive, and scientifically based resource to improve the quality of patient care, to monitor the safety and effectiveness of TVT devices, to serve as an analytic resource for TVT research, and to enhance communication among key stakeholders. PMID- 23644083 TI - Sex differences in hospital mortality in adults with congenital heart disease: the impact of reproductive health. AB - OBJECTIVES: The study objectives were to analyze sex differences in hospital mortality of adult patients with congenital heart disease (CHD) and to determine the impact of health services associated with pregnancy on outcomes in women. BACKGROUND: The determinants of sex differences in the demographic distribution of CHD are poorly understood. METHODS: The Quebec CHD database and the Dutch CONCOR (CONgenital CORvitia) registry were used to identify patients with CHD aged 18 to 65 years who were hospitalized between 1996 and 2005. Regression analyses were used to compare 30-day in-hospital mortality in men versus women and in women aged 18 to 45 years with versus without a pregnancy history, after adjustment for age, CHD severity, comorbidities, and admission diagnosis. RESULTS: Of 39,776 patients followed for 259,741 patient years, 19,099 patients (48%) had 54,195 admissions (62% among women). In those aged 18 to 45 years, 30 day in-hospital mortality was higher in men compared with women with nonpregnancy admissions (adjusted rate ratio: 1.36; 95% confidence interval: 1.02 to 1.81). The adjusted rate ratio for 30-day in-hospital mortality in women with a pregnancy history compared with those without was 0.49 (95% confidence interval: 0.24 to 0.99). A history of pregnancy was not associated with an overall increase in medical encounters. CONCLUSIONS: We demonstrated a protective effect of sex on in-hospital mortality in women with CHD of reproductive age that did not correlate with increased medical surveillance. Future studies need to explore other mechanisms to account for our observations. Understanding the determinants of the sex distribution of adults with CHD is important for our ability to predict demographic changes in the population with CHD. PMID- 23644084 TI - Patent foramen ovale, subclinical cerebrovascular disease, and ischemic stroke in a population-based cohort. AB - OBJECTIVES: The purpose of this study was to evaluate the relationship between patent foramen ovale (PFO), ischemic stroke, and subclinical cerebrovascular disease in the general population. BACKGROUND: PFO is found more frequently in stroke patients than in stroke-free controls. However, the PFO-related stroke risk in the general population is not well established, and the relationship between PFO and silent brain infarcts (SBI) is not known. METHODS: PFO presence was assessed by transthoracic echocardiography with saline contrast injection in 1,100 stroke-free individuals over age 39 of a community-based sample followed for a mean of 11 years. In addition, 360 participants underwent brain magnetic resonance imaging (MRI) for SBI detection. We evaluated the risk of stroke associated with PFO after adjusting for established stroke risk factors and examined the odds of having SBI among those with and without PFO. RESULTS: PFO was present in 164 participants (14.9%). Over a mean follow-up of 11.0 +/- 4.5 years, 111 ischemic strokes occurred (10.1%), 15 (9.2%) in the PFO+ and 96 (10.3%) in the PFO- groups. The 12.5-year cumulative risk of stroke was 10.1% (standard error: 2.5%) in the PFO+ and 10.4% (standard error: 1.1%) in the PFO- group (p = 0.46). The adjusted hazard ratio for PFO and stroke was 1.10 (95% confidence interval [CI]: 0.64 to 1.91). In the MRI subcohort, PFO was not associated with SBI (adjusted odds ratio: 1.15, 95% CI: 0.50 to 2.62). CONCLUSIONS: In this community-based cohort, PFO was not associated with an increased risk of clinical stroke or subclinical cerebrovascular disease. PMID- 23644085 TI - Coronary microvascular dysfunction and diastolic load correlate with cardiac troponin T release measured by a highly sensitive assay in patients with nonischemic heart failure. AB - OBJECTIVES: This study investigated factors associated with cardiac troponin T (cTnT) release from failing myocardium. BACKGROUND: Persistent and modest elevation of serum cTnT is frequently observed in heart failure (HF) patients free of coronary artery disease, although the mechanisms underlying this finding remain unclear. METHODS: We evaluated serum cTnT levels in the aortic root (Ao) and coronary sinus (CS) using a highly sensitive assay in 90 nonischemic HF patients and 47 non-HF patients. Transcardiac cTnT and plasma B-type natriuretic peptide (BNP) release were described as the differences between CS and Ao cTnT levels [DeltacTnT (CS-Ao)] and BNP levels [DeltaBNP (CS-Ao)], respectively. Coronary flow reserve (CFR) was measured in 68 HF patients using an intracoronary Doppler guidewire. RESULTS: DeltacTnT (CS-Ao) levels were available in 76 HF patients and 28 non-HF patients (84% vs. 60%; p = 0.001), and higher in HF patients than non-HF patients (p < 0.001). Among HF patients, log[DeltacTnT (CS Ao)] correlated with log[DeltaBNP (CS-Ao)] (r = 0.368, p = 0.001), pulmonary capillary wedge pressure (r = 0.253, p = 0.03) and left ventricular end-diastolic pressure (LVEDP) (r = 0.321, p = 0.005). Multivariate regression analysis identified LVEDP as an independent parameter that correlated with DeltacTnT (CS Ao). DeltacTnT (CS-Ao) levels were available in 58 HF patients who were evaluated for CFR. Coronary microvascular dysfunction, diagnosed by CFR <2.0, was observed in 18 HF patients. DeltacTnT (CS-Ao) was higher in patients with coronary microvascular dysfunction (4.8 [2.0 to 8.1] ng/l) than those without (2.0 [1.2 to 4.6] ng/l; p = 0.04). CONCLUSIONS: cTnT release from failing myocardium correlated with diastolic load and coronary microvascular dysfunction in nonischemic HF patients. PMID- 23644086 TI - Mitochondrial dysfunction as an arrhythmogenic substrate: a translational proof of-concept study in patients with metabolic syndrome in whom post-operative atrial fibrillation develops. AB - OBJECTIVES: This study sought to provide bedside evidence of the potential link between cardiac mitochondrial dysfunction and arrhythmia as reported in bench studies. BACKGROUND: Atrial fibrillation (AF) is a frequent complication of cardiac surgery. Underlying mechanisms of post-operative atrial fibrillation (POAF) remain largely unknown. Because cardiac mitochondrial dysfunction has been reported in clinical conditions with a high risk of POAF, we investigated whether a causal link exists between POAF onset and pre-operative function of cardiac mitochondria. METHODS: Pre-operative mitochondrial respiration and calcium retention capacity, respiratory complex activity, and myocardial oxidative stress were quantified in right atrial tissue from 104 consecutive patients with metabolic syndrome, in sinus rhythm, and undergoing coronary artery bypass graft surgery. RESULTS: In this high-risk population, POAF occurred in 44% of patients. Decreased pre-operative mitochondrial respiration and increased sensitivity to calcium-induced mitochondrial permeability transition pore opening were significantly associated with POAF. Adenosine diphosphate-stimulated mitochondrial respiration supported by palmitoyl-l-carnitine was significantly lower in POAF patients and remained independently associated with AF onset after adjustment for age, body mass index, heart rate, beta-blocker use, and statin medication (multivariate logistic regression coefficient per unit = -0.314 +/- 0.144; p = 0.028). Gene expression profile analysis identified a general downregulation of the mitochondria/oxidative phosphorylation gene cluster in pre operative atrial tissue of patients in whom AF developed. CONCLUSIONS: Our prospective study identifies an association between pre-operative mitochondrial dysfunction of the atrial myocardium and AF occurrence after cardiac surgery in patients with metabolic disease, providing novel insights into the link between mitochondria and arrhythmias in patients. PMID- 23644087 TI - Are post-operative arrhythmias in patients with metabolic syndrome a sign of dysfunctional mitochondria? PMID- 23644088 TI - Long-term results after simple versus complex stenting of coronary artery bifurcation lesions: Nordic Bifurcation Study 5-year follow-up results. AB - OBJECTIVES: This study sought to report the 5-year follow-up results of the Nordic Bifurcation Study. BACKGROUND: Randomized clinical trials with short-term follow-up have indicated that coronary bifurcation lesions may be optimally treated using the optional side branch stenting strategy. METHODS: A total of 413 patients with a coronary bifurcation lesion were randomly assigned to a simple stenting strategy of main vessel (MV) and optional stenting of side branch (SB) or to a complex stenting strategy, namely, stenting of both MV and SB. RESULTS: Five-year clinical follow-up data were available for 404 (98%) patients. The combined safety and efficacy endpoint of cardiac death, non-procedure-related myocardial infarction, and target vessel revascularization were seen in 15.8% in the optional SB stenting group as compared to 21.8% in the MV and SB stenting group (p = 0.15). All-cause death was seen in 5.9% versus 10.4% (p = 0.16) and non-procedure-related myocardial infarction in 4% versus 7.9% (p = 0.09) in the optional SB stenting group versus the MV and SB stenting group, respectively. The rates of target vessel revascularization were 13.4% versus 18.3% (p = 0.14) and the rates of definite stent thrombosis were 3% versus 1.5% (p = 0.31) in the optional SB stenting group versus the MV and SB stenting group, respectively. CONCLUSIONS: At 5-year follow-up in the Nordic Bifurcation Study, the clinical outcomes after simple optional side branch stenting remained at least equal to the more complex strategy of planned stenting of both the main vessel and the side branch. PMID- 23644089 TI - Severe aortic stenosis and coronary artery disease--implications for management in the transcatheter aortic valve replacement era: a comprehensive review. AB - Management of coronary artery disease (CAD) in patients with severe aortic stenosis (AS) referred for transcatheter aortic valve replacement (TAVR) is posing challenges. Due to limited and heterogeneous data on the prevalence and clinical impact of CAD on the outcomes of TAVR and the management strategies for CAD in patients undergoing TAVR, we performed a comprehensive review of the literature. Significant CAD is present in 40% to 75% of patients undergoing TAVR. The impact of CAD on outcomes after TAVR remains understudied. Based on existing data, not all patients require revascularization before TAVR. Percutaneous coronary intervention (PCI) should be considered for severely stenotic lesions in proximal coronaries that subtend a large area of myocardium at risk. Ongoing studies randomizing patients to surgical or percutaneous management strategies for severe AS will help provide valuable data regarding the impact of CAD on TAVR outcomes, the role of PCI, and its timing in relation to TAVR. PMID- 23644090 TI - Changes in plaque lipid content after short-term intensive versus standard statin therapy: the YELLOW trial (reduction in yellow plaque by aggressive lipid lowering therapy). AB - OBJECTIVES: This study sought to determine the impact of short-term intensive statin therapy on intracoronary plaque lipid content. BACKGROUND: Statin therapy significantly reduces the risk for thrombotic events. Whether or not these benefits are attributable to reduction in plaque lipid content remains to be properly documented in human obstructive coronary artery disease (CAD). METHODS: We randomized 87 patients with multivessel CAD undergoing percutaneous coronary intervention and at least 1 other severely obstructive (fractional flow reserve [FFR] <=0.8) nontarget lesion (NTL) to intensive (rosuvastatin 40 mg daily) or standard-of-care lipid-lowering therapy. NTLs were evaluated at baseline and after 7 weeks of therapy with FFR, near-infrared spectroscopy, and intravascular ultrasound. The primary endpoint was the change in lipid-core burden index at the 4-mm maximal segment (LCBI4mm max), wherever this occurred within the lesion. RESULTS: Upon follow-up, median reduction (95% confidence interval) in LCBI4mm max was significantly greater in the intensive versus standard group (-149.1 [ 210.9 to -42.9] vs. 2.4 [-36.1 to 44.7]; p = 0.01). Results remained consistent after adjustment for baseline differences in LCBI between groups and use of change in LCBI across the entire lesion as the dependent outcome. CONCLUSIONS: Short-term intensive statin therapy may reduce lipid content in obstructive lesions. These hypothesis-generating findings warrant confirmation in larger studies with longer follow-up. (Reduction in YEllow Plaque by Aggressive Lipid LOWering Therapy [YELLOW]); NCT01567826). PMID- 23644092 TI - Effectiveness of renal denervation therapy for resistant hypertension: a systematic review and meta-analysis. AB - OBJECTIVES: This study sought to determine the current effectiveness and safety of sympathetic renal denervation (RDN) for resistant hypertension. BACKGROUND: RDN is a novel approach that has been evaluated in multiple small studies. METHODS: We performed a systematic review and meta-analysis of published studies evaluating the effect of RDN in patients with resistant hypertension. Studies were stratified according to controlled versus uncontrolled design and analyzed using random-effects meta-analysis models. RESULTS: We identified 2 randomized controlled trials, 1 observational study with a control group, and 9 observational studies without a control group. In controlled studies, there was a reduction in mean systolic and diastolic blood pressure (BP) at 6 months of -28.9 mm Hg (95% confidence interval [CI]: -37.2 to -20.6 mm Hg) and -11.0 mm Hg (95% CI: -16.4 to -5.7 mm Hg), respectively, compared with medically treated patients (for both, p < 0.0001). In uncontrolled studies, there was a reduction in mean systolic and diastolic BP at 6 months of -25.0 mm Hg (95% CI: -29.9 to -20.1 mm Hg) and -10.0 mm Hg (95% CI: -12.5 to -7.5 mm Hg), respectively, compared with pre-RDN values (for both, p < 0.00001). There was no difference in the effect of RDN according to the 5 catheters employed. Reported procedural complications included 1 renal artery dissection and 4 femoral pseudoaneurysms. CONCLUSIONS: RDN resulted in a substantial reduction in mean BP at 6 months in patients with resistant hypertension. The decrease in BP was similar irrespective of study design and type of catheter employed. Large randomized controlled trials with long-term follow-up are needed to confirm the sustained efficacy and safety of RDN. PMID- 23644091 TI - Benefit of pulmonary vein isolation guided by loss of pace capture on the ablation line: results from a prospective 2-center randomized trial. AB - OBJECTIVES: This study was conducted to determine if an additional procedural endpoint of unexcitability (UE) to pacing along the ablation line reduces recurrence of atrial fibrillation (AF) or atrial tachycardia (AT) after radiofrequency catheter ablation. BACKGROUND: AF/AT recurrence is common after pulmonary vein isolation (PVI). METHODS: We included 102 patients from 2 centers (age 63 +/- 10 years; 33 women; left atrium 38 +/- 7 mm; left ventricular ejection fraction 61 +/- 6%) with symptomatic paroxysmal AF. A 3-dimensional mapping system and circumferential mapping catheter were used in all patients for PVI. In group 1 (n = 50), the procedural endpoint was bidirectional block across the ablation line. In group 2 (n = 52), additional UE to bipolar pacing at an output of 10 mA and 2-ms pulse width was required. The primary endpoint was freedom from any AF/AT (>30 s) after discontinuation of antiarrhythmic drugs. RESULTS: Procedural endpoints were successfully achieved in all patients. Procedure duration was significantly longer in group 2 (185 +/- 58 min vs. 139 +/ 57 min; p < 0.001); however, fluoroscopy times were not different (23 +/- 9 min vs. 23 +/- 9 min; p = 0.49). After a follow-up of 12 months in all patients, 26 patients (52%) in group 1 versus 43 (82.7%) in group 2 were free from any AF/AT (p = 0.001) after a single procedure. No major complications occurred. CONCLUSIONS: The use of pacing to ensure UE along the PVI line markedly improved near-term single-procedure success, compared with demonstration of bidirectional block alone. This additional endpoint significantly improved patient outcomes after PVI. (Unexcitability Along the Ablation as an Endpoint for Atrial Fibrillation Ablation; NCT01724437). PMID- 23644093 TI - On the asymmetry of mating in natural populations of the mushroom fungus Schizophyllum commune. AB - Before a mycelium of a mushroom-forming basidiomycete develops mushrooms, the monokaryotic mycelium needs to become fertilized. Although the mechanistic details of mating in mushrooms have been studied thoroughly in laboratory research, very little is known on mating patterns in nature. In this study, we performed fine-scale analyses of three populations of Schizophyllum commune from their natural substrate (i.e. dead beech branches). From the three branches, 24, 12, and 24 fruiting bodies were isolated and for each mushroom, the origins of its nuclei and cytoplasm were reconstructed using DNA markers. Nuclear genotypes were determined using sequencing data and mating types, and mitochondrial haplotypes using SNP markers. From these combined data we reconstructed colonization and mating patterns of the mycelia. On each branch, we found multiple dikaryons (3, 3, and 8, respectively); in two instances one nuclear haplotype was shared between two dikaryons and in two other cases a nuclear haplotype was shared between three dikaryons. Each dikaryon always had a single mitochondrial haplotype. These findings indicate that mating usually is not symmetrical and that a monokaryon is most likely fertilized by a small monokaryon, a spore or a dikaryon. Sharing of nuclear haplotype between different dikaryons resulted either from multiple fertilizations of a single monokaryon, if the dikaryons had identical mitochondrial haplotypes, or, if the dikaryons had different mitochondrial haplotypes, most likely from secondary matings between a monokaryon and a dikaryon (Buller phenomenon). We conclude that mating in S. commune between same-sized monokaryons with reciprocal migration, as generally described in textbooks, is rare in nature. We discuss the implications of non symmetric mating for basidiomycete evolution. PMID- 23644094 TI - 13C and 1H NMR ester region resonance assignments and the composition of human infant and child meibum. AB - Recent NMR studies suggest that unsaturation may contribute to tear film instability in adults and loss of cholesteryl esters and squalene could reduce tear film stability in adults with meibomian gland dysfunction. The proton resonances were tentatively assigned in those studies. In this current investigation, meibum from seven infants and children, one adult and a pool of adult meibum have been analyzed using an NMR spectrometer with greater sensitivity and spectral resolution. The goals of this work are to confirm/correct the previous assignments and to determine possible age-related changes in composition. The initial resonance assignments were confirmed using heteronuclear single quantum correlation spectroscopy. Because there were no significant interferences in the spectral region corresponding to the resonances for cholesteryl and wax esters, the areas of these resonances were used to calculate their molar ratios. We calculated a wax ester:cholesteryl ester molar ratio of 1:0.57 +/- 0.05 for all our meibum samples and there were no age-related differences. At lower film thicknesses, the rate of evaporation measured in vitro was lower for wax esters mixed with a long chain cholesteryl ester compared to wax esters alone. However, the film thicknesses tested were non-physiological. Longer chain cholesteryl esters increase the interactions between hydrocarbon chains. Hydrocarbon chains were more saturated in meibum from infants and children compared to adults. Unsaturation may contribute to tear film instability in adults. Loss of cholesteryl ester and squalene could destabilize tear film in adults with meibomian gland dysfunction. PMID- 23644095 TI - Complement expression in retinal pigment epithelial cells is modulated by activated macrophages. AB - Complement activation is involved in a variety of retinal diseases. We have shown previously that a number of complement components and regulators can be produced locally in the eye, and that retinal pigment epithelial (RPE) cells are the major source of complement expression at the retina-choroidal interface. The expression of complement components by RPE cells is regulated by inflammatory cytokines. Under aging or inflammatory conditions, microglia and macrophages accumulate in the subretinal space, where they are in close contact with RPE cells. In this study, we investigated the effect of activated macrophages on complement expression by RPE cells. Mouse RPE cells were treated with the supernatants from un-activated bone marrow-derived macrophages (BM-DMs), the classically activated BM-DMs (M1) and different types of the alternatively activated BM-DMs (M2a by IL 4, M2b by immune complex and lipopolysaccharide (LPS), M2c by IL-10). The expression of inflammatory cytokines and complement genes by RPE cells were determined by real-time RT-PCR. The protein expression of CFB, C3, C1INH, and C1r was examined by Western blot. Our results show that un-stimulated RPE cells express a variety of complement-related genes, and that the expression levels of complement regulators, including C1r, factor H (CFH), DAF1, CD59, C1INH, Crry, and C4BP genes are significantly higher than those of complement component genes (C2, C4, CFB, C3, and C5). Macrophage supernatants increased inflammatory cytokine (IL-1beta, IL-6, iNOS), chemokine (CCL2) and complement expression in RPE cells. The supernatants from M0, M2a and M2c macrophages mildly up-regulated (2-3.5-fold) CFB, CFH and C3 gene expression in RPE cells, whereas the supernatants from M1 and M2b macrophages massively increased (10-30-fold) CFB and C3 gene expression in RPE cells. The expression of other genes, including C1r, C2, C4, CFH, Masp1, C1INH, and C4BP in RPE cells was also increased by the supernatants of M1 and M2b macrophages; however, the increment levels were significantly lower than CFB and C3 genes. M1 and M2b macrophage supernatants enhanced CFB (Bb fragment) protein expression and C3 secretion by RPE cells. M1 macrophages may affect complement expression in RPE cells through the STAT1 pathway. Our results suggest that under inflammatory conditions, activated macrophages could promote the alternative pathway of complement activation in the retina via induction of RPE cell CFB and C3 expression. PMID- 23644097 TI - Detection of IgG antibodies in sera from patients with Cryptosporidium parvum and Cryptosporidium hominis. AB - OBJECTIVES: Detection of anti-Cryptosporidium immunoglobulin G (IgG) antibodies in human sera has been used to demonstrate population exposure to this gastro intestinal protozoan parasite. We characterised the dynamics of IgG antibody responses to two Cryptosporidium parvum (IOWA isolate) sporozoite antigens (15/17 kDa and 27 kDa) using longitudinal sera taken from laboratory-confirmed cryptosporidiosis cases in England and Wales. The effect of the infecting Cryptosporidium species was also investigated. METHODS: A mini-gel Western blot was used to test sera from ten Cryptosporidium stool-positive diarrhoea patients, taken soon after diagnosis and at 3 month intervals. RESULTS: Overall responses to the 15/17 kDa antigen complex were stronger and over a greater range than those to the 27 kDa antigen, but declined between 181 and 240 days and were barely detectable thereafter. Responses to the 27 kDa antigen were much weaker but remained detectable for a greater length of time. No differences were detected in either antibody response to infection with C. hominis or C. parvum. CONCLUSIONS: The assay appears to be applicable for the study of recent exposure to C. parvum or C. hominis in the United Kingdom population, with strong responses to the 15/17 kDa antigen occurring within 6 months of infection. PMID- 23644098 TI - Prevention and diagnosis of invasive fungal disease in high-risk patients within an integrative care pathway. AB - OBJECTIVES: The aim of this study was to assess the clinical utility of enhanced diagnostics on the management of invasive fungal disease in high risk patients within an integrated care pathway and to audit compliance and efficacy of antifungal prophylaxis. METHODS: A cohort of 549 high risk haematology and stem cell transplant recipients was followed over a 5 year period. The routine standard of care involved the use of antimould prophylaxis and a neutropenic care pathway utilizing twice weekly antigen and PCR testing. RESULTS: Prophylaxis with itraconazole was poorly tolerated and therapeutic levels could not be maintained. Antigen testing and PCR showed good clinical utility in the management of invasive aspergilosis with high sensitivity (98%) and negative predictive value (99.6%) when both tests were used together, allowing a diagnosis IA to be excluded and obviating the need for empirical antifungal agents. When used serially, multiple positive PCR and antigen test results enabled accurate diagnosis of IA with a specificity of 95% and a positive likelihood ratio of 11. Biomarkers preceded clinical signs in 85% of proven and probable invasive disease. CONCLUSION: The combination of both tests showed optimum clinical utility for the diagnosis and management of IA in this high risk group. PMID- 23644099 TI - Functional interaction of osteogenic transcription factors Runx2 and Vdr in transcriptional regulation of Opn during soft tissue calcification. AB - Loss of Abcc6 gene expression was identified to be responsible for dystrophic calcification of the heart (DCC) or vessels after acute injury in several strains of laboratory mice. This calcification shares features with osteogenesis and may involve osteogenic factors. Tissue expression of osteopontin (Opn) and 11 osteogenic transcription factors were studied in vivo in mouse models for DCC and in vitro using luciferase reporter gene assays. Compared with DCC-resistant C57BL/6 mice, a significant increase in Opn transcription was demonstrated in necrotic lesions of both DCC-susceptible C3H/He and B6.C3H(Dyscalc1) congenic mice at day 3 after injury. Significant increases in gene expression were also demonstrated for the transcription factors runt domain-containing transcription factor 2 (Runx2), vitamin D receptor (Vdr), SRY (sex-determining region Y)-box 9 protein, and Nfkb1 in C3H/He mice versus C57BL/6 controls. However, only Runx2 remained significantly increased in the B6.C3H(Dyscalc1) congenic mice, which carry only the Dyscalc1 locus with functional Abcc6 deletion on a C57BL/6 genetic background. Luciferase assay use increased Opn promoter activity, which was demonstrated after overexpression of Runx2. A poly-T stretch insertion was identified to stabilize the binding of Runx2, thus significantly enhancing Opn promoter activity. This Runx2-mediated activation was further enhanced by cotransfection with Vdr. Our data suggest a key role of Runx2 in the regulation of Opn in a model of cardiovascular calcification and demonstrate a synergistic cooperation of Runx2 and Vdr. PMID- 23644096 TI - Caffeine eye drops protect against UV-B cataract. AB - The purpose of this study was to investigate if topically applied caffeine protects against in vivo ultraviolet radiation cataract and if so, to estimate the protection factor. Three experiments were carried out. First, two groups of Sprague-Dawley rats were pre-treated with a single application of either placebo or caffeine eye drops in both eyes. All animals were then unilaterally exposed in vivo to 8 kJ/m(2) UV-B radiation for 15 min. One week later, the lens GSH levels were measured and the degree of cataract was quantified by measurement of in vitro lens light scattering. In the second experiment, placebo and caffeine pre treated rats were divided in five UV-B radiation dose groups, receiving 0.0, 2.6, 3.7, 4.5 or 5.2 kJ/m(2) UV-B radiation in one eye. Lens light scattering was determined after one week. In the third experiment, placebo and caffeine pre treated rats were UV-B-exposed and the presence of activated caspase-3 was visualized by immunohistochemistry. There was significantly less UV-B radiation cataract in the caffeine group than in the placebo group (95% confidence interval for mean difference in lens light scattering between the groups = 0.10 +/- 0.05 tEDC), and the protection factor for caffeine was 1.23. There was no difference in GSH levels between the placebo- and the caffeine group. There was more caspase 3 staining in UV-B-exposed lenses from the placebo group than in UV-B-exposed lenses from the caffeine group. Topically applied caffeine protects against ultraviolet radiation cataract, reducing lens sensitivity 1.23 times. PMID- 23644100 TI - Temporal and spatial pattern of RhoA expression in injured spinal cord of adult mice. AB - OBJECTIVE: To quantitatively analyze the temporal and spatial pattern of RhoA expression in injured spinal cord of adult mice. METHODS: A spinal cord transection model was established in adult mice. At 1, 3, 7, 14, 28, 56 and 112 days after the surgery, the spinal cords were dissected and cryosectioned for RhoA/NF200, RhoA/GFAP, RhoA/CNPase or RhoA/IBA1 double fluorescent immunohistochemistry to visualize RhoA expressions in the neurons, astrocytes, oligodendrocytes and microglia. The percentages as well as the immunostaining intensities of RhoA-positive cells in the parenchymal cells were quantitatively analyzed. RESULTS: RhoA was weakly expressed in a few neurons and oligodendrocytes in normal spinal cord. After spinal cord injury, the percentage of RhoA-positive cells and RhoA expression intensity in the spinal cord increased and peaked at 7 days post injury (dpi) in neurons, oligodendrocytes and astrocytes, followed by a gradual decrease till reaching a low level at 112 dpi. In the microglia, both the RhoA-positive cells and RhoA expression intensity reached the maximum at 14 dpi and maintained a high level till 112 dpi. CONCLUSION: Traumatic spinal cord injury can upregulate RhoA expression in the neurons as well as all the glial cells in the spinal cord. RhoA expression patterns vary with post-injury time, location and among different parenchymal cells in the injured spinal cord. PMID- 23644101 TI - Effects of sevoflurane on pulmonary cytosolic phospholipase A2 and clara cell secretory protein expressions in rabbits with one-lung ventilation-induced lung injury. AB - OBJECTIVE: To investigate the effects of sevoflurane on cytosolic phospholipase A2 (C-PLA2) and clara cell secretory protein (CCSP) in lung tissues of rabbits with one-lung ventilation (OLV)-induced lung injuries. METHODS: Thirty-six healthy Japanese white rabbits were randomized into sham-operated group, OLV group, and OLV plus sevoflurane group subdivided into 4 subgroups with sevoflurane concentrations of 1%, 2%, 3% and 4%. CCSP and C-PLA2 mRNA and protein expressions in rabbit lung tissues were detected by Western blotting and real time PCR, and the content of arachidonic acid (AA) was measured using ELISA. The severities of the lung injury were evaluated according to lung wet/dry weight (W/D) ratio and histological scores. RESULTS: In the OLV group and OLV+ sevoflurane groups, pulmonary CCSP expressions were significantly lower, while C PLA2 expression, lung W/D ratios and lung histological scores were significantly higher than those in the sham-operated group (P<0.05). Compared with OLV group, the OLV+sevoflurane groups showed significantly increased expressions of CCSP and reduced C-PLA2 expression, lung W/D ratios and histological scores (P<0.05). In the 4 OLV+sevoflurane groups, CCSP expressions underwent no significant changes as sevoflurane concentration increased, but C-PLA2 expressions, lung W/D ratios and histological scores all decreased gradually as the concentrations of sevoflurane increased (P<0.05). CONCLUSION: OLV can result in down-regulated CCSP expressions and up-regulated C-PLA2 expressions in rabbit lung tissues. Sevoflurane can protect against OLV-induced acute lung injury possibly by inhibiting C-PLA2 expression via up-regulation of CCSP expressions or through other mechanisms resulting in down-regulated expression of C-PLA2. PMID- 23644102 TI - ROS kinase fusions are not common in Chinese patients with cholangiocarcinoma. AB - OBJECTIVE: To investigate the expressions of different forms of ROS fusions in Chinese patients with cholangiocarcinoma (CCA). METHODS: RT-PCR was employed to examine formalin-fixed and paraffin-embedded CCA samples from stage I-IV patients for detection of ROS fusions involving Fused in Glioblastoma (FIG), solute carrier protein (SLC34A2) and major histocompatibility complex class II invariant chain (CD74). Serpin peptidase inhibitor clade A member 1 (SERPINA1) was detected as the reference gene. RESULTS: In all the 56 CCA samples, 80.4% (45/56) were positive for SERPINA1 expression as evaluable samples. Of these evaluable samples, none expressed the ROS fusions. CONCLUSION: ROS fusions are not common in Chinese CCA patients. PMID- 23644103 TI - [Role of calcium dyshomeostasis in 1-methyl-4-phenylpyridinium ion-induced apoptosis of human neuroblastoma SH-SY5Y cells]. AB - OBJECTIVE: To investigate the role of calcium dyshomeostasis in 1-methyl-4 phenylpyridinium ion (MPP+)-induced apoptosis of human neuroblastoma SH-SY5Y cells. METHODS: The viability of SH-SY5Y cells exposed to varying concentrations of MPP+ was assessed using MTT colorimetric assay, and MPP+-induced cell apoptosis was detected with hoechst 33342 staining and Annexin V+PI assay. Western blotting and rhodamine 123 staining were employed to examine the changes in cellular poly(ADP-ribose) polymerase (PARP) protein expression and mitochondrial membrane potential in response to MPP+ exposure. The effects of ruthenium red and/or MPP+ on calcium concentration in the cytoplasm, mitochondria and endoplasmic reticulum were evaluated using confocal microscopy. RESULTS: MPP+ induced apoptosis and caused reduced cell viability and mitochondrial membrane potential in SH-SY5Y cells. The cells exposed to MPP+ showed a lowered calcium concentration in the cytoplasm and endoplasmic reticulum and an increased mitochondrial Ca2+ uptake. Ruthenium red rescued MPP+-induced apoptosis and mitochondrial membrane potential reduction, reduced PARP cleavage, and inhibited the increase of mitochondrial matrix free Ca2+ in the cells exposed to MPP+. CONCLUSION: Mitochondrial calcium overload plays an important role in MPP+ induced apoptosis of SH-SY5Y cells, which is closely associated with dysregulation of intracellular Ca2+ homeostasis. PMID- 23644105 TI - [Expression of heat shock protein 90beta and its regulation in the reproductive system of male mice]. AB - OBJECTIVE: To study the expression and regulation of heat shock protein 90beta (HSP90beta) in the testis, epididymis and sperms of mice. METHODS: The localization and expression of HSP90beta mRNA and protein were investigated in the testis, epididymis and sperms of mice, and the regulation of HSP90beta in the male reproductive system was explored. RESULTS: HSP90beta was expressed at a higher level in the epididymis than in the testis. In the sperms of the mice, HSP90beta was localized in the acrosome area. The expression of HSP90beta in mouse epididymis decreased after castration and recovered the normal level after testosterone treatment. HSP90beta expression in the testis and epididymis also underwent changes during the postnatal development of the mice. CONCLUSION: HSP90beta may play an important role in spermiogenesis and fertilization, and its expression pattern in the epididymis after castration and during the postnatal development suggests its regulation by hormones and development. PMID- 23644104 TI - [Screening of hepatocyte proteins interacting with hepatitis B virus X protein using CytoTrap yeast two-hybrid technique]. AB - OBJECTIVE: To screen the hepatocyte proteins that interact with hepatitis B virus X protein (HBx). METHODS: The recombinant plasmid pSos-HBx was constructed by inserting Sos-HBx fragment into the bait vector, and after sequence verification the plasmid was transformed into competent yeast cells. The expression and self activation of Sos-HBx protein was detected in the yeast cells. The hepatocyte proteins interacting with the bait protein was screened with CytoTrap yeast two hybrid technique. RESULTS: The reconstructed plasmid harboring HBx gene expressed Sos-HBx protein in the yeast cells without self-activation of the protein. CytoTrap yeast two-hybrid system identified 6 hepatocyte proteins that interacted with HBx, including fibronectin 1, translationally controlled tumor protein, IQ motif and WD repeats 1, follistatin, orosomucoid 1, and disulfide isomerase family A member 3. CONCLUSION: Six HBx-binding hepatocyte proteins have been identified using the CytoTrap yeast two-hybrid system, which provides clues for further investigation of the role of HBx protein in hepatitis and liver cancer. PMID- 23644106 TI - [Optimal concentration of c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles for magnetic resonance imaging in tumor-bearing nude mice]. AB - OBJECTIVE: To determine the optimal concentration of c-erbB2 antisense probe labeled with superparamagnetic iron oxide (SPIO) nanoparticles for in vivo tumor imaging in mice using magnetic resonance imaging (MRI). METHODS: Thirty BALB/c mice bearing SK-Br-3 tumor were randomized into 5 groups to receive injections of different concentrations of SPIO-labeled c-erbB2 antisense probe (containing 6.0, 9.0, 12.0, 15.0, or 18.0 mg Fe/kg). MRI was performed before and 6 h after the injections, and the signal intensities of the tumor were compared among the groups. The tumor tissues were then dissected for microscopic examination with HE and Prussian blue staining. RESULTS: The tumor-bearing mice all survived after injections of the probe at doses of 6.0, 9.0 and 12.0 mg, but injections at higher doses (15.0 and 18.0 mg) caused death in some mice. Injections of the probe at the doses of 12.0, 15.0 and 18.0 mg resulted in significant signal enhancement of the tumor (P<0.001) to allow visual identification, but the changes showed no significant differences among the 3 groups (P>0.05). Pathological examination revealed irregular structures of the tumor issue containing numerous heterogeneous tumor cells aligned into cancer nests; Prussian blue staining visualized scattered blue iron particles in the tumor issue, which was especially obvious in mice injected with 12.0, 15.0 and 18.0 mg labeled probe. CONCLUSION: Injection of 12.0 mg/kg SPIO-labeled c-erbB2 antisense probe allows optimal tumor imaging in BALB/c mice using MRI. PMID- 23644108 TI - [Effect of homocysteine on gluconeogenesis in mice]. AB - OBJECTIVE: To investigate the expressions of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver of mice with hyperhomocysteinemia (HHcy) and explore the mechanism of gluconeogenesis induced by homocysteine. METHODS: Fifty mice were randomly divided into normal control group (n=25) and HHcy group (n=25) and fed with normal food and food supplemented with 1.5% methionine, respectively. After 3 months of feeding, the fasting blood glucose and insulin levels were determined, and HOMA insulin resistance index (HOMA-IR) was calculated. The expressions of G6Pase and PEPCK in the liver of mice were detected using RT-PCR and Western blotting. RESULTS: The fasting blood glucose and insulin levels and HOMA-IR were significantly higher in HHcy group than in the control group (P<0.05). RT-PCR and Western blotting showed that the hepatic expressions of G6Pase and PEPCK mRNA and proteins increased significantly in HHcy group compared with those in the control group (P<0.05). CONCLUSION: Homocysteine promotes gluconeogenesis to enhance glucose output and contribute to the occurrence of insulin resistance. PMID- 23644107 TI - [Syndrome differentiation-based treatment with traditional Chinese medicine for proteinuria in patients with chronic kidney disease: a randomized multicenter trial]. AB - OBJECTIVE: To evaluate the clinical efficacy of syndrome differentiation-based treatment with traditional Chinese medicine (TCM) versus losartan therapy in addition to basic treatment for management of proteinuria in patients with chronic kidney disease. METHODS: This multicenter, randomized, and case controlled clinical trial was conducted among 81 consecutive patients meeting the inclusion criteria. The patients were randomized consecutively to receive TCM treatments according to the syndrome patterns in TCM (spleen and kidney Qi and Yin deficiency, and spleen and kidney Qi and Yang deficiency, n=60) or oral losartan therapy (50 mg/day, n=21) in addition to the basic treatments. All the patients were followed up for 24 weeks to observe the clinical effects. RESULTS: The patients in TCM group showed a significantly higher overall response rate (93.33%) than those in losartan group (76.20%, P<0.05). The TCM score in the two groups were all decreased at week 24 as compared with baseline (P<0.01 or P<0.05). The TCM scores in both groups decreased significantly after the treatments as compared with the baseline scores (P<0.05). After a 8-week-long treatment, Scr, eGFR and Cys-C, U-Pro/24 h, and MA/Cr all decreased significantly in TCM group (P<0.05) but showed no significant changes in losartan group (P>0.05). CONCLUSION: Syndrome differentiation-based TCM treatment in addition to basic treatments can produce satisfactory therapeutic effects on proteinuria in patients with chronic kidney disease by improving the clinical symptoms, reducing TCM symptom scores and proteinuria, and protecting the renal functions. PMID- 23644109 TI - [Three-dimensional reconstruction and digitized visualization of the sacrum of women of Uygur and Han nationalities in Xinjiang]. AB - OBJECTIVE: To construct digitized three-dimensional models of the sacrum of women of Uygur and Han nationalities in Xinjiang and assess their value in anatomical studies. METHODS: Ninety Uygur women and 90 Han women of child-bearing age in Xinjiang were recruited. Digitized three-dimensional reconstruction was used to construct the sacrum models for morphological study and measurement of the physiological indices. RESULTS: The sacral forms of Han women were consistent with the standard anatomical descriptions. Of the Uygur women, 57 (63.3%) showed a standard type of the sacrum, 6 (6.7%) had 4 pairs of sacral foramens, 9 (10%) had 5 pairs of sacral foramens, and 18 (20%) had sacrococcygeal joint abnormalities. There were significant differences in sacral morphologies between the two nationalities (P<0.05). The depths of the sacrum foramen and sacral hiatus were significantly greater in Uyghur women than in Han women (P<0.05). Only a minor proportion of the cases had nonstandard sacral types, found only in Uygur women. CONCLUSIONS: Uygur and Han women of child-bearing age in Xinjiang have morphological and anatomical differences of the sacrum, which should be considered in clinical practice. PMID- 23644110 TI - [Intracellular localization and expression of importin 8 during osteoblast differentiation]. AB - OBJECTIVE: To observe the variations of intracellular localization and expression of importin 8 (IPO8) during osteoblast differentiation. METHODS: Alizarin red staining, immunocytochemistry and real-time PCR were employed to examine the changes in the intracellular localization and expression of IPO8 mRNA during induced osteogenic differentiation of human osteoblast-like SaOS-2 cells. RESULTS: Numerous red mineralized nodules were observed on day 10 in the induced cells with alizarin red staining. Immunocytochemical staining showed that IPO8 immunoreactivity was the strongest in the perinuclear cytoplasm of the cells. On day 3 of osteoblast differentiation, IPO8 immunoreactivity in the cell nuclei became stronger. On day 7, IPO8 was located mainly in the nuclei, and on day 10 the cells were osteocyte-like and IPO8 was distributed in the cytoplasm. Real time PCR showed a significantly increased expression of OPN mRNA during osteoblast differentiation, and the expression level of IPO8 mRNA was the highest on day 3 and declined on days 7 and 10. CONCLUSION: The intracellular localization and expression level of IPO8 undergo significant changes during osteogenesis, indicating its role in regulating osteoblast differentiation. PMID- 23644111 TI - [Blood and renal fractalkine expression in patients with lupus nephritis and its significance]. AB - OBJECTIVE: To investigate the expression of fractalkine (FKN) in the blood and renal tissues of patients with lupus nephritis and explore its significance. METHODS: According to the pathological classification, 48 patients with lupus nephritis were divided into mild group (22 cases) and severe group (26 cases), with 26 healthy subjects as the control group. RT-PCR and enzyme-linked immunosorbent assay were employed to detect the expression of FKN mRNA and protein in the blood of the subjects, and FKN expression and localization in the renal tissue of the patients with lupus nephritis were detected using immunohistochemical staining. RESULTS: The patients in both the mild and severe groups showed significantly increased expression of blood FKN mRNA and protein compared with the normal controls, and the increase was more obvious in severe cases (P<0.01). In the renal tissues of the patients, FKN was located mainly in the cytoplasm of the glomerular podocytes and renal tubular epithelial, and the number of positive glomerular cells number was significantly greater in severe cases than in the mild cases (P<0.01); FKN expression in the cortical interstitium did not show a significant difference between the 3 groups. CONCLUSION: FKN expression in the blood and glomeruli of patients with lupus nephritis is related to the severity of renal pathologies. PMID- 23644112 TI - [Glycosylation inhibitor 2-deoxy-D-glucose sensitizes oral cancer cells to TRAIL induced apoptosis]. AB - OBJECTIVE: To investigate the effect of 2-deoxy-D-glucose (2-DG) in enhancing the sensitivity of oral cancer cells to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis. METHODS: The oral cancer cell line KB was incubated in the presence of different concentrations (0, 0.625, 1.25, 2.5, 5, and 10 mmol/L) of 2-DG with or without TRAIL (200 ng/ml). The cell viability was measured using MTT assay and cell apoptosis was detected using flow cytometry with propidium iodide (PI) staining. KB cells treated with 5 mmol/L 2-DG with or without TRAIL for 0, 6, 16, or 24 h were examined with Western blotting for protein expressions of death receptor 5 (DR5) and caspase-3. RESULTS: Treatment of the cells with 5 mmol/L 2-DG for 24, 48 and 72 h resulted in a cell viability of 25.25%, 69.06%, and 59.19%, respectively. Combined treatment with 5 mmol/L 2 DG with TRAIL for 24 significantly enhanced the cell apoptotic rate (72.5%) as compared to the rate induced by TRAIL alone (45.3%) and by 2-DG (15.9%) alone. 2 DG treatment markedly up-regulated DR5 and caspase-3 expression and enhanced the inhibitory effect of TRAIL on cell colony formation. CONCLUSION: 2-DG sensitizes oral cancer cells to TRAIL- induced apoptosis by up-regulating DR5 and caspase-3 expressions. PMID- 23644113 TI - [SIRT1 expression and activity are up-regulated in the brain tissue of epileptic patients and rat models]. AB - OBJECTIVE: To investigate the expression and activity of silent information regulator 1 (SIRT1) in the temporal lobe of epileptic patients and rat models and explore its role in the occurrence and progression of epilepsy. METHODS: The temporal lobe tissue of epileptic patients and rat models (induced by lithium pilocarpine) were examined for SIRT1 expression using immunohistochemistry and Western blotting and also for SIRT1 activity using SIRT1 Deacetylase Assay Kit. RESULTS: Immunohistochemistry detected positive SIRT1 expression mainly in the cytoplasm of the neurons in both human and rat brains, and the epileptic groups showed stronger SIRT1 immunoreactivity than the control group. Western blotting and activity assay showed that the expression and activity of SIRT1 were significantly increased in the temporal lobe of patients with refractory epilepsy as compared with the tissues samples from non-epileptic patients (P<0.05). In the rat models of epilepsy, SIRT1 expression was up-regulated at 6, 24, and 72 h and at 7, 14, 30, and 60 days after kindling (P<0.05) and SIRT1 activity was significantly increased at 6, 24, and 72 h and at 7 and 14 days (P<0.05), with the peak level of SIRT1 expression and activity occurring at 72 h. CONCLUSION: Up regulation of SIRT1 expression and activity in the temporal lobe of epileptic patients and rat models may play an important role in the pathogenesis of epilepsy. PMID- 23644114 TI - [Relationship between adipose expression of 3-phosphoinositide-dependent protein kinase 1 and glycometabolism in a mouse model of hyperhomocysteinemia]. AB - OBJECTIVE: To study the effect of homcysteine on the expression of 3 phosphoinositide-dependent protein kinase 1 (PDK1) in the adipose tissue and explore whether PDK1 inhibits p-Akt(Thr-308) expression and affect PI3K/Akt signal pathway to decrease glucose uptake and utilization. METHODS: Forty mice were randomly divided into 4 groups (n=10), namely the fasting control group, feeding control group, fasting hyperhomocysteinemia group, and feeding hyperhomocysteinemia group. In the two hyperhomocysteinemia groups, the mice were given water containing 1.5% methionine to induce hyperhomocysteinemia. Blood glucose and insulin levels in each group were determined, and the expressions of PDK1 and Akt mRNA in the adipose tissue were detected using RT-PCR; the expressions of PDK1, p-Akt(Thr-308) and Akt proteins were detected using Western blotting. RESULTS: In the fasting and feeding hyperhomocysteinemia groups, blood glucose and insulin levels were significantly higher than those in the two control groups. The expressions of PDK1 mRNA and PDK1 and p-Akt(Thr-308) proteins were reduced in the two hyperhomocysteinemia groups, but Akt mRNA and protein expressions were comparable with those in the control groups. CONCLUSION: Homocysteine lowers the uptake and utilization of glucose by down-regulating PDK1 expression and affecting PI3K/Akt signal pathway to cause disturbance of glucose metabolism. PMID- 23644115 TI - [Value of four serum markers in the diagnosis of rheumatoid arthritis]. AB - OBJECTIVE: To systematically evaluate the values of 4 serum markers in the diagnosis of rheumatoid arthritis (RA). METHODS: Serum samples were obtained from 278 RA patients and 510 control subjects and the levels of rheumatoid factor (RF), anticyclic citrullinated peptide antibody (CCP), antikeratin antibody (AKA), and glucose-6-phosphate isomerase (GPI) were detected using immune turbidimetry, ELISA, indirect immunofluorescence, and ELISA, respectively. The values of these 4 serum markers and their combinations in RA diagnosis were systemically assessed. RESULTS: In RA diagnosis using one serum marker, two markers, and three or four markers, RF, RF+CCP, RF+CCP+GPI, respectively, had the highest sensitivity; CCP, CCP+AKA, and RF+CCP+AKA+GPI, respectively, had the highest specificity; CCP, CCP+GPI, and RF+CCP+AKA+GPI, respectively, had the highest positive predictive value; GPI, RF+CCP, and RF+CCP+GPI, respectively, had the highest negative predictive value; CCP, CCP+GPI, and RF+CCP+AKA+GPI, respectively, had the highest positive likely ratio; GPI, RF+CCP, and RF+CCP+GPI, respectively, had the lowest negative likely ratio. CONCLUSION: CCP, RF+CCP, and RF+CCP+GPI are the most ideal for RA diagnosis using one, two, and three or more markers, respectively. CCP is the essential marker for RA diagnosis, and a combined detection of the serum makers can significantly improve the diagnostic accuracy. PMID- 23644116 TI - [Correlation of aldehyde dehydrogenase-2 gene polymorphism with hypertension in patients with coronary heart disease complicated by diabetes mellitus]. AB - OBJECTIVE: To investigate the correlation of G487A polymorphism of aldehyde dehydrogenase-2 (ALDH2) gene with hypertension in patients with coronary heart disease complicated by type 2 diabetes. METHODS: This study was conducted among 167 patients with coronary heart disease complicated by diabetes mellitus. The polymorphisms of gene G487A ALDH2 were determined using polymerase chain reaction restricted fragments length polymorphism technique (PCR-RFLP). According to the genotypes, the patients were divided into GG group (n=105) and GA/AA group (n=62), and the incidence of hypertension, risk factors of hypertension, systolic and diastolic pressures, and pulse pressure indexes were compared between the two groups. Multivariate logistic regression analysis was performed to adjust the effects of the confounding factors. RESULTS: The incidence of hypertension in GA/AA group was significantly higher than that in GG group (P<0.05), and the former group showed a significantly greater differences between systolic and pulse pressure; the diastolic pressure was comparable between the two groups. Multivariate logistic regression analysis showed that GA/AA was associated with an increased risk of hypertension in synergy with high insulin level and insulin resistance. CONCLUSION: ALDH2 gene G487A polymorphism may be associated with hypertension in patients with coronary heart disease complicated by type 2 diabetes, and the patients with an A allele have a greater risk of developing hypertension. PMID- 23644117 TI - [Predictive value of anti-Mullerian hormone levels in serum and follicle fluid for IVF-ET outcomes in patients with polycystic ovarian syndrome]. AB - OBJECTIVE: To investigate the association of anti-Mullerian hormone (AMH) levels in the follicular fluid and serum with the outcomes of in vitro fertilization embryo transfer (IVF-ET) cycles in patients with polycystic ovarian syndrome (PCOS). METHODS: Serum and follicular fluid samples were obtained from 30 patients with PCOS and 34 healthy women (control) undergoing IVF/ICSI-ET in our center between October, 2007 and January, 2008. All the subjects received treatment with long luteal-phase down-regulation and controlled ovarian hyperstimulation protocol in IVF cycles, and their clinical characteristics were analyzed. The AMH levels in the serum and follicles fluid samples collected on the day of oocyte retrieval were assayed using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: The two groups showed no significant differences in the mean age, baseline levels of sex hormones, rate of high-quality embryos, implantation rate, pregnancy rate, abortion rate or ongoing pregnancy rate (P>0.05). Despite a significantly lower total gonadotropin dose, PCOS group had a significantly greater number of antral follicles than the control group (P<0.05). The recovery rates of oocytes in PCOS group were significantly lower than that in the control group (P<0.05). AMH levels in the serum and follicle fluid was significantly higher in PCOS group than in the control group (P<0.05), and in both groups, AMH levels in the follicular fluid were significantly higher in pregnant women than in non-pregnant women (P<0.05). AMH level in the follicular fluid was significantly correlated with the implantation rate in both PCOS and control groups (P<0.05). CONCLUSION: AMH level in the serum and follicle fluid on the day of oocyte retrieval is predictive of the treatment outcome of controlled ovarian hyperstimulation in POCS patients but not of pregnancy outcomes after IVF ET. PMID- 23644118 TI - [Expression of myeloid-derived suppressor cells in the peripheral blood and its clinical significance in renal carcinoma]. AB - OBJECTIVE: To investigate the expression of CD33+ HLA-DR- myeloid-derived suppressor cells (MDSCs) in the peripheral blood of patients with renal carcinoma and its correlation with the clinicopathological features of renal cancer. METHODS: Forty-four patients with renal carcinoma treated in our hospital between June, 2011 and October, 2012 and 18 healthy volunteers were enrolled in this study. Flow cytometry was performed to detect CD33+ HLA-DR- MDSCs in the peripheral blood, and its correlation with the clinicopathological features of the patients were analyzed. RESULTS: The positivity rate of CD33+ HLA-DR- MDSCs in the peripheral blood was significantly higher in the cancer patients than in the healthy controls [(1.91 +/- 0.66)% vs (0.62 +/- 0.22)%, P<0.001]. The expression levels of CD33+ HLA-DR- MDSCs in patients with renal carcinoma showed significant differences between stage I+II [(1.46 +/- 0.44)%] and stage III [(2.04 +/- 0.35)%] patients (P<0.01) and between stage III and stage IV patients [(2.50 +/- 0.64)%] (P<0.05), but did not differ significantly in respect of age or gender. CONCLUSION: CD33+ HLA-DR- MDSCs expression in the peripheral blood is associated with tumor stage and differentiation in renal carcinoma and may play an important role in predicting the prognosis and tumor immunology of renal carcinoma. PMID- 23644119 TI - [Exogenous hydrogen sulfide protects against myocardial injury after skeletal muscle ischemia/reperfusion by inhibiting inflammatory cytokines and oxidative stress in rats]. AB - OBJECTIVE: To assess the protective effect of exogenous hydrogen sulfide (H2S) against myocardial injury after skeletal muscle ischemia/reperfusion (IR) in rats and explore the mechanism. METHODS: Thirty-one Wistar rats were randomized into normal control (n=8), IR group (n=8, with a 4-h reperfusion following a 4-h ischemia of the bilateral hindlimbs induced using a tourniquet), NaHS group (n=8, with IR and intraperitoneal injection of 14 umol/kg NaHS), and DL propargylglycine (PPG) group (n=7, with IR and intraperitoneal injection of 50 mg/kg PPG). The plasma levels of CK-MB and the levels of MPO, TNF-alpha, MDA, T SOD, and CuZn-SOD in the plasma and myocardial tissues were measured. The expression of TNF-alpha in the myocardium was examined using immunohistochemistry. RESULTS Skeletal muscle IR induced significantly increased plasma CK-MB level (P<0.05) and the levels of MPO, TNF-alpha, and MDA in the plasma and myocardium, and significantly decreased plasma and myocardial levels of T-SOD and CuZn-SOD (P<0.05). NaHS treatment significantly decreased plasma CK MB level (P<0.05), reduced plasma and myocardial levels of MPO, TNF-alpha, and MDA, and increased plasma and myocardial T-SOD and CuZn-SOD in rats with IR (P<0.05), whereas PPG treatment did not produce any obvious responses (P>0.05). Immunohistochemistry showed an obviously reduced expression of TNF-alpha in the myocardium in rats with NaHS treatment compared with those in IR group. CONCLUSION: H2S treatment can alleviate myocardial injury induced by skeletal muscle IR in rats by inhibiting the inflammatory cytokines and oxidative stress. PMID- 23644120 TI - [Expressions of COX-2, PKC-alpha and miR-101 in gastric cancer and their correlations]. AB - OBJECTIVE: To investigate the expressions of miR-101, protein kinase C-alpha (PKC alpha), and cyclooxygenase-2 (COX-2) in gastric cancer (GC) tissue and their correlations. METHODS: RT-qPCR was used to examine miR-101 expression and Western blotting employed to detect PKC-alpha and COX-2 expressions in 57 cases of gastric cancer tissues and paired normal gastric mucosal tissues. RESULTS: The gastric cancer tissues showed a significantly lower miR-101 expression (Z=6.102, P<0.05) but significantly higher expressions of COX-2 (Z=14.436, P<0.05) and PKC alpha (Z=6.955, P<0.05) than the normal gastric tissues. The expression of COX-2 protein was significantly correlated with the degree of differentiation, invasion depth, lymph node metastasis and TNM stage (P<0.05); PKC-alpha protein expression was associated with lymph node metastasis and TNM stage (P<0.05). PKC-alpha expression was positively correlated (r=0.531, P<0.05) and miR-101 expression negatively correlated (r=-0.627, P<0.05) with COX-2 expression in gastric cancer tissues. CONCLUSIONS: miR-101, PKC-alpha and COX-2 all play a role in the tumorigenesis and progression of gastric cancer. miR-101 and PKC-alpha might be new potential therapeutic targets for inhibiting COX-2 in gastric cancer. PMID- 23644121 TI - [Changes of basic fibroblast growth factor expression in the spinal cord of rats with spared nerve injury of the sciatic nerve]. AB - OBJECTIVE: To observe the temporal changes of basic fibroblast growth factor (FGF 2) expression in the spinal cord of a rat model of spared nerve injury (SNI) of the sciatic nerve. METHODS: A total of 100 male SD rats were randomly divided into sham-operated group and SNI group. The paw withdrawal threshold to mechanical stimulation was recorded at 1 day before and at 1, 4, 7, 14 and 28 days after the operation. The expressions of FGF-2, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the L4-6 spinal cord segments of the rats were measured at the specified time points. RESULTS: The paw withdrawal threshold began to decline at 1 day after SNI, reached the lowest level at 7 days, and maintained a low level till 28 days (P<0.05). The expression of FGF-2 began to increase significantly on postoperative day 4, reached the peak level on day 14 and maintained the high level till day 28 (P<0.05). The rats with SNI showed significantly higher expressions of TNF-alpha and IL-6A in the spinal cord than those in the sham-operated group at each time point of measurement (P<0.05). CONCLUSIONS: SNI of the sciatic nerve can induce neuropathic tactile allodynia and causes up-regulation of FGF-2 and inflammatory cytokines in the spinal cord. PMID- 23644122 TI - [Comparison of two nucleic acid extraction methods for norovirus in oysters]. AB - OBJECTIVE: To explore a convenient and effective method for norovirus nucleic acid extraction from oysters suitable for long-term viral surveillance. METHODS: Two methods, namely method A (glycine washing and polyethylene glycol precipitation of the virus followed by silica gel centrifugal column) and method B (protease K digestion followed by application of paramagnetic silicon) were compared for their performance in norovirus nucleic acid extraction from oysters. Real-time RT-PCR was used to detect norovirus in naturally infected oysters and in oysters with induced infection. RESULTS: The two methods yielded comparable positive detection rates for the samples, but the recovery rate of the virus was higher with method B than with method A. CONCLUSION: Method B is a more convenient and rapid method for norovirus nucleic acid extraction from oysters and suitable for long-term surveillance of norovirus. PMID- 23644123 TI - [Role of PPARgamma signaling pathway in osteogenic differentiation of rat bone marrow- derived mesenchymal stem cells in simulated microgravity]. AB - OBJECTIVE: To explore the role of peroxisome proliferator-activated receptor gamma (PPARgamma) signaling pathway in osteo- blast differentiation of rat bone marrow mesenchymal stem cells (BMSCs) cultured in simulated microgravity. METHODS: Rat BMSCs were cultured in simulated microgravity (by rotating clinostat) in the presence of 10 umol/L pioglitazone, 10 umol/L GW9662, or both pioglitazone and GW9662, with the cells cultured in normal gravity as the control group. After osteogenic induction for 14 days, the cells were stained with alizarin red for the bone nodules and with oil red-O for the fat cells, and the fat rate was calculated. ALP activity in the cells was determined in each group, and RT-PCR was performed to detect cellular expressions of PPARgamma mRNA. RESULTS: Pioglitazone significantly inhibited osteoblast differentiation of the BMSCs, whereas GW9662 promoted the cell differentiation by suppressing the activation of PPARgamma. CONCLUSION: We hypothesize that the activation of PPARgamma signaling pathway is one of the main mechanisms for inhibited osteoblast differentiation of rat BMSCs in simulated microgravity, and inhibiting PPARgamma pathway activation can effectively prevent and treat microgravity induced osteoporosis. PMID- 23644124 TI - [Clinical analysis of 39 cases of multiple primary colorectal carcinoma]. AB - OBJECTIVE: To investigate the clinical features and prognosis of multiple primary colorectal carcinoma (MPCC). METHODS: Among the 1462 patients with colorectal cancer admitted in our department from January 2000 to December 2007, 39 patients with MPCC were identified based on the Warran and Gates MPC diagnosis criteria. The age of onset, 5-year survival rate, lesion location and therapies were analyzed retrospectively. RESULTS: The incidence of MPCC was 2.67% (39/1462). Eighteen of the patients had synchronous carcinomas and 21 were diagnosed to have metachronous carcinomas. Most of the tumors were located in the left colon and rectum. The average age of onset was (61.02?13.94) in these patients who had an overall 5-year survival rate of 61.76%. The patients with metachronous carcinomas had a better prognosis than those with synchronous carcinomas. The 5-year survival rate of 3 early-stage cases (TNM stage I) was 100% after radical surgery. Thirty advanced cases underwent radical surgery combined with adjuvant chemotherapy, and their 1-, 3- and 5-year survival rates were 93.33%, 83.33%, and 73.33%, respectively. The 1- and 3-year survival rates of 3 advanced cases undergoing palliative surgery and adjuvant chemotherapy were 66.67% and 0, respectively. The 1- and 3-year survival rates of another 3 advanced cases with palliative chemotherapy were 66.67% and 0, respectively. CONCLUSION: Early diagnosis and effective treatment can help prolong the survival of MPC patients. Surgical intervention and chemotherapy can improve the survival and prognosis of patients with advanced MPCC. PMID- 23644125 TI - [Expression of miR-143 in nasopharyngeal carcinoma cell lines and its effect on cell adhesion ability]. AB - OBJECTIVE: To detect miR-143 expression in human nasopharyngeal carcinoma (NPC) cell lines and explore the role of miR-143 in regulating the adhesion ability of NPC cells. METHODS: Fluorescence quantitative RT-PCR was used to detect miR-143 expression levels in 5 NPC cell lines (CEN1, CNE2, HONE1, 5-8F, and 6-10B) and an immortalized human nasopharyngeal epithelial cell line (NP69). The retrovirus plasmid pMSCV-puro-miR-143 was constructed and the packaged retroviruses pMSCV puro and pMSCV-puro-miR-143 were infected in 5-8F cells to establish a cell line with stable miR-143 overexpression, whose adhesion ability was tested with adhesion assay. RESULTS: The expression of miR-143 was down- regulated in the NPC cell lines, and the highly metastatic NPC cell line 5-8F had a expression of only 3.0% of the control level, as compared with the level of 63.59% in the tumorigenic but nonmetastatic NPC cell line 6-10B. The transfected 5-8F cells showed a 1080-fold increase of miR-143 expression (P<0.05) with a significantly lowered adhesion ability. CONCLUSION: miR-143 plays a role in regulating the invasiveness and metastasis of NPC, and overexpression of miR-143 causes a significant reduction of the adhesion ability of the highly metastatic NPC cell line 5-8F. PMID- 23644126 TI - [Matrix metalloproteinase-3 genotype distribution and its relation with blood pressure profiles in Guangzhou rural population]. AB - OBJECTIVE: To analyze the distribution of matrix metalloproteinase-3 (MMP-3) genotype and its association with the blood pressure profiles in Guangzhou rural population. METHODS: This study was conducted among 680 rural residents aged 40 70 years (including 314 men and 366 women) from 3 villages in an rural area of Guangzhou. The blood pressures of the subjects were measured and blood samples were collected for genotype analysis using polymerase chain reaction and direct sequencing of the MMP-3 gene promoter region to detect the 5 adenines (5A)/6 adenines (6A) polymorphisms. RESULTS: The frequencies of MMP-3 genotypes 6A/6A, 5A/5A, and 5A/6A were 82.6%, 1.8% and 15.6% among these residents, respectively. The distribution of MMP-3 genotypes and allele frequencies showed no significant gender- or age-related variations. The men with different genotypes (6A/6A vs 5A/6A+5A/5A) did not show significant differences in blood pressure levels, whereas the women with 5A/6A+5A/5A genotypes had higher systolic and diastolic blood pressures than those with a 6A/6A genotype. The allele 5A was highly frequent in the hypertensive residents as compared with the normotensive residents. CONCLUSIONS: The 6A homozygote is the predominant genotype of MMP-3 in Guangzhou rural population, which has a significantly lower proportion of 5A homozygote than the Western populations. The 5A allele is associated with a high risk of hypertension especially in women and may affect both systolic and diastolic blood pressures. PMID- 23644127 TI - [Relationship between glypican-3 and Notch1 expressions in hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the correlation between the expressions of glypican-3 (GPC3) and Notch1 and their roles in the tumorigenesis and progression of hepatocellular carcinoma (HCC). METHODS: Immunohistochemistry and computerized image analysis were utilized to quantitatively detect the expressions of GPC3 and Notch1 in 30 HCC tissue specimens. RESULTS: In the 30 HCC specimens, GPC3 expression decreased significantly as the grade of tumor differentiation increased (P<0.05 or P<0.01), while Notch1 expression presented with a reverse pattern of changes (P<0.05 or P<0.01). An obvious negative correlation was found between the expressions of GPC3 and Notch1 in HCC tissues (rp=-0.607, P=0.000; r= 0.692, P=0.000). CONCLUSION: The expressions of GPC3 and Notch1 show a negative correlation in HCC, suggesting a possible mechanism for mutual regulation between them to contribute to the tumorigenesis and progression of HCC. PMID- 23644128 TI - [Vasculogenic mimicry in tongue squamous cell carcinoma]. AB - OBJECTIVE: To investigate the presence of vasculogenic mimicry (VM) in tongue squamous cell carcinoma and explore its clinical significance. METHODS: Forty-two surgical specimens of tongue squamous cell carcinoma were examined for the presence of VM using HE staining and double staining of CD34 and PAS. RESULTS: Of the 42 specimens, 18 (42.86%) showed the presence of VM. VM was not correlated with the patients' age or gender, but with lymph node metastasis and the grade of tumor differentiation. Compared with tumors without VM, the tumors with VM had a significantly higher rate of lymph node metastasis (P<0.05) and a lower grade of differentiation (P<0.05). CONCLUSION: VM can be present in tongue squamous cell carcinoma, and the poorly differentiated tumors contain more VM, which is associated with a greater likeliness of lymph node metastasis and a poorer prognosis. PMID- 23644129 TI - [Effect of mannitol on serum tumor necrosis factor-alpha and interleukin-6 levels and the mechanism of its organ-protective effect in rabbits early after severe burn injury]. AB - OBJECTIVE: To investigate the protective effect of mannitol therapy on the vital organs and explore the underlying mechanisms in New Zealand rabbits with severe burn injury. METHODS: Twelve New Zealand rabbits with severe burn injury (30% of TBSA) were randomized to receive fluid resuscitation with saline (control) or mannitol therapy starting at 1 h after the injury. Serum and urine samples were collected before and at 1, 4, 8, 24, and 48 h after the injury for detection of TNF-alpha, IL-6, ALT, AST, GGT, CK, CK-MB, BUN and Cr levels using sandwich ELISA. RESULTS: One hour after sever burn injury, the serum levels of TNF-alpha and IL-6 began to increase along with ALT, AST, GGT, CK, CK-MB, BUN and Cr levels. Compared with control group, the rabbits in mannitol group showed significantly higher 48 h urine excretion of TNF-alpha (145 +/- 8 vs 78 +/- 1 0 pg/ml, P<0.05) and IL-6 (93 +/- 6 vs 40 +/- 8 pg/ml, P<0.05) but with lowered serum levels of TNF-alpha (0.62 +/- 0.02 vs 0.83 +/- 0.02 pg/ml, P<0.05) and IL-6 (0.45 +/- 0.03 vs 0.56 +/- 0.03 pg/ml, P<0.05) as well as lowered serum ALT, AST, GGT, CK, CK-MB, BUN and Cr levels (P<0.05). CONCLUSION: In rabbits with severe burn injury, mannitol therapy can decrease serum TNF-alpha and IL-6 levels early after the injury to ameliorate potential functional impairment of the heart, liver and kidneys. PMID- 23644130 TI - [A new method for distant Onyx injection for treatment of intracranial arteriovenous malformations: report of 26 cases]. AB - OBJECTIVE: To evaluate the feasibility, efficacy and safety of a new method for distant injection of Onyx for treatment of intracranial arteriovenous malformations (AVMs). METHODS: The clinical data of 26 patients with AVMs receiving distant injection of Onyx using the new method were retrospectively analyzed. Onyx was injected by the surgeon in the control room through a pressure transmission system. RESULTS: The 26 patients received a total of 31 embolization procedures, with an average estimated size reduction of AVMs of (61.48 +/- 26.85)%. Total obliteration was achieved in 3 AVMs. In one case, Onyx leakage occurred during the operation resulting from a broken microcatheter, and the patient developed hemiparesis after the operation. CONCLUSION: Endovascular treatment of intracranial AVMs with Onyx embolization using this new distant injection method is feasible, safe and effective. This method minimizes potential radiation exposure of the surgeons without increasing the risks of related complications. PMID- 23644132 TI - [Effect of dexmedetomidine in preventing shivering after general anesthesia for laparoscopic surgery: a randomized, single-blinded, and placebo-controlled trial]. AB - OBJECTIVE: To evaluate efficacy of dexmedetomidine in preventing shivering after general anesthesia in women undergoing laparoscopic surgery. METHODS: Eighty patients scheduled for laparoscopic gynecological surgery were randomized into dexmedetomidine group (n=40) and control group (n=40) to receive 1.0 ug/kg dexmedetomidine or an equal volume of saline slowly injected (for over 10 min) at 30 min before the anticipated completion of surgery. The postoperative incidences of shivering and the side effects were recorded. RESULTS: The patients in the control group showed a significantly higher postoperative incidence of shivering (37.5%) than those in dexmedetomidine group (P<0.05). Heart rate and mean arterial pressure showed significant variations postoperatively in dexmedetomidine group (P<0.05), which had a significantly greater sedation score (P<0.05), a higher incidence of dry mouth (P=0.000), but a significantly lower incidence of nausea and vomiting than the control group (P<0.05). CONCLUSION: Dexmedetomidine can lower the incidence of shivering after general anesthesia for laparoscopic gynecological surgery. PMID- 23644131 TI - [Pulmonary expression levels of fibroblast growth factor receptors and lung fibrosis in mice at different ages]. AB - OBJECTIVE: To explore the correlation of pulmonary expressions of fibroblast growth factor receptors (FGFR1-4) with lung fibrosis and aging. METHODS: Real time fluorescence quantitative PCR was used to detect the expression levels of FGFR1-4 in the lung tissues, and lung fibrosis was observed by HE and Masson staining in mice at different ages. RESULTS: The 4 subtypes of FGFR showed different expression levels in the lung tissues of mice, and FGFR2 had the highest expressions. The expression levels of all the 4 FGFR subtypes in 8-month old mice were significantly lower than those in 5-week-old mice. The 8-month-old mice tended to present with histological changes of lung fibrosis. CONCLUSION: FGFR expressions is down-regulated with aging in mice. Among the FGFR subtypes, FGFR2 is expressed at the highest level. The occurrence of lung fibrosis with aging is probably associated with down-regulated FGFR expression. FGF/FGFR signaling may participate in the aging process and regulation of lung fibrosis. PMID- 23644133 TI - [Expressions of fibroblast activation protein during skin scald burn healing in rats]. AB - OBJECTIVE: To investigate the time course of changes in the expression of fibroblast activation protein (FAP) during healing of skin scald burns in rats. METHODS: Adult Wistar rats were randomized into two equal groups (n=42) and subject to superficial second degree and deep second degree scald burns on the dorsal skin groups, with 6 normal rats serving as the control group. At 6 h, 12 h, and 1, 3, 7, 14, and 21 days after burns, 6 rats from each group were sacrificed to detect FAP expression by immunohistochemistry and Western blotting. RESULTS: FAP was expressed on the cell membrane and in the cytoplasm of the fibroblasts, especially those around the neovessels. In both burn groups, FAP expression increased significantly at 6 h after burns. In superficial burn group, FAP expression was comparable between 6 and 12 h and between 1 and 3 days (P>0.05), but showed significant differences between the other time points (P<0.05). In deep burn group, FAP expression was comparable between 12 h, 1 day and 3 days (P>0.05) but differed significantly between the other time points (P<0.05). In both burn groups, FAP expression reached the peak level at 7 days followed by a gradual declination. At 21 days after the burns, FAP maintained a significantly higher expression level than the control level (P<0.05). CONCLUSION: The time course of the changes of FAP expression following scald burns suggests an important role of FAP in the healing process of scald burns. PMID- 23644134 TI - [Diagnosis and treatment of glucagonoma: report of one case]. AB - OBJECTIVE: glucagonoma is a rare islet alpha-cell tumor. We report a case of glucagonoma in a 55-year-old male patient with such clinical findings of necrolytic migratory erythema, diabetes mellitus, body weight loss, and anemia. CT examination found a space-occupying lesion in the pancreas, and an elevated serum glucagon level indicate the diagnosis of glucagonoma, which was confirmed postoperatively by pathological examination of the tumor tissue. A definite diagnosis of glucagonoma relies on pathological report, and so far no standard treatment strategy has been available for this tumor. Surgical resection is an effective means for treatment of glucagonoma. PMID- 23644136 TI - In silico prediction of the effects of mutations in the human UDP-galactose 4' epimerase gene: towards a predictive framework for type III galactosemia. AB - The enzyme UDP-galactose 4'-epimerase (GALE) catalyses the reversible epimerisation of both UDP-galactose and UDP-N-acetyl-galactosamine. Deficiency of the human enzyme (hGALE) is associated with type III galactosemia. The majority of known mutations in hGALE are missense and private thus making clinical guidance difficult. In this study a bioinformatics approach was employed to analyse the structural effects due to each mutation using both the UDP-glucose and UDP-N-acetylglucosamine bound structures of the wild-type protein. Changes to the enzyme's overall stability, substrate/cofactor binding and propensity to aggregate were also predicted. These predictions were found to be in good agreement with previous in vitro and in vivo studies when data was available and allowed for the differentiation of those mutants that severely impair the enzyme's activity against UDP-galactose. Next this combination of techniques were applied to another twenty-six reported variants from the NCBI dbSNP database that have yet to be studied to predict their effects. This identified p.I14T, p.R184H and p.G302R as likely severely impairing mutations. Although severely impaired mutants were predicted to decrease the protein's stability, overall predicted stability changes only weakly correlated with residual activity against UDP galactose. This suggests other protein functions such as changes in cofactor and substrate binding may also contribute to the mechanism of impairment. Finally this investigation shows that this combination of different in silico approaches is useful in predicting the effects of mutations and that it could be the basis of an initial prediction of likely clinical severity when new hGALE mutants are discovered. PMID- 23644135 TI - Lactoferricin enhances BMP7-stimulated anabolic pathways in intervertebral disc cells. AB - Bone-morphogenetic protein-7 (BMP7) is a well-known anabolic and anti-catabolic growth factor on intervertebral disc (IVD) matrix and cell homeostasis. Similarly, Lactoferricin B (LfcinB) has recently been shown to have pro-anabolic, anti-catabolic, anti-oxidative and/or anti-inflammatory effects in bovine disc cells in vitro. In this study, we investigated the potential benefits of using combined peptide therapy with LfcinB and BMP7 for intervertebral disc matrix repair and to understand cellular and signaling mechanisms controlled by these factors. We studied the effects of BMP7 and LfcinB as individual treatments and combined therapy on bovine nucleus pulposus (NP) cells by assessing proteoglycan (PG) accumulation and synthesis, and the gene expression of matrix protein aggrecan and transcription factor SOX-9. We also analyzed the role of Noggin, a BMP antagonist, in IVD tissue and examined its effect after stimulation with LfcinB. To understand the molecular mechanisms by which LfcinB synergizes with BMP7, we investigated the ERK-SP1 axis as a downstream intracellular signaling regulator involved in BMP7 and LfcinB-mediated activities. Treatment of bovine NP cells cultured in alginate with LfcinB plus BMP7 synergistically stimulates PG synthesis and accumulation in part by upregulation of aggrecan gene expression. The synergism results from LfcinB-mediated activation of Sp1 and SMAD signaling pathways by (i) phosphorylation of SMAD 1/5/8; (ii) downregulation of SMAD inhibitory factors [i.e., noggin and SMAD6 (inhibitory SMAD)]; and (iii) upregulation of SMAD4 (universal co-SMAD). These data indicate that LfcinB suppression of Noggin may eliminate the negative feedback of BMP7, thereby maximizing biological activity of BMP7 and ultimately shifting homeostasis to a pro-anabolic state in disc cells. We propose that combination growth factor therapy using BMP7 and LfcinB may be beneficial for treatment of disc degeneration. PMID- 23644137 TI - Association between genetic polymorphisms of Toll-like receptor 2 (TLR2) and schizophrenia in the Korean population. AB - Immunological dysregulation has been suggested to be involved in the pathogenesis of schizophrenia. Accumulating evidences further implicate that activated inflammatory processes may be particularly relevant for the precipitation of negative and cognitive symptoms of schizophrenia. Toll-like receptor 2 (TLR2) plays an important role in innate immunity by sensing a variety of pathogens and inducing an acquired immunity. In the present study, we investigated whether the coding region of single nucleotide polymorphisms (SNPs) of the TLR2 gene was associated with schizophrenia as well as with clinical symptoms in schizophrenia patients. The study population consisted of 286 Korean schizophrenia patients and 305 Korean control subjects. The assessment of the Scale for the Assessment of Negative Symptoms was used to evaluate the negative symptoms of schizophrenia; the operational criteria checklist was used to measure general psychopathology. We selected two cSNPs [rs3804099 (Asn199Asn) and rs3804100 (Ser450Ser)] considering their heterozygosity and minor allele frequency. SNP genotyping was conducted using direct sequencing. We did not find any significant associations between SNPs and schizophrenia in the genotype and allelic frequencies. On the other hand, in the analysis of cognitive symptoms, rs3804099 showed significant differences in schizophrenia patients with poor concentration in the dominant model (TC/CC vs. TT, p=0.0099). Also, rs3804100 showed a significant association with poor concentration in the co-dominant (TC vs. TT, p=0.014) and the dominant models (TC/CC vs. TT, p=0.0035). We obtained no significant support for the association of the TLR2 gene with susceptibility to schizophrenia in the Korean population. However, our results provide possibility that C allele of rs3804099 and rs3804100 may be associated with poor concentration in schizophrenia patients. Further studies with larger samples are required to confirm our results. PMID- 23644138 TI - First evidence for the contribution of the genetic variations of BRCA1 interacting protein 1 (BRIP1) to the genetic susceptibility of cervical cancer. AB - BRIP1 (BRCA1-interacting protein 1), a DNA-dependent ATPase and a DNA helicase, is critical for BRCA-associated DNA damage repair functions, and may be involved in the development of cervical cancer. Genetic markers in different regions of the BRIP1 gene have a plausible role in modulating the risk of cervical cancer. In this study, we evaluate the association between the BRIP1 variations and the risk of cervix cancer. We examined the potential association between cervical cancer and eighteen single nucleotide polymorphisms (SNPs, rs2048718, rs16945692, rs4968451, rs6504074, rs4988344, rs8077088, rs10515211, rs9897121, rs9906313, rs2159450, rs4986764, rs11871785, rs4986763, rs11079454, rs7213430, rs34289250, rs4988345 and rs12937080) of the BRIP1 gene using the MassARRAY system. The participants enrolled in this study included 298 patients with cervical cancer and 286 healthy women as the healthy controls from a Chinese Han population. The results showed that rs16945692 (intron 1), rs4968451 (intron 4), rs4986764 (exon 18) and rs7213430 (3'UTR) were significantly associated with cervical cancer (P<0.05). Furthermore, strong linkage disequilibrium (LD) was observed in three blocks (D'>0.9), and significantly more T-A-C-A haplotypes (block 1) (P=0.001) were found in the patients with cervical cancer. Significantly higher frequencies of C-A-T haplotypes (block 2) (P=0.018) and A-A haplotypes (block 3) (P=0.009) were detected in the healthy controls than in the patients with cervical cancer, suggesting that they may show protective effects against cervical cancer. These findings point to a role for the BRIP1 gene polymorphisms in cervical cancer in a Chinese Han population, and may be informative for future genetic or biological studies on cervical cancer. PMID- 23644139 TI - High incidence of partial biotinidase deficiency cases in newborns of Greek origin. AB - Biotinidase deficiency (BTD) is an inherited disorder with severe clinical manifestations if not treated early. 63,119 neonates were tested for BTD according to a 3-step protocol. Biotinidase activity was initially estimated through standard colorimetric method on dried blood spots, then the suspected samples were subjected to molecular analysis of the BT gene and determination of BT activity in serum through an HPLC method. 14 infants with partial BTD (incidence 1:4508) were detected. Nine of them were homozygotes (D444H/D444H), and 4 compound heterozygotes carrying D444H combined with Q456H, T532M, C186Y and R157H, respectively. All were asymptomatic and supplemented with 10mg biotin. Although the number of screened neonates is rather small, it may be suggested that the incidence of the partial BTD infants is the highest ever reported. Detection of BTD should be added to the Greek national neonatal screening program. PMID- 23644140 TI - Genomic organization and expression analysis of a farnesyl diphosphate synthase gene (FPPS2) in apples (Malus domestica Borkh.). AB - A farnesyl diphosphate synthase gene (FPPS2), which contains 11 introns and 12 exons, was isolated from the apple cultivar "White Winter Pearmain". When it was compared to our previously reported FPPS1, its each intron size was different, its each exon size was the same as that of FPPS1 gene, 30 nucleotide differences were found in its coding sequence. Based on these nucleotide differences, specific primers were designed to perform expression analysis; the results showed that it expressed in both fruit and leaf, its expression level was obviously lower than that of FPPS1 gene in fruit which was stored at 4 degrees C for 5 weeks. This is the first report concerning two FPPS genes and their expression comparison in apples. PMID- 23644141 TI - Nobiletin protects against cerebral ischemia via activating the p-Akt, p-CREB, BDNF and Bcl-2 pathway and ameliorating BBB permeability in rat. AB - There is cumulative evidence that the serine-threonine kinase Akt and its downstream nuclear transcription factor CREB are involved in neuronal survival and protection. The Akt activates and phosphorylates CREB at Ser133, resulting in the up-regulation of pro-survival CREB target genes such as BDNF and Bcl-2. Thus, Akt/CREB signaling pathway may be one propitious target for treatment of ischemic cerebral injury. Nobiletin (NOB) exhibits a wide spectrum of beneficial biological properties including anti-inflammatory, antioxidant, anti-carcinogenic actions and contributes to reverse learning impairment in Alzheimer's disease rat. However, little is currently known regarding the exact role of NOB in ischemic stroke. Here, we designed to evaluate its possible therapeutic effect on cerebral ischemia. Adult male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (pMCAO) and randomly divided into five groups: Sham (sham-operated+0.05% Tween-80), MCAO (pMCAO+0.9% saline), Vehicle group (pMCAO+0.05% Tween-80), NOB-L (pMCAO+NOB 10 mg/kg) and NOB-H (pMCAO+NOB 25 mg/kg) groups. Rats were pre-administered intraperitoneally once daily for 3 days before surgery and then received once again immediately after surgery. Neurological deficit scores, brain water content and infarct volume were evaluated at 24 h after stroke. Additionally, the activities of Akt, CREB, BDNF, Bcl-2 and claudin 5 in ischemic brain cortex were analyzed by the methods of immunohistochemistry, western blot and RT-qPCR. Compared with Vehicle group, neurological deficits and brain edema were relieved in NOB-H group (P<0.05), infarct volume was lessened in both NOB-L and NOB-H groups (P<0.05) at 24 h after stroke. Immunohistochemistry, western blot and RT-qPCR analysis indicated that NOB dramatically promoted the activities of Akt, CREB, BDNF and Bcl-2 (P<0.05). Meanwhile, claudin-5 expression was also enhanced. On the basis of these findings, we concluded that NOB protected the brain from ischemic damage and it maybe through activating the Akt/CREB signaling pathway and ameliorating BBB permeability. PMID- 23644143 TI - Ionic liquid functionalized graphene/Au nanocomposites and its application for electrochemical immunosensor. AB - In this work, a new nanocomposite, which was composed of ionic liquid functionalized graphene sheet (IL-GS) loaded gold nanoparticles (AuNPs), was prepared. The IL-GS was directly synthesized by the electrochemical exfoliation of graphite in ionic liquid (IL). Due to the modification of the IL, IL-GS can not only be dispersed easily in aqueous solution to form a homogeneous colloidal suspension of individual sheet, but also exhibits an improved conductivity. Meanwhile, the loaded AuNPs on the nanocomposites can increase the specific surface area to capture a large amount of antibodies as well as improve the capability of electron transfer. The IL-GS-Au nanocomposites were successfully employed for the fabrication of a facile and sensitive electrochemical immunosensor. Carcinoembryonic antigen (CEA) was used as a model protein. The proposed immunosensor exhibits a wide linear detection range (LDR) from 1 fg mL-1 to 100 ng mL-1, and an ultralow limit of detection (LOD) of 0.1 fg mL-1 (S/N=3). In addition, for the detection of clinical serum samples, it is well consistent with the data determined by the developed immunoassay and ELISA, indicating that the immunosensor provides a possible application for the detection of CEA in clinical diagnostics. PMID- 23644142 TI - Effects of MK-801 and amphetamine treatments on allergic lung inflammatory response in mice. AB - Glutamate acts as a neurotransmitter within the Central Nervous System (CNS) and modifies immune cell activity. In lymphocytes, NMDA glutamate receptors regulate intracellular calcium, the production of reactive oxygen species and cytokine synthesis. MK-801, a NMDA receptor open-channel blocker, inhibits calcium entry into mast cells, thereby preventing mast cell degranulation. Several lines of evidence have shown the involvement of NMDA glutamate receptors in amphetamine (AMPH)-induced effects. AMPH treatment has been reported to modify allergic lung inflammation. This study evaluated the effects of MK-801 (0.25mg/kg) and AMPH (2.0mg/kg), given alone or in combination, on allergic lung inflammation in mice and the possible involvement of NMDA receptors in this process. In OVA-sensitized and challenged mice, AMPH and MK-801 given alone decreased cellular migration into the lung, reduced IL-13 and IL10 levels in BAL supernatant, reduced ICAM-1 and L-selectin expression in granulocytes in the BAL and decreased mast cell degranulation. AMPH treatment also decreased IL-5 levels. When both drugs were administered, treatment with MK-801 reversed the decrease in the number of eosinophils and neutrophils induced by AMPH in the BAL of OVA-sensitized and challenged mice as well as the effects on the expression of L-selectin and ICAM-1 in granulocytes, the IL-10, IL-5 and IL-13 levels in BAL supernatants and increased mast cell degranulation. At the same time, treatment with MK-801, AMPH or with MK-801+AMPH increased corticosterone serum levels in allergic mice. These results are discussed in light of possible indirect effects of AMPH and MK-801 via endocrine outflow from the CNS (i.e., HPA-axis activity) to the periphery and/or as a consequence of the direct action of these drugs on immune cell activity, with emphasis given to mast cell participation in the allergic lung response of mice. PMID- 23644144 TI - Time-resolved chemiluminescence strategy for multiplexed immunoassay of clenbuterol and ractopamine. AB - A novel time-resolved chemiluminescence (CL) strategy was proposed for immunoassay of multiple analytes in a single run. The strategy was performed based on the distinction of the kinetic characteristics of different CL reaction systems, which allowed detection of multiple analytes in different time windows. The strategy was evaluated by using clenbuterol and ractopamine as the model analytes. Horseradish peroxidase (HRP) and alkaline phosphatase (ALP) were adopted as the signal probes to tag the two antigens due to their very different CL kinetic characteristics. After the competitive immunoreactions, the two CL signals were simultaneously triggered by adding the CL coreactants. Then the signals for clenbuterol and ractopamine were in turn detected after 0.6 s and 25 min of the reaction triggering. Due to the distinguishable detection time windows for HRP and ALP, the cross-talk resulting from the mixed CL reaction systems was effectively avoided, which was frequently encountered in some other multiplexed immunoassays based on multi-label modes. The linear ranges for clenbuterol and ractopamine were both 1.0-500 ng/mL, with detection limits of 0.50 ng/mL (S/N=2). The results for real sample analysis demonstrated that this study could provide a simple, low-cost and fast approach toward multiplexed immunoassay. PMID- 23644145 TI - Indoor allergen assessment quantified by a thin-layer electrochemical cell and magnetic beads. AB - We report the electrochemical determination of mite allergen in real house dust by using a thin layer electrochemical flow cell and magnetic beads. Der p1, which is an allergen from Dermatophagoides pteronyssinus, was immunochemically sandwiched between two dispersed monoclonal antibodies; one was modified on the surface of magnetic beads and the other was modified with alkaline phosphatase. After washing the beads, a small volume of p-aminophenol phosphate (p-APP) was added to produce p-aminophenol (p-AP). And then the p-AP concentration was measured electrochemically with a homemade electrochemical cell. The Der p1 assay was completed within 30 min and a low detection limit of 0.3 ng/mL was achieved. This is because the diffusion distance of Der p1 and the detection antibody was reduced to 22.3 MUm by using dispersed magnetic beads. Only 10 min was required to complete the entire immunoreaction, and 54% of the Der p1 was confirmed to have immunoreacted in only 1 min of mixing. Furthermore, the p-APP volume could be reduced using the thin-layer electrochemical flow cell. This is advantageous in terms of concentrating p-AP, and provides a high signal-to-noise ratio measurement in a short time. We achieved a high correlation (r=0.967, p<0.001) between our assay and a conventional enzyme-linked immunosorbent assay (ELISA) for real house dust measurements. PMID- 23644146 TI - High-throughput single-cell analysis of low copy number beta-galactosidase by a laboratory-built high-sensitivity flow cytometer. AB - Single-cell analysis is vital in providing insights into the heterogeneity in molecular content and phenotypic characteristics of complex or clonal cell populations. As many essential proteins and most transcription factors are produced at a low copy number, analytical tools with superior sensitivity to enable the analysis of low abundance proteins in single cells are in high demand. beta-galactosidase (beta-gal) has been the standard cellular reporter for gene expression in both prokaryotic and eukaryotic cells. Here we report the development of a high-throughput method for the single-cell analysis of low copy number beta-gal proteins using a laboratory-built high-sensitivity flow cytometer (HSFCM). Upon fluorescence staining with a fluorogenic substrate, quantitative measurements of the basal and near-basal expression of beta-gal in single Escherichia coli BL21(DE3) cells were demonstrated. Statistical distribution can be determined quickly by analyzing thousands of individual cells in 1-2min, which reveals the heterogeneous expression pattern that is otherwise masked by the ensemble analysis. Combined with the quantitative fluorometric assay and the rapid bacterial enumeration by HSFCM, the beta-gal expression distribution profile could be converted from arbitrary fluorescence units to protein copy numbers per cell. The sensitivity and speed of the HSFCM offers great capability in quantitative analysis of low abundance proteins in single cells, which would help gaining a deeper insight into the heterogeneity and fundamental biological processes in microbial populations. PMID- 23644147 TI - Biomechanical properties of double- and single-row suture anchor repair for surgical treatment of insertional Achilles tendinopathy. AB - BACKGROUND: Because of intratendinous ossifications, retrocalcaneal bursitis, or intratendinous necrosis commonly found in insertional tendinosis, it is often necessary to detach the tendon partially or entirely from its tendon-to-bone junction. HYPOTHESIS: Double-row repair for insertional Achilles tendinopathy will generate an increased contact area and demonstrate higher biomechanical stability. STUDY DESIGN: Controlled laboratory study. METHODS: Eighteen cadaver Achilles tendons were split longitudinally and detached, exposing the calcaneus; an ostectomy was performed and the tendon was reattached to the calcaneus in 1 of 2 ways: 2 suture anchors (single row) or a 4-anchor (double row) construct. Footprint area measurements over time, displacement after cyclic loading (2000 cycles), and final load to failure were measured. RESULTS: The double-row refixation technique was statistically superior to the single-row technique in footprint area measurement initially and 5 minutes after repair (P = .009 and P = .01, respectively) but not after 24 hours (P = .713). The double-row construct demonstrated significantly improved measures for peak load (433.9 +/- 84.3 N vs 212.0 +/- 49.7 N; P = .042), load at yield (354.7 +/- 106.2 N vs 198.7 +/- 39.5 N; P = .01), and slope (51.8 +/- 9.9 N/mm vs 66.7 +/- 16.2 N/mm; P = .021). Cyclic loading did not demonstrate significant differences between the 2 constructs. CONCLUSION: Double-row construct for reinsertion of a completely detached Achilles tendon using proximal and distal rows resulted in significantly larger contact area initially and 5 minutes after repair and led to significantly higher peak load to failure on destructive testing. CLINICAL RELEVANCE: In treatment for insertional Achilles tendinosis, the tendon often has to be detached and anatomically reattached to its insertion at the calcaneus. To our knowledge there is a lack of biomechanical studies supporting either a number or a pattern of suture anchor fixation. Because the stresses going across the insertion site of the Achilles tendon are significant during rehabilitation and weightbearing activities, it is imperative to have a strong construct that allows satisfactory healing during the early postoperative process. PMID- 23644148 TI - Clinical and radiological outcomes of type 2 superior labral anterior posterior repairs in elite overhead athletes. AB - BACKGROUND: Although there are multiple reports on surgical outcomes of type 2 superior labral anterior posterior (SLAP) repairs, a literature review noted a paucity of data on clinical and radiological outcomes in elite overhead athletes. PURPOSE: To determine midterm clinical outcomes of type 2 SLAP repairs in elite overhead athletes and whether labral integrity provides consistent return to play. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Medical records were retrospectively reviewed of 24 elite overhead athletes who underwent arthroscopic type 2 SLAP repairs. There were 18 men and 6 women, and their mean age was 22.7 years (range, 19-30 years); the majority of them (16/24) were baseball players. Four outcome measures were used: visual analog scale (VAS) for pain and satisfaction, American Shoulder and Elbow Surgeons (ASES) score, subjective feeling of recovery, and return to play. Multidetector computed tomographic arthrography was performed to evaluate labral integrity after surgery. RESULTS: At a mean follow-up of 45.8 months (range, 24-68 months), overall pain and function improved significantly. The VAS for pain was 5.7 preoperatively and 2.0 postoperatively (P < .01), and VAS for satisfaction was 8.6. The ASES score was 55.8 preoperatively and 87.1 postoperatively (P < .01). The overall mean value of subjective feeling of recovery was approximately 76%. Twelve of 24 athletes (50%) returned to play after the operation. Although there was a trend toward higher return rate in the other overhead athletes (75%) compared with the baseball players (38%), this trend did not reach statistical significance (P = .097). Labral retear with clinical significance was noted in 2 athletes who failed to return to play. Osteolysis was observed in 2 athletes, 1 of whom had a retear. A statistical relation between the integrity of the repair and return to play was not found (P > .05). CONCLUSION: Arthroscopic SLAP repairs show favorable clinical and radiological outcomes; however, the study findings raise a concern that return to play may still be problematic in elite baseball players. This study also indicates that labral healing does not ensure consistent return to play in elite overhead athletes. PMID- 23644149 TI - Acetabular labral reconstruction with an iliotibial band autograft: outcome and survivorship analysis at minimum 3-year follow-up. AB - BACKGROUND: Injury to the acetabular labrum results from multiple causes including femoroacetabular impingement, dysplasia, and acute trauma. The patient's labrum can be reconstructed utilizing an iliotibial band autograft that is tubularized and fixed to the acetabular rim, substituting for the patient's own labrum. Purpose/ HYPOTHESIS: The purpose of this study was to evaluate the midterm results of this technique with a follow-up from 3 to 6 years after reconstruction. The hypothesis was that midterm results would show excellent patient-reported outcomes and high patient satisfaction with outcome. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A retrospective review of a prospectively collected registry was undertaken that identified 75 patients (76 hips) who underwent arthroscopic labral reconstruction using an iliotibial band autograft by a single surgeon from February 2005 to August 2008. Modified Harris Hip Score (mHHS), Hip Outcome Score (HOS), and patient satisfaction level (on a scale of 1-10) were recorded preoperatively and postoperatively annually. Survivorship analysis curves were created to evaluate the effectiveness of this technique. RESULTS: Among 76 hips, 19 progressed to total hip arthroplasty at an average of 28 months from the procedure. Mean survivor time (no arthroplasty) was 59.1 months (95% CI, 53.9-64.4). Follow-up on the surviving hips was available for 49 patients (86%) with a mean follow-up time of 49 months (range, 36-70 months). The mHHS significantly increased from a preoperative mean of 58.9 to the most recent follow-up score averaging 83 (P = .0001); HOS values in the sports and the activities of daily living subscales also increased significantly (P = .0001 and P = .001, respectively). Median patient satisfaction with outcome was 8. A joint space of <=2 mm was found to be a poor prognostic factor for survival of the hip. CONCLUSION: Arthroscopic labral reconstruction using an iliotibial band autograft resulted in a survivorship of 56 months. Of the 76% of patients who did not require total hip arthroplasty, improvement in function and high satisfaction with outcome were reported. Joint space of <=2 mm is a contraindication for acetabular labral reconstruction. PMID- 23644150 TI - conF and conJ contribute to conidia germination and stress response in the filamentous fungus Aspergillus nidulans. AB - Light induces various responses in fungi including formation of asexual and sexual reproductive structures. The formation of conidia in the filamentous fungus Aspergillus nidulans is regulated by red and blue light receptors. Expression of conidia associated con genes, which are widely spread in the fungal kingdom, increases upon exposure to light. We have characterized the light inducible conF and conJ genes of A. nidulans which are homologs of con-6 and con 10 of Neurospora crassa. con genes are expressed during conidia formation in asexual development. Five minutes light exposure are sufficient to induce conF or conJ expression in vegetative mycelia. Similar to N. crassa there were no significant phenotypes of single con mutations. A double conF and conJ deletion resulted in significantly increased cellular amounts of glycerol or erythritol. This leads to a delayed germination phenotype combined with increased resistance against desiccation. These defects were rescued by complementation of the double mutant strain with either conF or conJ. This suggests that fungal con genes exhibit redundant functions in controlling conidia germination and adjusting cellular levels of substances which protect conidia against dryness. PMID- 23644151 TI - Transcriptomic profiling of Aspergillus flavus in response to 5-azacytidine. AB - Aspergillus flavus is a common saprophyte and opportunistic pathogen producing aflatoxin (AF) and many other secondary metabolites. 5-Azacytidine (5-AC), a derivative of the nucleoside cytidine, is widely used for studies in epigenetics and cancer biology as an inactivator of DNA methyltransferase and is also used for studying secondary metabolism in fungi. Our previous studies showed that 5-AC affects development and inhibits AF production in A. flavus, and that A. flavus lacks DNA methylation. In this study, an RNA-Seq approach was applied to explore the mechanism of 5-AC's effect on A. flavus. We identified 240 significantly differentially expressed (Q-value<0.05) genes after 5-AC treatment, including two backbone genes respectively in secondary metabolite clusters #27 and #35. These two clusters are involved in development or survival of sclerotia. GO functional enrichment analysis showed that these significantly differentially expressed genes were mainly involved in catalytic activity and proteolytic functions. The expressed transcripts of most genes in the AF biosynthetic gene cluster in A. flavus showed no significant changes after treatment with 5-AC and were expressed at low levels, and the transcription regulator genes aflR and aflS in this cluster did not show differential expression relative to the sample without 5-AC treatment. We found that the veA gene, which encodes protein bridges VelB and LaeA, decreased profoundly the expressed transcripts, and brlA, which encodes an early regulator of development, increased its transcripts in A. flavus after 5-AC treatment. Our data support a model whereby 5-AC affects development through increasing the expression of brlA by depressing the expression of veA and AF production through suppressing veA expression and dysregulating carboxypeptidase activity, which then prevents the aflatoxisomes (vesicles) from performing their normal function in AF formation. Furthermore, the suppressed veA expression weakens or even interrupts the connection between VelB and LaeA, leading to dysregulation of the expression pattern of genes involved in development and secondary metabolism in A. flavus. The RNA-seq data presented in this work were also served to improve the annotation of the A. flavus genome. This work provides a comprehensive view of the transcriptome of A. flavus responsive to 5-AC and supports the conclusion that fungal development and secondary metabolism are co regulated. PMID- 23644152 TI - Diploptera punctata as a model for studying the endocrinology of arthropod reproduction and development. AB - The Pacific beetle cockroach, Diploptera punctata, has proven to be a valuable model insect in the study of the dynamics regulating juvenile hormone (JH) biosynthesis and metabolism, particularly during late nymphal development and reproduction. This stems in part from its unusual mode of reproduction, adenotrophic viviparity, in which females give birth to live young that have been nourished throughout embryonic development by a protein-rich 'milk' secreted by the wall of the brood sac or uterus. In this animal, as in most insects, JH regulates both vitellogenin production and its uptake by developing oocytes. However, JH has an antagonistic effect on embryonic development and following oviposition of the fertilized oocytes into the brood sac, JH production halts, in part through the action of a peptide family, the FGLa allatostatins. JH production remains at a low level throughout pregnancy and is only reinstated at the end of gestation, at which time, the next wave of oocytes begins to develop and enter vitellogenesis. Thus, JH production in this species is precisely regulated, since the appearance of JH at inappropriate times would result in abortion of the embryos. Numerous factors are responsible for the regulation of JH biosynthesis, including peptides, biogenic amines, neurotransmitters, ecdysteroids and second messenger effectors. In this review, we discuss these factors and highlight potentially fruitful areas of future research. Although several of the enzymes of the biosynthetic pathway have been cloned, the precise points of rate limitation remain uncertain. The dissection of the biosynthetic pathway and its control awaits the completion of the genome and transcriptome of this important model insect. PMID- 23644153 TI - Human chorionic gonadotropin (hCG) induces MAPK3/1 phosphorylation in the zebrafish ovarian follicle cells independent of EGF/EGFR pathway. AB - In mammals, human chorionic gonadotropin (hCG), a luteinizing hormone (LH) analogue, induces MAPK3/1 phosphorylation in the granulosa cells and this event is largely dependent on epidermal growth factor receptor (EGFR) activity. However, whether this mechanism also works in other vertebrates such as fish remains unknown. Here, we showed that treatment of cultured zebrafish ovarian follicle cells with hCG also resulted in MAPK3/1 phosphorylation without affecting the total protein level of MAPK3/1. The phosphorylation level peaked at 5 min and then declined to the basal level after 40 min of hCG treatment. Further experiment showed that H89 (a PKA inhibitor) could abolish hCG-stimulated MAPK3/1 phosphorylation, but had no effect on EGF-induced phosphorylation, suggesting a mediating role for cAMP/PKA in hCG activation of MAPK3/1. On the other hand, AG1478 (an EGFR inhibitor) completely blocked EGF-stimulated MAPK3/1 phosphorylation, but had no effect on the hCG-induced MAPK3/1 phosphorylation. These data indicate that similar to its action in mammals, hCG/LH also stimulated MAPK3/1 phosphorylation in the zebrafish ovarian follicle cells; however, unlike the situation in the mammalian ovary, the hCG-stimulated MAPK3/1 phosphorylation in cultured zebrafish ovarian follicle cells was independent of EGFR. PMID- 23644154 TI - Expression of CCT6A mRNA in chicken granulosa cells is regulated by progesterone. AB - CCT6A, the zeta subunit of the chaperonin containing TCP1 complex, is the only cytosolic chaperonin in eukaryotes and is estimated to assist in the folding of multiple proteins including actin, tubulin, cyclin E, myosin, transducin and the Von Hippel Lindau tumor suppressor. In this study, we examined the expression of CCT6A and progesterone receptor (PGR) mRNA in various tissues of chickens and the regulation of CCT6A and PGR mRNA in ovarian granulosa cells. Northern blot analysis revealed that CCT6A had one transcript and was highly expressed in the ovary tissues from chickens at both the sexually immature and mature stages. CCT6A mRNA expression was increased maximally from pre-hierarchy follicles to F5 follicles and subsequently declined in pre-ovulatory and post-ovulatory follicles. The expression of PGR mRNA exhibited the similar pattern to CCT6A. In granulosa cells isolated from pre-ovulatory follicles, follicle-stimulating hormone (FSH) inhibited the expression of CCT6A mRNA, whereas progesterone activated CCT6A and suppressed PGR expression in a time-dependent manner. We further investigated the regulation of CCT6A transcription by progesterone by constructing various progressive deletions and mutants and identified the core promoter element of CCT6A and the binding region of progesterone, which is located from -2056 to -2051. Taken together, our results indicate that CCT6A likely plays an important role in follicle growth, and in granulosa cells, progesterone activates CCT6A transcription via a progesterone response element (PRE) located in the distal promoter of CCT6A. PMID- 23644155 TI - Suppression effect of LHRH-A and hCG on Piwi expression in testis of Nile tilapia Oreochromis niloticus. AB - Piwi proteins as constituent factors of the piRNA pathway are required for germline maintenance, meiosis and gonad development. Previous study showed hCG could regulate the Piwi expression in ovary of teleosts. In this study, we revealed effects of LHRH-A and hCG on Piwi expression in testis of tilapia using Real-time PCR and Western blot. Both in vivo and in vitro study suggest that LHRH A and hCG significantly down-regulated Piwil-1 and Piwil-2 in mRNA or protein levels compared with controls. Meanwhile, tissue and cell distribution showed that Piwi proteins were mainly expressed in spermatocytes rather than mature sperms. These results indicated that HPG suppresses Piwis which may play a crucial role in testis differentiation and development. PMID- 23644156 TI - An anti-steroidogenic inhibitory primer pheromone in male sea lamprey (Petromyzon marinus). AB - Reproductive functions can be modulated by both stimulatory and inhibitory primer pheromones released by conspecifics. Many stimulatory primer pheromones have been documented, but relatively few inhibitory primer pheromones have been reported in vertebrates. The sea lamprey male sex pheromone system presents an advantageous model to explore the stimulatory and inhibitory primer pheromone functions in vertebrates since several pheromone components have been identified. We hypothesized that a candidate sex pheromone component, 7alpha, 12alpha-dihydroxy 5alpha-cholan-3-one-24-oic acid (3 keto-allocholic acid or 3kACA), exerts priming effects through the hypothalamic-pituitary-gonadal (HPG) axis. To test this hypothesis, we measured the peptide concentrations and gene expressions of lamprey gonadotropin releasing hormones (lGnRH) and the HPG output in immature male sea lamprey exposed to waterborne 3kACA. Exposure to waterborne 3kACA altered neuronal activation markers such as jun and jun N-terminal kinase (JNK), and lGnRH mRNA levels in the brain. Waterborne 3kACA also increased lGnRH-III, but not lGnRH-I or -II, in the forebrain. In the plasma, 3kACA exposure decreased all three lGnRH peptide concentrations after 1h exposure. After 2h exposure, 3kACA increased lGnRH-I and -III, but decreased lGnRH-II peptide concentrations in the plasma. Plasma lGnRH peptide concentrations showed differential phasic patterns. Group housing condition appeared to increase the averaged plasma lGnRH levels in male sea lamprey compared to isolated males. Interestingly, 15alpha hydroxyprogesterone (15alpha-P) concentrations decreased after prolonged 3kACA exposure (at least 24h). To our knowledge, this is the only known synthetic vertebrate pheromone component that inhibits steroidogenesis in males. PMID- 23644157 TI - The expression of human leukocyte antigen G (HLA-G) is associated with sacroiliitis stages of ankylosing spondylitis. AB - Recent studies have demonstrated that human leukocyte antigen G (HLA-G) may play an important role in autoimmune diseases. The present study is to investigate whether or not HLA-G is associated with sacroiliitis stages of ankylosing spondylitis (AS), a systemic autoimmune disease. Plasma levels of soluble HLA-G (sHLA-G) and HLA-G expression on the surface of peripheral blood mononuclear cells (PBMCs) were measured in 55 AS patients and 49 healthy controls by using a specific HLA-G ELISA and flow cytometric (FCM) analysis, respectively. Association of HLA-G expression with sacroiliitis stages of the patients was statistically analyzed. The plasma sHLA-G concentrations were noticeably lower in the AS patients when compared to the healthy controls while the mean fluorescence intensity (MFI) of the HLA-G expression on the surface of PBMCs was significantly higher in the AS patients than in the healthy controls (both P<0.0001). The HLA-G expression on the surface of PBMCs, plasma sHLA-G levels and HLA-B27 expression were significantly correlated to each other. Moreover, the plasma sHLA-G was inversely associated with the sacroiliitis stages (P=0.008), while the HLA-G expression on the surface of PBMCs increased from stage 0 to II but decreased in stage III (P=0.001). The significant association of HLA-G expressions with AS sacroiliitis stages suggests that HLA-G is possibly involved in the pathology of the disease. The detection of HLA-G expression may therefore be a useful laboratory test to reveal disease process in AS patients. PMID- 23644158 TI - Isoprostanes and neuroprostanes: total synthesis, biological activity and biomarkers of oxidative stress in humans. AB - Isoprostanes (IsoPs) and neuroprostanes (NeuroPs) are formed in vivo by a free radical non-enzymatic mechanism involving peroxidation of arachidonic acid (AA, C20:4 n-6) and docosahexaenoic acid (DHA, C22:6 n-3) respectively. This review summarises our research in the total synthesis of these lipid metabolites, as well as their biological activities and their utility as biomarkers of oxidative stress in humans. PMID- 23644160 TI - Differential effects of spaced vs. massed training in long-term object-identity and object-location recognition memory. AB - Here we tested whether the well-known superiority of spaced training over massed training is equally evident in both object identity and object location recognition memory. We trained animals with objects placed in a variable or in a fixed location to produce a location-independent object identity memory or a location-dependent object representation. The training consisted of 5 trials that occurred either on one day (Massed) or over the course of 5 consecutive days (Spaced). The memory test was done in independent groups of animals either 24h or 7 days after the last training trial. In each test the animals were exposed to either a novel object, when trained with the objects in variable locations, or to a familiar object in a novel location, when trained with objects in fixed locations. The difference in time spent exploring the changed versus the familiar objects was used as a measure of recognition memory. For the object-identity trained animals, spaced training produced clear evidence of recognition memory after both 24h and 7 days, but massed-training animals showed it only after 24h. In contrast, for the object-location-trained animals, recognition memory was evident after both retention intervals and with both training procedures. When objects were placed in variable locations for the two types of training and the test was done with a brand-new location, only the spaced-training animals showed recognition at 24h, but surprisingly, after 7 days, animals trained using both procedures were able to recognize the change, suggesting a post-training consolidation process. We suggest that the two training procedures trigger different neural mechanisms that may differ in the two segregated streams that process object information and that may consolidate differently. PMID- 23644159 TI - Optimising the quantification of cytokines present at low concentrations in small human mucosal tissue samples using Luminex assays. AB - Sensitive measurement of multiple cytokine profiles from small mucosal tissue biopsies, for example human gastric biopsies obtained through an endoscope, is technically challenging. Multiplex methods such as Luminex assays offer an attractive solution but standard protocols are not available for tissue samples. We assessed the utility of three commercial Luminex kits (VersaMAP, Bio-Plex and MILLIPLEX) to measure interleukin-17A (IL-17) and interferon-gamma (IFNgamma) concentrations in human gastric biopsies and we optimised preparation of mucosal samples for this application. First, we assessed the technical performance, limits of sensitivity and linear dynamic ranges for each kit. Next we spiked human gastric biopsies with recombinant IL-17 and IFNgamma at a range of concentrations (1.5 to 1000 pg/mL) and assessed kit accuracy for spiked cytokine recovery and intra-assay precision. We also evaluated the impact of different tissue processing methods and extraction buffers on our results. Finally we assessed recovery of endogenous cytokines in unspiked samples. In terms of sensitivity, all of the kits performed well within the manufacturers' recommended standard curve ranges but the MILLIPLEX kit provided most consistent sensitivity for low cytokine concentrations. In the spiking experiments, the MILLIPLEX kit performed most consistently over the widest range of concentrations. For tissue processing, manual disruption provided significantly improved cytokine recovery over automated methods. Our selected kit and optimised protocol were further validated by measurement of relative cytokine levels in inflamed and uninflamed gastric mucosa using Luminex and real-time polymerase chain reaction. In summary, with proper optimisation Luminex kits (and for IL-17 and IFNgamma the MILLIPLEX kit in particular) can be used for the sensitive detection of cytokines in mucosal biopsies. Our results should help other researchers seeking to quantify multiple low concentration cytokines in small tissue samples. PMID- 23644161 TI - A schizophrenia rat model induced by early postnatal phencyclidine treatment and characterized by Magnetic Resonance Imaging. AB - Better animal models are needed to aid the development of new medications to alleviate the cognitive deficits associated with schizophrenia. Growing evidence suggests neurodevelopmental insults and disturbances in NMDA receptor (NMDAR) signaling to be involved in the schizophrenia etiology. Acute administration of phencyclidine (PCP) induces schizophrenia-like symptoms in healthy volunteers and exacerbates symptoms in patients with schizophrenia. In this study, pharmacological Magnetic Resonance Imaging (phMRI) was used to evaluate if rats treated with 20mg/kg PCP on postnatal days 7, 9, and 11 (neoPCP), compared to saline (neoVeh), were hypersensitive to acute PCP administration in adulthood (acutePCP). Intravenous administration of 0.5mg/kg acutePCP produced robust and sustained relative cerebral blood volume (rCBV) increase in discrete frontal, neocortical, hippocampal, thalamic, and limbic brain structures in both neoPCP:acutePCP and neoVeh:acutePCP rats compared to acute saline treatment (Vehicle control group). AcutePCP injection significantly increased the rCBV response in the medial prefrontal cortex and nucleus accumbens compared to the Vehicle control group, without distinguishing neoPCP and neoVeh animals. However, at late time points (25-33min post acutePCP injection), neoPCP animals showed significantly higher rCBV values compared to the Vehicle control group, suggesting an altered sensitivity toward NMDAR blockade in adult rats subjected to this neurodevelopmental procedure. In combination with the observed cognitive deficits revealed in this animal model, the present findings indicate that altered NMDAR signaling might underlie the symptomatic changes seen in schizophrenia, adding to the construct and face validity of this model. PMID- 23644162 TI - Thermoluminescence responses of photon- and electron-irradiated lithium potassium borate co-doped with Cu+Mg or Ti+Mg. AB - New glasses Li2CO3-K2CO3-H3BO3 (LKB) co-doped with CuO and MgO, or with TiO2 and MgO, were synthesized by the chemical quenching technique. The thermoluminescence (TL) responses of LKB:Cu,Mg and LKB:Ti,Mg irradiated with 6 MV photons or 6 MeV electrons were compared in the dose range 0.5-4.0 Gy. The standard commercial dosimeter LiF:Mg,Ti (TLD-100) was used to calibrate the TL reader and as a reference in comparison of the TL properties of the new materials. The dependence of the responses of the new materials on (60)Co dose is linear in the range of 1 1000 Gy. The TL yields of both of the co-doped glasses and TLD-100 are greater for electron irradiation than for photon irradiation. The TL sensitivity of LKB:Ti,Mg is 1.3 times higher than the sensitivity of LKB:Cu,Mg and 12 times less than the sensitivity of TLD-100. The new TL dosimetric materials have low effective atomic numbers, good linearity of the dose responses, excellent signal reproducibility, and a simple glow curve structure. This combination of properties makes them suitable for radiation dosimetry. PMID- 23644163 TI - Genetic variation in brown fat activity and body weight regulation in mice: lessons for human studies. AB - The recent characterization of brown fat in humans has generated much excitement on the possibility that increased energy expenditure by heat production by this tissue will be able to reduce obesity. This expectation has largely been stimulated by studies with mice that show strong associations between increased brown fat activity and reductions in obesity and insulin resistance. Research in the mouse has been largely based upon the induction or suppression of brown fat and mitochondrial uncoupling protein by genetic methods. The review of this research literature underscores the idea that reductions in obesity in mice are secondary to the primary role of brown adipose tissue in the regulation of body temperature. Given that the variation in brown fat in humans, as detected by PET imaging, is highly associated with administration of adrenergic agonists and reductions in ambient temperature, the effects on obesity in humans may also be secondary to the regulation of body temperature. Induction of thermogenesis by reduced ambient temperature now becomes like muscle and physical activity, another natural method of increased energy expenditure to combat obesity. Furthermore, there is no evidence to indicate that heat production by adrenergic stimulation via cold exposure or drug treatment or the enriched physical environment is restricted to the thermogenic activity of the brown adipocyte. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. PMID- 23644164 TI - Hepatocystin/80K-H inhibits replication of hepatitis B virus through interaction with HBx protein in hepatoma cell. AB - Hepatitis B virus (HBV) X protein (HBx) is a key player in HBV replication as well as HBV-induced hepatocellular carcinoma (HCC). However, the pathogenesis of HBV infection and the mechanisms of host-virus interactions are still elusive. In this study, a combination of affinity purification and mass spectrometry was applied to identify the host factors interacting with HBx in hepatoma cells. Thirteen proteins were identified as HBx binding partners. Among them, we first focused on determining the functional significance of the interaction between HBx and hepatocystin. A physical interaction between HBx and hepatocystin was confirmed by co-immunoprecipitation and Western blotting. Immunocytochemistry demonstrated that HBx and hepatocystin colocalized in the hepatoma cells. Domain mapping of both proteins revealed that the HBx C-terminus (amino acids 110-154) was responsible for binding to the mannose 6-phosphate receptor homology domain (amino acids, 419-525) of hepatocystin. Using translation and proteasome inhibitors, we found that hepatocystin overexpression accelerated HBx degradation via a ubiquitin-independent proteasome pathway. We demonstrated that this effect was mediated by an interaction between both proteins using a HBx deletion mutant. Hepatocystin overexpression significantly inhibited HBV DNA replication and expression of HBs antigen concomitant with HBx degradation. Using the hepatocystin mutant constructs that bind HBx, we also confirmed that hepatocystin inhibited HBx-dependent HBV replication. In conclusion, we demonstrated for the first time that hepatocystin functions as a chaperon-like molecule by accelerating HBx degradation, and thereby inhibits HBV replication. Our results suggest that inducing hepatocystin may provide a novel therapeutic approach to control HBV infection. PMID- 23644165 TI - Media use and HIV/AIDS knowledge: a knowledge gap perspective. AB - Despite the widespread utilization of the mass media in HIV/AIDS prevention, little is known about the knowledge gap that results from disparities in mass media use. This study examined the relationship between HIV/AIDS-related mass media use and HIV/AIDS-related knowledge among urban and rural residents of northwestern Ethiopia. A hierarchical regression analysis indicated that HIV/AIDS related mass media use has both sequestering and mainstreaming effects in certain segments of the study population, although it was not a significant predictor of HIV/AIDS-related knowledge in the total population. The knowledge gaps between individuals with high and low education and between individuals who experience high and low levels of interpersonal communication about HIV/AIDS narrowed as HIV/AIDS-related media use increased, but the gap between urban and rural residents widened. The widening gap could be explained by differences in perceptions of information salience and several theoretical assumptions. Current mass media information campaigns, which are often prepared and broadcast from urban centers, may not only fail to improve the HIV/AIDS knowledge of the rural populace but also put rural populations at a disadvantage relative to their urban counterparts. Communication interventions informed by socioecological models might be helpful to redress and/or narrow the widening knowledge gap between urban and rural residents. PMID- 23644166 TI - Does the recommended lymphocyte cytokinesis-block micronucleus assay for human biomonitoring actually detect DNA damage induced by occupational and environmental exposure to genotoxic chemicals? AB - This commentary challenges the paradigm that the cytokinesis-block micronucleus assay (CBMN assay) with cultured human lymphocytes, as it is performed currently, is a sensitive and useful tool for detecting genotoxic effects in populations exposed occupationally or environmentally to genotoxic chemicals. Based on the principle of the assay and the available data, increased micronucleus (MN) frequencies in binucleated cells (BNC) are mainly due to MN produced in vitro during the cultivation period (i.e. MN produced in vivo do not substantially contribute to the MN frequency measured in BNC). The sensitivity of the assay for the detection of induced MN in BNC after an in vivo exposure to a genotoxic chemical is limited because cytochalasin B (Cyt-B) is added relatively late during the culture period and, therefore, the BNC that are scored do not always represent cells that have completed one cell cycle only. Furthermore, this delay means that damaged cells can be eliminated by apoptosis and/or that DNA damage induced in vivo can be repaired prior to the production of a MN in the presence of Cyt-B. A comparison with the in vitro CBMN assay used for genotoxicity testing leads to the conclusion that it is highly unlikely that DNA damage induced in vivo is the cause for increased MN frequencies in BNC after occupational or environmental exposure to genotoxic chemicals. This commentary casts doubt on the usefulness of the CBMN assay as an indicator of genotoxicity in human biomonitoring and questions the relevance of many published data for hazard identification and risk assessment. Thus, it seems worthwhile to reconsider the use of the CBMN assay as presently conducted for the detection of genotoxic exposure in human biomonitoring. PMID- 23644168 TI - Weight Gain While Switching from Polypharmacy to Ziprasidone: A Case Report. AB - Second-generation antipsychotics (SGAs), valproate, and sulpiride are related to significant weight gain and risk of metabolic syndrome (MetS). Among SGAs, olanzapine and clozapine are associated with the highest metabolic risk while ziprasidone is among one of the SGAs with the lowest risk. Several reports suggest that weight loss is observed in switching other antipsychotics to ziprasidone. Here we describe a female patient with chronic paranoid schizophrenia who had an unexpected weight gain and developed MetS during a cross switch from a polypharmacy of olanzapine, valproate and sulpiride to ziprasidone monotherapy. PMID- 23644167 TI - Late-onset psychosis and risedronate treatment for osteoporosis. AB - As women age and enter menopause, they are sometimes more susceptible than men to certain physical and mental disorders such as osteoporosis and late-onset schizophrenia. Risedronate (Actonel(c)) is a bisphosphonate used for the treatment of osteopenia. Early initiation of pharmacotherapy for osteopenia is recommended to prevent greater bone loss. The most common side effects of risedronate include fever and flu-like symptoms, hypocalcemia, bone and joint pain, peripheral edema, fatigue, change in bowel movements, osteonecrosis of the jaw, and atrial fibrillation. Though reports in the professional literature of psychotic reactions to risedronate are scant, there have been FDA reports as well as patient discussions of psychiatric side effects from this medication on popular websites. We report the case of M, age 59, who was treated with risedronate for osteoporosis, and was subsequently diagnosed with atypical psychosis after other organic causes were excluded. Though it is conceivable that age-related psychosocial and physical factors triggered late-onset schizophrenia, the temporal relationship between the termination of treatment with risedronate and the improvement in her mental state suggests that the risedronate might have triggered a psychotic reaction that resolved following cessation of treatment. PMID- 23644169 TI - Long-acting injectable aripiprazole: how might it fit in our tool box? AB - Schizophrenia is a severe mental illness with a lifetime prevalence of approximately one percent worldwide. Maintenance antipsychotic treatment has been effective in preventing relapses in long-term follow-up studies. Logically it can be proposed that long-acting injectable antipsychotics (LAI) might reduce both unintentional and intentional nonadherence. Long-acting injectable aripiprazole was approved for the treatment of schizophrenia by the U.S. FDA on 28th February 2013 and will be marketed under the name Abilify Maintena. Aripiprazole LAI (ALAI) is a lyophilized powder that needs to be reconstituted with sterile water to form an injectable suspension without affecting the original molecule. The monthly injection interval is very attractive since patients prefer fewer injections. From a tolerability perspective, ALAI appears to be both weight neutral and lacking metabolic side effects. This can confer an advantage over the other currently available second-generation antipsychotic LAIs. Simple constitution with sterile water and no requirement to refrigerate make storage and administration easier. Like all medications, there are always potential disadvantages to ALAI. There is a period of oral coverage, while not as long as for long-acting risperidone microspheres (RLAI), that is required. Care must be taken to review concomitant medications for the presence of metabolic inducers and inhibitors. One would also expect some patients to be sensitive to extrapyramidal symptoms, especially akathisia which is well documented in the oral preparation. All things considered, we welcome our new tool, ALAI, to our work-place and predict both clinical practice and post marketing analysis and studies will discover its true value. PMID- 23644170 TI - Social Stigma and Well-Being in a Sample of Schizophrenia Patients. AB - OBJECTIVE: The present study analyzes the existing relationship between three variables related to social rejection (perception of overt and subtle discrimination and stigma consciousness) and the psychological and subjective well-being among people with schizophrenia. Likewise, we will analyze the relationship between two possible strategies to cope with stigma (active coping and avoidant coping) and well-being. METHOD: A cross-sectional study was conducted in a sample of 50 people with schizophrenia recruited from the social care network for people with mental illness in the Community of Madrid. RESULTS: Results show, as expected, the existence of a negative association between the variables related to social rejection and psychological and subjective well being. It was also found that avoidant coping is negatively related to well being, while active coping is positively related, although in the latter case relations do not reach significance. CONCLUSIONS: In view of the implementation of interventions to improve the well-being of people with schizophrenia, our results suggest implementing strategies to reduce the perception of discrimination (especially subtle or indirect discrimination) and encouraging the use of active strategies to cope with stigma as opposed to avoidant-coping strategies. PMID- 23644171 TI - Arginine vasotocin and androgen pathways are associated with mating system variation in North American cichlid fishes. AB - Neuroendocrine pathways that regulate social behavior are remarkably conserved across divergent taxa. The neuropeptides arginine vasotocin/vasopressin (AVT/AVP) and their receptor V1a mediate aggression, space use, and mating behavior in male vertebrates. The hormone prolactin (PRL) also regulates social behavior across species, most notably paternal behavior. Both hormone systems may be involved in the evolution of monogamous mating systems. We compared AVT, AVT receptor V1a2, PRL, and PRL receptor PRLR1 gene expression in the brains as well as circulating androgen concentrations of free-living reproductively active males of two closely related North American cichlid species, the monogamous Herichthys cyanoguttatus and the polygynous Herichthys minckleyi. We found that H. cyanoguttatus males bond with a single female and together they cooperatively defend a small territory in which they reproduce. In H. minckleyi, a small number of large males defend large territories in which they mate with several females. Levels of V1a2 mRNA were higher in the hypothalamus of H. minckleyi, and PRLR1 expression was higher in the hypothalamus and telencephalon of H. minckleyi. 11-ketotestosterone levels were higher in H. minckleyi, while testosterone levels were higher in H. cyanoguttatus. Our results indicate that a highly active AVT/V1a2 circuit(s) in the brain is associated with space use and social dominance and that pair bonding is mediated either by a different, less active AVT/V1a2 circuit or by another neuroendocrine system. PMID- 23644172 TI - Epidermal growth factor receptor transactivation by intracellular prostaglandin E2-activated prostaglandin E2 receptors. Role in retinoic acid receptor-beta up regulation. AB - The pharmacological modulation of renoprotective factor vascular endothelial growth factor-A (VEGF-A) in the proximal tubule has therapeutic interest. In human proximal tubular HK-2 cells, treatment with all-trans retinoic acid or prostaglandin E2 (PGE2) triggers the production of VEGF-A. The pathway involves an initial increase in intracellular PGE2, followed by activation of EP receptors (PGE2 receptors, most likely an intracellular subset) and increase in retinoic acid receptor-beta (RARbeta) expression. RARbeta then up-regulates transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), which increases the transcription and production of VEGF-A. Here we studied the role in this pathway of epidermal growth factor receptor (EGFR) transactivation by EP receptors. We found that EGFR inhibitor AG1478 prevented the increase in VEGF-A production induced by PGE2- and all-trans retinoic acid. This effect was due to the inhibition of the transcriptional up-regulation of RARbeta, which resulted in loss of the RARbeta-dependent transcriptional up-regulation of HIF-1alpha. PGE2 and all-trans retinoic acid also increased EGFR phosphorylation and this effect was sensitive to antagonists of EP receptors. The role of intracellular PGE2 was indicated by two facts; i) PGE2-induced EGFR phosphorylation was substantially prevented by inhibitor of prostaglandin uptake transporter bromocresol green and ii) all-trans retinoic acid treatment, which enhanced intracellular but not extracellular PGE2, had lower effect on EGFR phosphorylation upon pre-treatment with cyclooxygenase inhibitor diclofenac. Thus, EGFR transactivation by intracellular PGE2-activated EP receptors results in the sequential activation of RARbeta and HIF-1alpha leading to increased production of VEGF-A and it may be a target for the therapeutic modulation of HIF-1alpha/VEGF-A. PMID- 23644173 TI - Dynamic metabolic flux analysis of plant cell wall synthesis. AB - The regulation of plant cell wall synthesis pathways remains poorly understood. This has become a bottleneck in designing bioenergy crops. The goal of this study was to analyze the regulation of plant cell wall precursor metabolism using metabolic flux analysis based on dynamic labeling experiments. Arabidopsis T87 cells were cultured heterotrophically with (13)C labeled sucrose. The time course of 13C labeling patterns in cell wall precursors and related sugar phosphates was monitored using liquid chromatography tandem mass spectrometry until steady state labeling was reached. A kinetic model based on mass action reaction mechanisms was developed to simulate the carbon flow in the cell wall synthesis network. The kinetic parameters of the model were determined by fitting the model to the labeling time course data, cell wall composition, and synthesis rates. A metabolic control analysis was performed to predict metabolic regulations that may improve plant biomass composition for biofuel production. Our results describe the routes and rates of carbon flow from sucrose to cell wall precursors. We found that sucrose invertase is responsible for the entry of sucrose into metabolism and UDP-glucose-4-epimerase plays a dominant role in UDP Gal synthesis in heterotrophic Aradidopsis cells under aerobic conditions. We also predicted reactions that exert strong regulatory influence over carbon flow to cell wall synthesis and its composition. PMID- 23644174 TI - Combinatorial biosynthesis of plant-specific coumarins in bacteria. AB - Coumarins are plant secondary metabolites that have demonstrated a variety of important therapeutic properties, such as antibacterial, anti-inflammatory, and anti-coagulant effects, as well as anti-cancer and anti-AIDS activities. However, knowledge regarding their biosynthesis is relatively limited even for the simplest coumarin molecule, which serves as the gateway molecule to many pharmaceutically important coumarin derivatives. Here we reported the design and validation of artificial pathways leading to the biosynthesis of plant-specific simple coumarins in bacteria. First, Escherichia coli strains were engineered to convert inexpensive phenylpropanoid acid precursors, 4-coumarate and ferulate to simple coumarins, umbelliferone (4.3 mg/L) and scopoletin (27.8 mg/L), respectively. Furthermore, we assembled the complete artificial pathways in E. coli and achieved de novo biosynthesis of umbelliferone and scopoletin without addition of precursors. This study lays the foundation for microbial production of more diverse coumarin compounds. PMID- 23644175 TI - Estimating chlamydia re-infection rates: an empirical example. AB - OBJECTIVE: Chlamydia re-infection data are used to inform and evaluate chlamydia control programmes. We quantitatively investigated the effect of denominator selection on estimating re-infection rates and trends. METHODS: Using data on women aged 15-44 years enrolled in Group Health Cooperative (GH), a Pacific Northwest health plan, annual chlamydia re-infection rates from 1998 to 2006 were calculated. Three different denominators were compared using person-years contributed by: (1) all women; (2) women with a prior documented chlamydial infection regardless of whether they were retested; and (3) women with a prior chlamydial infection who were retested within 14 months. RESULTS: From 1998 to 2006, among all women 15-44 years enrolled in GH, re-infection rates increased from 64 to 149 cases per 100 000 person-years. Among women with a prior infection, rates decreased from 10 857 to 8782 cases per 100 000 person-years. Among women with a prior infection who were retested, rates increased from 29 374 to 42 475 cases per 100 000 person-years. CONCLUSIONS: Using the same dataset, we demonstrate that it is possible to tell three different stories about the magnitude of rates and trends in chlamydia re-infection among women by using different denominators. All of these strategies have limitations, but restricting the denominator to women with a prior infection who are retested may best represent the population at-risk for re-infection. Still, rates do not account for additional factors influencing the number of re-infections diagnosed, including screening coverage and changes in test technology. Caution is needed in examining and comparing re-infection data. PMID- 23644177 TI - CD4+ effector and memory cell populations protect against Cryptosporidium parvum infection. AB - Cryptosporidium parvum is a protozoan parasite that infects the epithelial cells of the small intestine causing diarrheal illness in humans. While T cells are known to be important in resistance and recovery from infection, little has been characterized as to the phenotypic expression of surface effector and memory markers after infection. We used an acute model of infection (C57BL/6 interleukin 12p40), which develops long-standing resistance to re-infection, to characterize expression of different effector and memory cells. Using flow cytometry, we found that heterogeneous populations were generated after infection, consisting of both CD62L(high) central memory T cells (T(CM)) and CD62L(low) effector memory T cells (T(EM)) that were competent to produce the Th type 1 effector cytokine, IFN gamma. Both CD4+ and CD8+ T(CM) and T(EM) populations persisted in the absence of infection (up to 60 days post-infection). Additionally, transfer of either CD62L(low)CD4+ T(EM) or CD62L(high)CD4+ T(CM) into naive recipients resulted in a protective response. Taken together, these studies show that distinct subsets of effector and memory CD4+ T cells develop after infection with C. parvum, and mediate protective immunity to re-challenge. PMID- 23644176 TI - Mechanism of T-cell mediated protection in newborn mice against a Chlamydia infection. AB - To determine the immune components needed for protection of newborn mice against Chlamydia muridarum, animals born to Chlamydia-immunized and to sham-immunized dams were infected intranasally with C. muridarum at 2 post-natal days. T-cells isolated from immunized or sham-immunized adult mice were adoptively transferred to newborn mice at the time of infection. Also, to establish what cytokines are involved in protection, IFN-gamma, TNF-alpha, IL-10, and IL-12 were passively transferred to newborn mice. To assess the Chlamydia burden in the lungs mice were euthanized at 12 post-natal days. When T-cells from immunized adult mice were transferred, mice born to and fed by immunized dams were significantly protected as evidenced by the reduced number of Chlamydia isolated from the lungs compared to mice born to and fed by sham-immunized dams. Transfer of IFN-gamma and TNF-alpha also significantly reduced the number of Chlamydia in the lungs of mice born to immunized dams. Transfer of IL-10 or IL-12 did not result in a significant reduction of Chlamydia. In vitro T-cell proliferation data suggest that neonatal antigen presenting cells can present Chlamydia antigens to adult T cells. In conclusion, maternal antibodies and Chlamydia specific T-cells or Th1 cytokines are required for protection of neonates against this pathogen. PMID- 23644178 TI - Is attentional prioritisation of infant faces unique in humans?: Comparative demonstrations by modified dot-probe task in monkeys. AB - Humans innately perceive infantile features as cute. The ethologist Konrad Lorenz proposed that the infantile features of mammals and birds, known as the baby schema (kindchenschema), motivate caretaking behaviour. As biologically relevant stimuli, newborns are likely to be processed specially in terms of visual attention, perception, and cognition. Recent demonstrations on human participants have shown visual attentional prioritisation to newborn faces (i.e., newborn faces capture visual attention). Although characteristics equivalent to those found in the faces of human infants are found in nonhuman primates, attentional capture by newborn faces has not been tested in nonhuman primates. We examined whether conspecific newborn faces captured the visual attention of two Japanese monkeys using a target-detection task based on dot-probe tasks commonly used in human visual attention studies. Although visual cues enhanced target detection in subject monkeys, our results, unlike those for humans, showed no evidence of an attentional prioritisation for newborn faces by monkeys. Our demonstrations showed the validity of dot-probe task for visual attention studies in monkeys and propose a novel approach to bridge the gap between human and nonhuman primate social cognition research. This suggests that attentional capture by newborn faces is not common to macaques, but it is unclear if nursing experiences influence their perception and recognition of infantile appraisal stimuli. We need additional comparative studies to reveal the evolutionary origins of baby schema perception and recognition. PMID- 23644179 TI - Factors underlying regression of coronary atheroma with potent statin therapy. AB - AIMS: Statins can inhibit the progression of coronary atherosclerosis. We aimed to characterize clinical factors that associate with differing measures of coronary atheroma volume following potent statin therapy. METHODS AND RESULTS: SATURN employed serial intravascular ultrasound (IVUS) to monitor changes in measures of coronary atheroma burden [total atheroma volume (TAV) and per cent atheroma volume (PAV)] in 1039 patients with coronary artery disease, treated with rosuvastatin (40 mg) or atorvastatin (80 mg) daily for 24 months. Rosuvastatin-treated patients demonstrated greater reductions in low-density lipoprotein cholesterol (LDL-C, 47 vs. 40%, P < 0.001) and greater increases in high-density lipoprotein cholesterol (HDL-C, 13 vs. 10%, P = 0.02). These alterations in the lipid profile associated with greater TAV (-6.4 vs. -4.4 mm(3), P = 0.01), but not PAV (-1.22 vs. -0.99%, P = 0.17) regression. Greater TAV reductions with rosuvastatin vs. atorvastatin occurred in patients with diabetes (P = 0.01, treatment by diabetic status interaction P-value 0.05). Greater PAV reductions with rosuvastatin were evident in females (P = 0.01, treatment by sex interaction P-value 0.03) and in those with greater than or equal to median baseline LDL-C (P = 0.02, treatment by LDL-C group interaction P value 0.03) or HDL-C levels (P = 0.02, treatment by HDL-C group interaction P value 0.04). On multivariable analysis assessing change in TAV and PAV, both higher baseline TAV and PAV independently associated with TAV and PAV regression, respectively (standardized estimates: TAV -0.25, P < 0.001; PAV -0.23, P < 0.001). CONCLUSION: Higher-risk patients, particularly those with greater baseline coronary atheroma volume, are more likely to experience less disease progression with potent statin therapy. PMID- 23644180 TI - Risk stratification after myocardial infarction: is left ventricular ejection fraction enough to prevent sudden cardiac death? AB - Patients who have experienced a myocardial infarction (MI) are at increased risk of sudden cardiac death (SCD). With the advent of implantable cardioverter defibrillators (ICDs), accurate risk stratification has become very relevant. Numerous investigations have proven that a reduced left ventricular ejection fraction (LVEF) significantly increases the SCD risk. Furthermore, ICD implantation in patients with reduced LVEF confers significant survival benefit. As a result, LVEF is the cornerstone of current decision making for prophylactic ICD implantation after MI. However, LVEF as standalone risk stratifier has major limitations: (i) the majority of SCD cases occur in patients with preserved or moderately reduced LVEF, (ii) only relatively few patients with reduced LVEF will benefit from an ICD (most will never experience a threatening arrhythmic event, others have a high risk for non-sudden death), (iii) a reduced LVEF is a risk factor for both sudden and non-sudden death. Several other non-invasive and invasive risk stratifiers, such as ventricular ectopy, QRS duration, signal averaged electrocardiogram, microvolt T-wave alternans, markers of autonomic tone as well as programmed ventricular stimulation, have been evaluated. However, none of these techniques has unequivocally demonstrated the efficacy when applied alone or in combination with LVEF. Apart from their limited sensitivity, most of them are risk factors for both sudden and non-sudden death. Considering the multiple mechanisms involved in SCD, it seems unlikely that a single test will prove adequate for all patients. A combination of clinical characteristics with selected stratification tools may significantly improve risk stratification in the future. PMID- 23644182 TI - Neural correlates of episodic memory: associative memory and confidence drive hippocampus activations. AB - The present study used a study-test recognition memory task to examine the brain regions engaged in episodic and associative memory processes. Participants evaluated on a six-point rating scale how confident they were on whether or not an item was presented in a previous study phase. Neural activations for high- and low-confidence decisions were examined in old and new items at two levels of between-item-associations. Items had different amounts of associations within the stimulus set, while associations were defined by co-occurrence statistics. The medial frontal gyrus, the posterior cingulate gyrus, the superior temporal gyrus and the right hippocampus revealed U-shaped activation functions with greater activations for high-confidence OLD and NEW decisions. This was independent of the associative memory manipulation, which suggests that not episodic memory, but rather processes related to confidence account for the activation in these brain regions. In contrast, left hippocampus followed a different activation pattern that was modulated by the amount of associations. This provides evidence for the role of the left hippocampus in associative memory. PMID- 23644181 TI - Prognostic value of myocardial circumferential strain for incident heart failure and cardiovascular events in asymptomatic individuals: the Multi-Ethnic Study of Atherosclerosis. AB - AIMS: Left ventricular (LV) circumferential strain (Ecc) is a sensitive index of regional myocardial function. Currently, no studies have assessed its prognostic value in general population. We sought to investigate whether Ecc has a prognostic value for predicting incident heart failure (HF) and other major cardiovascular events in asymptomatic individuals without a history of previous cardiovascular diseases. METHODS AND RESULTS: We, prospectively, assessed incident HF and atherosclerotic events during a 5.5 +/- 1.3-year period in 1768 asymptomatic individuals aged 45-84 (mean age 65 years; 47% female) who underwent tagged magnetic resonance imaging for strain determination. During the follow-up period, 39 (2.2%) participants experienced incident HF and 108 (6.1%) participants had atherosclerotic cardiovascular events. Average of peak Ecc of 12 LV segments (Ecc-global) and mid-slice (Ecc-mid) was -17.0 +/- 2.4 and -17.5 +/- 2.7%, respectively. Participants with average absolute Ecc-mid lower than -16.9% had a higher cumulative hazard of incident HF (log-rank test, P = 0.001). In cox regression analysis, Ecc-mid predicted incident HF independent of age, diabetes status, hypertension, interim myocardial infarction, LV mass index, and LV ejection fraction (hazard ratio 1.15 per 1%, 95% CI: 1.01-1.31, P = 0.03). This relationship remained significant after adjustment for LV-end-systolic wall stress into covariates. In addition, by adding Ecc-mid to risk factors, LV ejection fraction, and the LV mass index, both the global chi(2) value (76.6 vs. 82.4, P = 0.04) and category-less net-reclassification index (P = 0.01, SE = 0.18, z = 2.53) were augmented for predicting HF. Circumferential strain was also significantly related to the composite atherosclerotic cardiovascular events, but its relationship was attenuated after introducing the LV mass index. CONCLUSION: Circumferential shortening provides robust, independent, and incremental predictive value for incident HF in asymptomatic subjects without any history of previous clinical cardiovascular disease. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00005487. PMID- 23644183 TI - Chronic unpredictable mild stress alters an anxiety-related defensive response, Fos immunoreactivity and hippocampal adult neurogenesis. AB - Previous results show that elevated T-maze (ETM) avoidance responses are facilitated by acute restraint. Escape, on the other hand, was unaltered. To examine if the magnitude of the stressor is an important factor influencing these results, we investigated the effects of unpredictable chronic mild stress (UCMS) on ETM avoidance and escape measurements. Analysis of Fos protein immunoreactivity (Fos-ir) was used to map areas activated by stress exposure in response to ETM avoidance and escape performance. Additionally, the effects of the UCMS protocol on the number of cells expressing the marker of migrating neuroblasts doublecortin (DCX) in the hippocampus were investigated. Corticosterone serum levels were also measured. Results showed that UCMS facilitates ETM avoidance, not altering escape. In unstressed animals, avoidance performance increases Fos-ir in the cingulate cortex, hippocampus (dentate gyrus) and basomedial amygdala, and escape increases Fos-ir in the dorsolateral periaqueductal gray and locus ceruleus. In stressed animals submitted to ETM avoidance, increases in Fos-ir were observed in the cingulate cortex, ventrolateral septum, hippocampus, hypothalamus, amygdala, dorsal and median raphe nuclei. In stressed animals submitted to ETM escape, increases in Fos-ir were observed in the cingulate cortex, periaqueductal gray and locus ceruleus. Also, UCMS exposure decreased the number of DCX-positive cells in the dorsal and ventral hippocampus and increased corticosterone serum levels. These data suggest that the anxiogenic effects of UCMS are related to the activation of specific neurobiological circuits that modulate anxiety and confirm that this stress protocol activates the hypothalamus-pituitary-adrenal axis and decreases hippocampal adult neurogenesis. PMID- 23644184 TI - Role of the gustatory thalamus in taste learning. AB - The present study re-examined the involvement of the gustatory thalamus (GT) in the acquisition of drug- and toxin-induced conditioned taste aversions (CTAs) using a standardized procedure involving 15-min taste trials in rats injected with morphine (Experiment 1), lithium chloride (Experiment 2) or amphetamine (Experiment 3). Contrary to previous results, GT lesions did not eliminate drug induced CTAs. Rather, GT-lesioned rats acquired aversions of comparable magnitude to non-lesioned subjects but from an elevated intake on the first conditioning trial. A similar pattern of lesion effects was found in the acquisition of an illness-induced CTA. Thus, we conclude that GT lesions do not differentially influence CTAs conditioned with drugs or toxins. The lesion-induced elevated intake of a novel tastant confirms an unappreciated role for the GT in taste neophobia. PMID- 23644185 TI - Influence of chronic moderate sleep restriction and exercise training on anxiety, spatial memory, and associated neurobiological measures in mice. AB - Sleep deprivation can have deleterious effects on cognitive function and mental health. Moderate exercise training has myriad beneficial effects on cognition and mental health. However, physiological and behavioral effects of chronic moderate sleep restriction and its interaction with common activities, such as moderate exercise training, have received little investigation. The aims of this study were to examine the effects of chronic moderate sleep restriction and moderate exercise training on anxiety-related behavior, spatial memory, and neurobiological correlates in mice. Male mice were randomized to one of four 11 week treatments in a 2 [sleep restriction (~4h loss/day) vs. ad libitum sleep] * 2 [exercise (1h/day/6 d/wk) vs. sedentary activity] experimental design. Anxiety related behavior was assessed with the elevated-plus maze, and spatial learning and memory were assessed with the Morris water maze. Chronic moderate sleep restriction did not alter anxiety-related behavior, but exercise training significantly attenuated anxiety-related behavior. Spatial learning and recall, hippocampal cell activity (i.e., number of c-Fos positive cells), and brain derived neurotrophic factor were significantly lower after chronic moderate sleep restriction, but higher after exercise training. Further, the benefit of exercise training for some memory variables was evident under normal sleep, but not chronic moderate sleep restriction conditions. These data indicate clear detrimental effects of chronic moderate sleep restriction on spatial memory and that the benefits of exercise training were impaired after chronic moderate sleep restriction. PMID- 23644186 TI - Learning-facilitated long-term depression requires activation of the immediate early gene, c-fos, and is transcription dependent. AB - De novo gene transcription is a prerequisite for long-term information storage in the brain. Learning-facilitated synaptic plasticity describes the ability of hippocampal synapses to respond with long-lasting synaptic plasticity to the coupling of afferent stimulation with a spatial learning experience. Strikingly, long-term depression (LTD) is facilitated by context-dependent spatial learning experiences suggesting it may play a role in information storage to enable spatial memory. Here, we investigated if learning-facilitated LTD requires the transcription factor, c-Fos and is transcription-dependent. Novel spatial learning about object-place configurations coupled with weak low frequency afferent stimulation induced robust LTD in control animals that persisted for >24h and was associated with elevations in hippocampal expression of c-Fos. Intracerebral application of a c-fos antisense oligonucleotide prevented the facilitation of LTD by novel spatial learning, inhibited elevations of c-Fos triggered by LTD and impaired spatial learning. The expression of the transcription factor zif268 was unaffected by the c-fos antisense oligonucleotide. Learning-facilitated LTD was prevented by a transcription inhibitor. These data support that learning-facilitated LTD requires elevations in c-Fos and is transcription dependent. The observation that LTD shares key regulatory mechanisms with learning and memory processes argues strongly for a role for this form of synaptic plasticity in long-term information storage in the hippocampus. PMID- 23644188 TI - Synthesis and antimicrobical evaluation of a novel class of 1,3,4-thiadiazole: derivatives bearing 1,2,4-triazolo[1,5-a]pyrimidine moiety. AB - A series of novel 1,3,4-thiadiazole derivatives bearing 1,2,4-triazolo[1,5 a]pyrimidine moiety were synthesized by the method of splicing active substructures. Among these derivatives, compounds 12, 13, 15-22 and 24-31 were firstly reported. All the compounds were assayed for antimicrobial activities against five fungi strains and four bacteria strains. The preliminary results indicated that compounds 25 and 28-31 showed good antifungal activities against Physaclospora piricola and Rhizoctonia solani. Compound 26 exhibited good antifungal activities against Cercospora beticola and R. solani. Most of the compounds showed better antibacterial activities against Gram-negative bacteria strains than Gram-positive bacteria strains. Compounds 25 and 28 showed the best activities against Pseudomonas fluorescence while compounds 30-31 showed good activities against Escherichia coli. PMID- 23644189 TI - Design, synthesis and antitumour activity of bisquinoline derivatives connected by 4-oxy-3-fluoroaniline moiety. AB - A series of novel bisquinoline derivatives connected by a 4-oxy-3-fluoroaniline moiety were synthesized and evaluated for their in vitro antitumour activities against a panel of five cancer cell lines (H460, HT-29, MKN-45, U87MG, and SMMC 7721). Most of compounds tested showed a potent activity and high selectivity towards the H460 and MKN-45 cell lines. Among the compounds tested, six (15d, 15e, 15m, 15n, 16a, and 16i) were further examined for their c-Met kinase activity; the compounds showed high efficacy with IC50 values in the single-digit nM range. An analysis of structure-activity relationships indicated that an unsubstituted or a halogen-substituted phenyl ring on the 2-arylquinoline-4 carboxamide moiety was favourable for antitumour activity. PMID- 23644187 TI - Increased anandamide uptake by sensory neurons contributes to hyperalgesia in a model of cancer pain. AB - Opioids do not effectively manage pain in many patients with advanced cancer. Because anandamide (AEA) activation of cannabinoid type-1 receptors (CB1R) on nociceptors reduces nociception, manipulation of AEA metabolism in the periphery may be an effective alternative or adjuvant therapy in the management of cancer pain. AEA is hydrolyzed by the intracellular enzyme fatty acid amide hydrolase (FAAH), and this enzyme activity contributes to uptake of AEA into neurons and to reduction of AEA available to activate CB1R. We used an in vitro preparation of adult murine dorsal root ganglion (DRG) neurons co-cultured with fibrosarcoma cells to investigate how tumors alter the uptake of AEA into neurons. Evidence that the uptake of [(3)H]AEA into dissociated DRG cells in the co-culture model mimicked the increase in uptake that occurred in DRG cells from tumor-bearing mice supported the utility of the in vitro model to study AEA uptake. Results with the fluorescent AEA analog CAY10455 confirmed that an increase in uptake in the co-culture model occurred in neurons. One factor that contributed to the increase in [(3)H]AEA uptake was an increase in total cellular cholesterol in the cancer condition. Treatment with the FAAH inhibitor URB597 reduced CAY10455 uptake in the co-culture model to the level observed in DRG neurons maintained in the control condition (i.e., in the absence of fibrosarcoma cells), and this effect was paralleled by OMDM-1, an inhibitor of AEA uptake, at a concentration that had no effect on FAAH activity. Maximally effective concentrations of the two drugs together produced a greater reduction than was observed with each drug alone. Treatment with BMS309403, which competes for AEA binding to fatty acid binding protein-5, mimicked the effect of OMDM-1 in vitro. Local injection of OMDM-1 reduced hyperalgesia in vivo in mice with unilateral tumors in and around the calcaneous bone. Intraplantar injection of OMDM-1 (5MUg) into the tumor bearing paw reduced mechanical hyperalgesia through a CB1R-dependent mechanism and also reduced a spontaneous nocifensive behavior. The same dose reduced withdrawal responses evoked by suprathreshold mechanical stimuli in naive mice. These data support the conclusion that OMDM-1 inhibits AEA uptake by a mechanism that is independent of inhibition of FAAH and provide a rationale for the development of peripherally restricted drugs that decrease AEA uptake for the management of cancer pain. PMID- 23644190 TI - Synthesis, antifungal and cytotoxic activities of 2-aryl-3-((piperidin-1 yl)ethyl)thiazolidinones. AB - A series of sixteen novel thiazolidinone derivatives were synthesized from the efficient one-pot reaction of 2-(piperidin-1-yl)ethylamine, arenealdehydes and mercaptoacetic acid in good yields. Identification and characterization of products were achieved by NMR and GC-MS techniques. The in vitro antifungal activities of all synthesized compounds were evaluated against seven fungi: Candida albicans, Candida parapsilosis, Candida guilliermondii, Cryptococcus laurentii, Geotrichum sp, Trichosporon asahii and Rhodotorula sp. The results are expressed as the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) and the best results were found against the Rhodotorula sp yeast. Two thiazolidinones (4h and 4l), MIC and MFC (16.5 MUg/mL) proved to be 1.6 times more active than fluconazole and four of them (4b, 4e, 4g and 4k (MIC and MFC 25 MUg/mL)) showed similar activity of standard drug to Rhodotorula sp. In addition, the cytotoxicity of thiazolidinones 4a-p was evaluated on cultured Vero cells and most of them displayed low toxicity (above 98 MUg/mL). These preliminary and important results could be considered a starting point for the development of new antifungal agents. PMID- 23644191 TI - Designing, structural elucidation, comparison of DNA binding, cleavage, radical scavenging activity and anticancer activity of copper(I) complex with 5-dimethyl 2-phenyl-4-[(pyridin-2-ylmethylene)-amino]-1,2-dihydro-pyrazol-3-one Schiff base ligand. AB - A novel copper(I) Schiff base complex has been synthesized and fully characterized by spectral, analytical and structural modes. Single crystal X-ray diffraction studies revealed that the copper(I) complex [CuCl(PPh3)L] has a distorted tetrahedral geometry around the central copper(I) ion. The interaction of the ligand and the complex with CT-DNA has been explored by absorption titration method which revealed that the compounds could interact with CT-DNA through intercalation. A gel electrophoresis assay demonstrated the ability of the complex to cleave the pBR322 DNA. The antioxidative properties showed that the copper(I) complex has a strong radical-scavenging potency than ligands. Further the cytotoxic effect of the compounds examined on cancerous cell lines showed that the complex exhibited substantial anticancer activity. PMID- 23644192 TI - (99m)Tc-labeled dibenzylideneacetone derivatives as potential SPECT probes for in vivo imaging of beta-amyloid plaque. AB - Four (99m)Tc-labeled dibenzylideneacetone derivatives and corresponding rhenium complexes were successfully synthesized and biologically evaluated as potential imaging probes for Abeta plaques using SPECT. All rhenium complexes (5a-d) showed affinity for Abeta(1-42) aggregates (Ki = 13.6-120.9 nM), and selectively stained the Abeta plaques on brain sections of transgenic mice. Biodistribution in normal mice revealed that [(99m)Tc]5a-d exhibited moderate initial uptake (0.31%-0.49% ID/g at 2 min) and reasonable brain washout at 60 min post-injection. Although additional optimizations are still needed to facilitate it's penetration through BBB, the present results indicate that [(99m)Tc]5a may be a potential SPECT probe for imaging Abeta plaques in Alzheimer's brains. PMID- 23644193 TI - Design, synthesis and antiproliferative activity studies of novel 1,2,3-triazole dithiocarbamate-urea hybrids. AB - A series of novel 1,2,3-triazole-dithiocarbamate-urea hybrids were designed, synthesized and their antiproliferative activities against four selected human cancer cell lines were evaluated. The results showed that a number of the hybrids exhibited potent activity in selected human cancer cell lines. Among them, compounds 27 and 34 showed broad spectrum anticancer activity with IC50 values ranging from 1.62 to 20.84 MUM and 0.76 to 13.55 MUM, respectively. Interestingly, compounds 27 and 34, being very potent against MGC-803 cells, exhibited no significant cytotoxicity against normal human embryonic kidney cells at up to 55 MUM and 70 MUM, respectively. Evidences of cell cycle arrest and apoptosis induction were obtained for the most effective compounds 27 and 34 by means of flow cytometry and microscopic techniques. PMID- 23644194 TI - Thiourea derivatives incorporating a hippuric acid moiety: synthesis and evaluation of antibacterial and antifungal activities. AB - New series of thiourea derivatives incorporating a hippuric acid moiety have been synthesized through the reaction of 4-hippuric acid isothiocyanate with various nitrogen nucleophiles such as aliphatic amines, aromatic amines, sulfa drugs, aminopyrazoles, phenylhydrazine and hydrazides. The synthesized compounds were tested against bacterial and fungal strains. Most of compounds, such as 2-(4-(3 (3-bromophenyl)thioureido)benzamido)acetic acid and 2-(4-(3-(4-(N-pyrimidin-2 ylsulfamoyl)phenyl)thioureido)benzamido)acetic acid, showed significant antibacterial and antifungal activities. These compounds comprise a new class of promising broad-spectrum antibacterial and antifungal agents. PMID- 23644195 TI - In vitro biosynthesis, isolation, and identification of predominant metabolites of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208). AB - The structures of the two predominant metabolites (M4 and M5) of RVX-208, observed both in in vitro human and animal liver microsomal incubations, as well as in plasma from animal in vivo studies, were determined. A panel of biocatalytic systems was tested to identify biocatalysts suitable for milligram scale production of metabolite M4 from RVX-208. Rabbit liver S9 fraction was selected as the most suitable system, primarily based on pragmatic metrics such as catalyst cost and estimated yield of M4 (~55%). Glucuronidation of RVX-208 catalyzed by rabbit liver S9 fraction was optimized to produce M4 in amounts sufficient for structural characterization. Structural studies using LC/MS/MS analysis and (1)H NMR spectroscopy showed the formation of a glycosidic bond between the primary hydroxyl group of RVX-208 and glucuronic acid. NMR results suggested that the glycosidic bond has the beta-anomeric configuration. A synthetic sample of M4 confirmed the proposed structure. Metabolite M5, hypothesized to be the carboxylate of RVX-208, was prepared using human liver microsomes, purified by HPLC, and characterized by LC/MS/MS and (1)H NMR. The structure was confirmed by comparison to a synthetic sample. Both samples confirmed M5 as a product of oxidation of primary hydroxyl group of RVX-208 to carboxylic acid. PMID- 23644196 TI - Discovery of novel bromophenol 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6 (isobutoxymethyl)benzyl)benzene-1,2-diol as protein tyrosine phosphatase 1B inhibitor and its anti-diabetic properties in C57BL/KsJ-db/db mice. AB - In an effort to develop novel small molecule PTP1B inhibitors, a series of bromophenol derivatives were designed, synthesized and evaluated in vitro and in vivo. All of the synthesized compounds displayed weak to potent PTP1B inhibitory activities (5.62-96.25%) at 20 MUg/mL. Among these compounds, 3,4-dibromo-5-(2 bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol (9) exhibited enhanced PTP1B inhibitory activity (IC50 = 1.50 MUM) than the lead compound BDDPM (IC50 = 2.42 MUM) and high selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). Results of anti-diabetic assay using C57BL/KsJ-db/db mouse model demonstrated that compound 9 was effective at lowering blood glucose, total cholesterol and HbA1c (P < 0.01). PMID- 23644197 TI - Synthesis and biological evaluation of novel phosphatidylinositol 3-kinase inhibitors: Solubilized 4-substituted benzimidazole analogs of 2-(difluoromethyl) 1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474). AB - A range of 4-substituted derivatives of the pan class I PI 3-kinase inhibitor 2 (difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) were prepared in a search for more soluble analogs. 4-Aminoalkoxy substituents provided the most potent derivatives, with the 4-O(CH2)3NMe2 analog (compound 14) being identified as displaying the best overall activity in combination with good aqueous solubility (25 mg/mL for the hydrochloride salt). This compound was tested in a U87MG xenograft model, but displayed less potency than ZSTK474 as a result of an unfavorable pharmacokinetic profile. PMID- 23644198 TI - Synthesis, structure and in vitro pharmacological evaluation of a novel 2-oxo-1,2 dihydroquinoline-3-carbaldehyde (2'-methylbenzoyl) hydrazone bridged copper(II) coordination polymer. AB - A novel ligand bridged copper(II) coordination polymer, [Cu(HL)(NO3)]n has been synthesized by reacting 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (2' methylbenzoyl) hydrazone (H2L) with Cu(NO3)2.3H2O, and characterized by X-ray diffraction studies. The DNA interaction studies revealed that the compounds could interact with CT-DNA through intercalation. A gel electrophoresis assay demonstrated the ability of the complex to cleave the pBR322 plasmid DNA. The protein binding studies indicated that the complex exhibited strong binding affinities. Investigations of antioxidative properties showed that the polymeric Cu(II) complex has strong radical scavenging potencies. The cytotoxic effect of the compounds showed that the polymeric complex exhibited excellent anticancer activity against Hep G2, and A431 cells which is six to ten times better than that of well-known commercial anticancer drug, cisplatin. PMID- 23644199 TI - Elucidation of the pharmacophore of echinocystic acid, a new lead for blocking HCV entry. AB - To elucidate the pharmacophore of echinocystic acid (EA), an oleanane-type triterpene displaying substantial inhibitory activity on HCV entry, two microbial strains, Rhizopus chinensis CICC 3043 and Alternaria alternata AS 3.4578, were utilized to modify the chemical structure of EA. Eight new metabolites with regio and stereo-selective introduction of hydroxyl and lactone groups at various inert carbon positions were obtained. The anti-HCV entry activity of the metabolites 2-13, along with their parental compound EA and other analogs 14-15, were evaluated. Most of the metabolites showed no improvement but detrimental effect on potency except compound 5 and 6, which showed similar and even a litter higher anti-HCV entry activity than that of EA. The results demonstrated that ring A, B, C and the left side of ring E of EA are highly conserved, while ring D and the right side of ring E of EA are flexible. Introduction of a hydroxyl group at C-16 enhanced the triterpene potency. Further analysis indicated that the hemolytic effect of EA disappeared upon such modifications. PMID- 23644200 TI - Glycosylation enhances the anti-migratory activities of isomalyngamide A analogs. AB - Three, new, fully synthetic glycosylated isomalyngamide A analogs 4-6 were prepared and evaluated for their anti-migratory activities in human breast cancer cells. The results of the study show that two glycosylated derivatives 4 and 5, containing mannose and galactose appendages, suppress metastatic events (e.g., migration, invasion and adhesion) in human breast adenocarcinoma MDA-MB-231 cells at "nontoxic" concentration levels. In contrast, derivative 6 that contains a lactose moiety, displays a less potent activity. The findings show that monosaccharide rather than disaccharide appendages to the isomalyngamide A backbone more greatly influence cell migration and invasive ability. Evidence has been gained for a mechanism for inhibition of metastatic activities in MDA-MB-231 cells by 4 and 5, involving inactivation of the expression of p-FAK and paxillin through the integrin-mediated antimetastatic pathway. PMID- 23644202 TI - Nitroimidazolyl hydrazones are better amoebicides than their cyclized 1,3,4 oxadiazoline analogues: In vitro studies and Lipophilic efficiency analysis. AB - Two series of compounds with hydrazone derivatives (HZ1-HZl2, series 1) and oxadiazoline derivatives (OZ1-OZ12, series 2) of the 2-methyl-5-nitro-1H imidazole scaffold were designed and synthesized. Physicochemical properties and Lipophilic efficiency (LipE) analysis predicted higher intrinsic quality of the acylhydrazone derivatives (series 1) than their corresponding oxadiazoline analogues (series 2). In vitro antiamoebic results supported the above findings and validated that the acylhydrazone derivatives (HZ1-HZl2) show better activity than the oxadiazoline derivatives (OZ1-OZ12). MTT assay, using HepG2 cell line, revealed noncytotoxic nature of the compounds. The most promising results were observed for compounds HZ5 (IC50 = 0.96 MUM) and HZ9 (IC50 = 0.81 MUM) both in silico and in vitro. Analysis of the Lipophilic efficiency (LipE) of the compounds provided new insight for the design of potent and selective amoebicides. PMID- 23644201 TI - Synthesis, characterization and in vitro pharmacological evaluation of new water soluble Ni(II) complexes of 4N-substituted thiosemicarbazones of 2-oxo-1,2 dihydroquinoline-3-carbaldehyde. AB - Four new Ni(II) complexes of general formula [Ni(H2-Qtsc-R)2](NO3)2 (H2-Qtsc-R = 4N-substituted thiosemicarbazones of 2-oxo-1,2-dihydroquinoline-3-carbaldehyde, where R = H (1), Me (2), Et (3), or Ph (4)) have been synthesized and characterized. The geometry of the complexes was confirmed by single crystal X ray crystallography for one of the complexes (3). The binding affinity of the complexes with DNA and protein have been studied which indicate that they could interact with calf thymus DNA and bovine serum albumin protein. Investigations of antioxidative properties showed that all the complexes have strong radical scavenging properties. Cytotoxic studies showed that the complexes exhibited effective cytotoxic activity against a panel of human cancer cells without affecting the normal cells much. PMID- 23644203 TI - Ligand-based design, synthesis, and experimental evaluation of novel benzofuroxan derivatives as anti-Trypanosoma cruzi agents. AB - A set of substituted-[N'-(benzofuroxan-5-yl)methylene]benzohydrazides (4a-t), previously designed and synthesized, was experimentally assayed against Trypanosoma cruzi, the etiological agent of Chagas' disease, one of the most neglected tropical diseases. Exploratory data analysis, Hansch approach and VolSurf formalism were applied to aid the ligand-based design of novel anti-T. cruzi agents. The best 2D-QSAR model showed suitable statistical measures [n = 18; s = 0.11; F = 42.19; R(2) = 0.90 and Q(2) = 0.77 (SDEP = 0.15)], and according to the optimum 3D-QSAR model [R(2) = 0.98, Q(2) = 0.93 (SDEP = 0.08)], three latent variables explained 62% of the total variance from original data. Steric and hydrophobic properties were pointed out as the key for biological activity. Based upon the findings, six novel benzofuroxan derivatives (4u-z) were designed, synthesized, and in vitro assayed to perform the QSAR external prediction. Then, the predictability for the both models, 2D-QSAR (Rpred(2) = 0.91) and 3D-QSAR (Rpred(2) = 0.77), was experimentally validated, and compound 4u was identified as the most active anti-T. cruzi hit (IC50 = 3.04 MUM). PMID- 23644204 TI - Enmein-type diterpenoid analogs from natural kaurene-type oridonin: Synthesis and their antitumor biological evaluation. AB - A series of enmein-type diterpenoid analogs (11-20) derived from natural kaurene type diterpenoid oridonin were synthesized and biologically evaluated. All target compounds showed improved anti-proliferative activities against four human cancer cell lines compared with natural oridonin and parent compound 10. Some compounds were more potent than positive control Taxol. Furthermore, mechanistic investigation showed that the representative compound 17 affected cell cycle and induced apoptosis at low micro-molar level in human hepatoma Bel-7402 cells, via an oxidative stress triggered mitochondria-related caspase-dependent pathway. PMID- 23644205 TI - N-alkylated 2,3,3-trimethylindolenines and 2-methylbenzothiazoles. Potential lead compounds in the fight against Saccharomyces cerevisiae infections. AB - The synthesis of a variety of N-alkylated 2,3,3-trimethylindolenines and 2 methylbenzothiazoles is reported herein. Their potential as antifungal agents is evaluated by preliminary screening against Saccharomyces cerevisiae (S. cerevisiae), Schizosaccharomyces pombe (S. pombe), and Candida albicans (C. albicans). Statistical analyses illustrate a strong relationship between chain length and growth inhibition for S. cerevisiae and S. pombe (p < 0.0001 in every case). Of particular interest is the activity of both sets of compounds against S. cerevisiae, as this is emerging as an opportunistic pathogen, especially in immunosuppressed and immunocompromised patients. Bioassays were set up to compare the efficacy of our range of N-alkylated compounds against classic antifungal agents; Amphotericin B and Thiabendazole. PMID- 23644206 TI - Synthesis, cytotoxic activity and DNA-interaction studies of novel anthraquinone thiosemicarbazones with tautomerizable methylene group. AB - A series of novel anthraquinone-thiosemicarbazone derivatives in a tautomerizable keto-imine form was synthesized and tested for their in vitro cytotoxic activity against human cancer cells (HeLa, MDA-MB-361, MDA-MB-453, K562, A549) and human normal MRC-5 cells. Several compounds efficiently inhibited cancer cell growth at micromolar concentrations, especially against K562 and HeLa cells. As determined by flow cytometric analysis, anthraquinone-thiosemicarbazone caused significant increase in the number of sub-G1 phase of HeLa cells and apoptosis in a concentration-dependent manner. Also, inhibition of caspase-3, -8, and -9 with specific caspase inhibitors reduced the apoptosis mediated by the tested compounds in HeLa cells. All anthraquinone-thiosemicarbazones exhibit calf thymus DNA-binding activity, but no cleavage of plasmid DNA was observed. PMID- 23644208 TI - Synthesis and evaluation of 4-substituted coumarins as novel acetylcholinesterase inhibitors. AB - A series of 4-hydroxycoumarin derivatives were designed and synthesized as new acetylcholinesterase (AChE) inhibitors which could be considered for Alzheimer's disease therapeutics. Among the 19 coumarin-derived compounds tested toward Electrophorus electricus acetylcholinesterase (eelAChE) and horse serum butyrylcholinesterase (eqBChE), N-(1-benzylpiperidin-4-yl)acetamide derivative 4m displayed highest AChE inhibitory activity (IC50 = 1.2 MUM) and good selectivity (37 times). The docking study of the most potent compound 4m, indicated that Phe330 is responsible for ligand recognition and trafficking by forming pi-cation interaction with benzylpiperidine moiety. Furthermore, the formation of an additional pi-pi interaction between coumarin moiety and Trp279 of peripheral anionic site could stabilize the ligand in the active site resulting in more potent inhibition of the enzyme. PMID- 23644207 TI - Anti-tubercular agents. Part 7: a new class of diarylpyrrole-oxazolidinone conjugates as antimycobacterial agents. AB - In an effort to discover new anti-tubercular agents, a series of new diarylpyrrole-oxazolidinone conjugates have been designed and synthesized. The anti-tubercular activity of these new conjugates (4a-n and 5a-d) against Mycobacterium tuberculosis H37Rv and drug resistance strains such as M. tuberculosis Rif(R) and M. tuberculosis XDR are discussed, wherein compound 4i has been found to be the most potent amongst the series. MTT assay was performed on the active conjugates of the series (4b-f, 4i and 5c) against mouse macrophage (J-774) cells to evaluate cytotoxic effects and selective index values. In addition, these conjugates (4a-n and 5a-d) are also tested against a panel of Gram-positive and Gram-negative bacterial strains. The docking studies have been carried out to provide some insight into the mechanism of action for this class of compounds. PMID- 23644209 TI - A potential antitumor agent, (6-amino-1-methyl-5-nitrosouracilato-N3) triphenylphosphine-gold(I): structural studies and in vivo biological effects against experimental glioma. AB - The synthesis and molecular and supramolecular structures of the compound (6 amino-1-methyl-5-nitrosouracilato-N3)-triphenylphosphine-gold(I) with interesting abilities to inhibit tumor growth in an animal model of experimental glioma are reported. Thus, its antitumor properties, effects on both enzyme and non-enzyme antioxidant defense systems and the response of several biochemical biomarkers have been analyzed. After seven days of treatment, the gold compound decreased the tumor growth to ca. one-tenth and reduced oxidative stress biomarkers (thiobarbituric acid-reactive substances (TBARS) and protein oxidation levels) compared to animals treated with the vehicle. Also, gold compound maintained non enzyme antioxidant defense systems as in non-tumor animals and increased enzyme antioxidant defenses, such as superoxide dismutase and glutathione peroxidase activities, and decreased catalase activity. Analysis of serum levels of electrolytes, nitrogenous compounds, glucose, lipids, total protein, albumin, transaminases and alkaline phosphatase indicated that gold compound treatment showed few adverse effects, while effectively inhibiting tumor growth through mechanisms that involved endogenous antioxidant defenses. PMID- 23644211 TI - Synthesis and in vitro anticancer studies of novel C-2 arylidene congeners of lantadenes. AB - The antitumor pentacyclic triterpenoids, Lantadene A (1) and B (2) were isolated from the leaves of weed Lantana camara L. (Verbenaceae) and were structurally transformed to bioactive intermediates 3-6. The Claisen-Schmidt reaction of 22beta-hydroxy-3-oxoolean-12-en-28-oic acid (5) with requisite aldehydes afforded 2-arylidene-22beta-hydroxy-3-oxoolean-12-en-28-oic acids (7-16). The compounds were evaluated for their in-vitro anticancer activity by National Cancer Institute (NCI), USA and some of these compounds showed marked cytotoxicity in micromolar range. The mean graph midpoint (MG_MID) value of compound 3 (MG_MID 5.69) was higher than standard drug cisplatin (MG_MID -5.66) while comparable in case of compound 12 (MG_MID -5.52). The NCI's COMPARE molecular mechanistic analysis showed that these compounds were in significant correlations with activity patterns of mechanistic set of compounds (PCC >= 0.60). PMID- 23644210 TI - Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4' piperidine] based histone deacetylase inhibitors. AB - Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H (1,3)-benzoxazine-2,4'-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues. PMID- 23644212 TI - Synthesis and biological evaluation of novel thiazolidinone derivatives as potential anti-inflammatory agents. AB - The modulation of pro-inflammatory cytokines provides a target for controlling inflammatory diseases and attracts much attention in current anti-inflammatory drug development. Here, four series of thiazolidinone derivatives were synthesized and screened for anti-inflammatory activities. A majority of these compounds showed excellent inhibition on the expression of TNF-alpha and IL-6 in LPS-stimulated macrophages. Discussions are given regarding the structure activity relationships. Compounds 12d and 12h inhibited LPS-induced TNF-alpha and IL-6 release in a dose-dependent manner. Furthermore, 12d exhibited a significant protection against LPS-induced septic death in mouse model. Together, these data present a series of new thiazolidinones with potential therapeutic effects in acute inflammatory diseases and they could be important leads in the continuing anti-inflammatory drug research. PMID- 23644213 TI - Low molecular weight dual inhibitors of factor Xa and fibrinogen binding to GPIIb/IIIa with highly overlapped pharmacophores. AB - Dual antithrombotic agents acting as anticoagulants and aggregation inhibitors could have substantial advantages over currently prescribed combinations of antithrombotic drugs. Herein, we report compounds with moderate inhibitory activity for factor Xa and fibrinogen GPIIb/IIIa binding (both in the micromolar range). These compounds resulted from our efforts to merge the pharmacophores of selective factor Xa inhibitor rivaroxaban with a mimic of the Arg-Gly-Asp (RGD) sequence of fibrinogen to obtain designed multiple ligands with potential antithrombotic activity. Resulting from this study, a structurally novel class of submicromolar fibrinogen GPIIb/IIIa binding inhibitor bearing 1,2,4-oxadiazol 5(4H)-one moiety is also described. PMID- 23644214 TI - Synthetic tactics of new class of 4-aminothieno[2,3-d]pyrimidine-6-carbonitrile derivatives acting as antimicrobial agents. AB - Thermal selective reactions were studied on oxothieno[2,3-d]pyrimidine-6 carboxamide 3 with POCl3 and PCl5. At 25-50 degrees C, the C7-amide rearranges to nitrile furnished compound 4 in 85-90% yield, while at 80-110 degrees C furnished mixture of products 4 and 5 in 28-68% yields. The chloro displacement with amines in compound 5 yielded 4-aminothieno[2,3-d]pyrimidine-6-carbonitrile derivatives 8(a-h) and 9(a-e). Antimicrobial activity of new compounds was studied against several bacteria such as Staphylococcus aureus MTCC-96, Escherichia coli MTCC-443, Pseudomonas aeruginosa MTCC-4 41, Streptococcus pyogenes MTCC-442 and fungi Aspergillus niger MTCC-282, Aspergillus clavatus MTCC 1323, Candida albicans MTCC-227 using broth microdilution method. Compounds 4, 8b, 8d, 8e, 8h and 9a showed promising antibacterial activity compared to ampicillin and compounds 8b, 8h showed better antifungal activity compared to greseofulvin. PMID- 23644215 TI - Novel 3,5-bis(arylidene)-4-piperidone dimers: potent cytotoxins against colon cancer cells. AB - Two novel series of dimeric 3,5-bis(arylidene)-4-piperidones 7 and 8 were prepared as cytotoxic agents. A specific objective of this study was the discovery of novel compounds displaying potent anti-proliferative activities against colon cancers. Most of the compounds demonstrate potent cytotoxicity against HCT116 and HT29 colon cancer cell lines in which the IC50 values range from low micromolar to nanomolar values. In general, the majority of the compounds showed greater cytotoxicity and some degree of selectivity toward HCT116 cells compared to HT29 cells. Compound 9 in which the amidic carbonyl groups were excised was substantially less potent than 8a in both cell lines suggested that the amide groups are important components of the molecules for exhibiting cytotoxicity. Virtually all the compounds were more potent than a reference drug 5-fluorouracil which is used in treating colon cancers as well as a related enone curcumin. QSAR studies were undertaken and some guidelines for amplification of the project have been formulated. Flow cytometry analysis of a representative potent compound 7f revealed that it induces apoptosis in HCT116 cells. PMID- 23644216 TI - Design, synthesis and antimicrobial evaluation of novel benzimidazole type of Fluconazole analogues and their synergistic effects with Chloromycin, Norfloxacin and Fluconazole. AB - A novel series of benzimidazole type of Fluconazole analogues were synthesized and characterized by (1)H NMR, (13)C NMR, IR, MS and HRMS spectra. All the new compounds were screened for their antimicrobial activities in vitro by two-fold serial dilution technique. The bioactive evaluation showed that 3,5 bis(trifluoromethyl)phenyl benzimidazoles gave comparable or even stronger antibacterial and antifungal efficiency in comparison with reference drugs Chloromycin, Norfloxacin and Fluconazole. The combination of 2,4-difluorobenzyl benzimidazole derivative 5m and its hydrochloride 7 respectively with antibacterial Chloromycin, Norfloxacin or antifungal Fluconazole showed better antimicrobial efficiency with less dosage and broader antimicrobial spectrum than the separated use of them alone. Notably, these combined systems were more sensitive to Fluconazole-insensitive Aspergillus flavus and methicillin-resistant MRSA. PMID- 23644217 TI - Exploring the anticancer potential of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives: the effect on apoptosis induction, cell cycle and proliferation. AB - In order to investigate their anticancer potential, four new pyrazolo[1,2 a]benzo[1,2,3,4]tetrazinone derivatives, designed through the chemometric protocol VLAK, and three of the most active compounds of the previous series have been evaluated on some cellular events including proliferation, apoptosis induction, and cell cycle. The NCI one dose (10 MUM) screening revealed that the 8,9-di-methyl derivative showed activity against Leukemia (CCRF-CEM) and Colon cancer cell line (COLO 205), reaching 81% and 45% of growth inhibition (GI), respectively. Replacement of the two methyl groups with two chlorine atoms maintained the activity toward Leukemia cell (CCRF-CEM, GI 77%) and selectively enhanced the activity against COLO 205 attaining a LD50 in the MUM range and against SW-620 a GI of 77%. Interestingly, an appreciable growth inhibition of 47% against therapeutically "refractory" Non-Small Cell Lung Cancer (NCI-H522) was observed. Moreover, the apoptosis induction, based on mitochondrial membrane depolarization, was found in the range EC50 3-5 MUM on HeLa cell, evidencing a well defined relationship with the related in vitro cell growth inhibitory assays (MTT) performed against other selected tumor cell lines not included in the NCI tumor panel (HeLa, cervix; H292, lung; LAN-5, CNS; CaCo-2, colon; 16HBE, normal human cell lung) and against MCF-7 tumor cell line (breast). Only for the most active compounds, further cell cycle tests on HeLa displayed a cell arrest on S phase. Thus, a promising new class of anticancer candidates, acting as valuable apoptotic inductors, is proposed. PMID- 23644218 TI - 2-Aminobenzothiazole derivatives: search for new antifungal agents. AB - A new series of 6-substituted 2-aminobenzothiazole derivatives were synthesized and screened in vitro as potential antimicrobials. Almost all the compounds showed antifungal activity. In particular, compounds 1n,o, designed on the basis of molecular modeling studies, were the best of the series, showing MIC values of 4-8 MUg/mL against Candida albicans, Candida parapsilosis and Candida tropicalis. None of the two compounds did show any cytotoxicity effect on human THP-1 cells. PMID- 23644219 TI - Synthesis and biological evaluation of N-(4-hydroxy-3-mercaptonaphthalen-1 yl)amides as inhibitors of angiogenesis and tumor growth. AB - A series of N-(4-hydroxy-3-mercaptonaphthalen-1-yl)amides were synthesized and investigated for their in vitro antiangiogenic activity. Among these compounds, 6d, which possesses an ortho-nitro group at the benzene ring, exhibited potent inhibitory effect on the proliferation of HUVECs, A549, K562, PC-3, HCT116, MDA MB-231 and MCF-7 cells (IC50 = 5.34, 40.53, 10.81, 52.52, 10.19, 21.37 and 2.81 MUM, respectively). Meanwhile, compound 6d inhibited in vitro angiogenesis markedly in both HUVECs tube formation assay and the rat thoracic aorta rings test. Further kinase assay study showed that compound 6d had good VEGFR2, ALK, AKT1 and ABL inhibitory activities and moderate EGFR and PDGFR-beta inhibitory activities. The data supports the further investigation of this class of compounds as potential antiangiogenic and anticancer agents. PMID- 23644220 TI - Effects of high pressure processing on fatty acid composition and volatile compounds in Korean native black goat meat. AB - This study investigated the effects of high pressure processing (HPP) on fatty acid composition and volatile compounds in Korean native black goat (KNBG) meat. Fatty acid content in KNBG meat was not significantly (p > 0.05) different among the control goats and those subjected HPP. The 9,12-octadecadienoic acid and octadecanoic acid, well-known causes of off-flavors, were detected from meat of some KNBG. A difference between the control and HPP treatment was observed in the discriminated function analysis using an electronic nose. The results suggest that the volatile compounds in KNBG meat were affected by HPP. PMID- 23644221 TI - Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction. AB - Acute myocardial infarction (MI) causes sterile inflammation, which is characterized by recruitment and activation of innate and adaptive immune system cells. Here we delineate the temporal dynamics of immune cell accumulation following MI by flow cytometry. Neutrophils increased immediately to a peak at 3 days post-MI. Macrophages were numerically the predominant cells infiltrating the infarcted myocardium, increasing in number over the first week post-MI. Macrophages are functionally heterogeneous, whereby the first responders exhibit high expression levels of proinflammatory mediators, while the late responders express high levels of the anti-inflammatory cytokine IL-10; these macrophages can be classified into M1 and M2 macrophages, respectively, based on surface marker expression. M1 macrophages dominated at 1-3 days post-MI, whereas M2 macrophages represented the predominant macrophage subset after 5 days. The M2 macrophages expressed high levels of reparative genes in addition to proinflammatory genes to the same levels as in M1 macrophages. The predominant subset of dendritic cells (DCs) was myeloid DC, which peaked in number on day 7. Th1 and regulatory T cells were the predominant subsets of CD4(+) T cells, whereas Th2 and Th17 cells were minor populations. CD8(+) T cells, gammadeltaT cells, B cells, natural killer (NK) cells and NKT cells peaked on day 7 post-MI. Timely reperfusion reduced the total number of leukocytes accumulated in the post MI period, shifting the peak of innate immune response towards earlier and blunting the wave of adaptive immune response. In conclusion, these results provide important knowledge necessary for developing successful immunomodulatory therapies. PMID- 23644222 TI - Time outdoors and the prevention of myopia. AB - Recent epidemiological evidence suggests that children who spend more time outdoors are less likely to be, or to become myopic, irrespective of how much near work they do, or whether their parents are myopic. It is currently uncertain if time outdoors also blocks progression of myopia. It has been suggested that the mechanism of the protective effect of time outdoors involves light-stimulated release of dopamine from the retina, since increased dopamine release appears to inhibit increased axial elongation, which is the structural basis of myopia. This hypothesis has been supported by animal experiments which have replicated the protective effects of bright light against the development of myopia under laboratory conditions, and have shown that the effect is, at least in part, mediated by dopamine, since the D2-dopamine antagonist spiperone reduces the protective effect. There are some inconsistencies in the evidence, most notably the limited inhibition by bright light under laboratory conditions of lens induced myopia in monkeys, but other proposed mechanisms possibly associated with time outdoors such as relaxed accommodation, more uniform dioptric space, increased pupil constriction, exposure to UV light, changes in the spectral composition of visible light, or increased physical activity have little epidemiological or experimental support. Irrespective of the mechanisms involved, clinical trials are now underway to reduce the development of myopia in children by increasing the amount of time they spend outdoors. These trials would benefit from more precise definition of thresholds for protection in terms of intensity and duration of light exposures. These can be investigated in animal experiments in appropriate models, and can also be determined in epidemiological studies, although more precise measurement of exposures than those currently provided by questionnaires is desirable. PMID- 23644223 TI - Variants at chromosome 10q26 locus and the expression of HTRA1 in the retina. AB - Variations in a locus at chromosome 10q26 are strongly associated with the risk of age-related macular degeneration (AMD). The most significantly associated haplotype includes a nonsynonymous SNP rs10490924 in the exon 1 of ARMS2 and rs11200638 in the promoter region of HTRA1. It is under debate which gene(s), ARMS2, HTRA1 or some other genes are functionally responsible for the genetic association. To verify whether the associated variants correlate with a higher HTRA1 expression level as previously reported, HTRA1 mRNA and protein were measured in a larger human retina-RPE-choroid samples (n = 82). Results show there is no significant change of HTRA1 mRNA level among genotypes at rs11200638, rs10490924 or an indel variant of ARMS2. Furthermore, two AMD-associated synonymous SNPs rs1049331 and rs2293870 in HTRA1 exon 1 do not change its protein level either. These results suggest that the AMD-associated variants in the chromosome 10q26 locus do not significantly affect the expression of HTRA1. PMID- 23644224 TI - Astigmatism and its role in emmetropization. AB - Astigmatism is a common refractive error caused by the difference in refractive power of the eye along different meridians. This causes two line foci that cannot be corrected by changing viewing distance or accommodation. Although human studies have ascribed astigmatism to multiple factors, its cause remains unclear. Studies in chicks and monkeys suggest that imposed astigmatic error may alter emmetropization, but McLean and Wallman (2003) showed that the early compensatory response to spherical defocus was not affected by concurrent high astigmatism in chicks. This review will focus on possible mechanisms leading to astigmatism and the influence of astigmatism on emmetropization in animal studies. PMID- 23644225 TI - SKUP3 randomised controlled trial: polysomnographic results after uvulopalatopharyngoplasty in selected patients with obstructive sleep apnoea. AB - OBJECTIVE: To assess the 6-month efficacy of uvulopalatopharyngoplasty (UPPP) compared with expectancy in selected patients with obstructive sleep apnoea syndrome (OSAS). DESIGN: A prospective single-centre randomised controlled trial with two parallel arms stratified by Friedman stage and body mass index (BMI). PARTICIPANTS: 65 consecutive patients with moderate to severe OSAS (apnoea hypopnoea index (AHI) >=15 events/h sleep), BMI <36 kg/m(2), Epworth sleepiness scale >=8, Friedman stage I or II. INTERVENTION: Surgical treatment with UPPP. The control group underwent UPPP after a delay of 6 months. OUTCOMES: Changes in AHI and other polysomnography parameters at baseline compared with the 6-month follow-up. RESULTS: All patients (32 in the intervention group and 33 in the control group) completed the trial. The mean (SD) AHI in the intervention group decreased significantly (p<0.001) by 60% from 53.3 (19.7) events/h to 21.1 (16.7) events/h . In the control group the mean AHI decreased by 11% from 52.6 (21.7) events/h to 46.8 (22.8) events/h, with a significant difference between the groups (p<0.001). The mean time in the supine position and the BMI were unchanged in both groups. Subgroup analyses for Friedman stage, BMI group and tonsil size all showed significant reductions in AHI in the intervention group compared with controls. There were no severe complications after surgery. CONCLUSIONS: This trial demonstrates the efficacy of UPPP in treating selected patients with OSAS with a mean reduction in AHI of 60% compared with 11% in controls, a highly significant and clinically relevant difference between the groups. TRIAL REGISTRATION NUMBER: NCT01659671. PMID- 23644226 TI - Re-evaluating preterm infants with the Bayley-III: patterns and predictors of change. AB - This study investigates the Third Edition of the Bayley Scales of Infant and Toddler Development (Bayley-III) and (1) mean difference scores, (2) test-retest correlation coefficients, (3) changes in rates of delay and classification from "delayed" to "not delayed," and (4) infant birth, neonatal and sociodemographic predictors of change in scores from the first to second year of life among 131 preterm infants. Cognitive, Receptive Language and Fine Motor Subscale scores decrease and mean Gross Motor Subscale scores remain consistent from the first to second year of life. Bayley-III test-retest reliability ranged from small/fair to moderate from 8 to 20 months corrected age. Classification of delay is not stable over the first two years of life. One in 6 infants' Language Index scores changed from a classification of not delayed at 8 months to delayed at 20 months. One in 10 infants' Gross Motor Subscale scores changed from a classification of delayed at 8 months to not delayed at 20 months. Small for gestational age status predicts improved to nearly consistent Bayley Language Index and Receptive Subscale scores. Public insurance and history of sepsis predict decline in Bayley Language Index and Receptive Subscale scores from 8 to 20 months. Lower gestational age, race, and history of necrotizing enterocolitis and/or intestinal perforation also predict decline in Bayley Cognitive Index from 8 to 20 months. Predictors of decline in performance confirm known neonatal risk factors, are consistent with emerging evidence of detrimental immune related processes, and highlight the importance of inclusion of sociodemographic variables in understanding development in preterm infants. PMID- 23644227 TI - Facilitating complex shape drawing in Williams syndrome and typical development. AB - Individuals with Williams syndrome (WS) produce drawings that are disorganised, likely due to an inability to replicate numerous spatial relations between parts. This study attempted to circumvent these drawing deficits in WS when copying complex combinations of one, two and three shapes. Drawing decisions were reduced by introducing a number of facilitators, for example, by using distinct colours and including facilitatory cues on the response sheet. Overall, facilitation improved drawing in the WS group to a comparable level of accuracy as typically developing participants (matched for non-verbal ability). Drawing accuracy was greatest in both groups when planning demands (e.g. starting location, line lengths and changes in direction) were reduced by use of coloured figures and providing easily distinguished and clearly grouped facilitatory cues to form each shape. This study provides the first encouraging evidence to suggest that drawing of complex shapes in WS can be facilitated; individuals with WS might be receptive to remediation programmes for drawing and handwriting. PMID- 23644228 TI - Impaired short-term memory for order in adults with dyslexia. AB - Verbal short-term memory (STM) deficits are consistently associated with dyslexia, but the nature of these deficits remains poorly understood. This study used the distinction between item and order retention processes to achieve a better understanding of STM deficits in adults with dyslexia. STM for item information has been shown to depend on the quality of underlying phonological representations, and hence should be impaired in dyslexia, which is characterized by poorly developed phonological representations. On the other hand, STM for order information is considered to reflect core STM processes, which are independent from language processing. Thirty adults with dyslexia and thirty control participants matched for age, education, vocabulary, and IQ were presented STM tasks, which distinguished item and order STM capacities. We observed not only impaired order STM in adults with dyslexia, but this impairment was independent of item STM impairment. This study shows that adults with dyslexia present a deficit in core verbal STM processes, a deficit which cannot be accounted for by the language processing difficulties that characterize dyslexia. Moreover, these results support recent theoretical accounts considering independent order STM and item STM processes, with a potentially causal involvement of order STM processes in reading acquisition. PMID- 23644229 TI - Hearing level in children with Down syndrome at the age of eight. AB - This study examines the prevalence of hearing loss in children with Down syndrome at the age of 8. All children were examined in the ENT-departments of public hospitals in Norway and the study population consisted of children born in Norway in 2002 with Down syndrome. Hearing loss was defined as pure-tone air-conduction reduction by on average more than 25 dB HL in the best hearing ear. A cross sectional clinical and audiological population based study was chosen as study design. Hearing loss more than 25 dB HL in the best hearing ear was found in 17/49 children (35%). Mild hearing loss was found in 13 children (26%), moderate in 3 (6%) children and severe hearing loss in 1 child (2%). Conductive hearing loss was found in 8 children (16%), 9 children (18%) had a sensory-neural hearing loss, and mixed hearing loss was found in 3 children. Mean hearing level among boys and girls were 30.0 dB HL (SD 15.7) and 25.5 dB HL (SD13.7) respectively, a non-significant difference (p=0.139). In conclusion this study indicates that both conductive and sensorineural hearing loss, is still common in children with Down syndrome children at the age of eight and as much as two thirds of the children may have a bilateral impairment. The study population was under diagnosed in terms of hearing loss and thus our findings underline the importance of continuous audiological follow up of this group of children throughout childhood. PMID- 23644230 TI - Virus-induced expression of retinoic acid inducible gene-I and melanoma differentiation-associated gene 5 in the cochlear sensory epithelium. AB - The inner ear has been regarded as an immunoprivileged site because of isolation by the blood-labyrinthine barrier. Several reports have indicated the existence of immune cells in the inner ear, but there are no reports showing immunocompetence of the cochlear tissue. In this report, we examined the potential involvement of retinoic acid inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), which are critical for initiating antiviral innate immune responses. We found that RIG-I and MDA5 are expressed in the mouse cochlear sensory epithelium, including Hensen's and Claudius' cells. Ex vivo viral infection using Theiler's murine encephalomyelitis virus revealed that the virus replicates in these cells and that protein levels of RIG-I and MDA5 are up-regulated. Furthermore, the critical antiviral transcription factor, interferon (IFN) regulatory factor-3, is activated in the infected cells as judged by its nuclear translocation and the accumulation of type I IFN transcripts. These results strongly suggest that RIG-I and MDA5 participate in innate antiviral responses in cochlear tissue. PMID- 23644231 TI - Precursor dynamics, incipient ferroelectricity and huge anharmonicity in antiferroelectric lead zirconate PbZrO3. AB - To better understand the phase transition mechanism of PbZrO3 (PZO), the lattice dynamics of this antiferroelectric compound are investigated within the polarizability model, with emphasis on the cubic to orthorhombic phase transition. Similarly to ferroelectric phase transitions in ABO3 perovskites, polar dynamical clusters develop and grow in size upon approaching T(C) from the high temperature side and never form a homogeneous state. Simultaneously, elastic anomalies set in and compete with polar cluster dynamics. These unusual dynamics are responsible for precursor effects that drive the PZO lattice towards an incipient ferroelectric state. Comparison of the model calculations with the temperature dependences of elastic coefficients measured on PZO single crystals reveals a striking similarity. PMID- 23644233 TI - Function and regulation of yeast ribonucleotide reductase: cell cycle, genotoxic stress, and iron bioavailability. AB - Ribonucleotide reductases (RNRs) are essential enzymes that catalyze the reduction of ribonucleotides to desoxyribonucleotides, thereby providing the building blocks required for de novo DNA biosynthesis. The RNR function is tightly regulated because an unbalanced or excessive supply of deoxyribonucleoside triphosphates (dNTPs) dramatically increases the mutation rates during DNA replication and repair that can lead to cell death or genetic anomalies. In this review, we focus on Saccharomyces cerevisiae class Ia RNR as a model to understand the different mechanisms controlling RNR function and regulation in eukaryotes. Many studies have contributed to our current understanding of RNR allosteric regulation and, more recently, to its link to RNR oligomerization. Cells have developed additional mechanisms that restrict RNR activity to particular periods when dNTPs are necessary, such as the S phase or upon genotoxic stress. These regulatory strategies include the transcriptional control of the RNR gene expression, inhibition of RNR catalytic activity, and the subcellular redistribution of RNR subunits. Despite class Ia RNRs requiring iron as an essential cofactor for catalysis, little is known about RNR function regulation depending on iron bioavailability. Recent studies into yeast have deciphered novel strategies for the delivery of iron to RNR and for its regulation in response to iron deficiency. Taken together, these studies open up new possibilities to explore in order to limit uncontrolled tumor cell proliferation via RNR. PMID- 23644234 TI - Microbial biofilms in endodontic infections: an update review. AB - Biofilms and microbial aggregates are the common mechanisms for the survival of bacteria in nature. In other words, the ability to form biofilms has been regarded as a virulence factor. Microbial biofilms play an essential role in several infectious diseases such as pulp and periradicular pathosis. The aim of this article was to review the adaptation mechanisms of biofilms, their roles in pulpal and periapical pathosis, factors influencing biofilm formation, mechanisms of their antimicrobial resistance, models developed to create biofilms, observation techniques of endodontic biofilms, and the effects of root canal irrigants and medicaments as well as lasers on endodontic biofilms. The search was performed from 1982 to December 2010, and was limited to papers in English language. The keywords searched on Medline were "biofilms and endodontics," "biofilms and root canal irrigation," "biofilms and intra-canal medicament," and "biofilms and lasers." The reference section of each article was manually searched to find other suitable sources of information. PMID- 23644235 TI - Pre-radiotherapy PSA level as a predictor for biochemical control in prostate cancer patients receiving radiotherapy after radical prostatectomy. AB - BACKGROUND: To report the outcome of patients receiving radiotherapy (RT) after radical prostatectomy (RP). METHODS: Between May 2001 and December 2008, 53 consecutive cases of prostate adenocarcinoma treated with RP and RT were reviewed. RESULTS: A total of 49 patients were eligible for this study. After a median follow-up of 53 months, the 4-year overall survival (OS) and biochemical progression-free survival (bPFS) for all patients were 91.0% and 68.9%, respectively. According to univariate and multivariate analysis, pre-RT prostate specific antigen (PSA) was the most significant factor for bPFS. Patients with pre-RT PSA levels of < 0.2 ng/ml and ? 0.2 ng/ml had a 4-year bPFS of 83.1% and 52.6%, respectively (p = 0.013). The incidence of chronic rectal toxicity was low, with no grade 3 toxicity reported and grade 2 toxicity found in only 6 patients (12.2%). However, long-term urinary toxicity of grade 2 or higher was found in 24 patients (49.0%). CONCLUSION: For patients with increasing PSA levels following RP, local RT should be administered prior to biochemical failure (PSA ? 0.2), to ensure good bPFS. PMID- 23644232 TI - Mammalian target of rapamycin (mTOR) pathways in neurological diseases. AB - The mammalian target of rapamycin (mTOR) pathway is an essential cellular signaling pathway involved in a number of important physiological functions, including cell growth, proliferation, metabolism, protein synthesis, and autophagy. Dysregulation of the mTOR pathway has been implicated in the pathophysiology of a number of neurological diseases. Hyperactivation of the mTOR pathway, leading to increased cell growth and proliferation, has been most convincingly shown to stimulate tumor growth in the brain and other organs in the genetic disorder, tuberous sclerosis complex (TSC). In addition, mTOR may also play a role in promoting epileptogenesis or maintaining seizures in TSC, as well as in acquired epilepsies following brain injury. Finally, the mTOR pathway may also be involved in the pathogenesis of cognitive dysfunction and other neurological deficits in developmental disorders and neurodegenerative diseases. mTOR inhibitors, such as rapamycin and its analogs, may represent novel, rational therapies for a variety of neurological disorders. PMID- 23644236 TI - Unstable pelvic fractures associated with femoral shaft fractures: a retrospective analysis. AB - BACKGROUND: Both pelvic fractures and femoral shaft fractures are caused by high energy injuries. When unstable pelvic fractures and femoral shaft fractures occur concomitantly, the optimal treatment method is controversial. The aim of this study was to establish a reasonable principle for treating such complicated injuries. METHODS: Forty patients sustaining unstable pelvic fractures and concomitant femoral shaft fractures were treated in a 7-year period. The initial management of the fractures was started at the emergency service according to the Advanced Trauma Life Support protocol. Unstable pelvic fractures were wrapped by cloth sheets and femoral shaft fractures were immobilized with a splint. Angiography was performed on patients with unstable hemodynamic status. The definitive treatment for combined fractures was performed after stabilizing the hemodynamics. Closed nailing was used for femoral shaft fractures, and pelvic fractures were treated with various techniques. RESULTS: The mortality rate was 12.5% (5/40) during admission. Thirty-three patients were followed up for an average of 32 months (range, 12-76 months). There were 33 cases of unstable pelvic fractures and 36 instances of femoral shaft fractures. The union rate for pelvic fractures was 100% (33/33), while femoral shaft fractures had a 94.4% (34/36) union rate. The average healing time was 3.3 months (range, 1.6-8.1 months) and 4.1 months (range, 2.5-18.2 months) for pelvic and femoral shaft fractures, respectively. After fracture, 34 hips (94%) achieved a satisfactory result in the Harris hip score and 30 knees (83%) achieved a satisfactory result in the Mize knee score. CONCLUSIONS: Stabilization of the hemodynamics in patients with combined fractures should be the first aim. Angiography to stop arterial bleeding in the pelvis is often life-saving. The definitive treatment for combined fractures, such as pelvic fractures and femoral shaft fractures, should wait until hemodynamics is stabilized. PMID- 23644237 TI - Retinopathy of prematurity in neonatal patients with birth weight greater than 1500 g in Taiwan. AB - BACKGROUND: To understand the characteristics, ophthalmic outcomes, and risk factors of retinopathy of prematurity (ROP) in patients with birth weight (BW) greater than 1500 g. The applicability of the ROP screening criteria to the Taiwanese population was also examined. METHODS: The study included 104 eyes from 54 ROP patients who had BW greater than 1500 g from 1981 to 2008. Demographic information, disease courses, ophthalmic outcomes, and possible systemic risk factors were recorded. The infants were divided into groups of mild and severe ROP for a risk factor analysis. RESULTS: The mean gestational age (GA) of the infants was 31 +/- 1.3 weeks, and the mean BW was 1675 +/- 249 g. Mild ROP regressed in 94 eyes (90%), and 10 eyes (10%) developed severe ROP. After various treatments, the regression rates for prethreshold or threshold ROP (n = 8) and stage 4 ROP (n = 2) were 100% and 50%, respectively. Forty-eight patients (85%) had at least three associated systemic risk factors. A multiple logistic regression analysis revealed that patients with an intraventricular hemorrhage were found to have an increased chance of developing severe ROP, especially those with BW greater than 1500 g (p = 0.015). There was also a significant association between patients who had severe ROP and an increased risk of having cerebral palsy (CP) at 1.5 years of age (p = 0.013). CONCLUSION: The majority of patients with BW greater than 1500 g developed mild ROP. However, advanced ROP with poor visual outcome was also encountered in some patients. PMID- 23644238 TI - Home-based exercise on functional outcome of the donor lower extremity in oral cancer patients after fibula flap harvest. AB - BACKGROUND: After harvesting the fibula flap, pain, sensory disturbance, weakness of donor leg, reduced walking endurance, ankle instability, and lower walking speed had been reported. The aim of this study was to quantitatively assess functional outcome of regular home-based exercise on donor ankle strength, endurance, and walking ability after free fibula flap for mandibular reconstruction. METHODS: Fourteen patients were recruited. Objective isokinetic testing and a 6-min walk test (6MWT) were used to evaluate ankle strength/endurance and walking ability, respectively. RESULTS: There was a significant increase in the peak torque of ankle dorsiflexion/foot inversion of the healthy leg and ankle dorsiflexion/foot eversion of the donor leg after exercise (p < 0.05). After home-based exercise, there was reduced asymmetry in the peak torques of ankle dorsiflexion and foot eversion and the total work of foot eversion between the donor and healthy legs. In 6MWT, no significant difference was found between the walking distances before and after exercise. CONCLUSION: Regular home-based exercise could improve the strength of ankle dorsiflexion and foot eversion of the donor leg, and get more symmetric ankle motor function between the donor and healthy legs. PMID- 23644239 TI - [New technologies in hand surgery]. PMID- 23644240 TI - [Smoking cessation in general practice: the general practitioner is the best medicine!]. PMID- 23644242 TI - [New technologies in planning and performance of osteotonics: example cases in hand surgery]. AB - New technologies improved the techniques of osteotomies, which remained over decades unchanged, and made bone cuts possible, which earlier on hardly were feasible. The introduction of simple applicable software can process CT data on a PC to reconstruct 3D models of a bone and to compare its shape with the mirror of the opposite side. This first allows an exact analysis of a malunion, the development of a plan for the correction and finally the virtual performance of the operation. The production of individualised drill-an saw-guides with the laser-sintering process (3D printer) which can be definitely positioned on the surface of the bone, implements exactly the planning into the operation. The new possibilities of this ostetomy technique are presented with 4 examples/cases from the hand surgery. PMID- 23644243 TI - [Dyslipidemia - when are lipid lowering medications useful in clinical practice?]. AB - Dyslipidemia is one of the main modifiable cardiovascular risk factors. There is strong evidence for the efficacy of lipid-lowering drugs in secondary prevention, as well as in primary prevention for patients at high cardiovascular risk. In primary prevention, indication for lipid-lowering interventions should be based on an individual assessment of the cardiovascular risk and on the LDL cholesterol level, despite less strong evidence for the efficacy of drug-based interventions in low risk patients. Treatment consists of statins, as well as lifestyle modifications such as body weight control and increased physical exercise. The latter constitute the primary intervention in patients at low cardiovascular risk. Secondary dyslipidemias due to an underlying medical condition and familial dyslipidemias such as Familial Hypercholesterolemia and Familial Combined Hyperlipidemia should be identified and treated accordingly, taking into account that the risk scoring systems are not appropriate in these situations. PMID- 23644244 TI - [Practical aspects of medication safety]. AB - The incidence of adverse drug events (ADE) in hospitalized patients and ambulatory care is high. Next to human suffering they cause considerable additional cost and a prolonged length of stay. The reduction of ADE incidence is badly needed. Measures to reach this goal next to teaching are electronic prescribing tools with decision support, clinical pharmacists on ward rounds, therapeutic drug monitoring, smart infusion pumps and identification tools such as bar-coding and radio-frequency identification for patients, drugs and health professionals. Importantly, while integrating these technical tools, workflows of health professionals have to be considered and should be combined with a scientific analysis to uphold and ameliorate patient safety. PMID- 23644245 TI - [Management of the patient with COPD: home case or hospitalization]. AB - Acute exacerbation of COPD is one of the most common causes of hospital admission in patients affected with this disease. In most cases, consideration of differential diagnoses and assessment of important comorbidities will allow to make the decision whether or not the patient needs to be hospitalized. A decision to hospitalize will be based on specific symptoms and signs, as well on the patient's history. Contrary to bronchial asthma, a systematic action plan strategy is lacking for COPD. However, a disease management plan involving all the health care providers may have the potential to improve the patient's well being and to decrease costs related to these exacerbations. PMID- 23644246 TI - [Myasthenia gravis]. PMID- 23644247 TI - [A rare complication after a violent coughing attack]. AB - A 85-year-old man presented to the emergency department with acute onset of right sided chest pain after vigorous coughing. Physical examination revealed a progressive hematoma and a palpable bulge that enlarged with expiration. A CT Scan confirmed a lateral lung herniation with a dissection of the intervertebral muscle. The Patient underwent a surgical reconstruction of the chest wall defect and an additional Mersilene Mesh repair of a consecutive diaphragmal rupture. The patient had an uneventful recovery and was discharged on postoperative day 11. PMID- 23644248 TI - [A generous transfusion protocol worsens the prognosis in acute upper gastrointestinal bleeding]. PMID- 23644249 TI - [Acupuncture for seasonal allergic rhinitis without clinically relevant effect]. PMID- 23644253 TI - Genome-wide analysis of the WRKY gene family in physic nut (Jatropha curcas L.). AB - The WRKY proteins, which contain highly conserved WRKYGQK amino acid sequences and zinc-finger-like motifs, constitute a large family of transcription factors in plants. They participate in diverse physiological and developmental processes. WRKY genes have been identified and characterized in a number of plant species. We identified a total of 58 WRKY genes (JcWRKY) in the genome of the physic nut (Jatropha curcas L.). On the basis of their conserved WRKY domain sequences, all of the JcWRKY proteins could be assigned to one of the previously defined groups, I-III. Phylogenetic analysis of JcWRKY genes with Arabidopsis and rice WRKY genes, and separately with castor bean WRKY genes, revealed no evidence of recent gene duplication in JcWRKY gene family. Analysis of transcript abundance of JcWRKY gene products were tested in different tissues under normal growth condition. In addition, 47 WRKY genes responded to at least one abiotic stress (drought, salinity, phosphate starvation and nitrogen starvation) in individual tissues (leaf, root and/or shoot cortex). Our study provides a useful reference data set as the basis for cloning and functional analysis of physic nut WRKY genes. PMID- 23644255 TI - Effects of passive smoking on breast cancer risk in pre/post-menopausal women as modified by polymorphisms of PARP1 and ESR1. AB - OBJECTIVES: The association between passive smoking and breast cancer risk differs in pre- and post-menopausal women. We aimed to explore the modification effects of PARP1 rs1136410 and ESR1 rs2234693 on the association between passive smoking and breast cancer risk among pre- and post-menopausal women. DESIGN AND METHODS: A case-control study of 839 breast cancer cases and 863 controls was conducted. The gene-environment interactions were tested after adjusting for potential breast cancer risk factors with unconditional logistic regression models. RESULTS: We found that the effect of passive smoking was modified by the genotypes in both pre- and post-menopausal women, but in opposite directions. The combination of the TC/CC genotypes of ESR1 rs2234693 and passive smoking significantly increased the risk of breast cancer [OR (95%CI): 2.06 (1.39-3.05)] in pre-menopausal women. A significant association was observed between TT genotype and passive smoking [OR (95%CI): 2.40 (1.27-4.53)] in postmenopausal women. For PARP1 rs1136410, similar differential associations were observed, but the interactions were not significant. CONCLUSIONS: These results imply that the risk of breast cancer from passive smoking may be influenced by genetic factors, and that the association may differ depending on menopausal status. PMID- 23644254 TI - Polymorphisms and phenotypic analysis of cytochrome P450 2D6 in the Tibetan population. AB - The cytochrome P450 2D6 enzyme (CYP2D6) metabolizes about 25% of prescribed drugs in the endoplasmic reticulum, and genetic polymorphisms in CYP2D6 can greatly affect its activity and lead to differences among individuals in drug efficacy and adverse drug reactions. To investigate genetic polymorphisms in CYP2D6 among Tibetan Chinese, we directly sequenced the whole gene in 96 unrelated, healthy Tibetans from The Tibet Autonomous Region of China and screened for genetic variants in the promoter, exons, introns, and 3'UTR. We detected fifty-one genetic polymorphisms in CYP2D6, and 16 of them are novel. The allele frequencies of CYP2D6*1, *2, *5, *10, *41, and *49 were 0.25, 0.43, 0.02, 0.29, 0.02, and 0.01, respectively. The frequency of CYP2D6*10, a putative poor-metabolizer allele, was lower in our sample population compared with that in the Han Chinese population (p<0.001). In addition, haplotype analysis allowed 15 CYP2D6 haplotypes to be classified into three groups. In conclusion, our results provide basic information about CPY2D6 alleles in Tibetans and suggest that the enzymatic activities of CYP2D6 may differ among the diverse ethnic populations of China. Our results provide a basis for safer drug administration and better therapeutic treatment among Tibetans. PMID- 23644256 TI - Ibuprofen plus isosorbide dinitrate treatment in the mdx mice ameliorates dystrophic heart structure. AB - BACKGROUND: Co-administration of ibuprofen (IBU) and isosorbide dinitrate (ISDN) provides synergistic beneficial effects on dystrophic skeletal muscle. Whether this treatment has also cardioprotective effects in this disease was still unknown. AIMS: To evaluate the effects of co-administration of IBU and ISDN (a) on left ventricular (LV) structure and function, and (b) on cardiac inflammatory response and fibrosis in mdx mice. METHODS: Three groups of mice were studied: mdx mice treated with IBU (50 mg kg-1)+ISDN (30 mg kg-1) administered daily in the diet, mdx mice that received standard diet without drugs and wild type aged matched mice. Animals were analysed after 10-11 months of treatment. Structural and functional parameters were evaluated by echocardiography while histological analyses were performed to evaluate inflammatory response, collagen deposition, cardiomyocyte number and area. RESULTS: Treatment for 10-11 months with IBU+ISDN preserved LV wall thickness and LV mass. Drug treatment also preserved the total number of cardiomyocytes in the LV and attenuated the increase in cardiomyocyte size, when compared to untreated mdx mice. Moreover, a trend towards a decreased number of inflammatory cells, a reduced LV myocardial interstitial fibrosis and an enhanced global LV function response to stress was observed in treated mdx mice. CONCLUSIONS: Treatment for 10-11 months with IBU+ISDN is effective in preventing the alterations in LV morphology of mdx mice while not reaching statistical significance on LV function and cardiac inflammation. PMID- 23644257 TI - A neurophysiological signature of motivational incongruence: EEG changes related to insufficient goal satisfaction. AB - Human behavior and psychological functioning is motivated and guided by individual goals. Motivational incongruence refers to states of insufficient goal satisfaction and is tightly related to psychological problems and even psychopathology. In the present study, individual levels of motivational incongruence were assessed with the incongruence-questionnaire (INC) in a healthy sample. In addition, multi-channel resting-state EEG was measured. Individual variations of EEG synchronization and spectral power were related to individual levels of motivational incongruence. For significant correlations, the relation to intracerebral sources of electrical brain activity was investigated with sLORETA. The results indicate that, even in a healthy sample with rather low degrees of motivational incongruence, this insufficient goal satisfaction is related to consistent changes in resting state brain activity. Upper Alpha band attenuation seems to be most indicative of increased levels of motivational incongruence. This is reflected not only in significantly reduced functional connectivity, but also in changes regarding the level of brain activation, as indicated by significant effects in the spectral power and LORETA analyses. Results are related to research investigating the upper Alpha band and are discussed in the framework of Grawe's consistency theory. PMID- 23644259 TI - Nursing methodologies. PMID- 23644258 TI - Differences in cardiovascular risk factors between patients with acute limb ischemia and intermittent claudication. AB - In this retrospective study, cardiovascular risk factors of patients with acute limb ischemia (ALI) were compared with those of intermittent claudication (IC). Furthermore, the association of ALI with environmental temperature and/or hematocrit level was tested. A total of 436 patients treated for ALI and 832 patients with IC were included in the analysis. Diabetes (P = .0001), smoking (P < .0001), and hypertension (P < .0001) were significantly less prevalent in the patients with ALI. Patients with IC had a higher rate of coronary artery disease (P = .003), and patients with ALI had a higher rate of cerebrovascular disease (P < .0001). There was no association between the outside temperature or hematocrit level and the occurrence of ALI. The hypothesis of seasonal incidence of ALI could not be confirmed, and there was no association of ALI with the hematocrit level. PMID- 23644260 TI - Philosophical inquiry and the goals of nursing: a critical approach for disciplinary knowledge development and action. AB - Philosophical inquiry remains critically important for nursing education, practice, and knowledge development. We propose a 3-level taxonomy of philosophical inquiry to guide nursing curricula and research development. Important background information about philosophy and the development of philosophical methods is given. Then philosophical inquiry is linked to the goals of nursing using our proposed taxonomy: level I-cultivating an attitude of "critical consciousness" related to all nursing situations and actions, level II analysis and application of philosophical perspectives to nursing problems and level III-generating new knowledge for nursing purposes including new theories of practice and research. PMID- 23644261 TI - Concept analysis: method to enhance interdisciplinary conceptual understanding. AB - This article is a presentation of a method of concept analysis designed to assist in understanding the unique manner in which various disciplines use the same word or group of words to describe differing conceptual ideas. Nurse researchers often borrow research instruments developed in other disciplines. However, research instruments are developed in accordance with the philosophical underpinnings of a specific discipline with the intent to contribute to the knowledge base of that discipline. Therefore, it is uncertain whether research instruments borrowed from other disciplines actually measure the conceptual phenomenon from a nursing perspective. PMID- 23644262 TI - Intellectual curiosity: a principle-based concept analysis. AB - The purpose of this principle-based concept analysis was to analyze intellectual curiosity across disciplines to explicate the current state of the science. The analysis was used to identify conceptual components of intellectual curiosity and the interrelationships between them. The findings have been integrated into a theoretical definition of intellectual curiosity and provided a beginning point for concept development. The findings are relevant to nursing education and hold significant implications for creating teaching-learning environments and curricula, which optimize or enhance preconditions, attributes, and consequences of intellectual curiosity. PMID- 23644263 TI - Use of the critical decision method in nursing research: an integrative review. AB - The focus of this article is the background and use of the critical decision method in nursing research. The purpose is to present a synthesis of the body of work whose authors used the critical decision method to explore nurses' cognitive work. For this integrative review of literature, I used the 5-step process: problem formulation, literature search, data evaluation, data analysis, and presentation. Synthesis of the 7 studies uncovered evidence of nurses' cognitive processes and demands of their practice environments and affirmed the method as a valuable tool for eliciting experienced nurses' practice knowledge making nursing expertise explicit. PMID- 23644264 TI - Critical feminist narrative inquiry: advancing knowledge through double hermeneutic narrative analysis. AB - Critical feminist narrative inquiry is informed by the theoretical triangulation of critical, feminist, and symbolic interactionist perspectives. We first locate this approach within narrative research and identify the epistemological underpinnings and assumptions supporting this innovative methodology. The analytic and interpretive objectives and processes involved to achieve a double hermeneutic narrative analysis are detailed. We conclude by proposing that this novel approach is suitable to advance knowledge about the nature and context of individual experiences, to expose circumstances leading to social injustice and health inequities, and ultimately to contribute to improved health outcomes for traditionally silenced, marginalized, or vulnerable populations. PMID- 23644265 TI - Practical guidelines for feminist research in nursing. AB - With increasing interests in oppressed groups, the number of feminist studies in nursing has steadily increased. Despite the increasing number of feminist studies, very few articles have been written to provide practical guidelines for feminist research in nursing. In this article, guidelines for feminist research in nursing are proposed on the basis of 3 previous feminist studies. First, characteristics of feminist research are concisely described. Then, the 3 studies that are the basis for the guidelines are described. Finally, practical guidelines for feminist nursing research are proposed on the basis of 10 idea categories related to issues/concerns from the 3 studies. PMID- 23644266 TI - Psychometric testing of an instrument measuring core competencies of nursing students: an application of Mokken scaling. AB - Assessing the core competencies of nursing students provides information about students' learning outcomes for educational evaluation and improvement. The aim of this study was to develop the Nursing Students Core Competencies scale to measure 8 core competencies of nursing students in Taiwan. The study employed factor analysis and Mokken scaling analysis for psychometric testing of this instrument between a group of nursing graduates and their evaluators. The results indicated that the Nursing Students Core Competencies scale has demonstrated evidence of internal consistency, structural validity, unidimensionality, and a hierarchy of items for students' self-assessment and instructor's rating. The use of Mokken scaling analysis extends the knowledge of developing competence assessment tools; it can be used to reveal the domains or items of competency nursing students perceive that are easy or difficult, providing information for curricular design. PMID- 23644267 TI - Comorbidities in the context of care transitions. AB - The growing number of individuals with comorbidities experiencing care transitions represents a challenge to the current health care system. A qualitative study of empirical literature, using the Dimensional Analysis approach, was conducted to elucidate the theoretical underpinnings of the phenomenon of individuals with comorbidities undergoing care transitions. The findings were arranged in a novel schematic demonstrating that the relationship among individual attributes, comorbidities, and care processes informed the individual's risk for adverse outcomes. This schematic is useful for future nursing research studies evaluating innovative programs implemented to improve health outcomes among vulnerable populations undergoing care transitions. PMID- 23644268 TI - Between the lines: generating good qualitative data in studies involving persons with aphasia. AB - High-quality data are essential for developing knowledge in qualitative inquiries. Language impairments affect the ability to meet the requirements that constitute good qualitative data. In this article, we focus on generating good qualitative data in persons with aphasia following stroke. We drew on experiences from a longitudinal nursing intervention to discuss how to maximize data generation in accordance with norms for data quality in this population. The longitudinal design, using a combination of research methods, and the iterative process of data generation and analysis over time constituted a continuity that enhanced communication, mutual understanding, and a trustful partnership. PMID- 23644269 TI - The timing of the literature review in grounded theory research: an open mind versus an empty head. AB - The timing of the literature review in grounded theory has been debated for decades, with previous recommendations to delay the review now under question. Mounting evidence suggests that a preliminary review can enhance theoretical sensitivity and rigor and may lead to innovative insights. However, researchers must acknowledge the influence of prior knowledge during data analysis and theory development to avoid bias. This article critically examines the ongoing debate and recommends that we should not seek to avoid preconceptions but ensure that they are well grounded in evidence and always subject to further investigation, revision, and refutation. If used reflexively, a preliminary literature review may well enhance grounded theory research. PMID- 23644270 TI - Theory development from studies with young women with breast cancer who are BRCA mutation negative. AB - Researchers and practitioners can use inductively derived theory to direct their research and practice. This article describes the ongoing development of a theory that can assist in explaining experiences of young women with breast cancer who have genetic testing for the BRCA mutation. Seventeen BRCA-negative women with breast cancer from a larger grounded theory study were interviewed. While receiving a negative BRCA mutation test result subsequent to a breast cancer diagnosis was described as a relief, the information was also confusing. The author's published Theory of Genetic Vulnerability is expanded to incorporate the outcomes of this analysis. PMID- 23644271 TI - Making meaning in qualitative research with conversational partnerships: a methodological discussion. AB - Rubin and Rubin's responsive interviewing method is based on the conversational partnership formed between researcher and participant. This method allows the researcher to understand experiences through the participant's words and stories to create meaning. In this article, the reader is guided through a 3-part interview series with a person living with traumatic spinal cord injury. The example focuses on how interview guides were developed and tailored to the participant, and how field notations were created. Findings include the importance of establishing trust and rapport in conversational partnerships for meaning making to occur. PMID- 23644272 TI - Recognizability: a strategy for assessing external validity and for facilitating knowledge transfer in qualitative research. AB - In this article, we argue in favor of quality assessment for qualitative studies and propose using a strategy we have labeled recognizability to assess external validity and facilitate knowledge transfer. To test our idea, we gathered data about recognizability in relation to a specific study on facial disfigurement. Four categories were identified: full recognition; partial recognition; recognition in others; and no recognition. In this article, we show how we used these categories both to evaluate the quality of our study and to assess its external validity. We also discuss the implications of recognizability for knowledge transfer. PMID- 23644273 TI - Role of metal mixtures (Ca, Cu and Pb) on Cd bioaccumulation and phytochelatin production by Chlamydomonas reinhardtii. AB - The goal of the study was to determine whether metal uptake and biological effects could be predicted by free ion concentrations when organisms were exposed to Cd and a second metal. Bioaccumulation and algal phytochelatin (PC) concentrations were determined for Chlamydomonas reinhardtii following a 6-h exposure. Bioaccumulation results, after six hours of exposure, showed that Cd uptake decreased in the presence of relatively high concentrations of Ca, Cu and Pb, however, Cd bioaccumulation increased in the presence of ca. equimolar concentrations of Cu. A good correlation was observed between the production of PCs and the amount of metals bioaccumulated for the binary mixtures of Cd-Pb and Cd-Cu, but not the Cd-Ca mixture. Overall, the results suggested that, in the case of mixtures, bioaccumulated metal rather than free ion concentrations would be a better predictor of biological effect. PMID- 23644274 TI - Metabolic and molecular methods to evaluate the organoclay effects on a bacterial community. AB - The aim of this work was to evaluate the influence exerted by two different commercial organoclays (DELLITE 43B and DELLITE 67G) on a model microbial consortium using microbial metabolic characterization with BIOLOG system and denaturing gradient gel electrophoresis (DGGE) molecular approach. The information obtained from the molecular analyses, in their complex, account for the differences in species composition induced on the reference consortium by the contact with the organoclays under study. DELLITE 43B resulted to produce a marked selective effect, stimulating the quantitative increase especially of Pseudomonas pseudoalcaligenes. A weaker effect was found for DELLITE 67G. On the other hand, Biolog analyses indicated a depressing action exerted by DELLITE 43B on the metabolic activity of the model microbial consortium as a whole. The presence of P. pseudoalcaligenes and B. borstelensis in the bacterial community after the treatments confirmed that a positive change in the microbial structure consortium occurred. PMID- 23644275 TI - Bioaccumulation of perfluoroalkyl carboxylates (PFCAs) and perfluoroalkane sulfonates (PFSAs) by earthworms (Eisenia fetida) in soil. AB - Earthworms were exposed to artificially contaminated soils with ten perfluoroalkyl substances (PFASs). PFASs with longer perfluorinated carbon chain displayed higher uptake rate coefficients (k(u)), longer half-life (t(1/2)) and time to steady-state (t(ss)) but lower elimination rate coefficients (k(e)) than the shorter ones. Similarly, perfluorosulfonates acids (PFSAs) displayed higher ku, longer t(1/2) and tss but lower ke than perflurocarboxylic acids (PFCAs) with the same perfluorinated chain length. All the studied PFASs, including those with seven or less perfluorinated carbons, were bioaccumulated in the earthworms and the biota-to-soil accumulation factors (BSAFs) increased with perfluorinated carbon chain length and were greater for PFSAs than for PFCAs of equal perfluoroalkyl chain length. The BSAFs were found to be dependent on the concentrations of PFASs in soil and decreased as the level of PFASs in soil increased. PMID- 23644276 TI - Carbonate minerals in porous media decrease mobility of polyacrylic acid modified zero-valent iron nanoparticles used for groundwater remediation. AB - The limited transport of nanoscale zero-valent iron (nZVI) in porous media is a major obstacle to its widespread application for in situ groundwater remediation. Previous studies on nZVI transport have mainly been carried out in quartz porous media. The effect of carbonate minerals, which often predominate in aquifers, has not been evaluated to date. This study assessed the influence of the carbonate minerals in porous media on the transport of polyacrylic acid modified nZVI (PAA nZVI). Increasing the proportion of carbonate sand in the porous media resulted in less transport of PAA-nZVI. Predicted travel distances were reduced to a few centimeters in pure carbonate sand compared to approximately 1.6 m in quartz sand. Transport modeling showed that the attachment efficiency and deposition rate coefficient increased linearly with increasing proportion of carbonate sand. PMID- 23644278 TI - Knock-down of a member of the isoflavone reductase gene family impairs plant growth and nodulation in Phaseolus vulgaris. AB - Flavonoids and isoflavonoids participate in the signaling exchange between roots of legumes and nitrogen-fixing rhizobia and can promote division of cortical cells during nodule formation by inhibiting auxin transport. Here, we report the characterization of a member of the common bean isoflavone reductase (EC 1.3.1.45, PvIFR1) gene family, an enzyme that participates in the last steps of the biosynthetic pathway of isoflavonoids. Transcript levels of PvIFR1 were detected preferentially in the susceptible zone of roots, augmented upon nitrogen starvation and in response to Rhizobium etli inoculation at very early stages of the interaction. Knockdown of PvIFR1 mediated by RNA interference (RNAi) in common bean composite plants resulted in a reduction of shoot and root length. Furthermore, reduction of PvIFR1 mRNAs also affected growth of lateral roots after emergence, a stage in which auxins are required to establish a persistent meristem. Upon inoculation, the number of nodules formed by different strains of R. etli was significantly lower in IFR RNAi than in control roots. Transcript levels of two auxin-regulated genes are consistent with lower levels of auxin in PvIFR1 silenced roots. These results suggest a complex role of PvIFR1 during plant growth, root development and symbiosis, all processes in which auxin transport is involved. PMID- 23644277 TI - Random and direct mutagenesis to enhance protein secretion in Ashbya gossypii. AB - To improve the general secretion ability of the biotechnologically relevant fungus Ashbya gossypii, random mutagenesis with ethyl methane sulfonate (EMS) was performed. The selection and screening strategy followed revealed mutants with improved secretion of heterologous Trichoderma reesei endoglucanase I (EGI), native alpha-amylase and/or native beta-glucosidase. One mutant, S436, presented 1.4- to 2-fold increases in all extracellular enzymatic activities measured, when compared with the parent strain, pointing to a global improvement in protein secretion. Three other mutants exhibited 2- to 3-fold improvements in only one (S397, B390) or two (S466) of the measured activities. A targeted genetic approach was also followed. Two homologs of the Saccharomyces cerevisiae GAS1, AgGAS1A (AGL351W) and AgGAS1B (AGL352W), were deleted from the A. gossypii genome. For both copies deletion, a new antibiotic marker cassette conferring resistance to phleomycin, BLE3, was constructed. GAS1 encodes an beta-1,3 glucanosyltransglycosylase involved in cell wall assembly. Higher permeability of the cell wall was expected to increase the protein secretion capacity. However, total protein secreted to culture supernatants and secreted EGI activity did not increase in the Aggas1ADelta mutants. Deletion of the AgGAS1B copy affected cellular morphology and resulted in severe retardation of growth, similarly to what has been reported for GAS1-defficient yeast. Thus, secretion could not be tested in these mutants. PMID- 23644279 TI - Synergistic bactericidal effect by combined exposure to Ag nanoparticles and UVA. AB - Broad and strong antimicrobial properties of silver (Ag) have been used for biomedical applications, water treatment, etc. In this study, a synergistic antibacterial effect between Ag nanoparticles (AgNPs) and ultraviolet (UV) light was examined. AgNPs (<0.1 MUm) with subsequent exposure to UVA (320-400 nm) showed pronounced toxicity in Escherichia coli, but micro-sized Ag particles (>1 MUm) with UVA and AgNPs with UVB (280-325 nm) did not. As significant bactericidal activity was also exhibited by hydrogen peroxide-treated AgNPs, the surface oxidation of AgNPs caused by UVA irradiation was considered to contribute to the enhanced antibacterial effect. Although no difference in NP-incorporation rates was observed with or without the surface oxidation of AgNPs, a particle size of less than 0.1 MUm was a factor for AgNPs uptake and an essential requirement for the antimicrobial function of Ag particles. Incorporated AgNPs oxidized by UVA irradiation released larger amounts of Ag ion inside cells than reduced AgNPs, which reacted with intercellular molecules having -SH groups such as glutathione. The synergistic use of AgNPs and UVA could become a powerful tool with broad antimicrobial applications. PMID- 23644280 TI - Influence of planting patterns on fluoroquinolone residues in the soil of an intensive vegetable cultivation area in northern China. AB - Recent studies have demonstrated the persistence of antibiotics in soil, especially in areas of vegetable cultivation. However, there are very few studies of the influence of planting regimes on the levels of antibiotic pollution. This work introduces geographical-detector models to investigate the relationship between planting patterns (vegetable planting model, manure type and quantity, planting age, greenhouse area, and topographic elevation) and residual fluoroquinolones (FQs) in soil in a pilot project in Shouguang County, Shandong Province (the largest vegetable-producing area in China). The results led to the following findings. 1. The vegetable planting model is the major determinant of the spatial stratification of FQ in the soil. For example, the "cucumber cucumber" model (growing cucumbers after cucumbers) has a three-fold power of determinant compared to the "pepper-melon" model (growing melons after peppers). 2. Planting age (years with continuous vegetable cultivation) does not necessarily affect the spatial distribution of FQ owing to their relatively short degradation period. 3. Interactions between risk factors were more significant than the individual factors for FQ pollution. In particular, the interaction between the vegetable planting model and amount of manure resulted in the highest pollution level. The findings of the present study make it possible to introduce effective and practical measures to alleviate pollution of soils by FQ in the study area. Adjustment of the vegetable cultivation models and application of chicken manure (less than 6 kg/m(2) manure annually with a more dry than fresh manure) could be an effective and flexible approach to alleviate FQ pollution. PMID- 23644281 TI - Spatial and temporal characteristics of particulate matter in Beijing, China using the Empirical Mode Decomposition method. AB - Air pollution has become a serious problem in Beijing, China. Daily PM10 mass concentration measurements were collected at 27 stations in Beijing over a 5-year period from January 1, 2008 to October 31, 2012. We used a new clustering method (kernel K-means) and a new period and trend decomposition method (Empirical Mode Decomposition, EMD) to explore the spatial and temporal characteristics of the PM10 mass concentration in the City. The temporal period and trend of each cluster center were decomposed using the EMD method, which is an adaptive data analysis method that requires no prior information. The daily PM10 mass concentrations varied greatly from 5 MUg/m(3) to more than 600 MUg/m(3). All of the stations were partitioned into three clusters by the kernel K-means method, and which represent the low-, middle- and high-pollution stations, respectively. The first cluster contained nine stations, mainly located in the north suburban area. The second cluster, whose degree of pollution was much more serious than the first cluster, contained 13 stations distributed in urban and peri-urban areas. The pollution level in the southern part of Beijing was much more serious than in the northern part of the City. The third cluster contained five stations located outside the second-cluster stations. The total decreased amplitudes of the three clusters during the whole period were 19 MUg/m(3), 10 MUg/m(3) and 4 MUg/m(3), respectively. Although the global trend of the PM10 mass concentration decreased in general, it was not the same for each season and station. The trends in summer and winter declined, while in spring, it has been increasing in recent years. Five types of trends can be found for stations, including monotonic decreasing, rise fall, fall rise fall, fall rise and rise. The rising trend of the regional background air pollution monitoring station, Miyun-reservoir, indicates an increase in the City's background PM10 mass concentration. PMID- 23644282 TI - Condom use and human papillomavirus in men. PMID- 23644283 TI - Consistent condom use reduces the genital human papillomavirus burden among high risk men: the HPV infection in men study. AB - BACKGROUND: Data supporting the efficacy of condoms against human papillomavirus (HPV) infection in males are limited. Therefore, we examined the effect of consistent condom use on genital HPV acquisition and duration of infection. METHODS: A prospective analysis was conducted within the HPV Infection in Men Study, a multinational HPV cohort study. Men who were recently sexually active (n = 3323) were stratified on the basis of sexual risk behaviors and partnerships. Using Cox proportional hazards regression, type-specific incidence of HPV infection and clearance were modeled for each risk group to assess independent associations with condom use. RESULTS: The risk of HPV acquisition was 2-fold lower among men with no steady sex partner who always used condoms, compared with those who never used condoms (hazard ratio, 0.54), after adjustment for country, age, race, education duration, smoking, alcohol, and number of recent sex partners. The probability of clearing an oncogenic HPV infection was 30% higher among nonmonogamous men who always used condoms with nonsteady sex partners, compared with men who never used condoms (hazard ratio, 1.29), after adjustment for country, age, race, education duration, marital status, smoking, alcohol, and number of recent sex partners. No protective effects of condom use were observed among monogamous men. CONCLUSIONS: Condoms should be promoted in combination with HPV vaccination to prevent HPV infection in men. PMID- 23644285 TI - In vivo single-molecule kinetics of activation and subsequent activity of the arabinose promoter. AB - Using a single-RNA detection technique in live Escherichia coli cells, we measure, for each cell, the waiting time for the production of the first RNA under the control of PBAD promoter after induction by arabinose, and subsequent intervals between transcription events. We find that the kinetics of the arabinose intake system affect mean and diversity in RNA numbers, long after induction. We observed the same effect on Plac/ara-1 promoter, which is inducible by arabinose or by IPTG. Importantly, the distribution of waiting times of Plac/ara-1 is indistinguishable from that of PBAD, if and only if induced by arabinose alone. Finally, RNA production under the control of PBAD is found to be a sub-Poissonian process. We conclude that inducer-dependent waiting times affect mean and cell-to-cell diversity in RNA numbers long after induction, suggesting that intake mechanisms have non-negligible effects on the phenotypic diversity of cell populations in natural, fluctuating environments. PMID- 23644286 TI - Monitoring eukaryotic and bacterial UDG repair activity with DNA-multifluorophore sensors. AB - We report the development of simple fluorogenic probes that report on the activity of both bacterial and mammalian uracil-DNA glycosylase (UDG) enzymes. The probes are built from short, modified single-stranded oligonucleotides containing natural and unnatural bases. The combination of multiple fluorescent pyrene and/or quinacridone nucleobases yields fluorescence at 480 and 540 nm (excitation 340 nm), with large Stokes shifts of 140-200 nm, considerably greater than previous probes. They are strongly quenched by uracil bases incorporated into the sequence, and they yield light-up signals of up to 40-fold, or ratiometric signals with ratio changes of 82-fold, on enzymatic removal of these quenching uracils. We find that the probes are efficient reporters of bacterial UDG, human UNG2, and human SMUG1 enzymes in vitro, yielding complete signals in minutes. Further experiments establish that a probe can be used to image UDG activity by laser confocal microscopy in bacterial cells and in a human cell line, and that signals from a probe signalling UDG activity in human cells can be quantified by flow cytometry. Such probes may prove generally useful both in basic studies of these enzymes and in biomedical applications as well. PMID- 23644284 TI - Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence. AB - Repair of large nerve defects with acellular nerve allografts (ANAs) is an appealing alternative to autografting and allotransplantation. ANAs have been shown to be similar to autografts in supporting axonal regeneration across short gaps, but fail in larger defects due to a poorly-understood mechanism. ANAs depend on proliferating Schwann cells (SCs) from host tissue to support axonal regeneration. Populating longer ANAs places a greater proliferative demand on host SCs that may stress host SCs, resulting in senescence. In this study, we investigated axonal regeneration across increasing isograft and ANA lengths. We also evaluated the presence of senescent SCs within both graft types. A sciatic nerve graft model in rats was used to evaluate regeneration across increasing isograft (~autograft) and ANA lengths (20, 40, and 60 mm). Axonal regeneration and functional recovery decreased with increased graft length and the performance of the isograft was superior to ANAs at all lengths. Transgenic Thy1-GFP rats and qRT-PCR demonstrated that failure of the regenerating axonal front in ANAs was associated with increased levels of senescence related markers in the graft (senescence associated beta-galactosidase, p16(INK4A), and IL6). Lastly, electron microscopy (EM) was used to qualitatively assess senescence-associated changes in chromatin of SCs in each graft type. EM demonstrated an increase in the presence of SCs with abnormal chromatin in isografts and ANAs of increasing graft length. These results are the first to suggest that SC senescence plays a role in limited axonal regeneration across nerve grafts of increasing gap lengths. PMID- 23644287 TI - Socioeconomic and country variations in cross-border cigarette purchasing as tobacco tax avoidance strategy. Findings from the ITC Europe Surveys. AB - BACKGROUND: Legal tobacco tax avoidance strategies such as cross-border cigarette purchasing may attenuate the impact of tax increases on tobacco consumption. Little is known about socioeconomic and country variations in cross-border purchasing. OBJECTIVE: To describe socioeconomic and country variations in cross border cigarette purchasing in six European countries. METHODS: Cross-sectional data from adult smokers (n=7873) from the International Tobacco Control (ITC) Surveys in France (2006/2007), Germany (2007), Ireland (2006), The Netherlands (2008), Scotland (2006) and the rest of the UK (2007/2008) were used. Respondents were asked whether they had bought cigarettes outside their country in the last 6 months and how often. FINDINGS: In French and German provinces/states bordering countries with lower cigarette prices, 24% and 13% of smokers, respectively, reported purchasing cigarettes frequently outside their country. In non-border regions of France and Germany, and in Ireland, Scotland, the rest of the UK and The Netherlands, frequent purchasing of cigarettes outside the country was reported by 2-7% of smokers. Smokers with higher levels of education or income, younger smokers, daily smokers, heavier smokers and smokers not planning to quit smoking were more likely to purchase cigarettes outside their country. CONCLUSIONS: Cross-border cigarette purchasing is more common in European regions bordering countries with lower cigarette prices and is more often reported by smokers with higher education and income. Increasing taxes in countries with lower cigarette prices, and reducing the number of cigarettes that can be legally imported across borders could help to avoid cross-border purchasing. PMID- 23644288 TI - Association of NALP2 polymorphism with arsenic induced skin lesions and other health effects. AB - Prolonged consumption of arsenic-laden water above the threshold limit of 10MUg/L causes a plethora of dermatological and non-dermatological multi-organ health problems, including cancer and death. Among several mechanisms of arsenic-induced toxicity and carcinogenicity studied so far, role of arsenic in impairment of immune system is less understood. Epidemiological data, animal model as well as cell line based studies have indicated that arsenic targets immune system and is associated with characteristic immunosupression, which may further adversely affect respiratory function. However, to the best of our knowledge, there is no study with respect to arsenic susceptibility investigating the role of genetic variation having immunological function. Hence, we have recruited a total of 432 arsenic-exposed individuals, of which 219 individuals with characteristic arsenic induced skin lesions (cases) and 213 individuals without arsenic-induced skin lesion(controls), from arsenic-exposed districts of West Bengal, India. To find any probable association between arsenicism and the exonic single nucleotide polymorphisms (SNPs) in NALP2 gene, an important component of inflammasome complex, we screened the entire coding region (exon) in all the study participants. Among 9 SNPs found in NALP2 gene, the A1052E polymorphism (at least with one minor allele), was significantly overrepresented in controls and hence implies decreased risk toward the development of skin lesions [OR=0.67, 95% CI: 0.46-0.97]. Since, development of non-dermatological health effects are also important factor to properly look into, we have attempted to correlate the genetic variation of NALP2 with the extent of cytogenetic damage as measured by chromosomal aberration assay and adverse health effects including peripheral neuropathy, eye problem and respiratory diseases in the study population. We observed individuals with the protective genotype had less chromosomal aberration (p<0.05), and were also less susceptible toward arsenic-related respiratory diseases [OR=0.47; 95%CI: 0.23-0.89]. These findings suggest that NALP2 A1052E SNP plays an important role toward development of arsenic-induced skin lesions, chromosomal damage and respiratory diseases. PMID- 23644289 TI - [What are veterinary functions?]. PMID- 23644290 TI - Effects of different types of solid feeds on health status and performance of Swiss veal calves. I. Basic feeding with milk by-products. AB - The objective of this study was to identify a suitable alternative to the current practice of complementing the feeding of milk by-products with straw. The influence of 5 different types of solid feeds on health and performance of Swiss veal calves was investigated in 2 production cycles of 200 veal calves each with a mean initial age of 40 days (d). The calves were housed in groups of 40 in stalls with outside pen. Liquid feeding consisted of a milk by-product combined with an additional skim milk powder ad libitum. Groups were assigned to 1 of the 5 following experimental solid feeds provided ad libitum: mix (composition: soy flakes, corn, barley, wheat, oat, barley middling, plant oil, molasses), whole plant corn pellets, corn silage, hay, and wheat straw as control. Daily dry matter intake per calf averaged 2.25 kg of the liquid food, 0.16 kg of straw, 0.33 kg of mix, 0.47 kg of corn silage, 0.38 kg of corn pellets, and 0.39 kg of hay. No significant differences (P > 0.05) among groups were found in calf losses that amounted to 4.8 % (68 % because of gastrointestinal disorders). Four percent of the calves were slaughtered prematurely. Daily doses of antibiotics were higher in the mix (36.9 d, P < 0.01) and in the corn silage groups (35 d, P < 0.01) compared to control. Compared to the 4 other groups, calves of the straw group showed the highest prevalence of abnormal ruminal content (73 %, P < 0.05), of abnormal ruminal papillae (42 %, P < 0.05), of abomasal fundic lesions (13.5 %, P < 0.1), and the lowest number of chewing movements per bolus (45, P < 0.05). The hemoglobin concentration averaged 85 g/l at the beginning and 99 g/l at the end of the fattening period with no significant differences among groups (P > 0.1). The duration of the fattening period averaged 114 d, slaughter age 157 d, and carcass weight 122 kg. The average daily weight gain (ADG) was highest in the control group straw (1.35 kg), and lowest in the hay group (1.22 kg, P < 0.01). The number of carcasses classified as C, H, and T (very high to medium quality) was lower in the hay group compared to straw (P < 0.01). No significant differences between groups were found in meat color (P > 0.1): 73 % of the carcasses were assessed as pale (267/364), 18 % as pink (66/364), and 9 % (31/364) as red. The results reveal that whole-plant corn pellets are most consistent with an optimal result combining the calves' health and fattening performance. Therefore, it can be recommended as an additional solid feed for veal calves under Swiss conditions. PMID- 23644291 TI - Effects of different types of solid feeds on health status and performance of Swiss veal calves. II. Basic feeding with whole milk. AB - The objective of this study was to identify a suitable alternative to the current practice of complementing the feeding of whole milk with straw. The influence of 3 different solid supplements on the health and performance of Swiss veal calves was investigated during 3 production cycles of 90 veal calves each with a mean initial age of 42 days and a mean initial weight of 68.7 kg. The calves were housed in groups of 30 in stalls strewn with wheat straw without outside pen. Liquid feeding consisted of whole milk combined with an additional skim milk powder ad libitum. Groups were assigned to one of the three following experimental solid feeds provided ad libitum: Pellet mix (composition: oat hulls, corn [whole plant], barley, sunflower seeds, squeezed grains of corn, molasses and a pellet binder), whole plant corn pellets, and wheat straw as control. Calves of the straw group showed significantly more abomasal lesions in the fundic part as compared to the pellet mix and corn pellets groups (P < 0.001), the prevalence of insufficient papillae was highest (P < 0.05), and ruminating behavior was unsatisfactory. In contrast to the pellet mix and straw groups, performance of calves in the corn pellets group was good. Additionally, prevalence of abomasal fundic lesions was lowest (P < 0.001), and rumen development was best in calves of the corn pellets group (P < 0.01). As in part I, the results reveal that whole-plant corn pellets are most consistent with an optimal result combining the calves' health and fattening performance. Therefore, it can be recommended as a solid supplement for veal calves basically fed whole milk under Swiss conditions. PMID- 23644292 TI - Investigation of border disease and bovine virus diarrhoea in sheep from 76 mixed cattle and sheep farms in eastern Switzerland. AB - The purpose of this study was to examine the occurrence of sheep persistently infected with Border disease virus (BDV) on 76 mixed cattle and sheep farms and whether seroconversion to BDV infection occurred in cattle of these farms. Seroprevalence of BDV and bovine viral disease virus (BVDV) infection in sheep was also investigated. Quantitative RT-PCR for pestivirus detection and an ELISA to detect pestivirus antibodies were used in 2'384 and 2'291 ovine blood samples, respectively. Another 27 seropositive sheep from ten flocks underwent serum neutralization testing to differentiate between BDV and BVDV antibodies. A BDV titre that was at least four times higher than the BVDV titre was interpreted as the result of BDV infection. Titres against BVDV were interpreted in an analogous fashion. All examined sheep were pestivirus-negative, 310 sheep were seropositive, 119 had an indeterminate titre and 1'862 were seronegative. The flock seroprevalence ranged from 0.0 to 73.9 %. Three of the 27 flocks that underwent serum neutralization testing were interpreted as BDV-infected because of 6 sheep with higher BDV titres, and 6 flocks were interpreted as BVDV-infected because of 14 sheep with higher BVDV titres. PMID- 23644294 TI - [In memory of Professor Dr. Konrad Zerobin (1931-2013)]. PMID- 23644293 TI - Distraction-stabilisation of two adjacent intervertebral spaces in a Dalmatian dog with caudal cervical spondylomyelopathy. AB - A 4-year-old, 40-kg, male, entire Dalmatian was presented for evaluation of chronic neck pain and pelvic limb ataxia. Myelography revealed ventrodorsal (hourglass) extradural compression over the intervertebral space between the 5th and 6th cervical vertebra and ventral extradural compression between the 6th and 7th cervical vertebra. Cranial compression disappeared and caudal compression markedly diminished after performing cervical traction. MRI scan confirmed protrusion of intervertebral discs and spinal cord compression in previously mentioned intervertebral spaces. Surgical distraction-stabilization of both intervertebral spaces was performed using threaded pins and polymethylmethacrylate. The convalescence from surgery was uneventful and the dog was walking without any signs of paresis until 5 months after surgery when radiography revealed implants loosening. The dog recovered fully of the implant removal and remained asymptomatic for more than 30 months. PMID- 23644298 TI - [Questions about the price announcement ordinance]. PMID- 23644299 TI - Non-invasive decision making in stable angina. PMID- 23644300 TI - Alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy: low incidence of sudden cardiac death and reduced risk profile. AB - BACKGROUND: The infarction induced by alcohol septal ablation (ASA) may predispose to arrhythmia and sudden cardiac death (SCD). OBJECTIVE: To assess survival, incidence of SCD after ASA and effects of ASA on the traditional risk factors (RFs) for SCD. DESIGN: An observational cohort-study (follow-up 8.4+/-4 years). SETTING: A dual-centre cohort. PATIENTS: 470 consecutive patients (age 56+/-14 years) with obstructive hypertrophic cardiomyopathy (HCM) (1996-2010). INTERVENTIONS: Clinically applied echo-contrast-guided ASA treatments. MAIN OUTCOME MEASURES: All-cause mortality, SCD and RFs for SCD before and after ASA. RESULTS: The 10-year survival was 88% (annual all-cause death rate 1.2%) after ASA compared with 84% (p=0.06) in a matched background population. The 10-year survival free of SCD was 95% (annual SCD rate 0.5%). ASA reduced the prevalence of abnormal blood pressure response (from 23% to 9%, p<0.001), syncope (26% to 2%, p<0.001), non-sustained ventricular tachycardia (NSVT) (23% to 17%, p<0.05) and maximal wall thickness >=30 mm (7% to 2%, p<0.001). There was a family history of SCD in 19% of the patients. The proportion of patients at high risk that is, two or more RFs (n=89), was reduced from 25% to 8% (p<0.001). A RF score >=2 before ASA was not associated with SCD (n=361, p=0.31). CONCLUSIONS: Survival in ASA-treated patients was similar to that in the background population. The number of RFs, including the prevalence of NSVT, was markedly reduced by ASA and the incidence of SCD was correspondingly low. Thus, clinically applied ASA was safe. PMID- 23644301 TI - Giant unruptured Sinus of Valsalva aneurysm: an unusual cause of aortic regurgitation. PMID- 23644302 TI - The nucleation site selection of vapour-liquid-solid nanowires. AB - Adopting twinning superlattice nanowires and III-V nanowires with [112-] sidewalls, whose cross-sections are irregular hexagons, the precise catalyst droplet surface area variation for the calculation of the nuclei formation enthalpy are obtained for possible nucleation positions at the nanowire growth front. Regular nanowires with hexagonal cross-section are also calculated. The nucleation site selection rules are drawn from the fact that the favorable site corresponds to a smaller nucleation barrier, which is not deducible from the spherical-cap shaped droplet approximation. The influence of droplet volume and nanowire geometry on the nucleation site selection should also be taken into consideration when calculations of the nanowire nucleation properties are involved. PMID- 23644304 TI - Actinic keratosis of external auditory canal. PMID- 23644303 TI - Near-dehiscence: clinical findings in patients with thin bone over the superior semicircular canal. AB - OBJECTIVE: To determine whether patients with thin bone over the superior semicircular canal can develop signs or symptoms of superior canal dehiscence syndrome (SCDS). STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: All patients from our institution found to have thin but not frankly dehiscent bone over the superior canal despite symptoms and signs of SCDS. MAIN OUTCOME MEASURES: Preoperative CT imaging, symptoms, audiometry, vestibular evoked myogenic potentials (VEMP), and intraoperative electrocochleography (ECochG) results were reviewed. Symptoms were assessed at least 1 month postoperatively in all patients, and postoperative physiologic data are presented when available. RESULTS: Ten patients (11 ears) had thin bone over the superior semicircular canal at surgery. All presented with autophony or sound and/or pressure-induced vertigo, in addition to at least 1 physiologic measure consistent with SCDS. CT imaging was read as showing either dehiscence (36%) or marked thinning of bone overlying the affected canal (64%). Preoperative median low-frequency air-bone gap (ABG) was elevated (10.9 dB; interquartile range [IQR], 8.8-12.5), with 4 patients demonstrating negative bone conduction thresholds. Patients had elevated oVEMP amplitude (median, 20.7; IQR, 6.7-22.1) MUV and ECochG SP/AP ratios (median, 0.59; IQR, 0.54-0.67). Postoperative ABG and SP/AP ratio decreased significantly compared with preoperative values (p < 0.05), and all patients reported symptomatic improvement. CONCLUSION: Symptoms typical of SCDS can occur in cases with thin but not dehiscent bone. Surgical plugging or resurfacing can reduce symptoms in such cases. PMID- 23644305 TI - Resting state functional magnetic resonance imaging: an emerging clinical tool. PMID- 23644306 TI - Prophylactic antiepileptic drugs in brain tumors: what evidence is enough evidence? PMID- 23644307 TI - Protein aggregates and regional disease spread in ALS is reminiscent of prion like pathogenesis. AB - Amyotrophic lateral sclerosis (ALS) typically commences in a discrete location in a limb or bulbar territory muscles and then spreads to the adjacent anatomical regions. This pattern is consistent with a contiguous spread of the disease process in motor neuron network resulting in progressive motor weakness. The etiology of ALS onset and the mechanism of the regional ALS spread remain elusive. Over the past 5 years, identification of mutations in two RNA binding proteins, trans active response (TAR) DNA-binding protein (TDP-43) and fused in sarcoma (FUS), in patients with familial ALS has led to a major shift in our understanding of the ALS disease mechanism. In addition to their role in RNA metabolism, TDP-43 and FUS form protein aggregates in the affected neurons. More recent findings demonstrating that both TDP-43 and FUS contain glutamine/asparagine (Q/N) residue-rich prion-like domains have spurred intense research interest. This brief review discusses the prion-related domains in TDP 43 and FUS and their implication in protein aggregate formation and disease spread in ALS. PMID- 23644308 TI - Minimally-invasive aspiration and drainage for management of traumatic epidural hematoma straddling transverse sinus. AB - AIMS: To investigate the therapeutic effect of minimally-invasive aspiration and drainage in traumatic epidural hematoma straddling transverse sinus (TEHSTS). MATERIALS AND METHODS: Fifty-eight patients (39 males and 19 females) with TEHSTS and initial admission Glasgow Coma Scale (GCS) score of 8-10 (mean = 9) were treated with minimally-invasive aspiration and drainage under computed tomography (CT) guidance. Urokinase was used for irrigation and drainage. Post-operatively CT scan was performed at 3 h, 3 days, and 5 days. The volume of hematoma was calculated, and Glasgow outcome scale (GOS) was evaluated 3 months after the operation. RESULTS: The volume of hematoma at 3 h and 3 days post-operation (20 +/- 5 ml and 15 +/- 2 ml; respectively) were significantly lower than that of pre operation (45 +/- 10 ml; P < 0.05). The hematoma was totally evacuated on 3-5 days post-operation. The GCS was 12 +/- 1 on the 5 th day after the operation, which was significantly higher than that of pre-operation (8 +/- 1; P < 0.05). Three months after operation, 45 (77%) patients had good recovery (GOS: 5) and 9 (15%) patients had moderate disability (GOS: 4). CONCLUSIONS: Minimally-invasive aspiration and drainage could be potentially effective in the treatment of TEHSTS with GCS score of equal or greater than 8 points. PMID- 23644309 TI - Microsurgical anatomy of the anterior cerebral artery in Indian cadavers. AB - BACKGROUND: The microanatomy features of cerebral arteries may be variable and may be different in different ethnic groups. AIM: To study the anterior cerebral artery (ACA) anatomy in North-West Indian cadavers. MATERIALS AND METHODS: Microanatomy features of the ACA were studied in 15 formalin fixed human cadaveric brains under microscope. The outer diameter, length, and number of perforating branches with respective anomalies were measured for each of the following vessels: ACA (proximal A1 segment to distal A2 segment), anterior communicating artery (ACoA), Recurrent artery of Heubner (RAH), and callosomarginal artery and photographed for documentation. RESULTS: The mean length and external diameter of right and left A1 segment was 12.09 mm and 12.0 mm and 2.32 mm and 2.36 mm respectively. Narrowing, duplication, and median ACA were seen in 6.6%, 3.3% and 6.6% of the vessels respectively. Complex ACoA type was seen in 40% cadavers. RAH originated at an average point of 0.2 mm distal to ACoA, but in one cadaver it arose 5 mm proximal to ACoA. Double RAH was found in 26.6%. The course of RAH in relation to A1 was superiorly in 60%, in anteriorly 30% and posteriorly in 10% of cadavers. The orbitofrontal artery (OFA) and frontopolar artery (FPA) arose from A2 in 83.3% to 40% respectively. The mean distance of OFA and FPA from ACoA was 4.17 mm and 8.5 mm respectively. After giving rise to central, callosal and cortical branches, pericallosal artery terminated near the splenium of the corpus callosum or on the precuneus as the inferomedial parietal artery. CONCLUSION: Knowledge of the microvascular anatomy is indispensable and it is mandatory to be aware of the possible variations in the anomalies to minimize morbidity. PMID- 23644310 TI - Surgical management of selected pituitary macroadenomas using extended endoscopic endonasal transsphenoidal approach: early experience. AB - BACKGROUND AND OBJECTIVES: The endoscopic transsphenoidal approach is commonly used surgical approach for pituitary adenomas. However, adenomas with dumbbell configuration, pure suprasellar location, and fibrous consistency are difficult to remove by this approach. Recently, the extended endoscopic endonasal approach (EEEA) has been utilized to excise this subgroup of pituitary adenomas successfully. MATERIALS AND METHODS: Between January 2009 and December 2011, 13 patients with pituitary macroadenomas were treated with EEEA. The tumor subgroups included: Dumbbell tumor configuration (4), pure suprasellar tumor location (2), and large suprasellar tumors with subfrontal extension (2). Five patients had fibrous/recurrent tumors and required addition of transtubercular-transplanum extension to the standard endoscopic endonasal exposure for radical resection. RESULTS: The tumor removal was gross total in 8 (61.5%) patients, subtotal in 4 (30.7%), and partial in 1 (7.7%) patient. Clinical improvement was observed in almost all patients, immediate relief in headaches in 88% and normalization of vision in 90% of patients with pre-operative visual disturbances. Three patients with secreting adenomas, two with growth hormone-secreting adenomas and one with prolactin-secreting adenoma, had normalization of hormonal status. Three patients developed temporary diabetes insipidus two patients suffered transient ischemic attacks and one patient with a recurrent giant pituitary adenoma experienced a serious injury to the perforating artery. Four patients (30.7%) developed post operative cerebrospinal rhinorrhea and two patients required surgical repair. CONCLUSIONS: Our early experience suggests that the EEEA offers a potentially viable treatment option in certain pituitary tumors which are difficult to remove by the standard endoscopic approaches. However, longer follow-up and larger series are needed to establish the efficacy of this approach. PMID- 23644311 TI - A retrospective two-center study of antiepileptic prophylaxis in patients with surgically treated high-grade gliomas. AB - BACKGROUND: The effectiveness of antiepileptic prophylaxis in patients with newly diagnosed high-grade glioma is debated. Craniotomy, surgical manipulation and bleeding are believed to favor the onset of seizures and, therefore, perioperative antiepileptic drugs (AEDs) are generally used. Nevertheless, evidence to initiate preoperative AED prophylaxis are weak. AIM: Aim of this paper was to evaluate the need for AED prophylaxis in surgically-treated malignant glioma patients without history of seizures. MATERIALS AND METHODS: We conducted a retrospective, two-center cohort study to assess the effectiveness of preoperative AED prophylaxis. Patients were divided in two groups: one with AED preoperative administration and the other without. Because of its non-hepatic metabolism, levetiracetam (LEV) was chosen. Logistic regression models were used to investigate the odds ratio for each group. The explanatory variables included the treatment received, sex, age, and site of lesion. The outcome measure of successful LEV prophylaxis was seizure vs. no seizure post-operatively, at three and six months after surgery. RESULTS: Our results showed that LEV prophylaxis was not a significant predictor of seizure occurrence, although the regression coefficient indicated a slight reduction in seizure risk following LEV administration. Patient's age was a significant predictor of seizure occurrence. Younger patients had a higher risk of seizure in the six months post-surgery. CONCLUSIONS: We conclude that AEDs prophylaxis does not provide a substantial benefit to surgically treated high-grade glioma patients and should not be administered routinely. Further investigations are required to detect subgroups of patients at higher risk of developing seizures in order to selectively administer AED. PMID- 23644312 TI - Molecular characteristics of meningiomas in a cohort of Indian patients: loss of heterozygosity analysis of chromosomes 22, 17, 14 and 10. AB - BACKGROUND: Though, loss of heterozygosity (LOH) at chromosome 22q is considered to be the most likely initiating event in the formation of meningiomas, LOH at other chromosomes (1, 3, 6, 9, 10, 11, 14.17, and 18) have been implicated in its progression. The aim of this study was to analyze microsatellite markers on a select set of chromosomes including, 22q, 10q, 14q, and 17p for LOH in patients with meningiomas. MATERIALS AND METHODS: Tumor tissue and its corresponding blood sample were collected from 27 patients with meningioma. Four polymorphic microsatellite markers (D10S520, D17S1289, D14S555, and D22S417) were characterized for LOH analysis. RESULTS: There were 14 World Health Organization (WHO) grade I, 12 WHO grade II and 1 WHO grade III meningiomas. LOH was seen most often at D22S417 with an equal distribution between the grades (33% of informative samples in each grade). Though, LOH at D14S555 was seen in 50% of informative WHO grade II tumors, compared to 11.1% of informative WHO grade I tumors it did not reach statistical significance. However, allelic imbalance (AI) at D14S555 was significantly associated with atypia (P = 0.05). LOH at D17S1289 was seen only in one tumor sample, and none of the informative samples displayed LOH at D10S520. CONCLUSION: The frequency and equal distribution of LOH at chromosome 22 supports the hypothesis that it is an early event in the tumorigenesis of meningiomas. The association of AI at D14S555 in WHO grade II meningiomas needs to be investigated on a larger set of samples. PMID- 23644313 TI - Utility of resting fMRI and connectivity in patients with brain tumor. AB - BACKGROUND: Resting state (task independent) Functional Magnetic Resonance Imaging (fMRI) has opened a new avenue in cognitive studies and has found practical clinical applications. MATERIALS AND METHODS: Resting fMRI analysis was performed in six patients with brain tumor in the motor cortex. For comparison, task-related mapping of the motor cortex was done. Connectivity analysis to study the connections and strength of the connections between the primary motor cortex, premotor cortex, and primary somatosensory cortex on the affected side was also performed and compared with the contralateral normal side and the controls. RESULTS: Resting fMRI in patients with brain tumor in the motor cortex mapped the motor cortex in a task-free state and the results were comparable to the motor task paradigm. Decreased connectivity on the tumor-affected side was observed, as compared to the unaffected side. CONCLUSION: Resting fMRI and connectivity analysis are useful in the presurgical evaluation of patients with brain tumors and may help in uncooperative or pediatric patients. They can also prognosticate the postoperative outcome. This method also has significant applications due to the ease of image acquisition. PMID- 23644314 TI - Incidence of malignancies in biopsy-proven inflammatory myopathy. AB - BACKGROUND: Inflammatory myopathy (IM) as a manifestation of paraneoplastic syndrome has been well-documented. However, the prevalence of malignancies reported varies across the studies. There are very few studies reported from Asia, only one from India. AIM: The aim of this analysis was to study the prevalence of malignancy in biopsy-proven cases of IM in India and to study the difference between malignant and non-malignant groups. MATERIALS AND METHODS: The study was a retrospective review of case records of patients with a biopsy-proven IM attending Tertiary Care University Hospital. RESULTS: Of the total 86 patients with biopsy-proven IM, 22 patients were polymyositis, 63 patients had dermatomyositis (DM) and one was with an inclusion body myositis, not included for further analysis. Associated malignancy was diagnosed in 6 (7%) patients, and five of them were females. Diagnosis of associated malignancy was identified at the time of diagnosis of IM in four (66.7%) patients. All the six patients with an associated malignancy had DM. Only one patient died within 1 year of diagnosis. Creatinine kinase was much lower in patients with malignancy associated IM than in patients with no malignancy (P < 0.0001). CONCLUSION: The prevalence of malignancy was very low in our cohort as compared to the studies from other countries. Breast cancer was the most common malignancy associated with DM. The type of associated malignancy was quite variable. PMID- 23644315 TI - Etiological profile of epilepsia partialis continua among adults in a tertiary care hospital. AB - BACKGROUND: Epilepsia partialis continua (EPC), is a subtype of status epilepticus, have a varied spectrum of etiology and the out-come depends on the etiology. AIMS AND OBJECTIVES: The present study is aimed to analyze the clinical characteristics and outcome. MATERIALS AND METHODS: This is a prospective analysis of 17 patients admitted to our center between August 2010 and April 2012. EPC was defined as regular or irregular clonic muscular twitches affecting a limited part of the body, occurring for a minimum of 1 h, and recurring at intervals of no more than 10 s. The data collected included etiology, radiological findings, electroencephalogram (EEG) abnormalities, associated comorbid conditions, and outcome. RESULTS: The mean age at presentation was 44.26 +/- 13.77 years and the mean duration was 2.7 +/- 1.5 days. There were ten patients with diabetic non-ketotic hyperosmolar state and one patient each of oligodendroglioma, varicella zoster vasculitis, central nervous demyelination, ischemic stroke, post traumatic seizure, arteriovenous malformation, and in one patient no cause could be established. Imaging showed abnormality only in five patients and EEG was abnormal in four patients. The EPC was controlled by one antiepileptic drug (AED) in eight patients, with two AEDs in seven patients and two patients required three AEDs. CONCLUSION: EPC is a rare type of focal motor status epilepticus. Treatment of the underlying cause in addition to controlling EPC is essential to achieve the good outcomes. PMID- 23644316 TI - Adult-onset leukoencephalopathy with brain stem and spinal cord involvement in Chinese Han population: a case report and literature review. AB - Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a recently described disorder with an autosomal recessive mode of inheritance. We report a case of rare adult-onset LBSL with typical magnetic resonance imaging (MRI) features. The DARS2 gene mutation analysis has identified a c. 228-20_21delTTinsC (p.R76SfsX5) mutation and a c. 850G > A (p. 284E > K) mutation. With glucocorticosteroid treatment the patient has had improvement in bladder symptoms. This is the first reported adult-onset LBSL case in the Chinese Han population. A review of the literature suggests that brain lactate elevation in adult-onset LBSL is lower than early-onset cases (P < 0.01), and early-onset cases show mild intelligence and cognition decline. These observations suggest that age of onset and brain lactate levels probably influence the prognosis of LBSL. PMID- 23644317 TI - Headache associated with airplane travel: a rare entity. AB - Airplane travel headache is rare and has recently been described as a new form of headache associated with a specific situation. Of the 1,208 patients with primary headaches attending a tertiary care neurology hospital, two (0.16%) patients satisfied the criteria for headache related to airplane travel. Both the patients fulfilled the proposed diagnostic criteria for airplane travel headache. This unique headache had a mean duration of 24 minutes, localized to the medial supraorbital region described as having an intense jabbing or stabbing character that occurred exclusively and maximally during aircraft landing or take-off, following which pain intensity subsided . This rare headache felt on aircraft descent is probably due to the squeeze effect on the frontal sinus wall, when air trapped inside it contracts producing a negative pressure leading to mucosal edema, transudation and intense pain. Use of nasal decongestants either alone or in combination with naproxen sodium prior to ascent and descent abated the headache episodes. Awareness about this unique entity is essential to provide proper treatment and avoid patient suffering. PMID- 23644318 TI - Reversible disconnection syndrome: an unusual presentation of vitamin B12 deficiency. PMID- 23644319 TI - Mineral deposition on magnetic resonance imaging in chorea-acanthocytosis: a pathogenic link with pantothenate kinase-associated neurodegeneration? PMID- 23644320 TI - Bilateral vertical gaze palsy in unilateral mesodiencephalic junction lesion: a case series. PMID- 23644321 TI - Isolated cortical vein thrombosis in a patient with sickle cell disease: treatment with decompressive craniotomy and anticoagulation and literature review. PMID- 23644322 TI - A novel PANK2 mutation in a 12-year-old Chinese boy with pantothenate kinase associated neurodegeneration. PMID- 23644323 TI - Horizontal gaze palsy with progressive myoclonic epilepsy: rare presentation of Gaucher's disease. PMID- 23644324 TI - Cerebral syphilitic gumma misdiagnosed as glioma: a case report and literature review. PMID- 23644325 TI - Sphenoid sinus tuberculosis: a rare cause of visual dysfunction in an adolescent girl. PMID- 23644326 TI - Distant cerebral venous sinus thrombosis in meningioma surgery: a rare complication. PMID- 23644328 TI - "Target sign" in an intracranial vertebral artery dissection with isolated vertigo. PMID- 23644327 TI - Isolated cortical vein thrombosis from lumbar puncture: high suspicion yields high diagnostic yield. PMID- 23644329 TI - Multiple fusiform distal aneurysms in an operated case of atrial myxoma: case report and review of literature. PMID- 23644330 TI - Clival tumor presenting with acromegaly. PMID- 23644331 TI - Ventral foramen magnum neurenteric cyst presenting as acute rapidly progressive quadriparesis and respiratory compromise: a case report and review of literature. PMID- 23644332 TI - Management issues in a complex case of basilar invagination associated with a large fourth ventricular dermoid and Klippel-Feil syndrome. PMID- 23644333 TI - An unusual intramedullary spinal cord tumour in a young female. PMID- 23644334 TI - Intracranial giant cell tumor of soft tissue: mimicking a glioma. PMID- 23644335 TI - Stone of folly: historical vignette revisited. PMID- 23644336 TI - Same side double chronic calcified epidural hematoma: case report and review of literature. PMID- 23644337 TI - Report of an unusual upper cervical spine injury: traumatic atlantoaxial rotatory subluxation with vertical odontoid fracture in a child. PMID- 23644338 TI - Subdural hematoma presenting with unilateral foot drop. PMID- 23644339 TI - Rare presentation of pial arteriovenous malformations as proptosis: case report and review of literature. PMID- 23644340 TI - Primary malignant non-Hodgkin's lymphoma of the skull vault in an immunocompetent patient. PMID- 23644341 TI - Imaging of a brain abscess with "raccoon eye"- like changes on imaging. PMID- 23644342 TI - Carotid dissection in Marfan's syndrome. PMID- 23644343 TI - A case of subdural empyema following chronic subdural hematoma drainage. PMID- 23644344 TI - Endovascular treatment of ruptured fusiform middle cerebral artery aneurysm. PMID- 23644345 TI - Fungal pituitary abscess: case report and review of the literature. PMID- 23644346 TI - Self-assembly properties, aggregation behavior and prospective application for sustained drug delivery of a drug-participating catanionic system. AB - In the present study, the self-assembly properties, aggregation behavior and potential application of mixed samples formed by an active drug (diclofenac sodium, DS) and conventional surfactant (didodecyldimethyl ammonium bromide, DDAB) are investigated with surface tension, transmission electron microscope (TEM), dynamic light scattering (DLS), zeta potential, conductivity, in vitro drug release and hemolytic toxicity measurements. The physicochemical parameters such as critical micelle concentration (CMC), the surface tension at CMC (gammaCMC), the maximum surface excess concentration (Gamma max) and the minimum area per molecule headgroup at the air/water interface (A min) and degree of counterion binding (beta) are obtained from the surface tension and electrical conductivity measurements. The results show that diclofenac sodium can decrease the surface tension of water and aggregate in the aqueous solution when its concentration is large enough. The CMC and gammaCMC of the DS/DDAB mixed systems are found to have values between that of individual DS and DDAB solutions. TEM and DLS results demonstrate the formation of spherical vesicles in a wide range of the molar ratio of the two components. The amount of charge on the vesicles and their stability can be tuned by controlling the amount of drug and surfactant. To evaluate the potential use of the as-prepared DS/DDAB catanionic vesicles in drug delivery systems, the in vitro drug release and hemolytic toxicity are carried out. The results indicate that both the drug release behavior and the hemolytic toxicity are dependent on the composition of the samples, X1 (X1=nDS/n(DS+DDAB), decreasing with the decrease of X1. The results of this work suggested that the drug-participating catanionic vesicles can be used as a safe and an efficient vehicle for sustained drug release. PMID- 23644347 TI - Controlled delivery of naltrexone by an intraoral device: in vivo study on human subjects. AB - Naltrexone is widely used in the treatment of opiate addiction but its current peroral administration is characterized by low bioavailability with various side effects. The development of a long-acting transbuccal delivery device (IntelliDrug) for NLX may be useful to improve patient compliance and the therapy effectiveness. The aims of the study are (a) to test basic safety and effectiveness of controlled transbuccal drug delivery on human subjects; (b) to compare NLX bioavailability following transbuccal delivery vs per os conventional delivery; and (c) to test the hypothesis that transbuccal delivery is more efficient than the conventional route. In this randomized cross-over pilot study, 12 healthy subjects received in a different order 2 types of NLX administration, per os or transbuccal delivery, based on which group they were randomized to. For per os administration 50mg NLX tablets were used, while for transbuccal administration, a NLX-loaded prototype of the IntelliDrug device was fixed on patients' dental arch. Serial blood samples were drawn and analysed for the NLX concentration. The IntelliDrug prototype functioned properly and it did not exert any adverse side-effect. The transbuccal route resulted in administration efficiency 4-17 times higher than conventional per os route. Transbuccal delivery of NLX appears to be a more efficient drug administration route compared to peroral one. It allows to reach a given therapeutic blood level using a small drug dose. PMID- 23644348 TI - Non-invasive imaging of acute allograft rejection after rat renal transplantation using 18F-FDG PET. AB - The number of patients with end-stage renal disease, and the number of kidney allograft recipients continuously increases. Episodes of acute cellular allograft rejection (AR) are a negative prognostic factor for long-term allograft survival, and its timely diagnosis is crucial for allograft function (1). At present, AR can only be definitely diagnosed by core-needle biopsy, which, as an invasive method, bares significant risk of graft injury or even loss. Moreover, biopsies are not feasible in patients taking anticoagulant drugs and the limited sampling site of this technique may result in false negative results if the AR is focal or patchy. As a consequence, this gave rise to an ongoing search for new AR detection methods, which often has to be done in animals including the use of various transplantation models. Since the early 60s rat renal transplantation is a well-established experimental method for the examination and analysis of AR (2). We herein present in addition small animal positron emission tomography (PET) using (18)F-fluorodeoxyglucose (FDG) to assess AR in an allogeneic uninephrectomized rat renal transplantation model and propose graft FDG-PET imaging as a new option for a non-invasive, specific and early diagnosis of AR also for the human situation (3). Further, this method can be applied for follow up to improve monitoring of transplant rejection (4). PMID- 23644349 TI - Imaging of the B1 distribution and background signal in a MAS NMR probehead using inhomogeneous B0 and B1 fields. AB - Several widely used methods for suppressing the "background" signal in (1)H magic angle spinning (MAS) NMR spectroscopy are based on the assumption of a significant difference between the B1 radiofrequency field experienced by the sample (within the MAS rotor) and that felt by static components of the probehead (where the background signal is believed to originate). In this work, a two dimensional correlation experiment employing inhomogeneous B0 and B1 fields is used to image the B1 distribution in a MAS NMR probehead. The experiment, which can be performed on any spectrometer, allows the distribution of the B1 field to be measured and also correlated with the spatial location of the NMR signal within the probehead. The method can also readily be combined with various "depth pulse" techniques for background suppression, allowing their performances to be more rigorously evaluated. PMID- 23644350 TI - Statistical reconstruction algorithms for continuous wave electron spin resonance imaging. AB - Electron spin resonance imaging (ESRI) is an important branch of ESR that deals with heterogeneous samples ranging from semiconductor materials to small live animals and even humans. ESRI can produce either spatial images (providing information about the spatially dependent radical concentration) or spectral spatial images, where an extra dimension is added to describe the absorption spectrum of the sample (which can also be spatially dependent). The mapping of oxygen in biological samples, often referred to as oximetry, is a prime example of an ESRI application. ESRI suffers frequently from a low signal-to-noise ratio (SNR), which results in long acquisition times and poor image quality. A broader use of ESRI is hampered by this slow acquisition, which can also be an obstacle for many biological applications where conditions may change relatively quickly over time. The objective of this work is to develop an image reconstruction scheme for continuous wave (CW) ESRI that would make it possible to reduce the data acquisition time without degrading the reconstruction quality. This is achieved by adapting the so-called "statistical reconstruction" method, recently developed for other medical imaging modalities, to the specific case of CW ESRI. Our new algorithm accounts for unique ESRI aspects such as field modulation, spectral-spatial imaging, and possible limitation on the gradient magnitude (the so-called "limited angle" problem). The reconstruction method shows improved SNR and contrast recovery vs. commonly used back-projection-based methods, for a variety of simulated synthetic samples as well as in actual CW ESRI experiments. PMID- 23644351 TI - Skew projection of echo-detected EPR spectra for increased sensitivity and resolution. AB - The measurement of EPR spectra during pulsed EPR experiments is commonly accomplished by recording the integral of the electron spin echo as the applied magnetic field is stepped through the spectrum. This approach to echo-detected EPR spectral measurement (ED-EPR) limits sensitivity and spectral resolution and can cause gross distortions in the resulting spectra because some of the information present in the electron spin echo is discarded in such measurements. However, Fourier transformation of echo shapes measured at a series of magnetic field values followed by skew projection onto either a magnetic field or resonance frequency axis can increase both spectral resolution and sensitivity without the need to trade one against the other. Examples of skew-projected spectra with single crystals, glasses and powders show resolution improvements as large as a factor of seven with sensitivity increases of as much as a factor of five. PMID- 23644352 TI - Restricted k-space sampling in pure phase encode MRI of rock core plugs. AB - In the study of rock core plugs with multidimensional MRI, the samples are of a regular cylindrical shape that yields well defined intensity distributions in reciprocal space. The high intensity k-space points are concentrated in the central region and in specific peripheral regions. A large proportion of the k space points have signal intensities that are below the noise level. These points can be zero-filled instead of being collected experimentally. k-space sampling patterns that collect regions of high intensity signal while neglecting low intensity regions can be naturally applied to a wide variety of pure phase encoding measurements, such as T2 mapping SESPI, hybrid-SESPI and SPRITE, since all imaging dimensions can be under-sampled. With a shorter acquisition time, as fewer experimental data points are required, the RF and gradient duty cycles are reduced, while the image SNR is improved. PMID- 23644353 TI - Room temperature strong coupling between a microwave oscillator and an ensemble of electron spins. AB - We demonstrate theoretically and experimentally the possibility to achieve the strong coupling regime at room temperature with a microwave electronic oscillator coupled with an ensemble of electron spins. The coupled system shows bistable behaviour, with a broad hysteresis and sharp transitions. The coupling strength and the hysteresis width can be adjusted through the number of spins in the ensemble, the temperature, and the microwave field strength. PMID- 23644354 TI - The Lesser Egyptian Gerbil (Gerbillus gerbillus) is a suitable host for the long term propagation of Cryptosporidium andersoni. AB - We describe the course of infection of Cryptosporidium andersoni LI03, originally isolated from cattle, in outbred Gerbillus gerbillus (Lesser Egyptian Gerbil), Meriones unguiculatus (Mongolian gerbil), and Meriones tristrami (Tristram's jird). While both Meriones spp. partially cleared the infection and shed a low number of oocysts (less than 15,000 oocysts per gram (OPG)), chronic infection with a mean infection intensity reaching 200,000 OPG was observed in G. gerbillus. These data suggest that G. gerbillus can be used as a laboratory model for the long-term maintenance and study of C. andersoni without the need for host immunosuppression. PMID- 23644355 TI - Audio-visual congruency alters power and coherence of oscillatory activity within and between cortical areas. AB - Dynamic communication between functionally specialized, but spatially distributed areas of the brain is essential for effective brain functioning. A candidate mechanism for effective neuronal communication is oscillatory neuronal synchronization. Here, we used magnetoencephalography (MEG) to study the role of oscillatory neuronal synchronization in audio-visual speech perception. Subjects viewed congruent audio-visual stimuli of a speaker articulating the vowels /a/ or /o/. In addition, we presented modified, incongruent versions in which visual and auditory signals mismatched. We identified a left hemispheric network for processing congruent audio-visual speech as well as network interaction between areas: low frequency (4-12 Hz) power was suppressed for congruent stimuli at auditory onset around auditory cortex, while power in the high gamma (120-140 Hz) band was enhanced in the Broca's area around auditory offset. In addition, beta power (20-30 Hz) was suppressed in supramarginal gyrus for incongruent stimuli. Interestingly, coherence analysis revealed a functional coupling between auditory cortex and Broca's area for congruent stimuli demonstrated by an increase of coherence. In contrast, coherence decreased for incongruent stimuli, suggesting a decoupling of auditory cortex and Broca's area. In addition, the increase of coherence was positively correlated with the increase of high gamma-power. The results demonstrate that oscillatory power in several frequency bands correlates with the processing of matching audio-visual speech on a large spatio-temporal scale. The findings provide evidence that coupling of neuronal groups can be mediated by coherence in the theta/alpha band and that low frequency coherence and high frequency power modulations are correlated in audio-visual speech perception. PMID- 23644356 TI - Aerosol mass spectrometric analysis of the chemical composition of non-refractory PM(1) samples from school environments in Brisbane, Australia. AB - Long-term exposure to vehicle emissions has been associated with detrimental health effects. Children are amongst the most susceptible group and schools represent an environment where they can experience significant exposure to vehicle emissions. However, there are limited studies on children's exposure to vehicle emissions in schools. The aim of this study was to quantify the concentration of organic aerosol (OA) and in particular, vehicle emissions that children are exposed to during school hours. Therefore an Aerodyne compact time of-flight aerosol mass spectrometer (TOF-AMS) was deployed at five urban schools in Brisbane, Australia. TOF-AMS enabled the chemical composition of the non refractory (NR-PM1) to be analysed with a high temporal resolution to assess the concentration of vehicle emissions and other OA components during school hours. The organic fraction at each school comprised the majority of NR-PM1. Primary emissions were found to dominate the OA at only one school which had an O:C ratio of 0.17, due to fuel powered gardening equipment used near the TOF-AMS. A significant source of the OA at two of the schools was aged vehicle emissions from nearby highways. More oxidised OA was observed at the remaining two schools, which also recorded strong biomass burning influences. In general, the diurnal cycle of the total OA concentration varied between schools and was found to be at a minimum during school hours. The major organic component that school children were exposed to during school hours was secondary OA at all schools. Peak exposure of school children to vehicle emissions occurred during school drop-off and pick-up times. Unless a school is located near major roads, children are exposed predominately to regional secondary OA as opposed to local emissions during school hours in urban environments. PMID- 23644357 TI - Variations of common riverine contaminants in reservoir sediments. AB - Organic molecules in reservoir sediments can be used as tracers of contaminant inputs into rivers. Vertical variations in the molecular records can be ascribed to pre-depositional alteration within the water column, or in situ post depositional alteration. We report the molecular stratigraphy of four common riverine contaminant groups in sediment of the largest reservoir on the Danube River, the Iron Gate I Reservoir. Sediments were rapidly deposited, with little variation in texture and, as revealed by analytical pyrolysis, in the concentration and composition of natural sedimentary organic matter. However, a detailed molecular inspection did reveal differences in distribution and organic carbon (OC)-normalized concentrations of contaminants. The OC-normalized concentrations of nonylphenol increased by one order of magnitude with depth down the 70 cm sediment core. There is a strong correlation between sediment depth and the ratio of nonylphenol to its precursor (nonylphenol monoethoxylate). This indicated that nonylphenol was produced in situ. While the relative proportions of C10-C14 linear alkylbenzenes remained constant with increasing depth, they exhibited variations in isomer distribution. These variations, which are due to different degrees of degradation, appear to have occurred within the water column prior to sedimentation of suspended solids. The distribution of 40 polycyclic aromatic hydrocarbons revealed origins from both pyrogenic and petrogenic sources. The differences in their compositions were not depth-related, but rather were associated with variations in the sorption capacities of texturally different sediments. Perylene showed slightly higher concentrations at greater depths, while the OC-normalized concentration of retene systematically increased with sediment depth. This is consistent with formation of retene and perylene via very early diagenetic transformation. The presence of petroleum biomarkers indicated minor contamination by fossil fuels. PMID- 23644358 TI - Temporal trends (1986-2005) of essential and non-essential elements in a terrestrial raptor in northern Europe. AB - In the recent decades, the atmospheric deposition of many metals has declined in northern Europe, mostly due to reductions of emissions in other parts of the Europe. However, less is known about the temporal trends at higher trophic levels in terrestrial food chains. In this study we measured 39 different essential and non-essential elements in tawny owl (Strix aluco) tail-feathers (n=633) collected annually between 1986 and 2005 in Central Norway. There was a strong decline in lead (Pb) concentrations (~94%) consistent with the termination of the use of Pb as a petrol additive. There were also significant declines in cadmium (Cd), cobalt (Co) and arsenic (As) concentrations. Zinc (Zn) may also have declined after 2000, but this is not yet clear due to possible analytical problems. More unexpected was a strong decline of boron (B) in the late 1980s and early 1990s with a subsequent leveling-off, but with high concentrations in 1999. The decline in B could be related to changes in the agricultural practices and use of fertilizers. Tin (Sn) showed an abrupt decline in the mid-1990s, after which the concentrations established at one fifth of the level before this time. Iron (Fe) was stable until the late 1990s, but showed an increase afterwards, whereas lanthanum (La) tended to increase up to the mid-1990s and then leveled-off. Aluminum (Al) showed decreasing levels until the mid-1990s, but a considerable increase afterwards. There was a small increase in praseodymium (Pr), but the only element showing a consistent strong increase over the study period (61%) was rubidium (Rb). The causes of the temporal trends in different elements may be changed input to the local ecosystem from local and trans-boundary sources, but possibly also variation in climate and feeding conditions for the owls. PMID- 23644359 TI - Time-lapse imaging of self- and cross-pollinations in Brassica rapa. AB - BACKGROUND AND AIMS: Pollination is an important process in the life cycle of plants and is the first step in bringing together the male and female gametophytes for plant reproduction. While pollination has been studied for many years, accurate knowledge of the morphological aspects of this process is still far from complete. This study therefore focuses on a morphological characterization of pollination, using time-series image analysis of self- and cross-pollinations in Brassica rapa. METHODS: Time-lapse imaging of pollen behaviour during self- and cross-pollinations was recorded for 90 min, at 1 min intervals, using a stereoscopic microscope. Using time-series digital images of pollination, characteristic features of pollen behaviours during self- and cross pollinations were studied. KEY RESULTS: Pollen exhibited various behaviours in both self- and cross-pollinations, and these were classified into six representative patterns: germination, expansion, contraction, sudden contraction, pulsation and no change. It is noteworthy that in 'contraction' pollen grains shrunk within a short period of 30-50 min, and in 'pulsation' repeated expansion and contraction occurred with an interval of 10 min, suggesting that a dehydration system is operating in pollination. All of the six patterns were observed on an individual stigma with both self- and cross-pollinations, and the difference between self- and cross-pollinations was in the ratios of the different behaviours. With regard to water transport to and from pollen grains, this occurred in multiple steps, before, during and after hydration. Thus, pollination is regulated by a combination of multiple components of hydration, rehydration and dehydration systems. CONCLUSIONS: Regulated hydration of pollen is a key process for both pollination and self-incompatibility, and this is achieved by a balanced complex of hydration, dehydration and nutrient supply to pollen grains from stigmatic papilla cells. PMID- 23644360 TI - Mathematical model of fructan biosynthesis and polymer length distribution in plants. AB - BACKGROUND AND AIMS: There are many unresolved issues concerning the biochemistry of fructan biosynthesis. The aim of this paper is to address some of these by means of modelling mathematically the biochemical processes. METHODS: A model has been constructed for the step-by-step synthesis of fructan polymers. This is run until a steady state is achieved for which a polymer distribution is predicted. It is shown how qualitatively different distributions can be obtained. KEY RESULTS: It is demonstrated how a set of experimental results on polymer distribution can by simulated by a simple parameter adjustments. CONCLUSIONS: Mathematical modelling of fructan biosynthesis can provide a useful tool for helping elucidate the details of the biosynthetic processes. PMID- 23644361 TI - Vulnerability to cavitation, hydraulic efficiency, growth and survival in an insular pine (Pinus canariensis). AB - BACKGROUND AND AIMS: It is widely accepted that hydraulic failure due to xylem embolism is a key factor contributing to drought-induced mortality in trees. In the present study, an attempt is made to disentangle phenotypic plasticity from genetic variation in hydraulic traits across the entire distribution area of a tree species to detect adaptation to local environments. METHODS: A series of traits related to hydraulics (vulnerability to cavitation and hydraulic conductivity in branches), growth performance and leaf mass per area were assessed in eight Pinus canariensis populations growing in two common gardens under contrasting environments. In addition, the neutral genetic variability (FST) and the genetic differentiation of phenotypic variation (QST) were compared in order to identify the evolutionary forces acting on these traits. KEY RESULTS: The variability for hydraulic traits was largely due to phenotypic plasticity. Nevertheless, the vulnerability to cavitation displayed a significant genetic variability (approx. 5 % of the explained variation), and a significant genetic * environment interaction (between 5 and 19 % of the explained variation). The strong correlation between vulnerability to cavitation and survival in the xeric common garden (r = -0.81; P < 0.05) suggests a role for the former in the adaptation to xeric environments. Populations from drier sites and higher temperature seasonality were less vulnerable to cavitation than those growing at mesic sites. No trade-off between xylem safety and efficiency was detected. QST of parameters of the vulnerability curve (0.365 for P50 and the slope of the vulnerability curve and 0.452 for P88) differed substantially from FST (0.091), indicating divergent selection. In contrast, genetic drift alone was found to be sufficient to explain patterns of differentiation for xylem efficiency and growth. CONCLUSIONS: The ability of P. canariensis to inhabit a wide range of ecosystems seemed to be associated with high phenotypic plasticity and some degree of local adaptations of xylem and leaf traits. Resistance to cavitation conferred adaptive potential for this species to adapt successfully to xeric conditions. PMID- 23644362 TI - High cytokinin levels induce a hypersensitive-like response in tobacco. AB - BACKGROUND AND AIMS: Cytokinins are positive regulators of shoot development. However, it has previously been demonstrated that efficient activation of the cytokinin biosynthesis gene ipt can cause necrotic lesions and wilting in tobacco leaves. Some plant pathogens reportedly use their ability to produce cytokinins in disease development. In response to pathogen attacks, plants can trigger a hypersensitive response that rapidly kills cells near the infection site, depriving the pathogen of nutrients and preventing its spread. In this study, a diverse set of processes that link ipt activation to necrotic lesion formation were investigated in order to evaluate the potential of cytokinins as signals and/or mediators in plant defence against pathogens. METHODS: The binary pOp ipt/LhGR system for dexamethasone-inducible ipt expression was used to increase endogenous cytokinin levels in transgenic tobacco. Changes in the levels of cytokinins and the stress hormones salicylic, jasmonic and abscisic acid following ipt activation were determined by ultra-performance liquid chromatography-electrospray tandem mass spectrometry (UPLC-MS/MS). Trends in hydrogen peroxide content and lipid peroxidation were monitored using the potassium iodide and malondialdehyde assays. The subcellular distribution of hydrogen peroxide was investigated using 3,3'-diaminobenzidine staining. The dynamics of transcripts related to photosynthesis and pathogen response were analysed by reverse transcription followed by quantitative PCR. The effects of cytokinins on photosynthesis were deciphered by analysing changes in chlorophyll fluorescence and leaf gas exchange. KEY RESULTS: Plants can produce sufficiently high levels of cytokinins to trigger fast cell death without any intervening chlorosis - a hallmark of the hypersensitive response. The results suggest that chloroplastic hydrogen peroxide orchestrates the molecular responses underpinning the hypersensitive-like response, including the inhibition of photosynthesis, elevated levels of stress hormones, oxidative membrane damage and stomatal closure. CONCLUSIONS: Necrotic lesion formation triggered by ipt activation closely resembles the hypersensitive response. Cytokinins may thus act as signals and/or mediators in plant defence against pathogen attack. PMID- 23644363 TI - Endogenous cytokinin in developing kiwifruit is implicated in maintaining fruit flesh chlorophyll levels. AB - BACKGROUND AND AIMS: Green kiwifruit (Actinidia deliciosa) retain high concentrations of chlorophyll in the fruit flesh, whereas in gold-fleshed kiwifruit (A. chinensis) chlorophyll is degraded to colourless catabolites during fruit development, leaving yellow carotenoids visible. The plant hormone group the cytokinins has been implicated in the delay of senescence, and so the aim of this work was to investigate the link between cytokinin levels in ripening fruit and chlorophyll de-greening. METHODS: The expression of genes related to cytokinin metabolism and signal transduction and the concentration of cytokinin metabolites were measured. The regulation of gene expression was assayed using transient activation of the promoter of STAY-GREEN2 (SGR2) by cytokinin response regulators. KEY RESULTS: While the total amount of cytokinin increased in fruit of both species during maturation and ripening, a high level of expression of two cytokinin biosynthetic gene family members, adenylate isopentenyltransferases, was only detected in green kiwifruit fruit during ripening. Additionally, high levels of O-glucosylated cytokinins were detected only in green kiwifruit, as was the expression of the gene for zeatin O-glucosyltransferase, the enzyme responsible for glucosylating cytokinin into a storage form. Season to season variation in gene expression was seen, and some de-greening of the green kiwifruit fruit occurred in the second season, suggesting environmental effects on the chlorophyll degradation pathway. Two cytokinin-related response regulators, RRA17 and RRB120, showed activity against the promoter of kiwifruit SGR2. CONCLUSIONS: The results show that in kiwifruit, levels of cytokinin increase markedly during fruit ripening, and that cytokinin metabolism is differentially regulated in the fruit of the green and gold species. However, the causal factor(s) associated with the maintenance or loss of chlorophyll in kiwifruit during ripening remains obscure. PMID- 23644364 TI - Peduncles elicit large-mammal endozoochory in a dry-fruited plant. AB - BACKGROUND AND AIMS: Plants have evolved a variety of seed dispersal mechanisms to overcome lack of mobility. Many species embed seeds in fleshy pulp to elicit endozoochory, i.e. disseminating seed through the animal gut. In contrast to well studied fleshy fruited plants, dry-fruited plants may exploit this dispersal mutualism by producing fleshy appendages as a nutritional reward to entice animals to swallow their diaspores, but this has been little studied. In this study, it is hypothesized that these accessory fruits represent co-adaptations facilitating the syndrome of mammalian endozoochorous dispersal. METHODS: Field observations (focal tree watches, faecal surveys and fruiting phenology) with experimental manipulations (examination of seed germination and feeding trials) were conducted over 2 years in a native population of the raisin tree, Hovenia dulcis, which produces enlarged, twisted brown peduncles with external black seeds, in central China. KEY RESULTS: Birds were not observed to swallow seeds or carry infructescences away during 190 h of focal tree watches. However, H. dulcis seeds were detected in 247 faecal samples, representative of two herbivore and four carnivore mammalian species. Feeding trials revealed that peduncles attracted mammals to consume the entire infructescence, thereby facilitating effective seed dispersal. The germination rate of egested seeds proved higher than that of unconsumed seeds. It was also noted that this mutualism was most vulnerable in degraded forest. CONCLUSIONS: Hovenia dulcis peduncle sets are confirmed to adapt primarily to mammalian endozoochory, a mutualistic association similar in function to fleshy pulp or foliage. This demonstrates that plant organ systems can be adapted to unique mutualisms that utilize animal dispersal agents. Such an ecological role has until now been attributed only to bird epizoochory. Future studies should consider more widely the putative role of peduncle sets and mammalian endozoochory as a dispersal mechanism, particularly for those plants that possess relatively large accessory fruits. PMID- 23644365 TI - How dangerous is a carotid plaque? PMID- 23644366 TI - To screen or not to screen: that is the question! PMID- 23644367 TI - Catheter-based treatment of ilio-femoral deep vein thrombosis - an update on current evidence. AB - Ilio-femoral deep vein thrombosis (DVT) has a high rate of long-term morbidity in the form of the postthrombotic syndrome (PTS). Therefore, management of acute thrombosis should not only focus on the prevention of acute complications such as propagation or embolisation of the initial clot but also on preventing PTS and recurrent thrombosis. Contemporary catheter-based treatments of deep vein thrombosis have proven to be safe and effective in selected patients. Current guidelines recommend medical therapy with anticoagulation alone for all but the most severe, limb-threatening thrombosis. They additionally allow for consideration of catheter-based treatment in patients with acute DVT and low risk of bleeding complications to prevent PTS. Recent studies favoring interventional therapy have not been included in these guidelines. Data on long-term outcome is expected to be published soon, clarifying and very likely strengthening the role of catheter-based treatments in the management of acute ilio-femoral DVT. PMID- 23644368 TI - Catheter venography for the assessment of internal jugular veins and azygous vein: position statement by expert panel of the International Society for Neurovascular Disease. AB - This document by an expert panel of the International Society for Neurovascular Disease is aimed at presenting current technique and interpretation of catheter venography of the internal jugular veins, azygous vein and other veins draining the central nervous system. Although interventionalists agree on general rules, significant differences exist in terms of details of venographic technique and interpretations of angiographic pictures. It is also suggested that debatable findings should be investigated using multimodal diagnostics. Finally, the authors recommend that any publication on chronic cerebrospinal venous insufficiency should include detailed description of venographic technique used, to facilitate a comparison of published results in this area. PMID- 23644369 TI - Association between estimated glomerular filtration rate, ankle-brachial index, and recurrent ischemic stroke in a Chinese population of ischemic stroke patients. AB - BACKGROUND: Very few studies have examined combined association of estimated glomerular filtration rate (eGFR) and ankle-brachial index (ABI) on recurrent ischemic stroke in patients with ischemic stroke in Chinese populations. PATIENTS AND METHODS: A Chinese population of 1219 ischemic stroke patients was followed up in this six-year prospective study. RESULTS: 1080 ischemic stroke patients with complete follow-up data were included in the statistical analysis. A total of 245 ischemic stroke patients (22.7 %) had recurrent ischemic stroke during follow-up. The Incidence of recurrent ischemic stroke was significantly increased with decreasing eGFR levels and that of patients with eGFR < 30 ml/min/1.73m2 was the highest. Hazard ratio (HR) of eGFR < 30 ml/min/1.73m2 to recurrent ischemic stroke was 2.633 (95 % CI: 1.653 - 4.194) compared with that of eGFR >= 60 ml/min/1.73m2 after adjusting for other potential confounders using Cox regression analysis. Incidence of recurrent ischemic stroke was significantly increased with simultaneously decreasing eGFR and ABI. The highest percentage (71.4 %) of patients with eGFR < 30 ml/min/1.73m2 and ABI <= 0.4 simultaneously had recurrent ischemic stroke during follow-up. HR of eGFR < 30 ml/min/1.73m2 and ABI <= 0.4 simultaneously with recurrent ischemic stroke was 9.415 (95 % CI: 3.479 - 25.483) compared with that of eGFR >= 60 ml/min/1.73m2 and ABI > 1.0 to <= 1.4 respectively CONCLUSIONS: Low ABI and low eGFR together had synergistic effects on increasing recurrent ischemic stroke of ischemic stroke patients during a long-term follow-up. PMID- 23644370 TI - Quantitative analysis of carotid plaque vasa vasorum by CEUS and correlation with histology after endarterectomy. AB - BACKGROUND: Intraplaque neovascularization and vasa vasorum (VV) proliferation contribute in the progression and rupture of atherosclerotic lesions. Contrast enhanced ultrasonography (CEUS) has been reported to attain data regarding intraplaque neovessels and VV. However, whether the detection of microbubbles by CEUS within atherosclerotic plaques truly represents microvessels is a point of concern. We aimed to evaluate stable and unstable carotid artery plaque (CAP) VV pattern by CEUS and its correlation with histology and immunochemistry. PATIENTS AND METHODS: Patients with CAP scheduled for plaque endarterectomy were enrolled. CAP was initially identified by conventional ultrasonography and subsequently CEUS (harmonic ultrasound imaging with simultaneous intravenous contrast agent injection) was performed. The recorded image loops were evaluated by a semi automated method. Plaque specimens were excised and underwent histological and immunochemical (for CD34, Vascular Endothelial Growth Factor, CD68 and CD3 antibodies) analysis. RESULTS: Fourteen patients (67.6 +/- 10.2 years, 10 males) with a 86.9 +/- 11.5 % degree of carotid artery stenosis were evaluated. Histology showed that half of the plaques were unstable. Enhancement of plaque brightness on CEUS was significant for both stable and unstable plaque subgroups (p = 0.018 for both). Immunochemistry showed that microvessels, as assessed by CD34 antibody, were more dense in unstable vs. stable plaques (36.6 +/- 17.4 vs. 13.0 +/- 7.2 respectively, p = 0.002). However, correlation between plaque brigthness enhancement on CEUS and microvessel density was significant only for stable (r = 0.800, p = 0.031) plaques. CONCLUSIONS: The identification of brightness enhacement during CEUS in carotid atherosclerotic plaques may not always reflect the presence of VV. PMID- 23644371 TI - Safety and mid-term outcome of endovascular therapy for internal carotid artery disease: a 15-year experience at a single-centre angiology institution. AB - BACKGROUND: Endovascular therapy of carotid artery disease has emerged as a potential alternative to endarterectomy and its clinical practise dramatically increased in many parts of the world. This study aims to determine the safety and mid-term outcome of carotid artery stenting (CAS) within a 15-year carotid program at a single-centre institution. PATIENTS AND METHODS: We retrospectively analysed all CAS-procedures performed at our institution between 1995 and 2009. RESULTS: During the observation period, a total of 497 CAS procedures were attempted in 460 patients with stenoses of the internal carotid artery of which 187 (37.6 %) were symptomatic and 310 (62.4 %) were asymptomatic. CAS was successful in 479 (96.4 %) cases and success rate significantly increased throughout the study (p < 0.001). The periprocedural complication rate for death, stroke, and transient ischemic attack (TIA) was 0.4 %, 1.2 %, and 2.6 %, respectively, and the cumulative event rate did not differ between symptomatic and asymptomatic patients (4.8 % vs. 3.9 %; p = 0.62). Age was the only significant predictor for the occurrence of any periprocedural adverse event (OR 2.08 [1.22 - 3.54]; p = 0.007). During a median follow-up of 24 [1; 141] months, the rate of stroke, TIA, and in-stent restenosis was 1.0 %, 2.2 %, and 2.7 %, respectively. CONCLUSIONS: Data from this large observation in everyday clinical patients demonstrate that endovascular therapy in carotid artery disease can be performed safely and with mid-term outcomes comparable to carotid endarterectomy. PMID- 23644372 TI - Initial results of a computerized screening alert for abdominal aortic aneurysm in patients undergoing vascular assessment. AB - BACKGROUND: Although routine ultrasound screening for abdominal aortic aneurysm (AAA) reduces mortality in subjects at risk, it is often omitted in clinical practice. Because computerized alerts may systematically identify subjects at risk of AAA, we hypothesized that such alerts would encourage physicians to perform an ultrasound screening test. PATIENTS AND METHODS: We designed and implemented a computer alert system into the patient database of our vascular outpatient clinic at a tertiary referral hospital in Switzerland. An electronic alert was issued instantaneously each time a physician accessed non-invasive arterial work-up data from a male subject aged >= 60 years. The physician was forced to acknowledge the alert and could then order or withhold ultrasound screening. RESULTS: From 2008 to 2012, alerts were issued for 1673 subjects. Following the alert, ultrasound screening was withheld in 1107 (65.6 %) subjects, and it was performed in 576 (34.4 %) of whom 155 were excluded for numerous reasons. Among 421 screened subjects, aortic diameters were < 25 mm in 353 (84 %), 25 to 29 mm in 20 (5 %), 30 to 54 mm in 40 (10 %), and >= 55 mm in 8 (2 %). CONCLUSIONS: The AAA prevalence among screened subjects with computerized alerts was high, confirming the necessity to routinely screen male subjects >= 60 years undergoing non-invasive arterial work-up. However, physician compliance with alerts was poor since only one quarter of subjects with alerts underwent screening. Further quality improvement initiatives are urgently required to facilitate routine AAA screening among subjects at high risk. PMID- 23644373 TI - Deep vein thrombosis of the penis: an unusual but severe complication of prostatic abscess. PMID- 23644374 TI - A rare clinical manifestation of lymphedema praecox affecting the upper extremity. PMID- 23644375 TI - Subclavian-axillary graft plus graft-carotid interposition in symptomatic radiation-induced occlusion of bilateral subclavian and common carotid arteries. PMID- 23644376 TI - A combined approach of a complex aortoiliac aneurysm with distal landing in internal iliac artery branch. PMID- 23644378 TI - Oxidized DNA induces an adaptive response in human fibroblasts. AB - Cell-free DNA (cfDNA) released from dying cells contains a substantial proportion of oxidized nucleotides, thus, forming cfDNA(OX). The levels of cfDNA(OX) are increased in the serum of patients with chronic diseases. Oxidation of DNA turns it into a stress signal. The samples of genomic DNA (gDNA) oxidized by N2O2in vitro (gDNA(OX)) induce effects similar to that of DNA released from damaged cells. Here we describe the effects of gDNA(OX) on human fibroblasts cultivated in the stressful conditions of serum withdrawal. In these cells, gDNA(OX) evokes an adaptive response that leads to an increase in the rates of survival in serum starving cell populations as well as in populations irradiated at the dose of 1.2Gy. These effects are not seen in control populations of fibroblasts treated with non-modified gDNA. In particular, the exposure to gDNA(OX) leads to a decrease in the expression of the proliferation marker Ki-67 and an increase in levels of RSNA, a decrease in the proportion of subG1- and G2/M cells, a decrease in proportion of cells with double strand breaks (DSBs). Both gDNA(OX) and gDNA suppress the expression of DNA sensors TLR9 and AIM2 and up-regulate nuclear factor-erythroid 2 p45-related factor 2 (NRF2), while only gDNA(OX) inhibits NF kappaB signaling. gDNA(OX) is a model for oxidized cfDNA(OX) that is released from the dying tumor cells and being carried to the distant organs. The systemic effects of oxidized DNA have to be taken into account when treating tumors. In particular, the damaged DNA released from irradiated cells may be responsible for an abscopal effects and a bystander mediated adaptive response seen in some cancer patients. These results indicate the necessity for the further study of the effects of oxidized DNA in both in vitro and in vivo systems. PMID- 23644379 TI - The cell biology of open and closed mitosis. AB - Mitosis is the process of one cell dividing into two daughters, such that each inherits a single and complete copy of the genome of their mother. This is achieved through the equal segregation of the sister chromatids between the daughter cells. However, beyond this simple principle, the partitioning of other cellular components between daughter cells appears to follow a large variety of patterns. We discuss here how the organization of the nuclear envelope during mitosis influences cell division and, subsequently, cellular identity. PMID- 23644380 TI - Major urinary metabolites of 6-keto-prostaglandin F2alpha in mice. AB - Western diets are enriched in omega-6 vs. omega-3 fatty acids, and a shift in this balance toward omega-3 fatty acids may have health benefits. There is limited information about the catabolism of 3-series prostaglandins (PG) formed from eicosapentaenoic acid (EPA), a fish oil omega-3 fatty acid that becomes elevated in tissues following fish oil consumption. Quantification of appropriate urinary 3-series PG metabolites could be used for noninvasive measurement of omega-3 fatty acid tone. Here we describe the preparation of tritium- and deuterium-labeled 6-keto-PGF2alpha and their use in identifying urinary metabolites in mice using LC-MS/MS. The major 6-keto-PGF2alpha urinary metabolites included dinor-6-keto-PGF2alpha (~10%) and dinor-13,14-dihydro-6,15 diketo-PGF1alpha (~10%). These metabolites can arise only from the enzymatic conversion of EPA to the 3-series PGH endoperoxide by cyclooxygenases, then PGI3 by prostacyclin synthase and, finally, nonenzymatic hydrolysis to 6-keto PGF2alpha. The 6-keto-PGF derivatives are not formed by free radical mechanisms that generate isoprostanes, and thus, these metabolites provide an unbiased marker for utilization of EPA by cyclooxygenases. PMID- 23644381 TI - Regulation of stem cell therapies under attack in Europe: for whom the bell tolls. AB - At the time of writing, the Italian Parliament is debating a new law that would make it legal to practice an unproven stem cell treatment in public hospitals. The treatment, offered by a private non-medical organization, may not be safe, lacks a rationale, and violates current national laws and European regulations. This case raises multiple concerns, most prominently the urgent need to protect patients who are severely ill, exposed to significant risks, and vulnerable to exploitation. The scientific community must consider the context-social, financial, medical, legal-in which stem cell science is currently situated and the need for stringent regulation. Additional concerns are emerging. These emanate from the novel climate, created within science itself, and stem cell science in particular, by the currently prevailing model of 'translational medicine'. Only rigorous science and rigorous regulation can ensure translation of science into effective therapies rather than into ineffective market products, and mark, at the same time, the sharp distinction between the striving for new therapies and the deceit of patients. PMID- 23644382 TI - Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer. AB - High-throughput techniques have identified numerous antisense (AS) transcripts and long non-coding RNAs (ncRNAs). However, their significance in cancer biology remains largely unknown. Here, we report an androgen-responsive long ncRNA, CTBP1 AS, located in the AS region of C-terminal binding protein 1 (CTBP1), which is a corepressor for androgen receptor. CTBP1-AS is predominantly localized in the nucleus and its expression is generally upregulated in prostate cancer. CTBP1-AS promotes both hormone-dependent and castration-resistant tumour growth. Mechanistically, CTBP1-AS directly represses CTBP1 expression by recruiting the RNA-binding transcriptional repressor PSF together with histone deacetylases. CTBP1-AS also exhibits global androgen-dependent functions by inhibiting tumour suppressor genes via the PSF-dependent mechanism thus promoting cell cycle progression. Our findings provide new insights into the functions of ncRNAs that directly contribute to prostate cancer progression. PMID- 23644383 TI - cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes. AB - Actin cytoskeletal damage induces inactivation of the oncoprotein YAP (Yes associated protein). It is known that the serine/threonine kinase LATS (large tumour suppressor) inactivates YAP by phosphorylating its Ser127 and Ser381 residues. However, the events downstream of actin cytoskeletal changes that are involved in the regulation of the LATS-YAP pathway and the mechanism by which LATS differentially phosphorylates YAP on Ser127 and Ser381 in vivo have remained elusive. Here, we show that cyclic AMP (cAMP)-dependent protein kinase (PKA) phosphorylates LATS and thereby enhances its activity sufficiently to phosphorylate YAP on Ser381. We also found that PKA activity is involved in all contexts previously reported to trigger the LATS-YAP pathway, including actin cytoskeletal damage, G-protein-coupled receptor activation, and engagement of the Hippo pathway. Inhibition of PKA and overexpression of YAP cooperate to transform normal cells and amplify neural progenitor pools in developing chick embryos. We also implicate neurofibromin 2 as an AKAP (A-kinase-anchoring protein) scaffold protein that facilitates the function of the cAMP/PKA-LATS-YAP pathway. Our study thus incorporates PKA as novel component of the Hippo pathway. PMID- 23644384 TI - The role of different anesthetic techniques in altering the stress response during cardiac surgery in children: a prospective, double-blinded, and randomized study. AB - OBJECTIVES: Our goal was to evaluate the role of three anesthetic techniques in altering the stress response in children undergoing surgery for repair of congenital heart diseases utilizing cardiopulmonary bypass in the setting of fast tracking or early tracheal extubation. Furthermore, we wanted to evaluate the correlation between blunting the stress response and the perioperative clinical outcomes. DESIGN: Prospective, randomized, double-blinded study. SETTING: Single center from December 2008 to May of 2011. PATIENTS: Forty-eight subjects (low dose fentanyl plus placebo, n = 16; high-dose fentanyl plus placebo, n = 17; low dose fentanyl plus dexmedetomidine, n = 15) were studied between ages 30 days to 3 years old who were scheduled to undergo repair for a ventricular septal defect, atrioventricular septal defect, or Tetralogy of Fallot. METHODS: Children undergoing surgical repair of congenital heart disease were randomized to receive low-dose fentanyl (10 mcg/kg; low-dose fentanyl), high-dose fentanyl (25mcg/kg; high-dose fentanyl), or low-dose fentanyl plus dexmedetomidine (as a 1 mcg/kg loading dose followed by infusion at 0.5mcg/kg/hr until separation from cardiopulmonary bypass. In addition, patients received a volatile anesthetic agent as needed to maintain hemodynamic stability. Blood samples were tested for metabolic, hormonal and cytokine markers at baseline, after sternotomy, after the start of cardiopulmonary bypass, at the end of the procedure and at 24 hours postoperatively. MEASUREMENTS AND MAIN RESULTS: Forty-eight subjects (low-dose fentanyl plus placebo, n = 16; high-dose fentanyl plus placebo, n = 17; low-dose fentanyl plus dexmedetomidine, n = 15) were studied. Subjects in the low-dose fentanyl plus placebo group had significantly higher levels of adrenocorticotropic hormone, cortisol, glucose, lactate, and epinephrine during the study period. The lowest levels of stress markers were seen in the high-dose fentanyl plus placebo group both over time (adrenocorticotropic hormone, p= 0.01; glucose, p = 0.007) and at individual time points (cortisol and lactate at the end of surgery, epinephrine poststernotomy; p < 0.05). Subjects in the low-dose fentanyl plus dexmedetomidine group had lower lactate levels at the end of surgery compared with the low-dose fentanyl plus placebo group (p < 0.05). Although there were no statistically significant differences in plasma cytokine levels between the three groups, the low-dose fentanyl plus placebo group had significantly higher interleukin-6:interleukin-10 ratio at 24 hours postoperatively (p < 0.0001). In addition, when compared with the low-dose fentanyl plus placebo group, the low-dose fentanyl plus dexmedetomidine group showed a lower norepinephrine level from baseline at poststernotomy, after the start of cardiopulmonary bypass, and at the end of surgery (p <= 0.05). Subjects in the low-dose fentanyl plus placebo group had more postoperative narcotic requirement (p = 0.004), higher prothrombin time (p <= 0.03), and more postoperative chest tube output (p < 0.05). Success of fast tracking was not significantly different between groups (low-dose fentanyl plus placebo 75%, high dose fentanyl plus placebo 82%, low-dose fentanyl plus dexmedetomidine 93%; p = 0.39). CONCLUSIONS: The use of low-dose fentanyl was associated with the greatest stress response, most coagulopathy, and highest transfusion requirement among our cohorts. Higher dose fentanyl demonstrated more favorable blunting of the stress response. When compared with low-dose fentanyl alone, the addition of dexmedetomidine improved the blunting of the stress response, while achieving better postoperative pain control. PMID- 23644385 TI - Efficacy and durability of radiofrequency ablation for Barrett's Esophagus: systematic review and meta-analysis. AB - BACKGROUND & AIMS: In patients with Barrett's esophagus (BE), radiofrequency ablation (RFA) safely and effectively eradicates dysplasia and intestinal metaplasia. We aimed to determine the efficacy and durability of RFA for patients with dysplastic and nondysplastic BE. METHODS: We performed a systematic review and meta-analysis of studies identified in PubMed and EMBASE that reported the proportion of patients treated with RFA who had complete eradication of dysplasia (CE-D) and intestinal metaplasia (CE-IM), and the proportion of patients with recurrent IM after successful treatment. Pooled estimates of CE-D, CE-IM, IM recurrence, and adverse events were calculated. RESULTS: We identified 18 studies of 3802 patients reporting efficacy and 6 studies of 540 patients reporting durability. Ten were prospective cohort studies, 9 were retrospective cohort studies, and 1 was a randomized trial. CE-IM was achieved in 78% of patients (95% confidence interval [CI], 70%-86%) and CE-D was achieved in 91% (95% CI, 87% 95%). After eradication, IM recurred in 13% (95% CI, 9%-18%). Progression to cancer occurred in 0.2% of patients during treatment and in 0.7% of those after CE-IM. Esophageal stricture was the most common adverse event and was reported in 5% of patients (95% CI, 3%-7%). Confidence in most summary estimates was limited by a high degree of heterogeneity, which did not appear to be caused by single outlier studies. CONCLUSIONS: Treatment of BE with RFA results in CE-D and CE-IM in a high proportion of patients, with few recurrences of IM after treatment and a low rate of adverse events. Despite the large amount of study heterogeneity, these data provide additional information for patients and providers to make informed treatment decisions. PMID- 23644386 TI - Increased quality of life among hepatocellular carcinoma patients treated with radioembolization, compared with chemoembolization. AB - BACKGROUND & AIMS: Quality of life (QoL) is an important aspect of any palliative treatment. However, few data are available from studies comparing how embolotherapy affects QoL for patients with hepatocellular carcinoma (HCC). We performed a health-related QoL study in patients with HCC treated by transarterial chemoembolization (TACE) or (90)Y radioembolization. METHODS: We performed a prospective study of patients undergoing (90)Y radioembolization (n = 29) or TACE (n = 27) for HCC. We assessed patients before treatment and 2 and 4 weeks after treatment using the Functional Assessment of Cancer Therapy Hepatobiliary (FACT-Hep) survey. We compared differences in health-related QoL between the treatment groups using linear regression repeated-measures analysis. RESULTS: At baseline, the groups had comparable baseline Child-Pugh class and performance statuses, although patients undergoing TACE had lower tumor burdens (P = .018) and less-advanced disease, based on United Network for Organ Sharing and Barcelona stage (P = .03 and P = .02, respectively), permitting injections at segmental arteries (P < .0001). There were no significant differences between groups in overall FACT-Hep health-related QoL scores (P = .055, effect size [ES], .54), owing to a limited sample size. Despite the more advanced disease of patients who received (90)Y radioembolization, they had a significantly better QoL, based on social well being (P = .019; ES, .65), functional well-being (P = .031; ES, .60), and embolotherapy-specific scores (P = .018; ES, .67). They also had a trend toward better overall QoL (P = .055; ES, .54) and higher Trial Outcome Index (P = .05; ES, .56) and FACT-Hep scores (P = .071; ES, .52). CONCLUSIONS: In a prospective study, although (90)Y radioembolization was used to treat patients with more advanced disease, those who received this treatment had significant increases in several features of QoL, whereas patients who received TACE had decreases in QoL scores. However, because of the limited sample size, there was no significant difference in overall FACT-Hep health-related QoL scores. The increase was greatest in the embolotherapy-specific score. ClinicalTrials.gov, number NCT00739167. PMID- 23644387 TI - Methods for diagnosis of bile acid malabsorption in clinical practice. AB - Altered concentrations of bile acid (BA) in the colon can cause diarrhea or constipation. More than 25% of patients with irritable bowel syndrome with diarrhea or chronic diarrhea in Western countries have BA malabsorption (BAM). As BAM is increasingly recognized, proper diagnostic methods are needed to help direct the most effective course of treatment for the chronic bowel dysfunction. We review the methodologies, advantages, and disadvantages of tools that directly measure BAM: the (14)C-glycocholate breath and stool test, the (75)selenium homotaurocholic acid test (SeHCAT), and measurements of 7 alpha-hydroxy-4 cholesten-3-one (C4) and fecal BAs. The (14)C-glycocholate test is laborious and no longer widely used. The (75)SeHCAT has been validated but is not available in the United States. Measurement of serum C4 is a simple and accurate method that can be used for most patients but requires further clinical validation. Assays to quantify fecal BA (total and individual levels) are technically cumbersome and not widely available. Regrettably, none of these tests are routinely available in the United States; assessment of the therapeutic effects of a BA binder is used as a surrogate for diagnosis of BAM. Recent data indicate the advantages to studying fecal excretion of individual BAs and their role in BAM; these could support the use of the fecal BA assay, compared with other tests. Measurement of fecal BA levels could become a routine addition to the measurement of fecal fat in patients with unexplained diarrhea. Availability ultimately determines whether the C4, SeHCAT, or fecal BA test is used; more widespread availability of such tests would enhance clinical management of these patients. PMID- 23644388 TI - Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a meta-analysis. AB - BACKGROUND & AIMS: Linaclotide is a minimally absorbed, 14-amino acid peptide used to treat patients with irritable bowel syndrome with constipation (IBS-C) or chronic constipation (CC). We performed a meta-analysis to determine the efficacy of linaclotide, compared with placebo, for patients with IBS-C or CC. METHODS: MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched for randomized, placebo-controlled trials examining the effect of linaclotide in adults with IBS-C or CC. Dichotomous results were pooled to yield a relative risk (RR), 95% confidence intervals (CIs), and number needed to treat (NNT). RESULTS: The search identified 7 trials of linaclotide in patients with IBS-C or CC; 6 were included in the analysis. Two of 3 trials of IBS-C used the end point recommended by the U.S. Food and Drug Administration: an increase from baseline of 1 or more complete spontaneous bowel movement (CSBM)/week and a 30% or more reduction from baseline in the weekly average of daily worst abdominal pain scores for 50% of the treatment weeks. On the basis of this end point, the RR for response to treatment with 290 MUg linaclotide, compared with placebo, was 1.95 (95% CI, 1.3-2.9), and the NNT was 7 (95% CI, 5-11). For CC, on the basis of data from 3 trials of patients with CC, the RR for the primary end point (more than 3 CSBMs/week and an increase in 1 or more CSBM/week, for 75% of weeks) was 4.26 for 290 MUg linaclotide vs placebo (95% CI, 2.80-6.47), and the NNT was 7 (95% CI, 5-8). Linaclotide also improved stool form and reduced abdominal pain, bloating, and overall symptom severity in patients with IBS-C or CC. CONCLUSIONS: On the basis of a meta-analysis, linaclotide improves bowel function and reduces abdominal pain and overall severity of IBS-C or CC, compared with placebo. PMID- 23644389 TI - Inflammatory bowel disease is associated with an increased risk of melanoma: a systematic review and meta-analysis. AB - BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has been associated with an increased risk of nonmelanoma skin cancer, particularly among patients treated with thiopurines. It is unclear whether IBD affects risk for melanoma. We performed a systematic review and meta-analysis of cohort studies to determine the risk of melanoma in patients with IBD. METHODS: We conducted a systematic search of bibliographic databases through March 2013. Cohort studies reporting incident melanoma after IBD diagnosis and an estimate of incidence rate ratio or standardized incidence rate were included in the analysis. Pooled relative risk (RR) estimates with 95% confidence intervals (CIs) were calculated using the random-effects model. RESULTS: Our analysis included 12 studies, comprising a total of 172,837 patients with IBD; 179 cases of melanoma were reported from 1940 to 2009. The pooled crude incidence rate of melanoma in patients with IBD was 27.5 cases/100,000 person-years (95% CI, 19.9-37.0). Overall, IBD was associated with a 37% increase in risk of melanoma (12 studies: RR, 1.37; 95% CI, 1.10 1.70). The risk was increased among patients with Crohn's disease (7 studies: RR, 1.80; 95% CI, 1.17-2.75) and ulcerative colitis (7 studies: RR, 1.23; 95% CI, 1.01-1.50). The risk of melanoma was higher in studies performed before introduction of biologic therapies (before 1998) (8 studies: RR, 1.52; 95% CI, 1.02-2.25) but not in studies performed after 1998 (2 studies: RR, 1.08; 95% CI, 0.59-1.96). CONCLUSIONS: Based on a meta-analysis, IBD has been associated with an increased risk of melanoma, independent of the use of biologic therapy. Patients diagnosed with IBD should be counseled on their risk for melanoma. PMID- 23644390 TI - Diagnosing irritable bowel syndrome: no more million dollar work-up? PMID- 23644392 TI - Magnetic properties of small cobalt-copper clusters. AB - Accurate first-principle calculations on bimetallic cobalt-copper clusters of up to six atoms (Perez et al 2012 J. Nanopart. Res. 14 933) revealed a close similarity of the ground-state magnetic properties to the ultimate jellium model, provided that a 2D to 3D geometric transition was invoked. We discuss this relationship in terms of partial occupancies of the valence electrons in both cases, with the jellium results described by nonperturbative spherical wavefunctions. Based upon this, we propose a scheme to predict magnetic properties of cobalt-copper clusters of up to twenty atoms using arguments of dimensionality and charge localization, and confirm some of these results with other independent density-functional calculations and experimental available data. The comparison with experiments is carried out for neutral and singly ionized cobalt clusters. Furthermore, a many-body tight-binding pseudopotential is used with Monte Carlo techniques to verify the stability of these new first principle solutions. PMID- 23644391 TI - The risk of fractures among patients with cirrhosis or chronic pancreatitis. AB - BACKGROUND & AIMS: Cirrhosis and chronic pancreatitis (CP) are accompanied by inflammation and malnutrition. Both conditions can have negative effects on bone metabolism and promote fractures. We evaluated the risk of fractures among patients with CP or cirrhosis and determined the effect of fat malabsorption on fracture risk among patients with CP. METHODS: We performed a retrospective cohort study using the Danish National Patient Register to identify patients diagnosed with CP or cirrhosis. We analyzed data collected from January 1, 1995, to December 31, 2010, on 20,769 patients (35.5% women with cirrhosis and 11,972 patients (33.5% women) with CP. Each patient was compared with 10 age- and sex matched controls. We also assessed the risk of fractures among patients with CP who received pancreatic enzyme substitution (PES) for fat malabsorption. RESULTS: During the study period, bone fractures occurred in 3954 patients with cirrhosis and 2594 patients with CP. The adjusted hazard ratio (HR) for any fracture was 2.4 in patients with cirrhosis (95% confidence interval [CI], 2.2-2.5) and 1.7 in patients with CP (95% CI, 1.6-1.8). The relative risk of low-trauma fractures was highest among individuals younger than 50 years old. Alcohol as an etiology was associated with an increased risk of fracture compared with patients with nonalcoholic cirrhosis (HR, 2.4 vs 1.5; P < .0001) and CP (HR, 2.0 vs 1.5; P < .0001). Patients with CP receiving PES for fat malabsorption had a lower risk of fractures than other CP patients (HR, 0.8; 95% CI, 0.7-0.9). However, increasing the duration of treatment with PES was associated with an increased risk of fracture. CONCLUSIONS: Patients, especially younger patients, with cirrhosis or CP have an increased risk of fractures of all types. PMID- 23644393 TI - Social and land use composition determinants of health: variability in health indicators. AB - Previous studies have shown that a community's socioeconomic status has a significant impact on its residents' health, and that vulnerability in deprived populations expresses itself as variability in health outcomes. The current study adds to this ecological research approach the notion that underlying community vulnerabilities are also related to the physical environment and population growth of a locality. The paper explores the variability in various health indicators in 252 localities in Israel as a function of the localities' socioeconomic status, population growth, and land use composition measures. The results indicate that a locality's socioeconomic status and its land use composition are both strongly associated with various health outcomes and their variability. These findings are of particular interest in light of the fact that the results were obtained from a country with a universal healthcare system. PMID- 23644394 TI - Tracking the relevance of the WHO Framework Convention on Tobacco Control in legislation and litigation through the online resource, Tobacco Control Laws. AB - The WHO Framework Convention on Tobacco Control is increasingly referenced and incorporated into the objectives, definitions and provisions of domestic legislation worldwide. It is also relied upon by courts in interpreting and upholding strong tobacco control measures challenged by the tobacco industry. In this special communication, we describe these trends and explore the important new online resource-Tobacco Control Laws (http://www.tobaccocontrollaws.org)- that has been used to track them. PMID- 23644396 TI - Lack of effect of superficial heat to the knee on quadriceps function in individuals with quadriceps inhibition. AB - CONTEXT: Quadriceps function improves after application of focal joint cooling or transcutaneous electrical nerve stimulation to the knee in patients with arthrogenic muscle inhibition (AMI), yet it is not known whether superficial heat is able to produce a similar effect. OBJECTIVE: To determine quadriceps function after superficial heat to the knee joint in individuals with AMI. DESIGN: Single blinded randomized crossover. SETTING: Laboratory. PATIENTS: 12 subjects (4 female, 8 males; 25.6 +/- 7.7 y, 177.2 +/- 12.7 cm, 78.4 +/- 18.2 kg) with a history of knee-joint pathology and AMI, determined with a quadriceps central activation ratio (CAR) of <90%. INTERVENTION: 3 treatment conditions for 15 min on separate days: superficial heat using a cervical moist-heat pack (77 degrees C), sham using a cervical moist pack (room temperature at about 24 degrees C), and control (no treatment). All subjects received all treatment conditions in a randomized order. MAIN OUTCOME MEASURES: Central activation ratio and knee extension torque during maximal voluntary isometric contraction with the knee flexed to 60 degrees were collected at pre, immediately post, 30 min post, and 45 min posttreatment. Skin temperature of the quadriceps and knee and room temperature were also recorded at the same time points. RESULTS: Three (treatment conditions) by 4 (time) repeated ANOVAs found that there were no significant interactions or main effects in either CAR or knee-extension torque (all P > .05). Skin-temperature 1-way ANOVAs revealed that the skin temperature in the knee during superficial heat was significantly higher than other treatment conditions at all time points (P < .05). CONCLUSIONS: Superficial heat to the knee joint using a cervical moist-heat pack did not influence quadriceps function in individuals with AMI in the quadriceps. PMID- 23644406 TI - Bacterial detection & identification using electrochemical sensors. AB - Electrochemical sensors are widely used for rapid and accurate measurement of blood glucose and can be adapted for detection of a wide variety of analytes. Electrochemical sensors operate by transducing a biological recognition event into a useful electrical signal. Signal transduction occurs by coupling the activity of a redox enzyme to an amperometric electrode. Sensor specificity is either an inherent characteristic of the enzyme, glucose oxidase in the case of a glucose sensor, or a product of linkage between the enzyme and an antibody or probe. Here, we describe an electrochemical sensor assay method to directly detect and identify bacteria. In every case, the probes described here are DNA oligonucleotides. This method is based on sandwich hybridization of capture and detector probes with target ribosomal RNA (rRNA). The capture probe is anchored to the sensor surface, while the detector probe is linked to horseradish peroxidase (HRP). When a substrate such as 3,3',5,5'-tetramethylbenzidine (TMB) is added to an electrode with capture-target-detector complexes bound to its surface, the substrate is oxidized by HRP and reduced by the working electrode. This redox cycle results in shuttling of electrons by the substrate from the electrode to HRP, producing current flow in the electrode. PMID- 23644407 TI - New and emerging risk factors for coronary heart disease. AB - Coronary heart disease (CHD) is one of the leading causes of death in the United States. Traditional risk factors such as family history, hypertension, hypercholesterolemia, diabetes mellitus and smoking cannot account for the entire risk for incident coronary events. Several other potential risk factors have been identified in an effort to improve risk assessment for CHD. This article reviews the current evidence on new and emerging risk factors for CHD and their current utility in screening, specifically focusing on coronary artery calcium score, C reactive protein, lipoprotein (a), carotid intima-media thickness, homocysteine, lipoprotein-associated phospholipase A2, as well as high-density lipoprotein functionality. PMID- 23644408 TI - Duplicated renal collecting system. PMID- 23644405 TI - Isolation and characterization of intestinal stem cells based on surface marker combinations and colony-formation assay. AB - BACKGROUND & AIMS: Identification of intestinal stem cells (ISCs) has relied heavily on the use of transgenic reporters in mice, but this approach is limited by mosaic expression patterns and difficult to directly apply to human tissues. We sought to identify reliable surface markers of ISCs and establish a robust functional assay to characterize ISCs from mouse and human tissues. METHODS: We used immunohistochemistry, real-time reverse-transcription polymerase chain reaction, and fluorescence-activated cell sorting (FACS) to analyze intestinal epithelial cells isolated from mouse and human intestinal tissues. We compared different combinations of surface markers among ISCs isolated based on expression of Lgr5-green fluorescent protein. We developed a culture protocol to facilitate the identification of functional ISCs from mice and then tested the assay with human intestinal crypts and putative ISCs. RESULTS: CD44(+)CD24(lo)CD166(+) cells, isolated by FACS from mouse small intestine and colon, expressed high levels of stem cell-associated genes. Transit-amplifying cells and progenitor cells were then excluded based on expression of GRP78 or c-Kit. CD44(+)CD24(lo)CD166(+) GRP78(lo/-) putative stem cells from mouse small intestine included Lgr5-GFP(hi) and Lgr5-GFP(med/lo) cells. Incubation of these cells with the GSK inhibitor CHIR99021 and the E-cadherin stabilizer Thiazovivin resulted in colony formation by 25% to 30% of single-sorted ISCs. CONCLUSIONS: We developed a culture protocol to identify putative ISCs from mouse and human tissues based on cell surface markers. CD44(+)CD24(lo)CD166(+), GRP78(lo/-), and c-Kit(-) facilitated identification of putative stem cells from the mouse small intestine and colon, respectively. CD44(+)CD24(-/lo)CD166(+) also identified putative human ISCs. These findings will facilitate functional studies of mouse and human ISCs. PMID- 23644409 TI - Cardiac rehabilitation and mortality reduction after myocardial infarction: the emperor's new clothes? Evidence against cardiac rehabilitation. AB - No trial of cardiac rehabilitation (CR) following myocardial infarction (MI) (not even the WHO European collaborative) demonstrates significant reduction of mortality, as do trials of secondary prevention. There is potential conflict of interest when therapists report self-evaluations. Reviews of published reports exaggerate publication bias. Meta-analyses show no significant effect of CR on mortality in recent years - since 1990, 23 trials, 6527 patients, relative risk 1.01 (0.88-1.15). It does no service to MI patients - or rehabilitation therapists - to repeat claims derived from poolings of historic trials, undertaken before many significant advances in diagnosis, acute treatment and effective secondary prevention. While CR has a role in good medical/nursing practice and continuity of care, rehabilitation therapists could be more effective elsewhere in the NHS. PMID- 23644410 TI - Cardiac rehabilitation and mortality reduction after myocardial infarction: the emperor's new clothes? Evidence in favour of cardiac rehabilitation. AB - This piece highlights the strength of evidence in favour of cardiac rehabilitation (CR) and postulates that the emperor is indeed well dressed. The reason why a single negative trial, in the UK, has caused such hullabaloo in the literature and clinical practice is examined against overwhelming evidence from over 40 positive randomised controlled trials. The lack of motivation to promote lifestyle change and the role of patients in determining outcome is also explored. To conclude, we set the scene for the final chapter of this story by outlining what needs to be done to answer the question about the real-world effectiveness of CR. PMID- 23644411 TI - Steroidal glycosides from the bulbs of Easter lily (Lilium longiflorum Thunb.) promote dermal fibroblast migration in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Preparations derived from bulbs of various Lilium species have been used to promote the healing of skin abrasions, sores and burns and to aid in healing wounds in Traditional Chinese and Greco-Roman Medicine. AIM OF THE STUDY: To evaluate fractionated Easter lily bulb extracts and their steroidal glycosides (1-5) for the promotion of dermal fibroblast migration in vitro, a model for the early events in wound healing. MATERIALS AND METHODS: An activity-guided screening approach was used by coupling sequential solvent extraction, gel permeation chromatography (GPC), and semi-preparative reverse phase high performance liquid chromatography (RP-HPLC) with an in vitro dermal fibroblast migration assay. Cytotoxicity was evaluated with methyl thiazole tetrazolium (MTT). To gain insight into the mode of action of the steroidal glycosides, nitric oxide (NO) production, and expression of genes for transforming growth factor beta-1 (TGF-beta) and its receptors were evaluated. RESULTS: Fractionated bulb extracts and the two isolated steroidal glycoalkaloids (1) and (2) induced NO production and TGF-beta receptor I mRNA expression in fibroblast cell culture. In a cytotoxicity assay, steroidal glycosides (1) and (3) had IC50 values of 8.2 and 8.7 uM, but the natural acetylation of the C-6"' hydroxy of the terminal glucose unit in (2) resulted in a 3-fold decrease in cell cytotoxicity when compared with (1). Results from the dermal fibroblast migration assay revealed that the steroidal glycoalkaloids (1) and (2), and the furostanol saponin (3) promoted fibroblast migration from the range of 23.7+/-5.7 to 37.7+/ 5.1%, as compared with the control. CONCLUSION: Collectively, our data demonstrate that the steroidal glycosides present in Easter lily bulbs induce, at least in part, the observed dermal fibroblast migration activity of the bulb extracts. This is the first evidence that steroidal glycosides from Lilium longiflorum may potentially play a role in the wound healing process and may provide a scientific basis for the historical use of lily bulbs for this purpose. PMID- 23644412 TI - Online health-searching behavior among HIV-seropositive and HIV-seronegative men who have sex with men in the Baltimore and Washington, DC area. AB - BACKGROUND: Searching online for health information is common among American adults. However, there have been few studies to investigate the online health searching behaviors among men who have sex with men (MSM) with human immunodeficiency virus (HIV). OBJECTIVE: To estimate the prevalence of Internet use among HIV-seropositive MSM and compare their online behaviors with HIV seronegative men with chronic disease(s). METHODS: This study was performed at the Baltimore/Washington, DC site of the Multicenter AIDS Cohort Study (MACS). A total of 200 MACS participants were asked to answer a self-administered questionnaire on a first-come basis during a semiannual study visit (from July to November 2011); 195 (97.5%) participants completed the survey. Multiple logistic regression models were used to investigate the factors influencing their online health-searching behaviors. RESULTS: The median age of the 195 MSM participants was 57 years, 64.6% were white, 59.0% were employed, and 88.2% had Internet access at home and/or other locations. Of the 95 HIV-seropositive participants, 89.5% currently used highly active antiretroviral therapy (HAART) and 82.1% had Internet access. After adjusting for age and race/ethnicity, the HIV-seropositive participants were less likely to perform online searches for general disease related information compared to the HIV-seronegative men with chronic disease(s) (OR 0.20, 95% CI 0.06-0.68, P=.01). There were no statistically significant associations with HIV status and searching for new medications/treatments (OR 0.55, 95% CI 0.19-1.55, P=.26) or support/advice from other patients (OR 0.52, 95% CI 0.18-1.53, P=.24). Increasing age by 5 years led to a decrease by 29% in the odds of online health-related searches for general information (OR 0.71, 95% CI 0.52-0.98, P=.03) and 26% for support/advice from other patients (OR 0.74, 95% CI 0.56-0.98, P=.03). A decrease of 25% for new medications/treatments was also seen, but was not statistically significant (OR 0.75, 95% CI 0.57-1.01, P=.06). CONCLUSIONS: This study shows that HIV-seropositive MSM have similar online health-searching behaviors as HIV-seronegative men with chronic disease(s). Independent of HIV status, older MSM are less likely to perform online health related searches. PMID- 23644413 TI - Spatial limits on the nonvisual self-touch illusion and the visual rubber hand illusion: subjective experience of the illusion and proprioceptive drift. AB - The nonvisual self-touch rubber hand paradigm elicits the compelling illusion that one is touching one's own hand even though the two hands are not in contact. In four experiments, we investigated spatial limits of distance (15 cm, 30 cm, 45 cm, 60 cm) and alignment (0 degrees , 90 degrees anti-clockwise) on the nonvisual self-touch illusion and the well-known visual rubber hand illusion. Common procedures (synchronous and asynchronous stimulation administered for 60s with the prosthetic hand at body midline) and common assessment methods were used. Subjective experience of the illusion was assessed by agreement ratings for statements on a questionnaire and time of illusion onset. The nonvisual self touch illusion was diminished though never abolished by distance and alignment manipulations, whereas the visual rubber hand illusion was more robust against these manipulations. We assessed proprioceptive drift, and implications of a double dissociation between subjective experience of the illusion and proprioceptive drift are discussed. PMID- 23644414 TI - Self-assembled G-quadruplex nanostructures: AFM and voltammetric characterization. AB - G-rich oligodeoxynucleotides (ODNs) have great medical and nanotechnological potential, because they can self-assemble into G-quadruplexes and higher-order nanostructures. The folding properties of d(G)10, d(TG9) and d(TG8T) ODNs were studied using atomic force microscopy (AFM) and voltammetry at carbon electrodes. Single-stranded ODNs, in Na(+) containing solutions and for short incubation times, were detected using AFM as network films and polymeric structures and using voltammetry by the occurrence of only the guanine oxidation peak. G quadruplexes, in Na(+) containing solutions and long incubation times, or in K(+) containing solutions, were detected using AFM as spherical aggregates and using voltammetry by the decrease of the guanine oxidation peak and the occurrence of the G-quartet oxidation peak. Concerning the self-assembling into higher-order nanostructures, d(G)10 was the only sequence forming G-nanowires observed using AFM, d(TG9) formed short G-based super-structures that adsorbed as rod-like shape aggregates, and d(TG8T) formed no nanostructures, due to the presence of thymine residues at both 5' and 3' ends. PMID- 23644415 TI - Affective facial expression processing in 15-month-old infants who have experienced maltreatment: an event-related potential study. AB - This study examined the neural correlates of facial affect processing in 15 month old maltreated and nonmaltreated infants. Event-related potentials (ERPs) were elicited while infants passively viewed standardized pictures of female models posing angry, happy, and neutral facial expressions. Differences between maltreated (N = 25) and nonmaltreated (N = 20) infants were observed on three ERP components: P1, P260, and Nc. The results for the P260 waveform were consistent with previous ERP findings in older maltreated children, showing a hyperresponsivity to angry facial affect relative to happy in maltreated infants. However, the findings for the P1 and Nc indicated a hyperresponsivity to relative affective novelty, whereby the maltreated infants had greater amplitude in response to happy facial affect, whereas nonmaltreated infants had greater responsivity to angry faces. The results provided further support for the hypothesis that the experience of maltreatment and the predominantly negative emotional tone in maltreating families alters the functioning of neural systems associated with the processing of facial emotion. In particular, the findings suggested that at this early stage in the development of facial affect recognition, novelty of facial emotion is especially salient. These results exemplify the importance of early preventive interventions focused on emotion for children who have experienced maltreatment early in life. PMID- 23644417 TI - HoCrO3 and YCrO3: a comparative study. AB - A comparative study on structural, optical and magnetic properties of orthorhombic perovskite-like isostructural compounds HoCrO3 and YCrO3 was carried out, wherein Ho(3(+)) is a magnetic ion and Y(3+) is non-magnetic. We found almost identical structural parameters for both compounds, however a significant difference was observed in low wavenumber Raman active phonon modes. The effect of local field on optical transitions of Cr ion is studied by diffused reflectance spectroscopy. In order to understand the effect due to the Ho(3(+)) local magnetic field on the magnetic ordering of Cr(3(+)) in ACrO3 (A=Ho, Y), dc magnetization measurements were carried out in a temperature range of 5-300 K and several isotherms were analyzed. Magnetization measurements reveal that Cr(3+) magnetic ordering temperature is insensitive to local fields (due to Ho(3+)) and very sensitive to thermal cycling in the presence of an external applied magnetic field. This behavior is related to magnetic disorder near the phase transition due to weak ferromagnetism and/or structural distortions which we observed as thermal hysteresis. The importance of this work lies with the fact that both Ho(3+) (10.6 MUB) and Y(3+) (0 MUB) have identical ionic radii and the electron correlation effects in both the systems have been studied using different experimental techniques. PMID- 23644416 TI - Combinatorial engineering for heterologous gene expression. AB - Tools for strain engineering with predictable outcome are of crucial importance for the nascent field of synthetic biology. The success of combining different DNA biological parts is often restricted by poorly understood factors deriving from the complexity of the systems. We have previously identified variants for different regulatory elements of the expression cassette XylS/Pm. When such elements are combined they act in a manner consistent with their individual behavior, as long as they affect different functions, such as transcription and translation. Interestingly, sequence context does not seem to influence the final outcome significantly. Expression of reporter gene bla could be increased up to 75 times at the protein level by combining three variants in one cassette. For other tested reporter genes similar results were obtained, except that the stimulatory effect was quantitatively less. Combination of individually characterized DNA parts thus stands as suitable method to achieve a desired phenotype. PMID- 23644418 TI - Monoisoamyl 2,3-dimercaptosuccinic acid attenuates arsenic induced toxicity: behavioral and neurochemical approach. AB - Chronic exposure to arsenic in drinking water is associated with skin lesions, neurological effects, hypertension and high risk of cancer. The treatment in use at present employs administration of thiol chelators, such as meso-2,3 dimercaptosuccinic acid (DMSA) which are compromised with number of limitations due to their lipophobic nature. To address this problem, therapeutic efficacy of monoisoamyl meso-2,3-dimercaptosuccinic acid (MiADMSA), an analog of DMSA having lipophilic character, was examined against chronic arsenic poisoning in rats. Adult male Wistar rats were orally exposed to arsenic (2mg sodium arsenite/kg body weight) for 10 weeks followed by treatment with MiADMSA (50mg/kg, orally, once daily for 5 consecutive days). As-exposed rats showed significant differences in behavioral functions (open field behavior, total locomotor activity, grip strength and exploratory behavior) and water maze learning. Further, the biochemical studies performed on three brain regions (cerebellum, cortex and hippocampus) also showed significant elevation in malondialdehyde (MDA) levels with a concomitant decrease in the oxidative stress marker enzymes Mn-superoxide dismutase (Mn-SOD), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST). The alterations were more pronounced in cortex compared to cerebellum and hippocampus. The results showed that MiADMSA significantly reversed the As-induced alterations in behavior and biochemical variables suggestive of oxidative injury. PMID- 23644420 TI - Degree of focal immunoglobulin heavy chain locus deletion as a measure of B-cell tumor purity. PMID- 23644419 TI - Analyzing and building nucleic acid structures with 3DNA. AB - The 3DNA software package is a popular and versatile bioinformatics tool with capabilities to analyze, construct, and visualize three-dimensional nucleic acid structures. This article presents detailed protocols for a subset of new and popular features available in 3DNA, applicable to both individual structures and ensembles of related structures. Protocol 1 lists the set of instructions needed to download and install the software. This is followed, in Protocol 2, by the analysis of a nucleic acid structure, including the assignment of base pairs and the determination of rigid-body parameters that describe the structure and, in Protocol 3, by a description of the reconstruction of an atomic model of a structure from its rigid-body parameters. The most recent version of 3DNA, version 2.1, has new features for the analysis and manipulation of ensembles of structures, such as those deduced from nuclear magnetic resonance (NMR) measurements and molecular dynamic (MD) simulations; these features are presented in Protocols 4 and 5. In addition to the 3DNA stand-alone software package, the w3DNA web server, located at http://w3dna.rutgers.edu, provides a user-friendly interface to selected features of the software. Protocol 6 demonstrates a novel feature of the site for building models of long DNA molecules decorated with bound proteins at user-specified locations. PMID- 23644421 TI - Combination of azacitidine and lenalidomide in myelodysplastic syndromes or acute myeloid leukemia-a wise liaison? AB - Treatment options for older patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) are limited and the prognosis remains poor, thereby warranting development of novel therapies. Aberrant epigenetic modifications, including altered DNA methylation, seem to contribute to the pathogenesis of these patients. In fact, hypomethylating agents (HMA) like azacitidine have been successfully used in clinical trials and achieved approval from health authorities. There is now growing evidence suggesting that the combination of drugs with different mechanisms of action might offer a potential benefit to these patients. This is especially done with the intention to synergize the positive effects of each drug on the defective hematopoiesis while sparing potential side effects and toxicities. Combination of HMA with histone deacetylase inhibitors, although mechanistically very tempting, have not yielded convincing improvement of the results in the majority of trials compared to single agent HMA treatment. Currently, combination therapies of azacitidine with lenalidomide appear to be promising thus making them an appealing option for treatment in these patients. PMID- 23644422 TI - Developmental characteristics of late preterm infants at six and twelve months: a prospective study. AB - AIM: To longitudinally assess the neurodevelopmental outcomes of late preterm infants (LPI) through the first year of life and to investigate for perinatal conditions that may affect developmental outcomes. METHODS: The study population comprised of 124 LPI, born in a single Israeli inborn center over an eight months period. Thirty-three term infants (TI) were recruited for comparison. Alberta Infant Motor Scale (AIMS) for gross motor evaluation was performed at 6 months of age and the Griffiths Mental Development Scales (GMDS) were performed at 12 months (chronological age). Maternal and neonatal covariates, potentially associated with low developmental scores, were analyzed by multivariate logistic regression models. RESULTS: At chronological age of 6 and 12 months, LPI performed significantly lower than TI on all subscales, but when scores were corrected for post conception age, developmental scores were similar in the two groups. In a multivariate model of logistic regression, male gender, emergent cesarean section and higher maternal education (>14 years) were found to be associated with increased risk for lower developmental scores at 12 month of age in LPI. CONCLUSIONS: LPI do not complete their neurodevelopmental maturation by the first year of life. Males and those born after emergent cesarean section (CS) are at increased risk for lower developmental scores. Correction of age to term birth in LPI may still be needed at this age. PMID- 23644423 TI - Marine natural products: synthetic aspects. AB - Covering: January to December 2010. Previous review: Nat. Prod. Rep., 2011, 28, 269. An overview of marine natural products synthesis during 2010 is provided. As with earlier installments in this series, the emphasis is on total syntheses of molecules of contemporary interest, new total syntheses, and syntheses that have resulted in structure confirmation or stereochemical assignments. PMID- 23644424 TI - Sit happens: Does sitting development perturb reaching development, or vice versa? AB - The development of reaching and of sitting during the first year of life is typically studied as separate yet related behaviors. Interestingly, very soon after learning to reach, 4-7-month-old infants start coordinating their arms with their trunk and legs for sitting. In this longitudinal study, we focused, for the first time, on how infants learn to use their arms for the dual tasks of reaching for objects while providing arm support as they learn to sit. We hypothesized that the use of arms for support during sitting development would be a temporary perturbation to reaching and result in a nonlinear progression of reaching skill. Eleven infants were studied monthly from the time they began to prop sit to the time of sitting independence (5-8 months of age). Behavioral coding, kinematics, and electromyography (EMG) characterized reaching and posture while infants sat as independently as possible. Results revealed significant changes across time in trunk movement and hand use as infants transitioned through three stages of sitting: with arm support, sitting briefly without arm support, and sitting independently. Infants used their hands more for contacting objects and less for posture support linearly across time. In contrast, changes in posture control as indicated by pelvis and trunk movement demonstrated a U-shaped curve with more movement of these two body segments during the middle stage of sitting than in the first or last stage. During the middle stage of sitting infants reached persistently even though posture control, measured by pelvis and trunk movement, appeared to be significantly challenged. Muscle activation consisted of tonic and variable combinations of muscle pairings in early sitting. As infants progressed to sitting without hand support, variable but successful strategies utilizing lower extremity muscles in a tight linkage with reach onset emerged to provide prospective control for reaching. Our findings support the contention that reaching both drives the development of sitting in infancy as well as perturbs sitting posture, factoring into the assembly of the complex dual sit-reach behavior that supports and expands flexible interaction with the environment. PMID- 23644440 TI - Comparison of AlloDerm and AlloMax tissue incorporation in rats. AB - BACKGROUND: Human acellular dermal matrices (HADMs) are used in a variety of settings. AlloMax is a new HADM currently being used for breast reconstruction and hernia repair. We compared the in vivo tissue integration of AlloMax to AlloDerm, a well-studied HADM, in rats. METHODS: We implanted AlloDerm and AlloMax patches into subcutaneous pockets on the backs of 32 male Sprague-Dawley rats. The animals were killed after either 4 or 8 weeks, and the patches were recovered and stained for histopathologic analyses. Microscopic end points included patch thickness, vascularization, tissue in-growth, fibroblast proliferation, and inflammation. RESULTS: All animals completed the study without complications or infection. There were no significant differences in graft thicknesses at 4 and 8 weeks. Microscopically, at 4 weeks, AlloDerm sections had significantly more microvessels than AlloMax (P = 0.02). This disparity increased by 8 weeks (P < 0.01). Similarly, we found greater tissue in-growth and fibroblast proliferation in AlloDerm than AlloMax sections at 4 (P < 0.01) and at 8 (P < 0.01) weeks. Inflammatory infiltrates consisted of lymphocytes, histiocytes, eosinophils, and plasma cells. Deep graft infiltration by predominately lymphocytic inflammatory cells was significantly higher in AlloDerm than AlloMax grafts at 4 (P = 0.01) and 8 (P = 0.02) weeks. Graft necrosis was uncommon, but marginal fibrosis was similar in both. CONCLUSIONS: AlloDerm grafts had greater neovascularization, tissue infiltration, fibroblast proliferation, and inflammatory reaction than AlloMax grafts when placed subcutaneously in rats. AlloDerm may be better incorporated than AlloMax when placed in vivo. PMID- 23644441 TI - Surgical treatment of gynecomastia: mastectomy compared to liposuction technique. AB - BACKGROUND: Gynecomastia is a benign enlargement of the male breast. Yet enlarged breasts cause anxiety, embarrassment, psychosocial discomfort, and fear of breast cancer. The aim of this study was to assess the experience of gynecomastia patients undergoing mastectomy and liposuction surgery. METHODS: Seven hundred thirty-three patients were analyzed for age, chief complaint, position, grade, operation approach, biopsy, and complication between mastectomy group and liposuction group, from 1990 to 2010. RESULTS: Four hundred two patients (436 breasts) were treated with mastectomy and 331 patients (386 breasts) were treated with liposuction techniques. Three hundred thirty (82%) patients complained of breast lump and lump with pain in mastectomy group, and 204 (61%) patients complained of enlargement breast and enlargement with pain in liposuction group (P < 0.05). All excision specimens were performed for routine histological analysis which showed pathologic diagnosis in patients with mastectomy (100%). One hundred fifty-nine (41%) patients with liposuction acquired pathologic diagnosis through fine needle aspiration and/or core biopsy (P < 0.05). The reoperation rates in mastectomy group and liposuction group were 1.4% and 0.5%, respectively. There were no nipple/areola necrosis and scars in liposuction group. CONCLUSIONS: The surgical treatment of gynecomastia required an individual approach, depending on symptoms (lump or enlargement) and requirements of patients. Patients who chose mastectomy were looking for reassurance that their pathologic diagnosis was benign. The increase in the number of liposuction patients was reflected in our study because it was associated with superior esthetic results and few complications. PMID- 23644442 TI - Topographic relationships between the transverse facial artery, branches of the facial nerve, and the parotid duct in the lateral midface in a Korean population. AB - BACKGROUND: The aims of the present study were to clarify the topographic relationships between various structures in the lateral midface and to provide important anatomical information pertinent to face lifting or treatment of damage to the midface structure. METHODS: Thirty-two fixed cadavers were dissected (23 males and 9 females; mean age, 66.8 years) and 55 sides of midface were used. The transverse facial artery (TFA), zygomatic branch (Zb) and buccal branch (Bb) of the facial nerve, and the parotid duct (PD) were identified. The structures of the lateral midface were measured relative to the zygion and tragion. The vertical average distances from the zygion to each structure increased in the following order: ZB of the facial nerve, TFA, first Bb of the facial nerve, and PD. The horizontal average distance from the tragion to the point of emergence from anterior border of the parotid gland was also measured. RESULTS: The TFA was the closest and the third Bb of the facial nerve was the farthest away. The angles between the horizontal line and ZB of the facial nerve, TFA, PD, and first Bb of the facial nerve were +10.4, -2.3, -18.5, and -27.1 degrees, respectively. CONCLUSIONS: These results may be used to establish the precise locations and the courses of the important midface structures, and represent valuable data that may help to prevent complications during surgery for face lifting and reconstruction of the facial nerve and PD. PMID- 23644443 TI - Incidence of pneumothorax during tissue expander-implant reconstruction and algorithm for intraoperative management. AB - BACKGROUND: Iatrogenic pneumothorax is a serious intraoperative complication of immediate breast reconstruction with tissue expanders. However, there is paucity of literature regarding incidence or management of intraoperative pneumothorax in the breast reconstruction patient population. METHODS: We performed a retrospective chart review on prospectively collected data from all patients undergoing immediate breast reconstruction with tissue expanders from 1992 to 2012 to determine institutional incidence. We also searched the Nationwide Inpatient Sample database from 1998 to 2008 to determine national incidence. RESULTS: A total of 9653 tissue expanders were placed in 6955 patients at the Memorial Sloan Kettering Cancer Center between 1992 and 2012. There were 3 cases of pneumothorax during immediate breast reconstruction with tissue expanders. The incidence of pneumothorax is 0.03% per expander and 0.04% per patient. From the national database, there were 153 cases of pneumothorax during immediate breast reconstruction with tissue expanders in 27,612 patients. The overall national incidence of pneumothorax is 0.55% per patient. CONCLUSIONS: Our algorithm for management includes a thoracic surgery consultation intraoperatively. A chest tube should be placed at a site distal to the pleurotomy. The site of injury should be repaired primarily or patched as necessary. If the patient remains stable, it is safe to proceed with placement of the tissue expander. PMID- 23644444 TI - Preparation and characterization, stable bismaleimide-triarylamine polymers with reversible electrochromic properties. AB - A series of novel polyimides were synthesized from bismaleimide containing different diaminetriarylamines by Michael addition reaction. The prepolymer is readily soluble in many common organic solvents, such as CHCl3, Tetrahydrofuran (THF) and N, N-dimethyl formamide (DMF). Prepolymers can be solution-cast into transparent, tough, and flexible films. These aromatic polyimides display good thermal stabilities, i.e. 5% weight-loss temperatures in excess of 200 degrees C under nitrogen. All obtained polyimides revealed excellent stability of electrochromic characteristics, changing color from original yellowish to green. The energies of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) levels of the investigated the polymers were estimated by experimental method are in the range of -4.78 eV to -4.98 eV and 1.64 eV to -2.09 eV vs the vacuum level, respectively. All the polymer films reveal good electrochemical and electrochromic stability under repeatedly switching electrode voltages, with coloration change from the yellow neutral state to green oxidized state. PMID- 23644445 TI - Acidity constant determination of novel drug precursor benzothiazolon derivatives including acyl and piperazine moieties. AB - In this study, protonation and deprotonation behaviors of eight new drug precursor benzothiazolon derivatives in all of acidic and basic scale (super acidic, pH, super basic regions) are analyzed by using UV-visible spectrophotometric technique. Acidity constants (pKa), elucidation of the structure and protonation mechanisms of the studied molecules are obtained. Substituent effect on acidity constant values is discussed. These molecules are protonated from oxygen atom of acetamide group in the keto form. The protonation is found to be considerably contributed by the keto form. PMID- 23644446 TI - DFT approach for FT-IR spectra and HOMO-LUMO energy gap for N-(p dimethylaminobenzylidene)-p-nitroaniline (DBN). AB - In the present work, a combined experimental and computational study for the optimized molecular structural parameters, FT-IR spectra, thermo-chemical parameters, total dipole moment and HOMO-LUMO energy gap for N-(p diethylaminobenzylidene)p-nitroaniline (DBN) have been investigated using B3LYP/6 311G basis set. Our calculated results have showed that the investigated compound possesses a dipole moment of 12 Debye and HOMO-LUMO energy gap of 2.94 eV which indicate high recommendations for photovoltaic devices fabrication. PMID- 23644447 TI - Production of recombinant immunotherapeutics for anticancer treatment: the role of bioengineering. AB - Cancer is one of the most important health problems because many cases are difficult to prevent. Cancer still has unknown mechanisms of pathogenesis, and its capacity to produce temporary or permanent damage, besides death, is very high. Although many anticancer therapies are available, finding a cure for cancer continues to be a difficult task. Thus, many efforts have been made to develop more effective treatments, such as immunotherapy based on a new class of tumor specific products that are produced using recombinant DNA technology. These recombinant products are used with the main objectives of killing the tumor and stimulating immune cells to respond to the cancer cells. The principal recombinant products in anticancer therapy are immunostimulants, vaccines, antibodies, immunotoxins and fusion proteins. This review focuses on the general aspects of these genetically engineered products, their clinical performance, current advances and future prospects for this type of anticancer therapy. PMID- 23644448 TI - Upregulation of RCAN1 causes Down syndrome-like immune dysfunction. AB - BACKGROUND: People with Down syndrome (DS) are more susceptible to infections and autoimmune disease, but the molecular genetic basis for these immune defects remains undetermined. In this study, we tested whether increased expression of the chromosome 21 gene RCAN1 contributes to immune dysregulation. METHODS: We investigated the immune phenotype of a mouse model that overexpresses RCAN1. RCAN1 transgenic (TG) mice exhibit T cell abnormalities that bear a striking similarity to the abnormalities described in individuals with DS. RESULTS: RCAN1 TG mice display T cell developmental defects in the thymus and peripheral immune tissues. Thymic cellularity is reduced by substantial losses of mature CD4 and CD8 thymocytes and medullary epithelium. In peripheral immune organs T lymphocytes are reduced in number and exhibit reduced proliferative capacity and aberrant cytokine production. These T cell defects are stem cell intrinsic in that transfer of wild type bone marrow into RCAN1-TG recipients restored medullary thymic epithelium and T cell numbers in the thymus, spleen and lymph nodes. However, bone marrow transplantation failed to improve T cell function, suggesting an additional role for RCAN1 in the non-haemopoietic compartment. CONCLUSIONS: RCAN1 therefore facilitates T cell development and function, and when overexpressed, may contribute to immune dysfunction in DS. PMID- 23644450 TI - Defective epidermal induction of S100A7/psoriasin associated with low frequencies of skin-infiltrating Th17 cells in dermatophytosis-prone adult T cell leukemia/lymphoma. PMID- 23644451 TI - Low C-peptide levels and decreased expression of TNF and CD45 in children with high risk of type 1 diabetes. AB - Type 1 diabetes (T1D) patients have numeral and functional defects in peripheral immune cells, but the pre-diabetic period is fairly uncharacterized. Our aim was to analyze expression of immunological markers in T1D high risk children and relate it to clinical/immunological parameters. Children from ABIS (All Babies in Southeast Sweden) with >=2 diabetes related autoantibodies were considered at high risk. Age-matched controls and new-onset T1D patients were included. Expression of genes related to immune cell function and different arms of the immune system was assessed in peripheral blood mononuclear cells using PCR array. Risk children had lower TNF and CD45, and although there were few differences between the groups, expression of many genes differed when comparing children with regard to residual insulin secretion. Hence, expression of immune related genes seemed related not only to the autoimmune process but rather to residual beta-cell function, which was decreased already during the pre-diabetic phase. PMID- 23644449 TI - Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. AB - BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype- genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones. PMID- 23644452 TI - CMV driven CD8(+) T-cell activation is associated with acute rejection in lung transplantation. AB - Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8(+) T-cell activity post-transplant. Peripheral and lung CMV-specific CD8(+) T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8(+) T-cells in the lung may play a role in promoting acute rejection. PMID- 23644453 TI - Long-term Ro60 humoral autoimmunity in primary Sjogren's syndrome is maintained by rapid clonal turnover. AB - Long-term humoral autoimmunity to RNA-protein autoantigens is considered a hallmark of systemic autoimmune diseases. We use high resolution Orbitrap mass spectrometric autoantibody sequencing to track the evolution of a Ro60-specific public clonotypic autoantibody in 4 patients with primary Sjogren's syndrome. This clonotype is specified by a VH3-23/VK3-20 heavy and light chain pairing. Despite apparent stability by conventional immunoassay, analysis of V-region molecular signatures of clonotypes purified from serum samples collected retrospectively over 7years revealed sequential clonal replacement. Prospective longitudinal studies confirmed clonotype loss and replacement at approximately three-monthly intervals. Levels of secreted anti-Ro60 clonotypes fluctuated markedly over time, despite minimal changes in clonal affinity. Our novel findings indicate a relentless turnover of short-lived clonotypic variants, masquerading as long-lived Ro60 humoral autoimmunity. PMID- 23644454 TI - The microRNA miR-235 couples blast-cell quiescence to the nutritional state. AB - The coordination of stem- and blast-cell behaviours, such as self-renewal, differentiation and quiescence, with physiological changes underlies growth, regeneration and tissue homeostasis. Germline stem and somatic blast cells in newly hatched Caenorhabditis elegans larvae can suspend postembryonic development, which consists of diverse cellular events such as migration, proliferation and differentiation, until the nutritional state becomes favourable (termed L1 diapause). Although previous studies showed that the insulin/insulin like growth factor (IGF) signalling (IIS) pathway regulates this developmental quiescence, the detailed mechanism by which the IIS pathway enables these multipotent cells to respond to nutrient availability is unknown. Here we show in C. elegans that the microRNA (miRNA) miR-235, a sole orthologue of mammalian miR 92 from the oncogenic miR-17-92 cluster, acts in the hypodermis and glial cells to arrest postembryonic developmental events in both neuroblasts and mesoblasts. Expression of mir-235 persists during L1 diapause, and decreases upon feeding in a manner dependent on the IIS pathway. Upregulation of one of the miR-235 targets, nhr-91, which encodes an orthologue of mammalian germ cell nuclear factor, is responsible for defects caused by loss of the miRNA. Our findings establish a novel role of a miR-92 orthologue in coupling blast-cell behaviours to the nutritional state. PMID- 23644455 TI - Sema3A regulates bone-mass accrual through sensory innervations. AB - Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance. Previous studies have demonstrated that Sema3a( /-) mice have multiple developmental defects due to abnormal neuronal innervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a(-/-) mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1(-/-) and Sema3aosx(-/-) mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin(-/-) and Sema3anestin(-/-) mice) had low bone mass, similar to Sema3a(-/-) mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin(-/-) mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin(-/-) mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a(-/-) mice, such as olfactory development, were identified in Sema3asynasin(-/-) mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a(-/-) mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts. PMID- 23644456 TI - Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. AB - Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice. PMID- 23644457 TI - Reconfiguration of the proteasome during chaperone-mediated assembly. AB - The proteasomal ATPase ring, comprising Rpt1-Rpt6, associates with the heptameric alpha-ring of the proteasome core particle (CP) in the mature proteasome, with the Rpt carboxy-terminal tails inserting into pockets of the alpha-ring. Rpt ring assembly is mediated by four chaperones, each binding a distinct Rpt subunit. Here we report that the base subassembly of the Saccharomyces cerevisiae proteasome, which includes the Rpt ring, forms a high-affinity complex with the CP. This complex is subject to active dissociation by the chaperones Hsm3, Nas6 and Rpn14. Chaperone-mediated dissociation was abrogated by a non-hydrolysable ATP analogue, indicating that chaperone action is coupled to nucleotide hydrolysis by the Rpt ring. Unexpectedly, synthetic Rpt tail peptides bound alpha pockets with poor specificity, except for Rpt6, which uniquely bound the alpha2/alpha3-pocket. Although the Rpt6 tail is not visualized within an alpha pocket in mature proteasomes, it inserts into the alpha2/alpha3-pocket in the base-CP complex and is important for complex formation. Thus, the Rpt-CP interface is reconfigured when the lid complex joins the nascent proteasome to form the mature holoenzyme. PMID- 23644458 TI - Lamin A/C and emerin regulate MKL1-SRF activity by modulating actin dynamics. AB - Laminopathies, caused by mutations in the LMNA gene encoding the nuclear envelope proteins lamins A and C, represent a diverse group of diseases that include Emery Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM), limb-girdle muscular dystrophy, and Hutchison-Gilford progeria syndrome. Most LMNA mutations affect skeletal and cardiac muscle by mechanisms that remain incompletely understood. Loss of structural function and altered interaction of mutant lamins with (tissue-specific) transcription factors have been proposed to explain the tissue-specific phenotypes. Here we report in mice that lamin-A/C-deficient (Lmna(-/-)) and Lmna(N195K/N195K) mutant cells have impaired nuclear translocation and downstream signalling of the mechanosensitive transcription factor megakaryoblastic leukaemia 1 (MKL1), a myocardin family member that is pivotal in cardiac development and function. Altered nucleo-cytoplasmic shuttling of MKL1 was caused by altered actin dynamics in Lmna(-/-) and Lmna(N195K/N195K) mutant cells. Ectopic expression of the nuclear envelope protein emerin, which is mislocalized in Lmna mutant cells and also linked to EDMD and DCM, restored MKL1 nuclear translocation and rescued actin dynamics in mutant cells. These findings present a novel mechanism that could provide insight into the disease aetiology for the cardiac phenotype in many laminopathies, whereby lamin A/C and emerin regulate gene expression through modulation of nuclear and cytoskeletal actin polymerization. PMID- 23644459 TI - The shaping and functional consequences of the microRNA landscape in breast cancer. AB - MicroRNAs (miRNAs) show differential expression across breast cancer subtypes, and have both oncogenic and tumour-suppressive roles. Here we report the miRNA expression profiles of 1,302 breast tumours with matching detailed clinical annotation, long-term follow-up and genomic and messenger RNA expression data. This provides a comprehensive overview of the quantity, distribution and variation of the miRNA population and provides information on the extent to which genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture, suggesting an important role for post-transcriptional regulation. The key clinical parameters and cellular pathways related to the miRNA landscape are characterized, revealing context-dependent interactions, for example with regards to cell adhesion and Wnt signalling. Notably, only prognostic miRNA signatures derived from breast tumours devoid of somatic copy number aberrations (CNA-devoid) are consistently prognostic across several other subtypes and can be validated in external cohorts. We then use a data-driven approach to seek the effects of miRNAs associated with differential co-expression of mRNAs, and find that miRNAs act as modulators of mRNA-mRNA interactions rather than as on-off molecular switches. We demonstrate such an important modulatory role for miRNAs in the biology of CNA-devoid breast cancers, a common subtype in which the immune response is prominent. These findings represent a new framework for studying the biology of miRNAs in human breast cancer. PMID- 23644462 TI - Nurses' interpretation of patient status descriptions on the Braden Scale. AB - The risk of pressure ulcers is widely assessed using the Braden Scale for Predicting Pressure Ulcer Risk, which describes patient characteristics for various severity levels. However, many of these characteristics are described in vague terms that nurses may interpret inconsistently, potentially threatening scale reliability. To examine the consistency of nurses' interpretations of five vaguely described patient characteristics on the Braden Scale we surveyed a convenience sample of 102 nurses and compared their interpretations with those of two nurse experts. The results show large variations in nurses' interpretations. Although the highest frequency of nurses' responses to the majority of descriptions was consistent with the experts' interpretation, the large variation in responses may seriously threaten consistent and accurate assessment of pressure-ulcer risk with the Braden Scale. Our findings suggest that training programs provide operational definitions of these vague patient descriptions, so the Braden Scale can be used consistently in patient care. PMID- 23644460 TI - Chromosome-specific nonrandom sister chromatid segregation during stem-cell division. AB - Adult stem cells undergo asymmetric cell division to self-renew and give rise to differentiated cells that comprise mature tissue. Sister chromatids may be distinguished and segregated nonrandomly in asymmetrically dividing stem cells, although the underlying mechanism and the purpose it may serve remain elusive. Here we develop the CO-FISH (chromosome orientation fluorescence in situ hybridization) technique with single-chromosome resolution and show that sister chromatids of X and Y chromosomes, but not autosomes, are segregated nonrandomly during asymmetric divisions of Drosophila male germline stem cells. This provides the first direct evidence, to our knowledge, that two sister chromatids containing identical genetic information can be distinguished and segregated nonrandomly during asymmetric stem-cell divisions. We further show that the centrosome, SUN-KASH nuclear envelope proteins and Dnmt2 (also known as Mt2) are required for nonrandom sister chromatid segregation. Our data indicate that the information on X and Y chromosomes that enables nonrandom segregation is primed during gametogenesis in the parents. Moreover, we show that sister chromatid segregation is randomized in germline stem cell overproliferation and dedifferentiated germline stem cells. We propose that nonrandom sister chromatid segregation may serve to transmit distinct information carried on two sister chromatids to the daughters of asymmetrically dividing stem cells. PMID- 23644463 TI - GATAD2B loss-of-function mutations cause a recognisable syndrome with intellectual disability and are associated with learning deficits and synaptic undergrowth in Drosophila. AB - BACKGROUND: GATA zinc finger domain containing 2B (GATAD2B) encodes a subunit of the MeCP1-Mi-2/nucleosome remodelling and deacetylase complex involved in chromatin modification and regulation of transcription. We recently identified two de novo loss-of-function mutations in GATAD2B by whole exome sequencing in two unrelated individuals with severe intellectual disability. METHODS: To identify additional individuals with GATAD2B aberrations, we searched for microdeletions overlapping with GATAD2B in inhouse and international databases, and performed targeted Sanger sequencing of the GATAD2B locus in a selected cohort of 80 individuals based on an overlap with the clinical features in the two index cases. To address whether GATAD2B is required directly in neurones for cognition and neuronal development, we investigated the role of Drosophila GATAD2B orthologue simjang (simj) in learning and synaptic connectivity. RESULTS: We identified a third individual with a 240 kb microdeletion encompassing GATAD2B and a fourth unrelated individual with GATAD2B loss-of-function mutation. Detailed clinical description showed that all four individuals with a GATAD2B aberration had a distinctive phenotype with childhood hypotonia, severe intellectual disability, limited speech, tubular shaped nose with broad nasal tip, short philtrum, sparse hair and strabismus. Neuronal knockdown of Drosophila GATAD2B orthologue, simj, resulted in impaired learning and altered synapse morphology. CONCLUSIONS: We hereby define a novel clinically recognisable intellectual disability syndrome caused by loss-of-function of GATAD2B. Our results in Drosophila suggest that GATAD2B is required directly in neurones for normal cognitive performance and synapse development. PMID- 23644464 TI - The role of potassium BK channels in anticonvulsant effect of cannabidiol in pentylenetetrazole and maximal electroshock models of seizure in mice. AB - Cannabidiol is a nonpsychoactive member of phytocannabinoids that produces various pharmacological effects that are not mediated through putative CB1/CB2 cannabinoid receptors and their related effectors. In this study, we examined the effect of the i.c.v. administration of potassium BK channel blocker paxilline alone and in combination with cannabidiol in protection against pentylenetetrazol (PTZ)- and maximal electroshock (MES)-induced seizure in mice. In the PTZ-induced seizure model, i.c.v. administration of cannabidiol caused a significant increase in seizure threshold compared with the control group. Moreover, while i.c.v. administration of various doses of paxilline did not produce significant change in the PTZ-induced seizure threshold in mice, coadministration of cannabidiol and paxilline attenuated the antiseizure effect of cannabidiol in PTZ-induced tonic seizures. In the MES model of seizure, both cannabidiol and paxilline per se produced significant increase in percent protection against electroshock-induced seizure. However, coadministration of cannabidiol and paxilline did not produce significant interaction in their antiseizure effect in the MES test. The results of the present study showed a protective effect of cannabidiol in both PTZ and MES models of seizure. These results suggested a BK channel-mediated antiseizure action of cannabidiol in PTZ model of seizure. However, such an interaction might not exist in MES-induced convulsion. PMID- 23644465 TI - The quest for myelin in the adult brain. AB - Although myelination largely occurs during early postnatal life, myelinating oligodendrocytes are still generated in the adult brain. Myelin turnover in the adult is necessary for proper neuronal function and is gravely compromised in myelin disorders. The lineage relationship between adult neural stem cells and adult-born oligodendrocytes has been clarified, highlighting molecular pathways that could potentially be targeted to favour de novo myelination in pathological situations. PMID- 23644466 TI - Oligodendrogliogenic and neurogenic adult subependymal zone neural stem cells constitute distinct lineages and exhibit differential responsiveness to Wnt signalling. AB - The adult mouse subependymal zone (SEZ) harbours adult neural stem cells (aNSCs) that give rise to neuronal and oligodendroglial progeny. However it is not known whether the same aNSC can give rise to neuronal and oligodendroglial progeny or whether these distinct progenies constitute entirely separate lineages. Continuous live imaging and single-cell tracking of aNSCs and their progeny isolated from the mouse SEZ revealed that aNSCs exclusively generate oligodendroglia or neurons, but never both within a single lineage. Moreover, activation of canonical Wnt signalling selectively stimulated proliferation within the oligodendrogliogenic lineage, resulting in a massive increase in oligodendrogliogenesis without changing lineage choice or proliferation within neurogenic clones. In vivo activation or inhibition of canonical Wnt signalling respectively increased or decreased the number of Olig2 and PDGFR- alpha positive cells, suggesting that this pathway contributes to the fine tuning of oligodendrogliogenesis in the adult SEZ. PMID- 23644467 TI - The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. AB - Increased stromal collagen deposition in human breast tumours correlates with metastases. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner. Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half life. DDR2-mediated stabilization of SNAIL1 promotes breast cancer cell invasion and migration in vitro, and metastasis in vivo. DDR2 expression was observed in most human invasive ductal breast carcinomas studied, and was associated with nuclear SNAIL1 and absence of E-cadherin expression. We propose that DDR2 maintains SNAIL1 level and activity in tumour cells that have undergone epithelial-mesenchymal transition (EMT), thereby facilitating continued tumour cell invasion through collagen-I-rich extracellular matrices by sustaining the EMT phenotype. As such, DDR2 could be an RTK (receptor tyrosine kinase) target for the treatment of breast cancer metastasis. PMID- 23644468 TI - CEP162 is an axoneme-recognition protein promoting ciliary transition zone assembly at the cilia base. AB - The transition zone is a specialized compartment found at the base of cilia, adjacent to the centriole distal end, where axonemal microtubules are heavily crosslinked to the surrounding membrane to form a barrier that gates the ciliary compartment. A number of ciliopathy molecules have been found to associate with the transition zone, but factors that directly recognize axonemal microtubules to specify transition zone assembly at the cilia base remain unclear. Here, through quantitative centrosome proteomics, we identify an axoneme-associated protein, CEP162 (KIAA1009), tethered specifically at centriole distal ends to promote transition zone assembly. CEP162 interacts with core transition zone components, and mediates their association with microtubules. Loss of CEP162 arrests ciliogenesis at the stage of transition zone assembly. Abolishing its centriolar tethering, however, allows CEP162 to stay on the growing end of the axoneme and ectopically assemble transition zone components at cilia tips. This generates extra-long cilia with strikingly swollen tips that actively release ciliary contents into the extracellular environment. CEP162 is thus an axoneme recognition protein pre-tethered at centriole distal ends before ciliogenesis to promote and restrict transition zone formation specifically at the cilia base. PMID- 23644472 TI - [Photodermatology]. PMID- 23644470 TI - Effect of nuclear architecture on the efficiency of double-strand break repair. AB - The most dangerous insults to the genome's integrity are those that break both strands of the DNA. Double-strand breaks can be repaired by homologous recombination; in this conserved mechanism, a global genomic homology search finds sequences similar to those near the break, and uses them as a template for DNA synthesis and ligation. Chromosomes occupy restricted territories within the nucleus. We show that yeast genomic regions whose nuclear territories overlap recombine more efficiently than sequences located in spatially distant territories. Tethering of telomeres and centromeres reduces the efficiency of recombination between distant genomic loci, lowering the chances of non-allelic recombination. Our results challenge present models that posit an active scanning of the whole nuclear volume by the broken chromosomal end; they demonstrate that the search for homology is a limiting step in homologous recombination, and emphasize the importance of nuclear organization in genome maintenance. PMID- 23644469 TI - Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. AB - Oligodendrocytes-the myelin-forming cells of the central nervous system-can be regenerated during adulthood. In adults, new oligodendrocytes originate from oligodendrocyte progenitor cells (OPCs), but also from neural stem cells (NSCs). Although several factors supporting oligodendrocyte production have been characterized, the mechanisms underlying the generation of adult oligodendrocytes are largely unknown. Here we show that genetic inactivation of SIRT1, a protein deacetylase implicated in energy metabolism, increases the production of new OPCs in the adult mouse brain, in part by acting in NSCs. New OPCs produced following SIRT1 inactivation differentiate normally, generating fully myelinating oligodendrocytes. Remarkably, SIRT1 inactivation ameliorates remyelination and delays paralysis in mouse models of demyelinating injuries. SIRT1 inactivation leads to the upregulation of genes involved in cell metabolism and growth factor signalling, in particular PDGF receptor alpha (PDGFRalpha). Oligodendrocyte expansion following SIRT1 inactivation is mediated at least in part by AKT and p38 MAPK-signalling molecules downstream of PDGFRalpha. The identification of drug-targetable enzymes that regulate oligodendrocyte regeneration in adults could facilitate the development of therapies for demyelinating injuries and diseases, such as multiple sclerosis. PMID- 23644473 TI - [Phototoxic and photoallergic reactions]. AB - Many artificial or naturally occurring substances are included under the term photosensitizer. After ultraviolet (UV) exposure such agents can lead to increased photosensitivity and subsequently to phototoxic or photoallergic reactions in the skin. From clinical observations and comprehensive studies typical reaction patterns can be deduced which can clarify the difference between phototoxic and photoallergic dermatitis.An illuminated epicutaneous test based on conventional epicutaneous tests, the photopatch test, was developed as a screening method for identification of photosensitizers. The diagnostic specificity and sensitivity of the test is comparable to conventional epicutaneous testing. If possible photosensitizers do not cause any relevant reactions with the photopatch test, other test procedures, such as the photoprick, photoscratch and illuminated intracutaneous tests are available. If the actual photosensitizer is not the test substance but a metabolite of the test substance, a systemic photoprovocation test can be indicated. PMID- 23644476 TI - Nurse-led Early Triage (NET) study of chest pain patients: a long term evaluation study of a service development aimed at improving the management of patients with non-ST-elevation acute coronary syndromes. AB - BACKGROUND: Patients presenting with non-ST-elevation acute coronary syndrome (NSTE-ACS) are at risk of early death. This may be reduced by timely assessment and treatment. OBJECTIVES: The purpose of this study was to evaluate if Nurse-led Early Triage (NET) in the coronary care unit (CCU) can improve time to assessment and management of NSTE-ACS patients. METHODS: Data on 79 consecutive chest pain patients admitted pre-NET to the acute admissions unit (AAU) and on 103 patients admitted in the first six months of the NET service in CCU, was re-examined and compared to subsequent data obtained on 92 patients admitted via NET five years later, in order to re-evaluate the service. RESULTS: NET resulted in significant improvements in: the number of patients with chest pain who had their 12-lead electrocardiogram (ECG) performed within 10 min of admission (94% vs 32%, p<0.001); the number of high-risk NSTE-ACS patients prescribed clopidogrel (72% vs 42%, p<0.01); and the number being managed in CCU (82% vs 34%, p<0.01). Comparison of the NET service at five years with the pre-NET service demonstrated measurable benefits were sustained (p<0.01) for the same comparative end points. There were no significant differences in these end-points of time to ECG, clopidogrel prescription nor management in CCU for high-risk patients between the NET groups at six months and five years, demonstrating that current triage is as effective as when first introduced. CONCLUSIONS: This study demonstrated the positive impact of nurse-led early triage for NSTE-ACS patients and that initial benefits have been sustained. PMID- 23644477 TI - Protein dynamics: Catch them if you can. PMID- 23644478 TI - Allosteric inhibition through suppression of transient conformational states. AB - The ability to inhibit binding or enzymatic activity is key to preventing aberrant behaviors of proteins. Allosteric inhibition is desirable as it offers several advantages over competitive inhibition, but the mechanisms of action remain poorly understood in most cases. Here we show that allosteric inhibition can be effected by destabilizing a low-populated conformational state that serves as an on-pathway intermediate for ligand binding, without altering the protein's ground-state structure. As standard structural approaches are typically concerned with changes in the ground-state structure of proteins, the presence of such a mechanism can go easily undetected. Our data strongly argue for the routine use of NMR tools suited to detect and characterize transiently formed conformational states in allosteric systems. Structure information on such important intermediates can ultimately result in more efficient design of allosteric inhibitors. PMID- 23644479 TI - A substrate radical intermediate in catalysis by the antibiotic resistance protein Cfr. AB - Cfr-dependent methylation of C8 of A2503 in 23S ribosomal RNA confers bacterial resistance to an array of clinically important antibiotics that target the large subunit of the ribosome, including the synthetic oxazolidinone antibiotic linezolid. The key element of the proposed mechanism for Cfr, a radical S adenosylmethionine enzyme, is the addition of a methylene radical, generated by hydrogen-atom abstraction from the methyl group of an S-methylated cysteine, onto C8 of A2503 to form a protein-nucleic acid crosslinked species containing an unpaired electron. Herein we use continuous-wave and pulsed EPR techniques to provide direct spectroscopic evidence for this intermediate, showing a spin delocalized radical with maximum spin density at N7 of the adenine ring. In addition, we use rapid freeze-quench EPR to show that the radical forms and decays with rate constants that are consistent with the rate of formation of the methylated product. PMID- 23644481 TI - Informing patient decisions regarding management of ductal carcinoma in situ. PMID- 23644480 TI - Modeling the effectiveness of initial management strategies for ductal carcinoma in situ. AB - BACKGROUND: The prevalence of ductal carcinoma in situ (DCIS) and the marked variability in patterns of care highlight the need for comparative effectiveness research. We sought to quantify the tradeoffs among alternative management strategies for DCIS with respect to disease outcomes and breast preservation. METHODS: We developed a disease simulation model integrating data from the published literature to simulate the clinical events after six treatments (lumpectomy alone, lumpectomy with radiation, lumpectomy with radiation and tamoxifen, lumpectomy with tamoxifen, and mastectomy with and without breast reconstruction) for women with newly diagnosed DCIS. Outcomes included disease free, invasive disease-free, and overall survival and breast preservation. RESULTS: For a cohort of 1 million simulated women aged 45 years at diagnosis, both mastectomy and lumpectomy with radiation and tamoxifen were associated with a 12-month improvement in overall survival relative to lumpectomy alone. Adding radiation therapy to lumpectomy resulted in a 6-month improvement in overall survival but decreased long-term breast-preservation outcomes (likelihood of lifetime breast preservation = 0.781 vs 0.843 for lumpectomy alone). This decrement with radiation therapy was mitigated by the addition of tamoxifen (likelihood of lifetime breast preservation = 0.846). CONCLUSIONS: Overall survival benefits of the six management strategies for DCIS are within 1 year, suggesting that treatment decisions can be informed by the patient's preference for breast preservation and disutility for recurrence. Our delineation of personalized outcomes for each strategy can help patients understand the implications of their treatment choice, so their decisions may reflect their own personal values and help improve the quality of care for patients with DCIS. PMID- 23644482 TI - [Primary plexiform ameloblastoma in the sinonasal tract of a 49-year-old female patient. Case report]. AB - Sinonasal ameloblastoma is a rare tumor, which most frequently affects male patients in the 6th-7th decade. We report on the case of 49-year-old female patient presenting with nasal obstruction. Computed tomography revealed a solid and hypodense mass filling the maxillary sinus and the nasal cavity. The histological examination showed a plexiform ameloblastoma without significant bone erosion. Viewing this together with the literature review, we suggest that sinonasal ameloblastoma in female patients becomes apparent approximately one decade earlier than in male patients. This tumor should be considered in the differential diagnosis of unilateral sinonasal symptoms. PMID- 23644483 TI - Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss. AB - Stress impairs cognition via corticotropin-releasing hormone receptor 1 (CRHR1), but the molecular link between abnormal CRHR1 signaling and stress-induced cognitive impairments remains unclear. We investigated whether the cell adhesion molecule nectin-3 is required for the effects of CRHR1 on cognition and structural remodeling after early-life stress exposure. Postnatally stressed adult mice had decreased hippocampal nectin-3 levels, which could be attenuated by CRHR1 inactivation and mimicked by corticotropin-releasing hormone (CRH) overexpression in forebrain neurons. Acute stress dynamically reduced hippocampal nectin-3 levels, which involved CRH-CRHR1, but not glucocorticoid receptor, signaling. Suppression of hippocampal nectin-3 caused spatial memory deficits and dendritic spine loss, whereas enhancing hippocampal nectin-3 expression rescued the detrimental effects of early-life stress on memory and spine density in adulthood. Our findings suggest that hippocampal nectin-3 is necessary for the effects of stress on memory and structural plasticity and indicate that the CRH CRHR1 system interacts with the nectin-afadin complex to mediate such effects. PMID- 23644486 TI - [Recurrent hypoglycemia with elevated insulin levels in a 75-year-old man]. AB - Hirata syndrome is a rare differential diagnosis for recurrent hypoglycemia. This immune-mediated disease is associated with the formation of autoantibodies targeting insulin. Although the syndrome resolves spontaneously in the majority of patients, our case illustrates that individual patients require continuous immunosuppressive therapy. PMID- 23644485 TI - GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. AB - Impaired GABA-mediated neurotransmission has been implicated in many neurologic diseases, including epilepsy, intellectual disability and psychiatric disorders. We found that inhibitory neuron transplantation into the hippocampus of adult mice with confirmed epilepsy at the time of grafting markedly reduced the occurrence of electrographic seizures and restored behavioral deficits in spatial learning, hyperactivity and the aggressive response to handling. In the recipient brain, GABA progenitors migrated up to 1,500 MUm from the injection site, expressed genes and proteins characteristic for interneurons, differentiated into functional inhibitory neurons and received excitatory synaptic input. In contrast with hippocampus, cell grafts into basolateral amygdala rescued the hyperactivity deficit, but did not alter seizure activity or other abnormal behaviors. Our results highlight a critical role for interneurons in epilepsy and suggest that interneuron cell transplantation is a powerful approach to halting seizures and rescuing accompanying deficits in severely epileptic mice. PMID- 23644484 TI - Sublinear integration underlies binocular processing in primary visual cortex. AB - Although we know much about the capacity of neurons to integrate synaptic inputs in vitro, less is known about synaptic integration in vivo. Here we address this issue by investigating the integration of inputs from the two eyes in mouse primary visual cortex. We find that binocular inputs to layer 2/3 pyramidal neurons are integrated sublinearly in an amplitude-dependent manner. Sublinear integration was greatest when binocular responses were largest, as occurs at the preferred orientation and binocular disparity, and highest contrast. Using voltage-clamp experiments and modeling, we show that sublinear integration occurs postsynaptically. The extent of sublinear integration cannot be accounted for solely by nonlinear integration of excitatory inputs, even when they are activated closely in space and time, but requires balanced recruitment of inhibition. Finally, we show that sublinear binocular integration acts as a divisive form of gain control, linearizing the output of binocular neurons and enhancing orientation selectivity. PMID- 23644487 TI - [Treatment strategies for infective endocarditis: early surgery versus conventional treatment in infective endocarditis (EASE)]. PMID- 23644488 TI - Frailty is independently associated with 1-year mortality for elderly patients with non-ST-segment elevation myocardial infarction. AB - BACKGROUND: For the large population of elderly patients with cardiovascular disease, it is crucial to identify clinically relevant measures of biological age and their contribution to risk. Frailty is denoting decreased physiological reserves and increased vulnerability. We analysed the manner in which the variable frailty is associated with 1-year outcomes for elderly non-ST-segment elevation myocardial infarction (NSTEMI) patients. METHODS AND RESULTS: Patients aged 75 years or older, with diagnosed NSTEMI were included at three centres, and clinical data including judgment of frailty were collected prospectively. Frailty was defined according to the Canadian Study of Health and Aging Clinical Frailty Scale. Of 307 patients, 149 (48.5%) were considered frail. By Cox regression analyses, frailty was found to be independently associated with 1-year mortality after adjusting for cardiovascular risk and comorbid conditions (hazard ratio 4.3, 95% CI 2.4-7.8). The time to the first event was significantly shorter for frail patients than for nonfrail (34 days, 95% CI 10-58, p = 0.005). CONCLUSIONS: Frailty is strongly and independently associated with 1-year mortality. The combined use of frailty and comorbidity may constitute an important risk prediction concept in regard to cardiovascular patients with complex needs. PMID- 23644489 TI - Achievement of LDL-C goals depends on baseline LDL-C and choice and dose of statin: an analysis from the VOYAGER database. AB - BACKGROUND: Reducing low-density lipoprotein cholesterol (LDL-C) levels decreases cardiovascular risk in direct proportion to the decrease in LDL-C. DESIGN: The aim of this study was to assess the importance of baseline LDL-C and choice and dose of statin in achievement of LDL-C goals of 100 and 70 mg/dl, using a novel statistical model. The analysis included 30,102 patient exposures to rosuvastatin 10-40 mg or atorvastatin 10-80 mg from 31 direct comparative trials in the VOYAGER database. METHODS: For each statin dose, percentage goal achievement was plotted for 20 equally large subgroups defined by baseline LDL-C. Logistic regression analysis was then performed for each statin dose to estimate the percentage of patients reaching target. Best-fit logistic regression curves were plotted 'pair-wise', comparing each rosuvastatin dose with equal or higher doses of atorvastatin. RESULTS: LDL-C <100 mg/dl was achieved by 53.7-85.5% of patients on rosuvastatin 10-40 mg and 43.3-80.0% of those on atorvastatin 10-80 mg, whereas LDL-C <70 mg/dl was achieved by 4.5-44.0% of rosuvastatin-treated patients and 6.5-41.4% of those on atorvastatin. Similar differences in efficacy favouring rosuvastatin over equal or double doses of atorvastatin were observed across the range of baseline LDL-C levels for both LDL-C goals, being more pronounced at higher baseline values. CONCLUSIONS: Baseline LDL-C and choice and dose of statin are important for LDL-C goal achievement. The present analysis may allow prediction of individual patient response to different statins at different doses. PMID- 23644490 TI - Multifaceted role of EZH2 in breast and prostate tumorigenesis: epigenetics and beyond. AB - Overexpression of EZH2 and other PRC2 subunits, such as SUZ12, is associated with tumor progression and poor prognosis in several human malignancies. Nevertheless, the underlying mechanisms driving aberrant EZH2 expression are poorly understood. This review provides molecular insights into the essential role of EZH2 in breast and prostate tumorigenesis. We addressed the current understanding on the oncogenic role of EZH2, with an emphasis on: (1) the less known PRC2-independent role of EZH2 in gene activation, in addition to its canonical role in transcriptional silencing as a histone methyltransferase catalyzing the trimethylation of histone H3 at lysine 27; (2) causes and consequences of its deregulation in tumor cells and; (3) collaboration of EZH2 with other epigenetic and hormone receptor-mediated oncogenic signaling pathways. We also summarize how EZH2 has emerged as a promising therapeutic target in hormone-refractory cancers and the prospects for integrating EZH2 blockade with available pharmacological inhibitors. PMID- 23644491 TI - Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. AB - Subunits of mammalian SWI/SNF (mSWI/SNF or BAF) complexes have recently been implicated as tumor suppressors in human malignancies. To understand the full extent of their involvement, we conducted a proteomic analysis of endogenous mSWI/SNF complexes, which identified several new dedicated, stable subunits not found in yeast SWI/SNF complexes, including BCL7A, BCL7B and BCL7C, BCL11A and BCL11B, BRD9 and SS18. Incorporating these new members, we determined mSWI/SNF subunit mutation frequency in exome and whole-genome sequencing studies of primary human tumors. Notably, mSWI/SNF subunits are mutated in 19.6% of all human tumors reported in 44 studies. Our analysis suggests that specific subunits protect against cancer in specific tissues. In addition, mutations affecting more than one subunit, defined here as compound heterozygosity, are prevalent in certain cancers. Our studies demonstrate that mSWI/SNF is the most frequently mutated chromatin-regulatory complex (CRC) in human cancer, exhibiting a broad mutation pattern, similar to that of TP53. Thus, proper functioning of polymorphic BAF complexes may constitute a major mechanism of tumor suppression. PMID- 23644492 TI - Genome-wide association study identifies common variants in SLC39A6 associated with length of survival in esophageal squamous-cell carcinoma. AB - We conducted a genome-wide scan of SNPs to identify variants associated with length of survival in 1,331 individuals with esophageal squamous-cell carcinoma (ESCC), with associations validated in 2 independent sets including 1,962 individuals with this cancer. We identified rs1050631 in SLC39A6 as associated with the survival times of affected individuals, with the hazard ratio for death from ESCC in the combined sample being 1.30 (95% confidence interval (CI) = 1.19 1.43; P = 3.77 * 10(-8)). rs7242481, located in the 5' UTR of SLC39A6, disturbs a transcriptional repressor binding site and results in upregulation of SLC39A6 expression. Immunohistochemical staining of ESCC tissues showed that higher expression of SLC39A6 protein was correlated with shorter length of survival in individuals with advanced ESCC (P = 0.013). Knockdown of SLC39A6 expression suppressed proliferation and invasion in ESCC cells. These results suggest that SLC39A6 has an important role in the prognosis of ESCC and may be a potential therapeutic target. PMID- 23644493 TI - Population genomics of post-vaccine changes in pneumococcal epidemiology. AB - Whole-genome sequencing of 616 asymptomatically carried Streptococcus pneumoniae isolates was used to study the impact of the 7-valent pneumococcal conjugate vaccine. Comparison of closely related isolates showed the role of transformation in facilitating capsule switching to non-vaccine serotypes and the emergence of drug resistance. However, such recombination was found to occur at significantly different rates across the species, and the evolution of the population was primarily driven by changes in the frequency of distinct genotypes extant before the introduction of the vaccine. These alterations resulted in little overall effect on accessory genome composition at the population level, contrasting with the decrease in pneumococcal disease rates after the vaccine's introduction. PMID- 23644494 TI - Insights into mitochondrial quality control pathways and Parkinson's disease. AB - The brain uses more energy than any other human organ, accounting for 20 % of the body's total demand. Mitochondria are energy-converting organelles with a pivotal role in meeting the energetic needs of the human brain. Therefore, the decline of these cellular powerhouses can have a negative impact on the function and plasticity of neurons and is believed to have a prominent role in ageing and in the occurrence of several neurological disorders, such as Parkinson's disease (PD). As a consequence of their physiological roles, mitochondria are subjected to high levels of stress and have therefore developed several stress-protective mitochondrial quality control mechanisms that ensure the optimal activity of their molecular machinery. Here, we review some of the most recent advances in our understanding of the regulation of mitochondrial stress pathways with particular emphasis on how defective mitochondrial quality control might contribute to PD. PMID- 23644495 TI - Determination of crenolanib in human serum and cerebrospinal fluid by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). AB - A LC-ESI-MS/MS method for the determination of crenolanib (CP-868,596) in human serum was developed and validated employing d4-CP-868,596 as an internal standard (ISTD). In addition to human serum, the method was also partially validated for crenolanib determination in human cerebrospinal fluid (CSF) samples. Sample aliquots (50MUl of serum or CSF) were prepared for analysis using liquid-liquid extraction (LLE) with tert-butyl methyl ether. Chromatography was performed using a phenomenex Gemini C18 column (3MUm, 100mm*4.6mm I.D.) in a column heater set at 50 degrees C and an isocratic mobile phase (methanol/water/formic acid at a volume ratio of 25/25/0.15, v/v/v). The flow rate was 0.45mL/min, and the retention time for both analyte and ISTD was less than 3.5min. Samples were analyzed with an API-5500 LC-MS/MS system (ESI) in positive ionization mode coupled to a Shimadzu HPLC system. The ion transitions monitored were m/z 444.4 >373.1 and m/z 448.2->374.2 for crenolanib and ISTD, respectively. The method was linear over the range of 5-1000ng/mL for serum and 0.5-1000ng/mL for CSF. For human serum, both intra-day and inter-day precision were <4%, while intra-day and inter-day accuracy were within 8% of nominal values. Recovery was greater than 50% for both the analyte and ISTD. For CSF samples, both intra-day and inter-day precision were <9% except at the lower limit of quantification (LLOQ) which was <17%. The intra-day and inter-day accuracy were within 11% of the nominal CSF concentrations. After validation, this method was successfully applied to the analysis of serial pharmacokinetic samples obtained from a child treated with oral crenolanib. PMID- 23644496 TI - Process integration for the recovery and purification of recombinant Pseudomonas fluorescens proline dehydrogenase using aqueous two-phase systems. AB - The integration of refolding, reconstitution and two-phase partitioning in aqueous two-phase systems (ATPS) which is composed of polyethylene glycol (PEG) and sodium carbonate (Na2CO3) was employed as a novel method for recovery and purification of recombinant Pseudomonas fluorescens proline dehydrogenase (ProDH). To obtain an optimal condition, the influence of different parameters, such as PEG molecular weight (MW), type and concentration of salt, pH, and NaCl addition on the partitioning features of target enzyme was also investigated. Combining the refolding, reconstitution and two-phase partitioning in an optimized ATPS of 14% (w/w) PEG-1000 and 12% (w/w) Na2CO3 at pH 8.0 resulted in a yield of 61.5%, purification factor of 27.0, recovery of 430.7% and specific activity of 600.0U/mg. The recombinant P. fluorescens enzyme was preferentially partitioned into the top PEG-rich phase. NaCl addition decreased greatly the partition coefficient and recovery of ProDH. In addition, the resulting protein pattern by SDS-PAGE demonstrated the adequacy of presented procedure for enzyme recovery. Overall, our data confirmed that the PEG-1000/Na2CO3 aqueous two-phase partitioning combined with refolding and reconstitution can be used as an efficient integrated process for recovery and purification of recombinant ProDH from inclusion bodies in only one step. PMID- 23644497 TI - Determination of N-methylcarbamate pesticides in vegetables by poly(methacrylic acid-co-ethylene glycol dimethacrylate) monolith microextraction coupled with high performance liquid chromatography. AB - A simple, rapid and sensitive method for simultaneous determination of three N methylcarbamate pesticides (carbaryl, pirimicarb, and isoprocarb) in vegetables was developed by coupling polymer monolith microextraction (PMME) to high performance liquid chromatography (HPLC). A poly(methacrylic acid-co-ethylene glycol dimethacrylate) monolith was selected as the extraction medium for PMME. To achieve optimum extraction performance, several parameters were investigated, including desorption solvent, desorption flow rate, sample flow rate, sample volume, sample pH values, inorganic salt and organic solvent content of the sample solution. Under the optimum experimental conditions, the method provides an acceptable linearity (5-5000MUg/kg), low limits of detection (0.36-2.6MUg/kg), good precision (intra-day relative standard deviations<2.53%, inter-day relative standard deviations <6.36%). Finally, the developed method was successfully applied to the determination of N-methylcarbamate pesticides in vegetables, and the trueness was evaluated by recovery experiments. The obtained relative recoveries were in the range of 70.4-98.5%. This PMME method integrates sample extraction, purification, and preconcentration of analytes into one single step and it also has several advantages such as solvent-free extraction, small sample volume, high enrichment, convenience, and flexibility operation. PMID- 23644499 TI - Prion protein (PrP(c)) interacts with histone H3 confirmed by affinity chromatography. AB - The histones including H2a, H2b, H3 and H4 purified from pig liver tissue were immobilized onto Sepharose 4B to create a histone-Sepharose column. During chromatography of cow milk casein by histone-Sepharose column, two isoforms of prion protein (PrP(c)) with 34 and 30kDa molecular mass corresponding to diglycosylated and monoglycosylated PrP(c) respectively were found to be captured by histone ligands. To further verify the interaction between histones and PrP(c), the PrP(c)-Sepharose column was prepared and used to separate the histones. Two chromatography processes and SDS-PAGE demonstrated that only H3 in the histones was found to interact with PrP(c). This study suggested H3 could be the target molecule of PrP(C) in nuclei, which might be useful for understanding the prion disease. PMID- 23644498 TI - Simultaneous determination of ten biogenic amines in a thymopolypeptides injection using ultra-performance liquid chromatography coupled with electrospray ionization tandem quadrupole mass spectrometry. AB - A selective and sensitive ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-MS) method was developed for the simultaneous determination of ten biogenic amines (tryptamine, 2 phenylethylamine, putrescine, cadaverine, histamine, tyramine, spermidine, adrenaline, dopamine and spermine) in a thymopolypeptides injection from the Chinese market for the first time. Biogenic amines (BAs) were pre-column derivatised by dansyl chloride after direct sample dilution. Dansylated amines were separated on an ACQUITY UPLC BEH Shield RP18 column (2.1mm*150mm I.D., 1.7MUm) using a gradient elution. Quantification was done by monitoring fragment ions of each derivative under the MS mode of multiple reaction monitoring (MRM). A satisfactory result of method validation was obtained. The linearity ranged from 0.32 to 1182.9MUg/L and the correlation coefficients (r) for all amines were above 0.99. The LOD ranged from 0.08MUg/L for 2-phenylethylamine and tyramine to 8.00MUg/L for adrenaline; the LOQ ranged from 0.32MUg/L for 2-phenylethylamine to 12.12MUg/L for dopamine. The recovery ranged from 75.8 to 110.3% after spiking standard solutions of BAs to a sample at three levels. The intra and inter-day precision RSD were 0.78-8.85% and 1.39-9.93% respectively. Eighty-four injections were analyzed by this method. Nine biogenic amines were found in them except adrenaline. Moreover, the relationship between the result of test for depressor substances and the content of BAs was statistically analyzed. PMID- 23644500 TI - Determination of acyl-CoA esters and acyl-CoA synthetase activity in mouse brain areas by liquid chromatography-electrospray ionization-tandem mass spectrometry. AB - The acyl-CoA levels and the acyl-CoA synthetase activities in 7 areas of mouse brain were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry. Twenty-one acyl-CoA esters of C2:0, C4:0, C6:0, C8:0, C10:0, C12:0, C14:1, C14:0, C16:0, C16:1, C18:0, C18:1, C18:2, C18:3, C20:0, C20:4, C20:5, C22:0, C22:5, C22:6 and C24:0 were detected in the olfactory bulb, cerebral cortex, hippocampus, cerebellum, hypothalamus, midbrain and medulla oblongata. The brain areas contained primarily the acyl-CoAs of the C16:0, C18:0, C18:1, C20:4 and C22:6 species. The relative abundances of the acyl-CoAs of C16:0, C18:0 and C18:1 were considerably higher than those of C20:4 and C22:6. The levels of medium-chain acyl-CoAs were only 1.2% that of the long-chain acyl CoAs. The differences in the acyl-CoA synthetase activities in each area of mouse brain were less dramatic. The order of the acyl-CoA synthetase activities for fatty acids of different chain lengths was palmitic acid>arachidonic acid>docosahexaenoic acid>octanoic acid. The analytical method proved to be very useful for the analysis of the acyl-CoA profile of tissues. Our results have important implications for understanding the regulation of acyl-CoA synthetase activity and long-chain fatty acid turnover in the phospholipids in the brain. PMID- 23644502 TI - Does suppression of VEGF alone lead to clinical recovery in POEMS syndrome? PMID- 23644501 TI - Clinical relevance and practical implications of trials of perfusion and angiographic imaging in patients with acute ischaemic stroke: a multicentre cohort imaging study. AB - BACKGROUND: In randomised trials testing treatments for acute ischaemic stroke, imaging markers of tissue reperfusion and arterial recanalisation may provide early response indicators. OBJECTIVE: To determine the predictive value of structural, perfusion and angiographic imaging for early and late clinical outcomes and assess practicalities in three comprehensive stroke centres. METHODS: We recruited patients with potentially disabling stroke in three stroke centres, performed magnetic resonance (MR) or CT, including perfusion and angiography imaging, within 6 h, at 72 h and 1 month after stroke. We assessed the National Institutes of Health Stroke Scale (NIHSS) score serially and functional outcome at 3 months, tested associations between clinical variables and structural imaging, several perfusion parameters and angiography. RESULTS: Among 83 patients, median age 71 (maximum 89), median NIHSS 7 (range 1-30), 38 (46%) received alteplase, 41 (49%) had died or were dependent at 3 months. Most baseline imaging was CT (76%); follow-up was MR (79%) despite both being available acutely. At presentation, perfusion lesion size varied considerably between parameters (p<0.0001); 40 (48%) had arterial occlusion. Arterial occlusion and baseline perfusion lesion extent were both associated with baseline NIHSS (p<0.0001). Recanalisation by 72 h was associated with 1 month NIHSS (p=0.0007) and 3 month functional outcome (p=0.048), whereas tissue reperfusion, using even the best perfusion parameter, was not (p=0.11, p=0.08, respectively). CONCLUSION: Early recanalisation on angiography appeared to predict clinical outcome more directly than did tissue reperfusion. Acute assessment with CT and follow-up with MR was practical and feasible, did not preclude image analysis, and would enhance trial recruitment and generalisability of results. PMID- 23644503 TI - Participants' perspectives on safety monitoring in clinical trials. AB - BACKGROUND: Minimizing the risk to study participants is an essential requirement of ethical research. Respecting the rights of subjects is also paramount, which includes respecting their autonomy by making available important information about the evolving safety profile of an investigational product as the trial progresses. Little is known about what trial participants understand and expect regarding monitoring and communication of serious adverse events during the conduct of a trial in which they have agreed to participate. PURPOSE: To explore understanding and expectations of potential trial participants concerning monitoring and communication of serious adverse events during a clinical trial. METHODS: A professional moderator led four 90-min, in-person focus groups: two groups with individuals who had never participated in a clinical trial and two groups with people who had. After relevant research terms were defined and existing regulations were explained, discussion focused on how participants expected safety to be monitored and communicated during the conduct of a clinical trial. Group comments were video-recorded and transcribed and then analyzed by the investigators. RESULTS: The 27 racially diverse focus group members were largely unaware of existing safeguards and regulations to manage risk in clinical trials. Many people expressed a desire for increased transparency about serious adverse events during the trial as well as shortened reporting deadlines. Focus group members also spontaneously expressed concerns about potential financial conflicts of interest in monitoring and reporting serious adverse events. LIMITATIONS: This was a single-site, qualitative study and is not meant to establish the prevalence of beliefs. CONCLUSIONS: Potential trial participants have limited understanding and a wide range of expectations about how safety monitoring in clinical trials should be managed and communicated. The overall tenor of opinion suggests unease about participant safety and a desire to have more information conveyed by sponsors to investigators and, in some cases, by investigators to participants. Additional study in other regions and settings may be useful to more broadly explore the range of participants' beliefs and expectations. In the meantime, engaging patient advocates in the design of clinical trials and clearly communicating to trial participants the plan for oversight of their safety may help ease the types of concerns expressed in this study. PMID- 23644504 TI - Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways. AB - Natural T helper 17 (nTH17) cells are a population of interleukin 17 (IL-17) producing cells that acquire effector function in the thymus during development. Here we demonstrate that the serine/threonine kinase Akt has a critical role in regulating nTH17 cell development. Although Akt and the downstream mTORC1-ARNT HIFalpha axis were required for generation of inducible TH17 (iTH17) cells, nTH17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for development of nTH17 cells. Moreover, distinct isoforms of Akt controlled the generation of TH17 cell subsets, as deletion of Akt2, but not of Akt1, led to defective generation of iTH17 cells. These findings define mechanisms regulating nTH17 cell development and reveal previously unknown roles of Akt and mTOR in shaping subsets of T cells. PMID- 23644505 TI - Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function. AB - Phagocytosis is a fundamental cellular process that is pivotal for immunity as it coordinates microbial killing, innate immune activation and antigen presentation. An essential step in this process is phagosome acidification, which regulates many functions of these organelles that allow phagosomes to participate in processes that are essential to both innate and adaptive immunity. Here we report that acidification of phagosomes containing Gram-positive bacteria is regulated by the NLRP3 inflammasome and caspase-1. Active caspase-1 accumulates on phagosomes and acts locally to control the pH by modulating buffering by the NADPH oxidase NOX2. These data provide insight into a mechanism by which innate immune signals can modify cellular defenses and establish a new function for the NLRP3 inflammasome and caspase-1 in host defense. PMID- 23644506 TI - T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. AB - During chronic infection, pathogen-specific CD8(+) T cells upregulate expression of molecules such as the inhibitory surface receptor PD-1, have diminished cytokine production and are thought to undergo terminal differentiation into exhausted cells. Here we found that T cells with memory-like properties were generated during chronic infection. After transfer into naive mice, these cells robustly proliferated and controlled a viral infection. The reexpanded T cell populations continued to have the exhausted phenotype they acquired during the chronic infection. Thus, the cells underwent a form of differentiation that was stably transmitted to daughter cells. We therefore propose that during persistent infection, effector T cells stably differentiate into a state that is optimized to limit viral replication without causing overwhelming immunological pathology. PMID- 23644508 TI - New potential cell source for hepatocyte transplantation: discarded livers from metabolic disease liver transplants. AB - Domino liver transplantation is a method used to increase the number of liver grafts available for orthotopic liver transplantation (OLT). Reports indicate that livers from patients with metabolic liver disease can be safely transplanted into select recipients if the donor's defect and the recipient's metabolic needs are carefully considered. The liver of patients with many types of metabolic liver disease is morphologically and biochemically normal, except for the mutation that characterizes that disease. Other biochemical functions normally performed by the liver are present and presumably "normal" in these hepatocytes. Hepatocytes were isolated from the liver of 35 organ donors and 35 liver tissues taken at OLT from patients with liver disease were analyzed for 9 different measures of viability and function. The data indicate that cells isolated from some diseased livers performed as well or better than those isolated from organ donors with respect to viability, cell yield, plating efficiency and in assays of liver function, including drug metabolism, conjugation reactions and ammonia metabolism. Cells from metabolic diseased livers rapidly and efficiently repopulated a mouse liver upon transplantation. CONCLUSIONS: As with domino liver transplantation, domino cell transplantation deserves consideration as method to extend the pool of available organs and cells for transplantation. PMID- 23644509 TI - Inhibition of DNA methyltransferases and histone deacetylases induces astrocytic differentiation of neural progenitors. AB - Understanding how to specify rapid differentiation of human neural progenitor towards enriched non-transformed human astrocyte progenitors will provide a critical cell source to further our understanding of how astrocytes play a pivotal role in neural function and development. Human neural progenitors derived from pluripotent embryonic stem cells and propagated in adherent serum-free cultures provide a fate restricted renewable source for quick production of neural cells; however, such cells are highly refractive to astrocytogenesis and show a strong neurogenic bias, similar to neural progenitors from the early embryonic central nervous system (CNS). We found that several astrocytic genes are hypermethylated in such progenitors potentially preventing generation of astrocytes and leading to the proneuronal fate of these progenitors. However, epigenetic modification by Azacytidine (Aza-C) and Trichostatin A (TSA), with concomitant signaling from BMP2 and LIF in neural progenitor cultures shifts this bias, leading to expression of astrocytic markers as early as 5days of differentiation, with near complete suppression of neuronal differentiation. The resultant cells express major astrocytic markers, are amenable to co-culture with neurons, can be propagated as astrocyte progenitors and are cryopreservable. Although previous reports have generated astrocytes from pluripotent cells, the differentiation required extensive culture or selection based on cell surface antigens. The development of a label free and rapid differentiation process will expedite future derivation of astrocytes from various sources pluripotent cells including, but not limited to, human astrocytes associated with various neurological diseases. PMID- 23644507 TI - The transcriptional landscape of alphabeta T cell differentiation. AB - The differentiation of alphabetaT cells from thymic precursors is a complex process essential for adaptive immunity. Here we exploited the breadth of expression data sets from the Immunological Genome Project to analyze how the differentiation of thymic precursors gives rise to mature T cell transcriptomes. We found that early T cell commitment was driven by unexpectedly gradual changes. In contrast, transit through the CD4(+)CD8(+) stage involved a global shutdown of housekeeping genes that is rare among cells of the immune system and correlated tightly with expression of the transcription factor c-Myc. Selection driven by major histocompatibility complex (MHC) molecules promoted a large-scale transcriptional reactivation. We identified distinct signatures that marked cells destined for positive selection versus apoptotic deletion. Differences in the expression of unexpectedly few genes accompanied commitment to the CD4(+) or CD8(+) lineage, a similarity that carried through to peripheral T cells and their activation, demonstrated by mass cytometry phosphoproteomics. The transcripts newly identified as encoding candidate mediators of key transitions help define the 'known unknowns' of thymocyte differentiation. PMID- 23644510 TI - Large-scale global identification of protein lysine methylation in vivo. AB - Lysine methylation mediated by methyltransferase enzymes is present on multiple proteins throughout the cell; however, methods to uncover and characterize global protein lysine methylation patterns do not readily exist. Here we developed pan specific methyl lysine antibodies that we utilized in immunoprecipitation experiments coupled with mass spectrometry to yield one of the first large-scale surveys of protein lysine methylation in vivo. In total, 552 different lysine methylation sites were determined, making this one of the most comprehensive global studies published to date. The large majority of these sites have not been yet reported. These sites showed significantly enriched sequence motifs and resided in proteins that are involved in diverse biological processes, particularly in chromatin organization. Our data provide a comprehensive view of lysine methylation in human cells and a powerful resource to facilitate investigations into the function of lysine methylation on non-histone proteins. PMID- 23644511 TI - Male wing color properties predict the size of nuptial gifts given during mating in the Pipevine Swallowtail butterfly (Battus philenor). AB - In many animals, males bear bright ornamental color patches that may signal both the direct and indirect benefits that a female might accrue from mating with him. Here we test whether male coloration in the Pipevine Swallowtail butterfly, Battus philenor, predicts two potential direct benefits for females: brief copulation duration and the quantity of materials the male passes to the female during mating. In this species, males have a bright iridescent blue field on the dorsal hindwing surface, while females have little or no dorsal iridescence. Females preferentially mate with males who display a bright and highly chromatic blue field on their dorsal hindwing. In this study, we show that the chroma of the blue field on the male dorsal hindwing and male body size (forewing length) significantly predict the mass of material or spermatophore that a male forms within the female's copulatory sac during mating. We also found that spermatophore mass correlated negatively with copulation duration, but that color variables did not significantly predict this potential direct benefit. These results suggest that females may enhance the material benefits they receive during mating by mating with males based on the coloration of their dorsal hindwing. PMID- 23644512 TI - From repulsion to attraction: species- and spatial context-dependent threat sensitive response of the spider mite Tetranychus urticae to predatory mite cues. AB - Prey perceiving predation risk commonly change their behavior to avoid predation. However, antipredator strategies are costly. Therefore, according to the threat sensitive predator avoidance hypothesis, prey should match the intensity of their antipredator behaviors to the degree of threat, which may depend on the predator species and the spatial context. We assessed threat sensitivity of the two spotted spider mite, Tetranychus urticae, to the cues of three predatory mites, Phytoseiulus persimilis, Neoseiulus californicus, and Amblyseius andersoni, posing different degrees of risk in two spatial contexts. We first conducted a no choice test measuring oviposition and activity of T. urticae exposed to chemical traces of predators or traces plus predator eggs. Then, we tested the site preference of T. urticae in choice tests, using artificial cages and leaves. In the no-choice test, T. urticae deposited their first egg later in the presence of cues of P. persimilis than of the other two predators and cue absence, indicating interspecific threat-sensitivity. T. urticae laid also fewer eggs in the presence of cues of P. persimilis and A. andersoni than of N. californicus and cue absence. In the artificial cage test, the spider mites preferred the site with predator traces, whereas in the leaf test, they preferentially resided on leaves without traces. We argue that in a nonplant environment, chemical predator traces do not indicate a risk for T. urticae, and instead, these traces function as indirect habitat cues. The spider mites were attracted to these cues because they associated them with the existence of a nearby host plant. PMID- 23644513 TI - Physical limitation and emotional well-being: gender and marital status variations. AB - Despite the proliferation of studies documenting the relationship between physical limitation and depressive symptoms in the United States, we currently do not know (1) whether physical impairment is associated with other dimensions of emotional well-being and (2) if these associations differ for men and women as well as married and nonmarried adults. We use panel data from two national samples to examine gender and marital status variations in the impact of physical limitation on four indicators of mental health. We find that physical limitation is associated with increases in depressive symptoms and negative feelings as well as decreases in positive emotions. Although the patterns are complex, we also find gender and marital status differences in these associations. Our results provide additional support for Aneshensel's (1992; Aneshensel, Rutter, and Lachenbruch 1991) argument about the highly contingent nature of stress reactivity and contribute to theory about both gender and marital status differences in the impact of stress on mental health. PMID- 23644514 TI - Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. AB - Anticancer chemotherapy drugs challenge hematopoietic tissues to regenerate but commonly produce long-term sequelae. Chemotherapy-induced deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes substantial sensory neuropathy. Here we demonstrate that chemotherapy-induced nerve injury in the bone marrow of mice is a crucial lesion impairing hematopoietic regeneration. Using pharmacological and genetic models, we show that the selective loss of adrenergic innervation in the bone marrow alters its regeneration after genotoxic insult. Sympathetic nerves in the marrow promote the survival of constituents of the stem cell niche that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuroregeneration by administration of 4-methylcatechol or glial-derived neurotrophic factor (GDNF) promotes hematopoietic recovery. These results demonstrate the potential benefit of adrenergic nerve protection for shielding hematopoietic niches from injury. PMID- 23644515 TI - Astrocyte-derived ATP modulates depressive-like behaviors. AB - Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a Gq G protein-coupled receptor only in astrocytes to enable selective activation of astrocytic Ca(2+) signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD. PMID- 23644516 TI - Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. AB - Substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor infiltrating lymphocytes (TILs) in phase 2 clinical trials. In addition, 40% of patients treated in a recent trial experienced complete regressions of all measurable lesions for at least 5 years following TIL treatment. To evaluate the potential association between the ability of TILs to mediate durable regressions and their ability to recognize potent antigens that presumably include mutated gene products, we developed a new screening approach involving mining whole-exome sequence data to identify mutated proteins expressed in patient tumors. We then synthesized and evaluated candidate mutated T cell epitopes that were identified using a major histocompatibility complex-binding algorithm for recognition by TILs. Using this approach, we identified mutated antigens expressed on autologous tumor cells that were recognized by three bulk TIL lines from three individuals with melanoma that were associated with objective tumor regressions following adoptive transfer. This simplified approach for identifying mutated antigens recognized by T cells avoids the need to generate and laboriously screen cDNA libraries from tumors and may represent a generally applicable method for identifying mutated antigens expressed in a variety of tumor types. PMID- 23644517 TI - [Malignant biliary obstruction, general review and clinical practice]. AB - This review recalls the clinical, anatomic, physiopathological and etiological features necessary in the management of patients with neoplastic bile duct obstruction and exposes the current practice concerning endoscopic and radiologic palliative drainage. Clinical practice according to the clinical situations is explained. This review exposes complications management for patients having undergone an endoscopic or percutaneous drainage of the biliary ducts, the particular case of periportal stenosis, the respective indications of endoscopic and transhepatic percutaneous drainage, usual immediate evolution according to the type of the stenosis and the technique used as well as the management in case of stent obstruction. PMID- 23644519 TI - The first multituberculate mammal from India. AB - Mesozoic deposits of the former Gondwanaland are depauperate in early mammals, in general, and multituberculate mammals, in particular. Until now, the oldest multituberculate mammals known from the Gondwanan continents come from the Early Cretaceous of Morocco, NW Africa. Here, we report the presence of a new multituberculate mammal, Indobaatar zofiae gen. et sp. nov., from the Lower/Middle Jurassic Kota Formation, Pranhita-Godavari valley in peninsular India. This is the first record of a multituberculate from the Mesozoic rocks of India and possibly predates the oldest known multituberculates from Gondwanan continents. The new specimen, representing an upper premolar (P(4)), compares well with the upper premolar morphology of Eobaatariinae multituberculates known from the Early Cretaceous of Mongolia, China, England, and Spain. Together with the recent findings of cimolodontan multituberculates from the Early Cretaceous of Australia and Late Cretaceous of South America, the new discovery indicates a wide temporal and spatial distribution for multituberculate mammals in the former Gondwanaland. PMID- 23644518 TI - Aberrant promoter hypermethylation of PBRM1, BAP1, SETD2, KDM6A and other chromatin-modifying genes is absent or rare in clear cell RCC. AB - Recent sequencing studies of clear cell (conventional) renal cell carcinoma (ccRCC) have identified inactivating point mutations in the chromatin-modifying genes PBRM1, KDM6A/UTX, KDM5C/JARID1C, SETD2, MLL2 and BAP1. To investigate whether aberrant hypermethylation is a mechanism of inactivation of these tumor suppressor genes in ccRCC, we sequenced the promoter region within a bona fide CpG island of PBRM1, KDM6A, SETD2 and BAP1 in bisulfite-modified DNA of a representative series of 50 primary ccRCC, 4 normal renal parenchyma specimens and 5 RCC cell lines. We also interrogated the promoter methylation status of KDM5C and ARID1A in the Cancer Genome Atlas (TCGA) ccRCC Infinium data set. PBRM1, KDM6A, SETD2 and BAP1 were unmethylated in all tumor and normal specimens. KDM5C and ARID1A were unmethylated in the TCGA 219 ccRCC and 119 adjacent normal specimens. Aberrant promoter hypermethylation of PBRM1, BAP1 and the other chromatin-modifying genes examined here is therefore absent or rare in ccRCC. PMID- 23644521 TI - H2 evolution at Si-based metal-insulator-semiconductor photoelectrodes enhanced by inversion channel charge collection and H spillover. AB - Photoelectrochemical (PEC) water splitting represents a promising route for renewable production of hydrogen, but trade-offs between photoelectrode stability and efficiency have greatly limited the performance of PEC devices. In this work, we employ a metal-insulator-semiconductor (MIS) photoelectrode architecture that allows for stable and efficient water splitting using narrow bandgap semiconductors. Substantial improvement in the performance of Si-based MIS photocathodes is demonstrated through a combination of a high-quality thermal SiO2 layer and the use of bilayer metal catalysts. Scanning probe techniques were used to simultaneously map the photovoltaic and catalytic properties of the MIS surface and reveal the spillover-assisted evolution of hydrogen off the SiO2 surface and lateral photovoltage driven minority carrier transport over distances that can exceed 2 cm. The latter finding is explained by the photo- and electrolyte-induced formation of an inversion channel immediately beneath the SiO2/Si interface. These findings have important implications for further development of MIS photoelectrodes and offer the possibility of highly efficient PEC water splitting. PMID- 23644520 TI - Negative correlation between nuptial throat colour and blood parasite load in male European green lizards supports the Hamilton-Zuk hypothesis. AB - During female mate choice, conspicuous male sexual signals are used to infer male quality and choose the best sire for the offspring. The theory of parasite mediated sexual selection (Hamilton-Zuk hypothesis) presumes that parasite infection can influence the elaboration of sexual signals: resistant individuals can invest more energy into signal expression and thus advertise their individual quality through signal intensity. By preferring these males, females can provide resistance genes for their offspring. Previous research showed that nuptial throat colour of male European green lizard, Lacerta viridis, plays a role in both inter- and intrasexual selections as a condition-dependent multiple signalling system. The aim of this study was to test the predictions of the Hamilton-Zuk hypothesis on male European green lizards. By blood sampling 30 adult males during the reproductive season, we found members of the Haemogregarinidae family in all but one individual (prevalence = 96%). The infection intensity showed strong negative correlation with the throat and belly colour brightness in line with the predictions of the Hamilton-Zuk hypothesis. In addition, we found other correlations between infection intensity and other fitness-related traits, suggesting that parasite load has a remarkable effect on individual fitness. This study shows that throat patch colour of the European green lizards not only is a multiple signalling system but also possibly acts as an honest sexual signal of health state in accordance with the Hamilton-Zuk hypothesis. PMID- 23644522 TI - Engineered doping of organic semiconductors for enhanced thermoelectric efficiency. AB - Significant improvements to the thermoelectric figure of merit ZT have emerged in recent years, primarily due to the engineering of material composition and nanostructure in inorganic semiconductors (ISCs). However, many present high-ZT materials are based on low-abundance elements that pose challenges for scale-up, as they entail high material costs in addition to brittleness and difficulty in large-area deposition. Here we demonstrate a strategy to improve ZT in conductive polymers and other organic semiconductors (OSCs) for which the base elements are earth-abundant. By minimizing total dopant volume, we show that all three parameters constituting ZT vary in a manner so that ZT increases; this stands in sharp contrast to ISCs, for which these parameters have trade-offs. Reducing dopant volume is found to be as important as optimizing carrier concentration when maximizing ZT in OSCs. Implementing this strategy with the dopant poly(styrenesulphonate) in poly(3,4-ethylenedioxythiophene), we achieve ZT = 0.42 at room temperature. PMID- 23644523 TI - Grains and grain boundaries in highly crystalline monolayer molybdenum disulphide. AB - Recent progress in large-area synthesis of monolayer molybdenum disulphide, a new two-dimensional direct-bandgap semiconductor, is paving the way for applications in atomically thin electronics. Little is known, however, about the microstructure of this material. Here we have refined chemical vapour deposition synthesis to grow highly crystalline islands of monolayer molybdenum disulphide up to 120 MUm in size with optical and electrical properties comparable or superior to exfoliated samples. Using transmission electron microscopy, we correlate lattice orientation, edge morphology and crystallinity with island shape to demonstrate that triangular islands are single crystals. The crystals merge to form faceted tilt and mirror twin boundaries that are stitched together by lines of 8- and 4-membered rings. Density functional theory reveals localized mid-gap states arising from these 8-4 defects. We find that mirror twin boundaries cause strong photoluminescence quenching whereas tilt boundaries cause strong enhancement. Meanwhile, mirror twin boundaries slightly increase the measured in-plane electrical conductivity, whereas tilt boundaries slightly decrease the conductivity. PMID- 23644524 TI - A transparent organic transistor structure for bidirectional stimulation and recording of primary neurons. AB - Real-time stimulation and recording of neural cell bioelectrical activity could provide an unprecedented insight in understanding the functions of the nervous system, and it is crucial for developing advanced in vitro drug screening approaches. Among organic materials, suitable candidates for cell interfacing can be found that combine long-term biocompatibility and mechanical flexibility. Here, we report on transparent organic cell stimulating and sensing transistors (O-CSTs), which provide bidirectional stimulation and recording of primary neurons. We demonstrate that the device enables depolarization and hyperpolarization of the primary neuron membrane potential. The transparency of the device also allows the optical imaging of the modulation of the neuron bioelectrical activity. The maximal amplitude-to-noise ratio of the extracellular recording achieved by the O-CST device exceeds that of a microelectrode array system on the same neuronal preparation by a factor of 16. Our organic cell stimulating and sensing device paves the way to a new generation of devices for stimulation, manipulation and recording of cell bioelectrical activity in vitro and in vivo. PMID- 23644525 TI - Solution-processed organic spin-charge converter. AB - Conjugated polymers and small organic molecules are enabling new, flexible, large area, low-cost optoelectronic devices, such as organic light-emitting diodes, transistors and solar cells. Owing to their exceptionally long spin lifetimes, these carbon-based materials could also have an important impact on spintronics, where carrier spins play a key role in transmitting, processing and storing information. However, to exploit this potential, a method for direct conversion of spin information into an electric signal is indispensable. Here we show that a pure spin current can be produced in a solution-processed conducting polymer by pumping spins through a ferromagnetic resonance in an adjacent magnetic insulator, and that this generates an electric voltage across the polymer film. We demonstrate that the experimental characteristics of the generated voltage are consistent with it being generated through an inverse spin Hall effect in the conducting polymer. In contrast with inorganic materials, the conducting polymer exhibits coexistence of high spin-current to charge-current conversion efficiency and long spin lifetimes. Our discovery opens a route for a new generation of molecular-structure-engineered spintronic devices, which could lead to important advances in plastic spintronics. PMID- 23644526 TI - [New advances in the management of thoracolumbar spine metastasis]. AB - Vertebral metastases affect 20 to 50% of cancer patients and represent a major turning point in the disease from the functional impact they generate. Early treatment is mandatory to prevent or treat any neurological compression. Due to the high variability of clinical and radiological presentations, best care requires a multidisciplinary team, involving oncologists, radiation oncologists, interventional radiologists and spine surgeons. Recent advances in radiotherapy and interventional radiology have offered various efficient therapeutic solutions with relatively low morbidity rate in the management of symptomatic spine metastases. However, surgery remains the standard treatment for patients with rapidly progressive spinal cord compression or significant osteolytic lesion leading to a high risk of fracture. However, conventional surgical strategies are associated with significant morbidity and contraindicated in patients in poor general condition. In addition, postoperative complications are likely to affect patient's quality of life and delay the initiation of anticancer therapies. In order to reduce iatrogenic lesions, new "minimally invasive" techniques were developed to achieve immediate stabilisation and decompression while reducing the morbidity of the approach. We aim to inform the reader of the existence of these techniques so that each patient can benefit from treatment best suited to their situation. PMID- 23644527 TI - CIP4 controls CCL19-driven cell steering and chemotaxis in chronic lymphocytic leukemia. AB - Solid tumor dissemination relies on the reprogramming of molecular pathways controlling chemotaxis. Whether the motility of nonsolid tumors such as leukemia depends on the deregulated expression of molecules decoding chemotactic signals remains an open question. We identify here the membrane remodeling F-BAR adapter protein Cdc42-interacting protein 4 (CIP4) as a key regulator of chemotaxis in chronic lymphocytic leukemia (CLL). CIP4 is expressed at abnormally high levels in CLL cells, where it is required for CCL19-induced chemotaxis. Upon CCL19 stimulation of CLL cells, CIP4 associates with GTP-bound Cdc42 and is recruited to the rear of the lamellipodium and along microspikes radiating through the lamellipodium. Consistent with its cellular distribution, CIP4 removal impairs both the assembly of the polarized lamellipodium and directional migration along a diffusible CCL19 gradient. Furthermore, CIP4 depletion results in decreased activation of WASP, but increased activation of PAK1 and p38 mitogen-activated protein kinase (MAPK). Notably, p38 MAPK inhibition results in impaired lamellipodium assembly and loss of directional migration. This suggests that CIP4 modulates both the WASP and p38 MAPK pathways to promote lamellipodium assembly and chemotaxis. Overall, our study reveals a critical role of CIP4 in mediating chemotaxis of CLL cells by controlling the dynamics of microspike-containing protrusions and cell steering. PMID- 23644528 TI - KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. AB - Lysine methylation is one of the most prominent histone posttranslational modifications that regulate chromatin structure. Changes in histone lysine methylation status have been observed during cancer formation, which is thought to be a consequence of the dysregulation of histone lysine methyltransferases or the opposing demethylases. KDM4/JMJD2 proteins are demethylases that target histone H3 on lysines 9 and 36 and histone H1.4 on lysine 26. This protein family consists of three ~130-kDa proteins (KDM4A-C) and KDM4D/JMJD2D, which is half the size, lacks the double PHD and Tudor domains that are epigenome readers and present in the other KDM4 proteins, and has a different substrate specificity. Various studies have shown that KDM4A/JMJD2A, KDM4B/JMJD2B, and/or KDM4C/JMJD2C are overexpressed in breast, colorectal, lung, prostate, and other tumors and are required for efficient cancer cell growth. In part, this may be due to their ability to modulate transcription factors such as the androgen and estrogen receptor. Thus, KDM4 proteins present themselves as novel potential drug targets. Accordingly, multiple attempts are under way to develop KDM4 inhibitors, which could complement the existing arsenal of epigenetic drugs that are currently limited to DNA methyltransferases and histone deacetylases. PMID- 23644529 TI - AMPK: a contextual oncogene or tumor suppressor? AB - The AMP-activated protein kinase (AMPK) functions to monitor and maintain energy homeostasis at the cellular and organism level. AMPK was perceived historically primarily as a component of the LKB1/STK11 tumor suppressor (LKB1 mutations cause the Peutz-Jegher cancer predisposition syndrome) cascade upstream of the TSC1/2/mTOR pathway and thus likely to be a tumor suppressor. However, AMPK has recently been shown to promote cancer cell survival in the face of extrinsic and intrinsic stressors including bioenergetic, growth factor, and oncogene stress compatible with studies showing that AMPK is required for oncogenic transformation. Thus, whether AMPK acts as a bona fide tumor suppressor or a contextual oncogene and, of particular importance, whether AMPK should be targeted for activation or inhibition during cancer therapy, is controversial and requires clarification. We aim to initiate discussions of these critical questions by reviewing the role of AMPK with an emphasis on cancer cell adaptation to microenvironment stress and therapeutic intervention. PMID- 23644530 TI - beta1 integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma. AB - Antiangiogenic therapies like bevacizumab offer promise for cancer treatment, but acquired resistance, which often includes an aggressive mesenchymal phenotype, can limit the use of these agents. Upregulation of beta1 integrin (ITGB1) occurs in some bevacizumab-resistant glioblastomas (BRG) whereby, mediating tumor microenvironment interactions, we hypothesized that it may mediate a mesenchymal type resistance to antiangiogenic therapy. Immunostaining analyses of beta1 integrin and its downstream effector kinase FAK revealed upregulation in 75% and 86% of BRGs, respectively, compared with pretreatment paired specimens. Furthermore, flow cytometry revealed eight-fold more beta1 integrin in primary BRG cells compared with cells from bevacizumab-naive glioblastomas (BNG). Fluorescence recovery after photobleaching of cells engineered to express a beta1 GFP fusion protein indicated that the mobile beta1 integrin fraction was doubled, and half-life of beta1 integrin turnover in focal adhesions was reduced markedly in BRG cells compared with bevacizumab-responsive glioblastoma multiforme cells. Hypoxia, which was increased with acquisition of bevacizumab resistance, was associated with increased beta1 integrin expression in cultured BNG cells. BRGs displayed an aggressive mesenchymal-like phenotype in vitro. We found that growth of BRG xenograft tumors was attenuated by the beta1 antibody, OS2966, allowing a 20-fold dose reduction of bevacizumab per cycle in this model. Intracranial delivery of OS2966 through osmotic pumps over 28 days increased tumor cell apoptosis, decreased tumor cell invasiveness, and blunted the mesenchymal morphology of tumor cells. We concluded that beta1 integrin upregulation in BRGs likely reflects an onset of hypoxia caused by antiangiogenic therapy, and that beta1 inhibition is well tolerated in vivo as a tractable strategy to disrupt resistance to this therapy. PMID- 23644532 TI - Neurological picture. Injury of the oculomotor nerve in a patient with traumatic brain injury: diffusion tensor tractography study. PMID- 23644533 TI - Neurological picture. Successful outcome after traumatic rupture and secondary thrombosis of the superior sagittal sinus. PMID- 23644536 TI - Pedestrian injuries due to mobile phone use in public places. AB - Research shows that pedestrians, similar to drivers, experience reduced situation awareness, distracted attention and unsafe behavior when talking or texting on their mobile phones. The present study centered on injuries related to mobile phone use among pedestrians. It used data from the US Consumer Product Safety Commission on injuries in hospital emergency rooms from 2004 through 2010. It found that mobile-phone related injuries among pedestrians increased relative to total pedestrian injuries, and paralleled the increase in injuries for drivers, and in 2010 exceeded those for drivers. Pedestrian injuries related to mobile phone use were higher for males and for people under 31 years old. Using a mobile phone while walking puts pedestrians at risk of accident, injury or death. PMID- 23644531 TI - Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor alphaSu/Fc fusion complex in syngeneic murine models of multiple myeloma. AB - ALT-803, a complex of an interleukin (IL)-15 superagonist mutant and a dimeric IL 15 receptor alphaSu/Fc fusion protein, was found to exhibit significantly stronger in vivo biologic activity on NK and T cells than IL-15. In this study, we show that a single dose of ALT-803, but not IL-15 alone, eliminated well established 5T33P and MOPC-315P myeloma cells in the bone marrow of tumor-bearing mice. ALT-803 treatment also significantly prolonged survival of myeloma-bearing mice and provided resistance to rechallenge with the same tumor cells through a CD8(+) T-cell-dependent mechanism. ALT-803 treatment stimulated CD8(+) T cells to secrete large amounts of IFN-gamma and promoted rapid expansion of CD8(+)CD44(high) memory T cells in vivo. These memory CD8(+) T cells exhibited ALT-803-mediated upregulation of NKG2D (KLRK1) but not PD-1 (PDCD1) or CD25 (IL2RA) on their cell surfaces. ALT-803-activated CD8(+) memory T cells also exhibited nonspecific cytotoxicity against myeloma and other tumor cells in vitro, whereas IFN-gamma had no direct effect on myeloma cell growth. ALT-803 lost its antimyeloma activity in tumor-bearing IFN-gamma knockout mice but retained the ability to promote CD8(+)CD44(high) memory T-cell proliferation, indicating that ALT-803-mediated stimulation of CD8(+)CD44(high) memory T cells is IFN-gamma-independent. Thus, besides well-known IL-15 biologic functions in host immunity, this study shows that IL-15-based ALT-803 could activate CD8(+)CD44(high) memory T cells to acquire a unique innate-like phenotype and secrete IFN-gamma for nonspecific tumor cell killing. This unique immunomodulatory property of ALT-803 strongly supports its clinical development as a novel immunotherapeutic agent against cancer and viral infections. PMID- 23644537 TI - The neuroanatomical phenotype of tuberous sclerosis complex: focus on radial migration lines. AB - INTRODUCTION: The contribution of radial migration lines (RMLs) to the neuroanatomical and neurocognitive phenotype of tuberous sclerosis complex (TSC) is unclear. The aim of this study was to perform a comprehensive evaluation of the neuroradiological phenotype of TSC, distinguishing RMLs from normal-appearing white matter (NAWM) using diffusion tensor imaging (DTI) and volumetric fluid attenuated inversion recovery imaging. METHODS: Magnetic resonance images of 30 patients with TSC were evaluated. The frequencies of RMLs, tubers, and subependymal nodules (SENs) were determined for every hemispheric lobe. Cerebellar lesions and subependymal giant cell tumors were counted. DTI metrics were obtained from the NAWM of every hemispheric lobe and from the largest RML and tuber. Analyses of variance and correlations were performed to investigate the associations between neuroanatomical characteristics and relationships between RML frequency and neurocognitive outcomes. NAWM DTI metrics were compared with measurements of 16 control patients. RESULTS: A mean of 47 RMLs, 27 tubers, and 10 SENs were found per patient, and the frequencies of these lesions were strongly correlated (p < 0.001). RML fractional anisotropy and mean diffusivity were strongly inversely correlated (p = 0.003). NAWM DTI metrics were similar to the controls (p = 0.26). RML frequency was strongly associated with age of seizure onset (p = 0.003), intelligence outcomes (p = 0.01), and level of autistic features (p = 0.007). CONCLUSION: A detailed neuroradiological phenotype is presented, showing that RMLs are the most frequent neuroanatomical lesion, are responsible for white matter DTI abnormalities, and are strongly associated with age of seizure onset, intelligence outcomes, and level of autistic features. PMID- 23644538 TI - Predictive factors of outcome and hemorrhage after acute ischemic stroke treated by mechanical thrombectomy with a stent-retriever. AB - INTRODUCTION: The study attempts to identify notable factors predicting poor outcome, death, and intracranial hemorrhage in patients with acute ischemic stroke undergoing mechanical thrombectomy with stent retriever. These data could be useful to improve the selection of patients for thrombectomy. METHODS: Patients with acute ischemic stroke treated with the Solitaire FR device were retrospectively analyzed from a prospectively collected database. We assessed the effect of selected demographic characteristics, clinical and imaging factors on poor outcome at 3 months (modified Rankin score 3-6), mortality at 3 months, and hemorrhage at day 1 (symptomatic and asymptomatic). RESULTS: From May 2010 to April 2012, 59 consecutive patients with an acute ischemic stroke underwent mechanical thrombectomy. At 3 months, 57.6% of the patients were functionally independent (modified Rankin Scale 0-2) and mortality was 20.4%. Multivariate analyses revealed that a thrombus length > 14 mm (p = 0.02; OR 7.55; 95% CI 1.35 42.31) and longer endovascular procedure duration (p = 0.01; OR 1.04; 95% CI 1.01 1.07) were independently associated with poor outcome. A higher baseline Alberta Stroke Program Early CT (ASPECT) score (p = 0.04; OR 0.79 per point; 95% CI 0.63 0.99) and successful recanalization (p = 0.02; OR 0.07; 95% CI 0.01-0.72) were independent predictors of good functional outcome. Baseline ASPECT score (p < 0.01; OR 0.65; 95% CI 0.54-0.78) independently predicted symptomatic intracranial hemorrhage at day 1. CONCLUSION: Absolute baseline ASPECT score reflects early symptomatic hemorrhage risk and functional outcome at 3 months. Thrombus length measured on MRI play an important role on functional outcome at 3 months after thrombectomy. Further analyses are needed to determine its importance in the selection of patients for mechanical thrombectomy. PMID- 23644539 TI - Noncontrast computed tomographic Hounsfield unit evaluation of cerebral venous thrombosis: a quantitative evaluation. AB - INTRODUCTION: Our objective is to determine the utility of noncontrast Hounsfield unit values, Hounsfield unit values corrected for the patient's hematocrit, and venoarterial Hounsfield unit difference measurements in the identification of intracranial venous thrombosis on noncontrast head computed tomography. METHODS: We retrospectively reviewed noncontrast head computed tomography exams performed in both normal patients and those with cerebral venous thrombosis, acquiring Hounsfield unit values in normal and thrombosed cerebral venous structures. Also, we acquired Hounsfield unit values in the internal carotid artery for comparison to thrombosed and nonthrombosed venous structures and compared the venous Hounsfield unit values to the patient's hematocrit. RESULTS: A significant difference is identified between Hounsfield unit values in thrombosed and nonthrombosed venous structures. Applying Hounsfield unit threshold values of greater than 65, a Hounsfield unit to hematocrit ratio of greater than 1.7, and venoarterial difference values greater than 15 alone and in combination, the majority of cases of venous thrombosis are identifiable on noncontrast head computed tomography. CONCLUSION: Absolute Hounsfield unit values, Hounsfield unit to hematocrit ratios, and venoarterial Hounsfield unit value differences are a useful adjunct in noncontrast head computed tomographic evaluation of cerebral venous thrombosis. PMID- 23644541 TI - Acute stroke trials: the elephant in the room. PMID- 23644540 TI - In vivo quantitative whole-brain diffusion tensor imaging analysis of APP/PS1 transgenic mice using voxel-based and atlas-based methods. AB - INTRODUCTION: Diffusion tensor imaging (DTI) has been applied to characterize the pathological features of Alzheimer's disease (AD) in a mouse model, although little is known about whether these features are structure specific. Voxel-based analysis (VBA) and atlas-based analysis (ABA) are good complementary tools for whole-brain DTI analysis. The purpose of this study was to identify the spatial localization of disease-related pathology in an AD mouse model. METHODS: VBA and ABA quantification were used for the whole-brain DTI analysis of nine APP/PS1 mice and wild-type (WT) controls. Multiple scalar measurements, including fractional anisotropy (FA), trace, axial diffusivity (DA), and radial diffusivity (DR), were investigated to capture the various types of pathology. The accuracy of the image transformation applied for VBA and ABA was evaluated by comparing manual and atlas-based structure delineation using kappa statistics. Following the MR examination, the brains of the animals were analyzed for microscopy. RESULTS: Extensive anatomical alterations were identified in APP/PS1 mice, in both the gray matter areas (neocortex, hippocampus, caudate putamen, thalamus, hypothalamus, claustrum, amygdala, and piriform cortex) and the white matter areas (corpus callosum/external capsule, cingulum, septum, internal capsule, fimbria, and optic tract), evidenced by an increase in FA or DA, or both, compared to WT mice (p < 0.05, corrected). The average kappa value between manual and atlas-based structure delineation was approximately 0.8, and there was no significant difference between APP/PS1 and WT mice (p > 0.05). The histopathological changes in the gray matter areas were confirmed by microscopy studies. DTI did, however, demonstrate significant changes in white matter areas, where the difference was not apparent by qualitative observation of a single slice histological specimen. CONCLUSION: This study demonstrated the structure specific nature of pathological changes in APP/PS1 mouse, and also showed the feasibility of applying whole-brain analysis methods to the investigation of an AD mouse model. PMID- 23644542 TI - The sheeping technique or how to avoid exchange maneuvers. AB - INTRODUCTION: The arteries of bifurcation aneurysms are sometimes so angulated or tortuous that an exchange maneuver is necessary to catheterize them with a balloon or stent delivery catheter. Because of the risk of distal wire perforation associated with exchange maneuvers, we sought to find an alternative technique. METHODS: Our experience shows that a microcatheter tends to preferentially follow a previously placed microcatheter, even if the initial catheterization might be challenging. Accessing an artery with two microcatheters simultaneously may thus be an alternative to an exchange maneuver. Because of this tendency for catheters to behave like sheep following one another, we named this method the sheeping technique (ST). The ST consists of (a) first placing a 1.7 French microcatheter into the division branch requiring balloon or stent protection to straighten the course of the arteries in order to facilitate and (b) positioning in the same artery of a larger and stiffer balloon or stent microcatheter. Once the second balloon or stent microcatheter is in place, the first microcatheter can be pulled back and used to coil the aneurysm. RESULTS: Between January 2009 and December 2012, The ST was successfully used in 208/246 procedures (85%). Conversion to an exchange maneuver was necessary in 38/246 (15%). There were no arterial perforations or ischemic events related to the handling of both microcatheters. CONCLUSION: The sheeping technique may improve safety by replacing the need for an exchange maneuver during difficult balloon- or stent-assisted coiling. PMID- 23644543 TI - C. elegans chemotaxis assay. AB - Many organisms use chemotaxis to seek out food sources, avoid noxious substances, and find mates. Caenorhabditis elegans has impressive chemotaxis behavior. The premise behind testing the response of the worms to an odorant is to place them in an area and observe the movement evoked in response to an odorant. Even with the many available assays, optimizing worm starting location relative to both the control and test areas, while minimizing the interaction of worms with each other, while maintaining a significant sample size remains a work in progress (1 10). The method described here aims to address these issues by modifying the assay developed by Bargmann et al.(1). A Petri dish is divided into four quadrants, two opposite quadrants marked "Test" and two are designated "Control". Anesthetic is placed in all test and control sites. The worms are placed in the center of the plate with a circle marked around the origin to ensure that non motile worms will be ignored. Utilizing a four-quadrant system rather than one 2 or two 1 eliminates bias in the movement of the worms, as they are equidistant from test and control samples, regardless of which side of the origin they began. This circumvents the problem of worms being forced to travel through a cluster of other worms to respond to an odorant, which can delay worms or force them to take a more circuitous route, yielding an incorrect interpretation of their intended path. This method also shows practical advantages by having a larger sample size and allowing the researcher to run the assay unattended and score the worms once the allotted time has expired. PMID- 23644544 TI - Immunological and structural remodeling in human papillomavirus-induced warts and Bowen disease. AB - Human papillomavirus-associated warts (HPV-warts) are persistent, evading host immune surveillance. However, these warts sometimes disappear spontaneously, following inflammation. Non-inflamed HPV-warts demonstrated decreased numbers of epidermal Langerhans cells (LCs), low expression levels of MIP3alpha and E cadherin, and no apoptotic cells. In the inflamed HPV-warts, on the other hand, various dendritic cell (DC) subsets and many CD8+ cytotoxic T lymphocytes (CTLs) were recruited in association with epidermal MIP3alpha expression. Many apoptotic keratinocytes were observed in the dermo-epidermal junction. Cellular events were different in HPV-induced Bowen disease (HPV-Bowen): a few LCs were retained in the lesional epidermis, and considerable numbers of B-cells and plasma cells were also observed in the infiltrates, with little or no infiltration of plasmacytoid DCs or dermal/mature DCs. Multiple HPV16-Bowen diseases in the same individuals showed the presence of different sizes of E6/E7-containing cellular transcripts, which indicated that HPV genomes were integrated into the different sites of chromosomes. Toll-like receptor (TLR) 3 was expressed by the lesional keratinocytes even in the non-inflamed HPV-warts, and type 1 interferons (IFNs) were produced in cultured keratinocytes by TLR3 stimulation. HPV-warts are protected from host immune responses and apoptotic signals because they are surrounded by LC-depleted epidermal walls, and viral anti-apoptotic molecules. The up-regulation of epidermal TLR3 signaling might inhibit further HPV spreading. PMID- 23644545 TI - Coexistence of interacting ferromagnetic clusters and small antiferromagnetic clusters in La0.5Ba0.5CoO3. AB - We report detailed dc magnetization and linear and nonlinear ac susceptibility measurements on the hole doped disordered cobaltite La0.5Ba0.5CoO3. Our results show that the magnetically ordered state of the system consists of coexisting non ferromagnetic phases along with percolating ferromagnetic clusters. The percolating ferromagnetic clusters possibly start a magnetic ordering at the Curie temperature of 201.5(5) K. The non-ferromagnetic phases mainly consist of antiferromagnetic clusters with size smaller than the ferromagnetic clusters. Below the Curie temperature the system exhibits an irreversibility in the field cooled and zero field cooled magnetization and a frequency dependence in the peak of ac susceptibility. These dynamical features indicate the possible coexistence of spin-glass phase along with ferromagnetic clusters similar to La(1-x)Sr(x)CoO3 (x >= 0.18), but the absence of field divergence in the third harmonic of ac susceptibility and zero field cooled memory clearly rule out any such possibility. We argue that the spin-glass phase in La(1-x)Sr(x)CoO3 (x >= 0.18) is associated with the presence of incommensurate antiferromagnetic ordering in non-ferromagnetic phases, which is absent in La0.5Ba0.5CoO3. Our analysis shows that the observed dynamical features in La0.5Ba0.5CoO3 may be due to progressive thermal blocking of ferromagnetic clusters, which is further confirmed by Wohlfarth's model of superparamagnetism. The frequency dependence of the peak of ac susceptibility obeys the Vogel-Fulcher law with tau0 ~ 10(-9) s. This together with the existence of an AT-line in H-T space indicates the presence of significant inter-cluster interaction among these ferromagnetic clusters. PMID- 23644546 TI - Live mammalian cell arrays. AB - High-content assays have the potential to drastically increase throughput in cell biology and drug discovery, but handling and culturing large libraries of cells such as primary tumor or cancer cell lines requires expensive, dedicated robotic equipment. We developed a simple yet powerful method that uses contact spotting to generate high-density nanowell arrays of live mammalian cells for the culture and interrogation of cell libraries. PMID- 23644547 TI - Electron counting and beam-induced motion correction enable near-atomic resolution single-particle cryo-EM. AB - In recent work with large high-symmetry viruses, single-particle electron cryomicroscopy (cryo-EM) has achieved the determination of near-atomic-resolution structures by allowing direct fitting of atomic models into experimental density maps. However, achieving this goal with smaller particles of lower symmetry remains challenging. Using a newly developed single electron-counting detector, we confirmed that electron beam-induced motion substantially degrades resolution, and we showed that the combination of rapid readout and nearly noiseless electron counting allow image blurring to be corrected to subpixel accuracy, restoring intrinsic image information to high resolution (Thon rings visible to ~3 A). Using this approach, we determined a 3.3-A-resolution structure of an ~700-kDa protein with D7 symmetry, the Thermoplasma acidophilum 20S proteasome, showing clear side-chain density. Our method greatly enhances image quality and data acquisition efficiency-key bottlenecks in applying near-atomic-resolution cryo-EM to a broad range of protein samples. PMID- 23644548 TI - Nonhybrid, finished microbial genome assemblies from long-read SMRT sequencing data. AB - We present a hierarchical genome-assembly process (HGAP) for high-quality de novo microbial genome assemblies using only a single, long-insert shotgun DNA library in conjunction with Single Molecule, Real-Time (SMRT) DNA sequencing. Our method uses the longest reads as seeds to recruit all other reads for construction of highly accurate preassembled reads through a directed acyclic graph-based consensus procedure, which we follow with assembly using off-the-shelf long-read assemblers. In contrast to hybrid approaches, HGAP does not require highly accurate raw reads for error correction. We demonstrate efficient genome assembly for several microorganisms using as few as three SMRT Cell zero-mode waveguide arrays of sequencing and for BACs using just one SMRT Cell. Long repeat regions can be successfully resolved with this workflow. We also describe a consensus algorithm that incorporates SMRT sequencing primary quality values to produce de novo genome sequence exceeding 99.999% accuracy. PMID- 23644549 TI - The effect of two golimumab doses on radiographic progression in ankylosing spondylitis: results through 4 years of the GO-RAISE trial. AB - OBJECTIVE: To evaluate radiographic progression in patients with ankylosing spondylitis (AS) receiving two different doses of the tumour necrosis factor antagonist golimumab. METHODS: 356 patients with AS were randomly assigned to placebo, or golimumab 50 mg or 100 mg every 4 weeks (wks). At wk16, patients with inadequate response early escaped with blinded dose adjustments (placebo >golimumab 50 mg, 50 mg->100 mg). At wk24, patients still receiving placebo crossed over to golimumab 50 mg. Lateral view radiographs of the cervical/lumbar spine were obtained at wk0, wk104 and wk208, and scored (two blinded readers, modified Stoke AS Spine Score (mSASSS)). Observed data were used for wk104 analyses; missing wk208 scores were linearly extrapolated. RESULTS: Wk104 changes from baseline in mSASSS averaged 1.6+/-4.6 for placebo crossover, 0.9+/-2.7 for 50 mg and 0.9+/-3.9 for 100 mg. By wk208, following golimumab therapy for 3.5-4 years, mean changes in mSASSS were 2.1+/-5.2 for placebo crossover, 1.3+/-4.1 for 50 mg and 2.0+/-5.6 for 100 mg. Less than a third of patients (placebo crossover, 19/66 (28.8%); 50 mg, 29/111 (26.1%); 100 mg, 35/122 (28.7%)) had a definitive change from baseline mSASSS (>2). Less radiographic progression was observed through wk208 in patients without baseline syndesmophytes (0.2 vs 2.8 in patients with >=1 syndesmophyte; p<0.0001) and with baseline C-reactive protein (CRP) levels <=1.5 mg/dl (0.9 vs 2.9 with CRP >1.5 mg/dl; p=0.0004). CONCLUSIONS: No difference in mSASSS change was observed between golimumab 50 mg and 100 mg. The radiographic progression rate remained stable at years 2 and 4, suggesting no acceleration of new bone formation over time. Golimumab-treated AS patients with no syndesmophytes and less systemic inflammation at baseline had considerably less radiographic progression. PMID- 23644550 TI - Hypoxia and hypoxia-inducible factor-1alpha provoke toll-like receptor signalling induced inflammation in rheumatoid arthritis. AB - OBJECTIVES: Hyperplasia of synovial fibroblasts, infiltration with lymphocytes and tissue hypoxia are major characteristics of rheumatoid arthritis (RA). Extensive data support a key role for toll-like receptors (TLRs) in RA. Little is known regarding the impact of hypoxia on TLR-induced inflammation in RA. The aim of this study was to reveal the effects of hypoxia and its regulator, hypoxia inducible factor-1alpha (HIF-1alpha), on the inflammatory response of RA synovial fibroblasts (RASF) to TLR ligands. METHODS: Hypoxia was induced in RASF by incubation with Na2S2O4. TLR3 ligand polyIC, TLR2 ligand peptidoglycan, TLR4 ligand LPS and TLR9 ligand CpG were used to stimulate the cells. Effects of hypoxia on TLR-induced inflammatory mediators were determined by RT-PCR, qPCR and ELISA. Overexpression of HIF-1alpha as well as knocking-down its expression was used to reveal its fundamental role. RASF-induced inflammatory T cell expansion was determined by flow cytometry analysis of T helper (Th)1/Th17 cells, and IFN gamma/IL-17 production by ELISA after RASF/T cell coculture. RESULTS: Hypoxia potentiated the expression of inflammatory cytokines, metalloproteinases and VEGF in RASF stimulated by different TLR ligands, especially polyIC, a synthetic mimic of dsRNA from viruses or apoptotic cells. HIF-1alpha played a fundamental role in this synergy. Moreover, HIF-1alpha overexpression enhanced RASF-mediated expansion of inflammatory Th1 and Th17 cells, leading to proinflammatory IFN gamma and IL-17 production. CONCLUSIONS: Our findings suggest that hypoxia and HIF-1alpha may function in conjunction with TLR-stimulated innate immune responses to drive inflammation in RA. This pathway may serve as a therapeutic target for the disease. PMID- 23644551 TI - Correlations between nailfold microangiopathy severity, finger dermal thickness and fingertip blood perfusion in systemic sclerosis patients. AB - OBJECTIVE: The aim of this study was to identify possible correlations between nailfold microangiopathy severity, finger dermal thickness (DT) and fingertip blood perfusion (FBP) in systemic sclerosis (SSc) patients. METHODS: Fifty-seven SSc patients and 37 healthy subjects were enrolled. All patients were evaluated by nailfold videocapillaroscopy (NVC) to classify and score the severity of microangiopathy. Both modified Rodnan skin score (mRss) and skin high-frequency ultrasound were used to detect finger DT. Laser Doppler flowmetry (LDF) was employed to detect FBP. RESULTS: A positive correlation was found between nailfold microvascular damage severity and both ultrasound-DT (p=0.028) and mRss values (p<0.0001). In particular, both ultrasound-DT and mRss were found progressively higher in patients with 'Early', 'Active' or 'Late' NVC pattern of microangiopathy. A negative correlation was observed between nailfold microvascular damage severity and FBP (p<0.0001), showing the lowest FBP of the patients with more advanced NVC patterns. A negative correlation was observed between FBP, and both ultrasound-DT (p=0.007) and mRss values (p=0.0002). SSc patients showed a higher ultrasound-DT at the level of the fingers, as well as a lower FBP than healthy subjects (p<0.0001). CONCLUSIONS: This study demonstrates a relationship between nailfold microangiopathy severity, DT and FBP in SSc patients. PMID- 23644553 TI - Differentiation of human dermal fibroblasts towards endothelial cells. AB - The ultimate goal of vascular tissue engineering is the production of functional grafts for clinical use. Difficulties acquiring autologous endothelial cells have motivated the search for alternative cell sources. Differentiation of dermal fibroblasts towards several mesenchymal lineages as well as endothelial cells has been proposed. The aim of the present study was to investigate the endothelial differentiation capacity of human dermal fibroblasts on a gene expression, protein expression and functional physiological level. Endothelial differentiation of fibroblasts was induced by culturing cells in 30% human serum, but not in fetal calf serum. Expression of proteins and genes relevant for endothelial function and differentiation was increased after induction. Furthermore, fibroblasts exposed to 30% human serum displayed increased uptake of low-density lipoprotein and formation of capillary-like networks. The results of this study may have an impact on cell sourcing for vascular tissue engineering, and the development of methods for vascularization of autologous tissue engineered constructs. PMID- 23644552 TI - High prevalence of anti-CD74 antibodies specific for the HLA class II-associated invariant chain peptide (CLIP) in patients with axial spondyloarthritis. AB - OBJECTIVES: The pathogenesis of axial spondyloarthritis (axSpA) is still unclear. There is a strong association with HLA-B27 and other genes. Recently, anti-CD74 antibodies with specificity to a class II-associated invariant chain peptide (anti-CLIP-ABs) were found in axSpA patients. We examined the prevalence, sensitivity and specificity of anti-CLIP-ABs in axSpA in comparison with controls. METHODS: Sera of axSpA and non-SpA patients were analysed for IgG antibodies against CD74 by ELISA with specificity for CLIP developed in cooperation with AESKU Diagnostics (Germany). A cut-off of >=4 SDs of arbitrary units (AU) from mean serum levels was used to differentiate the results. The laboratory workers were completely blinded for clinical data. RESULTS: We analysed 145 sera from 94 axSpA and 51 non-SpA patients. AxSpA patients were more often male and younger. HLA-B27 status was available in 72 patients. Anti-CLIP ABs were detected in 85.1% in axSpA but in only 7.8% in non-SpA patients (p<=0.0001). AxSpA patients showed higher levels of anti-CLIP-ABs versus non-SpA: mean 14.5 versus 0.8 AU (p<=0.0001). The sensitivity of anti-CLIP-ABs for diagnosing axSpA was 85.1%, specificity 92.2%, likelihood ratio (LR) LR+ was 10.8 and LR- was 0.08. Anti-CLIP-ABs and HLA-B27 were positive in 87.5% patients with axSpA, but only 14.9% were anti-CLIP-negative, while 23.6% were HLA-B27-negative. CONCLUSIONS: Anti-CLIP antibodies were strongly associated with axSpA. The LR for confirming axSpA by using anti-CLIP was even higher than by using HLA-B27. More studies using this promising new method in patients with non-radiographic axial SpA or peripheral SpA are needed to establish its usefulness in clinical practice. PMID- 23644554 TI - Transdifferentiation of mesenchymal stem cells-derived adipogenic-differentiated cells into osteogenic- or chondrogenic-differentiated cells proceeds via dedifferentiation and have a correlation with cell cycle arresting and driving genes. AB - It is generally accepted that after differentiation bone marrow mesenchymal stem cells (MSC) become lineage restricted and unipotent in an irreversible manner. However, current results imply that even terminally differentiated cells transdifferentiate across lineage boundaries and therefore act as a progenitor cells for other lineages. This leads to the questions that whether transdifferentiation occurs via direct cell-to-cell conversion or dedifferentiation to a progenitor cells and subsequent differentiation, and whether MSC potency decreases or increases during differentiation. To address these questions, MSC were differentiated into adipogenic lineage cells, followed by dedifferentiation. The process of dedifferentiation was also confirmed by single cell clonal analysis. Finally the dedifferentiated cells were used for adipogenesis, osteogenesis and chondrogenesis. Histology, FACS, qPCR and GeneChip analyses of undifferentiated MSC, adipogenic-differentiated and dedifferentiated cells were performed. Interestingly, gene profiling and bioinformatics demonstrated that upregulation (DHCR24, G0S2, MAP2K6, SESN3) and downregulation (DST, KAT2, MLL5, RB1, SMAD3, ZAK) of distinct genes have an association with cell cycle arrest in adipogenic-differentiated cells and perhaps narrow down the lineage potency. However, the upregulation (CCND1, CHEK, HGF, HMGA2, SMAD3) and downregulation (CCPG1, RASSF4, RGS2) of these genes have an association with cell cycle progression and maybe motivate dedifferentiation of adipogenic differentiated cells. We found that dedifferentiated cells have a multilineage potency comparable to MSC, and also observed the associative role of proliferation genes with cell cycle arrest and progression. Concluded, our results indicate that transdifferentiation of adipogenic-differentiated cells into osteogenic- or chondrogenic-differentiated cells proceeds via dedifferentiation and correlates with cell cycle arresting and deriving genes. Regarding clinical use, the knowledge of potency and underlying mechanisms are prerequisites. PMID- 23644556 TI - Improving the antifouling property of polysulfone ultrafiltration membrane by incorporation of isocyanate-treated graphene oxide. AB - In this paper, isocyanate-treated graphene oxide (iGO), which can be well dispersed in organic solvent, was prepared in a simple manner and showed excellent compatibility with polysulfone (PSF). iGO-PSF ultrafiltration membranes were prepared by the classical phase inversion method. The separation performance and the antifouling property of the prepared membranes were investigated in detail. The antifouling property of the prepared membranes was found to be greatly enhanced by the addition of iGO, and we attributed the enhanced antifouling property to the improved hydrophilicity, the more negative zeta potential and the improved smoothness of the membrane surface. PMID- 23644557 TI - Amaryllidaceae and Sceletium alkaloids. AB - Covering: July 2010 to June 2012. Previous review: Nat. Prod. Rep., 2011, 28, 1126-1142. Recent progress on the isolation, identification, biological activity and synthetic studies of structurally diverse alkaloids from plants of the family Amaryllidaceae is summarized in this review. In addition, the structurally related alkaloids isolated from Sceletium species are discussed as well. PMID- 23644555 TI - Effects of rosuvastatin versus atorvastatin on small dense low-density lipoprotein: a meta-analysis of randomized trials. AB - In addition to their high-intensity effects on the reduction in low-density lipoprotein (LDL) levels, rosuvastatin and atorvastatin would be expected to also reduce small dense LDL (sdLDL) levels. To determine which reduces sdLDL levels more, we performed the first meta-analysis and meta-regression of randomized head to-head trials of rosuvastatin versus atorvastatin therapy. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through April 2012. Eligible studies were prospective, randomized controlled trials of rosuvastatin versus atorvastatin therapy reporting final sdLDL (directly measured or calculated) levels as an outcome. For each study, data regarding final sdLDL levels in both the rosuvastatin and atorvastatin groups were used to generate mean differences (MD) and 95 % confidence intervals (CI). Meta-regression analysis was performed to determine whether the effects of rosuvastatin therapy were modulated by the prespecified factors. Of 159 potentially relevant articles screened initially, 28 reports of randomized trials enrolling a total of 7802 patients were included. Pooled analysis suggested a significant reduction in final sdLDL levels among patients randomized to rosuvastatin versus atorvastatin therapy (MD, -1.56 mg/dl; 95 % CI, -2.30 to -0.83 mg/dl; P < 0.0001). The meta regression coefficients were statistically significant for the baseline LDL/sdLDL level and the difference in LDL changes between the two groups. In conclusion, rosuvastatin rather than atorvastatin therapy is likely more effective in reduction of sdLDL levels. It should be further investigated whether the reduction in sdLDL levels implies overt clinical benefits of rosuvastatin over atorvastatin. PMID- 23644558 TI - Retinal inner nuclear layer microcystic changes in optic nerve atrophy: a novel spectral-domain OCT finding. AB - PURPOSE: Optic atrophy constitutes the final stage in the evolution of optic neuropathy. The aim of this study was to describe the presence of macular microcystic changes or pseudocysts in patients with advanced optic atrophy. METHODS: The medical records of 24 patients who had retinal pseudocysts in association with optic atrophy have been analyzed. All patients underwent a complete neuro-ophthalmologic assessment; peripapillary retinal nerve fiber layer thickness and macular screening with spectral-domain optical coherence tomography and optical coherence tomography "en face" imaging analysis were also performed. RESULTS: A total of 36 eyes were included in the study. Patients' mean age was 37 years. The major cause of optic atrophy was glaucoma (12 cases). The retinal pseudocysts were observed as hyporeflective lesions in the internal nuclear layer. Infrared images revealed a hyporeflective circular or semilunar shape corresponding to the location of the pseudocysts in all cases. In eyes with pseudocysts, mean thickness of the peripapillary retinal nerve fiber layer was statistically significantly less than that of fellow eyes (P = 0.0003), whereas macular thickness was statistically significantly higher compared with fellow eyes (P < 0.005). CONCLUSION: The presence of pseudocystic lesions always associated with severe optic nerve fiber loss is reported. The reason why pseudocystic lesions develop within the retina is not well understood. They might constitute the translation of degeneration of Muller cells in severe optic nerve fiber loss. Recognizing these pseudocysts is crucial because they may be confused with cystoid macular edema. Their prognostic value and role in the therapeutic process need to be further evaluated with prospective studies and molecular experiments in vivo. PMID- 23644559 TI - Optic pit: novel surgical management of complicated cases. PMID- 23644560 TI - Multimodal imaging of early stage 1 type 3 neovascularization with simultaneous eye-tracked spectral-domain optical coherence tomography and high-speed real-time angiography. AB - PURPOSE: To analyze the multimodal imaging features of eyes with early Type 3 neovascularization showing primarily intraretinal proliferation without evidence of choroidal involvement. METHODS: The multimodal imaging data for a consecutive series of patients with new onset stage 1 Type 3 neovascularization were reviewed and the changes at the site of early lesion development were analyzed. RESULTS: Nineteen eyes of 19 patients (12 women, mean age 79.9 +/- 6.3 years) were included for analysis. Both fluorescein angiography and indocyanine green angiography showed a focal hyperfluorescence corresponding to the intraretinal vascular complex (early Type 3 neovascularization) and disclosed a single retinal arteriole feeding this lesion. There was no angiographic evidence of a retinal choroidal anastomosis or underlying Type 1 or Type 2 neovascularization. In all study eyes, eye-tracked spectral-domain optical coherence tomography showed the intraretinal neovascular complex as a hyperreflective lesion located in the outer retina, which appeared adherent to the underlying retinal pigment epithelium. In all eyes, there seemed to be a focal discontinuity of the retinal pigment epithelium band through which the hyperreflective intraretinal lesions communicated with the underlying material of medium reflectivity within drusen or drusenoid pigment epithelium detachment. With spectral-domain optical coherence tomography, clear evidence of a communication with the choroid was not detected. CONCLUSION: Multimodal imaging seems to support available clinicopathologic findings showing primarily intraretinal proliferation and anastomoses between retinal vessels and evolving Type 1 (subretinal pigment epithelium) neovascular tissue within underlying drusen or drusenoid pigment epithelium detachments without evidence of anastomoses with the choroidal circulation. PMID- 23644561 TI - Choroidal thickness in healthy children. AB - PURPOSE: To evaluate the choroidal thickness profiles of healthy children using enhanced depth imaging optical coherence tomography. METHODS: Horizontal and vertical enhanced depth imaging optical coherence tomography crosshair scans through the fovea were obtained from 48 healthy children. Choroidal thickness was measured at the fovea, 1 mm and 3 mm nasal, temporal, superior, and inferior to the fovea, and comparisons of choroidal thickness at different measurement points were performed. RESULTS: The mean subfoveal choroidal thickness was 348.4 +/- 82.5 MUm and the thickness at 1 mm nasal, temporal, superior, and inferior to the fovea was 306.1 +/- 86.3, 352.0 +/- 84.8, 349.9 +/- 83.8, and 343.8 +/- 86.8 MUm, respectively. The thickness at 3 mm nasal, temporal, superior, and inferior to the fovea was 190.1 +/- 63.9, 339.2 +/- 89.8, 330.7 +/- 82.1, and 309.9 +/- 78.4 MUm, respectively. Subfoveal choroidal thickness was negatively correlated with age. CONCLUSION: The data, obtained using enhanced depth imaging optical coherence tomography, provide the choroidal thickness profile of healthy children. The characteristic choroidal thickness profile in children suggests a redistribution process of choroidal tissue with aging. PMID- 23644562 TI - 3-step approach towards evaluation and elimination of acid use in pre-treatment for a brackish water reverse osmosis process. AB - To control carbonate scale formation on reverse osmosis (RO) membrane surfaces, it is common practice to add acid as a pre-treatment chemical. However, advancements in the formulation of proprietary scale inhibitors have resulted in a re-evaluation of the need to suppress the pH of RO feedwater. In this study, a 3-step approach was taken to eliminate sulfuric acid pre-treatment at a 4.5 MGD (17,000 m(3)/day) brackish water RO plant operating for over 7 years without previous membrane replacement. The 3-Step approach adopted in this study to evaluate and eliminate use of acid in pre-treatment process involved first pilot testing the plan to reduce the dependence on acid. Secondly, implementing the plan on the full-scale system with conservative pH increments and thirdly continuously screening for scale formation potential using a "canary" monitoring device. This 3-step approach resulted in the successful elimination of sulfuric acid pre-treatment at the brackish water RO plant, with an estimated $105,000 minimum annual cost savings. PMID- 23644563 TI - Sex-specific effects of early life cadmium exposure on DNA methylation and implications for birth weight. AB - Dietary cadmium exposure was recently found to alter DNA methylation in adults, but data on effects early in life are lacking. Our objective was to evaluate associations between prenatal cadmium exposure, DNA methylation and birth weight. In total 127 mother-child pairs from rural Bangladesh were studied. For comparison, we included 56 children at 4.5 y. Cadmium concentrations in mothers' blood (gestational week 14) and children's urine were measured by ICPMS. Global DNA methylation was analyzed by Infinium HumanMethylation450K BeadChip in cord blood and children's blood. Maternal cadmium exposure was associated with cord blood DNA methylation (p-value < 10 (-16) ). The association was markedly sex specific. In boys, 96% of the top 500 CpG sites showed positive correlations (rS values > 0.50), whereas most associations in girls were inverse; only 29% were positive (rS > 0.45). In girls we found overrepresentation of methylation changes in genes associated with organ development, morphology and mineralization of bone, whereas changes in boys were found in cell death-related genes. Several individual CpG sites that were positively associated with cadmium were inversely correlated with birth weight, although none statistically significant after correction for multiple comparisons. The associations were, however, fairly robust in multivariable-adjusted linear regression models. We identified CpG sites that were significantly associated with cadmium exposure in both newborns and 4.5-y-old children. In conclusion, cadmium exposure in early life appears to alter DNA methylation differently in girls and boys. This is consistent with previous findings of sex-specific cadmium toxicity. Cadmium-related changes in methylation were also related to lower birth weight. PMID- 23644564 TI - Occurrence and partitioning of antibiotic compounds found in the water column and bottom sediments from a stream receiving two wastewater treatment plant effluents in northern New Jersey, 2008. AB - An urban watershed in northern New Jersey was studied to determine the presence of four classes of antibiotic compounds (macrolides, fluoroquinolones, sulfonamides, and tetracyclines) and six degradates in the water column and bottom sediments upstream and downstream from the discharges of two wastewater treatment plants (WWTPs) and a drinking-water intake (DWI). Many antibiotic compounds in the four classes not removed by conventional WWTPs enter receiving waters and partition to stream sediments. Samples were collected at nine sampling locations on 2 days in September 2008. Two of the nine sampling locations were background sites upstream from two WWTP discharges on Hohokus Brook. Another background site was located upstream from a DWI on the Saddle River above the confluence with Hohokus Brook. Because there is a weir downstream of the confluence of Hohokus Brook and Saddle River, the DWI receives water from Hohokus Brook at low stream flows. Eight antibiotic compounds (azithromycin (maximum concentration 0.24 MUg/L), ciprofloxacin (0.08 MUg/L), enrofloxacin (0.015 MUg/L), erythromycin (0.024 MUg/L), ofloxacin (0.92 MUg/L), sulfamethazine (0.018 MUg/L), sulfamethoxazole (0.25 MUg/L), and trimethoprim (0.14 MUg/L)) and a degradate (erythromycin-H2O (0.84 MUg/L)) were detected in the water samples from the sites downstream from the WWTP discharges. The concentrations of six of the eight detected compounds and the detected degradate compound decreased with increasing distance downstream from the WWTP discharges. Azithromycin, ciprofloxacin, ofloxacin, and trimethoprim were detected in stream-bottom sediments. The concentrations of three of the four compounds detected in sediments were highest at a sampling site located downstream from the WWTP discharges. Trimethoprim was detected in the sediments from a background site. Pseudo-partition coefficients normalized for streambed sediment organic carbon concentration were calculated for azithromycin, ciprofloxacin, and ofloxacin. Generally, there was good agreement between the decreasing order of the pseudo partition coefficients in this study and the order reported in the literature. PMID- 23644565 TI - Use of hydroacoustic measurements to characterize bottom sediments and guide sampling and remediation of organic contaminants in lake sediments. AB - Sampling of bed sediment for contamination characterization is often limited by the heterogeneity in sediment properties and distribution. In this study, we explored the use of hydroacoustic measurements to characterize sediment properties and guide sediment sampling in a small lake contaminated by organochlorine pesticides (OCPs) and PCBs. A dual frequency hydroacoustic survey was conducted to characterize sediment properties, distribution, and thickness in McGrath Lake, near Ventura, CA. Based upon these results, sediment core samples were collected from 15 sites on the lake, and sectioned into 20 cm intervals for sediment characterization and analysis of OCPs and PCBs. Very high concentrations of total DDT and total chlordane were found in the sediments, with mean values of 919 and 34.9 ng g(-1), respectively. Concentrations of OCPs were highest at 60-80 cm depth near the inflow at the north end of the lake. Total PCB concentrations were much lower (mean concentration of 4.5 ng g(-1)). Using the hydroacoustic and chemical data, it was estimated that nearly 30,000 m(3) of DDT- and chlordane contaminated sediment (above effects range median values) was present in the uppermost 1.2 m of sediment in the lake. A hydroacoustic survey can be a valuable tool used to delineate sediment distribution in a lake, identify areas with deeper organic sediment where hydrophobic contaminants would likely be found, and guide sampling. Sampling and chemical analyses are nonetheless needed to quantify contaminant levels in bottom sediments. When combined with hydroacoustic measurements, this approach can reasonably estimate the distributions and volumes of contaminated sediment important in the development of remediation strategies. PMID- 23644566 TI - Seasonal synchronicity of algal assemblages in three Midwestern agricultural streams having varying concentrations of atrazine, nutrients, and sediment. AB - Numerous studies characterizing the potential effects of atrazine on algal assemblages have been conducted using micro- or mesocosms; however, few evaluations focused on in situ lotic algal communities, potentially confounding risk assessment conclusions. This exploratory study, conducted at several sites in the midwestern United States where atrazine is commonly used, presents in situ observations of native algal communities relative to atrazine exposure and other parameters. Planktonic and periphytic algae from three streams in three Midwestern states, having historically differing atrazine levels, were sampled over a 16-week period in 2011 encompassing atrazine applications and the summer algal growth period at each site. Changes in abundance, diversity, and composition of algal communities were placed in the context of hydrological, climatic, and water quality parameters (including components sometimes present in agricultural runoff) also collected during the study. Diatoms dominated communities at each of the three sites and periphyton was much more abundant than phytoplankton. As expected, significant variations in algal community and environmental parameters were observed between sites. However, correspondence analysis plots revealed that patterns of temporal variation in algal communities at each site and in periphyton or phytoplankton were dominated by seasonal environmental gradients. Significant concordance in these seasonal patterns was detected among sites and between phytoplankton and periphyton communities (via procrustes Protest analysis), suggesting synchronicity of algal communities across a regional scale. While atrazine concentrations generally exhibited seasonal trends at the study watersheds; no effects on algal abundance, diversity or assemblage structure were observed as a result of atrazine pulses. This lack of response may be due to exposure events of insufficient concentration or duration (consistent with previously reported results) or the composition of the algal assemblages present. This was in contrast to the effects of elevated flow events, which were associated with significant changes in periphyton abundance, diversity and assemblage. PMID- 23644567 TI - Modeling regional deposited dose of submicron aerosol particles. AB - We developed a simple model to calculate the regional deposited dose of submicron aerosol particles in the respiratory system. This model incorporates measured outdoor and modeled indoor particle number size distributions, detailed activity patterns of three age groups (teens, adults, and the elderly), semi-empirical estimation of the regional deposition fraction, hygroscopic properties of urban aerosols, and reported breathing minute volumes. We calculated the total and regional deposited dose based on three concentration metrics: particle number (PN), mass (PM), and surface area (PSA). The 24-h total deposited dose of fine particles in adult males was around 40 MUg (57*109 particles, 8*102 mm(2)) and 41 MUg (40*109 particles, 8*102 mm(2)) on workdays and weekends, respectively. The total and regional 24-h deposited dose based on any of the metrics was at most 1.5 times higher in males than in females. The deposited dose values in the other age groups were slightly different than in adults. Regardless of the particle size fraction or the deposited dose metric, the pulmonary/alveolar region received the largest fraction of the deposited dose. These values represent the lowest estimate of the deposited dose and they are expected to be higher in real life conditions after considering indoor sources of aerosol particles and spatial variability of outdoor aerosols. This model can be extended to youngsters (<12 years old) after gaining accurate information about the deposition fraction inside their respiratory system and their breathing pattern. This investigation is foreseen to bridge the gap between exposure and response in epidemiological studies. PMID- 23644568 TI - Behavior of organophosphates and hydrophilic ethers during bank filtration and their potential application as organic tracers. A field study from the Oderbruch, Germany. AB - The behavior of organophosphates and ethers during riverbank filtration and groundwater flow was assessed to determine their suitability as organic tracers. Four sampling campaigns were conducted at the Oderbruch polder, Germany to establish the presence of chlorinated flame retardants (TCEP, TCPP, TDCP), non chlorinated plasticizers (TBEP, TiBP, TnBP), and hydrophilic ethers (1,4-dioxane, monoglyme, diglyme, triglyme, tetraglyme) in the Oder River, main drainage ditch, and anoxic aquifer. Selected parameters were measured in order to determine the hydro-chemical composition of both, river water and groundwater. The results of the study confirm that organophosphates (OPs) are more readily attenuated during bank filtration compared to ethers. Both in the river and the groundwater, TCPP was the most abundant OP with concentrations in the main drainage ditch ranging between 105 and 958 ng L(-1). 1,4-dioxane, triglyme, and tetraglyme demonstrated persistent behavior during bank filtration and in the anoxic groundwater. In the drainage ditch concentrations of 1,4-dioxane, triglyme, and tetraglyme ranged between 1090 and 1467 ng L(-1), 37 and 149 ng L(-1), and 496 and 1403 ng L(-1), respectively. A positive correlation was found for the inorganic tracer chloride with 1,4-dioxane and tetraglyme. These results confirm the possible application of these ethers as environmental organic tracers. Both inorganic and organic compounds showed temporal variability in the surface- and groundwater. Discharge of the river water, concentrations of analytes at the time of infiltration and attenuation were identified as factors influencing the variable amounts of the analytes in the surface and groundwater. These findings are also of great importance for the production of drinking water via bank filtration and natural and artificial groundwater recharge as the physicochemical properties of ethers create challenges in their removal. PMID- 23644569 TI - DNA sequencing using electrical conductance measurements of a DNA polymerase. AB - The development of personalized medicine-in which medical treatment is customized to an individual on the basis of genetic information-requires techniques that can sequence DNA quickly and cheaply. Single-molecule sequencing technologies, such as nanopores, can potentially be used to sequence long strands of DNA without labels or amplification, but a viable technique has yet to be established. Here, we show that single DNA molecules can be sequenced by monitoring the electrical conductance of a phi29 DNA polymerase as it incorporates unlabelled nucleotides into a template strand of DNA. The conductance of the polymerase is measured by attaching it to a protein transistor that consists of an antibody molecule (immunoglobulin G) bound to two gold nanoparticles, which are in turn connected to source and drain electrodes. The electrical conductance of the DNA polymerase exhibits well-separated plateaux that are ~3 pA in height. Each plateau corresponds to an individual base and is formed at a rate of ~22 nucleotides per second. Additional spikes appear on top of the plateaux and can be used to discriminate between the four different nucleotides. We also show that the sequencing platform works with a variety of DNA polymerases and can sequence difficult templates such as homopolymers. PMID- 23644570 TI - A magneto-DNA nanoparticle system for rapid detection and phenotyping of bacteria. AB - So far, although various diagnostic approaches for pathogen detection have been proposed, most are too expensive, lengthy or limited in specificity for clinical use. Nanoparticle systems with unique material properties, however, circumvent these problems and offer improved accuracy over current methods. Here, we present novel magneto-DNA probes capable of rapid and specific profiling of pathogens directly in clinical samples. A nanoparticle hybridization assay, involving ubiquitous and specific probes that target bacterial 16S rRNAs, was designed to detect amplified target DNAs using a miniaturized NMR device. Ultimately, the magneto-DNA platform will allow both universal and specific detection of various clinically relevant bacterial species, with sensitivity down to single bacteria. Furthermore, the assay is robust and rapid, simultaneously diagnosing a panel of 13 bacterial species in clinical specimens within 2 h. The generic platform described could be used to rapidly identify and phenotype pathogens for a variety of applications. PMID- 23644572 TI - Muscarine, imidaozle, oxazole and thiazole alkaloids. AB - Covering: July 2010 to June 2012. Previous review: Nat. Prod. Rep., 2011, 28, 1143-1191. Structurally diverse alkaloids containing five-membered heterocyclic subunits, such as imidazole, oxazole, thiazole, as well as their saturated congeners, are widely distributed in terrestrial and marine organisms and microorganisms. These naturally occurring secondary metabolites often exhibit extensive and pharmacologically important biological activities. The latest progress involving isolation, biological activities, chemical synthetic studies, and biosynthetic pathways of these natural products has been summarized in this review. PMID- 23644573 TI - C72: gaudiene, a hollow and aromatic all-carbon molecule. AB - A new allotropic form of carbon is proposed. The molecular structure of a cavernous C72 molecule has been optimized at the density functional theory level. The structure belonging to the Oh point group was found to be a minimum on the potential energy surface. Current-density calculations show that the gaudiene molecule with formally 72 pi electrons sustains strong diatropic currents when exposed to an external magnetic field. PMID- 23644571 TI - In vivo magnetic resonance imaging of hyperpolarized silicon particles. AB - Silicon-based micro- and nanoparticles have gained popularity in a wide range of biomedical applications due to their biocompatibility and biodegradability in vivo, as well as their flexible surface chemistry, which allows drug loading, functionalization and targeting. Here, we report direct in vivo imaging of hyperpolarized (29)Si nuclei in silicon particles by magnetic resonance imaging. Natural physical properties of silicon provide surface electronic states for dynamic nuclear polarization, extremely long depolarization times, insensitivity to the in vivo environment or particle tumbling, and surfaces favourable for functionalization. Potential applications to gastrointestinal, intravascular and tumour perfusion imaging at subpicomolar concentrations are presented. These results demonstrate a new background-free imaging modality applicable to a range of inexpensive, readily available and biocompatible silicon particles. PMID- 23644574 TI - Reply to the letter from Drs. JA Malheiros, MM Oliveira & P Steinbok "Re: Zhu X et al.: Choroid plexus coagulation for hydrocephalus not due to CSF overproduction: a review". PMID- 23644576 TI - Ground-state properties of the mixed-valence cobaltites Nd0.7Sr0.3CoO3, Nd0.7Ca0.3CoO3 and Pr0.7Ca0.3CoO3. AB - The electric, magnetic, and thermal properties of three perovskite cobaltites with the same 30% hole doping and ferromagnetic ground state were investigated down to very low temperatures. With decreasing size of large cations, the ferromagnetic Curie temperature and spontaneous moments of cobalt are gradually suppressed: TC = 130 K, 55 K and 25 K and m = 0.68 MUB, 0.34 MUB and 0.23 MUB for Nd0.7Sr0.3CoO3, Pr0.7Ca0.3CoO3 and Nd0.7Ca0.3CoO3, respectively. The moment reduction with respect to the moment of the conventional ferromagnet La0.7Sr0.3CoO3 (T(C) = 230 K, m = 1.71 MUB) in the so-called low spin/intermediate spin (IS/LS) state for Co(3+)/Co(4+) was originally interpreted using a phase-separation scenario. Based on the present results, mainly the analysis of the Schottky peak originating from Zeeman splitting of the ground state Kramers doublet of Nd(3+), we find, however, that the ferromagnetic phase in Nd0.7Ca0.3CoO3 and likely also in Pr0.7Ca0.3CoO3 is uniformly distributed over the whole sample volume, despite the severe drop of moments. The ground state of these compounds is identified with the LS/LS-related phase derived theoretically by Sboychakov et al (2009 Phys. Rev. B 80 024423). The ground state of Nd0.7Sr0.3CoO3 with an intermediate cobalt moment is inhomogeneous due to competition between the LS/LS and IS/LS phases. In the theoretical part of the study, the crystal field split levels for 4f(3) (Nd(3+)), 4f(2) (Pr(3+)) and 4f(1) (Ce(3+) or Pr(4+)) are calculated and their magnetic characteristics are presented. PMID- 23644575 TI - Preoperative embolization of hypervascular pediatric brain tumors: evaluation of technical safety and outcome. AB - BACKGROUND: Surgical management of pediatric hypervascular brain tumors is challenging because of the risk of bleeding. We sought to evaluate the technical factors associated with safety and outcome of preoperative embolization of pediatric hypervascular brain tumors. MATERIALS AND METHODS: Eight pediatric brain tumor patients received preoperative endovascular embolization during the past 8 years. The cases included four choroid plexus papillomas, one yolk sac tumor, one intraventricular meningioma, one astrocytoma, and one hemangioblastoma. Embolization was done by superselection of the feeding arteries with microcatheters followed by slow injection of either n-butyl 2-cyanoacrylate (NBCA) or tris-acryl gelatin microspheres (Embosphere). Surgery for tumor removal was done in the same session right after embolization in all but one patient. Blood loss during surgery and clinical outcome were recorded. RESULTS: Preoperative embolization was successfully done in all patients. Technical complication was noted in two patients. One patient developed bleeding while embolizing the tumor with Embospheres but was immediately embolized with NBCA without sequel. The other patient experienced tumor bleeding 4 h after embolization with Embospheres, and suffered left hemiparesis despite an emergency surgery. Surgical intervention was successfully done in all patients without procedure-related complication. Surgical blood loss ranged from 50 to 1,600 ml. CONCLUSION: Though associated with the risk of procedure-related bleeding, preoperative embolization of pediatric hypervascular brain tumors has high technical success rates and can enhance the surgical management. We suggest to perform the embolization and surgery in a single session and to use NBCA as the embolic agent to minimize the procedure-related risk. PMID- 23644577 TI - Hypertonic saline solution reduces mesenteric microcirculatory dysfunctions and bacterial translocation in a rat model of strangulated small bowel obstruction. AB - We examined the effects of hypertonic saline (HS) on inflammatory, metabolic variables, and bacterial translocation (BT) in rats submitted to intestinal obstruction and ischemia (IO). Male Wistar rats were submitted to IO and treated, 2 h thereafter, with lactated Ringer's (LR) (4 mL/kg per 5 min, i.v.) or HS (7.5% NaCl, 4 mL/kg per 5 min, i.v.). Twenty-four hours after IO, rats were also submitted to enterectomy/enteroanastomosis to resection of necrotized small bowel. Leukocyte-endothelial interactions were investigated by intravital microscopy and the expression of P-selectin and intercellular adhesion molecule 1 by immunohistochemistry. Bacterial cultures of mesenteric lymph nodes, liver, spleen, and blood were used to evaluate BT. Levels of chemokines (cytokine induced neutrophil chemoattractants 1 and 2), insulin, and corticosterone were determined by enzyme-linked immunosorbent assay. Intestinal histology, serum urea and creatinine levels, and hepatic enzymes activities were performed to evaluate local and remote damage. Relative to IO and LR-treated rats, which exhibited increases in the number of rolling (1.5-fold), adhered (3.5-fold) and migrated (9.0-fold) leukocytes, and increased expression of P-selectin (3-fold) and intercellular adhesion molecule 1 (3-fold) on mesenteric microcirculation, treatment with HS followed by enterectomy reduced leukocyte-endothelial interactions and expression of both adhesion molecules to values attained in sham rats. Serum chemokines were normalized after treatment with both solutions followed by enterectomy. Hypertonic saline-treated rats demonstrated a significant reduction in BT to 50% in liver and spleen samples and bacteremia (14%), compared with 82% of BT in liver and spleen samples of IO and LR-treated rats and bacteremia (57%). Local intestinal damage was attenuated, and renal and hepatic function preserved by treatment with HS followed by enterectomy. Survival rate increased to 86% up to 15 days. Data presented suggest that HS solution followed by enterectomy reduces mesenteric microcirculatory dysfunctions and BT, attenuating local and remote damage in a model of strangulated small bowel obstruction. PMID- 23644578 TI - Regulation and impairments of dynamic desmosome and corneodesmosome remodeling. AB - Desmosomes and corneodesmosomes are the most important adhering junctions to provide strength for the epidermal sheet structure made of living keratinocytes and enucleated corneocytes, respectively. These junctions are connected directly with transmembrane desmosomal cadherins, desmogleins (Dsgs) and desmocollins (Dscs), mainly Dsg1/Dsc1 and Dsg3/Dsc3 in desmosomes and Dsg1/Dsc1 with corneodesmosin in corneodesmosomes. Dsgs and Dscs are associated with several proteins at their inner cytoplasmic domains to anchor keratin intermediate filaments. Desmosomes are not static, but dynamic units that undergo regular remodeling to allow for keratinocyte outward-migration in the epidermis. Recently, two mutually-reversible desmosomal adhesion states have been recognized, i.e., "stable hyper-adhesion (Ca2+-independent)" and "dynamic weak adhesion (Ca2+-dependent)". A remarkable impairment of this remodeling is observed in pemphigus vulgaris (an autoimmune blistering disease), caused by anti Dsg3 antibodies, generating a weak-adhesion desmosome state. Immediately after formation, corneodesmosomes normally commit to degradation, which is complicatedly regulated by proteolytic cleavage of their respective extracellular portion(s), via kallikrein-regulated peptidases and cathepsins. This proteolytic activity is in turn controlled by a variety of inhibitory agents, including protease inhibitors, cholesterol sulfate, and an acidic gradient. The impairment of protease control causes keratinization disorders. This review focuses on the dynamic regulation of desmosomes and corneodesmosomes in relation to keratinization disorders. PMID- 23644579 TI - Factors that affect action possibility judgments: the assumed abilities of other people. AB - Judging what actions are possible and impossible to complete is a skill that is critical for planning and executing movements in both individual and joint actions contexts. The present experiments explored the ability to adapt action possibility judgments to the assumed characteristics of another person. Participants watched alternating pictures of a person's hand moving at different speeds between targets of different indexes of difficulty (according to Fitts' Law) and judged whether or not it was possible for individuals with different characteristics to maintain movement accuracy at the presented speed. Across four studies, the person in the pictures and the background information about the person were manipulated to determine how and under what conditions participants adapted their judgments. Results revealed that participants adjusted their possibility judgments to the assumed motor capabilities of the individual they were judging. However, these adjustments only occurred when participants were instructed to take the other person into consideration suggesting that the adaption process is a voluntary process. Further, it was observed that the slopes of the regression equations relating movement time and index of difficulty did not differ across conditions. All differences between conditions were in the y intercept of the regression lines. This pattern of findings suggests that participants formed the action possibility judgments by first simulating their own performance, and then adjusted the "possibility" threshold by adding or subtracting a correction factor to determine what is and is not possible for the other person to perform. PMID- 23644580 TI - Cool, but understanding...experiencing cooler temperatures promotes perspective taking performance. AB - The current research examined the impact of temperature cues on perspective taking. Individuals often start with their own point-of-view when taking another's perspective and thereby unintentionally project their own perspective onto others, which ultimately leads to egocentrically biased inferences of others' perspectives. Accordingly, perspective-taking is enhanced under conditions reducing this egocentric anchoring. In two studies, we show that perspective-taking is enhanced when participants are exposed to cooler rather than warmer temperature cues. Specifically, this is shown to be the case, because cooler temperatures reduce egocentric anchoring in perspective-taking (Study 2). Results are discussed with reference to the literature on (temperature) grounded cognition indicating a link between cold temperatures and social distance. Hence, whereas earlier research has shown that individuals feel more distant from each other when undergoing cooler thermal experiences, the present research suggests that this thermal experience prevents them from over-imputing their own perspectives onto others. PMID- 23644581 TI - Correlation between heavy metals and turtle abundance in ponds near the Paducah Gaseous Diffusion Plant, Kentucky, USA. AB - Reptiles are declining globally, and environmental contamination has been suggested as a contributing factor; however, few studies have investigated the relationship between contamination and reptile populations. We performed a mark recapture study at ponds near the Paducah Gaseous Diffusion Plant (PGDP), Kentucky, to determine if heavy metals had an impact on turtle populations. We measured concentrations of cadmium, chromium, copper, lead, and mercury in red eared slider turtle (Trachemys scripta elegans) tissues and pond sediment and determined the correlation between metal concentrations and red-eared slider density. Metal concentrations measured in the current study were low, and turtle density was not significantly correlated with metal concentrations in tissues or sediment. However, we observed a trend of decreasing turtle density in ponds that had greater metal concentrations. Sex ratio and proportion of juveniles were significantly different among ponds, but it is unclear if these differences are related to contamination associated with the PGDP. PMID- 23644582 TI - Effects of maternal cadmium exposure on female reproductive functions, gamete quality, and offspring development in zebrafish (Danio rerio). AB - Impacts of maternal Cd(2+) exposure on female zebrafish (Danio rerio) were observed in females as well as their offspring. In females, Cd disturbed fecundity and other reproductive functions. In their offspring, it retarded gamete development and growth and influenced gene expression. There was a positive relationship between Cd(2+) contents in ovaries of females and treatment doses of 0-8.9 MUM of Cd(2+). The mating rate decreased by 60 % when females were exposed to 8.9-35.6 MUM of Cd(2+) for 72 h compared with the control group. It was observed that growth is delayed by one somite stage in maternal-Cd(2+) embryos compared with control embryos, which grew at the sixth-somite stage. The ceratohyal angles of larvae of Cd-exposed adults (maternal Cd(2+)) at 72 h postfertilization (hpf) appeared to have a positive response after doses of maternal Cd. In addition, approximately 30 % of 96-hpf larvae that were treated with a dose of 35.6 MUM of maternal Cd(2+) appeared to have pericardial edema. At the 5-hpf stage of maternal Cd(2+) exposure, embryos showed 33 and 37 target genes, respectively, that were significantly downregulated and upregulated as shown by cDNA microarray analysis. A major effect of maternal Cd(2+) exposure on zebrafish embryo genes is that 18.9% of transcription functions were upregulated. In addition, 33.3% of transcripts relative to the function of protein biosynthesis were downregulated. These results showed that maternal Cd(2+) exposure influenced the reproduction ability of females and also caused their embryos to develop with abnormal gene expression. PMID- 23644583 TI - Motor excitability during visual perception of known and unknown spoken languages. AB - It is possible to comprehend speech and discriminate languages by viewing a speaker's articulatory movements. Transcranial magnetic stimulation studies have shown that viewing speech enhances excitability in the articulatory motor cortex. Here, we investigated the specificity of this enhanced motor excitability in native and non-native speakers of English. Both groups were able to discriminate between speech movements related to a known (i.e., English) and unknown (i.e., Hebrew) language. The motor excitability was higher during observation of a known language than an unknown language or non-speech mouth movements, suggesting that motor resonance is enhanced specifically during observation of mouth movements that convey linguistic information. Surprisingly, however, the excitability was equally high during observation of a static face. Moreover, the motor excitability did not differ between native and non-native speakers. These findings suggest that the articulatory motor cortex processes several kinds of visual cues during speech communication. PMID- 23644584 TI - Experimental methods for testing the effects of neurotrophic peptide, ADNF-9, against alcohol-induced apoptosis during pregnancy in c57bl/6 mice. AB - Experimental designs for investigating the effects of prenatal alcohol exposure during early embryonic stages in fetal brain growth are challenging. This is mostly due to the difficulty of microdissection of fetal brains and their sectioning for determination of apoptotic cells caused by prenatal exposure to alcohol. The experiments described here provide visualized techniques from mice breeding to the identification of cell death in fetal brain tissue. This study used C57BL/6 mice as the animal model for studying fetal alcohol exposure and the role of trophic peptide against alcohol-induced apoptosis. The breeding consists of a 2-hr matting window to determine the exact stage of embryonic age. An established fetal alcohol exposure model has been used in this study to determine the effects of prenatal alcohol exposure in fetal brains. This involves free access to alcohol or pair-fed liquid diets as the sole source of nutrients for the pregnant mice. The techniques involving dissection of fetuses and microdissection of fetal brains are described carefully, since the latter can be challenging. Microdissection requires a stereomicroscope and ultra-fine forceps. Step-by-step procedures for dissecting the fetal brains are provided visually. The fetal brains are dissected from the base of the primordium olfactory bulb to the base of the metencephalon. For investigating apoptosis, fetal brains are first embedded in gelatin using a peel-away mold to facilitate their sectioning with a vibratome apparatus. Fetal brains embedded and fixed in paraformaldehyde are easily sectioned, and the free floating sections can be mounted in superfrost plus slides for determination of apoptosis or cell death. TUNEL (TdT-mediated dUTP Nick End Labeling; TdT: terminal deoxynucleotidyl transferase) assay has been used to identify cell death or apoptotic cells. It is noteworthy that apoptosis and cell-mediated cytotoxicity are characterized by DNA fragmentation. Thus, the visualized TUNEL-positive cells are indicative of cell death or apoptotic cells. The experimental designs here provide information about the use of an established liquid diet for studying the effects of alcohol and the role of neurotrophic peptides during pregnancy in fetal brains. This involves breeding and feeding pregnant mice, microdissecting fetal brains, and determining apoptosis. Together, these visual and textual techniques might be a source for investigating prenatal exposure of harmful agents in fetal brains. PMID- 23644585 TI - Differences between endogenous and exogenous emotion inhibition in the human brain. AB - The regulation of emotions is an integral part of our mental health. It has only recently been investigated using brain imaging techniques. In most studies, participants are instructed by a cue to inhibit a specific emotional reaction. The aim of the present study was to investigate the alternative situation where a person decides to inhibit an emotion as an act of endogenous self-control. Healthy participants viewed highly arousing pictures with negative valence. In the endogenous condition, participants could freely choose on each trial to inhibit or feel the emotions elicited by the picture. In an exogenous condition, a visual cue instructed them to either feel or inhibit the emotion elicited by the picture. Participants' subjective ratings of intensity of experienced emotion showed an interaction effect between source of control (endogenous/exogenous) and feel/inhibit based on a stronger modulation between feel and inhibition for the endogenous compared to the exogenous condition. Endogenous inhibition of emotions was associated with dorso-medial prefrontal cortex activation, whereas exogenous inhibition was found associated with lateral prefrontal cortex activation. Thus, the brain regions for both endogenous and exogenous inhibition of emotion are highly similar to those for inhibition of motor actions in Brass and Haggard (J Neurosci 27:9141-9145, 2007), Kuhn et al. (Hum Brain Mapp 30:2834-2843, 2009). Functional connectivity analyses showed that dorsofrontomedial cortex exerts greater control onto pre-supplementary motor area during endogenous inhibition compared to endogenous feel. This functional dissociation between an endogenous, fronto-medial and an exogenous, fronto-lateral inhibition centre has important implications for our understanding of emotion regulation in health and psychopathology. PMID- 23644587 TI - Self-injurious behaviours are associated with alterations in the somatosensory system in children with autism spectrum disorder. AB - Children with autism spectrum disorder (ASD) frequently engage in self-injurious behaviours, often in the absence of reporting pain. Previous research suggests that altered pain sensitivity and repeated exposure to noxious stimuli are associated with morphological changes in somatosensory and limbic cortices. Further evidence from postmortem studies with self-injurious adults has indicated alterations in the structure and organization of the temporal lobes; however, the effect of self-injurious behaviour on cortical development in children with ASD has not yet been determined. Thirty children and adolescents (mean age = 10.6 +/- 2.5 years; range 7-15 years; 29 males) with a clinical diagnosis of ASD and 30 typically developing children (N = 30, mean age = 10.7 +/- 2.5 years; range 7-15 years, 26 males) underwent T1-weighted magnetic resonance and diffusion tensor imaging. No between-group differences were seen in cerebral volume, surface area or cortical thickness. Within the ASD group, self-injury scores negatively correlated with thickness in the right superior parietal lobule t = 6.3, p < 0.0001, bilateral primary somatosensory cortices (SI) (right: t = 4.4, p = 0.02; left: t = 4.48, p = 0.004) and the volume of the left ventroposterior (VP) nucleus of the thalamus (r = -0.52, p = 0.008). Based on these findings, we performed an atlas-based region-of-interest diffusion tensor imaging analysis between SI and the VP nucleus and found that children who engaged in self-injury had significantly lower fractional anisotropy (r = -0.4, p = 0.04) and higher mean diffusivity (r = 0.5, p = 0.03) values in the territory of the left posterior limb of the internal capsule. Additionally, greater incidence of self injury was associated with increased radial diffusivity values in bilateral posterior limbs of the internal capsule (left: r = 0.5, p = 0.02; right: r = 0.5, p = 0.009) and corona radiata (left: r = 0.6, p = 0.005; right: r = 0.5, p = 0.009). Results indicate that self-injury is related to alterations in somatosensory cortical and subcortical regions and their supporting white-matter pathways. Findings could reflect use-dependent plasticity in the somatosensory system or disrupted brain development that could serve as a risk marker for self injury. PMID- 23644586 TI - Effects of stress on AMPA receptor distribution and function in the basolateral amygdala. AB - Stress is a growing public health concern and can lead to significant disabilities. The neural response to stressors is thought to be dependent on the extended amygdala. The basolateral amygdala (BLA) is responsible for associations of sensory stimuli with emotional valence and is thought to be involved in stress induced responses. Previous behavioral and electrophysiological experiments demonstrate that, in response to stress, changes occur in glutamatergic neurotransmission within the BLA and, in particular in transmission at AMPA receptors. Given the established role of AMPA receptors in memory and synaptic plasticity, we tested the hypothesis that stress produces alterations in the distribution of these receptors in a way that might account for stress-induced alterations in amygdala circuitry function. We examined the subcellular localization of GluR1 subunits of the AMPA receptor and the electrophysiological characteristics of BLA principal neurons in an animal model of unpredictable stress. Compared to controls, we demonstrated an increase in the ratio of labeled spines to labeled dendritic shafts in the BLA of rats 6 and 14 days post-stress, but not 1 day post-stress. Furthermore, the frequency of mini-EPSCs was increased in stressed animals without a change in general membrane properties, mini-EPSC amplitude, or in paired pulse modulation of glutamate release. Taken together, these data suggest that the shift of GluR1-containing AMPA receptors from dendritic stores into spines may be in part responsible for the persistent behavioral alterations observed following severe stressors. PMID- 23644588 TI - Letter to Editor about: "Physical exercise increases GFAP expression and induces morphological changes in hippocampal astrocytes". PMID- 23644589 TI - Spatial UTA (S-UTA) - a new approach for raster-based GIS multicriteria suitability analysis and its use in implementing natural systems for wastewater treatment. AB - The identification of sites for locating new natural systems for wastewater treatment (NSWT), such as stabilization ponds and constructed wetlands, should combine multiple crucial factors (environmental, design, social and economic), and thus the implementation of multicriteria decision-making (MCDM) methods is required. In addition, the spatial nature of the site selection process necessitates the use of geographic information systems (GISs) because they are unanimously recognized as the most appropriate tool capable of supporting sophisticated spatial decision making. The resulting multicriteria spatial decision support systems (MC-SDSSs) provide a consistent framework for dealing with conflicting objectives while integrating the decision makers' (DMs') preferences in spatially related patterns/problems. A map-based, interactive UTAII implementation is presented, which provides a link between a well understood decision support method and exploratory geographic visualization. Spatial UTA (S-UTA) is applied in a real case study concerning the ranking of candidate sites for implementing natural systems for wastewater treatment in the Evros-Rodopi prefectures of northeastern Greece. Finally, the obtained results are compared with those derived using other MCDM approaches to evaluate the performance of S-UTA in GIS-based land use suitability analyses. PMID- 23644590 TI - Impact of system management on vegetative treatment system effluent concentrations. AB - Beef feedlots of all sizes are looking for more cost-effective solutions for managing feedlot runoff. Vegetative treatment systems are one potential option, but require performance evaluation for use on concentrated animal feeding operations. The performance of six vegetative treatment systems on open beef feedlots throughout Iowa was monitored from 2006 through 2009. These feedlots had interim, National Pollution Discharge Elimination System permits that allowed the use of vegetative treatment systems to control and treat runoff from the open feedlots. This manuscript focuses on making within site comparisons, i.e., from year-to-year and component-to-component within a site, to evaluate how management changes and system modifications altered performance. The effectiveness, in terms of effluent concentration reductions, of each system was evaluated; nutrient concentration reductions typically ranged from 60 to 99% during treatment in the vegetative components of the vegetative treatment systems. Monitoring results showed a consistent improvement in system performance during the four years of study. Much of this improvement can be attributed to improved management techniques and system modifications that addressed key performance issues. Specifically, active control of the solid settling basin outlet improved solids retention and allowed the producers to match effluent application rates to the infiltration rate of the vegetative treatment area, reducing the occurrence of effluent release. Additional improvements resulted from system maturation, increased operator experience, and the addition of earthen flow spreaders within the vegetative treatment area to slow flow and provide increased effluent storage within the treatment area, and switching to active management of settling basin effluent release. PMID- 23644591 TI - Hazardous waste to materials: recovery of molybdenum and vanadium from acidic leach liquor of spent hydroprocessing catalyst using alamine 308. AB - Recovery of valuable materials/metals from waste goes hand in hand with environmental protection. This paper deals with the development of a process for the recovery of metals such as Mo, V, Ni, Al from spent hydroprocessing catalyst which may otherwise cause a nuisance if dumped untreated. A detailed study on the separation of molybdenum and vanadium from the leach solution of spent hydroprocessing catalyst of composition: 27.15% MoO3, 1.7% V2O5, 3.75% NiO, 54.3% Al2O3, 2.3% SiO2 and 10.4% LOI is reported in this paper. The catalyst was subjected to roasting under oxidizing atmosphere at a temperature of about 550 degrees C and leaching in dilute sulphuric acid to dissolve molybdenum, vanadium, nickel and part of aluminium. Metals from the leach solution were separated by solvent extraction. Both molybdenum and vanadium were selectively extracted with a suitable organic solvent leaving nickel and dissolved aluminium in the raffinate. Various parameters such as initial pH of the aqueous feed, organic to aqueous ratio (O:A), solvent concentration etc. were optimized for the complete extraction and recovery of Mo and V. Molybdenum and vanadium from the loaded organic were stripped by ammonia solution. They were recovered as their corresponding ammonium salt by selective precipitation, and were further calcined to get the corresponding oxides in pure form. PMID- 23644592 TI - Analysis of the activity of virus internal ribosome entry site in silkworm Bombyx mori. AB - Internal ribosome entry site (IRES) has been widely used in genetic engineering; however, the application in silkworm (Bombyx mori) has hardly been reported. In this study, the biological activity of partial sequence of Encephalomyocarditis virus (EMCV) IRES, Rhopalosiphum padi virus (RhPV) IRES, and the hybrid of IRES of EMCV and RhPV were investigated in Spodoptera frugiperda (Sf9) cell line and silkworm tissues. The hybrid IRES of EMCV and RhPV showed more effective than EMCV IRES or RhPV IRES in promoting downstream gene expression in insect and silkworm. The activities of all IRESs in middle silk gland of silkworm were higher than those in the fat body and posterior silk gland. The hybrid IRES of EMCV and RhPV was integrated into silkworm genome by transgenic technology to test biological activity of IRES. Each of the positive transgenic individuals had significant expression of report gene EGFP. These results suggested that IRES has a potential to be used in the genetic engineering research of silkworm. PMID- 23644593 TI - Impact of Caesarean section on subsequent fertility: a systematic review and meta analysis. AB - STUDY QUESTION: Is there an association between a Caesarean section and subsequent fertility? SUMMARY ANSWER: Most studies report that fertility is reduced after Caesarean section compared with vaginal delivery. However, studies with a more robust design show smaller effects and it is uncertain whether the association is causal. WHAT IS KNOWN ALREADY: A previous systematic review published in 1996 summarizing six studies including 85 728 women suggested that Caesarean section reduces subsequent fertility. The included studies suffer from severe methodological limitations. STUDY DESIGN, SIZE, DURATION: Systematic review and meta-analysis of cohort studies comparing subsequent reproductive outcomes of women who had a Caesarean section with those who delivered vaginally. PARTICIPANTS/MATERIALS, SETTING, METHODS: Searches of Cochrane Library, Medline, Embase, CINAHL Plus and Maternity and Infant Care databases were conducted in December 2011 to identify randomized and non-randomized studies that compared the subsequent fertility outcomes after a Caesarean section and after a vaginal delivery. Eighteen cohort studies including 591 850 women matched the inclusion criteria. Risk of bias was assessed by the Newcastle-Ottawa scale (NOS). Data extraction was done independently by two reviewers. The meta-analysis was based on a random-effects model. Subgroup analyses were performed to assess whether the estimated effect was influenced by parity, risk adjustment, maternal choice, cohort period, and study quality and size. MAIN RESULTS AND THE ROLE OF CHANCE: The impact of Caesarean section on subsequent pregnancies could be analysed in 10 studies and on subsequent births in 16 studies. A meta-analysis suggests that patients who had undergone a Caesarean section had a 9% lower subsequent pregnancy rate [risk ratio (RR) 0.91, 95% confidence interval (CI) (0.87, 0.95)] and 11% lower birth rate [RR 0.89, 95% CI (0.87, 0.92)], compared with patients who had delivered vaginally. Studies that controlled for maternal age or specifically analysed primary elective Caesarean section for breech delivery, and those that were least prone to bias according to the NOS reported smaller effects. LIMITATIONS, REASONS FOR CAUTION: There is significant variation in the design and methods of included studies. Residual bias in the adjusted results is likely as no study was able to control for a number of important maternal characteristics, such as a history of infertility or maternal obesity. WIDER IMPLICATIONS OF THE FINDINGS: Further research is needed to reduce the impact of selection bias by indication through creating more comparable patient groups and applying risk adjustment. PMID- 23644594 TI - A genome-wide methylation study on obesity: differential variability and differential methylation. AB - Besides differential methylation, DNA methylation variation has recently been proposed and demonstrated to be a potential contributing factor to cancer risk. Here we aim to examine whether differential variability in methylation is also an important feature of obesity, a typical non-malignant common complex disease. We analyzed genome-wide methylation profiles of over 470,000 CpGs in peripheral blood samples from 48 obese and 48 lean African-American youth aged 14-20 y old. A substantial number of differentially variable CpG sites (DVCs), using statistics based on variances, as well as a substantial number of differentially methylated CpG sites (DMCs), using statistics based on means, were identified. Similar to the findings in cancers, DVCs generally exhibited an outlier structure and were more variable in cases than in controls. By randomly splitting the current sample into a discovery and validation set, we observed that both the DVCs and DMCs identified from the first set could independently predict obesity status in the second set. Furthermore, both the genes harboring DMCs and the genes harboring DVCs showed significant enrichment of genes identified by genome wide association studies on obesity and related diseases, such as hypertension, dyslipidemia, type 2 diabetes and certain types of cancers, supporting their roles in the etiology and pathogenesis of obesity. We generalized the recent finding on methylation variability in cancer research to obesity and demonstrated that differential variability is also an important feature of obesity-related methylation changes. Future studies on the epigenetics of obesity will benefit from both statistics based on means and statistics based on variances. PMID- 23644595 TI - Studies of IscR reveal a unique mechanism for metal-dependent regulation of DNA binding specificity. AB - IscR from Escherichia coli is an unusual metalloregulator in that both apo and iron sulfur (Fe-S)-IscR regulate transcription and exhibit different DNA binding specificities. Here, we report structural and biochemical studies of IscR suggesting that remodeling of the protein-DNA interface upon Fe-S ligation broadens the DNA binding specificity of IscR from binding the type 2 motif only to both type 1 and type 2 motifs. Analysis of an apo-IscR variant with relaxed target-site discrimination identified a key residue in wild-type apo-IscR that, we propose, makes unfavorable interactions with a type 1 motif. Upon Fe-S binding, these interactions are apparently removed, thereby allowing holo-IscR to bind both type 1 and type 2 motifs. These data suggest a unique mechanism of ligand-mediated DNA site recognition, whereby metallocluster ligation relocates a protein-specificity determinant to expand DNA target-site selection, allowing a broader transcriptomic response by holo-IscR. PMID- 23644596 TI - The octamer is the major form of CENP-A nucleosomes at human centromeres. AB - The centromere is the chromosomal locus that ensures fidelity in genome transmission at cell division. Centromere protein A (CENP-A) is a histone H3 variant that specifies centromere location independently of DNA sequence. Conflicting evidence has emerged regarding the histone composition and stoichiometry of CENP-A nucleosomes. Here we show that the predominant form of the CENP-A particle at human centromeres is an octameric nucleosome. CENP-A nucleosomes are very highly phased on alpha-satellite 171-base-pair monomers at normal centromeres and also display strong positioning at neocentromeres. At either type of functional centromere, CENP-A nucleosomes exhibit similar DNA wrapping behavior, as do octameric CENP-A nucleosomes reconstituted with recombinant components, having looser DNA termini than those on conventional nucleosomes containing canonical histone H3. Thus, the fundamental unit of the chromatin that epigenetically specifies centromere location in mammals is an octameric nucleosome with loose termini. PMID- 23644597 TI - Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming. AB - Homologous to E6-AP C terminus (HECT) E3 ligases recognize and directly catalyze ligation of ubiquitin (Ub) to their substrates. Molecular details of this process remain unknown. We report the first structure, to our knowledge, of a Ub-loaded E3, the human neural precursor cell-expressed developmentally downregulated protein 4 (Nedd4). The HECT(Nedd4)~Ub transitory intermediate provides a structural basis for the proposed sequential addition mechanism. The donor Ub, transferred from the E2, is bound to the Nedd4 C lobe with its C-terminal tail locked in an extended conformation, primed for catalysis. We provide evidence that the Nedd4-family members are Lys63-specific enzymes whose catalysis is mediated by an essential C-terminal acidic residue. PMID- 23644598 TI - CENP-A confers a reduction in height on octameric nucleosomes. AB - Nucleosomes with histone H3 replaced by CENP-A direct kinetochore assembly. CENP A nucleosomes from human and Drosophila have been reported to have reduced heights as compared to canonical octameric H3 nucleosomes, thus suggesting a unique tetrameric hemisomal composition. We demonstrate that octameric CENP-A nucleosomes assembled in vitro exhibit reduced heights, indicating that they are physically distinct from H3 nucleosomes and negating the need to invoke the presence of hemisomes. PMID- 23644600 TI - Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy. AB - Telomeres may regulate human disease by at least two independent mechanisms. First, replicative senescence occurs once short telomeres generate DNA-damage signals that produce a barrier to tumor progression. Second, telomere position effects (TPE) could change gene expression at intermediate telomere lengths in cultured human cells. Here we report that telomere length may contribute to the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a late onset disease genetically residing only 25-60 kilobases from the end of chromosome 4q. We used a floxable telomerase to generate isogenic clones with different telomere lengths from affected patients and their unaffected siblings. DUX4, the primary candidate for FSHD pathogenesis, is upregulated over ten-fold in FSHD myoblasts and myotubes with short telomeres, and its expression is inversely proportional to telomere length. FSHD may be the first known human disease in which TPE contributes to age-related phenotype. PMID- 23644599 TI - Structural basis for the recruitment of the human CCR4-NOT deadenylase complex by tristetraprolin. AB - Tristetraprolin (TTP) is an RNA-binding protein that controls the inflammatory response by limiting the expression of several proinflammatory cytokines. TTP post-transcriptionally represses gene expression by interacting with AU-rich elements (AREs) in 3' untranslated regions of target mRNAs and subsequently engenders their deadenylation and decay. TTP accomplishes these tasks, at least in part, by recruiting the multisubunit CCR4-NOT deadenylase complex to the mRNA. Here we identify an evolutionarily conserved C-terminal motif in human TTP that directly binds a central domain of CNOT1, a core subunit of the CCR4-NOT complex. A high-resolution crystal structure of the TTP-CNOT1 complex was determined, providing the first structural insight, to our knowledge, into an ARE-binding protein bound to the CCR4-NOT complex. Mutations at the CNOT1-TTP interface impair TTP-mediated deadenylation, demonstrating the significance of this interaction in TTP-mediated gene silencing. PMID- 23644601 TI - Chromatin remodeling of human subtelomeres and TERRA promoters upon cellular senescence: commonalities and differences between chromosomes. AB - Subtelomeres are patchworks of evolutionary conserved sequence blocks and harbor the transcriptional start sites for telomere repeat containing RNAs (TERRA). Recent studies suggest that the interplay between telomeres and subtelomeric chromatin is required for maintaining telomere function. To further characterize chromatin remodeling of subtelomeres in relation to telomere shortening and cellular senescence, we systematically quantified histone modifications and DNA methylation at the subtelomeres of chromosomes 7q and 11q in primary human WI-38 fibroblasts. Upon senescence, both subtelomeres were characterized by a decrease in markers of constitutive heterochromatin, suggesting relative chromatin relaxation. However, we did not find increased levels of markers of euchromatin or derepression of the 7q VIPR2 gene. The repressed state of the subtelomeres was maintained upon senescence, which could be attributed to a rise in levels of facultative heterochromatin markers at both subtelomeres. While senescence induced subtelomeric chromatin remodeling was similar for both chromosomes, chromatin remodeling at TERRA promoters displayed chromosome-specific patterns. At the 7q TERRA promoter, chromatin structure was co-regulated with the more proximal subtelomere. In contrast, the 11q TERRA promoter, which was previously shown to be bound by CCCTC-binding factor CTCF, displayed lower levels of markers of constitutive heterochromatin that did not change upon senescence, whereas levels of markers of facultative heterochromatin decreased upon senescence. In line with the chromatin state data, transcription of 11q TERRA but not 7q TERRA was detected. Our study provides a detailed description of human subtelomeric chromatin dynamics and shows distinct regulation of the TERRA promoters of 7q and 11q upon cellular senescence. PMID- 23644602 TI - Effect of a daily dose of Lactobacillus brevis CD2 lozenges in high caries risk schoolchildren. AB - OBJECTIVES: A double-blind, randomised, placebo-controlled clinical trial was performed to validate the hypothesis that the use of lozenges containing Lactobacillus brevis CD2 (Inersan(r), CD Investments srl) may reduce plaque pH, salivary mutans streptococci (ms) and bleeding on probing, during a 6-week period, in a sample of high caries risk schoolchildren. METHODS: A total of 191 children (aged 6-8 years), presenting two to three carious lesions and a salivary ms concentration of >=10(5) CFU/ml, were enrolled and divided into two groups, an L. brevis CD2 lozenge group and a no L. brevis lozenge group, and examined at baseline (t0), after 3 weeks (t1), after 6 weeks of lozenge use (t2) and 2 weeks after the cessation of lozenge use (t3). Plaque pH was assessed using the microtouch technique following a sucrose challenge. The area under the curve (AUC5.7 and AUC6.2) was recorded. Salivary ms were counted, and bleeding on probing was assessed. RESULTS: At t0, the plaque-pH and ms concentration values were similar in both groups. Mean areas (AUC5.7 and AUC6.2) were significantly greater in the control group at t1, t2 and t3. L. brevis CD2 lozenges significantly reduced salivary ms concentrations and bleeding. The subjects from the test group showed a statistically significant decrease (p = 0.01) in salivary ms concentration. At t2, a statistically significantly lower bleeding value was recorded in the test group compared with the control group (p = 0.02). CONCLUSIONS: Six weeks' use of lozenges containing L. brevis CD2 had a beneficial effect on some important variables related to oral health, including a reduction in plaque acidogenicity, salivary ms and bleeding on probing. (Trial Registration Number NCT01601145 08/21/2012). PMID- 23644603 TI - ASAIO journal farewell. PMID- 23644604 TI - Who truly benefits from extracorporeal membrane oxygenation: a call to develop predictive models. PMID- 23644605 TI - Extracorporeal Life Support Organization Registry Report 2012. AB - In this article, summary data from the annual international Extracorporeal Life Support Organization (ELSO) Registry Reports through July 2012 are presented. Nearly 51,000 patients have received extracorporeal life support (ECLS). Of the patients, 50% (>25,000) were neonatal respiratory failure, with a 75% overall survival to discharge or transfer. Congenital diaphragmatic hernia remains a major use of ECLS in this population with 51% survival. Extracorporeal life support use for pediatric respiratory failure has nearly doubled since 2000, with approximately 350 patients treated per year in the past 3 years examined (56% survival). Previously stable at about 100 cases a year for a decade, adult respiratory failure ECLS cases increased dramatically in 2009 with the H1N1 influenza pandemic and publication of the Conventional ventilation or ECMO for Severe Adult Respiratory failure (CESAR) trial results and have remained at approximately 400 cases a year through 2011 (55% survival). Use of ECLS for cardiac support represents a large area of consistent growth. Approximately 13,000 patients have been treated with survival to discharge rates of 40%, 49%, and 39% for neonates, pediatric, and adults, respectively. PMID- 23644606 TI - Cardiopulmonary resuscitation requiring extracorporeal membrane oxygenation in the elderly: a review of the Extracorporeal Life Support Organization registry. AB - The role of extracorporeal membrane oxygenation (ECMO) as part of cardiopulmonary resuscitation (ECPR) among the elderly is not clearly defined. We sought to query the international Extracorporeal Life Support Organization (ELSO) registry database to investigate the use of ECMO support among the elderly. The objective of this study was to investigate survival to hospital discharge among the elderly supported on ECMO. The ELSO registry database was queried, identifying all elderly patients (>65 years of age) supported on ECMO for ECPR from 1998 to 2009. The primary outcome variable was survival to hospital discharge. Clinical characteristics between survivors and nonsurvivors were compared using univariate analysis. Ninety-nine elderly patients requiring ECPR were identified from the ELSO registry for the study period. The median age of the cohort was 70 years (range 65-86 years). The median admission to time on ECMO was 32 hours (range 1 998 hours), median time on ECMO was 69 hours (range 1-459 hours), and median time off to discharge for survivors was 587 hours (range 3-2,166 hours). Overall, survival at hospital discharge was 22.2% (22/99). No significant differences were noted between survivors and nonsurvivors for demographics, secondary diagnoses, pre-ECMO variables, complications on ECMO, as well as the type and duration of ECMO support. Among listed comorbidities, only the presence of pre-ECMO acute renal failure was significantly more frequent in nonsurvivors compared with survivors (14 vs. 0; p = 0.04). Survival to hospital discharge among the elderly supported on ECMO is lower than that for younger adult patients (28.7% vs. 40.0%). However, it is higher than that after conventional CPR (17%), suggesting that age should not be a bar against consideration for the use of ECMO in older patients but should be considered on a case-by-case basis. PMID- 23644607 TI - Results with an anticoagulation protocol in 99 SynCardia total artificial heart recipients. AB - For 15 years, we employed a consistent anticoagulation protocol in 99 consecutive SynCardia Systems total artificial heart (TAH) recipients. Thromboelastography and platelet aggregation studies were used for evaluating and modulating therapy with dipyridamole, pentoxiphylline, aspirin, and heparin. Partial thromboplastin times, international normalized ratios, and platelet counts were also followed. After the second post-implant day in patients who were free of endo-device infection (97 patients), the embolic stroke incidence was 0.08 per patient year. This included 23.6 patient years of device support. There were no spontaneous hemorrhagic strokes. Two patients had endo-device infections and both had strokes. Postimplantation bleeding was seen in 20% of patients. All but two of these were within the first postoperative week. In all, 4% of patients had gastrointestinal bleeding. We did not observe heparin-induced thrombocytopenia in any patient. We conclude that stroke rates on TAH support have been low, and recommend this protocol. PMID- 23644608 TI - Benefits of aggressive medical management in a bovine model of chronic ischemic heart failure. AB - A major limitation in the development of mechanical circulatory support (MCS) devices has been the lack of a clinically relevant, stable, and reproducible large animal chronic heart failure (HF) model. High mortality rates have been reported with large animal chronic HF models. In this study, methods of medical management to improve survival rate (SR) were investigated. Chronic ischemic HF (IHF) was induced in Jersey calves using a microembolization technique via fluoroscopy-guided injection of 90 MUm microspheres into the coronary vasculature. Animals were divided into 1) Control--multiple embolization procedures with conservative therapy (n = 9); 2) treatment group 1 (TG1)--single embolization procedure with moderately aggressive therapy (n = 8); and 3) TG2- single embolization procedure with aggressive medical management (n = 20). The groups were not randomized with data analyzed retrospectively. Mean SR, body condition score, body weight, hemodynamic, echocardiography, and histopathology indices were recorded up to 60 days postembolization. SR improved from 56% (Control) to 75% (TG1) and 90% (TG2) using an aggressive medical management regimen of analgesia, diuretics, beta-blockade, antiarrhythmics, vasodilators, and inotropes. These findings support the hypothesis that a single coronary microembolization procedure and aggressive medical therapy produces a clinically relevant chronic IHF model with a significantly higher SR than conservative medical therapy. PMID- 23644609 TI - Design and numeric evaluation of a novel axial-flow left ventricular assist device. AB - Virtual design characteristics and performance of the first Turkish axial-flow left ventricular assist device (LVAD) are presented, with emphasis on rotor geometry. The patented rotor design includes a central flow channel carved inside the main block, which carries permanent magnets. A concentric rotor-stator gap minimizes the distance between respective magnets, improving electromagnetic efficiency and creating a second blood pathway. Dual sets of three helical blades, placed on the shaft and external surface of the rotor block, ensure unidirectionality. Hemodynamic performance was tested with computational fluid dynamics (CFD); and rotor-blade geometry was optimized, to maximize overall efficiency d and minimize backflow and wall shear stresses. For a shaft radius of 4.5 mm, rotor blade height of 2.5 mm, and blade inlet and exit metal angles of 67 degrees and 32 degrees , pump operation at the nominal head-flow combination (5 L/min and 100.4 mm Hg) was achieved at a rotor speed of 10,313 rpm. At the nominal point, backflow as percent of total flow was 7.29 and 29.87% at rotor inlet and exit, respectively; overall hydraulic efficiency reached 21.59%; and maximum area-averaged shroud shear was 520 Pa. Overall efficiency peaked at 24.07% for a pump flow of 6.90 L/min, and averaged at 22.57% within the flow range of 4-8 L/min. We concluded that the design satisfies initial rotor design criteria, and that continued studies with diffuser optimization and transient flow analysis are warranted. PMID- 23644610 TI - Improved hemodynamics with a novel miniaturized intra-aortic axial flow pump in a porcine model of acute left ventricular dysfunction. AB - Currently, long-term mechanical circulatory support (MCS) is limited to large, complex devices that require invasive, high-risk surgical implantation. These devices are mainly used in patients with late stage heart failure (HF). We are developing a novel percutaneous intra-aortic micro-axial fluid entrainment pump intended for long-term MCS in patients with earlier stage HF. This study examined the pump's hemodynamic effects in a porcine model of acute HF. In three porcine experiments, the pump was deployed in the thoracic aorta by standard cardiac catheterization techniques and was anchored with self-expanding struts. Acute cardiac dysfunction was induced by infusing esmolol continuously. Pump support increased cardiac output (+10.4%), stroke volume (+8.9%), and ejection fraction (+10.8%) while decreasing cardiac stroke work (-10.8%) and afterload (-22.7%). Furthermore, pump support significantly enhanced renal perfusion through sustained increases in both renal artery flow (+36.4%) and pressure (+73.6%). In a porcine model of acute HF, the catheter-based intra-aortic fluid entrainment pump improved hemodynamics and renal perfusion. These results suggest that the pump could improve HF outcomes and patients' quality of life by resting the heart, promoting reverse remodeling, and augmenting end-organ perfusion. Furthermore, the enhanced renal perfusion may help disrupt the cardiorenal syndrome cycle and improve HF treatment. PMID- 23644611 TI - MedTech Mag-Lev, single-use, extracorporeal magnetically levitated centrifugal blood pump for mid-term circulatory support. AB - Short- to mid-term extracorporeal ventricular assist devices (VADs) are recommended for critical cardiogenic shock patients. We have designed a preclinical, single-use MedTech Mag-Lev VAD for one-month extracorporeal use. The impeller-rotor of the pump was suspended by a two degree-of-freedom active magnetic bearing in a 300 MUm fluid gap, where the computational fluid dynamics analysis predicted a secondary flow of about 400-500 ml/min at a pump speed of 1800-2200 rpm. Three eddy current sensors were employed to implement noise- and drift-free magnetic levitation. The pump components were injection molded using polycarbonate for smooth surfaces as well as improved reproducibility, followed by coating with a biocompatible 2-methacryloyl-oxyethyl phosphorylcholine polymer. Chronic animal experiments were performed in nine calves. Three of the nine calves were excluded from analysis for problems with the circuit. Five of the six (83.3%) completed the 60 day duration of the study, while one prematurely died of massive bleeding due to inflow port detachment. The pump did not stop due to magnetic-levitation malfunction. Neither pump thrombosis nor major organ infarction was observed at autopsy. In comparison to machined surfaces, the injection-molded pump surfaces were thrombus-free after 60 day implantation. This study demonstrates the feasibility of MedTech Mag-Lev VAD for 60 day circulatory support. PMID- 23644612 TI - Mock circulatory system of the Fontan circulation to study respiration effects on venous flow behavior. AB - We describe an in vitro model of the Fontan circulation with respiration to study subdiaphragmatic venous flow behavior. The venous and arterial connections of a total cavopulmonary connection (TCPC) test section were coupled with a physical lumped parameter (LP) model of the circulation. Intrathoracic and subdiaphragmatic pressure changes associated with normal breathing were applied. This system was tuned for two patients (5 years, 0.67 m2; 10 years, 1.2 m2) to physiological values. System function was verified by comparison to the analytical model on which it was based and by consistency with published clinical measurements. Overall, subdiaphragmatic venous flow was influenced by respiration. Flow within the arteries and veins increased during inspiration but decreased during expiration, with retrograde flow in the inferior venous territories. System pressures and flows showed close agreement with the analytical LP model (p < 0.05). The ratio of the flow rates occurring during inspiration to expiration were within the clinical range of values reported elsewhere. The approach used to set up and control the model was effective and provided reasonable comparisons with clinical data. PMID- 23644613 TI - Flow modulation algorithms for intra-aortic rotary blood pumps to minimize coronary steal. AB - Intra-aortic rotary blood pumps (IARBPs) have been used for partial cardiac support during cardiogenic shock, myocardial infarction, percutaneous coronary intervention, and potentially viable for long-term circulatory support. Intra aortic rotary blood pump support continuously removes volume from the aortic root, which lowers left ventricular preload, external work (LVEW), and improves end-organ perfusion. However, IARBP support diminishes aortic root pressure and coronary artery. It may also create "coronary steal," which may produce a myocardial hypoxic state adversely affecting patient outcomes. Our objective was to develop IARBP flow modulation algorithms to eliminate coronary steal and improve the myocardial supply-demand ratio without compromising the clinical benefits of restored end-organ perfusion and reduced LVEW. The hemodynamic responses of the native ventricle, coronary, and systemic vasculature to timing and synchronization of IARBP flow modulation (cyclic variation of pump flow) were investigated using a clinical heart failure (HF) computer simulation model. A total of more than 150 combinations of varying pulse widths and time-shifts to modulate IARBP flow were tested at mean IARBP flow rates of 2, 3, and 4 L/min, and compared with HF baseline values (no IARBP support). Increasing IARBP support augmented cardiac output and diminished LVEW. Nonmodulated IARBP support significantly diminished mean diastolic coronary flow (-49%) and myocardial supply-demand ratio (-12%) compared with HF baseline. Intra-aortic rotary blood pump flow modulation increased mean diastolic coronary flow (+17%) and myocardial supply-demand ratio (+24%) compared with nonmodulated IARBP (constant flow). Modulation and synchronization of IARBP support augmented coronary artery perfusion and myocardial supply-demand ratio in simulated clinical HF while also restoring end-organ perfusion and reducing LVEW. Implementation of IARBP support with flow modulation may prevent myocardial hypoxia and improve patient outcomes. However, even with flow modulation, IARBP support provides a smaller improvement in myocardial supply demand ratio compared to ventricular assist devices and intra-aortic balloon pumps. PMID- 23644614 TI - Impact of minimized extracorporeal circulation on outcome in patients with preoperative anemia undergoing coronary artery bypass surgery. AB - Preoperative anemia and low hematocrit during cardiopulmonary bypass have been associated with worse outcome in patients undergoing cardiac surgery. The minimized extracorporeal circulation (MECC) allows a reduction of the negative effects associated with conventional extracorporeal circulation (CECC). In this study, the impact of the MECC on outcome of anemic patients after coronary artery bypass grafting (CABG) was assessed. Between January 2004 and December 2011, 1,945 consecutive patients with preoperative anemia underwent isolated CABG using CECC (44.8%) or MECC (55.2%). The cutoff point for anemia was 13 g/dl for men and 12 g/dl for women. The postoperative creatine kinase and lactate levels were significantly lower in the MECC group (p < 0.001). There was no difference in postoperative blood loss between the groups. However, the intraoperative and postoperative transfusion requirements were significantly lower in the MECC group (p < 0.05). Furthermore, MECC patients had lower incidences of postoperative acute renal failure, and low cardiac output syndrome, shorter intensive care unit lengths of stay and reduced 30-day mortality (p < 0.05). In conclusion, a reduced postoperative mortality, lower transfusion requirements, and less renal and myocardial damage encourage the use of MECC for CABG, especially in the specific high-risk subgroup of patients with anemia. PMID- 23644616 TI - Efficacy of vitamin E-bonded polysulfone dialyzer and polysulfone dialyzer on a series of non-anticoagulant hemodialysis. AB - Non-anticoagulant hemodialysis is conducted occasionally at limited numbers of hospitals on an empirical basis. This study examines the efficacy of polysulfone and vitamin E-bonded polysulfone dialyzer for non-anticoagulant hemodialysis. These dialyzers were assigned one after the other for a vintage hemodialysis patient complicated with uncontrollable bleeding. The patient's vital and console data throughout non-anticoagulant hemodialysis were monitored serially. Both dialyzers were reasonably applicable to hemodialysis without major clotting. The scheduled treatment period was completed. Vitamin E-bonded polysulfone dialyzer was superior to non-anticoagulant hemodialysis based on venous pressure observed during treatment. PMID- 23644615 TI - Toward optimization of a novel trileaflet polymeric prosthetic heart valve via device thrombogenicity emulation. AB - Aortic stenosis is the most prevalent and life-threatening form of valvular heart disease. It is primarily treated via open-heart surgical valve replacement with either a tissue or a mechanical prosthetic heart valve (PHV), each prone to degradation and thrombosis, respectively. Polymeric PHVs may be optimized to eliminate these complications, and they may be more suitable for the new transcatheter aortic valve replacement procedure and in devices like the total artificial heart. However, the development of polymer PHVs has been hampered by persistent in vivo calcification, degradation, and thrombosis. To address these issues, we have developed a novel surgically implantable polymer PHV composed of a new thermoset polyolefin called cross-linked poly(styrene-block-isobutylene block-styrene), or xSIBS, in which key parameters were optimized for superior functionality via our device thrombogenicity emulation methodology. In this parametric study, we compared our homogeneous optimized polcymer PHV to a prior composite polymer PHV and to a benchmark tissue valve. Our results show significantly improved hemodynamics and reduced thrombogenicity in the optimized polymer PHV compared to the other valves. These results indicate that our new design may not require anticoagulants and may be more durable than its predecessor, and validate the improvement, toward optimization, of this novel polymeric PHV design. PMID- 23644617 TI - 1H NMR-based metabolic profiling of human serum before and after renal transplantation. AB - Renal transplant success is closely tied to the ability to monitor transplant recipients. However, transplant monitoring still depends on relatively dated technologies. Thus, we applied a novel method of proton nuclear magnetic resonance (NMR)-based metabolomics to investigate the altered metabolic pattern in serum, seeking to identify biomarkers involved to different periods of renal transplant patients. Serum was obtained from 28 healthy controls (class 4) and from 20 renal transplant patients in different periods: pretransplant (class 1) and on the 1st (class 2) and the 7th day (class 3) after transplantation. After performing proton NMR spectroscopy, multivariate pattern recognition was applied to cluster the groups and establish disease-specific metabolite biomarker profiles. Compared with class 4, 19 different peaks and 10 potential biomarkers were identified in class 1, class 2, and class 3 (p < 0.0001). Nevertheless, there was no obvious difference between class 1, class 2, and class 3 (p > 0.05). Partial least squares-discriminant analysis models were able to identify patients with sensitivity and specificity of 98.7% and 95.4%, respectively. These results not only indicate that this novel method has sufficient sensitivity to distinguish renal transplant patients from controls but also identify biomarkers to monitor graft function, which could be developed to a clinically useful diagnostic tool. PMID- 23644618 TI - Development of an accurate fluid management system for a pediatric continuous renal replacement therapy device. AB - Acute kidney injury is common in critically ill children, and renal replacement therapies provide a life-saving therapy to a subset of these children. However, there is no Food and Drug Administration-approved device to provide pediatric continuous renal replacement therapy (CRRT). Consequently, clinicians adapt approved adult CRRT devices for use in children because of lack of safer alternatives. Complications occur using adult CRRT devices in children because of inaccurate fluid balance (FB) between the volumes of ultrafiltrate (UF) removed and replacement fluid (RF) delivered. We demonstrate the design and validation of a pediatric fluid management system for obtaining accurate instantaneous and cumulative FB. Fluid transport was achieved via multiple novel pulsatile diaphragm pumps. The conservation of volume principle leveraging the physical property of fluid incompressibility along with mechanical coupling via a crankshaft was used for FB. Accuracy testing was conducted in vitro for 8 hour long continuous operation of the coupled UF and RF pumps. The mean cumulative FB error was <1% across filtration flows from 300 to 3000 ml/hour. This approach of FB control in a pediatric-specific CRRT device would represent a significant accuracy improvement over currently used clinical implementations. PMID- 23644619 TI - Receptor for advanced glycation end products involved in lung ischemia reperfusion injury in cardiopulmonary bypass attenuated by controlled oxygen reperfusion in a canine model. AB - Controlled oxygen reperfusion could protect the lung against ischemia-reperfusion injury in cardiopulmonary bypass (CPB) by downregulating high mobility group box 1 (HMGB1), a high affinity receptor of HMGB1. This study investigated the effect of controlled oxygen reperfusion on receptor for advanced glycation end products (RAGE) expression and its downstream effects on lung ischemia-reperfusion injury. Fourteen canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest followed by 90 minutes of reperfusion. Animals were randomized to receive 80% FiO2 during the entire procedure (control group) or to a test group receiving a controlled oxygen reperfusion protocol. Pathologic changes in lung tissues, RAGE expression, serum interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha) were evaluated. The lung pathologic scores after 25 and 90 minutes of reperfusion were significantly lower in the test group compared with the control group (p < 0.001). RAGE expression, TNF-alpha, and IL-6 were downregulated by controlled oxygen treatment (p < 0.001). RAGE might be involved in the lung ischemia-reperfusion injury in canine model of CPB, which was downregulated by controlled oxygen reperfusion. PMID- 23644620 TI - In vitro comparison of novel polyurethane aortic valves and homografts after seeding and conditioning. AB - The aim of the study was to compare the behavior of seeded cells on synthetic and natural aortic valve scaffolds during a low-flow conditioning period. Polyurethane (group A) and aortic homograft valves (group B) were consecutively seeded with human fibroblasts (FB), and endothelial cells (EC) using a rotating seeding device. Each seeding procedure was followed by an exposure to low pulsatile flow in a dynamic bioreactor for 5 days. For further analysis, samples were taken before and after conditioning. Scanning electron microscopy showed confluent cell layers in both groups. Immunohistochemical analysis showed the presence of EC and FB before and after conditioning as well as the establishment of an extracellular matrix (ECM) during conditioning. A higher expression of ECM was observed on the scaffolds' inner surface. Real-time polymerase chain reaction showed higher inflammatory response during the conditioning of homografts. Endothelialization caused a decrease in inflammatory gene expression. The efficient colonization, the establishment of an ECM, and the comparable inflammatory cell reaction to the scaffolds in both groups proved the biocompatibility of the synthetic scaffold. The newly developed bioreactor permits conditioning and cell adaption to shear stress. Therefore, polyurethane valve scaffolds may offer a new option for aortic valve replacement. PMID- 23644621 TI - Sudden power loss in a HeartMate II left ventricular assist device due to intermittent pin contact with the battery: case report. AB - Left ventricular assist device technology has improved such that mechanical malfunction, particularly with newer generation continuous flow devices, is a relatively rare event. We present a case of sudden power loss in a HeartMate II caused by intermittent contact of the battery terminals after a clip was dropped with the battery inserted in it. The clip was replaced and the patient made a complete recovery. A new inspection and testing methodology, and amended approach to patient and caregiver training, designed to prevent future occurrences is described. PMID- 23644622 TI - Is severe cardiac dysfunction a contraindication for complex combined oncotherapy of Hodgkin's lymphoma? Not any more. AB - Hodgkin's lymphoma is a quite frequent diagnosis, particularly in younger patients, which is normally treated effectively with combined chemotherapy and radiotherapy. Cardiomyopathy induced by these treatments is not uncommon and may progress to advanced-stage heart failure. Due to the cardiotoxicity of chemotherapy for Hodgkin's disease, preexisting heart failure precludes usual therapy. We present a novel strategy of hemodynamic stabilization with an implantable left ventricular assist device (LVAD) prior to radical oncotherapy for Hodgkin's lymphoma. A 33-year-old man with a short history of progressive heart failure was hospitalized due to progressive symptoms. An echocardiogram revealed a dilated left ventricle with an ejection fraction of 18%, moderate right ventricular dysfunction, and moderate to severe tricuspid regurgitation. Supradiaphragmatic-stage Hodgkin's lymphoma was also diagnosed. Due to severe cardiac dysfunction, the patient was not a candidate for the usual chemotherapy and radiotherapy prescribed for this diagnosis. After multidisciplinary consultation and consent from the patient, an LVAD was implanted with tricuspid valve repair. Additionally, affected lymph nodes from the ventral upper mediastinum were excised, and pathological analysis confirmed the lymphoma diagnosis. The patient recovered from surgery and the postoperative course was uneventful. With LVAD support and normalized hemodynamics, chemotherapy and radiotherapy for his Hodgkin's lymphoma were completed, and the patient remains in complete remission documented by positron emission tomography/computed tomography and is well one since LVAD implantation. PMID- 23644623 TI - Dysphagia in the setting of left ventricular assist device hemolysis. AB - A 69-year-old man with advanced heart failure treated with a continuous-flow left ventricular assist device presented for evaluation of dark urine and severe dysphagia. Because of evidence of ongoing intravascular hemolysis with device dysfunction, there was a clinical suspicion for pump thrombosis. He had progressive end-organ dysfunction and was therefore treated with tissue plasminogen activator with prompt resolution in hemolysis and dysphagia. Although symptoms of smooth muscle dystonia could represent worsening heart failure in the setting of device failure, the observation may also be related to intravascular hemolysis as described in the prototypic hemolytic disease, paroxysmal nocturnal hemoglobinuria. PMID- 23644624 TI - Left ventricular outflow tract occluding thrombus after biventricular mechanical circulatory support as a bridge to recovery. AB - The role of mechanical circulatory support for cardiopulmonary failure is expanding. Anticoagulation in the setting of static blood, hypercoagulable states, extracorporeal circuits, and surgery presents an intricate and delicate balance. We present a patient with large, biventricular thrombi during and succeeding biventricular mechanical support. Management of the thrombi and device selection in this patient are discussed. PMID- 23644625 TI - Extracorporeal membrane oxygenation and severe acute respiratory distress secondary to Legionella: 10 year experience. AB - Legionella-associated respiratory failure has a high mortality, despite modern ventilation modalities. Extracorporeal membrane oxygenation (ECMO) is used to achieve gas exchange independent of pulmonary function in patients with severe respiratory failure. This was a retrospective review of the management and outcome of patients with Legionella-associated respiratory failure treated with ECMO support in a large ECMO center over the past 10 years. A retrospective review of patients with confirmed Legionella-associated severe respiratory failure managed with ECMO support at a single center. Between 2000 and 2010, 19 patients with severe respiratory failure caused by Legionella were managed with ECMO after failure to respond to conventional intensive care management. Median PaO2/FiO2 ratio was 66 and median pCO2 was 60 torr. Sixteen patients (84%) survived to hospital discharge. Extracorporeal membrane oxygenation should be considered in patients with Legionella-associated respiratory failure, who have failed conventional ventilation. PMID- 23644626 TI - Perioperative management of bridge-to-lung transplant using ECMO. AB - Respiratory failure requiring intubation has traditionally been a relative contraindication to lung transplantation due to increased morbidity and mortality. Advances in extracorporeal membranous oxygenation (ECMO) have made it possible to extubate patients and provide physical therapy with minimal native lung function. By "bridging" patients to lung transplant using ECMO, they are able to undergo rehabilitation and withstand the demands of surgery. However, providing anesthesia for these cases requires an understanding of ECMO physiology and the pharmacology associated with ECMO. We describe the anesthetic for four patients who were bridged to lung transplant and the complexities of their perioperative management. PMID- 23644627 TI - Exciton lifetime measurements on single silicon quantum dots. AB - We measured the exciton lifetime of single silicon quantum dots, fabricated by electron beam lithography, reactive ion etching and oxidation. The observed photoluminescence decays are of mono-exponential character with a large variation (5-45 MUs) from dot to dot, even for the same emission energy. We show that this lifetime variation may be the origin of the heavily debated non-exponential (stretched) decays typically observed for ensemble measurements. PMID- 23644628 TI - Clinical profile and evolution of infants with deformational plagiocephaly included in a conservative treatment program. AB - PURPOSE: The aim of this study was to evaluate the results of a conservative intervention in infants with plagiocephaly according to their specific clinical profile. METHODS: Prospective clinical trial in which 104 infants with plagiocephaly accompanied or not by congenital or positional torticollis were referred to Early Care and Monitoring Unit (USAT) of San Cecilio Hospital in Granada, between 2009 and 2012. All the infants, grouped into three categories of severity, were included in the physiotherapy protocol until adequate craniofacial morphology and motor development were achieved. The study included an assessment of parents and infants. Parents were assessed with a questionnaire about the mother's medical history and birth-related issues. The assessment of infants included anthropometric measures, a positional assessment, the observation of the head, the assessment of severity, and motor development. RESULTS: Birth characteristics were similar in the total sample but showed different clinical profiles according to treatment aspects. More specifically, infants with severe plagiocephaly were referred to treatment later and spent more time in treatment; use of an orthotic helmet was also more prevalent in this category. There were also significant differences (P < 0.05) in the acquisition of specific gross motor skills depending on the severity of plagiocephaly. CONCLUSION: The findings suggest that the physiotherapy protocol presented is effective to correct plagiocephaly. Severity of plagiocephaly is a marker that should be taken into account when designing actions aimed at improving gross motor skill development. PMID- 23644629 TI - An external validation of the ETVSS for both short-term and long-term predictive adequacy in 104 pediatric patients. AB - PURPOSE: This study aims to provide external validation of the "Endoscopic Third Ventriculostomy Success Score (ETVSS)" for both short-term and long-term predictive adequacy. METHODS: Between 1998 and 2007, we collected clinical follow up data (after 6 and 36 months) of all 104 hydrocephalic children (<18 years of age) treated by endoscopic third ventriculostomy (ETV) in our hospital. Predictive adequacy of ETVSS for 6- and 36-month periods was tested by means of an unpaired t test, Hosmer-Lemeshow "goodness-of- fit" test, and area under the receiver operating characteristic curve. RESULTS: Mean follow-up was 73.4 months. For both the short-term (6 months) and the long-term (36 months) periods, the mean predicted probability of ETV for the patients with successful ETV treatment was significantly higher than in the patients with failed ETV treatment. The areas under the curve for the short- and long-term periods were, respectively, 0.82 (95% CI 0.71-0.92) and 0.73 (95% CI 0.62-0.84). For patients with moderate ETVSS (50-70), the median age at first ETV was significantly higher for patients with successful ETV for both short- and long-term periods. CONCLUSION: In hydrocephalic children, the ETVSS is a useful tool for prediction of outcome after ETV treatment. The ETVSS is more adequate in predicting short-term than long-term success. In our population, it is suggested that success rate for patients with moderate ETVSS could be improved if more weight is attributed to age at first ETV. PMID- 23644630 TI - Oberlin transfer and partial radial to axillary nerve neurotization to repair an explosive traumatic injury to the brachial plexus in a child: case report. AB - PURPOSE: Explosive injuries to the pediatric brachial plexus are exceedingly rare and as such are poorly characterized in the medical literature. METHODS: Herein, we describe an 8-year-old who was struck in the neck by a piece of shrapnel and suffered multiple vascular injuries in addition to a suspected avulsion of the cervical 5 and 6 ventral rami. The patient had a complete upper brachial plexus palsy and failed to demonstrate any clinical improvement at 6-months follow-up. He was taken to the operating from for a partial ulnar to musculocutaneous nerve neurotization as well as a partial radial to axillary nerve neurotization. RESULTS: The patient's motor exam improved from a Medical Research Council scale 1 to 4+ for biceps brachii and 0 to 4 deltoid function with greater than 90 degrees of shoulder abduction. CONCLUSIONS: This outcome supports complex neurotization techniques as viable treatment options for persistent motor deficits following an upper brachial plexus injury in older, non-infant age, children. PMID- 23644631 TI - Effect of IFN-alpha on KC and LIX expression: role of STAT1 and its effect on neutrophil recruitment to the spleen after lipopolysaccharide stimulation. AB - The spleen is a crucial lymphoid organ. It is involved in the recruitment of various immunocytes to their correct locations using specific chemokines, but little is known concerning the role of type-I interferon (IFN) in the regulation of chemokines. In this study, we first used protein microarrays to assess the expression of keratinocyte-derived chemokine (KC) and lipopolysaccharide-induced CXC chemokine (LIX) in murine spleens. Both expressions were smoothly enhanced by IFN-alpha pretreatment after LPS injection. Then, we focused on the IFN-alpha regulation of KC, LIX, and their target cells, neutrophils, using an IFN-alpha neutralizing antibody and fludarabine (specific signal transducers and activators of transcription 1 - STAT1 inhibitor). Next, LPS was found to attenuate the production of KC and LIX in spleen. Even the elevated production of chemokines caused by exogenous IFN-alpha was found to be attenuated by fludarabine pretreatment. We later determined that the marginal zone and red pulp are the main sites of KC and LIX production. Last, we determined that the number of neutrophils was slightly increased by IFN-alpha treatment and diminished by IFN alpha neutralization or fludarabine treatment. Further, the elevated neutrophils due to exogenous IFN-alpha were partially reversed by fludarabine pretreatment. In this way, these results indicate that IFN-alpha facilitates KC and LIX expression in mouse spleens after an LPS challenge. This effect was found to be mainly dependent upon the activation of STAT1, it may be involved in the recruitment of neutrophils to the spleen for the clearance of pathogens. PMID- 23644634 TI - Physician burnout: "the call" derailed? PMID- 23644632 TI - Simple and efficient synthesis of cyclic carbonates using quaternized glycine as a green catalyst. AB - Microwave-assisted quaternization of glycine (GLY) resulted in the synthesis of an efficient catalyst, quaternized glycine (QGLY), for the solventless synthesis of cyclic carbonates from epoxides and CO2 under mild reaction conditions. Density functional theory was used to simulate the synergistic influence of the COOH group and the halide ion of QGLY in enhancing the catalytic activity. PMID- 23644635 TI - Physician burnout: a serious concern for the medical profession. PMID- 23644636 TI - Risk stratification for the development of post-ERCP pancreatitis by sphincter of Oddi dysfunction classification. AB - OBJECTIVES: To explore whether there is a difference in the frequency of postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in patients with manometrically confirmed sphincter of Oddi dysfunction (SOD) types I, II, and III. METHODS: A retrospective review of all of the patients who underwent an ERCP with SOD type I or patients with manometrically confirmed SOD type II or type III (mean basal sphincter pressure >= 40 mm Hg) from 2006 to 2010 was performed. The primary outcome measure was development of post-ERCP acute pancreatitis in each of the SOD groups. Factors associated with acute pancreatitis in each group were examined by univariate analysis. RESULTS: We identified 147 patients with SOD. Biliary sphincterotomy was performed in all of the patients, and pancreatic sphincterotomy was performed in 68 of the 147 (46%). All of the patients underwent stenting of the pancreatic duct. Post-ERCP pancreatitis occurred in 23% of the study cohort. Patients with SOD type III had a higher frequency of post-ERCP pancreatitis compared with the SOD type I and type II groups (31% vs 20% vs 6%, respectively; P = 0.024). Those with SOD type III had a greater frequency of post-ERCP pancreatitis (odds ratio 6.7; P = 0.05) compared with those with SOD type I. Patients with SOD type III had a two times greater frequency of developing post-ECRP pancreatitis compared with those with SOD type II. CONCLUSIONS: SOD type III is strongly associated with the development of post-ERCP pancreatitis compared with SOD type I. PMID- 23644637 TI - Commentary on "Risk Stratification for the Development of Post-ERCP Pancreatitis by Sphincter of Oddi Dysfunction Classification". PMID- 23644638 TI - Self-reported arthritis burden and management in South Carolina. AB - OBJECTIVE: Arthritis has garnered national attention as the leading cause of disability, yet it is important to survey the burden and management of this disabling condition at the state and local levels. This study explored the self reported burden and management of arthritis in South Carolina using state-based data relative to other prominent chronic diseases. METHODS: Data from 9580 adults in South Carolina who participated in the 2009 Behavioral Risk Factor Surveillance System were used to quantify the self-reported burden and management of arthritis within the past year. RESULTS: Estimates indicate that 31% (3043) of adults in South Carolina were diagnosed as having arthritis in 2009. The burden of arthritis was evident with 49% (1954) of the individuals with arthritis experiencing activity limitations, 39% (1500) reported arthritis affected their employment, 92% (3705) reported living with pain, and 44% (1787) reported restricted social activities. Self-reported arthritis management included advice to lose weight (37%), encouragement to exercise (57%), and limited education on proper management (11%). The majority (75%) of individuals reported that arthritis interferes with their ability to accomplish what they want. CONCLUSIONS: Arthritis is more prevalent and burdensome for individuals in South Carolina when compared with national estimates. These findings suggest that there are potential educational opportunities to increase awareness of the disease and its burden, as well as improve education and disease management. PMID- 23644639 TI - Smoking and respiratory conditions in pregnancy: associations with adverse pregnancy outcomes. AB - OBJECTIVES: Acute and chronic respiratory conditions affect a large segment of pregnant women. The purpose of the current study was to examine the concomitant effects of respiratory conditions and smoking during pregnancy on gestational age, birth weight, fetal distress, infant mortality, premature rupture of membranes, placenta abruption, and mode of delivery. METHODS: This study used data (n = 1,064,969) from the North Carolina linked birth/infant death files from 1999 to 2007. Logistic regression was used to compute odds ratios and 95% confidence intervals (CIs) in assessing risk of adverse pregnancy outcomes. RESULTS: We found that women with respiratory conditions/smoking status were significantly more likely than nonsmokers with no respiratory conditions to have a low-birth-weight infant, an infant with fetal distress, and experience preterm birth and an infant's death. Adjusted odds ratios also revealed that smokers with respiratory conditions were 2.37 (95% CI 1.69-3.32) times more likely than women with no respiratory conditions/nonsmoking status to have placenta abruption and 2.20 (95% CI 1.85-2.61) times more likely to have premature rupture of membranes. Regardless of smoking status, women with respiratory conditions were less likely to have a vaginal delivery. CONCLUSIONS: These findings underscore the need for clinical and public health programs to educate women, particularly those with respiratory diseases, of the immense array of adverse outcomes that may occur as a consequence of active maternal smoking during gestation. It is important for interventions to target mothers with respiratory conditions early on to ensure favorable birth outcomes. PMID- 23644640 TI - Anemia in general medical inpatients prolongs length of stay and increases 30-day unplanned readmission rate. AB - OBJECTIVES: Anemia, either chronic or newly developed in the hospital as a result of underlying disease and/or phlebotomy, is seen commonly among general medical inpatients, and its impact on the quality and efficiency of care is unknown. METHODS: This study investigated the relation among hemoglobin level, length of stay, and 30-day unplanned readmission rates in a cohort of 314 general medical inpatients 18 years old and older admitted to a teaching hospital during a period of 4 months in a large urban academic medical center, using retrospective chart review of the electronic health record. RESULTS: Anemia was common among this cohort of general medical inpatients (44.6%), and there was a statistically significant decrease in hemoglobin levels during their hospitalization. Anemic patients, as compared with nonanemic patients, had significantly longer mean and median length of stay. More important, the admission hemoglobin level and its change during hospitalization were significant predictors of increased length of stay. For every 1-U increase in admission hemoglobin level, the median length of stay was reduced by 0.5 days. For every 1-U increase in the level of hemoglobin change, the median length of stay was extended by 1.5 days. Likewise, the discharge hemoglobin level predicted the rate of 30-day unplanned readmission. For every 1-U decrease in discharge hemoglobin level, the readmission rate increased by nearly 4%. These relations remained after adjusting for common demographic and clinical variables, including age, sex, nutritional status, and number of comorbidities. CONCLUSIONS: Anemia is common among general medical inpatients and adversely affects their length of stay and 30-day unplanned readmission rate. PMID- 23644641 TI - High frequencies of negative pretreatment results following presumptive antibiotic treatment for chlamydia and gonorrhea. AB - INTRODUCTION: The purpose of this study was to determine the frequencies of negative test results among all patients aged 18 years and older receiving presumptive antibiotic treatment for chlamydia and/or gonorrhea at the Sexually Transmitted Disease Clinic of the Palm Beach County Health Department. The treatment algorithms were based on guidelines of the Centers for Disease Control and Prevention. METHODS: Clinic logs were retrospectively reviewed for a consecutive case series of all 1209 patients treated from November 1, 2007 to October 31, 2008. Urogenital specimens were collected and analyzed. Laboratory results were obtained from the Health Management System of the Palm Beach County Health Department. RESULTS: Of the 1209 patients, 556 (46%) were treated for chlamydia, 30 (2.5%) for gonorrhea, and 623 (51.5%) for both. The frequencies of negative results were 68% for chlamydia or gonorrhea, 70.9% for chlamydia, 86.6% for gonorrhea, and 65.2% for chlamydia + gonorrhea. CONCLUSIONS: These data indicate that implementation of the Centers for Disease Control and Prevention guidelines by the Sexually Transmitted Disease Clinic of the Palm Beach County Health Department results in presumptive treatment of more than two-thirds of patients with negative nucleic acid amplification test results for chlamydia, gonorrhea, or both. They also suggest the potential value of developing treatment algorithms to maximize treatment of patients with positive test results and minimize treatment of those with negative test results. One possible strategy to explore is the future utility of new testing and treatment methodologies in development. PMID- 23644642 TI - Predictors of failed primary abdominal closure in the trauma patient with an open abdomen. AB - BACKGROUND: We sought to characterize risk factors for failed closure after damage-control laparotomy and to examine the impact of two broad categories of open abdomen-management technique on rates of fascial approximation. METHODS: We retrospectively reviewed (January 2006-December 2008) all trauma patients with an open abdomen after damage-control laparotomy. Patients with definitive abdominal closure before discharge were classified as successful closure (SC) and those discharged with a planned ventral hernia were classified as failed closure (FC). Univariate stepwise logistical analyses were conducted to identify covariates related to resuscitation volumes and injury severity that were associated with FC. Surgical techniques were dichotomized as fascial based or vacuum based and compared with chi square. RESULTS: Sixty-two subjects met final eligibility (SC 44, FC 18). SC and FC were similar, with the exception of, respectively, initial base excess (-8.0 +/- 4.2 vs -11.4 +/- 4.9; P = 0.009), injury severity score (ISS; 29.0 +/- 15.2 vs 20.6 +/- 12.1; P = 0.04), and frequency of penetrating injury (47.7% vs 77.8%; P = 0.03). Stepwise regression showed significant associations between failed closure and increasing Penetrating Abdominal Trauma Index (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.01-1.11), worsening base excess on arrival (OR 0.79, 95% CI 0.66-0.93), and lower ISS (OR 0.94, 95% CI 0.89-1.00). Fascial-based versus vacuum-based management techniques had no effect on closure rates. CONCLUSIONS: Volume of blood transfused, crystalloid given, and open abdomen management technique were not related to closure rates; however, worsened base excess on arrival, penetrating trauma, higher Penetrating Abdominal Trauma Index, and a lower ISS were associated with FC. The latter was true despite an association also being found between FC and lower ISS scores, reflecting the propensity of ISS to underestimate injury burden after penetrating injury. PMID- 23644643 TI - Commentary on "predictors of failed primary abdominal closure in the trauma patient with an open abdomen". PMID- 23644644 TI - Parkinson disease: research update and clinical management. PMID- 23644645 TI - An appeal for humanity. PMID- 23644647 TI - Short stature in child with early-onset diabetes. AB - We present a girl who initially presented at 12 weeks of age with antibody negative diabetes. Genetic screening for common mutations of monogenic diabetes was negative. She was noted to have short stature at 8 years of age (height <0.4 centile), as well as overlapping toes and distal abnormalities of her fingers. On reevaluation, further investigation revealed an EIF2AK3 mutation, and a diagnosis of Wolcott Rallison syndrome was made. This case highlights the importance of close follow up of patients with neonatal diabetes for the development of syndromic features that may lead to a unifying diagnosis. PMID- 23644648 TI - Bronchopulmonary dysplasia and neurodevelopmental outcome in extremely preterm neonates. AB - We tested the hypothesis that the use of supplemental oxygen (sO2) at discharge from the NICU in extremely preterm neonates is associated with a greater risk of neurodevelopmental impairment (NDI) at 18 months corrected gestational age (CGA) than the risk of NDI of those neonates discharged in room air. Four hundred twenty-four charts were retrospectively reviewed from infants born at <27 weeks and transferred to Nationwide Children's Hospital from December 1, 2004 to June 14, 2010. Use of sO2 was evaluated on day of life (dol) 28, at 36 weeks post menstrual age (PMA), and at discharge. Logistic regression was used to identify postnatal risk factors associated with sO2 at discharge and NDI. At dol 28, 96 % of surviving patients received sO2, and therefore had bronchopulmonary dysplasia (BPD) by definition from a National Institutes of Child Health and Human Development workshop. At 36 weeks PMA, 89 % continued on sO2 (moderate/severe BPD), and at discharge, 74 % continued on sO2. When factors associated with NDI were examined, the need for mechanical ventilation >=28 days (adjOR = 3.21, p = 0.01), grade III-IV intraventricular hemorrhage (IVH) (adjOR = 4.61, p < 0.01), and discharge at >43 weeks PMA (adjOR = 2.12, p = 0.04) were the strongest predictors of NDI at 18 months CGA. There was no difference in Bayley Scales of Infant Development, third edition composite scores between patients with no/mild BPD and patients with moderate/severe BPD (cognitive p = 0.60, communication p = 0.53, motor p = 0.19) or those scores between patients on and off oxygen at discharge (cognitive p = 0.58, communication p = 0.70, motor p = 0.62). CONCLUSIONS: The need for sO2 at discharge is not associated with an increased risk of NDI in these patients. The strongest predictors of poor neurodevelopmental outcome in this population were prolonged positive pressure support, grade III-IV IVH, and discharge at >43 weeks PMA. PMID- 23644649 TI - Accuracy of the StatStrip versus SureStep Flexx glucose meter in neonates at risk of hypoglycemia. AB - The study was performed to evaluate the accuracy of the StatStrip (SS) and SureStep Flexx (SF) glucose meters compared to plasma glucose in infants at risk for neonatal hypoglycemia and to determine the effect of bilirubin and hematocrit on the results. A prospective cross-sectional study was conducted on 172 venous blood glucose samples from infants who had initial low point-of-care (POC) glucose tests measured simultaneously by SS and SF. Plasma glucose levels were compared to both POC instruments, and the effect of bilirubin and hematocrit levels on mean glucose differences were analysed. Mean (SD) plasma glucose was 2.12 (0.45) mmol/L; (range, 1.11-3.06 mmol/L). Mean (1.96SD) glucose differences of the SS versus SF were 0.21 (0.70) mmol/L and -0.04 (0.78) mmol/L, respectively. SS sensitivity was 94.7 % with an 86.1 % negative predictive value (NPV) at 2.8 mmol/L, while the SF had a 100 % sensitivity and NPV at the same cut off level. No correlations were identified between mean glucose differences and either hematocrit or bilirubin levels in both glucose meters. Both the SS and SF glucose meters have limited use when compared to plasma glucose. Hence, they can only be employed as screening tools in at-risk neonates with an appropriate, predetermined cut-off level. Hematocrit and bilirubin levels did not affect the accuracy of both devices. PMID- 23644650 TI - Comparison of two treatment eras and sonographic long-term outcome of blunt splenic injuries in children. AB - The treatment of blunt splenic injuries (BSI) has undergone a significant shift away from an operative approach to a conservative treatment regimen in the last decades. Data concerning long-term follow-up of children sustaining BSI are largely confined to telephone surveys. Children treated with BSI over a 33-year period were analyzed. In order to describe the changing treatment, patients were divided into two groups: group I included children treated between 1977 and 1999; group II children treated between 2000 and 2009. Additionally, patients treated nonoperatively between 2000 and 2009 were invited for a sonographic follow-up examination. In group I 81 patients and in group II 89 patients were treated. An increase of male patients from 69 to 88 % was observed, comparing the two eras. While children treated in the earlier period were 8.8-years-old mean (range 1 to 15), the patients treated between 2000 and 2009 were older (mean 10.4 years, range 1 to 17). Between 1977 and 1999, 79 % of the patients were treated nonoperatively. This rate considerably increased to 94 % in the second era. Follow-up examination was performed with a mean age of 6 years (range 1 to 11 years) post-injury. In 79 % of the cases, the spleen healed without sonographic long-term sequelae. In the remaining 21 % of the patients, a scar formation could be demonstrated. CONCLUSION: We were able to confirm that the majority of children sustaining BSI can be safely treated conservatively. PMID- 23644652 TI - An associative capacitive network based on nanoscale complementary resistive switches for memory-intensive computing. AB - We report on the implementation of an Associative Capacitive Network (ACN) based on the nondestructive capacitive readout of two Complementary Resistive Switches (2-CRSs). ACNs are capable of performing a fully parallel search for Hamming distances (i.e. similarity) between input and stored templates. Unlike conventional associative memories where charge retention is a key function and hence, they require frequent refresh cycles, in ACNs, information is retained in a nonvolatile resistive state and normal tasks are carried out through capacitive coupling between input and output nodes. Each device consists of two CRS cells and no selective element is needed, therefore, CMOS circuitry is only required in the periphery, for addressing and read-out. Highly parallel processing, nonvolatility, wide interconnectivity and low-energy consumption are significant advantages of ACNs over conventional and emerging associative memories. These characteristics make ACNs one of the promising candidates for applications in memory-intensive and cognitive computing, switches and routers as binary and ternary Content Addressable Memories (CAMs) and intelligent data processing. PMID- 23644651 TI - Exercise modality and metabolic efficiency in children. AB - Current exercise prescription guidelines for children recommend at least 60 min of moderate-to-vigorous physical activity every day. However, little is known about the efficacy of different cardiorespiratory exercise modalities prescribed to the pediatric cohort. Sixteen healthy children (8-12 years) completed 5-min trials of treadmill walking, cycling, and elliptical training in a randomized order. The treadmill walking speed was determined from measurements collected during a self-selected walking trial. The workloads for treadmill walking, cycling, and elliptical training were matched (40.3 W). Mechanical efficiency (ME%), perceived exertion (RPE), oxygen uptake, metabolic equivalents, and net energy expenditure were measured. ME% in walking was significantly higher than in cycling (P = 0.001) and elliptical training (P < 0.001), and cycling was significantly higher than elliptical training (P = 0.003). RPE in walking was significantly lower than in elliptical training (P = 0.006) but not from cycling (P = 0.314), and cycling resulted in significantly lower RPE than elliptical training (P = 0.021). CONCLUSION: Treadmill walking appears to be the most efficacious exercise prescription for otherwise healthy children; however, longitudinal studies need to be implemented to investigate the long-term benefits of each exercise modality. PMID- 23644653 TI - Introducing an angle adjustable cutting box for analyzing slice shear force in meat. AB - Research indicates the fibre angle of the longissimus muscle can vary, depending upon location within a steak and throughout the muscle. Instead of using the original fixed 45 degrees or 90 degrees cutting angle for testing shear force, a variable angle cutting box can be adjusted so the angles of the knives correspond to the fibre angle of each sample. Within 2 min after cooking to an internal temperature of 71 degrees C on an open-hearth grill set at 210 degrees C, a 1 cm by 5 cm core is cut from the steak, parallel to muscle fibre direction, using 2 knife blades set 1 cm apart. This warm core is then subjected to the Slice Shear Force protocol (SSF) to evaluate meat texture. The use of the variable angle cutting box and the SSF protocol provides an accurate representation of the maximal shear force, as the slice and muscle fibres are consistently parallel. Therefore, the variable angle cutting box, in conjunction with the SSF protocol, can be used as a high-throughput technique to accurately evaluate meat tenderness in different locations of the longissimus muscle and, potentially, in other muscles. PMID- 23644654 TI - BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways. AB - Simultaneous inhibition of the two major constitutive protein quality control (PQC) pathways, that is, the ubiquitin-proteasome system (UPS) and the aggresome autophagy system, has been suggested as a promising strategy to trigger cell death in cancer cells. However, we observed that one third of rhabdomyosarcoma (RMS) cells survives parallel inhibition of the UPS by Bortezomib and the aggresome-autophagy pathway by the cytoplasmic histone deacetylase 6 inhibitor ST80, and is able to regrow upon drug removal, thus pointing to the induction of compensatory pathways. Here, we identify Bcl-2-associated athanogene 3 (BAG3) as a critical mediator of inducible resistance in surviving cells after concomitant blockage of constitutive PQC pathways by mitigating ST80/Bortezomib-triggered proteotoxicity via selective autophagy. ST80/Bortezomib cotreatment upregulates BAG3 mRNA and protein levels in surviving cells in addition to triggering the accumulation of insoluble protein aggregates. Intriguingly, knockdown of BAG3 by RNA interference severely impairs clearance of protein aggregates, significantly increases cell death and reduces long-term survival and clonogenic growth during recovery after ST80/Bortezomib cotreatment. Similarly, inhibition of autophagy by inducible autophagy-related protein 7 knockdown prevents removal of protein aggregates and cell regrowth during recovery after ST80/Bortezomib cotreatment. Also, the inhibition of lysosomal degradation using the V-ATPase pump inhibitor Bafilomycin A1 enhances accumulation of protein aggregates, and completely abolishes regrowth after Bortezomib/ST80-induced proteotoxic stress. By identifying BAG3 as a key mediator of inducible resistance by mitigating proteotoxicity via selective autophagy after inhibition of constitutive PQC systems, our study provides new insights into the regulation of PQC pathways in cancer cells and identifies new targets for therapeutic intervention. PMID- 23644656 TI - Heparanase promotes lymphangiogenesis and tumor invasion in pancreatic neuroendocrine tumors. AB - Heparan sulfate proteoglycans are an important and abundant component of the extracellular matrix, which undergo substantial remodeling throughout tumorigenesis via the enzymatic activity of heparanase. Heparanase has been shown to be upregulated in many human cancers; however, its specific functions in human pancreatic neuroendocrine tumors (PanNETs) and spontaneous mouse models of cancer have not been evaluated. Here, we investigated the role of heparanase in PanNETs using patient samples and the RIP1-Tag2 (RT2) PanNET-transgenic mouse model. High heparanase expression significantly correlated with more advanced tumor stage, higher tumor grade and the presence of distant metastasis in PanNET patients. We genetically manipulated heparanase levels in the RT2 model using heparanase transgenic mice, which constitutively overexpress heparanase, and heparanase knockout mice. Heparanase was found to have a critical role in promoting tumor invasion, through both macrophage and cancer cell sources in the tumor microenvironment. In addition, elevated heparanase levels significantly increased peritumoral lymphangiogenesis in vivo and promoted the trans-differentiation of macrophages into lymphatic endothelial cell-like structures in culture. Conversely, we found that heparanase deletion led to increased angiogenesis and pericyte coverage. Together, these data identify important roles for heparanase in regulating several critical aspects of tumorigenesis, demonstrating that heparanase represents a potential therapeutic target for PanNET patients. PMID- 23644655 TI - Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y(1086), c-Src, Erk1/2 and Akt phosphorylation and smallGTPase activity. AB - The interactions between cancer cells and their microenvironment are crucial for malignant progression, as they modulate invasion-related activities. Tumor associated macrophages are generally considered allies in the process of tumor progression in several types of cancer, although their role on gastric and colorectal carcinomas is still poorly understood. In this report, we studied the influence of primary human macrophages on gastric and colorectal cancer cells, considering invasion, motility/migration, proteolysis and activated intracellular signaling pathways. We demonstrated that macrophages stimulate cancer cell invasion, motility and migration, and that these effects depend on matrix metalloproteinase (MMP) activity and on the activation of epidermal growth factor receptor (EGFR) (at the residue Y(1086)), PLC-gamma (phospholipase C-gamma) and Gab1 (GRB2-associated binding protein-1), as evidenced by siRNA (small interference RNA) experiments. Epidermal growth factor (EGF)-immunodepletion impaired macrophage-mediated cancer cell invasion and motility, suggesting that EGF is the pro-invasive and pro-motile factor produced by macrophages. Macrophages also induced gastric and colorectal cancer cell phosphorylation of Akt, c-Src and ERK1/2, and led to an increase of RhoA and Cdc42 activity. Interestingly, whereas macrophage-mediated cancer cell c-Src and ERK1/2 phosphorylation occurred downstream EGFR activation, Akt phosphorylation seems to be a parallel event, taking place in an EGFR-independent manner. The involvement of EGF, EGFR-downstream signaling partners and MMPs in macrophage-mediated invasion provides novel insights into the molecular crosstalk established between cancer cells and macrophages, opening new perspectives for the design of new and more efficient therapeutic strategies to counteract cancer cell invasion. PMID- 23644657 TI - Siah2 regulates tight junction integrity and cell polarity through control of ASPP2 stability. AB - Changes in cell adhesion and polarity are closely associated with epithelial cell transformation and metastatic capacity. The tumor suppressor protein ASPP (Apoptosis-Stimulating Proteins of p53) 2 has been implicated in control of cell adhesion and polarity through its effect on the PAR complex. Here we demonstrate that under hypoxic conditions, the ubiquitin ligase Siah (seven in absentia homolog)2 controls ASPP2 availability, with concomitant effect on epithelial cell polarity. LC-MS/MS analysis identified ASPP2 and ASPP1 as Siah2-interacting proteins. Biochemical analysis confirmed this interaction and mapped degron motifs within ASPP2, which are required for Siah2-mediated ubiquitination and proteasomal-dependent degradation. Inhibition of Siah2 expression increases ASPP2 levels and enhances ASPP2-dependent maintenance of tight junction (TJ) integrity, and polarized architecture in three dimensional (3D) organotypic culture. Conversely, increase of Siah2 expression under hypoxia decreases ASPP2 levels and the formation of apical polarity in 3D culture. In all, our studies demonstrate the role of Siah2 in regulation of TJ integrity and cell polarity under hypoxia, through its regulation of ASPP2 stability. PMID- 23644658 TI - Glioma tumor grade correlates with parkin depletion in mutant p53-linked tumors and results from loss of function of p53 transcriptional activity. AB - Gliomas represent the most frequent form of primary brain tumors in adults, the prognosis of which remains extremely poor. Inactivating mutations on the tumor suppressor TP53 were proposed as a key etiological trigger of glioma development. p53 has been recently identified as a transcriptional target of parkin. Interestingly, somatic mutations on parkin have also been linked to glioma genesis. We examined the possibility that a disruption of a functional interaction between p53 and parkin could contribute to glioma development in samples devoid of somatic parkin mutations or genetic allele deletion. We show here that parkin levels inversely correlate to brain tumor grade and p53 levels in oligodendrogliomas, mixed gliomas and glioblastomas. We demonstrate that p53 levels negatively and positively correlate to bax and Bcl2 respectively, underlying a loss of p53 transcriptional activity in all types of glial tumors. Using various cell models lacking p53 or harboring either transcriptionally inactive or dominant negative p53, as well as in p53 knockout mice brain, we establish that p53 controls parkin promoter transactivation, mRNA and protein levels. Furthermore, we document an increase of parkin expression in mice brain after p53-bearing viral infection. Finally, both cancer-related p53 inactivating mutations and deletion of a consensus p53 binding sequence located on parkin promoter abolish p53-mediated control of parkin transcription, demonstrating that p53 regulates parkin transcription via its DNA binding properties. In conclusion, our work delineates a functional interplay between mutated p53 and parkin in glioma genesis that is disrupted by cancer-linked pathogenic mutations. It also allows envisioning parkin as a novel biomarker of glioma biopsies enabling to follow the progression of this type of cancers. PMID- 23644659 TI - Human antibodies targeting the C-type lectin-like domain of the tumor endothelial cell marker clec14a regulate angiogenic properties in vitro. AB - It has been suggested that clec14a may be involved in tumor angiogenesis. However, a molecular mechanism has not been clearly identified. In this study, we show for the first time that C-type lectin-like domain (CTLD) of clec14a may be important for regulating cell migration and filopodia formation. Using phage display technology, recombinant human antibodies specific to the CTLDs of human and mouse clec14a (clec14a-CTLD (immunoglobulin G) IgG) were selected. Functional assays using the antibodies showed that clec14a-CTLD IgGs specifically blocked endothelial cell migration and tube formation without affecting cell viability or activation. Further, clec14a-CTLD IgGs inhibited clec14a-mediated cell-cell contact by blocking interaction between CTLDs. Finally, clec14a cross-linking by the clec14a-CTLD IgGs significantly downregulated clec14a expression on the surface of endothelial cells. These results strongly suggest that the clec14a CTLD may be a key domain in angiogenesis, and that clec14a-CTLD IgGs specifically inhibit angiogenesis by modulating CTLD-mediated cell interactions and clec14a expression on the surface of endothelial cells. PMID- 23644660 TI - Drosophila actin-Capping Protein limits JNK activation by the Src proto-oncogene. AB - The Src family kinases c-Src, and its downstream effectors, the Rho family of small GTPases RhoA and Jun N-terminal kinase (JNK) have a significant role in tumorigenesis. In this report, using the Drosophila wing disc epithelium as a model system, we demonstrate that the actin-Capping Protein (CP) alphabeta heterodimer, which regulates actin filament (F-actin) polymerization, limits Src induced apoptosis or tissue overgrowth by restricting JNK activation. We show that overexpressing Src64B drives JNK-independent loss of epithelial integrity and JNK-dependent apoptosis via Btk29A, p120ctn and Rho1. However, when cells are kept alive with the Caspase inhibitor P35, JNK acts as a potent inducer of proliferation via activation of the Yorkie oncogene. Reducing CP levels direct apoptosis of overgrowing Src64B-overexpressing tissues. Conversely, overexpressing capping protein inhibits Src64B and Rho1, but not Rac1-induced JNK signaling. CP requires the actin-binding domain of the alpha-subunit to limit Src64B-induced apoptosis, arguing that the control of F-actin mediates this effect. In turn, JNK directs F-actin accumulation. Moreover, overexpressing capping protein also prevents apoptosis induced by ectopic JNK expression. Our data are consistent with a model in which the control of F-actin by CP limits Src induced apoptosis or tissue overgrowth by acting downstream of Btk29A, p120ctn and Rho1, but upstream of JNK. In turn, JNK may counteract the effect of CP on F actin, providing a positive feedback, which amplifies JNK activation. We propose that cytoskeletal changes triggered by misregulation of F-actin modulators may have a significant role in Src-mediated malignant phenotypes during the early stages of cellular transformation. PMID- 23644661 TI - Translation factors and ribosomal proteins control tumor onset and progression: how? AB - Gene expression is shaped by translational control. The modalities and the extent by which translation factors modify gene expression have revealed therapeutic scenarios. For instance, eukaryotic initiation factor (eIF)4E activity is controlled by the signaling cascade of growth factors, and drives tumorigenesis by favoring the translation of specific mRNAs. Highly specific drugs target the activity of eIF4E. Indeed, the antitumor action of mTOR complex 1 (mTORc1) blockers like rapamycin relies on their capability to inhibit eIF4E assembly into functional eIF4F complexes. eIF4E biology, from its inception to recent pharmacological targeting, is proof-of-principle that translational control is druggable. The case for eIF4E is not isolated. The translational machinery is involved in the biology of cancer through many other mechanisms. First, untranslated sequences on mRNAs as well as noncoding RNAs regulate the translational efficiency of mRNAs that are central for tumor progression. Second, other initiation factors like eIF6 show a tumorigenic potential by acting downstream of oncogenic pathways. Third, genetic alterations in components of the translational apparatus underlie an entire class of inherited syndromes known as 'ribosomopathies' that are associated with increased cancer risk. Taken together, data suggest that in spite of their evolutionary conservation and ubiquitous nature, variations in the activity and levels of ribosomal proteins and translation factors generate highly specific effects. Beside, as the structures and biochemical activities of several noncoding RNAs and initiation factors are known, these factors may be amenable to rational pharmacological targeting. The future is to design highly specific drugs targeting the translational apparatus. PMID- 23644662 TI - Signaling through cyclin D-dependent kinases. AB - Research over the past quarter century has identified cyclin D-dependent kinases, CDK4 and CDK6, as the major oncogenic drivers among members of the CDK superfamily. CDK4/6 are rendered hyperactive in the majority of human cancers through a multitude of genomic alterations. Sustained activation of these protein kinases provides cancer cells with the power to enter the cell cycle continuously by triggering G1-S-phase transitions and dramatically shortening the duration of the G1 phase. It has also become clear, however, that CDK4/6 effectively counter cancer cell-intrinsic tumor suppression mechanisms, senescence and apoptosis, which must be overcome during cell transformation and kept at bay throughout all stages of tumorigenesis. As a central 'node' in cellular signaling networks, cyclin D-dependent kinases sense a plethora of mitogenic signals to orchestrate specific transcriptional programs. As the complexity of the cellular signaling network regulated by these oncogenic kinases unfolds, much remains to be learned about its architecture, its dynamics and the consequences of its perturbation. PMID- 23644663 TI - CD99 suppresses osteosarcoma cell migration through inhibition of ROCK2 activity. AB - CD99, a transmembrane protein encoded by MIC2 gene is involved in multiple cellular events including cell adhesion and migration, apoptosis, cell differentiation and regulation of protein trafficking either in physiological or pathological conditions. In osteosarcoma, CD99 is expressed at low levels and functions as a tumour suppressor. The full-length protein (CD99wt) and the short form harbouring a deletion in the intracytoplasmic domain (CD99sh) have been associated with distinct functional outcomes with respect to tumour malignancy. In this study, we especially evaluated modulation of cell-cell contacts, reorganisation of the actin cytoskeleton and modulation of signalling pathways by comparing osteosarcoma cells characterised by different metastasis capabilities and CD99 expression, to identify molecular mechanisms responsible for metastasis. Our data indicate that forced expression of CD99wt induces recruitment of N cadherin and beta-catenin to adherens junctions. In addition, transfection of CD99wt inhibits the expression of several molecules crucial to the remodelling of the actin cytoskeleton, such as ACTR2, ARPC1A, Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) as well as ezrin, an ezrin/radixin/moesin family member that has been clearly associated with tumour progression and metastatic spread in osteosarcoma. Functional studies point to ROCK2 as a crucial intracellular mediator regulating osteosarcoma migration. By maintaining c-Src in an inactive conformation, CD99wt inhibits ROCK2 signalling and this leads to ezrin decrease at cell membrane while N-cadherin and beta-catenin translocate to the plasma membrane and function as main molecular bridges for actin cytoskeleton. Taken together, we propose that the re-expression of CD99wt, which is generally present in osteoblasts but lost in osteosarcoma, through inhibition of c-Src and ROCK2 activity, manages to increase contact strength and reactivate stop-migration signals that counteract the otherwise dominant promigratory action of ezrin in osteosarcoma cells. PMID- 23644665 TI - Comparative evaluations on bio-treatment of hexavalent chromate by resting cells of Pseudochrobactrum sp. and Proteus sp. in wastewater. AB - Two marine bacterial strains, B5 and H24, were isolated from long-term Cr(VI) contaminated seawater and identified as Pseudochrobactrum and Proteus, respectively, based on 16S rRNA gene sequence analyses. Both strains were examined for their tolerance to Cr(VI) and other metal salts and their abilities to reduce Cr(VI) to trivalent chromium [Cr(III)]. Growing cells of Pseudochrobactrum sp. B5 and Proteus sp. H24 could tolerate Cr(VI) at a concentration of 2000 and 1500 mg/l and completely reduce 1000 mg/l Cr(VI) in LB medium within 96 and 144 h, respectively. Resting cells of the two strains were able to reduce 200mg/l Cr(VI) in Tris-HCl buffer within 16 and 24h, respectively. Furthermore, resting cells of both strains were able to reduce Cr(VI) in industrial wastewaters three times consecutively. Overall, this study provides evidence of the potential for application of chromate-reducing bacteria to direct Cr(VI) decontamination of industrial effluents. PMID- 23644664 TI - Performance of the heavy fraction of pyrolysis oil derived from waste printed circuit boards in modifying asphalt. AB - The focus of this research was the development of efficient and affordable asphalt modifiers. Pyrolysis oil was produced as a byproduct from the pyrolysis of waste printed circuit boards (WPCBs). The high boiling point fraction was separated from the pyrolysis oil through distillation and is referred to as the heavy fraction of pyrolysis oil (HFPO). The HFPO was tested as an asphalt modifier. Three asphalt modifiers were tested: HFPO; styrene-butadiene rubber (SBR); and HFPO + SBR (1:1). The physical properties and road performance of the three modified asphalts were measured and evaluated. The results have shown that when the amount of modifier was less than 10%, the HFPO modified asphalt had the highest softening point of the three. The dynamic stability (DS) and water resistance of the asphalt mixture with the HFPO modified asphalt was 10,161 cycles/mm and 87.2%, respectively. The DS was much larger than for the HFPO + SBR and SBR modified asphalt mixtures. These results indicate that using HFPO as an asphalt modifier has significant benefits not only for road engineering but also for resource recycling. PMID- 23644666 TI - Distribution, speciation, and risk assessment of selected metals in the gold and iron mine soils of the catchment area of Miyun Reservoir, Beijing, China. AB - In order to investigate the metal distribution, speciation, correlation and origin, risk assessment, 86 surface soil samples from the catchment area around the Miyun Reservoir, Beijing, including samples from gold and iron mine areas, were monitored for fractions of heavy metal and total contents. Most of the metal concentrations in the gold and iron mine soil samples exceeded the metal background levels in Beijing. The contents of most elements in the gold mine tailings were noticeably higher than those in the iron mine tailings. Geochemical speciation data of the metals showed that the residual fraction dominated most of the heavy metals in both mines. In both mine areas, Mn had the greatest the acid soluble fraction (F1) per portion. The high secondary-phase fraction portion of Cd in gold mine samples indicated that there was a direct potential hazard to organisms in the tested areas. Multivariate analysis coupled with the contents of selected metals, showed that Hg, Pb, Cr, and Ni in gold mine areas represented anthropogenic sources; Cd, Pb, and Cr in iron mine areas represented industrial sources. There was moderate to high contamination of a few metals in the gold and iron soil samples, the contamination levels were relatively higher in gold mine than in iron mine soils. PMID- 23644667 TI - Management of hospitals solid waste in Khartoum State. AB - This research had been conducted during year 2012 to review existing data on hospital waste management for some of Khartoum town hospitals and to try to produce appropriate proposals acceptable for waste management and final treatment methods. The overall status of hospital waste management in Khartoum has been assessed through direct visits and designated questionnaires. Eight main hospitals were covered in the study with an overall bed capacity of 2,978. The current waste management practice observed at all studied hospitals was that most of waste, office, general, food, construction debris, and hazardous chemical materials were all mixed together as they are generated, collected, and finally disposed of. Only a small portion of waste in some hospitals (part of potentially infectious, body parts, and sharps) are collected separately and treated in a central incinerator. The estimated value of per bed generation rate in the studied hospitals was found to be 0.87 kg/day, which lies within the range for the low-income countries. In all studied hospitals, it was found that workers were working under very poor unsafe conditions with very low salaries ($35 to $45 per month on average). About 90 % were completely illiterate or had very low education levels. At the national level, no laws considering hospital waste, or even hazardous waste, were found; only some federal general environmental regulations and some procedures from town and city localities for controlling general municipal waste exist. At the hospital level, no policies or rules were found, except in the radiotherapy center, where they manage radioactive wastes under the laws of the Sudanese Atomic Agency. Urgent actions are needed for the remediation and prevention of hazards associated with this type of waste. PMID- 23644668 TI - The responses of the hepatosomatic index (HSI), 7-ethoxyresorufin-O-deethylase (EROD) activity and glutathione-S-transferase (GST) activity in sea bass (Dicentrarchus labrax, Linnaeus 1758) caged at a polluted site: implications for their use in environmental risk assessment. AB - The present study investigates the response of three hepatic biomarkers in adult sea bass (Dicentrarchus labrax, Linnaeus 1758) caged at a wastewater outlet of an oil refinery with fish caged at a pristine site used as controls. The biomarkers that were investigated were the hepatosomatic index (HSI), 7-ethoxyresorufin-O deethylase (EROD) activity and glutathione-S-transferase (GST) activity. In addition, we have measured the levels of polycyclic aromatic hydrocarbons (PAHs) and selected heavy metals (lead, cadmium, mercury, copper and zinc) in sediment samples at the polluted site. Although the polluted site had high environmental levels of PAHs and heavy metals, there was no difference in hepatic EROD activity and HSI between fish caged at the polluted site and controls. On the other hand, GST activity was significantly lower in fish caged at the polluted site compared to controls. Our results point out that the studied biomarkers have limited use in environmental risk assessment studies, at least when caged adult sea bass is used as the sentinel species and complex toxicant mixtures are involved. PMID- 23644669 TI - Patients with non-Jo-1 anti-RNA-synthetase autoantibodies have worse survival than Jo-1 positive patients. PMID- 23644671 TI - The risk of gastrointestinal perforations in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the BSRBR-RA. AB - OBJECTIVES: To evaluate the risk of gastrointestinal perforation (GIP) in subjects with rheumatoid arthritis (RA) treated with antitumour necrosis factor (anti-TNF) therapy compared with non-biological disease-modifying antirheumatic drugs (nbDMARDs). METHODS: Using data from the British Society for Rheumatology Biologics Register, we compared the incidence of GIPs between 11 881 anti-TNF treated and 3393 nbDMARD-treated RA patients using Cox regression modelling. Hazard ratios (HRs) with confidence intervals (CI) were calculated. Adjustment was made for potential confounders including current steroid use. The study covered the time period between 2001 and 2011. RESULTS: There were 42 (upper 20, lower 22) GI perforations: five in the nbDMARD cohort and 37 in the anti-TNF cohort. After adjustment, treatment with TNF antagonists was associated with an HR of 1.6 (95% CI 0.4 to 6.0) for all GIPs, 2.7 (95% CI 0.4 to 18.1) for lower GIPs and 0.9 (95% CI 0.1 to 5.8) for upper GIPs. Current use of steroids was the single most important predictor of GI perforation with an adjusted HR of 2.9 (95% CI 1.5 to 5.4), but this risk was confined to lower GIPs (HR 8.0, 95% CI 2.6 to 24.1). CONCLUSIONS: We have not found a statistically significant association between anti-TNF treatment and the risk of GIP. PMID- 23644670 TI - Suppression of inflammation reduces endothelial microparticles in active systemic lupus erythematosus. AB - BACKGROUND: In a prospective observational study, we investigated whether patients with active systemic lupus erythematosus (SLE) had higher indices of endothelial damage and dysfunction than healthy controls and whether improved disease control was associated with improvement in these indices. METHODS: Twenty seven patients with active SLE (four or more American College of Rheumatology (ACR) criteria) and 22 age-matched controls were assessed. Endothelial microparticles (EMPs; CD31+/annexin V+/CD42b-) were quantified using flow cytometry. Brachial artery flow-mediated dilatation (FMD) was measured using automated edge-tracking software. Twenty-two patients had a second assessment at a median (IQR) of 20 (16, 22) weeks after initiating new immunosuppressive therapy. RESULTS: SLE patients had a median (IQR) baseline global British Isles Lupus Assessment Group Disease Activity Index (BILAG-2004) score of 14 (12, 22). CD31+/annexin V+/CD42b- EMPs were higher (157 548/ml (59 906, 272 643) vs 41 025(30 179, 98 082); p=0.003) and endothelial-dependent FMD was lower (1.63% ( 1.22, 5.32) vs 5.40% (3.02, 8.57); p=0.05) in SLE patients than controls. CD31+/annexin V+/CD42b- EMPs correlated inversely with FMD (%) (r(2) -0.40; p=0.006). At follow-up, the median (IQR) change in global BILAG-2004 score was 11 (-18, -3). CD31+/annexin V+/CD42b- EMP levels were reduced (166 982/ml (59 906, 278 775 vs 55 655(29 475, 188 659; p=0.02) and FMD had improved (0.33% ( 2.31, 4.1) vs 3.19% (0.98, 5.09); p=0.1) at the second visit. CONCLUSIONS: Active SLE is associated with evidence of increased endothelial damage and endothelial dysfunction, which improved with suppression of inflammation. Better control of active inflammatory disease may contribute to improved cardiovascular risk in patients with SLE. PMID- 23644672 TI - Neuropsychological characterization of patients with the WMT dementia profile. AB - The "dementia profile" is used to reduce false positives on the Word Memory Test (WMT). Provided that this profile reflects genuine memory impairment, corresponding cognitive deficits should be found in neuropsychological testing. We examined whether a WMT dementia profile is a significant indicator of cognitive impairment and/or decline. In addition, we evaluated the classification accuracy for the clinical diagnosis of dementia. Elderly patients (n = 167) with cognitive complaints were given an extensive neuropsychological test battery, including the WMT. This was repeated 2 years later. The results demonstrate that patients with the dementia profile have a higher chance of showing real cognitive impairment at baseline, and even more so 2 years later. They showed a faster cognitive decline than patients who passed the WMT effort subtasks. Sensitivity of the profile was a moderate 60%. However, the positive predictive value was high, viz. 81% at baseline and 93% at follow-up. PMID- 23644673 TI - Depressive symptoms and concussions in aging retired NFL players. AB - We examined the relationship between a remote history of concussions with current symptoms of depression in retired professional athletes. Thirty retired National Football League (NFL) athletes with a history of concussion and 29 age- and IQ matched controls without a history of concussion were recruited. We found a significant correlation between the number of lifetime concussions and depressive symptom severity using the Beck Depression Inventory II. Upon investigating a three-factor model of depressive symptoms (affective, cognitive, and somatic; Buckley et al., 2001) from the BDI-II, the cognitive factor was the only factor that was significantly related to concussions. In general, NFL players endorsed more symptoms of depression on all three Buckley factors compared with matched controls. Findings suggest that the number of self-reported concussions may be related to later depressive symptomology (particularly cognitive symptoms of depression). PMID- 23644674 TI - Liver resection in selected patients with metastatic breast cancer: a single centre analysis and review of literature. AB - PURPOSE: Despite the development of modern chemotherapeutics and target-specific drugs as well as improved surgical techniques, prognosis of metastatic breast cancer remains poor. Only a small number of selected patients will be eligible for liver resection and/or alternative metastatic ablation. Data on prognostic factors for patients with surgically resectable liver metastases of breast cancer are scarce at present. METHODS: From 1997 to 2010, 50 patients with hepatic metastases of breast cancer have undergone laparotomy with the intention to undergo a curative liver resection at our institution. Data from these patients were collected in a prospectively maintained standardized liver resection data base. RESULTS: Liver resection was performed in 34 patients. Resection margins were clear in 21 cases (R0). Nine patients lived for more than 60 months after liver resection. The observed 5-year survival rate was 21% for all 50 patients, 28% for resected patients and 38% after R0-resection. On univariate analysis, survival rates of the resected patients were statistically significantly influenced by R-classification, age, extrahepatic tumour at the time of liver resection, size of metastases and HER2 expression of liver metastases. Multivariate analysis revealed absence of HER2 expression, presence of extrahepatic tumour and patient's age >=50 years as independent factors of poor prognosis. CONCLUSIONS: Breast cancer patients younger than 50 years with technically resectable hepatic metastases, minimal extrahepatic tumour and positive HER2 expression appear to be suitable candidates for liver resection with curative intent. An aggressive multi-disciplinary management of those patients including surgical treatment may improve long-term survival. PMID- 23644675 TI - Building a tobacco cessation telehealth care management program for veterans with posttraumatic stress disorder. AB - BACKGROUND: Veterans with posttraumatic stress disorder (PTSD) have high rates of smoking. Motivational interviewing (MI) enhances readiness for change. OBJECTIVE: To test the feasibility and fidelity of home telehealth care management strategy to improve quit rates. DESIGN: A telehealth device delivered a cessation curriculum while a nurse supported veterans through weekly MI telephone calls. Treatment fidelity was evaluated. Outcomes measures included changes in smoking behaviors, stage of change, dose effect, and participant satisfaction with intervention. RESULTS: There was a correlation (r = -.677; p = .03) at the end of treatment between readiness to change and number of cigarettes smoked per day. As 11 participants progressed along stages of change, they smoked fewer cigarettes per day. Two (20%) quit smoking. The nurse adhered to MI principles. Participants were highly satisfied and 100% felt curriculum delivered new information and respected choices. CONCLUSIONS: It was feasible to deliver the home telehealth care management intervention with high treatment fidelity. Participants were motivated to change smoking behaviors. PMID- 23644676 TI - A clinical translation of the research article titled "Building a tobacco cessation telehealth care management program for veterans with posttraumatic stress disorder". PMID- 23644677 TI - Accelerating progress in psychiatric-mental health nursing through online communication. PMID- 23644678 TI - Digital natives, digital immigrants: dichotomy or diversity in psychiatric nursing? PMID- 23644680 TI - An investigation of crystal structure, surface area and surface chemistry of strontium niobate and their influence on photocatalytic performance. AB - Sr(1-x)NbO3 is an unusual material that displays both metallic type conduction and photocatalytic activity, despite being an NbIV oxide, and it sustains photo oxidation without degradation. The influence of crystal structure, surface area and surface chemistry on the photocatalytic activity of strontium niobate has been investigated. The crystal structure of strontium niobate depends on the Sr content of the A site, with cubic symmetry for Sr <= 0.92 and orthorhombic symmetry for 0.92 < Sr <= 0.97. The change of crystal structure from cubic to orthorhombic symmetry seems to have a negative effect on the photocatalytic activity, as the NbO6 octahedra become distorted and unfavourable for d-orbital overlapping. The photocatalytic activity increased significantly by enlarging the surface area through ball milling, nevertheless, a clear trend for the surface area effect on activity is not obtained among samples with different Sr content. An enrichment of Sr on the surface of strontium niobate was observed by XPS, which seems to be a governing factor for improving stability. PMID- 23644679 TI - Different modes of growth cone collapse in NG 108-15 cells. AB - In the fundamental process of neuronal path-finding, a growth cone at the tip of every neurite detects and follows multiple guidance cues regulating outgrowth and initiating directional changes. While the main focus of research lies on the cytoskeletal dynamics underlying growth cone advancement, we investigated collapse and retraction mechanisms in NG108-15 growth cones transiently transfected with mCherry-LifeAct and pCS2+/EMTB-3XGFP for filamentous actin and microtubules, respectively. Using fluorescence time lapse microscopy we could identify two distinct modes of growth cone collapse leading either to neurite retraction or to a controlled halt of neurite extension. In the latter case, lateral movement and folding of actin bundles (filopodia) confine microtubule extension and limit microtubule-based expansion processes without the necessity of a constantly engaged actin turnover machinery. We term this previously unreported second type fold collapse and suggest that it marks an intermediate term mode of growth regulation closing the gap between full retraction and small scale fluctuations. PMID- 23644681 TI - Platinum-TM (TM = Fe, Co) alloy nanoparticles dispersed nitrogen doped (reduced graphene oxide-multiwalled carbon nanotube) hybrid structure cathode electrocatalysts for high performance PEMFC applications. AB - The efforts to push proton exchange membrane fuel cells (PEMFC) for commercial applications are being undertaken globally. In PEMFC, the sluggish kinetics of oxygen reduction reactions (ORR) at the cathode can be improved by the alloying of platinum with 3d-transition metals (TM = Fe, Co, etc.) and with nitrogen doping, and in the present work we have combined both of these aspects. We describe a facile method for the synthesis of a nitrogen doped (reduced graphene oxide (rGO)-multiwalled carbon nanotubes (MWNTs)) hybrid structure (N-(G-MWNTs)) by the uniform coating of a nitrogen containing polymer over the surface of the hybrid structure (positively surface charged rGO-negatively surface charged MWNTs) followed by the pyrolysis of these (rGO-MWNTs) hybrid structure-polymer composites. The N-(G-MWNTs) hybrid structure is used as a catalyst support for the dispersion of platinum (Pt), platinum-iron (Pt3Fe) and platinum-cobalt (Pt3Co) alloy nanoparticles. The PEMFC performances of Pt-TM alloy nanoparticle dispersed N-(G-MWNTs) hybrid structure electrocatalysts are 5.0 times higher than that of commercial Pt-C electrocatalysts along with very good stability under acidic environment conditions. This work demonstrates a considerable improvement in performance compared to existing cathode electrocatalysts being used in PEMFC and can be extended to the synthesis of metal, metal oxides or metal alloy nanoparticle decorated nitrogen doped carbon nanostructures for various electrochemical energy applications. PMID- 23644682 TI - Molecular alterations of EGFR in small intestinal adenocarcinoma. AB - BACKGROUND AND AIMS: Molecular testing for epidermal growth factor receptor (EGFR) mutations has recently become a standard practice for the management of patients with non-squamous none small cell lung cancer. Primary small intestine adenocarcinoma (SIA) is an uncommon malignancy, and EGFR mutation in the cancer has not been well characterized due to its rarity. METHODS: A micro-tissue array with 53 SIAs and 24 surgically resected primary non-ampullary SIAs were studied. EGFR mutations were analyzed by DNA sequencing in 24 cases with formalin-fixed paraffin-embedded blocks. All 77 cases were examined by immunohistochemistry (IHC) using antibodies specific for the EGFR E746-A750 deletion in exon 19 (DEL), L858R point mutation in exon 21 (L858R), and total EGFR. EGFR amplifications were detected by fluorescence in situ hybridization. RESULTS: A positive reaction of DEL-specific, L858R-specific, and total EGFR antibodies was detected in seven (9.1%), 5 (6.5%) and 35 (45.5%) of 77 SIAs by IHC, respectively. Positive reaction of the three antibodies was not significantly correlated with patient's age, gender, differentiation, and stage. EGFR gene amplification was assayed in 77 SIAs in micro-tissue array. Of 24 SIA samples that had DNA sequencing, two (8.3%) harbored exon 19 deletion and one (4.2%) harbored L858R point mutation. Only one case with EGFR amplification and two cases with polysomy were shown. CONCLUSIONS: Our findings suggested that mutations and amplification in EGFR genes are minor events, and most of SIAs may be unsuitable to EGFR-TKIs treatment. PMID- 23644683 TI - A dual flowing continuum approach to model denitrification experiments in porous media colonized by biofilms. AB - We present a modeling exercise of solute transport and biodegradation in a coarse porous medium widely colonized by a biofilm phase. Tracer tests in large laboratory columns using both conservative (fluorescein) and biodegradable (nitrate) solutes are simulated by means of a dual flowing continuum approach. The latter clearly distinguishes concentrations in a flowing porous phase from concentrations conveyed in the biofilm. With this conceptual setting, it becomes possible to simulate the sharp front of concentrations at early times and the flat tail of low concentrations at late times observed on the experimental breakthrough curves. Thanks to the separation of flow in two phases at different velocities, dispersion coefficients in both flowing phases keep reasonable values with some physical meaning. This is not the case with simpler models based on a single continuum (eventually concealing dead-ends), for which inferred dispersivity may reach the unphysical value of twice the size of the columns. We also show that the behavior of the dual flowing continuum is mainly controlled by the relative fractions of flow passing in each phase and the rate of mass transfer between phases. These parameters also condition the efficiency of nitrate degradation, the degradation rate in a well-seeded medium being a weakly sensitive parameter. Even though the concept of dual flowing continuum appears promising for simulating transport in complex porous media, its inversion onto experimental data really benefits from attempts with simpler models providing a rough pre-evaluation of parameters such as porosity and mean fluid velocity in the system. PMID- 23644684 TI - In-situ zinc bioprecipitation by organic substrate injection in a high-flow, poorly reduced aquifer. AB - We investigated if in-situ metal bioprecipitation (ISMP) is applicable to remediate a highly permeable zinc-contaminated aquifer at a metal-processing factory in Maasmechelen, Belgium. A large (more than 200m long and 70m wide) groundwater contamination plume has developed, with zinc concentrations in the range of 1-100mg/L, whereas the legal Flemish clean-up standard is 0.5mg/L. The estimated groundwater flow velocity is in the range 0.2-1m/d. The groundwater is relatively oxidized, naturally low in DOC (<1mg/L) and relatively low in sulfate (40-50mg/L). We conducted both laboratory feasibility tests as well as a long term field pilot test in two sections of the plume. In the laboratory microcosm tests, zinc bioprecipitation (following addition of organic substrate and sulfate) removed more than 99% of the zinc from the water phase. Lactate, glycerol and vegetable oil were equally effective as substrates. 28-day anaerobic leaching tests indicated that the metal precipitates that were formed are stable, but they also suggested that substrate addition increases the solubility (leachability) of arsenic and manganese. In the field test, Zn concentrations were reduced by 2 to 3 orders of magnitude within the 232 day testing period and stayed low for the following 6 months in both pilot zones. In the field, no mobilization of arsenic occurred but manganese groundwater concentrations increased from 0.01-0.6mg/L to 0.4-6.5mg/L. Dissolved iron concentrations also increased markedly from below detection limits to concentrations as high as 67mg/L. Zinc concentrations in groundwater were closely correlated to pH and redox potential (Eh): plotting y=[Zn] against x=pH/log(Eh), an exponential relationship was found: PMID- 23644685 TI - Effect of 2 different thoracolumbar orthoses on the stability of the spine during various body movements. AB - STUDY DESIGN: Biomechanical volunteer study. OBJECTIVE: To quantify the stabilizing effect of 2 different semirigid thoracolumbar orthoses during various body movements. SUMMARY OF BACKGROUND DATA: Various spinal diseases need to be treated by immobilization. The literature shows, that the immobilizing effect of orthoses strongly depends on the orthosis design and on the loading direction. Few data are available for loading directions other than flexion and extension. METHODS: Ten young and healthy volunteers (22-44 yr, 5 male, 5 female) performed 4 different tasks: full active flexion/extension, lateral bending, and axial rotation as well as a full active everyday movement (flexion plus lateral bending plus axial rotation). These tasks were carried out without orthosis, with the DorsoFX (BORT GmbH, Weinstadt-Benzach, Germany) and with the SofTec Dorso orthosis (Bauerfeind AG, Zeulenroda-Triebes, Germany). The flexibility of the spine was measured using a 3-dimensional motion capturing system (Zebris Medical GmbH, Isny, Germany). Additionally, the pressure exerted by the orthoses on the subject's body surface was measured using a pressure sensor (Tekscan Inc., South Boston, MA). RESULTS: The range of motion significantly decreased in all loading planes by 42% to 69%. The movement with the largest decrease was axial rotation and the smallest decreases were observed in extension (DorsoFX), flexion and the everyday movement (SofTec Dorso), respectively. The differences between the 2 orthoses were small and not statistically significant. The pressure between orthosis and the body surface was similar for both orthoses but differed between the movements. CONCLUSION: Both orthoses had a similar stabilizing effect on the thoracolumbar spine. The stabilizing effect differed between the 4 movements, which indicates that all loading planes should be tested to understand the effect of an orthosis completely. Complete immobilization of the thoracolumbar spine was not possible with either of the 2 orthoses, but the stability increase was statistically significant. LEVEL OF EVIDENCE: N/A. PMID- 23644687 TI - Mechanisms of response to silver nanoparticles on Enchytraeus albidus (Oligochaeta): survival, reproduction and gene expression profile. AB - Silver has antimicrobial properties and silver nanoparticles (Ag-NPs) have been some of the most widely used NPs. Information regarding their effects is still insufficient, in particular for soil dwelling organisms. The standard soil Oligochaete Enchytraeus albidus was used to study the effects of Ag in soils, using differential gene expression (microarray) and population (survival, reproduction) response to Ag-NPs (PVP coated) and AgNO3. Results showed higher toxicity of AgNO3 (EC50<50 mg/kg) compared to toxicity of Ag-NPs (EC50=225 mg/kg). Based on the biological and material identity, the difference in toxicity between Ag-NPs and AgNO3 could possibly be explained by a release of Ag(+) ions from the particles or by a slower uptake of Ag-NPs. The indications were that the responses to Ag-NPs reflect an effect of Ag ions and Ag-NPs given the extent of similar/dissimilar genes activated. The particles characterization supports this deduction as there were limited free ions measured in soil extracts, maybe related to little oxidation and/or complexation in the soil matrix. The possibility that gene differences were due to different levels of biological impact (i.e. physiological responses) should not be excluded. Testing of Ag-NPs seem to require longer exposure period to be comparable in terms of effect/risk assessment with other chemicals. PMID- 23644688 TI - Chemometric assessment of enhanced bioremediation of oil contaminated soils. AB - Bioremediation is a promising technique for reclamation of oil polluted soils. In this study, six methods for enhancing bioremediation were tested on oil contaminated soils from three refinery areas in Iran (Isfahan, Arak, and Tehran). The methods included bacterial enrichment, planting, and addition of nitrogen and phosphorous, molasses, hydrogen peroxide, and a surfactant (Tween 80). Total petroleum hydrocarbon (TPH) concentrations and CHEMometric analysis of Selected Ion Chromatograms (SIC) termed CHEMSIC method of petroleum biomarkers including terpanes, regular, diaromatic and triaromatic steranes were used for determining the level and type of hydrocarbon contamination. The same methods were used to study oil weathering of 2 to 6 ring polycyclic aromatic compounds (PACs). Results demonstrated that bacterial enrichment and addition of nutrients were most efficient with 50% to 62% removal of TPH. Furthermore, the CHEMSIC results demonstrated that the bacterial enrichment was more efficient in degradation of n alkanes and low molecular weight PACs as well as alkylated PACs (e.g. C3-C4 naphthalenes, C2 phenanthrenes and C2-C3 dibenzothiophenes), while nutrient addition led to a larger relative removal of isoprenoids (e.g. norpristane, pristane and phytane). It is concluded that the CHEMSIC method is a valuable tool for assessing bioremediation efficiency. PMID- 23644689 TI - Thermal decomposition of hydroxylamine: isoperibolic calorimetric measurements at different conditions. AB - Thermal decomposition of hydroxylamine, NH2OH, was responsible for two serious accidents. However, its reactive behavior and the synergy of factors affecting its decomposition are not being understood. In this work, the global enthalpy of hydroxylamine decomposition has been measured in the temperature range of 130-150 degrees C employing isoperibolic calorimetry. Measurements were performed in a metal reactor, employing 30-80 ml solutions containing 1.4-20 g of pure hydroxylamine (2.8-40 g of the supplied reagent). The measurements showed that increased concentration or temperature, results in higher global enthalpies of reaction per unit mass of reactant. At 150 degrees C, specific enthalpies as high as 8 kJ per gram of hydroxylamine were measured, although in general they were in the range of 3-5 kJ g(-1). The accurate measurement of the generated heat was proven to be a cumbersome task as (a) it is difficult to identify the end of decomposition, which after a fast initial stage, proceeds very slowly, especially at lower temperatures and (b) the environment of gases affects the reaction rate. PMID- 23644690 TI - Dispersive liquid-liquid microextraction for the high performance liquid chromatographic determination of aldehydes in cigarette smoke and injectable formulations. AB - A dispersive liquid-liquid microextraction method (DLLME) combined with high performance liquid chromatography (HPLC) was developed for the extraction and determination of some aldehydes, such as benzaldehyde (BzA), butyraldehyde (BuA) and furfural (Fur) in mainstream cigarette smoke as well as BzA in injectable formulations. After trapping of combustion smoke into sulfuric acid with a laboratory-made smoking machine, aldehydes were converted into their hydrazone derivatives by the reaction with 2,4-dinitrophenylhydrazine (DNPH), and then rapidly extracted by DLLME. The effects of various experimental parameters on the derivatization and extraction were studied and optimized. Under the optimum extraction conditions, linear calibration curves in the range 0.025 to 1.0 MUg/mL with correlation coefficients of 0.9980-0.9996 were obtained for studied aldehydes. Limit of detections (LODs) for BzA, BuA and Fur were found to be 14.2, 21.3 and 7.92 MUg/L, respectively. The relative standard deviations (RSDs) for inter-and intra-day assays were lower than 8.50%. Average recoveries for spiked samples were in the range 88.0-109%. The proposed method was successfully applied to the determination of aldehydes in different real samples. PMID- 23644693 TI - Current world literature. Cardiopulmonary resuscitation & cardiopulmonary monitoring. PMID- 23644691 TI - Simultaneous derivatization and extraction of nitrophenols in soil and rain samples using modified hollow-fiber liquid-phase microextraction followed by gas chromatography-mass spectrometry. AB - A simple and sensitive method based on a modified hollow-fiber liquid-phase microextraction followed by gas chromatography-mass spectrometry has been successfully developed for the extraction and simultaneous derivatization of some nitrophenols (NPs) in soil and rain samples. Microwave-assisted solvent extraction was used for the extraction of NPs from the soil, while the rain sample was directly applied to the previously mentioned method. Briefly, in this method, the analytes were extracted from aqueous samples into a thin layer of organic solvent (dodecane + 10% tri-n-octylphosphine oxide) sustained in the pores of a porous hollow fiber. Then, they were back-extracted using a small volume of organic acceptor solution (25 MUl; 10 mg/L N-methyl-N (trimethylsilyl)trifluoroacetamide, as derivatization reagent, in acetonitrile) that was located inside the lumen of the hollow fiber. Under the optimized extraction conditions, enrichment factors of 255 to 280 and limits of detection of 0.1 to 0.2 MUg/L (S/N = 3) with dynamic linear ranges of 1-100 MUg/L were obtained for the analytes. The accuracy of the approach was tested by the relative recovery experiments on spiked samples, with results ranging from 93 to 113%. The method was shown to be rapid, cost-effective, and potentially interesting for screening purposes. PMID- 23644696 TI - Micro-particle image velocimetry for velocity profile measurements of micro blood flows. AB - Micro-particle image velocimetry (MUPIV) is used to visualize paired images of micro particles seeded in blood flows. The images are cross-correlated to give an accurate velocity profile. A protocol is presented for MUPIV measurements of blood flows in microchannels. At the scale of the microcirculation, blood cannot be considered a homogeneous fluid, as it is a suspension of flexible particles suspended in plasma, a Newtonian fluid. Shear rate, maximum velocity, velocity profile shape, and flow rate can be derived from these measurements. Several key parameters such as focal depth, particle concentration, and system compliance, are presented in order to ensure accurate, useful data along with examples and representative results for various hematocrits and flow conditions. PMID- 23644695 TI - Prevalence and burden of diseases presenting to a general pediatrics ward in Gondar, Ethiopia. AB - BACKGROUND: Little is known about pediatric hospital admissions in Ethiopia. METHODS: This cross-sectional study analyzed all data entered into the Gondar University Hospital pediatric ward's admission registration books over 1 year. Patient age, sex, origin, length of stay, diagnosis and discharge condition were transcribed into an electronic database for all observations. Missing data were retrieved by chart and death certificate review. Primary outcome measures included death and death in the first 24 h of admission. RESULTS: In all, 1927 patients were admitted to our facility during the year of study. Of these, 64.5% improved, 4.6% were discharged unchanged, 6.5% disappeared and 7.5% died; the remaining 17.0% of outcome data were registered as 'non-death' but could not be specified further. The median age of admission was 2.2 years (interquartile range 1-7 years), with more admissions for children younger than 5 years (70.3%) and more male subjects admitted than female subjects (59.6% male). The median length of stay was 4.0 days (interquartile range 2-10 days). Eighty-one percent of admissions originated from Gondar or its neighboring districts. Most admissions carried a respiratory, nutritional or infectious diagnosis (47.5, 46.8 and 36.5%, respectively). Conditions diagnosed most commonly (>200 cases) included community acquired pneumonia (812 cases), severe acute malnutrition (381), anemia (274) and acute gastroenteritis (219). Seven diagnoses were associated with mortality after adjusting for demographic covariates: severe acute malnutrition (odds ratio (OR) 2.5, P < 0.001), coma (OR 4.2, P < 0.001), meningitis (OR 2.3, P = 0.018), congestive heart failure (OR 2.4, P = 0.001), severe dehydration (OR 2.5, P = 0.004), aspiration pneumonia (OR 5.4, P < 0.001) and sepsis (OR 3.2, P < 0.001). Thirty-three percent of deaths occurred in the first 24 h of admission, with four diagnoses associated with first-24-h mortality after adjusting for demographic covariates: coma (OR 7.0, P < 0.001), meningitis (OR 3.2, P = 0.008), congestive heart failure (OR 3.1, P = 0.008) and aspiration pneumonia (OR 12.1, P < 0.001). CONCLUSIONS: This study demonstrates a mortality pattern at our hospital that differs considerably from Ethiopia as a whole, and may differ from other hospitals in sub-Saharan Africa. Hospitals must look beyond national and regional agenda when identifying mortality reduction targets. PMID- 23644697 TI - Silicon nanowires with controlled sidewall profile and roughness fabricated by thin-film dewetting and metal-assisted chemical etching. AB - This paper presents a non-lithographic approach to generate wafer-scale single crystal silicon nanowires (SiNWs) with controlled sidewall profile and surface morphology. The approach begins with silver (Ag) thin-film thermal dewetting, gold (Au) deposition and lift-off to generate a large-scale Au mesh on Si substrates. This is followed by metal-assisted chemical etching (MacEtch), where the Au mesh serves as a catalyst to produce arrays of smooth Si nanowires with tunable taper up to 13 degrees . The mean diameter of the thus fabricated SiNWs can be controlled to range from 62 to 300 nm with standard deviations as small as 13.6 nm, and the areal coverage of the wire arrays can be up to 46%. Control of the mean wire diameter is achieved by controlling the pore diameter of the metallic mesh which is, in turn, controlled by adjusting the initial thin-film thickness and deposition rate. To control the wire surface morphology, a post fabrication roughening step is added to the approach. This step uses Au nanoparticles and slow-rate MacEtch to produce rms surface roughness up to 3.6 nm. PMID- 23644698 TI - EGFR and KRAS mutational profiling in fresh non-small cell lung cancer (NSCLC) cells. AB - PURPOSE: Knowledge of tumor mutational status has become a priority for effective NSCLC-tailored treatment. NSCLC diagnosis is more often reached through biopsy; thus, there is a clear need to implement for routine tumor molecular profiling on small cytological samples. This work aims to screen and compare the EGFR and KRAS mutational prevalence in fresh tumor cells and in corresponding routinely processed samples derived from trans-thoracic fine-needle aspiration. The latter currently represents the most appropriate diagnostic procedure in case of peripheral lesions, such as adenocarcinomas, which account for almost 40% of all NSCLCs and for the highest EGFR mutational rates. METHODS: Two hundred and forty four patients carrying peripheral lung masses underwent CT-guided aspiration. The obtained material was split, and a part was addressed to conventional histopathological analysis while the remaining one was stored at -20 degrees C. In case of confirmation of adenocarcinoma, tumor genomic DNA was extracted from both fresh and fixed material, and EGFR and KRAS sequencing was performed. RESULTS: We identified 136 adenocarcinomas; from 134, we could recover enough material for the study. A full match was demonstrated between EGFR/KRAS mutational prevalences through the two approaches tested. We found EGFR mutations in 13 patients (9.7%); 7 were females and 11 never or former smokers. KRAS mutations occurred in 20 (14.9%) patients. EGFR and KRAS mutations were mutually exclusive. CONCLUSIONS: Mutational screening on fresh cancer cells is an achievable, safe and cost-effective procedure which might allow routinely tumor molecular profiling as powerful integration of conventional histopathological analysis. PMID- 23644700 TI - The Taussig-Bing anomaly: long-term results. AB - OBJECTIVES: The arterial switch operation (ASO) is the method of choice for the Taussig-Bing heart. The aim of the study was to analyse the long-term outcome of correction of the Taussig-Bing heart. METHODS: Between 1986 and 2011, 44 infants, including 18 newborns, underwent an ASO. The staged and the primary approach were used in 9 and 35 patients, respectively. Aortic arch (AA) obstruction (n = 26) and right ventricle outflow tract obstruction (n = 34) were common. The mean age at corrective surgery was 112.9 days; the mean weight was 4.17 kg. RESULTS: There were 1 early and 4 late deaths. Overall survival was 88% at 15 years, with a mean follow-up of 9.2 years. Freedom from reoperation was 67% at 15 years of follow up. Eight and 6 patients required right and left ventricular outflow tract surgery, respectively, including resection of the right ventricular outflow tract obstruction (n = 8), a transanular patch (n = 6), aortic valve reconstruction (n = 3), aortic valve replacement (n = 2) and AA reoperation (n = 4). Freedom from aortic regurgitation >mild or aortic valve replacement/reconstruction was 76% at 15 years of follow-up. Freedom from any event was 56% at 15 years of follow-up. All patients are in sinus rhythm, and biventricular function is well-preserved in 95% of patients. All patients are doing well; 86% of them are without medication. CONCLUSIONS: Corrective surgery offers excellent survival benefits and encouraging long-term functional outcomes, regardless of the coronary anatomy and associated lesions. Normal biventricular function is preserved in the vast majority of patients, and >3/4 of patients are without cardiac medication. Nevertheless, TBH associated with a complex anatomy continues to be a risk factor for long-term morbidity, and redos and reinterventions are equally common on both outflow tracts. Progressive neoaortic regurgitation and neoaortic root dilatation might be a problem in the future; therefore, close lifelong surveillance of patients is necessary. PMID- 23644699 TI - Association between promoters polymorphisms of matrix metalloproteinases and risk of digestive cancers: a meta-analysis. AB - PURPOSE: A variety of studies have been performed to elucidate the polymorphisms in promoter regions of matrix metalloproteinases (MMPs) associated with the risk of digestive cancers, and yet, results remain conflicting and heterogeneous. Thus, we undertook a systematic meta-analysis to determine the genetic susceptibility of MMPs to digestive cancers. METHODS: A computerized literature search was conducted in databases of PubMed, Embase, and ISI Web of Knowledge till October 2012 for any MMP genetic association study in oral squamous, gastric, esophageal, and colorectal carcinomas. Odds ratios (OR) and 95 % confidence interval (CI) were estimated for each gene under dominant and recessive models, and the heterogeneity between studies was assessed using Q test and I (2) value. Overall and subgroup analysis according to anatomical sites and ethnicity was carried out. Statistical analysis was performed with Review Manager 5.0. RESULTS: A total of 40 eligible publications with 68 comparisons were included in this study. For MMP1 nt-1607, individuals with 2G state could increase risk of digestive cancers in total analysis (dominant: OR = 1.31, 95 % CI = 1.16-1.48, P < 0.00001; recessive: OR = 1.29, 95 % CI = 1.11-1.50, P = 0.0009). In the subgroup of tumor sites, significant associations were also observed in esophageal cancer and colorectal cancer under both genetic models. For MMP2 nt-1306, CT or TT carriers performed significant protection against digestive cancer in the dominant model (OR = 0.69, 95 % CI = 0.55-0.85, P = 0.0007) of the overall. In the subgroup analysis, significant association was found in esophageal cancer, with borderline effects in gastric cancer and oral squamous cell carcinoma. For MMP7 -181 A/G, significant association was observed under two genetic models in the overall (dominant: OR = 1.26, 95 % CI = 1.10 1.43, P = 0.0009; recessive: OR = 1.33, 95 % CI = 1.11-1.60, P = 0.002) and in the individual cancer subgroup of esophageal cancer and gastric cancer. For MMP9 1,562 C/T, a borderline effect was found with digestive cancers in the total and stratified analysis of the colorectal cancer under dominant model. No association was observed in either the overall or subgroup analysis for MMP3 -1,171 5A/6A. CONCLUSIONS: Our meta-analysis demonstrated the fact that polymorphisms in promoter regions of MMP genes might be related to the susceptibility of digestive cancers, with cancer development for MMP1 and MMP7, and a protection against cancer for MMP2 and MMP9. Further evidences with adequate sample sizes need to be conducted. PMID- 23644701 TI - Preoperative SYNTAX score and graft patency after off-pump coronary bypass surgery. AB - OBJECTIVES: We examined the association between the preoperative SYNTAX score and graft patency after off-pump coronary artery bypass surgery (CABG). METHODS: Of 912 consecutive patients undergoing isolated CABG (906 by the off-pump technique) between 2002 and 2011, 217 underwent computed tomography (CT) angiography. From this cohort, we studied 189 patients for whom preoperative SYNTAX scores were retrospectively obtained. The primary endpoint was at least one graft occlusion on the follow-up CT angiography. Graft occlusion was defined as the absence of contrast agent along the course of the graft. In sequential grafts, each segment was analysed as a separate graft. The secondary endpoint was a composite of major adverse cardiac and cerebrovascular events (MACCE), which was defined as cerebrovascular accident, non-fatal myocardial infarction, admission due to pump failure and repeated revascularization. All arterial conduits were harvested with the skeletonization technique and used as in-situ grafts except one right-side internal thoracic artery (ITA). RESULTS: The mean interval from operation to angiogram was 4.7 +/- 2.4 years, range 0.8-10.0 years. Estimated 8-year graft patencies of ITA- left anterior descending artery, ITA-circumflex branch (CX), saphenous vein -CX and/or posterior descending artery (PDA), and gastroepiploic artery -PDA were 97.4 +/- 1.5, 89.3 +/- 4.2, 86.5 +/- 6.7, and 86.2 +/- 5.7%, respectively. Of the 666 total distal anastomoses, 27 in 21 patients were occluded. No significant difference was found in the preoperative SYNTAX scores between the 21 patients with at least one graft occlusion (mean 35.7; range 15.0 51.5) and the 168 patients without graft occlusion (mean 36.6; range 17.0-54.5) (unpaired t-test, P = 0.87). In univariate and multivariate logistic regression models, no significant association was found between at least one graft occlusion and individual components of the SYNTAX score. There was no significant difference in patients with low (<= 22), intermediate (23-32) and high (>= 33) SYNTAX scores in the cumulative rates of at least one graft occlusion (log-rank test, P = 0.88) and MACCE (log-rank test, P = 0.86). CONCLUSIONS: The preoperative SYNTAX score and its individual components are not associated with graft occlusion after off-pump CABG. PMID- 23644702 TI - Anomalous venous drainage of the lung to the brachiocephalic vein. PMID- 23644703 TI - Amiodarone is a cost-neutral way of preventing atrial fibrillation after surgery for lung cancer. AB - OBJECTIVES: Our aim was to estimate the costs and health benefits of routinely administered postoperative amiodarone as a prophylactic agent in reducing the risk of atrial fibrillation in patients undergoing surgery for lung cancer. METHODS: This was a cost-effectiveness study, based on the randomized, controlled, double-blinded PASCART study, using avoidance of atrial fibrillation as the measure of benefit. Two hundred and fifty-four eligible, consecutively enrolled patients, undergoing surgery for lung cancer at the department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Denmark, were included and randomized to receive either 300 mg of amiodarone or placebo (5% aqueous dextrose solution), administered intravenously over 20 min immediately after surgery, followed by 600 mg of amiodarone/placebo orally twice per day (8 a.m. and 6 p.m.) for the first five postoperative days. RESULTS: In the amiodarone group there were 11 cases of atrial fibrillation, compared with 38 in the control group (P < 0.001). There were no differences in the length of hospital stay or resources used. The mean total costs per patient were equal and amounted to ?7288 per patient (P = 0.23). There were no signs of adverse developments referable to amiodarone in this prophylactic regime. CONCLUSIONS: For patients undergoing surgery for lung cancer, routine use of postoperative prophylactic intravenous bolus and five subsequent days of oral amiodarone therapy reduces the risk of atrial fibrillation in a cost-neutral manner. PMID- 23644704 TI - Reducing severe intraprocedural complications during transcatheter aortic valve implantation with an interdisciplinary heart team approach. PMID- 23644705 TI - Leave no lymph nodes behind! PMID- 23644706 TI - Double valve replacement and reconstruction of the intervalvular fibrous body in patients with active infective endocarditis. AB - OBJECTIVES: Destruction of the intervalvular fibrous body, though uncommon, occurs due to paravalvular abscess formation following active infective endocarditis. This warrants a highly complex operation involving radical surgical debridement of the intervalvular fibrous body, followed by double valve (aortic and mitral) replacement with patch reconstruction of the anterior mitral annulus, the left ventricular outflow tract and the left atrial roof. The objective of this study was to review the early and mid-term outcomes in patients undergoing this operation. METHODS: A total of 25 patients underwent double valve replacement with reconstruction of the intervalvular fibrous body for extensive infective endocarditis between January 1999 and March 2012. The mean age was 64.3 +/- 10.5 years. Most of the patients (60%) were in New York Heart Association Class III-IV, 12% and in cardiogenic shock. Associated comorbidities like acute renal insufficiency and cerebrovascular accidents were observed in 40 and 20% of patients, respectively. Twenty patients had previous heart valve surgeries. The logistic EuroSCORE predicted risk of mortality was 55.1 +/- 22.9%. RESULTS: Overall, 30-day mortality was 32%. Postoperative complications like low cardiac output, stroke and acute renal failure developed in 16, 28 and 56%, respectively. Thirty-two percent of patients required re-exploration for bleeding. Nine patients were alive at a mean follow-up of 406 days (0-8 years). The 2- and 5 year survivals were 37.0 +/- 11.1 and 24.6 +/- 12.5%, respectively. CONCLUSIONS: Double valve replacement with reconstruction of the intervalvular fibrous body for infective endocarditis is a complex, technically challenging operation associated with high perioperative morbidity and mortality. Nevertheless, being the only option available for such complex disease, it should be performed in these patients who, otherwise, face 100% mortality. PMID- 23644707 TI - Infectious pseudoaneurysm at the proximal edge of the endograft, after hybrid aortic arch repair. PMID- 23644708 TI - Video-assisted thoracic surgery is effective in systemic lymph node dissection. PMID- 23644709 TI - Pancreaticoduodenectomy after coronary artery bypass grafting with use of an in situ right gastroepiploic artery graft. AB - Nowadays more old and comorbid patients, such as patients with a history of multiple coronary artery bypass grafting (CABG), are surgical candidates for pancreaticoduodenectomy. Harvesting of the right gastroepiploic artery (RGEA) is one of the most commonly used methods when multiple CABGs are required. We report a case of pancreaticoduodenectomy performed in a patient who had the RGEA used as an in situ graft for CABG. The RGEA was successfully preserved, with an uneventful postoperative course. PMID- 23644710 TI - Editorial comment: Setting the bar for complex aortic arch disease: implications for therapeutic options. PMID- 23644711 TI - Heart transplantation vs long-term mechanical assist devices: clinical equipoise? PMID- 23644713 TI - Establishing evidence for high-risk medical devices in orphan diseases. PMID- 23644712 TI - Recurrence of mediastinal node cancer after lobe-specific systematic nodal dissection for non-small-cell lung cancer. AB - OBJECTIVES: The standard surgical treatment for patients with non-small-cell lung cancer (NSCLC) is lobectomy with systematic nodal dissection (SND). Lobe-specific patterns of nodal metastases have been recognized, and lobe-specific SND (L-SND) has been reported. We performed L-SND depending on patient-related factors, such as age or the presence of diabetes or respiratory dysfunction, or in the context of specific tumour-related factors, such as the presence of a tumour with a wide area of ground-glass opacity. METHODS: Between September 2002 and December 2008, 335 consecutive patients with clinical and intraoperative N0 NSCLC underwent curative lobectomies at Shizuoka Cancer Center Hospital. Among these 335 patients, 206 underwent SND (Group A) and 129 underwent L-SND. Of the 129 patients undergoing L-SND, 98 underwent L-SND due to patient-related factors (Group B) and 31 underwent L-SND due to tumour-related factors (Group C). RESULTS: There were no significant differences in morbidity or blood loss between patients undergoing SND or L-SND, but there was a significant difference in the mean operative times. The 5-year disease-free survival (5-DFS) and 5-year overall survival (5-OS) of patients in Group C were 100%. Although the patients in Group B showed no significant difference in 5-DFS and 5-OS compared with Group A, patients in Group B had significantly more initial recurrence of mediastinal node cancer than did the Group A patients (P = 0.0050). CONCLUSIONS: The recurrence of mediastinal node cancer in patients undergoing L-SND was significantly greater than that in those undergoing SND. PMID- 23644714 TI - Cardiac failure due to a giant desmoid tumour of the posterior mediastinum. AB - We report a rare case of a giant desmoid tumour responsible for cardiac and respiratory failure. Complete removal was decided upon, despite an initial failure in another centre because of symptom severity. In such cases, wide local resection remains the best therapeutic approach, but the risk of local recurrence is high. Literature review confirms the exceptional presentation and the benefit of aggressive surgery. PMID- 23644716 TI - Fetal magnetic resonance imaging (MRI): a tool for a better understanding of normal and abnormal brain development. AB - Knowledge of the anatomy of the developing fetal brain is essential to detect abnormalities and understand their pathogenesis. Capability of magnetic resonance imaging (MRI) to visualize the brain in utero and to differentiate between its various tissues makes fetal MRI a potential diagnostic and research tool for the developing brain. This article provides an approach to understand the normal and abnormal brain development through schematic interpretation of fetal brain MR images. MRI is a potential screening tool in the second trimester of pregnancies in fetuses at risk for brain anomalies and helps in describing new brain syndromes with in utero presentation. Accurate interpretation of fetal MRI can provide valuable information that helps genetic counseling, facilitates management decisions, and guides therapy. Fetal MRI can help in better understanding the pathogenesis of fetal brain malformations and can support research that could lead to disease-specific interventions. PMID- 23644715 TI - The vanadyl chelate bis(acetylacetonato)oxovanadium(IV) increases the fractional uptake of 2-(fluorine-18)-2-deoxy-D-glucose by cultured human breast carcinoma cells. AB - Detection of breast cancer by positron emission tomography (PET) imaging with 2 (fluorine-18)-2-deoxy-D-glucose (FDG) as the tracer molecule is limited in part by both tumor dimension and metabolic activity. While some types of aggressive breast cancers are associated with a high capacity for FDG uptake, more indolent breast cancers are characterized by low FDG uptake. Moreover, detection of malignant lesions in most clinical settings requires tumor dimensions >=10 mm. Development of a method to increase the fractional uptake of FDG by cancer tissue would provide a means to detect smaller tumors. However, there is no clinically available pharmacologic reagent known to enhance the preferential uptake of FDG by cancer tissue. Because the vanadyl (VO(2+)) chelate bis(acetylacetonato)oxovanadium(IV) [VO(acac)2] is known to enhance cellular uptake of glucose, we have investigated whether VO(acac)2 facilitates enhanced uptake of FDG by cultured human breast carcinoma cells. We observed that the fractional uptake of FDG by cultured human MDA-MB-231 carcinoma cells is increased in the presence of VO(acac)2 in a dose dependent manner. Preliminary results with xenograft tumors generated in severely compromised, immunodeficient (SCID) female mice showed that VO(acac)2 treatment of mice 3-4 h prior to FDG injection enhanced FDG uptake by the malignant tissue by a factor >2.0 compared with that by normal surrounding tissue. PMID- 23644717 TI - Porous ZnO nanosheet arrays constructed on weaved metal wire for flexible dye sensitized solar cells. AB - Porous zinc oxide (ZnO) nanosheet (NS) arrays constructed by connected nanocrystallites were built on weaved metal wire (WMW) via hydrothermal treatment followed by calcination, and used as photoanodes for flexible dye-sensitized solar cells (DSSCs). An overall light-to-electricity conversion efficiency (eta) of 2.70% was achieved for the DSSC under 100 mW cm(-2) illumination, and this eta was found to be much higher than that of the DSSC with ZnO nanowire (NW) as the photoanode (0.71%). The far superior performance of the DSSC with ZnO-NS is essentially attributed to: (i) the film consisting of nanosheets with interconnected nanocrystallites can allow relatively direct pathways for the transportation of electrons as the nanosheets have a regular structure with the sheets being oriented to the electrode; (ii) the nanocrystallites assembly and porous character of the nanosheets can provide a large surface area for dye adsorption, which is in favor of enhancing the light absorption and the light propagation; (iii) the nanopores embedded in the nanosheet can act as "branch lines" for more efficient electrolyte diffusion into the interstice of the densely packed nanosheets in the array. A further improvement in the efficiency of the DSSC with ZnO-NS was achieved through the atomic layer deposition (ALD) of an ultrathin titanium oxide (TiO2) layer onto the ZnO-NS layer. The larger charge transfer resistance along with the introduction of a TiO2 shell is thought to reduce the surface recombination and thus contribute to the increase in the open circuit voltage (Voc) of the DSCs and higher conversion efficiency (3.09%). PMID- 23644719 TI - Fear of acupuncture enhances sympathetic activation to acupuncture stimulation. AB - BACKGROUND: Acupuncture treatment frequently evokes both pain and fear, causing patients to be hesitant about undergoing the procedure. This study investigated individual differences in autonomic response to acupuncture stimulation and its relationship to fear of the procedure. METHODS: Twenty-seven participants filled out the acupuncture fear scale (AFS) questionnaire and underwent acupuncture stimulation at the LI4 acupuncture point. Autonomic responses were measured by recording the skin conductance response (SCR) throughout acupuncture stimulation. Pearson correlation analysis was performed between the self-reported AFS scores and changes in SCR. RESULTS: After acupuncture stimulation, SCR significantly increased and there were greater individual differences in enhanced sympathetic activations to acupuncture stimulation. Changes in SCR correlated with scores for the painful sensation domain of the AFS. CONCLUSIONS: Our results indicate that fear of acupuncture-induced pain is associated with physiological arousal when people receive acupuncture stimulation. Fear of pain is the dominant factor in acupuncture-related fear and it should be considered in practice and in research. PMID- 23644718 TI - Invasive versus non-invasive cooling after in- and out-of-hospital cardiac arrest: a randomized trial. AB - INTRODUCTION: Mild induced hypothermia (MIH) is indicated for comatose survivors of sudden cardiac arrest (SCA) to improve clinical outcome. In this study, we compared the efficacy of two different cooling devices for temperature management in SCA survivors. METHODS: Between April 2008 and August 2009, 80 patients after survived in-hospital (IHCA) and out-of-hospital cardiac arrest (OHCA) were included in this prospective, randomized, single center study. Hypothermia was induced after randomization by either invasive Coolgard((r)) cooling or non invasive ArcticSun((r)) surface cooling at 33.0 degrees C core body temperature for 24 h followed by active rewarming. The primary endpoint was defined as the efficacy of both cooling systems, measured by neuron-specific enolase (NSE) levels as a surrogate parameter for brain damage. Secondary efficacy endpoints were the clinical and neurological outcome, time to start of cooling and reaching the target temperature, target temperature-maintenance and hypothermia-associated complications. RESULTS: NSE at 72 h did not differ significantly between the 2 groups with 16.5 ng/ml, interquartile range 11.8-46.5 in surface-cooled patients versus 19.0 ng/ml, interquartile range 11.0-42.0 in invasive-cooled patients, p = 0.99. Neurological and clinical outcome was similar in both groups. Target temperature of 33.0 degrees C was maintained more stable in the invasive group (33.0 versus 32.7 degrees C, p < 0.001). Bleeding complications were more frequent with invasive cooling (n = 17 [43.6 %] versus n = 7 [17.9 %]; p = 0.03). CONCLUSION: Invasive cooling has advantages with respect to temperature management over surface cooling; however, did not result in different outcome as measured by NSE release in SCA survivors. Bleeding complications were more frequently encountered by invasive cooling. PMID- 23644721 TI - The peptide motif of the single dominantly expressed class I molecule of the chicken MHC can explain the response to a molecular defined vaccine of infectious bursal disease virus (IBDV). AB - In contrast to typical mammals, the chicken MHC (the BF-BL region of the B locus) has strong genetic associations with resistance and susceptibility to infectious pathogens as well as responses to vaccines. We have shown that the chicken MHC encodes a single dominantly expressed class I molecule whose peptide-binding motifs can determine resistance to viral pathogens, such as Rous sarcoma virus and Marek's disease virus. In this report, we examine the response to a molecular defined vaccine, fp-IBD1, which consists of a fowlpox virus vector carrying the VP2 gene of infectious bursal disease virus (IBDV) fused with beta-galactosidase. We vaccinated parental lines and two backcross families with fp-IBD1, challenged with the virulent IBDV strain F52/70, and measured damage to the bursa. We found that the MHC haplotype B15 from line 15I confers no protection, whereas B2 from line 61 and B12 from line C determine protection, although another locus from line 61 was also important. Using our peptide motifs, we found that many more peptides from VP2 were predicted to bind to the dominantly expressed class I molecule BF2*1201 than BF2*1501. Moreover, most of the peptides predicted to bind BF2*1201 did in fact bind, while none bound BF2*1501. Using peptide vaccination, we identified one B12 peptide that conferred protection to challenge, as assessed by bursal damage and viremia. Thus, we show the strong genetic association of the chicken MHC to a T cell vaccine can be explained by peptide presentation by the single dominantly expressed class I molecule. PMID- 23644723 TI - Epidemiology of childhood conduct problems in Brazil: systematic review and meta analysis. AB - PURPOSE: This study aimed to review evidence on the prevalence of and risk factors for conduct problems in Brazil. METHODS: We searched electronic databases and contacted Brazilian researchers up to 05/2012. Studies were included in the review if they reported the prevalence of or risk factors for conduct problems, conduct disorder, or oppositional defiant disorder for 100 + Brazilian children aged <=18 years, systematically sampled in schools or the community. Prevalence rates and sex differences were meta-analysed. Risk factor studies were reviewed one by one. RESULTS: The average prevalence of conduct problems in screening questionnaires was 20.8%, and the average prevalence of conduct disorder/oppositional defiant disorder was 4.1%. There was systematic variation in the results of screening studies according to methodology: recruitment location, informants, instruments, impairment criterion for case definition, and response rates. Risk factors previously identified in high-income countries were mainly replicated in Brazil, including comorbid mental health problems, educational failure, low religiosity, harsh physical punishment and abuse, parental mental health problems, single parent family, and low socioeconomic status. However, boys did not always have higher risk for conduct problems than girls. CONCLUSIONS: Studies using screening questionnaires suggest that Brazilian children have higher rates of conduct problems than children in other countries, but diagnostic studies do not show this difference. Risk factors in Brazil were similar to those in high-income countries, apart from child sex. Future research should investigate developmental patterns of antisocial behaviour, employ a variety of research designs to identify causal risk mechanisms, and examine a broader range of risk factors. PMID- 23644724 TI - Displacement, county social cohesion, and depression after a large-scale traumatic event. AB - BACKGROUND: Depression is a common and potentially debilitating consequence of traumatic events. Mass traumatic events cause wide-ranging disruptions to community characteristics, influencing the population risk of depression. In the aftermath of such events, population displacement is common. Stressors associated with displacement may increase risk of depression directly. Indirectly, persons who are displaced may experience erosion in social cohesion, further exacerbating their risk for depression. METHODS: Using data from a population-based cross sectional survey of adults living in the 23 southernmost counties of Mississippi (N = 708), we modeled the independent and joint relations of displacement and county-level social cohesion with depression 18-24 months after Hurricane Katrina. RESULTS: After adjustment for individual- and county-level socio demographic characteristics and county-level hurricane exposure, joint exposure to both displacement and low social cohesion was associated with substantially higher log-odds of depression (b = 1.34 [0.86-1.83]). Associations were much weaker for exposure only to low social cohesion (b = 0.28 [-0.35-0.90]) or only to displacement (b = 0.04 [-0.80-0.88]). The associations were robust to additional adjustment for individually perceived social cohesion and social support. CONCLUSION: Addressing the multiple, simultaneous disruptions that are a hallmark of mass traumatic events is important to identify vulnerable populations and understand the psychological ramifications of these events. PMID- 23644722 TI - Social support and physical activity as moderators of life stress in predicting baseline depression and change in depression over time in the Women's Health Initiative. AB - PURPOSE: To determine whether social support and/or physical activity buffer the association between stressors and increasing risk of depression symptoms at baseline and at 3-year follow-up. METHODS: This is a secondary analysis of data from the Women's Health Initiative Observational Study. 91,912 community-dwelling post-menopausal women participated in this prospective cohort study. Depression symptoms were measured at baseline and 3 years later; social support, physical activity, and stressors were measured at baseline. RESULTS: Stressors at baseline, including verbal abuse, physical abuse, caregiving, social strain, negative life events, financial stress, low income, acute pain, and a greater number of chronic medical conditions, were all associated with higher levels of depression symptoms at baseline and new onset elevated symptoms at 3-year follow up. Social support and physical activity were associated with lower levels of depressive symptoms. Contrary to expectation, more social support at baseline strengthened the association between concurrent depression and physical abuse, social strain, caregiving, and low income. Similarly, more social support at baseline increased the association between financial stress, income, and pain on new onset depression 3 years later. Physical activity similarly moderated the effect of caregiving, income, and pain on depression symptoms at baseline. CONCLUSION: Stressors, social support, and physical activity showed predicted main effect associations with depression. Multiplicative interactions were small in magnitude and in the opposite direction of what was expected. PMID- 23644725 TI - ABC Schizophrenia study: an overview of results since 1996. AB - PURPOSE: The ABC Schizophrenia study, led by a single research team, investigated a schizophrenia sample systematically over quarter of a century. This paper summarises results from 1996 onwards. The initial goals were to explain the considerably higher age at first admission in women, and to obtain precise information on the onset and early course of schizophrenia as a prerequisite for early intervention. METHOD: The study was hypothesis-driven. People with schizophrenia were compared in the prodrome and at first admission to those with unipolar depression and to healthy controls. We analysed the medium-term (5-year) and the long-term (12-year) course of schizophrenia, its symptom dimensions, social parameters and predictors. SAMPLES: (1) 276 population-based first admissions (232 first episodes) of schizophrenia (age range 12-59 years); (2) a subsample of 130 first admissions for schizophrenia; (3) 130 first admissions for unipolar depression; (4) 130 healthy population controls and (5) 1,109 consecutive first admissions for schizophrenia spectrum disorder without an age limit. RESULTS: The prodromal stages of schizophrenia and depression were very similar until positive symptoms appeared. The most frequent symptom in schizophrenia was depressed mood. The course of psychosis from prodrome to 12 years following first admission was very variable. From 5 to 12 years after first admission the course was characterised by irregular exacerbations of the main symptom dimensions, with no overall deterioration or improvement. CONCLUSIONS: Schizophrenic psychosis and severe affective disorder, rather than representing discrete illnesses, probably mark different stages in the manifestation of psychopathology produced by various degrees of brain dysfunction. PMID- 23644726 TI - Rearing temperature affects Senegalese sole (Solea senegalensis) larvae protein metabolic capacity. AB - The present work examined the short- and long-term effects of three rearing temperatures on protein metabolism and growth trajectories of Senegalese sole larvae using 14C-labelled Artemia protein as feed. A first feeding trial was performed on larvae reared at 15, 18 and 21 degrees C (at 26, 17 and 14 days post-hatching (dph), respectively) and a second trial conducted on post-larvae after transfer to the same rearing temperature (~20 degrees C) (49, 35 and 27 dph, in larvae initially reared at 15, 18 and 21 degrees C, respectively). Temperature greatly influenced larvae relative growth rate (RGR) and survival, since growth at 15 degrees C was severely depressed. Protein digestibility and retention was highest at 18 degrees C during the first trial (85.35 +/- 1.16 and 86.34 +/- 2.33 %, respectively). However, during the second trial, post-larvae from 15 degrees C had the highest feed intake and protein digestibility (3.58 +/ 1.54 and 75.50 +/- 1.35 %, respectively), although retention was similar between treatments. Furthermore, after transfer to 20 degrees C larvae from 15 degrees C experienced compensatory growth, which was observed until 121 dph, and confirmed by RGR values, which were significantly higher at 15 oC than at 21 oC or 18 oC. Results from the present study show that Solea senegalensis larval development, survival and protein digestion and retention are highly affected by thermal history. PMID- 23644727 TI - Reconstruction of recurrent diaphragmatic eventration with an elongated polytetrafluoroethylene sheet. AB - We report the case of a 31-year old woman with recurrence of left diaphragmatic eventration 3 years after a previous surgery for this condition. At the initial occurrence, she had experienced dyspnoea on exercise and subsequently underwent laparoscopic plication of the diaphragm with an endo-stapler at a local hospital. Immediately after the operation, the diaphragm was torn and the intestine entered the thorax. Therefore, plication involving sewing was performed. Then, 3 years later, the patient again experienced dyspnoea and was diagnosed as having recurrence of left diaphragmatic eventration. Observation under thoracoscopy revealed that the centre of the left diaphragm was thin but not torn. We reconstructed the left diaphragm with an elongated polytetrafluoroethylene sheet on the naive diaphragm. The patient was discharged from our hospital 5 days after surgery. Her respiratory function improved and she has not experienced recurrence. PMID- 23644728 TI - The STS score is the strongest predictor of long-term survival following transcatheter aortic valve implantation, whereas access route (transapical versus transfemoral) has no predictive value beyond the periprocedural phase. AB - OBJECTIVES: Transcatheter aortic valve implantation (TAVI) was developed as a promising new therapy for inoperable and surgical high-risk patients as an alternative to traditional aortic valve replacement. After a successful procedure, prognosis may mainly be determined by comorbidities. However, no appropriate risk score to predict long-term outcome following TAVI is currently available. The aim of this study was to identify predictors of adverse short- and long-term outcomes. METHODS: This is a two-centre registry study including a total of 426 TAVI procedures (274 transfemoral [TF] and 152 transapical [TA]) performed at the University Hospital and CardioVascular Center of Frankfurt (Germany) between 2005 and 2011. RESULTS: Observed 30-day mortality was 4.8% among TF and 12.6% among TA patients (hazard ratio [HR] TF vs TA was 0.38; 95% confidence interval [CI] 0.19-0.77). Patients with a higher Society of Thoracic Surgeons (STS) score experienced a 6% elevation in the 30-day mortality per point (HR 1.06; 95% CI 1.03-1.10), whereas the predictive value of the logistic EuroSCORE (HR 1.03; 95% CI 1.01-1.05) and EuroSCORE 2 (HR 1.04; 95% CI 1.01-1.07) was slightly lower. Most interestingly, older age (>80 years) and the access type were predictors of 30-day mortality. However, the only independent predictor of long-term mortality in a 30-day landmark analysis was the STS score (HR 1.05; 95% CI 1.02-1.09). CONCLUSIONS: The STS score outperforms the logistic EuroSCORE in predicting adverse outcomes following TAVI. The transapical approach is associated with higher perioperative mortality, but does not exert any influence on long-term prognosis beyond the periprocedural phase. PMID- 23644730 TI - Does the use of thiopental provide added cerebral protection during deep hypothermic circulatory arrest? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: Does the use of thiopental provide added cerebral protection during deep hypothermic circulatory arrest (DHCA)? Altogether, more than 62 papers were found using the reported search, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Four of the seven papers used thiopental alongside other neuroprotective methods and agents. The methods included the use of ice packs to the head and core systemic hypothermia. Agents used alongside thiopental included nicardipine and mannitol. Thiopental was found to have the ability to lower oxygen consumption, where oxygen consumption was measured using the phosphocreatinine and adenosine triphosphate ratio. The neuroprotective effect of thiopental was evaluated by assessing the electrical activity of the brain during circulatory arrest, by which it was shown to be advantageous. However, other trials suggested that adding thiopental during circulatory arrest did not provide any extra protection to the brain. The timing of thiopental administration is of importance in order to gain positive outcomes, as it's ability to lower the cerebral energy state may result in unfavourable results if added before hypothermic circulatory arrest, where this may lead to an ischaemic event. We conclude that the use of thiopental during deep hypothermic circulatory arrest is beneficial, but if administered too early, it may replete the cerebral energy state before arrest and prove to be detrimental. PMID- 23644731 TI - Comparison of only T3 and T3-T4 sympathectomy for axillary hyperhidrosis regarding treatment effect and compensatory sweating. AB - OBJECTIVES: Patients diagnosed with axillary hyperhidrosis can face psychosocial issues that can ultimately hinder their quality of life both privately and socially. The routine treatment for axillary hyperhidrosis is T3-T4 sympathectomy, but compensatory sweating is a serious side effect that is commonly seen with this approach. This study was designed to evaluate whether a T3 sympathectomy was effective for the treatment of axillary hyperhidrosis and whether this treatment led to less compensatory sweating than T3-T4 sympathectomies among our 60-patient population. METHODS: One hundred and twenty endoscopic thoracic sympathectomies were performed on 60 patients who had axillary hyperhidrosis. The sympathectomies were accomplished by means of a single-lumen endotracheal tube and a single port. The axillary hyperhidrosis patients were randomly divided into two groups with 17 patients in Group 1 undergoing T3-T4 sympathectomies and 43 in Group 2 undergoing only T3 sympathectomies. We analysed the data associated with the resolution of axillary hyperhidrosis, the degree of patient satisfaction with the surgical outcome and the quality of life in parallel with compensatory sweating after the procedure as reported by the patient and confirmed by the examiner. Moreover, the results were compared statistically. RESULTS: No statistically significant difference was observed between the groups based on age (P=0.56), gender (P=0.81), duration of the surgery (P=0.35) or postoperative satisfaction levels (P=0.45). However, the incidence and degree of compensatory sweating were lower in the T3 group than the T3-T4 group at the 1-year follow-up (P=0.008). CONCLUSIONS: T3 sympathectomy was as effective as T3-T4 sympathectomy for the treatment of axillary hyperhidrosis based on the patients' reported postoperative satisfaction, and the T3 group demonstrated lower compensatory sweating at the 1-year follow-up. PMID- 23644729 TI - Emerging role of echocardiographic strain/strain rate imaging and twist in systolic function evaluation and operative procedure in patients with aortic stenosis. AB - Systolic function of the left ventricle is vital for patients with aortic stenosis. Unfortunately, the most widely used clinical parameter, the left ventricular ejection fraction, is not sensitive enough, especially for patients with left ventricular hypertrophy. Echocardiographic strain/strain rate and twist are emerging parameters for left ventricular systolic and diastolic function evaluation. Aortic stenosis could reduce strain/strain rate while magnifying twist. Furthermore, strain/strain rate correlates well with the prognosis of patients with aortic stenosis. Most importantly the circumferential strain, strain rate and twist also play a role in differentiating cardiac compensation or decompensation. In any case, these parameters could normalize after successful surgical aortic valve replacement or transcatheter aortic valve replacement. Regardless of these advantages, clinical evidence is needed to ensure their usefulness. PMID- 23644733 TI - Modified Nuss procedure in the treatment of recurrent pectus excavatum after open repair. AB - OBJECTIVES: The purpose of this study was to evaluate the efficacy of the modified Nuss procedure with a subxiphoid incision in correcting recurrent pectus excavatum. METHODS: From August 2006 to July 2010, 28 patients with recurrent pectus excavatum underwent a secondary repair using the modified Nuss procedure with a subxiphoid incision and bilateral thoracoscopy. Data concerning symptoms, operative course, complications, pulmonary function and early outcome were recorded. RESULTS: Prior repairs of the reoperation patients included 16 Ravitch, 9 modified Ravitch and 3 sterno-turnover procedures. The median Haller index was 4.52 for the redo patients. Presenting symptoms included decreased endurance, dyspnoea on exertion, chest pain, frequent respiratory infections and palpitations. The median duration of reoperation was slightly longer than that of the primary surgeries. Blood loss and postoperative hospitalization were similar between groups. Complications from pectus reoperations included pneumothorax, pleural effusion, postoperative pain and wound infection in the lateral incision. There were no perioperative deaths or cardiac perforations. Initial postoperative results varied from excellent to good. The patients were followed up for 24-74 months. No steel bar malposition or stabilizer displacement was found in any case. CONCLUSIONS: The modified Nuss procedure with subxiphoid incision and bilateral thoracoscopy can avoid cardiac injury to the greatest degree. It would be a minimally invasive and safe approach for patients with recurrent pectus excavatum after failed open repair. PMID- 23644732 TI - Reduced port video-assisted thoracoscopic surgery using a needle scope for lung and mediastinal lesions. AB - OBJECTIVES: There are many recent and minimally invasive surgical innovations, yet there has been little evaluation of the limitations of such techniques, particularly those related to video-assisted thoracoscopic surgery. The aims of this study were to determine the usefulness and limitations of video-assisted thoracoscopic surgery using one-port access and needle scope and to evaluate the feasibility of this procedure based on our institutional experience. METHODS: This retrospective study involved 127 patients who underwent video-assisted thoracoscopic surgery using the one-window and puncture method at our institute from 1997 to 2011. One hundred patients underwent surgical treatment and 27 underwent diagnostic procedures. If there was one lesion present with only mild adhesion that did not require lymph node dissection, we decided to opt for the one-direction approach that provisionally indicates the one-window and puncture method. We compared the conversion and success groups for factors like age, sex, laterality of surgery, objective of surgery, target organ and surgery location. RESULTS: Of 127 cases, 115 (91%) successfully underwent the one-window and puncture procedure. Twelve cases (9%) were converted to the two-window method or thoracotomy. Compared with those targeting the lung, patients with mediastinal lesions demonstrated a higher tendency for conversion (P<0.05). However, age (P=0.89), sex (P=0.46), laterality of surgery (P=0.34) and purpose of surgery (P=0.68) did not show any significant differences between the groups. CONCLUSIONS: For lung and mediastinal diseases, video-assisted thoracoscopic surgery with the one-window and puncture method can be performed at any location (upper, middle and lower lobe of lung and anterior, middle and posterior of the mediastinum) under limited indications that include the possibility of one-way resection, mild adhesion and no requirement of lymph node dissection. Under provisional criteria, the procedure may be feasible. PMID- 23644734 TI - Practice of laryngectomy rehabilitation interventions: a perspective from Australia. AB - PURPOSE OF REVIEW: To provide a perspective of contemporary practice in rehabilitation of speech and swallowing in patients undergoing total laryngectomy in Australia. RECENT FINDINGS: In Australia, the preferred method of voice rehabilitation is by the use of tracheo-oesophageal voice prosthesis. Dysphagia is an ongoing problem and the use of adjuvant radiation and chemotherapy compounds this problem. There are difficulties associated with surgery because of the variation in disease involvement of pharyngeal mucosa and musculature, as well as difficulties associated with healing in previously chemoradiated surgical fields. SUMMARY: This article demonstrates the need for careful consideration of surgical technique, particularly in closure of the neopharynx in the chemoradiated patient. It encourages further research into the problems of speech and particularly swallowing in this patient population, as these problems impact significantly on the quality of life. PMID- 23644735 TI - Allergy treatment: myths, reality, and misperceptions. PMID- 23644736 TI - Current world literature. Speech therapy and rehabilitation. PMID- 23644738 TI - Development, expansion, and in vivo monitoring of human NK cells from human embryonic stem cells (hESCs) and and induced pluripotent stem cells (iPSCs). AB - We present a method for deriving natural killer (NK) cells from undifferentiated hESCs and iPSCs using a feeder-free approach. This method gives rise to high levels of NK cells after 4 weeks culture and can undergo further 2-log expansion with artificial antigen presenting cells. hESC- and iPSC-derived NK cells developed in this system have a mature phenotype and function. The production of large numbers of genetically modifiable NK cells is applicable for both basic mechanistic as well as anti-tumor studies. Expression of firefly luciferase in hESC-derived NK cells allows a non-invasive approach to follow NK cell engraftment, distribution, and function. We also describe a dual-imaging scheme that allows separate monitoring of two different cell populations to more distinctly characterize their interactions in vivo. This method of derivation, expansion, and dual in vivo imaging provides a reliable approach for producing NK cells and their evaluation which is necessary to improve current NK cell adoptive therapies. PMID- 23644739 TI - Predictive simulations and optimization of nanowire field-effect PSA sensors including screening. AB - We apply our self-consistent PDE model for the electrical response of field effect sensors to the 3D simulation of nanowire PSA (prostate-specific antigen) sensors. The charge concentration in the biofunctionalized boundary layer at the semiconductor-electrolyte interface is calculated using the propka algorithm, and the screening of the biomolecules by the free ions in the liquid is modeled by a sensitivity factor. This comprehensive approach yields excellent agreement with experimental current-voltage characteristics without any fitting parameters. Having verified the numerical model in this manner, we study the sensitivity of nanowire PSA sensors by changing device parameters, making it possible to optimize the devices and revealing the attributes of the optimal field-effect sensor. PMID- 23644740 TI - Septin9 is involved in T-cell development and CD8+ T-cell homeostasis. AB - SEPTIN9 (SEPT9) is a filament-forming protein involved in numerous cellular processes. We have used a conditional knock out allele of Sept9 to specifically delete Sept9 in T-cells. As shown by fluorescence-activated cell sorting, loss of Sept9 at an early thymocyte stage in the thymus results in increased numbers of double-negative cells indicating that SEPT9 is involved in the transition from the double-negative stage during T-cell development. Accordingly, the relative numbers of mature T-cells in the periphery are decreased in mice with a T-cell specific deletion of Sept9. Proliferation of Sept9-deleted CD8(+) T-cells from the spleen is decreased upon stimulation in culture. The altered T-cell homeostasis caused by the loss of Sept9 results in an increase of CD8(+) central memory T-cells. PMID- 23644741 TI - Temporospatial gene expression of Prx1 and Prx2 is involved in morphogenesis of cranial placode-derived tissues through epithelio-mesenchymal interaction during rat embryogenesis. AB - Paired-related homeobox transcription factors, PRX1 and PRX2, are verified to play essential roles in limb, heart and craniofacial development by analyses of knockout animals. Their gene expression in the embryonic primordia derived from the mesoderm and neural crest is confirmed by in situ hybridization. Nevertheless, a detailed localization of PRX1 and PRX2 was not carried out because of a lack of specific antibodies for each factor. We have previously confirmed the presence of PRX proteins in rat embryonic pituitary by using an antibody that recognizes both PRX1 and PRX2. However, the pituitary originates in the cranial placodes, not the mesoderm or neural crest. In this study, we analyze the temporospatial distribution of PRX1 and PRX2 with novel antibodies specific for each factor, together with a stem/progenitor marker SOX2 (sex-determining region Y-box 2) in the primordia formed by epithelio-mesenchymal interaction. We observe immunoreactive signals of both PRX proteins in rat embryo, showing a similar pattern to that obtained by in situ hybridization. In early embryogenesis, PRX proteins are not co-localized with SOX2 but PRX2 and/or PRX1 positive cells are present in the border or periphery of SOX2-positive primordia originating in the cranial placode. During advanced embryogenesis, either PRX2 positive cells become condensed in the border of SOX2-positive cells or PRX1 and/or PRX2 become co-localized with SOX2. Our results suggest that PRX proteins, especially PRX2, play a role in the morphogenesis of the primordial tissues formed by the epithelio-mesenchymal interaction and that neural crest cells contribute to the morphogenesis of tissues derived from the cranial placode. PMID- 23644742 TI - Minimal incision transinguinal repair for incarcerated obturator hernia. AB - BACKGROUND: Patients with incarcerated obturator hernia are usually elderly, frail, and physically inactive women with serious comorbidities. Although a laparotomy is standard surgical intervention for emergency incarcerated or strangulated obturator hernia, it is invasive particularly for these high-risk patients. The aim of this study is to show the feasibility of minimum open inguinal approach to reduce surgical risk for preoperatively diagnosed incarcerated obturator hernia. METHODS: Between April 2008 and July 2012, 3 consecutive incarcerated obturator hernia patients at Kamitsuga General Hospital who were diagnosed preoperatively by computed tomography underwent the following procedure. First a 4 cm inguinal hernia incision and preperitoneal dissection through the opening of the deep inguinal ring are made. The obturator hernia can be easily found 2 cm dorsally from the Cooper's ligament extraperitoneally. A small incision is made at medial sharp edge of the hernia defect. The hernia sac and its content can then be reduced. If the incarcerated bowel is viable, a prosthetic mesh is placed as a patch. If the bowel is necrotic, the damaged bowel loop is withdrawn through the wound and easily reconstructed extra-abdominally. RESULTS: All operations were successfully completed with this procedure. All patients recovered without incident. CONCLUSIONS: Minimal incision transinguinal repair for diagnosed incarcerated obturator hernia is feasible and provides an improved option to more invasive procedures. PMID- 23644743 TI - Spectral characteristics of carbonyl substituted 2,2'-bithiophenes in polymer matrices and low polar solvents. AB - The spectral characteristics of monosubstituted derivatives of 2,2'-bithiophene (1-BT) with simple carbonyl substituents, including -COCF3 (trifluoroacetyl, 2 BTCF), -COCH2CN (oxopropanenitrile, 3-BTCN) and -COCH3 (acetyl, 4-BTCE), and the more complex 5'-((9H-fluoren-9-ylidene)methyl)-3-methyl, 5-methyl carboxylate (5 BTFL) were investigated. Absorption and fluorescence spectra and fluorescence lifetimes were measured in solvents with various polarities and compared with those in polymer matrices (polystyrene, PS; polymethyl methacrylate, PMMA; and polyvinyl chloride, PVC). Although the parent, 1-BT, absorbed near 300 nm and exhibited no or weak fluorescence, the substitution of 1-BTwith simple substituents at position 5 resulted in a bathochromic shift of approximately 50 nm or more in absorption and distinct fluorescence above 400 nm. The largest shift in absorption and fluorescence was observed for the complex 5-BTFL with fluorene as a substituent for 1-BT. The most intense fluorescence was observed for the derivative 2-BTCF with trifluoroacetyl as a substituent in the polar PVC matrix. The lifetimes of fluorescence of all substituted 2,2'-bithiophenes were in the range from 0.3 to 3 ns. The polymer matrices increased the intensity of fluorescence to some extent and prolonged the lifetime of the 2,2'-bithiophene derivatives. The reasons for the variation in the fluorescence intensity resulting from the substitution of the parent dimer are discussed. PMID- 23644744 TI - Imputation-based association analyses identify new lung cancer susceptibility variants in CDK6 and SH3RF1 and their interactions with smoking in Chinese populations. AB - Cell cycle regulation, apoptosis, oxidative stress and inflammation response play critical roles in the development of smoking-induced lung cancer. However, it is still not well known whether their genetic variants are associated with lung cancer susceptibility. In this study, we performed imputation-based association analyses to investigate the influence of common genetic variants in these pathways and their interactions with smoking on lung cancer susceptibility. We first selected 24 042 unvalidated genetic variants in 798 genes from the imputed dataset of the previous lung cancer genome-wide association study in 2331 cases and 3077 controls, and then conducted additional two-stage validations in 4133 cases and 4522 controls. We found a genome-wide significant (P < 5.0 * 10(-8)) association for rs2282987 in CDK6 at 7q21.2 [odds ratio (OR) = 1.18, combined P add = 2.27 * 10(-9)] and a consistent association for rs2706748 in SH3RF1 at 4q32.3 (OR = 1.17, combined P add = 5.10 * 10(-6)). Interaction analyses showed that rs2282987 and rs2706748 interacted with both smoking status (P interaction were 1.04 * 10(-2) and 3.03 * 10(-2), respectively) and smoking history (P interaction were 1.21 * 10(-2) and 5.21 * 10(-2), respectively) to contribute to lung cancer susceptibility in subjects aged 51-60 years. These results further underscore the contribution of genetic variants involved in pathways of cell cycle regulation and apoptosis to lung cancer susceptibility, and highlight gene environment interactions in lung cancer etiology, especially in subjects aged 51 60 years. PMID- 23644745 TI - Dosimetry modelling of transient radon and progeny concentration peaks: results from in situ measurements in Ikaria spas, Greece. AB - Radon and progeny ((218)Po, (214)Pb, (214)Bi and (214)Po) are radioactive indoor pollutants recognised for the human radiation burden that they induce. Bathing in thermal spas causes transient concentration peaks of radon and progeny and additional short-term impact in patients and personnel. This paper reports a semi empirical non-linear first order model for describing radon and progeny variations in treatment rooms of the Ikaria spas. Non-measured physical parameters were estimated from in situ measurements in Ikaria through non-linear numerical solving. Exposure and dose variations were additionally modelled. Attachment rate constants were found to be between 0.44 and 55 h(-1). Deposition rate constants were between 0.28 and 7.3 h(-1) for attached nuclei and 0.42 and 64 h(-1) for unattached nuclei. Unattached progeny peaks were right-shifted compared to those of radon. Modelled effective doses ranged between 0.001 mSv per year and 0.589 mSv per year for patients and between 0.001 mSv per year and 18.9 mSv per year for workers. Apollon spas presented quite high doses. These were the highest reported in Greece and are significant worldwide. PMID- 23644746 TI - An enoate reductase Achr-OYE4 from Achromobacter sp. JA81: characterization and application in asymmetric bioreduction of C=C bonds. AB - A putative enoate reductase, Achr-OYE4, was mined from the genome of Achromobacter sp. JA81, expressed in Escherichia coli, and was characterized. Sequence analysis and spectral properties indicated that Achr-OYE4 is a typical flavin mononucleotide-dependent protein; it preferred NADH over NADPH as a cofactor. The heterologously expressed protein displayed good activity and excellent stereoselectivity toward some activated alkenes in the presence of NADH, NADPH, or their recycling systems. The glucose dehydrogenase-based recycling system yielded the best results in most cases, with a product yield of up to 99 % and enantiopurity of >99 % ee. Achr-OYE4 is an important addition to the asymmetric reduction reservoir as an "old yellow enzyme" from Achromobacter. PMID- 23644747 TI - A D-psicose 3-epimerase with neutral pH optimum from Clostridium bolteae for D psicose production: cloning, expression, purification, and characterization. AB - D-Tagatose 3-epimerase family enzymes can efficiently catalyze the epimerization of free keto-sugars, which could be used for D-psicose production from D fructose. In previous studies, all optimum pH values of these enzymes were found to be alkaline. In this study, a D-psicose 3-epimerase (DPEase) with neutral pH optimum from Clostridium bolteae (ATCC BAA-613) was identified and characterized. The gene encoding the recombinant DPEase was cloned and expressed in Escherichia coli. In order to characterize the catalytic properties, the recombinant DPEase was purified to electrophoretic homogeneity using nickel-affinity chromatography. Ethylenediaminetetraacetic acid was shown to inhibit the enzyme activity completely; therefore, the enzyme was identified as a metalloprotein that exhibited the highest activity in the presence of Co2+. Although the DPEase demonstrated the most activity at a pH ranging from 6.5 to 7.5, it exhibited optimal activity at pH 7.0. The optimal temperature for the recombinant DPEase was 55 degrees C, and the half-life was 156 min at 55 degrees C. Using D psicose as the substrate, the apparent K(m), k(cat), and catalytic efficiency (k(cat)/K(m)) were 27.4 mM, 49 s-1, and 1.78 s-1 mM-1, respectively. Under the optimal conditions, the equilibrium ratio of D-fructose to D-psicose was 69:31. For high production of D-psicose, 216 g/L D-psicose could be produced with 28.8 % turnover yield at pH 6.5 and 55 degrees C. The recombinant DPEase exhibited weak acid stability and thermostability and had a high affinity and turnover for the substrate D-fructose, indicating that the enzyme was a potential D-psicose producer for industrial production. PMID- 23644748 TI - Engineering of bacterial strains and their products for cancer therapy. AB - The use of live bacteria in cancer therapies offers exciting possibilities. Nowadays, an increasing number of genetically engineered bacteria are emerging in the field, with applications both in therapy and diagnosis. In parallel, purified bacterial products are also gaining relevance as new classes of bioactive products to treat and prevent cancer growth and metastasis. In the first part of the article, we review the latest findings regarding the use of live bacteria and products as anti-cancer agents, paying special attention to immunotoxins, proteins, and peptides. In particular, we focus on the recent results of using azurin or its derived peptide as anticancer therapeutic agents. In the second part, we discuss the challenges of using metagenomic techniques as a distinctive approach for discovering new anti-cancer agents from bacterial origin. PMID- 23644749 TI - Biofouling inhibition in MBR by Rhodococcus sp. BH4 isolated from real MBR plant. AB - It has been reported that an indigenous quorum quenching bacterium, Rhodococcus sp. BH4, which was isolated from a real plant of membrane bioreactor (MBR) has promising potential to control biofouling in MBR. However, little is known about quorum quenching mechanisms by the strain BH4. In this study, various characteristics of strain BH4 were investigated to elucidate its behavior in more detail in the mixed liquor of MBR. The N-acyl homoserine lactone hydrolase (AHL lactonase) gene of strain BH4 showed a high degree of identity to qsdA in Rhodococcus erythropolis W2. The LC-ESI-MS analysis of the degradation product by strain BH4 confirmed that it inactivated AHL activity by hydrolyzing the lactone bond of AHL. It degraded a wide range of N-acyl homoserine lactones (AHLs), but there was a large difference in the degradation rate of each AHL compared to other reported AHL-lactonase-producing strains belonging to Rhodococcus genus. Its quorum quenching activity was confirmed not only in the Luria-Bertani medium, but also in the synthetic wastewater. Furthermore, the amount of strain BH4 encapsulated in the vessel as well as the material of the vessel substantially affected the quorum quenching activity of strain BH4, which provides useful information, particularly for the biofouling control in a real MBR plant from an engineering point of view. PMID- 23644750 TI - Effects of high-tryptophan diet on pre- and postnatal development in rats: a morphological study. AB - PURPOSE: Tryptophan is an essential amino acid, precursor of serotonin. Serotonin (5HT) regulates the secretion of pituitary growth hormone (GH), which in turn stimulates the liver to produce insulin-like growth factor-I (IGF-I) that is necessary for development and growth. The aim of our study was to investigate the effects of an excess of tryptophan in the diet of pregnant rats on the differentiation of skeletal muscle tissue. METHODS: We conducted an immunohistochemical study on the IGF-I expression in hepatic and muscle tissues in offspring, and then, we associated this molecular data with morphological effects on the structure of the muscle fibers and hepatic tissue at different postnatal weeks, from birth to sexual maturity. Measurements of 5HT, GH in blood, and of tryptophan hydroxylase (Tph) activity in gastrointestinal tracts tissue were also taken. RESULTS: Hyperserotonemia and higher values of Tph activity were detected in both pregnant rats and pups. Very low levels of GH were detected in experimental pups. Morphological alterations of the muscle fibers and lower IGF-I expression in hepatic and muscle tissue in pups were found. CONCLUSIONS: Our data suggest that an excess of tryptophan in the diet causes hyperserotonemia in fetus. Hyperserotonemia results in an excess of serotonin in the brain where it has an adverse effect on the development of serotonergic neurons. The affected neurons do not regulate optimally the secretion of pituitary GH that consequently decreases. This limits stimulation in the liver to produce IGF-I, crucial for development and growth of pups. PMID- 23644751 TI - Comparison of the cigarette dependence scale with four other measures of nicotine involvement: correlations with smoking history and smoking treatment outcome in smokers with substance use disorders. AB - The cigarette dependence scale (CDS) was developed to assess principal aspects of smoking dependence. In a French longitudinal survey, CDS showed stronger relationships to urge and change in smoking rate than the Fagerstrom test for nicotine dependence (FTND). Neither measure predicted abstinence at follow-up in that survey but there was no treatment or cessation induction. The present study investigated concurrent and predictive validity of the CDS in a treatment population by comparing the CDS to the FTND and other measures of tobacco involvement as (1) a correlate of smoking and cessation history and (2) a predictor of short-term smoking abstinence among smokers with substance use disorders (SUD) receiving smoking treatment. METHODS: Smokers (10+ cigarettes per day) in substance treatment received brief advice and nicotine patch for 8 weeks; half also received contingent vouchers for smoking cessation. Assessments were conducted pretreatment and 7, 14 and 30 days after treatment initiation, with abstinence verified biochemically. RESULTS: At baseline (n=305), the 12-item and 5-item CDS versions showed excellent and marginal reliability, respectively. FTND shared 43 and 61% of variance with CDS-12 and CDS-5, respectively. FTND and CDS scales correlated positively with cigarettes per day, and negatively with time to first cigarette, motivation to quit and age at first daily smoking. Only CDS correlated with the number of past quit attempts. Neither CDS nor FTND predicted abstinence within treatment, unlike the motivation measure and time to first cigarette. CONCLUSION: In moderate-heavy smokers with SUD in smoking treatment in the U.S., the CDS is largely equivalent to the FTND as an indicator of tobacco dependence but the CDS-5 is less reliable. Motivation was the most consistent predictor of outcome, and time to first cigarette was the only tobacco dependence measure that predicted smoking abstinence during treatment. PMID- 23644752 TI - A systematic review of postural control during single-leg stance in patients with untreated anterior cruciate ligament injury. AB - PURPOSE: The aim of this review was to determine whether postural control is impaired in patients with anterior cruciate ligament (ACL) injury as compared to healthy controls. METHODS: The relevant papers were retrieved through electronic databases including PubMed, EMBASE, Web of Science, and Sport Discus followed by hand search and contact with the authors. Studies that evaluated static postural control during single-leg stance without applying external perturbations were included. Also, the patients should not have undergone ACL reconstruction or any surgical repair on the injured knee. RESULTS: In total, 12 studies were selected for full review. The included studies showed larger postural sway amplitudes or velocities during single-leg stance on the injured leg and the uninjured leg when compared to healthy controls with medium to large effect size. Also, no significant difference was found between the injured and uninjured legs of ACL injured patients during eyes open condition in all studies supported by small effect size. However, the within-group difference was found to be significant during eyes closed condition, with injured leg displaying larger sway. CONCLUSIONS: The present review indicates that postural control is impaired in both legs, especially injured leg. The result of within-group difference in eyes open condition confirms bilateral deficit of postural control. However, the within-group difference during eyes closed condition indicates again that ACL injury affects the injured leg more than the uninjured leg. In designing rehabilitation protocols, clinicians should consider training postural control of not just the injured but also the uninjured leg. PMID- 23644753 TI - Organ trafficking and transplant tourism: the role of global professional ethical standards-the 2008 Declaration of Istanbul. AB - By 2005, human organ trafficking, commercialization, and transplant tourism had become a prominent and pervasive influence on transplantation therapy. The most common source of organs was impoverished people in India, Pakistan, Egypt, and the Philippines, deceased organ donors in Colombia, and executed prisoners in China. In response, in May 2008, The Transplantation Society and the International Society of Nephrology developed the Declaration of Istanbul on Organ Trafficking and Transplant Tourism consisting of a preamble, a set of principles, and a series of proposals. Promulgation of the Declaration of Istanbul and the formation of the Declaration of Istanbul Custodian Group to promote and uphold its principles have demonstrated that concerted, strategic, collaborative, and persistent actions by professionals can deliver tangible changes. Over the past 5 years, the Declaration of Istanbul Custodian Group organized and encouraged cooperation among professional bodies and relevant international, regional, and national governmental organizations, which has produced significant progress in combating organ trafficking and transplant tourism around the world. At a fifth anniversary meeting in Qatar in April 2013, the DICG took note of this progress and set forth in a Communique a number of specific activities and resolved to further engage groups from many sectors in working toward the Declaration's objectives. PMID- 23644754 TI - Human natural killer cells exhibit negative regulatory function by ectopic expression of hFoxp3 gene. AB - BACKGROUND: Foxp3 is a key marker of CD4CD25 regulatory T cells and appears highly specific for regulatory T cells. Human dendritic cells transfected with foxp3 gene also exhibit immunosuppressive functions. We want to understand whether natural killer (NK) cells could be endowed with regulatory properties by transduction of Foxp3 gene. METHODS: A recombinant vector (pRV.GFP Foxp3) or control vector (pRV.GFP WWRR) was transferred into NKL/NK-92 cells by an electroporation method. The hFoxp3 gene-modified NK cells were characterized with regard to their proliferation, cytokine production, and cytotoxicity and their regulatory effects on activated human peripheral blood mononuclear cells (hPBMCs) in vitro and trans vivo delayed-type hypersensitivity assay. RESULTS: We found that the ectopic expression of hFoxp3 in human NK cells resulted in the high production of the immunosuppressive cytokine, interleukin (IL)-10. Luciferase reporter assay showed that the expression of IL-10 is directly regulated by Foxp3. We observed that NKL.Foxp3 cells inhibited the proliferation and activation of phorbol-12-myristate-13-acetate/ionomycin-stimulated hPBMCs; furthermore, NKL.Foxp3 cells significantly suppressed the delayed-type hypersensitivity response, which was induced by anti-CD3 monoclonal antibody activated hPBMCs. NKL.Foxp3 cell-mediated negative regulatory function was dependent on IL-10 production. CONCLUSIONS: Our findings indicated that NK cells acquired IL-10 phenotype by transduction with foxp3 gene and provided evidence that Foxp3 could exert regulatory function not only in regulatory T cells but also in NK cells. These results suggested that Foxp3 gene-modified NK cells might be potential usefulness on graft-versus-host disease or some autoimmune diseases. PMID- 23644755 TI - Assessing neurodegenerative phenotypes in Drosophila dopaminergic neurons by climbing assays and whole brain immunostaining. AB - Drosophila melanogaster is a valuable model organism to study aging and pathological degenerative processes in the nervous system. The advantages of the fly as an experimental system include its genetic tractability, short life span and the possibility to observe and quantitatively analyze complex behaviors. The expression of disease-linked genes in specific neuronal populations of the Drosophila brain, can be used to model human neurodegenerative diseases such as Parkinson's and Alzheimer's (5). Dopaminergic (DA) neurons are among the most vulnerable neuronal populations in the aging human brain. In Parkinson's disease (PD), the most common neurodegenerative movement disorder, the accelerated loss of DA neurons leads to a progressive and irreversible decline in locomotor function. In addition to age and exposure to environmental toxins, loss of DA neurons is exacerbated by specific mutations in the coding or promoter regions of several genes. The identification of such PD-associated alleles provides the experimental basis for the use of Drosophila as a model to study neurodegeneration of DA neurons in vivo. For example, the expression of the PD linked human alpha-synuclein gene in Drosophila DA neurons recapitulates some features of the human disease, e.g. progressive loss of DA neurons and declining locomotor function (2). Accordingly, this model has been successfully used to identify potential therapeutic targets in PD (8). Here we describe two assays that have commonly been used to study age-dependent neurodegeneration of DA neurons in Drosophila: a climbing assay based on the startle-induced negative geotaxis response and tyrosine hydroxylase immunostaining of whole adult brain mounts to monitor the number of DA neurons at different ages. In both cases, in vivo expression of UAS transgenes specifically in DA neurons can be achieved by using a tyrosine hydroxylase (TH) promoter-Gal4 driver line (3, 10). PMID- 23644756 TI - [De-growth. Nursing and Research]. PMID- 23644758 TI - [Decreasing preoperative anxiety by music: experimental study in a vascular surgery unit]. AB - INTRODUCTION: Preoperative anxiety is common in patients undergoing surgical interventions. Several international studies have shown the positive effect of music before minor surgery and invasive procedures, but the effect of music before major surgery was not explored. AIM: The aim of this study was to assess the effectiveness of music on anxiety in patients undergoing vascular surgery (aortic aneurism and thromboendarterectomy). Methods. Surgical patients were randomized to listening to music before surgery (music group) or to routine care. Anxiety was measured with the STAI-Y, administered three hours before surgery (Time 1) and before the induction of anesthesia (Time 2). After Time 1, only patients assigned to the music group listened to music. RESULTS: The groups were comparable for the main characteristics. In the Music group (N 50) anxiety decreased after listening to music v the controls (N 50) (STAI-Y mean scores 52.2 and 31.1 respectively; p < 0.001). The differences between the two groups in the two measurements explained the 73% of the variance. DISCUSSION: Listening to music is effective in decreasing anxiety in patients undergoing vascular surgery. PMID- 23644757 TI - [Intensity of care during the night shift: a descriptive study of planned and unplanned activities]. AB - INTRODUCTION: The night shift guarantees the continuity of care with activities that may vary across wards, thus the intensity of care and the organization of night activities may vary. AIMS: To describe the night nurses' activities and to analyze their frequency, answer times and activities performed by nurses when answering to patients' needs. METHODS: Nurses on night shift in a neurology and surgical ward were observed for 7 nights. Night activities were recorded (type and time), distinguishing planned and unplanned activities. Data on the number of complex patients, number of calls (time, reason, activities interrupted and time needed to answer) were also collected. RESULTS: Overall 55 patients in neurology and 46 in the surgery ward and 4 nurses per night were observed. In neurology ward nurses were mainly involved in basic care and surveillance, while surveillance and the administration of drug therapy where prevalent in the surgical ward. In neurology, on average patients called once every 50 minutes, mainly in the first hours of the shift while once every 24 minutes in the surgical ward, during tha all night, mainly for pain and drug treatments. Nurses answered to patients calls in less than 2 minutes. CONCLUSIONS: The different intensity of activities is influenced by patient conditions but also by the organization of care. In both wards planned activities and patients calls are distributed during the all night. PMID- 23644759 TI - [Predictors of intention to leave the nursing profession in two Italian hospitals]. AB - AIM: Nursing shortage is acknowledged as worldwide issue: understanding the factors that foster nurses' intention to leave the profession (ITL) is therefore essential in lessening its impact. The present study aims at providing insight into the factors influencing nurses' ITL, taking into account personal characteristics, context characteristics and job satisfaction factors. METHOD: The study was conducted in two hospitals of Northern Italy, by a questionnaire administered to all nurses employed; 746 questionnaires were distributed, of which 525 (70.4%) were returned completed. The questionnaire consisted of four sections: personal characteristics, context characteristics, job satisfaction (44 items of Italian adaptation of Stamps' Index of Work Satisfaction), and ITL (single-item). Descriptive statistics, reliability analysis, univariate analysis and multiple logistic regression model were carried using Pasw18. RESULTS: A higher job satisfaction was registered for Interaction with nurses, Professional status, and Autonomy; on the other hand, a perception of dissatisfaction was registered for Pay and Job requirements; 14.6% of respondents reported ITL. Finally, a low job satisfaction for Professional status, Pay, and Work organization policies, age < 30 years, and part-time schedule are associated to higher ITL. DISCUSSION: The study allowed to identify various predictors of ITL, enhancing the importance of regular monitoring of ITL. To limit ITL, organizations should: invest on some job satisfaction factors, promote organizational integration of newcomers, and prevent the escalation of work family and work-life conflict. PMID- 23644760 TI - [Five scenarios for five... and many more drugs]. AB - The report of the National Observatory on drug is the occasion for a reflection on the different perspectives offered from data on populations and the analysis of patients stories. Five scenarios are presented and briefly commented on of real-life drug prescriptions to elderly patients. Irrational-not evidence based prescriptions, open questions related to the compatibility of some drugs associations, and the limitedness of an answer to patients problems based mainly on drugs, are the main take home messages. A close surveillance oriented to problems and not to drugs, could be the strategy for reconsidering and restoring dignity to what should be a priority research area. PMID- 23644761 TI - [30+1. Profession: research]. AB - The title of the text could be seen as the best and at the same time the main message of the paper. 30+1 is somehow an acronym which is spelled as follows: last year the 30th anniversary of the Journal was celebrated. One year later we try to translate that celebration into a conceptual, methodological, operational plan for a future, whose definition is the second part of the title: to be a responsible professional today coincide with the capacity of being, specifically in the area of nursing, a "full-time researcher". The reasons are detailed with the help of 5 slides whose synthetic text provides the rest of the : in a world society which is changing the term of reference for the role of health care in the society, the nursing profession cannot be trapped in increasingly administrative/managerial roles. Nurses must assume the old provocative task of representing, for the health care systems, (and the societies where they are expected to be indicator of rights) those who remind, and document that, technologies, or procedures, or package of interventions or supportive care cannot be appropriate nor cost effective if they are not a dependent variable with respect to the personal needs and care of the individual person/patient or populations. PMID- 23644762 TI - [Delays in wound healing due to drugs]. AB - Many drugs may delay the cicatrization or healing of a wound. Cytotoxic drugs, inhibitors of vascular endothelial growth factor, epidermal growth factor receptor, and immunosuppressive drugs, may be responsible of these delays. When a wound does not heal, is not infected but there are constant blood or serum losses, it is reasonable to suspect that a drug may play a role. PMID- 23644763 TI - [The world of the oldest old: is the effectiveness of an intervention measurable? Geriatric occupational therapy program created by a group of nurses as described by Paola D'Ovidio and Francesca Perego]. AB - A group of women who assumed the role of providing an integration of the routine care of a nursing home through the activation of various laboratories (from writing, to painting, to manual activities, to music), report on the criteria and the methodologies of their intervention, as well as the results obtained, over a period of three years, by giving a central place to the testimony of the "oldest old" population. The narrative of this experience is proposed not only as a strategy which can be reproduced but also as a methodology of evaluation for a setting which could be hardly assessed with standardized instruments based on quantitative rules and scores. PMID- 23644764 TI - Functionalized AFM probes for force spectroscopy: eigenmode shapes and stiffness calibration through thermal noise measurements. AB - The functionalization of an atomic force microscope (AFM) cantilever with a colloidal bead is a widely used technique when the geometry between the probe and the sample must be controlled, particularly in force spectroscopy. But some questions remain: how does a bead glued at the end of a cantilever influence its mechanical response? And more importantly for quantitative measurements, can we still determine the stiffness of the AFM probe with traditional techniques?In this paper, the influence of the colloidal mass loading on the eigenmode shape and resonant frequency is investigated by measuring the thermal noise on rectangular AFM microcantilevers with and without beads attached at their extremities. The experiments are performed with a home-made ultra-sensitive AFM, based on differential interferometry. The focused beam from the interferometer probes the cantilever at different positions and the spatial shapes of the modes are determined up to the fifth resonance, without external excitation. The results clearly demonstrate that the first eigenmode is almost unchanged by mass loading. However the oscillation behavior of higher resonances presents a marked difference: with a particle glued at its extremity, the nodes of the modes are displaced towards the free end of the cantilever. These results are compared to an analytical model taking into account the mass and inertial moment of the load in an Euler-Bernoulli framework, where the normalization of the eigenmodes is explicitly worked out in order to allow a quantitative prediction of the thermal noise amplitude of each mode. A good agreement between the experimental results and the analytical model is demonstrated, allowing a clean calibration of the probe stiffness. PMID- 23644765 TI - Differential effects of undernourishment on the differentiation and maturation of rat enteric neurons. AB - The colocalization, number, and size of various classes of enteric neurons immunoreactive (IR) for the purinergic P2X2 and P2X7 receptors (P2X2R, P2X7R) were analyzed in the myenteric and submucosal plexuses of control, undernourished, and re-fed rats. Pregnant rats were exposed to undernourishment (protein-deprivation) or fed a control diet, and their offspring comprised the following experimental groups: rats exposed to a normal diet throughout gestation until postnatal day (P)42, rats protein-deprived throughout gestation and until P42, and rats protein-deprived throughout gestation until P21 and then given a normal diet until P42. Immunohistochemistry was performed on the myenteric and submucosal plexuses to evaluate immunoreactivity for P2X2R, P2X7R, nitric oxide synthase (NOS), choline acetyltransferase (ChAT), calbindin, and calretinin. Double-immunohistochemistry of the myenteric and submucosal plexuses demonstrated that 100% of NOS-IR, calbindin-IR, calretinin-IR, and ChAT-IR neurons in all groups also expressed P2X2R and P2X7R. Neuronal density increased in the myenteric and submucosal plexuses of undernourished rats compared with controls. The average size (profile area) of some types of neurons in the myenteric and submucosal plexuses was smaller in the undernourished than in the control animals. These changes appeared to be reversible, as animals initially undernourished but then fed a normal diet at P21 (re-feeding) were similar to controls. Thus, P2X2R and P2X7R are present in NOS-positive inhibitory neurons, calbindin- and calretinin-positive intrinsic primary afferent neurons, cholinergic secretomotor neurons, and vasomotor neurons in rats. Alterations in these neurons during undernourishment are reversible following re-feeding. PMID- 23644766 TI - Acidophilic granulocytes in the gills of gilthead seabream Sparus aurata: evidence for their responses to a natural infection by a copepod ectoparasite. AB - Immunohistochemical and ultrastructural studies were conducted on the gills of gilthead seabream, Sparus aurata L., naturally infected with the copepod ectoparasite Ergasilus lizae (Kroyer, 1863) in order to assess pathology and the host immune cell response. Gills of 56 gilthead seabream were screened for ectoparasites; 36 specimens (64.3%) harbored E. lizae. Intensity of infection was 32.7 +/- 8.7 (mean +/- SE). Pathological alterations to the gills of the host were more pronounced in close proximity to the copepod site of attachment. The parasite attached to the gills by means of its modified second antennae, occluded the arteries, provoked epithelial hyperplasia and hemorrhages and most often caused lamellar disruption. Numerous granular cells were encountered near the site of E. lizae attachment. In both infected and uninfected gills, the granular cells lay within the filaments and frequently occurred within the connective tissue inside and outside the blood vessels of the filaments. The type of granular cell was identified by immunohistochemical staining by using the monoclonal antibody G7 (mAb G7), which specifically recognizes acidophilic granulocytes (AGs) of S. aurata and with an anti-histamine antibody (as a marker for mast cells, MCs) on sections from 13 uninfected gills and 21 parasitized gills. The use of mAb G7 revealed that, in gills harboring copepods, the number of G7-positive cells (i.e., AGs; 32.9 +/- 3.9, mean number of cells per 45,000 MUm2 +/- SE) was significantly higher than the density of the same cells in uninfected gills (15.3 +/- 3.8; ANOVA, P < 0.05). Few histamine-positive granular cells (i.e., MCs) were found in the uninfected and parasitized gills. Here, we show, for the first time in S. aurata infected gills, that AGs rather than MCs are recruited and involved in the response to E. lizae infection in seabream. PMID- 23644767 TI - Intestinal epithelial cell proliferation and migration in Atlantic salmon, Salmo salar L.: effects of temperature and inflammation. AB - A 28-day feeding trial was carried out to characterise intestinal epithelial cell (IEC) turnover in Atlantic salmon (Salmo salar L.) post-smolts in seawater. Four groups of fish raised at two temperatures of 8 degrees C or 12 degrees C and fed two different diets were investigated. The diets included a reference maize gluten and fishmeal-based diet (FM) and an experimental enteropathy-causing diet containing 20% extracted soybean meal (SBM). IEC proliferation and migration were investigated by labelling cells with the in vivo proliferation marker 5-bromo-2' deoxyuridine (BrdU). Proliferating cell nuclear antigen (PCNA) labelling was used as a control for identifying proliferating cells. Samples of the proximal (PI), mid (MI) and distal (DI) intestinal regions were collected at five time points (3 h-28 days) over the experimental period. Histologically, FM-fed fish had normal mucosa, whereas the SBM-fed fish developed DI enteropathy. Major zones of cell proliferation were observed in the mucosal fold bases for all intestinal regions. Over time, BrdU-labelled cells migrated up mucosal folds to the tips before being lost. Migration rates were dependent on intestinal region, temperature and diet. Highest migration rates were observed in the PI followed by the MI and DI for FM fed fish. Diet and temperature barely affected migration in the PI and MI. Migration in the DI was most sensitive to diet and temperature, with both SBM and the higher water temperature increasing proliferation and migration rates. The slow IEC turnover in the DI might help to explain the sensitivity of this region to dietary SBM-induced enteropathy. PMID- 23644769 TI - Response of Saccharomyces cerevisiae to D-limonene-induced oxidative stress. AB - In the present study, we investigated the mode of cell response induced by D limonene in Saccharomyces cerevisiae. D-limonene treatment was found to be accompanied by intracellular accumulation of reactive oxygen species (ROS). Since ROS impair cell membranes, an engineered strain with enhanced membrane biosynthesis exhibited a higher tolerance to D-limonene. Subsequent addition of an ROS scavenger significantly reduced the ROS level and alleviated cell growth inhibition. Thus, D-limonene-induced ROS accumulation plays an important role in cell death in S. cerevisiae. In D-limonene-treated S. cerevisiae strains, higher levels of antioxidants, antioxidant enzymes, and nicotinamide adenine dinucleotide phosphate (NADPH) were synthesized. Quantitative real-time PCR results also verified that D-limonene treatment triggered upregulation of genes involved in the antioxidant system and the regeneration of NADPH at the transcription level in S. cerevisiae. These data indicate that D-limonene treatment results in intracellular ROS accumulation, an important factor in cell death, and several antioxidant mechanisms in S. cerevisiae were enhanced in response to D-limonene treatment. PMID- 23644770 TI - Generation of biologically contained, readily transformable, and genetically manageable mutants of the biotechnologically important Bacillus pumilus. AB - Bacillus pumilus mutants were generated by targeted deletion of a set of genes eventually facilitating genetic handling and assuring biological containment. The well-defined and stable mutants do not form functional endospores due to the deletion of yqfD, an essential sporulation gene; they are affected in DNA repair, as DeltauvrBA rendered them UV hypersensitive and, thus, biologically contained; they are deficient for the uracil phosphoribosyl-transferase (Deltaupp), allowing for 5-fluorouracil-based counterselection facilitating rapid allelic exchanges; and they are readily transformable due to the deletion of the restrictase encoding locus (DeltahsdR) of a type I restriction modification system. Vegetative growth as well as extracellular enzyme production and secretion are in no case affected. The combination of such gene deletions allows for development of B. pumilus strains suited for industrial use and further improvements. PMID- 23644771 TI - Biodegradation of tributyl phosphate using Klebsiella pneumoniae sp. S3. AB - Tributyl phosphate (TBP) has enormous applications in the field of extraction, fuel reprocessing, as defoamers and/or plasticizers. Excessive usage of this organophosphorus compound, poses an environmental threat. The present study deals with microbial degradation of TBP using Klebsiella pneumoniae S3 isolated from the soil. Diauxic growth curve pattern explains a preferential utilization of TBP. The strain S3 was able to biotransform TBP (1,000 mg L-1) to dibutyl phosphate within 48 h and showed higher tolerance towards TBP up to 17.0 g L-1. Toxicity of the parent as well as degraded product was assessed using comet assay. Generation of reactive oxygen species elaborates the oxidative stress imposed upon the bacterial strain by TBP. The antioxidant defense mechanism was studied using various biomarkers namely catalase, glutathione-S-transferase, and superoxide dismutase. The present study describes a faster and eco-friendly alternative for disposal of TBP. PMID- 23644772 TI - Geochemical assessments and classification of coal mine spoils for better understanding of potential salinity issues at closure. AB - Coal mining wastes in the form of spoils, rejects and tailings deposited on a mine lease can cause various environmental issues including contamination by toxic metals, acid mine drainage and salinity. Dissolution of salt from saline mine spoil, in particular, during rainfall events may result in local or regional dispersion of salts through leaching or in the accumulation of dissolved salts in soil pore water and inhibition of plant growth. The salinity in coal mine environments is from the geogenic salt accumulations and weathering of spoils upon surface exposure. The salts are mainly sulfates and chlorides of calcium, magnesium and sodium. The objective of the research is to investigate and assess the source and mobility of salts and trace elements in various spoil types, thereby predicting the leaching behavior of the salts and trace elements from spoils which have similar geochemical properties. X-ray diffraction analysis, total digestion, sequential extraction and column experiments were conducted to achieve the objectives. Sodium and chloride concentrations best represented salinity of the spoils, which might originate from halite. Electrical conductivity, sodium and chloride concentrations in the leachate decreased sharply with increasing leaching cycles. Leaching of trace elements was not significant in the studied area. Geochemical classification of spoil/waste defined for rehabilitation purposes was useful to predict potential salinity, which corresponded with the classification from cluster analysis based on leaching data of major elements. Certain spoil groups showed high potential salinity by releasing high sodium and chloride concentrations. Therefore, the leaching characteristics of sites having saline susceptible spoils require monitoring, and suitable remediation technologies have to be applied. PMID- 23644773 TI - Medical talc increases the incidence of seroma formation following onlay repair of major abdominal wall hernias. AB - PURPOSE: Seroma is a well established complication of the repair of major abdominal wall hernias, occasionally requiring aspiration and reoperation. Medical talc seromadesis (MTS) has been described in the literature. The aim of this study was to determine the effect of MTS on seroma formation after onlay repair of incisional hernia. METHODS: A retrospective review of a prospective database was conducted for 5 months from April 2011, when 21 consecutive patients received MTS. Outcomes were compared with a published and validated series from the same unit. RESULTS: There were no differences in basic demographics and co morbidities between the two groups. The mean BMI was 34 for the MTS group. The incidence of recurrent incisional hernia prior to surgery was greater in MTS (9/21 vs. 36/116, p = 0.39). The mean area of fascial defect measured intra operatively and mesh used to cover the incisional hernia defect was 170 and 309 cm(2) for the MTS group. The mean operating time was 152 min and a mean of 10 g of medical talc was used for seromadesis. The seroma rate increased from 11/116 (9.5 %) to 16/21 (76 %) (p = 0.001) as did the rate of superficial wound infection 10/116 (8.6 %) to 9/21 (43 %) (p = 0.03) in the MTS group. There was no difference in the length of in-hospital stay between the two groups. CONCLUSIONS: The application of medical talc increased the rate of seroma formation and superficial wound infection in patients undergoing open 'onlay' repair of major abdominal wall hernia. PMID- 23644774 TI - Prediction of contralateral inguinal hernias in children: a prospective study of 357 unilateral inguinal hernias. AB - PURPOSE: Previously, we established a pre-operative risk scoring system to predict contralateral inguinal hernia in children with unilateral inguinal hernias. The current study aimed to verify the usefulness of our pre-operative scoring system. METHODS: This was a prospective study of patients undergoing unilateral inguinal hernia repair from 2006 to 2009 at a single institution. Gender, age at initial operation, birth weight, initial operation side, and the pre-operative risk score were recorded. We analyzed the incidence of contralateral inguinal hernia, risk factors, and the usefulness of our pre operative risk scoring system. The follow-up period was 36 months. We used forward multiple logistic regression analysis to predict contralateral hernia. RESULTS: Of the 372 patients who underwent unilateral hernia repair, 357 (96.0 %) were completely followed-up for 36 months, and 23 patients (6.4 %) developed a contralateral hernia. Left-sided hernia (OR = 5.5, 95 %, CI = 1.3-24.3, p = 0.023) was associated with an increased risk of contralateral hernia. The following covariates were not associated with contralateral hernia development: gender (p = 0.702), age (p = 0.215), and birth weight (p = 0.301). The pre operative risk score (cut-off point = 4.5) of the patients with a contralateral hernia was significantly higher, compared with the patients without a contralateral hernia using the area under the receiver operating characteristic curve (p = 0.024). CONCLUSIONS: Using multivariate analysis, we confirmed usefulness of our pre-operative scoring system and initial side of the inguinal hernia, together, for the prediction of contralateral inguinal hernia in children. PMID- 23644775 TI - Effect of extraperitoneal bupivacaine analgesia in laparoscopic inguinal hernia repair: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Laparoscopic total extraperitoneal (TEP) inguinal hernioplasty is significantly less painful than open repair, but it is not completely painless. Local anesthetics are thought to decrease postoperative pain when placed at the surgical site. We conducted a systematic review of randomized controlled trials (RCTs) to evaluate the efficacy of extraperitoneal bupivacaine treatment during laparoscopic inguinal hernia repair for the reduction of postoperative pain. METHODS: We conducted a systematic review and meta-analysis of RCTs that investigated the outcomes of extraperitoneal bupivacaine analgesia versus control in laparoscopic TEP hernia repair. Pain was assessed using a visual analog scale at 4-6 h and at 24 h following the surgery. The secondary outcomes included complications and analgesia consumption. RESULTS: We reviewed eight trials that included a total of 373 patients. We found no difference between the groups in postoperative pain reduction following laparoscopic TEP inguinal hernia repair. The intensity of pain was not significantly different between the bupivacaine treatment group and the control group. The pooled mean differences in pain scores were -0.26 (95% CI -0.72 to 0.21) at 4-6 h and -0.47 (95% CI -1.24 to 0.29) at 24 h. No bupivacaine-related complications were reported. CONCLUSION: Extraperitoneal bupivacaine treatment during laparoscopic TEP inguinal hernioplasty is not more efficacious for the reduction of postoperative pain than placebo. PMID- 23644776 TI - An evaluation of hernia education in surgical residency programs. AB - PURPOSE: The purpose of this study was to evaluate surgical residents' educational experience related to ventral hernias. METHODS: A 16-question survey was sent to all program coordinators to distribute to their residents. Consent was obtained following a short introduction of the purpose of the survey. Comparisons based on training level were made using chi(2) test of independence, Fisher's exact, and Fisher's exact with Monte Carlo estimate as appropriate. A p value <0.05 was considered significant. RESULTS: The survey was returned by 183 residents from 250 surgical programs. Resident postgraduate year (PG-Y) level was equivalent among groups. Preferred techniques for open ventral hernia varied; the most common (32 %) was intra-abdominal placement of mesh with defect closure. Twenty-two percent of residents had not heard of the retrorectus technique for hernia repair, 48 % had not performed the operation, and 60 % were somewhat comfortable with and knew the general categories of mesh prosthetics products. Mesh choices, biologic and synthetic, varied among the different products. The most common type of hernia education was teaching in the operating room in 87 %, didactic lecture 69 %, and discussion at journal club 45 %. Number of procedures, comfort level with open and laparoscopic techniques, indications for mesh use and technique, familiarity and use of retrorectus repair, and type of hernia education varied significantly based on resident level (p < 0.05). CONCLUSION: Exposure to hernia techniques and mesh prosthetics in surgical residency programs appears to vary. Further evaluation is needed and may help in standardizing curriculums for hernia repair for surgical residents. PMID- 23644777 TI - Comment to Sylwia Olechnowicz-Tietz et al.: The risk of atherosclerosis in patients with chronic kidney disease. PMID- 23644779 TI - Design of a biaxial mechanical loading bioreactor for tissue engineering. AB - We designed a loading device that is capable of applying uniaxial or biaxial mechanical strain to a tissue engineered biocomposites fabricated for transplantation. While the device primarily functions as a bioreactor that mimics the native mechanical strains, it is also outfitted with a load cell for providing force feedback or mechanical testing of the constructs. The device subjects engineered cartilage constructs to biaxial mechanical loading with great precision of loading dose (amplitude and frequency) and is compact enough to fit inside a standard tissue culture incubator. It loads samples directly in a tissue culture plate, and multiple plate sizes are compatible with the system. The device has been designed using components manufactured for precision-guided laser applications. Bi-axial loading is accomplished by two orthogonal stages. The stages have a 50 mm travel range and are driven independently by stepper motor actuators, controlled by a closed-loop stepper motor driver that features micro stepping capabilities, enabling step sizes of less than 50 nm. A polysulfone loading platen is coupled to the bi-axial moving platform. Movements of the stages are controlled by Thor-labs Advanced Positioning Technology (APT) software. The stepper motor driver is used with the software to adjust load parameters of frequency and amplitude of both shear and compression independently and simultaneously. Positional feedback is provided by linear optical encoders that have a bidirectional repeatability of 0.1 MUm and a resolution of 20 nm, translating to a positional accuracy of less than 3 MUm over the full 50 mm of travel. These encoders provide the necessary position feedback to the drive electronics to ensure true nanopositioning capabilities. In order to provide the force feedback to detect contact and evaluate loading responses, a precision miniature load cell is positioned between the loading platen and the moving platform. The load cell has high accuracies of 0.15% to 0.25% full scale. PMID- 23644778 TI - Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype. AB - Andersen-Tawil syndrome (ATS) is characterized by dysmorphic features, periodic paralyses and abnormal ventricular repolarization. After genotyping a large set of patients with congenital long-QT syndrome, we identified two novel, heterozygous KCNJ2 mutations (p.N318S, p.W322C) located in the C-terminus of the Kir2.1 subunit. These mutations have a different localization than classical ATS mutations which are mostly located at a potential interaction face with the slide helix or at the interface between the C-termini. Mutation carriers were without the key features of ATS, causing an isolated cardiac phenotype. While the N318S mutants regularly reached the plasma membrane, W322C mutants primarily resided in late endosomes. Co-expression of N318S or W322C with wild-type Kir2.1 reduced current amplitudes only by 20-25 %. This mild loss-of-function for the heteromeric channels resulted from defective channel trafficking (W322C) or gating (N318S). Strikingly, and in contrast to the majority of ATS mutations, neither mutant caused a dominant-negative suppression of wild-type Kir2.1, Kir2.2 and Kir2.3 currents. Thus, a mild reduction of native Kir2.x currents by non dominant-negative mutants may cause ATS with an isolated cardiac phenotype. PMID- 23644781 TI - Artificial nutrition and hydration in Catholic healthcare: balancing tradition, recent teaching, and law. AB - Roman Catholics have a long tradition of evaluating medical treatment at the end of life to determine if proposed interventions are proportionate and morally obligatory or disproportionate and morally optional. There has been significant debate within the Catholic community about whether artificially delivered nutrition and hydration can be appreciated as a medical intervention that may be optional in some situations, or if it should be treated as essentially obligatory in all circumstances. Recent statements from the teaching authority of the church have attempted to clarify this issue, especially for those with a condition known as the persistent vegetative state. I argue that these recent teachings constitute a "general norm" whereby artificial nutrition and hydration are considered obligatory for most patients, but that these documents allow for exception in cases of complication from the means used to deliver nutrition and hydration, progressive illness, or clear refusal of such treatment by patients. While the recent clarifications do not constitute a major deviation from traditional understanding and will rarely conflict with advance directives or legal statutes, there may be rare instances in which remaining faithful to church teaching may conflict with legally enshrined patient prerogatives. Using the Texas Advance Directives Act as an example, I propose ways in which ethics committees can remain faithful to their Roman Catholic identity while respecting patient autonomy and state law pertaining to end of life health care. PMID- 23644780 TI - Making the call: a proactive ethics framework. AB - This manuscript proposes a proactive framework for preventing or mitigating disruptive ethical conflicts that often result from delayed or avoided conversations about the ethics of care. Four components of the framework are explained and illustrated with evidenced-based actions. Clinical implications of adopting a prevention-based, system-wide ethics framework are discussed. While some aspects of ethically-difficult situations are unique, system patterns allow some issues to occur repeatedly--often with lingering effects such as healthcare providers' disengagement and moral distress (McAndrew et al. Journal of Trauma Nursing 18(4):221-230, 2011), compromised inter-professional relationships (Rosenstein and O'Daniel American Journal of Nursing, 105(1):54-64, 2005), weakened ethical climates (Pauly et al. HEC Forum 24:1-11, 2012), and patient safety concerns (Cimiotti et al. American Journal of Infection Control 40:486 490, 2012). This work offers healthcare providers and clinical ethicists a framework for developing a comprehensive set of proactive, ethics-specific, and evidence-based strategies for mitigating ethical conflicts. Furthermore, the framework aims to encourage innovative research and novel ways of collaborating to reduce such conflicts and the moral distress that often results. PMID- 23644782 TI - Seasonal variation of the phytoplankton community structure in the Sao Joao River, Iguacu National Park, Brazil. AB - The limnological characteristics and the phytoplankton community of the pelagic region of the Sao Joao River, tributary of the Iguacu River, Iguacu National Park were analyzed from August 2008 to July 2009. 221 taxa were identified and the Bacillariophyceae class was the most representative. Bacillariophyceae and Chrysophyceae were the dominant classes in density and Bacillariophyceae in biovolume. According to the DCA carried out for phytoplankton density and biovolume, significant differences were identified between the periods, and between the sites and study periods, respectively. The highest richness of species reached 40 taxa in September 2008 at station 1. The Shannon-Wiener diversity indexes and evenness, calculated from the density of phytoplankton, were temporally heterogeneous and spatially similar. In general, the significant temporal variations in the composition of the phytoplankton community were due to variations in limnological conditions, mainly temperature, transparency and nutrients. Spatially the structure was more similar due to the proximity among the stations. Moreover, the similarity of the distribution of communities in lotic environments were due to the unidirectional flow. PMID- 23644784 TI - Philodryas chamissonis (Reptilia: Squamata: Colubridae) preys on the arboreal marsupial Dromiciops gliroides (Mammalia: Microbiotheria: Microbiotheriidae). AB - Philodryas chamissonis, the Chilean long-tailed snake, is a diurnal predator mainly of Liolaemus lizards, but also of amphibians, birds, rodents and juvenile rabbits. Dromiciops gliroides (Colocolo opossum) is an arboreal marsupial endemic of temperate rainforest of southern South America. Little information is available about this marsupial's biology and ecology. Here we report the predation of one Colocolo opossum by an adult female P. chamissonis in a mixed Nothofagus forest, composed mainly by N. dombeyi, N. glauca and N. alpina trees, in the "Huemules de Niblinto" National Reserve, Nevados de Chillan, Chile. Since these two species have different activity and habitat use patterns, we discuss how this encounter may have occurred. Although it could just have been an opportunistic event, this finding provides insights into the different components of food chains in forest ecosystems of Chile. PMID- 23644785 TI - Is nematode colonisation in the presence of Scolelepis in tropical sandy-beach sediment similar to the colonisation process in temperate sandy beaches? AB - The role of a dominant macrobenthic polychaete, Scolelepis squamata, in the colonisation of defaunated tropical sediments by sandy-beach nematodes was investigated and compared with a previous colonisation experiment carried out on a temperate sandy beach. Experimental cylinders, equipped with lateral windows allowing infaunal colonisation, were filled with defaunated sediment containing two treatments, with and without S. squamata. These cylinders were inserted into microcosms containing sediment with indigenous meiofauna collected from the field. The treatments were incubated in the laboratory at ambient temperature and salinity for 7, 14 and 21 days. The nematode assemblages in both treatments did not differ in composition between treatments and from the natural assemblages, suggesting that all the species were equally able to colonise the experimental cores. The presence of the polychaete did not affect the development of the nematode community composition, in contrast to the results from a previous temperate-beach experiment. However, our results did not indicate whether the difference in results was caused by the different behaviour of the polychaete specimens, or by the different composition and response of the present nematode community. PMID- 23644786 TI - Comparison of two mammalian surveys made with camera traps in southeastern Brazil, focusing the abundance of wild mammals and domestic dogs. AB - Sampling allows assessing the impact of human activities on mammal communities. It is also possible to assess the accuracy of different sampling methods, especially when the sampling effort is similar. The present study aimed at comparing two mammalian surveys carried out over a three-year interval, in terms of sampling effort, capture success, abundance of domestic dogs, impact of human activities, and relative biomass using camera traps, in the Serra do Japi Biological Reserve and surroundings, located in Jundiai, state of Sao Paulo, southeastern Brazil. The total richness recorded was 13 species, one domestic and 12 wild mammals. Sampling effort in both surveys was similar, but capture success and number of captures differed. The abundance of wild mammals and dogs did also differ between surveys. There was a highly significant correlation between abundance of wild mammals and capture effort for the survey performed in 2006/2007, but not for the survey performed in 2009/2010. The difference between samples may be related to human disturbance, since the number of domestic mammals photographed was higher in the second survey, three years after the first survey. Despite being a reserve, the area is still under pressure from urbanization, biological invasion, environmental degradation, and hunting, which may reduce the abundance of wild mammals. PMID- 23644787 TI - Zooplankton assemblages in eutrophic reservoirs of the Brazilian semi-arid. AB - Species composition, density, and temporal dynamics of zooplankton were studied in six reservoirs in a semi-arid region in tropical northeastern Brazil (Rio Grande do Norte state). All the reservoirs are highly eutrophic, with high contents of total nitrogen (minimum of 1200 ug.L(-1)) and total phosphorus (minimum of 10 ug.L(-1)), and extremely high algal biomass was registered (surpassing 20 ug Chl a.L(-1)). All the reservoirs showed an enduring condition of high turbidity and phytoplankton assemblages dominated by cyanobacteria. Zooplankton also showed quantitative patterns suggestive of eutrophic conditions, expressed by high densities, mainly in Passagem das Trairas and Sabugi reservoirs. A spatial differentiation in the composition of the zooplankton community was registered. Rotifers (especially Keratella tropica, Brachionus havanensis, and Keratella americana) were the dominant forms in the zooplankton community of Itans, Passagem das Trairas, and Sabugi reservoirs, while calanoid copepods (mainly Notodiaptomus cearensis) dominated in the Armando Ribeiro, Gargalheiras, and Parelhas systems. The existence of novel relationships in zooplankton community composition in eutrophic reservoirs in this tropical semi arid region must be considered in designating zooplankton indicators of eutrophic conditions. PMID- 23644788 TI - A time series analysis of Prochilodus nigricans landings caught by small-scale fisheries in the lower stretch of the Amazon River. AB - We developed a time series analysis using data on curimata (Prochilodus nigricans), which landed in Santarem, a small city located on the right banks of the Amazon River. A 10-year record of monthly average catches per day of P. nigricans was analyzed using forecasting procedures in the open-source software GRETL 1.7.8. We established two models from the identifications made with the correlograms of hyperparametrization and seasonal differences. The autoregressive terms of the model reach three years, indicating that individuals of the species are being caught around the age of three. This may indicate that the curimatas in the landings at Santarem from 1992 to 2002 were more than two years old, potentially a sign of a lack of fishing pressure on the lower age groups. PMID- 23644789 TI - Ecological aspects of helminth fauna of Magellanic penguins, Spheniscus magellanicus (aves: Spheniscidae), from the Northern Coast of the State of Sao Paulo, Brazil. AB - The aim of the present study was to evaluate the helminth fauna found in the Magellanic penguin, Spheniscus magellanicus, relating parasite population and community ecological parameters to life aspects of the host species. The study involved 237 specimens of S. magellanicus taken from the northern shore of the state of Sao Paulo (23 degrees 46' S, 45 degrees 57' W) and southern shore of the state of Rio de Janeiro (23 degrees 02' S, 44 degrees 13' W), Brazil. The following helminth fauna were found: the nematode Contracaecum pelagicum (core species), found in the stomach; the digenetic Cardiocephaloides physalis and the cestode Tetrabothrius lutzi (satellite species), both collected from the initial portion of the small intestine. Comparisons using the Shannon Diversity Index revealed that the parasite community in juvenile penguins is less diverse in the migratory season than the breeding season. Parasitological studies on penguins and other migratory animals provide important information on species during the time in which they remain pelagic and constitute a useful tool for the acquisition of data that is difficult to obtain through other means, thereby favoring the conservation of the species. PMID- 23644790 TI - Floristic analysis and dispersal syndromes of woody species of the Serra de Maracaju, Mato Grosso do Sul, Brazil. AB - This paper presents a floristic survey of the wood component of cerrado s.s. (eastern face) and gallery forest (western face) areas carried out in the southern part of the Serra de Maracaju. The dispersal syndromes and floristic relations of this portion of the Serra were compared to those of other formations from different regions of Brazil. Between October 2007 and September 2008, monthly collections identified 144 species. As for dispersal syndromes, zoochory prevails, followed by autochory and anemochory. The gallery forest is a heterogeneous formation that shelters floristic elements shared with the Atlantic rain forest, the Amazonian forest, semi-deciduous seasonal forests and dry forests of the Pantanal. Low similarity between the two areas analyzed makes this region unique and suggests that the Serra de Maracaju is greatly influenced by the semi-deciduous seasonal forests of the southeastern region. PMID- 23644791 TI - Fishes of the Taquari-Antas river basin (Patos Lagoon basin), southern Brazil. AB - The aquatic habitats of the Taquari-Antas river basin (in the Patos Lagoon basin, southern Brazil) are under marked environmental transformation because of river damming for hydropower production. In order to provide an information baseline on the fish fauna of the Taquari-Antas basin, we provide a comprehensive survey of fish species based on primary and secondary data. We found 5,299 valid records of fish species in the basin, representing 119 species and 519 sampling sites. There are 13 non-native species, six of which are native to other Neotropical river basins. About 24% of the total native species are still lacking a taxonomic description at the species level. Three native long-distance migratory species were recorded (Leporinus obtusidens, Prochilodus lineatus, Salminus brasiliensis), as well as two potential mid-distance migrators (Parapimelodus nigribarbis and Pimelodus pintado). Although there is only one officially endangered species in the basin (S. brasiliensis), restricted range species (21.7% of total species) should be considered in conservation efforts. PMID- 23644792 TI - Structure of bird assemblages in dry and seasonally flooded grasslands in Itirapina Ecological Station, Sao Paulo state. AB - Grasslands are characteristic physiognomies of the Brazilian Cerrado domain. One of last remnants of these threatened environments in the state of Sao Paulo is located in Itirapina Ecological Station, considered as an Important Bird Area (IBA). We investigated bird assemblages that use seasonally flooded grasslands, and predominantly dry grasslands, from August 2010 until July 2011. We focused on aspects of assemblage structure, and possible responses of birds to environmental changes. We recorded 76 species, of which 23.7% are threatened. Some basic aspects of assemblages were similar between environments, such as diversity descriptors, and the tendency of increase richness in the same periods. Other parameters differed between environments, such as absolute richness, recorded monthly (lower in seasonally flooded grasslands). Considering time dimension in analyses, we observed differences in assemblage structure over time, within and between environments. When birds were grouped in guilds, assemblage structure did also differ. We identified significant correlations between the abundance of some guilds and environmental variables. Changes in the availability of resources and microhabitats may affect structure and organization of the studied bird assemblages. PMID- 23644793 TI - Diel horizontal distribution of microcrustaceans and predators throughout a year in a shallow neotropical lake. AB - The focus of this study is to investigate if microcrustaceans undergo diel horizontal migration (DHM) in a tropical shallow lake on a yearly basis and analyse the adaptive value regarding predation. Abundance of invertebrate predators, chaoborid larvae and water mites, and microcrustaceans (cladocerans and copepods) were evaluated on a monthly basis in three stations located on a transect during the day and at night. Both invertebrate predators were predominantly pelagic. Cladocerans did not undergo significant DHM, distributing indistinctly onshore and offshore or being mostly pelagic. Nauplii, copepodites of two copepod species and adults of Tropocyclops prasinus meridionalis Kiefer were mostly distributed offshore, and did not perform DHM. The limnological features (temperature, dissolved oxygen, pH, and conductivity) were suitable for the organisms in both zones of the lake. Algal food concentration was a little lower in the littoral than in the limnetic zone during the day, but it seems to be suitable for the organisms. However, as the algae quality was not evaluated, it is not possible to be conclusive concerning its influence. The results indicated that DHM was not performed by the microcrustaceans and is not, therefore, a strategy for decreasing predation by both invertebrates, Chaoborus brasiliensis Theobald and Krendowskia sp., on a yearly basis in this shallow lake. PMID- 23644794 TI - The influence of Castanhao reservoir on nutrient and suspended matter transport during rainy season in the ephemeral Jaguaribe river (CE, Brazil). AB - Measurements of nutrient and suspended matter concentrations and loads entering and leaving the Castanhao reservoir during the rainy season were carried out to assess the influence of this large reservoir on land-sea fluvial transport in the ephemeral Jaguaribe river basin. Spatial variation indicated statistically significant attenuation of concentrations only for total phosphorous and suspended matter across the reservoir. Strong retention of nutrients and suspended matter loads by the reservoir was observed with average trapping efficiency of 89% for dissolved silicon, 98% of soluble reactive phosphorus, 71% for ammonium, 87% for total nitrogen, 98% for total phosphorus and 97% for suspended matter compared to the reservoir inflow. The dam operational procedure defined by the ephemeral conditions of the river reduced water releases compared to reservoir inflow and induced strong retention of nutrient and suspended matter loads within the reservoir when fluvial transfer occurs in this semiarid watershed. PMID- 23644795 TI - The zooplankton biodiversity of some freshwater environments in Parnaiba basin (Piaui, Northeastern Brazil). AB - The plankton fauna of the state of Piaui, Northeastern Brazil, especially in the Parnaiba basin, is still poorly known; the results of most studies of the subject have not been published and can only be found in grey literature (unpublished scientific works), such as course completion work and consulting reports. Thus, this paper presents data from samples taken recently from different water bodies in Piaui and represents the second study to be published on the region's zooplankton since the pioneering work of Spandl (1926). A total of 38 species were recorded, including 23 new occurrences of rotifers, 10 of cladocerans and 2 of copepods for the state of Piaui. The greatest richness was observed for the rotifers, of which the genus Brachionus must be highlighted, especially at the Joana reservoir. Among the crustaceans, the greatest richness was observed at the Bezerra reservoir, where cladocerans of the genus Bosmina were prominent. The rotifers Brachionus havanaensis Rousselet, 1911 and Filinia longiseta (Ehrenberg, 1834); the cladocerans Diaphanosoma spinulosum Herbst, 1967 and Moina micrura Kurz, 1874; and the copepods Notodiaptomus cearensis Wright, 1936 and Thermocyclops decipiens Kiefer, 1927 occurred in all or in most environments in which the respective groups were studied. The results presented here expand the taxonomic list of zooplankton for the state of Piaui, including a total fauna of 30 species of rotifers, 15 of cladocerans and 3 of copepods. The zooplankton richness was considered low in the studied reservoirs compared to other freshwater ecosystems from Northeastern Brazil; however, the few studies developed in the Parnaiba basin suggest that the diversity for these organisms should be higher. PMID- 23644796 TI - Spatial variation in the structure and composition of the herbaceous community in a semiarid region of northeastern Brazil. AB - In the arid and semiarid environments of the world, microhabitats serve as models for the structure of vegetation communities. The goal of this study was to identify differences in the structures of the herbaceous communities growing on a crystalline substrate and those growing on a sedimentary substrate in a semiarid region of northeastern Brazil. One hundred 1 * 1 m plots were established in each area for quantitative sampling, with 69 species recorded in the crystalline area and 76 in the sedimentary area. The average plant density was higher in the sedimentary area, and average diameters and heights were greater in the crystalline area. The families and species with a high Importance Value Index (IVI) and a high Mixed Ecological Value Index (MEVI) differed between the areas. Of the species with high densities, only four were found in both areas. Shannon Weiner diversity index values in the crystalline (2.96 nats/ind.(-1)) and sedimentary (2.89 nats/ind.(-1)) areas were similar. Evenness values on both substrates were also similar (0.72 and 0.71 in the crystalline and sedimentary areas, respectively). This study shows that variations in plant establishment conditions between crystalline and sedimentary areas in a semiarid region of northeastern Brazil should be considered as structure-modeling factors for the herbaceous community. PMID- 23644797 TI - Aquatic macroinvertebrates associated with Eichhornia azurea (Swartz) Kunth and relationships with abiotic factors in marginal lentic ecosystems (Sao Paulo, Brazil). AB - Marginal lakes are characterised by their having high biological diversity due to the presence of aquatic macrophytes in their coastal zones, providing habitats for refuge and food for animal community members. Among the fauna components associated with macrophytes, aquatic macroinvertebrates are important because they are an energy source for predators and fish. In six lakes and two different seasons (March and August 2009), the ecological attributes of aquatic macroinvertebrate community associated with Eichhornia azurea were compared and the controlling environmental factors were identified. Since the attributes of macroinvertebrate community are strictly associated with abiotic variables of each distinct habitat, our hypothesis was that each site associated with the same floating aquatic macrophyte (E. azurea) should have a typical composition and density of organisms. We identified 50 taxa of macroinvertebrates, with greater taxa richness for aquatic insects (37 taxa) divided into eight orders; the order Diptera being the most abundant in the two study periods. On the other hand, higher values of total taxa richness were recorded in August. Dissolved oxygen and pH presented the greatest number of significant positive correlations with the different taxa. The animals most frequently collected in the six lakes in March and August 2009 were Hirudinea, Oligochaeta, Hydrachnidae, Conchostraca, Ostracoda, Noteridae, Ceratopogonidae, Chironomidae, Culicidae, Caenidae, Pleidae, Aeshnidae, Libellulidae, Coenagrionidae and Nematoda. Only densities of Trichoptera, Ostracoda and Conchostraca presented the highest significant differences between lakes in both study periods and considering the composition of macroinvertebrates no significant differences were registered for macroinvertebrate composition. PMID- 23644798 TI - Phytoplankton assemblages in lateral lagoons of a large tropical reservoir. AB - This study aimed to analyse the composition and ecological attributes of the phytoplankton assemblages in four lateral lagoons and in the main channel of Rosana Reservoir (Paranapanema River, SE Brazil). Fieldwork was carried out in September and November/2004 and January, March, May and August/2005. A total of 283 taxa was identified. Zygnemaphyta was the most specious group, followed by Chlorophyta and Bacillariophyta. Higher richness, abundance and biomass were observed in the lagoons when compared with the river-reservoir sampling point, especially during the rainy period. Cryptophyceae and Bacillariophyceae dominated numerically. Cryptomonas brasiliensis Castro, Bicudo and Bicudo was the main species of the phytoplankton in terms of abundance and frequency of occurrence. The dynamics of the most important taxa are discussed and the results showed that the phytoplankton assemblages are mainly influenced by meteorological factors and nutrient availability (the main driving forces). Correlation analyses indicated that the assemblage abundance was limited by nutrient (nitrogen and phosphorus). The phytoplankton abundance influenced positively the zooplankton abundance, what indicates the prevalence of bottom-up control routes in the lateral lagoons system. The results validate the hypotheses that lateral lagoons have a prominent ecological role on the phytoplankton diversity, as already previously demonstrated for fish and zooplankton. Therefore, the incorporation of the lateral lagoons in environmental programmes should be a target strategy for the conservation of the regional aquatic biota, minimising the negative impact of the dam. PMID- 23644799 TI - Effects of cigarette smoke inhalation and coffee consumption on bone formation and osseous integration of hydroxyapatite implant. AB - The present study aims to assess the effects of cigarette smoke inhalation and/or coffee consumption on bone formation and osseous integration of a dense hydroxyapatite (DHA) implant in rats. For this study, 20 male rats were divided into four groups (n = 5): CT (control) group, CE (coffee) group, CI (cigarette) group and CC (coffee + cigarette) group. During 16 weeks, animals in the CI group were exposed to cigarette smoke inhalation equivalent to 6 cigarettes per day; specimens in the CE group drank coffee as liquid diet; and rats in the CC group were submitted to both substances. In the 6th week a 5 mm slit in the parietal bone and a 4 mm slit in the tibia were performed on the left side: the former was left open while the latter received a DHA implant. As soon as surgeries were finished, the animals returned to their original protocols and after 10 weeks of exposure they were euthanised (ethically sacrificed) and the mentioned bones collected for histological processing. Data showed that exposure to cigarette smoke inhalation and coffee consumption did not interfere in weight gain and that solid and liquid diet consumption was satisfactory. Rats in the CC group showed a decrease in bone neoformation around the tibial DHA implant (31.8 +/- 2.8) as well as in bone formation in the parietal slit (28.6 +/- 2.2). On their own, cigarette smoke inhalation or coffee consumption also led to diminished bone neoformation around the implant and delayed the bone repair process in relation to the CT group. However, reduction in the bone repair process was accentuated with exposure to both cigarette smoke inhalation and coffee consumption in this study. PMID- 23644800 TI - Herpetogramma bipunctalis (Lepidoptera: Crambidae) biology and techniques for rearing on leaves of the blackberry (Rubus spp., Rosaceae). AB - The larvae of the southern beet webworm Herpetogramma bipunctalis (Fabricius, 1794) damage the leaves of species in the plant genus Rubus. The present study investigated the biology of H. bipunctalis and developed a protocol for raising H. bipunctalis under laboratory conditions. On the basis of the biological data, we devised a life table. In order to develop the rearing procedures, we determined which oviposition substrate and blackberry cultivar were the most appropriate for larval development. The mean durations of the egg, larval, and pupal stages were 5.59 days, 26.37 days, and 13.37 days, respectively, and the corresponding survival rates were 80.83%, 49.07%, and 83.23%. The mean pupal weight was 0.0491 g for males and 0.0536 g for females. The mean life cycle (egg to-adult) period was 45.33 days, and overall survival to adulthood was 33.01%. H. bipunctalis females laid a mean of 252.63 eggs over a mean of 13.60 days of oviposition; the mean pre-oviposition period was 2.67 days. Mean female and male life spans were 17.51 and 19.25 days, respectively, and the sex ratio was 0.51. The life-table data indicated that H. bipunctalis can reproduce 57.9 times per generation. Each cage contained one blackberry leaf placed on a paper towel. This method allowed us to obtain the greatest number of eggs. The larval stage was shorter for insects reared on leaves of the Guarani cultivar than for those reared on leaves of the Xavante cultivar (22.63 vs. 26.37 days). These basic data can aid in establishing strategies for the management of H. bipunctalis on blackberry farms. PMID- 23644801 TI - Anomalous colour in Neotropical mammals: a review with new records for Didelphis sp. (Didelphidae, Didelphimorphia) and Arctocephalus australis (Otariidae, Carnivora). AB - Anomalous colourations occur in many tropical vertebrates. However, they are considered rare in wild populations, with very few records for the majority of animal taxa. We report two new cases of anomalous colouration in mammals. Additionally, we compiled all published cases about anomalous pigmentation registered in Neotropical mammals, throughout a comprehensive review of peer reviewed articles between 1950 and 2010. Every record was classified as albinism, leucism, piebaldism or eventually as undetermined pigmentation. As results, we report the new record of a leucistic specimen of opossum (Didelphis sp.) in southern Brazil, as well as a specimen of South American fur seal (Arctocephalus australis) with piebaldism in Uruguay. We also found 31 scientific articles resulting in 23 records of albinism, 12 of leucism, 71 of piebaldism and 92 records classified as undetermined pigmentation. Anomalous colouration is apparently rare in small terrestrial mammals, but it is much more common in cetaceans and michrochiropterans. Out of these 198 records, 149 occurred in cetaceans and 30 in bats. The results related to cetaceans suggest that males and females with anomolous pigmentation are reproductively successful and as a consequence their frequencies are becoming higher in natural populations. In bats, this result can be related to the fact these animals orient themselves primarily through echolocation, and their refuges provide protection against light and predation. It is possible that anomalous colouration occurs more frequently in other Neotropical mammal orders, which were not formally reported. Therefore, we encourage researchers to publish these events in order to better understand this phenomenon that has a significant influence on animal survival. PMID- 23644802 TI - Body length of Hylodes cf. ornatus and Lithobates catesbeianus tadpoles, depigmentation of mouthparts, and presence of Batrachochytrium dendrobatidis are related. AB - A fungal pathogen Batrachochytrium dendrobatidis (Bd), which can cause morbidity and death of anurans, has affected amphibian populations on a worldwide basis. Availability of pure cultures of Bd isolates is essential for experimental studies to understand the ecology of this pathogen. We evaluated the relationships of body length of Hylodes cf. ornatus and Lithobates catesbeianus tadpoles to depigmentation of mouthparts and determined if dekeratinization indicated an infection by Batrachochytrium dendrobatidis. A strong association existed for both species, one from South America (Brazil: Sao Paulo) and one from North America (USA: Maine). We believe it prudent not to kill adult amphibians if avoidable, thus obtaining tissue for isolating Bd from tadpoles is reasonable because infected specimens of some species can be selectively collected based on depigmentation of mouthparts. PMID- 23644803 TI - Penial morphology in three species of Brazilian tuco-tucos, Ctenomys torquatus, C. minutus, and C. flamarioni (Rodentia: Ctenomyidae). AB - The present study analyses the glans penis and baculum morphology of three Brazilian tuco-tucos, Ctenomys torquatus Lichtenstein, 1830, Ctenomys minutus Nehring, 1887 and Ctenomys flamarioni Travi, 1981, in order to identify possible variations and understand some more about this taxonomically complex group. We used fixed penis from 15 previously listed adult specimens. For a more detailed baculum analysis, the penis underwent dissection and diaphanisation, whereas to analyse the glans penis surface we used Scanning Electron Microscopy (SEM). Results showed striking differences in baculum morphology among the three species. While C. minutus have a particular V-shaped proximal baculum tip, C. flamarioni baculum is thin throughout the shaft with rounded proximal and distal tips. Ctenomys torquatus have a shorter and larger baculum, similar to what has previously been described for the species. Glans penis surface microstructure analyses also revealed inter-specific differences, with penial spines varying in shape, size and, especially density. Although C. torquatus has a relatively small penis, it has the largest penial spine density, which suggests a more complex penial ornamentation in this species. PMID- 23644804 TI - Dung beetles (Coleoptera: Scarabaeoidea) in three landscapes in Mato Grosso do Sul, Brazil. AB - Dung beetles (Coleoptera: Scarabaeoidea) in three landscapes in Mato Grosso do Sul, Brazil. Dung Beetles are important for biological control of intestinal worms and dipterans of economic importance to cattle, because they feed and breed in dung, killing parasites inside it. They are also very useful as bioindicators of species diversity in agricultural or natural environments. The aims of this paper were to study the species richness, and abundance of dung beetles, helping to answer the question: are there differences in the patterns of dung beetle diversity in three environments (pasture, agriculture and forest) in the municipality of Dourados, in the state of Mato Grosso do Sul. A total of 105 samplings were carried out weekly, from November 2005 to November 2007, using three pitfall traps in each environment. The traps were baited with fresh bovine dung, and 44,355 adult dung beetles from 54 species were captured: two from Hyborosidae and 52 from Scarabaeidae. Five species were constant, very abundant and dominant on the pasture, two in the agricultural environment, and two in the environment of Semideciduous forest. Most of the species were characterised as accessories, common and not-dominant. The species with higher abundance was Ataenius platensis Blanchard, 1844. The indexes of Shannon-Wiener diversity were: 2.90 in the pasture, 2.84 in the agricultural environment and 2.66 in the area of native forest. The medium positive presence of dung beetles in the traps in each environment were: 36.88, 42.73 and 20.18 individuals per trap, in the pasture, agricultural environment and in the native forest, respectively. The pasture environment presented a higher diversity index. The species diversity of dung beetles was superior where there was higher abundance and regularity of resource (bovine dung). PMID- 23644805 TI - Occurrence of Lysiphlebus testaceipes (Cresson, 1880) (Hymenoptera: Braconidae: Aphidiinae) parasitizing Aphis forbesi weed, 1889 (Hemiptera: Aphididae) in the strawberries crop in the metropolitan region of Curitiba, Parana, Brazil. PMID- 23644806 TI - Lateralized behavior in Guiana dolphins, Sotalia guianensis, at Pipa Beach, RN, Brazil. PMID- 23644807 TI - Occurrence of Amphiorchis indicus Mehrotra, 1973 (Digenea, Spirorchiidae) infecting green turtle Chelonia mydas Linnaeus, 1758 (Testudines, Cheloniidae) in Brazil. PMID- 23644808 TI - Altitudinal records of data-deficient and threatened frog species from the Atlantic Rainforest of the Serra dos Orgaos mountains, in southeastern Brazil. PMID- 23644809 TI - Editor's note. PMID- 23644810 TI - Prenatal ultrasound screening of congenital heart disease in the general population: general concepts, guidelines, differential diagnoses. AB - Congenital heart diseases (CHDs) carry a high prevalence rate in the general population (0.8%-1%). Most fetal CHDs occur in patients without any risk factors. The prenatal recognition of CHD has major impacts on the pregnancy and its outcome. The aforementioned data justify prenatal ultrasound (US) screening of CHD in the general low-risk population. As demonstrated in the literature, the application of an extended basic US cardiac examination improves the detection of CHD, in particular the conotruncal anomalies. The stepwise method suggested for fetal heart US screening during the mid-second trimester sonogram is based on 4 routine axial views of heart and great vessels: (1) a transverse view of the superior abdomen, (2) a 4-chamber view, (3) a 3-vessel view, and (4) a transverse view of the aortic arch. This protocol can be obtained rapidly because these scans are easy to perform. Despite the fact that the sequential segmental approach universally used in the postnatal diagnosis of CHD is not specifically addressed here, the detected anomalies can be categorized according to these views, and a short differential diagnosis proposed. Abnormal cardiac and/or vascular landmarks shown on these key scans should lead to a referral in the fetal cardiac center for a more precise evaluation, as well as for counseling. PMID- 23644811 TI - The effect of obesity on fecal incontinence symptom distress, quality of life, and diagnostic testing measures in women. AB - INTRODUCTION AND HYPOTHESIS: Weight-loss has been demonstrated to result in an improvement in fecal incontinence (FI) severity; however, there is a paucity of data addressing the differential impact of FI on the quality of life (QOL) and results of diagnostic testing across BMI categories. We wished to evaluate symptom distress, QOL, and diagnostic testing parameters among normal, overweight, and obese women with fecal incontinence. METHODS: Women undergoing evaluation for FI between 2003 and 2012 were identified. Participants completed validated, symptom-specific distress, impact, and general QOL measures including the Modified Manchester Questionnaire (MMHQ), which includes the Fecal Incontinence Severity Index (FISI), and the mental and physical component summary scores, MCS and PCS, respectively, of the Short Form-12. Anorectal manometry measures were also included. Multivariate regression analyses were performed. RESULTS: Participants included 407 women with a mean age +/- SD of 56 +/- 13. Multivariate analyses revealed no differences in symptom-specific distress and impact as measured by MMHQ, MCS, and PCS across BMI groups; however, obese women had increased resting and squeeze pressures compared with normal and overweight BMI women (p < 0.0001 and p < 0.0001; p = 0.007 and p = 0.004 respectively). CONCLUSIONS: Obese women with FI did not have more general impact and symptom specific distress and impact on quality of life compared with normal and overweight women. Obese women with FI had higher baseline anal resting and squeeze pressures suggesting a lower threshold to leakage with pressure increases. PMID- 23644812 TI - Quality-of-care indicators for pelvic organ prolapse: development of an infrastructure for quality assessment. AB - INTRODUCTION AND HYPOTHESIS: A paucity of data exists addressing the quality of care provided to women with pelvic organ prolapse (POP). We sought to develop a means of measuring this quality through the development of quality-of-care indicators (QIs). METHODS: QIs were modeled after those previously described in the Assessing the Care of Vulnerable Elders (ACOVE) project. The indicators were then presented to a panel of nine experts. Using the RAND Appropriateness Method, we analyzed each indicator's preliminary rankings. A forum was then held in which each indicator was thoroughly discussed by the panelists as a group, after which panelists individually re-rated the indicators. QIs with median scores of at least 7 were considered valid. RESULTS: QIs were developed that addressed screening, diagnosis, work-up, and both nonsurgical and surgical management. Areas of controversy included whether screening should be performed to identify prolapse, whether pessary users should undergo a vaginal examination by a health professional every 6 months versus annually, and whether a colpocleisis should be offered to older women planning to undergo surgery for POP. Fourteen out of 21 potential indicators were rated as valid for pelvic organ prolapse (median score >=7). CONCLUSION: We developed and rated 14 potential quality indicators for the care of women with POP. Once these QIs are tested for feasibility they can be used on a larger scale to measure and compare the care provided to women with prolapse in different clinical settings. PMID- 23644814 TI - Preparation of high-quality biocompatible carbon dots by extraction, with new thoughts on the luminescence mechanisms. AB - Recently, carbon dots (CDs) have been among the most promising emerging fluorescent labels for cellular imaging. In this work, a new facile synthesis method was developed for fabricating CDs from polystyrene foam waste and common organic solvents. The CDs obtained have tunable emission from blue to orange and are expected to be of use for labeling different cellular structures simultaneously. Transmission electron microscopy, x-ray diffraction, Raman spectra, Fourier transform infrared spectrometry, UV-vis, and fluorescence spectrophotometry (PL) were employed to investigate the structures and luminescence properties of CDs. The highest quantum yield (QY) achieved was 36%. The mechanisms for the formation and luminescence of the CDs are analyzed. The ability of the solvent to disperse the CDs plays a very important role in the origin of PL. The type of organic solvent has an important influence on the position of emission peaks and the QY. Different emissive traps play the dominant role in the luminescence of carbon materials. Furthermore, a hemolysis assay was performed to evaluate the biocompatibility of these CDs in vitro. The biocompatibility of the CDs, even at very high doses, ensures their potential in biomedical applications. PMID- 23644813 TI - Highly purified collagen coating enhances tissue adherence and integration properties of monofilament polypropylene meshes. AB - INTRODUCTION AND HYPOTHESIS: Complications related to tissue integration of polypropylene implants used in the treatment of pelvic organ prolapse are relatively prevalent. Collagen, a biocompatible, less immunogenic material with modulating properties on the inflammatory process, may improve polypropylene integration. The objective was to study biomechanical and histological effects of monofilament polypropylene mesh coated with purified collagen gel. METHODS: Forty rats were implanted with two fragments of polypropylene mesh in their abdominal walls (one on each side of the linea alba). One of the fragments had a collagen gel coating (group I) while the other one did not (group II). The animals were euthanized at 7, 14, 90, and 180 days after implantation and their abdominal walls were excised for analysis. RESULTS: The biomechanical study showed that mesh adherence to neighboring tissue increased significantly in group II (p < 0.05). Acute (p < 0.001) and chronic (p = 0.004) inflammatory responses as well as granulation tissue formation (p = 0.001) were less intense in group II at 7 and 14 days. Granulomatous inflammation and foreign body reaction was less significant at 7 days in group II (p = 0.029 and p < 0.001). The birefringence analysis showed higher mean brightness density in the late phase of implantation in group II meshes (p = 0.000). CONCLUSION: Polypropylene mesh coated with purified collagen gel increases adherence to tissue, promotes a less intense and lasting inflammatory response and triggers a greater organization and packing arrangement of collagen fibers in the late phase of implantation. PMID- 23644815 TI - Variants of callous-unemotional conduct problems in a community sample of adolescents. AB - Callous-unemotional traits are believed to be a childhood precursor to psychopathy, and among youth with conduct problems they designate those showing a particularly severe, stable, and aggressive pattern of antisocial behavior. Youth with callous-unemotional traits are a heterogeneous population and, analogous to adults with psychopathy, research suggests that lower anxious primary and high anxious secondary variants exist. Using a community sample of 2,306 Greek-Cypriot adolescents (M age = 16 years; 49.7 % female), the first aim of the study was to examine whether variants of callous-unemotional traits could be identified using latent profile analysis of scores on measures of callous-unemotional traits, conduct problems, and anxiety. Additional aims of the study were to compare the identified clusters on external measures theorized to distinguish them (i.e., self-esteem, narcissism, impulsivity, sensation seeking and proactive/reactive aggression) and social factors relevant to adolescent development. Results indicated that, in addition to low risk (i.e., low scores on callous-unemotional traits, conduct problems, and anxiety) and anxious (i.e., high scores on anxiety, low scores on callous-unemotional traits and conduct problems) subgroups, two groups of youth scoring high on callous-unemotional traits and conduct problems were identified. High-anxious secondary callous-unemotional variants were distinguished by lower self-esteem in combination with greater narcissism, aggression, and markedly higher conduct problems, whereas lower anxious primary variants showed higher self-esteem. Secondary callous-unemotional variants also reported greater susceptibility to peer pressure and popularity striving than primary variants. Both variants exhibited poorer outcomes relative to low risk and anxious youth, although anxious youth reported lower self-esteem and higher impulsivity and reactive aggression scores in comparison with low risk youth. Findings integrate two lines of inquiry focused on subtyping children and adults with psychopathic traits and antisocial behaviors. They also support the utility of subtyping callous-unemotional traits based on conduct problems and anxiety levels and provide information on common and distinct risk factors associated with primary and secondary callous-unemotional variants in a community sample of adolescent boys and girls. PMID- 23644816 TI - Telephone based cognitive behavioral therapy targeting major depression among urban dwelling, low income people living with HIV/AIDS: results of a randomized controlled trial. AB - This pilot randomized controlled trial evaluated a previously developed manualized telephone based cognitive behavioral therapy (T-CBT) intervention compared to face-to-face (f2f) therapy among low-income, urban dwelling HIV infected depressed individuals. The primary outcome was the reduction of depressive symptoms as measured by the Hamliton rating scale for depression scale. The secondary outcome was adherence to HAART as measured by random telephone based pill counts. Outcome measures were collected by trained research assistants masked to treatment allocation. Analysis was based on intention-to treat. Thirty-four participants met eligibility criteria and were randomly assigned to receive T-CBT (n = 16) or f2f (n = 18). There was no statistically significant difference in depression treatment outcomes comparing f2f to T-CBT. Within group evaluation demonstrated that both the T-CBT and the f2f psychotherapy groups resulted in significant reductions in depressive symptoms. Those who received the T-CBT were significantly more likely to maintain their adherence to antiretroviral medication compared to the f2f treatment. None of the participants discontinued treatment due to adverse events. T-CBT can be delivered to low-income, urban dwelling HIV infected depressed individuals resulting in significant reductions in depression symptoms and improved adherence to antiretroviral medication. TRIAL REGISTRY: Clinical Trial.gov identifier: NCT01055158. PMID- 23644817 TI - Associations between perceived characteristics of the peer social network involving significant others and risk of HIV transmission among men who have sex with men in China. AB - The HIV epidemic among men who have sex with men (MSM) in China is severe. Peer can induce risky and preventive behaviors among MSM. We interviewed 220 MSM who had at least one significant other who was a peer MSM (SOPM). Interviews were conducted at two gay venues in Suzhou, China, which reported five HIV-related outcomes: HIV (8.2 %), syphilis (16.4 %), self-reported sexually transmitted infection symptoms (14.6 %), unprotected anal intercourse (UAI; 58.6 %) and having had taken up HIV testing (40.4 %). Adjusting for significant background variables, participants' perceived characteristics of the social network of SOPM, such as practicing risk behavior (e.g. UAI) or preventive behaviors (e.g. HIV antibody testing), or possessing HIV-related perceptions (e.g. dislike in condom use), were significantly associated with some of the five aforementioned outcomes (p < 0.05). Peer education and peer-based interventions involving significant others are hence potentially important in HIV prevention targeting MSM. Future pilot intervention studies are warranted. PMID- 23644818 TI - First evidence of DNA methylation in insect Tribolium castaneum: environmental regulation of DNA methylation within heterochromatin. AB - DNA methylation has been studied in many eukaryotic organisms, in particular vertebrates, and was implicated in developmental and phenotypic variations. Little is known about the role of DNA methylation in invertebrates, although insects are considered as excellent models for studying the evolution of DNA methylation. In the red flour beetle, Tribolium castaneum (Tenebrionidae, Coleoptera), no evidence of DNA methylation has been found till now. In this paper, a cytosine methylation in Tribolium castaneum embryos was detected by methylation sensitive restriction endonucleases and immuno-dot blot assay. DNA methylation in embryos is followed by a global demethylation in larvae, pupae and adults. DNA demethylation seems to proceed actively through 5 hydroxymethylcytosine, most probably by the action of TET enzyme. Bisulfite sequencing of a highly abundant satellite DNA located in pericentromeric heterochromatin revealed similar profile of cytosine methylation in adults and embryos. Cytosine methylation was not only restricted to CpG sites but was found at CpA, CpT and CpC sites. In addition, complete cytosine demethylation of heterochromatic satellite DNA was induced by heat stress. The results reveal existence of DNA methylation cycling in T. castaneum ranging from strong overall cytosine methylation in embryos to a weak DNA methylation in other developmental stages. Nevertheless, DNA methylation is preserved within heterochromatin during development, indicating its role in heterochromatin formation and maintenance. It is, however, strongly affected by heat stress, suggesting a role for DNA methylation in heterochromatin structure modulation during heat stress response. PMID- 23644820 TI - Androgen-dependent impairment of myogenesis in spinal and bulbar muscular atrophy. AB - Spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disease caused by expansion of a polyglutamine (polyQ) tract in the androgen receptor (AR). SBMA is triggered by the interaction between polyQ-AR and its natural ligands, testosterone and dihydrotestosterone (DHT). SBMA is characterized by the loss of lower motor neurons and skeletal muscle fasciculations, weakness, and atrophy. To test the hypothesis that the interaction between polyQ-AR and androgens exerts cell-autonomous toxicity in skeletal muscle, we characterized the process of myogenesis and polyQ-AR expression in DHT-treated satellite cells obtained from SBMA patients and age-matched healthy control subjects. Treatment with androgens increased the size and number of myonuclei in myotubes from control subjects, but not from SBMA patients. Myotubes from SBMA patients had a reduced number of nuclei, suggesting impaired myotube fusion and altered contractile structures. The lack of anabolic effects of androgens on myotubes from SBMA patients was not due to defects in myoblast proliferation, differentiation or apoptosis. DHT treatment of myotubes from SBMA patients increased nuclear accumulation of polyQ-AR and decreased the expression of interleukin-4 (IL-4) when compared to myotubes from control subjects. Following DHT treatment, exposure of myotubes from SBMA patients with IL-4 treatment rescued myonuclear number and size to control levels. This supports the hypothesis that androgens alter the fusion process in SBMA myogenesis. In conclusion, these results provide evidence of an androgen-dependent impairment of myogenesis in SBMA that could contribute to disease pathogenesis. PMID- 23644819 TI - Longitudinal assessment of tau and amyloid beta in cerebrospinal fluid of Parkinson disease. AB - Tau gene has been consistently associated with the risk of Parkinson disease in recent genome wide association studies. In addition, alterations of the levels of total tau, phosphorylated tau [181P], and amyloid beta 1-42 in cerebrospinal fluid have been reported in patients with sporadic Parkinson disease and asymptomatic carriers of leucine-rich repeat kinase 2 mutations, in patterns that clearly differ from those typically described for patients with Alzheimer disease. To further determine the potential roles of these molecules in Parkinson disease pathogenesis and/or in tracking the disease progression, especially at early stages, the current study assessed all three proteins in 403 Parkinson disease patients enrolled in the DATATOP (Deprenyl and tocopherol antioxidative therapy of parkinsonism) placebo-controlled clinical trial, the largest cohort to date with cerebrospinal fluid samples collected longitudinally. These initially drug-naive patients at early disease stages were clinically evaluated, and cerebrospinal fluid was collected at baseline and then at endpoint, defined as the time at which symptomatic anti-Parkinson disease medications were determined to be required. General linear models were used to test for associations between baseline cerebrospinal fluid biomarker levels or their rates of change and changes in the Unified Parkinson Disease Rating Scale (total or part III motor score) over time. Robust associations among candidate markers are readily noted. Baseline levels of amyloid beta were weakly but negatively correlated with baseline Unified Parkinson Disease Rating Scale total scores. Baseline phosphorylated tau/total tau and phosphorylated tau/amyloid beta were significantly and negatively correlated with the rates of the Unified Parkinson Disease Rating Scale change. While medications (deprenyl and/or tocopherol) did not appear to alter biomarkers appreciably, a weak but significant positive correlation between the rate of change in total tau or total tau/amyloid beta levels and the change of the Unified Parkinson Disease Rating Scale was observed. Notably, these correlations did not appear to be influenced by APOE genotype. These results are one of the very first pieces of evidence suggesting that tau and amyloid beta are critically involved in early Parkinson disease progression, potentially by a different mechanism than that in Alzheimer disease, although their applications as Parkinson disease progression markers will likely require the addition of other proteins. PMID- 23644821 TI - The protective effect of recombinant FomA-expressing Lactobacillus acidophilus against periodontal infection. AB - A number of studies have shown that the outer membrane protein FomA found in Fusobacterium nucleatum demonstrates great potential as an immune target for combating periodontitis. Lactobacillus acidophilus is a useful antigen delivery vehicle for mucosal immunisation, and previous studies by our group have shown that L. acidophilus acts as a protective factor in periodontal health. In this study, making use of the immunogenicity of FomA and the probiotic properties of L. acidophilus, we constructed a recombinant form of L. acidophilus expressing the FomA protein and detected the FomA-specific IgG in the serum and sIgA in the saliva of mice through oral administration with the recombinant strains. When serum containing FomA-specific antibodies was incubated with the F. nucleatum in vitro, the number of Porphyromonas gingivalis cells that coaggregated with the F. nucleatum cells was significantly reduced. Furthermore, a mouse gum abscess model was successfully generated, and the range of gingival abscesses in the immune mice was relatively limited compared with the control group. The level of IL 1beta in the serum and local gum tissues of the immune mice was consistently lower than in the control group. Our findings indicated that oral administration of the recombinant L. acidophilus reduced the risk of periodontal infection with P. gingivalis and F. nucleatum. PMID- 23644822 TI - High quality methylome-wide investigations through next-generation sequencing of DNA from a single archived dry blood spot. AB - The potential importance of DNA methylation in the etiology of complex diseases has led to interest in the development of methylome-wide association studies (MWAS) aimed at interrogating all methylation sites in the human genome. When using blood as biomaterial for a MWAS the DNA is typically extracted directly from fresh or frozen whole blood that was collected via venous puncture. However, DNA extracted from dry blood spots may also be an alternative starting material. In the present study, we apply a methyl-CpG binding domain (MBD) protein enrichment-based technique in combination with next generation sequencing (MBD seq) to assess the methylation status of the ~27 million CpGs in the human autosomal reference genome. We investigate eight methylomes using DNA from blood spots. This data are compared with 1,500 methylomes previously assayed with the same MBD-seq approach using DNA from whole blood. When investigating the sequence quality and the enrichment profile across biological features, we find that DNA extracted from blood spots gives comparable results with DNA extracted from whole blood. Only if the amount of starting material is <= 0.5ug DNA we observe a slight decrease in the assay performance. In conclusion, we show that high quality methylome-wide investigations using MBD-seq can be conducted in DNA extracted from archived dry blood spots without sacrificing quality and without bias in enrichment profile as long as the amount of starting material is sufficient. In general, the amount of DNA extracted from a single blood spot is sufficient for methylome-wide investigations with the MBD-seq approach. PMID- 23644823 TI - Iron deficiency generates secondary thrombocytosis and platelet activation in IBD: the randomized, controlled thromboVIT trial. AB - BACKGROUND: Secondary thrombocytosis is a common clinical feature. In patients with cancer, it is a risk factor for venous thromboembolic events. In inflammatory bowel disease (IBD), thrombocytosis is so far considered a marker of active disease and may contribute to the increased thromboembolic risk in this population. Observed effects of iron therapy on normalization of platelet counts led us to hypothesize that iron itself may regulate megakaryopoiesis. Here, we want to test the effect of iron replacement on platelet count and activity in IBD associated thrombocytosis. METHODS: We performed a randomized, single-blinded placebo-controlled trial testing the effect of ferric carboxymaltose (FCM) in patients with IBD with secondary thrombocytosis (platelets > 450 G/L). Changes in platelet counts, hemoglobin, iron parameters, disease activity, megakaryopoietic growth factors, erythropoietin, and platelet activity were assessed. Patients received placebo or up to 1500 mg iron as FCM. Endpoints were evaluated at week 6. RESULTS: A total of 26 patients were included in the study, 15 patients were available for the per protocol analysis. A drop in platelets >25% (primary endpoint) was observed in 4 of 8 (50%, iron group) and 1 of 7 patients (14%, placebo group, P = 0.143). Mean platelet counts dropped on FCM but not on placebo (536 G/L to 411 G/L versus 580 G/L to 559 G/L; P = 0.002). Disease activity and megakaryopoietic growth factors remained unchanged and hemoglobin and iron parameters increased on FCM. The normalization of platelet counts was associated with a decrease in platelet aggregation and P-selectin expression. CONCLUSION: FCM lowers platelet counts and platelet activation in patients with IBD associated secondary thrombocytosis. PMID- 23644826 TI - Weight status, body image and bullying among adolescents in the Seychelles. AB - We investigated the relationship between being bullied and measured body weight and perceived body weight among adolescents of a middle-income sub Saharan African country. Our data originated from the Global School-based Health Survey, which targets adolescents aged 13-15 years. Student weights and heights were measured before administrating the questionnaire which included questions about personal data, health behaviors and being bullied. Standard criteria were used to assess thinness, overweight and obesity. Among 1,006 participants who had complete data, 16.5% (95%CI 13.3-20.2) reported being bullied >= 3 days during the past 30 days; 13.4% were thin, 16.8% were overweight and 7.6% were obese. Categories of actual weight and of perceived weight correlated only moderately (Spearman correlation coefficient 0.37 for boys and 0.57 for girls; p < 0.001). In univariate analysis, both actual obesity (OR 1.76; p = 0.051) and perception of high weight (OR 1.63 for "slightly overweight"; OR 2.74 for "very overweight", both p < 0.05) were associated with being bullied. In multivariate analysis, ORs for categories of perceived overweight were virtually unchanged while ORs for actual overweight and obesity were substantially attenuated, suggesting a substantial role of perceived weight in the association with being bullied. Actual underweight and perceived thinness also tended to be associated with being bullied, although not significantly. Our findings suggest that more research attention be given to disentangling the significant association between body image, overweight and bullying among adolescents. Further studies in diverse populations are warranted. PMID- 23644825 TI - A history of ashes: an 80 year comparative portrait of smoking initiation in American Indians and Non-Hispanic whites--the Strong Heart Study. AB - The consequences of starting smoking by age 18 are significant. Early smoking initiation is associated with higher tobacco dependence, increased difficulty in smoking cessation and more negative health outcomes. The purpose of this study is to examine how closely smoking initiation in a well-defined population of American Indians (AI) resembles a group of Non-Hispanic white (NHW) populations born over an 80 year period. We obtained data on age of smoking initiation among 7,073 AIs who were members of 13 tribes in Arizona, Oklahoma and North and South Dakota from the 1988 Strong Heart Study (SHS) and the 2001 Strong Heart Family Study (SHFS) and 19,747 NHW participants in the 2003 National Health Interview Survey. The participants were born as early as 1904 and as late as 1985. We classified participants according to birth cohort by decade, sex, and for AIs, according to location. We estimated the cumulative incidence of smoking initiation by age 18 in each sex and birth cohort group in both AIs and NHWs and used Cox regression to estimate hazard ratios for the association of birth cohort, sex and region with the age at smoking initiation. We found that the cumulative incidence of smoking initiation by age 18 was higher in males than females in all SHS regions and in NHWs (p < 0.001). Our results show regional variation of age of initiation significant in the SHS (p < 0.001). Our data showed that not all AIs (in this sample) showed similar trends toward increased earlier smoking. For instance, Oklahoma SHS male participants born in the 1980s initiated smoking before age 18 less often than those born before 1920 by a ratio of 0.7. The results showed significant variation in age of initiation across sex, birth cohort, and location. Our preliminary analyses suggest that AI smoking trends are not uniform across region or gender but are likely shaped by local context. If tobacco prevention and control programs depend in part on addressing the origin of AI smoking it may be helpful to increase the awareness in regional differences. PMID- 23644824 TI - How does genotype influence disease phenotype in inflammatory bowel disease? AB - Inflammatory bowel diseases (Crohn's disease and ulcerative colitis) are chronic immunologically mediated diseases of the gut. Advances in genetics have revolutionized our understanding of the pathogenesis of these conditions with 163 risk loci identified, encompassing a variety of immunologic functions. There is substantial heterogeneity in the natural history of these diseases with respect to disease onset, course, and progression to complications. There are also significant variations in response to therapies and susceptibility to therapy related and disease-related complications. An important need in the field is to identify predictors of disease course, complications, and likelihood of response and adverse events to allow for targeted therapeutic decision making. The genotype of an individual in constant and non-modifiable, and thus could potentially fulfill the role of important predictors of these outcomes. In this review, we discuss the existing literature on the prediction of various disease phenotypes in Crohn's disease and ulcerative colitis using underlying genotype. We also identify gaps in the literature and suggest future directions for research. There is need for large, multi-institutional, and international collaborative consortia with efficient and detailed cohort accrual, phenotypic definition, genotyping, and dynamic assessments of external (e.g., diet) and internal (microbiome) environment to allow us to progress toward personalized and precision medicine in the management of these complex diseases. PMID- 23644827 TI - Decreased IgA+ B cells population and IgA, IgG, IgM contents of the cecal tonsil induced by dietary high fluorine in broilers. AB - Fluoride is an environmental and industrial pollutant that affects various organs in humans and animals. The cecal tonsil is an important component of the mucosal immune system and performs important and unique immune functions. In the present study, we investigated the effects of dietary high fluorine on the quantities of IgA+ B cells in the cecal tonsil by immunohistochemistry, and the immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM) contents in the cecal tonsil by ELISA. A total of 280 one-day-old avian broilers were divided into four groups and fed on a corn-soybean basal diet as control diet (fluorine 22.6 mg/kg) or the same diet supplemented with 400, 800 and 1,200 mg/kg fluorine (high fluorine groups I, II and III) in the form of sodium fluoride, respectively, throughout a 42-day experimental period. The results showed that the quantities of IgA+ B cells were lower (p < 0.05 or p < 0.01) and the IgA, IgG, and IgM contents were decreased (p < 0.05 or p < 0.01) in high fluorine groups II and III in comparison with those of control group. It was concluded that dietary fluorine, in the 800-1,200 mg/kg range, could reduce the numbers of the IgA+ B cells and immunoglobulin contents in the cecal tonsil, implying the local mucosal immune function was ultimately impacted in broilers. PMID- 23644828 TI - The Hispanic Paradox and older adults' disabilities: is there a healthy migrant effect? AB - The "Hispanic Paradox" suggests that despite rates of poverty similar to African Americans, Hispanics have far better health and mortality outcomes, more comparable to non-Hispanic White Americans. Three prominent possible explanations for the Hispanic Paradox have emerged. The "Healthy Migrant Effect" suggests a health selection effect due to the demands of migration. The Hispanic lifestyle hypothesis focuses on Hispanics' strong social ties and better health behaviors. The reverse migration argument suggests that the morbidity profile in the USA is affected when many Hispanic immigrants return to their native countries after developing a serious illness. We analyzed data from respondents aged 55 and over from the nationally representative 2006 American Community Survey including Mexican Americans (13,167 U.S. born; 11,378 immigrants), Cuban Americans (314 U.S. born; 3,730 immigrants), and non-Hispanic White Americans (629,341 U.S. born; 31,164 immigrants). The healthy migrant effect was supported with SES adjusted disability comparable between Mexican, Cuban and non-Hispanic Whites born in the USA and all immigrants having lower adjusted odds of functional limitations than U.S. born non-Hispanic Whites. The reverse migration hypothesis was partially supported, with citizenship and longer duration in the USA associated with higher rates of SES-adjusted disability for Mexican Americans. The Hispanic healthy life-style explanation had little support in this study. Our findings underline the importance of considering nativity when planning for health interventions to address the needs of the growing Hispanic American older adult population. PMID- 23644829 TI - Stress, depression and coping among Latino migrant and seasonal farmworkers. AB - Research shows that one in four migrant farmworkers experienced an episode of one or more mental health disorders such as stress, depression, or anxiety in their lifetime. The purpose of this mixed methods study was to explore experiences and perceptions related to stress and depression among Latino migrant and seasonal farmworkers (MSFWs), and to identify their coping behaviors for dealing with these mental health conditions. Using a mixed methods research approach, three focus group interviews of a sample of Latino MSFWs (N = 29) were conducted and a quantitative survey was implemented (N = 57) at community sites in eastern North Carolina. Four major themes emerged from the focus group data: (1) physical stress related to working conditions; (2) mental stress related to family situations, work environment, documentation status, and lack of resources; (3) depression related to separation from family and the lack of resources; and (4) use of positive and negative mechanisms for coping with stress and depression. A discussion of these themes, results from the survey findings, implications for intervention and outreach programs, along with recommendations for further research, are provided. PMID- 23644830 TI - The effect of precipitation on the transmission of Japanese encephalitis (JE) virus in nature: a complex effect on antibody-positive rate to JE virus in sentinel pigs. AB - Japanese encephalitis (JE) is one of the most important mosquito-borne viral diseases in Asia. Pigs are a natural host and the amplifier of JE virus. The sero conversion rate to JE virus in sentinel pigs reflects the activity of JE virus in the region. We analyzed whether precipitation has any effect on the sero conversion rate to JE virus in sentinel pigs. Linear regression analysis was performed to determine the correlations between the levels of precipitation and sero-conversion rates to JE virus, in the entire year and during summertime over the period of 32 years from 1969 to 2000. The levels of the annual and summertime precipitation demonstrated statistically significant positive correlations with sero-conversion rates for the whole of the country and for some regions in Japan. The levels of the summertime precipitation, on the other hand, demonstrated statistically significant inverse correlations with the sero-conversion rates in other regions. Further, the levels of precipitation during preceding 10-day periods from days 1-40 before blood collection showed inverse correlation with antibody-positive rates in some regions. The results indicate that the relationship between the annual and summertime precipitation, and the sero conversion rate to JE virus is complex; both positive and inverse effects are demonstrated depending on the regions. PMID- 23644831 TI - Valuing human leptospirosis prevention using the opportunity cost of labor. AB - Leptospirosis is a serious public health concern in the Philippines, not only because of its increasing incidence rate, but also because of its significant health and economic impacts. Despite its relatively high seroprevalence, knowledge on the economic burden of disease, particularly on the value that the society places on disease prevention remains limited. Obtaining such information is important within the context of public health policy. This study was conducted in Metro Manila to determine the economic burden of leptospirosis, by asking respondents about their willingness to contribute to labor (WTCL) for the prevention of leptospirosis. The respondents pledged an average labor contribution of 10.66 h/month. The average WTCL corresponded to a monetary value of US$4.01 per month when valued using the opportunity cost of labor (leisure rate of time). From the monetized labor contribution, the total economic value of preventing leptospirosis was estimated at US$124.97 million per annum, which represents 1.13% of Metro Manila's gross domestic product (GDP). Estimates from a Tobit regression model identified the respondents' knowledge regarding leptospirosis, the susceptibility of their homes to flooding, and the proximity of their homes to sewers as significant factors to consider when developing resource contribution programs for leptospirosis prevention. More efforts need to be made in developing community level preventive programs, and in improving public's knowledge and awareness about leptospirosis. PMID- 23644832 TI - Furry pet allergens, fungal DNA and microbial volatile organic compounds (MVOCs) in the commercial aircraft cabin environment. AB - There has been concern about the cabin environment in commercial aircraft. We measured cat, dog and horse allergens and fungal DNA in cabin dust and microbial volatile organic compounds (MVOCs) in cabin air. Samples were collected from two European airline companies, one with cabins having textile seats (TSC) and the other with cabins having leather seats (LSC), 9 airplanes from each company. Dust was vacuumed from seats and floors in the flight deck and different parts of the cabin. Cat (Fel d1), dog (Can f1) and horse allergens (Equ cx) were analyzed by ELISA. Five sequences of fungal DNA were analyzed by quantitative PCR. MVOCs were sampled on charcoal tubes in 42 TSC flights, and 17 compounds were analyzed by gas chromatography mass spectrometry (GC-MS) with selective ion monitoring (SIM). MVOC levels were compared with levels in homes from Nordic countries. The weight of dust was 1.8 times larger in TSC cabins as compared to LSC cabins (p < 0.001). In cabins with textile seats, the geometric mean (GM) concentrations of Fel d1, Can f1 and Equ cx were 5359 ng g(-1), 6067 ng g(-1), and 13 703 ng g(-1) (GM) respectively. Levels of Fel d1, Can f1 and Equ cx were 50 times, 27 times and 75 times higher respectively, in TSC cabins as compared to LSC cabins (p < 0.001). GM levels of Aspergillus/Penicillium DNA, Aspergillus versicolor DNA, Stachybotrys chartarum DNA and Streptomyces DNA were all higher in TSC as compared to LSC (p < 0.05). The sum of MVOCs in cabin air (excluding butanols) was 3192 ng m(-3) (GM), 3.7 times higher than in homes (p < 0.001) and 2-methyl-1 butanol and 3-methyl-1-butanol concentrations were 15-17 times higher as compared to homes (p < 0.001). Concentrations of isobutanol, 1-butanol, dimethyldisulfide, 2-hexanone, 2-heptanone, 3-octanone, isobutyl acetate and ethyl-2-methylbutyrate were lower in cabin air as compared to homes (p < 0.05). In conclusion, textile seats are much more contaminated by pet allergens and fungal DNA than leather seats. The use of seats with smooth surfaces should be encouraged. The MVOC levels differed between cabin air and homes. PMID- 23644833 TI - "Triangle of safety": anatomic considerations in transvaginal natural orifice surgery. AB - BACKGROUND: The introduction of transvaginal (TV) natural orifice transluminal endoscopic surgery (NOTES) brings the loss of traditionally used cutaneous landmarks for safe peritoneal access. This video describes the use of landmarks within the posterior vaginal fornix to define a "triangle of safety" wherein the peritoneal cavity can be accessed while minimizing the risk of injury to surrounding structures. METHODS: The triangle of safety is best identified in the following way. The cervix and posterior fornix are visualized. Then an imaginary clock located at the base of the cervix is envisioned. The superior two corners of the triangle are represented by the 4 and 8 o'clock positions on this imaginary clock. Sometimes the cervix needs to be grasped and elevated anteriorly so that the inferior apex of the triangle delineated by the center of the rectovaginal fold is better visualized. RESULTS: During hybrid TV NOTES, the rectovaginal pouch of Douglas is visualized from the umbilicus, and the vaginal port can then be safely passed through the center of the triangle. It is important that the vaginal port should be angled upward, aiming toward the umbilicus to avoid injury to the rectum. During pure TV NOTES, the incision is made with electrocautery from the 5 o'clock position to the 7 o'clock position within the triangle. The peritoneum is sharply entered, and the colpotomy is dilated with the surgeons' fingers. CONCLUSIONS: The triangle of safety defines a set of landmarks between the base of the cervix and the rectovaginal fold. It allows for a safe TV access for hybrid and pure TV NOTES while minimizing the risk of injury to surrounding structures. PMID- 23644835 TI - Impact of transoral incisionless fundoplication (TIF) on subjective and objective GERD indices: a systematic review of the published literature. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) remains a significant problem for the medical community. Many endoluminal treatments for GERD have been developed with little success. Currently, transoral incisionless fundoplication (TIF) attempts to recreate a surgical fundoplication through placement of full thickness polypropylene H-fasteners. This, the most recent procedure to gain FDA approval, has shown some promise in the early data. However, questions of its safety profile, efficacy, and durability remain. METHODS: The Cochrane Library and MEDLINE through PubMed were searched to identify published studies reporting on subjective and objective GERD indices after TIF. The search was limited to human studies published in English from 2006 up to March 2012. Data collected included GERD-HRQL and RSI scores, PPI discontinuation and patient satisfaction rates, pH study metrics, complications, and treatment failures. Statistical analysis was performed with weighted t tests. RESULTS: Titles and abstracts of 214 papers were initially reviewed. Fifteen studies were found to be eligible, reporting on over 550 procedures. Both GERD-HRQL scores (21.9 vs. 5.9, p < 0.0001) and RSI scores (24.5 vs. 5.4, p <= 0.0001) were significantly reduced after TIF. Overall patient satisfaction was 72 %. The overall rate of PPI discontinuation was 67 % across all studies, with a mean follow-up of 8.3 months. pH metrics were not consistently normalized. The major complication rate was 3.2 % and the failure rate was 7.2 % across all studies. CONCLUSION: TIF appears to provide symptomatic relief with reasonable levels of patient satisfaction at short-term follow-up. A well-designed prospective clinical trial is needed to assess the effectiveness and durability of TIF as well as to identify the patient population that will benefit from this procedure. PMID- 23644834 TI - Feasibility and yield of a novel 22-gauge histology EUS needle in patients with pancreatic masses: a multicenter prospective cohort study. AB - BACKGROUND: The option of obtaining tissue samples for histological examination during endoscopic ultrasound (EUS) has theoretical and practical advantages over cytology alone. The aim of this study was to evaluate the feasibility, yield, and diagnostic accuracy of a new EUS 22-G fine-needle biopsy (FNB) device in patients with solid pancreatic masses in a multicenter, prospective study. METHODS: All consecutive patients who underwent EUS-guided fine-needle biopsy (EUS-FNB) using a newly developed 22-G FNB needle between September 2010 and October 2010 were enrolled in the study. The EUS-FNB technique was standardized among the participating endoscopists. Only a single needle pass was performed. RESULTS: A total of 61 patients (35 males, mean age 64.2 +/- 12.4 years) with solid pancreatic masses with a mean size of 32.4 +/- 8.5 mm (range 13-90 mm) participated. EUS-FNB was performed through the duodenum in 35 cases (57.4 %) and was technically feasible in all but one of the 61 (98.4 %) patients without complications. Tissue samples for histological examination were obtained from 55 patients (90.2 %) and were deemed adequate in 54 of the cases (88.5 %). The diagnoses established by EUS-FNB were adenocarcinoma (39 patients), neuroendocrine tumors (5), chronic focal pancreatitis (5), sarcoma (2), lymphoma (1), acinar cellular tumor (1), and pancreatic metastasis from renal cell carcinoma (1). In an intention-to-treat (ITT) analysis, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the histologic diagnosis of a pancreatic mass were 87.5, 100, 100, 41.7, and 88.5 %, respectively. CONCLUSIONS: EUS-FNB was technically feasible in 98 % of patients with a solid pancreatic mass. A suitable sample for histological evaluation was obtained in 88.5 % of the cases after only one single needle pass. The apparently low negative predictive value is likely to be improved by increasing the number of needle passes. PMID- 23644836 TI - What is the optimal time for laparoscopic cholecystectomy in gallbladder empyema? AB - PURPOSE: With the accumulating experience in laparoscopic surgery, early laparoscopic cholecystectomy (LC) is increasingly offered for acute cholecystitis. However, early LC without percutaneous transhepatic gallbladder drainage (PTGBD) for gallbladder empyema is still believed to be unsafe. The purpose of this study was to determine the optimal time for LC in gallbladder empyema. METHODS: A retrospective analysis was carried out of patients who underwent LC without PTGBD for gallbladder empyema between August 2007 and December 2010. All cases were confirmed by biopsy. The patients were divided into two groups on the basis of a cutoff of 72 h. RESULTS: LC for gallbladder empyema was performed without PTGBD in 61 patients during the study period. The overall conversion rate was 6.6 %. Based on the 72 h cutoff, there were 33 patients in the early group and 28 in the delayed group. There were no significant differences between early and late patients with respect to operation duration (75.5 vs. 71.4 min, p = 0.537), postoperative hospital stay (4.2 vs. 3.3 days, p = 0.109), conversion rate (12.1 vs. 0 %, p = 0.118), and complication rate (12.1 vs. 3.6 %, p = 0.363). However, the early group had a significantly shorter total hospital stay (5.3 vs. 8.7 days, p = 0.001). CONCLUSIONS: Early LC without PTGBD is safe and feasible for gallbladder empyema and is associated with a low conversion rate. Delayed LC for gallbladder empyema has no advantages and results in longer total hospital stays. LC should be performed as soon as possible within 72 h after admission to decrease length of hospital stay. PMID- 23644837 TI - 200 consecutive laparoscopic pancreatic resections performed with a robotically controlled laparoscope holder. AB - INTRODUCTION: Because of the potential benefit of robotics in pancreatic surgery, we review our experience at two minimally invasive pancreatic surgery centers that utilize a robotically controlled laparoscope holder to see if smaller robots that enable the operating surgeon to maintain contact with the patient may have a role in the treatment of pancreatic disease. METHODS: From March 1994 to June 2011, a total of 200 laparoscopic pancreatic procedures utilizing a robotically controlled laparoscope holder were performed. RESULTS: A total of 72 duodenopancreatectomies, 67 distal pancreatectomies, 23 enucleations, 20 pancreatic cyst drainage procedures, 5 necrosectomies, 5 atypical pancreatic resections, 4 total pancreatectomies, and 4 central pancreatectomies were performed. Fourteen patients required conversion to an open approach and eight a hand-assisted one. A total of 24 patients suffered a major complication. Sixteen patients developed a pancreatic leak and 19 patients required reoperation. Major complications occurred in 14 patients and pancreatic leaks occurred in 13 patients. Ten patients required conversion to a lap-assisted or open approach and six patients required reoperation. CONCLUSIONS: Currently, a robotically assisted approach using a camera holder seems the only way to incorporate some of the benefits of robotics in pancreatic surgery while maintaining haptics and contact with the patient. PMID- 23644838 TI - Risk factors for complications and mortality of percutaneous endoscopic gastrostomy: a multicenter, retrospective study. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is performed to provide nutrition to patients with swallowing difficulties. A multicenter study was conducted to evaluate the predictors of complications and mortality after PEG placement. METHODS: This study retrospectively analyzed patients who underwent initial PEG placement between January 2004 and December 2011 at seven tertiary hospitals in the Republic of Korea. RESULTS: All 1,625 patients underwent PEG placement by the pull-string method. The median age of the patients was 66 years, and 1,108 of the patients were men. The median follow-up period was 254 days. The common indications were stroke (31.6%) and malignancy (18.9%). The complication rate was 13.2%. The prophylactic use of antibiotics (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.38-0.88; p = 0.010) reduced the PEG-related infection rate, but the actual usage rate was 81.1%. The use of anticoagulants (OR, 7.26; 95% CI, 2.23-23.68; p = 0.001) and the presence of diabetes mellitus (OR, 4.02; 95% CI, 1.49-10.87; p = 0.006) increased the risk of bleeding, but antiplatelet therapy did not. The procedural, 30-day, and overall mortality rates were 0.2, 2.4 and 14.0%, respectively. Serum albumin levels lower than 31.5 g/L (OR, 8.55; 95% CI, 3.11-23.45; p < 0.001) and C-reactive protein levels higher than 21.5 mg/L (OR, 3.01; 95% CI, 1.27-7.16; p = 0.012) increased the risk of 30-day mortality, and the patients who had both risk factors had a significantly shorter median survival time than those who did not (1,740 vs 3,181 days) (p < 0.001, log rank). CONCLUSIONS: The findings showed PEG to be a safe and feasible procedure, but the patient's nutritional and inflammatory status should be considered in predicting the outcomes of PEG placement. PMID- 23644839 TI - The application of the V-Loc closure device for gastrointestinal sutures: a preliminary study. AB - BACKGROUND: Leakage is one of the major complications in gastrointestinal surgery. This preliminary study compared a new barbed absorbable thread for gastrointestinal sutures with monofil suture material in a cadaver model. METHODS: In this study, mechanical experiments were performed in 20 recently deceased individuals. Incisions were made in the small intestine, colon, and stomach, and then sutures were created with the V-Loc closure device and monofil suture material. Intestinal bursting pressure was measured by inserting a balloon and slowly filling it with air until there was a dehiscence, or wall or suture rupture. RESULTS: The bursting pressures differed significantly between the two sutures in the small intestine, showing the advantage of the V-Loc closure device, which had a mean bursting pressure of 116.2 mmHg compared with 110 mmHg for the monofil suture (p = 0.003). The mean bursting pressure did not differ significantly between the two sutures in the colon and the stomach. The mean bursting pressures for the V-Loc closure device were 141.3 mmHg (stomach) and 137.2 mmHg (colon) compared with the monofil suture material bursting pressures of 133 mmHg (stomach) and 134.8 mmHg (colon). CONCLUSIONS: Because the bursting strength of the sutures created with monofil suture material differs significantly from that of the V-Loc closure device, the V-Loc suture material should be used for gastrointestinal sutures. Although the two sutures did not differ significantly in the colon or the stomach, the V-Loc closure device should be used for these as well because its advantages may overrule those of the monofil suture. No knot tying is required, and the operating time can be shorter. Especially for laparoscopic surgery, the V-Loc closure device is recommended. PMID- 23644840 TI - No differences in short-term morbidity and mortality after robot-assisted laparoscopic versus laparoscopic resection for colonic cancer: a case-control study of 263 patients. PMID- 23644841 TI - The feasibility score for the Laparoscopic Appendicitis Score. PMID- 23644843 TI - Prominent electric properties of BiFeO3 shells sputtered on ZnO-nanorod cores with LaNiO3 buffer layers. AB - In this work, template-assisted methods were adopted to grow BiFeO3 (BFO)-nanorod arrays on substrates. Well-aligned ZnO-nanorod arrays (ZNAs) grown hydrothermally were chosen as positive templates. It was found that perovskite BFO could not be radio frequency (RF)-magnetron sputtered directly on a ZNA at elevated temperatures. Only amorphous BFO was obtained. However, polycrystalline BFO shells could be fabricated by RF-magnetron sputtering on ZNA templates by the introduction of LaNiO3 (LNO) buffer layers. The LNO buffer layer deposited on the ZNA by RF-magnetron sputtering was demonstrated to improve the adhesion and crystallization of the sequentially sputtered BFO shells. The electrical properties were evaluated by conductive atomic force microscopy and piezoresponse force microscopy. Bulk-limited Poole-Frenkel emission dominates the conduction of BFO shells at positive bias, while barrier-limited Schottky emission accounts for the conduction at negative bias due to the interface between the Pt/Ir-coated tip and the BFO. The piezoelectric coefficient (d33) was estimated to be ~32.93 pm V( 1) and a polarization of 133 MUC cm(-2) was derived. These values are higher than those reported previously for BFO films. PMID- 23644842 TI - Reply to: doi:10.1007/s00464-013-2987-3: re: optimization of sympathectomy to treat palmar hyperhidrosis. PMID- 23644844 TI - Connective tissue diseases following silicone breast implantation: where do we stand? PMID- 23644846 TI - Etiology of liver cirrhosis in Brazil: chronic alcoholism and hepatitis viruses in liver cirrhosis diagnosed in the state of Espirito Santo. AB - OBJECTIVES: To report the etiology of liver cirrhosis cases diagnosed at the University Hospital in Vitoria, Espirito Santo, Brazil. METHODS: The medical charts of patients with liver cirrhosis who presented to the University Hospital in Vitoria were reviewed. Chronic alcoholism and the presence of hepatitis B or C infections (HBV and HCV, respectively) were pursued in all cases. RESULTS: The sample consisted of 1,516 cases (male:female ratio 3.5:1, aged 53.2 +/- 12.6 years). The following main etiological factors were observed: chronic alcoholism alone (39.7%), chronic alcoholism in association with HBV or HCV (16.1 %), HCV alone (14.5%) and in association with alcoholism (8.6%) (total, 23.1 %), and HBV alone (13.1%) and in association with alcoholism (7.5%, total 20.6%). The remaining etiologies included cryptogenic cases (9.8%) and other causes (6.0%). The mean patient age was lower and the male-to-female ratio was higher in the cirrhosis cases that were associated with alcoholism or HBV compared with other causes. Intravenous drug abuse and a history of surgery or blood transfusion were significantly associated with HCV infection. Hepatocellular carcinoma was present at the time of diagnosis in 15.4% of cases. Chronic alcoholism associated with HCV infection was significantly associated (p<0.001) with reduced age (at the time of cirrhosis diagnosis) and increased prevalence of hepatocellular carcinoma (p = 0.052). CONCLUSION: Alcoholism, HCV and HBV are the main factors associated with liver cirrhosis in the state of Espirito Santo. Chronic alcoholism associated with HCV infection reduced the age of patients at the time of liver cirrhosis diagnosis. PMID- 23644845 TI - 99mTc-thymine scintigraphy may be a promising method in the diagnosis of breast cancer. AB - OBJECTIVE: Mammography has been established as the gold standard for the detection of breast cancer, and imaging techniques such as ultrasonography, magnetic resonance imaging, scintigraphy and positron emission tomography may be useful to improve its sensitivity and specificity. The objective of this study with breast scintigraphy was to evaluate the uptake of 99mTc-thymine in mammary lesions. METHODS: A total of 45 patients were included in this study. Thirty three patients (73%) were subjected to surgery or percutaneous biopsy, providing histopathological data. The other 12 patients who remained under surveillance received clinical examinations and biannual mammography with a normal follow-up of at least three years, the data from which were used for comparison with the scintimammography results. RESULTS: The majority of patients (64.4%) had clinically impalpable lesions with a mammogram diagnosis of microcalcifications, impalpable nodules, or focal asymmetry. Of the studied lesions, 87% were smaller or equal to 20 mm in diameter, and 22% had malignant histopathological findings. Scintigraphy with 99mTc-thymine had a sensitivity of 70%, a specificity of 85.7%, positive and negative predictive values of 58.3% and 90.9%, respectively, and an accuracy of 82.2%. CONCLUSIONS: The results of this study are consistent with those previously reported by other authors. The good specificity and high negative predictive value of this technique and the absence of uptake in the heart indicate that it may be a promising complementary method in clinical practice and that it may contribute to reducing unnecessary benign biopsies. PMID- 23644847 TI - Prima-1 induces apoptosis in bladder cancer cell lines by activating p53. AB - OBJECTIVES: Bladder cancer represents 3% of all carcinomas in the Brazilian population and ranks second in incidence among urological tumors, after prostate cancer. The loss of p53 function is the main genetic alteration related to the development of high-grade muscle-invasive disease. Prima-1 is a small molecule that restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Our aim was to investigate the ability of Prima-1 to induce apoptosis after DNA damage in bladder cancer cell lines. METHOD: The therapeutic effect of Prima-1 was studied in two bladder cancer cell lines: T24, which is characterized by a p53 mutation, and RT4, which is the wild-type for the p53 gene. Morphological features of apoptosis induced by p53, including mitochondrial membrane potential changes and the expression of thirteen genes involved in apoptosis, were assessed by microscopic observation and quantitative real-time PCR (qRT-PCR). RESULTS: Prima-1 was able to reactivate p53 function in the T24 (p53 mt) bladder cancer cell line and promote apoptosis via the induction of Bax and Puma expression, activation of the caspase cascade and disruption of the mitochondrial membrane in a BAK-independent manner. CONCLUSION: Prima-1 is able to restore the transcriptional activity of p53. Experimental studies in vivo may be conducted to test this molecule as a new therapeutic agent for urothelial carcinomas of the bladder, which characteristically harbor p53 mutations. PMID- 23644848 TI - Is there a relationship between endothelial nitric oxide synthase gene polymorphisms and ankylosing spondylitis? AB - OBJECTIVE: Nitric oxide is produced by endothelial nitric oxide synthase, and its production can be influenced by polymorphisms of the endothelial nitric oxide synthase gene. Because candidate genes responsible for susceptibility to ankylosing spondylitis are mostly unknown and available data suggest that there may be problems related to the nitric oxide pathway, such as endothelial dysfunction and increased asymmetric dimethylarginine, this study aimed to assess the association of common endothelial nitric oxide synthase gene polymorphisms with ankylosing spondylitis. METHODS: One hundred ninety-four unrelated Turkish ankylosing spondylitis patients and 113 healthy without apparent cardiovascular disease, hypertension or diabetes mellitus were included. All individuals were genotyped by PCR-RFLP for two single-nucleotide polymorphisms, namely 786T>C (rs2070744, promoter region) and 786 Glu298Asp (rs1799983, exon 7). Variable numbers of tandem repeat polymorphisms in intron 4 were also studied and investigated by direct electrophoresis on agarose gel following polymerase chain reaction analysis. The Bath ankylosing spondylitis metrology index of the patients was calculated, and human leukocyte antigen B27 was studied. RESULTS: All studied polymorphisms satisfied Hardy-Weinberg equilibrium. Sex distributions were similar between the patient and control groups. No significant differences were found in the distributions of allele and genotype frequencies of the studied endothelial nitric oxide synthase polymorphisms between patients and controls. There were no correlations between endothelial nitric oxide synthase polymorphisms, disease duration, Bath ankylosing spondylitis metrology index or human leukocyte antigen B27. CONCLUSION: The results presented in this study do not support a major role of common endothelial nitric oxide synthase polymorphisms in Turkish ankylosing spondylitis patients. PMID- 23644849 TI - Objective evaluation of plantar hyperhidrosis after sympathectomy. AB - OBJECTIVE: The aim of the present study was to prospectively, randomly, blindly, and objectively investigate how surgery affects plantar sudoresis in patients with palmar and plantar hyperhidrosis over a one-year period using a sudorometer (VapoMeter). METHODS: From February 2007 to May 2009, 40 consecutive patients with combined palmar hyperhidrosis and plantar hyperhidrosis underwent video assisted thoracic sympathectomy at the T3 or T4 ganglion level (15 women and 25 men, with a mean age of 25 years). RESULTS: Immediately after the operation and during the one-year follow-up, all of the patients were free from palmar hyperhidrosis episodes. Compensatory hyperhidrosis of varying degrees was observed in 35 (87.5%) patients after one year. Only two (2.5%) patients suffered from severe compensatory hyperhidrosis. There was a large initial improvement in plantar hyperhidrosis in 46.25% of the cases, followed by a progressive regression of that improvement, such that only 30% continued to show this improvement after one year. The proportion of patients whose condition worsened increased progressively (from 21.25% to 47.50%), and the proportion of stable patients decreased (32.5% to 22.50%). This was not related to resection level; however, a lower intensity of plantar hyperhidrosis prior to sympathectomy correlated with worse evolution. CONCLUSION: Patients with palmar hyperhidrosis and plantar hyperhidrosis who underwent video-assisted thoracic sympathectomy to treat their palmar hyperhidrosis exhibited good initial improvement in plantar hyperhidrosis, which then decreased to lesser degrees of improvement over a one year period following the surgery. For this reason, video-assisted thoracic sympathectomy should not be performed when only plantar hyperhidrosis is present. PMID- 23644850 TI - Giant cell arteritis: a multicenter observational study in Brazil. AB - OBJECTIVE: To describe demographic features, disease manifestations and therapy in patients with giant cell arteritis from referral centers in Brazil. METHODS: A retrospective cohort study was performed on 45 giant cell arteritis patients from three university hospitals in Brazil. Diagnoses were based on the American College of Rheumatology classification criteria for giant cell arteritis or temporal artery biopsy findings. RESULTS: Most patients were Caucasian, and females were slightly more predominant. The frequencies of disease manifestations were as follows: temporal headache in 82.2%, neuro-ophthalmologic manifestations in 68.9%, jaw claudication in 48.9%, systemic symptoms in 44.4%, polymyalgia rheumatica in 35.6% and extra-cranial vessel involvement in 17.8% of cases. Aortic aneurysms were observed in 6.6% of patients. A comparison between patients with biopsy-proven giant cell arteritis and those without temporal artery biopsies did not yield significant differences in disease manifestations. All patients were treated with oral prednisone, and intravenous methylprednisolone was administered to nearly half of the patients. Methotrexate was the most commonly used immunosuppressive agent, and low-dose aspirin was prescribed to the majority of patients. Relapses occurred in 28.9% of patients, and aspirin had a protective effect against relapses. Females had higher prevalences of polymyalgia rheumatica, systemic manifestations and jaw claudication, while permanent visual loss was more prevalent in men. CONCLUSIONS: Most of the clinical features of Brazilian giant cell arteritis patients were similar to those found in other studies, except for the high prevalence of neuro-ophthalmic manifestations and permanent blindness in the Brazilian patients. Aspirin had a protective effect on relapses. PMID- 23644851 TI - Comparison of 7.2% hypertonic saline - 6% hydroxyethyl starch solution and 6% hydroxyethyl starch solution after the induction of anesthesia in patients undergoing elective neurosurgical procedures. AB - OBJECTIVE: The ideal solution for fluid management during neurosurgical procedures remains controversial. The aim of this study was to compare the effects of a 7.2% hypertonic saline - 6% hydroxyethyl starch (HS-HES) solution and a 6% hydroxyethyl starch (HES) solution on clinical, hemodynamic and laboratory variables during elective neurosurgical procedures. METHODS: Forty patients scheduled for elective neurosurgical procedures were randomly assigned to the HS-HES group orthe HES group. Afterthe induction of anesthesia, patients in the HS-HES group received 250 mL of HS-HES (500 mL/h), whereas the patients in the HES group received 1,000 mL of HES (1000 mL/h). The monitored variables included clinical, hemodynamic and laboratory parameters. Chictr.org: ChiCTR-TRC 12002357 RESULTS: The patients who received the HS-HES solution had a significant decrease in the intraoperative total fluid input (p<0.01), the volume of Ringer's solution required (p<0.05), the fluid balance (p<0.01) and their dural tension scores (p<0.05). The total urine output, blood loss, bleeding severity scores, operation duration and hemodynamic variables were similar in both groups (p>0.05). Moreover, compared with the HES group, the HS-HES group had significantly higher plasma concentrations of sodium and chloride, increasing the osmolality (p<0.01). CONCLUSION: Our results suggest that HS-HES reduced the volume of intraoperative fluid required to maintain the patients undergoing surgery and led to a decrease in the intraoperative fluid balance. Moreover, HS HES improved the dural tension scores and provided satisfactory brain relaxation. Our results indicate that HS-HES may represent a new avenue for volume therapy during elective neurosurgical procedures. PMID- 23644852 TI - Adverse reactions to antituberculosis drugs in Manguinhos, Rio de Janeiro, Brazil. AB - OBJECTIVES: This study aimed to characterize and estimate the frequency of adverse reactions to antituberculosis drugs in the population treated at the Centro de Saude Escola Germano Sinval Faria, a primary health care clinic in Manguinhos, Rio de Janeiro City, and to explore the relationship between adverse drug reactions and some of the patients' demographic and health characteristics. METHODS: This descriptive study was conducted via patient record review of incident cases between 2004 and 2008. RESULTS: Of the 176 patients studied, 41.5% developed one or more adverse reactions to antituberculosis drugs, totaling 126 occurrences. The rate of adverse reactions to antituberculosis drugs was higher among women, patients aged 50 years or older, those with four or more comorbidities, and those who used five or more drugs. Of the total reactions, 71.4% were mild. The organ systems most affected were as follows: the gastrointestinal tract (29.4%), the skin and appendages (21.4%), and the central and peripheral nervous systems (14.3%). Of the patients who experienced adverse reactions to antituberculosis drugs, 65.8% received no drug treatment for their adverse reactions, and 4.1% had one of the antituberculosis drugs suspended because of adverse reactions. "Probable reactions" (75%) predominated over "possible reactions" (24%). In the study sample, 64.3% of the reactions occurred during the first two months of treatment, and most (92.6%) of the reactions were ascribed to the combination of rifampicin + isoniazid + pyrazinamide (Regimen I). A high dropout rate from tuberculosis treatment (24.4%) was also observed. CONCLUSION: This study suggests a high rate of adverse reactions to antituberculosis drugs. PMID- 23644853 TI - Primary myelofibrosis: risk stratification by IPSS identifies patients with poor clinical outcome. AB - OBJECTIVES: To evaluate whether risk scores used to classify patients with primary myelofibrosis and JAK-2 V617F mutation status can predict clinical outcome. METHODS: A review of clinical and laboratory data from 74 patients with primary myelofibrosis diagnosed between 1992 and 2011. The IPSS and Lille scores were calculated for risk stratification and correlated with overall survival. RESULTS: A V617F JAK2 mutation was detected in 32 cases (47%), with no significant correlation with overall survival. The patients were classified according to the scores: Lille - low, 53 (73.%); intermediate, 13 (18%); and high, 5 (7%); and IPSS- low, 15 (26%); intermediate-1, 23 (32%); intermediate-2, 19 (26%); and high, 15 (31%). Those patients presenting a higher risk according to the IPSS (high and intermediate-2) had a significantly shorter overall survival relative to the low risk groups (intermediate-1 and low) (p = 0.02). CONCLUSIONS: These results emphasize the importance of the IPSS prognostic score for risk assessment in predicting the clinical outcome of primary myelofibrosis patients. PMID- 23644854 TI - Electrical impedance tomography to evaluate air distribution prior to extubation in very-low-birth-weight infants: a feasibility study. AB - OBJECTIVES: Nasal continuous positive airway pressure is used as a standard of care after extubation in very-low-birth-weight infants. A pressure of 5 cmH2O is usually applied regardless of individual differences in lung compliance. Current methods for evaluation of lung compliance and air distribution in the lungs are thus imprecise for preterm infants. This study used electrical impedance tomography to determine the feasibility of evaluating the positive end-expiratory pressure level associated with a more homogeneous air distribution within the lungs before extubation. METHODS: Ventilation homogeneity was defined by electrical impedance tomography as the ratio of ventilation between dependent and non-dependent lung areas. The best ventilation homogeneity was achieved when this ratio was equal to 1. Just before extubation, decremental expiratory pressure levels were applied (8, 7, 6 and 5 cmH(2)0; 3 minutes each step), and the pressure that determined the best ventilation homogeneity was defined as the best positive end-expiratory pressure. RESULTS: The best positive end-expiratory pressure value was 6.3 +/- 1.1 cmH(2)0, and the mean continuous positive airway pressure applied after extubation was 5.2 +/- 0.4 cmH(2)0 (p = 0.002). The extubation failure rate was 21.4%. X-Ray and blood gases after extubation were also checked. CONCLUSION: This study demonstrates that electrical impedance tomography can be safely and successfully used in patients ready for extubation to suggest the best ventilation homogeneity, which is influenced by the level of expiratory pressure applied. In this feasibility study, the best lung compliance was found with pressure levels higher than the continuous positive airway pressure levels that are usually applied for routine extubation. PMID- 23644855 TI - Zinc, vitamin A, and glutamine supplementation in Brazilian shantytown children at risk for diarrhea results in sex-specific improvements in verbal learning. AB - OBJECTIVE: To identify the impact of supplemental zinc, vitamin A, and glutamine, alone or in combination, on long-term cognitive outcomes among Brazilian shantytown children with low median height-for-age z-scores. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in children aged three months to nine years old from the urban shanty compound community of Fortaleza, Brazil. Demographic and anthropometric information was assessed. The random treatment groups available for cognitive testing (total of 167 children) were: (1) placebo, n = 25; (2) glutamine, n = 23; (3) zinc, n = 18; (4) vitamin A, n = 19; (5) glutamine+zinc, n = 20; (6) glutamine+vitamin A, n = 21; (7) zinc+vitamin A, n = 23; and (8) glutamine+zinc+vitamin A, n = 18. Neuropsychological tests were administered for the cognitive domains of non verbal intelligence and abstraction, psychomotor speed, verbal memory and recall ability, and semantic and phonetic verbal fluency. Statistical analyses were performed using SPSS, version 16.0. ClinicalTrials.gov: NCT00133406. RESULTS: Girls receiving a combination of glutamine, zinc, and vitamin A had higher mean age-adjusted verbal learning scores than girls receiving only placebo (9.5 versus 6.4, p = 0.007) and girls receiving zinc+vitamin A (9.5 versus 6.5, p = 0.006). Similar group differences were not found between male study children. CONCLUSIONS: The findings suggest that combination therapy offers a sex-specific advantage on tests of verbal learning, similar to that seen among female patients following traumatic brain injury. PMID- 23644856 TI - Association between muscle strength and the cardiopulmonary status of individuals living with HIV/AIDS. AB - OBJECTIVE: The purpose of this study was to compare aerobic function [anaerobic threshold (%VO(2)-AT), respiratory compensation point (%VO(2)-RCP) and peak oxygen uptake (VO(2)peak)] between physically active patients with HIV/AIDS and matched controls and to examine associations between disease status, poor muscle strength, depression (as estimated by the profile of mood states questionnaire) and the aerobic performance of patients. METHODS: Progressive treadmill test data for %VO(2)-AT (V-slope method), RCP and (VO(2)peak) were compared between 39 male patients with HIV/AIDS (age 40.6 +/- 1.4 years) and 28 male controls (age 44.4 +/ 2.1 years) drawn from the same community and matched for habitual physical activity. Within-patient data were also examined in relation to CD4+ counts (nadir and current data) and peak isokinetic knee torque. RESULTS: AT, RCP and (VO(2)peak) values were generally similar for patients and controls.Within the patient sample, binary classification suggested that AT, RCP and (VO(2)peak) values were not associated with either the nadir or current CD4+ count, but treadmill test variables were positively associated with peak isokinetic knee torque. CONCLUSION: The aerobic performance of physically active patients with HIV/AIDS is generally well conserved. Nevertheless, poor muscle strength is observed in some HIV/AIDS patients, which is associated with lower anaerobic power and (VO(2)peak), suggesting the possibility of enhancing the aerobic performance of patients with weak muscles through appropriate muscle strengthening activities. PMID- 23644857 TI - The 'silence' of silent brain infarctions may be related to chronic ischemic preconditioning and nonstrategic locations rather than to a small infarction size. AB - OBJECTIVE: Silent brain infarctions are the silent cerebrovascular events that are distinguished from symptomatic lacunar infarctions by their 'silence'; the origin of these infarctions is still unclear. This study analyzed the characteristics of silent and symptomatic lacunar infarctions and sought to explore the mechanism of this 'silence'. METHODS: In total, 156 patients with only silent brain infarctions, 90 with only symptomatic lacunar infarctions, 160 with both silent and symptomatic lacunar infarctions, and 115 without any infarctions were recruited. Vascular risk factors, leukoaraiosis, and vascular assessment results were compared. The National Institutes of Health Stroke Scale scores were compared between patients with only symptomatic lacunar infarctions and patients with two types of infarctions. The locations of all of the infarctions were evaluated. The evolution of the two types of infarctions was retrospectively studied by comparing the infarcts on the magnetic resonance images of 63 patients obtained at different times. RESULTS: The main risk factors for silent brain infarctions were hypertension, age, and advanced leukoaraiosis; the main factors for symptomatic lacunar infarctions were hypertension, atrial fibrillation, and atherosclerosis of relevant arteries. The neurological deficits of patients with only symptomatic lacunar infarctions were more severe than those of patients with both types of infarctions. More silent brain infarctions were located in the corona radiata and basal ganglia; these locations were different from those of the symptomatic lacunar infarctions. The initial sizes of the symptomatic lacunar infarctions were larger than the silent brain infarctions, whereas the final sizes were almost equal between the two groups. CONCLUSIONS: Chronic ischemic preconditioning and nonstrategic locations may be the main reasons for the 'silence' of silent brain infarctions. PMID- 23644858 TI - Conjoined twins: twenty years' experience at a reference center in Brazil. AB - OBJECTIVE: This study reports on the experience of one hospital regarding the surgical aspects, anatomic investigation and outcomes of the management of 21 conjoined twin pairs over the past 20 years. METHODS: All cases of conjoined twins who were treated during this period were reviewed. A careful imaging evaluation was performed to detail the abdominal anatomy (particularly the liver), inferior vena cava, spleen and pancreas, either to identify the number of organs or to evaluate the degree of organ sharing. RESULTS: There were eight sets of ischiopagus twins, seven sets of thoracopagus twins, three sets of omphalopagus twins, two sets of thoraco-omphalo-ischiopagus twins and one set of craniopagus twins. Nine pairs of conjoined twins could not be separated due to the complexity of the organs (mainly the liver and heart) that were shared by both twins; these pairs included one set of ischiopagus twins, six sets of thoracopagus twins and one set of thoraco-omphalo-ischiopagus twins. Twelve sets were separated, including seven sets of ischiopagus twins, three sets of omphalopagus twins, one set of thoracopagus twins and one set of craniopagus conjoined twins. The abdominal wall was closed in the majority of patients with the use of mesh instead of the earlier method of using tissue expanders. The surgical survival rate was 66.7%, and one pair of twins who did not undergo separation is currently alive. CONCLUSION: A detailed anatomic study of the twins and surgical planning must precede separation. A well-prepared pediatric surgery team is sufficient to surgically manage conjoined twins. PMID- 23644859 TI - Fetuin-A levels in hyperthyroidism. AB - OBJECTIVE: Fetuin-A is a protein secreted from the liver that inhibits arterial calcification deposition and can contribute to insulin resistance. Hyperthyroidism is also associated with insulin resistance. It is not known whether hyperthyroidism has an effect on fetuin-A levels. METHODS: We measured fetuin-A levels and homeostasis model of assessment-insulin resistance before hyperthyroidism treatment was initiated and after euthyroidism was achieved. A total of 42 patients diagnosed with hyperthyroidism were enrolled in this study. Fetuin-A, insulin, high-sensitivity C-reactive protein, fasting blood glucose, free T3 (fT3), free T4 (fT4), and thyrotropin were measured before and after euthyroidism was established. RESULTS: Basal fasting blood glucose, high sensitivity C-reactive protein, insulin, c-peptide, homeostasis model of assessment-insulin resistance, fT3, fT4 and fetuin-A levels were significantly decreased after euthyroidism was achieved (Table 1). Basal fasting blood glucose (r:0.407, p:0.008), high-sensitivity C-reactive protein (r:0.523, p<0.0001), insulin (r:0.479, p:0.001), homeostasis model of assessment-insulin resistance (r:0.541, p<0.0001), fT3 (r:0.492, p:0.001) and fT4 (r:0.473, p:0.002) were positively correlated with basal fetuin-A levels. Basal thyrotropin levels were significantly negatively correlated (r:-0.553, p<0.0001) with basal fetuin-A levels. CONCLUSION: Our findings suggest that hyperthyroidism influences fetuin-A levels. PMID- 23644860 TI - The influence of sleep deprivation and obesity on DNA damage in female Zucker rats. AB - OBJECTIVE: The aim of this study was to evaluate overall genetic damage induced by total sleep deprivation in obese, female Zucker rats of differing ages. METHOD: Lean and obese Zucker rats at 3, 6, and 15 months old were randomly distributed into two groups for each age group: home-cage control and sleep deprived (N = 5/group). The sleep-deprived groups were deprived sleep by gentle handling for 6 hours, whereas the home-cage control group was allowed to remain undisturbed in their home-cage. At the end of the sleep deprivation period, or after an equivalent amount of time for the home-cage control groups, the rats were brought to an adjacent room and decapitated. The blood, brain, and liver tissue were collected and stored individually to evaluate DNA damage. RESULTS: Significant genetic damage was observed only in 15-month-old rats. Genetic damage was present in the liver cells from sleep-deprived obese rats compared with lean rats in the same condition. Sleep deprivation was associated with genetic damage in brain cells regardless of obesity status. DNA damage was observed in the peripheral blood cells regardless of sleep condition or obesity status. CONCLUSION: Taken together, these results suggest that obesity was associated with genetic damage in liver cells, whereas sleep deprivation was associated with DNA damage in brain cells. These results also indicate that there is no synergistic effect of these noxious conditions on the overall level of genetic damage. In addition, the level of DNA damage was significantly higher in 15-month old rats compared to younger rats. PMID- 23644861 TI - Blockade of CXCR1/2 chemokine receptors protects against brain damage in ischemic stroke in mice. AB - OBJECTIVE: Ischemic stroke may result from transient or permanent reductions of regional cerebral blood flow. Polymorphonuclear neutrophils have been described as the earliest inflammatory cells to arrive in ischemic tissue. CXCR1/2 receptors are involved in the recruitment of these cells. However, the contribution of these chemokine receptors during transient brain ischemia in mice remains poorly understood. In this work, we investigated the effects of reparixin, an allosteric antagonist of CXCR1/2 receptors, in a model of middle cerebral artery occlusion and reperfusion in mice. METHODS: C57BL/6J male mice treated with reparixin or vehicle were subjected to a middle cerebral artery occlusion procedure 1 h after the treatment. Ninety minutes after ischemia induction, the monofilament that prevented blood flow was removed. Twenty-four hours after the reperfusion procedure, behavioral changes, including motor signs, were analyzed with the SmithKline/Harwell/lmperial College/Royal Hospital/Phenotype Assessment (SHIRPA) battery. The animals were sacrificed, and brain tissue was removed for histological and biochemical analyses. Histological sections were stained with hematoxylin and eosin, neutrophil infiltration was estimated by myeloperoxidase activity and the inflammatory cytokine IL-ibeta was measured by ELISA. RESULTS: Pre-treatment with reparixin reduced the motor deficits observed in this model of ischemia and reperfusion. Myeloperoxidase activity and IL-ibeta were reduced in the reparixin-treated group. Histological analysis revealed that ischemic injury was also attenuated by reparixin pre treatment. CONCLUSIONS: Our results suggest that the blockade of the CXCR1/2 receptors by reparixin promotes neuroprotective effects by reducing the levels of polymorphonuclear infiltration in the brain and the tissue damage associated with middle cerebral artery occlusion and reperfusion. PMID- 23644862 TI - Hemodynamic and ventilatory response to different levels of hypoxia and hypercapnia in carotid body-denervated rats. AB - OBJECTIVE: Chemoreceptors play an important role in the autonomic modulation of circulatory and ventilatory responses to changes in arterial O(2) and/or CO(2). However, studies evaluating hemodynamic responses to hypoxia and hypercapnia in rats have shown inconsistent results. Our aim was to evaluate hemodynamic and respiratory responses to different levels of hypoxia and hypercapnia in conscious intact or carotid body-denervated rats. METHODS: Male Wistar rats were submitted to bilateral ligature of carotid body arteries (or sham-operation) and received catheters into the left femoral artery and vein. After two days, each animal was placed into a plethysmographic chamber and, after baseline measurements of respiratory parameters and arterial pressure, each animal was subjected to three levels of hypoxia (15, 10 and 6% O(2)) and hypercapnia (10% CO(2)). RESULTS: The results indicated that 15% O(2) decreased the mean arterial pressure and increased the heart rate (HR) in both intact (n = 8) and carotid body-denervated (n = 7) rats. In contrast, 10% O(2) did not change the mean arterial pressure but still increased the HR in intact rats, and it decreased the mean arterial pressure and increased the heart rate in carotid body-denervated rats. Furthermore, 6% O(2) increased the mean arterial pressure and decreased the HR in intact rats, but it decreased the mean arterial pressure and did not change the HR in carotid body-denervated rats. The 3 levels of hypoxia increased pulmonary ventilation in both groups, with attenuated responses in carotid body-denervated rats. Hypercapnia with 10% CO(2) increased the mean arterial pressure and decreased HR similarly in both groups. Hypercapnia also increased pulmonary ventilation in both groups to the same extent. CONCLUSION: This study demonstrates that the hemodynamic and ventilatory responses varied according to the level of hypoxia. Nevertheless, the hemodynamic and ventilatory responses to hypercapnia did not depend on the activation of the peripheral carotid chemoreceptors. PMID- 23644863 TI - Current strategies for preventing renal dysfunction in patients with heart failure: a heart failure stage approach. AB - Renal dysfunction is common during episodes of acute decompensated heart failure, and historical data indicate that the mean creatinine level at admission has risen in recent decades. Different mechanisms underlying this change over time have been proposed, such as demographic changes, hemodynamic and neurohumoral derangements and medical interventions. In this setting, various strategies have been proposed for the prevention of renal dysfunction with heterogeneous results. In the present article, we review and discuss the main aspects of renal dysfunction prevention according to the different stages of heart failure. PMID- 23644864 TI - What has changed in brachial plexus surgery? AB - Brachial plexus injuries, in all their severity and complexity, have been extensively studied. Although brachial plexus injuries are associated with serious and often definitive sequelae, many concepts have changed since the 1950s, when this pathological condition began to be treated more aggressively. Looking back over the last 20 years, it can be seen that the entire approach, from diagnosis to treatment, has changed significantly. Some concepts have become better established, while others have been introduced; thus, it can be said that currently, something can always be offered in terms of functional recovery, regardless of the degree of injury. Advances in microsurgical techniques have enabled improved results after neurolysis and have made it possible to perform neurotization, which has undoubtedly become the greatest differential in treating brachial plexus injuries. Improvements in imaging devices and electrical studies have allowed quick decisions that are reflected in better surgical outcomes. In this review, we intend to show the many developments in brachial plexus surgery that have significantly changed the results and have provided hope to the victims of this serious injury. PMID- 23644866 TI - Hyperventilation increases the rate of the rise in arterial blood desflurane concentration during induction - a Gas Man(r) simulation. PMID- 23644865 TI - Eat as much as you burn - a good diet and eating less should be more important than an intense exercise program for decreasing morbidity and mortality. PMID- 23644867 TI - Which device should be chosen for the percutaneous closure of post-traumatic ventricular septal defects? PMID- 23644868 TI - Medical information technologies can increase quality and reduce costs. PMID- 23644869 TI - Can fasting plasma glucose and glycated hemoglobin levels predict oral complications following invasive dental procedures in patients with type 2 diabetes mellitus? A preliminary case-control study. AB - OBJECTIVE: To evaluate the effects of the levels of glycemic control on the frequency of clinical complications following invasive dental treatments in type 2 diabetic patients and suggest appropriate levels of fasting blood glucose and glycated hemoglobin considered to be safe to avoid these complications. METHOD: Type 2 diabetic patients and non-diabetic patients were selected and divided into three groups. Group I consisted of 13 type 2 diabetic patients with adequate glycemic control (fasting blood glucose levels <140 mg/dl and glycated hemoglobin (HbA1c) levels <7%). Group II consisted of 15 type 2 diabetic patients with inadequate glycemic control (fasting blood glucose levels >140 mg/dl and HbA1c levels >7%). Group III consisted of 18 non-diabetic patients (no symptoms and fasting blood glucose levels <100 mg/dl). The levels of fasting blood glucose, glycated HbA1c, and fingerstick capillary glycemia were evaluated in diabetic patients prior to performing dental procedures. Seven days after the dental procedure, the frequency of clinical complications (surgery site infections and systemic infections) was examined and compared between the three study groups. In addition, correlations between the occurrence of these outcomes and the glycemic control of diabetes mellitus were evaluated. RESULTS: The frequency of clinical outcomes was low (4/43; 8.6%), and no significant differences between the outcome frequencies of the various study groups were observed (p>0.05). However, a significant association was observed between clinical complications and dental extractions (p = 0.02). CONCLUSIONS: Because of the low frequency of clinical outcomes, it was not possible to determine whether fasting blood glucose or glycated HbA1c levels are important for these clinical outcomes. PMID- 23644870 TI - Design and baseline characteristics of a coronary heart disease prospective cohort: two-year experience from the strategy of registry of acute coronary syndrome study (ERICO study). AB - OBJECTIVES: To describe the ERICO study (Strategy of Registry of Acute Coronary Syndrome), a prospective cohort to investigate the epidemiology of acute coronary syndrome. METHODS: The ERICO study, which is being performed at a secondary general hospital in Sao Paulo, Brazil, is enrolling consecutive acute coronary syndrome patients who are 35 years old or older. The sociodemographic information, medical assessments, treatment data and blood samples are collected at admission. After 30 days, the medical history is updated, and additional blood and urinary samples are collected. In addition, a retinography, carotid intima media thickness, heart rate variability and pulse-wave velocity are performed. Questionnaires about food frequency, physical activity, sleep apnea and depression are also applied. At six months and annually after an acute event, information is collected by telephone. RESULTS: From February 2009 to September 2011, 738 patients with a diagnosis of an acute coronary syndrome were enrolled. Of these, 208 (28.2%) had ST-elevation myocardial infarction (STEMI), 288 (39.0%) had non-ST-elevation myocardial infarction (NSTEMI) and 242 (32.8%) had unstable angina (UA). The mean age was 62.7 years, 58.5% were men and 77.4% had 8 years or less of education. The most common cardiovascular risk factors were hypertension (76%) and sedentarism (73.4%). Only 29.2% had a prior history of coronary heart disease. Compared with the ST-elevation myocardial infarction subgroup, the unstable angina and non-ST-elevation myocardial infarction patients had higher frequencies of hypertension, diabetes, prior coronary heart disease (p<0.001) and dyslipidemia (p = 0.03). Smoking was more frequent in the ST-elevation myocardial infarction patients (p = 0.006). CONCLUSIONS: Compared with other hospital registries, our findings revealed a higher burden of CV risk factors and less frequent prior CHD history. PMID- 23644871 TI - Impact of the association between elevated oestradiol and low testosterone levels on erectile dysfunction severity. AB - Our aim was to assess the impact of the association between elevated oestradiol (E2) and low testosterone (T) levels on erectile dysfunction (ED) severity. A total of 614 male patients with ED and a normal or low T level in association with normal or elevated E2 levels were enrolled. Patients underwent routine laboratory investigations in addition to measurements of total T, total E2, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin. We compared the responses to the erectile function domain, Q3 (achieving erection) and Q4 (maintaining erection) of the International Index for Erectile Function (IIEF) score in patients with the following: normal T and E2 levels; low T level; low T level and elevated E2 level; and elevated E2 level. Of the patients included, 449 (73.1%) had normal T and E2 levels, 110 (17.9%) had a low T level, 36 (5.9%) had a low T level and an elevated E2 level, and 19 (3.1%) had an elevated E2 level. Increased ED severity was significantly associated with low T levels, elevated E2 levels, and both a low T level and an elevated E2 level. Additionally, the mean values of the EF-domain, Q3 and Q4 were significantly lower in patients with both a low T level and an elevated E2 level compared to patients with any condition alone. In conclusion, a low T level had the primary effect on erectile function; however, a concomitantly elevated E2 level had an additive impairment effect. PMID- 23644872 TI - Primary malignant lymphoma of the glans penis: a rare case report and review of the literature. PMID- 23644873 TI - Is it necessary and feasible to increase the efficiency of 2-um thulium laser resection of the prostate? PMID- 23644874 TI - Trabecular bone deterioration at the greater trochanter of mice with unilateral obstructive nephropathy. AB - Our previous study showed the early molecular responses of bone in response to obstructive nephropathy in a unilateral ureteral obstruction (UUO) mouse model. Here, we addressed the changes in trabecular bone properties at greater trochanter, the proximal and the distal metaphysis of femur in UUO mice. The male mice were subjected to UUO (n=10) or sham operation (n=10). All mice were killed on day 7 after the surgical operation. The micro-computed tomography (micro-CT) analysis for different femoral trabecular bone sites demonstrated pathological alterations of trabecular bone mass and micro-networks at greater trochanter as shown by decreases in bone mineral density/bone volume (P<0.05) and trabecular number (P<0.05) and increases in trabecular separation (P<0.01) and bone surface/bone volume (P<0.05) in UUO mice. The present study demonstrates that UUO induced unilateral obstructive nephropathy has markedly detrimental effects on the trabecular trochanter of the femur. PMID- 23644876 TI - SRPK1 contributes to malignancy of hepatocellular carcinoma through a possible mechanism involving PI3K/Akt. AB - Protein kinases are important regulators in biologic processes. Aberrant expression of protein kinases often causes diseases including cancer. In the present study, we found that the serine-arginine protein kinase 1 (SRPK1) might be involved in hepatocellular carcinoma (HCC) proliferation from a kinome screen using a loss-of-function approach. In clinical samples, SRPK1 was frequently up regulated in HCCs as compared with adjacent non-tumor tissues at both mRNA and protein levels. Functional studies indicated that overexpression of wild-type SRPK1 promoted HCC cell proliferation, while forced expression of the kinase-dead mutant of SRPK1 or RNA interference against SRPK1 suppressed cell growth and malignancy as measured in soft agar assay. The kinase-dead mutant of SRPK1 also inhibited subcutaneous xenografts' growth of HCC cells in nude mice. Furthermore, western bolt analysis showed overexpression of wild-type SRPK1 enhanced Akt phosphorylation and knockdown of SRPK1 by RNA interference attenuated Akt phosphorylation induced by epidermal growth factor. Meanwhile, overexpression of wild-type SRPK1 also induced a concurrent increase in the total tyrosine phosphorylation of phosphotidylinositol-3 kinase p110alpha subunit, indicating a functional link between SRPK1 and PI3K/Akt signaling. Our findings suggest that SRPK1 plays an oncogenic role and could be a potential therapeutic target in HCC. PMID- 23644875 TI - Enoxacin inhibits growth of prostate cancer cells and effectively restores microRNA processing. AB - Prostate cancer (PCa) is one of the most incident malignancies worldwide. Although efficient therapy is available for early-stage PCa, treatment of advanced disease is mainly ineffective and remains a clinical challenge. microRNA (miRNA) dysregulation is associated with PCa development and progression. In fact, several studies have reported a widespread downregulation of miRNAs in PCa, which highlights the importance of studying compounds capable of restoring the global miRNA expression. The main aim of this study was to define the usefulness of enoxacin as an anti-tumoral agent in PCa, due to its ability to induce miRNA biogenesis in a TRBP-mediated manner. Using a panel of five PCa cell lines, we observed that all of them were wild type for the TARBP2 gene and expressed TRBP protein. Furthermore, primary prostate carcinomas displayed normal levels of TRBP protein. Remarkably, enoxacin was able to decrease cell viability, induce apoptosis, cause cell cycle arrest, and inhibit the invasiveness of cell lines. Enoxacin was also effective in restoring the global expression of miRNAs. This study is the first to show that PCa cells are highly responsive to the anti tumoral effects of enoxacin. Therefore, enoxacin constitutes a promising therapeutic agent for PCa. PMID- 23644877 TI - The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing. AB - SUMMARY: The present study shows no adverse effects of the anti-diabetic drug metformin on bone mass and fracture healing in rodents but demonstrates that metformin is not osteogenic in vivo, as previously proposed. INTRODUCTION: In view of the increased incidence of fractures in patients with type 2 diabetes mellitus (T2DM), we investigated the effects of metformin, a widely used T2DM therapy, on bone mass and fracture healing in vivo using two different rodent models and modes of metformin administration. METHODS: We first subjected 12-week old female C57BL/6 mice to ovariectomy (OVX). Four weeks after OVX, mice received either saline or metformin administered by gavage (100 mg/kg/daily). After 4 weeks of treatment, bone micro-architecture and cellular activity were determined in tibia by micro-CT and bone histomorphometry. In another experiment, female Wistar rats aged 3 months were given only water or metformin for 8 weeks via the drinking water (2 mg/ml). After 4 weeks of treatment, a mid-diaphyseal osteotomy was performed in the left femur. Rats were sacrificed 4 weeks after osteotomy and bone architecture analysed by micro-CT in the right tibia while fracture healing and callus volume were determined in the left femur by X-ray analysis and micro CT, respectively. RESULTS: In both models, our results show no significant differences in cortical and trabecular bone architecture in metformin-treated rodents compared to saline. Metformin had no effect on bone resorption but reduced bone formation rate in trabecular bone. Mean X-ray scores assessed on control and metformin fractures showed no significant differences of healing between the groups. Fracture callus volume and mineral content after 4 weeks were similar in both groups. CONCLUSIONS: Our results indicate that metformin has no effect on bone mass in vivo or fracture healing in rodents. PMID- 23644878 TI - Higher serum uric acid is associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in healthy postmenopausal women. AB - Higher serum uric acid (UA) was associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in postmenopausal women. Furthermore, UA suppressed osteoclastogenesis and decreased production of reactive oxygen species in osteoclast precursors, indicating UA may have beneficial effects on bone metabolism as an antioxidant. INTRODUCTION: UA is known to play a physiological role as an antioxidant, and oxidative stress has detrimental effects on bone metabolism. In the present study, we investigated the association of serum UA level with the osteoporosis-related phenotypes and its direct effect on bone-resorbing osteoclasts using in vitro systems. METHODS: This is a large cross-sectional study, including 7,502 healthy postmenopausal women. Bone mineral density (BMD) and serum UA concentrations were obtained from all subjects. Data on bone turnover markers and lateral thoracolumbar radiographs were available for 1,023 and 6,918 subjects, respectively. An in vitro study investigated osteoclastogenesis and reactive oxygen species (ROS) levels according to UA treatment. RESULTS: After adjusting for multiple confounders, serum UA levels were positively associated with BMD at all sites (all p < 0.001). Compared with the participants in the highest UA quartile, the odds for osteoporosis were 40 % higher in those in the lowest quartile. The serum UA levels were inversely related to both serum C-terminal telopeptide of type I collagen and osteocalcin levels (p < 0.001 and p = 0.004, respectively). Consistently, subjects with vertebral fracture had lower serum UA levels, compared with those without it (p = 0.009). An in vitro study showed that UA decreased osteoclastogenesis in a dose-dependent manner and reduced the production of ROS in osteoclast precursors. CONCLUSION: These results provide epidemiological and experimental evidence that serum UA may have a beneficial effect on bone metabolism as an antioxidant in postmenopausal women. PMID- 23644879 TI - Ultrasound of talocalcaneal coalition: retrospective study of 11 patients. AB - OBJECTIVE: To present the ultrasound appearance of talocalcaneal coalitions (TCC). MATERIALS AND METHODS: We present a retrospective review of 11 patients (8 women and 3 men, age range 17-58 years, mean age 35.3 years) in which ultrasound, the first imaging study carried out, detected a TCC that was not known or suspected clinically. Patients were subsequently examined by standard radiographs, computed tomography (CT) or magnetic resonance imaging (MRI). RESULTS: In 9 patients with fibrous coalition ultrasound showed a reduced joint space of the medial aspect of the anterior talocalcaneal joint associated with an irregular, pointed appearance of its outline. In 2 patients with osseous coalitions ultrasound revealed a smooth continuity of the hyperechoic bone surface between the medial talus and the substentaculum tali. The diagnosis was confirmed in 4 patients with CT and in 3 with MRI. In the remaining 4 patients standard radiographs were consistent with TCC. CONCLUSION: Owing to its tomographic capabilities ultrasound can detect TCC. We suggest that study of the anterior subtalar joint should be a part of every ankle ultrasound examination as it can show a clinically unsuspected TCC. Confirmation of the coalition by CT or MRI is required in the preoperative assessment to better assess the type and extent of the congenital anomaly as well as the adjacent joints. PMID- 23644880 TI - The role of MRI in image-guided needle biopsy of focal bone and soft tissue neoplasms. AB - Magnetic resonance imaging (MRI) plays a critical role in the management pathway of both soft tissue and bone neoplasms, from diagnosis through to post-treatment follow-up. There are a wide range of surgical, oncological, and combined treatment regimes but these rely on accurate histopathological diagnosis. This article reviews the role of MRI in the planning of image-guided needle biopsy for suspected soft tissue and bone tumors. PMID- 23644881 TI - Isolation and characterization of ten polymorphic microsatellite loci in Ixodes arboricola, and cross-amplification in three other Ixodes species. AB - We characterized ten polymorphic microsatellite loci from the tree-hole tick, Ixodes arboricola. Loci were screened in 11-18 individuals from three Belgian populations and five to ten alleles were found at each locus. Seven loci did not show deviations from Hardy-Weinberg equilibrium conditions and there were no indications for null alleles at these loci. The three other loci showed significant heterozygote deficiencies in at least one population, and a high potential for the occurrence of null alleles. We observed no effect of potential host DNA on the scoring of the microsatellites. Cross-amplification of the microsatellites was tested in eight specimens of three congeneric species: I. ricinus, I. hexagonus and I. frontalis. Depending on the species, six or seven of the loci were amplified in >= 4 of the 8 specimens and were polymorphic in each of these species (except for Ixaf 11 in I. frontalis and I. ricinus). These loci thus provide a tool for population genetic analysis of I. arboricola. The suitability of these markers needs to be further investigated in its congeners. PMID- 23644882 TI - Quercetin alleviates inflammation after short-term treatment in high-fat-fed mice. AB - Consumption of a high-fat diet (HFD) promotes reactive oxygen species (ROS) which ultimately trigger inflammation. The aim of this study was to investigate the role of Moringa oleifera leaf extract (MoLE) and its active component quercetin in preventing NF-kappaB-mediated inflammation raised by short-term HFD. Quercetin was found to be one of the major flavonoid components from HPLC of MoLE. Swiss mice were fed for 15 days on HFD, both with or without MoLE/quercetin. The antioxidant profile was estimated from liver homogenate. NF-kappaB and some relevant inflammatory markers were evaluated by immunoblotting, RT-PCR and ELISA. Significantly (P < 0.05) lower antioxidant profile and higher lipid peroxidation was found in HFD group compared to control (P < 0.05). Increased nuclear import of NF-kappaB and elevated expressions of pro-inflammatory markers were further manifestations in the HFD group. All these changes were reversed in the MoLE/quercetin-treated groups with significant improvement of antioxidant activity compared to the HFD group. MoLE was found to be rich in polyphenols and both MoLE and quercetin showed potent free radical and hydroxyl radical quenching activity. Thus, the present study concluded that short-term treatment with MoLE and its constituent quercetin prevent HFD-mediated inflammation in mice. PMID- 23644883 TI - Drought stress acclimation imparts tolerance to Sclerotinia sclerotiorum and Pseudomonas syringae in Nicotiana benthamiana. AB - Acclimation of plants with an abiotic stress can impart tolerance to some biotic stresses. Such a priming response has not been widely studied. In particular, little is known about enhanced defense capacity of drought stress acclimated plants to fungal and bacterial pathogens. Here we show that prior drought acclimation in Nicotiana benthamiana plants imparts tolerance to necrotrophic fungus, Sclerotinia sclerotiorum, and also to hemi-biotrophic bacterial pathogen, Pseudomonas syringae pv. tabaci. S. sclerotiorum inoculation on N. benthamiana plants acclimated with drought stress lead to less disease-induced cell death compared to non-acclimated plants. Furthermore, inoculation of P. syringae pv. tabaci on N. benthamiana plants acclimated to moderate drought stress showed reduced disease symptoms. The levels of reactive oxygen species (ROS) in drought acclimated plants were highly correlated with disease resistance. Further, in planta growth of GFPuv expressing P. syringae pv. tabaci on plants pre-treated with methyl viologen showed complete inhibition of bacterial growth. Taken together, these experimental results suggested a role for ROS generated during drought acclimation in imparting tolerance against S. sclerotiorum and P. syringae pv. tabaci. We speculate that the generation of ROS during drought acclimation primed a defense response in plants that subsequently caused the tolerance against the pathogens tested. PMID- 23644884 TI - HDAC6 and ovarian cancer. AB - The special class IIb histone deacetylase, HDAC6, plays a prominent role in many cellular processes related to cancer, including oncogenesis, the cell stress response, motility, and myriad signaling pathways. Many of the lessons learned from other cancers can be applied to ovarian cancer as well. HDAC6 interacts with diverse proteins such as HSP90, cortactin, tubulin, dynein, p300, Bax, and GRK2 in both the nucleus and cytoplasm to carry out these cancerous functions. Not all pro-cancer interactions of HDAC6 involve deacetylation. The idea of using HDAC6 as a target for cancer treatment continues to expand in recent years, and more potent and specific HDAC6 inhibitors are required to effectively down-regulate the tumor-prone cell signaling pathways responsible for ovarian cancer. PMID- 23644885 TI - Targeting signaling pathways in epithelial ovarian cancer. AB - Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies. PURPOSE: We want to give an overview on the molecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets. In Depth Review of Existing Data: In 2012, the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with chemotherapy. CONCLUSION: Ongoing studies of targeted agents in conjunction with chemotherapy will show whether there are alternative options to bevacizumab available for OC patients. Novel targets which can be assessed before therapy to predict efficacy are needed. The assessment of therapeutic targets is continuously improved by molecular pathological analyses on tumor tissue. A careful selection of patients for personalized treatment will help to reduce putative side effects and toxicity. PMID- 23644886 TI - Antioxidant systems from Pepper (Capsicum annuum L.): involvement in the response to temperature changes in ripe fruits. AB - Sweet pepper is susceptible to changes in the environmental conditions, especially temperatures below 15 degrees C. In this work, two sets of pepper fruits (Capsicum annuum L.) which underwent distinct temperature profiles in planta were investigated. Accordingly, two harvesting times corresponding to each set were established: Harvest 1, whose fruits developed and ripened at 14.9 degrees C as average temperature; and Harvest 2, with average temperature of 12.4 degrees C. The oxidative metabolism was analyzed in all fruits. Although total ascorbate content did not vary between Harvests, a shift from the reduced to the oxidized form (dehydroascorbate), accompanied by a higher ascorbate peroxidase activity, was observed in Harvest 2 with respect to Harvest 1. Moreover, a decrease of the ascorbate-generating enzymatic system, the gamma-galactono lactone dehydrogenase, was found at Harvest 2. The activity values of the NADP dependent dehydrogenases analyzed seem to indicate that a lower NADPH synthesis may occur in fruits which underwent lower temperature conditions. In spite of the important changes observed in the oxidative metabolism in fruits subjected to lower temperature, no oxidative stress appears to occur, as indicated by the lipid peroxidation and protein oxidation profiles. Thus, the antioxidative systems of pepper fruits seem to be involved in the response against temperature changes. PMID- 23644888 TI - Isolation of multipotent nestin-expressing stem cells derived from the epidermis of elderly humans and TAT-VHL peptide-mediated neuronal differentiation of these cells. AB - A specialized population of cells residing in the hair follicle is quiescent but shows pluripotency for differentiating into epithelial-mesenchymal lineage cells. Therefore, such cells are hoped to be useful as implantable donor cells for regenerative therapy. Recently, it was reported that intracellular delivery of TAT-VHL peptide induces neuronal differentiation of skin-derived precursors. In the present study, we successfully isolated multipotent stem cells derived from the epidermis of elderly humans, characterized these cells as being capable of sphere formation and strong expression of nestin, fibronectin, and CD34 but not of keratin 15, and identified the niche of these cells as being the outer root sheath of the hair follicles. In addition, we showed that TAT-VHL peptide induced their neuronal differentiation in vitro, and confirmed by fluorescence immunohistochemistry the neuronal differentiation of such peptide-treated cells implanted into rodent brains. These multipotent nestin-expressing stem cells derived from human epidermis are easily accessible and should be useful as donor cells for neuronal regenerative cell therapy. PMID- 23644889 TI - Chebulagic acid, a hydrolyzable tannin, exhibited antiviral activity in vitro and in vivo against human enterovirus 71. AB - Human enterovirus 71 is one of the major causative agents of hand, foot and mouth disease in children under six years of age. Presently, no vaccines or antiviral drugs have been clinically available to employ against EV71. In this study, we demonstrate that treatment with chebulagic acid reduced the viral cytopathic effect on rhabdomyosarcoma cells with an IC50 of 12.5 MUg/mL. The utilization of the chebulagic acid treatment on mice challenged with a lethal dose of enterovirus 71 was able to efficiently reduce mortality and relieve clinical symptoms through the inhibition of viral replication. Chebulagic acid may represent a potential therapeutic agent to control infections to enterovirus 71. PMID- 23644887 TI - Where do they come from and where do they go: candidates for regulating extracellular vesicle formation in fungi. AB - In the past few years, extracellular vesicles (EVs) from at least eight fungal species were characterized. EV proteome in four fungal species indicated putative biogenesis pathways and suggested interesting similarities with mammalian exosomes. Moreover, as observed for mammalian exosomes, fungal EVs were demonstrated to be immunologically active. Here we review the seminal and most recent findings related to the production of EVs by fungi. Based on the current literature about secretion of fungal molecules and biogenesis of EVs in eukaryotes, we focus our discussion on a list of cellular proteins with the potential to regulate vesicle biogenesis in the fungi. PMID- 23644892 TI - Correction: Wiedmann, M., et al. Exploration of the Role of the Non-Coding RNA SbrE in L. monocytogenes Stress Response. Int. J. Mol. Sci. 2013, 14, 378-393. AB - The original version of the paper in Section 3.8 reports that "The peptide mass tolerance and fragment mass tolerance values were 10 ppm and 30 mDa, respectively" [1] (p. 387). To help others who may want to use the same methods in the future, the authors would like to correct the wording to: "The peptide mass tolerance and fragment mass tolerance values were 30 ppm and 0.15 Da, respectively. In order to decrease the probability of false peptide identification, only peptides with significance scores above the identity threshold (at the 95% confidence interval), defined by Mascot probability analysis (www.matrixscience.com/help/scoring_help.html#PBM), were considered to be confidently identified and used for protein identification. Furthermore, only proteins identified in all four iTRAQ samples through at least two peptides with a p-value of <0.05 (expectation value) were further analyzed". The authors would like to apologize for any inconvenience this may have caused to the readers of this journal. PMID- 23644890 TI - Molecular motors and apical CFTR traffic in epithelia. AB - Intracellular protein traffic plays an important role in the regulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channels. Microtubule and actin-based motor proteins direct CFTR movement along trafficking pathways. As shown for other regulatory proteins such as adaptors, the involvement of protein motors in CFTR traffic is cell-type specific. Understanding motor specificity provides insight into the biology of the channel and opens opportunity for discovery of organ-specific drug targets for treating CFTR-mediated diseases. PMID- 23644891 TI - Physiological, biochemical, and molecular mechanisms of heat stress tolerance in plants. AB - High temperature (HT) stress is a major environmental stress that limits plant growth, metabolism, and productivity worldwide. Plant growth and development involve numerous biochemical reactions that are sensitive to temperature. Plant responses to HT vary with the degree and duration of HT and the plant type. HT is now a major concern for crop production and approaches for sustaining high yields of crop plants under HT stress are important agricultural goals. Plants possess a number of adaptive, avoidance, or acclimation mechanisms to cope with HT situations. In addition, major tolerance mechanisms that employ ion transporters, proteins, osmoprotectants, antioxidants, and other factors involved in signaling cascades and transcriptional control are activated to offset stress-induced biochemical and physiological alterations. Plant survival under HT stress depends on the ability to perceive the HT stimulus, generate and transmit the signal, and initiate appropriate physiological and biochemical changes. HT-induced gene expression and metabolite synthesis also substantially improve tolerance. The physiological and biochemical responses to heat stress are active research areas, and the molecular approaches are being adopted for developing HT tolerance in plants. This article reviews the recent findings on responses, adaptation, and tolerance to HT at the cellular, organellar, and whole plant levels and describes various approaches being taken to enhance thermotolerance in plants. PMID- 23644893 TI - Comparison of the ability of chondroitin sulfate derived from bovine, fish and pigs to suppress human osteoclast activity in vitro. AB - Chondroitin sulfate (CS) compounds are commonly used to manage OA symptoms. Recent literature has indicated that abnormal subchondral bone metabolism may have a role in the pathogenesis of OA. The aim of this study was to access the effects of chondroitin sulfate obtained from bovine, fish and porcine sources on human osteoclast formation and activity in vitro. Human osteoclasts were generated from blood mononuclear cells. Cells were cultured over 17 days with the addition of macrophage colony stimulating factor (M-CSF) and then stimulated with receptor activator of nuclear factor kappa B ligand from day 7. Cells were treated with the CS commencing from day 7 onwards. To assess effects on osteoclasts, tartrate resistant acid phosphatate (TRAP) expression and resorption of whale dentine assays were used. Bovine-derived CS consistently suppressed osteoclast activity at concentrations as low as 1 MUg/ml. Fish and porcine CS was less consistent in their effects varying with different donor cells. All CS compounds had little effect on TRAP activity. mRNA analysis using real-time PCR of bovine CS treated cells indicated that the inhibition of activity was not due to inhibition of the late stage NFATc1 transcription factor (p > 0.05). These results are consistent with CS inhibition of mature osteoclast activity rather than the formation of mature osteoclasts. It would appear that there are differences in activity of the different CS compounds with bovine-derived CS being the most consistently effective inhibitor of osteoclast resorption, but the results need to be confirmed. PMID- 23644894 TI - Autologous skin reconstruction by combining epidermis and acellular dermal matrix tissue derived from the skin of giant congenital melanocytic nevi. AB - Giant congenital melanocytic nevi (GCMN) are defined as nevi greater than 20 cm in diameter. It is difficult to completely remove GCMN because of the lack of available skin grafts for covering the resultant defects. This study examined whether it is possible to produce reconstructed skin by combining epidermal and acellular dermal matrix (ADM) tissue derived from excised GCMN. GCMN skin samples were obtained with the informed consent of volunteer patients. The abilities of hypertonic saline (1 N NaCl), 0.05% trypsin, 0.1% SDS (sodium dodecyl sulfate), and phosphate buffered saline (PBS) to decellularize GCMN tissue were compared. The specimens were incubated in one of the test solutions at 37 degrees C for 48 h, before being washed with PBS at 4 degrees C for 14 days. Residual nuclei, residual DNA, nevus tissue viability, and the structural integrity of the basement membrane and capillaries were evaluated before treatment, and after 48 h' treatment with or without 7 or 14 days' washing. We tried to produce reconstructed skin by combining the resultant ADM with enzymatically separated GCMN epidermal tissue. The histological structure of the reconstructed skin was examined after it had been cultured for 5 days. In the SDS group, most cells had been removed after 48 h, and the DNA content of the ADM was significantly lower than in the other groups. As for viability, no significant difference was detected among the groups. The basement membrane and capillaries remained intact in all groups. After 5 days' culturing, the epidermis had become attached to the ADM in all groups, except the SDS group. SDS displayed a superior decellularization ability compared with the other methods; however, it cannot be used to produce reconstructed skin because of its toxicity. In conclusion, we produced reconstructed skin that was devoid of nevus cells by combining GCMN epidermal tissue with GCMN-derived ADM produced with NaCl or trypsin. This is a promising treatment strategy for giant nevus. PMID- 23644895 TI - The influence of steroid administration on systemic response in laminoplasty for cervical myelopathy. AB - INTRODUCTION: The excessive systemic inflammatory response caused by surgery has been associated with the development of major complications, such as postoperative confusion and acute respiratory distress syndrome. The serum IL-6 has been used as a predictor in the extent of surgical trauma. Several trials have reported that steroid administration reduced excessive systemic response. We investigated the systemic response caused by surgical trauma in patients with cervical laminoplasty and evaluated the influence of steroid administration on systemic response. MATERIALS AND METHODS: Thirty patients were included in this study. The patients were divided into three groups of ten each: preoperative steroid group, intraoperative steroid group, and non-steroid group. The same dose of steroid was administered to the patients in preoperative group and intraoperative group. Venous blood samples were taken at the following times: before surgery, at the end of surgery, 6 h after the surgery, the first, the third and the seventh day after the surgery. Outcome measures were serum IL-6, IL 10, C-reactive protein (CRP), white blood cells including neutrophil and lymphocyte counts. RESULTS: The mean serum IL-6 levels on the first day in preoperative and intraoperative steroid groups were significantly lower than in control group. The serum IL-6 levels in preoperative steroid group were lower than the serum levels in the intraoperative steroid group from the end of surgery to the third day after surgery. The CRP levels in steroids groups were also lower than in control group on the third day. There were no significant differences in the postoperative neutrophil count between the three groups. There was no postoperative infectious complication or suture failure. CONCLUSIONS: This study shows that the preoperative administration of steroids modified the systemic inflammatory response caused by surgical trauma in patients with cervical laminoplasty. PMID- 23644896 TI - Closed reduction of distal radius fractures: does instability mean irreducibility? AB - INTRODUCTION: The belief that not all distal radius fractures can be initially anatomically reduced with conservative means is rising. The aim of this study was to examine whether adequate reduction with a closed reduction technique is possible and to assess the importance of each step. MATERIALS AND METHODS: We prospectively enrolled 63 distal radius fractures (62 patients). A standardized reduction technique was implemented. Reduction was radiologically evaluated in hanging traction, after reduction, and in plaster. Subgroup analysis was performed for fracture-dependent and fracture-independent factors on their influence on reduction. RESULTS: The mean radiological values (radial inclination, dorsal tilt, ulnar variance) showed near anatomic reduction of all fractures in plaster. Fracture severity according to AO classification, initial displacement, number of instability criteria and patient age did not affect the reduction outcome. CONCLUSIONS: All types of enrolled fractures were nearly anatomically reduced. This contradicts the opinion that some "severe" fractures are too unstable to be initially reduced by closed means. PMID- 23644897 TI - Intramedullary nail versus extramedullary plate fixation for unstable intertrochanteric fractures: decision analysis. AB - BACKGROUND: The best options of internal fixation for unstable intertrochanteric femoral fractures in elderly osteoporotic patients remain controversial. We determined whether intramedullary nail or extramedullary plate provides better treatment for unstable intertrochanteric fractures using a decision analysis tool that considers quality of life. METHODS: A decision analysis model was constructed containing final outcome score and the probability of mortality within 1 year, infection, and mechanical complications. Final outcome was defined as health-related quality of life and was used as a utility in the decision tree. Probabilities were obtained by literature review, and health-related quality of life was evaluated by asking 30 orthopedic experts to complete a questionnaire. A roll back tool was used to determine the best surgical option, and sensitivity analysis was performed to compensate for decision model uncertainty. RESULTS: The decision model favored intramedullary nailing in terms of quality of life. In one way sensitivity analysis, intramedullary nailing was more beneficial than the extramedullary plating, when probability of mechanical complication after intramedullary nailing was below 0.258. CONCLUSIONS: In terms of quality of life, the decision analysis model showed that intramedullary nailing was more beneficial for patients with an unstable intertrochanteric fracture. PMID- 23644898 TI - Combined liver and kidney transplantation in children. AB - Simultaneous combined liver-kidney transplantation (CLKT) is a rare operation in pediatric patients so that annually only 10-30 operations are performed worldwide. The main indications for CLKT are primary hyperoxaluria type 1 and autosomal recessive polycystic kidney disease. In addition, CLKT is indicated in individual patients with metabolic or cirrhotic liver diseases and end-stage kidney disease. The surgery and immediate post-operative management of CLKT remain challenging in infants and small children. The patients should be operated on before they become severely ill or develop major systemic manifestations of their metabolic disorder. The liver allograft is immunologically protective of the kidney graft in simultaneous CLKT, often resulting in well-preserved kidney function. The long-term outcome after CLKT is nowadays comparable to that of isolated liver and kidney transplantations. PMID- 23644899 TI - Stoichiometry dependent electron transport and gas sensing properties of indium oxide nanowires. AB - The effect of stoichiometry of single crystalline In2O3 nanowires on electrical transport and gas sensing was investigated. The nanowires were synthesized by vapor phase transport and had diameters ranging from 80 to 100 nm and lengths between 10 and 20 MUm, with a growth direction of [001]. Transport measurements revealed n-type conduction, attributed to the presence of oxygen vacancies in the crystal lattice. As-grown In2O3 nanowires were shown to have a carrier concentration of ~5 * 10(17) cm(-3), while nanowires that were annealed in wet O2 showed a reduced carrier concentration of less than 10(16) cm(-3). Temperature dependent conductivity measurements on the as-grown nanowires and analysis of the thermally activated Arrhenius conduction for the temperature range of 77-350 K yielded an activation energy of 0.12 eV. This is explained on the basis of carrier exchange that occurs between the surface states and the bulk of the nanowire, resulting in a depleted surface layer of thickness of the order of the Debye length (LD), estimated to be about 3-4 nm for the as-grown nanowires and about 10 times higher for the more stoichiometric nanowires. Significant changes in the electrical conductance of individual In2O3 nanowires were also observed within several seconds of exposure to NH3 and O2 gas molecules at room temperature, thus demonstrating the potential use of In2O3 nanowires as efficient miniaturized chemical sensors. The sensing mechanism is dominated by the nanowire channel conductance, and a simple energy band diagram is used to explain the change in conductivity when gas molecules adsorbed on the nanowire surface influence its electrical properties. Less stoichiometric nanowires were found to be more sensitive to oxidizing gases while more stoichiometric nanowires showed significantly enhanced response to reducing gases. PMID- 23644900 TI - Automated analysis of courtship suppression learning and memory in Drosophila melanogaster. AB - Study of the fruit fly, Drosophila melanogaster, has yielded important insights into the underlying molecular mechanisms of learning and memory. Courtship conditioning is a well-established behavioral assay used to study Drosophila learning and memory. Here, we describe the development of software to analyze courtship suppression assay data that correctly identifies normal or abnormal learning and memory traits of individual flies. Development of this automated analysis software will significantly enhance our ability to use this assay in large-scale genetic screens and disease modeling. The software increases the consistency, objectivity, and types of data generated. PMID- 23644902 TI - Oxygen tomography by Cerenkov-excited phosphorescence during external beam irradiation. AB - The efficacy of radiation therapy depends strongly on tumor oxygenation during irradiation. However, current techniques to measure this parameter in vivo do not facilitate routine monitoring in patients. Herein, we demonstrate a noninvasive method for tomographic imaging of oxygen partial pressure (pO(2)) in deep tissue using the phosphorescence decay of an oxygen-sensitive probe excited by Cerenkov radiation induced by external beam radiotherapy. Tissue-simulating scattering phantoms (60 mm diameter with a 20 mm anomaly) containing platinum(II)-G4 (PtG4), a dendritic porphyrin-based phosphor, whose phosphorescence is quenched in the presence of oxygen, were irradiated with a clinical linear accelerator. The emitted phosphorescence was measured at various positions on the phantom boundary using a spectrograph coupled to an intensified charge-coupled device (ICCD). At each position, PtG4 phosphorescence decay curves were measured by synchronizing the ICCD to the linear accelerator pulses. Tomographic images of phosphorescence yield and lifetime were recovered for phantoms with homogenous PtG4 concentrations and heterogeneous pO(2). Since PtG4 lifetime is strongly and predictably dependent on pO(2) through the Stern-Volmer relationship, tomographic images of pO(2) were also reported, and showed excellent agreement with independent oxygenation measurements. Translating this approach to the clinic could facilitate direct sensing of pO(2) during radiotherapy. PMID- 23644901 TI - CPAP therapy prevents increase in blood pressure after upper airway surgery for obstructive sleep apnoea. AB - OBJECTIVE: The aim of this study was to investigate the efficacy of continuous positive airway pressure (CPAP) therapy following uvulopalatopharyngoplasty (UPPP) to prevent blood pressure (BP) elevation during sleep. METHODS: Sixteen normotensive patients with OSA were subjected to UPPP with or without septoplasty. These patients were instrumented for 24 h of ambulatory BP recording, polysomnography, nocturnal urinary catecholamine and pain evaluation using a visual analogue scale in the day prior to surgery (D-1), following the surgery (D+1) and 30 days later (D+30). For the D+1, the patients were divided into two groups: the without CPAP therapy group and the with CPAP therapy group. RESULTS: The apnoea-hypopnoea index (AHI) significantly increased in the patients without CPAP therapy compared with the D-1 (74 +/- 23 vs. 35 +/- 6 times/h, p < 0.05), and in the CPAP group, there was a significant reduction in the average AHI value to 14 +/- 6 times/h, p < 0.01. During D+1, we observed an increase in the nocturnal systolic BP (10 %), diastolic BP (12 %) and heart rate (14 %) in the group without CPAP. These metrics were re-established in the CPAP group to values that were similar to those that were observed on the D-1. The absence of nocturnal dipping in the group without CPAP was followed by a significant increase in nocturnal norepinephrine (42 +/- 12 MUg/l/12 h) and epinephrine (8 +/ 2 MUg/l/12 h) levels compared with the D-1 (norepinephrine 17 +/- 3; epinephrine 2 +/- 0.3 MUg/l/12 h, p < 0.001). In the patients who used the CPAP treatment, the nocturnal catecholamine levels were similar to D-1. The effectiveness of intravenous analgesic therapy was verified by a significant decrease in the pain scores in patients both with and without CPAP therapy. CONCLUSION: These data confirm an increase in the AHI on the night following UPPP with or without septoplasty. This increase promotes an absence of nocturnal dipping and a significant increase in urinary catecholamine levels. CPAP therapy was effective to prevent the transitory increase in BP. PMID- 23644903 TI - Adaptive optics optical coherence tomography for in vivo mouse retinal imaging. AB - Small animal models of retinal diseases are important to vision research, and noninvasive high resolution in vivo rodent retinal imaging is becoming an increasingly important tool used in this field. We present a custom Fourier domain optical coherence tomography (FD-OCT) instrument for high resolution imaging of mouse retina. In order to overcome aberrations in the mouse eye, we incorporated a commercial adaptive optics system into the sample arm of the refractive FD-OCT system. Additionally, a commercially available refraction canceling lens was used to reduce lower order aberrations and specular back reflection from the cornea. Performance of the adaptive optics (AO) system for correcting residual wavefront aberration in the mice eyes is presented. Results of AO FD-OCT images of mouse retina acquired in vivo with and without AO correction are shown as well. PMID- 23644904 TI - LC-MS/MS assay for the quantitation of the HDAC inhibitor belinostat and five major metabolites in human plasma. AB - The histone deacetylase inhibitor belinostat is being evaluated clinically as a single agent in the treatment of peripheral T-cell lymphomas and in combination with other anticancer agents to treat a wide range of human cancers including acute leukemias and solid tumors. To determine the pharmacokinetics of belinostat in the NCI ODWG liver dysfunction study, we developed and validated an LC-MS/MS assay for the quantitation of belinostat and five major metabolites in 0.05 mL human plasma. After protein precipitation, chromatographic separation was achieved with a Waters Acquity BEH C18 column and a linear gradient of 0.1% formic acid in acetonitrile and water. Detection with an ABI 4000Q mass spectrometer utilized both electrospray positive and negative mode ionization. The assay was linear from 30 to 5000 ng/mL for all six analytes and proved to be accurate (92.0-104.4%) and precise (CV <13.7%), and fulfilled FDA criteria for bioanalytical method validation. We demonstrated the suitability of this assay for measuring parent drug and five major metabolites in plasma from a patient who was administered belinostat IV at a dose of 400 mg/m(2). The LC-MS/MS assay that has been developed will be an essential tool to further define the metabolism and pharmacology of belinostat in the ongoing liver organ dysfunction as well as other studies that investigate belinostat with other anticancer agents. PMID- 23644905 TI - Immunomagnetic molecular probe with UHPLC-MS/MS: a promising way for reliable bronchial asthma diagnostics based on quantification of cysteinyl leukotrienes. AB - A sensitive and precise method for simultaneous quantification of cysteinyl leukotrienes (=cys LTs) - leukotriene C4 (=LTC4), leukotriene D4 (=LTD4) and leukotriene E4 (=LTE4) - essential biomarkers of bronchial asthma present in exhaled breath condensate (=EBC) was developed. An immunomagnetic molecular probe was prepared by anchoring cysteinyl leukotrienes antibody on the surface of functionalized monodispersed magnetic particles and used to selectively isolate cys LTs from biological matrices - EBC, plasma and urine. Immobilization and the immunoaffinity capture procedures were optimized to maximize the amount of separated cys LTs, which were detected "off-beads" after acidic elution by UHPLC ESI-MS/MS operated in a multiple reaction monitoring mode. The developed method was characterized with high precision <=13.6% (intra-day precision determined as RSD) and <=14.5% (inter-day precision determined as RSD), acceptable accuracy <=18.5% (determined as RE), and high recovery of immunoseparation (>=93.1%) in aforementioned biological matrices. The applicability of the method was demonstrated on EBC, plasma and urine clinical samples of patients with various subtypes of bronchial asthma (occupational, steroid-resistant, moderate with and without corticosteroids therapy) and healthy subjects where reasonable differences in cys LTs concentration levels were found. Combining extremely selective immunomagnetic separation with highly sensitive and precise detection step, the developed method was used to aid diagnosis, predict the most effective therapy, and monitor the response to treatment. The detection of elevated inflammatory mediators (cys LTs) in EBC of subjects with relatively asymptomatic asthma and normal pulmonary function tests could offer a novel way for monitoring the lung inflammation and perhaps initiating treatment in an earlier stage. PMID- 23644906 TI - Chloroquine-N-oxide, a major oxidative degradation product of chloroquine: identification, synthesis and characterization. AB - Chloroquine (CQ) (1) which has endured as one of the most powerful antimalarial drugs was subjected to oxidative stress conditions and the degradation profile was studied. The oxidative stress condition of CQ furnished one major degradation product along with other minor degradation products. The unknown major degradation product was identified in HPLC and pure impurity was isolated using column chromatography. The structure of this major product was elucidated using UV, FT-IR, (1)H NMR, (13)C NMR, 2D NMR (HSQC) and mass spectral data. Based on the results obtained from the different spectroscopic studies, it was confirmed that the N-oxide was formed at the tertiary amine nitrogen instead of the pyridine nitrogen. Subsequently, an efficient and simple synthetic approach was developed for the synthesis of chloroquine-N-oxide using a work-up procedure that does not require chromatography techniques for further purification. It was observed that the spectral data of the isolated degradation product coincided appropriately with the synthesized product spectral data. PMID- 23644907 TI - An efficient chemical analysis of phenolic acids and flavonoids in raw propolis by microwave-assisted extraction combined with high-performance liquid chromatography using the fused-core technology. AB - A closed-vessel microwave-assisted extraction (MAE) technique was optimized for the first time for the extraction of polyphenols from raw propolis. The results obtained by means of response surface experimental design methodology showed that the best global response was reached when the extraction temperature was set at 106 degrees C, the solvent composition close to EtOH-H2O 80:20 (v/v), with an extraction time of 15 min. In comparison with other techniques, such as maceration, heat reflux extraction (HRE) and ultrasound-assisted extraction (UAE), the extraction with MAE was improved by shorter extraction time and lower volume of solvent needed. The HPLC analyses of propolis extracts were carried out on a fused-core Ascentis Express C18 column (150 mm * 3.0 mm I.D., 2.7 MUm), with a gradient mobile phase composed by 0.1% formic acid in water and acetonitrile. Detection was performed by DAD and MS. The method validation indicated that the correlation coefficients were >0.999; the limit of detection was in the range 0.5 0.8 MUg/ml for phenolic acids and 1.2-3.0 MUg/ml for flavonoids; the recovery range was 95.3-98.1% for phenolic acids and 94.1-101.3% for flavonoids; the intra and inter-day %RSD values for retention times and peak areas were <= 0.3 and 2.2%, respectively. The quali- and quantitative analysis of polyphenols in Italian samples of raw propolis was performed with the validated method. Total phenolic acids ranged from 5.0 to 120.8 mg/g and total flavonoids from 2.5 to 168.0mg/g. The proposed MAE procedure and HPLC method can be considered reliable and useful tools for the comprehensive multi-component analysis of polyphenols in propolis extracts to be used in apitherapy. PMID- 23644908 TI - Reproducibility of the anti-Factor Xa and anti-Factor IIa assays applied to enoxaparin solution. AB - Enoxaparin is a widely used subcutaneously administered antithrombotic agent comprising a complex mixture of glycosaminoglycan chains. Owing to this complexity, its antithrombotic potency cannot be defined by physicochemical methods and is therefore evaluated using an enzymatic assay of anti-Xa and anti IIa activity. Maintaining consistent anti-Xa activity in the final medicinal product allows physicians to ensure administration of the appropriate dosage to their patients. Bioassays are usually complex and display poorer reproducibility than physicochemical tests such as HPLC assays. Here, we describe the implementation of a common robotic platform and standard release potency testing procedures for enoxaparin sodium injection (Lovenox, Sanofi, Paris, France) products at seven quality control sites within Sanofi. Qualification and analytical procedures, as well as data handling, were optimized and harmonized to improve assay reproducibility. An inter-laboratory study was performed in routine release conditions. The coefficients of variation for repeatability and reproducibility in assessments of anti-Xa activity were 1.0% and 1.2%, respectively. The tolerance interval in reproducibility precision conditions, expressed as percentage potency, was 96.8-103.2% of the drug product target of 10,000 IU/ml, comparing favorably with the United States of America Pharmacopeia specification (90-110%). The maximum difference between assays in two different laboratories is expected to be 4.1%. The reproducibility characteristics of anti IIa activity assessments were found to be similar. These results demonstrate the effectiveness of the standardization process established and allow for further improvements to quality control in Lovenox manufacture. This process guarantees closeness between actual and target potencies, as exemplified by the results of release assays obtained during a three-year period. PMID- 23644909 TI - Clinical and histological evaluation of postextraction platelet-rich fibrin socket filling: a prospective randomized controlled study. AB - OBJECTIVES: The aims were to investigate whether the use of platelet-rich fibrin membranes (PRF) for socket filling could improve microarchitecture and intrinsic bone tissue quality of the alveolar bone after premolar extraction and to assess the influence of the surgical procedure before implant placement. MATERIAL AND METHODS: Twenty-three patients requiring premolar extraction followed by implant placement were randomized to three groups: (1) simple extraction and socket filling with PRF, (2) extraction with mucosal flap and socket filling with PRF, and (3) controls with simple extraction without socket filling. Implant placement was performed at week 8, and a bone biopsy was obtained for histomorphometric analysis. RESULTS: Analysis by microcomputed tomography showed better bone healing with improvement of the microarchitecture (P < 0.05) in group 1. This treatment had also a significant effect (P < 0.05) on intrinsic bone tissue quality and preservation of the alveolar width. An invasive surgical procedure with a mucosal flap appeared to completely neutralize the advantages of the PRF. CONCLUSIONS: These results support the use of a minimally traumatic procedure for tooth extraction and socket filling with PRF to achieve preservation of hard tissue. PMID- 23644910 TI - A six-year follow-up of full-arch immediate restorations fabricated with an intraoral welding technique. AB - PURPOSE: The aim of this study was to evaluate the 6-year effectiveness of maxillary and mandibular full-arch immediately loaded prostheses fabricated using an intraoral welding technique. METHODS: All patients received the same day of surgery a fixed, full-arch prosthesis supported by an intraorally welded titanium framework created directly in the patient's mouth using a titanium bar. Life table analysis of implant survival, complications, and any other adverse events were recorded at yearly follow-up for a period of 6 years. RESULTS: One hundred twenty-four (86.11%) of 144 implants placed in maxillary cases and 87 (77.68%) of 112 implants placed in mandible cases completed the planned 6-year follow-up. At the 72-month follow-up, the accumulated mean marginal bone loss was, respectively, 1.39 mm (SD = 0.67) for the implants placed in the maxilla (n = 124) and 1.29 mm (SD = 0.71) for the implants placed in the mandible (n = 87). Fracturing of the composite resin superstructure was the most common adverse event. CONCLUSIONS: After a 6-year follow-up period, the intraoral welding technique proved to be a predictable technique for successfully rehabilitating the fully edentulous patient with a fixed and immediate prosthesis. PMID- 23644911 TI - The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample. AB - RATIONALE: To improve outcomes for patients undergoing extinction-based therapies (e.g., exposure therapy) for anxiety disorders such as post-traumatic stress disorder (PTSD), there has been interest in identifying pharmaceutical compounds that might facilitate fear extinction learning and recall. Oxytocin (OT) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses. Little is known, however, about the effects of OT treatment on conditioned fear responding and extinction in humans. OBJECTIVES: The purpose of the present study was to assess the effects of OT in a fear potentiated startle task of fear conditioning and extinction. METHODS: A double blind, placebo-controlled study of 44 healthy human participants was conducted. Participants underwent a conditioned fear acquisition procedure, after which they were randomized to treatment group and delivered OT (24 IU) or placebo via intranasal (IN) spray. Forty-five minutes after treatment, participants underwent extinction training. Twenty-four hours later, subjects were tested for extinction recall. RESULTS: Relative to placebo, the OT group showed increased fear potentiated startle responding during the earliest stage of extinction training relative to placebo; however, all treatment groups showed the same level of reduced responding by the end of extinction training. Twenty-four hours later, the OT group showed significantly higher recall of extinction relative to placebo. CONCLUSIONS: The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans. These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear related disorders. PMID- 23644912 TI - Greater risk sensitivity of dorsolateral prefrontal cortex in young smokers than in nonsmokers. AB - RATIONALE: Despite a national reduction in the prevalence of cigarette smoking, ~19% of the adult US population persists in this behavior, with the highest prevalence among 18-25-year-olds. Given that the choice to smoke imposes a known health risk, clarification of brain function related to decision-making, particularly involving risk-taking, in smokers may inform prevention and smoking cessation strategies. OBJECTIVES: This study aimed to compare brain function related to decision-making in young smokers and nonsmokers. METHODS: The Balloon Analogue Risk Task (BART) is a computerized risky decision-making task in which participants pump virtual balloons, each pump associated with an incremental increase in potential payoff on a given trial but also with greater risk of balloon explosion and loss of payoff. We used this task to compare brain activation associated with risky decision-making in smokers (n = 18) and nonsmokers (n = 25), while they performed the BART during functional magnetic resonance imaging (fMRI). The participants were young men and women, 17-21 years of age. RESULTS: Risk level (number of pumps) modulated brain activation in the right dorsolateral and ventrolateral prefrontal cortices more in smokers than in nonsmokers, and smoking severity (Heaviness of Smoking Index) was positively related to this modulation in an adjacent frontal region. CONCLUSIONS: Given evidence for involvement of the right dorsolateral and ventrolateral prefrontal cortices in inhibitory control, these findings suggest that young smokers have a different contribution of prefrontal cortical substrates to risky decision-making than nonsmokers. Future studies are warranted to determine whether the observed neurobiological differences precede or result from smoking. PMID- 23644913 TI - Trehalose induced antidepressant-like effects and autophagy enhancement in mice. AB - RATIONALE: The disaccharide trehalose protects cells from hypoxic and anoxic injury and suppresses protein aggregation. In vivo studies with trehalose show cellular and behavioral beneficial effects in animal models of neurodegenerative diseases. Moreover, trehalose was shown to enhance autophagy, a process that had been recently suggested to be involved in the therapeutic action of antidepressant and mood-stabilizing drugs. OBJECTIVE: The present study was therefore designed to explore antidepressant and mood-stabilizing activity of trehalose in animal models for depression and mania. METHODS: Trehalose 1 or 2% was administered for 3 weeks as a drinking solution to Black Swiss mice (a model of manic-like behaviors) or 2% to ICR mice and their behavior evaluated in a number of tests related to depression or mania. The effects of trehalose were compared with similar chronic administration of the disaccharide maltose as well as with a vehicle (water) control. RESULTS: Chronic administration of trehalose resulted in a reduction of frontal cortex p62/beclin-1 ratio suggesting enhancement of autophagy. Trehalose had no mood-stabilizing effects on manic-like behavior in Black Swiss mice but instead augmented amphetamine-induced hyperactivity, an effect similar to antidepressant drugs. In ICR mice, trehalose did not alter spontaneous activity or amphetamine-induced hyperactivity but in two separate experiments had a significant effect to reduce immobility in the forced swim test, a standard screening test for antidepressant-like effects. CONCLUSIONS: The results suggest that trehalose may have antidepressant-like properties. It is hypothesized that these behavioral changes could be related to trehalose effects to enhance autophagy. PMID- 23644914 TI - Cortical excitability in smoking and not smoking individuals with and without nicotine. AB - RATIONAL: Activation of nicotinic acetylcholine receptors has a major neuromodulatory impact on central nervous system function. Beyond acute activation, chronic nicotine intake has long-lasting effects on cortical excitability in animal experiments, caused by receptor up- or down-regulation. Knowledge about the impact of nicotine on cortical excitability in humans, however, is limited. OBJECTIVES: We therefore aimed to explore the effect of nicotine intake on cortical excitability in healthy human smokers and non smokers. METHODS: The primary motor cortex served as model, and cortical excitability was monitored via transcranial magnetic stimulation (TMS). Corticospinal excitability and intracortical excitability were recorded before and after application of nicotine patch in both groups. Corticospinal excitability was explored by motor threshold and input/output curve (I/O curve), and intracortical excitability was explored by means of paired-pulse TMS techniques (intracortical facilitation (ICF), short-latency intracortical inhibition (SICI), I-wave facilitation and short-latency afferent inhibition (SAI)). RESULTS: The results show that smokers during nicotine withdrawal display increased corticospinal excitability with regard to the I/O curve (TMS intensity 150 % of resting motor threshold) compared to non-smokers and furthermore enhanced SAI and diminished ICF at the intracortical circuit level. After administration of nicotine, intracortical facilitation in smokers increased, while in non-smokers, inhibition (SICI, SAI) was enhanced. CONCLUSION: Our results show that chronic nicotine consumption in smokers alters cortical excitability independent from acute nicotine consumption and that acute nicotine has different effects on motor cortical excitability in both groups. PMID- 23644915 TI - A cost of illness study of children with high-functioning autism spectrum disorders and comorbid anxiety disorders as compared to clinically anxious and typically developing children. AB - The study's aim was to estimate the societal costs of children with high functioning ASD and comorbid anxiety disorder(s) (ASD + AD-group; n = 73), and to compare these costs to children with anxiety disorders (AD-group; n = 34), and typically developing children (controls; n = 87). Mean total costs for the ASD + AD-group amounted 17,380 per year. Societal costs were estimated at almost 142 million euro per year. Costs in the ASD + AD-group were four times higher compared to the AD-group, and 27 times higher compared to controls. ASD-related costs were higher in the ASD + AD-group; anxiety-related costs did not differ between the ASD + AD- and AD-group; costs due to physical or other reasons did not differ across groups. The findings suggest that costs can be decreased if effective treatment options for treating anxiety in ASD are established, however, the remaining costs associated with ASD would still be large. A limitation of the study is that a group of children with ASD without anxiety disorders is lacking. PMID- 23644916 TI - Asperger's disorder will be back. AB - This review focuses on identifying up-to-date number of publications that compared DSM-IV/ICD-10 Asperger's disorder (AspD) to Autistic Disorder/High functioning Autism (AD/HFA). One hundred and twenty-eight publications were identified through an extensive search of major electronic databases and journals. Based on more than 90 clinical variables been investigated, 94 publications concluded that there were statistically significant or near significant level of quantitative and/or qualitative differences between AspD and AD/HFA groups; 4 publications found both similarities and differences between the two groups; 30 publications concluded with no differences between the two groups. Although DSM-5 ASD will eliminate Asperger's disorder. However, it is plausible to predict that the field of ASD would run full circle during the next decade or two and that AspD will be back in the next edition of DSM. PMID- 23644917 TI - Peer deviance, alcohol expectancies, and adolescent alcohol use: explaining shared and nonshared environmental effects using an adoptive sibling pair design. AB - Previous research suggests adolescent alcohol use is largely influenced by environmental factors, yet little is known about the specific nature of this influence. We hypothesized that peer deviance and alcohol expectancies would be sources of environmental influence because both have been consistently and strongly correlated with adolescent alcohol use. The sample included 206 genetically related and 407 genetically unrelated sibling pairs assessed in mid to-late adolescence. The heritability of adolescent alcohol use (e.g., frequency, quantity last 12 months) was minimal and not significantly different from zero. The associations among peer deviance, alcohol expectancies, and alcohol use were primarily due to shared environmental factors. Of special note, alcohol expectancies also significantly explained nonshared environmental influence on alcohol use. This study is one of few that have identified specific environmental variants of adolescent alcohol use while controlling for genetic influence. PMID- 23644919 TI - A prospective study of fertility-sparing treatment with megestrol acetate following hysteroscopic curettage for well-differentiated endometrioid carcinoma and atypical hyperplasia in young women. AB - PURPOSE: To investigate the feasibility and efficacy of curettage with hysteroscopy followed by megestrol acetate (MA) for well-differentiated endometrioid carcinoma (EC) confined to the endometrium and for atypical hyperplasia (AH) in young women. PATIENTS AND METHODS: Fourteen patients with EC and 12 patients with AH were prospectively enrolled in this study. All of the patients received at least 12 weeks of oral MA (160 mg/day) following thorough curettage with hysteroscopy. The response was assessed histologically every 12 weeks. The primary endpoint was the complete response rate. Adverse events, pregnancy rates and recurrence rates were secondary end points. RESULTS: Twenty one (80.8 %) patients responded to treatment. The median time to response was 12 weeks. After a median follow-up of 32 months, 6 patients had recurrences. Significantly, more patients with infertility or PCOS experienced recurrence (P = 0.040, P = 0.015). Eight patients attempted to conceive after complete response; two spontaneous conceptions and one normal delivery were achieved. No disease related or treatment-related deaths were observed. CONCLUSIONS: Fertility-sparing treatment with MA following entirely hysteroscopic curettage is effective, demonstrating the least toxicity for rigorously selected young women with well differentiated EC confined to the endometrium or with AH; however, close follow up is required for the potential consequences of improper patient selection and a substantial rate of recurrence. PMID- 23644920 TI - Management of acute hydrocephalus due to pregnancy with ventriculoperitoneal shunt. PMID- 23644918 TI - Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington's disease motor onset. AB - Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3' UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations. PMID- 23644921 TI - Does immediate postpartum curettage of the endometrium accelerate recovery from preeclampsia-eclampsia? A randomized controlled trial. AB - OBJECTIVES: To evaluate the effect of immediate postpartum curettage on rapid resolution of clinical and laboratory indices in pre-eclampsia and eclampsia women. METHODS: A randomized controlled study, comprised of 420 pre-eclamptic or eclamptic women with singleton pregnancy 24 weeks gestation and more. Patients were divided into two groups: 220 patients underwent immediate postpartum curettage and 200 patients as a control group. RESULTS: The clinical and laboratory prenatal parameters showed no statistical significant differences between both groups. The follow-up for the postnatal clinical and laboratory data showed significant improvement for the mean arterial blood pressure in the curettage group over 6, 12, and 24 h after delivery and significant improvement in the platelet count as well. The average time required for MAP to reach 105 mmHg or less was significantly shorter (P < 0.05) in the curettage group (40 +/- 3.15 h) than the control group (86 +/- 5.34 h). Two patients in the curettage group developed convulsions versus 11 patients in the control group within the first 24 h after delivery. No maternal mortalities were reported in both groups. CONCLUSION: Immediate postpartum curettage is a safe and effective procedure and can accelerate recovery from pre-eclampsia or eclampsia. PMID- 23644922 TI - The contribution of catumaxomab in the treatment of malignant ascites in patients with ovarian cancer: a review of the literature. AB - The approval of the first specific drug catumaxomab for the treatment of malignant ascites is the subject of this review. This trifunctional antibody is known to kill EpCAM-positive tumor cells and therefore attacks the primary cause of malignant ascites formation in the peritoneal cavity. Until today catumaxomab is the only EpCam-targeted antibody approved by the European Medicines Agency. Ovarian cancer is caused by epithelial tumors cells which overexpress epithelial cell adhesion molecule (EpCAM). The existing literature concerning the use of catumaxomab for the treatment of malignant ascites associated with ovarian cancer until today is reported in this article. It is very encouraging that different prospective studies from diverse scientific teams recently presented positive results concerning the efficacy and the safety of catumaxomab in the treatment of malignant ascites in patients with ovarian cancer. A case of a patient with ovarian cancer FIGO IIIc is also referred in this article. A complete remission and stable disease was found after 4 i.p. infusions of catumaxomab. PMID- 23644923 TI - Squamous intraepithelial lesions in HIV-infected women: prevalence, incidence, progression and regression. AB - PURPOSE: To evaluate the impact of HIV immune depletion, highly active antiretroviral therapy (HAART) and patient characteristics on the occurrence of cervical squamous intraepithelial lesions (SIL). METHODS: A total of 898 HIV positive women were evaluated at the time of their first Pap smear and 388 of them received additional Pap smears during follow-up in a cohort study. The patients were enrolled from July 1997 to April 2007. Prevalence and incidence of SIL in Pap smears were studied. Progression and regression were evaluated in follow-up of patients presenting low-grade SIL. RESULTS: Pap smear results at baseline were: 741 normal (82.5 %), 56 atypical squamous cells of indeterminate significance (ASCUS) (6.2 %), 78 low-grade SIL (8.7 %), 22 high-grade SIL (2.4 %), and 1 invasive cervical cancer (0.1 %). SIL cumulative incidence rate was 9.7 %. Progression and regression occurred in 15.9 and 62 %, respectively. Multivariate analysis of CD4 counts <= 200 cells/mm(3) (aHR = 2.1; 95 % CI 1.3 3.5; P = 0.004) and age less than 30 years (aHR = 3.2; 95 % CI 1.5-6.8; P = 0.01) or less than 40 years old (aHR = 2.6; 95 % CI 1.2-5.7; P = 0.01) were significantly associated with SIL prevalence. CD4 counts <= 200 cells/mm(3) (aHR = 3.0; 95 % CI 1.2-7.2; P = 0.01) and higher viral load counts (for each log increase) were associated with SIL incidence (aHR = 1.4; 95 % CI 1-1.9; P = 0.048). CONCLUSIONS: Prevalence and incidence of SIL in HIV-positive women were associated with severity of HIV disease. Interventions to increase access to Pap smears and further diagnostic tests should be implemented and targeted to HIV positive women. PMID- 23644924 TI - Frequency of cervical intraepithelial neoplasia grade II or worse in women with a persistent low-grade squamous intraepithelial lesion seen by Papanicolaou smears. AB - PURPOSE: We investigated the frequency of cervical intraepithelial neoplasia (CIN) grade II or worse in low-income Brazilian women with persistent low-grade squamous intraepithelial lesions (LSIL). METHODS: A retrospective review of medical records was performed for all patients who underwent a loop electrosurgical excision procedure (LEEP) with "see and treat" strategy for persistent LSIL seen on Papanicolaou (Pap) smears (persisting >12 months in at least two consecutive tests, over a 50-month period. We assessed the colposcopy and histopathology results at the time of the procedure and at follow-up, using Pap and histopathology. RESULTS: Of 106 women, 48 (45.3 %) had no dysplasia by histopathology, 18 (17.0 %) had CIN I, 29 (27.4 %) had CIN II and 10 (9.4 %) had CIN III. Among the patients with CIN, 38 (66.7 %) performed the follow-up. Of these, only 4 (10.5 %) were classified as follow-up (+), all had CIN I. Women with initial CIN I had 16.7 % (n = 2) recurrences; those with initial CIN II had 5.9 % (n = 1); and those with initial CIN III had 11.1 % (n = 1) (p > 0.05). CONCLUSIONS: A very high proportion of the women with persistent LSIL had CIN II/III on post-LEEP histopathology. Recurrence rates were equal to than those that originally caused the patients to be subjected to LEEP (LSIL). The benefits of the "see and treat" protocol by LEEP for persistent LSIL outweigh the risk of overtreatment, principally in low-resource settings where poor patient compliance is expected, as in Brazil. PMID- 23644925 TI - Neuritogenic and neuroprotective effects of polar steroids from the Far East starfishes Patiria pectinifera and Distolasterias nipon. AB - The neuritogenic and neuroprotective activities of six starfish polar steroids, asterosaponin R1, (25S)-5alpha-cholestane 3beta,4beta,6alpha,7alpha,8,15alpha,16beta,26-octaol, and (25S)-5alpha-cholestane 3beta,6alpha,7alpha,8,15alpha,16beta,26-heptaol (1-3) from the starfish Patiria pectinifera and distolasterosides D1-D3 (4-6) from the starfish Distolasterias nipon were analyzed using the mouse neuroblastoma (NB) C-1300 cell line and an organotypic rat hippocampal slice culture (OHSC). All of these compounds enhanced neurite outgrowth in NB cells. Dose-dependent responses to compounds 1-3 were observed within the concentration range of 10-100 nM, and dose-dependent responses to glycosides 4-6 were observed at concentrations of 1-50 nM. All the tested substances exhibited notable synergistic effects with trace amounts of nerve growth factor (NGF, 1 ng/mL) or brain-derived neurotrophic factor (BDNF, 0.1 ng/mL). Using NB cells and OHSCs, it was shown for the first time that starfish steroids 1-6 act as neuroprotectors against oxygen-glucose deprivation (OGD) by increasing the number of surviving cells. Altogether, these results suggest that neurotrophin-like neuritogenic and neuroprotective activities are most likely common properties of starfish polyhydroxysteroids and the related glycosides, although the magnitude of the effect depended on the particular compound structure. PMID- 23644926 TI - Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. AB - Kidney toxicity is one of the most frequent adverse events reported during drug development. The lack of accurate predictive cell culture models and the unreliability of animal studies have created a need for better approaches to recapitulate kidney function in vitro. Here, we describe a microfluidic device lined by living human kidney epithelial cells exposed to fluidic flow that mimics key functions of the human kidney proximal tubule. Primary kidney epithelial cells isolated from human proximal tubule are cultured on the upper surface of an extracellular matrix-coated, porous, polyester membrane that splits the main channel of the device into two adjacent channels, thereby creating an apical 'luminal' channel and a basal 'interstitial' space. Exposure of the epithelial monolayer to an apical fluid shear stress (0.2 dyne cm(-2)) that mimics that found in living kidney tubules results in enhanced epithelial cell polarization and primary cilia formation compared to traditional Transwell culture systems. The cells also exhibited significantly greater albumin transport, glucose reabsorption, and brush border alkaline phosphatase activity. Importantly, cisplatin toxicity and Pgp efflux transporter activity measured on-chip more closely mimic the in vivo responses than results obtained with cells maintained under conventional culture conditions. While past studies have analyzed kidney tubular cells cultured under flow conditions in vitro, this is the first report of a toxicity study using primary human kidney proximal tubular epithelial cells in a microfluidic 'organ-on-a-chip' microdevice. The in vivo-like pathophysiology observed in this system suggests that it might serve as a useful tool for evaluating human-relevant renal toxicity in preclinical safety studies. PMID- 23644927 TI - Association between the characteristics of metabolic syndrome and Alzheimer's disease. AB - Various epidemiological studies have shown that type 2 diabetes and metabolic syndrome are highly correlated with Alzheimer's disease (AD). Here, we sought to assess the impact of metabolic syndrome characteristics on the progression of AD. Five-week-old male, spontaneously hypertensive (n = 32) and Wistar Kyoto (abbreviated WKY; n = 8) rats were divided into 5 groups (each n = 8): WKY, hypertension (HTN), streptozotocin-induced diabetes (STZ), high-fat diet (HFD), and STZ + high-fat diet-induced diabetes mellitus (DM). All animals were sacrificed and samples of the blood, liver, and brain were collected for further biological analysis. During the 15-week period of induction, the STZ and DM groups (animals injected with low-dose STZ) had significantly higher fasting glucose levels; the HFD group had elevated insulin levels, but normal blood glucose levels. The HFD and DM groups had hypercholesterolemia and higher hepatic levels of triglycerides and cholesterol. Additionally, correlations between HFD and elevated brain amyloid-beta 42 (Abeta-42), hyperglycemia and down-regulation of brain insulin receptor, and serum Abeta-42 and hepatic triglyceride concentrations (r(2) = 0.41, p < 0.05) were observed. Serum C-reactive protein and malondialdehyde did not appear to have a significant influence on the association with biomarkers of AD. Thus, our study demonstrated that rats with characteristics of metabolic syndrome had a large number of biomarkers predicting AD; however, no relationship between traditional inflammatory and oxidative markers and AD was found. Further studies are necessary to prove that these findings in rats are relevant to AD processes in humans. PMID- 23644929 TI - A 3N rule for the electronic properties of doped graphene. AB - Doping a graphene sheet with different atoms is a promising method for tuning its electronic properties. We report a first-principle investigation on the electronic properties of N, B, S, Al, Si or P doped graphene. It is revealed that the doped graphene can show an interesting physical regularity, which can be described by a simple 3N rule: a doped graphene has a zero gap or a neglectable gap at the Dirac point when its primitive cell is 3N * 3N (N is an integer), otherwise there is a gap tunable by the dopant concentration. This unique 3N rule provides a useful guideline for the design of doped graphene for electronic applications. PMID- 23644928 TI - Restoration of antioxidant enzymes in the therapeutic use of selenium in septic patients. AB - A prospective observational study of parenteral selenium supplementation started in January 2008 which included 72 septic patients with APACHE II scores ranging from 19 to 40 after admission.Patients were divided into two major groups: one with a continual infusion of sodium selenite at 750 ug/24 h for 6 days and a placebo group followed by subgroups according to the presence or absence of surgical procedure. Routine biochemical and hematological para-meters were determined continuously. Sequential Organ Failure Assessment (SOFA) scores were calculated in two-day intervals.Patients who died had a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score, lower albumin on the 3rd days of therapy and higher C-reactive protein (CRP) on the 6th days of therapy. Statistically, there was no significant difference in the comparison of CRP, fibrinogen, albumin, plasma proteins, or neutrophil to lymphocyte counts during the 6 days in all subgroups. There was a significant difference in the comparison of leukocytes on the 6th day of therapy. Glutathione peroxidase and glutathione reductase activity was increased in selenium subgroups with negative correlation in placebo subgroups during the therapy. A downward trend in SOD activity, more appreciable in selenium groups, seemed to be a reflection of lower superoxide radical production. This is biased more as a result of GPx activity restoration, preventing further peroxidation of organic substrates and cyclic formation of other radicals, than actual attenuation of their production.Selenium substitution increased selenium dependent antioxidant enzyme activity and, in comparing mortality in groups, we found a 16.7 % decrease in mortality in favor of supplementation with selenium. PMID- 23644930 TI - Clinical efficacy on fracture risk and safety of 0.5 mg or 1 mg/month intravenous ibandronate versus 2.5 mg/day oral risedronate in patients with primary osteoporosis. AB - This randomized, double-blind study assessed the antifracture efficacy and safety of intermittent intravenous (IV) ibandronate versus oral daily risedronate in Japanese patients with primary osteoporosis. Ambulatory patients aged >=60 years were randomized to receive 0.5 or 1 mg/month IV ibandronate plus oral daily placebo or 2.5 mg/day oral risedronate, the licensed dose in Japan, plus IV placebo. The primary end point was noninferiority of ibandronate versus risedronate for first new or worsening vertebral fracture over 3 years. A total of 1,265 patients were randomized. A total of 1,134 patients formed the per protocol set. Both ibandronate doses were noninferior to risedronate: 0.5 mg, hazard ratio (HR) 1.09 [95 % confidence interval (CI) 0.77-1.54]; 1 mg, HR 0.88 (95 % CI 0.61-1.27). The rate of first new vertebral fracture over 3 years was 16.8 % (95 % CI 12.8-20.8) for 0.5 mg ibandronate, 11.6 % (95 % CI 8.2-15.0) for 1 mg ibandronate, and 13.2 % (95 % CI 9.6-16.9) for risedronate. Significant increases in bone mineral density relative to baseline were observed with all treatments after 6 months, with substantial reductions in bone turnover markers after 3 months. Greatest efficacy was obtained with 1 mg ibandronate. Analyses in women only showed similar results to the overall population. No new safety concerns were identified. This study demonstrated the noninferiority of IV ibandronate to the licensed Japanese dose of oral risedronate and suggested that 1 mg/month is an effective dose in Japanese patients with primary osteoporosis. PMID- 23644931 TI - Hepatic transplantation: postoperative complications. AB - Advances in surgical techniques and immunosuppression have made orthotopic liver transplantation a first-line treatment for many patients with end-stage liver disease. The early detection and treatment of postoperative complications has contributed significantly to improved graft and patient survival with imaging playing a critical role in detection. Complications that can lead to graft failure or patient mortality include vascular abnormalities, biliary abnormalities, allograft rejection, and recurrent or post-transplant malignancy. Vascular abnormalities include stenosis and thrombosis of the hepatic artery, portal vein, and inferior vena cava, as well as hepatic artery pseudoaneurysm, arteriovenous fistula, and celiac stenosis. Biliary abnormalities include strictures, bile leak, obstruction, recurrent disease, and infection. While imaging is not used to diagnose allograft rejection, it plays an important role in identifying complications that can mimic rejection. Ultrasound is routinely performed as the initial imaging modality for the detection and follow-up of both early and delayed complications. Cholangiography and magnetic resonance cholangiopancreatography are used to characterize biliary complications and computed tomography is used to confirm abnormal findings on ultrasound or for the evaluation of postoperative collections. The purpose of this article is to describe and illustrate the imaging appearances and management of complications associated with liver transplantation. PMID- 23644933 TI - Relationship between left ventricular sphericity and trabeculation indexes in patients with dilated cardiomyopathy: a cardiac magnetic resonance study. AB - AIMS: To study the relationship between left ventricular (LV) trabeculations, volume, and sphericity in patients with dilated cardiomyopathy (DCM) by cardiac magnetic resonance imaging (CMR). METHODS AND RESULTS: Eighty-two patients with DCM were prospectively explored by CMR. The segmental trabeculation index (STI) was defined by the ratio of trabeculated layer thickness on compacted layer thickness per segment. The global trabeculation index (GTI) was defined by the ratio of the sum of the total trabeculated layer thickness to the sum of the total compacted layer thickness. The apex was excluded from the analysis. The mean number of segments with trabeculation per patient was 10 +/- 2 with a mean GTI of 0.68 +/- 0.32. The LV sphericity index was inversely correlated with LV ejection fraction (R = -0.42, P = 0.0002) and positively with the brain natriuretic peptide (BNP) level (R = 0.34, P = 0.003). The maximal STI was positively correlated with the indexed LV end-diastolic volume (R = 0.32, P = 0.004) and the LV sphericity index (R = 0.25, P = 0.02), but not with the BNP level or LV ejection fraction. The GTI was positively correlated with the LV sphericity index (R = 0.27, P = 0.016) but not with indexed LV end-diastolic volume, BNP levels, or LV ejection fraction. CONCLUSION: Trabeculation indexes depend on LV shape and are positively correlated with LV sphericity. These results encourage interpreting LV trabeculation with caution in patients with DCM, considering additional morphologic criteria such as LV geometry. PMID- 23644932 TI - Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. AB - IMPORTANCE: Oral supplementation with the Age-Related Eye Disease Study (AREDS) formulation (antioxidant vitamins C and E, beta carotene, and zinc) has been shown to reduce the risk of progression to advanced age-related macular degeneration (AMD). Observational data suggest that increased dietary intake of lutein + zeaxanthin (carotenoids), omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] + eicosapentaenoic acid [EPA]), or both might further reduce this risk. OBJECTIVES: To determine whether adding lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation decreases the risk of developing advanced AMD and to evaluate the effect of eliminating beta carotene, lowering zinc doses, or both in the AREDS formulation. DESIGN, SETTING, AND PARTICIPANTS: The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, randomized, double masked, placebo-controlled phase 3 study with a 2 * 2 factorial design, conducted in 2006-2012 and enrolling 4203 participants aged 50 to 85 years at risk for progression to advanced AMD with bilateral large drusen or large drusen in 1 eye and advanced AMD in the fellow eye. INTERVENTIONS: Participants were randomized to receive lutein (10 mg) + zeaxanthin (2 mg), DHA (350 mg) + EPA (650 mg), lutein + zeaxanthin and DHA + EPA, or placebo. All participants were also asked to take the original AREDS formulation or accept a secondary randomization to 4 variations of the AREDS formulation, including elimination of beta carotene, lowering of zinc dose, or both. MAIN OUTCOMES AND MEASURES: Development of advanced AMD. The unit of analyses used was by eye. RESULTS: Median follow-up was 5 years, with 1940 study eyes (1608 participants) progressing to advanced AMD. Kaplan-Meier probabilities of progression to advanced AMD by 5 years were 31% (493 eyes [406 participants]) for placebo, 29% (468 eyes [399 participants]) for lutein + zeaxanthin, 31% (507 eyes [416 participants]) for DHA + EPA, and 30% (472 eyes [387 participants]) for lutein + zeaxanthin and DHA + EPA. Comparison with placebo in the primary analyses demonstrated no statistically significant reduction in progression to advanced AMD (hazard ratio [HR], 0.90 [98.7% CI, 0.76 1.07]; P = .12 for lutein + zeaxanthin; 0.97 [98.7% CI, 0.82-1.16]; P = .70 for DHA + EPA; 0.89 [98.7% CI, 0.75-1.06]; P = .10 for lutein + zeaxanthin and DHA + EPA). There was no apparent effect of beta carotene elimination or lower-dose zinc on progression to advanced AMD. More lung cancers were noted in the beta carotene vs no beta carotene group (23 [2.0%] vs 11 [0.9%], nominal P = .04), mostly in former smokers. CONCLUSIONS AND RELEVANCE: Addition of lutein + zeaxanthin, DHA + EPA, or both to the AREDS formulation in primary analyses did not further reduce risk of progression to advanced AMD. However, because of potential increased incidence of lung cancer in former smokers, lutein + zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00345176. PMID- 23644934 TI - Non-invasive assessment of experimental autoimmune myocarditis in rats using a 3 T clinical MRI scanner. AB - AIMS: The aim of this study was to assess the use of a 3 T clinical cardiac magnetic resonance (CMR) scanner to detect injury to the heart in experimental autoimmune myocarditis (EAM). METHODS AND RESULTS: The use of 3 T CMR for the detection of cardiac injury was assessed in EAM (n = 55) and control (n = 10) male Lewis rats. Animals were evaluated with serial CMR imaging studies, using a 3 T scanner, and with 2D echocardiography before, and at 2 and 5 weeks after EAM induction. By CMR, regional wall motion abnormalities were noted in seven out of eight rats with myocarditis 5 weeks after induction. Subsequently, the rats developed significant left ventricular (LV) dilatation, wall thickening, and pericardial effusion. Average LV systolic and diastolic volumes increased from 131 +/- 10 to 257 +/- 20 uL (P = 0.0008), and from 309 +/- 14 to 412 +/- 24 uL (P < 0.0001), and ejection fraction markedly deteriorated (from 58 +/- 2 to 37 +/- 5%; P = 0.0003). Areas of fibrosis were located by late gadolinium enhancement (LGE) CMR at the subepicardium, mainly within the anterior, lateral, and inferior walls. The extent and location of LGE were highly correlated (r = 0.94; P < 0.0001) with areas of myocardial fibrosis by histopathology, with 85% sensitivity and 86% specificity. CONCLUSION: A clinical 3 T CMR scanner enables accurate detection, quantification, and monitoring of experimental myocarditis in rats, and could be used for translational research to study the pathophysiology of the disease and evaluate novel therapies. PMID- 23644935 TI - Late gadolinium enhancement cardiac magnetic resonance imaging in prognostic assessment of hypertrophic cardiomyopathy. PMID- 23644936 TI - Feasibility and reliability of point-of-care pocket-size echocardiography performed by medical residents. AB - AIMS: To study the feasibility and reliability of pocket-size hand-held echocardiography (PHHE) by medical residents with limited experience in ultrasound. METHODS AND RESULTS: A total of 199 patients admitted to a non university medical department were examined with PHHE. Six out of 14 medical residents were randomized to use a focused protocol and examine the heart, pericardium, pleural space, and abdominal large vessels. Diagnostic corrections were made and findings were confirmed by standard diagnostics. The median time consumption for the examination was 5.7 min. Each resident performed a median of 27 examinations. The left ventricle was assessed to satisfaction in 97% and the pericardium in all patients. The aortic and atrioventricular valves were assessed in at least 76% and the abdominal aorta in 50%, respectively. Global left ventricular function, pleural, and pericardial effusion showed very strong correlation with reference method (Spearman's r >= 0.8). Quantification of aortic stenosis and regurgitation showed strong correlation with r = 0.7. Regurgitations in the atrioventricular valves showed moderate correlations, r = 0.5 and r = 0.6 for mitral and tricuspid regurgitation, respectively, similar to dilatation of the left atrium (r = 0.6) and detection of regional dysfunction (r = 0.6). Quantification of the abdominal aorta (aneurysmatic or not) showed strong correlation, r = 0.7, while the inferior vena cava diameter correlated moderately, r = 0.5. CONCLUSION: By adding a PHHE examination to standard care, medical residents were able to obtain reliable information of important cardiovascular structures in patients admitted to a medical department. Thus, focused examinations with PHHE performed by residents after a training period have the potential to improve in-hospital diagnostic procedures. PMID- 23644937 TI - Transoral laser resection versus lip-split mandibulotomy in the management of oropharyngeal squamous cell carcinoma (OPSCC): a case match study. AB - The objective of this study was to compare transoral laser microsurgery (TLM) with lip-split mandibulotomy (LSM) and radial forearm free-flap reconstruction, for the resection of squamous cell carcinoma of the oropharynx (SCCOP). This study is designed as a case-control study matching 24 patients treated with TLM for SCCOP with those treated with LSM. Patients were matched by age (in 5-year epochs), sex, TNM stage, tumour sub site and type of neck dissection. Each group comprised 20 males and 4 females (mean age 56 years). Seven patients treated with TLM had an elective tracheostomy compared with all patients undergoing LSM. Moreover, the time for decanulation was reduced in patients undergoing tracheostomy for TLM. Although similar rates of patients were able to swallow to some degree on discharge, 29% of patients having LSM were discharged requiring enterostomy feeding compared with 4% of patients treated using TLM. Of those able to swallow on discharge, patients who had TLM resumed swallowing in half the time taken for those having LSM. Moreover, those treated with TLM remained in hospital for half the length of time than those treated with LSM. Due to these factors, overall cost for TLM is reduced in comparison with LSM. In comparison with LSM, TLM for the treatment of SCCOP results in fewer tracheostomies and shorter time to decanulation; a quicker recovery of swallowing function and a reduced length of hospital stay. As a result of this, treatment with TLM is on average cheaper. These factors should be considered when deciding on the surgical treatment of a patient with SCCOP. PMID- 23644938 TI - Non-vestibular head and neck schwannomas: a 10-year experience. AB - Schwannomas are rare and slow growing tumours, arising from Schwann cells which provide myelin; less than 1% of them degenerate into a malignant state. Although most studies are based on acoustic schwannomas, the majority of these tumours are non-vestibular and extracranial. Up to 45% of them can be localised in head and neck districts, where they represent a diagnostic challenge because they are in differential diagnosis with lipoma, brachial cyst, paraganglioma and adenopathy. Between February 2002 and September 2012 our experience considers 18 patients affected by schwannomas localised in the neck in 14 cases, in the oral cavity in 2 cases, in the upper lip in 1 case and finally in the nose in 1 case. A painless neck mass was the major symptom referred, as well as dysphonia and oral pain. Ultrasound scan with fine needle aspiration biopsy was done in half of the group and was diagnostic in 30%, whereas magnetic resonance imaging was diagnostic in 77%, confirming its primary role in diagnostic work-up. The surgical approach was mainly by cervical incision and the intraneural extracapsular enucleation was the technique used without nerve injury in 89% of cases. Follow-up period was 6-120 months and no evidence of relapse was registered. PMID- 23644939 TI - Outcome of patients treated with palliative weekly paclitaxel plus cetuximab in recurrent head and neck cancer after failure of platinum-based therapy. AB - Few therapeutic options are available for recurrent/metastatic head and neck cancer when progression occurs after initial chemotherapy. We analyzed retrospectively the efficacy of weekly Paclitaxel plus Cetuximab as second line of palliative chemotherapy. Patients with squamous carcinoma of head and neck with documented progression after initial treatment were enrolled. Tumor response was evaluated through the response evaluation criteria in solid tumor criteria. The retrospective analysis focused on overall survival (OS) and progression-free survival (PFS). Between 2008 and 2011, 33 consecutive patients were treated. A response rate of 55% was observed, with median response duration of 5.0 months (95% CI 3.3-11.1). The median PFS was 4.0 months (95% CI 2.9-5.0) and the median OS time was 10.0 months (95% CI 7.9-12.0). Acne-like rash/Folliculitis and chronic anemia were the most common adverse events. A weekly schedule of Paclitaxel plus Cetuximab is a promising regimen for patients with advanced head and neck cancer after failure of platinum-based therapy. Good tolerance of this treatment suggests that would be used in fragile patients. PMID- 23644941 TI - Editorial to: "Transoral resection of large parapharyngeal space tumors" by Hussain et al. PMID- 23644940 TI - Cross-contamination and cross-infection risk of otoscope heads. AB - Adequate disinfection level of the medical equipments should be maintained to prevent cross-contamination between patients. Otoscope specula are usually cleaned and disinfected appropriately after each use by disinfectant solutions. However, since otoscope heads are electrical instruments with irregular inner surface they may still harbor pathogenic microorganisms. According to manufacturers' instructions, otoscope heads can be cleaned externally with a damp cloth and they can be disinfected with aldehydes, tensides, and alcohols. Instrument heads should not be placed in liquids. Alcohols cannot be used on glass surfaces. How often an otoscope head must be cleaned to limit contamination is not well established. This study aimed to determine whether the otoscope heads harbor pathogenic microorganisms or not. A total of 53 otoscope heads were included in the study. Swab samples were obtained from the inner parts of the otoscope heads. For bacteriological examination, cotton swabs were inoculated onto 5 % sheep blood agar, chocolate agar, and eosine methylene blue agar plates. For fungal evaluation, cotton swabs were inoculated onto Sabouraud dextrose agars. Cultured microorganisms were evaluated macroscopically and microscopically. Of the 53 otoscope heads, 22 were found to be contaminated with bacteria and/or fungi. Eleven of them were colonized by one organism, 11 were colonized by more than one organism. Only one Pseudomonas species isolated as gram-negative microorganism. Gram-positive microorganisms were isolated from the remaining 19 samples. Staphylococcus species were the most common bacteria isolated. The most common fungal isolates were Aspergillus species. Two cultures were positive with Candida albicans. The results show that decontamination of the otoscope heads is usually ignored. However, they can harbor considerable amount of pathogenic microorganisms. The probability of contamination and the risk of cross-infection is high if they are used by otolaryngologists. In order to prevent cross-contamination between patients, guidelines indicating appropriate methods and frequency of cleaning and disinfection of otoscope heads needed to be described. PMID- 23644942 TI - Pathogen-driven adaptive evolution of myxovirus resistance (Mx) genes in fishes. AB - Myxovirus resistance (Mx) proteins, which belong to the dynamin super-family, are known to inhibit RNA viral replication in a wide range of taxonomic groups, including fishes. Given their crucial role in host immune defense, the key amino acid residues in the GTP effector domain (GED) near the C-terminus are expected to evolve adaptively in order to protect the host against invading viral pathogens. The present study reveals the role of recombination and positive selection in the evolution of Mx proteins in fishes. While the GTP-binding domain in the N-terminal domain has experienced purifying selection, several amino acid residues in GED have evolved under positive selection, thus indicating adaptive evolution. Given the antiviral activity of GED, the adaptive evolutionary changes that were observed in this region are therefore predicted to be pathogen-driven. PMID- 23644943 TI - Influence of matrix metalloproteinase-1 gene -1607 (1G/2G) (rs1799750) promoter polymorphism on circulating levels of MMP-1 in chronic pancreatitis. AB - This study investigated the role of -1607 (1G/2G) (rs1799750) polymorphism of the MMP-1 gene in chronic pancreatitis. We genotyped 100 patients with chronic pancreatitis and 100 control subjects using tetra-primer ARMS-PCR followed by agarose gel electrophoresis. Serum levels of MMP-1 were determined by Elisa. Statistical analysis was applied to test the significance of the results. The genotypic and allelic distribution varied significantly between the disease group and the control subjects [OD = 1.981 (1.236-3.181), p = 0.004]. MMP-1 levels were higher in subjects homozygous for the 2G allele than in subjects with the 1G allele. The present study revealed a significant association of the MMP-1 -1607 1G/2G (rs1799750) gene promoter polymorphism with chronic pancreatitis, and it can be considered a biological marker in the etiology of chronic pancreatitis. PMID- 23644944 TI - Opine dehydrogenases in marine invertebrates. AB - It is well known today that opine production anaerobic pathways are analogs to the classical glycolytic pathway (lactate production pathway). These pathways, catalyzed by a group of enzymes called opine dehydrogenases (OpDHs), ensure continuous flux of glycolysis and a constant supply of ATP by maintaining the NADH/NAD(+) ratio during exercise and hypoxia, thus regulating the cytosolic redox balance in glycolysis under anoxia. OpDHs are distributed in a wide range of marine invertebrate phyla, including sponges (Porifera). Phylogenetic analyses supported with enzymatic assays strongly indicate that sponge OpDHs constitute an enzyme class unrelated to other OpDHs. Therefore, OpDHs in marine invertebrates are divided into two groups, a mollusk/annelid type and a sponge type, which belongs to the OCD/mu-crystallin family. PMID- 23644945 TI - Preparation and characterization of magnetic Fe3O 4/CNT nanoparticles by RPO method to enhance the efficient removal of Cr(VI). AB - This work described a novel method for the synthesis of high-ferromagnetism nanoparticles (Fe3O4/CNTs) to efficiently remove Cr(VI) from aqueous solution. The Fe3O4/carbon nanotubes (CNTs) were prepared by in situ reduction with post oxidation method by using cheap and environmentally friendly precursor under mild condition. Magnetic hysteresis loops revealed that Fe3O4/CNTs had superior saturation magnetization (152 emu/g), enabling the highly efficient recovery of Fe3O4/CNTs from aqueous solution by magnetic separation at low magnetic field gradients. FTIR, Raman, XPS, and TEM observations were employed to characterize the physical-chemical properties of Fe3O4/CNTs, demonstrating that CNTs were successfully coated with iron oxide matrix. The adsorption equilibrium of Cr(VI) on Fe3O4/CNTs was reached within 30 min. Langmuir, Freundlich, and Dubinin Radushkevich isotherm were chosen to analyze the equilibrium data. The results indicated that Langmuir model can well describe the equilibrium data with the maximum adsorption capacity of 47.98 mg/g at room temperature and 83.54 mg/g at 353 K. The adsorption capacity of Fe3O4/CNTs for Cr(VI) was greatly improved as compared to raw CNTs and other similar adsorbents reported. The pseudo-second order kinetic model provided the best description of Cr(VI) adsorption on Fe3O4/CNTs. Most importantly, possible synthesis mechanism and Cr(VI) removal mechanism were explored. The results suggest that large amounts of Cr(VI) were adsorbed on Fe3O4/CNTs surface by substituting the surface position of -OH and then reducing it to Cr(OH)3 and Cr2O3. PMID- 23644947 TI - Concentrations and source apportionment of PM10 and associated elemental and ionic species in a lignite-burning power generation area of southern Greece. AB - Ambient concentrations of PM10 and associated elemental and ionic species were measured over the cold and the warm months of 2010 at an urban and two rural sites located in the lignite-fired power generation area of Megalopolis in Peloponnese, southern Greece. The PM10 concentrations at the urban site (44.2 +/- 33.6 MUg m(-3)) were significantly higher than those at the rural sites (23.7 +/- 20.4 and 22.7 +/- 26.9 MUg m(-3)). Source apportionment of PM10 and associated components was accomplished by an advanced computational procedure, the robotic chemical mass balance model (RCMB), using chemical profiles for a variety of local fugitive dust sources (power plant fly ash, flue gas desulfurization wet ash, feeding lignite, infertile material from the opencast mines, paved and unpaved road dusts, soil), which were resuspended and sampled through a PM10 inlet onto filters and then chemically analyzed, as well as of other common sources such as vehicular traffic, residential oil combustion, biomass burning, uncontrolled waste burning, marine aerosol, and secondary aerosol formation. Geological dusts (road/soil dust) were found to be major PM10 contributors in both the cold and warm periods of the year, with average annual contribution of 32.6 % at the urban site vs. 22.0 and 29.0 % at the rural sites. Secondary aerosol also appeared to be a significant source, contributing 22.1 % at the urban site in comparison to 30.6 and 28.7 % at the rural sites. At all sites, the contribution of biomass burning was most significant in winter (28.2 % at the urban site vs. 14.6 and 24.6 % at the rural sites), whereas vehicular exhaust contribution appeared to be important mostly in the summer (21.9 % at the urban site vs. 11.5 and 10.5 % at the rural sites). The highest contribution of fly ash (33.2 %) was found at the rural site located to the north of the power plants during wintertime, when winds are favorable. In the warm period, the highest contribution of fly ash was found at the rural site located to the south of the power plants, although it was less important (7.2 %). Moderate contributions of fly ash were found at the urban site (5.4 and 2.7 % in the cold and the warm period, respectively). Finally, the mine field was identified as a minor PM10 source, occasionally contributing with lignite dust and/or deposited wet ash dust under dry summer conditions, with the summertime contributions ranging between 3.1 and 11.0 % among the three sites. The non-parametric bootstrapped potential source contribution function analysis was further applied to localize the regions of sources apportioned by the RCMB. For the majority of sources, source regions appeared as being located within short distances from the sampling sites (within the Peloponnesse Peninsula). More distant Greek areas of the NNE sector also appeared to be source regions for traffic emissions and secondary calcium sulfate dust. PMID- 23644946 TI - Dietary antioxidants (selenium and N-acetylcysteine) modulate paraoxonase 1 (PON1) in PCB 126-exposed rats. AB - Environmental pollutants polychlorinated biphenyls (PCBs), especially dioxin-like PCBs, cause oxidative stress and associated toxic effects, including cancer and possibly atherosclerosis. We previously reported that PCB 126, the most potent dioxin-like PCB congener, not only decreases antioxidants such as hepatic selenium (Se), Se-dependent glutathione peroxidase, and glutathione (GSH) but also increases levels of the antiatherosclerosis enzyme paraoxonase 1 (PON1) in liver and serum. To probe the interconnection of these three antioxidant systems, Se, GSH, and PON1, we examined the influence of varying levels of dietary Se and N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS) and precursor for GSH synthesis, on PON1 in the absence and presence of PCB 126 exposure. Male Sprague-Dawley rats, fed diets with differing Se levels (0.02, 0.2, or 2 ppm) or NAC (1%), were treated with a single intraperitoneal injection of corn oil or various doses of PCB 126 and euthanized 2 weeks later. PCB 126 significantly increased liver PON1 mRNA, protein level and activity, and serum PON1 activity in all dietary groups but did not consistently increase thiobarbituric acid levels (thiobarbituric acid reactive substances, TBARS), an indicator of lipid oxidation and oxidative stress, in liver or serum. Inadequate (high or low) dietary Se decreased baseline and PCB 126-induced aryl hydrocarbon receptor (AhR) expression but further increased PCB 126-induced cytochrome P450 1A1 (CYP1A1) expression, the enzyme believed to be the cause for PCB 126-induced oxidative stress. In addition, a significant inverse relationship was observed not only between dietary Se levels and PON1 mRNA and PON1 activity but also with TBARS levels in the liver, suggesting significant antioxidant protection from dietary Se. NAC lowered serum baseline TBARS levels in controls and increased serum PON1 activity but lowered liver PON1 activities in animals treated with 1 MUmol/kg PCB 126, suggesting antioxidant activity by NAC primarily in serum. These results also show an unexpected predominantly inverse relationship between Se or NAC and PON1 during control and PCB 126 exposure conditions. These interactions should be further explored in the development of dietary protection regimens. PMID- 23644948 TI - Bioaccumulation of perfluoroalkyl acids in dairy cows in a naturally contaminated environment. AB - Beef and dairy products may be important vectors of human exposure to perfluoroalkyl acids (PFAAs), but the understanding of how PFAAs are accumulated and transferred through agricultural food chains is very limited. Here, the bioaccumulation of PFAAs in dairy cows receiving naturally contaminated feed and drinking water was investigated by conducting a mass balance of PFAAs for a herd of dairy cows in a barn on a typical Swedish dairy farm. It was assumed that the cows were able to reach steady state with their dietary intake of PFAAs. Perfluorooctane sulfonic acid (PFOS) and perfluoroalkyl carboxylic acids (PFCAs) with 8 to 12 carbons were detected in cow tissue samples (liver, muscle, and blood) at concentrations up to 130 ng kg(-1). Mass balance calculations demonstrated an agreement between total intake and excretion within a factor of 1.5 and consumption of silage was identified as the dominant intake pathway for all PFAAs. Biomagnification factors (BMFs) were highly tissue and homologue specific. While BMFs of PFOS and PFCAs with 9 and 10 fluorinated carbons in liver ranged from 10 to 20, perfluorooctanoic acid (PFOA) was not biomagnified (BMF<1) in any of the investigated tissues. Biotransfer factors (BTFs; defined as the concentration in tissue divided by the total daily intake) were calculated for muscle and milk. Log BTFs ranged from -1.95 to -1.15 day kg(-1) with the highest BTF observed for PFOS in muscle. Overall, the results of this study suggest that long-chain PFAAs have a relatively high potential for transfer to milk and beef from the diet of dairy cows. However, a low input of PFAAs to terrestrial systems via atmospheric deposition and low bioavailability of PFAAs in soil limits the amount of PFAAs that enter terrestrial agricultural food chains in background contaminated environments and makes this pathway less important than aquatic exposure pathways. The BTFs estimated here provide a useful tool for predicting human exposure to PFAAs via milk and beef under different contamination scenarios. PMID- 23644950 TI - A comparison of the Cook single lumen immature ovum IVM needle to the Steiner-Tan pseudo double lumen flushing needle for oocyte retrieval for IVM. AB - PURPOSE: This study compared the impact of using the Steiner-Tan pseudo double lumen needle for antral follicle oocyte retrieval to using a conventional non flushing needle. The Steiner-Tan needle has a much smaller dead space than the needles commonly used for IVM oocyte retrievals. METHODS: This was a retrospective cohort study. The patient population was determined by the time period in which a patient underwent IVM in a single physician's IVF practice. The following data was abstracted from clinical and embryology records: oocytes retrieved, oocytes matured, early maturing oocytes, oocytes fertilized, embryo quality measures, retrieval time, needle punctures, clot formation, and clinical pregnancy rate. RESULTS: The Steiner-Tan needle did not increase the number of oocytes retrieved. It also did not increase the time required for retrieval. However, flushing of antral follicles significantly decreased clot formation in fluid aspirates. Use of the Steiner-Tan needle also significantly decreased the number of vaginal needle punctures during each case. There was a trend toward improved embryo quality, but statistical power was inadequate to show a difference. CONCLUSIONS: The primary benefit of the Steiner-Tan needle was on the embryological aspects of IVM. Decreased blood and blood clots in the aspirates made an IVM retrieval more like conventional IVF for the embryologist. The patient also experienced less tissue trauma without increasing anesthesia or surgical time. There was no improvement in the number of oocytes retrieved, but based on the results, we hypothesized that oocytes were more commonly retrieved from slightly large follicles than when using a routine needle. PMID- 23644951 TI - Where's the evidence? PMID- 23644952 TI - Parents' experience of support in Sweden: its availability, accessibility, and quality. AB - Semi-structured interviews were conducted with six parents of children with intellectual disabilities, in the Western region of Sweden. The aim of the study was to explore and to gain a deeper understanding of parents' experiences of received support for them and their children with intellectual disabilities. We focused particularly on their experiences of the availability, accessibility, and the quality of services. Parents in this study were unsure about what the diagnosis meant specifically for their child as well as for their whole family. Moreover, the parents experienced great difficulty in obtaining information about available services, which resulted in feelings of helplessness to some. Parents also reported that although services are available, they were not easily accessible. Lastly, parents felt that the quality of care and support were to some extent inadequate, as no attention was paid by professionals to their actual needs or wishes. PMID- 23644953 TI - Tackling stigma associated with intellectual disability among the general public: a study of two indirect contact interventions. AB - Although evidence abounds that people with intellectual disabilities are exposed to stigma and discrimination, few interventions have attempted to tackle stigma among the general public. This study set out to assess the impact of two brief indirect contact interventions on lay people's inclusion attitudes, social distance and positive behavioral intentions, and to explore emotional reactions towards the two interventions. 925 participants completed the first online survey. Participants were randomized to watch either a 10 min film based on intergroup contact theory, or a film based on a protest message. In total, 403 participants completed the follow-up survey at one month. Both interventions were effective at changing inclusion attitudes and social distance in the short term and these effects were partially maintained at one month. The protest based intervention had a greater effect compared to the contact one on aspects of inclusion attitudes and evoked stronger emotional reactions. Despite small effect sizes, brief indirect contact interventions may have a potential role in tackling public stigma associated with intellectual disability but their effects on behavioral intentions are questionable. PMID- 23644955 TI - Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life. AB - OBJECTIVES: Despite the fact that food and diet are central issues, that concern patients with irritable bowel syndrome (IBS), the current understanding about the association between the intake of certain foods/food groups and the gastrointestinal (GI) symptom pattern, psychological symptoms, and quality of life is poor. The aim of this study was to determine which food groups and specific food items IBS patients report causing GI symptoms, and to investigate the association with GI and psychological symptoms and quality of life. METHODS: We included 197 IBS patients (mean age 35 (18-72) years; 142 female subjects) who completed a food questionnaire in which they specified symptoms from 56 different food items or food groups relevant to food intolerance/allergy. The patients also completed questionnaires to assess depression and general anxiety (Hospital Anxiety and Depression), GI-specific anxiety (Visceral Sensitivity Index), IBS symptoms (IBS-Severity Scoring System), somatic symptoms (Patient Health Questionnaire-15), and quality of life (Irritable Bowel Syndrome Quality of Life Questionnaire). RESULTS: In all, 84% of the studied population reported symptoms related to at least one of the food items surveyed. Symptoms related to intake of food items with incompletely absorbed carbohydrates were noted in 138 (70%) patients; the most common were dairy products (49%), beans/lentils (36%), apple (28%), flour (24%), and plum (23%). Of these, 58% experienced GI symptoms from foods rich in biogenic amines, such as wine/beer (31%), salami (22%), and cheese (20%). Histamine-releasing foods, such as milk (43%), wine/beer (31%), and pork (21%), were also considered causes of symptoms in IBS patients. GI symptoms were also frequently reported after intake of fried and fatty foods (52%). With increasing IBS symptom severity, patients reported more food items responsible for their GI symptoms (P=0.004), and this was also found in patients with more severe somatic symptoms (P<0.0001). Women tended to report more food items causing symptoms than men (P=0.06). A high number of food items causing GI symptoms was also associated with reduced quality of life and this was significant for the following domains: sleep (r=-0.25; P=0.001), energy (r=-0.21; P=0.005), food (r=-0.29; P<0.001), social functioning (r=-0.23; P=0.001), and physical status (r=-0.16; P<0.05). However, the number of food items reported to provoke GI symptoms was unrelated to body mass index, age, IBS subtype, anxiety, depression, or GI-specific anxiety. CONCLUSIONS: The majority of IBS patients believe that certain food items are important triggers of their GI symptoms. This is especially true for foods containing carbohydrates and fat, and also may be relevant for histamine-releasing food items and foods rich in biogenic amines. Self-reported food intolerance is associated with high symptom burden and reduced quality of life. PMID- 23644956 TI - What gastroenterologists should know about the gray market, herbal remedies, and compounded pharmaceuticals and their regulation by the Food and Drug Administration. PMID- 23644958 TI - Images of the month: Hypertriglyceridemia causing acute pancreatitis. PMID- 23644957 TI - Villous atrophy and negative celiac serology: a diagnostic and therapeutic dilemma. AB - OBJECTIVES: Patients with villous atrophy (VA) and negative celiac disease (CD) serologies pose a diagnostic and therapeutic dilemma. When a definitive etiology for VA is not determined, patients are characterized as having unclassified sprue (US), the optimal management of which is unknown. METHODS: We studied adult patients with VA on biopsy and negative celiac serologies, evaluated at our tertiary referral center over a 10-year period. Testing for HLA DQ2/8 alleles, antienterocyte antibodies, giardia stool antigen, bacterial overgrowth, total serum immunoglobulins, and HIV was noted. Treatment, response, and repeat-biopsy findings were recorded. RESULTS: The most common diagnoses of the 72 patients were seronegative CD, medication-related villous atrophy, and US. Of those with US, the majority reported symptomatic improvement with immunosuppressive therapy. Some patients initially labeled as unclassified were found to have VA associated with olmesartan use. CONCLUSIONS: The role of medications in the development of VA and the optimal dose and length of immunosuppression for patients with US should be investigated further. PMID- 23644963 TI - Functional (non-ulcer) dyspepsia and gastroesophageal reflux disease: one not two diseases? AB - Functional dyspepsia is a very common, distressful, and costly condition. New data indicate that heartburn and regurgitation occur frequently in functional dyspepsia, even after objective gastroesophageal reflux disease has been exhaustively excluded by appropriate testing. Arbitrarily excluding heartburn in functional dyspepsia studies appears misguided. PMID- 23644964 TI - An altered gut microbiome profile in a child affected by Crohn's disease normalized after nutritional therapy. PMID- 23644965 TI - Response to Shaikh et al. PMID- 23644966 TI - Variable use of sedation during colonoscopy and impact on outcome. PMID- 23644967 TI - When cure becomes worse than the disease. PMID- 23644968 TI - An electrocardiograph should be examined in patients with a hypersensitive esophagus before a trial of citalopram. PMID- 23644969 TI - Successful use of thalidomide for refractory esophageal Crohn's disease. PMID- 23644970 TI - Successful use of infliximab in the treatment of corticosteroid dependent collagenous colitis. PMID- 23644971 TI - Fosfomycin-containing second-line treatment for Helicobacter pylori infection. PMID- 23644972 TI - Disease-modifying anti-inflammatory bowel disease drugs (DMAIDs): the missing term in the literature. PMID- 23644973 TI - Segmented filamentous bacteria-like organisms in histological slides of ileo cecal valves in patients with ulcerative colitis. PMID- 23644975 TI - Characterisation of phenolic compounds in South African plum fruits (Prunus salicina Lindl.) using HPLC coupled with diode-array, fluorescence, mass spectrometry and on-line antioxidant detection. AB - Phenolic compounds are abundant secondary metabolites in plums, with potential health benefits believed to be due to their antioxidant activity, amongst others. Phenolic characterisation of South African Prunus salicina Lindl. plums is necessary to fully evaluate their potential health benefits. An HPLC method using diode-array detection (DAD) for quantification of phenolic compounds was improved and fluorescence detection (FLD) was added for quantification of flavan-3-ols. Validation of the HPLC-DAD-FLD method showed its suitability for quantification of 18 phenolic compounds, including flavan-3-ols using FLD, and phenolic acids, anthocyanins and flavonols using DAD. The method was suitable for characterisation of the phenolic composition of 11 South African plum cultivars and selections, including various types with yellow and red skin and flesh. The method was used in conjunction with mass spectrometry (MS) to identify 24 phenolic compounds. Neochlorogenic acid and cyanidin-3-O-glucoside were the major compounds in most of the plums, while cyanidin-3-O-glucoside was absent in Sun Breeze plums with yellow skin and flesh. Post-column on-line coupling of the ABTS*+ scavenging assay with HPLC-DAD enabled qualitative evaluation of the relative contribution of individual phenolic compounds to the antioxidant activity. The flavan-3-ols, neochlorogenic acid and cyanidin-3-O-glucoside displayed the largest antioxidant response peaks. PMID- 23644976 TI - Potential energy surfaces and quantum yields for photochromic diarylethene reactions. AB - Photochromic diarylethenes (DAEs) are among the most promising molecular switching systems for future molecular electronics. Numerous derivatives have been synthesized recently, and experimental quantum yields (QYs) have been reported for two categories of them. Although the QY is one of the most important properties in various applications, it is also the most difficult property to predict before a molecule is actually synthesized. We have previously reported preliminary theoretical studies on what determines the QYs in both categories of DAE derivatives. Here, reflecting theoretical analyses of potential energy surfaces and recent experimental results, a rational explanation of the general guiding principle for QY design is presented for future molecular design. PMID- 23644977 TI - C-5 hydroxyethyl and hydroxypropyl acyclonucleosides as substrates for thymidine kinase of herpes simplex virus type 1 (HSV-1 TK): syntheses and biological evaluation. AB - The efficient syntheses of 5-(2-hydroxyethyl)- and 5-(3-hydroxypropyl) substituted pyrimidine derivatives bearing 2,3-dihydroxypropyl, acyclovir-, ganciclovir- and penciclovir-like side chains are reported. A synthetic approach that included the alkylation of an N-anionic-5-substituted pyrimidine intermediate (method A) provided the target acyclonucleosides in significantly higher overall yields in comparison to those obtained by method B using sylilation reaction. The phosphorylation assays of novel compounds as potential substrates for thymidine kinase of herpes simplex virus type 1 (HSV-1 TK) showed that solely pyrimidine 5-substituted acyclonucleosides with a penciclovir-like side chain acted as a fraudulent substrates of HSV-1 TK. Moreover, the uracil derivative with penciclovir-like side chain with less bulky 2-hydroxyethyl substituent at C-5 proved to be a better substrate than the corresponding one with a 3-hydroxypropyl substituent. Therefore, this acyclonucleoside was selected as a lead compound for the development of a positron emission tomography HSV-1 TK activity imaging agent. PMID- 23644978 TI - Herb-herb combination for therapeutic enhancement and advancement: theory, practice and future perspectives. AB - Herb-herb combinations have been used in Chinese medicine practice for thousands of years, yet scientific evidence of their therapeutic benefits is lacking. With increasing interest in shifting from the one-drug-one-target paradigm to combination therapy or polypharmacy to achieve therapeutic benefits for a number of diseases, there is momentum to explore new knowledge by tapping the past empirical experiences of herb-herb combinations. This review presents an overview of the traditional concept and practice of herb-herb combination in Chinese medicine, and highlights the available scientific and clinical evidence to support the combined use of herbs. It is hoped that such information would provide a lead for developing new approaches for future therapeutic advancement and pharmaceutical product development. Very likely modern technologies combined with innovative research for the quality control of herbal products, identification of active components and understanding of the molecular mechanism, followed by well-designed animal and clinical studies would pave the way in advancing the wealth of empirical knowledge from herb-herb combination to new therapeutic modalities. PMID- 23644979 TI - A facile synthesis of functionalized dispirooxindole derivatives via a three component 1,3-dipolar cycloaddition reaction. AB - An efficient synthesis of novel dispirooxindoles has been achieved through three component 1,3-dipolar cycloaddition of azomethine ylides generated in situ by the decarboxylative condensation of isatin and an alpha-amino acid with the dipolarophile 5-benzylideneimidazolidine-2,4-dione. The improved procedure features mild reaction conditions, high yields, high diastereoselectivities, a one-pot procedure and operational simplicity. PMID- 23644980 TI - Measuring nanoparticle flow with the image structure function. AB - We present a technique to measure the velocity and flow profiles of a nanofluid in a microfluidic channel. Importantly, we extract the flow velocity from a series of standard brightfield images without employing particle tracking or laser-enhanced methods. Our analysis retrieves the flow information from the image structure function of sub-diffraction limited nanoparticles in suspension. We are able to spatially resolve the flow velocity and map out the parabolic flow profile across the width of a microfluidic channel. PMID- 23644981 TI - R gene expression changes related to Cercospora hydrangeae L. AB - Nursery growing as well as common landscape hydrangeas are all susceptible to leaf spot fungus Cercospora hydrangeae. Warm and rainy weather causes the fungal spores to germinate quickly and spread over the plant leaves forming small purple or brown spots. Although Hydrangea plants are not killed by leaf spot, it detracts from the value of plants through the reduction of flowering and plant vigor. The aim of our study was to isolate, characterize and investigate the expression profile of Hydrangea macrophylla resistance (R) gene transcripts under C. hydrangeae fungus infection and examine their evolutionary relationships by phylogenetic analysis. R-genes are thought to be one of the components of the genetic resistance in plants and most of them encode nucleotide binding site leucine rich repeat (NBS-LRR) proteins. A cDNA-NBS strategy was carried out using as template cDNAs isolated from control and infected plant leaves. The cDNA-NBS profiling gave an excellent bands reproducibility. Twenty new transcripts corresponding to NBS-LRR proteins were identified only in infected plants. The extent of positivity between the aminoacid sequences at NBS region varied from 45 to 90 %, which indicates the diversity among the RGAs. The results of this paper will provide a genomic framework for the further isolation of candidate disease resistance NBS-encoding genes in Hortensia, and contribute to the understanding of the evolutionary mode of NBS-encoding genes in Hydrangeaceae crops. PMID- 23644982 TI - Cloning and characterization of GPAT gene from Lepidium latifolium L.: a step towards translational research in agri-genomics for food and fuel. AB - Glycerol-3-phosphate acyltransferase (GPAT) catalyzes first and the rate limiting step in glycerolipid synthesis pathway, which in turn contribute to stabilization of plasma membrane structure and oil lipid synthesis in plant cells. Here, we report cloning and characterization of GPAT gene from Lepidium latifolium (LlaGPAT). The cDNA sequence (1,615 bp) of LlaGPAT gene consisted of 1,113 bp ORF encoding a protein of 370 aa residues, with deduced mass of 41.2 kDa and four acyltransferase (AT) motifs having role in catalysis and in glycerol-3-phosphate binding. Southern blot analysis suggested presence of a single copy of the gene in the genome. Tissue specific expression of the gene was seen more abundantly in aerial parts, compared to the roots. Quantitative real-time PCR indicated down regulation of the gene by cold (4 degrees C), drought (PEG6000), salt (300 mM NaCl) and ABA (100 MUM) treatments. Considering the vitality of the function of encoded enzyme, LlaGPAT can be considered a potential candidate gene for genetic engineering of oil yields and abiotic stress management in food as well as fuel crops. PMID- 23644983 TI - The phenylalanine ammonia-lyase gene family in Salvia miltiorrhiza: genome-wide characterization, molecular cloning and expression analysis. AB - Salvia miltiorrhiza Bunge is a well-known material of traditional Chinese medicine. Hydrophilic phenolic acids, such as rosmarinic acid and salvianolic acid B, are a group of pharmaceutically important compounds in S. miltiorrhiza. The biosynthesis of rosmarinic acid requires the coordination of the phenylpropanoid pathway and the tyrosine-derived pathway. Phenylalanine ammonia lyase (PAL) is the first key enzyme of the phenylpropanoid pathway. Systematic analysis of the SmPAL gene family has not been carried out. We report here the identification of three SmPALs through searching the recently obtained working draft of the S. miltiorrhiza genome and full-length cDNA cloning. Bioinformatic and phylogenetic analyses showed that SmPAL1 and SmPAL3 clustered in a sub-clade of dicot PALs, whereas SmPAL2 fell into the other one. Some important cis elements were conserved in three SmPAL promoters, whereas the others were not. SmPAL1 and SmPAL3 were highly expressed in roots and leaves of S. miltiorrhiza, but SmPAL2 were predominately expressed in stems and flowers. It indicates that SmPAL1 and SmPAL3 function redundantly in rosmarinic acid biosynthesis. All SmPALs were induced in roots treated with PEG and MeJA, but the time and degree of responses were different, suggesting the complexity of SmPAL-associated metabolic network in S. miltiorrhiza. This is the first comprehensive study dedicated to SmPAL gene family characterization. The results provide a basis for elucidating the role of SmPAL genes in the biosynthesis of bioactive compounds. PMID- 23644984 TI - The effects of Nanos2 on Boule and Stra8 in male germline stem cells (mGSCs). AB - The mitosis-meiosis switch is a key event in the differentiation of germ cells. Meiosis is important in development biology, however, it has not been clear what is the regulation mechanism in mammals. Our previous study showed that Boule could activate Stra8 directly and result in the meiosis initiation of dairy goat male germline stem cells (mGSCs). Nanos2, a RNA-binding protein, plays critical roles in the suppression of meiosis by preventing Stra8 expression and maintain the male germ cell development. The main purpose of this study was to explore whether Nanos2 represses Stra8 transcription through Boule or not. We found ectopic over-expression of Nanos2 in GC-1 and mGSCs down-regulated Stra8 transcription and translation, and Boule expression was not affected. It was in consistent with our expectation that RA could up-regulate Boule and Stra8 expression, but down-regulate Nanos2 expression in mGSCs. In dairy goat, the expression levels of Boule and Stra8 would rise with the increase of age, but the expression level of Nanos2 in 90 dpp and adult testis had not shown a clear change. In conclusion, Nanos2 represses Stra8 expression but not through Boule in dairy goat mGSCs. PMID- 23644985 TI - The development of 10 novel polymorphic microsatellite markers through next generation sequencing and a preliminary population genetic analysis for the endangered Glenelg spiny crayfish, Euastacus bispinosus. AB - The Glenelg spiny crayfish, Euastacus bispinosus, is an iconic freshwater invertebrate of south eastern Australia and listed as 'endangered' under the Environment Protection and Biodiversity Conservation Act 1999, and 'vulnerable' under the International Union for Conservation of Nature's Red List. The species has suffered major population declines as a result of over-fishing, low environmental flows, the introduction of invasive fish species and habitat degradation. In order to develop an effective conservation strategy, patterns of gene flow, genetic structure and genetic diversity across the species distribution need to be clearly understood. In this study we develop a suite of polymorphic microsatellite markers by next generation sequencing. A total of 15 polymorphic loci were identified and 10 characterized using 22 individuals from the lower Glenelg River. We observed low to moderate genetic variation across most loci (mean number of alleles per locus = 2.80; mean expected heterozygosity = 0.36) with no evidence of individual loci deviating significantly from Hardy Weinberg equilibrium. Marker independence was confirmed with tests for linkage disequilibrium, and analyses indicated no evidence of null alleles across loci. Individuals from two additional sites (Crawford River, Victoria; Ewens Ponds Conservation Park, South Australia) were genotyped at all 10 loci and a preliminary investigation of genetic diversity and population structure was undertaken. Analyses indicate high levels of genetic differentiation among sample locations (F ST = 0.49), while the Ewens Ponds population is genetically homogeneous, indicating a likely small founder group and ongoing inbreeding. Management actions will be needed to restore genetic diversity in this and possibly other at risk populations. These markers will provide a valuable resource for future population genetic assessments so that an effective framework can be developed for implementing conservation strategies for E. bispinosus. PMID- 23644986 TI - Genetic polymorphisms of vascular endothelial growth factor and risk for retinopathy of prematurity in South of Iran. AB - Retinopathy of prematurity (ROP) is a multifactorial disease, that cause visual impairment in premature children. The exact pathogenesis and etiology of ROP is unknown and genetic susceptibility is considered as risk factor. Vascular endothelial growth factor (VEGF) plays a major role in retinal neovascularization and subsequently retinal detachment. VEGF polymorphism is associated with proliferative ROP in some studies. We examined the possible association of the VEGF gene polymorphisms with ROP in preterm infants in south of Iran. A total of 111 preterm infants were examined by ophthalmologist and after that were genotyped. Genotyping of the VEGF +405 (rs2010963) and VEGF +936 (rs3025039) was done by the polymerase chain reaction and restriction fragment length polymorphism methods. The frequency of VEGF alleles, genotypes and haplotype distribution were compared between groups. The patients were divided in three groups: 66 to the normal group (normal fundoscopy), and 45 to the ROP group; 30 infants were not treated with Lasertherapy (Regressive group) and 15 treated with Lasertherapy. The frequency of VEGF +405 and VEGF +936 G/C genotypes as well as allele frequencies was not different between groups. No significant difference was found between ROP with treatment and ROP without lasertherapy. Our report indicate that there is no association between the carrier states of gene polymorphisms VEGF +405, VEGF +936 and progression or spontaneous regression of ROP in preterm infants in Iranian population. However, it should be considered that angiogenesis is a complex process and genetic factors in addition to environmental factors are contributed in this pathway. PMID- 23644987 TI - Effects of single and combined genotypes of MC4R and POU1F1 genes on two production traits in Langshan chicken. AB - The objective of this study was to analyze the effects of single and combined genotypes of MC4R and POU1F1 genes in Chinese well-known indigenous chicken (Langshan chicken) population. Genetic variants within MC4R gene and POU1F1 gene were screened through PCR-SSCP and DNA sequencing methods. A C/T mutation at nt 944 in MC4R gene (NC_006089.2:g. 944C>T) and a G/A mutation at nt 3109 in POU1F1 gene (NC_006088.2:g. 3109 G>A) were identified. Associations between the mutations of the two genes with two production traits were analyzed. The results showed that, at MC4R locus, individuals with BB and AB genotypes had highly significantly higher body weight at 16 weeks (p < 0.01) than did those with the AA genotype. And, individuals within AA and AB genotypes had significantly higher egg numbers at 300 days (p < 0.05). At POU1F1 locus, individuals with CD genotype had higher body weight at 16 weeks and egg numbers at 300 days (p < 0.05). Furthermore, combined genotypes from these two loci were found to be associated with egg numbers at 300 days (p < 0.05). The individuals within combined genotype AB/CD had higher egg production. Therefore, variations identified within the MC4R and POU1F1genes are suitable for future use in identifying chickens with the genetic potential of higher body weight and reproductive traits, at least in the population of Langshan chickens. PMID- 23644988 TI - Exercise mitigates cardiac doxorubicin accumulation and preserves function in the rat. AB - PURPOSE: Doxorubicin (DOX) is an effective antineoplastic agent with well characterized cardiotoxic effects. Although exercise has been shown to protect against DOX cardiotoxicity, a clear and concise mechanism to explain its cardioprotective effects is lacking. The purpose of this study was to determine if exercise training reduces cardiac DOX accumulation, thereby providing a possible mechanism to explain the cardioprotective effects of exercise against DOX toxicity. METHODS: Sprague-Dawley rats were randomly assigned to 1 of 3 primary experimental groups: sedentary (n = 77), wheel running (n = 65), or treadmill (n = 65). Animals in wheel running and treadmill groups completed 10 weeks of exercise before DOX treatment. DOX was administered 24 hours after the last training session as a bolus intraperitoneal injection at 10 mg/kg. Subgroups of rats from each primary group were killed at 1, 3, 5, 7, and 9 days after DOX exposure to assess cardiac function and DOX accumulation. RESULTS: Ten weeks of exercise preconditioning reduced myocardial DOX accumulation, and this reduction in accumulation was associated with preserved cardiac function. CONCLUSIONS: These data suggest that the cardioprotective effects of exercise against DOX induced injury may be due, in part, to a reduction in myocardial DOX accumulation. PMID- 23644989 TI - NGF promotes hemodynamic recovery in a rabbit hindlimb ischemic model through trkA- and VEGFR2-dependent pathways. AB - Nerve growth factor (NGF) has been reported to play an important role in physiological and pathological angiogenesis. Based on these observations, we hypothesized that NGF may induce the formation of functional blood vessels in a hindlimb ischemic rabbit model. Hindlimb ischemia was induced in 34 rabbits bilaterally by endovascular embolization of femoral arteries. On the 7th, 14th, and 20th postembolization days, NGF was injected intramuscularly, in 1 ischemic limb, and vehicle was injected in the contralateral control limb. On the 40th day, newly developed collateral vessels (diameter >500 MUm) were quantified by transauricular intraarterial subtraction angiography. Perfusion analysis of an in vivo dynamic computed tomography study was performed to the limbs to investigate the hemodynamic recovery of the distal ischemic tissues. Functional estimation of limb perfusion showed a statistically significant increase of blood flow and blood volume for NGF. However, the increase of the collateral vessels was not detectable angiographically, providing evidence for the existence of a NGF stimulated capillary angiogenic network but not increase of arteriogenesis. The combination of NGF with either tropomyosin-related kinase type A or vascular endothelial growth factor receptor 2 antagonists abolished the NGF-induced hemodynamic recovery. These findings provide new insights into understanding the involvement of NGF in vascular formation and its applications in therapeutic angiogenesis. PMID- 23644990 TI - Nanoscale, electric field-driven water bridges in vacuum gaps and lipid bilayers. AB - Formation of a water bridge across the lipid bilayer is the first stage of pore formation in molecular dynamic (MD) simulations of electroporation, suggesting that the intrusion of individual water molecules into the membrane interior is the initiation event in a sequence that leads to the formation of a conductive membrane pore. To delineate more clearly the role of water in membrane permeabilization, we conducted extensive MD simulations of water bridge formation, stabilization, and collapse in palmitoyloleoylphosphatidylcholine bilayers and in water-vacuum-water systems, in which two groups of water molecules are separated by a 2.8 nm vacuum gap, a simple analog of a phospholipid bilayer. Certain features, such as the exponential decrease in water bridge initiation time with increased external electric field, are similar in both systems. Other features, such as the relationship between water bridge lifetime and the diameter of the water bridge, are quite different between the two systems. Data such as these contribute to a better and more quantitative understanding of the relative roles of water and lipid in membrane electropore creation and annihilation, facilitating a mechanism-driven development of electroporation protocols. These methods can be extended to more complex, heterogeneous systems that include membrane proteins and intracellular and extracellular membrane attachments, leading to more accurate models of living cells in electric fields. PMID- 23644991 TI - Correlation between composition of the outer layer and phase asymmetry for vesicles ruptured by phospholipase D. AB - Spherical phospholipid bilayers, vesicles, were prepared by using the layer-by layer double emulsion technique, which allows individual layers to be formed asymmetrically. Phases of the layers were adjusted by selecting the lipid tail group. The head group composition of the vesicle outer layer varied 0-100 % of phosphatidylcholine (PC) by 10 % under the condition that the diameter of the vesicle was kept constant. On the outer layer of the vesicle, the phospholipase D (PLD) reacted to convert PC to phosphatidic acid. The reaction induced a curvature change of the vesicles, which eventually led them to rupture. Response time from the PLD injection to the rupture was measured against the different compositions of the outer layer at each phase (solid and liquid) using the fluorescence intensity change of pH-sensitive dye encapsulated in the vesicles. From this measurement, the rupture caused by the PLD reaction was analyzed with respect to the phase asymmetry of the layers and the composition of the outer layer. These results were interpreted with the lipid density and stability of the layers. It was observed that the solid phase of the outer layer had a variance in response time according to the phase of the inner layer, whereas the liquid phase did not. Additionally, the response of the solid phase of the outer layer at the liquid phase of the inner layer was faster than at the solid phase of the inner layer as a result of its stability. PMID- 23644992 TI - The efficacy of triplet antiemetic therapy with 0.75 mg of palonosetron for chemotherapy-induced nausea and vomiting in lung cancer patients receiving highly emetogenic chemotherapy. AB - BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are some of the most problematic symptoms for cancer patients. Triplet therapy consisting of a 5HT3 receptor antagonist, aprepitant, and dexamethasone is a guideline-recommended antiemetic prophylaxis for highly emetogenic chemotherapy (HEC). The efficacy and safety of triplet therapy using a 0.75-mg dose of palonosetron have not yet been investigated. We performed a prospective phase II study using triplet antiemetic therapy with 0.75 mg of palonosetron. METHODS: Chemotherapy-naive lung cancer patients scheduled to receive HEC were enrolled. The eligible patients were pretreated with antiemetic therapy consisting of the intravenous administration of 0.75 mg of palonosetron, and 9.9 mg of dexamethasone and the oral administration of 125 mg of aprepitant on day 1, followed by the oral administration of 80 mg of aprepitant on days 2-3 and the oral administration of 8 mg of dexamethasone on days 2-4. The primary endpoint was the complete response rate (the CR rate; no vomiting and no rescue medication) during the overall phase (0-120 h). RESULTS: The efficacy analysis was performed in 63 patients. The CR rates during the overall, acute and delayed phases were 81.0, 96.8, and 81.0%, respectively. The no nausea and no significant nausea rate during the overall phase were 54.0 and 66.7%, respectively. The most common adverse event was grade 1 or 2 constipation. CONCLUSIONS: Triplet antiemetic therapy using a 0.75-mg dose of palonosetron shows a promising antiemetic effect in preventing CINV in lung cancer patients receiving HEC. PMID- 23644994 TI - Long distance multiple-site directed plasmid mutagenesis by one-step PCR using non-overlapped primers. AB - Site-directed mutagenesis is a very important technique in molecular biological researches. We have developed a new method for long distance multiple-site plasmid mutation by one-step PCR using non-overlap primers. These primers were carefully designed and contained desired mutations in the middle of the primers flanked with 18-25 bp of correct sequence. One pair of the primers was able to generate a short megaprimer. Decreases in the concentrations of these primers increased efficiency of the multiple-site plasmid mutation. All of the mutant PCRs were performed at a common annealing temperature at 55 degrees C. This method could be widely used in all multiple-site plasmid mutations. PMID- 23644993 TI - The use of biomarkers in the patient with heart failure. AB - Heart failure is a major burden to the health care system in terms of not only cost, but also morbidity and mortality. Appropriate use of biomarkers is critically important to allow rapid identification and optimal risk stratification and management of patients with both acute and chronic heart failure. This review will discuss the biomarkers that have the most diagnostic, prognostic, and therapeutic value in patients with heart failure. We will discuss established biomarkers such as natriuretic peptides as well as emerging biomarkers reflective of myocyte stress, myocyte injury, extracellular matrix injury, and both neurohormonal and cardio-renal physiology. PMID- 23644996 TI - Management of persistent tracheoesophageal puncture. AB - Tracheoesophageal puncture with placement of a voice prosthesis (VP) provides successful speech rehabilitation after total laryngectomy. However, enlargement of the tracheoesophageal puncture is a challenging complication as it results in leakage around the VP into the airway and may eventually lead to aspiration pneumonia and respiratory complications. It necessitates removal of the VP and permanent closure of the tracheoesophageal fistula. We present our own experience for surgical closure of persistent tracheoesophageal puncture. A non-controlled prospective study was conducted at the Department of Oto-Rhino-Laryngology and Head and Neck Surgery, Zagazig University Hospitals, Zagazig, Egypt. This study included five patients with an enlarged tracheoesophageal puncture. They had persistent leakage around the VP with resulting recurrent chest infections. None of the patients underwent previous surgical intervention for closure of the tracheoesophageal fistula. This surgical technique involved identification and exposure of the tracheoesophageal fistula tract by blunt dissection and its ligation by non-resorbable sutures at two points close to the posterior wall of the trachea without dividing the fistula tract. The mean follow-up period was 14.4 months. Successful closure of the fistula was achieved in all patients (100%). All patients tolerated full diet well and had uneventful recovery and no further episodes of aspiration. This surgical technique is simple, easily feasible technically, and effective. It enables early oral feeding and allows a short hospital stay, thus increasing the patient's comfort. PMID- 23644997 TI - Decreased PLUNC expression in nasal polyps is associated with multibacterial colonization in chronic rhinosinusitis patients. AB - PLUNC (palate, lung, and nasal epithelium clone) is an epithelium-secreted protein that plays a crucial role in the host's defense against bacterial infection. The function of PLUNC in the sinus remains poorly understood. To examine whether the expression levels of PLUNC could serve as a predictive outcome biomarker for patients with CRSwNP and bacterial colonization, we investigated the association of PLUNC expression levels with bacterial colonization in the sinuses. A total of 174 patients who underwent sinus surgery for chronic rhinosinusitis with nasal polyps (CRSwNP) were enrolled in this study. The tissue samples obtained from patients were examined using preoperative sinus computed tomography (CT) scans, postoperative bacterial cultures, and nasal polyp examinations. PLUNC mRNA and protein expression were quantified using RT PCR and immunohistochemistry. We identified that decreased PLUNC expression is associated with multibacterial colonization (P = 0.0001), specifically those mediated by Staphyloccocus aureus (P = 0.037) and Pseudomonas aeruginosa (P = 0.002). The patients who required repeated sinus surgeries for recurrent or persistent sinusitis also presented much lower PLUNC expression than those who did not require repeated sinus surgery (P = 0.001). However, gender, age, and CT scores were not associated with PLUNC expression. These results suggest that reduced PLUNC expression is associated with bacterial colonization as well as treatment outcome in CRSwNP patients. Investigation of the association between PLUNC expressions and chronic rhinosinusitis may lead to the development of a novel biomarker for treatment outcome in CRSwNP patients. PMID- 23644998 TI - Effect of endoscopic marsupialization of paranasal sinus mucoceles involving the orbit: a review of 27 cases. AB - Paranasal sinus mucoceles (PSMs) can involve the orbit because the topographic anatomies of the paranasal sinuses and orbit are interrelated. We encountered 27 patients with PSMs involving the orbit that caused orbital symptoms. In this study, we evaluated the frequent symptoms and signs of PSMs involving the orbit, and report postoperative changes of orbital symptoms including the effects on visual acuity. A retrospective chart review, radiologic evaluation, and interviews were conducted after Institutional Review Board approval was obtained. Over the past 11 years, we encountered 27 patients with PSMs involving the orbit. We classified the patients according to orbital symptoms and PSM origin, and evaluated the surgical outcomes. A total of 27 patients (17 males and 10 females) with PSMs involving the orbit were included in the present study. The mean patient age was 51.0 +/- 9.7 years (range 32-90) and the mean follow-up period was 20.5 months (range 2-84). Proptosis (15/27, 56%) was the most common symptom. Other common symptoms included orbital pain (9/27, 33%), decreased visual acuity or vision loss (9/27, 33%), and diplopia (7/27, 26%). All symptoms except for vision loss were improved by endoscopic marsupialization regardless of the disease period. Four out of five patients with decreased visual acuity experienced complete recovery. The remaining patient showed partial improvement after surgery. Four patients who were blind when they initially visited the hospital did not show any improvement after surgery. For PSM patients with decreased visual acuity, we can predict that vision will improve after surgery regardless of the disease duration. However, blindness will probably not resolve after endoscopic marsupialization. Even if the orbital symptoms (except for blindness) have persisted for a long time, surgery could still produce positive outcomes. PMID- 23644999 TI - Successful surgical repair of complex Christmas-tree pattern tracheo-bronchial anatomy with stenosis. AB - Congenital anomalies of bronchial division are extremely rare. Presence of complete cartilaginous rings in bronchial tree with co-existent bronchial division anomalies make surgical correction more challenging, and needs a well structured surgical pathway. We report a case of complex airway pattern similar to Christmas-tree appearance with associated stenosis due to complete rings, treated by modified sliding tracheoplasty with a successful outcome. PMID- 23644995 TI - Effects of targeting higher vs lower arterial oxygen saturations on death or disability in extremely preterm infants: a randomized clinical trial. AB - IMPORTANCE: The goal of oxygen therapy is to deliver sufficient oxygen to the tissues while minimizing oxygen toxicity and oxidative stress. It remains uncertain what values of arterial oxygen saturations achieve this balance in preterm infants. OBJECTIVE: To compare the effects of targeting lower or higher arterial oxygen saturations on the rate of death or disability in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind trial in 25 hospitals in Canada, the United States, Argentina, Finland, Germany, and Israel in which 1201 infants with gestational ages of 23 weeks 0 days through 27 weeks 6 days were enrolled within 24 hours after birth between December 2006 and August 2010. Follow-up assessments began in October 2008 and ended in August 2012. INTERVENTIONS: Study participants were monitored until postmenstrual ages of 36 to 40 weeks with pulse oximeters that displayed saturations of either 3% above or below the true values. Caregivers adjusted the concentration of oxygen to achieve saturations between 88% and 92%, which produced 2 treatment groups with true target saturations of 85% to 89% (n = 602) or 91% to 95% (n = 599). Alarms were triggered when displayed saturations decreased to 86% or increased to 94%. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of death, gross motor disability, cognitive or language delay, severe hearing loss, or bilateral blindness at a corrected age of 18 months. Secondary outcomes included retinopathy of prematurity and brain injury. RESULTS: Of the 578 infants with adequate data for the primary outcome who were assigned to the lower target range, 298 (51.6%) died or survived with disability compared with 283 of the 569 infants (49.7%) assigned to the higher target range (odds ratio adjusted for center, 1.08; 95% CI, 0.85 to 1.37; P = .52). The rates of death were 16.6% for those in the 85% to 89% group and 15.3% for those in the 91% to 95% group (adjusted odds ratio, 1.11; 95% CI, 0.80 to 1.54; P = .54). Targeting lower saturations reduced the postmenstrual age at last use of oxygen therapy (adjusted mean difference, -0.8 weeks; 95% CI, -1.5 to -0.1; P = .03) but did not alter any other outcomes. CONCLUSION AND RELEVANCE: In extremely preterm infants, targeting oxygen saturations of 85% to 89% compared with 91% to 95% had no significant effect on the rate of death or disability at 18 months. These results may help determine the optimal target oxygen saturation. TRIAL REGISTRATIONS: ISRCTN Identifier: 62491227; ClinicalTrials.gov Identifier: NCT00637169. PMID- 23645000 TI - Heavy metal levels in gonad and liver tissues-effects on the reproductive parameters of natural populations of Aphanius facsiatus. AB - The impact of heavy metal levels (Cd, Cu, and Zn) on the reproductive parameters in natural populations of the Mediterranean killifish Aphanius fasciatus was monitored in four sites of the Tunisian coast. Our study covered a period of the reproductive cycle, from April to November 2009. The significantly higher levels of Cd, Cu, and Zn in the liver and gonads for both sexes (p<0.05) were observed in the most polluted site (Sfax coast). During the reproductive cycle of A. fasciatus, an unbalanced sex ratio in favor to females was observed for all the studied populations. The progression of the hepato- (HSI), gonadosomatic (GSI), and K-factor revealed a spatio-temporal variation between populations during the sampling period. Estradiol-17beta amounts in the gonad tissues of females captured from the studied sites showed a significant difference, and the highest concentrations were noticed in the control site (Luza). Taking together, our data provide the first evidence of a physiologically stress and a disturbance of the reproductive status in natural populations of A. fasciatus. PMID- 23645001 TI - Protective role of a methanolic extract of spinach (Spinacia oleracea L.) against Pb toxicity in wheat (Triticum aestivum L.) seedlings: beneficial effects for a plant of a nutraceutical used with animals. AB - Spinach extracts contain powerful natural antioxidants and have been used to improve the response of animal cells to various stress factors. The aim of the present study was to assess the effects of a methanolic extract of spinach (SE) used at two concentrations (21.7 and 217 ppm) on the growth, certain enzymes and antioxidant systems in wheat seedlings under lead stress. When wheat seedlings were grown for 7 days in a solution containing Pb(NO3)2 (3 mM), germination and growth were impaired, while signs of oxidative stress were observed. SE (217 ppm) pretreatment was able to protect seedlings from Pb toxicity by both reducing Pb uptake and Pb-induced oxidative stress. As a consequence, almost normal germination, elongation, biomass and alpha-amylase activity were restored by SE (217 ppm) pretreatment of wheat seedlings, in spite of the presence of Pb. Our results support the protective role and the antioxidant effect of SE against Pb. These results show an amazing similarity to the effects of SE in animals, which suggests that providing "nutraceuticals" to plants could improve their "health" status. PMID- 23645002 TI - Study on the binding interaction between perfluoroalkyl acids and DNA. AB - Perfluoroalkyl acids (PFAAs) are carcinogens, and elucidating their DNA binding properties is crucial for understanding PFAA genotoxicity. We have investigated the binding mode and affinity of five PFAAs to seven DNA molecules using fluorescence displacement and molecular docking analysis. DNA conformational changes upon PFAA binding were also examined by circular dichroism (CD). The data revealed that DNA intercalation was the dominant interaction mode of the PFAAs; however, these molecules also bound to grooves. The dissociation constants for the PFAAs ranged between 0.11 and 1,217.14 MUM, and between 3.46 and 2,141.21 MUM for DNA intercalation and groove binding, respectively. PFAAs that contain longer carbon chains had stronger DNA intercalation affinities. Binding to DNA was stronger for perfluoroalkyl sulfonates than for perfluorcarboxyl acids that contain the same number of carbons. This observation is postulated to arise from the presence of more fluorine and oxygen atoms in perfluoroalkyl sulfonates acting as hydrogen bond donors that facilitate stronger DNA intercalation. The binding of the PFAAs to DNA showed some CT-DNA sequence selectivity. Molecular docking analysis confirmed the DNA binding mode and affinities of the PFAAs. CD analysis revealed that the PFAAs weakened DNA base stacking and loosened DNA helicity. The present study has improved our understanding of the formation of PFAA-DNA adducts. PMID- 23645003 TI - Comparison of artificial total disc replacement versus fusion for lumbar degenerative disc disease: a meta-analysis of randomized controlled trials. AB - PURPOSE: To compare the efficacy and safety of TDR to that of the fusion for the treatment of lumbar degenerative disc disease (LDDD). METHODS: Randomized controlled trials comparing TDR with any other intervention for LDDD were acquired by a comprehensive search in PubMedCentral, MEDLINE, EMBASE, BIOSIS, ClinicalTrials.gov, and the FDA trials register. Methodologic quality was assessed and relevant data were retrieved, and appropriate meta-analysis was performed. Two review authors independently selected studies, extracted data, and assessed risk of bias. Results and upper bounds of confidence intervals were compared with predefined clinically relevant differences. RESULTS: Six relevant randomized controlled trials (RCTs) involving 1,603 patients were identified and reported two year follow-up results. Patients in TDR group compared with lumbar fusion group demonstrated significant improvements in ODI, VAS scores and complication rates at the two year follow-up. Meanwhile, except for operating time in anterior group, intra-operative blood loss, operating time in posterior group, and reoperation rate were without clinical significance between the two groups. In addition, the range of motion (ROM) was maintained within normal ranges after TDR. CONCLUSIONS: The results showed the TDR has significant safety and efficacy comparable to lumbar fusion at two year follow-up. Although superiority compared to fusion could not be proved, by comparing clinical symptoms relieved, motion preserved, and the low reoperation rate during long term follow-up on TDR, TDR was considered safe and effective. Therefore, the authors suggest adopting TDR on a large scale; with failure of TDR, interbody fusion would be performed. PMID- 23645004 TI - Anterior internal fixator versus a femoral distractor and external fixation for sacroiliac joint compression and single stance gait testing: a mechanical study in synthetic bone. AB - PURPOSE: The purpose of this study was to evaluate the biomechanical stability and compressive forces across the sacroiliac (SI) joint of an anterior internal fixator compared to the femoral distractor and external fixator for vertically unstable pelvic fractures. METHODS: Five composite pelvises with a simulated APC type III injury fixed with a femoral distractor, external fixator, or anterior internal fixator were tested. A pressure-sensitive film (Tekscan) was placed in the disrupted SI joint recording the magnitude of force. Then, in a single-leg stance model (Instron machine), a load was applied through the sacrum. We recorded displacement at the pubic symphysis and SI joint using high-speed video. Peak load and displacement were measured, and axial stiffness was calculated. Values were compared using a Student's t-test (p < 0.05). RESULTS: The SI joint was compressed significantly (p < 0.001) more using the anterior internal fixator (18.9 N) and femoral distractor (18.6 N) than the two-pin external fixator (2.5 N). There was no significant difference between the anterior internal fixator and the femoral distractor in displacement at the SI joint. The pubic symphysis displaced less with the femoral distractor than the anterior internal fixator (5.5 mm vs. 4.1 mm; p < 0.05). CONCLUSIONS: The anterior pedicle screw internal fixator allows for indirect compression across the sacroiliac joint that is superior to two-pin external fixation and comparable to the femoral distractor. The anterior internal fixator may be an option for temporary anterior pelvic fixation in situations where external fixation or the femoral distractor have otherwise been used. PMID- 23645005 TI - Time-dependent resource use and costs associated with different states of disease in patients diagnosed with HER-2-positive metastatic breast cancer. AB - Adequate reflection of disease progression and costs over time is essential in cost-effectiveness analyses based on health state-transition models. However, costing studies normally investigate the burden of metastatic breast cancer (MBC) without explicitly examining the impact of specific-disease states on health care costs over time. The objective of this study was to assess time-dependent costs of different health states of human epidermal receptor-2 (HER-2) positive MBC and the factors contributing to these costs. In the Netherlands, HER-2-positive MBC patients were identified in three different hospitals. Resource use was collected during 24 months, which was linked to unit costs and related to time with respect to date of MBC diagnosis, disease progression and death for each individual patient. Subsequently, monthly costs for different health states were calculated. Finally, a nonlinear mixed-effect modelling approach was used to provide a quantitative description of the time course of cumulative progression costs. Costs during stable disease were constant over time with a mean of $4,158. In contrast, monthly costs for progressive disease demonstrated a change over time with the largest costs in the first 2 months after diagnosis (p < 0.005). The developed mixed-effect model adequately described cumulative cost-time course and associated variability. During the last months of life, costs varied over time, with the last month of life as the most expensive one with a mean of $5,811 per patient per month. To reflect costs of HER-2-positive MBC accurately in Markov models, costs for stable disease can be defined time independent, however, costs of progressive disease should be defined time dependent, and costs related to the final months of life should be modelled as such. The mixed-effect model we have developed could now be considered for adequate description of the time-dependent cost of progressive disease. PMID- 23645006 TI - Black race as a prognostic factor in triple-negative breast cancer patients treated with breast-conserving therapy: a large, single-institution retrospective analysis. AB - Triple-negative breast cancer (TNBC) disproportionately affects black women. However, black race as a prognostic factor in TNBC has not been well studied. We evaluated the effect of race, among other variables, on outcomes in women with TNBC. A total of 704 patients with stages I-III TNBC treated with breast conserving surgery +/- adjuvant radiation therapy (RT) and chemotherapy were identified from an institutional database. Competing risk analyses, Kaplan-Meier methods, and Cox proportional hazards models identified associations among clinicopathologic variables on locoregional recurrence (LRR), distant recurrence (DR), and overall survival (OS). LRR was defined as a biopsy proven, triple receptor-negative recurrence in the ipsilateral breast or regional lymph nodes. At a median follow-up of 51 months, there were 55 LRR, 61 DR, and 111 death events. Compared to non-black women, black women had higher disease stage and were more likely to receive axillary lymph node dissection, chemotherapy, and nodal irradiation (all P < 0.05). After adjustment for stage, age, lymphovascular invasion, chemotherapy, and RT on multivariate analysis, black race was prognostic for increased risk of LRR (hazard ratio [HR] = 3.17; 95 % confidence interval: 1.7-5.8; P = 0.0002). The 5-year risk of regional recurrence was higher in black women (10 vs. 2 %, P < 0.0001), but local failures were similar between groups (3.0 vs. 5.3 %, P = 0.15). RT was an independent predictor for decreased LRR and increased OS on multivariate analyses (P = 0.0006 and P = 0.0003, respectively). Black women with TNBC had equivalent local control, but higher risk of regional nodal failure, compared with non-black counterparts. The routine use of comprehensive nodal irradiation may be beneficial for black women with TNBC. PMID- 23645007 TI - A phase II study of bevacizumab in combination with vinorelbine and trastuzumab in HER2-positive metastatic breast cancer. AB - We aimed to evaluate the efficacy and feasibility of combining trastuzumab/vinorelbine with bevacizumab in patients with first-or second-line HER2-positive, metastatic breast cancer (MBC). Eligible patients had HER2 positive measureable MBC, with no more than one prior line of chemotherapy, and were treated with trastuzumab (4 mg/kg * 2 mg/kg weekly thereafter), vinorelbine (25 mg/m(2) weekly), and bevacizumab (10 mg/kg every 2 weeks). Co-primary endpoints were (a) the proportion of patients alive and progression-free at 1 year and (b) safety profile/feasibility. Feasibility was defined as a rate of grade 3/4 non-hematologic toxicity attributable to protocol-based therapy <20 %. Twenty-nine patients were enrolled (n = 22 first-line, n = 7 second-line). Median age was 48 years (range 37-68). The median number of cycles received was 8 (1-23) and median duration on treatment was 7.4 months (range 1-22). The study was closed early due to higher-than-expected rates of grade 3/4 non-hematologic toxicities, with 50 events in 20 patients. A total of six patients (21 %) were taken off study for treatment-related toxicity. Most common treatment-related toxicities included fatigue (n = 7), febrile neutropenia (n = 4), and headache (n = 3). At 1 year, 8/22 first-line (36 %) and 2/7 second-line (29 %) patients were alive and progression-free. Median PFS was 9.9 months and 7.8 months in the first and second-line cohorts, respectively. Objective responses were observed in 16/22 (73 %) and 5/7 (71 %) patients in the first- and second-line settings. Although the combination of vinorelbine, trastuzumab, and bevacizumab showed notable activity in HER2-positive MBC, the proportion of first-line patients alive and progression-free at 1 year was deemed unlikely to reach the pre-defined threshold for declaring success. Additionally, unacceptable toxicity was observed, at rates greater than previously reported with vinorelbine/trastuzumab or vinorelbine/bevacizumab doublet combinations. PMID- 23645008 TI - Characteristics and outcomes of patients administered blood in the prehospital environment by a road based trauma response team. AB - OBJECTIVE: To describe the characteristics, clinical interventions and the outcomes of patients administered packed red blood cells (pRBCs) by a metropolitan, road based, doctor-paramedic trauma response team (TRT). METHODS: A retrospective cohort study examining 18 months of historical data collated by the Queensland Ambulance Service TRT, the Pathology Queensland Central Transfusion Laboratory, the Royal Brisbane and Women's Hospital and the Princess Alexandra Hospital Trauma Services was undertaken. RESULTS: Over an 18-month period (1 January 2011 to 30 June 2012), 71 trauma patients were administered pRBCs by the TRT. Seven patients (9.9%) died on scene and 39 of the 64 patients (60.9%) transported to hospital survived to hospital discharge. 57 (89.1%) of the transported patients had an Injury Severity Score (ISS) > 15, with a mean ISS, Revised Trauma Score (RTS) and Trauma-Injury Severity Score of 32.11, 4.70 and 0.57, respectively. No patients with an RTS < 2 survived to hospital discharge. 53 patients (82.8%) received additional pRBCs in hospital with 17 patients (26.6%) requiring greater than 10 units pRBCs in the first 24 h. 47 patients (73.4%) required surgical or interventional radiological procedures in the first 24 h. CONCLUSIONS: There is a potential role for prehospital pRBC transfusions in an integrated civilian trauma system. The RTS calculated using the initial set of observations may be a useful tool in determining in which patients the administration of prehospital pRBC transfusions would be futile. PMID- 23645009 TI - Novel ferrocenyl derivatives exert anti-cancer effect in human lung cancer cells in vitro via inducing G1-phase arrest and senescence. AB - AIM: To investigate the effects of 7 novel 1-ferrocenyl-2-(5-phenyl-1H-1,2,4 triazol-3-ylthio) ethanone derivatives on human lung cancer cells in vitro and to determine the mechanisms of action. METHODS: A549 human lung cancer cells were examined. Cell viability was analyzed with MTT assay. Cell apoptosis and senescence were examined using Hoechst 33258 and senescence-associated-beta galactosidase (SA-beta-gal) staining, respectively. LDH release was measured using a detection kit. Cell cycle was analyzed using a flow cytometer. Intracellular ROS level was measured with the 2',7'-dichlorodihydrofluorescein probe. Phosphorylation of p38 was determined using Western blot. RESULTS: Compounds 5b, 5d, and 5e (40 and 80 MUmol/L) caused significant decrease of A549 cell viability, while other 4 compounds had no effect on the cells. Compounds 5b, 5d, and 5e (80 MUmol/L) induced G1-phase arrest (increased the G1 population by 22.6%, 24.23%, and 26.53%, respectively), and markedly increased SA-beta-gal positive cells. However, the compounds did not cause nuclear DNA fragmentation and chromatin condensation in A549 cells. Nor did they affect the release of LDH from the cells. The compounds significantly elevated the intracellular ROS level, decreased the mitochondrial membrane potential, and increased p38 phosphorylation in the cells. In the presence of the antioxidant and free radical scavenger N acetyl-L-cysteine (10 mmol/L), above effects of compounds 5b, 5d, and 5e were abolished. CONCLUSION: The compounds 5b, 5d, and 5e cause neither apoptosis nor necrosis of A549 cells, but exert anti-cancer effect via inducing G1-phase arrest and senescence through ROS/p38 MAP-kinase pathway. PMID- 23645010 TI - Mycophenolic acid derivative 118 improves outcome of skin grafts by suppressing IL-17 production. AB - AIM: To investigate the effects and underlying mechanisms of 118, a novel derivative of mycophenolic acid, in a murine allogeneic skin graft model. METHODS: Skin grafts were conducted by grafting BALB/c donor tail skin into C57BL/6 skin beds (allograft) or by grafting female C57BL/6 donor tail skin into female C57BL/6 skin beds (syngraft). The mice were treated with the derivative 118 (40 mg.kg(-1).d(-1), po) for 13 d (3 d before and 10 d after transplantation). Skin grafts, splenocytes and graft-infiltrated lymphocytes were isolated and examined ex vivo. The effects of the derivative 118 on naive CD4(+) T cell differentiation were examined in vitro. RESULTS: Treatment with the derivative 118 dramatically increased the survival rate of murine allogeneic skin grafts. Flow cytometric analysis and H&E staining showed that the derivative significantly decreased inflammatory cell infiltration into the grafts. The levels of the chemokines CXCL1, CXCL2, CCL7, and CCL2 were reduced in the derivative 118-treated grafts. Additionally, the derivative 118 significantly suppressed the IL-17 levels in the grafts but did not affect the differentiation of systemic helper T cells in the murine allogeneic skin graft model. Furthermore, IL-23p19 expression was suppressed in the grafts from the derivative 118-treated group, which might be due to decreases in TLR4 and MyD88 expression. Finally, the derivative 118 did not exert direct influences on helper T cell differentiation in vitro. CONCLUSION: Treatment with the mycophenolic acid derivative 118 improves murine allogeneic skin grafts by decreasing IL-23 expression and suppressing local IL-17 secretion in the grafts, rather than directly inhibiting Th17 differentiation. PMID- 23645011 TI - Stem cells and small molecule screening: haploid embryonic stem cells as a new tool. AB - Stem cells can both self-renew and differentiate into various cell types under certain conditions, which makes them a good model for development and disease studies. Recently, chemical approaches have been widely applied in stem cell biology by promoting stem cell self-renewal, proliferation, differentiation and somatic cell reprogramming using specific small molecules. Conversely, stem cells and their derivatives also provide an efficient and robust platform for small molecule and drug screening. Here, we review the current research and applications of small molecules that modulate stem cell self-renewal and differentiation and improve reprogramming, as well as the applications that use stem cells as a tool for small molecule screening. Moreover, we introduce the recent advance in haploid embryonic stem cells research. Haploid embryonic stem cells maintain haploidy and stable growth over extensive passages, possess the ability to differentiate into all three germ layers in vitro and in vivo, and contribute to the germlines of chimeras when injected into blastocysts. Androgenetic haploid stem cells can also be used in place of sperm to produce fertile progeny after intracytoplasmic injection into mature oocytes. Such characteristics demonstrate that haploid stem cells are a new approach for genetic studies at both the cellular and animal levels and that they are a valuable platform for future small molecule screening. PMID- 23645012 TI - A novel hemostatic sealant composed of gelatin, transglutaminase and thrombin effectively controls liver trauma-induced bleeding in dogs. AB - AIM: novel hemostatic sealant based on the in situ gel formation of gelatin catalyzed by thrombin and crosslinked by transglutaminase was designed. The aim of this study was to investigate the efficacy of the hemostatic sealant in control of bleeding caused by liver trauma in dogs. METHODS: Hepatic trauma that mimicked the grade III-IV rupture of liver was made in 20 dogs. The traumatic lesion was topically administered the hemostatic sealant (treatment group, n=10), or a thrombin solution (control group, n=10). The time to achieve hemostasis and the blood loss were measured. Contrast-enhanced ultrasound (CEUS) examination was performed in each animal on d 3, d 7, and d 10 d postoperatively to study the healing of the lesions. RESULTS: The mean time to achieve hemostasis in the treatment group was significantly shorter than that in the control group (1.20+/ 0.33 vs 6.70+/-0.64 min, P<0.05). The mean blood loss in the treatment group was significantly less than that in the control group (47.22+/-8.61 vs 79.29+/-11.97 mL, P<0.05). In CEUS examination, the traumatic lesions in the treatment group became significantly smaller on d 3, and disappeared on d 7, whereas the lesions in the control group still existed on d 10. Ascites were never found during 10 d follow-up in the treatment group but were observed on d 3 and d 7 in the control group. CONCLUSION: Compared with thrombin, the novel hemostatic sealant shows much better efficacy in hemostasis and may promote wound healing in dog liver trauma. PMID- 23645014 TI - Microfluidic large scale integration of viral-host interaction analysis. AB - Viral-host interactions represent potential drug targets for novel antiviral strategies (Flisiak et al., Hepatology, 2008, 47, 817-26). Hence, it is important to establish an adequate platform for identifying and analyzing such interactions. In this review, we discuss bottlenecks in conventional protein protein interaction methodologies and present the contribution of innovative microfluidic-based technologies towards a solution to these problems with respect to viral-host proteomics. PMID- 23645013 TI - Curcumin inhibits LPS-induced inflammation in rat vascular smooth muscle cells in vitro via ROS-relative TLR4-MAPK/NF-kappaB pathways. AB - AIM: To investigate whether curcumin (Cur) suppressed lipopolysaccharide (LPS) induced inflammation in vascular smooth muscle cells (VSMCs) of rats, and to determine its molecular mechanisms. METHODS: Primary rat VSMCs were treated with LPS (1 MUg/L) and Cur (5, 10, or 30 MUmol/L) for 24 h. The levels of MCP-1, TNF alpha, and iNOS were measured using ELISA and real-time RT-PCR. NO level was analyzed with the Griess reaction. Western-blotting was used to detect the activation of TLR4, MAPKs, IkappaBalpha, NF-kappaB p65, and the p47(phox) subunit of NADPH oxidase in the cells. RESULTS: Treatment of VSMCs with LPS dramatically increased expression of inflammatory cytokines MCP-1 and TNF-alpha, expression of TLR4 and iNOS, and NO production. LPS also significantly increased phosphorylation of IkappaBalpha, nuclear translocation of NF-kappaB (p65) and phosphorylation of MAPKs in VSMCs. Furthermore, LPS significantly increased production of intracellular ROS, and decreased expression of p47(phox) subunit of NADPH oxidase. Pretreatment with Cur concentration-dependently attenuated all the aberrant changes in LPS-treated VSMCs. The LPS-induced overexpression of MCP-1 and TNF-alpha, and NO production were attenuated by pretreatment with the ERK inhibitor PD98059, the p38 MAPK inhibitor SB203580, the NF-kappaB inhibitor PDTC or anti-TLR4 antibody, but not with the JNK inhibitor SP600125. CONCLUSION: Cur suppresses LPS-induced overexpression of inflammatory mediators in VSMCs in vitro via inhibiting the TLR4-MAPK/NF-kappaB pathways, partly due to block of NADPH mediated intracellular ROS production. PMID- 23645015 TI - Lactobacillus delbrueckii subsp. jakobsenii subsp. nov., isolated from dolo wort, an alcoholic fermented beverage in Burkina Faso. AB - Lactobacillus delbrueckii is divided into five subspecies based on phenotypic and genotypic differences. A novel isolate, designated ZN7a-9(T), was isolated from malted sorghum wort used for making an alcoholic beverage (dolo) in Burkina Faso. The results of 16S rRNA gene sequencing, DNA-DNA hybridization and peptidoglycan cell-wall structure type analyses indicated that it belongs to the species L. delbrueckii. The genome sequence of isolate ZN7a-9(T) was determined by Illumina based sequencing. Multilocus sequence typing (MLST) and split-decomposition analyses were performed on seven concatenated housekeeping genes obtained from the genome sequence of strain ZN7a-9(T) together with 41 additional L. delbrueckii strains. The results of the MLST and split-decomposition analyses could not establish the exact subspecies of L. delbrueckii represented by strain ZN7a-9(T) as it clustered with L. delbrueckii strains unassigned to any of the recognized subspecies of L. delbrueckii. Strain ZN7a-9(T) additionally differed from the recognized type strains of the subspecies of L. delbrueckii with respect to its carbohydrate fermentation profile. In conclusion, the cumulative results indicate that strain ZN7a-9(T) represents a novel subspecies of L. delbrueckii closely related to Lactobacillus delbrueckii subsp. lactis and Lactobacillus delbrueckii subsp. delbrueckii for which the name Lactobacillus delbrueckii subsp. jakobsenii subsp. nov. is proposed. The type strain is ZN7a-9(T) = DSM 26046(T) = LMG 27067(T). PMID- 23645016 TI - Lechevalieria nigeriaca sp. nov., isolated from arid soil. AB - A novel actinobacterium, designated strain NJ2035(T), was isolated from soil collected from Abuja, Nigeria and was characterized to determine its taxonomic position. The isolate was found to have chemical and morphological properties associated with members of the genus Lechevalieria. Phylogenetic analyses based on almost-complete 16S rRNA gene sequences indicated that the isolate was closely related to members of the genus Lechevalieria, and was shown to form a distinct phyletic line in the Lechevalieria phylogenetic tree. Strain NJ2035(T) was most closely related to Lechevalieria roselyniae C81(T), Lechevalieria atacamensis C61(T) and Lechevalieria deserti C68(T) (98.5 % 16S rRNA gene sequence similarity). Sequence similarities with other members of the genus Lechevalieria were less than 98.2 %. The cell wall of the novel strain contained meso diaminopimelic acid, and galactose, mannose and rhamnose as the diagnostic sugars. The predominant menaquinone was MK-9(H4). The polar lipids detected were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol. DNA-DNA relatedness and phenotypic data showed that the novel isolate and L. roselyniae C81(T), L. atacamensis C61(T) and L. deserti C68(T) belong to distinct genomic species. On the basis of data from this taxonomic study using a polyphasic approach, strain NJ2035(T) represents a novel species of the genus Lechevalieria, for which the name Lechevalieria nigeriaca sp. nov. is proposed. The type strain is NJ2035(T) ( = DSM 45680(T) = KCTC 29057(T) = NRRL B-24881(T)). PMID- 23645017 TI - Saccharothrix saharensis sp. nov., an actinomycete isolated from Algerian Saharan soil. AB - The taxonomic position of a novel actinomycete, strain SA152(T), isolated from a sample of Algerian Saharan soil, was determined using a polyphasic taxonomic approach. The strain produced abundant aerial mycelium and fragmented substrate mycelium on most media tested. Chemotaxonomically and phylogenetically, the strain was related to the members of the genus Saccharothrix. Results of 16S rRNA gene sequence comparison revealed that strain SA152(T) shared the highest degree of 16S rRNA gene sequence similarity with Saccharothrix xinjiangensis NBRC 101911(T) (99.3 %) and Saccharothrix texasensis NRRL B-16134(T) (98.9 %). However, DNA-DNA hybridization studies showed only 16.2 % relatedness with S. xinjiangensis DSM 44896(T) and 33.9 % relatedness with S. texasensis DSM 44231(T). Based upon genotypic and phenotypic differences from other members of the genus, a novel species, Saccharothrix saharensis sp. nov., is proposed, with SA152(T) ( = DSM 45456(T) = CCUG 60213(T)) as the type strain. PMID- 23645018 TI - Amycolatopsis cihanbeyliensis sp. nov., a halotolerant actinomycete isolated from a salt mine. AB - A novel halotolerant actinomycete, designated strain BNT52(T), was isolated from soil collected from Cihanbeyli Salt Mine in the central Anatolia region of Turkey, and examined using a polyphasic taxonomic approach. The isolate was found to have chemical and morphological properties typical of the genus Amycolatopsis and formed a distinct phyletic line in the 16S rRNA gene tree. Strain BNT52(T) was most closely related to Amycolatopsis nigrescens CSC17Ta-90(T) (96.7 %), Amycolatopsis magusensis KT2025(T) (96.6 %), Amycolatopsis sulphurea DSM 46092(T) (96.6 %), Amycolatopsis dongchuanensis YIM 75904(T) (96.5 %), Amycolatopsis ultiminotia RP-AC36(T) (96.4 %) and Amycolatopsis sacchari DSM 44468(T) (96.4 %). Sequence similarities with other strains of species of the genus Amycolatopsis were lower than 96.2 %. The isolate grew at 20-37 degrees C, pH 6-12 and in the presence of 0-10 % (w/v) NaCl. The cell wall of the novel strain contained meso diaminopimelic acid and arabinose and galactose as the diagnostic sugars. Major fatty acids were iso-C16 : 0 2-OH and iso-C16 : 0. The predominant menaquinone was MK-9(H4). The polar lipids detected were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylmethylethanolamine. The genomic DNA G+C content was 68.8 mol%. On the basis of the data from this polyphasic taxonomic study, strain BNT52(T) represents a novel species within the genus Amycolatopsis for which the name Amycolatopsis cihanbeyliensis sp. nov. is proposed (type strain BNT52(T) = KCTC 29065(T) = NRRL B-24886(T) = DSM 45679(T)). PMID- 23645019 TI - Streptomyces kebangsaanensis sp. nov., an endophytic actinomycete isolated from an ethnomedicinal plant, which produces phenazine-1-carboxylic acid. AB - A spore-forming streptomycete designated strain SUK12(T) was isolated from a Malaysian ethnomedicinal plant. Its taxonomic position, established using a polyphasic approach, indicates that it is a novel species of the genus Streptomyces. Morphological and chemical characteristics of the strain were consistent with those of members of the genus Streptomyces. Analysis of the almost complete 16S rRNA gene sequence placed strain SUK12(T) in the genus Streptomyces where it formed a distinct phyletic line with recognized species of this genus. The strain exhibited highest sequence similarity to Streptomyces corchorusii DSM 40340(T) (98.2 %) followed by Streptomyces chrestomyceticus NRRL B-3310(T) (98.1 %). The G+C content of the genomic DNA was 74 mol%. Chemotaxonomic data [MK-9(H8) as the major menaquinone; LL-diaminopimelic acid as a component of cell-wall peptidoglycan; C12 : 0, C14 : 0, C15 : 0 and C17 : 1 as the major fatty acids; phospholipid type II] supported the affiliation of strain SUK12(T) to the genus Streptomyces. The results of the phylogenetic analysis and phenotypic data derived from this and previous studies allowed the genotypic and phenotypic differentiation of strain SUK12(T) from the related species of the genus Streptomyces. The DNA-DNA relatedness value between strain SUK12(T) and S. corchorusii DSM 40340(T) is 18.85+/-4.55 %. Strain SUK12(T) produces phenazine-1 carboxylic acid, known as tubermycin B, an antibacterial agent. It is proposed, therefore, that strain SUK12(T) ( = DSM 42048(T) = NRRL B-24860(T)) be classified in the genus Streptomyces as the type strain of Streptomyces kebangsaanensis sp. nov. PMID- 23645020 TI - Nocardioides daeguensis sp. nov., a nitrate-reducing bacterium isolated from activated sludge of an industrial wastewater treatment plant. AB - A Gram-reaction-positive, rod-shaped, non-spore-forming bacterium (strain 2C1 5(T)) was isolated from activated sludge of an industrial wastewater treatment plant in Daegu, South Korea. Its taxonomic position was investigated by using a polyphasic approach. On the basis of 16S rRNA gene sequence similarity, the closest phylogenetic relatives were the type strains of Nocardioides nitrophenolicus (98.6 % similarity), N. kongjuensis (98.5 %), N. caeni (98.4 %), N. simplex (98.3 %), N. aromaticivorans (98.1 %) and N. ginsengisoli (97.5 %); the phylogenetic distance from other species with validly published names within the genus Nocardioides was greater than 3 %. Strain 2C1-5(T) was characterized chemotaxonomically as having ll-2,6-diaminopimelic acid in the cell-wall peptidoglycan, MK-8(H4) as the predominant menaquinone and iso-C16 : 0, C16 : 0 and C17 : 1omega6c as the major fatty acids. The G+C content of the genomic DNA was 74.9 mol%. These chemotaxonomic properties and phenotypic characteristics supported the affiliation of strain 2C1-5(T) to the genus Nocardioides. The results of physiological and biochemical tests allowed genotypic and phenotypic differentiation of strain 2C1-5(T) from existing species with validly published names. Therefore, strain 2C1-5(T) represents a novel species of the genus Nocardioides, for which the name Nocardioides daeguensis sp. nov. is proposed, with the type strain 2C1-5(T) ( = JCM 17460(T) = KCTC 19799(T)). PMID- 23645021 TI - Azospirillum fermentarium sp. nov., a nitrogen-fixing species isolated from a fermenter. AB - An aerobic, Gram-stain-negative, spiral or rod-shaped, non-spore-forming, diazotrophic bacterium (strain CC-LY743(T)) was isolated from a fermentative tank in Taiwan. Strain CC-LY743(T) was able to grow at 20-37 degrees C and pH 6.0-8.0 and tolerated up to 3.0 % (w/v) NaCl. It was positive for nitrogen fixation, with activity of 10.6 nmol ethylene h(-1). 16S rRNA gene sequence analysis of strain CC-LY743(T) showed highest similarity to Azospirillum picis DSM 19922(T) (96.1 %), Azospirillum oryzae JCM 21588(T) (96.0 %) and Azospirillum rugosum DSM 19657(T) (96.0 %) and lower similarity (<96.0 %) to all other Azospirillum species. Highest nifH gene sequence similarities were obtained with Azospirillum brasilense BCRC 12270(T) (92.0 %), Azospirillum formosense BCRC 80273(T) (92.3 %) and A. rugosum DSM 19657(T) (91.8 %). It was positive in the rapid identification by a genus-specific primer set. The predominant quinone system was ubiquinone 10 (Q-10) and the DNA G+C content was 69.6+/-0.1 mol%. The major fatty acids found in strain CC-LY743(T) were n-C16 : 0, C19 : 0 cyclo omega8c, C14 : 0 3-OH/C16 : 1 iso I, C16 : 1omega7c/C16 : 1omega6c and C18 : 1omega7c/C18 : 1omega6c. Based on its phylogenetic, phenotypic and chemotaxonomic features, strain CC-LY743(T) is considered to represent a novel species within the genus Azospirillum for which the name Azospirillum fermentarium sp. nov. is proposed. The type strain is CC LY743(T) ( = BCRC 80505(T) = JCM 18688(T) = LMG 27264(T)). PMID- 23645022 TI - Azoarcus olearius sp. nov., a nitrogen-fixing bacterium isolated from oil contaminated soil. AB - A novel nitrogen-fixing strain, designated DQS-4(T), was isolated from oil contaminated soil in Taiwan and was characterized using a polyphasic taxonomic approach. Cells of strain DQS-4(T) stained Gram-negative, contained poly-beta hydroxybutyrate granules and were motile rods, surrounded by a thin capsule. Cells displayed a strictly aerobic type of metabolism and fixed nitrogen microaerobically. Growth occurred at 10-45 degrees C (optimum, 35-40 degrees C), at pH 7.0-8.0 (optimum, pH 7.0) and with 0-2 % NaCl (optimum, 0.5-1 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain DQS 4(T) belonged to the genus Azoarcus, and its closest neighbours were Azoarcus indigens VB32(T) and Azoarcus communis SWub3(T), with sequence similarities of 97.4 and 96.4 %, respectively. The major cellular fatty acids of strain DQS-4(T) were summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0 and C18 : 1omega7c. The major cellular hydroxy fatty acid was C10 : 0 3-OH. The DNA G+C content was 64.5 mol%. The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and several uncharacterized aminophospholipids and phospholipids. The mean level of DNA-DNA relatedness between strain DQS-4(T) and A. indigens LMG 9092(T) was 27.4 %. On the basis of the genotypic and phenotypic data, strain DQS-4(T) represents a novel species in the genus Azoarcus, for which the name Azoarcus olearius sp. nov. is proposed. The type strain is DQS-4(T) ( = BCRC 80407(T) = KCTC 23918(T) = LMG 26893(T)). PMID- 23645023 TI - Taibaiella smilacinae gen. nov., sp. nov., an endophytic member of the family Chitinophagaceae isolated from the stem of Smilacina japonica, and emended description of Flavihumibacter petaseus. AB - A light-yellow-coloured bacterium, designated strain PTJT-5(T), was isolated from the stem of Smilacina japonica A. Gray collected from Taibai Mountain in Shaanxi Province, north-west China, and was subjected to a taxonomic study by using a polyphasic approach. The novel isolate grew optimally at 25-28 degrees C and pH 6.0-7.0. Flexirubin-type pigments were produced. Cells were Gram-reaction negative, strictly aerobic, rod-shaped and non-motile. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain PTJT-5(T) was a member of the phylum Bacteroidetes, exhibiting the highest sequence similarity to Lacibacter cauensis NJ-8(T) (87.7 %). The major cellular fatty acids were iso-C15 : 0, iso C15 : 1 G, iso-C17 : 0 and iso-C17 : 0 3-OH. The only polyamine was homospermidine and the major polar lipid was phosphatidylethanolamine. The only respiratory quinone was MK-7 and the DNA G+C content was 40.3 mol%. Based on the phenotypic, phylogenetic and genotypic data, strain PTJT-5(T) is considered to represent a novel species of a new genus in the family Chitinophagaceae, for which the name Taibaiella smilacinae gen. nov., sp. nov. is proposed. The type strain of Taibaiella smilacinae is PTJT-5(T) ( = CCTCC AB 2013017(T) = KCTC 32316(T)). An emended description of Flavihumibacter petaseus is also proposed. PMID- 23645024 TI - Remote ischemic preconditioning improves spatial learning and memory ability after focal cerebral ischemia-reperfusion in rats. AB - OBJECTIVE: Using a rodent model of middle cerebral artery occlusion (MCAO), we investigated the effect of remote ischemic preconditioning (RIPC) on spatial learning and memory ability after focal cerebral ischemia-reperfusion (I/R). METHOD: Thirty-six male Sprague-Dawley rats were randomly allocated into 3 groups (n=12, each): sham group, rats were subjected to sham operations without MCAO and RIPC; I/R group, rats were subjected to 1h of MCAO followed by 3 days of reperfusion; I/R+RIPC group, rats were subjected to RIPC and 1h MCAO followed by 3 days of reperfusion. The spatial learning and memory ability of the rats was measured by the Morris water maze task.The activity of cholineacetyltransferase (ChAT) in the hippocampus CA1 region was observed by an immunohistochemistry method. RESULTS: In the Morris water maze task, MCAO elicited a significant decrease of the ability of spatial learning and memory in contrast to the sham group. Meanwhile, RIPC induced a significantly shorter prolongation of the escape latency (p<0.05); greater number passing through the platform (p<0.05) and less time for exploring the target quadrant (p<0.05) as compared with values for the I/R group. Furthermore, the number of ChAT positive cells in the CA1 region in the I/R+RIPC group was strikingly more than those of the I/R group (p<0.05). CONCLUSIONS: RIPC could improve the ability of spatial learning and memory after focal cerebral ischemia-reperfusion probably due to its protection of the cholinergic neurons in the hippocampal CA1 region. PMID- 23645025 TI - Fermentation profiles of wheat dextrin, inulin and partially hydrolyzed guar gum using an in vitro digestion pretreatment and in vitro batch fermentation system model. AB - This study investigated the fermentation and microbiota profiles of three fibers, wheat dextrin (WD), partially hydrolyzed guar gum (PHGG), and inulin, since little is known about the effects of WD and PHGG on gut microbiota. A treatment of salivary amylase, pepsin, and pancreatin was used to better physiologic digestion. Fibers (0.5 g) were fermented in triplicate including a control group without fiber for 0, 4, 8, 12, and 24 h. Analysis of pH, gas volume, hydrogen and methane gases, and short chain fatty acid (SCFA) concentrations were completed at each time point. Quantitative polymerase chain reaction (qPCR) was used to measure Bifidobacteria and Lactobacillus CFUs at 24 h. WD produced the least gas during fermentation at 8, 12, and 24 h (P < 0.0001), while inulin produced the most by 8 h (P < 0.0001). Each fiber reached its lowest pH value at different time points with inulin at 8 h (mean +/- SE) (5.94 +/- 0.03), PHGG at 12 h (5.98 +/- 0.01), and WD at 24 h (6.17 +/- 0.03). All fibers had higher total SCFA concentrations compared to the negative control (P < 0.05) at 24 h. At 24 h, inulin produced significantly (P = 0.0016) more butyrate than WD with PHGG being similar to both. An exploratory microbial analysis (log(10) CFU/uL) showed WD had CFU for Bifidobacteria (6.12) and Lactobacillus (7.15) compared with the control (4.92 and 6.35, respectively). Rate of gas production is influenced by fiber source and may affect tolerance in vivo. Exploratory microbiota data hint at high levels of Bifidobacteria for WD, but require more robust investigation to corroborate these findings. PMID- 23645027 TI - Targeted editing of goat genome with modular-assembly zinc finger nucleases based on activity prediction by computational molecular modeling. AB - Zinc finger nuclease (ZFN) technology can mediate targeted genome modification to produce transgenic animals in a high-efficient and biological-safe way. Modular assembly is a rapid, convenient and open-source method for the synthesis of ZFNs. However, this biotechnology is hampered by multistep construction, low-efficiency editing and off-target cleavage. Here we synthesized and tested six pairs of three- or four-finger ZFNs to target one site in goat beta-lactoglobulin (BLG, a dominant allergen in goat milk) gene. Homology modeling was applied to build the structure model of ZFNs to predict their editing activities targeting at goat BLG gene. Goat fibroblast cells were transfected with plasmids that encoded ZFN pairs, and genomic DNA was isolated 72 h later for genome editing efficiency assay. The results of editing efficiency assay demonstrated that ZFNs with optimal interaction modes can edit goat BLG gene more efficiently, whereas ZFNs with unexpected interaction modes showed lower activities in editing BLG gene. We concluded that modular-assembly ZFNs can provide a rapid, public-available, and easy-to-practice platform for transgenic animal research and molecular modeling would help as a useful tool for ZFNs activity prediction. PMID- 23645026 TI - Dietary patterns in pregnancy and effects on nutrient intake in the Mid-South: the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study. AB - Dietary patterns are sensitive to differences across socio-economic strata or cultural habits and may impact programing of diseases in later life. The purpose of this study was to identify distinct dietary patterns during pregnancy in the Mid-South using factor analysis. Furthermore, we aimed to analyze the differences in the food groups and in macro- and micronutrients among the different food patterns. The study was a cross-sectional analysis of 1155 pregnant women (mean age 26.5 +/- 5.4 years; 62% African American, 35% Caucasian, 3% Other; and pre pregnancy BMI 27.6 +/- 7.5 kg/m(2)). Using food frequency questionnaire data collected from participants in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study between 16 and 28 weeks of gestation, dietary patterns were identified using factor analysis. Three major dietary patterns, namely, Healthy, Processed, and US Southern were identified among pregnant women from the Mid-South. Further analysis of the three main patterns revealed four mixed dietary patterns, i.e., Healthy-Processed, Healthy-US Southern, Processed-US Southern, and overall Mixed. These dietary patterns were different (p < 0.001) from each other in almost all the food items, macro- and micro nutrients and aligned across socioeconomic and racial groups. Our study describes unique dietary patterns in the Mid-South, consumed by a cohort of women enrolled in a prospective study examining the association of maternal nutritional factors during pregnancy that are known to affect brain and cognitive development by age 3. PMID- 23645028 TI - Direct amplification of new cellulase genes from woodland soil purified DNA. AB - Eight genes encoding cellulolytic enzymes were obtained by direct PCR amplification of genomic DNA recovered from woodland soil samples. The direct amplifications were carried out by using primers designed from available online cellulase nucleotide sequences. The isolated genes were all different from each other and homologous to endo-beta-1,4-glucanases of Bacillus subtilis. The cellulases were functionally expressed in Escherichia coli and tested on soluble substrate at 37 and 60 degrees C, showing different cellulolytic activities. Among these, the enzyme renamed CelWS6 exhibited good activity at higher temperatures. Further analysis of CelWS6 showed a high performance in acid environments (between pH 4.0 and 6.0) and at elevated temperatures with its maximum activity at pH 5.0 and 50 degrees C. At the optimum pH, it was very stable since more than 80 % of its original activity was maintained after an incubation of 120 min at 60 degrees C. Because the cellulases had different cellulolytic activities, but similar amino acid sequences, it was possible to assess the relationship between sequence and protein function. PMID- 23645030 TI - Spectroscopic exploring the affinities, characteristics, and mode of binding interaction of curcumin with DNA. AB - Curcumin is a polyphenolic bioactive compound found in the spice turmeric endowed with diverse pharmacological and biological activities. In this study, fluorescence spectroscopy in combination with UV-Vis absorbance spectroscopy was employed to investigate the high affinity binding of curcumin to herring sperm DNA (hs-DNA). From the series of studies undertaken in the present program, for example, steady-state emission; absorption; the effect of denaturants; competition experiment; and anion (iodide) ion-induced fluorescence quenching; the mode of binding of curcumin into the DNA helix has been substantiated to be principally intercalative. Binding parameters calculating from Stern-Volmer method and Scatchard method showed that curcumin bind to hs-DNA with the binding affinities of the order 10(4 )L mol(-1). The effects of ionic strength, chemical denaturants, thermal denaturation and pH were studied to show the factors of the interaction, and provided further support for the intercalative binding mode. In addition, the methods and techniques used in the present work can also be exploited to study the interaction of curcumin with other biological, biomimicking assemblies and drug delivery vehicles, and so forth. PMID- 23645029 TI - Biophysical studies on the interactions of jatrorrhizine with bovine serum albumin by spectroscopic and molecular modeling methods. AB - The interaction between jatrorrhizine (JAT) and bovine serum albumin (BSA) has been studied. The studies were carried out in a buffer medium at pH 7.4 using fluorescence spectroscopy, UV-vis spectroscopy, and molecular modeling methods. The results of fluorescence quenching and UV-vis absorption spectra experiments indicated the formation of the complex of BSA-JAT. Binding parameters were determined using the Stern-Volmer equation and Scatchard equation. The results of thermodynamic parameters DeltaG, DeltaH and DeltaS at different temperatures indicate that the electrostatic interactions and hydrogen bonds play a major role for JAT-BSA association. Site marker competitive displacement experiments and molecular modeling calculation demonstrating that JAT is mainly located within the hydrophobic pocket of the subdomain IIIA of BSA. Furthermore, The distance between donor (BSA) and acceptor (JAT) was estimated according to fluorescence resonance energy transfer. PMID- 23645031 TI - Characterization of three Delta9-fatty acid desaturases with distinct substrate specificity from an oleaginous fungus Cunninghamella echinulata. AB - In oleaginous fungus Cunninghamella echinulata, Delta9-fatty acid desaturase introduces the first double bond into a saturated fatty acid. Three distinct genes, designated as d9dma, d9dmb and d9dmc, all encoding putative Delta9-fatty acid desaturases were isolated from this strain. The predicted proteins showed 79 87 % identity to other fungal Delta9-fatty acid desaturases. They all contain three conserved histidine boxes, C-terminal cytochrome b 5 fusion and four transmembrane domains characteristic of Delta9-desaturase. Each putative Delta9 desaturase gene from C. echinulata was able to complement the ole1 mutation in Saccharomyces cerevisiae L8-14C through heterologous expression. Analysis of the fatty acid composition of the transgenic yeast revealed that the conversion rates of 16:0 and 18:0 by D9DMA were obviously higher than those of D9DMB and D9DMC. In addition, D9DMA, D9DMB and D9DMC all had a substrate preference for 18:0 compared with 16:0. Of interest, D9DMA could saturate 12:0, 14:0, 16:0, 17:0, 18:0 and 20:0, while D9DMB saturated 14:0, 16:0, 17:0, 18:0 and 20:0. We also noticed that the transcriptional level of d9dma in C. echinulata was stimulated by cell growth but not by decline in temperature. In contrast, expression of d9dmb and d9dmc was regulated by neither cell growth nor decline in temperature in this strain. PMID- 23645032 TI - No important role for genetic variation in the Chibby gene in monogenic and complex obesity. AB - Chibby (CBY) has been identified as a potent proadipogenic factor required for adipocyte differentiation. It has been shown that CBY inhibits the canonical Wnt pathway, and therefore promotes the development of new fat cells. Our objective therefore is to investigate the contribution of rare and common genetic variation in CBY to the development of human obesity. A mutation analysis was performed on a total of 566 obese patients and 432 lean individuals. To investigate the involvement of CBY in complex obesity, we performed a genetic association analysis of the entire CBY gene region on 1,011 obese individuals and 523 control samples. Four rare, novel variants were identified in either obese patients or lean control subjects, among which two non-synonymous variations and one frameshift mutation. In addition, four previously reported CBY variants were found. In the association analysis, logistic and linear regression showed no association between common genetic variation in CBY and obesity parameters. Several novel variations were found, but no definite role in the pathogenesis of obesity could be confirmed. Results from the association analysis suggest that common variation in CBY is not a cause for obesity in the Belgian population. PMID- 23645033 TI - Cotton GASL genes encoding putative gibberellin-regulated proteins are involved in response to GA signaling in fiber development. AB - GAST (GA-stimulated transcript)-like genes have been reported as targets of GA regulation in some plant species. In this study, we isolated seven GAST-like cDNAs from cotton (Gossypium hirsutum) cDNA libraries (designated as GhGASL1 GhGASL7). Meanwhile, the genomic DNA clones corresponding to the seven GhGASL genes were isolated by using PCR amplification technique. Analysis of gene structure revealed that four genes (GhGASL1/3/5/6) contain two exons and one intron, while the rest have four exons and three introns. All of the deduced GhGASL proteins contain a putative signal peptide in the N-terminus and a conservative cysteine-rich C-terminal domain. Quantitative RT-PCR analysis indicated that the seven GhGASL genes are differentially expressed in cotton tissues. Among them, GhGASL1/4/7 were predominantly expressed in cotyledons, while the transcripts of GhGASL2/5 were preferentially accumulated at hypocotyls. GhGASL3 mRNA was largely accumulated in fibers, while GhGASL6 transcripts were mainly detected in ovules. Furthermore, GhGASL2/3/5 displayed a relatively high expression levels during early fiber elongation stages, and were regulated by GA. These data suggested that GhGASL genes may be involved in fiber elongation and in response to GA signaling during fiber development. PMID- 23645034 TI - Ethylene promotes induction of aerenchyma formation and ethanolic fermentation in waterlogged roots of Dendranthema spp. AB - The role of ethylene in induction of aerenchyma formation and ethanolic fermentation in waterlogged roots of Dendranthema zawadskii and D. nankingense, two species that differ with respect to waterlogging tolerance, was examined. In the more tolerant D. zawadskii, but not in D. nankingense, ethylene accelerated programmed cell death and promoted formation of lysigenous aerenchyma, both of which were inhibited by treatment with the ethylene inhibitor 1 methylcyclopropene. Waterlogged D. zawadskii roots generated a higher quantity of endogenous ethylene than did those of D. nankingense. In waterlogged D. zawadskii roots, transcription of the genes encoding alcohol dehydrogenase (EC 1.1.1.1) and pyruvate decarboxylase (EC 4.1.1.1) increased rapidly but transiently, whereas expression of these genes in D. nankingense increased gradually and over a longer period. In D. nankingense, waterlogging elevated both alcohol dehydrogenase and pyruvate decarboxylase activity, and the production of ethanol and acetaldehyde was increased in the presence of exogenous ethylene and inhibited by 1 methylcyclopropene. In D. zawadskii, in contrast, after a prolonged episode of waterlogging stress, exogenous supply of ethylene suppressed the production of ethanol and acetaldehyde, whereas exogenous 1-methylcyclopropene enhanced their production. In the more tolerant Dendranthema species, ethylene appeared to signal an acceleration of both waterlogging-induced programmed cell death and aerenchyma formation and to alleviate ethanolic fermentation, whereas in the more sensitive species ethylene activated fermentation and increased the release of ethanol and acetaldehyde, which are by-products probably responsible for the collapse of the waterlogging-damaged root. PMID- 23645035 TI - Evaluation of potential reference genes for use in gene expression studies in the conifer pathogen (Heterobasidion annosum). AB - The basidiomycete Heterobasidion annosum is the causative agent of butt and root rot disease of conifer trees and it's one of the most destructive conifer pathogen in the northern hemisphere. Because of the intrinsic difficulties in genome manipulation in this fungus, most studies have been focused on gene expression analysis using quantitative real time polymerase chain reaction (qPCR). qPCR is a powerful technique but its reliability resides in the correct selection of a set of reference genes used in the data normalization. In this study, we determined the expression stability of 11 selected reference genes in H. annosum. Almost nothing has so far been published about validation of a set of reference genes to be used in gene expression experiments in this fungus. Eleven reference genes were validated in H. annosum which was grown on three different substrates: pine bark, pine heartwood, and pine sapwood. Bestkeeper and NormFinder Excel-based software were used to evaluate the reference gene transcripts' stability. The results from these two programs indicated that three reference genes namely Tryp metab, RNA Pol3 TF, and Actin were stable in H. annosum in the conditions studied. Interestingly, the GAPDH transcript which has been extensively used in qPCR data normalization is not the best choice when a wide reference gene selection is available. This work represents the first extensive validation of reference genes in H. annosum providing support for gene expression studies and benefits for the wider forest pathology community. PMID- 23645036 TI - An integrated analysis of the association between Ts gene polymorphisms and clinical outcome in gastric and colorectal cancer patients treated with 5-FU based regimens. AB - Thymidylate synthetase is the major target of 5-fluorouracil (5-FU), which is widely used for the treatment of gastric cancer (GC) and colorectal cancer (CRC). This meta-analysis aimed to elucidate the effect of Ts polymorphisms on the efficacy of 5-FU-based chemotherapy in GC and CRC patients. Individual data were analyzed from 10 studies of 1102 GC and CRC patients treated with 5-FU-based regimens. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS). Data were pooled using the program STATA version 10.0 (Stata Corporation, College Station, TX). The relationship between the Ts polymorphism and survival following 5FU-based treatment of GC and CRC patients was systematically summarized. Compared with the C allele, the G allele was associated with shorter PFS but with similar OS in Caucasian CRC patients. Compared with the 3R/3R genotype, the 2R/3R or 2R/2R genotype was associated with the same PFS, but with a shorter OS, particularly in Caucasian CRC patients. These results show a correlation between survival following 5-FU-based therapy and tumor genotype in Caucasian CRC patients. Larger studies and further clinical trials are required to confirm this observation. PMID- 23645037 TI - Betaine-homocysteine methyltransferase 742G>A polymorphism and risk of down syndrome offspring in a Brazilian population. AB - Down syndrome (DS) is the most common form of mental retardation of genetic etiology. Several polymorphisms in genes involved with the folic acid cycle have been associated to the risk of bearing a DS child; however, the results are controversial. Betaine-homocysteine methyltransferase (BHMT) is a key enzyme of folate pathway, and catalyzes the remethylation of homocysteine into methionine. Recent studies suggest that the polymorphism BHMT 742G>A may be associated with a decreased risk of having a DS child. We herein investigate the association of this polymorphism with the occurrence of DS in a Brazilian population. We have genotyped 94 mothers of DS infants (DSM) and 134 control mothers (CM) for this polymorphism through PCR-RFLP, and found significant differences for both BHMT 742G>A genotype (P=0.04) and allele (P=0.03) frequencies between DSM and CM. The observed genotypic frequencies were GG=0.45; GA=0.45 and AA=0.10 in CM, and GG=0.54; GA=0.38 and AA=0.02 in DSM. Allelic frequencies were G=0.68 and A=0.32 in CM and G=0.78 and A=0.22 in DSM. The presence of the mutant BHMT 742 A allele decreases 40% the risk of bearing a DS child (OR=0.61; 95% CI: 0.40-0.93; P=0.03), and the risk is diminished up to >80% in association with the homozygous genotype (OR=0.17; 95% CI: 0.04-0.80; P=0.01). Our results indicate that women harboring the single nucleotide polymorphism BHMT 742G>A have a decreased risk of a DS pregnancy, and further studies are necessary to confirm this protective effect. PMID- 23645038 TI - Does hydatid disease have protective effects against lung cancer? AB - We hypothesized that solid tumors rarely occur in patients with hydatid disease. We obtained the serum of 14 patients diagnosed with hydatid disease, the serum of 10 patients who did not have a history of hydatid disease, and the hydatid cyst fluid from six patients. These sera and fluid samples were added at different concentrations to NCI-H209/An1 human lung small cell carcinoma cells and L929 mouse fibroblasts as a control group. Sera of patients with hydatid diseases had cytotoxic effects on NCI-H209/An1 cells, but they did not have cytotoxic effects on fibroblast cells. Sera from healthy subjects did not have a cytotoxic effect on the tumor cell line or control fibroblasts. Cyst fluid, also, did not have toxic effects on the NCI-H209/An1 cell line, but was toxic to fibroblasts up to a 1:32 dilution. Sera from patients with hydatid disease had cytotoxic effects on human small cell lung cancer cells in vitro. PMID- 23645039 TI - High prevalence of CYP2C19*2 allele in Roma samples: study on Roma and Hungarian population samples with review of the literature. AB - The purpose of our study was to characterise the CYP2C19*2 and CYP2C19*3 alleles in healthy Roma and Hungarian populations. DNA of 500 Roma and 370 Hungarian subjects were genotyped for CYP2C19*2 (G681A, rs4244285) and CYP2C19*3 (G636A, rs4986893) by PCR-RFLP assay and direct sequencing. Significant differences were found comparing the Roma and Hungarian populations in CYP2C19 681 GG (63.6 vs. 75.9%), GA (31.8 vs. 23.0%), AA (4.6 vs. 1.1%), GA+AA (36.4 vs. 24.1%) and A allele frequencies (0.205 vs. 0.125) (p<0.004). Striking differences were found between Roma and Hungarian samples in CYP2C19*1 (79.5 vs. 87.4%) and CYP2C19*2 (20.5 vs. 12.6%) alleles, respectively (p<0.001). None of the subjects was found to carry the CYP2C19*3 allele. Frequencies of the intermedier metabolizer phenotype defined by the *1/*2 genotype (0.318 vs. 0.230, p<0.005) and poor metabolizer predicted by the *2/*2 genotype (0.046 vs. 0.011, p<0.005) was significantly higher in Roma than in Hungarians, respectively. Genotype distribution of the Roma population was similar to those of the population of North India, however, a major difference was found in the frequency of the CYP2C19*2 allele, which is likely a result of admixture with European lineages. In conclusion, the frequencies of the CYP2C19 alleles, genotypes and corresponding extensive, intermediate and poor metabolizer phenotypes studied here in the Hungarian population are similar to those of other European Caucasian populations, but display clear differences when compared to the Roma population. PMID- 23645040 TI - Association of TGF-beta1 +869C/T promoter polymorphism with susceptibility to autoimmune diseases: a meta-analysis. AB - Many case-control studies have investigated the role of TGF-beta1 gene +869C/T promoter polymorphism in autoimmune diseases, but the results are inconsistent. To clarify this point, we performed a meta-analysis based on all available studies in Pubmed, Elsevier Science Direct, Google Searching, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure. Crude odds ratios (ORs) with 95% confidence intervals were calculated to estimate the strength of the association. A fixed or random effects model was used on the basis of heterogeneity. A total of 21 papers including 2,693 cases and 3,036 controls were considered in the current meta-analysis. These studies encompass two ankylosing spondylitis (AS), eight rheumatoid arthritis (RA), four systemic lupus erythematosus (SLE), and seven systemic sclerosis (SSc). The results showed that TGF-beta1 +869C/T promoter polymorphism were associated with susceptibility to RA (CC vs. TT: OR=0.65, 95% CI=0.48-0.88, P=0.005; CC vs. CT+TT: OR=0.56, 95% CI=0.45-0.69, P=0.000; C vs. T: OR=0.81, 95% CI=0.71-0.93, P=0.003). When stratified by race, significant association was observed only in Asian population. However, we failed to reveal the association between this gene promoter polymorphism and AS, SLE, and SSc. Therefore, this meta-analysis suggests a possible association between TGF-beta1 +869C/T promoter polymorphism and RA, especially in Asian population. PMID- 23645043 TI - Invasive thoughts: Should we abandon femoral access for STEMIs? PMID- 23645041 TI - Influence of survivin (BIRC5) and caspase-9 (CASP9) functional polymorphisms in renal cell carcinoma development: a study in a southern European population. AB - Renal cell carcinoma (RCC) is the most common cancer of the adult kidney and its incidence and mortality has increase in the last 20 years. The disruption of cellular death is one the mechanism involved in cancer development. This process is precise regulated by apoptotic and anti-apoptotic molecules. Survivin (BIRC5) is a member of the inhibitor of apoptosis protein family and has the ability to inhibit the activation of the pro-apoptotic caspase-9 (CASP9). Thus BIRC5 and CASP9 functional polymorphisms might modulate the apoptosis and consequently RCC development. Our purpose was to investigate the potential role of BIRC5-31G/C and CASP9+83C/T functional polymorphisms in the risk for the development of RCC and metastatic disease. We studied the BIRC5-31G/C and CASP9+83C/T functional polymorphisms by PCR-RFLP and allelic discrimination using the 7300 real-time polymerase chain reaction system, respectively, in 178 RCC patients and in 305 healthy individuals. Regarding the BIRC5-31G/C polymorphism, there is a trend to an overrepresentation of CC genotype in RCC group compared with normal controls (aOR, 1.94; P=0.053). We observed, after gender stratification and age adjustment, that BIRC5-31CC and CASP9+83CT/TT genotypes were associated with an increased risk for RCC development in the female group of our southern European study population (aOR=3.85; P=0.019; aOR=2.98; P=0.028; respectively). Concerning the waiting time for onset of metastatic disease, we observed that BIRC5-31CC homozygous developed metastasis 8 years earlier than the G carriers using a Cox proportional hazard model with gender as covariate (HR=4.9, P=0.038, P bootstrap=0.009). The Cox regression proportional hazard model was validated using bootstrap statistic with 1,000 samples of the same number of patients as the original dataset. Our results suggest that individual differences influence the susceptibility to RCC and tumor behavior. This genetic profile may help to define higher risk groups that would benefit from individualized chemoprevention strategies and therapies. PMID- 23645042 TI - IL2/IL21 region polymorphism influences response to rituximab in systemic lupus erythematosus patients. AB - To determine whether the IL2/IL21 region, a general autoimmunity locus, contributes to the observed variation in response to rituximab in patients with systemic lupus erythematosus as well as to analyze its influence in a cohort including other autoimmune diseases. rs6822844 G/T polymorphism at the IL2-IL21 region was analyzed by TaqMan assay in 84 systemic lupus erythematosus (SLE) and 60 different systemic autoimmune diseases Spanish patients receiving rituximab. Six months after the first infusion patients were classified, according to the EULAR criteria, as good responders, partial responders and non-responders. A statistically significant difference was observed in GG genotype frequency between responder (total and partial response) (83.56%) and non-responder (45.45%) SLE patients (p=0.010, odds ratio (OR)=6.10 [1.28-29.06]). No association with the response was evident in the group of patients with autoimmune diseases other than lupus. Furthermore, when both groups of patients were pooled in a meta-analysis, a reduced statistical significance of the association was observed (p=0.024, OR=3.53 [1.06-11.64]). Our results show for a first time that IL2-IL21 region seems to play a role in the response to rituximab in SLE patients but not in other autoimmune diseases. PMID- 23645044 TI - The feasibility, safety, and mid-term outcomes of concomitant percutaneous transluminal renal artery stenting in acute coronary syndrome patients at high clinical risk of renal artery stenosis. AB - BACKGROUND: Concomitant renal artery stenosis (RAS) aggravates the presentations and outcomes of coronary artery disease. To date, no reports have been published on the feasibility, safety, and outcomes of concomitant percutaneous renal artery stenting (PTRS) in patients presenting with acute coronary syndrome (ACS) at high clinical risk of RAS. METHODS: This was a retrospective study. Eighty-two patients who were at high clinical risk of RAS, undergoing simultaneous coronary and renal angiographies between January 2005 and July 2011, were queried from the data of 2186 ACS patients. RESULTS: A total of 80 patients (48 males; age, 77 +/- 8 years) were enrolled. Thirty-five patients (43.8%) were found to have significant RAS and all received PTRS. Peripheral arterial disease (PAD) was found to be the only predictive factor for RAS in multivariate analysis. There were no significant differences in the total procedural/fluoroscopic times or the volume of contrast used between RAS/PTRS and non-RAS groups. No extra procedure related morbidities occurred in the RAS/PTRS group. There were no significant differences in serum creatinine, estimated glomerular filtration rate, or clinical outcomes between the groups at different follow-up points. However, the mean number of antihypertensives decreased significantly 3 months after PTRS. The systolic and diastolic blood pressures also significantly lowered 6 months after PTRS. CONCLUSIONS: Significant RAS was not infrequently found in ACS patients at high clinical risk. PAD was the only independent predictive factor. Concomitant PTRS could be safely and effectively performed in the same session as coronary interventions with favorable outcomes. PMID- 23645045 TI - Outcomes of culprit versus multivessel PCI in patients with multivessel coronary artery disease presenting with ST-elevation myocardial infarction complicated by shock. AB - BACKGROUND: The optimal revascularization strategy in patients with multivessel coronary artery disease (MVCAD) who present with ST-elevation myocardial infarction (STEMI) and shock is undefined. We aimed to determine differences in survival among patients with MVCAD presenting with STEMI complicated by shock treated with percutaneous coronary intervention (PCI) of the infarct-related artery alone (culprit-only PCI) versus multivessel PCI (MVPCI). METHODS: Patients with MVCAD and STEMI complicated by shock who underwent PCI between January 1, 2002 and May 31, 2010 were identified (n = 199). Differences in survival between patients undergoing culprit-only PCI versus MVPCI were assessed using a multiphase survival model and propensity matching. RESULTS: MVPCI was used in 22% of patients (n = 43). Patient characteristics were similar in the groups, although more patients treated with MVPCI met the National Cardiovascular Data Registry definition of shock. Death was higher in patients treated with MVPCI at 1 month (27% vs 46%) and 8 years (65% vs 75%; P=.04). The early risk of death was higher in the patients treated with MVPCI when compared to patients treated with culprit-only PCI (coefficient: 0.66 +/- 0.25; P=.009), but not the late risk of death (coefficient: -0.18 +/- 0.58; P=.70). However, in a propensity-matched cohort (n = 64), there were no differences in the risk of death over the early (coefficient: 0.50 +/- 0.37; P=.16) or late phase (P>.90). CONCLUSION: Patients undergoing MVPCI for STEMI-related shock are clinically different than those treated with culprit PCI only; however, after risk adjustment both groups have similar short- and long-term outcomes. Prospective studies are needed to determine the optimal revascularization strategy in this high-risk population. PMID- 23645046 TI - Clinical manifestations of heart failure abate with transcatheter aortic paravalvular leak closure using Amplatzer vascular plug II and III devices. AB - OBJECTIVES: To evaluate the transcatheter paravalvular leak closure (TPVLC) aptitude to reduce manifestations of heart failure caused by aortic paravalvular leak (PVL). BACKGROUND: TPVLC is a valuable alternative to reoperation. While technical feasibility of the method is well established, data on long-term clinical outcome are less abundant. METHODS: We launched a prospective registry of patients with clinically significant aortic PVL. They were scheduled for TPVLC with Amplatzer vascular plug (AVP) II and III devices serving as occluders. The efficacy and safety were monitored at 6-month follow-up exam. RESULTS: The occluder deployment reached a success rate of nearly 90%. Following the procedure, we recorded significant improvement both in terms of patient functional capacity and echocardiographic determinants of left ventricular performance. Simultaneously, NT-proBNP plasma concentration and hemolysis markers decreased. Only local complications related to puncture site occurred. CONCLUSIONS: Heart failure caused by aortic PVL can be safely and efficiently treated with TPVLC using AVP II and III devices as occluders. PMID- 23645047 TI - Evaluation of QT, QT dispersion, and T-wave peak to end time changes after primary percutaneous coronary intervention in patients presenting with acute ST elevation myocardial infarction. AB - BACKGROUND: Acute ST-elevation myocardial infarction (STEMI) is associated with significant arrhythmia and cardiac arrest. QT prolongation can occur in the setting of ischemia or acute STEMI as a risk factor for arrhythmia. The goal of this study was to investigate corrected QT interval (QTc), QT dispersion (QTd), and T-wave peak to end (TPE) times in this patient population and evaluate the effect of primary percutaneous coronary intervention (PCI) in STEMI patients on these indices. METHODS: This study was a clinical trial, whereby eligible patients presenting with acute STEMI who were appropriate candidates for primary PCI were enrolled. QTc, QTd, and TPE indices were calculated before and after the procedure. RESULTS: Eighty patients (60 male, 20 female) with a mean age of 58.8 years were evaluated. We found significant reduction in QTd after PCI (mean, 5.8 ms before PCI vs 3.6 ms after PCI; P<.001) and significant reduction in TPE after PCI (mean, 9.7 ms before PCI vs 7 ms after PCI; P<.001). QTc did not show significant changes before or after PCI (44.9 vs 43.7; P=.057). CONCLUSION: Our study showed that primary PCI was effective in reducing the degree of arrhythmogenic indices such as QTd and TPE. Our findings suggest that ischemia induced QTd and TPE are important arrhythmogenic parameters responding to successful primary PCI and may be used as markers for successful repercussion. PMID- 23645048 TI - Recovery after balloon aortic valvuloplasty in patients with aortic stenosis and impaired left ventricular function: predictors and prognostic implications. AB - AIMS: The aim of this study was to evaluate predictors of recovery after balloon aortic valvuloplasty (BAV) among patients with aortic stenosis and depressed left ventricular ejection fraction (LVEF). Predictors for recovery after BAV are not clearly defined. B-type natriuretic peptide (BNP) predicts outcome after surgical and transcatheter aortic valve replacement. METHODS AND RESULTS: Among 151 consecutive patients treated in our institution by BAV, a total of 59 with poor LVEF underwent an echocardiography at 1 month. In these 59 patients, LVEF significantly improved in 22 patients (group 1) from 27 +/- 5% to 45 +/- 6% (P<.0001) and remained unchanged in 37 patients (group 2) from 29 +/- 8% to 30 +/ 11% (P=NS). BNP plasma levels at 24 hours only decreased in group 1 from 2170 +/ 967 pg/mL to 1208 +/- 662 pg/mL (P=.001). By multivariate analysis, BNP reduction >300 pg/mL was the strongest independent predictor of LVEF improvement at 30 days (hazard ratio, 5.459; 95% confidence interval, 1.580-18.860; P=.007). Kaplan-Meier analysis showed that 1-year survival after BAV was significantly higher in patients of group 1 than in group 2 (95 +/- 4% vs 51 +/- 8%, respectively; P=.02). CONCLUSIONS: BAV in patients with poor left ventricular function resulted in LVEF improvement at 30 days in 37% of cases, which was detected by a reduction of BNP levels already seen at 24 hours. Survival at 1 year was significantly higher in patients with such an improved LVEF after BAV. PMID- 23645049 TI - Primary percutaneous coronary intervention in nonagenarians: six-month outcomes from a single-center registry. AB - Little is known about the efficacy and medium-term outcomes of primary percutaneous coronary intervention (PCI) in very old patients. We evaluated in hospital and 6-month outcomes in a retrospective cohort of nonagenarian patients presenting at our hospital with ST-segment elevation myocardial infarction (STEMI) and treated by primary PCI from January 2003 to May 2012. During this period, primary PCI was performed in 1598 consecutive patients; twenty-seven patients (age, 92.5 +/- 2.5 years) were enrolled in the study. Four patients (15%) were in advanced Killip class at presentation. STEMI location was anterior in 44%. Patients received aspirin, 300 mg clopidogrel loading dose, and heparin. Abciximab was given to 41% of patients. Coronary angiography showed multivessel disease in 52% of patients. Pain-to-balloon and door-to-balloon times were 375.0 +/- 410.2 minutes and 107.3 +/- 47.6 minutes, respectively. Intra-aortic balloon pump was implanted in 1 patient. An average of 1.3 +/- 0.7 stents (95% bare-metal stents) were implanted per patient. Procedural success rate, defined as Thrombolysis in Myocardial Infarction (TIMI) flow grade >= 2 and residual stenosis <20%, was 89%. Hospital mortality was 18.5%. TIMI major bleeding and acute renal failure, defined as an absolute increase of 0.5 mg/dL serum creatinine, occurred in 7% and 22% of patients, respectively. Overall 6-month survival rate was 67%. Our data suggest that primary PCI can be performed in nonagenarian patients with high success rate and with an acceptable bleeding risk, even when aggressive antithrombotic drugs, such as glycoprotein IIb/IIIa inhibitors, are given. PMID- 23645050 TI - Emergency transcatheter aortic valve implantation for decompensated aortic stenosis. AB - We report the case of an 84-year-old male presenting with syncope and dynamic ST T wave changes due to decompensated severe valvular aortic stenosis undergoing successful emergency transcatheter aortic valve implantation. PMID- 23645051 TI - Evaluation of bivalirudin hyper- and hypo-ACT responses in the setting of percutaneous coronary intervention. AB - BACKGROUND: Bivalirudin has emerged as a suitable alternative anticoagulant to unfractionated heparin and low-molecular-weight heparins during percutaneous coronary intervention (PCI) procedures in the management of coronary artery disease and acute coronary syndromes (ACS). In clinical trials, bivalirudin dosing was standardized, and activated clotting time (ACT) did not influence dosing adjustments. The role of ACT monitoring of bivalirudin in PCI is not defined based on current practice guidelines. HYPOTHESIS: The hypothesis of this study is that hyper- and hypo-ACT responses to bivalirudin in PCI may be associated with excessive bleeding or thrombotic complications. METHODS: The planned protocol screened all patients who received bivalirudin therapy and ACT monitoring during PCI in a single center's cardiac catheterization laboratory from July 2009 to June 2010. The first ACT monitored 5 to 60 minutes after bivalirudin initiation was screened for inclusion. Values above 800 seconds and below 300 seconds were included as hyper- and hypo-ACT responses, respectively. Outcomes assessed include thrombotic and bleeding complications. RESULTS: There were 32 patients identified as hyper-responders and 20 patients identified as hypo-responders. There were no significant thrombotic or bleeding complications in the hyper-responder group. There was 1 case (1/20, 5%) of angiographically confirmed acute stent thrombosis immediately following the placement of 5 adjoining bare-metal stents in the right coronary artery of a hypo-responder. CONCLUSIONS: Hyper-ACT responses to bivalirudin therapy in PCI were not associated with additional bleeding risk. Bivalirudin may not adequately protect hypo-ACT responders against thrombotic complications during PCI. PMID- 23645052 TI - Transradial versus transfemoral approach for primary percutaneous coronary interventions in elderly patients. AB - BACKGROUND: The use of transradial approach (TRA) in the STEMI setting is still debated because of the worry that TRA intervention can lead to a delay in the reperfusion time, especially in the elderly, where more advanced atherosclerosis is usually encountered. The aim of this study is to compare the reperfusion time between radial versus femoral approach in patients older than 75 years of age undergoing primary percutaneous coronary intervention (PCI). METHODS: From January 2008 to December 2011, a total of 283 consecutive patients older than 75 years of age underwent primary PCI at our institution. Of these, 177 were treated using the TRA while the remaining 106 had the transfemoral approach (TFA). Demographic and procedural data including door-to-balloon time, time of arterial puncture, and inflation of the balloon were recorded. RESULTS: Door-to-balloon time was 103.1 +/- 58.4 minutes in the TRA group compared with 110.3 +/- 62.4 minutes in the TFA group (P=NS). Time of arterial puncture was 10.6 +/- 4.1 minutes in the TRA group compared with 12.1 +/- 4.5 minutes in the TFA group (P<.01). Time of balloon inflation was 19.6 +/- 8.7 minutes in the TRA group compared with 24.2 +/- 14.9 minutes in the TFA group (P<.01). CONCLUSIONS: Our data suggest that the radial approach does not lead to a lengthening of the door to-balloon time, suggesting the efficacy of this approach in STEMI patients without cardiogenic shock at presentation. PMID- 23645053 TI - Transcatheter closure of secundum atrial septal defects. AB - Atrial septal defect (ASD) is one of the most common congenital heart defects, accounting for 7%-10% of all congenital heart disease (CHD) in children and 30% 33% of defects diagnosed in adults with CHD. This review highlights the evolution of transcatheter ASD closure, indications, follow-up, outcomes, and complications with a focus on the erosion issue with certain devices. PMID- 23645054 TI - Transcatheter closure of left coronary cameral fistula with Amplatzer duct occluder II. AB - The surgical and transcatheter coil closure of coronary arterial fistulas are described in the literature. We report our experience with the successful transcatheter closure of a coronary arterial fistula, arising from the left coronary artery and draining into the right ventricle, with the new Amplatzer duct occluder II device. PMID- 23645055 TI - The clinical spectrum of longitudinal deformation of coronary stents: from a mere angiographic finding to a severe complication. AB - BACKGROUND: Longitudinal deformation of coronary stents has been recently described and seems to be more frequent with certain contemporary stent platforms. Indeed, in order to increase flexibility and deliverability, stent manufacturers have reduced strut thickness and the number of connectors within cells; this could negatively affect other mechanical properties of the device, such as the resistance to longitudinal stress. Moreover, longitudinal deformation has been associated to adverse events, such as stent thrombosis. METHODS: We report 3 cases of longitudinal stent deformation observed at our institution. RESULTS: The first case was a consequence of postdilatation of the stent with a non-compliant balloon, whereas the other 2 cases involved the treatment of bifurcation lesions. One case was complicated by acute, intraprocedural stent thrombosis; such a dreadful complication, to the best of our knowledge, has not been previously reported. CONCLUSIONS: Although longitudinal stent deformation is an infrequent finding, usually not associated with adverse events, at least in the short term, it can sometimes turn into a catastrophic, life-threatening complication. The growing number of reports about this issue in recent years should prompt the operators to carefully select coronary stents, especially when dealing with certain lesion subsets, such as ostial lesions, bifurcations, and long lesions. PMID- 23645056 TI - Carotid artery thrombosis treated with catheter intervention using proximal occlusion and flow reversal. AB - We present a case of symptomatic carotid artery thrombosis treated with catheter intervention under proximal occlusion and flow reversal embolic protection. Although catheter intervention is contraindicated in carotid artery thrombosis due to the risk of distal embolization, the introduction of proximal occlusion embolic protection devices allow interventionalists to use catheter intervention where it was previously deemed too high a risk. A Gore Flow Reversal device was used in a 57-year-old male with obesity, uncontrolled type I diabetes mellitus, hypertension, hyperlipidemia, and prior stroke who had previously undergone left internal carotid artery revascularization with carotid artery endarterectomy and patch angioplasty. Since balloon disruption and manual aspiration through the balloon sheath of the flow reversal device was unable to remove the thrombosis, an AngioJet 4 Fr RX catheter was used to mechanically remove material via mechanical thrombectomy. As there was still residual stenosis, a stent was placed in the area to decrease the remaining blockage. Follow-up carotid artery duplex scanning showed that the procedure eliminated the carotid occlusion. The embolic protection device and the procedural technical aspects are described herein, as are reports of both clinical and anatomical follow-up. We show that by using a Gore Flow Reversal protection device, we were able to use catheter therapy to treat a carotid thrombosis, which was previously contraindicated for this condition. PMID- 23645057 TI - Percutaneous repair of aortic puncture with Amplatzer closure device during attempted transseptal puncture. AB - Attempted atrial transseptal puncture in a 63-year-old man undergoing an ablative procedure for atrial fibrillation was complicated by inadvertent delivery of an 8 Fr sheath across the aorta. Due to obesity-related perioperative risks, we opted for percutaneous repair rather than open-heart corrective surgery. Our case is unique for the novel percutaneous delivery of an Amplatzer atrial septal defect (ASD) closure device to the defect in the non-coronary aortic cusp through an 8 Fr left atrial multipurpose sheath not designed for this purpose. At 9-month follow-up, he had a mild residual internuclear ophthalmoplegia. PMID- 23645058 TI - Alcohol septal ablation as a bail-out procedure for suicide left ventricle after transcatheter aortic valve implantation. AB - With the advent of transcatheter aortic valve implantation (TAVI), many AS patients, formerly considered inoperable, can receive effective treatment. The relief of the left ventricular pressure overload could lead, in some cases, to the occurrence of dynamic intracavity pressure gradients (DIG) with deleterious clinical impact. This phenomenon resembles the physiology seen in hypertrophic obstructive cardiomyopathy. We report a case in which alcohol septal ablation was used as a bail-out therapy for the acutely developed intracavity obstruction after TAVI. Potential dynamic intracavity gradients should always be excluded in the acutely deteriorated patient postoperatively. Alcohol septal ablation can be considered as a salvage therapeutic tool when other therapies are ineffective to treat subvalvular obstruction. PMID- 23645059 TI - Customized covered stent graft for percutaneous closure of Fontan baffle leak. AB - We report the innovation of both a partly-covered and completely-covered, variable-diameter, balloon-expandable stent that was custom-designed by NuMed, Inc for percutaneous closure of a baffle leak after total caval pulmonary connection (TCPC). A 50-year-old patient, born with tricuspid atresia, who had undergone TCPC, developed severe persistent cyanosis due to a right-to-left shunt through a TCPC baffle leak. Re-operation was deemed too high risk. Therefore, considering his complex anatomy, a custom-made, partly-covered, tapered, balloon expandable stent was designed and successfully deployed. Months later, the shunt recurred at the junction of the covered to uncovered stent cells; subsequently, a second fully-covered, custom-made, tapered stent was implanted with an excellent outcome. The use of covered or partly-covered customized variable-diameter stents for closure of baffle leak after TCPC is feasible and resulted in marked clinical improvement. Customized balloon-expandable stents may be superior to traditional cylindrical stents because of better anchoring and apposition. PMID- 23645060 TI - Severe thrombocytopenia complicating transcatheter occlusion of a patent ductus arteriosus. AB - Transcatheter closure of a patent ductus arteriosus (PDA) is a well-established technique that may occasionally be complicated by severe thrombocytopenia. We report herein 6 cases of PDA in which circulating platelet counts were notably reduced within 18-48 hours following the procedure. A number of interventions, including blood-pressure control, protection against hemorrhage, and eradication of residual flow, were performed. Platelet counts in all patients were restored to preprocedural levels through intravenous infusion of dexamethasone and human gamma globulin. PMID- 23645061 TI - A coronary pseudoaneurysm within a restenotic stent treated by implantation of a pericardium-covered stent and drug-eluting balloon. AB - Coronary pseudoaneurysm after bare-metal stent implantation is a rare event. Observation, surgical resection, or implantation of another stent, bare or covered, are alternative and equivalent management options. Since no option prevails over the other, the most appropriate treatment should be evaluated in every single patient. We report the case of a pseudoaneurysm within a stent with diffuse restenosis, treated with implantation of a pericardium-covered stent, followed by postdilation with a paclitaxel-eluting balloon. PMID- 23645062 TI - Transcollateral approach for percutaneous revascularization of complex superficial femoral artery chronic total occlusion. AB - Chronic total occlusions of the superficial femoral artery occur in approximately 40% of patients with symptomatic peripheral arterial disease. When antegrade revascularization fails or is not feasible, a retrograde approach should be considered. This is usually via the popliteal or tibial vessels. Alternatively, transcollateral revascularization has been reported. This report describes the use of transcollateral retrograde revascularization of the superficial femoral artery in two patients with failed antegrade crossing. Retrograde recanalization was achieved via a branch of the profunda femoris artery. Unlike previous reports that describe retrograde crossing and subsequent snaring of the wire, these cases were performed with retrograde passage of a low-profile balloon. Following retrograde balloon dilation, the vessel was rewired from an antegrade approach and the procedure was completed with complications. PMID- 23645065 TI - Analysis of patterns of patient compliance after an abnormal Pap smear result: the influence of demographic characteristics on patient compliance. AB - OBJECTIVE: This study aimed to determine population characteristics that correlate to suboptimal follow-up after an abnormal cervical cytology result. MATERIALS AND METHODS: Nonpregnant women, ages 21 to 65 years, with newly diagnosed abnormal cervical cytology result between January 2009 and January 2012 at an urban clinic were eligible for inclusion in this retrospective chart review. Cervical cytology data and demographic characteristics such as age, ethnicity, employment, marital and smoking status, health insurance and number of pregnancies were abstracted from electronic medical record. A log-linear model was used to determine which factors influenced patient compliance. RESULTS: Of the total of 206 women, 78 (37.9%) had optimal follow-up and 128 (62.1%) had suboptimal follow-up. The 3 variables that were statistically significant in influencing patient follow-up after adjusted analyses included severity of cytology result (p = .0013), ethnicity (p = .02), and employment status (p = .0159). The risk ratio for optimal follow-up for those with severe cytology result was 1.81; for the non-whites, 1.77; and for the employed, 1.53. CONCLUSIONS: Ethnicity, severity of cervical cytology result, and employment status play an important role in patient follow-up after an abnormal cervical cytology result. Detecting trends in our patient population that influence adherence to follow-up will help health care providers formulate strategies that target this problem. PMID- 23645066 TI - Primary vaginal non-Hodgkin lymphoma: gynecologic diagnosis of a hematologic malignancy. AB - BACKGROUND: Non-Hodgkin lymphoma (NHL) predominantly affects the lymph nodes and bone marrow. Extranodal sites of NHL include the thymus, spleen, and Waldeyer ring. Very rarely NHL affects the gynecologic tract (<0.5%), and secondary spread is more common than primary involvement. CASE REPORT: We report a case of primary NHL of the vagina diagnosed in a young woman who presented with a painless vaginal mass. Although the initial clinical diagnosis was that of an inflamed Gartner duct, atypical presentation of the mass prompted further imaging, such as pelvic ultrasonographic imaging and magnetic resonance imaging. The latter showed presence of similar masses in the posterior cervix and vagina, and after a multidisciplinary team discussion, biopsy of the mass showed primary vaginal NHL. Subsequently, we referred her to hematologists who commenced chemotherapy. Only 57 cases of primary vaginal NHL have been reported in the literature, and our case elucidates the workup of atypical vaginal masses to facilitate a diagnosis and appropriate management. CONCLUSIONS: NHL of the female genital tract is uncommon. Early diagnosis translates to better survival for these women because extranodal NHLs bear a worse prognosis when compared with that of nodal lymphomas mainly owing to delay in diagnosis. PMID- 23645067 TI - Characterization of squamous cell cancers of the vulvar anterior fourchette by human papillomavirus, p16INK4a, and p53. AB - OBJECTIVE: The incidence of vulvar squamous cell carcinomas located between the clitoris and urethra in young women is rising in distinct geographic regions, but characteristics of the tumors indicating certain carcinogenic mechanisms are unknown. The present study aimed at characterizing these vulvar cancers for their human papillomavirus (HPV), p16(INK4a), and p53 status, revealing potential pathways of carcinogenesis. MATERIALS AND METHODS: Squamous cell vulvar cancers of the anterior fourchette were retrospectively collected from 8 German hospitals, with additional squamous cell cancers located at other sites of the vulva from 2 of the hospitals. All tumors were analyzed for HPV DNA by polymerase chain reaction and for p16(INK4a) and p53 expression by immunohistochemistry. RESULTS: Potentially HPV-associated tumors (HPV and p16(INK4a) positive, 21.4% [27/126] of the anterior fourchette and 27.7% [13/47] from other locations), p53 overexpressing tumors (35.7% [45/126] and 29.8% [14/47]), and a third group (HPV/p16(INK4a) negative/p53 not overexpressed, 42.9% [54/126] and 42.6% [20/47]) were observed among tumors from the anterior fourchette as well as among vulvar cancers from other locations. Women with vulvar cancers of the anterior fourchette were of young age irrespective of the HPV/p16(INK4a)/p53 status. CONCLUSIONS: Different types of vulvar cancers can be found in squamous cell tumors of the anterior fourchette, similar to the finding in vulvar cancers from other locations and to what has previously been reported for vulvar squamous cell carcinomas in general. PMID- 23645068 TI - Agreement of colposcope and gynocular in assessment of cervical lesions by swede score: a randomized, crossover pilot trial. AB - OBJECTIVE: This study aimed to determine if criterion standard colposcopy could be provided by a pocket-sized battery-driven colposcope, the Gynocular. MATERIALS AND METHODS: The study was a randomized, crossover, pilot clinical trial for evaluating agreement of diagnosis of cervical lesions by colposcopy using a standard colposcope and a pocket-sized battery-driven colposcope, the Gynocular, in 69 women positive for visual inspection with acetic acid. Swede scores were used at the time of colposcopy and compared with the final histological diagnosis after directed cervical biopsy. To test the level of agreement between the colposcopy and Gynocular, we calculated the percentage agreement and the kappa statistic. We calculated the detection rates of cervical lesions of the Gynocular and a standard colposcope using biopsy results as criterion standards. All included patients also underwent a Pap smear. RESULTS: The level of agreement of Swede score between the Gynocular and colposcope was 70.1% and the kappa statistic was 0.65 (p < .001). Biopsy identified 4 women (6.7%) with cervical intraepithelial neoplasia 1 (CIN 1) and 1 woman (1.7%) with CIN 2; 2 women (3.4%) had CIN 3, and 2 women had invasive cervical cancer (CIN 3+). Pap smear detected 2 women (3.1%) with CIN 1 but did not identify any high-grade cervical lesion. Cervicitis was present in 17 (27.4%) of the Pap smears and in 34 (57.6%) of the biopsies. CONCLUSIONS: The study shows that in visual inspection with acetic acid positive women, a battery-driven, pocket-sized colposcope has a significant level of agreement with stationary colposcopy in assessing cervical lesions. PMID- 23645069 TI - Arteriovenous malformation of the vulva: a case report. AB - OBJECTIVE: To report the case of a patient with a large and symptomatic vulvar lesion, necessitating surgical excision. CASE: We report the case of a 57-year old postmenopausal woman with a 6-month history of an enlarging vulvar lesion associated with vulvar pruritus. On examination, a pedunculated 7 * 5 * 4-cm soft tissue mass attached to the left labium majus was noted. Surgical excision was performed and histopathologic evaluation revealed variably dilated, submucosal vessels with thick muscular walls and intimal thickening, but without endothelial atypia or multilayering. These findings were consistent with a final diagnosis of arteriovenous malformation of the vulva. CONCLUSIONS: Given the complex anatomy of the vulva, the differential diagnosis for vulvar vascular lesions can be challenging. Hence, surgical excision and histopathologic evaluation become imperative to distinguish them from other dermatologic and neoplastic conditions of the vulva. PMID- 23645070 TI - Histological evaluation of obliterative phlebitis for the diagnosis of autoimmune pancreatitis. AB - BACKGROUND: Obliterative phlebitis is a useful pathological finding for the diagnosis of lymphoplasmacytic sclerosing pancreatitis (LPSP), or type 1 autoimmune pancreatitis. The present study evaluated histological findings of obliterative phlebitis, including the significance of adding Elastica van Gieson stain (EVG) in comparison with other pancreatic conditions. METHODS: Specimens of LPSP (n = 18), chronic pancreatitis (CP; n = 24), and pancreatic ductal adenocarcinoma (PDA; n = 45) were enrolled. Obliterative venous lesions (OVLs), defined as the presence of inflammatory cells and/or fibrosis inside the tunica adventitia, were counted and compared between hematoxylin and eosin stain (H&E) and EVG. OVLs were classified into three types: OVL-1, lymphoplasmacytic infiltration and fibrosis against a loose textured background; OVL-2, dense fibrosis with minimal or no lymphoplasmacytic infiltration; and OVL-3, densely packed lymphoplasmacytic infiltration without fibrosis. OVL type and OVL size were compared between disease groups. RESULTS: OVL counts in LPSP, CP, and PDA were significantly higher with EVG than with H&E (p < 0.001). OVL-1 was most common in LPSP (H&E 92.4 %, EVG 79.8 %), and was identified in almost all cases of LPSP, but was less common in CP and PDA. Maximum diameter and OVL count in 1 cm(2) of OVL-1 were high for LPSP. Maximum diameter of OVL-1 >=150 MUm was observed in 17 LPSP, 0 CP, and 1 PDA cases (sensitivity 94.4 %, specificity 98.6 %). CONCLUSIONS: Additional EVG is useful for excluding conditions mimicking OVL 1 or detecting OVL in small specimens. The presence of OVL-1 with diameter >=150 MUm is highly diagnostic for LPSP. PMID- 23645071 TI - Cognitive enhancement in aged mice after chronic administration of Cedrus deodara Loud. and Pinus roxburghii Sarg. with demonstrated antioxidant properties. AB - Cedrus deodara and Pinus roxburghii, plants mentioned in Indian literature, have been described to possess central nervous system effects and are used in Ayurvedic medicine to treat disorders of the mind. To investigate the memory enhancing activity of volatile oil and chloroform extracts of C. deodara and P. roxburghii in the Morris water maze paradigm as well as evaluating their antioxidant properties. Aged albino mice were used to study the effect of oil and chloroform extracts on learning and memory by using the Morris water maze paradigm. The chloroform extract of C. deodara produced a significant decrease in escape latency over 7 days of training in both reference and working memory training in comparison to the control group. In the probe trial on day 8, mice in the chloroform extract of C. deodara group crossed the target area more often and spent more time in the target quadrant. Amongst the oils and extracts tested for oxidative stress parameters, only the chloroform extract of C. deodara at doses of 100 mg/kg produced a significant decrease in malondialdehyde (MDA) with a simultaneous significant increase in the level of glutathione (GSH) in both the frontal cortex and hippocampus. The present findings indicate that the chloroform extract of C. deodara has the best memory-enhancing effect due to its strong antioxidant properties from compounds like terpenoids and flavonoids. The study provides a scientific rationale for the traditional use of C. deodara in the management of memory dysfunction and related disorders. PMID- 23645072 TI - Oxygenation targets and outcomes in premature infants. PMID- 23645073 TI - Heterologous overexpression, purification and characterisation of an alcohol dehydrogenase (ADH2) from Halobacterium sp. NRC-1. AB - Replacement of chemical steps with biocatalytic ones is becoming increasingly more interesting due to the remarkable catalytic properties of enzymes, such as their wide range of substrate specificities and variety of chemo-, stereo- and regioselective reactions. This study presents characterisation of an alcohol dehydrogenase (ADH) from the halophilic archaeum Halobacterium sp. NRC-1 (HsADH2). A hexahistidine-tagged recombinant version of HsADH2 (His-HsADH2) was heterologously overexpressed in Haloferax volcanii. The enzyme was purified in one step by immobilised Ni-affinity chromatography. His-HsADH2 was halophilic and mildly thermophilic with optimal activity for ethanol oxidation at 4 M KCl around 60 degrees C and pH 10.0. The enzyme was extremely stable, retaining 80 % activity after 30 days. His-HsADH2 showed preference for NADP(H) but interestingly retained 60 % activity towards NADH. The enzyme displayed broad substrate specificity, with maximum activity obtained for 1-propanol. The enzyme also accepted secondary alcohols such as 2-butanol and even 1-phenylethanol. In the reductive reaction, working conditions for His-HsADH2 were optimised for acetaldehyde and found to be 4 M KCl and pH 6.0. His-HsADH2 displayed intrinsic organic solvent tolerance, which is highly relevant for biotechnological applications. PMID- 23645074 TI - Are emergency departments appropriately treating adolescent pelvic inflammatory disease? PMID- 23645075 TI - Neutrino mass and mixing with discrete symmetry. AB - This is a review paper about neutrino mass and mixing and flavour model building strategies based on discrete family symmetry. After a pedagogical introduction and overview of the whole of neutrino physics, we focus on the PMNS mixing matrix and the latest global fits following the Daya Bay and RENO experiments which measure the reactor angle. We then describe the simple bimaximal, tri-bimaximal and golden ratio patterns of lepton mixing and the deviations required for a non zero reactor angle, with solar or atmospheric mixing sum rules resulting from charged lepton corrections or residual trimaximal mixing. The different types of see-saw mechanism are then reviewed as well as the sequential dominance mechanism. We then give a mini-review of finite group theory, which may be used as a discrete family symmetry broken by flavons either completely, or with different subgroups preserved in the neutrino and charged lepton sectors. These two approaches are then reviewed in detail in separate chapters including mechanisms for flavon vacuum alignment and different model building strategies that have been proposed to generate the reactor angle. We then briefly review grand unified theories (GUTs) and how they may be combined with discrete family symmetry to describe all quark and lepton masses and mixing. Finally, we discuss three model examples which combine an SU(5) GUT with the discrete family symmetries A4, S4 and Delta(96). PMID- 23645076 TI - TRACKING THROUGH CHANGES IN SCALE. AB - We propose a tracking system that is especially well-suited to tracking targets which change drastically in size or appearance. To accomplish this, we employ a fast, two phase template matching algorithm along with a periodic template update method. The template matching step ensures accurate localization while the template update scheme allows the target model to change over time along with the appearance of the target. Furthermore, the algorithm can deliver real-time results even when targets are very large. We demonstrate the proposed method with good results on several sequences showing targets which exhibit large changes in size, shape, and appearance. PMID- 23645077 TI - Improved angiogenic cell penetration in vitro and in vivo in collagen scaffolds with internal channels. AB - Porous scaffolds are limited in volume due to diffusion constraint and delay of vascular network formation. Channels have the potential to speed up cellular penetration. Their effectiveness in improving angiogenic cell penetration was assessed in vitro and in vivo in 3-D collagen scaffolds. In vitro, channelled and non-channelled scaffolds were seeded with vascular smooth muscle cells. Results demonstrated that the scaffolds supported angiogenic cell ingrowth in culture and the channels improved the depth of cell penetration into the scaffold (P < 0.05). The cells reside mainly around and migrate along the channels. In vivo, channels increased cell migration into the scaffolds (P < 0.05) particularly angiogenic cells (P < 0.05) resulting in a clear branched vascular network of microvessels after 2 weeks in the channelled samples which was not apparent in the non channelled samples. Channels could aid production of tissue engineered constructs by offering the possibility of rapid blood vessel infiltration into collagen scaffolds. PMID- 23645079 TI - High throughput and high yield nanofabrication of precisely designed gold nanohole arrays for fluorescence enhanced detection of biomarkers. AB - Fluorescence excitation enhancement by plasmonic nanostructures such as gold nanohole arrays has been a hot topic in biosensing and bioimaging in recent years. However, the high throughput and high yield fabrication of precisely designed metal nanostructures for optimized fluorescence excitation remains a challenge. Our work is the first report combining nanopattern nickel mould fabrication and UV imprinting for gold nanostructure mass fabrication in high yield. We report our successful gold nanohole array mass fabrication on a 4'' glass wafer, by first fabricating a high fidelity nickel mould, then using the mould for UV nanoimprinting on a polymer coated on the glass, evaporating the gold film on the glass wafer, and lifting off the polymer to obtain a gold nanohole array on the glass. Our optimized process for wafer fabrication can achieve almost 100% yield from nanoimprinting to gold lift-off, while the fabricated nickel mould has >70% defect-free area with the rest having a few scattered defects. In our work, the size and pitch of the gold nanohole array are designed to enhance the fluorescent dye Alexa 647. When the fabricated gold nanohole array is used for prostate specific antigen (PSA) detection by establishing a sandwiched fluorescence assay on the gold surface, a detection limit of 100 pg ml(-1) is achieved, while with a same thickness of gold film, only 1 ng ml(-1) is detected. PMID- 23645080 TI - Operative versus non-operative treatment for clavicle fracture: a meta-analysis. AB - PURPOSE: The purpose of this study was to assess the effects of operative and non operative treatment on clavicle fractures. METHOD: Relevant clinical trials on the operative and non-operative treatment for clavicle fractures were retrieved through searching the databases MEDLINE, Embase, OVID and the Cochrane Central Register of Controlled Trials up to December 2011. The quality of the included studies was assessed by two authors. A meta-analysis was carried out on homogeneous studies. Five studies involving 633 clavicle fractures were included. RESULTS: The differences in nonunion [risk ratio (RR) 0.12, 95 % confidence interval (CI) 0.05-0.29], malunion (RR 0.11, 95 % CI 0.04-0.29) and neurological complications (RR 0.45, 95 % CI 0.25-0.81) were statistically significant between operative and non-operative treatment. There was no statistically significant difference in delayed union (RR 0.78, 95 % CI 0.31-1.95). CONCLUSION: Operative treatment is better than non-operative treatment, but decisions should be made in accordance with specific conditions for clinical application. PMID- 23645081 TI - Enhanced migration of human bone marrow stromal cells in modified collagen hydrogels. AB - PURPOSE: Collagen I hydrogels are widely used as scaffolds for regeneration of articular cartilage defects. We hypothesised that ingrowth might be improved by removing the superficial layer of a compressed hydrogel. The control group consisted of the original unmodified product. METHODS: The migration of human bone marrow stromal cells (hBMSCs) into the hydrogel was evaluated by confocal microscopy. We quantified the DNA concentration of the hydrogel for each group and time point and evaluated the chondrogenic differentiation of cells. RESULTS: After one week, the detectable amount of cells at the depth of 26-50 MUm was significantly higher in the modified matrix (MM) than in the non-modified matrix (NM) (p = 0.011). The maximum depth of penetration was 75 MUm (NM) and 200 MUm (MM). After three weeks, the maximum depth of penetration was 175 MUm (NM) and 200 MUm (MM). Likewise, at a depth of 0-25 MUm the amount of detectable cells was significantly higher in the MM group (p = 0.003). After 14 days, the concentration of DNA was significantly higher in the samples of the MM than in the control group (p = 0.000). Staining of histological sections and labelling with collagen II antibodies showed that a chondrogenic differentiation of cells in the scaffold can occur during in vitro cultivation. CONCLUSIONS: Removing the superficial layer is essential to ensuring proper ingrowth of cells within the compressed hydrogel. Compressed hydrogels contribute better to cartilage regeneration after surface modification. PMID- 23645082 TI - Refractory osteitis condensans ilii: outcome of a novel mini-invasive surgical approach. AB - PURPOSE: Osteitis condensans Ilii (OCI) is an orthopaedic mystery until now and the refractory type poses a great challenge in its management. Surgical resection and sacroiliac arthrodesis are major procedures with no guarantee of success for an unknown disease entity with a normal sacroiliac joint. The aim of this retrospective study was to evaluate results of a novel mini-invasive surgical approach for the refractory type after failure of conservative management. MATERIALS AND METHODS: Fourteen females were included with an average age 35.5 +/ 5.8 years. Nine cases were multiparous and five were nulliparous. The pathology was bilateral in all cases; however, seven cases suffered bilateral symptoms, while seven cases had only unilateral complaints. Preoperative computed tomography was mandatory. All cases had three to five percutaneous iliac core decompressions through a cannulated drill bit. The Bath ankylosing spondylitis functional index (BASFI) was used for functional outcome evaluation. RESULTS: The mean follow up was 23.3 +/- 4.1 months. The mean BASFI improved from 3.7 +/- 0.6 preoperatively to 1.3 +/- 0.2 during follow up (P = <0.001). There was a significant improvement with the four drillings over five decompression drillings (P = 0.011). Sacral side sclerosis was associated significantly (P = 0.009) with less improvement. No relapse or substantial complications were encountered. CONCLUSIONS: This novel approach can be of great benefit for refractory OCI cases with almost no added morbidity or complications. It has advantages of the mini invasive techniques in addition to sparing the physiological functions of the affected sacroiliac joints. PMID- 23645083 TI - Dexamethasone induces osteogenesis via regulation of hedgehog signalling molecules in rat mesenchymal stem cells. AB - PURPOSE: Hedgehog signalling plays an important role during the development of tissues and organs, including bone and limb. Dexamethasone (DEX), a synthetic and widely used glucocorticoid, affects osteogenesis of bone marrow mesenchymal stem cells (MSCs), while the signalling pathway by which DEX affects osteoblast differentiation remains obscure. This study aimed to investigate expressions of hedgehog signalling molecules Shh, Ihh and Gli1 during DEX-induced osteogenesis of rat MSCs in vitro. METHODS: DEX promoted osteoblast differentiation of MSCs at 10(-8) mol/L from seven days to 21 days, demonstrated by enhancing alkaline phosphatase (ALP) activity and osteoblast-associated marker type I collagen expression during osteoblastic differentiation. Gene and protein expressions of hedgehog signalling molecules, Shh, Ihh and Gli1 were tested by RT-PCR and western blot analysis during osteoblast differentiation. RESULTS: Shh expression was increased compared to the control while Ihh and Gli1 expressions were decreased on both mRNA and protein level during DEX-induced osteoblast differentiation of MSCs from seven days to 21 days. Altogether, these data demonstrate that DEX can enhance Shh expression via a Gli1-independent mechanism during osteoblast differentiation of MSCs. CONCLUSIONS: These results indicate that different patterns of hedgehog signalling are involved in DEX-induced osteogenesis and these findings provide insights into the mechanistic link between glucocorticoid-induced osteogenesis and hedgehog signalling pathway. PMID- 23645084 TI - New horizon in autophagy research. PMID- 23645085 TI - Association of microparticles and preeclampsia. AB - Preeclampsia (PE) is a syndrome characterized by poor placentation and endothelial dysfunction. The diagnosis for this syndrome is based in hypertension and proteinuria presented after the 20th week of pregnancy. Despite intensive research, PE is still one of the leading causes of maternal mortality, although reliable screening tests or effective treatments of this disease have yet to be proposed. Microparticles (MPs) are small vesicles released after cell activation or apoptosis, which contain membrane proteins that are characteristic of the original parent cell. MPs have been proven to play key role in thrombosis, inflammation, and angiogenesis, as well as to mediate cell-cell communication by transferring mRNAs and microRNA from the cell of origin to target cells. Placenta derived syncytiotrophoblast MPs are one of the most increased MPs during PE and may play an important role in the pathogenesis of this syndrome. Therefore, a better overall understanding of the role of MPs in PE may be useful for new clinical diagnoses and therapeutic approaches. PMID- 23645086 TI - Aberrant upregulation of LRRC1 contributes to human hepatocellular carcinoma. AB - Loss of apico-basal polarity often results in a malignant phenotype in epithelial tissues. Aberrant expression of polarity mediator proteins is closely associated with this process. LRRC1/LANO, a putative cell polarity regulator, was previously screened from our gene expression profiling in which its expression was significantly upregulated in hepatocellular carcinoma (HCC). In the present study, we provide evidences that LRRC1 plays a potential oncogenic function in HCC. Consistent with the microarray data, quantitative real-time PCR results showed LRRC1 was aberrantly upregulated in 37/56 (66.1 %, more than twofolds) of HCC specimens compared with adjacent non-cancerous livers. Furthermore, the cellular expression of LRRC1 in all HCC cell lines examined exhibited much higher level than that in normal adult liver tissue. Functional analyses revealed that overexpression of LRRC1 promoted, while knockdown of LRRC1 by RNA interference inhibited the growth and colony formation of HCC cells. Importantly, enhanced expression of LRRC1 conferred NIH3T3 cells the ability of cell transformation. In a xenograft tumor model, we found LRRC1 overexpression increased the tumorigenicity of HCC cells. Thus, our collective findings suggest that LRRC1 contributes to HCC development, and may be a potential target for therapeutic intervention in this disease. PMID- 23645087 TI - Analysis on cDNA sequence, alternative splicing and polymorphisms associated with timing of puberty of Lin28B gene in goats. AB - Recently, variations in or near Lin28B gene were reported to be associated with timing of human puberty by genome-wide association studies. There have been no reports on that in other mammals. In the present study, a fragment of 5,353 bp of goat Lin28B cDNA, encoding 247 amino acids, was amplified, which contains 744 bp coding region and 4,410 bp 3'-untranslated region (UTR). Two alternative transcripts of Lin28BS (encoding 247 aa) and Lin28BL (encoding 261 aa) were found. Eight mutations in 3'-UTR were detected in nine goat breeds, and the T allele frequencies of A2934T and C3053T in the five sexual precocious breeds were higher than that of the four sexual late-maturing breeds (p<0.05). This may indicate that both the 2934 and 3053 locus may be associated with the age of goat puberty. Our results might expand understanding of the biological pathway of Lin28B gene regulating the timing of mammal puberty. PMID- 23645088 TI - Mitochondrial DNA mutations and polymorphisms in asthenospermic infertile men. AB - In this study we performed a systematic sequence analysis of 6 mitochondrial genes (cytochrome oxidase I, cytochrome oxidase II, cytochrome oxidase III, adenosine triphosphate synthase6, ATP synthase8, and cytochrome b] in 66 infertile men suffering from asthenospermia (n=34) in comparison to normospermic infertile men (n=32) and fertile men (n=100) from Tunisian population. A total of 72 nucleotide substitutions in blood cells mitochondrial DNA were found; 63 of them were previously identified and reported in the human mitochondrial DNA database ( www.mitomap.org ) and 9 were novel. We also detected in 3 asthenospermic patients a novel heteroplasmic missense mitochondrial mutation (m.9387 G>A) in COXIII gene (8.8%) that was not found in any of normospermic infertile and fertile men. This mutation substituting the valine at position 61 to methionine in a conserved amino acid in the transmembrane functional domain of the polypeptide, induces a reduction of the hydropathy index (from +1.225 to +1.100) and a decrease of the protein 3D structures number (from 39 to 32) as shown by PolyPhen bioinformatic program. PMID- 23645089 TI - Interaction of artemisinin and its derivatives with human serum albumin studied using spectroscopies and molecular modeling methods. AB - The interactions of artemisinins including artemisinin, dihydroartemisinin, artemether and artesunate with human serum albumin (HSA) were studied by fluorescence spectroscopy, UV-Vis absorption spectroscopy, synchronous fluorescence, three-dimensional fluorescence, circular dichroism (CD) and molecular modeling. Results obtained from analysis of fluorescence spectrum and fluorescence intensity indicated that the artemisinins had a strong ability to quench the intrinsic fluorescence of HSA through a static quenching procedure. Furthermore, the association constants K a and the corresponding thermodynamic parameters DeltaH, DeltaG and DeltaS at various temperatures were also calculated. Based on the mechanism of Forster's non-radiative energy transfer theory, the distance between the acceptors and HSA were found. In addition, alteration of the secondary structure of HSA in the presence of the artemisinins was tested by CD spectroscopy. Molecular modeling revealed that the artemisinins were bounded in the large hydrophobic cavity of the site I of HSA. PMID- 23645090 TI - Cytokine gene polymorphism and graft-versus-host disease: a survey in Iranian bone marrow transplanted patients. AB - Graft versus host disease (GVHD) is a major complication of bone marrow transplantation (BMT). Numerous studies have shown the potential role of cytokine genotypes in the occurrence of GVHD. In this retrospective, case-control study we aimed to investigate the association between 13 cytokine genes and acute GVHD (aGVHD) after HLA-identical sibling BMT in 91 Iranian subjects. Negative association was found between aGVHD and donor IL-10/GCC haplotype or donor IL-4Ra A allele in the population study. When compared within the leukemia subgroup, we observed positive association between recipient IL-1alpha -889/C allele and aGVHD. Also there were negative association between recipient IL-10/CAA haplotype and donor IL-4Ra/A allele and development of aGVHD. Among the different genotypes only donor IL-4Ra and donor IL-12 showed significant association. We conclude that several cytokine polymorphisms are positively and negatively associated with aGVHD in Iranian HLA matched siblings, of which IL-4Ra and IL-12 may play important roles. PMID- 23645091 TI - Decreased serum interleukin 27 in Brazilian systemic lupus erythematosus patients. AB - The immunological role of interleukin 27 has been reported in various inflammatory diseases, but its importance in systemic lupus erythematosus pathogenesis is not completely established. The aim of this study was to evaluate serum levels of IL-27 in SLE patients and its correlation with clinical manifestations and disease activity. IL-27 levels were assessed in 70 SLE patients and 30 healthy controls by ELISA. Clinical and laboratory parameters were recorded. Statistic analyzes were performed by Graph Prism 3.02 software. The IL-27 serum levels were significantly decreased in SLE patients compared with controls (mean 899.92 and 1,531.22 pg/ml, P=0.0005). There was a correlation between IL-27 levels and C3 levels (P=0.004). Nevertheless, there was no association of serum IL-27 levels with disease activity evaluated by SLEDAI score (P=0.9605). No significant difference was found regarding IL-27 levels between SLE patients with and without nephritis, haematuria, proteinuria and positive anti-dsDNA. Correlation analysis between serum IL-27 levels and SLEDAI, SLICC, proteinuria levels, C4 and CH50 levels also showed no association. These data demonstrated decreased serum levels of IL-27 in SLE patients but further studies are needed to clarify the precise role of this cytokine and its potential use as therapeutic target. PMID- 23645092 TI - Alterations in growth and fatty acid profiles under stress conditions of Hansenula polymorpha defective in polyunsaturated fatty acid synthesis. AB - Using chemical mutagenesis, mutants of Hansenula polymorpha that were defective in fatty acid synthesis were selected based on their growth requirements on saturated fatty acid mixtures. One mutant (S7) was incapable of synthesizing polyunsaturated fatty acids (PUFA), linoleic and alpha-linolenic acids. A genetic analysis demonstrated that the S7 strain had a double lesion affecting fatty acid synthesis and Delta(12)-desaturation. A segregant with a defect in PUFA synthesis (H69-2C) displayed normal growth characteristics in the temperature range of 20 42 degrees C through a modulation of the cellular fatty acid composition. Compared with the parental strain, this yeast mutant had increased sensitivity at low and high temperatures (15 and 48 degrees C, respectively) with an increased tolerance to oxidative stress. The responses to ethanol stress were similar for the parental and PUFA-defective strains. Myristic acid was also determined to play an essential role in the cell growth of H. polymorpha. These findings suggest that both the type of cellular fatty acids and the composition of fatty acids might be involved in the stress responsive mechanisms in this industrially important yeast. PMID- 23645093 TI - What DSM-5 could mean to children with autism and their families. AB - The American Psychiatric Association will update its Diagnostic and Statistical Manual of Mental Disorders to its fifth edition (DSM-5). With this new edition, the classification and diagnostic criteria for the spectrum of autistic disorders will change and become more specific and potentially more restrictive. Rather than maintaining several subcategories of autism including Asperger syndrome, there will be one new category called autism spectrum disorder. This change may alter which children are diagnosed as having autism as well as modify eligibility for treatment, educational, and other support services. We review the history and rationale for the proposed changes as well as several recent studies that have attempted to gauge the impact of these changes on children and families. We also consider how the proposed changes are likely to create new challenges for parents who are attempting to organize their children's care and for pediatricians who are providing that care and assisting with care coordination. PMID- 23645094 TI - Leprosy in a rheumatology setting: a challenging mimic to expose. AB - Leprosy can manifest arthritis both as a complication and a comorbid disorder and can be a challenging differential diagnosis in rheumatology practice due to several common features. Uncommonly, it may present as acute severe polyarthritis with skin lesions and neurological deficit or a digital vasculitis and gangrene. We demonstrate this profile in a retrospective case series analysis of 33 patients (13 females, median age 55 years) in a community-based clinic setting over the period 1998-2012; an electronic search of case records of 41,000 patients was carried out. Rheumatoid arthritis (RA) coexisted in seven patients (three lepromatous, two tuberculoid, and two polyneuritic). Serological rheumatoid factor and antinuclear antibody were often false positive. Several patients of RA were on long-term supervised methotrexate. Rheumatologists should be aware of this clinical mimic to avoid errors in diagnosis and management. PMID- 23645095 TI - Zinc-induced interaction of the metal-binding domain of amyloid-beta peptide with DNA. AB - The interaction of the 16-mer synthetic peptide (Abeta16), which represents the metal-binding domain of the amyloid-beta with DNA, was studied employing the surface plasmon resonance technique. It has been shown that Abeta16 binds to the duplex DNA in the presence of zinc ions and thus the metal-binding domain can serve as a zinc-dependent DNA-binding site of the amyloid-beta. The interaction of Abeta16 with DNA most probably depends on oligomerization of the peptide and is dominated by interaction with phosphates of the DNA backbone. PMID- 23645096 TI - Chronic administration of Dimebon does not ameliorate amyloid-beta pathology in 5xFAD transgenic mice. AB - Dimebon has been tested as a potential modifier of Alzheimer's disease (AD), resulting in mixed clinical trial outcomes. Originally utilized as an antihistamine, Dimebon was later found to ameliorate AD symptoms in initial human trials. Although subsequent trials have reportedly failed to replicate these finding, there is a growing body of evidence that Dimebon might be neuroprotective in certain models of neurodegeneration. The precise mechanism by which Dimebon is thought to act in AD is unclear, though changes in receptor activity, mitochondria function, and autophagy activity have been proposed. It is thus necessary to test Dimebon in transgenic animal model systems to determine if and how the drug affects development and manifestation of pathology, and which pathogenic processes are altered. In the present study we treated mice harboring five familial mutations associated with hereditary AD (5xFAD line) with a chronic regime of Dimebon. The compound was not found to improve the general health or motor behavior of these mice, nor prevent accumulation of Abeta peptides in the brain. Modest changes in response to an anxiogenic task were, however, detected, suggesting Dimebon might improve behavioral abnormalities and cognition in disease in a mechanism independent of protecting against amyloidosis. PMID- 23645097 TI - Screening by telephone in the Alzheimer's disease anti-inflammatory prevention trial. AB - Compared with in-person assessment methods, telephone screening for dementia and other cognitive syndromes may improve efficiency of large population studies or prevention trials. We used data from the Alzheimer's Disease Anti-Inflammatory Prevention Trial to compare performance of a four-test Telephone Assessment Battery (TAB) that included the Telephone Interview for Cognitive Status (TICS) to that of a traditional in-person Cognitive Assessment Battery. Among 1,548 elderly participants with valid telephone and in-person screening results obtained within 90 days of each other, 225 persons were referred for a full cognitive diagnostic evaluation that was completed within six months of screening. Drawing on results from this panel of 225 individuals, we used the Capture-Recapture method to estimate population numbers of cognitively impaired participants. The latter estimates enabled us to compare the performance characteristics of the two screening batteries at specified cut-offs for detection of dementia and milder forms of impairment. Although our results provide relatively imprecise estimates of the performance characteristics of the two batteries, a comparison of their relative performance suggests that, at selected cut-off points, the TAB produces results broadly comparable to in-person screening and may be slightly more sensitive in detecting mild impairment. TAB performance characteristics also appeared slightly better than those of the TICS alone. Given its benefits in time and cost when screening for cognitive disorders, telephone screening should be considered for large samples. PMID- 23645098 TI - Docosahexaenoic acid reduces amyloid-beta induced toxicity in cells of the neurovascular unit. AB - Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta peptides (Abeta) as perivascular deposits and senile plaques in the brain. The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and reduced risk in AD in several epidemiological trials; however the exact underlying molecular mechanism remains to be elucidated. The aim of the study was to test whether DHA can exert a direct protective effect on the elements of the neurovascular unit, such as neurons, glial cells, brain endothelial cells, and pericytes, treated with Abeta42 (15 MUM). A dose-dependent high cellular toxicity was found in viability assays in all cell types and on acute hippocampal slices after treatment with Abeta42 small oligomers prepared in situ from an isopeptide precursor. The cell morphology also changed dramatically in all cell types. In brain endothelial cells, damaged barrier function and increased para- and transcellular permeability were observed after peptide treatment. The production of reactive oxygen species was elevated in pericytes and endothelial and glial cells. DHA (30 MUM) significantly decreased the Abeta42-induced toxic effects in all cell types measured by viability assays, and protected the barrier integrity and functions of brain endothelial cells. DHA also decreased the elevated rhodamine 123 accumulation in brain endothelial cells pre-treated with Abeta42 indicating an effect on efflux pump activity. These results indicate for the first time that DHA can protect not only neurons but also the other elements of the neurovascular unit from the toxic effects of Abeta42 and this effect may be beneficial in AD. PMID- 23645100 TI - Serum sclerostin levels following treatment with parathyroid hormone. PMID- 23645099 TI - Effect of acute and chronic vitamin D administration on systemic renin angiotensin system in essential hypertensives and controls. AB - AIM: To investigate the systemic renin-angiotensin system (RAS) in essential hypertensives (EH) and controls (C) after short- and long-term vitamin D receptor activation. DESIGN: Ten consecutive EH (under controlled low-salt diet) and 10 C underwent calcitriol administration (0.25 MUg bid) for 1 week (Group A). Eighteen consecutive EH under angiotensin II receptor antagonist therapy received a single oral dose of 300,000 IU of cholecalciferol and were followed up for 8 weeks (Group B). METHODS: In basal conditions and at the end of the study (1 week in Group A and 8 weeks in Group B), plasma renin activity (PRA), plasma active renin, aldosterone, and angiotensin II were evaluated, as well as blood pressure, plasma 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and PTH. RESULTS: In Group A, plasma 25(OH)D levels in EH and C were below the normal range, although lower levels were found in the former. No association between basal plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS components was observed either in the whole group or in the two subgroups. Calcitriol administration did not affect any RAS parameter either in EH or in C. In Group B, cholecalciferol significantly increased 25(OH)D and 1,25(OH)2D levels without interfering with the angiotensin II receptor antagonist-induced increase in RAS components. No correlation was found between plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS parameters before and after cholecalciferol administration. CONCLUSIONS: The present data suggest that, in our experimental conditions, vitamin D receptor activation is unable to influence systemic RAS activity. PMID- 23645101 TI - Brain activation deficit in increased-load working memory tasks among adults with ADHD using fMRI. AB - Working memory (WM) is impaired among adults with attention-deficit hyperactivity disorder (ADHD). This study aimed to investigate the brain activation deficit for low-level or increased-load WM among adults with ADHD. A total of 20 adults with ADHD and controls were recruited according to diagnostic interviewing by a psychiatrist. Phonological and visual-spatial 2-back and 3-back tasks were performed under functional magnetic resonance scanning. The results demonstrated that both the adults with ADHD and the controls exhibited activation of the fronto-parietal network for WM, and the intensity was greater in the adult ADHD group. The ADHD group had higher brain activation over the bilateral anterior cingulate, left inferior frontal lobe, hippocampus, and supplementary motor area (SMA) for phonological WM than the control group. When the task loading increased from 2-back to 3-back tasks, the adults with ADHD perceived greater difficulty. The control group exhibited increased brain activation over the frontal-parietal network in response to increased phonological WM load. However, the ADHD group showed decreased brain activation over the left precuneus, insula, and SMA. Further analysis demonstrated that the ADHD group exhibited a greater decrease in brain activation over the left fronto-parietal network, including the precuneus, SMA, insula/inferior frontal lobe, and dorsolateral prefrontal cortex, than the control group. These results suggest that adults with ADHD pay more effort to low demanding phonological WM. On the other hand, brain activation of the left fronto parietal network is impaired when the demands of WM exceed the capacity of adults with ADHD. PMID- 23645102 TI - Evaluation of autonomic nervous system by salivary alpha-amylase level and heart rate variability in patients with schizophrenia. AB - Several researches indicate that autonomic nervous system (ANS) dysfunction in patients with schizophrenia. Recently, salivary alpha-amylase (sAA) has been employed as a useful marker for ANS function. We investigated the extent of ANS dysfunction by measuring sAA and heart rate variability (HRV) of 25 patients with schizophrenia compared with controls. Schizophrenia group demonstrated a significant increase in sAA and markedly lower parasympathetic nervous system (PNS) activity in the HRV. However, there were no significant differences between two groups in sympathetic nervous system (SNS) activity. We concluded that PNS might be suppressed and the SNS shows relatively high activity in schizophrenia. PMID- 23645103 TI - Immunogenicity analysis following human immunodeficiency virus recombinant DNA and recombinant vaccinia virus Tian Tan prime-boost immunization. AB - This study assessed and compared the immunogenicity of various immunization strategies in mice using combinations of recombinant DNA (pCCMp24) and recombinant attenuated vaccinia virus Tian Tan (rddVTT-CCMp24). Intramuscular immunization was performed on days 0 (prime) and 21 (boost). The immunogenicity of the vaccine schedules was determined by measuring human immunodeficiency virus (HIV)-specific binding antibody levels and cytokine (interleukin-2 and interleukin-4) concentrations in peripheral blood, analyzing lymphocyte proliferation capacity against HIV epitopes and CD4(+)/CD8(+) cell ratio, and monitoring interferon-gamma levels at different times post-immunization. The results showed that pCCMp24, rddVTT-CCMp24 and their prime-boost immunization induced humoral and cellular immune responses. The pCCMp24/rddVTT-CCMp24 immunization strategy increased CD8(+) T cells and induced more IFN-gamma secreting cells compared with single-shot rDNA. The prime-boost immunization strategy also induced the generation of cellular immunological memory to HIV epitope peptides. These results demonstrated that prime-boost immunization with rDNA and rddVTT-CCMp24 had a tendency to induce greater cellular immune response than single-shot vaccinations, especially IFN-gamma response, providing a basis for further studies. PMID- 23645104 TI - A drug from poison: how the therapeutic effect of arsenic trioxide on acute promyelocytic leukemia was discovered. AB - It is surprising that, while arsenic trioxide (ATO) is now considered as "the single most active agent in patients with acute promyelocytic leukemia (APL)", the most important discoverer remains obscure and his original papers have not been cited by a single English paper. The discovery was made during the Cultural Revolution when most Chinese scientists and doctors struggled to survive. Beginning with recipes from a countryside practitioner that were vague in applicable diseases, Zhang TingDong and colleagues proposed in the 1970s that a single chemical in the recipe is most effective and that its target is APL. More than 20 years of work by Zhang and colleagues eliminated the confusions about whether and how ATO can be used effectively. Other researchers, first in China and then in the West, followed his lead. Retrospective analysis of data from his own group proved that APL was indeed the most sensitive target. Removal of a trace amount of mercury chloride from the recipe by another group in his hospital proved that only ATO was required. Publication of Western replication in 1998 made the therapy widely accepted, though neither Western, nor Chinese authors of English papers on ATO cited Zhang's papers in the 1970s. This article focuses on the early papers of Zhang, but also suggests it worth further work to validate Chinese reports of ATO treatment of other cancers, and infers that some findings published in Chinese journals are of considerable value to patients and that doctors from other countries can benefit from the clinical experience of Chinese doctors with the largest population of patients. PMID- 23645105 TI - Discrete and polymeric, mono- and dinuclear silver complexes of a macrocyclic tetraoxime ligand with AgI-AgI interactions. AB - Macrocyclic compounds that can bind cationic species efficiently and selectively with their cyclic cavities have great potential as excellent chemosensors for metal ions. Recently, we have developed a tetraoxime-type tetraazamacrocyclic ligand 1 formed through a facile one-pot cyclization reaction. Aiming to explore and bring out the potential of the tetraoxime macrocycle 1 as a chelating sensor, we report herein the preparation of several kinds of silver complexes of 1 and their unique coordination structures determined by single-crystal X-ray diffraction analyses. As a result, the formation of two kinds of discrete structures, monomeric complexes [Ag(1)X] (X = counter anions) and a dimeric complex [Ag2(1)2]X2, and two kinds of polymeric structures from a mononuclear complex, [Ag(1)]nXn, and from a dinuclear complex, [Ag2(1)X2]n, was demonstrated. In the resulting complexes, the structurally flexible macrocyclic ligand 1 was found to provide several different coordination modes. Notably, in some silver complexes of 1, AgI-AgI interactions were observed with different AgI-AgI distances which depend on the kind of counter anions and the chemical composition. PMID- 23645106 TI - Selective detection and automated counting of fluorescently-labeled chrysotile asbestos using a dual-mode high-throughput microscopy (DM-HTM) method. AB - Phase contrast microscopy (PCM) is a widely used analytical method for airborne asbestos, but it is unable to distinguish asbestos from non-asbestos fibers and requires time-consuming and laborious manual counting of fibers. Previously, we developed a high-throughput microscopy (HTM) method that could greatly reduce human intervention and analysis time through automated image acquisition and counting of fibers. In this study, we designed a dual-mode HTM (DM-HTM) device for the combined reflection and fluorescence imaging of asbestos, and automated a series of built-in image processing commands of ImageJ software to test its capabilities. We used DksA, a chrysotile-adhesive protein, for selective detection of chrysotile fibers in the mixed dust-free suspension of crysotile and amosite prepared in the laboratory. We demonstrate that fluorescently-stained chrysotile and total fibers can be identified and enumerated automatically in a high-throughput manner by the DM-HTM system. Combined with more advanced software that can correctly identify overlapping and branching fibers and distinguish between fibers and elongated dust particles, the DM-HTM method should enable fully automated counting of airborne asbestos. PMID- 23645107 TI - UV/Vis spectroelectrochemistry as a tool for monitoring the fabrication of sensors based on silver nanoparticle modified electrodes. AB - A new controlled current multipulse methodology has been developed to modify the screen-printed electrode surface with silver nanoparticles (AgNPs). Spectroelectrochemistry has provided not only information about the type of nanoparticles (NPs) deposited on the electrode surface, but also about the electrosynthesis process. Small NPs without plasmon band are initially generated. Next, these nuclei grow to form bigger NPs in the reduction pulses with a characteristic plasmon band centered at 400 nm. Most of the NPs are generated during the first reduction pulses and a linear growth of the absorbance at a lower reaction rate was obtained in the subsequent pulses. Oxidation pulses do not redissolve completely silver NPs but only partially, meaning that very stable NPs are generated. AgNPs-modified electrodes have been successfully used to determine hydrogen peroxide. Spectroelectrochemistry has also yielded very useful information to understand the voltammetric signal obtained during the reduction of H2O2 on silver modified electrodes. PMID- 23645108 TI - Introduction to the special issue on "New trends towards automatic vehicle control and perception systems". PMID- 23645109 TI - Design and characterization of a fully differential MEMS accelerometer fabricated using MetalMUMPs technology. AB - This paper presents a fully differential single-axis accelerometer fabricated using the MetalMUMPs process. The unique structural configuration and common centriod wiring of the metal electrodes enables a fully differential sensing scheme with robust metal sensing structures. CoventorWare is used in structural and electrical design and simulation of the fully differential accelerometer. The MUMPs foundry fabrication process of the sensor allows for high yield, good process consistency and provides 20 MUm structural thickness of the sensing element, which makes the capacitive sensing eligible. In device characterization, surface profile of the fabricated device is measured using a Veeco surface profilometer; and mean and gradient residual stress in the nickel structure are calculated as approximately 94.7 MPa and -5.27 MPa/MUm, respectively. Dynamic characterization of the sensor is performed using a vibration shaker with a high end commercial calibrating accelerometer as reference. The sensitivity of the sensor is measured as 0.52 mV/g prior to off-chip amplification. Temperature dependence of the sensing capacitance is also characterized. A -0.021fF/ degrees C is observed. The findings in the presented work will provide useful information for design of sensors and actuators such as accelerometers, gyroscopes and electrothermal actuators that are to be fabricated using MetalMUMPs technology. PMID- 23645110 TI - A high-throughput antibody-based microarray typing platform. AB - Many rapid methods have been developed for screening foods for the presence of pathogenic microorganisms. Rapid methods that have the additional ability to identify microorganisms via multiplexed immunological recognition have the potential for classification or typing of microbial contaminants thus facilitating epidemiological investigations that aim to identify outbreaks and trace back the contamination to its source. This manuscript introduces a novel, high throughput typing platform that employs microarrayed multiwell plate substrates and laser-induced fluorescence of the nucleic acid intercalating dye/stain SYBR Gold for detection of antibody-captured bacteria. The aim of this study was to use this platform for comparison of different sets of antibodies raised against the same pathogens as well as demonstrate its potential effectiveness for serotyping. To that end, two sets of antibodies raised against each of the "Big Six" non-O157 Shiga toxin-producing E. coli (STEC) as well as E. coli O157:H7 were array-printed into microtiter plates, and serial dilutions of the bacteria were added and subsequently detected. Though antibody specificity was not sufficient for the development of an STEC serotyping method, the STEC antibody sets performed reasonably well exhibiting that specificity increased at lower capture antibody concentrations or, conversely, at lower bacterial target concentrations. The favorable results indicated that with sufficiently selective and ideally concentrated sets of biorecognition elements (e.g., antibodies or aptamers), this high-throughput platform can be used to rapidly type microbial isolates derived from food samples within ca. 80 min of total assay time. It can also potentially be used to detect the pathogens from food enrichments and at least serve as a platform for testing antibodies. PMID- 23645111 TI - Dual-specific interaction to detect DNA on gold nanoparticles. AB - An approach to selectively and efficiently detect single strand DNA is developed by using streptavidin coated gold nanoparticles (StAuNPs) as efficient quenchers. The central concept for the successful detection is the combination the of streptavidin-biotin interaction with specific probe-target DNA hybridization. Biotin labeled probe DNAs act as "bridges" to bring Cy5 labeled targets to the particle surface and the fluorophore dye can be rapidly and efficiently quenched by StAuPNs. By measuring the changes of photoluminescence intensity of Cy5, an efficient, selective, and reversed detection of DNA hybridization is realized. The methodology may pave a new way for simple and rapid detections of biomolecules. PMID- 23645112 TI - A split-path schema-based RFID data storage model in supply chain management. AB - In modern supply chain management systems, Radio Frequency IDentification (RFID) technology has become an indispensable sensor technology and massive RFID data sets are expected to become commonplace. More and more space and time are needed to store and process such huge amounts of RFID data, and there is an increasing realization that the existing approaches cannot satisfy the requirements of RFID data management. In this paper, we present a split-path schema-based RFID data storage model. With a data separation mechanism, the massive RFID data produced in supply chain management systems can be stored and processed more efficiently. Then a tree structure-based path splitting approach is proposed to intelligently and automatically split the movement paths of products . Furthermore, based on the proposed new storage model, we design the relational schema to store the path information and time information of tags, and some typical query templates and SQL statements are defined. Finally, we conduct various experiments to measure the effect and performance of our model and demonstrate that it performs significantly better than the baseline approach in both the data expression and path-oriented RFID data query performance. PMID- 23645113 TI - Parallel acquisition of 3D-HA(CA)NH and 3D-HACACO spectra. AB - We present here an NMR pulse sequence with 5 independent incrementable time delays within the frame of a 3-dimensional experiment, by incorporating polarization sharing and dual receiver concepts. This has been applied to directly record 3D-HA(CA)NH and 3D-HACACO spectra of proteins simultaneously using parallel detection of (1)H and (13)C nuclei. While both the experiments display intra-residue backbone correlations, the 3D-HA(CA)NH provides also sequential 'i - 1 -> i' correlation along the (1)Halpha dimension. Both the spectra contain special peak patterns at glycine locations which serve as check points during the sequential assignment process. The 3D-HACACO spectrum contains, in addition, information on prolines and side chains of residues having H-C-CO network (i.e., (1)Hbeta, (13)Cbeta and (13)COgamma of Asp and Asn, and (1)Hgamma, (13)Cgamma and (13)COdelta of Glu and Gln), which are generally absent in most conventional proton detected experiments. PMID- 23645114 TI - Adverse childhood experiences and child health in early adolescence. AB - IMPORTANCE: Child maltreatment and other adverse childhood experiences, especially when recent and ongoing, affect adolescent health. Efforts to intervene and prevent adverse childhood exposures should begin early in life but continue throughout childhood and adolescence. OBJECTIVES: To examine the relationship between previous adverse childhood experiences and somatic concerns and health problems in early adolescence, as well as the role of the timing of adverse exposures. DESIGN: Prospective analysis of the Longitudinal Studies of Child Abuse and Neglect interview and questionnaire data when target children were 4, 6, 8, 12, and 14 years old. SETTING: Children with reported or at risk for maltreatment in the South, East, Midwest, Northwest, and Southwest United States Longitudinal Studies of Child Abuse and Neglect sites. PARTICIPANTS: A total of 933 children who completed an interview at age 14 years, including health outcomes. EXPOSURES: Eight categories of adversity (psychological maltreatment, physical abuse, sexual abuse, neglect, caregiver's substance use/alcohol abuse, caregiver's depressive symptoms, caregiver treated violently, and criminal behavior in the household) experienced during the first 6 years of life, the second 6 years of life, the most recent 2 years, and overall adversity. MAIN OUTCOMES AND MEASURES: Child health problems including poor health, illness requiring a doctor, somatic concerns, and any health problem at age 14 years. RESULTS: More than 90% of the youth had experienced an adverse childhood event by age 14 years. There was a graded relationship between adverse childhood exposures and any health problem, while 2 and 3 or more adverse exposures were associated with somatic concerns. Recent adversity appeared to uniquely predict poor health, somatic concerns, and any health problem. CONCLUSIONS AND RELEVANCE: Childhood adversities, particularly recent adversities, already show an impact on health outcomes by early adolescence. Increased efforts to prevent and mitigate these experiences may improve the health outcome for adolescents and adults. PMID- 23645115 TI - Impact of community-associated methicillin resistant Staphylococcus aureus on HIV infected patients. AB - Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as an increasingly important pathogen, causing infections in persons who have no significant healthcare exposures. Persons with human immunodeficiency virus (HIV) infection have been disproportionately affected by CA-MRSA, with increased colonization and infection documented. Several factors are likely involved in the increased CA-MRSA burden observed among HIV-infected patients, including immune factors as well as healthcare and community exposures. Proposed community exposures that have been associated with increased CA-MRSA risk include substance abuse, incarceration, geographic area of residence, and social networks. This article explores these associations and reviews the current knowledge of the epidemiology, pathogenesis, clinical manifestations, and treatment of CA-MRSA in HIV-infected persons. PMID- 23645117 TI - Defining "term" pregnancy: recommendations from the Defining "Term" Pregnancy Workgroup. PMID- 23645116 TI - Architecture of the PPR gene family in the moss Physcomitrella patens. AB - Pentatricopeptide repeat (PPR) proteins are widespread in eukaryotes and in particular, include several hundred members in land plants. The majority of PPR proteins are localized in mitochondria and plastids, where they play a crucial role in various aspects of RNA metabolism at the post-transcriptional level in gene expression. However, many of their functions remain to be characterized. In contrast to vascular plants, the moss Physcomitrella patens has only 105 PPR genes. This number may represent a minimum set of PPR proteins required for post transcriptional regulation in plant organelles. Here, we review the overall structure of the P. patens PPR gene family and the current status of the functional characterization of moss PPR proteins. PMID- 23645118 TI - Anthocyanins protect against ethanol-induced neuronal apoptosis via GABAB1 receptors intracellular signaling in prenatal rat hippocampal neurons. AB - Here, we investigated the possible involvement of gamma-aminobutyric acid B1 receptor (GABAB1R) in mediating the protective effects of black soybean anthocyanins against ethanol-induced apoptosis in prenatal hippocampal neurons because GABARs are known to play an important role in the development of central nervous system. Treatments were performed on primary cultures of prenatal rat hippocampal neurons transfected with or without GABAB1R small interfering RNA (siRNA). The results showed that, when ethanol treatment was followed by anthocyanins treatment, cellular levels of proapoptotic proteins such as Bax, activated caspase-3, and cleaved poly (ADP-ribose) polymerase 1 (PARP-1) were decreased, and the cellular level of the antiapoptotic protein Bcl-2 was increased compared to treatment with ethanol alone. Furthermore, the effects of ethanol on cellular levels of GABAB1R and its downstream signaling molecules such as protein kinase A, calcium/calmodulin-dependent protein kinase II (CaMKII), and phosphorylated cAMP response element binding protein were diminished or reversed by anthocyanins treatment. The ability of anthocyanins to reverse the effects of ethanol on cellular levels of Bax, Bcl-2, active caspase-3, cleaved PARP-1, GABAB1R, and CaMKII were abrogated in cells transfected with GABAB1R siRNA. In a GABAB1R-dependent manner, anthocyanins also inhibited the ability of ethanol to elevate intracellular free Ca(2+) level and increase the proportion of cells with low mitochondrial membrane potential in the population. Cell apoptosis assay and morphological studies also confirmed the neuroprotective effect of anthocyanins against ethanol via GABAB1R. Our data suggest that GABAB1R plays an important role in the neuroprotective effects of anthocyanins against ethanol. PMID- 23645119 TI - Water-avoidance stress enhances gastric contractions in freely moving conscious rats: role of peripheral CRF receptors. AB - BACKGROUND: Stress alters gastrointestinal motility through central and peripheral corticotropin-releasing factor (CRF) pathways. Accumulating evidence has demonstrated that peripheral CRF is deeply involved in the regulation of gastric motility, and enhances gastric contractions through CRF receptor type 1 (CRF1) and delays gastric emptying (GE) through CRF receptor type 2 (CRF2). Since little is known whether water-avoidance stress (WAS) alters gastric motility, the present study tried to clarify this question and the involvement of peripheral CRF receptor subtypes in the mechanisms. METHODS: We recorded intraluminal gastric pressure waves using a perfused manometric method. The rats were anesthetized and the manometric catheter was inserted into the stomach 4-6 days before the experiments. We assessed the area under the manometric trace as the motor index (MI), and compared this result with those obtained 1 h before and after initiation of WAS in nonfasted conscious rats. Solid GE for 1 h was also measured. RESULTS: WAS significantly increased gastric contractions. Intraperitoneal (ip) administration of astressin (100 MUg/kg, 5 min prior to stress), a nonselective CRF antagonist, blocked the response to WAS. On the other hand, pretreatment (5 min prior to stress) with neither astressin2-B (200 MUg/kg, ip), a selective CRF2 antagonist, nor urocortin 2 (30 MUg/kg, ip), a selective CRF2 agonist, modified the response to WAS. These drugs did not alter the basal MI. WAS did not change GE. CONCLUSIONS: WAS may activate peripheral CRF1 but not CRF2 signaling and stimulates gastric contractions without altering GE. PMID- 23645120 TI - Evaluation of a semi-automatic segmentation algorithm in 3D intraoperative ultrasound brain angiography. AB - In this work, we adapted a semi-automatic segmentation algorithm for vascular structures to extract cerebral blood vessels in the 3D intraoperative contrast enhanced ultrasound angiographic (3D-iUSA) data of the brain. We quantitatively evaluated the segmentation method with a physical vascular phantom. The geometrical features of the segmentation model generated by the algorithm were compared with the theoretical tube values and manual delineations provided by observers. For a silicon tube with a radius of 2 mm, the results showed that the algorithm overestimated the lumen radii values by about 1 mm, representing one voxel in the 3D-iUSA data. However, the observers were more hindered by noise and artifacts in the data, resulting in a larger overestimation of the tube lumen (twice the reference size). The first results on 3D-iUSA patient data showed that the algorithm could correctly restitute the main vascular segments with realistic geometrical features data, despite noise, artifacts and unclear blood vessel borders. A future aim of this work is to provide neurosurgeons with a visualization tool to navigate through the brain during aneurysm clipping operations. PMID- 23645122 TI - Brachydactyly mental retardation syndrome in differential diagnosis of pseudopseudohypoparathyroidism. AB - Patients with Albright hereditary osteodystrophy (AHO) phenotype are usually seen in pediatric endocrinology policlinics when they are evaluated for short stature and/or obesity. Brachydactyly mental retardation syndrome (BDMR, OMIM #600430) is a rare genetic disorder caused by aberrations of chromosomal region 2q37 and characterized with AHO-like phenotype without any hormone resistance. Diagnosis of BDMR is based on the detection of the deletion on the long arm of chromosome 2. Diagnosis can usually be made with karyotype analysis but sometimes chromosomal deletion can only be detected by fluorescent in situ hybridization (FISH) screening. We report a patient with the AHO phenotype whose karyotype was normal but who was diagnosed with BDMR with FISH analysis showing 2q deletion. In pediatric endocrinology practice, in patients with AHO phenotype but without parathormone (PTH) resistance, BDMR should be considered. For the diagnosis of BDMR, the subtelomeric region of chromosome 2 should be screened for deletion by FISH analysis even in patients with normal karyotypes. PMID- 23645121 TI - The influence of exposure to maternal diabetes in utero on the rate of decline in beta-cell function among youth with diabetes. AB - Abstract We explored the influence of exposure to maternal diabetes in utero on beta cell decline measured by fasting C-peptide (FCP) among 1079 youth <20 years with diabetes, including 941 with type 1 and 138 with type 2 diabetes. Youths exposed to maternal diabetes had FCP levels that were 17% lower among youth with type 2 diabetes [95% confidence interval (CI): -34%, +6%] and 15% higher among youth with type 1 diabetes (95%CI: -14%, +55%) than their unexposed counterparts, although differences were not statistically significant (p=0.13 and p=0.35, respectively). Exposure to maternal diabetes was not associated with FCP decline in youth with type 2 (p=0.16) or type 1 diabetes (p=0.90); nor was the effect of in utero exposure on FCP modified by diabetes type. Findings suggest that exposure to maternal diabetes in utero may not be an important determinant of short-term beta-cell function decline in youth with type 1 or type 2 diabetes. PMID- 23645123 TI - Gait and cognition in Parkinson's disease: implications for rehabilitation. AB - An increasing awareness of the interaction between gait and cognition has occurred over recent time. This interaction is even more prominent in Parkinson's disease (PD), where the alteration of striatal dopamine deficiency places a greater emphasis on cognition to compensate for the gait disturbances seen in PD. This dissertation aims to provide an insight into this interaction in PD and demonstrate how normal gait control mechanisms are altered in PD to more cognitive control. Evidence will be provided which demonstrates a shift between attention and automatic gait control mechanisms toward attention. In addition, it will be demonstrated that, because of the cognitive dysfunction that also occurs in PD, the capacity to normalize gait still remains impaired and becomes more subject to the effects of external environmental influences. Further, a rationale will be provided to utilize this interaction in a more beneficial manner, to assist the attention control mechanisms to return gait towards normal. This latter approach is applicable to all aspects of gait disorders in PD and forms a basis for possible intervention therapies. PMID- 23645124 TI - Influence of sample type and delayed separation from cells on the measurement of B-type natriuretic peptide with the Architect system. PMID- 23645127 TI - Why do nonsurvivors from community-acquired pneumonia not receive ventilatory support? AB - OBJECTIVE: We investigated rates and predictors of ventilatory support during hospitalization in seemingly not severely compromised nonsurvivors of community acquired pneumonia (CAP). METHODS: We used the database from the German nationwide mandatory quality assurance program including all hospitalized patients with CAP from 2007 to 2011. We selected a population not residing in nursing homes, not bedridden, and not referred from another hospital. Predictors of ventilatory support were identified using a multivariate analysis. RESULTS: Overall, 563,901 patients (62.3% of the whole population) were included. Mean age was 69.4 +/- 16.6 years; 329,107 (58.4%) were male. Mortality was 39,895 (7.1%). A total of 28,410 (5.0%) received ventilatory support during the hospital course, and 76.3% of nonsurvivors did not receive ventilatory support (62.6% of those aged <65 years and 78% of those aged >=65 years). Higher age (relative risk (RR) 0.48, 95% confidence interval (CI) 0.44-0.51), failure to assess gas exchange (RR 0.18, 95% CI 0.14-0.25) and to administer antibiotics within 8 h of hospitalization (RR 0.48, 95% CI 0.39-0.59) were predictors of not receiving ventilatory support during hospitalization. Death from CAP occurred significantly earlier in the nonventilated group (8.2 +/- 8.9 vs. 13.1 +/- 14.1 days; p < 0.0001). CONCLUSIONS: The number of nonsurvivors without obvious reasons for withholding ventilatory support is disturbingly high, particularly in younger patients. Both performance predictors for not being ventilated remain ambiguous, because they may reflect either treatment restrictions or deficient clinical performance. Elucidating this ambiguity will be part of the forthcoming update of the quality assurance program. PMID- 23645128 TI - MMSET is the key molecular target in t(4;14) myeloma. PMID- 23645129 TI - Application of fluorescence in robotic general surgery: review of the literature and state of the art. AB - The initial use of the indocyanine green fluorescence imaging system was for sentinel lymph node biopsy in patients with breast or colorectal cancer. Since then, application of this method has received wide acceptance in various fields of surgical oncology, and it has become a valid diagnostic tool for guiding cancer treatment. It has also been employed in numerous conventional surgical procedures with much success and benefit to the patient. The advent of minimally invasive surgery brought with it a new use for fluorescence in helping to improve the safety of these procedures, particularly for single-site procedures. In 2010, a near-infrared camera was integrated into the da Vinci Si System, creating a combination of technical and minimally invasive advantages that have been embraced by several experienced surgeons. The use of fluorescence, although useful, is considered challenging. Only a few studies are currently available on the use of fluorescence in robotic general surgery, whereas many articles have focused on its application in open and laparoscopic surgery. Many of these reports describe promising and satisfactory results, although with some shortcomings. The purpose of this article is to review the current status of the use of fluorescence in general surgery and particularly its role in robotic surgery. We also review potential uses in the future. PMID- 23645130 TI - Preservation of the celiac branch of the vagus nerve during laparoscopy-assisted distal gastrectomy: impact on postprandial changes in ghrelin secretion. AB - BACKGROUND: Ghrelin is a brain-gut peptide with GH-releasing and appetite inducing properties. Because ghrelin is secreted mainly by the stomach, fasting levels fall after distal gastrectomy. The vagal nerve is responsible for periprandial changes. The presents study investigated the impact of preserving the celiac branch of the vagus nerve during laparoscopy-assisted distal gastrectomy on postoperative ghrelin secretion. METHOD: Between May 2009 and July 2010, 42 consecutive patients who underwent LADG were divided into two groups, the first in which the celiac branch of the vagus was preserved ("Preserved," n = 21) and the second in which it was not ("Not Preserved," n = 21). Blood samples were collected for assays of several hormones, including ghrelin, leptin, and insulin; these were taken before and 2 h after breakfast on postoperative day 7. RESULTS: There were no significant differences in the background characteristics of the two groups. Plasma fasting ghrelin decreased significantly after LADG, by about 50 % of the baseline values in both groups. Postprandial plasma ghrelin levels in the Preserved group were significantly lower than those in the Not Preserved group (23 +/- 8 vs 32 +/- 9 fmol/ml; p = 0.0058). The ratio of the total ghrelin concentration after breakfast to that before was defined as the A/B ratio. The mean preoperative and postoperative A/B ratios were almost the same in the Preserved group (preoperative vs postoperative: 0.41 vs 0.44; p = 0.52). On the other hand, the mean A/B ratio in the Not Preserved group increased from 0.41 to 0.61 postoperatively (preoperative vs postoperative; p = 0.0003). Preservation of the celiac branch of the vagus nerve during LADG was related to the prandial ghrelin changes. PMID- 23645131 TI - Evaluation of high-pitch flash scan for pulmonary venous CTA on a 128-slice dual source CT: compared with prospective ECG-triggered sequence scan. AB - To compare the image quality (IQ) and radiation dose of high-pitch scan and prospective ECG-triggered sequence scan on a 128-slice DSCT system for patients with atrial fibrillation (AF). Pulmonary venous (PV) CTA was performed with two protocols, including high-pitch scan and prospective ECG-triggered sequence scan. For each protocol, 20 sex, age and body-mass-index (mean 24.2 kg/m(2)) matched patients were identified. Two experienced radiologists, who were blinded to the scan protocols, independently graded the CT images of the two groups by a 5-point scale for subjective IQ assessment. Measured CT attenuation (Hounsfield units +/- standard deviation), signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) at various anatomic locations were also recorded for objective IQ evaluation. Radiation exposure parameters [dose length product (DLP) and effective radiation dose (ERD)] were compared. Twenty-three patients (57.5 %) showed an ECG pattern of AF in total. Subjective IQ was rated excellent in 100 % for the high-pitch scan group, while minor step artifacts were observed in two patients (10 %) with arrhythmia for the prospective ECG-triggered sequence group. There was no significant difference on IQ, neither by subjective, nor by objective measures (SNR, CNR) between the two groups. The ERD of high-pitch flash scan and prospective ECG-triggered sequence scan were 0.9 (+/- 0.25) and 2.9 (+/- 0.69) mSv, respectively. Significantly lower radiation was achieved by using high pitch flash scan (P < 0.05). High-pitch flash scan can provide similar subjective and objective IQ compared with prospective ECG-triggered sequence scan for PV CTA, while radiation exposure was significantly reduced. PMID- 23645132 TI - Programmable and automated bead-based microfluidics for versatile DNA microarrays under isothermal conditions. AB - Advances in modern genomic research depend heavily on applications of various devices for automated high- or ultra-throughput arrays. Micro- and nanofluidics offer possibilities for miniaturization and integration of many different arrays onto a single device. Therefore, such devices are becoming a platform of choice for developing analytical instruments for modern biotechnology. This paper presents an implementation of a bead-based microfluidic platform for fully automated and programmable DNA microarrays. The devices are designed to work under isothermal conditions as DNA immobilization and hybridization transfer are performed under steady temperature using reversible pH alterations of reaction solutions. This offers the possibility for integration of more selection modules onto a single chip compared to maintaining a temperature gradient. This novel technology allows integration of many modules on a single reusable chip reducing the application cost. The method takes advantage of demonstrated high-speed DNA hybridization kinetics and denaturation on beads under flow conditions, high fidelity of DNA hybridization, and small sample volumes are needed. The microfluidic devices are applied for a single nucleotide polymorphism analysis and DNA sequencing by synthesis without the need for fluorescent removal step. Apart from that, the microfluidic platform presented is applicable to many areas of modern biotechnology, including biosensor devices, DNA hybridization microarrays, molecular computation, on-chip nucleic acid selection, high throughput screening of chemical libraries for drug discovery. PMID- 23645133 TI - Development of in vitro macrophage system to evaluate phagocytosis and intracellular fate of Penicillium marneffei conidia. AB - Penicillium marneffei is a pathogenic fungus that can cause a life-threatening systemic mycosis in the immunocompromised hosts. We established the model for the phagocytosis of P. marneffei conidia by RAW264.7 murine macrophages and designated the fate of P. marneffei in RAW264.7 cells with respect to persistence, phagosome-lysosome-fusion. And we impaired the immune status of mouse and compared the fate and phagosome-lysosome-fusion of P. marneffei in immunocompetent and immunosuppressed mouse peritoneal macrophages cells. We found that conidia could germinate and survive in macrophages. Within 30 min and up to 2 h of heat-killed conidia internalization, the majority of all phagosome types were labeled for the EEA1 (endosomal markers) and LAMP-1 (lysosomal markers), respectively. But both the percentages of LAMP-1 and EEA1 that associated with live conidia were significantly lower than that with heat-killed conidia. Administration of cyclophosphamide resulted in a significant suppression of macrophages function (phagocytic and fungicidal) against P. marneffei that were not apparently seen. Our data provide the evidence that (i) intracellular conversion of P. marneffei conidia into yeast cells still could be observed in macrophages. (ii) Phagosomes containing live Penicillium marneffei conidia might inhibit the phagosome-lysosome-fusion and result to no acidification surrounding the organisms. (iii) Immunity impaired by cyclophosphamide could not influence the function, including phagocytosis, fungicidal activity and phagosome-lysosome fusion, of macrophages against P. marneffei. PMID- 23645135 TI - A case of relapsed chromoblastomycosis due to Fonsecaea monophora: antifungal susceptibility and phylogenetic analysis. AB - Chromoblastomycosis is a chronic cutaneous and subcutaneous mycosis. The management of this infection continues to be challenging because there is no consensus on the therapeutic regimen. We report here a case of a 69-year-old male patient with cauliflower-like lesions on his left leg and foot. He had already been treated with itraconazole at a dose of 200 mg/day for 5 months, with mycological cure for all the affected areas. However, the lesions relapsed at both sites, and treatment with itraconazole was resumed at the dose previously used. Initially, direct mycological examination, cultural, and microculture slide observation were performed. Afterward, sequencing of the ITS1-5.8S rDNA-ITS2 region of the fungal DNA and evaluation of its susceptibility to antifungal agents alone and in combination were performed. In direct mycological examination, the presence of sclerotic cells was verified, and the fungus was identified as Fonsecaea based on cultural and microscopic examinations. Identification as Fonsecaea monophora was confirmed after sequencing of the ITS region and phylogenetic analysis. The isolate was susceptible to itraconazole and terbinafine. The combinations of amphotericin B and terbinafine and terbinafine and voriconazole were synergistic. The use of drugs for which the causative agent is susceptible to singly or in combination may be an alternative for the treatment of mycosis. Furthermore, the identification of the agent by molecular techniques is important for epidemiological purposes. To the best of our knowledge, this is the first case of relapsed chromoblastomycosis caused by F. monophora in Brazil. PMID- 23645136 TI - Heart rate and the cardiometabolic risk. AB - Resting heart rate is a well recognized marker of autonomic nervous system tone, and in many population studies has been found to be a significant correlate of blood pressure, increased body mass index, and metabolic disturbances. This association is particularly striking in patients with hypertension or diabetes, and cardiovascular morbidity related to high heart rate in these conditions seems to depend mainly on the clustering of these risk factors. The prospective relationship between tachycardia and metabolic abnormalities found in longitudinal studies indicates that the adrenergic overdrive is the cause rather than the consequence of the insulin resistance state. Findings from observational studies and clinical trials have shown that heart rate measured during the follow up provides prognostic information over and above heart rate measured at baseline, whereas the predictive value of heart rate measured out of the office is still debated. Antihypertensive drugs that decrease blood pressure and heart rate through a reduction of the sympathetic outflow may be more beneficial in clinical situations characterized by heightened sympathetic activity associated to insulin resistance. PMID- 23645138 TI - Mutation of tyrosine 470 of human dopamine transporter is critical for HIV-1 Tat induced inhibition of dopamine transport and transporter conformational transitions. AB - HIV-1 Tat protein plays a crucial role in perturbations of the dopamine (DA) system. Our previous studies have demonstrated that Tat decreases DA uptake, and allosterically modulates DA transporter (DAT) function. In the present study, we have found that Tat interacts directly with DAT, leading to inhibition of DAT function. Through computational modeling and simulations, a potential recognition binding site of human DAT (hDAT) for Tat was predicted. Mutation of tyrosine470 (Y470H) attenuated Tat-induced inhibition of DA transport, implicating the functional relevance of this residue for Tat binding to hDAT. Y470H reduced the maximal velocity of [3H]DA uptake without changes in the K(m) and IC50 values for DA inhibition of DA uptake but increased DA uptake potency for cocaine and GBR12909, suggesting that this residue does not overlap with the binding sites in hDAT for substrate but is critical for these inhibitors. Furthermore, Y470H also led to transporter conformational transitions by affecting zinc modulation of DA uptake and WIN35,428 binding as well as enhancing basal DA efflux. Collectively, these findings demonstrate Tyr470 as a functional recognition residue in hDAT for Tat-induced inhibition of DA transport and transporter conformational transitions. The consequence of mutation at this residue is to block the functional binding of Tat to hDAT without affecting physiological DA transport. PMID- 23645139 TI - Clinical analysis of trigeminal neuralgia caused by vertebrobasilar dolichoectasia. AB - Our objective is to explore the clinical manifestations, imaging features, and therapy of trigeminal neuralgia (TN) caused by vertebrobasilar dolichoectasia (VBD). Clinical and imaging data of 11 cases with trigeminal neuralgia caused by VBD were retrospectively analyzed, and relevant literatures were reviewed. Of these 11 patients, 8 were male, and 10 suffered from hypertension. Imaging findings revealed that the vertebrobasilar arteries were pathologically enlarged and tortuous. Facial pain disappeared or was relieved after the microvascular decompression (MVD) in all 11 patients; no recrudescence was found with an average of 22-month follow-up. We concluded that TN caused by VBD, a rare clinical disease, mainly occurred in older men with a history of hypertension. CT, MRI, and MRA have great significance in the diagnosis of this disease; MVD is a preferred treatment method. PMID- 23645140 TI - Sylvian fissure arteriovenous malformations: long-term prognosis and risk factors. AB - BACKGROUND AND OBJECTIVE: Sylvian fissure arteriovenous malformations (AVMs) are among the most challenging AVMs to manage surgically. The estimates of their risk factors and prediction of their long-term prognosis are crucial for clinical decision-making. The authors conducted a retrospective review to patients with sylvian AVMs treated microsurgically to evaluate the risk factors associated with long-term prognosis. METHODS: Forty-one patients with sylvian fissure AVMs treated microsurgically between June 2009 and December 2011 were retrospectively reviewed with a mean follow-up time of 23 months (range 6-35 months). Chi-square test was utilized to compare proportions and rank-sum test to compare ordinal materials. Odds ratios (ORs) were used to assess risk factors associated with postoperative short-term outcome and long-term adverse outcome (mRS scores 3-6). RESULTS: One patient died in 1 month after surgery. Eighteen (43.9%) patients had postoperative transient neurological deterioration. Good outcomes (mRS scores 0 2) were observed in 29 (72.5%) patients in the follow-up. From the multiple logistic regression, a history of AVM bleeding and deep venous drainage increase the risk of postoperative transient neurological deterioration, with OR = 8.211 and OR = 4.869, respectively. A history of AVM bleeding was a risk factor for long-term adverse outcome, with OR = 7. CONCLUSIONS: Despite different Sugita classification subtypes, sylvian fissure AVMs' long-term results with microsurgical resection are better than expected; a history of AVM bleeding is a risk factor for postoperative temporary neurological deterioration and for long term adverse outcome, while the AVM deep venous drainage is a risk factor only for temporary neurological deterioration. PMID- 23645142 TI - Combining self-help and professional help to minimize barriers to physical activity in persons with multiple sclerosis: a trial of the "Blue Prescription" approach in New Zealand. AB - BACKGROUND AND PURPOSE: Increasing participation in physical activity is a goal for many health care providers working with persons with disability. In order to reduce the physical and social barriers to participation, there is a need to develop approaches that integrate self-help with professional help for autonomous yet supported health promotion. This study reports on an innovative program, entitled the "Blue Prescription approach", in which physical therapists work collaboratively with persons with a disability to promote community-based physical activity participation. METHODS: We trialed this collaborative approach with two physical therapists and 27 participants with multiple sclerosis (MS) over a three month period. We gathered qualitative data from four sources: (i) individual interviews with our participants, (ii) individual interviews with the physical therapists, (iii) clinical notes, and (iv) Advisory Group meeting notes. We then analyzed these data for categories to inform the content and resources required for delivery of the approach. RESULTS: For most participants, the Blue Prescription approach facilitated regular engagement in the physical activity of their choice. The Advisory Group provided advice to help solve individual contexts that presented as challenges to participants. Based on review of interview transcripts, we identified four strategies or issues to inform the further development of Blue Prescription. DISCUSSION AND CONCLUSIONS: Evidence indicated that the Blue Prescription approach can provide a collaborative and flexible way for physical therapists to work with individuals with MS, to increase participation in community-based physical activity. To further develop the approach, there is a need to address issues related to the use of standardized measures and develop strategies to train physical therapists in collaborative approaches for promotion of physical activity.The integration of self-help and professional help provided by the Blue Prescription approach appeared to result in successful promotion of physical activity in persons with MS. Additional testing is required to examine its efficacy in other health care systems, in conditions beyond MS, and in terms of its economic impact.Video Abstract available (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A46) for more insights from the authors. PMID- 23645143 TI - Advocacy: why now? PMID- 23645137 TI - Evidence for a dysregulated immune system in the etiology of psychiatric disorders. AB - There is extensive bi-directional communication between the brain and the immune system in both health and disease. In recent years, the role of an altered immune system in the etiology of major psychiatric disorders has become more apparent. Studies have demonstrated that some patients with major psychiatric disorders exhibit characteristic signs of immune dysregulation and that this may be a common pathophysiological mechanism that underlies the development and progression of these disorders. Furthermore, many psychiatric disorders are also often accompanied by chronic medical conditions related to immune dysfunction such as autoimmune diseases, diabetes and atherosclerosis. One of the major psychiatric disorders that has been associated with an altered immune system is schizophrenia, with approximately one third of patients with this disorder showing immunological abnormalities such as an altered cytokine profile in serum and cerebrospinal fluid. An altered cytokine profile is also found in a proportion of patients with major depressive disorder and is thought to be potentially related to the pathophysiology of this disorder. Emerging evidence suggests that altered immune parameters may also be implicated in the neurobiological etiology of autism spectrum disorders. Further support for a role of immune dysregulation in the pathophysiology of these psychiatric disorders comes from studies showing the immunomodulating effects of antipsychotics and antidepressants, and the mood altering effects of anti-inflammatory therapies. This review will not attempt to discuss all of the psychiatric disorders that have been associated with an augmented immune system, but will instead focus on several key disorders where dysregulation of this system has been implicated in their pathophysiology including depression, schizophrenia and autism spectrum disorder. PMID- 23645144 TI - Mortality risk among children initially treated with dialysis for end-stage kidney disease, 1990-2010. AB - IMPORTANCE: Most children with end-stage kidney disease (ESKD) are treated with dialysis prior to transplant. It is not known whether their outcomes have changed in recent years. OBJECTIVE: To determine if all-cause, cardiovascular, and infection-related mortality rates for children and adolescents beginning dialysis improved between 1990 and 2010. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of patients younger than 21 years initially treated with dialysis for ESKD, recorded in the United States Renal Data System between 1990 and 2010. Children with a prior kidney transplant were excluded. We used Cox proportional hazard models to estimate the hazard ratios (HRs) for mortality associated with a 5-year increment in year of ESKD treatment initiation. Primary analyses censored observation at kidney transplant. MAIN OUTCOMES AND MEASURES: All-cause, cardiovascular, and infection-related mortality. RESULTS: A total of 3450 children younger than 5 years and 19,951 children 5 years or older started dialysis from 1990-2010. Of those younger than 5 years, 705 died during dialysis treatment (98.8/1000 person-years); mortality rates were 112.2 and 83.4 per 1000 person-years in those initiating dialysis in 1990-1994 and 2005-2010, respectively. Of those 5 years and older at treatment initiation, 2270 died during dialysis treatment (38.6/1000 person-years). Their mortality rates were 44.6 and 25.9 per 1000 person-years in those initiating dialysis in 1990-1994 and 2005-2010, respectively. Each 5-year increment in calendar year of dialysis initiation was associated with an adjusted HR of 0.80 (95% CI, 0.75-0.85) among children younger than 5 years at initiation and an HR of 0.88 (95% CI, 0.85-0.92) among those 5 years and older. RESULTS: A total of 23,401 children and adolescents who initiated ESKD treatment with dialysis at younger than 21 years between 1990 and 2010 were identified. Crude mortality rates during dialysis treatment were higher among children younger than 5 years at the start of dialysis compared with those who were 5 years and older. Mortality rates for both children and adolescents being treated for ESKD with dialysis decreased significantly between 1990 and 2010. CONCLUSIONS AND RELEVANCE: In the United States, there was a substantial decrease in mortality rates over time among children and adolescents initiating ESKD treatment with dialysis between 1990 and 2010. Further research is needed to determine the specific factors responsible for this decrease. PMID- 23645145 TI - Representativeness of two sampling procedures for an internet intervention targeting cancer-related distress: a comparison of convenience and registry samples. AB - Internet interventions often rely on convenience sampling, yet convenience samples may differ in important ways from systematic recruitment approaches. The purpose of this study was to evaluate potential demographic, medical, and psychosocial differences between Internet-recruited and registry-recruited cancer survivors in an Internet-based intervention. Participants were recruited from a cancer registry (n = 80) and via broad Internet outreach efforts (n = 160). Participants completed a set of self-report questionnaires, and both samples were compared to a population-based sample of cancer survivors (n = 5,150). The Internet sample was younger, better educated, more likely to be female, had longer time since diagnosis, and had more advanced stage of disease (p's < .001), and the registry-sample was over-represented by men and those with prostate or other cancer types (p's < .001). The Internet sample also exhibited lower quality of life and social support and greater mood disturbance (p's < .001). Understanding how convenience and systematic samples differ has important implications for external validity and potential for dissemination of Internet based interventions. PMID- 23645146 TI - Socioeconomic status and health: education and income are independent and joint predictors of ambulatory blood pressure. AB - Epidemiological research suggests that different indicators of socioeconomic status (SES) such as income and education may have independent and/or interactive effects on health outcomes. In this study, we examined both simple and more complex associations (i.e., interactions) between different indicators of SES and ambulatory blood pressure (ABP) during daily life. Our sample consisted of 94 married couples who completed a one-day ABP protocol. Both income and education were independently related to systolic blood pressure and only income was significantly related to diastolic blood pressure. There were also statistical interactions such that individuals with high levels of both income and education evidenced the lowest ABP. Gender moderated these findings. Three-way interactions revealed that, in general, women appear to benefit from either indicator of SES, whereas men appear to benefit more from income. The findings are consistent with epidemiological research and suggest one important physiological mechanism by which income and education may have independent and interactive effects on health. PMID- 23645147 TI - The impact of age on outcomes in chronic obstructive pulmonary disease differs by relationship status. AB - Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that can lead to early-onset chronic obstructive pulmonary disease (COPD). The objective of this study was to examine the impact of age on psychological and clinical outcomes among individuals with AATD-associated COPD. 468 individuals with AATD-associated COPD (age 32-84 at baseline) completed questionnaires at baseline, 1- and 2-year follow-up. Age was examined as a predictor of depression, anxiety, health-related quality of life, and breathlessness at all three time points using linear mixed models. Age was associated with anxiety (b = -0.09, SE = 0.02, p < 0.001) and health-related quality of life (b = -0.29, SE = 0.09, p < 0.001). Age also had a statistically significant interaction with relationship status when predicting depression, health-related quality of life, and breathlessness. Among individuals who were single, younger age was associated with more symptoms of depression (b = -0.08, SE = 0.03, p < 0.01), worse health-related quality of life (b = -0.61, SE = 0.16, p < 0.001), and more breathlessness (b = -0.023, SE = 0.009, p < 0.01) throughout the 2-year study. Age was not associated with these three outcomes among individuals who were married/part of an unmarried couple. Results suggest that individuals who develop a chronic illness at a young age, particularly those who are single, may be more likely to have worse psychological and clinical outcomes. PMID- 23645148 TI - Decreased expression of long noncoding RNA AC096655.1-002 in gastric cancer and its clinical significance. AB - Long noncoding RNAs (lncRNAs) are newfound noncoding RNAs that are greater than 200 nucleotides in length. They have emerged recently as major players in governing fundamental biological processes. However, the expression level of lncRNAs and their clinical significances are not well understood. To investigate the lncRNA expression in gastric cancer, real-time reverse transcriptase polymerase chain reaction was conducted. Then, the association between the level of AC096655.1-002, one of lncRNA, in gastric cancer tissues and the clinicopathological features of patients with gastric cancer was further analyzed. Receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic values. The results showed that AC096655.1-002 was significantly downregulated in gastric cancer tissues compared with paired adjacent non-tumorous tissues (P < 0.001). Its expression level was significantly correlated with lymph node metastasis (P < 0.001), distant metastasis (P < 0.001), tumor-node-metastasis stages (P < 0.001), and differentiation (P = 0.030). The area under the ROC curve of AC096655.1-002 was up to 0.731. For the detection of gastric cancer, the use of AC096655.1-002 showed a remarkable improvement compared with the use of serum carcinoembryonic antigen. These results indicated that lncRNA AC096655.1-002 may be a potential biomarker in the diagnosis of gastric carcinoma. PMID- 23645149 TI - Models of physician-patient relationships in pharmaceutical direct-to-consumer advertising and consumer interviews. AB - The rise of direct-to-consumer advertising (DTCA) has mirrored, if not facilitated, the shift toward more active health care consumers. We used content analysis to identify models of physician-patient interaction in DTCA from the 1997 to 2006 issues of a broad sample of women's, men's, and common readership magazines. We also conducted 36 in-depth interviews to examine the ways consumers receive and regard advertising messages, and to explore their preferences for clinical communication and decision making. We identified four models of physician-patient relationships that vary in their locus of control (physician, patient, or shared) and the form of support sought or obtained in the relationship (emotional or instrumental). Whereas consumer interviews reflected references to all four models of interaction, only two appeared in DTCA. The limited range of interactions seen in these advertisements creates a lack of congruity between interaction styles found in advertisements vs. styles reported by actual consumers. PMID- 23645150 TI - Producing the "problem" of addiction in drug treatment. AB - In this article, we argue that the "problem" of addiction emerges as an effect of treatment policy and practice as well as a precursor to it. We draw on the work of Marrati to analyze interviews with policy makers and practitioners in Australia. The interviews suggest that the episode-of-care system governing service activity, outcomes, and funding relies on certain notions of addiction and treatment that compel service providers to designate service users as addicts to receive funding. This has a range of effects, not least that in acquiring the label of "addict," service users enter into bureaucratic and epidemiological systems aimed at quantifying addiction. Rather than treating pre-existing addicts, the system produces "addicts" as an effect of policy imperatives. Because addiction comes to be produced by the very system designed to treat it, the scale of the problem appears to be growing rather than shrinking. PMID- 23645152 TI - Alternative splice variants of the rainbow trout leptin receptor encode multiple circulating leptin-binding proteins. AB - In mammals, leptin (Lep) binding proteins (LepBPs) derived from Lep receptor (LepR) gene or protein bind most of the circulating Lep, but to date, information on LepBPs in nonmammalian vertebrate classes is lacking. This study details the characterization of multiple LepBPs in rainbow trout (Oncorhynchus mykiss), an early poikilothermic vertebrate, and presents the complete coding sequences for 3 of them. Size-exclusion chromatography and cross-linking assay identified plasma proteins bound to Lep ranging from 70 to 100 kDa. LepBPs were isolated from plasma by affinity chromatography, and their binding specificity was assessed by a competitive binding assay. A RIA for LepBPs indicates that plasma LepBP levels decline after fasting for 3 weeks. Immunoblotting of LepBPs using antibodies against different LepR epitopes shows that the LepBPs are indeed LepR isoforms. The alternatively spliced LepR transcripts (LepR(S1-3)) that include only the extracellular segment transcribe the 90-kDa LepBP1, the 80-kDa LepBP2, and the 70 kDa LepBP3, respectively. LepR(S1) generally has lower expression than the long form LepR in most tissues. LepR(S2) is primarily expressed in adipose tissue, whereas LepR(S3) is expressed abundantly in brain and spleen, and moderately in liver and gills. The mRNA levels of hepatic LepR(S3) increase after 2 weeks of fasting. This study demonstrates a mechanism in fish for the generation of LepBPs that differs from that seen in mammals and indicates that the physiologic action of Lep in these poikilothermic vertebrates can be modulated, both centrally and peripherally, by the differentiated, tissue-specific expression of multiple LepBPs. PMID- 23645151 TI - Amylin acts in the central nervous system to increase sympathetic nerve activity. AB - The pancreatic hormone amylin acts in the central nervous system (CNS) to decrease food intake and body weight. We hypothesized that amylin action in the CNS promotes energy expenditure by increasing the activity of the sympathetic nervous system. In mice, ip administration of amylin significantly increased c Fos immunoreactivity in hypothalamic and brainstem nuclei. In addition, mice treated with intracerebroventricular (icv) amylin (0.1 and 0.2 nmol) exhibited a dose-related decrease in food intake and body weight, measured 4 and 24 hours after treatment. The icv injection of amylin also increased body temperature in mice. Using direct multifiber sympathetic nerve recording, we found that icv amylin elicited a significant and dose-dependent increase in sympathetic nerve activity (SNA) subserving thermogenic brown adipose tissue (BAT). Of note, icv injection of amylin also evoked a significant and dose-related increase in lumbar and renal SNA. Importantly, icv pretreatment with the amylin receptor antagonist AC187 (20 nmol) abolished the BAT SNA response induced by icv amylin, indicating that the sympathetic effects of amylin are receptor-mediated. Conversely, icv amylin-induced BAT SNA response was enhanced in mice overexpressing the amylin receptor subunit, RAMP1 (receptor-activity modifying protein 1), in the CNS. Our data demonstrate that CNS action of amylin regulates sympathetic nerve outflow to peripheral tissues involved in energy balance and cardiovascular function. PMID- 23645153 TI - Effects of Clostridium difficile toxin A and B on human T lymphocyte migration. AB - Bacterial products such as toxins can interfere with a variety of cellular processes, leading to severe human diseases. Clostridium difficile toxins, TcdA and TcdB are the primary contributing factors to the pathogenesis of C. difficile associated diseases (CDAD). While the mechanisms for TcdA and TcdB mediated cellular responses are complex, it has been shown that these toxins can alter chemotactic responses of neutrophils and intestinal epithelial cells leading to innate immune responses and tissue damages. The effects of C. difficile toxins on the migration and trafficking of other leukocyte subsets, such as T lymphocytes, are not clear and may have potential implications for adaptive immunity. We investigated here the direct and indirect effects of TcdA and TcdB on the migration of human blood T cells using conventional cell migration assays and microfluidic devices. It has been found that, although both toxins decrease T cell motility, only TcdA but not TcdB decreases T cell chemotaxis. Similar effects are observed in T cell migration toward the TcdA- or TcdB-treated human epithelial cells. Our study demonstrated the primary role of TcdA (compared to TcdB) in altering T cell migration and chemotaxis, suggesting possible implications for C. difficile toxin mediated adaptive immune responses in CDAD. PMID- 23645154 TI - Sedimentation patterns of toxin-producing Microcystis morphospecies in freshwater reservoirs. AB - Understanding the annual cycle of Microcystis is essential for managing the blooms of this toxic cyanobacterium. The current work investigated the sedimentation of microcystin-producing Microcystis spp. in three reservoirs from Central Spain during the summer and autumn of 2006 and 2007. We confirmed remarkable settling fluxes during and after blooms ranging 10(6)-10(9) cells m( 2) d(-1), which might represent 0.1%-7.6% of the organic matter settled. A comprehensive analysis of the Valmayor reservoir showed average Microcystis settling rates (0.04 d(-1)) and velocities (0.7 m d(-1)) that resembled toxin settling in the same reservoir and were above most reported elsewhere. M. aeruginosa settling rate was significantly higher than that of M. novacekii and M. flos-aquae. Despite the fact that colony sizes did not differ significantly in their average settling rates, we observed extremely high and low rates in large colonies (>5000 cells) and a greater influence of a drop in temperature on small colonies (<1000 cells). We found a 4-14 fold decrease in microcystin cell quota in settling Microcystis of the Cogotas and Valmayor reservoirs compared with pelagic populations, and the hypothetical causes of this are discussed. Our study provides novel data on Microcystis settling patterns in Mediterranean Europe and highlights the need for including morphological, chemotypical and physiological criteria to address the sedimentation of complex Microcystis populations. PMID- 23645155 TI - Insights into diphthamide, key diphtheria toxin effector. AB - Diphtheria toxin (DT) inhibits eukaryotic translation elongation factor 2 (eEF2) by ADP-ribosylation in a fashion that requires diphthamide, a modified histidine residue on eEF2. In budding yeast, diphthamide formation involves seven genes, DPH1-DPH7. In an effort to further study diphthamide synthesis and interrelation among the Dph proteins, we found, by expression in E. coli and co-immune precipitation in yeast, that Dph1 and Dph2 interact and that they form a complex with Dph3. Protein-protein interaction mapping shows that Dph1-Dph3 complex formation can be dissected by progressive DPH1 gene truncations. This identifies N- and C-terminal domains on Dph1 that are crucial for diphthamide synthesis, DT action and cytotoxicity of sordarin, another microbial eEF2 inhibitor. Intriguingly, dph1 truncation mutants are sensitive to overexpression of DPH5, the gene necessary to synthesize diphthine from the first diphthamide pathway intermediate produced by Dph1-Dph3. This is in stark contrast to dph6 mutants, which also lack the ability to form diphthamide but are resistant to growth inhibition by excess Dph5 levels. As judged from site-specific mutagenesis, the amidation reaction itself relies on a conserved ATP binding domain in Dph6 that, when altered, blocks diphthamide formation and confers resistance to eEF2 inhibition by sordarin. PMID- 23645158 TI - The effect of intravenous magnesium sulfate on serum levels of N-terminal pro brain natriuretic peptide (NT pro-BNP) in elective CABG with cardiopulmonary bypass. AB - INTRODUCTION: Nowadays, many patients undergo coronary artery bypass grafting (CABG) with a cardiopulmonary bypass (CPB); while a number of therapeutic agents have been used to suppress its related inflammatory process. Magnesium sulfate (MgSO4) solution has been used as an anti-inflammatory agent. Among the cardiac biomarkers, N-terminal pro brain natriuretic peptide (NT Pro-BNP) is one of the most widely recognized. We performed this study to assess the effect of MgSO4 solution on NT Pro-BNP levels in patients undergoing CABG with CPB. MATERIALS AND METHODS: In a double-blind clinical trial, after IRB approval for ethical considerations, during a 12-month period, 88 adult patients aged 40-70 years qualified for the study after inclusion and exclusion criteria were considered. After random allocation of the patients between the two groups, anesthesia, surgical procedure, cardiopulmonary bypass (CPB) methods, and postoperative care were made as similar as possible; however, one group received a MgSO4 infusion (15 mg/kg/h) and the other group saline (placebo). Pre- and post-operative levels of NT Pro-BNP were assessed using an electrochemical luminescence immunoassay in an Elecsys 2010 (Roche, Indianapolis, IN, USA). The results were compared using a Student's t-test. A P value less than 5% was considered significant. RESULTS: The MgSO4 group had shorter postoperative mechanical ventilation, lower postoperative morphine requirements and lower postoperative pain scores. Also, 24 h postoperative NT Pro-BNP levels were significantly lower in the MgSO4 group. CONCLUSION: Administration of MgSO4 in elective CABG with CPB can decrease the postoperative NT Pro-BNP levels; also, it decreases their time of postoperative mechanical ventilation. PMID- 23645160 TI - Controlling DNA replication origins in response to DNA damage - inhibit globally, activate locally. AB - DNA replication in eukaryotic cells initiates from multiple replication origins that are distributed throughout the genome. Coordinating the usage of these origins is crucial to ensure complete and timely replication of the entire genome precisely once in each cell cycle. Replication origins fire according to a cell type-specific temporal programme, which is established in the G1 phase of each cell cycle. In response to conditions causing the slowing or stalling of DNA replication forks, the programme of origin firing is altered in two contrasting ways, depending on chromosomal context. First, inactive or 'dormant' replication origins in the vicinity of the stalled replication fork become activated and, second, the S phase checkpoint induces a global shutdown of further origin firing throughout the genome. Here, we review our current understanding on the role of dormant origins and the S phase checkpoint in the rescue of stalled forks and the completion of DNA replication in the presence of replicative stress. PMID- 23645161 TI - CORVET and HOPS tethering complexes - coordinators of endosome and lysosome fusion. AB - Protein and lipid transport along the endolysosomal system of eukaryotic cells depends on multiple fusion and fission events. Over the past few years, the molecular constituents of both fission and fusion machineries have been identified. Here, we focus on the mechanism of membrane fusion at endosomes, vacuoles and lysosomes, and in particular on the role of the two homologous tethering complexes called CORVET and HOPS. Both complexes are heterohexamers; they share four subunits, interact with Rab GTPases and soluble NSF attachment protein receptors (SNAREs) and can tether membranes. Owing to the presence of specific subunits, CORVET is a Rab5 effector complex, whereas HOPS can bind efficiently to late endosomes and lysosomes through Rab7. Based on the recently described overall structure of the HOPS complex and a number of in vivo and in vitro analyses, important insights into their function have been obtained. Here, we discuss the general function of both complexes in yeast and in metazoan cells in the context of endosomal biogenesis and maturation. PMID- 23645162 TI - Impact of machines on plan quality: volumetric modulated arc therapy and intensity modulated radiation therapy. AB - PURPOSE: To evaluate the impact of different machines on plan quality using both intensity modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) techniques. MATERIALS AND METHODS: Eight patients with squamous cell carcinoma of the oropharynx were selected at random. Plans were computed for IMRT and VMAT Smart Arc, using Pinnacle TPS for an Elekta (IMRT-E, VMAT-E) and Varian linac (IMRT-V, VMAT-V). A three-dose level prescription was used to deliver 70, 63 and 58.1 Gy to regions of macroscopic, microscopic high- and low-risk disease, respectively. All doses were given in 35 fractions. Comparisons were performed on dose-volume histogram data, monitor units (MU), and delivery time. RESULTS: VMAT E plans resulted slightly MU efficient (-24 % p < 0.05) compared to VMAT-V while IMRT-V shortened delivery time (-19 % p < 0.05) compared to IMRT-E. All the delivery techniques resulted in equivalent target coverage in terms of D(98) % and D(2) %. For VMAT technique, a significant improvement of 7 % in homogeneity index (HI) for PTV58.1 was observed for Varian machine. A slight improvement in OARs sparing was observed with Elekta machine both for IMRT and VMAT techniques. CONCLUSION: Similar plan quality was observed for Elekta and Varian linacs, significant differences were observed in delivery efficiency, as MU number and delivery times, in favor of Elekta and Varian, respectively. PMID- 23645163 TI - Possible involvement of PPAR-gamma in the anticonvulsant effect of Aegle marmelos (L.) Correa. AB - Aegle marmelos is well documented for antihyperglycemic effect and PPAR-gamma activation has been suggested to be the molecular mechanism of its action. Also, the plant has been used in Ayurveda as a brain tonic and has been postulated to have antidepressant activities. The present study was designed to investigate the anticonvulsant effects of A. marmelos leaf extract (AME) in pentylenetetrazole and maximal electroshock induced convulsions; involvement of PPAR-gamma, nitric oxide pathway and effect of chronic AME treatment on post-ictal depression. AME was administered at doses of 50, 100 and 200 mg kg(-1) in PTZ and MES model. Severity of convulsions was noted in both the models. Pretreatment with bisphenol A diglycidyl ether (BADGE) was used to study the involvement of PPAR-gamma and L arginine and N-nitro-L-arginine methyl ester hydrochloride (L-NAME) to study the involvement of nitric oxide (NO). Chronic treatment with AME interspersed with sub maximal doses of PTZ (50 mg kg(-1)) on every fifth day up to 15 days was given to study post-ictal depression using forced swimming and actophotometer. AME showed significant increase in the onset time and decrease in the duration of convulsions in PTZ and MES models dose dependently. In MES a dose of 100 mg kg( 1) had effect comparable to phenytoin. Pretreatment with BADGE and L-arginine reversed the protective effect while L-NAME did not alter the protective effect, thereby indicating possible involvement of PPAR-gamma and inhibition of NO. Chronic AME treatment ameliorated the post-seizure depression significantly as evidenced by increase in the locomotor activity and decrease in the immobility time. PMID- 23645164 TI - Prolonged rapamycin treatment led to beneficial metabolic switch. PMID- 23645165 TI - Allele frequencies for 15 autosomal STRs in a population sample from the Federal District (Brazil)-a territory that arose from nothing. AB - The Federal District (Brazil) was created in 1960 in the Central-West Region of Brazil in a previously unpopulated area. In 2010, this artificially founded district was populated by 2,562,963 inhabitants. In this study, the genetic variations of the 15 Next Generation Multiplex (NGM(TM)) short tandem repeat loci were analyzed. The results indicate that the NGM(TM) is a highly informative genetic system in this population, which is more similar to the southeastern, northeastern, and overall Brazil populations. This conclusion agrees with the population composition reported in the 2010 National Survey Inquiries, in which most of the immigrants were from the northeast and the southeast. PMID- 23645167 TI - To transplant or not: a dilemma for treatment of elderly AML patients in the twenty-first century. AB - AML treatment presents significant challenges in the elderly, who more often have poor risk cytogenetic and molecular markers, comorbidities and compromised performance status. Although population-based studies indicate that treated patients' survival is better than those who are not treated, there is an understandable reluctance of physicians to choose aggressive therapy. Even in this older population 40-60% CR rates are achievable. Several scoring systems and web-based programs help to predict TRM and CR rates. These sources can assist physicians in the difficult decision-making process of aggressive therapy in an individual patient. Clofarabine and hypomethylating agents are reasonable options and can induce CR in patients who cannot receive standard induction with anthracyclines and cytarabine. Despite encouraging CR rates, median survival remains short (<12 months) in elderly AML patients. Even those patients achieving CR have limited long-term survival (~20% at 3 years) without allogeneic hematopoietic cell transplantation (alloHCT). AlloHCT is feasible and can provide approximately 40% survival at 2 years in appropriately selected patients. Although increased age is associated with poorer survival, higher comorbidities and poor performance status have more negative impact than age per se. The short duration of CR demands that leukemia and transplant physicians collaborate immediately after diagnosis to move quickly toward alloHCT. This collaboration is also essential to choosing the right individuals to transplant and to bridging post-remission therapy (intermediate-dose cytarabine, a hypomethylating agent or FLT-3 inhibitor) in this sometimes frail population. Future studies should be designed not only to address who should receive alloHCT, but also to improve our understanding of AML biology and the process of its cure. PMID- 23645166 TI - A systematic review and meta-analysis of changes in cognitive functioning in adults undergoing hematopoietic cell transplantation. AB - Evidence is mixed regarding the effects of hematopoietic cell transplantation (HCT) on changes in cognitive functioning among adults. Meta-analysis, which is designed to help reconcile conflicting findings, has not yet been conducted on studies of adults receiving HCT. To fill this gap, the current study provides a systematic review and meta-analysis of cognitive functioning in adults receiving HCT. A search of PubMed, PsycInfo, CINAHL, and Cochrane Library yielded 732 abstracts, which were independently evaluated by pairs of raters. Seventeen studies were systematically reviewed; 11 were retained for meta-analysis. There was agreement that cognitive impairments are evident for a subset of patients before HCT. Meta-analytical findings of 404 patients revealed no significant changes in cognitive functioning pre- to post HCT (P-values >0.05). Age, time since transplant and TBI were not associated with changes in cognitive functioning. Patients who received autologous transplants were more likely to demonstrate improvements in attention (P=0.004). The systematic review identified several limitations of existing literature, including small, clinically heterogeneous samples. Large, cooperative group studies are needed to address these design limitations. Nevertheless, results from the current meta-analysis suggest that cognitive functioning does not significantly change following HCT. PMID- 23645168 TI - BK-virus prophylaxis: still no answer. PMID- 23645169 TI - Cellular immunotherapy for plasma cell myeloma. AB - Allogeneic hematopoietic cell transplantation for plasma cell myeloma can lead to graft-vs-myeloma immunity and long-term survivorship, but limited efficacy and associated toxicities have prevented its widespread use. Cellular immunotherapies seek to induce more specific, reliable and potent antimyeloma immune responses with less treatment-related risk than is possible with allogeneic transplantation. Strategies under development include infusion of vaccine-primed and ex vivo expanded/costimulated autologous T cells after high-dose melphalan, genetic engineering of autologous T cells with receptors for myeloma-specific epitopes, administration of DC/plasma cell fusions and administration expanded marrow-infiltrating lymphocytes. In addition, novel immunomodulatory drugs such as inhibitors of the programmed death-1 T cell regulatory pathway may synergize with cellular immunotherapies. PMID- 23645170 TI - A brachioulnoradial artery: a short report. AB - Variations in the number and/or course of the arteries of the upper limb have clinical and surgical significance. During routine dissection of the left upper limb of a 50-year-old male cadaver, a brachial artery was noted that bifurcated into superficial and deep branches in the middle arm. The ulnar and radial arteries had a high origin from the superficial branch and proceeded superficially in the forearm, but had a normal termination in the hand. The common interosseous artery was termination of the deep branch. This report is a rare variation in arteries of upper limb and was not additional vessels. PMID- 23645171 TI - The mucosal folds at the pancreaticobiliary junction. AB - PURPOSE: The structure and function of the mucosal folds in the terminal bile and pancreatic ducts and hepatopancreatic ampulla are poorly characterised. The distribution, muscularity, and innervation of these folds were investigated. METHODS: The pancreaticobiliary junction was excised from ten cadavers (five male, 66-90 years) and examined histologically by serially sectioning (4-MUm thickness) along the length of the terminal bile and pancreatic ducts from the tip of the major duodenal papilla. Three surgical specimens (two male, 63-72 years) were also evaluated. Sections were stained with haematoxylin and eosin, anti-actin (smooth muscle), anti-S100 (innervation), and anti-cholecystokinin (CCK)-A receptor antibodies. ImageJ software was used to compare relative radial fold projection and semi-quantitatively assess the smooth muscle and nerve content. In one additional cadaver specimen, folds were examined by scanning electron microscopy. RESULTS: Mucosal folds in the terminal bile duct were arranged circumferentially in a lattice-like arrangement and were distributed over an average distance of 7.3 mm along the terminal bile duct compared to 4.2 mm along the pancreatic duct (P = 0.001), projected further into the lumen, and were more densely innervated than those in the terminal pancreatic duct. Folds in both ducts contained smooth muscle which was more prominent in folds nearest to the major duodenal papilla. Mucosal folds in cadaver and surgical specimens showed no evidence of CCK-A receptor immunoreactivity. CONCLUSIONS: This study demonstrates that the mucosal folds of the terminal bile and pancreatic ducts contain muscle and nerve fibres, suggesting an active rather than purely passive function. PMID- 23645172 TI - Workshop meeting report Organs-on-Chips: human disease models. AB - The concept of "Organs-on-Chips" has recently evolved and has been described as 3D (mini-) organs or tissues consisting of multiple and different cell types interacting with each other under closely controlled conditions, grown in a microfluidic chip, and mimicking the complex structures and cellular interactions in and between different cell types and organs in vivo, enabling the real time monitoring of cellular processes. In combination with the emerging iPSC (induced pluripotent stem cell) field this development offers unprecedented opportunities to develop human in vitro models for healthy and diseased organ tissues, enabling the investigation of fundamental mechanisms in disease development, drug toxicity screening, drug target discovery and drug development, and the replacement of animal testing. Capturing the genetic background of the iPSC donor in the organ or disease model carries the promise to move towards "in vitro clinical trials", reducing costs for drug development and furthering the concept of personalized medicine and companion diagnostics. During the Lorentz workshop (Leiden, September 2012) an international multidisciplinary group of experts discussed the current state of the art, available and emerging technologies, applications and how to proceed in the field. Organ-on-a-chip platform technologies are expected to revolutionize cell biology in general and drug development in particular. PMID- 23645174 TI - Persistence and intergenerational transmission of differentially expressed genes in the testes of intracytoplasmic sperm injection conceived mice. AB - Intracytoplasmic sperm injection (ICSI) is commonly used to solve male infertility problems. Previous studies showed that early environmental exposure of an embryo may influence postnatal development. To detect whether ICSI operations affect the reproductive health of a male or his offspring, we established assisted reproductive technologies (ART) conceived mouse models, and analyzed gene expression profiles in the testes of both ICSI and naturally conceived (NC) newborn F1 mice using micro-array analysis. Among the differentially expressed genes, we focused on the expression of eight male reproduction-related genes. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze the expression of these genes in the testes of both adult and old F1 generation mice and adult F2 generation mice. Our results showed that down-regulated and somatic cell expressed genes in newborn mice retained their differential expression patterns in adult and old F1 generation individuals, implying the persistence and fetal origin of the alteration in the expression of these genes. The intergenerational transmission of differential gene expression was observed, but most changes tended to be reduced in adult F2 generations. Controlled ovarian hyperstimulation (COH) and in vitro fertilization (IVF) mice models were added to explore the precise factors contributing to the differences in ICSI offspring. The data demonstrated that superovulation, in vitro culture, and mechanical stimulation involved in ICSI had a cumulative effect on the differential expression of these male reproductive genes. PMID- 23645173 TI - Long-term follow-up of children conceived through assisted reproductive technology. AB - Children conceived via assisted reproductive technologies (ART) are nowadays a substantial proportion of the population. It is important to follow up these children and evaluate whether they have elevated health risks compared to naturally conceived (NC) children. In recent years there has been a lot of work in this field. This review will summarize what is known about the health of ART conceived children, encompassing neonatal outcomes, birth defects, growth and gonadal developments, physical health, neurological and neurodevelopmental outcomes, psychosocial developments, risk for cancer, and epigenetic abnormalities. Most of the children conceived after ART are normal. However, there is increasing evidence that ART-conceived children are at higher risk of poor perinatal outcome, birth defects, and epigenetic disorders, and the mechanism(s) leading to these changes have not been elucidated. Continuous follow up of children after ART is of great importance as they progress through adolescence into adulthood, and new ART techniques are constantly being introduced. PMID- 23645175 TI - Protective effect of hydrogen-rich saline on ischemia/reperfusion injury in rat skin flap. AB - OBJECTIVE: Skin damage induced by ischemia/reperfusion (I/R) is a multifactorial process that often occurs in plastic surgery. The mechanisms of I/R injury include hypoxia, inflammation, and oxidative damage. Hydrogen gas has been reported to alleviate cerebral I/R injury by acting as a free radical scavenger. Here, we assessed the protective effect of hydrogen-rich saline (HRS) on skin flap I/R injury. METHODS: Abdominal skin flaps of rats were elevated and ischemia was induced for 3 h; subsequently, HRS or physiological saline was administered intraperitoneally 10 min before reperfusion. On postoperative Day 5, flap survival, blood perfusion, the accumulation of reactive oxygen species (ROS), and levels of cytokines were evaluated. Histological examinations were performed to assess inflammatory cell infiltration. RESULTS: Skin flap survival and blood flow perfusion were improved by HRS relative to the controls. The production of malondialdehyde (MDA), an indicator of lipid peroxidation, was markedly reduced. A multiplex cytokine assay revealed that HRS reduced the elevation in the levels of inflammatory cytokines, chemokines and growth factors, with the exception of RANTES (regulated on activation, normal T-cell expressed and secreted) growth factor. HRS treatment also reduced inflammatory cell infiltration induced by I/R injury. CONCLUSIONS: Our findings suggest that HRS mitigates I/R injury by decreasing inflammation and, therefore, has the potential for application as a therapy for improving skin flap survival. PMID- 23645176 TI - Serum lipids and other risk factors for diabetic retinopathy in Chinese type 2 diabetic patients. AB - OBJECTIVE: To investigate the association of serum lipids and other risk factors with diabetic retinopathy (DR) in Chinese type 2 diabetic patients. METHODS: Five hundred and twenty-three type 2 diabetic patients underwent ophthalmic examination by experienced retinal specialists to assess their DR. Serum lipids, including triglycerides, total cholesterol, high density lipoprotein cholesterol (HDLC), and low density lipoprotein cholesterol (LDLC), were measured using Roche automated clinical chemistry analyzers. The concentration of very low density lipoprotein cholesterol (VLDLC) was calculated based on total cholesterol, HDLC and LDLC. Hyperlipidemia was defined as a total cholesterol concentration of 6.2 mmol/L or higher or the use of lipid-lowering medications. The association of risk factors with any DR or proliferative diabetic retinopathy (PDR) was assessed using the odds ratio (OR) and its 95% confidence interval (CI), calculated from logistic regression models. RESULTS: In multivariate logistic regression models, hyperlipidemia (OR=2.39, 95% CI: 1.02-5.66), higher VLDLC (OR=1.59, 95% CI: 1.14 2.23), and higher triglyceride (OR=1.18, 95% CI: 1.03-1.37) were associated with increased risk of DR. A longer diabetic duration was associated with increased risk of DR (P<0.0001) and PDR (P=0.002) in a dose-response manner. Higher systolic blood pressure (P=0.02) and higher serum creatinine (P=0.01) were independently associated with increased risk of DR, and female gender was associated with increased risk of PDR (P=0.03). CONCLUSIONS: Among Chinese type 2 diabetic patients, hyperlipidemia, higher VLDLC, and higher triglyceride were independently associated with increased risk of DR, suggesting control of serum lipids may decrease the risk of DR. PMID- 23645177 TI - Levosimendan versus dobutamine in critically ill patients: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the clinical efficacy of levosimendan versus dobutamine in critically ill patients requiring inotropic support. METHODS: Clinical trials were searched in PubMed, EMBASE, and the Cochrane Central Registry of Clinical Trials, as well as Web of Science. Studies were included if they compared levosimendan with dobutamine in critically ill patients requiring inotropic support, and provided at least one outcome of interest. Outcomes of interest included mortality, incidence of hypotension, supraventricular arrhythmias, and ventricular arrhythmias. RESULTS: Data from a total of 3052 patients from 22 randomized controlled trials (RCTs) were included in the analysis. Overall analysis showed that the use of levosimendan was associated with a significant reduction in mortality (269 of 1373 [19.6%] in the levosimendan group, versus 328 of 1278 [25.7%] in the dobutamine group, risk ratio (RR)=0.81, 95% confidence interval (CI) 0.70-0.92, P for effect=0.002). Subgroup analysis indicated that the benefit from levosimendan could be found in the subpopulations of cardiac surgery, ischemic heart failure, and concomitant beta-blocker therapy in comparison with dobutamine. There was no significant difference in the incidence of hypotension, supraventricular arrhythmias, or ventricular arrhythmias between the two drugs. CONCLUSIONS: In contrast with dobutamine, levosimendan is associated with a significant improvement in mortality in critically ill patients requiring inotropic support. Patients having cardiac surgery, with ischemic heart failure, and receiving concomitant beta-blocker therapy may benefit from levosimendan. More RCTs are required to address the questions about no positive outcomes in the subpopulation in a cardiology setting, and to confirm the advantages in long-term prognosis. PMID- 23645178 TI - Short-term microbiological effects of scaling and root planing and essential-oils mouthwash in Chinese adults. AB - OBJECTIVE: To assess the short-term effect of scaling and root planing (SRP) and essential-oils mouthwash on the levels of specific bacteria in Chinese adults. METHODS: Fifty Chinese adults with chronic periodontitis were randomly assigned to full-mouth SRP or a 7-d essential-oils mouthwash regimen. In addition, 22 periodontally healthy adults used essential-oils mouthwash for 7 d. Clinical examination and plaque/saliva sampling were performed at baseline and on Day 7. Quantitative real-time polymerase chain reaction (PCR) was used to measure Aggregatibacter actinomycetemcomitans (Aa), Fusobacterium nucleatum (Fn), Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), and total bacterial loads in saliva, supra- and sub-gingival plaque samples. RESULTS: The detection frequencies of four tested species remained unchanged after either treatment. However, the bacterial loads of Fn, Pg, and Pi were significantly reduced by SRP; the mean reduction of bacterial counts in saliva ranged from 52.2% to 62.5% (p<0.01), in supragingival plaque from 68.2% to 81.0% (p<0.05), and in subgingival plaque from 67.9% to 93.0% (p<0.01). Total bacterial loads were reduced after SRP in supra- and sub-gingival plaque (p<0.05). Essential-oils mouthwash reduced Fn levels in supragingival plaque by a mean of 53.2%, and reduced total bacterial loads in supra- and sub-gingival plaque (p<0.01). In subgingival plaque from periodontal patients, Pg and Pi reductions were high after SRP compared to essential-oils mouthwash (93.0% vs. 37.7% and 87.0% vs. 21.0%, p<0.05). No significant bacterial reduction was observed in periodontally healthy subjects using essential-oils mouthwash. CONCLUSIONS: SRP and essential oils mouthwash both have an impact on saliva and gingival plaque flora in Chinese periodontitis patients in 7 d, with greater microbiological improvement by SRP. PMID- 23645179 TI - Effects of sodium ferulate on preventing steroid-induced femoral head osteonecrosis in rabbits. AB - The aim of this study is to investigate the effects and possible mechanisms of sodium ferulate (SF) on anti-apoptosis in steroid-induced femoral head osteonecrosis in rabbits. Japanese white rabbits were randomly divided into three groups (control group, treatment group, and model group), each with 24 rabbits. The model and treatment groups were first injected with an intravenous dose of horse serum, 10 ml/kg, three weeks later with an intravenous dose of 7.5 ml/kg, and two weeks later with an intramuscular dose of methylprednisolone, 45 mg/kg, three times in order to establish rabbit models of osteonecrosis. Concurrently, the treatment group was injected with intravenous doses of SF 20 mg/kg for two weeks, once per day. Three time points, Weeks 2, 4, and 8, were selected after modeling was completed. Osteonecrosis was verified by histopathology with haematoxylin-eosin (HE) staining. The apoptosis rate of osteonecrosis was observed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The apoptosis expressions of caspase-3 and Bcl-2 were analyzed by immunohistochemistry and Western blot. The rabbit models of osteonecrosis were successfully established and observed by HE staining. SF was effective in intervening in apoptosis and decreasing the apoptosis rate in femoral head necrosis by the immunohistochemistry and TUNEL assay (P<0.01). Western blot analysis indicated that there were statistical significances in the protein levels of caspase-3 and Bcl-2 (P<0.01). SF has a protective effect by reducing the incidence of early steroid-induced femoral head necrosis in rabbits, effectively intervening in apoptosis through decreasing caspase-3 expression and up-regulating Bcl-2 expression. PMID- 23645180 TI - Long-term comparison of full-bed deep anterior lamellar keratoplasty and penetrating keratoplasty in treating keratoconus. AB - OBJECTIVE: To compare postoperative outcomes of full-bed deep anterior lamellar keratoplasty (DALK) with penetrating keratoplasty (PK) in treating keratoconus. METHODS: Seventy-five eyes of 64 patients who received full-bed DALK and 52 eyes of 51 patients who received PK between June 2000 and August 2010 were included in this retrospective study. Full-bed DALK was performed using Yao's hooking detaching technique. PK was performed using a standard technique. Intraoperative and postoperative complications, visual acuity, rejection, graft survival, endothelial cell density, corneal sensation recovery, and re-innervation were compared between the two groups. RESULTS: A best correct visual acuity of 0.5 or better was achieved in 90.7% of eyes after full-bed DALK and in 92.3% of eyes after PK (P=0.75). By the fifth postoperative year, graft endothelial cell loss reached 34.6% in the PK group vs. 13.9% in the full-bed DALK group (P<0.001). There were no statistical differences in corneal sensitivity recovery or corneal re-innervation between the groups (P>0.05). Intraoperative microperforation occurred in seven out of 75 (9.3%) eyes with a temporally postoperative double anterior chamber in two eyes in the full-bed DALK group. Postoperative complications in the PK vs. the full-bed DALK groups respectively were: rejection (7.7% vs. 0%, P=0.015), high intraocular pressure (IOP) (46.2% vs. 1.3%, P<0.001), secondary glaucoma (9.6% vs. 0%, P=0.006), complicated cataract (19.2% vs. 0%, P<0.001), and wound dehiscence (9.6% vs. 0%, P=0.006). CONCLUSIONS: Both full-bed DALK and PK can offer long-term satisfactory visual outcomes for keratoconus. Graft rejection, secondary glaucoma, complicated cataracts, and constant endothelial cell loss were observed in eyes only after PK. PMID- 23645183 TI - Burning mouth syndrome: a review of recent literature. AB - Burning mouth syndrome (BMS) is a complex chronic disorder of orofacial sensation that is challenging in both diagnosis and treatment. The diagnosis of BMS is primarily one of exclusion, and recently classification of the disorder has been challenged. Although the exact pathophysiology of primary BMS is unknown, there has been a growing body of work to provide insight into the pathogenesis of the disorder over the past few years. Pharmacological treatments recently reported to have some success in BMS include anxiolytics, anticonvulsants, antidepressants, atypical antipsychotics, histamine receptor antagonist, and dopamine agonists. In addition, other therapies and treatments are being considered. This paper reports many of the most recent data related to BMS and its classification, diagnosis, impact on quality of life, pathophysiology, co-morbidities, and pharmacological and non-pharmacological treatments. PMID- 23645184 TI - Pediatric headache: associated psychosocial factors and psychological treatment. AB - All relevant databases (i.e., Pubmed, PsycINFO) were searched for studies published in 2011-2013 focusing on the association of behavioral, cognitive emotional, and psychosocial factors with recurrent headache in children and adolescents. Only 3 studies were found dealing with psychological intervention for headache; only 2 of them presented empirical data but were not conducted as a RCT. Eleven studies (clinical and population) were concerned with the association of psychosocial factors, dysfunctional psychological traits, and symptoms and headache or examined certain pain features (triggers, course over time, disability). Most studies were interested in the association of cognitive emotional symptoms (e.g., internalizing symptoms, anxiety) and their relation to headache, including a meta-analysis. In nearly all studies, a close bond between negative affectivity and headache, especially migraine, was revealed. PMID- 23645185 TI - Assessment of antimicrobial prophylaxis to prevent perioperative infection in patients undergoing prostate brachytherapy: multicenter cohort study. AB - To propose an appropriate prophylactic antimicrobial therapy for patients undergoing brachytherapy, we evaluated the relationships between various antimicrobial prophylaxis (AMP) protocols and the incidence of postimplant infections in a multicenter cohort study conducted in Japan. The records of 826 patients with localized prostate cancer who underwent a transperineal (125)I brachytherapy procedure between January 2009 and December 2010 were retrospectively reviewed. Perioperative infections, including surgical site and remote infections, were recorded up to postoperative day 30. A total of 6 (0.73%) patients had a perioperative infection following seed implantation, of whom all received AMP for 1 or more days. None of the patients who received a single-dose protocol of AMP using fluoroquinolone p.o. or penicillin with a beta-lactamase inhibitor i.v. developed a perioperative infection. Statistical analysis showed that a single-dose protocol was more significantly related to a lower risk of perioperative infection as compared to the other AMP protocols examined (p = 0.045). Furthermore, our results indicated that bacteriuria and preoperative hair removal were risk factors of perioperative infection with statistical significance (p = 0.007, p = 0.004). Analysis of patient clinical parameters, including age, American Society of Anesthesiologists score, diabetes mellitus, prostate volume, numbers of implanted seeds and needle punctures, operation time, and indwelling duration time of the Foley catheter, did not reveal significant differences in terms of perioperative infection. Our results indicated that a single-dose AMP protocol is sufficient to prevent perioperative infections following seed implantation. On the other hand, AMP is only one of several measures to prevent perioperative infectious complications. It is necessary to know that the patient must have no bacteriuria and that preoperative hair removal should be avoided. PMID- 23645186 TI - Assessment of identity and quality of life in diabetic and renal transplant adolescents in comparison to healthy adolescents. AB - Identity development represents a central task of adolescence. Identity achievement is characterized by a coherent sense of who one is following a period of exploration and can help navigate the challenges of adulthood. This study examined identity within a quality of life (QOL) context in 85 adolescents with a renal transplant or with Type 1 diabetes in comparison to 90 healthy controls. Results revealed significant differences in ideological identity, with patients showing higher levels of diffusion and controls showing higher levels of foreclosure. No differences with respect to interpersonal identity, QOL, perceived control over the QOL domains, and perceived opportunities for growth and development were found. Future research should assess identity and QOL over a longer period of time to determine whether differences between chronically ill and healthy young adults can be detected. PMID- 23645187 TI - Association of major depression with sexual dysfunction in men. AB - The effect of type and severity of depression on sexual functioning was examined before treatment in 591 men with Major Depression (MDD) or Atypical Depression, as determined by percentage of subjects meeting Diagnostic and Statistical Manual, 4th Edition (DSM-IV) sexual dysfunction criteria (A and B only), and percentage with Derogatis Inventory of Sexual Function (DISF) scores greater than 1 standard deviation below normal. Sexual dysfunction rates were higher for MDD than for Atypical Depression. Depression affected DISF domains differently: orgasm was most impaired, whereas sexual desire was preserved. More severe depression resulted in greater sexual dysfunction. PMID- 23645188 TI - Preordering school lunch encourages better food choices by children. PMID- 23645189 TI - New group in the Leptospirillum clade: cultivation-independent community genomics, proteomics, and transcriptomics of the new species "Leptospirillum group IV UBA BS". AB - Leptospirillum spp. are widespread members of acidophilic microbial communities that catalyze ferrous iron oxidation, thereby increasing sulfide mineral dissolution rates. These bacteria play important roles in environmental acidification and are harnessed for bioleaching-based metal recovery. Known members of the Leptospirillum clade of the Nitrospira phylum are Leptospirillum ferrooxidans (group I), Leptospirillum ferriphilum and "Leptospirillum rubarum" (group II), and Leptospirillum ferrodiazotrophum (group III). In the Richmond Mine acid mine drainage (AMD) system, biofilm formation is initiated by L. rubarum; L. ferrodiazotrophum appears in later developmental stages. Here we used community metagenomic data from unusual, thick floating biofilms to identify distinguishing metabolic traits in a rare and uncultivated community member, the new species "Leptospirillum group IV UBA BS." These biofilms typically also contain a variety of Archaea, Actinobacteria, and a few other Leptospirillum spp. The Leptospirillum group IV UBA BS species shares 98% 16S rRNA sequence identity and 70% average amino acid identity between orthologs with its closest relative, L. ferrodiazotrophum. The presence of nitrogen fixation and reverse tricarboxylic acid (TCA) cycle proteins suggest an autotrophic metabolism similar to that of L. ferrodiazotrophum, while hydrogenase proteins suggest anaerobic metabolism. Community transcriptomic and proteomic analyses demonstrate expression of a multicopper oxidase unique to this species, as well as hydrogenases and core metabolic genes. Results suggest that the Leptospirillum group IV UBA BS species might play important roles in carbon fixation, nitrogen fixation, hydrogen metabolism, and iron oxidation in some acidic environments. PMID- 23645190 TI - Novel Rickettsiella bacterium in the leafhopper Orosius albicinctus (Hemiptera: Cicadellidae). AB - Bacteria in the genus Rickettsiella (Coxiellaceae), which are mainly known as arthropod pathogens, are emerging as excellent models to study transitions between mutualism and pathogenicity. The current report characterizes a novel Rickettsiella found in the leafhopper Orosius albicinctus (Hemiptera: Cicadellidae), a major vector of phytoplasma diseases in Europe and Asia. Denaturing gradient gel electrophoresis (DGGE) and pyrosequencing were used to survey the main symbionts of O. albicinctus, revealing the obligate symbionts Sulcia and Nasuia, and the facultative symbionts Arsenophonus and Wolbachia, in addition to Rickettsiella. The leafhopper Rickettsiella is allied with bacteria found in ticks. Screening O. albicinctus from the field showed that Rickettsiella is highly prevalent, with over 60% of individuals infected. A stable Rickettsiella infection was maintained in a leafhopper laboratory colony for at least 10 generations, and fluorescence microscopy localized bacteria to accessory glands of the female reproductive tract, suggesting that the bacterium is vertically transmitted. Future studies will be needed to examine how Rickettsiella affects host fitess and its ability to vector phytopathogens. PMID- 23645191 TI - Enzymatic synthesis and characterization of fructooligosaccharides and novel maltosylfructosides by inulosucrase from Lactobacillus gasseri DSM 20604. AB - The ability of an inulosucrase (IS) from Lactobacillus gasseri DSM 20604 to synthesize fructooligosaccharides (FOS) and maltosylfructosides (MFOS) in the presence of sucrose and sucrose-maltose mixtures was investigated after optimization of synthesis conditions, including enzyme concentration, temperature, pH, and reaction time. The maximum formation of FOS, which consist of beta-2,1-linked fructose to sucrose, was 45% (in weight with respect to the initial amount of sucrose) and was obtained after 24 h of reaction at 55 degrees C in the presence of sucrose (300 g liter(-1)) and 1.6 U ml(-1) of IS-25 mM sodium acetate buffer-1 mM CaCl2 (pH 5.2). The production of MFOS was also studied as a function of the initial ratios of sucrose to maltose (10:50, 20:40, 30:30, and 40:20, expressed in g 100 ml(-1)). The highest yield in total MFOS was attained after 24 to 32 h of reaction time and ranged from 13% (10:50 sucrose/maltose) to 52% (30:30 sucrose/maltose) in weight with respect to the initial amount of maltose. Nuclear magnetic resonance (NMR) structural characterization indicated that IS from L. gasseri specifically transferred fructose moieties of sucrose to either C-1 of the reducing end or C-6 of the nonreducing end of maltose. Thus, the trisaccharide erlose [alpha-d glucopyranosyl-(1->4)-alpha-d-glucopyranosyl-(1->2)-beta-d-fructofuranoside] was the main synthesized MFOS followed by neo-erlose [beta-d-fructofuranosyl-(2->6) alpha-d-glucopyranosyl-(1->4)-alpha-d-glucopyranose]. The formation of MFOS with a higher degree of polymerization was also demonstrated by the transfer of additional fructose residues to C-1 of either the beta-2,1-linked fructose or the beta-2,6-linked fructose to maltose, revealing the capacity of MFOS to serve as acceptors. PMID- 23645192 TI - Preconditioning with cations increases the attachment of Anoxybacillus flavithermus and Geobacillus species to stainless steel. AB - Preconditioning of Anoxybacillus flavithermus E16 and Geobacillus sp. strain F75 with cations prior to attachment often significantly increased (P <= 0.05) the number of viable cells that attached to stainless steel (by up to 1.5 log CFU/cm(2)) compared with unconditioned bacteria. It is proposed that the transition of A. flavithermus and Geobacillus spp. from milk formulations to stainless steel product contact surfaces in milk powder manufacturing plants is mediated predominantly by bacterial physiological factors (e.g., surface-exposed adhesins) rather than the concentrations of cations in milk formulations surrounding bacteria. PMID- 23645194 TI - Engineering the soil bacterium Pseudomonas putida for arsenic methylation. AB - Accumulation of arsenic has potential health risks through consumption of food. Here, we inserted the arsenite [As(III)] S-adenosylmethionine methyltransferase (ArsM) gene into the chromosome of Pseudomonas putida KT2440. Recombinant bacteria methylate inorganic arsenic into less toxic organoarsenicals. This has the potential for bioremediation of environmental arsenic and reducing arsenic contamination in food. PMID- 23645193 TI - Insights into exo- and endoglucanase activities of family 6 glycoside hydrolases from Podospora anserina. AB - The ascomycete Podospora anserina is a coprophilous fungus that grows at late stages on droppings of herbivores. Its genome encodes a large diversity of carbohydrate-active enzymes. Among them, four genes encode glycoside hydrolases from family 6 (GH6), the members of which comprise putative endoglucanases and exoglucanases, some of them exerting important functions for biomass degradation in fungi. Therefore, this family was selected for functional analysis. Three of the enzymes, P. anserina Cel6A (PaCel6A), PaCel6B, and PaCel6C, were functionally expressed in the yeast Pichia pastoris. All three GH6 enzymes hydrolyzed crystalline and amorphous cellulose but were inactive on hydroxyethyl cellulose, mannan, galactomannan, xyloglucan, arabinoxylan, arabinan, xylan, and pectin. PaCel6A had a catalytic efficiency on cellotetraose comparable to that of Trichoderma reesei Cel6A (TrCel6A), but PaCel6B and PaCel6C were clearly less efficient. PaCel6A was the enzyme with the highest stability at 45 degrees C, while PaCel6C was the least stable enzyme, losing more than 50% of its activity after incubation at temperatures above 30 degrees C for 24 h. In contrast to TrCel6A, all three studied P. anserina GH6 cellulases were stable over a wide range of pHs and conserved high activity at pH values of up to 9. Each enzyme displayed a distinct substrate and product profile, highlighting different modes of action, with PaCel6A being the enzyme most similar to TrCel6A. PaCel6B was the only enzyme with higher specific activity on carboxymethylcellulose (CMC) than on Avicel and showed lower processivity than the others. Structural modeling predicts an open catalytic cleft, suggesting that PaCel6B is an endoglucanase. PMID- 23645195 TI - Two novel class II hydrophobins from Trichoderma spp. stimulate enzymatic hydrolysis of poly(ethylene terephthalate) when expressed as fusion proteins. AB - Poly(ethylene terephthalate) (PET) can be functionalized and/or recycled via hydrolysis by microbial cutinases. The rate of hydrolysis is however low. Here, we tested whether hydrophobins (HFBs), small secreted fungal proteins containing eight positionally conserved cysteine residues, are able to enhance the rate of enzymatic hydrolysis of PET. Species of the fungal genus Trichoderma have the most proliferated arsenal of class II hydrophobin-encoding genes among fungi. To this end, we studied two novel class II HFBs (HFB4 and HFB7) of Trichoderma. HFB4 and HFB7, produced in Escherichia coli as fusions to the C terminus of glutathione S-transferase, exhibited subtle structural differences reflected in hydrophobicity plots that correlated with unequal hydrophobicity and hydrophily, respectively, of particular amino acid residues. Both proteins exhibited a dosage dependent stimulation effect on PET hydrolysis by cutinase from Humicola insolens, with HFB4 displaying an adsorption isotherm-like behavior, whereas HFB7 was active only at very low concentrations and was inhibitory at higher concentrations. We conclude that class II HFBs can stimulate the activity of cutinases on PET, but individual HFBs can display different properties. The present findings suggest that hydrophobins can be used in the enzymatic hydrolysis of aromatic-aliphatic polyesters such as PET. PMID- 23645196 TI - Activity and viability of methanogens in anaerobic digestion of unsaturated and saturated long-chain fatty acids. AB - Lipids can be anaerobically digested to methane, but methanogens are often considered to be highly sensitive to the long-chain fatty acids (LCFA) deriving from lipids hydrolysis. In this study, the effect of unsaturated (oleate [C18:1]) and saturated (stearate [C18:0] and palmitate [C16:0]) LCFA toward methanogenic archaea was studied in batch enrichments and in pure cultures. Overall, oleate had a more stringent effect on methanogens than saturated LCFA, and the degree of tolerance to LCFA was different among distinct species of methanogens. Methanobacterium formicicum was able to grow in both oleate- and palmitate degrading enrichments (OM and PM cultures, respectively), whereas Methanospirillum hungatei only survived in a PM culture. The two acetoclastic methanogens tested, Methanosarcina mazei and Methanosaeta concilii, could be detected in both enrichment cultures, with better survival in PM cultures than in OM cultures. Viability tests using live/dead staining further confirmed that exponential growth-phase cultures of M. hungatei are more sensitive to oleate than are M. formicicum cultures; exposure to 0.5 mM oleate damaged 99% +/- 1% of the cell membranes of M. hungatei and 53% +/- 10% of the cell membranes of M. formicicum. In terms of methanogenic activity, M. hungatei was inhibited for 50% by 0.3, 0.4, and 1 mM oleate, stearate, and palmitate, respectively. M. formicicum was more resilient, since 1 mM oleate and >4 mM stearate or palmitate was needed to cause 50% inhibition on methanogenic activity. PMID- 23645197 TI - Environmental factors influencing the prevalence of a Clostridium botulinum type C/D mosaic strain in nonpermanent Mediterranean wetlands. AB - Between 1978 and 2008, 13 avian botulism outbreaks were recorded in the wetlands of Mancha Humeda (central Spain). These outbreaks caused the deaths of around 20,000 birds from over 50 species, including globally endangered white-headed ducks (Oxyura leucoceophala). Here, a significant association was found between the number of dead birds recorded in each botulism outbreak and the mean temperature in July (always >26 degrees C). The presence of Clostridium botulinum type C/D in wetland sediments was detected by real-time PCR (quantitative PCR [qPCR]) in 5.8% of 207 samples collected between 2005 and 2008. Low concentrations of Cl(-) and high organic matter content in sediments were significantly associated with the presence of C. botulinum. Seventy-five digestive tracts of birds found dead during botulism outbreaks were analyzed; C. botulinum was present in 38.7% of them. The prevalence of C. botulinum was 18.2% (n = 22 pools) in aquatic invertebrates (Chironomidae and Corixidae families) and 33.3% (n = 18 pools) in necrophagous invertebrates (Sarcophagidae and Calliphoridae families), including two pools of adult necrophagous flies collected around bird carcasses. The presence of the bacteria in the adult fly form opens up new perspectives in the epidemiology of avian botulism, since these flies may be transporting C. botulinum from one carcass to another. PMID- 23645198 TI - Uncovering the Lactobacillus plantarum WCFS1 gallate decarboxylase involved in tannin degradation. AB - Lactobacillus plantarum is a lactic acid bacterium able to degrade tannins by the subsequent action of tannase and gallate decarboxylase enzymes. The gene encoding tannase had previously been identified, whereas the gene encoding gallate decarboxylase is unknown. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of gallic-acid induced L. plantarum extracts showed a 54-kDa protein which was absent in the uninduced cells. This protein was identified as Lp_2945, putatively annotated UbiD. Homology searches identified ubiD-like genes located within three-gene operons which encoded the three subunits of nonoxidative aromatic acid decarboxylases. L. plantarum is the only bacterium in which the lpdC (lp_2945) gene and the lpdB and lpdD (lp_0271 and lp_0272) genes are separated in the chromosome. Combination of extracts from recombinant Escherichia coli cells expressing the lpdB, lpdC, and lpdC genes demonstrated that LpdC is the only protein required to yield gallate decarboxylase activity. However, the disruption of these genes in L. plantarum revealed that the lpdB and lpdC gene products are essential for gallate decarboxylase activity. Similar to L. plantarum tannase, which exhibited activity only in esters derived from gallic and protocatechuic acids, purified His6-LpdC protein from E. coli showed decarboxylase activity against gallic and protocatechuic acids. In contrast to the tannase activity, gallate decarboxylase activity is widely present among lactic acid bacteria. This study constitutes the first genetic characterization of a gallate decarboxylase enzyme and provides new insights into the role of the different subunits of bacterial nonoxidative aromatic acid decarboxylases. PMID- 23645199 TI - Adaptation of the hydrocarbonoclastic bacterium Alcanivorax borkumensis SK2 to alkanes and toxic organic compounds: a physiological and transcriptomic approach. AB - The marine hydrocarbonoclastic bacterium Alcanivorax borkumensis is able to degrade mixtures of n-alkanes as they occur in marine oil spills. However, investigations of growth behavior and physiology of these bacteria when cultivated with n-alkanes of different chain lengths (C6 to C30) as the substrates are still lacking. Growth rates increased with increasing alkane chain length up to a maximum between C12 and C19, with no evident difference between even- and odd-numbered chain lengths, before decreasing with chain lengths greater than C19. Surface hydrophobicity of alkane-grown cells, assessed by determination of the water contact angles, showed a similar pattern, with maximum values associated with growth rates on alkanes with chain lengths between C11 and C19 and significantly lower values for cells grown on pyruvate. A. borkumensis was found to incorporate and modify the fatty acid intermediates generated by the corresponding n-alkane degradation pathway. Cells grown on distinct n-alkanes proved that A. borkumensis is able to not only incorporate but also modify fatty acid intermediates derived from the alkane degradation pathway. Comparing cells grown on pyruvate with those cultivated on hexadecane in terms of their tolerance toward two groups of toxic organic compounds, chlorophenols and alkanols, representing intensely studied organic compounds, revealed similar tolerances toward chlorophenols, whereas the toxicities of different n-alkanols were significantly reduced when hexadecane was used as a carbon source. As one adaptive mechanism of A. borkumensis to these toxic organic solvents, the activity of cis-trans isomerization of unsaturated fatty acids was proven. These findings could be verified by a detailed transcriptomic comparison between cultures grown on hexadecane and pyruvate and including solvent stress caused by the addition of 1-octanol as the most toxic intermediate of n-alkane degradation. PMID- 23645200 TI - Comparative genomics of Bifidobacterium animalis subsp. lactis reveals a strict monophyletic bifidobacterial taxon. AB - Strains of Bifidobacterium animalis subsp. lactis are extensively exploited by the food industry as health-promoting bacteria, although the genetic variability of members belonging to this taxon has so far not received much scientific attention. In this article, we describe the complete genetic makeup of the B. animalis subsp. lactis Bl12 genome and discuss the genetic relatedness of this strain with other sequenced strains belonging to this taxon. Moreover, a detailed comparative genomic analysis of B. animalis subsp. lactis genomes was performed, which revealed a closely related and isogenic nature of all currently available B. animalis subsp. lactis strains, thus strongly suggesting a closed pan-genome structure of this bacterial group. PMID- 23645201 TI - A functional approach to uncover the low-temperature adaptation strategies of the archaeon Methanosarcina barkeri. AB - Low-temperature anaerobic digestion (LTAD) technology is underpinned by a diverse microbial community. The methanogenic archaea represent a key functional group in these consortia, undertaking CO2 reduction as well as acetate and methylated C1 metabolism with subsequent biogas (40 to 60% CH4 and 30 to 50% CO2) formation. However, the cold adaptation strategies, which allow methanogens to function efficiently in LTAD, remain unclear. Here, a pure-culture proteomic approach was employed to study the functional characteristics of Methanosarcina barkeri (optimum growth temperature, 37 degrees C), which has been detected in LTAD bioreactors. Two experimental approaches were undertaken. The first approach aimed to characterize a low-temperature shock response (LTSR) of M. barkeri DSMZ 800(T) grown at 37 degrees C with a temperature drop to 15 degrees C, while the second experimental approach aimed to examine the low-temperature adaptation strategies (LTAS) of the same strain when it was grown at 15 degrees C. The latter experiment employed cell viability and growth measurements (optical density at 600 nm [OD600]), which directly compared M. barkeri cells grown at 15 degrees C with those grown at 37 degrees C. During the LTSR experiment, a total of 127 proteins were detected in 37 degrees C and 15 degrees C samples, with 20 proteins differentially expressed with respect to temperature, while in the LTAS experiment 39% of proteins identified were differentially expressed between phases of growth. Functional categories included methanogenesis, cellular information processing, and chaperones. By applying a polyphasic approach (proteomics and growth studies), insights into the low-temperature adaptation capacity of this mesophilically characterized methanogen were obtained which suggest that the metabolically diverse Methanosarcinaceae could be functionally relevant for LTAD systems. PMID- 23645203 TI - Characterization of Escherichia coli O157:H7 strains isolated from supershedding cattle. AB - Previous reports have indicated that a small proportion of cattle shedding high levels of Escherichia coli O157:H7 is the main source for transmission of this organism between animals. Cattle achieving a fecal shedding status of 10(4) CFU of E. coli O157:H7/gram or greater are now referred to as supershedders. The aim of this study was to investigate the contribution of E. coli O157:H7 strain type to supershedding and to determine if supershedding was restricted to a specific set of E. coli O157:H7 strains. Fecal swabs (n = 5,086) were collected from cattle at feedlots or during harvest. Supershedders constituted 2.0% of the bovine population tested. Supershedder isolates were characterized by pulsed field gel electrophoresis (PFGE), phage typing, lineage-specific polymorphism assay (LSPA), Stx-associated bacteriophage insertion (SBI) site determination, and variant analysis of Shiga toxin, tir, and antiterminator Q genes. Isolates representing 52 unique PFGE patterns, 19 phage types, and 12 SBI clusters were obtained from supershedding cattle, indicating that there is no clustering to E. coli O157:H7 genotypes responsible for supershedding. While being isolated directly from cattle, this strain set tended to have higher frequencies of traits associated with human clinical isolates than previously collected bovine isolates with respect to lineage and tir allele, but not for SBI cluster and Q type. We conclude that no exclusive genotype was identified that was common to all supershedder isolates. PMID- 23645202 TI - Insights into the structure and metabolic function of microbes that shape pelagic iron-rich aggregates ("iron snow"). AB - Microbial ferrous iron [Fe(II)] oxidation leads to the formation of iron-rich macroscopic aggregates ("iron snow") at the redoxcline in a stratified lignite mine lake in east-central Germany. We aimed to identify the abundant Fe-oxidizing and Fe-reducing microorganisms likely to be involved in the formation and transformation of iron snow present in the redoxcline in two basins of the lake that differ in their pH values. Nucleic acid- and lipid-stained microbial cells of various morphologies detected by confocal laser scanning microscopy were homogeneously distributed in all iron snow samples. The dominant iron mineral appeared to be schwertmannite, with shorter needles in the northern than in the central basin samples. Total bacterial 16S rRNA gene copies ranged from 5.0 * 10(8) copies g (dry weight)(-1) in the acidic central lake basin (pH 3.3) to 4.0 * 10(10) copies g (dry weight)(-1) in the less acidic (pH 5.9) northern basin. Total RNA-based quantitative PCR assigned up to 61% of metabolically active microbial communities to Fe-oxidizing- and Fe-reducing-related bacteria, indicating that iron metabolism was an important metabolic strategy. Molecular identification of abundant groups suggested that iron snow surfaces were formed by chemoautotrophic iron oxidizers, such as Acidimicrobium, Ferrovum, Acidithiobacillus, Thiobacillus, and Chlorobium, in the redoxcline and were rapidly colonized by heterotrophic iron reducers, such as Acidiphilium, Albidiferax-like, and Geobacter-like groups. Metaproteomics yielded 283 different proteins from northern basin iron snow samples, and protein identification provided a glimpse into some of their in situ metabolic processes, such as primary production (CO2 fixation), respiration, motility, and survival strategies. PMID- 23645204 TI - Differential blood contamination levels and powder-liquid ratios can affect the compressive strength of calcium phosphate cement (CPC): a study using a transpedicular vertebroplasty model. AB - PURPOSE: Calcium phosphate cement (CPC) is a potentially useful alternative to polymethylmethacrylate (PMMA) for transpedicular injection into osteoporotic vertebral fractures. Unlike PMMA, CPC is both biocompatible and osteoconductive without producing heat from polymerization, but it has lower compressive strength compared to PMMA. This in vitro model experiment analyzed how different CPC powder-liquid ratios (P/L ratios) and injection methods may minimize blood contamination in the CPC and, thereby its reduction in compressive strength. METHODS: (1) CPC of different P/L ratios of 4.0, 3.5, and 3.2 was equally mixed with different amounts of freshly obtained human venous blood, producing cylindrically shaped CPC samples. (2) Using a transpedicular vertebroplasty model containing blood in the bottom, CPC pastes of different P/L ratios were injected with the nozzle of an injection gun affixed either to the bottom (Bottom method) or to the top of the container (Top method). All cylindrical CPC samples thus obtained were immersed in simulated body fluid and then underwent compressive strength tests at 3 h-7 days post-immersion. RESULTS: In CPC equally mixed with blood, lower P/L ratios and a larger amount of blood contamination reduced compressive strength more significantly. Of the two methods of CPC injection, the 'Bottom method' produced significantly greater compressive strength values than the 'Top method'. CONCLUSIONS: When performing CPC-assisted vertebroplasty, a greater load bearing-support can be obtained by injecting CPC paste of a high P/L ratio of 4.0 into the deepest part of the space inside the vertebral body to minimize blood contamination. PMID- 23645205 TI - Phonographic signal with a fractional-order chaotic system: a novel and simple algorithm for analyzing residual arteriovenous access stenosis. AB - To detect the early developmental stages of arteriovenous access (AVA) stenosis in hemodialysis patients, this study explored a stenosis detector based on the Burg method and the fractional-order chaos system (FOCS). The bruit developed by the blood flowing through AVA can be a viable noninvasive strategy for monitoring AVA functions. We used the Burg method of the autoregressive model to estimate the frequency spectra of phonographic signals recorded by an electronic stethoscope in patients' AVAs and to identify the spectral peaks in the region of 25-800 Hz. The frequency spectra differed significantly between normal and stenosis statuses in AVA. We found that the frequency and amplitude in power spectra analysis varied in accordance with the severity of AVA stenosis. However, the correlation of these parameters for classifying the degree of stenosis is limited when only using the Burg method. Therefore, we used an FOCS to monitor the differing frequency spectra between the normal condition and AVA stenosis. The variances of these two conditions were dynamic errors that were the coupling variables that tracked the responses between the master system and the slave system. A total of 42 patients who had received percutaneous transluminal angioplasty (PTA) for their failing AVAs was recruited for this study. In this study, the dynamic error, Index Psi, was used to calculate the frequency spectrum redistribution in patients undergoing PTA. In addition, DeltaImp was the index used to evaluate improvements in the luminal diameter between pre- and post-PTA. Therefore, we used linear regression to model the relationship between DeltaImp and Index Psi. The findings indicate that the proposed method has enhanced efficiency, especially in the venous anastomosis (V-site). The FOCS is a novel and simple algorithm for analyzing the residual AVA stenosis of PTA treatment. PMID- 23645206 TI - ZNF313 is a novel cell cycle activator with an E3 ligase activity inhibiting cellular senescence by destabilizing p21(WAF1.). AB - ZNF313 encoding a zinc-binding protein is located at chromosome 20q13.13, which exhibits a frequent genomic amplification in multiple human cancers. However, the biological function of ZNF313 remains largely undefined. Here we report that ZNF313 is an ubiquitin E3 ligase that has a critical role in the regulation of cell cycle progression, differentiation and senescence. In this study, ZNF313 is initially identified as a XIAP-associated factor 1 (XAF1)-interacting protein, which upregulates the stability and proapoptotic effect of XAF1. Intriguingly, we found that ZNF313 activates cell cycle progression and suppresses cellular senescence through the RING domain-mediated degradation of p21(WAF1). ZNF313 ubiquitinates p21(WAF1) and also destabilizes p27(KIP1) and p57(KIP2), three members of the CDK-interacting protein (CIP)/kinase inhibitor protein (KIP) family of cyclin-dependent kinase inhibitors, whereas it does not affect the stability of the inhibitor of CDK (INK4) family members, such as p16(INK4A) and p15(INK4B). ZNF313 expression is tightly controlled during the cell cycle and its elevation at the late G1 phase is crucial for the G1-to-S phase transition. ZNF313 is induced by mitogenic growth factors and its blockade profoundly delays cell cycle progression and accelerates p21(WAF1)-mediated senescence. Both replicative and stress-induced senescence are accompanied with ZNF313 reduction. ZNF313 is downregulated during cellular differentiation process in vitro and in vivo, while it is commonly upregulated in many types of cancer cells. ZNF313 shows both the nuclear and cytoplasmic localization in epithelial cells of normal tissues, but exhibits an intense cytoplasmic distribution in carcinoma cells of tumor tissues. Collectively, ZNF313 is a novel E3 ligase for p21(WAF1), whose alteration might be implicated in the pathogenesis of several human diseases, including cancers. PMID- 23645207 TI - Foxc2 induces Wnt4 and Bmp4 expression during muscle regeneration and osteogenesis. AB - Proliferation and fusion of myoblasts is a well-orchestrated process occurring during muscle development and regeneration. Although myoblasts are known to originate from muscle satellite cells, the molecular mechanisms that coordinate their commitment toward differentiation are poorly understood. Here, we present a novel role for the transcription factor Forkhead box protein C2 (Foxc2) in regulating proliferation and preventing premature differentiation of activated muscle satellite cells. We demonstrate that Foxc2 expression is upregulated early in activated mouse muscle satellite cells and then diminishes during myogenesis. In undifferentiated C2C12 myoblasts, downregulation of endogenous Foxc2 expression leads to a decrease in proliferation, whereas forced expression of FOXC2 sustains proliferation and prevents differentiation into myotubes. We also show that FOXC2 induces Wnt signaling by direct interaction with the Wnt4 (wingless-type MMTV integration site family member-4) promoter region. The resulting elevated expression of bone morphogenetic protein-4 (Bmp4) and RhoA-GTP proteins inhibits the proper myoblast alignment and fusion required for myotube formation. Interestingly, continuous forced expression of FOXC2 alters the commitment of C2C12 myoblasts toward osteogenic differentiation, which is consistent with FOXC2 expression observed in patients with myositis ossificans, an abnormal bone growth within muscle tissue. In summary, our results suggest that (a) Foxc2 regulates the proliferation of multipotent muscle satellite cells; (b) downregulation of Foxc2 is critical for myogenesis to progress; and (c) sustained Foxc2 expression in myoblast cells suppresses myogenesis and alters their lineage commitment toward osteogenesis by inducing the Wnt4 and Bmp4 signaling pathways. PMID- 23645208 TI - AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. AB - Inflammasomes are protein complexes assembled upon recognition of infection or cell damage signals, and serve as platforms for clustering and activation of procaspase-1. Oligomerisation of initiating proteins such as AIM2 (absent in melanoma-2) and NLRP3 (NOD-like receptor family, pyrin domain-containing-3) recruits procaspase-1 via the inflammasome adapter molecule ASC (apoptosis associated speck-like protein containing a CARD). Active caspase-1 is responsible for rapid lytic cell death termed pyroptosis. Here we show that AIM2 and NLRP3 inflammasomes activate caspase-8 and -1, leading to both apoptotic and pyroptotic cell death. The AIM2 inflammasome is activated by cytosolic DNA. The balance between pyroptosis and apoptosis depended upon the amount of DNA, with apoptosis seen at lower transfected DNA concentrations. Pyroptosis had a higher threshold for activation, and dominated at high DNA concentrations because it happens more rapidly. Gene knockdown showed caspase-8 to be the apical caspase in the AIM2- and NLRP3-dependent apoptotic pathways, with little or no requirement for caspase 9. Procaspase-8 localised to ASC inflammasome 'specks' in cells, and bound directly to the pyrin domain of ASC. Thus caspase-8 is an integral part of the inflammasome, and this extends the relevance of the inflammasome to cell types that do not express caspase-1. PMID- 23645209 TI - GAPDH binds to active Akt, leading to Bcl-xL increase and escape from caspase independent cell death. AB - Increased glucose catabolism and resistance to cell death are hallmarks of cancers, but the link between them remains elusive. Remarkably, under conditions where caspases are inhibited, the process of cell death is delayed but rarely blocked, leading to the occurrence of caspase-independent cell death (CICD). Escape from CICD is particularly relevant in the context of cancer as apoptosis inhibition only is often not sufficient to allow oncogenic transformation. While most glycolytic enzymes are overexpressed in tumors, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is of particular interest as it can allow cells to recover from CICD. Here, we show that GAPDH, but no other glycolytic enzymes tested, when overexpressed could bind to active Akt and limit its dephosphorylation. Active Akt prevents FoxO nuclear localization, which precludes Bcl-6 expression and leads to Bcl-xL overexpression. The GAPDH-dependent Bcl-xL overexpression is able to protect a subset of mitochondria from permeabilization that are required for cellular survival from CICD. Thus, our work suggests that GAPDH overexpression could induce Bcl-xL overexpression and protect cells from CICD-induced chemotherapy through preservation of intact mitochondria that may facilitate tumor survival and chemotherapeutic resistance. PMID- 23645210 TI - Genetic deletion of caspase-2 accelerates MMTV/c-neu-driven mammary carcinogenesis in mice. AB - Despite being the most evolutionarily conserved of the mammalian caspases, little is understood about the cellular function of caspase-2 in normal tissues or what role caspase-2 may have in the progression of human disease. It has been reported that deletion of the caspase-2 gene (Casp2), accelerates EMU-myc lymphomagenesis in mice, and thus caspase-2 may act as a tumor suppressor in hematological malignancies. Here, we sought to extend these findings to epithelial cancers by examining the potential role of caspase-2 as a tumor suppressor in the mouse mammary carcinogenesis model; MMTV/c-neu. The rate of tumor acquisition was significantly higher in multiparous Casp2(-/-)/MMTV mice compared with Casp2(+/+)/MMTV and Casp2(+/-)/MMTV mice. Cells from Casp2(-/-)/MMTV tumors were often multinucleated and displayed bizarre mitoses and karyomegaly, while cells from Casp2(+/+)/MMTV and Casp2(+/-)/MMTV tumors never displayed this phenotype. Tumors from Casp2(-/-)/MMTV animals had a significantly higher mitotic index than tumors from Casp2(+/+)/MMTV and Casp2(+/-)/MMTV animals. Cell cycle analysis of Casp2(-/-) E1A/Ras-transformed mouse embryonic fibroblasts (MEF) also indicated a higher proliferative rate in the absence of caspase-2. In vitro assays further illustrated that MEF had increased genomic instability in the absence of caspase 2. This appears to be due to disruption of the p53 pathway because we observed a concomitant decrease in the induction of the p53 target genes, Pidd, p21 and Mdm2. Thus caspase-2 may function as a tumor suppressor, in part, through regulation of cell division and genomic stability. PMID- 23645211 TI - Role of quercetin in cadmium-induced oxidative stress, neuronal damage, and apoptosis in rats. AB - The present study was carried out to evaluate the neuroprotective effect of quercetin (QE) in protecting the cadmium (Cd)-induced neuronal injury in frontal cortex of rats. A total of 30 adult male Sprague-Dawley rats were randomly divided into three groups of 10 animals each: control, Cd treated and Cd treated with QE. The Cd-treated group was injected subcutaneously with cadmium chloride (CdCl2) dissolved in saline at a dose of 2 ml/kg/day for 30 days, resulting in a dosage of 1 mg/kg Cd. The rats in QE-treated groups were given QE (15 mg/kg body weight) once a day intraperitoneally starting 2 days prior to Cd injection, during the study period. Rats were sacrificed at the end of the study and the frontal cortex tissues were removed for biochemical and histopathological investigation. To date, there is no available information on the effect of QE on neuronal injury after Cd exposure. Rats intoxicated with Cd for 30 days, significantly increased tissue malondialdehyde (MDA) levels and significantly decreased enzymatic antioxidants superoxide dismutase, glutathione peroxidase and catalase in the frontal cortex tissue. Administration of QE with Cd significantly diminished the levels of MDA and significantly elevated the levels of enzymatic antioxidants in the frontal cortex tissue. The histopathological studies in the brain of rats also supported that QE markedly reduced the Cd-induced histopathological changes and well preserved the normal histological architecture of the frontal cortex tissue. The caspase-3 immunopositivity was increased in degenerating neurons of the Cd group. Treatment with QE markedly reduced the immunoreactivity of degenerating neurons. In conclusion, the results of the current study suggest that QE may be beneficial in combating the Cd-induced neurotoxicity in the brain of rats. We believe that further preclinical research into the utility of QE may indicate its usefulness as a potential treatment for neurodegeneration after Cd exposure in rats. PMID- 23645212 TI - Association between epidermal growth factor gene rs4444903 polymorphism and risk of glioma. AB - The development of glioma is a complex process which may be influenced by many factors including the epidermal growth factor (EGF) gene polymorphism. Previous studies showed that EGF rs4444903 polymorphism could result in increased risk of tumorigenesis in multiple human cancers, but published data regarding the association between EGF rs4444903 polymorphism and glioma risk were inconsistent. To derive a more precise estimation of the association between EGF rs4444903 polymorphism and glioma risk, we performed a systematic review and meta-analysis of previous published studies. PubMed, Embase, and the Wanfang databases were systematically searched to identify relevant studies. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were calculated to assess the strength of the association. Ten published studies with 1,891 glioma cases and 2,836 controls were finally included into the study. Overall, there was a significant association between EGF rs4444903 polymorphism and glioma risk in all four genetic models (the allele model: OR=1.25, 95 % CI 1.15-1.37, P<0.001; the codominant model: OR=1.65, 95 % CI 1.36-1.99, P<0.001; the dominant model: OR=1.27, 95 % CI 1.12-1.44, P<0.001; the recessive model: OR=1.48, 95 % CI 1.25 1.75, P<0.001). Subgroup analyses by ethnicity showed that EGF rs4444903 polymorphism resulted in a higher risk of glioma among both Asians and Caucasians. In conclusion, the results suggest that there is a significant association between EGF rs4444903 polymorphism and glioma risk, and genotypes of EGF rs4444903 mutation contribute to increased host susceptibility to glioma. PMID- 23645213 TI - Reduced succinate dehydrogenase B expression is associated with growth and de differentiation of colorectal cancer cells. AB - Succinate dehydrogenases (SDH), including SDHA, SDHB, SDHC, and SDHD, form the respiratory complex II in the mitochondria and play an important role in cell growth and homeostasis. In order to evaluate the expression and functional significance of SDH in colorectal cancer, the expression of four SDH subunits was analyzed, and SDHB protein was found to be significantly lower in colorectal cancer tissues. In vitro experiments including cell growth assay, colony formation assay, cell cycle analysis, and nude mouse xenograft of SDHB transfected colorectal cancer cell line SW620 were performed. Notably, reduced SDHB expression in tumor tissues was associated with tumor de-differentiation, and restoration of SDHB could inhibit the growth of cancer cells both in vitro and in vivo. Furthermore, cDNA microarray of SDHB-transfected cell line showed that most of the differentially expressed genes are related to cell cycle control and cell proliferation. Thus, we conclude that SDHB expression is significantly decreased in human colorectal cancer tissues, and reconstitution of SDHB in colorectal cancer may be a potential therapeutic approach to inhibit aggressiveness of colorectal cancer. PMID- 23645214 TI - Cytogenetic characterization of an N-butyl-N-(4-hydroxybutyl) nitrosamine-induced mouse papillary urothelial carcinoma. AB - Chemically-induced urinary bladder cancer in rodents has long been used as a reliable model to study the biopathology of urinary bladder neoplasia and to develop therapeutic strategies against human tumors. Knowledge of the genetic basis underlying carcinogenesis would greatly enhance usability and usefulness of this model for the purposes of comparative pathology. However, little is known about the cytogenetic characteristics of rodent urinary bladder tumors. Accordingly, pathological and negative control specimens were collected for cytogenetic evaluation, from an ongoing mouse urinary bladder N-butyl-N-(4 hydroxybutyl) nitrosamine-induced carcinogenesis study. Histopathological analysis characterized the pathological sample as a papillary urothelial carcinoma. Conventional cytogenetic analysis revealed the presence of 66.3 % tetraploid cells. Fluorescent in situ hybridization using chromosome paint probes allowed the detection of a reciprocal translocation involving chromosomes 4 and 14 (containing the murine homologues to human p16 and retinoblastoma tumor suppressor genes) in 42 % of tetraploid cells. The control sample showed no histological or cytogenetic changes. CDKN2A and RB1 loss of heterozygosity is associated with human early and advanced urinary bladder cancer, respectively. Thus, the present data paves the way for further studies concerning the molecular mechanisms of urinary bladder carcinogenesis. PMID- 23645216 TI - Azidothymidine hinders arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells by induction of p21 and attenuation of G2/M arrest. AB - To enhance anticancer efficacy of the arsenic trioxide (ATO), the combination of ATO and azidothymidine (AZT), with convergence anti-telomerase activity, were examined on acute promyelocytic leukemia (APL) cell line, NB4. In spite of an induction of apoptosis by both drugs separately and a synergistic effect of them on hTERT down-regulation and telomerase inhibition, the ATO-induced cytotoxicity was reduced when it was used in combination with AZT. AZT attenuated the ATO effects on viability, metabolic activity, DNA synthesis, and apoptosis. These observations, despite the deflection from the main goal of this study, dedicate an especial opportunity to elucidate the importance of some of the mechanisms that have been suggested by which ATO induces apoptosis. Cell cycle distribution, ROS level, and caspase-3 activation analyses suggest that AZT reduced the ATO induced cytotoxic effect possibly via relative induction and diminution of cells accumulated in (G1, S) and (G2/M) phase, respectively, as well as through attenuation of ROS generation and subsequent caspase-3 inhibition. QRT-PCR assay revealed that induction of p21expression by the combined AZT/ATO compared to ATO alone could be a reason for the relative decline of cells accumulation in G2/M and the increase of cells in G1 and S phases. Therefore, the G2/M arrest and ROS generation are likely principle mediators for the ATO-induced apoptosis and can be used as a guide to design rational combinatorial strategies involving ATO and agents with G2/M arrest or ROS generation capacity to intensify ATO-induced apoptosis. PMID- 23645215 TI - Recombinant bacterial amylopullulanases: developments and perspectives. AB - Pullulanases are endo-acting enzymes capable of hydrolyzing alpha-1, 6-glycosidic linkages in starch, pullulan, amylopectin, and related oligosaccharides, while amylopullulanases are bifunctional enzymes with an active site capable of cleaving both alpha-1, 4 and alpha-1, 6 linkages in starch, amylose and other oligosaccharides, and alpha-1, 6 linkages in pullulan. The amylopullulanases are classified in GH13 and GH57 family enzymes based on the architecture of catalytic domain and number of conserved sequences. The enzymes with two active sites, one for the hydrolysis of alpha-1, 4- glycosidic bond and the other for alpha-1, 6 glycosidic bond, are called alpha-amylase-pullulanases, while amylopullulanases have only one active site for cleaving both alpha-1, 4- and alpha-1, 6-glycosidic bonds. The amylopullulanases produced by bacteria find applications in the starch and baking industries as a catalyst for one step starch liquefaction saccharification for making various sugar syrups, as antistaling agent in bread and as a detergent additive. PMID- 23645217 TI - Centrosome aberrations in bone marrow cells from patients with myelodysplastic syndromes correlate with chromosomal instability. AB - Centrosomes play important roles in the maintenance of genetic stability and centrosomal aberrations are a hallmark of cancer. Deregulation of centriole duplication leads to supernumerary centrosomes, sister chromatid missegregation and could result in chromosomal instability (CIN) and aneuploidy. CIN is a common feature in at least 45% of patients with myelodysplastic syndromes (MDS). Therefore, we sought to investigate the centrosomal status and its role for development of CIN in bone marrow (BM) cells of MDS patients. BM cells of 34 MDS patients were examined cytogenetically. Furthermore, cells were immunostained with a centrosome-specific antibody to pericentrin to analyze the centrosomal status. Umbilical cord blood specimens and BM cells of healthy persons (n = 11 and n = 4) served as controls. In addition, the protein expression of the protease separase responsible for genetic stability was examined by western blot analysis. Centrosome abnormalities were detected in 10% (range, 4-17%) of cells of MDS samples, but in only 2% (range, 0-4%) of cells of healthy controls. Normal karyotypes were found in control cells and in BM cells of 16/34 MDS patients. The incidence of centrosomal alterations was higher in BM cells of patients with cytogenetic alterations (mean, 12%) compared to BM cells of patients without cytogenetic changes (mean, 7%). Our results indicate that centrosome alterations are a common and early detectable feature in MDS patients and may contribute to the acquisition of chromosomal aberrations. We assume that centrosome defects could be involved in disease progression and may serve as a future prognostic marker. PMID- 23645218 TI - Clinical significance of knowledge about the structure, function, and impairments of working memory. AB - A review of contemporary research on the working memory system (WMS) is important, both due to the need to focus the discussion on further necessary investigations on the structure and function of this key part of the human brain, as well as to share this knowledge with clinicians. In our introduction we try to clarify the actual terminology and provide an intuitively understandable model for 3 basic cognitive operations: perception, recognition, imagery, and manipulation of recalled mental images. We emphasize the importance of knowledge of the structure and function of the WMS for the possibility to demonstrate the links between genetic polymorphisms and the prevalence to some mental disorders. We also review current knowledge of working memory dysfunction in the most common diseases and specific clinical situations such as maturation and aging. Finally, we briefly discuss methods for assessment of WMS capacity. This article establishes a kind of compendium of knowledge for clinicians who are not familiar with the structure and operation of the WMS. PMID- 23645219 TI - Rebound after Fingolimod suspension in a pediatric-onset multiple sclerosis patient. PMID- 23645220 TI - Immunoglobulin G level variations in treated chronic inflammatory demyelinating polyneuropathy: clues for future treatment regimens? AB - Intravenous immunoglobulins (IVIg) are effective for treating chronic inflammatory demyelinating polyneuropathy (CIDP), although treatment needs are variable and need to be individualized. Dose and frequency requirements are not currently predictable in advance. In Guillain-Barre syndrome, IVIg interpatient pharmacokinetic variations have been demonstrated in relation to clinical outcome. We studied 15 patients with CIDP following two routine courses of IVIg. IgG levels were assessed pretreatment and 14 days post-treatment. Best clinical response (BCR) was ascertained in each case, predefined, according to individual patients' circumstances, on the 10 m walk, or MRC sum score, or Jamar grip dynamometry. Correlations between IgG level variations, doses administered, weight, body mass index, BCR and infusion interval were determined. Postinfusion rise in IgG levels were correlated in individual patients (p = 0.005), but interpatient variability was high. No correlations were ascertained between IgG level variation and weight, body mass index, BCR, total dose of IVIg administered, or dose of IVIg administered per kilogram per week. There were significant correlations between total dose administered and post-infusion IgG level at 14 days (p = 0.004) and between infusion interval and mean rise in IgG level (p = 0.001) These findings suggest significant variability in IgG metabolism between patients, unrelated to minimal effective dose administered, weight, body mass index or degree of functional improvement. Required frequency of IVIg infusions may, however, importantly relate to patient-specific post infusion rise in IgG levels hence possibly explaining inter-patient differences in treatment frequency needs. IgG level monitoring may be helpful in establishing optimum treatment regimens in individual cases. PMID- 23645221 TI - Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study. AB - Intracerebral hemorrhage (ICH) is the most devastating complication of oral anticoagulation (OAC). As the number of patients on long-term OAC is expected to rise, the proportion of intracerebral hemorrhage related to OAC (OAC-ICH) in relation to spontaneous ICH (spont-ICH) is expected to increase as well. We determined the proportion of OAC-ICH in consecutive stroke patients and explored differences between OAC-ICH and spont-ICH regarding initial volume, hematoma expansion and outcome. Our prospective study consecutively enrolled patients with supra- and infratentorial ICH. The National Institute of Health Stroke Scale Score and the modified Rankin Scale (mRS) score at baseline and after 3 months, medical history and demographic variables were recorded. All admission and follow up CTs/MRIs were analysed regarding ICH volume using the ABC/2-method. Intraventricular hemorrhage (IVH) was quantified using the Graeb score. Within 19 months, 2,282 patients were admitted to our ER. 206 ICH patients were included. Overall, 24.8 % of all ICH were related to OAC. Compared to patients with spont ICH, OAC-ICH patients were older (p = 0.001), more frequently had initial extension of ICH into the ventricles (p = 0.05) or isolated primary IVH (p = 0.03) and a higher Graeb score upon admission (p = 0.01). In contrast, initial ICH volume (p = 0.16) and ICH expansion (p = 0.9) in those receiving follow-up imaging (n = 152) did not differ between the two groups. After correction for age, there was a trend towards poorer outcome in OAC-ICH (p = 0.08). One-fourth of all ICH are related to OAC. Initial extension of ICH into the ventricles and primary IVH are more frequent in OAC-ICH. The rate of hematoma expansion in OAC ICH patients is similar to non-anticoagulated ICH patients. PMID- 23645222 TI - Rotenone could activate microglia through NFkappaB associated pathway. AB - Parkinson's disease (PD) is a common neurodegenerative disease, and its etiology remains obscure. Increasing evidence has suggested an important role for environmental factors such as exposure to pesticides in increasing the risk of developing PD and inflammation is the early incident during the process of PD. In this study, we measure the pro-inflammatory cytokines by enzyme-linked immunosorbnent assay and RT-PCR methods; analyze the reactive oxygen species by DCFH-DA; detected nuclear factor kappaB (NFkappaB) translocation by western blot and immunofluorescence methods; and analyze the phosphorylation of mitogen activated protein (MAP) kinase and protein level of Nurr1 by western blot. Results showed that rotenone could induce tumor neurosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) release from BV-2 cells, enhance TNFalpha and IL 1beta mRNA levels in substantia nigra lesioned by rotenone; also, rotenone could increase the phosphorylation of inhibitor of kappaB (IkappaB), extracellular regulated protein kinase , c-Jun N-terminal kinase, p38 MAP kinases and promote p65 subunit of NFkappaB translocation to nuclear; at the same time, rotenone could decrease the protein level of Nurr1 in nuclear. So, rotenone exerted toxicity through activating microglia, and its mechanism might be associated with NFkappaB signal pathway. PMID- 23645223 TI - Measurement of bone mineral density by dual energy X-ray absorptiometry in juvenile idiopathic arthritis. AB - OBJECTIVE: To evaluate bone mineral density using dual X-ray absorptiometry in Juvenile Idiopathic Arthritis (JIA) patients and factors affecting it, if any. METHODS: A cross sectional study was conducted by enrolling thirty five patients of JIA and age and sex matched controls. Bone Mineral Density (BMD) and Z score of whole body, total body less head, lumbar spine and distal radius were obtained and adjusted for age, sex, weight and BMI in both cases and controls. Dietary intake of calcium, vitamin D intake, sunlight exposure, weight bearing physical activity, age of onset, duration of disease, disease activity score and treatment received (prednisolone and methotrexate) were recorded. RESULTS: BMD was significantly lower among patients as compared to controls. Decreased dietary intake of vitamin D and calcium, decreased weight bearing physical activity and sunlight exposure were the major factors for low BMD. Use of steroid also decreased BMD to some extent, whereas use of methotrexate, disease duration and severity did not have a significant correlation with BMD. CONCLUSIONS: Apart from disease control, it is important to improve the dietary intake of calcium, vitamin D and encourage more physical activities and exposure to sunlight in JIA patients. PMID- 23645224 TI - Variation in bowel habits of healthy indian children aged up to two years. AB - OBJECTIVE: To study the normal bowel habits of healthy Indian children up to 2 y of age. METHODS: This cross sectional study was conducted in medical college associated teaching hospital in Delhi. Ethical clearance was obtained from Institutional Ethical Committee. A total of 500 infants and toddlers up to 2 y of age were recruited for the study. Data were collected by interviewing parents of the eligible children who came for immunisation using pre designed Performa. RESULTS: There was steady decline in stool frequency with increasing age. Maximum decline in stool frequency was noted after 1 mo of age. Variation in stool frequency between children was maximum in 0-3 mo of age and decreased with increasing age. Stools at 4 wk were usually semiliquid, watery and semisolid. By 6 mo of age 55 % infants were passing semisolid stools and 40 % were passing formed stools. At 24 mo of age, 89.2 % children usually passed formed stools. CONCLUSIONS: This is the first study in India to date documenting the frequency and consistency of the stools of young children. These results make an important contribution to defining normal stool patterns in young Indian children. PMID- 23645226 TI - Efficacy and safety of piperacillin/tazobactam versus biapenem in late elderly patients with nursing- and healthcare-associated pneumonia. AB - Pneumonia is associated with an extremely high mortality rate in patients of late elderly age. Piperacillin/tazobactam and carbapenems are drugs of first choice for hospitalized patients with potentially resistant bacteria. We compared the efficacy and safety of piperacillin/tazobactam and biapenem. Among elderly patients with nursing- and healthcare-associated pneumonia, we extracted 53 patients treated with piperacillin/tazobactam and 53 patients treated with biapenem who were matched for sex, age, and severity of pneumonia. The average age was more than 80 years; most of the patients were middle- to oldest old in age. Although clinical efficacy was equally good, patients in the piperacillin/tazobactam group achieved significantly faster improvements on chest X-ray and body temperature on day 7. However, in the piperacillin/tazobactam group, nephrotoxicity frequently led to a need for a reduction in the dose or complete discontinuation of treatment. The average age of patients who developed significant nephrotoxicity was high, at 83.2 years. The biapenem group exhibited significantly better continuation of treatment than the piperacillin/tazobactam group. Toxicity profiles were different between the two groups. Hepatic toxicity was significantly higher in the biapenem group, whereas nephrotoxicity was significantly more common in the piperacillin/tazobactam group. Rate of decrease in bacteria was equally good between the two groups. Providing careful follow-up and conducting more detailed examinations, including studies to determine optimal dose and timing of administration, are necessary for the treatment of late elderly patients with numerous underlying diseases and potential organ dysfunctions. PMID- 23645227 TI - Lutein/zeaxanthin for the treatment of age-related cataract: AREDS2 randomized trial report no. 4. AB - IMPORTANCE: Age-related cataract is a leading cause of visual impairment in the United States. The prevalence of age-related cataract is increasing, with an estimated 30.1 million Americans likely to be affected by 2020. OBJECTIVE: To determine whether daily oral supplementation with lutein/zeaxanthin affects the risk for cataract surgery. DESIGN, SETTING, AND PATIENTS: The Age-Related Eye Disease Study 2 (AREDS2), a multicenter, double-masked clinical trial, enrolled 4203 participants, aged 50 to 85 years, at risk for progression to advanced age related macular degeneration. INTERVENTIONS: Participants were randomly assigned to daily placebo; lutein/zeaxanthin, 10mg/2mg; omega-3 long-chain polyunsaturated fatty acids, 1 g; or a combination to evaluate the effects on the primary outcome of progression to advanced age-related macular degeneration. MAIN OUTCOMES AND MEASURES: Cataract surgery was documented at annual study examination with the presence of pseudophakia or aphakia, or reported during telephone calls at 6 month intervals between study visits. Annual best-corrected visual acuity testing was performed. A secondary outcome of AREDS2 was to evaluate the effects of lutein/zeaxanthin on the subsequent need for cataract surgery. RESULTS: A total of 3159 AREDS2 participants were phakic in at least 1 eye and 1389 of 6027 study eyes underwent cataract surgery during the study, with median follow-up of 4.7 years. The 5-year probability of progression to cataract surgery in the no lutein/zeaxanthin group was 24%. For lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratios for progression to cataract surgery was 0.96 (95% CI, 0.84 1.10; P = .54). For participants in the lowest quintile of dietary intake of lutein/zeaxanthin, the hazard ratio comparing lutein/zeaxanthin vs no lutein/zeaxanthin for progression to cataract surgery was 0.68 (95% CI, 0.48 0.96; P = .03). The hazard ratio for 3 or more lines of vision loss was 1.03 (95% CI, 0.93-1.13; P = .61 for lutein/zeaxanthin vs no lutein/zeaxanthin). CONCLUSIONS AND RELEVANCE: Daily supplementation with lutein/zeaxanthin had no statistically significant overall effect on rates of cataract surgery or vision loss. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00345176. PMID- 23645228 TI - Apoptosis of endplate chondrocytes in post-laminectomy cervical kyphotic deformity. An in vivo animal model in sheep. AB - PURPOSE: The present study was performed to establish an animal model of cervical kyphosis after laminectomy (C2-C5), and to determine the role of endplate chondrocytes apoptosis in cervical kyphosis after laminectomy. METHODS: Twenty four 3-month-old sheep were randomly divided into two groups: the laminectomy group (n = 12), and the control group (n = 12). The cervical spine alignment was evaluated on a lateral cervical spine X-ray using Harrison's posterior tangent method before surgery and at follow-up. Cartilaginous endplate chondrocyte apoptosis was confirmed using transmission electron microscopy and terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP nick-end labelling. RESULTS: The mean preoperative cervical curvature (C2-5) in the surgery group was -15.8 degrees . The cervical curvature was 19.1 degrees at 3 months post-operation and decreased to 20.2 degrees at the final follow-up postoperatively. The cervical curvature was significantly decreased in the laminectomy group compared with the control group at the last follow-up (P < 0.001), which was a direct indication of kyphotic change. The incidence of apoptotic cells in the surgery group was significantly higher at the 3- and 6-month follow-up than the incidence in the control group. CONCLUSIONS: The frequency of endplate chondrocyte apoptosis in the laminectomy group was significantly higher than in the control group, indicating that chondrocyte apoptosis may play a pivotal role in the progress of post-laminectomy cervical kyphosis. PMID- 23645229 TI - The emerging role of dipeptidyl peptidase-4 inhibitors in cardiovascular protection: current position and perspectives. AB - Dipeptidyl peptidase-4 (DPP-4 or CD26) inhibitors, a new class of oral anti hyperglycemic agents that prolong the bioavailability of the endogenously secreted incretin hormone glucagon-like peptide-1 (GLP-1) and the glucose dependent insulinotropic polypeptide (GIP), are effective in the treatment of diabetes. Accumulating data have indicated that DPP-4 inhibitors play important protective roles in the cardiovascular system. DPP-4 inhibitors act to decrease myocardial infarct size, stabilize the cardiac electrophysiological state during myocardial ischemia, reduce ischemia/reperfusion injury, and prevent left ventricular remodeling after myocardial infarction. Moreover, DPP-4 inhibitors can mobilize stem/progenitor cells to move to sites of cardiovascular injury, thus further promoting tissue repair. In addition, DPP-4 inhibitors not only improve myocardial metabolism but also regulate cardioactive peptides. DPP-4 inhibitors can also protect the vasculature through their anti-inflammatory and anti-atherosclerotic effects and through the ability of the inhibitors to promote vascular relaxation. Finally, the potential effects of DPP-4 inhibitors on blood pressure and lipid metabolism have also been investigated. However, some reports on the cardioprotective activities of DPP-4 inhibitors are controversial. Herein, we summarize the available data on cardiovascular protection by DPP-4 inhibitors that have emerged in recent years and discuss current position and future perspectives concerning the use of DPP-4 inhibitors in cardiovascular medicine. PMID- 23645230 TI - Magnetically-controllable zigzag structures as cell microgripper. AB - We designed and fabricated a micro-scaled cell gripper based on two highly flexible magnetic zigzag structures that can be actuated by a magnetic field. Elongated single domain magnetic thin films with high magnetic shape anisotropy were deposited on the zigzag structures. By adjusting the external magnetic field we were able to control the torque applied on the magnetic films that was responsible for the actuation. We measured and discussed the displacement of the zigzag structures under different magnetic fields, and we observed a hysteresis characteristic in the actuation. Furthermore, we demonstrated the ability of gripping a single cell in water solution using the designed cell microgripper. The cell microgripper proposed in this study can provide important information for future biochip and biomedical applications. PMID- 23645231 TI - [Illness severity and prognosis assessment with acute physiology and chronic health evaluation II for patients after cardiovascular surgery]. AB - OBJECTIVE: To evaluate illness severity and to assess the prognosis with acute physiology and chronic health evaluation II (APACHE II) for patients after cardiovascular surgery. METHODS: APACHE II scores of 234 patients in the cardiac surgical intensive care unit (CSICU) were calculated, and the actual mortality and the predicted mortality were obtained based on the score. RESULTS: The APACHE II score of the 234 patients was 14.22+/-6.77. The difference in the APACHE II score between the survivors, the patients with complications and the death group was significant; the difference in the APACHE II score between patients with different preoperative cardiac functions was significant; the detention time in the CSICU was positively related to APACHE II scores; and the ROC area under the curve of APACHE II was 0.991+/-0.006. With the predicted rate >30% as the standard for death, sensitivity of APACHE II score for mortality risk prediction was 80.00%, specificity was 99.12%, and the accuracy was 98.72%. According to the score, we divided the patients into 3 groups (<10 points, 10-20 points, >20 points), forecast mortality in the >20 point group was in the 95% confidence interval of actual mortality. CONCLUSION: APACHE II is a good index for illness severity and prognosis assessment for patients after cardiovascular surgery. PMID- 23645232 TI - Role of hypoxia in viability and endothelial differentiation potential of UC-MSCs and VEGF interference. AB - OBJECTIVE: To investigate the effect of hypoxia on cell viability and the endothelial differentiation potential in human umbilical cord derived mesenchymal stem cells (UC-MSCs), and to assess the in vitro protective role of VEGF under low oxygen tension. METHODS: MSCs were isolated from human umbilical cords and cultured in vitro. The morphological and phenotypic characterizations of human UC MSCs were analyzed. The hypoxia induction was performed with or without the presence of 50 ng/mL of VEGF for different lengths of time. The cell proliferation, apoptosis, and reactive oxygen species (ROS) generation were assessed. Meanwhile, the endothelial differentiation potential of the UC-MSCs was measured. RESULTS: An increased apoptosis and ROS generation but reduced proliferation rate were observed at early stages (6, 12 h) after transferring the UC-MSCs from the atmospheric condition to the hypoxia condition. However, the UC MSCs presented equal proliferation and apoptosis levels under hypoxic condition as compared with those under the atmospheric condition at the later stages (24, 72 h). A high concentration of exogenous VEGF (50 ng/mL) attenuated the increased apoptosis and inhibited the proliferation of UC-MSCs, induced by a short-term hypoxia treatment. After 14 days of exogenous VEGF induction under the hypoxia condition, the UC-MSCs acquired an early endothelial phenotype consisting of a mature endothelial molecule and some endothelial functions. CONCLUSION: UC-MSCs progressively adapt to hypoxia in a step-by-step manner and maintain differentiation potential under hypoxia condition. VEGF can protect the UC-MSCs from cell damage and induce a differentiation of UC-MSCs toward endothelial lineage under hypoxic conditions. PMID- 23645233 TI - [miR-125b regulates osteogenic differentiation of human bone marrow mesenchymal stem cells by targeting Smad4]. AB - OBJECTIVE: To investigate whether miR-125b regulates the osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs) by modulating Smad4, a predicted target in silicon. METHODS: Smad4 3'-UTR-luciferase vector was constructed and dual-luciferase reporter gene assay was employed to examine the effect of miR-125b on luciferase activity. MSCs were isolated and cultured from human bone marrow, and then transfected with miR-125b mimics followed by induction of osteogenic differentiation. qRT-PCR and Western blot were used to detect the expressions of Smad4 mRNA and protein. MSCs were induced into the osteoblasts after transfecting with Smad4 siRNA, and the effect of Smad4 downregulation on osteogenic differentiation was observed by AKP activity and RUNX2 mRNA levels. RESULTS: miR-216b bound Smad4 3'-UTR and inhibited the luciferase activity (P<0.05). Smad4 mRNA and protein expressions were significantly down-regulated in the MSCs induced into osteogenic differentiation when miR-125b was overexpressed. Downregulation of Smad4 suppressed the AKP activity and RUNX2 mRNA expression, indicating that Smad4 siRNA simulated at least in part the function of miR-125b as the regulator of MSCs osteogenic differentiation. CONCLUSION: miR-125b can suppress MSCs osteogenic differentiation by directly targeting Smad4. PMID- 23645234 TI - [Effect of different transplantations with bone-marrow derived mesenchymal stem cells on diabetic foot ulcers in rats]. AB - OBJECTIVE: To assess the therapeutic effect of treating diabetic foot ulcers (DFUs) in rats by subcutaneously transplanting around the wounds and intramuscularly into the leg with bone marrow derived mesenchymal stem cells (BM MSCs). METHODS: BM-MSCs from male Wistar rats were cultured by the whole bone marrow adherence method until the third generation. The BM-MSCs were labeled by 4,6-diamino-2-phenylindole (DAPI) in vitro. Forty-eight male Wistar rats were randomly divided into 4 groups: group A (n=12), rats with DFUs receiving BM-MSCs subcutaneous transplantation; group B (n=12), rats with DFUs receiving BM-MSCs intramuscular transplantation; group C (n=12), nondiabetic rats with foot ulcers; and group D (n=12), rats with DFUs receiving no BM-MSCs. A diabetic rat model was induced by intraperitoneally injecting streptozotocin (STZ). Then DFU model was established by removing a 3 mm * 7 mm rectangular full-thickness skin on the 2 back dorsum pedis surfaces. On day 2, 5, 8 and 11 after the transplantation, the rate of wound closure was raised; trace of DAPI labeled-BM-MSCs in the wound tissues was observed on frozen sections and the thickness of granulation tissues was detected by HE stain. Immunohistochemistry was performed to detect the expression of CD31 and Ki-67. The expression of vascular endothelial growth factor (VEGF) in the wound tissues was detected by ELISA and RT-PCR. RESULTS: The wound closure in group C was faster than in other groups (P<0.05). The rate of wound healing in group B was higher than group A on day 11 (P<0.05). The intensity and area of the fluorescence in group B were higher than group A on day 2 and 5 on the frozen sections. HE stain showed that the granulation tissue formation in group B was thicker than group A on day 5. Immunohistochemistry of CD31 demonstrated that the mean number of small blood vessels in group B was more than in group A on day 5 and 8 (P<0.05). Immunohistochemistry of Ki-67 showed it had no difference between group A and group B. ELISA and RT-PCR revealed that the expression level of VEGF in the wound tissues in group B was higher than in group A on day 8 and 11 (P<0.05, P<0.001, respectively). CONCLUSION: Both transplantations promote the wound healing of DFUs in rats. The intramuscular transplantation into the leg shows a better persistence and a higher expression level of VEGF in the wound tissues at later stages. PMID- 23645235 TI - [Molecular mechanism of cardiac differentiation in P19 embryonal carcinoma cells regulated by Foxa2]. AB - OBJECTIVE: To investigate the involvement of transcription factor Foxa2 in cardiac differentiation in P19 embryonal carcinoma cells and its molecular mechanism. METHODS: P19 cells were induced to differentiate into cardiomyocytes by adding dimethyl sulfoxide (DMSO) into the culture medium of their embryoid bodies (EBs). The mRNA levels of pluripotency markers of embryonic pluripotent stem cells, cardiac differentiation related genes, and Foxa2 in the cell samples at different time points of cardiac differentiation were detected by reverse transcription PCR (RT-PCR). Differentiated and mature cardiomyocytes were identified by immunofluorescence. Eukaryotic expression plasmid pCMV-rFoxa2 (rat Foxa2) was transfected into P19 cells, and clonal populations of P19 cells that stably expressed green fluorescence protein (GFP)-rFoxa2 were isolated to enhance the expression levels of Foxa2 in P19 cells. The mRNA and protein levels of pluripotency markers and cardiac differentiation related genes in the above cell samples were detected by RT-PCR and Western blot. The mRNA levels of cardiac differentiation related genes in EBs differentiation system were also examined. RESULTS: P19 cells differentiated into cardiomyocytes in the presence of DMSO, accompanied by stimulated expression of Foxa2. Transfection of pCMV-rFoxa2 plasmids into P19 cells upregulated rFoxa2 expression transiently and activated the transcription of its downstream cardiac inducer Cerberus1 (Cer1). The expression of pluripotency marker Nanog was suppressed and the expression of cardiac inducer Sonic Hedgehog (Shh) was elevated in GFP-rFoxa2 P19 cells. The expression of Cer1 and cardiac muscle marker actin, alpha cardiac muscle 1 (Actc1) was upregulated in EBs of GFP-rFoxa2 P19 cells. CONCLUSION: Foxa2 participates in cardiac differentiation in P19 embryonal carcinoma cells. Foxa2 may inhibit Nanog expression and stimulate the expression of Cer1 and Shh directly during cardiac differentiation in P19 cells in the presence of DMSO. PMID- 23645236 TI - [Effects of ziprasidone and olanzapine on glucose and lipid metabolism in first episode schizophrenia]. AB - OBJECTIVE: To investigate the effect of ziprasidone and olanzapine on glucose and lipid metabolism in first-episode schizophrenia. METHODS: A total of 260 schizophrenics were assigned randomly to receive ziprasidone or olanzapine for 6 weeks. The weight was measured at baseline, week 2, 4 and 6. Fasting blood glucose (FBS), fasting insulin, high-density lipoprotein (HDL), total-cholesterol (TC) and triglycerides (TG) were measured at baseline and the end of 6-week treatment. Low-density lipoprotein (LDL) was measured in some patients at baseline and the end of 6-week treatment. Body mass index (BMI) and insulin resistance index (IRI) were counted. RESULTS: A total of 245 patients completed the trial, including 121 ziprasidone patients and 124 olanzapine patients. The average dose was 137.5 mg/d for ziprasidone and 19.5 mg/d for olanzapine. Patients treated with olanzapine had higher weight gain than those treated with ziprasidone [(4.55+/-3.37) kg vs (-0.83+/-2.05) kg, P<0.001]. After the treatment, FBS, fasting insulin, HDL, TC, TG, LDL and IRI levels were significantly increased in the olanzapine group (all P values<0.001 ). However, in the ziprasidone group, FBS decreased significantly and HDL and TG levels increased significantly after the 6-week treatment (all P values<0.05). The mean changes of FBS, fasting insulin, TC, TG, LDL and IRI were significantly different in the two groups (all P values<0.001). CONCLUSION: Ziprasidone has less glucose and lipid metabolic effect for first-episode schizophrenia patients in short-term treatment. However, olanzapine induces weight gain and dysfunction of glucose and lipid metabolism significantly, which is associated with increased risk of complications. When the doctors choose antipsychotics in the clinic, they should consider the side effects of the medication. PMID- 23645237 TI - [Velocity vector imaging assessment of early epirubicin-induced myocardial damage]. AB - OBJECTIVE: To assess the left ventricular (LV) longitudinal systolic and diastolic function in patients treated by epirubicin by velocity vector imaging (VVI) and to discuss the important clinical value of VVI in quantitatively evaluating the regional longitudinal function. METHODS: Thirty patients with breast cancer treated with epirubicin chemotherapy and 30 normal controls were included in the study. Dynamic images of apical long axis, four-chamber and two chamber view were obtained in all subjects, and the longitudinal systolic and diatolic parameters were measured in all subjects, including systolic maximum velocity (Vs), systolic maximum strain (SS), systolic maximum strain rate (SSR), diastolic maximum velocity (Vd), and diastolic maximum strain rate (DSR). The parameters were compared between the 2 groups. The conventional echcardiographic parameters were also obtained. RESULTS: There was no significant change in all baseline parameters before the chemotherapy in 30 breast cancer patients compared with the normal controls (P>0.05). After the second chemotherapy cycle, DSR was lower in every segment, Vd was lower in the free wall, mainly the lateral, anterior and inferior wall (P<0.05), while Vd didn't change significantly in the septum wall (P>0.05). After the third chemotherapy cycle, Vd, DSR and SSR decreased significantly in all segments (P<0.05). Vs and SS didn't change significantly (P>0.05). CONCLUSION: VVI can monitor the epirubicin cardiotoxicity early and is more sensitive than echocardiograph. PMID- 23645238 TI - [Expression of thioredoxin-2 for monitoring minimal residual disease in acute leukemia]. AB - OBJECTIVE: To investigate the significance of human thioredoxin-2 (TRX-2) in monitoring minimal residual disease (MRD) in acute leukemia (AL). METHODS: We used real-time quantitative PCR to serially quantitize TRX-2 expression levels in the bone marrow of AL patients at diagnosis (n=68), at complete hematologic remission (CHR, n=57) and at relapse (n=25). Another 25 normal donors served as normal controls. The upper limit of the bone marrow at 91 was regarded as the reference. TRX-2 expression level at CHR with <5% blast cells in the bone marrow of relapse patients was analyzed and compared with MRD by flow cytometry. RESULTS: The TRX-2 levels between the CHR patients and newly diagnosed patients, and between the CHR patients and the relapse patients had significant difference. TRX-2 expression level of 21(21/25) relapse patients at CHR with <5% blast cells in the bone marrow was higher than the reference (>91). TRX-2 level was correlated to the expression level of MRD. CONCLUSION: TRX-2 may be the marker for AL and used in MRD monitoring. PMID- 23645239 TI - [Prognostic value of procalcitonin, endotoxin and common inflammatory markers combining MELD score in patients with chronic severe hepatitis]. AB - OBJECTIVE: To evaluate the mid-term prognostic value of procalcitonin (PCT), endotoxin and common inflammatory markers combining the model for end-stage liver disease (MELD) score in patients with chronic severe hepatitis. METHODS: A total of 124 chronic severe hepatitis patients were enrolled, who were hospitalized in the Department of Infectious Diseases, Xiangya Hospital, Central South University from May 2011 to December 2011. Indexes of inflammation, liver and kidney function tests and MELD were determined within 24 h after the admission, and blood samples were collected for measurement of endotoxin , procalcitonin (PCT), and C-reactin protein (CRP). The outcome was confirmed after discharge follow-up at the end of the 3rd month. According to the outcome, the 124 patients were divided into a survival group (n=58) and a death group(n=66). RESULTS: 1) Of the 124 patients, 66 died and 58 survived, with statistical difference in age, MELD score, white blood cell (WBC), polymorphonuclear (PMN), CRP and PCT by single factor analysis between the 2 groups(P<0.05). Binary logistic regression analysis indicated that age, MELD scores and PCT were highly correlated with the outcome (OR=1.07, 1.42 and 1.02 respectively, P<0.05), which could be used to predict the 3 month mid-term mortality of chronic severe hepatitis. 2)There was significant correlation between the MELD scores and the mid-term mortality. Age was positively correlated with the MELD score, and Pearson's correlation coefficient was 0.21 (P<0.05). PCT was also positively correlated with the MELD, and Spearman's correlation coefficient was 0.54 (P<0.01). 3)According to the receiver operation characteristic (ROC) curve analysis , the area under the curve (AUC) of MELD score and PCT were 0.91 and 0.77 respectively, higher than those of other indexes (P<0.01). When the MELD score was up to 30.09 or higher, the predicted mortality risk among these tested patients was the highest(82.26%). The mortality risk predicted by PCT combining MELD score and PCT alone was lower than by MELD score alone (75.00%), but the specificity of MELD score combining PCT was 100%, and the positive prediction value was 1.00. CONCLUSION: Endotoxin and common inflammatory markers (WBC, PMN, and CRP) are not reliable indicators to predict the prognosis in patients with chronic-severe hepatitis. MELD score is significantly correlated with the outcome of mid-term chronic severe hepatitis, PCT and age are both positively correlated with the MELD score. PCT and age combining MELD score can be used to predict the 3 month mid-term mortality of chronic severe hepatitis. MELD score has better prognostic value than PCT. MELD score combining PCT can improve the specificity of prediction. PMID- 23645240 TI - [QT dispersion in acute pulmonary embolism]. AB - OBJECTIVE: To explore the alteration and the clinical significance of QT dispersion in acute pulmonary embolism (PE). METHODS: From May 2011 to April 2012, 42 hospitalized PE patients in Xiangya Hospital of Central South University were enrolled, and divided into a high-risk group and a non-high-risk group according to the clinic state on admission. Another 30 healthy subjects with matched age and genders were enrolled as a normal control group. QT interval was measured manually in 12- lead conventional electrocardiogram within 24 hours on admission and after the treatment. QT dispersion (QTd) and heart rate-corrected QT dispersion (QTcd) were also calculated. All patients were followed up during hospitalization, and were divided to a death group and a survival group. RESULTS: QTd and QTcd in the high-risk group [(70.2+/-34.0), (88.1+/-43.3) ms] and the non high-risk group [(49.3+/-21.8), (59.1+/-26.2) ms] were significantly higher than those in the normal control group[(33.2+/-12.4), (36.7+/-14.2) ms] (P<0.05), while QTd and QTcd in the high-risk group were significantly higher than those in the non-high-risk group (P<0.05). The interval of electrocardiogram was (5.6+/ 2.5) days between 24 hours on admission and after the treatment (ECG). QTd and QTcd were reduced significantly after the treatment in the survival group [(41.0+/-16.4), (47.4+/-18.0)ms] compared with those on admission [(54.0+/-33.0), (67.2+/-40.5)ms] (P<0.05), but the QTd and QTcd after the treatment were also significantly higher than those in the normal control group (P<0.05). There was no significant difference in the QTd and QTcd between 24 hours on admission and after the treatment in the death group (P>0.05). Logistic regression showed that high-risk of PE, right ventricular dysfunction and high QTcd after the treatment were the main risk factors of hospital death. CONCLUSION: QTd and QTcd are increased in PE. PE patients with right ventricular dysfunction, high-risk of PE, and high QTcd after the treatment suggest weak prognosis. PMID- 23645241 TI - [Application and evaluation of invasive prenatal diagnostic techniques and analysis of chromosomal karyotype]. AB - OBJECTIVE: To evaluate the safety, effectiveness and complications of serial invasive prenatal diagnostic techniques, and to investigate the prenatal diagnosis indication as well as to analyze the abnormal chromosomal karyotype. METHODS: We retrospectively studied all patients from March 2005 to May 2012 who received amniocentesis and cordocentesis in the prenatal diagnosis center of Second Xiangya Hospital. The indication of the procedure, successful rate and complications were evaluated, and 25 abnormal chromosome nuclear types were analyzed. RESULTS: A total of 669 patients received invasive prenatal diagnosis from March 2005 to May 2012 in Second Xiangya Hospital: 598 received amniocentesis and 71 cordocentesis carried out. Compared with the cordocentesis group, the amniocentesis group had higher achievement ratio (91.54% vs 100%, P<0.05), lower spontaneous abortion rate (1.41% vs 0.33%, P<0.05), fewer abnormal karyotypes (11.27% vs 2.84%, P<0.05) and lower expenditure (880 yuan vs 800 yuan, P<0.05). Positive screening, advanced maternal age, and ultrasonography abnormality were the top 3 indications of amniocentesis and cordocentesis. We found 25 abnormal karyotypes, including 6 cases of trisomy 21, 4 sex chromosomal abnormalities, 7 autosomal balanced translocations, 1 marker chromosome, and 7 mosaics. CONCLUSION: As a widely used invasive prenatal diagnosis, amniocentesis is safe and effective. The complications of cordocentesis are much higher than those of amniocentesis, which is not a proper routine procedure for prenatal diagnosis of abnormal karyotype. The analysis of karyotype not only can identify fetal chromosome abnormality, but also provide the scientific basis for pregnancy continuation, thus reducing the ratio of birth defect. PMID- 23645242 TI - [Preliminary screen of metastasis-related genes in cervical squamaous cell carcinoma]. AB - OBJECTIVE: To explore the differentially expressed gene profile in cervical squamous cell carcinoma tissues with and without pelvic lymph node metastasis by microarray technique and to screen tumor metastasis-related genes. METHODS: Cancer tissue samples were collected from 4 cervical squamous cell carcinoma patients with pelvic lymph metastasis and 6 patients without metastasis before the treatment. Differentially expressed gene profile was identified between cervical squamous cell carcinoma tissues with and without pelvic lymph node metastasis by NimbleGen microarray. Fluorescent real-time quantitative PCR was employed to validate the accuracy of the microarray by detecting the expression of genes picked from the differentially expressed gene profile. We screened tumor metastasis-related genes through the gene bank, PUBMED and gene ontology analysis. RESULTS: With the application of microarray, 329 genes were identified as markedly differentially expressed genes between cervical squamous cell carcinoma tissues with and without pelvic lymph node metastasis. Real-time PCR was in accordance with microarray. Forty-four genes associated with tumor metastasis were identified from the differentially expressed gene profile. CONCLUSION: Gene profile in cervical squamous cell carcinoma tissues associated with pelvic lymph node metastasis is preliminarily identified, indicating that lymph node metastasis of cervical squamous cell carcinoma is a process involving numerous genes. PMID- 23645243 TI - [Change of serum myeloperoxidase and lipoxin A4 level in coronary heart disease patients with anxiety and/or depression]. AB - OBJECTIVE: To investigate the change of serum myeloperoxidase (MPO) and lipoxin A4 (LXA4) in coronary heart disease (CHD) patients with anxiety and depression and its clinical significance. METHODS: From December 2010 to February 2011, 143 CHD patients and 44 non-CHD patients (the control group) hospitalized in the Department of Cardiology at the Second Xiangya Hospital were enrolled. The hospital anxiety and depression scale (HADS) was used to evaluate the psychological state of all patients and the CHD patients were assigned to an anxiety and depression group (n=57) or a non-depression and anxiety group (n=86). The serum levels of high sensitive C-reactive protein (Hs-CRP), MPO, and LXA4 were examined, and the ratio of MPO and LXA4 (M/L) was calculated. RESULTS: The levels of Hs-CRP, MPO, and LXA4 as well as M/L ratios in both CHD groups were significantly higher than those in the control group (all P<0.01). Compared with the non-anxiety and depression group, the levels of MPO and LXA4, and M/L ratios in the anxiety and depression group increased (all P<0.05). Correlation analysis showed that MPO was positively correlated with the score of HADS-total (HADS-t), HADS-anxiety (HADS-a), or HADS-depression (HADS-d), while LXA4 was negatively correlated with HADS-t or HADS-d. Multiple ordinal logistic regression analysis revealed that higher HADS-t score, stable angina, unstable angina, and acute myocardial infarction were the independent impact factors for the elevation of M/L ratio. CONCLUSION: Anxiety and depression may aggravate the inflammatory response in CHD patients. The imbalance between inflammation and anti inflammation may be part of the mechanism. PMID- 23645244 TI - [A population based study on incidence and determinants of preterm birth in Liuyang Hunan]. AB - OBJECTIVE: To describe the incidence and to discuss the risk factors of premature birth in rural areas of Liuyang. METHODS: We collected subjects from villages and towns in Liuyang through cluster sampling method. Before enrolling in this cohort, all of them had established health records from January 2010 to December 2011. We followed up the early, middle and late stages of pregnancy until delivery, and collected medical records and maternal health care manual of this cohort as our data materials. We explored the main influence factors of premature delivery by chi2 test and unconditional logistic regression analysis for single factor and multivariate analysis. RESULTS: Among 6270 women who enrolled in our cohort, 259 were diagnosed as premature birth. The incidence (4.13%) was lower than the national average level. Non-conditional logistic regression analysis showed that the risk factors of premature birth were as follows: OR of placental abruption was 7.678 (95% CI: 2.249-26.215), that of premature rupture of fetal membranes (PROM) was 5.177 (95% CI: 3.945-6.793), that of uterine abnormal and deformity was 2.675 (95% CI: 1.007-7.107), that of placenta anomaly was 2.633 (95% CI: 1.666-4.162), that of hypertension in pregnancy was 2.172 (95% CI: 1.044 4.521), that of pregnancy complications was 1.806 (95% CI: 1.033-3.157), that of male fetus was 1.429 (95% CI: 1.086-1.881). Protective factors of preterm birth were too frequent prenatal examination (OR=0.502, 95% CI: 1.033-3.157) and single pregnancy (OR=0.155, 95% CI: 0.075-0.319). CONCLUSION: Preterm delivery is caused by complicated factors, such as placental abruption, PROM and male fetus. Comprehensive measures should be taken to reduce preterm birth. PMID- 23645245 TI - [Correlation between self-management behaviors and blood glucose control in patients with type 2 diabetes mellitus in community]. AB - OBJECTIVE: To investigate the self-management behaviors of patients with type 2 diabetes mellitus (DM) in a community and to explore the relationship between self-management behaviors and the glycemic control. METHODS: A total of 211 type 2 DM patients in a community were selected by stratified random sampling. Patients were grouped according to the scores of self-management behaviors. The fasting plasma glucose (FPG), 2 h postprandial plasma glucose (2hPG) and glycated hemoglobin (HbA1C) level were tested. The differences between groups and relationship between self-management behaviors and glycemic control were analyzed. RESULTS: Self-management behaviors of most patients were not effective, and 2hPG and HbA1C were affected by different levels of the self-management behaviors (P<0.05). The self-management behaviors were negatively related to FPG (r=-0.277, P=0.015), 2hPG (r=-0.453, P=0.001), and HbA1C (r=-0.435, P=0.001). Glycemic control of the patients whose course of disease was over 5 years was significantly different due to different self-management behaviors. FPG level of the patients was positively related to alimentary control. The 2hPG level of the patients was positively related to alimentary control, medication persistence, and blood glucose self-monitoring. The HbA1C level of the patients was positively related to alimentary control and medication persistence. The times the patients received DM education, the way to use insulin, and the disease course of the patients were important factors to affect self-management behaviors of type 2 DM in the community. CONCLUSION: Self-management behaviors of type 2 DM patients in the community are not effective. Satisfactory self-management behaviors, specially the control of 2hPG and HbA1C are beneficial to glycemic control. We can improve the self-management behaviors in type 2 DM patients by paying attention to the disease course, the treatment method, and the contents and effect of DM education. PMID- 23645246 TI - [Research progress of Th17 cells and glomerulonephritis]. AB - T helper (Th) 17 cells are a kind of Th cell subset, and are distinct from the Th1 and Th2 cells and produce interleukin-17A (IL-17A, IL-17). Th17 cells have a mechanism of independent differentiation and developmental regulation. The differentiation and cytokine secretion of Th17 cells are regulated by TGF-beta, IL-6, IL-23 and orphan nuclear receptor (RORgammat). IL-17A induces pro inflammatory cytokines and chemokines, mediating neutrophil recruitment. Increasing evidence implicated involvement of Th17 cells in anti-glomerular basement membrane disease, lupus nephritis and pauciimmune glomerulonephritis. In this review, we discussed the discovery of Th17 subset, its properties, its relationship with other Th subsets and involvement of Th17 cells in glomerulonephritis. PMID- 23645247 TI - Building a new biomedical ecosystem: Pfizer's Centers for Therapeutic Innovation. PMID- 23645248 TI - Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules? AB - Benign and malignant thyroid nodules are more prevalent in females than in males. Experimental data suggest that the proliferative effect of oestrogen rather than polymorphisms is responsible for this gender difference. This study analysed whether both differentiated thyroid cells and thyroid stem and progenitor cells are targets of oestrogen action. In thyroid stem/progenitor cells derived from nodular goitres, the ability of 17beta-oestradiol (E2) to induce the formation of thyrospheres and the expression of oestrogen receptors (ERs) and the effect of E2 on the growth and expression of markers of stem cells and thyroid differentiation (TSH receptor, thyroperoxidase, thyroglobulin and sodium iodide symporter (NIS)) were analysed. E2 induced thyrosphere formation, albeit to a lower extent than other growth factors. Thyroid stem and progenitor cells expressed ERalpha (ESR1) and ERbeta (ESR2) with eight times higher expression levels of ERalpha mRNA compared with the differentiated thyrocytes. E2 was a potent stimulator of the growth of thyroid stem/progenitor cells. In contrast, TSH-induced differentiation of progenitor cells, in particular, the expression of NIS, was significantly inhibited by E2. In conclusion, oestrogen stimulated the growth and simultaneously inhibited the differentiation of thyroid nodule-derived stem/progenitor cells. From these data and based on the concept of cellular heterogeneity, we hypothesize a supportive role of oestrogen in the propagation of thyroid stem/progenitor cells leading to the selection of a progeny of growth prone cells with a decreased differentiation. These cells may be the origin of hypofunctioning or non-functioning thyroid nodules in females. PMID- 23645249 TI - Repression of mammary adipogenesis by genistein limits mammosphere formation of human MCF-7 cells. AB - Mammary adipose tissue may contribute to breast cancer development and progression by altering neighboring epithelial cell behavior and phenotype through paracrine signaling. Dietary exposure to soy foods is associated with lower mammary tumor risk and reduced body weight and adiposity in humans and in rodent breast cancer models. Despite the suggested linkage between obesity and breast cancer, the local influence of bioactive dietary components on mammary adiposity for antitumor effects remains unknown. Herein, we report that post weaning dietary exposure to soy protein isolate and its bioactive isoflavone genistein (GEN) lowered mammary adiposity and increased mammary tumor suppressor PTEN and E-cadherin expression in female mice, relative to control casein diet. To ascertain GEN's role in mammary adipose deposition that may affect underlying epithelial cell phenotype, we evaluated GEN's effects on SV40-immortalized mouse mammary stromal fibroblast-like (MSF) cells during differentiation into adipocytes. MSF cells cultured in a differentiation medium with 40 nM GEN showed reductions in mature adipocyte numbers, triglyceride accumulation, and Ppargamma (Pparg) and fatty acid synthase transcript levels. GEN inhibition of adipose differentiation was accompanied by increased estrogen receptor beta (Erbeta (Esr2)) gene expression and was modestly recapitulated by ERbeta-selective agonist 2,3-bis-(4-hydroxyphenyl)-propionitrile (DPN). Reduction of Erbeta expression by siRNA targeting increased Ppargamma transcript levels and stromal fibroblast differentiation into mature adipocytes; the latter was reversed by GEN but not by DPN. Conditioned medium from GEN-treated adipocytes diminished anchorage-independent mammosphere formation of human MCF-7 breast cancer cells. Our results suggest a mechanistic pathway to support direct regulation of mammary adiposity by GEN for breast cancer prevention. PMID- 23645255 TI - Picture of the month: spinal and scapular tuberculosis. PMID- 23645257 TI - If your child is hospitalized: the hospital health care team. PMID- 23645258 TI - The vacuolar channel VvALMT9 mediates malate and tartrate accumulation in berries of Vitis vinifera. AB - Vitis vinifera L. represents an economically important fruit species. Grape and wine flavour is made from a complex set of compounds. The acidity of berries is a major parameter in determining grape berry quality for wine making and fruit consumption. Despite the importance of malic and tartaric acid (TA) storage and transport for grape berry acidity, no vacuolar transporter for malate or tartrate has been identified so far. Some members of the aluminium-activated malate transporter (ALMT) anion channel family from Arabidopsis thaliana have been shown to be involved in mediating malate fluxes across the tonoplast. Therefore, we hypothesised that a homologue of these channels could have a similar role in V. vinifera grape berries. We identified homologues of the Arabidopsis vacuolar anion channel AtALMT9 through a TBLASTX search on the V. vinifera genome database. We cloned the closest homologue of AtALMT9 from grape berry cDNA and designated it VvALMT9. The expression profile revealed that VvALMT9 is constitutively expressed in berry mesocarp tissue and that its transcription level increases during fruit maturation. Moreover, we found that VvALMT9 is targeted to the vacuolar membrane. Using patch-clamp analysis, we could show that, besides malate, VvALMT9 mediates tartrate currents which are higher than in its Arabidopsis homologue. In summary, in the present study we provide evidence that VvALMT9 is a vacuolar malate channel expressed in grape berries. Interestingly, in V. vinifera, a tartrate-producing plant, the permeability of the channel is apparently adjusted to TA. PMID- 23645259 TI - Identification, characterization of an AP2/ERF transcription factor that promotes adventitious, lateral root formation in Populus. AB - Using activation tagging in Populus, we have identified five mutant lines showing changes in their adventitious rooting. Among the affected lines, three showed increased and two decreased adventitious rooting. We have positioned the tag in the mutant lines via recovering genomic sequences flanking the left-hand border of the activation tagging vector and validated the transcriptional activation of the proximal genes. We further characterized one line in which the cause of the observed rooting phenotype was up-regulation of a gene encoding a transcription factor of the AP2/ERF family of unknown function (PtaERF003). We show, through retransformation, that this gene has a positive effect on both adventitious and lateral root proliferation. Comparative expression analyses show that the phenotype does not result from ectopic expression but rather up-regulation of the native expression pattern of the gene. PtaERF003 function is linked to auxin signal transduction pathway, as suggested by the rapid induction and accentuated phenotypes of the transgenic plants in presence of the hormone. Upregulation of PtaERF003 led to most significant metabolic changes in the shoot suggesting of a broader regulatory role of the gene that is not restricted to root growth and development. Our study shows that dominant tagging approaches in poplar can successfully identify novel molecular factors controlling adventitious and lateral root formation in woody plants. Such discoveries can lead to technologies that can increase root proliferation and, thus, have significant economic and environmental benefits. PMID- 23645284 TI - Pulmonary alveolar proteinosis secondary to Pneumocystis jiroveci infection in an infant with common variable immunodeficiency. AB - The authors report an infant with common variable immunodeficiency (CVID) with Pneumocystis pneumonia who developed secondary pulmonary alveolar proteinosis (PAP). This is the youngest infant reported to develop PAP secondary to Pneumocystis infection in an immunocompromised state. He was effectively managed with anti-microbials, frequent lung toilet, optimized mechanical ventilation, and supportive care. PMID- 23645286 TI - Comparison of National/Regional Diabetes Guidelines for the Management of Blood Glucose Control in non-Western Countries. AB - INTRODUCTION: Development of higher standards for diabetes care is a core element of coping with the global diabetes epidemic. Diabetes guidelines are part of the approach to raising standards. The epidemic is greatest in countries with recent rises in income from a low base. The objective of the current study was to investigate the availability and nature of locally produced diabetes guidelines in such countries. METHODS: Searches were conducted using Medline, Google, and health ministry and diabetes association websites. RESULTS: Guidelines were identified in 33 of 75 countries outside North America, western Europe, and Australasia. In 25 of these 33 countries, management strategies for type 1 diabetes were included. National guidelines relied heavily on pre-existing national and international guidelines, with reference to American Diabetes Association standards of medical care and/or other consensus statements by 55%, International Diabetes Federation by 36%, European Association for the Study of Diabetes by 12%, and American Association of Clinical Endocrinologists by 9%. The identified guidelines were generally evidence-based, though there was some use of secondary evidence reviews, including other guidelines, rather than original literature reviews and evidence synthesis. In type 1 diabetes guidelines, the option of different insulin regimens (mostly meal-time + basal or premix regimens) was recommended depending on patient need. Type 2 diabetes guidelines either recommended a glycosylated hemoglobin target of <7.0% (<53 mmol/mol) (70% of guidelines) or <6.5% (<47 mmol/mol) (30% of guidelines) as the ideal glycemic target. Most guidelines recommended a target fasting plasma glucose that fell within the range of 3.8-7.2 mmol/L. Most guidelines also set a 2-h post-prandial glucose target value within the range of 4.0-8.3 mmol/L. CONCLUSION: While only a first step in achieving a high quality of disease management, national guidelines of quality and with fair consistency of recommendations are becoming prevalent globally. A further challenge is implementation of guidelines, by integration into local care processes. PMID- 23645285 TI - Role of targeted agents in metastatic colorectal cancer. AB - Despite a decrease in incidence and mortality, colorectal cancer (CRC) still represents the second leading cause of cancer worldwide. Recurrence following surgery and adjuvant treatment and the metastatic disease are still a major problem with a median overall survival of approximately 24 months. Nevertheless, there has been an improvement in outcome due to the introduction into clinical practice of new cytotoxic and targeted agents. The targeted agents that have improved the efficacy of the available chemotherapeutic regimens in CRC are the ones that target the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). In particular, bevacizumab, a recombinant humanized monoclonal antibody against VEGF, cetuximab, and panitumumab, two monoclonal antibodies that target the EGFR, have been approved for the treatment of metastatic CRC (mCRC). While for anti-EGFR agents, predictive biomarkers have been found, no good biomarkers have been found yet for anti-VEGF agents. Aflibercept and regorafenib have recently also been approved in patients with mCRC. This article reviews in an extensive way the data of large randomized clinical trials for the use of anti-VEGF and anti-EGFR in CRC. Aim of this review is also to describe the current status of biomarkers discovery and highlight how to improve the therapeutic index of these targeted agents by selecting in advance the subgroup of patients who will benefit from these treatments. PMID- 23645287 TI - Host resistance influences patterns of experimental viral adaptation and virulence evolution. AB - Infectious diseases are major threats to all living systems, so understanding the forces of selection that limit the evolution of more virulent pathogens is of fundamental importance; this includes the practical application of identifying possible mitigation strategies for at-risk host populations. The evolution of more virulent pathogens has been classically understood to be limited by the tradeoff between within-host growth rate and transmissibility. Importantly, heterogeneity among hosts can influence both of these factors. However, despite our substantial understanding of how the immune system operates to control pathogen replication during infection, we have only a limited appreciation of how variability in intrinsic (i.e., genetically determined) levels of host resistance influences patterns of pathogen adaptation and virulence evolution. Here, we describe results from experimental evolution studies using a model host-pathogen (virus-mammal) system; we demonstrate that variability in intrinsic levels of resistance among host genotypes can have significant effects on patterns of pathogen adaptation and virulence evolution during serial passage. Both the magnitude of adaptive response as well as the degree of pathogen specialization was positively correlated with host resistance, while mean overall virulence of post-passage virus was negatively correlated with host resistance. These results are consistent with a model whereby resistant host genotypes impose stronger selection on adapting pathogen populations, which in turn leads to the evolution of more specialized pathogen variants whose overall (i.e., mean) virulence across host genotypes is reduced. PMID- 23645288 TI - Phase I study of weekly kahalalide F as prolonged infusion in patients with advanced solid tumors. AB - PURPOSE: Kahalalide F (KF) is a dehydroaminobutyric acid-containing peptide from marine origin with activity against several human malignant cell lines. This dose escalating phase I clinical trial evaluated the maximum tolerated dose (MTD), and the recommended dose for further phase II studies (RD) of weekly KF given as a prolonged (3- to 24-h) intravenous (i.v.) infusion. METHODS: Eligible patients with advanced solid tumors and adequate performance status, hematologic, renal, and hepatic function were recruited into this study. RESULTS: A total of 106 patients were treated with KF at four different weekly schedules: 3-h (n = 40), 24-h (n = 59), and two transitional schedules [6-h (n = 4) and 12-h (n = 3)]. For the 3-h weekly schedule, the MTD was 1,200 MUg/m2 and the RD was 1,000 MUg/m2. For the 24-h weekly schedule, the MTD was reached (6,650 MUg/m2), but the RD could not be confirmed. Asymptomatic and reversible grade 3/4 transaminase increase was the most common dose-limiting toxicity in both schedules. Fatigue, paresthesia, pruritus, nausea, vomiting, and rash were the most common KF-related adverse events. No major deviations from linearity were detected in the pharmacokinetic (PK) profiles of both schedules, which showed a narrow distribution and short body residence. Prolonged disease stabilization (>=3 months) occurred in eight patients: two with the 3-h schedule and six with the 24 h schedule. CONCLUSIONS: Administration of KF as prolonged weekly infusion appears feasible, with 3-h and 24-h infusion times having an acceptable safety profile. PMID- 23645289 TI - miR-181b modulates glioma cell sensitivity to temozolomide by targeting MEK1. AB - PURPOSE: Recent studies have reported that miR-181b contributes to chemoresistance in several cancer types and functions as a tumor suppressor in glioma. This study aimed to explore whether miR-181b could enhance the chemotherapeutic effect of temozolomide in glioma cells and sought to identify the candidate target genes which mediated the effect. METHODS: Using 48 frozen samples from patients with glioma who had received in vitro chemosensitivity assay, we measured MGMT promoter methylation status by methylation-specific PCR and miR-181b expression by qRT-PCR. Then, miR-181b expression level was correlated with temozolomide IC50 and MGMT promoter methylation status. To investigate the mechanism of miR-181b-induced chemosensitivity, assays were performed using stable miR-181b-expressing transfectants of glioma cell lines created by a lentiviral system. RESULTS: Glioma cells rich in miR-181b were more sensitive to temozolomide. miR-181b expression was not correlated with MGMT promoter methylation status. miR-181b combined with temozolomide enhanced glioma cell sensitivity and apoptosis. The effects were through posttranscriptional repression of MEK1. We demonstrated that miR-181b bound directly to the 3' untranslated regions of MEK1, thus reducing both the mRNA and protein levels of MEK1. Additionally, knockdown of MEK1 using small interfering RNA resulted in effects similar to ectopic miR-181b expression, whereas enforced expression of MEK1 lacking the 3' untranslated regions abrogated the effects. Finally, inverse correlation between miR-181b and MEK1 was established in glioma specimens. CONCLUSION: miR-181b independently predicted chemoresponse to temozolomide and enhanced temozolomide sensitivity via MEK1 downregulation. A combination of miR 181b and temozolomide may be an effective therapeutic strategy for gliomas. PMID- 23645290 TI - ERCC1 predicts outcome in patients with gastric cancer treated with adjuvant cisplatin-based chemotherapy. AB - BACKGROUND: Adjuvant chemotherapy is gaining an increasing role in resectable gastric cancer. Customizing chemotherapy on the basis of chemosensitivity may improve outcome, and putative predictive molecular markers have been mostly evaluated in Asian patients. We profiled key DNA and damage signaling factors and correlated them with outcome, in a European cohort. METHODS: Formalin-fixed tumor samples obtained from surgical specimens of patients treated with adjuvant cisplatin-based chemotherapy for gastric cancer were analyzed. Immunohistochemistry (IHC) was performed to analyze excision repair cross complementing gene 1 (ERCC1) and thymidylate synthase (TS) expression, and p53 mutations were detected with direct sequencing. RESULTS: Among the 68 patient recruited, the median age was 69 (range 30-74), and UICC stage was III in 44 patients (65 %). With a median follow-up of 40.5 months, disease-free and overall survival were 18.0 (95 % CI 13.4-22.76) and 56 months (95 % CI 44.87-67.13), respectively. ERCC1 score was 0 in 14 out 67 (21 %) cases, 1 in 19 (28 %), 2 in 20 (30 %) and 3 in 14 cases (21 %). Longer overall survival (p = 0.04) was found in patients categorized as ERCC1 negative by IHC according to median score. TS score was 0 in 16 out 67 (24 %) cases, 1 in 27 (40 %), 2 in 16 (24 %) and 3 in 8 cases (12 %). Mutations of p53 were found in 21 out 66 (32 %) cases. Neither TS nor p53 were found to correlate with outcome. CONCLUSION: Excision repair cross complementing gene 1 by IHC might predict patients more likely to benefit from adjuvant cisplatin-based chemotherapy in curatively resected gastric cancer. In patients exhibiting ERCC1 positive tumors, alternative regimens should be evaluated. PMID- 23645291 TI - CAM 5.2 shows specific reactivity for cytokeratin 8, but less strict reactivity for cytokeratin 7 and no reactivity for cytokeratin 18: in response to "Fujikawa T, Tanaka A, Abe T et al. 'Undifferentiated carcinoma of the common bile duct with intraductal tumor thrombi: report of a case'. Surg today 2011;41(4):579 84.". PMID- 23645292 TI - Carcinosarcoma of the liver: report of a case. AB - A 64-year-old Japanese woman without a history of viral hepatitis was admitted for investigation of a huge liver mass. The tumor, measuring 14 * 12 * 22 cm, had invaded the diaphragm, right lung, and inferior vena cava. Serum examinations demonstrated high levels of carbohydrate antigen 19-9 (CA19-9), and the Child Pugh score was A. She underwent right lobectomy of the liver and partial resection of the right diaphragm, right lung, and inferior vena cava. Radio- and chemotherapy were also given, but she died of recurrence 3 months after surgery. Microscopically, the tumor exhibited intermingled adenocarcinomatous and atypical mesenchymal components. The carcinomatous component was positive for cytokeratins 7, 19, and 20, chromogranin A, epithelial membrane antigen, c-KIT, and vimentin. The sarcomatous component was positive for vimentin and c-KIT. A review of 36 cases of hepatic carcinosarcoma revealed the following: chronic hepatitis or cirrhosis in 57 % of the patients; increased serum CA19-9 levels in 30 %; a mean tumor diameter of 10 cm; invasion of the adjacent organs or metastasis to distant organs in 47 %; wide intrahepatic infiltration in 44 %; and 50 % survival of only 5 months. Significant differences were seen according to tumor diameter (diameter >5 cm; p < 0.05), wide intrahepatic infiltration (p < 0.05), and extrahepatic invasion/metastasis (p < 0.01). Neither chemotherapy nor radiotherapy contributed to prognosis, but surgical resection resulted in some improvement (p < 0.05). PMID- 23645293 TI - Pituitary carcinoma with endolymphatic sac metastasis. AB - Pituitary carcinoma is characterized by the presence of a metastatic lesion(s) in a location non-contiguous with the original pituitary tumor. The mechanism(s) of malignant transformation are not known. A 15 year-old male was diagnosed in 1982 with a pituitary macroadenoma and acromegaly (random GH 67 ng/ml and no suppression by oral glucose). His prolactin was normal between 18 and 23 ng/ml. Transcranial resection in July 1983 was followed by radiation therapy. The tumor was immunopositive for GH and prolactin. The proliferation MIB-1 index was 0-1%. With aqueous Octreotide 100 mcg 4* daily both GH and IGF-1 became normal. The patient was lost to follow-up and was treated by his local physician. In 2001, his IGF-1 level was 1271 ng/ml, and his random GH was 1.8-2.4 ng/ml by ILMA despite progressive increase in the dose of Sandostatin LAR to 140 mg/month in divided doses. Prolactin remained normal or minimally increased between 15 and 25 ng/ml. In 2009 he was diagnosed with the tumor in the location of left endolymphatic sac. Histological examination showed low grade pituitary carcinoma strongly immunopositive for prolactin but negative for GH. MIB-1 antibody labeled 0-5% cells. In 2012 endoscopic resection of the pituitary tumor remnant was attempted. Immunohistochemical stains were strongly immunopositive for both prolactin and GH, similar to his original pituitary tumor. The MIB-1 proliferation index was low from 0 to 1%. To our knowledge this is the first case of pituitary carcinoma in the endolymphatic sac region. The dichotomy between the cell population of the pituitary lesion (GH/prolactin producing) and the metastasis (purely prolactin-producing) may suggest that the metastatic pituitary lesion derived from a clone distinct from the original one. PMID- 23645294 TI - Initial treatment of Parkinson's disease: an update. AB - OPINION STATEMENT: This is an update to an article published in this journal in 2006, which covered the initial treatment of Parkinson's disease (PD). In this update, we review new research into symptomatic treatments, potential disease modifying ("neuroprotective") agents, and evidence-based reviews of current treatment. We discuss the usage of the MAO-B inhibitors, including the controversy surrounding the possible neuroprotective effects of rasagiline. Usage of extended release formulations of pramipexole and ropinirole, as well as the transdermal dopamine agonist rotigotine, are reviewed. Side effects of the dopamine agonists are discussed, including the cardiac side effects of ergot derived dopamine agonists, and the impulse control disorders associated with the dopamine agonists. The use of zonisamide as an agent for PD tremor is reviewed. We touch on the clinical research into the benefits of exercise in PD, and briefly review some of the current studies for new formulations of levodopa and other medications and treatments with novel mechanisms of action. PMID- 23645295 TI - Behavior Therapy for Tourette Syndrome: A Systematic Review and Meta-analysis. AB - OPINION STATEMENT: When tics caused by Tourette Syndrome cause meaningful impairment for patients, a comprehensive treatment approach includes education of patients, peers, and family, treatment of comorbid behavioral disorders if present, and consideration of behavior therapy and pharmacotherapy for tics themselves. This systematic review and meta-analysis demonstrates that behavior therapies based on Habit Reversal Therapy, including the Comprehensive Behavioral Intervention for Tics are effective in reducing tic severity when compared with supportive psychotherapy. When these behavior therapies are unavailable, Exposure with Response Prevention may also be effective. Both face-to-face and telehealth delivery methods for behavior therapy improve tic severity, and broader distribution of behavior therapy through increased training or telehealth methods is encouraged. High-quality randomized trials comparing behavior therapies for tics with pharmacotherapy are needed. PMID- 23645296 TI - Volvulus and intestinal perforation following magnet toy ingestion. PMID- 23645297 TI - Resilience, trauma, context, and culture. AB - This article reviews the relationship between factors associated with resilience, and aspects of the individual's social ecology (environment) that promote and protect against the negative impact of exposure to traumatic events. It is shown that the Environment * Individual interactions related to resilience can be understood using three principles: (1) Resilience is not as much an individual construct as it is a quality of the environment and its capacity to facilitate growth (nurture trumps nature); (2) resilience looks both the same and different within and between populations, with the mechanisms that predict positive growth sensitive to individual, contextual, and cultural variation (differential impact); and (3) the impact that any single factor has on resilience differs by the amount of risk exposure, with the mechanisms that protect against the impact of trauma showing contextual and cultural specificity for particular individuals (cultural variation). A definition of resilience is provided that highlights the need for environments to facilitate the navigations and negotiations of individuals for the resources they need to cope with adversity. The relative nature of resilience is discussed, emphasizing that resilience can manifest as either prosocial behaviors or pathological adaptation depending on the quality of the environment. PMID- 23645298 TI - Frontiers in natural killer cell immunology. PMID- 23645302 TI - Thymoproteasome: role in thymic selection and clinical significance as a diagnostic marker for thymic epithelial tumors. AB - The thymoproteasome is a specialized type of proteasomes expressed exclusively in the thymic cortex. It has a unique catalytic subunit beta5t with unusual enzymatic activity. The thymoproteasome exhibits lower chymotrypsin-like activity than other forms of proteasomes such as constitutive proteasomes and immunoproteasomes. Its cleavage specificity appears uniquely suited for the production of peptides that mediate positive selection of CD8+ T cells. Similar to major histocompatibility complex molecules and T/B-cell receptors, the thymoproteasome occurs only in jawed vertebrates, suggesting that it evolved concomitant with the cardinal elements of adaptive immunity. beta5t can be used as a marker in the differential diagnosis of thymic tumors. It is expressed in most type B and some type AB thymomas, but not in type A thymoma, thymic carcinoma, or tumors of non-thymic epithelial origin. PMID- 23645303 TI - Bipolar affective disorder and psychoeducation. AB - OBJECTIVE: Bipolar affective disorder runs a natural course of frequent relapses and recurrences. Despite significant strides in the pharmacological treatment of bipolar disorder, most bipolar patients cannot be treated only by drugs. The limitations of using medication alone in symptomatic, relapse prevention, and satisfaction/quality of life terms have long prompted interest in wider forms of management. One of the promising way how to enhance remission seems to be combination of pharmacotherapy and psychoeducation. METHODS: Studies were identified through PUBMED, Web of Science and Scopus databases as well as existing reviews. The search terms included "bipolar disorder", "psychoeducation", "psychotherapy", "psychosocial treatment", "family therapy", "individual therapy", "group therapy", and "psychoeducation". The search was performed by repeated use of the words in different combinations with no language or time limitations. This article is a review with conclusions concerned with psychoeducation in bipolar disorder. CONCLUSIONS: Randomized controlled trials of cognitive behavioral therapy, interpersonal and social rhythm therapy, individual, group and family psychoeducation show that these approaches augment stabilizing effect of pharmacotherapy. Patients and their families should be educated about bipolar disorder, triggers, warning signs, mood relapse, suicidal ideation, and the effectiveness of early intervention to reduce complications. Psychosocial approaches are important therapeutic strategies for reducing relapse and rehospitalization in bipolar disorder. PMID- 23645304 TI - Struma ovarii maligna. AB - INTRODUCTION: Malignant struma ovarii is a rare ovarian neoplasm composed predominantly of mature thyroid tissue. CASE REPORT: A right ovarian tumor was discovered at ultrasound examination in a 20-year-old woman. Complete right ovariectomy was done - histopathological examination revealed papillary thyroid carcinoma arising in struma ovarii (malignant struma ovarii). Patient underwent subsequent total thyroidectomy - the thyroid was found to be without any pathological lesions. After operations the patient received ablative radioiodine treatment (200 mCi 131I). An 131I posttherapeutic whole-body radioiodine scintigraphy was performed and showed uptake in bone metastases. L-thyroxine TSH suppresive doses followed radioiodine ablation and thyroglobulin level is monitored. Next doses of radioiodine has been scheduled. DISCUSSION: Authors suggest that the management of malignant struma ovarii should be the same as differentiated thyroid cancer, so after surgical excision of ovarian neoplasm, we recommend thyroidectomy, radiotherapy with 131I and levothyroxine suppressive therapy. Long-term follow-up for the detection of metastases or tumor recurrence by serial serum thyroglobulin measurements and 131I scan may be required in patients with this rare tumor. PMID- 23645305 TI - Autoimmune hypophysitis may eventually become empty sella. AB - Autoimmune hypophysitis (AH) is commonly believed to be a rare chronic inflammatory condition of the pituitary gland. In clinical practice, however, the disease is often seen indeed. It typically presents with hypopituitarism and pituitary mass found by MRI. We report here unusual presentations of two females with AH followed by empty sella syndrome. The two females, aged at 64 and 57 years-old, presented with anterior pituitary dysfunction, diplopia and diabetes insipidus. By MRI the two patients shared the common characteristics with diffuse homogenous contrast enhancement of the gland and increased stalk thickness. After a long period treatment with glucocorticoids, empty sella was eventually detected by MRI. PMID- 23645306 TI - Primary hyperparathyroidism presenting as a giant cell tumor of the jaws. AB - OBJECTIVE: Giant cell tumors of the maxillofacial skeleton are uncommon, they are usually late manifestation of primary hyperparathyroidism. A series of five clinical cases in four women and one man presenting as the giant cell lesions in the maxilla and/or mandible are discussed. METHODS: Biopsy of the lesions, biochemical and hormonal analyses, densitometry and parathyroid scintigraphy were carried out. RESULTS: Biopsy of the lesions showed giant cell tumor of bone. The medical history and laboratory analyses showed primary hyperparathyroidism. Bone density loss was documented and scintigraphy revealed the presence of parathyroid adenomas in four cases. Surgical treatment of hyperparathyroidism, and in the second step - after 6-12 months - the subsequent excision of residual brown tumors in all cases was performed. CONCLUSIONS: One should have in mind that osteolytic bone lesions may be due to metabolic disease of the bone. Accurate diagnosis enabling the proper treatment should be carried out, avoiding unnecessary harm to the patients. PMID- 23645307 TI - Skull base secretory meningioma. Value of histological and immunohistochemical findings for peritumoral brain edema formation. AB - Meningiomas are very common neurosurgical problem. Their histological appearance, different size and localization, adherence to vital neural and vascular structures or extensive peritumoral brain edema (PTBE), especially in deep seated tumors, may lead to severe, life-threatening complications. We report a case of tuberculum sellae meningioma (TSM). A 48-year old female presented with 7-month history of blurred vision and progressive visual impairment. Intracranial tumor was confirmed by magnetic resonance imaging (MRI). After ophtalmological and endocrinological evaluation, the patient underwent surgical removal of the tumor. She immediately recovered from her visual disturbances and no tumor recurrences were seen during follow-up. Pathological diagnosis showed a meningioma of the secretory subtype (MS). We discuss the role of immunohistochemical staining in the diagnosis and the role of different factors in the PTBE formation. Selection of surgical route to the TSM is discussed, as well. Review of the literature is presented. PMID- 23645308 TI - Phosphorylation of cAMP response element-binding protein in the extended amygdala of male rats is induced by novel environment and attenuated by estrous female bedding. AB - OBJECTIVE: We examined whether female pheromone, which would be contained in female-soiled bedding, affected the expression of phosphorylated cAMP response element-binding protein-like (pCREB) immunoreactive cells in the extended amygdala. METHODS: Male rats were exposed to following conditions: maintained in their home cage (home cage group), or relocated to a cage containing clean bedding (clean-bedding exposed group), ovariectomized (OVX) rat-soiled bedding (OVX-bedding exposed group) or estrogen-treated OVX rat-soiled bedding (OVX+E2 bedding exposed group). Rats were sacrificed 10-20 min after exposure and brain sections were subject to immunocytochemical processing. RESULTS: In the medial subdivision of the bed nucleus of the stria terminalis (BST) and the central amygdala (CeA), the number of pCREB immunoreactive (pCREB-ir) cells in the clean bedding exposed group was significantly larger than in the home cage group, while the number of pCREB-ir cells in the OVX+E2-bedding exposed group did not differ from that in the home cage group. The bedding soiled by OVX rats was less effective. No significant difference in the number of pCREB-ir cells was detected in the other regions of the extended amygdala among all groups. CONCLUSIONS: The present study suggests that the exposure of clean bedding to male rats induces the expression of pCREB-ir in the medial BST and the CeA; exposure to female pheromone attenuates this expression. PMID- 23645309 TI - Plasma NPY concentrations in women with acute ischemic stroke. AB - OBJECTIVE: It has been reported that plasma NPY levels were increased in obesity, type 2 diabetes mellitus and hypertension. The symptoms of metabolic syndrome frequently appear in patients with acute ischemic stroke. The association between plasma NPY levels and metabolic markers in women with acute ischemic stroke was investigated in the current study. METHODS: Plasma NPY concentrations were determined using radioimmunoassay in 58 women aged 60-85 (mean age: 76.5+/-0.8) with acute ischemic stroke and in 24 women aged 63-67 (mean age: 65.6+/-0.6) of the control group. Stroke was defined according to the NIHSS (National Institute of Health Stroke Scale) and was confirmed using CT or MR scan. RESULTS: The prevalence of type 2 diabetes, hypertension and insulin resistance was higher in the group of patients with stroke. Plasma NPY levels measured during the 1st day and 10 days after the acute phase of stroke were significantly lower (p<0.001) compared to the control group. CONCLUSION: In women with acute ischemic stroke plasma NPY concentrations were decreased in spite of higher frequency of the occurrence of the symptoms of metabolic syndrome. PMID- 23645310 TI - Bisphenol A significantly modulates long-term depression in the hippocampus as observed by multi-electrode system. AB - OBJECTIVE: Low dose exposure to endocrine disrupters (environmental chemicals) may induce hormone-like effects on wildlife and humans. bisphenol A (BPA) might disturb the neuronal signaling regulated by endogenous estrogens. We investigated the rapid modulation effects of 10nM BPA, a typical endocrine disruptor, on long term depression (LTD) of adult rat hippocampal slices. METHOD: LTD was induced by a transient perfusion of 30 uM NMDA for 3 min. And measured with multielectrode probes. RESULTS: A 30 min perfusion of 10 nM BPA rapidly enhanced LTD in CA1, however, BPA suppressed LTD in dentate gyrus (DG). An ERRgamma antagonist, 4-OH tamoxifen, suppressed LTD in CA1 and DG. Inhibitor of estrogen receptor ICI 182,780 did not disturb BPA effects. On the other hand, tributyltin (TBT), another endocrine disruptor, did not have any effect on LTD in CA1 and DG. CONCLUSION: ERRgamma, but not estrogen receptors, is a high affinity BPA receptor in LTD processes, since the effect of BPA on LTD was suppressed by an ERRgamma antagonist. A possible mechanisms of BPA-induced enhancement of LTD could be described with ERRgamma, MAPK activation and phosphorylation of MMDA receptors. PMID- 23645311 TI - "Mesodiencephalic" modulation in the treatment of diabetic neuropathy. AB - OBJECTIVE: Aim of the study was to verify the efficacy of "mesodiencephalic" modulation (MDM), as named by the commercial promoters, in reducing symptoms accompanying painful diabetic neuropathy and in improving mental health. METHODS: 32 patients with type 1 and 2 diabetes mellitus, with painful neuropathy, were enrolled in the prospective, double-blind, placebo-controlled, cross-over study. The modulation was performed using MDM electrotherapeutic device (ZAT a.s), sham modulation was used as a placebo. Pain relief (visual analogue scale-VAS; total symptom score-TSS) and changes in mental state (Beck Depression Inventory-BDI-II; OSWESTRY and SF-36 questionnaires) were evaluated. RESULTS: The study was completed by 30 patients. Pain evaluation: VAS: pain relief was statistically insignificantly higher after real (R) compared to sham (S) modulation (-0.7 vs. 0.3; p=0.06), effect of both modulations was equal after 1 month (-0.4 vs. 0.0; p=0.46). TSS: the effect of R and S modulation did not differ immediately after the procedure (-1.3 vs. -1.0; p=0.27), nor after 1 month (-1.5 vs. -0.34; p=0.9). Psychological tests: according to SF-36, the physical health improved considerably after R compared to S (2.5 vs. -2.0; p<0.01), however, changes in the mental health were equal (-1.5 vs. 0.0; p=0.78). Oswestry (0 vs. 0; p=0.95) and BDI-II (-0.5 vs. -1.0; p=0.42) were comparable after R and S modulation. Order of the procedures (R vs. S) did not affect results. CONCLUSION: The study did not demonstrate any positive effect of MDM on painful diabetic neuropathy compared to placebo, relative to pain or mental state evaluations. The study emphasizes the need of using placebo-controlled studies, especially when testing a new analgesic drug or a method for pain modulation. PMID- 23645312 TI - Alterations of reproductive hormones and receptors of male rats at the winter and summer solstices and the effects of pinealectomy. AB - BACKGROUND: Photoperiodic changes mediate certain physiological or pathological alterations in organisms. Solstices represent either the longest or shortest photoperiod of a year. OBJECTIVES: Intact and pinealectomized rats were used to investigate the potential changes of reproductive hormones in the hypothalamus pituitary-testis (HPT) axis including GnRH, FSH, LH, testosterone and melatonin, and their receptors at summer solstice (SS) and winter solstices (WS). METHODS: The levels of reproductive hormones in HPT axis and the binding characteristics of their receptors were examined using radioimmunoassay and radioreceptor assay techniques, respectively. RESULTS: The results indicate that in the intact male rat, GnRH, LH and testosterone are higher at the SS than at the WS. However, FSH exhibited no significant seasonal changes. In the testis, Bmax and Kd of LH receptors are higher at the WS than at the SS while those of FSH receptors are higher at the SS than at the WS. In addition, the melatonin in HPT axis appeared significant differences between WS and SS. Bmax and Kd of melatonin receptors in the hypothalamus and pituitary also showed higher at the WS than at the SS. Moreover, reproductive hormone production lost their seasonal rhythms after pinealectomy. CONCLUSION: The most important discovery in this study is that we first reported that pinealectomy had profound effects on the binding characteristics of melatonin with its subtype receptors. Especially at the hypothalamus, the dominated melatonin receptors shifted from MT1 to MT2 after pinealectomy at the two solstices. PMID- 23645313 TI - Patients with chronic hepatitis type C and interferon-alpha-induced hyperthyroidism in two-years clinical follow-up. AB - OBJECTIVES: Interferon-alpha (IFN-alpha) is a gold standard in the therapy of viral chronic hepatitis type C (CHC). However, such treatment might lead to thyroid dysfunction. Patients usually present hypothyroidism, but rarely also hyperthyroidism may develop. The aim of the study is to present two-year clinical follow-up of patients with CHC and IFN-alpha-induced hyperthyroidism (IIH), with special regard to the methods and efficacy of the therapy. METHODS: A group of 106 patients with CHC and IIH were analyzed. Subjects were divided into two groups according to etiology: group 1, with Graves' disease (GD) and group 2, with Hashitoxicosis (HT). The diagnosis of GD and HT was based on: clinical signs of hyperthyroidism, hormonal profile (TSH, fT4, fT3), level of thyroid autoantibodies (Tg-Abs, TPO-Abs, TSHRAbs). Treatment of hyperthyroidism was monitored by repeated clinical assessment and laboratory tests. RESULST: 28 patients (26 with GD of which 5 exhibited mild orbitopathy and 2 with HT) were treated with radioiodine [the average dose of was 17 mCi [668 MBq]. In adition 78 out of 80 patients with HT mostly beta-blocker therapy was successful (transient hyperthyroidism). At the end of the observation period, in group 1 remission was achieved in 17 (65.4%) cases, 6 (23.1%) patients showed hypothyroidism and 3 (11.5%) presented recurrence of hyperthyroidism. CONCLUSIONS: Most patients with IIH present Hashitoxicosis, while a minority of them develop Graves' disease. In a majority of patients with HT spontaneous remission of disease occurs. In patients with long-term hyperthyroidism, radioiodine therapy is an effective and well-tolerated. PMID- 23645314 TI - What are demographic and EEG differences between responding and non-responding panic disorder patients. AB - BACKGROUND: Standardized low-resolution electromagnetic tomography (sLORETA) is a new quantitative EEG method for determining distribution of neuronal electrical activity in the form of three-dimensional images of current density of the cerebral cortex. Unlike standard quantitative EEG, it allows noninvasive and detailed localization of neuronal generators responsible for surface EEG with zero localization error. The study aimed at finding electrotomographic differences between patients with panic disorder who respond well to cognitive behavioral therapy (CBT) and those with an inadequate response and to determine factors predicting a response to treatment. METHODS: The study comprised 24 patients diagnosed with panic disorder with or without agoraphobia (ICD-10 F41.0). The severity of symptoms was measured with the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Sheehan Anxiety Scale, subjective and objective Clinical Global Impression (CGI) and Dissociative Experiences Scale (DES). Additionally, quality of life was evaluated using the Q-LES-Q questionnaire. Based on final BAI score decreases by 25%, the patients were classified into two groups - responders and non-responders. 21-channel EEGs were recorded at baseline and after completion of therapy. Power spectra and intracortical tomography were computed by sLORETA in seven frequency bands and compared between (responders vs. non-responders) and within (pre- vs. post treatment) groups. RESULTS: There were no differences between responders and non responders with respect to age, gender and baseline disorder symptomatology. Statistical analysis of sLORETA values demonstrated no significant inter-group differences in the pretreatment current density distribution. After treatment, only responders showed a significant decrease of alpha-2 sources (p<0.05) in the occipital lobes and cuneus and a statistical trend for increased beta-3 sources (p<0.10) in the posterior cingulate. In non-responders, there were no statistically significant changes in sLORETA findings following therapy. CONCLUSIONS: The study failed to use pretreatment sLORETA in the prediction of therapeutic response in patients with panic disorder. However, we clearly demonstrated that only treatment response was associated with significant changes of electric neuronal activity. An analysis of demographic data suggested that duration of the disease, age, level of dissociation and employment may be considered as factors influencing the response. PMID- 23645315 TI - Announcement effects of health policy reforms: evidence from the abolition of Austria's baby bonus. AB - We analyze the short-run fertility and health effects resulting from the early announcement of the abolition of the Austrian baby bonus in January 1997. The abolition of the benefit was publicly announced about 10 months in advance, creating the opportunity for prospective parents to (re-)schedule conceptions accordingly. We find robust evidence that, within the month before the abolition, about 8 % more children were born as a result of (re-)scheduling conceptions. At the same time, there is no evidence that mothers deliberately manipulated the date of birth through medical intervention. We also find a substantial and significant increase in the fraction of birth complications, but no evidence for any resulting adverse effects on newborns' health. PMID- 23645317 TI - Rapid bonding of polydimethylsiloxane to stereolithographically manufactured epoxy components using a photogenerated intermediary layer. AB - We describe a low cost, photo-induced, room-temperature bonding technique for bonding epoxy components to flexible PDMS membranes in less than half an hour. Bond strengths (~350 kPa) were characterized by ISO-conform tensile testing for a popular stereolithography resin and found comparable bond strengths as reported for PDMS/PDMS bonds. PMID- 23645316 TI - Holobiont nutrition: considering the role of the gastrointestinal microbiota in the health benefits of whole grains. AB - Intake of whole grains and other food products high in dietary fiber have long been linked to the prevention of chronic diseases associated with inflammation. A contribution of the gastrointestinal microbiota to these effects has been suggested, but little is known on how whole grains interact with gut bacteria. We have recently published the first human trial that made use of next-generation sequencing to determine the effect of whole grains (whole grain barley, brown rice or a mixture of the two) on fecal microbiota structure and tested for associations between the gut microbiota and blood markers of inflammation, glucose and lipid metabolism. Our study revealed that whole grains impacted gut microbial ecology by increasing microbial diversity and inducing compositional alterations, some of which are considered to have beneficial effects on the host. Interestingly, whole grains, and in particular the combination of whole grain barley and brown rice, caused a reduction in plasma interleukin-6 (IL-6), which was linked to compositional features of the gut microbiota. Therefore, the study provided evidence that a short-term increased intake of whole grains led to compositional alterations of the gut microbiota that coincided with improvements in systemic inflammation. In this addendum, we summarize the findings of the study and provide a perspective on the importance of regarding humans as holobionts when considering the health effects of dietary strategies. PMID- 23645319 TI - Interstitial deletion 14q31.1q31.3 transmitted from a mother to her daughter, both with features of hemifacial microsomia. PMID- 23645318 TI - Mutational analysis in podocin-associated hereditary nephrotic syndrome in Polish patients: founder effect in the Kashubian population. AB - Hereditary nephrotic syndrome is caused by mutations in a number of different genes, the most common being NPHS2. The aim of the study was to identify the spectrum of NPHS2 mutations in Polish patients with the disease. A total of 141 children with steroid-resistant nephrotic syndrome (SRNS) were enrolled in the study. Mutational analysis included the entire coding sequence and intron boundaries of the NPHS2 gene. Restriction fragment length polymorphism (RFLP) and TaqMan genotyping assay were applied to detect selected NPHS2 sequence variants in 575 population-matched controls. Twenty patients (14 %) had homozygous or compound heterozygous NPHS2 mutations, the most frequent being c.1032delT found in 11 children and p.R138Q found in four patients. Carriers of the c.1032delT allele were exclusively found in the Pomeranian (Kashubian) region, suggesting a founder effect origin. The 14 % NPHS2 gene mutation detection rate is similar to that observed in other populations. The heterogeneity of mutations detected in the studied group confirms the requirement of genetic testing the entire NPHS2 coding sequence in Polish patients, with the exception of Kashubs, who should be initially screened for the c.1032delT deletion. PMID- 23645320 TI - Invasibility of nectarless flowers in plant-pollinator systems. AB - This paper considers plant-pollinator systems in which plants are divided into two categories: The plants that secret a substantial volume of nectar in their flowers are called secretors, while those without secreting nectar are called nonsecretors (cheaters). The interaction between pollinators and secretors is mutualistic, while the interaction between pollinators and nonsecretors is parasitic. Both interactions can be described by Beddington-DeAngelis functional responses. Using dynamical systems theory, we show global dynamics of a pollinator-secretor-cheater model and demonstrate mechanisms by which nectarless flowers/nonsecretors can invade the pollinator-secretor system and by which the three species could coexist. We define a threshold in the nonsecretors' efficiency in translating pollinator-cheater interaction into fitness, which is determined by parameters (factors) in the systems. When their efficiency is above the threshold, non-secretors can invade the pollinator-secretor system. While the nonsecretors' invasion often leads to their persistence in pollinator-secretor systems, the model demonstrates situations in which the non-secretors' invasion can drive secretors into extinction, which consequently leads to extinction of the nonsecretors themselves. PMID- 23645321 TI - Syndromic versus nonsyndromic atlantoaxial dislocation: do clinico-radiological differences have a bearing on management? AB - BACKGROUND: This prospective study attempts to study the clinico-radiological differences between patients with syndromic AAD (SAAD), non-syndromic AAD (NSAAD), and AAD with Klippel-Feil anomaly (AADKFA) that may impact management. METHODS: In 46 patients with AAD [SAAD (including Morquio, Down, Larson and Marshall syndrome and achondroplasia; n = 6); NSAAD(n = 20); and, AADKFS (n = 20)], myelopathy was graded as mild (n = 17, 37 %), moderate (15, 32.5 %) or severe (14, 30.5 %) based on Japanese Orthopaedic Association Score modified for Indian patients (mJOAS). Basilar invagination (BI), basal angle, odontoid hypoplasia, facet-joint angle, effective canal diameter, Ishihara curvature index, and angle of retroversion of odontoid and vertebral artery (VA) variations were also studied. STATISTICS: Clinico-radiological differences were assessed by Fisher's exact test, and mean craniometric values by Kruskal-Wallis test (p value <= 0.05 significant) RESULTS: Incidence of irreducible AAD in SAAD (n = 0), NSA AD (11.55 %) and AADKFS (n = 18.90 %) showed significant difference (p = 0.01). High incidence of kyphoscoliosis (83 %) and odontoid hypoplasia (83 %) in SAAD, and assimilated atlas and BI in NSAAD and AADKFA groups were found. In AADKFA, effective canal diameter was significantly reduced(p = 0.017) with increased Ishihara index and increased angle of odontoid retroversion; 61 % patients had VA variations. Thirty-five patients underwent single-stage transoral decompression with posterior fusion (for irreducible AAD) or direct posterior stabilization (for reducible AAD). Postoperative mJOAS evaluation often revealed persistent residual myelopathy despite clinical improvement. CONCLUSIONS: Myelopathy is induced by recurrent cord trauma due to reducible AAD in SAAD, and compromised cervicomedullary canal diameter in NSAAD and AADKFA. SAAD in children may be missed due to incomplete odontoid ossification or coexisting angular deformities. In AADKFA, decisions regarding vertebral levels to be included in posterior stabilization should take into consideration intact intervening motion segments and compensatory cervical hyperlordosis. Following VA injury, endovascular primary vessel occlusion/stenting across pseudoaneurysm preempts delayed rehemorrhage. PMID- 23645322 TI - Pathophysiology of shunt dysfunction in shunt treated hydrocephalus. AB - BACKGROUND: We hypothesized that shunt dysfunction in the ventricular catheter and the shunt valve is caused by different cellular responses. We also hypothesized that the cellular responses depend on different pathophysiological mechanisms. METHODS: Removed shunt material was collected. Macroscopic tissue in the catheters was paraffin-embedded and HE-stained. Valves were incubated with trypsin-EDTA in order to detach macroscopically invisible biomaterial, which was then cytospinned and HE-stained. Associated aetiological and surgical data were collected by reviewing patient files, and ventricular catheter position was examined using preoperative radiology (CT scans). RESULTS: We examined eleven ventricular catheters and ten shunt valves. Catheters: 6/11 catheters contained intraluminal tissue consisting of vascularised glial tissue and inflammatory cells (macrophages/giant cells and a few eosinophils). Catheter adherence correlated with the presence of intraluminal tissue, and all tissue containing catheters had some degree of ventricle wall contact. All obstructed catheters contained intraluminal tissue, except one catheter that was dysfunctional because of lost ventricular contact. Valves: Regardless of intraoperative confirmation of valve obstruction, all ten valves contained an almost uniform cellular response of glial cells (most likely ependymal cells), macrophages/giant cells, and lymphomonocytic cells. Some degree of ventricle wall catheter contact was present in all examined valves with available radiology (9/10). CONCLUSIONS: The same cellular responses (i.e., glial cells and inflammatory cells) cause both catheter obstruction and valve obstruction. We propose two synergistic pathophysiological mechanisms. (1) Ventricle wall/parenchymal contact by the catheter causes mechanical irritation of the parenchyma including ependymal exfoliation. (2) The shunt material provokes an inflammatory reaction, either nonspecific or specific. In combination, these mechanisms cause obstructive tissue ingrowth (glial and inflammatory) in the catheter and clogging of the valve by exfoliated glial cells and reactive inflammatory cells. PMID- 23645323 TI - Long-term control of ambulatory hypertension in children: improving with time but still not achieving new blood pressure goals. AB - BACKGROUND: Short-term therapy can decrease blood pressure (BP) to less than the 95th percentile in only about 50% of children. The aim of our study was to investigate the long-term control of hypertension (HT) in children using ambulatory BP monitoring (ABPM). METHODS: We analyzed data from all children who started ramipril monotherapy in our center. Controlled HT was defined according to the most current guidelines as systolic and diastolic BP at daytime and nighttime <90th percentile in primary HT and <75th percentile in renoparenchymal HT. RESULTS: Thirty-eight children who were on therapy >=1 year were included. Thirty-two children had renoparenchymal, and 6 had primary HT. The median age at the beginning of therapy was 13.6 years (range = 4.1-18.0 years), and the median time of antihypertensive therapy was 2.6 years (range = 1.0-11.8 years). Thirty four percent of children received combination therapy; the median number of antihypertensive drugs was 1.5 drugs/patient (range = 1-4). Sixty-eight percent of children had BP <95th percentile, but only 34% of the children had controlled HT. Children with uncontrolled HT had a tendency to have a higher daytime diastolic BP index before the start of therapy than children with controlled HT (0.99+/-0.11 vs. 0.94+/-0.11; P = 0.09). There was a significant decrease in prevalence of nondipping (from 47% to 16%; P = 0.006) with therapy. CONCLUSIONS: This first pediatric study focusing on long-term control of HT using ABPM showed that long-term control of HT is better than short-term control, but still only one-third of children achieve the new BP goals. The low control of HT might be improved by more intensive therapy. PMID- 23645324 TI - Hypertension is difficult to control in children, too. PMID- 23645325 TI - Associations between nocturnal blood pressure dipping and the metabolic syndrome in high- vs. low-acculturated Mexican American women. AB - BACKGROUND: Less nocturnal blood pressure (BP) dipping has been associated with greater odds for the metabolic syndrome (MetS), a constellation of risk factors associated with cardiovascular disease (CVD). Little work has examined this association in Hispanics, who have elevated rates of MetS, or investigated differences in this relationship by level of acculturation. The purpose of this study was to examine the association between BP dipping and MetS in Hispanic women and to determine if this association is moderated by acculturation status. METHODS: Two hundred eighty-six Mexican American women underwent assessment of MetS components (BP, waist circumference, fasting glucose, high-density lipoprotein cholesterol, and triglycerides) and completed a 36-hour ambulatory BP monitoring protocol, during which systolic BP (SBP) and diastolic BP readings were obtained. Nocturnal BP dipping was calculated as the percentage difference between average daytime and nighttime BP. Acculturation was defined by the language (Spanish, English) in which participants preferred to complete study instruments. RESULTS: Although no significant main effects for BP dipping or acculturation emerged for MetS, the SBP dipping by acculturation interaction was significantly related to MetS (P < 0.01). Simple slope analyses revealed that less SBP dipping related to greater odds of MetS in high-acculturated women, but SBP dipping and MetS were unrelated in low-acculturated women. CONCLUSIONS: The strength of the association between BP dipping and CVD risk (as measured by MetS) appears to vary by acculturation in Hispanic women. Future studies should explore mechanisms behind the BP dipping and CVD risk association and relevant modifying factors. PMID- 23645326 TI - Phenotypic and functional alterations of primary human PBMCs induced by HCV non enveloped capsid-like particles uptake. AB - Hepatitis C virus non-enveloped particles circulate in the serum of HCV-infected patients and are believed to be involved in viral persistence. It was previously demonstrated that recombinant HCVne particles can efficiently enter T cells. In this study we investigated the effect of this entry on the phenotype and function of PBMCs, focused on the CD4+ and CD8+ T-cells. We have generated recombinant HCVne in the absence of other viral proteins. PBMCs from healthy donors were sampled after incubation either with HCVne or the control at different time points. Levels of expression of CD107a, CD25, CTLA-4, and T regulatory cells were estimated and cytokine expression and secretion were also monitored. Peripheral T cells expressed elevated CD127. The intracellular expression of the inhibitory marker CTLA-4 (CD152) increased significantly on peripheral T cells at late hours post-treatment, compared to the respective non-treated group. Despite the fact that there was an initial immune response due to HCVne uptake, T cells were driven to a partial exhausted phenotype. A significant induction of CD4+CD25+(hi)CD127-regulatory T cells at late hours was observed. Consistently, Foxp3+CD4+ T cells were also increased. In parallel, a significant transcriptional activation and increased secretion of IL-2, IL-10, and IFN-gamma, was recorded. Moreover, mRNA transcription of TGF-beta was considerably elevated. HCVne particles have the potential to shape the immune response by modifying specific phenotypic and functional markers mainly on CD4+ T cells and driving them to partial exhaustion as well as to Treg expansion. PMID- 23645328 TI - Prospectively ECG-triggered sequential dual-source coronary CT angiography in patients with atrial fibrillation: comparison with retrospectively ECG-gated helical CT. AB - OBJECTIVE: To investigate the feasibility of applying prospectively ECG-triggered sequential coronary CT angiography (CCTA) to patients with atrial fibrillation (AF) and evaluate the image quality and radiation dose compared with a retrospectively ECG-gated helical protocol. METHODS: 100 patients with persistent AF were enrolled. Fifty patients were randomly assigned to a prospective protocol and the other patients to a retrospective protocol using a second-generation dual source CT (DS-CT). Image quality was evaluated using a four-point grading scale (1 = excellent, 2 = good, 3 = moderate, 4 = poor) by two reviewers on a per segment basis. The coronary artery segments were considered non-diagnostic with a quality score of 4. The radiation dose was evaluated. RESULTS: Diagnostic segment rate in the prospective group was 99.4 % (642/646 segments), while that in the retrospective group was 96.5 % (604/626 segments) (P < 0.001). Effective dose was 4.29 +/- 1.86 and 11.95 +/- 5.34 mSv for each of the two protocols (P < 0.001), which was a 64 % reduction in the radiation dose for prospective sequential imaging compared with retrospective helical imaging. CONCLUSION: In AF patients, prospectively ECG-triggered sequential CCTA is feasible using second-generation DS-CT and can decrease >60 % radiation exposure compared with retrospectively ECG gated helical imaging while improving diagnostic image quality. KEY POINTS: * Coronary computed tomographic angiography (CCTA) can be difficult in patients with arrhythmias. * Prospectively ECG-triggered sequential CCTA is feasible in patients with atrial fibrillation. * Prospective sequential imaging can improve quality compared with retrospective analysis. * Prospective sequential imaging decreases radiation exposure by 64 % compared with retrospective mode. PMID- 23645329 TI - Accuracy of multidetector-row CT for restaging after neoadjuvant treatment in patients with oesophageal cancer. AB - OBJECTIVES: To assess the diagnostic accuracy of 64-multidetector CT (MDCT) for restaging of patients with oesophageal cancer undergoing neoadjuvant therapy. METHODS: Results of pathological staging were correlated with those from 64-MDCT before and after neoadjuvant treatment in 35 patients using the American Joint Committee on Cancer/TNM classification (7th edition). CT response was determined using the Response Evaluation Criteria in Solid Tumours (RECIST) method, modified for one-dimensional tumour diameter measurement. RESULTS: 64-MDCT predicted T stage correctly in 34 % (12/35), overstaged in 49 % (17/35) and understaged in 17 % (6/35). Sensitivity/specificity values were as follows: T0, 20 %/92 %; T1-T2, 31 %/59 %; T3, 60 %/64 %; T4, 100 %/4 %. Negative predictive values for T3/T4 were 80 %/100 %. MDCT accurately predicted complete histopathological response in 20 % (accuracy 74 %) and overstaged in 80 %. Tumour regression grade was predicted correctly in only 8 % (2/25) and underestimated in 68 % (17/25). Accurate N stage was noted in 69 % (24/35). CONCLUSION: Although MDCT tends to be able to exclude advanced tumour stages (T3, T4) with a higher likelihood, the diagnostic accuracy of high resolution MDCT for restaging oesophageal cancer and assessing the response to neoadjuvant therapy has not improved in comparison to older-generation CT. Therefore, the future assessment of oesophageal tumour response should focus on combined morphologic and metabolic imaging. KEY POINTS: * Multidetector CT (MDCT) has been beneficial for the evaluation of many tumours. * However diagnostic accuracy for restaging oesophageal cancer has not improved with MDCT. * MDCT tends to be able to exclude advanced tumour stages (T3/T4). * MDCT has a low accuracy for determining lymph node metastasis. * Oesophageal tumour response should be assessed by combined morphological and metabolic imaging. PMID- 23645330 TI - Contrast-enhanced time-resolved 4D MRA of congenital heart and vessel anomalies: image quality and diagnostic value compared with 3D MRA. AB - OBJECTIVES: To evaluate time-resolved interleaved stochastic trajectories (TWIST) contrast-enhanced 4D magnetic resonance angiography (MRA) and compare it with 3D FLASH MRA in patients with congenital heart and vessel anomalies. METHODS: Twenty six patients with congenital heart and vessel anomalies underwent contrast enhanced MRA with both 3D FLASH and 4D TWIST MRA. Images were subjectively evaluated regarding total image quality, artefacts, diagnostic value and added diagnostic value of 4D dynamic imaging. Quantitative comparison included signal to-noise ratio (SNR), contrast-to-noise ratio (CNR) and vessel sharpness measurements. RESULTS: Three-dimensional FLASH MRA was judged to be significantly better in terms of image quality (4.0 +/- 0.6 vs 3.4 +/- 0.6, P < 0.05) and artefacts (3.8 +/- 0.4 vs 3.3 +/- 0.5, P < 0.05); no difference in diagnostic value was found (4.2 +/- 0.4 vs 4.0 +/- 0.4); important additional functional information was found in 21/26 patients. SNR and CNR were higher in the pulmonary trunk in 4D TWIST, but slightly higher in the systemic arteries in 3D FLASH. No difference in vessel sharpness delineation was found. CONCLUSIONS: Although image quality was inferior compared with 3D FLASH MRA, 4D TWIST MRA yields robust images and added diagnostic value through dynamic acquisition was found. Thus, 4D TWIST MRA is an attractive alternative to 3D FLASH MRA. KEY POINTS: * New magnetic resonance angiography (MRA) techniques are increasingly introduced for congenital cardiovascular problems. * Time-resolved angiography with interleaved stochastic trajectories (TWIST) is an example. * Four-dimensional TWIST MRA provided inferior image quality compared to 3D FLASH MRA but without significant difference in vessel sharpness. * Four-dimensional TWIST MRA gave added diagnostic value. PMID- 23645331 TI - How far can the radiation dose be lowered in head CT with iterative reconstruction? Analysis of imaging quality and diagnostic accuracy. AB - OBJECTIVE: To evaluate the imaging quality of head CT at lowered radiation dose by combining filtered back projection (FBP) and iterative reconstruction (IR) algorithms. METHODS: Experimental group A (n = 66) underwent CT with 43 % tube current reduction, and group B (n = 58) received an equivalent reduced dose by lowering the tube voltage. An age- and sex-matched control group (n = 72) receiving the conventional radiation dose was retrospectively collected. Imaging for the control group was reconstructed by FBP only, while images for groups A and B were reconstructed by FBP and IR. The signal-to-noise ratios (SNRs), contrast-to-noise ratios (CNRs), sharpness, number of infarcts and severity of subcortical arteriosclerotic encephalopathy (SAE) were compared to assess imaging quality and diagnostic accuracy. RESULTS: There were no significant differences in SNRs and CNRs between group A and the control group. There were significantly decreased SNRs and increased CNRs in group B. Image sharpness decreased in both groups. Correlations between detected infarcts and severity of SAE across FBP and IR were high (r = 0.73-0.93). Head diameter was the only significant factor inversely correlated with infratentorial imaging quality. CONCLUSION: Head CT with 43 % reduced tube current reconstructed by IR provides diagnostic imaging quality for outpatient management. KEY POINTS: * Cranial CT using iterative reconstruction provides diagnostic images with 43 % mAs reduction. * Blurring of infratentorial images becomes evident using low-radiation head CT. * Head diameter was inversely correlated with imaging quality in the infratentorium. * Lowering tube kilovoltage requires a higher radiation dose to maintain image quality. PMID- 23645332 TI - Seven-Tesla MRI of the female pelvis. AB - OBJECTIVES: The aim of this study was to investigate the feasibility of 7-T contrast-enhanced MR imaging of the female pelvis. METHODS: Ten healthy female volunteers were examined on a 7-T whole-body MR system utilising a custom-built eight-channel transmit/receive radiofrequency body coil. The examination protocol included (1) T1-weighted fat-saturated 2D spoiled gradient echo (FLASH), (2) dynamic T1-weighted fat-saturated 3D FLASH, and (3) T2-weighted TSE sequences. For qualitative image analysis pelvic anatomy, uterine zonal anatomy and image impairment due to artefacts was assessed using a five-point scale. For quantitative analysis contrast ratios between the junctional zone and myometrium were obtained for T2-weighted MRI. RESULTS: Two-dimensional FLASH MRI offered the best overall image quality (meancontrast-enhanced 4.9) and highest tissue contrast (meancontrast-enhanced 4.7). T2-weighted TSE imaging provided a moderate to high conspicuity of the uterine zonal anatomy with mean scores ranging from 3.5 for endometrium to 4.65 for myometrium. Overall image impairment was rated strongest for T2-weighted MRI (2.9) and least for 2D FLASH MRI (mean 4.2). CONCLUSION: This study demonstrated the feasibility of 7-T T1-weighted MRI of the female pelvis and current constraints associated with T2-weighted MRI. KEY POINTS: * Dynamic contrast-enhanced female pelvis MR imaging at 7 T is feasible. * Unenhanced T1-weighted MRI offers inherent hyperintense delineation of pelvic arterial vasculature. * Two-dimensional FLASH MRI provided best overall image quality and least artefact impairment. PMID- 23645335 TI - Triple combination therapy for hepatitis C with telaprevir exhibits greater early antiviral activity than with boceprevir. AB - BACKGROUND: Achievement of early viral suppression is important in patients with chronic HCV infection treated with telaprevir (TLV) or boceprevir (BOC) to avoid selection of drug resistance and attain cure. No head-to-head studies comparing TLV and BOC have been performed so far. METHODS: All consecutive individuals who initiated triple HCV therapy with TLV or BOC outside clinical trials at three European clinics were evaluated. Rapid virological response (RVR) was defined as unquantifiable HCV RNA (<25 IU/ml) at week 4 for TLV and at week 8 for BOC (4 weeks after lead-in). RESULTS: A total of 106 patients were evaluated, 33 treated with BOC and 73 with TLV. Median age, gender, body mass index, baseline HCV RNA, HCV subtype 1a (45% versus 42%) and IL28B-CC alleles (29% versus 23%) did not differ significantly in BOC and TLV groups, respectively. HIV coinfection was more prevalent in patients on TLV than BOC (24% versus 44%). Conversely, more patients on BOC than TLV had previously failed pegylated interferon plus ribavirin (82% versus 64%). RVR was achieved by 82% of patients on TLV versus 59% on BOC (P=0.001). Multivariate logistic regression analysis confirmed that TLV use was the strongest predictor of RVR (OR 3.54 [95% CI 1.23, 10.24]; P=0.02), others being HCV subtype 1b versus 1a (OR 3.26 [95% CI 1.17, 9.09]; P=0.02) and low baseline HCV RNA (OR 0.41 [95% CI 0.16, 1.03]; P=0.06). Prior interferon exposure, HIV coinfection or absence of advanced liver fibrosis did not influence the likelihood of RVR. CONCLUSIONS: Compared to BOC, triple therapy with TLV produces greater RVR rates. TLV might be a better option in more difficult-to cure patients, such as those with high baseline HCV RNA and/or HCV 1a subtype. HIV coinfection does not influence early HCV RNA responses. PMID- 23645336 TI - Reliability and validity of measuring acetabular component orientation by plain anteroposterior radiographs. AB - BACKGROUND: Inaccurate placement of an acetabular cup can cause impingement, dislocation, and accelerated wear. However, there is no universally agreed-on approach to measuring cup position using plain radiographs. OBJECTIVES/PURPOSES: Our goal was to evaluate the reliability and validity of measuring the orientation of acetabular components on plain anteroposterior (AP) radiographs. METHODS: We obtained plain AP radiographs and CT scans for 60 patients who underwent 60 primary total hip arthroplasties (THAs). The method devised by Lewinnek et al. was used to measure the orientation of acetabular components on plain AP radiographs, and three-dimensional (3-D) CT scans were used to measure both the radiographic anteversion angle and the inclination angle. Reliability was evaluated by analysis of the agreement between inter- and intraobserver measurements using plain AP radiographs. Measurements on 3-D CT scans were regarded as the reference standard; validity was assessed by comparing radiographic measurements with the CT scans. RESULTS: Inter- and intraobserver reliability for measuring component orientation on plain AP radiographs was nearly perfect with intraclass correlation coefficients of 0.896 and 0.969 for anteversion and 0.984 and 0.993 for inclination. Measurement of cup inclination angles differed between plain radiographs and CT scans, but the difference was small, and the difference, although statistically significant, probably was not clinically important (2.3 degrees +/- 1.8 degrees , p < 0.001). There was no significant difference between the anteversion as measured on CT scan versus that measured on plain radiographs (p = 0.19). CONCLUSIONS: Measurement of the orientation of acetabular components on plain AP radiographs is reliable and accurate compared with measurement on CT. PMID- 23645327 TI - Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors. AB - Multiple endocrine neoplasia type 1 (MEN1) is classically characterized by the development of functional or nonfunctional hyperplasia or tumors in endocrine tissues (parathyroid, pancreas, pituitary, adrenal). Because effective treatments have been developed for the hormone excess state, which was a major cause of death in these patients in the past, coupled with the recognition that nonendocrine tumors increasingly develop late in the disease course, the natural history of the disease has changed. An understanding of the current causes of death is important to tailor treatment for these patients and to help identify prognostic factors; however, it is generally lacking.To add to our understanding, we conducted a detailed analysis of the causes of death and prognostic factors from a prospective long-term National Institutes of Health (NIH) study of 106 MEN1 patients with pancreatic endocrine tumors with Zollinger-Ellison syndrome (MEN1/ZES patients) and compared our results to those from the pooled literature data of 227 patients with MEN1 with pancreatic endocrine tumors (MEN1/PET patients) reported in case reports or small series, and to 1386 patients reported in large MEN1 literature series. In the NIH series over a mean follow-up of 24.5 years, 24 (23%) patients died (14 MEN1-related and 10 non-MEN1-related deaths). Comparing the causes of death with the results from the 227 patients in the pooled literature series, we found that no patients died of acute complications due to acid hypersecretion, and 8%-14% died of other hormone excess causes, which is similar to the results in 10 large MEN1 literature series published since 1995. In the 2 series (the NIH and pooled literature series), two-thirds of patients died from an MEN1-related cause and one-third from a non-MEN1-related cause, which agrees with the mean values reported in 10 large MEN1 series in the literature, although in the literature the causes of death varied widely. In the NIH and pooled literature series, the main causes of MEN1-related deaths were due to the malignant nature of the PETs, followed by the malignant nature of thymic carcinoid tumors. These results differ from the results of a number of the literature series, especially those reported before the 1990s. The causes of non MEN1-related death for the 2 series, in decreasing frequency, were cardiovascular disease, other nonendocrine tumors > lung diseases, cerebrovascular diseases. The most frequent non-MEN1-related tumor deaths were colorectal, renal > lung > breast, oropharyngeal. Although both overall and disease-related survival are better than in the past (30-yr survival of NIH series: 82% overall, 88% disease related), the mean age at death was 55 years, which is younger than expected for the general population.Detailed analysis of causes of death correlated with clinical, laboratory, and tumor characteristics of patients in the 2 series allowed identification of a number of prognostic factors. Poor prognostic factors included higher fasting gastrin levels, presence of other functional hormonal syndromes, need for >3 parathyroidectomies, presence of liver metastases or distant metastases, aggressive PET growth, large PETs, or the development of new lesions.The results of this study have helped define the causes of death of MEN1 patients at present, and have enabled us to identify a number of prognostic factors that should be helpful in tailoring treatment for these patients for both short- and long-term management, as well as in directing research efforts to better define the natural history of the disease and the most important factors determining long-term survival at present. PMID- 23645337 TI - Statistical considerations in the psychometric validation of outcome measures. AB - BACKGROUND: The evaluation of the outcomes of total knee arthroplasty requires measurement tools that are valid, reliable, and responsive to change. However, the accuracy of any outcome measurement is determined by the validity and reliability of the instrument used. To ensure this accuracy, it is imperative that each instrument used in orthopaedics is free of biases leading to inaccurate estimates of treatment effects. WHERE ARE WE NOW?: Many patient-derived outcome instruments have been developed and tested through the application of the standard assessments that form the basis of classical test theory: validity, reliability, and responsiveness. These assessments determine if the instrument reliably measures what it is intended to measure, and if it captures differences among groups of patients or changes over time. WHERE DO WE NEED TO GO?: Thorough evaluation of the outcome instruments used in orthopaedics is a critical prerequisite for the continued improvement of effective patient care. Additional steps of psychometric testing that are sometimes overlooked include testing for differential item functioning (DIF) and the effects of the mode of administration of the outcome instrument. The use of suitable approaches to test for these potential sources of bias would facilitate the development of more robust outcome assessment in research and clinical practice. HOW DO WE GET THERE?: Testing for DIF, including the effects of mode of administration, may be performed using several analytical approaches. This will allow optimal application of each outcome instrument with respect to patient characteristics, time and mode of the administration, and modification, as necessary. PMID- 23645338 TI - Targeted use of vancomycin as perioperative prophylaxis reduces periprosthetic joint infection in revision TKA. AB - BACKGROUND: The role of vancomycin in surgical antimicrobial prophylaxis and high risk patients who are most likely to benefit remains unclear. QUESTIONS/PURPOSES: We determined the impact of targeted use of vancomycin on (1) the incidence of periprosthetic joint infection (PJI); and (2) the incidence of PJI from methicillin-resistant organisms in patients undergoing revision total knee arthroplasty (TKA) at our institution. METHODS: In an effort to reduce PJI rates, we added vancomycin to cefazolin as surgical antimicrobial prophylaxis for patients undergoing revision TKA in October 2010. Internal data indicated a high rate of PJI in revision TKA and in particular PJI resulting from methicillin resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). We retrospectively reviewed infection control surveillance data on 414 revision TKAs performed between July 2008 and June 2012 (fiscal years 2009-2012). RESULTS: The overall rate of PJI in fiscal years 2009-2010 among 190 patients undergoing revision TKA was 7.89%. After the change in surgical antimicrobial prophylaxis, there was a significant reduction in PJI among patients undergoing revision TKA in fiscal years 2011-2012 to 3.13% (p = 0.046). In particular, we observed a reduction in PJI resulting from methicillin-resistant organisms over this same time period, from 4.21% to 0.89% (p = 0.049). CONCLUSIONS: Targeted use of vancomycin in patients undergoing revision TKA was effective in reducing the rate of PJI and PJI resulting from methicillin-resistant organisms in an institution with a high baseline rate of PJI due to MRSA and MRSE. Identification of high-risk subgroups of patients within a surgical population can help target infection prevention strategies to those who are most likely to benefit and thus minimize potential risks (eg, selection of resistant organisms, adverse drug events) associated with broader application of such an intervention. PMID- 23645339 TI - What are the rates and causes of hospital readmission after total knee arthroplasty? AB - BACKGROUND: Total knee arthroplasty (TKA) and related interventions such as revision TKA and the treatment of infected TKAs are commonly performed procedures. Hospital readmission rates are used to measure hospital performance, but risk factors (both medical and surgical) for readmission after TKA, revision TKA, and treatment for the infected TKA have not been well characterized. QUESTIONS/PURPOSES: We measured (1) the unplanned hospital readmission rate in primary TKA and revision TKA, including antibiotic-spacer staged revision TKA to treat infection. We also evaluated (2) the medical and surgical causes of readmission and (3) risk factors associated with unplanned hospital readmission. METHODS: This retrospective cohort study included a total of 1408 patients (1032 primary TKAs, 262 revision TKAs, 113 revision of infected TKAs) from one institution. All hospital readmissions within 90 days of discharge were evaluated for timing and cause. Diagnoses at readmission were categorized as surgical or medical. Readmission risk was assessed using a Cox proportional hazards model that incorporated patient demographics and medical comorbidities. RESULTS: The unplanned readmission rate for the entire cohort was 4% at 30 days and 8% at 90 days. At 90 days postoperatively, revision of an infected TKA had the highest readmission rate, followed by revision TKA, with primary TKA having the lowest rate. Approximately three-fourths of readmissions were the result of surgical causes, mostly infection, arthrofibrosis, and cellulitis, whereas the remainder of readmissions were the result of medical causes. Procedure type (primary TKA versus revision TKA or staged treatment for infected TKA), hospital stay more than 5 days, discharge destination, and a fluid/electrolyte abnormality were each associated with risk of unplanned readmission. CONCLUSIONS: Patients having revision TKA, whether for infection or other causes, are more likely to have an unplanned readmission to the hospital than are patients having primary TKA. When assessing hospital performance for TKA, it is important to distinguish among these surgical procedures. PMID- 23645341 TI - Trauma care in India and Germany. AB - BACKGROUND: Road traffic accidents are among the leading causes of death worldwide in individuals younger than 45 years. In both India and Germany, there has been an increase in registered motor vehicles over the last decades. However, while the number of traffic accident victims steadily dropped in Germany, there has been a sustained increase in India. We analyze this considering the sustained differences in rescue and trauma system status. QUESTIONS/PURPOSES: We compared India and Germany in terms of (1) vehicular infrastructure and causes of road traffic accident-related trauma, (2) burden of trauma, and (3) current trauma care and prevention, and (4) based on these observations, we suggested how India and other countries can enhance trauma care and prevention. METHODS: Data for Germany were obtained from federal statistical databases, German Automobile Club, and German Trauma Registry. Data from India were available from the Ministry of Road Transport and Highways. We also performed a standardized literature search of PubMed for India and Germany using the following key words: "road traffic accidents", "prevention", "prehospital trauma care", "trauma system", "trauma registry", "trauma centers", and "development of vehicles." RESULTS: The total number of registered motor vehicles increased 473-fold in India and 100-fold in Germany from 1951 to 2011. The number of road traffic deaths increased in both countries until 1970, but thereafter decreased in Germany (3606 in 2012) while continuing to increase in India (142,485 in 2011). The differences between Germany and India relate to the relative sizes and populations of the countries (1:9 and 1:15, respectively), and differences in prevention and prehospital care (nationwide versus big cities) and hospital trauma systems (nationwide versus exceptional). CONCLUSIONS: Improvement requires attention to three major issues: (1) prevention through infrastructure, traffic laws, mandatory licensing; (2) establishment of a prehospital care system; and (3) establishment of regional trauma centers and a trauma registry. PMID- 23645340 TI - Preemptive low-dose dexamethasone reduces postoperative emesis and pain after TKA: a randomized controlled study. AB - BACKGROUND: Dexamethasone is a potent analgesic and antiemetic. However, the benefit of dexamethasone after TKA is unclear, as is the efficacy in a current multimodal regime. QUESTIONS/PURPOSES: We determined (1) whether the addition of dexamethasone to a protocol including ramosetron further reduces postoperative emesis compared with ramosetron alone; (2) whether it reduces postoperative pain; and (3) whether it increases the risk for wound complications in a current multimodal regime after TKA. METHODS: We randomized 269 patients undergoing TKAs to receive dexamethasone (10 mg) 1 hour before surgery and ramosetron immediately after surgery (Dexa-Ra group, n = 135), or ramosetron alone (Ra group, n = 134). We recorded the incidence of postoperative nausea and vomiting (PONV), severity of nausea, incidence of antiemetic requirement, complete response, pain level, and opioid consumption. Patients were assessed 0 to 6, 6 to 24, 24 to 48, and 48 to 72 hours postoperatively. In addition, patients were evaluated for wound complications and periprosthetic joint infections at a minimum of 1 year after surgery. RESULTS: The Dexa-Ra group had a lower incidence of PONV during the entire 72-hour evaluation period and experienced less severe nausea for the first 6 hours after TKA, although not between 6 to 72 hours. Overall use of a rescue antiemetic was less frequent, and complete response was more frequent in the Dexa Ra group. Patients in the Dexa-Ra group experienced lower pain and consumed less opioids during the 6- to 24-hour period and during the overall study period. No differences were found in wound complications between the groups, and each group had one case of periprosthetic joint infection. CONCLUSIONS: Patients who received prophylactic dexamethasone in addition to ramosetron had reduced postoperative emesis and pain without increased risks for wound complications, compared with patients who received ramosetron alone in patients managed using a multimodal regimen after TKA. PMID- 23645342 TI - Comparative analyses of stress-responsive genes in Arabidopsis thaliana: insight from genomic data mining, functional enrichment, pathway analysis and phenomics. AB - Biotic and abiotic stresses adversely affect agriculture by reducing crop growth and productivity worldwide. To investigate the abiotic stress-responsive genes in Arabidopsis thaliana, we compiled a dataset of stress signals and differentially upregulated genes (>= 2.5 fold change) from Stress-responsive transcription Factors DataBase (STIFDB) with additional set of stress signals and genes curated from PubMed and Gene Expression Omnibus. A dataset of 3091 genes differentially upregulated due to 14 different stress signals (abscisic acid, aluminum, cold, cold-drought-salt, dehydration, drought, heat, iron, light, NaCl, osmotic stress, oxidative stress, UV-B and wounding) were curated and used for the analysis. Details about stress-responsive enriched genes and their association with stress signals can be obtained from STIFDB2 database . The gene-stress-signal data were analyzed using an enrichment-based meta-analysis framework consisting of two different ontologies (Gene Ontology and Plant Ontology), biological pathway and functional domain annotations. We found several shared and distinct biological processes, cellular components and molecular functions associated with stress responsive genes. Pathway analysis revealed that stress-responsive genes perturbed the pathways under the "Metabolic pathways" category. We also found several shared and stress-signal specific protein domains, suggesting functional mechanisms regulating stress-response. Phenomic characteristics of abiotic stress responsive genes were ascertained for several stresses and found to be shared by multiple stresses in both anatomy and temporal categories of Plant Ontology. We found several constitutive stress-responsive genes that are differentially upregulated due to perturbation of different stress signals, for example a gene (AT1G68440) involved in phenylpropanoid metabolism and polyamine catabolism as responsive to seven different stress signals. We also performed structure function prediction of five genes associated responsive to multiple abiotic stress signals. We envisage that results from our analysis that provide insight into functional repertoire, metabolic pathways and phenomic characteristics common and specifically associated with stress signals would help to understand abiotic stress regulome in Arabidopsis thaliana and may also help to develop an improved plant variety using molecular breeding and genetic engineering techniques that are rapidly stress-responsive and tolerant. PMID- 23645343 TI - Growing up wired: social networking sites and adolescent psychosocial development. AB - Since the advent of social networking site (SNS) technologies, adolescents' use of these technologies has expanded and is now a primary way of communicating with and acquiring information about others in their social network. Overall, adolescents and young adults' stated motivations for using SNSs are quite similar to more traditional forms of communication-to stay in touch with friends, make plans, get to know people better, and present oneself to others. We begin with a summary of theories that describe the role of SNSs in adolescents' interpersonal relationships, as well as common methodologies used in this field of research thus far. Then, with the social changes that occur throughout adolescence as a backdrop, we address the ways in which SNSs intersect with key tasks of adolescent psychosocial development, specifically peer affiliation and friendship quality, as well as identity development. Evidence suggests that SNSs differentially relate to adolescents' social connectivity and identity development, with sociability, self-esteem, and nature of SNS feedback as important potential moderators. We synthesize current findings, highlight unanswered questions, and recommend both methodological and theoretical directions for future research. PMID- 23645344 TI - Segmentation, feature extraction, and multiclass brain tumor classification. AB - Multiclass brain tumor classification is performed by using a diversified dataset of 428 post-contrast T1-weighted MR images from 55 patients. These images are of primary brain tumors namely astrocytoma (AS), glioblastoma multiforme (GBM), childhood tumor-medulloblastoma (MED), meningioma (MEN), secondary tumor metastatic (MET), and normal regions (NR). Eight hundred fifty-six regions of interest (SROIs) are extracted by a content-based active contour model. Two hundred eighteen intensity and texture features are extracted from these SROIs. In this study, principal component analysis (PCA) is used for reduction of dimensionality of the feature space. These six classes are then classified by artificial neural network (ANN). Hence, this approach is named as PCA-ANN approach. Three sets of experiments have been performed. In the first experiment, classification accuracy by ANN approach is performed. In the second experiment, PCA-ANN approach with random sub-sampling has been used in which the SROIs from the same patient may get repeated during testing. It is observed that the classification accuracy has increased from 77 to 91 %. PCA-ANN has delivered high accuracy for each class: AS-90.74 %, GBM-88.46 %, MED-85 %, MEN-90.70 %, MET 96.67 %, and NR-93.78 %. In the third experiment, to remove bias and to test the robustness of the proposed system, data is partitioned in a manner such that the SROIs from the same patient are not common for training and testing sets. In this case also, the proposed system has performed well by delivering an overall accuracy of 85.23 %. The individual class accuracy for each class is: AS-86.15 %, GBM-65.1 %, MED-63.36 %, MEN-91.5 %, MET-65.21 %, and NR-93.3 %. A computer-aided diagnostic system comprising of developed methods for segmentation, feature extraction, and classification of brain tumors can be beneficial to radiologists for precise localization, diagnosis, and interpretation of brain tumors on MR images. PMID- 23645345 TI - Underwater locomotion strategy by a benthic pennate diatom Navicula sp. AB - The mechanism of diatom locomotion has been widely researched but still remains a hypothesis. There are several questionable points on the prevailing model proposed by Edgar, and some of the observed phenomena cannot be completely explained by this model. In this paper, we undertook detailed investigations of cell structures, locomotion, secreted mucilage, and bending deformation for a benthic pennate diatom Navicula species. According to these broad evidences, an updated locomotion model is proposed. For Navicula sp., locomotion is realized via two or more pseudopods or stalks protruded out of the frustules. The adhesion can be produced due to the pull-off of one pseudopod or stalk from the substratum through extracellular polymeric substances. And the positive pressure is generated to balance the adhesion because of the push-down of another pseudopod or stalk onto the substratum. Because of the positive pressure, friction is generated, acting as a driving force of locomotion, and the other pseudopod or stalk can detach from the substratum, resulting in the locomotion. Furthermore, this model is validated by the force evaluation and can better explain observed phenomena. This updated model would provide a novel aspect on underwater locomotion strategy, hence can be useful in terms of artificial underwater locomotion devices. PMID- 23645346 TI - GUS activity for miR165a/166b, REV, and WUS/CLV3 in in vitro direct Arabidopsis thaliana shoot regeneration. AB - In Arabidopsis thaliana, the process of shoot regeneration in vitro requires the presence of specific miRNAs. We describe here the beta-glucuronidase (GUS) expression domains for miR165a/166b, REV, and WUS/CLV3 during direct shoot regeneration. Increased GUS activity of miR166b and REV were first detected within the shoot apical meristem of explants, while no pmiR165a::GUS activity appeared there. The zone of pWUS::GUS activity covered the inner sides of developing protuberances, while that of pCLV3::GUS was more restricted. Once the primary shoot had emerged from the protuberance, pREV::GUS activity was turned on throughout the protuberance. pmiR165a::GUS activity was detected in a small number of protuberance surface cells, while pWUS::GUS activity was restricted to within a few cells beneath the protuberance surface. After the differentiation of leaf-like structures, GUS activity for miR165a and miR166b appeared largely on their abaxial surface, while pWUS::GUS activity was concentrated at the apex of the primary shoot, and no pCLV3::GUS activity was detectable. Following the formation of secondary shoots, pmiR165a::GUS activity was detected on their abaxial surface. GUS activity for miR166b, REV, and WUS/CLV3 were concentrated in the stem apical meristem. The observations suggested that each member of this set of genes might play a distinct role in both primary and secondary shoot regeneration. PMID- 23645347 TI - Efficacy and mechanism of action of Deguelin in suppressing metastasis of 4T1 cells. AB - Cancer related deaths in breast cancer patients are due to metastasis of the disease. Murine 4T1 cells (Murine mammary cancer cell line developed from 6 thioguanine resistant tumor) provide an excellent research tool for metastasis related studies because these cells are highly aggressive and readily metastasize to the lungs. In this study we determined the effect of Deguelin on in vivo/vitro growth and metastasis of 4T1 cells. Deguelin inhibited the in vitro growth of 4T1 cells in a time and dose dependent manner accompanied with reduced nuclear PCNA immunostaining. In cells treated with Deguelin, reduced expression of nuclear c Met, and its downstream targets such p-ERK and p-AKT was observed. Deguelin reduced the cell migration in 4T1 cells as determined by scratch wound assay. Combined treatment with Deguelin + ERK or PI3K/AKT inhibitor had no additional effect on cell migration. These results indicated that the action of Deguelin on cell migration may be mediated by AKT and ERK mediated signaling pathways. In vivo, Deguelin treatment significantly inhibited growth of 4T1 cells. Deguelin also reduced the occurrence of metastatic lung lesions by 33 % when cells were injected intravenously into Balb/c female mice. There was no difference in the body weight, nor was there a difference in liver and spleen weights between vehicle treated-control and Deguelin-treated animals, which indicated that Deguelin was nontoxic at the dose used in the present study. These results provide rationale for developing Deguelin as a chemotherapeutic agent for triple negative breast cancer patients. PMID- 23645348 TI - Tumefactive demyelination in a patient with human immunodeficiency virus. PMID- 23645349 TI - How you screen is as important as whether you screen: a qualitative analysis of violence screening practices in reproductive health clinics. AB - Adolescent and young adult women are disproportionately burdened by violence at the hands of dating and intimate partners. Evidence supports routine screening in clinical settings for detection and intervention. Although screening for intimate partner violence in reproductive health care settings is widely endorsed, little is known about screening practices. We conducted qualitative in-depth interviews with healthcare providers (n = 14) in several urban reproductive health clinics in Baltimore City, Maryland to understand screening practices, including related barriers and motivations. Interviews were transcribed verbatim and analyzed using inductive content analysis. Findings demonstrated substantial variation in screening practices as well as related referral and follow-up, despite the existence of a screening tool. Factors that appeared to undermine consistent and successful screening implementation included lack of a common goal for screening, lack of clarity in staff roles, a gap in on-site support services, as well as lack of time and confidence. Findings affirm the value of applying a systems model to intimate partner violence (IPV) screening programs. This research advances the understanding of the implementation challenges for violence-related screening for high-risk populations such as adolescents and young adults in reproductive health care settings and is particularly relevant given the recent endorsement by the DHHS to cover IPV screening under the Affordable Care Act. PMID- 23645350 TI - Expression of caspase 14 and filaggrin in oral squamous carcinoma. AB - Caspase 14 is one of the latter discovered members of the caspase enzyme family and, although sharing sequence homologies with the other caspases, it is not involved in apoptosis. Together with its co-factor filaggrin, it plays an important role in skin barrier formation. It is already known that caspase 14 proteins are reduced during neoplastic dedifferentiation in cervical intraepithelial neoplasms and in invasive cervical carcinomas. Oral squamous carcinoma tissues have not been systematically evaluated for caspase 14 expression yet. Formalin-fixed and paraffin-embedded samples from oral squamous carcinomas (n = 36 tumours from 34 patients), metastases (n = 15) and controls (leukoplakia, n = 10) were analysed by immunohistochemistry. In carcinomas, human papilloma virus (HPV) infection was tested by PCR. Here we demonstrate that, in oral epithelia, caspase 14 is expressed mainly by cells of the intermediate and superficial cell layers while filaggrin is expressed only in keratinising foci in leukoplakia. Caspase 14 and filaggrin are co-localised. In invasive oral carcinomas, reduced expression of caspase 14 was detectable in 47 % of tumours but was not associated with keratinisation, tumour differentiation or HPV infection. Filaggrin was detectable in a subfraction of tumours (56 %) and was restricted to keratinising areas of the carcinomas. In summary, in contrast to cervical carcinomas, partial loss of caspase 14 is not associated with dedifferentiation in neoplastic lesions of the oral mucosa or HPV infection. PMID- 23645352 TI - Transconjunctival lower blepharoplasty: a 2-sided assessment of results and subjects' satisfaction. AB - PURPOSE: To assess the results and satisfaction after transconjunctival lower blepharoplasty, evaluate the effect of associated aesthetic procedures on the satisfaction, and compare surgeon versus subjects' perspective on the results. METHODS: In a retrospective cross-sectional study, a chart review was performed on transconjunctival lower blepharoplasty procedures performed by 1 eye plastic surgeon from April 2003 to April 2009. Subjects with less than 6 months follow-up time or reoperation were excluded. Demographic data, associated surgical procedures, intra and postoperative complications, subjects and surgeon's perspectives on postoperative results, photographs (before and after the operation), and satisfaction score (Visual analogue scale score) at last follow up time were recorded. RESULTS: There were 164 subjects (133 women, 81.1%) with mean age of 50.7 years (standard deviation=11.6, range: 23-80). Mean follow-up time was 22.8 months (standard deviation=11.5, range=6-60 months). Complications, observed by the surgeon and subjects, were undercorrected fat excision (4.9% vs. 3.7%), eyelid retraction (1.2% vs. 1.2%), and tear trough deformity (9.7% vs. 0.6%). Subjects reported less complication rate (5.4%) than surgeon (15.8%). Mean visual analogue scale score was 92.8 (standard deviation=0.36), which was significantly higher in subjects who had simultaneous upper blepharoplasty and lower in subjects with postoperative eyelid retraction. CONCLUSIONS: Transconjunctival lower blepharoplasty is associated with a high satisfaction. Subjects reported less complication rate than surgeon especially for tear trough deformity. Postoperative eyelid retraction significantly decreased and simultaneous upper blepharoplasty procedure significantly increased the satisfaction. PMID- 23645351 TI - Expression of EGFR, VEGF, and NOTCH1 suggest differences in tumor angiogenesis in HPV-positive and HPV-negative head and neck squamous cell carcinoma. AB - There is current interest in anti-angiogenesis therapies for head and neck squamous cell carcinomas (HNSCC), although the utility of these therapies in human papillomavirus (HPV) positive and HPV-negative HNSCC is unclear. Therefore, we explored heterogeneity in expression of a distal factor in angiogenesis (EGFR, the epidermal growth factor receptor), a proximal factor in angiogenesis (VEGF, the vascular endothelial growth factor) and a putative factor in angiogenesis (NOTCH1) in a HNSCC case series using immunohistochemistry in N = 67 cases (27 HPV-positive, 40 HPV-negative, by in situ hybridization). Box plots and the Wilcoxon rank sum or Kruskal-Wallis tests were used to compare staining scores (intensity * percent of cells staining) by HPV status and lifestyle factors. Associations between EGFR, VEGF, and NOTCH1 were assessed using box plots and Spearman correlation (rho) in all cases, and stratified by HPV status. HPV negative HNSCC over-expressed EGFR [median (range): 30 (0-300)] relative to HPV positive HNSCC [7.5 (0-200)] (P = 0.006). VEGF and NOTCH1 were unrelated to HPV status (P > 0.05). EGFR was associated with VEGF in HPV-negative (rho = 0.40, P = 0.01) but not HPV-positive HNSCC (rho = 0.25, P = 0.20). NOTCH1 and VEGF were associated in HPV-negative (rho = 0.40, P = 0.01) but not HPV-positive tumors (rho = -0.12, P = 0.57). NOTCH1 was not associated with EGFR (P > 0.05). Our results are suggestive of heterogeneity in HNSCC angiogenesis. Future studies should explore angiogenesis mechanisms in HPV-positive and HPV-negative HNSCC. PMID- 23645353 TI - Orbital invasion by ACTH-secreting pituitary adenomas. AB - Orbital invasion by pituitary tumors is rare. To the best of the authors' knowledge, adrenocorticotrophin (ACTH)-secreting pituitary tumors with orbital invasion have not been described in MEDLINE indexed literature. The authors report 2 cases of ACTH-secreting tumors with orbital invasion. One patient had a history of endoscopic transsphenoidal subtotal resection of an ACTH-secreting tumor and presented with recurrence in the orbit. The second patient had a long history of visual loss considered to be secondary to glaucoma. Neuroimaging revealed a destructive mass involving the sella turcica with extension in the right orbit. Debulking of the mass was performed via a transsphenoidal approach, and histopathology revealed an ACTH-secreting adenoma. ACTH-secreting adenoma should be considered in the differential of tumors involving the sella turcica with orbital invasion. PMID- 23645354 TI - Orbital metastasis as the initial presentation in bilateral lobular invasive carcinoma of the breast. PMID- 23645355 TI - Radiographic patterns of orbital involvement in IgG4-related disease. AB - PURPOSE: Immunoglobin G4 (IgG4)-related disease is a systemic condition characterized by lymphoplasmacytic infiltrates that can involve the orbit. The purpose of this study was to identify the various patterns of orbital IgG4 related disease on imaging. METHODS: Retrospective review of radiologic examinations including CT, MRI, and positron emission tomography was performed in patients with proven cases of IgG4-related disease. RESULTS: A total of 9 patients with orbital IgG4-related disease were identified, including 9 with CT, 4 with MRI, and 4 with 18-fluorodeoxyglucose positron emission tomography. Patterns of involvement included lacrimal gland enlargement, lacrimal sac involvement, extraocular muscle thickening, preseptal involvement, orbital fat involvement, and cranial nerve involvement, many of which occurred simultaneously. Associated demineralization of the orbital wall was evident on CT in 2 cases. On T2-weighted MRI, the lesions appeared as hypointense in 2 cases, heterogeneously hypointense to isointense in 1 case, and hyperintense in 1 case. Diffuse enhancement was present in all 3 cases in which postcontrast T1-weighted sequences were available. The lesions were hypermetabolic on positron emission tomography in 3 of 4 cases. There was definite extraorbital involvement by IgG4 related disease in 3 of the 9 patients and suspected involvement in another 3 of the 9 patients. CONCLUSIONS: IgG4-related disease displays a wide variety of imaging manifestations in the orbit. Extraorbital disease is often present and can help suggest the diagnosis. PMID- 23645356 TI - Repair of eyelid retraction due to a trabeculectomy bleb: case series and review of the literature. AB - Superior limbal trabeculectomy remains a common surgical treatment for glaucoma. Positional effects on the overlying upper eyelid-both ptosis and retraction-have been associated with the procedure. More than 1 mechanism may explain retraction; however, the eyelid may elevate mechanically due to the underlying raised superior bulbar conjunctiva. PMID- 23645357 TI - Prophylactic postoperative antibiotics for enucleation and evisceration. AB - PURPOSE: To investigate the necessity and usefulness of prophylactic postoperative antibiotics in patients undergoing enucleation or ocular evisceration. METHODS: A retrospective, multicenter, comparative case series was designed. After obtaining Institutional Review Board authorization, a medical records' review was conducted. Demographics, indication for surgery, surgical technique, postoperative antibiotic dosing, and postoperative course were evaluated. Records were grouped according to antibiotic protocols, and presence or absence of postoperative wound infection (orbital cellulitis) was recorded. Rates of postoperative infection were analyzed statistically. RESULTS: Between 1996 and 2011, 666 evisceration or enucleation surgeries were conducted at 4 institutions. Six hundred forty-eight records were available for analysis, of which 4 were excluded due to insufficient follow-up data. All the remaining 644 patients received a single, perioperative, intravenous dose of antibiotics. Five hundred seventy-eight patients (90%) received an orbital implant, while 66 (10%) did not. Three hundred eighty-one patients (59%) received postoperative antibiotics, and 263 patients (41%) did not. Two cases were identified with signs suggestive of infection, but no culture-positive infections were found, and no patient was admitted to the hospital for management. Of the 2 suspicious cases, 1 was found in the group that received postoperative antibiotics (group 1) and 1 in the group that did not receive postoperative antibiotics (group 2). No statistically significant difference in postoperative infection rate was noted between the 2 groups (p=0.52). While patients with infectious indications for surgery were more likely to receive postoperative antibiotics (p<0.001), there was no statistically significant difference in rates of infection among patients with infectious indications for surgery based on receiving or not receiving postoperative antibiotics (p=0.79), and no patients with infectious indications for surgery not receiving postoperative antibiotics developed a postoperative infection. CONCLUSIONS: This study demonstrates the clinical safety of withholding postoperative prophylactic antibiotics in orbital surgery even when implanting alloplastic material in a sterile field. Furthermore, Centers for Disease Control and Prevention guidelines mandate cessation of postoperative antibiotics within 24 hours of surgery. Surgeons are cautioned not to generalize these results to nonsterile surgery such as sinonasal or nasolacrimal surgery. PMID- 23645358 TI - Clonality analysis suggests that STK11 gene mutations are involved in progression of lobular endocervical glandular hyperplasia (LEGH) to minimal deviation adenocarcinoma (MDA). AB - Lobular endocervical glandular hyperplasia (LEGH) is a benign proliferative disease of cervical glands. Although histological resemblance of minimal deviation adenocarcinoma (MDA) to LEGH and frequent association of LEGH with MDA have been reported, it still remains unclear whether LEGH is a precancerous lesion of MDA. The present study was undertaken to examine the pathogenetic relationship between LEGH and MDA using a clonality analysis and mutational analyses of the STK11 gene, of which mutations have been reported in MDA. Of nine cases of LEGH only, four were polyclonal and five were monoclonal in composition. Of six LEGH lesions associated with MDA or adenocarcinoma, two were polyclonal and four were monoclonal. In cases of MDA or adenocarcinoma coexisting with LEGH, the patterns of X chromosome inactivation in malignant lesions were identical to those in coexisting LEGH lesions. A mutation of STK11 was only identified in one MDA, but not in LEGH. These results indicate that a subset of LEGH may be a precursor to malignant tumors including MDA and that a mutation of STK11 may be involved in progression of LEGH to MDA. PMID- 23645359 TI - How persons with a neuromuscular disease perceive employment participation: a qualitative study. AB - INTRODUCTION: A qualitative study was carried out to understand how people with a slow progressive adult type neuromuscular disease (NMD) perceive employment participation. METHODS: 16 paid employed persons with NMD were interviewed in open, in-depth interviews. Data were analyzed using the constant comparison method. RESULTS: Four themes were identified in the analyses: (1) Experiences regarding the meaning of work; (2) Solving problems oneself; (3) Reaching a turning point; and (4) Taking into account environmental aspects. Persons with NMD highlighted benefits of staying at work as well as the tension they felt how to shape decisions to handle progressive physical hindrances in job retention. This study shows how participants at work with NMD were challenged to keep up appearances at work and at home, the tension felt around when and if to disclose, the effect of their condition on colleagues and work reorganisation challenges. Participants experienced that disclosure did not always make things better. With increasing disability participants' focus shifted from the importance of assistive products towards considerate colleague, in particular superior's willingness in supporting job retention. CONCLUSIONS: Implications for health professionals might include awareness of the significant impact of changes in physical condition on employment. Timely communication and if appropriate referral to a health or occupational professional may empower employees with NMD to handle employment issues at a for themselves appropriate way. Assistive products and a supportive superior might enhance employment participation. PMID- 23645360 TI - Differential regulation of Arabidopsis plastid gene expression and RNA editing in non-photosynthetic tissues. AB - RNA editing is one of the post-transcriptional processes that commonly occur in plant plastids and mitochondria. In Arabidopsis, 34 C-to-U RNA editing events, affecting transcripts of 18 plastid genes, have been identified. Here, we examined the editing and expression of these transcripts in different organs, and in green and non-green seedlings (etiolated, cia5-2, ispF and ispG albino mutants, lincomycin-, and norflurazon-treated). The editing efficiency of Arabidopsis plastid transcripts varies from site to site, and may be specifically regulated in different tissues. Steady state levels of plastid transcripts are low or undetectable in etiolated seedlings, but most editing sites are edited with efficiencies similar to those observed in green seedlings. By contrast, the editing of some sites is completely lost or significantly reduced in other non green tissues; for instance, the editing of ndhB-149, ndhB-1255, and ndhD-2 is completely lost in roots and in lincomycin-treated seedlings. The editing of ndhD 2 is also completely lost in albino mutants and norflurazon-treated seedlings. However, matK-640 is completely edited, and accD-794, atpF-92, psbE-214, psbF-77, psbZ-50, and rps14-50 are completely or highly edited in both green and non-green tissues. In addition, the expression of nucleus-encoded RNA polymerase dependent transcripts is specifically induced by lincomycin, and the splicing of ndhB transcripts is significantly reduced in the albino mutants and inhibitor-treated seedlings. Our results indicate that plastid gene expression, and the splicing and editing of plastid transcripts are specifically and differentially regulated in various types of non-green tissues. PMID- 23645369 TI - Towards ultrasound probe positioning optimization during prostate needle biopsy using pressure feedback. AB - PURPOSE: Accurate Transrectal Ultrasound (TRUS)-guided prostate needle biopsy requires registering preoperative 3D TRUS or MR image, in which tumors and other suspicious areas are visible, to intraoperative 2D TRUS images. Such image registration is time-consuming while its real-time implementation is yet to be developed. To bypass this registration step, robotic needle biopsy systems can be used to place the US probe at the same position relative to the prostate during the 3D and 2D image acquisition to ensure similar prostate deformation. To have such similar deformation, only visual feedback is not sufficient as such feedback can be used to only guarantee that the whole prostate is within the field of view irrespective of the probe's orientation. As such, contact pressure feedback can be utilized to ensure consistent minimum contact between the probe and prostate. METHOD: A robotic system is proposed where a TRUS probe with pressure sensor array is used. The contact pressure can be measured during imaging and used to provide feedback in conjunction with an optimization algorithm for consistent probe positioning. The robotic system is driven by the feedback to position the probe such that pressure pattern of the sensors during 2D image acquisition is similar to the pressure pattern during 3D image acquisition. The proposed method takes into account the patient's body movement expected during image acquisition. In this study, an in silico phantom is used where the simulated contact pressure distribution required in the optimization algorithm is obtained using a prostate finite element model. RESULT: Starting from an arbitrary position where the probe contacts the phantom, this position was varied systematically until a position corresponding to maximum pressure pattern similarity between contact pressure patterns corresponding to the 2D and 3D imaging was achieved successfully. CONCLUSION: Results obtained from the in silico phantom study indicate that the proposed technique is capable of ensuring having only minimal relative prostate deformation between preoperative image acquisition and intraoperative imaging used for guiding needle biopsy, paving the way for faster and more accurate registration. PMID- 23645371 TI - Protein deposition and its effect on bacterial adhesion to contact lenses. AB - PURPOSE: Bacterial adhesion to contact lenses is believed to be the initial step for the development of several adverse reactions that occur during lens wear such as microbial keratitis. This study examined the effect of combinations of proteins on the adhesion of bacteria to contact lenses. METHODS: Unworn balafilcon A and senofilcon A lenses were soaked in commercially available pure protein mixtures to achieve the same amount of various proteins as found ex vivo. These lenses were then exposed to Pseudomonas aeruginosa and Staphylococcus aureus. Following incubation, the numbers of P. aeruginosa or S. aureus that adhered to the lenses were measured. The possible effect of proteins on bacterial growth was investigated by incubating bacteria in medium containing protein. RESULTS: Although there was a significant (p < 0.003) increase in the total or viable counts of one strain of S. aureus (031) on balafilcon A lenses soaked in the lysozyme/lactoferrin combination, the protein adhered to lenses did not alter the adhesion of any other strains of P. aeruginosa or S. aureus (p > 0.05). Growth of S. aureus 031 (p < 0.0001) but not of P. aeruginosa 6294 was stimulated by addition of lysozyme/lactoferrin combination (2.8/0.5 mg/mL). Addition of lipocalin did not affect the growth of any strains tested (p > 0.05). CONCLUSIONS: Adsorption of amounts of lysozyme and lactoferrin or lipocalin equivalent to those extracted from worn contact lenses did not affect the adhesion of most strains of S. aureus or P. aeruginosa to lens surfaces. PMID- 23645370 TI - Amygdala functional connectivity is reduced after the cold pressor task. AB - The amygdala forms a crucial link between central pain and stress systems. Previous research indicates that psychological stress affects amygdala activity, but it is less clear how painful stressors influence subsequent amygdala functional connectivity. In the present study, we used pulsed arterial spin labeling (PASL) to investigate differences in healthy male adults' resting-state amygdala functional connectivity following a cold pressor versus a control task, with the stressor and control conditions being conducted on different days. During the period of peak cortisol response to acute stress (approximately 15-30 min after stressor onset), participants were asked to rest for 6 min with their eyes closed during a PASL scanning sequence. The cold pressor task led to reduced resting-state functional connectivity between the amygdalae and orbitofrontal cortex (OFC) and ventromedial prefrontal cortex, and this occurred irrespective of cortisol release. The stressor also induced greater inverse connectivity between the left amygdala and dorsal anterior cingulate cortex (ACC), a brain region implicated in the down-regulation of amygdala responsivity. Furthermore, the degree of poststressor left amygdala decoupling with the lateral OFC varied according to self-reported pain intensity during the cold pressor task. These findings indicate that the cold pressor task alters amygdala interactions with prefrontal and ACC regions 15-30 min after the stressor, and that these altered functional connectivity patterns are related to pain perception rather than cortisol feedback. PMID- 23645372 TI - High myopia-partial reduction ortho-k: a 2-year randomized study. AB - PURPOSE: To investigate if the combination of partial reduction (PR) orthokeratology (ortho-k) and spectacles for residual refractive errors in the daytime was effective to slow myopic progression in high myopic children. METHODS: High myopic children (aged 8 to 11 years) with spherical equivalent refraction at least -5.75 diopters (D) and myopia -5.00 D or more myopic were recruited and randomly assigned into PR ortho-k and control groups. Subjects in the PR ortho-k group were fitted with custom made four-zone ortho-k lenses with target reduction of 4.00 D for both eyes, and the residual refractive errors were corrected with single-vision spectacles for clear vision in the daytime. Control subjects were fully corrected with single-vision spectacles. Axial length of each eye of all subjects was measured with the IOLMaster at 6-month intervals by a masked examiner. This study was registered at www.clinicaltrial.gov with the identifier NCT00977236. RESULTS: Fifty-two subjects were recruited and randomized to the PR ortho-k and control groups. Twelve PR ortho-k and 16 control subjects completed the study. Compared with the residual refractive errors at the 1-month visit (after stabilization of ortho-k treatment), the median increase in noncycloplegic residual myopia at the 24-month visit was 0.13 D. In the control group, the median increase in myopia was 1.00 D at the end of the study. The mean +/- SD increases in axial length were 0.19 +/- 0.21 mm in the PR ortho-k group and 0.51 +/- 0.32 mm in the control group (95% confidence interval, -0.55 to 0.12; unpaired t test, p = 0.005). CONCLUSIONS: This single-masked randomized study showed that PR ortho-k effectively slowed myopic progression in high myopes. Axial length elongation was 63% slower in PR ortho-k-treated children compared with children wearing spectacles. PMID- 23645373 TI - Clinical management of trichotillomania with bimatoprost. AB - PURPOSE: This case report presents the use of bimatoprost 0.03% to help regrow eyelashes on a patient suffering from trichotillomania. Trichotillomania is characterized by repetitive compulsive hair pulling that leads to noticeable hair loss. Trichotillomania sufferers are affected by this condition in many ways including shame, embarrassment, guilt, and lower self-esteem. Although a formal therapy regimen does not exist, current treatment approaches include behavioral therapy and pharmacotherapy. In cases where a patient pulls the eyelashes, topical bimatoprost (Latisse) may be used to treat madarosis of the eyelashes by increasing growth, including length, thickness, and darkness. CASE REPORT: A 55 year-old white female presented to the clinic with an interest in using bimatoprost ophthalmic solution (Latisse; Allergan). The patient reported a history of eyelash pulling since age 12 and began treatment to control the impulses with amitriptyline 1 week before her appointment. Follow-up appointments showed increased lash growth bilaterally over a 4-month period as a result of Latisse usage. CONCLUSIONS: Those who pull their eyelashes may benefit from using bimatoprost 0.03%. The management of trichotillomania involving the eyelashes presents an opportunity for eye care professionals to collaborate with mental health providers for the betterment of shared patients. By expediting the patient's lash growth, Latisse can improve patients' self-image, reinforce compliance, and play an important adjunctive role in any therapy regimen. PMID- 23645374 TI - Impact of silicone hydrogel lenses and solutions on corneal epithelial permeability. AB - PURPOSE: The primary purpose of this pilot study was to compare epithelial barrier function (EBF) and staining in a small group of participants using a silicone hydrogel (SH) lens worn on a daily basis with two different care regimens. Secondarily, the aim was to see if there was any correlation between corneal staining and EBF. METHODS: The corneal EBF of 10 non-lens wearers (control) and 15 age-matched asymptomatic SH contact lens wearers (test) were assessed using fluorophotometry. Biomicroscopy was performed to assess corneal staining after the EBF was measured. The lens wearers wore PureVision (FDA group V) SH lenses for two consecutive 1-month periods while using either Alcon Opti Free Express or Renu Fresh using a randomized, investigator-masked, crossover design. Control subjects were assessed on one occasion, and lens wearers were examined before fitting with lenses and after 7, 14, and 28 days of lens wear, with each combination. RESULTS: Compared with the control group, both study groups had an increase in epithelial permeability at baseline (p <= 0.04). There were no changes in EBF during the treatment period for either solution (p = 0.87). A significant difference in EBF was found between the test groups during the treatment period (p = 0.02), with greater permeability in the Renu Fresh disinfected lenses. There was poor correlation between corneal staining and EBF (r = 0.35, p > 0.05) because of large individual variations. CONCLUSIONS: Daily wear of highly oxygen-permeable SH lenses increases corneal epithelial permeability to fluorescein probably because of increased mechanical effects. In addition, certain lens-solution interactions can add to this effect, as seen in this study. Despite having a low amount of central corneal staining in the Renu Fresh group, staining and EBF did not prove to be well correlated. The presence of central corneal staining is a confounding factor when measuring EBF. PMID- 23645375 TI - Spatial structure of contextual modulation. AB - Contextual effects are ubiquitous in vision and provide a means for detectors with localized receptive fields to encode global properties of a stimulus. Although the nature of the neural connections is complex, the majority of evidence supports the Gestalt idea of collinearity; interactions are greatest when the target and surround orientations are spatially aligned to form a contour. Here we create a novel stimulus that simultaneously probes all areas around a detector to determine which spatial positions influence perception in human observers. We find that the surrounding spatial areas that contribute most to contextual effects for our perception of orientation and motion are not confined to a specific location. Rather our results reveal that human perception displays some interobserver variability in the weighting of detector interactions that is largely independent of collinear structure. We propose that these more extensive surround stimuli reveal how complex visual structure may modulate performance in a manner that is not easily predictable using more conventional stimuli. PMID- 23645376 TI - Light-harvesting in photosystem I. AB - This review focuses on the light-harvesting properties of photosystem I (PSI) and its LHCI outer antenna. LHCI consists of different chlorophyll a/b binding proteins called Lhca's, surrounding the core of PSI. In total, the PSI-LHCI complex of higher plants contains 173 chlorophyll molecules, most of which are there to harvest sunlight energy and to transfer the created excitation energy to the reaction center (RC) where it is used for charge separation. The efficiency of the complex is based on the capacity to deliver this energy to the RC as fast as possible, to minimize energy losses. The performance of PSI in this respect is remarkable: on average it takes around 50 ps for the excitation to reach the RC in plants, without being quenched in the meantime. This means that the internal quantum efficiency is close to 100% which makes PSI the most efficient energy converter in nature. In this review, we describe the light-harvesting properties of the complex in relation to protein and pigment organization/composition, and we discuss the important parameters that assure its very high quantum efficiency. Excitation energy transfer and trapping in the core and/or Lhcas, as well as in the supercomplexes PSI-LHCI and PSI-LHCI-LHCII are described in detail with the aim of giving an overview of the functional behavior of these complexes. PMID- 23645380 TI - Refractory bleeding from a malignant duodenal ulcer treated with placement of a fully-covered gastroduodenal stent. PMID- 23645379 TI - On pseudo-onion bulb intraneural proliferations of the non-major nerves of the oral mucosa. AB - Perineurial cells (PCs) participate in reactive and neoplastic processes, of the latter pure perineurial being intraneural (IP) and soft tissue perineuriomas with oral examples being reported in both. In our review of over 500 peripheral nerve sheath tumors including granular cell tumor, we identified a single ostensible case of IP occurring on the tongue of a 45-year-old African-American male that was characterized by classic perineurial pseudo-onion bulbs (PsOb), proliferating PCs among these PsOb, sclerosis apparently due to long term duration and a plexiform pattern. We have also encountered 37 examples of apparently reactive, hyperplastic or traumatic, PsOb intraneural pseudoperineuriomatous proliferation (IPP) simulating microscopically some of the properties of IP. The majority of the lesions occurred in women and close to 80 % affected the tongue. Three microscopic patterns were appreciated. Type I lesions were those where IPP was seen only focally, type II where it was seen in roughly half of the lesion, and type III where the majority of the lesional tissue or the lesion itself was characterized by IPP. Immunohistochemically, IPP featured PsOb with generally a single layer of PCs decorated by epithelial membrane antigen, glut-1 or claudin 1, and decreased numbers of S-100 positive Schwann cells. The number of axons was not apparently altered. A prominent collagenous intraneural component was occasionally evident among PsOb and the affected nerve featured discontinuous or absent perineurial envelop. While type I and II IPP can be distinguished from IP, the distinction from type III lesions can be problematic. However, the discontinuity of the perineurium of the affected nerve, the spacing and collagenization among PsOb, the limited perineurial cell layer defining the pseudo-onion bulbs, the absence of proliferating PCs between PsObs and the decreasing number of Schwann cells may be of help in the distinction from IP. PMID- 23645381 TI - Infliximab-related hepatitis: a case study and literature review. PMID- 23645382 TI - Mixed-effects beta regression for modeling continuous bounded outcome scores using NONMEM when data are not on the boundaries. AB - Beta regression models have been recommended for continuous bounded outcome scores that are often collected in clinical studies. Implementing beta regression in NONMEM presents difficulties since it does not provide gamma functions required by the beta distribution density function. The objective of the study was to implement mixed-effects beta regression models in NONMEM using Nemes' approximation to the gamma function and to evaluate the performance of the NONMEM implementation of mixed-effects beta regression in comparison to the commonly used SAS approach. Monte Carlo simulations were conducted to simulate continuous outcomes within an interval of (0, 70) based on a beta regression model in the context of Alzheimer's disease. Six samples per subject over a 3 years period were simulated at 0, 0.5, 1, 1.5, 2, and 3 years. One thousand trials were simulated and each trial had 250 subjects. The simulation-reestimation exercise indicated that the NONMEM implementation using Laplace and Nemes' approximations provided only slightly higher bias and relative RMSE (RRMSE) compared to the commonly used SAS approach with adaptive Gaussian quadrature and built-in gamma functions, i.e., the difference in bias and RRMSE for fixed-effect parameters, random effects on intercept, and the precision parameter were <1-3 %, while the difference in the random effects on the slope was <3-7 % under the studied simulation conditions. The mixed-effect beta regression model described the disease progression for the cognitive component of the Alzheimer's disease assessment scale from the Alzheimer's Disease Neuroimaging Initiative study. In conclusion, with Nemes' approximation of the gamma function, NONMEM provided comparable estimates to those from SAS for both fixed and random-effect parameters. In addition, the NONMEM run time for the mixed beta regression models appeared to be much shorter compared to SAS, i.e., 1-2 versus 20-40 s for the model and data used in the manuscript. PMID- 23645383 TI - Characterization of Clostridium thermocellum strains with disrupted fermentation end-product pathways. AB - Clostridium thermocellum is a thermophilic, cellulolytic anaerobe that is a candidate microorganism for industrial biofuels production. Strains with mutations in genes associated with production of L-lactate (Deltaldh) and/or acetate (Deltapta) were characterized to gain insight into the intracellular processes that convert cellobiose to ethanol and other fermentation end-products. Cellobiose-grown cultures of the Deltaldh strain had identical biomass accumulation, fermentation end-products, transcription profile, and intracellular metabolite concentrations compared to its parent strain (DSM1313 Deltahpt Deltaspo0A). The Deltapta-deficient strain grew slower and had 30 % lower final biomass concentration compared to the parent strain, yet produced 75 % more ethanol. A Deltaldh Deltapta double-mutant strain evolved for faster growth had a growth rate and ethanol yield comparable to the parent strain, whereas its biomass accumulation was comparable to Deltapta. Free amino acids were secreted by all examined strains, with both Deltapta strains secreting higher amounts of alanine, valine, isoleucine, proline, glutamine, and threonine. Valine concentration for Deltaldh Deltapta reached 5 mM by the end of growth, or 2.7 % of the substrate carbon utilized. These secreted amino acid concentrations correlate with increased intracellular pyruvate concentrations, up to sixfold in the Deltapta and 16-fold in the Deltaldh Deltapta strain. We hypothesize that the deletions in fermentation end-product pathways result in an intracellular redox imbalance, which the organism attempts to relieve, in part by recycling NADP+ through increased production of amino acids. PMID- 23645384 TI - Quorum-sensing inhibitory compounds from extremophilic microorganisms isolated from a hypersaline cyanobacterial mat. AB - In this study, extremely halophilic and moderately thermophilic microorganisms from a hypersaline microbial mat were screened for their ability to produce antibacterial, antidiatom, antialgal, and quorum-sensing (QS) inhibitory compounds. Five bacterial strains belonging to the genera Marinobacter and Halomonas and one archaeal strain belonging to the genus Haloterrigena were isolated from a microbial mat. The strains were able to grow at a maximum salinity of 22-25 % and a maximum temperature of 45-60 degrees C. Hexanes, dichloromethane, and butanol extracts from the strains inhibited the growth of at least one out of nine human pathogens. Only butanol extracts of supernatants of Halomonas sp. SK-1 inhibited growth of the microalga Dunaliella salina. Most extracts from isolates inhibited QS of the acyl homoserine lactone producer and reporter Chromobacterium violaceum CV017. Purification of QS inhibitory dichloromethane extracts of Marinobacter sp. SK-3 resulted in isolation of four related diketopiperazines (DKPs): cyclo(L-Pro-L-Phe), cyclo(L-Pro-L-Leu), cyclo(L Pro-L-isoLeu), and cyclo(L-Pro-D-Phe). QS inhibitory properties of these DKPs were tested using C. violaceum CV017 and Escherichia coli-based QS reporters (pSB401 and pSB1075) deficient in AHL production. Cyclo(L-Pro-L-Phe) and cyclo(L Pro-L-isoLeu) inhibited QS-dependent production of violacein by C. violaceum CV017. Cyclo(L-Pro-L-Phe), cyclo(L-Pro-L-Leu), and cyclo(L-Pro-L-isoLeu) reduced QS-dependent luminescence of the reporter E. coli pSB401 induced by 3-oxo-C6-HSL. Our study demonstrated the ability of halophilic and moderately thermophilic strains from a hypersaline microbial mat to produce biotechnologically relevant compounds that could be used as antifouling agents. PMID- 23645385 TI - MRI-guided percutaneous coaxial cutting needle biopsy of small pulmonary nodules: feasibility. AB - OBJECTIVES: To prospectively evaluate the feasibility, safety and accuracy of magnetic resonance imaging (MRI)-guided percutaneous coaxial cutting needle biopsy of small (<=2.0 cm in diameter) pulmonary nodules. METHODS: Ninety-six patients (56 men and 40 women) with 96 small lung nodules underwent MRI-guided percutaneous coaxial cutting needle biopsy. These lesions were divided into two groups according to maximum nodule diameters: 0.5-1.0 cm (n = 25) and 1.1-2.0 cm (n = 71). The diagnostic accuracy, sensitivity and specificity were calculated, and comparison of the two groups was performed using Fisher's exact test. RESULTS: All specimens obtained were sufficient for diagnosis. Histological examination of needle biopsy revealed 64 malignant, 30 benign and 2 indeterminate nodules. The final diagnoses from surgery or clinical follow-up were 67 malignant nodules and 29 benign nodules. The diagnostic performance of MRI-guided percutaneous coaxial cutting needle biopsy in diagnosing malignant tumours was as follows: accuracy, 97 %; sensitivity, 96 %; specificity, 100 %; positive predictive value, 100 %; and negative predictive value, 91 %. There was no significant difference between the two groups (P > 0.05, Fisher's exact test). No serious complications occurred. CONCLUSIONS: MRI-guided percutaneous coaxial cutting needle biopsy is a safe and accurate diagnostic technique in the evaluation of small lung nodules. KEY POINTS: * MRI-guided biopsy helps clinicians to assess patients with small lung nodules. * Differentiation of malignant and benign nodules is possible with 97 % accuracy. * MRI guidance enables accurate lung biopsy without ionising radiation. * No serious complications occurred in MRI-guided lung biopsy. PMID- 23645386 TI - Small molecules interacting with alpha-synuclein: antiaggregating and cytoprotective properties. AB - Curcumin, a dietary polyphenol, has shown a potential to act on the symptoms of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, as a consequence of its antioxidant, anti-inflammatory and anti-protein aggregation properties. Unfortunately, curcumin undergoes rapid degradation at physiological pH into ferulic acid, vanillin and dehydrozingerone, making it an unlikely drug candidate. Here, we evaluated the ability of some curcumin by-products: dehydrozingerone (1), its O-methyl derivative (2), zingerone (3), and their biphenyl analogues (4-6) to interact with alpha-synuclein (AS), using CD and fluorescence spectroscopy. In addition, the antioxidant properties and the cytoprotective effects in rat pheochromocytoma (PC12) cells prior to intoxication with H2O2, MPP+ and MnCl2 were examined while the Congo red assay was used to evaluate the ability of these compounds to prevent aggregation of AS. We found that the biphenyl zingerone analogue (6) interacts with high affinity with AS and also displays the best antioxidant properties while the biphenyl analogues of dehydrozingerone (4) and of O-methyl-dehydrozingerone (5) are able to partially inhibit the aggregation process of AS, suggesting the potential role of a hydroxylated biphenyl scaffold in the design of AS aggregation inhibitors. PMID- 23645387 TI - Role of protein and amino acids in promoting lean mass accretion with resistance exercise and attenuating lean mass loss during energy deficit in humans. AB - Amino acids are major nutrient regulators of muscle protein turnover. After protein ingestion, hyperaminoacidemia stimulates increased rates of skeletal muscle protein synthesis, suppresses muscle protein breakdown, and promotes net muscle protein accretion for several hours. These acute observations form the basis for strategized protein intake to promote lean mass accretion, or prevent lean mass loss over the long term. However, factors such as protein dose, protein source, and timing of intake are important in mediating the anabolic effects of amino acids on skeletal muscle and must be considered within the context of evaluating the reported efficacy of long-term studies investigating protein supplementation as part of a dietary strategy to promote lean mass accretion and/or prevent lean mass loss. Current research suggests that dietary protein supplementation can augment resistance exercise-mediated gains in skeletal muscle mass and strength and can preserve skeletal muscle mass during periods of diet induced energy restriction. Perhaps less appreciated, protein supplementation can augment resistance training-mediated gains in skeletal muscle mass even in individuals habitually consuming 'adequate' (i.e., >0.8 g kg-1 day-1) protein. Additionally, overfeeding energy with moderate to high-protein intake (15-25 % protein or 1.8-3.0 g kg-1 day-1) is associated with lean, but not fat mass accretion, when compared to overfeeding energy with low protein intake (5 % protein or ~0.68 g kg-1 day-1). Amino acids represent primary nutrient regulators of skeletal muscle anabolism, capable of enhancing lean mass accretion with resistance exercise and attenuating the loss of lean mass during periods of energy deficit, although factors such as protein dose, protein source, and timing of intake are likely important in mediating these effects. PMID- 23645388 TI - Spectroscopic and in silico evaluation of interaction of DNA with six anthraquinone derivatives. AB - Anthraquinones consist of several hundreds of derivatives that differ in the nature and positions of substituent groups which are known to have several biological activities including antitumor properties. Interaction of molecules with DNA persists to be an extremely vital parameter while endeavouring to formulate therapeutics. In this study, few anthraquinone derivatives such as 1,2 dihydroxyanthraquinone (alizarin), 1,4-dihydroxyanthraquinone (quinizarin), 1,8 dihydroxyanthraquinone (danthron), 1,2,4-trihydroxyanthraquinone (purpurin), 1,4 diaminoanthraquinone, and 1-methylaminoanthraquinone were analyzed for its possible interaction with calf-thymus DNA through spectroscopy and in silico analysis. Our UV spectroscopic results indicate that all selected anthraquinones interact with DNA probably by external binding. Molar extinction coefficient has been calculated for chosen six anthraquinones. FT-IR results suggest that significant shifts of peaks as well as disappearance of certain characteristic peaks were indicators of the plausible interaction going on due to dye-DNA adduct formation. Among the six dyes used, purpurin showed better results and indicates the relatively strong binding affinity with DNA. Our molecular modeling results also show that purpurin has comparatively higher DNA interaction with a score of 6.18 compared with the ethidium bromide of -5.02 and intercalate the DNA. PMID- 23645389 TI - Two-pass dual-energy CT imaging for simultaneous detection, characterization, and volume measurement of urinary stones with excretory-phase CT urography alone: a phantom study. AB - PURPOSE: To evaluate if two-pass dual-energy CT imaging--i.e., simultaneous three material and two-material decomposition analysis--can depict and characterize urinary stones in various concentrations of iodine solution in vitro. MATERIALS AND METHODS: Twelve urinary stones were scanned with a dual-source CT scanner. First, each stone (in a saline-filled tube) underwent single- and dual-energy mode CT scans in order to measure the volume of the stone. Each stone was then placed in various concentrations of contrast medium and scanned in dual-energy mode to calculate its volume via three-material decomposition analysis. Two-pass dual-energy CT imaging analysis software for the Matlab environment, which was developed specifically to process simultaneous three-material and two-material decomposition, was applied to characterize and calculate the volume of each stone. RESULTS: Although the virtual non-contrast images from three-material decomposition analysis clearly visualized all of the stones in contrast medium with up to 80 mgI/mL, the volumes of the uric acid stones were overestimated. Two pass dual-energy CT imaging was able to depict and characterize non-uric-acid stones in diluted contrast medium with up to 80 mgI/mL, whereas uric acid stones were correctly evaluated in diluted contrast medium with 40 mgI/mL or less. CONCLUSIONS: Two-pass dual-energy CT imaging is able to depict and characterize urinary stones in contrast medium. PMID- 23645390 TI - Sterically tuned Ag(I)- and Pd(II)-N-heterocyclic carbene complexes of imidazol-2 ylidenes: synthesis, crystal structures, and in vitro antibacterial and anticancer studies. AB - Unsymmetrically substituted sterically tuned Pd(II)-NHC complexes of the general formula [PdCl2(NHC)2] (NHC = 1-allyl-3-methylimidazolin-2-ylidene, 7; 1-allyl-3 butylimidazol-2-ylidene, 8; 1-benzyl-3-butyl imidazolin-2-ylidene, 9) were prepared through transmetallation from their corresponding Ag(I)-NHC complexes. The Pd complexes were structurally characterized by different spectroscopic and X ray diffraction methods. Complexes 7 and 9 adopted a trans-anti arrangement of the NHC ligands, whereas complex 8 adopted a cis-syn arrangement. Preliminary antibiogram studies using Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria showed that Ag(I)-NHC complexes demonstrate higher activity compared with Pd(I)-NHC complexes. Furthermore, Pd(II)-NHC complexes were evaluated for their anticancer potential using the human colorectal cancer cell line. A higher anticancer activity was observed for complexes 8 and 9, with 26.5 and 6.6 mM IC50 values, respectively. PMID- 23645391 TI - How activation, entanglement, and searching a semantic network contribute to event memory. AB - Free-association norms indicate that words are organized into semantic/associative neighborhoods within a larger network of words and links that bind the net together. We present evidence indicating that memory for a recent word event can depend on implicitly and simultaneously activating related words in its neighborhood. Processing a word during encoding primes its network representation as a function of the density of the links in its neighborhood. Such priming increases recall and recognition and can have long-lasting effects when the word is processed in working memory. Evidence for this phenomenon is reviewed in extralist-cuing, primed free-association, intralist-cuing, and single item recognition tasks. The findings also show that when a related word is presented in order to cue the recall of a studied word, the cue activates the target in an array of related words that distract and reduce the probability of the target's selection. The activation of the semantic network produces priming benefits during encoding, and search costs during retrieval. In extralist cuing, recall is a negative function of cue-to-distractor strength, and a positive function of neighborhood density, cue-to-target strength, and target-to-cue strength. We show how these four measures derived from the network can be combined and used to predict memory performance. These measures play different roles in different tasks, indicating that the contribution of the semantic network varies with the context provided by the task. Finally, we evaluate spreading-activation and quantum-like entanglement explanations for the priming effects produced by neighborhood density. PMID- 23645392 TI - Partial word knowledge in the absence of recall. AB - Attributes of words can be known even when the words are not currently retrievable. Although repeatedly demonstrated for semantic and contextual dimensions, the evidence is ambiguous for structural characteristics. The present research demonstrates significant above-chance first-letter knowledge across four ordinal levels of retrieval confidence for nonretrieved words--tip of the tongue (TOT), high familiar, low familiar, unfamiliar. Contrary to prior research, there was minimal evidence for syllable number knowledge, even at highest confidence levels. Initial letter recognition in the absence of retrieval resembles the recognition without identification in episodic memory (Cleary, Current Directions in Psychological Science 17: 353-357, 2008), and such implicit familiarity may contribute more generally to confidence assessments of word knowledge in both semantic and episodic memory domains. Furthermore, this outcome suggests that word feature priming in the form of partial phonological activation may occur to some extent for all words during a retrieval attempt, and even for ones that are judged to be unknown. PMID- 23645393 TI - Comparison of 12-w versus 14-w endovenous laser ablation in the treatment of great saphenous varicose veins: 5-year outcomes from a randomized controlled trial. AB - INTRODUCTION: Endovenous laser ablation (EVLA) has been demonstrated to be an effective treatment for lower limb varicose veins in the short and midterm results. This study reports the 5-year outcomes of EVLA technique at different power settings. METHODS: Patients with primary symptomatic, unilateral varicose veins secondary to saphenofemoral junction (SFJ) incompetence and great saphenous vein (GSV) reflux were recruited and randomized to either 12W (intermittent laser withdrawal) or 14W (continuous laser withdrawal). They were assessed at baseline, 1, 6, 12, 52, 104 weeks, and 5 years. Outcome measures included: Venous Clinical Severity Score (VCSS), pain scores, time taken to return to normal functions, complications, recurrence, quality of life (QoL), and duplex ultrasound findings. RESULTS: 76 consecutive patients, M: F 30:46, median age 54(IQR: 37.3-59) years were randomized. Intragroup analysis: Significant improvement was seen in both groups in VCSS, pain scores, Aberdeen varicose vein questionnaire (AVVQ) scores, Shortform-36 (SF-36) and Euroqol (EQ-5D) domains over the follow-up period (P < 0.05). Intergroup analysis: Over 5 years, clinically recurrent varicosities and duplex detected SFJ incompetence was less frequent and patient satisfaction with cosmetic outcome significantly higher in the 14W group (P < 0.05). There was no significant difference between the groups in duration of procedure, postoperative pain scores, return to normal functioning, complications, VCSS, disease specific (AVVQ) and generic (SF36, EQ-5D) QoL measures (P > 0.05). CONCLUSION: Late outcomes following EVLA were superior for the 14W continuous power settings achieving better long term venous occlusion and lowered recurrence rates without increasing post-operative morbidity. Hence 14W continuous setting should be the energy delivery mode of choice. PMID- 23645394 TI - Endovascular removal of a permanent "TrapEase" inferior vena cava filter. AB - Inferior vena cava (IVC) filter placement has seen a rising trend over the past decade. Although effective in the prevention of future pulmonary emboli, filters are associated with several long-term complications including deep venous thrombosis, filter migration, filter fracture, and caval thrombosis. The IVC filters have evolved over the years to minimize these unwarranted sequelae. We describe a technique to remove a permanent IVC filter in a patient who no longer required mechanical protection. PMID- 23645395 TI - Applying qualitative comparative analysis (QCA) in public health: a case study of a health improvement service for long-term incapacity benefit recipients. AB - BACKGROUND: This paper explores the value of qualitative comparative analysis (QCA) in public health research using the example of a pilot case management intervention for long-term incapacity benefit recipients. It uses QCA to examine how the 'health improvement' effects of the intervention varied by individual and service characteristics. METHODS: Data for 131 participants receiving the intervention were collected over 9 months. Health improvement was measured using the EuroQual Visual Analogue Scale. Socio-demographic, health behaviour data were also collected. Data on service use was obtained from the provider's client records. Crisp set QCA was conducted to identify which individual and service characteristics were most likely to produce a health benefit after participation in the intervention. RESULTS: Health improvement was most likely amongst younger participants, men aged over 50 and those with an occupational history of skilled manual work or higher and less likely amongst older women, those with a musculoskeletal condition and those with semi- or un-skilled backgrounds. Service characteristics had no impact. CONCLUSIONS: The QCA identified potential causal pathways for health improvement from the intervention with important potential implications for health inequalities. QCA should be considered as a viable and practical method in the public health evaluation tool box. PMID- 23645396 TI - Gaps in knowledge and data driving uncertainty in models of photosynthesis. AB - Regional and global models of the terrestrial biosphere depend critically on models of photosynthesis when predicting impacts of global change. This paper focuses on identifying the primary data needs of these models, what scales drive uncertainty, and how to improve measurements. Overall, there is a need for an open, cross-discipline database on leaf-level photosynthesis in general, and response curves in particular. The parameters in photosynthetic models are not constant through time, space, or canopy position but there is a need for a better understanding of whether relationships with drivers, such as leaf nitrogen, are themselves scale dependent. Across time scales, as ecosystem models become more sophisticated in their representations of succession they needs to be able to approximate sunfleck responses to capture understory growth and survival. At both high and low latitudes, photosynthetic data are inadequate in general and there is a particular need to better understand thermal acclimation. Simple models of acclimation suggest that shifts in optimal temperature are important. However, there is little advantage to synoptic-scale responses and circadian rhythms may be more beneficial than acclimation over shorter timescales. At high latitudes, there is a need for a better understanding of low-temperature photosynthetic limits, while at low latitudes the need is for a better understanding of phosphorus limitations on photosynthesis. In terms of sampling, measuring multivariate photosynthetic response surfaces are potentially more efficient and more accurate than traditional univariate response curves. Finally, there is a need for greater community involvement in model validation and model-data synthesis. PMID- 23645397 TI - Psychological aspects of the role of religion in identity construction. AB - Religious plurality can generate fears through identity destabilization. Religions offer ressources for coping with fears. On one side, production of stereotypes follows a defensive way. On the other side, claim to be universal help to cross boundaries and to cope with stigmatization, misrecognition and discrimination. Coping strategies combine at least five aspects: community, intimate relationship, rules, construction of identity, and worlview. This article shows how these aspects are intertwined. PMID- 23645398 TI - The addition of erlotinib to gemcitabine and cisplatin does not appear to improve median survival in metastatic pancreatic cancer. AB - Metastatic pancreatic cancer carries a poor prognosis, with median survival on the order of several months. There is evidence that combining gemcitabine with either erlotinib or cisplatin may be superior to single agent gemcitabine in patients with good performance (PS 0-1). We retrospectively compared outcomes of patients treated with either the three drug regimen of gemcitabine, cisplatin, and erlotinib (GCE) or the doublet of gemcitabine and cisplatin (GC) in order to assess the potential benefit of erlotinib. We also evaluated the role of erlotinib among smokers and non-smokers. We retrospectively analyzed 145 patients who presented between 2006 and 2009 with previously untreated metastatic pancreatic cancer initially treated at the M.D. Anderson cancer center with either GC or GCE. Information on tumor characteristics and overall survival time (OS) was collected by medical record review. Kaplan-Meier curves were used to estimate OS. Log rank tests were used to compare OS between groups. The Cox proportional hazards regression model was used to evaluate the ability of patient prognostic variables or treatment group to predict OS. A total of 71 patients were treated with GC, while 74 were treated with GCE. Cox analyses found no significant difference in overall survival (median 5.5 vs. 8.0 months, respectively, p-value=0.1). Small sampling numbers may have contributed to this result. One year survival was 23 % in the GCE group and 13 % in the GC group. Patients with poor performance status (PS=2-3) had worse survival as compared to patients with better performance status (PS=0-1, p=0.001). As in earlier studies, patients treated with more lines of therapy tended to have better survival (p <0.0001), and CA19-9 was found to be a significant predictor for OS (p=0.001). No statistical evidence of a survival difference was found between smokers and non smokers in both treatment groups (p=0.72). In conclusion, though there was a trend towards improved survival with the addition of erlotinib to gemcitabine and cisplatin, this does not reach statistical significance. PMID- 23645400 TI - Cold-adapted RTX lipase from antarctic Pseudomonas sp. strain AMS8: isolation, molecular modeling and heterologous expression. AB - A new strain of psychrophilic bacteria (designated strain AMS8) from Antarctic soil was screened for extracellular lipolytic activity and further analyzed using molecular approach. Analysis of 16S rDNA showed that strain AMS8 was similar to Pseudomonas sp. A lipase gene named lipAMS8 was successfully isolated from strain AMS8, cloned, sequenced and overexpressed in Escherichia coli. Sequence analysis revealed that lipAMS8 consist of 1,431 bp nucleotides that encoded a polypeptide consisting of 476 amino acids. It lacked an N-terminal signal peptide and contained a glycine- and aspartate-rich nonapeptide sequence at the C-terminus, which are known to be the characteristics of repeats-in-toxin bacterial lipases. Furthermore, the substrate binding site of lipAMS8 was identified as S(207), D(255) and H(313), based on homology modeling and multiple sequence alignment. Crude lipase exhibited maximum activity at 20 degrees C and retained almost 50 % of its activity at 10 degrees C. The molecular weight of lipAMS8 was estimated to be 50 kDa via sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE). The optimal expression level was attained using the recombinant plasmid pET32b/BL21(DE3) expressed at 15 degrees C for 8 h, induced by 0.1 mM isopropyl beta-D thiogalactoside (IPTG) at E. coli growth optimal density of 0.5. PMID- 23645401 TI - Purification, spectroscopic characterization and o-diphenoloxidase activity of hemocyanin from a freshwater gastropod: Pila globosa. AB - Hemocyanins are multi-subunit oxygen carrier proteins, found in select species of arthropoda and mollusca. Here, we have purified native hemocyanin from Pila globosa, a freshwater gastropod, verified using mass spectrometry and determined its molecular weight, secondary structure and the spectral properties, using Ultraviolet/visible, Fourier transform infra-red and Circular dichroism spectroscopy. Our results reveal the oligomeric and glycosylated nature of the protein, comprising of 400 kDa subunits, organized predominantly into a thermo stable, alpha-helical conformation. Further, biochemical assays confirm catecholoxidase-like activity in hemocyanin, which has been used to develop a first-generation optical sensor, for the detection of phenols. PMID- 23645402 TI - Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study. AB - The hypothesis was that prediction of asthma exacerbations in children is possible by profiles of exhaled volatile organic compounds (VOCs), a noninvasive measure of airway inflammation. The aims of the present study were to determine: 1) whether VOCs in exhaled breath are able to predict asthma exacerbations; and 2) the time course and chemical background of the most predictive VOCs. A prospective study was performed in 40 children with asthma over 1 year. At standard 2-month intervals, exhaled nitric oxide fraction (FeNO), VOC profiles in exhaled breath samples, lung function and symptoms were determined in a standardised way. VOC profiles were analysed by gas chromatography-time-of-flight mass spectrometry. 16 out of 40 children experienced an exacerbation. With support vector machine analysis, the most optimal model of baseline measurements versus exacerbation within patients was based on six VOCs (correct classification 96%, sensitivity 100% and specificity 93%). The model of baseline values of patients with compared to those without an exacerbation consisted of seven VOCs (correct classification 91%, sensitivity 79% and specificity 100%). FeNO and lung function were not predictive for exacerbations. This study indicates that a combination of different exhaled VOCs is able to predict exacerbations of childhood asthma. PMID- 23645404 TI - Serum uric acid as a predictor of mortality and future exacerbations of COPD. AB - Serum uric acid is increased in respiratory disease, especially in the presence of hypoxia and systemic inflammation. We evaluated serum uric acid as a biomarker for prediction of mortality and future acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Serum uric acid was measured in 314 eligible consecutive patients on admission for AECOPD. Patients were evaluated monthly for 1 year. Uric acid levels were higher in patients with more severe airflow limitation and in those experiencing frequent exacerbations. High uric acid levels (>=6.9 mg.dL(-1)) were an independent predictor of 30-day mortality in multivariate Cox regression analysis (HR 1.317, 95% CI 1.011-1.736; p=0.044), but not of 1-year mortality. Patients with high serum uric acid required more prolonged hospitalisation, and more often needed noninvasive ventilation and admission to the intensive care unit within 30 days. In addition, high uric acid levels were associated with increased risk and hospitalisation for AECOPD in 1 year in multivariate Poisson regression analysis (incidence rate ratio 1.184 (95% CI 1.125-1.246) and 1.190 (95% CI 1.105-1.282), respectively; both p<0.001). Serum uric acid is associated with increased 30-day mortality and risk for AECOPD and hospitalisations in 1-year follow-up. This low-cost biomarker may be useful in the identification of high-risk chronic obstructive pulmonary disease patients that could benefit from intensive management. PMID- 23645403 TI - Lung adenocarcinoma subtypes based on expression of human airway basal cell genes. AB - Lung cancer, including lung adenocarcinoma, is a heterogeneous disease, which evolves from molecular alterations in the airway epithelium. This study explores whether a subtype of lung adenocarcinomas expresses the unique molecular features of human airway basal cells (BCs), and how expression of the airway BC features correlates with the molecular, pathological and clinical phenotype of lung adenocarcinoma. Three independent lung adenocarcinoma data sets were analysed for expression of genes that constitute the airway BC signature. Expression of the BC signature in lung adenocarcinoma was then correlated to clinical and biological parameters. Remarkable enrichment of airway BC signature genes was found in lung adenocarcinomas. A subset of lung adenocarcinomas (BC-high adenocarcinoma) exhibited high expression of BC signature genes in association with poorer tumour grade, higher frequency of vascular invasion and shorter survival than adenocarcinomas with lower expression of these genes. At the molecular level, BC high adenocarcinomas displayed a higher frequency of KRAS mutations, activation of transcriptional networks and pathways related to cell cycle, extracellular matrix organisation, and a distinct differentiation pattern with suppression of ciliated and exocrine bronchiolar cell (Clara cell)-related genes. Activation of the airway BC programme is a molecular feature of a distinct, aggressive subtype of lung adenocarcinoma. PMID- 23645405 TI - Calcineurin inhibitors in bronchiolitis obliterans syndrome following stem cell transplantation. AB - Bronchiolitis obliterans is a complication after allogeneic haematopoietic stem cell transplantation (HSCT). Management of bronchiolitis obliterans comprises intensive immunosuppression, but treatment response is poor. We investigated the effect of cyclosporine A (CsA), tacrolimus (FK506), methylprednisolone (mPRED), mycophenolate mofetil (MMF) and everolimus on the proliferation of primary lung myofibroblasts from HSCT patients with bronchiolitis obliterans syndrome (BOS). Cells were isolated from surgical lung biopsies of eight HSCT patients with BOS. Proliferation was assessed by [(3)H]-thymidine incorporation. Biopsies revealed constrictive bronchiolitis obliterans in three patients and lymphocytic bronchiolitis in five patients. CsA and FK506 significantly induced proliferation of myofibroblasts. mPRED and MMF caused a significant inhibition of proliferation, whereas everolimus had no effect. Costimulation with FK506, mPRED and MMF significantly inhibited proliferation. Serial pulmonary function tests over 12 months after lung biopsy and under triple therapy demonstrated that patients with lymphocytic bronchiolitis had a significant improvement in forced expiratory volume in 1 s (FEV1), whereas FEV1 of patients with bronchiolitis obliterans was unchanged. Our data demonstrate a pro-proliferative effect of calcineurin inhibitors on primary human lung myofibroblasts obtained from patients with BOS after HSCT. In contrast, based on the observed antiproliferative capacity of MMF in vitro, MMF-based calcineurin inhibitor-free treatment strategies should be further evaluated in patients with bronchiolitis obliterans after HSCT. PMID- 23645407 TI - Respiratory syncytial virus: co-infection and paediatric lower respiratory tract infections. AB - Comprehensive population-based data on the role of respiratory viruses in the development of lower respiratory tract infections (LRTIs) remain unclear. We investigated the incidence and effect of single and multiple infections with respiratory viruses on the risk of LRTIs in Vietnam. Population-based prospective surveillance and a case-control study of hospitalised paediatric patients with acute respiratory infection (ARI) were conducted from April 2007 through to March 2010. Healthy controls were randomly recruited from the same community. Nasopharyngeal samples were collected and tested for 13 respiratory viruses using multiplex PCRs. 1992 hospitalised ARI episodes, including 397 (19.9%) with LRTIs, were enrolled. Incidence of hospitalised LRTIs among children aged <24 months was 2171.9 per 100 000 (95% CI 1947.9-2419.7). The majority of ARI cases (60.9%) were positive for at least one virus. Human rhinovirus (24.2%), respiratory syncytial virus (20.1%) and influenza A virus (12.0%) were the most common and 9.5% had multiple-viral infections. Respiratory syncytial virus and human metapneumovirus infections independently increased the risk of LRTIs. Respiratory syncytial virus further increased the risk, when co-infected with human rhinovirus, human metapneumovirus and parainfluenza virus-3 but not with influenza A virus. The case-control analysis revealed that respiratory syncytial virus and influenza A virus increased the risk of ARI hospitalisation but not human rhinovirus. Respiratory syncytial virus is the leading pathogen associated with risk of ARI hospitalisation and LRTIs in Vietnam. PMID- 23645406 TI - FAQs about the GOLD 2011 assessment proposal of COPD: a comparative analysis of four different cohorts. AB - Since the publication of the new Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposal for the assessment of chronic obstructive lung disease (COPD), four studies have used existing cohorts to explore the characteristics, temporal variability and/or relationship with outcomes of the four resulting patient categories (A, B, C and D). Here, we compare their results and address a number of frequently asked questions (FAQs) on the topic. The most salient findings were that: 1) the prevalence of these four groups depends on the specific population studied, C being the least prevalent; 2) comorbidities are particularly prevalent in the two "high-symptom" groups (B and D); 3) patients classifiedZ as A or D tend to remain in the same group over time, whereas those classified as B or C change substantially during follow-up; 4) mortality at 3 years was lowest in A and worst in D but surprisingly similar (and intermediate) in B and C; and 5) the incidence of exacerbations during follow-up increases progressively from A to D but that of hospitalisations behave similarly to mortality. These results identify several strengths and shortcomings of the new GOLD assessment proposal, particularly that group B is associated with more morbidity and high mortality. PMID- 23645408 TI - Plasma advanced glycation end-products and skin autofluorescence are increased in COPD. AB - Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation and oxidative stress. These conditions may lead to the formation of advanced glycation end-products (AGEs). In this study we investigated in 88 COPD patients and 55 control subjects (80% ex-smokers) the association of the plasma protein-bound AGEs N(epsilon)-(carboxymethyl)lysine (CML), pentosidine, N(epsilon)-(carboxyethyl)lysine (CEL), and AGE accumulation in skin by skin autofluorescence (AFR), with lung function. Mean +/- sd plasma CML was decreased (COPD 61.6 +/- 15.6 nmol . mmol(-1) lysine, never-smokers 80.7 +/- 19.8 nmol . mmol(-1) lysine and ex-smokers 82.9 +/- 19.3 nmol . mmol(-1) lysine) and CEL (COPD 39.1 +/- 10.9 nmol . mmol(-1) lysine, never-smokers 30.4 +/- 5.0 nmol . mmol(-1) lysine and ex-smokers 27.7 +/- 6.4 nmol . mmol(-1) lysine) and AFR (COPD 3.33 +/- 0.67 arbitrary units (AU), never-smokers 2.24 +/- 0.45 AU and ex-smokers 2.31 +/- 0.47 AU) were increased in COPD patients compared to controls. Disease state was inversely associated with CML, and linearly associated with CEL and AFR. Performing regression analyses in the total group, CEL and AFR showed a negative association and CML a positive association with lung function, even after correction for potential confounders. In conclusion, CEL and AFR were negatively and CML was positively associated with disease state. In the total group only the AGEs showed an association with forced expiratory volume in 1 s. Our data suggest that AGEs are involved in the pathophysiology of COPD, although their exact role remains to be determined. PMID- 23645409 TI - Paediatrics in Vienna. AB - The aim of this update is to describe, in the context of the current literature, major papers from the seven groups of the Paediatric Assembly (Respiratory Physiology; Asthma and Allergy; Cystic Fibrosis; Respiratory Infection and Immunology; Neonatology and Paediatric Intensive Care; Respiratory Epidemiology; and Bronchology) presented during the annual European Respiratory Society congress held in 2012 in Vienna, Austria. PMID- 23645410 TI - Orchialgia and the chronic pelvic pain syndrome. AB - This review paper highlights the important health issue of orchialgia and the chronic pelvic pain syndrome. There are a number of specific and non-specific etiologies and different treatment options based on the sub-categorization of orchialgia. The focus of this article is on the specific etiologies of chronic orchialgia as well as non-specific scrotal pain, and the diagnostic evaluation and optimal management of these men. The clinician must be cautious about assuming that orchialgia is constitutive in the chronic pelvic pain syndrome, and must be diligent in ruling out specific etiologies for scrotal pain prior to managing orchialgia as a non-specific chronic pain syndrome. PMID- 23645411 TI - Expanding utilization of robotic partial nephrectomy for clinical T1b and complex T1a renal masses. AB - INTRODUCTION: Partial nephrectomy is the standard of care for cT1a renal masses, offering equivalent oncologic outcomes and lower renal function impairment when compared to radical nephrectomy, with excellent overall survival results. Robot assisted partial nephrectomy (RAPN) allows to perform a precise tumor excision, simplifying the reconstruction steps of the procedure, especially in the treatment of complex or large renal tumors. Aim of this study was to summarize the available perioperative, functional, and oncological outcomes of RAPN performed for complex and/or large (cT1b) renal cell carcinoma (RCC). MATERIALS AND METHODS: We performed a nonsystematic review of the literature using a free text protocol in the Medline database, using the terms "robot-assisted partial nephrectomy" and "robotic partial nephrectomy." Two Authors reviewed separately to select RAPN series reporting data about complex and cT1b RCC. Other significant studies cited in the reference lists of the selected papers were also evaluated. EVIDENCE SYNTHESIS: According to the currently available evidences, RAPN offers promising results in terms of perioperative, functional, and oncological outcomes for the conservative management of complex or large renal tumors, even when compared with open and laparoscopic partial nephrectomy. Robot assisted procedure allows surgeons to treat large and challenging renal masses, even if with higher warm ischemia time, operating time, and estimated blood loss in comparison with those obtained for the treatment of smaller lesions. CONCLUSIONS: In the hands of experienced surgeons, RAPN is a safe and reproducible approach for the treatment of cT1b and more challenging renal tumors, and could represent the way to expand the indications for minimally invasive conservative approach to RCC. PMID- 23645412 TI - [Conservative lymphedema therapy - lymphological rehabilitation treatment]. AB - The most important column in the conservative lymphedema therapy still represents the complex decongestive physical therapy/KPE.This is a multimodal therapy, which consists of four components. (1) skin restoration and/or skin care, (2) manual lymphatic drainage, (3) compression therapy and (4) decongestive exercises. The KPE is also divided into two phases. Phase 1-the decongestion-serves primarily the mobilization and transporting away the banked protein-rich oedema fluid and seamless transition into the Phase 2-the maintenance phase, which serves to preserve the achieved treatment success. The implementation of the KPE should be stage-adjusted, but depends also on the location (genital, head, face), and on co existing comorbidities (congestive heart failure, diabetes mellitus, obesity, muscular-skeletal disorders, mental illness, etc.). It should be modified for children, elderly persons and for patients with malignant lymphedema. PMID- 23645414 TI - Face detection differs from categorization: evidence from visual search in natural scenes. AB - In this study, we examined whether the detection of frontal, 3/4, and profile face views differs from their categorization as faces. In Experiment 1, we compared three tasks that required observers to determine the presence or absence of a face, but varied in the extents to which participants had to search for the faces in simple displays and in small or large scenes to make this decision. Performance was equivalent for all of the face views in simple displays and small scenes, but it was notably slower for profile views when this required the search for faces in extended scene displays. This search effect was confirmed in Experiment 2, in which we compared observers' eye movements with their response times to faces in visual scenes. These results demonstrate that the categorization of faces at fixation is dissociable from the detection of faces in space. Consequently, we suggest that face detection should be studied with extended visual displays, such as natural scenes. PMID- 23645413 TI - Appearances can be deceiving: instructor fluency increases perceptions of learning without increasing actual learning. AB - The present study explored the effects of lecture fluency on students' metacognitive awareness and regulation. Participants watched one of two short videos of an instructor explaining a scientific concept. In the fluent video, the instructor stood upright, maintained eye contact, and spoke fluidly without notes. In the disfluent video, the instructor slumped, looked away, and spoke haltingly with notes. After watching the video, participants in Experiment 1 were asked to predict how much of the content they would later be able to recall, and participants in Experiment 2 were given a text-based script of the video to study. Perceived learning was significantly higher for the fluent instructor than for the disfluent instructor (Experiment 1), although study time was not significantly affected by lecture fluency (Experiment 2). In both experiments, the fluent instructor was rated significantly higher than the disfluent instructor on traditional instructor evaluation questions, such as preparedness and effectiveness. However, in both experiments, lecture fluency did not significantly affect the amount of information learned. Thus, students' perceptions of their own learning and an instructor's effectiveness appear to be based on lecture fluency and not on actual learning. PMID- 23645415 TI - Visualizing hepatic copper release in Long-Evans cinnamon rats using single photon emission computed tomography. AB - The potential utility of an imaging agent for the detection of hepatic copper was investigated in a Wilson's disease animal model. Solid-phase peptide synthesis was used to construct an imaging agent which consisted of a copper-binding moiety, taken from the prion protein, and a gamma ray-emitting indium radiolabel. Long-Evans Cinnamon (LEC) rats were used for the Wilson's disease animal model. Our evaluation methodology consisted of administering the indium-labeled agent to both LEC and genetically healthy Long-Evans (LE) cohorts via a tail vein injection and following the pharmacokinetics with single-photon emission computed tomography (SPECT) over the course of an hour. The animals were then sacrificed and their livers necropsied. An additional control agent, lacking the copper binding moiety, was used to gauge whether any change in the hepatic uptake might be caused by other physiological differences between the two animal models. LEC rats injected with the indium-labeled agent had roughly double the amount of hepatic radioactivity as compared to the healthy control animals. The control agent, without the copper-binding moiety, displayed a hepatic signal similar to that of the control LE animals. Additional intraperitoneal spiking with CuSO4 in C57BL/6 mice also found that the pharmacokinetics of the indium-labeled, prion based imaging agent is profoundly altered by exposure to in vivo pools of extracellular copper. The described SPECT application with this compound represented a significant improvement over a previous MRI application using the same base peptide sequence. PMID- 23645416 TI - Identification and quantification of genetically modified Moonshade carnation lines using conventional and TaqMan real-time polymerase chain reaction methods. AB - Genetically modified carnation (Dianthus caryophyllus L.) Moonshade was approved for planting and commercialization in several countries from 2004. Developing methods for analyzing Moonshade is necessary for implementing genetically modified organism labeling regulations. In this study, the 5'-transgene integration sequence was isolated using thermal asymmetric interlaced (TAIL)-PCR. Based upon the 5'-transgene integration sequence, conventional and TaqMan real time PCR assays were established. The relative limit of detection for the conventional PCR assay was 0.05 % for Moonshade using 100 ng total carnation genomic DNA, corresponding to approximately 79 copies of the carnation haploid genome, and the limits of detection and quantification of the TaqMan real-time PCR assay were estimated to be 51 and 254 copies of haploid carnation genomic DNA, respectively. These results are useful for identifying and quantifying Moonshade and its derivatives. PMID- 23645417 TI - An improved micropropagation of Arnebia hispidissima (Lehm.) DC. and assessment of genetic fidelity of micropropagated plants using DNA-based molecular markers. AB - An efficient and improved in vitro propagation method has been developed for Arnebia hispidissima, a medicinally and pharmaceutically important plant species of arid and semiarid regions. Nodal segments (3-4 cm) with two to three nodes obtained from field grown plants were used as explants for shoot proliferation. Murashige and Skoog's (MS) medium supplemented with cytokinins with or without indole-3-acetic acid (IAA) or naphthalene acetic acid was used for shoot multiplication. Out of different PGRs combinations, MS medium containing 0.5 mg l(-1) 6-benzylaminopurine and 0.1 mg l(-1) IAA was optimal for shoot multiplication. On this medium, explants produced the highest number of shoots (47.50 +/- 0.38). About 90 % of shoots rooted ex vitro on sterile soilrite under the greenhouse condition when the base (2-4 mm) of shoots was treated with 300 mg l(-1) of indole-3-butyric acid for 5 min. The plantlets were hardened successfully in the greenhouse with 85-90 % survival rate. Random amplified polymorphic DNA (RAPD) and inter-simple sequence repeat (ISSR) markers were employed to assess the genetic stability of in vitro-regenerated plants of A. hispidissima. Out of 40 (25 RAPD and 15 ISSR) primers screened, 15 RAPD and 7 ISSR primers produced a total number of 111 (77 RAPD and 34 ISSR) reproducible amplicons. The amplified products were monomorphic across all the micropropagated plants and were similar to the mother plant. To the best of our knowledge, it is the first report on the assessment of the genetic fidelity in micropropagated plants of A. hispidissima. PMID- 23645419 TI - Unnecessary tests and procedures in patients presenting with solid tumors of the pancreas. AB - BACKGROUND: A computed tomography (CT) scan is often the only study needed prior to surgery for resectable solid pancreas masses. However, many patients are evaluated with multiple studies and interventions that may be unnecessary. METHODS: We conducted a retrospective review of patients who presented to the Johns Hopkins Multidisciplinary Pancreas Cancer Clinic with a clearly resectable solid pancreas mass, >1 cm in size over a 2-year period (6/2007-6/2009) and underwent resection. Pancreas specialists reviewed patient records and identified an index CT with a solid pancreas mass deemed to be resectable for curative intent. Data were collected on all studies and interventions between the index CT and the surgery. RESULTS: A total of 101 patients had an index CT. Following the index CT and before surgery, 78 patients had at least one CT, 19 had magnetic resonance imaging, 9 had a positron emission tomography scan, and 66 underwent pancreatic biopsy. Patients underwent a mean of three studies with a mean added cost of $3,371 per patient. Preoperative tests and interventions were associated with a longer time to definitive surgical intervention. CONCLUSION: Wide variation exists for evaluation of newly discovered resectable solid pancreas masses, which is associated with delays to surgical intervention and added costs. PMID- 23645420 TI - Evolution of image-guided liver surgery: transition from open to laparoscopic procedures. AB - INTRODUCTION: Indications for liver surgery to treat primary and secondary hepatic malignancies are broadening. Utilizing data from B-mode or 2-D intraoperative ultrasound, it is often challenging to replicate the findings from preoperative CT or MRI scans. Additional data from more recently developed image guidance technology, which registers preoperative axial imaging to a 3-D real time model, may be used to improve operative planning, locate difficult to find hepatic tumors, and guide ablations. METHODS: Laparoscopic liver procedures are often more challenging than their open counterparts. Image-guidance technology can assist in overcoming some of the obstacles to minimally invasive liver procedures by enhancing ultrasound findings and ablation guidance. This manuscript describes a protocol that evaluated an open image-guidance system, and a subsequent protocol that directly compared, for validation, a laparoscopic with an open image-guidance system. Both protocols were limited to ablations within the liver. DISCUSSION: The laparoscopic image-guidance system successfully creates a 3-D model at both 7 and 14 mm Hg that is similar to the open 3-D model. Ultimately, improving intraoperative image guidance can help expand the ability to perform both laparoscopic and open liver surgeries. PMID- 23645421 TI - Depression and anxiety following myocardial infarction and their inverse associations with future health behaviors and quality of life. AB - BACKGROUND: Post-myocardial infarction (MI) depression and anxiety were found to predict prognosis and quality of life. PURPOSE: The purpose of this study was to test a behavioral pathway from post-MI depression/anxiety to future quality of life. METHODS: This is a longitudinal cohort study. Five hundred forty patients (<=65 years old) filled out questionnaires after a first MI, including socio demographics, pre-MI health status and behaviors, MI severity, social support, sense of coherence, depression, and anxiety. Reports of health behaviors were obtained 5 years and of quality of life 10 years later. RESULTS: A structural equations model confirmed that depression and anxiety were directly related to poorer quality of life 10 years later. These relationships were partly mediated by a positive association between anxiety and health behaviors at 5 years and a negative one between depression and health behaviors. CONCLUSIONS: The opposite effects of anxiety and depression underscore the need to attend to both emotional reactions to MI while encouraging preventive health behaviors. PMID- 23645423 TI - BCVA calls for a new kind of partnership to tackle bovine TB. PMID- 23645422 TI - Tempe consumption modulates fecal secondary bile acids, mucins, immunoglobulin A, enzyme activities, and cecal microflora and organic acids in rats. AB - The present study investigated the effect of dietary tempe, a fermented soy product, on the colonic environment of rats fed high-fat (HF, 30 % fat; experiment 1) or low-fat (LF, 6 % fat; experiment 2) diets. Growing male rats were fed the experimental diets with or without 25 % tempe for 21 days. Tempe consumption slightly but significantly increased the growth of rats fed both the HF and LF diets (P < 0.05). With both the HF and LF diets, dietary tempe markedly reduced a harmful fecal secondary bile acid, lithocholic acid (a risk factor of colon cancer) (P < 0.05), and markedly elevated fecal mucins (indices of intestinal barrier function) and immunoglobulin A (IgA, an index of intestinal immune function) (P < 0.05). With the HF diet, dietary tempe increased cecal acetate, butyrate, propionate, and succinate concentrations (P < 0.05). Analysis of the profile of cecal microflora revealed lower Bacteroides and higher Clostridium cluster XIVa levels in the tempe group of rats fed the HF diet (P < 0.05). Compared with the control group, the fecal activity of beta-glucosidase was markedly higher in the tempe group (P < 0.05), while that of urease was lower (P < 0.05) with both the HF and LF diets. The present results suggest that tempe consumption modulates the colonic environment in rats. PMID- 23645425 TI - Too many vets, not enough work: supply and demand in the USA. PMID- 23645426 TI - Microchipping to become compulsory for dogs in Wales. PMID- 23645427 TI - Keeping an eye on Rift Valley fever. PMID- 23645428 TI - EMS awards for charity placements. PMID- 23645429 TI - Proving the crime: how veterinary forensics can help. PMID- 23645430 TI - We need to talk... PMID- 23645431 TI - The BSAVA presents its awards. PMID- 23645433 TI - Epidemiology of parasitic gastroenteritis in beef suckler herds. PMID- 23645434 TI - Proposed ban on wild animals in circuses. PMID- 23645435 TI - Proposed ban on wild animals in circuses. PMID- 23645436 TI - Leptospirosis in horses. PMID- 23645437 TI - Election of VBF directors. PMID- 23645446 TI - Sensory biology of aquatic mammals. PMID- 23645447 TI - A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575). AB - PURPOSE: To establish the recommended phase II dose of the oral gamma-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity. METHODS: Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. Gemcitabine was administered at 1,000 mg/m(2) on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1). RESULTS: A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or >= grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers). CONCLUSIONS: RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m(2). Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0-24 h (AUC(0-24)) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified. PMID- 23645451 TI - Using patients like my patient for clinical decision support: institution specific probability of celiac disease diagnosis using simplified near-neighbor classification. AB - BACKGROUND: Interpretation of a diagnostic test result requires knowing what proportion of patients with a "similar" result has the condition in question. This information is often not readily available from the medical literature, or may be based on different clinical populations that make it nonapplicable. In certain settings, where correlated screening parameters and diagnostic data are available in electronic medical records, a representation of diagnostic test performance on "patients like my patient" can be obtained. OBJECTIVE: We sought to integrate patient demographic and physician practice information using a simplified nearest neighbor algorithm. We used this method to illustrate the relationship between tTG IgA test result and duodenal biopsy for celiac disease in a local diagnostic context. PARTICIPANTS: We used a data set of 1,461 paired tissue transglutaminase (tTG) IgA and definitive duodenal biopsy results from Intermountain Healthcare with data on patient age and ordering physician specialty. This was split into a discovery set of 1,000 and a validation set of 461 paired results. MAIN MEASURES: Accuracy of the local discovery data set in predicting probability of positive duodenal biopsy and confidence intervals around predicted probability in the test data compared to probabilities of positive biopsy implied from published logistic regression and from published sensitivity and specificity studies. KEY RESULTS: The near-neighbor method could estimate probability of clinical outcomes with predictive performance equivalent to other methods while adjusting probability estimates and confidence intervals to fit specific clinical situations. CONCLUSIONS: Data from clinical encounters obtained from electronic medical records can yield prediction estimates that are tailored to the individual patient, local population, and healthcare delivery processes. Local analysis of diagnostic probability may be more clinically meaningful than probabilities inferred from published studies. This local utility may come at the expense of external validity and generalizability. PMID- 23645448 TI - Bortezomib overcomes MGMT-related resistance of glioblastoma cell lines to temozolomide in a schedule-dependent manner. AB - Development of drug resistance after standard chemotherapy for glioblastoma multiforme (GBM) with temozolomide (TMZ) is associated with poor prognosis of GBM patients and is at least partially mediated by a direct DNA repair pathway involving O6-methylguanine methyltransferase (MGMT). This enzyme is under post translational control by a multisubunit proteolytic cellular machinery, the 26S proteasome. Inhibition of the proteasome by bortezomib (BZ), a boronic acid dipeptide already in clinical use for the treatment of myeloma, has been demonstrated to induce growth arrest and apoptosis in GBM cells. In this study we investigated the effect of sequential treatment with BZ and TMZ on cell proliferation-viability and apoptosis of the human T98G and U87 GBM cell lines. We also tested for an effect of treatment on MGMT expression and important upstream regulators of the latter, including nuclear factor kappa B (NFkappaB), p44/42 mitogen-activated protein kinase (MAPK), p53, signal transducer and activator of transcription 3 (STAT3) and hypoxia-inducible factor 1alpha (HIF 1alpha). The sequence of drug administration for maximal cytotoxicity favored BZ prior to TMZ in T98G cells while the opposite was the case for U87 cells. Maximal efficacy was associated with downregulation of MGMT, reduced IkappaBalpha mediated proteasome-dependent nuclear accumulation of NFkappaB, attenuation of p44/42 MAPK, AKT and STAT3 activation, and stabilization of p53 and inactive HIF 1alpha. Collectively, these results suggest that proteasome inhibition by BZ overcomes MGMT-mediated GBM chemoresistance, with scheduling of administration being critical for obtaining the maximal tumoricidal effect of combination with TMZ. PMID- 23645452 TI - Reducing racial/ethnic disparities in diabetes: the Coached Care (R2D2C2) project. AB - BACKGROUND: Despite numerous efforts to change healthcare delivery, the profile of disparities in diabetes care and outcomes has not changed substantially over the past decade. OBJECTIVE: To understand potential contributors to disparities in diabetes care and glycemic control. DESIGN: Cross sectional analysis. SETTING: Seven outpatient clinics affiliated with an academic medical center. PATIENTS: Adult patients with type 2 diabetes who were Mexican American, Vietnamese American or non-Hispanic white (n = 1,484). MEASUREMENTS: Glycemic control was measured as hemoglobin A1c (HbA1c) level. Patient, provider and system characteristics included demographic characteristics; access to care; quality of process of care including clinical inertia; quality of interpersonal care; illness burden; mastery (diabetes management confidence, passivity); and adherence to treatment. RESULTS: Unadjusted HbA1c values were significantly higher for Mexican American patients (n = 782) (mean = 8.3 % [SD:2.1]) compared with non-Hispanic whites (n = 389) (mean = 7.1 % [SD:1.4]). There were no significant differences in HbA1c values between Vietnamese American and non Hispanic white patients. There were no statistically significant group differences in glycemic control after adjustment for multiple measures of access, and quality of process and interpersonal care. Disease management mastery and adherence to treatment were related to glycemic control for all patients, independent of race/ethnicity. LIMITATIONS: Generalizability to other minorities or to patients with poorer access to care may be limited. CONCLUSIONS: The complex interplay among patient, physician and system characteristics contributed to disparities in HbA1c between Mexican American and non-Hispanic white patients. In contrast, Vietnamese American patients achieved HbA1c levels comparable to non Hispanic whites and adjustment for numerous characteristics failed to identify confounders that could have masked disparities in this subgroup. Disease management mastery appeared to be an important contributor to glycemic control for all patient subgroups. PMID- 23645453 TI - Statin use and osteoarthritis. The authors' reply. PMID- 23645454 TI - Mitochondrial transcription factor A regulated ionizing radiation-induced mitochondrial biogenesis in human lung adenocarcinoma A549 cells. AB - Mitochondrial transcription factor A (TFAM), the first well-characterized transcription factor from vertebrate mitochondria, is closely related to mitochondrial DNA (mtDNA) maintenance and repair. Recent evidence has shown that the ratio of mtDNA to nuclearDNA (nDNA) is increased in both human cells and murine tissues after ionizing radiation (IR). However, the underlying mechanism has not as yet been clearly identified. In the present study, we demonstrated that in human lung adenocarcinoma A549 cells, expression of TFAM was upregulated, together with the increase of the relative mtDNA copy number and cytochrome c oxidase (COX) activity after alpha-particle irradiation. Furthermore, short hairpin RNA (shRNA)-mediated TFAM knockdown inhibited the enhancement of the relative mtDNA copy number and COX activity caused by alpha-particles. Taken together, our data suggested that TFAM plays a crucial role in regulating mtDNA amplification and mitochondrial biogenesis under IR conditions. PMID- 23645455 TI - Variability in the point to which single direct field irradiation is prescribed for spinal bone metastases: a survey of practice patterns in Japan. AB - Direct single fields are commonly used in radiotherapy for spinal bone metastases, and it is crucial to define the point for which the dose is prescribed. According to the guidelines from the International Bone Metastases Consensus Working Party (IBMCWP) updated in 2010, different opinions exist on whether this therapy should be prescribed to the mid-vertebral or anterior vertebral body. To our knowledge, no previous studies have surveyed practice patterns regarding this discrepancy. Therefore, we performed an Internet-based survey of members of the Japanese Radiation Oncology Study Group (JROSG) to investigate the current practice patterns in Japan. The respondents mentioned the point to which they prescribed radiotherapy for a single direct field. A total of 52 radiation oncologists from 50 institutions (36% of JROSG institutions) responded. Respondent prescription for radiotherapy varied widely. Only 21% and 6% of respondents prescribed irradiation to the mid-vertebral body and anterior vertebral body, respectively. A larger proportion of respondents (27%) prescribed irradiation to the spinal cord (center of the spinal canal). Still another group of respondents (27%) stated that they never use a single direct field. In conclusion, the point to which irradiation dosages are prescribed varies widely for a single direct field in cases of spinal bone metastases. This variation may lead some radiation oncologists to misunderstand the tolerance dosage of the spinal cord, especially in cases of re-irradiation. Thus, careful consideration is required before any prescriptions are made. PMID- 23645456 TI - Measuring synovial fluid procalcitonin levels in distinguishing cases of septic arthritis, including prosthetic joints, from other causes of arthritis and aseptic loosening. AB - OBJECTIVES: Differentiating septic arthritis from non-septic arthritis can be challenging as the clinical pictures are similar and an efficacious diagnostic test is not yet available. Our objectives in this study were to establish if procalcitonin (PCT) could be reproducibly measured from synovial fluid, if there is a difference in synovial procalcitonin values between patients with septic and non-septic arthritis, respectively, including those with implants and to determine cut-off levels that could be used as a practical tool in the management of these conditions. METHODS: Using a standard serum assay, synovial fluid PCT levels were measured retrospectively in 26 septic and 50 non-septic predefined arthritis cases. The reproducibility of synovial PCT was also assessed at various concentrations. RESULTS: Synovial PCT can be measured and is reproducible. In this cohort, statistically significant higher synovial PCT levels were found in cases of septic arthritis than in non-septic arthritis. Sensitivities, specificities and positive and negative predictive values varied at different cut off levels. CONCLUSION: The test could be added to other microbiological and biochemical tests and may be used to supplement other clinical, radiological and laboratory findings in the assessment of patients with acute painful joints. In our cohort, findings of very high synovial PCT levels supported an infection process, including in prosthesis-related infections. The high negative predictive value of low synovial PCT levels could exclude infection in both native and prosthetic joints. Larger prospective studies are needed to further validate these results and to examine the cost effectiveness of synovial PCT. PMID- 23645457 TI - Gold nanoparticles attenuates antimycin A-induced mitochondrial dysfunction in MC3T3-E1 osteoblastic cells. AB - Gold nanoparticles have shown promising biological applications due to their unique properties. Understanding the interaction mechanisms between nanomaterials and biological cells is important for the control and manipulation of these interactions for biomedical applications. In the present study, we investigated the effects of gold nanoparticles on the differentiation of osteoblastic MC3T3-E1 cells and antimycin A-induced mitochondrial dysfunction. The results showed that gold nanoparticles (5, 10, and 20 nm) caused a significant elevation of cell growth, alkaline phosphatase activity, collagen synthesis, and osteocalcin content in the cells (P < 0.05). Moreover, pretreatment with gold nanoparticles prior to antimycin A exposure significantly reduced antimycin A-induced cell damage by preventing mitochondrial membrane potential dissipation, complex IV inactivation, ATP loss, cytochrome c release, cardiolipin peroxidation, and reactive oxygen species generation. Taken together, our study indicated that gold nanoparticles may improve the differentiation and have protective effects on mitochondrial dysfunction of osteoblastic cells. PMID- 23645458 TI - Psychometric evaluation of the National Eye Institute Visual Function Questionnaire and Visual Function Questionnaire Utility Index in patients with non-infectious intermediate and posterior uveitis. AB - OBJECTIVE: To evaluate the psychometric properties of the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) and Visual Function Questionnaire Utility Index (VFQ-UI) in patients with non-infectious intermediate and posterior uveitis. METHODS: Secondary analysis of pooled data from a 26-week, multicenter, masked, randomized, sham-controlled Phase 3 clinical trial. Health-related quality of life was assessed using the NEI VFQ-25, the EQ-5D, and SF-36. Internal consistency reliability, reproducibility, convergent validity, and known groups of BCVA and vitreous haze severity were assessed. Clinically significant difference was assessed using anchor-based and distribution-based methods. RESULTS: The study included 224 subjects with non-infectious intermediate (80.4 %) or posterior uveitis (19.6 %). The NEI VFQ-25 and the VFQ-UI demonstrated good internal consistency (Cronbach's alpha 0.87-0.94) and test-retest reliability (ICCs 0.58-0.88). Spearman's product-moment rank correlations between the NEI VFQ 25 and VFQ-UI scores and the SF-6D, EQ-5D, and BCVA ranged from small to moderate. There was a significant association between visual functioning and known groups of visual acuity (p < 0.05). Clinical significance, using the anchor based method (difference between visual acuity groups >=10-<15 letter better and no change), was 10.2 for change from baseline to week 26 for the NEI VFQ-25 composite score and 0.05 for the VFQ-UI. Using the distribution-based method, the clinical significance was 3.86 for the composite score and 0.04 for the VFQ-UI. CONCLUSION: The NEI VFQ-25 and the VFQ-UI are reliable and valid measures of vision-related functioning and preference-based status in patients with non infectious intermediate and posterior uveitis. PMID- 23645459 TI - High occupancy of stream salamanders despite high ranavirus prevalence in a southern appalachians watershed. AB - The interactive effects of environmental stressors and emerging infectious disease pose potential threats to stream salamander communities and their headwater stream ecosystems. To begin assessing these threats, we conducted occupancy surveys and pathogen screening of stream salamanders (Family Plethodontidae) in a protected southern Appalachians watershed in Georgia and North Carolina, USA. Of the 101 salamanders screened for both chytrid fungus (Batrachochytrium dendrobatidis) and Ranavirus, only two exhibited low-level chytrid infections. Prevalence of Ranavirus was much higher (30.4% among five species of Desmognathus). Despite the ubiquity of ranaviral infections, we found high probabilities of site occupancy (>=0.60) for all stream salamander species. PMID- 23645460 TI - Tissue-specific effects of acetylcholine in the canine heart. AB - Acetylcholine (ACh) release from the vagus nerve slows heart rate and atrioventricular conduction. ACh stimulates a variety of receptors and channels, including an inward rectifying current [ACh-dependent K+ current (IK,ACh)]. The effect of ACh in the ventricle is still debated. We compared the effect of ACh on action potentials in canine atria, Purkinje, and ventricular tissue as well as on ionic currents in isolated cells. Action potentials were recorded from ventricular slices, Purkinje fibers, and arterially perfused atrial preparations. Whole cell currents were recorded under voltage-clamp conditions, and unloaded cell shortening was determined on isolated cells. The effect of ACh (1-10 MUM) as well as ACh plus tertiapin, an IK,ACh-specific toxin, was tested. In atrial tissue, ACh hyperpolarized the membrane potential and shortened the action potential duration (APD). In Purkinje and ventricular tissues, no significant effect of ACh was observed. Addition of ACh to atrial cells activated a large inward rectifying current (from -3.5 +/- 0.7 to -23.7 +/- 4.7 pA/pF) that was abolished by tertiapin. This current was not observed in other cell types. A small inhibition of Ca2+ current (ICa) was observed in the atria, endocardium, and epicardium after ACh. ICa inhibition increased at faster pacing rates. At a basic cycle length of 400 ms, ACh (1 MUM) reduced ICa to 68% of control. In conclusion, IK,ACh is highly expressed in atria and is negligible/absent in Purkinje, endocardial, and epicardial cells. In all cardiac tissues, ACh caused rate-dependent inhibition of ICa. PMID- 23645461 TI - Flow restoration post revascularization predicted by stenosis indexes: sensitivity to hemodynamic variability. AB - The expected blood flow improvement following a coronary intervention is inversely related to the stenotic-to-normal flow ratio Qs/Qn. Since Qn cannot be measured prior to intervention, treatment decisions rely on stenosis-severity indexes, e.g., area stenosis (%AS), hyperemic stenosis resistance (HSR), and fractional flow reserve (FFR), where treatment cut-off levels have been established for each index based on presence of inducible ischemia. Here, we studied the dependence of these indexes-predicted Qs/Qn under physiological perturbations of stenosis features and of hemodynamic and mechanical conditions. Dynamic coronary flow was simulated based on measured coronary morphometric data and a physics-based computational model. Simulations were used to evaluate the relationship between each index level and Qs/Qn. Under each perturbation, an independence measure (IM) was calculated for each index based on the relative change in Qs/Qn associated with each perturbation. The results show that while %AS prediction of Qs/Qn is largely independent (IM > 90%) of physiological changes in heart rate, venous pressure, and lesion length and location on the epicardial tree, HSR is also independent of changes in left ventricle pressure. FFR-predicted Qs/Qn is also independent of changes in aortic pressure, blood hematocrit, and stenotic vessel stiffness. Nevertheless, independence of all indexes is substantially compromised (IM < 70%) under changes in vasculature stiffness. Specifically, a physiological stiffening elevates Qs/Qn value by 21% at the FFR cut-off value (0.75). These findings suggest that the current FFR cut off value for treatment of stenotic lesions overestimates the benefit of coronary intervention in patients with a stiffer coronary vasculature (e.g., diabetics, hypertensives). PMID- 23645462 TI - Rat model of exercise-induced cardiac hypertrophy: hemodynamic characterization using left ventricular pressure-volume analysis. AB - Long-term exercise training is associated with characteristic structural and functional changes of the myocardium, termed athlete's heart. Several research groups investigated exercise training-induced left ventricular (LV) hypertrophy in animal models; however, only sporadic data exist about detailed hemodynamics. We aimed to provide functional characterization of exercise-induced cardiac hypertrophy in a rat model using the in vivo method of LV pressure-volume (P-V) analysis. After inducing LV hypertrophy by swim training, we assessed LV morphometry by echocardiography and performed LV P-V analysis using a pressure conductance microcatheter to investigate in vivo cardiac function. Echocardiography showed LV hypertrophy (LV mass index: 2.41 +/- 0.09 vs. 2.03 +/- 0.08 g/kg, P < 0.01), which was confirmed by heart weight data and histomorphometry. Invasive hemodynamic measurements showed unaltered heart rate, arterial pressure, and LV end-diastolic volume along with decreased LV end systolic volume, thus increased stroke volume and ejection fraction (73.7 +/- 0.8 vs. 64.1 +/- 1.5%, P < 0.01) in trained versus untrained control rats. The P-V loop-derived sensitive, load-independent contractility indexes, such as slope of end-systolic P-V relationship or preload recruitable stroke work (77.0 +/- 6.8 vs. 54.3 +/- 4.8 mmHg, P = 0.01) were found to be significantly increased. The observed improvement of ventriculoarterial coupling (0.37 +/- 0.02 vs. 0.65 +/- 0.08, P < 0.01), along with increased LV stroke work and mechanical efficiency, reflects improved mechanoenergetics of exercise-induced cardiac hypertrophy. Despite the significant hypertrophy, we observed unaltered LV stiffness (slope of end-diastolic P-V relationship: 0.043 +/- 0.007 vs. 0.040 +/- 0.006 mmHg/MUl) and improved LV active relaxation (tau: 10.1 +/- 0.6 vs. 11.9 +/- 0.2 ms, P < 0.01). According to our knowledge, this is the first study that provides characterization of functional changes and hemodynamic relations in exercise induced cardiac hypertrophy. PMID- 23645463 TI - Functional role of peripheral opioid receptors in the regulation of cardiac spinal afferent nerve activity during myocardial ischemia. AB - Thinly myelinated Adelta-fiber and unmyelinated C-fiber cardiac sympathetic (spinal) sensory nerve fibers are activated during myocardial ischemia to transmit the sensation of angina pectoris. Although recent observations showed that myocardial ischemia increases the concentrations of opioid peptides and that the stimulation of peripheral opioid receptors inhibits chemically induced visceral and somatic nociception, the role of opioids in cardiac spinal afferent signaling during myocardial ischemia has not been studied. The present study tested the hypothesis that peripheral opioid receptors modulate cardiac spinal afferent nerve activity during myocardial ischemia by suppressing the responses of cardiac afferent nerve to ischemic mediators like bradykinin and extracellular ATP. The nerve activity of single unit cardiac afferents was recorded from the left sympathetic chain (T2-T5) in anesthetized cats. Forty-three ischemically sensitive afferent nerves (conduction velocity: 0.32-3.90 m/s) with receptive fields in the left and right ventricles were identified. The responses of these afferent nerves to repeat ischemia or ischemic mediators were further studied in the following protocols. First, epicardial administration of naloxone (8 MUmol), a nonselective opioid receptor antagonist, enhanced the responses of eight cardiac afferent nerves to recurrent myocardial ischemia by 62%, whereas epicardial application of vehicle (PBS) did not alter the responses of seven other cardiac afferent nerves to ischemia. Second, naloxone applied to the epicardial surface facilitated the responses of seven cardiac afferent nerves to epicardial ATP by 76%. Third, administration of naloxone enhanced the responses of seven other afferent nerves to bradykinin by 85%. In contrast, in the absence of naloxone, cardiac afferent nerves consistently responded to repeated application of ATP (n = 7) or bradykinin (n = 7). These data suggest that peripheral opioid peptides suppress the responses of cardiac sympathetic afferent nerves to myocardial ischemia and ischemic mediators like ATP and bradykinin. PMID- 23645464 TI - Uncoupling the mitochondria facilitates alternans formation in the isolated rabbit heart. AB - Alternans of action potential duration (APD) and intracellular calcium ([Ca2+]i) transients in the whole heart are thought to be markers of increased propensity to ventricular fibrillation during ischemia-reperfusion injuries. During ischemia, ATP production is affected and the mitochondria become uncoupled, which may affect alternans formation in the heart. The aim of our study was to investigate the role of mitochondria on the formation of APD and [Ca2+]i alternans in the isolated rabbit heart. We performed dual voltage and [Ca2+]i optical mapping of isolated rabbit hearts under control conditions, global no flow ischemia (n = 6), and after treatment with 50 nM of the mitochondrial uncoupler FCCP (n = 6). We investigated the formation of alternans of APD, [Ca2+]i amplitude (CaA), and [Ca2+]i duration (CaD) under different rates of pacing. We found that treatment with FCCP leads to the early occurrence of APD, CaD, and CaA alternans; an increase of intraventricular APD but not CaD heterogeneity; and significant reduction in conduction velocity compared with that of control. Furthermore, we demonstrated that FCCP and global ischemia have similar effects on the prolongation of [Ca2+]i transients, whereas ischemia induces a significantly larger reduction of APD compared with that in FCCP treatment. In conclusion, our results demonstrate that uncoupling of mitochondria leads to an earlier occurrence of alternans in the heart. Thus, in conditions of mitochondrial stress, as seen during myocardial ischemia, uncoupled mitochondria may be responsible for the formation of both APD and [Ca2+]i alternans in the heart, which in turn creates a substrate for ventricular arrhythmias. PMID- 23645467 TI - Differential growth inhibition of cancer cell lines and antioxidant activity of extracts of red, brown, and green marine algae. AB - As the use of various anticancer drugs is associated with many undesirable side effects, there is an urgent need for the discovery of new, better, and specific anticancer compounds. Antioxidant and antiproliferative activities as well as effects on cell morphology were investigated for methanol (M), chloroform (C), ethyl acetate (E), and aqueous (A) extracts of Caulerpa peltata, Gelidiella acerosa, Padina gymnospora, and Sargassum wightii using 2,2-diphenyl-1 picrylhydrazyl radical-scavenging, ferrous ion chelation, and resazurin-based growth inhibition (in A549, HCT-15, MG-63, and PC-3 cell lines) assays. A general trend was the greater extraction of phenols and flavonoids by chloroform and ethyl acetate, which showed higher activity in many assays. These non-polar C and E extracts showed higher DPPH radical-scavenging and growth inhibitory activities in A549, HCT-15, and PC-3 cells. However, higher ferrous ion chelation (A extracts) and growth inhibition in MG-63 cells (M and A extracts) were seen for the polar extracts. Furthermore, P. gymnospora and C. peltata emerged as promising sources for antiproliferative agents that could be explored for their own activity and as leads for the development of other compounds. PMID- 23645465 TI - Mechanisms of rapid vasodilation after a brief contraction in human skeletal muscle. AB - A monophasic increase in skeletal muscle blood flow is observed after a brief single forearm contraction in humans, yet the underlying vascular signaling pathways remain largely undetermined. Evidence from experimental animals indicates an obligatory role of vasodilation via K+-mediated smooth muscle hyperpolarization, and human data suggest little to no independent role for nitric oxide (NO) or vasodilating prostaglandins (PGs). We tested the hypothesis that K+-mediated vascular hyperpolarization underlies the rapid vasodilation in humans and that combined inhibition of NO and PGs would have a minimal effect on this response. We measured forearm blood flow (Doppler ultrasound) and calculated vascular conductance 10 s before and for 30 s after a single 1-s dynamic forearm contraction at 10%, 20%, and 40% maximum voluntary contraction in 16 young adults. To inhibit K+-mediated vasodilation, BaCl2 and ouabain were infused intra arterially to inhibit inwardly rectifying K+ channels and Na+-K+-ATPase, respectively. Combined enzymatic inhibition of NO and PG synthesis occurred via NG-monomethyl-L-arginine (L-NMMA; NO synthase) and ketorolac (cyclooxygenase), respectively. In protocol 1 (n = 8), BaCl2 + ouabain reduced peak vasodilation (range: 30-45%, P < 0.05) and total postcontraction vasodilation (area under the curve, ~55-75% from control) at all intensities. Contrary to our hypothesis, L NMMA + ketorolac had a further impact (peak: ~60% and area under the curve: ~80% from control). In protocol 2 (n = 8), the order of inhibitors was reversed, and the findings were remarkably similar. We conclude that K+-mediated hyperpolarization and NO and PGs, in combination, significantly contribute to contraction-induced rapid vasodilation and that inhibition of these signaling pathways nearly abolishes this phenomenon in humans. PMID- 23645468 TI - Fatty acid composition of porcine cumulus oocyte complexes (COC) during maturation: effect of the lipid modulators trans-10, cis-12 conjugated linoleic acid (t10,c12 CLA) and forskolin. AB - The effect of maturation and of two lipid modulators supplementation along in vitro maturation (IVM) on fatty acid (FA) and dimethylacetal (DMA) composition of porcine cumulus oocyte complexes (COC) were studied. Abattoir-derived immature COC were analyzed for FA and DMA or submitted to IVM as follows: control group; t10,c12 CLA group, t10,c12 CLA supplementation for 44 h; Forskolin group, forskolin supplementation during the initial 2 h; t10,c12 CLA + forskolin group, t10,c12 CLA for 44 h and forskolin for just 2h. Each experimental group had five replicates. FA analysis of oocytes, cumulus cells (CC), follicular fluid, and culture media were performed by gas-liquid chromatography. Oocytes and their CC had different FA composition. Oocytes were richer in saturated FA (SFA) preferentially maintaining their FA profile during maturation. Mature CC had the highest polyunsaturated FA (PUFA) content. Five individual and total SFA, and monounsaturated FA (MUFA), notably oleic acid (c9-18:1), percentages were lower (P <= 0.023) in mature than in immature CC. t10,c12 CLA was accumulated by COC from t10,c12 CLA and t10,c12 CLA + forskolin groups, mostly in CC where MUFA and an eicosatrienoic isomer decreased (P <= 0.043). Nevertheless, PUFA or FA and DMA total content were not affected. Arachidonic acid was reduced in t10,c12 CLA + forskolin CC and hexadecanal-DMA-16:0 in t10,c12 CLA CC. Forskolin alone increased (P <= 0.043) c9-18:1 in oocytes. In conclusion, maturation process clearly changed porcine COC FA and DMA profiles, mostly of CC, also more susceptible to modifications induced by t10,c12 CLA. This possibility of manipulating COC lipid composition during IVM could be used to improve oocyte quality/cryopreservation efficiency. PMID- 23645470 TI - Pulmonary cerium dioxide nanoparticle exposure differentially impairs coronary and mesenteric arteriolar reactivity. AB - Cerium dioxide nanoparticles (CeO2 NPs) are an engineered nanomaterial (ENM) that possesses unique catalytic, oxidative, and reductive properties. Currently, CeO2 NPs are being used as a fuel catalyst but these properties are also utilized in the development of potential drug treatments for radiation and stroke protection. These uses of CeO2 NPs present a risk for human exposure; however, to date, no studies have investigated the effects of CeO2 NPs on the microcirculation following pulmonary exposure. Previous studies in our laboratory with other nanomaterials have shown impairments in normal microvascular function after pulmonary exposures. Therefore, we predicted that CeO2 NP exposure would cause microvascular dysfunction that is dependent on the tissue bed and dose. Twenty four-hour post-exposure to CeO2 NPs (0-400 MUg), mesenteric, and coronary arterioles was isolated and microvascular function was assessed. Our results provided evidence that pulmonary CeO2 NP exposure impairs endothelium-dependent and endothelium-independent arteriolar dilation in a dose-dependent manner. The CeO2 NP exposure dose which causes a 50 % impairment in arteriolar function (EC50) was calculated and ranged from 15 to 100 MUg depending on the chemical agonist and microvascular bed. Microvascular assessments with acetylcholine revealed a 33-75 % reduction in function following exposure. Additionally, there was a greater sensitivity to CeO2 NP exposure in the mesenteric microvasculature due to the 40 % decrease in the calculated EC50 compared to the coronary microvasculature EC50. CeO2 NP exposure increased mean arterial pressure in some groups. Taken together, these observed microvascular changes may likely have detrimental effects on local blood flow regulation and contribute to cardiovascular dysfunction associated with particle exposure. PMID- 23645471 TI - Whole-brain black-blood imaging with magnetization-transfer prepared spin echo like contrast: a novel sequence for contrast-enhanced brain metastasis screening at 3T. AB - In contrast-enhanced (CE) brain metastasis screening, coexistence of enhanced blood vessel suppression and higher tumor-to-parenchyma contrast may improve radiologists' performances in detecting brain metastases compared with conventional sequences. In this study, we propose a new scheme, allowing both suppression of blood signals and improvement of tumor-to-parenchyma contrast, using motion-sensitized driven equilibrium prepared 3D low-refocusing flip-angle turbo spin echo (TSE) ("magnetization transfer prepared spin echo"-like contrast volume examination: MATLVE) for brain metastasis screening at 3.0 T, and we compare MATLVE to conventional three-dimensional (3D)-gradient recalled echo (GRE) and 3D-TSE sequences. With the use of MATLVE, the signal intensity of CE blood decreased substantially. Furthermore, the contrast ratio of tumor-to-white matter was significantly higher than in either conventional 3D-GRE or 3D-TSE. MATLVE can be used for 3D volumetric post-CE black-blood imaging, and it may be effective in detecting small brain metastases by selectively enhancing tumor signals while suppressing blood signals. PMID- 23645472 TI - Pharmacology of the new target-specific oral anticoagulants. AB - Oral anticoagulation therapy is transforming with the advent of the target specific oral anticoagulants, particularly, the direct thrombin inhibitors and factor Xa inhibitors. These agents have demonstrated clinical efficacy and safety and offer several potential advantages over current standard of care therapy, warfarin. Nevertheless, the pharmacology between the newly approved oral anticoagulants differs and must be considered for appropriate management and patient selection. The pharmacodynamics and pharmacokinetics of dabigatran etexilate, rivaroxaban, apixaban and edoxaban are discussed in detail, which may translate into considerable clinical implications. PMID- 23645473 TI - Propensity for young reticulated platelet recruitment into arterial thrombi. AB - Atherosclerosis reduces platelet survival and thereby increases the percentage of younger platelets in the circulation assuming steady-state thrombocytopoiesis. We hypothesized that younger platelets have an increased propensity for arterial thrombus participation compared to older counterparts. Platelet-rich thrombi were generated by perfusing human heparinized whole blood from normal donors over arterial cross-sections under shear conditions (3,350 s(-1)) corresponding to significant coronary artery stenosis using a perfusion chamber. Harvested thrombi were disaggregated, stained with thiazole orange, anti-integrin beta3, glycoprotein (GP) Ibalpha, GP IX and P-selectin, and compared to paired whole blood samples from the same donor by flow cytometry. Thiazole orange staining intensity provides a measure of platelet m-RNA content and age. Thiazole orange staining intensity (MN +/- SEM) of platelets harvested from thrombi (62 +/- 13) was twofold greater compared to paired intra-individual whole blood samples (31 +/- 1). Integrin beta3 receptor density was also greater for thrombus platelets (12.0 +/- 1.0) compared to whole blood platelets (7.0 +/- 0.6; p < 0.0001). GPs Ibalpha and IX were reduced from thrombus platelets possibly reflecting shedding. Younger "reticulated" platelets appear to have a greater propensity for thrombus participation under shear conditions of coronary artery stenosis compared to older counterparts. This predisposition may be explained by an increased receptor density of integrin beta3 in younger platelets. By this mechanism, the atherosclerotic process may enhance the individual propensity for arterial thrombosis. PMID- 23645474 TI - Bloodstream infections in patients with or without cancer in a large community hospital. AB - PURPOSE: Cancer is associated with an increased risk of acquiring bloodstream infection (BSIs). Most knowledge on pathogens and outcome are derived from specialised cancer centres. We here sought to compare causative micro-organisms in BSIs in patients with or without cancer in a 600-bed teaching community hospital. METHODS: We analysed all positive blood cultures from adult patients between January 2005 and January 2011. RESULTS: A total of 4,918 episodes of BSI occurred in 2,891 patients, of whom 13.4% had a diagnosis of cancer (85.5% with a solid tumour). In both patient groups, Gram-positive isolates were more prevalent (58.7 and 61.4% in patients with and without cancer, respectively) than Gram negative isolates (31.8 and 32.3%, respectively). Amongst Gram-positive organisms, coagulase-negative staphylococci, Staphylococcus aureus and enterococci were the most frequently isolated in both patient groups; in cancer patients, twice as many BSIs were caused by Enterococcus faecalis and E. faecium. Amongst Gram-negative organisms, Escherichia coli was the most common isolate; in cancer patients, twice as many BSIs were caused by Pseudomonas aeruginosa and Enterobacter cloacae. Yeasts were grown from 3.0% of blood cultures from cancer patients compared to 1.5% of cultures from non-cancer patients. Cancer patients had a 90-day mortality of 35.8% following BSI compared to 23.5% in patients without cancer. CONCLUSION: These data demonstrate distinct BSI pathogens and impaired outcomes in patients with cancer in the setting of a large community teaching hospital. PMID- 23645475 TI - Uraemic dyslipidaemia revisited: role of high-density lipoprotein. AB - Chronic kidney disease (CKD) is accompanied by strong cardiovascular risk. In a rather rigid picture of lipoprotein biology, low-density lipoprotein (LDL) is referred to as 'bad cholesterol', while high-density lipoprotein (HDL) is referred to as 'good cholesterol'. However, recent experimental evidence suggests that HDL may be rendered dysfunctional regarding its effects on the vasculature under various clinical conditions such as CKD. Indeed, HDL from the blood of CKD patients has been shown to transform into a particle which promotes endothelial dysfunction, endothelial proinflammatory activation and, thereby, sets the conditions for the development of atherosclerotic disease. Notably, pharmaceutical interventions to raise serum HDL-cholesterol levels have not been proven beneficial so far. Collectively, these findings indicate that HDL cholesterol levels do not represent a valuable marker for indicating the vascular properties of HDL. PMID- 23645476 TI - Validation of the kidney failure risk equation in European CKD patients. AB - BACKGROUND: Patients with chronic kidney disease (CKD) are at risk for progression to kidney failure. Using data of Canadian CKD patients, Tangri et al. recently developed models to predict the progression of CKD stages 3-5 to kidney failure within 5 years. We validated this kidney failure risk equation (KFRE) in European CKD patients. METHODS: We selected non-transplanted patients with CKD stages 3-5 who participated in the MASTERPLAN study, a randomized controlled trial in patients with CKD. Kidney failure was defined as the initiation of chronic dialysis or kidney transplantation within 5 years. Patients who died before kidney failure were censored. Patients followed for <5 years, who did not develop kidney failure and did not die, were excluded. The 5-year kidney failure risk was predicted using three different models developed by Tangri et al. and compared with the actual kidney failure rate in MASTERPLAN. Model performance was evaluated using the area under the receiver operating characteristic curve (ROC AUC), the net reclassification index (NRI) and by comparing the observed and predicted rates of kidney failure. RESULTS: A total of 595 patients were included; 114 developed kidney failure. (Overall observed kidney failure risk in our cohort was 5% lower than in the Canadian validation cohort.) Discrimination of the eight-variable model [including age, sex, estimated glomerular filtration rate (eGFR), albuminuria, calcium, phosphate, bicarbonate, albumin] was similar to that of the four-variable model (including age, sex, eGFR, albuminuria) and the three-variable model (including age, sex, eGFR); ROC-AUCs were 0.89 [95% confidence interval (CI) 0.86-0.92], 0.88 (95% CI 0.85-0.91) and 0.88 (95% CI 0.85-0.92), respectively. Using the NRI, the eight-variable model slightly outperformed the four-variable model (NRI 6.5%) and the three-variable model (NRI 12.4%). The mean differences between the observed and predicted kidney failure risk were -4.0, -7.1 and -7.4% for the eight-, four-, and three-variable model, respectively. CONCLUSIONS: The KFRE accurately predicted the progression to kidney failure in European CKD patients. Discrimination of the three models was similar. Calibration of the eight-variable model was slightly better than that of the simpler models. We question whether this outweighs its added complexity. PMID- 23645477 TI - Diverse effects of interdialytic intervals on central wave augmentation in haemodialysis patients. AB - BACKGROUND: Increased arterial stiffness is a common finding and independent predictor of mortality in end-stage renal disease (ESRD) patients. A long interdialytic interval was associated with increased risk of cardiovascular death in patients receiving conventional haemodialysis (HD). This is the first study to examine the effects of a long (3-day) versus short (2-day) interdialytic period on arterial elasticity in HD patients. METHODS: Seventy ESRD patients receiving standard HD three times per week were studied at the start and end of a 3-day and a 2-day interdialytic interval. At each time point, applanation tonometry of peripheral arteries was performed to assess arterial stiffness and wave reflection parameters. Aortic and brachial pulse wave velocities (PWV) were recorded as measures of arterial stiffness and augmentation index (AIx) as a measure of wave reflections. RESULTS: AIx, heart-rate-adjusted AIx and augmentation pressure were significantly increased during both interdialytic intervals, whereas aortic and brachial PWVs remained unchanged. The interdialytic increases in all the three AIx parameters were significantly higher during the 3 day interval in comparison to the 2-day interval (P < 0.001 for all comparisons). In contrast, no significant differences in interdialytic changes of aortic (P = 0.355) and brachial (P = 0.319) PWVs were noted between the two intervals. Mixed linear model analysis revealed that central aortic systolic blood pressure (SBP) and body weight, but not aortic or brachial PWV, were independent determinants of the change in heart-rate-adjusted AIx throughout the study. CONCLUSIONS: AIx is increased between HD sessions, whereas arterial elasticity is not. This interdialytic increase in central wave augmentation is more pronounced during the 3-day interval, suggesting a mechanism possibly involved in the elevated cardiovascular risk of HD patients at this time point. PMID- 23645478 TI - Pollution distribution of heavy metals in surface soil at an informal electronic waste recycling site. AB - We studied distribution of heavy metals [lead (Pb), copper (Cu) and zinc (Zn)] in surface soil at an electronic-waste (e-waste) recycling workshop near Metro Manila in the Philippines to evaluate the pollution size (spot size, small area or the entire workshop), as well as to assess heavy metal transport into the surrounding soil environment. On-site length-of-stride-scale (~70 cm) measurements were performed at each surface soil point using field-portable X-ray fluorescence (FP-XRF). The surface soil at the e-waste recycling workshop was polluted with Cu, Zn and Pb, which were distributed discretely in surface soil. The site was divided into five areas based on the distance from an entrance gate (y-axis) of the e-waste recycling workshop. The three heavy metals showed similar concentration gradients in the y-axis direction. Zn, Pb and Cu concentrations were estimated to decrease to half of their maximum concentrations at ~3, 7 and 7 m from the pollution spot, respectively, inside the informal e-waste recycling workshop. Distance from an entrance may play an important role in heavy metal transport at the soil surface. Using on-site FP-XRF, we evaluated the metal ratio to characterise pollution features of the solid surface. Variability analysis of heavy metals revealed vanishing surficial autocorrelation over metre ranges. Also, the possibility of concentration prediction at unmeasured points using geostatistical kriging was evaluated, and heavy metals had a relative "small" pollution scales and remained inside the original workshop compared with toxic organohalogen compounds. Thus, exposure to heavy metals may directly influence the health of e-waste workers at the original site rather than the surrounding habitat and environmental media. PMID- 23645479 TI - Warfarin users prone to coagulopathy in first 30 days after hospital discharge from gastric bypass. AB - BACKGROUND: Lehigh Valley Health Network (LVHN), a nonprofit tertiary care facility in Allentown, Pennsylvania, is an accredited American College of Surgeons Bariatric Surgery Center Network (ACSBSCN) Level 1 site performing 400+ bariatric procedures annually. Bariatric data submission began in April 2008. Complication review revealed that approximately 17 % of patients on chronic anticoagulation (warfarin) therapy preoperatively were readmitted with supratherapeutic international normalized ratios (INRs), postsurgical bleeding, anastomotic ulcer, or other intraluminal hemorrhage. Opinion level recommendations have been published regarding the adjustment of warfarin dosages post-bariatric procedures with no widespread consensus. Case series have been published detailing perioperative hemorrhage risk for bariatric patients on preoperative anticoagulation. Little data of post-discharge hemorrhage rates have been published. With increasing numbers of bariatric surgical procedures performed annually, there is a potential for developing serious coagulopathic complications in those patients who resume their anticoagulation therapy postoperatively. METHODS: Retrospective review of LVHN data from the ACSBSCN database was analyzed for 30-day readmissions due to documented extra- or intraluminal hemorrhage with INR and coagulopathy. Follow-up INR and warfarin doses were collected up to 6 months postoperatively. RESULTS: Over a 3-year period, 38 patients undergoing bariatric procedures were identified as being on preoperative warfarin therapy. Six of 38 developed hemorrhage within 30 days. Two patients presented beyond 30 days with bleeding. Supratherapeutic INR was present in five of six readmitted patients. Mean INR was 5.8. Warfarin sensitivity was present in a statistically significant higher number of patients within 30 days of surgery. After 30 days, a resistance to warfarin was demonstrated. CONCLUSIONS: Bariatric surgery patients taking warfarin are prone to coagulopathy in the early post-op period requiring vigilant monitoring to prevent supratherapeutic INR and corresponding risk of hemorrhage. PMID- 23645480 TI - Bariatric surgery outcomes in a European Centre of Excellence (CoE). AB - Bariatric Surgery Centres of Excellence have been promoted by the International Federation for the Surgery of Obesity and Metabolic Disorders European Chapter to improve outcomes and security of patients. A retrospective analysis of our prospective database has been performed. Between May 2001 and September 2012, we operated on 690 patients, first with open gastric bypass (2001-2005), then laparoscopy (2006-2009), introduced robotics and finally the Centre of Excellence period (2012). Complication rate was 18.9 % in the first period and 3 % in the last. We reoperated on 9 % of patients in two early periods and none in the last. Mortality rate was 2, 0.85, 0.47 and 0 % in the four periods. Teams that are just at the beginning of their experience in bariatric surgery in order to avoid complications and deal with better long-term results. PMID- 23645481 TI - REG1A expression status suggests chemosensitivity among advanced thoracic esophageal squamous cell carcinoma patients treated with esophagectomy followed by adjuvant chemotherapy. AB - BACKGROUND: Regenerating gene 1A (REG1A) plays an important role in tissue regeneration and in cell proliferation in the mucous membrane of the gastrointestinal tract. We previously reported that the positive expression status of REG1A was predictive of chemoradiosensitivity in patients treated with preoperative chemoradiotherapy before esophagectomy or with definitive chemoradiotherapy. To further confirm the utility of REG1A as a chemosensitivity marker, we carried out an additional retrospective clinical study aimed at determining whether REG1A is a reliable chemosensitivity marker in patients treated with esophagectomy followed by adjuvant chemotherapy. METHOD: A total of 177 patients with T2-4 thoracic esophageal squamous cell carcinoma received curative surgery without preoperative treatment at Akita University Hospital between 2001 and 2011. A tissue microarray was constructed, and REG1A expression status was analyzed immunohistochemically. We then statistically analyzed the relationships between REG1A expression status and 5-year overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). RESULTS: In the adjuvant group (n=105), REG1A-positive patients showed significantly better prognoses than REG1A-negative patients. (5-year OS, p=.0022; DSS, p=.0004; and DFS, p=.0040). However, there were no significant differences between REG1A positive and REG1A-negative patients in the surgery group (n=72). Univariate and multivariate analyses showed REG1A expression status to be a significant prognostic factor affecting 5-year DSS, comparable to lymph node metastatic status. CONCLUSION: The present study suggests REG1A expression status has the potential to be a highly reliable and clinically useful chemosensitivity marker in patients treated with advanced thoracic esophageal squamous cell carcinoma. REG1A expression status will provide a good indication of treatment strategy and enable more individualized treatment for patients. PMID- 23645482 TI - Embedded cervical esophagogastrostomy: a simple and convenient method using a circular stapler after esophagectomy for esophageal carcinomas. AB - BACKGROUND: Cervical esophagogastrostomy is currently the most common method for esophageal reconstruction after esophagectomy. The advantages and disadvantages of hand-sewn, linear-stapled, or circular-stapled anastomoses have been subject to debate in recent years. We explored a new method of end-to-side anastomosis using a circular stapler that embeds the anastomosis and the remaining esophageal tissue into the gastric cavity to reduce the occurrence of anastomotic leakage and to prevent gastroesophageal reflux. METHODS: In 127 patients with esophageal carcinomas, end-to-side anastomoses with esophageal embedding were performed by connecting the anvil and body of the circular stapler inside the stomach before firing and embedding the anastomosis and remaining esophagus into the stomach after esophagectomy. Retrospective investigations on postoperative complications such as leakage, stricture, and gastroesophageal reflux were conducted. RESULTS: A total of 123 patients (96.9%) had successful surgery, and 4 patients (3.3%) developed anastomotic leakage, with the total morbidity of 20 of 123 (16.3%) and in-hospital mortality of 1 of 123 (0.8%). The incidence of stricture (<1 cm) affected 14 of 123 patients (11.4%). Eight patients underwent dilatation treatment as a result of severe dysphagia (6.5%). Half of the patients [62 of 123 (50.4%)] experienced postoperative heartburn, 11 of 123 patients (8.9%) experienced acid regurgitation, and 16 of 123 patients (13.0%) experienced nocturnal cough. CONCLUSIONS: Embedded cervical esophagogastrostomy with circular stapler is a simple and convenient method, with low incidence of anastomotic leakage and a good antireflux effect. PMID- 23645483 TI - Sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with cytologically proven node-positive breast cancer at diagnosis. AB - BACKGROUND: The performance of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NCT) was investigated in patients with locally advanced breast cancer (LABC). METHODS: After NCT of 178 patients with cytology-proven axillary/supraclavicular nodes metastasis at the time of diagnosis, SLNB using radioisotope was performed including completion node dissection between 2008 and 2011. The detection rate, sensitivity, false negative rate (FNR), negative predictive value (NPV) and accuracy of SLNB were analyzed. RESULTS: SLNB was successfully performed in 169 (94.9%) patients. Tumor nonresponse and extensive residual nodal disease were found to be significantly associated with detection failure of sentinel nodes. Sensitivity, FNR, NPV, and accuracy of SLNB were 78.0, 22.0, 75.8, and 87.0%, respectively, and a greater number of retrieved SLNs increased all four of these performance measures. Conversion to node-negative disease was achieved in 69 (40.8%) patients: 24% of patients with the luminal A subtype, 51.6% of patients with the luminal B, 51.7% of patients with the HER2 enriched, and 58.5% of patients with the triple-negative breast cancer (TNBC) subtype. Luminal B, HER2-enriched, and TNBC subtypes showed comparable responses to NCT; however, the TNBC subtype had a significantly better FNR and accuracy. CONCLUSIONS: SLNB was found to be technically feasible, but its routine use was not recommended for LABCs after NCT. However, acceptable performance was noted for locally advanced TNBCs, and thus SLNB might be safely considered in these selected patients. PMID- 23645484 TI - Estimates of gastrocnemius muscle length during simulated pathological gait. AB - The purpose of this study was to compare estimates of gastrocnemius muscle length (GML) obtained using a segmented versus straight-line model in children. Kinematic data were acquired on eleven typically developing children as they walked under the following conditions: normal gait, crouch gait, equinus gait, and crouch with equinus gait. Maximum and minimum GML, and GML change were calculated using two models: straight-line and segmented. A two-way RMANOVA was used to compare GML characteristics. Results indicated that maximum GML and GML change during simulated pathological gait patterns were influenced by model used to calculate gastrocnemius muscle length (interaction: P = .004 and P = .026). Maximum GML was lower in the simulated gait patterns compared with normal gait (P < .001). Maximum GML was higher with the segmented model compared with the straight-line model (P = .030). Using either model, GML change in equinus gait and crouch with equinus gait was lower compared with normal gait (P < .001). Overall, minimum GML estimated with the segmented model was higher compared with the straight-line model (P < .01). The key findings of our study indicate that GML is significantly affected by both gait pattern and method of estimation. The GML estimates tended to be lower with the straight-line model versus the segmented model. PMID- 23645485 TI - A functional PCA model for the study of time series of pressure maps. AB - Principal component analysis and functional regression are combined in a model to analyze a time series of pressure maps. The model is tested measuring the pressures over a chair seat while a subject performs a combination of simple movements. A sampling rate of 3 Hz is adequate for applying the model in sitting postures. The model is able to detect patterns of movement over time, although more variables are necessary if the movements produce similar pressure distributions. PMID- 23645486 TI - Runners with anterior knee pain use a greater percentage of their available pronation range of motion. AB - "Excessive" pronation is often implicated as a risk factor for anterior knee pain (AKP). The amount deemed excessive is typically calculated using the means and standard deviations reported in the literature. However, when using this method, few studies find an association between pronation and AKP. An alternative method of defining excessive pronation is to use the joints' available range of motion (ROM). The purposes of this study were to (1) evaluate pronation in the context of the joints' ROM and (2) compare this method to traditional pronation variables in healthy and injured runners. Thirty-six runners (19 healthy, 17 AKP) had their passive pronation ROM measured using a custom-built device and a motion capture system. Dynamic pronation angles during running were captured and compared with the available ROM. In addition, traditional pronation variables were evaluated. No significant differences in traditional pronation variables were noted between healthy and injured runners. In contrast, injured runners used significantly more of their available ROM, maintaining a 4.21 degrees eversion buffer, whereas healthy runners maintained a 7.25 degrees buffer (P = .03, ES = 0.77). Defining excessive pronation in the context of the joints' available ROM may be a better method of defining excessive pronation and distinguishing those at risk for injury. PMID- 23645494 TI - Multi-joint coordination of functional arm reaching: induced position analysis. AB - Functional arm reaching involves multilinked joints: shoulder, elbow, and wrist. We propose that induced position analysis is a useful analytical tool for multijoint coordination of arm reaching. This method was used to compute the contributions of the net joint moment to the hand position when reaching forward. We describe the method and give examples of validating this model with motion capture data. The shoulder and elbow were prime movers of the arm: both acted together with an "overshoot" and "undershoot" pattern respectively to move the hand forward into the final position. PMID- 23645495 TI - Interactive effects of joint angle, contraction state and method on estimates of achilles tendon moment arms. AB - The muscle-tendon moment arm is an important input parameter for musculoskeletal models. Moment arms change as a function of joint angle and contraction state and depend on the method being employed. The overall purpose was to gain insights into the interactive effects of joint angle, contraction state and method on the Achilles tendon moment arm using the center of rotation (COR) and the tendon excursion method (TE). Achilles tendon moment arms were obtained at rest (TErest, CORrest) and during a maximum voluntary contraction (CORMVC) at four angles. We found strong correlations between TErest and CORMVC for all angles (.72 <= r <= .93) with Achilles tendon moment arms using CORMVC being 33-36% greater than those obtained from TErest. The relationship between Achilles tendon moment arms and angle was similar across both methods and both levels of muscular contraction. Finally, Achilles tendon moment arms for CORMVC were 1-8% greater than for COR(rest). PMID- 23645496 TI - Modeling serotonin uptake in the lung shows endothelial transporters dominate over cleft permeation. AB - A four-region (capillary plasma, endothelium, interstitial fluid, cell) multipath model was configured to describe the kinetics of blood-tissue exchange for small solutes in the lung, accounting for regional flow heterogeneity, permeation of cell membranes and through interendothelial clefts, and intracellular reactions. Serotonin uptake data from the Multiple indicator dilution "bolus sweep" experiments of Rickaby and coworkers (Rickaby DA, Linehan JH, Bronikowski TA, Dawson CA. J Appl Physiol 51: 405-414, 1981; Rickaby DA, Dawson CA, and Linehan JH. J Appl Physiol 56: 1170-1177, 1984) and Malcorps et al. (Malcorps CM, Dawson CA, Linehan JH, Bronikowski TA, Rickaby DA, Herman AG, Will JA. J Appl Physiol 57: 720-730, 1984) were analyzed to distinguish facilitated transport into the endothelial cells (EC) and the inhibition of tracer transport by nontracer serotonin in the bolus of injectate from the free uninhibited permeation through the clefts into the interstitial fluid space. The permeability-surface area products (PS) for serotonin via the inter-EC clefts were ~0.3 ml.g-1.min-1, low compared with the transporter-mediated maximum PS of 13 ml.g-1.min-1 (with Km = ~0.3 MUM and Vmax = ~4 nmol.g-1.min-1). The estimates of serotonin PS values for EC transporters from their multiple data sets were similar and were influenced only modestly by accounting for the cleft permeability in parallel. The cleft PS estimates in these Ringer-perfused lungs are less than half of those for anesthetized dogs (Yipintsoi T. Circ Res 39: 523-531, 1976) with normal hematocrits, but are compatible with passive noncarrier-mediated transport observed later in the same laboratory (Dawson CA, Linehan JH, Rickaby DA, Bronikowski TA. Ann Biomed Eng 15: 217-227, 1987; Peeters FAM, Bronikowski TA, Dawson CA, Linehan JH, Bult H, Herman AG. J Appl Physiol 66: 2328-2337, 1989) The identification and quantitation of the cleft pathway conductance from these studies affirms the importance of the cleft permeation. PMID- 23645498 TI - The epidemiology of heart failure, based on data for 2.1 million inhabitants in Sweden. AB - AIMS: The epidemiology of congestive heart failure (CHF) is likely to have changed due to changes in demography, risk factors, diagnostic procedures, and medical care. Prevailing information is in part old, incomplete, and to some extent contradictory. We determined the current prevalence, incidence, mortality, and 5-year survival rate of CHF, and possible temporal changes in Sweden. METHODS AND RESULTS: This was a cross-sectional study on individual patient data from an administrative health data register in the Stockholm region, Sweden, comprising 2.1 million inhabitants. This contained all recorded diagnoses on all consultations in primary and secondary care (defined as specialist outpatient care), and on all hospitalizations. Prevalence, incidence, and mortality were estimated for the entire Swedish population, adjusted for demographic composition in 2010. The study population consisted of 88 038 patients (51% women). The prevalence was 2.2% (both women and men), the incidence was 3.8/1000 person-years (both women and men), and mortality was 3.2/1000 person-years in women and 3.0/1000 person-years in men (P < 0.001); the 5-year survival rate was 48%. Mortality (age adjusted; hazard ratio and 95% confidence intervals) was higher in men, 1.29, 1.24-1.34; P < 0.001. Prevalence remained essentially unchanged from 2006 to 2010, while incidence decreased by 24% (P < 0.001) and mortality by 19% (both women and men; P < 0.001). CONCLUSIONS: The estimated prevalence of CHF in Sweden is 2.2%, incidence 3.8/1000 person-years, and mortality 3.1/1000 person years. There has been a decrease in incidence and mortality from 2006 to 2010 in both women and men, with no major change in prevalence over time. PMID- 23645499 TI - Central sleep apnoea and inflammation are independently associated with arrhythmia in patients with heart failure. AB - AIMS: We examined whether the severity of central sleep apnoea (CSA) and the level of C-reactive protein are associated with the prevalence and complexity of arrhythmias, and whether these factors contribute to increased risk of nocturnal sudden death. METHODS AND RESULTS: We prospectively examined 178 patients (age 70 +/- 1 years) who were admitted to our hospital due to worsening heart failure. We recorded a simultaneous overnight cardiorespiratory polygraph and Holter ECG. Obstructive sleep apnoea was excluded and patients were dichotomized based on the median value of the central apnoea index (CAI) of 7.5/h. The prevalence and complexity of arrhythmias were compared between daytime (06:00 h to 15:00 h) and night-time (21:00 h to 06:00 h). A multivariate logistic regression analysis revealed that the CAI was associated with prevalence of atrial fibrillation (AF) [odds ratio 1.03, 95% confidence interval (CI) 1.02-2.51)] and sinus pause during the night-time period (1.12, 95% CI 1.08-1.35). The CAI and C-reactive protein were independently associated with non-sustained ventricular tachycardia during both daytime (1.22, 95% CI 1.00-6.92; and 5.82, 2.58-56.1, respectively) and night-time periods (3.57, 95% CI 1.06-13.1; and 10.7, 3.30-44.4, respectively). During a mean follow-up period of 22 months, 30 (17%) patients had cardiovascular deaths and the CSA was an independent predictor (hazard ratio 1.29, 95% CI 1.16 2.32); only 5 (2.8%) of them died due to ventricular tachyarrhythmia, occurring during wakefulness. CONCLUSIONS: We demonstrated that the severity of CSA and C reactive protein levels are independently associated with the prevalence and complexity of arrhythmias. CSA was associated with increased mortality risk, but it was not related directly to nocturnal death due to ventricular tachyarrhythmia. PMID- 23645497 TI - Oncogenic H-ras reprograms Madin-Darby canine kidney (MDCK) cell-derived exosomal proteins following epithelial-mesenchymal transition. AB - Epithelial-mesenchymal transition (EMT) is a highly conserved morphogenic process defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. EMT is associated with increased aggressiveness, invasiveness, and metastatic potential in carcinoma cells. To assess the contribution of extracellular vesicles following EMT, we conducted a proteomic analysis of exosomes released from Madin-Darby canine kidney (MDCK) cells, and MDCK cells transformed with oncogenic H-Ras (21D1 cells). Exosomes are 40-100 nm membranous vesicles originating from the inward budding of late endosomes and multivesicular bodies and are released from cells on fusion of multivesicular bodies with the plasma membrane. Exosomes from MDCK cells (MDCK-Exos) and 21D1 cells (21D1-Exos) were purified from cell culture media using density gradient centrifugation (OptiPrepTM), and protein content identified by GeLC-MS/MS proteomic profiling. Both MDCK- and 21D1-Exos populations were morphologically similar by cryo-electron microscopy and contained stereotypical exosome marker proteins such as TSG101, Alix, and CD63. In this study we show that the expression levels of typical EMT hallmark proteins seen in whole cells correlate with those observed in MDCK- and 21D1-Exos, i.e. reduction of characteristic inhibitor of angiogenesis, thrombospondin-1, and epithelial markers E-cadherin, and EpCAM, with a concomitant up-regulation of mesenchymal makers such as vimentin. Further, we reveal that 21D1-Exos are enriched with several proteases (e.g. MMP-1, -14, -19, ADAM-10, and ADAMTS1), and integrins (e.g. ITGB1, ITGA3, and ITGA6) that have been recently implicated in regulating the tumor microenvironment to promote metastatic progression. A salient finding of this study was the unique presence of key transcriptional regulators (e.g. the master transcriptional regulator YBX1) and core splicing complex components (e.g. SF3B1, SF3B3, and SFRS1) in mesenchymal 21D1-Exos. Taken together, our findings reveal that exosomes from Ras-transformed MDCK cells are reprogrammed with factors which may be capable of inducing EMT in recipient cells. PMID- 23645500 TI - To assess exertional breathlessness you must exert the breathless. PMID- 23645501 TI - GmTMT2a from soybean elevates the alpha-tocopherol content in corn and Arabidopsis. AB - Tocochromanol, or vitamin E, plays a crucial role in human and animal nutrition and is synthesized only by photosynthetic organisms. gamma-Tocopherol methyltransferase (gamma-TMT), one of the key enzymes in the tocopherol biosynthetic pathway in plants, converts gamma, delta-tocopherols into alpha-, beta-tocopherols. Tocopherol content was investigated in 15 soybean cultivars and GmTMT2 was isolated from five varieties based on tocopherol content. GmTMT2a was expressed in E. coli and the purified protein effectively converted gamma tocopherol into alpha-tocopherol in vitro. Overexpression of GmTMT2a enhanced alpha-tocopherol content 4-6-fold in transgenic Arabidopsis, and alpha-tocopherol content increased 3-4.5-fold in transgenic maize seed, which correlated with the accumulation of GmTMT2a. Transgenic corn that is alpha-tocopherol-rich may be beneficial for animal health and growth. PMID- 23645502 TI - Production of laccase and manganese peroxidase by Pleurotus pulmonarius in solid state cultures and application in dye decolorization. AB - The production of ligninolytic enzymes (laccase and Mn-dependent peroxidase) by the white-rot fungus Pleurotus pulmonarius (FR.) Quelet was studied in solid state cultures using agricultural and food wastes as substrate. The highest activities of laccase were found in wheat bran (2,860 +/- 250 U/L), pineapple peel (2,450 +/- 230 U/L), and orange bagasse (2,100 +/- 270 U/L) cultures, all of them at an initial moisture level of 85 %. The highest activities of Mn peroxidase were obtained in pineapple peel cultures (2,200 +/- 205 U/L) at an initial moisture level of 75 %. In general, the condition of high initial moisture level (80-90 %) was the best condition for laccase activity, while the best condition for Mn peroxidase activity was cultivation at low initial moisture (50-70 %). Cultures containing high Mn peroxidase activities were more efficient in the decolorization of the industrial dyes remazol brilliant blue R (RBBR), Congo red, methylene blue, and ethyl violet than those containing high laccase activity. Also, crude enzymatic extracts with high Mn peroxidase activity were more efficient in the in vitro decolorization of methylene blue, ethyl violet, and Congo red. The dye RBBR was efficiently decolorized by both crude extracts, rich in Mn peroxidase activity or rich in laccase activity. PMID- 23645503 TI - Evaluation of the strain identity between isolates from caries lesions and root canals in early childhood caries cases. AB - Early childhood caries (ECC) has become a serious medical problem worldwide in the last decade. Bacterial microflora of the dental plaque and oral cavity is considered an important factor in the formation and progression of dental caries. The aim of this study was strain typing and comparison of bacterial isolates retrieved from caries lesions and root canal contents of the same teeth. In total, 18 pairs of presumptive streptococci and lactobacilli retrieved from dental caries and root canals isolated from ECC-affected children, were selected on the basis of biotyping results and rep-PCR fingerprinting with (GTG)5 primer. Strain typing was further done using the RiboPrinter microbial characterization system (DuPont Qualicon). The automated ribotyping determined 14 pairs of the strains (77.8 %) to be identical. The results obtained confirmed that identical bacterial strains colonized both the decayed dental surface and the necrotic content of the dental pulp cavity during the cariogenesis. Our finding supports the assumption that bacteria could penetrate through the damaged dental surface to the inner parts of the teeth. PMID- 23645504 TI - Pulsed dye laser in the treatment of localized scleroderma and its effects on CD34+ and factor XIIIa+ cells: an immunohistochemical study. AB - BACKGROUND: Localized scleroderma (morphea) is characterized by hardening and thickening of the dermis due to excessive collagen deposition. A decreased number of CD34+ cells and an increased number of Factor XIIIa+ cells are seen in the affected skin. The flashlamp pulsed dye laser (FLPDL) has been used in the treatment of localized morphea with promising results. OBJECTIVE: The purpose of this study was to evaluate the therapeutic effectiveness of the pulsed dye laser in localized scleroderma and to assess its effect on CD34+ cells, Factor XIIIa+ cells, and blood vessels. STUDY DESIGN: Thirty patients with plaque morphea were treated with a FLPDL (585 nm wavelength, 450 MUs pulse duration). Fluence ranged from 7.5 to 8.5 J/cm(2). Sessions were performed biweekly for a maximum of 6 months. Clinical, histopathologic, and immunohistochemical assessments were performed. RESULTS: Patients showed varying degrees of improvement of indurated skin. There was no worsening or further improvement at the treated sites during the follow-up assessments at 3, 6, and 12 months. An increased number of CD34+ cells were found in both the upper and the lower dermis, and a decreased number of Factor XIIIa+ cells were found in the lower dermis. CONCLUSION: The FLPDL is effective in the treatment of morphea, as confirmed by the changes in the pathologic tissue and levels of CD34+ and Factor XIIIa+ cells. PMID- 23645505 TI - Hazardous alcohol consumption is associated with increased levels of B-type natriuretic peptide: evidence from two population-based studies. AB - Russia has very high mortality from cardiovascular disease (CVD), with evidence that heavy drinking may play a role. To throw further light on this association we have studied the association of alcohol with predictors of CVD risk including B-type natriuretic peptide (BNP). Levels of BNP increase primarily in response to abnormal cardiac chamber wall stretch which can occur both as a result of atherosclerosis as well as due to other types of damage to the myocardium. No previous population-based studies have investigated the association with alcohol. We analysed cross-sectional data on drinking behaviour in 993 men aged 25-60 years from the Izhevsk Family Study 2 (IFS2), conducted in the Russian city of Izhevsk in 2008-2009. Relative to non-drinkers, men who drank hazardously had an odds ratio (OR) of being in the top 20 % of the BNP distribution of 4.66 (95 % CI 2.13, 10.19) adjusted for age, obesity, waist-hip ratio, and smoking. Further adjustment for class of hypertension resulted in only slight attenuation of the effect, suggesting that this effect was not secondary to the influence of alcohol on blood pressure. In contrast hazardous drinking was associated with markedly raised ApoA1 and HDL cholesterol levels, but had little impact on levels of ApoB and LDL cholesterol. Similar but less pronounced associations were found in the Belfast (UK) component of the PRIME study conducted in 1991. These findings suggest that the association of heavy drinking with increased risk of cardiovascular disease may be partly due to alcohol-induced non-atherosclerotic damage to the myocardium. PMID- 23645509 TI - The prevalence of psychiatric disease in emergency department patients with unexplained syncope. AB - Current data suggest that up to 60 % of patients presenting to the emergency department with syncope leave the hospital without a defined etiology. Prior studies suggest a prevalence of psychiatric disease as high as 26 % in patients with syncope of unknown etiology. The objective of this study was to determine whether psychiatric disease is associated with an increased incidence of syncope of unknown etiology. Prospective, observational, cohort study of consecutive ED patients >18 presenting with syncope was conducted from 6/03 to 7/06. Patients were queried in the ED and charts reviewed for a history of psychiatric disease and use of psychiatric medication. Data were analyzed using SAS v9.2 with Fisher's exact tests. We enrolled 518 patients who presented to the ED after syncope, 161 (31 %) did not have an identifiable etiology for their syncopal event; 166 patients (32 %) had a history of or current psychiatric disease. Among men with psychiatric disease, 37 % had an unknown etiology of their syncopal event, compared to 23 % of men without psychiatric disease (p = 0.04). However, among women with syncope of unknown etiology, there was no significant difference between those with and without psychiatric disease (34.4 vs. 32.7 %) with p = 0.77. Our results suggest that men with psychiatric disease have an increased incidence of syncope of unknown etiology. Given this relationship, clinicians might consider screening for psychiatric disorders in syncopal patients when no clear etiology can be identified. PMID- 23645508 TI - COPD patients with and without metabolic syndrome: clinical and functional differences. AB - Chronic obstructive pulmonary disease (COPD) and the metabolic syndrome (MetS) are considered public health challenges of the 21st century. The coexistence of MetS in COPD patients and any clinical differences between COPD patients with and without MetS have not been extensively studied. We aimed to describe the clinical characteristics of patients with MetS and COPD. An observational, multicenter study of 375 patients hospitalized for a COPD exacerbation with spirometric confirmation was performed. We measured the components of the MetS and collected comorbidity information using the Charlson index and other conditions. Dyspnea, use of steroids, exacerbations, and hospitalizations were also investigated. The overall prevalence of MetS in COPD patients was 42.9 %, was more frequent in women (59.5 %) than men (40.8 %), p = 0.02, but with no differences in age and smoking history. COPD patients with MetS had greater % predicted FEV1, more dyspnea, and more comorbidity and used more inhaled steroids (all p < 0.05). Diabetes, osteoporosis, coronary artery disease, and heart failure were more frequent in patients with MetS. They had been hospitalized more frequently for any cause but not for COPD. In multivariate analysis, the presence of MetS was independently associated with greater FEV1, inhaled steroids use, osteoporosis, diabetes, and heart failure. MetS is a frequent condition in COPD patients, and it is associated with greater FEV1, more dyspnea, and more comorbidities. PMID- 23645510 TI - A man with drug-induced psychosis attempts to swallow his cellular phone. PMID- 23645511 TI - A device for continuous monitoring of true central fixation based on foveal birefringence. AB - A device for continuous monitoring of central fixation utilizes birefringence, the property of the Henle fibers surrounding the human fovea, to change the polarization state of light. A circular scan of retinal birefringence, where the scanning circle encompasses the fovea, allows identification of true central fixation-an assessment much needed in various applications in ophthalmology, psychology, and psychiatry. The device allows continuous monitoring for central fixation over an extended period of time in the presence of fixation targets and distracting stimuli, which may be helpful in detecting attention deficit hyperactivity disorder, autism spectrum disorders, and other disorders characterized by changes in the subject's ability to maintain fixation. A proof of-concept has been obtained in a small study of ADHD patients and normal control subjects. PMID- 23645512 TI - The Stochastic Component of the Postural Sway Variability is Higher in Children with Balance Impairments. AB - Children with balance impairments have an increased amount of variability in the sway of the center of pressure (COP) during standing. Limited efforts have been made to quantify the nature of the variability. This exploratory investigation examined the deterministic and stochastic features that comprise the time dependent postural sway variability during standing. We measured the COP in standing of a heterogeneous group of children with balance impairments and an age matched cohort of typically developing children, both with and without vision. The standard deviation of the COP was used to quantify the amount of variability present in the postural sway. A Langevin equation methodology was additionally employed to reconstruct the deterministic and stochastic features that comprised the postural sway variability. Our experiment resulted in three key findings: (1) removal of visual information increased the stochastic features of the postural sway variability, (2) the stochastic features were greater for the children with balance impairments, (3) the change in the amount of variability was strongly correlated with change the stochastic features. These results imply that the inability to suppress the stochastic features present in the nervous system may play a prominent role in the balance problems of children. Moreover, our results imply that alterations in the stochastic features drive the postural system away from successful balance strategies. PMID- 23645513 TI - Genetics and non-genetics parameters of body weight for post-weaning traits in Raini Cashmere goats. AB - Genetic parameters were estimated for 6-month weight (W6), 9-month weight (W9), 12-month weight (W12), average daily gain from birth to 6 months old (ADG6), and Kleiber ratio at 6 months (KL6) traits using 6,442 records obtained from a Raini Cashmere goat flock. The parameters were estimated using the restricted maximum likelihood procedure and applying four animal models excluding or including maternal additive genetic and permanent environmental effects. Heritability estimates for W6, W9, W12, ADG6, and KL6, under the most appropriate model were 0.028, 0.26, 0.29, 0.02, and 0.25, respectively. The estimates of genetic and phenotypic correlations among W6, W9, W12, and ADG6 were high and ranged from 0.73 to 0.99. The estimates of genetic and phenotypic correlations among KL6 and others traits were negative and low. Thus, these estimates of genetic parameters may provide a basis for deriving selection indices for postweaning growth traits also low genetic correlation between growth traits with KL6, it is possible to increase efficiency in Raini kids by multitrait selection. PMID- 23645514 TI - Influence of colostral quality on serum proteins in dairy calves raised in smallholder farms in Thailand. AB - The objective of this study was to analyze the influence of colostral quality on serum proteins in calves. Samples were collected from visited farms in Kasetsart University Veterinary Teaching Hospital at Kamphaeng Saen and Nong Pho Animal Hospital. In total, 35 dairy farms contributed 80 dams and calves' samples. Colostrum samples from 80 dairy cows and blood samples from their calves were taken to evaluate colostral immunoglobulins (Ig) and immunoglobulin G (IgG), and calf serum protein and IgG. Total colostral Ig, colostral and serum IgG, and serum protein were measured by a colostrometer, single radial immunodiffusion, and refractrometer, respectively. Immunoglobulin G and serum protein concentrations increased in the 1st day after birth, and maximum concentrations were seen in the 2nd day and then decreased in the 7th and 14th days. Average +/- SD total colostral IgG concentrations at calving date and at 1 and 2 days after calving were 93.85 +/- 33.89, 37.11 +/- 23.51, and 17.23 +/- 9.4 mg/mL, respectively. The profile of total Ig and IgG concentrations in colostrum had a similar pattern, with the maximum concentrations obtained in calving date and rapidly decreased thereafter. Low IgG concentrations were seen in the 7th and 14th day after calving. The calves that were fed with high quality colostrum had higher serum protein at 1 day of age, 7.49 +/- 1.01 g/dL, than calves fed with low quality colostrum, 6.40 +/- 0.86 g/dL (P < 0.01). The increase in serum protein after first colostrum feeding of high and low quality colostrum was 1.55 +/- 1.07 and 0.81 +/- 0.69 g/dL, respectively (P = 0.02). PMID- 23645515 TI - Antibodies to Schmallenberg virus in domestic livestock in Turkey. AB - This, partly retrospective study, was designed to determine the seroprevalence of Schmallenberg virus (SBV), a new Orthobunyavirus first reported in Germany in late 2011, in domestic ruminants from the Middle Black Sea, West, and Southeast regions of Turkey. An indirect enzyme-linked immunosorbent assay was used to screen serum samples collected from slaughterhouse animals between 2006 and 2013. The overall seroprevalence was 335/1,362 (24.5 %) with 325/816 (39.8 %), 5/307 (1.6 %), 3/109 (2.8 %), and 2/130 (1.5 %) recorded in cattle, sheep, goats, and Anatolian water buffalo, respectively. This is the first study to demonstrate the presence of antibodies to SBV in Turkish ruminants; it indicates that cattle are more susceptible to infection than sheep, goats, or buffalo and that exposure of domestic ruminants to SBV in Turkey may have occurred up to 5 years prior to the first recorded outbreak of the disease in 2011. PMID- 23645516 TI - An analysis of the epidemiological and etiological factors of oral tumors of young adults in a Central-Eastern European population. AB - The etiology of tumors in young age is not precisely known yet, but studies on the topic generally agree that in this group of patients the traditionally known behavioural risk factors (tobacco and alcohol abuse) play no or a significantly less important role. Oral squamous cell carcinoma occurring at a young age is a topic of utmost importance that is extensively and intensively researched as, while the overall incidence of oral cancer is decreasing worldwide, that of squamous cell carcinoma diagnosed in young adults is steadily increasing. The present article aims at presenting the main questions and characteristics of tumors in young adults in Central-Eastern Europe and in developed West European countries as contrasted to tumors found in middle aged and elderly patients. Factors influencing the development of oral cancer include regulatory factors of the cell cycle, the inherited vulnerability of the genetic code of certain proteins and the presence of HPV infection with an oncogenic genotype. The connections of HPV infection and genetic damages are studied intensively. It is known that the prevalence of oral HPV infections is growing with a background of potentially changing sexual habits. It is debated, however, whether smoking and alcohol consumption could have a connection to HPV associated oral cancer and whether the spread of HPV in itself could be an explanation for the growing occurrence of young-age tumors. There is no consensus in the literature as to the prognostic significance of age. Some research groups have found a better life expectancy for young patients, while other authors found a worse prognosis for these patients. It is known that the prognosis of head and neck tumors, the prevalence of HPV infections as well as genetic mutations show regional and ethnic variations. This might be explained by differences in the degree of development of a preventive system, in the quality of care and in the attitudes of young patients towards visiting a doctor. The study is made difficult by incomparable patient selection criteria as well as by the question of the intraoral localisation of tumors as an independent risk factor. PMID- 23645517 TI - Molecular profiling of ADAM12 and ADAM17 genes in human malignant melanoma. AB - ADAM12 and ADAM17 proteins belong to a family of transmembrane disintegrin containing metalloproteinases (ADAMs) involved in the proteins ectodomain shedding and cell-cell and cell-matrix interactions. However, the specific biological functions of ADAMs are still unclear and, until now, these proteins were not investigated yet in melanoma. The aim of this study was to analyze the splicing variants of ADAM12 (L and S) and ADAM17 gene expression in melanoma at transcriptional and translational level in comparison with control (non-tumor) tissues. Taking in account that ADAM17 sheddase is involved in the modulation of TNF-alpha (tumor necrosis factor alpha), we analyzed also this cytokine in the plasma of the same patients before any treatment, and we compared the results with healthy controls. Quantitative-RT-PCR and immunohistochemistry were used to analyze ADAM12 and ADAM17 genes expression and the analysis of TNF-alpha expression was carried out in the plasma using ELISA. We demonstrated that ADAM12L splicing variant together with ADAM17 gene are strongly overexpressed in melanomas, whereas ADAM12S, although up-regulated when compared with the non tumor controls, the difference was not statistically significant. When we compared the levels of expression for the ADAMs genes according to the tumor stage, we observed that all three investigated genes were significantly overexpressed in advanced stage in comparison with early stage melanomas. In the plasma of the same patients, the expression of TNF-alpha was up-regulated and significantly correlated with the expression of ADAM17 and respectively, with the advanced tumor stage. PMID- 23645520 TI - New anti-rebate legislation in South Korea. AB - The South Korean Government recently announced a reform in the drug anti-rebate law, with the purpose of eradicating pervasive, unethical, and illegal rebate practices in pharmaceutical marketing. The main objective of this reform is to have the ability to bring criminal charges against doctors and pharmacists for receiving illegal kickbacks from drug companies. Previously, provision of illegal kickbacks by drug companies led to criminal punishment of the drug companies alone, leaving doctors and pharmacists unpunished as the recipients. With the introduction of the "Dual Punishment System (DPS)" reform, criminal punishment for illegal rebates is extended to those receiving illegal kickbacks. Although bitter controversy erupted among stakeholders when the reform was first drafted, a civic group participated in the reform process and effectively influenced the legislative process to a successful end. Some interim outcomes from the DPS in terms of bringing illegal practices to account have already been reported since the policy's implementation in November 2010. The reform background, goals, potential issues, and policy implications are explored in this study with the objective of providing further insight into drug policy for other countries that face similar challenges in the area of drug marketing. PMID- 23645521 TI - The role of financial wellbeing, sociopolitical attitude, self-interest, and lifestyle in one's attitude toward social health insurance. AB - BACKGROUND: There has been continuous debate in the United States, Germany, and China about their respective healthcare systems. While these three countries are dealing with their own unique problems, the question of how social a healthcare system should be is a topic in this debate. OBJECTIVE: This study examined how strongly college students' attitudes toward a social healthcare system relate to ideological orientation and self-interest. METHODS: We used samples of college students in the People's Republic of China, Germany, and the US, and extracted factors measuring "financial wellbeing," "sociopolitical attitude," "self interest," and "lifestyle" to explain the "attitude toward social health insurance" (ASHI) construct developed in recent literature (Loh et al. in Eur J Health Econ 13:707-722). RESULTS: The results of regression analysis showed that sociopolitical attitude/progressivism is positively related to the ASHI, but the degree of association varies considerably from country to country. We also found that a self-interest factor, measured by health status, seems to be inversely related to an individual's ASHI in the US, but not in China or Germany. Individuals with relatively healthy lifestyle choices were less likely to have a favorable ASHI in Germany, but no such relationship was found in China and the US. These results indicate that while some commonalities exist, there are also considerable differences in the structure of ASHI across these three countries. CONCLUSION: Ultimately, the results reported here could help to develop a predictive model that can be utilized to forecast a country's ASHI. Such a predictive model could be used by politicians to gauge the popularity of a healthcare plan that is under consideration in a particular country. PMID- 23645518 TI - Tumor-related gene changes in immunosuppressive Syrian hamster cholangiocarcinoma. AB - The results of a previous study demonstrated that prednisolone enhanced cholangiocarcinogenesis. Therefore, to clarify molecular changes during immunosuppressive cholangiocarcinogenesis, Syrian hamsters were divided into 8 groups: uninfected controls; immunosuppressed Syrian hamsters using prednisolone (P); normal Syrian hamsters administered N-nitrosodimethylamine (ND); immunosuppressed Syrian hamsters administered N-nitrosodimethylamine (NDis); normal Syrian hamsters infected with Opisthorchis viverrini (OV); immunosuppressed Syrian hamsters infected with O. viverrini (OVis); normal Syrian hamsters infected with O. viverrini and administered N-nitrosodimethylamine (CCA); and immunosuppressed Syrian hamsters infected with O. viverrini and administered N-nitrosodimethylamine (CCAis). Syrian hamster livers were used for analysis of tumor-related gene expression and immunohistochemistry through cytokeratin 19 (CK19) and proliferating cell nuclear antigen (PCNA) staining. The tumor-related gene expression results show that CCAis groups at all time points exhibited upregulation of COX-2, IL-6, SOD1, CAT and iNOS and downregulation of p53, which correlated with the predominant expression of CK19 and PCNA in liver tissue. These results suggest that prednisolone enhances cholangiocarcinoma development, which was confirmed by molecular changes. PMID- 23645522 TI - Screening for new primary cancers in cancer survivors compared to non-cancer controls: a systematic review and meta-analysis. AB - PURPOSE: The goal of this study was to synthesize evidence comparing cancer screening receipt between cancer survivors and non-cancer controls by conducting a systematic review and meta-analysis. METHODS: We searched PubMed, EMBASE, and CINAHL databases from inception through April 1, 2010 using search terms related to cancer, survivorship, and cancer screening. Studies were included if they reported a comparison of cancer screening receipt between cancer survivors and non-cancer controls. We performed a meta-analysis on the effect of cancer survivorship on breast, cervical, colorectal, and prostate cancer screening receipt. RESULTS: Our search strategy identified 1,778 titles, of which 20 met our inclusion/exclusion criteria. In our meta-analyses, cancer survivors were more likely to be screened for breast, cervical, colorectal, and prostate cancer than non-cancer controls (pooled odds ratio, 1.27; 95 % CI, 1.19-1.36). We observed significant heterogeneity between studies, most of which remained unexplained after subgroup and sensitivity analyses. Important contextual factors, such as how screening programs operate, were not reported in the primary literature. Many cancer survivors (along with non-cancer controls) still did not receive cancer screening. CONCLUSION: Compared with non-cancer controls, cancer survivors receive more frequent screening for new primary breast, cervical, colorectal, and prostate cancers. Future research should seek to determine whether increased uptake of cancer screening is associated with improved outcomes during cancer survivorship. IMPLICATIONS FOR CANCER SURVIVORS: Our systematic review and meta-analysis demonstrated that cancer survivors received more frequent screening for second primary breast, cervical, colorectal, and prostate cancers than non-cancer controls. As many cancer survivors are at an increased risk of developing a second primary cancer, future research should seek to determine whether this increased uptake of cancer screening in cancer survivors leads to improved outcomes during cancer survivorship. PMID- 23645524 TI - Forthcoming practical framework for ethics committees and researchers on post trial access to the trial intervention and healthcare. PMID- 23645523 TI - Diagnostic biomarkers of differentiated thyroid cancer. AB - The incidence of thyroid cancer has been increasing all around the world in the past decades. Early detection is one of the keys to reduce the mortality. Currently, fine-needle aspiration (FNA) guides the management of patients with a thyroid nodule. The use of FNA can reduce unnecessary thyroid surgery by twenty five percent. However, the prevalence of non-diagnostic and indeterminate cytology from FNA is still high, approximately thirty percent. Many biomarkers were developed to differentiate between the benign and malignant thyroid nodule. This review summarizes each diagnostic biomarker of differentiated thyroid cancer. Sensitivity, specificity, and positive and negative predictive values of individual cytological laboratory need to be considered before implementation of each biomarker. Moreover, follow-up is still mandatory in negative biomarker tests because all genomic and proteomic alterations in thyroid cancer are still unknown. PMID- 23645525 TI - Rape, consent and intoxication: a legal practitioner's perspective. PMID- 23645526 TI - Diagnostic laparoscopy in the era of modern imaging--retrospective analysis from a single center. AB - INTRODUCTION: A retrospective analysis of utility and outcomes of diagnostic laparoscopy at our center in the last 5 years was done. MATERIAL AND METHODS: In the last 5 years, we subjected 90 patients to diagnostic laparoscopy (DL) when final diagnosis could not be achieved after all necessary imaging methods and serological, cytological, and microbiological investigations. DL was performed under sedation and local anesthesia, and patients were discharged within 24 h. Video documentation along with guided biopsies/collection of the samples for culture and other tests was performed. RESULTS: The commonest indication was ascites (46/90), followed by diffuse liver disease (15), focal liver disease (9), intraabdominal malignancies (10), and miscellaneous (10). Overall accuracy of DL was 91 %. In 64 % of patients, laparoscopy confirmed the clinical diagnosis, and in 27 % of patients, laparoscopy was useful in correcting the diagnosis. DL was performed in 46 patients with low-serum ascitic fluid albumin gradient ascites and ascites of mixed etiology. DL confirmed the suspected diagnosis in 48 %, corrected in 38 %, and yielded unsuspected diagnosis in 15 % patients. In 6 % of patients, laparoscopy was inconclusive. In three patients, there were extensive intraperitoneal adhesions, and adequate examination was not possible. No serious complications were encountered. Minor complications of pain at the port site, ascitic fluid leakage, and port site infection were seen in three, two, and one patient, respectively. CONCLUSION: DL is useful in patients when diagnosis and extent of the disease were unclear especially in ascites of undetermined etiology. PMID- 23645527 TI - Renoprotective effect of Alpiniae oxyphyllae Fructus on ischemia/reperfusion induced acute renal failure. AB - The present study was designed to examine whether water extract of Alpiniae oxyphyllae Fructus (AAO) has an effect on renal functional parameters in association with the expression of water channels and sodium potassium pump in ischemia/reperfusion-induced acute renal failure (ARF). Polyuria caused by down regulation of renal AQP-2, 3 in the ischemia/reperfusion-induced ARF rats was markedly restored by administration of AAO (200 mg/kg/day p.o.) with restoring expression of AQP-2, 3 in the kidney. The expression of Na,K-ATPase alpha1 subunit was also restored in the ischemia/reperfusion-induced ARF rat by administration of AAO. The renal functional parameters including urinary sodium excretion, urinary osmolality, and solute-free reabsorption were also markedly restored in ischemia-ARF rats by administration of AAO. In histopathologic study, administration of AAO improved tubular damage such as necrosis of tubular segment. Ischemia/reperfusion-induced ARF decreased the expressions of AQP-2, 3, and Na,K-ATPase in renal medulla. However, administration of AAO markedly restored the expression levels of AQP-2, 3 and Na,K-ATPase. Taken together, the present study suggested that A. oxyphyllae ameliorates the urine concentration and renal functions in ischemia/reperfusion-induced ARF, through the restoring of AQP-2, 3 and Na,K-ATPase. PMID- 23645528 TI - Caffeic acid-conjugated chitosan derivatives and their anti-tumor activity. AB - In this study, we synthesized caffeic acid (CFA)-conjugated chitosan (ChitoCFA) as an anti-cancer compound. CFA was conjugated to the amine groups of chitosan (ChitoCFA) and its chemical composition was confirmed using (1)H nuclear magnetic resonance spectra, which indicates that specific peaks of CFA was observed at ChitoCFA conjugates. The anti-cancer effects of CFA and ChitoCFA were studied using CT26 colorectal carcinoma cells. In this cytotoxicity study, CFA and ChitoCFA revealed a dose-dependent decrease of cell viability while chitosan had lower cytotoxicity against tumor cells. CFA and ChitoCFA also proved an anti proliferative effect against tumor cells. In comparison with CFA, ChitoCFA may accelerate an apoptosis of tumor cells. Furthermore, ChitoCFA demonstrated good anti-invasive efficacy at Matrigel((r)) invasion assay against tumor cells. We suggest that ChitoCFA is a promising candidate as an anti-cancer compound. PMID- 23645529 TI - Advanced techniques for chronic lead extraction: heading from the laser towards the evolution system. AB - AIM: The evolution mechanical dilator sheath has been reported to be an effective tool for chronic lead extraction (LE). We examined safety and efficacy of evolution system as compared with laser system. METHODS AND RESULTS: From 2005 to 2009, all extractions requiring the use of a powered sheath were performed using the excimer laser system (n = 73). Since 2009, laser system was no longer available and the evolution system was introduced as the first-line method for powered extraction (n = 48). All procedures were performed by a single first operator. Success and complications were defined according to the current guidelines. Patients of the evolution group compared with those of the laser group had a greater number of extracted leads per patient (2.77 vs. 2.4, P = 0.049) and a longer implant duration (101.1 vs. 62.4 months, P = 0.001). Additional use of snare was required in 27.1% of the evolution group and 8.2% of the laser group (P = 0.005). Complete procedural success was achieved in 91.7% of the evolution group and 97.3% of the laser group (P = 0.16). There was also no difference between evolution and laser groups in clinical success (97.9 vs. 98.6%, P = 0.76), as well as regarding major (4.2 vs. 2.7%, P = 0.66) or minor complications (4.2 vs. 5.5%, P = 0.76). CONCLUSION: Use of the recently introduced evolution system for LE exhibit acceptably high levels of safety, as well as of procedural and clinical success, although additional use of snare was required more frequently in the evolution compared with the laser group. PMID- 23645531 TI - Heavy metal enrichment in surface sediments from the SW Gulf of Mexico. AB - The south west coastal zone in the Gulf of Mexico is an area with great industrial and agricultural development, which experiences intensive prospecting and extraction of hydrocarbons. After running through industrial, agricultural, and urban areas, waters from both the Jamapa River and La Antigua River arrive here. The rivers' discharge areas of influence were estimated considering the textural and chemical composition of the supplied sediments. The main factors that determine sediment distribution were mineralogy, heavy minerals, carbonates, and anthropic contributions. The presence of metals in excess was evaluated using various pollution indicators, such as the enrichment factor, contamination factor, modified contamination factor, and geo-accumulation indexes. Data from different used contamination indexes show metal enrichments in As, Cu, Zn, Co, Cr, and V in La Antigua; As, Cu, and Cr in Jamapa; and As, Zn, and Pb in the Continental slope area. The adverse effects of metals on aquatic organisms were assessed using sediment quality guidelines that show Ni, As, Cu, and Cr may produce adverse effects on coastal areas. There was no evidence of contamination associated to the oil industry. PMID- 23645530 TI - The quality of quality measures: HEDIS(r) quality measures for medication management in the elderly and outcomes associated with new exposure. AB - BACKGROUND: Clinical validation studies of the Healthcare Effectiveness Data and Information Set (HEDIS(r)) measures of inappropriate prescribing in the elderly are limited. OBJECTIVES: The objective of this study was to examine associations of new exposure to high-risk medication in the elderly (HRME) and drug-disease interaction (Rx-DIS) with mortality, hospital admission, and emergency care. METHODS: A retrospective database study was conducted examining new use of HRME and Rx-DIS in fiscal year 2006 (Oct 2005-Sep 2006; FY06), with index date being the date of first HRME/Rx-DIS exposure, or first day of FY07 if no HRME/Rx-DIS exposure. Outcomes were assessed 1 year after the index date. The participants were veterans who were >=65 years old in FY06 and received Veterans Health Administration (VA) care in FY05-06. A history of falls/hip fracture, chronic renal failure, and/or dementia per diagnosis codes defined the Rx-DIS subsample. The variables included a number of new unique HRME drug exposures and new unique Rx-DIS drug exposure (0, 1, >1) in FY06, and outcomes (i.e., 1-year mortality, hospital admission, and emergency care) up to 1 year after exposure. Descriptive statistics summarized variables for the overall HRME cohort and the Rx-DIS subset. Multivariable statistical analyses using generalized estimating equations (GEE) models with a logit link accounted for nesting of patients within facilities. For these latter analyses, we controlled for demographic characteristics, chronic disease states, and indicators of disease burden the previous year (e.g., number of prescriptions, emergency/hospital care). RESULTS: Among the 1,807,404 veterans who met inclusion criteria, 5.2 % had new HRME exposure. Of the 256,388 in the Rx-DIS cohort, 3.6 % had new Rx-DIS exposure. Multivariable analyses found that HRME was significantly associated with mortality [1: adjusted odds ratio (AOR) = 1.62, 95 % CI 1.56-1.68; >1: AOR = 1.80, 95 % CI 1.45-2.23], hospital admission (1: AOR = 2.31, 95 % CI 2.22-2.40; >1: AOR = 3.44, 95 % CI 3.06-3.87), and emergency care (1: AOR = 2.59, 95 % CI 2.49-2.70; >1: AOR = 4.18, 95 % CI 3.71-4.71). Rx-DIS exposure was significantly associated with mortality (1: AOR = 1.60, 95 % CI 1.51-1.71; >1: AOR = 2.00, 95 % CI 1.38-2.91), hospital admission for one exposure (1: AOR = 1.12, 95 % CI 1.03 1.27; >1: AOR = 1.18, 95 % CI 0.71-1.95), and emergency care for two or more exposures (1: AOR = 1.06, 95 % CI 0.97-1.15; >1: AOR = 2.0, 95 % CI 1.35-3.10). CONCLUSIONS: Analyses support the link between HRME/Rx-DIS exposure and clinically significant outcomes in older veterans. Now is the time to begin incorporating input from both patients who receive these medications and providers who prescribe to develop approaches to reduce exposure to these agents. PMID- 23645532 TI - Clinical utility of KAP-1 expression in thyroid lesions. AB - Although there are evidences of the involvement of KAP-1 in other tumors, data on differentiated thyroid carcinomas (DTC) are still lacking. We aimed to evaluate KAP-1 clinical utility in the diagnosis and prognosis of DTC. We used both visual immunohistochemistry and a semiquantitative analysis to evaluate KAP-1 expression in 230 thyroid carcinomas and 131 noncancerous thyroid nodules. There were 43 follicular carcinomas (FC) and 187 papillary thyroid carcinomas (PTC), including 130 classic (CPTC), 4 tall cells (TCPTC), and 53 follicular variants (FVPTC). Patients were followed up for 53.8 +/- 41 months. They were classified as free-of disease (142 cases) or poor outcome (25 cases--10 deaths), according to their serum Tg levels and image evidences. KAP-1 was identified in 78 % PTC, 75 % TCPTC, 74 % FC, 72 % FVPTC, 55 % FA, 44 % hyperplasia, and 11 % normal thyroid tissues. A ROC analysis identified malignant nodules with 69 % sensitivity and 75 % specificity, using a cutoff of 73.19. In addition to distinguishing benign from malignant thyroid tissues (p < 0.0001), KAP-1 expression differentiated CPTC from nodular hyperplasia (p < 0.0001), CPTC from FA (p = 0.0028), FVPTC from hyperplasia (p = 0.0039), and FC from hyperplasia (p = 0.0025). Furthermore, KAP 1 was more expressed in larger tumors (>4 cm; p = 0.0038) and in individuals who presented recurrences/metastases (p = 0.0130). We suggest that KAP-1 may help diagnose thyroid nodules, characterize follicular-patterned thyroid lesions, and identify individuals with poor prognosis. PMID- 23645533 TI - CDH5 is specifically activated in glioblastoma stemlike cells and contributes to vasculogenic mimicry induced by hypoxia. AB - BACKGROUND: A proportion of glioblastoma stemlike cells (GSCs) expressing endothelial cell marker CDH5 (vascular-endothelial-cadherin or CD144) can transdifferentiate into endothelial cells and form blood vessels. However, the implications of CDH5 expression in gliomas and how it is regulated in GSCs remain to be clarified. METHODS: The mRNA and protein levels of CDH5 were detected in glioma samples and cultured cell lines, and the prognostic value of the CDH5 expression level for GBM patients was evaluated. Bioinformatics analysis was performed to reveal the potential functional roles of CDH5 in glioblastoma multiforme. Gene knockdown induced by short hairpin RNA, chromatin immunoprecipitation analysis, and a vasculogenic tube formation assay were performed to investigate the relationships among hypoxia, CDH5 expression level, and angiogenesis. RESULTS: CDH5 was overexpressed in gliomas, correlated with tumor grades, and was an independent adverse prognostic predictor for glioblastoma multiforme patients. CDH5 was specifically activated in GSCs but not in non-GSCs or neural stem cells, and CDH5(+) cells could produce xenografts in immunocompromised mice. Bioinformatics analysis demonstrated that CDH5 might interact directly with hypoxia-inducible factor (HIF)2alpha. CDH5 expression was significantly upregulated in GSCs, but not in non-GSCs or normal neural stem cells, under a 1% O2 condition. Both HIF1alpha and HIF2alpha positively regulated CDH5 level in GSCs and could bind to the promoter of CDH5. Furthermore, CDH5 contributed to the vasculogenic mimicry of GSCs, especially under hypoxic conditions. CONCLUSIONS: The specific expression of CDH5 in GSCs may contribute to GSC-derived neovasculogenesis in glioblastoma multiforme, especially under hypoxic conditions, revealing novel tumorigenic mechanisms contributed by GSCs. PMID- 23645534 TI - Magnetic resonance spectroscopy as an early indicator of response to anti angiogenic therapy in patients with recurrent glioblastoma: RTOG 0625/ACRIN 6677. AB - BACKGROUND: The prognosis for patients with recurrent glioblastoma remains poor. The purpose of this study was to assess the potential role of MR spectroscopy as an early indicator of response to anti-angiogenic therapy. METHODS: Thirteen patients with recurrent glioblastoma were enrolled in RTOG 0625/ACRIN 6677, a prospective multicenter trial in which bevacizumab was used in combination with either temozolomide or irinotecan. Patients were scanned prior to treatment and at specific timepoints during the treatment regimen. Postcontrast T1-weighted MRI was used to assess 6-month progression-free survival. Spectra from the enhancing tumor and peritumoral regions were defined on the postcontrast T1-weighted images. Changes in the concentration ratios of n-acetylaspartate/creatine (NAA/Cr), choline-containing compounds (Cho)/Cr, and NAA/Cho were quantified in comparison with pretreatment values. RESULTS: NAA/Cho levels increased and Cho/Cr levels decreased within enhancing tumor at 2 weeks relative to pretreatment levels (P = .048 and P = .016, respectively), suggesting a possible antitumor effect of bevacizumab with cytotoxic chemotherapy. Nine of the 13 patients were alive and progression free at 6 months. Analysis of receiver operating characteristic curves for NAA/Cho changes in tumor at 8 weeks revealed higher levels in patients progression free at 6 months (area under the curve = 0.85), suggesting that NAA/Cho is associated with treatment response. Similar results were observed for receiver operating characteristic curve analyses against 1-year survival. In addition, decreased Cho/Cr and increased NAA/Cr and NAA/Cho in tumor periphery at 16 weeks posttreatment were associated with both 6-month progression free survival and 1-year survival. CONCLUSION: Changes in NAA and Cho by MR spectroscopy may potentially be useful as imaging biomarkers in assessing response to anti-angiogenic treatment. PMID- 23645535 TI - Spontaneous disappearance of coronary pseudoaneurysm due to coronary artery perforation following percutaneous coronary intervention. AB - In recent years, while therapeutic outcome after percutaneous coronary intervention is improving due to the introduction of drug-eluting stent and device development, procedure-related complications including coronary perforation may ineluctably occur though at low-frequency, even if careful manipulations are performed under IVUS guidance. Meanwhile, coronary pseudoaneurysm subsequent to coronary perforation is one of the complications at chronic phase infrequently experienced following percutaneous coronary intervention. To date, the incidence and natural history of pseudoaneurysm following coronary artery perforation remain unclear. We experienced a case with coronary pseudoaneurysm developed 2 weeks after Ellis II-type coronary artery perforation which spontaneously disappeared 4 months later. As the mechanism of disappearance, thrombotic occlusion was confirmed upon intravascular ultrasound. PMID- 23645536 TI - Analysis of the inhibitory activity of Abeliophyllum distichum leaf constituents against aldose reductase by using high-speed counter current chromatography. AB - We isolated five phenolic glycosides (acteoside, eutigoside B, isoacteoside, rutin and cornoside) from Abeliophyllum distichum leaves by high-speed counter current chromatography (HSCCC) using a solvent system of ethyl acetate:n butanol:water (8:0.7:5). We determined the purity of the 5 compounds by high performance liquid chromatography, and confirmed their chemical structures by using nuclear magnetic resonance data. We examined the inhibitory effect of these compounds on rat lens aldose reductase. Among these compounds, acteoside (1) showed the most potent inhibitory effect, with an IC50 value of 1.39 MUM. The inhibitory effect of 1 was 5.0 times greater than that of quercetin (7.05 MUM), which was used as a positive control. These results suggest that acteoside may be a promising agent for the prevention or treatment of diabetic complications. Moreover, HSCCC is a promising method for the isolation and purification of biologically active compounds from natural products. PMID- 23645537 TI - Debunking some judicial myths about epidemiology and its relevance to UK tort law. AB - Due to the limitations of current medical knowledge, claimants in complicated disease litigation often experience difficulties in proving causation. This paper aims to demonstrate that in some instances these difficulties could be overcome through greater use of epidemiological evidence. To encourage greater use of such evidence, it is first of all necessary to address and correct a series of common judicial misconceptions of epidemiology as a scientific discipline. By distinguishing epidemiology from the application of bare statistics, and by explaining that the courts are not automatically bound by an epidemiological result of 51+% to hold that causation has been established, this paper seeks to allay common judicial concerns about epidemiological evidence. It further seeks to demonstrate that the current judicial approach to determining questions of probabilistic causation is fundamentally flawed and that it could be significantly improved through greater use of specialist epidemiological expert witnesses. On the issue of expertise, the paper goes on to highlight the problems associated with the tendency of UK lawyers to turn to clinicians as experts on all matters of biomedical science. PMID- 23645538 TI - Facility characteristics associated with the use of electronic health records in residential care facilities. AB - The integration of electronic health records (EHRs) across care settings including residential care facilities (RCFs) promises to reduce medical errors and improve coordination of services. Using data from the 2010 National Survey of Residential Care Facilities (n=2302), this study examines the association between facility structural characteristics and the use of EHRs in RCFs. Findings indicate that in 2010, only 3% of RCFs nationwide were using an EHR. However, 55% of RCFs reported using a computerized system for one or more (but not all) of the functionalities defined by a basic EHR. Ownership, chain membership, staffing levels, and facility size were significantly associated with the use of one or more core EHR functionalities. These findings suggest that facility characteristics may play an important role in the adoption of EHRs in RCFs. PMID- 23645539 TI - Understanding the cost-effectiveness of influenza vaccination in children: methodological choices and seasonal variability. AB - BACKGROUND: The universal vaccination of children for influenza has recently been recommended in the UK and is being considered in other developed countries. OBJECTIVES: The aim of this study was to explore the potential costs and benefits of childhood influenza vaccination to gain a better understanding of the key drivers of cost-effectiveness. METHODS: As our case study we examined the cost effectiveness of vaccination in Australian schoolchildren using an age-stratified Susceptible Exposed Infectious Recovered model. RESULTS: The results of this study highlight the critical role that methodological choices play in determining the cost-effectiveness of influenza vaccination. These choices include decisions about the structure of the model (including/excluding herd immunity) and what costs and benefits to include in the analysis. In scenarios where herd protection was included we estimated that the program was likely to be cost-effective. The study also illustrates the importance of the inherent seasonal variability of influenza, which can produce counter-intuitive results, with low transmission seasons being easier to control by vaccination but resulting in fewer benefits. CONCLUSIONS: Universal childhood influenza vaccination is likely to be cost effective if a substantial herd protection effect can be achieved by the program. However, it is important that decision makers understand the role of seasonal variability and the impact of alternative methodological choices in economic evaluations of influenza vaccination. PMID- 23645540 TI - Photodynamic therapy in gastroenterology. AB - INTRODUCTION: Photodynamic therapy (PDT) is a minimally invasive and promising new modality to combat cancer. Upon illumination and in the presence of oxygen, the tissue-localized nontoxic sensitizer generates cytotoxic reactive oxygen species, and as a result, the selective destruction of a targeted tumor may be achieved. The major advantages of PDT compared to traditional standard of care for cancer treatment are higher selectivity and lower toxicity. The high degree of selectivity offered by this modality has been applied to cancer diagnosis by fluorescence. PURPOSE: This article is a review the clinical effectiveness of PDT in the treatment of Barrett's esophagus and the following cancers: esophageal, gastric, biliary tract, pancreatic, and colon. This review highlights the clinical responses to PDT and discusses the possibility of enhancing the efficacy of treatment by combination with targeted therapy. PMID- 23645541 TI - Diet supplementation with beta-carotene improves the serum lipid profile in rats fed a cholesterol-enriched diet. AB - The present study investigated the underlying mechanism associated with the hypocholesterolemic activity of beta-carotene by examining its effects on the serum lipid profile, fecal cholesterol excretion, and gene expression of the major receptors, enzymes, and transporters involved in cholesterol metabolism. Female Fischer rats were divided into three groups and were fed either a control or a hypercholesterolemic diet supplemented or not supplemented with 0.2 % beta carotene. After 6 weeks of feeding, blood, livers, and feces were collected for analysis, and quantitative real-time polymerase chain reaction (qRT-PCR) was performed. Dietary supplementation with 0.2 % beta-carotene decreased serum total cholesterol, non-HDL cholesterol, the atherogenic index, and hepatic total lipid and cholesterol contents. These changes were accompanied by an increase in the total lipid and cholesterol contents excreted in the feces. The qRT-PCR analyses demonstrated that the hypercholesterolemic diet promoted a decrease in the gene expression of sterol regulatory element-binding protein 2, 3-hydroxy-3 methylglutaryl CoA reductase, and low-density lipoprotein receptor and an increase in the gene expression of peroxisome proliferator-activated receptor alpha and cholesterol-7a-hydroxylase. The expression of these genes and gene expression of ATP-binding cassette subfamily G transporters 5and 8 were unaffected by beta-carotene supplementation. In conclusion, the decrease in serum cholesterol and the elevation of fecal cholesterol obtained following beta carotene administration indicate that this substance may decrease cholesterol absorption in the intestine and increase cholesterol excretion into the feces without a direct effect on the expression of cholesterol metabolism genes. PMID- 23645542 TI - Prognostic significance of pathologic complete response and Ki67 expression after neoadjuvant chemotherapy in breast cancer. AB - BACKGROUND: Recent studies have indicated that response to chemotherapy and the prognostic impact of a pathologic complete response (pCR) after neoadjuvant chemotherapy differ among breast cancer subtypes. METHODS: Women with Stage I to III breast cancer treated with anthracycline and taxane-based neoadjuvant chemotherapy (four cycles of docetaxel every 3 weeks followed by four cycles of FEC every 3 weeks) between 2006 and 2011 were retrospectively analyzed. Trastuzumab was concurrently added to docetaxel for HER2-positive breast cancer. Expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens. Predictive factors for neoadjuvant chemotherapy and prognosis were analyzed by breast cancer subtype. RESULTS: Of 64 patients, 30 (47 %) were ER-positive (ER+) HER2-negative (HER2-), including eight as luminal A (Ki67 labeling index (LI) <14 %) and 22 as luminal B (Ki67 LI >= 14 %) subtypes, 11 (17 %) were ER+ HER2 positive (HER2+), 12 (19 %) were ER-negative (ER-) HER2+, and 11 (17 %) were ER- HER2-. The clinical response rates were significantly higher in luminal B, ER+ HER2+, and ER- HER2+ subtypes compared with luminal A subtype. Patients whose tumors contained high Ki67 expression effectively responded to neoadjuvant chemotherapy. Ki67 LI was a predictive marker for pCR, and all patients whose tumors achieved pCR are currently disease-free. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free and overall survival regardless of subtype. CONCLUSIONS: It is necessary to establish additional strategies to improve survival for patients whose residual tumors show high Ki67 expression after neoadjuvant chemotherapy. PMID- 23645543 TI - 2013 AAHA/AAFP fluid therapy guidelines for dogs and cats. AB - Fluid therapy is important for many medical conditions in veterinary patients. The assessment of patient history, chief complaint, physical exam findings, and indicated additional testing will determine the need for fluid therapy. Fluid selection is dictated by the patient's needs, including volume, rate, fluid composition required, and location the fluid is needed (e.g., interstitial versus intravascular). Therapy must be individualized, tailored to each patient, and constantly re-evaluated and reformulated according to changes in status. Needs may vary according to the existence of either acute or chronic conditions, patient pathology (e.g., acid-base, oncotic, electrolyte abnormalities), and comorbid conditions. All patients should be assessed for three types of fluid disturbances: changes in volume, changes in content, and/or changes in distribution. The goals of these guidelines are to assist the clinician in prioritizing goals, selecting appropriate fluids and rates of administration, and assessing patient response to therapy. These guidelines provide recommendations for fluid administration for anesthetized patients and patients with fluid disturbances. PMID- 23645545 TI - Evaluation of push-out bond strength of a new MTA-based sealer. AB - AIM: To evaluate the push-out bond strength of MTA Fillapex (Angelus) and compare it with ProRoot MTA (Dentsply) and AH Plus (Dentsply). DESIGN: Thirty extracted single-rooted teeth were selected and prepared using a rotary system. The samples were divided randomly into three groups (n = 10) and obturated, respectively, with: (1) AH Plus + gutta-percha (DiaDent); (2) MTA Fillapex + gutta-percha; (3) ProRoot MTA. Each root was sectioned into 1-mm-thick slices and 30 samples for each group were obtained. The samples were subjected to push-out test. Failure modes were examined under 30* magnification. The results were analysed statistically by one-way ANOVA and Tukey's test. RESULTS: Mean push-out bond strength values were ranked as follows: ProRoot MTA > AH Plus > MTA Fillapex. Statistically significant differences were found among all groups (p < 0.05). CONCLUSION: ProRoot MTA had the highest bond strength, whilst MTA Fillapex displayed the lowest values among the groups. PMID- 23645546 TI - Vitamin D3 levels and insulin resistance in papillary thyroid cancer patients. AB - Both insulin resistance (IR) and vitamin D deficiency (VDD) are found to be associated with many cancer types. In this study, we evaluated the presence of IR and VDD in thyroid cancer patients based on controls. Total 344 papillary thyroid cancer and 116 controls were part of the study. Glucose, insulin, homeostasis model analysis-insulin resistance (HOMA-IR) (control group 2.12 +/- 0.9 and patient group 3.6 +/- 1.1; p < 0.0001), LDL were significantly high; HOMA-S and vitamin D3 levels (control group 19.11 +/- 8 and patient group 17 +/- 16; p = 0.004) were significantly low in the patient group. Vitamin D deficiency (64/108 in controls vs 166/235; p = 0.026) and insulin resistance (24/108; 115/235; p < 0.0001) were more frequent in papillary thyroid cancer patients. After regression analysis, tumor diameter showed significant association with log-HOMA-IR (B = 0.315; p = 0.017) and log-vitamin D3 (B = 0.207; p = 0.04). Vitamin D deficiency and insulin resistance frequencies show no difference between micro- and macropapillary thyroid cancers. Receiver operating characteristic curve shows the best cutoff point for tumor diameter showing that the presence of lymph node metastasis was 0.65 cm with 81.2 % sensitivity and 52 % specificity. Best cutoff point for the capsular invasion tumor diameter was 0.75 cm with 83.3 % sensitivity and 60.4 % specificity. No difference between follicular and classical type papillary thyroid carcinomas has been yet discovered. As a result, thyroid cancer patients are more insulin resistant and vitamin D3 deficient. Vitamin D3 levels and HOMA-IR index may affect tumor diameter. Tumor size that is lower than 1 cm (0.65-0.75 cm) may be related with capsular invasion and lymph node involvement. PMID- 23645547 TI - Findings from the Community Health Intervention Program in South Carolina: implications for reducing cancer-related health disparities. AB - The South Carolina Cancer Prevention and Control Research Network (SC-CPCRN) implemented the Community Health Intervention Program (CHIP) mini-grants initiative to address cancer-related health disparities and reduce the cancer burden among high-risk populations across the state. The mini-grants project implemented evidence-based health interventions tailored to the specific needs of each community. This study aims to support the SC-CPCRN's goals of moving toward greater dissemination and implementation of evidence-based programs in the community to improve public health, prevent disease, and reduce the cancer burden. Three community-based organizations were awarded $10,000 each to implement one of the National Cancer Institute's evidence-based interventions. Each group had 12 months to complete their project. SC-CPCRN investigators and staff provided guidance, oversight, and technical assistance for each project. Grantees provided regular updates and reports to their SC-CPCRN liaisons to capture vital evaluation information. The intended CHIP mini-grant target population reach was projected to be up to 880 participants combined. Actual combined reach of the three projects reported upon completion totaled 1,072 individuals. The majority of CHIP participants were African-American females. Participants ranged in age from 19 to 81 years. Evaluation results showed an increase in physical activity, dietary improvements, and screening participation. The success of the initiative was the result of a strong community-university partnership built on trust. Active two-way communication and an honest open dialogue created an atmosphere for collaboration. Communities were highly motivated. All team members shared a common goal of reducing cancer-related health disparities and building greater public health capacity across the state. PMID- 23645548 TI - A retrospective audit of 200 cases of CNS tumours and their surgical management in a tertiary care centre. AB - AIMS: To study the nature of the tumours managed in the Irish population. METHODS: This audit research was completed via a retrospective medical review on 200 patients with CNS tumours managed in a tertiary care centre between 2008 and 2009. RESULTS: The mean age was 53 years. The male:female ratio was 2:1. The majority were glioblastomas and astrocytomas. Grade IV tumours were predominant (65.5 %). Headaches (37 %), motor weakness (32 %) and seizures (25.5 %) were the highest presentations. The commonest sites affected were the left parietal and left temporal lobes. There were 17.5 % operative morbidities with motor weakness (22.9 %), seizure (14.3 %) and thrombo-embolism (14.3 %) dominating and significant association to surgical radicality (p = 0.041). 3.5 % operative mortalities were reported. 52.5 and 62.5 % of patients received adjuvant chemotherapy and radiotherapy, respectively. CONCLUSIONS: Patients with CNS tumours typically had multiple presentations. More extensive surgical resection was associated with higher postoperative morbidities (p = 0.041). The 30-day postoperative morbidity (17.5 %) and mortality (3.5 %) were concordant with the currently available literature. PMID- 23645549 TI - The transforming growth factor-beta-bone morphogenetic protein type signalling pathway in pulmonary vascular homeostasis and disease. AB - Germ-line mutations in the bone morphogenetic protein type II receptor (BMPR2; BMPR-II) gene, a transforming growth factor-beta (TGFbeta) receptor superfamily member, cause the majority of cases of heritable pulmonary arterial hypertension (PAH). Pulmonary arterial hypertension is a subset of pulmonary hypertension (PH) disorders, which also encompass hypoxia-related lung diseases. Bone morphogenetic proteins (BMPs), via BMPR-II, activate the canonical Smad1/5/9 pathway, whereas TGFbetas (TGFbeta1-3) activate the Smad2/3 pathway via the ALK5 receptor. Dysregulated TGFbeta1 signalling is pathogenic in fibrotic diseases. We compared two rat PH models, monocrotaline-induced PAH (MCT-PAH) and chronic normobaric hypoxia (fractional inspired O2 10%), to address whether BMPR-II loss is common to PH and permits pathogenic TGFbeta1 signalling. Both models exhibited reduced lung BMPR-II expression, but increased TGFbeta1 signalling and decreased BMP signalling were observed only in MCT-PAH. Furthermore, a pharmacological ALK5 inhibitor prevented disease progression in the MCT-PAH model, but not in hypoxia. In vitro studies using human pulmonary artery smooth muscle cells showed that TGFbeta1 directly inhibits BMP-Smad signalling. In conclusion, BMPR-II loss is common to the hypoxic and MCT-PAH models, but systemic ALK5 inhibition is effective only in the MCT model, highlighting a specific role for TGFbeta1 in vascular remodelling in MCT-PAH, potentially via direct inhibition of BMP signalling. PMID- 23645550 TI - Consecutive transcranial magnetic stimulation twitches reduce flow limitation during sleep in apnoeic patients. AB - NEW FINDINGS: What is the central question of this study? A transcranial magnetic stimulation (TMS)-induced twitch applied on isolated single breaths over the motor cortex somatotopic representation of the tongue briefly recruits submental muscles and improves airflow dynamics of flow-limited respiratory cycles without arousing sleep apnoea patients. However, the mechanical impact of the TMS-induced twitch applied during consecutive breathing cycles on airflow dynamics remains unknown. What is the main finding and what is its importance? Our results show that application of TMS with the stimulator output set at the sleep submental motor threshold intensity on consecutive respiratory cycles increases inspiratory flow and reduces the turbulent airflow component. These results indicate an improvement of airflow pattern after two single consecutive TMS-induced twitches without arousing sleep apnoea patients. Transcranial magnetic stimulation (TMS) induced twitches applied on isolated breaths briefly recruit upper airway dilator muscles and improve airflow and inspiratory volume without arousing apnoeic patients from sleep, but the effects of applying such twitches consecutively on airflow dynamics is unknown. The objective of this study was to quantify the effects of five consecutive TMS-induced twitches applied on sleep-induced obstructive hypopnoeic breaths in 10 obstructive sleep apnoea patients. Submental muscle motor threshold (SUBMT) and motor-evoked potential were measured during wakefulness and sleep. The TMS-induced twitches were applied during stable non rapid eye movement (NREM) sleep, at the beginning of inspiration of consecutive flow-limited respiratory cycles, with the stimulator output set at sleep SUBMT. Maximal inspiratory flow, inspiratory volume, inspiratory time, shifts of electroencephalogram frequency and pulse rate variability were assessed. During sleep, SUBMT increased (wakefulness, 25.3 +/- 4.9%; NREM sleep, 27.0 +/- 6.2%; P = 0.02). During each series of stimulations there was a rise in maximal inspiratory flow (from 306.7 +/- 123.2 to 359.8 +/- 154.1 ml s(-1); P = 0.0002) and in inspiratory volume (from 346.1 +/- 128.1 to 414.9 +/- 171.2 ml; P = 0.02) without differences in thoraco-abdominal efforts and inspiratory time. These responses were observed in the absence of arousals and ceased immediately after TMS interruption. Transcranial magnetic stimulation-induced cortical and/or autonomic arousal was observed in 30.2% of all series of stimulation. Consecutive twitch TMS of submental muscles may lead to arousals in a minority of patients but can be applied on consecutive respiratory cycles during sleep and can significantly improve maximal inspiratory flow and inspiratory volume of flow limited cycles. PMID- 23645551 TI - Assessing the stages of the grieving process in chronic obstructive pulmonary disease (COPD): validation of the Acceptance of Disease and Impairments Questionnaire (ADIQ). AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) encounter many (gradual) losses due to their disease, which trigger a grieving process. This process is characterized by stages of denial, resistance, sorrow, and acceptance. PURPOSE: This study examined whether these stages are conceptually distinct and whether the Acceptance of Disease and Impairments Questionnaire (ADIQ) can validly and reliably measure these stages in three samples of patients with COPD in the Netherlands. METHODS: Exploratory factor analysis (EFA) was performed on 145 outpatients with moderate to severe COPD. Confirmatory factor analyses were performed on 303 outpatients with mild to very severe COPD and 127 patients entering an inpatient pulmonary rehabilitation program. Furthermore, internal reliability, construct validity, sensitivity to change, and floor and ceiling effects were examined. RESULTS: EFA yielded a four-factor solution that explained 73.2 % of variance. Confirmatory factor analyses showed a good fit of the four-factor structure in all study samples. Cronbach's alpha reliability coefficients were .79 or higher. Subscales showed to be sensitive to change. CONCLUSIONS: Four distinct stages of grief are recognized in COPD. The ADIQ is a valid and reliable instrument to measure these stages: denial, resistance, sorrow, and acceptance. Measuring the stages of grieving is important for disease management: addressing patients with a specific therapeutic approach for the stage they are in could help to motivate patients to engage in self-management and change their lifestyle. PMID- 23645553 TI - Identifying medical terms in patient-authored text: a crowdsourcing-based approach. AB - BACKGROUND AND OBJECTIVE: As people increasingly engage in online health-seeking behavior and contribute to health-oriented websites, the volume of medical text authored by patients and other medical novices grows rapidly. However, we lack an effective method for automatically identifying medical terms in patient-authored text (PAT). We demonstrate that crowdsourcing PAT medical term identification tasks to non-experts is a viable method for creating large, accurately-labeled PAT datasets; moreover, such datasets can be used to train classifiers that outperform existing medical term identification tools. MATERIALS AND METHODS: To evaluate the viability of using non-expert crowds to label PAT, we compare expert (registered nurses) and non-expert (Amazon Mechanical Turk workers; Turkers) responses to a PAT medical term identification task. Next, we build a crowd labeled dataset comprising 10 000 sentences from MedHelp. We train two models on this dataset and evaluate their performance, as well as that of MetaMap, Open Biomedical Annotator (OBA), and NaCTeM's TerMINE, against two gold standard datasets: one from MedHelp and the other from CureTogether. RESULTS: When aggregated according to a corroborative voting policy, Turker responses predict expert responses with an F1 score of 84%. A conditional random field (CRF) trained on 10 000 crowd-labeled MedHelp sentences achieves an F1 score of 78% against the CureTogether gold standard, widely outperforming OBA (47%), TerMINE (43%), and MetaMap (39%). A failure analysis of the CRF suggests that misclassified terms are likely to be either generic or rare. CONCLUSIONS: Our results show that combining statistical models sensitive to sentence-level context with crowd-labeled data is a scalable and effective technique for automatically identifying medical terms in PAT. PMID- 23645552 TI - The discriminatory cost of ICD-10-CM transition between clinical specialties: metrics, case study, and mitigating tools. AB - OBJECTIVE: Applying the science of networks to quantify the discriminatory impact of the ICD-9-CM to ICD-10-CM transition between clinical specialties. MATERIALS AND METHODS: Datasets were the Center for Medicaid and Medicare Services ICD-9-CM to ICD-10-CM mapping files, general equivalence mappings, and statewide Medicaid emergency department billing. Diagnoses were represented as nodes and their mappings as directional relationships. The complex network was synthesized as an aggregate of simpler motifs and tabulation per clinical specialty. RESULTS: We identified five mapping motif categories: identity, class-to-subclass, subclass to-class, convoluted, and no mapping. Convoluted mappings indicate that multiple ICD-9-CM and ICD-10-CM codes share complex, entangled, and non-reciprocal mappings. The proportions of convoluted diagnoses mappings (36% overall) range from 5% (hematology) to 60% (obstetrics and injuries). In a case study of 24 008 patient visits in 217 emergency departments, 27% of the costs are associated with convoluted diagnoses, with 'abdominal pain' and 'gastroenteritis' accounting for approximately 3.5%. DISCUSSION: Previous qualitative studies report that administrators and clinicians are likely to be challenged in understanding and managing their practice because of the ICD-10-CM transition. We substantiate the complexity of this transition with a thorough quantitative summary per clinical specialty, a case study, and the tools to apply this methodology easily to any clinical practice in the form of a web portal and analytic tables. CONCLUSIONS: Post-transition, successful management of frequent diseases with convoluted mapping network patterns is critical. The http://lussierlab.org/transition-to ICD10CM web portal provides insight in linking onerous diseases to the ICD-10 transition. PMID- 23645554 TI - Genome analysis of Elysia chlorotica Egg DNA provides no evidence for horizontal gene transfer into the germ line of this Kleptoplastic Mollusc. AB - The sea slug Elysia chlorotica offers a unique opportunity to study the evolution of a novel function (photosynthesis) in a complex multicellular host. Elysia chlorotica harvests plastids (absent of nuclei) from its heterokont algal prey, Vaucheria litorea. The "stolen" plastids are maintained for several months in cells of the digestive tract and are essential for animal development. The basis of long-term maintenance of photosynthesis in this sea slug was thought to be explained by extensive horizontal gene transfer (HGT) from the nucleus of the alga to the animal nucleus, followed by expression of algal genes in the gut to provide essential plastid-destined proteins. Early studies of target genes and proteins supported the HGT hypothesis, but more recent genome-wide data provide conflicting results. Here, we generated significant genome data from the E. chlorotica germ line (egg DNA) and from V. litorea to test the HGT hypothesis. Our comprehensive analyses fail to provide evidence for alga-derived HGT into the germ line of the sea slug. Polymerase chain reaction analyses of genomic DNA and cDNA from different individual E. chlorotica suggest, however, that algal nuclear genes (or gene fragments) are present in the adult slug. We suggest that these nucleic acids may derive from and/or reside in extrachromosomal DNAs that are made available to the animal through contact with the alga. These data resolve a long-standing issue and suggest that HGT is not the primary reason underlying long-term maintenance of photosynthesis in E. chlorotica. Therefore, sea slug photosynthesis is sustained in as yet unexplained ways that do not appear to endanger the animal germ line through the introduction of dozens of foreign genes. PMID- 23645555 TI - Subfunctionalization via adaptive evolution influenced by genomic context: the case of histone chaperones ASF1a and ASF1b. AB - Gene duplication is regarded as the main source of adaptive functional novelty in eukaryotes. Processes such as neo- and subfunctionalization impact the evolution of paralogous proteins where functional divergence is frequently key to retain the gene copies. Here, we examined antisilencing function 1 (ASF1), a conserved eukaryotic H3-H4 histone chaperone, involved in histone dynamics during replication, transcription, and DNA repair. Although yeast feature a single ASF1 protein, two paralogs exist in most vertebrates, termed ASF1a and ASF1b, with distinct cellular roles in mammals. To explain this division of tasks, we integrated evolutionary and comparative genomic analyses with biochemical and structural approaches. First, we show that a duplication event at the ancestor of jawed vertebrates, followed by ASF1a relocation into an intron of the minichromosome maintenance complex component 9 (MCM9) gene at the ancestor of tetrapods, provided a different genomic environment for each paralog with marked differences of GC content and DNA replication timing. Second, we found signatures of positive selection in the N- and C-terminal regions of ASF1a and ASF1b. Third, we demonstrate that regions outside the primary interaction surface are key for the preferential interactions of the human paralogs with distinct H3-H4 chaperones. On the basis of these data, we propose that ASF1 experienced subfunctionalization shaped by the adaptation of the genes to their respective genomic context, reflecting a case of genomic context-driven escape from adaptive conflict. PMID- 23645556 TI - Notch3 overexpression associates with poor prognosis in human non-small-cell lung cancer. AB - Notch3 receptor is one of the mammalian Notch family receptors (Notch1-4) which plays an important role in the regulation of cellular proliferation, differentiation, and apoptosis. Overexpression of Notch3 is associated with tumorigenesis. In order to assess the expression of Notch3 in Chinese non-small cell lung cancer (NSCLC) patients and determine its association with prognosis, we designed a prospective study with five years of follow-up to evaluate Notch3 expression in NSCLC tissues and adjacent non-cancerous normal lung tissues from 131 patients undergoing surgical treatment by immunohistochemistry and western blot analysis. Notch3 had high expression in 67 of 131 cases of NSCLC (51.1 %), which was significantly higher than in adjacent noncancerous lung tissues. Moreover, Notch3 overexpression was significantly correlated with TNM stage (P = 5.41e-07 in squamous cell carcinoma, P = 5.338e-07 in adenocarcinoma) and lymph node metastasis (P = 0.00764 in squamous cell carcinoma, P = 0.01491 in adenocarcinoma). Kaplan-Meier survival analysis showed that the overall survival times in patients expressing Notch3 in NSCLC were shorter. Multivariate analysis further demonstrated that Notch3 was an independent prognostic factor for patients with NSCLC. Therefore, Notch3 might be a useful biomarker to predict the prognosis of patients with NSCLC. PMID- 23645563 TI - Expression of the chemokines CXCL12 and CX3CL1 and their receptors in human nerve sheath tumors. AB - Peripheral nerve sheath tumors are in most cases slowly growing neoplasms that can be adequately cured by surgical resection. However, facing the risk of a neurosurgical intervention and the trend of multiple relapses of nerve sheath tumors the development of additional therapy strategies seems to be favourable, and therefore substantiated knowledge of molecular and cellular mechanisms in nerve sheath tumors should be achieved. Here, we firstly describe the expression of the chemokines CXCL12 (SDF-1) and CX3CL1 (fractalkine) and their respective receptors CXCR4, CXCR7 and CX3CR1 in different entities of human nerve sheath tumors and normal control tissues. Both ligands and their receptors are expressed in high to moderate levels on mRNA and protein level in benign and malignant nerve sheath tumors. While CXCL12 was mainly found in schwannoma cells (S100+) in situ, its receptor CXCR4 is also partly found on CD11b-positive macrophages / microglia and its alternative receptor CXCR7 is also expressed by endothelial cells and macrophages. CX3CL1 is expressed by parts of the schwannoma and endothelial cells, whereas its receptor CX3CR1 is expressed by nearly all tumor cells and macrophages, but not by endothelial cells. Taken together, we could show the presence of CXCL12 and CX3CL1 and their respective receptors in benign and malignant human nerve sheath tumors. Further investigations may show their functional role in health and disease. PMID- 23645564 TI - Improving uptake of the copper intrauterine device for emergency contraception by educating pharmacists in the community. AB - OBJECTIVES: The copper intrauterine device (Cu-IUD) is the most effective method of emergency contraception (EC) and provides ongoing contraception, yet few women choose this option. This study evaluates the impact of an educational initiative involving pharmacists on uptake of Cu-IUDs for EC in an integrated sexual health clinic in the North East of England. METHODS: Since November 2010, local pharmacists have received intensive education detailing EC options including Cu IUDs. At the same time a rapid access referral pathway for fitting of an emergency Cu-IUD was established. The impact of this initiative has been assessed by analysing case notes of women attending a large city centre sexual health service who received an emergency Cu-IUD during September and October 2010 (prior to the initiative) and the same 2 months in 2011 (9 months after the start of the intervention). RESULTS: The number of women fitted with an emergency Cu-IUD increased by almost three-fold from 11 fitted in September and October 2010 to 30 fitted in these 2 months in 2011. One woman was referred from a pharmacist to the service in the first audit period compared with 17 in the second. No pregnancies occurred in the first month after Cu-IUD insertion in these 41 women. CONCLUSIONS: Educating pharmacists has increased referral and uptake of Cu-IUD used for EC and this has the potential to reduce unintended pregnancies now and in the future. PMID- 23645567 TI - Retraction note to: Prevention of PONV with granisetron, droperidol or metoclopramide in patients with postoperative emesis. PMID- 23645568 TI - Retraction note to: Cardiovascular responses to tracheal extubation or LMA removal in normotensive and hypertensive patients. PMID- 23645565 TI - The changing mutational landscape of acute myeloid leukemia and myelodysplastic syndrome. AB - Over the past few years, large-scale genomic studies of patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have unveiled recurrent somatic mutations in genes involved in epigenetic regulation (DNMT3A, IDH1/2, TET2, ASXL1, EZH2 and MLL) and the spliceosomal machinery (SF3B1, U2AF1, SRSF2, ZRSR2, SF3A1, PRPF40B, U2AF2, and SF1). The identification of these mutations and their impact on prognostication has led to improvements in risk stratification strategies and has also provided new potential targets for the treatment of these myeloid malignancies. In this review, we discuss the most recently identified genetic abnormalities described in MDS and AML and appraise the current status quo of the dynamics of acquisition of mutant alleles in the pathogenesis of AML, during the transformation from MDS to AML, and in the context of relapse after conventional chemotherapy. IMPLICATIONS: Identification of somatic mutations in AML and MDS suggests new targets for therapeutic development. PMID- 23645566 TI - Imaging findings of mucopolysaccharidoses: a pictorial review. AB - INTRODUCTION: Mucopolysaccharidosis (MPS) represent a heterogeneous group of inheritable lysosomal storage diseases in which the accumulation of undegraded glycosaminoglycans (GAGs) leads to progressive damage of affected tissues. The typical symptoms include organomegaly, dysostosis multiplex, mental retardation and developmental delay. Definitive diagnosis is usually possible through enzymatic assays of the defective enzyme in cultured fibroblasts or leukocytes. IMAGING FINDINGS: Radiological and neuroradiological findings are reported. The most important neuroradiological features include abnormal signal intensity in the white matter, dilatation of periventricular spaces, widening of cortical sulci, brain atrophy, enlargement of extraventricular spaces and spinal cord compression. With reference to the skeletal system, most important radiological findings include multiplex dysostosis, which is represented by several bone malformations found in the skull, hands, legs, arms and column. The abnormal storage of GAGs leads to liver and spleen enlargement; it also damages cartilage layers and synovial recesses in the joints. CONCLUSION: The aim of this pictorial essay is to describe the imaging findings of MPS, represented by skeletal and neurological features; skeletal X-ray and MR allow an assessment of the severity of disease, to plan medical and surgical therapy and to evaluate response to treatment. TEACHING POINTS: * To describe the imaging findings common to different types of MPS. * To describe multiplex dysostosis encountered in the axial and appendicular skeleton. * To evaluate neuroradiological features of MPS, including brain abnormal signal intensity and atrophy. * To evaluate important otorhinolaryngological problems, such as otitis media and airways obstruction. PMID- 23645569 TI - Retraction note to: Prevention of PONV with granisetron, droperidol and metoclopramide in female patients with history of motion sickness. PMID- 23645570 TI - Histological approach to Bacillus subtilis colony-biofilm: evolving internal architecture and sporulation dynamics. AB - Bacillus subtilis has been used as a classic model to study biofilm formation and sporulation process. Colonies of wild-type strains usually have a complex external morphology, but the details of their internal architecture are still undisclosed. Since bacterial biofilms fulfill the criteria to be considered tissues, the aim of this work was to analyse B. subtilis colony-biofilm internal architecture evolution and sporulation dynamics using histological techniques. Transversal sections of colony-biofilms incubated from 24 hours up to 20 days were stained using histochemical techniques to analyse the internal structure by light and electron microscopy. A morphometric study of the different structural biofilm components was performed by image analysis, and an application to quantify spores was developed. Internal biofilm architecture was characterised by a stratified pattern, which evolved from 3 strata at 24 hours, up to 5 strata at 20 days. At 48 hours, strata at the central area of the biofilm was folded, resulting in elevated structures (vein-like structures) that could reach up to 465 MUm in height. Sporulation started at 48 hours, at the top of the vein-like structures, at the interface between the two uppermost strata. At 20 days spores formed a continuous central layer, representing 7.5% of the total biofilm. In summary, our results demonstrate that B. subtilis colony-biofilm has a complex and organized internal architecture, evolving over time, and taking place in different cell subpopulations with different functionalities. Furthermore, in situ spore quantification described in this work could be a good alternative to the classical chamber counting. PMID- 23645571 TI - Sustainable growth rate 2013: time for definitive intervention. AB - Federal healthcare spending has been a subject of intense concern as the US Congress continues to search for ways to reduce the budget deficit. The Congressional Budget Office (CBO) estimated that, even though it is growing more slowly than previously projected, federal spending on Medicare, Medicaid and the State Children's Health Insurance Program (SCHIP) will reach nearly $900 billion in 2013. In 2011 the Medicare program paid $68 billion for physicians and other health professional services, 12% of total Medicare spending. Since 2002 the sustainable growth rate (SGR) correction has called for reductions to physician reimbursements; however, Congress has typically staved off these reductions, although the situation remains precarious for physicians who accept Medicare. The fiscal cliff agreement that came into focus at the end of 2012 averted a 26.5% reduction to physician reimbursements related to the SGR correction. Nonetheless, the threat of these devastating cuts continues to loom. The Administration, Congress and others have devised many options to fix this unsustainable situation. This review explores the historical development of the SGR, touches on elements of the formula itself and outlines current proposals for fixing the SGR problem. A recent CBO estimate reduces the potential cost of a 10-year fix of SGR system to $138 billion. This has provided new hope for resolution of this long standing issue. PMID- 23645572 TI - Mechanical thrombectomy with the Solitaire device in acute basilar artery occlusion. AB - AIMS: To evaluate the efficacy and safety of mechanical thrombectomy with the Solitaire FR device in revascularization of patients with acute basilar artery occlusion (ABAO) and to identify the predictive factors for clinical outcome. METHODS: This prospective single-center study included 31 patients with acute ischemic stroke attributable to ABAO treated within the first 24 h after onset of symptoms with the Solitaire device. Nineteen patients simultaneously received intravenous thrombolysis. Recanalization rates after stent retrieval were determined and the clinical outcome and mortality rate were assessed 180 days after treatment. RESULTS: The mean +/-SD age of the patients was 61+/-17 years, the median prethrombectomy NIH Stroke Scale score was 38 (IQR 9-38) and the median Glasgow Coma Scale (GCS) score was 7 (IQR 4-14). Successful recanalization (TICI 3 or 2b) was achieved in 23 patients (74%). Five symptomatic intracranial hemorrhages were related to the procedure. Ten symptomatic distal migrations of thrombotic material occurred. A favorable outcome, defined as a modified Rankin Score (mRS) of 0-2, was observed in 35% of patients (11/31). Overall mortality rate was 32% (10/31). In the univariate analysis, elevated baseline glucose (p=0.008) was significantly associated with a poor outcome (mRS >2), whereas a tendency towards significance was observed with age (p=0.06), GCS on admission (p=0.07) and symptom-related lesions on T2 sequences (p=0.10). Patients with successful recanalization tended to have a better outcome (p=0.20). CONCLUSION: Mechanical thrombectomy with the Solitaire FR device can rapidly and effectively contribute to a high rate of recanalization and improve functional outcome in patients with ABAO and has an acceptable complication rate. PMID- 23645573 TI - Onyx embolization of infectious intracranial aneurysms. AB - BACKGROUND: Infectious intracranial aneurysms (IIAs) are rare and potentially devastating. First-line management involves intravenous antibiotics, with surgical or endovascular management reserved for cases of failed medical treatment or aneurysmal rupture. Endovascular therapy has become the primary approach for treating these small, distally located aneurysms. Liquid embolic agents are well suited for use because of their ability to fill the aneurysm and parent vessel. We present our experience in treating these aneurysms via Onyx embolization and review the literature. METHODS: We retrospectively reviewed the endovascular treatment of IIAs at our institution from 2010 to 2012. Eight patients with 16 IIAs ranging in size from 1 to 16 mm underwent treatment. Seven of the patients initially presented after aneurysmal rupture. Onyx was pushed until the aneurysm and parent artery were filled. Confirmation of aneurysmal occlusion was made by repeat cerebral angiography. RESULTS: One symptomatic stroke occurred after embolization. Fourteen of the 16 aneurysms have been evaluated with follow-up angiography and remain occluded. CONCLUSIONS: Treatment of IIAs using an endovascular approach with Onyx is safe and effective. PMID- 23645575 TI - Femur-fibula-ulna complex. PMID- 23645574 TI - The use of shear stress for targeted drug delivery. AB - Stenosed segments of arteries significantly alter the blood flow known from healthy vessels. In particular, the wall shear stress at critically stenosed arteries is at least an order of magnitude higher than in healthy situations. This alteration represents a change in physical force and might be used as a trigger signal for drug delivery. Mechano-sensitive drug delivery systems that preferentially release their payload under increased shear stress are discussed. Therefore, besides biological or chemical markers, physical triggers are a further principle approach for targeted drug delivery. We hypothesize that such a physical trigger is much more powerful to release drugs for vasodilation, plaque stabilization, or clot lysis at stenosed arteries than any known biological or chemical ones. PMID- 23645576 TI - Definition of neonatal hypoglycaemia: time for a rethink? PMID- 23645577 TI - Measurement of subcutaneous adipose tissue thickness by near-infrared. AB - Obesity is strongly associated with the risks of diabetes and cardiovascular disease, and there is a need to measure the subcutaneous adipose tissue (SAT) layer thickness and to understand the distribution of body fat. A device was designed to illuminate the body parts by near-infrared (NIR), measure the backscattered light, and predict the SAT layer thickness. The device was controlled by a single-chip microcontroller (SCM), and the thickness value was presented on a liquid crystal display (LCD). There were 30 subjects in this study, and the measurements were performed on 14 body parts for each subject. The paper investigated the impacts of pressure and skin colour on the measurement. Combining with principal component analysis (PCA) and support vector regression (SVR), the measurement accuracy of SAT layer thickness was 89.1 % with a mechanical caliper as reference. The measuring range was 5-11 mm. The study provides a non-invasive and low-cost technique to detect subcutaneous fat thickness, which is more accessible and affordable compared to other conventional techniques. The designed device can be used at home and in community. PMID- 23645578 TI - The relationship between depressive symptoms and erythropoietin resistance in stable hemodialysis patients with adequate iron stores. AB - INTRODUCTION: Resistance to erythropoietin (EPO) treatment has been associated with inflammation and malnutrition in hemodialysis (HD) patients. Depression has also been associated with both inflammation and malnutrition; however, the specific relationship between depressive symptoms and EPO resistance is not known. In the current study, the relationship between depressive symptoms and EPO resistance as evaluated by erythropoiesis stimulating agent (ESA) hyporesponsiveness index (EHRI) was analyzed. ? METHODS: Study participants had their medical history taken and underwent physical examination; dialysis adequacy calculation, biochemical analysis and evaluation of depressive symptoms by Beck Depression Inventory (BDI) were performed. EHRI was calculated as the weekly dose of EPO divided by per kilogram of body weight divided by the hemoglobin level.? RESULTS: The mean BDI score of the patients was 10.99 +/- 3.94. Pearson correlation analysis revealed that the logarithmically converted EHRI score was correlated with albumin (r = -0.270, p = 0.011), hs-CRP (r = 0.383, P<0.0001), hemoglobin (r = -0.617, p<0.0001), intact PTH (r = 0.215, p = 0.043) and logarithmically converted BDI (r = 0.299, p = 0.004). The stepwise linear regression analysis revealed that being female (p = 0.012), presence of diabetes mellitus (p = 0.119), hs-CRP (p = 0.009) and BDI score (p = 0.037) were independently related with logarithmically converted EHRI (as a dependent variable).? CONCLUSION: Depressive symptoms were independently related with EHRI in HD patients. Studies are needed to highlight underlying mechanisms between depression and EHRI. PMID- 23645579 TI - Predictors of failure of catheter salvage in incident hemodialysis patients. AB - PURPOSE: Catheter-related bloodstream infection is a frequent complication for patients who use catheter as dialysis access. This study was performed to identify the risk factors for failed catheter salvage. ? METHODS: We enrolled patients who received non-tunneled catheters as initial vascular access during a two-year period. Catheter salvage was attempted in all symptomatically mild patients. Patients were prospectively followed for 8 weeks starting from the day of infection. Risk factors for salvage failure were explored. RESULTS: A total of 77 bacteremia episodes occurred in 69 patient, with an infection rate of 1.61 per 1,000 catheter days. Salvage was successful in 73.4% of all episodes. We found that higher ferritin levels (greater vs. lower than 500 mg/l, (odds ratio (OR) 6.388, 95% confidence interval (CI) 2.073, 19.686), higher phosphate levels (greater vs. lower than 5.5 mg/dl, OR 4.084, 95% CI 1.391, 11.978) and shorter time intervals between catheterization and infection (within vs. beyond 3 weeks, OR 4.190, 95% CI 1.279, 13.725) predicted salvage failure. CONCLUSIONS: Catheter salvage can be a reasonable initial strategy for symptomatically mild patients. We propose salvaging aggressively and waiting watchfully; however, clinical judgment is prior to any specific management protocol. PMID- 23645580 TI - Cardiac autonomic dysfunction in the early phase after left ventricular assist device implant: Implications for surgery and follow-up. AB - PURPOSE: In congestive heart failure (CHF) patients, a profound cardiac autonomic derangement, clinically expressed by reduced heart rate variability (HRV), is present and is related to the degree of ventricular dysfunction. Implantation of a left ventricular assist device (LVAD) can progressively improve HRV, associated with an increased circulatory output. Data from patients studied at different times after LVAD implantation are controversial. The aims of this study were to assess cardiac autonomic function in the early phases after axial-flow LVAD implantation, and to estimate the potential relevance of recent major surgical stress on the autonomic balance.? METHODS: HRV (time-domain; 24-h Holter) was evaluated in 14 patients, 44.8 +/- 25.8 days after beginning of Jarvik-2000 LVAD support; 47 advanced stage CHF, 24 cardiac surgery (CS) patients and ?30 healthy subjects served as control groups. INCLUSION CRITERIA: sinus rhythm, stable clinical conditions, no diabetes or other known causes of HRV alteration.? RESULTS: HRV was considerably reduced in LVAD patients in the early phases after device implantation in comparison to all control groups. A downgrading of HRV parameters was also present in CS controls. Circadian oscillations were highly depressed in LVAD and CHF patients, and slightly reduced in CS patients.? CONCLUSIONS: In CHF patients supported by a continuous-flow LVAD, a profound cardiac dysautonomia is still evident in the first two months from the beginning of circulatory support; the degree of cardiac autonomic imbalance is even greater in comparison to advanced CHF patients. The recent surgical stress could be partly linked to these abnormalities. PMID- 23645581 TI - Tissue engineering and ureter regeneration: is it possible? AB - Large ureter damages are difficult to reconstruct. Current techniques are complicated, difficult to perform, and often associated with failures. The ureter has never been regenerated thus far. Therefore the use of tissue engineering techniques for ureter reconstruction and regeneration seems to be a promising way to resolve these problems. For proper ureter regeneration the following problems must be considered: the physiological aspects of the tissue, the type and shape of the scaffold, the type of cells, and the specific environment (urine). ?This review presents tissue engineering achievements in the field of ureter regeneration focusing on the scaffold, the cells, and ureter healing. PMID- 23645582 TI - Artificial placenta--lung assist devices for term and preterm newborns with respiratory failure. AB - Respiratory insufficiency is a major cause of neonatal mortality and long-term morbidity, especially in very low birth weight infants. Today, non-invasive and mechanical ventilation are commonly accepted procedures to provide respiratory support to newborns, but they can reach their limit of efficacy. To overcome this technological plateau and further reduce mortality rates, the technology of an "artificial placenta", which is a pumpless lung assist device connected to the umbilical vessels, would serve to expand the therapeutic spectrum when mechanical ventilation becomes inadequate to treat neonates with severe respiratory insufficiency.?The first attempts to create such an artificial placenta took place more than 60 years ago. However, there has been a recent renaissance of this concept, including developments of its major components like the oxygenator, vascular access via umbilical vessels, flow control, as well as methods to achieve hemocompatibility in extracorporeal circuits. This paper gives a review of past and current development, animal experiments and human case studies of artificial placenta technology. PMID- 23645583 TI - PCR screening for the N526K substitution in isolates of Haemophilus influenzae and Haemophilus haemolyticus. AB - OBJECTIVES: Firstly, to evaluate the current PBP3-S primers of Hasegawa et al. (Microb Drug Resist 2003; 9: 39-46) and develop new primers for the amplification of N526 in isolates of Haemophilus haemolyticus. Secondly, to develop a new PCR assay for the detection (by amplification) of the N526K substitution, encoded by either the AAA or AAG single nucleotide polymorphism (SNP) at position 1576-1578 of the ftsI gene, in isolates of both Haemophilus influenzae and H. haemolyticus. METHODS: A total of 50 H. influenzae and 50 H. haemolyticus isolates, comprising N526 and N526K genotypes, were used to evaluate the performance of SNP-based PCR primers for the detection of the beta-lactamase-negative ampicillin resistance (BLNAR)-defining N526K substitution in H. influenzae and H. haemolyticus, using a real-time PCR platform. RESULTS: The PBP3-S primers of Hasegawa et al. failed to amplify H. haemolyticus isolates, irrespective of their N526/N526K status, owing to an inability of the forward primer to bind the H. haemolyticus ftsI sequence, giving an overall sensitivity of 100% and a specificity of 40% when using all of the isolates. However, the PBP3-N526 and PBP3-N526K PCR primers designed in this study were 100% sensitive and specific, and 84% sensitive and 100% specific, respectively, for the detection of N526K-positive isolates. CONCLUSIONS: Although antibiotic resistance surveillance studies on H. influenzae should include a definitive test for H. influenzae/H. haemolyticus identification, the new primers from this study will not only allow for PCR characterization of both H. influenzae and H. haemolyticus with respect to the N526K BLNAR substitutions, they will also stop incorrect characterization of susceptible H. haemolyticus isolates as low-BLNAR H. influenzae. PMID- 23645584 TI - Treatment of Chagas' disease with itraconazole: electrocardiographic and parasitological conditions after 20 years of follow-up. AB - OBJECTIVES: To evaluate cases of chronic Chagas' disease for the long-term effects of treatment with itraconazole on Trypanosoma cruzi infections and the regression or development of ECG abnormalities. METHODS: In March 1992, we treated 46 patients with chronic Chagas' disease with 6 mg/kg/day of itraconazole for 120 days in a blind evaluation. The patients came from an area of Chile where the disease was endemic and were checked for ECG abnormalities and with xenodiagnosis (XD) or real-time XD-quantitative PCR (XD-qPCR) for Trypanosoma cruzi infection before treatment and once a year for 20 years. RESULTS: Twenty one patients proved to be uninfected after 20 years and 15 of the patients had a normal ECG. Of the latter cases, 32.6% could be considered cured, although all of them had positive serology. Itraconazole prevents the development of ECG abnormalities, because after 20 years of treatment only 10.86% of patients developed ECG abnormalities (Z = 1.70, P = 0.046). XD-qPCR performed on 16 patients demonstrated 10 cases with <1.42 parasites/mL: eight with <1 parasite/mL, one with 1.42 parasites/mL and one with 1.01 parasites/mL. Five patients had more than 11.75 parasites/mL, all of them with a positive XD; these cases correspond to therapy failure, since re-infection was ruled out. In one case, XD-qPCR did not present amplification. CONCLUSIONS: Itraconazole is useful in the treatment of chronic Chagas' disease as it prevented the development of ECG abnormalities and cured 32.6% of patients. PMID- 23645585 TI - Diaryltriazine non-nucleoside reverse transcriptase inhibitors are potent candidates for pre-exposure prophylaxis in the prevention of sexual HIV transmission. AB - OBJECTIVES: Pre-exposure prophylaxis and topical microbicides are important strategies in the prevention of sexual HIV transmission, especially since partial protection has been shown in proof-of-concept studies. In search of new candidate drugs with an improved toxicity profile and with activity against common non nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV, we have synthesized and investigated a library of 60 new diaryltriazine analogues. METHODS: From this library, 15 compounds were evaluated in depth using a broad armamentarium of in vitro assays that are part of a preclinical testing algorithm for microbicide development. Antiviral activity was assessed in a cell line, and in primary human cells, against both subtype B and subtype C HIV-1 and against viruses resistant to therapeutic NNRTIs and the candidate NNRTI microbicide dapivirine. Toxicity towards primary blood-derived cells, cell lines originating from the female reproductive tract and female genital microflora was also studied. RESULTS AND CONCLUSIONS: We identified several compounds with highly potent antiviral activity and toxicity profiles that are superior to that of dapivirine. In particular, compound UAMC01398 is an interesting new candidate that warrants further investigation because of its superior toxicity profile and potent activity against dapivirine-resistant viruses. PMID- 23645586 TI - High burden of extended-spectrum beta-lactamase-producing Enterobacteriaceae in Gabon. AB - OBJECTIVES: Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL E) are sporadically reported from infections in sub-Saharan Africa. Travellers returning from the tropics have a high risk of ESBL-E colonization, which suggests a high prevalence of ESBL-E in Africa. Our objective was to assess the burden of rectal ESBL-E colonization and associated risk factors in Gabon, Central Africa PATIENTS AND METHODS: We performed a cross-sectional study on 200 hospitalized children in Gabon, Central Africa, on rectal ESBL-E colonization and applied a standardized questionnaire to assess risk factors. The antimicrobial resistance and the type of beta-lactamase (SHV, TEM and CTX-M) were analysed for each isolate. Isolates associated with nosocomial spread were further genotyped. RESULTS: The overall colonization rate of ESBL-E was 45% (n = 90) and increased from 33.6% (n = 37) at admission to 94.1% (n = 16) during hospitalization. Risk factors for ESBL-E carriage were age <5 years, hospitalization for >=5 days and a hospital stay during the past year. All isolates were susceptible to meropenem, but non-susceptible to ciprofloxacin in 52.8% (n = 57). CTX-M-15 was the predominant beta-lactamase. Genotyping revealed a polyclonal structure of nosocomial isolates. CONCLUSIONS: ESBL colonization in hospitalized children in Gabon is high. The risk of nosocomial transmission of ESBL-E is a challenge in rural Africa and underlines the need for sentinel surveillance in the absence of a broad decentralized microbiology laboratory. PMID- 23645587 TI - Efficacy of a synthetic antimicrobial peptidomimetic versus vancomycin in a Staphylococcus epidermidis device-related murine peritonitis model. AB - OBJECTIVES: Biofilm-forming Staphylococcus epidermidis is a prevalent cause of peritonitis during peritoneal dialysis. We compared the efficacy of a synthetic antimicrobial peptidomimetic (Ltx21) versus vancomycin in a murine model mimicking a device-related peritonitis. METHODS: Silicone implants, pre-colonized with an S. epidermidis biofilm, were inserted into the peritoneal cavity of BALB/c mice. Three groups (36 mice in each) with pre-colonized implants received intraperitoneal treatment with Ltx21, vancomycin or placebo. Mice were euthanized on day 3 (n = 12), day 6 (n = 12) or day 8 (n = 12) post-implantation. Controls were mice with sterile implants (n = 18) and mice without surgery (n = 6). Bacterial reductions in cfu were analysed from implants and peritoneal fluid (PF). Inflammatory responses in serum and PF were measured. RESULTS: Vancomycin resulted in a stronger reduction in cfu counts, both on pre-colonized implants and in PF, compared with Ltx21 and placebo. Complete bacterial clearance of the implants was not achieved in any of the groups. The implants pre-colonized with S. epidermidis 1457 resulted in a low-grade peritonitis. We observed, only on day 6, a significant increase in the PF leucocyte count in the group with pre colonized implants compared with the group with sterile implants (P = 0.0364). CONCLUSIONS: Treatment with vancomycin or Ltx21 was not sufficient to achieve complete bacterial clearance of implants, underlining the difficulties of treating such infections. The low-grade infection may attenuate the inflammatory response and contribute to impaired bacterial clearance. PMID- 23645588 TI - A Plasmodium falciparum screening assay for anti-gametocyte drugs based on parasite lactate dehydrogenase detection. AB - OBJECTIVES: Plasmodium gametocytes, responsible for malaria parasite transmission from humans to mosquitoes, represent a crucial target for new antimalarial drugs to achieve malaria elimination/eradication. We developed a novel colorimetric screening method for anti-gametocyte compounds based on the parasite lactate dehydrogenase (pLDH) assay, already standardized for asexual stages, to measure gametocyte viability and drug susceptibility. METHODS: Gametocytogenesis of 3D7 and NF54 Plasmodium falciparum strains was induced in vitro and asexual parasites were depleted with N-acetylglucosamine. Gametocytes were treated with dihydroartemisinin, epoxomicin, methylene blue, primaquine, puromycin or chloroquine in 96-well plates and the pLDH activity was evaluated using a modified Makler protocol. Mosquito infectivity was measured by the standard membrane feeding assay (SMFA). RESULTS: A linear correlation was found between gametocytaemia determined by Giemsa staining and pLDH activity. A concentration dependent reduction in pLDH activity was observed after 72 h of drug treatment, whereas an additional 72 h of incubation without drugs was required to obtain complete inhibition of gametocyte viability. SMFA on treated and control gametocytes confirmed that a reduction in pLDH activity translates into reduced oocyst development in the mosquito vector. CONCLUSIONS: The gametocyte pLDH assay is fast, easy to perform, cheap and reproducible and is suitable for screening novel transmission-blocking compounds, which does not require parasite transgenic lines. PMID- 23645589 TI - A systematic review of strategies for reporting of neonatal hospital-acquired bloodstream infections. AB - OBJECTIVE: To examine the reporting of hospital-acquired bloodstream infection (HABSI) and central line-associated BSI (CLABSI) rates in neonatal intensive care units (NICUs). DESIGN: Systematic review of evidence published after 2000 reporting HABSI cumulative incidence, crude HABSI and/or CLABSI rate and total patient-days and/or central line-days for single NICU. SETTING: Inpatient. PATIENTS: Neonates admitted to NICU. MAIN OUTCOME MEASURES: To consider the reporting of and relationship between cumulative incidence of BSI and HABSI and/or CLABSI rates. RESULTS: 18 studies fulfilled inclusion criteria. There was a wide variability in reporting of HABSI indicators and risk-adjustment strategies with reported crude HABSI and/or CLABSI rates showing an approximately sevenfold variation between centres. Information about NICU size and level of care was not always available. Many studies provided insufficient information about case mix, such as surgical care provision and prematurity. The proportion of total patient-days that were central venous catheters (CVC)-days ranged from 11.7% to 85.4%. Only six studies reported HABSI and CLABSI incidence. Comparing HABSI and CLABSI ranking, we found a relationship between rates. CONCLUSIONS: We found significant variability in HABSI rate reporting. Although there appears to be an association between CLABSI and HABSI rates, non-CVC-related BSIs are likely to be highly relevant in some NICUs. If confirmed, and given CLABSI rates are more challenging to collect, it may be more appropriate to use HABSI rates for monitoring NICU healthcare-associated infection (HAI) in some settings. A European network of NICUs using a standardised methodology is required to determine the feasibility and reliability of different risk-adjusted measured of HAI rates. PMID- 23645590 TI - Aerosol administration of phospho-sulindac inhibits lung tumorigenesis. AB - Phospho-sulindac is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of phospho-sulindac might overcome first-pass metabolism and produce high levels of intact drug in lung tumors. Here, we developed a system for aerosolization of phospho-sulindac and evaluated the antitumor efficacy of inhaled phospho-sulindac in an orthotopic model of human non-small cell lung cancer (A549 cells). We found that administration by inhalation delivered high levels of phospho-sulindac to the lungs and minimized its hydrolysis to less active metabolites. Consequently, inhaled phospho-sulindac (6.5 mg/kg) was highly effective in inhibiting lung tumorigenesis (75%; P < 0.01) and significantly improved the survival of mice bearing orthotopic A549 xenografts. Mechanistically, phospho-sulindac suppressed lung tumorigenesis by (i) inhibiting EGF receptor (EGFR) activation, leading to profound inhibition of Raf/MEK/ERK and PI3K/AKT/mTOR survival cascades; (ii) inducing oxidative stress, which provokes the collapse of mitochondrial membrane potential and mitochondria-dependent cell death; and (iii) inducing autophagic cell death. Our data establish that inhalation delivery of phospho-sulindac is an efficacious approach to the control of lung cancer, which merits further evaluation. PMID- 23645591 TI - Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma. AB - Inhibitors of the mitogen-activated protein kinases (MAPK), BRAF, and MAP-ERK kinase (MEK) induce tumor regression in the majority of patients with BRAF-mutant metastatic melanoma. The clinical benefit of MAPK inhibitors is restricted by the development of acquired resistance with half of those who benefit having progressed by 6 to 7 months and long-term responders uncommon. There remains no agreed treatment strategy on disease progression in these patients. Without published evidence, fears of accelerated disease progression on inhibitor withdrawal have led to the continuation of drugs beyond formal disease progression. We now show that treatment with MAPK inhibitors beyond disease progression can provide significant clinical benefit, and the withdrawal of these inhibitors led to a marked increase in the rate of disease progression in two patients. We also show that MAPK inhibitors retain partial activity in acquired resistant melanoma by examining drug-resistant clones generated to dabrafenib, trametinib, or the combination of these drugs. All resistant sublines displayed a markedly slower rate of proliferation when exposed to MAPK inhibitors, and this coincided with a reduction in MAPK signaling, decrease in bromodeoxyuridine incorporation, and S-phase inhibition. This cytostatic effect was also associated with diminished levels of cyclin D1 and p-pRb. Two short-term melanoma cultures generated from resistant tumor biopsies also responded to MAPK inhibition, with comparable inhibitory changes in proliferation and MAPK signaling. These data provide a rationale for the continuation of BRAF and MEK inhibitors after disease progression and support the development of clinical trials to examine this strategy. PMID- 23645592 TI - Multivalent scaffold proteins as superagonists of TRAIL receptor 2-induced apoptosis. AB - Activation of TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) can induce apoptosis in a variety of human cancer cell lines and xenografts, while lacking toxicity in normal cells. The natural ligand and agonistic antibodies show antitumor activity in preclinical models of cancer, and this had led to significant excitement in the clinical potential of these agents. Unfortunately, this optimism has been tempered by trial data that, thus far, are not showing clear signs of efficacy in cancer patients. The reasons for discrepant preclinical and clinical observations are not understood, but one possibility is that the current TRAILR2 agonists lack sufficient potency to achieve a meaningful response in patients. Toward addressing that possibility, we have developed multivalent forms of a new binding scaffold (Tn3) that are superagonists of TRAILR2 and can induce apoptosis in tumor cell lines at subpicomolar concentrations. The monomer Tn3 unit was a fibronectin type III domain engineered for high-affinity TRAILR2 binding. Multivalent presentation of this basic unit induced cell death in TRAILR2-expressing cell lines. Optimization of binding affinity, molecular format, and valency contributed to cumulative enhancements of agonistic activity. An optimized multivalent agonist consisting of 8 tandem Tn3 repeats was highly potent in triggering cell death in TRAIL-sensitive cell lines and was 1 to 2 orders of magnitude more potent than TRAIL. Enhanced potency was also observed in vivo in a tumor xenograft setting. The TRAILR2 superagonists described here have the potential for superior clinical activity in settings insensitive to the current therapeutic agonists that target this pathway. PMID- 23645593 TI - Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease. AB - OBJECTIVES: Previous associations between mitochondrial DNA (mtDNA) and idiopathic Parkinson disease (PD) have been inconsistent and contradictory. Our aim was to resolve these inconsistencies and determine whether mtDNA has a significant role in the risk of developing PD. METHODS: Two-stage genetic association study of 138 common mtDNA variants in 3,074 PD cases and 5,659 ethnically matched controls followed by meta-analysis of 6,140 PD cases and 13,280 controls. RESULTS: In the association study, m.2158T>C and m.11251A>G were associated with a reduced risk of PD in both the discovery and replication cohorts. None of the common European mtDNA haplogroups were consistently associated with PD, but pooling of discovery and replication cohorts revealed a protective association with "super-haplogroup" JT. In the meta-analysis, there was a reduced risk of PD with haplogroups J, K, and T and super-haplogroup JT, and an increase in the risk of PD with super-haplogroup H. CONCLUSIONS: In a 2 stage association study of mtDNA variants and PD, we confirm the reduced risk of PD with super-haplogroup JT and resolve this at the J1b level. Meta-analysis explains the previous inconsistent associations that likely arise through sampling effects. The reduced risk of PD with haplogroups J, K, and T is mirrored by an increased risk of PD in super-haplogroup HV, which increases survival after sepsis. Antagonistic pleiotropy between mtDNA haplogroups may thus be shaping the genetic landscape in humans, leading to an increased risk of PD in later life. PMID- 23645594 TI - Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology. AB - OBJECTIVES: We sought to identify demographic and clinical features that were associated with expression of symptoms in the presence of Alzheimer disease (AD) neuropathologic changes. METHODS: We studied 82 asymptomatic (Clinical Dementia Rating global score = 0) and 824 symptomatic subjects (Clinical Dementia Rating score >0) with low to high AD neuropathologic changes at autopsy who were assessed at 1 of 34 National Institute on Aging-funded Alzheimer's Disease Centers. All subjects underwent a clinical examination within 1 year of death. Logistic regression was used to evaluate factors associated with the odds of being asymptomatic vs symptomatic. RESULTS: Asymptomatic subjects tended to have low neurofibrillary tangle scores but a wide range of neuritic plaque frequencies. There were, however, a few asymptomatic subjects with very high tangle and neuritic plaque burden, as well as symptomatic subjects with few changes. In the multivariable model, asymptomatic subjects were older (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 1.01-1.07), had lower clinical Hachinski Ischemic Score (OR = 0.82; 95% CI = 0.69-0.97), were less likely to have an APOE epsilon4 allele (OR = 0.36; 95% CI = 0.16-0.83), and had lower neurofibrillary tangle score (OR = 0.28; 95% CI = 0.17-0.45) compared with symptomatic subjects. CONCLUSIONS: Dissociating clinical symptoms from pathologic findings better allows for investigation of preclinical AD. Our results suggest that although the severity of the pathology, particularly neurofibrillary tangles, has a large role in determining the extent of symptoms, other factors, including age, APOE status, and comorbidities such as cerebrovascular disease also explain differences in clinical presentation. PMID- 23645595 TI - Pilot trial of clenbuterol in spinal and bulbar muscular atrophy. AB - OBJECTIVE: To test the efficacy and tolerability of clenbuterol in patients with spinal and bulbar muscular atrophy (SBMA). METHODS: Twenty patients with a diagnosis of SBMA were given oral clenbuterol (0.04 mg/d) for 12 months. The primary efficacy end point was the change from baseline of the walking distance covered in 6 minutes at 12 months. Secondary end points included the change over time in muscle strength assessed with the Medical Research Council scale, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and forced vital capacity values. Safety was assessed by a series of laboratory and instrumental tests, as well as reporting of adverse events. RESULTS: Sixteen patients completed the study. There was a significant and sustained increase in walking distance covered in 6 minutes and forced vital capacity between the baseline and the 12-month assessments (p < 0.001). No differences were recorded in Medical Research Council or ALSFRS-R scores between baseline and follow-up assessments. Serious side effects, including those on heart function, were absent. A significant increase in serum creatine kinase levels was observed. CONCLUSIONS: Our findings suggest a positive effect of clenbuterol on SBMA disease progression. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that clenbuterol is effective in improving motor function in SBMA. PMID- 23645596 TI - Application of the National Institute on Aging-Alzheimer's Association AD criteria to ADNI. AB - OBJECTIVE: We describe the operationalization of the National Institute on Aging Alzheimer's Association (NIA-AA) workgroup diagnostic guidelines pertaining to Alzheimer disease (AD) dementia in a large multicenter group of subjects with AD dementia. METHODS: Subjects with AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with at least 1 amyloid biomarker (n = 211) were included in this report. Biomarker data from CSF Abeta42, amyloid PET, fluorodeoxyglucose-PET, and MRI were examined. The biomarker results were assessed on a per-patient basis and the subject categorization as defined in the NIA-AA workgroup guidelines was determined. RESULTS: When using a requirement that subjects have a positive amyloid biomarker and single neuronal injury marker having an AD pattern, 87% (48% for both neuronal injury biomarkers) of the subjects could be categorized as "high probability" for AD. Amyloid status of the combined Pittsburgh compound B-PET and CSF results showed an amyloid-negative rate of 10% in the AD group. In the ADNI AD group, 5 of 92 subjects fit the category "dementia unlikely due to AD" when at least one neuronal injury marker was negative. CONCLUSIONS: A large proportion of subjects with AD dementia in ADNI may be categorized more definitively as high-probability AD using the proposed biomarker scheme in the NIA-AA criteria. A minority of subjects may be excluded from the diagnosis of AD by using biomarkers in clinically categorized AD subjects. In a well-defined AD dementia population, significant biomarker inconsistency can be seen on a per-patient basis. PMID- 23645597 TI - Arabidopsis NRT1.1 is a bidirectional transporter involved in root-to-shoot nitrate translocation. PMID- 23645598 TI - The type F6 neurotoxin gene cluster locus of group II clostridium botulinum has evolved by successive disruption of two different ancestral precursors. AB - Genome sequences of five different Group II (nonproteolytic) Clostridium botulinum type F6 strains were compared at a 50-kb locus containing the neurotoxin gene cluster. A clonal origin for these strains is indicated by the fact that sequences were identical except for strain Eklund 202F, with 10 single nucleotide polymorphisms and a 15-bp deletion. The essential topB gene encoding topoisomerase III was found to have been split by the apparent insertion of 34.4 kb of foreign DNA (in a similar manner to that in Group II C. botulinum type E where the rarA gene has been disrupted by a neurotoxin gene cluster). The foreign DNA, which includes the intact 13.6-kb type F6 neurotoxin gene cluster, bears not only a newly introduced topB gene but also two nonfunctional botulinum neurotoxin gene remnants, a type B and a type E. This observation combined with the discovery of bacteriophage integrase genes and IS4 elements suggest that several rounds of recombination/horizontal gene transfer have occurred at this locus. The simplest explanation for the current genotype is that the ancestral bacterium, a Group II C. botulinum type B strain, received DNA firstly from a strain containing a type E neurotoxin gene cluster, then from a strain containing a type F6 neurotoxin gene cluster. Each event disrupted the previously functional neurotoxin gene. This degree of successive recombination at one hot spot is without precedent in C. botulinum, and it is also the first description of a Group II C. botulinum genome containing more than one neurotoxin gene sequence. PMID- 23645600 TI - Genomic dynamics of transposable elements in the western clawed frog (Silurana tropicalis). AB - Transposable elements (TEs) are repetitive DNA sequences that can make new copies of themselves that are inserted elsewhere in a host genome. The abundance and distributions of TEs vary considerably among phylogenetically diverse hosts. With the aim of exploring the basis of this variation, we evaluated correlations between several genomic variables and the presence of TEs and non-TE repeats in the complete genome sequence of the Western clawed frog (Silurana tropicalis). This analysis reveals patterns of TE insertion consistent with gene disruption but not with the insertional preference model. Analysis of non-TE repeats recovered unique features of their genome-wide distribution when compared with TE repeats, including no strong correlation with exons and a particularly strong negative correlation with GC content. We also collected polymorphism data from 25 TE insertion sites in 19 wild-caught S. tropicalis individuals. DNA transposon insertions were fixed at eight of nine sites and at a high frequency at one of nine, whereas insertions of long terminal repeat (LTR) and non-LTR retrotransposons were fixed at only 4 of 16 sites and at low frequency at 12 of 16. A maximum likelihood model failed to attribute these differences in insertion frequencies to variation in selection pressure on different classes of TE, opening the possibility that other phenomena such as variation in rates of replication or duration of residence in the genome could play a role. Taken together, these results identify factors that sculpt heterogeneity in TE distribution in S. tropicalis and illustrate that genomic dynamics differ markedly among TE classes and between TE and non-TE repeats. PMID- 23645599 TI - Plant mitochondrial genome evolution can be explained by DNA repair mechanisms. AB - Plant mitochondrial genomes are notorious for their large and variable size, nonconserved open reading frames of unknown function, and high rates of rearrangement. Paradoxically, the mutation rates are very low. However, mutation rates can only be measured in sequences that can be aligned--a very small part of plant mitochondrial genomes. Comparison of the complete mitochondrial genome sequences of two ecotypes of Arabidopsis thaliana allows the alignment of noncoding as well as coding DNA and estimation of the mutation rates in both. A recent chimeric duplication is also analyzed. A hypothesis is proposed that the mechanisms of plant mitochondrial DNA repair account for these features and includes different mechanisms in transcribed and nontranscribed regions. Within genes, a bias toward gene conversion would keep measured mutation rates low, whereas in noncoding regions, break-induced replication (BIR) explains the expansion and rearrangements. Both processes are types of double-strand break repair, but enhanced second-strand capture in transcribed regions versus BIR in nontranscribed regions can explain the two seemingly contradictory features of plant mitochondrial genome evolution--the low mutation rates in genes and the striking expansions of noncoding sequences. PMID- 23645601 TI - Eep confers lysozyme resistance to enterococcus faecalis via the activation of the extracytoplasmic function sigma factor SigV. AB - Enterococcus faecalis is a commensal bacterium found in the gastrointestinal tract of most mammals, including humans, and is one of the leading causes of nosocomial infections. One of the hallmarks of E. faecalis pathogenesis is its unusual ability to tolerate high concentrations of lysozyme, which is an important innate immune component of the host. Previous studies have shown that the presence of lysozyme leads to the activation of SigV, an extracytoplasmic function (ECF) sigma factor in E. faecalis, and that the deletion of sigV increases the susceptibility of the bacterium toward lysozyme. Here, we describe the contribution of Eep, a membrane-bound zinc metalloprotease, to the activation of SigV under lysozyme stress by its effects on the stability of the anti-sigma factor RsiV. We demonstrate that the Deltaeep mutant phenocopies the DeltasigV mutant in lysozyme, heat, ethanol, and acid stress susceptibility. We also show, using an immunoblot analysis, that in an eep deletion mutant, the anti-sigma factor RsiV is only partially degraded after lysozyme exposure, suggesting that RsiV is processed by unknown protease(s) prior to the action of Eep. An additional observation is that the deletion of rsiV, which results in constitutive SigV expression, leads to chaining of cells, suggesting that SigV might be involved in regulating cell wall-modifying enzymes important in cell wall turnover. We also demonstrate that, in the absence of eep or sigV, enterococci bind significantly more lysozyme, providing a plausible explanation for the increased sensitivity of these mutants toward lysozyme. PMID- 23645602 TI - Enterococcal Rgg-like regulator ElrR activates expression of the elrA operon. AB - The Enterococcus faecalis leucine-rich protein ElrA promotes virulence by stimulating bacterial persistence in macrophages and production of the interleukin-6 (IL-6) cytokine. The ElrA protein is encoded within an operon that is poorly expressed under laboratory conditions but induced in vivo. In this study, we identify ef2687 (renamed elrR), which encodes a member of the Rgg (regulator gene for glucosyltransferase) family of putative regulatory proteins. Using quantitative reverse transcription-PCR, translational lacZ fusions, and electrophoretic mobility shift assays, we demonstrate that ElrR positively regulates expression of elrA. These results correlate with the attenuated virulence of the DeltaelrR strain in a mouse peritonitis model. Virulence of simple and double elrR and elrA deletion mutants also suggests a remaining ElrR independent expression of elrA in vivo and additional virulence-related genes controlled by ElrR. PMID- 23645603 TI - Low-pH rescue of acid-sensitive Salmonella enterica Serovar Typhi Strains by a Rhamnose-regulated arginine decarboxylase system. AB - For Salmonella, transient exposure to gastric pH prepares invading bacteria for the stresses of host-cell interactions. To resist the effects of low pH, wild type Salmonella enterica uses the acid tolerance response and the arginine decarboxylase acid resistance system. However, arginine decarboxylase is typically repressed under routine culture conditions, and for many live attenuated Salmonella vaccine strains, the acid tolerance response is unable to provide the necessary protection. The objective of this study was to enhance survival of Salmonella enterica serovar Typhi vaccine strains at pHs 3.0 and 2.5 to compensate for the defects in the acid tolerance response imposed by mutations in rpoS, phoPQ, and fur. We placed the arginine decarboxylase system (adiA and adiC) under the control of the ParaBAD or PrhaBAD promoter to provide inducible acid resistance when cells are grown under routine culture conditions. The rhamnose-regulated promoter PrhaBAD was less sensitive to the presence of its cognate sugar than the arabinose-regulated promoter ParaBAD and provided tighter control over adiA expression. Increased survival at low pH was only observed when adiA and adiC were coregulated by rhamnose and depended on the presence of rhamnose in the culture medium and arginine in the challenge medium. Rhamnose regulated acid resistance significantly improved the survival of DeltaaroD and DeltaphoPQ mutants at pHs 3 and 2.5 but only modestly improved the survival of a fur mutant. The construction of the rhamnose-regulated arginine decarboxylase system allowed us to render S. Typhi acid resistant (to pH 2.5) on demand, with survival levels approximately equivalent to that of the native arginine decarboxylase system. PMID- 23645604 TI - Ubiquinone and menaquinone electron carriers represent the yin and yang in the redox regulation of the ArcB sensor kinase. AB - The Arc two-component system, comprising the ArcB sensor kinase and the ArcA response regulator, modulates the expression of numerous genes in response to respiratory growth conditions. Under aerobic growth conditions, the ubiquinone electron carriers were proposed to silence the kinase activity of ArcB by oxidizing two cytosol-located redox-active cysteine residues that participate in intermolecular disulfide bond formation. Here, we confirm the role of the ubiquinone electron carriers as the silencing signal of ArcB in vivo, we show that the redox potential of ArcB is about -41 mV, and we demonstrate that the menaquinols are required for proper ArcB activation upon a shift from aerobic to anaerobic growth conditions. Thus, an essential link in the Arc signal transduction pathway connecting the redox state of the quinone pool to the transcriptional apparatus is elucidated. PMID- 23645605 TI - Dissecting the metal selectivity of MerR monovalent metal ion sensors in Salmonella. AB - Two homologous transcription factors, CueR and GolS, that belong to the MerR metalloregulatory family are responsible for Salmonella Cu and Au sensing and resistance, respectively. They share similarities not only in their sequences, but also in their target transcription binding sites. While CueR responds similarly to Au, Ag, or Cu to induce the expression of its target genes, GolS shows higher activation by Au than by Ag or Cu. We showed that the ability of GolS to distinguish Au from Cu resides in the metal-binding loop motif. Here, we identify the amino acids within the motif that determine in vivo metal selectivity. We show that residues at positions 113 and 118 within the metal binding loop are the main contributors to metal selectivity. The presence of a Pro residue at position 113 favors the detection of Cu, while the presence of Pro at position 118 disfavors it. Our results highlight the molecular bases that allow these regulators to coordinate the correct metal ion directing the response to a particular metal injury. PMID- 23645606 TI - Mobile contingency management as an adjunctive smoking cessation treatment for smokers with posttraumatic stress disorder. AB - INTRODUCTION: Smokers with posttraumatic stress disorder (PTSD) smoke at higher prevalence rates and are more likely to relapse early in a quit attempt. Innovative methods are needed to enhance quit rates, particularly in the early quit period. Web-based contingency-management (CM) approaches have been found helpful in reducing smoking among other difficult-to-treat smoker populations but are limited by the need for computers. This pilot study builds on the web-based CM approach by evaluating a smartphone-based application for CM named mobile CM (mCM). METHODS: Following a 2-week training period, 22 smokers with PTSD were randomized to a 4-week mCM condition or a yoked (i.e., noncontingent 4-week mCM condition). All smokers received 2 smoking cessation counseling sessions, nicotine replacement, and bupropion. Participants could earn up to $690 ($530 for mCM, $25.00 for assessments and office visits [up to 5], and $35.00 for equipment return). The average earned was $314.00. RESULTS: Compliance was high during the 2-week training period (i.e., transmission of videos) (93%) and the 4-week treatment period (92%). Compliance rates did not differ by group assignment. Four week quit rates (verified with CO) were 82% for the mCM and 45% for the yoked controls. Three-month self-report quit rates were 50% in the mCM and 18% in the yoked controls. CONCLUSIONS: mCM may be a useful adjunctive smoking cessation treatment component for reducing smoking among smokers with PTSD, particularly early in a smoking quit attempt. PMID- 23645607 TI - Primary and dual users of little cigars/cigarillos and large cigars: demographic and tobacco use profiles. AB - BACKGROUND: Although cigarettes are regulated through the Family Smoking Prevention and Tobacco Control Act, cigars are currently not regulated and tend to be lower in price. Despite the rising use of cigars in the United States, little is known about the prevalence of use of little cigars/cigarillos (LCCs) versus large cigars (LCs) and the profile of these distinct cigar users. METHODS: This study uses data from Legacy's Young Adult Cohort, a nationally representative study of 4,215 young adults, ages 18-34. Cigar use was divided into three groups: ever use of LCCs only, ever use of LCs only, and ever dual users. Multinomial regression was used to determine the differential demographic characteristics and tobacco use behaviors associated with the three cigar-use groups. RESULTS: Ever cigar use was reported by 37.9% (n = 1,596) of the young adult cohort. Of the cigar smokers, 21.5% (n = 344) had used only LCCs, 32.3% (n = 515) had used only LCs, and 46.2% (n = 737) were dual users of both. In comparison with LC-only users, LCC-only users were more like to be younger (relative risk ratio [RRR] = 0.40, p < .001 for 25-34 vs. 18-24 years), female (RRR = 4.92, p < .001), non-Hispanic Black (RRR = 2.91, p < .001), and smoke cigarettes daily. Dual users were more likely than LC-only users to be female (RRR = 1.61, p = .03), non-Hispanic Black (RRR = 2.06, p = .04), and use a higher numbers of tobacco products (RRR = 4.44, p < .001). CONCLUSIONS: Cigar use is prevalent among young adults with the highest proportion using both LCCs and LCs. Interventions to curb use should consider the differential demographic and tobacco use patterns of cigar users. PMID- 23645608 TI - Pictorial health warnings on cigarette packages in qatar: preimplementation awareness and perceptions of ever-smokers versus never-smokers. AB - INTRODUCTION: Studies have demonstrated that pictorial health warnings (PHWs) on cigarette packages were significantly associated with increased awareness of smoking-related health hazards and behavior change. A new legislation on PHWs was recently endorsed and PHWs have recently been introduced in Qatar. This study aims to evaluate the general public's awareness, beliefs, and perceptions on antitobacco PHW labels on cigarette packs prior to the implementation of the new regulation. METHODS: A cross-sectional survey using a pretested 23-item questionnaire was conducted among randomly approached adults in Qatar. Data were analyzed using IBM SPSS((r)) version 19. Demographic characteristics and other outcomes of interest were compared using chi-square or Fisher's exact tests. RESULTS: A total of 500 participants (59% male) responded to the survey. Most notably, ever-smokers did not significantly differ from never-smokers on awareness of PHW. About one third of the respondents had no idea about any specific text warning messages on tobacco products sold and nearly 45% of them did not know what a PHW was. Furthermore, a substantial proportion (more than 20%) of the respondents in both groups did not believe that introducing PHWs will enhance smoking behavior change. Nonsmokers generally tended to have more positive attitudes than smokers toward perceived impact of PHWs. CONCLUSION: These findings suggest the needs for increased awareness about the value of PHWs and call for further research to determine the effectiveness of PHW labels on cigarette packages in Qatar and greater Middle Eastern region, where legislations on PHWs are still at infancy. PMID- 23645609 TI - Different patterns by age-group and gender of socioeconomic inequalities in smoking in Colombia. AB - INTRODUCTION: Evidence on socioeconomic inequalities in smoking from low- and middle-income countries has shown some inconsistency between countries. We have studied the socioeconomic inequalities in current smoking, ever smoking, and smoking cessation in Colombia by age-group and gender. METHODS: Sixty thousand, three hundred and forty-nine Colombian men and women aged 12-69 years were selected at random from the results of a national survey. We used Pearson's chi square and Robust Poisson regression analyses to estimate adjusted prevalence ratios between smoking behaviors and 2 indicators of socioeconomic position; individuals' educational level and household socioeconomic stratum. RESULTS: In men aged 45-69 years, higher socioeconomic stratum and higher education were associated with a lower rate of current smoking (PR = 0.49 [95% CI, 0.32-0.73] and PR = 0.64 [95% CI, 0.47-0.86], respectively), a history of smoking (PR = 0.67 [95% CI, 0.53-0.85] and PR = 0.75 [95% CI, 0.63-0.90], respectively), or a higher rate of smoking cessation (PR = 1.37 [95% CI, 1.09-1.72] and PR = 0.18 [95% CI, 0.99-1.72], respectively). In men aged 18-44 years, higher education was associated with lower odds of current and history of smoking (PR = 0.75 [95% CI, 0.61-0.92 and PR = 0.81 [95% CI, 0.67-0.98], respectively). Results in women and adolescents were mixed. CONCLUSIONS: In Colombia, the overall declining prevalence of smoking in men seems to be accompanied by a narrowing of smoking inequalities in successive birth cohorts, suggesting a favorable evolution of the tobacco epidemic. Further research will be required to identify factors that have contributed these optimal circumstances in tobacco control. PMID- 23645611 TI - Comparing JEMs in population-based studies: what if expert assessment and measurements are not available? Authors' response. PMID- 23645610 TI - Personal and workplace psychosocial risk factors for carpal tunnel syndrome: a pooled study cohort. AB - BACKGROUND: Between 2001 and 2010, six research groups conducted coordinated multiyear, prospective studies of carpal tunnel syndrome (CTS) incidence in US workers from various industries and collected detailed subject-level exposure information with follow-up symptom, physical examination, electrophysiological measures and job changes. OBJECTIVE: This analysis of the pooled cohort examined the incidence of dominant-hand CTS in relation to demographic characteristics and estimated associations with occupational psychosocial factors and years worked, adjusting for confounding by personal risk factors. METHODS: 3515 participants, without baseline CTS, were followed-up to 7 years. Case criteria included symptoms and an electrodiagnostic study consistent with CTS. Adjusted HRs were estimated in Cox proportional hazard models. Workplace biomechanical factors were collected but not evaluated in this analysis. RESULTS: Women were at elevated risk for CTS (HR=1.30; 95% CI 0.98 to 1.72), and the incidence of CTS increased linearly with both age and body mass index (BMI) over most of the observed range. High job strain increased risk (HR=1.86; 95% CI 1.11 to 3.14), and social support was protective (HR=0.54; 95% CI 0.31 to 0.95). There was an inverse relationship with years worked among recent hires with the highest incidence in the first 3.5 years of work (HR=3.08; 95% CI 1.55 to 6.12). CONCLUSIONS: Personal factors associated with an increased risk of developing CTS were BMI, age and being a woman. Workplace risk factors were high job strain, while social support was protective. The inverse relationship between CTS incidence and years worked among recent hires suggests the presence of a healthy worker survivor effect in the cohort. PMID- 23645612 TI - A special focus on diseases of aquatic animals. PMID- 23645614 TI - The ACVP certification process: change is needed. PMID- 23645615 TI - SNE is not NLE is not GME. PMID- 23645616 TI - Response. PMID- 23645617 TI - Meeting report: Urinary Pathology; sixth Research Triangle Park Rodent Pathology Course. AB - Urinary system toxicity is a significant concern to pathologists in the hazard identification, drug and chemical safety evaluation, and diagnostic service industries worldwide. There are myriad known human and animal urinary system toxicants, and investigatory renal toxicology and pathology is continually evolving. The system-specific Research Triangle Park (RTP) Rodent Pathology Course biennially serves to update scientists on the latest research, laboratory techniques, and debates. The Sixth RTP Rodent Pathology Course, Urinary Pathology, featured experts from the government, pharmaceutical, academic, and diagnostic arenas sharing the state of the science in urinary pathology. Speakers presented on a wide range of topics including background lesions, treatment related non-neoplastic and neoplastic lesions, transgenic rodent models of human disease, diagnostic imaging, biomarkers, and molecular analyses. These seminars were accompanied by case presentation sessions focused on usual and unusual lesions, grading schemes, and tumors. PMID- 23645619 TI - Obesity and colorectal cancer. PMID- 23645620 TI - Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras mediated pancreatic neoplastic initiation. AB - OBJECTIVES: Emerging evidence from mouse models suggests that mutant Kras can drive the development of pancreatic ductal adenocarcinoma (PDA) precursors from acinar cells by enforcing ductal de-differentiation at the expense of acinar identity. Recently, human genome-wide association studies have identified NR5A2, a key regulator of acinar function, as a susceptibility locus for human PDA. We investigated the role of Nr5a2 in exocrine maintenance, regeneration and Kras driven neoplasia. DESIGN: To investigate the function of Nr5a2 in the pancreas, we generated mice with conditional pancreatic Nr5a2 deletion (PdxCre(late); Nr5a2(c/c)). Using this model, we evaluated acinar differentiation, regeneration after caerulein pancreatitis and Kras driven pancreatic neoplasia in the setting of Nr5a2 deletion. RESULTS: We show that Nr5a2 is not required for the development of the pancreatic acinar lineage but is important for maintenance of acinar identity. Nr5a2 deletion leads to destabilisation of the mature acinar differentiation state, acinar to ductal metaplasia and loss of regenerative capacity following acute caerulein pancreatitis. Loss of Nr5a2 also dramatically accelerates the development of oncogenic Kras driven acinar to ductal metaplasia and PDA precursor lesions. CONCLUSIONS: Nr5a2 is a key regulator of acinar plasticity. It is required for maintenance of acinar identity and re-establishing acinar fate during regeneration. Nr5a2 also constrains pancreatic neoplasia driven by oncogenic Kras, providing functional evidence supporting a potential role as a susceptibility gene for human PDA. PMID- 23645621 TI - Dose-response relationship between hand-transmitted vibration and hand-arm vibration syndrome in a tropical environment. AB - OBJECTIVES: The dose-response relationship for hand-transmitted vibration has been investigated extensively in temperate environments. Since the clinical features of hand-arm vibration syndrome (HAVS) differ between the temperate and tropical environment, we conducted this study to investigate the dose-response relationship of HAVS in a tropical environment. METHODS: A total of 173 male construction, forestry and automobile manufacturing plant workers in Malaysia were recruited into this study between August 2011 and 2012. The participants were interviewed for history of vibration exposure and HAVS symptoms, followed by hand functions evaluation and vibration measurement. Three types of vibration doses-lifetime vibration dose (LVD), total operating time (TOT) and cumulative exposure index (CEI)-were calculated and its log values were regressed against the symptoms of HAVS. The correlation between each vibration exposure dose and the hand function evaluation results was obtained. RESULTS: The adjusted prevalence ratio for finger tingling and numbness was 3.34 (95% CI 1.27 to 8.98) for subjects with lnLVD>=20 ln m(2) s(-4) against those <16 ln m(2) s(-4). Similar dose-response pattern was found for CEI but not for TOT. No subject reported white finger. The prevalence of finger coldness did not increase with any of the vibration doses. Vibrotactile perception thresholds correlated moderately with lnLVD and lnCEI. CONCLUSIONS: The dose-response relationship of HAVS in a tropical environment is valid for finger tingling and numbness. The LVD and CEI are more useful than TOT when evaluating the dose-response pattern of a heterogeneous group of vibratory tools workers. PMID- 23645622 TI - Single high flow exhaled nitric oxide is an imperfect proxy for distal nitric oxide. PMID- 23645623 TI - Long- and short-term weight change and incident coronary heart disease and ischemic stroke: the Atherosclerosis Risk in Communities Study. AB - Weight gain increases the prevalence of obesity, a risk factor for cardiovascular disease. Nevertheless, unintentional weight loss can be a harbinger of health problems. The Atherosclerosis Risk in Communities Study (1987-2009) included 15,792 US adults aged 45-64 years at baseline and was used to compare associations of long-term (30 years) and short-term (3 years) weight change with the risks of coronary heart disease (CHD) and ischemic stroke. Age-, gender-, and race-standardized incidence rates were 4.9 (95% confidence interval (CI): 4.6, 5.2) per 1,000 person-years for CHD and 2.5 (95% CI: 2.3, 2.8) per 1,000 person years for stroke. After controlling for baseline body mass index and other covariates, long-term weight gain (since age 25 years) of more than 2.7% was associated with elevated CHD risk, and any long-term weight gain was associated with increased stroke risk. Among middle-aged adults, short-term (3-year) weight loss of more than 3% was associated with elevated immediate CHD risk (hazard ratio = 1.46, 95% CI: 1.18, 1.81) and stroke risk (hazard ratio = 1.45, 95% CI: 1.10, 1.92). Risk tended to be larger in adults whose weight loss did not occur through dieting. Avoidance of weight gain between early and middle adulthood can reduce risks of CHD and stroke, but short-term, unintentional weight loss in middle adulthood may be an indicator of immediate elevated risk that has not previously been well recognized. PMID- 23645624 TI - Breast cancer risk prediction with heterogeneous risk profiles according to breast cancer tumor markers. AB - Relationships between some risk factors and breast cancer incidence are known to vary by tumor subtype. However, breast tumors can be classified according to a number of markers, which may be correlated, making it difficult to identify heterogeneity of risk factors with specific tumor markers when using standard competing-risk survival analysis. In this paper, we propose a constrained competing-risk survival model that allows for assessment of heterogeneity of risk factor associations according to specific tumor markers while controlling for other markers. These methods are applied to Nurses' Health Study data from 1980 2006, during which 3,398 incident invasive breast cancers occurred over 1.4 million person-years of follow-up. Results suggested that when estrogen receptor (ER) and progesterone receptor (PR) status are mutually considered, some risk factors thought to be characteristic of "estrogen-positive tumors," such as high body mass index during postmenopause and increased height, are actually significantly associated with PR-positive tumors but not ER-positive tumors, while other risk factors thought to be characteristic of "estrogen-negative tumors," such as late age at first birth, are actually significantly associated with PR-negative rather than ER-negative breast cancer. This approach provides a strategy for evaluating heterogeneity of risk factor associations by tumor marker levels while controlling for additional tumor markers. PMID- 23645625 TI - Impact of time to maternal interview on interview responses in the National Birth Defects Prevention Study. AB - Prenatal exposures often are assessed using retrospective interviews. Time from exposure to interview may influence data accuracy. We investigated the association of time to interview (TTI) with aspects of interview responses in the National Birth Defects Prevention Study, a population-based case-control study of birth defects in 10 US states. Mothers completed a computer-assisted telephone interview 1.5-24 months after their estimated date of delivery. Proxy metrics for interview quality were whether certain exposures were reported, whether the start month of reported medication use or illness was reported, or whether responses were missing. Interaction by case status was assessed. Interviews were completed with 30,542 mothers (22,366 cases and 8,176 controls) who gave birth between 1997 and 2007. Mothers of cases were interviewed later than were mothers of controls (11.7 months vs. 9.5 months, respectively). In adjusted analyses, having a TTI that was greater than 6 months was associated with only a few aspects of interview responses (e.g., start month of pseudoephedrine use). Interaction by case-control status was observed for some exposures; mothers of controls had a greater reduction in interview quality with increased TTI in these instances (e.g., report of morning sickness, start month of acetaminophen use and ibuprofen use). The results suggest that TTI might impact interview responses; however, the impact may be minimal and specific to the type of exposure. PMID- 23645627 TI - Mechanisms of postprandial abdominal bloating and distension in functional dyspepsia. AB - OBJECTIVE: Patients with irritable bowel syndrome and abdominal bloating exhibit abnormal responses of the abdominal wall to colonic gas loads. We hypothesised that in patients with postprandial bloating, ingestion of a meal triggers comparable abdominal wall dyssynergia. Our aim was to characterise abdominal accommodation to a meal in patients with postprandial bloating. DESIGN: A test meal (0.8 kcal/ml nutrients plus 27 g/litre polyethylenglycol 4000) was administered at 50 ml/min as long as tolerated in 10 patients with postprandial bloating (fulfilling Rome III criteria for postprandial distress syndrome) and 12 healthy subjects, while electromyographic (EMG) responses of the anterior wall (upper and lower rectus, external and internal oblique via bipolar surface electrodes) and the diaphragm (via six ring electrodes over an oesophageal tube in the hiatus) were measured. Means +/- SD were calculated. RESULTS: Healthy subjects tolerated a meal volume of 913+/-308 ml; normal abdominal wall accommodation to the meal consisted of diaphragmatic relaxation (EMG activity decreased by 15+/-6%) and a compensatory contraction (25+/-9% increase) of the upper abdominal wall muscles (upper rectus and external oblique), with no changes in the lower anterior muscles (lower rectus and internal oblique). Patients tolerated lower volume loads (604+/-310 ml; p=0.030 vs healthy subjects) and developed a paradoxical response, that is, diaphragmatic contraction (14+/-3% EMG increment; p<0.01 vs healthy subjects) and upper anterior wall relaxation (9+/-4% inhibition; p<0.01 vs healthy subjects). CONCLUSIONS: In functional dyspepsia, postprandial abdominal distension is produced by an abnormal viscerosomatic response to meal ingestion that alters normal abdominal accommodation. PMID- 23645626 TI - The use of benzodiazepines could be a protective factor for community-acquired pneumonia (CAP) in <= 60-year-old subjects. PMID- 23645628 TI - Disruption of the ndhF1 gene affects Chl fluorescence through state transition in the Cyanobacterium Synechocystis sp. PCC 6803, resulting in apparent high efficiency of photosynthesis. AB - In Synechocystis sp. PCC 6803, the disruption of the ndhF1 gene (slr0844), which encodes a subunit of one of the NDH-1 complexes (NDH-1L complex) serving for respiratory electron transfer, causes the largest change in Chl fluorescence induction kinetics among the kinetics of 750 disruptants searched in the Fluorome, the cyanobacterial Chl fluorescence database. The cause of the explicit phenotype of the ndhF1 disruptant was examined by measurements of the photosynthetic rate, Chl fluorescence and state transition. The results demonstrate that the defects in respiratory electron transfer obviously have great impact on Chl fluorescence in cyanobacteria. The inactivation of NDH-1L complexes involving electron transfer from NDH-1 to plastoquinone (PQ) would result in the oxidation of the PQ pool, leading to the transition to State 1, where the yield of Chl fluorescence is high. Apparently, respiration, although its rate is far lower than that of photosynthesis, could affect Chl fluorescence through the state transition as leverage. The disruption of the ndhF1 gene caused lower oxygen-evolving activity but the estimated electron transport rate from Chl fluorescence measurements was faster in the mutant than in the wild-type cells. The discrepancy could be ascribed to the decreased level of non-photochemical quenching due to state transition. One must be cautious when using the Chl fluorescence parameter to estimate photosynthesis in mutants defective in state transition. PMID- 23645629 TI - Beyond scoring: a modern interpretation of disease progression in chronic liver disease. PMID- 23645631 TI - Comprehensive protein-based artificial microRNA screens for effective gene silencing in plants. AB - Artificial microRNA (amiRNA) approaches offer a powerful strategy for targeted gene manipulation in any plant species. However, the current unpredictability of amiRNA efficacy has limited broad application of this promising technology. To address this, we developed epitope-tagged protein-based amiRNA (ETPamir) screens, in which target mRNAs encoding epitope-tagged proteins were constitutively or inducibly coexpressed in protoplasts with amiRNA candidates targeting single or multiple genes. This design allowed parallel quantification of target proteins and mRNAs to define amiRNA efficacy and mechanism of action, circumventing unpredictable amiRNA expression/processing and antibody unavailability. Systematic evaluation of 63 amiRNAs in 79 ETPamir screens for 16 target genes revealed a simple, effective solution for selecting optimal amiRNAs from hundreds of computational predictions, reaching ~100% gene silencing in plant cells and null phenotypes in transgenic plants. Optimal amiRNAs predominantly mediated highly specific translational repression at 5' coding regions with limited mRNA decay or cleavage. Our screens were easily applied to diverse plant species, including Arabidopsis thaliana, tobacco (Nicotiana benthamiana), tomato (Solanum lycopersicum), sunflower (Helianthus annuus), Catharanthus roseus, maize (Zea mays) and rice (Oryza sativa), and effectively validated predicted natural miRNA targets. These screens could improve plant research and crop engineering by making amiRNA a more predictable and manageable genetic and functional genomic technology. PMID- 23645630 TI - Antagonistic basic helix-loop-helix/bZIP transcription factors form transcriptional modules that integrate light and reactive oxygen species signaling in Arabidopsis. AB - The critical developmental switch from heterotrophic to autotrophic growth of plants involves light signaling transduction and the production of reactive oxygen species (ROS). ROS function as signaling molecules that regulate multiple developmental processes, including cell death. However, the relationship between light and ROS signaling remains unclear. Here, we identify transcriptional modules composed of the basic helix-loop-helix and bZIP transcription factors PHYTOCHROME-INTERACTING FACTOR1 (PIF1), PIF3, ELONGATED HYPOCOTYL5 (HY5), and HY5 HOMOLOGY (HYH) that bridge light and ROS signaling to regulate cell death and photooxidative response. We show that pif mutants release more singlet oxygen and exhibit more extensive cell death than the wild type during Arabidopsis thaliana deetiolation. Genome-wide expression profiling indicates that PIF1 represses numerous ROS and stress-related genes. Molecular and biochemical analyses reveal that PIF1/PIF3 and HY5/HYH physically interact and coordinately regulate the expression of five ROS-responsive genes by directly binding to their promoters. Furthermore, PIF1/PIF3 and HY5/HYH function antagonistically during the seedling greening process. In addition, phytochromes, cryptochromes, and CONSTITUTIVE PHOTOMORPHOGENIC1 act upstream to regulate ROS signaling. Together, this study reveals that the PIF1/PIF3-HY5/HYH transcriptional modules mediate crosstalk between light and ROS signaling and sheds light on a new mechanism by which plants adapt to the light environments. PMID- 23645633 TI - Biomineralization toolkit: the importance of sample cleaning prior to the characterization of biomineral proteomes. PMID- 23645632 TI - Ubiquitin-specific proteases UBP12 and UBP13 act in circadian clock and photoperiodic flowering regulation in Arabidopsis. AB - Protein ubiquitination is involved in most cellular processes. In Arabidopsis (Arabidopsis thaliana), ubiquitin-mediated protein degradation regulates the stability of key components of the circadian clock feedback loops and the photoperiodic flowering pathway. Here, we identified two ubiquitin-specific proteases, UBP12 and UBP13, involved in circadian clock and photoperiodic flowering regulation. Double mutants of ubp12 and ubp13 display pleiotropic phenotypes, including early flowering and short periodicity of circadian rhythms. In ubp12 ubp13 double mutants, CONSTANS (CO) transcript rises earlier than that of wild-type plants during the day, which leads to increased expression of FLOWERING LOCUS T. This, and analysis of ubp12 co mutants, indicates that UBP12 and UBP13 regulate photoperiodic flowering through a CO-dependent pathway. In addition, UBP12 and UBP13 regulate the circadian rhythm of clock genes, including LATE ELONGATED HYPOCOTYL, CIRCADIAN CLOCK ASSOCIATED1, and TIMING OF CAB EXPRESSION1. Furthermore, UBP12 and UBP13 are circadian controlled. Therefore, our work reveals a role for two deubiquitinases, UBP12 and UBP13, in the control of the circadian clock and photoperiodic flowering, which extends our understanding of ubiquitin in daylength measurement in higher plants. PMID- 23645636 TI - Healing power of honey. PMID- 23645634 TI - Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema. AB - Alveolar fluid clearance driven by active epithelial Na(+) and secondary Cl(-) absorption counteracts edema formation in the intact lung. Recently, we showed that impairment of alveolar fluid clearance because of inhibition of epithelial Na(+) channels (ENaCs) promotes cardiogenic lung edema. Concomitantly, we observed a reversal of alveolar fluid clearance, suggesting that reversed transepithelial ion transport may promote lung edema by driving active alveolar fluid secretion. We, therefore, hypothesized that alveolar ion and fluid secretion may constitute a pathomechanism in lung edema and aimed to identify underlying molecular pathways. In isolated perfused lungs, alveolar fluid clearance and secretion were determined by a double-indicator dilution technique. Transepithelial Cl(-) secretion and alveolar Cl(-) influx were quantified by radionuclide tracing and alveolar Cl(-) imaging, respectively. Elevated hydrostatic pressure induced ouabain-sensitive alveolar fluid secretion that coincided with transepithelial Cl(-) secretion and alveolar Cl(-) influx. Inhibition of either cystic fibrosis transmembrane conductance regulator (CFTR) or Na(+)-K(+)-Cl(-) cotransporters (NKCC) blocked alveolar fluid secretion, and lungs of CFTR(-/-) mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride reproduced alveolar fluid and Cl(-) secretion that were again CFTR-, NKCC-, and Na(+)-K(+)-ATPase-dependent. Our findings show a reversal of transepithelial Cl(-) and fluid flux from absorptive to secretory mode at hydrostatic stress. Alveolar Cl(-) and fluid secretion are triggered by ENaC inhibition and mediated by NKCC and CFTR. Our results characterize an innovative mechanism of cardiogenic edema formation and identify NKCC1 as a unique therapeutic target in cardiogenic lung edema. PMID- 23645637 TI - Intramural gas in stomach along with acute calculus cholecystitis: an unusual association. AB - Intramural gas in stomach is a rare finding, but differential diagnosis of this condition into gastric emphysema and emphysematous gastritis is clinically important because of vastly different aetiologies and prognosis. Emphysematous gastritis is caused by gas producing micro-organisms inside the stomach wall and is a potentially fatal condition, while, on the other hand, gas enters stomach wall through mucosal breach in the case of gastric emphysema and prognosis is usually good with complete resolution. To date, no case has been reported in the literature showing gas in the stomach wall in a patient with acute calculus cholecystitis. We present a case of a young man with upper abdominal pain, and who, upon diagnostic work up was diagnosed with acute calculus cholecystitis with associated intramural gas in the stomach with no known aetiological factors to be positive. Conservative management with close observation resulted in complete symptomatic resolution. PMID- 23645635 TI - Flow induces epithelial-mesenchymal transition, cellular heterogeneity and biomarker modulation in 3D ovarian cancer nodules. AB - Seventy-five percent of patients with epithelial ovarian cancer present with advanced-stage disease that is extensively disseminated intraperitoneally and prognosticates the poorest outcomes. Primarily metastatic within the abdominal cavity, ovarian carcinomas initially spread to adjacent organs by direct extension and then disseminate via the transcoelomic route to distant sites. Natural fluidic streams of malignant ascites triggered by physiological factors, including gravity and negative subdiaphragmatic pressure, carry metastatic cells throughout the peritoneum. We investigated the role of fluidic forces as modulators of metastatic cancer biology in a customizable microfluidic platform using 3D ovarian cancer nodules. Changes in the morphological, genetic, and protein profiles of biomarkers associated with aggressive disease were evaluated in the 3D cultures grown under controlled and continuous laminar flow. A modulation of biomarker expression and tumor morphology consistent with increased epithelial-mesenchymal transition, a critical step in metastatic progression and an indicator of aggressive disease, is observed because of hydrodynamic forces. The increase in epithelial-mesenchymal transition is driven in part by a posttranslational up-regulation of epidermal growth factor receptor (EGFR) expression and activation, which is associated with the worst prognosis in ovarian cancer. A flow-induced, transcriptionally regulated decrease in E cadherin protein expression and a simultaneous increase in vimentin is observed, indicating increased metastatic potential. These findings demonstrate that fluidic streams induce a motile and aggressive tumor phenotype. The microfluidic platform developed here potentially provides a flow-informed framework complementary to conventional mechanism-based therapeutic strategies, with broad applicability to other lethal malignancies. PMID- 23645638 TI - Coexistence of allergic bronchopulmonary aspergillosis and allergic aspergillus sinusitis in a patient without clinical asthma. AB - All patients with prolonged cough with a history of atopy, even if not clinically asthmatic, should be evaluated for allergic bronchopulmonary aspergillosis (ABPA); also, we suspect that we may miss the early diagnosis of ABPA if bronchial asthma is considered as a major criteria for the diagnosis of ABPA. PMID- 23645639 TI - Haemophilus influenzae type f meningitis in a previously healthy boy. AB - Non-serotype b strains of Haemophilus influenzae are extremely rare causes of acute bacterial meningitis in immunocompetent individuals. We report a case of acute bacterial meningitis in a 14-year-old boy, who was previously healthy and had been immunised against H influenzae serotype b (Hib). The causative pathogen was identified as H influenzae serotype f (Hif), and was successfully treated with ceftriaxone. An immunological evaluation revealed transient low levels of immunoglobulins but no apparent immunodeficiency was found 2 years after the clinical insult. PMID- 23645640 TI - The reprogramming therapy for a patient with advanced hepatocellular carcinoma by using human-induced pluripotent stem (iPS) cells technology. AB - Therapeutic methods to reprogramme and destroy human solid tumour cells have not been developed. We show a proof-of-concept for the direct reprogramming therapy of human solid tumour cells. Furthermore, our study is the first to report on the development of a new treatment by using human-induced pluripotent stem cells technology. PMID- 23645641 TI - Neuropsychiatric side effects of cyclobenzaprine. AB - Cyclobenzaprine is commonly used as a muscle relaxant and analgesic. Given its tricyclic properties, serotonin syndrome is a potential side effect of this drug. We report an unusual case of a patient who experienced symptoms of delirium and hyperkinetic movement disorders shortly after initiating treatment with cyclobenzaprine and oxycodone. Symptoms resolved within 48 h of discontinuing cyclobenzaprine. This case serves to remind clinicians to monitor for serotonin syndrome when initiating cyclobenzaprine, and when adding opiate or antidepressant medications to the regimen. PMID- 23645642 TI - Eosinophilic pneumonia associated with concomitant cigarette and marijuana smoking. AB - A 29-year-old Caucasian man presented for the evaluation of a new onset of shortness of breath associated with cough and wheeze for 1 day. The history was significant for a recent travel of 20 h duration to Houston, a new onset of cigarette smoking for 2 weeks and marijuana smoking. The patient was afebrile and did not have any leg swelling; initial diagnosis of community-acquired pneumonia was made and the patient was started on antibiotics. Despite being on antibiotics, his medical condition continued to deteriorate and extensive diagnostic workup for infectious and autoimmune aetiology including bronchoalveolar lavage was completed and was inconclusive. Ultimately, the patient underwent video-assisted thoracoscopic lung biopsy which led to the diagnosis of acute eosinophilic pneumonia. Steroids were started with a good treatment response. The patient was discharged on a tapering dose of steroids; a follow-up chest x ray at 6 weeks was within normal limits. PMID- 23645643 TI - Desmoplastic ameloblastoma: a rare odontogenic neoplasm with unusual radiographic and histomorphological presentation. AB - Desmoplastic ameloblastoma (DA) is a newly recognised, rare odontogenic neoplasm that is a histological variant of ameloblastoma. In this type, the islands of ameloblastoma are surrounded and often compressed by a dense and sometimes hyalinised fibrous connective tissue. Although ameloblastomas are usually located in the mandible, this variant often occurs in the anterior maxilla. In view of the paucity of DA case series and only limited understanding of its biological behaviour and prognosis, proper treatment strategies for DA are not entirely defined so far. The purpose of this paper was to review the literature and to demonstrate a rare case for an improved understanding of the behaviour and prognosis of DA. PMID- 23645644 TI - Delayed presentation of severe ocular injury from a button battery. AB - A 2-year-old girl presented to the emergency department at 3:00 h with severe pain in her right eye and a rust coloured, blood stained frothy discharge that had woken her. An examination of her eye revealed a shiny metallic looking foreign body, which was immediately removed by the on-call ophthalmologist. That morning the patient underwent ocular examination under anaesthesia and was found to have severe tissue necrosis resulting from an electrochemical burn. She was treated with daily rodding for 3 days and betamethasone ointment four times a day, which was gradually tapered. At 3 months her only eye pathology was a mild symblepharon between the bulbar and tarsal conjunctiva. This is the first case of delayed symptoms after placement of a button battery into the conjunctival fornix. This case highlights the serious nature of button battery injuries to the eye and the potential to miss the diagnosis owing to a delayed onset of symptoms. PMID- 23645645 TI - Masseter muscle cysticercosis: a common disease with uncommon presentation. AB - Cysticercosis in humans is caused by Taenia solium larvae infestation. Oral cysticercosis is a rare condition and is challenging to diagnose. We present a case of masseter cysticercosis in a young woman who presented with painful recurrent cheek swelling. Diagnosis confirmed it after neuroimaging and histopathological examination of the excised lesion from masseter muscle. PMID- 23645646 TI - Sepsis caused by Mycobacterium terrae complex in a patient with sickle cell disease. AB - Infections are a significant cause of morbidity and mortality in patients with sickle cell disease. Loss of splenic function in these patients makes them highly susceptible to some bacterial infections. Non-tuberculous mycobacterial infections in patients with sickle cell disease are extremely rare and only two cases have been reported previously. We describe a case of sepsis caused by non tuberculous mycobacterium, Mycobacterium terrae complex in a patient with febrile sickle cell disease. M terrae complex is a rare clinical pathogen and this is the first reported case of sepsis secondary to this organism in a patient with sickle cell disease. The patient responded to imipenem and amikacin therapy. PMID- 23645647 TI - Multiple endocrine neoplasia 2B: delayed presentation, rapid diagnosis. AB - Multiple endocrine neoplasia (MEN) refers to the synchronous or metachronous development of tumours in two or more endocrine organs. MEN 2B is associated with medullary thyroid carcinoma and phaeochromocytoma along with classic morphological features such as marfanoid habitus and mucosal neuromas. Dominantly inherited germline mutations involving the REarranged during Transfection (RET) proto-oncogene are responsible. Affected patients usually present in childhood with thyroid mass or gastrointestinal symptoms. We describe the case of a 28-year old man who presented to us with metastatic medullary thyroid carcinoma. He lacked the classic marfanoid habitus, but had mucosal neuromas and thickened corneal nerves. Whole-body metaiodobenzyl guanidine scan (MIBG) showed tracer uptake in adrenal and thyroid-confirming phaeochromocytoma and medullary thyroid carcinoma. This case exemplifies the late presentation of multiple endocrine neoplasia 2B and emphasises the need to screen all cases of medullary thyroid carcinoma for phaeochromocytoma. PMID- 23645648 TI - Another reason for abdominal pain: mesenteric panniculitis. PMID- 23645649 TI - Use of heparin in aortic dissection: beware the misdiagnosis of acute pulmonary embolism. AB - We present a case which highlights the diagnostic difficulties between a Stanford type A aortic dissection (AD) and a pulmonary embolism (PE) and the impact it has on subsequent management. A 75-year-old man presenting with chest pain, shortness of breath and dizziness was initially suspected of having a PE and started on low molecular-weight-heparin (LMWH). The patient was correctly diagnosed afterwards with CT of the chest to have an aortic dissection. The detrimental use of LMWH may have caused a propagation of the dissection and delayed surgical intervention of an acutely life-threatening condition. When the diagnosis is unclear, the early use of CT can help differentiate AD from PE. This in-turn can guide the management as well as the use of LMWH, which should be avoided until the correct diagnosis is confirmed. PMID- 23645650 TI - Temporomandibular joint involvement in ankylosing spondylitis. AB - Frequency of temporomandibular joint (TMJ) involvement in patients with ankylosing spondylitis (AS) has varied from 4% to 35%. It is more common in men and produces generalised stiffness in involved joints. Clinician should be suspicious of AS when a patient reports with painful restricted movements of joint, neck or back and with no trauma history. Conventional radiographic methods have allowed the demonstration of TMJ abnormalities in patients with AS, but CT is necessary to establish joint space relations and bony morphology. We describe a case of severe AS with TMJ involvement in a 40-year-old female patient and demonstrated TMJ changes on CT. A CT was able to demonstrate articular cartilage changes, disc- and joint abnormalities. Thus, if conventional radiographs in a symptomatic patient with rheumatic diseases are unable to demonstrate changes, CT can provide valuable additional information of the changes in the TMJ. PMID- 23645651 TI - Palatal tremor in relation to brainstem tumour involvement. PMID- 23645652 TI - A rheumatoid nodule in an unusual location: mediastinal lymph node. AB - Rheumatoid arthritis (RA) is a multisystem inflammatory disease characterised by destructive synovitis and varied extra-articular involvement. Rheumatoid lung nodules are the most common pulmonary manifestations of RA. Rheumatoid nodules in mediastinal lymph nodes are extremely uncommon. We describe a male patient with long-standing RA and subcutaneous rheumatoid nodules presenting with multiple lung nodules and mediastinal lymphadenopathies. Definite histopathology of a lymph node was consistent with necrobiotic granuloma due to RA. Clinicians should be aware of rheumatoid nodules as a potential cause of mediastinal lymphadenopathies, mainly in advanced rheumatoid arthritis. PMID- 23645653 TI - A rare case of open bicondylar Hoffa fracture with extensor mechanism disruption. AB - The incidence of open bicondylar Hoffa fractures is extremely rare. We report one such case of a 42-year-old woman who presented to the emergency department with an open injury over the knee. Imaging revealed bicondylar Hoffa fracture. The patient was taken up for debridement and internal fixation. Intraoperative findings included an entrapped patella between the fracture fragments and extensor mechanism disruption. Hoffas fracture was fixed with lag screws and patellar tendon repaired on to the inferior patella. The patient was started on early postoperative range of motion exercises. The fracture united at 12 weeks with 120 degrees knee flexion at 2 year follow-up. PMID- 23645654 TI - An intracerebral mass: tuberculosis or sarcoidosis? AB - Sarcoidosis is an idiopathic, chronic granulomatous disease and it can affect almost any organ. In autopsy series, it has been reported that the central nervous system involvement has occurred in 5-16% of the patients with sarcoidosis, while the neurological symptoms have occurred only in 3-9% of them. A 40-year-old female patient was admitted to the hospital with complaints of aphasia, balance disorder and drowsiness. An intracerebral mass was detected on cranial CT scans and neurosarcoidosis was diagnosed with clinical, radiological and histopathological findings. PMID- 23645655 TI - Mucormycosis: an atrocious mate of patients with diabetes. AB - Mucormycosis also called zygomycosis is a rare infection caused by saprophytic aerobic fungus that belongs to a group of fungi called Mucoromycotina in the order Mucorales. Earlier these fungi were called Zygomycota but this scientific name has recently been changed. Mucormycosis can result in an acute, rapidly advancing and occasionally fatal disease caused by different fungi typically found in the soil and in association with decaying organic matter such as leaves, compost piles or rotten wood. These fungal infections are relatively infrequent; however, they occur in individuals who are debilitated in some major way and occasionally in groups of people with multiple penetrating injuries that are contaminated with soil and water from the environment. Mucormycosis is not contagious and does not spread from person to person. PMID- 23645656 TI - IgG4-related multiorgan disease: report of the first autopsy case. AB - IgG4-related disease (IgG4RD) is a chronic recurring fibro-inflammatory pathology that is considered to be of autoimmune origin. Histopathology is considered to be the gold standard method for diagnosis. IgG4RD affects multiple organs. IgG4RD was first identified in the pancreas and was called autoimmune pancreatitis (AIP). During the following years, the disease spectrum was expanded and it was realised that the extrapancreatic lesions can precede, coexist or appear after the diagnosis of AIP. At present, several illnesses such as Mikulicz disease, Kuttner tumour, multifocal fibrosclerosis, etc, are considered to be part of the IgG4RD spectrum. The symptoms of the disease tend to appear over months and years and diagnosis is achieved on average 13.5 months (4-60 months) after the onset. The purpose of this report was to provide information about a case that was sadly fatal but that permitted a complete histopathological study of the damaged tissues. PMID- 23645657 TI - The use of rituximab and bendamustine in treating chronic lymphocytic leukaemia (CLL) in end-stage renal disease (ESRD). AB - A patient with a history of type 2 diabetes mellitus and chronic lymphocytic leukaemia has renal failure with large kidneys. The patient refused kidney biopsy to determine the aetiology of her renal failure. She uses peritoneal dialysis to treat renal failure. She received rituximab and bendamustine to treat chronic lymphocytic leukaemia. Adenopathy resolves with treatment and she does not experience any electrolyte disturbances or decrease in urine output as a result of chemotherapy in the setting of renal failure. Renal function did not recover with chemotherapy. PMID- 23645658 TI - Mononeuritis multiplex and painful ulcers as the initial manifestation of hepatitis B infection. AB - Hepatitis B virus infection leads to multisystem manifestations owing to involvement of kidney, skin, vasculature, haematopoietic and nervous system. The hepatitis B infection can cause neuropathy either to vasculitis associated with polyarteritis nodosa or immune-mediated neural damage. In this submission, we report a young woman, who presented with mononeuritis multiplex and painful ulcerations as the first manifestation of chronic hepatitis B virus infection. The antiviral therapy along with steroids led to remarkable recovery. The clinical settings of hepatitis B virus infection should not be ignored in the presentation of mononeuritis multiplex with ulcers, although the commonest cause is leprosy in the Indian sub-continent. PMID- 23645659 TI - Postoperative pulmonary calcification in a child with truncus arteriosus. AB - Pulmonary calcification is uncommon in children. It is rarely described following cardiac surgery. Here, the authors describe the case of an infant who developed extensive pulmonary calcification following the repair of truncus arteriosus. PMID- 23645660 TI - T-cell prolymphocytic leukaemia (T-PLL): a rare disease with a grave prognosis. AB - T-cell prolymphocytic leukaemia (T-PLL) is an extremely uncommon haematological malignancy that has an aggressive course and a grave prognosis. We describe a patient who presented with lymphocytosis, scalp erythema, ascites and splenomegaly and was diagnosed with T-PLL. He was treated with alemtuzumab with a good response and was referred for allogeneic stem cell transplantation. PMID- 23645661 TI - Irreducible lateral dislocation of patella. PMID- 23645662 TI - Severe rheumatoid arthritis hand deformity. PMID- 23645663 TI - Double embolic protection during carotid artery stenting with persistent hypoglossal artery. AB - A woman presented with 75% stenosis of the right internal carotid artery (ICA) with extension to the origin of a persistent hypoglossal artery (PHA). The PHA is a rare fetal variant of carotid-basilar anastomosis that elevates the risk of ischemia and embolic infarction within the posterior cerebral circulation in patients with carotid disease proximal to the anastomosis. Our case is highly unique because of the extremely rare nature of the PHA with associated ICA stenosis that extended to the PHA. Additionally, a novel treatment approach was employed by stenting and angioplasty while protecting both the anterior and posterior cerebral circulations. PMID- 23645664 TI - Prevalence of and risk factors for chronic arthralgia and rheumatoid-like polyarthritis more than 2 years after infection with chikungunya virus. AB - OBJECTIVES: Chikungunya virus (CHIKV), transmitted to humans from infected mosquitoes, causes acute fever, arthralgia and rash. There is increasing evidence that it also causes longer-term rheumatic symptoms. In a circumscribed part of Mauritius where infectivity was high, a cohort of inhabitants was surveyed with the objectives of assessing the prevalence of and risk factors for chronic musculoskeletal symptoms and for a rheumatoid arthritis-like condition at 27.5 months after initial infection. METHODS: Participants were recruited May-November 2008 and invited to complete a questionnaire. CHIKV was diagnosed clinically. The primary outcomes for the analyses were (a) self-reported ongoing musculoskeletal symptoms and (b) fulfilment of modified diagnostic criteria for rheumatoid arthritis. Risk factors for these outcomes were explored in univariate analyses using logistic regression. Subsequently, multivariate logistic regression was used to identify factors that were independently associated with the outcomes. RESULTS: 173 individuals were identified with CHIKV, of whom 136 (78.6%) reported persisting musculoskeletal symptoms 27.5 months after infection. Persistent symptoms were associated with older age at time of infection, female gender and baseline symmetrical distribution of joint symptoms. We found that 5% of those infected with CHIKV fulfilled a modified version of the American College of Rheumatology criteria for rheumatoid arthritis 27.5 months after infection. CONCLUSIONS: CHIKV is associated with a high prevalence of persistent rheumatic symptoms. Physicians need to be aware of CHIKV as a cause of acute and chronic rheumatic symptoms. PMID- 23645665 TI - Low dose ultraviolet B irradiation increases hyaluronan synthesis in epidermal keratinocytes via sequential induction of hyaluronan synthases Has1-3 mediated by p38 and Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling. AB - Hyaluronan, a major epidermal extracellular matrix component, responds strongly to different kinds of injuries. This also occurs by UV radiation, but the mechanisms involved are poorly understood. The effects of a single ultraviolet B (UVB) exposure on hyaluronan content and molecular mass, and expression of genes involved in hyaluronan metabolism were defined in monolayer and differentiated, organotypic three-dimensional cultures of rat epidermal keratinocytes. The signals regulating the response were characterized using specific inhibitors and Western blotting. In monolayer cultures, UVB increased hyaluronan synthase Has1 mRNA already 4 h postexposure, with a return to control level by 24 h. In contrast, Has2 and Has3 were persistently elevated from 8 h onward. Silencing of Has2 and especially Has3 decreased the UVB-induced accumulation of hyaluronan. p38 and Ca(2+)/calmodulin-dependent protein kinase II pathways were found to be involved in the UVB-induced up-regulation of Has2 and Has3 expression, respectively, and their inhibition reduced hyaluronan deposition. However, the expressions of the hyaluronan-degrading enzymes Hyal1 and Hyal2 and the hyaluronan receptor Cd44 were also up-regulated by UVB. In organotypic cultures, UVB treatment also resulted in increased expression of both Has and Hyal genes and shifted hyaluronan toward a smaller size range. Histochemical stainings indicated localized losses of hyaluronan in the epidermis. The data show that exposure of keratinocytes to acute, low dose UVB increases hyaluronan synthesis via up-regulation of Has2 and Has3. The simultaneously enhanced catabolism of hyaluronan demonstrates the complexity of the UVB-induced changes. Nevertheless, enhanced hyaluronan metabolism is an important part of the adaptation of keratinocytes to radiation injury. PMID- 23645666 TI - The bacterial translocon SecYEG opens upon ribosome binding. AB - In co-translational translocation, the ribosome funnel and the channel of the protein translocation complex SecYEG are aligned. For the nascent chain to enter the channel immediately after synthesis, a yet unidentified signal triggers displacement of the SecYEG sealing plug from the pore. Here, we show that ribosome binding to the resting SecYEG channel triggers this conformational transition. The purified and reconstituted SecYEG channel opens to form a large ion-conducting channel, which has the conductivity of the plug deletion mutant. The number of ion-conducting channels inserted into the planar bilayer per fusion event roughly equals the number of SecYEG channels counted by fluorescence correlation spectroscopy in a single proteoliposome. Thus, the open probability of the channel must be close to unity. To prevent the otherwise lethal proton leak, a closed post-translational conformation of the SecYEG complex bound to a ribosome must exist. PMID- 23645667 TI - A mechanism for protein monoubiquitination dependent on a trans-acting ubiquitin binding domain. AB - The length of the ubiquitin chain on a substrate dictates various functional outcomes, yet little is known about its regulation in vivo. The yeast arrestin related protein Rim8/Art9 is monoubiquitinated in vivo by the Rsp5 ubiquitin ligase. This also requires Vps23, a protein that displays an ubiquitin-E2 variant (UEV) domain. Here, we report that binding of the UEV domain to Rim8 interferes with ubiquitin chain elongation and directs Rim8 monoubiquitination. We propose that Vps23 UEV competes with Rsp5 HECT N-lobe for binding to the first conjugated ubiquitin, thereby preventing polyubiquitination. These findings reveal a novel mechanism to control ubiquitin chain length on substrates in vivo. PMID- 23645668 TI - Sodium solute symporter and cadherin proteins act as Bacillus thuringiensis Cry3Ba toxin functional receptors in Tribolium castaneum. AB - Understanding how Bacillus thuringiensis (Bt) toxins interact with proteins in the midgut of susceptible coleopteran insects is crucial to fully explain the molecular bases of Bt specificity and insecticidal action. In this work, aminopeptidase N (TcAPN-I), E-cadherin (TcCad1), and sodium solute symporter (TcSSS) have been identified by ligand blot as putative Cry3Ba toxin-binding proteins in Tribolium castaneum (Tc) larvae. RNA interference knockdown of TcCad1 or TcSSS proteins resulted in decreased susceptibility to Cry3Ba toxin, demonstrating the Cry toxin receptor functionality for these proteins. In contrast, TcAPN-I silencing had no effect on Cry3Ba larval toxicity, suggesting that this protein is not relevant in the Cry3Ba toxin mode of action in Tc. Remarkable features of TcSSS protein were the presence of cadherin repeats in its amino acid sequence and that a TcSSS peptide fragment containing a sequence homologous to a binding epitope found in Manduca sexta and Tenebrio molitor Bt cadherin functional receptors enhanced Cry3Ba toxicity. This is the first time that the involvement of a sodium solute symporter protein as a Bt functional receptor has been demonstrated. The role of this novel receptor in Bt toxicity against coleopteran insects together with the lack of receptor functionality of aminopeptidase N proteins might account for some of the differences in toxin specificity between Lepidoptera and Coleoptera insect orders. PMID- 23645670 TI - Vascular Ehlers-Danlos syndrome mutations in type III collagen differently stall the triple helical folding. AB - Vascular Ehlers-Danlos syndrome (EDS) type IV is the most severe form of EDS. In many cases the disease is caused by a point mutation of Gly in type III collagen. A slower folding of the collagen helix is a potential cause for over modifications. However, little is known about the rate of folding of type III collagen in patients with EDS. To understand the molecular mechanism of the effect of mutations, a system was developed for bacterial production of homotrimeric model polypeptides. The C-terminal quarter, 252 residues, of the natural human type III collagen was attached to (GPP)7 with the type XIX collagen trimerization domain (NC2). The natural collagen domain forms a triple helical structure without 4-hydroxylation of proline at a low temperature. At 33 degrees C, the natural collagenous part is denatured, but the C-terminal (GPP)7-NC2 remains intact. Switching to a low temperature triggers the folding of the type III collagen domain in a zipper-like fashion that resembles the natural process. We used this system for the two known EDS mutations (Gly-to-Val) in the middle at Gly-910 and at the C terminus at Gly-1018. In addition, wild-type and Gly-to-Ala mutants were made. The mutations significantly slow down the overall rate of triple helix formation. The effect of the Gly-to-Val mutation is much more severe compared with Gly-to-Ala. This is the first report on the folding of collagen with EDS mutations, which demonstrates local delays in the triple helix propagation around the mutated residue. PMID- 23645671 TI - The Hog1 stress-activated protein kinase targets nucleoporins to control mRNA export upon stress. AB - The control of mRNA biogenesis is exerted at several steps. In response to extracellular stimuli, stress-activated protein kinases (SAPK) modulate gene expression to maximize cell survival. In yeast, the Hog1 SAPK plays a key role in reprogramming the gene expression pattern required for cell survival upon osmostress by acting during transcriptional initiation and elongation. Here, we genetically show that an intact nuclear pore complex is important for cell survival and maximal expression of stress-responsive genes. The Hog1 SAPK associates with nuclear pore complex components and directly phosphorylates the Nup1, Nup2, and Nup60 components of the inner nuclear basket. Mutation of those factors resulted in a deficient export of stress-responsive genes upon stress. Association of Nup1, Nup2, and Nup60 to stress-responsive promoters occurs upon stress depending on Hog1 activity. Accordingly, STL1 gene territory is maintained at the nuclear periphery upon osmostress in a Hog1-dependent manner. Cells containing non-phosphorylatable mutants in Nup1 or Nup2 display reduced expression of stress-responsive genes. Together, proper mRNA biogenesis of stress responsive genes requires of the coordinate action of synthesis and export machineries by the Hog1 SAPK. PMID- 23645669 TI - The Lhs1/GRP170 chaperones facilitate the endoplasmic reticulum-associated degradation of the epithelial sodium channel. AB - The epithelial sodium channel, ENaC, plays a critical role in maintaining salt and water homeostasis, and not surprisingly defects in ENaC function are associated with disease. Like many other membrane-spanning proteins, this trimeric protein complex folds and assembles inefficiently in the endoplasmic reticulum (ER), which results in a substantial percentage of the channel being targeted for ER-associated degradation (ERAD). Because the spectrum of factors that facilitates the degradation of ENaC is incomplete, we developed yeast expression systems for each ENaC subunit. We discovered that a conserved Hsp70 like chaperone, Lhs1, is required for maximal turnover of the ENaC alpha subunit. By expressing Lhs1 ATP binding mutants, we also found that the nucleotide exchange properties of this chaperone are dispensable for ENaC degradation. Consistent with the precipitation of an Lhs1-alphaENaC complex, Lhs1 holdase activity was instead most likely required to support the ERAD of alphaENaC. Moreover, a complex containing the mammalian Lhs1 homolog GRP170 and alphaENaC co precipitated, and GRP170 also facilitated ENaC degradation in human, HEK293 cells, and in a Xenopus oocyte expression system. In both yeast and higher cell types, the effect of Lhs1 on the ERAD of alphaENaC was selective for the unglycosylated form of the protein. These data establish the first evidence that Lhs1/Grp170 chaperones can act as mediators of ERAD substrate selection. PMID- 23645672 TI - Seven in absentia homolog 2 (Siah2) protein is a regulator of NF-E2-related factor 2 (Nrf2). AB - Under pathological conditions such as ischemia-reperfusion, Nrf2 acts as a key regulator of cellular oxidative response. Provided that Nrf2 is sensitive to hypoxia during ischemia, Nrf2 may affect reactive oxygen species metabolism during reoxygenation. In this study, hypoxia suppressed Nrf2 protein, and its hypoxic suppression was not recovered with knockdown of the Nrf2 repressor Keap1. Moreover, an Nrf2 mutant lacking the Keap1 binding domain was suppressed under hypoxia, suggesting that Keap1 does not contribute to hypoxic Nrf2 suppression. HIF-1alpha and Siah2 are both key regulators of hypoxic responses. Hypoxia induced the Siah2 protein. Although inhibition or knockdown of Siah2 prevented the suppression of Nrf2, knockdown of HIF-1alpha did not. Moreover, Siah2 interacted with Nrf2 through a binding motif, suggesting that Siah2 contributes to the suppression of Nrf2. Some cytosolic kinases also play important roles in Nrf2 regulation. In this study, PKC phosphorylates serine residues of Nrf2 during hypoxia. Knockdown of Siah2 rescued hypoxic decreases in an Nrf2 mutant that mimicked phosphorylation at serine 40 or lacked this phosphorylation site, suggesting that Siah2 contributes to the degradation of Nrf2 irrespective of its phosphorylation status. Moreover, knockdown of Siah2 attenuated ubiquitination of the Nrf2 mutant, suggesting that association of Siah2 with Nrf2 causes proteasome mediated degradation of Nrf2. PMID- 23645673 TI - Selective enhancing effect of early mitotic inhibitor 1 (Emi1) depletion on the sensitivity of doxorubicin or X-ray treatment in human cancer cells. AB - Chemotherapy and radiation in addition to surgery has proven useful in a number of different cancer types, but the effectiveness in normal tissue cannot be avoided in these therapies. To improve the effectiveness of these therapies selectively in cancer tissue is important for avoiding side effects. Early mitotic inhibitor 1 (Emi1) is known to have the function to inhibit anaphase promoting complex/cyclosome ubiquitin ligase complex, which ubiquitylates the cell cycle-related proteins. It recently has been shown that Emi1 knockdown prevents transition from S to G2 phase by down-regulating geminin via anaphase promoting complex/cyclosome activation. At present, anticancer drugs for targeting DNA synthesis to interfere with rapidly dividing cells commonly are used. As Emi1 depletion interferes with completion of DNA synthesis in cancer cells, we thought that Emi1 knockdown might enhance the sensitivity for anticancer agents. Here, we confirmed that Emi1 siRNA induced polyploidy for preventing transition from S to G2 phase in several cancer cell lines. Then, we treated Emi1 depleted cells with doxorubicin. Interestingly, increased apoptotic cells were observed after doxorubicin treatment in Emi1 siRNA-treated cancer cells. In addition, Emi1 depletion enhanced the sensitivity of x-ray irradiation in cancer cells. Importantly, synergistic effect of Emi1 knockdown in these combination therapies was not observed in normal cells. These results suggest that Emi1 siRNA can be a useful tool for enhancing of sensitivity of cancer cells to anticancer reagents and radiation. PMID- 23645674 TI - Suppression of autophagy in osteocytes mimics skeletal aging. AB - Bone mass declines with age but the mechanisms responsible remain unclear. Here we demonstrate that deletion of a conditional allele for Atg7, a gene essential for autophagy, from osteocytes caused low bone mass in 6-month-old male and female mice. Cancellous bone volume and cortical thickness were decreased, and cortical porosity increased, in conditional knock-out mice compared with control littermates. These changes were associated with low osteoclast number, osteoblast number, bone formation rate, and wall width in the cancellous bone of conditional knock-out mice. In addition, oxidative stress was higher in the bones of conditional knock-out mice as measured by reactive oxygen species levels in the bone marrow and by p66(shc) phosphorylation in L6 vertebra. Each of these changes has been previously demonstrated in the bones of old versus young adult mice. Thus, these results demonstrate that suppression of autophagy in osteocytes mimics, in many aspects, the impact of aging on the skeleton and suggest that a decline in autophagy with age may contribute to the low bone mass associated with aging. PMID- 23645675 TI - Dynamic ubiquitination of the mitogen-activated protein kinase kinase (MAPKK) Ste7 determines mitogen-activated protein kinase (MAPK) specificity. AB - Ubiquitination is a post-translational modification that tags proteins for proteasomal degradation. In addition, there is a growing appreciation that ubiquitination can influence protein activity and localization. Ste7 is a prototype MAPKK in yeast that participates in both the pheromone signaling and nutrient deprivation/invasive growth pathways. We have shown previously that Ste7 is ubiquitinated upon pheromone stimulation. Here, we show that the Skp1/Cullin/F box ubiquitin ligase SCF(Cdc4) and the ubiquitin protease Ubp3 regulate Ste7 ubiquitination and signal specificity. Using purified components, we demonstrate that SCF(Cdc4) ubiquitinates Ste7 directly. Using gene deletion mutants, we show that SCF(Cdc4) and Ubp3 have opposing effects on Ste7 ubiquitination. Although SCF(Cdc4) is necessary for proper activation of the pheromone MAPK Fus3, Ubp3 is needed to limit activation of the invasive growth MAPK Kss1. Finally, we show that Fus3 phosphorylates Ubp3 directly and that phosphorylation of Ubp3 is necessary to limit Kss1 activation. These results reveal a feedback loop wherein one MAPK limits the ubiquitination of an upstream MAPKK and thereby prevents spurious activation of a second competing MAPK. PMID- 23645676 TI - A self-defeating anabolic program leads to beta-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux. AB - Endoplasmic reticulum (ER) stress-induced responses are associated with the loss of insulin-producing beta-cells in type 2 diabetes mellitus. beta-Cell survival during ER stress is believed to depend on decreased protein synthesis rates that are mediated via phosphorylation of the translation initiation factor eIF2alpha. It is reported here that chronic ER stress correlated with increased islet protein synthesis and apoptosis in beta-cells in vivo. Paradoxically, chronic ER stress in beta-cells induced an anabolic transcription program to overcome translational repression by eIF2alpha phosphorylation. This program included expression of amino acid transporter and aminoacyl-tRNA synthetase genes downstream of the stress-induced ATF4-mediated transcription program. The anabolic response was associated with increased amino acid flux and charging of tRNAs for branched chain and aromatic amino acids (e.g. leucine and tryptophan), the levels of which are early serum indicators of diabetes. We conclude that regulation of amino acid transport in beta-cells during ER stress involves responses leading to increased protein synthesis, which can be protective during acute stress but can lead to apoptosis during chronic stress. These studies suggest that the increased expression of amino acid transporters in islets can serve as early diagnostic biomarkers for the development of diabetes. PMID- 23645677 TI - Gain-of-function mutations in transient receptor potential C6 (TRPC6) activate extracellular signal-regulated kinases 1/2 (ERK1/2). AB - Gain-of-function mutations in the canonical transient receptor potential 6 (TRPC6) gene are a cause of autosomal dominant focal segmental glomerulosclerosis (FSGS). The mechanisms whereby abnormal TRPC6 activity results in proteinuria remain unknown. The ERK1/2 MAPKs are activated in glomeruli and podocytes in several proteinuric disease models. We therefore examined whether FSGS-associated mutations in TRPC6 result in activation of these kinases. In 293T cells and cultured podocytes, overexpression of gain-of-function TRPC6 mutants resulted in increased ERK1/2 phosphorylation, an effect dependent upon channel function. Pharmacologic inhibitor studies implicated several signaling mediators, including calmodulin and calcineurin, supporting the importance of TRPC6-mediated calcium influx in this process. Through medium transfer experiments, we uncovered two distinct mechanisms for ERK activation by mutant TRPC6, a cell-autonomous, EGF receptor-independent mechanism and a non-cell-autonomous mechanism involving metalloprotease-mediated release of a presumed EGF receptor ligand. The inhibitors KN-92 and H89 were able to block both pathways in mutant TRPC6 expressing cells as well as the prolonged elevation of intracellular calcium levels upon carbachol stimulation seen in these cells. However, these effects appear to be independent of their effects on calcium/calmodulin-dependent protein kinase II and PKA, respectively. Phosphorylation of Thr-70, Ser-282, and Tyr 31/285 were not necessary for ERK activation by mutant TRPC6, although a phosphomimetic TRPC6 S282E mutant was capable of ERK activation. Taken together, these results identify two pathways downstream of mutant TRPC6 leading to ERK activation that may play a role in the development of FSGS. PMID- 23645678 TI - Alcohol consumption negates estrogen-mediated myocardial repair in ovariectomized mice by inhibiting endothelial progenitor cell mobilization and function. AB - We have shown previously that estrogen (estradiol, E2) supplementation enhances voluntary alcohol consumption in ovariectomized female rodents and that increased alcohol consumption impairs ischemic hind limb vascular repair. However, the effect of E2-induced alcohol consumption on post-infarct myocardial repair and on the phenotypic/functional properties of endothelial progenitor cells (EPCs) is not known. Additionally, the molecular signaling of alcohol-estrogen interactions remains to be elucidated. This study examined the effect of E2-induced increases in ethanol consumption on post-infarct myocardial function/repair. Ovariectomized female mice, implanted with 17beta-E2 or placebo pellets were given access to alcohol for 6 weeks and subjected to acute myocardial infarction. Left ventricular functions were consistently depressed in mice consuming ethanol compared with those receiving only E2. Alcohol-consuming mice also displayed significantly increased infarct size and reduced capillary density. Ethanol consumption also reduced E2-induced mobilization and homing of EPCs to injured myocardium compared with the E2-alone group. In vitro, exposure of EPCs to ethanol suppressed E2-induced proliferation, survival, and migration and markedly altered E2-induced estrogen receptor-dependent cell survival signaling and gene expression. Furthermore, ethanol-mediated suppression of EPC biology was endothelial nitric oxide synthase-dependent because endothelial nitric oxide synthase-null mice displayed an exaggerated response to post-acute myocardial infarction left ventricular functions. These data suggest that E2 modulation of alcohol consumption, and the ensuing EPC dysfunction, may negatively compete with the beneficial effects of estrogen on post-infarct myocardial repair. PMID- 23645679 TI - p39, the primary activator for cyclin-dependent kinase 5 (Cdk5) in oligodendroglia, is essential for oligodendroglia differentiation and myelin repair. AB - Cyclin-dependent kinase 5 (Cdk5) plays key roles in normal brain development and function. Dysregulation of Cdk5 may cause neurodegeneration and cognitive impairment. Besides the well demonstrated role of Cdk5 in neurons, emerging evidence suggests the functional requirement of Cdk5 in oligodendroglia (OL) and CNS myelin development. However, whether neurons and OLs employ similar or distinct mechanisms to regulate Cdk5 activity remains elusive. We report here that in contrast to neurons that harbor high levels of two Cdk5 activators, p35 and p39, OLs express abundant p39 but negligible p35. In addition, p39 is selectively up-regulated in OLs during differentiation along with elevated Cdk5 activity, whereas p35 expression remains unaltered. Specific knockdown of p39 by siRNA significantly attenuates Cdk5 activity and OL differentiation without affecting p35. Finally, expression of p39, but not p35, is increased during myelin repair, and remyelination is impaired in p39(-/-) mice. Together, these results reveal that neurons and OLs harbor distinct preference of Cdk5 activators and demonstrate important functions of p39-dependent Cdk5 activation in OL differentiation during de novo myelin development and myelin repair. PMID- 23645680 TI - Crystal structure of peroxide stress regulator from Streptococcus pyogenes provides functional insights into the mechanism of oxidative stress sensing. AB - Regulation of oxidative stress responses by the peroxide stress regulator (PerR) is critical for the in vivo fitness and virulence of group A Streptococcus. To elucidate the molecular mechanism of DNA binding, peroxide sensing, and gene regulation by PerR, we performed biochemical and structural characterization of PerR. Sequence-specific DNA binding by PerR does not require regulatory metal occupancy. However, metal binding promotes higher affinity PerR-DNA interactions. PerR metallated with iron directly senses peroxide stress and dissociates from operator sequences. The crystal structure revealed that PerR exists as a homodimer with two metal-binding sites per subunit as follows: a structural zinc site and a regulatory metal site that is occupied in the crystals by nickel. The regulatory metal-binding site in PerR involves a previously unobserved HXH motif located in its unique N-terminal extension. Mutational analysis of the regulatory site showed that the PerR metal ligands are involved in regulatory metal binding, and integrity of this site is critical for group A Streptococcus virulence. Interestingly, the metal-binding HXH motif is not present in the structurally characterized members of ferric uptake regulator (Fur) family but is fully conserved among PerR from the genus Streptococcus. Thus, it is likely that the PerR orthologs from streptococci share a common mechanism of metal binding, peroxide sensing, and gene regulation that is different from that of well characterized PerR from Bacillus subtilis. Together, our findings provide key insights into the peroxide sensing and regulation of the oxidative stress adaptive responses by the streptococcal subfamily of PerR. PMID- 23645681 TI - Developmentally regulated linker histone H1c promotes heterochromatin condensation and mediates structural integrity of rod photoreceptors in mouse retina. AB - Mature rod photoreceptor cells contain very small nuclei with tightly condensed heterochromatin. We observed that during mouse rod maturation, the nucleosomal repeat length increases from 190 bp at postnatal day 1 to 206 bp in the adult retina. At the same time, the total level of linker histone H1 increased reaching the ratio of 1.3 molecules of total H1 per nucleosome, mostly via a dramatic increase in H1c. Genetic elimination of the histone H1c gene is functionally compensated by other histone variants. However, retinas in H1c/H1e/H1(0) triple knock-outs have photoreceptors with bigger nuclei, decreased heterochromatin area, and notable morphological changes suggesting that the process of chromatin condensation and rod cell structural integrity are partly impaired. In triple knock-outs, nuclear chromatin exposed several epigenetic histone modification marks masked in the wild type chromatin. Dramatic changes in exposure of a repressive chromatin mark, H3K9me2, indicate that during development linker histone plays a role in establishing the facultative heterochromatin territory and architecture in the nucleus. During retina development, the H1c gene and its promoter acquired epigenetic patterns typical of rod-specific genes. Our data suggest that histone H1c gene expression is developmentally up-regulated to promote facultative heterochromatin in mature rod photoreceptors. PMID- 23645682 TI - Specific requirement of Gli transcription factors in Hedgehog-mediated intestinal development. AB - Hedgehog (Hh) signaling is involved in multiple aspects of embryonic gut development, including mesenchymal growth and smooth muscle differentiation. The Gli family transcription factors is thought to collectively mediate Hh signaling in mammals. However, the function of different Gli proteins in gut development remains uncharacterized. Here, we genetically dissect the contribution of Gli transcriptional activation and de-repression in intestinal growth and patterning. We find that removal of the Gli3 repressor is dispensable for intestinal development and does not play a major role in Hh-controlled gut development. However, Gli2 activation is able to fully rescue the Smoothened (Smo)-null intestinal phenotype, suggesting that the Gli2 transcription factor is the main effector for Hh signaling in the intestine. To understand further the molecular mechanism underlying Hh/Gli function in the developing gut, we identify a subset of small leucine-rich glycoproteins (SLRPs) that may function downstream of Hh signaling in the mesenchyme. We show that osteoglycin, a SLRP, inhibits Hh induced differentiation toward the smooth muscle lineage in C3H10T1/2 pluripotent mesenchymal cells. Taken together, our study reveals, for the first time, the distinct roles of Gli proteins in intestine development and suggests SLRPs as novel regulators of smooth muscle cell differentiation. PMID- 23645683 TI - Proteolytic processing regulates placental growth factor activities. AB - Placental growth factor (PlGF) is a critical mediator of blood vessel formation, yet mechanisms of its action and regulation are incompletely understood. Here we demonstrate that proteolytic processing regulates the biological activity of PlGF. Specifically, we show that plasmin processing of PlGF-2 yields a protease resistant core fragment comprising the vascular endothelial growth factor receptor-1 binding site but lacking the carboxyl-terminal domain encoding the heparin-binding domain and an 8-amino acid peptide encoded by exon 7. We have identified plasmin cleavage sites, generated a truncated PlGF118 isoform mimicking plasmin-processed PlGF, and explored its biological function in comparison with that of PlGF-1 and -2. The angiogenic responses induced by the diverse PlGF forms were distinct. Whereas PlGF-2 increased endothelial cell chemotaxis, vascular sprouting, and granulation tissue formation upon skin injury, these activities were abrogated following plasmin digestion. Investigation of PlGF/Neuropilin-1 binding and function suggests a critical role for heparin-binding domain/Neuropilin-1 interaction and its regulation by plasmin processing. Collectively, here we provide new mechanistic insights into the regulation of PlGF-2/Neuropilin-1-mediated tissue vascularization and growth. PMID- 23645684 TI - The universal epitope of influenza A viral neuraminidase fundamentally contributes to enzyme activity and viral replication. AB - The only universally conserved sequence among all influenza A viral neuraminidases is located between amino acids 222 and 230. However, the potential roles of these amino acids remain largely unknown. Through an array of experimental approaches including mutagenesis, reverse genetics, and growth kinetics, we found that this sequence could markedly affect viral replication. Additional experiments revealed that enzymes with mutations in this region demonstrated substantially decreased catalytic activity, substrate binding, and thermostability. Consistent with viral replication analyses and enzymatic studies, protein modeling suggests that these amino acids could either directly bind to the substrate or contribute to the formation of the active site in the enzyme. Collectively, these findings reveal the essential role of this unique region in enzyme function and viral growth, which provides the basis for evaluating the validity of this sequence as a potential target for antiviral intervention and vaccine development. PMID- 23645685 TI - Monitoring the interaction between beta2-microglobulin and the molecular chaperone alphaB-crystallin by NMR and mass spectrometry: alphaB-crystallin dissociates beta2-microglobulin oligomers. AB - The interaction at neutral pH between wild-type and a variant form (R3A) of the amyloid fibril-forming protein beta2-microglobulin (beta2m) and the molecular chaperone alphaB-crystallin was investigated by thioflavin T fluorescence, NMR spectroscopy, and mass spectrometry. Fibril formation of R3Abeta2m was potently prevented by alphaB-crystallin. alphaB-crystallin also prevented the unfolding and nonfibrillar aggregation of R3Abeta2m. From analysis of the NMR spectra collected at various R3Abeta2m to alphaB-crystallin molar subunit ratios, it is concluded that the structured beta-sheet core and the apical loops of R3Abeta2m interact in a nonspecific manner with the alphaB-crystallin. Complementary information was derived from NMR diffusion coefficient measurements of wild-type beta2m at a 100-fold concentration excess with respect to alphaB-crystallin. Mass spectrometry acquired in the native state showed that the onset of wild-type beta2m oligomerization was effectively reduced by alphaB-crystallin. Furthermore, and most importantly, alphaB-crystallin reversibly dissociated beta2m oligomers formed spontaneously in aged samples. These results, coupled with our previous studies, highlight the potent effectiveness of alphaB-crystallin in preventing beta2m aggregation at the various stages of its aggregation pathway. Our findings are highly relevant to the emerging view that molecular chaperone action is intimately involved in the prevention of in vivo amyloid fibril formation. PMID- 23645686 TI - Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood. AB - Corticosteroid can induce osteonecrosis in children with leukemia. Few studies have been designed to assess the influence of a wide range of cumulative steroid dose on this side effect. Prevalence, risk factors of symptomatic osteonecrosis and its impact on adults' Quality of Life were assessed in 943 patients enrolled in the French "Leucemies de l'Enfant et de l'Adolescent" (LEA) cohort of childhood leukemia survivors. During each medical visit, data on previous osteonecrosis diagnosis were retrospectively collected. Patients without a history but with suggestive symptoms were investigated with magnetic resonance imaging. The total steroid dose in equivalent of prednisone was calculated for each patient and its effect on osteonecrosis occurrence was studied in multivariate models. Cumulative incidence was 1.4% after chemotherapy alone versus 6.8% after transplantation (P<0.001). A higher cumulative steroid dose, age over ten years at diagnosis, and treatment with transplantation significantly increased the risk of osteonecrosis. A higher post-transplant steroid dose and age over ten years at time of transplantation were significant factors in the transplanted group. With patients grouped according to steroid dose quartile, cumulative incidence of osteonecrosis reached 3.8% in the chemotherapy group for a dose beyond 5835 mg/m(2) and 23.8% after transplantation for a post-transplant dose higher than 2055 mg/m(2). Mean physical composite score of Quality of Life was 44.3 in patients with osteonecrosis versus 54.8% in patients without (P<0.001). We conclude that total and post-transplant cumulative steroid dose may predict the risk of osteonecrosis, a rare late effect with a strong negative impact on physical domains of Quality of Life. PMID- 23645687 TI - Brentuximab vedotin in relapsed/refractory Hodgkin's lymphoma: the Italian experience and results of its use in daily clinical practice outside clinical trials. AB - Clinical trial results indicate that brentuximab vedotin brings considerable promise for the treatment of patients with relapsed or refractory Hodgkin's lymphoma. A retrospective multicenter study was conducted on 65 heavily pretreated patients who underwent therapy through a Named Patient Program in Italy (non trial-setting). The primary study endpoint was the objective response rate; secondary endpoints were safety, overall survival and progression-free survival. The best overall response rate (70.7%), including 21.5% complete responses, was observed at the first restaging after the third cycle of treatment. After a median follow up of 13.2 months, the overall survival rate at 20 months was 73.8% while the progression-free survival rate at 20 months was 24.2%. Globally nine patients are in continuous complete response with a median follow up of 14 months (range, 10-19 months). Four patients proceeded to autotransplantation and nine to allotransplantation. The most frequent extra hematologic toxicity was peripheral neuropathy, observed in 21.5% of cases (9 patients with grade 1/2 and 5 patients with grade 3/4); neurological toxicity led to discontinuation of treatment in three patients and to dose reduction in four. In general the treatment was well tolerated and toxicities, both hematologic and extra-hematologic, were manageable. This report indicates and confirms that brentuximab vedotin as a single agent is effective and safe also when used in standard, everyday clinical practice outside a clinical trial. Best overall responses were recorded after three or four cycles and showed that brentuximab vedotin provides an effective bridge to further therapeutic interventions. PMID- 23645688 TI - Natural history and prognostic impact of oligoclonal humoral response in patients with multiple myeloma after autologous stem cell transplantation: long-term results from a single institution. AB - The emergence of an oligoclonal humoral response, resulting in the appearance of a different serum M-protein to that observed at diagnosis is a well-recognized event after autologous stem cell transplantation in multiple myeloma in complete response, and it has been considered to be a benign phenomenon. The aim of the present study was to investigate the incidence, biological characteristics and prognostic value of the oligoclonal bands in patients with myeloma who underwent autologous transplantation at our institution in the last 18 years. We proceed with a retrospective systematic review of all serum and urine immunofixation studies performed in the 211 patients with multiple myeloma who underwent melphalan-based autologous transplantation. Oligoclonal bands were observed in 34% of the patients, with a significantly higher prevalence with the use of novel agents versus conventional chemotherapy in induction (63% vs. 22%; P=0.0001). The incidence of oligoclonal bands was most frequent in non-IgG isotype, particularly in light chain only myeloma. The oligoclonal phenomenon was almost exclusive to patients in complete remission compared to other degrees of response (87% vs. 13%; P=0.0001), and lasted for a median of 1.35 years, persisting during follow up in all patients except in those who relapsed. In prognostic terms, the presence of oligoclonality resulted in a significantly longer progression-free and overall survival. Patients with oligoclonal humoral response lasting for more than one year after transplantation had a significantly longer clinical progression-free and overall survival than those with shorter duration (P=0.008 and P=0.0001, respectively), likely reflecting the importance of a robust humoral immune response. PMID- 23645689 TI - High modal number and triple trisomies are highly correlated favorable factors in childhood B-cell precursor high hyperdiploid acute lymphoblastic leukemia treated according to the NOPHO ALL 1992/2000 protocols. AB - Between 1992 and 2008, 713 high hyperdiploid acute lymphoblastic leukemias in children aged 1-15 years were diagnosed and treated according to the Nordic Society for Pediatric Hematology and Oncology acute lymphoblastic leukemia 1992/2000 protocols. Twenty (2.8%) harbored t(1;19), t(9;22), der(11q23), or t(12;21). The median age of patients with "classic" high hyperdiploidy was lower than that of patients with translocation-positive high hyperdiploidy (P<0.001). Cases with triple trisomies (+4, +10, +17), comprising 50%, had higher modal numbers than the triple trisomy-negative cases (P<0.0001). The probabilities of event-free survival and overall survival were lower for those with white blood cell counts >= 50 * 10(9)/L (P=0.017/P=0.009), >= 5% bone marrow blasts at day 29 (P=0.001/0.002), and for high-risk patients (P<0.001/P=0.003), whereas event free, but not overall, survival, was higher for cases with gains of chromosomes 4 (P<0.0001), 6 (P<0.003), 17 (P=0.010), 18 (P=0.049), and 22 (P=0.040), triple trisomies (P=0.002), and modal numbers >53/55 (P=0.020/0.024). In multivariate analyses, modal number and triple trisomies were significantly associated with superior event-free survival in separate analyses with age and white blood cell counts. When including both modal numbers and triple trisomies, only low white blood cell counts were significantly associated with superior event-free survival (P=0.009). We conclude that high modal chromosome numbers and triple trisomies are highly correlated prognostic factors and that these two parameters identify the same subgroup of patients characterized by a particularly favorable outcome. PMID- 23645690 TI - Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP interferon plus rituximab in follicular lymphoma. AB - Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for patients treated with rituximab. However, no long-term follow up (i.e. > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-alpha2a or a similar chemotherapy-based regimen plus rituximab, and outcome was up-dated. With a median follow up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary end point) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P<0.0001 and P=0.001, respectively). Considering long-term toxicity, the addition of rituximab in the first-line setting was confirmed as safe with regards to development of secondary malignancies. Long-term follow up of patients with follicular lymphoma treated in the FL2000 study confirms the sustained clinical benefit of rituximab without long-term toxicity. PMID- 23645691 TI - A low fixed dose of prothrombin complex concentrate is cost effective in emergency reversal of vitamin K antagonists. PMID- 23645692 TI - Association of D-dimer levels with all-cause mortality in a healthy adult population: findings from the MOLI-SANI study. AB - Elevated D-dimer levels are reportedly associated with higher risk of total mortality in patients with different diseases. We investigated whether a similar association could be found in a large, apparently healthy population. A large sample of individuals (N=17,359, 47% men, age >= 35 years) free of clinically recognized cardiovascular and cancer disease, for whom baseline D-dimer level was available, were studied within the MOLI-SANI cohort, randomly recruited from the general adult population of Southern Italy. The cohort was followed for a median of 4.2 years (73,807 person-years). D-dimer was measured in fresh citrated plasma by an automated latex-enhanced immunoassay. Hazard ratios were calculated using three Cox-proportional hazard models. Two hundred and eighty deaths were recorded. When modeled as a continuous variable, D-dimer level at baseline showed a non-linear association with mortality, whose incidence increased only in the upper quartile of the distribution (D-dimer >= 221 ng/mL). Thus, the group of individuals with D-dimer <221 ng/mL (75% of the population) acted as the reference group, while the remaining individuals were subdivided in tertiles and compared with the former group. Multivariable hazard ratios for mortality were 1.06, 1.45 and 1.97, respectively (P for trend <0.0001) across the three categories of increasing D-dimer concentration. The association was slightly attenuated, but still highly significant (P for trend 0.0002), after further adjustment for white blood cell count and C-reactive protein. In conclusion, Elevated D-dimer levels were independently associated with increased risk of death from any cause in an apparently healthy adult population. PMID- 23645693 TI - Impact of being underweight or overweight on factor VIII dosing in hemophilia A patients. AB - Since 1981, the number of factor VIII units to infuse into patients with hemophilia A in order to achieve adequate circulating factor VIII levels has been calculated using the formula: [body weight(kg)* desired factor VIII increase(%)]/2, assuming a factor VIII recovery value of 2 for all patients. This study's aim was to evaluate the impact of several morphometric parameters and various coagulation factor concentrates on factor VIII recovery.The analysis included 201 hemophilia A adults (>18 years of age) who were carefully selected from eight pharmacokinetic clinical trials using three recombinant factor VIII concentrates (Advate(r), Kogenate(r) FS, or ReFactoAF(r)/Xyntha(r)). Regression tree analysis was used to identify factor VIII recovery predictors. The median factor VIII recovery was 2.16 for all patients. Using regression tree analysis, patients were separated into three groups on the basis of body mass index: below 20.3 kg/m(2), between 20.3 and 29.5 kg/m(2), and 29.6 kg/m(2) or more. Each group had a significantly different median factor VIII recovery (P<0.001): 1.60, 2.14, and 2.70, respectively. The type of coagulation factor concentrate had no influence on recovery in the regression tree. In conclusion, factor VIII dosing should be adapted to underweight and overweight patients, as a factor VIII recovery of 2 does not apply to these patients. Ideal body weight should be considered instead of actual body weight in the dose calculations. PMID- 23645694 TI - A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. AB - This study assessed the safety and preliminary efficacy of escalated dose subcutaneous alemtuzumab in combination with rituximab in chronic lymphocytic leukemia. Twenty-eight patients with relapsed refractory chronic lymphocytic leukemia were treated on four dosing cohorts of weekly rituximab at 375 mg/m(2) and alemtuzumab doses that started at 30 mg three times per week and escalated to weekly dosing over four weeks, culminating with 90 mg weekly. One dose limiting toxicity of a rituximab infusion reaction was seen in cohort 2, but the regimen was otherwise well tolerated without evidence of differential toxicity by cohort. The overall response rate by National Cancer Institute-Working Group criteria was 61%, and the rate of complete bone marrow response was 43%, most of whom were negative for minimal residual disease. The addition of CT scan evaluation per International Workshop on Chronic Lymphocytic Leukemia 2008 criteria reduced the overall response rate to 14%. Median overall survival was 35 months, with 12 patients able to proceed to stem cell transplantation. Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80% of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab, and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance. We conclude that escalated subcutaneous doses of alemtuzumab given weekly are well tolerated and result in excellent bone marrow clearance of chronic lymphocytic leukemia, helping patients to proceed to stem cell transplantation. This study is registered at ClinicalTrials.gov (Identifier:00330252). PMID- 23645695 TI - A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. AB - Painful episodes of vaso-occlusion are the leading cause of hospitalizations and emergency department visits in sickle cell disease, and are associated with increased mortality. Low nitric oxide bioavailability contributes to vasculopathy in sickle cell disease. Since arginine is the obligate substrate for nitric oxide production, and an acute deficiency is associated with pain, we hypothesized that arginine may be a beneficial treatment for pain related to sickle cell disease. Thirty-eight children with sickle cell disease hospitalized for 56 episodes of pain were randomized into this double-blinded placebo-controlled trial. Patients received L-arginine (100 mg/kg tid) or placebo for 5 days or until discharge. A significant reduction in total parenteral opioid use by 54% (1.9 +/- 2.0 mg/kg versus 4.1 +/- 4.1 mg/kg, P=0.02) and lower pain scores at discharge (1.9 +/- 2.4 versus 3.9 +/- 2.9, P=0.01) were observed in the treatment arm compared to the placebo one. There was no significant difference in hospital length of stay (4.1 +/- 01.8 versus 4.8 +/- 2.5 days, P=0.34), although a trend favored the arginine arm, and total opioid use was strongly correlated with the duration of the admission (r=0.86, P<0.0001). No drug-related adverse events were observed. Arginine therapy represents a novel intervention for painful vaso-occlusive episodes. A reduction of narcotic use by >50% is remarkable. Arginine is a safe and inexpensive intervention with narcotic-sparing effects that may be a beneficial adjunct to standard therapy for sickle cell-related pain in children. A large multi-center trial is warranted in order to confirm these observations. PMID- 23645697 TI - Quadrivalvular heart disease of mixed congenital and rheumatic aetiology with concomitant ostium secundum atrial septal defect and Ebstein's anomaly of the tricuspid valve. AB - We describe a 34-year-old man with an ostium secundum atrial septal defect, Ebstein's anomaly of the tricuspid valve with severe tricuspid regurgitation, congenital valvular pulmonary stenosis, rheumatic mitral stenosis and regurgitation with aortic regurgitation, who presented with decompensated heart failure after developing atrial fibrillation. The complex haemodynamic interplay of these lesions is also discussed. PMID- 23645696 TI - Phosphorylation of KRAB-associated protein 1 (KAP1) at Tyr-449, Tyr-458, and Tyr 517 by nuclear tyrosine kinases inhibits the association of KAP1 and heterochromatin protein 1alpha (HP1alpha) with heterochromatin. AB - Protein tyrosine phosphorylation regulates a wide range of cellular processes at the plasma membrane. Recently, we showed that nuclear tyrosine phosphorylation by Src family kinases (SFKs) induces chromatin structural changes. In this study, we identify KRAB-associated protein 1 (KAP1/TIF1beta/TRIM28), a component of heterochromatin, as a nuclear tyrosine-phosphorylated protein. Tyrosine phosphorylation of KAP1 is induced by several tyrosine kinases, such as Src, Lyn, Abl, and Brk. Among SFKs, Src strongly induces tyrosine phosphorylation of KAP1. Nucleus-targeted Lyn potentiates tyrosine phosphorylation of KAP1 compared with intact Lyn, but neither intact Fyn nor nucleus-targeted Fyn phosphorylates KAP1. Substitution of the three tyrosine residues Tyr-449/Tyr-458/Tyr-517, located close to the HP1 binding-motif, into phenylalanine ablates tyrosine phosphorylation of KAP1. Immunostaining and chromatin fractionation show that Src and Lyn decrease the association of KAP1 with heterochromatin in a kinase activity-dependent manner. KAP1 knockdown impairs the association of HP1alpha with heterochromatin, because HP1alpha associates with KAP1 in heterochromatin. Intriguingly, tyrosine phosphorylation of KAP1 decreases the association of HP1alpha with heterochromatin, which is inhibited by replacement of endogenous KAP1 with its phenylalanine mutant (KAP1-Y449F/Y458F/Y517F, KAP1-3YF). In DNA damage, KAP1-3YF repressed transcription of p21. These results suggest that nucleus-localized tyrosine kinases, including SFKs, phosphorylate KAP1 at Tyr 449/Tyr-458/Tyr-517 and inhibit the association of KAP1 and HP1alpha with heterochromatin. PMID- 23645698 TI - Biopsy-proven drug-induced tubulointerstitial nephritis in a patient with acute kidney injury and alcoholic severe acute pancreatitis. AB - We report a 49-year-old man with alcoholic severe acute pancreatitis (SAP) complicated by drug-induced acute tubulointerstitial nephritis (DI-AIN). Oliguria persisted and became anuric again on day 17 despite improvement of pancreatitis. He presented rash, fever and eosinophilia from day 20. Renal biopsy was performed for dialysis-dependent acute kidney injury (AKI), DI-AIN was revealed, and prompt use of corticosteroids fully restored his renal function. This diagnosis might be missed because it is difficult to perform renal biopsy in such a clinical situation. If the patient's general condition allows, renal biopsy should be performed and reversible AKI must be distinguished from many cases of irreversible AKI complicated by SAP. This is the first report of biopsy-proven DI AIN associated with SAP, suggesting the importance of biopsy for distinguishing DI-AIN in persisting AKI of SAP. PMID- 23645699 TI - Pituitary granulomatosis with polyangiitis. AB - Granulomatosis with polyangiitis (GPA) is a small vessel vasculitis that can affect several organs, most commonly the respiratory tract and kidneys. Pituitary involvement is exceptionally rare. Most case reports of GPA of the pituitary gland have been described in middle-aged women who have concomitant ears, nose and throat involvement. The most frequent manifestation is diabetes insipidus due to a preponderance of posterior pituitary infiltration. The majority of cases sustain permanent damage to the pituitary gland even with remission of the underlying granulomatous disease. Here, the authors describe a case of pituitary GPA involving both the anterior and posterior pituitary glands with permanent residual pituitary insufficiency. PMID- 23645700 TI - Hyperphosphatemic tumoral calcinosis. AB - Tumoral calcinosis (TC) is a rare locally aggressive lesion characterised by extra-articular soft tissue deposition of the calcium phosphate around large joints. The exact aetiology is not known. A 19-year-old boy presented with a painful progressive swelling around the bilateral elbow and left hip joints over a 6-month duration. Routine laboratory results showed a normal haemogram, and normal calcium and high phosphate levels. Imaging showed a soft tissue calcified mass around these joints. The cut surface of the excised mass showed myxoid material with areas of calcification. On microscopy, there were typical features of TC. Our case is being presented due to the rarity of the entity and the peculiar dual energy CT (DECT) finding which are being described for the first time in this pathology. PMID- 23645701 TI - Renovascular hypertension in an 8-year-old girl. AB - Secondary hypertension is the most common form of hypertension in childhood, particularly in the young age group: parenchymal disease and lesions of the renal artery account for the majority of such cases. Renal artery aneurysms (RAA) are rare and are usually diagnosed by Doppler ultrasonography or angiography performed in the investigation of specific clinical symptoms. We report herein a case of severe arterial hypertension in an 8-year-old girl arising from a large saccular RAA. Intravenous antihypertensive drugs were necessary to achieve blood pressure control and the final diagnosis was obtained from angio-CT scan and selective angiography that demonstrated a large saccular aneurysm of the left renal artery with parietal calcification. After confirmation of inexistent function of the entire left kidney by Tc99m-MAG3 renal isotope scan, nephrectomy was performed. The child's blood pressure further normalised and, 1 month after surgery, she had ceased any antihypertensive therapy. PMID- 23645702 TI - Primary group A streptococcal septic shock syndrome simulating perforated appendicitis in a previously healthy girl. AB - A previously healthy 6-year-old girl that initially presented with presumed viral gastrointestinal infection for a week and later developed catastrophic primary peritonitis and septic shock requiring resuscitation and emergency exploratory laparotomy without any identifiable intra-abdominal cause of the sepsis and the peritoneal exudates grew group A streptococci. Appropriate antibiotic therapy was instituted and she made a complete recovery. PMID- 23645703 TI - Familial exudative vitreoretinopathy presenting with unilateral rhegmatogenous retinal detachment in a Malay teenager. AB - To describe a case of familial exudative vitreoretinopathy presenting with unilateral rhegmatogenous retinal detachment in a Malay teenager. PMID- 23645704 TI - Mediastinal involvement in ovarian cancer. PMID- 23645706 TI - The effect of violent and nonviolent video games on heart rate variability, sleep, and emotions in adolescents with different violent gaming habits. AB - OBJECTIVE: To study cardiac, sleep-related, and emotional reactions to playing violent (VG) versus nonviolent video games (NVG) in adolescents with different gaming habits. METHODS: Thirty boys (aged 13-16 years, standard deviation = 0.9), half of them low-exposed (<=1 h/d) and half high-exposed (>=3 h/d) to violent games, played a VG/NVG for 2 hours during two different evenings in their homes. Heart rate (HR) and HR variability were registered from before start until next morning. A questionnaire about emotional reactions was administered after gaming sessions and a sleep diary on the following mornings. RESULTS: During sleep, there were significant interaction effects between group and gaming condition for HR (means [standard errors] for low-exposed: NVG 63.8 [2.2] and VG 67.7 [2.4]; for high-exposed: NVG 65.5 [1.9] and VG 62.7 [1.9]; F(1,28) = 9.22, p = .005). There was also a significant interaction for sleep quality (low-exposed: NVG 4.3 [0.2] and VG 3.7 [0.3]); high-exposed: NVG 4.4 [0.2] and VG 4.4 [0.2]; F(1,28) = 3.51, p = .036, one sided), and sadness after playing (low-exposed: NVG 1.0 [0.0] and VG 1.4 [0.2]; high-exposed: NVG 1.2 [0.1] and VG 1.1 [0.1]; (F(1,27) = 6.29, p = .009, one sided). CONCLUSIONS: Different combinations of the extent of (low versus high) previous VG and experimental exposure to a VG or an NVG are associated with different reaction patterns-physiologically, emotionally, and sleep related. Desensitizing effects or selection bias stand out as possible explanations. PMID- 23645707 TI - Association of elevated blood pressure with low distress and good quality of life: results from the nationwide representative German Health Interview and Examination Survey for Children and Adolescents. AB - OBJECTIVE: Quality of life is often impaired in patients with known hypertension, but it is less or not at all reduced in people unaware of their elevated blood pressure. Some studies have even shown less self-rated distress in adults with elevated blood pressure. In this substudy of the nationwide German Health Interview and Examination Survey for Children and Adolescents (KIGGS), we addressed the question whether, also in adolescents, hypertensive blood pressure is linked to levels of distress and quality of life. METHODS: Study participants aged 11 to 17 years (N = 7688) received standardized measurements of blood pressure, quality of life (using the Children's Quality of Life Questionnaire), and distress (Strengths and Difficulties Questionnaire). RESULTS: Elevated blood pressure was twice as frequent as expected, with 10.7% (n = 825) above published age-, sex- and height-adjusted 95th percentiles. Hypertensive participants were more likely to be obese and to report on adverse health behaviors, but they showed better academic success than did normotensive participants. Elevated blood pressure was significantly and positively associated with higher self- and parent rated quality of life (for both, p <= .006), less hyperactivity (for both, p < .005), and lower parent-rated emotional (p < .001), conduct (p = .021), and overall problems (p = .001). Multiple regression analyses confirmed these findings. CONCLUSIONS: Our observation linking elevated blood pressure to better well-being and low distress can partly be explained by the absence of confounding physical comorbidity and the unawareness of being hypertensive. It also corresponds to earlier research suggesting a bidirectional relationship with repressed emotions leading to elevated blood pressure and, furthermore, elevated blood pressure serving as a potential stress buffer. PMID- 23645709 TI - Estimated dose from diagnostic nuclear medicine patients to people outside the Nuclear Medicine department. AB - Patients undergoing nuclear medicine scans can be a source of radiation exposure for staff, family and the public. In this paper, 12 common nuclear medicine scans are considered. Doses are estimated for a range of scenarios, to hospital staff, to the public and to the patients' co-workers and family. Estimates are based on dose rates measured as patients left the Nuclear Medicine department. Radiopharmaceutical clearance is calculated from biokinetic models described in International Commission on Radiological Protection publications 53, 80 and 106. For all scan types, and all scenarios, doses are estimated to be substantially less than the trigger level of 300 uSv. Within the hospital, Intensive Care Unit staff receive the highest dose (up to 80 uSv) from patients who have had a myocardial scan or a positron emission tomography scan. For out-patients, the highest doses (up to 100 uSv) are associated with travel on public transport (for 4 h) on the same day as the scan. PMID- 23645708 TI - RNA localization in Xenopus oocytes uses a core group of trans-acting factors irrespective of destination. AB - The 3' untranslated region of mRNA encoding PHAX, a phosphoprotein required for nuclear export of U-type snRNAs, contains cis-acting sequence motifs E2 and VM1 that are required for localization of RNAs to the vegetal hemisphere of Xenopus oocytes. However, we have found that PHAX mRNA is transported to the opposite, animal, hemisphere. A set of proteins that cross-link to the localization elements of vegetally localized RNAs are also cross-linked to PHAX and An1 mRNAs, demonstrating that the composition of RNP complexes that form on these localization elements is highly conserved irrespective of the final destination of the RNA. The ability of RNAs to bind this core group of proteins is correlated with localization activity. Staufen1, which binds to Vg1 and VegT mRNAs, is not associated with RNAs localized to the animal hemisphere and may determine, at least in part, the direction of RNA movement in Xenopus oocytes. PMID- 23645710 TI - Association of mitochondrial letm1 with epileptic seizures. AB - Leucine zipper-EF-hand containing transmembrane protein 1 (Letm1) is a mitochondrial protein that is associated with seizure attacks in Wolf-Hirschhorn syndrome. This study aimed to investigate the expression pattern of Letm1 in patients with temporal lobe epilepsy (TLE) and pilocarpine-induced rat model of epilepsy, and to determine if altered Letm1 leads to mitochondrial dysfunction and increased susceptibility to seizures. Using immunohistochemical, immunofluorescent, western blotting, and transmission electron microscopic methods, we have found that Letm1 was significantly decreased in TLE patients, and gradually decreased in experimental rats from 1 to 7 days after onset of seizures. Letm1 knock-down by a lentivirus bearing LV-Letm1-sh resulted in mitochondrial swelling and decreased expression of Letm1 target protein mitochondrially encoded cytochrome B (MT-CYB). Behavioral study revealed that inhibition of Letm1 caused early onset of the first seizure, increased seizure frequency, and duration. However, administration of Letm1 homolog nigericin failed to prevent epilepsy. These results indicate that inhibition of Letm1 and mitochondrial dysfunctions contributes to the development of epileptic seizures. Appropriate Letm1 level may be critical for maintaining normal neuronal functions. PMID- 23645711 TI - Oscillatory alpha modulations in right auditory regions reflect the validity of acoustic cues in an auditory spatial attention task. AB - Anticipation of targets in the left or right hemifield leads to alpha modulations in posterior brain areas. Recently using magnetoencephalography, we showed increased right auditory alpha activity when attention was cued ipsilaterally. Here, we investigated the issue how cue validity itself influences oscillatory alpha activity. Acoustic cues were presented either to the right or left ear, followed by a compound dichotically presented target plus distractor. The preceding cue was either informative (75% validity) or uninformative (50%) about the location of the upcoming target. Cue validity * side-related alpha modulations were identified in pre- and posttarget periods in a right lateralized network, comprising auditory and nonauditory regions. This replicates and extends our previous finding of the right hemispheric dominance of auditory attentional modulations. Importantly, effective connectivity analysis showed that, in the pretarget period, this effect is accompanied by a pronounced and time-varying connectivity pattern of the right auditory cortex to the right intraparietal sulcus (IPS), with influence of IPS on superior temporal gyrus dominating at earlier intervals of the cue-target period. Our study underlines the assumption that alpha oscillations may play a similar functional role in auditory cortical regions as reported in other sensory modalities and suggests that these effects may be mediated via IPS. PMID- 23645712 TI - Cortical surface area and cortical thickness demonstrate differential structural asymmetry in auditory-related areas of the human cortex. AB - This investigation provides an analysis of structural asymmetries in 5 anatomically defined regions (Heschl's gyrus, HG; Heschl's sulcus, HS; planum temporale, PT; planum polare, PP; superior temporal gyrus, STG) within the human auditory-related cortex. Volumetric 3-dimensional T1-weighted magnetic resonance imaging scans were collected from 104 participants (52 males). Cortical volume (CV), cortical thickness (CT), and cortical surface area (CSA) were calculated based on individual scans of these anatomical traits. This investigation demonstrates a leftward asymmetry for CV and CSA that is observed in the HG, STG, and PT regions. As regards CT, we note a rightward asymmetry in the HG and HS. A correlation analysis of asymmetry indices between measurements for distinct regions of interest (ROIs) yields significant correlations between CT and CV in 4 of 5 ROIs (HG, HS, PT, and STG). Significant correlation values between CSA and CV are observed for all 5 ROIs. The findings suggest that auditory-related cortical areas demonstrate larger leftward asymmetry with respect to the CSA, while a clear rightward asymmetry with respect to CT is salient in both the primary and the secondary auditory cortex only. In addition, we propose that CV is not an ideal neuromarker for anatomical measurements. CT and CSA should be considered independent traits of anatomical asymmetries in the auditory-related cortex. PMID- 23645713 TI - Dynamical reorganization of synchronous activity patterns in prefrontal cortex hippocampus networks during behavioral sensitization. AB - Neural synchrony exhibits temporal variability and, therefore, the temporal patterns of synchronization and desynchronization may have functional relevance. This study employs novel time-series analysis to explore how neural signals become transiently phase locked and unlocked in the theta frequency band in prefrontal cortex and hippocampus of awake, behaving rats during repeated injections of the psychostimulant, d-Amphetamine (AMPH). Short (but frequent) desynchronized events dominate synchronized dynamics in each of the animals we examined. After the first AMPH injection, only increases in the relative prevalence of short desynchronization episodes (but not in average synchrony strength) were significant. Throughout sensitization, both strength and the fine temporal structure of synchrony (measured as the relative prevalence of short desynchronizations) were similarly altered with AMPH injections, with each measure decreasing in the preinjection epoch and increasing after injection. Sensitization also induced decoupling between locomotor activity and synchrony. The increase in numerous short desynchronizations (as opposed to infrequent, but long desynchronizations) in AMPH-treated animals may indicate that synchrony is easy to form yet easy to break. These data yield a novel insight into how synchrony is dynamically altered in cortical networks by AMPH and identify neurophysiological changes that may be important to understand the behavioral pathologies of addiction. PMID- 23645714 TI - Anticipation increases tactile stimulus processing in the ipsilateral primary somatosensory cortex. AB - Stimulus anticipation improves perception. To account for this improvement, we investigated how stimulus processing is altered by anticipation. In contrast to a large body of previous work, we employed a demanding perceptual task and investigated sensory responses that occur beyond early evoked activity in contralateral primary sensory areas: Stimulus-induced modulations of neural oscillations. For this, we recorded magnetoencephalography in 19 humans while they performed a cued tactile identification task involving the identification of either a proximal or a distal stimulation on the fingertips. We varied the cue target interval between 0 and 1000 ms such that tactile targets occurred at various degrees of anticipation. This allowed us to investigate the influence of anticipation on stimulus processing in a parametric fashion. We observed that anticipation increases the stimulus-induced response (suppression of beta-band oscillations) originating from the ipsilateral primary somatosensory cortex. This occurs in the period in which the tactile memory trace is analyzed and is correlated with the anticipation-induced improvement in tactile perception. We propose that this ipsilateral response indicates distributed processing across bilateral primary sensory cortices, of which the extent increases with anticipation. This constitutes a new and potentially important mechanism contributing to perception and its improvement following anticipation. PMID- 23645715 TI - Beyond the language given: the neural correlates of inferring speaker meaning. AB - Even though language allows us to say exactly what we mean, we often use language to say things indirectly, in a way that depends on the specific communicative context. For example, we can use an apparently straightforward sentence like "It is hard to give a good presentation" to convey deeper meanings, like "Your talk was a mess!" One of the big puzzles in language science is how listeners work out what speakers really mean, which is a skill absolutely central to communication. However, most neuroimaging studies of language comprehension have focused on the arguably much simpler, context-independent process of understanding direct utterances. To examine the neural systems involved in getting at contextually constrained indirect meaning, we used functional magnetic resonance imaging as people listened to indirect replies in spoken dialog. Relative to direct control utterances, indirect replies engaged dorsomedial prefrontal cortex, right temporo parietal junction and insula, as well as bilateral inferior frontal gyrus and right medial temporal gyrus. This suggests that listeners take the speaker's perspective on both cognitive (theory of mind) and affective (empathy-like) levels. In line with classic pragmatic theories, our results also indicate that currently popular "simulationist" accounts of language comprehension fail to explain how listeners understand the speaker's intended message. PMID- 23645716 TI - The effects of focal and nonfocal cues on the neural correlates of prospective memory: insights from ERPs. AB - The present study is the first designed to investigate behavioral and event related potential (ERP) correlates of the processes involved in focal and nonfocal prospective memory (PM) tasks. Focal tasks are those in which the features of the PM cue are easily extracted from the ongoing activity, whereas the process is more indirect in nonfocal tasks. Strategic monitoring was associated with a slowing of reaction times in ongoing trials and with frontal and parietal ERP modulations. These effects were greater in the nonfocal task, whereas they were smaller, or even absent for some individuals, in the focal task. This indicates that strategic monitoring is engaged to a greater extent in nonfocal tasks, whereas it is less extensively recruited, or not recruited at all by some individuals, in focal tasks. Indeed, the recognition of the PM cue might also occur automatically in focal tasks, as suggested by the FN400 increase in focal PM trials. Nonfocal tasks are supported by more controlled resources not only in retrieval, but also in postretrieval monitoring and coordinating processes. This was reflected in the enhancement of the prospective positivity and frontal slow wave observed in nonfocal PM trials. We interpreted these results as supporting the multiprocess view of PM. PMID- 23645717 TI - Neuromagnetic evidence of abnormal movement-related beta desynchronization in Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder associated with debilitating motor, posture, and gait abnormalities. Human studies recording local field potentials within the subthalamic nucleus and scalp-based electroencephalography have shown pathological beta synchronization throughout the cortical-basal ganglia motor network in PD. Suppression of such pathological beta synchronization has been associated with improved motor function, which may explain the effectiveness of deep-brain stimulation. We used magnetoencephalography (MEG) to investigate neural population-level beta responses, and other oscillatory activity, during a motor task in unmedicated patients with PD and a matched group of healthy adults. MEG is a noninvasive neurophysiological technique that permits the recording of oscillatory activity during movement planning, execution, and termination phases. Each of these phases was independently examined using beamforming to distinguish the brain areas and movement phases, where pathological oscillations exist during motor control. Patients with PD exhibited significantly diminished beta desynchronization compared with controls prior to and during movement, which paralleled reduced alpha desynchronization. This study is the first to systematically investigate neural oscillatory responses in PD during distinct stages of motor control (e.g. planning, execution, and termination) and indicates that these patients have significant difficulty suppressing cortical beta synchronization during movement planning, which may contribute to their diminished movement capacities. PMID- 23645719 TI - The right anterior intraparietal sulcus is critical for bimanual grasping: a TMS study. AB - Grasping with 2 limbs in opposition to one another is older than the hand, yet the neural mechanisms for bimanual grasps remain unclear. Similar to unimanual grasping, bimanual grasping may require regions in the parietal cortex that use visual object-feature information to find matching stable grasp points on the object. The localization of matching points is computationally expensive, so it might make sense for the signals to converge in a single cortical area. To examine this, we use transcranial magnetic stimulation (TMS) to probe the contribution of cortical areas known to be associated with unimanual grasping, while participants performed bimanual grasps. We applied TMS to the anterior and caudal portion of the intra-parietal sulcus (aIPS and cIPS) in each hemisphere during a size-perturbation task using the index fingers of both hands to grasp an object whose orientation might or might not change. We found significant interaction effects between TMS and perturbation of the grasp-relevant object dimension that increased grip aperture only for the right aIPS. These results indicate that the aIPS is involved not only in unimanual, but also bimanual grasping, and the right aIPS is critically involved in bimanual grasps. This suggests that information from both hemispheres converges in the right hemisphere to achieve bimanual grasps. PMID- 23645720 TI - Fragile X carrier screening in Korean women of reproductive age. AB - OBJECTIVE: To estimate the distribution of the FMR1 alleles and the prevalence of the premutaion (PM) and full mutation (FM) of the FMR1 gene in Korean women of reproductive age. METHODS: Using polymerase chain reaction and Southern blot, 5829 women of reproductive age were screened (low-risk group n = 5470 and high risk group n = 359) and 11 prenatal diagnoses were completed between September 2003 and December 2011. RESULTS: Of the 5829 women screened, normal FMR1 alleles (11,607) had a bimodal distribution with most alleles having 29 (37.87%) and 30 (31.87%) CGG repeats. Of the 5470 women in the low-risk group, 7 PM were identified, giving a PM carrier frequency of 1:781; none of the women had Fragile X syndrome. We also identified 38 intermediate alleles, with a reported incidence of 1:143. Of the 11 prenatal diagnoses, five were normal, five had a premutation, and one had a full mutation allele. CONCLUSIONS: The carrier frequency is 1/781 (0.13%) in Korean women of reproductive age. This is lower than among Caucasians, but relatively higher than in other Asian populations. Although there may be a founder effect, these results might be valuable in understanding Fragile X syndrome in Koreans and Asians as a whole. PMID- 23645718 TI - Fixation-related FMRI analysis in the domain of reading research: using self paced eye movements as markers for hemodynamic brain responses during visual letter string processing. AB - The present study investigated the feasibility of using self-paced eye movements during reading (measured by an eye tracker) as markers for calculating hemodynamic brain responses measured by functional magnetic resonance imaging (fMRI). Specifically, we were interested in whether the fixation-related fMRI analysis approach was sensitive enough to detect activation differences between reading material (words and pseudowords) and nonreading material (line and unfamiliar Hebrew strings). Reliable reading-related activation was identified in left hemisphere superior temporal, middle temporal, and occipito-temporal regions including the visual word form area (VWFA). The results of the present study are encouraging insofar as fixation-related analysis could be used in future fMRI studies to clarify some of the inconsistent findings in the literature regarding the VWFA. Our study is the first step in investigating specific visual word recognition processes during self-paced natural sentence reading via simultaneous eye tracking and fMRI, thus aiming at an ecologically valid measurement of reading processes. We provided the proof of concept and methodological framework for the analysis of fixation-related fMRI activation in the domain of reading research. PMID- 23645722 TI - Current status in chemotherapy for advanced pancreatic adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal types of cancer in the United States. Surgical resection remains the only curative treatment, but fewer than 20% of patients qualify as candidates. The past two decades saw major changes in the treatment of advanced PDA, a shift of standard protocol from 5 fluorouracil to gemcitabine and gemcitabine-based combinations, the introduction of molecular target therapy and multi-agent regimens. However, even with advancements in medicine, PDA is still extremely resistant to currently available regimens, which results in poor prognosis, with only 5.2% of patients alive at three years. This provides a challenge to scientists as they seek to find the best active regimen with the least side-effects. In this article, we review the current recommended guidelines from the National Comprehensive Cancer Network. In addition, we highlight major clinical trials since 2011. PMID- 23645723 TI - Denosumab and anti-angiogenetic drug-related osteonecrosis of the jaw: an uncommon but potentially severe disease. AB - Osteonecrosis of the jaw (ONJ) is a rare but serious lesion of the jaw characterized by exposed necrotic bone and is related to several drugs usually used for treating patients with advanced malignancies. Common therapies inducing ONJ are nitrogen-containing bisphosphonates (BPs), the human monoclonal antibody to the receptor activator of nuclear factor-kappa B ligand denosumab and some anti-angiogenic drugs, alone or in combination with BPs. The real incidence of ONJ is unknown. Several cases of ONJ in patients with cancer who underwent denosumab therapy have been reported and it seems that the overall incidence of denosumab-related ONJ is similar to that for BP-related in this population, ranging between 1-2%. The cell-surface vascular endothelial growth factor (VEGF) receptor plays a major role in cancer progression and can be targeted by drugs inhibiting the tyrosine kinase activator or other second messengers. Most angiogenesis inhibitors, such as the monoclonal antibody bevacizumab and the kinase inhibitor sunitinib, target the VEGF signaling pathway. Unfortunately, cases of bevacizumab-induced ONJ have been reported, especially in patients treated with bevacizumab and BPs in combination. There are only few studies reporting sunitinib-related ONJs. In patients with advanced cancer and malignancy associated hypercalcemia undergoing BP, denosumab or bevacizumab therapy, enquiry into current dental health and dental examination is mandatory. Good oral hygiene, limiting of alcohol intake and stopping smoking should be suggested for all patients requiring such treatments. PMID- 23645721 TI - Functional connectivity and brain activation: a synergistic approach. AB - Traditional functional magnetic resonance imaging (fMRI) studies exploit endogenous brain activity for mapping brain activation during "periodic" cognitive/emotional challenges or brain functional connectivity during the "resting state". Previous studies demonstrated that these approaches provide a limited view of brain function which can be complemented by each other. We hypothesized that graph theory functional connectivity density (FCD) mapping would demonstrate regional FCD decreases between resting-state scan and a continuous "task-state" scan. Forty-five healthy volunteers underwent functional connectivity MRI during resting-state as well as a continuous visual attention task, and standard fMRI with a blocked version of the visual attention task. High resolution data-driven FCD mapping was used to measure task-related connectivity changes without a priori hypotheses. Results demonstrate that task performance was associated with FCD decreases in brain regions weakly activated/deactivated by the task. Furthermore, a pronounced negative correlation between blood oxygen level-dependent-fMRI activation and task-related FCD decreases emerged across brain regions that also suggest the disconnection of task-irrelevant networks during task performance. The correlation between improved accuracy and stronger FCD decreases further suggests the disconnection of task-irrelevant networks during task performance. Functional connectivity can potentiate traditional fMRI studies and offer a more complete picture of brain function. PMID- 23645724 TI - Hydrogen peroxide enhances radiation-induced apoptosis and inhibition of melanoma cell proliferation. AB - The efficacy of radiation therapy (RT) for melanoma is limited in part by its radioresistance. Here, we examined the radiosensitizing effect of hydrogen peroxide (H(2)O(2)) on a radioresistant melanoma cell line, HTB-65. We found that H(2)O(2) synergized with RT to inhibit melanoma cell proliferation and promote apoptosis. The antiproliferative effect of H(2)O(2)/RT correlated with increased expression of p15 and reduced expression of cyclin D, cyclin E, cyclin-dependent kinase (CDK)2 and CDK4. The pro-apoptotic effect of H(2)O(2) /RT correlated with reduced expression of the B-cell CLL/lymphoma (BCL)2. These data highlight the potential of H(2)O(2) as a radiation sensitizer for melanoma treatment and show that this warrants further study. PMID- 23645725 TI - Premalignant lesions skew spleen cell responses to immune modulation by adipocytes. AB - Obesity can promote a chronic inflammatory state and is associated with an increased risk for cancer. Since adipocytes can produce mediators that can regulate conventional immune cells, this study sought to determine if the presence of premalignant oral lesions would skew how immune cells respond to adipocyte-derived mediators to create an environment that may be more favorable for their progression toward cancer. While media conditioned by adipocytes stimulated normal spleen cell production of the T helper (Th) type-1 cytokines interleukin (IL)-2, interferon-gamma (IFN-gamma), IL-12 and granulocyte-monocyte colony-stimulating factor (GM CSF), media from premalignant lesion cells either blocked or had no added affect on the adipocyte-stimulated Th1 cytokine production. In contrast, media conditioned by premalignant lesion cells exacerbated adipocyte-stimulated spleen cell production of the Th2 cytokines IL 10 and IL-13, although it did not further enhance the adipocyte-stimulated spleen cell production of IL-4 and TGF-beta. The premalignant lesion environment also heightened the adipocyte-stimulated spleen cell production of the inflammatory mediators IL 1alpha, IL-1beta, IL-6 and IL-9, although it did not further increase the adipocyte-stimulated production of tumor necrosis factor-alpha (TNF alpha). IL 17 production was unaffected by the adipocyte-derived mediators, but was synergistically triggered by adding media from premalignant lesion cells. These stimulatory effects on spleen cell production of Th2 and inflammatory mediators were not induced in the absence of media conditioned by adipocytes. In contrast, media conditioned by adipocytes did not stimulate production of predominantly monocyte-derived chemokine C-X-C motif ligand (CXCL)9, chemokine C C motif ligand (CCL)3 or CCL4, although it stimulated production of CCL2 and the predominantly T cell-derived chemokine CCL5, which was the only chemokine whose production was further increased by media from premalignant lesions. These results suggest that the responsiveness of spleen cells to adipocyte-derived mediators is influenced by mediators from premalignant lesion cells to favor conventional immune cell production of a Th2 and inflammatory cytokines. PMID- 23645726 TI - Safety and efficacy field study of artesunate for dogs with non-resectable tumours. AB - The anti-malarial drug artesunate has shown anticancer activity in vitro and in preliminary animal experiments, but experience in patients with cancer is very limited. Pre-clinical studies in dogs indicated morbidity at high dosage levels. This study evaluated the effects of artesunate in canine cancer cell lines and in canine cancer patients. Four canine cell lines were tested in vitro for sensitivity towards artesunate and dihydroartemisinin (DHA; active metabolite of artesunate). The half-maximal inhibitory concentration (IC50) values for artesunate or DHA were 2-60 MUM in three cell lines, while one cell line was much less sensitive to artesunate (IC50 337 MUM) than to DHA (IC50 50 MUM). A safety/efficacy field study with artesunate was conducted in 23 dogs with non resectable tumours. Artesunate was administered for 7-385 days at a dosage of 651 1178 (median 922) mg/m(2). No neurological or cardiac toxicity was observed and seven dogs exhibited no adverse effects at all. Fever and haematological/gastrointestinal toxicity, mostly transient, occurred in 16 dogs. One dog died from pneumonia. Plasma artesunate and DHA levels fell below the limit of detection within 8-12 h after artesunate administration, while levels after two hours were close to 1 MUM. Artesunate produced a long-lasting complete remission in one case of cancer and short-term stabilization of another seven cases. PMID- 23645727 TI - Ellagic Acid, a Dietary Polyphenol, Selectively Cytotoxic to HSC-2 Oral Carcinoma Cells. AB - BACKGROUND: The antiproliferative and apoptotic effects of ellagic acid, a dietary polyphenol, were studied. MATERIALS AND METHODS: The neutral red cytotoxicity assay compared the sensitivities of gingival fibroblasts and HSC-2 oral carcinoma cells to ellagic acid. The ferrous ion oxidation xylenol orange assay and levels of intracellular reduced glutathione were used to assess pro oxidant nature of ellagic acid. Antioxidant activity was demonstrated in cells co treated with H2O2 and ellagic acid by 2',7'-dichlorodihydrofluorescein diacetate staining and in cells co-treated with gallic acid and ellagic acid by morphological analysis. Apoptosis was assessed by microscopy, flow cytometry, luminescence, and immunoblotting. RESULTS: Ellagic acid was cytotoxic to carcinoma cells, but not to normal cells. Its pro-oxidant nature was minimal, whereas its antioxidant property was biologically significant. Ellagic acid treated cells demonstrated apoptotic morphology, induction of apoptosis (flow cytometry), increase in caspase 3/7 activities (luminescence), and activation of caspase 3 and cleavage of poly ADP ribose polymerase (immunoblot). CONCLUSION: Ellagic acid exhibited significant antioxidant, but not pro-oxidant, activity and was selectively cytotoxic to oral carcinoma cells. PMID- 23645728 TI - Salmonella typhimurium A1-R tumor targeting in immunocompetent mice is enhanced by a traditional Chinese medicine herbal mixture. AB - We have developed a bacterial cancer therapy strategy using the genetically engineered strain Salmonella typhimurium A1-R (A1-R). A1-R is auxotrophic for leu and arg which attenuates bacterial growth in normal tissue but allows high tumor virulence. A1-R is effective against metastatic human and murine cancer cell lines in clinically-relevant nude-mouse models. However, A1-R treatment of tumors in immunocompetent mouse models with high doses is limited by toxicity. The current study evaluated a traditional Chinese medicine (TCM) herbal mixture in combination with A1-R therapy in a syngeneic metastatic immunocompetent mouse model of highly aggressive lung cancer. In a model of Lewis lung carcinoma, the combination of a TCM herbal mixture and S. typhimurium A1-R enabled bacteria to be safely administered at the large dose of 2 * 10(7) colony forming units once a week i.v. with increased treatment efficacy and reduced toxicity compared to monotherapy with A1-R. The herbal mixture prevented body weight loss, spleen weight gain and liver infection by A1-R, as well as hemorrhagic lesions on the skin, liver, and spleen, all observed with A1-R monotherapy. The results of the present study suggest that the combination of A1-R and TCM has important potential for therapy of highly aggressive types of cancer, including those which are resistant to standard therapy. PMID- 23645729 TI - The mTOR inhibitor RAD001 potentiates autophagic cell death induced by temozolomide in a glioblastoma cell line. AB - We have studied the consequences of the combination of the mammalian target of rapamycin (mTOR) inhibitor RAD001 and temozolomide on the growth and cell death of the glioblastoma cell line U-87 in vitro. A progressive decrease of cell proliferation was recorded with increasing concentrations of temozolomide, which was markedly reinforced and prolonged by the addition of RAD001. While this combination treatment resulted in only a low level of apoptosis, it led to a pronounced enhancement of autophagic cell death. When combined with gamma-ray irradiation, a significant reinforcement of the overall cytotoxicity was obtained, suggesting the efficacy of such a multipronged approach for the treatment of glioblastoma. RAD001 strongly contributes to the reinforcement of temozolomide-induced autophagy, which appears to represent a major form of cell death in glioblastoma. The association of such combined chemotherapies with radiotherapy could be useful for the management of these hard-to-treat malignancies. PMID- 23645730 TI - Identification of HLA class I-binding peptides derived from unique cancer associated proteins by mass spectrometric analysis. AB - BACKGROUND/AIM: Since antigenic peptides of the cancer-associated antigens presented on human leukocyte antigen (HLA) molecules are recognized by specific cytotoxic T-lymphocytes, they have the potential to becoming effective peptide vaccines for cancer immunotherapy. MATERIALS AND METHODS: Peptides binding to HLA A*0201 and HLA-A*2402 obtained from human prostate cancer cells by acid-elution were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and source proteins of the peptides were determined based on the HLA-binding capacity listed on the Syfpeithi. RESULTS: We identified TKLSA possibly derived from absent in melanoma 1-like protein (AIM1L), and RLRYT from trans-membrane protein 191C (TMEM 191C) or c20orf201. Messenger RNAs encoding these proteins were expressed in various cancer cell types but none or very few in non-cancerous tissues except for testis, cerebellum and ovary. CONCLUSION: HLA class I-binding peptides of unique cancer-associated proteins were identified by MS analysis, and might become a promising tool for the generation of novel cancer vaccines. PMID- 23645731 TI - Antiproliferative and apoptosis-inducing activity of curcumin against human gallbladder adenocarcinoma cells. AB - AIM: Curcumin has potent antitumor activity against many types of human cancers. However, the inhibitory effects and possible mechanisms of curcumin on gallbladder cancer remains to be determined. MATERIALS AND METHODS: Using HAG-1 human gallbladder adenocarcinoma cells, we investigated the effects of curcumin on cell proliferation, apoptosis, cell-cycle perturbation, and signal proteins for survival, proliferation, and apoptosis. RESULTS: Curcumin exhibited dose dependent antitumor activity against HAG-1 cells, arresting the cells in G2/M phase, with progressive expansion of the apoptotic cell population. Upon curcumin treatment, AKT activation was substantially suppressed, with subsequent reduction of activities of mammalian target of rapamycin (mTOR) and its downstream molecules S6 kinase-1 (S6K1) and elF4E-binding protein-1 (4E-BP1), but constitutive activity of extracellular signal-regulated kinase (ERK1/2) was clearly enhanced. Curcumin reduced the expression and phosphorylation of anti apoptotic Bcl-2, but did not affect the expressions of pro-apoptotic Bax and anti apoptotic nuclear factor (NF-kappaB). CONCLUSION: These results suggest that curcumin induces G2/M arrest and apoptosis through multiple mechanisms involving enhanced mitogen-activated protein (MAP) kinase activity, reduced AKT-mTOR activity, and reduced Bcl-2 function. These data provide a mechanistic rationale for the potential use of curcumin in the treatment of gallbladder cancer. PMID- 23645732 TI - The Indole-3-carbinol cyclic tetrameric derivative CTet synergizes with cisplatin and doxorubicin in triple-negative breast cancer cell lines. AB - BACKGROUND/AIM: The indole-3-carbinol cyclic tetrameric derivative (CTet) inhibits breast cancer cell proliferation by endoplasmic reticulum stress and autophagy-related cell death induction, AKT/PKB (protein kinase B) activity inhibition and p53-independent overexpression of cyclin-dependent kinase inhibitor-1A (p21/CDKN1A). In the present study we evaluated the synergistic activity of CTet in combination with cisplatin and doxorubicin in triple-negative breast cancer cell lines. MATERIALS AND METHODS: Synergisms were evaluated in terms of cell viability, induction of autophagy and overexpression of microtubule associated protein-1 light chain-3 beta (MAP1LC3B) autophagy-related gene in MDA MB-231 and BT-20 triple-negative breast cancer cells. RESULTS: We demonstrated that CTet in combination with both cisplatin and doxorubicin synergistically inhibits cell viability and induces autophay. The MAP1LC3B gene was synergistically overexpressed in MDA-MB-231 cells treated with CTet-cisplatin combination. Moreover, the cytotoxic activity of CTet was improved in cells pre treated with cisplatin and doxorubicin. CONCLUSION: This preliminary in vitro study confirms the potential of CTet as a chemopreventive agent or chemotherapeutic in combination with standard approaches for triple-negative breast cancer. PMID- 23645733 TI - Broussoflavonol B restricts growth of ER-negative breast cancer stem-like cells. AB - Accumulating experimental and clinical evidence has indicated that tumor initiating or cancer stem-like cells are a sub-population of tumor cells capable of initiating and driving tumor growth, and cancer stem-like cells are resistant to most current cancer therapies, including chemo- and radiation therapy. More effective targeted-therapeutic approaches are urgently needed to eliminate cancer stem-like cells. Here, we report that broussoflavonol B, a chemical purified from the bark of the Paper Mulberry tree (broussonetia papyrifera), exhibited potent growth inhibitory activity towards estrogen receptor (ER)-negative breast cancer SK-BR-3 cells at sub-micromolar concentrations. Broussoflavonol B more potently inhibited growth and induced differentiation of stem-like SK-BR-3 cells-compared to the anti-estrogen tamoxifen. In addition, broussoflavonol B treatment also reduced the steady, state levels of the Human epidermal growth factor receptor-2 (HER2) and ER-alpha36, a variant of ER-alpha. Our results, thus, indicate that broussoflavonol B is a potent growth inhibitor of ER-negative breast cancer stem like cells and provide a rationale for pre-clinical and clinical evaluation of broussoflavonol B for breast cancer therapy. PMID- 23645734 TI - Changes in CO2 concentration increase the invasive ability of colon cancer cells. AB - BACKGROUND/AIM: We studied the effects of CO(2) concentration changes on the invasive ability of colon cancer cells. MATERIALS AND METHODS: Colon cancer cell lines and human samples derived from a peritoneal metastasis were incubated in a hypercapnic environment, followed by incubation in 5% CO(2). The invasive ability of colon cancer cells incubated with CO(2) were analyzed using an invasion assay system. RESULTS: In comparison with the colon cancer cell lines incubated in 5% CO(2) only, the invasive ability of cells increased in all the colon cancer cell lines subjected to incubation in 20% CO(2) followed by incubation in 5% CO(2), with a concomitant increase in the mRNA expressions of matrix metalloproteinase-2 (MMP2) and MMP9. The invasive capability of peritoneal metastatic cells in the human-derived specimen also increased on CO(2) concentration changes. CONCLUSION: CO(2) concentration changes enhanced the invasive capacity of colon cancer cells. PMID- 23645735 TI - Blood oxygen level-dependent MRI for evaluation of early response of liver tumors to chemoembolization: an animal study. AB - AIM: To evaluate the feasibility of carbogen-challenge blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) for assessing the early response of liver tumors to chemoembolization in a rat hepatoma model. MATERIALS AND METHODS: In a 9.4-Tesla scanner, a multiple gradient-recalled echo sequence was utilized for R2* measurement at 11 and 13 days after tumor implantation, first during room air breathing and then with carbogen gas (95% O2/5% CO2) breathing, to calculate the percentage changes of R2* values [DeltaR2*(%)]. Transarterial chemoembolization was conducted 12 days after tumor implantation. RESULTS: The DeltaR2* value of the tumors was 10.61 +/- 8.94% on pre chemoembolization images and -0.16 +/- 1.85% on post-chemoembolization images. There was a significant difference in the DeltaR2* value of the tumors between pre-chemoembolization and post-chemoembolization BOLD MRI (p=0.013). CONCLUSION: Carbogen-challenge BOLD MRI can be a non-invasive and useful method for the evaluation of early response of liver tumors to chemoembolization. PMID- 23645736 TI - Increased plasma caveolin-1 levels are associated with progression of prostate cancer among Japanese men. AB - AIM: Up-regulation of caveolin-1 (CAV1) is associated with aggressive prostate cancer. Among Caucasian and African-American patients, plasma CAV1 levels are elevated in patients with castration-resistant prostate cancer (CRPC), but not in those with hormone-sensitive prostate cancer (non-CRPC), which implies that CAV1 could be a therapeutic target for CRPC. Here, we evaluated associations between plasma CAV1 levels and these types of cancer in Japanese men, and CAV1 expression in PC3 (CRPC) and LNCaP (non-CRPC) cell lines. MATERIALS AND METHODS: Plasma samples were obtained from 58 patients with prostate cancer: 36 with CRPC and 22 with non-CRPC. Enzyme-linked immuno sorbent assay (ELISA) kits were used to determine CAV1 plasma levels; qRT-PCR and western blots were used to evaluate the expression of CAV1 mRNA and protein in cell lines. RESULTS: Plasma CAV1 levels in patients with CRPC were greatly higher than in those with non-CRPC (1.46+/-1.37 ng/ml in CRPC; 0.56+/-0.32 ng/ml in non-CRPC, p<0.004). Western blot and real time qRT-PCR showed CAV1 protein and mRNA in PC3 cells to be significantly overexpressed compared to its expression in LNCaP cells (p<0.0001). CONCLUSION: Our results showed a relationship between CAV1 expression and prostate cancer progression, and support the possibility of CAV1 as a therapeutic target for CRPC. PMID- 23645737 TI - Mutations in adenosine deaminase-like (ADAL) protein confer resistance to the antiproliferative agents N6-cyclopropyl-PMEDAP and GS-9219. AB - BACKGROUND/AIM: GS 9219 is a double prodrug of antiproliferative nucleotide analog 9-(2-Phosphonylmethoxyethyl)guanine (PMEG), with potent in vivo efficacy against various hematological malignancies. This study investigates the role of adenosine deaminase-like (ADAL) protein in the intracellular activation of GS 9219. MATERIALS AND METHODS: A cell line resistant to 9-(2 Phosphonylmethoxyethyl)-N(6)-cyclopropyl-2,6-diaminopurine (cPrPMEDAP), an intermediate metabolite of GS-9219, was generated and characterized. RESULTS: The resistant cell line was cross-resistant to cPrPMEDAP and GS-9219, due to a defect in the deamination of cPrPMEDAP to PMEG. Mutations in the ADAL gene (H286R and S180N) were identified in the resistant cells that adversely-affected its enzymatic activity. Introduction of the wild-type ADAL gene re-sensitized resistant cells to both cPrPMEDAP and GS-9219. CONCLUSION: The ADAL protein plays an essential role in the intracellular activation of GS-9219 by catalyzing the deamination of cPrPMEDAP metabolite to PMEG. Mutations affecting the activity of ADAL confer resistance to both GS-9219 and its metabolite cPrPMEDAP. PMID- 23645738 TI - Angiogenesis of lung cancer utilizes existing blood vessels rather than developing new vessels using signals from carcinogenesis. AB - Cancer cells metastasize via angiogenesis and are a long-standing therapeutic target in malignant tumors. Vascular endothelial growth factor (VEGF) antibodies have been developed for clinical use, with limited benefits. Therefore, identifying the underlying mechanisms of angiogenesis regarding whether tumor vessels are derived from cancer cells or blood vessels in existence, is highly anticipated. Recently, epidermal growth factor receptor (EGFR) antibodies were utilized to detect cancer cells with somatic mutations of EGFR. The concordance rate is high for detection between immunohistochemical staining and polymerase chain reaction (PCR)-based methods. We hypothesized that endothelial cells exhibiting lymphatic and venous tumor invasiveness will be immunoreactive if new blood vessels are derived from the lung cancer itself, because EGFR mutations occur at a relatively early phase in carcinogenesis. We examined endothelial cells with EGFR mutations exhibiting lymphatic and venous tumor invasiveness using these antibodies. Tumor samples were obtained from 848 consecutive patients with lung cancer. Among 153 of 595 adenocarcinomas with EGFR-sensitive mutations, the number of lymphatic and venous invasive tumors was 35 and 19, respectively. Consequently, 12 available tumor specimens (five specimens for delE746-A750 and seven specimens for L858R) with both factors were evaluated. The main cancer cells were highly immunoreactive; however, no obvious lesions were detected with endothelial cells exhibiting lymphatic or venous invasiveness. Therefore, the angiogenesis of lung cancer seems to utilize blood vessels in existence, rather than create new vessels using signals from carcinogenesis. PMID- 23645739 TI - Expression of bone morphogenetic protein-10 (BMP10) in human urothelial cancer of the bladder and its effects on the aggressiveness of bladder cancer cells in vitro. AB - BACKGROUND: Bone morphogenetic protein-10 (BMP10), a novel member of the bone morphogenetic protein (BMP) family, has been indicated as a possible tumour suppressor in prostate and breast cancer. However, its role in urothelial tumours remains unknown. In the present study, we examined the role of BMP10 in urothelial cancer cells and the expression of BMP10 in human urethelial cancer of the bladder. MATERIALS AND METHODS: The expression of BMP10 was examined in human bladder tissues and in the T24 human bladder cancer cell line using immunochemical staining and reverse transcription polymerase chain reaction (RT PCR), respectively. The biological impact of modifying BMP10 expression, through genetic manipulation, in urothelial cancer cells was evaluated using in vitro models. RESULTS: mRNA for BMP10 and receptors of BMPs was expressed in T24 cell lines. BMP10 protein expression was observed in normal urothelial and stromal cells, but was found to be decreased in or absent from urothelial cancer cells. The frequency of positive staining in normal tissues (9/9) was significantly higher than that in urothelial cancer tissues (6/15) (p=0.007). T24 cells were transfected with BMP10 expression plasmid. It was further demonstrated that overexpression of BMP10 reduced the growth rate of T24 cells, and markedly reduced the motility, and adhesion of T24 cells in vitro. No significant effects were seen on in vitro invasiveness of T24 cells following BMP10 transfection. CONCLUSION: Expression of BMP10 protein is reduced in cancer cells of bladder tumours. Overexpression of BMP10 has an inhibitory effect on the growth, adhesion, and migration of bladder cancer cells in vitro. This would suggest a potential tumour suppressor role of BMP10 in bladder cancer. PMID- 23645740 TI - Tumor-derived tenascin-C promotes the epithelial-mesenchymal transition in colorectal cancer cells. AB - BACKGROUND: Tenascin-C (TNC) is an extracellular matrix glycoprotein, usually derived from myofibroblasts in the cancer microenvironment. Recently, however, the significance of tumor-derived TNC in initiation of cancer metastasis was disclosed. We investigated the clinical significance of cancer-derived TNC in colorectal cancer (CRC) cases. MATERIALS AND METHODS: TNC expression in 170 cases of CRC was analyzed by quantitative real-time polymerase chain reaction (PCR). In addition, gene expression arrays using purely-separated cancer tissues of another 86 cases was performed and the functional implications of cancer-specific TNC were investigated. RESULTS: The expression of TNC mRNA was significantly higher in CRC tissues than in the corresponding normal tissues. Cancer cell-specific TNC expression was a significant prognostic factor in CRC cases. Moreover, cancer cell-derived TNC was associated with the epithelial-mesenchymal transition (EMT) signature. CONCLUSION: Cancer cell-derived TNC promotes cancer invasiveness via EMT regulation, and not cancer tissue TNC but cancer cell-specific TNC is a novel indicator of poor prognosis. PMID- 23645741 TI - Thymidylate synthase gene copy number as a predictive marker for response to pemetrexed treatment of lung adenocarcinoma. AB - BACKGROUND: Pemetrexed is a key drug for therapy of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: In a search for biomarkers for study of the efficacy of pemetrexed treatment, we examined the thymidylate synthase (TYMS) copy number in NSCLC cell lines and in clinical NSCLC samples treated with pemetrexed, combined with platinum drugs. RESULTS: TYMS copy numbers in lung adenocarcinoma cell lines were significantly lower than in squamous cell carcinoma (p=0.0105), and a significant correlation was found between the TYMS copy number and the 50% inhibitory concentration value for pemetrexed in all 17 lung cancer cell lines tested (r=0.6814, p=0.0026). Moreover, TYMS copy number was significantly lower in clinical NSCLC samples responsive to treatment with pemetrexed combined with platinum drugs (p=0.0067). Furthermore, the decrease in the baseline CT size measurement of pemetrexed combined with platinum drug treatment correlated significantly with TYMS copy number (r=0.7967, p=0.0011). CONCLUSION: To our knowledge, this is the first report of a significant association between TYMS copy number and response to pemetrexed treatment in tumor biopsy specimens. Our results suggest that TYMS copy number could be a predictive biomarker for pemetrexed based chemotherapy. PMID- 23645742 TI - Quercetin inhibits migration and invasion of SAS human oral cancer cells through inhibition of NF-kappaB and matrix metalloproteinase-2/-9 signaling pathways. AB - Quercetin, a principal flavanoid compound in onions, has been shown to possess a wide spectrum of pharmacological properties, including anticancer activities. Our earlier study showed that quercetin induced cytotoxic effects on SAS human oral cancer cells. In this study, we found that quercetin significantly reduced wound closure of SAS cells in culture plates after 12- and 24-h treatments. Results indicated that quercetin inhibited the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9, as measured by western blotting and gelatin zymography. The results from western blotting also showed that quercetin reduced the protein levels of MMP-2, -7, -9 and -10, vascular endothelial growth factor (VEGF), nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB) p65, inductible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), urokinase-type plasminogen activator (uPA), phosphatidylinositide-3 kinases (PI3K), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IKBalpha), IKB-alpha/beta, phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor kinase, alpha/beta (p IKKalpha/beta), focal adhesion kinase (FAK), son of sevenless homolog-1 (SOS1), growth factor receptor-bound protein-2 (GRB2), mitogen-activated protein kinase kinase kinase-3 (MEKK3), MEKK7, extracellular-signal-regulated kinase 1/2 (ERK1/2), p-ERK1/2, c-Jun N-terminal kinase 1/2 (JNK1/2), p38, p-p38, Jun proto oncogene (c-JUN) and p-c-JUN but it did not affect Ras homolog gene family, member A (RhoA), Protein kinase C (PKC) and rat sarcoma viral oncogene homolog (RAS) in SAS cells. Confocal laser microscopy also showed that quercetin promoted the expressions of RhoA and Rho-associated, coiled-coil containing protein kinase 1 (ROCK1), but inhibited the expression of NF-kappaB p65 in SAS cells. It is concluded from these data that inhibition of migration and invasion of SAS cells by quercetin is associated with the down-regulation of PKC and RhoA by blocking MAPK and PI3K/AKT signaling pathways and NF-kappaB and uPA, resulting in inhibition of MMP-2 and MMP-9 signaling. PMID- 23645744 TI - Influence of sex differences on the progression of cancer-induced bone pain. AB - BACKGROUND: Pain caused by bone metastases has a severe impact on the quality of life for many patients with cancer. Good translational in vivo models are required to understand the molecular mechanism and develop better treatment. In the current study we evaluated the influence of sex differences on the progression of cancer-induced bone pain. MATERIALS AND METHODS: 4T1-luc2 mammary cancer cells were introduced into the femoral cavity of female and male BALB/cJ mice. Bioluminescence tumor signal, pain-related behavior and bone degradation were monitored for 14 days. RESULTS: Female mice demonstrated a significantly greater bioluminescence signal on day 2 compared to male mice and, in addition, a significant earlier onset of pain-related behavior was observed in the females. No sex difference was observed for bone degradation. Finally, a strong correlation between pain-related behavior and bone degradation was observed for both sexes. CONCLUSION: Although differences were observed between the sexes, these were minor and did not affect the overall progression of the pain state. PMID- 23645743 TI - Chemotherapeutic alteration of VEGF, PDGF and PDGFRalpha/beta expression under 5 FU vs. docetaxel in HPV-transformed squamous cell carcinoma compared to HPV negative HNSCC in vitro. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the most common malignant epithelial tumor in the upper aerodigestive tract. The incidence of HNSCC induced by the oncogenic human papilloma virus (HPV) is rising, indicating a growing importance of the viral etiology. Cell proliferation, migration and tumor vascularization are regulated by a set of angiogenic peptides such as PDGF (platelet-derived growth factor), PDGFRalpha/beta (platelet-derived growth factor receptor alpha/beta) and VEGF (vascular endothelial growth factor). In locally advanced HNSCC docetaxel is used for induction chemotherapy (ICT) combined with platinum-based chemotherapy and 5-fluorouracil (5-FU). This study sought to evaluate the expression of angiogenic factors (VEGF, PDGF and PDGFRalpha/beta) in HPV-positive (CERV196) and HPV-negative squamous cell carcinoma (HNSCC 11A and 14C) and the efficacy of chemotherapy with docetaxel as a potential treatment modality, compared to 5-FU as a single-drug application. MATERIALS AND METHODS: Tumor cell lines were incubated with 5-FU or docetaxel at a concentration of 1.0 and 5.0 MUmol/ml. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemical analyses were carried out after 48, 72, 120, 192 and 240 hours, in order to identify changes in protein expression of VEGF, PDGF and PDGFRalpha/beta. RESULTS: We demonstrated a significant reduction of VEGF and PDGFRbeta expression after incubation with docetaxel by ELISA and of PDGF by immunohistochemistry, irrespective of the HPV status, whereas the application of 5-FU had a significantly weaker impact on the expression of angiogenic peptides. HPV-positive CERV196 cells were characterized by a reduced susceptibility to a docetaxel-altered expression. CONCLUSION: Although neither of the applied drugs are selective anti-angiogenic agents, docetaxel surprisingly was demonstrated to cause a significant decrease of angiogenic factors in this study. PMID- 23645745 TI - Evaluation of E-cadherin, Ki-67 and lymphatic vessel invasion in abdominal metastases of human breast cancer. AB - BACKGROUND: Abdominal metastasis is a rare finding in human breast cancer and is associated with a poor prognosis. Previous data suggest that mainly invasive lobular carcinomas tend to metastasize to the abdomen. The aim of the present study was to offer deeper insight into the biology of this rare kind of tumor spread. MATERIALS AND METHODS: The expression of the cell adhesion protein E cadherin, the cell proliferation marker Ki-67, as well as lymphatic vessel invasion (LVI), determined by staining with D2-40, were analyzed by immunohistochemistry in samples of primary breast cancer (n=12) and their associated abdominal metastases. RESULTS: In nine cases the tumors and their abdominal metastases were E-cadherin-positive and biologically belonged to the invasive ductal subtype. In three E-cadherin-positive cases, abdominal metastasis was an earlier event compared to E-cadherin-negative cases (90 months versus 37 months). None of the primary tumors showed LVI after immunostaining with D2-40. Higher Ki-67 levels were found in the E-cadherin-positive primaries and metastases. CONCLUSION: Most of the investigated tumors biologically belonged to the invasive ductal subtype. The findings of this analysis provided evidence that metastatic spread to the abdomen does not predominantly appear in lobular invasive carcinomas. PMID- 23645746 TI - Mitogen-inducible Gene-2 (MIG2) and migfilin expression is reduced in samples of human breast cancer. AB - BACKGROUND: Cell adhesion proteins that connect each cell to neighboring cells and the extracellular matrix play a fundamental role in metastasis. Mitogen inducible gene-2 (MIG2), is a cell-matrix adhesion protein, which through migfilin, interacts with filamin-A, being linked to actin cytoskeleton. AIM: Recent studies have implicated both MIG2 and migfilin in cancer, but little is known regarding their expression in breast cancer. In this study, we investigated this topic. MATERIALS AND METHODS: mRNA and protein expression was examined in 30 breast cancer samples and compared to that of normal adjacent tissue using real time-polymerase chain reaction (PCR) and western blotting. RESULTS: Our results showed that expression of MIG2 and migfilin was significantly reduced in the majority of the breast cancer tissues compared to normal tissues regardless of metastatic status and disease stage. CONCLUSION: Both MIG2 and migfilin are down regulated in breast cancer. PMID- 23645747 TI - Characterization of low molecular weight protein tyrosine phosphatase isoforms in human breast cancer epithelial cell lines. AB - BACKGROUND: Low molecular weight protein tyrosine phosphatase (LMW-PTP) is a polymorphic protein with two major isoforms whose role in tumorigenesis is currently controversial. MATERIALS AND METHODS: We characterized LMW-PTP genotype, isoform expression and activity in six different human breast cancer epithelial cell lines (ZR75, MDA-MB-231, MDA-MB-231BO, MCF7, MDA-MB-231BO2, MDA MB-435) and compared them with MCF10A, a normal breast epithelial cell line. RESULTS: mRNA expression of the slow isoform was increased in almost all breast cancer cell lines and that of the fast isoform was reduced (p<0.05) in all breast cancer cell lines. Regarding enzymatic activity, only MCF7 had significantly lower (p<0.05) LMW-PTP activity compared to MCF10A. CONCLUSION: Since these are novel and previously unreported findings, we propose that the differential expression of LMW-PTP fast and slow isoforms suggests their opposite roles in the tumorigenic process, with the fast isoform being anti-oncogenic and the slow isoform being oncogenic. PMID- 23645748 TI - Evaluation of melphalan, oxaliplatin, and paclitaxel in colon, liver, and gastric cancer cell lines in a short-term exposure model of chemosaturation therapy by percutaneous hepatic perfusion. AB - BACKGROUND: The goal of this study was to determine whether liver, gastric, or colonic cancer may be suitable targets for chemosaturation therapy with percutaneous hepatic perfusion (CS-PHP) and to assess the feasibility of utilizing other cytotoxic agents besides melphalan in the CS-PHP system. MATERIALS AND METHODS: Forty human cell lines were screened against three cytotoxic chemotherapeutic agents. Specifically, the dose-dependent effect of melphalan, oxaliplatin, and paclitaxel on proliferation and apoptosis in each cell line was evaluated. These agents were also evaluated for their ability to induce apoptosis in normal primary human hepatocytes. A high-dose short-term drug exposure protocol was employed to simulate conditions encountered during CS-PHP. RESULTS: The average concentration of melphalan required for inducing significant apoptosis was 61 MUM, or about 3-fold less than the theoretical concentration of 192 MUM, achieved in the hepatic artery during CS-PHP dosing with melphalan. Additionally, we found that gastric cancer cell lines were 2-5 fold more sensitive to apoptosis than liver cancer cell lines to all three compounds, suggesting that in addition to colonic and gastric cancer metastases to the liver, primary gastric cancer may also be amenable to management by CS-PHP using an appropriate therapeutic agent. Significantly, at concentrations that are predicted using the CS-PHP system, these agents caused apoptosis of colonic, gastric, and liver cancer cells but were not toxic to primary human hepatocytes. CONCLUSION: The compounds tested are potential candidates for use in the CS-PHP system to treat patients with gastric and colonic metastases, and primary cancer of the liver. PMID- 23645749 TI - Human lung cancer-associated fibroblasts enhance motility of non-small cell lung cancer cells in co-culture. AB - The metastatic potential of non-small cell lung cancer (NSCLC) cells has been shown to be associated with the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment, regulating tumor cell function by secreting growth factors, chemokines, and extracellular matrix (ECM). In this study, we examined the role of CAFs in the tumor progression of NSCLC. Firstly, we established primary cultures of CAFs and matched normal fibroblasts (NFs) from patients with resected NSCLC. CAFs exhibited greater expression of the pan-mesenchymal marker alpha-smooth muscle actin (alpha-SMA) than did NFs, although they displayed similar morphology. Furthermore, we employed a direct co-culture assay with human NSCLC A549 and H358 cells, and found that CAFs were more potent in inducing the epithelial-to mesenchymal transition (EMT) phenotype than NFs, as indicated by an elongated and disseminated appearance. CAF-induced EMT led to an increase in motility and a decrease in proliferation of NSCLC cells through SMAD family number-3 (SMAD3) dependent up-regulation of the growth inhibitory gene p21(CIP1) [cyclin-dependent kinase inhibitor-1A (CDKN1A)] and alpha-SMA. Taken together, these findings provide evidence that lung CAFs have tumor-promoting capacity distinct from NFs and might play a significant role in the metastatic potential of NSCLC. PMID- 23645750 TI - Ex vivo expansion of natural killer cells using cryopreserved irradiated feeder cells. AB - Currently, feeder cells are gamma-irradiated immediately before use for the ex vivo expansion of natural killer (NK) cells from human peripheral blood. Storing irradiated feeder cells by cryopreserving them in multiple vials would be more convenient than irradiating cells each time they are needed. We compared NK cell expansion using cryopreserved-irradiated feeder cells (cryopreserved group) and freshly-irradiated feeder cells (fresh group). To expand NK cells, peripheral blood mononuclear cells were isolated and co-cultured with-100 Gy-irradiated K562 leukemia cells that had been modified to express 4-1BB ligand and membrane-bound (mb) interleukin (IL)-15 (K562-mb15-41BBL cells) for three weeks in the presence of IL-2 and IL-15. Fresh and cryopreserved K562-mb15-41BBL feeder cells expressed similar levels of 4-1BB ligand, whereas membrane-bound IL-15 expression was lower in the cryopreserved cells than in the fresh cells. The NK cell expansion rate did not differ between the two groups (980-fold vs. 1058-fold, respectively), although the mean NK cell purity was higher in the fresh-group than in the cryopreserved-group at day 14 (94.1% vs. 92.5%, respectively) and day 21 (97.1% vs. 95.4%, respectively). The NK cells from the two feeder cell groups did not differ in cytotoxicity against various malignant cell lines at effector-to-target ratios of 4:1, 2:1, and 1:1, or in the expression pattern of NK cell receptors [cluster of differentiation (CD)-16, natural killer group-2, member D (NKG2D), CD69, NKp30, NKp44, NKp46, and CD158b] and level of interferon-gamma secretion. Our results demonstrate that cryopreserved irradiated feeder cells can be used for the ex vivo expansion of human NK cells and provide a convenient improvement on current methods. PMID- 23645751 TI - Effects of two disiloxanes ALIS-409 and ALIS-421 on chemoprevention in model experiments. AB - Morpholino-disiloxane (ALIS-409) and piperazino-disiloxane (ALIS-421) compounds were developed as inhibitors of multidrug resistance of various types of cancer cells. In the present study, the effects of ALIS-409 and ALIS-421 compounds were investigated on cancer promotion and on co-existence of tumor and normal cells. The two compounds were evaluated for their inhibitory effects on Epstein-Barr virus immediate-early antigen (EBV-EA) expression induced by tetradecanoyl phorbol-acetate (TPA) in Raji cell cultures. The method is known as a primary screening test for antitumor effect, below the (IC50) concentration. ALIS-409 was more effective in inhibiting EBV-EA (100 MUg/ml) and tumor promotion, than ALIS 421, in the concentration range up to 1000 MUg/ml. However, neither of the compounds were able to reduce tumor promotion significantly, expressed as inhibition of TPA-induced tumor antigen activation. Based on the in vitro results, the two disiloxanes were investigated in vivo for their effects on mouse skin tumors in a two-stage mouse skin carcinogenesis study. The application of dimethyl-benzanthracene (DMBA; 390 nmol) as a tumor initiator was followed by exposure to TPA (1.7 nmol/l) as a tumor promoter. The experiments showed that ALIS-409 at a concentration of 85 nmol/l had a weak EBV-EA inhibitory effect in vitro and a moderate antitumor activity, compared to the positive control of DMBA plus TPA-treated mice. Flow cytometry by differential staining demonstrated interactions in co-cultures of MCF7 breast cancer and MRC5 human lung fibroblasts. The growth rate of tumor cells in mixed populations of MCF7 breast cancer and MRC5 normal fibroblast cells was reduced in the presence of ALIS-409, as compared to the control non-treated cell populations. The two disiloxanes were moderately-effective in chemoprevention in DMBA-induced and TPA-promoted in vivo tumor formation. Authors suggest that the inhibition of tumor cell and fibroblast interaction by ALIS409 might have some perspective in the development of anti stromal therapy. PMID- 23645753 TI - Antifolate response in replication arrest mutants of Saccharomyces cerevisiae. AB - AIM: Thymidine deprivation is a common cancer treatment. This study examines the role of replication arrest and uracil DNA repair in response to thymidine deprivation. MATERIALS AND METHODS: Strains of S. cerevisiae deficient in various replication and DNA repair functions were tested for sensitivity to thymidine deprivation induced by the antifolate aminopterin. Cell survival and DNA content were assayed following drug treatment. RESULTS: Most arrest mutants were more sensitive to aminopterin than was the parental strain. Inactivation of uracil glycosylase in arrest mutants led to a partial reduction in toxicity for some double-mutants. DNA content during exposure to aminopterin was similar in parental and single mutants. However, cells deficient in both arrest and uracil glycosylase functions exhibited continued DNA synthesis, suggesting that uracil glycosylase activity contributes to replication arrest during thymidine deprivation. CONCLUSION: Replication arrest and uracil DNA repair are important and overlapping determinants of cellular response to thymidine deprivation. PMID- 23645752 TI - Regulation of target genes of PAX3-FOXO1 in alveolar rhabdomyosarcoma. AB - BACKGROUND: The majority of alveolar rhabdomyosarcoma (ARMS) are distinguished through the paired box 3-forkhead box protein O1 (PAX3-FOXO1) fusion oncoprotein, being generated by a 2;13 chromosomal translocation. This fusion-positive ARMS is the most clinically difficult type of rhabdomyosarcoma. The present study characterized four genes [gremlin 1 (GREM1), death-associated protein kinase-1 (DAPK1), myogenic differentiation-1 (MYOD1), and hairy/enhancer-of-split related with YRPW motif-1 (HEY1)] as targets of PAX3-FOXO1. MATERIALS AND METHODS: The expression of the four genes, PAX3-FOXO1, and v-myc myelocytomatosis viral related oncogene, neuroblastoma-derived (avian) (MYCN) was determined in various ARMS cell models and primary tumors. The roles of PAX3-FOXO1 and MYCN expression were examined. RESULTS: Pulse-chase and cycloheximide experiments suggest that GREM1, DAPK1, and MYOD1 are directly regulated by PAX3-FOXO1. PAX3-FOXO1 appears to indirectly down-regulate HEY1 by up-regulating MYCN. Data reveal that the growth-suppressive activity of high PAX3-FOXO1 expression is closely-associated with up-regulation of the GREM1 and DAPK1 tumor-suppressor genes. CONCLUSION: This study characterized four downstream targets of PAX3-FOXO1 that contribute to the biological activities of growth suppression and myogenic differentiation. PMID- 23645754 TI - Comparison of antitumor effects of native and recombinant human interferon-alpha on non-small cell lung cancer cells. AB - BACKGROUND: In the present work, we compared the antitumor effects of native human interferon-alpha (IFN-alpha) (nHuIFN-alpha) and recombinant human IFN-alpha (rHuIFN-alpha) on human lung adenocarcinoma A549 cells. MATERIALS AND METHODS: The antitumor activity was determined by measuring cell viability and apoptosis, while the abundance of mRNA, measured by polymerase chain reaction (PCR), determined the potential role of p21 and survivin in antitumor activity of nHuIFN alpha. RESULTS: The results show that nHuIFN-alpha significantly reduced A549 cell viability, compared to rHuIFN-alpha. The most potent effect of nHuIFN-alpha was also observed when apoptosis was measured. A549 cells treated with nHuIFN alpha expressed a significantly higher amount of p21 mRNA, while the amount of survivin mRNA was significantly reduced. CONCLUSION: Considering both the anti proliferative and anti-apoptotic effects of each IFN-alpha, we conclude that further elucidation of the mechanisms of the antitumor activity of nHuIFN-alpha will help in producing more effective and less toxic therapeutic protocols and preparations. PMID- 23645756 TI - Prolonged survival of patients with breast cancer-related leptomeningeal metastases. AB - BACKGROUND/AIM: Prolonged overall survival (OS) has been reported for selected patients with leptomeningeal metastases (LM). The management and treatment of such patients is poorly-described. We report our experience on breast cancer (BC) associated LM and patients with prolonged survival. PATIENTS AND METHODS: Eleven patients with BC and LM had an OS >12 months in which treatment is described. RESULTS: Combined intra-cerebro spinal fluid (CSF) and systemic treatment were administered until disease progression or toxicity in all but two patients. Involved-field radiotherapy was administered to two patients. Median OS in this selected cohort following LM diagnosis, was 21.0 (range=13-33.3) months. CONCLUSION: Prolonged OS but also prolonged responses can be observed in BC with LM. An individualized and multi-disciplinary approach is advised for the management of these patients. PMID- 23645755 TI - Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas. AB - Immunotherapy has the potential to improve clinical outcomes with little toxicity for pediatric patients with brain tumors. We conducted a pilot feasibility study of tumor lysate-pulsed dendritic cell (DC) vaccination in pediatric patients (1 to 18 years old) with newly diagnosed or recurrent high-grade glioma (HGG). A total of nine DC vaccine doses, each containing 1 * 10(6) cells per dose were administered to three out of the seven originally enrolled patients. Toxicities were limited to mild side-effects, except in one case of elevated alkaline phosphatase, which resolved without clinical consequences. Two patients with primary lesions amongst the three vaccinated were alive at the time of writing, both without evidence of disease. Pre- and post-vaccination tumor samples from a patient with an anaplastic oligoastrocytoma that recurred failed to demonstrate immune cell infiltration by immunohistochemistry. Peripheral cytokine levels were evaluated in one patient following DC vaccination and demonstrated some changes in relation to vaccination. DC vaccine is tolerable and feasible with some limitations for pediatric patients with HGG. Dendritic cell based immunotherapy may provide some clinical benefit in pediatric patients with glioma, especially for patients with minimal residual disease, but further investigation of this modality is required. PMID- 23645757 TI - VEGFR1 and NRP1 endothelial expressions predict distant relapse after radical prostatectomy in clinically localized prostate cancer. AB - Prostate cancer can usually be treated at a clinically localized stage by radical prostatectomy. Unfortunately, within 10 years following surgery, 30% of patients experience local or distant relapse. Few data exist on the association of markers of angiogenesis and distant relapse after radical prostatectomy. By immunohistochemistry in tissue microarray, we compared the expression pattern of hypoxia inducible factor 1, alpha subunit (HIF1alpha) and vascular endothelial growth factor (VEGF) and its receptors in 45 patients with distant relapse and 68 patients without relapse after radical prostatectomy. Expressions of HIF1alpha and VEGF were assessed in prostate tumor cells and those of VEGFR1, VEGFR2 and neuropilin 1 in tumor and endothelial cells. The five molecules studied were expressed by all tumors, with the exception of neuropilin 1 in endothelial cells for one tumor. Strong endothelial expression of VEGFR1 appeared to be an independent predictor of distant relapse. A moderate to strong endothelial expression of neuropilin 1 was in turn an independent predictor of absence of distant relapse. No significant difference was found for HIF1alpha, VEGF, VEGFR1, VEGFR2 and neuropilin 1 expression in tumor cells, nor for VEGFR2 in endothelial cells, between the two groups. To our knowledge, this is the first study to evaluate the prognostic value of VEGFR1, VEGFR2 and neuropilin 1 in endothelial cells in prostate cancer after radical prostatectomy. The evaluation by immunohistochemistry of endothelial expression of neuropilin 1 and VEGFR1 could be an additional tool in the assessment of tumor aggressiveness of clinically localized prostate cancer to better identify patients at high risk of distant relapse. PMID- 23645758 TI - Transarterial chemoembolization using DEBIRI for treatment of hepatic metastases from colorectal cancer. AB - BACKGROUND/AIM: Dismal survival rates of metastatic colorectal cancer (mCRC) to the liver have been recorded. Transarterial chemoembolization (TACE) with irinotecan eluting beads (DEBIRI) may be a safe palliative treatment with fewer serious adverse effects (SAEs). We aimed to establish the safety and efficacy of DEBIRI TACE in the treatment of hepatic metastases from colorectal cancer (CRC). PATIENTS AND METHODS: A retrospective analysis of DEBIRI TACE was performed. Response was assessed using the m-RECIST criteria. The Common Terminology Criteria for Adverse Events (CTCAE v3.0) were used to record toxicity. Survival was estimated using Kaplan Meier analysis. RESULTS: Twenty-eight patients treated with 47 DEBIRI TACE procedures were followed from September 2008 until February 2012. Twenty-two had metastases from colonic cancer and six metastases from rectal cancer; three patients (15%) had complete response, six (30%) partial response, four (20%) stable disease and disease progression was recorded in seven (35%); computer tomography (CT) scans were unavailable for eight patients. AEs included gastrointestinal and acid-base disturbances, hypertension, fever, insomnia, chest pain, pruritus, and neutropenia; five patients did not present AEs. The median time from diagnosis of liver metastases to initial DEBIRI treatment was 19.6 months. The median follow-up was 6.9 months. The median overall survival from first treatment was 13.3 months (95% confidence interval=6.8-19.8 months). CONCLUSION: DEBIRI is a well-tolerated treatment option that can be used safely in the palliative treatment of hepatic metastases from CRC. PMID- 23645759 TI - The implementation of minimally-invasive esophagectomy does not impact short-term outcome in a high-volume center. AB - BACKGROUND: Esophagectomy represents the gold standard in the treatment of resectable esophageal cancer. Despite significant improvements in perioperative care, postoperative morbidity and mortality rates remain high. Minimally-invasive surgical techniques introduced to the surgical treatment of esophageal malignancies have been shown to successfully diminish surgical trauma and postoperative morbidity. AIM: In the present report we present the stepwise implementation of minimally-invasive techniques in the treatment of esophageal cancer at a high-volume center and its influence on overall patient outcome. PATIENTS AND METHODS: A total of 165 consecutive patients with esophagectomy, in two 4-year periods, namely that before (period A) and that after (period B) the implementation of minimally-invasive esophagectomy (MIE) for cancer, were compared. Patients' characteristics, and perioperative, surgical, oncological and survival outcomes were compared. RESULTS: In time period A, 73 patients were treated with open esophagectomy (OE), whereas in time period B 37 patients (40.2%) underwent an OE and 55 (59.8%) a minimally-invasive esophagectomy. Surgical and non-surgical complications did not differ significantly between groups (B: 44.6% vs. A: 54.8%; B: 38% vs. A: 35.6%; p>0.05). Duration of ventilation (B: 1.8 days vs. A: 6.7 days), ICU (B: 5.7 days vs. A: 12.2 days) and hospital stay (B: 20.5 days vs. A: 28.4 days) were significantly reduced in patients of time period B. The number of lymph nodes removed and complete resection rates were comparable (mean=18.1 +/- 10.1 lymph nodes; B: 87% R0 vs. A: 93.2% R0). No significant differences between the groups were detectable regarding short-term disease-free or overall survival. CONCLUSION: The implementation of minimally-invasive esophagectomy is feasible, safe and has the potential to reduce perioperative morbidity without compromising oncological outcome. PMID- 23645760 TI - D-dimer elevation and paresis predict thromboembolic events during bevacizumab therapy for recurrent malignant glioma. AB - BACKGROUND: The major side-effects of bevacizumab in glioma treatment are venous thromboembolic events (VTE). We retrospectively evaluated factors potentially predictive of thromboembolic events. PATIENTS AND METHODS: Bevacizumab, alone or in combination with chemotherapy was used as salvage therapy for recurrence in malignant glioma every two weeks. None but one patient received anti-coagulants. Before each bevacizumab cycle differential blood cell count, kidney and liver parameters, D-dimers, neurological status, body-mass index, vital signs and signs of venous thrombosis were assessed. RESULTS: Thirty-eight patients received 428 cycles of bevacizumab. In five patients (13%), six VTE were observed. These complications were preceded four weeks before the onset of symptoms by D-dimer elevation above 0.865 mg/l [p<0.0001; sensitivity=89% (95% confidence interval=83 93%); specificity=89% (95% CI=52-100%)]. An existing hemiparesis constituted a 27 fold risk elevation for thrombotic complication (p<0.0001, chi(2)-test). CONCLUSION: D-Dimer elevation or hemiparesis predict VTE under bevacizumab and chemotherapy, four weeks before the event becomes clinically apparent. Future investigations should determine if prophylactic anti-coagulants for patients at risk may reduce the risk of VTE. PMID- 23645761 TI - Role of marker lesion when applying intravesical instillations of IL-2 for non muscle-invasive bladder cancer comparison of the therapeutic effects in two pilot studies. AB - AIM: Comparison of the therapeutic effect of treatment of non-muscle invasive bladder carcinoma (NMIBC) after intravesical Interleukin-2 (IL-2) instillations in the presence and absence of a marker tumour. MATERIALS AND METHODS: Two pilot studies were performed in patients with NMIBC. The first study (10 patients) was performed in Krakow (Poland), the second (26 patients) in Vilnius (Lithuania). In Krakow the tumours were treated with incomplete transurethral resection (TUR) leaving a marker tumour of 0.5-1.0-cm followed by IL-2 instillations (3 * 10(6) IU IL-2) on five consecutive days. In Vilnius the tumours were treated with complete TUR, followed by IL-2 instillations (9 * 10(6) IU IL-2) on five consecutive days. RESULTS: During 30 months follow-up, the recurrence-free survival was 5/10 (50%) and 6/26 (23%) after incomplete and complete TUR, respectively. So, the ratio of the recurrence-free survival after incomplete/complete TUR of 50/23=2.2. The median of the recurrence-free survival is >20.5 months and 7 months after incomplete and complete TUR, respectively. So, this ratio was >20.5/7= >2.9. The hazard ratio which combines both the chance of the disease recurrence and its timing for both censored and uncensored cases was 0.53, again confirming the better outcome after incomplete TUR. CONCLUSION: A possible explanation for the better therapeutic effects after incomplete TUR compared with complete TUR is that the marker tumour has tumour-associated antigens (TAA) that could lead to an immune reaction that is stimulated by local application of IL-2. After complete TUR, no TAA are available to initiate and to stimulate an immune reaction; consequently, local IL-2 therapy is less effective after complete TUR. The results of these two pilot studies have led to the recent start of a randomised prospective clinical trial in which therapeutic effects of local IL-2 therapy after complete and incomplete TUR are compared. PMID- 23645762 TI - Clinical significances of cancer stem cells markers in patients with intrahepatic cholangiocarcinoma who underwent hepatectomy. AB - The present study aimed to elucidate the relationship between cancer stem cells markers (CSCs), according to cell adhesion molecule (CD44) and glioma-associated oncogene homolog-1 (GLI1) expression, and clinicopathological factors and prognosis in 38 patients with intrahepatic cholangiocarcinoma (ICC) who underwent hepatectomy. CD44 and GLI1 expression was examined by immunohistochemical staining methods. The relationship with tumor angiogenesis or proliferation activity was also analyzed. Positivity of CD44 was 18% and that of GLI1 was 39%, but there was no significant correlation between the expressions of both. On macroscopic findings, CD44 expression in the periductal infiltration-type of ICC was significantly higher than in other types (p<0.01), and this type showed significantly worse survival after hepatectomy. Positive expression of GLI1 was significantly associated with older age. Although expression of neither CD44 nor GLI1 was significantly associated with disease-free survival, positive expression of both CD44 and GLI1 led to a significantly lower 3-year disease-free survival rate (0%; p<0.05). With respect to 5-year overall survival after hepatectomy, expression of both CD44 and GLI1 was not significantly associated with survival rate. CSCs might be useful markers for tumor-free survival in patients with ICC after hepatectomy and further investigation in larger series is warranted. PMID- 23645763 TI - A trial of autologous ex vivo-expanded NK cell-enriched lymphocytes with docetaxel in patients with advanced non-small cell lung cancer as second- or third-line treatment: phase IIa study. AB - BACKGROUND: New strategies are still needed to enhance the treatment outcome for advanced non-small cell lung cancer, in spite of recent remarkable developments. Cancer immunotherapy has been attractive since a long time, with diverse clinical attempts and results. In particular, natural killer (NK) cells have received considerable attention because of their potential role in immune surveillance in vivo by destroying infected or transformed cells. Major histocompatibility complex class I-related chain A/B (MICA/B) on tumor cells, known as the representative ligand for NKG2D receptor on NK cells, has been reported to be modulated by a variety of stress factors, including some chemotherapeutic agents, and it is anticipated that enhancing MICA/B expression will be contributory to anticancer treatment. With recent development of expanding autologous ex vivo NK cell-enriched lymphocytes (NKL), we designed a trial to augment the anticancer effect by co-administering NKL and docetaxel, one of the second-line agents used for treatment of patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Eligible patients were between the age of 20 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and previously received one chemotherapy or two regimens including one epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, stage IIIB/IV, histologically- or cytologically-proven NSCLC with measurable lesions. NKL were kindly prepared and provided from NKBIO Co. (Seongnam City, Korea). Feasibility, adverse effects, progression-free survival (PFS) were evaluated and compared with the historical control of weekly docetaxel regimen. RESULTS: Nineteen patients were enrolled before early closure. NKL production and administration were feasible in all cases, even in those with disseminated disease. No additional adverse events were observed in addition to those reported for docetaxel-alone. PFS of 3 months and 10.5% response rate (RR), with two cases of partial response, were observed and were similar to the historical control (PFS=2.9 months, RR=8.0%). CONCLUSION: To our knowledge, this is the first report on the combination of NKL with docetaxel in patients with advanced NSCLC. Autologous NKL production and co-administration with docetaxel were feasible without further toxicity or complication. Benefit in PFS and RR, as compared with the historical control, was not detected in this study population with advanced NSCLC. In order to determine whether the combination of NKL and chemotherapy has any anticancer effect, an additional study should be performed in patients with low tumor burden, such as those with less advanced disease or those in remission. PMID- 23645764 TI - Clinical significance of expression of cancer/testis antigen and down-regulation of HLA class-I in patients with stage I non-small cell lung cancer. AB - AIM: The purpose of this study was to investigate the clinical significance of expression of cancer/testis (CT) antigen and down-regulation of HLA class-I in patients with stage I non-small cell lung cancer (NSCLC), which underwent complete surgical resection. PATIENTS AND METHODS: The expression of HLA class-I molecules was evaluated in 136 resected NSCLC specimens by immunohistochemistry. The results were scored as the percentage of stained tumor cells and categorized into two groups: 0-79%, reduced expression; and >80%, normal expression. The expression of CT antigen was performed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The expression of HLA class-I was normal in 49 tumors (36%), and there was reduced expression in 87 tumors (64%). The expression of Melanoma antigen (MAGE)-A3, MAGE-A4, and Kita-Kyushu lung cancer antigen-1 (KK-LC 1) was positive in 34 (25.0%), 22 (16.2%), and 42 (30.9%) patients, respectively. There was no significant difference in the proportion of HLA class-I expression associated with the expression of any of the CT antigens. Among the patients with positive expression of at least one of the CT antigens, the 5-year survival rate of the patients with the normal expression of HLA class-I was 87.5%; however, it was 63.4% in patients with the reduced expression of HLA class-I (p=0.0477). CONCLUSION: Reduced expression of HLA class-I was an unfavorable prognostic factor in patients with positive expression of CT antigen, and represents an important hurdle to antigen-based cancer immunotherapy. PMID- 23645765 TI - KRAS mutations in patients with colorectal cancer as detected by high-resolution melting analysis and direct sequencing. AB - BACKGROUND: Direct sequencing (DS) has often been used for detection of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. High-resolution melting analysis (HRMA) is another method to detect mutations by using a light scanner, and is more rapid, lower in cost, and more sensitive than DS. We confirmed correspondence between DS and HRMA for KRAS mutation detection in colorectal cancer (CRC). PATIENTS AND METHODS: From 102 patients with CRC, intended to receive cetuximab treatment at the National Cancer Center Hospital between September 2008 and July 2009, formalin-fixed paraffin-embedded tissues were retrospectively analyzed for KRAS status using HRMA and DS. Cetuximab efficacy was evaluated. RESULTS: Success rates of analysis by DS and HRMA were 100 out of the 102 patients (98.0%) and 99 out of the 102 patients (97.1%), respectively. The cases which failed by one method were analyzed by the other. KRAS mutant-type was detected by DS in 47 out of 100 samples (47.0%), and by HRMA in 45 out of 99 samples (45.5%). The concordance between the two methods was 94.8%. Forty-six out of the 53 patients with wild-type KRAS, as detected by DS received cetuximab and the response and disease control rates were 19.6% and 63.0%, respectively. With a median follow-up of 8.8 months, the median progression-free survival was 5.6 months and median overall survival was 11.1 months. The efficacy of two discordant cases which received cetuximab showed that the best responses were stable disease and progressive disease in one each, progression-free survival was 2.9 and 1.1 months and overall survival was 5.3 and 1.2 months, respectively. CONCLUSION: HRMA is a useful optional method for detection of KRAS mutations in CRC in light of accuracy, cost performance and rapidity. PMID- 23645766 TI - Synchronous quadruple primary tumors of thyroid, breast, pancreas, and stomach: a case report. AB - We herein present the first case to be reported of synchronous quadruple primary cancer of the thyroid, breast, pancreas and stomach in a 70-year-old female. Fluorine-18-fluorodeoxyglucose (FDG)-positron-emission tomography/computed tomography (PET/CT) revealed increased FDG activity in the thyroid, left breast, pancreatic body and antrum of the stomach. To make a definitive diagnosis of synchronous quadruple primary tumors, ultrasound-guided fine-needle aspiration (FNA) cytology and biopsy of the thyroid, breast, pancreas and stomach were performed. FNA cytology and biopsy findings showed papillary carcinoma of the thyroid, invasive ductal adenocarcinoma of the breast, adenocarcinoma of the pancreas and gastrointestinal stromal tumor. To the best of our knowledge, this combination of synchronous multiple primary tumors has not been reported. PMID- 23645767 TI - Evaluation of current prognostic and predictive markers in breast cancer: a validation study of tissue microarrays. AB - BACKGROUND: Tissue microarrays (TMAs) are an attractive alternative to analysis of whole sections (WS). For breast carcinomas, the recent recommendations for cut offs (i.e. Ki67, H-score) have necessitated the re-evaluation of TMAs. MATERIALS AND METHODS: TMA results of immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH) testing for Estrogen receptors (ER), Progesterone receptors (PgR), Ki67 and HER2 were compared against the results of WS for 88 breast carcinomas. RESULTS: We found excellent agreement between the two methods for ER and PgR IHC evaluation, using the H-score (Kappa coefficient 0.972 and 0.9, respectively). There was also excellent correlation for HER2 IHC (Kappa coefficient 1) and amplification (Kappa coefficient 0.933). Furthermore, scoring of Ki67 was highly-correlated between TMAs and WS (Kappa coefficient 0.954). The latter excellent correlation has not, to our knowledge, been previously reported. CONCLUSION: For breast cancer, TMAs are an efficient and reliable alternative to the use of WS, using the currently recommended markers, evaluation protocols and cut-off values. PMID- 23645768 TI - The Lynch syndrome: a management dilemma. AB - The case of a familial Lynch syndrome is reported. The criteria for early diagnosis, management and surveillance are briefly reviewed. A germline mutation of genes responsible for mismatch repair is at the basis of the Lynch syndrome. Carriers are predisposed to colorectal cancer and other tumors. Two members of the presently reported family developed colorectal cancer, whereas two others developed other neoplasms. The syndrome was confirmed in members of the same family with appropriate genetic workup. Clinical examination and endoscopy were consequently scheduled once-a-year. Given the high risk of neoplastic disease, such yearly controls can be proposed as the standard follow-up of this condition. PMID- 23645769 TI - Radiation therapy in the treatment of HIV-related Kaposi's sarcoma. AB - BACKGROUND: Kaposi's sarcoma (KS) is the most frequent neoplasm occurring in patients with HIV-related AIDS and very often exhibits multifocal distribution so that a systemic approach is needed. KS is considered a radiosensitive tumor and (RT) has always played an important role in the therapeutic strategy of its various forms. RT is a valuable means of pain relief, bleeding control and edema palliation, but it is also an effective treatment modality for local control of skin and mucosal lesions in KS. The purpose of the present article is to report the results obtained by the Radiotherapy Unit of S. Camillo-Forlanini Hospital in Rome in the management of 38 AIDS-associated KS lesions and to assess the efficacy of RT in the treatment and local control of KS. PATIENTS AND METHODS: Eighteen patients histologically-diagnosed with HIV-related KS underwent RT in the period between January 2002 and January 2012 at the Radiotherapy Unit of S. Camillo-Forlanini Hospital in Rome. In all cases, the lesions caused pain or discomfort and a thorough careful clinical evaluation had indicated a radiation treatment. A total of 38 lesions were treated with radiotherapy. Fifteen patients received systemic chemotherapy. Eight patients with multiple cutaneous lesions on their legs and arms were treated with a radiation schedule prescribing extended cutaneous irradiation using 6-18 MeV electron beam energy, 200 cGy per fraction and a total dose between 24-30 Gy, according to the depth of lesions. One of these patients had also a cutaneous lesion on an eyelid that was treated with a radiation schedule using 6 MeV electron beam energy and bolus of 1 cm, 200 cGy per fraction and a total dose of 30 Gy. Seven patients with single cutaneous lesions on the legs and arms were treated using a photon regimen of 6 Mv energy, 200 cGy per fraction and a total dose between 20 and 36 Gy. Two patients had oral mucosa lesions and they were treated with a radiation schedule prescribing irradiation using 6 Mev photon regimen and personal mask, 200 cGy per fraction and a total dose of 24 and 30 Gy, respectively. A patient with a single bone lesion on the spinal column was treated with irradiation using 6 Mev photon regimen, 300 cGy per fraction and a total dose of 30 Gy. RESULTS: At the time of reporting, 14 patients were alive and four patients had died. One patient died due to complications from HIV infection. The follow-up from the end of the treatment ranged from four to 124 months (mean=51.17 months). The overall survival for the group was 88.8% at one year. The mean overall survival was 57.4 months. A complete response was achieved for 31 lesions (83.8 %); a partial response with a tumor regression was observed for six lesions (16.2 %). No relapses were observed during the period of follow-up, but we observed new lesions in one patient. According to the Radiation Therapy Oncology Group scale we observed erythematic and dry desquamation (grade 1) in eight sites (21%); in only one patient (2.6%) did stomatitis occur (grade 1). Good cosmetic results were described for 25 (65.7%) out of 31 lesions. Effective palliative action was obtained for all lesions except for two (5.2%) located in a vertebra and hard palate. CONCLUSION: RT will be a mainstay of cure for this group of patients especially when of young age and the will to preserve the cosmetic appearance is a primary need. PMID- 23645770 TI - Surgical resection of brain metastases from breast cancer in the modern era: clinical outcome and prognostic factors. AB - BACKGROUND: Incidence of brain metastases (BM) from breast cancer (BC) is increasing. However, prognostic evaluation and treatment strategies are still a matter of debate. AIM: To describe the clinical outcome of BM from BC treated by neurosurgical resection and to identify the actual prognostic factors in this specific population. PATIENTS AND METHODS: We retrospectively reviewed all patients (n=49) with BM from BC treated at our institutions by surgical resection, between December 2001 and July 2011. Patient, tumor and treatment characteristics were recorded. RESULTS: Median cerebral progression-free survival (CPFS) was 11.3 months (95% Confidence Interval (CI)=6.0-16.6 months) and median overall survival (OS) was 19.4 months (95% CI=16.1-22.7 months). By multivariate analyses, altered Mini Mental Status (MMS) (CPFS: p=0.012, OS: p=0.009), multiple systemic metastases (CPFS: p=0.020, OS: p<0.001) and absence of post-operative chemotherapy (CPFS: p=0.013, OS: p=0.006) had independent adverse prognostic values. Hormonal receptors, Human epidermal growth factor-2 (HER2) and molecular subtype were not significantly correlated to survival. CONCLUSION: Surgical resection is an effective treatment in selected patients with BM from BC. MMS, number of systemic metastases and the use of postoperative systemic treatment are associated with better outcome. PMID- 23645771 TI - Complete necrosis of a giant cell tumor with high expression of PPARgamma: a case report. AB - Giant cell tumor of the bone (GCTB) is a common primary benign tumor, but in some cases, it behaves aggressively, resulting in tumor recurrence. The standard treatment for GCT is thorough curettage with adjuvant treatment such as phenol, liquid nitrogen, high-speed burr, or methylmethacrylate cement. This article presents the case of a 30-year-old male with GCT of the right distal femur, which demonstrated a complete necrosis of GCTB. Interestingly, the specimen also showed adipocytic lineage, and strong expression of apoptotic markers by [terminal deoxynucleotidyl-transferase dUTP nick-end labelling (TUNEL) and caspase-3] and peroxisome proliferator-activated receptor gamma (PPARgamma). To the Authors' knowledge, this is the first reported case of complete necrosis of GCTB concurrent with adipocytic lineage and high expression of PPARgamma. PPARgamma is a master regulator of fat differentiation. PPARgamma possesses antitumor activity through suppression of tumor proliferation and invasion and induction of differentiation and apoptosis. Although we could not conclude on the exact cause of complete necrosis and high expression of PPARgamma in this case, we focused on the medical history, where this patient took zaltoprofen (240 mg/day) for four weeks before the biopsy to alleviate his pain. Zaltoprofen is a propionic-acid derivative non-steroidal anti-inflammatory drug, and it is reported to act as a direct ligand for PPARgamma. We speculated that one of the possible mechanisms of PPARgamma activation in this case was induction by zaltoprofen, at least in part. Although further analysis using cultured tumor cells with ligands specific to the receptor is necessary, PPARgamma may be a novel therapeutic target in GCTB. PMID- 23645772 TI - Radiotherapy in the management of pancreatic neuroendocrine tumors (PNET): experience at three institutions. AB - AIM: Advanced pancreatic neuroendocrine tumor (PNET) presents a therapeutic challenge as many are unresectable and relatively resistant to systemic therapy with a high malignant potential. We share our experience using concurrent capecitabine or infusional 5-fluorouracil with radiation for patients with resected and locally advanced PNET. PATIENTS AND METHODS: Six patients (two females, four males) with PNET were treated with capecitabine or infusional 5-FU and concurrent radiation. RESULTS: The median age was 52 years (range: 38 to 63 years), with ECOG Performance Status (PS) 0-1, grade 0-1 weight loss, and grade 0 1 pain. One patient underwent resection with negative margins, two with positive margins, and three had unresectable locally advanced disease. All six patients demonstrated partial radiographic response and sustained local control. The treatment was tolerable with only grade 2 hand-foot syndrome and grade 1 mucositis observed. CONCLUSION: Prospective studies to further investigate the role of chemoradiation in this setting are warranted. PMID- 23645773 TI - The mRNA expression of inhibitors of DNA binding-1 and -2 is associated with advanced tumour stage and adverse clinical outcome in human breast cancer. AB - Inhibitors of DNA binding (ID) are known to have a role in embryogenesis and oncogenesis. In this study, we analyzed the role of ID1 and ID2 in breast cancer, by assessing associations of mRNA expression with clinicopathological parameters. MATERIALS AND METHODS: Breast cancer tissues (n=152) and adjacent normal tissues (n=31) underwent reverse transcription and quantitative- polymerase chain reaction (qPCR). Transcript levels were correlated with clinicopathological data. RESULTS: Patients who were disease-free had significantly lower ID1 mRNA expression than all other patients (p=0.0033). Higher expression was associated with worse disease-free (p=0.001) and overall survival (p=0.02). ID2 expression was directly associated with the Nottingham Prognostic Index (NPI) (NPI 2 vs. 3; p=0.0062) and worsening clinical outcome (disease-free vs. mortality: p=0.0004), and with worse disease-free (p=0.01) and overall survival (p=0.005). CONCLUSION: Our findings are suggestive of a role for ID1 and ID2 in human breast cancer as possible prognostic markers and therapeutic targets meriting further validating investigations, by immunohistochemistry and mechanistic studies. PMID- 23645774 TI - P14ARF is down-regulated during tumour progression and predicts the clinical outcome in human breast cancer. AB - The objective of this study was to determine the mRNA expression for p14 and p16 in a cohort of women with breast cancer. MATERIALS AND METHODS: Breast cancer specimens (N= 127) and normal tissue (N=23) specimens were studied. Transcript levels were determined using quantitative polymerase chain reaction (PCR), and were correlated with clinicopathological data collected over 10 years. RESULTS: Higher p14 mRNA transcript levels were associated with non-cancerous background tissue specimens (median copy numbers: 103 vs. 4, p=0.0095), with better overall and disease-free survival, and in TNM2 stage tumours (TNM2 vs. TNM1, 27.2 vs. 3.5, p=0.049; TNM1/TNM2 vs. TNM3/4, 26 vs. 2, p=0.009). There was no significant relationship between p16 levels and clinicopathological parameters. A correlation between p14 and human telomerase reverse transcriptase (hTERT) levels was observed (r=0.406, p=0.00005). CONCLUSION: p14 expression seems to increase initially in early breast cancer and decrease with further tumour progression. p14 may be induced to counteract immortalisation and hTERT surge. PMID- 23645775 TI - Contribution of immunohistochemical profile in assessing histological grade of endometrial cancer. AB - BACKGROUND: The aim of this study was to correlate immunostaining expression profiles with histological grade using a predictive model. PATIENTS AND METHODS: Samples were collected from 69 women with endometrial cancer. Immunostaining for expression of estrogen receptor (ER), progesteron receptor (PR), Ki67 and p53 in grade 1 or 2 and grade 3 tumors were compared. After determining optimal immunostaining cut-offs, we built a model to predict the final histological grade. RESULTS: Higher immunostaining of ER and PR was found in grade 1 or 2 (p=0.01) compared with grade 3 tumors. Higher immunostaining for Ki67 (p<0.0001) and p53 (p<0.001) was found in grade 3 than in grade 1 or 2 tumors. The recursive partitioning model predicted a grade 1 or 2 tumor in 98% of cases when Ki67 and p53 were underexpressed. The mis-classification rate was 13%. CONCLUSION: Our results show that integrating immunohistochemical profiles in a simple predictive model could help predict the final histological grade of endometrial tumors, especially for grade 1 or 2. PMID- 23645777 TI - Missense polymorphisms in XIAP-associated factor-1 (XAF1) and risk of papillary thyroid cancer: correlation with clinicopathological features. AB - X-Linked inhibitor of apoptosis (XIAP)-associated factor-1 (XAF1) antagonizes XIAP-mediated caspase inhibition. XAF1 also serves as a tumor-suppressor gene, and loss of XAF1 expression correlates with tumor progression. This study investigated whether XAF1 missense single-nucleotide polymorphisms (SNPs) are associated with the development of papillary thyroid cancer (PTC) and their clinicopathological features in a Korean population. Eighty-nine cases of PTC and 276 controls were enrolled. Two missense SNPs [rs34195599 (Glu85Gly) and rs2271232 (Arg132His)] in XAF1 were genotyped using direct sequencing. The SNPStats, SNPAnalyzer, Helixtree, and Haploview version 4.2 programs were used to evaluate genetic data. Multiple logistic regression models were used to determine odds ratios (ORs), 95% confidence intervals (CIs), and p-values. Missense SNP rs34195599 was weakly-associated with the development of PTC (p=0.046 in genotypic distributions; p=0.048 in allelic distributions). For the clinicopathological features, rs34195599 was strongly related to multifocality [unifocality (A/G, 1.7%) vs. multifocality (A/G, 16.7%), OR=11.44, 95% CI=1.27 103.26, p=0.015 in genotypic distributions] [unifocality (G, 0.8%) vs. multifocality (G, 8.3%), OR=10.64, 95% CI=1.21-93.23, p=0.017 in allelic distributions] and location [one lobe (A/G, 1.6%) vs. both lobes (A/G, 19.2%), OR=15.63, 95% CI=1.62-150.46, p=0.008 in genotypic distributions] [one lobe (G, 0.8%) vs. both lobes (G, 9.6%), OR=13.30, 95% CI=1.51-116.82, p=0.009 in allelic distributions]. Our data suggest that the G allele of rs34195599 of XAF1 may be a risk factor for the clinicopathological features of PTC, especially for multifocality and location (both lobes). PMID- 23645776 TI - Postoperative radiotherapy for uterine cervical cancer: impact of lymph node and histological type on survival. AB - AIM: To retrospectively analyze the treatment results of postoperative radiotherapy (PORT) in patients with early-stage uterine cervical cancer. PATIENTS AND METHODS: Records of 141 patients with stage IB-IIB uterine cervical cancer treated with PORT from 1985 to 2004 were retrospectively reviewed. The majority of patients received whole-pelvic radiotherapy with antero-posterior fields, and the total radiation doses ranged from 10.8-60 Gy (median: 50.4 Gy). The median follow-up of all 141 patients was 106 months (range: 0.8-273.7 months). RESULTS: Multivariate analysis revealed that positive lymph node status (p=0.001) and histological type (p=0.015) were independent prognostic factors for overall survival. The group with three or more involved lymph nodes was significantly more likely to have extra-pelvic recurrence when compared with the groups with no (p=0.006) and up to two lymph nodes (p=0.024), respectively. CONCLUSION: PORT yielded excellent pelvic control rates for early-stage uterine cervical cancer. Lymph node status and histological type were significant prognostic factors for overall survival of patients with these tumors. PMID- 23645778 TI - Relation between antibody to hepatitis B core antigen and survival after curative therapy for non-B non-C hepatocellular carcinoma. AB - BACKGROUND/AIM: We aimed to examine the relationship between antibodies to hepatitis B core antigen (anti-HBc) positivity and survival in patients with non B non-C hepatocellular carcinoma (NBNC-HCC) who underwent curative treatment. PATIENTS AND METHODS: A total of 260 patients with NBNC-HCC who underwent curative therapy were analyzed. They included 124 anti-HBc-positive patients (47.7%) and 136 anti-HBc-negative patients (52.3%). Overall survival (OS) and recurrence-free survival (RFS) rates were compared. RESULTS: The 3-year cumulative OS rates were 75.9% in the anti-HBc-positive group and 82.3% in the anti-HBc-negative group (p=0.069). The corresponding RFS rates were 29.8% in the anti-HBc-positive group and 43.0% in the anti-HBc-negative group (p=0.001). Multivariate analyses identified anti-HBc positivity (p=0.006), aspartate aminotransferase >= 40 IU/l (p=0.037) and des-gamma-carboxy prothrombin >= 100 mAU/ml (p=0.046) as significant adverse predictors were linked to RFS. CONCLUSION: Anti-HBc positivity can be a useful predictor for recurrence in patients with NBNC-HCC after curative therapy. PMID- 23645779 TI - Normalization of serum p53 antibody levels in patients after curative resection for colorectal cancer. AB - BACKGROUND: The aim of this study was to evaluate the significance of high serum p53 antibody (p53Ab) levels in relation to curative resection of colorectal cancer. PATIENTS AND METHODS: Between 2007 and 2010, 24 patients with colorectal cancer with higher-than-normal preoperative serum p53Ab, measured by enzyme linked immunosorbent assay, were enrolled in this study. After curative resection, their serum p53Ab and carcinoembryonic antigen (CEA) levels were measured at one, six, 12, 18, and 24 months after surgery. The relationship between clinicopathological features and the presence of serum p53Ab was evaluated. RESULTS: None of the patients developed recurrence up to 24 months after the surgery. The positive rate for CEA was 33.3% before surgery, 16.7% at one month after surgery, and 0% at six months and more, while the rate for p53Ab was 75% at six months, 70.8% at 12 months, 58.3% at 18 months, and 54.2% at 24 months after surgery. The positive rate for serum p53Ab at 24 months after the surgery correlated with the one before and that at one month after the surgery. CONCLUSION: For patients with colorectal cancer and high preoperative serum p53Ab levels, serum p53Ab does not seem to be a useful marker of recurrence after curative resection, since normalization of serum p53Ab levels requires years after surgery. PMID- 23645780 TI - Prognostic factors for male breast cancer: similarity to female counterparts. AB - AIM: To assess whether prognostic factors in male (MBC) and female (FBC) breast cancer have similar impact on survival. PATIENTS AND METHODS: Charts for men and women diagnosed with breast cancer referred to the London Regional Cancer Program (LRCP) were reviewed. Patients with distant metastatic diseases were excluded. Data on prognostic factors including age, nodal status, resection margin, use of hormonal therapy, chemotherapy with/without hormone and radiation therapy (RT), overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) were analyzed. Survival estimates were obtained using the Kaplan-Meier methodology. The Cox regression interaction was used to compare male and female differences in prognostic factors. RESULTS: From 1963-2006 there were 75 cases of MBC and 1,313 of FBC totaling in 1,388 breast cancer cases. The median age of the cohort was 53 (range=23-90) years. The median follow-up was 90 (range=0.4-339) months. Of the prognostic factors considered, nodal status had a significant Cox regression interaction. For OS, p=0.001 with hazard ratios of 0.83 (95% confidence interval CI=0.42-1.64) and 2.88 (95% CI=2.36-3.52) for males and females, respectively. For CSS p=0.041 with hazard ratios of 1.22 (95% CI=0.45 3.27) and 3.52 (95% CI=2.76-4.48) for males and females, respectively. For node positive cases, distant disease recurrence-free survival was worse for MBC (log rank, p<0.001). CONCLUSION: This large series showed that the nodal status influences survival differently in MBC and FBC. The findings of this study need confirmation from a more complete prospective database and further investigations on improving high-risk node-positive MBC management are warranted. PMID- 23645781 TI - Relationship between circulating tumor cells and peripheral T-cells in patients with primary breast cancer. AB - BACKGROUND: Detection of circulating tumor cells (CTCs) in the peripheral blood of patients with primary breast cancer is associated with poor clinical outcome. Recent studies have found evidence for immunological influence on tumor cell dormancy. We therefore investigated the relationship between peripheral T-cells and CTCs, as immunological factors may contribute to the fate of CTCs. MATERIALS AND METHODS: The peripheral blood immune status of 116 patients with primary breast cancer was analyzed by flow cytometry. Results were correlated with the presence of CTCs and clinicopathological parameters of these patients. RESULTS: Appearance of CTCs was significantly associated with grade III tumors (p<0.05). Interestingly, CTC-positive patients presented with a significant increase of peripheral CD95(FAS)-positive T-helper cells. As immune response is regulated by CD95(APO-1/FAS)-CD95ligand interaction and tumor cells induce apoptosis via the CD95/CD95L (ligand) pathway, this might lead to tumor cell escape by apoptotic T helper cells. CONCLUSION: Absence of T-cell help at the time of priming may result in a loss of long-term antigen-activation of CD8 lymphocytes and could lead to an ineffective anti-tumor cell response. This might contribute to systemic immunosuppression and open the door for tumor cell dormancy. PMID- 23645813 TI - Challenges in recognising significant back pain in a child with learning difficulties. PMID- 23645782 TI - Monitoring of circulating tumor cells in patients undergoing surgery for hepatic metastases from colorectal cancer. AB - The aim of our study was to describe the frequency of occurrence of circulating tumor cells (CTCs) in patients undergoing surgery for liver metastases from colorectal cancer in relation to treatment (chemotherapy and surgery). We monitored the presence of CTCs before, during and after surgery. PATIENTS AND METHODS: This prospective study involved 14 patients (9 men and 5 women) undergoing surgical resection or termoablation of liver metastases from colorectal carcinoma. Ten of them received chemotherapy before surgery. Samples of central blood (7.5 ml) were drawn preoperatively, at the time of mobilization of the liver during the surgical procedure, immediately after surgery, and at two and seven days postoperatively. CTCs were detected by ColonCancerSelect and ColonCancerDetect kits (AdnaGen, Langenhagen, Germany). RESULTS: CTCs were detected in three out of 14 patients. For each of the three patients, CTCs were detected via a different gene [tumor-associated antigen GA733-2, carcinoembryonic antigen (CEA) and epidermal growth factor receptor (EGFR)]. This demonstrates the heterogeneity of the CTC population among patients. In one patient, we recorded long-term presence of CTCs, in one patient we detected CTCs only during surgery and in one patient we detected CTCs only before surgery. CTC-positive patients are described in the form of case reports. CONCLUSION: We detected CTCs only in a minority of patients with liver metastases from colorectal cancer. Observations show that the surgical procedure itself can cause the presence of CTCs in the peripheral blood. PMID- 23645814 TI - Normal voiding does not exclude posterior urethral valves. PMID- 23645816 TI - Further steps in TANGO: improved taxonomic assignment in metagenomics. AB - MOTIVATION: TANGO is one of the most accurate tools for the taxonomic assignment of sequence reads. However, because of the differences in the taxonomy structures, performing a taxonomic assignment on different reference taxonomies will produce divergent results. RESULTS: We have improved the TANGO pipeline to be able to perform the taxonomic assignment of a metagenomic sample using alternative reference taxonomies, coming from different sources. We highlight the novel pre-processing step, necessary to accomplish this task, and describe the improvements in the assignment process. We present the new TANGO pipeline in details, and, finally, we show its performance on four real metagenomic datasets and also on synthetic datasets. AVAILABILITY: The new version of TANGO, including implementation improvements and novel developments to perform the assignment on different reference taxonomies, is freely available at http://sourceforge.net/projects/taxoassignment/. PMID- 23645815 TI - RegaDB: community-driven data management and analysis for infectious diseases. AB - SUMMARY: RegaDB is a free and open source data management and analysis environment for infectious diseases. RegaDB allows clinicians to store, manage and analyse patient data, including viral genetic sequences. Moreover, RegaDB provides researchers with a mechanism to collect data in a uniform format and offers them a canvas to make newly developed bioinformatics tools available to clinicians and virologists through a user friendly interface. AVAILABILITY AND IMPLEMENTATION: Source code, binaries and documentation are available on http://rega.kuleuven.be/cev/regadb. RegaDB is written in the Java programming language, using a web-service-oriented architecture. PMID- 23645817 TI - A universal open-source Electronic Laboratory Notebook. AB - MOTIVATION: Laboratory notebooks remain crucial to the activities of research communities. With the increase in generation of electronic data within both wet and dry analytical laboratories and new technologies providing more efficient means of communication, Electronic Laboratory Notebooks (ELN) offer equivalent record keeping to paper-based laboratory notebooks (PLN). They additionally allow more efficient mechanisms for data sharing and retrieval, which explains the growing number of commercial ELNs available varying in size and scope but all are increasingly accepted and used by the scientific community. The International Agency for Research on Cancer (IARC) having already an LIMS and a Biobank Management System for respectively laboratory workflows and sample management, we have developed a free multidisciplinary ELN specifically dedicated to work notes that will be flexible enough to accommodate different types of data. AVAILABILITY AND IMPLEMENTATION: Information for installation of our freeware ELN with source codes customizations are detailed in supplementary data. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23645819 TI - Postoperative minimal overcorrection in the surgical management of intermittent exotropia. AB - PURPOSE: To investigate the effect of initial postoperative minimal overcorrection on the result of the surgical management of intermittent exotropia based on long-term follow-up results. METHODS: 111 patients who underwent surgery for intermittent exotropia and were followed up for at least 5 years after surgery were retrospectively reviewed. The outcome was judged to be successful when there was 10 prism dioptres (PD) or less of exodeviation and less than 5 PD of esodeviation without any reoperation at the final follow-up visit. We evaluated the success, recurrence, overcorrection rate and the duration of diplopia according to their initial deviation. RESULTS: We divided patients into four groups based on their initial deviation: orthophoria or undercorrection (Ortho group, 31 patients), minimally overcorrected at 5 PD or less (MO group, 20 patients), usually overcorrected between 6 PD and 10 PD (UO group, 35 patients), and highly overcorrected at more than 10 PD (HO group, 25 patients). The success rate was 43-60% between the four groups (p=0.52). The recurrence rate was 28-57% (p=0.105), but post hoc analysis showed borderline p values between the Ortho and HO group (p=0.024). No overcorrection was noted in the Ortho and MO groups (p=0.04). The duration of diplopia was 0-2.5 weeks, showing statistically significant difference among groups (p<0.001). CONCLUSIONS: The amount of initial postoperative overcorrection may not predict the long-term success rate. However, the MO group showed a lower recurrence rate than the Ortho group and also showed no overcorrection and a shorter duration of postoperative diplopia than the UO and HO groups. PMID- 23645818 TI - Local treatment failure after globe-conserving therapy for choroidal melanoma. AB - Local treatment failure after globe-conserving therapy for choroidal melanoma is a surgical complication with significant morbidity to the vision and eye. Few reports in the literature have addressed this complication exclusively. A review of the published literature with reference to local treatment failure in the management of choroidal melanoma was performed to make known the potential differences in failure rates between treatment modalities and methods. A search of the literature regarding local treatment failure was performed to identify relevant studies using combinations of the following keywords on PubMed: uveal melanoma, choroidal melanoma, local recurrence, local failure, endoresection, gamma knife, radiotherapy, helium, iodine, proton, palladium, ruthenium, trans scleral resection, transpupillary thermotherapy. Further studies were found by searching the text and references of previously identified studies for articles reporting local treatment failure rates in choroidal melanoma. Among the 49 studies identified, the local treatment failure rate ranged from 0% to 55.6%, with follow-up ranging from 10 to 150 months. The two most widely used forms of radiation therapy, iodine-125 and ruthenium-106 brachytherapy, were both associated with a local recurrence rate of 9.6%. The weighted-average of treatment failure in all radiation therapies was 6.15% compared with 18.6% in surgical and 20.8% in laser therapies. Rates of local treatment failure for globe conserving therapy of choroidal melanoma varied widely between modalities and between centres using similar modalities. Radiation therapy overall resulted in lower local treatment failures compared with surgical or transpupillary thermotherapy. PMID- 23645820 TI - Appearance and location of retinal haemorrhages in critically ill children. AB - BACKGROUND: There are few high-quality studies describing the appearance and location of retinal haemorrhages in critically ill children not due to birth or abusive head trauma. METHODS: Prospective study from February 2008 to December 2009 of emergency admissions to a paediatric intensive care unit aged over 6 weeks. Children with a penetrating eye injury or suspected or proven abusive head injury were excluded. The children underwent either dilated funduscopy performed by a paediatric ophthalmologist or RetCam imaging. RESULTS: Retinal haemorrhages were identified in 24/159 (15%) patients. 50% of the haemorrhages were bilateral. The severity was mild (<5 retinal haemorrhages) or moderate (5-20 retinal haemorrhages) in 75%. The location was in zone 1 in 45.8%, zones 1 and 2 in 33.3%, zone 2 alone in 8.3% and not described in 8.3%. Schisis cavities and perimacular folds were identified in two patients with one having a pseudohypopyon appearance; a further one patient had bilateral haemorrhagic retinal detachments. Three patients had exudates or scarring consistent with cytomegalovirus infection. CONCLUSIONS: Retinal haemorrhages are seen in a proportion of critically ill children, however most retinal bleeding is not extensive as indicated by location within the retina or layer of bleeding. Higher numbers and extent of retinal haemorrhages were only observed in the presence of severe coagulopathy, leukaemia, one victim of a road traffic accident, and one child who sustained a fatal witnessed fall down the stairs; all circumstances that would be readily distinguished by history and laboratory testing from abusive head injury. PMID- 23645821 TI - Comparison of bilateral lateral rectus recession and unilateral recession resection for basic type intermittent exotropia in children. AB - AIMS: To compare surgical outcome of bilateral lateral rectus recession (BLR-rec) and unilateral lateral rectus recession combined with medial rectus resection (R&R) for the basic type of intermittent exotropia (IXT) in children. METHODS: Eighty-five consecutive patients aged 3-15 years old with the basic type IXT who underwent surgery and had a minimum postoperative follow-up of 6 months were retrospectively reviewed. Thirty-eight patients underwent BLR-rec and 47 underwent R&R. Successful surgical alignment was defined as esophoria/tropia <=5 PD (prism dioptres) to exophoria/tropia <=8 PD in primary gaze while viewing distant or near targets. RESULTS: After a mean follow-up of 14.8 +/- 9.5 months, the subjects who had undergone R&R surgery had a significantly higher success rate than those who had BLR-rec surgery (85.1% vs 65.8%, p=0.037). The undercorrection rate was significantly lower in the R&R group than in the BLR-rec group (6.4% vs 23.7%, p=0.023) and there was no significant difference in the overcorrection rate between the two groups (10.5% vs 8.5%, p=1.000). CONCLUSIONS: R&R is more effective than BLR-rec surgery in the long term for the basic type IXT in children. PMID- 23645823 TI - A young woman with proptosis. PMID- 23645822 TI - In vivo high-frequency contrast-enhanced ultrasonography of choroidal melanoma in rabbits: imaging features and histopathologic correlations. AB - PURPOSE: To evaluate the use of in vivo imaging of rabbit model of choroidal melanoma using high-frequency contrast-enhanced ultrasound (HF-CE-US) with two dimensional (2D) or three-dimensional (3D) modes and to correlate the sonographic findings with histopathologic characteristics. METHODS: Five New Zealand white rabbits, which were immunosuppressed with daily cyclosporin A (CsA), were inoculated into their right eyes with aliquots of 1.5*10(6)/50 MUl of 92.1 human uveal melanoma cells cultured in RPMI. At week 4, the tumour-bearing eyes were imaged using high-frequency ultrasound (HF-US) with microbubble contrast agent to determine the 2D tumour size and relative blood volume and by 3D mode to determine tumour volume. Histologic tumour burden was quantified in enucleated eyes by ImageJ software, and mean vascular density (MVD) was determined by counting vascular channels in periodic acid Schiff (PAS) without haematoxylin sections. RESULTS: Using HF-CE-US, melanomas were visualised as relatively hyperechoic regions in the images. The correlation coefficients of sonographic size and volume compared with histologic area were 0.72 and 0.70, respectively. The sonographic tumour relative blood volume correlated with the histologic tumour vascularity (r(2)=0.92, p=0.04). CONCLUSIONS: There is a positive correlation between in vivo sonographic tumour volume/size and histologic tumour size in our rabbit choroidal melanoma model. HF-CE-US corresponds to MVD and blood volume. PMID- 23645828 TI - Determination of chlorobenzenes in water samples by solid-phase disk extraction and gas chromatography-electron capture detection. AB - A simple, rapid, sensitive and high throughput method is described, based on solid-phase disk extraction (SPDE) and gas chromatography-electron capture detection, for the determination of chlorobenzens (CBs) in water samples. The proposed SPDE sample pretreatment method was initially optimized and the optimum experimental conditions were found to be as follows: 500 mL water sample (pH 2.5) extracted and enriched by an Empore 3-stn C18 (octadecyl) SPE disk at flow rate of 5 to 50 mL/min, eluted by 5 mL of acetone and 3 * 5 mL of methylene dichloride. The linearity of the method ranged from 0.02 to 0.4 ug/L for dichlorobenzene isomers, 0.0022-0.044 ug/L for trichlorobenzene isomers, 0.005 0.01 ug/L for tetrachlorobenzene isomers and 0.00025 to 0.005 ug/L for pentachlorobenzenes and hexachlorobenzenes, with correlation coefficients ranging between 0.9991 and 0.9999. The limits of detection were in the low ng/L level, ranging between 0.05 and 4 ng/L. The recoveries of spiked CBs with the external calibration method at different concentration levels in deionized/distilled water, tap water and sea water samples were 99-115, 91-106% and 96-110%, respectively, and with relative standard deviations of 4.5-7.6, 4.2-6.8 and 3.6 6.6% (n = 5), respectively. It is concluded that this method can successfully be applied for the determination of CBs in deionized/distilled water, tap water and sea water samples. PMID- 23645829 TI - The contribution of preintervention blood pressure, VO2max, BMI, autonomic function and gender to exercise-induced changes in heart rate variability. AB - INTRODUCTION: The quantification of heart rate variability (HRV) is a tool to assess the interaction between exercise and autonomic control, as well as the pathophysiology of diseases affecting autonomic function. Little is known about the influence of genetically influenced physiology on exercise-induced changes in autonomic cardiac regulation. It was theorised that preintervention values for blood pressure, VO2max, body mass index (BMI), autonomic function and gender contribute significantly to the exercise-induced changes in HRV. METHODS: A 12 week, medium-to-high intensity exercise intervention was completed by 183 volunteers (18-22 years). Data were sampled at baseline and after 12 weeks. Standard time domain, frequency domain and Poincare HRV quantification techniques were implemented. Regression analysis was performed to determine the influences of the predictors (baseline values for low frequency (LF), high frequency (HF), BMI, VO2max, gender, blood pressure) on the exercise-induced response of the dependent variables (changes in HRV-indicator values). RESULTS: Parameters found to be significant (p<0.05) predictors of exercise-induced changes were LF, HF and systolic blood pressure in, respectively, 10, 5 and 2 of the 12 regressions performed. The results indicated that the independent variables contribute between 12.83% and 29.82%, depending on the specific HRV indicator, to the exercise-induced changes in the autonomic nervous system. CONCLUSIONS: Preintervention autonomic status, as represented specifically by LF, is the most important determinant of cardiac autonomic response to an exercise intervention in a healthy study population. Baseline autonomic function could thus be a significant confounder in the outcome of exercise study results. PMID- 23645830 TI - Online registration of monthly sports participation after anterior cruciate ligament injury: a reliability and validity study. AB - BACKGROUND: The current methods measuring sports activity after anterior cruciate ligament (ACL) injury are commonly restricted to the most knee-demanding sports, and do not consider participation in multiple sports. We therefore developed an online activity survey to prospectively record the monthly participation in all major sports relevant to our patient-group. OBJECTIVE: To assess the reliability, content validity and concurrent validity of the survey and to evaluate if it provided more complete data on sports participation than a routine activity questionnaire. METHODS: 145 consecutively included ACL-injured patients were eligible for the reliability study. The retest of the online activity survey was performed 2 days after the test response had been recorded. A subsample of 88 ACL reconstructed patients was included in the validity study. The ACL-reconstructed patients completed the online activity survey from the first to the 12th postoperative month, and a routine activity questionnaire 6 and 12 months postoperatively. RESULTS: The online activity survey was highly reliable (kappa ranging from 0.81 to 1). It contained all the common sports reported on the routine activity questionnaire. There was a substantial agreement between the two methods on return to preinjury main sport (kappa=0.71 and 0.74 at 6 and 12 months postoperatively). The online activity survey revealed that a significantly higher number of patients reported to participate in running, cycling and strength training, and patients reported to participate in a greater number of sports. CONCLUSIONS: The online activity survey is a highly reliable way of recording detailed changes in sports participation after ACL injury. The findings of this study support the content and concurrent validity of the survey, and suggest that the online activity survey can provide more complete data on sports participation than a routine activity questionnaire. PMID- 23645831 TI - The incidence of concussion in professional and collegiate ice hockey: are we making progress? A systematic review of the literature. AB - BACKGROUND: The fast, random nature and characteristics of ice hockey make injury prevention a challenge as high-velocity impacts with players, sticks and boards occur and may result in a variety of injuries, including concussion. METHODS: Five online databases (January 1970 and May 2012) were systematically searched followed by a manual search of retrieved papers. RESULTS: Seventeen studies met the inclusion criteria. The heterogeneous diagnostic procedures and criteria for concussion prevented a pooling of data. When comparing the injury data of European and North American or Canadian leagues, the latter show a higher percentage of concussions in relation to the overall number of injuries (2-7% compared with 5.3-18.6%). The incidence ranged from 0.2/1000 to 6.5/1000 game hours, 0.72/1000 to 1.81/1000 athlete-exposures and was estimated at 0.1/1000 practice-hours. DISCUSSION AND CONCLUSIONS: The included studies indicate a high incidence of concussion in professional and collegiate ice hockey. Despite all efforts there is no conclusive evidence that rule changes or other measures lead to a decrease in the actual incidence of concussions over the last few decades. This review supports the need for standardisation of the diagnostic criteria and reporting protocols for concussion to allow interstudy comparisons in the future. PMID- 23645832 TI - Injuries affect team performance negatively in professional football: an 11-year follow-up of the UEFA Champions League injury study. AB - BACKGROUND: The influence of injuries on team performance in football has only been scarcely investigated. AIM: To study the association between injury rates and team performance in the domestic league play, and in European cups, in male professional football. METHODS: 24 football teams from nine European countries were followed prospectively for 11 seasons (2001-2012), including 155 team seasons. Individual training and match exposure and time-loss injuries were registered. To analyse the effect of injury rates on performance, a Generalised Estimating Equation was used to fit a linear regression on team-level data. Each team's season injury rate and performance were evaluated using its own preceding season data for comparison in the analyses. RESULTS: 7792 injuries were reported during 1 026 104 exposure hours. The total injury incidence was 7.7 injuries/1000 h, injury burden 130 injury days lost/1000 h and player match availability 86%. Lower injury burden (p=0.011) and higher match availability (p=0.031) were associated with higher final league ranking. Similarly, lower injury incidence (p=0.035), lower injury burden (p<0.001) and higher match availability (p<0.001) were associated with increased points per league match. Finally, lower injury burden (p=0.043) and higher match availability (p=0.048) were associated with an increase in the Union of European Football Association (UEFA) Season Club Coefficient, reflecting success in the UEFA Champions League or Europa League. CONCLUSIONS: Injuries had a significant influence on performance in the league play and in European cups in male professional football. The findings stress the importance of injury prevention to increase a team's chances of success. PMID- 23645833 TI - The effect of changes in the score on injury incidence during three FIFA World Cups. AB - OBJECTIVE: To study the effect of changes in the score and of different playing positions, as well as the effect of recovery time on injury incidence during Federation Internationale de Football Association (FIFA) World Cups. DESIGN: Prospective injury surveillance at three international championships in 2002, 2006 and 2010. Official match statistics were obtained for all the games played in the three championships. SETTING: 2002, 2006 and 2010 FIFA World Cups. PARTICIPANTS: National team players as well as the team doctors reporting all the injuries at the 2002, 2006 and 2010 FIFA World Cups. MAIN OUTCOME MEASURES: Injury incidence and incidence rate ratios. RESULTS: There were statistically significant differences in injury incidence related to changes in the score (p=0.026) and to the teams' current drawing/losing/winning status (p=0.008). Injury incidence was lowest (54.8/1000 match-hours (mh), 95% CI 46.4 to 64.3) during the initial 0-0 score and highest (81.2/1000 mh, 60.5 to 106.8) when the score was even but goals had been scored. Winning teams had a tendency towards a higher injury incidence (81.0/1000 mh, 67.5 to 96.4) than losing or drawing teams (55.5/1000 mh, 44.4 to 68.4 and 59.7/1000 mh, 51.8 to 68.6, respectively). There were also statistically significant differences in injury incidence between the playing positions (p<0.001), with forwards having the highest injury incidence (85.7/1000 mh, 69.8 to 104.2). There was a linear relationship (p=0.043) between an increasing number of recovery days between matches and a higher injury incidence. CONCLUSIONS: There is a considerable variation in injury incidence during a match in international men's football related to changes in the score. Players in a winning team run a higher risk of suffering an injury than players in a drawing or losing team. Identifying time periods with a high injury incidence may be of major importance to players and team personnel, as it may enable them to take precautions. PMID- 23645834 TI - Return to play after thigh muscle injury in elite football players: implementation and validation of the Munich muscle injury classification. AB - BACKGROUND: Owing to the complexity and heterogeneity of muscle injuries, a generally accepted classification system is still lacking. AIMS: To prospectively implement and validate a novel muscle injury classification and to evaluate its predictive value for return to professional football. METHODS: The recently described Munich muscle injury classification was prospectively evaluated in 31 European professional male football teams during the 2011/2012 season. Thigh muscle injury types were recorded by team medical staff and correlated to individual player exposure and resultant time-loss. RESULTS: In total, 393 thigh muscle injuries occurred. The muscle classification system was well received with a 100% response rate. Two-thirds of thigh muscle injuries were classified as structural and were associated with longer lay-off times compared to functional muscle disorders (p<0.001). Significant differences were observed between structural injury subgroups (minor partial, moderate partial and complete injuries) with increasing lay-off time associated with more severe structural injury. Median lay-off time of functional disorders was 5-8 days without significant differences between subgroups. There was no significant difference in the absence time between anterior and posterior thigh injuries. CONCLUSIONS: The Munich muscle classification demonstrates a positive prognostic validity for return to play after thigh muscle injury in professional male football players. Structural injuries are associated with longer average lay-off times than functional muscle disorders. Subclassification of structural injuries correlates with return to play, while subgrouping of functional disorders shows less prognostic relevance. Functional disorders are often underestimated clinically and require further systematic study. PMID- 23645835 TI - Forced miR-146a expression causes autoimmune lymphoproliferative syndrome in mice via downregulation of Fas in germinal center B cells. AB - By inhibiting target gene expression, microRNAs (miRNAs) play major roles in various physiological and pathological processes. miR-146a, a miRNA induced upon lipopolysaccharide (LPS) stimulation and virus infection, is also highly expressed in patients with immune disorders such as rheumatoid arthritis, Sjogren's syndrome, and psoriasis. Whether the high level of miR-146a contributes to any of these pathogenesis-related processes remains unknown. To elucidate the function of miR-146a in vivo, we generated a transgenic (TG) mouse line overexpressing miR-146a. Starting at an early age, these TG mice developed spontaneous immune disorders that mimicked human autoimmune lymphoproliferative syndrome (ALPS) with distinct manifestations, including enlarged spleens and lymph nodes, inflammatory infiltration in the livers and lungs, increased levels of double-negative T cells in peripheral blood, and increased serum immunoglobulin G levels. Moreover, with the adoptive transfer approach, we found that the B-cell population was the major etiological factor and that the expression of Fas, a direct target of miR-146a, was significantly dampened in TG germinal center B cells. These results indicate that miR-146a may be involved in the pathogenesis of ALPS by targeting Fas and may therefore serve as a novel therapeutic target. PMID- 23645836 TI - Mast cell and macrophage chemokines CXCL1/CXCL2 control the early stage of neutrophil recruitment during tissue inflammation. AB - Neutrophil recruitment is an important early step in controlling tissue infections or injury. Here, we report that this influx depends on both tissue resident mast cells and macrophages. Mice with mast cell deficiency recruit reduced numbers of neutrophils in the first few hours of intraperitoneal lipopolysaccharide (LPS) stimulation. Conversely, in mice with clodronate-ablated macrophages, neutrophils extravasate, but have limited ability to reach the peritoneal fluid. Tissue macrophages synthesize neutrophil chemoattractants CXCL1/CXCL2 (CXC chemokine ligands 1/2) in response to LPS. Mast cells also produce these chemokines of which a proportion are preformed in granules. Release of the granules and new CXCL1/CXCL2 synthesis is Toll-like receptor 4-dependent. Both in vivo studies with blocking monoclonal antibodies and in vitro chemotaxis experiments show the neutrophil response to mast cells and macrophages to be CXCL1/CXCL2-dependent. The data are in keeping with the model that mast cells, optimally positioned in close proximity to the vasculature, initiate an early phase of neutrophil recruitment by releasing the chemoattractants CXCL1/CXCL2. Having arrived within the stimulated tissue, neutrophils penetrate further in a macrophage-dependent manner. Therefore, we demonstrate a positive role for mast cells in tissue inflammation and define how this comes about with contribution from a second tissue cell, the macrophage. PMID- 23645837 TI - Increased risk of CVD after VT is determined by common etiologic factors. AB - Patients with venous thrombosis (VT) have an increased risk of subsequent CVD (CVD), but the underlying pathophysiology is unclear. Using data from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis follow-up study, 4480 patients with VT, 2926 partner control participants, and 2638 random digit dialing (RDD) control participants were followed-up between 1999 and 2008. Incidence rates and hazard ratios with 95% confidence intervals (95% CIs) of CVD (defined as myocardial infarction or ischemic stroke) were calculated for patients vs controls. Measurable confounders (age, sex, body mass index, smoking, chronic disease, malignancy, genetic thrombophilia, and procoagulant markers) were adjusted for when comparing patients with RDD controls. Unmeasured lifestyle-related factors were also considered by comparing patients with their partners. During a median follow-up time of 5 years, 124 CVD events occurred. Incidence of CVD per 1000 person-years was 3.2 (95% CI, 2.5-4.0) in patients, 2.2 (95% CI, 1.5-3.0) in partners, and 1.6 (95% CI, 0.9-2.6) in RDD controls. Crude hazard ratio was 2.2 (95% CI, 1.2-3.8) in patients compared with RDD controls and 1.5 (95% CI, 1.0-2.3) in patients compared with partners. After adjustment for all confounders, these risks attenuated to 1.8 (95% CI, 0.8-4.2) and 1.3 (95% CI, 0.7-2.5) for patients compared with RDD control participants and partners, respectively. In conclusion, individuals with VT had an increased risk of CVD. This could be explained by common etiologic factors. PMID- 23645838 TI - Inhibition of HPA-1a alloantibody-mediated platelet destruction by a deglycosylated anti-HPA-1a monoclonal antibody in mice: toward targeted treatment of fetal-alloimmune thrombocytopenia. AB - Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is often caused by maternal alloantibodies against the human platelet antigen (HPA)-1a, which opsonizes fetal platelets (PLTs). Subsequent PLT destruction is mediated via the Fc part of the alloantibodies. The monoclonal antibody (mAb) SZ21 binds to the HPA-1a epitope and inhibits the binding of maternal alloantibodies. However, it also promotes complement activation and phagocytosis. Deglycosylation of antibodies abrogates the Fc-related effector functions. We modified the N-glycan of SZ21 by endoglycosidase F. The in vivo transplacental transport of N-glycan-modified (NGM)-SZ21 was not impaired. When injected into pregnant mice, both native-SZ21 and NGM-SZ21 were transported equally into fetal circulation (8.9% vs 8.7%, respectively, P = .58). Neither the binding properties of NGM-SZ21 to HPA-1a in surface plasmon resonance, nor the inhibition of anti-HPA-1a-induced PLT phagocytosis, were affected by N-glycan modification. NGM-SZ21 prevented PLT destruction induced by maternal anti-HPA-1a antibodies in vivo in a mouse model (PLT clearance after 5 hours; 18% vs 62%, in the presence or absence of NGM-SZ21, respectively, P = .013). Deglycosylation of SZ21 abrogates Fc-effector functions without interfering with placental transport or the ability to block anti-HPA-1a binding. Humanized, deglycosylated anti-HPA-1a mAbs may represent a novel treatment strategy to prevent anti-HPA-1a-mediated PLT destruction in FNAIT. PMID- 23645840 TI - Long noncoding RNAs in biology and hematopoiesis. AB - Genome and transcriptome sequencing have revealed a rich assortment of noncoding RNAs in eukaryote cells, including long noncoding RNAs (lncRNAs), which regulate gene expression independent of protein coding potential. LncRNAs modulate protein coding gene expression in many cell types by regulating multiple processes, including epigenetic control of transcription, mRNA stability, and protein localization. Although little is known about lncRNAs in hematopoiesis, they are likely to exert widespread roles in this process. PMID- 23645839 TI - AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/beta-catenin signaling pathway. AB - Developing novel therapies that suppress self-renewal of leukemia stem cells may reduce the likelihood of relapses and extend long-term survival of patients with acute myelogenous leukemia (AML). AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Previously, using a zebrafish model of AE and a whole-organism chemical suppressor screen, we have discovered that AE induces specific hematopoietic phenotypes in embryonic zebrafish through a cyclooxygenase (COX)-2 and beta-catenin-dependent pathway. Here, we show that AE also induces expression of the Cox-2 gene and activates beta-catenin in mouse bone marrow cells. Inhibition of COX suppresses beta catenin activation and serial replating of AE(+) mouse HSPCs. Genetic knockdown of beta-catenin also abrogates the clonogenic growth of AE(+) mouse HSPCs and human leukemia cells. In addition, treatment with nimesulide, a COX-2 selective inhibitor, dramatically suppresses xenograft tumor formation and inhibits in vivo progression of human leukemia cells. In summary, our data indicate an important role of a COX/beta-catenin-dependent signaling pathway in tumor initiation, growth, and self-renewal, and in providing the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments. PMID- 23645842 TI - Update on the long-term complications of renal transplantation. AB - INTRODUCTION: Powerful immunosuppressive regimens have reduced rejection risk, leading to an expanding cohort of long-term kidney transplant recipients who are likely to encounter practitioners in other specialties. SOURCES OF DATA: Key review papers and primary literature identified through searches of PubMed, Google Scholar and Medline. AREAS OF AGREEMENT: Death from cardiovascular disease and malignancy remain the chief causes of transplant loss. Risk factors and phenotypes for these differ from the general population. AREAS OF CONTROVERSY: Many guidelines for renal transplant recipients are based on extrapolation from studies on non-transplant cohorts and may not be appropriate. Emerging studies demonstrate that established interventions in the general population are less efficacious in transplant recipients. GROWING POINTS: The influence of immunosuppression on the development of complications. AREAS TIMELY FOR DEVELOPING RESEARCH: Markers to guide individualized optimal immunosuppression and predict the development of complications would allow for targeted early intervention. PMID- 23645841 TI - Endemic Burkitt lymphoma is associated with strength and diversity of Plasmodium falciparum malaria stage-specific antigen antibody response. AB - Endemic Burkitt lymphoma (eBL) is linked to Plasmodium falciparum (Pf) infection geographically, but evidence from individual-level studies is limited. We investigated this issue among 354 childhood eBL cases and 384 age-, sex-, and location-matched controls enrolled in Ghana from 1965 to 1994. Immunoglobulin G1 (IgG1) and immunoglobulin G3 (IgG3) antibodies to antigens diagnostic of recent infection Pf histidine-rich protein-II (HRP-II) and 6NANP, Pf-vaccine candidates SE36 and 42-kDa region of the 3D7 Pf merozoite surface protein-1 (MSP-1), and tetanus toxoid were measured by indirect enzyme-linked immunoassay. Odds ratios (ORs) and 95% confidence intervals (CIs) for association with eBL were estimated using unconditional logistic regression. After adjustments, eBL was positively associated with HRP-IIIgG3 seropositivity (adjusted OR: 1.60; 95% CI 1.08-2.36) and inversely associated with SE36IgG1 seropositivity (adjusted OR: 0.37; 95% CI 0.21-0.64) and with tetanus toxoidIgG3 levels equal or higher than the mean (adjusted OR: 0.46; 95% CI 0.32-0.66). Anti-MSP-1IgG3 and anti-6NANPIgG3 were indeterminate. eBL risk was potentially 21 times higher (95% CI 5.8-74) in HRP IIIgG3-seropositive and SE36IgG1-seronegative responders compared with HRP-IIIgG3 seronegative and SE36IgG1-seropositive responders. Our results suggest that recent malaria may be associated with risk of eBL but long-term infection may be protective. PMID- 23645843 TI - Meeting the challenges of micronutrient malnutrition in the developing world. AB - BACKGROUND: Malnutrition still remains one of the major public health challenges, particularly in developing countries. Major risk factors for undernutrition such as suboptimal breastfeeding and micronutrient deficiencies (vitamin A and zinc) are responsible for more than one-third of all under five child deaths and 11% of the global total disease burden. SOURCES OF DATA: Several strategies have been employed to supplement micronutrients. These include education, dietary modification, food provision, supplementation and fortification either alone or in combination. AREAS OF AGREEMENT: Supplementation is the most widely practiced intervention while fortification can also be a potentially cost-effective public health intervention and target a larger population through a single strategy. Universal coverage with the full bundle of interventions including micronutrient provision, complementary foods, treatments for worms and diarrheal diseases and behavior change programs package could be the way forward in achieving the Millennium Development Goals (MDGs). AREAS OF CONTROVERSY: Bio-fortification and agricultural interventions including home and school gardening are relatively newer strategies and require further research as they have the potential to impact nutritional status of populations at large. GROWING POINTS: Effectiveness of the various interventions is well recognized; however, consensus needs to be built around approaches to scale up coverage and delivery strategies to reduce disparities and provide equitable access. AREAS TIMELY FOR DEVELOPING RESEARCH: Future studies should focus on evaluating various approaches to address malnutrition with a standard methodology and defined outcomes. This will help gauge the actual morbidity and mortality impacts of these specific interventions and the long-term viability of these programs. On a broader scale, strategies to address food insecurity and poverty alleviation are the key as these are complex sustainable development issues, linked to health through malnutrition, but also to sustainable economic development, environment and trade. PMID- 23645844 TI - Infectious threats after Iran's Bushehr earthquake. PMID- 23645845 TI - Urinary tract infections: current and emerging management strategies. AB - Acute cystitis is one of the most commonly encountered bacterial infections and is responsible for substantial morbidity and high medical costs in the United States and across the globe. Though generally considered to be self-limiting and easily treated with antibiotics, urinary tract infections (UTIs) are often incompletely resolved by antibiotic therapy and frequently recur. This is in part due to the ability of uropathogenic bacteria to invade, replicate, and persist within host epithelial cells. The biological complexity of these infections combined with a dramatic rise in antibiotic-resistant pathogens highlight the need for alternative therapies. In this review we examine current management strategies for UTIs, as well as emerging treatments, including novel compounds that block bacterial interactions with the urothelium and vaccines focused on preventing both acute and recurrent infections. PMID- 23645847 TI - Skewing of the CD4(+) T-cell pool toward monofunctional antigen-specific responses in patients with immune reconstitution inflammatory syndrome in The Gambia. AB - BACKGROUND: A common complication of starting antiretroviral therapy (ART) for human immunodeficiency virus (HIV) is the development of immune reconstitution inflammatory syndrome (IRIS) in approximately 25% of patients. Despite similarities with paradoxical reactions to tuberculosis and reversal reactions in leprosy, the exact mechanisms, and therefore potential determinants, of IRIS are still unknown. METHODS: In this longitudinal cohort study, we analyzed 20 patients who developed IRIS following initiation of ART and 16 patients who did not, matched for ART time point. Peripheral blood mononuclear cells were stimulated overnight with a positive control antigen and 2 tuberculosis-specific antigens (purified protein derivative [PPD] and ESAT-6/CFP10), followed by polychromatic flow cytometry for analysis of cytokine production from CD4(+) and CD8(+) T cells. RESULTS: Responses to PPD were significantly higher in IRIS patients compared to controls during the IRIS time point, but CD4(+) and CD8(+) T cell responses to the positive control stimulation were significantly lower in IRIS patients at all time points. Furthermore, whereas control patients had rejuvenated polyfunctional T-cell responses by 3 months after ART, IRIS patients were strikingly monofunctional (generally interferon gamma alone), even up to 6 months of ART in response to all stimulations. CONCLUSIONS: Our findings suggest that the peripheral T-cell responses to the underlying pathogen are exaggerated in IRIS patients but that the overall quality of the peripheral T-cell pool is significantly reduced compared to non-IRIS patients. Furthermore, these effects are apparent at least up to 3 months after cessation of IRIS. PMID- 23645849 TI - Does empirical Clostridium difficile infection (CDI) therapy result in false negative CDI diagnostic test results? AB - BACKGROUND: Patients with suspected Clostridium difficile infection (CDI) often receive empirical therapy prior to collection of stool specimens for diagnostic testing. The likelihood that such empirical therapy might result in false negative CDI test results is unknown. METHODS: We conducted a prospective study of CDI patients to determine the time to conversion of CDI test results, including polymerase chain reaction (PCR) for toxin B genes, glutamate dehydrogenase, and toxigenic culture, from positive to negative during CDI therapy. We evaluated the frequency of and risk factors for persistence of positive CDI tests. For patients receiving empirical therapy, we assessed the frequency of conversion of positive CDI test results at the time of the test order to negative by the time clinical staff collected stool specimens for testing. RESULTS: For 51 CDI patients, PCR, glutamate dehydrogenase, and toxigenic culture results converted to negative at similar rates. For PCR, 14%, 35%, and 45% of positive CDI tests converted to negative after 1, 2, and 3 days of treatment, respectively. Increased age and infection with North American pulsed-field gel electrophoresis strains were associated with persistent positive PCR results. For CDI patients diagnosed at the time of the test order, conversion to negative PCR results by the time clinical stool specimens were collected occurred in 4 of 9 (44%) patients who were prescribed empirical CDI therapy versus 0 of 23 (0%) who were not (P = .004). CONCLUSIONS: Empirical treatment for suspected CDI cases may result in false-negative PCR results if there are delays in stool specimen collection. PMID- 23645848 TI - Next-generation whole genome sequencing identifies the direction of norovirus transmission in linked patients. AB - BACKGROUND: Noroviruses are a highly transmissible and major cause of nosocomial gastroenteritis resulting in bed and hospital-ward closures. Where hospital outbreaks are suspected, it is important to determine the routes of spread so that appropriate infection-control procedures can be implemented. To investigate a cluster of norovirus cases occurring in children undergoing bone marrow transplant, we undertook norovirus genome sequencing by next-generation methods. Detailed comparison of sequence data from 2 linked cases enabled us to identify the likely direction of spread. METHODS: Norovirus complementary DNA was amplified by overlapping polymerase chain reaction (PCR) from 13 stool samples from 5 diagnostic real-time PCR-positive patients. The amplicons were sequenced by Roche 454, the genomes assembled by de novo assembly, and the data analyzed phylogenetically. RESULTS: Phylogenetic analysis indicated that patients were infected by viruses similar to 4 distinct GII.4 subtypes and 2 patients were linked by the same virus. Of the 14 sites at which there were differences between the consensus sequences of the 2 linked viral genomes, 9 had minor variants present within one or the other patient. Further analysis confirmed that minor variants at all 9 sites in patient B w ere present as the consensus sequence in patient A. CONCLUSIONS: Phylogenetic analysis excluded a common source of infection in this apparent outbreak. Two of 3 patients on the same ward had closely related viruses, raising the possibility of cross-infection despite protective isolation. Analysis of deep sequencing data enabled us to establish the likely direction of nosocomial transmission. PMID- 23645850 TI - Obesity as a risk factor for Clostridium difficile infection. AB - BACKGROUND: Obesity and Clostridium difficile infection (CDI) are both related to an increased Firmicutes/Bacteroidetes ratio in the intestinal microbiota. However, an association between obesity and CDI is unknown. We aimed to assess the association between obesity and CDI in hospitalized patients. METHODS: We conducted a retrospective case-control study. From January to December 2011, all consecutive patients hospitalized with CDI, in 2 internal medical departments in 2 hospitals, were included. Patients with CDI were compared to hospitalized patients without diarrhea, during the same period and in the same departments, and matched by age, sex, Charlson score, length of hospitalization, and antibiotic use during the last 3 months. RESULTS: Of the 6300 patients hospitalized, 178 were diagnosed with CDI. CDI prevalence was 2.8% (178/6300). Thirty patients were excluded from the study. The 148 cases with CDI were compared to 148 hospitalized controls. Mean body mass index (BMI) in the CDI group was 33.6 (SD, 4.3) versus 28.9 (SD, 5.4) in the control group (P = .001). The multivariable model of conditional logistic regression for matched pairs showed that a history of intra-abdominal surgery (odds ratio [OR] = 2.865; 95% confidence interval [CI], 1.26-6.52) and a high BMI value (OR = 1.196 per 1-unit increase in the BMI scale; 95% CI, 1.12-1.27) were the only variables found to be significantly associated with CDI. CONCLUSIONS: Our findings suggest that obesity is associated with the risk of CDI. Further studies are needed to reveal the exact mechanisms underlying this association. PMID- 23645851 TI - Pregnancy-related group a streptococcal infections: temporal relationships between bacterial acquisition, infection onset, clinical findings, and outcome. AB - Puerperal sepsis caused by group A Streptococcus (GAS) remains an important cause of maternal and infant mortality worldwide, including countries with modern antibiotic regimens, intensive care measures and infection control practices. To provide insights into the genesis of modern GAS puerperal sepsis, we reviewed the published cases and case series from 1974 to 2009, specifically seeking relationships between the likely source of pathogen acquisition, clinical signs, and symptoms at infection onset and patient outcomes that could provide clues for early diagnosis. Results suggest that the pathogenesis of pregnancy-related GAS infections in modern times is complex and not simply the result of exposure to GAS in the hospital setting. Additional research is needed to further explore the source of GAS, the specific M types involved, and the pathogenesis of these pregnancy-related infections to generate novel preventative and therapeutic strategies. PMID- 23645853 TI - Reply to Liao et al. PMID- 23645852 TI - Lack of association between interleukin 28B polymorphisms and spontaneous viral clearance in hepatitis B virus patients. PMID- 23645854 TI - Alternative excision repair pathways. AB - Alternative excision repair (AER) is a category of excision repair initiated by a single nick, made by an endonuclease, near the site of DNA damage, and followed by excision of the damaged DNA, repair synthesis, and ligation. The ultraviolet (UV) damage endonuclease in fungi and bacteria introduces a nick immediately 5' to various types of UV damage and initiates its excision repair that is independent of nucleotide excision repair (NER). Endo IV-type apurinic/apyrimidinic (AP) endonucleases from Escherichia coli and yeast and human Exo III-type AP endonuclease APEX1 introduce a nick directly and immediately 5' to various types of oxidative base damage besides the AP site, initiating excision repair. Another endonuclease, endonuclease V from bacteria to humans, binds deaminated bases and cleaves the phosphodiester bond located 1 nucleotide 3' of the base, leading to excision repair. A single-strand break in DNA is one of the most frequent types of DNA damage within cells and is repaired efficiently. AER makes use of such repair capability of single-strand breaks, removes DNA damage, and has an important role in complementing BER and NER. PMID- 23645856 TI - The association between height and birth order: evidence from 652,518 Swedish men. AB - BACKGROUND: Birth order is associated with outcomes such as birth weight and adult socioeconomic position (SEP), but little is known about the association with adult height. This potential birth order-height association is important because height predicts health, and because the association may help explain population-level height trends. We studied the birth order-height association and whether it varies by family characteristics or birth cohort. METHODS: We used the Swedish Military Conscription Register to analyse adult height among 652,518 men born in 1951-1983 using fixed effects regression models that compare brothers and account for genetic and social factors shared by brothers. We stratified the analysis by family size, parental SEP and birth cohort. We compared models with and without birth weight and birth length controls. RESULTS: Unadjusted analyses showed no differences between the first two birth orders but in the fixed effects regression, birth orders 2, 3 and 4 were associated with 0.4, 0.7 and 0.8 cm (p<0.001 for each) shorter height than birth order 1, respectively. The associations were similar in large and small and high-SEP and low-SEP families, but were attenuated in recent cohorts. Birth characteristics did not explain these associations. CONCLUSIONS: Birth order is an important determinant of height. The height difference between birth orders 3 and 1 is larger than the population-level height increase achieved over 10 years. The attenuation of the effect over cohorts may reflect improvements in living standards. Decreases in family size may explain some of the secular-height increases in countries with decreasing fertility. PMID- 23645855 TI - Cell-free hemoglobin and its scavenger proteins: new disease models leading the way to targeted therapies. AB - Hemoglobin (Hb) has multiple pathophysiologic effects when released into the intravascular space during hemolysis. The extracellular effects of Hb have resulted in novel models of toxicity, which help to explain endothelial dysfunction and cardiovascular complications that accompany genetic hemolytic anemias, malaria, blood transfusion, and atherosclerosis. The majority of models focus on nitric oxide (NO) depletion; however, in local tissue environments, Hb can also act as a pro-oxidant and inflammatory agent. This can alter cellular differentiation with the potential to deviate immune responses. The understanding of these mechanisms set in the context of natural scavenger and detoxification systems may accelerate the development of novel treatment strategies. PMID- 23645858 TI - Expect analgesic failure; pursue analgesic success. PMID- 23645859 TI - Mark Walport: government's Wellcome new source of advice. Interviewed by Tony Delamothe. PMID- 23645857 TI - Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta analysis. AB - OBJECTIVE: To review the diagnostic accuracy of D-dimer testing in older patients (>50 years) with suspected venous thromboembolism, using conventional or age adjusted D-dimer cut-off values. DESIGN: Systematic review and bivariate random effects meta-analysis. DATA SOURCES: We searched Medline and Embase for studies published before 21 June 2012 and we contacted the authors of primary studies. STUDY SELECTION: Primary studies that enrolled older patients with suspected venous thromboembolism in whom D-dimer testing, using both conventional (500 ug/L) and age adjusted (age * 10 ug/L) cut-off values, and reference testing were performed. For patients with a non-high clinical probability, 2 * 2 tables were reconstructed and stratified by age category and applied D-dimer cut-off level. RESULTS: 13 cohorts including 12,497 patients with a non-high clinical probability were included in the meta-analysis. The specificity of the conventional cut-off value decreased with increasing age, from 57.6% (95% confidence interval 51.4% to 63.6%) in patients aged 51-60 years to 39.4% (33.5% to 45.6%) in those aged 61-70, 24.5% (20.0% to 29.7% in those aged 71-80, and 14.7% (11.3% to 18.6%) in those aged >80. Age adjusted cut-off values revealed higher specificities over all age categories: 62.3% (56.2% to 68.0%), 49.5% (43.2% to 55.8%), 44.2% (38.0% to 50.5%), and 35.2% (29.4% to 41.5%), respectively. Sensitivities of the age adjusted cut-off remained above 97% in all age categories. CONCLUSIONS: The application of age adjusted cut-off values for D dimer tests substantially increases specificity without modifying sensitivity, thereby improving the clinical utility of D-dimer testing in patients aged 50 or more with a non-high clinical probability. PMID- 23645860 TI - Network of high quality cancer hospitals is planned for India. PMID- 23645861 TI - Government policies will make health equality harder to achieve, conference hears. PMID- 23645862 TI - US panel recommends HIV screening for everyone aged 15 to 64 years. PMID- 23645863 TI - Ireland poised to allow abortion when mother's life at risk. PMID- 23645864 TI - New centres aim to marry biological data to the increasing power of IT systems to make sense of them. PMID- 23645865 TI - Consultant input to children's intensive care at weekends keeps mortality at weekday rates. PMID- 23645866 TI - Low environmentally relevant levels of bioactive xenobiotics and associated degradation products cause cryptic perturbations of metabolism and molecular stress responses in Arabidopsis thaliana. AB - Anthropic changes and chemical pollution confront wild plant communities with xenobiotic combinations of bioactive molecules, degradation products, and adjuvants that constitute chemical challenges potentially affecting plant growth and fitness. Such complex challenges involving residual contamination and mixtures of pollutants are difficult to assess. The model plant Arabidopsis thaliana was confronted by combinations consisting of the herbicide glyphosate, the fungicide tebuconazole, the glyphosate degradation product aminomethylphosphonic acid (AMPA), and the atrazine degradation product hydroxyatrazine, which had been detected and quantified in soils of field margins in an agriculturally intensive region. Integrative analysis of physiological, metabolic, and gene expression responses was carried out in dose-response experiments and in comparative experiments of varying pesticide combinations. Field margin contamination levels had significant effects on plant growth and metabolism despite low levels of individual components and the presence of pesticide degradation products. Biochemical and molecular analysis demonstrated that these less toxic degradation products, AMPA and hydroxyatrazine, by themselves elicited significant plant responses, thus indicating underlying mechanisms of perception and transduction into metabolic and gene expression changes. These mechanisms may explain observed interactions, whether positive or negative, between the effects of pesticide products (AMPA and hydroxyatrazine) and the effects of bioactive xenobiotics (glyphosate and tebuconazole). Finally, the metabolic and molecular perturbations induced by low levels of xenobiotics and associated degradation products were shown to affect processes (carbon balance, hormone balance, antioxidant defence, and detoxification) that are likely to determine environmental stress sensitivity. PMID- 23645867 TI - Solar rhythm in the regulation of photoperiodic flowering of long-day and short day plants. AB - In photoperiodic flowering, long-day (LD) plants are induced to flower seasonally when the daylight hours are long, whereas flowering in short-day (SD) plants is promoted under short photoperiods. According to the widely accepted external coincidence model, flowering occurs in LD Arabidopsis when the circadian rhythm of the gene CONSTANS (CO) peaks in the afternoon, when it is light during long days but dark when the days are short. Nevertheless, extending this explanation to SD flowering in rice, Oriza sativa, requires LD and SD plants to have 'opposite light requirements' as the CO orthologue in rice, HEADING-DATE1 (Hd1), promotes flowering only under short photoperiods. This report proposes a role of the plant's solar rhythm in promoting seasonal flowering. The interaction between rhythmic genes entrained to the solar clock and those entrained to the circadian clock form the basis of an internal coincidence model that explains both LD and SD flowering equally well. The model invokes no presumption of opposite light requirements between LD and SD plants, and further argues against any specific requirement of either light or darkness for SD flowering. Internal coincidence predicts the inhibition of SD flowering of the rice plant by a night break (a brief interruption of light), while it also provides a plausible explanation for how a judiciously timed night break promotes Arabidopsis flowering even on short days. It is the timing of the light transitions (sunrise and sunset) rather than the duration of light or darkness per se that regulates photoperiod-controlled flowering. PMID- 23645868 TI - Is white clover able to switch to atmospheric sulphur sources when sulphate availability decreases? AB - Sulphur (S) is one of the very few nutrients that plants can absorb either through roots as sulphate or via leaves in a gas form such as SO2 or H2S. This study was realized in a non-S-enriched atmosphere and its purpose was to test whether clover plants can increase their ability to use atmospheric S when sulphate availability decreases. A novel methodology measuring the dilution of (34)S provided from a nutrient solution by atmospheric (32)S was developed to measure S acquisition by Trifolium repens L. Clones of white clover were grown for 140 d in a hydroponic system with three levels of sulphate concentrations. S concentration in plants decreased with S deficiency and plant age. In the experimental conditions used here, S derived from atmospheric deposition (Sdad) constituted from 36% to 100% of the total S. The allocation of S coming from atmospheric and pedospheric sources depends on organs and compounds. Nodules appeared as major sinks for sulphate. A greater proportion of atmospheric S was observed in buffer-soluble proteins than in the insoluble S fraction. Decreasing the S concentration in the nutrient solution resulted in an increase in the Sdad:leaf area ratio and in an increase in the leaf:stolon and root:shoot mass ratios, suggesting that a plasticity in the partitioning of resources to organs may allow a higher gain of S by both roots and leaves. This study shows that clover can increase its ability to use atmospheric S even at low concentration when pedospheric S availability decreases. PMID- 23645869 TI - The twenty-year war over England's National Health Service: a report from the battlefield. AB - This article analyzes the latest battle in the twenty-year war to change England's National Health Service (NHS), starting with the internal market reforms introduced by the Thatcher government and now carried one step farther by David Cameron's coalition government. The government's program of change is characterized by (1) its wide scope and the organizational upheavals involved and (2) the fact that it is being introduced at a time when the NHS faces unprecedented fiscal pressures. The legislation faced strong political, public, and professional hostility both from those who saw it as a crime against the founding principles of the NHS and from those who saw it as a disruptive blunder that created more problems than it solved. This article asks three questions. Why did the coalition government embark on a policy course guaranteed to lose it votes? How will the much-amended legislation work out in practice: what are the risks and uncertainties? What will be the program's impact: will it, like previous waves of change, disappoint both the prophets of doom and the visionaries of transformation? The conclusion drawn is that the essential, defining characteristics of the NHS are not under threat. It continues to be a publicly funded service, freely available to all. It is not being privatized. But it is moving toward the kind of pluralistic system that would have been established by Britain's last, wartime coalition government, had not Aneurin Bevan nationalized the hospital service in 1948. PMID- 23645870 TI - Are local laws the key to ending childhood lead poisoning? AB - Although lead paint was banned by federal law in 1978, it continues to poison children living in homes built before that time. The lifelong effects of childhood exposure to even small amounts of lead are well established by medical research. Federal and state laws have reduced rates of lead poisoning significantly in the past three decades. However, pockets of high rates of lead poisoning remain, primarily in low-income urban neighborhoods with older housing stock. Recently, several municipalities have passed local lead laws to reduce lead hazards in high-risk areas. There has been no systematic attempt to compare the design and effectiveness of these local policies. To address this gap, we conducted comparative case studies of eight innovative lead laws promulgated since 2000. The laws used a wide variety of legal structures and tools, although certain elements were common. The impact of the policies was intertwined with local housing, economic, and legal environments. While data do not yet exist to systematically evaluate the impact of these laws on lead poisoning rates, our analysis suggests that local laws hold great promise for reducing lead hazards in children's homes. PMID- 23645871 TI - Philadelphia's Lead Court is making a difference. AB - The Philadelphia Lead Court (PLC) was created as an innovative law enforcement strategy to compel property owners to comply with city health codes to remediate their properties of lead hazards, which had led to elevated blood lead levels and lead poisoning in resident children. This study presents a detailed account of and analyzes the opinions of fifteen key informants drawn from the Philadelphia health and law departments and judicial system that staff and run the PLC in response to a fifteen-question structured survey. Main themes reviewed include the effectiveness of the PLC as compared with precourt law enforcement strategies and within the context of a specialized court, the use of fines, the impact of grant funding for remediation work, the major advantages and disadvantages of the PLC, and suggested changes to improve court function, followed by key recommendations. The article concludes that our informants found that the PLC has been very effective and successful. This model could be replicated by other cities with similar health code enforcement challenges. PMID- 23645872 TI - A response to Rudolf Klein: a battle may have been won but perhaps not the war. AB - The British National Health Service (NHS) is undergoing possibly the most far reaching set of changes in its sixty-five-year history. While some commentators (like Rudolf Klein) insist that little of substance is likely to change, others consider that the politics of reform may prove quite different on this occasion. The coalition government is committed to restructuring the welfare state and public services and to rolling back the state. The NHS as a popular monopoly public service runs counter to its neoliberal ideology. While (for now) remaining committed to a publicly funded system of health care that is largely free at point of use, the government wishes to encourage much greater diversity in the provision of care, including a much larger role for the for-profit private sector. Despite significant opposition to its proposals, few concessions have been forthcoming, and the legislation that passed onto the statute book in March 2012 remained essentially unchanged. Notwithstanding the lack of convincing evidence, the government is wedded to encouraging greater competition and choice. Thosewho believe the changes will amount to far less than its architects hope for are being too complacent and overlooking the strength of the government's ideological convictions. These threaten to dismantle the NHS and replace it with a more costly, fragmented, and less effective system of care that is driven by profit in place of the public interest. PMID- 23645873 TI - Editors' introduction. PMID- 23645874 TI - Changes in the British National Health Service. PMID- 23645875 TI - The politics of HPV vaccination policy formation in the United States. AB - This article explores the political dimensions of policy formation for the human papillomavirus (HPV) vaccine through case studies of six states: California, Indiana, New Hampshire, New York, Texas, and Virginia. Using thematic content analysis of semistructured key informant interviews with policy stakeholders, newspaper articles, and archival materials, we describe the trajectory of public health policy developments for HPV immunization and analyze key influences on policy outcomes through the theoretical lens of the Multiple Streams framework. Specifically, we examine factors influencing the extent to which HPV was perceived as a problem meriting policy action; political forces that facilitated and impeded policy adoption, including interest-group opposition and structural and ideological features of the states' political environments; and factors affecting which policy alternatives received consideration. We find that effective policy entrepreneurship played a critical role in determining policy outcomes. We conclude by discussing lessons from the case of HPV vaccination for future efforts to craft vaccination policies. PMID- 23645876 TI - Testing the results of municipal mixed-use zoning ordinances: a novel methodological approach. AB - Municipal mixed-use zoning (MUZ) is one public health strategy to create more walkable neighborhoods by reducing the separation of daily activities. This study uses a novel data-gathering methodology to evaluate municipal zoning ordinances in twenty-two California cities in conjunction with the walkability potential of resulting mixed-use zones, to explore the extent to which variations in uses mandated by MUZ ordinances are correlated with variations in walking opportunities. We find that, after controlling for population, socioeconomic status, and zone size, significant relationships exist between the range and precision of uses mandated by MUZ ordinances and the mixture and breadth of walking destinations in these zones. The study also demonstrates that analysis of municipal zoning codes and a novel data-gathering methodology yield valid data. The analysis of MUZ ordinances is a significant complement to other approaches to measuring walkability and can be used across cities. PMID- 23645877 TI - How do public health safeguards in Indian patent law affect pharmaceutical patenting in practice? AB - The 1995 Trade Related Intellectual Property Rights (TRIPS) agreement required developing countries to grant product patents in pharmaceuticals. Developing countries have since explored various measures to ameliorate potential negative effects of the new laws on public health. A prominent example is India, whose post-TRIPS patent laws include a provision, section 3(d), that restricts patents on incremental pharmaceutical innovations. Its critics and supporters alike suggest that this provision makes Indian patent law very different from that in other jurisdictions. Yet there are concerns that given resource constraints facing the Indian patent office, this novel feature of Indian patent laws on the books may not have an effect on Indian patent prosecution in practice. We test this by examining the prosecution outcomes of 2,803 applications filed in both India and Europe, coded by whether they include claims that trigger 3(d) considerations. We find that having the 3(d) provision on the books does not translate into very different patent outcomes in practice in India, relative to Europe, a jurisdiction without this provision. PMID- 23645878 TI - An (un)clear conscience clause: the causes and consequences of statutory ambiguity in state contraceptive mandates. AB - Since 1996, twenty-eight states have adopted legislation mandating insurance coverage of prescription contraceptives for women. Most of these policies include language that allows providers to opt out of the requirement because of religious or moral beliefs-conscience clause exemptions. There is striking variation in how these exemptions are defined. This article investigates the sources and consequences of ambiguous versus precise statutory language in conscience clauses. We find that some forms of political and institutional fragmentation (party polarization and gubernatorial appointment power) are correlated with the degree of policy specificity in state contraceptive mandates. This finding reinforces previous law and policy scholarship that has shown that greater fragmentation promotes ambiguous statutory language because broad wording acts as a vehicle for compromise when actors disagree. Interestingly, it is the more precisely worded statutes that have prompted court battles. We explain this with reference to the asymmetry of incentives and mobilizing costs between those disadvantaged by broad (primarily female employees) versus precisely worded statutes (primarily Catholic organizations). Our findings suggest that the impact of statutory ambiguity on court intervention is heavily contextualized by the resources and organization of affected stakeholders. PMID- 23645879 TI - Anti-inflammatory mechanisms of the annexin A1 protein and its mimetic peptide Ac2-26 in models of ocular inflammation in vivo and in vitro. AB - Annexin A1 (AnxA1) is a protein that displays potent anti-inflammatory properties, but its expression in eye tissue and its role in ocular inflammatory diseases have not been well studied. We investigated the mechanism of action and potential uses of AnxA1 and its mimetic peptide (Ac2-26) in the endotoxin-induced uveitis (EIU) rodent model and in human ARPE-19 cells activated by LPS. In rats, analysis of untreated EIU after 24 and 48 h or EIU treated with topical applications or with a single s.c. injection of Ac2-26 revealed the anti inflammatory actions of Ac2-26 on leukocyte infiltration and on the release of inflammatory mediators; the systemic administration of Boc2, a formylated peptide receptor (fpr) antagonist, abrogated the peptide's protective effects. Moreover, AnxA1(-/-) mice exhibited exacerbated EIU compared with wild-type animals. Immunohistochemical studies of ocular tissue showed a specific AnxA1 posttranslational modification in EIU and indicated that the fpr2 receptor mediated the anti-inflammatory actions of AnxA1. In vitro studies confirmed the roles of AnxA1 and fpr2 and the protective effects of Ac2-26 on the release of chemical mediators in ARPE-19 cells. Molecular analysis of NF-kappaB translocation and IL-6, IL-8, and cyclooxygenase-2 gene expression indicated that the protective effects of AnxA1 occur independently of the NF-kappaB signaling pathway and possibly in a posttranscriptional manner. Together, our data highlight the role of AnxA1 in ocular inflammation, especially uveitis, and suggest the use of AnxA1 or its mimetic peptide Ac2-26 as a therapeutic approach. PMID- 23645881 TI - Regulation of the expression of GARP/latent TGF-beta1 complexes on mouse T cells and their role in regulatory T cell and Th17 differentiation. AB - GARP/LRRC32 was defined as a marker of activated human regulatory T cells (Tregs) that is responsible for surface localization of latent TGF-beta1. We find that GARP and latent TGF-beta1 are also found on mouse Tregs activated via TCR stimulation; however, in contrast to human Tregs, GARP is also expressed at a low level on resting Tregs. The expression of GARP can be upregulated on mouse Tregs by IL-2 or IL-4 exposure in the absence of TCR signaling. GARP is expressed at a low level on Tregs within the thymus, and Treg precursors from the thymus concomitantly express GARP and Foxp3 upon exposure to IL-2. The expression of GARP is independent of TGF-beta1 and TGF-beta1 loading into GARP and is independent of furin-mediated processing of pro-TGF-beta1 to latent TGF-beta1. Specific deletion of GARP in CD4(+) T cells results in lack of expression of latent TGF-beta1 on activated Tregs. GARP-deficient Tregs develop normally, are present in normal numbers in peripheral tissues, and are fully competent suppressors of the activation of conventional T cells in vitro. Activated Tregs expressing GARP/latent TGF-beta1 complexes are potent inducers of Th17 differentiation in the presence of exogenous IL-6 and inducers of Treg in the presence of IL-2. Induction of both Th17-producing cells and Tregs is caused preferentially by Tregs expressing the latent TGF-beta1/GARP complex on their cell surface rather than by secreted latent TGF-beta1. PMID- 23645880 TI - IL-2-independent and TNF-alpha-dependent expansion of Vbeta5+ natural regulatory T cells during retrovirus infection. AB - Friend virus infection of mice induces the expansion and activation of regulatory T cells (Tregs) that dampen acute immune responses and promote the establishment and maintenance of chronic infection. Adoptive transfer experiments and the expression of neuropilin-1 indicate that these cells are predominantly natural Tregs rather than virus-specific conventional CD4(+) T cells that converted into induced Tregs. Analysis of Treg TCR Vbeta chain usage revealed a broadly distributed polyclonal response with a high proportionate expansion of the Vbeta5(+) Treg subset, which is known to be responsive to endogenous retrovirus encoded superantigens. In contrast to the major population of Tregs, the Vbeta5(+) subset expressed markers of terminally differentiated effector cells, and their expansion was associated with the level of the antiviral CD8(+) T cell response rather than the level of Friend virus infection. Surprisingly, the expansion and accumulation of the Vbeta5(+) Tregs was IL-2 independent but dependent on TNF-alpha. These experiments reveal a subset-specific Treg induction by a new pathway. PMID- 23645882 TI - Increased Th17 cells in the tumor microenvironment is mediated by IL-23 via tumor secreted prostaglandin E2. AB - Tumor cell-derived molecules such as cytokines and lipid mediators play a critical role in inducing chronic inflammation in the tumor microenvironment. We found that Th17 cells were increased in the peripheral blood, spleen, and tumor tissues of mammary gland tumor-bearing mice. The Th17 cell survival factor, IL 23, was also overexpressed in tumor tissues isolated from mice and human breast cancer patients. Soluble molecules secreted from breast tumor cells, but not normal breast epithelial cells, induced IL-23 protein secretion in dendritic cells via induction of p19 mRNA expression. Our data further indicate that tumor secreted PGE2 through EP2 and EP4 receptors enhanced IL-23 p19 gene transcription through binding to the cAMP-response element in the p19 promoter. Blocking PGE2 synthesis by NS398, a COX2 inhibitor, abrogated the enhancement of p19 expression both in vitro and in vivo. Furthermore, blocking protein kinase A (PKA) by H89 completely abrogated the inductive effects of tumor-conditioned medium and PGE2 on p19 transcription, whereas the cAMP active analog, Forskolin, mimics the PGE2 effect. Taken together, our results indicate that tumor-secreted PGE2 induces IL 23, but not IL-12, production in the tumor microenvironment, leading to Th17 cell expansion. This inductive effect of PGE2 on IL-23 p19 transcription is mediated through cAMP/PKA signaling transduction pathway. PMID- 23645883 TI - Aspergillus fumigatus-induced IL-22 is not restricted to a specific Th cell subset and is dependent on complement receptor 3. AB - Th cell responses induced by Aspergillus fumigatus have been extensively investigated in mouse models. However, the requirements for differentiation and the characteristics of A. fumigatus-induced human Th cell subsets remain poorly defined. We demonstrate that A. fumigatus induces Th1 and Th17 subsets in human PBMCs. Moreover, we show that the cytokine IL-22 is not restricted to a specific Th subset, in contrast to IL-17A. The pattern recognition and cytokine pathways that skew these Aspergillus-induced Th cell responses are TLR4- and IL-1-, IL-23 , and TNF-alpha-dependent. These pathways are of specific importance for production of the cytokines IL-17A and IL-22. Additionally, our data reveal that the dectin-1/Syk pathway is redundant and that TLR2 has an inhibitory effect on Aspergillus-induced IL-17A and IL-22 production. Notably, blocking complement receptor (CR)3 significantly reduced Aspergillus-induced Th1 and Th17 responses, and this was independent on the activation of the complement system. CR3 is a known receptor for beta-1,3-glucan; however, blocking CR3 had significant effects on Th cell responses induced by heat-killed Aspergillus conidia, which have minimal beta-glucan expression on their cell surface. Collectively, these data characterize the human Th cell subsets induced by Aspergillus, demonstrate that the capability to produce IL-22 is not restricted to a specific T cell subset, and provide evidence that CR3 might play a significant role in the adaptive host defense against Aspergillus, although the ligand and its action remain to be elucidated. PMID- 23645884 TI - A critical analysis of the clinical use of incretin-based therapies: The benefits by far outweigh the potential risks. AB - There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to an increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative preceding the counterpoint narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative provided below, Dr. Nauck provides a defense of incretin-based therapies and that benefits clearly outweigh any concern of risk. PMID- 23645885 TI - A critical analysis of the clinical use of incretin-based therapies: Are the GLP 1 therapies safe? AB - There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns reported regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to a potential risk for the increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider the use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative following the contribution by Dr. Butler and colleagues, Dr. Nauck provides a defense of incretin-based therapies and that the benefits clearly outweigh any concern of risk. PMID- 23645886 TI - Randomized trial of continuous subcutaneous delivery of exenatide by ITCA 650 versus twice-daily exenatide injections in metformin-treated type 2 diabetes. AB - OBJECTIVE: To evaluate ITCA 650, a continuous subcutaneous miniature osmotic pump delivery system of exenatide versus twice-daily exenatide injections (Ex-BID) in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a randomized, two-stage, 24-week, open-label, phase 2 study in type 2 diabetes inadequately controlled with metformin. Stage I: 155 subjects were randomized to 20 or 40 MUg/day of ITCA 650 or Ex-BID 5 -> 10 MUg. Stage II: 131 subjects were rerandomized to 20, 40, 60, or 80 MUg/day of ITCA 650. Change from baseline for HbA1c, weight, and fasting plasma glucose were evaluated at weeks 12 and 24. RESULTS: HbA1c was significantly lower in all groups after 12 and 24 weeks. Stage I: mean change in HbA1c from a mean baseline of 7.9-8.0% was -0.98, -0.95, and 0.72% for the 20 and 40 MUg/day ITCA 650 and Ex-BID groups, respectively, with 63, 65, and 50% of subjects achieving HbA1c levels <= 7% (P < 0.05). Stage II: significant (P < 0.05) reductions in HbA1c (~ 1.4% from baseline) were achieved with 60 and 80 MUg/day ITCA 650, and 86 and 78% of subjects achieved HbA1c <= 7% at 24 weeks; respectively. Weight was reduced by 2.8-3.7 kg (P < 0.05) at 24 weeks in all except the 20 -> 20 MUg/day group. ITCA 650 was well tolerated; nausea was lower and transient with 20 MUg/day relative to Ex-BID; and 60 MUg/day had the best profile of tolerability and HbA1c lowering. CONCLUSIONS: ITCA 650 significantly reduced HbA1c and weight and was well tolerated. The 20 -> 60 MUg/day regimen was considered the best dose for further examination in phase 3. PMID- 23645887 TI - Loss of population data sources when health systems are not responsible for geographically defined populations: implications of the Health and Social Care Act of 2012 in England. AB - Biomedical health services and health systems research require timely, complete, accurate and accessible data relating to geographical populations in order to facilitate needs assessment and planning of medical care, new medicines and technology. The international trend towards competition and privatisation has largely proceeded as if data generation were immune to market fragmentation and loss of universal coverage. By examining recent reforms to the English National Health Service, the authors show that this is not the case. Routine and population data are products of administrative systems and the nature, completeness and quality of data available to clinical and public health researchers are substantially impaired by market reforms. PMID- 23645888 TI - Meta-analysis shows limited benefit of lowering blood pressure below 130/80 mm Hg in patients with type 2 diabetes. PMID- 23645889 TI - Coronary revascularisation in patients with diabetes: a chance to be better. PMID- 23645891 TI - Administrators need clinical experience. PMID- 23645892 TI - Sex discrimination claim is wrong in unfair dismissal case. PMID- 23645893 TI - Judgment in unfair dismissal case discriminates against other workers. PMID- 23645894 TI - The devil is in the detail of the government's response to the Francis report. PMID- 23645895 TI - The government's response to the Francis report does not mention death certification and inquests. PMID- 23645896 TI - The (political) science of salt revisited. PMID- 23645897 TI - Killing the Quality and Outcomes Framework won't decrease prescribing for depression. PMID- 23645898 TI - Asking older patients about their memory is simply practising evidence based medicine properly. PMID- 23645899 TI - Understanding H7N9 avian flu. PMID- 23645900 TI - Maintenance treatment is not rocket science. PMID- 23645901 TI - NCAS performance assessment is seriously flawed. PMID- 23645902 TI - US approves "morning after" pill without prescription for women 15 years or older. PMID- 23645903 TI - NHS England announces inquiry into ailing 111 service. PMID- 23645904 TI - Minimum alcohol price is compatible with EU law, says Scottish court. PMID- 23645905 TI - NHS referrals and children's surgery are suspended at BMI Healthcare's Mount Alvernia Hospital. PMID- 23645906 TI - Cord milking at delivery improves the iron status of term infants at 6 weeks. PMID- 23645908 TI - Body mass index and perioperative complications after oesophagectomy for adenocarcinoma: a systematic database review. AB - OBJECTIVE: Given the increasing rate of obesity, the effects of excessive body weight on surgical outcomes constitute a relevant quality of care concern. Our aim was to determine the relationship between preoperative body mass index (BMI) on perioperative complications after oesophagectomy for adenocarcinoma of the oesophagus. DESIGN: Retrospective database review. SETTING: Single institution high volume oncological tertiary care referral centre. PARTICIPANTS: From our comprehensive oesophageal cancer database consisting of 709 patients, we stratified patients according to BMI: 155 normal-weight (BMI 20-24), 198 overweight (BMI 25-29) and 187 obese (BMI >=30) patients. INTERVENTIONS: All patients underwent oesophagectomy for cancer. PRIMARY AND SECONDARY OUTCOME MEASURES: Incidences of preoperative risk factors and perioperative complications in each group were analysed. RESULTS: The patient cohort consisted of 474 men and 66 women with a mean age of 64.3 years (28-86). They were similar in terms of demographics and comorbidities, with the exception of a younger age (65.2 vs 65.4 vs 62.5 years, p=0.0094), and a higher incidence of diabetes (9.1% vs 13.2% vs 22.7%, p=0.001), hiatal hernia (16.8% vs 17.8% vs 28.8%, p=0.009) and Barrett oesophagus (24.7% vs 25.4% vs 36.2%, p=0.025) for obese patients. The type of surgery performed, overall blood loss, extent of lymphadenectomy, R0 resections and complications were not influenced by BMI on univariate and multivariate analysis. CONCLUSIONS: In our experience, patients with an elevated BMI and oesophageal adenocarcinoma do not experience an increase in morbidity and mortality after oesophagectomy as stated in previous reports, when performed at a high volume centre. Additionally, BMI did not affect the quality of oncological resection as determined by number of harvested lymph-nodes and rates of R0 resections. TRIAL REGISTRATION: MCC 15030, IRB 105286. PMID- 23645909 TI - A systematic review of the effect of red blood cell transfusion on mortality: evidence from large-scale observational studies published between 2006 and 2010. AB - OBJECTIVE: To carry out a systematic review of recently published large-scale observational studies assessing the effects of red blood cell transfusion (RBCT) on mortality, with particular emphasis on the statistical methods used to adjust for confounding. Given the limited number of randomised trials of the efficacy of RBCT, clinicians often use evidence from observational studies. However, confounding factors, for example, individuals receiving blood generally being sicker than those who do not, make their interpretation challenging. DESIGN: Systematic review. INFORMATION SOURCES: We searched MEDLINE and EMBASE for studies published from 1 January 2006 to 31 December 2010. ELIGIBILITY CRITERIA FOR INCLUDED STUDIES: We included prospective cohort, case-control studies or retrospective analyses of databases or disease registers where the effect of risk factors for mortality or survival was examined. Studies must have included more than 1000 participants receiving RBCT for any cause. We assessed the effects of RBCT versus no RBCT and different volumes and age of RBCT. RESULTS: -32 studies were included in the review; 23 assessed the effects of RBCT versus no RBCT; 5 assessed different volumes and 4 older versus newer RBCT. There was a considerable variability in the patient populations, study designs and level of statistical adjustment. Overall, most studies showed a higher rate of mortality when comparing patients who received RBCT with those who did not, even when these rates were adjusted for confounding; the majority of these increases were statistically significant. The same pattern was observed in studies where protection from bias was likely to be greater, such as prospective studies. CONCLUSIONS: Recent observational studies do show a consistently adverse effect of RBCT on mortality. Whether this is a true effect remains uncertain as it is possible that even the best conducted adjustments cannot completely eliminate the impact of confounding. PMID- 23645910 TI - Injecting drug users, sex workers and men who have sex with men: a national cross sectional study to develop a framework and prevalence estimates for national HIV/AIDS programmes in the Republic of Serbia. AB - OBJECTIVE: The aim of this study was to develop a framework and best estimates of prevalence for the most at risk populations (MARPs) for HIV/AIDS to include sex workers (SW), men who have sex with men (MSM) and injecting drug users (IDUs) in order to evaluate national HIV/AIDS programmatic targets across the Republic of Serbia. DESIGN: A national, cross-sectional study and direct enumeration, multiplier and benchmark methods with integrated bio-behavioural surveys, capture/recapture and methods with Wald and Clopper-Pearson CIs were used. SETTING: This study was carried out in the three largest cities and main regions of Serbia, the capital city, Belgrade, (population 1 639 121 persons), the Vojvodina region with main city Novi Sad (population 335 701) and the rest of Serbia with main city Nis (population 257 867). PARTICIPANTS: A total of 1301 respondents from the defined MARPs completed the survey in the 2009/2010 period across the three cities. PRIMARY OUTCOME MEASURES: Estimates of the hidden numbers at risk of HIV/AIDS. RESULTS: It was estimated that there were 1775-6027 SW between 18 and 49 years in Serbia in 2009. For MSM, national estimates for 2009 ranged from 20 789 to 90 104 individuals aged between 20 and 49 years. For IDU, a possible range of 12 682-48 083 individuals aged between 15 and 59 years in 2009 was estimated. CONCLUSIONS: For service planning across Central and Eastern Europe, it is important to highlight how credible estimates can be achieved and compared with numbers within HIV/AIDS-prevention programmes. Within needle exchange programmes, only 5.4-20.5% of the estimated population was observed and this proportion was lower within methadone treatment data. Results have implications for future IDU treatment and HIV incidence and spread across all populations at risk. PMID- 23645911 TI - INvolvement of breast CAncer patients during oncological consultations: a multicentre randomised controlled trial--the INCA study protocol. AB - INTRODUCTION: Studies on patient involvement show that physicians make few attempts to involve their patients who ask few questions if not facilitated. On the other hand, the patients who participate in the decision-making process show greater treatment adherence and have better health outcomes. Different methods to encourage the active participation during oncological consultation have been described; however, similar studies in Italy are lacking. The aims of the present study are to (1) assess the effects of a preconsultation intervention to increase the involvement of breast cancer patients during the consultation, and (2) explore the role of the attending companions in the information exchange during consultation. METHODS AND ANALYSIS: All female patients with breast cancer who attend the Oncology Out-patient Services for the first time will provide an informed consent to participate in the study. They are randomly assigned to the intervention or to the control group. The intervention consists of the presentation of a list of relevant illness-related questions, called a question prompt sheet. The primary outcome measure of the efficacy of the intervention is the number of questions asked by patients during the consultation. Secondary outcomes are the involvement of the patient by the oncologist; the patient's perceived achievement of her information needs; the patient's satisfaction and ability to cope; the quality of the doctor-patient relationship in terms of patient-centeredness; and the number of questions asked by the patient's companions and their involvement during the consultation. All outcome measures are supposed to significantly increase in the intervention group. ETHICS AND DISSEMINATION: The study was approved by the local Ethics Committee of the Hospital Trust of Verona. Study findings will be disseminated through peer reviewed publications and conference presentations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01510964. PMID- 23645912 TI - Job strain and supervisor support in primary care health centres and glycaemic control among patients with type 2 diabetes: a cross-sectional study. AB - OBJECTIVES: This study investigates associations between healthcare personnel's perceived job strain, supervisor support and the outcome of care in terms of glycaemic control among patients with type 2 diabetes. DESIGN: A cross-sectional study from 2006. SETTING: 18 primary care health centres (HCs) from five municipalities in Finland. PARTICIPANTS: Aggregated survey data on perceived job strain and supervisor support from healthcare personnel (doctors, n=122, mean age 45.5 years, nurses, n=300, mean age 47.1 years) were combined with registered data (Electronic Medical Records) from 8975 patients (51% men, mean age 67 years) with type 2 diabetes. OUTCOME MEASURE: Poor glycaemic control (glycated haemoglobin (HbA1c) >=7%). RESULTS: The mean HbA1c level among patients with type 2 diabetes was 7.1 (SD 1.2, range 4.5-19.1), and 43% had poor glycaemic control (HbA1c >=7%). Multilevel logistic regression analyses, adjusted for patient's age and sex, and HC and HC service area-level characteristics, showed that patients' HbA1c-levels were less optimal in high-strain HCs than in low-strain HCs (OR 1.44, 95% CI 1.12 to 1.86). Supervisor support in HCs was not associated with the outcome of care. CONCLUSIONS: The level of job strain among healthcare personnel may play a role in achieving good glycaemic control among patients with type 2 diabetes. PMID- 23645913 TI - A cross-sectional survey of healthcare professionals to determine what they believe constitutes 'specialist' care for teenage and young adult patients with cancer. AB - OBJECTIVES: To examine the attitudes of UK healthcare professionals towards what they believe constitutes specialist care for teenage and young adult (TYA) patients with cancer, to determine which factors they considered to be the most important components of specialist TYA care, and whether opinion varied between clinical specialties and reflected the drivers for care improvements within National Health Service (NHS) policy. DESIGN AND METHODS: The study utilised a cross-sectional survey, using Likert scales, to assess attitudes towards specialist care. Responses were grouped using model-based clustering methods implemented in LatentGold 4.5. SETTING: Participants from 98 NHS trusts in the UK were invited to participate in the study. PARTICIPANTS: 691 healthcare professionals involved in the management of TYA patients were approached; of these, 338 responded. RESULTS: 338 healthcare professionals responded (51.9% of those invited). Responses were grouped into three clusters according to the pattern of responses to the questions. One cluster rated age-appropriate care above all else, the second rated both age and site-appropriate care highly while the third assigned more importance to site-specific care. Overall, the psychosocial and supportive aspects of care were rated highest while statements relating to factors known to be important (access to clinical trials, treatment at a high volume centre and specialist diagnostics) were not rated as highly as expected. CONCLUSIONS: Attitudes varied widely between professionals treating TYA patients with cancer as to what constitutes key aspects of specialist care. Further work is needed to quantify the extent to which this influences practice. PMID- 23645914 TI - Publication rate for funded studies from a major UK health research funder: a cohort study. AB - OBJECTIVES: This study aimed to investigate what percentage of National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme-funded projects have published their final reports in the programme's journal HTA and to explore reasons for non-publication. DESIGN: Retrospective cohort study. SETTING: Failure to publish findings from research is a significant area of research waste. It has previously been suggested that potentially over 50% of studies funded are never published. PARTICIPANTS: All NIHR HTA projects with a planned submission date for their final report for publication in the journal series on or before 9 December 2011 were included. PRIMARY AND SECONDARY OUTCOME MEASURES: The projects were classified according to the type of research, whether they had been published or not; if not yet published, whether they would be published in the future or not. The reasons for non-publication were investigated. RESULTS: 628 projects were included: 582 (92.7%) had published a monograph; 19 (3%) were expected to publish a monograph; 13 (2.1%) were discontinued studies and would not publish; 12 (1.9%) submitted a report which did not lead to a publication as a monograph; and two (0.3%) did not submit a report. Overall, 95.7% of HTA studies either have published or will publish a monograph: 94% for those commissioned in 2002 or before and 98% for those commissioned after 2002. Of the 27 projects for which there will be no report, the majority (21) were commissioned in 2002 or before. Reasons why projects failed to complete included failure to recruit; issues concerning the organisation where the research was taking place; drug licensing issues; staffing issues; and access to data. CONCLUSIONS: The percentage of HTA projects for which a monograph is published is high. The advantages of funding organisations requiring publication in their own journal include avoidance of publication bias and research waste. PMID- 23645915 TI - Influenza-like illness in acute myocardial infarction patients during the winter wave of the influenza A H1N1 pandemic in London: a case-control study. AB - OBJECTIVE: To investigate recent respiratory and influenza-like illnesses (ILIs) in acute myocardial infarction patients compared with patients hospitalised for acute non-vascular surgical conditions during the second wave of the 2009 influenza A H1N1 pandemic. DESIGN: Case-control study. SETTING: Coronary care unit, acute cardiology and acute surgical admission wards in a major teaching hospital in London, UK. PARTICIPANTS: 134 participants (70 cases and 64 controls) aged >=40 years hospitalised for acute myocardial infarction and acute surgical conditions between 21 September 2009 and 28 February 2010, frequency-matched for gender, 5-year age-band and admission week. PRIMARY EXPOSURE: ILI (defined as feeling feverish with either a cough or sore throat) within the last month. SECONDARY EXPOSURES: Acute respiratory illness within the last month not meeting ILI criteria; nasopharyngeal and throat swab positive for influenza virus. RESULTS: 29 of 134 (21.6%) participants reported respiratory illness within the last month, of whom 13 (9.7%) had illnesses meeting ILI criteria. The most frequently reported category for timing of respiratory symptom onset was 8-14 days before admission (31% of illnesses). Cases were more likely than controls to report ILI-adjusted OR 3.17 (95% CI 0.61 to 16.47)-as well as other key respiratory symptoms, and were less likely to have received influenza vaccination adjusted OR 0.46 (95% CI 0.19 to 1.12)-although the differences were not statistically significant. No swabs were positive for influenza virus. CONCLUSIONS: Point estimates suggested that recent ILI was more common in patients hospitalised with acute myocardial infarction than with acute surgical conditions during the second wave of the influenza A H1N1 pandemic, and influenza vaccination was associated with cardioprotection, although the findings were not statistically significant. The study was underpowered, partly because the age groups typically affected by acute myocardial infarction had low rates of infection with the pandemic influenza strain compared with seasonal influenza. PMID- 23645916 TI - Comparison of health confidence in rural, suburban and urban areas in the UK and the USA: a secondary analysis. AB - OBJECTIVE: Confidence in healthcare may influence the patients' utilisation of healthcare resources and perceptions of healthcare quality. We sought to determine whether self-reported confidence in healthcare differed between the UK and the USA, as well as by rurality or urbanicity. DESIGN: A secondary analysis of a subset of survey questions regarding self-reported confidence in healthcare from the 2010 Commonwealth Fund International Health Policy Survey. SETTING: Telephone survey of participants from the UK and the USA. PARTICIPANTS: Our final analysis included 1511 UK residents (688 rural, 446 suburban, 372 urban, 5 uncategorised) and 2501 US residents (536 rural, 1294 suburban, 671 urban). OUTCOME MEASURES: Questions assessed respondents' confidence in the effectiveness and affordability of the treatment. We compared survey outcomes from these questions between, and within, the two regions and among, and within, residence types (rural, suburban and urban). RESULTS: Significant differences were found in self-reported confidence in healthcare between the UK and US, among residence types, and between the two regions within residence types. Reported levels were higher in the UK. Within regions, significant differences by residence type were found for the US, but not the UK. Within the US, suburban respondents had the highest self-reported confidence in healthcare. CONCLUSIONS: Significant differences exist between the UK and US in confidence in healthcare. In the US, but not in the UK, self-reported confidence is related to residence type. Within countries, significant differences by residence type were found for the US, but not the UK. Our findings warrant the examination of causes for relative confidence levels in healthcare between regions and among US residence types. PMID- 23645907 TI - Novel insights on thyroid-stimulating hormone receptor signal transduction. AB - The TSH receptor (TSHR) is a member of the glycoprotein hormone receptors, a subfamily of family A G protein-coupled receptors. The TSHR is of great importance for the growth and function of the thyroid gland. The TSHR and its endogenous ligand TSH are pivotal proteins with respect to a variety of physiological functions and malfunctions. The molecular events of TSHR regulation can be summarized as a process of signal transduction, including signal reception, conversion, and amplification. The steps during signal transduction from the extra- to the intracellular sites of the cell are not yet comprehensively understood. However, essential new insights have been achieved in recent years on the interrelated mechanisms at the extracellular region, the transmembrane domain, and intracellular components. This review contains a critical summary of available knowledge of the molecular mechanisms of signal transduction at the TSHR, for example, the key amino acids involved in hormone binding or in the structural conformational changes that lead to G protein activation or signaling regulation. Aspects of TSHR oligomerization, signaling promiscuity, signaling selectivity, phenotypes of genetic variations, and potential extrathyroidal receptor activity are also considered, because these are relevant to an understanding of the overall function of the TSHR, including physiological, pathophysiological, and pharmacological perspectives. Directions for future research are discussed. PMID- 23645917 TI - Do social interactions explain ethnic differences in psychological distress and the protective effect of local ethnic density? A cross-sectional study of 226 487 adults in Australia. AB - BACKGROUND: A frequently proposed, but under-researched hypothesis is that ethnic density benefits mental health through increasing social interactions. We examined this hypothesis in 226 487 adults from 19 ethnic groups aged 45 years and older in Australia. METHODS: Multilevel logit regression was used to measure the association between ethnicity, social interactions, own-group ethnic density and scores of 22+ on the Kessler scale of psychological distress. Self-reported ancestry was used as a proxy for ethnicity. Measures of social interactions included a number of times in the past week were (i) spent with friends or family participants did not live with; (ii) talked to someone on the telephone; (iii) attended meetings of social groups and (iv) how many people could be relied upon outside their home, but within 1 h of travel. Per cent own-group ethnic density was measured at the Census Collection District scale. RESULTS: Psychological distress was reported by 11% of Australians born in Australia. The risk of experiencing psychological distress varied among ethnic minorities and by country of birth (eg, 33% for the Lebanese born in Lebanon and 4% for the Swiss born in Switzerland). These differences remained after full adjustment. Social interactions varied between ethnic groups and were associated with lower psychological distress and ethnic density. Ethnic density was associated with reduced psychological distress for some groups. This association, however, was explained by individual and neighbourhood characteristics and not by social interactions. CONCLUSIONS: Social interactions are important correlates of mental health, but fully explain neither the ethnic differences in psychological distress nor the protective effect of own-group density. PMID- 23645918 TI - Role of public and private funding in the rising caesarean section rate: a cohort study. AB - OBJECTIVE: The caesarean section rates have been rising in the developed world for over two decades. This study assessed the involvement of the public and private health sectors in this increase. DESIGN: Population-based, retrospective cohort study. SETTING: Public and private hospitals in Western Australia. PARTICIPANTS: Included in this study were 155 646 births to nulliparous women during 1996-2008. MAIN OUTCOME MEASURES: Caesarean section rates were calculated separately for four patient type groups defined according to mothers' funding source at the time of birth (public/private) and type of delivery hospital (public/private). The average annual per cent change (AAPC) for the caesarean section rates was calculated using joinpoint regression. RESULTS: Overall, there were 45 903 caesarean sections performed (29%) during the study period, 24 803 in labour and 21 100 prelabour. Until 2005, the rate of caesarean deliveries increased most rapidly on average annually for private patients delivering in private hospitals (AAPC=6.5%) compared with public patients in public hospitals (AAPC=4.3%, p<0.0001). This increase could mostly be attributed to an increase in prelabour caesarean deliveries for this group of women and could not be explained by an increase in breech deliveries, placenta praevia or multiple pregnancies. CONCLUSIONS: Our results indicate that an increase in the prelabour caesarean delivery rate for private patients in private hospitals has been driving the increase in the caesarean section rate for nulliparous women since 1996. Future research with more detailed information on indication for the prelabour caesarean section is needed to understand the reasons for these findings. PMID- 23645920 TI - Access to medicines in Latin America and the Caribbean (LAC): a scoping study. AB - OBJECTIVE: To assess scientific publication and map research gaps on access to medicines (ATM) in Latin American and the Caribbean low-income and middle-income countries (LMIC). DESIGN: Scoping review. Two independent reviewers assessed studies for inclusion and extracted data from each study. INFORMATION SOURCES: Search strategies were developed and the following databases were searched: MEDLINE, ISI, SCOPUS and Lilacs, from 2000 to 2010. ELIGIBILITY CRITERIA: Research articles and reviews published in English, Spanish and Portuguese were included. Studies including only high-income countries were excluded, as well as those carried out in very limited settings and discussion papers. RESULTS: The 77 articles retained were categorised through consensus among the research team according to the level of the health system addressed, ATM domain and research issues covered. Publications on ATM have increased over time during the study period (r 0.93, p=0.00; R(2) 0.85). The top five countries covered were Brazil (68.8%), Mexico (15.6%), Colombia (11.7%), Argentina (10.4%) and Peru (10.4%). 'Health services delivery' and 'patients, household and communities' were the health system levels most frequently covered. The ATM domains 'leadership and governance', 'sustainable financing, affordability and price of medicines', 'medicines selection and use' and 'availability of medicines' were the top four explored. There are research gaps in important areas such as 'human resources for health', 'global policies and human rights', 'production of medicines' and 'traditional medicine'. CONCLUSIONS: The upward trend on scientific publication reflects a growing research capacity in the region, which is concentrated on research teams in selected countries. The gaps on research capacity could be overcome through research collaboration among countries. It is important to strengthen these collaborations, assuring that interests and needs from the LMIC are addressed and local capacity building is promoted. PMID- 23645919 TI - A survey of attitudes of glaucoma subspecialists in England and Wales to visual field test intervals in relation to NICE guidelines. AB - OBJECTIVES: To establish the attitudes of glaucoma specialists to the frequency of visual field (VF) testing in the UK, using the NICE recommendations as a standard for ideal practice. DESIGN: Interview and postal survey. SETTING: UK and Eire Glaucoma Society national meeting 2011 in Manchester, UK, with a second round of surveys administered by post. PARTICIPANTS: All consultant glaucoma specialists in England and Wales were invited to complete the survey. PRIMARY AND SECONDARY OUTCOME MEASURES: (1) Compliance of assigned follow-up VF intervals with NICE guidelines for three hypothetical patient scenarios, with satisfactory treated intraocular pressure and (a) no evidence of VF progression; (b) evidence of VF progression and (c) uncertainty about VF progression, and respondents were asked to provide typical follow-up intervals representative of their practice; (2) attitudes to research recommendations for six VF in the first 2 years for newly diagnosed patients with glaucoma. RESULTS: 70 glaucoma specialists completed the survey. For each of the clinical scenarios a, b and c, 14 (20%), 33 (47%) and 28 (40%) responses, respectively, fell outside the follow-up interval recommended by NICE. Nearly half of the specialists (46%) agreed that 6 VF tests in the first 2 years was ideal practice, while 16 (28%) said this was practice 'not possible', with many giving resources within the NHS setting as a limiting factor. CONCLUSIONS: The results from this survey suggest that there is a large variation in attitudes to follow-up intervals for patients with glaucoma in the UK, with assigned intervals for VF testing which are, in many cases, inconsistent with the guidelines from NICE. PMID- 23645921 TI - Differences in drug utilisation between men and women: a cross-sectional analysis of all dispensed drugs in Sweden. AB - OBJECTIVES: Ascertain the extent of differences between men and women in dispensed drugs since there is a lack of comprehensive overviews on sex differences in the use of prescription drugs. DESIGN: Cross-sectional population database analysis. METHODS: Data on all dispensed drugs in 2010 to the entire Swedish population (9.3 million inhabitants) were obtained from the Swedish Prescribed Drug Register. All pharmacological groups with ambulatory care prescribing accounting for >75% of the total volume in Defined Daily Doses and a prevalence of >1% were included in the analysis. Crude and age-adjusted differences in prevalence and incidence were calculated as risk ratios (RRs) of women/men. RESULTS: In all, 2.8 million men (59%) and 3.6 million women (76%) were dispensed at least one prescribed drug during 2010. Women were dispensed more drugs in all age groups except among children under the age of 10. The largest sex difference in prevalence in absolute numbers was found for antibiotics that were more common in women, 265.5 patients (PAT)/1000 women and 191.3 PAT/1000 men, respectively. This was followed by thyroid therapy (65.7 PAT/1000 women and 13.1 PAT/1000 men) and antidepressants (106.6 PAT/1000 women and 55.4 PAT/1000 men). Age-adjusted relative sex differences in prevalence were found in 48 of the 50 identified pharmacological groups. The pharmacological groups with the largest relative differences of dispensed drugs were systemic antimycotics (RR 6.6 CI 6.4 to 6.7), drugs for osteoporosis (RR 4.9 CI 4.9 to 5.0) and thyroid therapy (RR 4.5 CI 4.4 to 4.5), which were dispensed to women to a higher degree. Antigout agents (RR 0.4 CI 0.4 to 0.4), psychostimulants (RR 0.6 CI 0.6 to 0.6) and ACE inhibitors (RR 0.7 CI 0.7 to 0.7) were dispensed to men to a larger proportion. CONCLUSIONS: Substantial differences in the prevalence and incidence of dispensed drugs were found between men and women. Some differences may be rational and desirable and related to differences between the sexes in the incidence or prevalence of disease or by biological differences. Other differences are more difficult to explain on medical grounds and may indicate unequal treatment. PMID- 23645922 TI - Living with HIV postdiagnosis: a qualitative study of the experiences of Nairobi slum residents. AB - OBJECTIVES: To characterise the experiences of heterosexual men and women living with HIV postdiagnosis and explain these experiences in relation to their identity and sexuality. DESIGN: Qualitative study using in-depth interviews and a theoretically informed biographic disruption theory. SETTING: Interviews were conducted in two Nairobi slums (Kenya). PARTICIPANTS: 41 HIV-infected heterosexual men and women aged 18 years or older. RESULTS: People living with HIV have divergent experiences surrounding HIV diagnosis. Postdiagnosis, there are multiple phases of identity transition, including status (non-)disclosure, and attempts at identity repair and normalcy. For some people, this process involves a transition to a new self-identity, incorporating both HIV and antiretroviral treatment (ART) into their lives. For others, it involves a partial transition, with some aspects of their prediagnosis identity persisting, and for others it involves a rejection of HIV identity. Those people who were able to incorporate HIV/AIDS in their identity, without it being disruptive to their biography, were pursuing safer sexual and reproductive lives. By contrast, those people with a more continuous biography continued to reflect their prediagnosis identity and sexual behaviour. CONCLUSIONS: People living with HIV/AIDS (PLWHA) had to rework their sense of identity following diagnosis in the context of living in a slum setting. Men and women living with HIV in slums are poorly supported by health systems and services as they attempt to cope with a diagnosis of HIV. Given the availability of ART, health services and professionals need to support the rights of PLWHA to be sexually active if they want to and achieve their fertility goals, while minimising HIV transmission risk. PMID- 23645923 TI - Overactive bladder symptom severity is associated with falls in community dwelling adults: LOHAS study. AB - OBJECTIVES: To examine the association between overactive bladder (OAB) symptom severity and falls and the contribution of OAB symptoms to falls in a community dwelling population. DESIGN: Cross-sectional study. SETTING: 2 Japanese municipalities. PARTICIPANTS: A total of 2505 residents aged over 40 years, who participated in health check-ups conducted in 2010. OAB symptom assessed via overactive bladder symptom score (OABSS) was divided into six categories based on distribution and Japanese clinical guidelines. Mobility problems and depressive symptoms were assessed via the Timed Up and Go test and the short form of the Center for Epidemiologic Studies Depression Scale, respectively. PRIMARY OUTCOME MEASURES: Self-reported any fall and frequent fall (>=2) over the 1-month period. Independent contributions to any fall and frequent falls were assessed via logistic regression to generate population-attributable fractions (PAFs), assuming separate causal relationships between OAB symptoms, mobility problems and depressive symptoms and any or frequent falls. RESULTS: Among the total 1350 participants (mean age: 68.3 years) analysed, any fall and frequent falls were reported by 12.7% and 4.4%, respectively. Compared with no OABSS score, moderate to-severe OAB and mild OAB were associated with any fall (adjusted ORs 2.37 (95% CI 1.12 to 4.98) and 2.51 (95% CI 1.14 to 5.52), respectively). Moderate-to severe OAB was also strongly associated with frequent falls (adjusted OR 6.90 (95% CI 1.50 to 31.6)). Adjusted PAFs of OAB symptoms were 40.7% (95% CI 0.7% to 64.6%) for any fall and 67.7% (95% CI -23.1% to 91.5%) for frequent falls. Further, these point estimates were similar to or larger than those of mobility problems and depressive symptoms. CONCLUSIONS: An association does indeed exist between OAB symptom severity and falls, and OAB symptoms might be important contributors to falls among community-dwelling adults. Further longitudinal studies are warranted to examine whether or not OAB symptoms predict risk of future falls and fall-related injuries. PMID- 23645924 TI - Nodding syndrome in Ugandan children--clinical features, brain imaging and complications: a case series. AB - OBJECTIVES: Nodding syndrome is a devastating neurological disorder of uncertain aetiology affecting children in Africa. There is no diagnostic test, and risk factors and symptoms that would allow early diagnosis are poorly documented. This study aimed to describe the clinical, electrophysiological and brain imaging (MRI) features and complications of nodding syndrome in Ugandan children. DESIGN: Case series. PARTICIPANTS: 22 children with nodding syndrome brought to Mulago National Referral Hospital for assessment. OUTCOME MEASURES: Clinical features, physical and functional disabilities, EEG and brain MRI findings and a staging system with a progressive development of symptoms and complications. RESULTS: The median age of symptom onset was 6 (range 4-10) years and median duration of symptoms was 8.5 (range 2-11) years. 16 of 22 families reported multiple affected children. Physical manifestations and complications included stunting, wasting, lip changes and gross physical deformities. The bone age was delayed by 2 (range 1-6) years. There was peripheral muscle wasting and progressive generalised wasting. Four children had nodding as the only seizure type; 18 in addition had myoclonic, absence and/or generalised tonic-clonic seizures developing 1-3 years after the onset of illness. Psychiatric manifestations included wandering, aggression, depression and disordered perception. Cognitive assessment in three children demonstrated profound impairment. The EEG was abnormal in all, suggesting symptomatic generalised epilepsy in the majority. There were different degrees of cortical and cerebellar atrophy on brain MRI, but no hippocampal changes. Five stages with worsening physical, EEG and brain imaging features were identified: a prodrome, the development of head nodding and cognitive decline, other seizure types, multiple complications and severe disability. CONCLUSIONS: Nodding syndrome is a neurological disorder that may be characterised as probably symptomatic generalised epilepsy. Clinical manifestations and complications develop in stages which might be useful in defining treatment and rehabilitation. Studies of risk factors, pathogenesis, management and outcome are urgently needed. PMID- 23645925 TI - Assessing the short-term outcomes of a community-based intervention for overweight and obese children: The MEND 5-7 programme. AB - OBJECTIVE: The aim of this study was to report outcomes of the UK service level delivery of MEND (Mind,Exercise,Nutrition...Do it!) 5-7, a multicomponent, community-based, healthy lifestyle intervention designed for overweight and obese children aged 5-7 years and their families. DESIGN: Repeated measures. SETTING: Community venues at 37 locations across the UK. PARTICIPANTS: 440 overweight or obese children (42% boys; mean age 6.1 years; body mass index (BMI) z-score 2.86) and their parents/carers participated in the intervention. INTERVENTION: MEND 5-7 is a 10-week, family-based, child weight-management intervention consisting of weekly group sessions. It includes positive parenting, active play, nutrition education and behaviour change strategies. The intervention is designed to be scalable and delivered by a range of health and social care professionals. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was BMI z-score. Secondary outcome measures included BMI, waist circumference, waist circumference z-score, children's psychological symptoms, parenting self-efficacy, physical activity and sedentary behaviours and the proportion of parents and children eating five or more portions of fruit and vegetables. RESULTS: 274 (62%) children were measured preintervention and post-intervention (baseline; 10-weeks). Post intervention, mean BMI and waist circumference decreased by 0.5 kg/m(2) and 0.9 cm, while z-scores decreased by 0.20 and 0.20, respectively (p<0.0001). Improvements were found in children's psychological symptoms (-1.6 units, p<0.0001), parent self-efficacy (p<0.0001), physical activity (+2.9 h/week, p<0.01), sedentary activities (-4.1 h/week, p<0.0001) and the proportion of parents and children eating five or more portions of fruit and vegetables per day (both p<0.0001). Attendance at the 10 sessions was 73% with a 70% retention rate. CONCLUSIONS: Participation in the MEND 5-7 programme was associated with beneficial changes in physical, behavioural and psychological outcomes for children with complete sets of measurement data, when implemented in UK community settings under service level conditions. Further investigation is warranted to establish if these findings are replicable under controlled conditions. PMID- 23645926 TI - Dabigatran use in Danish atrial fibrillation patients in 2011: a nationwide study. AB - OBJECTIVE: Dabigatran was recently approved for anticoagulation in patients with atrial fibrillation (AF); data regarding real-world use, comparative effectiveness and safety are sparse. DESIGN: Pharmacoepidemiological cohort study. METHODS/SETTINGS: From nationwide registers, we identified patients with an in-hospital or outpatient-clinic AF diagnosis who claimed a prescription of dabigatran 110 or 150 mg, or vitamin K antagonist (VKA), between 22 August and 31 December 2011. HRs of thromboembolic events (ischaemic stroke, transitory ischaemic attack and peripheral artery embolism) and bleedings were estimated using Cox regression analyses in all patients and stratified by previous VKA use. RESULTS: Overall, 1612 (3.1%) and 1114 (2.1%) patients claimed a prescription of dabigatran 110 and 150 mg, and 49640 (94.8%) of VKA. Patients treated with dabigatran 150 mg were younger with less comorbidity than those treated with dabigatran 110 mg and VKA, as were VKA naive patients compared with previous VKA users. Recommendations set by the European Medicine Agency (EMA) for dabigatran were met in 90.3% and 55.5% of patients treated with 110 and 150 mg. Patients treated with 150 mg dabigatran, who did not fulfil the recommendations by EMA, were >80 years, patients with liver or kidney disease, patients with previous bleeding. Compared with VKA, the thromboembolic risk associated with dabigatran 110 and 150 mg was HR 3.52 (1.40 to 8.84) and 5.79 (1.81 to 18.56) in previous VKA users, and HR 0.95(0.47 to 1.91) and 1.14(0.60 to 2.16) in VKA naive patients. Bleeding risk was increased in previous VKA users receiving dabigatran 110 mg, but not in patients with 150 mg dabigatran, nor in the VKA naive users. CONCLUSIONS: Deviations from the recommended use of dabigatran were frequent among patients treated with 150 mg. With cautious interpretation, dabigatran use in VKA naive patients seems safe. Increased risk of thromboembolism and bleeding with dabigatran among previous VKA users was unexpected and may reflect patient selection and 'drug switching' practices. PMID- 23645927 TI - Morality: incomplete without the cerebellum? PMID- 23645929 TI - Non-invasive method for rapid bedside estimation of inotropy: theory and preliminary clinical validation. AB - BACKGROUND: There are numerous techniques which attempt to quantify inotropy (or myocardial contractility). None has yet found general acceptance in anaesthesia and critical care as a practical method. We report a novel approach to the determination of inotropy as a bedside procedure which could identify low inotropy states in patients with clinical heart failure. METHODS: We estimated the potential and kinetic energy delivered by the left ventricle using continuous wave Doppler ultrasound (ultrasonic cardiac output monitor, Uscom, Sydney, Australia) and data available at the point of care. A formula to calculate effective inotropy [Smith-Madigan inotropy index (SMII)] was tested against historical haemodynamic data for 250 control subjects (ASA I patients from preoperative clinic) and 83 patients with acute left ventricular failure (LVF) of New York Heart Association Grade 4 (LVF group). The ratio of potential to kinetic energy (PKR) was investigated as a measure of arterial impedance. RESULTS: Significant differences were found between the control and LVF groups for cardiac index, mean (range)=3.37 (2.84-5.32) vs 1.84 (1.43-2.26) litre min(-1) m(-2); stroke volume index (SVI), 49.2 (39-55) vs 34.3 (23-37) ml m(-2); systemic vascular resistance, 893 (644-1242) vs 1960 (1744-4048) dyn s cm(-5); SMII, 1.78 (1.35-2.24) vs 0.73 (0.43-0.97) W m(-2); and PKR, 29:1 (24-35:1) vs 124:1 (96 174:1), P<0.001 in each case. Normal ranges were calculated for SMII and PKR as mean (+/-1.96) standard deviations, yielding 1.6-2.2 W m(-2) for SMII, and 25 34:1 for PKR. CONCLUSION: The method clearly identified the two clinical groups with no overlap of data points. The discriminant power of SMII and PKR may offer valuable diagnostic methods and monitoring tools in anaesthesia and critical care. This is the first report of normal ranges for SMII and PKR. PMID- 23645931 TI - Home is Hard to Find: Neighborhoods, Institutions, and the Residential Trajectories of Returning Prisoners. AB - Poor urban communities experience high rates of incarceration and prisoner reentry. This paper examines the residences where former prisoners live after prison, focusing on returns to pre-prison social environments, residential mobility, and the role of intermediate sanctions. Drawing on a unique dataset that follows a cohort of Michigan parolees released in 2003 over time using administrative records, we examine returns to pre-prison environments, both immediately after prison and in the months and years after release. We then investigate the role of intermediate sanctions - punishments for parole violations that are less severe than returning to prison - in residential mobility among parolees. Our results show low rates of return to former neighborhoods and high rates of residential mobility after prison, a significant portion of which is driven by intermediate sanctions resulting from criminal justice system supervision. These results suggest that, through parole supervision, the criminal justice system generates significant residential mobility. PMID- 23645932 TI - Bright Futures in Malawi's New Dawn: Educational Aspirations as Assertions of Identity. AB - Imagined futures, once a vital topic of theoretical inquiry within the sociology of culture, have been sidelined in recent decades. Rational choice models cannot explain the seemingly irrational optimism of youth aspirations, pointing to the need to explore other alternatives. This article incorporates insights from pragmatist theory and cognitive sociology to examine the relationship between imagined futures and present actions and experiences in rural Malawi, where future optimism appears particularly unfounded. Drawing from in-depth interviews and archival sources documenting ideological campaigns promoting schooling, the author shows that four elements are understood to jointly produce educational success: ambitious career goals, sustained effort, unflagging optimism, and resistance to temptation. Aspirations should be interpreted not as rational calculations, but instead as assertions of a virtuous identity, claims to be "one who aspires." PMID- 23645930 TI - Chromatin architecture, CCCTC-binding factor, and V(D)J recombination: managing long-distance relationships at antigen receptor loci. AB - The rearrangement of T and B lymphocyte Ag receptor loci occurs within a highly complex chromosomal environment and is orchestrated through complex mechanisms. During the past decade, a large body of literature has highlighted the significance of chromatin architecture at Ag receptor loci in supporting the genomic assembly process: in preparation for recombination, these loci tend to contract and form multiple loops that shorten the distances between gene segments and facilitate recombination events. CCCTC-binding factor, CTCF, has received much attention in this regard since it has emerged as an important regulator of chromatin organization and transcription. In this review, we summarize recent work outlining conformational dynamics at Ag receptor loci during lymphocyte development and we discuss the role of CTCF in Ag receptor locus conformation and repertoire development. PMID- 23645933 TI - Surface modification of plasmonic nanostructured materials with thiolated oligonucleotides in 10 seconds using selective microwave heating. AB - This study demonstrates the proof-of-principle of rapid surface modification of plasmonic nanostructured materials with oligonucleotides using low power microwave heating. Due to their interesting optical and electronic properties, silver nanoparticle films (SNFs, 2 nm thick) deposited onto glass slides were used as the model plasmonic nanostructured materials. Rapid surface modification of SNFs with oligonucleotides was carried out using two strategies (1) Strategy 1: for ss-oligonucleotides, surface hybridization and (2) Strategy 2: for ds oligonucleotides, solution hybridization), where the samples were exposed to 10, 15, 30 and 60 seconds microwave heating. To assess the efficacy of our new rapid surface modification technique, identical experiments carried out without the microwave heating (i.e., conventional method), which requires 24 hours for the completion of the identical steps. It was found that SNFs can be modified with ss and ds-oligonucleotides in 10 seconds, which typically requires several hours of incubation time for the chemisorption of thiol groups on to the planar metal surface using conventional techniques. PMID- 23645934 TI - Quenching of p-Cyanophenylalanine Fluorescence by Various Anions. AB - To expand the spectroscopic utility of the non-natural amino acid p cyanophenylalanine (PheCN), we examine the quenching efficiencies of a series of commonly encountered anions toward its fluorescence. We find that iodide exhibits an unusually large Stern-Volmer quenching constant, making it a convenient choice in PheCN fluorescence quenching studies. Indeed, using the villin headpiece subdomain as a testbed we demonstrate that iodide quenching of PheCN fluorescence offers a convenient means to reveal protein conformational heterogeneity. Furthermore, we show that the amino group of PheCN strongly quenches its fluorescence, suggesting that PheCN could be used as a local pH sensor. PMID- 23645935 TI - The local Dirichlet process. AB - As a generalization of the Dirichlet process (DP) to allow predictor dependence, we propose a local Dirichlet process (lDP). The lDP provides a prior distribution for a collection of random probability measures indexed by predictors. This is accomplished by assigning stick-breaking weights and atoms to random locations in a predictor space. The probability measure at a given predictor value is then formulated using the weights and atoms located in a neighborhood about that predictor value. This construction results in a marginal DP prior for the random measure at any specific predictor value. Dependence is induced through local sharing of random components. Theoretical properties are considered and a blocked Gibbs sampler is proposed for posterior computation in lDP mixture models. The methods are illustrated using simulated examples and an epidemiologic application. PMID- 23645936 TI - Mass Spectrometry-Based Multiplexing for the Analysis of Biomarkers in Drug Development and Clinical Diagnostics- How Much is too Much? AB - Biomarkers, or more specifically molecular markers, can detect biochemical changes associated with disease processes and drug effects before histopathological and pathophysiological changes occur. Multiplexing technologies such as high-performance liquid chromatography/mass spectrometry (LC-MS) allow for the measurement of molecular marker patterns that confer significantly more information than the measurement of a single parameter alone. The use of multiplexing assays for drug development, and as diagnostic tools, is attractive but will require regulatory review and approval and thus requires validation following regulatory guidances. Multiplexing assays always constitute a compromise. The number of analytes that can reasonably be included in a mass spectrometry-based multiplexing assay depend on the physico-chemical properties of the analytes and their integration into a single assay in terms of extraction, HPLC separation, ionization conditions and mass spectrometry detection. Another aspect includes biomedical considerations such as the differences in physiological concentrations of analytes, the required concentration range, and how much variability is acceptable before the clinical utility of a marker is negatively affected. Regulatory considerations include validation and quality control during sample analysis. Current bioanalytical regulatory guidelines have mostly been developed for single drug compounds and are not always adequate for multiplexing molecular marker assays that often quantify endogenous compounds. Specific guidances for multiplexing assays should be developed. Even if it is possible to integrate a wide variety and large number of analytes into a multiplexing assay, it should always be taken into consideration that a set of shorter, more specialized assays, may offer a more manageable and efficient alternative. PMID- 23645937 TI - Seasonal variation in functional properties of microbial communities in beech forest soil. AB - Substrate quality and the availability of nutrients are major factors controlling microbial decomposition processes in soils. Seasonal alteration in resource availability, which is driven by plants via belowground C allocation, nutrient uptake and litter fall, also exerts effects on soil microbial community composition. Here we investigate if seasonal and experimentally induced changes in microbial community composition lead to alterations in functional properties of microbial communities and thus microbial processes. Beech forest soils characterized by three distinct microbial communities (winter and summer community, and summer community from a tree girdling plot, in which belowground carbon allocation was interrupted) were incubated with different 13C-labeled substrates with or without inorganic N supply and analyzed for substrate use and various microbial processes. Our results clearly demonstrate that the three investigated microbial communities differed in their functional response to addition of various substrates. The winter communities revealed a higher capacity for degradation of complex C substrates (cellulose, plant cell walls) than the summer communities, indicated by enhanced cellulase activities and reduced mineralization of soil organic matter. In contrast, utilization of labile C sources (glucose) was lower in winter than in summer, demonstrating that summer and winter community were adapted to the availability of different substrates. The saprotrophic community established in girdled plots exhibited a significantly higher utilization of complex C substrates than the more plant root associated community in control plots if additional nitrogen was provided. In this study we were able to demonstrate experimentally that variation in resource availability as well as seasonality in temperate forest soils cause a seasonal variation in functional properties of soil microorganisms, which is due to shifts in community structure and physiological adaptations of microbial communities to altered resource supply. PMID- 23645939 TI - Functional random effect time-varying coefficient model for longitudinal data. AB - We propose a functional random effect time-varying coefficient model to establish the dynamic relationship between the response and predictor variables in longitudinal data. This model allows us not only to interpret time-varying covariate effects, but also to depict random effects via time-varying profiles that are characterized by functional principal components. We develop the functional profiling-backfitting method to estimate model components, which includes the profiling and backfitting procedures via a set of least squares type estimating equations. Asymptotic properties of the resulting estimator are obtained. Furthermore, we investigate the finite sample performance of the proposed method through simulation studies and present an application to primary biliary cirrhosis data. PMID- 23645940 TI - Estimating Optimal Treatment Regimes from a Classification Perspective. AB - A treatment regime maps observed patient characteristics to a recommended treatment. Recent technological advances have increased the quality, accessibility, and volume of patient-level data; consequently, there is a growing need for powerful and flexible estimators of an optimal treatment regime that can be used with either observational or randomized clinical trial data. We propose a novel and general framework that transforms the problem of estimating an optimal treatment regime into a classification problem wherein the optimal classifier corresponds to the optimal treatment regime. We show that commonly employed parametric and semi-parametric regression estimators, as well as recently proposed robust estimators of an optimal treatment regime can be represented as special cases within our framework. Furthermore, our approach allows any classification procedure that can accommodate case weights to be used without modification to estimate an optimal treatment regime. This introduces a wealth of new and powerful learning algorithms for use in estimating treatment regimes. We illustrate our approach using data from a breast cancer clinical trial. PMID- 23645938 TI - The role of plant-associated bacteria in the mobilization and phytoextraction of trace elements in contaminated soils. AB - Phytoextraction makes use of trace element-accumulating plants that concentrate the pollutants in their tissues. Pollutants can be then removed by harvesting plants. The success of phytoextraction depends on trace element availability to the roots and the ability of the plant to intercept, take up, and accumulate trace elements in shoots. Current phytoextraction practises either employ hyperaccumulators or fast-growing high biomass plants; the phytoextraction process may be enhanced by soil amendments that increase trace element availability in the soil. This review will focus on the role of plant-associated bacteria to enhance trace element availability in the rhizosphere. We report on the kind of bacteria typically found in association with trace element - tolerating or - accumulating plants and discuss how they can contribute to improve trace element uptake by plants and thus the efficiency and rate of phytoextraction. This enhanced trace element uptake can be attributed to a microbial modification of the absorptive properties of the roots such as increasing the root length and surface area and numbers of root hairs, or by increasing the plant availability of trace elements in the rhizosphere and the subsequent translocation to shoots via beneficial effects on plant growth, trace element complexation and alleviation of phytotoxicity. An analysis of data from literature shows that effects of bacterial inoculation on phytoextraction efficiency are currently inconsistent. Some key processes in plant-bacteria interactions and colonization by inoculated strains still need to be unravelled more in detail to allow full-scale application of bacteria assisted phytoremediation of trace element contaminated soils. PMID- 23645941 TI - Bayesian modeling of the dependence in longitudinal data via partial autocorrelations and marginal variances. AB - Many parameters and positive-definiteness are two major obstacles in estimating and modelling a correlation matrix for longitudinal data. In addition, when longitudinal data is incomplete, incorrectly modelling the correlation matrix often results in bias in estimating mean regression parameters. In this paper, we introduce a flexible and parsimonious class of regression models for a covariance matrix parameterized using marginal variances and partial autocorrelations. The partial autocorrelations can freely vary in the interval (-1, 1) while maintaining positive definiteness of the correlation matrix so the regression parameters in these models will have no constraints. We propose a class of priors for the regression coefficients and examine the importance of correctly modeling the correlation structure on estimation of longitudinal (mean) trajectories and the performance of the DIC in choosing the correct correlation model via simulations. The regression approach is illustrated on data from a longitudinal clinical trial. PMID- 23645942 TI - MULTIVARIATE VARYING COEFFICIENT MODEL FOR FUNCTIONAL RESPONSES. AB - Motivated by recent work studying massive imaging data in the neuroimaging literature, we propose multivariate varying coefficient models (MVCM) for modeling the relation between multiple functional responses and a set of covariates. We develop several statistical inference procedures for MVCM and systematically study their theoretical properties. We first establish the weak convergence of the local linear estimate of coefficient functions, as well as its asymptotic bias and variance, and then we derive asymptotic bias and mean integrated squared error of smoothed individual functions and their uniform convergence rate. We establish the uniform convergence rate of the estimated covariance function of the individual functions and its associated eigenvalue and eigenfunctions. We propose a global test for linear hypotheses of varying coefficient functions, and derive its asymptotic distribution under the null hypothesis. We also propose a simultaneous confidence band for each individual effect curve. We conduct Monte Carlo simulation to examine the finite-sample performance of the proposed procedures. We apply MVCM to investigate the development of white matter diffusivities along the genu tract of the corpus callosum in a clinical study of neurodevelopment. PMID- 23645943 TI - A webcam in Bayer-mode as a light beam profiler for the near infra-red. AB - Beam profiles are commonly measured with complementary metal oxide semiconductors (CMOS) or charge coupled devices (CCD). The devices are fast and reliable but expensive. By making use of the fact that the Bayer-filter in commercial webcams is transparent in the near infra-red (>800 nm) and their CCD chips are sensitive up to about 1100 nm, we demonstrate a cheap and simple way to measure laser beam profiles with a resolution down to around +/-1 MUm, which is close to the resolution of the knife-edge technique. PMID- 23645944 TI - A Bayesian Procedure for File Linking to Analyze End-of-Life Medical Costs. AB - End-of-life medical expenses are a significant proportion of all health care expenditures. These costs were studied using costs of services from Medicare claims and cause of death (CoD) from death certificates. In the absence of a unique identifier linking the two datasets, common variables identified unique matches for only 33% of deaths. The remaining cases formed cells with multiple cases (32% in cells with an equal number of cases from each file and 35% in cells with an unequal number). We sampled from the joint posterior distribution of model parameters and the permutations that link cases from the two files within each cell. The linking models included the regression of location of death on CoD and other parameters, and the regression of cost measures with a monotone missing data pattern on CoD and other demographic characteristics. Permutations were sampled by enumerating the exact distribution for small cells and by the Metropolis algorithm for large cells. Sparse matrix data structures enabled efficient calculations despite the large dataset (~1.7 million cases). The procedure generates m datasets in which the matches between the two files are imputed. The m datasets can be analyzed independently and results combined using Rubin's multiple imputation rules. Our approach can be applied in other file linking applications. PMID- 23645945 TI - Developing an Older Adult Volunteer Program in a New York Chinese Community: An Evidence-Based Approach. AB - This study reports the results of a pilot volunteer project for older Chinese immigrants and documents benefits for both volunteers and caregiver recipients. Using a social marketing approach, the volunteer project was designed as a social model to promote better health among older Chinese immigrants in New York City. The packaging of this health promotion project as a volunteer program was based on a strengths perspective. In the program, 18 older Chinese immigrants were trained to provide support and referral to family caregivers of ill relatives in the Chinese community. At 6 months, outcomes were evaluated for both volunteers and caregivers. The older volunteers perceived benefits associated with volunteering, specifically, a greater sense of well-being and satisfaction with life. In addition, the majority of volunteers felt empowered by training and volunteering (100 %), felt the skills they learned improved communication with their own families (90 %), and reported physical and emotional health benefits (61 %). At the same time, caregivers reported stress reduction following volunteer support. Findings suggest that a volunteer program model may be an effective health promotion intervention for older Chinese immigrants. PMID- 23645946 TI - Advancing Research on Productive Aging Activities in Greater Chinese Societies. AB - The public discourse on productive aging as a research and policy initiative has just begun in greater China. Two conferences in Mainland China in 2009 and 2011 and subsequent conferences in Taiwan and Hong Kong in 2012 have set it in motion. Because applied social science research has just started in greater China, researchers in Chinese societies will benefit from the experience and rich literature accumulated over the last three decades in the West. In this paper, I review and reflect on the research methods used in productive aging research in both Chinese societies and in the West. I believe that to advance productive aging research in greater China, we need to (1) discuss and agree upon a definition of productive aging, (2) identify and differentiate outputs and outcomes of productive aging activities in greater China, (3) develop precise measures for productive aging involvement, (4) focus on institutional (program and public policy) factors that promote productive aging involvement, (5) use a strong research design (such as a quasi-experimental design) to establish the internal validity of productive aging programs, and (6) be theory-driven. Lastly, productive aging should be seen as a choice, not an obligation for older people; otherwise, the productive aging agenda will be seen as exploiting older people. It is important that Chinese researchers and policy-makers have this in mind when they are advocating productive engagement of older people in China. PMID- 23645948 TI - The relationship of placement experience to school absenteeism and changing schools in young, school-aged children in foster care. AB - BACKGROUND: Chronic school absenteeism and frequent school changes, particularly among younger children, may be antecedents for the high rates of school failure and subsequent dropout among youth in foster care. However, the relationship of foster care experience to absenteeism and school change has not been well studied. OBJECTIVE: This study examined the association of placement experience with absenteeism and changing schools among 209 urban children in foster care enrolled in public elementary schools. METHODS: A cohort of children aged 5 to 8 years who entered non-relative or kinship foster care from 2006-2008 were followed longitudinally for 2 years from entry into foster care. Children residing in foster care were categorized at the end of the study as early stable, late stable, or unstable, if they achieved a permanent placement prior to 45 days, between 45 days and 9 months, or failed to do so within 9 months, respectively. Children who reunified home were classified as a fourth category. Poisson regression, controlling for baseline factors, was used to compare days absent and number of schools attended across categories of placement experience. RESULTS: Among the 209 children, 51% were male, 79% were African American, and 55% were initially placed with kin. One third of children reunified home; among children who did not reunify, one half was early stable, and a third was unstable. Adjusted rates of school absenteeism increased in stepwise fashion as children's placements became more unstable; children with unstable placements were 37% more likely to be absent than those with early placement stability (p=0.029). Children who reunified during the study demonstrated the highest rates of absenteeism; however, there was no significant difference in absenteeism before or after reunification. Number of schools attended increased as stability worsened, with the standardized rate of schools attended reaching 3.6 schools (95% CI 3.1-4.1) over a two year period among children in unstable placements. CONCLUSIONS: The relationship between placement experience and school absenteeism and school change illustrates the need to better coordinate the educational experience of high-risk children in foster care. The secondary finding of high absenteeism among children in the process of returning home illustrates that educational challenges for youth may be equally if not more concerning among the greater majority of youth in child welfare who remain home with birth parents. PMID- 23645947 TI - EXPLANATIONS FOR EDUCATION GRADIENTS IN DEPRESSION-THE CASE OF KOREA. AB - OBJECTIVES: We examine gender differences in educational gradients in depressive symptoms of married couples and identify what accounts for education gradients for husbands and wives. METHODS: We use a nationally representative sample of married couples from the 2006 Korean Longitudinal Study of Aging, which collected information about depressive symptoms and risk factors for both spouses. RESULTS: For married couples, we find significant education gradients in depressive symptoms for both husbands and wives. Economic resources, physical health, children, and the relationship of spouse explain educational gradients of both husbands and wives. On the other hand, work and organized social activities are important pathways for husbands, but not for wives. In contrast, spouse's educational attainment accounts for wives' educational gradient, but not husbands'. CONCLUSIONS: Education is a strong predictor of depressive symptoms, but the pathways linking education to depressive symptoms differ between men and women. PMID- 23645949 TI - Adult Resilience among Maltreated Children: A Prospective Investigation of Main Effect and Mediating Models. PMID- 23645950 TI - STUDY OF THE NEAR INFRARED-MEDIATED HEATING OF DISPERSIONS OF PROTEIN-COATED PRISTINE AND CARBOXYLATED SINGLE-WALLED CARBON NANOTUBES. AB - Previously, we demonstrated the selective NIR-mediated ablation of tumor cells in vitro using pristine single-walled carbon nanotubes (SWNTs) with adsorbed tumor targeting ligands and carboxylated SWNTs with covalently-attached ligands. The covalent approach is advantageous in ensuring that protein ligands remain associated with the NIR-absorbing SWNTs in biological matrices and the noncovalent approach has the advantage of enabling SWNT functionalization without perturbation of the SWNT lattice and photothermal properties. Herein, we compare the ability of moderately-carboxylated (~4 at.% carboxylic acid groups) and pristine SWNT materials to absorb 808 nm radiation and convert it to heat. Under conditions of a constant 808 nm laser power density, the approach involved measuring the temperature of aqueous dispersions of protein-coated SWNTs as a function of the irradiation time. Nearly identical temperature profiles were observed for dispersions of moderately-carboxylated and pristine SWNTs possessing matched 808 nm optical densities and equivalent concentrations of carbonaceous species (i.e., SWNTs and amorphous carbon impurities). The results indicate that the amount of carbonaceous species in purified dispersions of protein-coated SWNTs is more important for converting absorbed 808 nm radiation into heat than whether or not the SWNTs were moderately carboxylated, and that moderately carboxylated SWNTs could be the SWNT-material of choice for the targeted photothermal ablation of tumor cells. PMID- 23645951 TI - Design-based random permutation models with auxiliary information AB - We extend the random permutation model to obtain the best linear unbiased estimator of a finite population mean accounting for auxiliary variables under simple random sampling without replacement (SRS) or stratified SRS. The proposed method provides a systematic design-based justification for well-known results involving common estimators derived under minimal assumptions that do not require specification of a functional relationship between the response and the auxiliary variables. PMID- 23645953 TI - Evaluation of Ki67, p16 and CK17 Markers in Differentiating Cervical Intraepithelial Neoplasia and Benign Lesions. AB - BACKGROUND: Cervical intraepithelial neoplasia (CIN) is a premalignant lesion capable of progressing to cervical cancer. Despite the existing well-defined criteria, the histomorphologic diagnosis is subject to high rates of discordance among pathologists. The aim of this study was to evaluate Ki-67 (MIB-1), CK17 and p16 (INK4a) (p16) markers by immunohistochemical methods in differentiating CIN from benign cervical lesions. METHODS: The present study reviewed and re classified 77 cervical biopsies, originally diagnosed as 31 non-CIN, and 46 CIN, as 54 non-CIN, and 23 CIN based on at least two similar diagnoses. Immunostaining by Ki67, p16 and CK17 markers was performed on all cases and the results were compared with pervious and consensus diagnosis. RESULTS: The overall agreement between pervious and consensus diagnosis was 67.5% (Kappa=0.39, P<0.001). The sensitivity and specificity of Ki67 immunostaining were 95.6% and 85.1% respectively, while for p16 the corresponding values were 91.3% and 98.1%. The overall agreement, for both p16 and Ki67, with consensus diagnosis were significant (P<0.001). The sensitivity and specificity of CK17 negative staining in CIN detection were 39.1% and 40.7% respectively. CONCLUSION: Ki67 and p16 markers are recommended as complementary tests for differentiating between dysplastic and non-dysplastic lesions. CK17 does not discriminate between immature metaplasia with and without dysplasia. PMID- 23645954 TI - A symptom profile analysis of depression in a sample of Iranian patients. AB - BACKGROUND: In some cultures, including ours, direct explanation of inner psychic world is inhibited and stigmatized, therefore finding alternative modes of expression. The aim of this cross-sectional study was to assess the frequency of somatization in the depressed patients. METHODS: The present study comprised 500 patients referred to the outpatient clinic of Shiraz University of Medical Sciences, and diagnosed with major depressive disorders based on DSM-IV-TR. The presenting complaints of these patients were assessed through psychiatric interview. The presenting symptoms were divided into three main categories including mental symptoms, pain, and physical symptoms without pain. Statistical analysis (chi-square and logistic regression) were performed to determine the relationship between presenting symptoms and some demographic variables such as age, gender, marital status, educational level and cultural background (urban or rural). RESULTS: Physical symptoms other than pain, mental symptoms, and pain were found in 193 (38.6%), 186 (37.2%), and in 121 (24.2%) patients respectively. Pain and physical complaints were more common in patients with rural cultural background, lower education, women and the married individuals. Headache (15.2%), irritability (10.6%) and pain in different parts of the body (10.4%) were the most frequent chief complaints of the patients. Hypochondriasis, suicidal idea, crying, irritability and insomnia were significant symptoms associated with the complaint of somatization. CONCLUSION: Somatic symptoms, especially pain, have a significant weight in the chief complaints of depressed patients. Physicians need to pay particular attention to this important issue in order to better understand these patients. PMID- 23645952 TI - Unusual locations of the hydatid cyst: a review from iran. AB - Hydatid disease is caused by Echinococcus granulosus and is endemic in many parts of the world, including Iran. This parasitic tapeworm can produce cysts in almost every organ of the body, with the liver and lung being the most frequently targeted organs. However, the cyst tends to appear in different and sometimes unusual body sites in various geographical areas of the world. This review provides information on the reported cases of the unusual body sites of the hydatid cyst from Iran in the last 20 years. A literature search was performed through PubMed, Scopus, Google Scholar, IranMedex, Society Information Display (SID), Magiran, and Irandoc using the keywords of "hydatid cyst and Iran" and "Echinococcus granulosus and Iran", and 463 published cases of the hydatid cyst in unusual body sites from Iran were reviewed, evaluated, and discussed. The most common locations were the central nervous system (brain, spinal cord, and orbit), musculoskeletal system, heart, and kidney, while some less common locations were the spleen, pancreas, appendix, thyroid, salivary gland, adrenal gland, breast, and ovary. PMID- 23645955 TI - Clinical, toxicological, biochemical, and hematologic parameters in lead exposed workers of a car battery industry. AB - BACKGROUND: Lead is a toxic element which causes acute, subacute or chronic poisoning through environmental and occupational exposure. The aim of this study was to investigate clinical and laboratory abnormalities of chronic lead poisoning among workers of a car battery industry. METHODS: Questionnaires and forms were designed and used to record demographic data, past medical histories and clinical manifestations of lead poisoning. Blood samples were taken to determine biochemical (using Auto Analyzer; Model BT3000) and hematologic (using Cell Counter Sysmex; Model KX21N) parameters. An atomic absorption spectrometer (Perkin-Elmer, Model 3030, USA) was used to determine lead concentration in blood and urine by heated graphite atomization technique. RESULTS: A total of 112 men mean age 28.78+/-5.17 years, who worked in a car battery industry were recruited in the present study. The most common signs/symptoms of lead poisoning included increased excitability 41.9%, arthralgia 41.0%, fatigue 40.1%, dental grey discoloration 44.6%, lead line 24.1%, increased deep tendon reflexes (DTR) 22.3%, and decreased DTR (18.7%). Blood lead concentration (BLC) was 398.95 ug/L+/ 177.40, which was significantly correlated with duration of work (P=0.044) but not with the clinical manifestations of lead poisoning. However, BLC was significantly correlated with urine lead concentration (83.67 ug/L+/-49.78; r(2)=0.711; P<0.001), mean corpuscular hemoglobin (r=-0.280; P=0.011), mean corpuscular hemoglobin concentration (r=-0.304; P=0.006) and fasting blood sugar or FBS (r=-0.258; P=0.010). CONCLUSION: Neuropsychiatric and skeletal findings were common manifestations of chronic occupational lead poisoning. BLC was significantly correlated with duration of work, urine lead concentration, two hemoglobin indices and FBS. PMID- 23645956 TI - Effect of probiotics on lipid profile, glycemic control, insulin action, oxidative stress, and inflammatory markers in patients with type 2 diabetes: a clinical trial. AB - BACKGROUND: The dramatic increase in the incidence of diabetes and its associated complications require a natural and safe solution to control and delay such complications. The present study tested the hypothesis that probiotics may affect biochemical indices of diabetic patients Methods: Thirty four types 2 diabetic patients aged between 25 to 65 years, and diagnosed with diabetes for less than 15 years were selected for this single- blinded clinical trial. Using balanced block random sampling, the patients were divided into two groups of intervention (probiotics) and placebo. Blood samples tested for baseline glucose, insulin, TG, total cholesterol, LDL-C, HDL-C, malondialdehyde, high sensitive CRP (hs-CRP) and IL-6. After six weeks of experiment, fasting blood samples were re-tested and the data obtained were analyzed using SPSS software. RESULTS: There were no significant differences between anthropometric data including body mass index and waist to hip ratio in placebo and treatment groups. There was no significant difference in FBS, Serum TG concentration total cholesterol and LDL-C levels between placebo and treatment groups. HDL-C levels were slightly elevated after probiotic treatment, which were not statistically significant. Insulin, MDA and IL-6 levels were reduced and high sensitive CRP hs.CRP levels were elevated, although, not statistically significant. CONCLUSION: The result of this study indicates a non- significant declining trend in the level of TG, MDA and IL-6 and insulin resistance after consumption of probiotics. PMID- 23645957 TI - The Antibacterial Activity of Selected Labiatae (Lamiaceae) Essential Oils against Brucella melitensis. AB - BACKGROUND: Brucellosis, a zoonosis caused by four species of brucella, has a high morbidity. The major cause of brucellosis worldwide is brucella melitensis. Medicinal plants are considered as new antibacterial sources that could replace conventional antibiotics in the treatment of antibiotic-resistant bacteria. The aim of this study was to evaluate the efficacy of some native plants, alone and in combination with some antibiotics, in the treatment of brucellosis. METHODS: The present experimental in vitro study was carried out to evaluate the anti brucella activities of essential oils of Rosmarinus officinalis L., Origanum syriacum, Thymus syriacus, Salvia palaestina Benth, Mentha piperia, and Lavandula stoechas L., alone and in combination with some antibiotics. The activity against 16 tetracycline-resistant B. melitensis isolates was determined by disc diffusion method incorporating a concentration of 5%. Antibiotic discs were also used as a control. Microdilution brucella broth susceptibility assay was used in order to determine the MICs of essential oils and five antibiotics. RESULTS: Among all the herbs evaluated, only the essential oils of O. syriacum and T. syriacus plants demonstrated most effective anti-brucella activity, and were then chosen for MIC study. The minimal inhibitory concentrations (MIC50) of essential oils of O. syriacum and T. syriacus against tetracycline-resistant B. melitensis were 3.125 ul/ml and 6.25 ul/ml, respectively. CONCLUSION: Among the essential oils studied, those of O. syriacum and T. syriacus were most effective. Since a combination of levofloxacin and Thymus syriacus essential oil increased the efficacy of this antibiotic, O. syriacum and T. syriacus are recommended to be used as bactericidal agents against B. melitensis. PMID- 23645958 TI - Determination of blood glucose concentration by using wavelet transform and neural networks. AB - BACKGROUND: Early and non-invasive determination of blood glucose level is of great importance. We aimed to present a new technique to accurately infer the blood glucose concentration in peripheral blood flow using non-invasive optical monitoring system. METHODS: The data for the research were obtained from 900 individuals. Of them, 750 people had diabetes mellitus (DM). The system was designed using a helium neon laser source of 632.8 nm wavelength with 5mW power, photo detectors and digital storage oscilloscope. The laser beam was directed through a single optical fiber to the index finger and the scattered beams were collected by the photo detectors placed circumferentially to the transmitting fiber. The received signals were filtered using band pass filter and finally sent to a digital storage oscilloscope. These signals were then decomposed into approximation and detail coefficients using modified Haar Wavelet Transform. Back propagation neural and radial basis functions were employed for the prediction of blood glucose concentration. RESULTS: The data of 450 patients were randomly used for training, 225 for testing and the rest for validation. The data showed that outputs from radial basis function were nearer to the clinical value. Significant variations could be seen from signals obtained from patients with DM and those without DM. CONCLUSION: The proposed non-invasive optical glucose monitoring system is able to predict the glucose concentration by proving that there is a definite variation in hematological distribution between patients with DM and those without DM. PMID- 23645959 TI - Quality of publication ethics in the instructions to the authors of Iranian journals of medical sciences. AB - Providing a perfect instruction to authors can prevent most potential publication ethics errors. This study was conducted to determine the quality of ethical considerations in the instructions to the authors of Iranian research scientific journals of medical sciences (accredited by the Commission for Accreditation and Improvement of Iranian Medical Journals) in October 2011. Checklist items (n=15) were extracted from the national manual of ethics in medical research publications, and the validity of the manual of ethics was assessed. All the accredited Iranian journals of medical sciences (n=198) were entered into the study. The instructions to the authors of 160 accredited Iranian journals were available online and were reviewed. The ANOVA and Kendall Correlation coefficient were performed to analyze the results. A total of 76 (47.5%) of the 160 journals were in English and 84 (52.5%) were in Farsi. The most frequently mentioned items related to publication ethics comprised "commitment not to send manuscripts to other journals and re-publish manuscripts" (85%, 83.8%), "aim and scope" of the journal (81.9%), "principles of medical ethics in the use of human samples" (74.4%), and "review process" (74.4%). On the other hand, the items of "principles of advertising" (1.2%), "authorship criteria" (15%), and "integrity in publication of clinical trial results" (30.6%) were the least frequently mentioned ones. Based on the study findings, the quality of publication ethics, as instructed to the authors, can improve the quality of the journals. PMID- 23645960 TI - Scrotal herniation of bladder: a case report. AB - Inguinal bladder hernia is a rare clinical condition, with 1-3% of all inguinal hernias involving the bladder. Any portion of the bladder may herniate, from a small portion or a diverticulum to most of the bladder. We present a 55-year-old male with an intermittent right scrotal mass of 6 months' duration. The mass lesion protruded through the right inguinal canal before voiding and reduced after that. Scrotal sonography revealed a hypoechoic lesion in the scrotum that stretched cranially to the intra-abdominal portion of the bladder. Excretory urography showed a duplicated system in the left kidney and deviation of the left orifice to the right side of the trigon. Finally, cystography illustrated herniation of the bladder to the right scrotum. Surgical repair of the hernia was done with mesh. Follow-up cystography one month postoperatively revealed no herniation. PMID- 23645961 TI - A rare case of non-small cell carcinoma of lung presenting as miliary mottling. AB - Miliary mottling on chest radiography is seen in miliary tuberculosis, certain fungal infections, sarcoidosis, coal miner's pneumoconiosis, silicosis, hemosiderosis, fibrosing alveolitis, acute extrinsic allergic alveolitis, pulmonary eosinophilic syndrome, pulmonary alveolar proteinosis, and rarely in hematogenous metastases from the primary cancers of the thyroid, kidney, trophoblasts, and some sarcomas. Although very infrequent, miliary mottling can be seen in primary lung cancers. Herein, we report the case of a 28-year-old female with chest X-ray showing miliary mottling. Thoracic computed tomography (CT) features were suggestive of tuberculoma with miliary tuberculosis. CT-guided fine needle aspiration cytology confirmed the diagnosis as lower-lobe, left lung non-small cell carcinoma (adenocarcinoma). It is rare for the non-small cell carcinoma of the lung to present as miliary mottling. The rarity of our case lies in the fact that a young, non-smoking female with miliary mottling was diagnosed with non-small cell carcinoma of the lung. PMID- 23645962 TI - Early Marjolin's Ulcer after Minimal Superficial Burn. PMID- 23645963 TI - MATHEMATICAL METHODS IN MEDICAL IMAGE PROCESSING. AB - In this paper, we describe some central mathematical problems in medical imaging. The subject has been undergoing rapid changes driven by better hardware and software. Much of the software is based on novel methods utilizing geometric partial differential equations in conjunction with standard signal/image processing techniques as well as computer graphics facilitating man/machine interactions. As part of this enterprise, researchers have been trying to base biomedical engineering principles on rigorous mathematical foundations for the development of software methods to be integrated into complete therapy delivery systems. These systems support the more effective delivery of many image-guided procedures such as radiation therapy, biopsy, and minimally invasive surgery. We will show how mathematics may impact some of the main problems in this area, including image enhancement, registration, and segmentation. PMID- 23645964 TI - Arsenic removal from water using flame-synthesized iron oxide nanoparticles with variable oxidation states. AB - We utilized gas-phase diffusion flame synthesis, which has potential for large scale production of metal oxide nanoparticles, to produce iron oxide nanoparticles (IONPs) with variable oxidation states. The efficacy of these materials in removal of arsenate (As(V) ) from water was assessed. Two different flame configurations, a diffusion flame (DF) and an inverse diffusion flame (IDF), were employed to synthesize six different IONPs by controlling flame conditions. The IONPs produced in the IDF configuration (IDF-IONPs) had smaller particle diameters (4.8 - 8.2 nm) and larger surface areas (141-213 m2/g) than the IONPs produced in the DF configuration (29 nm, 36 m2/g), which resulted in their higher adsorption capacities. As(V) adsorption capacities of the IDF-IONPs increased when the IONPs were synthesized in more oxidizing conditions. The fully oxidized IDF-IONPs, maghemite (gamma-Fe2O3), showed the highest As(V) adsorption capacity, comparable to that of magnetite nanocrystals synthesized by thermal decomposition of iron pentacarbonyl and equivalent to three to four times higher capacity than that of a commonly used goethite-based adsorbent. All IONPs were magnetically responsive, which is of great importance for solid-liquid separation. This study demonstrates that the IONPs synthesized in gas-phase flame, particularly IDF-IONPs, are excellent adsorbents because of their high As(V) sorption capacity, potential for large-scale production, and useful magnetic property. PMID- 23645966 TI - Comparisons of levels and predictors of mothers' and fathers' engagement with their preschool aged children. AB - Self-report data from 112 two-parent families were used to compare levels and predictors of four types of mothers' and fathers' engagement with their preschool aged children: socialization, didactic, caregiving, and physical play. Mothers were more involved than fathers in socialization, didactic, and caregiving, whereas fathers were more involved than mothers in physical play. Mothers' greatest engagement was in caregiving, whereas fathers were about equally engaged in didactic, caregiving, and physical play. Mothers who contributed more to family income were less engaged in socialization and caregiving, whereas fathers with nontraditional beliefs about their roles were more engaged in didactic and caregiving. Children with greater temperamental effortful control received more didactic and physical play engagement from mothers. Fathers were more likely to engage in socialization activities with earlier-born children, whereas mothers were more likely to engage in socialization with girls high in effortful control. Mothers were more likely to engage in physical play with boys and with later-born children. PMID- 23645967 TI - Clarifying Prehistoric Parasitism from a Complementary Morphological and Molecular Approach. AB - This paper reports an approach to the identification of prehistoric parasitic infection, which integrates traditional morphological methods with molecular methods. The approach includes the strengths of each method while mitigating the limitations. Demonstrating the efficacy of this approach, we provide a case study from a 1,400 year old desiccated fecal sample from La Cueva de los Muertos Chiquitos, archaeological site, near Rio Zape, Durango, Mexico. Traditionally prepared microscope slides were processed via microscopy and tentative ascarids were identified. Information regarding the parasites' developmental stage was recorded. DNA was then extracted directly from the slide material. From this DNA extract, a small segment of the 18S ribosomal RNA gene variant that is specific to Ascaris, and its phylogenetically close relatives, was targeted for PCR amplification and sequencing. Phylogenetic analysis of the DNA sequence best matched a member of physalopterids, rather than ascarids, with a single exception of a match to Contracaecum spiculigerum. Subsequent extractions, amplifications and sequencing of the original rehydrated coprolite material confirmed these results. The C. spiculigerum sequence represented a phylogenetic anomaly and subsequent analysis determined the sequence was an error in the BLAST database, likely attributable to misidentification of juvenile specimens prior to sequencing and submission. Physaloptera are a difficult genus to identify morphologically and can carry major health burdens. They may be underreported in humans, in part, because of morphological similarities to the more common human parasites belonging to ascarids. We conclude that integrating traditional morphological methods with molecular methods can help resolve this issue, in both contemporary and prehistoric populations. PMID- 23645968 TI - Sex differences in survival costs of reproduction in a promiscuous primate. AB - In sexually promiscuous mammals, female reproductive effort is mainly expressed through gestation, lactation, and maternal care, whereas male reproductive effort is mainly manifested as mating effort. In this study, we investigated whether reproduction has significant survival costs for a seasonally breeding, sexually promiscuous species, the rhesus macaque, and whether these costs occur at different times of the year for females and males, namely in the birth and the mating season, respectively. The study was conducted with the rhesus macaque population on Cayo Santiago, Puerto Rico. Data on 7,402 births and 922 deaths over a 45-year period were analyzed. Births were concentrated between November and April, while conceptions occurred between May and October. As predicted, female mortality probability peaked in the birth season whereas male mortality probability peaked in the mating season. Furthermore, as the onset of the birth season gradually shifted over the years in relation to climatic changes, there was a concomitant shift in the seasonal peaks of male and female mortality. Taken together, our findings provide the first evidence of sex differences in the survival costs of reproduction in nonhuman primates and suggest that reproduction has significant fitness costs even in environments with abundant food and absence of predation. PMID- 23645969 TI - Cultural Adaptation of a Cognitive Behavior Therapy Guided Self-Help Program for Mexican American Women With Binge Eating Disorders. AB - Data on the compatibility of evidence-based treatment in ethnic minority groups are limited. This study utilized focus group interviews to elicit Mexican American women's (N = 12) feedback on a cognitive behavior therapy guided self help program for binge eating disorders. Findings revealed 6 themes to be considered during the cultural adaptation process and highlighted the importance of balancing the fidelity and cultural relevance of evidence-based treatment when disseminating it across diverse racial/ethnic groups. PMID- 23645971 TI - Prevalence and Correlates of Intimate Partner Violence Among Young, Middle, and Older Women of Korean Descent in California. AB - This research examined the prevalence and correlates of intimate partner violence (IPV) among younger, middle-aged, and older Korean American women. Data were drawn from telephone interviews of a population-based, representative probability sample (N = 592) of female adults of Korean descent residing in California, with a completion rate of 70%. Data were grouped by age. In each group, psychological aggression was the most common type of IPV in the past year, followed by a moderate form of sexual coercion, while physical assault and injury were infrequent. Immigration stress was associated with psychological aggression in all three groups, and partner alcohol use was associated in none. Other predictors varied by group. Results suggest that psychological abuse is a serious issue, and that women's life stage is an important consideration in IPV among Korean Americans. Findings, which sometimes diverged from those of prior studies of this population, merit further investigation. PMID- 23645972 TI - Effects of early maternal employment on maternal health and well-being. AB - This study uses data from the National Institute of Child Health and Human Development Study on Early Child Care to examine the effects of maternal employment on maternal mental and overall health, self-reported parenting stress, and parenting quality. These outcomes are measured when children are 6 months old. Among mothers of 6-month-old infants, maternal work hours are positively associated with depressive symptoms and parenting stress and negatively associated with self-rated overall health. However, maternal employment is not associated with quality of parenting at 6 months, based on trained assessors' observations of maternal sensitivity. PMID- 23645970 TI - Long non-coding RNAs (lncRNAs) and viral infections. AB - In this review, we focus on the roles of lncRNAs, including cellular and viral lncRNAs, in virus replication in infected cells. We survey the interactions and functions of several cellular lncRNAs such as XIST, HOTAIR, NEAT1, BIC and several virus encoded lncRNAs. PMID- 23645973 TI - Contingencies in Mother-Child Teaching Interactions and Behavior Regulation and Dysregulation in Early Childhood. AB - Predictable patterns in early parent-child interactions may help lay the foundation for how children learn to self-regulate. The present study examined contingencies between maternal teaching and directives and child compliance in mother-child problem-solving interactions at age 3.5 and whether they predicted children's behavioral regulation and dysregulation (inhibitory control and externalizing behaviors) as rated by mothers, fathers, and teachers at a 4-month follow-up (N = 100). The predictive utility of mother- and child-initiated contingencies was also compared to that of frequencies of individual mother and child behaviors. Structural equation models revealed that a higher probability that maternal directives were followed by child compliance predicted better child behavioral regulation, whereas the reverse pattern and the overall frequency of maternal directives did not. For teaching, stronger mother- and child-initiated contingencies and the overall frequency of maternal teaching all showed evidence for predicting better behavioral regulation. Findings depended on which caregiver was rating child outcomes. We conclude that dyadic measures are useful for understanding how parent-child interactions impact children's burgeoning regulatory abilities in early childhood. PMID- 23645974 TI - Infants' grasp of others' intentions. AB - The perception of others as intentional agents is fundamental to human experience and foundational to development. Recent research reveals that this cornerstone of social perception has its roots early in infancy, and that it draws structure from the universal, early emerging human experience of engaging in goal-directed action. Infants' own action capabilities correlate with their emerging tendency to view others' actions as organized by goals. Moreover, interventions that facilitate new goal-directed actions alter infants' perception of those same actions in others. These effects seem to depend on the first-person aspects of infants' experience. These findings open new questions about how doing leads to knowing in the social domain. PMID- 23645975 TI - All in the Family: Comparing Siblings to Test Causal Hypotheses Regarding Environmental Influences on Behavior. AB - Psychologists in both basic and applied fields are keenly interested in the environmental influences that shape our lives. Therefore, researchers test causal hypotheses to construct models of environmental influences that can withstand attempts at refutation. Randomized experiments provide the strongest tests of causal hypotheses, but are not always feasible and their assumptions cannot always be met. In such cases, a number of quasi-experimental research designs can be used to substantially reduce confounding in tests of causal hypotheses. Sibling-comparison designs provide robust quasi-experimental tests of causal environmental hypotheses, but they are underused in psychology in spite of their power, feasibility, and convenience. PMID- 23645976 TI - Parametrically Guided Generalized Additive Models with Application to Mergers and Acquisitions Data. AB - Generalized nonparametric additive models present a flexible way to evaluate the effects of several covariates on a general outcome of interest via a link function. In this modeling framework, one assumes that the effect of each of the covariates is nonparametric and additive. However, in practice, often there is prior information available about the shape of the regression functions, possibly from pilot studies or exploratory analysis. In this paper, we consider such situations and propose an estimation procedure where the prior information is used as a parametric guide to fit the additive model. Specifically, we first posit a parametric family for each of the regression functions using the prior information (parametric guides). After removing these parametric trends, we then estimate the remainder of the nonparametric functions using a nonparametric generalized additive model, and form the final estimates by adding back the parametric trend. We investigate the asymptotic properties of the estimates and show that when a good guide is chosen, the asymptotic variance of the estimates can be reduced significantly while keeping the asymptotic variance same as the unguided estimator. We observe the performance of our method via a simulation study and demonstrate our method by applying to a real data set on mergers and acquisitions. PMID- 23645977 TI - Reliability and Validity of the Dyadic Observed Communication Scale (DOCS). AB - We evaluated the reliability and validity of the Dyadic Observed Communication Scale (DOCS) coding scheme, which was developed to capture a range of communication components between parents and adolescents. Adolescents and their caregivers were recruited from mental health facilities for participation in a large, multi-site family-based HIV prevention intervention study. Seventy-one dyads were randomly selected from the larger study sample and coded using the DOCS at baseline. Preliminary validity and reliability of the DOCS was examined using various methods, such as comparing results to self-report measures and examining interrater reliability. Results suggest that the DOCS is a reliable and valid measure of observed communication among parent-adolescent dyads that captures both verbal and nonverbal communication behaviors that are typical intervention targets. The DOCS is a viable coding scheme for use by researchers and clinicians examining parent-adolescent communication. Coders can be trained to reliably capture individual and dyadic components of communication for parents and adolescents and this complex information can be obtained relatively quickly. PMID- 23645979 TI - Literacy Growth in the Academic Year versus Summer from Preschool through Second Grade: Differential Effects of Schooling across Four Skills. AB - Differences in literacy growth over the summer versus the school year were examined in order to isolate how schooling affects children's literacy development from preschool through second grade across four literacy skills. Children (n = 383) were tested individually twice each year for up to four years on measures of phonological awareness, decoding, reading comprehension, and vocabulary. Growth curve analyses indicated that schooling effects were greatest for decoding skills and reading comprehension, were medium in size for phonological awareness, and were less evident for vocabulary. Except for vocabulary, relatively small amounts of growth were observed for preschoolers, followed by a period of rapid growth for kindergarteners and first graders, which slowed again for second graders. Findings demonstrate the differential effect of schooling on four separate literacy skills during the crucial school transition period. PMID- 23645978 TI - Cognitive Behavioral Treatment for Recurrent Binge Eating in Adolescent Girls: A Pilot Trial. AB - There is a need for treatment interventions to address the high prevalence of disordered eating throughout adolescence and early adulthood. We developed an adolescent-specific manualized CBT protocol to treat female adolescents with recurrent binge eating and tested its efficacy in a small, pilot randomized controlled trial. We present lessons learned in recruiting adolescents, a description of our treatment approach, acceptability of the treatment for teens and parents, as well as results from the pilot trial. Participants in the CBT group had significantly fewer posttreatment eating binges than those in a treatment as usual/delayed treatment (TAU-DT) control group; 100% of CBT participants were abstinent at follow-up. Our results provide preliminary support for the efficacy of this adolescent adaptation of evidence-based CBT for recurrent binge eating. The large, robust effect size estimate observed for the main outcome (NNT=2) places this among the larger effects observed for any mental health intervention. PMID- 23645980 TI - Decreased Epidermal Growth Factor (EGF) Associated with HMGB1 and Increased Hyperactivity in Children with Autism. AB - BACKGROUND: Autism spectrum disorders (ASDs), characterized by impaired social interactions and deficits in verbal and nonverbal communication, are thought to affect 1 in 88 children in the United States. There is much support for the role of growth factors in the etiology of autism. Recent research has shown that epithelial growth factor (EGF) is decreased in young autistic children (2-4 years of age). This study was designed to determine plasma levels of EGF in an older group of autistic children (mean age 10.6 years) and to correlate these EGF levels with putative biomarkers HGF, uPA, uPAR, GAD2, MPO GABA, and HMGB1, as well as symptom severity of 19 different symptoms. SUBJECTS AND METHODS: Plasma from 38 autistic children, 11 children with pervasive developmental disorder (PDD NOS) and 40 neurotypical, age and gender similar controls was assessed for EGF concentration using ELISAs. Severity of 19 symptoms (awareness, expressive language, receptive language, (conversational) pragmatic language, focus/attention, hyperactivity, impulsivity, perseveration, fine motor skills, gross motor skills, hypotonia (low muscle tone), tiptoeing, rocking/pacing, stimming, obsessions/fixations, eye contact, sound sensitivity, light sensitivity, and tactile sensitivity) was assessed and then compared to EGF concentrations. RESULTS: In this study, we found EGF levels in autistic children and those with PDD-NOS to be significantly lower when compared with neurotypical controls. EGF levels correlated with HMGB1 levels but not the other tested putative biomarkers, and EGF correlated negatively with hyperactivity, gross motor skills, and tiptoeing but not other symptoms. CONCLUSIONS: These results suggest an association between decreased plasma EGF levels and selected symptom severity. We also found a strong correlation between plasma EGF and HMGB1, suggesting inflammation is associated with decreased EGF. PMID- 23645982 TI - The oncogene mcts1. AB - The oncogene MCTS1, discovered as an amplified product in a subset of T-cell lymphoma lines, has been implicated in cell cycle progression and conferring a growth advantage in lymphomas and breast cancer. Recent research shows that it modulates the MAPK pathway and acts as a translational activator both in vivo and in vitro. In breast cancer cells, expression of MCTS1 confers aggressive properties and inhibits apoptosis. This article will review these data and its implications on our understanding of cancer. PMID- 23645983 TI - Urokinase-type Plasminogen Activator (uPA) is Inhibited with QLT0267 a Small Molecule Targeting Integrin-linked Kinase (ILK). AB - Urokinase-type plasminogen activator (uPA) is associated with cancer recurrence where the most evidence comes from studies in breast cancer. According to the European Organization for Research and Treatment of Cancer, uPA is considered one of the most prominent biomarkers for cancer recurrence and therefore new agents are needed to inhibit it. Whether uPA is also expressed in pediatric cancers is yet unknown. If it is then uPA inhibitors might also help children with recurrent cancers. In this study, we addressed whether the integrin-linked kinase inhibitor (ILK), QLT0267, could suppress uPA. We previously showed that uPA expression is maximally inhibited when both the Akt and MAP kinase pathways were blocked which we anticipated can be achieved via QLT0267. In MDA-MB-231 breast cancer cells, QLT0267 blocked signaling through Akt and MAP kinase with a correlative decrease in uPA protein and mRNA, which corresponded to an inhibition of c-Jun phosphorylation. Consistent with these findings, cellular invasion was inhibited with either QLT0267 or with small interfering RNA against ILK. We then questioned whether uPA was commonly expressed in childhood sarcomas and if QLT0267 might be effective in this setting. We determined for the first time that uPA was highly expressed in rhabdomyosarcomas (RMS), but not Ewings sarcomas by screening cell lines (n = 31) and patient samples (n = 200) using Affymetrix microarrays. In alveolar RMS (ARMS) cell lines, QLT0267 blocked cell signaling, uPA production, invasion and ultimately survival. We concluded that QLT0267 blocks the production of uPA providing a new target for the management of recurrent cancers. PMID- 23645984 TI - A Comprehensive Profile of ChIP-Seq-Based STAT1 Target Genes Suggests the Complexity of STAT1-Mediated Gene Regulatory Mechanisms. AB - Interferon-gamma (IFNgamma) plays a key role in macrophage activation, T helper and regulatory cell differentiation, defense against intracellular pathogens, tissue remodeling, and tumor surveillance. The diverse biological functions of IFNgamma are mediated by direct activation of signal transducer and activator of transcription 1 (STAT1) as well as numerous downstream effector genes. Because a perturbation in STAT1 target gene networks is closely associated with development of autoimmune diseases and cancers, it is important to characterize the global picture of these networks. Chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) provides a highly efficient method for genome-wide profiling of DNA-binding proteins. We analyzed the STAT1 ChIP-Seq dataset of IFNgamma-stimulated HeLa S3 cells derived from the ENCODE project, along with transcriptome analysis on microarray. We identified 1,441 stringent ChIP-Seq peaks of protein-coding genes. They were located in the promoter (21.5%) and more often in intronic regions (72.2%) with an existence of IFNgamma-activated site (GAS) elements. Among the 1,441 STAT1 target genes, 212 genes are known IFN regulated genes (IRGs) and 194 genes (13.5%) are actually upregulated in response to IFNgamma by transcriptome analysis. The panel of upregulated genes constituted IFN-signaling molecular networks pivotal for host defense against infections, where interferon-regulatory factor (IRF) and STAT transcription factors serve as a hub on which biologically important molecular connections concentrate. The genes with the peak location in intronic regions showed significantly lower expression levels in response to IFNgamma. These results indicate that the binding of STAT1 to GAS is not sufficient to fully activate target genes, suggesting the high complexity of STAT1-mediated gene regulatory mechanisms. PMID- 23645981 TI - Tetracycline regulated systems in functional oncogenomics. AB - The increasing number of proteomic and DNA-microarray studies is continually providing a steady acquisition of data on the molecular abnormalities associated with human tumors. Rapid translation of this accumulating biological information into better diagnostics and more effective cancer therapeutics in the clinic depends on the use of robust function-testing strategies. Such strategies should allow identification of molecular lesions that are essential for the maintenance of the transformed phenotype and enable validation of potential drug-targets. The tetracycline regulated gene expression/ suppression systems (Tet-systems) developed and optimized by bioengineers over recent years seem to be very well suited for the function-testing purposes in cancer research. We review the history and latest improvements in Tet-technology in the context of functional oncogenomics. PMID- 23645985 TI - Butyrate Induced IGF2 Activation Correlated with Distinct Chromatin Signatures Due to Histone Modification. AB - Histone modification has emerged as a very important mechanism regulating the transcriptional status of the genome. Insulin-like growth factor 2 (IGF2) is a peptide hormone controlling various cellular processes, including proliferation and apoptosis. H19 gene is closely linked to IGF2 gene, and IGF2 and H19 are reciprocally regulated imprinted genes. The epigenetic signature of H19 promoter (hypermethylation) on the paternal allele plays a vital role in allowing the expression of the paternal allele of IGF2.46 Our previous studies demonstrate that butyrate regulates the expression of IGF2 as well as genes encoding IGF Binding proteins. To obtain further understanding of histone modification and its regulatory potentials in controlling IGF2/H19 gene expression, we investigated the histone modification status of some key histones associated with the expression of IGF2/H19 genes in bovine cells using RNA-seq in combination with Chip-seq technology. A high-resolution map of the major chromatin modification at the IGF2/H19 locus induced by butyrate was constructed to illustrate the fundamental association of the chromatin modification landscape that may play a role in the activation of the IGF2 gene. High-definition epigenomic landscape mapping revealed that IGF2 and H19 have distinct chromatin modification patterns at their coding and promoter regions, such as TSSs and TTSs. Moreover, the correlation between the differentially methylated regions (DMRs) of IGF2/H19 locus and histone modification (acetylation and methylation) indicated that epigenetic signatures/markers of DNA methylation, histone methylation and histone acetylation were differentially distributed on the expressed IGF2 and silenced H19 genes. Our evidence also suggests that butyrate-induced regional changes of histone acetylation statusin the upstream regulation domain of H19 may be related to the reduced expression of H19 and strong activation of IGF2. Our results provided insights into the mechanism of butyrate-induced loss of imprinting (LOI) of IGF2 and regulation of gene expression by histone modification. PMID- 23645986 TI - miR-Explore: Predicting MicroRNA Precursors by Class Grouping and Secondary Structure Positional Alignment. AB - MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expressions by targeting the mRNAs especially in the 3'UTR regions. The identification of miRNAs has been done by biological experiment and computational prediction. The computational prediction approach has been done using two major methods: comparative and noncomparative. The comparative method is dependent on the conservation of the miRNA sequences and secondary structure. The noncomparative method, on the other hand, does not rely on conservation. We hypothesized that each miRNA class has its own unique set of features; therefore, grouping miRNA by classes before using them as training data will improve sensitivity and specificity. The average sensitivity was 88.62% for miR-Explore, which relies on within miRNA class alignment, and 70.82% for miR-abela, which relies on global alignment. Compared with global alignment, grouping miRNA by classes yields a better sensitivity with very high specificity for pre-miRNA prediction even when a simple positional based secondary and primary structure alignment are used. PMID- 23645987 TI - Recognizing scientific artifacts in biomedical literature. AB - Today's search engines and digital libraries offer little or no support for discovering those scientific artifacts (hypotheses, supporting/contradicting statements, or findings) that form the core of scientific written communication. Consequently, we currently have no means of identifying central themes within a domain or to detect gaps between accepted knowledge and newly emerging knowledge as a means for tracking the evolution of hypotheses from incipient phases to maturity or decline. We present a hybrid Machine Learning approach using an ensemble of four classifiers, for recognizing scientific artifacts (ie, hypotheses, background, motivation, objectives, and findings) within biomedical research publications, as a precursory step to the general goal of automatically creating argumentative discourse networks that span across multiple publications. The performance achieved by the classifiers ranges from 15.30% to 78.39%, subject to the target class. The set of features used for classification has led to promising results. Furthermore, their use strictly in a local, publication scope, ie, without aggregating corpus-wide statistics, increases the versatility of the ensemble of classifiers and enables its direct applicability without the necessity of re-training. PMID- 23645988 TI - Comorbidity profile among patients with rheumatoid arthritis and the impact on prescriptions trend. AB - Comorbid conditions play a pivotal role in rheumatoid arthritis management and outcomes. We estimated the percentage of comorbid illness among rheumatoid arthritis patients and explored the relationship between this comorbidity and different prescriptions. A cross-sectional study of patients with rheumatoid arthritis in three centers in Saudi Arabia was carried out. Comorbidity and antirheumatoid medication regimens prescribed were recorded on a specially designed Performa. The association between comorbidity and different drugs was analyzed. A total of 340 patients were included. The most comorbidities were hypertension 122 (35.9%), diabetes 105 (30.9%), osteoporosis 88 (25.8%), and dyslipidemia in 66 (19.4). The most common drug prescribed was prednisolone in 275 (80.8%) patients followed by methotrexate in 253 (74.4%) and biological therapy in 142 (41.5%) patients. Glucocorticoids were prescribed considerably more frequently in hypertensive and diabetic patients as well as in patients with osteoporosis and dyslipidemia. Most patients with rheumatoid arthritis suffered from comorbid diseases. PMID- 23645989 TI - Unique and Varied Contributions of Traditional CVD Risk Factors: A Systematic Literature Review of CAD Risk Factors in China. AB - This study is the first systematic review of risk factors for stroke in China and supports the importance of current public health initiatives to manage the risk factors appropriately to reduce risk of stroke in high risk patients. Additionally, this study has been co-authored by prominent Chinese and US physicians and researchers with expertise in cardiovascular disease, neurologic disorders, epidemiology, and real world data. While there have been several systematic reviews of real world associations of risk factors for coronary artery disease, none focus specifically on the population of China, where there is growing evidence that such risk factors are poorly treated or uncontrolled, especially in rural areas. BACKGROUND: To better understand the impact of traditional cardiovascular risk factors on risk of coronary artery disease (CAD) in China, a systematic review of all Chinese observational studies published in either English or Chinese in MEDLINE and EMBASE over the last 5 years was performed and the association between any of 5 traditional risk factors (ie, hypertension, diabetes, elevated lipid levels, obesity, and smoking) and the risk of CAD was studied. METHODS AND RESULTS: The study found a consistent relationship between lipid levels and CAD. Higher low-density lipoprotein cholesterol values were associated with greater risk of CAD, with an odds ratio as high as 3.31. Other factors found to be significant contributors to the risk of CAD included hypertension (crude odds ratio range of 1.40-5.11), diabetes (1.50-5.97), and smoking (1.37-5.19). An association between obesity and CAD in China was observed, but the evidence supporting this was considered weak due to the paucity of studies found as part of this review. CONCLUSIONS: This review provides a systematic summary of CAD risk factors in China and demonstrates the important differences that exist in CAD risk factors between countries and regions. Approaches to reduce CAD globally must take into account the unique risk factors that drive CAD in each country and region as is demonstrated by these findings. PMID- 23645990 TI - Graves' thyrotoxicosis-induced reversible cardiomyopathy: a case report. AB - The objective of this report is to present a case of Graves' thyrotoxicosis induced cardiomyopathy. This is a case of a 26 year old woman that presented with severe symptomatic congestive heart failure and was subsequently diagnosed with dilated cardiomyopathy secondary to Graves' disease. Despite an initial left ventricular systolic ejection fraction of 20% on echocardiography, treatment with anti-thyroid agents led to rapid improvement of her clinical status and normalization of her ejection fraction. The proposed mechanisms underlying the development of systolic dysfunction in thyrotoxicosis are discussed and the literature on similar cases previously reported is highlighted. Cardiomyopathy should be considered even in young patients with Graves' thyrotoxicosis. PMID- 23645992 TI - Warm Autoimmune Hemolytic Anemia with a Direct Antiglobulin Test Positive for C3 and Negative for IgG: A Case Study and Analytical Literature Review of Incidence and Severity. AB - Polygenic IgG autoantibodies are implicated in majority of the cases of warm autoimmune hemolytic anemia (WAIHA). In some of these cases, complement (C3) proteins accompany the IgG antibodies. WAIHA mediated by C3 alone is relatively rare. We present an interesting case of WAIHA with a direct antiglobulin test (DAT) positive for C3 but negative for IgG in a 79-year-old woman and perform an analytical literature review of the incidence and severity of this clinical entity. PMID- 23645991 TI - Metabolic and nutritional needs to normalize body mass index by doubling the admission body weight in severe anorexia nervosa. AB - Anorexia nervosa exhibits one of the highest death rates among psychiatric patients and a relevant fraction of it is derived from undernutrition. Nutritional and medical treatment of extreme undernutrition present two very complex and conflicting tasks: (1) to avoid "refeeding syndrome" caused by a too fast correction of malnutrition; and (2) to avoid "underfeeding" caused by a too cautious refeeding. To obtain optimal treatment results, the caloric intake should be planned starting with indirect calorimetry measurements and electrolyte abnormalities accurately controlled and treated. This article reports the case of an anorexia nervosa young female affected by extreme undernutrition (BMI 9.6 kg/m(2)) who doubled her admission body weight (from 22.5 kg to 44 kg) in a reasonable time with the use of enteral tube feeding for gradual correction of undernutrition. Refeeding syndrome was avoided through a specialized and flexible program according to clinical, laboratory, and physiological findings. PMID- 23645993 TI - Estimation of ultrafine particle concentrations at near-highway residences using data from local and central monitors. AB - Ultrafine particles (UFP; aerodynamic diameter < 0.1 micrometers) are a ubiquitous exposure in the urban environment and are elevated near highways. Most epidemiological studies of UFP health effects use central site monitoring data, which may misclassify exposure. Our aims were to: (1) examine the relationship between distant and proximate monitoring sites and their ability to predict hourly UFP concentration measured at residences in an urban community with a major interstate highway and; (2) determine if meteorology and proximity to traffic improve explanatory power. Short-term (1 - 3 weeks) residential monitoring of UFP concentration was conducted at 18 homes. Long-term monitoring was conducted at two near-highway monitoring sites and a central site. We created models of outdoor residential UFP concentration based on concentrations at the near-highway site, at the central site, at both sites together and without fixed sites. UFP concentration at residential sites was more highly correlated with those at a near-highway site than a central site. In regression models of each site alone, a 10% increase in UFP concentration at a near-highway site was associated with a 6% (95% CI: 6%, 7%) increase at residences while a 10% increase in UFP concentration at the central site was associated with a 3% (95% CI: 2%, 3%) increase at residences. A model including both sites showed minimal change in the magnitude of the association between the near-highway site and the residences, but the estimated association with UFP concentration at the central site was substantially attenuated. These associations remained after adjustment for other significant predictors of residential UFP concentration, including distance from highway, wind speed, wind direction, highway traffic volume and precipitation. The use of a central site as an estimate of personal exposure for populations near local emissions of traffic-related air pollutants may result in exposure misclassification. PMID- 23645995 TI - Fracture of ECAP-deformed iron and the role of extrinsic toughening mechanisms. AB - The fracture behaviour of pure iron deformed by equal-channel angular pressing via route A was examined. The fracture toughness was determined for different specimen orientations and measured in terms of the critical plane strain fracture toughness, KIC , the critical J integral, JIC , and the crack opening displacement for crack initiation, CODi . The results demonstrate that the crack plane orientation has a pronounced effect on the fracture toughness. Different crack plane orientations lead to either crack deflection or delamination, resulting in increased fracture resistance in comparison to one remarkably weak specimen orientation. The relation between the microstructure typical for the applied deformation route and the enormous differences in the fracture toughness depending on the crack plane orientation will be analyzed in this paper. PMID- 23645994 TI - Nanocrystals for the parenteral delivery of poorly water-soluble drugs. AB - Nanocrystals have drawn increasing interest in pharmaceutical industry because of the ability to improve dissolution of poorly water-soluble drugs. Nanocrystals can be produced by top-down and bottom-up technologies and have been explored for a variety of therapeutic applications. Here we review the methods of nanocrystal production and parenteral applications of nanocrystals. We also discuss remaining challenges in the development of nanocrystal products. PMID- 23645996 TI - Review: Groundwater flow and transport modeling of karst aquifers, with particular reference to the North Coast Limestone aquifer system of Puerto Rico. AB - Karst systems have a high degree of heterogeneity and anisotropy, which makes them behave very differently from other aquifers. Slow seepage through the rock matrix and fast flow through conduits and fractures result in a high variation in spring response to precipitation events. Contaminant storage occurs in the rock matrix and epikarst, but contaminant transport occurs mostly along preferential pathways that are typically inaccessible locations, which makes modeling of karst systems challenging. Computer models for understanding and predicting hydraulics and contaminant transport in aquifers make assumptions about the distribution and hydraulic properties of geologic features that may not always apply to karst aquifers. This paper reviews the basic concepts, mathematical descriptions, and modeling approaches for karst systems. The North Coast Limestone aquifer system of Puerto Rico (USA) is introduced as a case study to illustrate and discuss the application of groundwater models in karst aquifer systems to evaluate aquifer contamination. PMID- 23645997 TI - Segmentation of time series with long-range fractal correlations. AB - Segmentation is a standard method of data analysis to identify change-points dividing a nonstationary time series into homogeneous segments. However, for long range fractal correlated series, most of the segmentation techniques detect spurious change-points which are simply due to the heterogeneities induced by the correlations and not to real nonstationarities. To avoid this oversegmentation, we present a segmentation algorithm which takes as a reference for homogeneity, instead of a random i.i.d. series, a correlated series modeled by a fractional noise with the same degree of correlations as the series to be segmented. We apply our algorithm to artificial series with long-range correlations and show that it systematically detects only the change-points produced by real nonstationarities and not those created by the correlations of the signal. Further, we apply the method to the sequence of the long arm of human chromosome 21, which is known to have long-range fractal correlations. We obtain only three segments that clearly correspond to the three regions of different G + C composition revealed by means of a multi-scale wavelet plot. Similar results have been obtained when segmenting all human chromosome sequences, showing the existence of previously unknown huge compositional superstructures in the human genome. PMID- 23645998 TI - "That Don't Work for Me": Patients' and Family Members' Perspectives on Palliative Care and Hospice in Late-Stage Heart Failure. PMID- 23645999 TI - Factors That Impact End-of-Life Decision Making in African Americans With Advanced Cancer. AB - SIGNIFICANCE: African Americans with cancer are less likely to use hospice services and more likely to die in the hospital than white patients with the same diagnosis. However, there is much that is not understood about the factors that lead African Americans to choose options for end-of-life care. DESIGN: A qualitative, descriptive design was used in this pilot study. METHODS: Interviews were conducted with two groups of African Americans with advanced-stage cancer (people enrolled in hospice and those who were not under hospice care). FINDINGS: End-of-life decisions were primarily guided by clinical factors, the patient related physical, emotional, and cognitive symptoms that are sequelae of the underlying disease or medical treatments. The physician was the healthcare provider most likely to be involved in decision making with patients, family members, and caregivers. Individual factors, such as personal beliefs, influenced end-of-life decision making. Religion and spirituality were a topic in many interviews, but they did not consistently influence decision making. DISCUSSION: Future studies should include interviews with family members, caregivers, and healthcare professionals so that factors that impact end-of-life decision making can be fully described. Strategies to facilitate recruitment will need to be added to future protocols. PMID- 23646000 TI - Children's Use of Social Categories in Thinking About People and Social Relationships. AB - A series of studies investigated White U.S. three- and four-year-old children's use of gender and race information to reason about their own and others' relationships and attributes. Three-year-old children used gender- but not race based similarity between themselves and others to decide with whom they wanted to be friends, as well as to determine which children shared their own preferences for various social activities. Four-year-old (but not younger) children attended to gender and racial category membership to guide inferences about others' relationships, but did not use these categories to reason about others' shared activity preferences. Taken together, the findings provide evidence for three suggestions about these children's social category-based reasoning. First, gender is a more potent category than race. Second, social categories are initially recruited for first-person reasoning, but later become broad enough to support third-person inferences. Finally, at least for third-person reasoning, thinking about social categories is more attuned to social relationships than to shared attributes. PMID- 23646001 TI - Oculomotor Exploration of Impossible Figures in Early Infancy. AB - Previous studies with young infants revealed that young infants can distinguish between displays of possible or impossible figures, which may require detection of inconsistent depth relations among local line junctions that disrupt global object configurations. Here, we used an eye-tracking paradigm to record eye movements in young infants during an object discrimination task with matched pairs of possible and impossible figures. Our goal was to identify differential patterns of oculomotor activity as infants viewed pictures of possible and impossible objects. We predicted that infants would actively attend to specific pictorial depth cues that denote shape (e.g., T-junctions), and in the context of an impossible figure that they would fixate to a greater extent in anomalous regions of the display relative to other parts. By the age of 4 months, infants fixated reliably longer overall on displays of impossible vs. possible cubes, specifically within the critical region where the incompatible lines and irreconcilable depth relations were located, implying an early capacity for selective attention to critical line junction information and integration of local depth cues necessary to perceive object coherence. PMID- 23646003 TI - Initial subspecialty certification in epilepsy application deadline april 15. PMID- 23646002 TI - Physiological Regulation at 9 Months of Age in Infants Prenatally Exposed to Cigarettes. AB - The primary purpose of this study was to examine the association between prenatal cigarette exposure and physiological regulation at 9 months of age. Specifically, we explored the possibility that any association between prenatal cigarette exposure and infant physiological regulation was moderated by postnatal environmental tobacco smoke (ETS) exposure or infant gender. We evaluated whether male infants with prenatal cigarette exposure or infants who were also exposed to ETS after birth had the highest levels of physiological dysregulation. Respiratory sinus arrhythmia (RSA) was obtained from 206 (142 exposed and 64 nonexposed) infants during a baseline period and during procedures designed to elicit both positive and negative affect. There was a significant suppression of RSA during the negative affect task for nonexposed infants but not for exposed infants. Postnatal ETS exposure did not moderate this association; however, gender did moderate this association such that boys with prenatal cigarette exposure had a significant increase in RSA rather than the suppression seen among both nonexposed boys and girls. These results provide additional support for the idea that boys are particularly vulnerable to the effects of prenatal cigarette exposure. PMID- 23646004 TI - Editorial Comment (Safety in the EMU: Reaching Consensus). PMID- 23646006 TI - Cerebral vasospasm after temporal lobe epilepsy surgery: clinically important? PMID- 23646007 TI - Treatment of catamenial epilepsy is still up in the air. PMID- 23646005 TI - Epilepsy associated with systemic autoimmune disorders. AB - Systemic autoimmune disorders affect multiple organ systems. Brain involvement commonly causes seizures, which may be the presenting symptom. Systemic lupus erythematosus, Sjorgren's syndrome, Wegener's granulomatosis, sarcoidsosis, celiac disease, Crohn's disease, Behcet's, and Hashimoto's encephalopathy are reviewed. Mechanisms underlying CNS pathology in systemic autoimmune disorders and specifically factors predisposing these patients-are discussed, including vascular disease (e.g., prothrombotic state, anticardiolipin antibody, emboli, vasculitis), antineuronal antibodies, immune complexes, cytokines, metabolic disorders, infection, and therapy. Diagnostic and therapeutic strategies must be individualized for both the disorder and the patient. Systemic autoimmune disorders affect multiple organ systems and frequently involve the central and peripheral nervous systems. Seizures are among the most common neurological manifestation and occasionally can be the presenting symptom. There are many causes of seizures in systemic autoimmune disorders (Table 1), and the first clinical challenge is to determine not only the cause but also the significance of seizures. In some cases, they are clues to metabolic or infectious disorders or medication toxicity; in other cases, seizures herald a life-threatening progression of the underlying illness. PMID- 23646008 TI - Pharmacoresistance and cognitive delays in children: a bidirectional relationship. PMID- 23646009 TI - The art of switching antiepileptic medications: keep trying or just let it be. PMID- 23646010 TI - Blurring the lines between lesional and nonlesional MRI. PMID- 23646011 TI - Slim evidence for cannabinoids for epilepsy. PMID- 23646012 TI - Levetiracetam treatment does not result in broken bones. PMID- 23646013 TI - Cognition and quality of life in children with new-onset epilepsy. PMID- 23646014 TI - Difficult-to-Localize Intractable Focal Epilepsy: An "In-Depth" Look. PMID- 23646015 TI - Is DTI Increasing the Connectivity Between the Magnet Suite and the Clinic? PMID- 23646016 TI - "Maestro" Hub Neurons Orchestrate the Immature GABA Network Symphony. PMID- 23646017 TI - Shining light on epilepsy: optical approaches for treating seizures. PMID- 23646018 TI - Cognitive and social impairment in mouse models mirrors dravet syndrome. PMID- 23646019 TI - Neuronal firing in human epileptic cortex: the ins and outs of synchrony during seizures. PMID- 23646021 TI - Safety in the EMU: Reaching Consensus. PMID- 23646020 TI - Dietary therapies for epilepsy and other neurological disorders: highlights of the 3rd international symposium. PMID- 23646022 TI - Assessment and evaluation is not a gut feeling: integrating assessment and evaluation into library operations. PMID- 23646023 TI - Bibliotherapy: tracing the roots of a moral therapy movement in the United States from the early nineteenth century to the present. PMID- 23646024 TI - Comparative effectiveness research designs: an analysis of terms and coverage in Medical Subject Headings (MeSH) and Emtree. AB - OBJECTIVES: We analyzed the extent to which comparative effectiveness research (CER) organizations share terms for designs, analyzed coverage of CER designs in Medical Subject Headings (MeSH) and Emtree, and explored whether scientists use CER design terms. METHODS: We developed local terminologies (LTs) and a CER design terminology by extracting terms in documents from five organizations. We defined coverage as the distribution over match type in MeSH and Emtree. We created a crosswalk by recording terms to which design terms mapped in both controlled vocabularies. We analyzed the hits for queries restricted to titles and abstracts to explore scientists' language. RESULTS: Pairwise LT overlap ranged from 22.64% (12/53) to 75.61% (31/41). The CER design terminology (n = 78 terms) consisted of terms for primary study designs and a few terms useful for evaluating evidence, such as opinion paper and systematic review. Patterns of coverage were similar in MeSH and Emtree (gamma = 0.581, P = 0.002). CONCLUSIONS: Stakeholder terminologies vary, and terms are inconsistently covered in MeSH and Emtree. The CER design terminology and crosswalk may be useful for expert searchers. For partially mapped terms, queries could consist of free text for modifiers such as nonrandomized or interrupted added to broad or related controlled terms. PMID- 23646025 TI - Mapping the literature of addictions treatment. AB - OBJECTIVES: This study analyzes and describes the literature of addictions treatment and indexing coverage for core journals in the field. METHODS: Citations from three source journals for the years 2008 through 2010 were analyzed using the 2010 Mapping the Literature of Nursing and Allied Health Professions Project Protocol. The distribution of cited journals was analyzed by applying Bradford's Law of Scattering. RESULTS: More than 40,000 citations were analyzed. Journals (2,655 unique titles) were the most frequently cited form of literature, with 10 journals providing one-third of the cited journal references. Drug and Alcohol Dependence was the most frequently cited journal. The frequency of cited addictions journals, formats cited, age of citations, and indexing coverage is identified. CONCLUSIONS: Addictions treatment literature is widely dispersed among multidisciplinary publications with relatively few publications providing most of the citations. Results of this study will help researchers, students, clinicians, and librarians identify the most important journals and bibliographic indexes in this field, as well as publishing opportunities. PMID- 23646026 TI - Measures of health sciences journal use: a comparison of vendor, link-resolver, and local citation statistics. AB - OBJECTIVE: Libraries require efficient and reliable methods to assess journal use. Vendors provide complete counts of articles retrieved from their platforms. However, if a journal is available on multiple platforms, several sets of statistics must be merged. Link-resolver reports merge data from all platforms into one report but only record partial use because users can access library subscriptions from other paths. Citation data are limited to publication use. Vendor, link-resolver, and local citation data were examined to determine correlation. Because link-resolver statistics are easy to obtain, the study library especially wanted to know if they correlate highly with the other measures. METHODS: Vendor, link-resolver, and local citation statistics for the study institution were gathered for health sciences journals. Spearman rank-order correlation coefficients were calculated. RESULTS: There was a high positive correlation between all three data sets, with vendor data commonly showing the highest use. However, a small percentage of titles showed anomalous results. DISCUSSION AND CONCLUSIONS: Link-resolver data correlate well with vendor and citation data, but due to anomalies, low link-resolver data would best be used to suggest titles for further evaluation using vendor data. Citation data may not be needed as it correlates highly with other measures. PMID- 23646027 TI - Mapping the literature of radiation therapy. AB - OBJECTIVE: This study characterizes the literature of the radiation therapy profession, identifies the journals most frequently cited by authors writing in this discipline, and determines the level of coverage of these journals by major bibliographic indexes. METHOD: Cited references from three discipline-specific source journals were analyzed according to the Mapping the Literature of Allied Health Project Protocol of the Nursing and Allied Health Resources Section of the Medical Library Association. Bradford's Law of Scattering was applied to all journal references to identify the most frequently cited journal titles. RESULTS: Journal references constituted 77.8% of the total, with books, government documents, Internet sites, and miscellaneous sources making up the remainder. Although a total of 908 journal titles were cited overall, approximately one third of the journal citations came from just 11 journals. MEDLINE and Scopus provided the most comprehensive indexing of the journal titles in Zones 1 and 2. The source journals were indexed only by CINAHL and Scopus. CONCLUSION: The knowledgebase of radiation therapy draws heavily from the fields of oncology, radiology, medical physics, and nursing. Discipline-specific publications are not currently well covered by major indexing services, and those wishing to conduct comprehensive literature searches should search multiple resources. PMID- 23646028 TI - Knowledge flow and exchange in interdisciplinary primary health care teams (PHCTs): an exploratory study. AB - OBJECTIVE: Improving the process of evidence-based practice in primary health care requires an understanding of information exchange among colleagues. This study explored how clinically oriented research knowledge flows through multidisciplinary primary health care teams (PHCTs) and influences clinical decisions. METHODS: This was an exploratory mixed-methods study with members of six PHCTs in Ontario, Canada. Quantitative data were collected using a questionnaire and analyzed with social network analysis (SNA) using UCINet. Qualitative data were collected using semi-structured interviews and analyzed with content analysis procedures using NVivo8. RESULTS: It was found that obtaining research knowledge was perceived to be a shared responsibility among team members, whereas its application in patient care was seen as the responsibility of the team leader, usually the senior physician. PHCT members acknowledged the need for resources for information access, synthesis, interpretation, or management. CONCLUSION: Information sharing in interdisciplinary teams is a complex and multifaceted process. Specific interventions need to be improved such as formalizing modes of communication, better organizing knowledge-sharing activities, and improving the active use of allied health professionals. Despite movement toward team-based models, senior physicians are often gatekeepers of uptake of new evidence and changes in practice. PMID- 23646029 TI - Evaluation of health information outreach: theory, practice, and future direction. AB - OBJECTIVE: Convincing evidence of the effectiveness of health information outreach projects is essential to ensure their continuity. This paper reviews the current state of health information outreach evaluation, characterizes strengths and weaknesses in projects' ability to measure their impact, and assesses enablers of and barriers to projects' success. It also relates the projects' characteristics to evaluation practices. The paper then makes recommendations for strengthening evaluation. METHODS: Upon conducting a literature search, the authors identified thirty-three articles describing consumer health information outreach programs, published between 2000 and 2010. We then analyzed the outreach projects with respect to their goals and characteristics, evaluation methods and measures, and reported outcomes. RESULTS: The results uncovered great variation in the quality of evaluation methods, outcome measures, and reporting. Outcome measures did not always match project objectives; few quantitative measures employed pretests or reported statistical significance; and institutional change was not measured in a structured way. While papers reported successful outcomes, greater rigor in measuring and documenting outcomes would be helpful. CONCLUSION: Planning outcome evaluation carefully and conducting research into mediators between health information and behavior will strengthen the ability to identify best practices and develop a theoretical framework and practical guidance for health information outreach. PMID- 23646030 TI - Analysis of inconsistencies in terminology of spinal and bulbar muscular atrophy and its effect on retrieval of research. PMID- 23646031 TI - Survey of user preferences from a comparative trial of UpToDate and ClinicalKey. PMID- 23646032 TI - Exploring the impact of tablet computers on medical training at an academic medical center. PMID- 23646033 TI - Personality-Related Risk and Resilience Factors in Coping with Daily Stress among Adult Cancer Patients. AB - We employed a diary design to study personality-related risk and resilience factors in adult cancer patients coping with daily stress. We focused on individuals' self-concept incoherence (SCI) as a personality-related risk factor and on psychological well-being (PWB) at baseline and daily beliefs of control as resilience factors. Reactivity to daily stress was assessed in terms of negative daily mood. Multilevel modeling analyses yielded significant main effects of daily stress, PWB at baseline, and daily control. These main effects were qualified by significant two- and three-way interactions. The significant Stress X Control interaction indicated that individuals reported more negative mood in response to daily stress on low-control days compared to high-control days. Similarly, a significant SCI X Control interaction suggested that individuals with a more coherent self-concept benefited more from feeling in control in terms of experiencing less increase in negative mood compared to individuals with a more incoherent self-concept. Significant three-way interactions also indicated that the associations between stress, control and negative daily mood differed by level of SCI and level of PWB at the beginning of the study. Overall, the findings from this study show the complex associations between risk and resilience factors and daily emotional well-being in a sample of adults who were affected by a life-threatening illness. PMID- 23646034 TI - Accurate Molecular Polarizabilities Based on Continuum Electrostatics. AB - A novel approach for representing the intramolecular polarizability as a continuum dielectric is introduced to account for molecular electronic polarization. It is shown, using a finite-difference solution to the Poisson equation, that the Electronic Polarization from Internal Continuum (EPIC) model yields accurate gas-phase molecular polarizability tensors for a test set of 98 challenging molecules composed of heteroaromatics, alkanes and diatomics. The electronic polarization originates from a high intramolecular dielectric that produces polarizabilities consistent with B3LYP/aug-cc-pVTZ and experimental values when surrounded by vacuum dielectric. In contrast to other approaches to model electronic polarization, this simple model avoids the polarizability catastrophe and accurately calculates molecular anisotropy with the use of very few fitted parameters and without resorting to auxiliary sites or anisotropic atomic centers. On average, the unsigned error in the average polarizability and anisotropy compared to B3LYP are 2% and 5%, respectively. The correlation between the polarizability components from B3LYP and this approach lead to a R2 of 0.990 and a slope of 0.999. Even the F2 anisotropy, shown to be a difficult case for existing polarizability models, can be reproduced within 2% error. In addition to providing new parameters for a rapid method directly applicable to the calculation of polarizabilities, this work extends the widely used Poisson equation to areas where accurate molecular polarizabilities matter. PMID- 23646035 TI - A Pilot Study of Mood Ratings Captured by Mobile Phone Versus Paper-and-Pencil Mood Charts in Bipolar Disorder. AB - OBJECTIVE: Patient reported mood charts are frequently used in management of bipolar disorder. Although mood charts have recently been programmed in electronic devices such as mobile phones, little is known about the impact of the method of data capture on the psychometric properties and validity of these data. METHODS: In an ongoing pilot study, a sample of outpatients with bipolar disorder were randomized to either complete mood charts on a mobile phone or a standard paper-and-pencil mood chart as part of a 12 week-intervention (primary outcomes for the trial await study completion). We compared these conditions across single item rating of mood state, and we hypothesized that mobile phone based data capture would produce greater compliance to mood ratings, variability between and within participants, and concurrent validity with blinded clinician-rated affective symptom severity. RESULTS: A total of 56 participants were randomized and 40 participants were included in the analyses. There were no significant differences between conditions on demographic or clinical variables. The rate of compliance was significantly higher in paper-and-pencil versus mobile phone ratings. Ratings demonstrated significantly more variability within individuals in the mobile phone condition. Mobile phone mood ratings were significantly correlated with clinician-rated depressive symptom severity across the study and with manic symptom severity at the Week 6 assessment, whereas paper-and-pencil ratings were not significantly associated with clinician-rated depression or mania. CONCLUSIONS: Although preliminary, our results suggest a lower rate of compliance with mobile phones compared to paper-and-pencil daily mood rating in bipolar disorder, yet a greater ability to capture variability and concurrent validity in quantifying affective symptoms. This clinical trial is registered at http://www.clinicaltrials.gov as NCT01670123. PMID- 23646036 TI - The "Virtual" Panel: A Computerized Model for LGBT Speaker Panels. AB - Recent societal trends indicate more tolerance for homosexuality, but prejudice remains on college campuses. Speaker panels are commonly used in classrooms as a way to educate students about sexual diversity and decrease negative attitudes toward sexual diversity. The advent of computer delivered instruction presents a unique opportunity to broaden the impact of traditional speaker panels. The current investigation examined the influence of an interactive "virtual" gay and lesbian speaker panel on cognitive, affective, and behavioral homonegativity. Findings suggest the computer-administered panel is lowers homonegativity, particularly for affective experiential homonegativity. The implications of these findings for research and practice are discussed. PMID- 23646037 TI - Encapsulation and Delivery of Crystalline Hydrophobic Nutraceuticals using Nanoemulsions: Factors Affecting Polymethoxyflavone Solubility. AB - Polymethoxyflavones (PMF) isolated from citrus peel have potent anti-cancer activity, however their utilization as functional ingredients in foods is currently limited because of their high melting point and poor water-solubility. The influence of oil type and concentration, hydrophilic polymer addition, and simulated intestinal conditions on PMF (5-hydroxytangeretin) solubility in solutions and nanoemulsions was examined. The saturation concentration of PMF in water was relatively low (0.93 uM), but could be increased appreciably by adding certain hydrophilic polymers: polyethylene glycol (PEG) and beta-cyclodextrin (CD) were ineffective at increasing solubility, but poly(vinyl alcohol) (PVA) and hydroxypropyl methylcellulose (HPMC) greatly enhanced solubility (e.g., > 6 uM for 0.5 % polymer). PMF was more soluble in medium chain triglycerides (MCT, 6.1 mM) than long chain triglycerides (LCT, 4.2 mM). The encapsulation efficiency of PMF in oil-in-water nanoemulsions was higher when MCT was used as the oil phase rather than LCT, and could be increased by increasing the oil droplet content. The solubility of PMF in simulated small intestinal fluids was increased by solubilization in bile micelles and mixed micelles formed during lipid digestion. These results have important implications for the development of functional foods fortified with bioactive hydrophobic components aimed at improving human health and wellness. PMID- 23646038 TI - Porous Shape Memory Polymers. AB - Porous shape memory polymers (SMPs) include foams, scaffolds, meshes, and other polymeric substrates that possess porous three-dimensional macrostructures. Porous SMPs exhibit active structural and volumetric transformations and have driven investigations in fields ranging from biomedical engineering to aerospace engineering to the clothing industry. The present review article examines recent developments in porous SMPs, with focus given to structural and chemical classification, methods of characterization, and applications. We conclude that the current body of literature presents porous SMPs as highly interesting smart materials with potential for industrial use. PMID- 23646039 TI - Free fatty acid oxidation in insulin resistance and obesity. AB - The growing worldwide epidemic of obesity and diabetes portends a significant increase in cardiovascular disease. Obesity is associated with insulin resistance, and there is growing evidence that these conditions independently increase the risk of heart failure. Changes in myocardial substrate utilization develop in obesity and insulin resistance, and are characterized by increased fatty acid oxidation and utilization, and decreased glucose utilization. This paper will review the evidence for altered myocardial fatty acid utilization in obesity and insulin resistance, review mechanisms that are responsible, and discuss the relative contributions of systemic and myocardial insulin resistance in the regulation of fatty acid utilization in the heart. PMID- 23646040 TI - Qualitative Characterization of the Rat Liver Mitochondrial Lipidome using LC-MS Profiling and High Energy Collisional Dissociation (HCD) All Ion Fragmentation. AB - Lipids play multiple roles essential for proper mitochondrial function, from their involvement in membrane structure and fluidity, cellular energy storage, and signaling. Lipids are also major targets for reactive species, and their peroxidation byproducts themselves mediate further damage. Thousands of lipid species, from multiple classes and categories, are involved in these processes, suggesting lipid quantitative and structural analysis can help provide a better understanding of mitochondrial physiological status. Due to the diversity of lipids that contribute to and reflect mitochondrial function, analytical methods should ideally cover a wide range of lipid classes, and yield both quantitative and structural information. We developed a high resolution LC-MS method that is able to monitor the major lipid classes found in biospecimens (ie. biofluids, cells and tissues) with relative quantitation in an efficient, sensitive, and robust manner while also characterizing individual lipid side-chains, by all ion HCD fragmentation and chromatographic alignment. This method was used to profile the liver mitochondrial lipids from 192 rats undergoing a dietary macronutrient study in which changes in mitochondria function are related to changes in the major fat and glycemic index component of each diet. A total of 381 unique lipids, spanning 5 of the major LIPID MAPS defined categories, including fatty acyls, glycerophospholipids, glycerolipids, sphingolipids and prenols, were identified in mitochondria using the non-targeted LC-MS analysis in both positive and negative mode. The intention of this report is to show the breadth of this non-targeted LC-MS profiling method with regards to its ability to profile, identify and characterize the mitochondrial lipidome and the details of this will be discussed. PMID- 23646041 TI - Self-assembling doxorubicin silk hydrogels for the focal treatment of primary breast cancer. AB - Standard care for early stage breast cancer includes tumor resection and local radiotherapy to achieve long-term remission. Systemic chemotherapy provides only low locoregional control of the disease; therefore, we describe self-assembling silk hydrogels that can retain and then deliver doxorubicin locally. Self assembling silk hydrogels show no swelling, are readily loaded with doxorubicin under aqueous conditions and release drug over 4 weeks in amounts that can be fine-tuned by varying the silk content. Following successful in vitro studies, locally injected silk hydrogels loaded with doxorubicin show excellent antitumor response in mice, outperforming the equivalent amount of doxorubicin delivered intravenously. In addition to reducing primary tumor growth, doxorubicin-loaded silk hydrogels reduce metastatic spread and are well tolerated in vivo. Thus, silk hydrogels are well suited for the local delivery of chemotherapy and provide a promising approach to improve locoregional control of breast cancer. PMID- 23646042 TI - The role of echocardiography in coronary artery disease and acute myocardial infarction. AB - Echocardiography is a non-invasive diagnostic technique which provides information regarding cardiac function and hemodynamics. It is the most frequently used cardiovascular diagnostic test after electrocardiography and chest X-ray. However, in a patient with acute chest pain, Transthoracic Echocardiography is essential both for diagnosing acute coronary syndrome, zeroing on the evaluation of ventricular function and the presence of regional wall motion abnormalities, and for ruling out other etiologies of acute chest pain or dyspnea, including aortic dissection and pericardial effusion. Echocardiography is a versatile imaging modality for the management of patients with chest pain and assessment of left ventricular systolic function, diastolic function, and even myocardial and coronary perfusion and is, therefore, useful in the diagnosis and triage of patients with acute chest pain or dyspnea. This review has focused on the current applications of echocardiography in patients with coronary artery disease and myocardial infarction. PMID- 23646043 TI - Mid-Term Follow-Up of Drug-Eluting Stenting for In-Stent Restenosis: Bare-Metal Stents versus Drug-Eluting Stents. AB - BACKGROUND: Despite major advances in percutaneous coronary intervention (PCI), in-stent restenosis (ISR) remains a therapeutic challenge. We sought to compare the mid-term clinical outcomes after treatment with repeat drug-eluting stent (DES) implantation ("DES sandwich" technique) with DES placement in the bare metal stent (DES-in-BMS) in a "real world" setting. METHODS: We retrospectively identified and analyzed clinical and angiographic data on 194 patients previously treated with the DES who underwent repeat PCI for ISR with a DES or a BMS. ISR was defined, by visual assessment, as a luminal stenosis greater than 50% within the stent or within 5 mm of its edges. We recorded the occurrence of major adverse cardiac events (MACE), defined as cardiac death, non-fatal myocardial infarction, and the need for target vessel revascularization (TVR). RESULTS: Of the 194 study participants, 130 were men (67.0%) and the mean +/- SD of age was 57.0 +/- 10.4 years, ranging from 37 to 80 years. In-hospital events (death and Q wave myocardial infarction) occurred at a similar frequency in both groups. Outcomes at twelve months were also similar between the groups with cumulative clinical MACE at one-year follow-up of 9.6% and 11.3% in the DES-in-BMS and the DES-in-DES groups, respectively (p value = 0.702). Although not significant, there was a trend toward a higher TVR rate in the intra-DES ISR group as compared to the intra-BMS ISR group (0.9% BMS vs. 5.2% DES; p value = 0.16). CONCLUSION: Our study suggests that the outcome of the patients presenting with ISR did not seem to be different between the two groups of DES-in-DES and DES-in-BMS at one year follow-up, except for a trend toward more frequent TVR in the DES-in-DES group. Repeat DES implantation for DES restenosis could be feasible and safe with a relatively low incidence of MACE at mid-term follow-up. PMID- 23646044 TI - Effect of Hypertonic Saline Infusion versus Normal Saline on Serum NGAL and Cystatin C Levels in Patients Undergoing Coronary Artery Bypass Graft. AB - BACKGROUND: Acute kidney injury (AKI) is a common and life-threatening complication following coronary artery bypass graft (CABG). Neutrophil gelatinase associated lipocalin (NGAL) and Cystatin C have shown to be good predictive factors for AKI. Recently, there has been a growing interest in the use of hypertonic saline in cardiac operations. The purpose of this study was to evaluate the prophylactic anti-inflammatory effect of hypertonic saline (Group A) infusion versus normal saline (Group B) on serum NGAL and Cystatin C levels as the two biomarkers of AKI in CABG patients. METHODS: This randomized double blinded clinical trial recruited 40 patients undergoing CABG in Tehran Heart Center, Tehran, Iran. After applying exclusion criteria, the effects of preoperative hypertonic saline (294 meq Na) versus normal saline (154 meq Na) infusion on serum NGAL and Cystatin C levels were investigated in three intervals: before surgery and 24 and 48 hours postoperatively. The probable intraoperative or postoperative confounders, including pump time, cross-clamp time, heart rate, systolic and diastolic blood pressures, central venous pressure, arterial pH, partial pressure of arterial oxygen, fraction of inspired oxygen, blood sugar, Na, K, Mg, hemoglobins, white blood cells, hematocrits, and platelets, were recorded and compared between the two groups of study. RESULTS: The study population comprised 40 patients, including 25 (62.5%) males, at a, mean age +/- SD of 61.75 +/- 8.13 years. There were no statistically significant differences between the patients' basic, intraoperative, and postoperative characteristics, including intraoperative and postoperative hemodynamic variables and supports such as inotropic use. Intra-aortic balloon pump use and mortality were not seen in our cases. Three patients in the normal saline group and one patient in the hypertonic saline group had serum NGAL levels greater than 400 ng/ml. Moreover, 10 patients in Group A and 17 patients in group B showed a rise in serum Cystatin C levels above 1.16 mg/dl. Patients with AKI had significantly elevated NGAL and Cystatin C levels (p value < 0.001), but there were no significant differences in the decrease in the NGAL level in the hypertonic saline group versus the normal saline group (230.91 +/- 92.68 vs. 239.74 +/- 116.58 ng/ml, respectively; p value = 0.792), or in the decrease in the Cystatin C level in the hypertonic saline group versus the normal saline group (1.05 +/- 0.26 vs. 1.06 +/- 0.31, respectively; p value = 0.874). CONCLUSION: Pre-treatment of CABG patients with hypertonic saline had no significant effect on serum NGAL and Cystatin C levels compared to the normal saline-receiving group. Our present data, albeit promising, have yet to fully document outcome differences. PMID- 23646045 TI - Intracoronary adenosine to prevent myonecrosis in patients with stable angina undergoing percutaneous interventions: a double-blinded randomized controlled trial. AB - BACKGROUND: Significant elevation of cardiac biomarkers after percutaneous coronary intervention (PCI) is associated with increased mortality. However, clinical importance of lesser degrees of cardiac enzyme elevation has not been well understood. Multiple factors might have an etiologic role, and the incidence of myonecrosis has not changed dramatically despite pharmacological and technological advances in PCI. The aim of this study was to evaluate the role of intracoronary (IC) Adenosine in preventing the elevation of cardiac enzymes as a marker of myonecrosis after PCI in patients with chronic stable angina. METHODS: Two hundred sixty patients with chronic stable angina who were candidates for PCI were randomly assigned to double-blinded pretreatment with IC Adenosine or placebo before crossing of the guide wire. The patients were observed during the hospital course, and blood samples were obtained in standard intervals after the intervention for cardiac biomarkers. The primary end point of this study was post PCI myonecrosis, and secondary end point was safety of IC Adenosine administration in the setting of PCI in patients with chronic stable angina. RESULTS: Of the 260 patients, who were initially randomized, finally 83 patients were analyzed in the placebo and 96 in the Adenosine arms. The study patients were comparable in clinical and angiographic characteristics. The mean of the patients' age was 57.3 years (range = 35 to 79 years), and 71.5% were male. There were no differences in the mean serum cardiac biomarkers between the study groups (mean creatine kinase-MB [CK.MB] level of 29.5 +/- 14.5 IU/L in the placebo group and 31.5 +/- 18.5 IU/L in the control group; p value = 0.41; mean cardiac troponin I (cTnI) level of 0.097 +/- 0.178 MUg/L in the placebo group and 0.167 +/- 0.5 MUg/L in the control group; p value = 0.24). CONCLUSION: Despite promising results in primary PCI, our study showed that a strategy of IC Adenosine pretreatment is not beneficial in reducing post-PCI myonecrosis in patients with chronic stable angina and should not be routinely used. PMID- 23646046 TI - Comparison of right and left side heart functions in patients with thalassemia major, patients with thalassemia intermedia, and control group. AB - BACKGROUND: Heart disease is the main cause of mortality and morbidity in patients with beta thalassemia, rendering its early diagnosis vital. We studied and compared echocardiographic findings in patients with beta thalassemia major, patients with beta thalassemia intermedia, and a control group. METHODS: Eighty asymptomatic patients with thalassemia major and 22 asymptomatic cases with thalassemia intermedia (8-25 years old) were selected from those referred to Ali Asghar Hospital (Zahedan-Iran) between June 2008 and June 2009. Additionally, 80 healthy individuals within the same age and sex groups were used as controls. All the individuals underwent echocardiography, the data of which were analyzed with the Student t-test. RESULTS: The mean value of the pre-ejection period/ejection time ratio of the left ventricle during systole, the diameter of the posterior wall of the left ventricle during diastole, the left and right isovolumic relaxation times, and the right myocardial performance index in the patients with beta thalassemia major and intermedia increased significantly compared to those of the controls, but the other parameters were similar between the two patient groups. The mean values of the left and right pre-ejection periods, left ventricular end systolic dimension, and left isovolumic contraction time in the patients with thalassemia intermedia increased significantly compared to those of the controls. In the left side, myocardial performance index, left ventricular mass index, isovolumic contraction time, and deceleration time exhibited significant changes between the patients with thalassemia major and those with thalassemia intermedia, whereas all the echocardiographic parameters of the right side were similar between these two groups. CONCLUSION: The results showed that the systolic and diastolic functions of the right and left sides of the heart would be impaired in patients with thalassemia major and thalassemia intermedia. Consequently, serial echocardiography is suggested in asymptomatic patients with beta thalassemia for an early diagnosis of heart dysfunction and proper treatment. PMID- 23646048 TI - Impact of Intact Pleura during Left Internal Mammary Artery Harvesting on Clinical Outcome. AB - BACKGROUND: Pleurotomy during coronary artery bypass grafting (CABG) may cause post-operative events, mostly pulmonary complications. In this study, we evaluated the influence of pleurotomy during CABG on the clinical outcome following left internal mammary artery (LIMA) harvesting. METHODS: Between March and August 2009, 102 patients who underwent cardiac surgery were enrolled in this study and divided into two groups: group A (n = 48, 36 male and 12 female patients at a mean age of 56.5 +/- 11.2 years) underwent routine CABG and pleurotomy and group B (n = 54, 46 male and 8 female patients at a mean age of 55.4 +/- 10.3 years) had CABG with intact pleura. The patients were compared regarding their demographic data, surgical data, and postoperative events. RESULTS: THE INCIDENCE OF POSTOPERATIVE PERICARDIAL EFFUSION WAS SIMILAR BETWEEN THE GROUPS, BUT THE INCIDENCE OF POSTOPERATIVE PULMONARY COMPLICATIONS SUCH AS PLEURAL EFFUSION (EXCEPT FOR MILD PLEURAL EFFUSION) ON THE SECOND (NO: 10.4%, mild: 41.7%, moderate: 45.8% and severe: 2.1% in group A versus no: 42.6%, mild: 44.4%, moderate: 13%, and severe: 0 in group B) and fifth postoperative days (no: 27.1%, mild: 33.3%, moderate: 35.4%, and severe: 4.2% in group A versus no: 42.6%, mild: 44.4%, moderate: 13%, and severe: 0 in group B) was significantly lower in group B (p value < 0.001 and p value = 0.007, respectively). Also, the incidence of atelectasis (except for mild atelectasis) on the second (no: 2.1%, mild: 22.9%, moderate: 72.9%, and severe: 2.1% in group A versus no: 9.2%, mild: 59.3%, moderate: 31.5%, and severe: 0 in group B) and fifth postoperative days (no: 22.9%, mild: 39.6%, moderate: 35.4%, and severe: 2.1% in group A versus no: 39.6%, mild: 49.1%, moderate: 11.3%, and severe: 0 in group B) was significantly higher in group A (p value < 0.001 and p value = 0.004, respectively). Postoperative partial oxygen pressure and O2 saturation were similar between the groups, but partial carbon dioxide pressure was significantly lower in group A (p value = 0.017). Amount of bleeding (p value = 0.008) and duration of hospitalization (p value = 0.002) were significantly higher in group A than those in group B. CONCLUSION: Our results indicate that keeping the pleura intact has beneficial effects on the respiratory function, without increasing the incidence of postoperative pericardial effusion. PMID- 23646047 TI - Cardiac variables as main predictors of endotracheal reintubation rate after cardiac surgery. AB - BACKGROUND: Reintubation in patients after cardiac surgery is associated with undesirable consequences. The purpose of the present study was to identify variables that could predict reintubation necessity in this group of patients. METHODS: We performed a prospective study in 1000 consecutive adult patients undergoing cardiac surgery with cardiopulmonary bypass. The patients who required reintubation after extubation were compared with patients not requiring reintubation regarding demographic and preoperative clinical variables, including postoperative complications and in-hospital mortality. RESULTS: Postoperatively, 26 (2.6%) of the 1000 patients studied required reintubation due to respiratory, cardiac, or neurological reasons. Advanced age and mainly cardiac variables were determined as univariate intra- and postoperative predictors of reintubation (all p values < 0.05). Multiple logistic regression analysis revealed lower preoperative (p = 0.014; OR = 3.00, 95%CI: 1.25 - 7.21), and postoperative ejection fraction (p = 0.001; OR = 11.10, 95%CI: 3.88 - 31.79), valvular disease (p = 0.043; OR = 1.84, 95%CI: 1.05 - 3.96), arrhythmia (p = 0.006; OR = 3.84, 95%CI: 1.47 - 10.03), and postoperative intra-aortic balloon pump requirement (p = 0.019; OR = 4.20, 95%CI: 1.26 - 14.00) as the independent predictors of reintubation. CONCLUSIONS: These findings reveal that cardiac variables are more common and significant predictors of reintubation after cardiac surgery in adult patients than are respiratory variables. The incidence of this complication, reintubation, is low, although it could result in significant postoperative morbidity and mortality. PMID- 23646049 TI - Positive family history as the single traditional risk factor for developing extensive very premature coronary artery disease: a case report. AB - Although coronary artery disease (CAD) is not common among individuals younger than 40-45 years of age, a small percentage of this age group needs to undergo surgical revascularization because of CAD. Why some people are at higher risk of developing premature CAD is not clearly known. Increased number of traditional risk factors or genetic predisposition may play significant roles in this regard. A 22-year-old man with a negative history for all traditional risk factors except for a family history of premature CAD referred to our center due to an episode of myocardial infarction of one month's duration. He had no congenital heart disease and no hypercoagulable state, and there was a negative history of drug abuse. His coronary angiography showed extensive CAD. He underwent coronary artery bypass grafting and he left the hospital in good healthy condition. One year after surgery, his follow-up showed that he was symptom free and he still had no new traditional risk factor. It seems that a positive family history of premature CAD is an important and independent risk factor for developing premature CAD and individuals with this type of history should be treated more cautiously. PMID- 23646050 TI - Left pulmonary artery stenting with glenn shunt: introducing a hybrid procedure. AB - Complexity of some congenital heart diseases sometimes necessitates a combination of interventional procedures and surgery, amongst which intraoperative stent implantation is one of the most common. We herein report a successful hybrid procedure in a cyanotic adult patient who had undergone no procedure in childhood. The patient was a 24-year-old cyanotic male (oxygen saturation in the room air was 65%) who presented with dyspnea. According to echocardiography, catheterization, and cardiac magnetic resonance imaging data, the patient was amenable to the Fontan surgery. However, because of significant left pulmonary stenosis and his age, he first underwent a hybrid procedure (Glenn shunt and left pulmonary artery [LPA] stenting). After the procedure, oxygen saturation rose to 83%. At six months' follow-up of the patient, exercise capacity and cyanosis had improved significantly, with O2 saturation having reached near 85% by pulse oximetry. PMID- 23646051 TI - A Limb-Saving Procedure for Treatment of Arterial Cement Embolism during Lumbar Percutaneous Vertebroplasty: A Case Report. AB - As the major hazard of percutaneous vertebroplasty (PV), cement extravasation into the venous system, systemic embolism, and spinal canal has been previously reported. However, to our knowledge, only one case of the arterial migration of cement has been previously reported that is directly associated with this technique without any symptom in the immediate post-intervention and in the follow-up period. An arterial embolus of cement occurred in a 46-year-old woman undergoing lumbar PV for breast cancer metastasis. Less than one hour later, the patient complained of severe pain and numbness in her left leg. A diagnosis of acute left leg ischemia due to the acute occlusion of the infrapopliteal arteries by the cement was made. Transluminal angioplasty (PTA) for the infrapopliteal arteries was recommended because there were diffuse and long vessel involvements, leaving no distal targets for bypass vascular surgery. The patient's postoperative course was uncomplicated; the extremity tenderness and mottled skin were improved. A follow-up ultrasound 2 months later revealed an acceptable distal flow in the arteries of the affected limb, and the patient remained asymptomatic (except for a mild leg pain on exertion) at the one-year follow-up examination. In conclusion, PTA may save the limb from amputation in case of peripheral arterial embolism caused by cement during PV. PMID- 23646052 TI - Endoscopic treatment of vesicoureteral reflux in pediatric patients. AB - Endoscopic treatment is a minimally invasive treatment for managing patients with vesicoureteral reflux (VUR). Although several bulking agents have been used for endoscopic treatment, dextranomer/hyaluronic acid is the only bulking agent currently approved by the U.S. Food and Drug Administration for treating VUR. Endoscopic treatment of VUR has gained great popularity owing to several obvious benefits, including short operative time, short hospital stay, minimal invasiveness, high efficacy, low complication rate, and reduced cost. Initially, the success rates of endoscopic treatment have been lower than that of open antireflux surgery. However, because injection techniques have been developed, a recent study showed higher success rates of endoscopic treatment than open surgery in the treatment of patients with intermediate- and high-grade VUR. Despite the controversy surrounding its effectiveness, endoscopic treatment is considered a valuable treatment option and viable alternative to long-term antibiotic prophylaxis. PMID- 23646053 TI - Expression of peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR gamma in the lung tissue of obese mice and the effect of rosiglitazone on proinflammatory cytokine expressions in the lung tissue. AB - PURPOSE: We investigated the mRNA levels of peroxisome proliferator-activated receptor (PPAR)-alpha, PPAR-gamma, adipokines, and cytokines in the lung tissue of lean and obese mice with and without ovalbumin (OVA) challenge, and the effect of rosiglitazone, a PPAR-gamma agonist. METHODS: We developed 6 mice models: OVA challenged lean mice with and without rosiglitazone; obese mice with and without rosiglitazone; and OVA-challenged obese mice with and without rosiglitazone. We performed real-time polymerase chain reaction for leptin, leptin receptor, adiponectin, vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, PPAR-alpha and PPAR-gamma from the lung tissue and determined the cell counts and cytokine levels in the bronchoalveolar lavage fluid. RESULTS: Mice with OVA challenge showed airway hyperresponsiveness. The lung mRNA levels of PPARalpha and PPAR-gamma increased significantly in obese mice with OVA challenge compared to that in other types of mice and decreased after rosiglitazone administeration. Leptin and leptin receptor expression increased in obese mice with and without OVA challenge and decreased following rosiglitazone treatment. Adiponectin mRNA level increased in lean mice with OVA challenge. Lung VEGF, TNF-alpha, and TGF-beta mRNA levels increased in obese mice with and without OVA challenge compared to that in the control mice. However, rosiglitazone reduced only TGF-beta expression in obese mice, and even augmented VEGF expression in all types of mice. Rosiglitazone treatment did not reduce airway responsiveness, but increased neutrophils and macrophages in the bronchoalveolar lavage fluid. CONCLUSION: PPAR-alpha and PPAR gamma expressions were upregulated in the lung tissue of OVA-challenged obese mice however, rosiglitazone treatment did not downregulate airway inflammation in these mice. PMID- 23646054 TI - p-Cresyl sulfate and indoxyl sulfate in pediatric patients on chronic dialysis. AB - PURPOSE: Indoxyl sulfate and p-cresyl sulfate are important protein-bound uremic retention solutes whose levels can be partially reduced by renal replacement therapy. These solutes originate from intestinal bacterial protein fermentation and are associated with cardiovascular outcomes and chronic kidney disease progression. The aims of this study were to investigate the levels of indoxyl sulfate and p-cresyl sulfate as well as the effect of probiotics on reducing the levels of uremic toxins in pediatric patients on dialysis. METHODS: We enrolled 20 pediatric patients undergoing chronic dialysis; 16 patients completed the study. The patients underwent a 12-week regimen of VSL#3, a high-concentration probiotic preparation, and the serum levels of indoxyl sulfate and p-cresyl sulfate were measured before treatment and at 4, 8, and 12 weeks after the regimen by using fluorescence liquid chromatography. To assess the normal range of indoxyl sulfate and p-cresyl sulfate we enrolled the 16 children with normal glomerular filtration rate who had visited an outpatient clinic for asymptomatic microscopic hematuria that had been detected by a school screening in August 2011. RESULTS: The baseline serum levels of indoxyl sulfate and p-cresyl sulfate in the patients on chronic dialysis were significantly higher than those in the children with microscopic hematuria. The baseline serum levels of p-cresyl sulfate in the peritoneal dialysis group were significantly higher than those in the hemodialysis group. There were no significant changes in the levels of these uremic solutes after 12-week VSL#3 treatment in the patients on chronic dialysis. CONCLUSION: The levels of the uremic toxins p-cresyl sulfate and indoxyl sulfate are highly elevated in pediatric patients on dialysis, but there was no significant effect by probiotics on the reduction of uremic toxins in pediatric dialysis patients. Therefore, studies for other medical intervention to reduce uremic toxins are also necessary in pediatric patients on dialysis. PMID- 23646055 TI - Occurrence and characterization of oseltamivir-resistant influenza virus in children between 2007-2008 and 2008-2009 seasons. AB - PURPOSE: There was a global increase in the prevalence of oseltamivir-resistant influenza viruses during the 2007-2008 influenza season. This study was conducted to investigate the occurrence and characteristics of oseltamivir-resistant influenza viruses during the 2007-2008 and 2008-2009 influenza seasons among patients who were treated with oseltamivir (group A) and those that did not receive oseltamivir (group B). METHODS: A prospective study was conducted on 321 pediatric patients who were hospitalized because of influenza during the 2007 2008 and 2008-2009 influenza seasons. Drug resistance tests were conducted on influenza viruses isolated from 91 patients. RESULTS: There was no significant difference between the clinical characteristics of groups A and B during both seasons. Influenza A/H1N1, isolated from both groups A and B during the 2007-2008 and 2008-2009 periods, was not resistant to zanamivir. However, phenotypic analysis of the virus revealed a high oseltamivir IC50 range and that H275Y substitution of the neuraminidase (NA) gene and partial variation of the hemagglutinin (HA) gene did not affect its antigenicity to the HA vaccine even though group A had a shorter hospitalization duration and fewer lower respiratory tract complications than group B. In addition, there was no significant difference in the clinical manifestations between oseltamivir-susceptible and oseltamivir-resistant strains of influenza A/H1N1. CONCLUSION: Establishment of guidelines to efficiently treat influenza with oseltamivir, a commonly used drug for treating influenza in Korean pediatric patients, and a treatment strategy with a new therapeutic agent is required. PMID- 23646056 TI - The hybrid perventricular closure of apical muscular ventricular septal defect with Amplatzer duct occluder. AB - PURPOSE: Apical muscular ventricular septal defects (MVSDs), especially in small infants, can be difficult to manage using surgical and percutaneous closure. An intraoperative perventricular procedure is a good option for closing apical MVSDs in small children with or without associated cardiac anomalies. We evaluated the results of hybrid perventricular closure of apical MVSDs performed using an Amplatzer duct occluder (ADO). METHODS: We retrospectively reviewed the medical records of 5 patients who underwent hybrid perventricular closure of MVSDs with ADOs, from March 2006 to May 2011. The median patient age at the time of the procedure was 12 months (range, 25 days to 25 months), and the median body weight was 9.1 kg (range, 4.3 to 15 kg). Two patients had multiple ventricular septal defects (VSDs; additional perimembranous VSD in 1 patient and multiple MVSDs in the other) and 3 patients had associated cardiac anomalies; complete transposition of the great arteries in 1 patient and an atrial septal defect in 2 patients. All the procedures were performed on beating hearts, exception in 1 case. The ADO selected for the aortic side was at least 1 to 2 mm larger than the largest VSD in the left ventricle side. RESULTS: The procedure was successful in all patients and each device was well positioned. During the median follow-up of 2.4 years, a small residual VSD was noted in 2 patients who had multiple VSDs and no leakage was seen in the other 3 patients. CONCLUSION: Perventricular closure of MVSD with an ADO is a good option for patients with apical MVSD. However, careful manipulation is important, especially in the case of small infants. PMID- 23646057 TI - An unusual cause of duodenal perforation due to a lollipop stick. AB - Children have a natural tendency to explore objects with their mouths; this can result in the swallowing of foreign objects. Most ingested foreign bodies pass uneventfully through the gastrointestinal tract. However, some foreign bodies cause obstruction or perforation of the gastrointestinal tract, requiring surgical intervention. Perforation of the gastrointestinal tract may be associated with considerable morbidity and mortality. The most common sites of intestinal foreign body perforation are the ileocecal and rectosigmoid regions. Foreign body perforation of the duodenum is relatively uncommon. We report the first Korean case of duodenal perforation by an ingested 8-cm lollipop stick. Lollipops are popular with the children and fairly accessible to them, as most parents are not aware of their potential harm. Pediatric clinicians should be aware of the risks associated with lollipop stick ingestion. Our report also describes the feasibility and safety of laparoscopic diagnosis and management of pediatric patients with peritonitis induced by the ingestion of foreign bodies. PMID- 23646058 TI - Lung torsion after tracheoesophageal fistula repair in an infant. AB - Lung torsion is a very rare event that has been reported in only 9 cases in the pediatric literature but has not yet been reported in Korean infants. We present a case of lung torsion after tracheoesophageal fistula repair in an infant. Bloody secretion from the endotracheal tube and chest radiographs and computed tomographic scan results indicated lung torsion. Emergency exploration indicated 180 degrees torsion of the right upper lobe (RUL) and right middle lobe (RML). After detorsion of both lobes, some improvement in the RUL color was observed, but the color change in the RML could not be determined. Although viability of the RML could not be proven, pexy was performed for both the lobes. Despite reoperation, clinical signs and symptoms did not improve. The bronchoscopy revealed a patent airway in the RUL but not in the RML. Finally, the RML was surgically removed. The patient was discharged on the 42nd day after birth. PMID- 23646059 TI - Alzheimer's Disease Drug Discovery: In-vivo screening using C. elegans as a model for beta-amyloid peptide-induced toxicity. AB - Alzheimer's disease (AD) is a complex human neurodegenerative disease. Currently the therapeutics for AD only treat the symptoms. While numbers of excellent studies have used mammalian models to discover new compounds, the time and effort involved with screening large numbers of candidates is prohibitive. Cultured mammalian neurons are of often used to perform high through-put screens (HTS) however, cell culture lacks the organismal complexity involved in AD. To address these issues a number of researchers are turning to the round worm, C. elegans. C. elegans has numerous models of both Tau and Abeta induced toxicity; the two prime components observed to correlate with AD pathology. These models have lead to the discovery of numerous AD modulating candidates. Further, the ease of performing RNAi for any gene in the C. elegans genome allows for identification of proteins involved in the mechanism of drug action. These attributes make C. elegans well positioned to aid in the discovery of new AD therapies. PMID- 23646060 TI - Zebrafish based small molecule screens for novel DMD drugs. AB - Recently, a number of chemical and drug screens using zebrafish embryos have been published. Using zebrafish dystrophin mutants, we screened a chemical library for small molecules that modulate the muscle phenotype and identified seven small molecules that influence muscle pathology in dystrophin-null zebrafish. One chemical, aminophylline, which is known to be a non-selective phosphodiesterase (PDE) inhibitor, had the greatest ability to restore normal muscle structure and to up-regulate cAMP-dependent protein kinase (PKA) in treated dystrophin deficient fish. Our methodologies, which combine drug screening with assessment of the chemical effects by genotyping and staining with anti-dystrophin, provide a powerful means to identify template structures potentially relevant to the development of novel human muscular dystrophies therapeutics. PMID- 23646062 TI - Divergent Streams: Race-Gender Achievement Gaps at Selective Colleges and Universities. AB - In this paper, we extend previous research on racial performance gaps at 28 selective US colleges and universities by examining differences in grade achievement and graduate rates across race-gender categories. Using data from the National Longitudinal Survey of Freshmen, we show that black males, black females, and Hispanic males attain significantly lower grades than other race gender groups, and that black males are 35% less likely to graduate on-time than other race-gender groups. Analyses consider an array of personal and institutional indicators of academic performance. Grades and graduation rates are improved by academic preparation (particularly high school GPA), scholarly effort, and, for graduation rates, membership in career-oriented or majority white campus groups. Grade performance and graduation rates are undermined by a hostile racial climate on campus, family stress, and stereotype threat, all of which disproportionately affect minority students. We conclude with recommendations to college administrators for ways of selecting and supporting minority students to reduce differentials in academic achievement across race gender groups. PMID- 23646061 TI - Epigenetic Modulations of Induced Pluripotent Stem Cells: Novel Therapies and Disease Models. AB - Recent breakthroughs in induced pluripotent stem cell (iPSC) technology hold promise for novel cell-based therapies as well as for effective drug development. The therapeutic potential of iPSCs makes it important to understand the reprogramming mechanisms and iPSC differentiation process. Epigenetic states that mediate exogenous stimulations on cell-intrinsic transcriptional features play a key role in iPSCs. This review focuses on epigenetic mechanisms that control iPSC pluripotency and differentiation. We discuss the potential application of epigenetic modulations in development of iPSC-based therapies and disease models. PMID- 23646063 TI - Low intensity ultrasound perturbs cytoskeleton dynamics. AB - Therapeutic ultrasound is widely employed in clinical applications but its mechanism of action remains unclear. Here we report prompt fluidization of a cell and dramatic acceleration of its remodeling dynamics when exposed to low intensity ultrasound. These physical changes are caused by very small strains (10 5) at ultrasonic frequencies (106 Hz), but are closely analogous to those caused by relatively large strains (10-1) at physiological frequencies (100 Hz). Moreover, these changes are reminiscent of rejuvenation and aging phenomena that are well-established in certain soft inert materials. As such, we suggest cytoskeletal fluidization together with resulting acceleration of cytoskeletal remodeling events as a mechanism contributing to the salutary effects of low intensity therapeutic ultrasound. PMID- 23646064 TI - Reactions, beliefs and concerns associated with providing hair specimens for medical research among a South African sample: a qualitative approach. AB - In order to optimize treatment outcome among antiretroviral therapy users, there is a strong imperative to engage in continued monitoring and maintenance of therapeutic drug levels in patients. The aim of this study was to document the perspectives, beliefs, and concerns of South African antiretroviral therapy users providing hair specimens to determine antiretroviral drug levels. Twenty-one women living with HIV were recruited from a community health center in the Western Cape. Interviews were recorded and transcribed, and analyzed using Atlas.ti version 6. Although participants identified several cultural beliefs influencing their decision to provide hair specimens for drug level measurement, nearly all agreed that they would be willing to do so if provided with enough information by the researcher. PMID- 23646065 TI - Personalizing behavioral interventions: the case of late-life depression. AB - This article reviews the potential utility of behavioral interventions in personalized depression treatment. The paper begins with a definition of personalized treatment, moves to current thinking regarding the various causes of depression, and proposes how those causes can be used to inform the selection of behavioral interventions. Two examples from the late-life depression field will illustrate how a team of researchers at Cornell University (NY, USA) and University of California, San Francisco (CA, USA) created a research partnership to select and study behavioral interventions for older adults with risk factors associated with poor response to selective serotonin reuptake inhibitor medications. The paper ends with a discussion of how the process used by the Cornell University-University of California, San Francisco team can be applied to the selection and development of behavioral interventions for other psychiatric disorders. PMID- 23646067 TI - Regulation of Adipose Tissue Metabolism in Humans: Analysis of Responses to the Hyperinsulinemic-Euglycemic Clamp Experiment. AB - The suppression of lipolysis is one of the key metabolic responses of the adipose tissue during hyperinsulinemia. The failure to respond and resulting increase in plasma fatty acids could contribute to the development of insulin resistance and perturbations in the fuel homeostasis in the whole body. In this study, a mechanistic, computational model of adipose tissue metabolism in vivo has been enhanced to simulate the physiological responses during hyperinsulinemic euglycemic clamp experiment in humans. The model incorporates metabolic intermediates and pathways that are important in the fed state. In addition, it takes into account the heterogeneity of triose phosphate pools (glycolytic vs. glyceroneogenic), within the adipose tissue. The model can simulate not only steady-state responses at different insulin levels, but also concentration dynamics of major metabolites in the adipose tissue venous blood in accord with the in vivo data. Simulations indicate that (1) regulation of lipoprotein lipase (LPL) reaction is important when the intracellular lipolysis is suppressed by insulin; (2) intracellular diglyceride levels can affect the regulatory mechanisms; and (3) glyceroneogenesis is the dominant pathway for glycerol-3 phosphate synthesis even in the presence of increased glucose uptake by the adipose tissue. Reduced redox and increased phosphorylation states provide a favorable milieu for glyceroneogenesis in response to insulin. A parameter sensitivity analysis predicts that insulin-stimulated glucose uptake would be more severely affected by impairment of GLUT4 translocation and glycolysis than by impairment of glycogen synthesis and pyruvate oxidation. Finally, simulations predict metabolic responses to altered expression of phosphoenolpyruvate carboxykinase (PEP-CK). Specifically, the increase in the rate of re esterification of fatty acids observed experimentally with the overexpression of PEPCK in the adipose tissue would be accompanied by the up-regulation of acyl Co A synthase. PMID- 23646066 TI - Examining the role of lipid mediators in diabetic retinopathy. AB - Diabetic retinopathy is the most disabling complication of diabetes, affecting 65% of patients after 10 years of the disease. Current treatment options for diabetic retinopathy are highly invasive and fall short of complete amelioration of the disease. Understanding the pathogenesis of diabetic retinopathy is critical to the development of more effective treatment options. Diabetic hyperglycemia and dyslipidemia are the main metabolic insults that affect retinal degeneration in diabetes. Although the role of hyperglycemia in inducing diabetic retinopathy has been studied in detail, much less attention has been paid to dyslipidemia. Recent clinical studies have demonstrated a strong association between dyslipidemia and development of diabetic retinopathy, highlighting the importance of understanding the exact changes in retinal lipid metabolism in diabetes. This review describes what is known on the role of dyslipidemia in the development of diabetic retinopathy, with a focus on retinal-specific lipid metabolism and its dysregulation in diabetes. PMID- 23646068 TI - Cytoplasmic dynein: tension generation on microtubules and the nucleus. AB - Cytoplasmic dynein is a microtubule dependent motor protein that is central to vesicle transport, cell division and organelle positioning. Recent studies suggest that dynein can generate significant pulling forces on intracellular structures as it motors along microtubules. In this review, we discuss how dynein generated pulling forces position the nucleus and the centrosome. PMID- 23646069 TI - Light-scattering-based analysis of biomolecular interactions. AB - While light scattering has long been applied to the analysis of biomolecular interactions, recent advances have extended the practical use of light scattering techniques to cover a rather broad range of phenomena. In this paper I review essential light scattering theory as applied to specific interactions under thermodynamically ideal conditions and present examples showing how light scattering elucidates the dynamic equilibrium and kinetic behavior of proteins and other biomacromolecules. PMID- 23646070 TI - Hydrodynamic modelling of protein conformation in solution: ELLIPS and HYDRO. AB - The last three decades has seen some important advances in our ability to represent the conformation of proteins in solution on the basis of hydrodynamic measurements. Advances in theoretical modeling capabilities have been matched by commensurate advances in the precision of hydrodynamic measurements. We consider the advances in whole-body (simple ellipsoid-based) modeling-still useful for providing an overall idea of molecular shape, particularly for those systems where only a limited amount of data is available-and outline the ELLIPS suite of algorithms which facilitates the use of this approach. We then focus on bead modeling strategies, particularly the surface or shell-bead approaches and the HYDRO suite of algorithms. We demonstrate how these are providing great insights into complex issues such as the conformation of immunoglobulins and other multi domain complexes. PMID- 23646071 TI - Associations between the concurrent use of clinical decision support and computerized provider order entry and the rates of appropriate prescribing at discharge. AB - INTRODUCTION: Electronic health record systems used in conjunction with clinical decision support (CDS) or computerized provider order entry (CPOE) have shown potential in improving quality of care, yet less is known about the effects of combination use of CDS and CPOE on prescribing rates at discharge. OBJECTIVES: This study investigates the effectiveness of combination use of CDS and CPOE on appropriate drug prescribing rates at discharge for AMI or HF patients. METHODS: Combination use of CDS and CPOE is defined as hospitals self-reporting full implementation across all hospital units of CDS reminders, CDS guidelines, and CPOE. Appropriate prescribing rates of aspirin, ACEI/ARBs, or beta blockers are defined using quality measures from Hospital Compare. Multivariate linear regressions are used to test for differences in mean appropriate prescribing rates between hospitals reporting combination use of CDS and CPOE, compared to those reporting the singular use of one or the other, or the absence of both. Covariates include hospital size, region, and ownership status. RESULTS: Approximately 10% of the sample reported full implementation of both CDS and CPOE, while 7% and 17% reported full use of only CPOE or only CDS, respectively. Hospitals reporting full use of CDS only reported between 0.2% (95% CI 0.04 - 1.0) and 1.6% (95% CI 0.6 - 2.6) higher appropriate prescribing rates compared to hospitals reporting use of neither system. Rates of prescribing by hospitals reporting full use of both CPOE and CDS did not significantly differ from the control group. CONCLUSIONS: Although associations found between full implementation of CDS and appropriate prescribing rates suggest that clinical decision tools are sufficient compared to basic EHR systems in improving prescribing at discharge, the modest differences raise doubt about the clinical relevance of the findings. Future studies need to continue investigating the causal nature and clinical relevance of these associations. PMID- 23646072 TI - Health information exchange and ambulatory quality of care. AB - BACKGROUND: Health information exchange is a national priority, but there is limited evidence of its effectiveness. OBJECTIVE: We sought to determine the effect of health information exchange on ambulatory quality. METHODS: We conducted a retrospective cohort study over two years of 138 primary care physicians in small group practices in the Hudson Valley region of New York State. All physicians had access to an electronic portal, through which they could view clinical data (such as laboratory and radiology test results) for their patients over time, regardless of the ordering physician. We considered 15 quality measures that were being used by the community for a pay-for-performance program, as well as the subset of 8 measures expected to be affected by the portal. We adjusted for 11 physician characteristics (including health care quality at baseline). RESULTS: Nearly half (43%) of the physicians were portal users. Non-users performed at or above the regional benchmark on 48% of the measures at baseline and 49% of the measures at followup (p = 0.58). Users performed at or above the regional benchmark on 57% of the measures at baseline and 64% at follow-up (p<0.001). Use of the portal was independently associated with higher quality of care at follow-up for those measures expected to be affected by the portal (p = 0.01), but not for those not expected to be affected by the portal (p = 0.12). CONCLUSIONS: Use of an electronic portal for viewing clinical data was associated with modest improvements in ambulatory quality. PMID- 23646073 TI - The effects of health information technology change over time: a study of Tele ICU functions. AB - OBJECTIVES: Longitudinal studies exploring the evolution of health information technology functions provide valuable information about how technology systems are integrated and exploited in situ. This study reports changes in the distribution of functions for a specific health information technology, the tele ICU, over time. The studied tele-ICU provided care to six remote ICUs within a local geographic region in the same state and had nursing staff around the clock. METHODS: The intervention logs of tele-ICU nurses were collected during two discrete times and coded into nine emergent functional categories, who initiated the intervention and, if required, subsequent escalation. All coded functional categories were investigated for significant changes over time in the nursing logged interventions. RESULTS: A total of 1927 interventions were coded into the nine emergent functional categories. Seven of the nine categories (78%) were significantly different between 2005 and 2007. The functions of the tele-ICU system continue to change and develop over time. CONCLUSION: These findings suggest that the tele-ICU increased support when ICU nurses were off the unit, inter-hospital coordinating and adherence to best practices, while simultaneously decreasing real-time support for ICU nurses. This research suggests that sustaining safety features in a new technology over time have post-conditions after implementation. PMID- 23646074 TI - Classifying health information technology patient safety related incidents - an approach used in Wales. AB - Interest in the field of patient safety incident reporting and analysis with respect to Health Information Technology (HIT) has been growing over recent years as the development, implementation and reliance on HIT systems becomes ever more prevalent. One of the rationales for capturing patient safety incidents is to learn from failures in the delivery of care and must form part of a feedback loop which also includes analysis; investigation and monitoring. With the advent of new technologies and organizational programs of delivery the emphasis is increasingly upon analyzing HIT incidents. This thematic review had two objectives, to test the applicability of a framework specifically designed to categorize HIT incidents and to review the Welsh incidents as communicated via the national incident reporting system in order to understand their implications for healthcare. The incidents were those reported as IT/ telecommunications failure/ overload. Incidents were searched for within a national reporting system using a standardized search strategy for incidents occurring between 1(st) January 2009 and 31(st) May 2011. 149 incident reports were identified and classified. The majority (77%) of which were machine related (technical problems) such as access problems; computer system down/too slow; display issues; and software malfunctions. A further 10% (n = 15) of incidents were down to human computer interaction issues and 13% (n = 19) incidents, mainly telephone related, could not be classified using the framework being tested. On the basis of this review of incidents, it is recommended that the framework be expanded to include hardware malfunctions and the wrong record retrieved/missing data associated with a machine output error (as opposed to human error). In terms of the implications for clinical practice, the incidents reviewed highlighted critical issues including the access problems particularly relating to the use of mobile technologies. PMID- 23646075 TI - Dealing with the archetypes development process for a regional EHR system. AB - OBJECTIVES: This paper aims to present the archetype modelling process used for the Health Department of Minas Gerais State, Brazil (SES/MG), to support building its regional EHR system, and the lessons learned during this process. METHODS: This study was undertaken within the Minas Gerais project. The EHR system architecture was built assuming the reference model from the ISO 13606 norm. The whole archetype development process took about ten months, coordinated by a clinical team co-ordinated by three health professionals and one systems analyst from the SES/MG. They were supported by around 30 health professionals from the internal SES/MG areas, and 5 systems analysts from the PRODEMGE. Based on a bottom-up approach, the project team used technical interviews and brainstorming sessions to conduct the modelling process. RESULTS: The main steps of the archetype modelling process were identified and described, and 20 archetypes were created. LESSONS LEARNED: -The set of principles established during the selection of PCS elements helped the clinical team to keep the focus in their objectives; The initial focus on the archetype structural organization aspects was important; The data elements identified were subjected to a rigorous analysis aimed at determining the most suitable clinical domain;-Levelling the concepts to accommodate them within the hierarchical levels in the reference model was definitely no easy task, and the use of a mind mapping tool facilitated the modelling process;-Part of the difficulty experienced by the clinical team was related to a view focused on the original forms previously used;-The use of worksheets facilitated the modelling process by health professionals;-It was important to have a health professional that knew about the domain tables and health classifications from the Brazilian Federal Government as member in the clinical team. CONCLUSION: The archetypes (referencing terminology, domain tables and term lists) provided a favorable condition for the use of a controlled vocabulary between the central repository and the EMR systems and, probably, will increase the chances of preserving the semantics from the knowledge domain. Finally, the reference model from the ISO 13606 norm, along with the archetypes, proved sufficient to meet the specificities for the creation of an EHR system for basic healthcare in a Brazilian state. PMID- 23646076 TI - Improving access to longitudinal patient health information within an emergency department. AB - We designed and implemented an electronic patient tracking system with improved user authentication and patient selection. We then measured access to clinical information from previous clinical encounters before and after implementation of the system. Clinicians accessed longitudinal information for 16% of patient encounters before, and 40% of patient encounters after the intervention, indicating such a system can improve clinician access to information. We also attempted to evaluate the impact of providing this access on inpatient admissions from the emergency department, by comparing the odds of inpatient admission from an emergency department before and after the improved access was made available. Patients were 24% less likely to be admitted after the implementation of improved access. However, there were many potential confounders, based on the inherent pre post design of the evaluation. Our experience has strong implications for current health information exchange initiatives. PMID- 23646077 TI - Impact of implementing an EMR on physical exam documentation by ambulance personnel. AB - OBJECTIVES: Georgetown University has a student run Emergency Medical Services (EMS) organization with over 100 emergency medical technicians (EMTs). We set out to determine whether implementing an electronic patient care report (ePCR) system was associated with improved physical exam documentation. METHODS: This study evaluated documentation of the physical exam on prehospital patient care reports (PCRs). An ePCR system was implemented. ePCR documentation was compared to that of the previously used paper PCRs. This study looked retrospectively at 154 PCRs. 77 were hand written PCRs from before the electronic system. The PCRs involved chief complaints that were primarily respiratory, neurologic, or both. 77 ePCRs of matching chief complaint categories were used for comparison. Each chart was reviewed for completion of certain physical exam findings. The mean percentage of documented components from the ePCRs was compared to that of the hand written PCRs. The null hypothesis was that the absolute increase in the mean was not more than 20 percent. The two exclusion criteria were PCRs completed by study investigators after the design of the project and partially or completely missing PCRs. RESULTS: The absolute increase in mean physical exam component documentation was 36% (95% CI = 29-43%). A weighted kappa of 0.894 showed very good agreement between chart reviewers. CONCLUSIONS: This study rejected the null hypothesis that the ePCR system was associated with a mean increase of no more than 20%. It observed increase in physical exam documentation. Limitations of this study included the inability to determine whether documentation of physical exam findings reflected performance of the physical exam, and what components of the ePCR system bundle were responsible for the increase in physical exam component documentation. PMID- 23646078 TI - Understanding why clinicians answer or ignore clinical decision support prompts. AB - INTRODUCTION: The identification of key factors influencing responses to prompts and reminders within a computer decision support system (CDSS) has not been widely studied. The aim of this study was to evaluate why clinicians routinely answer certain prompts while others are ignored. METHODS: We utilized data collected from a CDSS developed by our research group--the Child Health Improvement through Computer Automation (CHICA) system. The main outcome of interest was whether a clinician responded to a prompt. RESULTS: This study found that, as expected, some clinics and physicians were more likely to address prompts than others. However, we also found clinicians are more likely to address prompts for younger patients and when the prompts address more serious issues. The most striking finding was that the position of a prompt was a significant predictor of the likelihood of the prompt being addressed, even after controlling for other factors. Prompts at the top of the page were significantly more likely to be answered than the ones on the bottom. CONCLUSIONS: This study detailed a number of factors that are associated with physicians following clinical decision support prompts. This information could be instrumental in designing better interventions and more successful clinical decision support systems in the future. PMID- 23646079 TI - An integrated EHR at Northern California Kaiser Permanente: pitfalls, challenges, and benefits experienced in transitioning. AB - As legacy information systems age, transition to newer systems is inevitable, but at times fraught with challenge. This brief article addresses some of the pitfalls, challenges, and benefits we experienced at Kaiser Permanente as we transitioned several key clinical information systems to Epic Systems for our integrated comprehensive Electronic Health Record (EHR). PMID- 23646080 TI - Usability of selected databases for low-resource clinical decision support. AB - BACKGROUND: Smartphones are increasingly important for clinical decision support, but smartphone and Internet use are limited by cost or coverage in many settings. txt2MEDLINE provides access to published medical evidence by text messaging. Previous studies have evaluated this approach, but we found no comparisons with other tools in this format. OBJECTIVES: To compare txt2MEDLINE with other databases for answering clinical queries by text messaging in low-resource settings. METHODS: Using varied formats, we searched txt2MEDLINE and five other search portals (askMEDLINE, Cochrane, DynaMed, PubMed PICO, and UpToDate) to develop optimal strategies for each. We then searched each database again with five benchmark queries, using the customized search-optimization formats. We truncated the results to less than 480 characters each to simulate delivering them to a maximum of three text messages. Clinicians with practice experience in low-resource areas scored the results on a 5-point Likert scale. RESULTS: Median scores and standard deviations from 17 reviewers were: txt2M2MEDLINE, 3.2+/-0.82 (control); askMEDLINE, 3.2+/-0.90 (p = 0.918); Cochrane, 3.8+/-0.58 (p = 0.073); DynaMed, 3.6+/-0.65 (p = 0.105); PubMed PICO, 3.6+/-0.82 (p = 0.005); and UpToDate, 4.0+/-0.52 (p = 0.002). Our sample size was sufficiently powered to find differences of 1.0 point. CONCLUSIONS: Comparing several possible sources for texting-based clinical-decision-support information, our results did not demonstrate one-point differences in usefulness on a scale of 1 to 5. PubMed PICO and UpToDate were significantly better than txt2MEDLINE, but with relatively small improvements in Likert score (0.4 and 0.8, respectively). In a texting-only setting, txt2MEDLINE is comparable to simulated alternatives based on established reference sources. PMID- 23646081 TI - Measuring the impact of health information technology. PMID- 23646082 TI - Initial implementation and evaluation of a Hepatitis C treatment clinical decision support system (CDSS): a nurse practitioner-driven quality improvement initiative. AB - BACKGROUND: Clinician compliance with clinical guidelines in the treatment of patients with Hepatitis C (HCV) has been reported to be as low as 18.5%. Treatment is complex and patient compliance is often inconsistent thus, active clinician surveillance and support is essential to successful outcomes. A clinical decision support system (CDSS) embedded within an electronic health record can provide reminders, summarize key data, and facilitate coordination of care. To date, the literature is bereft of information describing the implementation and evaluation of a CDSS to support HCV treatment. OBJECTIVE: The purpose of this case report is to describe the design, implementation, and initial evaluation of an HCV-specific CDSS while piloting data collection metrics and methods to be used in a larger study across multiple practices. METHODS: The case report describes the design and implementation processes with preliminary reporting on impact of the CDSS on quality indicator completion by comparing the pre-CDSS group to the post-CDSS group. RESULTS: The CDSS was successfully designed and implemented using an iterative, collaborative process. Pilot testing of the clinical outcomes of the CDSS revealed high rates of quality indicator completion in both the pre- and post-CDSS; although the post-CDSS group received a higher frequency of reminders (4.25 per patient) than the pre-CDSS group (.25 per patient). CONCLUSIONS: This case report documents the processes used to successfully design and implement an HCV CDSS. While the small sample size precludes generalizability of findings, results did positively demonstrate the feasibility of comparing quality indicator completion rates pre-CDSS and post CDSS. It is recommended that future studies include a larger sample size across multiple providers with expanded outcomes measures related to patient outcomes, staff satisfaction with the CDSS, and time studies to evaluate efficiency and cost effectiveness of the CDSS. PMID- 23646083 TI - Case report medical eponyms: an applied clinical informatics opportunity. AB - Medical eponyms are medical words derived from people's names. Eponyms, especially similar sounding eponyms, may be confusing to people trying to use them because the terms themselves do not contain physiologically descriptive words about the condition they refer to. Through the use of electronic health records (EHRs), embedded applied clinical informatics tools including synonyms and pick lists that include physiologically descriptive terms associated with any eponym appearing in the EHR can significantly enhance the correct use of medical eponyms. Here we describe a case example of two similar sounding medical eponyms- Wegener's disease and Wegner's disease-- which were confused in our EHR. We describe our solution to address this specific example and our suggestions and accomplishments developing more generalized approaches to dealing with medical eponyms in EHRs. Integrating brief physiologically descriptive terms with medical eponyms provides an applied clinical informatics opportunity to improve patient care. PMID- 23646084 TI - Transitioning from a legacy EHR to a commercial, vendor-supplied, EHR: one academic health system's experience. AB - OBJECTIVE: Describe the planning, decisions, and implementation results experienced during the large-scale transition from one EHR to another throughout a large academic health system, which occurred simultaneously throughout both in patient and all ambulatory settings. METHODS: Review of internal decision-making documents, interviews with key participants, and data from conversion software. RESULTS: Over 7,000 unique users caring for a population of more than 1.2 million patients in both inpatient and outpatient venues and distributed across two states were successfully transitioned to a new EHR simultaneously. Challenges in data conversion were encountered resulting in more work for end-users than desired or anticipated. Users continued to access older information (principally schedules) in the legacy EHR one year later. CONCLUSION: Data conversion from one EHR to another can be unsuccessful due to differences in how EHR's structure data obtained from underlying feeder applications or databases. Abstraction of only the pertinent clinical content is difficult in the context of transitioning to a new EHR. Clinicians require facile access to legacy content that can be achieved by implanting CCOW compliant solutions. PMID- 23646085 TI - Duplicate orders: an unintended consequence of computerized provider/physician order entry (CPOE) implementation: analysis and mitigation strategies. AB - OBJECTIVE: Computerized provider/physician order entry (CPOE) with clinical decision support (CDS) is designed to improve patient safety. However, a number of unintended consequences which include duplicate ordering have been reported. The objective of this time-series study was to characterize duplicate orders and devise strategies to minimize them. METHODS: Time series design with systematic weekly sampling for 84 weeks. Each week we queried the CPOE database, downloaded all active orders onto a spreadsheet, and highlighted duplicate orders. We noted the following details for each duplicate order: time, order details (e.g. drug, dose, route and frequency), ordering prescriber, including position and role, and whether the orders originated from a single order or from an order set (and the name of the order set). This analysis led to a number of interventions, including changes in: order sets, workflow, prescriber training, pharmacy procedures, and duplicate alerts. RESULTS: Duplicates were more likely to originate from different prescribers than from same prescribers; and from order sets than from single orders. After interventions, there was an 84.8% decrease in the duplication rate from weeks 1 to 84 and a 94.6% decrease from the highest (1) to the lowest week (75). Currently, we have negligible duplicate orders. CONCLUSIONS: Duplicate orders can be a significant unintended consequence of CPOE. By analyzing these orders, we were able to devise and implement generalizable strategies that significantly reduced them. The incidence of duplicate orders before CPOE implementation is unknown, and our data originate from a weekly snapshot of active orders, which serves as a sample of total active orders. Thus, it should be noted that this methodology likely under-reports duplicate orders. PMID- 23646086 TI - The false security of blind dates: chrononymization's lack of impact on data privacy of laboratory data. AB - BACKGROUND: The reuse of clinical data for research purposes requires methods for the protection of personal privacy. One general approach is the removal of personal identifiers from the data. A frequent part of this anonymization process is the removal of times and dates, which we refer to as "chrononymization." While this step can make the association with identified data (such as public information or a small sample of patient information) more difficult, it comes at a cost to the usefulness of the data for research. OBJECTIVES: We sought to determine whether removal of dates from common laboratory test panels offers any advantage in protecting such data from re-identification. METHODS: We obtained a set of results for 5.9 million laboratory panels from the National Institutes of Health's (NIH) Biomedical Translational Research Information System (BTRIS), selected a random set of 20,000 panels from the larger source sets, and then identified all matches between the sets. RESULTS: We found that while removal of dates could hinder the re-identification of a single test result, such removal had almost no effect when entire panels were used. CONCLUSIONS: Our results suggest that reliance on chrononymization provides a false sense of security for the protection of laboratory test results. As a result of this study, the NIH has chosen to rely on policy solutions, such as strong data use agreements, rather than removal of dates when reusing clinical data for research purposes. PMID- 23646087 TI - Impact of a prototype visualization tool for new information in EHR clinical documents. AB - BACKGROUND: EHR clinical document synthesis by clinicians may be time-consuming and error-prone due to the complex organization of narratives, excessive redundancy within documents, and, at times, inadvertent proliferation of data inconsistencies. Development of EHR systems that are easily adaptable to the user's work processes requires research into visualization techniques that can optimize information synthesis at the point of care. OBJECTIVE: To evaluate the effect of a prototype visualization tool for clinically relevant new information on clinicians' synthesis of EHR clinical documents and to understand how the tool may support future designs of clinical document user interfaces. METHODS: A mixed methods approach to analyze the impact of the visualization tool was used with a sample of eight medical interns as they synthesized EHR clinical documents to accomplish a set of four pre-formed clinical scenarios using a think-aloud protocol. RESULTS: Differences in the missing (unretrieved) patient information (2.3+/-1.2 [with the visualization tool] vs. 6.8+/-1.2 [without the visualization tool], p = 0.08) and accurate inferences (1.3+/-0.3 vs 2.3+/-0.3, p = 0.09) were not statistically significant but suggest some improvement with the new information visualization tool. Despite the non-significant difference in total times to task completion (43+/-4 mins vs 36+/-4 mins, p = 0.35) we observed shorter times for two scenarios with the visualization tool, suggesting that the time-saving benefits may be more evident with certain clinical processes. Other observed effects of the tool include more intuitive navigation between patient details and increased efforts towards methodical synthesis of clinical documents. CONCLUSION: Our study provides some evidence that new information visualization in clinical notes may positively influence synthesis of patient information from EHR clinical documents. Our findings provide groundwork towards a more effective display of EHR clinical documents using advanced visualization applications. PMID- 23646089 TI - Clinician perceptions of pediatric growth chart use and electronic health records in Kentucky. AB - BACKGROUND: Growth chart recording is a key component of pediatric care. EHR systems could provide several growth charting functionalities compared to paper methods. To our knowledge, there has been no U.S. study exploring clinicians' perceptions and practices related to recording of growth parameters as they adapt to electronic methods. OBJECTIVES: To explore clinician practices regarding recording growth parameters as they adapt to electronic health records (EHR) and to investigate clinician perceptions of electronic growth charting using EHR. METHODS: An online survey of pediatricians and family practitioners in Kentucky inquiring about EHR usage, specifically use of growth charting with EHR, was conducted. RESULTS: Forty-six percent of respondents utilized EHRs, with pediatricians lagging family practitioners, and academic pediatricians lagging non-academicians. There was no consensus on EHR platforms being used. Almost a third of those who used EHR did not utilize electronic growth charting. Clinicians using EHR reported that electronic growth charts would improve clinician satisfaction and clinical efficiency as well as parent satisfaction and parent education. Only 12% of respondents provided copies of growth charts to parents at the end of their visit and discussed growth parameters with parents, with clinicians using EHR more likely to engage in these activities than non-EHR users. CONCLUSION: Although Kentucky clinicians continue to slowly adopt EHRs, clinician perceptions and practices reflect enduring barriers to widespread use of electronic growth charting in pediatric and family practice. However, our results suggest that electronic growth charting has important benefits for both clinicians and patients, and greater adoption is expected as EHRs become standard across health care systems. PMID- 23646088 TI - Exploring the value of clinical data standards to predict hospitalization of home care patients. AB - BACKGROUND: There is a critical need to reduce hospitalizations for Medicare patients and electronic health record (EHR) home care data provide new opportunities to evaluate risk of hospitalization for patients. OBJECTIVES: The objectives of this study were to 1) develop a measure to predict risk of hospitalization among home care patients, the Hospitalization Risk Score (HRS), and 2) compare it with an existing severity of illness measure, the Charlson Index of Comorbidity (CIC). METHODS: A convenience sample of clinical data from 14 home care agencies' EHRs, representing 1,643 home care patient episodes was used for the study. The development of the HRS was based on review of the literature, and expert panel evaluation to construct the HRS. Descriptive statistics and generalized linear models were used for comparative analysis; areas under curve (AUC) values were compared for receiver operating curves (ROC), and cut points predicting hospitalization were evaluated. RESULTS: The HRS for this sample ranged from 0 to 5.6, with a median of 1.25. The CIC for this sample ranged from 0 to 9 and with a median of 0. Nearly three fourths of the sample was hospitalized at an HRS of 2, and a CIC of 1. AUC values for ROC were 0.63 for HRS and 0.59 for the CIC. The ROC curves were significantly different (t = -7.59, p <0.003). CONCLUSIONS: This preliminary study demonstrates the potential value of the HRS using Omaha System EHR data. There was a statistically significant difference for predicting hospitalization of home care patients with the HRS versus the CIC; however the AUC values for both were low. Continued research is needed to further refine the HRS, determine whether it is more sensitive for particular subgroups of patients, and combine it with additional risk factors in understanding rehospitalization. PMID- 23646090 TI - Health information technology knowledge and skills needed by HIT employers. AB - OBJECTIVE: To evaluate the health information technology (HIT) workforce knowledge and skills needed by HIT employers. METHODS: Statewide face-to-face and online focus groups of identified HIT employer groups in Austin, Brownsville, College Station, Dallas, El Paso, Houston, Lubbock, San Antonio, and webinars for rural health and nursing informatics. RESULTS: HIT employers reported needing an HIT workforce with diverse knowledge and skills ranging from basic to advanced, while covering information technology, privacy and security, clinical practice, needs assessment, contract negotiation, and many other areas. Consistent themes were that employees needed to be able to learn on the job and must possess the ability to think critically and problem solve. Many employers wanted persons with technical skills, yet also the knowledge and understanding of healthcare operations. CONCLUSION: The HIT employer focus groups provided valuable insight into employee skills needed in this fast-growing field. Additionally, this information will be utilized to develop a statewide HIT workforce needs assessment survey. PMID- 23646091 TI - Use of more than one electronic medical record system within a single health care organization. AB - Healthcare organizations vary in the number of electronic medical record (EMR) systems they use. Some use a single EMR for nearly all care they provide, while others use EMRs from more than one vendor. These strategies create a mixture of advantages, risks and costs. Based on our experience in two organizations over a decade, we analyzed use of more than one EMR within our two health care organizations to identify advantages, risks and costs that use of more than one EMR presents. We identified the data and functionality types that pose the greatest challenge to patient safety and efficiency. We present a model to classify patterns of use of more than one EMR within a single healthcare organization, and identified the most important 28 data types and 4 areas of functionality that in our experience present special challenges and safety risks with use of more than one EMR within a single healthcare organization. The use of more than one EMR in a single organization may be the chosen approach for many reasons, but in our organizations the limitations of this approach have also become clear. Those who use and support EMRs realize that to safely and efficiently use more than one EMR, a considerable amount of IT work is necessary. Thorough understanding of the challenges in using more than one EMR is an important prerequisite to minimizing the risks of using more than one EMR to care for patients in a single healthcare organization. PMID- 23646092 TI - Insight into the sharing of medical images: physician, other health care providers, and staff experience in a variety of medical settings. AB - BACKGROUND: Scant knowledge exists describing health care providers' and staffs' experiences sharing imaging studies. Additional research is needed to determine the extent to which imaging studies are shared in diverse health care settings, and the extent to which provider or practice characteristics are associated with barriers to viewing external imaging studies on portable media. OBJECTIVE: This analysis uses qualitative data to 1) examine how providers and their staff accessed outside medical imaging studies, 2) examine whether use or the desire to use imaging studies conducted at outside facilities varied by provider specialty or location (urban, suburban, and small town) and 3) delineate difficulties experienced by providers or staff as they attempted to view and use imaging studies available on portable media. METHODS: Semi-structured interviews were conducted with 85 health care providers and medical facility staff from urban, suburban, and small town medical practices in North Carolina and Virginia. The interviews were audio recorded, transcribed, then systematically analyzed using ATLAS.ti. RESULTS: Physicians at family and pediatric medicine practices rely primarily on written reports for medical studies other than X-rays; and thus do not report difficulties accessing outside imaging studies. Subspecialists in urban, suburban, and small towns view imaging studies through internal communication systems, internet portals, or portable media. Many subspecialists and their staff report experiencing difficulty and time delays in accessing and using imaging studies on portable media. CONCLUSION: Subspecialists have distinct needs for viewing imaging studies that are not shared by typical primary care providers. As development and implementation of technical strategies to share medical records continue, this variation in need and use should be noted. The sharing and viewing of medical imaging studies on portable media is often inefficient and fails to meet the needs of many subspeciality physicians, and can lead to repeated imaging studies. PMID- 23646093 TI - Drivers and barriers in health IT adoption: a proposed framework. AB - Despite near (and rare) consensus that the adoption and diffusion of health information technology (health IT) will bolster outcomes for organizations, individuals, and the healthcare system as a whole, there has been surprisingly little consideration of the structures and processes within organizations that might drive the adoption and effective use of the technology. Management research provides a useful lens through which to analyze both the determinants of investment and the benefits that can ultimately be derived from these investments. This paper provides a conceptual framework for understanding health IT adoption. In doing so, this paper highlights specific organizational barriers or enablers at different stages of the adoption process - investment, implementation, and use - and at different levels of organizational decision making - strategic, operational, and frontline. This framework will aid both policymakers and organizational actors as they make sense of the transition from paper-based to electronic systems. PMID- 23646094 TI - Echocardiographic Characterization of Postnatal Development in Mice with Reduced Arterial Elasticity. AB - PURPOSE: Decreased expression of elastin results in smaller, less compliant arteries and high blood pressure. In mice, these differences become more significant with postnatal development. It is known that arterial size and compliance directly affect cardiac function, but the temporal changes in cardiac function have not been investigated in elastin insufficient mice. The aim of this study is to correlate changes in arterial size and compliance with cardiac function in wildtype (WT) and elastin haploinsufficient (Eln+/- ) mice from birth to adulthood. METHODS: Ultrasound scans were performed at the ages of 3, 7, 14, 21, 30, 60, and 90 days on male and female WT and Eln+/- mice. 2-D ultrasound and pulse wave Doppler images were used to measure the dimensions and function of the left ventricle (LV), ascending aorta and carotid arteries. RESULTS: Eln+/- arteries are smaller and less compliant at most ages, with significant differences from WT as early as 3 days old. Surprisingly, there are no correlations (R2 < 0.2) between arterial size and compliance with measures of LV hypertrophy or systolic function. There are weak correlations (0.2 < R2 < 0.5) between arterial size and compliance with measures of LV diastolic function. CONCLUSIONS: Eln+/- mice have similar cardiac function to WT throughout postnatal development, demonstrating the remarkable ability of the developing cardiovascular system to adapt to mechanical and hemodynamic changes. Correlations between arterial size and compliance with diastolic function show that these measures may be useful indicators of early diastolic dysfunction. PMID- 23646095 TI - Effects of Leaflet Stiffness on In Vitro Dynamic Bioprosthetic Heart Valve Leaflet Shape. AB - Advances in the development of replacement heart valves require a deeper understanding of the valve dynamics. In the present study, dynamic aortic valve (AV) leaflet geometries were quantified in vitro using a structured laser-light imaging system (Iyengar et al., ABME 29(11):963-973, 2001). Native AV leaflets were first imaged under simulated physiological flow conditions within a rigid glass conduit with simulated anatomic sinuses. Next, the valve/glass conduit combination was removed from the loop and immersed in a 0.625% aqueous glutaraldehyde solution at room temperature for 24 h to produce a bioprosthetic heart valve (BHV). The BHV leaflets were then re-imaged under identical flow conditions while kept in the same position in the glass conduit to minimize artifacts associated with removal/reinsertion of the valve. We observed that: (1) the native leaflet exhibited small, high frequency shifts in shape; (2) the BHV leaflet demonstrated a more stabile shape, as well as focal regions of prolonged, high curvature; (3) the BHV leaflet opened and closed faster by ~10 ms compared to native leaflet; (4) in both the BHV and native states, the AV opened from basal region leading to free edge (5) when closing, both the native and BHV close with both free edge and circumferential together. The high bending observed in the BHV leaflet correlated with known locations of tissue deterioration previously reported in our laboratory. Thus, in order to minimize leaflet tissue damage, methods of chemical modification utilized in BHVs that maintain leaflet flexibility are necessary to minimize the onset and progression of tissue damage. We conclude that leaflet stiffness can have a considerable effect on dynamic valve motion, and can induce deleterious bending behaviors that may be associated with tissue breakdown and valve failure. Moreover, these unique data can provide much needed quantitative information for computational simulation of heart valve leaflet stiffness on heart valve function. PMID- 23646097 TI - Adapting the Facilitating Conditions Questionnaire (FCQ) for Bilingual Filipino Adolescents: Validating English and Filipino Versions. AB - This study examined the applicability of the English and Filipino versions of the Facilitating Conditions Questionnaire (FCQ) among Filipino high school students. The FCQ measures the external forces in students' social environments that can influence their motivation for school. It is composed of 11 factors: university intention, school valuing, parent support, teacher support, peer help, leave school, pride from others, negative parent influence, affect to school, negative peer influence, and positive peer influence. It was translated into conversational Filipino. Seven hundred sixty-five high school students answered one of the two language versions. Both within-network and between-network approaches to construct validation were used. Confirmatory factor analyses (CFA) of the two versions showed good fit. Results of the multigroup CFA indicated that there was invariance in terms of factor loadings for the two versions. Results of the between-network test also showed that the factors in the FCQ correlated systematically with theoretically relevant constructs. Taken together, this study supports the applicability of the FCQ for use with Filipino bilingual adolescents. PMID- 23646096 TI - "It's up to you and God": understanding health behavior change in older African American survivors of colorectal cancer. AB - This study investigated the beliefs and attitudes of older African American colorectal cancer (CRC) survivors that may influence health behavior changes after treatment. Drawing from existing theories of health behavior change and cultural beliefs about health, a semi-structured interview guide was developed to elicit survivors' perspectives. Qualitative focus groups and interviews were conducted with 17 survivors identified through the Detroit Surveillance Epidemiology and End Results registry. Using verbatim transcripts from the sessions and NVivo software, thematic analysis was conducted to analyze patterns of responses. Transcripts were coded for seven categories (health behaviors, who/what motivates change, self-efficacy, fatalism, religion/spirituality, beliefs about cancer, race/ethnicity). Five themes emerged from the data (personal responsibility, resilience, desire for information, intentions to change, beliefs in divine control). Findings support the relevance of existing theories of health behavior change to older African American CRC survivors. Cultural considerations are suggested to improve interventions seeking to maximize changes in diet and exercise among this group of survivors. PMID- 23646098 TI - Putting Youth on the Map: A Pilot Instrument for Assessing Youth Well-Being. AB - Extant measures of adolescent well-being in the United States typically focus on negative indicators of youth outcomes. Indices comprised of such measures paint bleak views of youth and orient action toward the prevention of problems over the promotion of protective factors. Their tendency to focus analyses at a state or county geographic scale produces limited information about localized outcome patterns that could inform policymakers, practitioners and advocacy networks. We discuss the construction of a new geo-referenced index of youth well-being based on positive indicators of youth development. In demonstrating the index for the greater Sacramento, California region of the United States, we find that overall youth well-being falls far short of an optimal outcome, and geographic disparities in well-being appear to exist across school districts at all levels of our analysis. Despite its limitations, the sub-county geographic scale of this index provides needed data to facilitate local and regional interventions. PMID- 23646099 TI - A rapid non invasive L-DOPA-13C breath test for optimally suppressing extracerebral AADC enzyme activity - toward individualizing carbidopa therapy in Parkinson's disease. AB - BACKGROUND: Peripheral carbidopa (CD) levels directly impact on central dopamine (DA) production in Parkinson disease (PD) through extracerebral inhibition of dopa decarboxylase (AADC) resulting in an increase in levodopa (LD) bioavailability. OBJECTIVE: Recent data suggests that higher CD doses than those presently used in PD treatment may result in improved clinical response. Optimizing CD doses in individual patients may, therefore, result in ideal individualized treatment. METHODS: A single center, randomized, double-blind study was carried out recruiting 5 Parkinson's disease (PD) patients already on LD/CD and 1 treatment nave PD patient using stable isotope labeled LD-1-13C as a substrate for a noninvasive breath test to evaluate individual AADC enzyme activity. Each patient was studied five times, receiving 200 mg LD-13C at each visit along with one of five randomized CD doses (0, 25, 50, 100 and 200 mg). The metabolite 13CO2 in breath was measured for evaluating AADC enzyme activity and plasma metabolite levels for LD-13C and homovanillic acid (HVA) were measured for 4 hours. RESULTS: HVA in plasma and 13CO2 in breath are metabolic products of LD. We found a significant positive correlation of 13CO2 DOB AUC0-240 with serum HVA AUC0-240 following the oral dose of LD-1-13C for all 5 doses of CD (r2 = 0.9378). With increasing inhibition of AADC enzyme activity with CD, we observed an increase in the plasma concentration of LD.We found an inverse correlation of the 13CO2 DOB AUC with serum LD-13C AUC. Our studies indicate the optimal dose of CD for maximal suppression of AADC enzyme activity can be determined for each individual from 13CO2 generation in breath. CONCLUSIONS: The LD-breath test can be a useful noninvasive diagnostic tool for evaluation of AADC enzyme activity using the biomarker 13CO2 in breath, a first step in personalizing CD doses for PD patients. PMID- 23646100 TI - Impact of age on treatment trends and clinical outcome in patients with metastatic renal cell carcinoma. AB - OBJECTIVES: Clinical outcomes in older adults with metastatic renal cell carcinoma (mRCC) are poorly understood, particularly in the era of targeted therapies. We characterize survival and relevant treatment-related variables in a modern series. MATERIALS AND METHODS: From an institutional database including 562 patients with RCC, a total of 219 patients with metastatic disease were identified for the current analysis. Survival was assessed in four age-based cohorts: (1) age<55, (2) age 55-64, (3) age 65-74, and(4) age>=75. The number of lines of therapy rendered was collected for each patient, and the reason for treatment discontinuation was characterized. RESULTS: Of the 219 patients assessed, median age was 58 (range, 26-87), and most patients had clear cell histology (82%) and prior nephrectomy (70.9%). The majority of patients were characterized as intermediate-risk (53%) by MSKCC criteria. Median survival in patients age>=75 was 12.5 months, as compared to 26.4 months for patients age<75 (P=0.003). Patients age>=75 received fewer lines of systemic therapy as compared to other age-based subsets, and more frequently discontinued therapies due to toxicity. CONCLUSIONS: Older adults represent a unique subpopulation of patients with mRCC, with distinct clinical outcomes. Further research is warranted to better understand the safety and tolerability of current therapies for mRCC in this group. PMID- 23646101 TI - Priming for performance: valence of emotional primes interact with dissociable prototype learning systems. AB - Arousal Biased Competition theory suggests that arousal enhances competitive attentional processes, but makes no strong claims about valence effects. Research suggests that the scope of enhanced attention depends on valence with negative arousal narrowing and positive arousal broadening attention. Attentional scope likely affects declarative-memory-mediated and perceptual-representation-mediated learning systems differently, with declarative-memory-mediated learning depending on narrow attention to develop targeted verbalizable rules, and perceptual representation-mediated learning depending on broad attention to develop a perceptual representation. We hypothesize that negative arousal accentuates declarative-memory-mediated learning and attenuates perceptual-representation mediated learning, while positive arousal reverses this pattern. Prototype learning provides an ideal test bed as dissociable declarative-memory and perceptual-representation systems mediate two-prototype (AB) and one-prototype (AN) prototype learning, respectively, and computational models are available that provide powerful insights on cognitive processing. As predicted, we found that negative arousal narrows attentional focus facilitating AB learning and impairing AN learning, while positive arousal broadens attentional focus facilitating AN learning and impairing AB learning. PMID- 23646102 TI - Prevalence of self-reported pain, joint complaints and knee or hip complaints in adults aged >= 40 years: a cross-sectional survey in Herne, Germany. AB - BACKGROUND: Pain and musculoskeletal complaints are among the most common symptoms in the general population. Despite their epidemiological, clinical and health economic importance, prevalence data on pain and musculoskeletal complaints for Germany are scarce. METHODS: A cross-sectional survey of a random sample of citizens of Herne, Germany, aged >= 40 years was performed. A detailed self-complete postal questionnaire was used, followed by a short reminder questionnaire and telephone contacts for those not responding. The questionnaire contained 66 items, mainly addressing pain of any site, musculoskeletal complaints of any site and of knee and hip, pain intensities, the Western Ontario MacMaster Universities (WOMAC) index, medication, health care utilization, comorbidities, and quality of life. RESULTS: The response rate was 57.8% (4,527 of 7,828 individuals). Survey participants were on average 1.3 years older, and the proportion of women among responders tended to be greater than in the population sample. There was no age difference between the population sample and 2,221 participants filling out the detailed questionnaire. The following standardized prevalences were assessed: current pain: 59.7%, pain within the past four weeks: 74.5%, current joint complaints: 49.3%, joint complaints within the past four weeks and twelve month: 62.8% and 67.4%, respectively, knee as the site predominantly affected: 30.9%, knee bilateral: 9.7%, hip: 15.2%, hip bilateral: 3.5%, knee and hip: 5.5%. Pain and musculoskeletal complaints were significantly more often reported by women. A typical relationship of pain and joint complaints to age could be found, i.e. increasing prevalences with increasing age categories, with a drop in the highest age groups. In general, pain and joint pain were associated with comorbidity and body mass index as well as quality of life. CONCLUSIONS: Our data confirm findings of other recent national as well as European surveys. The high site specific prevalences of knee and hip complaints underline the necessity to further investigate characteristics and consequences of pain and symptomatic osteoarthritis of these joints in adults in Germany. PMID- 23646103 TI - What caused the UK's largest common dolphin (Delphinus delphis) mass stranding event? AB - On 9 June 2008, the UK's largest mass stranding event (MSE) of short-beaked common dolphins (Delphinus delphis) occurred in Falmouth Bay, Cornwall. At least 26 dolphins died, and a similar number was refloated/herded back to sea. On necropsy, all dolphins were in good nutritive status with empty stomachs and no evidence of known infectious disease or acute physical injury. Auditory tissues were grossly normal (26/26) but had microscopic haemorrhages (5/5) and mild otitis media (1/5) in the freshest cases. Five lactating adult dolphins, one immature male, and one immature female tested were free of harmful algal toxins and had low chemical pollutant levels. Pathological evidence of mud/seawater inhalation (11/26), local tide cycle, and the relative lack of renal myoglobinuria (26/26) suggested MSE onset on a rising tide between 06:30 and 08?21 hrs (9 June). Potential causes excluded or considered highly unlikely included infectious disease, gas/fat embolism, boat strike, by-catch, predator attack, foraging unusually close to shore, chemical or algal toxin exposure, abnormal weather/climatic conditions, and high-intensity acoustic inputs from seismic airgun arrays or natural sources (e.g., earthquakes). International naval exercises did occur in close proximity to the MSE with the most intense part of the exercises (including mid-frequency sonars) occurring four days before the MSE and resuming with helicopter exercises on the morning of the MSE. The MSE may therefore have been a "two-stage process" where a group of normally pelagic dolphins entered Falmouth Bay and, after 3-4 days in/around the Bay, a second acoustic/disturbance event occurred causing them to strand en masse. This spatial and temporal association with the MSE, previous associations between naval activities and cetacean MSEs, and an absence of other identifiable factors known to cause cetacean MSEs, indicates naval activity to be the most probable cause of the Falmouth Bay MSE. PMID- 23646105 TI - Machine learning prediction of cancer cell sensitivity to drugs based on genomic and chemical properties. AB - Predicting the response of a specific cancer to a therapy is a major goal in modern oncology that should ultimately lead to a personalised treatment. High throughput screenings of potentially active compounds against a panel of genomically heterogeneous cancer cell lines have unveiled multiple relationships between genomic alterations and drug responses. Various computational approaches have been proposed to predict sensitivity based on genomic features, while others have used the chemical properties of the drugs to ascertain their effect. In an effort to integrate these complementary approaches, we developed machine learning models to predict the response of cancer cell lines to drug treatment, quantified through IC50 values, based on both the genomic features of the cell lines and the chemical properties of the considered drugs. Models predicted IC50 values in a 8 fold cross-validation and an independent blind test with coefficient of determination R2 of 0.72 and 0.64 respectively. Furthermore, models were able to predict with comparable accuracy (R2 of 0.61) IC50s of cell lines from a tissue not used in the training stage. Our in silico models can be used to optimise the experimental design of drug-cell screenings by estimating a large proportion of missing IC50 values rather than experimentally measuring them. The implications of our results go beyond virtual drug screening design: potentially thousands of drugs could be probed in silico to systematically test their potential efficacy as anti-tumour agents based on their structure, thus providing a computational framework to identify new drug repositioning opportunities as well as ultimately be useful for personalized medicine by linking the genomic traits of patients to drug sensitivity. PMID- 23646104 TI - Epistatic interaction between BANK1 and BLK in rheumatoid arthritis: results from a large trans-ethnic meta-analysis. AB - BACKGROUND: BANK1 and BLK belong to the pleiotropic autoimmune genes; recently, epistasis between BANK1 and BLK was detected in systemic lupus erythematosus. Although BLK has been reproducibly identified as a risk factor in rheumatoid arthritis (RA), reports are conflicting about the contribution of BANK1 to RA susceptibility. To ascertain the real impact of BANK1 on RA genetic susceptibility, we performed a large meta-analysis including our original data and tested for an epistatic interaction between BANK1 and BLK in RA susceptibility. PATIENTS AND METHODS: We investigated data for 1,915 RA patients and 1,915 ethnically matched healthy controls genotyped for BANK1 rs10516487 and rs3733197 and BLK rs13277113. The association of each SNP and RA was tested by logistic regression. Multivariate analysis was then used with an interaction term to test for an epistatic interaction between the SNPs in the 2 genes. RESULTS: None of the SNPs tested individually was significantly associated with RA in the genotyped samples. However, we detected an epistatic interaction between BANK1 rs3733197 and BLK rs13277113 (P(interaction) = 0.037). In individuals carrying the BLK rs13277113 GG genotype, presence of the BANK1 rs3733197 G allele increased the risk of RA (odds ratio 1.21 [95% confidence interval 1.04-1.41], P = 0.015. Combining our results with those of all other studies in a large trans ethnic meta-analysis revealed an association of the BANK1 rs3733197 G allele and RA (1.11 [1.02-1.21], P = 0.012). CONCLUSION: This study confirms BANK1 as an RA susceptibility gene and for the first time provides evidence for epistasis between BANK1 and BLK in RA. Our results illustrate the concept of pleiotropic epistatic interaction, suggesting that BANK1 and BLK might play a role in RA pathogenesis. PMID- 23646107 TI - The proximate phonological unit of Chinese-English bilinguals: proficiency matters. AB - An essential step to create phonology according to the language production model by Levelt, Roelofs and Meyer is to assemble phonemes into a metrical frame. However, recently, it has been proposed that different languages may rely on different grain sizes of phonological units to construct phonology. For instance, it has been proposed that, instead of phonemes, Mandarin Chinese uses syllables and Japanese uses moras to fill the metrical frame. In this study, we used a masked priming-naming task to investigate how bilinguals assemble their phonology for each language when the two languages differ in grain size. Highly proficient Mandarin Chinese-English bilinguals showed a significant masked onset priming effect in English (L2), and a significant masked syllabic priming effect in Mandarin Chinese (L1). These results suggest that their proximate unit is phonemic in L2 (English), and that bilinguals may use different phonological units depending on the language that is being processed. Additionally, under some conditions, a significant sub-syllabic priming effect was observed even in Mandarin Chinese, which indicates that L2 phonology exerts influences on L1 target processing as a consequence of having a good command of English. PMID- 23646106 TI - Repeated cocaine exposure facilitates the expression of incentive motivation and induces habitual control in rats. AB - There is growing evidence that mere exposure to drugs can induce long-term alterations in the neural systems that mediate reward processing, motivation, and behavioral control, potentially causing the pathological pursuit of drugs that characterizes the addicted state. The incentive sensitization theory proposes that drug exposure potentiates the influence of reward-paired cues on behavior. It has also been suggested that drug exposure biases action selection towards the automatic execution of habits and away from more deliberate goal-directed control. The current study investigated whether rats given repeated exposure to peripherally administered cocaine would show alterations in incentive motivation (assayed using the Pavlovian-to-instrumental transfer (PIT) paradigm) or habit formation (assayed using sensitivity to reward devaluation). After instrumental and Pavlovian training for food pellet rewards, rats were given 6 daily injections of cocaine (15 mg/kg, IP) or saline, followed by a 10-d period of rest. Consistent with the incentive sensitization theory, cocaine-treated rats showed stronger cue-evoked lever pressing than saline-treated rats during the PIT test. The same rats were then trained on a new instrumental action with a new food pellet reward before undergoing a reward devaluation testing. Although saline-treated rats exhibited sensitivity to reward devaluation, indicative of goal-directed performance, cocaine-treated rats were insensitive to this treatment, suggesting a reliance on habitual processes. These findings, when taken together, indicate that repeated exposure to cocaine can cause broad alterations in behavioral control, spanning both motivational and action selection processes, and could therefore help explain aberrations of decision making that underlie drug addiction. PMID- 23646108 TI - Differential effects of phosphatase inhibitors on the calcium homeostasis and migration of HaCaT keratinocytes. AB - Changes in intracellular calcium concentration ([Ca2+]i) as well as in the phosphorylation state of proteins have been implicated in keratinocyte wound healing revealed in scratch assays. Scratching confluent HaCaT monolayers decreased the number of cells displaying repetitive Ca2+ oscillations as well as the frequency of their Ca2+-transients in cells close to the wounded area and initiated migration of the cells into the wound bed. In contrast, calyculin-A (CLA) and okadaic acid (OA), known cell permeable inhibitors of protein phosphatase-1 and 2A, increased the level of resting [Ca2+]i and suppressed cell migration and wound healing of HaCaT cells. Furthermore, neither CLA nor OA influenced how scratching affected Ca2+ oscillations. It is assumed that changes in and alterations of the phosphorylation level of Ca2+-transport and contractile proteins upon phosphatase inhibition mediates cell migration and wound healing. PMID- 23646109 TI - Quantifying spatial genetic structuring in mesophotic populations of the precious coral Corallium rubrum. AB - While shallow water red coral populations have been overharvested in the past, nowadays, commercial harvesting shifted its pressure on mesophotic organisms. An understanding of red coral population structure, particularly larval dispersal patterns and connectivity among harvested populations is paramount to the viability of the species. In order to determine patterns of genetic spatial structuring of deep water Corallium rubrum populations, for the first time, colonies found between 58-118 m depth within the Tyrrhenian Sea were collected and analyzed. Ten microsatellite loci and two regions of mitochondrial DNA (mtMSH and mtC) were used to quantify patterns of genetic diversity within populations and to define population structuring at spatial scales from tens of metres to hundreds of kilometres. Microsatellites showed heterozygote deficiencies in all populations. Significant levels of genetic differentiation were observed at all investigated spatial scales, suggesting that populations are likely to be isolated. This differentiation may by the results of biological interactions, occurring within a small spatial scale and/or abiotic factors acting at a larger scale. Mitochondrial markers revealed significant genetic structuring at spatial scales greater then 100 km showing the occurrence of a barrier to gene flow between northern and southern Tyrrhenian populations. These findings provide support for the establishment of marine protected areas in the deep sea and off shore reefs, in order to effectively maintain genetic diversity of mesophotic red coral populations. PMID- 23646110 TI - On-chip cryopreservation: a novel method for ultra-rapid cryoprotectant-free cryopreservation of small amounts of human spermatozoa. AB - Cryopreservation of human spermatozoa free from cryoprotectant can avoid toxicity caused by highly concentrated cryoprotectant and a series of specific carriers have been previously explored, except for PDMS chip. Our study is aimed at exploring a novel device for ultra-rapid cryopreservation of small numbers of spermatozoa without cryoprotectant based on polydimethylsiloxane (PDMS) chips. Spermatozoa from 25 healthy men were involved in this study, comparing on-chip cryopreservation with different micro-channel height (group A: 10 um height, group B: 50 um height, group C: 100 um height) and conventional freezing (group D) in liquid nitrogen for 72 h. The viability, motility, DNA integrity by comet assay and acrosome integrity by fluorescein isothiocyanate-conjugated peanut agglutinin (FITC-PNA) staining of frozen-thawed spermatozoa of each group were compared. The motility and viability of post-thawed spermatozoa was significantly decreased than that of pre-freezing spermatozoa. There was no difference of viability and motility of frozen-thawed spermatozoa between group A and D, while viability and motility of group B and C decreased compared to group A. Comet assay showed that no matter for group A or D, there was no difference of CR, TL, TD and OTM between pre-frozen and post-thawed spermatozoa. There was no difference of CR, TL, TD and OTM of post-thawed spermatozoa between group A and group D neither, while spermatozoa DNA damage was more serious in group B and group C with increasing height of micro-channel compared with group A. The proportion of intact acrosome of post-thawed spermatozoa in group A was the highest when compared with group B and group C, though similar to that of group D. In conclusion, PDMS chip with 10 um height micro-channel is ideal for ultra rapid cryopreservation of small quantity of spermatozoa without cryoprotectant. PMID- 23646111 TI - Neurocognitive function in HIV infected patients on antiretroviral therapy. AB - OBJECTIVE: To describe factors associated with neurocognitive (NC) function in HIV-positive patients on stable combination antiretroviral therapy. DESIGN: We undertook a cross-sectional analysis assessing NC data obtained at baseline in patients entering the Protease-Inhibitor-Monotherapy-Versus-Ongoing-Triple therapy (PIVOT) trial. MAIN OUTCOME MEASURE: NC testing comprised of 5 domains. Raw results were z-transformed using standard and demographically adjusted normative datasets (ND). Global z-scores (NPZ-5) were derived from averaging the 5 domains and percentage of subjects with test scores >1 standard deviation (SD) below population means in at least two domains (abnormal Frascati score) calculated. Patient characteristics associated with NC results were assessed using multivariable linear regression. RESULTS: Of the 587 patients in PIVOT, 557 had full NC results and were included. 77% were male, 68% Caucasian and 28% of Black ethnicity. Mean (SD) baseline and nadir CD4+ lymphocyte counts were 553(217) and 177(117) cells/uL, respectively, and HIV RNA was <50 copies/mL in all. Median (IQR) NPZ-5 score was -0.5 (-1.2/-0) overall, and -0.3 (-0.7/0.1) and -1.4 (-2/-0.8) in subjects of Caucasian and Black ethnicity, respectively. Abnormal Frascati scores using the standard-ND were observed in 51%, 38%, and 81%, respectively, of subjects overall, Caucasian and Black ethnicity (p<0.001), but in 62% and 69% of Caucasian and Black subjects using demographically adjusted ND (p = 0.20). In the multivariate analysis, only Black ethnicity was associated with poorer NPZ-5 scores (P<0.001). CONCLUSIONS: In this large group of HIV infected subjects with viral load suppression, ethnicity but not HIV-disease factors is closely associated with NC results. The prevalence of abnormal results is highly dependent on control datasets utilised. TRIAL REGISTRY: ClinicalTrials.gov, NCT01230580. PMID- 23646112 TI - Short- and long-term effects of LRRK2 on axon and dendrite growth. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) underlie an autosomal-dominant form of Parkinson's disease (PD) that is clinically indistinguishable from idiopathic PD. The function of LRRK2 is not well understood, but it has become widely accepted that LRRK2 levels or its kinase activity, which is increased by the most commonly observed mutation (G2019S), regulate neurite growth. However, growth has not been measured; it is not known whether mean differences in length correspond to altered rates of growth or retraction, whether axons or dendrites are impacted differentially or whether effects observed are transient or sustained. To address these questions, we compared several developmental milestones in neurons cultured from mice expressing bacterial artificial chromosome transgenes encoding mouse wildtype-LRRK2 or mutant LRRK2-G2019S, Lrrk2 knockout mice and non-transgenic mice. Over the course of three weeks of development on laminin, the data show a sustained, negative effect of LRRK2 G2019S on dendritic growth and arborization, but counter to expectation, dendrites from Lrrk2 knockout mice do not elaborate more rapidly. In contrast, young neurons cultured on a slower growth substrate, poly-L-lysine, show significantly reduced axonal and dendritic motility in Lrrk2 transgenic neurons and significantly increased motility in Lrrk2 knockout neurons with no significant changes in length. Our findings support that LRRK2 can regulate patterns of axonal and dendritic growth, but they also show that effects vary depending on growth substrate and stage of development. Such predictable changes in motility can be exploited in LRRK2 bioassays and guide exploration of LRRK2 function in vivo. PMID- 23646113 TI - Lifelong exposure to multilingualism: new evidence to support cognitive reserve hypothesis. AB - OBJECTIVE: Investigate the protective effect of multilingualism on cognition in seniors. METHODS: As part of the MemoVie study conducted on 232 non-demented volunteers aged 65 and more, neurogeriatric and neuropsychological evaluations were performed. Participants were classified as presenting either cognitive impairment without dementia (CIND) or being free of any cognitive impairment (CIND-free). Language practices, socio-demographic data and lifestyle habits were recorded. In this retrospective nested case-control design, we used as proxies of multilingualism: number of languages practiced, age of acquisition and duration of practice, emphasizing the temporal pattern of acquisition, and the resulting practice of several languages sequentially or concomitantly during various periods of life. This special angle on the matter offered to our work a dimension particularly original and innovative. RESULTS: 44 subjects (19%) had CIND, the others were cognitively normal. All practiced from 2 to 7 languages. When compared with bilinguals, participants who practiced more than 2 languages presented a lower risk of CIND, after adjustment for education and age (odds ratio (OR) = 0.30, 95% confidence limits (95%CL) = [0.10-0.92]). Progressing from 2 to 3 languages, instead of staying bilingual, was associated with a 7-fold protection against CIND (OR = 0.14, 95%CL = [0.04-0.45], p = 0.0010). A one year delay to reach multilingualism (3 languages practiced being the threshold) multiplied the risk of CIND by 1.022 (OR = 1.022, 95%CL = [1.01-1.04], p = 0.0044). Also noteworthy, just as for multilingualism, an impact of cognitively stimulating activities on the occurrence of CIND was found as well (OR = 0.979, 95%CL = [0.961-0.998], p = 0.033). CONCLUSION: The study did not show independence of multilingualism and CIND. Rather it seems to show a strong association toward a protection against CIND. Practicing multilingualism from early life on, and/or learning it at a fast pace is even more efficient. This protection might be related to the enhancement of cognitive reserve and brain plasticity, thereby preserving brain functions from alterations during aging. PMID- 23646114 TI - A fourteen gene GBM prognostic signature identifies association of immune response pathway and mesenchymal subtype with high risk group. AB - BACKGROUND: Recent research on glioblastoma (GBM) has focused on deducing gene signatures predicting prognosis. The present study evaluated the mRNA expression of selected genes and correlated with outcome to arrive at a prognostic gene signature. METHODS: Patients with GBM (n = 123) were prospectively recruited, treated with a uniform protocol and followed up. Expression of 175 genes in GBM tissue was determined using qRT-PCR. A supervised principal component analysis followed by derivation of gene signature was performed. Independent validation of the signature was done using TCGA data. Gene Ontology and KEGG pathway analysis was carried out among patients from TCGA cohort. RESULTS: A 14 gene signature was identified that predicted outcome in GBM. A weighted gene (WG) score was found to be an independent predictor of survival in multivariate analysis in the present cohort (HR = 2.507; B = 0.919; p<0.001) and in TCGA cohort. Risk stratification by standardized WG score classified patients into low and high risk predicting survival both in our cohort (p = <0.001) and TCGA cohort (p = 0.001). Pathway analysis using the most differentially regulated genes (n = 76) between the low and high risk groups revealed association of activated inflammatory/immune response pathways and mesenchymal subtype in the high risk group. CONCLUSION: We have identified a 14 gene expression signature that can predict survival in GBM patients. A network analysis revealed activation of inflammatory response pathway specifically in high risk group. These findings may have implications in understanding of gliomagenesis, development of targeted therapies and selection of high risk cancer patients for alternate adjuvant therapies. PMID- 23646115 TI - Association between ambient temperature and acute myocardial infarction hospitalisations in Gothenburg, Sweden: 1985-2010. AB - Cardiovascular disease (CVD) is the number one cause of death globally and evidence is steadily increasing on the role of non-traditional risk factors such as meteorology and air pollution. Nevertheless, many research gaps remain, such as the association between these non-traditional risk factors and subtypes of CVD, such as acute myocardial infarction (AMI). The objective of this study was to investigate the association between daily ambient temperature and AMI hospitalisations using a case-crossover design in Gothenburg, Sweden (1985-2010). A secondary analysis was also performed for out-of-hospital ischemic heart disease (IHD) deaths. Susceptible groups by age and sex were explored. The entire year as well as the warm (April-September) and cold periods (October-March) were considered. In total 28,215 AMI hospitalisations (of 22,475 people) and 21,082 out-of-hospital IHD deaths occurred during the 26-year study period. A linear exposure-response corresponding to a 3% and 7% decrease in AMI hospitalisations was observed for an inter-quartile range (IQR) increase in the 2-day cumulative average of temperature during the entire year (11 degrees C) and the warm period (6 degrees C), respectively, with and without adjustment for PM10, NO2, NOx or O3. No heat waves occurred during the warm period. No evidence of an association in the cold period nor any association between temperature and IHD deaths in the entire year, warm or cold periods--with and without adjusting for PM10, NO2, NOx or O3 was found. No susceptible groups, based on age or sex, were identified either. The inverse association between temperature and AMI hospitalisations (entire year and warm period) in Gothenburg is in accordance with the majority of the few other studies that investigated this subtype of CVD. PMID- 23646116 TI - A synthetic podophyllotoxin derivative exerts anti-cancer effects by inducing mitotic arrest and pro-apoptotic ER stress in lung cancer preclinical models. AB - Some potent chemotherapy drugs including tubulin-binding agents had been developed from nature plants, such as podophyllotoxin and paclitaxel. However, poor cytotoxic selectivity, serious side-effects, and limited effectiveness are still the major concerns in their therapeutic application. We developed a fully synthetic podophyllotoxin derivative named Ching001 and investigated its anti tumor growth effects and mechanisms in lung cancer preclinical models. Ching001 showed a selective cytotoxicity to different lung cancer cell lines but not to normal lung cells. Ching001 inhibited the polymerization of microtubule resulting in mitotic arrest as evident by the accumulation of mitosis-related proteins, survivin and aurora B, thereby leading to DNA damage and apoptosis. Ching001 also activated pro-apoptotic ER stress signaling pathway. Intraperitoneal injection of 2 mg/kg Ching001 significantly inhibited the tumor growth of A549 xenograft, while injection of 0.2 mg/kg Ching001 decreased the lung colonization ability of A549 cells in experimental metastasis assay. These anti-tumor growth and lung colonization inhibition effects were stronger than those of paclitaxel treatment at the same dosage. The xenograft tumor tissue stains further confirmed that Ching001 induced mitosis arrest and tumor apoptosis. In addition, the hematology and biochemistry tests of blood samples as well as tissue examinations indicated that Ching001 treatment did not show apparent organ toxicities in tested animals. We provided preclinical evidence that novel synthetic microtubule inhibitor Ching001, which can trigger DNA damage and apoptosis by inducing mitotic arrest and ER stress, is a potential anti-cancer compound for further drug development. PMID- 23646117 TI - Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans. AB - We investigated the antifungal activity of fused Mannich ketone (FMK) congeners and two of their aminoalcohol derivatives. In particular, FMKs with five-membered saturated rings were shown to have minimum inhibitory concentration (MIC90s) ranging from 0.8 to 6 ug/mL toward C. albicans and the closely related C. parapsilosis and C. krusei while having reduced efficacy toward C. glabrata and almost no efficacy against Aspergillus sp. Transcript profiling of C. albicans cells exposed for 30 or 60 min to 2-(morpholinomethyl)-1-indanone, a representative FMK with a five-membered saturated ring, revealed a transcriptional response typical of oxidative stress and similar to that of a C. albicans Cap1 transcriptional activator. Consistently, C. albicans lacking the CAP1 gene was hypersensitive to this FMK, while C. albicans strains overexpressing CAP1 had decreased sensitivity to 2-(morpholinomethyl)-1-indanone. Quantitative structure-activity relationship studies revealed a correlation of antifungal potency and the energy of the lowest unoccupied molecular orbital of FMKs and unsaturated Mannich ketones thereby implicating redox cycling-mediated oxidative stress as a mechanism of action. This conclusion was further supported by the loss of antifungal activity upon conversion of representative FMKs to aminoalcohols that were unable to participate in redox cycles. PMID- 23646118 TI - Effects of CYP2C19 loss-of-function variants on the eradication of H. pylori infection in patients treated with proton pump inhibitor-based triple therapy regimens: a meta-analysis of randomized clinical trials. AB - BACKGROUND: There are inconsistent conclusions about whether CYP2C19 variants could affect H. pylori eradication rate in patients treated with the proton pump inhibitor (PPI)-based therapy. We therefore performed a meta-analysis of randomized clinical trials (RCTs) to re-evaluate the impact of CYP2C19 variants on PPI-based triple therapy for the above indication. METHODS: All relevant RCTs in the PubMed, Cochrane Library, EMBASE, Web of Science and two Chinese databases (up to February 2013) were systematically searched, and a pooled analysis was performed with the odds ratio (OR) and 95% confidence interval (CI) by the STATA software. RESULTS: Sixteen RCT datasets derived from 3680 patients were included. There was no significant heterogeneity across the data available in this meta analysis. There were significant differences in that rate between homozygous (HomEMs) and heterozygous (HetEMs) extensive metabolizers (OR 0.724; 95% CI 0.594 0.881), between HomEMs and poor metabolizers (PM) (OR 0.507; 95%CI 0.379-0.679), or between HetEMs and PMs (OR 0.688; 95%CI 0.515-0.920), regardless of the PPI being taken. Furthermore, sub-analysis of individual PPIs was carried out to explore the difference across all the PPIs used. A significantly low rate was seen in HomEMs vs. HetEMs taking either omeprazole (OR 0.329; 95%CI 0.195-0.553) or lansoprazole (OR 0.692; 95%CI 0.485-0.988), and also in HomEMs vs. PMs for omeprazole (OR 0.232; 95%CI 0.105-0.515) or lansoprazole (OR 0.441; 95%CI 0.252 0.771). However, there was no significant difference between HetEMs and PMs taking either one. No significant differences were observed for rabeprazole or esomeprazole across the CYP2C19 genotypes of interest. CONCLUSIONS: Carriage of CYP2C19 loss-of-function variants is associated with increased H. pylori eradication rate in patients taking PPI-based triple therapies when omeprazole or lansoprazole is chosen. However, there is no a class effect after use of rabeprazole or esomeprazole. PMID- 23646119 TI - The regulation of the Z- and G-box containing promoters by light signaling components, SPA1 and MYC2, in Arabidopsis. AB - Although many transcription factors and regulatory proteins have been identified and functionally characterized in light signaling pathways, photoperception to transcription remains largely fragmented. The Z-box is one of the LREs (Light responsive elements) that plays important role in the regulation of transcription during light-controlled Arabidopsis seedling development. The involvement of photoreceptors in the modulation of the activity of the Z-box containing promoters has been demonstrated. However, the role of downstream signaling components such as SPA1 and MYC2/ZBF1, which are functionally interrelated, remains unknown. In this study, we have investigated the regulation of the Z-box containing synthetic and native promoters by SPA1 and MYC2 by using stable transgenic lines. Our studies suggest that SPA1 negatively regulates the expression of CAB1 native promoter. MYC2 negatively regulates the activity of Z- and/or G-box containing synthetic as well as native promoters irrespective of light quality. Moreover, MYC2 negatively regulates the expression of Z/G-NOS101 GUS even in the darkness. Furthermore, analyses of tissue specific expression in adult plants suggest that MYC2 strongly regulates the activity of Z- and G-box containing promoters specifically in leaves and stems. In roots, whereas MYC2 positively regulates the activity of the Z-box containing synthetic promoter, it does not seem to control the activity of the G-box containing promoters. Taken together, these results provide insights into SPA1- and MYC2-mediated transcriptional regulation of the Z- and G-box containing promoters in light signaling pathways. PMID- 23646120 TI - Tissue-dependent consequences of Apc inactivation on proliferation and differentiation of ciliated cell progenitors via Wnt and notch signaling. AB - The molecular signals that control decisions regarding progenitor/stem cell proliferation versus differentiation are not fully understood. Differentiation of motile cilia from progenitor/stem cells may offer a simple tractable model to investigate this process. Wnt and Notch represent two key signaling pathways in progenitor/stem cell behavior in a number of tissues. Adenomatous Polyposis Coli, Apc is a negative regulator of the Wnt pathway and a well known multifunctional protein. Using the cre-LoxP system we inactivated the Apc locus via Foxj1-cre, which is expressed in cells committed to ciliated cell lineage. We then characterized the consequent phenotype in two select tissues that bear motile cilia, the lung and the testis. In the lung, Apc deletion induced beta-catenin accumulation and Jag1 expression in ciliated cells and by lateral induction, triggered Notch signaling in adjacent Clara cells. In the bronchiolar epithelium, absence of Apc blocked the differentiation of a subpopulation of cells committed to the ciliogenesis program. In the human pulmonary adenocarcinoma cells, Apc over-expression inhibited Jag1 expression and promoted motile ciliogenic gene expression program including Foxj1, revealing the potential mechanism. In the testis, Apc inactivation induced beta-catenin accumulation in the spermatogonia, but silenced Notch signaling and depleted spermatogonial stem cells, associated with reduced proliferation, resulting in male infertility. In sum, the present comparative analysis reveals the tissue-dependent consequences of Apc inactivation on proliferation and differentiation of ciliated cell progenitors by coordinating Wnt and Notch signaling. PMID- 23646121 TI - The clinical significance and risk factors of anti-platelet factor 4/heparin antibody on maintenance hemodialysis patients: a two-year prospective follow-up. AB - BACKGROUND: Heparin-induced thrombocytopenia is an immune response mediated by anti-PF4/heparin antibody, which is clinically characterized by thrombocytopenia and thromboembolic events. In this study, a prospective and multi-center clinical investigation 1) determined the positive rate of anti-PF4/heparin antibody in maintenance hemodialysis patients in China, 2) identified the related risk factors, and 3) further explored the effect of the anti-PF4/heparin antibody on bleeding, thromboembolic events, and risk of death in the patients. METHODS: The serum anti-PF4/heparin antibody was measured in 661 patients from nine hemodialysis centers, detected by IgG-specific ELISA and followed by confirmation with excess heparin. Risk factors of these patients were analyzed. Based on a two year follow-up, the association between the anti-PF4/heparin antibody and bleeding, thromboembolic events, and risk of death in the patients was investigated. RESULTS: 1) The positivity rate of the anti-PF4/heparin antibody in maintenance hemodialysis patients was 5.6%. With diabetes as an independent risk factor, the positivity rate of the anti-PF4/heparin antibody decreased in the patients undergoing weekly dialyses >=3 times. 2) The positivity rate of the anti PF4/heparin antibody was not related to the occurrence of clinical thromboembolic events and was not a risk factor for death within two years in maintenance hemodialysis patients. 3) Negativity for the anti-PF4/heparin antibody combined with a reduction of the platelet count or combined with the administration of antiplatelet drugs yielded a significant increase in bleeding events. However, the composite determination of the anti-PF4/heparin antibody and thrombocytopenia, as well as the administration of antiplatelet drugs, was not predictive for the risk of thromboembolic events in the maintenance hemodialysis patients. CONCLUSIONS: A single detection of the anti-PF4/heparin antibody did not predict the occurrence of clinical bleeding, thromboembolic events, or risk of death in the maintenance hemodialysis patients. PMID- 23646122 TI - Characterisation of the plasmidome within Enterococcus faecalis isolated from marginal periodontitis patients in Norway. AB - The present study aimed to identify and characterize plasmids in a national collection of oral Enterococcus faecalis (n = 106) isolated from patients with marginal periodontitis. Plasmid replicon typing was performed by multiplex-PCR and sequencing with specific primers for 18 rep-families and 1 unique sequence. Additional plasmid analysis by S1-PFGE was performed for comparison. Totally 120 plasmid replicon amplicons of seven rep-families were identified in 93 E. faecalis strains, e.g. rep9 (prototype pCF10), rep6 (prototype pS86), rep2 (prototype pRE25/pEF1), and rep8 (prototype pAM373). Rep9 was the most predominant rep-family being detected in 81 (76.4%) strains. Forty of these strains were tetracycline resistant and three were erythromycin resistant. Rep6 was the second predominant rep-family being detected in 22 (20.8%) strains. Rep2 was detected in eight (7.5%) strains. All rep2-positive strains were resistant to tetracycline and/or erythromycin and six of them contained Tn916/Tn1545 genes. The rep-positive E. faecalis exhibited divergence in multilocus sequence types (STs). There was a significant correlation between rep9 and ST21, while multiple rep-families appeared in ST40. Totally 145 plasmid bands were identified in 95 E. faecalis strains by S1-PFGE, 59 strains carrying one plasmid, 27 carrying two, five carrying three, three carrying four, and one strain carrying five plasmids. Plasmid sizes varied between 5-150 kbp. There was a significant correlation between the number of plasmids identified by PCR rep-typing and by S1-PFGE. The results indicate that the majority of E. faecalis of marginal periodontitis are likely to be a reservoir for diverse mobile genetic elements and associated antimicrobial resistance determinants. PMID- 23646123 TI - Dynamics of peripheral blood lymphocyte subpopulations in the acute and subacute phase of Legionnaires' disease. AB - STUDY OBJECTIVE: Absolute lymphocytopenia is recognised as an important hallmark of the immune response to severe infection and observed in patients with Legionnaires' disease. To explore the immune response, we studied the dynamics of peripheral blood lymphocyte subpopulations in the acute and subacute phase of LD. METHODS AND RESULTS: EDTA-anticoagulated blood was obtained from eight patients on the day the diagnosis was made through detection of L. pneumophila serogroup 1 antigen in urine. A second blood sample was obtained in the subacute phase. Multiparametric flow cytometry was used to calculate lymphocyte counts and values for B-cells, T-cells, NK cells, CD4+ and CD8+ T-cells. Expression of activation markers was analysed. The values obtained in the subacute phase were compared with an age and gender matched control group. Absolute lymphocyte count (*109/l, median and range) significantly increased from 0.8 (0.4-1.6) in the acute phase to 1.4 (0.8-3.4) in the subacute phase. B-cell count showed no significant change, while T-cell count (*106/l, median and range) significantly increased in the subacute phase (495 (182-1024) versus 979 (507-2708), p = 0.012) as a result of significant increases in both CD4+ and CD8+ T-cell counts (374 (146-629) versus 763 (400-1507), p = 0.012 and 119 (29-328) versus 224 (107-862), p = 0.012). In the subacute phase of LD, significant increases were observed in absolute counts of activated CD4+ T-cells, naive CD4+ T-cells and memory CD4+ T cells. In the CD8+ T-cell compartment, activated CD8+ T-cells, naive CD8+ T-cell and memory CD8+ T-cells were significantly increased (p<0.05). CONCLUSION: The acute phase of LD is characterized by absolute lymphocytopenia, which recovers in the subacute phase with an increase in absolute T-cells and re-emergence of activated CD4+ and CD8+ T cells. These observations are in line with the suggested role for T-cell activation in the immune response to LD. PMID- 23646124 TI - Use of the non-pneumatic anti-shock garment (NASG) for life-threatening obstetric hemorrhage: a cost-effectiveness analysis in Egypt and Nigeria. AB - OBJECTIVE: To assess the cost-effectiveness of a non-pneumatic anti-shock garment (NASG) for obstetric hemorrhage in tertiary hospitals in Egypt and Nigeria. METHODS: We combined published data from pre-intervention/NASG-intervention clinical trials with costs from study sites. For each country, we used observed proportions of initial shock level (mild: mean arterial pressure [MAP] >60 mmHg; severe: MAP <=60 mmHg) to define a standard population of 1,000 women presenting in shock. We examined three intervention scenarios: no women in shock receive the NASG, only women in severe shock receive the NASG, and all women in shock receive the NASG. Clinical data included frequencies of adverse health outcomes (mortality, severe morbidity, severe anemia), and interventions to manage bleeding (uterotonics, blood transfusions, hysterectomies). Costs (in 2010 international dollars) included the NASG, training, and clinical interventions. We compared costs and disability-adjusted life years (DALYs) across the intervention scenarios. RESULTS: For 1000 women presenting in shock, providing the NASG to those in severe shock results in decreased mortality and morbidity, which averts 357 DALYs in Egypt and 2,063 DALYs in Nigeria. Differences in use of interventions result in net savings of $9,489 in Egypt (primarily due to reduced transfusions) and net costs of $6,460 in Nigeria, with a cost per DALY averted of $3.13. Results of providing the NASG for women in mild shock has smaller and uncertain effects due to few clinical events in this data set. CONCLUSION: Using the NASG for women in severe shock resulted in markedly improved health outcomes (2-2.9 DALYs averted per woman, primarily due to reduced mortality), with net savings or extremely low cost per DALY averted. This suggests that in resource limited settings, the NASG is a very cost-effective intervention for women in severe hypovolemic shock. The effects of the NASG for mild shock are less certain. PMID- 23646125 TI - Simultaneous analysis of anthocyanin and non-anthocyanin flavonoid in various tissues of different lotus (Nelumbo) cultivars by HPLC-DAD-ESI-MS(n). AB - A validated HPLC-DAD-ESI-MS(n) method for the analysis of non-anthocyanin flavonoids was applied to nine different tissues of twelve lotus genotypes of Nelumbo nucifera and N. lutea, together with an optimized anthocyanin extraction and separation protocol for lotus petals. A total of five anthocyanins and twenty non-anthocyanin flavonoids was identified and quantified. Flavonoid contents and compositions varied with cultivar and tissue and were used as a basis to divide tissues into three groups characterized by kaempferol and quercetin derivatives. Influences on flower petal coloration were investigated by principal components analyses. High contents of kaempferol glycosides were detected in the petals of N. nucifera while high quercetin glycoside concentrations occurred in N. lutea. Based on these results, biosynthetic pathways leading to specific compounds in lotus tissues are deduced through metabolomic analysis of different genotypes and tissues and correlations among flavonoid compounds. PMID- 23646126 TI - No prior entry for threat-related faces: evidence from temporal order judgments. AB - Previous research showed that threat-related faces, due to their intrinsic motivational relevance, capture attention more readily than neutral faces. Here we used a standard temporal order judgment (TOJ) task to assess whether negative (either angry or fearful) emotional faces, when competing with neutral faces for attention selection, may lead to a prior entry effect and hence be perceived as appearing first, especially when uncertainty is high regarding the order of the two onsets. We did not find evidence for this conjecture across five different experiments, despite the fact that participants were invariably influenced by asynchronies in the respective onsets of the two competing faces in the pair, and could reliably identify the emotion in the faces. Importantly, by systematically varying task demands across experiments, we could rule out confounds related to suboptimal stimulus presentation or inappropriate task demands. These findings challenge the notion of an early automatic capture of attention by (negative) emotion. Future studies are needed to investigate whether the lack of systematic bias of attention by emotion is imputed to the primacy of a non-emotional cue to resolve the TOJ task, which in turn prevents negative emotion to exert an early bottom-up influence on the guidance of spatial and temporal attention. PMID- 23646128 TI - Social relationships and depression: ten-year follow-up from a nationally representative study. AB - BACKGROUND: Social network characteristics have long been associated with mental health, but their longitudinal impact on depression is less known. We determined whether quality of social relationships and social isolation predicts the development of depression. METHODS: The sample consisted of a cohort of 4,642 American adults age 25-75 who completed surveys at baseline in 1995-1996 and at ten-year follow-up. Quality of relationships was assessed with non-overlapping scales of social support and social strain and a summary measure of relationship quality. Social isolation was measured by presence of a partner and reported frequency of social contact. The primary outcome was past year major depressive episode at ten-year follow-up. Multivariable logistic regression was conducted, adjusting for the presence of potential confounders. RESULTS: Risk of depression was significantly greater among those with baseline social strain (OR, 1.99; 95% CI, 1.47-2.70), lack of social support (OR, 1.79; 95% CI, 1.37-2.35), and poor overall relationship quality (OR 2.60; 95% CI, 1.84-3.69). Those with the lowest overall quality of social relationships had more than double the risk of depression (14.0%; 95% CI, 12.0-16.0; p<.001) than those with the highest quality (6.7%; 95% CI, 5.3-8.1; p<.001). Poor quality of relationship with spouse/partner and family each independently increased risk of depression. Social isolation did not predict future depression, nor did it moderate the effect of relationship quality. CONCLUSIONS: Quality of social relationships is a major risk factor for major depression. Depression interventions should consider targeting individuals with low quality of social relationships. PMID- 23646127 TI - Tissue-specific, development-dependent phenolic compounds accumulation profile and gene expression pattern in tea plant [Camellia sinensis]. AB - Phenolic compounds in tea plant [Camellia sinensis (L.)] play a crucial role in dominating tea flavor and possess a number of key pharmacological benefits on human health. The present research aimed to study the profile of tissue-specific, development-dependent accumulation pattern of phenolic compounds in tea plant. A total of 50 phenolic compounds were identified qualitatively using liquid chromatography in tandem mass spectrometry technology. Of which 29 phenolic compounds were quantified based on their fragmentation behaviors. Most of the phenolic compounds were higher in the younger leaves than that in the stem and root, whereas the total amount of proanthocyanidins were unexpectedly higher in the root. The expression patterns of 63 structural and regulator genes involved in the shikimic acid, phenylpropanoid, and flavonoid pathways were analyzed by quantitative real-time polymerase chain reaction and cluster analysis. Based on the similarity of their expression patterns, the genes were classified into two main groups: C1 and C2; and the genes in group C1 had high relative expression level in the root or low in the bud and leaves. The expression patterns of genes in C2-2-1 and C2-2-2-1 groups were probably responsible for the development dependent accumulation of phenolic compounds in the leaves. Enzymatic analysis suggested that the accumulation of catechins was influenced simultaneously by catabolism and anabolism. Further research is recommended to know the expression patterns of various genes and the reason for the variation in contents of different compounds in different growth stages and also in different organs. PMID- 23646129 TI - Population diversification in Staphylococcus aureus biofilms may promote dissemination and persistence. AB - The biofilm mode of growth can lead to diversification of the bacterial population by promoting the emergence of variants. Here we report the identification and characterization of two major subpopulations of morphological variants arising in biofilms of S. aureus. One of these lacked pigmentation (termed white variants; WVs), whilst the other formed colonies on agar that were larger and paler than the parental strain (termed large pale variants; LPVs). WVs were unable to form biofilms, and exhibited increased proteolysis and haemolysis; all phenotypes attributable to loss-of-function mutations identified in the gene encoding the alternative sigma factor, sigB. For LPVs, no differences in biofilm forming capacity or proteolysis were observed compared with the parental strain. Genetic analysis of LPVs revealed that they had undergone mutation in the accessory gene regulator system (agrA), and deficiency in agr was confirmed by demonstrating loss of both colony spreading and haemolytic activity. The observation that S. aureus biofilms elaborate large subpopulations of sigB and agr mutants, both genotypes that have independently been shown to be of importance in staphylococcal disease, has implications for our understanding of staphylococcal infections involving a biofilm component. PMID- 23646130 TI - Effect of hydrogen peroxide on immersion challenge of rainbow trout fry with Flavobacterium psychrophilum. AB - An experimental model for immersion challenge of rainbow trout fry (Oncorhynchus mykiss) with Flavobacterium psychrophilum, the causative agent of rainbow trout fry syndrome and bacterial cold water disease was established in the present study. Although injection-based infection models are reliable and produce high levels of mortality attempts to establish a reproducible immersion model have been less successful. Various concentrations of hydrogen peroxide (H2O2) were evaluated before being used as a pre-treatment stressor prior to immersion exposure to F. psychrophilum. H2O2 accelerated the onset of mortality and increased mortality approximately two-fold; from 9.1% to 19.2% and from 14.7% to 30.3% in two separate experiments. Clinical signs observed in the infected fish corresponded to symptoms characteristically seen during natural outbreaks. These findings indicate that pre-treatment with H2O2 can increase the level of mortality in rainbow trout fry after exposure to F. psychrophilum. PMID- 23646131 TI - Revisiting the effect of capture heterogeneity on survival estimates in capture mark-recapture studies: does it matter? AB - Recently developed capture-mark-recapture methods allow us to account for capture heterogeneity among individuals in the form of discrete mixtures and continuous individual random effects. In this article, we used simulations and two case studies to evaluate the effectiveness of continuously distributed individual random effects at removing potential bias due to capture heterogeneity, and to evaluate in what situation the added complexity of these models is justified. Simulations and case studies showed that ignoring individual capture heterogeneity generally led to a small negative bias in survival estimates and that individual random effects effectively removed this bias. As expected, accounting for capture heterogeneity also led to slightly less precise survival estimates. Our case studies also showed that accounting for capture heterogeneity increased in importance towards the end of study. Though ignoring capture heterogeneity led to a small bias in survival estimates, such bias may greatly impact management decisions. We advocate reducing potential heterogeneity at the sampling design stage. Where this is insufficient, we recommend modelling individual capture heterogeneity in situations such as when a large proportion of the individuals has a low detection probability (e.g. in the presence of floaters) and situations where the most recent survival estimates are of great interest (e.g. in applied conservation). PMID- 23646133 TI - End of the century pCO2 levels do not impact calcification in Mediterranean cold water corals. AB - Ocean acidification caused by anthropogenic uptake of CO2 is perceived to be a major threat to calcifying organisms. Cold-water corals were thought to be strongly affected by a decrease in ocean pH due to their abundance in deep and cold waters which, in contrast to tropical coral reef waters, will soon become corrosive to calcium carbonate. Calcification rates of two Mediterranean cold water coral species, Lophelia pertusa and Madrepora oculata, were measured under variable partial pressure of CO2 (pCO2) that ranged between 380 uatm for present day conditions and 930 uatm for the end of the century. The present study addressed both short- and long-term responses by repeatedly determining calcification rates on the same specimens over a period of 9 months. Besides studying the direct, short-term response to elevated pCO2 levels, the study aimed to elucidate the potential for acclimation of calcification of cold-water corals to ocean acidification. Net calcification of both species was unaffected by the levels of pCO2 investigated and revealed no short-term shock and, therefore, no long-term acclimation in calcification to changes in the carbonate chemistry. There was an effect of time during repeated experiments with increasing net calcification rates for both species, however, as this pattern was found in all treatments, there is no indication that acclimation of calcification to ocean acidification occurred. The use of controls (initial and ambient net calcification rates) indicated that this increase was not caused by acclimation in calcification response to higher pCO2. An extrapolation of these data suggests that calcification of these two cold-water corals will not be affected by the pCO2 level projected at the end of the century. PMID- 23646132 TI - Uncovering a dynamic feature of the transcriptional regulatory network for anterior-posterior patterning in the Drosophila embryo. AB - Anterior-posterior (AP) patterning in the Drosophila embryo is dependent on the Bicoid (Bcd) morphogen gradient. However, most target genes of Bcd also require additional inputs to establish their expression domains, reflective of the operation of a cross-regulatory network and contributions of other maternal signals. This is in contrast to hunchback (hb), which has an anterior expression domain driven by an enhancer that appears to respond primarily to the Bcd input. To gain a better understanding of the regulatory logic of the AP patterning network, we perform quantitative studies that specifically investigate the dynamics of hb transcription during development. We show that Bcd-dependent hb transcription, monitored by the intron-containing nascent transcripts near the P2 promoter, is turned off quickly--on the order of a few minutes--upon entering the interphase of nuclear cycle 14A. This shutdown contrasts with earlier cycles during which active hb transcription can persist until the moment when the nucleus enters mitosis. The shutdown takes place at a time when the nuclear Bcd gradient profile in the embryo remains largely intact, suggesting that this is a process likely subject to control of a currently unknown regulatory mechanism. We suggest that this dynamic feature offers a window of opportunity for hb to faithfully interpret, and directly benefit from, Bcd gradient properties, including its scaling properties, to help craft a robust AP patterning outcome. PMID- 23646134 TI - Psychophysiological response patterns to affective film stimuli. AB - Psychophysiological research on emotion utilizes various physiological response measures to index activation of the defense system. Here we tested 1) whether acoustic startle reflex (ASR), skin conductance response (SCR) and heart rate (HR) elicited by highly arousing stimuli specifically reflect a defensive state and 2) the relation between resting heart rate variability (HRV) and affective responding. In a within-subject design, participants viewed film clips with a positive, negative and neutral content. In contrast to SCR and HR, we show that ASR differentiated between negative, neutral and positive states and can therefore be considered as a reliable index of activation of the defense system. Furthermore, resting HRV was associated with affect-modulated characteristics of ASR, but not with SCR or HR. Interestingly, individuals with low-HRV showed less differentiation in ASR between affective states. We discuss the important value of ASR in psychophysiological research on emotion and speculate on HRV as a potential biological marker for demarcating adaptive from maladaptive responding. PMID- 23646135 TI - Textrous!: extracting semantic textual meaning from gene sets. AB - The un-biased and reproducible interpretation of high-content gene sets from large-scale genomic experiments is crucial to the understanding of biological themes, validation of experimental data, and the eventual development of plans for future experimentation. To derive biomedically-relevant information from simple gene lists, a mathematical association to scientific language and meaningful words or sentences is crucial. Unfortunately, existing software for deriving meaningful and easily-appreciable scientific textual 'tokens' from large gene sets either rely on controlled vocabularies (Medical Subject Headings, Gene Ontology, BioCarta) or employ Boolean text searching and co-occurrence models that are incapable of detecting indirect links in the literature. As an improvement to existing web-based informatic tools, we have developed Textrous!, a web-based framework for the extraction of biomedical semantic meaning from a given input gene set of arbitrary length. Textrous! employs natural language processing techniques, including latent semantic indexing (LSI), sentence splitting, word tokenization, parts-of-speech tagging, and noun-phrase chunking, to mine MEDLINE abstracts, PubMed Central articles, articles from the Online Mendelian Inheritance in Man (OMIM), and Mammalian Phenotype annotation obtained from Jackson Laboratories. Textrous! has the ability to generate meaningful output data with even very small input datasets, using two different text extraction methodologies (collective and individual) for the selecting, ranking, clustering, and visualization of English words obtained from the user data. Textrous!, therefore, is able to facilitate the output of quantitatively significant and easily appreciable semantic words and phrases linked to both individual gene and batch genomic data. PMID- 23646136 TI - Resilient plant-bird interactions in a volcanic island ecosystem: pollination of Japanese Camellia mediated by the Japanese White-eye. AB - Observations of interspecies interactions during volcanic activity provide important opportunities to study how organisms respond to environmental devastation. Japanese camellia (Camellia japonica L.) and its main avian pollinator, the Japanese White-eye (Zosterops japonica), offer an excellent example of such an interaction as key members of the biotic community on Miyake jima, which erupted in 2000 and continues to emit volcanic gases. Both species exhibit higher resistance to volcanic damage than other species. We examined the effects of volcanic activity on this plant-pollinator system by estimating pollen flow and the genetic diversity of the next generation. The results showed that despite a decrease in Camellia flowers, the partitioning of allelic richness among mother-tree pollen pools and seeds decreased while the migration rate of pollen from outside the study plot and the pollen donor diversity within a fruit increased as the index of volcanic damage increased. In areas with low food (flower) density due to volcanic damage, Z. japonica ranged over larger areas to satisfy its energy needs rather than moving to areas with higher food density. Consequently, the genetic diversity of the seeds (the next plant generation) increased with the index of volcanic damage. The results were consistent with previously published data on the movement of Z. japonica based on radio tracking and the genetic diversity of Camellia pollen adhering to pollinators. Overall, our results indicated that compensation mechanisms ensured better pollination after volcanic disturbance. PMID- 23646137 TI - A new class of small molecule inhibitor of BMP signaling. AB - Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-beta signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development. PMID- 23646138 TI - The pvc operon regulates the expression of the Pseudomonas aeruginosa fimbrial chaperone/usher pathway (cup) genes. AB - The Pseudomonas aeruginosa fimbrial structures encoded by the cup gene clusters (cupB and cupC) contribute to its attachment to abiotic surfaces and biofilm formation. The P. aeruginosa pvcABCD gene cluster encodes enzymes that synthesize a novel isonitrile functionalized cumarin, paerucumarin. Paerucumarin has already been characterized chemically, but this is the first report elucidating its role in bacterial biology. We examined the relationship between the pvc operon and the cup gene clusters in the P. aeruginosa strain MPAO1. Mutations within the pvc genes compromised biofilm development and significantly reduced the expression of cupB1-6 and cupC1-3, as well as different genes of the cupB/cupC two-component regulatory systems, roc1/roc2. Adjacent to pvc is the transcriptional regulator ptxR. A ptxR mutation in MPAO1 significantly reduced the expression of the pvc genes, the cupB/cupC genes, and the roc1/roc2 genes. Overexpression of the intact chromosomally-encoded pvc operon by a ptxR plasmid significantly enhanced cupB2, cupC2, rocS1, and rocS2 expression and biofilm development. Exogenously added paerucumarin significantly increased the expression of cupB2, cupC2, rocS1 and rocS2 in the pvcA mutant. Our results suggest that pvc influences P. aeruginosa biofilm development through the cup gene clusters in a pathway that involves paerucumarin, PtxR, and different cup regulators. PMID- 23646139 TI - Inhibition of DEPDC1A, a bad prognostic marker in multiple myeloma, delays growth and induces mature plasma cell markers in malignant plasma cells. AB - High throughput DNA microarray has made it possible to outline genes whose expression in malignant plasma cells is associated with short overall survival of patients with Multiple Myeloma (MM). A further step is to elucidate the mechanisms encoded by these genes yielding to drug resistance and/or patients' short survival. We focus here on the biological role of the DEP (for Disheveled, EGL-10, Pleckstrin) domain contained protein 1A (DEPDC1A), a poorly known protein encoded by DEPDC1A gene, whose high expression in malignant plasma cells is associated with short survival of patients. Using conditional lentiviral vector delivery of DEPDC1A shRNA, we report that DEPDC1A knockdown delayed the growth of human myeloma cell lines (HMCLs), with a block in G2 phase of the cell cycle, p53 phosphorylation and stabilization, and p21(Cip1) accumulation. DEPDC1A knockdown also resulted in increased expression of mature plasma cell markers, including CXCR4, IL6-R and CD38. Thus DEPDC1A could contribute to the plasmablast features of MMCs found in some patients with adverse prognosis, blocking the differentiation of malignant plasma cells and promoting cell cycle. PMID- 23646140 TI - Recombinant adeno-associated virus serotype 6 efficiently transduces primary human melanocytes. AB - The study of melanocyte biology is important to understand their role in health and disease. However, current methods of gene transfer into melanocytes are limited by safety or efficacy. Recombinant adeno-associated virus (rAAV) has been extensively investigated as a gene therapy vector, is safe and is associated with persistent transgene expression without genome integration. There are twelve serotypes and many capsid variants of rAAV. However, a comparative study to determine which rAAV is most efficient at transducing primary human melanocytes has not been conducted. We therefore sought to determine the optimum rAAV variant for use in the in vitro transduction of primary human melanocytes, which could also be informative to future in vivo studies. We have screened eight variants of rAAV for their ability to transduce primary human melanocytes and identified rAAV6 as the optimal serotype, transducing 7-78% of cells. No increase in transduction was seen with rAAV6 tyrosine capsid mutants. The number of cells expressing the transgene peaked at 6-12 days post-infection, and transduced cells were still detectable at day 28. Therefore rAAV6 should be considered as a non integrating vector for the transduction of primary human melanocytes. PMID- 23646141 TI - Nuclear localization of the mitochondrial factor HIGD1A during metabolic stress. AB - Cellular stress responses are frequently governed by the subcellular localization of critical effector proteins. Apoptosis-inducing Factor (AIF) or Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH), for example, can translocate from mitochondria to the nucleus, where they modulate apoptotic death pathways. Hypoxia-inducible gene domain 1A (HIGD1A) is a mitochondrial protein regulated by Hypoxia-inducible Factor-1alpha (HIF1alpha). Here we show that while HIGD1A resides in mitochondria during physiological hypoxia, severe metabolic stress, such as glucose starvation coupled with hypoxia, in addition to DNA damage induced by etoposide, triggers its nuclear accumulation. We show that nuclear localization of HIGD1A overlaps with that of AIF, and is dependent on the presence of BAX and BAK. Furthermore, we show that AIF and HIGD1A physically interact. Additionally, we demonstrate that nuclear HIGD1A is a potential marker of metabolic stress in vivo, frequently observed in diverse pathological states such as myocardial infarction, hypoxic ischemic encephalopathy (HIE), and different types of cancer. In summary, we demonstrate a novel nuclear localization of HIGD1A that is commonly observed in human disease processes in vivo. PMID- 23646142 TI - Mediterranean diet, telomere maintenance and health status among elderly. AB - Leukocyte telomere length (LTL) and rate of telomere shortening are known biomarkers of aging while, numerous studies showed that Mediterranean diet (MD) may boost longevity. We studied association between telomere length, telomerase activity and different adherence to MD and its effects on healthy status. The study was conducted in 217 elderly subjects stratified according Mediterranean diet score (MDS) in low adherence (MDS<=3), medium adherence (MDS 4-5) and high adherence (MDS>=6) groups. LTL was measured by quantitative polymerase chain reaction and telomerase activity by a PCR-ELISA protocol. High adherence group showed longer LTL (p = 0.003) and higher telomerase activity (p = 0.013) compared to others. Linear regression analysis including age, gender, smoking habit and MDS showed that MDS was independently associated with LTL (p = 0.024) and telomerase activity levels (p = 0.006). Telomerase activity was independently associated with LTL (p = 0.007) and negatively modulated by inflammation and oxidative stress. Indeed, telomerase levels were associated with healthy status independently of multiple covariates (p = 0.048). These results support a novel role of MD in promoting health-span suggesting that telomere maintenance, rather than LTL variability is the major determinant of healthy status among elderly. PMID- 23646143 TI - MAR elements and transposons for improved transgene integration and expression. AB - Reliable and long-term expression of transgenes remain significant challenges for gene therapy and biotechnology applications, especially when antibiotic selection procedures are not applicable. In this context, transposons represent attractive gene transfer vectors because of their ability to promote efficient genomic integration in a variety of mammalian cell types. However, expression from genome integrating vectors may be inhibited by variable gene transcription and/or silencing events. In this study, we assessed whether inclusion of two epigenetic control elements, the human Matrix Attachment Region (MAR) 1-68 and X-29, in a piggyBac transposon vector, may lead to more reliable and efficient expression in CHO cells. We found that addition of the MAR 1-68 at the center of the transposon did not interfere with transposition frequency, and transgene expressing cells could be readily detected from the total cell population without antibiotic selection. Inclusion of the MAR led to higher transgene expression per integrated copy, and reliable expression could be obtained from as few as 2-4 genomic copies of the MAR-containing transposon vector. The MAR X-29-containing transposons was found to mediate elevated expression of therapeutic proteins in polyclonal or monoclonal CHO cell populations using a transposable vector devoid of selection gene. Overall, we conclude that MAR and transposable vectors can be used to improve transgene expression from few genomic transposition events, which may be useful when expression from a low number of integrated transgene copies must be obtained and/or when antibiotic selection cannot be applied. PMID- 23646144 TI - Identifying microRNAs involved in degeneration of the organ of corti during age related hearing loss. AB - MicroRNAs (miRNAs), a class of short non-coding RNAs that regulate the expression of mRNA targets, are important regulators of cellular senescence and aging. We questioned which miRNAs are involved in age-related degeneration of the organ of Corti (OC), the auditory sensory epithelium that transduces mechanical stimuli to electrical activity in the inner ear. Degeneration of the OC is generally accepted as the main cause of age-related hearing loss (ARHL), a progressive loss of hearing in individuals as they grow older. To determine which miRNAs are involved in the onset and progression of ARHL, miRNA gene expression in the OC of two mouse strains, C57BL/6J and CBA/J, was compared at three different ages using GeneChip miRNA microarray and was validated by real-time PCR. We showed that 111 and 71 miRNAs exhibited differential expression in the C57 and CBA mice, respectively, and that downregulated miRNAs substantially outnumbered upregulated miRNAs during aging. miRNAs that had approximately 2-fold upregulation included members of miR-29 family and miR-34 family, which are known regulators of pro apoptotic pathways. In contrast, miRNAs that were downregulated by about 2-fold were members of the miR-181 family and miR-183 family, which are known to be important for proliferation and differentiation, respectively. The shift of miRNA expression favoring apoptosis occurred earlier than detectable hearing threshold elevation and hair cell loss. Our study suggests that changes in miRNA expression precede morphological and functional changes, and that upregulation of pro apoptotic miRNAs and downregulation of miRNAs promoting proliferation and differentiation are both involved in age-related degeneration of the OC. PMID- 23646145 TI - Predictors of reducing sexual and reproductive risk behaviors based on the information-motivation-behavioral skills (IMB) model among unmarried rural-to urban female migrants in Shanghai, China. AB - BACKGROUND: Due to the increase of premarital sex and the lack of reproductive health services, unmarried rural-to-urban female migrants experience more risks of sex and reproductive health (SRH). This study was designed to describe SRH related knowledge, attitude and risk behaviors among unmarried rural-to-urban female migrants and examine the predictors of reducing sexual and reproductive risk behaviors based on information-motivation-behavioral skills (IMB) model and to describe the relationships between the constructs. METHODS: We conducted a cross-sectional study to assess SRH related information, motivation, behavioral skills and preventive behaviors among unmarried rural-to-urban female migrants in Shanghai, one of the largest importers of migrant laborers in China. Structural equation modeling (SEM) was used to assess the IMB model. RESULTS: A total of 944 subjects completed their questionnaires. The mean age was 21.2 years old (SD = 2.3; range 16 to 28). Over one-fourth of participants reported having had premarital sex (N = 261, 27.6%) and among whom 15.3% reported having had the experience of unintended pregnancy, 14.6% with the experience of abortion. The final IMB model provided acceptable fit to the data (CFI = 0.99, RMSEA = 0.034). Reducing sexual and reproductive risk behaviors was significantly predicted by SRH related information (beta = 0.681, P<0.001) and behavioral skills(beta = 0.239, P<0.001). Motivation (beta = 0.479, P<0.001) was the significant indirect predictor of reducing sexual and reproductive risk behaviors mediated through behavioral skills. CONCLUSIONS: The results highlight the importance and necessity of conducting reproductive health promotion among unmarried rural-to urban female migrants in China. The IMB model could be used to predict reducing sexual and reproductive risk behaviors and it suggests future interventions should focus on improving SRH related information and behavioral skills. PMID- 23646146 TI - Effects of an ecosystem engineer on belowground movement of microarthropods. AB - Ecosystem engineers affect other species by changing physical environments. Such changes may influence movement of organisms, particularly belowground where soil permeability can restrict dispersal. We investigated whether earthworms, iconic ecosystem engineers, influence microarthropod movement. Our experiment tested whether movement is affected by tunnels (i.e., burrows), earthworm excreta (mucus, castings), or earthworms themselves. Earthworm burrows form tunnel networks that may facilitate movement. This effect may be enhanced by excreta, which could provide resources for microarthropods moving along the network. Earthworms may also promote movement via phoresy. Conversely, negative effects could occur if earthworms alter predator-prey relationships or change competitive interactions between microarthropods. We used microcosms consisting of a box connecting a "source" container in which microarthropods were present and a "destination" container filled with autoclaved soil. Treatments were set up within the boxes, which also contained autoclaved soil, as follows: 1) control with no burrows; 2) artificial burrows with no excreta; 3) abandoned burrows with excreta but no earthworms; and 4) earthworms (Lumbricus rubellus) present in burrows. Half of the replicates were sampled once after eight days, while the other half were sampled repeatedly to examine movement over time. Rather than performing classical pairwise comparisons to test our hypotheses, we used AIC(c) to assess support for three competing models (presence of tunnels, excreta, and earthworms). More individuals of Collembola, Mesostigmata, and all microarthropods together dispersed when tunnels were present. Models that included excreta and earthworms were less well supported. Total numbers of dispersing Oribatida and Prostigmata+Astigmata were not well explained by any models tested. Further research is needed to examine the impact of soil structure and ecosystem engineering on movement belowground, as the substantial increase in movement of some microarthropods when corridors were present suggests these factors can strongly affect colonization and community assembly. PMID- 23646147 TI - Evidence inhibition responds reactively to the salience of distracting information during focused attention. AB - Along with target amplification, distractor inhibition is regarded as a major contributor to selective attention. Some theories suggest that the strength of inhibitory processing is proportional to the salience of the distractor (i.e., inhibition reacts to the distractor intensity). Other theories suggest that the strength of inhibitory processing does not depend on the salience of the distractor (i.e., inhibition does not react to the distractor intensity). The present study aimed to elucidate the relationship between the intensity of a distractor and its subsequent inhibition during focused attention. A flanker task with a variable distractor-target stimulus-onset asynchrony (SOA) was used to measure both distractor interference and distractor inhibition. We manipulated the intensity of the distractor in two separate ways, by varying its distance from the target (Experiment 1) and by varying its brightness (Experiment 2). The results indicate that more intense distractors were associated with both increased interference and stronger distractor inhibition. The latter outcome provides novel support for the reactive inhibition hypothesis, which posits that inhibition reacts to the strength of distractor input, such that more salient distractors elicit stronger inhibition. PMID- 23646148 TI - Machine learning approach for the outcome prediction of temporal lobe epilepsy surgery. AB - Epilepsy surgery is effective in reducing both the number and frequency of seizures, particularly in temporal lobe epilepsy (TLE). Nevertheless, a significant proportion of these patients continue suffering seizures after surgery. Here we used a machine learning approach to predict the outcome of epilepsy surgery based on supervised classification data mining taking into account not only the common clinical variables, but also pathological and neuropsychological evaluations. We have generated models capable of predicting whether a patient with TLE secondary to hippocampal sclerosis will fully recover from epilepsy or not. The machine learning analysis revealed that outcome could be predicted with an estimated accuracy of almost 90% using some clinical and neuropsychological features. Importantly, not all the features were needed to perform the prediction; some of them proved to be irrelevant to the prognosis. Personality style was found to be one of the key features to predict the outcome. Although we examined relatively few cases, findings were verified across all data, showing that the machine learning approach described in the present study may be a powerful method. Since neuropsychological assessment of epileptic patients is a standard protocol in the pre-surgical evaluation, we propose to include these specific psychological tests and machine learning tools to improve the selection of candidates for epilepsy surgery. PMID- 23646149 TI - Rosiglitazone treatment of type 2 diabetic db/db mice attenuates urinary albumin and angiotensin converting enzyme 2 excretion. AB - Alterations within the renal renin angiotensin system play a pivotal role in the development and progression of cardiovascular and renal disease. Angiotensin converting enzyme 2 (ACE2) is highly expressed in renal tubules and has been shown to be renoprotective in diabetes. The protease, a disintegrin and metalloprotease (ADAM) 17, is involved in the ectodomain shedding of several transmembrane proteins including ACE2. Renal ACE2 and ADAM17 were significantly increased in db/db mice compared to controls. We investigated the effect of the insulin sensitizer, rosiglitazone, on albuminuria, renal ADAM17 protein expression and ACE2 shedding in db/db diabetic mice. Rosiglitazone treatment of db/db mice normalized hyperglycemia, attenuated renal injury and decreased urinary ACE2 and renal ADAM17 protein expression. Urinary excreted ACE2 is enzymatically active. Western blot analysis of urinary ACE2 demonstrated two prominent immunoreactive bands at approximately 70 & 90 kDa. The predominant immunoreactive band is approximately 20 kDa shorter than the one demonstrated for kidney lysate, indicating possible ectodomain shedding of active renal ACE2 in the urine. Therefore, it is tempting to speculate that renoprotection of rosiglitazone could be partially mediated via downregulation of renal ADAM17 and ACE2 shedding. In addition, there was a positive correlation between blood glucose, urinary albumin, plasma glucagon, and triglyceride levels with urinary ACE2 excretion. In conclusion, urinary ACE2 could be used as a sensitive biomarker of diabetic nephropathy and for monitoring the effectiveness of renoprotective medication. PMID- 23646150 TI - Suppression of cholangiocarcinoma cell growth by human umbilical cord mesenchymal stem cells: a possible role of Wnt and Akt signaling. AB - Emerging evidence indicates that human mesenchymal stem cells (hMSCs) can be recruited to tumor sites, and affect the growth of human malignancies. However, little is known about the underlying molecular mechanisms. Here, we observed the effects of hMSCs on the human cholangiocarcinoma cell line, HCCC-9810, using an animal transplantation model, and conditioned media from human umbilical cord derived mesenchymal stem cells (hUC-MSCs). Animal studies showed that hUC-MSCs can inhibit the growth of cholangiocarcinoma xenograft tumors. In cell culture, conditioned media from hUC-MSCs inhibited proliferation and induced apoptosis of tumor cells in a dose- and time-dependent manner. The proliferation inhibition rate increased from 6.21% to 49.86%, whereas the apoptosis rate increased from 9.3% to 48.1% when HCCC-9810 cells were cultured with 50% hUC-MSC conditioned media for 24 h. Immunoblot analysis showed that the expression of phosphor-PDK1 (Ser241), phosphor-Akt (Ser 437 and Thr308), phosphorylated glycogen synthase kinase 3beta (phospho-GSK-3beta(Ser9)), beta-catenin, cyclin-D1, and c-myc were down-regulated. We further demonstrated that CHIR99021, a GSK-3beta inhibitor reversed the suppressive effects of hUC-MSCs on HCCC-9810 cells and increased the expression of beta-catenin. The GSK-3beta activator, sodium nitroprusside dehydrate (SNP), augmented the anti-tumor effects of hUC-MSCs and decreased the expression of beta-catenin. IGF-1 acted as an Akt activator, and also reversed the suppressive effects of hUC-MSCs on HCCC-9810 cells. All these results suggest that hUC-MSCs could inhibit the malignant phenotype of HCCC-9810 human cholangiocarcinoma cell line. The cross-talk role of Wnt/beta-catenin and PI3K/Akt signaling pathway, with GSK-3beta as the key enzyme bridging these pathways, may contribute to the inhibition of cholangiocarcinoma cells by hUC MSCs. PMID- 23646151 TI - Uncoupling of natural IgE production and CD23 surface expression levels. AB - CD23, the low affinity receptor for immunoglobulin E (IgE), has been proposed to play a critical role in the regulation of IgE production, based on altered IgE levels in CD23-deficient mice and transgenic mouse models, as well as in mouse strains with mutations in the CD23 gene, e.g. 129 substrains. Here, we have investigated a mouse line termed LxT1 that expresses reduced CD23 surface levels on B cells, and its influence on natural IgE production. Extensive phenotypic analysis showed that CD23 surface expression was reduced in LxT1 compared to the control, without affecting B cell development in general. This CD23(low) surface level in LxT1 mice is not as a result of reduced CD23 mRNA expression levels or intracellular accumulation, but linked to a recessive locus, a 129-derived region spanning 28 Mb on chromosome 8, which includes the CD23 gene. Sequence analysis confirmed five mutations within the CD23 coding region in LxT1 mice, the same as those present in New Zealand Black (NZB) and 129 mice. However, this CD23(low) phenotype was not observed in all 129 substrains despite carrying these same CD23 mutations in the coding region. Moreover, serum IgE levels in LxT1 mice are as low as those in the C57BL/6 (B6) strain, and much lower than those in 129 substrains. These data indicate that the CD23 surface level and serum IgE level are uncoupled and that neither is directly regulated by the mutations within the CD23 coding region. This study suggests that caution should be taken when interpreting the immunological data derived from mice with different genetic background, especially if the gene of interest is thought to influence CD23 surface expression or serum IgE level. PMID- 23646153 TI - Assisted knowledge discovery for the maintenance of clinical guidelines. AB - BACKGROUND: Improving antibiotic prescribing practices is an important public health priority given the widespread antimicrobial resistance. Establishing clinical practice guidelines is crucial to this effort, but their development is a complex task and their quality is directly related to the methodology and source of knowledge used. OBJECTIVE: We present the design and the evaluation of a tool (KART) that aims to facilitate the creation and maintenance of clinical practice guidelines based on information retrieval techniques. METHODS: KART consists of three main modules 1) a literature-based medical knowledge extraction module, which is built upon a specialized question-answering engine; 2) a module to normalize clinical recommendations based on automatic text categorizers; and 3) a module to manage clinical knowledge, which formalizes and stores clinical recommendations for further use. The evaluation of the usability and utility of KART followed the methodology of the cognitive walkthrough. RESULTS: KART was designed and implemented as a standalone web application. The quantitative evaluation of the medical knowledge extraction module showed that 53% of the clinical recommendations generated by KART are consistent with existing clinical guidelines. The user-based evaluation confirmed this result by showing that KART was able to find a relevant antibiotic for half of the clinical scenarios tested. The automatic normalization of the recommendation produced mixed results among end-users. CONCLUSIONS: We have developed an innovative approach for the process of clinical guidelines development and maintenance in a context where available knowledge is increasing at a rate that cannot be sustained by humans. In contrast to existing knowledge authoring tools, KART not only provides assistance to normalize, formalize and store clinical recommendations, but also aims to facilitate knowledge building. PMID- 23646152 TI - Deep sequencing reveals transcriptome re-programming of Taxus * media cells to the elicitation with methyl jasmonate. AB - BACKGROUND: Plant cell culture represents an alternative source for producing high-value secondary metabolites including paclitaxel (Taxol(r)), which is mainly produced in Taxus and has been widely used in cancer chemotherapy. The phytohormone methyl jasmonate (MeJA) can significantly increase the production of paclitaxel, which is induced in plants as a secondary metabolite possibly in defense against herbivores and pathogens. In cell culture, MeJA also elicits the accumulation of paclitaxel; however, the mechanism is still largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: To obtain insight into the global regulation mechanism of MeJA in the steady state of paclitaxel production (7 days after MeJA addition), especially on paclitaxel biosynthesis, we sequenced the transcriptomes of MeJA-treated and untreated Taxus * media cells and obtained ~ 32.5 M high quality reads, from which 40,348 unique sequences were obtained by de novo assembly. Expression level analysis indicated that a large number of genes were associated with transcriptional regulation, DNA and histone modification, and MeJA signaling network. All the 29 known genes involved in the biosynthesis of terpenoid backbone and paclitaxel were found with 18 genes showing increased transcript abundance following elicitation of MeJA. The significantly up regulated changes of 9 genes in paclitaxel biosynthesis were validated by qRT-PCR assays. According to the expression changes and the previously proposed enzyme functions, multiple candidates for the unknown steps in paclitaxel biosynthesis were identified. We also found some genes putatively involved in the transport and degradation of paclitaxel. Potential target prediction of miRNAs indicated that miRNAs may play an important role in the gene expression regulation following the elicitation of MeJA. CONCLUSIONS/SIGNIFICANCE: Our results shed new light on the global regulation mechanism by which MeJA regulates the physiology of Taxus cells and is helpful to understand how MeJA elicits other plant species besides Taxus. PMID- 23646155 TI - Ecological segregation in space, time and trophic niche of sympatric planktivorous petrels. AB - The principle of competitive exclusion postulates that ecologically-similar species are expected to partition their use of resources, leading to niche divergence. The most likely mechanisms allowing such coexistence are considered to be segregation in a horizontal, vertical or temporal dimension, or, where these overlap, a difference in trophic niche. Here, by combining information obtained from tracking devices (geolocator-immersion and time depth recorders), stable isotope analyses of blood, and conventional morphometry, we provide a detailed investigation of the ecological mechanisms that explain the coexistence of four species of abundant, zooplanktivorous seabirds in Southern Ocean ecosystems (blue petrel Halobaena caerulea, Antarctic prion Pachyptila desolata, common diving petrel Pelecanoides urinatrix and South Georgian diving petrel P. georgicus). The results revealed a combination of horizontal, vertical and temporal foraging segregation during the breeding season. The stable isotope and morphological analyses reinforced this conclusion, indicating that each species occupied a distinct trophic space, and that this appears to reflect adaptations in terms of flight performance. In conclusion, the present study indicated that although there was a degree of overlap in some measures of foraging behaviour, overall the four taxa operated in very different ecological space despite breeding in close proximity. We therefore provide important insight into the mechanisms allowing these very large populations of ecologically-similar predators to coexist. PMID- 23646154 TI - Evidence of maternal offloading of organic contaminants in white sharks (Carcharodon carcharias). AB - Organic contaminants were measured in young of the year (YOY) white sharks (Carcharodon carcharias) incidentally caught in southern California between 2005 and 2012 (n = 20) and were found to be unexpectedly high considering the young age and dietary preferences of young white sharks, suggesting these levels may be due to exposure in utero. To assess the potential contributions of dietary exposure to the observed levels, a five-parameter bioaccumulation model was used to estimate the total loads a newborn shark would potentially accumulate in one year from consuming contaminated prey from southern California. Maximum simulated dietary accumulation of DDTs and PCBs were 25.1 and 4.73 ug/g wet weight (ww) liver, respectively. Observed SigmaDDT and SigmaPCB concentrations (95+/-91 ug/g and 16+/-10 ug/g ww, respectively) in a majority of YOY sharks were substantially higher than the model predictions suggesting an additional source of contaminant exposure beyond foraging. Maternal offloading of organic contaminants during reproduction has been noted in other apex predators, but this is the first evidence of transfer in a matrotrophic shark. While there are signs of white shark population recovery in the eastern Pacific, the long-term physiological and population level consequences of biomagnification and maternal offloading of environmental contaminants in white sharks is unclear. PMID- 23646156 TI - The influence of the Val158Met catechol-O-methyltransferase polymorphism on the personality traits of bipolar patients. AB - INTRODUCTION: Certain personality traits and genetic polymorphisms are contributing factors to bipolar disorder and its symptomatology, and in turn, this syndrome influences personality. The aim of the present study is to compare the personality traits of euthymic bipolar patients with healthy controls and to investigate the effect of the catechol-O-methyltransferase (COMT) Val158Met genotype on those traits. We recruited thirty seven bipolar I patients in euthymic state following a manic episode and thirty healthy controls and evaluated their personality by means of the Cloninger's Temperament and Character Inventory (version TCI-R-140). We assessed the influence of the polymorphism Val158Met in the COMT gene on the personality of these patients. The patients scored higher than controls in harm avoidance (61.3+/-12.5 vs. 55.3+/-8.1) and self-transcendence (45.3+/-12.8 vs. 32.7+/-8.2) and scored lower than controls in self-directedness (68.8+/-13.3 vs. 79.3+/-8.1), cooperativeness (77.1+/-9.1 vs. 83.9+/-6.5) and persistence (60.4+/-15.1 vs. 67.1+/-8.9). The novelty seeking dimension associates with the Val158Met COMT genotype; patients with the low catabolic activity genotype, Met/Met, show a higher score than those with the high catabolic activity genotype, Val/Val. CONCLUSIONS: Suffering from bipolar disorder could have an impact on personality. A greater value in harm avoidance may be a genetic marker for a vulnerability to the development of a psychiatric disorder, but not bipolar disorder particularly, while a low value in persistence may characterize affective disorders or a subgroup of bipolar patients. The association between novelty seeking scores and COMT genotype may be linked with the role dopamine plays in the brain's reward circuits. PMID- 23646157 TI - Ser/Thr kinase-like protein of Nicotiana benthamiana is involved in the cell-to cell movement of Bamboo mosaic virus. AB - To investigate the plant genes affected by Bamboo mosaic virus (BaMV) infection, we applied a cDNA-amplified fragment length polymorphism technique to screen genes with differential expression. A serine/threonine kinase-like (NbSTKL) gene of Nicotiana benthamiana is upregulated after BaMV infection. NbSTKL contains the homologous domain of Ser/Thr kinase. Knocking down the expression of NbSTKL by virus-induced gene silencing reduced the accumulation of BaMV in the inoculated leaves but not in the protoplasts. The spread of GFP-expressing BaMV in the inoculated leaves is also impeded by a reduced expression of NbSTKL. These data imply that NbSTKL facilitates the cell-to-cell movement of BaMV. The subcellular localization of NbSTKL is mainly on the cell membrane, which has been confirmed by mutagenesis and fractionation experiments. Combined with the results showing that active site mutation of NbSTKL does not change its subcellular localization but significantly affects BaMV accumulation, we conclude that NbSTKL may regulate BaMV movement on the cell membrane by its kinase-like activity. Moreover, the transient expression of NbSTKL does not significantly affect the accumulation of Cucumber mosaic virus (CMV) and Potato virus X (PVX); thus, NbSTKL might be a specific protein facilitating BaMV movement. PMID- 23646158 TI - Baicalein reduces airway injury in allergen and IL-13 induced airway inflammation. AB - BACKGROUND: Baicalein, a bioflavone present in the dry roots of Scutellaria baicalensis Georgi, is known to reduce eotaxin production in human fibroblasts. However, there are no reports of its anti-asthma activity or its effect on airway injury. METHODOLOGY/PRINCIPAL FINDINGS: In a standard experimental asthma model, male Balb/c mice that were sensitized with ovalbumin (OVA), treated with baicalein (10 mg/kg, ip) or a vehicle control, either during (preventive use) or after OVA challenge (therapeutic use). In an alternate model, baicalein was administered to male Balb/c mice which were given either IL-4 or IL-13 intranasally. Features of asthma were determined by estimating airway hyperresponsiveness (AHR), histopathological changes and biochemical assays of key inflammatory molecules. Airway injury was determined with apoptotic assays, transmission electron microscopy and assessing key mitochondrial functions. Baicalein treatment reduced AHR and inflammation in both experimental models. TGF beta1, sub-epithelial fibrosis and goblet cell metaplasia, were also reduced. Furthermore, baicalein treatment significantly reduced 12/15-LOX activity, features of mitochondrial dysfunctions, and apoptosis of bronchial epithelia. CONCLUSION/SIGNIFICANCE: Our findings demonstrate that baicalein can attenuate important features of asthma, possibly through the reduction of airway injury and restoration of mitochondrial function. PMID- 23646160 TI - Real-time analysis and visualization for single-molecule based super-resolution microscopy. AB - Accurate multidimensional localization of isolated fluorescent emitters is a time consuming process in single-molecule based super-resolution microscopy. We demonstrate a functional method for real-time reconstruction with automatic feedback control, without compromising the localization accuracy. Compatible with high frame rates of EM-CCD cameras, it relies on a wavelet segmentation algorithm, together with a mix of CPU/GPU implementation. A combination with Gaussian fitting allows direct access to 3D localization. Automatic feedback control ensures optimal molecule density throughout the acquisition process. With this method, we significantly improve the efficiency and feasibility of localization-based super-resolution microscopy. PMID- 23646159 TI - Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations. AB - BACKGROUND: Pulmonary exacerbations (PEx), frequently associated with airway infection and inflammation, are the leading cause of morbidity in cystic fibrosis (CF). Molecular microbiologic approaches detect complex microbiota from CF airway samples taken during PEx. The relationship between airway microbiota, inflammation, and lung function during CF PEx is not well understood. OBJECTIVE: To determine the relationships between airway microbiota, inflammation, and lung function in CF subjects treated for PEx. METHODS: Expectorated sputum and blood were collected and lung function testing performed in CF subjects during early (0 3d.) and late treatment (>7d.) for PEx. Sputum was analyzed by culture, pyrosequencing of 16S rRNA amplicons, and quantitative PCR for total and specific bacteria. Sputum IL-8 and neutrophil elastase (NE); and circulating C-reactive protein (CRP) were measured. RESULTS: Thirty-seven sputum samples were collected from 21 CF subjects. At early treatment, lower diversity was associated with high relative abundance (RA) of Pseudomonas (r = -0.67, p<0.001), decreased FEV(1%) predicted (r = 0.49, p = 0.03) and increased CRP (r = -0.58, p = 0.01). In contrast to Pseudomonas, obligate and facultative anaerobic genera were associated with less inflammation and higher FEV1. With treatment, Pseudomonas RA and P. aeruginosa by qPCR decreased while anaerobic genera showed marked variability in response. Change in RA of Prevotella was associated with more variability in FEV1 response to treatment than Pseudomonas or Staphylococcus. CONCLUSIONS: Anaerobes identified from sputum by sequencing are associated with less inflammation and higher lung function compared to Pseudomonas at early exacerbation. CF PEx treatment results in variable changes of anaerobic genera suggesting the need for larger studies particularly of patients without traditional CF pathogens. PMID- 23646161 TI - The effects of p38 MAPK inhibition combined with G-CSF administration on the hematoimmune system in mice with irradiation injury. AB - The acute and residual (or long-term) bone marrow (BM) injury induced by ionizing radiation (IR) is a major clinic concern for patients receiving conventional radiotherapy and victims accidentally exposed to a moderate-to-high dose of IR. In this study, we investigated the effects of the treatment with the p38 inhibitor SB203580 (SB) and/or granulocyte colony-stimulating factor (G-CSF) on the hematoimmune damage induced by IR in a mouse model. Specifically, C57BL/6 mice were exposed to a sublethal dose (6 Gy) of total body irradiation (TBI) and then treated with vehicle, G-CSF, SB, and G-CSF plus SB. G-CSF (1 ug/mouse) was administrated to mice by intraperitoneal (ip) injection twice a day for six successive days; SB (15 mg/kg) by ip injection every other day for 10 days. It was found that the treatment with SB and/or G-CSF significantly enhanced the recovery of various peripheral blood cell counts and the number of BM mononuclear cells 10 and 30 days after the mice were exposed to TBI compared with vehicle treatment. Moreover, SB and/or G-CSF treatment also increased the clonogenic function of BM hematopoietic progenitor cells (HPCs) and the frequency of BM lineage -Sca1+c-kit+ cells (LSK cells) and short-term and long term hematopoietic stem cells (HSCs) 30 days after TBI, in comparison with vehicle treated controls. However, the recovery of peripheral blood B cells and CD4+ and CD8+ T cells was not significantly affected by SB and/or G-CSF treatment. These results suggest that the treatment with SB and/or G-CSF can reduce IR-induced BM injury probably in part via promoting HSC and HPC regeneration. PMID- 23646162 TI - Challenges of diagnosing acute HIV-1 subtype C infection in African women: performance of a clinical algorithm and the need for point-of-care nucleic-acid based testing. AB - BACKGROUND: Prompt diagnosis of acute HIV infection (AHI) benefits the individual and provides opportunities for public health intervention. The aim of this study was to describe most common signs and symptoms of AHI, correlate these with early disease progression and develop a clinical algorithm to identify acute HIV cases in resource limited setting. METHODS: 245 South African women at high-risk of HIV 1 were assessed for AHI and received monthly HIV-1 antibody and RNA testing. Signs and symptoms at first HIV-positive visit were compared to HIV-negative visits. Logistic regression identified clinical predictors of AHI. A model-based score was assigned to each predictor to create a risk score for every woman. RESULTS: Twenty-eight women seroconverted after a total of 390 person-years of follow-up with an HIV incidence of 7.2/100 person-years (95%CI 4.5-9.8). Fifty seven percent reported >=1 sign or symptom at the AHI visit. Factors predictive of AHI included age <25 years (OR = 3.2; 1.4-7.1), rash (OR = 6.1; 2.4-15.4), sore throat (OR = 2.7; 1.0-7.6), weight loss (OR = 4.4; 1.5-13.4), genital ulcers (OR = 8.0; 1.6-39.5) and vaginal discharge (OR = 5.4; 1.6-18.4). A risk score of 2 correctly predicted AHI in 50.0% of cases. The number of signs and symptoms correlated with higher HIV-1 RNA at diagnosis (r = 0.63; p<0.001). CONCLUSIONS: Accurate recognition of signs and symptoms of AHI is critical for early diagnosis of HIV infection. Our algorithm may assist in risk-stratifying individuals for AHI, especially in resource-limited settings where there is no routine testing for AHI. Independent validation of the algorithm on another cohort is needed to assess its utility further. Point-of-care antigen or viral load technology is required, however, to detect asymptomatic, antibody negative cases enabling early interventions and prevention of transmission. PMID- 23646163 TI - Integrin alpha1 has a long helix, extending from the transmembrane region to the cytoplasmic tail in detergent micelles. AB - Integrin proteins are very important adhesion receptors that mediate cell-cell and cell-extracellular matrix interactions. They play essential roles in cell signaling and the regulation of cellular shape, motility, and the cell cycle. Here, the transmembrane and cytoplasmic (TMC) domains of integrin alpha1 and beta1 were over-expressed and purified in detergent micelles. The structure and backbone relaxations of alpha1-TMC in LDAO micelles were determined and analyzed using solution NMR. A long helix, extending from the transmembrane region to the cytoplasmic tail, was observed in alpha1-TMC. Structural comparisons of alpha1 TMC with reported alphaIIb-TMC domains indicated different conformations in the transmembrane regions and cytoplasmic tails. An NMR titration experiment indicated weak interactions between alpha1-TMC and beta1-TMC through several alpha1-TMC residues located at its N-terminal juxta-transmembrane region and C terminal extended helix region. PMID- 23646164 TI - Development of an optimized medium, strain and high-throughput culturing methods for Methylobacterium extorquens. AB - Methylobacterium extorquens strains are the best-studied methylotrophic model system, and their metabolism of single carbon compounds has been studied for over 50 years. Here we develop a new system for high-throughput batch culture of M. extorquens in microtiter plates by jointly optimizing the properties of the organism, the growth media and the culturing system. After removing cellulose synthase genes in M. extorquens strains AM1 and PA1 to prevent biofilm formation, we found that currently available lab automation equipment, integrated and managed by open source software, makes possible reliable estimates of the exponential growth rate. Using this system, we developed an optimized growth medium for M. extorquens using response surface methodologies. We found that media that used EDTA as a metal chelator inhibited growth and led to inconsistent culture conditions. In contrast, the new medium we developed with a PIPES buffer and metals chelated by citrate allowed for fast and more consistent growth rates. This new Methylobacterium PIPES ('MP') medium was also robust to large deviations in its component ingredients which avoided batch effects from experiments that used media prepared at different times. MP medium allows for faster and more consistent growth than other media used for M. extorquens. PMID- 23646165 TI - Bilaterally symmetric populations of chicken dI1 (commissural) axons cross the floor plate independently of each other. AB - Axons use temporal and directional guidance cues at intermediate targets to set the rate and direction of growth towards their synaptic targets. Our recent studies have shown that disrupting the temporal guidance process, by unilaterally accelerating the rate at which spinal dI1 (commissural) axons grow, resulted in turning errors both in the ventral spinal cord and after crossing the floor plate. Here we investigate a mechanistic explanation for these defects: the accelerated dI1 axons arrive in the ventral spinal cord before necessary fasciculation cues from incoming dI1 axons from the opposite side of the spinal cord. The identification of such an interaction would support a model of selective fasciculation whereby the pioneering dI1 axons serve as guides for the processes of the bilaterally symmetrical population of dI1 neurons. To test this model, we first developed the ability to "double" in ovo electroporate the embryonic chicken spinal cord to independently manipulate the rate of growth of the two bilateral populations of dI1 axons. Second, we examined the requirement for a putative bilateral interaction by unilaterally ablating the dI1 population in cultured explants of chicken embryonic spinal cord. Surprisingly, we find no evidence for a bilateral dI1 axon interaction, rather dI1 axons appear to project independently of each other. PMID- 23646167 TI - Neural correlates of the perception for novel objects. AB - Perception of novel objects is of enormous importance in our lives. People have to perceive or understand novel objects when seeing an original painting, admiring an unconventional construction, and using an inventive device. However, very little is known about neural mechanisms underlying the perception for novel objects. Perception of novel objects relies on the integration of unusual features of novel objects in order to identify what such objects are. In the present study, functional Magnetic Resonance Imaging (MRI) was employed to investigate neural correlates of perception of novel objects. The neuroimaging data on participants engaged in novel object viewing versus ordinary object viewing revealed that perception of novel objects involves significant activation in the left precuneus (Brodmann area 7) and the right visual cortex. The results suggest that the left precuneus is associated with the integration of unusual features of novel objects, while the right visual cortex is sensitive to the detection of such features. Our findings highlight the left precuneus as a crucial component of the neural circuitry underlying perception of novel objects. PMID- 23646166 TI - Refinement of neuronal synchronization with gamma oscillations in the medial prefrontal cortex after adolescence. AB - The marked anatomical and functional changes taking place in the medial prefrontal cortex (PFC) during adolescence set grounds for the high incidence of neuropsychiatric disorders with adolescent onset. Although circuit refinement through synapse pruning may constitute the anatomical basis for the cognitive differences reported between adolescents and adults, a physiological correlate of circuit refinement at the level of neuronal ensembles has not been demonstrated. We have recorded neuronal activity together with local field potentials in the medial PFC of juvenile and adult mice under anesthesia, which allowed studying local functional connectivity without behavioral or sensorial interference. Entrainment of pyramidal neurons and interneurons to gamma oscillations, but not to theta or beta oscillations, was reduced after adolescence. Interneurons were synchronized to gamma oscillations across a wider area of the PFC than pyramidal neurons, and the span of interneuron synchronization was shorter in adults than juvenile mice. Thus, transition from childhood to adulthood is characterized by reduction of the strength and span of neuronal synchronization specific to gamma oscillations in the mPFC. The more restricted and weak ongoing synchronization in adults may allow a more dynamic rearrangement of neuronal ensembles during behavior and promote parallel processing of information. PMID- 23646168 TI - Characterization of a novel metal-dependent D-psicose 3-epimerase from Clostridium scindens 35704. AB - The noncharacterized protein CLOSCI_02528 from Clostridium scindens ATCC 35704 was characterized as D-psicose 3-epimerase. The enzyme showed maximum activity at pH 7.5 and 60 degrees C. The half-life of the enzyme at 50 degrees C was 108 min, suggesting the enzyme was relatively thermostable. It was strictly metal dependent and required Mn2+ as optimum cofactor for activity. In addition, Mn2+ improved the structural stability during both heat- and urea-induced unfolding. Using circular dichroism measurements, the apparent melting temperature (T m) and the urea midtransition concentration (C m) of metal-free enzyme were 64.4 degrees C and 2.68 M. By comparison, the Mn2+-bound enzyme showed higher T m and C m with 67.3 degrees C and 5.09 M. The Michaelis-Menten constant (K m), turnover number (k cat), and catalytic efficiency (k cat/K m) values for substrate D-psicose were estimated to be 28.3 mM, 1826.8 s-1, and 64.5 mM-1 s-1, respectively. The enzyme could effectively produce D-psicose from D-fructose with the turnover ratio of 28%. PMID- 23646169 TI - Angiotensin II is a new component involved in splenic T lymphocyte responses during Plasmodium berghei ANKA infection. AB - The contribution of T cells in severe malaria pathogenesis has been described. Here, we provide evidence for the potential role of angiotensin II (Ang II) in modulating splenic T cell responses in a rodent model of cerebral malaria. T cell activation induced by infection, determined by 3 to 4-fold enhancement in CD69 expression, was reduced to control levels when mice were treated with 20 mg/kg losartan (IC50 = 0.966 mg/kg/d), an AT1 receptor antagonist, or captopril (IC50 = 1.940 mg/kg/d), an inhibitor of angiotensin-converting enzyme (ACE). Moreover, the production of interferon-gamma and interleukin-17 by CD4+ T cells diminished 67% and 70%, respectively, by both treatments. Losartan reduced perforin expression in CD8+ T cells by 33% while captopril completely blocked it. The upregulation in chemokine receptor expression (CCR2 and CCR5) observed during infection was abolished and CD11a expression was partially reduced when mice were treated with drugs. T cells activated by Plasmodium berghei ANKA antigens showed 6-fold enhance in AT1 levels in comparison with naive cells. The upregulation of AT1 expression was reduced by losartan (80%) but not by captopril. Our results suggest that the AT1/Ang II axis has a role in the establishment of an efficient T cell response in the spleen and therefore could participate in a misbalanced parasite-induced T cell immune response during P. berghei ANKA infection. PMID- 23646171 TI - Development and validation of real-time PCR for rapid detection of Mecistocirrus digitatus. AB - Hematophagous activity of Mecistocirrus digitatus, which causes substantial blood and weight loss in large ruminants, is an emerging challenge due to the economic loss it brings to the livestock industry. Infected animals are treated with anthelmintic drugs, based on the identification of helminth species and the severity of infection; however, traditional methods such as microscopic identification and the counting of eggs for diagnosis and determination of level of infection are laborious, cumbersome and unreliable. To facilitate the detection of this parasite, a SYBR green-based real-time PCR was standardized and validated for the detection of M. digitatus infection in cattle and buffaloes. Oligonucleotides were designed to amplify partial Internal Transcribed Spacer (ITS)-1 sequence of M. digitatus. The specificity of the primers was confirmed by non-amplification of DNA extracted from other commonly occurring gastrointestinal nematodes in ruminants. Plasmids were ligated with partial ITS-1 sequence of M. digitatus, serially diluted (hundred fold) and used as standards in the real-time PCR assay. The quantification cycle (Cq) values were plotted against the standard DNA concentration to produce a standard curve. The assay was sensitive enough to detect one plasmid containing the M. digitatus DNA. Clinical application of this assay was validated by testing the DNA extracted from the faeces of naturally infected cattle (n = 40) and buffaloes (n = 25). The results were compared with our standard curve to calculate the quantity of M. digitatus in each faecal sample. The Cq value of the assay depicted a strong linear relationship with faecal DNA content, with a regression coefficient of 0.984 and efficiency of 99%. This assay has noteworthy advantages over the conventional methods of diagnosis because it is more specific, sensitive and reliable. PMID- 23646170 TI - Regulation of TAK1/TAB1-mediated IL-1beta signaling by cytoplasmic PPARbeta/delta. AB - The peroxisome proliferator-activated receptor subtypes PPARalpha, PPARbeta/delta, PPARgamma are members of the steroid hormone receptor superfamily with well-established functions in transcriptional regulation. Here, we describe an unexpected cytoplasmic function of PPARbeta/delta. Silencing of PPARbeta/delta expression interferes with the expression of a large subset of interleukin-1beta (IL-1beta)-induced target genes in HeLa cells, which is preceded by an inhibition of the IL-1beta-induced phosphorylation of TAK1 and its downstream effectors, including the NFkappaBalpha inhibitor IkappaBalpha (NFKBIA) and the NFkappaBalpha subunit p65 (RELA). PPARbeta/delta enhances the interaction between TAK1 and the small heat-shock protein HSP27, a known positive modulator of TAK1-mediated IL 1beta signaling. Consistent with these findings, PPARbeta/delta physically interacts with both the endogenous cytoplasmic TAK1/TAB1 complex and HSP27, and PPARbeta/delta overexpression increases the TAK1-induced transcriptional activity of NFkappaB. These observations suggest that PPARbeta/delta plays a role in the assembly of a cytoplasmic multi-protein complex containing TAK1, TAB1, HSP27 and PPARbeta/delta, and thereby participates in the NFkappaB response to IL-1beta. PMID- 23646172 TI - A cell-permeant amiloride derivative induces caspase-independent, AIF-mediated programmed necrotic death of breast cancer cells. AB - Amiloride is a potassium-sparing diuretic that has been used as an anti kaliuretic for the chronic management of hypertension and heart failure. Several studies have identified a potential anti-cancer role for amiloride, however the mechanisms underlying its anti-tumor effects remain to be fully delineated. Our group previously demonstrated that amiloride triggers caspase-independent cytotoxic cell death in human glioblastoma cell lines but not in primary astrocytes. To delineate the cellular mechanisms underlying amiloride's anti cancer cytotoxicity, cell permeant and cell impermeant derivatives of amiloride were synthesized that exhibit markedly different potencies in cancer cell death assays. Here we compare the cytotoxicities of 5-benzylglycinyl amiloride (UCD38B) and its free acid 5-glycinyl amiloride (UCD74A) toward human breast cancer cells. UCD74A exhibits poor cell permeability and has very little cytotoxic activity, while UCD38B is cell permeant and induces the caspase-independent death of proliferating and non-proliferating breast cancer cells. UCD38B treatment of human breast cancer cells promotes autophagy reflected in LC3 conversion, and induces the dramatic swelling of the endoplasmic reticulum, however these events do not appear to be the cause of cell death. Surprisingly, UCD38B but not UCD74A induces efficient AIF translocation from the mitochondria to the nucleus, and AIF function is necessary for the efficient induction of cancer cell death. Our observations indicate that UCD38B induces programmed necrosis through AIF translocation, and suggest that its cytosolic accessibility may facilitate drug action. PMID- 23646173 TI - Variation in heterozygosity predicts variation in human substitution rates between populations, individuals and genomic regions. AB - The "heterozygote instability" (HI) hypothesis suggests that gene conversion events focused on heterozygous sites during meiosis locally increase the mutation rate, but this hypothesis remains largely untested. As humans left Africa they lost variability, which, if HI operates, should have reduced the mutation rate in non-Africans. Relative substitution rates were quantified in diverse humans using aligned whole genome sequences from the 1,000 genomes project. Substitution rate is consistently greater in Africans than in non-Africans, but only in diploid regions of the genome, consistent with a role for heterozygosity. Analysing the same data partitioned into a series of non-overlapping 2 Mb windows reveals a strong, non-linear correlation between the amount of heterozygosity lost "out of Africa" and the difference in substitution rate between Africans and non Africans. Putative recent mutations, derived variants that occur only once among the 80 human chromosomes sampled, occur preferentially at the centre of 2 Kb windows that have elevated heterozygosity compared both with the same region in a closely related population and with an immediately adjacent region in the same population. More than half of all substitutions appear attributable to variation in heterozygosity. This observation provides strong support for HI with implications for many branches of evolutionary biology. PMID- 23646174 TI - Epithelial cell proliferation arrest induced by lactate and acetate from Lactobacillus casei and Bifidobacterium breve. AB - In an attempt to identify and characterize how symbiotic bacteria of the gut microbiota affect the molecular and cellular mechanisms of epithelial homeostasis, intestinal epithelial cells were co-cultured with either Lactobacillus or Bifidobacterium as bona fide symbionts to examine potential gene modulations. In addition to genes involved in the innate immune response, genes encoding check-point molecules controlling the cell cycle were among the most modulated in the course of these interactions. In the m-ICcl2 murine cell line, genes encoding cyclin E1 and cyclin D1 were strongly down regulated by L. casei and B. breve respectively. Cell proliferation arrest was accordingly confirmed. Short chain fatty acids (SCFA) were the effectors of this modulation, alone or in conjunction with the acidic pH they generated. These results demonstrate that the production of SCFAs, a characteristic of these symbiotic microorganisms, is potentially an essential regulatory effector of epithelial proliferation in the gut. PMID- 23646175 TI - Overexpression of WsSGTL1 gene of Withania somnifera enhances salt tolerance, heat tolerance and cold acclimation ability in transgenic Arabidopsis plants. AB - BACKGROUND: Sterol glycosyltrnasferases (SGT) are enzymes that glycosylate sterols which play important role in plant adaptation to stress and are medicinally important in plants like Withania somnifera. The present study aims to find the role of WsSGTL1 which is a sterol glycosyltransferase from W. somnifera, in plant's adaptation to abiotic stress. METHODOLOGY: The WsSGTL1 gene was transformed in Arabidopsis thaliana through Agrobacterium mediated transformation, using the binary vector pBI121, by floral dip method. The phenotypic and physiological parameters like germination, root length, shoot weight, relative electrolyte conductivity, MDA content, SOD levels, relative electrolyte leakage and chlorophyll measurements were compared between transgenic and wild type Arabidopsis plants under different abiotic stresses--salt, heat and cold. Biochemical analysis was done by HPLC-TLC and radiolabelled enzyme assay. The promoter of the WsSGTL1 gene was cloned by using Genome Walker kit (Clontech, USA) and the 3D structures were predicted by using Discovery Studio Ver. 2.5. RESULTS: The WsSGTL1 transgenic plants were confirmed to be single copy by Southern and homozygous by segregation analysis. As compared to WT, the transgenic plants showed better germination, salt tolerance, heat and cold tolerance. The level of the transgene WsSGTL1 was elevated in heat, cold and salt stress along with other marker genes such as HSP70, HSP90, RD29, SOS3 and LEA4-5. Biochemical analysis showed the formation of sterol glycosides and increase in enzyme activity. When the promoter of WsSGTL1 gene was cloned from W. somnifera and sequenced, it contained stress responsive elements. Bioinformatics analysis of the 3D structure of the WsSGTL1 protein showed functional similarity with sterol glycosyltransferase AtSGT of A. thaliana. CONCLUSIONS: Transformation of WsSGTL1 gene in A. thaliana conferred abiotic stress tolerance. The promoter of the gene in W.somnifera was found to have stress responsive elements. The 3D structure showed functional similarity with sterol glycosyltransferases. PMID- 23646176 TI - Genomic analysis of sequence-dependent DNA curvature in Leishmania. AB - Leishmania major is a flagellated protozoan parasite of medical importance. Like other members of the Trypanosomatidae family, it possesses unique mechanisms of gene expression such as constitutive polycistronic transcription of directional gene clusters, gene amplification, mRNA trans-splicing, and extensive editing of mitochondrial transcripts. The molecular signals underlying most of these processes remain under investigation. In order to investigate the role of DNA secondary structure signals in gene expression, we carried out a genome-wide in silico analysis of the intrinsic DNA curvature. The L. major genome revealed a lower frequency of high intrinsic curvature regions as well as inter- and intra- chromosomal distribution heterogeneity, when compared to prokaryotic and eukaryotic organisms. Using a novel method aimed at detecting region-integrated intrinsic curvature (RIIC), high DNA curvature was found to be associated with regions implicated in transcription initiation. Those include divergent strand switch regions between directional gene clusters and regions linked to markers of active transcription initiation such as acetylated H3 histone, TRF4 and SNAP50. These findings suggest a role for DNA curvature in transcription initiation in Leishmania supporting the relevance of DNA secondary structures signals. PMID- 23646177 TI - Phylogenetic and phylodynamic analyses of human metapneumovirus in Buenos Aires (Argentina) for a three-year period (2009-2011). AB - Human metapneumovirus, which belongs to the Paramyxoviridae family and has been classified as a member of the Pneumovirus genus, is genetically and clinically similar to other family members such as human respiratory syncytial virus. A total of 1146 nasopharyngeal aspirates from pediatric patients with moderate and severe acute lower respiratory tract infections, hospitalized at the Ricardo Gutierrez Childrens Hospital (Buenos Aires, Argentina), were tested by real time RT-PCR for human metapneumovirus. Results showed that 168 (14.65%) were positive. Thirty-six of these 168 samples were randomly selected to characterize positive cases molecularly. The phylogenetic analysis of the sequences of the G and F genes showed that genotypes A2 and B2 cocirculated during 2009 and 2010 and that only genotype A2 circulated in 2011 in Argentina. Genotype A2 prevailed during the study period, a fact supported by a higher effective population size (Netau) and higher diversity as compared to that of genotype B2 (10.9% (SE 1.3%) vs. 1.7% (SE 0.4%), respectively). The phylogeographic analysis of the G protein gene sequences showed that this virus has no geographical restrictions and can travel globally harbored in hosts. The selection pressure analysis of the F protein showed that although this protein has regions with polymorphisms, it has vast structural and functional constraints. In addition, the predicted B-linear epitopes and the sites recognized by previously described monoclonal antibodies were conserved in all Argentine sequences. This points out this protein as a potential candidate to be the target of future humanized antibodies or vaccines. PMID- 23646179 TI - Long-term impacts of forest ditching on non-aquatic biodiversity: conservation perspectives for a novel ecosystem. AB - Artificial drainage (ditching) is widely used to increase timber yield in northern forests. When the drainage systems are maintained, their environmental impacts are likely to accumulate over time and along accompanying management, notably after logging when new forest develops on decayed peat. Our study provides the first comprehensive documentation of long-term ditching impacts on terrestrial and arboreal biodiversity by comparing natural alder swamps and second-generation drained forests that have evolved from such swamps in Estonia. We explored species composition of four potentially drainage-sensitive taxonomic groups (vascular plants, bryophytes, lichens, and snails), abundance of species of conservation concern, and their relationships with stand structure in two-ha plots representing four management types (ranging from old growth to clearcut). We found that drainage affected plot-scale species richness only weakly but it profoundly changed assemblage composition. Bryophytes and lichens were the taxonomic groups that were most sensitive both to drainage and timber-harvesting; in closed stands they responded to changed microhabitat structure, notably impoverished tree diversity and dead-wood supply. As a result, natural old-growth plots were the most species-rich and hosted several specific species of conservation concern. Because the most influential structural changes are slow, drainage impacts may be long hidden. The results also indicated that even very old drained stands do not provide quality habitats for old-growth species of drier forest types. However, drained forests hosted many threatened species that were less site type specific, including early-successional vascular plants and snails on clearcuts and retention cuts, and bryophytes and lichens of successional and old forests. We conclude that three types of specific science based management tools are needed to mitigate ditching effects on forest biodiversity: (i) silvicultural techniques to maintain stand structural complexity; (ii) context-dependent spatial analysis and planning of drained landscapes; and (iii) lists of focal species to monitor and guide ditching practices. PMID- 23646178 TI - Early-stage psychotherapy produces elevated frontal white matter integrity in adult major depressive disorder. AB - BACKGROUND: Psychotherapy has demonstrated comparable efficacy to antidepressant medication in the treatment of major depressive disorder. Metabolic alterations in the MDD state and in response to treatment have been detected by functional imaging methods, but the underlying white matter microstructural changes remain unknown. The goal of this study is to apply diffusion tensor imaging techniques to investigate psychotherapy-specific responses in the white matter. METHODS: Twenty-one of forty-five outpatients diagnosed with major depression underwent diffusion tensor imaging before and after a four-week course of guided imagery psychotherapy. We compared fractional anisotropy in depressed patients (n = 21) with healthy controls (n = 22), and before-after treatment, using whole brain voxel-wise analysis. RESULTS: Post-treatment, depressed subjects showed a significant reduction in the 17-item Hamilton Depression Rating Scale. As compared to healthy controls, depressed subjects demonstrated significantly increased fractional anisotropy in the right thalamus. Psychopathological changes did not recover post-treatment, but a novel region of increased fractional anisotropy was discovered in the frontal lobe. CONCLUSIONS: At an early stage of psychotherapy, higher fractional anisotropy was detected in the frontal emotional regulation-associated region. This finding reveals that psychotherapy may induce white matter changes in the frontal lobe. This remodeling of frontal connections within mood regulation networks positively contributes to the "top-down" mechanism of psychotherapy. PMID- 23646180 TI - Comparison of the hematological profile of elite road cyclists during the 2010 and 2012 GiroBio ten-day stage races and relationships with final ranking. AB - Cycling stage races are strenuous endurance events during which exercise-induced variations in hematological parameters are consistently observed. However, specific literature on such changes is scarce and published data have been derived from small samples of athletes. The aims of this study were: (1) to determine the hematological response to middle-term strenuous endurance; and (2) to determine whether a relationship exists between the athlete-specific hematological profile and final placement in a cycling stage race. The study population was male professional cyclists (n = 253) competing in the 2010 (n = 144) and 2012 (n = 109) GiroBio 10-day stage races. Blood draws taken before the start of the race, at mid-race, and at end-race were performed in strict compliance with academic and anti-doping pre-analytical warnings. Blood chemistry included white blood cell, red blood cell, hemoglobin concentration, hematocrit, mean corpuscular volume (MCV), mean hemoglobin content (MCH), mean corpuscular hemoglobin content (MCHC), platelets, and reticulocyte relative and absolute counts. Compared to baseline values, erythrocyte, hemoglobin, hematocrit, MCHC, platelet and reticulocyte counts were all consistently lower at mid-race, but returned to normal by race-end, while leukocytes were increased in the final phase. MCV increased during both events. MCH increased in the first part to then return to baseline in the 2012 race. The calculated OFF-score consistently decreased in the first half of the race before increasing, but remained lower than the baseline value. The trends of variation in hematological parameters were substantially similar in both events. There was an inverse, albeit weak, relationship between placement and erythrocyte, platelet, hemoglobin, hematocrit and OFF-score values in the 2010, but not in the 2012 race. In conclusion, the data confirm that, in this large series of elite road cyclists, the strenuous effort a rider sustains during a stage race induces appreciable changes in the hematological profile. PMID- 23646181 TI - The impact of Lactobacillus plantarum WCFS1 teichoic acid D-alanylation on the generation of effector and regulatory T-cells in healthy mice. AB - To date it remains unclear how probiotics affect the immune system. Bacterial envelope components may play an essential role, as these are the first to establish bacterial-host cell interactions. Teichoic acids (TAs), and especially lipoteichoic acids, are the most pro-inflammatory components of the gram-positive bacterial envelope. This effect is dependent on D-alanyl substitution of the TA backbone and interactions with TLR2 on host cells. Although the pro-inflammatory properties of TAs have been established in vitro, it remains unclear how TAs affect immunomodulation in vivo. In this study, we investigated the role of TA D alanylation on L. plantarum-induced intestinal and systemic immunomodulation in vivo. For this, we compared the effect of L. plantarum WCFS1 and its TA D Alanylation negative derivative (dltX-D) on the distribution of dendritic cell and T cell populations and responses in healthy mice. We demonstrated that the majority of the L. plantarum-induced in vivo immunomodulatory effects were dependent on D-alanylation (D-Ala), as some L. plantarum WCFS1-induced immune changes were not observed in the dltX-D-treated group and some were only observed after treatment with dltX-D. Strikingly, not only pro-inflammatory immune responses were abolished in the absence of D-Ala substitution, but also anti inflammatory responses, such as the L. plantarum-induced generation of regulatory T cells in the spleen. With this study we provide insight in host-microbe interactions, by demonstrating the involvement of D-alanylation of TAs on the bacterial membrane in intestinal and systemic immunomodulation in healthy mice. PMID- 23646182 TI - Complex formation between NheB and NheC is necessary to induce cytotoxic activity by the three-component Bacillus cereus Nhe enterotoxin. AB - The nonhemolytic enterotoxin (Nhe) is known as a major pathogenicity factor for the diarrheal type of food poisoning caused by Bacillus cereus. The Nhe complex consists of NheA, NheB and NheC, all of them required to reach maximum cytotoxicity following a specific binding order on cell membranes. Here we show that complexes, formed between NheB and NheC under natural conditions before targeting the host cells, are essential for toxicity in Vero cells. To enable detection of NheC and its interaction with NheB, monoclonal antibodies against NheC were established and characterized. The antibodies allowed detection of recombinant NheC in a sandwich immunoassay at levels below 10 ng ml-1, but no or only minor amounts of NheC were detectable in natural culture supernatants of B. cereus strains. When NheB- and NheC-specific monoclonal antibodies were combined in a sandwich immunoassay, complexes between NheB and NheC could be demonstrated. The level of these complexes was directly correlated with the relative concentrations of NheB and NheC. Toxicity, however, showed a bell-shaped dose response curve with a plateau at ratios of NheB and NheC between 50:1 and 5:1. Both lower and higher ratios between NheB and NheC strongly reduced cytotoxicity. When the ratio approached an equimolar ratio, complex formation reached its maximum resulting in decreased binding of NheB to Vero cells. These data indicate that a defined level of NheB-NheC complexes as well as a sufficient amount of free NheB is necessary for efficient cell binding and toxicity. Altogether, the results of this study provide evidence that the interaction of NheB and NheC is a balanced process, necessary to induce, but also able to limit the toxic action of Nhe. PMID- 23646183 TI - C-terminal binding protein (CtBP) activates the expression of E-box clock genes with CLOCK/CYCLE in Drosophila. AB - In Drosophila, CLOCK/CYCLE heterodimer (CLK/CYC) is the primary activator of circadian clock genes that contain the E-box sequence in their promoter regions (hereafter referred to as "E-box clock genes"). Although extensive studies have investigated the feedback regulation of clock genes, little is known regarding other factors acting with CLK/CYC. Here we show that Drosophila C-terminal binding protein (dCtBP), a transcriptional co-factor, is involved in the regulation of the E-box clock genes. In vivo overexpression of dCtBP in clock cells lengthened or abolished circadian locomotor rhythm with up-regulation of a subset of the E-box clock genes, period (per), vrille (vri), and PAR domain protein 1epsilon (Pdp1epsilon). Co-expression of dCtBP with CLK in vitro also increased the promoter activity of per, vri, Pdp1epsilon and cwo depending on the amount of dCtBP expression, whereas no effect was observed without CLK. The activation of these clock genes in vitro was not observed when we used mutated dCtBP which carries amino acid substitutions in NAD+ domain. These results suggest that dCtBP generally acts as a putative co-activator of CLK/CYC through the E-box sequence. PMID- 23646184 TI - Phylogenetic and evolutionary analysis of Chinese Leishmania isolates based on multilocus sequence typing. AB - Leishmaniasis is a debilitating infectious disease that has a variety of clinical forms. In China, visceral leishmaniasis (VL) is the most common symptom, and L. donovani and/or L. infantum are the likely pathogens. In this study, multilocus sequence typing (MLST) of five enzyme-coding genes (fh, g6pdh, icd, mpi, pgd) and two conserved genes (hsp70, lack) was used to investigate the phylogenetic relationships of Chinese Leishmania strains. Concatenated alignment of the nucleotide sequences of the seven genes was analyzed and phylogenetic trees were constructed using neighbor-joining and maximum parsimony models. A set of additional sequences from 25 strains (24 strains belong to the L. donovani complex and one strain belongs to L. gerbilli) were retrieved from GenBank to infer the molecular evolutionary history of Leishmania from China and other endemic areas worldwide. Phylogenetic analyses consolidated Chinese Leishmania into four groups: (i) one clade A population comprised 13 isolates from different foci in China, which were pathogenic to humans and canines. This population was subdivided into two subclades, clade A1 and clade A2, which comprised sister organisms to the remaining members of the worldwide L. donovani complex; (ii) a population in clade B consisted of one reference strain of L. turanica and five Chinese strains from Xinjiang; (iii) clade C (SELF-7 and EJNI-154) formed a population that was closely related to clade B, and both isolates were identified as L. gerbilli; and (iv) the final group, clade D, included Sauroleishmania (LIZRD and KXG-E) and was distinct from the other strains. We hypothesize that the phylogeny of Chinese Leishmania is associated with the geographical origins rather than with the clinical forms (VL or CL) of leishmaniasis. To conclude, this study provides further molecular information on Chinese Leishmania isolates and the Chinese isolates appear to have a more complex evolutionary history than previously thought. PMID- 23646185 TI - Toxicant induced changes on delayed fluorescence decay kinetics of cyanobacteria and green algae: a rapid and sensitive biotest. AB - Algal tests have developed into routine tools for testing toxicity of pollutants in aquatic environments. Meanwhile, in addition to algal growth rates, an increasing number of fluorescence based methods are used for rapid and sensitive toxicity measures. The present study stresses the suitability of delayed fluorescence (DF) as a promising parameter for biotests. DF is based on the recombination fluorescence at the reaction centre of photosystem II, which is emitted only by photosynthetically active cells. We analyzed the effects of three chemicals (3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), 3,5 Dichlorophenol (3,5 DCP) and copper) on the shape of the DF decay kinetics for potential use in phytoplankton toxicity tests. The short incubation tests were done with four phytoplankton species, with special emphasis on the cyanobacterium Microcystis aeruginosa. All species exhibited a high sensitivity to DCMU, but cyanobacteria were more affected by copper and less by 3,5 DCP than the tested green algae. Analyses of changes in the DF decay curve in response to the added chemicals indicated the feasibility of the DF decay approach as a rapid and sensitive testing tool. PMID- 23646186 TI - Cigarette smoking and risk of breast cancer in a New Zealand multi-ethnic case control study. AB - BACKGROUND: The association between breast cancer and tobacco smoke is currently unclear. The aim of this study was to assess the effect of smoking behaviours on the risk of breast cancer among three ethnic groups of New Zealand women. METHODS: A population-based case-control study was conducted including breast cancer cases registered on the New Zealand Cancer Registry between 2005 and 2007. Controls were matched by ethnicity and 5-year age-group. Logistic regression was used to estimate the association between breast cancer and smoking at different time points across the lifecourse, for each ethnic group. Estimated odds ratios (OR) were adjusted for established risk factors. RESULTS: The study comprised 1,799 cases (302 Maori, 70 Pacific, 1,427 non-Maori/non-Pacific) and 2,540 controls (746 Maori, 191 Pacific, 1,603 non-Maori/non-Pacific). There was no clear association between smoking and breast cancer for non-Maori/non-Pacific women, although non-Maori/non-Pacific ex-smokers had statistically significant increased risk of breast cancer when smoking duration was 20 years or more, and this remained significant in the fully adjusted model (OR 1.31, 95% CI 1.03 to 1.66). Maori showed more consistent increased risk of breast cancer with increasing duration among current smokers (<20 years OR 1.61, 95% CI 0.55 to 4.74; 20+ years OR 2.03, 95% CI 1.29 to 3.22). There was a clear pattern of shorter duration since smoking cessation being associated with increased likelihood of breast cancer, and this was apparent for all ethnic groups. CONCLUSION: There was no clear pattern for cigarette smoking and breast cancer incidence in non-Maori/non-Pacific women, but increased risks were observed for Maori and Pacific women. These findings suggest that lowering the prevalence of smoking, especially among Maori and Pacific women, could be important for reducing breast cancer incidence. PMID- 23646187 TI - Multiple pathways suppress non-allelic homologous recombination during meiosis in Saccharomyces cerevisiae. AB - Recombination during meiosis in the form of crossover events promotes the segregation of homologous chromosomes by providing the only physical linkage between these chromosomes. Recombination occurs not only between allelic sites but also between non-allelic (ectopic) sites. Ectopic recombination is often suppressed to prevent non-productive linkages. In this study, we examined the effects of various mutations in genes involved in meiotic recombination on ectopic recombination during meiosis. RAD24, a DNA damage checkpoint clamp-loader gene, suppressed ectopic recombination in wild type in the same pathway as RAD51. In the absence of RAD24, a meiosis-specific recA homolog, DMC1, suppressed the recombination. Homology search and strand exchange in ectopic recombination occurred when either the RAD51 or the DMC1 recA homolog was absent, but was promoted by RAD52. Unexpectedly, the zip1 mutant, which is defective in chromosome synapsis, showed a decrease, rather than an increase, in ectopic recombination. Our results provide evidence for two types of ectopic recombination: one that occurs in wild-type cells and a second that occurs predominantly when the checkpoint pathway is inactivated. PMID- 23646188 TI - Enterococcus faecalis infection causes inflammation, intracellular oxphos independent ROS production, and DNA damage in human gastric cancer cells. AB - BACKGROUND: Achlorhydria caused by e.g. atrophic gastritis allows for bacterial overgrowth, which induces chronic inflammation and damage to the mucosal cells of infected individuals driving gastric malignancies and cancer. Enterococcus faecalis (E. faecalis) can colonize achlohydric stomachs and we therefore wanted to study the impact of E. faecalis infection on inflammatory response, reactive oxygen species (ROS) formation, mitochondrial respiration, and mitochondrial genetic stability in gastric mucosal cells. METHODS: To separate the changes induced by bacteria from those of the inflammatory cells we established an in vitro E. faecalis infection model system using the gastric carcinoma cell line MKN74. Total ROS and superoxide was measured by fluorescence microscopy. Cellular oxygen consumption was characterized non-invasively using XF24 microplate based respirometry. Gene expression was examined by microarray, and response pathways were identified by Gene Set Analysis (GSA). Selected gene transcripts were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Mitochondrial mutations were determined by sequencing. RESULTS: Infection of MKN74 cells with E. faecalis induced intracellular ROS production through a pathway independent of oxidative phosphorylation (oxphos). Furthermore, E. faecalis infection induced mitochondrial DNA instability. Following infection, genes coding for inflammatory response proteins were transcriptionally up regulated while DNA damage repair and cell cycle control genes were down regulated. Cell growth slowed down when infected with viable E. faecalis and responded in a dose dependent manner to E. faecalis lysate. CONCLUSIONS: Infection by E. faecalis induced an oxphos-independent intracellular ROS response and damaged the mitochondrial genome in gastric cell culture. Finally the bacteria induced an NF-kappaB inflammatory response as well as impaired DNA damage response and cell cycle control gene expression. TRANSCRIPT PROFILING: Array Express accession number E-MEXP-3496. PMID- 23646190 TI - Synaptic NMDA receptor-dependent Ca2+ entry drives membrane potential and Ca2+ oscillations in spinal ventral horn neurons. AB - During vertebrate locomotion, spinal neurons act as oscillators when initiated by glutamate release from descending systems. Activation of NMDA receptors initiates Ca2+-mediated intrinsic membrane potential oscillations in central pattern generator (CPG) neurons. NMDA receptor-dependent intrinsic oscillations require Ca2+-dependent K+ (K(Ca)2) channels for burst termination. However, the location of Ca2+ entry mediating K(Ca)2 channel activation, and type of Ca2+ channel- which includes NMDA receptors and voltage-gated Ca2+ channels (VGCCs)--remains elusive. NMDA receptor-dependent Ca2+ entry necessitates presynaptic release of glutamate, implying a location at active synapses within dendrites, whereas VGCC dependent Ca2+ entry is not similarly constrained. Where Ca2+ enters relative to K(Ca)2 channels is crucial to information processing of synaptic inputs necessary to coordinate locomotion. We demonstrate that Ca2+ permeating NMDA receptors is the dominant source of Ca2+ during NMDA-dependent oscillations in lamprey spinal neurons. This Ca2+ entry is synaptically located, NMDA receptor-dependent, and sufficient to activate K(Ca)2 channels at excitatory interneuron synapses onto other CPG neurons. Selective blockade of VGCCs reduces whole-cell Ca2+ entry but leaves membrane potential and Ca2+ oscillations unaffected. Furthermore, repetitive oscillations are prevented by fast, but not slow, Ca2+ chelation. Taken together, these results demonstrate that K(Ca)2 channels are closely located to NMDA receptor-dependent Ca2+ entry. The close spatial relationship between NMDA receptors and K(Ca)2 channels provides an intrinsic mechanism whereby synaptic excitation both excites and subsequently inhibits ventral horn neurons of the spinal motor system. This places the components necessary for oscillation generation, and hence locomotion, at glutamatergic synapses. PMID- 23646189 TI - Evidence for a pro-proliferative feedback loop in prostate cancer: the role of Epac1 and COX-2-dependent pathways. AB - OBJECTIVE: In human prostate cancer cells, a selective Epac agonist, 8-CPT-2Me cAMP, upregulates cell proliferation and survival via activation of Ras-MAPK and PI- 3-kinase-Akt-mTOR signaling cascades. Here we examine the role of inflammatory mediators in Epac1-induced cellular proliferation by determining the expression of the pro-inflammatory markers p-cPLA2, COX-2, and PGE2 in prostate cancer cells treated with 8-CPT-2Me-cAMP. METHODS: We employed inhibitors of COX 2, mTORC1, and mTORC2 to probe cyclic AMP-dependent pathways in human prostate cancer cells. RNAi targeting Epac1, Raptor, and Rictor was also employed in these studies. RESULTS: 8-CPT-2Me-cAMP treatment caused a 2-2.5-fold increase of p cPLA2(S505), COX-2, and PGE2 levels in human prostate cancer cell lines. Pretreatment of cells with the COX-2 inhibitor SC-58125 or the EP4 antagonist AH 23848, or with an inhibitor of mTORC1 and mTORC2, Torin1, significantly reduced the Epac1-dependent increase of p-cPLA2 and COX-2, p-S6-kinase(T389), and p AKT(S473). In addition, Epac1-induced protein and DNA synthesis were greatly reduced upon pretreatment of cells with either COX-2, EP4, or mTOR inhibitors. Transfection of prostate cancer cells with Epac1 dsRNA, Raptor dsRNA, or Rictor dsRNA profoundly reduced Epac1-dependent increases in p-cPLA2 and COX-2. CONCLUSION: We show that Epac1, a downstream effector of cAMP, functions as a pro inflammatory modulator in prostate cancer cells and promotes cell proliferation and survival by upregulating Ras-MAPK, and PI 3-kinase-Akt-mTOR signaling. PMID- 23646191 TI - Effectiveness of MF59TM adjuvanted influenza A(H1N1)pdm09 vaccine in risk groups in the Netherlands. AB - BACKGROUND: The aim of the present study was to estimate the effectiveness of the MF59TM-adjuvanted influenza A(H1N1)pdm09 vaccine against medically attended influenza-like illness and RT-PCR confirmed influenza in the at-risk population and persons over 60 in the Netherlands. METHODS: We conducted a retrospective cohort study in a Dutch based GP medical record database between 30 November 2009 and 1 March 2010 to estimate the vaccine effectiveness against influenza-like illness. Within the cohort we nested a test negative case-control study to estimate the effectiveness against laboratory confirmed influenza. RESULTS: The crude effectiveness in preventing diagnosed or possible influenza-like illness was 17.3% (95%CI: -8.5%-36.9%). Of the measured covariates, age, the severity of disease and health seeking behaviour through devised proxies confounded the association between vaccination and influenza-like illness. The adjusted vaccine effectiveness was 20.8% (95%CI: -5.4%, 40.5%) and varied significantly by age, being highest in adults up to 50 years (59%, 95%CI: 23%, 78%), and non-detectable in adults over 50 years. The number of cases in the nested case control study was too limited to validly estimate the VE against confirmed influenza. CONCLUSIONS: With our study we demonstrated that the approach of combining a cohort study in a primary health care database with field sampling is a feasible and useful option to monitor VE of influenza vaccines in the future. PMID- 23646193 TI - Effects of 5-fluorouracil in nuclear and cellular morphology, proliferation, cell cycle, apoptosis, cytoskeletal and caveolar distribution in primary cultures of smooth muscle cells. AB - Colon cancer is one of the most prevalent types of cancer in the world and is one of the leading causes of cancer death. The anti-metabolite 5- fluorouracil (5-FU) is widely used in the treatment of patients with colon cancer and other cancer types. 5-FU-based chemotherapy has been shown to be very efficient in the improvement of overall survival of the patients and for the eradication of the disease. Unfortunately, common side effects of 5-FU include severe alterations in the motility of the gastrointestinal tissues. Nevertheless, the molecular and cellular effects of 5-FU in smooth muscle cells are poorly understood. Primary smooth muscle cell cultures are an important tool for studies of the biological consequences of 5-FU at the cellular level. The avian gizzard is one of the most robust organs of smooth muscle cells. Here we studied the molecular and cellular effects of the chemotherapic drug 5-FU in a primary culture of chick gizzard smooth muscle cells. We found that treatment of smooth muscle cells with 5-FU inhibits cell proliferation by the arrest of cells in the G1 phase of cell cycle and induce apoptosis. 5-FU induced a decrease in the percentage of histone H3 positive cells. Treatment of cells with 5-FU induced changes in cellular and nuclear morphology, a decrease in the number of stress fibers and a major decrease in the number of caveolin-3 positive cells. Our results suggest that the disorganization of the actin cytoskeleton and the reduction of caveolin-3 expression could explain the alterations in contractility observed in patients treated with 5-FU. These findings might have an impact in the understanding of the cellular effects of 5-FU in smooth muscle tissues and might help the improvement of new therapeutic protocols for the treatment of colon cancer. PMID- 23646194 TI - Facilitated uptake of a bioactive metabolite of maritime pine bark extract (pycnogenol) into human erythrocytes. AB - Many plant secondary metabolites exhibit some degree of biological activity in humans. It is a common observation that individual plant-derived compounds in vivo are present in the nanomolar concentration range at which they usually fail to display measurable activity in vitro. While it is debatable that compounds detected in plasma are not the key effectors of bioactivity, an alternative hypothesis may take into consideration that measurable concentrations also reside in compartments other than plasma. We analysed the binding of constituents and the metabolite delta-(3,4-dihydroxy-phenyl)-gamma-valerolactone (M1), that had been previously detected in plasma samples of human consumers of pine bark extract Pycnogenol, to human erythrocytes. We found that caffeic acid, taxifolin, and ferulic acid passively bind to red blood cells, but only the bioactive metabolite M1 revealed pronounced accumulation. The partitioning of M1 into erythrocytes was significantly diminished at higher concentrations of M1 and in the presence of glucose, suggesting a facilitated transport of M1 via GLUT-1 transporter. This concept was further supported by structural similarities between the natural substrate alpha-D-glucose and the S-isomer of M1. After cellular uptake, M1 underwent further metabolism by conjugation with glutathione. We present strong indication for a transporter-mediated accumulation of a flavonoid metabolite in human erythrocytes and subsequent formation of a novel glutathione adduct. The physiologic role of the adduct remains to be elucidated. PMID- 23646195 TI - Multivoxel pattern analysis reveals auditory motion information in MT+ of both congenitally blind and sighted individuals. AB - Cross-modal plasticity refers to the recruitment of cortical regions involved in the processing of one modality (e.g. vision) for processing other modalities (e.g. audition). The principles determining how and where cross-modal plasticity occurs remain poorly understood. Here, we investigate these principles by testing responses to auditory motion in visual motion area MT+ of congenitally blind and sighted individuals. Replicating previous reports, we find that MT+ as a whole shows a strong and selective responses to auditory motion in congenitally blind but not sighted individuals, suggesting that the emergence of this univariate response depends on experience. Importantly, however, multivoxel pattern analyses showed that MT+ contained information about different auditory motion conditions in both blind and sighted individuals. These results were specific to MT+ and not found in early visual cortex. Basic sensitivity to auditory motion in MT+ is thus experience-independent, which may be a basis for the region's strong cross-modal recruitment in congenital blindness. PMID- 23646196 TI - Differential ligand binding affinities of human estrogen receptor-alpha isoforms. AB - Rapid non-genomic effects of 17beta-estradiol are elicited by the activation of different estrogen receptor-alpha isoforms. Presence of surface binding sites for estrogen have been identified in cells transfected with full-length estrogen receptor-alpha66 (ER66) and the truncated isoforms, estrogen receptor-alpha46 (ER46) and estrogen receptor-alpha36 (ER36). However, the binding affinities of the membrane estrogen receptors (mERs) remain unknown due to the difficulty of developing of stable mER-transfected cell lines with sufficient mER density, which has largely hampered biochemical binding studies. The present study utilized cell-free expression systems to determine the binding affinities of 17beta-estradiol to mERs, and the relationship among palmitoylation, membrane insertion and binding affinities. Saturation binding assays of human mERs revealed that [3H]-17beta-estradiol bound ER66 and ER46 with Kd values of 68.81 and 60.72 pM, respectively, whereas ER36 displayed no specific binding within the tested concentration range. Inhibition of palmitoylation or removal of the nanolipoprotein particles, used as membrane substitute, reduced the binding affinities of ER66 and ER46 to 17beta-estradiol. Moreover, ER66 and ER46 bound differentially with some estrogen receptor agonists and antagonists, and phytoestrogens. In particular, the classical estrogen receptor antagonist, ICI 182,780, had a higher affinity for ER66 than ER46. In summary, the present study defines the binding affinities for human estrogen receptor-alpha isoforms, and demonstrates that ER66 and ER46 show characteristics of mERs. The present data also indicates that palmitoylation and membrane insertion of mERs are important for proper receptor conformation allowing 17beta-estradiol binding. The differential binding of ER66 and ER46 with certain compounds substantiates the prospect of developing mER-selective drugs. PMID- 23646197 TI - Mismatch responses in the awake rat: evidence from epidural recordings of auditory cortical fields. AB - Detecting sudden environmental changes is crucial for the survival of humans and animals. In the human auditory system the mismatch negativity (MMN), a component of auditory evoked potentials (AEPs), reflects the violation of predictable stimulus regularities, established by the previous auditory sequence. Given the considerable potentiality of the MMN for clinical applications, establishing valid animal models that allow for detailed investigation of its neurophysiological mechanisms is important. Rodent studies, so far almost exclusively under anesthesia, have not provided decisive evidence whether an MMN analogue exists in rats. This may be due to several factors, including the effect of anesthesia. We therefore used epidural recordings in awake black hooded rats, from two auditory cortical areas in both hemispheres, and with bandpass filtered noise stimuli that were optimized in frequency and duration for eliciting MMN in rats. Using a classical oddball paradigm with frequency deviants, we detected mismatch responses at all four electrodes in primary and secondary auditory cortex, with morphological and functional properties similar to those known in humans, i.e., large amplitude biphasic differences that increased in amplitude with decreasing deviant probability. These mismatch responses significantly diminished in a control condition that removed the predictive context while controlling for presentation rate of the deviants. While our present study does not allow for disambiguating precisely the relative contribution of adaptation and prediction error processing to the observed mismatch responses, it demonstrates that MMN-like potentials can be obtained in awake and unrestrained rats. PMID- 23646192 TI - Fecal microbial diversity in pre-weaned dairy calves as described by pyrosequencing of metagenomic 16S rDNA. Associations of Faecalibacterium species with health and growth. AB - In this study, we use barcoded pyrosequencing of the 16S rRNA gene to characterize the fecal microbiota of neonatal calves and identify possible relationships of certain microbiota profiles with health and weight gain. Fecal samples were obtained weekly from 61 calves from birth until weaning (seventh week of the calves' life). Firmicutes was the most prevalent phylum, with a prevalence ranging from 63.84% to 81.90%, followed by Bacteroidetes (8.36% to 23.93%), Proteobacteria (3.72% to 9.75%), Fusobacteria (0.76% to 5.67%), and Actinobacteria (1.02% to 2.35%). Chao1 index gradually increased from the first to the seventh postnatal week. Chao1 index was lower during the third, fourth, and fifth week of life in calves that suffered from pneumonia and were treated with antibiotics. Diarrhea incidence during the first four weeks of the calves' life was also associated with a reduction of microbial diversity during the third week of life. Increased fecal microbial diversity after the second week of life was associated with higher weight gain. Using discriminant analysis we were able to show differences in the microbiota profiles between different weeks of life, between high and low weight gain groups of calves, and between calves affected and not affected with diarrhea during the first four weeks life. The prevalence of Faecalibacterium spp. in the first week of life was associated with weight gain and the incidence of diarrhea, with higher prevalence being associated with higher weight gain and less diarrhea. Representative sequences from Faecalibacterium spp. were closely affiliated to Faecalibacterium prausnitzii. Results presented here provide new information regarding the intestinal microbiota of neonatal calves and its association with health and growth. Fecal microbial diversity was associated with calf age, disease status and growth rates. Results suggesting a possible beneficial effect of Faecalibacterium spp. on health and growth are promising. PMID- 23646198 TI - Ablation of C/EBP homologous protein does not protect T17M RHO mice from retinal degeneration. AB - Despite the proposed link between ablation of the CHOP protein and delay of the onset of ER stress-mediated disorders including diabetes, Alzheimer Disease, and cardiac hypertrophy, the role of CHOP protein in photoreceptor cell death associated with Autosomal Dominant Retinitis Pigmentosa (ADRP) has not been investigated. T17M RHO transgenic mice carry a mutated human rhodopsin transgene, the expression of which in retina leads to protein misfolding, activation of UPR and progressive retinal degeneration. The purpose of this study is to investigate the role of CHOP protein in T17M RHO retina. Wild-type, CHOP-/-, T17M RHO and T17M RHO CHOP-/-mice were used in the study. Evaluation of the impact of CHOP ablation was performed using electroretinography (ERG), spectral-domain optical coherence tomography (SD-OCT), quantitative Real-Time PCR (qRT-PCR) and western blot analysis. Dark-adapted ERG analysis demonstrated that by 1 month, the T17M RHO CHOP-/- mice had a 70% reduction of the a-wave amplitude compared to the T17M RHO mice. The loss of function in T17M RHO CHOP-/- photoreceptors was associated with a 22-24% decline in the thickness of the outer nuclear layer. These mice had significant reduction in the expression of transcription factors, Crx and Nrl, and also in mouse Rho, and human RHO. The reduction was associated with an 8-fold elevation of the UPR marker, p-eIf2alpha protein and 30% down-regulation of sXbp1 protein. In addition, the histone deacetylase 1 (Hdac1) protein was 2-fold elevated in the T17M RHO CHOP-/- retina. The ablation of CHOP led to a reduction in the expression of photoreceptor-specific transcriptional factors, and both endogenous and exogenous RHO mRNA. Thus, despite its role in promoting apoptosis, CHOP protects rod photoreceptors carrying an ADRP mutation. PMID- 23646199 TI - Sema6B, Sema6C, and Sema6D expression and function during mammalian retinal development. AB - In the vertebrate retina, the formation of neural circuits within discrete laminae is critical for the establishment of retinal visual function. Precise formation of retinal circuits requires the coordinated actions of adhesive and repulsive molecules, including repulsive transmembrane semaphorins (Sema6A, Sema5A, and Sema5B). These semaphorins signal through different Plexin A (PlexA) receptors, thereby regulating distinct aspects of retinal circuit assembly. Here, we investigate the physiological roles of three Class 6 transmembrane semaphorins (Sema6B, Sema6C, and Sema6D), previously identified as PlexA receptor ligands in non-retinal tissues, in mammalian retinal development. We performed expression analysis and also phenotypic analyses of mice that carry null mutations in each of genes encoding these proteins using a broad range of inner and outer retinal markers. We find that these Class 6 semaphorins are uniquely expressed throughout postnatal retinal development in specific domains and cell types of the developing retina. However, we do not observe defects in stereotypical lamina specific neurite stratification of retinal neuron subtypes in Sema6B-/- or Sema6C /-; Sema6D-/- retinas. These findings indicate these Class 6 transmembrane semaphorins are unlikely to serve as major PlexA receptor ligands for the assembly of murine retinal circuit laminar organization. PMID- 23646200 TI - CNVrd, a read-depth algorithm for assigning copy-number at the FCGR locus: population-specific tagging of copy number variation at FCGR3B. AB - The extent of contribution from common gene copy number (CN) variants in human disease is currently unresolved. Part of the reason for this is the technical difficulty in directly measuring CN variation (CNV) using molecular methods, and the lack of single nucleotide polymorphisms (SNPs) that can tag complex CNV that has arisen multiple times on different SNP haplotypes. One CNV locus implicated in human disease is FCGR. Here we aimed to use next-generation sequencing (NGS) data from the 1000 Genomes Project to assign CN at FCGR3A and FCGR3B and to comprehensively assess the ability of SNPs to tag specific CN variants. A read depth algorithm was developed (CNVrd) and validated on a subset of HapMap samples using CN assignments that had previously been determined using molecular and microarray methods. At 7 out of 9 other complex loci there was >90% concordance with microarray data. However, given that some prior knowledge of CN is required, the generalizability of CNVrd is limited and should be applied to other complex CNV loci with caution. Subsequently, CN was assigned et FCGR3B using CNVrd in a total of 952 samples from the 1000 Genomes Project, using three classes and SNPs that correlated with duplication were identified. The best tag SNP was observed in the Mexican-American sample set for duplication at FCGR3B. This SNP (rs117435514, r2 = 0.79) also tagged similar duplication in Chinese and Japanese (r2 = 0.35-0.60), but not in Caucasian or African. No tag SNP for duplication at FCGR3A or deletion at FCGR3B was identified in any population. We conclude that it is possible to tag CNV at the FCGR locus, but CN and SNPs have to be characterized and correlated on a population-specific basis. PMID- 23646202 TI - Clinical value of the Ottawa ankle rules for diagnosis of fractures in acute ankle injuries. AB - BACKGROUND: The Ottawa ankle rules (OAR) are clinical decision guidelines used to identify whether patients with ankle injuries need to undergo radiography. The OAR have been proven that their application reduces unnecessary radiography. They have nearly perfect sensitivity for identifying clinically significant ankle fractures. OBJECTIVES: The purpose of this study was to assess the applicability of the OAR in China, to examine their accuracy for the diagnosis of fractures in patients with acute ankle sprains, and to assess their clinical utility for the detection of occult fractures. METHODS: In this prospective study, patients with acute ankle injuries were enrolled during a 6-month period. The eligible patients were examined by emergency orthopedic specialists using the OAR, and then underwent ankle radiography. The results of examination using the OAR were compared with the radiographic results to assess the accuracy of the OAR for ankle fractures. Patients with OAR results highly suggestive of fracture, but no evidence of a fracture on radiographs, were advised to undergo 3-dimensional computed tomography (3D-CT). RESULTS: 183 patients with ankle injuries were enrolled in the study and 63 of these injuries involved fractures. The pooled sensitivity, specificity, positive predictive value and negative predictive value of the OAR for detection of fractures of the ankle were 96.8%, 45.8%, 48.4% and 96.5%, respectively. Our results suggest that clinical application of the OAR could decrease unnecessary radiographs by 31.1%. Of the 21 patients with positive OAR results and negative radiographic findings who underwent 3D-CT examination, five had occult fractures of the lateral malleolus. CONCLUSIONS: The OAR are applicable in the Chinese population, and have high sensitivity and modest specificity for the diagnosis of fractures associated with acute ankle injury. They may detect some occult fractures of the malleoli that are not visible on radiographs. PMID- 23646201 TI - Rapid discrimination of Haemophilus influenzae, H. parainfluenzae, and H. haemolyticus by fluorescence in situ hybridization (FISH) and two matrix-assisted laser-desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS) platforms. AB - BACKGROUND: Due to considerable differences in pathogenicity, Haemophilus influenzae, H. parainfluenzae and H. haemolyticus have to be reliably discriminated in routine diagnostics. Retrospective analyses suggest frequent misidentifications of commensal H. haemolyticus as H. influenzae. In a multi center approach, we assessed the suitability of fluorescence in situ hybridization (FISH) and matrix-assisted laser-desorption-ionization time-of flight mass-spectrometry (MALDI-TOF-MS) for the identification of H. influenzae, H. parainfluenzae and H. haemolyticus to species level. METHODOLOGY: A strain collection of 84 Haemophilus spp. comprising 50 H. influenzae, 25 H. parainfluenzae, 7 H. haemolyticus, and 2 H. parahaemolyticus including 77 clinical isolates was analyzed by FISH with newly designed DNA probes, and two different MALDI-TOF-MS systems (Bruker, Shimadzu) with and without prior formic acid extraction. PRINCIPAL FINDINGS: Among the 84 Haemophilus strains analyzed, FISH led to 71 correct results (85%), 13 uninterpretable results (15%), and no misidentifications. Shimadzu MALDI-TOF-MS resulted in 59 correct identifications (70%), 19 uninterpretable results (23%), and 6 misidentifications (7%), using colony material applied directly. Bruker MALDI-TOF-MS with prior formic acid extraction led to 74 correct results (88%), 4 uninterpretable results (5%) and 6 misidentifications (7%). The Bruker MALDI-TOF-MS misidentifications could be resolved by the addition of a suitable H. haemolyticus reference spectrum to the system's database. In conclusion, no analyzed diagnostic procedure was free of errors. Diagnostic results have to be interpreted carefully and alternative tests should be applied in case of ambiguous test results on isolates from seriously ill patients. PMID- 23646203 TI - LPS challenge regulates gene expression and tissue localization of a Ciona intestinalis gene through an alternative polyadenylation mechanism. AB - A subtractive hybridization strategy for the identification of differentially expressed genes was performed between LPS-challenged and naive Ciona intestinalis. This strategy allowed the characterization of two transcripts (Ci8short and Ci8long) generated by the use of two Alternative Polyadenylation sites. The Ci8long transcript contains a protein domain with relevant homology to several components of the Receptor Transporting Protein (RTP) family not present in the Ci8short mRNA. By means of Real Time PCR and Northern Blot, the Ci8short and Ci8long transcripts showed a different pattern of gene expression with the Ci8short mRNA being strongly activated after LPS injection in the pharynx. In situ hybridization analysis demonstrated that the activation of the APA site also influenced the tissue localization of the Ci8short transcript. This analysis showed that the Ci8long mRNA was expressed in hemocytes meanwhile the Ci8short mRNA was highly transcribed also in vessel endothelial cells and in the epithelium of pharynx. These findings demonstrated that regulation of gene expression based on different polyadenylation sites is an ancestral powerful strategy influencing both the level of expression and tissue distribution of alternative transcripts. PMID- 23646204 TI - Host restrictions of avian influenza viruses: in silico analysis of H13 and H16 specific signatures in the internal proteins. AB - Gulls are the primary hosts of H13 and H16 avian influenza viruses (AIVs). The molecular basis for this host restriction is only partially understood. In this study, amino acid sequences from Eurasian gull H13 and H16 AIVs and Eurasian AIVs (non H13 and H16) were compared to determine if specific signatures are present only in the internal proteins of H13 and H16 AIVs, using a bioinformatics approach. Amino acids identified in an initial analysis performed on 15 selected sequences were checked against a comprehensive set of AIV sequences retrieved from Genbank to verify them as H13 and H16 specific signatures. Analysis of protein similarities and prediction of subcellular localization signals were performed to search for possible functions associated with the confirmed signatures. H13 and H16 AIV specific signatures were found in all the internal proteins examined, but most were found in the non-structural protein 1 (NS1) and in the nucleoprotein. A putative functional signature was predicted to be present in the nuclear export protein. Moreover, it was predicted that the NS1 of H13 and H16 AIVs lack one of the nuclear localization signals present in NS1 of other AIV subtypes. These findings suggest that the signatures found in the internal proteins of H13 and H16 viruses are possibly related to host restriction. PMID- 23646205 TI - Kruppel-like factor 4 transcriptionally regulates TGF-beta1 and contributes to cardiac myofibroblast differentiation. AB - Angiotensin II (Ang II) plays a major role in the pathogenesis of cardiac fibrosis in hypertension. It is known that Ang II induces TGF-beta1 expression. How transcription mediates Ang II-induced TGF-beta1 expression, as well as its contribution to cardiac fibrosis, is unknown. We studied the role of Kruppel-like family transcription factors in Ang II-induced myofibroblast formation. We found that among the Kruppel-like family members, Kruppel-like factor 4 (Klf4) was the highest expressed form in isolated cardiac fibroblasts after Ang II treatment. Klf4 increased expression of alpha-SMA and collagen, as well as increased myofibroblast formation. ChIP assays showed that Klf4 specifically bound to the TGF-beta1 promoter. Deletion and mutagenesis analysis showed that the sites at 184~-180 bp and -45~-41 bp in the TGF-beta1 promoter were responsible for Klf4 transactivation of the TGF-beta1 promoter. Our studies demonstrate that Klf4 plays a pivotal role in Ang II-induced cardiac myofibroblast differentiation and collagen synthesis through transcriptional upregulation of TGF-beta1. PMID- 23646206 TI - Glucocorticoid receptor localizes to adherens junctions at the plasma membrane of keratinocytes. AB - Glucocorticoids are important regulators of epidermal tissue homeostasis. As such, their clinical applications are widespread, ranging from inflammatory skin disorders to keloids and cancer. Glucocorticoids exert their effect by binding to glucocorticoid receptor (GR) which translocates to the nucleus and regulates gene expression (genomic effect). In addition, GR has rapid non- genomic effects that are mediated by cell signaling proteins and do not involve gene transcription. Although genomic effects of GR in the epidermis are well documented, the non genomic effects are not completely understood. Therefore, we utilized immunostaining and immunoprecipitations to determine specific localization of the GR in human keratinocytes that may contribute to non-genomic effects of glucocorticoid action. Here we describe a novel finding of GR localization to the plasma membrane of keratinocytes. Immunocytochemistry showed co-localization of GR with alpha-catenin. Immunoprecipitation of the membranous fraction revealed an association of GR with alpha-catenin, confirming its localization to adherens junctions. We conclude that GR localization to adherens junctions of keratinocytes provides a new mechanism of non-genomic signaling by glucocorticoids which may have significant biological and clinical impact. PMID- 23646207 TI - A 45-year old man with recurrent syncope: an unusual presentation of coronary artery disease. AB - A 45-year old normotensive, euglycaemic, non-smoker was referred from a peripheral hospital to the Cardiology unit of the University College Hospital, Nigeria for evaluation of recurrent exercise induced syncope. Initial 12-lead electrocardiogram (ECG), 24-hr ambulatory ECG, trans-thoracic echocardiogram and electroencephalogram (EEG) were normal. A repeat episode of syncope warranted further investigation. Immediate post syncope ECG showed deeply inverted symmetrical T waves in the anterior leads. He underwent coronary angiogram which revealed distal left main disease and 70-80% stenosis of the proximal Left Anterior Descending Artery (LAD). The Circumflex artery was non dominant with normal Right Coronary artery. He subsequently had Percutaneous Transluminal Coronary Angioplasty (PTCA) of the LAD. Post-revascularisation course has been satisfactory with no recurrence of syncope. In view of the rising trend of cardiac death in the country, there is the need for high index of suspicion in making diagnosis of coronary artery disease in patients with syncope. PMID- 23646208 TI - Chromatographic immunoassays for Helicobacter pylori detection--are they reliable in Mali, West Africa? AB - INTRODUCTION: Gastrointestinal diseases are major reasons for morbidity in Mali. As Helicobacter pylori is known to play a major role in gastritis and gastric ulcer we wanted to find a simple method for detection. METHODS: Twenty-nine volunteers with confirmed gastric ulcer by gastroscopy and 59 randomly selected volunteers were diagnosed by using the rapid serological test Clearview((r)) H. Pylori. The ImmunoCard STAT!((r)) HpSA((r))test was applied on stool from 65 volunteers seeking help for gastrointestinal related ailments. RESULTS: A Helicobacter pylori prevalence of 21% was found among the individuals with confirmed gastric ulcer, 44% among the randomly selected volunteers and 14% in individuals with gastrointestinal related ailments. CONCLUSION: According to what is already known about the aetiology of gastric ailments and the prevalence of Helicobacter pylori in neighboring countries, the infection rates in our study appear strikingly low. This might indicate that Clearview((r)) H. Pylori and ImmunoCard STAT!((r)) HpSA((r)) have low sensitivities in the populations studied. Strain variability of H. pylori may be an explanation. The tests need to be properly evaluated in Mali before they can be relied upon as diagnostic tools. PMID- 23646209 TI - [Rapidly fatal Boerhaave syndrome: an emergency not to ignore]. PMID- 23646210 TI - Screening for refractive error among primary school children in Bayelsa State, Nigeria. AB - INTRODUCTION: BACKGROUND: Vision screening study in primary school children has not been done in Bayelsa State. This study aims to screen for refractive error among primary school children in Bayelsa State and use the data to plan for school Eye Health Program. METHODS: A cross sectional study on screening for refractive error in school children was carried out in Yenagoa Local Government Area of Bayelsa State in June 2009. A multistage sampling technique was used to select the study population (pupils aged between 5-15 years). Visual acuity (VA) for each eye, was assessed outside the classroom at a distance of 6 meters. Those with VA <=6/9 were presented with a pinhole and the test repeated. Funduscopy was done inside a poorly lit classroom. An improvement of the VA with pinhole was considered refractive error. Data was analyzed with EPI INFO version 6. RESULTS: A total of 1,242 school children consisting of 658 females and 584 males were examined. About 97.7% of pupils had normal VA (VA of 6/6) while 56 eyes had VAs <= 6/9. Of these 56 eyes, the visual acuity in 49 eyes (87.5%) improved with pinhole. Twenty seven pupils had refractive error, giving a prevalence of 2.2%. Refractive error involved both eyes in 22 pupils (81.5%) and the 8-10 years age range had the highest proportion (40.7%) of cases of refractive error followed by the 9-13 year-old age range (37%). CONCLUSION: The prevalence of refractive error was 2.2% and most eyes (97.7%) had normal vision. PMID- 23646211 TI - Feeding patterns and stunting during early childhood in rural communities of Sidama, South Ethiopia. AB - INTRODUCTION: The period from birth to two years of age is a "critical window" of opportunity for the promotion of optimal growth, health and behavioral development of children. Poor child feeding patterns combined with household food insecurity can lead to malnutrition which is a major public health problem in developing countries like Ethiopia. METHODS: A community based cross-sectional study that involved 575 participants from rural Sidama was conducted from February to March 2011. A two-stage stratified sampling procedure was employed to select the required households. Multivariable logistic regression analyses were performed to compare stunting by feeding patterns and other characteristics. RESULTS: Only 14.4% of mothers fed their children optimally. Prevalence of stunting was higher for infants aged 6 to 8 months (43%) than for those in 0-5 months (26.6%) or 9-23 months (39%) category. Women who did not receive antenatal care (ANC) during pregnancy were 1.5 times more likely to practice pre-lacteal feeding and 2.8 and 1.9 times more likely to feed their children below minimum dietary diversity and minimum meal frequency, respectively (P=0.01). Mothers older than 18 years during the birth of index child were 86% less likely to feed their child below minimum meal frequency than their younger counterparts (P=0.01). Children who started complementary food either before or after the recommended 6 months time, were more likely to be stunted (P=0.01). CONCLUSION: The feeding practices of most mothers did not meet WHO recommendations. Behavior change communication about the importance of optimal complementary feeding and ANC attendance should be strengthened through extensive use of the Health Extension Workers to reduce the level of child stunting in the study area. PMID- 23646212 TI - [Cervical vagus nerve schwannoma: diagnostic and therapeutic strategies]. PMID- 23646213 TI - [Calcified plantar angioleiomyoma]. PMID- 23646214 TI - Ball back in Africa's court: funding malaria control and elimination. PMID- 23646215 TI - Is it a rights violation or lack of knowledge about options? An examination of HIV counselors views on whether women infected with HIV should procreate. PMID- 23646216 TI - Contraception among bankers in an urban community in Lagos State, Nigeria. AB - INTRODUCTION: Contraception means procedures employed to interfere at one stage or the other with the normal sequence of events in the process of reproduction leading to a failure in conception. It means voluntary techniques adopted to achieve birth control. Its use remains sensitive worldwide. Within the same society, contraception varies amongst people of different socio-cultural, educational, religious, or occupational affiliations. It also varies between urban and rural settlements. Some contraceptive techniques also prevent sexually transmitted infections (STIs). The prevalence of STIs also varies with these same factors. There is very limited literature on contraception exclusively amongst bankers. We sought to investigate the level of awareness and practice of contraception amongst bankers in an urban society in Lagos State, Nigeria. METHODS: In this descriptive cross-sectional study, 200 self-administered structured questionnaires were retrieved from bankers from 5 banks selected by simple random sampling in Surulere Local Government Area of Lagos State, Nigeria. Data was subsequently statistically analyzed using SPSS. RESULTS: The age range was 21-45 years, mean 28.8+/-1.4 years, 51.7% were males (72% single, 27% married, 1% separated) and 48.3% were females (52.4% single, 47.6% married). All (100%) respondents were aware of contraception, 93.3% males and 91.7% females were sexually active, 88.9% males and 84.5% females believe contraception is useful. Most (71.4%) respondents practice contraception, males (81%) being more than females (61.1%), p < 0.05. More (71.4%) females and fewer (37.8%) males believe that contraception prevents pregnancy but not STIs, 28.6% of females and 46.6% of males believe it prevents both pregnancy and STIs, whereas 14% of males and no female believe contraception prevents STIs but not pregnancy. CONCLUSION: The awareness of and practice of contraception was very high among the bankers but more male bankers practice contraception whereas more female bankers perceive contraceptives to be for the married only. PMID- 23646217 TI - [Pseudotumoral form of pulmonary tuberculosis and diagnosis difficulties: about a case]. PMID- 23646218 TI - [Giant goiter associated with dyspnea]. PMID- 23646219 TI - [Result of surgical treatment of pulmonary aspergillosis secondary to a sequelae of tuberculosis in CHU/JRA]. PMID- 23646220 TI - An unusual presentation of carcinoma stomach. AB - Symptomatic gastric malignancy usually presents with symptoms which mimic peptic ulcer disease.Usual presenting features include weight loss and abdominal pain. Other symptoms include nausea, vomiting, dysphagia, melena and early satiety. Gastric malignancy presenting with hemetemesis, macular skin lesions of DIC and low backache due to bone metastasis from the primary is rare. Also bone metastasis in gastric cancer in the absence of hepatic metastasis is also rare. PMID- 23646221 TI - Reaction to Ilesanmi O S et al. The managed hypertensive: the costs of blood pressure control in a Nigerian town. PMID- 23646222 TI - Evaluating the acute flaccid paralysis surveillance system in South Africa, 2005 2009--an analysis of secondary data. AB - INTRODUCTION: Acute Flaccid Paralysis (AFP) surveillance was adopted by World Health Organization (WHO) to monitor progress towards poliomyelitis eradication. South Africa Department of Health (DoH) routinely collects AFP surveillance data but has no documented evidence of its epidemiological use. The study discusses the epidemiology of AFP in South Africa from 2005-9, evaluates performance of the AFP surveillance system, and identifies components that require strengthening. METHODS: A retrospective descriptive analysis was conducted on secondary AFP surveillance data for South Africa for the period 2005-2009, consisting of all children. RESULTS: South Africa reported 1501 AFP cases between 2005 and 2009. Of these, 67.2% were <5 years of age, and 54.3% were male. None of the cases were confirmed poliomyelitis, and ten (0.7%) were classified as polio-compatible. The national annualized non-polio AFP detection rate increased from 1.6 in 2005 to 2.1 non-polio AFP cases/100,000 children <15 years in 2008-9. All performance indicators met the WHO-specified targets except two. Between 2007 and 2009, 51.5%, 55.3% and 65% of specimens, respectively, reached the laboratory within 72 hours of being sent (WHO target is >=80%). Proportion of stool specimens where non-polio enterovirus was isolated decreased from 22.5% in 2006 to <1% in 2008 and 2009 (WHO target is >=10%). CONCLUSION: The AFP surveillance system met most WHO-specified epidemiological and laboratory performance standards. The surveillance programme needs to address problems of delayed specimen arrival to the laboratory and incomplete documentation of laboratory findings in the national AFP surveillance database. PMID- 23646223 TI - Chronic non-communicable disease as a new epidemic in Africa: focus on The Gambia. AB - INTRODUCTION: Recent epidemiological data suggest increasing burden of NCDs in many African countries but these diseases have not been given adequate attention due to the overwhelming burden of infectious diseases. There are no recent reports or studies on NCDs or related issues in The Gambia, consequently, this report intends to stimulate further epidemiological studies and also policy initiatives to forestall an epidemic. METHODS: Routine data on morbidity (in and out-patients), hospitalisation and mortality due to NCDs from health facilities in The Gambia between 2008 and 2011 were used. Other relevant data from multiple sources were also used. RESULTS: There is an increasing trend in the morbidity, hospitalisation and mortality due to NCDs in the Gambia between 2008 and 2011; 19.8%, 9.9% and 23.4% increments respectively. There is evidence of gender differences in these variables; more males suffer higher mortality from NCDs than females (p < 0.001). Furthermore, there is dearth of highly skilled health workforce as well as poor health infrastructures in The Gambia. CONCLUSION: NCDs are becoming a public health challenge and the capacity to respond to NCDs in most African countries, particularly, The Gambia is very weak. There is need for a population-based study to accurately quantify the burden and their risk factors as a first step towards policy formulation and effective implementation. Furthermore, there is dire need for increased investments on health workforce as well as medical products and technologies towards addressing the consequences of this emerging epidemic. PMID- 23646224 TI - [Cervicofacial cellulitis: about 130 cases]. PMID- 23646225 TI - Prevalence of hepatitis B co-infection amongst HIV infected children attending a care and treatment centre in Owerri, South-eastern Nigeria. AB - INTRODUCTION: Hepatitis B infection impacts negatively on disease progression in HIV infected children thereby increasing morbidity and mortality. In spite of the foregoing, there is paucity of data on Hepatitis B co-infection in children living with HIV in Owerri, South Eastern Nigeria.This study set out to determine the prevalence of Hepatitis B Co- infection in HIV infected children attending the Paediatric HIV Care and Treatment clinic of the Federal Medical Centre Owerri. METHODS: The study period was between February and July 2010. Testing for Hepatitis B infection was done using the ACON Hepatitis B surface antigen Rapid test strip. (Acon Laboratories Inc. San Diego.CA). RESULTS: A total of 139 HIV infected children were enrolled during the study period. The overall prevalence of Hepatitis B Co- infection was 5.8% (8/139). The prevalence in males was 8.2% (5/61) while in females it was 3.8% (3/78). The prevalence of Hepatitis B Co- infection amongst patients on antiretroviral therapy was 4.6%. They accounted for 62.5% of Hepatitis B Co- infection in our study. Previous blood transfusion, gender and age of patient did not show statistically significant relationship with Hepatitis B Co-infection. CONCLUSION: Though our study shows a low prevalence of Hepatitis B co infection in HIV infected children in our centre, reduction of the rate is still strongly desirable. Reduction can be achieved by strengthening the uptake of Hepatitis B vaccine as part of the routine childhood immunization programme. PMID- 23646226 TI - [Idiopathic scrotal calcinosis]. PMID- 23646227 TI - Reporting Guidelines for Music-based Interventions. AB - Music-based interventions are used to address a variety of problems experienced by individuals across the developmental lifespan (infants to elderly adults). In order to improve the transparency and specificity of reporting music-based interventions, a set of specific reporting guidelines is recommended. Recommendations pertain to reporting seven different components of music-based interventions including intervention theory, intervention content, intervention delivery schedule, interventionist, treatment fidelity, setting, and unit of delivery. Recommendations are intended to support CONSORT and TREND statements for transparent reporting of interventions while taking into account the variety, complexity, and uniqueness of music-based interventions. PMID- 23646228 TI - Does "Tiger Parenting" Exist? Parenting Profiles of Chinese Americans and Adolescent Developmental Outcomes. AB - "Tiger parenting," as described by Chua (2011), has put parenting in Asian American families in the spotlight. The current study identified parenting profiles in Chinese American families and explored their effects on adolescent adjustment. In a three-wave longitudinal design spanning eight years, from early adolescence to emerging adulthood, adolescents (54% female), fathers and mothers from 444 Chinese American families reported on eight parenting dimensions (e.g., warmth and shaming) and six developmental outcomes (e.g., GPA and academic pressure). Latent profile analyses on the eight parenting dimensions demonstrated four parenting profiles: supportive, tiger, easygoing, and harsh parenting. Over time, the percentage of parents classified as tiger parents decreased among mothers but increased among fathers. Path analyses showed that the supportive parenting profile, which was the most common, was associated with the best developmental outcomes, followed by easygoing parenting, tiger parenting, and harsh parenting. Compared with the supportive parenting profile, a tiger parenting profile was associated with lower GPA and educational attainment, as well as less of a sense of family obligation; it was also associated with more academic pressure, more depressive symptoms and a greater sense of alienation. The current study suggests that, contrary to the common perception, tiger parenting is not the most typical parenting profile in Chinese American families, nor does it lead to optimal adjustment among Chinese American adolescents. PMID- 23646229 TI - Lymphocyte subsets in alcoholic liver disease. AB - AIM: To compare lymphocyte subsets between healthy controls and alcoholics with liver disease. METHODS: The patient cohort for this study included individuals who were suspected to have alcoholic liver disease (ALD) and who had undergone liver biopsy (for disease grading and staging, doubts about diagnosis, or concurrent liver disease; n = 56). Normal controls included patients who were admitted for elective cholecystectomy due to non-complicated gallstones (n = 27). Formalin-fixed, paraffin-embedded liver biopsy specimens were sectioned and stained with hematoxylin and eosin and Perls' Prussian blue. The non-alcoholic steatohepatitis score was used to assess markers of ALD. Lymphocyte population subsets were determined by flow cytometry. T lymphocytes were identified (CD3(+)), and then further subdivided into CD4(+) or CD8(+) populations. B lymphocytes (CD19(+)) and natural killer (NK) cell numbers were also measured. In addition to assessing lymphocyte subpopulation differences between ALD patients and controls, we also compared subsets of alcoholic patients without cirrhosis or abstinent cirrhotic patients to normal controls. RESULTS: The patient cohort primarily consisted of older men. Active alcoholism was present in 66.1%. Reported average daily alcohol intake was 164.9 g and the average lifetime cumulative intake was 2211.6 kg. Cirrhosis was present in 39.3% of the patients and 66.1% had significant fibrosis (perisinusoidal and portal/periportal fibrosis, bridging fibrosis, or cirrhosis) in their liver samples. The average Mayo end-stage liver disease score was 7.6. No hereditary hemochromatosis genotypes were found. ALD patients (n = 56) presented with significant lymphopenia (1.5 * 10(9)/L +/- 0.5 * 10(9)/L vs 2.1 * 10(9)/L +/- 0.5 * 10(9)/L, P < 0.0001), due to a decrease in all lymphocyte subpopulations, except for NK lymphocytes: CD3(+) (1013.0 +/- 406.2/mm(3) vs 1523.0 +/- 364.6/mm(3), P < 0.0001), CD4(+) (713.5 +/- 284.7/mm(3) vs 992.4 +/- 274.7/mm(3), P < 0.0001), CD8(+) (262.3 +/- 140.4/mm(3) vs 478.9 +/- 164.6/mm(3), P < 0.0001), and CD19(+) (120.6 +/- 76.1/mm(3) vs 264.6 +/- 88.0/mm(3), P < 0.0001). CD8(+) lymphocytes suffered the greatest reduction, as evidenced by an increase in the CD4(+)/CD8(+) ratio (3.1 +/- 1.3 vs 2.3 +/- 0.9, P = 0.013). This ratio was associated with the stage of fibrosis on liver biopsy (r s = 0.342, P = 0.01) and with Child-Pugh score (r s = 0.482, P = 0.02). The number of CD8(+) lymphocytes also had a positive association with serum ferritin levels (r s = 0.345, P = 0.009). Considering only patients with active alcoholism but not cirrhosis (n = 27), we found similar reductions in total lymphocyte counts (1.8 * 10(9)/L +/- 0.3 * 10(9)/L vs 2.1 * 10(9)/L +/- 0.5 * 10(9)/L, P = 0.018), and in populations of CD3(+) (1164.7 +/- 376.6/mm(3) vs 1523.0 +/- 364.6/mm(3), P = 0.001), CD4(+) (759.8 +/- 265.0/mm(3) vs 992.4 +/- 274.7/mm(3), P = 0.003), CD8(+) (330.9 +/- 156.3/mm(3) vs 478.9 +/- 164.6/mm(3), P = 0.002), and CD19(+) (108.8 +/- 64.2/mm(3) vs 264.6 +/- 88.0/mm(3), P < 0.0001). In these patients, the CD4(+)/CD8(+) ratio and the number of NK lymphocytes was not significantly different, compared to controls. Comparing patients with liver cirrhosis but without active alcohol consumption (n = 11), we also found significant lymphopenia (1.3 * 10(9)/L +/- 0.6 * 10(9)/L vs 2.1 * 10(9)/L +/- 0.5 * 10(9)/L, P < 0.0001) and decreases in populations of CD3(+) (945.5 +/- 547.4/mm(3) vs 1523.0 +/- 364.6/mm(3), P = 0.003), CD4(+) (745.2 +/- 389.0/mm(3) vs 992.4 +/- 274.7/mm(3), P = 0.032), CD8(+) (233.9 +/- 120.0/mm(3) vs 478.9 +/- 164.6/mm(3), P < 0.0001), and CD19(+) (150.8 +/- 76.1/mm(3) vs 264.6 +/- 88.0/mm(3), P = 0.001). The NK lymphocyte count was not significantly different, but, in this group, there was a significant increase in the CD4(+)/CD8(+) ratio (3.5 +/- 1.3 vs 2.3 +/- 0.9, P = 0.01). CONCLUSION: All patient subsets presented with decreased lymphocyte counts, but only patients with advanced fibrosis presented with a significant increase in the CD4(+)/CD8(+) ratio. PMID- 23646230 TI - Dyspnea and respiratory muscle strength in end-stage liver disease. AB - AIM: To investigate the prevalence of chronic dyspnea and its relationship to respiratory muscle function in end-stage liver disease. METHODS: Sixty-eight consecutive, ambulatory, Caucasian patients with end-stage liver disease, candidates for liver transplantation, were referred for preoperative respiratory function assessment. Forty of these (29 men) were included in this preliminary study after applying strict inclusion and exclusion criteria. Seventeen of 40 patients (42%) had ascites, but none of them was cachectic. Fifteen of 40 patients (38%) had a history of hepatic encephalopathy, though none of them was symptomatic at study time. All patients with a known history and/or presence of co-morbidities were excluded. Chronic dyspnea was rated according to the modified medical research council (mMRC) 6-point scale. Liver disease severity was assessed according to the Model for end-stage liver disease (MELD). Routine lung function tests, maximum static expiratory (Pemax) and inspiratory (Pimax) mouth pressures were measured. Respiratory muscle strength (RMS) was calculated from Pimax and Pemax values. In addition, arterial blood gases and pattern of breathing (VE: minute ventilation; VT: tidal volume; VT/TI: mean inspiratory flow; TI: duration of inspiration) were measured. RESULTS: Thirty-five (88%) of 40 patients aged (mean +/- SD) 52 +/- 10 years reported various degrees of chronic dyspnea (mMRC), ranging from 0 to 4, with a mean value of 2.0 +/- 1.2. MELD score was 14 +/- 6. Pemax, percent of predicted (%pred) was 105 +/- 35, Pimax, %pred was 90 +/- 29, and RMS, %pred was 97 +/- 30. These pressures were below the normal limits in 12 (30%), 15 (38%), and 14 (35%) patients, respectively. Furthermore, comparing the subgroups of ascites to non-ascites patients, all respiratory muscle indices measured were found significantly decreased in ascites patients. Patients with ascites also had a significantly worse MELD score compared to non-ascites ones (P = 0.006). Significant correlations were found between chronic dyspnea and respiratory muscle function indices in all patients. Specifically, mMRC score was significantly correlated with Pemax, Pimax, and RMS (r = -0.53, P < 0.001; r = -0.42, P < 0.01; r = -0.51, P < 0.001, respectively). These correlations were substantially closer in the non ascites subgroup (r = -0.82, P < 0.0001; r = -0.61, P < 0.01; r = -0.79, P < 0.0001, respectively) compared to all patients. Similar results were found for the relationship between mMRC vs MELD score, and MELD score vs respiratory muscle strength indices. In all patients the sole predictor of mMRC score was RMS (r = 0.51, P < 0.001). In the subgroup of patients without ascites this relationship becomes closer (r = -0.79, P < 0.001), whilst this relationship breaks down in the subgroup of patients with ascites. The disappearance of such a correlation may be due to the fact that ascites acts as a "confounding" factor. PaCO2 (4.4 +/ 0.5 kPa) was increased, whereas pH (7.49 +/- 0.04) was decreased in 26 (65%) and 34 (85%) patients, respectively. PaO2 (12.3 +/- 0.04 kPa) was within normal limits. VE (11.5 +/- 3.5 L/min), VT (0.735 +/- 0.287 L), and VT/TI (0.449+/-0.129 L/s) were increased signifying hyperventilation in both subgroups of patients. VT/TI was significantly higher in patients with ascites than without ascites. Significant correlations, albeit weak, were found for PaCO2 with VE and VT/TI (r = -0.44, P < 0.01; r = -0.41, P < 0.01, respectively). CONCLUSION: The prevalence of chronic dyspnea is 88% in end-stage liver disease. The mMRC score closely correlates with respiratory muscle strength. PMID- 23646231 TI - Occult hepatitis B virus infection among Egyptian blood donors. AB - AIM: To identify blood donors with occult hepatitis B virus (HBV) infection (OBI) to promote safe blood donation. METHODS: Descriptive cross sectional study was conducted on 3167 blood donors negative for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab) and human immunodeficiency virus Ab. They were subjected to the detection of alanine aminotransferase (ALT) and aspartate transaminase (AST) and screening for anti-HBV core antibodies (total) by two different techniques; [Monoliza antibodies to hepatitis B core (Anti-HBc) Plus Bio-Rad] and (ARC-HBc total-ABBOT). Positive samples were subjected to quantitative detection of antibodies to hepatitis B surface (anti-HBs) (ETI-AB AUK-3, Dia Sorin-Italy). Serum anti-HBs titers > 10 IU/L was considered positive. Quantitative HBV DNA by real time polymerase chain reaction (PCR) (QIAGEN Germany) with 3.8 IU/mL detection limit was estimated for blood units with negative serum anti-HBs and also for 32 whose anti-HBs serum titers were > 1000 IU/L. Also, 265 recipients were included, 34 of whom were followed up for 3-6 mo. Recipients were investigated for ALT and AST, HBV serological markers: HBsAg (ETI MAK-4, Dia Sorin-Italy), anti-HBc, quantitative detection of anti-HBs and HBV DNA. RESULTS: 525/3167 (16.6%) of blood units were positive for total anti-HBc, 64% of those were anti-HBs positive. Confirmation by ARCHITECT anti-HBc assay were carried out for 498/525 anti-HBc positive samples, where 451 (90.6%) confirmed positive. Reactivity for anti-HBc was considered confirmed only if two positive results were obtained for each sample, giving an overall prevalence of 451/3167 (14.2%) for total anti-HBc. HBV DNA was quantified by real time PCR in 52/303 (17.2%) of anti-HBc positive blood donors (viral load range: 5 to 3.5 x 10(5) IU/mL) with a median of 200 IU/mL (mean: 1.8 x 10(4) +/- 5.1 x 10(4) IU/mL). Anti-HBc was the only marker in 68.6% of donors. Univariate and multivariate logistic analysis for identifying risk factors associated with anti HBc and HBV-DNA positivity among blood donors showed that age above thirty and marriage were the most significant risk factors for prediction of anti-HBc positivity with AOR 1.8 (1.4-2.4) and 1.4 (1.0-1.9) respectively. Other risk factors as gender, history of blood transfusion, diabetes mellitus, frequent injections, tattooing, previous surgery, hospitalization, Bilharziasis or positive family history of HBV or HCV infections were not found to be associated with positive anti-HBc antibodies. Among anti-HBc positive blood donors, age below thirty was the most significant risk factor for prediction of HBV-DNA positivity with AOR 3.8 (1.8-7.9). According to HBV-DNA concentration, positive samples were divided in two groups; group one with HBV-DNA >= 200 IU/mL (n = 27) and group two with HBV-DNA < 200 IU/mL (n = 26). No significant difference was detected between both groups as regards mean age, gender, liver enzymes or HBV markers. Serological profiles of all followed up blood recipients showed that, all were negative for the studied HBV markers. Also, HBV DNA was not detected among studied recipients, none developed post-transfusion hepatitis (PTH) and the clinical outcome was good. CONCLUSION: OBI is prevalent among blood donors. Nucleic acid amplification/HBV anti core screening should be considered for high risk recipients to eliminate risk of unsafe blood donation. PMID- 23646232 TI - Significance of serum leptin and adiponectin levels in Egyptian patients with chronic hepatitis C virus associated hepatic steatosis and fibrosis. AB - AIM: To study serum levels of leptin and adiponectin in patients with chronic hepatitis C virus infection genotype-4 (HCV-4) related steatosis and fibrosis. METHODS: We prospectively studied 45 untreated men with chronic HCV-4, with proven steatosis (group I, 30 patients), and fibrosis (group II, 15 patients), on liver biopsy. In addition, 15 healthy men (group III), matched for age, and body mass index were included. However, we excluded another five patients with steatohepatitis, and six patients with cirrhosis. We measured total serum leptin and adiponectin levels, as potential predictors for liver steatosis and fibrosis. Also, a correlation between these adipokines and various clinical and laboratory data were evaluated. All subjects were selected from Tropical and Internal medicine departments, Menoufiya University Hospital, Menoufiya, Egypt, during the period from February 2010 to August 2011. RESULTS: In group I, severity of hepatic steatosis was mild, moderate, and severe, in 19 patients (63.5%), 8 patients (26.5%), and 3 patients (10%), respectively. In contrast, in group II, hepatic fibrosis was found to be in stage 1, 2, and 3, in 6 patients (40%), in 6 patients (40%), and in 3 patients (20%), respectively. On comparing group I with group II, there was a significant decrease in serum adiponectin levels (131.4 +/- 7.91 pg/mL vs 436 +/- 9.75 pg/mL, P < 0.001), while there was no significant difference between both groups regarding serum leptin levels (34.69 +/- 7.69 ng/mL vs 35.17 +/- 1.06 ng/mL, P > 0.05). However, in the same group, when compared with group III, there was a significant increase in serum leptin levels (34.69 +/- 7.69 ng/mL vs 10.69 +/- 0.84 ng/mL, P < 0.001), while there was a significant decrease in serum adiponectin levels (131.4 +/- 7.91 pg/mL vs 342.4 +/- 44.48 pg/mL, P < 0.001). In contrast, in group II, when compared with group III, there was a significant increase in serum leptin and adiponectin levels (35.17 +/- 1.06 ng/mL vs 10.69 +/- 0.84 ng/mL, P < 0.001, and 436 +/- 9.75 pg /mL vs 342.4 +/- 44.48 pg/mL, P < 0.05, respectively), while there was no significant difference between both groups regarding serum creatinine (0.83 +/- 0.34 vs 0.89 +/- 0.24, P > 0.05). On the other hand, serum leptin was not correlated with serum adiponectin in group I and in group II (r = 0.09, P > 0.05, and r = -0.1, P > 0.05, respectively). However, serum adiponectin was significantly negatively correlated with serum aspartate transaminase in group I, but no correlation detected in group II (r =-0.39, P > 0.05, and r = -0.03, P > 0.05). CONCLUSION: In male patients with chronic HCV-4, serum adiponectin levels are elevated in hepatic fibrosis, but decreased in steatosis. Therefore, in contrast to leptin, adiponectin may be used as a non-invasive marker. PMID- 23646233 TI - Acute renal failure associated with acute non-fulminant hepatitis B. AB - A 38-year-old female presenting with a high fever of 39 degrees C developed severe liver dysfunction and acute renal failure (ARF). In tests for a hepatitis associated virus, an Immunoglobulin M-anti-hepatitis B virus core antibody was the only positive finding. Moreover, the progression of ARF coincided with the pole period of liver damage and all the other assumed causes for the ARF were unlikely. Therefore, this case was diagnosed as ARF caused by acute hepatitis B. ARF associated with non-fulminant hepatitis has been infrequently reported, usually in association with acute hepatitis A. This case is considered to be an extremely rare and interesting case. PMID- 23646234 TI - Myxedema ascites with high CA-125: Case and a review of literature. AB - Ascites appearing in a previously healthy female patient is usually ascribed to a variety of causes, among which, is a cancerous process, especially if it comes with a raised CA-125 level. Although the CA-125 antigen is present on more than 80% of malignant epithelial ovarian tissue of non-mucinous type, it is also found on both healthy and malignant cells of mesothelial and non-mesothelial origin. Myxedema ascites which is caused by hypothyroidism is a rare entity, but on the other hand is easy to treat. It is one of the differential diagnoses when the ascites is refractory to treatment and no other obvious cause can be identified. If the diagnosis is delayed, patients will frequently receive unnecessary procedures, while treatment has very good response rates and ascites resolve with serum CA-125 normalization after adequate hormonal treatment. PMID- 23646235 TI - Accurate Quantitation of Dystrophin Protein in Human Skeletal Muscle Using Mass Spectrometry. AB - Quantitation of human dystrophin protein in muscle biopsies is a clinically relevant endpoint for both diagnosis and response to dystrophin-replacement therapies for dystrophinopathies. A robust and accurate assay would enable the use of dystrophin as a surrogate biomarker, particularly in exploratory Phase 2 trials. Currently available methods to quantitate dystrophin rely on immunoblot or immunohistochemistry methods that are not considered robust. Here we present a mass spectrometry based approach to accurately quantitate dystrophin protein in a total protein extract from human muscle biopsies. Our approach uses a combination of stable isotope labeled dystrophin as a spike-in standard, gel electrophoresis and high precision mass spectrometry to detect and quantitate multiple peptides of dystrophin within a complex protein mixture. The method was found highly reproducible and linear over a wide dynamic range, detecting as low as 5% of dystrophin relative to the normal amount in healthy individuals. PMID- 23646236 TI - Magnetic Gold Nanoshells: Step-wise Changing of Magnetism through Step-wise Biofunctionalization. AB - We report step-wise changing of magnetic behavior of iron oxide core gold shell nanoparticles from super paramagnetic to permanent magnetism at room temperature, on step-wise bio-functionalization with leutenizing hormone and releasing hormone (LHRH) through cysteamine linker. The observed permanent magnetism at room temperature in LHRH-capped gold nanoshells provides opportunities to extend fundamental investigations of permanent magnetism to other novel nanostructures and biofunctionalized nano gold architectures, simultaneously opening the way to newer applications, especially to those in biomedicine. PMID- 23646237 TI - Awake intubation with video-assisted laryngoscope or intubating stylet. PMID- 23646238 TI - Antihyperalgesic effects of dexmedetomidine on high-dose remifentanil-induced hyperalgesia. AB - BACKGROUND: Dexmedetomidine is a highly selective alpha2 adrenergic agonist that has been shown to decrease the intensity of opioid-induced hyperalgesia (OIH). We aimed to investigate the antihyperalgesic effects of dexmedetomidine on high-dose remifentanil-induced hyperalgesia. METHODS: Ninety American Society of Anesthesiologists physical status I-II patients undergoing laparoscopically assisted vaginal hysterectomy (LAVH) were randomly assigned to one of the following three groups, each of which received either dexmedetomidine (an initial dose of 1.0 ug/kg for 10 min, followed by a continuous infusion of 0.7 ug/kg/hr) or placebo saline 15 min before the induction of anesthesia and intraoperative remifentanil infusion: group C received a placebo and 0.05 ug/kg/min remifentanil; group RH received a placebo and 0.3 ug/kg/min remifentanil; and group DRH received dexmedetomidine and 0.3 ug/kg/min remifentanil. RESULTS: The mechanical hyperalgesia threshold 24 hr after surgery was significantly lower in group RH than in the other two groups. Postoperative pain intensity using visual analog scale (VAS) and cumulative volume of a patient-controlled analgesia (PCA) containing morphine over 24 hr were significantly greater in group RH than in group DRH. The time to the first postoperative analgesic requirement was significantly shorter in group RH than in the other two groups. The desflurane requirement was significantly greater in group C than in the other groups. The frequency of hypotension and bradycardia was significantly higher, but shivering and postoperative nausea and vomiting were significantly lower in group DRH than in the other two groups. CONCLUSIONS: High-doses of remifentanil induced hyperalgesia, which presented a decreased mechanical hyperalgesia threshold, enhanced pain intensity, a shorter time to first postoperative analgesic requirement, and greater morphine consumption, but dexmedetomidine efficiently alleviated those symptoms. Dexmedetomidine may be a novel and effective treatment option for preventing or attenuating OIH. PMID- 23646239 TI - The causes of difficult tracheal intubation and preoperative assessments in different age groups. AB - BACKGROUND: We studied the differences in airway assessment factors among old, middle, and young age groups, and evaluated the frequency and causes of difficult intubation among these groups. METHODS: Patients were divided into young (< 40 yr, n = 75 ), middle (40-59 yr, n = 83), and old (>= 60 yr, n = 89) group. Airway assessment factors such as head and neck movement, thyromental distance, interincisor gap, dentition, Mallampati score, and Arne score were assessed. After muscle relaxation, cervical joint rigidity and Cormack-Lehane (C-L) grade were assessed. The differences in airway assessment factors between difficult (C L grade 3, 4) and easy (C-L grade 1, 2) intubation were then examined. Logistic regression analysis was also carried out to identify the extent to which airway assessment factors reflected difficult intubation. RESULTS: As aging, head and neck movement, thyromental distance, and interincisor gap decreased, the grade of dentition, Mallampati score, cervical joint rigidity and the ratio of Arne score > 11 increased. In the old and middle group, the incidence of difficult intubation was increased compared with the young group. Dentition in the young group, Mallampati score and interinsisor gap in the middle group and Mallampati score, cervical joint rigidity in the old group respectively predicted difficult intubation. CONCLUSIONS: Compared to young individuals, middle-aged or elderly adults are likely to experience more difficulty in endotracheal intubation and its predictive factors could vary by age group. PMID- 23646240 TI - The Pentax airway scope versus the Macintosh laryngoscope: Comparison of hemodynamic responses and concentrations of plasma norepinephrine to tracheal intubation. AB - BACKGROUND: The Pentax Airway Scope (AWS) is a video laryngoscope designed to facilitate tracheal intubation with a high-resolution image. The Pentax AWS has been reported to cause less hemodynamic stress than the Macintosh laryngoscope. The aims of this study are to investigate the differences in hemodynamic responses and norepinephrine concentrations to tracheal intubation between procedures using he Pentax AWS and the Macintosh laryngoscope. METHODS: Forty patients (American Society of Anesthesiologists class I-II, age range: 18-60 years) were randomly assigned to be intubated with either the Pentax AWS or the Macintosh laryngoscope while under general anesthesia. Routine monitoring, including invasive arterial blood pressure and bispectral index, were applied. Thiopental (4 mg/kg), fentanyl (1 ug/kg), midazolam (0.05 mg/kg), and rocuronium (0.6 mg/kg) were administered for anesthetic induction. Systolic, diastolic, and mean blood pressures and heart rates were recorded pre-intubation, immediately post-intubation (T0), and over the following 10 minutes at one minute intervals (T1, T2, T3, T4, T5...T10). Patient blood was sampled for norepinephrine concentrations pre-intubation (baseline) and post-intubation (T1). Evidence of sore throat was evaluated 30 min and 24 hr after extubation. Data were transformed to % basal and expressed as mean +/- SD. RESULTS: The systolic, diastolic, and mean blood pressure, and heart rate at T0 and T4 were significantly different between the two groups. There was no significant difference in plasma norepinephrine between the two groups. The difference in incidence of sore throat was not significant between the two groups. CONCLUSIONS: Pentax-AWS for tracheal intubation has greater hemodynamic stability than the Macintosh blade laryngoscope. PMID- 23646241 TI - Popliteal sciatic nerve block versus spinal anesthesia in hallux valgus surgery. AB - BACKGROUND: We compared clinical properties and patient satisfaction between spinal anesthesia and popliteal sciatic nerve block (PSNB) for hallux valgus surgery. METHODS: Forty patients undergoing hallux valgus surgery were divided into spinal group (spinal anesthesia with 2.5 ml of 0.5% bupivacaine [n = 20]) and PSNB group (PSNB with 30 ml of 0.75% ropivacaine mixed with 10 ml of normal saline solution using a nerve stimulator [n = 20]). The PSNB group used a patient controlled-analgesia (PCA) pump for postoperative pain control. The quality and side effects were compared between the two groups. A questionnaire was used to evaluate patient satisfaction with the use of anesthetic techniques and postoperative pain control in the PSNB group. This study was assessed 3 days postoperatively by a blinded observer. RESULTS: Procedure time and time from anesthesia until start of sugery were significantly shorter in the spinal group than those in the PSNB group (P < 0.01). Anesthesia-related complications such as hypotension, bradycardia, shivering, nausea/vomitting, post-dural puncture headache (PDPH) and urinary retension were observed in 15%, 10%, 5%, 5%, 10%, and 20% of patients in the spinal group, respectively. PSNB was not associated with these complications. Patient satisfaction was slightly higher for PSNB than for spinal anesthesia. In the PSNB group, patient satisfaction with postoperative pain-control was 95% above ordinary satisfaction. CONCLUSIONS: Despite the long duration of the procedure, PSNB is relatively safe, provides an adequate level of anesthesia, effectively controls postoperative pain and reduces side effects. Therefore, PSNB could be a potential anesthetic technique for hallux valgus surgery. PMID- 23646242 TI - Ultrasound does not shorten the duration of procedure but provides a faster sensory and motor block onset in comparison to nerve stimulator in infraclavicular brachial plexus block. AB - BACKGROUND: Infraclaviculr Brachial plexus (ICBP) block is useful for upper extremity surgery. The aim of this study was to compare the ultrasound (US) technique with the nerve stimulation (NS) technique in their success rates and times to perform ICBP block. METHODS: 60 patients undergoing surgery of the upper limb were randomly allocated into two groups (n = 30 per group). Group 1; US, and Group 2; NS. Procedure time (including time for initial ultrasound examination), the success rate and the onset time of sensory and motor blockade were assessed. RESULTS: The time needed to perform the ICBP block is similar in both groups (220 seconds +/- 130 in US group versus 281 +/- 134 seconds in NS group; P = 0.74). The success rate of all the nerve blocks in the US group was 100%. The success rate in the NS group was 73.3%, 76.7%, 76.7% and 100% for radial, ulnar, medial, and musculocutaneous nerve, respectively. A significantly faster onset of sensory block for the radial, ulnar, median, musculocutaneous, and the four nerves considered together were observed. The onset of motor block for the radial, ulnar, and medial nerves was faster in the US group. However, the onset of motor block for the musculocutaneous nerve and the four nerves considered together was comparable between the two groups. CONCLUSIONS: The ultrasound-guided infraclavicular brachial plexus block is a significantly efficacious method with faster onset but similar procedure time compared to the nerve stimulation technique. PMID- 23646243 TI - Effect of ulinastatin on perioperative organ function and systemic inflammatory reaction during cardiac surgery: a randomized double-blinded study. AB - BACKGROUND: This study evaluated the efficacy of ulinastatin for attenuating organ injury and the release of proinflammatory cytokines due to cardiopulmonary bypass (CPB) during cardiac surgery. METHODS: Patients undergoing valvular heart surgery employing CPB were assigned to receive either ulinastatin (group U, n = 13) or a placebo (group C, n = 11) before the commencement of CPB. Hemodynamic data, parameters of major organ injury and function, and proinflammatory cytokines were measured after the induction of anesthesia (T1), after CPB (T2), at the end of anesthesia (T3), and at 24 hours after surgery (POD). RESULTS: The demographic data, CPB duration, and perioperative transfusions were not different between the groups. PaO2/FiO2 in group U was significantly higher than that in group C at T3 (3.8 +/- 0.8 vs. 2.8 +/- 0.7, P = 0.005) and at POD (4.0 +/- 0.7 vs. 2.8 +/- 0.7, P < 0.001). Creatine kinase-MB at POD in group U was significantly lower than that in group C (17.7 +/- 8.3 vs. 33.7 +/- 22.1, P = 0.03), whereas troponin I at POD was not different between the groups. Creatinine clearance and the extubation time were not different between the groups at POD. The dopamine infusion rate during the post-CPB period in group U was significantly lower than that in group C (1.6 +/- 1.6 vs. 5.5 +/- 3.3 ug/kg/min, P = 0.003). The interleukin-6 and tumor necrosis factor-alpha concentrations at T1, T2, and T3 as well as the incidences of postoperative cardiac, pulmonary and kidney injuries were not different between the groups. CONCLUSIONS: Ulinastatin pretreatment resulted in an improved oxygenation profile and reduced inotropic support, probably by attenuating the degree of cardiopulmonary injury; however, it did not reduce the levels of proinflammatory cytokines. PMID- 23646244 TI - Duration of remission phase of 36 Korean patients with glossopharyngeal neuralgia. AB - BACKGROUND: Glossopharyngeal neuralgia has the characteristic of a long remission phase between the pain attack phases. Although the concept of remission is very important for the treatment of patients with glossopharyngeal neuralgia, due to the rarity of the disease, clear statistical studies on the remission phase for glossopharyngeal neuralgia are almost non-existent. METHODS: Previous chart reviews and phone interviews were conducted on a total of 38 patients. Among these study subjects, two patients were excluded because of their known secondary glossopharyngeal neuralgia from their brain tumors. Hence, the average duration of remission was investigated on 36 patients with idiopathic glossopharyngeal neuralgia. RESULTS: For the 27 patients who experienced their first remission, the average duration of the remission was 3.1 years. Among them, the average duration of the second remission of the 17 patients was 2.5 years, and for 4 patients who experienced a third remission, the average duration of the remission phase was 1.9 years. CONCLUSIONS: The difference in the mean duration of the remission phase of the 1(st), 2(nd), and 3(rd) are not statistically significant, and the occurrence rate of the left or right side and of the gender, male or female, are also statistically insignificant. However, it is possible to infer that a patient might face a pain attack phase when his or her remission phase has lapsed for about three years. This prediction may be applied when developing treatment plans for patients with glossopharyngeal neuralgia. PMID- 23646245 TI - Do bupivacaine, clindamycin, and gentamicin at their clinical concentrations enhance rocuronium-induced neuromuscular block? AB - BACKGROUND: Bupivacaine, clindamycin, and gentamicin inhibit neuromuscular (NM) conduction. When they are combined, they may synergistically reduce the effective concentration of each to the therapeutic concentration in augmenting rocuronium induced NM block. Thus, the aim of this study was to investigate whether combinations of the three drugs, at around their therapeutic concentrations, potentiate rocuronium-induced NM block. METHODS: Fifty-seven left-phrenic nerve hemidiaphragms (Male S-D rats, 150-250 g) were hung in a 20-ml organ bath filled with Krebs solution. Three consecutive single-twitch tensions (0.1 Hz) and one tetanic tension (50 Hz for 1.9 s) were obtained. A Krebs solution was premixed with concentration sets of bupivacaine and clindamycin, bupivacaine and gentamicin, or bupivacaine, clindamycin and gentamicin. Then, the concentration of rocuronium was cumulatively increased in the Krebs solution (1, 3, 5, 7, 9, 12, 14, 16, 18, and 20 uM) until an 80% to 90% reduction in single twitch was attained. The effective concentrations for each experiment were determined with the probit model. RESULTS: The combinations of bupivacaine, clindamycin, and gentamicin enhanced rocuronium-induced NM block. When the three drugs were applied simultaneously, their concentrations were reduced to near-therapeutic levels in potentiating the action of rocuronium. CONCLUSIONS: Bupivacaine, clindamycin, and gentamicin blocked NM conduction, and when all three drugs were applied together, they augmented rocuronium-induced NM block at their near therapeutic concentrations. Clinicians should be aware of the cooperability in NM block between drugs that interrupt NM conduction. PMID- 23646246 TI - Lipid emulsion-mediated reversal of toxic-dose aminoamide local anesthetic induced vasodilation in isolated rat aorta. AB - BACKGROUND: Intravenous lipid emulsion has been used to treat systemic toxicity of local anesthetics. The goals of this in vitro study were to determine the ability of two lipid emulsions (Intralipid(r) and Lipofundin(r) MCT/LCT) to reverse toxic dose local anesthetic-induced vasodilation in isolated rat aortas. METHODS: Isolated endothelium-denuded aortas were suspended for isometric tension recording. Vasodilation was induced by bupivacaine (3 * 10(-4) M), ropivacaine (10(-3) M), lidocaine (3 * 10(-3) M), or mepivacaine (7 * 10(-3) M) after precontraction with 60 mM KCl. Intralipid(r) and Lipofundin(r) MCT/LCT were then added to generate concentration-response curves. We also assessed vasoconstriction induced by 60 mM KCl, 60 mM KCl with 3 * 10(-4) M bupivacaine, and 60 mM KCl with 3 * 10(-4) M bupivacaine plus 1.39% lipid emulsion (Intralipid(r) or Lipofundin(r) MCT/LCT). RESULTS: The two lipid emulsions reversed vasodilation induced by bupivacaine, ropivacaine, and lidocaine but had no effect on vasodilation induced by mepivacaine. Lipofundin(r) MCT/LCT was more effective than Intralipid(r) in reversing bupivacaine-induced vasodilation. The magnitude of lipid emulsion-mediated reversal of vasodilation induced by high dose local anesthetics was as follows (from highest to lowest): 3 * 10(-4) M bupivacaine-induced vasodilation, 10(-3) M ropivacaine-induced vasodilation, and 3 * 10(-3) M lidocaine-induced vasodilation. CONCLUSIONS: Lipofundin(r) MCT/LCT mediated reversal of bupivacaine-induced vasodilation was greater than that of Intralipid(r); however, the two lipid emulsions equally reversed vasodilation induced by ropivacaine and lidocaine. The magnitude of lipid emulsion-mediated reversal of vasodilation appears to be correlated with the lipid solubility of the local anesthetic. PMID- 23646247 TI - Unexpected and fatal hemodynamic collapse during transapical transcatheter aortic valve implantation -A case report-. AB - Although transcatheter aortic valve implantation (TAVI) is generally accepted as an alternative or promising treatment option for patients with decompensated cardiovascular disease in an inoperable or high-risk condition, severe hypotension and/or arrhythmia associated with rapid ventricular pacing still poses a challenge to many clinicians. This report describes a 79-year-old patient who experienced fatal hemodynamic collapse, which suddenly developed after a rapid ventricular pacing in spite of pre-administration of vasopressor. The procedure and anesthesia were uneventful until the first rapid ventricular pacing was applied. Following rapid ventricular pacing, his cardiovascular state was severely compromised and could not be recovered. Despite early initiation of extracorporeal membrane oxygenation device and supportive care, he died from heart failure on post-procedure day four. PMID- 23646248 TI - Complete atrioventricular nodal block after propofol administration in an elderly patient undergoing total knee replacement arthroplasty -A case report-. AB - Complete atrioventricular (AV) block is defined as a dissociation of atrial and ventricular activities. Complete AV block that occurs during the perioperative period is difficult to reverse and usually requires implantation of a pacemaker. Propofol does not affect a normal AV conduction system but may act as a trigger for AV block. It can also potentiate vagal stimulation factors and reduce sympathetic activity. We report a case of complete AV block that may have been related to administration of propofol. PMID- 23646249 TI - Pneumomediastinum after functional endoscopic sinus surgery under general anesthesia -A case report-. AB - The occurrences of pneumothorax and pneumomediastinum are rare, but considered to be potentially life-threatening conditions in patients undergoing functional endoscopic sinus surgery under general anesthesia. Tracheobronchial rupture may results in serious complications, such as pneumothorax and pneumomediastinum. It may occur accidentally by endotracheal tube when the patient's neck is flexed or extended. We report the case of a 48-year-old female patient who developed massive subcutaneous emphysema, pneumothorax, pneumomediastinum and pneumoperitoneum seven hours after functional endoscopic sinus surgery under general anesthesia. PMID- 23646250 TI - Anesthetic management of a pregnant woman undergoing laparoscopic surgery for pheochromocytoma -A case report-. AB - Pheochromocytoma is a rare catecholamine producing tumor. Anesthetic management for the resection of pheochromocytoma is hard and challenging issue to anesthesiologist, because of its potentially lethal cardiovascular complications. It becomes more complicated when the patient is pregnant. Clinicians must keep the safety of both mother and fetus in mind. The timing of surgery for pheochromocytoma in pregnancy is very important for the maternal and fetal safety and depends on the gestational age when diagnosis is made, clinical response to medical treatment, the surgical accessibility of the tumor, and the presence of fetal distress. We report anesthetic experience of a laparoscopic resection for pheochromocytoma in 25th week gestational woman. PMID- 23646251 TI - Pneumomediastinum after arthroscopic shoulder surgery -A case report-. AB - An 86-year-old female with a history of right rotator cuff injury was admitted for arthroscopic shoulder surgery under general anesthesia. There were no remarkable immediate postoperative complications. However, while recovering in the general ward, she developed dyspnea with hypoxia. She was immediately treated with oxygen, and antibiotics after pneumomediastinum was confirmed on both chest x-ray and chest computed tomography. Subcutaneous emphysema on either face or neck followed by arthroscopic shoulder surgery was common, but pneumomediastinum with hypoxia is a rare but extremely dangerous complication. Thus we would like to report our case and its pathology, the diagnosis, the treatment and prevention, with literature review. PMID- 23646252 TI - A misplaced and entrapped pulmonary artery catheter. PMID- 23646253 TI - Complete obstruction of an endotracheal tube due to an unexpected blood clot in a patient with a hemo-pneumothorax after repositioning of the patient for lumbar spine surgery. PMID- 23646254 TI - Conversion of orotracheal to nasotracheal intubation using a fiberoptic bronchoscope in a patient with intraoral hematoma. PMID- 23646255 TI - Clinical experience of one lung ventilation using an endobronchial blocker in a patient with permanent tracheostomy after total laryngectomy. PMID- 23646256 TI - Spinal subarachnoid hematoma after spinal anesthesia. PMID- 23646257 TI - Optiscope(r) may have less stimulation on hemodynamic changes. PMID- 23646259 TI - Violence, mental illness, and the brain - A brief history of psychosurgery: Part 1 - From trephination to lobotomy. AB - Psychosurgery was developed early in human prehistory (trephination) as a need perhaps to alter aberrant behavior and treat mental illness. The "American Crowbar Case" provided an impetus to study the brain and human behavior. The frontal lobe syndrome was avidly studied. Frontal lobotomy was developed in the 1930s for the treatment of mental illness and to solve the pressing problem of overcrowding in mental institutions in an era when no other forms of effective treatment were available. Lobotomy popularized by Dr. Walter Freeman reached a zenith in the 1940s, only to come into disrepute in the late 1950s. Other forms of therapy were needed and psychosurgery evolved into stereotactic functional neurosurgery. A history of these developments up to the 21st century will be related in this three-part essay-editorial, exclusively researched and written for the readers of Surgical Neurology International (SNI). PMID- 23646258 TI - Quality of life measures as a preliminary clinical indicator in patients with primary brain tumors. AB - BACKGROUND: The health-related quality of life (HRQOL) measures serve as valuable indicators of survival in patients with newly diagnosed primary brain tumors (PBTs). HRQOL outcomes may benefit clinical decision-making by individualizing patient treatment and improving communications between the doctor, patient, and families. Exploring the individual items of the European Organization and Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QOL) measures may be predictive of prognosis. METHODS: We prospectively collected the validated HRQOL and standard clinical and radiological measures from 48 patients with newly diagnosed PBT. The patients were followed every 3 months over 2 years. No proxies were allowed. Questionnaire responses were compared between two groups: Patients with recurrence and/or death (n = 26) and patients without a recurrence (n = 22). A total of 17 patients succumbed to a tumor-related death. Statistical analysis utilizing nonparametric t-tests and Wilcoxon sign tests assessed QOL responses. RESULTS: Significant group differences were noted in the QOL measures with more negative responses in the recurrence group. EORTC QLQ-C30 questions revealed a poor global HRQOL scale (P < 0.005) and pain interfering with daily activities (P < 0.05). EORTC QLQ-BN20 questions revealed weakness of the legs (P < 0.05), coordination difficulties (P < 0.005), and unsteady gait (P < 0.05). Hospital Anxiety and Depression Scale (HADS) questions reflected a patient who is slowed down (P < 0.01) and "frightened" (P < 0.05). CONCLUSION: Our analysis of longitudinal HRQOL measures may shed light on the prognostic significance of HRQOL measures in patients with newly diagnosed PBT. Further research is warranted to determine which selected individual measures of the EORTC QOL measures may be predictive of a patient's progression-free and overall survival and to test their validity and reliability in clinical trials. PMID- 23646260 TI - Multidisciplinary approach to psychiatric symptoms in mild traumatic brain injury: Complex sequelae necessitate a cadre of treatment providers. PMID- 23646261 TI - Reproducibility of quantitative fiber tracking measurements in diffusion tensor imaging of frontal lobe tracts: A protocol based on the fiber dissection technique. AB - BACKGROUND: Diffusion tensor imaging (DTI)-based tractography is a noninvasive in vivo method for tracing white matter bundles. This raises possibilities for qualitative and quantitative assessment of the structural organization of tracts. Nevertheless, questions remain about neuroanatomical accuracy, reproducibility for clinical purposes, and accessibility of the best method for broader application. The aim of this study was to combine the fiber dissection technique and tractography to provide more pertinent insight into brain anatomy and, as a result, to test a protocol for reconstruction of six major frontal lobe tracts. METHODS: A combination of fiber dissection of formalin-fixed brain tissue after freezing (Klingler's technique) and virtual dissection (tractography) was used to develop a protocol to reconstruct major frontal tracts. Apparent diffusion coefficient (ADC), fractional anisotropy (FA), number of voxels (NVO), volume (VOL), number (NTR), and length (LEN) of tracts were evaluated to assess intra- and interobserver reproducibility. Statistical reliability was evaluated using intraclass correlation coefficients (ICCs) and the Pearson association coefficient (r). RESULTS: The virtual dissection obtained by tractography seemed to reproduce the anatomic knowledge of the white matter tracts obtained through the classic method. In reliability study, most ICC and r values corresponded at least to large correlation. The magnitude of correlation was very high (ICC 0.7 0.9) or almost perfect (ICC 0.9-1.0) for the FA and ADC measures of every tract studied. CONCLUSION: The DTI protocol proposed herein provided a reliable method for analysis of reconstructed frontal lobe tracts, especially for the FA and ADC variables. PMID- 23646263 TI - What are the three major changes/challenges in your life? PMID- 23646262 TI - Simultaneous Muir-Torre and Turcot's syndrome: A case report and review of the literature. AB - BACKGROUND: Muir-Torre syndrome (MTS) is an autosomal dominant syndrome characterized by neoplasms of the sebaceous gland or keratoacanthomas, in addition to visceral malignancies. Cerebral neoplasms in patients with hereditary nonpolyposis colorectal cancer (HNPCC) or familial adenomatous polyposis suffer from Turcot's syndrome. Genetic mutations in MutS homolog (MSH)-2, MutL homolog (MLH)-1, and MutS homolog (MSH)-6 DNA mismatch repair genes are the most common in MTS with MSH-2 being the most predominant. In HNPCC MLH-1 and MSH-2 mutations are approximately equal in prevalence. CASE DESCRIPTION: We present the case of a 58-year-old male with a prior history of being treated for colonic adenocarcinoma and skin lesions leading to a diagnosis of MTS. The patient later developed a World Health Organization (WHO) grade 4 glioma requiring surgical resection. Pathology revealed mutations in MSH-2 and MSH-6 mismatch repair genes. CONCLUSIONS: This case represents the first report of Turcot's and MTS with extensive molecular testing on the cerebral neoplasm demonstrating a molecular relationship between Turcot's and MTS and only the second published report of simultaneous Turcot's and MTS. PMID- 23646264 TI - Intracranial granuloma mimicking a brain tumor in a patient with scleroderma. AB - BACKGROUND: Intracranial granulomatous masses presenting as space occupying lesions, although rare, have been described in the literature. Causes include infections, systemic granulomatous disorders, and iatrogenic from previous surgery. We present a case demonstrating that spontaneous intracranial granuloma can exist, often mimicking a brain tumor. CASE DESCRIPTION: A 62-year-old female presented with a short history of left sided partial seizures and a left hemiparesis. Magnetic resonance imaging revealed a right sided parafalcine lesion. Histopathology demonstrated chronic inflammation of granulomatous type. She responded to steroid treatment. CONCLUSION: She responded to steroid treatment. Our case demonstrated that spontaneous intracranial granuloma exists. Although rare, it should be considered in patients presenting with space occupying lesions. They can successfully be managed with steroid treatment. PMID- 23646265 TI - Hemangiopericytoma of neck extending to craniovertebral junction treated by surgery, pre- and postoperative radiotherapy. AB - BACKGROUND: Hemangiopericytoma (HPC) is a rare tumor of uncertain malignant potential arising from mesenchymal cells with pericytic differentiation. It accounts for 3-5% of soft tissue sarcomas, and 1% of vascular tumors. The treatment of choice is a primary wide surgical resection with adjuvant radiotherapy (RT) reserved for cases of incomplete removal. CASE DESCRIPTION: We report a case of a 24-year-old female with a rapidly growing, highly vascular swelling in nape of the neck extending deep into the craniovertebral (CV) junction accompanied by extradural/intraspinal, and intracranial involvement. An incisional biopsy revealed a cellular, highly vascular tumor with HPC-like features. The patient received preoperative RT, which reduced both the size and vascularity of the lesion, facilitating subsequent near complete resection. Further postoperative RT resulted in a good clinical outcome, with no tumor recurrence observed at 2 postoperative years. CONCLUSION: HPC of the soft tissues of neck accompanied by deep extension to the CV junction is uncommon. A high index of suspicion is required to diagnose these cases. which may be treated with preoperative RT (to reduce the lesion size/vascularity), aggressive surgical resection, followed by postoperative adjunctive radiation treatment as well. PMID- 23646266 TI - Endoscopic third ventriculostomy for shunt malfunction. PMID- 23646267 TI - Anaplastic lymphoma kinase-positive large cell lymphoma of the anterior skull base: Report of an unusual case and review of the literature. AB - BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a rare peripheral T-cell lymphoma, accounting for approximately 3% of adult non-Hodgkin lymphomas (NHL). In this report we describe an unusual case of an ALK(+) ALCL, which presented as an aggressive mass involving upper nasal cavity and anterior skull base. The pathogenesis, histopathology with radiologic correlations, and management of this case are reviewed. CASE DESCRIPTION: A 28-year-old Asian female presented with a 3-month history of nasal congestion culminating in epistaxis. Physical examination was notable for a tissue mass obstructing nasal cavity and the sphenoid sinus. Computed tomography (CT) and magnetic resonance (MR) imaging revealed a lesion primarily involving the upper nasal cavity extending intracranially through the cribriform plates into the anterior cranial fossa. Histologic and immunohistochemical analysis of the specimen obtained through a transnasal biopsy revealed an ALK(+) ALCL. The patient underwent two cycles of chemotherapy and focal radiation therapy, achieving minimal residual disease. The patient remained neurologically unchanged with stable minimal residual disease at the 1-year follow-up. CONCLUSIONS: To the best of our knowledge, this is the first case of an ALK(+) ALCL that presented as an aggressive upper nasal cavity and anterior skull base lesion. This case report highlights the importance of multi-modality approaches including preoperative imaging and tissue biopsy for definitive diagnosis. PMID- 23646268 TI - Chronic subdural hematoma: A survey of neurosurgeons' practices in Nigeria. AB - BACKGROUND: Chronic subdural hematoma (CSDH) is a commonly encountered condition in neurosurgical practice. In Nigeria, a developing country, patients with CSDH are less likely to be diagnosed and treated by surgical drainage early. Aware of the reported variations in neurosurgeons' practices regarding CSDH in many parts of the world, we sought to determine the current practices of Nigerian neurosurgeons in managing CSDH. METHODS: An Internet-based survey was carried out in which all Nigerian neurosurgeons listed in the Nigerian Academy of Neurological Surgeons directory during the July-December 2012 time period were asked to participate. Questions asked in the survey were: (1) Type of treatment used in patients with CSDH, (2) Use of drains postoperatively, (3) Postoperative patient positioning, (4) Postoperative mobilization, (5) Postoperative complications, and (6) Postoperative computed tomography (CT) scan monitoring. RESULTS: Survey information was sent to the 25 practicing neurosurgeons in Nigeria who met the criteria listed above for being included in this study. Each of the 14 neurosurgeons who responded reported that CSDH is often misdiagnosed initially, usually as a stroke having occurred. Once a diagnosis of CSDH was made, the most common method of treatment reported was placement of one or two burr-holes for drainage of the hematoma. Reported, but used in only a few cases, were twist drill craniostomy, craniectomy, and craniotomy. Each neurosurgeon who responded reported irrigation of the subdural space with sterile saline, and in some cases an antibiotic had been added to the irrigation solution. Six of the 14 neurosurgeons left drains in the subdural space for 24-72 hours. Seven neurosurgeons reported positioning patients with their heads elevated 30 degrees during the immediate postoperative period. No neurosurgeon responding reported use of steroids, and only one acknowledged routine use of anticonvulsive medication for patients with CSDH. Only 3 of the 14 neurosurgeons taking part in the study said they routinely order CT scans postoperatively. CONCLUSION: There are several differences in the ways Nigerian neurosurgeons manage CSDH. Future studies may help to streamline the approaches to managing CSDH. PMID- 23646269 TI - Orbital metastasis of pituitary growth hormone secreting carcinoma causing lateral gaze palsy. AB - BACKGROUND: Although pituitary adenoma is one of the most common intracranial tumors, it rarely progresses secondarily into a metastatic carcinoma. Commonalities in reported cases include subtotal resection at presentation, treatment with radiation therapy, and delayed metastatic progression. Pathologic descriptions of these lesions are varying and inconsistent. CASE DESCRIPTION: A 52-year-old male was diagnosed with acromegaly and pituitary tumor in 1996. He underwent four subtotal resections and five courses of stereotactic radiosurgery over 14 years. He developed left eye lateral gaze palsy, and was found to have a distant orbital metastasis with involvement of the left lateral rectus and lateral orbital wall. He underwent left orbital craniotomy via eyebrow incision for resection of this lesion. Pathologic evaluation showed a markedly elevated Ki67 level of 30%. CONCLUSION: While overall incidence of metastatic progression of pituitary adenoma after radiotherapy appears to be low, it appears to be a possible complication, and could be more likely in patients receiving multiple doses of radiotherapy. Our review of reported cases showed that 45/46 (97.8%) of patients developing carcinoma had prior radiation exposure. These patients may also have more aggressive pathologic characteristics of their lesions. PMID- 23646271 TI - Commentary on research of bone morphogenetic protein discussed in review article: Genetic advances in the regeneration of the intervertebral disc. AB - BACKGROUND: In Maerz, Herkowitz and Baker's review, Molecular and Genetic Advances in the Regeneration of the Intervertebral Disc, they also included an assessment of both in vivo and in vitro complications attributed to Bone Morphogenetic Protein ((BMP): BMP-2, BMP-7). This topic is of particular interest to spinal surgeons, as INFUSE/BMP (Medtronic, Memphis, TN, USA) is utilized, mostly off-label in the cervical, thoracic, and lumbar spine, where it has been associated with significant perioperative and postoperative complications. METHODS: BMP-2 and BMP-7 are the only human recombinant growth factors approved by the Food and Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) in combination with the Lumbar Tapered Fusion Device (LT Cage: Medtronic, Memphis, TN, USA). BMP, however, is more typically utilized "off-label" in many other areas of the spine, where it has been associated with numerous complications. RESULTS: Maerz, et al. documented multiple in vivo and in vitro laboratory-based animal studies dating back to the early 2000's in which BMP (INFUSE is the clinically available product: Medtronic, Memphis, TN) contributed to multiple complications, especially when utilized at higher doses. These complications included; inflammation/inflammatory processes, increased vascularity, fibroblastic proliferation, and catabolism. CONCLUSION: Maerz, et al. reviewed the increased risks associated with utilizing high dose BMP=INFUSE in spinal surgery, particularly when utilized "off-label". The authors clearly indicate that BMP/INFUSE should be further investigated (based on the old and new findings) to better determine/confirm its safety, efficacy, and dosing. PMID- 23646270 TI - Unusual causes of papilledema: Two illustrative cases. AB - BACKGROUND: Neurosurgeons are frequently among the first physicians asked to evaluate patients with papilledema, and the patient is often referred with the implication that they may require shunting. After an initial evaluation to exclude potential neurosurgical emergencies, the physician should carefully consider various etiologies of papilledema to prevent unnecessary neurosurgical operations. CASE DESCRIPTION: THE AUTHORS REPORT TWO ILLUSTRATIVE CASES OF UNUSUAL CAUSES OF PAPILLEDEMA: Anemia and leukemic infiltration of the central nervous system. In each case, a complete blood count provided clues for the diagnosis. A review of the literature is also included. CONCLUSIONS: Both patients responded to medical management/treatment of the underlying disease and did not require neurosurgical operative intervention. Papilledema may be caused by other etiologies besides increased intracranial pressure. The authors present two unusual cases leading to papilledema and provide an outline for the workup of these conditions. PMID- 23646272 TI - Surgical treatment of adult and pediatric C1/C2 subluxation with intraoperative computed tomography guidance. AB - BACKGROUND: Surgical treatment of C1/C2 subluxation has evolved significantly over the past 2 decades, from the relatively simpler posterior wiring to more technically demanding instrumentations such as C1 lateral mass screws - C2 pedicle screws, C1/C2 transarticular screws, and occipital cervical fusion. Navigation with fluoroscopy is currently the standard of practice in most centers. However, fluoroscopy at this level carries several major drawbacks, such as blockage by the mandible and inability to produce axial images for assessment of the reduction of rotatory subluxation. METHODS: The authors report a series of 21 patients with C1/C2 subluxation treated surgically with intraoperative computed tomography (ICT) guidance. RESULTS: There were 7 children and 14 adults. Eight patients underwent C1/C2 fixation with a Harm's construct, and 13 patients underwent occipital cervical fusion. One out of 17 (6%) C1 lateral mass screws has breached the medial wall of lateral mass by 1 mm. Two out of 20 (10%) C2 pedicle screws have breached the foramen transversarium by 1 mm (Neo classification grade 1). The position of all subaxial screws (49 lateral mass screws and 13 pedicle screws) and occipital screws (50 screws) appeared satisfactory. No neurovascular damage occurred in all the patients. CONCLUSIONS: Ninety eight percent of the screws were placed in ideal position with the aid of ICT. Only 2% of the screws deviated from the planned position, but the breaches were not clinically significant and hence no revision was required. This showed that ICT guidance can help to achieve a high accuracy of surgical instrumentation for the treatment of C1/C2 subluxation. PMID- 23646273 TI - Cerebrospinal fluid leak secondary to chiropractic manipulation. AB - BACKGROUND: There is a paucity of quality data on the incidence of adverse outcomes of chiropractic manipulation. Spontaneous intracranial hypotension (SIH) subsequent to cervical spinal manipulation has been documented. However, no imaging correlates have previously been presented demonstrating a clear causal relationship to manipulation with follow-up and correlating with clinical symptomatology. CASE DESCRIPTION: We present a case of subacute cervical cerebrospinal fluid (CSF) leak resulting from chiropractic manipulation of the cervical spine. The patient is a 29-year-old female who received manipulation one week prior to developing symptoms of severe orthostatic headache, nausea, and vomiting. Magnetic resonance imaging (MRI) revealed a new C5-C6 ventral CSF collection. Symptomatic onset corresponded with the recent cervical chiropractic adjustment. We present serial imaging correlating with her symptomatology and review the pertinent literature on complications of chiropractic manipulation. CONCLUSION: Our case of ventral CSF leak with symptoms of intracranial hypotension demonstrated spontaneous symptomatic resolution without permanent neurological sequelae. PMID- 23646275 TI - Posterior fusion for an unstable axial fracture dislocation. AB - BACKGROUND: Management of avulsion fractures in the upper cervical spine remains the subject of debate. Currently, most experts favor nonoperative management of an isolated injury. However, these injuries can be complicated by soft-tissue trauma, which may require a different clinical approach to management. Accurate diagnosis of soft-tissue injuries depends on the choice of imaging modality and consideration of unique patient-specific factors. CASE DESCRIPTION: A morbidly obese 34-year-old woman was involved in a low-velocity motor vehicle collision that caused a forceful extension of the cervical spine. Initial computed tomographic imaging demonstrated a displaced avulsion fracture of the C2 body and widening of the C2-C3 facet. However, subsequent imaging using magnetic resonance demonstrated more extensive injuries. Because bracing was not feasible due to cervical instability, the injury was treated with posterior C2-4 fusion and bone grafting. CONCLUSIONS: Even in low-velocity collisions and limited injury on imaging, patient-specific factors should be considered in management decisions. Magnetic resonance imaging showed significant ligamentous compromise and marked cervical instability, revealing potential damage to vulnerable neural structures. Magnetic resonance imaging should be considered in the initial approach to any patient with these injuries. PMID- 23646274 TI - Randomized trial demonstrates that extended-release epidural morphine may provide safe pain control for lumbar surgery patients. AB - BACKGROUND: Safe and effective postoperative pain control remains an issue in complex spine surgery. Spinal narcotics have been used for decades but have not become commonplace because of safety or re-dosing concerns. An extended release epidural morphine (EREM) preparation has been used successfully in obstetric, abdominal, thoracic, and extremity surgery done with epidural anesthesia. This has not been studied in open spinal surgery. METHODS: Ninety-eight patients having complex posterior lumbar surgery were enrolled in a partially randomized clinical trial (PRCT) of low to moderate doses of EREM. Surgery included levels from L3 to S1 with procedures involving combinations of decompression, instrumented arthrodesis, and interbody grafting. The patients were randomized to receive either 10 or 15 mg of EREM through an epidural catheter placed under direct vision at the conclusion of surgery. Multiple safety measures were employed to prevent or detect respiratory depression. Postoperative pain scores, narcotic utilization, and adverse events were recorded. RESULTS: There were no significant differences between the two groups as to supplemental narcotic requirements, pain scores, or adverse events. There were no cases of respiratory depression. The epidural narcotic effect persisted from 3 to 36 hours after the injection. CONCLUSION: By utilizing appropriate safety measures, EREM can be used safely for postoperative pain control in lumbar surgery patients. As there was no apparent advantage to the use of 15 mg, the lower 10 mg dose should be used. PMID- 23646276 TI - Klippel-Feil syndrome associated with a craniocervico-thoracic dermoid cyst. AB - BACKGROUND: Uncommonly, Klippel-Feil syndrome (KFS) has been associated with intracranial or spinal tumors, most frequently dermoid or epidermoid cysts. Although the associated dermoid cyst (DC) is usually located in the posterior fossa, isolated upper cervical DC has been reported. Extension from the posterior fossa to the upper cervical spine (C2) has been reported once. We report a rare case of KFS in association with a posterior fossa DC that extended down to the upper thoracic spine and review the current literature. CASE DESCRIPTION: A 47 year-old female with presented cervical myelopathy related to a cranio-cervico thoracic DC in association with KPS-related cervicothoracic fusion (C2-T6) and thoracic kyphosis. The patient underwent complete tumor resection following sub occipital craniectomy and C1-C4 cervical laminectomy. The patient exhibited complete resolution of symptoms with no tumor recurrence and no deformity at 6 year follow-up. CONCLUSION: DC should be added to the list of congenital central nervous system abnormalities, which should be sought in patients with KFS. Therefore, the presence of a cystic lesion in the posterior fossa, the craniocervical junction or the anterior cervical spine should suggest the possibility of a DC in patients with KFS. In cases of cranio-cervical DC, the tumor may extend quite far down the spinal column (reaching the thoracic spine), as demonstrated in the present case. PMID- 23646277 TI - Transforaminal lumbar interbody fusion and posterior lumbar interbody fusion utilizing BMP-2 in treatment of degenerative spondylolisthesis: neither safe nor cost effective. AB - BACKGROUND: With the rise of health care costs, there is increased emphasis on evaluating the cost of a particular surgical procedure for quality adjusted life year (QALY) gained. Recent data have shown that surgical intervention for the treatment of degenerative spondylolisthesis (DS) is as cost-effective as total joint arthroplasty. Despite these excellent outcomes, some argue that the addition of interbody fusion supplemented with bone morphogenetic protein (BMP) enhances the value of this procedure. METHODS: This review examines the current research regarding the cost-effectiveness of the surgical management of lumbar DS utilizing interbody fusion along with BMP. RESULTS: Posterolateral spinal fusion with instrumentation for focal lumbar spinal stenosis with DS can provide and maintain improvement in self-reported quality of life. Based on the available literature, including nonrandomized comparative studies and case series, the addition of interbody fusion along with BMP does not lead to significantly better clinical outcomes and increases costs when compared with more routine posterolateral fusion techniques. CONCLUSIONS: To enhance the value of the surgical management for DS, costs must decrease or there should be substantial improvement in effectiveness as measured by clinical outcomes. To date, there is insufficient evidence to support the use of interbody fusion devices along with BMP to treat routine cases of focal stenosis accompanied by DS, which are routinely adequately treated utilizing posterolateral fusion techniques. PMID- 23646278 TI - The risks of epidural and transforaminal steroid injections in the Spine: Commentary and a comprehensive review of the literature. AB - BACKGROUND: Multiple type of spinal injections, whether epidural/translaminar or transforaminal, facet injections, are offered to patients with/without surgical spinal lesions by pain management specialists (radiologists, physiatrists, and anesthesiologists). Although not approved by the Food and Drug Administration (FDA), injections are being performed with an increased frequency (160%), are typically short-acting and ineffective over the longer-term, while exposing patients to major risks/complications. METHODS: For many patients with spinal pain alone and no surgical lesions, the "success" of epidural injections may simply reflect the self-limited course of the disease. Alternatively, although those with surgical pathology may experience transient or no pain relief, undergoing these injections (typically administered in a series of three) unnecessarily exposes them to the inherent risks, while also delaying surgery and potentially exposing them to more severe/permanent neurological deficits. RESULTS: Multiple recent reports cite contaminated epidural steroid injections resulting in meningitis, stroke, paralysis, and death. The Center for Disease Control (CDC) specifically identified 25 deaths (many due to Aspergillosis), 337 patients sickened, and 14,000 exposed to contaminated steroids. Nevertheless, many other patients develop other complications that go unreported/underreported: Other life-threatening infections, spinal fluid leaks (0.4-6%), positional headaches (28%), adhesive arachnoiditis (6-16%), hydrocephalus, air embolism, urinary retention, allergic reactions, intravascular injections (7.9-11.6%), stroke, blindness, neurological deficits/paralysis, hematomas, seizures, and death. CONCLUSIONS: Although the benefits for epidural steroid injections may include transient pain relief for those with/without surgical disease, the multitude of risks attributed to these injections outweighs the benefits. PMID- 23646280 TI - In this issue of Small GTPases. PMID- 23646279 TI - Molecular and genetic advances in the regeneration of the intervertebral disc. AB - BACKGROUND: Owing to the debilitating nature of degenerative disc disease (DDD) and other spine pathologies, significant research has been performed with the goal of healing or regenerating the intervertebral disc (IVD). Structural complexity, coupled with low vascularity and cellularity, make IVD regeneration an extremely challenging task. METHODS: Tissue engineering-based strategies utilize three components to enhance tissue regeneration; scaffold materials to guide cell growth, biomolecules to enhance cell migration and differentiation, and cells (autologous, or allogeneic) to initiate the process of tissue formation. Significant advances in IVD regeneration have been made utilizing these tissue engineering strategies. RESULTS: The current literature demonstrates that members of the transforming growth factor beta (TGF-beta) superfamily are efficacious in the regeneration of an anabolic response in the IVD and to facilitate chondrogenic differentiation. Gene therapy, though thwarted by safety concerns and the risk of ectopic transfection, has significant potential for a targeted and sustained regenerative response. Stem cells in combination with injectable, biocompatible, and biodegradable scaffolds in the form of hydrogels can differentiate into de novo IVD tissue and facilitate regeneration of the existing matrix. Therapies that address both anabolism and the inherent catabolic state of the IVD using either direct inhibitors or broad-spectrum inhibitors show extensive promise. CONCLUSION: This review article summarizes the genetic and molecular advances that promise to play an integral role in the development of new strategies to combat DDD and promote healing of injured discs. PMID- 23646281 TI - MCH and apomorphine in combination enhance action potential firing of nucleus accumbens shell neurons in vitro. AB - The MCH and dopamine receptor systems have been shown to modulate a number of behaviors related to reward processing, addiction, and neuropsychiatric conditions such as schizophrenia and depression. In addition, MCH and dopamine receptors can interact in a positive manner, for example in the expression of cocaine self-administration. A recent report (Chung et al., 2011a) showed that the DA1/DA2 dopamine receptor activator apomorphine suppresses pre-pulse inhibition, a preclinical model for some aspects of schizophrenia. Importantly, MCH can enhance the effects of lower doses of apomorphine, suggesting that co modulation of dopamine and MCH receptors might alleviate some symptoms of schizophrenia with a lower dose of dopamine receptor modulator and thus fewer potential side effects. Here, we investigated whether MCH and apomorphine could enhance action potential firing in vitro in the nucleus accumbens shell (NAshell), a region which has previously been shown to mediate some behavioral effects of MCH. Using whole-cell patch-clamp electrophysiology, we found that MCH, which has no effect on firing on its own, was able to increase NAshell firing when combined with a subthreshold dose of apomorphine. Further, this MCH/apomorphine increase in firing was prevented by an antagonist of either a DA1 or a DA2 receptor, suggesting that apomorphine acts through both receptor types to enhance NAshell firing. The MCH/apomorphine-mediated firing increase was also prevented by an MCH receptor antagonist or a PKA inhibitor. Taken together, our results suggest that MCH can interact with lower doses of apomorphine to enhance NAshell firing, and thus that MCH and apomorphine might interact in vivo within the NAshell to suppress pre-pulse inhibition. PMID- 23646282 TI - Effects of adult aging on reading filtered text: evidence from eye movements. AB - Objectives. Sensitivity to spatial frequencies changes with age and this may have profound effects on reading. But how the actual contributions to reading performance made by the spatial frequency content of text differs between young (18-30 years) and older (65+ years) adults remains to be fully determined. Accordingly, we manipulated the spatial frequency content of text and used eye movement measures to assess the effects on reading performance in both age groups. Method. Sentences were displayed as normal or filtered to contain only very low, low, medium, high, or very high spatial frequencies. Reading time and eye movements were recorded as participants read each sentence. Results. Both age groups showed good overall reading ability and high levels of comprehension. However, for young adults, normal performance was impaired only by low and very low spatial frequencies, whereas normal performance for older adults was impaired by all spatial frequencies but least of all by medium. Conclusion. While both young and older adults read and comprehended well, reading ability was supported by different spatial frequencies in each age group. Thus, although spatial frequency sensitivity can change with age, adaptive responses to this change can help maintain reading performance in later life. PMID- 23646283 TI - Conservation genetics of extremely isolated urban populations of the northern dusky salamander (Desmognathus fuscus) in New York City. AB - Urbanization is a major cause of amphibian decline. Stream-dwelling plethodontid salamanders are particularly susceptible to urbanization due to declining water quality and hydrological changes, but few studies have examined these taxa in cities. The northern dusky salamander (Desmognathus fuscus) was once common in the New York City metropolitan area, but has substantially declined throughout the region in recent decades. We used five tetranucleotide microsatellite loci to examine population differentiation, genetic variation, and bottlenecks among five remnant urban populations of dusky salamanders in NYC. These genetic measures provide information on isolation, prevalence of inbreeding, long-term prospects for population persistence, and potential for evolutionary responses to future environmental change. All populations were genetically differentiated from each other, and the most isolated populations in Manhattan have maintained very little genetic variation (i.e. <20% heterozygosity). A majority of the populations also exhibited evidence of genetic bottlenecks. These findings contrast with published estimates of high genetic variation within and lack of structure between populations of other desmognathine salamanders sampled over similar or larger spatial scales. Declines in genetic variation likely resulted from population extirpations and the degradation of stream and terrestrial paths for dispersal in NYC. Loss of genetic variability in populations isolated by human development may be an underappreciated cause and/or consequence of the decline of this species in urbanized areas of the northeast USA. PMID- 23646284 TI - Transcranial Doppler ultrasound to assess cerebrovascular reactivity: reliability, reproducibility and effect of posture. AB - Transcranial Doppler ultrasound (TCD) allows measurement of blood flow velocities in the intracranial vessels, and can be used to assess cerebral vasodilator responses to a hypercapnic stimulus. The reliability of this technique has not been established, nor is there agreement about whether the technique should be performed in sitting or lying postures. We tested the intra- and inter-rater reliability of measures of cerebrovascular reactivity (CVR) in 10 healthy adults, in sitting and lying postures. Participants underwent triplicate bilateral ultrasound assessment of flow velocities in the middle cerebral arteries whilst sitting and lying supine prior to and during inhalation of Carbogen (5% CO2, 95% O2) for 2 min. This procedure was performed twice by each of two raters for a total of four sessions. CVR was calculated as the difference between baseline and the peak blood flow velocity attained during CO2 inhalation. Intraclass correlation coefficients (ICCs) for intra-rater reliability were greater sitting than lying for both raters (e.g. Rater 1 ICC sitting = 0.822, lying = 0.734), and inter-rater reliability was also greater in sitting (e.g. sitting ICC = 0.504, lying = 0.081). These results suggest that assessment of CVR using TCD should be performed with participants sitting in order to maximise CVR measurement reliability. PMID- 23646285 TI - Genome-wide association study of HLA-DQB1*06:02 negative essential hypersomnia. AB - Essential hypersomnia (EHS), a sleep disorder characterized by excessive daytime sleepiness, can be divided into two broad classes based on the presence or absence of the HLA-DQB1*06:02 allele. HLA-DQB1*06:02-positive EHS and narcolepsy with cataplexy are associated with the same susceptibility genes. In contrast, there are fewer studies of HLA-DQB1*06:02 negative EHS which, we hypothesized, involves a different pathophysiological pathway than does narcolepsy with cataplexy. In order to identify susceptibility genes associated with HLA DQB1*06:02 negative EHS, we conducted a genome-wide association study (GWAS) of 125 unrelated Japanese EHS patients lacking the HLA-DQB1*06:02 allele and 562 Japanese healthy controls. A comparative study was also performed on 268 HLA DQB1*06:02 negative Caucasian hypersomnia patients and 1761 HLA-DQB1*06:02 negative Caucasian healthy controls. We identified three SNPs that each represented a unique locus- rs16826005 (P = 1.02E-07; NCKAP5), rs11854769 (P = 6.69E-07; SPRED1), and rs10988217 (P = 3.43E-06; CRAT) that were associated with an increased risk of EHS in this Japanese population. Interestingly, rs10988217 showed a similar tendency in its association with both HLA-DQB1*06:02 negative EHS and narcolepsy with cataplexy in both Japanese and Caucasian populations. This is the first GWAS of HLA-DQB1*06:02 negative EHS, and the identification of these three new susceptibility loci should provide additional insights to the pathophysiological pathway of this condition. PMID- 23646286 TI - Whose name is it anyway? Varying patterns of possessive usage in eponymous neurodegenerative diseases. AB - There has been long-standing debate over whether use of the possessive form of the names of eponymous neurological disorders should be abandoned. Which view has actually predominated in practice? We empirically assessed current and historical usage in the scientific literature. The PubMed database was queried for the percentage of titles published each year from 1960-2012 which contained the possessive form of Parkinson's (PD), Alzheimer's (AD), Huntington's (HD), Wilson's (WD), and Gaucher's (GD) diseases (e.g. Huntington's disease or chorea vs Huntington disease or chorea). Down syndrome (DS), well known for its changes in terminology, was used as a reference. The possessive form was nearly universal in all conditions from 1960 until the early 1970s. In both DS and GD it then declined at an approximately constant rate of 2 percentage points per year to drop below 15%. The possessive forms of both PD and AD began to decline at the same time but stabilised and have since remained above 80%, with a similar but more volatile pattern in HD. WD, meanwhile, is intermediate between the DS/GD and PD/AD/HD patterns, with a slower decline to its current value of approximately 60%. Declining possessive form usage in GD and DS papers has been remarkably uniform over time and has nearly reached completion. PD and AD appear stable in remaining predominantly possessive. The larger volume of papers published in those fields and their possibly greater public recognition and involvement may make that unlikely to change in the short-term. In a secondary analysis restricted to PD, we found that practices have switched dramatically several times in each of three US-published general neurology journals. Meanwhile, in two UK-published journals, and in the specialist title "Movement Disorders", the possessive form has been maintained consistently. The use of eponyms in neurology shows systematic variation across time, disorders, and journals. PMID- 23646287 TI - Differential expression of miR-1, a putative tumor suppressing microRNA, in cancer resistant and cancer susceptible mice. AB - Mus spretus mice are highly resistant to several types of cancer compared to Mus musculus mice. To determine whether differences in microRNA (miRNA) expression account for some of the differences in observed skin cancer susceptibility between the strains, we performed miRNA expression profiling of skin RNA for over 300 miRNAs. Five miRNAs, miR-1, miR-124a-3, miR-133a, miR-134, miR-206, were differentially expressed by array and/or qPCR. miR-1 was previously shown to have tumor suppressing abilities in multiple tumor types. We found miR-1 expression to be lower in mouse cutaneous squamous cell carcinomas (cSCCs) compared to normal skin. Based on the literature and our expression data, we performed detailed studies on predicted miR-1 targets and evaluated the effect of miR-1 expression on two murine cSCC cell lines, A5 and B9. Following transfection of miR-1, we found decreased mRNA expression of three validated miR-1 targets, Met, Twf1 and Ets1 and one novel target Bag4. Decreased expression of Ets1 was confirmed by Western analysis and by 3' reporter luciferase assays containing wildtype and mutated Ets1 3'UTR. We evaluated the effect of miR-1 on multiple tumor phenotypes including apoptosis, proliferation, cell cycle and migration. In A5 cells, expression of miR-1 led to decreased proliferation compared to a control miR. miR 1 expression also led to increased apoptosis at later time points (72 and 96 h) and to a decrease in cells in S-phase. In summary, we identified five miRNAs with differential expression between cancer resistant and cancer susceptible mice and found that miR-1, a candidate tumor suppressor, has targets with defined roles in tumorigenesis. PMID- 23646288 TI - Artifactual pyrosequencing reads in multiple-displacement-amplified sediment metagenomes from the Red Sea. AB - The Multiple Displacement Amplification (MDA) protocol is reported to introduce different artifacts into DNA samples with impurities. In this study, we report an artifactual effect of MDA with sediment DNA samples from a deep-sea brine basin in the Red Sea. In the metagenomes, we showed the presence of abundant artifactual 454 pyrosequencing reads over sizes of 50 to 220 bp. Gene fragments translocated from neighboring gene regions were identified in these reads. Occasionally, the translocation occurred between the gene fragments from different species. Reads containing these gene fragments could form a strong stem loop structure. More than 60% of the artifactual reads could fit the structural models. MDA amplification is probably responsible for the massive generation of the artifactual reads with the secondary structure in the metagenomes. Possible sources of the translocations and structures are discussed. PMID- 23646289 TI - Phylogeny of the plant genus Pachypodium (Apocynaceae). AB - Background. The genus Pachypodium contains 21 species of succulent, generally spinescent shrubs and trees found in southern Africa and Madagascar. Pachypodium has diversified mostly into arid and semi-arid habitats of Madagascar, and has been cited as an example of a plant group that links the highly diverse arid adapted floras of Africa and Madagascar. However, a lack of knowledge about phylogenetic relationships within the genus has prevented testing of this and other hypotheses about the group. Methodology/Principal Findings. We use DNA sequence data from the nuclear ribosomal ITS and chloroplast trnL-F region for all 21 Pachypodium species to reconstruct evolutionary relationships within the genus. We compare phylogenetic results to previous taxonomic classifications and geography. Results support three infrageneric taxa from the most recent classification of Pachypodium, and suggest that a group of African species (P. namaquanum, P. succulentum and P. bispinosum) may deserve taxonomic recognition as an infrageneric taxon. However, our results do not resolve relationships among major African and Malagasy lineages of the genus. Conclusions/Significance. We present the first molecular phylogenetic analysis of Pachypodium. Our work has revealed five distinct lineages, most of which correspond to groups recognized in past taxonomic classifications. Our work also suggests that there is a complex biogeographic relationship between Pachypodium of Africa and Madagascar. PMID- 23646290 TI - Predicting and mapping soil available water capacity in Korea. AB - The knowledge on the spatial distribution of soil available water capacity at a regional or national extent is essential, as soil water capacity is a component of the water and energy balances in the terrestrial ecosystem. It controls the evapotranspiration rate, and has a major impact on climate. This paper demonstrates a protocol for mapping soil available water capacity in South Korea at a fine scale using data available from surveys. The procedures combined digital soil mapping technology with the available soil map of 1:25,000. We used the modal profile data from the Taxonomical Classification of Korean Soils. The data consist of profile description along with physical and chemical analysis for the modal profiles of the 380 soil series. However not all soil samples have measured bulk density and water content at -10 and -1500 kPa. Thus they need to be predicted using pedotransfer functions. Furthermore, water content at -10 kPa was measured using ground samples. Thus a correction factor is derived to take into account the effect of bulk density. Results showed that Andisols has the highest mean water storage capacity, followed by Entisols and Inceptisols which have loamy texture. The lowest water retention is Entisols which are dominated by sandy materials. Profile available water capacity to a depth of 1 m was calculated and mapped for Korea. The western part of the country shows higher available water capacity than the eastern part which is mountainous and has shallower soils. The highest water storage capacity soils are the Ultisols and Alfisols (mean of 206 and 205 mm, respectively). Validation of the maps showed promising results. The map produced can be used as an indication of soil physical quality of Korean soils. PMID- 23646292 TI - Prodrug enzymes and their applications in image-guided therapy of cancer: tracking prodrug enzymes to minimize collateral damage. AB - Many cytotoxic therapies are available to kill cancer cells. Unfortunately, these also inflict significant damage on normal cells. Identifying highly effective cancer treatments that have minimal or no side effects continues to be a major challenge. One of the strategies to minimize damage to normal tissue is to deliver an activating enzyme that localizes only in the tumor and converts a nontoxic prodrug to a cytotoxic agent locally in the tumor. Such strategies have been previously tested but with limited success due in large part to the uncertainty in the delivery and distribution of the enzyme. Imaging the delivery of the enzyme to optimize timing of the prodrug administration to achieve image guided prodrug therapy would be of immense benefit for this strategy. Here, we have reviewed advances in the incorporation of image guidance in the applications of prodrug enzymes in cancer treatment. These advances demonstrate the feasibility of using clinically translatable imaging in these prodrug enzyme strategies. PMID- 23646291 TI - Serum Dihydrolipoamide Dehydrogenase Is a Labile Enzyme. AB - Dihydrolipoamide dehydrogenase (DLDH) is a multifunctional oxidoreductase and is well known as an essential component of four mammalian mitochondrial multienzyme complexes: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, branched chain alpha-keto acid dehydrogenase, and the glycine cleavage system. However, existence of extracellular DLDH in mammals, if any, has not been clearly defined. The present article reports identification and biochemical characterization of serum DLDH. Proteomic analysis of rat serum using blue native polyacrylamide gel electrophoresis (BN-PAGE) and mass spectrometry peptide sequencing led to generation of 6 tryptic peptides in one band that matched to mitochondrial DLDH, indicating the existence of DLDH in rat serum. Measurement of enzymatic activity also indicated the existence of DLDH in human and mouse serum. Further biochemical analysis of rat serum DLDH revealed that this enzyme lacked diaphorase activity and could not be detected on Western blots probed with antibodies that recognized mitochondrial DLDH. Moreover, both ammonium sulfate fractioning and gel filtration of serum samples rendered a great loss in DLDH activity, indicating that the enzyme activity of this serum protein, unlike that of mitochondrial DLDH, is very labile. When DTT was supplemented in the buffer used for gel filtration, DLDH activity was found to be largely preserved; indicating that serum DLDH is susceptible to air-implicated inactivation. Results of the present study indicate that serum DLDH differs from mitochondrial DLDH in that it is a very labile enzyme. PMID- 23646293 TI - Patients attended by palliative care teams: are they always comparable populations? AB - Patients attended by palliative care teams: are they always comparable populations? To answer this question we have compared the basic epidemiological characteristics of patients attended by home palliative care teams (HPCT) in two autonomous regions of Spain. We carried out a coordinated analytical, observational and prospective study in two Spanish autonomous regions: Aragon and Catalonia. Data were kept during each home care visit according to patients' needs. Inclusion criteria were: advanced cancer, over 18 years old and first contact with a HPCT. The recruitment period was 6 months. Variables included were: Survival time (days), age, sex, primary disease and extension, place of residence. Functional and cognitive state, and co-morbidity. 10 signs/symptoms: asthenia, anorexia, cachexia, dysphagia, xerostomy, dyspnoea, oedemas, level of consciousness, presence of delirium, presence of pressure ulcers and some treatment data. Others variables considered were: responsible team, origin, destination when discharge, date and place of death, number of visits made and duration of monitoring. We developed a comparison between groups by Chi-squared test or the non-parametric Mann-Whitney U test and a survival analysis by Kaplan Meier curves and the logrank test to determine differences between factors. The SPSS version 15.0 software package was used. 698 patients were included, 56.2% from Aragon and 43.8% from Catalonia. 60.3% were males, without differences between the regions. Characteristics relative to age, sex, place of residence and extension of oncological diseases were similar for both groups. We found significant differences between the two populations relative to survival time, co morbidity, functional state, presence and intensity of a number of symptoms and the treatments, patient monitoring and the their destination after discharge. We can conclude that palliative care teams cover different profiles of patients with regard to their co-morbidity, functional, cognitive and symptomatic states. It must be pointed that the organization of palliative care services and their experience appears to condition the profile of patients they attend. There is a need of consensus on the basic descriptors for palliative care patients in order to ensure that results will be comparable. PMID- 23646294 TI - Sedation of children for auditory brainstem response using ketamine-midazolam atropine combination - a retrospective analysis. AB - Authors investigated sedation quality in children for auditory brainstem response testing. Two-hundred and seventy-six sedation procedures were retrospectively analyzed using recorded data focusing on efficacy of sedation and complications. Intramuscular ketamine-midazolam-atropine combination was administered on sedation preceded by narcotic suppository as pre-medication. On using the combination vital parameters remained within normal range, the complication rate was minimal. Pulse rate, arterial blood pressure and pulse oxymetry readings were stable, hypoventilation developed in 4, apnoea in none of the cases, post sedation agitation occurred in 3 and nausea and/or vomiting in 2 cases. Repeated administration of narcotic agent was necessary in a single case only. Our practice is suitable for the sedation assisting hearing examinations in children. It has no influence on the auditory brainstem testing, the conditions necessary for the test can be met entirely with minimal side-effects. Our practice provides a more lasting sedation time in children during the examination hence there is no need for the repetition of the narcotics. PMID- 23646295 TI - Poor asthma control in obese children may be overestimated because of enhanced perception of dyspnea. AB - BACKGROUND: Although studies in adults have shown a non-TH2 obese asthma phenotype, whether a similar phenotype exists in children is unclear. OBJECTIVE: We hypothesized that asthmatic children with obesity, defined as a body mass index above the 95th percentile for age and sex, would have poorer asthma control as well as decreased quality of life, increased health care utilization, and decreased pulmonary function measures as a function of increased TH1 versus TH2 polarization. METHODS: This study involved a post hoc analysis of cross sectional data from 269 children 6 to 17 years of age enrolled in the National Heart, Lung, and Blood Institute Severe Asthma Research Program. Children answered questionnaires and underwent spirometry, plethysmography, exhaled nitric oxide determination, and venipuncture for TH1/TH2 cytokine determination. Asthma control was defined according to national asthma treatment guidelines that are based on prespecified thresholds for lung function and symptom frequency. RESULTS: Fifty-eight children (22%) were overweight and 67(25%) were obese. Obese children did not have poorer asthma control but were more likely to report nonspecific symptoms such as dyspnea and nocturnal awakenings. Obese children did have decreased asthma-related quality of life and increased health care utilization, but this was not associated with airflow limitation. Instead, obese children had decreased functional residual capacity. A unique pattern of TH1 or TH2 polarization was not observed. CONCLUSIONS: Poor asthma control in obese children with asthma may be overestimated because of enhanced perception of nonspecific symptoms such as dyspnea that results from altered mechanical properties of the chest wall. Careful assessment of physiologic as well as symptom-based measures is needed in the evaluation of obese children with respiratory symptoms. PMID- 23646297 TI - Chemical composition of essential oils and in vitro antioxidant activity of fresh and dry leaves crude extracts of medicinal plant of Lactuca Sativa L. native to Sultanate of Oman. AB - OBJECTIVE: To isolate and analyse the chemical composition in the essential oils and free radical scavenging activity of different crude extracts from the fresh and dry leaves of vegetable plants of Lactuca sativa L. (L. sativa). METHODS: The essential oils and volatile chemical constituents were isolated from the fresh and dry leaves of L. sativa (lettuce) grown in Sultanate of Oman by hydro distillation method. The antioxidant activity of the crude extracts was carried out by well established free radical scavenging activity (DPPH) method. RESULTS: About 20 chemical compounds of different concentration representing 83.07% and 79.88% respectively were isolated and identified by gas chromatography-mass spectroscopy in the essential oils isolated from the fresh and dry leaves as alpha-pinene (5.11% and 4.05%), gamma-cymene (2.07% and 1.92%), thymol (11.55% and 10.73%), durenol (52.00% and 49.79%), alpha-terpinene (1.66% and 1.34%), thymol acetate (0.99% and 0.67%), caryophyllene (2.11% and 1.98%), spathulenol (3.09% and 2.98%), camphene (4.11% and 3.65%), limonene (1.28% and 1.11%) representing these major chemical compounds. However, some other minor chemical constituents were also isolated and identified from the essential oil of lettuce including beta-pinene, alpha-terpinolene, linalool, 4-terpineol, alpha-terpineol, o-methylthymol, L-alloaromadendrene and viridiflorene. CONCLUSIONS: The chemical constituents in the essential oils from the locally grown lettuce were identified in the following classes or groups of chemical compounds such as monoterpenes, sesquiterpenes volatile organic compounds and their oxygenated hydrocarbons. Therefore, the essential oils and the crude extracts from Omani vegetable species of lettuce are active candidates which would be used as antioxidant, antifungal or antimicrobial agents in new drugs preparation for therapy of infectious diseases. PMID- 23646296 TI - A review on therapeutic potential of Nigella sativa: A miracle herb. AB - Nigella sativa (N. sativa) (Family Ranunculaceae) is a widely used medicinal plant throughout the world. It is very popular in various traditional systems of medicine like Unani and Tibb, Ayurveda and Siddha. Seeds and oil have a long history of folklore usage in various systems of medicines and food. The seeds of N. sativa have been widely used in the treatment of different diseases and ailments. In Islamic literature, it is considered as one of the greatest forms of healing medicine. It has been recommended for using on regular basis in Tibb-e Nabwi (Prophetic Medicine). It has been widely used as antihypertensive, liver tonics, diuretics, digestive, anti-diarrheal, appetite stimulant, analgesics, anti-bacterial and in skin disorders. Extensive studies on N. sativa have been carried out by various researchers and a wide spectrum of its pharmacological actions have been explored which may include antidiabetic, anticancer, immunomodulator, analgesic, antimicrobial, anti-inflammatory, spasmolytic, bronchodilator, hepato-protective, renal protective, gastro-protective, antioxidant properties, etc. Due to its miraculous power of healing, N. sativa has got the place among the top ranked evidence based herbal medicines. This is also revealed that most of the therapeutic properties of this plant are due to the presence of thymoquinone which is major bioactive component of the essential oil. The present review is an effort to provide a detailed survey of the literature on scientific researches of pharmacognostical characteristics, chemical composition and pharmacological activities of the seeds of this plant. PMID- 23646298 TI - Hypoglycemic and anti-hyperglycemic study of Gynura procumbens leaf extracts. AB - OBJECTIVE: To study the antidiabetic activity of Gynura procumbens (G. procumbens) used in the traditional management of diabetes in Southern Asia. METHODS: G. procumbens leaves were extracted sequentially with graded percentage of ethanol in water (95%, 75%, 50%, 25% and 0%), and the extracts were tested for antidiabetic activity using acute (7 h), subcutaneous glucose tolerance test and sub-chronic (14 d) test in non-diabetic and streptozotocin-induced diabetic rats. The extracts were further subjected to phytochemical studies. RESULTS: In acute dose (1 g/kg), the extracts significantly lowered fasting blood glucose (FBG) in streptozotocin-induced diabetic rats (P<0.05). However, the FBG-lowering effect of the 25% extract compared to the other extracts, was rapid (47% after 2 h) and the highest: 53%, 53% and 60% in the 3rd, 5th, and 7th h, respectively (P<0.05), comparable only to the effect of metformin. Furthermore, the extracts suppressed peak FBG in subcutaneous glucose tolerance test, but only the 0% and 25% extracts, and metformin sustained the decrease until the 90th min (P<0.05). Moreover, in the 14 days study, the 25% extract exerted the highest FBG-lowering effect, namely 49.38% and 65.43% on days 7 and 14, respectively (P<0.05), similar to the effect of metformin (46.26% and 65.42%). Total flavanoid and phenolic contents in the extracts were found to decrease with increase in polarity of extraction solvents. The composition of reference compounds (chlorogenic acid, rutin, astragalin and kaempferol-3-O-rutinoside) followed a similar trend. CONCLUSIONS: G. procumbens contains antidiabetic principles, most extracted in 25% ethanol. Interaction among active components appears to determine the antidiabetic efficacy, achieved likely by a metformin-like mechanism. PMID- 23646299 TI - A study of in vitro antibacterial activity of lanthanides complexes with a tetradentate Schiff base ligand. AB - OBJECTIVE: To establish the antibacterial activity of lanthanides complexes with a tetradentate Schiff base ligand L. METHODS: (N, N'-bis (1-naphthaldimine)-o phenylenediamine) was prepared from the condensation of 2-hydroxy-1 naphthaldehyde with o-phenylenediamine in a molar ratio of 2:1. The antimicrobial activity of the resultant Ln (III) complexes was investigated using agar well diffusion and micro-broth dilution techniques; the latter was used to establish the minimum inhibitory concentrations for each compound investigated. RESULTS: Most of Ln (III) complexes were found to exhibit antibacterial activities against a number of pathogenic bacteria with MICs ranging between 1.95-250.00 ug/mL. Staphylococcus aureus was the most susceptible bacterial species to [LaL(NO3)2(H2O)](NO3) complex while Shigella dysenteriae and Escherichia coli required a relatively higher MIC (250 ug/mL). The complexes La (III) and Pr (III) were effective inhibitors against Staphylococcus aureus, whereas Sm (III) complex was effective against Serratia marcescens. On the other hand, Gd (III), La (III) and Nd (III) were found to be more potent inhibitors against Pseudomonas aeruginosa than two of commonly used antibiotics. The remaining Ln (III) complexes showed no remarkable activity as compared to the two standard drugs used. CONCLUSIONS: Tetradentate Schiff base ligand L and its complexes could be a potential antibacterial compounds after further investigation. PMID- 23646300 TI - Cardioprotective and hepatoprotective effects of Citrus hystrix peels extract on rats model. AB - OBJECTIVE: To observe the combination effect of doxorubicin and Citrus hystrix (kaffir lime's) peel ethanolic extract (ChEE) on blood serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity and cardio hepato-histopathology of female Sprague Dawley rats. METHODS: Doxorubicin and ChEE (5 rats per group) were administered in five groups of 3 rats each for 11 d. Group I: doxorubicin (dox) 4.67 mg/kg body weight; Group II: dox+ChEE 500 mg/kg body weight; Group III: dox+ChEE 1 000 mg/kg body weight; Group IV: ChEE 1 000 mg/kg body weight; Group V: untreated (control). RESULTS: ChEE repaired cardiohistopathology profile of doxorubicin induced cardiotoxicity and hepatotoxicity rats, but did not repair neither hepatohistopathology profile nor reduce serum activity of ALT and AST. CONCLUSION: ChEE has potency to be developed as cardioprotector agent in chemotherapy. PMID- 23646301 TI - In vitro effects of Salvia officinalis L. essential oil on Candida albicans. AB - OBJECTIVE: To determine the anticandidal activities of Salvia officinalis L. (S. officinalis) essential oil against Candida albicans (C. albicans) and the inhibitory effects on the adhesion of C. albicans to polymethyl methacrylate (PMMA) resin surface. METHODS: Disc diffusion method was first used to test the anticandidal activities of the S. officinalis L. essential oil against the reference strain (ATCC 90028) and 2 clinical strains of C. albicans. Then the minimal inhibitory concentration (MIC) and minimal lethal concentration (MLC) were determined by modified membrane method. The adhesion of C. albicans to PMMA resin surface was assessed after immersion with S. officinalis L. essential oil at various concentrations of 1*MIC, 0.5*MIC and 0.25*MIC at room temperature for 30 min. One-way ANOVA was used to compare the Candida cell adhesion with the pretreatment agents and Tukey's test was used for multiple comparisons. RESULTS: S. officinalis L. essential oil exhibited anticandidal activity against all strains of C. albicans with inhibition zone ranging from 40.5 mm to 19.5 mm. The MIC and MLC of the oil were determined as 2.780 g/L against all test strains. According to the effects on C. albicans adhesion to PMMA resin surface, it was found that immersion in the essential oil at concentrations of 1*MIC (2.780 g/L), 0.5*MIC (1.390 g/L) and 0.25*MIC (0.695 g/L) for 30 min significantly reduced the adhesion of all 3 test strains to PMMA resin surface in a dose dependent manner (P<0.05). CONCLUSIONS: S. officinalis L. essential oil exhibited anticandidal activities against C. albicans and had inhibitory effects on the adhesion of the cells to PMMA resin surface. With further testing and development, S. officinalis essential oil may be used as an antifungal denture cleanser to prevent candidal adhesion and thus reduce the risk of candida-associated denture stomatitis. PMID- 23646302 TI - Evaluation of PCR-ELISA as a tool for monitoring transmission of Wuchereria bancrofti in District of Gampaha, Sri Lanka. AB - OBJECTIVE: To compare Wuchereria bancrofti (W. bancrofti) infection rates of Culex quinquefasciatus, using dissection and PCR-ELISA in two consecutive time periods (from 2007 to 2008 and from 2008 to 2009). METHODS: Mosquitoes were collected in 30 sentinel and 15 non-sentinel sites in 15 Medical Officer of Health areas of Gampaha District known for the presence of W. bancrofti transmission in two consecutive time period of 2007 to 2008 and 2008 to 2009. Captured mosquitoes were dissected to determine the W. bancrofti larvae (L1, L2, L3). PCR was carried out using DNA extracted from mosquito pools (15 body parts/pool) utilizing the primers specific for Wb-SspI repeat. PCR products were analyzed by hybridization ELISA using fluorescein-labeled wild type specific probes. The prevalence of infected/infective mosquitoes in PCR pools (3 pools/site) was estimated using the PoolScreenTM algorithm and a novel probability-based method. RESULTS: Of 45 batches of mosquitoes dissected, W. bancrofti infected mosquitoes were found in 19 and 13 batches, with an infection rate of 13.29% and 3.10% with mean larval density of 8.7 and 1.0 larvae per mosquito for two study periods in the Gampaha District. Total of 405 pools of head, thorax and abdomen were processed by PCR-ELISA for each year. Of these, 51 and 31 pools were positive for W. bancrofti in the two study periods respectively. The association of dissection based prevalence rates with PCR based rates as determined by the Pearson correlation coefficient were 0.176 and 0.890 respectively for the two periods. CONCLUSIONS: Data indicate that PCR-ELISA is more sensitive than the traditional dissection techniques for monitoring transmission intensity. PMID- 23646303 TI - In vivo antioxidant assessment of two antimalarial plants-Allamamda cathartica and Bixa orellana. AB - OBJECTIVE: To determine the free radical scavenging potentials pytochemical constituents of ethanol leaves extracts of Allamanda cathartica (A. cathartica) and Bixa orellana (B. orellana) and thus their effects in antimalarial activities. METHODS: Both ethanol extracted plant samples were administered at 50 mg/mL, 100 mg/mL and 200 mg/mL to Albino rats and then administered with CCl4 at 1 mL/kg body weight, in liquid paraffin (1:1, v/v) for 2 days (negative control) and compared with 5% Tween 80 (placebo) and vitamin E (positive control) pretreatments. Thiobarbituric acid reactive substances (TBARS), glutathione (GSH) and catalase (CAT) activities in blood and liver tissues were assessed. RESULTS: In CCl4 treated rats, TBARS levels significantly increased, while decreased GSH and CAT levels were recorded for both plant extracts. Generally, higher TBARS and GSH values were recorded for blood than for liver homogenates; with reverse trend observed for CAT level. Increased concentrations of A. cathartica extract recorded significant antioxidant levels similar to tocopherol (vitamin E). Reducing sugars, saponins, flavonoids were recorded for both species; alkaloids in A. cathartica and terpenoids in B. orellana. CONCLUSIONS: A. cathartica, possess phytochemicals that recorded significant antioxidative defense activities for blood and liver tissues with increasing concentration. However B. orellana did not record similar results. PMID- 23646304 TI - In vivo antioxidant effect of aqueous root bark, stem bark and leaves extracts of Vitex doniana in CCl4 induced liver damage rats. AB - OBJECTIVE: The antioxidant effects of aqueous root bark, stem bark and leaves of Vitex doniana (V. doniana) were evaluated in carbon tetrachloride (CCl4) induced liver damage and non induced liver damage albino rats. METHODS: A total of 60 albino rats (36 induced liver damage and 24 non induced liver damage) were assigned into liver damage and non liver damage groups of 6 rats in a group. The animals in the CCl4 induced liver damage groups, were induced by intraperitoneal injection with a single dose of CCl4 (148 mg.ml(-1).kg(-1) body weight) as a 1:1 (v/v) solution in olive oil and were fasted for 36 h before the subsequent treatment with aqueous root bark, stem bark and leaves extracts of V. doniana and vitamin E as standard drug (100 mg/kg body weighy per day) for 21 d, while the animals in the non induced groups were only treated with the daily oral administration of these extracts at the same dose. The administration of CCl4 was done once a week for a period of three weeks. RESULTS: The liver of CCl4 induced not treated group showed that the induction with CCl4, significantly (P<0.05) increased thiobarbituric acid reactive substance (TBARS) and significantly (P<0.05) decreased superoxide dismutase (SOD) and catalase (CAT). However there was no significant (P>0.05) difference between TBARS, SOD and CAT in the liver of the induced treated groups and normal control group. In the kidney, TBARS showed no significant (P>0.05) difference between the normal and the induced groups, SOD was significantly (P<0.05) reduced in the CCl4 group compared to standard drug and normal control groups, CAT was significantly (P<0.05) increased in root and vitamin E groups when compared to induced not treated group. The studies also showed that when the extracts were administered to normal animals, there was no significant (P>0.05) change in the liver and kidney level of TBARS, SOD and CAT compared with the normal control except in the kidney of animals treated with stem extract where TBARS was significantly (P<0.05) lowered compared to control group. CONCLUSION: The result of the present study suggests that application of V. doniana plant would play an important role in increasing the antioxidant effect and reducing the oxidative damage that formed both in liver and in kidney tissues. However stem bark has potential to improve renal function in normal rats. PMID- 23646306 TI - Food safety knowledge and practices of abattoir and butchery shops and the microbial profile of meat in Mekelle City, Ethiopia. AB - OBJECTIVE: To assess the food safety knowledge and practices in meat handling, and to determine microbial load and pathogenic organisms in meat at Mekelle city. METHODS: A descriptive survey design was used to answer questions concerning the current status of food hygiene and sanitation practiced in the abattoir and butcher shops. Workers from the abattoir and butcher shops were interviewed through a structured questionnaire to assess their food safety knowledge. Bacterial load was assessed by serial dilution method and the major bacterial pathogens were isolated by using standard procedures. RESULTS: 15.4% of the abattoir workers had no health certificate and there was no hot water, sterilizer and cooling facility in the abattoir. 11.3% of the butchers didn't use protective clothes. There was a food safety knowledge gap within the abattoir and butcher shop workers. The mean values of bacterial load of abattoir meat, butcher shops and street meat sale was found to be 1.1*10(5), 5.6*10(5) and 4.3*10(6) cfu/g, respectively. The major bacterial pathogens isolated were Escherichia coli, Staphylococcus aureus and Bacillus cereus. CONCLUSIONS: The study revealed that there is a reasonable gap on food safety knowledge by abattoir and butcher shop workers. The microbial profile was also higher compared to standards set by World Health Organization. Due attention should be given by the government to improve the food safety knowledge and the quality standard of meat sold in the city. PMID- 23646305 TI - Opportunistic infection of Aspergillus and bacteria in captive Cape vultures (Gyps coprotheres). AB - OBJECTIVE: To describe clinical signs, pathology, diagnosis and treatment of Cape vultures in which Aspergillus fumigatus (A. fumigatus) and mixed species of bacteria were isolated. METHODS: Six Cape vultures sourced from South Africa for exhibition at Al Ain Zoo developed illness manifesting as anorexia, dyspnea, polyuria and lethargy. Three vultures died manifesting "pneumonia-like syndrome". These three vultures were necropsied and gross lesions recorded, while organ tissues were collected for histopathology. Internal organs were swabbed for bacteriology and mycology. From live vultures, blood was collected for hematology and biochemistry, oropharyngeal and cloacal swabs were collected for mycology and bacteriology. RESULTS: A. fumigatus was isolated from the three dead vultures and two live ones that eventually survived. One of the dead vulture and two live vultures were co-infected with A. fumigatus and mixed species of bacteria that included Clostridium perfringens, Pseudomonas, Staphylococcus, Escherichia, Proteus, Enterococcus and Enterbacter. One of the Cape vulture and a Lappet-faced vulture, however, were free of Aspergillus or bacterial infections. At necropsy, intestinal hemorrhages were observed and the lungs were overtly congested with granulomas present on caudal air sac. Histopathological examinations demonstrated granulomatous lesions that were infiltrated by mononuclear cells and giant cells. CONCLUSIONS: Aspergillosis is a persistent threat to captive birds and we recommend routine health assessments so that early diagnosis may prompt early treatment. It is likely that prompt prophylaxis by broad spectrum antibiotics and antifungals medication contributed to the survival of some of the vultures. PMID- 23646307 TI - Occurrence of trichoepithelioma in a cat: Histopathologic and immunohistochemical study. AB - Trichoepitheliomas are benign follicular appendage tumors with differentiation to all three segments of the hair follicle. A 2 years old female domestic short hair cat presented with a mass on the tail. The mass was surgically excised and for histopathologic and immunohistochemical studies, was sent to Department of Pathology. Histologically, the tumor was encapsulated and consisted of many islands of follicular epithelium and also cysts structures which varied in size and shape. The cells of epithelium islands were round to oval and had variable amounts of slightly, eosinophilic cytoplasm and euchromatic nuclei. The cystic structures were lined by a complex layer of squamous epithelium. Often, cells under went an abrupt transition between basal layers and keratinization without the development of a granular cell layer. No tendency of malignancy was seen in this case. According to mentioned characteristics, trichoepithelioma was diagnosed. By immunohistochemical study it was confirmed that this tumor had epithelial origin because squamous tumor cells reacted with the pan-cytokeratin antibody. The expression of beta-catenin was predominately cytoplasmic and also together with numerous positive nuclei but membranous expression was inconsistenet. Distribution of neoplastic cells with beta-catenin expression was more than 75% and labeling intensity was strong in both cytoplasm and nuclei. According to author's knowledge, this is the first report of trichoepithelioma in cat in Iran and also investigation of beta-catenin expression in feline trichoepithelioma in veterinary literature. PMID- 23646308 TI - A case of cerebral malaria and dengue concurrent infection. AB - Cerebral malaria and dengue are the common infections which cause higher mortality and morbidities in every part of the world especially in India. Concurrent infection of cerebral malaria and dengue is rare entity due to different habitat of vectors and it was reported rarely from Southeast Asia. In this case report, the authors reported a case of concurrent cerebral malaria and dengue which was recovered after eight days of admission with increase in morbidity. PMID- 23646310 TI - Analysis of the occupational stress of Korean surgeons: a pilot study. AB - PURPOSE: Surgeons serve one of the most challenging and stressful professions. Ineffective control of occupational stress leads to burnout of the surgeon. The aim of this study was to obtain preliminary data on the sources and the degree of stress of surgeons and to determine the feasibility of the survey. METHODS: A total of 63 surgeons in our three affiliated hospitals were enrolled in this study. Fifty-five questions were used to assess the demographics, characteristics and Korean occupational stress scale (KOSS), which were prepared and validated by the National Study for Development and Standardization of Occupational Stress. RESULTS: Forty-seven of the 63 surgeons participated in this study (74.6%). The mean KOSS score of the survey was 50.9 +/- 8.55, which was significantly higher than that of other professions (P < 0.01). Drinking and smoking habits were not related to the KOSS score. Doing exercise was related to a low KOSS score in terms of low KOSS total score (P < 0.01). Average duty hours (P < 0.01) and night duty days per week (P = 0.01) were strongly related to higher KOSS in the linear regression analysis. CONCLUSION: This is the first study to evaluate job stress of surgeons in Korea. This study showed that Korean Surgeons had higher occupational stress than other Korean professions. A larger study based on this pilot study will help generate objective data for occupational stress of Korean Surgeons by performing a survey of the members of the Korean Surgical Society. PMID- 23646309 TI - Giemsa and Grocott in the recognition of Histoplasma capsulatum in blood smears. AB - OBJECTIVE: To facilitate the recognition of intracellular yeasts of Histoplasma capsulatum and differentiate it from Leishmania amastigotes and other parasites, using the combination of Giemsa and a rapid modification of Grocott stains to peripheral blood smears in a hematological study. METHODS: The combination of both stains was applied consecutively (first Grocott and then Giemsa) to previously fixed peripheral blood smears. Microscopy was performed with 400* and 1 000*, the latter using immersion oil. RESULTS: The yeasts of Histoplasma capsulatum were observed into the cytoplasm of leukocytes as brownish oval elements, with 3-4 um in diameter. CONCLUSIONS: The combination of both techniques is a simple and fast method to facilitate recognition of intracellular yeasts and it is different from intracellular parasitic elements. Moreover, it allows distinguishing the cell elements that are in the microscopic preparations. It may be very helpful in those cases in which the presumptive diagnosis of histoplasmosis has not been established yet and where other more sophisticated methods are not available. PMID- 23646311 TI - Primary breast lymphoma: a single institution's experience. AB - PURPOSE: Primary breast lymphoma is a very rare disease, accounting for 0.4-0.5% of all breast malignancies. Due to the rarity, there are only limited reports of this disease in Korean women. In this reason, we report the experience of a single institution in Korea with primary breast lymphoma (PBL). METHODS: We retrospectively reviewed the medical records of 9 patients with PBL and evaluated the clinicopathologic characteristics and treatment outcomes. RESULTS: All nine patients were female and had diffuse large B-cell lymphoma (DLBL). The median age at diagnosis was 47.9 years and the median tumor size was 3.8 cm in diameter. The most common symptom was a painless palpable mass. Five patients were classified as stage IEA and four patients were IIEA according to the Ann Arbor staging system. Four patients underwent excisional biopsy and one patient underwent a lumpectomy with sentinel lymph node biopsy due to uncertain histology of the preoperative core needle biopsy. Nine patients received anthracycline containing combined chemotherapy; among them, five patients were treated with a rituximab containing regimen. Four patients received radiotherapy combined with chemotherapy. A complete response was achieved in eight patients. During the 44 months of the median follow-up period, three cases of relapse occurred, and among them, two patients died due to disease progression. CONCLUSION: Most PBLs are B cell origin, with DLBL being the most common histologic type. A combined treatment modality has been known to have positive effects on prognosis, and surgery should be limited to a diagnostic purpose. PMID- 23646312 TI - Neoadjuvant human epidermal growth factor receptor-2 targeted therapy in patients with locally advanced breast cancer. AB - PURPOSE: We analyzed the responses of patients with locally advanced breast cancer to neoadjuvant chemotherapy (NAC) and NAC combined with neoadjuvant human epidermal growth factor receptor-2 (HER2) targeted therapy (NCHTT). METHODS: We retrospectively reviewed 59 patients with HER2 amplified locally advanced breast cancer among patients who were treated surgically after neoadjuvant therapy at Samsung Medical Center between 2005 and 2009. Thirty-one patients received conventional NAC and 28 patients received NCHTT. Pathologic responses were assessed according to response evaluation criteria in solid tumors (RECIST) guidelines. RESULTS: Pathologic complete response (pCR) was achieved in 13 out of 28 patients treated with NCHTT and in 6 out of 31 patients treated with NAC alone (46.4% vs. 19.4%, respectively, P = 0.049). Breast conserving surgery (BCS) was more frequently performed in the NCHTT group than in the NAC only group (71.4% vs. 19.4%, P < 0.001). The 3-year recurrence-free survival (RFS) rate was 100% in the NCHTT group and 76.4% in the NAC group (P = 0.014). Together, NCHTT, type of operation (BCS vs. mastectomy) and pathologic nodal status were significant prognostic factors for RFS in univariate analysis. CONCLUSION: We found that NCHTT produced higher pCR rates than NAC alone in locally advanced breast cancer. PMID- 23646313 TI - Afferent loop obstruction following laparoscopic distal gastrectomy with Billroth II gastrojejunostomy. AB - PURPOSE: Afferent loop (A-loop) obstruction is an uncommon postgastrectomy complication following Billroth-II (B-II) or Roux-en-Y reconstruction. Moreover, its development after laparoscopic gastrectomy has not been reported. Here we report 4 cases of A-loop obstructions after laparoscopic distal gastrectomy (LDG) with B-II reconstruction. METHODS: Among the 396 patients who underwent LDG with a B-II anastomosis between April 2004 and December 2011, 4 patients had A-loop obstruction. Their data were obtained from a prospectively maintained institutional database and analyzed for outcomes. RESULTS: Four patients (1.01%) developed A-loop obstruction. All were male, and their median age was 52 years (range, 30 to 73 years). The interval between the initial gastrectomies and the operation for A-loop obstruction ranged from 4 to 540 days (median, 33 days). All 4 patients had symptoms of vomiting and abdominal pain and were diagnosed by abdominal computed tomographic (CT) scan. The causes of the A-loop obstructions were adhesions (2 cases) and internal herniations (2 cases) that were treated with Braun anastomoses and reduction of the herniated small bowels, respectively. All patients recovered following the emergency operations. CONCLUSION: A-loop obstruction is a rare but serious complication following laparoscopic and open gastrectomy. It should be considered when a patient complains of continuous abdominal pain and/or vomiting after LDG with B-II reconstruction. Prompt CT scan may play an important role in diagnosis and treatment. PMID- 23646314 TI - Outcome of the patients with chronic mesh infection following open inguinal hernia repair. AB - PURPOSE: Hernia repairs are the most common elective abdominal wall procedures performed by general surgeons. The use of a mesh has become the standard for hernia repair surgery. Herein, we discuss a management strategy for chronic mesh infections following open inguinal hernia repair with onlay prosthetic mesh. METHODS: In this study, 15 patients with chronic mesh infections following open inguinal hernia repairs were included. The medical records of these patients were retrospectively reviewed and information regarding presentation, type of previous hernia repair, type of mesh, operative findings and bacteriological examination results were obtained. In all cases, the infected mesh was removed completely and the patients were treated with antibiotic regimens and local wound care. RESULTS: Fifteen mesh removals due to chronic infection were performed between January 2000 and March 2012. The mean interval of hernia repair to mesh removal was 49 months. All patients were followed up for a median period of 62 months (range, 16 to 115 months). In all patients, the infections were resolved successfully and none were persistent or recurrent. However, one patient developed recurrent hernia and one developed nerve injury. CONCLUSION: Chronic mesh infection following hernia repair mandates removal of the infected mesh, which rarely results in hernia recurrence. PMID- 23646315 TI - The results of aspiration thrombecomy in the endovascular treatment for iliofemoral deep vein thrombosis. AB - PURPOSE: The aim of this study is to evaluate the results of aspiration thrombectomy (AT) in the endovascular treatment for iliofemoral deep vein thrombosis (DVT) through the comparison of catheter directed thrombolysis (CDT) alone group and CDT with AT group. METHODS: From November 2001 to April 2011, 100 patients received endovascular treatment with CDT alone or CDT with AT for iliofemoral DVT at Yeungnam University Medical Center. We compared procedure, clinical outcomes and complications between the two groups. RESULTS: The mean age of patients was 60.48 +/- 14.57 years. The patients consisted of 41 men and 59 women. CDT alone and CDT with AT were performed in 29 and 71 patients, respectively. The mean procedural time of the CDT-alone group was longer than the CDT with AT group (P < 0.001) and dose of urokinase used during the procedure significantly decreased in the CDT with AT group (P < 0.001). There were no statistically significant differences in clinical outcomes between the two groups. Cases of pulmonary embolism was not noted in each group in our series, but entrapped thrombus during procedure was noted in 6 of 37 in the CDT with AT group and 0 of 9 in the CDT-alone group among 46 patients with prophylactic inferior vena cava (IVC) filter insertion. CONCLUSION: In conclusion, CDT with AT is safe and effective for the treatment of an acute iliofemoral DVT. In AT treatment, prophylactic IVC filter insertion should be considered for the prevention of pulmonary embolism by floating thrombi. PMID- 23646316 TI - Prevention of venous thromboembolism with enoxaparin in bariatirc surgery. AB - PURPOSE: Venous thromboembolism (VTE) after bariatric surgery is a significant cause of morbidity and mortality. Current modalities of thromboprophylaxis include subcutaneous injection of unfractionated or low-molecular-weight heparin (LMWH), pneumatic compression, elastic stockings, and inferior vena cava filters. Despite universal agreement on the need for thromboprophylaxis, no clear consensus has been reached regarding the best regimen and treatment duration of bariatric surgery. METHODS: From April, 2009 to December, 2011, we performed 200 bariatric surgery (191 with primary intent, 9 with revisional intent). There was no history of VTE prior to surgery. Clexane therapy was done with 4000 U SQ once daily for 2 weeks to the day before surgery. Development of VTE was assessed by direct interview, physical examination in out-patient clinic, and phone calls to patients for history taking if needed. The history taking was presented in questionnaire format. The patients were asked to state their symptoms of VTE by answering the questionnaire. The patients were followed up for a minimum of 6 months after surgery to determine the incidence of clinical VTE. RESULTS: Two week Clexane therapy was completed in 193 patients. Clexane was stopped in 5 due to surgical related complications (4 bleeding, 1 reoperation due to leak), in 2 due to Clexane related complications (1 epistaxis, 1 metrorrhagia). Follow-up of out-patient clinic were 68%, those who could follow up by telephone were 89%. There was no evidence of VTE. CONCLUSION: A 2-week VTE prophylaxis regimen using LMWH is simple, effective and associated with a low incidence of complications. PMID- 23646317 TI - Laparoscopy-assisted gastrectomy with para-aortic lymphadenectomy after palliative chemotherapy for advanced gastric cancer with isolated para-aortic lymph node metastasis. AB - Prophylactic para-aortic lymphadenectomy is not recommended in curable advanced gastric cancer. However, there are few reports on therapeutic para-aortic lymphadenectomy after palliative chemotherapy in far advanced gastric cancer. We report three cases of laparoscopy-assisted gastrectomy with para-aortic lymphadenectomy after palliative chemotherapy for the first time in Korea. Three gastric cancer patients with isolated para-aortic lymph node (PAN) metastasis showed partial response to capecitabine-based chemotherapy, and laparoscopy assisted gastrectomy with para-aortic lymphadenectomy was performed with curative intent. The mean total operation time was 365 minutes (range, 310 to 415 minutes), and the mean estimated blood loss was 158 mL (range, 125 to 200 mL). The mean number of retrieved PAN was 9 (range, 8 to 11), and all pathologic results showed no metastasis of para-aortic region. All patients recovered and were discharged without any significant complications. PMID- 23646318 TI - Heterotopic pancreas of the gallbladder associated with segmental adenomyomatosis of the gallbladder. AB - Heterotopic pancreas in the gallbladder is extremely rare and usually incidentally discovered at the pathologic examination followed by cholecystectomy for symptomatic gallbladder disease. Up to the presents, only about 30 cases have been reported. We report the case of a 36-year-old female who presented with symptoms of cholecystitis. The histological analysis followed by cholecystectomy revealed heterotopic pancreas of the cystic duct. PMID- 23646319 TI - Miniscrew design and bone response: defining a correlation. AB - AIM: This prospective clinical trial aims at correlating miniscrew implant (MSI) micro/macro architecture, the method of placement, and biologic markers in peri MSI crevicular fluid (PMICF) as indicators of bone response. A comparative evaluation of surface morphology of the MSIs before placement and after retrieval defines a correlation between the architecture of the MSIs and the bone- implant contact ratio. METHODS: Two types of MSIs (hybrid and cylindric) were placed in ten patients using a split-mouth technique with the aid of a restricted random number table. Each of the MSIs was placed in the intraradicular area between the second premolar and first molar in the attached gingiva, 4 mm from the cementoenamel junction. The MSIs were immediately loaded, and PMICF was collected on days 0, 7, 14, 21, 28, and 42 and evaluated using a standard laboratory protocol. Surface morphology before placement and after retrieval of the MSI was observed using scanning electron microscopy (SEM) at a magnification of *11, *40, and *1,000. RESULTS: Alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels observed were lower in the hybrid MSI in comparison to the cylindric MSI. For both MSIs, ALP and AST levels showed a trend of significant increase at days 0, 7, and 14 and then a significant decrease on days 21, 28, and 42. Observations from SEM showed an oxide layer over the entire surface of the bone expanding hybrid MSI; this layer was observed only at the tip of the cylindric MSI. CONCLUSIONS: Levels of both the diagnostic tissue destruction biologic markers ALP and AST are significantly higher in cylindric MSIs compared with hybrid MSIs, indicating a correlation to the type and method of placement of the MSI. The inflammatory markers show a definitive trend, with an elevation until day 14 and a decline after that, indicating an active inflammatory process until day 14 that could be correlated to tissue trauma. Observations from the SEM show a greater oxide layer formation in the hybrid MSI, which could imply a better bone-MSI contact ratio. PMID- 23646320 TI - In vitro evaluation of different methods of ligation on friction in sliding mechanics. AB - AIM: The aim of this study was to evaluate the effect of different methods of ligation in tie configurations on friction in dry and wet conditions. METHODS: Four methods of ligations were used: regular round tie, figure eight, twist, and diagonal. Materials used were Alastik (3M Unitek), Power O module (ORMCO), O-ring ligatures (JES), stainless steel ligatures (TP Orthodontics), 0.019 * 0.025-inch straight-length stainless steel archwires and stainless steel MBT 0.022-inch slot brackets (3M Unitek). RESULTS: Figure eight ligation had the highest friction, followed by round, twist, and diagonal ligation, in the descending order. Comparisons were statistically significant with a 100-g load. Dry group samples had higher friction than the wet group. These comparisons were statistically significant with a 50-g load. CONCLUSIONS: The study concluded that figure eight ligation had the highest friction, and diagonal ligation produced the least friction. Among the dry and wet groups, lubrication showed significant reduction in friction. PMID- 23646321 TI - Retention: type, duration and need for common guidelines. A survey of Norwegian orthodontists. AB - AIMS: To survey retention protocols and need for practical retention guidelines among orthodontists in Norway and to compare the results with similar studies in other countries. METHODS: A questionnaire was mailed to all members of the Norwegian Association of Orthodontists. It included questions about their background and their current retention protocol, as well as their perceived need for common retention guidelines. RESULTS: The response rate was 77.7% (69.3% males and 30.7% females). The most common maxillary retainer was a combination of a fixed and removable retainer, followed by a clear thermoplastic retainer. In the mandible, a fixed retainer bonded to all anterior teeth was most common (66.4%). Retention in the maxilla lasted 2 to 3 years (34.7%) or 3 to 5 years (23.8%). In the mandible, 41.5% of the orthodontists left the retainer in place for >5 years. When retention lasted more than 3 years, 70% of the orthodontists left the responsibility for retainer checkups to the patients or the general practitioners. The main reason for choosing a certain retention protocol was clinical experience (57.4%). Only 3.5% of the orthodontists based their protocols on information from the literature. Half?of the orthodontists, significantly women, expressed a need for common retention guidelines. CONCLUSIONS: In Norway, bonded retainers alone were reported to be most commonly used in the mandible, while bonded retainers used in combination with a removable retainer appear to be the most commonly used appliances in the maxilla. This is similar to the most frequently used retainers in other countries, but there are disparities in duration and follow-up protocols. Most female orthodontists desire common retention guidelines. PMID- 23646322 TI - Uprighting of mandibular second molars with the sectional modified Loca system. AB - A new way to upright the mandibular second molar is described. The principles of the Loca system, originally used for molar distalization, are employed in the mandibular arch. PMID- 23646323 TI - Orthodontic and orthognathic management of a complex mandibular asymmetry. AB - The application of a combined surgical-orthodontic procedure for the treatment of major facial deformities (eg, asymmetries) and associated malocclusions has become an increasingly prevalent treatment modality over the past few decades. Development of sound conjoint treatment principles made possible the correction of skeletal and dental dysplasias that were unyielding to either surgical or orthodontic treatment alone. The presence and severity of dentofacial asymmetries has been the subject of many commentaries and investigations. Treatment of facial asymmetry has always been a challenge with respect to the cause and the rationale behind the corrective procedures adopted. This case report describes a 23-year old male patient whose chief complaint was attributed solely to the clinically discernible facial asymmetry. A combined orthodontic and surgical approach was done to correct both the dental and skeletal asymmetry. The reasons for selecting this treatment protocol and the 5-year postretention stability of the final results obtained are highlighted in this report. PMID- 23646324 TI - Distalization of maxillary molars using a lever arm and mini-implant. AB - This article describes the orthodontic treatment of a young woman with a Class II malocclusion and maxillomandibular prognathism. One orthodontic mini- implant was placed in the posterior area of the palate to provide anchorage for?a transpalatal arch. The force for molar distalization was applied using an elastic chain from the lever arm inserted on the transpalatal arch to the mini-implant. Two sliding jigs were applied buccally as a complement for Class II malocclusion correction. This system created an efficient mechanotherapy for maxillary molar distalization. The active treatment period was 19 months. Normal overjet and reduction of maxillomandibular prognathism were obtained, and labial balance was improved. PMID- 23646325 TI - Osteogenesis imperfecta and pneumatization of bone-- a hidden reality. AB - Osteogenesis imperfecta is a bone disorder in which three factors that influence bone strength (quality, mass, and geometry of osseous tissue) are affected. Pneumatization refers to the development of air-filled cavities inside the bone. Knowledge about these air-filled cavities provides valuable information for understanding the diagnosis and spread of various pathologic entities like hemangiomas, giant cell tumors, eosinophilic granulomas, and even metastatic tumor deposits. This paper presents a case in which radiologic, clinical, biochemical, and karyotypic evaluations lead to a diagnosis of osteogenesis imperfecta. PMID- 23646326 TI - The use of miniscrew as orthodontic anchorage in correction of maxillary protrusion with occlusal cant, spaced arch, and midline deviation without surgery. AB - This report describes the use of the miniscrew as orthodontic anchorage in maxillary protrusion with a spaced arch and midline deviation in a 16-year-old female patient. In cases with midline deviation, a cant in the maxillary occlusal plane is often observed. Thus, the authors used the miniscrew to control the vertical dimension, thereby flattening the maxillary occlusal plane, and to close and retract the incisors to improve her convex profile. Effective incisor intrusion to correct the deep overbite was also observed. In addition, functional evaluation by a 6-degrees-of-freedom jaw movement recording system was performed. Significant improvement in the jaw movement was observed during maximum opening and lateral excursion during the retention phase. The authors suggest that miniscrews are effective in correcting midline deviation due to maxillary occlusal cant and intrusion and retraction of incisors, and may result in favorable functional movement of the jaw. PMID- 23646327 TI - The orthodontic and surgical management of Zimmerman-Laband syndrome. AB - Zimmermann-Laband syndrome (ZLS) is a rare autosomal disorder characterized by gingival fibromatosis, abnormalities of the nose and/or ears, hypoplasia of the nails or terminal phalanges of the hands and feet, hyperextensibility of joints, hepatosplenomegaly, hirsutism, and intellectual disability. The characteristics of the syndrome are highly variable and complicated. This paper reports a case of ZLS and the clinical manifestations encountered in relation to the current available literature. The comprehensive management of the patient's dentition is described, focusing on the orthodontic and surgical considerations clinicians should be aware of when treating patients with the syndrome. PMID- 23646328 TI - Modified fixed nanobite tandem appliance for rapid correction of developing Class III malocclusion. AB - AIM: Rapid correction of developing Class III malocclusion in pediatric patients using a method with decreased reliance on patient compliance and increased patient comfort. METHOD: The modified fixed nanobite tandem appliance (MFNTA) consists of three components, two fixed and one removable. The maxillary fixed appliance consists of a nickel-titanium fixed maxillary expander and a soldered buccal arm used for Class III elastic traction. The mandibular appliance consists of modified fixed nanobite and buccal headgear tubes welded to the mandibular first molar band for facebow attachment. RESULT: Pre- and posttreatment records revealed significant skeletal improvement without increase in the vertical dimension and marked improvement in facial balance and esthetics. CONCLUSION: MFNTA has the potential to be an effective tool in the treatment of developing Class III malocclusion and relief of the psychologic trauma caused by an anterior crossbite. PMID- 23646329 TI - Torque control in lingual orthodontics with lever arm mechanics: a case report. AB - The aim of this report is to illustrate treatment mechanics for torque control in lingual mechanotherapy using a lever arm and transpalatal arch (TPA) tab system during en masse retraction of anterior teeth. An 18-year-old female with bimaxillary dentoalveolar proclination with crowding was treated with a lever arm TPA tab system. The retraction tabs bent into the TPA placed across the maxillary second molars were used as anchorage. The retraction force on the maxillary anterior teeth was applied using lever arm hooks soldered between the lateral incisors and canines on a lingual mushroom archwire. By applying a retraction force to the lever arm hooks, the maxillary anterior teeth experienced greater palatal root movement as compared to the conventional retraction forces applied at the crown level. The tabs, placed high in the TPA, produced a distal tipping moment on the maxillary second molars, reinforcing their anchorage. The retraction force applied to the long lever arm hooks from the TPA tabs at the level of center of resistance (CRes) of anterior and posterior teeth is advantageous mainly in two aspects. First, it reinforces the anchorage, and second, it favors the palatal root movement of anterior teeth, thus obtaining better control over the torque during en masse retraction. PMID- 23646330 TI - Comparison of the effects of modified and full-coverage thermoplastic retainers on occlusal contacts. AB - AIM: The purpose of this prospective study was to determine the number of contacts in centric occlusion during retention with modified and full-coverage thermoplastic Essix retainers. METHODS: This research was based on 36 patients who were randomly assigned to wear either modified (18 patients) or full-coverage (18 patients) Essix retainers. Silicone-based bite registrations were used to record occlusal contacts at the beginning (T1), end of full-time (6 months; T2), and end of night-time (3 months; T3) wear of retainers. The occlusal contacts determined in treated patients were compared with the values of 18 untreated "normal" Class I subjects. Bonferroni-adjusted Wilcoxon and Kruskal-Wallis tests were used to evaluate intra- and intergroup differences. RESULTS: Total posterior contacts increased significantly at T3 compared to T1 and T2 only in the modified Essix group. Non-ideal and total contacts on premolars, non- ideal and actual contacts on first molars, and actual contacts on second molars increased significantly at T3 in the modified Essix group. No significant increase was determined in the final total posterior contacts in the full-coverage Essix group. Actual contacts on premolars and first molars and total posterior actual contacts were significantly greater at T3 in the modified Essix group compared to the full-coverage Essix Group. Also the number of final posterior ideal contacts in the modified Essix group was greater than in the normal sample. Total anterior contacts decreased significantly in the modified Essix group, whereas they increased significantly in the full-coverage Essix group. CONCLUSIONS: Increase in posterior contacts was achieved only during night-time wear of modified Essix retainers. PMID- 23646331 TI - Anteroposterior relationship of the maxillary central incisors to the forehead in adult white males. AB - AIM: To evaluate and compare the anteroposterior relationship of the maxillary central incisors to the forehead in white male adults with harmonious profiles and white male adult orthodontic patients. METHODS: Photographs of 101 white male adults with good facial harmony (control sample) were compared with photographs of 97 white male adults seeking orthodontic treatment (study sample). All were profile images with the maxillary central incisors and foreheads in full view. The images were imported into an image editing software program, resized, and rotated to the upright head position. Reference lines were constructed to assess the anteroposterior positions of the maxillary central incisors and forehead inclinations. RESULTS: In the control sample, the maxillary central incisors were positioned between the forehead facial axis (FFA) point and glabella in 91%, posterior to the FFA point in 8%, and anterior to the glabella in <1%. The position of the maxillary central incisors was moderately correlated with forehead inclination (r2 = 0.37). In the study sample, the maxillary central incisors were positioned between the FFA point and glabella in 34%, posterior to the FFA point in 59%, and anterior to the glabella in 7%. Maxillary central incisor position and forehead inclination were strongly correlated (r2 = 0.53). The anteroposterior maxillary incisor position relative to the forehead between the control and study groups was significantly different (P < .0001). In addition, the forehead inclination between the control and study group was significantly different (P < .05). CONCLUSION: The forehead is an important landmark for anteroposterior maxillary incisor positioning for adult white male patients seeking improved facial harmony. PMID- 23646332 TI - Controlling mechanical undesirable side effects with a tooth indicated for extraction: free anchorage. AB - This manuscript describes the use of a tooth indicated for extraction due to orthodontic reasons as an anchorage aid to receive undesirable side effects caused by orthodontic uprighting of a contralateral molar tooth. The mandibular right second molar was mesially tipped as a result of loss of the adjacent first molar. Since the treatment plan involved extraction of the mandibular left first premolar, undesirable side effects associated with the molar uprighting movement were transferred to this tooth. Once the second molar was vertical, the premolar was extracted and the treatment continued. The results suggest that treatment time can be reduced if undesirable orthodontic mechanical side effects can be directed to a tooth whose extraction is indicated. PMID- 23646333 TI - Prevention of enamel demineralization during orthodontic treatment: an in vitro comparative study. AB - AIM: Enamel demineralization is considered to be the most prevalent and significant iatrogenic effect associated with fixed orthodontic treatment and can seriously jeopardize both tooth longevity and dental esthetics. This in vitro study was undertaken to compare the effectiveness of four different commercially available surface treatment medicaments for the inhibition of enamel demineralization. METHODS: Seventy-five intact maxillary premolars extracted from patients undergoing orthodontic treatment were divided into five equal groups and were subjected to one of the following protocols: no treatment (control group) or treatment with one of the following four medicaments: fluoride varnish (Fluor Protector [FP]), casein phosphopeptide-amorphous calcium phosphate (GC Tooth Mousse [TM]), calcium sodium phosphosilicate (SHY-NM), and casein phosphopeptide amorphous calcium phosphate with fluoride (GC Tooth Mousse Plus [TMP]). All the teeth were subjected to ten Cate demineralization solution?for 96 hours and subsequently evaluated under polarized light microscopy to obtain the mean depths of enamel demineralization. One-way analysis of variance and Bonferroni comparison tests were used to obtain statistically significant differences between the five different groups at P < .05. RESULTS: All four surface treatment medicaments provided statistically significant reduction in the depths of enamel demineralization as compared with the control group. FP provided the greatest protection of enamel surface in terms of reduction of lesion depth, followed by TMP, SHY-NM, and TM. CONCLUSIONS: The use of these commercially available medicaments could prove to be beneficial for patients undergoing orthodontic treatment and who are at a risk for developing enamel decalcification. PMID- 23646334 TI - Unilateral scissors bite treated with a removable plate that incorporates a Ti-Ni wire. AB - A plate that incorporates a Ti-Ni alloy wire can rapidly correct scissors bite. This article describes its use in the successful treatment of scissors bite. A female patient aged 7 years, 5 months with mixed dentition presented with a Class I molar relationship, Class I skeletal pattern, and average Frankfort-mandibular plane angle. The maxillary right central incisor was in a crossbite. A unilateral posterior scissors bite was also present on the left side. The plate was fitted and prescribed for nighttime wear. Positive overjet was achieved after 1 month of treatment. The posterior scissors bite was corrected after 3 months of treatment, and the midline shift was ameliorated. Because a Ti-Ni wire maintained a weak continuous force, the treatment period was minimized. PMID- 23646335 TI - Maxillary molar distalization with the indirect Palatal miniscrew for Anchorage and Distalization Appliance (iPANDA). AB - AIM: Distalization of the maxillary molars is an important treatment option for the correction of Class II malocclusions. The purposes of this study were to introduce the clinical application of the indirect Palatal miniscrew Anchorage and Distalization Appliance (iPanda) and to describe the dental and skeletal effects obtained with this innovative appliance. METHODS: Pretreatment (TO), post distalization (T1), and posttreatment (T2) lateral cephalometric radiographs and dental casts of 20 consecutively treated adult patients (mean age 23.2 +/- 4.7 years) with Class II molar relationship were analyzed. All patients were treated with the iPanda for maxillary molar distalization. The iPanda was anchored on a pair of midpalatal miniscrew implants to deliver the distalizing force to the maxillary first molars. The iPanda was the only appliance used during the distalization phase of treatment. A paired t test analysis was used to statistically assess the effects of treatment. RESULTS: A Class I molar relationship was obtained in a mean period of 3.2 +/- 0.6 months. Cephalometric analysis demonstrated that the maxillary first molars were significantly distalized by an average 4.5 +/- 1.5 mm (P < .001) and were intruded by a mean of 1.0 mm +/- 0.8 mm (P < .05). No significant change in the inclination of the first molars was observed. No significant change in the mandibular plane was observed. Dental model analysis demonstrated an asymmetric pattern of distalization between right (4.5 +/- 2.2 mm) and left (3.1 +/- 2.1 mm) first molars. The transverse width of the dental arch was maintained. No significant rotation of the first molars was observed. CONCLUSIONS: This study demonstrated that the innovative iPanda is effective to bodily distalize the maxillary molars into a Class I molar relationship and to provide maximum anchorage. PMID- 23646336 TI - Changes in nasal profile following maxillomandibular osteotomy for prognathism. AB - AIM: This article is based on a pre- and postoperative retrospective analysis of a sample of patients affected by progenic syndrome who underwent maxillary bone repositioning by maxillomandibular osteotomies. Pre- and postoperative clinical, photographic, and cephalometric analysis are carried out to assess modifications of the nasal shape due to maxillary osteotomies. METHODS: The sample group studied was made up of 25 patients (13 women, 12 men) who underwent orthodontic surgical treatment for correction of maxillomandibular deformities. The sample group was divided into two groups: the first (group A) was made up of patients who underwent maxillomandibular repositioning with advancement and lowering of the maxilla, and the second (group B) comprised patients who, as a consequence of surgical repositioning, had a maxilla that was advanced and raised. Surgical treatment was based on Le Fort I and quadrangular Le Fort osteotomies. CONCLUSION: Evaluation of angular and linear measurements, derived from both photographic and cephalometric material, allowed the authors to compare the two groups of patients and the modifications of the nasal region. These results are then compared with those available from current scientific literature so as to define the predictability of nasal shape modification. In conclusion, it is inadvisable to perform rhinoplasty at the time of orthognathic surgery to correct pre-existing defects, such as a dorsal hump, a nasal base that is too wide or too narrow, a nasal pyramid deviation, or other esthetic defects resulting from orthognathic surgery. PMID- 23646337 TI - Determination of optimum adhesive thickness using varying degrees of force application with light-cured adhesive and its effect on the shear bond strength of orthodontic brackets: an in vitro study. AB - AIM: The thickness of the adhesive layer under a bracket may be an important factor that affects the final tooth position and bond strength. With increasing use of preadjusted brackets, it is important to ensure that a consistently even layer of composite is placed under each bracket to take full advantage of bracket design and to avoid the need for compensatory bends to be placed in the archwire. Therefore, the present study is aimed at determining the optimum adhesive thickness by varying the force of application and observing the effect on the shear bond strength of orthodontic brackets. METHODS: Sixty premolars extracted for orthodontic purposes were divided into three groups of 20 samples each. Adhesive thickness was measured by varying the force of application while bonding brackets with light-cured adhesive and tested on a universal testing machine to evaluate the shear bond strength. RESULTS: The study showed that adhesive thickness is inversely proportional to applied force. In addition, the shear bond strength has a tendency to increase with a decrease in adhesive thickness up to a certain extent and then decrease. CONCLUSION: Adhesive thickness between bracket base and tooth surface decreases with an increase in the amount of force application from 1 to 3 oz. Mean shear bond strength increases when adhesive thickness decreases from 0.99 to 0.83 mm, and then it has a tendency to decrease when adhesive thickness decreases to 0.72 mm. Optimum adhesive thickness should be considered to be 0.83 mm, which is the thickness required to achieve sufficient bond strength to prevent chances of bond failure. PMID- 23646339 TI - Color stability of five orthodontic clear elastic ligatures. AB - AIM: In this study the color stability of five commercially available orthodontic clear elastic ligatures daily exposed to a staining agent (red wine) was investigated. METHODS: The commercial brands tested were 3M Unitek, Abzil, American Orthodontics, Dentsply GAC, and Morelli. Baseline color readings (Commission Internationale de l'Eclairage [CIE] L*a*b* parameters) of 20 ligatures for each brand were carried out using a spectrophotometer. The ligatures were divided in two groups (n = 10): one group remained immersed in distilled water (control) throughout the period, while the other group was daily exposed to red wine (1 hour of immersion). Immersion media were daily renewed. Successive color readings were carried out after 7, 14, 21, and 28 days, and the chromatic variations calculated. Color variation data were analyzed by two-way repeated measures analysis of variance and Student-Newman-Keuls test (P < .05). RESULTS: Storage in water increased staining until 14 days, and color receded after this period, irrespective of the brand. After 28 days of immersion in water, no significant difference among the commercial brands was observed. For the groups exposed to red wine, a significant increase in staining over the course of time was detected, irrespective of the brand. Ligatures from GAC and Morelli showed higher staining than the other materials, irrespective of the evaluation time. Ligatures from 3M Unitek and American generally showed lower pigmentation than the other brands. CONCLUSION: Exposure to a staining agent, cumulative exposure time, and commercial brand are factors that influence the color stability of clear elastic ligatures. PMID- 23646338 TI - Growth modulation using functional appliances--cephalometric predictors of successful response. AB - AIM: The aim of this study was to determine any skeletal morphologic features evident on a pretreatment lateral cephalogram that may be used to predict improvement in the sagittal relationship during functional appliance therapy in Class II patients and compare changes between cases with and without a favorable response to growth modulation. METHOD: Pretreatment and postfunctional lateral cephalograms were analyzed, and the change in the ANB angle was used to determine the skeletal response to treatment with a functional appliance. Based on the change in the ANB angle, the patients were divided into two groups of 12 patients each. Comparisons were made between the mean pretreatment (T1) cephalometric parameters of group I (skeletal) and group II (nonskeletal) to assess any pretreatment parameters that were significantly different between the groups. Changes due to functional appliance therapy from the pretreatment (T1) to postfunctional (T2) stage was measured as T2-T1 in both groups. The mean changes seen in group I and group II were then compared to assess the difference between changes brought about by growth modulation using functional appliances. Comparative statistical analysis of the data was done using one-way analysis of variance F test. RESULTS AND CONCLUSION: This study showed that not all cases respond favorably to growth modulation. The pretreatment parameters that correlated to a favorable response were low mandibular plane angle, low basal plane angle, and a high Jarabak ratio. In those cases that responded favorably, the changes seen were an increase in Co-Go (ramus height), decrease in overjet, increase in SNB, and increase in the Jarabak ratio. PMID- 23646340 TI - Relationship between crown-root angulation (collum angle) of maxillary central incisors in Class II, division 2 malocclusion and lower lip line. AB - AIM: The present study aimed to measure the magnitude of the collum angle (crown root angulation) of maxillary central incisors present in Class II, division 2 malocclusion and to relate the changes in its magnitude with variations in the lower lip line. METHODS: A set of 120 conventional lateral cephalograms were selected and divided into three groups of 40 each based on the type of malocclusion presented: Class II, division 2 (group 1); Class II, division 1 (group 2); and Class I (group 3). The collum angle of the maxillary central incisor was measured, and the lower lip line was recorded. RESULTS: Analysis of variance (ANOVA) revealed that the mean collum angle was statistically significantly different in the three groups. The mean collum angle was greatest in Class II, division 2 malocclusion (group 1). The mean collum angles were 3.24 +/- 4.69 degrees, 0.95 +/- 1.06 degrees, and 1.05 +/- 1.50 degrees in groups 1, 2, and 3 respectively. In chi 2 test comparison of the location of the lower lip line (incisal, middle, or apical third of the central incisor) among the three groups, the lower lip line was found to contact the middle third of the central incisor most frequently in Class II, division 2 malocclusion. ANOVA followed by Tukey honestly significant difference (HSD) test showed that the mean collum angle is significantly increased when the lower lip is in the middle third (P < .05) of the central incisor. CONCLUSION: Variations in magnitude of the collum angle with the change in the lower lip line suggest a probable etiologic role of the lower lip line in the development of the collum angle. PMID- 23646341 TI - Nickel and chromium levels in the saliva of patients with fixed orthodontic appliances. AB - AIM: The purpose of this study was to investigate the salivary concentration of nickel and chromium of patients undergoing orthodontic treatment. METHODS: In this study 32 patients who presented to the orthodontic clinic were selected. The salivary samples were taken from the patients in four stages: before appliance placement and 20 days, 3 months, and 6 months following appliance placement. The salivary samples were collected in a plastic tube and were stored in the freezer before analysis. The samples were then transferred to the laboratory, and the amounts of metals were determined by graphite furnace atomic absorption spectrometry with an autosampler. Each sample was analyzed three times, and the average was reported. RESULTS: It was found that the average amount of nickel in the saliva 20 days after appliance placement was 0.8 MUg/L more than before placement. Also, the amount of salivary nickel 20 days after the appliance placement was more than at the other stages, but the differences were not significant. The average amount of chromium in the saliva was found to be between 2.6 and 3.6 MUg/L. The amount of chromium at all stages after appliance placement was more than before, but the differences between the chromium levels of saliva at all stages were not significant. CONCLUSION: There was no significant difference in the average amount of salivary nickel and chromium of patients at various stages of orthodontic appliance placement. PMID- 23646343 TI - Individualized orthodontic treatment: The Insignia system. AB - This clinical report presents a case treated by a currently available customized orthodontic treatment system. The use of patient-specific brackets, indirect bonding transfer devices, and customized archwires decreases treatment and chairside time, making orthodontic cases more predictable, accurate, and efficient. The need for time-consuming adjustments is greatly reduced, and appliance customization further facilitates the achievement of the final desired occlusion from the first day of treatment. PMID- 23646342 TI - Shear bond strength of orthodontic brackets bonded to porcelain following etching with Er:YAG laser versus hydrofluoric acid. AB - AIM: The purpose of the present study was to evaluate the shear bond strength of orthodontic brackets bonded to porcelain following etching with erbium-doped yttrium aluminum garnet (Er:YAG) laser compared with 9.6% hydrofluoric acid (HF). METHODS: A total of 100 porcelain disk samples were divided into four groups, and after removing their glazed layer, the first group was etched with 9.6% HF, and the other three groups were etched with Er:YAG lasers of 1.6, 2, and 3.2 W, respectively. After application of silane on the disk surfaces, central incisor brackets were bonded with composite on the disks. The disks were mounted on an acrylic stand for measuring the shear bond strengths. The shear bond strengths were measured by a testing machine. RESULTS: The mean shear bond strength in the laser group with power of 1.6 W (7.88 MPa) was more than that of the HF (7.4MPa), 2-W power (7.52 MPa), and 3.2-W power (7.45 MPa) groups, but this difference was not statistically significant. Examination with an electron microscope showed different patterns of etching by HF and laser. Also, etching by laser and HF had not resulted in cracks on the porcelain surface. CONCLUSION: Er:YAG laser can be a suitable method for bonding of orthodontic brackets to porcelain surfaces. PMID- 23646344 TI - Speedy orthodontics: a case report. AB - Management of severe rotation poses a great challenge for the orthodontist, especially when cortical anchorage occurs. The conventional methods require excessive treatment time, rely on patient compliance, and can cause root resorption. A groundbreaking new procedure developed by Wilcko et al, which is actually a modification of the conventional corticotomy procedure, amalgamates the orthodontic mechanics, alveolar decortications, and augmentation procedure to make treatment time three to four times faster than conventional orthodontic techniques. This procedure uses the dynamics of bone physiology and redirects the emphasis in tooth movement to the manner in which supporting bone responds to orthodontic forces applied to the tooth. This article includes a case report in which the technique is used on a patient who has a severely rotated mandibular left canine. PMID- 23646345 TI - Comparative local analysis of metabolites, lipids and proteins in intact fish tissues by LAESI mass spectrometry. AB - Direct mass spectrometric analysis of animal tissues is an emerging field enabled by recent developments in ambient ion sources. Label-free in situ analysis of metabolites, lipids, and peptides/proteins from intact tissues in whole fish specimens of different gender and age were performed by laser ablation electrospray ionization (LAESI) mass spectrometry (MS). Hypertrophied glandular tissue (gill gland) of adult male Aphyocharax anisitsi (bloodfin tetra) was compared with gill tissues in females of the same species. Comparison of a large number of sample-specific ions was aided by a multivariate statistical method based on orthogonal projections to latent structures discriminant analysis. More than 200 different ions were detected in the mass spectra corresponding to primary metabolites, hormones, lipids and peptides/proteins. The gill tissues of the sexually mature males exhibited multiply charged ions in the 6+ to 10+ charge states corresponding to a protein with a molecular weight of 11 380 Da. This protein was present only in the mature male gill glands but absent in the corresponding area of the female and immature male specimens. An additional nine proteins were detected by LAESI-MS in both the male and female gill tissues. PMID- 23646346 TI - Label-free methods of reporting biomolecular interactions by optical biosensors. AB - Reporting biomolecular interactions has become part and parcel of many applications of science towards an in-depth understanding of disease and gene regulation. Apart from that, in diagnostic applications where biomolecules (antibodies and aptamers) are vastly applied, meticulous monitoring of biomolecular interaction is vital for clear-cut diagnosis. Several currently available methods of analyzing the interaction of the ligands with the appropriate analytes are aided by labeling using fluorescence or luminescence techniques. However, labeling is cumbersome and can occupy important binding sites of interactive molecules to be labeled, which may interfere with the conformational changes of the molecules and increase non-specificity. Optical based sensing can provide an alternative way as a label-free procedure for monitoring biomolecular interactions. Optical sensors affiliated with different operating principles, including surface plasmon changes, scattering and interferometry, can impart a huge impact for in-house and point-of-care applications. This optical-based biosensing permits real-time monitoring, obviating the use of hazardous labeling molecules such as radioactive tags. Herein, label-free ways of reporting biomolecular interactions by various optical biosensors were gleaned. PMID- 23646348 TI - The catalytic versatility of low toxicity dialkyltriazolium salts: in situ modification facilitates diametrically opposed catalysis modes in one pot. AB - The ability of triazolium salts to serve as a precatalyst for both an acid and a powerful base/nucleophile (controlled by additives) has been exploited in a process characterised by a unique in situ catalyst modification strategy. PMID- 23646347 TI - A bioreducible linear poly(beta-amino ester) for siRNA delivery. AB - Described here is the synthesis and characterization of a novel, bioreducible linear poly(beta-amino ester) designed to condense siRNA into nanoparticles and efficiently release it upon entering the cytoplasm. Delivery of siRNA using this polymer achieved near-complete knockdown of a fluorescent marker gene in primary human glioblastoma cells with no cytotoxicity. PMID- 23646349 TI - Simultaneous electrochemical synthesis of few-layer graphene flakes on both electrodes in protic ionic liquids. AB - Here we illustrate a simple and moderate electrochemical strategy to simultaneously harvest high-quality few-layer graphene flakes (<5 layers) from both a graphite anode and a graphite cathode in the protic ionic liquids. Specifically, the graphene flakes detached from cathodic graphite receive a defect healing. PMID- 23646350 TI - A high energy density all solid-state tungsten-air battery. AB - An all solid-state tungsten-air battery is reported here, which is based on a new metal-air chemistry, featuring decoupled design of electrodes and energy storage. Benefited from higher specific density and better redox kinetics of tungsten, the new tungsten-air battery exhibits roughly higher energy density (W h L(-1)) than the previously reported iron-air battery. PMID- 23646351 TI - Mechanochemistry: a web themed issue. PMID- 23646352 TI - A rapid identification of hit molecules for target proteins via physico-chemical descriptors. AB - We report here a novel computationally fast protocol (RASPD) for identifying good candidates for any target protein from any molecule/million molecule database. A QSAR-type equation sets up the extent of complementarity of the physico-chemical properties of the target protein and the candidate molecule and an estimate of the binding energy is generated. A correlation coefficient of 0.84 and an average error +/-1.45 kcal mol(-1) are obtained for the calculated protein-ligand binding energies against experiment for more than 380 protein-ligand complexes. RASPD is seen to perform better than other popular scoring functions in predicting binding energies. The most interesting feature of this methodology is that it takes only a fraction of a second for calculating the binding energy of any ligand without docking in the active site of the target protein as opposed to several minutes for regular docking and scoring methods, while the accuracy in sorting good candidates remains comparable to that of conventional techniques. An entire million compound library, a (~10(5) compound) natural product library and a (~10(5) compound) NCI database can be scanned against a specified target protein within a few minutes for identifying hit molecules. The RASPD methodology is freely accessible at . PMID- 23646353 TI - A simple reduction process to synthesize MoO2/C composites with cage-like structure for high-performance lithium-ion batteries. AB - Large-scale MoO2/carbon composites with a cage-like nanostructure have been synthesized by a simple hydrothermal reduction process. During the hydrothermal process, ammonium molybdate tetrahydrate ((NH4)6Mo7O24.4H2O) was employed as starting material and ascorbic acid as a structure directing agent, reductive agent and carbon source. MoO2/C nanospheres with diameters of about 15-25 nm were interconnected to form a cage-like architecture. Time-dependent experiments illustrated that the cage-like structure was transformed from tightly packed MoO2 nanoparticles. Furthermore, with a water-soluble binder (sodium alginate), the cage-like MoO2/C composites exhibited a high discharge capacity and significantly improved cycling performance compared to previously reported MoO2-based anode materials. The electrodes with the MoO2/C composites can deliver a capacity of 692.5 mA h g(-1) after 80 charge-discharge cycles at a current density of 200 mA g(-1). After C-rate measurement, the battery still can maintain excellent cycling stability (about 550 mA h g(-1) reversible capacity retained even after 475 cycles). The excellent electrochemical performance can be ascribed to the cage like structure, which integrates three advantages: porous structure, interconnected MoO2/C framework and small nano-crystals. PMID- 23646354 TI - beta-MnO2 as a cathode material for lithium ion batteries from first principles calculations. AB - The search for excellent cathodes for lithium batteries is the main topic in order to meet the requirements of low cost, high safety, and high capacity in many real applications. beta-MnO2, as a potential candidate, has attracted great attention because of its high stability and potential high capacity among all the phases. Because of the complexity of beta-MnO2, some fundamental questions at the atomic level during the charge-discharge process, remain unclear. The lithiation process of beta-MnO2 has been systematically examined by first-principles calculations along with cluster expansion techniques. Five stable configurations during the lithium intercalation process are firstly determined, and the electrochemical voltages are from 3.47 to 2.77 eV, indicating the strongly correlated effects of the beta-MnO2-LiMnO2 system. During the lithiation process, the changes in the lattice parameters are not symmetric. The analysis of electronic structures shows that Mn ions are in the mixed valence states of Mn(3+) and Mn(4+) during the lithiation process, which results in Jahn-Teller distortion in Mn(3+)O6 octahedra. Such results uncover the intrinsic origin of the asymmetric deformation during the charge-discharge process, resulting in the irreversible capacity fading during cycling. From the analysis of the thermal reduction of delithiated LixMnO2, the formation of oxygen is thermodynamically infeasible in the whole extraction process. Our results indicate that beta-MnO2 has great potential as a cathode material for high capacity Li-ion batteries. PMID- 23646355 TI - Molecular spectroscopy and dynamics: a polyad-based perspective. AB - The efficiency and insight of global, polyad-based modeling in overtone spectroscopy and dynamics is demonstrated. Both vibration and vibration-rotation polyads are considered. The spectroscopic implications of polyad Hamiltonians derive from their ability to account for the detailed line positions and intensities of spectral features and their unique predictive power. The dynamical implications of polyad Hamiltonians include classical bifurcations that lead to the birth of new vibrational modes and intramolecular vibrational-rotational energy redistribution over multiple timescales. The literature is reviewed, with emphasis on acetylene results. PMID- 23646356 TI - Can mitochondrial dysfunction be initiated by dissociative electron attachment to xenobiotics? AB - Resonance attachment of low-energy electrons to xenobiotic molecules, 2,4 dichlorophenoxyacetic acid (2,4-D), dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE), was investigated under gas-phase conditions by means of complementary experimental techniques. Electron transmission spectroscopy (ETS) and dissociative electron attachment spectroscopy (DEAS), in the 0-6 eV and 0-15 eV energy range, respectively, were applied with the aim of modeling the behavior of these pesticide molecules under reductive conditions in vivo. Formation of long-lived parent molecular anions and fragment negative ions was observed at incident electron energies very close to zero, in agreement with the results of density functional theory calculations. The gas phase DEA process, analogous to dissociative electron transfer in solution, was considered as a model for the initial step which occurs in the intermembrane space of mitochondria when a xenobiotic molecule captures an electron "leaked" from the respiratory chain. A possible involvement of the fragments produced by DEA to the pesticides under investigation into cellular processes is discussed. It is concluded that the free radicals and potential DNA adducts formed by DEA are expected to be dangerous for mitochondrial functionalities, while several of the products observed could act as messenger molecules, thus interfering with the normal cellular signaling pathways. PMID- 23646357 TI - Study of the tryptophan-terbium FRET pair coupled to silver nanoprisms for biosensing applications. AB - Plasmonic coupling between fluorophores and metal surfaces has become a focal point of optical research during the last two decades, however, the interactions of FRET couples with metal surfaces remain relatively unexplored. In this study, interactions of the tryptophan-Tb(3+) FRET pair with silver nanoprisms for potential biosensor development have been investigated. For this purpose an engineered lanthanide binding peptide (LBTtrp) containing tryptophan as the sensitizer for bound lanthanide ions (Tb(3+)) as well as a trypsin cleavage site was synthesized. The modified LBTtrp peptide contained two N-terminal cysteine residues to provide a stronger coupling to the silver nanoprisms (~6 nm high, ~50 nm wide). This study investigated the interaction between tryptophan, chelated Tb(3+) ions, and silver nanoprisms in solution using fluorescence and transient absorption spectroscopy. We have found that Tb(3+) luminescence decreases upon binding of the LBTtrp-Tb(3+) to silver nanoprisms and increases upon trypsin cleavage. The transient absorption spectroscopy measurements showed a significant decrease in the lifetime of the excited singlet state of tryptophan upon Tb(3+) chelation, while coupling to the silver nanoprisms did not show a significant effect on tryptophan. The results obtained in this work demonstrate a first proof of concept for a new sensitive optical biosensor in solution. PMID- 23646358 TI - Screening metal-organic frameworks for selective noble gas adsorption in air: effect of pore size and framework topology. AB - The adsorption of noble gases and nitrogen by sixteen metal-organic frameworks (MOFs) was investigated using grand canonical Monte Carlo simulation. The MOFs were chosen to represent a variety of net topologies, pore dimensions, and metal centers. Three commercially available MOFs (HKUST-1, AlMIL-53, and ZIF-8) and PCN 14 were also included for comparison. Experimental adsorption isotherms, obtained from volumetric and gravimetric methods, were used to compare krypton, argon, and nitrogen uptake with the simulation results. Simulated trends in gas adsorption and predicted selectivities among the commercially available MOFs are in good agreement with experiment. In the low pressure regime, the expected trend of increasing adsorption with increasing noble gas polarizabilty is seen. For each noble gas, low pressure adsorption correlates with several MOF properties, including free volume, topology, and metal center. Additionally, a strong correlation exists between the Henry's constant and the isosteric heat of adsorption for all gases and MOFs considered. Finally, we note that the simulated and experimental gas selectivities demonstrated by this small set of MOFs show improved performance compared to similar values reported for zeolites. PMID- 23646359 TI - Cervical intramedullary ependymoma masquerading as cervical spondylotic myelopathy on MRI analysis. PMID- 23646360 TI - Erratum to "Applicability of in vitro tests for skin irritation and corrosion to regulatory classification schemes: substantiating test strategies with data from routine studies" [Regul. Toxicol. Pharmacol. (2012) 402-414]. AB - Skin corrosion or irritation refers to the production of irreversible or reversible damage to the skin following the application of a test substance, respectively. Traditionally, hazard assessments are conducted using the in vivo Draize skin test, but recently in vitro tests using reconstructed human epidermis (RhE) models have gained regulatory acceptance. In this study, skin corrosion (SCT) and irritation tests (SIT) using a RhE model were implemented to reduce the number of in vivo tests required by regulatory bodies. One hundred and thirty four materials were tested from a wide range of substance classes included 46 agrochemical formulations. Results were assessed according to UN GHS, EU-CLP, ANVISA and US EPA classification schemes. There was high correlation between the two in vitro tests. Assessment of the SCT sensitivity was not possible due to the limited number of corrosives in the data set; SCT specificity and accuracy were 89% for all classification systems. Accuracy (63-76%) and sensitivity (53-67%) were low in the SIT. Specificity and concordance for agrochemical formulations alone in both the SCT and SIT were comparable to the values for the complete data set (SCT: 91% vs. 89% specificity, 91% vs. 89% accuracy and SIT: 64-88% vs. 70 85% specificity, 56-75% vs. 63-76% accuracy). PMID- 23646361 TI - In memory of Professor Hideshi Kobayashi. PMID- 23646362 TI - Plan for the future. PMID- 23646363 TI - Fields of gold. PMID- 23646364 TI - Freed speech. PMID- 23646365 TI - Crowd-funding: Cash on demand. PMID- 23646368 TI - Response to letter regarding article, "Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging". PMID- 23646369 TI - Response to letter regarding article, "Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type". PMID- 23646370 TI - Response to letter regarding article, "Atrial fibrillation and the risk of ischemic stroke--does it still matter in patients with a CHA2DS2-VASc score of 0 or 1?". PMID- 23646371 TI - Response to letter regarding article, "Incidence of infective endocarditis due to viridans group streptococci before and after publication of the 2007 American Heart Association's endocarditis prevention guidelines". PMID- 23646372 TI - Too many statistical errors for meaningful interpretation. Response to letter to the editor. PMID- 23646373 TI - Earwax type and osmidrosis: prognostic factor for breast cancer? Response to letter to the editor. PMID- 23646374 TI - Response to letters regarding article, "Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial". PMID- 23646375 TI - Regulatory science: Researchers in the pipeline. PMID- 23646376 TI - Payment for home health services and hospice care to non-VA providers. Final rule. AB - The Department of Veterans Affairs (VA) amends its regulations concerning the billing methodology for non-VA providers of home health services and hospice care. Because the newly applicable methodology cannot supersede rates for which VA has specifically contracted, this rulemaking will only affect home health and hospice care providers who do not have existing negotiated contracts with VA. This rule also rescinds internal guidance documents that could be interpreted as conflicting with this final rule. PMID- 23646377 TI - The importance of proper concussion management. PMID- 23646381 TI - Existence of 'food deserts' questioned. PMID- 23646382 TI - HIV and AIDS surveillance. PMID- 23646383 TI - Communicable diseases surveillance. National Notifiable Diseases Surveillance System. PMID- 23646384 TI - Childhood obesity possibly linked to caesarean delivery. PMID- 23646386 TI - Communicable diseases surveillance. Tables. PMID- 23646385 TI - Communicable diseases surveillance. PMID- 23646388 TI - Communicable diseases surveillance. PMID- 23646387 TI - [Comments on the suture technic of m. levatoris without pelvic floor defects]. PMID- 23646389 TI - [Treating stress incontinence safely, gently, simply]. PMID- 23646390 TI - [Transobturator route with low morbidity]. PMID- 23646391 TI - [Pediatric urology at the 58th Urology Congress]. PMID- 23646392 TI - [Management assumes surgical division of WaveLight AG]. PMID- 23646393 TI - [ASCO 2006: temsirolimus increases survival]. PMID- 23646394 TI - [Laparoscopy belongs today to the modern standard in urology]. PMID- 23646395 TI - [Dutasteride provides chemoprevention]. PMID- 23646396 TI - [Drug now immediately available in Germany]. PMID- 23646397 TI - [Changes in the incontinence aids directory]. PMID- 23646398 TI - [Alkalicitrate continued insurance coverage]. PMID- 23646399 TI - [Especially the elderly and diabetic patients are affected]. PMID- 23646400 TI - [As always, still current]. PMID- 23646401 TI - [High patient satisfaction with the transdermal system]. PMID- 23646402 TI - Aware of the heart. PMID- 23646403 TI - Spoiled identity. PMID- 23646404 TI - The health care question. PMID- 23646405 TI - Romneycare and HIV/AIDS. PMID- 23646406 TI - Take two apps and call me in the morning. PMID- 23646407 TI - Model behavior. PMID- 23646408 TI - Hooking up to social media. PMID- 23646409 TI - A pill to prevent HIV. PMID- 23646410 TI - Going back to basics. PMID- 23646411 TI - Age discrimination lies behind poor diabetes care. PMID- 23646412 TI - Care of older people will be litmus test for renewed NHS. PMID- 23646414 TI - Why not share the cost of growing old? PMID- 23646413 TI - Campaign piles on pressure to end two decades of hospital food failure. PMID- 23646415 TI - Dignity and continence care. PMID- 23646416 TI - The mental capacity act and dementia research. AB - For research to have an impact on people with dementia, they need to be involved in studies. However, undertaking research with participants who may lack capacity to consent poses many challenges for researchers. This article explores the practical application of the Mental Capacity Act 2005 in the process and provides realistic advice on implementing its principles in research. The Integrated Research Application System, NHS research ethics committees and NHS research and development departments can provide additional guidance. Knowledge of the practicalities of implementing aspects of the act that relate to research will ensure that researchers who wish to involve people with dementia can do so with ethical expertise. PMID- 23646417 TI - Attitudes towards caring for older people: literature review and methodology. AB - Care of older people is often referred to as a 'Cinderella' service and is not seen as an attractive career option in health care, but with the global population continuing to age, caring for this group will become increasingly important. This article outlines the literature that formed the basis for two studies investigating the attitudes of healthcare staff towards working with older people, including respondents' perceptions of other healthcare professionals' attitudes toward this important area of work. The Multifactorial Attitudes Questionnaire was designed to examine five major themes identified from the literature: ageism; learning environment; working environment; professional esteem; and specialist status. This study is presented in two parts: this article discusses the literature and the design of the questionnaire. The second article, to be published in a subsequent issue of the journal, presents the results from two studies done in Scotland, the first in 1999, with a replication study in 2009. PMID- 23646418 TI - Bringing memories to life. AB - Age Exchange is a charity based in south London that uses reminiscence-based creative activities to engage older people with dementia and mental health problems. The charity celebrates its 30th anniversary this year. It provides training for health and social care staff in the practical application of reminiscence work and programmes designed to promote learning, creativity and understanding between generations. PMID- 23646420 TI - Living every moment. PMID- 23646419 TI - Identification and management of patients' nutritional needs. AB - As individuals age a number of physical and cognitive changes affect their nutritional intake. Sensory losses affect the ability to obtain food or eat independently, while cognitive changes, such as dementia, may affect a person's understanding of how to eat. This article aims to familiarise readers with the main concerns associated with caring for older people's nutritional needs while they are in hospital. Strategies to address these challenges are presented. If they are not addressed, they can have major implications for patient recovery and discharge planning. PMID- 23646421 TI - [Supracricoid partial laryngectomy]. PMID- 23646422 TI - [Cochlear implants for the patients with cochlear nerve defects]. AB - OBJECTIVE: By watching the effects of cochlear implants in the children with cochlear nerve defects, to evaluate the relationship and efficiency of HRCT AND MRI in diagnostic for cochlear nerve defects. METHOD: The imaging dates and the post-operative effects of the 10 cochlear nerve defect patients were retrospectively analyzed. RESULT: Three patients with bilateral IAC stenosis by HRCT and cochlear nerve defects by MRI but no other abnormal. Seven other patients showed normal IAC by HRCT including 1 showed type IP- I plus vestibular semi circular canal dysplasia. These 7 patients MRI showed 3 bilateral cochlear nerve absent and 4 bilateral cochlear nerve dysplasia. Ten cases of children after 12-32 month follow-up, 3 patients began speaking simple language, whose MAIS scale, CAP and SIR scores improved. One case just began speaking but pronunciation vague. Four cases had reactions to sounds, and can say monosyllabic words. Two cases without effects (1 CI abolished). Compared with other patients with normal cochlear nerve, the effects of the 10 cases were disappointed. CONCLUSION: The effects of cochlear implant for the patients with cochlear nerve defects were poor. The preoperative MRI as sessment including oblique sagittal view for cochlear nerve is necessary. The preoperative communication with the parents telling ineffective result possibility is important. PMID- 23646423 TI - [Electrophysiological characteristics of EABR and its value assessment of cochlear implant]. AB - OBJECTIVE: To evaluate the electrophysiological characteristics of electrically evoked auditory brainstem responses (EABR) and its application in cochlear implantation, especially in evaluating acoustic nerve survival. METHOD: An auditory evoked potential instrument was used to record responses and Cochlear Nucleus 24CA implants were used to generate electrical stimulation. We measured EABR in 23 patients with cochlear implants and compared EABR with behavioral measures and neural response telemetry (NRT). RESULT: EABR III-V waveforms were recognized in all of the 23 patients. The characteristics and origins of EABR waveforms were similar to those of ABR. The average EABR threshold was (172.61 +/ 14.61) CL. At 20 CL above threshold, the average latencies of Wave III, V were (2.93 +/- 0.18)ms, (4.80 +/- 0.28)ms which were 1-2 ms shorter than ABR latencies. But III-V intervals remained at (1.86 +/- 0.18)ms. EABR thresholds were strongly correlated with behavioral performance and NRT thresholds, while EABR input-output function is correlated with behavioral dynamic range (DR). CONCLUSION: EABR is such an effective method to objectively evaluate the function of auditory pathway which can estimate residual spiral ganglion cell count. This is consistent with the foreign study leading to the conclusion that DR reflects spiral ganglion cell survival. PMID- 23646424 TI - [Outcome analysis of hearing aids fitting for 2 635 hearing-impaired people]. AB - OBJECTIVE: To investigate the reasons that hearing-impaired patients who owned the indication of hearing aid fitting but were not successfully fitted. METHOD: Analyzing the records of hearing aid fitting for 2 635 hearing-impaired people from 2005 to 2010, especially for the people who were not successfully fitted. RESULT: In general, there were 1 700 people having proper hearing aids. The success rate of hearing aid fitting is 64.52%, which increased year by year. According to the analysis of records about hearing-impaired people who were not successfully fitting, the primary factor was economic constraints (23.64%), the second was the patients could not accept them (18.61%), and the third was acceptation and satisfaction for the professional centers (10.27%). The another factor also included the dissatisfaction for the hearing aid (8.13%). Meanwhile, it showed the success rate in the auditory specialist clinic was significantly lower than that in the general otolaryngologist clinic (P < 0.05). In addition, the success rate (61.29%) in the group patients' ages were lower than 50 years old was significantly lower than that (66.33%) in the group patients' ages were more than 50 years old (P < 0.05). CONCLUSION: The research shows that so many factors could lead to the success of hearing aid fitting. So its necessary for us to do some special things to overcome them, including disseminating the knowledge about hearing rehabilitation and improving our abilities. They are the only solutions to improve the patients confidence and make them get the better rehabilitation from the hearing aids. PMID- 23646425 TI - [Characteristics and aeromedical evaluation of Meniere's disease in flight aircrew]. AB - OBJECTIVE: To find out the clinical characteristics of Meniere's disease in flight aircrew and discuss relevant principles of clinical aviation medicine, in order to summarize experience in medical evaluation of aircrew. METHOD: Collect the data of 35 cases that were diagnosed with Meniere's disease from 1966 to 2011 in our hospital and analyze the clinical characteristics, diagnosis and flight conclusion of them. RESULT: Among the 35 cases, 34 patients complained of vertigo. 27 patients complained of tinnitus and 21 patients complained of hearing loss. (1) 18 cases manifested typical symptoms of Meniere's disease (paroxysmal vertigo, fluctuating neurosensory hearing loss, tinnitus and ear fullness); (2) 7 patients showed the symptoms of vertigo and tinnitus, not complaining of significant hearing loss (after inspection. 4 of them proved the low-frequency hearing loss); (3) 7 patients only manifested as vertigo; (4) 2 patients manifested as tinnitus and hearing loss. 1 patients manifested only hearing loss. On the basis of the diagnostic criteria of Meniere's disease formulated hy Committee on Hearing and Equilibrium of the American Academy of Otolaryngology Head and Neck Surgery. 22 patients were diagnosed with definite Meniere's disease, 2 patients were diagnosed with probable Meniere's disease, 11 patients were diagnosed with possible Meniere's disease. For patients with definite Meniere's disease and probable Meniere's disease, the phases of the disease were: 11 cases of phase I, 7 case of phase II and 6 case of phase III. The flight conclusion of all the 35 patients was permanent grounding. The time from the attack of the disease to receiving the conclusion of permanent grounding fluctuated from three months to 11 years. CONCLUSION: The diagnosis of Meniere's disease of flight aircrew must he cautious. For patients with atypical symptoms of Meniere's disease, the diagnosis should be made in the case of completely ruling out other possible diseases. Once be diagnosed, a patient should normally be flight unqualified. The flying waiver would he recommended only under exceptional circumstances. The criterion of waiver condition need to be further explored in the future. PMID- 23646426 TI - [Canalplasty for inlay myringoplasty]. AB - OBJECTIVE: To explore the effect of the canalplasty for inlay myringoplasty. METHOD: A retrospective study was performed on 125 patients (130 ears) who underwent canalplasty and myringoplasty for the treatment of the chronic otitis media. The postauricular incisions was made, then the separation of the flap of posterior canal skin and the tympanic membrane epithelium, mill addition to part of the canal bone of the top, bottom, behind. Lift forward on the anterior canal skin, until the formation of the external auditory canal skin tube. Metal sheets was used to protect the skin tube, mill addition to the prominent bone of the anterior canal, reveal the tympanic anulus fully. Explore the ossicular chain activities, fascia covering the canal and fiber layer surface of the drum remnant was used as an inlay graft, and the canal skin was replaced. The canal was filled with hemostatic gauze and hemostatic sponge. Stitches a week after surgery. Removal of filling material in the external auditory canal two weeks after surgery, and re-filling with sterile gauze until healed. RESULT: All 125 patients had successful grafts with 100% survival rate and healed in stage I. Average improvement in air-bone gap for all patients was 8.9 dB. Stenosis of the external auditory canal and lateralization of the grafted drum did not occur. Follow-up was conducted for 1-3 years. Three ears had reperforation and eight ears had late atelectasis. Fifteen ears had myringitis and healed by halometasone cream. CONCLUSION: Canalplasty is an important surgical procedure on inlay myringoplasty. It can make the narrow and curved canal to large, eliminate the prominent bone of the anterior wall, expose the perforation edge fully, further facilitate the survival of the graft and post-operative care. PMID- 23646427 TI - [Application of ocular-vestibular evoked myogenic potentials in patients with Meniere's disease]. AB - OBJECTIVE: To evaluate the reliability and the value of clinical application of ocular-vestibular evoked myogenic potentials in the patients with Meniere's disease. METHOD: Thirty healthy people (control group) and Twenty-seven patients with lateral Meniere's disease (therapy group) were underwent clinical audiological audiometer test and the ocular-vestibular evoked myogenic potential test. RESULT: In the control group, the average potential of n10 wave was (10.13 +/- 0.48)ms, and the average potential of p15 wave was (15.23 +/- 0.46)ms. The average amplitude of n10-peak to p15-peak were (6.58 +/- 2.65) microV. According to the control group, eight patients had abnormal waveform, and nineteen with normal in the therapy group. CONCLUSION: The oVEMPs test is a modest stimulus to the subject which is brief, safe and objective. It represented the function of the utricle and the superior vestibular nerve, the procedure is easily repeatable and acceptable, and worthily applied in patients with Meniere's disease. PMID- 23646428 TI - [Influence on vestibular function caused by acute low-tone sensorineural hearing loss]. AB - OBJECTIVE: To study the vestibular function of patients with acute low-tone sensorineural hearing loss (ALHL). So we can know whether their vestibular function was influence. METHOD: Vestibular function tests were performed on fifty two ALHL patients by recording electronystagmography (ENG) and static posturography (SPG) before and after their therapy. Then made a comparison with normal. RESULT: Length of locus and velocity of postural sway of the ALHL subjects were significantly increased in comparison with normal (P < 0.05) when eyes closed. After therapy, two (3.8%) ALHL subjects were still recorded abnormal ENG results. CONCLUSION: Most ALHL subjects without vertigo symptom, but their vestibular function was abnormal, so vestibular function tests should be performed on patients with ALHL. PMID- 23646429 TI - [Destrution of ossicular chain and it's impact on hearing of patients with tympanosclerosis]. AB - OBJECTIVE: To study the destruction ossicular chain's impact on hearing of patients with tympanosclerosis. METHOD: A retrospective review was conducted in 115 patients with tympanosclerosis, all patients were divided into 3 groups, including normal ossicular chain structure (A group), fixed ossicular chain(B group), and interrupted ossicular chain (C group). The audiological feature of the patients were compared between the 3 group. RESULT: Difference were significant for PTA, 0.5, 1.0, 2.0, 4.0 kHz air conduction threshold between 3 group (P < 0.01). Difference were significant for air bone gap (ABG) between A, B groups and C group (P < 0.01), there was no difference for ABG between A and B group (P > 0.01). Difference were significant for air conduction threshold between 0.5, 1.0 kHz and 2, 4 kHz in A, B groups (P < 0.01), but there was no significant for same data in C group (P > 0.01). Difference were significant for average bone conduction, 1, 2, 4 kHz bone-conduction threshold between A group and B, C group (P < 0.01). The rate of Carhart notch was low and had no difference between 3 group (P > 0.01). CONCLUSION: The ossicular chain was fixed in patients who's PTA > or = (54.31 +/-13.19) dB HL and was interrupted who's PTA > or = (63.90 +/- 20.29) dB HL or ABG > or = (33.23 +/- 8.49) dB HL. The rising shaped curve in air-conduction audiograph may indicate the ossicular chain was fixed,and the smooth shape curve may indicate the ossicular chain was interrupted. PMID- 23646430 TI - [Clinical characteristics of benign paroxysmal positional vertigo secondary to sudden deafness]. AB - OBJECTIVE: To retrospectively analyze the clinical characteristics of the benign paroxysmal positional vertigo (BPPV) secondary to the sudden deafness (SD) and to explore pathogenetic mechanism. METHOD: One hundred and seventy-eight cases of the SD in our department were retrospectively analyzed. They were all treated under the guidance of clinical guidelines. RESULT: (1) In all these patient's with SD, there were 31 cases with BPPV secondary to the SD. There were 26 cases of BPPV of posterior semicircular canal and 5 cases of BPPV of lateral BPPV semicircular canal. All patients with BPPV were diagnosed as the same ears as the SD, including 16 cases on left sides and 15 on right sides. (2) The interval between the onset of SD and BPPV was less than one week in 27 cases, between one week and one month in 3 cases, and between one and three months in 1 case. (3) All patients with BPPV secondary to the SD were cured with Epley maneuver or Barbecue roll maneuver. CONCLUSION: The occurrence of BPPV may follow SD, and the major of BPPV secondary to the SD occurs in the posterior semicircular canal. The canalith repositioning is an effective therapy to the secondary BPPV. PMID- 23646431 TI - [Experimental study on distortion product otoacoustic emission used for hearing monitoring in the oto-neurosurgery operation]. AB - OBJECTIVE: To explore the feasibility of distortion product otoacoustic emission (DPOAE) used for hearing monitoring in the oto-neurosurgery operation. METHOD: Twenty-four rabbits were equally divided into 3 groups: none operation (group A, n = 8); pressing the cerebella after the cerebellopontine angle was exposed (group B, n = 8); Blood flow of internal auditory artery were occlusion for 5 min after the facial-acoustic nerve complex was pressed(group C, n = 8). DPOAE value and histologic were observed. RESULT: In the state of pressing the cerebellar and blood flow of inner hearing artery were occlusion, DPOAE amplitude values changed, part of the frequencies could not be induced, DPOAE amplitude values of induced frequencies descend and nael significant difference (P < 0.05) to preoperation, as well as correspond to histology changes. CONCLUSION: DPOAE could monitor the hearing loss effectively and would be one of ideal monitoring methods in the oto-neurosurgery operation. PMID- 23646432 TI - [The result of BAHA fitting in single sided deafness]. AB - OBJECTIVE: To learn the benefit of the unilateral profound sensorineural hearing loss patients wear bone conduction hearing aid BAHA. METHOD: Sixteen unilateral profound sensorineural hearing loss patients done BAHA aided pure tone test and speech recognition threshold test in the quiet environment and MHINT test respectively. We can learn the effect of wearing BAHA by doing the unaided and aided speech recognition threshold test in different environment. RESULT: BAHA had good compensation of aided threshold but have no obvious im prove of speech recognition threshold both in quiet and noise environment. CONCLUSION: According to the research and feedback of patients, BAHA have no obvious benefit to unilateral profound hearing loss. The related benefit test should he done first before deciding whether or not to implant BAHA. The long-term BAHA wearing benefit still need to further understand with unilateral profound sensorineural hearing loss patients. PMID- 23646433 TI - [Related factor analysis of the degree of tinnitus in sudden sensorineural hearing loss patients]. AB - OBJECTIVE: To provide the theory basis for clinical diagnosis, treatment and prognosis of sudden deafness patients, we detected the relative factors of degree of tinnitus of the patients with sudden deafness. METHOD: Prospective analysis was used to compare degree of tinnitus with sex, ears, age, degree of hearing lose, hearing curve type and curative effect of tinnitus and sudden deafness. RESULT: Tinnitus was detected in 87.2% in the 70 patients who with sudden deafness, and the most and least degree of tinnitus patients was the degree 3 (32.9%) and the degree 5 and 6 (0). The total effective rate of sudden deafness and tinnitus was 66.2% and 74.3%, respectively. The statistical analysis shown the degree of tinnitus was not related to sex, ears, age, degree of hearing lose, auditory curve type and curative effect of tinnitus and sudden deafness (P > 0.05). CONCLUSION: There was a high rate of tinnitus occurrence in sudden deafness patients, and the moderate degree predominated. The curative effect of tinnitus was better than sudden deafness. There was no relationship between the degree of tinnitus and sex, ears, age, degree of hearing lose, auditory curve type and curative effect of tinnitus and sudden deafness. PMID- 23646435 TI - [Comparative study of two different approaches on treatment of zygomatic complex fracture]. PMID- 23646434 TI - [Effect analysis of nasal inverted papilloma in nasal cavity and paranasal sinus by radiofrequency ablation under nasal endoscopy]. PMID- 23646436 TI - [Children OSAHS and middle ear function analysis]. PMID- 23646437 TI - [Adolescent treatment of late refractory sensorineural deafness by tympanic intratympanic injection of steroid therapy clinical observation]. PMID- 23646438 TI - [Report of two cases of calcifying epithelioma in children]. AB - The presenting symptom of calcifying epithelioma was a hard, slowly growing subcutaneous mass. The two cases in this paper were both girls. The five and eight year-old girls were occurred in anteri or inferior of ear lobe and in preauricular respectively. This tumor was composed of two cell types: the shadow cells and basophilic cells with small calcifying areas. The tumor was finally removed without replase in a year follow-up. PMID- 23646439 TI - [A case of tympanic foreign body]. AB - A 22 years old male was hospitalized with 1 month history of endaural foreign body retention at 7th May, 2011. Patient complained an invicible bug was placed into right outer ear canal. The foreign body could not be taken out because of the intoleration to pain under the local anesthesia, and major symptoms were swell-sore, fullness, and obvious hearing loss. Physical examination showed congestion and swelling in right ear canal, and only 3mm diameter for the stenosis ear canal. The incrustation make the invicible foreign body and the tympanic membrane. CT showed the foreign body retention near tympanic membrane left ear was normal. After hospitalization, the patient received an exploratory operation under the general anesthesia. The foreign body incarceration was found near the tympanic ring which in the tympanic cavity. PMID- 23646440 TI - [A case of tracheal papilloma]. AB - A 63-year-old male patient, with 5 years history of progressive dyspnea and aggravation for 1 year, was hospitalized in our hospital; and there was a slight cough, but no cough phlegm, chest pain, hemoptysis or hoarseness. Physical examination showed that there was a third-degree respiratory distress, obvious three depression sign, but no mass in the neck. Electronic laryngoscopy examination reported a mulberry-like mass in trachea about 1.5cm from the glottis. The tumor occupied 90% range of lumen with its base close to the anterior wall of trachea,and tumor could move up and down with cough airflow. After hospitalization, this patient received intratracheal tumor resection under local anesthesia, and postoperative pathology report showed endotracheal papillomatosis, covered by ciliated columnar epithelium. PMID- 23646441 TI - [Development and application of bone-anchored hearing aid]. AB - Bone-anchored hearing aid is a hearing assisting technology that raise the hearing level via bone conduct and is also the only implantable hearing assisting device working by bone conduct. Because of the superior performance and simple process of implantation, it brings gospel to the patients who are not fitting the air conducting hearing devices. This article is a review of bone-anchored hearing aid from 6 aspects, including history, principle, indication, consulting, surgery and complication. PMID- 23646442 TI - [Evaluation of immunosuppressive treatment on homocystein levels in patients after kidney transplantation during a 2 year observation period]. AB - The aim of the study was to evaluate the influence of the type of prescribed immunosuppression: cyclosporine A (CsA) vs. tacrolimus (Tac) on remote homocystein levels in patients (pts) after kidney transplantation (Ktx). PATIENTS AND METHODS: The study included 51 pts (17 F, 34 M) aged 15 to 62 years (mean 38.1) after cadaver Ktx. The mean observation period equaled 21.2 months (6 -24); while total observation period was 90 personlyears. Before Ktx, 46 pts were treated with maintenance hemodialysis (HD), while 5 by peritoneal dialysis (PD). After Ktx, patients had immunosuppression prescribed according to the following schemes: prednisone (P) + CsA + azathioprine (AZA) - 12 pts; P + CsA + mycophenolate mofetil (MMF) -26 pts; P + Tac + MMF - 11 pts; and P + Tac + AZA - 2 pts. Hcy level was measured using high performance liquid chromatography (HPLC). Serum creatinine level was measured by standard method using the Hitachi 917 analyzer. Creatinine clearance was calculated based on the Cockcroft-Gault formula. Patient's blood was drawn before Ktx and 3, 6, 9, 12,15, 18, 21 and 24 months post procedure. RESULTS: Delayed graft function (DGF) after Ktx was diagnosed in 29 pts (56.9%) and this group required from 4 to 28 HD sessions (mean 14 sessions). Hcy level did not significantly differ between pts requiring (29 pts) and not requiring (22 pts) HD treatment after Ktx. It was also noted that the number of performed HD sessions did not significantly correlate with Hcy levels 24 months after Ktx (R =0.04, p=0.81). No relationship was found (non parametric Spearman test) between the drop in Hcy level 3 months after Ktx as compare with value before Ktx and ischemia time (R=0.09, p=0.49), number of compatible HLA A and B (R=0.07, p=0.63), and DR antigens (R=0.09, p=0.51). Decrease in Hcy level (before Ktx and 24 months after Ktx) did not significantly correlate with the above parameters, respectively: R=-0.14, p=0.40; R=0.06, p=0.73; R=0.12, p=0.45; R=0.11, p=0.50. Decrease in Hcy level (before Ktx and 3 months after) did not differ significantly when compared to pts receiving immunosuppressive therapy CsA vs. Tac (p=0.18). Even though notable differences were observed in the drop in Hcy level (immunosuppressive treatment scheme CsA vs. Tac) in measurements before Ktx and 24 months post (respectively: 27% and 57.6%), no statistical significance was noted (p=0.13). Using the Mann-Whitneys' Test, no statistical significance was noted (p=0.13) when comparing differences in creatinine clearance between the group of pts receiving CsA and Tac 24 months after Ktx. Patients treated with Tac achieved a higher creatinine clearance by 16.5% when compared with those receiving CsA. No significant differences were observed between these two groups (p=0.65) when serum creatinine levels were evaluated. CONCLUSIONS: Incidence of DGF, as well as prescribed immunosuppressive therapy does not have an influence on remote Hey levels in pts after Ktx. Graft function seems to be the main predictor that influences Hcy levels after Ktx in this group of pts. PMID- 23646443 TI - [Morphological changes of the colon in patients with irritable bowel syndrome]. AB - INTRODUCTION: Irritable bowel syndrome (IBS) is a common disease belonging to the group of chronic functional gastrointestinal disorders. Variety of symptoms and lack of macroscopic and structural pathologies in colon, make IBS a challenge both in diagnosis and in medication. According to the last reports, the role of chronic minimal inflammation in colon mucosa is becoming more relevant. AIMS: The aim of this study was to verify the microscopic and macroscopic changes in colon mucosa in patients with IBS. METHODS: A retrospective study of microscopic changes and macroscopic lesions in colon, due to endoscopy biopsies in the group of 89 patients diagnosed with IBS in an average age of 47 years. RESULTS: Mild inflammation of colonic mucosa in lamina propria was observed in 92% patients, 34% presented other inflammatory cells. No statistical relationship between macroscopic lesions (in 44% cases) and lymphatic infiltration was observed. CONCLUSIONS: Low grade inflammation of lamina propria in colon was observed among patients with IBS. Beside the edema of the lamina propria, no correlation between macroscopic and microscopic changes was found. Despite the fact that IBS is a functional disorder, in many patients occur morphological changes in colon mucosa. Further studies are necessary. PMID- 23646444 TI - [The modified Elmslie-Trillat procedure for the treatment of recurrent patellar dislocation and instability]. AB - Habitual patella dislocation and instability in the absence of effective conservative treatment requires surgery. Surgical procedures can be divided into bone, soft tissue and mixed methods. In many studies the authors emphasize the good results of Elmslie-Trillat procedure. METHODS: In 2005-2008, we operated 20 patients by modified Elmslie-Trillat procedure but 2 patients were excluded from the study because of lack of control after surgery. We modified surgical technique by type of tibial tuberosity osteotomy and reconstruction of soft tissues. RESULTS: We used a subjective clinical evaluation (evaluation of Q angle, patella traction in the dynamic tests) and the Tegner and Lysholm scale. In the Tegner scale, we obtained an average improvement of 3.4 points (from 0 to 8), and in Lysholm scale average of 46.7 points (from 14 points to 65 points). CONCLUSIONS: Correction of recurrent patellar dislocation and instability by a modified Elmslie-Trillat method is effective and good results are obtained. Only the appropriate selection of surgical procedure depending on the cause of disease provides a permanent cure. PMID- 23646445 TI - Prevalence of HPV-DNA in Pap smears containing ASC and AGC performed within Population Programme of Prophylaxis and Early Detection of Early Cervical Cancer. AB - AIM: to assess the incidence of HPV -DNA in women with ASC/AGC compared to patients with normal Pap smears. MATERIAL AND METHODS: The study group consisted of 242 women (207 ASC and 35 AGC cases). The control group counted 200 age matched women with negative Pap smears. Cervical samples collected from all the participants were tested for the presence of HPV-DNA using the Hybrid Capture-2 test. RESULTS: Total HPV infection was significantly higher in the study than in the control group (43.0% vs.14.0%) (p=0.005). There was no difference in the incidence of HPV -DNA between ASC and AGC groups. Prevalence of HPV-DNA ASC-H was significantly higher in ASC-US group (83.3% vs. 40.5%) (p=0.004). HPV positive endometrial AGC significantly outnumbered HPV positive endocervical AGC (88.9% vs. 26.9%) (p=0.003). Similar trends were observed for the high-risk type of HPV (p<0.001). CONCLUSIONS: The significant difference in HPV -DNA incidence between the study and control groups suggests that HPV plays a role in the development of ASC and AGC. The implementation of HPV testing in all women diagnosed with ASC or AGC can lead to tailored therapeutic management and more careful follow-up care. PMID- 23646446 TI - [Influence of increased mean heart rate at rest on mortality and ventricular tachycardia resulting in adequate intervention in patients after implantable cardioverter-defibrillator implantation]. AB - INTRODUCTION: Increased heart rate at rest (HR) is a risk factor of sudden cardiac death (SCD) and cardiovascular mortality. AIM: Retrospective assessment of increased HR influence on mortality and ventricular tachycardia followed by adequate ICD intervention. MATERIAL AND METHODS: 350 patients (52 female, 298 male), mean age 65.1+/-10.1 years (22-89 years) with ICD without resynchronization function implanted between 2008 and 2010 were examined. ECGs at rest were used to determine HR. In case of atrial fibrillation, mean value of 2 shortest and longest RR intervals was calculated to determine HR. RESULTS: During the mean observation period of 387+/-300 days, 73 patients (66 male, 7 female), mean age 63.7+/-12.2 years (22-89) had an arrhythmial/intervention, and 46 patients (9 male, 37 feamle), mean age 68.8+/-10.3 years (43-86) died. To optimize sensitivity and specificity of HR, cut off point was established using ROC curve (79/min). Number of patients with HR>79/min was significantly higher (64.7% vs 19,1%, p<0.022) in the group of patients with arrhyth-mialintervention vs no arrhythmial/intervention, and in dead vs alive patients (73.9% vs 19.5%, p<0,001). Kaplan-Meier univariate analysis proved, that HR79/ min particularly predisposed to fast ventricular arrhythmias and interventions - CV (p<0.092). In Cox multivariate analysis, HR< or =79/min was a protective factor only in death risk (HR=0.2362, 95%CI=0.1094-0.5099, p<0.0002). CONCLUSIONS: An important factor increasing probability of survival without ventricular arrhythmia or death was a mean heart rate below 79/min. The cycle length of the baseline rhythm determine the arrhythmia cycle length. PMID- 23646447 TI - [Echocardiographic assessment of left atrial volume in asymptomatic ambulatory patients with metabolic syndrome and/or arterial hypertension - is it parameter worth into considerate?]. AB - INTRODUCTION: Early identification of high-risk patients, including those with arterial hypertension (AH) andlor metabolic syndrome (MS), have a positive effect on the treatment and the cost. Left atrial volume is a well-known, easy to examine prognostic factor in cardiovascular diseases. Impaired function and enlargement of the left atrium could be present in even when asymptomatic patients with AH, but in subjects with MS has not been well documented. OBJECTIVE: The aim of the study was to estimate the left atrial volume index (LAVI) among asymptomatic patients with AH and/or MS. PATIENTS AND METHODS: One hundred and fourteen consecutive patients were divided into three groups as follows: 54 patients with MS, 34 with AH and 26 in a control group; next they were underwent the echocardiographic examination. A statistical analysis of LAVI was carried out using the Whitney-Mann test. RESULTS: The mean LAVI was: 25.20 ml/m2 for the AH group (woman 24.90 ml/m2; men 25.49 ml/m2); 24.90 ml/m2 for the MS (woman 25.78 ml/m2; men 23.63 ml/m2) and 19.20 ml/m2 for the control group (woman 21.77 ml/m2; men 17.97 ml/m2). There was a positive correlation between increased LAVI and AH or/and MS presence. CONCLUSIONS: The results suggest that left atrial volume index enlargement is more common among even asymptomatic patients suffering from hypertension andlor metabolic syndrome. The estimation of LAVI is possible in a routine echocardiographic examination and seems to be an additional useful parameter in description of risk in cardiovascular diseases. PMID- 23646448 TI - [New trends and safety of photodynamic therapy]. AB - Photodynamic therapy (PDT) is used mainly in tumor diagnosis and treatment. It is obvious that PDT can increase the efficiency of traditional methods such as surgery, chemotherapy or radiotherapy. Unfortunately, photosensitizers used in the treatment are still imperfect. According to severe side effects, patients need to change their life habits even for several weeks. The problem is attributed to insufficient selectivity of dyes toward cancer tissues. Safety of PDT can be improved by application of various carriers including liposomes, nanotubes or nanoparticles. Binding of photosensitizers to tumor specific molecules opens broad new possibilities for PDT. PMID- 23646449 TI - [Seasonal influenza in children - the underestimated problem]. AB - Influenza in children is an important clinical, epidemiological and economic problem - but underestimated problem. The aim of the paper was to describe a current knowledge concerning epidemiology of influenza in children, including situation in Poland, its impact on ambulatory visits and hospitalizations. The beneficial effect of vaccination against influenza on economic and clinical issues was also underlined. It is estimated that annually 10-40% cases of febrile respiratory infections have influenza aetiology. In Poland, similar to other countries, the incidence of the diseases among children younger than 14 years is higher compared to the general population. However, the influenza vaccine coverage among children younger than 5 years in Poland is extremely low (<2%). Vaccinations against influenza in children are effective and safe and protect against the disease and its complications not only vaccinated children but also persons from close contacts. The most important method of prevention of influenza among children and adolescents aged 6 months-18 years is vaccination. Vaccination against influenza has been recommended in Poland since 1994. More educational activities addressed for patients and medical professionals are required to increase the influenza vaccine coverage among children and adolescents in Poland. PMID- 23646450 TI - [Percutaneous renal denervation as a new method of treatment of resistant arterial hypertension]. AB - The sympathetic nervous system plays an important role in the progression of arterial hypertension. This paper describes percutaneous renal denervation as a new, minimally invasive method of treating resistant hypertension. The procedure is based on ablation of the renal sympathetic nerves using radiofrequency energy after insertion of the Simplicity catheter into the renal artery. We discuss the indications and contraindications for renal artery denervation and describe the procedure itself. The results of large randomized trials such as Simplicity HTN-1 and HTN-2, are very promising. They show a significant decrease in blood pressure observed within 3 months after the denervation procedure, with few complications, without pathological effects on renal function. It is suggested that besides the impact on blood pressure, renal artery denervation can also improve carbohydrate metabolism, as well as sleep apnea and the treatment results of heart failure. PMID- 23646451 TI - [Connective tissue diseases during pregnancy - therapeutic aspect. Part 1: SLE, antiphosholipid syndrome]. AB - Connective tissue diseases, defined as chronic, multi-system autoimmune dysfunctions, occur predominantly in women of childbearing age. Pregnancy, as a specific state of hormonal and immunological diversity, may involve adverse influence on maternal disease activity, causing remission or exacerbation necessitating appropriate therapy. In the first part of the article the influence of female hormones on the immunological cells is presented, as well as their role in the autoimmunological process. The special emphasis is put on most frequent connective tissue diseases among young women- systemic lupus erythematosus and antiphospholipid syndrome. The article also highlights the risk of potential obstetric complications, the gravity of careful planning, restrictive monitoring and necessary treatment to minimalize the risk of intricacy. PMID- 23646452 TI - [Connective tissue diseases during pregnancy - therapeutic aspect. Part 2: the other connective tissue diseases]. AB - Pregnancy in women with connective tissue diseases is classified as a high risk pregnancy. Therefore, a proper treatment which is safe both for mother and child, arouses a problem. The second part of the article presents main pregnancy complications among women with systemic sclerosis, rheumatoid arthritis, ankylosing spondylitis and dermatomyositis. General groups of medications are discussed, which are most frequently used in treatment of pregnant women with connective tissue diseases. Furthermore, the article presents treatment schedule which obtained the United States Food and Drug Administration (FDA) recommendation. Nowadays, advancing technology and treatment improved outcomes in connective tissue diseases pregnancies. PMID- 23646453 TI - [Effective application of therapeutic plasma exchange in a case of acute dermatomyositis]. AB - We present a case of 22-year-old male with acute dermatomyositis who did not respond to a standard immunosuppressive therapy. Due to rapidly deteriorating clinical status a series of plasmapheresis was performed subsequent to which a quick clinical improvement was observed. PMID- 23646454 TI - [Hereditary hemochromatosis and mild unconjugated hyperbilirubinemia in patient with ulcerative colitis]. AB - We present the case of 51 year old man with 10 year history of ulcerative colitis. Results of laboratory test revealed increased serum levels of iron, ferritin as well as moderate hiperbilirubinemia. Transferrin saturation index was high, 98,7% (N< 50%). Long lasting remission of inflammatory bowel disease, including lack of bleeding from gastrointestinal tract disclosed hereditary hemochromatosis presence in that patient. PMID- 23646455 TI - [Abortion, an important problem of modern societies]. AB - Each civilization is faced with an issue of choosing to be for or against life. Likewise, the society we are currently building cannot evade answering the question of on which side it stands, that of life or that of death? Consumptionist and hedonistic lifestyles of a majority of people make the answer to this question still more important. The mass-media do not inform societies about the true scale of havoc wrought both in somatic and psychic dimension in women who submit themselves to abortion. The actual trend is to try to suppress the humane sensitivity and consciousness which rise against lack of respect for the Godbegotten gift of a new life. PMID- 23646456 TI - [Letter to the editor of Przeglad Lekarsarski regarding an article about a biographical analysis]. PMID- 23646457 TI - Timing and T-cells. PMID- 23646458 TI - Mapping out a strategy. PMID- 23646459 TI - Find your HIV drug here. PMID- 23646460 TI - Keeping standards. PMID- 23646461 TI - Treating hepatitis B and C. PMID- 23646462 TI - Don't break the bank. PMID- 23646464 TI - [Syndrome typing based strategies for postoperative gastrointestinal dysfunction in the perioperative phase]. AB - By summarizing the literature and clinical experiences, the author analyzed the pathogenesis of gastrointestinal functions and the diagnosis and treatment progress of Chinese medicine and Western medicine. The author addressed the main reason for gastrointestinal dysfunction was enteroparalysis (lack of motive power). Its pathogenesis was mainly due to deficiency syndrome, or to dominant deficiency syndrome with mingled deficiency and excess. According to the principle of treating different diseases by the same method, syndrome typing based strategies for treating postoperative gastrointestinal dysfunction in the perioperative phase should strengthen body resistance and supplement deficiency, or strengthen body resistance and dispel evil pathogens as the main principal method. Although purgations such as Dachengqi Decoction played a role in promoting gastrointestinal motive power, they were not suitable for major patients with selective surgeries induced gastrointestinal dysfunction. They were mainly suitable for acute abdomen patients with heat accumulation in Fu-organs as main symptoms, or for individual patients with interior heat induced excess syndrome. PMID- 23646465 TI - [Effects of Xingpi Yang'er granule on serum gastrin, plasma motilin, and somatostatin contents in children patients with pneumonia induced diarrhea]. AB - OBJECTIVE: To observe the effects of Xingpi Yang'er Granule (XYG) on serum gastrin (GAS), plasma motilin (MOT), and somatostatin (SS) in children patients with pneumonia induced diarrhea. METHODS: Recruited were 120 children inpatients with pneumonia induced diarrhea at the Department of Pediatrics, Liaocheng People's Hospital from June 2011 to June 2012. They were randomly assigned to two groups, the treatment group and the control group, 60 in each group. Those in the treatment group were treated with XYG, while those in the control group were treated with Live Combined Bifidobacterium and Lactobacillus Tablets. Besides, 30 healthy children who received physical examinations at our hospital were recruited as the healthy control group. The clinical efficacy, changes of GAS, MOT, and SS contents were observed. RESULTS: The total effective rate was 95.0% in the treatment group and 93.3% in the control group, showing no statistical difference (P > 0.05). Compared with healthy control group, the GAS and MOT contents increased, and SS decreased before treatment in the other two groups (P < 0.05). Compared with the same group before treatment, GAS and MOT contents obviously decreased, and SS increased in the other two groups after treatment (P<0.05). Compared with the control group at the same time point, GAS and MOT decreased, and SS increased in the treatment group after treatment, showing statistical differences (P < 0.05). CONCLUSIONS: The levels of GAS, MOT, and SS were obviously changed in children patients with pneumonia induced diarrhea. XYG had obvious regulation on their GAS, MOT and SS contents. PMID- 23646466 TI - [Research on differentially expressed genes related to substance and energy metabolism between healthy volunteers and splenasthenic syndrome patients with chronic superficial gastritis]. AB - OBJECTIVE: To analyze the metabolic states of the lipids, protein, carbohydrate, and nucleic acid for chronic superficial gastritis patients of splenasthenic syndrome (SS), and to explore the pathogenesis mechanism of SS based on substance and energy metabolisms. METHODS: During June 2004 to March 2005, recruited were four chronic superficial gastritis patients of SS who visited at the First Hospital of Guangzhou University of Chinese Medicine and Guangdong Provincial Hospital of Traditional Chinese Medicine. Four healthy volunteers were recruited from Guangzhou University of Chinese Medicine. Their gastric mucosa was extracted to perform experiments of DNA microarray. The dual-channel DNA microarray data were mined and bioinformatics analyzed by BRB ArrayTools and IPA software. RESULTS: Fifteen genes were involved in substance and energy metabolisms in 20 differentially expressed genes, accounting for 75%.Among these genes, one gene was up-regulated, 14 genes down-regulated, and 11 genes were enzyme gene. Differentially expressed genes related to lipid metabolism included ACAA2 and CYP20A1, manifested as fatty acid catabolism and cholesterol transformation. Genes related to protein metabolism included ALDH9A1, ASL, ASS1, PCY-OX1L, RPS28, UBE2D2, UBXN1, B3GNT1, GCNT1, and PPP1R3C, manifested as decreased amino acid metabolism that may affect the biologic processes such as autonomic nerve, urea cycle, etc., reduced protein synthesis, increased ubiquitination of fault fold proteins, and decreased post-translated modification of glycosylation and dephosphorylation. Genes related to carbohydrate metabolism included PPP1R3C, B3GNT1, and GCNT1, manifested as decreased glycogen and glycan syntheses. Genes related to nucleic acid metabolism included RMI1, SMARCD3, and PARP1, manifested as degraded DNA duplication and transcription, and increased DNA damage repair. CONCLUSIONS: The metabolisms of the lipids, protein, carbohydrate, and nucleic acid in chronic superficial gastritis patients of SS obviously decreased, manifested mainly as down-regulated enzyme gene expression. We inferred that these might be one of the vital pathogenesis mechanisms for nutrition dysmetabolism of SS. PMID- 23646463 TI - Cardiorespiratory biomarker responses in healthy young adults to drastic air quality changes surrounding the 2008 Beijing Olympics. AB - Associations between air pollution and cardiorespiratory mortality and morbidity have been well established, but data to support biologic mechanisms underlying these associations are limited. We designed this study to examine several prominently hypothesized mechanisms by assessing Beijing residents' biologic responses, at the biomarker level, to drastic changes in air quality brought about by unprecedented air pollution control measures implemented during the 2008 Beijing Olympics. To test the hypothesis that changes in air pollution levels are associated with changes in biomarker levels reflecting inflammation, hemostasis, oxidative stress, and autonomic tone, we recruited and retained 125 nonsmoking adults (19 to 33 years old) free of cardiorespiratory and other chronic diseases. Using the combination of a quasi-experimental design and a panel-study approach, we measured biomarkers of autonomic dysfunction (heart rate [HR*] and heart rate variability [HRV]), of systemic inflammation and oxidative stress (plasma C reactive protein [CRP], fibrinogen, blood cell counts and differentials, and urinary 8-hydroxy-2'-deoxyguanosine [8-OHdG]), of pulmonary inflammation and oxidative stress (fractional exhaled nitric oxide [FeNO], exhaled breath condensate [EBC] pH, EBC nitrate, EBC nitrite, EBC nitrite+nitrate [sum of the concentrations of nitrite and nitrate], and EBC 8-isoprostane), of hemostasis (platelet activation [plasma sCD62P and sCD40L], platelet aggregation, and von Willebrand factor [vWF]), and of blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]). These biomarkers were measured on each subject twice before, twice during, and twice after the Beijing Olympics. For each subject, repeated measurements were separated by at least one week to avoid potential residual effects from a prior measurement. We measured a large suite of air pollutants (PM2.5 [particulate matter < or = 2.5 microm in aerodynamic diameter] and constituents, sulfur dioxide [SO2], carbon monoxide [CO], nitrogen dioxide [NO2], and ozone [O3]) throughout the study at a central Beijing site near the residences and workplaces of the subjects on a daily basis. Total particle number (TPN) was also measured at a separate site. We used a time-series analysis to assess changes in pollutant concentration by period (pre-, during-, and post-Olympics periods). We used mixed-effects models to assess changes in biomarker levels by period and to estimate changes associated with increases in pollutant concentrations, controlling for ambient temperature, relative humidity (RH), sex, and the day of the week of the biomarker measurements. We conducted sensitivity analyses to assess the impact of potential temporal confounding and exposure misclassification. We observed reductions in mean concentrations for all measured pollutants except O3 from the pre-Olympics period to the during-Olympics period. On average, elemental carbon (EC) changed by -36%, TPN by -22%, SO2 by 60%, CO by -48%, and NO2 by -43% (P < 0.05 for all these pollutants). Reductions were observed in mean concentrations of PM2.5 (by -27%), sulfate (SO4(2-)) (by 13%), and organic carbon (OC) (by -23%); however, these values were not statistically significant. Both 24-hour averages and 1-hour maximums of O3 increased (by 20% and 17%, respectively) from the pre-Olympics to the during Olympics period. In the post-Olympics period after the pollution control measures were relaxed, mean concentrations of most pollutants (with the exception of SO4(2 ) and O3) increased to levels similar to or higher than pre-Olympics levels. Concomitantly and consistent with the hypothesis, we observed, from the pre Olympics to the during-Olympics period, statistically significant (P < or = 0.05) or marginally significant (0.05 < P < 0.1) decreases in HR (-1 bpm or -1.7% [95% CI, -3.4 to -0.1]), SBP (-1.6 mmHg or -1.8% [95% CI, -3.9 to 0.4]), 8-OHdG ( 58.3% [95% CI, -72.5 to -36.7]), FeNO (-60.3% [95% CI, -66.0 to -53.6]), EBC nitrite (-30.0% [95% CI, -39.3 to -19.3]), EBC nitrate (-21.5% [95% CI, -35.5 to 4.5]), EBC nitrite+nitrate (-17.6% [95% CI, -28.4 to -5.1]), EBC hydrogen ions ( 46% [calculated from EBC pH], or +3.5% in EBC pH [95% CI, 2.2 to 4.9]), sCD62P ( 34% [95% CI, -38.4 to -29.2]), sCD40L (-5.7% [95% CI, -10.5 to -0.7]), and vWF ( 13.1% [95% CI, -18.6 to -7.5]). Moreover, the percentages of above-detection values out of all observations were significantly lower for plasma CRP and EBC 8 isoprostane in the during-Olympics period compared with the pre-Olympics period. In the post-Olympics period, the levels of the following biomarkers reversed (increased, either with or without statistical significance) from those in the during-Olympics period: SBP (10.7% [95% CI, 2.8 to 18.6]), fibrinogen (4.3% [95% CI, -1.7 to 10.2), neutrophil count (4.7% [95% CI, -7.7 to 17.0]), 8-OHdG (315% [95% CI, 62.0 to 962]), FeNO (130% [95% CI, 62.5 to 225]), EBC nitrite (159% [95% CI, 71.8 to 292]), EBC nitrate (161% [95% CI, 48.0 to 362]), EBC nitrite+nitrate (124% [95% CI, 50.9 to 233]), EBC hydrogen ions (146% [calculated from EBC pH] or -4.8% in EBC pH [95% CI, -9.4 to -0.21), sCD62P (33.7% [95% CI, 17.7 to 51.8]), and sCD40L (9.1% [95% CI, -3.7 to 23.5]). Furthermore, these biomarkers also showed statistically significant associations with multiple pollutants across different lags after adjusting for meteorologic parameters. The associations were in the directions hypothesized and were consistent with the findings from the comparisons between periods, providing further evidence that the period effects were due to changes in air quality, independent of season and meteorologic conditions or other potential confounders. Contrary to our hypothesis, however, we observed increases in platelet aggregation, red blood cells (RBCs) and white blood cells (WBCs) associated with the during-Olympics period, as well as significant negative associations of these biomarkers with pollutant concentrations. We did not observe significant changes in any of the HRV indices and DBP by period. However, we observed associations between a few HRV indices and pollutant concentrations. Changes in air pollution levels during the Beijing Olympics were associated with acute changes in biomarkers of pulmonary and systemic inflammation, oxidative stress, and hemostasis and in measures of cardiovascular physiology (HR and SBP) in healthy, young adults. These changes support the prominently hypothesized mechanistic pathways underlying the cardiorespiratory effects of air pollution. PMID- 23646467 TI - [Research on the application role of yin-yang consumption theory in evaluating the inflammatory immune state and prognosis of patients with abdominal surgical]. AB - OBJECTIVE: To study the differences of the inflammation immune state, severity, and prognosis of patients with abdominal surgical critical illness between yin consumption and yang consumption, to clarify the clinical application of yin-yang consumption theory in evaluating their inflammatory immune state, pathological severity, and prognosis. METHODS: One hundred and forty-five patients with abdominal surgical critical illness were recruited from Surgical Intensive Care Unit, Tianjin Nankai Hospital from January 2007 to March 2010. According to syndrome typing, all patients were assigned to yang deficiency group (82 cases) and yin deficiency group (63 cases). The patient's vital signs were measured, including body temperature, pulse, respiration, mean arterial pressure (MAP), and so on. The acute physiology and chronic health evaluation II (APACHE II) score was performed. The patients' white blood cell (WBC) count, C-reactive protein (CRP), human leukocyte antigen DR-site (HLA-DR), as well as regulatory T lymphocytes (Treg) were determined. The CU length of stay, the total hospitalization time, the hospitalization cost, and the mortality, were also statistically recorded. RESULTS: There was no statistical difference in gender, age, or primary disease between the two groups (P > 0.05) . The APACHE U score, the number of organ dysfunction, MAP, HLA-DR, the ICU length of stay, the total hospitalization time, and the hospitalization cost were significantly higher in yang deficiency group than in yin deficiency group (P < 0.05). But the body temperature, heart rate, respiration, WBC count, CRP, and Treg were significantly lower in yang deficiency group than in yin deficiency group (P < 0.05). There was no statistical difference in the mortality between the two groups (P > 0.05). CONCLUSIONS: In the domain of abdominal surgical critical diseases, the differences in yang consumption and yin consumption of primary disease could help judge the severity of patient's condition and immunodissonance. Yin-yang consumption theory had stronger application value in assistant diagnosis and treatment. PMID- 23646468 TI - [Effects of rhubarb powder on serum complement 3, complement 4, and hs-CRP in patients with intracerebral hemorrhage]. AB - OBJECTIVE: To investigate the effects of rhubarb powder on serum complement 3 (C3), complement 4 (C4), and hypersensitive C-reactive protein (hs-CRP) levels in patients with hypertensive intracerebral hemorrhage (HICH) after operation. METHODS: Forty inpatients with HICH after operation were recruited from Department of Cerebral Surgery, Affiliated Hospital of Shaanxi College of Traditional Chinese Medicine from July 2009 to March 2010. They were randomly assigned to the treatment group (20 cases) and the control group (20 cases). From the 4th day after surgery, all patients received routine Western medical treatment. The rhubarb powder, 5-10 g dissolving in 40 mL warm water, was administered or nasally fed to those in the treatment group, 2 -3 times daily for 10 successive days. The contents of serum C3, C4, and hs-CRP were detected in the two groups on the 7th day and the 14th day after operation. The serum hs-CRP content was detected using latex particle enhanced immunoturbidimetric assay. The Scandinavia Stroke Scale (SSS) scores were recorded in the two groups. RESULTS: Compared with the same group on the 4th day after operation, the levels of serum C3 and C4 increased on the 7th day after operation, and SSS score increased on the 14th day after operation in the control group (P < 0.05). The contents of C4 and hs-CRP decreased, and the SSS score increased on the 14th day after operation in the treatment group (P < 0.05). Compared with the same group on the 7th day after operation, the contents of C4 and hs-CRP decreased and the SSS score increased on the 14th day after operation in the treatment group (P < 0.05). Compared with the control group at the same time points, the contents of C4 and C3 decreased on the 7th day after operation; the contents of C3, C4, and hs-CRP decreased, and SSS score increased in the treatment group on the 14th day after operation (P < 0.05). CONCLUSION: The rhubarb powder could significantly decrease the serum levels of C3, C4, and hs-CRP, and improve the curative effect in patients with HICH after operation. PMID- 23646469 TI - [Effects of qingyang toujie mixture in combination with prednisone tablet on Th1/Th2 cytokines in patients suffering from systemic lupus erythematosus]. AB - OBJECTIVE: To research the effects of Qingyang Toujie Mixture (QTM) in combination with prednisone tablet on the balance of Th1 and Th2 (Th1/Th2) of systemic lupus erythematosus (SLE) patients of yin deficiency syndrome (YDS). METHODS: Totally 42 patients with SLE were recruited from clinics of internal medicine and hospitalization department of First Hospital Affiliated to Guangzhou University of Traditional Chinese Medicine from August 2009 to March 2011. They were randomly assigned to the treatment group (22 cases) and the control group (20 cases) according to the random digit table. Another 12 healthy subjects were recruited as the healthy control group from employees of First Hospital Affiliated to Guangzhou University of Traditional Chinese Medicine and healthy students in physical examinations. All patients took prednisone tablet. The dosage was adjusted according to the severity of SLE activity index and the condition: 40 -60 mg per day for severe active stage; 20-40 mg per day for moderate active stage; 15 -20 mg per day for light active stage; and less than 15 mg per day for those in the stable stage, respectively. When patients' condition had been stabilized for 1 to 2 weeks, the dosage was gradually reduced according to the method of hormone reduction. In case of the recurrence of symptoms or when complicated with lupus nephritis or lupus encephalitis uncontrollable, standard shock therapy with Cyclophosphamide Injection (0.5-1 g/m2 body surface area, intravenous dripping, once every 4 weeks) was performed. Patients in the treatment group took QTM additionally, one dose daily, taken in two portions, once in the morning and once in the evening. Those in the control group took placebos additionally, one dose daily, taken in two portions, once in the morning and once in the evening. The therapeutic course was 6 months for all. No measure was taken for those in the healthy control group. Venous blood was withdrawal before and after treatment. Th1 cytokines (IFN-gamma, IL-12) and Th2 cytokines (IL-10, IL-4) were detected by ELISA. RESULTS: Compared with the healthy control group, the serum Th1 cytokines such as IL-12 and IFN-gamma, Th2 cytokines such as IL-10 and IL-4 increased, the Th1/Th2 ratios such as IFN-gamma/IL-4 and IL-12/IL 10 decreased in the treatment group and the control group before treatment (P < 0.01). Compared with before treatment in the same group, the serum Th1 cytokines such as IL-12 and IFN-gamma decreased, the serum Th2 cytokines such as IL-10 and IL-4 decreased, the ratios of Th1/Th2 cytokines such as IFN-gamma/IL-4 and IL 12/IL-10 increased in the treatment group (all P < 0.05). Compared with the control group after treatment, IL-4 decreased, and the ratio of IFN-gamma/IL-4 increased in the treatment group (P < 0.05). Fewer patients suffered from adverse reactions in the treatment group than in the control group (P < 0.01). CONCLUSION: QTM in combination with prednisone tablet was effective to improve the balance of Th1/Th2 cytokines, and alleviate the toxic and adverse reactions of hormone or immune inhibitors. PMID- 23646470 TI - [Clinical efficacy of Yiqi Qushi Recipe in treating myasthenia gravis and observation of its immunomodulatory effects]. AB - OBJECTIVE: To observe the efficacy of Yiqi Qushi Recipe (YQR) in treating myasthenia gravis (MG) patients and its effects on their immune functions. METHODS: Recruited were 40 type I and II MG patients from clinics and wards of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from January 2009 to June 2011. They were randomly assigned to the treatment group (20 cases) and the control group (20 cases). Patients in the treatment group took YQR, one dose daily, while those in the control group took pyridostigmine 60 mg, three times a day. The therapeutic course consisted of eight weeks. The clinical efficacy, immunization indicators before and after treatment were observed. Meanwhile, the safety evaluation was performed. RESULTS: The cured and effective rate was 75% and the total effective rate was 95% in the treatment group. They were 45% and 85% in the control group. Better results were obtained in the treatment group. Compared with the same group before treatment, IgA, IgG, and CD8 increased, IgM, CD4, and CD4/CD8 decreased in the treatment group, showing statistical difference (P < 0.05). There was no obvious change in each index of the control group after treatment (P > 0.05). Compared with the control group after treatment, IgA, IgG, and CD8 increased, CD4 and CD4/CD8 decreased in the treatment group, showing statistical difference (P < 0.05). During the course of treatment, mild diarrhea, nausea, and vomit occurred in two patients of the control group, while no adverse reaction occurred in those of the treatment group. CONCLUSION: YQR could significantly improve clinical symptoms of MG patients, regulate their immune functions, with no obvious adverse reaction. PMID- 23646471 TI - [Effects of Baidanhuang lavage fluid nasal irrigation on the postoperative patients with chronic rhinosinusitis with nasal polyps]. AB - OBJECTIVE: To observe the clinical efficacy of Baidanhuang lavage fluid nasal irrigation (BLFNI) on postoperative patients with chronic sinusitis with nasal polyps (CRwNP). METHODS: Ninety postoperative patients with CRwNP were randomly assigned to two groups, the treatment group (60 cases) and the control group (30 cases). After nasal endoscopic surgery, all patients received routine therapies, while the nasal cavity perfusion device was used to irrigate. Patients in the treatment group were treated with BLFNI, while those in the control group were irrigated with physiologic saline with dexamethasone and gentamycin. The physic liquor was maintained in the nasal cavity for 15 min, 14 days as one therapeutic course: once per 3 days in first treatment course; once per 5 days in the second treatment course; once per 7 days in the third treatment course. The irrigation times gradually reduced as time went by. The VAS scoring was performed in four clinical symptoms, such as nasal obstruction, rhinorrhea, olfaction disorders, discomforts or pain in the face or head. The Lund-Kenenedy quantification scoring method was used for nasal endoscopy to assess the polyps size, mucous membrane, scar, surface scab, and quality of life (QOL). The SNOT-20 rating scales were filled to investigate the QOL. All the assessments were carried out before surgery, 1.5, 3, and 6 months, respectively. The comprehensive efficacy assessment was conducted 1 year later. RESULTS: The 1-year cure rate was 79.25% in the treatment group and 76.92% in the control group, and the total effective rate was 90.57% in the treatment group and 84.62% in the control group. There was no statistical difference between the two groups (P > 0.05). The nasal cavity cleaning time and the epithelization time was (2.15 +/- 0.13) weeks and (9.17 +/- 1.67) weeks respectively in the treatment group, earlier than those in the control group [(2.65 +/- 0.15) weeks and (10.71 +/- 3.12) weeks, P < 0.05]. At week eight 22 patients in the treatment group ended the lavage due to recovery, while 5 patients in the control group ended the lavage, showing statistical difference (P < 0.05). Compared with the control group, better results were obtained in the treatment group in relieving the total VAS score at postoperative 6 weeks and 3 months, in the single score of symptoms at 3 months after operation, the rhinorrhea at postoperative 6 months and 1 year (P < 0.05). The total endoscopic score, and the single score for nasal mucous membrane edema, and nasal secretion at postoperative 1.5 month were lower in the treatment group than in the control group (P < 0.05). The total score of SNOT-20 questionnaire, and the integrals for five major indicators at postoperative 1.5 and 3 months were lower in the treatment group than in the control group (P < 0.05). CONCLUSIONS: The perioperative application of BLFNI could alleviate postoperative mucosal inflammation, shorten the cavity cleaning time, speed up the process of epithelization, improve the QOL, and elevate the operative efficacy. Its therapeutic roles were more prominent within perioperative 1.5-3 months. PMID- 23646472 TI - [Effects of Guizhi Fuling Decoction on YKL-40 and hs-CRP of patients with non-ST segment elevation acute coronary syndrome]. AB - OBJECTIVE: To investigate the changes of serum levels of chitinase-3-like-1 protein (YKL-40) and high-sensitivity C-reactive protein (hs-CRP) in patients with non-ST segment elevation acute coronary syndrome (ACS), to explore its correlation with its severity, and to observe the effects of Guizhi Fuling Decoction (GFD) on levels of blood lipids, YKL-40, and hs-CRP. METHODS: Recruited were 72 patients with unstable angina (UA) or non-ST segment elevation myocardial infarction (NSTEMI) at Department of Integrative Medicine, First Affiliated Hospital of Xinxiang Medical College from August 2010 to June 2011. They were randomly assigned to the treatment group (36 cases) and the control group (36 cases). All patients were treated by routine treatment, but patients in the treatment group took GFD additionally. The course of treatment was four weeks. According to the severity degree, all patients were graded to four ranks: low risk group of UA, medium-risk group of UA, high-risk group of UA, and NSTEMI. The levels of YKL-40 and hs-CRP, and the correlation of severity degree were analyzed. Before and after treatment levels of triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) were measured. Before treatment, at two weeks, and after treatment the serum levels of YKL-40 and hs-CRP were detected. The relationship of YKL-40, hs-CRP and the severity of the disease were analyzed. RESULTS: Levels of YKL-40 and hs-CRP were positively correlated with the severity of the disease respectively (r = 0.729, P < 0.05; r = 0.655, P < 0.05). The positive correlation also existed between YKL-40 and hs-CRP (r = 0.848, P < 0.05). There was no statistical difference in the levels of blood lipids, YKL-40, or hs-CRP between the two groups before treatment (P > 0.05). Compared with before treatment, the levels of YKL-40 and hs-CRP significantly decreased in both groups after two weeks of treatment (P < 0.05). The levels of TG, TC, LDL-C, YKL 40, and hs-CRP significantly decreased, while the HDL-C level increased in both groups after treatment (P < 0.05). The level of HDL-C in the treatment group was higher, while levels of YKL-40 and hs-CRP were lower after treatment, when compared with the control group (all P < 0.05). CONCLUSION: On the basis of anti inflammation and adjusting blood lipids by Western medicine, GFD could further reduce the serum levels of YKL-40 and hs-CRP of ACS patients, elevate the HDL-C level, and play anti-atherosclerosis effects. PMID- 23646473 TI - [Effects of yangxin decoction on metabolomics of patients with unstable angina]. AB - OBJECTIVE: To primarily seek for unstable angina (UA) correlated metabolic markers and to observe the effects of Yangxin Decoction on the plasma metabolism of UA patients. METHODS: Ten UA patients from clinics of No. 2 Circulation Department, First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine from November 2009 to December 2010 were recruited as the treatment group. Another 10 healthy volunteers were recruited as the control group (Group D). The changes of plasma metabolic components were observed in UA patients after they took Yangxin Decoction for 28 days, using liquid chromatography mass spectrometry (LC-MS). Analysis was conducted using principle component analysis (PCA) and partial least squares (PLS) to seek for UA correlated metabolic markers. RESULTS: Results of PCA among Group D (the healthy group), Group M (UA group before medication), and Group G (UA group after medication): all samples of the three groups were centrally distributed in the four score plot of the oval regions (95% confidence interval). In Group M, the relative dispersion of the sample 8, 9, and 10 was near to Group D. The samples of the three groups could be separated. The samples of Group M (before medication) and Group G (after medication) could be basically separated. Comparison of metabolic end products between Group D and Group M: In the metabolites of UA group, ceramide, glycocholic acid, allocholic acid, lithocholic acid, leukotriene B4 obviously increased. CONCLUSIONS: Ceramide, glycocholic acid, allocholic acid, lithocholic acid, leukotriene B4 might be metabolic markers of UA. Yangxin Decoction might have effects on some plasma metabolites or metabolic pathways of UA patients. PMID- 23646474 TI - [Study on the distribution of Chinese medical constitutions of hypertension complicated diabetes patients]. AB - OBJECTIVE: To investigate the distribution features of Chinese medical constitutions in hypertension complicated diabetes patients. METHODS: Recruited were 251 primary hypertension inpatients at the Department of Neurology and the Department of Cardiology, Mindong Hospital of Ningde City from October 2010 to March 2011. They were assigned to two groups according to whether they were complicated with diabetes, i.e., the primary hypertension complicated diabetes (as the case group, 78 cases) and the primary hypertension without complicated diabetes (as the control group, 173 cases). The constitution types were investigated by questionnaire. The constitution type distribution was compared between the two groups. The data including gender, age, and the distribution of the constitution type were compared between the two groups. The levels of TG, TC, LDL-C, Hb, FPG, and ALB were detected on the 2nd day after admission. The levels of TG, TC, LDL-C, Hb, and ALB were compared be- tween the two groups in patients of yin deficiency constitution, phlegm dampness constitution, and qi deficiency constitution. RESULTS: There was no statistical difference in the hypertension grading, the disease course, and chronic disease complications between the two groups (P > 0.05). The main constitution types were yin deficiency (accounting for 26.0%), phlegm dampness (accounting for 19.1%), and qi deficiency (accounting for 19.1%) in the control group. The main constitution types were yin deficiency (accounting for 32.1%), phlegm dampness (accounting for 30.8%), and qi deficiency (accounting for 17.9%) in the case group. The ratio of phlegm dampness type in the case group was higher than that in the control group with statistical difference (P = 0.041). There was no statistical difference in the constitution distribution in the same gender between the two groups (P > 0.05). There was no statistical difference in the constitution distribution in those younger than 80 years between the two groups (P > 0.05). Compared with those older than 80 years in the control group, the ratio of phlegm dampness was higher, and the ratios of yang deficiency, yin deficiency, qi deficiency, and dampness heat were lower in the case group with statistical difference (P = 0.020). There was no statistical difference in the constitution distribution among different age stages in the case group (P > 0. 05). But there was statistical difference in the constitution distribution among different age stages in the control group (P < 0.05). The yin deficiency and qi deficiency constitutions were dominated in thinner patients of the control group, while yin deficiency constitution was dominated in thinner patients of the case group, showing no statistical difference between the two groups (P > 0.05). There was no statistical difference in the distribution of constitution type in overweight patients between the two groups (P = 0.458). Compared with those of gentle type constitution in the same group, the levels of TC and LDL-C increased in those of phlegm dampness constitution in the two groups (P < 0.05). The level of TC increased in those of qi deficiency constitution in the case group. The level of Hb decreased in those of qi deficiency constitution in the control group (P < 0.05). Compared with those of qi deficiency constitution in the same group, the levels of TC and Hb obviously increased in those of phlegm dampness constitution in the control group (P < 0.05). The level of ALB increased in those of yin deficiency constitution in the case group (P < 0. 05). Compared with the control group, the level of FPG of those of each constitution increased in the case group (P < 0.05) ,.and the level of TC increased in those of qi deficiency constitution (P = 0.007). CONCLUSIONS: The main constitution types of hypertension complicated diabetes patients were yin deficiency, phlegm dampness, and qi deficiency. The ratio of phlegm dampness was higher in hypertension complicated diabetes patients than hypertension without complicated diabetes patients. The levels of TC and LDL-C were higher in those of phlegm dampness constitution type. The level of TC was higher in hypertension complicated diabetes patients of qi deficiency constitution. PMID- 23646475 TI - [Treatment of multiple organ dysfunction syndrome by Xuebijing Injection: a clinical research]. AB - OBJECTIVE: To observe the effects and mechanisms of Xuebijing Injection (XI) on multiple organ dysfunction syndrome (MODS) patients. METHODS: Recruited were 76 MODS patients at ICU, Zhejiang Provincial Quhua Hospital from February 2009 to September 2011. They were randomly assigned to the control group (36 cases) and the treatment group (40 cases). All patients received conventional treatment. Those in the treatment group were intravenously injected with XI (prepared by adding 100 mL QI in 100 mL normal saline), twice daily for seven successive days. The APACHE II score, SOFA score, serum procalcitonin (PCT), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and 10 (IL-10) of the two groups were observed in the two groups before treatment, at 3 days and 7days after treatment. The ICU stay time and the 28-day mortality were compared between the two groups. RESULTS: After seven days of treatment, the APACHE II score, SOFA score, TNF alpha, IL-6, IL-10, and PCT significantly decreased in the treatment group, showing statistical difference when compared with the control group at the same time point (P < 0.05). The 28-day mortality, the ICU stay time, APACHE II score, and SOFA score decreased more significantly in the treatment group than in the control group, showing statistical difference (P < 0.05). CONCLUSION: XI could significantly reduce the ICU stay time of MODS patients, and its mechanisms might be correlated to regulating inflammatory reactions. PMID- 23646477 TI - [Treatment of hepatic cancer in mice by beta-elemene combined DC/Dribble vaccine: an immune mechanism research]. AB - OBJECTIVE: To observe the therapeutic effects of beta-elemene combined DC/Dribble vaccine in treating mice with hepatic cancer, thus exploring their anti-tumor mechanisms. METHODS: Dentritic cells were derived from Balb/c mice's spleen and their phenotypes were identified. Using hepatic cancer cell line BNL1MEA.7R.1 (abbreviated as BNL) originated from Balb/c mice as target cell, DC/Dribble vaccine was prepared via raising the antigen representing carrier autophagosomes (DRips in Blebs, DRibbles), which were rich in tumor antigen information. The mice previously immunized were divided into 4 groups, i.e., the control group, the beta-elemene group, the vaccine group, and the combined group. The PBS was subcutaneously and intraperitoneally injected to mice in the control group. The beta-elemene was intraperitoneally injected at the daily dose of 50 mg/kg to mice in the beta-elemene group and the combined group for 7 successive days. DC/Dribble vaccine was injected into the lymph node of mice in the vaccine group and the combined group on the 1st day, and DC/Dribble vaccine was subcutaneously injected on the 3rd day and the 5th day. All the mice were sacrificed on the 10th day. Their spleens were obtained sterilely, and the suspension was incubated with or without Dribble. The cells were inoculated for 72 h. The contents of IFN-gamma in the supernatant were measured by ELISA. In addition, the spleen cells obtained from the combined group were incubated with different stimulations for 72 h, which were then divided into the control group, the DRibble group, the DC group, and the DC/Dribble vaccine group. The supernatant of cultured cells were collected and the contents of IFN-gamma were measured by ELISA. The liver tumor bearing mouse model was established, and then the BNL bearing mice were randomly divided into 4 groups, i.e., the control group, the beta-elemene group, the vaccine group, and the combined group. The treatment ways were the same as the immune ways. The tumor size and the survival period were observed in each group. On the 23rd day the mice were sacrificed. The tumor tissue was stripped and stained by HE staining. The pathomorphological manifestations of the tumor tissue were observed by light microscope. RESULTS: In vitro detection of mice immunized previously by different ways showed that the secretion of IFN-gamma was significantly higher in the combined group than in the rest groups (P < 0.01). The secretion of IFN-gamma was significantly higher in the beta-elemene group and the vaccine group than in the control group (P < 0.01). The spleen cells could be stimulated to secrete a large amount of IFN-gamma in the vaccine group and the Dribble group (P < 0.01). When the beta-elemene was 10 microg/mL as the stimulating dose, the secretion of IFN-gamma obviously increased (P < 0.01). In vivo observation showed that the growth velocity of tumors in mice of the combined group was slowed down. There was statistical difference in the tumor area or the survival period of mice in the combined group, when compared with the other groups (P < 0.01). In HE staining, the surrounding connective tissues of the tumor were wrapped tightly and compactedly, with infiltration of a large amount of inflammatory cells. CONCLUSIONS: beta-elemene combined DC/Dribble vaccine could induce specific immune cells to secrete secretory cells, thus exerting its anti-tumor effect. Its immunological effects might be associated with enhancing the DC antigen presenting function. PMID- 23646476 TI - [Effects of Bushen Jiedu Recipe and Jianpi Jiedu Recipe containing plasma on dendritic cells of chronic hepatitis B virus infection patients under different immune states]. AB - OBJECTIVE: To compare the effects of Bushen Jiedu Recipe (BJR) and Jianpi Jiedu Recipe (JJR) containing plasma on dendritic cells (DCs) of chronic hepatitis B virus (HBV) infection patients under different immune states. METHODS: Recruited were 36 chronic HBV infection outpatients from First Affiliated Hospital of Hunan University of Traditional Chinese Medicine from April 2010 to January 2011. They were assigned to the immune tolerance group (18 cases) and the immune clearance group (18 cases).Another 10 healthy subjects were recruited as the healthy control group. Their anticoagulated peripheral venous blood was respectively collected. The peripheral blood mononuclear cells (PBMCs) were isolated and further extracted for incubating DCs. The DCs were intervened by BJR and JJR containing plasma. The morphology of DCs was identified. The expressions of CD1alpha, CD80, CD86, and HLA-DR were detected. The level of interferon-alpha (IFN-alpha) in the supernatant was observed by ELISA. RESULTS: The CD80 expression level was lower in the immune clear group than in the healthy control group before intervention (P < 0.05). The expression levels of CD80, CD86, and HLA-DR were lower in the immune tolerance group than in the healthy control group before intervention (P < 0.05).The IFN-alpha expression level was lower in the immune tolerance group and the immune clearance group than in the healthy control group before intervention (P < 0.05). The expression levels of CD80, HLA-DR, and IFN-alpha were lower in the immune tolerance group than in the immune clearance group before intervention (P < 0.05). Compared with the same group before intervention, the CD80 expression significantly increased in each treatment group (P < 0.05). After intervention the expression levels of CD80 and HLA-DR were higher in the immune tolerance group than in the immune clearance group in the same time phase, and the CD86 expression level was higher in the BJR group than in the immune clearance group in the same time phase, showing statistical difference (P < 0.05). CONCLUSIONS: The middle dose BJR and the small dose JJR both could promote the recovery of DCs in chronic HBV infection patients. Besides, BJR showed more prominent effects on the function of DCs in chronic HBV infection patients in the immune tolerance stage. PMID- 23646478 TI - [Effects of the ultra-filtration extract mixture from Hedysarum Polybotrys on human liver cells HepG2 radiosensitivity]. AB - OBJECTIVE: To investigate the effects of the ultra-filtration extract mixture from Hedysarum Polybotrys (UEMHP) on the radiosensitivity of HepG2 cells, and to explore its possible mechanisms. METHODS: The proliferation inhibition effects of UEMHP on HepG2 cells was detected by CCK-8 assay. The colony formation assay was used for the survival fraction (SF) analysis. The distribution of the cell cycle and the apoptosis rate were detected using flow cytometry (FCM). The survivin mRNA expression level was detected using reverse transcription-PCR assay. RESULTS: The inhibition of UEMHP on HepG2 cells was time-and dose-dependent at the concentration ranging between 5 -50 mg/L (P < 0.05). The parameters of the two curve for SF (P < 0.05) showed statistical difference between the irradiation group and the UEMHP irradiation group. UEMHP could inhibit the clone formation of HepG2 cells and enhance the radiosensitivity of HepG2 cells. The results of FCM showed that UEMHP could induce G2/M phase arrest. The apoptosis rate in the UEMHP irradiation group (21.42% +/- 3.74%) was higher than that in the control group (5.35% +/- 0.41%), the only UEMHP group (10.36% +/- 1.75%), or the irradiation group (10.58% +/- 2.01%) (P < 0.01). RT-PCR showed that the survivin mRNA expression level was lower in the UEMHP irradiation group (0.31 +/- 0.02) than in the control group (0.82 +/- 0.06) and the irradiation group (0.58 +/- 0.04) respectively, showing statistical difference (P < 0.01). CONCLUSION: UEMHP can enhance the radiosensitivity of HepG2 cells, and its possible mechanisms might be correlated to down-regulating the survivin mRNA expression and promoting the apoptosis. PMID- 23646479 TI - [Effects of polydatin on ALT, AST, TNF-alpha, and COX-2 in sepsis model mice]. AB - OBJECTIVE: To investigate the protective effects of polydatin on sepsis-induced acute liver injury (ALI) in mice, and to preliminarily study its mechanisms. METHODS: The sepsis model was established using cecal ligation and puncture (CLP).A sham-operation control group was also set up. Polydatin (50, 100, and 300 mg/kg, respectively) was administrated to mice 1 h before CLP. The survival and liver injury were evaluated subsequently per 6 h after CLP. The survived mice were scarified 24 h later. The serum and the liver tissue sample were collected. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by colorimetric method. The content of tumor necrosis factor-alpha (TNF-alpha) was assayed by ELISA. The cyclooxygenase-2 (COX-2) expression in the liver tissue was detected by Western blot. The pathological changes of the hepatic tissue were analyzed by hematoxylin and eosin stain. RESULTS: The mortality of mice reached as high as 50% at 24 h after CLP. The biochemical indices and the pathological changes of the liver tissue showed obvious lesion. The success rate of modeling was 90%. Compared with the sham-operation control group, the serum ALT,AST activity, the TNF-alpha content, and the hepatic COX-2 protein expression markedly increased in the CLP group (P < 0.01). Polydatin improved the sepsis-induced mortality dose-dependently, inhibited increased ALT, AST activity and TNF-alpha, decreased the hepatic COX-2 protein expression, and attenuated the pathological injury of the liver (P < 0.05). CONCLUSION: Polydatin could effectively protect sepsis-induced ALI, which might be achieved possibly through inhibiting serum TNF-alpha production and hepatic COX-2 expression. PMID- 23646480 TI - [Effects of ginsenoside Rg1 on the expressions of p-eRK1/2 and p-JNK in local cerebral ischemia/reperfusion injury rats]. AB - OBJECTIVE: To study the possible anti-apoptotic mechanism of ginsenoside Rg1 on the apoptosis of hippocampal neuron after cerebral ischemia/reperfusion (I/R) injury rats. METHODS: Totally 120 healthy male adult SD rats were randomly divided into the cerebral I/R model group (the model group), the low dose ginsenoside Rg1 group (10 mg/kg), the middle dose ginsenoside Rg1 group (20 mg/kg), the high dose ginsenoside Rg1 group (40 mg/kg), and the sham-operation group, 18 in each group. Rats received medication by peritoneal injection. Equal volume of normal saline was peritoneally injected to rats in the sham-operation group and the model group, once daily, for 7 successive days. The cerebral I/R injury model was prepared by 2-h middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion. Rats in the sham-operation group received the same surgical procedure without the carotid arteries occluded. The neurofunction was assessed using Longa EZ method. The injury of hippocampal pyramidal cells was observed by Nissel staining and TUNEL assay. The nerve cell apoptosis rate was calculated. The protein expression levels of extracellular signal-regulated kinase 1/2 (ERK1/2), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), c Jun N-terminal kinases (JNK), and phosphorylated c-Jun N-terminal kinase (p-JNK) were detected using Western blot. RESULTS: Compared with the sham-operation group, the score of neurofunction, the apoptosis rate, the expression levels of p JNK and p-ERK1/2 increased, the survived number of pyramidal cells decreased in the model group (P < 0.05, P < 0.01). Compared with the model group, the score of neurofunction and the apoptosis rate decreased in each ginsenoside Rg1 group (P < 0.05, P < 0.01). The survived number of pyramidal cells increased in the high and middle dose ginsenoside Rg1 groups, the expression of p-JNK in the hippocampal CA1 region decreased, and the expression level of p-ERK1/2 increased (P < 0.05, P < 0.01). Compared with the low dose ginsenoside Rg1 group, the score of neurofunction, the apoptosis rate, the p-JNK protein expression decreased, the survived number of pyramidal cells increased, the expression of p-ERK1/2 increased in the high and middle dose ginsenoside Rg1 groups (P < 0.05, P < 0.01). Three to four layers of pyramidal cells were arranged tightly and compactly in the hippocampal CA1 region of the sham - operation group. The nucleus was big and round under high power lens, with 1 -2 kernel. After cerebral I/R injury, the hippocampal nerve cells were severely injured. Normal structure was lost in the CA1 region, with disarranged cell line and reduced cell amount. Partial neurons were shrunken, and the kernel was condensed and darkenedly stained. They were in triangular, long strip, fusiform, or irregular shape. The staining of nucleus was clustered and the kernel was not clear. Ginsenoside Rg1 (20 and 40 mg/kg) could improve the morphology of ischemic nerve cells, reduce their loss. Of them, stronger effects were shown in the high dose ginsenoside Rg1 group than in the middle dose ginsenoside Rg1 group. The JNK protein band was divided into two subzones, JNK1 (46 kD) and JNK2 (54 kD). ERK protein band was also divided into two subzones, ERK1 (44 kD) and ERK2 (42 kD). CONCLUSION: The protective effect of ginsenoside Rg1 on cerebral I/R injury was correlated with inhibiting the apoptosis of hippocampal neurons, regulating the expression levels of p-ERK1/2 and p-JNK. PMID- 23646481 TI - [The role of adenosine deaminase in the electroacupuncture preconditioning induced rapid tolerance to focal cerebral ischemia]. AB - OBJECTIVE: To observe the electroacupuncture (EA) pretreatment at Baihui (GV20) on the concentration of adenosine deaminase (ADA) and adenosine, and to evaluate its effects on the neurologic function score and the infarction volume after middle cerebral artery occlusion (MCAO) ischemia/reperfusion (I/R), thus exploring its mechanisms for relieving the ischemia/reperfusion injury. METHODS: Totally 54 male SD rats were randomly divided into 3 groups, the sham-EA group, the EA group, and the control group, 18 in each group. Rats in the control group were not intervened after anesthesia. Rats in the EA group were needled at Baihui (GV20) for 30 min. Rats in the sham-EA group received the same procedure as those performed in the EA group without electricity connected. The changes of adenosine and ADA contents were detected at 30, 60, and 120 min after EA respectively. The I/R model was established. Totally 48 male SD rats were randomly divided into 6 groups, i.e., the model group (Group A), the EA group (Group B), the EA +8 Cyclopentyl-1,3-dipropylxanthine (DPCPX) group (Group C), the EA + DMSO group (Group D), the Deoxycoformycin (Deo) group (Group E), and the normal saline group (Group F). Rats in Group B, C, and D received EA for 30 min before modeling. Rats in Group C and D were peritoneally injected with DPCPX (1 mg/kg) and DMSO (1 mL/kg) at 30 min before EA. The neurologic function score was evaluated and the infarct volumes were detected after 24-h reperfusion. RESULTS: Compared with the sham-EA group, there was no statistical difference in the contents of the adenosine or ADA in the control group at each time point (P > 0.05). Compared with the control group at the same time point, the content of ADA significantly decreased at 60 min in the EA group [(315.0 +/- 22.9 U/L), P < 0.05], and restored to the normal level at 120 min after EA. The content of adenosine increased in the EA group at 120 min [(20.4 +/- 2.2) ng/microL, P < 0.05]. Compared with the model group, the neurologic function score decreased (P < 0.05) and the infarct volumes were obviously reduced (P < 0.01) in Group B, D and E. There was no statistical difference in the neurologic function score or the infarct volumes in other groups, when compared with the model group (P > 0.05) CONCLUSION: EA at Baihui (GV20) showed protective effects on the cerebral I/R rats, which might be achieved through lowering the ADA concentration and elevating the adenosine content, and further activating adenosine A1 receptor. PMID- 23646482 TI - [Effects of curcumin on ischemia/reperfusion induced apoptosis of H9c2 myocardial cells and the expression of glycogen synthase kinase-3 and its phosphorylation]. AB - OBJECTIVE: To investigate the effects of curcumin on the apoptosis of ischemia/reperfusion (I/R) induced H9c2 myocardial cells and the expression of glycogen synthase kinase-3 (GSK-3) and its phosphorylation state. METHODS: I/R of H9c2 cells in vitro was simulated by an ischemic Tyrode solution. Cells were randomly divided into 3 groups, i.e., the model group (exposed to ischemic solution for 90 min followed by 30 min reperfusion with the normal Tyrode solution), the curcumin group (7.5 micromol/L curcumin added at the onset of reperfusion for 30 min), and the control group (exposed to normal Tyrode solution for 120 min). Then, the cell apoptosis was detected in 3 groups by flow cytometry. The expression levels of GSK-3, phosphotyrosine-GSK-3 (pTyr-GSK-3), and phosphoserine-GSK-3 (pSer-GSK-3) were detected by Western blot. RESULTS: Compared with the control group,the apoptosis rate was obviously enhanced in the model group (t = 10.439, P = 0.000). And the relative expression levels of both pTyr-GSK-3 and pSer-GSK-3 significantly increased in the model group (t = 5.208, P = 0.006; t = 5.854, P = 0.004, respectively). Compared with the model group, the apoptosis rate and the expression of pTyr-GSK-3 significantly decreased in the curcumin group (t = -8.325, P = 0.001; t = -3.607, P = 0.023). Compared with the model group, the rate of viable cells and the expression of pSer-GSK-3 were significantly enhanced in the curcumin group (t = 9.165, P = 0.001; t = 3.747, P = 0.02). CONCLUSIONS: Both pTyr-GSK-3 and pSer-GSK-3 might participate in the IR injured myocardial cells. Curcumin could reduce apoptosis of I/R injured myocardial cells, which might be correlated with GSK-3 inhibition by decreasing tyrosine phosphorylation and increasing serine phosphorylation. PMID- 23646483 TI - [Research of Dangua Recipe on intervening the glycolipid metabolism and oxidative stress in diabetic rats with atherosclerosis]. AB - OBJECTIVE: To explore the effects of Dangua Recipe (DGR) on glycolipid metabolism, serum reactive oxygen species (ROS) level, nuclear factor kappa B (NF kappaB) positive expression and its mRNA expression level in the thoracic aorta of diabetic rats with atherosclerosis, thus revealing its partial mechanisms for intervening chronic diabetic complications. METHODS: Recruited 40 Goto-Kakisaki (GK) Wistar rats were fed with high fat forage containing metabolic inhibition Propylthiouracil, and peritoneally injected with endothelial NOS inhibitor N nitro-L-arginine methyl ester to establish a high fat diabetes model with atherosclerosis. The modeled GK rats were stratified by body weight, and then, by blood glucose level from high to low, randomly divided into the DGR group (at the daily dose of 8 mL/kg), the metformin group (MET, at the daily dose of 150 mg/kg), the simvastatin group (SIM, at the daily dose of 2 mg/kg), and the model group (MOD, fed with pure water, at the daily dose of 8 mL/kg) according to the random number table, 10 in each group. Another 10 Wistar rats of the same ages and comparable body weight level were recruited as the normal control group. All the interventions lasted for 24 weeks by gastrogavage. The fasting blood glucose (FBG) and body weight were monitored. The HbA1c, TC, LDL-C, HDL-C, TG, serum ROS were determined. The aortic NF-kappaB level was analyzed with immunohistochemical assay. The expression of NF-kappaB (P65) mRNA in the aorta was detected with Real time PCR. RESULTS: The body weight in the normal control group was eventually heavier than others (P < 0.01). There was no difference among the four groups of GK modeled rats (P > 0.05). The FBG in the four GK modeled groups were higher than that in the normal control group (P < 0.01, P < 0.05). There was no statistical difference in the blood glucose level at the first visit and at the baseline among the GK modeled groups (P > 0.05). The last FBG level was obviously lower in the MET and DGR groups than in the MOD group (P < 0.01) and the SIM group (P < 0.05). Twenty-four weeks after intervention, the level of FBG, HbA1c, TC, LDL-C, HDL-C, and NF-kappaB positive expression rate of the thoracic aorta of the four groups of GK modeled rats, and NF-kappaB mRNA expression in the thoracic aorta in the MOD group, the MET group, and the DGR group were significantly higher than those in the normal control group (P < 0.01, P < 0.05). The TG level, serum ROS in the MET, DGR, and SIM groups, and the NF-kappaB mRNA expression level in the thoracic aorta in the SIM group were significantly lower than those in the normal control group (P < 0.01, P < 0.05). The levels of FBG, TC, LDL-C, serum ROS, NF-kappaB mRNA expression level in the thoracic aorta in three drug intervention groups, and NF-kappaB positive expression rate in the DGR and MET groups, and the levels of HbA1c, TG in the DGR group were significantly lower than those in the MOD group (P < 0.01, P < 0.05). The level of FBG in the MET and DGR groups were lower than that in the SIM group (P < 0.05). The level of NF kappaB mRNA expression in the thoracic aorta of the SIM and DGR groups, and the levels of TC and LDL-C in the DGR group were significantly lower than those in the MET group (P < 0.01). CONCLUSION: DGR played a role in preventing and treating chronic diabetic complications by comprehensively regulating blood glucose and serum lipids, as well as down-regulating oxidative stress. PMID- 23646484 TI - [Acceleration of Jingui Shenqi Pill on the testis telomerase activity in mice of Shen-yang deficiency]. AB - OBJECTIVE: To explore the effects of Jingui Shenqi Pill (JSP) on the testis telomerase activity in mice of Shen-yang deficiency syndrome (SYDS). METHODS: The SYDS model was prepared in 30 mice by over-fatigue and sexual overstrain. They were randomly divided into the model group and the JSP group, 15 in each group. Another 15 normal male mice were selected as the normal group. Mice in the normal group were fed routinely, with distilled water administered intragastrically at the daily dose of 0.1 mL/10 g. Mice in the model group were also administered intragastrically with distilled water at the daily dose of 0.1 mL/10 g while modeling establishment. Mice in the treatment group were administered intragastrically with JSP suspension at 0.1 mL/10 g (the concentration was 0.241 g/mL). The intervention lasted for 4 weeks. Four weeks later, the testis telomerase activity was detected in the three groups by ELISA. RESULTS: The SYDS model was replicated successfully by over-fatigue and sexual overstrain. JSP could improve the signs of mice of SYDS. Compared with the normal group, the activity of testis telomerase decreased in the model group (P < 0.01). Compared with the model group, the testis telomerase activity markedly increased in the treatment group (P < 0.01). CONCLUSIONS: The testis telomerase activity in mice of SYDS caused by over-fatigue and sexual overstrain obviously decreased, when compared with that in mice of the normal group. JSP could recover its activity. PMID- 23646485 TI - [Effects of zhengqing fengtongning tablet and methotrexate on the serum OPG/RANKL and IL-17 of collagen-induced arthritis rats]. AB - OBJECTIVE: To study the effects of Zhengqing Fengtongning Tablet (ZFT) and methotrexate (MTX) on the expression of osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB ligand (RANKL), and interleukin 17 (IL-17) in collagen induced arthritis (CIA) rats, thus addressing their bone protection. METHODS: The CIA rat model was established by intradermally injecting type II collagen emulsion from the rats' back and tail. Totally 28 successfully modeled rats [with the arthritis index (AI) more than 2] were randomly divided into the model group, the Chinese medicine (CM) treatment group, the MTX group, and the ZFT + MTX treatment group, 7 rats in each group. Another 7 rats were recruited as the normal control group. Rats were administered from the 7th day of modeling. Rats in the MTX group were treated with MTX at 3.8 mg/kg once a week. Those in the CM group were treated with ZFT at the daily dose of 130 mg/kg, once a day. Those in the ZFT + MTX treatment group were treated with both MTX (at 3.8 mg/kg once a week) and ZFT (at the daily dose of 130 mg/kg, once a day). Those in the model group and the normal control group were administered with normal saline of the equal volume by gastrogavage. All the intervention lasted for 26 days. The destruction of joints in the four limbs were observed using X-ray. The AI was recorded. The expression levels of serum OPG, RANKL, and IL-17 were detected at the end of the experiment. RESULTS: During the whole process, all rats except those in the model group were in a good condition. On the 21st day of modeling the AI of all rats reached the peak, but it decreased after treatment. Compared with the model group, the AI decreased in the CM treatment group, the MTX group, and the ZFT + MTX treatment group with statistical difference (P < 0.05). Compared with the model group, the OPG increased and RANKL decreased in the MTX group; the OPG and OPG/RANKL increased in the CM treatment group; the OPG, RANKL, and OPG/RANKL increased, and IL-17 decreased in the ZFT + MTX treatment group, all showing statistical difference (P < 0.05). Compared with the MTX and the ZFT + MTX treatment group, OPG/RANKL increased and IL-17 decreased in the ZFT + MTX treatment group (both P < 0.05). CONCLUSION: ZFT + MTX could synergistically elevate peripheral OPG/RANKL and down-regulate IL-17 in CIA model rats. PMID- 23646486 TI - [Regulation effects of liuwei dihuang pill, jingui shenqi pill, jiangu erxian pill containing serums on adipogenic and osteogenic differentiation-related genes expressions in the differentiation process of preadipocytes to osteoblasts]. AB - OBJECTIVE: To study the effects of Chinese medical recipes for invigorating Shen on rat bone marrow mesenchymal stem cells (BMSCs)-derived preadipocytes' differentiation to osteoblasts. METHODS: The BMSCs were cultured using whole bone marrow adherence wall method. The BMSCs were induced to preadipocytes by classic chemical method. The osteogenic differentiation process of preadipocytes was intervened by Liuwei Dihuang Pill (LDP), Jingui Shenqi Pill (JSP), or Jiangu Erxian Pill (JEP)-containing serums (with the concentRation of 10%, on behalf of tonifying Shen yin, tonifying Shen yang, and tonifying Shen essence). Reverse transcription-real time fluorescent quantitative-PCR (RT real time qPCR) was used to detect RUNX2, ALP, BGP, BMP2, BMP4, SPP1, and IGF1 mRNA expressions of osteogenic differentiation-related genes, mRNA expressions of LPL, FABP4, and PPARgamma of adipogenic differentiation-related genes on the 6th, the 12th, and the 18th day. RESULTS: As for the osteogenic differentiation-related gene, when compared with the control group, there was no statistical difference in the gene expression level in the experimental groups on the 6th day (2.0 > Ratio > 0.5). On the 12th day, the mRNA expressions of IGF1 and Runx2 increased more significantly in the JSP group, with their relative quantification (Ratio) being 2.97 and 1.81 respectively. On the 18th day the IGF1 mRNA expression significantly increased, being the Ratio value of 3.74, 12.60, and 8.35, respectively, in the LDP group, the JSP group, and the JEP group. The SPP1 mRNA expression also significantly increased, with the Ratio value of 2.94, 3.18, and 2.62, respectively, in the LDP group, the JSP group, and the JEP group. As for adipogenic differentiation-related genes, on the 6th day, when compared with the control group, FABP4 mRNA expression significantly decreased in the LDP group and the JSP group (with the Ratio value of 0.47 and 0.40 respectively). The expression levels of other genes were all down-regulated, but not significantly. On the 12th day and 18th day, there was no statistical change in the adipogenic differentiation-related genes expressions (2.0 > Ratio > 0.5). CONCLUSIONS: Up regulation of osteogenic differentiation-related genes expression occurred in later time, while down-regulation of adipogenic differentiation-related genes expression occurred in earlier time after treatment by Chinese medical recipes for invigorating Shen. In general, above data indicated that tonifying Shen yang was more effective in promoting osteogenic differentiation and inhibiting adipogenic differentiation of BMSCs. PMID- 23646487 TI - [Exploring the pathogenesis and therapy of liver cancer from "damp-heat insidious pathogen" to "cancer toxin"]. AB - From a macro-level analysis of the attributes and pathogenic features of HBV, the main pathogenic factor for chronic liver diseases including viral hepatitis, cirrhosis, and liver cancer, the concept of damp-heat insidious pathogen was obtained, according to which, in-depth discussions were undertaken. Adopting syndrome typing of Wei (defense), qi (vital energy), Ying (nutrients), and blood, the pathogens leading to different syndromes as well as new products such as pathological "sputum", "stasis" in the disease process were understood, and then, the pathological "sputum" and "stasis", as the hub, playing a role in chronic lesions of the liver collateral were explained. Finally the pathological "sputum" and "stasis" blend and form cancer toxin. Through a comprehensive understanding of the development of chronic liver diseases, it is clear that damp-heat insidious pathogen, as its initiating factor, always exists in the whole process. We summed up heat clearing, dampness resolving, and detoxification was the principle for treating chronic liver disease. PMID- 23646488 TI - [Preliminary study of establishing clinical effect evaluation methods of Chinese medicine based on combination of disease and syndrome, systematic staging, and multi-dimension index]. AB - The clinical effect evaluation of Chinese medicine (CM) has been the bottleneck restricting its development. Based on the current situation, in this study, we integrated and combined previous results of clinical effect evaluation of CM, and proposed the clinical effect evaluation method of CM based on combination of disease and syndrome, systematic staging, and multi-dimension index. We also made a specific exposition on the connotation, establishment methods and practice of the clinical effect evaluation methods of CM based on combination of disease and syndrome, systematic staging, and multi-dimension index. PMID- 23646489 TI - [Discussion on relevant concepts of mechanism based medicine]. AB - Mechanism based medicine (MBM) is the new medical mode proposed by the author. Relevant concepts of MBM were described in this paper, such as essential mechanism, analysis of MBM, experiments of MBM,clinics of MBM, and diagram of MBM, thus helping readers to understand this new mode. PMID- 23646491 TI - [Advance in the pharmacological effects of earthworm]. PMID- 23646490 TI - [Advance of resveratrol in treating diabetes mellitus]. PMID- 23646492 TI - [Advance in treatment of polycystic ovary syndrome]. PMID- 23646493 TI - The impact of gender, age and tissues in vitro on estimating postmortem interval by FTIR spectroscopy. AB - To investigate the influence of such individual factors as gender, age and tissues in vitro to the postmortem interval (PMI) by the Fourier transform infrared (FTIR) spectrometer in animal experiments. SD rats were classified into male and female groups, different age groups (21-day, 42-day and 63-day group), and tissues in vitro and in vivo groups. The rats were sacrificed by cervical dislocation, whose bodies were kept in a controlled environmental chamber set at (20+/-2) degrees C and 50% humidity. The liver, kidney, spleen, myocardium, brain, lung and skeletal muscle tissues were collected for measurement from time zero to 48 h postmortem. With the change of PMI, no obvious changes were found in the main FTIR absorbance peaks and their ratios at different time points. All the experimental groups showed no significant changes when compared with the controls. The gender, age and tissues in vitro were not found to be contributing factors in the estimation of PMI via FTIR spectroscopy. PMID- 23646494 TI - Electroretinogram and histopathologic changes of the retina after methanol intoxication. AB - In order to study the functional and structural alterations of the retina in SD rat model after methanol intoxication, 35 rats were divided randomly into five groups administrated with saline, 3-day high dose, 7-day high dose, 3-day low dose and 7-day low dose methanol separately. The retinal function of each group was assessed by flash electroretinogram (F-ERG) 3 and 7 days after methanol poisoning. The microstructure and ultrastructure of the retina were observed at the same time. The high-dose methanol intoxication induced irreversible retinal functional and structural damages 3 days after poisoning, which included prolonged latency and reduced amplitude of the Max-reaction of F-ERG. These injuries were aggravated 7 days after poisoning. Meanwhile, the latency and amplitude of the Cone-reaction of F-ERG were also affected 3 days after poisoning, but there were no further worsening tendency 7 days after poisoning. The retinal histological analysis showed cellular edema, heteromorphy and disarrangement, tissular loosen of the inner nuclear layer and photoreceptors layer. The mitochondrial damage began at the photoreceptors layer and developed further into the inner nuclear layer. The low-dose methanol intoxication only caused transient damage of the retina. Our results showed that the function and structure of the photoreceptor and inner nuclear layer were the primary target of methanol intoxication and that the rod cells were more sensitive to methanol intoxication than the cone cells. The mitochondrial damage developed from outer layer to inner layer of the retina. PMID- 23646495 TI - [Skeletal age estimation by pelvic X-ray of Han teenagers in Sichuan]. AB - OBJECTIVE: To estimate the chronological age of Han teenagers in Sichuan by the epiphyses development characteristics of iliac crest and ischial tuberosity in X ray digital images. METHODS: According to TW2 classification principle, combining with the age range of our subjects and epiphyses development regularity, the degree of epiphyses development of iliac crest and ischial tuberosity had been divided into 8 grades (0-7) and 7 grades (0-6), respectively. Based on the degrees, the pelvic X-rays digital images of 691 samples of 16-20 aged teenagers were read and statistically analyzed by SPSS 19.0 software. The multiple linear regression equation was established by skeletal age (Y), development degree of iliac crest epiphyses (X1) and ischial tuberosity epiphyses (X2). RESULTS: There were no statistical differences between two sides of epiphyses development of iliac crest and ischial tuberosity (P>0.05). There were no statistical difference between genders (P>0.05). The re-substitution method of the samples showed that the accuracy of equation as Y=15.269+0.444X1+0.236 X2 was high. The result of the re-substitution method showed a high accuracy of the equation. CONCLUSION: The multiple linear regression equation could be used to identify the skeletal age for providing the scientific basis to identify the 18-year-old Han population in Sichuan. PMID- 23646496 TI - [Applying multiple displacement amplification to DNA typing in the pathological section]. AB - OBJECTIVE: To investigate the feasibility of applying multiple displacement amplification (MDA) to DNA typing in forensic pathological section. METHODS: Ninety-eight pieces of pathological sections were prepared in terms of 3 factors as the period of preservation, tissue types and death ages, and randomized into groups by Latin square by double 7-order design. Silicon bead method was used to extract the DNA template. Compared with the PCR amplification performed directly by AmpFlSTR Identifiler kit in the control group, MDA was performed before amplification in the experimental group. Based on the samples from fresh autopsies as the standard genotypes, the number of detection and the detection rate were analyzed and compared between the experimental group and the control group. RESULTS: Between the control group and the experimental group, there was significantly statistical difference regarding the rate of DNA typing in each period of the tissue sections preserved (P<0.01). The detection rate of the 16 loci in the experimental group was more than 95% when the period of the tissue sections were preserved within 360d. There was significant difference in different tissue types (P<0.01). But there was no significant difference in different death ages (P>0.01). CONCLUSION: MDA is efficacious in DNA typing of forensic pathological sections, for it can improve the DNA template quantification through abating the inhibiting factor's concentration of PCR and reducing the rate of allele drop out (ADO). However, the period of the sections preserved and tissue types would affect the results of genotyping by MDA. PMID- 23646497 TI - [Genetic polymorphisms of SNP loci in the 5' and 3' region of TPH2 gene in Northern Chinese Han population]. AB - OBJECTIVE: To investigate the genetic polymorphism in the 5' and 3' region of TPH2 gene of Northern Chinese Han population and to explore its application value in forensic medicine. METHODS: The sequence variants and the genetic polymorphisms of 6 SNP loci (rs4570625, rs11178997, rs11178998, rs41317118, rs17110747 and rs41317114) within a 905 bp 5' flanking region and a 1,104bp 3' flanking region of TPH2 gene were analyzed by DNA sequencing in a total of 244 unrelated healthy individuals in Northern Chinese Han population. The statistical analysis was carried out by Haploview v4.2 software. RESULTS: The genotypic distributions of the 6 SNP loci in the TPH2 gene were in accordance with Hardy Weinberg equilibrium. One C/T variant in 92922 site was found. There was a high linkage disequilibrium among the 3 SNP loci (rs4570625, rs11178997 and rs11178998) in the 5' region and the 3 SNP loci (rs41317118, rs17110747 and rs41317114) in the 3' region of TPH2 gene, respectively. The parameters of population genetics of 6 SNP loci were obtained. CONCLUSION: There are great polymorphisms in the 5' and 3' region of TPH2 gene in Northern Chinese Han population, which could be used as genetic indexes for association analysis of the related diseases, as well as for forensic individual identification and paternity testing. PMID- 23646498 TI - [Distribution of deltamethrin in acute poisoned rats]. AB - OBJECTIVE: To establish an animal model in acute poisoned rat by deltamethrin and an analysis method for determination of deltamethrin by gas chromatography electron capture detector (GC-ECD) and to study the distribution of deltamethrin in rats in order to provide the references for forensic medicine identification about such cases. METHODS: Rats were administered with deltamethrin of different doses(512 and 1,024 mg/kg) and killed 1.5 h later to be dissected rapidly for tissues (blood, hearts, livers, lungs, kidneys and brains etc.). Samples were dehydrated by anhydrous sodium sulfate and extracted with petroleum ether and acetone (V:V=4:1). The level of deltamethrin was determined by GC-ECD. RESULTS: There was a good separate between deltamethrin and endogenous impurities. The limit of quantification for deltamethrin in blood and liver were 0.1 microg/mL and 0.1 microg/g (S/N> or =10), respectively. The recovery rate of deltamethrin in blood was 91.55%-134.37% and both inter-day and intra-day precisions were less than 5.67%. The distribution of deltamethrin in poisoned rats with 512 mg/kg was as follow: lungs > livers > hearts > kidneys > blood > brains and with 1 024 mg/kg dose was lungs > blood > hearts > kidneys > brains > livers (P<0.05). CONCLUSION: The GC-ECD method is sensitive for determination of deltamethrin. The distribution of deltamethrin in rats has a dose-dependent manner. The study suggests that samples of blood, hearts, livers, lungs, kidneys and brains are suitable for deltamethrin poisoned analysis. PMID- 23646499 TI - [Analysis of distribution and pathological characteristics of 9 fatal trichinosis cases in Yunnan]. AB - OBJECTIVE: To explore forensic pathology features of the fatal trichinosis cases and to summarize the population distribution characteristics of trichinosis in Yunnan. METHODS: Nine recent fatal trichinosis cases were collected from the Forensic Science Identification Center of Kunming Forensic Hospital. Pathological and epidemiological characteristics of trichinosis were analyzed. RESULTS: The nine cases were all died in heart failure due to myocarditis. Among them, 1 case was complicated by encephalitis and 3 cases were complicated by pneumonia. The population mainly involved Bai and Dai nationalities. The geographic distribution was concentrated in Dali, Dehong, Lincang, Xishuangbanna, etc. The cases commonly appeared in winter and spring. CONCLUSION: The cause of trichinosis is closely due to the habit of eating raw pork. It can be diagnosis through the pathological changes of the muscle system in the death cases. PMID- 23646500 TI - [Retrospective forensic analysis of 483 solved homicide cases in Suzhou city]. AB - OBJECTIVE: To summarize the solved homicide cases taking place in Suzhou city and to find out the characteristics and commonness of them in order to analyze the key points of investigation at the scene. METHODS: The data of 483 solved homicide cases occurring from January 2006 to March 2010 in the city were analyzed. RESULTS: Most cases involved 1 victim and 1 suspect, with young male adults dominated. Most of them were non-local residents. The majority of suspects were intentional by passion due to quarrel and dispute. The most common weapons were sharp instruments generally carried by the suspects. Mechanical asphyxia and mechanical injury were the two most common causes of death in these cases. CONCLUSION: The social characteristics of suspects, criminal motivation, injury instruments, distribution of injuries, cause of death, and manner of death in Suzhou showed similar general characteristics as the experience for detecting homicide cases in the future. PMID- 23646501 TI - [Forensic identification of 50 phalangeal fracture cases]. AB - OBJECTIVE: To study the characteristics of forensic identification of phalangeal fracture and to use a combination of medical records, imaging materials, and forensic examination data in identification. METHODS: Fifty cases of phalangeal fracture involved in the forensic identification were collected from 2009 to 2011. The general situation, the distribution of fracture, the fracture morphology, the injury-causing objects and the results of identification were analyzed retrospectively. RESULTS: Majority of the cases of phalangeal fracture were young and middle-aged men. The index finger and distal phalanx fractures were common. There was no difference in the number of phalangeal fracture between left and right hand. Most of the injury-causing objects were knives and sticks, followed by bricks and stones. CONCLUSION: The injury-causing objects and modes are related to the morphology of fracture, the distribution of fracture and the severity of the injury. The comprehensive analysis is helpful in forensic identification of phalangeal fracture. PMID- 23646502 TI - [Genetic polymorphisms of four SNP loci in D5 gene of dopamine receptor in Northern Chinese Han population]. AB - OBJECTIVE: To reveal the genetic polymorphisms of four SNP loci (rs77434921, rs2076907, rs6283, rs1800762) in D5 gene of dopamine receptor (DRD5) in Northern Chinese Han population. METHODS: Four SNP loci of the DRD5 gene of 206 unrelated individuals in Northern Chinese Han population were separately amplified and sequenced by PCR technique and statistically analyzed by Haploview v4.1 software. RESULTS: In Northern Chinese Han population, the genotype frequency distribution of rs77434921, rs2076907, rs6283 and rs1800762 loci in the DRD5 gene were all in accordance with Hardy-Weinberg equilibrium. DP value was 0.145, 0.532, 0.602 and 0.159, while PE value was 0.004, 0.079, 0.196 and 0.007. A linkage disequilibrium among these four SNP loci was also demonstrated, which might infer five haplotypes. CONCLUSION: rs2076907 and rs6283 loci of DRD5 gene in the Northern Chinese Han population have high genetic polymorphisms, which can be useful for forensic identification of individuals. PMID- 23646503 TI - [The role and significance of microRNA in human cardiovascular disease and forensic science]. AB - microRNA (miRNA or miR) is a small single stranded non-coding RNA (21-25nt) that regulates gene expression in almost creatures. Currently, plenty of researches on how miRNA affects human cardiovascular disease have been reported. This review highlights recent findings about the role of miRNA in heart tissue and circulation correlated with human cardiovascular disease and explores the application of miRNA in sudden cardiac death in forensic science. PMID- 23646504 TI - [Progress in application of microbeam X-ray fluorescence spectroscopy in forensic science]. AB - Microbeam X-ray fluorescence (micro-XRF) spectrometry has been raised as an analytical technique of microbeam during the recent years. With its advantages of high sensitivity, small sample requirement, high testing accuracy and non destruction, the technique is widely utilized in forensic science. This review bases on recent researches at home and abroad, describes its applications including identification of gunshot residue, visualization of fingerprints, discrimination of drug source, production process, and other material evidences of analysis in crime scene. Thanks to the advances in technology, intelligent and portable micro-XRF equipment has appeared to be applied. It is believed that it may be more popular and frequent in administration of forensic science in the near future. PMID- 23646505 TI - [Progress in isokinetic technology in testing and training for assessment of muscle function]. AB - Isokinetic technology in testing and training is the most advanced practical technique in the evaluation of muscle function. This method is a continuous dynamic test in the full range of the joint motion which has strong pertinence at the aspect of assessing muscle strength, and is an objective and quantitative method for reflecting each point's muscle strength in the range of the joint motion. This article reviews the key concepts, brief history of development and influencing factors of isokinetic technology in testing and training, introduces the progress in the field of rehabilitation medicine and sport science, etc., and discusses the future exploration in forensic science. PMID- 23646506 TI - Planar microelectrode chip for synchronous simulative neurochemical and neuroelectrial monitoring. AB - The microfabricated microelectrode arrays on glass substrate combined with homemade multichannel detection system as a powerful tool for synchronous neurochemical and neuroelectrial monitoring was described. The dual-mode (neurochemical and neuroelectrial: simultaneous recording of spikes, and dopamine overflow on the same spatiotemporal scale) recording was carried in PBS buffer. The neurochemical constant potential amperometry was carried at +0.4 V working potential for nM-microM dopamine detection and nM level dopamine concentration increase can be detected by the device. The microelectrode chip showed high sensitivity of 0.88 nA/nM mm2 during nM range and 0.43 nA/nM mm2 during microM range for the determination of DA. The amperometric method used to detect dopamine (DA) did not significantly influence electrophysiological activity at low concentration (< 200 nM) and have a quickly clear away strike at high concentration (> 2 microM). The system uniquely affords synchronous measurement of chemical and electrical neural activity at the adjacent recording sites on the same chip. The sensitivity and resolution of the device allows for simultaneous recoding of electrical and chemical signaling, which may be useful for examining specific spatiotemporal relationships between electrical and chemical signaling in vitro. PMID- 23646507 TI - In vitro investigation on the magnetic thermochemotherapy mediated by magnetic nanoparticles combined with methotrexate for breast cancer treatment. AB - Cancer comprehensive treatment has been fully recognized as it can provide an effective multimodality approach for fighting cancers. In therapeutic oncology, hyperthermic adjuvant chemotherapy termed as thermochemotherapy plays an increasing role in multimodality cancer treatment. Currently, targeted nanothermotherapy is one of the effective hyperthermia approach based on magnetic nanoparticles (MNPs), which can be achieved by applying biocompatible nanoscaled metallic particles that convert electromagnetic energy into heat, for instance, magnetic fluid hyperthermia (MFH) mediated by superparamagnetic iron oxide nanoparticles (SPIONs). Upon exposure under alternative magnetic field (AMF), SPIONs can generate heat through oscillation of their magnetic moment. Nowadays, clinical trials at phase II are now under investigations for MFH on patients in Germany and Japan and demonstrate very inspiring for cancer therapy. In this work we explore the feasibility and effectiveness of magnetic thermochemotherapy mediated by magnetic nanoparticles combined with methotrexate, an anti-cancer drug, for breast cancer comprehensive treatment. Amino silane coated MNPs as agent of MFH were prepared by the chemical precipitation method. Physiochemical characterizations on MNPs have been systematically carried out by various instrumental analyses. Inductive heating property of the MNPs was evaluated by monitoring the temperature increase of the MNPs suspension under AMF. The in vitro cytotoxicity results on human breast cancer cell MCF-7 by CCK-8 assay indicated the bi-modal cancer treatment approach for combined MFH and chemotherapy is more effective than mono-modal treatment, indicating a thermal enhancement effect of hyperthermia on drug cytocoxicity. The magnetic thermochemotherapy mediated by MNPs combined with methotrexate can realize cancer comprehensive treatment thus has great potential in clinical application. PMID- 23646508 TI - Functionalized superparamagnetic nanoparticles for highly-efficient gene delivery. AB - Functionalized superparamagnetic iron oxide nanoparticles (SPIONs) can play crucial roles for medical applications such as cancer magnetic induction hyperthermia, magnetic resonance imaging, and magnetofection. Gene therapy is an emerging area of biomedicine and has the potential to revolutionize the treatment of human disease. Herein we report the results of modified magnetic nanoparticles coated with protamine containing nuclear localization signal sequences. Thermogravimetric analysis, X-ray powder diffraction, cellular uptake, and gene magnetofection efficiency of protamine modified SPIONs were evaluated. SPIONs modified with protamine resulted in more cellular uptake and higher-efficient gene transfection in HepG2 cells. The work demonstrates that protamine modified SPIONs can be used as a novel kind of highly efficient magnetic mediator for magnetic induction hyperthermia combined with gene therapy. PMID- 23646509 TI - UV-enhanced cytotoxicity of CdTe quantum dots in PANC-1 cells depend on their size distribution and surface modification. AB - The cytotoxicity of quantum dots (QDs) under normal conditions has received more and more attention, but their cytotoxicity under light illumination has not been fully investigated. In this study, different sized CdTe QDs coated with mercaptopropionic acid (MPA) and N-acetylcysteine (NAC) were employed to investigate the influences of size distribution and surface modification on their UV-enhanced cytotoxicity and mechanism. The results indicated that different sized MPA-CdTe QDs exhibited distinct cytotoxicity under UV illumination and the smaller-sized QDs presented more obviously damages to cells than the larger-sized QDs. Comparing with MPA-CdTe QDs, NAC-CdTe QDs had better cellular metabolizability and lower cytotoxicity. The generation of reactive oxygen species (ROS) were also investigated. The results revealed that ROS in cells containing MPA-CdTe QD538 were about 1.7 times of NAC-CdTe QD538 under UV illumination. ROS might play an important role in the UV-enhanced cytotoxicity of QDs. By selecting appropriate surface modifications and particle sizes, the cytotoxicity of QDs under UV illumination could be controlled. PMID- 23646510 TI - Supramolecular hydrogel based on graphene oxides for controlled release system. AB - Supramolecular hydrogel drug delivery system that composed of F127 modified small sized graphene oxide (F127-SGO) and alpha-CD was prepared and the controlled release behavior was studied using doxorubicin hydrochloride (DOX) as a model drug. As compared with native hydrogel formed from F127 and alpha-CD, the SGO containing hybrid hydrogel system shows multiple binding sites to load drug molecules and a more controllable release process that facilitates to tune the drug delivery system. These properties make the supramolecular hydrogel a potential candidate for controlled drug delivery system. PMID- 23646511 TI - Effects of growth conditions on the GaAs/AlAs superlattices by grazing incidence X-ray reflectivity. AB - The effects of growth conditions on the structural properties of the GaAs/AlAs superlattices were investigated by grazing incidence X-ray reflectivity (GIXRR), transmission electron microscopy (TEM), Auger electron spectroscopy (AES) and X ray photoelectron spectroscopy (XPS). The GaAs/AlAs superlattices were prepared by molecular beam epitaxy (MBE) at different growth temperatures (500 degrees C, 600 degrees C and 660 degrees C) and growth rates (1.0 microm/h and 0.7 microm/h for GaAs). And the thicknesses, surface/interface roughnesses and densities of the GaAs/AlAs superlattices were obtained by GIXRR by fitting the whole spectral reflectance curves based on the Parratt recurrence formula. The homogeneity of samples was also studied at different growth conditions. The results indicate that the superlattices grown at a high temperature and large growth rate ratio (rate of AlAs to that of GaAs) possess better structure and more homogeneity. PMID- 23646512 TI - Observing the resistive switching of MgZnO thin film via conducting atomic force microscopy. AB - Conducting atomic force microscopy (C-AFM) is used to observe the formation and removal of conducting filaments of Mg0.6Zn0.4O thin film at a nanoscale in order to study the mechanisms of resistive switching. C-AFM probe with Pt coating is used as a movable top electrode for measuring local I-V and for C-AFM imaging. Writing and reading of micro-bits on the resistive switching thin film are demonstrated. The local I-V behavior is similar to the macroscopic behavior of the resistive switching thin film. However, the probability for successful in situ detection of resistive switching of formation in the current experiment is only one quarter, much less than that with a macroscopic top electrode. Experimental results are explained using the filament model which illustrates the switching mechanism of the thin film. The current work would be useful for the improvement of resistive switching thin films and their applications. PMID- 23646513 TI - Numerical and experimental assessment of charge control in III-V nano-metal-oxide semiconductor field-effect transistor. AB - III-V Metal-Oxide-Semiconductor Field-Effect Transistor (MOSFET) with a gate stack based on high-kappa dielectric appears as an appealing solution to increase the performance of either microwave or logic circuits with low supply voltage (V(DD)). The main objective of this work is to provide a theoretical model of the gate charge control in III-V MOS capacitors (MOSCAPs) using the accurate self consistent solution of 1D and 2D Poisson-Schrodinger equations. This study allows us to identify the major mechanisms which must be included to get theoretical calculations in good agreement with experiments. Actually, our results obtained for an Al2O3/In0.53Ga0.47As MOSCAP structure are successfully compared to experimental measurements. We evaluate how III-V MOS technology is affected by the density of interface states which favors the Fermi level pinning at the Al2O3/In0.53Ga0.47As interface in both depletion and inversion regimes, which is a consequence of the poor gate control of the mobile inversion carrier density. The high energy valleys (satellite valleys) contribution observed in many theoretical calculations appears to be fully negligible in the presence of interface states. The enhancement of doping density in the channel is shown to improve the short-channel effect (SCE) immunity but to the price of higher sensitivity to the interface trap effect which manifests through a low Fermi level movement efficiency at interface in OFF-state and a low inversion carrier density in ON-state, even in the long channel case. PMID- 23646514 TI - Anisotropic nano-column arrays of bismuth and its conductivity. AB - Anisotropic nanostructures are becoming more and more attractive due to their unique properties different from isotropic nanostructures. However, previous most of studies are limited to high melting point materials with poor crystalline, which has confined their extended applications. In this work, we successfully prepared the anisotropic nano-column arrays of bismuth (melting point: 271.3 degrees C) with improved crystallinity by glancing angle deposition. The anisotropic conductivity of the products is investigated, and its origin is ascribed to the anisotropic scattering of the carriers in the boundary layer. Our work is not only helpful to understand the anisotropic nanostructures fabricated by glancing angle deposition on both their growth and properties, as well as provides an approachable route for constructing functional devices based on Bi and its anisotropic nanostructures. PMID- 23646515 TI - Fabrication and properties of dual-level hierarchical structures mimicking gecko foot hairs. AB - In nature, geckos have extraordinary adhesive capabilities. The multi-scale hierarchical structure of the gecko foot hairs, especially the high-aspect-ratio structure of its micro-scale seta and nano-scale spatulae is the critical factor of the gecko's ability to adopt and stick to any different surface with powerful adhesion force. In this paper, we present a simple and effective approach to fabricate dual-level hierarchical structures mimicking gecko foot hairs. Polydimethyl-siloxane (PDMS) hierarchical arrays were fabricated by demolding from a double stack mold that was composed of an SU-8 mold by thick film photolithography and a silicon mold by inductively coupled plasma (ICP) etching. Top pillars of the fabricated structures have 3 micom diameter and 18 microm in height, while base pillars have 25 microm diameter and 40 microm in height. The water droplet contact angle tests indicate that the hierarchical structures increase the hydrophobic property significantly compared with the single-level arrays and the unstructured polymers, exhibiting superhydrophobicity (154.2 degrees) like the Tokay gecko's (160.9 degrees). The shear force tests show that the top pillars make attachment through side contact with a value of about 0.25 N/cm2, and moreover, the hierarchical structures are demonstrated to be more suitable for contacting with rough surfaces. PMID- 23646516 TI - CdSe nanocrystal sensitized anatase TiO2 (001) tetragonal nanosheet-array films for photovoltaic application. AB - CdSe nanocrystal sensitized TiO2 nanosheet array heterostructure films were fabricated by a two-step method. Firstly, a single crystalline anatase TiO2 tetragonal nanosheet-array film on a transparent conductive fluorine-doped tin oxide (FTO) substrate was successfully prepared by hydrothermal method. Then, CdSe nanocrystalline sensitizers were deposited on the TiO2 nanosheet array by CBD method. The products were characterized with XRD, SEM, TEM and UV-vis absorption spectroscopy. The effect of the CdSe nanocrystal deposition time and the length of the TiO2 sheet on the photovoltaic performance of the resulting CdSe/TiO2 nanosheet array electrodes were also investigated. In comparison with the non-sensitized TiO2 nanosheet array, the photocurrent of CdSe sensitized TiO2 nanosheet has a great enhancement, which gives some insight to the fundamental mechanism of the performance improvement. PMID- 23646517 TI - Preparation and microwave absorbing properties of carbon/cobalt ferromagnetic composites. AB - Carbon/cobalt ferromagnetic light composites with high performance of microwave absorbing properties were prepared by hydrothermal method using starch and hollow cobalt ferrites. It was concluded that after carbonization the spinel structure ferrites changed to Co3Fe7 alloys and the temperature of graphitization was significantly decreased for the catalytic of CoFe2O4/Co3Fe7. The increase of carbon content, and exist of CoFe2O4/Co3Fe7 heightened the microwave absorbing properties. Electromagnetic parameters were tested with 40% of the titled materials and 60% of paraffin wax composites by using HP8722ES vector network analyzer. The reflection was also simulated through transmission line theory. The microwave absorbers exhibited a maximum reflection loss -43 dB and the electromagnetic wave absorption less than -10 dB was found to exceed 3.0 GHz between 11.6 GHz and 15 GHz for an absorber thickness of 2 mm. PMID- 23646518 TI - Novel narrow band-gap InAsSbP-based quantum dot mid-infrared photodetectors: fabrication, optoelectronic and electrophysical properties. AB - The InAsSbP quantum dots were grown on InAs(100) substrate by modified version of liquid phase epitaxy. The morphology, dimensions and distribution density of the quantum dots were investigated by an atomic force microscope. Two mid-infrared photodetectors made of InAs(100) substrate with and without InAsSbP quantum dots are fabricated and investigated. Current-voltage characteristics are measured and a deviation from linearity is detected for the quantum dot photodetector. Room temperature photoresponse spectra at low applied voltages are investigated. An anomalous photovoltaic effect is detected. Open circuit voltage and short circuit current generated in the quantum dot photodetector under irradiation of He-Ne laser operating at 3.39 microm are measured. Our measurements showed that voltage and current responsivities at room temperature are equal to 2 V/W and 82 mA/W, respectively. Specific dips in the quantum dot photodetector's room temperature capacitance-voltage characteristics are observed. Magnetic field up to 1.6 T was applied to measure the magnetoresistance at room temperature. Specific oscillations on magnetoresistance curve for the quantum dot photodetector are observed. PMID- 23646519 TI - Low-temperature performance of accumulation-mode p-channel wrap-gated FinFETs. AB - In this work, accumulation-mode (AM) p-channel wrap-gated FinFETs and AM p channel planar FETs are fabricated using top-down strategies, and compared in performance at temperatures from 6 K to 295 K. The threshold voltage variation of the AM wrap-gated FinFET is slightly larger than that of the AM planar FET. The drain current and the peak transconductance in the AM wrap-gated FinFET are larger than those in the AM planar FET, and those differences are temperature dependent. We attribute those to the body current enhancement in the AM wrap gated FinFET as temperature increases. The subthreshold swings (SS) of both types of the FETs improve with temperature decreasing and get lower than 10 mV/dec at 6 K. The higher SS in the AM wrap-gated FinFET is likely due to a high interface state density at the fin sidewalls arising from the fin patterning induced defects. PMID- 23646520 TI - Characterisation of nano-particles in colloids: relationship between particle size and electrical impedance spectra. AB - The nano-particles in colloidal dispersions usually carry an electrical charge and have an electrical double layer associated with their surfaces, however, while remaining electrically neutral overall. Under the effect of an external electric field, the electrical double layer is deformed or in other words, the suspension is polarized. The mechanism of electrochemical polarization is partially dependent on the surface charge and the size of particles. It is known that properties of nano-particles in suspensions may affect the colloids' electrical-impedance spectroscopic properties, e.g., the complex impedance, complex permittivity, complex conductivity, relaxation frequency, and phase angle. However, reports on colloids' electrical-impedance spectroscopic properties are very limited in the current literature. In this paper a simple system, aqueous silica suspensions, was studied using electrical impedance spectroscopy (EIS). A series of experiments were designed to reveal the effect of particle size on the electrical impedance spectra of silica suspensions. The size effect was studied on silica suspensions with the same concentration (10.0 wt%) but different principle particle size (12 nm, 35 nm, 70 nm, 90 nm and 220 nm). The EIS results show that the relaxation frequency decreased with increasing of particle size. This tendency is explained by the polarization effect of electrical double layer and two dispersion mechanisms were analysed in this study. The results provide supportive information for on-line characterisation of nano-particles using electrical impedance spectroscopy. PMID- 23646521 TI - Density function theory study on adsorption and dissociation of H2O on Pd nanowire. AB - The adsorption and dissociation of H2O in Pd nanowire have been investigated by the density functional theory (DFT) studies. First, we construct Pd nanowire by basin-hopping method and use DFT calculation to find the ground state of Pd nanowire, and put the H2O molecular on different adsorption sites and the H2O molecule is found to preferentially absorb on a Top (T) site. The H2O molecule lies parallel to the Pd nanowire surface, while the O atom is bound at a Top site. We also calculate the partial density of state (PDOS) and election density difference. In addition, our calculated results demonstrate that the bonding between H2O and Pd nanowire is contributed by d orbitals of Pd nanowire and p orbitals of O atom. The nudged elastic band (NEB) method is applied to locate transition states and minimum energy pathways (MEP), and we discuss the dissociation behavior of the side-on H2O molecules on the top site of hexagonal and tetragonal planes, respectively. PMID- 23646522 TI - Fabrication and optical properties of pyrene-Eu hybrid materials. AB - Lanthanide-containing organic-inorganic hybrid materials have drawn much attention in the research of materials with multifunctional and modulated optical properties. Here, large area pyrene-Eu hybrid nanostructures constructed of a large amount of nanowires are successfully fabricated through physical vapor codeposition method at low temperature (77 K). Further optical property characterizations indicate that the pyrene-Eu hybrid nanostructures exhibit enhanced green light emission under blue light excitation compared with other fabricated samples (pyrene nanostructures, Eu nanoparticles, and pyrene/Cu hybrid nanostructures). The results indicate the occurrence of an energy transfer process from the sensitizing pyrene nanostructures to Eu. Pyrene-Eu hybrid nanostructures with unique photoluminescence properties may have promising applications in phosphors, light-emitting device, and UV-vis photo sensor. The results also prove that the physical vapor codeposition method is an effective way for design of organic-inorganic hybrid materials with controllable and tunable optical properties. PMID- 23646523 TI - Anisotropic laser-induced damage threshold and residual stress of TiO2 sculptured thin films. AB - The residual stress and laser-induced damage threshold (LIDT) of TiO2 sculptured thin films prepared by glancing angle electron beam evaporation were studied. UV Vis-NIR spectra and optical interferometer were employed to characterize the optical and mechanical properties, respectively. Optical microscopy and Raman spectra were used to observe damage morphology and analyze damage microstructure, respectively. It was found that the residual stress changed from compressive into tensile with increasing deposition angle. The LIDT was anisotropic with p- and s polarization light, which was due to the anisotropic nanostructure and optical properties. Simultaneously, an optimum deposition angle for the maximum threshold of TiO2 film was about 60 degrees. The mechanism of laser-induced damage was thermal in nature. The process of thermal damage with crystallization is proved by Raman spectra. PMID- 23646524 TI - The study on SiO2 pattern fabrication using Ge1.5Sn0.5Sb2Te5 as resists. AB - Ge1.5Sn0.5Sb2Te5 (GSST) can be easily induced to phase transition from amorphous state to crystalline state by a laser direct writing (LDW) system. The results show that the crystalline phase of GSST is more durable against acid solution corrosion than the amorphous phase. So nano-scale patterns and structures can be formed on the GSST film resists using laser-induced phase change and wet etching. Moreover, reactive ion etching (RIE) technology was applied to transfer these patterns onto the SiO2 substrate. The result shows to the extent that GSST material has thermal resist characteristics with high resolution and well etching selectivity to SiO2 when etched in the CHF3, which is compatibility with the future nanofabricate processing. PMID- 23646525 TI - Formation and characterization of multilayer GeSi nanowires on miscut Si (001) substrates. AB - A multilayer of GeSi nanowires separated with Si spacers was readily self assembled on miscut Si (001) substrates with 8 degrees off toward (110). The nanowires oriented along the miscut direction were very small and compactly arranged on the vicinal surface. Systematic photoluminescence (PL) spectroscopy studies were carried out on the GeSi nanowires. With increasing excitation power, a sublinear power dependent PL intensity and a blue-shift of -7 meV/decade with nearly constant full width of half maximum (FWHM) of PL peaks from multilayer GeSi nanowires was observed. These results indicated a typical type-III band alignment of GeSi nanowires/Si. The blue-shift was attributed to band bending effect with the increase of photon-generated carriers. The nearly independent FWHM of PL peaks with the excitation power was explained in terms of the formation of mini-band due to strong coupling of holes in closely neighboring nanowires. An activation energy of -12 meV was extracted from the temperature dependent intensity of PL peaks of the nanowires, which was assigned to be the exciton binding energy around the nanowires. Based on Raman spectra, the Ge content in GeSi nanowires was estimated to be -61%. PMID- 23646526 TI - Unidirectional water transfer effect from fabrics having a superhydrophobic-to hydrophilic gradient. AB - In this study, we demonstrate that fabrics having a wettability gradient from superhydrophobic to hydrophilic through the thickness direction show a novel directional water transfer effect: water can transfer from the superhydrophobic to the hydrophilic side, but not in the opposite direction unless an external force is applied. A sol-gel technology was used to prepare a nano-structured superhydrophobic coating on fabrics, and the coated fabrics showed water contact angle as high as 165 degrees. When the coated fabric was subjected to a photochemistry treatment from one fabric side, the irradiated surface turned hydrophilic permanently, while the back side still maintained the superhydrophobicity. The treated fabric can transfer water droplet rapidly from hydrophobic to hydrophilic side, and the pressure allowing water breakthrough the fabric are different considerably between the two fabric sides. The directional water transfer effect is affected by the wettability gradient. Such a directional water transfer coating may be useful to develop new functional fabrics for defence applications. PMID- 23646527 TI - Homogeneous field intensity control during multi-needle electrospinning via finite element analysis and simulation. AB - In the current study, finite element analysis is employed to simulate the process control of multi-needle electrospinning, by manipulating needle length, needle spacing, plastic casing of needle, and the way the voltage is applied to the needles, to facilitate the efficient production of homogeneous nanofibrous webs at high performance versus cost. The simulation results indicate that it is possible to control the field intensity homogeneity of multi-needle electrospinning process in terms of the vector sum of electric field intensity by adjusting the needle length, needle spacing, changing voltage application method and separating each needle with a plastic casing, etc. Measures such as capping each needle with a plastic casing, applying voltage directly to the needles, shortening the probed length of the needles at the edge sides, and reducing the distance between edge needles, as well as imparting additional voltage to the needles in the middle of the row could significantly decrease the field intensity of edge needles and thus improve the field intensity of the needles across one row and increase the potential of industrializing the needle type electrospinning technology. PMID- 23646528 TI - An investigation on Eu3+ doped CaLa2ZnO5 novel red emitting phosphors for white light-emitting diodes. AB - A novel phosphor namely CaLa2ZnO5 doped with Eu3+ ions were prepared by conventional solid state reaction method. We have studied and optimized various constraints like sintering temperature, sintering time and dopant concentration. XRD, SEM profiles have been studied to explore its structural properties. Luminescence properties of these phosphors have been characterized by means of their photoluminescence (PL) spectra. We have noticed that the emission intensity of CaLa2ZnO5:Eu3+ phosphors strongly depend on its sintering temperature and Eu3+ concentration. Moreover, their PL spectra reveals that CaLa2ZnO5:Eu3+ phosphors exhibits a strong luminescence of 5D(0)_7F(2) transition at 627 nm under the excitation of 468 nm, which correspond to the popular emission line from a GaN based blue light-emitting diode (LED) chip. The obtained results of the prepared Eu3+ doped phosphors are very much encouraging and they are potentially useful in the development of new solid-state lightning devices. PMID- 23646529 TI - Hydrothermal preparation of copper doped NaTaO3 nanoparticles and study on the photocatalytic mechanism. AB - Effects of copper cations doping into wide band gap semiconductor photocatalysts of tantalate on morphology, visible light response, and photocatalytic performance were studied. A series of Cu-doped NaTaO3 catalysts were prepared by hydrothermal method. XRD and XPS results suggested that copper were successfully doped into the NaTaO3 nanocrystal in the Cu2+ state. TEM studies showed the formation of the cube shape nanoparticles of NaTaO3 as well as Cu-doped NaTaO3. UV-Vis diffuse reflectance spectra clearly indicated the red-shift in the series of copper doped NaTaO3 catalysts, resulting in a decrease in the band gap of NaTaO3. The trend of red shift was increased with an increase of copper doping concentration, whereas the photo-degradation methylene blue (MB) is not improved by the doping of copper ions. The simulation of energy band structure by density functional theory unfolded that the substitution of Ta5+ ions by Cu2+ ions results in forming an intermediate band (IB) upper the top of the valence band (VB), which is mainly attributed to the state of Cu 3d. The intermediate band is responsible for the red-shift caused by the doping of Cu ions. Meanwhile Cu species can become the recombination centers of photoinduced electrons and holes. Thus, the quickly recombination of e(-)h(+) pairs is one of the most significant factors which deteriorate the photoactivity of Cu-doped NaTaO3. PMID- 23646530 TI - Controlling the fluorescent properties of aqueous CdTe nanocrystals by modulating the growth rate. AB - Although high quality aqueous CdTe and CdTeS alloyed quantum dots (QDs) have been synthesized in recent years, the relationship between the fluorescent properties and the growth kinetics has not been well documented yet. In this paper, 3 mercaptopropionic acid stabilized aqueous CdTe nanocrystals (NCs) are generally prepared with an improvement of the "traditional" synthetic approach, where the preparation of the red emission NCs is usually time-consuming due to the slow growth rate. The investigation on the kinetic and thermodynamic growth process shows that the growth can be effectively accelerated by decreasing the ligand concentration from 0.06 to 0.01 mol/L or elevating the growth temperature from 120 to 240 degrees C. In contrast to previous results, the quantum yield (QY) of the CdTe NCs is heightened to 45% only by increasing properly the growth rate. Our experiments depict that high growth rate favours high concentration of free monomers and thus decreases the number of the surface Te atoms of the NCs, leading to the enhancement of the photoluminescence (PL) QY. PMID- 23646531 TI - Microstructure and gas-sensing property of the ordered mesoporous Co3O4. AB - We report the microstructure, gas-sensing properties of the ordered mesoporous Co3O4 prepared by modified KIT-6 template method. Highly ordered mesoporous nanostructures of the as-prepared products have been characterized by X-ray diffraction (XRD), extended X-ray absorption fine structure (EXAFS), high resolution transmission electron microscopy (HRTEM) and N2 adsorption/desorption analysis. We find that the ordered mesoporous Co3O4 enables a significant improvement of sensor response and selectivity to ethanol, which demonstrates the potential use of the ordered mesoporous Co3O4 as alcohol gas-sensing material. Through the analysis of microstructure including HRTEM and N2 adsorption/desorption, the sensing properties for the ordered mesoporous Co3O4 can be attributed qualitatively to its large specific surface area and porous morphology. Moreover, the results of EXAFS illustrate that the disorder degree and unsaturated bond of the ordered mesoporous Co3O4 increase, which agree well with the results observed in gas sensors. This makes the nanostructured ordered mesoporous Co3O4 a promising sensor material for detecting the alcohol gas. PMID- 23646532 TI - A novel CO sensor based on the point contact between Pd decorated TiO2 nanotubes array. AB - To obtain a high sensitive CO sensor, a new nanostructure based on the point contact between Pd decorated TiO2 nanotubes was proposed in this paper. TiO2 nanotubes array was fabricated on titanium wire by electrochemical anodic oxidation, and Pd catalytic nanoparticles were modified by the micro-emulsion electrochemical deposition. The surface morphology was characterized by field emission scanning electron microscopy (FE-SEM), and CO sensitivity of the point contact between TiO2 nanotubes was investigated through the current-voltage (I-V) characteristic measurement. It was found that Pd epitaxially grew along the tube walls, and they were distributed on the surface of the nanotubes. The point contact based sensor between Pd decorated TiO2 nanotubes exhibited a strong temperature dependent sensitivity towards CO. From the I-V curves, we found the Schottky barrier was formed on the contact and the barrier height was also calculated. PMID- 23646533 TI - Tunable multimode and narrowband in a photonic quasicrystal waveguide. AB - In this work, we propose a photonic quasicrystal waveguide, which contains a hollow core surrounded by coaxial dielectric quasiperiodic multilayer. Due to the self-similarity in the cladding structure, multiple omnidirectional photonic band gaps (PBGs) exist in the waveguide. The light waves with the frequencies within the omnidirectional PBGs are totally reflected, thereafter, the transport of multimodes is achieved in the quasiperiodic waveguide. Further, it is shown that the centre frequency and the width of the omnidirectional PBG can be tuned by the refractive indexes or the generations of the quasiperiodic sequence in the cladding multilayer. As a consequence, both the quality factor and the confinement performance of the waveguide can be significantly enhanced by decreasing the width of the omnidirectional PBGs. The investigations make it possible to design miniaturized multifunctional optical devices, such as on-chip narrowband waveguide-based filters and laser resonators. PMID- 23646534 TI - Fabrication and characterization of single electron tunneling device on Au/SiO2 nanocomposite films. AB - Amino-functionalized mesoporous silica thin films (AF-MSTFs) have been directly dip-coated on silica wafers by co-condensation of tetraethoxysilane (TEOS) and 3 aminopropyltriethoxysilane (APTES) in the presence of Brij56 (C16H33(OCH2CH2)10OH) under acidic condition. Using the AF-MSTFs as templates, gold nanoparticles (GNPs) are well formed within the mesopores. The transmission electron microscope images and X-ray diffraction patterns demonstrate that the MSTFs are consistent with well ordered mesostructures and the GNPs are well crystallized in the templates. A single electron tunneling device based on self assembled GNPs of the Au/SiO2 nanocomposite film has been fabricated by using nanolithographic definitions. The device shows Coulomb stair-cases at 77 K. The data are interpreted as single electron tunneling through the GNP which served as a Coulomb island between the source and drain electrodes. The charging energy is estimated to be much larger than the thermal energy at 77 K. The Coulomb island size calculated from the experimental data is -3.8 nm, which is consistent with the size of the GNPs self-assembled in the MSTFs. PMID- 23646535 TI - Formation scheme of quantum point contacts based on nanogaps using field-emission induced electromigration. AB - We propose a new fabrication scheme of quantum point contacts (QPCs) composed of nanogaps at room temperature. This scheme is based on electromigration induced by a field emission current, which is so-called "activation." By applying the activation to ferromagnetic Ni nanogaps with sub-10 nm separation, QPCs can be easily obtained at room temperature. The conductance changed in quantized steps of 0.5G0 (G0 = 2e2/h) at the final stage of activation with a preset current Is of 0.5 mA. Then, the conductance during the activation was varied from 2G0 to 9.5G0 by increasing the preset current Is from 0.5 mA to 1.5 mA. Furthermore, after performing the activation with the preset current Is of 1.5 mA, the QPC device formed by the activation exhibited magnetoresistance (MR) ratio of approximately 1.5%. These results indicate that few-atom Ni contacts are achieved using Ni nanogaps controlled by the activation with precisely tuned preset current. PMID- 23646536 TI - Nanoscale dynamic behavior of surface magnetic domains on a La0.7Sr0.3MnO3 thin film. AB - An oscillating magnetic tip can be used to induce the striped magnetic ripple pattern with alternating up-and-down striped magnetic domains on a ferromagnetic La0.7Sr0.3MnO3 (LSMO) thin film surface. Magnetic force microscopy (MFM) images show that the surface magnetic domains (SMDs) can be aligned in a well-ordered alternating up-and-down c(2 x 2) structure on the stripe magnetic domains, indicating that the oscillating magnetic tip turns the ferromagnetic LSMO surface into a canted antiferromagnetic state. The orientation of the SMDs is determined by their discrete phase distribution. A three-dimensional (3D) SMD orientation model is built to understand dynamic behavior of the SMDs. PMID- 23646537 TI - The deformation mechanism of Ni-Ta bulk metallic glasses after tensile: molecular dynamics study. AB - The mechanical properties of Ni-Ta crystallizationand binary bulk metallic glasses (BMG) were investigated for this study at the nanoscale. First, the Ta9Ni3 crystals are formed by space group, and structures with different ratios (Ta1Ni1, BTa8Ni4, BTa9Ni3, BTa7Ni5) were put into unit cell randomly. The optimizations of BMG structures are performed by Density functional theory (DFT) calculation to find the stable amorphous structures and corresponding energy. The FMM is utilized to obtain the suitable parameters of tight-binding potential bystable amorphous structures and corresponding energies. Finally, we employ molecular dynamics (MD) simulation to study mechanical properties of Ni/Ta crystallization and BMG, such as atomistic stress-strain, plastic and elastic deformation, and elastic modulus. PMID- 23646538 TI - Variation in the nanostructural features of Nc-Si:H films with radio frequency power conditions. AB - The effect of radio frequency (RF) power on the variation in the nanostructures, chemical features and surface morphology of nc-Si:H thin films was investigated. SiH4 and H2 gases were used as source materials for the films. The films were prepared by plasma enhanced chemical vapor deposition (PECVD) techniques and the power ranged from 100 to 300 W. The average crystal size of the films varied from -1 to -12 nm and the highest crystalline volume fraction reached up to -33% when the applied RF power was 300 W. At the RF power of 300 W, the relative fraction of Si-H bond in the films (R(MONO) = Si-H/sigma[Si-H(n)]n = 1,2,3) was increased up to -29%. The variation in the nanostructures and surface features of the films with applied RF power can be interpreted by the change in the collision impact of the precursor on top of the growing films. PMID- 23646539 TI - Enhanced microwave absorption performance of hollow alpha-MnO2 nanourchins. AB - Three dimensional (3D) hierarchical nanostructures are expected to provide enhanced microwave absorption properties for nanomaterials. In this report we prepared hollow urchinlike alpha-MnO2 nanostructures and dispersed alpha-MnO2 nanorods via a facile hydrothermal method. The complex permittivity and permeability of the hollow alpha-MnO2 nanourchins/paraffin wax composites with different manganese dioxide loadings were investigated in the range of 2-18 GHz, based on which the corresponding reflection loss were simulated. A minimum reflection loss of -36 dB was obtained from the composites with 50 wt% MnO2 nanostructures. Furthermore, the microwave absorption properties of dispersed alpha-MnO2 nanorods were studied for comparison, which indicate the unique morphology of the hollow urchinlike nanostructures is of significant effect to their microwave absorption properties. PMID- 23646540 TI - Growth of single crystal zinc oxide beaded nanowires. AB - Reported here is the growth of single crystal zinc oxide beaded nanowires. The beaded nanowires are composed of nanobeads and ultrafine joint nanorods, which alternatively epitaxially grow along [001] direction of zinc oxide wurtzite structure. The growth mechanism was discussed and a zinc-rich process was proposed. Due to the size confinement, the bandgap along the beaded nanowires is modulated by their diameter and like multiple quantum well structure. Different from traditional multiple quantum well structures through alternate heterogeneous epitaxial growth of semiconductors, this kind of quasi-one-dimensional homogeneous multiple quantum well structures is composed of same substance. Their bandgap is modulated through alternately adjusting their diameter along single crystal nanowires. Further studies exhibit that they are of special properties on photoluminescence and Raman spectra. The demonstration would open the route to synthesize homogeneous multiple quantum well structures, study their fundamental physical phenomena, and exploit their applications. PMID- 23646541 TI - Modified chemical vapor deposition synthesis of ultralong V2O5 nanobelt and its electronic properties. AB - The fascinating properties and wide applications of the V2O5 nanostructures have attracted significant attention over the past decades. In this paper, ultralong (centimeter-scale) single-crystal V2O5 nanobelts are successfully fabricated by modified chemical vapor deposition. The wide of the V2O5 nanobelts are 20-500 nm. The aspect ratio exceeds 10(5). The structure and crystal orientation of the nanobelts are investigated. X-ray diffractometer (XRD) patterns and Raman spectrum show the substrate temperature affecting the size and morphology of the V2O5 nanobelts. And the growth mechanism and electronic properties of the ultralong V2O5 nanobelt are studied in detail. The activation energy 0.12 eV is calculated. The fastest growth orientation along the [010] direction has been observed. Our work demonstrates that the single-crystal V2O5 nanobelt has potential applications in field-emitters, lithium-ion batteries, photodetectors, interconnect, and optoelectronic devices, etc. PMID- 23646542 TI - A high quality BiOCl film with petal-like hierarchical structures and its visible light photocatalytic property. AB - BiOCl film with petal-like hierarchical structures is obtained by dipping bismuth film into the mixed solution of H2O2 and HCl. To obtain a high quality BiOCI film, a connecting layer of Chromium is deposited between the substrate and Bismuth film. The product is easy-synthesized, high productive, reusable and environment-friendly. The structural analysis indicates that the BiOCI film is composed by petals with smooth surfaces, and the nanopetals grow along the (101) directions. Raman spectroscopy shows that the film has a good stress-resist feature. The PL spectrum shows that the defect energy levels of BiOCI nanostructure contribute to the excellent photoactivity of degradation the rhodamine B (RhB) under visible-light irradiation (A > 420 nm). This photocatalyst can keep stable photoactivity after it has been reused for 6 rounds. All those properties ensure the photocatalyst a bright future in the application of the pollution treatment. PMID- 23646543 TI - CdS nanobubbles and Cd-DMS nanosheets: solvothermal synthesis and formation mechanism. AB - CdS nanobubbles and Cd-DMS nanosheets have been prepared by a solvothermal method from a solution of Cd2+ in dimethyl sulfoxide in the absence of elemental S. A formation mechanism for the nanobubble morphology arising during the CdS nanocrystal growth has been proposed, based on the results of transmission electron microscopy and photoluminescence spectrophotometry. The correlation of the morphology with reaction time was also suggested, and may be applicable to the solvothermal synthesis of other nanomaterials. PMID- 23646545 TI - Synthesis of functional carbon nanospheres by a composite-molten-salt method and amperometric sensing of hydrogen peroxide. AB - Functional carbon nanospheres have been synthesized from analytically pure glucose by a composite-molten-salt (CMS) method. Field emission scanning electron microscopy, transmission electron microscopy, Raman and Fourier transformation infra-red spectroscopy indicate the carbon nanospheres are solid, bond hybridisation (sp2/sp3) and with many functional groups on their surfaces. Amperometric sensor based on the synthesized carbon nanospheres have been fabricated without pretreatment or modification. The detection of hydrogen peroxide exhibits high sensitivity and good selectivity. The electrochemical measurement of these nanospheres demonstrates much superior performance to those of the carbon nanospheres synthesized by hydrothermal method. PMID- 23646544 TI - Efficient and large scale synthesis of graphene from coal and its film electrical properties studies. AB - Coal, which is abundant and has an incompact structure, is a good candidate to replace graphite as the raw material for the production of graphene. Here, a new solution phase technique for the preparation of graphene from coal has been developed. The precursor: graphene oxide got from coal was examined by atomic force microscopy, dynamic light scattering and X-ray diffraction, the results showed the GO was a small and single layer sheet. The graphene was examined by X ray photoelectron spectroscopy, and Raman spectroscopy. Furthermore, graphene films have been prepared using direct solution process and the electrical conductivity and Hall effect have been studied. The results showed the conductivity of the films could reach as high as 2.5 x 10(5) Sm(-1) and exhibited an n-type behavior. PMID- 23646546 TI - Effect of reducing agent on the chemical reduction of graphene oxides. AB - The effect of treatment on the de-oxygenation and restoration of pi-pi conjugation of graphene oxides (GO), through basic (sodium hydroxide (NaOH), sodium borohydride (NaBH4), hydrazine hydrate, and NaBH4 and hydrazine hydrate) and neutral (superheated H2O) reducing agents has been studied. Reduced GO samples were extensively characterized by Raman spectroscopy, X-ray photoelectron spectroscopy, transmission electron microscopy, elemental analysis, thermogravimetric analysis, and electrical conductivity measurements. It was found that treatment with hydrazine hydrate was the most effective for the reduction of GO. NaBH4 and superheated H2O were the next best performing reducing agents, and NaOH was the least efficient. This study demonstrates that by varying the reducing agent, one can modify the physical and chemical properties of reduced GO, including electrical conductivity and thermal stability. PMID- 23646547 TI - Enhanced transparent conductive properties of graphene/carbon nano-composite films. AB - Transparent conductive graphene/carbon nano-composite films are produced based on graphene oxide (GO) sheets and phenolic resins that are layer-by-layer deposited on a quartz substrate using a spin coating technique. The graphene/carbon nano composite films with high graphitization degree and high crystallization exhibit exceptionally high electrical conductivity and transparency after thermal reduction. A remarkable sheet resistance of 1.98 komega/square at 81.3% transparency in the wavelength of 550 nm is obtained, which significantly outperforms that (3.29 komega/square at 81.7% transparency) of the film produced from pure GO sheets after thermal reduction. PMID- 23646548 TI - Supramolecular surface modification and dispersion of graphene in water and organic solvents. AB - Graphene sheets have been dispersed in water and organic solvents by noncovalent surface modification with the assistance of bifunctional molecule pyrene adamantane (Py-Ad) carrying a pyrene moiety. Lipophilic graphene sheets have been obtained in the form of graphene-Py-Ad in a wide variety of organic solvents, such as dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N'-dimethylformamide, and tetrahydrofuran, in which the adamantane moieties served as the three-dimensional steric groups keeping the graphene sheets from stacking. Supramolecular complexes were employed as the dispersing agent for graphene formed through in situ reduction by hydrazine or hydroquinone. Water-dispersible graphene sheets have been obtained in the form of graphene-Py-Ad-bMCD (methylated beta-cyclodextrin, bMCD), in which the pyrene moiety attached to graphene by pi-pi stacking interaction and hydrophobic effect, and the adamantane group formed complex with bMCD, yielding a supramolecular system that made graphene sheets dissolved in water through the formed hydrophilic cyclodextrin shell. The resulting supramolecular complexes were characterized by atomic force microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, thermal gravimetric analysis, transmission electron microscopy, ultraviolet-visible spectroscopy, fluorescence spectroscopy, and Raman spectroscopy. PMID- 23646549 TI - Preliminary investigation of solution diffusive behavior on V-doped TiO2 nanotubes array by electrochemical impedance spectroscopy. AB - V-doped TiO2 nanotubes array was successfully fabricated on a Ti-V alloy via an electrochemical anodization process. The crystal phase and surface morphology of the nanostructured film were characterized by X-ray diffraction (XRD) and field emission scanning electron microscopy (FESEM). The solution diffusive behavior on TiO2 nanotubes was investigated by electrochemical impedance spectroscopy (EIS) analysis in an aqueous electrolyte containing 0.05 M Na2SO3. A schematic diagram of the interface solution induced into nanotube by photocatalysis on V-doped TiO2 under visible light irradiation was proposed in the study. Considerable photogenerated holes migrate to the interface of TiO2/electrolyte and react with OH-, forming hydroxyl radicals, which induce the electrolyte into the nanotube and improve the hydrophilicity. It was found that the photoelectrocatalytic reaction of TiO2 nanotubes determined the diffusion behavior of the solution; faster diffusion was observed on the V-doped TiO2 nanotubes array under visible light irradiation. The results also demonstrated that EIS is a powerful tool for characterizing the complicate diffusion behavior within the porous nanostructures. PMID- 23646550 TI - Quantum dots coupled ZnO nanowire-array panels and their photocatalytic activities. AB - Fabrication and characterization of a heterojunction structured by CdS quantum dots@ZnO nanowire-array panels were presented. Firstly, ZnO nanowire-array panels were prepared by using a chemical bath deposition approach where wurtzite ZnO nanowires with a diameter of about 100 nm and 3 microm in length grew perpendicularly to glass substrate. Secondly, CdS quantum dots were deposited onto the surface of the ZnO nanowire-arrays by using successive ion layer absorption and reaction method, and the CdS shell/ZnO core heterojunction were thus obtained. Field emission scanning electron microscopy and transmission electron microscope were employed to characterize the morphological properties of the as-obtained CdS quantum dots@ZnO nanowire-array panels. X-ray diffraction was adopted to characterize the crystalline properties of the as-obtained CdS quantum dots@ZnO nanowire-array panels. Methyl orange was taken as a model compound to confirm the photocatalytic activities of the CdS shell/ZnO core heterojunction. Results indicate that CdS with narrow band gap not only acts as a visible-light sensitizer but also is responsible for an effective charge separation. PMID- 23646551 TI - Dielectric properties of carbon nanotubes/epoxy composites. AB - Material with high dielectric properties possesses the effect of energy storage and electric field homogenization, which plays an important role in the electrical and electronics domain, especially in the capacitor, electrical machinery and cable realm. In this paper, epoxy-based nanocomposites with high dielectric constant were fabricated by adding pristine and ozone functionalized multi-wall carbon nanotubes (MWCNTs). In the process-related aspect, the favorable technological parameter was obtained via reasonable arrangement and consideration of the dispersing methods including high-speed stirring and three roller mill. As a result, a uniform dispersion status of MWCNTs in matrix has been guaranteed, which was observed by scanning and transmission electron microscopy. Meanwhile, the influence of different MWCNTs contents and diverse frequencies on the dielectric properties was compared. It was found that the dielectric constant of nano-composites decreased gradually with the increasing of frequency (10(3)-10(6) Hz). Moreover, as the content of MWCNTs increasing, the dielectric constant reached to a maximum of about 1,328 at 10(3) Hz when the pristine MWCNTs content was 0.5 wt.%. Accordingly, the DC conductivity results could interpret the peak value phenomenon by percolation threshold of MWCNTs. In addition, at the fixed content, the dielectric constant of epoxy-based nano composites with ozone functionalized MWCNTs was lower than that of pristine ones. PMID- 23646552 TI - Synthesis of nano-Se/bamboo charcoal composites via hydrothermal method and their application on remaining fresh of cutting roses. AB - Nano-Se/bamboo charcoal (BC) composites were prepared successfully by hydrothermal method. The composites were characterized by SEM, XRD, Atomic Absorption Spectroscopy (AAS) and Atomic fluorescence spectroscopy (AFS) analysis. The effects of the synthesized conditions on the morphologies of Se particles on BC were investigated. The results showed that the reaction time, the adding order of reagents and the concentration of hydrazine have much influence on the formation of nano-Se/BC composites. The application of composites on the keeping fresh of cutting rose flowers was also studied, the experiment results indicate that Nano-Se/BC composites have better effect on the keeping fresh of cutting rose flowers than single BC, Nano-Se, distilled water and commercial "flower food" nutrient solution, the florescence of cutting rose flowers is distinctly extend by Nano-Se/BC composites up to 48 and 24 days in winter and summer respectively. "Synergy effects" and "Delayed release capsule effects" were used to explain the mechanism of Nano-Se/BC composites on the keeping fresh of cutting rose flowers. PMID- 23646553 TI - Study on the crystallization process of GaSb-Sb2Te3 pseudobinary films for phase change random access memory. AB - Non-isothermal change in electrical resistance was used to investigate the crystallization process of GaSb-Sb2Te3 pseudobinary films prepared by co sputtering using GaSb and Sb2Te3 targets. The crystallization parameters were determined directly by in-situ electrical resistance-temperature measurements. The activation energy of crystallization and rate factor were deduced from the Kissinger's plot. The kinetics exponent was calculated using the Ozawa's method. The crystallization temperature (185-228 degrees C) and activation energy (2.01 5.65 eV) increased monotonically with increasing Ga concentration from 5 to 34 mol%, while the average kinetics exponent decreased from 1.63 to 1.02. The crystallization mechanism of the compositions with Ga concentration more than 10 mol% was one-dimensional growth from the nuclei due to the average kinetics exponent smaller than 1.5. Crystallization time of the studied compositions was estimated theoretically by the Johnson-Mehl-Avrami equation and measured experimentally by the reflectivity change induced by the laser pulse. It is shown that Ga27Sb47Te26 film exhibited the shortest crystallization time, suggesting a potential candidate for phase-change random access memory application. PMID- 23646554 TI - Synthesis of quantum-sized ZnO nanoparticles in different medium and their application to NO2 sensors. AB - Quantum-sized ZnO nanoparticles were synthesized using zinc acetate dihydrate through a sol-gel process in different mediums: water, ethanol and methanol. Three types of modifiers: tetraethyl orthosilicate (TEOS), sodium dodecyl sulfate (SDS) and oleic acid (OA) were added to control the growth of the ZnO nanoparticles and inhibit Ostwald ripening. X-ray Diffraction (XRD) analyses revealed that ZnO have a hexagonal crystal structure, the estimated average crystallite sizes of modified ZnO are in the range of 4.5-10 nm, while the crystallite sizes of non-modified ZnO are large than 20 nm. X-ray photoelectron spectroscopy (XPS) analyses obtained the surface composition and chemical states of the products of ZnO. In this paper, the obtained quantum-sized ZnO nanoparticles as a novel sensing material were used to detect NO2 in environment. The sensing tests indicated that the ZnO based sensors not only have high response to NO2 but also exhibited high selectivity to CO and CH4 at low operating temperature of 290 degrees C. PMID- 23646555 TI - A detector of an invisible carpet cloaking structure. AB - Based on transformation optics, we propose a device to detect the presence of a carpet cloaking structure at near field. By using complementary media, the detective device can optically cancel a certain volume of reflective metal and reveal the hidden medium inside the metal. The detective performance of this device is confirmed by full-wave finite-element simulations. It is shown that the detective device is invisible when there is no carpet cloak in the system, yet it becomes visible with the presence of the carpet cloak. The device works at near field, but the response can be found even at the far field. Furthermore, it is shown that the device can detect both anisotropic and isotropic carpet cloaking structures. The investigation may provide a unique method to detect a carpet cloak and contribute to the design of novel optical devices, such as far field detectors for a nanoscale medium. PMID- 23646556 TI - Benzene sensors based on multi-walled carbon nanotube networks decorated with metal nanoclusters. AB - This paper demonstrates sensors based on multi-walled carbon nanotube (MWNT) networks decorated with metal nanoclusters for benzene vapor detection at room temperature. MWNT networks were deposited between the interdigitated metal electrodes on a Si/SiO2 substrate by AC dielectrophoresis. Metal nanoclusters including Au, Pt, Ti and Ni were deposited by magnetron sputtering onto the MWNT networks with a controlled loading of equivalent thickness of 1.5-1.8 nm as the active sensing layer. The resistances of MWNT networks are reduced after functionalized with metal nanoclusters. Experimental results show that resistances of unmodified and metal-functionalized MWNT networks increase after exposing to benzene, ethanol and water vapor. The MWNT networks decorated with Au, Pt and Ti have more sensitivity than bare MWNT networks while Ni decoration did not enhance the sensitivity of MWNT networks to benzene vapor. The MWNT networks decorated with Pt exhibited highest resistance response to benzene vapor, with a less interference of ethanol vapor and humidity. PMID- 23646557 TI - Control parameters for fabrication of single-electron transistors using field emission-induced electromigration. AB - We report a simple method for the control of electrical characteristics of planar type metal-based single-electron transistors (SETs) using field-emission-induced electromigration. The advantages of this method are as follows: (1) the fabrication of SETs is achieved by only passing a field emission current through a nanogap and (2) the charging energy of SETs can be controlled by adjusting the magnitude of the applied current during the procedure. In order to better control the electrical properties of the SETs, we investigate the relation between control parameters of the method and electrical characteristics of the SETs. When the field-emission-induced electromigration with the preset current of 500 nA was applied to the nanogaps, current-voltage characteristics of the nanogaps displayed the suppression of electrical current at low-bias voltages known as Coulomb blockade at 16 K. In addition, Coulomb blockade voltage was clearly modulated by the gate voltage periodically at 16 K, resulting in the formation of single island in the SETs by the field-emission-induced electromigration. Furthermore, as the preset current was increased, the charging energy of the SETs was decreased with decreasing the initial gap separation of the nanogaps. These results imply that the electrical characteristics of the SETs are controllable by the preset current of the method and the initial gap separation of the nanogaps. Field-emission-induced electromigration procedure allows us to simply control electrical characteristics of planar-type metal-based SETs. PMID- 23646558 TI - The periodicity effect on the charge storage characteristic of multistacked nc-Si floating gate. AB - Nanocrystalline (nc)-Si/SiO2 multistacked floating gate have been prepared by electron beam evaporation of SiO(x) and SiO2 followed by thermal annealing. HRXTEM reveals that the density of multiply stacked nc-Si quantum dots reaches 9.1 x 10(11) cm(-2) with size of 2-3 nm. The periodicity effect of nc-Si/SiO2 multilayers on the charge storage characteristics of nc-Si floating gate is investigated carefully by using capacitance-voltage (C-V) and conductance-voltage (G-V) measurements at room temperature. It is found the charge storage ability enhances obviously with the periodicity of the multiply stacked nc-Si layer increasing from 2 to 9. The up limit of the thickness for multistacked nc-Si/SiO2 layer is less than 100 nm, which is close to the mean free path of electron in multistacked nc-Si. Charge diffusion among the multistacked nc-Si quantum dots is used to explain the charge storage and retention characteristics. PMID- 23646559 TI - Effective photoluminescence in a large-area array of Ta2O5 nanodots. AB - We describe here the synthesis of a large-area Ta2O5 nanodot array by utilizing the hot filament metal vapor deposition technique. The Ta2O5 nanodots arranged in a large-area array on a Si wafer had an average diameter of -8 nm. X-ray photoemission spectroscopy (XPS) revealed the stoichiometric Ta and O compositions of the Ta2O5 nanodots. Raman spectroscopy showed the Ta2O5 nanodots to be of orthorhombic (beta) crystal. Photoluminescence (PL) spectroscopy showed the green and red light emissions of the beta-Ta2O5 nanodots at room temperature. PMID- 23646560 TI - Au core/Au-Ag alloy shell nanorods: composition- and shape-tailored optical responses. AB - A feasible way is developed to prepare Au core/Au-Ag alloy shell nanorods (Au@Au(x)Ag(1-x) NRs) based on co-reduction of gold and silver ions under the guidance of Au NRs templates. Alloy nanorods with a wide composition range (x tunable from 0 to 1) are obtained. The Ag+/Au3+ ratios are found to affect the detailed morphology of the endcaps, which is responsible for the abnormal red shift of localized surface plasmon resonance (SPR) mode. In consensus with theoretical prediction, dielectric sensitivity of the alloy NRs is mainly determined by the maximum of the LSPR band. Due to the change in electron structure, the alloy shells exhibit lower SERS activities than pure Ag shell. PMID- 23646561 TI - Base effects on fluorescence and surface-enhanced Raman scattering of crystal violet adsorbed on Au nanoparticles surface. AB - The Surface enhanced fluorescence (SEF) and Surface Enhanced Raman Scattering (SERS) of Au nanoparticle films deposited on Si and SiO2 substrates are presented. From the experimental results, it is concluded that the fluorescence peak intensity changes in a similar way with the Raman intensity for the various substrates. Both the fluorescence and the Raman intensity were much stronger on SiO2 substrate than on the Si substrate. That is due to the Crystal Violet (CV) adsorbed on the substrate having different refractive index effect the electrical field near the nanoparticles. The nanoparticle size effect on the Raman and fluorescence was also studied. PMID- 23646562 TI - Coupling of surface plasmons and excited optical modes in metal/dielectric grating stacks. AB - In this work, we investigate the coupling of surface plasmons and excited optical modes in metal/dielectric grating stacks theoretically and experimentally. We have observed three kinds of modes in these structures: the cavity mode, the propagated surface plasmon (PSP) mode and the localized surface plasmon (LSP) mode, which can enhance the optical transmission. Firstly, it is shown that the cavity mode is excited in the grating stacks. And the cavity mode has redshift if we enhance the thickness of metal layers, while it has blueshift when we increase the thickness of dielectric layers. The redshift of the cavity mode also occurs when the number of repeating layers is increased. Secondly, the PSP mode is also excited, which can be described by the effective permittivity method. It is found that the PSP modes are coupled with each other, which leads to a modified dispersion relation of surface plasmon polaritons (SPP). The theoretical analysis is in good agreement with the observed transmission enhancement in the grating stacks. And the coupling of PSPs also leads to a blueshift when the number of metal layers is increased. Thirdly, the LSP mode, generated in single metal strip, can also enhance the optical transmission of the grating stacks. Yet the transmission intensity induced by LSP decreases rapidly with increasing the number of metal layers. The investigations here may have potential applications in designing plasmonic metamaterials and subwavelength optical devices. PMID- 23646563 TI - Temperature effect of activation energy for GaSb quantum dots using variable temperature photoluminescence. AB - The excitation power dependence of radiative transitions in the type-II GaSb/GaAs quantum dots structure has been studied by the photoluminescence (PL) at different temperatures. The QDs' photoluminescence exhibits a strong blue-shift with increasing the excitation power and the peak energy (E(PL)) is proportional to the third root of excitation power. With the increase of excitation power, the nonlinear change for both the PL peak and the intensity was observed, which is attributed to the excited state transition. The thermal process and activation energy (E(a)) of electron-hole pairs at different excitation powers has also been studied for GaSb QDs. As the excitation power increases, the activation energy decreases, while E(PL) +E(a) keeps nearly constant, which is smaller than the band gap of GaAs. The decrease of E(a) is probably caused by the band bending effect. PMID- 23646564 TI - Beam focusing by tapered metallic nano-slits. AB - In this study, we discussed the influence of tapered metallic subwavelength slit array with variant width of slits on beam focus properties. In order to analyze the phenomenon, a finite-difference time-domain numerical algorithm and phase matching theory were adopted for computational numerical simulation of the nano structures. The structures were flanked with the penetrated slits through a metal film coated on a quartz substrate. We found that the phase delay of each slit will grow with the decrease of slit width. Optical transmission of each slit can be adjusted by using an optimum choice of the taper angle, taper slit width and the wavelength of incident light. So by optimizing the slit width of the input and output apertures, the trapezoidal slit array can show focusing property. The focal width and focal intensity can be controlled effectively by regulating the aperture width of slits. These results are very encouraging for further study on nano-optics and the applied planar lenses. PMID- 23646565 TI - Exploration of defect structures on graphene. AB - For graphene obtained by chemical vapor deposition, there are large amount of defects in the crystalline structures. The carbon atoms from the feedstock can attack the graphene surface in annealing process, which may be one of the reasons affecting the structure of graphene. In order to explore some defect structures on graphene, we investigate the adsorption of carbon adatoms and vacancies on graphene using first-principles calculations. It is demonstrated that the adatoms can form strong covalent bonds with the graphene and the C-C dimmer adsorption may be the most prolific defect model. The C adatom can even fill simple vacancy of graphene. Our numerical simulations also show that the defect structures can lead to the splitting of the mid-gap peak of perfect graphene in the electronic structures. It is suggested that its conductivity would be lower than that of the perfect graphene, which can explain the low mobility of the charge carriers in some experiments. PMID- 23646566 TI - Increased electronic coupling in silicon nanocrystal networks doped with F4-TCNQ. AB - The modification of the electronic structure of silicon nanocrystals using an organic dopant, 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4-TCNQ), is investigated using first-principles calculations. It is shown that physisorbed F4-TCNQ molecules have the effect of oxidizing the nanocrystal, attracting the charge density towards the F4-TCNQ-nanocrystal interface, and decreasing the excitation energy of the system. In periodic F4-TCNQ/nanocrystal superlattices, F4-TCNQ is suggested to enhance exciton separation, and in the presence of free holes, to serve as a bridge for electron/hole transfer between adjacent nanocrystals. PMID- 23646567 TI - Electronic and optical properties of chlorinated silicon nanoparticles. AB - First-principles calculations are used to investigate the structure, electronic and optical properties of silicon nanocystals with chlorine-passivated surface. The nanocrystals considered were approximately spherical, with diameters between 1.5 and 3.0 nm. We show that the nanocrystals with chlorinated surface have a smaller bandgap, lower optical absorption threshold, and greater ionization energy and electron affinity than hydrogenated silicon nanocrystals of the same size. PMID- 23646568 TI - Magnetic vortex core dynamics in correlated double plates of permalloy. AB - In this work, we theoretically investigate the dynamics of magnetic vortex in a double-plate nanostructure, in which two square permalloy plates are joined together by imposing closely on a thin permalloy film. It is found that magnetic vortices have been formed in the two square permalloy plates. Due to the involving of the joint, the out-of-plane magnetization can also be observed at the sidewalls between the square plates and the joint area. The ground states with the vortex polarities (1,1) and (1,-1) are obtained when the thickness of the joint area is varied. By applying a short in-plane magnetic field pulse, the vortices deviate from their equilibrium positions and gyrate with damping radius. Interestingly, the vortex polarity can be switched if the strength of magnetic field approaches the threshold of switching field. Particularly by changing the strength of magnetic field, the two vortices can be switched alternatively in the double-plate nanostructure. The investigations may provide potential applications in magnetic vortex memories. PMID- 23646569 TI - Molecular dynamics simulation of Anatase TiO2 nanoparticles. AB - Nanoparticles, which are desirable to a wide range of industries, have been shown to exhibit enhanced properties compared to their bulk counterparts. This enhancement has mostly been attributed to their large surface area-to-volume ratio and has attracted huge research interest in recent years. In this work, molecular dynamics simulations have been performed on anatase TiO2 nanoparticles with sizes ranging between 2 and 6 nm and at different temperatures. Thermodynamic and structural properties such as total system energies and radial distribution functions are reported for the different nanoparticle sizes and their dependence on temperature, revealed. At high temperatures, the structures are seen to transform from a highly crystalline to liquid form. Studies conducted on the change of final structure (after simulation) with respect to the initial structure (before simulation) revealed that after simulation, structural disordering (i.e., change in atom position) is more visible at the surface layer compared to the bulk of the final structure. Surface energies for the different particle sizes are also reported and it is observed that surface energy at 300 K increases to a maximum (optimum value) as the particle size increases after which no further significant increase is observed. A study on the sphericity of the nanoparticles showed that the particles became less spherical with increase in temperature. PMID- 23646570 TI - Tuning the electronic properties of N@C60 molecule: a theoretical study. AB - We used first-principle calculations to explore the electronic and transport properties of N@C60 molecule. The calculated results indicate that the N atom locates at either slight or significant off-center in C60 cage under various different chemical environments. The localized N atomic magnetic moment in N@C60 molecule is about 3.0 microB, which is not sensitive to the chemical environment, such as the carrier doping, the external electric field, and the molecule substrate interaction. On the other hand, the magnetism of N@C60 can be effectively tuned by carrier doping and the cage chemical modification. The C60 cage with delocalized pi-electrons character demonstrates a significant shielding (about 80%) of the encapsulated N atom from the applied external electric field. We do not observe obvious transmission spin polarization in N@C60 molecular junctions and the transmission spectra of two spin channels are similar near the Fermi level. PMID- 23646571 TI - Thermal vibrations of single-layered graphene sheets by molecular dynamics. AB - Dynamics problems in the thermal vibration of single-layered graphene sheets (SLGSs) are investigated using molecular dynamics (MD) method based on the Brenner's second-generation reactive empirical bond order (REBO) potential. The in plane stiffness and Poisson ratio of SLGSs are calculated by stretching SLGSs. The effective thickness of SLGSs is obtained by MD simulations for the thermal vibration of SLGSs through the natural frequency. The natural frequencies for SLGSs of different sizes with initial stress in different temperatures are calculated through MD. The thin plate theory can predict the MD results very well in a certain range of strain. For the nonlinear relation between stress and strain when the strain is very large, the deviation between the MD results and plate theory becomes larger when the strain increases. The difference between the plate theory and the MD results becomes more and more obvious, when the size of graphene sheet is very small. PMID- 23646572 TI - Molecular dynamics simulations of friction process between diamond-like carbon and Si-DLC films. AB - Diamond-like carbon (DLC) films have been extensively studied over the past decades due to their unique combination of properties; in particular, silicon doped DLC (Si-DLC) films are of significant interest for tribological effects, they had a very low friction coefficient and possessed the potential to improve wear performance in humid atmospheres and at higher temperatures. But many experimental results of the Si-DLC films showed that their tribological properties changed greatly on different silicon content. In the paper, molecular dynamics (MD) simulations were used to study microstructure of amorphous Si-DLC films and a sliding friction process between DLC and Si-DLC films on un lubricated and oil-lubricated conditions respectively. The results show that silicon atoms are almost surrounded by carbon atoms in all Si-DLC films. The sp3/sp2 ratio in Si-DLC films increases with the increasing silicon content. After sliding, a transfer film between the DLC and Si-DLC films is formed on the un-lubricated condition. In contrast, a boundary lubrication layer is found on the oil-lubricated condition. Moreover, the friction forces on the un-lubricated condition are larger than those on the oil-lubricated condition. PMID- 23646573 TI - Density function theory study of the adsorption and dissociation of carbon monoxide on tungsten nanoparticles. AB - The adsorption and dissociation properties of carbon monoxide (CO) molecule on tungsten W(n) (n = 10-15) nanoparticles have been investigated by density functional theory (DFT) calculations. The lowest-energy structures for W(n) (n = 10-15) nanoparticles are found by the basin-hopping method and big-bang method with the modified tight-binding many-body potential. We calculated the corresponding adsorption energies, C-O bond lengths and dissociation barriers for adsorption of CO on nanoparticles. The electronic properties of CO on nanoparticles are studied by the analysis of density of state and charge density. The characteristic of CO on W(n) nanoparticles are also compared with that of W bulk. PMID- 23646574 TI - A molecular dynamics simulation study on the initial stage of Si(001) oxidation under biaxial strain. AB - We have studied the very early stage of the room temperature oxidation of the externally-strained Si(001) surface using molecular dynamics simulation. It was found that the different treatment history of the sample under the same strain resulted in the difference in the number density of dimer. The as-prepared samples of different treatment history with 12.15% strain were used to investigate the initial oxidation behavior of Si(001). 500 times of independent deposition of single oxygen molecule onto the random position of clean Si(001) surface was simulated. Oxidation behavior was statistically analyzed for various dimer density of the surface which is dependent on strain-treatment history. Oxygen uptake and penetration depth profile showed an important role of dimers on the surface oxidation behavior. PMID- 23646575 TI - Controlled synthesis of different metal oxide nanostructures by direct current arc discharge. AB - Direct current (DC) arc discharge method gives high temperature in a short time, which has been widely used to prepare carbon nanotubes. We use this simple approach to synthesize metal oxide nanostructures (MgO, SnO2) without any catalyst. Different morphologies (nanowires, nanobelts, nanocubes, and nanodisks) of metal oxide nanostructures can be controllably synthesized by changing the content of air in buffer gas. The growth mechanisms for these nanostructures are discussed in detail. Oxygen partial pressure is supposed to be one of the most important key factors. The methodology might be used to synthesize similar nanostructures of other functional oxide materials and non-oxide materials. PMID- 23646576 TI - Optical and electrical performance of HfO2 coated ZnO nanorod arrays. AB - In this paper, we demonstrate the optical and electrical performance of ZnO nanorod arrays after surface passivation. The material of larger band gaps (HfO2) was chosen for the surface passivation layer through atom layer deposition (ALD), in order to confine the carriers within the core material efficiently. In the case of nanorods with high defects, HfO2 coating treatment not only improved near band edge (NBE) but also greatly enhanced the defect luminescence, while in the case of nanorods with low defects, surface coating suppressed defect luminescence and promoted the NBE emission as well as electrical performance therein. PL investigation at 10 K displayed that after surface coating phonon related emission was confined along c-axis and the exciton emission related to surface states was largely restrained. Therefore, it's suggested that surface passivation of ZnO nanorod arrays decreases the surface defect, enhances the side confinement of nanorod, and thus improves the optical and electrical performance efficiently. PMID- 23646577 TI - Effect of high magnetic field on structure and oxygen adsorption of CuO films. AB - CuO films have been fabricated by a two-step method: depositing Cu films on single crystal Si substrates by magnetron sputtering; thermal oxidation of the as deposited Cu films in the air at 600 degrees C. To investigate the effect of magnetic field on CuO film growth, a series of static fields are added along the substrate in the oxidation process. Field emission scanning electron microscopy shows that the high magnetic field promotes the densification and the grain refinement of the films. The X-ray diffraction results reveal that the films have monoclinic structure of CuO. The relative intensity of (111) peak strengthens gradually with increasing the magnetic field intensity, implying that the magnetic field facilitates the growth along [111] direction. X-ray photoelectron spectra of Cu 2p core-level indicate that +2 is the main valence state for Cu ions in CuO films, and the magnetic field produces deeper oxidation of the samples. The high binding energy part of O 1s XPS spectra, which reflects the oxygen adsorption ability, shrinks at low magnetic field, and then expands with the further increase of the magnetic field. The mediation of oxygen adsorption is related to the improvement of crystallinity as well as the enlarged boundary areas. The present study opens a new way to fabricate CuO films, and the high magnetic field is an effective way to tuning the oxygen adsorption. PMID- 23646578 TI - Microwave frequency performance and high magnetic anisotropy of nanocrystalline Fe70Co30-B films prepared by composition gradient sputtering. AB - The fabrication and high-frequency ferromagnetic performances of nanocrystalline Fe70Co30-B soft magnetic films were investigated. It is revealed that the composition gradient sputtering method dramatically improves the high-frequency soft magnetic properties of the as-prepared films. This method gives rise to almost a linearly-increased distribution of compositions and residual stress. As a result, a very high ferromagnetic resonance frequency up to 6.7 GHz, high uniaxial magnetic anisotropic field up to 450 Oe, and low magnetic loss were obtained in as-deposited samples, which are particularly in favor of the integration between magnetic films and microwave components. PMID- 23646579 TI - Large pore size and high porosity of TiO2 photoanode for excellent photovoltaic performance of CdS quantum dot sensitized solar cell. AB - While holding great potential as sunlight absorbers, quantum dots (QDs), which are generally much larger than dye molecule in size, which makes it more difficult to deposit them on the surface of TiO2. As a result, relatively low QD loading is now one of the most challenging issues for improving the photovoltaic performance of QD-sensitized solar cells (QDSSC). In this study, TiO2 photoanodes with different pore sizes and porosities were constructed by systematically varying the solid content of the TiO2 paste. It was confirmed that reducing the solid content resulted in both larger pore sizes and higher porosities. CdS quantum dots were then deposited on these different electrodes by the successive ionic layer adsorption and reaction (SILAR) method, with either 4 or 7 repetitive cycles. By correlating the photovoltaic performances of QDSSCs with different solid contents of TiO2 paste and number of SILAR cycles of CdS QD deposition, it was found that the combination of 7 SILAR cycles with 10% electrode solid content yielded the highest overall energy conversion efficiency. In particular this cell exhibited an outstanding open-circuit photovoltage up to 640 mV using a polysulfide electrolyte, which currently ranks the highest among reported literature. This outcome is due to the fact that a 10%-solid-content provided the largest pore sizes and the highest porosity for the QDs deposition, while the 7 SILAR cycles guaranteed the sufficient CdS QD loading which is favorable for light harvesting. PMID- 23646580 TI - Polystyrene-microsphere-assisted patterning of ZnO nanostructures: growth and characterization. AB - In this work, periodic arrays of various ZnO nanostructures were fabricated on both Si and GaN substrates via a facile hydrothermal process. To realize the site specific growth, two kinds of masks were introduced. The polystyrene (PS) microsphere self-assembled monolayer (SAM) was employed as the mask to create a patterned seed layer to guide the growth of ZnO nanostructures. However, the resulting ZnO nanostructures are non-equidistant, and the diameter of the ZnO nanostructures is uncontrollable. As an alternative, TiO2 sol was used to replicate the PS microsphere SAM, and the inverted SAM (ISAM) mask was obtained by extracting the PS microspheres with toluene. By using the ISAM mask, the hexagonal periodic array of ZnO nanostructures with high uniformity were readily produced. Furthermore, the effect of the underlying substrates on the morphology of ZnO nanostructures has been investigated. It is found that the highly ordered and vertically aligned ZnO nanorods epitaxially grow on the GaN substrate, while the ZnO nanoflowers on Si substrates are random oriented. PMID- 23646581 TI - Synthesis and electrochemical properties of Sb2Se3 nanowires prepared by a gas induced reduction method. AB - Sb2Se3 nanowires have been prepared by a novel gas induced reduction (GIR) method. The precursor solution prepared by dissolving Sb2(OCH2CH2O)3 and SeO2 in a certain solvent was initially separated from the reductant, hydrazine hydrate. The reductant evaporated during the heating process, dissolved into the precursor solution and reacted with Sb3+ and SeO2 and finally Sb2Se3 nanostructures formed. Different solvents including diethanolamine, glycerol, ethylene glycol, deionized water, absolute ethanol and isopropyl alcohol were respectively used for comparison. It was found that when ethylene glycol was used as a solvent, pure, relatively homogeneous, and high aspect-ratio Sb2Se3 nanowires (40-120 nm in diameter and -100 microm in length) were prepared. Growth mechanism of the Sb2Se3 nanowires was proposed. The electrochemistry character of the nanowires was investigated via assembling into lithium ion batteries. The discharge capacity of Sb2Se3/Li cell cycled between 0.3 and 2.5 V was performed in the range of 142 1036 mA x h x g(-1) during the first 30 cycles, with the charge/discharge efficiency increasing from 89.4% to 97.5%. PMID- 23646582 TI - Mediating distribution of magnetic Co ions by surfactant in Co-doped SnO2 nanorods. AB - We demonstrate a method to control the distribution of magnetic Co ions in Co doped SnO2 nanorods by the surfactant. The nanorods with nanoflower morphology have been synthesized by surfactant-assisted hydrothermal method. The X-ray absorption fine structure spectra at Co K-edge reveal that Co ions substitute for Sn site in SnO2 lattice. The X-ray absorption fine structure spectra at O K-edge with its simulated spectra have been performed to investigate the local environment of Co ions. In the experimental spectra, the pre-edge peak continues to decline with the addition of the surfactant. It shows the same trend when the number of clustered Co ions in the simulated spectra is reduced, which indicates that the surfactant suppresses the formation of Co clusters. The effect of surfactant in mediating Co distribution arises from the strong interactions between the Co2+ ions and the CTA+ ions. In the Co K-edge experimental spectra, the weakened pre-edge peak reflects the electron transfer from the CTA+ ions to Co 3d band. Such electron transfer changes the charge state of Co ions and modifies the electrostatic interactions among dopant ions, leading to the uniform distribution of substitutional Co dopants. These results provide experimental guidance in the synthesis of the homogeneous-doped metal oxide semiconductors. PMID- 23646583 TI - Environmentally friendly approaches toward the production of processable graphene by exfoliation of graphite using ionic liquid. AB - A facile, low-cost and environmentally friendly method was developed to prepare processable graphene materials by direct exfoliation of expandable graphite flakes under wet ball milling conditions in ionic liquids. The graphene nano sheets obtained in this method were characterized by AFM, Raman spectroscopy, UV NIR. Thin-film field-effect transistors made from this graphene sheets exhibit ambipolar effect, an average hole mobility of -0.29 cm2 V(-1) s(-1), electron mobility of -0.57 cm2 V(-1) s(-1) was obtained. PMID- 23646584 TI - Impact of polymer matrix on the electromagnetic interference shielding performance for single-walled carbon nanotubes-based composites. AB - Composites of acrylonitrile butadiene styrene (ABS), epoxy and soluble cross linked polyurethane (SCPU) with various loadings of single-walled carbon nanotubes (SWCNTs) were prepared. Their electromagnetic interference (EMI) shielding effectiveness (SE) in the frequency range of 8.2-12.4 GHz (X band) was studied. Well-dispersed SWCNT composites were created in these three representative polymer matrixes. The choice of polymer matrix greatly affects the conductivity, percolation threshold, and EMI shielding properties of the SWCNT/polymer composites. Enhanced EMI SE performances were observed for the composites with better dispersed SWCNTs. Moreover, the EMI SE performances strongly correlated with SWCNT loading in the polymer matrix. The best SWCNT dispersion was achieved in the epoxy matrix: 20-30 dB EMI SE was obtained with 15 wt% SWCNTs. PMID- 23646585 TI - Negative and positive magnetoresistance of graphenes at room-temperature. AB - Graphenes were prepared via micromechanical cleavage of natural graphite flakes and transferred onto a silicon wafers with a 285 nm SiO2 thick film on the surface. Nickel was used as the electrodes to study the magnetoresistance of graphenes devices at room temperature. We find that the magnetoresistances of graphenes shows positive sign while the magnetoresistances of pure nickel have negative sign at the same external magnetic field when a Z-direction magnetic field (0.24 T, graphenes on the X-Y plane) is applied. The magnitude of magnetoresistance of graphenes is about +0.20% and 5 times larger than that of the same thickenss pure nickel film. When the magnetic field is along the X direction (-0.26 T, perpendicular to Y-direction current), the magnetoresistance of graphenes and nickel film both have negative sign and value of -0.04% and 0.03%, respectively. The magnetoresistance of graphenes and nickel film both have positive sign and value of +0.09% and +0.04%, when the magnetic field is along the Y-direction (-0.24 T, parallel to Y-direction current), respectively. The mechanism of these observations is attributed to the edge ferromagnetism of graphenes. Our work shows that grapheses may play an important role in spin device operated at room temperature. PMID- 23646586 TI - Sol-gel autocombustion synthesis of graphene/cobalt magnetic nanocomposites. AB - Here we describe a versatile new strategy for producing graphene/cobalt magnetic nanocomposites by combining the sol-gel method and autocombustion. We used graphene oxide (GO), cobalt nitrate and citric acid as starting materials and prepared a dry gel of them through a routine sol-gel approach. After the autocombustion was activated at 300 degrees C in a tube furnace under an argon atmosphere, reducing agents such as H2 and CH4 were produced and then in situ reduced GO and cobalt nitrate to get graphene/cobalt magnetic nanocomposites. X ray photoelectron spectroscopic and X-ray powder diffraction analysis showed that the nanoparticles loaded on graphene are cobalt but not cobalt oxide. Transmission electron microscopy and scanning electron microscopy revealed that cobalt nanoparticles, with an average diameter of -10 nm, were homogeniously deposited on the surface of graphene. Further more, other metal nanoparticles such as Ni, Cu, Ag and Bi can also be loaded on graphene using the same method. PMID- 23646587 TI - Fabrication of graphene/polyaniline composite for high-performance supercapacitor electrode. AB - Composite films of graphene and polyaniline nanofibers are prepared by in situ polymerization of aniline monomer in graphene suspension. The morphology and microstructure of samples are examined by scanning electron microscopy (SEM), transition electron microscopy (TEM), and X-ray diffraction (XRD). Electrochemical performances are characterized by cyclic voltammetry (CV) and galvanostatic charge/discharge measurements. Graphene is homogeneously coated by polyaniline nanofibers with diameter of 40 nm. Supercapacitors based on the graphene/polyaniline conductive composite films exhibit large electrochemical capacitance (994 F/g) at a discharge rate of 2.0 A/g in 1 M H2SO4 solution, which is much higher than the graphene (320 F/g) and polyaniline electrode (210 F/g). The excellent performance is not only due to the graphene which can provide more active sites for nucleation of polyaniline, but also associated with a good redox activity of ordered polyaniline nanofibers. Moreover, the composite films exhibit excellent long cycle life during charge/discharge processes. After 1000 cycles, the specific capacitance decreases 11% of initial capacitance compared to 28% for polyaniline nanofibers. The resulting composite is a promising electrode material for high-performance electrical energy storage devices. PMID- 23646588 TI - Mechanical behaviors of carbon nanoscrolls. AB - Theoretical analysis and molecular dynamics simulations are presented to study the mechanical behaviors of Carbon nanoscrolls (CNSs). The study shows that a graphene sheet can rapidly self-scroll onto a carbon nanotube. The van der Waals interaction between the graphene sheet and the nanotube is the driving force of self-assemble process. During self-assemble process, the van der Waals energy of the system is partially balanced with the bending energy of the graphene walls and partially converted to the kinetic energy of the CNS. If a new graphene sheet is attached to the nanoscroll with end to end joint, the new graphene will self assemble into the CNS and the spontaneously formed CNSs will rotate around the nanotube. If a new graphene sheet is attached the CNS with lap joint, the new graphene sheet will self-scroll onto the CNS and the spontaneously formed CNSs will oscillate around the nanotube with high frequency. PMID- 23646589 TI - Enhanced photocatalytic activity of titanium oxide nanotubes after heating treatment. AB - Titanium oxide nanotubes were obtained by an electrochemical anodization method. Scanning electron microscope results demonstrate that the diameter of the tubes is about 120 nm and the length of the tubes is around 13 microm. Transmission electron microscope results indicate that the nanotubes are assembled by numerous nanoparticles and tube-like structure remains well after heat treatment at 400 600 degrees C. The photocatalysis performance of the nanotubes was evaluated in terms of the decomposition rate of methyl orange under UV irradiation. The results show that the photocatalytic activity was enhanced through the heating treatment of the nanotubes, and the nanotubes heated at 600 degrees C exhibits the best photocatalytic activity. X-ray diffraction patterns indicate that there is no phase transformation during the heat treatment. Therefore, the enhanced activity can be attributed to the improvement of nanotubes crystallinity, which may provide more insights about the effect of the crystallinity on the photocatalytic performance. PMID- 23646590 TI - In-situ Raman spectra of single-walled carbon nanotube/epoxy nanocomposite film under strain. AB - In-situ Raman spectra under continuous strain have been carried out to follow the load transfer efficiency in a single-walled carbon nanotube/epoxy nanocomposite film, which was fabricated by a facile and filter-free infiltration method using directly synthesized SWNT film as skeleton. It was found that in the low elastic range of 1%, with the increase of applied strain, the G- and G+ Raman bands downshift nearly lineally with corresponding ultrahigh rates up to -12 and -17 cm(-1)/% strain, respectively. As the applied strain decrease, these Raman bands upshift to their original frequencies with almost the same rates. These precise relationships between the Raman band shift and the applied strain enable this nanocomposite film promising stress or stain sensors. Furthermore, some Raman radial breathing modes (RBMs) disappear (appear) under larger strain (1.6%) and recover (vanish) when the strain is released, also verify the effective deformation of micro SWNTs induced by extra macro strain applied on the nanocomposite film. More interestingly, these frequency shifts and intensity vibrations are recoverable and repeatable, indicating the high elasticity of deformation in this strain region of 2%. PMID- 23646591 TI - Template-assisted fabrication of gold nanowire arrays for ethanol electro oxidation. AB - Gold nanowires are considered a promising candidate in the area of electrocatalysis because of their extremely high surface-to-volume ratios and other special properties. In this paper, highly ordered gold nanowire arrays have been fabricated by direct electrodeposition utilizing highly ordered anodic aluminum oxide (AAO) templates. The morphology and microstructure of AAO templates and gold nanowire arrays were characterized by field emission scanning electron microscopy (FESEM) and X-ray diffraction (XRD), respectively. The results showed that the average diameter of gold nanowires was on the order of 80 nm, which was in accordance with the diameter of AAO pores. The electro-oxidation of ethanol on gold nanowire arrays in alkaline medium was measured by cyclic voltammetry. The results indicated that gold nanowire arrays showed excellent electrocatalytic activity and stability towards the electro-oxidation of ethanol, which made gold nanowire arrays an excellent electrocatalyst in the applications of direct ethanol fuel cell. PMID- 23646592 TI - Synthesis of SiO(x) powder using DC arc plasma. AB - SiO(x) was prepared by DC arc plasma and applied to the anode material of lithium ion batteries. A pellet of a mixture of Si and SiO2 was used as the raw material. The ratios of the silicon and silicon dioxide (SiO2) mixtures were varied by controlling the Si-SiO2 molar ratio (Si-SiO2 = 1-4). Hydrogen gas was used as the reduction atmosphere in the chamber. The prepared SiO(x) was collected on the chamber wall. The obtained SiO(x) was characterized by X-ray diffraction (XRD), field emission-scanning electron microscopy (FE-SEM), energy dispersive spectroscopy (EDS), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). XRD and TEM showed that the phase composition of the prepared particles was composed of amorphous SiO(x) and crystalline Si. The prepared SiO(x) showed wire and spherical morphology. XPS indicated the bonding state and 'x' value of the prepared SiO(x), which was close to one. The result of prepared SiO(x) is discussed from thermodynamic equilibrium calculations. The electrochemical behavior of the silicon monoxide anode was investigated. PMID- 23646593 TI - Synthesis and characterization of NiO nanowire/In2O3 nanoparticle heterostructures. AB - A facile method is presented for synthesis of novel pearl-string-like NiO nanowire/In2O3 nanoparticle heterostructures. The synthesis was carried out by using a chemical vapor deposition method with Indium granules and Nickel (II) Chloride Hexahydrate as precusors. The structures were investigated by X-ray diffraction and transmission electron microscopy. Room and low temperature photoluminescence of the heterostructures was studied. Our work provides a new strategy for fabrication of novel nano-heterostructures and is promising for future device applications. PMID- 23646594 TI - Enhanced photocurrent from organic polymers-based photodiodes by blending PbS colloidal quantum dots. AB - Enhanced photocurrent from organic polymer-based photodiodes by blending PbS colloidal quantum dots (CQDs) are presented. The absorption spectra of nanocomposites of PbS CQDs and organic polymers, Poly[2-methoxy-5-(2' ethylhexyloxy-pphenylenevinylene)] (MEH-PPV) and [6,6]-phenyl-C61-butyric acid methylester (PCBM), are the superposition of those of pristine constituents, indicating the absorption of the PbS CQDs contributes to the effective near infrared light absorption for the photodiodes. The enhanced photocurrent for photodiodes made of MEH-PPV:PCBM:PbS is attributed to the excitons dissociation at the interfaces of PbS/MEH-PPV and PbS/PCBM, as well as charge transport in MEH PPV and PCBM. PMID- 23646595 TI - Photovoltaic activity of ZnO nanorods arrays co-sensitized by CdS and CuInS2 quantum dots. AB - One-dimensional ZnO nanorods arrays were self-assembly grown on a ZnO thin film, and then CdS quantum dots were deposited on the ZnO nanorods arrays by a successive ionic layer adsorption and reaction process. Scanning electron microscopy and transmission electron microscopy results indicate that the CdS quantum dots can be uniformly deposited on the ZnO nanorods arrays and the thickness of the CdS shell can be controlled through varying the number of the adsorption and reaction cycle. For a typical sample prepared by the adsorption and reaction cycles of 10 times, the thickness of the CdS is about 4.0 nm. Monodispersed CulnS2 quantum dots with a size of 3.5 nm were synthesized by a solvothermal route and then deposited on the ZnO nanorods arrays coated with the CdS quantum dots by using an electrophoretic deposition technique. Optical and electrical properties indicate that the as-fabricated ZnO/CdS/CulnS2 heterojunction structure not only exhibits a high absorption of the incident light in visible region but also can reduce a leakage current as compared to the ZnO/CdS heterojunction structure. Electrical impedance spectroscopy is used to analyze the electrochemical reaction of the interfaces. PMID- 23646596 TI - Resistive switching memory based on three-dimensionally confined Ag quantum dots embedded in ultra thin polyimide layers. AB - Resistive switching memory devices based on three-dimensionally confined Ag quantum dots (QDs) embedded in polyimide (PI) layers were fabricated by using spin-coating and thermal evaporation. The Ag QDs embedded in PI layer were distributed uniformly with sizes of approximately 4-6 nm and with surface density of approximately 1.25 x 10(11) cm(-2). The electrical properties of the Ag/PI (10 nm)/Ag QDs/PI (10 nm)/Ag devices were investigated at room temperature. Current voltage (I-V) measurements on the devices showed a counterclockwise electrical hysteresis behavior with reliable and reproducible resistive switching to the existence of the Ag QDs. The memory device transformed from its original high resistance state to low-resistance state under positive bias, and regained its original high-resistance state under negative bias. The maximum ON/OFF ratio of the current bistability was 1 x 10(4). The device also revealed excellent endurance ability at ambient conditions. The possible operating mechanisms concerning the interaction between Ag QDs and PI matrix for the resistance transform phenomenon were analyzed on the basis of the I-V results. PMID- 23646597 TI - A novel NO2 sensor based on TiO2 nanotubes array with in-situ Au decoration. AB - Au decorated TiO2 nanotubes array was successfully fabricated on a Ti-Au alloy via an electrochemical anodization process. The crystal phase and microstructure of the TiO2 nanotubes array were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM), respectively. Au particles were well distributed among TiO2 nanotubes and acted as the catalyst. It was found that the sensor based on Ti-Au alloy anodization can be a promising sensor which was highly sensitive to low concentrations of nitrogen dioxide (NO2), and response at room temperature. The sensitivity of Au-decorated TiO2 nanotubes sensor was 36.11 to 8 ppm NO2 at room temperature. Meanwhile, the resistance signal of Au-decorated TiO2 sensor changes quickly within 80 s upon exposure to 8 ppm NO2 at 35 degrees C, the undecorated TiO2 however takes much more time (>110 s) to respond and the resistance signal remains unstable. PMID- 23646598 TI - Tunable microwave frequency performance of nanocomposite Co2MnSi/PZN-PT magnetoelectric coupling structure. AB - Nanocrystalline Co2MnSi Heusler alloy films were deposited on the PZN-PT substrates by a composition gradient sputtering method. It is revealed that this multiferroic heterostructure shows very strong magnetoelectric coupling, leading to continuously tunable microwave frequency characteristics by electric field. With the increase of electric field intensity from 0 to 6 kV/cm, the magnetic anisotropy field H(K) increases from 90 Oe to 182 Oe with an increment of 102%, corresponding to a ME coefficient of 15.3 Oe cm/kV; the ferromagnetic resonance frequency f(FMR) shifts from 3.38 to 4.82 GHz with an increment of deltaf(FMR) = 1440 MHz or deltaf(FMR)/f(FMR) = 43%; moreover, the damping constant alpha dramatically decreases from 0.035 to 0.018. These merits demonstrate that this nanocomposite multiferroic structure is promising in fabrication of tunable microwave components. PMID- 23646599 TI - Application of three-step epitaxial process to dual trench epitaxial diode array. AB - The application of three-step Epitaxial (EPI) process to dual trench epitaxial diode array for high density phase change random access memory (PCRAM) was reported in this paper. With three-step EPI process condition, both vertical and lateral Arsenic auto-doping were suppressed effectively from Arsenic heavily doped substrate. It was found that EPI layer (- 300 nm) with high-quality single crystalline and good thickness uniformity within 200 mm diameter wafer could be achieved. It was also found that both lateral and vertical Arsenic auto-doping concentration could be reduced by 2-3 orders by adding high temperature and low deposition rate EPI step before main EPI process, as compared to the conventional CVD EPI process. As a result, diode breakdown voltage was improved above 11 V and the On/Off current ratio of diode is greater than 9 orders of magnitude. PMID- 23646600 TI - H2 sensing properties of pd modified WO3-Fe2O3 nanostructured composite films prepared by amorphous W-Fe dealloying. AB - Tungsten trioxide nanopetal with Fe2O3 composite films were synthesized by dealloying the W-Fe alloy film in HCl aqueous solution; nano-Pd particles were directly electrochemical deposited on the surface of dealloying films in a micro emulsion system and following thermal oxidation in air. The structure, morphology, chemical composition and quality of the prepared WO3 nanopetal with Fe2O3 composite films were characterized by field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM), respectively. The results showed that the thickness of the WO3 nanopetals were less than 50 nm, which were monoclinic phase after controlled thermal oxidation process, and the nano-Pd particles were evenly dispersed on the WO3 film surface with controlled diameters ranging from 20 to 40 nm. The sensors were tested for 25-2000 ppm H2 at temperatures from 50 to 200 degrees C; and the H2 sensing properties of Pd loading (1.54 at.%) WO3-Fe2O3 composited films exibited the best response at the low working temperature of 125 degrees C. PMID- 23646601 TI - Ion-sensitive field effect transistor as a pH sensor. AB - In this work, both the static and dynamic behaviors as well as the signal read out circuits of ISFETs were studied. The standard NMOS structure in conjunction with the insulator-electrolyte capacitor was used to model the ISFET under study. The site-binding theory was incorporated to describe the chemistry occurring at the insulator/electrolyte interface. The mechanism of the threshold voltage drift was further explored. We propose that to better understand the drift, both slow responding sites and hydration effects need to be considered. It was found that, to better simulate the voltage drift, two exponential terms had to be employed with one governing the initial drift and the other the long term drift. In addition, a low noise differential signal read-out circuit was designed and simulation was carried out using LTspice. The output voltage of the system changes from -2.1 V to 0.5 V when the pH of the electrolyte changes from 12 to 0. PMID- 23646602 TI - Fabrication of sub-20 nm width ferromagnetic nanocontact structures by shadow evaporation. AB - The movement of the magnetic domain wall could result in the changing of the contact resistance. Such a resistance change is named as the domain wall Magnetoresistance (DWMR), which can be used as a basic signal of nanodevices. For application, a large DWMR is necessary to improve the device performance. An approach to improve the DWMR value is to fabricate magnetic structures with narrow contact width. However, due to the proximity effect during the process of electron beam lithography (EBL), it is not easy to fabricate sub-20 nm width structures by EBL technique directly. In this paper, we investigated the fabrication of sub-20 nm width nanocontact structures by combined techniques of EBL and shadow evaporation. Upon optimizing the resist thickness, opening width, and the evaporation angle, the contact width was tuned and the corresponding variation trends with these parameters were explored. Using the optimized fabrication conditions, 14 nm wide ferromagnetic contact structures were successfully fabricated. PMID- 23646603 TI - Optically powered ZnO nanowires with symmetric and asymmetric contacts. AB - In this paper, we show large photovoltage and photocurrent obtained in individual ZnO nanowire devices with symmetrical and asymmetrical contacts. Ti/Au terminal electrodes were deposited for symmetrical contacts, while Ti/Au and Au electrodes were employed for asymmetrical contacts. Photovoltage and photocurrent measurements were carried out on individual ZnO nanowires devices without external bias. The symmetric nanowire devices exhibited -3 mV photovoltage and 10 nA photocurrent powered by UV laser illumination, while -60 mV photovoltage and -10 nA photocurrent were obtained for asymmetric contacts. Furthermore, the photovoltage were noticeably dependent on the local excitation position. Further calculation showed that the laser illumination reduced the Schottky barrier heights. The above results can be understood on the basis of illumination controlled Schottky barrier heights at nanowire-metal contacts and surface oxygen adsorption-desorption. We demonstrate that the simple two-terminal devices can be useful for self-powered and position sensitive photodetection, optically powered circuit, and nanowire based integrated nanophotonics. PMID- 23646604 TI - Potential application of titanium dioxide nanoparticles in the prevention of osteosarcoma and chondrosarcoma recurrence. AB - Osteosarcoma and chondrosarcoma are malignant bone tumors, and they significantly affect the life quality of patients including children and adults. The main treatment method is surgical amputation of the malignant lesion, despite that recurrence often occurs. Recently, it has been observed that TiO2 NPs killed HeLa cells effectively via photocatalysis in vitro, which indicates titanium dioxide (TiO2) nanoparticles (NPs) might be used to reduce the recurrence of osteosarcoma and chondrosarcoma by inducing cytotoxicity to bone tumor cells. In this study, we investigated the potential effects of TiO2 NPs in two cancer cell lines in vitro: U-2 OS (osteosarcoma) and SW 1353 (chondrosarcoma). We assessed cell viability, the levels of reactive oxygen species (ROS) and glutathione (GSH) after exposure to TiO2 NPs at different concentrations (0.1-100 microg/ml) for varying exposure periods (12-48 hours). Compared to the NP-free control, TiO2 NPs induced cell death in a dosage-dependent and time-dependent manner. The median inhibitory concentration (IC50) of TiO2 NPs at 24 hours was 211.3 +/- 15.2 microg/ml and 5408.8 +/- 45.9 microg/ml for SW 1353 and U-2 OS cell lines, respectively. TiO2 NPs concentrations above 1 microg/ml were more efficient to reduce the cell viability of SW 1353 than U-2 OS of NPs at all exposure times. The increased ROS and reduced GSH levels indicated that TiO2 NPs killed cancer cells through oxidative stress. These results suggested that the TiO2 NPs can be potentially used to minimize/prevent the recurrence of osteosarcoma and chondrosarcoma. PMID- 23646605 TI - A novel nanoprobe based on single-walled carbon nanotubes/photosensitizer for cancer cell imaging and therapy. AB - Nanomedicine and nanotechnology have provided an effective platform for integration of therapeutic and diagnostic agents. Single-walled carbon nanotubes (SWCNTs), a highly effective means of transporting cargos of various sizes and types across the cell membrane, are gradually playing a bigger and more important role in the field of nanomedicine. In this study, a novel nanoprobe based on SWCNTs and a fluorescent photosensitizer pyropheophorbide a (PPa), was developed and was used for cancer cell imaging and therapy in vitro. Phospholipids bearing polyehylene-glycol modified SWCNTs that can provide an interface for the conjugation of PPa were prepared by ultrasonication. The polyehylene-glycol modified SWCNTs were then conjugated with PPa by using covalent functionalization method to construct SWCNT-PEG-PPa nanoprobe. The functionalization of SWCNTs was evidenced by UV-vis absorption spectra and fluorescence spectra. Imaging of cancer cells with SWCNT-PEG-PPa nanoprobe was confirmed using two cancer cell lines via laser scanning confocal microscope tests, and killing of cancer cells with SWCNT-PEG-PPa was demonstrated using cytotoxicity tests. Moreover, the stability of SWCNT-PEG-PPa was further investigated. Our experiments indicated that the resulting SWCNT-PEG-PPa nanoprobe should have a great potential to be a potent candidate for cancer imaging and therapy. PMID- 23646606 TI - Hydrogen-bond-assisted supramolecular assembly of 1,3,5-tris(5 carboxyamyloxy)benzene at the liquid-solid interface: an scanning tunneling microscopy study. AB - The well-ordered self-assembled structure of 1,3,5-tris(5-carboxyamyloxy)benzene (TCAB) on Au(111) has been studied by electrochemical scanning tunneling microscopy (ECSTM) in HClO4 solution. Close examination indicates that the complex supramolecular network is formed by the TCAB molecules with flat-lying adsorption geometry and mainly stabilized by the hydrogen bonding interactions between carboxyl groups, except for the molecule-substrate interactions. It is particularly noteworthy that two types of hydrogen bonds, the dimers and tetramers of carboxyl group, coexist at the interface to balance the molecule molecule and molecule-substrate interactions as well as to minimize the surface energy. Interestingly, the propeller-like motifs in STM image are fabricated by the bent alkoxy chains from four neighboring molecules respectively, bonded together by the cyclic carboxyl group tetramers. Moreover, there are two propellers in one lattice of TCAB adlayer, rotating in the clockwise and counterclockwise directions, respectively. Careful inspection shows that two structure domains of the TCAB adlayer are mirror images of each other since the molecular self-organization breaks the reflection symmetry of the substrate underneath. Our results give a good example of the flexibility adopted by alkyl chains functionalized by carboxyl group for the supramolecular assemblies at the liquid-solid interface. PMID- 23646607 TI - Synthesis of rhombic dodecahedral gold nanocrystals by dimethylformamide reduction. AB - We report a facile and low-cost wet chemical method for preparation of gold (Au) nanocrystals with morphology of well-defined rhombic dodecahedron (RD). The Au nanocrystals with the RD shape have been synthesized by reducing HAuCl4 in N,N dimethylformamide (DMF) solvent in an autoclave for 15-24 h at 90 degrees C. Thus synthesized Au nanocrystals have been characterized by a scanning electron microscopy (SEM), transmission electron microscopy (TEM), and selected-area electron diffraction (SAED). The results show that the RD nanocrystals are exclusively enclosed by twelve {110}-type facets. Furthermore, concave RD Au nanocrystals can also be produced only by changing reaction time or adding ascorbic acid (AA). A possible evolution mechanism of the RD Au nanocrystals has been suggested. PMID- 23646608 TI - Self-assembly of thiophene derivatives on highly oriented pyrolytic graphite: hydrogen bond effect. AB - In this paper, to elucidate the hydrogen bond effect on the assembly behavior, we studied the assembly structures of two carboxylic substituted thiophene derivatives on highly oriented pyrolytic graphite (HOPG) by scanning tunneling microscopy. Here thiophene-2-carboxylic acid (TCA) and thiophene-2,5-dicarboxylic acid (TDA) were employed. TDA molecules spontaneously adsorb on the HOPG surface and self-organize into a two-dimensional (2D) assembly with well-defined structure. Two types of domain could be observed. Each TDA molecule appears as a round circle with two small faint dots and forms hydrogen bonds with neighbours. Besides monolayer structure, a bilayer structure of TDA adlayer on HOPG was also observed in this research. Remnant TDA molecules adsorb on the monolayer of TDA and bilayer structure is formed. In contrast to TDA, no ordered structure of TCA on HOPG can be observed. TCA molecules have high propensity to form dimers through H-bond between carboxylic groups. But TCA dimer is not stable enough for either adsorption or imaging. Our result provides a new example for understanding hydrogen effect on stabilizing and controlling two-dimensional assembly structure and is helpful for surface nanofabrication and development of electric nanodevices. PMID- 23646609 TI - A novel electromagnetic apparatus for rapid multiplex single molecule force spectroscopy. AB - Single-molecule force spectroscopy has revolutionized our ability to probe the details of molecular structures and interactions, but the numbers of individual measurements required for achieving a statistically reliable result can sometimes prove daunting. To overcome this problem, a number of instruments have recently been developed that are capable of monitoring the behavior of tens of individual biomolecules simultaneously. In this work, we have constructed a novel electromagnetic apparatus for multiplex single molecule force measurements utilizing magnetic microspheres. In this system, the magnetic field is generated with an electron-lens of an electron microscope mated with a high voltage flash light circuit to rapidly attain a stable magnetic field. We show that this instrument can generate a uniform magnetic force of up to -20 pN within 5 ms, over a region spanning 1 mm. The successful application of this apparatus to the force-dependent extension of dsDNA fully validates this approach. Furthermore, the lens-like design of the pole piece is fully compatible with optical imaging, thus allowing for the integration of single molecule fluorescence capabilities that should make this system a particularly powerful apparatus for multi dimensional characterization of fast processes within interacting single molecules. PMID- 23646610 TI - Influence of the interlayer on coupling of surface plasmons in a sandwiched structure with periodic array of nanoapertures. AB - In this work, we investigate the optical properties of a multilayer structure, where a SiO2 film is sandwiched by silver films with periodic array of sub wavelength apertures. Due to the coupling of surface plasmons (SPs) between different layers, electric and magnetic resonances have been observed. By varying the thickness of the interlayer SiO2, we can modify relative phase of the SPs resonance and control the shifts of transmission peaks. Experimentally the multilayers are fabricated by magnetron sputtering and the array of apertures is milled by focused-ion-beam facility. The measured optical transmission spectra reasonably agree with our numerical calculation, which bases on three-dimensional finite-difference time-domain method. To understand the shifts of the peaks, we present a phenomenological explanation, considering the transmission peaks as energy levels, and the coupling of localized surface plasmons as perturbation. These results may have potential applications in designing plasmonic devices and tuning electromagnetic wave in nanophotonics. PMID- 23646611 TI - Fabrication of nanoporous arrays from photosensitive organic-inorganic hybrid materials by using an UV soft nanoimprint technique. AB - A honeycomb-like regular nanoporous pattern built in the photosensitive organic inorganic hybrid film was fabricated by an UV soft nanoimprint technique. Polydimethylsiloxane (PDMS) soft mold was firstly replicated from an anodic aluminum oxide (AAO) template obtained by using a two-step anodization method. Scanning electron microscopy images show that the AAO template has a regular honeycomb-like nanoporous structure, while the PDMS soft mold has a relief structure of nanopillar arrays. Photosensitive TiO2-contained organic-inorganic hybrid films, which were prepared by combining a low temperature sol-gel process with a spin-coating technique, were used as the imprinted layer. Thus, a honeycomb-like regular nanoporous pattern built in the hybrid film can be easily obtained by imprinting the PDMS soft mold into the photosensitive hybrid film under an UV-irradiation. The as-fabricated organic-inorganic regular nonporous arrays have potential applications in two-dimensional photonic crystal. PMID- 23646612 TI - Spin-dependent energy bands and spin polarization in two-dimensional spin-orbit lateral superlattices. AB - In this work, we theoretically investigate the spin-split energy bands of electrons and spin-polarized transport in two-dimensional (2D) spin-orbit lateral superlattices (SOLSLs), where the square rods with Rashba spin-orbit coupling (SOC) are distributed periodically by applying gate voltages on the semiconductor. Within the Landauer framework of ballistic transport, the energy bands, the electrical conductance, the spin polarization and the spin-dependent electronic charge distributions have been calculated. It is found that the energy minibands are formed and the energy levels are split up by the Rashba SOC. As a result, the spin-polarized conductance is obtained even in the absence of external magnetic fields and magnetic materials. Meanwhile, the spin polarization can approach high values in the SOLSLs by manipulating the strength of SOC. Furthermore, the spin-dependent electronic charge distributions have been obtained, which present a clear picture of spin-polarized conductance. Our investigations have the potential applications in spin-based quantum devices and semiconductor spintronics. PMID- 23646613 TI - Graphene based dots and antidots: a comparative study from first principles. AB - Graphene based quantum dots and antidots are two nanostructures of primary importance for their fundamental physics and technological applications, particularly in the emerging field of graphene-based nanoelectronics and nanospintronics. Herein, based on first principles density functional theory calculations, we report a comparative study on the electronic structure of these two structurally complementary entities, where the bandgap opening, edge magnetism and the role of hydrogenation are investigated. Our results show the diversity of electronic structures of various dots and antidots, whose properties are sensitive to the edge detailed geometry (including size and shape and edge type). Hydrogen passivation plays an essential roal in affecting the related properties, in particular, it leads to larger bandgap values and suppress the edge magnetism. The frontier orbital analysis is employed to rationalize and compare the complicated nature of dots and antidots. Based on the specific geometrical consideration and the total energy competition of the ground antiferromagnetic and the ferromagnetic states, some magnetic structures (the unpassivated 42-atom-antidot and 54-atom-dot) are proposed to be useful as magnetic switches. PMID- 23646614 TI - The dynamics behavior of Rh nanoclusters on boron nitride sheet. AB - The configurations and corresponding adsorption energies of Rh(n) (n = 4-13) nanoclusters on the boron nitride sheet are investigated by density functional theory (DFT). We use the force-matching method (FMM) to modify parameters of Morse and Tersoff potential functions. To elucidate the dynamical behaviors of Rh nanoclusters on the boron nitride sheet, molecular dynamics (MD) is applied with modified Morse potential function parameter. Finally, the square displacement (SD) is utilized the dynamics behavior of different size Rh nanoclusters at different temperatures. PMID- 23646615 TI - Predicting the size- and shape-dependent cohesive energy and order-disorder transition temperature of Co-Pt nanoparticles by embedded-atom-method potential. AB - The cohesive energy (CE) of CoPt nanoparticles (NPs) with different sizes and shapes have been calculated by embedded-atom-method (EAM) potential. It is shown that CE of NPs with order or disorder structures decreases with the decrease of particle size, while the shape effects become obvious only at small size. The CE difference per atom between order and disorder structures decreases with the decrease of particle size, indicating that the possibility of order-disorder transition in small size becomes larger compared with these in large size. Significantly, the CE difference varies in proportion to order-disorder transition temperature (T(c)), which suggests that one can predict order-disorder transition of NPs by calculation the cohesive energy. The present calculated T(c) of CoPt NPs is consistent with recent experiments, simulation and theoretical predictions, and the method can also be applied to study the order-disorder transition of FePt, FePd, and so on. PMID- 23646616 TI - Facile synthesis and application of CuS nanospheres in aqueous and organic lithium ion batteries. AB - Monodispersed CuS nanospheres with a diameter of about 200 nm consisted of nanoplates have been hydrothermally synthesized via a facile process without any surfactant at 120 degrees C. The morphologies of the hierarchical CuS nanospheres were explored by X-ray diffraction, field emission scanning and transmission electron microscopy. In addition, CuS nanospheres cathode material for lithium ion batteries were studied both in Organic and Aqueous phase. In organic electrolyte, the discharge capacity at first cycle with a cutoff voltage of 3-1.5 V is up to 628 mAh/g. When the voltage range is fixed from 1.8 to 2.6 V, the first discharge capacity reaches 225 mAh/g. After 30 cycles the discharge capacity has still kept at 90 mAh/g. On the other hand, it is well worth noting that here we first report the electrochemical behavior of CuS in aqueous lithium ion batteries. In aqueous phase, different from other materials which have a drastic decay, it still keeps its initiative capacity 45 mAh/g after 100 cycles. PMID- 23646617 TI - Comparative bio-effects of SiO2/Gd2O3 nanoparticles depending on their core-shell structures. AB - Engineered nanoparticles (NPs) can produce negative impacts on human health even in low doses. In this study, Gd2O3 nanoparticles were synthesized via the polyol route and coated with silicon to form particles with different sizes. Although all the SiO2/Gd2O3 NPs did not induce obvious cell death at 10 microg/mL on a macrophage-like cell line (RAW 264.7), their DNA damaging effects, which is measured by single cell gel electrophoresis (SCGE), is prominent in cells treated with the sample with an overall size of 120 nm. Besides, the NPs with core size of 20 nm induced greater damaging effect than NPs with similar total size but core size of 50 nm. Further test applying the modified SCGE with endonuclease III indicated that the DNA damaging effect was greatly associated with oxide pyridine after the treatment. Using immunoblotting, we found that p53 protein is activated and accumulated after the damage occurred. These results provide a new insight into the adverse effect of nanoparticles with core-shell structures, that not only the overall size but the core size of the particles determines their effect in cells. PMID- 23646618 TI - Copper nanoparticles decorated inside or outside carbon nanotubes used for methyl acetate hydrogenation. AB - Copper nanoparticles loaded inside or outside carbon nanotubes (CNTs) were prepared by a simple wet chemistry method. The structures and physicochemical properties of the obtained materials were characterized by X-ray diffraction (XRD) and transmission electron microscopy (TEM). Methyl acetate (MA) hydrogenation forming methanol and ethanol was chosen as the application to explore the catalytic performances of copper inside and outside CNTs. The reaction results indicated that the catalytic activity of Cu-inside-CNTs catalyst was significantly higher than that of Cu-outside-CNTs because of the space confined effects. Furthermore, the influences of Cu content on CNTs to the catalytic performance were also investigated. PMID- 23646619 TI - Phase-transfer based size refining of metal nanoparticles from arbitrary particle size distributions. AB - The size-dependent phase-transfer property of metal nanoparticles is used to develop a simple experimental procedure that can effectively refine the particle size from colloidal solutions prepared by wet-chemistry. The protocol calls for firstly the mixing of the metal hydrosol with an ethanol solution of dodecylamine, and then the extraction of the dodecylamine-stabilized metal nanoparticles into toluene. This method offers an effective approach to prepare metal nanoparticles with narrow size distribution from an arbitrary particle size distribution. PMID- 23646620 TI - High yield synthesis of Au25 nanoclusters by controlling the reduction process. AB - The syntheses of gold nanoclusters, namely, the 25-gold-atom nanocluster (Au25(SR)18) and 38-gold-atom nanocluster (Au38(SR)24), with SR representing the thiol ligand, were described in previously reported studies. The synthesis was via a fast reduction process using sodium borohydride. The ratio of Au:HSR:NaBH4 was 1:3:10. Herein we report that the Au25 nanocluster can also be synthesized via a slow reduction process through a dropwise addition of an aqueous solution of sodium borohydride. The ratio of Au:S:NaBH4 is also changed to 1:3:5. This method synthesized Au25 nanoclusters at a high yield (47%). Pure Au25 nanoclusters were obtained after extraction, and the product was fully characterized by UV-vis spectroscopy, thermogravimetric analysis (TGA) and Matrix Assisted Laser Desorption/Ionization (MALDI) mass spectrometry. The possible formation mechanism is discussed in this paper. This work contributes to a better understanding of the mechanism of Au25 formation and provides a basis for further study of gold nanoclusters. PMID- 23646621 TI - Synthesis of novel hollow ZnSnO3 cubic nanocages and their HCHO sensing properties. AB - Designed assembly of hollow nanostructures with well-defined non-spherical shapes is of great scientific and practical value and remains a great challenge. This paper presents a facile and one-pot hydrothermal synthesis of ZnSnO3 nanocages with geometrical cube-shape. The time-dependent hollowing evolution of the ZnSnO3 samples reveals a self-templating organization process, in which solid nanocubes of ZnSnO3 are formed firstly. Then due to the rapid coprecipitation process, the metastable inner part of the solid cubes dissolves and redeposits to the outer surface via Ostwald ripening, and finally the resultant hollowing process is achieved and ZnSnO3 crystallites reorganize into hollow archetectures. Moreover, the gas-sensing performance of these ZnSnO3 nanocages to formaldehyde (HCHO) is investigated. Due to the hollow interiors and good-permeation surfaces, these ZnSnO3 nanocages exhibit higher response, faster response-recovery, and other better sensing characteristics to HCHO compared with the solid ZnSnO3 nanocubes. PMID- 23646622 TI - A facile method to fabricate ultrathin vertical ZnO nanowall arrays. AB - We demonstrate a facile method to synthesize ultrathin vertical ZnO nanowall arrays only through a one-step catalyst fabrication procedure. After being coated with uniformly dispersed gold particles, the substrates were polished gently to create discrete gold nanoparticle alignment as catalyst. The commercial ZnO powder and activated carbon powder with an atom ratio of 1:1 were utilized as source materials, and the whole growth process occurred in a conventional tube furnace chemical vapor deposition (CVD) system. The SEM images confirm that the ZnO nanowall arrays grow vertically along certain tracks made by polishing. The walls are about 17 nm wide, 90 nm high and 1 microm long after 90 min growth. After second growth, the nanowalls become 20 nm wide, 205 nm high, and 2 microm long. AFM images indicate that the alignment of discrete Au particles with certain separations due to polishing plays the key role in realizing vertical ZnO nanowall arrays. PMID- 23646623 TI - Preparation and characterization of organic-functionalized mesoporous silica as heavy metal adsorbents. AB - Novel organic-inorganic hybrid mesoporous materials have attracted much attention because the functional organic groups can bring these materials special properties, such as selective absorption and new catalytic properties. In this paper, two kind of bis(triethoxysilyl) organic skeleton (EtO)3Si-(CH2)3-NH-C(O)-X C(O)-NH-(CH2)3-Si(OEt)3 (X = 1,4-benzene (BSPB), 2,5-thienyl (BSPT)) precursors were synthesized firstly. Then bridged organic-inorganic hybrid mesoporous materials were prepared by direct grafting on MCM-41. The MCM-41 was obtained under basic conditions using cetyltrimethylammonium bromide (CTAB) as a template with tetraethyl orthosilicate. FT-IR spectra showed the acylamino, carbonyl, phenyl and thienyl groups had been introduced into the materials. The structures of these materials were further confirmed by X-ray diffraction (XRD) and the N2 adsorption-desorption. In addition, the adsorption capacity of heavy metal ions such as mercury, cadmium, and lead, was evaluated. The results indicated that the functionalized mesoporous materials with high porosity and specific surface area were successfully prepared, and the new prepared materials exhibited good adsorption capacity for heavy metal ions Hg2+, Cd2+, and Pb2+. PMID- 23646624 TI - Indium tin oxide nanowires grown by one-step thermal evaporation-deposition process at low temperature. AB - Indium tin oxide (ITO), as one of the most important transparent conducting oxide, is widely used in electro-optical field. We have developed a simple one step method to synthesize ITO nanowires at low temperature of 600 degrees C. In detail, mixtures of InN nanowires and SnO powder, with the molar ratio of 10:1, have been used as precursors for the thermal evaporation-deposition of ITO nanowires on silicon/quartz slices. During the growth process, the evaporation temperature is maintained at 600 degrees C, which favors the decomposition of InN and oxidation of In, with a limited incorporation of Sn in the resulting compound (In:Sn approximately 11:1 in atomic ratio). As far as we know, this is the lowest growth temperature reported on the thermal deposition of ITO nanowires. The diameters of the nanowires are about 120 nm and the lengths are up to tens of micrometers. XRD characterization indicates the high crystallization of the nanowires. HRTEM results show the nanowires grow along the [200] direction. The transmittance of the nanowire film on quartz slice is more than 75% in the visible region. Based on photolithography and lift-off techniques, four-terminal measurement was utilized to test the resistivity of individual nanowire (6.11 x 10(-4) omega x cm). The high crystallization quality, good transmittance and low resistivity make as-grown ITO nanowires a promising candidate as transparent electrodes of nanoscale devices. PMID- 23646626 TI - CuS nanoflakes, microspheres, microflowers, and nanowires: synthesis and lithium storage properties. AB - CuS nanostructured materials, including nanoflakes, microspheres composed of nanoflakes, microflowers, and nanowires have been selectively synthesized by a facile hydrothermal method using CuSO4 and thiourea as precursors under different conditions. The morphology of CuS particles were affected by the following synthetic parameters: temperature, time, surfactant, pH value, solvent, and concentration of the two precursors. The synthesized CuS nanomaterials were characterized by X-ray diffraction, Brunauer-Emmett-Teller N2 adsorption, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. The electrochemical tests, including constant current charge-discharge and cyclic voltammetry, show the specific capacities of the different morphologies, as well as their rate capability. The nanowire electrode has near theoretical specific capacity and the best rate capability. PMID- 23646625 TI - Morphology variation and optical properties of ZnO nanostructures grown using bio template. AB - ZnO nanostructures of different morphologies were grown by immersing eggshell membranes into Zn(NO3)2 ethanol solution with different pH values and subsequently sintered at 500 degrees C. Effects of the solution pH value, immersing time and Mg incorporation on the nanostructure morphology and photoluminescence were studied. ZnO nanostructure morphology was very sensitive to pH value of the solution, immersing time and layer of the templates. Different morphologies of nanofibers, nanotubes, hexagonal nanosheets and hexagonal nanosheets with tips were grown. All nanostructures had strong green emission at 520 nm and weak ultraviolet emission at 377 nm. The green emission weakened in the interwoven nanofibers while the ultraviolet emission enhanced in the hexagonal nanosheets. Incorporation of Mg ions in the solution with a pH of 7 would result in combination of the interwoven nanofibers and enhance the green emission greatly. UV emission at 355 nm from ZnMgO alloys was observed in Mg incorporated nanofibers. PMID- 23646627 TI - Synthesis and characterization of K(Ta(x)Nb(1_x))O3 particles by high temperature mixing method under hydrothermal and solvothermal conditions. AB - KTa(x)Nb(1_x)O3 (KTN) particles with an orthorhombic perovskite structure were synthesized via a high temperature mixing method (HTMM) under hydrothermal and solvothermal conditions. The obtained products were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), transmission electron microscopy (TEM), selected area electron diffraction (SAED), and high-resolution transmission electron microcopy (HRTEM). The influences of alkaline concentration and Ta doping amounts on the phase structure and morphology of the obtained powders were investigated. The results showed that KTN powders could be solvothermally prepared when the KOH concentration is as low as 0.5 M. In comparison with the hydrothermal process, supercritical isopropanol plays an important role in synthesizing KTN particles under milder conditions. The KTa(0.4)Nb(0.6)O3 particles solvothermally synthesized in isopropanol are made of well crystallized and single crystalline particles with a size of about 100-200 nm. Room temperature PL studies excited at different wavelengths reveal five emission bands centered at about 421 nm, 446 nm, 468 nm, 488 nm, and 498 nm, respectively. The supercritical process proposed here provides a new potential route for synthesizing other perovskite-type materials. PMID- 23646628 TI - Self-supporting hierarchically-structured hollow ordered porous carbon spheres from spatially tangent compression. AB - Self-supporting hierarchically-structured hollow ordered porous carbon spheres (HOPCSs) have been synthesized successfully using hollow ordered mesoporous silica spheres (HOMSSs) with MCM-41 pore structure within shells as templates. The SEM and TEM observations show that the final HOPCS product presents spherical morphology with hollow interiors. The results of HRTEM, small angle X-ray Diffraction (SAXRD) and N2 adsorption-desorption isotherms confirm that the HOPCS inversely replicate the MCM41 hexagonally-stacked ordered microstructures within shells and possess the ordered porosity. Furthermore, the formation of ordered porous structures within HOPCSs is due to the two aspects below: (i) the inverse carbonaceous replicas filling in hexagonally-stacked mesopores in HOMSSs are compacted tangentially due to curvature difference along the radial direction, self-supporting ordered porous structures after removing silica template; (ii) the additional carbon deposition layers exist on the outside surface of the replicas, cooperatively cementing the carbon fillers. PMID- 23646629 TI - Temperature dependent resistance of as-grown and chemical treated single walled carbon nanotubes films. AB - Single Walled Carbon Nanotube (SWCNT) films were directly synthesized via Floating Catalyst Chemical Vapor Deposition (FCCVD) method. Temperature dependent resistance measurements were carried out on the as-grown and chemical treated SWCNTs films. A "U" shaped curve was obtained for each sample, with a significant variation in the crossover temperatures between the as-grown and treated samples. A heterogeneous model was adopted to interpret the experimental data, revealing the coexistence of anisotropic 1D metallic conduction, conventional metallic conduction and fluctuation assisted tunneling. Our results implied very low barriers, verifying the good intertube and interbundle contacts in the directly synthesized SWCNTs films. We speculated that oxidization and acid treatments would affect the overall configuration of the films, leading to the changes in the temperature dependence of resistance. In addition, Raman and absorption spectra indicated that oxidization and acid process would cause moderate changes in the hole carrier concentration of the films. PMID- 23646630 TI - Fluorination of edges and central areas of monolayer graphene by SF6 and CHF3 plasma treatments. AB - In this work, we report the fluorination of edges and central areas of monolayer graphene by SF6 and CHF3 plasma treatments. After fluorination by SF6 plasma, G and 2D peaks of Raman spectroscopy for the edges have upshifts, which are much bigger than the upshifts for central areas of monolayer graphene. For the intensity ratio of I(2D)/I(G), it becomes smaller after SF6 plasma treatments and magnitude of change is similar for the edges and that of the central areas. These observations indicate that the fluorination by SF6 plasma treatments can induce p doping to graphene, which is more significant for the edges comparing to the central areas. Moreover, the ratio of I(D)/I(G) becomes larger both for the edges and the central areas. For CHF3 plasma treatments, although similar results can be obtained, the p-doping to graphene is less and more defects are introduced comparing to SF6 plasma treatment. Therefore, for fluorination of monolayer graphene, SF6 plasma is better than CHF3 plasma. PMID- 23646631 TI - Thermoelectric power of a single-walled carbon nanotubes rope. AB - In this work, a rope of single-walled carbon nanotubes is prepared by using a diamond wire drawing die. At atmospheric condition, the electrical conductance and the thermoelectric voltage of single-walled carbon nanotubes rope have been investigated with the hot-side temperature ranging from 292 to 380 K, and cold side temperature at 292 K. For different temperatures in the range of 292 to 380 K at hot-side, the current-voltage curves are almost parallel to each other, indicating that the electrical conductance does not change. The dynamic characteristics of voltage at positive, zero and negative current bias demonstrate that a thermoelectric voltage is induced with a direction from hot- to cold-side. The induced thermoelectric voltage shows linear dependence on the temperature difference between hot- and cold-side. The thermoelectric power of single-walled carbon nanotubes rope is found to be positive and has a value about 17.8 +/- 1.0 microV/K. This result suggests the hole-like carriers in single walled carbon nanotubes rope. This study will pave the way for single-walled carbon nanotubes based thermoelectric devices. PMID- 23646632 TI - Low percolation threshold carbon-black/ nitrile-butadiene-rubber composites and their electromagnetic shielding effects. AB - Nitrile-butadiene-rubber composites, filled with super conducting carbon black, are successfully prepared with low percolation threshold, high conductivity and electromagnetic shielding effectiveness. Percolation theory is used to represent the system's conductivity, and the corresponding result is close to the experimental value. The fitting curve also gives the weight fraction threshold and conductivity exponent of the conducting polymer. The percolation threshold of the composite is 9.2 phr, which is much smaller than previous homologous findings and lower than the value of short carbon fiber counterparts reported. The volume resistivity becomes 3.17 omega x cm for the 20 phr sample and decreases to 0.66 omega x cm for the 40 phr sample. At 1.8 GHz for 40 phr sample, the shielding effectiveness is -43 dB. PMID- 23646633 TI - Two-photon induced photopolymerization using photoinitiator with an intramolecular radical quenching moiety for nanolithography. AB - We have investigated the photoinitiating properties of the photoinitiator 3,6 bis[2-(4-nitrophenyl)-ethynyl]-9-(4-methoxy-benzyl)-carbazole (BNMBC), which has an intramolecular radical quenching group "p-methoxybenzyl," in the substrate lines fabrication of two-photon induced photopolymerization (TPIP). Another photoinitiator 3,6-bis[2-(4-nitrophenyl)-ethynyl]-9-benzyl-carbazole (BNBC) with similar chemical structure but not radical quenching group was studied for comparison. Their photopolymerization properties were studied with resins in which BNBC and BNMBC were used as photoinitiators with a molar ratio of 0.02%, respectively. The linewidth of polymer lines fabricated by TPIP of the photoresist that contained BNMBC could be decreased to 65% of those using BNBC. Besides, we introduced a radical quencher, phenyl methyl ether (PhOCH3), to BNBC and further studied the photopolymerization properties by using BNBC, BNBC/PhOCH3 and BNMBC as photoinitiators with a molar ratio of 0.1%. The results further indicated that BNMBC was effective to confine the radical diffusion in polymerization due to the radical quenching effect of moiety. This intramolecular radical quenching moiety exhibited more effective confining effect of radical diffusion compared to the intermolecular radical quencher PhOCH3. Furthermore, arbitrary complex three-dimensional (3D) microstructure was achieved using the photoresist with photoinitiator BNMBC. The approach could open up broad prospect for improving the resolution in TPIP. PMID- 23646634 TI - Multicolor and fast electrochromic P(DTB-EDOT)/ZnO nanocomposite film. AB - In this work, uniform and controllable size of ZnO nanoparticles were fabricated via solution-phase approach, and the copolymer based on the monomers of 1,4 di(thiophen-3-yl)benzene (DTB) and 3,4-ethylenedioxythiophene (EDOT) was successfully synthesized with electrochemical polymerization. A new P(DTB EDOT)/ZnO nanocomposite film was obtained via situ preparation. Cyclic voltammogram and spectroelectrochemical characterization showed that the composite film had a stable and well-defined reversible redox process as well as electrochromic behavior. Besides, the composite film exhibited fast switching time (1 s at 746 nm), significant optical contrast and a variety of colors (red, ochre, green and blue) under different potentials. PMID- 23646635 TI - Template-free fabrication and thermoelectric properties of pbse modified poly(p phenylenediamine) nanowires. AB - In this paper, we presented a template-free method to prepare poly(p phenylenediamine) (PpPD) nanowires. PpPD nanowires were synthesized by chemical oxidative polymerization in aqueous solution, using ammonium persulfate as initiator and beta-naphthalenesulfonic acid as soft template. The obtained polymer powder was treated with Pb(NO3)2 and Na2SeSO3 solutions in sequence to form PbSe nanoparticle modified PpPD. The products were characterized by X-ray powder diffraction, infrared spectroscopy, and transmission electron microscopy, respectively. The thermoelectric properties of the powders after cold pressing were measured at room temperature. The pure dedoped PpPD nanowires exhibited very large Seebeck coefficient (2692 microV K(-1)) but very low electrical conductivity. As the PbSe content increased, the electrical conductivity of the PbSe/PpPD composite increased, whereas the Seebeck coefficient decreased, and the power factor monotonically increased. The sample with 41.5 wt% PbSe had a highest power factor, 0.189 microW m(-1) K(-2) which is -270 times as large as that of the pure PpPD nanowires (8.7 x 10(-4) microW min(-1) K(-2)). PMID- 23646636 TI - Erosion effects of atomic oxygen on polyhedral oligomeric silsesquioxane polyimide hybrid films in low earth orbit space environment. AB - A novel polyimide (PI) hybrid nanocomposite containing polyhedral oligomeric silsesquioxane (POSS) had been prepared by copolymerization of trisilanolphenyl POSS, 4,4'-oxydianiline (ODA), and pyromellitic dianhydride (PMDA). The AO resistance of these PI/POSS hybrid films was tested in the ground-based AO simulation facility. Exposed and unexposed surfaces were characterized by SEM and X-ray photoelectron spectroscopy. SEM images showed that the surface of the 20 wt% PI/POSS became much less rough than that of the pristine polyimide. Mass measurements of the samples showed that the erosion yield of the PI/POSS (20 wt.%) hybrid film was 1.2 x 10(-25) cm3/atom, and reduced to 4% of the polyimide film. The XPS data indicated that the carbon content of the near-surface region was decreased from 60.1 to 13.2 at% after AO exposure. The oxygen and silicon concentrations in the near-surface region increased to 1.96 after AO exposure. The nanometer-sized structure of POSS, with its large surface area, had led AO irradiated samples to form a SiO2 passivation layer, which protected the underlying polymer from further AO attack. The incorporation of POSS into the polyimide could dramatically improve the AO resistance of polyimide films in low earth orbit environment. PMID- 23646637 TI - Effect of cobalt content on wear and corrosion behaviors of electrodeposited Ni Co/WC nano-composite coatings. AB - Metal-ceramic composite coatings are widely used in automotive and aerospace industries as well as micro-electronic systems. Electrodeposition is an economic method for application of these coatings. In this research, nickel-cobalt coatings reinforced by nano WC particles were applied on carbon steel substrate by pulse electrodeposition from modified Watts bath containing different amounts of cobalt sulphate as an additive. Saccharin and sodium dodecyl sulphate (SDS) were also added to electroplating bath as grain refiner and surfactant, respectively. The effect of cobalt content on wear and corrosion behavior of the coatings was investigated. Wear and corrosion properties were assessed by pin-on disk and potentiodynamic polarization methods, respectively. Phase analysis was performed by X-ray diffraction (XRD) using CuK(alpha) radiation and the worn surfaces were studied by means of Scanning Electron Microscopy (SEM). The results showed that the addition of cobalt improved the wear resistance of the coatings. In the presence of 18 g/L cobalt in electrodeposition bath, the wear rate of the coating decreased to 0.002 mg/m and the coefficient of friction reduced to 0.695 while they were 0.004 mg/m and 0.77 in the absence of cobalt, respectively. This improvement in wear properties can be attributed to the formation of hcp phase in metallic matrix. Meanwhile, the corrosion resistance of the coatings slightly reduced because cobalt is more active metal with respect to nickel. PMID- 23646638 TI - Fabrication of hollow ZnO particles and its photocatalytic property by modifying of nano ZnS. AB - Large scale hollow ZnO spheres were prepared by a solvothermal method with the help of the solvent. And ZnS nanoparticles were successfully fabricated on the surface of ZnO via a hydrothermal process. These heterostructured ZnO/ZnS core/shell particles are around 1-2 microm in diameter, the ZnS shell formed on the surface of hollow ZnO sphere is comprise of the primary crystals about 30 nm in diameter. The products prepared were characterized by field emission scanning electron microscope (FE-SEM), X-ray powder diffraction (XRD), transmission electron microscope (TEM), and photo-luminescence spectroscope (PL). Theoretical calculation and experimental results have demonstrated that the combination of ZnO and ZnS (two wide band gap semiconductors) could yield a novel material with the photoexcitation threshold energy lower than the individual components. The electron transfers between ZnO core and ZnS shell, which strongly affect the photoluminescence and photocatalytic performances. The photocatalytic activities of the products were evaluated by methyl orange degradation as a probe reaction. The relationship of ZnO/ZnS core/shell particles as excellent photocatalyst could be anticipated. PMID- 23646639 TI - Energy transfer from CdSe quantum dots to porphyrin via two-photon excitation. AB - CdSe quantum dots have been used as energy donors to activate meso-tetra (4 sulfonatophenyl) porphine dihydrochloride. Pulses of 130 fs duration at a wavelength of 800 nm are used as the two-photon excitation light source. After excitation, steady-state and time-resolved fluorescence spectra are collected for samples with different ratio between the amount of porphyrins and quantum dots. Decay kinetic curves of CdSe quantum dots with and without porphyrins are well fitted by the biexponential decay curve, which indicates a combination of two components (excitonic and trapping state) in the luminescence behavior of CdSe quantum dots. Relative intensity weights of the excitonic and trapping state, total and nonradiative energy transfer efficiency, average luminescence lifetimes of donors are calculated. The nonradiative transfer mechanism becomes the leading factor as the concentration of acceptors gets higher. It is considered to take place through the channel of trapping states of CdSe quantum dots, which is expressed by the weight change between the fast and slow luminescence components. This deduction presents a new way of raising the energy transfer efficiency by increasing the trapping state proportion of the quantum dots, which can be easily realized by surface modification. PMID- 23646640 TI - Preparation of nano-polycrystalline WO3 thin films and their solid-state electrochromic display devices. AB - In this paper, nano-polycrystalline WO3 thin films with the thickness in the range of 100-200 nm have been uniformly prepared on the designed regions of ITO (indium tin oxide) glass substrates by thermal evaporation deposition. Their crystal structures, surface morphologies and uniformities are investigated by X ray diffraction (XRD), scanning electron microscopy (SEM), and atomic force microscopy (AFM), respectively. The solid-state electrochromic display (ECD) devices based on these nano-polycrystalline WO3 thin films have been also fabricated and have demonstrated to have better performance than normal thin films, including shorter response time, higher contrast, and furthermore, higher stability to keep the colored state without power consumption. These results demonstrate nano-polycrystalline WO3 thin films can be applied to improve the performance of ECD devices, especially suitable to static display. PMID- 23646641 TI - Preparation and photoelectrochemical properties of an electrostatically self assembled film based on [BW11Zn(H2O)O39]7- and a bipolar hemicyanine. AB - A new electrostatically self-assembled film has successfully been prepared on quartz and indium-tin-oxide (ITO) substrates by alternating adsorption of [BW11Zn(H2O)O39](7-) (BW11Zn) and a hemicyanine of (E)-1,1'-(hexane-1,6 diyl)bis(4-(4-(dimethylamino)styryl)pyridinium) bromide (H6Br2). The UV-visible absorption spectra showed that the film was uniformly deposited and the interaction between the two film-forming components occurred in the film. The (BW11Zn/H6)n film exhibited stable cathodic photocurrent as irradiated with white light. The photocurrents were found to increase linearly with increasing the deposited bilayers increased up to 3 layers. The photocurrent action spectrum indicated that the cathodic photocurrents were generated from charge transfer excitation of H6 in the (BW11Zn/H6)n film. The effects of applied bias voltages, electron donor and acceptor added in the electrolyte, and layer number n of (BW11Zn/H6)n film on the photocurrent generation have also been examined. PMID- 23646642 TI - Study of vanadium doped ZnO films prepared by dc reactive magnetron sputtering at different substrate temperatures. AB - ZnO films doped with vanadium (ZnO:V) have been prepared by dc reactive magnetron sputtering technique at different substrate temperatures (RT-500 degrees C). The effects of the substrate temperature on ZnO:V films properties have been studied. XRD measurements show that only ZnO polycrystalline structure has been obtained, no V2O5 or VO2 crystal phase can be observed. It has been found that the film prepared at low substrate temperature has a preferred orientation along the (002) direction. As the substrate temperature is increased, the (002) peak intensity decreases. When the substrate temperature reaches the 500 degrees C, the film shows a random orientation. SEM measurements show a clear formation of the nano grains in the sample surface when the substrate temperature is higher than 400 degrees C. The optical properties of the films have been studied by measuring the specular transmittance. The refractive index has been calculated by fitting the transmittance spectra using OJL model combined with harmonic oscillator. PMID- 23646643 TI - ZnO nanowires grown on carbon cloth for flexible cold cathode. AB - Nanostructures grown on carbon cloth are recently attracted great interests for flexible field emitter and cold cathode. In this paper, we report high-aspect ratio ZnO nanowires grown on carbon cloth by a low-temperature solution chemical approach that can be used as a flexible and high performance cold cathode. The carbon cloth is covered by outward-grown ZnO nanowires uniformly and densely with spiny structures. The hybrid structures exhibits a turn-on electrical field of 4.36 V/microm and a field enhancement factor of 1157, which benefit from the high aspect ratios of both ZnO nanowires and carbon cloth. These results demonstrate a low cost and scalable approach for flexible cold cathode lighting and field emission display. PMID- 23646644 TI - Investigation on epitaxial lateral overgrowth of InGaN/GaN multi-quantum-well nanowires. AB - To achieve semipolar InGaN/GaN multi-quantum-well (MQW) structure, we fabricate InGaN/GaN MQW nanowires by using a combination of selectively epitaxial lateral overgrowth and patterned GaN/sapphire substrate techniques. Basing on the SEM observations, the nanowires along different crystal orientation of GaN substrate have various surface morphologies. Furthermore, cathodoluminescence measurements exhibit the dependence of the emission peaks of InGaN quantum wells on the axial direction of nanowires, being mainly attributed to the change of the morphology situation of the side facet. The shift of the peaks is larger than 30 nm as the axial direction of a nanowire varies between [1120] and [1100]. PMID- 23646645 TI - On the change in bacterial growth and magnetosome formation for Magnetospirillum sp. strain AMB-1 under different concentrations of reducing agents. AB - Magnetosome produced by Magnetospirillum AMB-1 is highly crystalline, monodisperse, bioengineerable and a better nanomagnetic material candidate for a broad range of applications, ranging from medicine, biology and electronics to aerospace engineering. Many efforts have been made to get the optimal growth conditions and improve the accumulation of magnetosome. Studies have showed that oxygen concentration is a key factor to the formation of magnetosome. The effects of various of reducing agents in different concentrations on the growth of Magnetospirillum AMB-1 and the corresponding magnetosome formation have been examined in our study. The results show that the growth of the bacterial cells and the synthesis of magnetosome are both influenced in the presence of different concentrations of reducing agents. PMID- 23646647 TI - Two-dimensional self-assembly of dendritic amphiphilic molecule with ferroncenyl subsitutuents at the liquid/solid interface. AB - Two-dimensional self-assembly of dendritic amphiphilic molecule with ferroncenyl subsitutuents (2,3,4-tri-(11-ferroncenyl)undecyloxybenzoic acid, Fc3COOH) on highly oriented pyrolytic graphite surface was investigated by scanning tunneling microscopy at the liquid/solid interface. Fc3COOH molecule formed an ordered molecular nanostructure--an alternating big/small bright dots pattern on the graphite surface extended to several hundred nanometers. On the basis of the simulation and combined with our STM results, it is concluded that the molecular adsorption conformation has an appreciable effect on the interactions of molecule molecule and molecule-substrate. The pi-pi interactions between ferrocene groups together with the van der Waals interactions between alkyl chains direct the stacking behavior of Fc3COOH molecules. Due to the steric constraints, no hydrogen bonding between the carboxyl groups was formed during the self-assembly. PMID- 23646646 TI - P-glycoprotein targeted nanoscale drug carriers. AB - Multi-drug resistance (MDR) is a trend whereby tumor cells exposed to one cytotoxic agent develop cross-resistance to a range of structurally and functionally unrelated compounds. P-glycoprotein (P-gp) efflux pump is one of the mostly studied drug carrying processes that shuttle the drugs out of tumor cells. Thus, P-gp inhibitors have attracted a lot of attention as they can stop cancer drugs from being pumped out of target cells with the consumption of ATP. Using quantitive structure activity relationship (QSAR), we have successfully synthesized a series of novel P-gp inhibitors. The obtained dihydropyrroloquinoxalines series were fully characterized and then tested against bacterial and tumor assays with over-expressed P-gps: All compounds were bioactive especially compound 1 c that had enhanced antibacterial activity. Furthermore, these compounds were utilized as targeting vectors to direct drug delivery vehicles such as silica nanoparticles (SNPs) to cancerous Hela cells with over expressed P-gps. Cell uptake studies showed a successful accumulation of these decorated SNPs in tumor cells compared to undecorated SNPs. The results obtained show that dihydropyrroloquinoxalines constitute a promising drug candidate for targeting cancers with MDR. PMID- 23646648 TI - Localized surface plasmon resonance light-scattering sensor for mercury(II) ion with label-free gold nanoparticles. AB - A localized surface plasmon resonance (LSPR) light-scattering sensor for Hg2+ was developed with unmodified gold nanoparticles (AuNPs) based upon the specific recognition property of Hg2+ with T-T mismatched base pair. Oligonucleotide 5' GTTCTTTGTCTTCA-3'(oligo-1) and 5'-TGTAGTCTATGTAC-3'(oligo-2) can adsorb on the surface of AuNPs, which can prevent them from aggregation because of electrostatic repulsion. However, the DNA hybridization occurred between oligo-1 and oligo-2 upon addition of Hg2+, can induce the desorption of oligonucleotide from the surface of AuNPs, and trigger the aggregation of AuNPs accompany with the increase of LSPR light-scattering intensity. Under the optimum conditions, the intensity was proportional to the concentration of Hg2+ over the range 53.1 530 nM, and the detection limit was 29.4 nM. PMID- 23646649 TI - Stimulated emission of hydrothermal growth ZnO nanorods with low threshold. AB - The optically pumped stimulated emission was observed from random growth ZnO nanorods. A thin metal layer was sputtered on Si wafer serving as a substrate. ZnO nanorods were grown on the thin metal layer using a hydrothermal method. Photoluminescence (PL) measurements were adopted to analyze the optical properties of the ZnO nanorods. A strong UV emission and a weak deep-level emission were observed. Under the excitation of 350 nm fs laser, a sharp ultra violet emission peak located at around 388 nm was observed. Furthermore, with increasing the pump intensity the width of the emission peak narrowed. The analysis of the emission behavior suggested the stimulated emission was generated with a low threshold of 28 kW/cm2. PMID- 23646650 TI - A density functional theory study on the structure stability of silica nanoclusters. AB - The studies of silica nanoclusters are of substantial interest for large potential in applications as diverse as photonics/optics, microelectronics and catalysis. In this study, we used the basing-hopping method with Buckingham potential to get the stable structures of silica nanoclusters ((SiO2)(n) = 1-13). The global minimum geometry of silica nanoclusters were determined by density functional theory calculation. We investigated the energy gap, binding energy and second order energy difference of nanoclusters to determine their structural stability with different sizes. We also calculate the second-order energy difference, binding energy to determine the magic number. PMID- 23646651 TI - Preparation and growth mechanism of chrysanthemum-like ZnO nanowire clusters. AB - With sodium hydroxide (NaOH), ammonia water (NH3 x H2O) and hexamethylenetetramine (HMT, C6H12N4) respectively as alkaline source material, a simple hydrothermal process was employed to prepare chrysanthemum-like ZnO nanowire clusters. The morphologies and crystalline structures of the as-prepared products were investigated by X-ray diffractometer (XRD), field emission environment scanning electron microscope (SEM), and high-resolution transmission electron microscopy (TEM). The experimental results indicate that the as-prepared products all have three-dimensional chrysanthemum-like structure in which the petal-like nanowires are ZnO single crystalline with hexagonal wurtzite structure, that the flower bud saturation degree F(d) is slightly different under different alkaline source materials, and that the proposed growth mechanism of chrysanthemum-like ZnO nanowire clusters is reasonable. PMID- 23646652 TI - Synthesis and characterization of hollow cadmium oxide sphere with carbon microsphere as template. AB - Cadmium Oxide (CdO) hollow spheres have been synthesized by using carbon microsphere as sacrificial template. The products were characterized by X-ray powder diffraction (XRD), scanning electronic microscopy (SEM) and transmission electron microscopy (TEM). The average diameter and shell thickness of as prepared hollow spheres are about 600 nm and 50 nm, respectively. The formation of hollow spheres was investigated and it was found that the shell formed when the heating temperature reached about 673 K and the sequential heat treatment could remove the carbon template. Moreover, the influence of other experimental parameters including concentration (0.1-5 M) and type of cadmium salts (cadmium chloride, cadmium acetate and cadmium nitrate, etc.) as well as type of solvents (water, ethanol and dimethylfomamide) were also investigated. PMID- 23646653 TI - Fungus-mediated synthesis of gold nanoparticles: a novel biological approach to nanoparticle synthesis. AB - The biological effects of nanoparticles and their uses as molecular probes are research areas of growing interest. The present study demonstrates an eco friendly biosynthesis of gold nanoparticles. The pure colonies of penicillium aurantiogriseum, penicillium citrinum, and penicillium waksmanii were cultured in fluid czapek dox broth. Then, their supernatants were examined for the ability to produce gold nanoparticles. In this step, 1 mM solution of AuCl added to the reaction matrixes separately. The reactions were performed in a dark environment at 28 degrees C. After 24 hours, it was observed that the color of the solutions turned to dark purple from light yellow. Synthesized gold nanoparticles were characterized by using UV-Visible Spectroscopy, Nano Zeta Sizer, Scanning Electron Microscopy and Fourier transformed infrared spectroscopy. The results showed that the gold nanoparticles were formed fairly uniform with spherical shape with the Z-average diameter of 153.3 nm, 172 nm and 160.1 nm for penicillium aurantiogriseum, penicillium citrinum, and penicillium waksmanii, respectively. The Fourier transformed infrared spectra revealed the presence of different functional groups to gold nanoparticles which were present in the fungal extract. The current approach suggests that the rapid synthesis of nanoparticles would be proper for developing a biological process for mass scale production. PMID- 23646654 TI - Alumina hollow fiber supported ZIF-7 membranes: synthesis and characterization. AB - ZIF-7 membrane has been prepared on the outer surface of alumina hollow fibers by the solvothermal synthesis. The synthesis conditions, including reaction temperature, time, and solution concentration, are investigated. At the reaction temperature of 100 degrees C for 8 h, microsized ZIF-7 crystals are grown on the outer surface of the hollow fibers. A continuous and dense ZIF-7 membrane with a thickness of about 5 microm is obtained after twice crystallization at 100 degrees C for 8 h. The gas separation test indicates the as-prepared ZIF-7 membranes have intercrystalline defects as the H2/N2 ideal selectivity is less than the Knudsen diffusion. After post-modification with beta-cyclodextrin aqueous solution, the micropore defects of ZIF-7 membrane is significantly reduced and the membrane has H2/N2 ideal selectivity of 3.9. The gas permeances for H2 and N2 are almost constant from room temperature to 150 degrees C for the ZIF-7 hollow fiber membranes before and after beta-cyclodextrin modification. PMID- 23646656 TI - Electrical and magnetic properties of multilayer polymer structures with nano inclusions as prepared by selective laser sintering. AB - Selective laser sintering (SLS) was used to prepare porous polymer nanocomposites comprising of a polycarbonate (PC) matrix doped with 30-50 wt% nano Ni or/and 10 30 wt% nano Cu. The electrical conductivity was measured at f = 1 MHz, bias dc voltage 40 V, and 300-400 K. Magnetic measurements were carried out at r.t. in magnetic fields of up to 10 kOe. Temperature dependence of electrophysical properties was studied for 3D samples derived from PC-Cu powders. Magnetic properties were measured for alternating ferromagnetic/non-magnetic layers with Ni and/or Cu core/polymer shell structures. Temperature dependencies for a real part of a dielectric permeability, loss tangent, and magnetization were found to have a hysteresis character. The structure of sintered items was found to depend of external dc magnetic field. PMID- 23646655 TI - Enhanced distribution and anti-tumor activity of ergosta-4,6,8(14),22-tetraen-3 one by polyethylene glycol liposomalization. AB - Ergosta-4,6,8(14),22-tetraen-3-one (ergone) was isolated from P. umbellatus, which has been demonstrated to possess a variety of pharmacological activities in vivo and in vitro. The purpose of this study was to evaluate the potent ergone formulations for cancer chemotherapy, the liposomal formulations were less toxic and provide longer systemic circulation time were selected as candidates of nanocarriers for ergone. The effect of modification polyethylene glycol (PEG) on the pharmacokinetics of liposome showed that the retaining time of ergone in blood circulation was prolonged by modified PEG. Moreover, the results of pharmacokinetic analysis showed that of PEG liposome was about 2.8 times higher than that of free PEG liposome after intravenous injection into normal rats due to the lower distribution into the reticuloendothelial system tissues. Since PEG liposome was able to stably encapsulate ergone in blood, area under plasma concentration-time curve of ergone was also extensively enhanced after intravenous dosing of ergone-PEG liposome into normal rats. In the in vivo studies utilizing solid tumor-bearing mice, it was confirmed that ergone-PEG liposome delivered remarkably larger amount of ergone to tumor tissue and provided more significant anti-tumor activity than free ergone. In conclusion, PEG liposome was an effective delivery formulation to achieve increased ergone release in tumor and therapeutic efficacy. PMID- 23646657 TI - Amphiphilic poly(L-aspartic acid) copolymer nanoparticles for cyclosporine A delivery. AB - In this paper, novel cyclosporine A (CsA)-loaded amphiphilic poly(L-aspartic acid co-L-lactic acid) (PAL)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) copolymer nanoparticles (NPs) were successfully fabricated using an emulsion/solvent evaporation technique. The CsA-loaded NPs were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The CsA-loaded NPs size, size distribution, encapsulation efficiency (EE) and drug loading content (LC) were influenced by polyvinyl alcohol (PVA) concentration and the weight ratio of the copolymer to CsA. In vitro release behavior of CsA-loaded NPs showed a sustained release. With the increasing of copolymer/CsA weight ratio, the release of CsA from NPs is rapid. The poly(L-aspartic acid) derivatives NPs have a promising potential in hydrophobic drug delivery system. PMID- 23646658 TI - Photochromic and self-cleaning properties of TiO2-AgCl/TiO2-xCu thin film. AB - The TiO2-AgCl/TiO2-xCu thin films were prepared by sol-gel method and dip coated on glass slide. The prepared films were synthesized at the temperature of 400 degrees C for 2 h with a heating rate of 10 degrees C/min. The microstructure and properties of synthesized TiO2-AgCl/TiO2-xCu thin films were characterized by X ray diffraction, scanning electron microscopy, atomic forced microscope and UV vis diffuse reflectance spectroscopy. Finally, the hydrophilic property was evaluated by means of contact angle of water droplet on the films. The results show all samples have film thickness in range of 400-500 nm and their surfaces are dense and strong with a large surface area according to the image of atomic forced microscope. It can be noted that TiO2-AgCl/TiO2-5Cu thin films exhibit the highest photochromic (or the lowest capability of light transmittance) at 250-400 nm. The TiO2-AgCl/TiO2-xCu thin films can block UV C, UV B and UV A rays and exhibit self-cleaning effect (small contact angle, 3.9 degrees ) under UV irradiation. PMID- 23646659 TI - Ag nanoparticles decorated TiO2 nanotube arrays for ultrasensitive gas sensing. AB - Anodic TiO2 nanotube arrays have attracted extensive interests in the past decade, especially for monitoring or sensing of the gas. In this paper, an ameliorated two-step anodization process was adopted for the preparation of highly ordered and vertically aligned TiO2 nanotube arrays on the Ti metal substrate. The as-prepared TiO2 nanotube arrays were successfully decorated with uniformly distributed Ag nanoparticles through a wetting-ultraviolet radiation deoxidation technology using the AgNO3 solution as precursor and source for Ag element. Field-emission scanning electron microscope (FESEM) was employed for the structural and morphological characterization of the Ag nanoparticles decorated TiO2 nanotube arrays. Then the as-prepared TiO2 nanotube arrays and Ag-decorated TiO2 nanotube arrays were both evaluated for room temperature ethanol gas sensing and the results showed that the Ag-decorated TiO2 nanotube arrays exhibited much higher sensitivity, as well as the reponse speed and recovery rate, than the pure TiO2 nanotube arrays. This phenomenon indicated that the well dispersed Ag nanoparticles onto the TiO2 nanotube arrays could effectively optimize their gas sensing properties. The mechanism of the improvement of gas sensitivity was also discussed in this paper. PMID- 23646660 TI - Characterization of nano-sized SiC@Ni composite fabricated by electroless plating method. AB - A nano-sized SiC@Ni composite was prepared by simple electroless plating method. Nickel can be reduced by Na2H2PO2 under the catalysis of Pd to despite onto the surface of SiC nanoparticles. The composite structure was characterized by means of TEM images, XRD and the components were analyzed using EDS. The coating layer on the SiC particles was several nanometers thick and mainly in a form of fine Ni crystalline grain and amorphous Ni-P alloy. By increasing the concentration of Na2H2PO2 in the plating bath, the uniformity of the coating layer can be improved obviously. Both of the magnetism and crystallinity of Ni coatings depends on the P content in the coating which can be decreased by increasing the pH values of plating solutions. The SiC@Ni particles exhibited soft magnetic characteristics. PMID- 23646661 TI - Visible light photocatalysis via 3D-ordered macroporous TiO2 films sensitized with CdS quantum dots. AB - CdS quantum dots (QDs)-sensitized TiO2 film with three-dimensionally (3D) ordered macropores was synthesized via a two-step method on ITO glass substrate. 3D ordered macroporous TiO2 film was firstly fabricated on an ITO glass via layer-by layer deposition and hydrolysis of tetrabutyl titanate using 3D-ordered latex film as organic template, followed by calcination at 450 degrees C for 2 h to remove the template. Then, the CdS QDs were deposited on the 3D-ordered macroporous TiO2 film by successive ionic layer adsorption and reaction technique. The as-prepared CdS-sensitized TiO2 film was characterized with X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, transmission electron microscopy, diffusive reflectance UV-visible absorption spectra, and photoelectrochemical measurements. Its photocatalytic activity was evaluated by the photocatalytic degradation of crystal violet aqueous solution at ambient temperature. It was revealed in our results that the CdS QDs-sensitized 3D-ordered macroporous TiO2 film exhibits enhanced photocatalytic activity for the photodegradation of crystal violet than that of the CdS-free 3D-ordered macroporous TiO2 film and that of CdS QD-sensitized TiO2 film without 3D-ordered macropores under the irradiation of visible light due to the co-existence of 3D ordered interconnected macropores and the sensitization of CdS QDs. PMID- 23646662 TI - Preparation and biocompatibility evaluation of polyurethane filled with multiwalled carbon nanotubes. AB - Biocompatibility has been one of the most crucial performances that determine the clinical application potentials of biomaterials and implants. As carbon is one inner substance and possesses clinical accepted blood compatibility, carbon nanotubes may bring improved hemocompatibility of polymeric materials when used as fillers. In this work, a kind of composite composed of polyurethane and multiwalled carbon nanotubes has been developed using a customized sol-gel technique. The cytotoxicity of the composite was evaluated by examining viability of the endothelium cells seeded on the composite or cultured with composite extraction using MTS assay and Environmental Scanning Electronic Microscope. Tissue compatibility was evaluated by subcutaneous implantation of the composite film in the paraspinal skin incision of rat. Dynamic clotting test of the composite were conducted to evaluate blood compatibility. Experiments results revealed that multiwalled carbon nanotubes were well dispersed into the polyurethane matrix. More functional endothelial cell grew on the composite than polyurethane. When implanted subcutaneously, the composite did not induce long term inflammation in the implanted sites and exhibited good tissue compatibility. The dynamic clotting test showed that the composite had longer clotting time than PU, indicating that anti-coagulant property of the composite was improved. PMID- 23646664 TI - A highly sensitive voltage interrogation method using electro-optically tunable waveguide coupled surface plasmon resonance sensors. AB - We present a highly sensitive detection method using electro-optically (EO) tunable waveguide coupled surface plasmon resonance (WCSPR) sensors by theoretical simulation. In this method, light is focused through a prism onto metal surface of the WCSPR sensor and the reflection is collected with a bicell photodetector. Time varied scanning DC electrical signal is applied on the waveguide layer of the WCSPR sensor and the ratio of the differential signal to the sum signal of the photodetector is calculated after each change. For each analyte, we get voltage-ratio curve after voltage scanning. Taking the ratio for a reference analyte calculated with null DC voltage applied as resonant ratio, different resonant voltages can be found in the voltage-ratio curves for different analytes. Theoretical simulation shows a high linearity between the resonant voltages and the refractive index (RI) of analytes. A sensitivity as high as 2.34 x 10(5) V/RIU can be expected in this method. PMID- 23646663 TI - Nanoparticle surface and nanocore properties determine the effect on radiosensitivity of cancer cells upon ionizing radiation treatment. AB - For correctly selected and reasonably designed nanoscale radiosensitizers, it is necessary to investigate whether nanoparticle (NPs) coatings, nanocores (we defined it as naked NPs) or other precursors cause cellular response upon ionizing radiation (IR) at first. In this paper, we mainly discussed the effect of nanoparticle surface and nanocore properties on anti-proliferation of cancer cells upon IR treatment. We examined different kinds of modifiers of the same nanocores, as well as distinct nanocores with the same surface. We obtained some different results and demonstrated silver NPs would have significant radiosensitization on cancer cells in virtue of the nanocore property. PMID- 23646665 TI - Size-dependent eutectic temperature of Ag-Pb alloy nanoparticles. AB - In terms of size-dependent cohesive energy model, we have deduced an analytic model to describe the size dependence of the eutectic temperature for Ag-Pb alloy nanoparticles. The eutectic temperature is found to drop with decreasing of the particle diameter. Moreover, a linear relationship exists between the eutectic temperature and the reciprocal of the particle diameter when the diameter is large enough (e.g., 5 nm). The model predictions correspond to the experimental observations. PMID- 23646666 TI - Design, synthesis and characteristics on novel D-pi-A dye chromophore: fluorochromism effects. AB - Recently, photophysical property with fluorescence function has been attracted and studied because there are promising potentials in academic and industrial applications. Organic materials having fluorescence effect, especially fluorochromism can be utilized in the sensing or probing with absorption/emission changes. Herein, the prepared dye chromophore can be changed to their optical properties with polar/non-polar environmental media. In this work, we synthesized a new fluorochromism dye, namely 5-[2-(4-diphenylamino-phenyl)-vinyl]-2,2 dimethyl-[1,3]dioxane-4,6-dione using 3-formyl triphenylamine and 2,2-dimethyl [1,3]dioxane-4,6-dione. We investigated absorption and fluorescent emission in various solvent media. Furthermore, cyclovoltammogram was used to determine energy levels of HOMO/LUMO from their redox onset potentials. Measured energy levels of HOMO/LUMO were compared with the results of simulated computational calculation. PMID- 23646667 TI - A theoretical study on the electronic and electrical properties of the single walled carbon nanotubes with dichlorocarbene addition. AB - Electronic and electrical properties of several single-walled carbon nanotubes as well as their derived structures with multi-dichlorocarbene addition are investigated by using self-consistent field crystal orbital method based on density functional theory. The addition can convert metallic tubes into semiconducting ones and increase their carrier mobilities, which are comparable with those of the pristine semiconducting tube. With small amount of dichlorocarbenes, the mobility of semiconducting single-walled carbon nanotube does not decrease. The dichlorocarbene addition can be a good pathway for processing high mobility electronic devices for mixtures of semiconducting and metallic single-walled carbon nanotubes. PMID- 23646668 TI - Preparation, characterization, and photocatalytic activity of mesoporous TiO2 thin films. AB - Cubic-based ordered mesoporous TiO2 thin films were prepared by an evaporation induced self-assembly method through a carefully controlling the hydrolysis/condensation conditions. The obtained sample exhibits mesoporous structure with a narrow pore size distribution. The TiO2 thin films have thick inorganic walls composed of nanocrystalline anatase. A reasonable explanation is also proposed to elucidate the formation of thick and stable mesoporous TiO2 films. The mesoporous TiO2 exhibits good photocatalytic activity. Nearly all the methyl orange has been degraded by the mesoporous TiO2 calcined at 500 degrees C. PMID- 23646669 TI - Synthesis of CePO4 nano-wires with improved photoluminescent properties by co crystallizing with nano-sized CeO2. AB - By adjusting experimental parameters, such as reaction time and ratios, CeO2/CePO4 composites have been prepared through a single-step hydrothermal process, in which CeO2 octahedra and CePO4 nanowires mingled with each other to form many interfaces. The formation of the particular structure can be explained by heterogeneous nucleation theory: the existed CePO4 nanowires at the early stage of hydrothermal process provide many thermodynamically favorable sites, on which the nucleation energy of octahedral CeO2 is the lowest. The photoluminescent (PL) properties of CeO2/CePO4 composites showed that the strongest PL emission can be achieved with initial Ce/P of 4 and hydrothermal time of 24 h. And final Ce/P of the samples at this point was the maximum value by the EDS analysis. So it was proposed that the interaction between more CeO2 and the more coatings of CeO2 to CePO4 are responsible for the best PL properties. PMID- 23646670 TI - A general dealloying route to synthesize nanoporous non-noble metals. AB - At present, most studies focus upon the synthesis of nanoporous noble metals such as Au, Ag, Pt and Pd. Here we show that the dealloying route can be generally used to fabricate nanoporous non-noble metals like Bi, Ga and Sn, and rapidly solidified Mg-based (Mg-Bi, Mg-Ga and Mg-Sn) precursors were utilized. The microstructure of the as-obtained nanoporous metals has been characterized using X-ray diffraction, scanning electron microscopy and energy dispersive X-ray analysis. These nanoporous metals show a three-dimensional bicontinuous ligament channel structure. It has been found that the more active Mg atoms were selectively etched away during dealloying, and the residual elements (Bi, Ga and Sn) diffused and agglomerated to form the nanoporous structure. PMID- 23646671 TI - Highly sensitive and thermal stable CO gas sensor based on SnO2 modified by SiO2. AB - Effects of surface chemical modification with SiO2 on the thermal stability and CO gas-sensing properties of SnO2 were investigated. The SiO2 on the SnO2 surface effectively inhibits the nanocrystal growth of SnO2. The average size of modified SnO2 sintered at 600 degrees C is 5.8 nm. The gas sensitivity to CO was found to be markedly enhanced by the surface chemical modification. The CO gas as low as 5 ppm can be effectively detected by the modified SnO2-based sensors. At the same time, the modified SnO2-based sensor has excellent selectivity to CO, fast response and recovery properties. PMID- 23646672 TI - Facile one-step solvothermal synthesis of iron oxide/polypyrrole nanocomposites and their magnetic properties. AB - Iron oxide/polypyrrole (PPy) nanocomposites (NCs) were prepared by a facile one step solvothermal process using FeCl3 x 6H2O and pyrrole as starting materials. The resultant products were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC) and superconducting quantum interference device magnetometer (SQUID). TEM image suggested the mesoporosity of the iron oxide/polypyrrole nanocomposites and pyrrole is found to play an important role in controlling the final morphology and porosity of the products. Magnetic hysteresis measurement reveals that nanocomposite shows a superparamagnetic behavior, and possesses a larger saturation magnetization strength (M(s)) of about 15.06 emu/g at room temperature, which allows its application in adsorption or separation as magnetically recyclable materials. PMID- 23646673 TI - Shape controlled hydrothermal synthesis and characterization of LiFePO4 for lithium ion batteries. AB - Various LiFePO4 microstructures were synthesized via hydrothermal or solvothermal routes using different additives. In an aqueous solution, LiFePO4 spindles whose length was about 2 microm were obtained with the assistance of polyvinyl pyrrolidone (PVP). As PVP and P2O7(4-) added in water, ellipsoidal LiFePO4 particles which composed of nanoparticles around 100 nm in diameter were obtained. If the additive was cetyltrimethyl ammonium bromide (CTAB), sheet-like LiFePO4 crystals with the width of 100 nm were prepared. In the mixed solvents of water together with ethanol or acetylacetone, when adding CTAB or polyethylene glycol (20000), LiFePO4 plates or nanoparticles were obtained. The ellipsoidal LiFePO4 had the best electrochemical properties among all these products. It is found that the annealed samples were significantly better than the corresponding unannealed ones. Take the ellipsoidal LiFePO4 for example, the initial discharge capacity of annealed (161 mAh/g) was much higher than the unannealed ones (85 mAh/g) at 0.1 C and the former cell still could deliver a capacity of 143 mAh/g after 30 cycles. PMID- 23646674 TI - Nano-sized nickel oxide powder synthesized by organic-inorganic solution route. AB - Nano-sized nickel oxide powders were synthesized by an organic-inorganic solution route employing polyvinyl alcohol (PVA) as an organic carrier. In this study, it was possible to control the physical properties of the nickel oxide powders by change of the PVA content. The experimental factors, such as the PVA content, heating temperature and time, were studied for the synthesis of nano crystalline powders. Nickel nitrate, (Ni(NO3)2, reagent grade) was used as a source of nickel cation. Once the cation source was completely dissolved in de-ionized (DI) water, 5 wt% PVA solution was added to the sol solution. The resulting gel-type precursors were completely dried and then calcined or crystallized at various temperatures in an air atmosphere in a box furnace. In the high PVA content of 2:1 mixing ratio, nano crystallite nickel oxide powders of below 5 nm in size with a high specific surface area of 151.19 m2/g were obtained at low temperature of 400 degrees C for 1 h. The PVA polymer contributed to homogeneous nickel cations in atomic scale through the fabrication process of the sol precursor. In this paper, the PVA solution technique for the fabrication of nano-sized nickel oxide powders is introduced. The effects of PVA content and heating time on the powder crystallization, morphology and specific surface area are also studied. The characterization of the synthesized powders is examined by using XRD, DTA/TG, TEM and nitrogen gas adsorption. PMID- 23646675 TI - Low-temperature synthesis and nanomagnetism of large-area alpha-Fe2O3 nanobelts. AB - Large-area one dimensional (1D) alpha-Fe2O3 nanostructures were grown on iron substrates by catalyst-free thermal oxidation process at low temperatures in air. The structure characterization revealed that the nanostructures are single crystalline alpha-Fe2O3. Two kinds of alpha-Fe2O3 nanostructures, nanobelts and nanoflakes, were obtained due to the different growth temperature range. A surface diffusion mechanism is proposed to account for the nanobelts and nanoflakes growth. The Morin temperature T(M) of pure 1D alpha-Fe2O3 nanostructures is 121 K, which is far below their bulk counterparts. The coercive field depends on temperature, and takes values 471 Oe at 5 K and about 260 Oe when the temperature is greater than T(M), respectively. PMID- 23646676 TI - Template-free synthesis of mesoporous hollow CuO microspheres as anode materials for Li-ion batteries. AB - We report the preparation and characterization of mesoporous hollow CuO (MPH-CuO) microspheres by thermal decomposition of hollow copper oxalate microspheres synthesized via the reaction of ammonium oxalate and copper chloride without using any template. The sample was characterized by Nitrogen adsorption, X-ray diffraction, transmission electron microscopy, and scanning electron microscopy. The electrochemical performance of MPH-CuO microspheres as anode materials in Li ion batteries was evaluated. It was found that the MPH-CuO microspheres possessed an average diameter of 2.5 microm, a pore size of 17.5 nm, and a BET surface area of 15.2 m2/g. Their shells were composed of CuO nanocrystals with a size of 17.9 nm. Compared with the dense CuO microspheres, the obtained MPH-CuO shows an enhanced electrochemical performance with a higher capacity of 599.4 mAh/g and a better cyclability (484 mAh/g after 15 cycles) because of its mesoporous hollow structure that provides quick intercalation and large accommodation of lithium ions together with short diffusion distance for lithium ions, suggesting a potential application in Li-ion batteries. PMID- 23646677 TI - Research on high rate capabilities B-substituted LiFePO4. AB - LiFePO4 is currently recognized as one of the most promising electrode materials for large-scale application of lithium ion batteries. However, the limitation of rate capability is believed to be intrinsic to this family of compounds due to the existence of larger tetrahedral (PO4)3- unit and quasi-hexagonal close-packed oxygen array. This paper report here a systematic investigation of the enhancement of rate performance by partly substitution of light small triangle oxyanion, (BO3)3-, for the larger tetrahedral (PO4)3- units in LiFePO4. Cathode electrode materials LiFeB(x)P(1_x)O(4-delta), in which X = 0, 3, 6 and 9, mol%, were synthesized by solid-state method. The as-synthesized products were characterized by X-Ray Diffraction (XRD), Scanning Electron Microscope (SEM) and Electrochemical Measurements. The results showed that 6 mol% of boron substitution had no effect on the structure of LiFePO4 material, but significantly improved its rate performance. The initial discharge capacity of the LiFeB0.06P0.94O(4-delta) sample was 145.62 mAh/g at 0.1 C, and the capacity retention ratios of 81% at 2 C and 76% at 5 C were obtained, demonstrating that a proper amount of boron substitution (lower than 6 mol%) could significantly improve the rate performance of LiFePO4 cathode material. PMID- 23646678 TI - Superhydrophobic micro/nano dual-scale structures. AB - In this paper, we present superhydrophobic micro/nano dual structures (MNDS). By KOH-etching of silicon, well-designed microstructures, including inverted pyramids and V-shape grooves, are first fabricated with certain geometry sizes. Nanostructures made of high-compact high-aspect-ratio nanopillars are then formed atop microstructures by an improved controllable deep reactive ion etching (DRIE) process without masks, thus forming MNDS. Resulting from both the minimized liquid-solid contact area and the fluorocarbon layer atop deposited during the DRIE process, the MNDS show a reliable superhydrophobicity. The contact angle and contact angle hysteresis are -165 degrees and less than 1 degrees, respectively. This superhydrophobicity of MNDS is very stable according to squeezing and dropping test, even in high voltage conditions with the electrowetting threshold voltage of -300 V. Therefore, this micro/nano dual-scale structure has strong potential applications to the self-cleaning surface and superhydrophobic micro/nano fluidics. PMID- 23646679 TI - The phase transition of W-doped VO2 nanoparticles synthesized by an improved thermolysis method. AB - High-quality thermochromic monoclinic VO2(M) and series of W-doped V(1 x)W(x)O2(M) nanoparticles were successfully synthesized by an improved thermolysis method. The products were investigated using X-ray diffraction (XRD), transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) technologies. The measurement of DSC revealed that the metal insulator phase transition (MIT) of 2.0% W-doped VO2 sample occurred at 25.6 degrees C, which was much lower than the MIT of host VO2(M) nanoparticles at 67.6 degrees C. The results showed that the proportion of the transmittance of tetragonal phase reached only about 29% of that of monoclinic phase for 0.5% W doped VO2 at the wavenumber 900 cm(-1), which indicated W-doped VO2(M) was an intelligent window and optical switch materials. PMID- 23646680 TI - Synthesis and evaluation of Bingel-Hirsch multiadducts of paramagnetic gadofullerene as potential magnetic resonance imaging contrast agents. AB - Water-soluble malonate multiadducts of paramagnetic gadolinium endohedral metallofullerene, Gd@C82[C(COOH)2]6 and Gd@C82[C(COOH)2]8, were synthesized by Bingel-Hirsch reaction. Gd@C82 was firstly reacted with diethyl bromomalonate in the presence of alkali metal hydride to produce malonic ester multiadducted derivatives, Gd@C82[C(COOCH2CH3)2]x (x = 3-8), by Bingel reaction. They were isolated and purified to obtain Gd@C82[C(COOCH2CH3)2]6 and Gd@C82[C(COOCH2CH3)2]8 by silica-gel column chromatography with a gradient elution method, which were subsequently hydrolyzed to yield water-soluble Gd@C82[C(COOH)2]6 and Gd@C82[C(COOH)2]8 by Hirsch reaction. The structures of the derivatives were characterized by Fourier transform infrared spectrometry and matrix assisted laser desorption ionization time-of-flight mass spectrometry. The longitudinal relaxivities of Gd@C82[C(COOH)2]8 and Gd@C82[C(COOH)2]6, in buffer solution, were found to be 18.20 and 11.08 mM(-1) s(-1) at concentration range between 0.001 0.025 mM Gd, and to be 12.71 and 6.73 mM(-1) s(-1) between 0.050-0.200 mM Gd, respectively. The results showed that the measured relaxivities for malonate derivatives of Gd@C82 were dependent on the concentration of these solutions and the number of hydrophilic carboxyl groups appended on the surface of the Gd@C82 cage. PMID- 23646681 TI - Mechanical evaluation of nHAp scaffold coated with poly-3-hydroxybutyrate for bone tissue engineering. AB - Regeneration of bone, cartilage and osteochondral tissues by tissue engineering has attracted intense attention due to its potential advantages over the traditional replacement of tissues with synthetic implants. Nevertheless, there is still a dearth of ideal or suitable scaffolds based on porous biomaterials, and the present study was undertaken to develop and evaluate a useful porous composite scaffold system. In this study, nano hydroxyapatite (nHAp) powder made (about 35-45 nm) by heating at temperature of 900 degrees C and porous hydroxyapatite (40, 50 and 60 wt% solution) for making scaffold, by using Polyurethane sponge replication method. In order to increase the scaffolds mechanical properties, they coated with 2, 4 and 6 wt% Poly-3-hydroxybutyrate (P3HB) for 30 sec and 60 sec, respectively; after the scaffold coated by Polymer and survey results, this scaffold is nHAp/P3HB composite. Based on these results, this scaffold is an optimized one among three tested above mentioned composition and can be utilized in bone tissue engineering. In the result, the best of scaffold is with 50 wt% HAp and 6 wt% P3HB and porosity of present is between 80 90% with compressive strength and modulus 1.51 MPa and 22.73 MPa, respectively, that it can be application in bone tissue engineering. PMID- 23646682 TI - Poly(pyrocatechol-3,5-disodiumsulfonate)/multi-walled carbon nanotubes composite for simultaneous determination of dopamine, ascorbic acid and uric acid. AB - A novel poly(pyrocatechol-3,5-disodiumsulfonate)/multi-walled carbon nanotubes (PPD/MWCNT) composite film modified glassy carbon electrode (GCE) was fabricated and successfully used to simultaneously determine ascorbic acid (AA), dopamine (DA) and uric acid (UA). Owing to the synergistic effects of PPD and MWCNTs, the electrochemical responses of AA, DA and UA at PPD/MWCNTs/GCE were clearly superior to those at bare GCE. Additionally, the PPD/MWCNTs composite film could reduce the potential overlap of AA, DA and UA so as to favor simultaneous determination of the three substances. Under the optimum conditions, the linear calibration curves of AA, DA and UA were obtained by differential pulse voltammetry in the range of 10-1000, 1-100 and 4-1200 microM, and the detection limits were 5, 0.5 and 0.5 microM (S/N = 3) respectively. The results showed PPD/MWCNTs/GCE possessed good reproducibility and stability, and it could be applied to determine UA in human urine with satisfying recovery by standard addition method. PMID- 23646683 TI - Microwave-assisted solvothermal synthesis of Ag-Si codoped TiO2 nanoparticles for enhanced visible light photocatalytic activity. AB - Ag-Si codoped TiO2 nanoparticles were successfully synthesized via a rapid and energy frugal microwave-assisted solvothermal method. The obtained materials were characterized by XRD, BET, TEM, XPS, and UV-Vis DRS. These characterizations revealed that the obtained materials possessed good crystallinity, small particle size and large surface area. In this system, silicon could enter into the crystal lattice of TiO2, leading to smaller particle size and larger surface area compared to pure TiO2; silver dispersed on the surface of TiO2 particles, contributing to the visible light response and benefiting the efficient separation of photoelectrons and holes. Thus, the synthesized materials should achieve enhanced photoactivity under visible light irradiation, and that was evaluated by the decomposition of Rhodamine B in the aqueous solution. It was found that the Ag-Si codoped TiO2 photocatalyst exhibited higher photocatalytic activity compared with pure TiO2 and Ag or Si doped TiO2. The doping amount of the silver showed significant effect on the photocatalytic activity, and the optimal activity was achieved with Ag content of 1 mol%. PMID- 23646684 TI - Influence of carbon nanotubes microstructures inside composites on the loading role of nanotubes bore. AB - To fully utilize the extraordinary mechanical properties of carbon nanotubes (CNTs) in composites, great attention has been paid to prepare CNTs based composites with uniformly dispersion and strong interfacial adhesion. With the help of micro-Raman spectroscopy, herein, we study the influence of nanotube microstructures (e.g., dispersion and orientation) on the loading role of nanotubes bore. By using the same batch of composite solutions, two types of composite materials with different nanotube morphologies were prepared by electrospun and solution casting methods. Raman results have revealed that the loading-role of nanotubes bore in the electrospun nonwoven mats is much stronger than that of regular composite films owing to its uniformly dispersion as well as high orientation. PMID- 23646685 TI - A potential nonthrombogenic small-diameter vascular scaffold with polyurethane/poly(ethylene glycol) hybrid materials by electrospinning technique. AB - A small-diameter vascular graft (inner diameter 4 mm) was fabricated from polyurethane (PU) and poly(ethylene glycol) (PEG) solutions by electrospinning technology. The fiber diameter decreased from 1023 +/-185 nm to 394 +/- 106 nm with increasing weight ratio of PEG in electrospinning solutions. The PU/PEG scaffolds showed randomly nanofibrous morphology and well-interconnected porous structure. The hydrophilicity of these scaffolds was improved significantly with increasing weight ratio of PEG. The mechanical properties of electrospun PU/PEG scaffolds were obviously different from that of pure PU scaffold, which was caused by plasticizing or hardening effect imparted by PEG composition. Under hydrated state, the PU/PEG scaffolds demonstrated low mechanical performance due to the hydrophilic property of materials. Compared with dry PU/PEG scaffolds with the same weight ratio of PEG, the tensile strength and elastic modulus of hydrated PU/PEG scaffolds decreased significantly, while the elongation at break increased. The results demonstrated that the electrospun PU/PEG hybrid tubular scaffolds are potential candidates for artificial blood vessels. PMID- 23646686 TI - Multiple constituents co-assembly of ordered mesoporous Al2O3-SiO2-carbon nanocomposites. AB - Ordered mesoporous Al2O3-SiO2-carbon nanocomposites have been synthesized via the direct triblock-copolymer self-assembly route using soluble phenolic resols as polymer precursors, aluminium chloride hexahydrate as an aluminum precursor, tetraethoxysilane as a silica precursor, and Pluronic F127 as a template. Characterization of XRD, N2 sorption isotherms, TEM, solid-state NMR, TG, and NH3 TPD techniques is used to investigate the mesostructure, pore properties, phase composition, metal incorporation state, and acidic properties. Ordered mesoporous nanocomposites have "reinforced concrete"-structured frameworks, in which the oxide and carbon components are microphase separated and homogenously dispersed inside pore walls. Al species are tetrahedrally incorporated into silica frameworks to compose the inorganic oxide compounds which provides acidic center. The nanocomposites have the ordered 2-D hexagonal mesostructure, high surface areas (291-360 m2/g), large pore volumes (0.25-0.42 cm3/g), large pore diameters (- 5 nm) and accessible acidic sites. PMID- 23646687 TI - Effect of nano-SiC incorporation on mechanical properties of micro and nano structured Ni-Co electrodeposits. AB - Ni-Co/SiC nano-composites were electrodeposited from modified Watts bath containing SiC particles with 50 nm average size, SDS as surfactant and saccharin as grain refiner in appropriate amounts. The effect of grain size and nano particle incorporation on microstructure and mechanical properties of electrodeposits was investigated. The grain size of the deposits was calculated from X-ray diffraction (XRD) patterns using Williamson-Hall equation and surface morphology of the coatings was studied by means of scanning electron microscopy (SEM). The mechanical properties of electrodeposits were investigated by Vickers microhardness and tensile tests. The results indicated that incorporation of SiC nano-particles increased the microhardness and yield strength of micro-grained deposits due to the change in crystallographic texture, decrease in grain size as well as dispersion hardening. But dispersion hardening mechanism could not be confirmed in nano-structured deposits. Moreover, the increase in the concentration of uniformly dispersed SiC particles initially improved and then decreased the elongation to failure of coarse-grained deposits while a continuous increase was observed for nano-structured deposits. PMID- 23646688 TI - Reactive ion etching of Si(x)Sb2Te in CF4/Ar plasma for nonvolatile phase-change memory device. AB - Si(x)Sb2Te material system is novel for phase-change random access memory applications. Its properties are more outstanding than the widely used material Ge2Sb2Te5. Etching process is one of the critical steps in the device fabrication. The etching characteristics of phase-change material Si(x)Sb2Te were studied with CF4/Ar gas mixture by a reactive ion etching system. The changes of etching rate, etching profile and surface root-mean-square roughness resulted from variation of the gas-mixing ratio were investigated under constant pressure (50 mTorr) and applying power (200 W). Si0.34Sb2Te is with the highest phase change speed and the lowest power consumption in the PCRAM memory among these compositions, which means it is the most promising candidate for the PCRAM applications. So the most optimized CF4/Ar gas ratio for Si0.34Sb2Te was studied, the value is 25/25. The etching rate is 155 nm/min, and the selectivity of Si0.34Sb2Te to SiO2 is as high as 3.4 times. Furthermore, the smooth surface was achieved with this optimized gas ratio. PMID- 23646689 TI - Highly selective and sensitive determination of dopamine using Nafion coated microelectrode arrays. AB - The present study concerns methodological issue of electrochemical recordings using Nafion-coated microelectrode arrays fabricated by MEMS technology for voltammetric and amperometric measurements of dopamine (DA). The properties of Nafion-coated different temperature dried microelectrodes were determined by cyclic voltammetry. The electrochemical characteristics of the 120 degrees C dried Nafion-coated microelectrode for measures of dopamine and ascorbic acid (AA) were studied by chronoamperometry. These studies showed that the 120 degrees C dried Nafion-coated microelectrode had better recording properties: enlarged electrochemical signal for DA and high selectivity for DA versus AA. The linear response was obtained in the range of 0.1 to 50 microM with a low detection limit. The modified microelectrode arrays providing 30 microm diameter multiple sites showed the capability to simultaneously detect DA from cells, neurons and brain slices. PMID- 23646690 TI - Finite element model of surface acoustic wave method for mechanical characterization of patterned thin films of the ultra-large scaled integrated interconnect. AB - Surface acoustic waves (SAWs) technique is a promising method to determine the mechanical properties of thin low dielectric constant (low-k) dielectrics by matching the experimental dispersion curve with the theoretical dispersion curves. However, it is difficult to calculate the dispersion curves when SAWs propagate along patterned structure. In this paper, finite element method (FEM) is applied to obtain the numerical dispersion results of SAWs propagating on patterned film. Periodic boundary condition and plane-strain model is used to improve the computation speed. Four structures of bulk silicon, single layered low-k film, two layered Cu and SiO2 film, and patterned film, are simulated in this paper. The dispersion curves of single low-k films derived from the FEM simulation agree very well with those calculated by traditional method, which verifies the correct employment of the FEM approach. Dispersion curves of two patterned film structure of Cu and SiO2 with difference metal wire width are obtained. Effective Young's moduli are achieved by fitting the FEM simulated results with those of traditional theoretical calculation through least square error method. PMID- 23646691 TI - Hyper-branched CdTe nanostructures based on the self-assembling of quantum dots and their optical properties. AB - As the priority of interconnects and active components in nanoscale optical and electronic devices, three-dimensional hyper-branched nanostructures came into focus of research. Recently, a novel crystallization route, named as "nonclassical crystallization," has been reported for three-dimensional nanostructuring. In this process, Quantum dots are used as building blocks for the construction of the whole hyper-branched structures instead of ions or single molecules in conventional crystallization. The specialty of these nanostructures is the inheritability of pristine quantum dots' physical integrity because of their polycrystalline structures, such as quantum confinement effect and thus the luminescence. Moreover, since a longer diffusion length could exist in polycrystalline nanostructures due to the dramatically decreased distance between pristine quantum dots, the exciton-exciton interaction would be different with well dispersed quantum dots and single crystal nanostructures. This may be a benefit for electron transport in solar cell application. Therefore, it is very necessary to investigate the exciton-exciton interaction in such kind of polycrystalline nanostructures and their optical properites for solar cell application. In this research, we report a novel CdTe hyper-branched nanostructures based on self-assembly of CdTe quantum dots. Each branch shows polycrystalline with pristine quantum dots as the building units. Both steady state and time-resolved spectroscopy were performed to investigate the properties of carrier transport. Steady state optical properties of pristine quantum dots are well inherited by formed structures. While a suppressed multi-exciton recombination rate was observed. This result supports the percolation of carriers through the branches' network. PMID- 23646692 TI - The formation and properties of Pt4 clusters on the defective graphene support. AB - The formation energies, stable configurations, electronic and magnetic properties of the Pt4 (the 4-atom Pt cluster) clusters adsorbed nearby a single-vacancy (SV) defect on a graphene surface were investigated using the first-principles density functional theory method. It is found that on the pristine graphene the base atoms of the Pt4 cluster prefer to be adsorbed at the bridge or top sites of the carbon atoms. On the defective graphene with a single-vacancy, the Pt4 cluster prefers to be trapped at the defective site with enhanced formation energies and distorted structures. The graphene substrate plays a direct role in regulating the formation, electronic structure and magnetic properties of the Pt4 clusters. The catalytic activity of the adsorbed Pt4 clusters was also studied through adsorption of a probe molecule CO. PMID- 23646693 TI - Advances in bionanomaterials for bone tissue engineering. AB - Bone is a specialized form of connective tissue that forms the skeleton of the body and is built at the nano and microscale levels as a multi-component composite material consisting of a hard inorganic phase (minerals) in an elastic, dense organic network. Mimicking bone structure and its properties present an important frontier in the fields of nanotechnology, materials science and bone tissue engineering, given the complex morphology of this tissue. There has been a growing interest in developing artificial bone-mimetic nanomaterials with controllable mineral content, nanostructure, chemistry for bone, cartilage tissue engineering and substitutes. This review describes recent advances in bionanomaterials for bone tissue engineering including developments in soft tissue engineering. The significance and basic process of bone tissue engineering along with different bionanomaterial bone scaffolds made of nanocomposites and nanostructured biopolymers/bioceramics and the prerequisite biomechanical functions are described. It also covers latest developments in soft-tissue reconstruction and replacement. Finally, perspectives on the future direction in nanotechnology-enabled bone tissue engineering are presented. PMID- 23646694 TI - Development and applications of the heterostructures synthesis based on CdS nanowires. AB - Semiconducting nanowire heterostructures are of particular interest because of their fascinating properties and potential applications in the field of nanoscale science. CdS, with a direct bandgap of 2.42 eV, is considered to be an excellent material for various optoelectronic applications in the visible range of the electromagnetic spectrum. On account of this, the diverse heterostructures based on CdS nanowires have drawn great attention owing to their novel properties. Here, we focus on recent routes used to synthesize diverse heterostructures based on CdS nanowires and the emergent properties of the one-dimensional nanowires heterostructures, and discuss their potential applicability in different fields. In particular, the mechanisms of various synthetic methods for the heterostructure based on the CdS nanowires are discussed detailedly. PMID- 23646695 TI - Advances in applications of dendritic compounds. AB - Dendritic compounds (so-called dendrimers) with nano-scale represent unique symmetric and spherical structures. They are usually prepared through two fundamental methods based on molecular level which involved the convergent method and divergent method, although the synthetic methods have a tendency towards the diversity and functionalization. The outershell of dendrimers with rich peripheral reactive sites are easily modified by small functional molecules. Moreover, the higher generation dendrimers also possess more exposed functional groups on the surface prior to the previous one and they are much easily customized for much more applications. Consequently, based on previous researches, this review summarized wide applications of dendritic compounds in many fields which were investigated in detail, including gene vector, drug carrier, catalysis, sensor industry, photoelectric material, etc. Dendrimers provide promising tools for the cellular delivery of molecular cargos ranging in size from small molecules and peptides to proteins and DNA. More importantly, it is necessary to explore new synthetic methods and undiscovered applications of new dendrimers. PMID- 23646696 TI - Epigenetic deregulations in gastric cancer. AB - Abnormal functioning of many cellular processes such as cell cycle, DNA repair, angiogenesis and cell-cell adhesion has been reported in all types of cancer. In the context of cancer, genes responsible to sustain integrity of the cells can be categorized into tumor suppressor genes and oncogenes. In normal conditions, these genes maintain a state of equilibrium and imbalance of these two groups of genes leads to a malignant form of cells known as Cancer. Genetics and epigenetics are the two main mechanisms that regulate expression of these genes. Silencing of tumor suppressor genes has been observed in different cancer while, on the other hand, silent oncogenes are active in cancer and confer growth advantage to malignant cells as compared with the contemporary normal cells. Gastric cancer (GC), like other cancers, is a complex disease. Multiple factors including bacterial infection, dietary habits, smoking and genetic polymorphisms determine the risk for GC development. Epigenetic modifications have been attributed as an initial event in the development of GC. Here, we have summarized recent findings in the field of epigenetics which correlated with GC. PMID- 23646697 TI - Inhibitions by hydrogen-occluding silica microcluster to melanogenesis in human pigment cells and tyrosinase reaction. AB - We investigated the anti-melanogenetic efficacy of hydrogen-occluding silica microcluster (H2-Silica), which is a silsesquioxane-based compound with hydrogen interstitially embedded in a matrix of caged silica, against melanogenesis in HMV II human melanoma cells and L-DOPA-tyrosinase reaction [EC1.14.18.1]. HMV-II cells were subjected to oxidative stress by ultraviolet ray-A (UVA) exposure of 3 times of 0.65 J/cm2 summed up to 1.95 J/cm2. After UVA irradiation, HMV-II cells were stimulated to produce melanin by 2.72-fold more abundantly than unirradiated control. When HMV-II cells were treated with H2-Silica of 20 ppm or kojic acid of 28.4 ppm before and after UVA-irradiation, the amount of melanin was repressed to 12.2% or 14.5% as compared to that of UVA-irradiated control, respectively. That is, H2-Silica exhibited a comparable efficacy to the whitening agent kojic acid. The H2-Silica could prevent melanogenesis in HMV-II cells by low-level doses at 1 10 ppm, and cell viability and apoptosis event did not change even by high-level doses at 100-1000 ppm. On the contrary, kojic acid was cytotoxic at the concentration of 14-28 ppm or more. By microscopic observation, H2-Silica suppressed such properties indicative of melanin-rich cells as cellular hypertrophy, cell process formation, and melanogenesis around the outside of nuclei. The enzymatic assay using L-DOPA and mushroom tyrosinase demonstrated that H2-Silica restrained UVA-mediated melanin formation owing to down-regulation of tyrosinase activity, which could be attributed to scavenging of free radicals and inhibition of L-DOPA-to-dopachrome oxidation by hydrogen released from H2 Silica. Thus H2-Silica has a potential to prevent melanin production against UVA and serves as a skin-lightening ingredient for supplements or cosmetics. PMID- 23646698 TI - Prussian blue modified ferritin as peroxidase mimetics and its applications in biological detection. AB - Ferritins are natural nanoscale structures composed with 24 subunits endowed with similar three-dimensional structures. The iron is stored in the form of ferrihydrite phosphate in the hollow spherical ferritin shells. Prussian blue nanoparticles (PBNPs) have been certified a kind of mimetic enzyme with the advantages of stability, high catalytic activity and low prices. In this context, we designed a strategy to synthesize PBNPs of small size using ferritin as template and meanwhile retain the biological properties of ferritin. Our results show the resulting nanostructures (Prussian blue modified ferritin nanoparticles, PB-Ft NPs) got very small size and relatively high catalytic activity, furthermore, PB-Ft NPs successfully combined the intrinsic enzyme mimetic activity of PBNPs and the specificity of ferritin. Peroxidase-like activity which fits well the Michaelis-Menten kinetics was found strongly depending on pH, temperature and the concentration of PB-Ft NPs. Then a sensitive method for glucose detection was developed using glucose oxidase (GOx) and PB-Ft NPs. The consequence of Enzyme-linked immunosorbent assay (ELISA) shows PB-Ft NPs possess both specificity and peroxidase-like activity, which suggests that PB-Ft NPs can be served as a useful reagent in some biological detections. PMID- 23646700 TI - Interaction of bacterial cells with cluster-assembled nanostructured titania surfaces: an atomic force microscopy study. AB - The nanoscale interaction of bacterial cells with solid surfaces is a key issue in biomedicine because it constitutes the first pathogenic event in the complex series of biofilm development on prosthetic devices. We report on an Atomic Force Microscopy study of the interaction of Escherichia coli and Pseudomonas aeruginosa bacterial cells with nanostructured titania thin films with controlled and reproducible nanometer-scale morphology, produced by assembling Ti clusters from the gas phase in a Supersonic Cluster Beam Deposition apparatus. The results demonstrate that bacterial adhesion and biofilm formation are significantly influenced by a pure physical stimulus, that is, the nanoscale variation of surface topography. The increase of nanoscale film roughness promotes bacterial adhesion with respect to flat substrates; remarkably, Pseudomonas aeruginosa cells lose their flagella on nanostructured TiO2 thin films upon adhesion, as opposed to same bacteria onto reference smooth glass substrates. Further, we have observed increased cell biovolume and other biofilm properties on nanostructured substrates in comparison with smooth glasses. These findings suggest that the design of innovative biomaterials with a suitable patterning of biomaterials surfaces can be an effective approach to control the adhesion of microorganisms to in vivo implant surfaces with active biological functionalities. PMID- 23646699 TI - Synthesis, characterization, and application of amino-terminated poly(ethylene glycol)-block-poly(epsilon-caprolactone) copolymer for paclitaxel. AB - In this paper, we successfully synthesized amino-terminated poly(ethylene glycol) block-poly (epsilon-caprolactone) (NH2-PEG-PCL) block copolymer from polyethylene glycol 2000, epsilon-caprolactone (epsilon-CL) and hydrazine hydrate. The obtained copolymer was characterized by nuclear magnetic resonance (1H-NMR), the molecular weight and distribution of NH2-PEG-PCL were characterized by Gel permeation chromatography (GPC). The NH2-PEG-PCL copolymer could self-assemble into micelles in water. Paclitaxel (PTX) loaded NH2-PEG-PCL (PNPP) micelles were prepared by solid dispersion technique without organic solvent. The micelles were characterized by XRD, TEM and Malvern laser particle size. The results of this work indicated that PNPP micelles were uniform and spherical shapes in solution. The average size and zeta potential of PNPP (DL = 8%) in water was about 97.1 +/- 1.2 nm, +13.9 +/- 0.6 mV, respectively. The in vitrodrug release profile of PNPP micelles showed a clear slow-release effect. The results suggested that NH2-PEG PCL copolymer might be an excellent carrier for hydrophobic drugs such as PTX. In particular, the NH2-PEG-PCL polymer has potential value for modifying with ligands to work as active targeting drug delivery carriers, which has great significance for cancer therapeutics. PMID- 23646701 TI - Structural, optical and field emission properties of urchin-shaped ZnO nanostructures. AB - In this work, well-crystallized urchin-shaped ZnO structures were synthesized on silicon substrate by simple non-catalytic thermal evaporation process by using metallic zinc powder in the presence of oxygen as source materials for zinc and oxygen, respectively. The synthesized ZnO structures were characterized in detail in terms of their morphological, structural, optical and field emission properties. The detailed morphological investigations revealed that the synthesized structures possess urchin-shape and grown in high-density over the substrate surface. The detailed structural and optical characterizations revealed that the synthesized urchin-shaped ZnO structures are well-crystallized and exhibiting good optical properties. The field emission analysis for urchin-shaped ZnO structures exhibits a turn-on field of 4.6 V/microm. The emission current density reached to 0.056 mA/cm2 at an applied electrical field of 6.4 V/microm and shows no saturation. The calculated field enhancement factor 'beta', from the F-N plot, was found to be approximately 2.2 x 10(3). PMID- 23646702 TI - TiO2 nanotubes as animal drug delivery system and in vitro controlled release. AB - The enrofloxacin hydrochloride (Enro), an anti-inflammatory drug for the animals, was loaded on the TNTs through physical absorption due to the high specific surface area and excellent surface activity of the TiO2 nanotubes. The samples were characterized by XRD, BET, TEM, TG and FTIR. The in vitro controlled release behavior at different temperatures was studied in detail. The results showed that the obtained TNTs were uniform and mainly amorphous crystal phase with a diameter of 10-15 nm and a length of 350-400 nm. By investigating the effect of the hydrothermal reaction process of the obtained TiO2 nanotubes and the drug loading frequency on the loading content of Enro drugs, the results indicated that the increasing loading frequency of the drug was available for the drug loading and the maximum loading content of drug reached to 33.28%. Enro-TNTs performed a better release profile at low temperature than at high temperature in PBS solution. The Higuchi square root models are suitable to explain the in vitro drug release behavior of Enro from Enro-TNTs. PMID- 23646703 TI - Magnetite nanoparticles-chitosan composite containing carbon paste electrode for glucose biosensor application. AB - This work was aimed to develop reusable magnetite chitosan composite containing carbon paste electrode for biosensor application. Glucose oxidase (GOx) enzyme was used to prepare GOx-magnetite-chitosan nanocomposite containing carbon paste electrode for sensitive detection of glucose. The immobilized enzyme retained its bioactivity, exhibited a surface confined reversible electron transfer reaction, and had good stability. The surface parameters like surface coverage (tau), Diffusion coefficient (D0), and rate constant (kS) were studied. The carbon paste modified electrode virtually eliminated the interference during the detection of glucose. The excellent performance of the biosensor is attributed to large surface-to-volume ratio, high conductivity and good biocompatibility of chitosan, which enhances the enzyme absorption and promotes electron transfer between redox enzymes and the surface of electrode. The shelf life of the developed electrode system is about 12 weeks under refrigerated conditions. We report for the first time in the fabrication of carbon paste bioelectrode containing magnetite chitosan-GOx. PMID- 23646704 TI - Modification of antioxidative and antiapoptotic genes expression in irradiated K562 cells upon fullerenol C60(OH)24 nanoparticle treatment. AB - Recent data established the prospective applications for fullerenol (C60(OH)24) nanoparticle (FNP) in many fields, such as antioxidants, neuroprotective agents, and potential anti-radiation drugs. Leukemia cell sensitization to apoptosis induced by ionizing radiation is achieved by upregulation of ROS production and/or downregulation of antioxidative enzymes. Therefore, our aim was to analyze the potential role of fullerenol nanoparticle in modulation of the leukemic cellular response to irradiation. We used the qRT-PCR to analyze the expression level of mRNA for 11 genes in irradiated and FNP pre-treated irradiated K562 cells, and compared the gene expression level with the overall cell survival. Our results of the improved cell survival in FNP-treated irradiated cells and significant overexpression of anti-apoptotic Bcl-2 and Bcl-xL and cytoprotective genes such as GSTA4, MnSOD, NOS, CAT and HO-1 genes, may indicate that FNP exerts cytoprotective function in K562 leukemic cells, rendering K562 cells more tolerant to radiotherapy. PMID- 23646705 TI - Cinnamon oil nanoemulsion formulation by ultrasonic emulsification: investigation of its bactericidal activity. AB - Cinnamon oil (extracted from Cinnamomum zeylanicum) nanoemulsion was formulated using Tween 80 and water by ultrasonic emulsification. Process of nanoemulsion formulation was optimized for parameters such as surfactant concentration, oil surfactant mixing ratio and emulsification time. Surfactant concentration was found to be inversely related to droplet size and directly related to stability. Increase in emulsification time resulted in decrease in droplet diameter. Stable cinnamon oil formulation (CF3) having droplet diameter of 65 nm was formulated after sonication for 30 min. Formulated nanoemulsion was evaluated for bactericidal efficacy against Bacillus cereus. Time and concentration dependent killing of B. cereus cells was observed upon treatment with nanoemulsion. Even at a higher dilution of CF3, significant reduction in bacterial population was observed. Alteration in membrane permeability of interacted samples was suggested by quantifying the release of UV absorbing materials. Bacterial staining with acridine orange/ethidium bromide supported kinetics of killing data and also substantiated the above findings of alteration in membrane permeability. FTIR illustrated disappearance of peak corresponding phosphate vibration at 1078 cm( 1) and 536 cm(-1), and peak associated with vibration of acyl chains of lipid at 2852 cm(-1) was shifted to 2854 cm(-1) which suggested deformation of membrane phospholipids in nanoemulsion treated cells. SEM observations demonstrated membrane distortion leading to cell lysis. These results propose the potential use of cinnamon oil nanoemulsion for preservation of minimally processed food. PMID- 23646706 TI - Real-time dynamic optical imaging of ACC-M tumor cells killed by HSV-tk/ACV system. AB - HSV-tk/ACV induced and killed human adenoid cystic carcinoma cell (ACC-M) in vivo and in vitro, which were observed through optical imaging and green fluorescence protein (GFP) tagging technique. ACC-M was transfected with TK-GFP, and the single clone cell ACC-M-TK-GFP was selected by G418. With fluorescent stereomicroscope, whole-body fluorescent imaging system and fluorescent microscope, we could observe ACV treated ACC-M-TK-GFP cells in cell level and nude mice. The therapies of tumor were visualized clearly with optical imaging. This study proves that optical imaging is a very good approach for studying the effect of HSV-tk/ACV on the ACC-M tumor cells and decreasing the amount of vessel about tumors cell. Optical imaging will become a visual groundwork for monitoring tumor growth and evaluating in vivo curative effect of antitumor drugs. PMID- 23646707 TI - Preparation and characterization of folate-chitosan-gemcitabine core-shell nanoparticles for potential tumor-targeted drug delivery. AB - For the purpose of achieving targeted chemotherapy of pancreatic cancer, we prepared core-shell nanoparticles by coaxial electrospray technology, with folate chitosan as the polymeric coating material and gemcitabine as the encapsulated drug. The effects of various solution properties and processing parameters on nanoparticles formation were investigated. By optimizing the electrospray parameters, the diameter of the core-shell nanoparticles was in the range of 200 300 nm with drug loading and encapsulation efficiency of 3.91 +/- 0.12% and 85.37 +/- 4.9%. The drug release kinetics revealed a controlled initial burst release followed by a sustained release over a period of 72 h at pH 7.4 and pH 5.0, and at pH 5.0 the drug released more quickly. Moreover, the cellular uptake experiment confirmed that the folate conjugated core-shell nanoparticles had high pancreatic cancer (BXPC3) cells uptake efficiency. And the cell cytotoxicity test displayed that they had remarkable cytotoxicity towards BXPC3 cells. This study indicates that coaxial electrospray is a facile technique in producing core-shell nanoparticles encapsulating hydrophilic small molecule drugs, and clearly infers that the folate conjugated core-shell nanoparticles is very much effective to use as a pancreatic tumor-targeted delivery carrier for anticancer drugs. PMID- 23646708 TI - Detection of single nucleotide polymorphisms using a biosensor-containing titanium-well array. AB - The rapid identification and verification of single nucleotide polymorphisms (SNPs) were demonstrated using a well array sensor containing anti-biofouling titanium (Ti). Probe single-stranded DNA (ssDNA) was immobilized inside a titanium-well array on amine-modified glass surfaces with anti-biofouling behavior via a streptavidin-biotin interaction. Fluorescence intensity changes originating from the hybridization of nucleic acids to protein-bound nucleic acids linked to Alexa Fluor (FL) 647 were observed. The protocol was highly sensitive and reproducible for the detection of DNA hybridization. Significant changes in fluorescence signals were observed when using target DNA with a single base mismatch, indicating that this method is applicable to SNP detection. The microarray technology for the detection of SNPs using anti-biofouling Ti and other methods can be used as a highly sensitive in vitro medical sensor, as highlighted by an increase in genotyping accuracy. PMID- 23646709 TI - Phospholipase-catalyzed hydrolysis in an artificial cell membrane in the presence of melittin. AB - Biomimicry involves the use of the structure and function of biological systems as models for the design and engineering of materials and machines. An artificial cell membrane was developed using biomembrane components, and the membrane, formed by a lipid bilayer, was analyzed using surface plasmon resonance (SPR) to monitor hydrolysis by phospholipase (PL). The simultaneous atomic force microscope (AFM) images show that PL catalyzed the nanometer-scale hydrolysis of the artificial lipid biomembranes through enzymatic hydrolysis. In addition, it was confirmed that the combination of PL and melittin allowed the control of enzyme hydrolysis for the degradation of the lipid bilayer. Regarding the expected activating effect of melittin on hydrolysis, no difference with respect to the non-treated lipid membrane was observed in the AFM images. It is assumed that the partitioning of melittin into the membrane might prevent the binding or hydrolysis of Phospholipase A2 (PLA2). This study provides basic knowledge on a new approach for patterning biomimicking lipid membranes on a nano-scale. PMID- 23646710 TI - Preparation, in vitro and in vivo evaluation of budesonide loaded core/shell nanofibers as oral colonic drug delivery system. AB - Budesonide (BUD) loaded ethylcellulose (EC)-core/Eudragit S100-shell nanofibers (BUD-core/shell-NFs) have been successfully prepared using a coaxial electrospinning technique. The drug encapsulation efficiency was 90.48%. SEM and TEM analysis showed that fine core-shell structured nanofibers with an average diameter 190 nm and uniform core diameters 74 nm were prepared. The BUD-loaded Eudragit S100/EC composite nanofibers (BUD-NFs) were prepared using a blend electrospinning method and used as a control. In vitro release tests in HCl 0.1 N, phosphate buffer solutions pH 6.8 and 7.4 were studied. Moreover, the colon specific characteristics were directly proven in vivo by the content of BUD in different segments of the gastrointestinal (GI) tract in rats after oral administration. Taken together, the results confirmed that BUD-core/shell-NFs had desired pH-dependent drug release profile, displayed a sustained and complete drug release in the colon, as well as protected BUD from being released completely in the upper portion of the GI tract. Compared with BUD-NFs, the BUD core/shell-NFs have much better potential to be developed as oral colon-specific drug delivery system (OCDDS) to overcome the disadvantages of current oral formulations of BUD. PMID- 23646711 TI - Fabrication and characterization of photoluminescent silicon nanoparticles for drug delivery applications. AB - Photoluminescent silicon nanoparticles containing camptothecin (CPT) were fabricated by using a CPT-derivatized porous silicon (PSi). PSi samples displaying red photoluminescence (PL) were prepared by an electrochemical etch of n-type silicon under the illumination with a 300 W tungsten filament bulb for the duration of etch. For the drug-derivatized PSi, luminescent PSi was oxidized and derivatized with CPT. Silicon nanoparticles containing CPT were obtained by fracturing of luminescent PSi with ultrasono-method. Optical characteristic of drug-derivatized silicon particles were investigated in aqueous buffer solution. The release of CPT was measured by UV-vis spectrometer. The intensity of fluorescence of the silicon nanoparticles was measured with a drug release. The concentration of released drug exhibited non-linear relationship with a release time. PMID- 23646712 TI - Cytotoxic and genotoxic effects of silver nanoparticles on primary Syrian hamster embryo (SHE) cells. AB - Silver-nanoparticles (NPs) have become increasingly common in various applications, raising some safety concerns. In this study, the cytotoxic and genotoxic effects of silver-NPs on primary Syrian hamster embryo (SHE) cells were investigated. Cell viability was assessed using a methyl tetrazolium (MTT) assay, and genotoxic potential was evaluated using a cytokinesis-block micronucleus (CBMN) assay. The results showed that dose-dependent cytotoxicity was induced after 24 h of exposure to silver-NPs. The micronucleation frequency (MNF) also increased significantly in a dose-dependent manner (P < 0.05), suggesting that silver-NPs induce genotoxicity. This is consistent with an increased MNF observed in primary SHE cells. The results of cell cycle analysis indicate that the cell cycles became arrested in the GO/G1 phase and that the S phase shortened after only 8 h of silver-NP exposure, suggesting that DNA replication had been inhibited, which in turn inhibited further cell proliferation. The rate of late stage apoptosis increased after 12 h of silver-NP exposure, and both early- and late-stage apoptosis were obviously increased after 72 h of exposure than in controls. This study demonstrated that silver-NPs could induce strong cytotoxicity and significant genotoxicity in primary SHE cells and that this is probably due to silver-NP-induced apoptosis and the inhibition of cell proliferation. PMID- 23646713 TI - Clinical analysis and significance of cholangiography for biliary cast/stone after orthotopic liver transplantation. AB - Cholangiography is an important method for the diagnosis of biliary complications after orthotopic liver transplantation. The cholangiography after orthotopic liver transplantation presents special challenges, especially in patients with biliary cast/stone and biliary stenosis. We described the T-tube cholangiography combined therapeutic fibro-choledochoscopy for the diagnosis and treatment of biliary cast following after orthotopic liver transplantation. Fourteen patients who developed biliary cast/stone after liver transplantation were analyzed retrospectively. The complications were divided into three temporal stages, early, medium, and late. Hepatic functions and the characteristics of the bile duct were observed by T-tube cholangiography and endoscopy. The biliary cast after liver transplantation was divided into three categories: Solitary, multiple, and columnar. Three months after liver transplantation, bile ducts appeared fuzzy by T-tube cholangiography, but no evidence of biliary cast was found. The bile duct was feculent with flocculation during the middle stage 3-6 months after liver transplantation. At six months after transplantation, bile ducts (especially intrahepatic bile ducts) were distended; cholangiectasis was obvious with biliary cast. The intrahepatic bile duct stricture was observed on occasion by T-tube cholangiography and the intrahepatic bile duct could be thin and distended, and resembled withered branches or strings of beads. The intrahepatic bile ducts even disappeared at this stage; hepatic functions were usually unacceptable and the icterus gradually aggravated. Four cases were diagnosed earlier according to the categories of stone and stage. Curative therapy was performed promptly and the clinical outcome was acceptable. Biliary tracts of the transplanted livers could be observed by T-tube channels and biliary complications were treated effectively by therapeutic fibro choledochoscopy. It is necessary to combine T-tube cholangiography with fibro choledochoscopy for the diagnosis and treatment of biliary complications after orthotopic liver transplantation. PMID- 23646714 TI - Stealth cationic liposomes modified with anti-CAGE single-chain fragment variable deliver recombinant methioninase for gastric carcinoma therapy. AB - Stealth cationic liposomes (SCLs) modified with tumor-targeting single-chain fragment variable (scFV) antibody for systemic delivery of recombinant methioninase (rMETase) for gastric cancer were prepared successfully. These functional SCL nanoparticles are composed of cationic lipids, dioleoylphosphatidylethanolamine, and distearoylphosphatidylethanolamine polyethylene glycol, which have lower gene transfection efficiencies compared with Lipofectamine 2000, and can also be used as effective gene delivery vectors. Increased therapeutic efficiency of rMETase-loaded scFV-SCLs were tested in SGC 7901 cells and compared with free rMETase in solution and rMETase-loaded SCLs. In addition, scFV-SCLs (effective diameter: 185.7 nm; polydispersity index: 0.236) can significantly boost rhodamine 123 cellular accumulation in the cytoplasm. The scFV-targeted SCLs can be used as a potentially effective drug delivery system. PMID- 23646715 TI - Regulation of cellular RNA nano-particle assembly by splicing factor SRp20. AB - Cellular RNA nano-particles (RNA granules) such as stress granule (SG) and P-body (PB) are translationally silenced mRNA-protein complexes. Previously, a genome wide loss-of-function screen using oligomeric siRNAs targeting potential drug target genes was performed to identify genes that are involved in SG and PB assembly. SRp20 (SRSF3), a splicing regulator, was identified as a potential regulator for the RNA granule assembly. Here, we show that SRp20 is a bona-fide RNA granule component using antibody against SRp20 as well as Flag-tagged SRp20 through immunofluorescence microscopy. More importantly, upon knockdown of SRp20 using siRNA, RNA granule formation was potently disrupted indicating that SRp20 is one of the major structural components of SGs and PBs. Interestingly, polysome profiling analyses displayed that SRp20 is distributed in all ribosomal fractions suggesting a potential role of SRp20 as a post-transcriptional mRNA regulator. These results broaden the functional role of SRp20 from the nuclear RNA processing events to the cytoplasmic post-transcriptional mRNA regulatory events through RNA granules that are critical for the regulation of gene expression. PMID- 23646716 TI - Electrical and mechanical characterisation of single wall carbon nanotubes based composites for tissue engineering applications. AB - This paper presents the realisation of conductive matrices for application to tissue engineering research. We used poly(L-lactide (PLLA)), poly(epsilon caprolactone) (PCL), and poly(lactide-co-glycolide) (PLGA) as polymer matrix, because they are biocompatible and biodegradable. The conductive property was integrated to them by adding single wall carbon nanotubes (SWNTs) into the polymer matrix. Several SWNTs concentrations were introduced aiming to understand how they influence and modulate mechanical properties, impedance features and electric percolation threshold of polymer matrix. It was observed that a concentration of 0.3% was able to transform insulating matrix into conductive one. Furthermore, a conductive model of the SWNT/polymer was developed by applying power law of percolation threshold. PMID- 23646717 TI - Surface modification and conjugation with immunoglobin G of highly luminescent CdSe/Cd0.5Zn0.5S quantum dots. AB - Hydrophobic CdSe/Cd0.5Zn0.5S core-shell quantum dots (QDs) with high photoluminescence (PL) efficiency and tunable PL have been fabricated through a controlled two-step synthesis. The size of CdSe cores depended strongly on the injection speed of trioctylphosphine selenium and reaction temperature and time. With increasing size, the morphology of the cores varied from spherical to rod. A Cd05Zn0.5S shell coating resulted in a high PL efficiency up to 80% and tunable PL spectra from green to red. Because resulting core/shell QDs exhibited narrow PL spectra (full-width at half-maximum of less than 30 nm) and high PL efficiencies, they were surface-modified by a SiO2 layer with functional groups for biological applications through a controlled reverse micelle route. Partially hydrolyzed tetraethyl orthosilicate (TEOS) play an important role for the QDs transferred into water phase from oil phase. The thickness of SiO2 layer was adjusted less than 5 nm through controlling the amount of TEOS and reaction time. Aminopropyltrimethoxysilane were added to attach functional groups on the SiO2 layer of the QDs. The functional SiO2-coated QDs were conjugated with immunoglobin G (IgG) antibody by using small molecules as cross linkers. Because the QDs revealed a high PL efficiency up to 30% after conjugation with IgG, they will have important applications in biological and medical research fields. PMID- 23646718 TI - Uptake of cerium oxide nanoparticles and their influences on functions of A549 cells. AB - The cerium oxide nanoparticles (NPs) have been widely used in the fields of fuel additives, cosmetics, commodities, pharmaceuticals and other industries. Exposure of the CeO2 NPs causes a public concern on their potential health risk. In this study, the interactions between two commercial CeO2 NPs and human bronchoalveolar carcinoma-derived A549 cells were investigated to provide a fast and in-depth understanding of the biological influences of the NPs. In the culture medium containing 10% fetal bovine serum, both of the D-CeO2 and PC-CeO2 NPs had an extremely small solubility (< 0.1 ng/mL) and were aggregated from 20 nm and 8 nm (in a dry state) to approximately 190 nm and approximately 60 nm, respectively. Both types of the CeO2 NPs showed slightly negative surface charge due to the adsorption of serum proteins. They had rather weak cytotoxicity even at the highest concentration of 200 microg/mL. Cellular uptake of the CeO2 NPs increased along with the increase of concentration and incubation time. The internalized CeO2 NPs were dispersed in vacuoles and cytoplasm. Uptake of the particles resulted in slight change of the cell cycles, i.e., more cells stayed in the G1 phase, and could suppress the production of reactive oxygen species but brought negligible influence on the mitochondrial membrane potential. However, the cytoskeleton organization and the cell adhesion ability were affected to some extent. PMID- 23646719 TI - Preparation of doxorubicin-hydrochloride nanoliposomes by ethanol injection-pH gradient method and their safety evaluation. AB - A new type of ethanol injection-pH gradient method was established to produce Doxorubicin-Hydrochloride Nanoliposome (DHNP). The characteristics of DHNP were examined by Zetasizer. The acute toxicity and chronic toxicity trials were conducted in Kuming mice with different doses of DHNP. The results showed that the DHNP had the uniform distribution size, diameter ranged in 140-170 nm, its entrapment rate could reach as high as 99.85%, and it was relatively stable in low temperature. The LD50 of the DHNP is 31.69 mg/kg. In the chronic toxicity study, body weight, hematocrit, the mean red blood cell volume, platelets counts and percentage of eosinophil at the dose of 6 mg/kg and 9 mg/kg groups were significantly different (p < 0.05) compared with control group, while the other parameters had no significantly difference. In the tissue analysis, pathological change was found in the lung at the treated group, and its pathological degree increased as the dose increased, while there were no other pathological changes detected in other tissues. This study demonstrates that the DHNP prepared by ethanol injection-pH gradient method possesses the advantage of uniform distribution size, high encapsulation efficiency, big drug loading rate, and its toxicity is lower than free doxorubicin. PMID- 23646720 TI - Time-course effects of intravenously administrated silica nanoparticles on blood coagulation and endothelial function in rats. AB - Among the most used inorganic nanomaterials, silica nanoparticles (NPs) have been considered as either drug carriers or contrast agents. Though the distribution of silica NPs via the circulation appears highly probable, to date, there are few studies investigating the vascular effects of silica NPs in vivo. This study was designed specifically to investigate whether silica NPs with intravenous injection could lead to blood coagulation disorder and endothelium dysfunction in vivo. The time-course effect of silica NPs on blood coagulation, oxidative stress and the expression of soluble E-selectin (sE-selectin) and tissue factor (TF) in the plasma of Sprague Dawley (SD) rats were presented. Our data showed that a shortened prothrombin time (PT) was observed on 1 day after exposure to silica NPs, while activated partial thromboplastin time (APTT) was not affected at any time-points. After the post-injection respectively, the levels of fibrinogen (Fbg) were increased by silica NPs from 1 day to 3 days, and returned to normal value on the 7th day. Meanwhile, a sustained increase in the levels of TF and sE selectin was elicited by silica NPs during 7 days after the injection. In addition, after 7 days of intravenously injection of silica NPs, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) in the plasma of SD rats were decreased significantly, whereas the level of malondialdehyde (MDA) was not changed obviously. In conclusion, intravenously administration of silica NPs could shorten PT but not APTT increase TF and sE-selectin release and reduce GSH-px and SOD activity in the plasma of SD rats, indicating exposure to silica NPs could early activate coagulation cascade via the extrinsic pathway, and may be dependent on endothelium dysfunction and oxidative stress. PMID- 23646721 TI - Multiarray formation of CHO spheroids cocultured with feeder cells for highly efficient protein production in serum-free medium. AB - Functional proteins like antibody, cytokine and growth factor have been widely used for basic biological research, diagnosis and cancer therapy. Particularly, antibody drugs as attractive biopharmaceuticals will be expected to create an enormous new market. Chinese hamster ovay (CHO) cells are being increasingly used in industry for the production of recombinant therapeutic proteins including antibody drugs. Although three-dimensional culture is preferred to two dimensional monolayer culture for the efficient large scale culture of CHO cells and subsequent mass production of recombinant proteins, it has the limitation of low protein production. Therefore, a new cell culture em essentially required for an efficient protein production. Here we report on a new three-dimensional cell culture system as a spheroid cell culture on the micropattern array for efficient production of protein in CHO cells. Furthermore, cocultivation of CHO spheroids with feeder cells including bovine aortic endothelial cells (BAEC) and NIH 3T3 was essential to more increase a protein production. The results indicated that CHO heterospheroids cocultured with BAECs were much superior to either CHO monolayers or CHO homospheroids in protein production. Significantly, the above cocultured spheroids in the serum-free medium drastically enhanced protein expression level up to 3-fold compared with CHO spheroids in serum medium, suggesting that a coculture of spheroid system with feeder layer cells is a promising method to enhance protein production under serum-free condition. The spheroid array constructed here is highly usuful as a platform of biopharmaceutical manufacturing as well as tissue and cell based biosensors to detect a wide variety of clinically active compounds through a cellular physiological response. PMID- 23646722 TI - Synthesis and characterization of superparamagnetic CoFe2O4/MWCNT hybrids for tumor-targeted therapy. AB - Owing to their great potentialities of carbon nanotubes (CNTs)-based magnetic nano-composites, numerous applications of them have been found in nanotechnology, integrated functional system, and in medicine. Herein, nearly monodisperse CoFe2O4 nanoparticles have been deposited on multi-walled carbon nanotubes (MWCNTs) by high-temperature hydrolysis and inorganic polymerization of ionic Co(II) and Fe(III) salts and MWCNTs in a polyol solution. X-ray diffraction, energy-dispersive X-ray spectrometry and transmission electron microscopy were used to characterize the final products. The average size of CoFe2O4 nanoparticles and their coverage density on MWCNTs can be adjusted to some extent by altering the reaction parameters. A proposed formation mechanism of the magnetic hybrids is presented. Magnetic measurements showed that the hybrids were superparamagnetic at room temperature and their saturation magnetization could be fine tuned by changing the loading of CoFe2O4 nanoparticles on the MWCNTs. PMID- 23646723 TI - Dimensional optimization of nanowire--complementary metal oxide--semiconductor inverter. AB - This study is the first to demonstrate dimensional optimization of nanowire complementary metal-oxide-semiconductor inverter. Noise margins and inflection voltage of transfer characteristics are used as limiting factors in this optimization. Results indicate that optimization depends on both dimensions ratio and digital voltage level (Vdd). Diameter optimization reveals that when Vdd increases, the optimized value of (Dp/Dn) decreases. Channel length optimization results show that when Vdd increases, the optimized value of Ln decreases and that of (Lp/Ln) increases. Dimension ratio optimization reveals that when Vdd increases, the optimized value of Kp/Kn decreases, and silicon nanowire transistor with suitable dimensions (higher Dp and Ln with lower Lp and Dn) can be fabricated. PMID- 23646724 TI - Electrochemical and physical properties of electroplated CuO thin films. AB - Cupric oxide thin films have been prepared on ITO glass substrates from an aqueous electrolytic bath containing CuSO4 and tartaric acid. Growth mechanism has been analyzed using cyclic voltammetry. The role of pH on the structural, morphological, compositional, electrical and optical properties of CuO films is investigated. The structural studies revealed that the deposited films are polycrystalline in nature with a cubic structure. The preferential orientation of CuO thin films is found to be along (111) plane. X-ray line profile analysis has been carried out to determine the microstructural parameters of CuO thin films. The pyramid shaped grains are observed from SEM and AFM images. The optical band gap energy and electrical activation energy is found to be 1.45 and 0.37 eV, respectively. Also, the optical constants of CuO thin films such as refractive index (n), complex dielectric constant (epsilon) extinction coefficient (k) and optical conductivity (sigma) are evaluated. PMID- 23646725 TI - N-TiO2/gamma-Al2O3 granules: preparation, characterization and photocatalytic activity for the degradation of 2,4-dichlorophenol. AB - Nitrogen doping TiO2 and gamma-Al2O3 composite oxide granules (N-TiO2/gamma Al2O3) were prepared by co-precipitation/oil-drop/calcination in gaseous NH3 process using titanium sulphate and aluminum nitrate as raw materials. After calcination at 550 degrees C in NH3 atmosphere, the composite granules showed anatase TiO2 and gamma-Al2O3 phases with the granularity of 0.5-1.0 mm. The anatase crystallite size of composite granules was range from 3.5-25 nm calculated from XRD result. The UV-Vis spectra and N 1s XPS spectra indicated that N atoms were incorporated into the TiO2 crystal lattice. The product granules could be used as a photocatalyst in moving bed reactor, and was demonstrated a higher visible-light photocatalytic activity for 2,4 dichlorophenol degradation compared with commercial P25 TiO2. When the mole ratio of TiO2 to Al2O3 equal to 1.0 showed the highest catalytic activity, the degradation percentage of 2,4-chlorophenol could be up to 92.5%, under 60 W fluorescent light irradiation for 9 hours. The high visible-light photocatalytic activity might be a synergetic effect of nitrogen doping and the form of binary metal oxide of TiO2 and gamma-Al2O3. PMID- 23646726 TI - Superparamagnetic state by linear and non-linear AC magnetic susceptibility in Mn0.5Zn0.5Fe2O4 ferrites nanoparticles. AB - The Mn0.5Zn0.5Fe2O4 nanoparticles has been synthesized using citrate-gel precursor method. The direct mixing of nitrates and acetates yields homogeneous nanoparticles. Phase formation and crystal structure of the synthesized powder were examined through the X-ray diffraction (XRD). Fourier transform infrared (FTIR) spectra of the sample confirm the spinel structure. The average particle size was determined by transmission electron microscopy (TEM) and field emission scanning electron microscopy (FESEM). The average particle size is found to be about 13 nm. Superparamagnetic-like nature of the nanoparticles of Mn0.5Zn0.5Fe2O4 has been revealed through various dc and linear and non-linear ac magnetization measurements. However, the nanoparticles do not behave like ideal non-interacting superparamagnets. The magnetic particle size is found to be about 8 nm with saturation magnetization about 18.1 emu/g. The blocking temperature (T(B)) of the nanoparticle assembly is found to be about 150 K as observed from dc and ac magnetization measurements. The frequency dependence of the blocking temperature (T(B)) is found to follow Vogel-Fulcher law. The associated characteristic time tau0 is found to be 10(-5) s. This value is different from that generally found for non-interacting superparamagnetic (SPM) systems (tau0 = 10(-9)-10(-10) s). PMID- 23646727 TI - Preparation of insulating SiO2 nanostructured thin films by the sol-gel process. AB - Organic dispersion agents can effectively decrease the surface roughness of films. Here, films containing organic dispersion agents are used to produce metal insulator-metal structures. It was found that addition of Triton caused films to become denser, and thicker, and the leak current of devices to decrease by 10 times compared with that without Triton because of its uniform dispersion in the films. The resulting films were used as the insulator layer of thin film transistors containing a semiconductor layer of evaporated pentacene. The interface between the insulator and semiconductor layers was found to affect the arrangement of pentacene, and O2 plasma was used to improve the interface activity to increase the order of the pentacene molecules and enhance the carrier mobility of the devices. PMID- 23646728 TI - Adsorption and desorption characteristics of gradient distributed Bragg reflector porous silicon layers. AB - Adsorption and desorption characteristics of gradient distributed Bragg reflector (DBR) porous silicon (PSi) were investigated under the exposure of organic vapors. Gradient DBR PSi whose average pore size decreased as the lateral distance from the Pt electrode increased was generated by using an asymmetric etching configuration. The reflection resonances were measured as a function of lateral distance from a point closest to the plate Pt electrode to a position on the silicon surface. Two types of gradient DBR PSi (H- and HO-terminated gradient DBR PSi) were used in this study. The detection of volatile organic compounds (VOCs) using the gradient DBR PSi had been achieved. When the vapor of VOCs condensed in the nanopores, the gradient DBR PSi modified with hydrophobic and hydrophilic functionality exhibited different pore adsorption and desorption characteristics. PMID- 23646729 TI - Effects of electron transport material on blue organ light-emitting diode with fluorescent dopant of BCzVBi. AB - High efficiency blue organic light emitting diodes (OLEDs), based on 2-me-thyl 9,10-di(2-naphthyl) anthracene (MADN) doped with 4,4'-bis(9-ethyl-3 carbazovinylene)-1,1'-biphenyl (BCzVBi), were fabricated using two different electron transport layers (ETLs) of tris(8-hydroxyquinolino)-aluminum (Alq3) and 4,7-di-phenyl-1,10-phenanthroline (Bphen). Bphen ETL layers favored the efficient hole-electron recombination in the emissive layer of the BCzVBi-doped blue OLEDs, leading to high luminous efficiency and quantum efficiency of 8.34 cd/A at 100 mA/cm2 and 5.73% at 100 cd/m2, respectively. Maximum luminance of blue OLED with Bphen ETL and Alq3 ETL were 10670 cd/m2, and CIExy coordinates of blue OLEDs were (0.180, 0279) and (0.155, 0.212) at 100 cd/m2. PMID- 23646730 TI - Optical properties of CdSe nanoparticles embedded in polyvinyl alcohol matrix. AB - Polymer capped CdSe nanoparticles have been grown using a simple chemical process. Transmission electron microscopy study revealed the formation of isolated CdSe nanoparticles encapsulated in polyvinyl alcohol matrix. The optical band gap of nanoparticle has been found to be blue shifted from the bulk value due to quantum confinement of carriers. The recombination dynamics of polymer encapsulated nanoparticles has been studied in details using time resolved photoluminescence measurements. Room temperature photoluminescence decay has been used to explain the biexponential decay characteristics originated from the delocalized and localized carriers. The spectral photocurrent measurements of CdSe-polymer composite materials have also been studied. PMID- 23646731 TI - The nanostructure of nitrogen atom linked carbon nanotubes with platinum employed to the electrocatalytic oxygen reduction. AB - Multi-walled carbon nanotube grafted Pt nanoparticles via nitrogen atom (MWCNT-N Pt) has chemically synthesized and characterized as an efficient oxygen reduction reaction (ORR) catalysts. Structural and morphological properties of the electrocatalyst have characterized by transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), and X-ray photoelectron spectroscopy (XPS) techniques. The electrochemical properties have evaluated using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and hydrodynamic voltammetry techniques. The electrochemical properties toward ORR of MWCNT-N-Pt have evaluated in 0.1 mol L(-1) HClO4 aqueous solution. The electrocatalytic reduction of O2 at the MWCNT-N-Pt catalyst establishes a pathway of four-electron transfer reduction into H2O. Hydrodynamic voltammetry reveals that the modified electrode has catalyzed effectively at higher potential. The value of transferred electron number and other kinetic parameters have demonstrated that the MWCNT-N Pt is highly facilitated than that of bulk Pt to electrocatalytic oxygen reduction with comparatively low Pt content (27.04 Wt%) and higher electrochemical surface area (ESA(Pt)) 94.34 m2 gPt(-1). PMID- 23646732 TI - Observation of electrical switching, reverse rectification and hysteresis in nanostructured organic-organic heterojunction. AB - Nanostructured organic-organic (O-O) heterojunction was fabricated by using the thin films of a hole transporting material, copper phthalocyanine (CuPc) and an electron transporting material, copper hexadecafluoro-phthalocyanine (F16CuPc). The nanostructured thin films were characterized by optical absorption spectra, FESEM, AFM, X-ray diffraction, etc. Grain size of CuPc and F16CuPc on the substrate surface was different. XRD analysis shows that the crystallinity of the double layer films/heterojunction decreases as compared to the single layer film. The heterojunction sandwich structure ITO/F16CuPc/CuPc/Al, in the present study has shown a good diode like current-voltage (I-V) characteristics with reverse rectifying characteristics. In addition, electrical switching and hysteresis phenomena have also been observed in both sides of the voltage polarities. Interestingly, the single layer sandwich structure of the type ITO/CuPc/Al and ITO/F16CuPc/Al did not show any noticeable electrical switching and hysteresis in I-V characteristics as compared to double layer heterostructure. The reverse rectification has been explained on the basis of band bending due to the accumulation of charge carriers near the junction and the electrical switching has been explained considering the charge carriers trapping and detrapping at the O-O interface. PMID- 23646733 TI - Fabrication of silica nano/micro-fibers doped with one-dimensional assembly of silver nanoparticles. AB - Nano/micro fibers doped with metal nanocrystals are of great interest both theorectically and practically. Nevertheless, the ordered assembly of metal nanocrystals with desired patterns in nano/micro fibers still remains a big challenge, which constrains the further development of the performance of the material. In this investigation, we propose a facile strategy based on the sol gel and coaxial electrospinning technique to fabricate silica submicron fibers incorporating ordered 1D array of silver nanoparticles. The silver nanoparticles align strictly in a head-to-tail manner in silica fibers, and their size, shape and population are conveniently controlled through tailoring the properties of the precursor solutions and the electrospinning parameters. Therefore, the plasmon property of the obtained fibers is tuned with great freedom. The fabrication method applied here holds great potential for low-cost preparation of metal/glass composite fibers for nano/micro optical applications in general. PMID- 23646734 TI - One-dimensional (1D) ZnO nanowires dye sensitized solar cell. AB - High ordered one-dimensional (1D) Zinc oxide (ZnO) nanowires were grown on FTO substrate by using the hydrothermal method. Nanowires structures were used as the wide band-gap semiconducting photo-electrode in dye sensitized solar cell (DSSCs). Solar cell made from ZnO nanowire at 50 nm radius and several tens micron lengths showed high solar conversion efficiency (eta) of 2.1% and incident photon current efficiency (IPCE) 35% using nanowire/N719 dye/I-/I3- electrolyte. We also compared Ru N719 dye and N3 dye on ZnO nanowire against each other in respect to solar conversion efficiency and IPCE measurements. In the case of the N3 dye on ZnO nanowire conversion efficiency (eta) of 1.32% and IPCE 23% were obtained under an illumination of 100 mW/cm2. It was found that the performance of the Ru N719 dyes was better than about 50% that of the N3 dye in ZnO nanowire dye-sensitized solar cells. PMID- 23646735 TI - Dehydration of glycerol over niobia-supported silicotungstic acid catalysts. AB - Liquid-phase dehydration of glycerol to acrolein over nanosized niobia-supported silicotungstic acid catalysts was performed to investigate the effect of the silicotungstic acid loading on the catalytic performance of the catalysts. The catalysts were prepared by following an impregnation method with different HSiW loadings in the range of 10-50 wt%. The prepared catalysts were characterized by N2 physisorption, XRD, FT-IR, TPD of ammonia, and TGA. Dehydration of glycerol was conducted in an autoclave reactor under the conditions of controlled reaction temperatures under corresponding pressure. Increasing HSiW loading rapidly increased the acidity of HSiW/Nb205 catalyst and rate of glycerol conversion, but acrolein selectivity decreased due to enhanced deactivation of the catalyst by carbon deposit. Consequently, it was confirmed that catalytic activity for the dehydration of glycerol to acrolein was dependant on the acidity of catalyst and can be controlled by HSiW loading. PMID- 23646736 TI - Uniform and well-dispersed YbVO4 hierarchical nanoarchitectures: synthesis and luminescence properties. AB - The YbVO4 micro-doughnuts were successfully fabricated by a facile hydrothermal method. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) spectra, scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), and photoluminescence (PL) were used to characterize the resulting samples. The diameter and thickness of YbVO4 micro-doughnuts are around 750 nm and 480 nm, respectively. It is found that trisodium citrate (Na3Cit) is essential for obtaining YbVO4 microdoughnuts. Moreover, the crystal growth process was thoroughly discussed through a series of time-dependent experiments and a possible formation mechanism was proposed. Furthermore, the up-conversion (UC) luminescent properties as well as the emission mechanisms of YbVO4:Ln3+ (Ln3+ = Er3+, Tm3+ and Ho3+) microcrystals were systematically investigated. PMID- 23646737 TI - Effects of nanofiber on the electrical properties of anisotropic conductive adhesives (ACAs). AB - The effects of nanofiber on the electrical properties of anisotropic conductive films (ACFs) were investigated from the perspectives of the joint and insulation resistances. To obtain stable electrical properties for fine-pitch chip-on-film (COF) packages, two kinds of nanofiber ACFs were demonstrated: (1) polystyrene (PS) and polyacrylonitrile (PAN) nanofiber ACFs, which were formed by laminating ACFs on the top and bottom sides of PS and PAN nanofibers, and (2) PAN nanofiber coupled with conductive particle (PAN/Cp nanofiber) ACF, which was made by laminating non conductive films (NCFs) on both sides of a PAN/Cp nanofiber. The effects of the nanofiber thickness, melting, and structure on the electrical properties of the nanofiber ACFs were analyzed. Among the two different nanofiber ACFs, the PAN/Cp nanofiber ACF showed the most stable joint resistance (below 4 mOmega) and insulation resistance (above 10(8) Omega (between 7 microm bump space) due to the thin insulation layer. PMID- 23646738 TI - Facile synthesis of TiO2 nanocrystals using NH4F as morphology-controlling agent and its influences on photocatalytic activity. AB - Controllable synthesis of nanomaterials with different morphologies can significantly affect their properties. Here we report that the morphology and facet orientation of TiO2 nanocrystals can be readily modulated via a hydrothermal method using a simple morphology-controlling agent of NH4F. The photocatalytic activity of resultant TiO2 has been evaluated by photodegradation of methyl orange. The results indicate that the introduction of NH4F can be used to modulate the mophology and, thereby, the photocatalytic activity of TiO2. The obtained TiO2 with high-energy facet, small size, and large surface area can exhibit an improved photocatalytic efficiency, which may be promising for real application. PMID- 23646739 TI - Design of multi-porous layer for dye-sensitized solar cells by doping with TiO2 nanoparticles. AB - We propose a multi-layer dye-sensitized solar cell (DSSC). Conventional DSSC components use a singular TiO2 particle size and a mono-layer active layer, but we demonstrate a multi-layer and multi-scale TiO2 particle based DSSC. Doping with large TiO2 particles can produce light scattering inside the DSSC component. Light scattering effects reduce TiO2 absorption at wavelengths of 200-300 nm. The unabsorbed light zig-zags between the Pt back electrode layer and the substrate, and enhances the Ru-dye absorption. To enhance the scattering, we doped the active layer with 20 wt% of large diameter TiO2. The multi-layer DSSC increases efficiency by about 15% compared with standard DSSCs. PMID- 23646740 TI - Facile synthesis of ZnO/TiO2 core-shell nanostructures and their photocatalytic activities. AB - We reveal a new strategy for synthesizing ZnO/TiO2 core-shell nanostructures with different TiO2 shell thickness by wet chemical method. This is a facile and rapid process, requires inexpensive precursors with excellent fidelity. The thickness of a typical core-shell nanostructure ranges from 20-50 nm in size with TiO2 shell thickness of 3-6 nm which were confirmed by Transmission electron microscopy (TEM). X-ray diffraction peaks intensity of TiO2 gradually increased while we increase precursor ratio which confirmed the increase of shell thickness. X-ray photoelectron spectroscopy (XPS) results indicated that zinc ions did not enter TiO, lattice and more likely to bonded with oxygen atoms to form TiO2 coupled on the surface of ZnO. However, the PL intensity gradually increased with the increase of the TiO2 shell thickness, indicating charge transfer between the two materials of the ZnO/TiO2 core-shell nanostructures. Further investigation, revealed that the core-shell nanostructures possessed significantly higher solar light photocatalytic activity which was twice than that of original 1-D ZnO nanostructures. The mechanism of the optimal TiO2 shell thickness to reach the maximum photocatalytic activity in the ZnO/TiO2 core-shell nanostructures are proposed and discussed. It is believed that this facile, rapid wet chemical process is scalable and can be applied to synthesize other (oxide/oxide) core-shell nanostructures for various applications. PMID- 23646741 TI - ZnSe/ZnSe:Ag nanoparticles: synthesis, characterizations, optical and raman studies. AB - Nanoparticles (NPs), grown in liquid media, stand out over other classes of inorganic nanomaterials due to the high degree of control with which their crystal structure, size, shape, and surface functionalities can be engineered in the synthesis stage and to the versatility with which they can be processed and implemented into a large spectrum of devices and processes. In present work pure and Ag-doped ZnSe NPs were successfully synthesized from the solution phase chemistry and investigated with respect to their structural and optical properties. The resulting powder consists of nanocrystalline particles were characterized by X-ray diffraction (XRD), UV-Visible spectroscopy, photoluminescence spectroscopy, transmission electron microscopy (TEM), high resolution transmission electron microscopy (HRTEM), energy dispersive X-ray analysis (EDX) techniques and Raman spectroscopy. A UV emission peak was observed from the excitons transition at 380 nm in the room temperature photo luminescent (PL) spectra. The blue emission band was assigned to the Zn interstitial and vacancy level transition. Even though Ag ions known to act as an efficient non radiative loss center for near band gap emission (NBE), a decreased NBE is obtained at room temperature even for a nominal Ag concentration. XRD data analysis shows that the Ag dopant atoms are incorporated into the cubic ZnSe host lattice. PMID- 23646742 TI - Synthesis and optical characterization of silicon nanoparticles. AB - Various reaction conditions, such as quantity of reducing agent and reaction time were investigated with the aim of finding a simple, optimized synthetic route for the synthesis of luminescent silicon nanoparticles (SiNPs). Si NPs were synthesized from the reaction of ethylenediammonium chloride and magnesium silicide via a low temperature solution route. Optical characterizations of silicon nanoparticles were achieved by using ultraviolet-visible (UV-Vis) and photoluminescence (PL) spectroscopy. As the reaction time longer, silicon nanoparticles grew and their emission wavelength shifted to the longer wavelength. The monotonic shift of the photoluminescence as a function of excitation wavelength resulted in the excitation of different sizes of nanocrystals that had different optical transition energies. PMID- 23646743 TI - Controlled synthesis of PbTe nanorods and nanotubes. AB - A hydrothermal route has been developed to synthesize lead telluride (PbTe) nanostructures through the reaction between Pb(CH3COO)2 and Na2TeO3. When the surfactant poly(vinyl pyrrolidone) (PVP) was introduced into the solution, uniform PbTe nanorods with a diameter of about 30 nm could be prepared, while absent of PVP, PbTe nanotubes could be synthesized. Furthermore, some interesting Y-, V-, crisscross-shaped PbTe nanotubes were reported for the first time. The resulting materials were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM) and high-resolution TEM (HRTEM). Two different mechanisms are identified to explain the formation of the nanorods and nanotubes herein. A surfactant-assisted oriental attachment mechanism is explained to describe the formation of PbTe nanorods, whereas, we deduce PbTe nanotubes follow a self-generated template route. PMID- 23646744 TI - Transformation of the deformation mechanism from dislocation-mediated slip to homogeneous slip in silver nanowires. AB - The tensile deformation behavior of silver (Ag) wires with nanometer widths (nanowires (NWs)) was observed by in situ high-resolution transmission electron microscopy combined with subnanonewton force measurements. The Young's modulus, strength, and critical shear stress of the Ag NWs were investigated based on the mechanics of materials at the atomic scale. It was found that when the minimum cross-sectional area of the NWs decreased to less than approximately 3.2 nm2, the critical shear stress increased with a decrease in the area. In addition, when the minimum cross-sectional area decreased to less than approximately 0.5 nm2 before fracture, the critical shear stress reached 0.96 GPa, which exceeded the theoretical shear stress of bulk Ag crystals on {1111} along (110). The present results indicate that the deformation mechanism of Ag NWs transformed from dislocation-mediated slip to homogeneous slip. Therefore, it can be concluded that size reduction to nanometer scale leads to a considerable increase in strength. PMID- 23646745 TI - Effect of nano-silica spheres template on CO2 capture of exchange resin-based nanoporous carbons. AB - In this work, a nanoporous carbon-based adsorbent with a higher specific surface area was directly prepared from polystyrene-based cation exchange resin (PCER) by carbonization of a mixture of nano-silica spheres. The silica/PCER composites were carbonized at 1173 K with different silica/PCER ratios. The effects of nano silica spheres content on the pore structures of nanoporous carbons were investigated by N2 full isotherms. The CO2 capture capacity was measured by CO2 isothermal adsorption at 298 K and 1 bar. From the results, it was found that the nano-silica spheres/PCER ratio had a major influence on the CO2 capture capacity and the textural properties of the prepared nanoporous carbons. The specific surface area and total pore volume, as well as the pore size of the nanoporous carbons increased with increasing silica/PCER ratio. PMID- 23646746 TI - Influence of sintering temperature on the microstructure and thermoelectric properties of polycrystalline Fe1.9925P0.0075O3. AB - The solution combustion process is used to synthesize Fe1.9925P0.0075O3 nano powders. The sintered Fe1.9925P0.0075O3 bodies are alpha-Fe2O3-based single phase with the rhombohedral structure. The electrical conductivity increases with an increase in sintering temperature because of an increase in grain size and density. The absolute value of the Seebeck coefficient escalates with an increase in sintering temperature up to 1000 degrees C, and then decreases with a further rise in its sintering temperature. The Fe1.9925P0.0075O3 sintered at 1000 degrees C shows the highest power factor, i.e., 1.39 x 10(-5) W m(-1) K(-2) at 700 degrees C. PMID- 23646747 TI - Preparation and antibacterial property of waterborne polyurethane/Zn-Al layered double hydroxides/ZnO nanocomposites. AB - In this work, a novel environmental-friendly waterborne polyurethane/ZnAl-layered double hydroxides/ZnO nanoparticles composite (WPU/ZnAl-LDHs/ZnO) was synthesized via in-situ polymerization. ZnAl-LDHs and ZnAl-LDHs/ZnO were synthesized by refluxing in an oil bath. In order to disperse ZnAl-LDHs/ZnO homogeneously into WPU matrix, ZnAl-LDHs/ZnO was firstly functionalized by isophorone diisocyanate. The incorporated content of ZnAl-LDHs/ZnO in the composite has profound effect on such physical properties as mechanical strength, thermal stability and water swelling. It is demonstrated that appropriate amount of ZnAl-LDHs/ZnO with good dispersion in the WPU matrix significantly improves the physical performance of the composites. Finally, the antibacterial activity of the composite was tested against G(-) Escherichia coli and G(+) Staphylococcus aureus. The results indicate that WPU incorporated with ZnAl-LDHs/ZnO shows strong antibacterial activity upon contact. PMID- 23646748 TI - Selective targeting of cellular nucleus using positively-charged quantum dots. AB - Developing highly selective probes for subcellular regions such as nucleus and cytoplamic organelles is of great interest for cellular imaging and high content screening analysis for biology and medicine. Cytoplasmic delivery of QDs has been well-understood, while nuclear delivery of QDs has been a challenge due to the unique structural characteristics of cell nucleus. In this study, we systematically investigated nucleus penetrating properties of small-sized ligand exchanged QDs with either positive or negative surface charges in the similar size range of hydrodynamic diameter (7-10 nm). We found that the positively charged QDs efficiently stain the nucleus in fixed HeLa cells as well as label nucleolar compartments in live HeLa cells. In contrast, the negatively charged QDs with the similar size range stain only the cytoplam in either fixed or live cells. The charge-dependent labeling pattern allowed us to simultaneously perform multiplex imaging of nuclues and cytoplasm. This study offers an insight into efficient nuclear delivery of nanoparticles such as QDs of which surface charge and size are critical for intracelllar localization and delivery. PMID- 23646749 TI - Catalytic oxidation of benzene with ozone over Mn/KIT-6. AB - Benzene is one of the target compounds to be removed from air owing to its carcinogenicity. In this study, benzene oxidation with ozone over a MnOx/KIT-6 catalyst was carried out for the first time. MnOx/KIT-6 was synthesized using two different Mn precursors: Mn acetate and Mn nitrate. The characteristics of the synthesized catalysts were examined by X-ray diffraction, X-ray photoelectron spectroscopy, temperature-programmed reduction, Brunauer-Emmett-Teller (BET) surface area, and N2 adsorption-desorption. The catalytic activity was found to be dependent on the amount of ozone consumed and the dispersion and reducibility of MnOx on the catalyst surface. PMID- 23646750 TI - Growth morphology and optical properties of ZnO nanostructures on different substrates. AB - Growth of ZnO nano and microstructures were carried out by low temperature hydrothermal method on glass and silicon substrates without seed layer. Crystallographic orientation and morphology of the samples were studied by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The transmittance measurements were done by Fourier transformed infrared (FTIR) spectroscopy and a Raman spectrometer was also deployed to understand the vibrational properties of ZnO nanocrystals. XRD and Raman studies showed the formation of hexagonal wurtzite phase of ZnO on both the substrates. Cactus and needle like nanostructures forming rosette superstructure were observed for ZnO on glass substrate. On Si(100), nanorods, tetrapods and multipodes were found with smaller crystallite size. More preferential growth and crystalline nature of ZnO on silicon substrate is discussed on the basis of lattice compatibility between ZnO and Si. The role of interface SiO2 layer, the effective growth mechanism and properties of these nanostructures are also discussed. PMID- 23646751 TI - Enhanced fluorescence, morphological and thermal properties of CdSe/ZnS quantum dots incorporated in silicone resin. AB - Our research focused on the morphological and optical properties of core/shell cadmium selenide/zinc sulfide (CdSe/ZnS) quantum dots incorporated in silicone resin. After dispersing ligand-coated quantum dots into Dow Corning two-component silicone resins (OE6630A and OE6630B at 1:4 mixing ratio by weight), the resins were cured at 150 degrees C for 1.5 hours to produce the quantum dot-silicone resin nanocomposites. The optical, morphological and thermal properties of the quantum dot incorporated in silicone resin were investigated by ultraviolet visible, fluorescence, atomic force microscopy, field emission scanning electron microscopy, differential scanning calorimetry and thermogravimetric analysis. When the quantum dots, originally coated with trioctylamine ligand, were transferred from a chloroform solvent to methyl phenyl silicone oil and silicone resins of high viscosity, the quantum dots showed increased turbidity and lowered fluorescence intensity. Fluorescence enhancement was investigated by using various functional ligands such as poly(1, 1-dimethyl silazane) (multi-silazane), hexamethylenediamine (diamine), cysteamine (amino-thiol), triethylsilane (reactive hydrosilane), hexamethyldisilazane, nonamethyltrisilazane, octamethylcyclotetrasilazane (reactive amines). The results showed that the reactive amines were good additive ligands for enhancing the fluorescence of CdSe/ZnS quantum dots dispersed in the silicone resins, providing 1.2-2.48 Im/W and 4.2-5.56% higher luminous efficiency and photoluminescence conversion efficiency, respectively. We speculate that these reactive amines donate electrons to the surface electron traps, thereby reducing charge recombination. In addition, quantum dots aggregate to form quantum dot clusters with a relatively homogeneously dispersed in the silicone resin matrices, showing good emission properties due to surface passivation and good colloidal stability with the addition of silazane compounds to the resin. Furthermore, the addition of silazane compounds to quantum dots-silicone resin system also shows the improved thermal stability of the as-synthesized nanocomposites. PMID- 23646752 TI - Hydrogen storage behaviors of Ni-doped graphene Oxide/MIL-101 hybrid composites. AB - In this work, Ni-doped graphene oxide/MIL-101 hybrid composites (Ni--GO/MIL) were prepared to investigate their hydrogen storage behaviors. Ni--GO/MIL was synthesized by adding Ni--GO in situ during the synthesis of MIL-101 using a hydrothermal process, which was conducted by conventional convection heating with Cr(III) ion as a metal center and telephthalic acid as organic ligands. The crystalline structures and morphologies were measured by X-ray diffraction (XRD) and scanning electron microscopy (SEM), respectively. The specific surface area and micropore volume were investigated by N2/77 K adsorption isotherms using the Brunauer-Emmett-Teller (BET) method and Dubinin-Radushkevic (D-R) equation, respectively. The hydrogen storage capacity was investigated by BEL-HP at 77 K and 1 bar. The obtained results show that Ni--GO/MIL presents new directions for achieving novel hybrid materials with higher hydrogen storage capacity. PMID- 23646753 TI - ZnO/p-GaN heterostructure for solar cells and the effect of ZnGa2O4 interlayer on their performance. AB - We report the usage of ZnO material as an alternative for n-GaN for realizing III nitride based solar cell. The fabricated solar cell shows large turn-on voltage of around 8 volts and a rapid decrease of photocurrent at low bias voltage under darkness and 1-sun illumination conditions, respectively. This phenomenon can be attributed to the formation of high-resistive ultra-thin layers at the ZnO/ p-GaN junction interface during high temperature deposition. Transmission electron microscopy (TEM) studies carried out on the grown samples reveals that the ultra thin layer consists of ZnGa2O4. It is found that the presence of insulating ZnGa2O4 film is detrimental in the performance of proposed heterostructure for solar cells. PMID- 23646754 TI - Chemically derived graphene sheets top assembled over multi-walled carbon nanotube thin film by Langmuir Blodgett method for improved dual field emission. AB - Graphene and carbon nanotubes are very much known as effective field emitter materials. However field emission applications with hybrid carbon nanostructures have mostly remained elusive so far. Here we report, top assembly of very thin layer of reduced graphene oxide (RGO) by Langmuir Blodgett method over a multi walled carbon nanotubes (MWCNTs) thin film/ITO substrate to investigate the dual field emission property of the hybrid structure. The non-functionalized type of attachment in between the hybrid carbon nanostructures mainly due to van der Waals force of attraction ensured easy fabrication procedure. Evidence of uniform distribution of web like networks of very thin transparent RGO sheets top assembled over densely packed MWCNTs thin film was found from the field emission scanning electron microscopy analysis. The base layer conductivity was enhanced due to the incorporation of MWCNTs bottom layer over ITO and the former also additionally facilitated as emitter site pockets in between RGO planes. Finally, the RGO top assembly resulted in achieving significant improvement in current density and turn-on field in tandem with MWCNTs bottom layer bed making this hybrid system a much feasible candidate for future field emission (FE) based device applications. PMID- 23646755 TI - Solvotermal synthesis of NiO, Ni and NiS nanoparticles. AB - Nanoparticles of NiO, Ni or NiS have been obtained by solvothermal decomposition of different molecular precursors. The influence of several parameters, such as temperature, reaction time, solvent or capping agent used, in the nature and size of the obtained nanoparticle has been studied. The characterization by XRD and TEM techniques indicates that the nanoparticles of NiO exhibit average sizes of 3 8 nm, while those of Ni are in the 30-40 nm range. This difference in size has been attributed to the presence of molecules of the capping agent (n-octylamine or oleic acid) that surround the NiO nanoparticles but were not present in the nickel ones. The capping agent is, thus, preventing the aggregation of the smallest nanoparticles. The use of either a S-donor capping agent (4 mercaptopyridine) or a precursor having S-donor ligands (diethyldithiocarbamate) have led to the formation of NiS with average sizes around 35 nm. The magnetic properties of the nanoparticles have been studied, showing superparamagnetism and magnetic hysteresis below the blocking temperature, which, in time, is dependent of the particle size. PMID- 23646756 TI - Self-assembled hierarchical nanostructures composed of novel chalcopyrite nanosheets for photovoltaic properties. AB - Self-assembled nanostructures of CulnGaSe2 (CIGS) comprising of nanosheets with sheet thickness of 20 nm have been developed via one-step electrochemically alloying technique. These self-assembled nanoplates exhibit highly intersecting behavior and transform from CuSe to CIGS as the reduction potential was varied. The morphological analysis indicated that the process resulted in a progression of crystallites to a series of heavy dense intersecting nanoplates. Further analyses revealed that the nanostructures keep their integrity on heat treatment. The structure confirms the inclusion of Indium and Gallium at higher reduction potentials and its transition from pseudoamorphous to polycrystalline structure. A strong correlation between reduction potential, and the composition was established. The spectroscopic and optical spectra clearly prove that the direct band gap for the as-grown and annealed thin films, and appropriate for solar cell applications. These self-assembled dense interweaved nanoplates structure have not been observed previously in CIGS semiconductor system and have potential implications forenergy applications. PMID- 23646757 TI - Effect of surface stress on stress intensity factors of a nanoscale crack via double cantilever beam model. AB - This paper studies the influence of surface elasticity on crack growth for a nanoscale crack advance. A crack is modeled as a double cantilever beam with consideration of surface stress. Using the Euler-Bernoulli beam theory incorporating with surface effects, a governing equation of static bending is derived and bending solution of a cantilever nanowire is obtained for a concentrated force at the free end. Based on the viewpoint of energy balance, the elastic strain energy is given and energy release rate is determined. The influences of the Surface stress and the surface elasticity on crack growth are discussed. Obtained results indicate that consideration of the surface effects decreases stress intensity factors or energy release rates. The residual surface tension impedes propagation of a nanoscale crack and apparent fracture toughness of nanoscale materials is effectively enhanced. PMID- 23646758 TI - Effects of crystallization and non-lattice oxygen atoms on Cu(x)O-based resistive switching memory. AB - In this work, the effects of crystallization and non-lattice oxygen atoms on the Cu(x)O-based memory device are investigated. The 150 degrees C-deposited Cu(x)O film possesses a larger amount of non-lattice oxygen atoms than those deposited at the higher temperatures, leading to the formation of AIOy interface layer during the sputtering deposition of Al top electrode. Resistive switching occurring within the interface layer is easily controlled, so the set and reset voltages are decreased. In addition, it is demonstrated that the set and reset processes agree with the formation and rupture of a conductive filament in the Cu(x)O film. The 150 degrees C-deposited Cu(x)O-based memory device with good non volatility is possibly used in the next-generation non-volatile memory. PMID- 23646759 TI - Facile synthesis of low-defect-density graphene/MnO2 composite and its electrochemical performance. AB - A facile chemical strategy was developed to anchor MnO2 nanoparticles on the surface of graphene sheet. Compared with literature, this approach requires neither extra pretreatment of acid functionalization of graphite nor any post treatment for the conductivity compensation. Graphene sheet serves as both the nucleation center of the MnO2 nanoparticles and high-efficiency miniature current collectors, endowing an effective rise in electrochemical performance of the overall system. Meanwhile, few layers graphene restrain the aggregation of MnO2 nanoparticles and act as template for the "sandwich structure," which boosts accessible surface areas for the high rates charge and discharge processes. The internal resistance drops of the electrode were small, which is propitious to the high discharge delivery. And the nanocomposite with the unique structure displayed a specific capacitance as high as 340.5 F g(-1). Moreover, the capacitance decrease was only 3.7% after 1000 cycles. PMID- 23646760 TI - Nanoscale silver-assisted wet etching of crystalline silicon for anti-reflection surface textures. AB - We report here an electro-less metal-assisted chemical etching (MacEtch) process as light management surface-texturing technique for single crystalline Si photovoltaics. Random Silver nanostructures were formed on top of the Si surface based on the thin film evaporation and annealing process. Significant reflection reduction was obtained from the fabricated Si sample, with approximately 2% reflection over a wide spectra range (300 to 1050 nm). The work demonstrates the potential of MacEtch process for anti-reflection surface texture fabrication of large area, high efficiency, and low cost thin film solar cell. PMID- 23646761 TI - Spectroscopic studies of In2O3 nanostructures; photovoltaic demonstration of In2O3/p-Si heterojunction. AB - The thermal oxidation process of the indium nitride (InN) nanorods (NRs) was studied. The SEM studies reveal that the cracked and burst mechanism for the formation of indium oxide (In2O3) nanostructures by oxidizing the InN NRs at higher temperatures. XRD results confirm the bcc crystal structure of the as prepared In2O3 nanostructures. Strong and broad photoluminescence spectrum located at the green to red region with maximum intensity at 566 nm along with a weak ultraviolet emission at 338 nm were observed due to oxygen vacancy levels and free excitonic transitions, respectively. The valence band onset energy of 2.1 eV was observed from the XPS valence band spectrum, clearly justifies the alignment of Fermi level to the donor level created due to the presence of oxygen vacancies which were observed in the PL spectrum. The elemental ratio In:O in as prepared In2O3 was found to be 42:58 which is in close agreement with the stoichiometric value of 40:60. A downward shift was observed in the Raman peak positions due to a possible phonon confinement effect in the nanoparticles formed in bursting mechanism. Such single junction devices exhibit promising photovoltaic performance with fill factor and conversion efficiency of 21% and 0.2%, respectively, under concentrated AM1.5 illumination. PMID- 23646762 TI - Nickel titanates hollow shells: nanosphere, nanorod, and their photocatalytic properties. AB - Two kinds of hollow shell structured nickel titanates (nanosphere, nanorod) were prepared by the microwave-assisted hydrothermal method using carbon material as the template. Their phase structure, morphology, and optical properties were well characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and UV-vis diffuse reflectance spectroscopy (DRS). Comparing with the template-free NiTiO3 (NiTiO3-TF), the two kinds of hollow shell structured NiTiO3 have larger Brunauer-Emmet-Teller (BET) surface areas. Both NiTiO3 nanosphere (NiTiO3-NS) and nanorod (NiTiO3-NR) showed remarkably photocatalytic H2 evolution from the methanol aqueous solution under full-arc lamp and visible light. Additional, their photocatalytic activities were also determined by photo-degradation of methyl blue (MB), and the degradation yield reached nearly 100% within 100 min on NiTiO3-NR under visible light. Whatever in photocatalytic H2 evolution or MB degradation, their photocatalytic activities all followed the order: NiTiO3-NR > NiTiO3-NS > NiTiO3-TF. The higher photocatalytic activities of the hollow shelled NiTiO3 should be due to their larger BET surface areas and more utilization of the incident light. PMID- 23646763 TI - Microstructure and texture of a nano-grained complex Al alloy fabricated by accumulative roll-bonding of dissimilar Al alloys. AB - An ultrafine grain (UFG) complex lamella aluminum alloy sheet was successfully fabricated by ARB process using AA1050 and AA6061. The lamella thickness of the alloy became thinner and elongated to the rolling direction with increasing the number of ARB cycles. By TEM observation, it is revealed that the aspect ratio of UFGs formed by ARB became smaller with increasing the number of ARB cycles. In addition, the effect of ARB process on the development of deformation texture at the quarter thickness of ARB-processed sheets was clarified. ARB process leaded to the formation of the rolling texture with shear texture and weak cube orientation. The subdivision of the grains to the rolling direction began to occur after 3 cycles of the ARB, resulting in formation of ultrafine grains with small aspect ratio. After 5 cycles, the ultrafine grained structure with the average grain diameter of 560 nm develops in almost whole regions of the sample. PMID- 23646764 TI - Synthesis and enhanced photocatalytic activity of hierarchical ZnO nanostructures. AB - In this report, hierarchical ZnO nanostructures were successfully synthesized by a simple chemical method at room temperature. The scanning electron microscopy and transmission electron microscope result indicated that this unique structure was assembled by nanoneedles which of the needle tips and roots were about 5 nm and 20 nm, respectively. The photocatalytic activity of the ZnO nanostructures was evaluated by photodegradation reaction of methylene blue (MB). The as prepared hierarchical ZnO nanostructures exhibited a significantly enhanced photocatalytic activity than commercial ZnO and TiO2. This was mainly attributed to the larger specific surface area and stability against aggregation. PMID- 23646765 TI - Study of palladium catalyzation for electroless copper plating on polyimide film. AB - In order to form flexible printed circuits through inkjet printing technique, the Pd(ll) catalyst ink was printed on the surface of polyimide film modified with KOH solution and then reduced with NaBH4 solution to extract the Pd(O) catalyst nuclei. The concentration of the Pd(ll) catalyst ink and reduction time showed a significant influence on the microstructure of the Pd(O) catalyst nuclei and the formation of Cu patterns through electroless plating. When reduction time exceeded 1 minute, and as the concentration of the Pd(II) catalyst ink increased above 0.02 M, the catalyst nuclei began aggregation, resulting in Cu patterns with thick and more defects. PMID- 23646766 TI - Self-organized CdSe quantum dots onto the low bandgap 3-hexylthiophene/pyridine copolymers. AB - The low bandgap 3-hexylthiophene/pyridine copolymers (P3HT/PY) were synthesized and the composites of P3HT/PY and CdSe QDs were prepared. The characterization are performed with 1H NMR, UV-vis, PL, TEM, XPS and cyclic voltammetry (CV). The results show that the P3HT/PY copolymers have an electrochemical bandgap of 1.67 eV, while the composites show a broader absorption and a lower bandgap than the copolymers. The highly efficient fluorescence quenching of the composites indicates that the ultrafast charge transfer happened between the P3HT/PY copolymers and the CdSe QDs. The composites show a uniform dispersion and good compatibility, and the surface chemistry study verified the chemical bonding between them. In addition, both the copolymers and the composites exhibited p- and n-type doping ability, and the P3HT/PY/CdSe composites have a better donor acceptor match, which is a promising p-n type semiconductor material. PMID- 23646767 TI - Facile synthesis of multifunctional beta-NaGdF4:Yb3+/Er3+ nanoparticles in oleylamine. AB - Multifunctional beta-NaGdF4:Yb3+/Er3+ nanoparticles (NPs) were successfully synthesized using oleylamine as both solvent and stabilizer via the thermolysis method. They have uniform morphology with a mean size of 12.7 nm and show efficient up-conversion emission when excited by a 980 nm laser. The up conversion NPs demonstrated a nearly quadratic dependence of the photoluminescence intensity on the excitation power, which indicated a two-photon induced process. In addition, these NPs exhibit paramagnetic characteristics at both 300 and 77 K. The magnetic properties of beta-NaGdF4:Yb3+/Er3+ NPs are intrinsic to the Gd3+ ions. The measured mass magnetic susceptibility value of 0.79 x 10(-4) em mu/g x Oe at room temperature is close to reported values of other NPs for bioseparation and optical-magnetic dual modal nanoprobes in biomedical imaging. PMID- 23646768 TI - Synthesis, structure and gas-sensing properties of Pd-functionalized ZnSnO3 rods. AB - ZnSnO3 one-dimensional (1D) strutures were synthesized by using an evaporation technique. The morphology, crystal structure, and enhanced sensing properties of the ZnSnO3 structures functionalized with Pd to CO gas at 300 degrees C were investigated. The diameters of the 1D structures ranged from a few hundreds to a few thousands of nanometers and that the lengths were up to a few hundreds of micrometers. The gas sensors fabricated from multiple networked ZnSnO3 rods functionalized with Pd showed the enhanced electrical responses to CO gas. The responses of the rods were improved 10.7, 13.7, 13.4, and 12.5 fold at the CO concentrations of 10, 25, 50, and 100 ppm, respectively. In addition, the mechanism for the enhancement in the gas sensing properties of ZnSnO3 rods by Pd functionalization is discussed. PMID- 23646769 TI - Physicochemical characterization of the comb-type pyridine-co-poly(ethylene glycol) copolymer at the interface. AB - The novel amphiphilic comb-type copolymers were synthesized by copolymerization of a unit A that contains a pyridine (Py) portion and a unit B that contains a poly(ethylene glycol) (PEG) portion. The obtained copolymers consist of methoxy endend PEG as a hydrophiphilic segment and Py as a hydrophobic and metal affinity segment (Py-co-PEG). Py-co-PEGs formed micelles and their physicochemical properties were intensively investigated in terms of critical micelle concentration, pyrene solubilization, and micelle size distribution. Furthermore, the gold nanoparticles (Au-NPs) were prepared using the Py-co-PEG polymeric micelles. Py-co-PEG has attained the long term interfacial stability by employing the multi-point adsorption of the Py unit on the gold surface, although usually prepared Au-NPs by thiol derivative are well-known to readily lose the dispersion stability under physiological and oxidative condition. It is important to note that Au-NPs protected by Py-co-PEG were drastically enhanced their dispersion stability under high ionic physiological and air oxidative conditions. PMID- 23646770 TI - Improvement in crystal quality and optical properties of n-type GaN employing nano-scale SiO2 patterned n-type GaN substrate. AB - n-type GaN epitaxial layers were regrown on the patterned n-type GaN substrate (PNS) with different size of silicon dioxide (SiO2) nano dots to improve the crystal quality and optical properties. PNS with SiO2 nano dots promotes epitaxial lateral overgrowth (ELOG) for defect reduction and also acts as a light scattering point. Transmission electron microscopy (TEM) analysis suggested that PNS with SiO2 nano dots have superior crystalline properties. Hall measurements indicated that incrementing values in electron mobility were clear indication of reduction in threading dislocation and it was confirmed by TEM analysis. Photoluminescence (PL) intensity was enhanced by 2.0 times and 3.1 times for 1 step and 2-step PNS, respectively. PMID- 23646771 TI - Characterization and photocatalytic activity of Ag-Cu/TiO2 nanoparticles prepared by sol-gel method. AB - In this study, monometallic and bimetallic silver and copper doped TiO2 nanoparticles were prepared by sol-gel method. Structural and morphological characterizations of prepared nanoparticles were performed by X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX) and N2 physisorption techniques. Co-doped TiO2 nanoparticles displayed pure anatase phase with 20-30 nm particle size and a humdrum distribution. The stability of anatase phase was increased with co-doping of silver and copper to TiO2 lattice. In addition, the co-doped TiO2 nanoparticles had a mesoporous structure with slit-shaped pores. The photocatalytic activity of all samples was evaluated in the photocatalytic removal of C.I. Acid Orange 7. Co-doped TiO2 nanoparticles by Ag and Cu were shown to have highest activity as compared with the Ag/TiO2, Cu/TiO2 and pure TiO2 nanoparticles. The best performance of co-doped TiO2 nanoparticles was observed for a sample calcined under 550 degrees C, containing optimum molar contents of silver (0.08 mol%) and copper (0.01 mol%) dopant ions. PMID- 23646772 TI - Red fluorescent emitting materials based on di-tert-butyl chromene derivatives for organic light-emitting diodes. AB - In this paper are described two di-tert-butyl chromene-containing red fluorescent materials (Red 1 and Red 2). To explore the electroluminescence properties of these materials, multilayered OLEDs using these materials as dopants in a Alq3 host were fabricated. In particular, a device using Red 2 as the dopant material showed maximum luminous efficiencies and power efficiencies of 1.14 cd/A and 0.58 Im/W, respectively. The CIEx,y coordinates of this device were (0.67, 0.32) at 7.0 V. PMID- 23646773 TI - Electrochemical aptamer sensor for thrombin detection based on Au nanoneedle and enzymatic ascorbic acid oxidization. AB - In this article, we describe an aptamer-based sandwich-type electrochemical sensor for the detection of human alpha-thrombin. Au nanoneedles were synthesized in the hole of the naked polycarbonate (PC) template using electrodepositing strategy. The thiolated thrombin aptamer I was immobilized as the capture probe on the gold nanoneedles through Au-S bond. After the thrombin was captured, the biotinylated aptamer II, used as the detection probe, was bound to thrombin. Then, the streptavidin-conjugated alkaline phosphatase (SA-ALP) was linked to the biotinylated aptamer II and catalyze hydrolyzation reaction of ascorbic acid 2 phosphate to produce ascorbic acid. Differential pulse voltammetry was used to detect the oxidizing current of ascorbic acid, which is proportional to the concentration of thrombin bound on the electrode surface ranging from 0.24 nM to 150 nM with a detection limit of 0.1 nM at 3 sigma. This assay is rapid, simple, sensitive and highly specific. It could be applied to detect thrombin in complex real sample. PMID- 23646774 TI - Structural and optical investigation of GaInP quantum dots according to the growth thickness for the 700 nm light emitters. AB - We investigate Ga0.33In0.67P quantum dot structures appropriate for special lighting applications in terms of structural and optical behaviors. The Ga0.33In0.67P materials form from 2-dimentional to 3-dimensional dots as the nominal growth thickness increases from 0.5 nm to 6.0 nm, indicating a Stranski Krastanov growth mode. As the ambient temperature is increased to 300 K, the PL spectrum of the B-type dots is annihilated quickly because the large dot size induces a defect-related nonradiative recombination process. In contrast, the PL spectrum of the A-type dots is well maintained to 300 K. These data indicate that the Ga0.33In0.67P material is appropriate for an active layer of 700 nm light emitters. PMID- 23646775 TI - Optical properties of Ag hemisphere-like nanoparticles. AB - We investigated the optical properties of Ag hemisphere-like nanoparticles. The nanoparticles were prepared by using magnetron sputtering and post-thermal annealing. The scanning-electron microscopy images reveal that hemisphere-like nanoparticles were successfully produced. The transmission spectra exhibit the surface plasmon resonance effect. From the spatial intensity distributions obtained by solving Maxwell equations using the three-dimensional, finite difference time-domain method, we found that there is strong confinement of the optical field near the nanoparticle. This optical confinement makes it easy to exhibit the plasmon resonance effect. PMID- 23646776 TI - Growth of cotton, spherical and polygonal-like morphologies of silver-polymer nanocomposites. AB - Silver nanostructures with different morphologies have been prepared by direct reduction of silver ions in solution using tannic acid as a reducing agent. Ethylene glycol and poly(ethylene glycol) have been used as dispersing, capping and structure directing agent. XRD analyses showed that the deposited powders after reduction are pure polycrystalline Ag. Various morphologies have been observed for the silver nanoparticles as illustrated from SEM images. Cotton-, dendrite- and sphere-like morphologies are examples of various structures that could be obtained upon using various dispersing agents. This work addresses a simple technique to prepare metallic nanoparticles with various morphologies. The obtained morphologies can find applications in many fields such as catalysis, antimicrobial and in microelectronic connections as a conducting paste. PMID- 23646778 TI - Nanofibrous rutile-titania/graphite composite derived from natural cellulose substance. AB - Calcination and carbonization of ultrathin titania gel film pre-coated cellulose nanofibers of ordinary laboratory filter paper at 1300 degrees C under argon atmosphere yielded a hierarchical nanofibrous rutile-titania/carbon composite material. The carbon fibers derived from the initial cellulose nanofibers possess a core-shell structure with amorphous carbon at the inner part and graphite state carbon at the outer part. The initial titania gel films were converted into rutile phase titania nanoparticles with sizes of 20-50 nm anchored on the surface of the carbon fibers. The resulting composite possesses considerable electric conductivity as well as decolorization activity towards dye-bearing wastewater. PMID- 23646777 TI - Thermal and mechanical properties of hydroxyl-terminated polybutadiene-based polyurethane/polyhedral oligomeric silsesquioxane nanocomposites plasticized with DOA. AB - Thermal and mechanical properties of PU/POSS nanocomposites plasticized with DOA were investigated. These hybrid materials were prepared using one-step method through the incorporation of flexible HTPB prepolymer, reactive or non-reactive POSS nanoparticle, and DOA plasticizer under IPDI curative system. The plasticizer added into PU/POSS composites decreased glass transition temperature, mechanical strength and modulus, while the change of thermal stability was modest. Thermal stability of these hybrid composites was found to depend preferably on characteristics of POSS molecules incorporated. PMID- 23646779 TI - Incorporation of Ag metallic nanoparticles in 3D gelatin matrix via the green strategy solution plasma. AB - The environmental concern pays much attention to the recent cause of the global warming effect. The reduction of the chemical uses is one of many ways to avoid this crucial problem. Herein, the green process for silver nanometallic particle formation and incorporation in gelatin are proposed. By using a novel discharge process in solution named solution plasma, the silver nanometallic particle formation and its incorporation in gelatin could be accomplished in one-batch reactor during discharge by using silver nitrate (AgNO3) solution as the precursor and controlling systematical parameters. The three-dimensional scaffolds of gelatin/silver biocomposite were fabricated using lyophilizer and the water-soluble property of gelatin was improved by irradiation of ultraviolet ray. The well dispersed silver nanoparticles with the mean particle size 10-20 nm in the good texture of gelatin matrix were obtained. The density of micropore in gelatin/silver scaffold was proportional to the gelatin concentration. In addition, thermal stability of prepared samples had no change comparing with pure gelatin, indicating that the incorporation of silver nanoparticles in gelatin matrix did not affect to the nature of gelatin. PMID- 23646780 TI - Aqueous phase reforming of glycerol over nanosize Cu-Ni catalysts. AB - In this work, hydrogen production from glycerol by aqueous phase reforming (APR) is studied by using nanosize Ni-Cu catalysts supported on LaAlO3 perovskite in order to investigate the effects of the copper loading amount and the reaction conditions. Nanosize copper-promoted nickel-based catalysts were prepared by the precipitation method. The structure of the nanosize catalysts is characterized by XRD analysis. The surface area, morphology, dispersion and reducibility of the nanosize catalysts is examined by BET, TEM and TPR, respectively. It was found that 15Ni-5Cu/LaAlO3 catalyst showed the highest glycerol conversion and hydrogen selectivity. The highest activity found in the 15Ni-5Cu/LaAlO3 was attributed to it having the proper copper loading amount. It also has the lowest metal crystal size and the highest surface area, which have an effect on the catalytic activity and hydrogen selectivity. The 15Ni-5Cu/LaAlO3 catalyst showed the best performance for hydrogen production at a reaction temperature of 250 degrees C, a reaction pressure of 20 bar and a feed rate of 5 ml/h. PMID- 23646781 TI - Automated manipulation of carbon nanotubes using atomic force microscopy. AB - The manipulation of carbon nanotubes is an important and essential step for carbon-based nanodevice or nanocircuit assembly. However, the conventional push and-image approach of manipulating carbon nanotubes using atomic force microscopy has low efficiency on account of the reduplicated scanning process during manipulation. In this article, an automated manipulation system is designed and tested. This automated manipulation system, which includes an atomic force microscope platform and a self-developed computer program for one-dimensional manipulation, is capable of automatically moving any assigned individual carbon nanotube to a defined target location without any intermediate scanning procedure. To demonstrate the high-efficiency of this automated manipulation system and its potential applications in nanoassembly, two experiments were conducted. The first experiment used this system to manipulate a carbon nanotube to a defined target location. In the second experiment, this system was used to automatically manipulate several carbon nanotubes for generating and translating a defined pattern of nanotubes. PMID- 23646782 TI - Immobilization of proteins onto poly(2-hydroxyethyl methacrylate) functionalized Fe-Au/core-shell nanoparticles via adsorption strategy. AB - Biocompatible magnetic nanocomposites of Fe-AuNPs and poly(2-hydroxylethyl methacrylate) (PHEMA) were employed as a strategic protein immobilization platform. The hybrid magnetic nanocomposites were prepared by applying a 'grafting to' ATRP protocol. Fe-AuNPs having Fe core and Au shell were initially prepared by the inverse micelle method. Disulfide-containing PHEMA (DT-PHEMA) was grafted to the Fe-AuNPs surface by taking the advantages of the thiol chemistry. The grafting of DT-PHEMA to the Fe-AuNPs was confirmed by relevant spectroscopic analyses. The superparamagnetic property, a basic requirement for facile protein immobilization, of the magnetic nanocomposites was measured by the SQUID analysis. Lysozyme, gamma-globulins and bovine serum albumin (BSA) were immobilized onto magnetic nanocomposites via the adsorption strategy. The absorption intensity of lysozyme, gamma-globulins and BSA on the PHEMA grafted Fe AuNPs were observed to be higher than that of bare Fe-AuNPs. PMID- 23646783 TI - Ultrasonic agitation-floating classification of nano-sized Ba-Mg ferrites particles formed by using self-propagating high temperature synthesis and fabrication of nickel-ferrites thin sheet by pulse-electroforming. AB - Nickel-nano-sized ferrites composites sheet for electromagnetic shielding was produced by pulse-electroforming in a modified nickel sulfamate solution. The ferrite particles were prepared by self-propagating high temperature synthesis (SHS) followed by mechanical milling, and classified with an ultrasonic agitation floating unit to obtain about 100 nm in size. Average combustion temperature and combustion propagating rate during SHS reaction were 1190 K and 5.8 mm/sec at the oxygen pressure of 1.0 MPa, respectively. The nickel-ferrite composite sheet had preferred orientation which (100) pole clearly concentrated to normal direction, whereas, (110) and (111) poles tended to split to the longitudinal direction, respectively. Maximum magnetization, residual magnetization and coercive force of the nano-sized ferrites were 27.13 A x m2/kg, 6.4 A x m2/kg and 14.58 kA/m, respectively. Complex permeability of the composites decreased with an increase in frequency, and its real value (mu'r) had the maximum at about 0.3 GHz. The dielectric constants of the composites were epsilon'r = 6.7 and epsilon"r = 0. PMID- 23646784 TI - Well-defined strontium tungstate hierarchical microspheres: synthesis and photoluminescence properties. AB - Uniform and well-dispersed SrWO4 microspheres have been successfully synthesized through a hydrothermal method by using trisodium citrate and SDS as surfactants. XRD and SEM results demonstrate that the as-synthesized SrWO4 particles are high purity well crystallized and exhibit a relatively uniform spherical morphology. The as-obtained SrWO4:Ln3+ (Ln = Tb, Eu, Dy, and Sm) microspheres show intense light emissions with different colors coming from different Ln3+ ions under ultraviolet excitation, which might find potential applications in the fields such as light emitting phosphors, advanced flat panel displays, and light emitting diodes (LEDs). PMID- 23646785 TI - Effect of Mg ion bioactivity on the TiO2 nano-network surface. AB - Magnesium (Mg) ion is well known for improving the Ca-P nucleation and growth. TiO2 nano-network (NT) surface was prepared by alkali-treatment. To introduce the Mg ion to TiO2 NT surface, acrylic acid plasma polymerization was used. Bioactivity of the Mg ions coated samples was evaluated by immersed in simulated body fluid (SBF). Surface morphology and chemical composition of all samples were characterized by SEM, XRD and XPS. Mg ion promotes hydroxyapatite (HA) nucleation and growth on TiO2 NT in SBF and improves crystallinity of HA deposited layer. PMID- 23646786 TI - Oxygen electroreduction on multi-walled carbon nanotube supported metal phthalocyanines and porphyrins in alkaline media. AB - Metal phthalocyanine and porphyrin modified electrodes were prepared using multi walled carbon nanotubes (MWCNTs) as a support material. The catalyst materials were heat-treated before electrochemical testing. X-ray photoelectron spectroscopic study was carried out in order to examine the surface composition. The electroreduction of oxygen has been investigated on Fe phthalocyanine/MWCNT, Co phthalocyanine/MWCNT, Fe porphyrin/MWCNT and Co porphyrin/MWCNT catalysts. Electrochemical experiments were carried out in 0.1 M KOH employing the rotating disk electrode (RDE) method. The glassy carbon (GC) disk electrodes were modified with MN4 macrocycle/MWCNT catalysts using Tokuyama AS-4 ionomer. Electrochemical characterization of the materials showed that all the MN4 macrocycle/MWCNT modified GC electrodes are highly active for the reduction of oxygen in alkaline solutions. Particularly high electrocatalytic activity was observed for porphyrin based electrodes heat-treated at 800 degrees C. The RDE results obtained are significant for the development of alkaline membrane fuel cells. PMID- 23646787 TI - Effect of Al2O3 nano-filler on properties of glass-based seals for solid oxide fuel cells. AB - This study compares the viscosity and strength of three glass-based seals prepared with or without nano or micron-sized alumina powder used as filler material. Measurements of the viscosity and bending strength of the glass-based seals showed that addition of the nano-sized alumina powder to the glass increased both the high-temperature viscosity and the strength of the sintered glass matrix. Strength tests and observations of the microstructure of the fracture surface of the seal samples confirmed the strengthening of the glass network structure. Conversion of non-bridging oxygen to bridging oxygen is presumed to occur upon the addition of alumina to the glass sample. The strengthening of the alumina-glass composite seal was attributed to the alumina nano-filler and prolonged heat treatment at elevated temperatures. PMID- 23646788 TI - Epigallocatechin-3-Gallate (EGCG) inhibits cell proliferation and migratory behaviour of triple negative breast cancer cells. AB - Previous studies indicate that green tea extract may inhibit breast cancer progression by blocking angiogenesis, although the molecular mechanisms are not well defined. Epigallocatechin-3-gallate (EGCG) is the major biologically active component of green tea. In this study we evaluated the cell proliferation and relative gene expression of vascular endothelial growth factor (VEGF) expression on Hs578T human breast cancer cell line at 24, 48 and 72 hours after 10 microM of EGCG treatment. Also, we evaluated the effect of this natural compound on the cell migratory behaviour based on real-time XCELLigence data. Cell proliferation becomes significantly low at 72 hours. EGCG had a dual effect on the VEGF gene expression timeline: after a first increase at 24 hours, it started to decrease at 48 and 72 hours. The inhibition of cell proliferation at 72 hours suggests a possible reactivation of apoptosis. The dual effect on VEGF expression in the presence of EGCG suggests the complexity of the angiogenic switch leading to the modulation of the cell migration processes. It also emphasizes the importance of the metabolite products in the modulation of these effects. Our findings have shown that EGCG suppresses the growth, migration and invasion of human breast cancer cells by inhibiting VEGF expression. A better understanding of this mechanism may lead to an improved strategy for tumor therapy based on the inhibition of angiogenesis. PMID- 23646789 TI - Facile synthesis and characterization of silver nanoparticle/bis(o phenolpropyl)silicone composites using a gold catalyst. AB - The generation of silver nanoparticle/bis(o-phenolpropyl)silicone composites have been facilitated by the addition of sodium tetrachloroaurate or gold(Ill) chloride (< 1 wt% of NaAuCl4 or AuCl3) to the reaction of silver nitrate (AgNO3) with bis(o-phenolpropyl)silicone [BPPS, (o-phenolpropyl)2(SiMe2O)n, n = 2,3,8,236]. TEM and FE-SEM data showed that the silver nanoparticles having the size of < 20 nm are well dispersed throughout the BPPS silicone matrix in the composites. XRD patterns are consistent with those for polycrystalline silver. The size of silver nanoparticles augmented with increasing the relative molar concentration of AgNO3 added with respect to BPPS. The addition of gold complexes (1-3 wt%) did not affect the size distribution of silver nanoparticles appreciably. In the absence of BPPS, the macroscopic precipitation of silver by agglomeration, indicating that BPPS is necessary to stabilize the silver nanoparticles surrounded by coordination. PMID- 23646790 TI - Functionalisation of CdSe semiconductor nanoparticles with polystyrene brushes by radical polimerization. AB - CdSe nanoparticles with polystyrene (PS) brushes are obtained by "grafting through" technique starting from solely aqueously synthesized nanoparticles. Mercaptoethanol (ME) capped nanoparticles are used to achieve double bond functional groups on the surface by condensation reaction with methacryloxypropyltrimethoxysilane (MPS). PS polymerization starts from these double bonds. Spectroscopic, diffraction and thermal techniques are used to characterize the nanoparticles. Infrared spectroscopy shows the formation of robust bonding between CdSe nanoparticles and the organic ligand, as well as the presence of the functional double bond on the surface of nanoparticles. Thermal analysis reveals changes in thermal properties of PS, as thermal stability of PS in the functionalised nanoparticles is improved. UV-vis and fluorescence measurements show that PS-CdSe nanoparticles exhibit good optical properties and transmission electron microscope (TEM) micrographs shows good level of dispersion of CdSe nanoparticles in a PS matrix. PMID- 23646791 TI - Effect of ceria on hydrogen production by auto-thermal reforming of propane over supported nickel catalysts. AB - Autothermal reforming of propane was studied with respect to the addition of ceria to the supported Ni catalysts. Ni/Al2O3 catalysts showed a higher activity than Ni/MgAl catalysts. It was related to the ease of the catalyst reduction. Ni/Ce/MgAl and Ni/Ce/Al2O3 catalysts showed higher propane conversions and higher hydrogen yields. These were related to the particle size and the reducibilities of the catalysts. XRD analysis showed that the added CeO2 decreased the particle sizes of the supported Ni, but increased the amount of NiO on the catalyst surface, thus it improved the resistance to coking. PMID- 23646792 TI - Steam reforming of glycerol for hydrogen production over supported nickel catalysts on alumina. AB - The experiment was carried out to produce hydrogen through steam reforming of glycerol over nano-sized Ni catalysts supported on alumina (Al2O3). The catalysts were characterized by BET surface area, metal dispersion, XRD, TPR, NH3-TPD and SEM. 15 wt% Ni/Al2O3 catalysts presented carbon nano fiber after the catalyst was used. However, when the Ni loading was higher than that of 15 wt%, the catalytic activity reduced, and the increase of the Ni particle size and the formation of graphitic carbon occurred. The Ni/SiO2(70)-Al2O3 with the high surface area and the small Ni particle size promoted the catalytic activity and could easily reduce from NiO to Ni, inhibiting the formation of NiAl2O4. PMID- 23646793 TI - One-pot synthesis of ZnO2/ZnO composite with enhanced photocatalytic performance for organic dye removal. AB - The ZnO2/ZnO photocatalysts with various ZnO2 contents were prepared by one-pot synthesis method using ZnO and H2O2 as raw materials. The photocatalysts were characterized by XRD, UV-vis DRS, SEM, EDS, FT-IR spectra, fluorescence emission spectra, and BET specific area. The photocatalytic performance of the photocatalyst was evaluated by photocatalytic degradation of methyl orange (MO) and rhodamine B (RhB). The results showed that the photocatalytic activity of the ZnO2/ZnO was much higher than that of single-phase ZnO or ZnO2. The optimum ZnO2 content was 1.0 wt.%. The maximal degradation rate constant of MO and RhB was 4.1 times and 2.2 times that observed for pure ZnO, respectively. The stability of the prepared photocatalyst in the photocatalytic process was also investigated. The active species in dye degradation were examined by adding a series of scavengers. The possible mechanisms involved in the photocatalytic degradation of dye were also discussed. PMID- 23646794 TI - Generalized TV and sparse decomposition of the ultrasound image deconvolution model based on fusion technology. AB - Ultrasound image deconvolution involves noise reduction and image feature enhancement, denoising need equivalent the low-pass filtering, image feature enhancement is to strengthen the high-frequency parts, these two requirements are often combined together. It is a contradictory requirement that we must be reasonable balance between these two basic requirements. Image deconvolution method of partial differential equation model is the method based on diffusion theory, and sparse decomposition deconvolution is image representation-based method. The mechanisms of these two methods are not the same, effect of these two methods own characteristics. In contourlet transform domain, we combine the strengths of the two deconvolution method together by image fusion, and introduce the entropy of local orientation energy ratio into fusion decision-making, make a different treatment according to the actual situation on the low-frequency part of the coefficients and the high-frequency part of the coefficient. As deconvolution process is inevitably blurred image edge information, we fusion the edge gray-scale image information to the deconvolution results in order to compensate the missing edge information. Experiments show that our method is better than the effect separate of using deconvolution method, and restore part of the image edge information. PMID- 23646795 TI - Surface modification of electrospun polyvinylidene fluoride nanofiber membrane by plasma treatment for protein detection. AB - Electrospun polyvinylidene fluoride (PVDF) nanofiber membranes have 3-dementional (3-D) open pore channel and hence have excellent application potential in Western blot. In this study we have modified electrospun PVDF nanofiber membrane by argon (Ar) plasma treatment to improve the surface hydrophilic and detection sensitivity. The results showed that the detection sensitivity of the Ar plasma treated PVDF nanofiber membrane increased with increasing plasma treatment time without the need for a methanol pre-wet step. This suggests that the Ar plasma treated PVDF nanofiber membrane can be useful in Western blot with high sensitivity and without methanol pre-wet step. PMID- 23646796 TI - Impact of nano and bulk ZrO2, TiO2 particles on soil nutrient contents and PGPR. AB - Currently, nanometal oxides are used extensively in different industries such as medicine, cosmetics and food. The increased consumption of nanoparticles (NPs) leads the necessity to understand the fate of the nanoparticles in the environment. The present study focused on the ecotoxicological behaviour of bulk and nano ZrO2 (Zirconia) and TiO2 (Titania) particles on PGPR (plant growth promoting rhizobacteria), soil and its nutrient contents. The microbial susceptibility study showed that nano TiO2 had 13 +/- 0.9 mm (B. megaterium), 15 +/- 0.2 mm (P. fluorescens), 16 +/- 0.2 mm (A. vinelandii) and 12 +/- 0.3 mm (B. brevis) zones of inhibition. However, nano and bulk ZrO2 particles were non-toxic to PGPR. In addition, it was found that toxicity varied depends on the medium of reaction. The soil study showed that nano TiO2 was found to be highly toxic, whereas bulk TiO2 was less toxic towards soil bacterial populations at 1000 mg L( 1). In contrast, nano and bulk ZrO2 were found to be inert at 1000 mg L(-1). The observed zeta potential and hydrophobicity of TiO2 particles causes more toxic than ZrO2 in parallel with particle size. However, nano TiO2 decreases the microbial population as well as nutrient level of the soil but not zirconia. Our finding shows that the mechanism of toxicity depends on size, hydrophobic potential and zeta potential of the metal oxide particles. Thus, it is necessary to take safety measures during the disposal and use of such toxic nanoparticles in the soil to prevent their hazardous effects. PMID- 23646797 TI - Optical properties of self-assembled TiO2-SiO2 double-layered photonic crystals. AB - The optical properties of self-assembled TiO2/SiO2 double-layered photonic crystals were examined using SiO2 and TiO2 nanopowders. The SiO2 and TiO2 nanopowders were fabricated using the well-known Stober process, and the double layered structure was self-assembled by an evaporation method. Self-assembled TiO2 thin film was coated at a 1.2 mm thickness by the evaporation process, and 3 atomic layers of the SiO2 layer was coated onto the TiO2 thin film. The relative reflectance peak intensity of the photonic bandgap in the specimen was 13% before thermal treatment. The peak value was increased by sequential heat-treatments and reached the highest value of 21% at 400 degrees C. PMID- 23646798 TI - Electrodeposition of nanocrystalline Ni-W coatings with citric acid system. AB - Ni-W alloy coatings were prepared by electrodeposition technique with citric acid as a complexing agent. The influence of the main technical parameters on W content in the Ni-W alloy coatings were investigated by electron dispersive spectroscopy (EDS), and the microstructure of the coatings was characterized and analyzed by employing X-ray diffractometer (XRD), scanning electron microscope (SEM). The results showed that bright and compact Ni-W alloy coatings with 25.78 wt% W were obtained when the concentration of Na2WO4 x 2H2O was 50 g/L, the concentration of NH4Cl was 20 g/L, the bath pH value was 8.0 and the bath temperature was 70 degrees C. The surface of Ni-W alloy coatings were bright, flat and compact, the mircostructure of the alloy coatings were nanocrystalline and the average grain size was about 38 nm by calculating using Scherrer Equation. PMID- 23646799 TI - A facile route towards the synthesis of polystyrene/zinc oxide nanocomposites. AB - ZnO nanoparticles were covalently wrapped by polystyrene (PS) through surface thiol-lactam initiated radical polymerization using the grafting from approach. The surface of ZnO nanoparticles was initially modified by 3-mercapto propyltrimethoxysilane to afford thiol functionalized ZnO nanoparticles (ZnO-SH). The controlled radical polymerization of styrene (St) was subsequently accomplished by using an initiating system of ZnO-SH and butyrolactam. FT-IR, XPS, XRD, TGA, DSC, TEM and DLS were employed to investigate the chemical structure, morphology, thermal properties, the size and size distribution of nanocomposites. The dispersibility of ZnO nanoparticles was observed to be significantly improved upon functionalization by PS brushes. The controlled nature of the surface initiated thiol-lactam aided polymerization of St from the ZnO nanoparticles surface was confirmed by GPC analysis. PMID- 23646800 TI - Osteoblastic cell response and bone formation of phosphate ion coated on plasma polymerized Ti surface. AB - This study examined the bone formation ability and cell response on a phosphate (PO3(4-)) ion exchanged amine plasma polymerized titanium (Ti) surface. The enhanced bone-like apatite (hydroxyapatite, HAp)-forming ability was attributed to the PO3(4-) ion exchanged amine plasma polymerized Ti (P/NH2/Ti) surface, which was formed by the reduction of PO3(4-) ions. PO3(4-) ions promote HAp nucleation and growth on Ti in SBF, and PO3(4-) ions improve the crystallinity of the HAp deposited layer. The cell viability tests revealed significantly greater cell viability on the P/NH2/Ti surfaces than on the other surfaces. PMID- 23646801 TI - One-pot synthesis and structural characterization of poly(alkoxysilane)s catalyzed by silver-gold complexes. AB - Combinative one-pot Si-Si/Si-O dehydrocoupling of hydrosilanes with alcohols (1:1.5 mole ratio), mediated by a mixture of AgNO3-AuCl3 (100/1 mole ratio) rapidly produced poly(alkoxysilane)s in reasonably high yield. The addition of small amount of gold complex to the reaction mixture effectively accelerated the coupling reaction compared to the reaction rate with AgNO3 alone. The hydrosilanes include p-X-C6H4SiH3 (X = H, CH3, OCH3, F), PhCH2SiH3, and (PhSiH2)2. The alcohols include MeOH, EtOH, iPrOH, PhOH, and CF3(CF2)2CH2OH. The weight average molecular weight and polydispersity of the poly(alkoxysilane)s were in the range of 1,600-8,000 Dalton and 1.4-3.5, respectively. The dehydrocoupling reactions of phenylsilane with ethanol (1:3 mole ratio) in the presence of the Ag-Au complexes gave only triethoxyphenylsilane. PMID- 23646802 TI - Improvement of the oral bioavailability of coenzyme Q10 with lecithin nanocapsules. AB - Coenzyme Q10-loaded lecithin nanocapsules (CoQ10-LNCs), composed of a CoQ10/lecithin/ GTCC/glycerol aqueous solution, were prepared by high-pressure homogenization. The zeta potential of the CoQ10-LNCs above -60 mV was determined on a Malvern Zetasize 2000 (Malvern Instruments, UK). The spherical shape of the CoQ10-LNCs was observed by using freeze-fracture transmission electron microscopy (FF-TEM), and the particle size was found to be below 100 nm. The supercooled state of the CoQ10-LNCs was observed by differential scanning calorimetry (DSC). In an oral bioavailability study, the CoQ10 plasma level after administering CoQ10-LNCs was higher than that after administering a CoQ10 tablet over 24 hours, and the relative bioavailability of CoQ10 was improved to 176.6% in mice. Based on the above results, the LNC delivery system might be a potential vehicle for improving the oral bioavailability of CoQ10. PMID- 23646803 TI - X-ray photoelectron spectroscopy study of SnO2 and SnO2+x thin films. AB - SnO2 thin films were fabricated using low-pressure thermal chemical vapor deposition. The results of X-ray photoelectron spectroscopy revealed that the SiO2 layer with an O1S-binding energy of 531.2 eV was formed before the SnO2 layer with an O1S-binding energy of 530.5 eV was formed. In the beginning, the SnO2 thin film showed Sn3d5-binding energy peaks of 485 eV and 486.5 eV. Subsequently, it grew in the direction of 486.5 eV. The Sn3d5-binding strength of the SnO2+x thin film that was annealed in oxygen atmosphere was weaker than that of the SnO2 thin film. Additionally, the Sn3d5-binding strength decreased linearly as the depth of the thin film increased. The surface O1S-binding strength of the SnO2+x thin film annealed in oxygen atmosphere was stronger than that of the SnO2 thin film; however, this strength became weaker than that that of the SnO2 thin film when the depth of the thin film was 2500A or higher. PMID- 23646804 TI - Hydroconversion of n-dodecane over nanoporous catalysts. AB - Platinum catalysts impregnated on different nanoporous materials, Meso-MFI, Si SBA-15 and AI-SBA-15, were synthesized, and the hydroconversion of n-dodecane over these catalysts was performed. The catalytic characteristics were analyzed by Brunauer-Emmett-Teller surface area, X-ray diffraction, N2-adsorption desorption and temperature programmed desorption of NH3. The effects of operation parameters, such as temperature and pressure, on the catalytic activities were investigated. The catalytic activities were affected considerably by the acidic properties of the catalysts, temperature and pressure. Higher acidity, high temperature and low hydrogen pressure resulted in higher hydroconversion and facilitated hydrocracking. The weak acidity, low temperature and high hydrogen pressure resulted in lower hydroconversion and higher selectivity to i-dodecane. PMID- 23646805 TI - Catalytic pyrolysis of waste mandarin over nanoporous materials. AB - Catalytic pyrolysis of waste mandarin was performed using nanoporous catalysts. AI-MCM-41 and Meso-MFI, which had different acid characteristics, were used. In addition, the characteristics of Pt/Meso-MFI were compared with those of Meso MFI. To analyze the characteristics of the catalyst samples, Brunauer-Emmett Teller surface area, temperature programmed desorption of NH3, and N2 adsorption desorption analyses were performed. In addition, pyrolysis gas chromatography/mass spectrometry was used to facilitate the direct analysis of the pyrolytic products. The products obtained from catalytic pyrolysis contained a greater amount of valuable components than did those obtained from non catalytic pyrolysis, indicating that catalytic pyrolysis improved the quality of the bio-oil. Additionally, valuable products such as furan and aromatic compounds were produced in greater quantities when Meso-MFI was used. When Pt/Meso-MFI was used, the amounts of furan and aromatic compounds produced increased even further. PMID- 23646806 TI - The effects of low-intensity pulsed ultrasound and nanomagnet applications on the expressions of MMP-13 and MAPKs in rabbit knee osteoarthritis. AB - An animal model of Osteoarthritis (OA) was established to observe the influences of low-intensity pulsed ultrasound (LIPUS) and nano magnet application (NMA) on Collagenase 3 (MMP-13) expression and the activation status of mitogen activated protein kinases (MAPKs) in rabbit. 24 experimental rabbits from New Zealand were randomly divided into four groups: LIPUS, NMA, LIPUS + NMA group, and control group. The experimental rabbit OA model was established in the right knee joint of rabbits received ACLT operation. Rabbits in LIPUS group received LIPUS treatment and rabbits in NMA group were given NMA treatment. In LIPUS + NMA group, both treatments were applied on experimental rabbits everyday. However, the rabbits in control group only underwent ACLT operation. Four weeks later all rabbits were killed and changes of histopathology in rabbit articular cartilage were assessed and evaluated using Mankin method (Modified Mankin Scale). The protein expressions of MMP-13 and MAPKs were estimated using Western Blot. The results showed that both LIPUS and NMA treatments could significantly decrease the Mankin scores and suppress the expression level of MMP-13. However, there were some inverse results of MAPKs expression in these two applications and imply their treatment mechanisms of OA were different from each other. PMID- 23646807 TI - Patterned forests of vertically-aligned multiwalled carbon nanotubes using metal salt catalyst solutions. AB - A simple method for producing patterned forests of multiwalled carbon nanotubes (MWCNTs) is described. An aqueous metal salt solution is spin-coated onto a substrate patterned with photoresist by standard methods. The photoresist is removed by acetone washing leaving the acetone-insoluble catalyst pattern on the substrate. Dense forests of vertically aligned (VA) MWCNTs are grown on the patterned catalyst layers by chemical vapour deposition. The procedures have been demonstrated by growing MWCNT forests on two substrates: silicon and conducting graphitic carbon films. The forests adhere strongly to the substrates and when grown directly on carbon film, offer a simple method of preparing MWCNT electrodes. PMID- 23646808 TI - CPHVA awards: reflecting excellence in practice. PMID- 23646809 TI - Poll shows mixed opinions among members. PMID- 23646810 TI - Best beginnings mobile apps: the transition to parenthood. PMID- 23646811 TI - Summary care records: an update. PMID- 23646812 TI - School nurse 121 campaign.ool Camp Nurse. PMID- 23646814 TI - Nurturing values. PMID- 23646813 TI - Could Savile happen again? PMID- 23646815 TI - An intervention aimed at helping parents with their emotional attunement to their child. AB - Comfort Zone for Children is an intervention that practitioners in a range of settings can use in their work with parents, with the aim of enhancing parental emotional attunement to their child. This article describes the development and evaluation of the intervention using preliminary outcomes, focus groups and interviews with staff and parents. The ongoing development of the intervention in the light of the feedback and future development is discussed. PMID- 23646816 TI - Developing health visitor prescribing. AB - Prescribing is an essential element of the health visitor's role. However, in one inner-city locality prescribing in practice was evaluated to be at a low level. A number of barriers to prescribing were identified through a focus group. A project to support health visitors was planned and delivered. The project involved clinical updates and improvement to the registration process, thereby reducing delays for practitioners in getting prescribing pads. The result was that prescribing confidence improved and prescribing activity increased. PMID- 23646817 TI - Are the rights of children and young people to reach their potential severely compromised by school exclusion? AB - A review of the literature revealed that the overarching risk to children and young people around the time of expulsion from school was social exclusion. Factors such as gender, antisocial behaviour, crime, drug taking and suicide were also identified as risks. The effects of the increased use of short-term and in house exclusions, and poor parental control, also emerged within this area. In considering application to practice, the specialist community public health nurse (SCPHN) needs to work as part of a multidisciplinary team offering targeted support to those most vulnerable, together with preventive work via the Personal, Social and Health Education (PSHE) curriculum. PMID- 23646818 TI - The fight is on to 'save our NHS'. PMID- 23646819 TI - Growing up in an online world: the impact of the internet on children and young people. PMID- 23646820 TI - Clinical update: recognising brain tumours early in children. AB - Brain tumour accounts for a quarter of all childhood cancers and is the leading cause of cancer related deaths in children. Initial symptoms can be misleading and is often misinterpreted as being caused by a less serious childhood illness. Available statistics show that it takes almost three times longer for the brain tumour in children to get diagnosed in the United Kingdom in comparison to other developed countries. Head Smart campaign was launched in the UK in 2011 with an aim to decrease the time from the onset of symptoms to diagnosis; initial results have been highly encouraging. Community practitioners play an important role in not only identifying symptoms (by following Head Smart symptom card) and selecting patients for reassurance, review or early referral but also by providing valuable support to the family post diagnosis in the community. PMID- 23646821 TI - The NHS in England: what do staff think? PMID- 23646822 TI - Photon-driven reduction of Zn2+ to Zn metal. AB - Easily oxidized metals are of interest as a means of storing solar energy in the form of fuels. While their efficient metal/air batteries make them attractive solar fuel candidates, the photoreduction of the corresponding metal ions remains difficult. Accordingly, this work describes the photon driven reduction of Zn(2+) by an iridium(III) photosensitizer (PS) and catalyst. [Ir(ppy)2(dtbbpy)](PF6) (ppy = 2-phenylpyridine, dtbbpy = 4,4'-di-tert-butyl-2,2'-bipyridine) was found to be the most robust photocatalyst, and the use of ZnCl2 as the Zn(2+) starting material and acetonitrile as the solvent afforded the highest yield of Zn metal product. Under these conditions, a maximum of 430 catalyst turnover numbers were achieved. Cyclic voltammetry of ZnCl2 in different solvents and of different zinc salts in acetonitrile (MeCN) demonstrated the roles of MeCN and Cl(-) in the photoreduction mechanism. Kinetics measurements revealed a first order dependence of the initial rate on both [Ir(ppy)2(dtbbpy)](PF6) and ZnCl2. A first order decay of the reaction rate was also observed. PMID- 23646823 TI - Enantiomeric separation of free L- and D-amino acids in hydrolyzed protein fertilizers by capillary electrophoresis tandem mass spectrometry. AB - Two capillary electrophoresis-tandem mass spectrometry (CE-MS(2)) methods were optimized in this work using cyclodextrins (CDs) as chiral selectors in order to determine the degree of racemization of the free amino acids contained in different hydrolyzed protein fertilizers used as plant biostimulants. The methodologies developed were characterized by the specificity of MS(2) experiments enabling the identification of all protein amino acids, except for cysteine. The enantiomeric separation of up to 14 amino acids was achieved with resolutions above 1.0 and limits of detection between 0.02 and 0.8 MUM. The methods were applied to the analysis of complex samples such as hydrolyzed protein fertilizers to evaluate the presence of d-amino acids after different kinds of hydrolysis treatments. The results corroborated the absence or almost negligible presence of enantiomeric conversions of the L-amino acids into D-amino acids in the case of fertilizers obtained by enzymatic hydrolysis, as well as the high racemization rate for those obtained through a chemical hydrolysis. PMID- 23646824 TI - Probing the physical determinants of thermal expansion of folded proteins. AB - The magnitude and sign of the volume change upon protein unfolding are strongly dependent on temperature. This temperature dependence reflects differences in the thermal expansivity of the folded and unfolded states. The factors that determine protein molar expansivities and the large differences in thermal expansivity for proteins of similar molar volume are not well understood. Model compound studies have suggested that a major contribution is made by differences in the molar volume of water molecules as they transfer from the protein surface to the bulk upon heating. The expansion of internal solvent-excluded voids upon heating is another possible contributing factor. Here, the contribution from hydration density to the molar thermal expansivity of a protein was examined by comparing bovine pancreatic trypsin inhibitor and variants with alanine substitutions at or near the protein-water interface. Variants of two of these proteins with an additional mutation that unfolded them under native conditions were also examined. A modest decrease in thermal expansivity was observed in both the folded and unfolded states for the alanine variants compared with the parent protein, revealing that large changes can be made to the external polarity of a protein without causing large ensuing changes in thermal expansivity. This modest effect is not surprising, given the small molar volume of the alanine residue. Contributions of the expansion of the internal void volume were probed by measuring the thermal expansion for cavity-containing variants of a highly stable form of staphylococcal nuclease. Significantly larger (2-3-fold) molar expansivities were found for these cavity-containing proteins relative to the reference protein. Taken together, these results suggest that a key determinant of the thermal expansivities of folded proteins lies in the expansion of internal solvent-excluded voids. PMID- 23646825 TI - Nephila clavipes Flagelliform silk-like GGX motifs contribute to extensibility and spacer motifs contribute to strength in synthetic spider silk fibers. AB - Flagelliform spider silk is the most extensible silk fiber produced by orb weaver spiders, though not as strong as the dragline silk of the spider. The motifs found in the core of the Nephila clavipes flagelliform Flag protein are GGX, spacer, and GPGGX. Flag does not contain the polyalanine motif known to provide the strength of dragline silk. To investigate the source of flagelliform fiber strength, four recombinant proteins were produced containing variations of the three core motifs of the Nephila clavipes flagelliform Flag protein that produces this type of fiber. The as-spun fibers were processed in 80% aqueous isopropanol using a standardized process for all four fiber types, which produced improved mechanical properties. Mechanical testing of the recombinant proteins determined that the GGX motif contributes extensibility and the spacer motif contributes strength to the recombinant fibers. Recombinant protein fibers containing the spacer motif were stronger than the proteins constructed without the spacer that contained only the GGX motif or the combination of the GGX and GPGGX motifs. The mechanical and structural X-ray diffraction analysis of the recombinant fibers provide data that suggests a functional role of the spacer motif that produces tensile strength, though the spacer motif is not clearly defined structurally. These results indicate that the spacer is likely a primary contributor of strength, with the GGX motif supplying mobility to the protein network of native N. clavipes flagelliform silk fibers. PMID- 23646827 TI - Mutations in ALDH1A3 cause microphthalmia. AB - Microphthalmia is an important inborn error of eye development that can be associated with multisystem involvement. Anophthalmia is more severe and rarer. Single mutations in an expanding list of genes are known to cause this spectrum of anomaly. In one branch of a multiplex family with microphthalmia and anophthalmia, autozygome analysis excluded all known microphthalmia genes at the time of doing this study. Exome sequencing and autozygome filtration identified a novel homozygous variant in ALDH1A3. Subsequently, we identified another homozygous variant in 2 of the 10 probands with microphthalmia we specifically screened for mutations in ALDH1A3. Interestingly, the other branch of the original family was found to segregate anophthalmia/syndactyly with a novel homozygous SMOC1 variant. Our data support the very recent and independent identification of ALDH1A3 as a disease gene in microphthalmia. Locus heterogeneity should be considered in consanguineous families even for extremely rare phenotypes. PMID- 23646829 TI - Emergence of new poisons: a case of pendimethalin poisoning from rural India. PMID- 23646828 TI - Prolonged tachycardia following analytically confirmed cyclizine ingestion. PMID- 23646830 TI - Theoretical innovations in social and personality psychology and implications for health: introduction to special issue. PMID- 23646826 TI - Efficacy and ligand bias at the MU-opioid receptor. AB - In order to describe drug action at a GPCR, a full understanding of the pharmacological terms affinity, efficacy and potency is necessary. This is true whether comparing the ability of different agonists to produce a measurable response in a cell or tissue, or determining the relative ability of an agonist to activate a single receptor subtype and produce multiple responses. There is a great deal of interest in the MU-opioid receptor (MOP receptor) and the ligands that act at this GPCR not only because of the clinically important analgesic effects produced by MOP agonists but also because of their liability to induce adverse effects such as respiratory depression and dependence. Our understanding of the mechanisms underlying these effects, as well as the ability to develop new, more effective MOP receptor drugs, depends upon the accurate determination of the efficacy with which these ligands induce coupling of MOP receptors to downstream signalling events. In this review, which is written with the minimum of mathematical content, the basic meaning of terms including efficacy, intrinsic activity and intrinsic efficacy is discussed, along with their relevance to the field of MOP receptor pharmacology, and in particular in relation to biased agonism at this important GPCR. PMID- 23646831 TI - Affective science and health: the importance of emotion and emotion regulation. AB - OBJECTIVE: The goal of this article is to provide insight into how recent findings from affective science may be translated into the health arena. METHODS: We first review definitional issues related to the key concepts of emotion and stress. We then review relevant research that informs our understanding of the affect-health relationship. Subsequently, we highlight findings that are the most informative and also ripe for translation into the domains of health and health related behaviors. RESULTS: We identify several domains of affect-relevant processes (e.g., emotion-regulation, stress response) that would benefit from increased elaboration. Three themes may guide how best to broaden our understanding across multiple domains: the need to use a differentiated emotion based approach, the need to consider potential synergistic and oppositional effects of emotion that can occur in parallel, and the need to examine the impact of emotions with respect to regulation and coping at both the intra- and interindividual levels. Building on insights derived from these themes, we suggest a broad integrative framework for use with future investigations. This framework categorizes potential emotion-related effects on health according to whether they influence health directly (e.g., shaping physiological responses) or indirectly (e.g., guiding decision making and behavior). Using this approach will allow researchers to examine systematically the often simultaneous and sometimes opposing influences of emotion on distinct health-relevant cognitive and physiological mechanisms, and to integrate across potentially disparate findings. CONCLUSIONS: We conclude by suggesting opportunities for future work that we see as most fruitful based on the presented framework. PMID- 23646832 TI - Self-regulation of health behavior: social psychological approaches to goal setting and goal striving. AB - OBJECTIVE: The goal of this article is to review and highlight the relevance of social psychological research on self-regulation for health-related theory and practice. METHODS: We first review research on goal setting, or determining which goals to pursue and the criteria to determine whether one has succeeded. We discuss when and why people adopt goals, what properties of goals increase the likelihood of their attainment, and why people abandon goals. We then review research on goal striving, which includes the planning and execution of actions that lead to goal attainment, and the processes that people use to shield their goals from being disrupted by other competing goals, temptations, or distractions. We describe four types of strategies that people use when pursuing goals. RESULTS: We find that self-regulation entails the operation of a number of psychological mechanisms, and that there is no single solution that will help all people in all situations. We recommend a number of strategies that can help people to more effectively set and attain health-related goals. CONCLUSIONS: We conclude that enhancing health behavior requires a nuanced understanding and sensitivity to the varied, dynamic psychological processes involved in self regulation, and that health is a prototypical and central domain in which to examine the relevance of these theoretical models for real behavior. We discuss the implications of this research for theory and practice in health-related domains. PMID- 23646834 TI - Intergroup relations and health disparities: a social psychological perspective. AB - OBJECTIVE: This article considers how the social psychology of intergroup processes helps to explain the presence and persistence of health disparities between members of socially advantaged and disadvantaged groups. METHOD: Social psychological theory and research on intergroup relations, including prejudice, discrimination, stereotyping, stigma, prejudice concerns, social identity threat, and the dynamics of intergroup interactions, is reviewed and applied to understand group disparities in health and health care. Potential directions for future research are considered. RESULTS: Key features of group relations and dynamics, including social categorization, social hierarchy, and the structural positions of groups along dimensions of perceived warmth and competence, influence how members of high status groups perceive, feel about, and behave toward members of low status groups, how members of low status groups construe and cope with their situation, and how members of high and low status groups interact with each other. These intergroup processes, in turn, contribute to health disparities by leading to differential exposure to and experiences of chronic and acute stress, different health behaviors, and different quality of health care experienced by members of advantaged and disadvantaged groups. Within each of these pathways, social psychological theory and research identifies mediating mechanisms, moderating factors, and individual differences that can affect health. CONCLUSIONS: A social psychological perspective illuminates the intergroup, interpersonal, and intrapersonal processes by which structural circumstances which differ between groups for historical, political, and economic reasons can lead to group differences in health. PMID- 23646833 TI - Close relationship processes and health: implications of attachment theory for health and disease. AB - OBJECTIVES: Health psychology has contributed significantly to understanding the link between psychological factors and health and well-being, but it has not often incorporated advances in relationship science into hypothesis generation and study design. We present one example of a theoretical model, following from a major relationship theory (attachment theory) that integrates relationship constructs and processes with biopsychosocial processes and health outcomes. METHOD: We briefly describe attachment theory and present a general framework linking it to dyadic relationship processes (relationship behaviors, mediators, and outcomes) and health processes (physiology, affective states, health behavior, and health outcomes). We discuss the utility of the model for research in several health domains (e.g., self-regulation of health behavior, pain, chronic disease) and its implications for interventions and future research. RESULTS: This framework revealed important gaps in knowledge about relationships and health. Future work in this area will benefit from taking into account individual differences in attachment, adopting a more explicit dyadic approach, examining more integrated models that test for mediating processes, and incorporating a broader range of relationship constructs that have implications for health. CONCLUSIONS: A theoretical framework for studying health that is based in relationship science can accelerate progress by generating new research directions designed to pinpoint the mechanisms through which close relationships promote or undermine health. Furthermore, this knowledge can be applied to develop more effective interventions to help individuals and their relationship partners with health-related challenges. PMID- 23646835 TI - The interactive effect of mortality reminders and tobacco craving on smoking topography. AB - OBJECTIVE: Although fatal consequences of smoking are often highlighted in health communications, the question of how awareness of death affects actual smoking behavior has yet to be addressed. Two experiments informed by the terror management health model were conducted to examine this issue. Previous research suggests that the effects of mortality reminders on health-related decisions are often moderated by relevant individual difference or situational variables. Thus, a moderated effect was hypothesized here, and cigarette cravings were tentatively explored in this regard. METHODS: In both studies, relatively light smokers completed a brief questionnaire about cigarette cravings, were reminded of their mortality or a control topic, and then smoked five puffs from a cigarette while the topography (i.e., volume, duration, and velocity) of their inhalations was recorded. RESULTS: Significant craving * death reminder interactions emerged in both experiments. After reminders of mortality, stronger cravings predicted greater smoking intensity. Further, reminders of mortality increased smoking intensity for those with stronger cravings in both studies, and there was also some indication that mortality reminders decreased smoking intensity for those with weaker cravings. CONCLUSIONS: Although there are limitations in the present research's utilization of light smokers as opposed to heavy smokers, these findings indicate a nuanced effect of mortality reminders on smoking intensity and suggest that careful consideration needs to be given to when and how reminders of death are used in communications about smoking. The discussion also highlights the benefits of social psychologically informed theory for understanding health and smoking behavior. PMID- 23646836 TI - A dual-process model of early substance use: tests in two diverse populations of adolescents. AB - OBJECTIVE: We tested a dual-process model based on behavioral and emotional regulation constructs, which posits that good self-control and poor regulation make independent contributions and have different types of pathways to outcomes. The utility of the model for predicting substance use was tested in two diverse populations of younger adolescents. METHOD: A survey was administered in classrooms to middle-school students in Westchester County, New York (N = 601) and Honolulu, Hawaii (N = 881). The New York sample was 8% African American, 5% Asian American, 47% Caucasian, 31% Hispanic, and 9% other ethnicity. The Hawaii sample was 21% Asian American, 8% Caucasian, 26% Native Hawaiian/Pacific Islander, 34% Filipino, and 10% other ethnicity. Structural equation modeling analyses tested pathways from the four regulation variables through six hypothesized mediators to a criterion construct of substance use (tobacco, alcohol, and marijuana). RESULTS: Results were replicated across samples and were consistent with prediction. Unique contributions were found for good self-control and poor regulation, including both behavioral and emotional aspects. Good self control had an inverse effect on substance use primarily through relations to higher levels of protective factors (e.g., academic competence). Poor regulation independently had a risk-promoting effect on substance use through relations to higher levels of risk factors (e.g., negative life events). CONCLUSIONS: Two field studies showed the dual-process model is robust across different populations. Substance prevention programs should consider approaches for enhancing good self-control as well as procedures for reducing poor regulation and minimizing its impact. Extensions to health behaviors including dietary intake and physical activity are discussed. PMID- 23646837 TI - The effects of racial discrimination on the HIV-risk cognitions and behaviors of Black adolescents and young adults. AB - OBJECTIVE: Two studies examined the impact of racial discrimination on HIV-risk (substance use and risky sex) behaviors (Study 1) and cognitions (Study 2) among African Americans. METHODS: Study 1 examined longer-term effects of cumulative discrimination on HIV-risk behaviors among 833 adolescents. In Study 2, Black young adults were excluded or included in an online game (Cyberball) by White peers. RESULTS: Study 1 revealed that discrimination was associated with greater HIV-risk behaviors contemporaneously, and with an increase in these behaviors over a 3-year period. In Study 2, excluded participants tended to attribute their exclusion to racial discrimination and reported greater risky sex and substance use willingness. In Study 1, the relation between discrimination and risky sex was mediated by substance use behavior. In Study 2, substance use willingness mediated the relation between perceived discrimination and risky sex willingness. CONCLUSIONS: Findings highlight the importance of examining the effects of discrimination on HIV risk among Black youth. The studies also demonstrate the utility of assessing social-psychological processes when examining the effects of discrimination on HIV-risk cognitions and behavior. PMID- 23646838 TI - Correcting injunctive norm misperceptions motivates behavior change: a randomized controlled sun protection intervention. AB - OBJECTIVE: Despite long-standing social psychological research supporting the influence of injunctive norms (i.e., what is commonly approved or disapproved) on behavior, support for this influence on health behaviors is limited. We examined the utility of correcting misperceptions of injunctive norms for improving sun protection and whether changes in attitudes mediated the injunctive norm intention relationship. METHOD: At baseline 263 community residing primarily White women, aged 37 to 77 years, reported their beliefs about sun protection and tanning and their perceptions of "typical women's" approval of sun protection versus tanning. Women underestimated approval of sun protection and overestimated approval of tanning. In a randomized trial, 189 of these women received either information about sun protection or information plus personalized normative feedback (PNF). PNF compared each woman's own perceptions of typical women's approval of tanning and sun protection with actual normative values, both measured at baseline. PNF communicated that most women approve of others who sun protect. RESULTS: PNF led to more positive sun protection injunctive norms, attitudes, and intentions at immediate posttest and more positive intentions and self-reported behavior at 4-week follow-up. Baseline discrepancy between a woman's beliefs and actual normative values related negatively to changes in sun protection in the control condition but positively in the PNF condition. As hypothesized, changes in attitudes partially mediated the influence of PNF on changes in intentions. CONCLUSIONS: The present research demonstrates the utility of correcting injunctive norm misperceptions for promoting healthy behaviors. That attitudes changed in response to PNF and mediated the norm-intention relationship suggests a method for influencing attitudes that may limit reactance. PMID- 23646839 TI - When risk communication backfires: randomized controlled trial on self affirmation and reactance to personalized risk feedback in high-risk individuals. AB - OBJECTIVE: Health promotion often faces the problem that populations with high behavioral risk profiles respond defensively to health promotion messages by negating risk or reactant behavior. Self-affirmation theory proposes that defensive reactions are an attempt of the self-system to maintain integrity. In this article, we examine whether a self-affirmation manipulation can mitigate defensive responses to personalized visual risk feedback in the skin cancer prevention context (ultraviolet [UV] photography), and whether the effects pertain to individuals with high behavioral risk status (high personal relevance of tanning). METHOD: We conducted a full-factorial randomized controlled trial (N = 292; age 11-71) following a 2 * 2 design (UV photo yes/no, self-affirmation yes/no). Follow-up period was 2 weeks. Subsequent tanning behavior, sun avoidance intentions, and risk perception. RESULTS: A multivariate analysis of variance (MANOVA) revealed a three-way interaction between risk feedback, the self affirmation manipulation, and risk status for the three outcome measures. Follow up analyses of variance (ANOVAs) indicated that high-risk individuals receiving only the risk feedback intervention reacted defensively and reported higher exposure. A self-affirmation manipulation mitigates this reactance effect both on the level of cognitions and behavior. CONCLUSION: Self-affirmation has influential implications not only for Social Psychology but also for health prevention measures. The findings support the effectiveness of self-affirmation in reducing reactant and defensive reactions to personalized visual risk feedback. Interactions with health risk status indicate that self-affirmation might increase the effectiveness of health promotion messages in high-risk populations. PMID- 23646840 TI - Automatic risk behavior: direct effects of binge drinker stereotypes on drinking behavior. AB - OBJECTIVE: We investigated whether research on stereotype priming effects can increase understanding of binge drinking among young people. Four studies tested whether evaluations of the binge drinker stereotype have a direct and automatic effect on binge drinking behavior, and whether a self-regulation intervention can overcome stereotype effects on drinking behavior. METHODS: Studies 1a and 1b were prospective surveys conducted over two weeks. Study 2 was a field experiment with a 1-week behavioral follow-up. Study 3 was an exploratory RCT that tested whether implementation intentions can override binge drinker stereotype effects on behavior over one month. Participants were college students (Studies 1a, 1b, and 2; Ns = 226, 72, and 255, respectively) and school-age youth (Study 3, N = 202). RESULTS: Correlational (Studies 1a and 1b) and experimental (Study 2) evidence indicated that favorable binge drinker stereotypes had direct effects on binge drinking among experienced drinkers. These effects were automatic in the sense that participants were neither aware of, nor intended, this influence. Study 3 showed that implementation intentions geared at increasing self-focused attention overcame stereotype effects on binge drinking behavior. CONCLUSION: These findings suggest that stereotype priming research can offer valuable insights into binge drinking behavior. Implications for health behavior theories and behavior change interventions are outlined. PMID- 23646841 TI - Moving from theory to practice and back in social and health psychology. AB - Progressive advancement of interventions in health psychology requires improvements in underlying theory. The theoretical advances described in this special issue offer a number of possibilities for intervention development. These include advances in understanding the role of cognitive biases, priming effects, effective planning, the role of specific affective states, and the influence of attachment style on response to interventions. For these advances to translate into progressive improvements in interventions and realized gains in public health, we propose that the theories should: (a) be explicitly linked to the major theories from which they draw; (b) reflect the context sensitivity and dynamic nature of the intervention target; (c) show convincing evidence of improved effectiveness of interventions they spawn according to rigorous criteria; and (d) address the full translation process, including implementation by health care providers and engagement by the target population. PMID- 23646842 TI - Some methodological considerations in theory-based health behavior research. AB - As this special issue shows, much research in social and personality psychology is directly relevant to health psychology. In this brief commentary, we discuss three topics in research methodology that may be of interest to investigators involved in health-related psychological research. The first topic is statistical analysis of mediated and moderated effects. The second is measurement of latent constructs. The third is the Multiphase Optimization Strategy, a framework for translation of innovations from social and personality psychology into behavioral interventions. PMID- 23646843 TI - Applying theory across settings, behaviors, and populations: translational challenges and opportunities. AB - Basic social psychological theories have much to contribute to our understanding of health problems and health-related behaviors and may provide potential avenues for intervention development. However, for these theories to have broader reach and applicability to the field of health psychology, more work needs to be done in integrating contexts into these theories and addressing more specifically their application across settings, behaviors, and populations. We argue that integration of these theories into a broader multidisciplinary and multilevel ecological framework is needed to enhance their translation into real-world applications. To enhance this translation, we make several recommendations, including breaking down silos between disciplinary perspectives and enhancing bidirectional communication and translation; analyzing boundary conditions of theories; expanding research approaches to move outside the laboratory and maintain a focus on external validity; and conducting efficacy testing of theories with meaningful, relevant endpoints. PMID- 23646844 TI - Three strategies for bridging different levels of analysis and embracing the biopsychosocial model. AB - The five review articles in this special issue describe the progress that has been made forging links between personality and social psychological theories, methods, and results with biological, social, and cultural factors related to physical health. However, many efforts have fallen short of the goals of the biopsychosocial model. The rationale and description of 3 strategies to achieve a fuller integration across different levels of analysis are highlighted: (a) more cross-disciplinary research collaborations and training; (b) systematic efforts to make research and theory more clinically relevant; and (c) striving for more representative samples, settings, and outcomes. PMID- 23646845 TI - Advancing innovations in social/personality psychology and health: opportunities and challenges. AB - Social, personality, and health psychologists have a long tradition of active and productive collaborations that have advanced the development of intervention strategies that promote health and well-being and the specification of the theoretical principles that underlie those strategies. This special issue is designed to continue this tradition of collaboration and to highlight areas of research and investigative strategies that offer opportunities for innovation. This concluding paper examines how investigators construe the interface between theory and practice and, with that lens, considers several themes that have emerged across the papers that comprise this special issue. As evidenced by the papers in this special issue, investigators are well-positioned to leverage advances in understanding of human health and well-being. However, to capitalize on this opportunity, investigators need to commit to cultivating a culture of scientific activity that prioritizes the engagement of theory and practice-the pursuit of both understanding and use. PMID- 23646846 TI - Pd-catalyzed Suzuki-Miyaura cross-coupling reactions between sulfamates and potassium Boc-protected aminomethyltrifluoroborates. AB - Sulfamates were studied as the electrophilic partners in the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction with potassium Boc-protected primary and secondary aminomethyltrifluoroborates. A broad range of substrates was successfully coupled to provide the desired products. Complex molecules containing a new carbon-carbon bond and an aminomethyl moiety could be prepared through this developed method. PMID- 23646847 TI - Prefabrication of a vascularized bone graft with Beta tricalcium phosphate using an in vivo bioreactor. AB - We aimed to introduce an in vivo bioreactor-vascular pedicle threaded through the central portion of a scaffold in which a vascularized bone graft was prefabricated using adenoviral human BMP-2 gene (AdBMP2)-modified bone marrow mesenchymal stem cells (BMSCs), beta tricalcium phosphate (beta-TCP), a vessel bundle, and muscularis membrane(group A). As controls, Adbetagal-BMSCs/beta-TCP granules, vessel bundle, and the muscularis membrane (group B); BMSCs/beta-TCP granules, vessel bundle, and muscularis membrane (group C); and beta-TCP granules, vessel bundle, and muscularis membrane (group D) were prepared. Formation of bone tissue and a vascular network was assessed by microangiography and histological methods 4 weeks after prefabrication. New cartilage and bone tissue in the space between beta-TCP granules (mainly endochondral bone) were confirmed by histology, and a de novo vascular network circulating from the vessel bundle through newly formed bone tissue was observed in group A. Formation of bone or cartilage was not observed in the control groups. We concluded that the in vivo bioreactor is a promising method for prefabrication of vascularized functional bone. PMID- 23646848 TI - Surgical treatment for patients with periodontal disease reduces risk of end stage renal disease: a nationwide population-based retrospective cohort study. AB - BACKGROUND: The association between periodontal disease treatment and end-stage renal disease (ESRD) remains unclear. This study aims to determine whether surgical periodontal treatment reduces ESRD risk. METHODS: From the insurance claims data of patients with periodontal disease who were free of ESRD from 1997 to 2009, 35,496 patients were identified who underwent surgery for subgingival curettage and/or periodontal flap and are considered the treatment cohort. For comparison, 141,824 patients who did not undergo these treatments were considered the no-treatment cohort. Follow-ups were performed until the end of 2009 to estimate the incidence and risk of ESRD in these two cohorts. Cox proportional hazard regression was used to estimate the related hazard ratio (HR) and 95% confidence interval (CI) of ESRD. RESULTS: The incidence of ESRD was lower in the treatment cohort than in the no-treatment cohort (4.66 versus 7.38 per 10,000 person-years), with an adjusted HR of 0.59 (95% CI = 0.46 to 0.75). Sex- and age specific analysis showed that the incidence rate ratio of the treatment cohort to the no-treatment cohort was higher for women than for men and declined with age. The risks of ESRD were consistently lower in the treatment cohort even when compared by comorbidity. CONCLUSIONS: Patients with periodontal disease who undergo procedures for subgingival curettage and/or periodontal flap have a remarkably decreased risk of ESRD. PMID- 23646849 TI - Combining salivary pathogen and serum antibody levels improves their diagnostic ability in detection of periodontitis. AB - BACKGROUND: Initiation and progression of periodontitis correlates with increased quantities of periodontitis-associated bacteria in periodontal biofilms. In the present study, the aim is to measure Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis amounts in saliva and their antibody (immunoglobulin [Ig]A and IgG) levels in serum and evaluate their diagnostic abilities, together or alone, in chronic periodontitis. METHODS: The study population comprised 230 Finnish dentate adults: 84 with generalized chronic periodontitis (GCP), 65 with localized chronic periodontitis (LCP), and 81 controls without periodontitis. General and oral health information was obtained by questionnaires, interviews, and clinical and radiographic examinations. Salivary and serum samples were analyzed by quantitative single copy gene-based real-time polymerase chain reaction and multiserotype enzyme-linked immunosorbent assay, respectively. RESULTS: Pathogen carriers suffered mostly from GCP and seldom from LCP. A. actinomycetemcomitans and P. gingivalis quantities in saliva were strongly associated with corresponding serum IgA and IgG values (P <0.001) and with severity of disease (P <0.001). P. gingivalis exhibited more straightforward associations among salivary bacterial burdens, corresponding antibody formation, and periodontitis severity than A. actinomycetemcomitans. The combination of information on age, sex, smoking, and P. gingivalis results provided an area under the curve of 0.817 (95% confidence interval 0.76 to 0.87, P <0.001) for GCP. CONCLUSION: The combination of saliva P. gingivalis quantity with pathogen specific host response may be used to diagnose periodontitis with high accuracy. PMID- 23646850 TI - Detection of eight periodontal microorganisms and distribution of Porphyromonas gingivalis fimA genotypes in Chinese patients with aggressive periodontitis. AB - BACKGROUND: The microbiologic feature of aggressive periodontitis (AgP) in Chinese patients has not yet been determined. This study aims to investigate the prevalence of eight periodontal microorganisms and the distribution of the Porphyromonas gingivalis fimA genotype in a cohort of Chinese patients with AgP. METHODS: Saliva and pooled subgingival plaque samples were collected from 81 patients with AgP (25 with incisor-first molar type and 56 with generalized type [GAgP]) and 34 periodontally healthy controls. Eight periodontal microorganisms, including Aggregatibacter actinomycetemcomitans, P. gingivalis, Tannerella forsythia, Treponema denticola, Campylobacter rectus, Prevotella intermedia, Prevotella nigrescens, and Fusobacterium nucleatum were detected in these samples by the polymerase chain reaction (PCR). In addition, the distribution of fimA genotypes was assessed in P. gingivalis-positive individuals by PCR. RESULTS: The prevalence of P. gingivalis, T. forsythia, T. denticola, C. rectus, P. intermedia, F. nucleatum, and A. actinomycetemcomitans in patients with AgP was significantly higher than that in healthy controls. The prevalence of A. actinomycetemcomitans in patients with GAgP was relatively low (30.4%) compared with other pathogens. Results of logistic regression analysis showed that younger patients were more likely to harbor A. actinomycetemcomitans (odds ratio = 2.85). Type II was the most prevalent fimA genotype of P. gingivalis in patients with AgP. CONCLUSIONS: P. gingivalis, T. forsythia, T. denticola, C. rectus, P. intermedia, and F. nucleatum were the predominant periodontal pathogens of patients with GAgP in China. Type II of fimA was the most prevalent genotype of P. gingivalis in patients with AgP. The prevalence of A. actinomycetemcomitans in patients with GAgP was relatively low. PMID- 23646851 TI - Assessment of vascular endothelial growth factor and matrix metalloproteinase-9 in the periodontium of rats treated with atorvastatin. AB - BACKGROUND: The aim of this study is to examine, for the first time, the role of systemic and local atorvastatin application on periodontium using histomorphometric and immunohistochemical analysis during and after experimental periodontitis induction with or without the presence of microbial dental biofilm. METHODS: One hundred ten male Wistar rats were used. Silk ligatures were placed around the cervical area of the mandibular first molars; rats in the healthy control group received no ligatures (n = 10). In experimental periodontitis groups (n = 90), systemic and local atorvastatin and saline were administered in three different periods; the control periodontitis group (n = 10) received no treatment. Histomorphometric analysis, which included alveolar bone area, alveolar bone level, and attachment loss, and immunohistochemical analysis, which included immunoreactivity of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9, were performed after the rats were sacrificed at the end of the experimental procedure. RESULTS: There was a greater increase in alveolar bone area and VEGF immunoreactivity, as well as a greater decrease in alveolar bone and attachment loss and MMP-9 immunoreactivity, with systemic and local atorvastatin application during and after induction of experimental periodontitis. Local atorvastatin application showed better results on periodontium with regard to alveolar bone findings. CONCLUSIONS: Systemic and local atorvastatin application showed beneficial effects on periodontium during and after induction of experimental periodontitis. Within the limits of this study, it can be concluded that atorvastatin, which is used for hypercholesterolemia treatment, can also be used as a protective and therapeutic agent for periodontal disease. PMID- 23646852 TI - Comparative analysis of serum proteins in relation to rheumatoid arthritis and chronic periodontitis. AB - BACKGROUND: Rheumatoid arthritis (RA) and chronic periodontitis (CP) are chronic inflammatory conditions and share many pathologic features. The common molecular pathogenesis of the two inflammatory diseases is unclear. The aim of the present study is to evaluate serum protein profiles specific for patients with RA and CP by a comprehensive proteomic analysis. METHODS: The study participants were: 10 patients with RA, 10 patients with CP, 10 patients with RA and CP, and 10 healthy controls. All groups were balanced for age, sex, and smoking status. Serum protein spot volume was examined with two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. Proteins with significant differences in abundance among the four groups were determined with computer image analysis and identified with mass spectrometry and protein databases. RESULTS: A total of 1,694 protein spots were obtained in sera of the four groups. Seven spots were significantly different in abundance among the four groups. Of these, three spots (complement component 3, complement factor H, and ceruloplasmin) were significantly different in the RA+CP group compared with the other three groups (P <0.05). The similar profiles of complement component 3, complement factor H, and ceruloplasmin were observed by enzyme-linked immunosorbent assay. CONCLUSION: These results suggest that patients with RA and CP may exhibit three serum proteins with different abundance compared with healthy controls and patients with RA only or CP only. PMID- 23646853 TI - Metastatic tumors to the gingiva and the presence of teeth as a contributing factor: a literature analysis. AB - BACKGROUND: Gingiva that is prone to inflammation may serve as a pre-metastatic niche for the attraction of circulating malignant cells. The aim of this study is to analyze cases of metastatic lesions to the gingiva compared with cases metastasizing to other oral mucosal sites. The pathogenesis of gingival metastases is discussed, with emphasis on the role of inflammation. METHODS: The English-language literature between 1916 and 2011 was searched for cases of metastatic lesions to the oral mucosa; only cases metastasizing in the oral mucosa, gingiva, and periodontium were included. RESULTS: Two hundred seven cases were included. The gingiva was the most common site (60.4%), followed by tongue and tonsil. The most common primary sites were lung (24.2%), kidney (13.5%), skin (10.6%), and breast (8.7%). In 27%, the oral lesion was the first sign of a malignant disease. In most cases, the lesion appeared as an exophytic mass (96%) diagnosed clinically as a reactive gingival lesion. The presence of teeth was significantly associated with the development of gingival metastases: in 108 of 125 gingival metastases, the lesion was found adjacent to teeth (P <0.001; odds ratio = 8.2). The average life expectancy after diagnosis of the metastasis was 3.7 months. CONCLUSIONS: The gingiva is the most common site for metastases to oral soft tissues, with strong association with the presence of teeth. This finding may be related to the role of inflammation in the attraction of metastatic cells to chronically inflamed gingiva. PMID- 23646854 TI - Characterization of periodontal structures of enamelin-null mice. AB - BACKGROUND: Enamelin-null (ENAM(-/-)) mice have no enamel. When characterizing ENAM(-/-) mice, alveolar bone height reduction was observed, and it was hypothesized that enamel defects combined with diet are associated with the periodontal changes of ENAM(-/-)mice. The aim of the present study is to compare the dimension of interradicular bone of ENAM(-/-) (knock-out [KO]) with wild-type (WT) mice, maintained on hard (HC) or soft (SC) chow. METHODS: A total of 100 animals divided into four groups were studied at 3, 8, and 24 weeks of age: 1) KO/HC; 2) KO/SC; 3) WT/HC; and 4) WT/SC. Microcomputed tomography was performed, and the following measurements were made between mandibular first (M1) and second (M2) molars: relative alveolar bone height (RBH), crestal bone width (CBW), bone volume (BV), bone mineral content (BMC), and bone mineral density (BMD). The position of M1 and M2 in relation to the inferior border of the mandible was also determined at 24 weeks. All variables were analyzed by one-way analysis of variance and Dunnett test for pairwise comparisons. Morphologic analyses were conducted on hematoxylin and eosin-stained sections. RESULTS: Radiographically, the enamel layer was absent in ENAM(-/-) mice. Interproximal open contacts were observed exclusively in ENAM(-/-) mice, and the prevalence decreased over time, suggesting that a shifting of tooth position had occurred. Additionally, in the two ENAM(-/-) groups, RBH was significantly lower at 8 and 24 weeks (P <0.02); CBW, BV, and BMC were significantly less (P <0.05) at 24 weeks. No differences in BMD were found among the four groups. The molars migrated to a more coronal position in ENAM(-/-) mice and mice on HC. Histologic findings were consistent with radiographic observations. After eruption, the junctional epithelium was less organized in ENAM(-/-) mice. CONCLUSION: The interdental bone density was not affected in the absence of enamelin, but its volume was, which is likely a consequence of alternations in tooth position. PMID- 23646856 TI - Efficient metal-free electrocatalysts for oxygen reduction: polyaniline-derived N and O-doped mesoporous carbons. AB - The oxygen reduction reaction (ORR)-one of the two half-reactions in fuel cells is one of the bottlenecks that has prevented fuel cells from finding a wide range of applications today. This is because ORR is inherently a sluggish reaction; it is also because inexpensive and sustainable ORR electrocatalysts that are not only efficient but also are based on earth-abundant elements are hard to come by. Herein we report the synthesis of novel carbon-based materials that can contribute to solving these challenges associated with ORR. Mesoporous oxygen- and nitrogen-doped carbons were synthesized from in situ polymerized mesoporous silica-supported polyaniline (PANI) by carbonization of the latter, followed by etching away the mesoporous silica template from it. The synthetic method also allowed the immobilization of different metals such as Fe and Co easily into the system. While all the resulting materials showed outstanding electrocatalytic activity toward ORR, the metal-free, PANI-derived mesoporous carbon (dubbed PDMC), in particular, exhibited the highest activity, challenging conventional paradigms. This unprecedented activity by the metal-free PDMC toward ORR was attributed to the synergetic activities of nitrogen and oxygen (or hydroxyl) species that were implanted in it by PANI/mesoporous silica during pyrolysis. PMID- 23646855 TI - Increased nucleic Acid receptor expression in chronic periodontitis. AB - BACKGROUND: Nucleic acid sensing has emerged as one of the important components of the immune system triggering inflammation. The aim of this study is to determine the expression of bacterial DNA sensors, including Toll-like receptor 9 (TLR-9), DNA-dependent activator of interferon-regulatory factors (DAI), and absent in melanoma 2 (AIM2) in chronic periodontitis (CP versus healthy) (H) tissues. METHODS: Thirty-five CP and 27 H gingival biopsies were included. Real time quantitative polymerase chain reaction was performed to determine mRNA levels of AIM2, DAI, and TLRs (TLR-1 through TLR-9). The difference in gene expression for each sensor between CP and H tissues was calculated using analysis of covariance. The Spearman test was used to determine correlations among innate receptors. The expression of TLR-9, AIM2, and DAI in gingival tissues was further confirmed using immunohistochemistry. RESULTS: The present results reveal statistically significant upregulation of TLR-9 (P <0.006), DAI (P <0.001), and TLR-8 (P <0.01) in CP tissues compared to H sites. Although mRNA expression was not changed significantly between groups for other receptors, the present results reveal significant correlations between receptors (P <0.05), suggesting that cooperation between multiple components of the host immune system may influence the overall response. Immunohistochemistry further confirmed expression of TLR-9, AIM2, and DAI in gingival tissues. CONCLUSIONS: This study highlights a possible role for nucleic acid receptors in periodontal inflammation. Future investigations will determine whether cytoplasmic receptors and their ligands can be targeted to improve clinical outcomes in periodontitis. PMID- 23646857 TI - A comparison of methods to identify alcohol involvement in youth injury-related emergency department presentation data. AB - INTRODUCTION AND AIMS: The study aims to compare methods for identifying alcohol involvement in injury-related emergency department (ED) presentation in Queensland youth, and explore alcohol terminology used in triage text. DESIGN AND METHODS: ED Information System data were provided for patients aged 12-24 years with an injury-related diagnosis code for a 5-year period 2006-2010 presenting to a Queensland ED (n=348,895). Three approaches were used to estimate alcohol involvement: (i) analysis of coded data; (ii) mining of triage text; and (iii) estimation using an adaptation of alcohol attributable fractions. RESULTS: Around 6.4% of these injury presentations overall had some documentation of alcohol involvement, with higher proportions of alcohol involvement documented for 18 to 24-year-olds, females, indigenous youth, where presentations occurred on a Saturday or Sunday, and where presentations occurred between midnight and 5 am. The most common alcohol terms identified for all subgroups were generic alcohol terms (e.g. ethanol or alcohol), with almost half of the cases where alcohol involvement was documented having a generic alcohol term recorded in the triage text. DISCUSSION AND CONCLUSIONS: ED data are useful sources of information for identification of high-risk sub-groups to target intervention opportunities, though it is not a reliable source of data for incidence or trend estimation in its current unstandardised form. Improving the accuracy and consistency of identification, documenting and coding of alcohol involvement at the point of data capture in the ED is the most desirable long-term approach to produce a more solid evidence base to support policy and practice in this field. PMID- 23646858 TI - Studies of bicalutamide-excipients interaction by combination of molecular docking and molecular dynamics simulation. AB - While the effects of hydrophilic excipients in enhancing the dissolution rate of water-insoluble drugs have been validated, the underlying mechanism remains poorly understood, particularly at a molecular level. In this work, a combination of docking calculations and MD simulations was applied to investigate the molecular interactions between bicalutamide (BIC) and each of three excipients: lactose (LAC), hydroxypropyl methylcellulose (HPMC), and mannitol (MAN). The calculated results indicated that BIC interacted with HPMC and MAN mainly by Lennard-Jones (LJ) interactions but with LAC mainly by Coulomb (Coul) interactions. There was no hydrogen bond formed between BIC and excipient. It was shown that BIC/LAC had the biggest total solvent accessible surface area with the biggest hydrophilic area and formed the most hydrogen bonds between excipient and water. In addition to the structure analyses, BIC/LAC had both the lowest interaction energy between BIC and excipient and the lowest interaction energy between BIC/excipient and water. All these led to the best dissolution performance of BIC/LAC, which could correspond to the experimental results of dissolution test. The present study suggests that a combination of docking calculations and MD simulations, which aims at complementing the experimental work, could provide a molecular insight into the interaction between drug and excipient. It also holds the great potential to simplify the optimization process of drug delivery system and reduce both time and costs. PMID- 23646859 TI - Emerging trends in strigolactone research. PMID- 23646860 TI - Uncommon ectomycorrhizal networks: richness and distribution of Alnus-associating ectomycorrhizal fungal communities. PMID- 23646862 TI - A review of the global literature on dental therapists. AB - OBJECTIVE: Access to adequate oral health care is deficient in many parts of the world. Many countries are now using dental therapists to increase access, particularly for children. To inform the discussion on dental therapists in the workforce, particularly in the United States, the W.K. Kellogg Foundation funded a review of the global literature to identify as many documents as possible related to the practice of dental therapists since the establishment of the School Dental Service in New Zealand in 1921. METHODS: Consultants in each of the countries considered to have a substantive literature on dental therapists were asked to participate in the research; seventeen in total. In addition to identifying and reviewing published articles, a focus of the research was on identifying 'gray' documents. Standard databases were searched for key words associated with dental therapists. In addition, searches were conducted of the governmental and dental association websites of all countries known to have dental therapists in their oral health workforce. RESULTS: Fifty-four countries, both developing and developed, were identified where dental therapists are members of the workforce. Eleven hundred documents were identified from 26 of these countries, with over 2/3 of them cited in the published monograph. Reliable evidence from the related literature and verbal communication confirmed the utilization of dental therapists in an additional 28 countries. Thirty-three of the countries were members of the Commonwealth of Nations, suggesting a mechanism of spread from New Zealand. Variable lengths of training/education existed for dental therapists with the tradition being 2 years postsecondary. In a few countries, the training of therapists and hygienists is now being combined in a three academic year program. Historically, dental therapists have been employed by government agencies caring for children, typically in school-based programs. Initiatives in some countries allow limited care for adults by dental therapists with additional training. CONCLUSIONS: The evidence indicates that dental therapists provide effective, quality, and safe care for children in an economical manner and are generally accepted both by the public and where their use is established, by the dental profession. PMID- 23646863 TI - Practical algorithm for diagnosing patients with recurrent wheals or angioedema. AB - BACKGROUND: Chronic urticaria is a common disorder characterized by recurrent wheals, angioedema, or both. Several differential diagnoses need to be considered in patients presenting with wheals and/or angioedema. These include rare diseases such as autoinflammatory syndromes and urticarial vasculitis in patients with recurrent wheals and bradykinin-mediated angioedema in patients with recurrent swellings. AIM AND RESULT: In order to not miss these conditions, we have developed a symptom-based diagnostic algorithm for the management of patients with wheals and/or angioedema. DISCUSSION AND CONCLUSION: By asking the right questions and performing a limited diagnostic workup as suggested here, this algorithm may help to establish the right diagnosis and treat patients early and more effectively. PMID- 23646864 TI - Air-stable efficient inverted polymer solar cells using solution-processed nanocrystalline ZnO interfacial layer. AB - In this work, efficient bulk heterojunction (BHJ) organic solar cells (OSC) in inverted configuration have been demonstrated. Power conversion efficiency (PCE) of 3.7% is reported for OSC employing silver top electrodes, molybdenum trioxide (MoO3) as the hole-transport interlayer (HTL), active layer comprising of poly-3 hexylthiophene (P3HT) and [6,6]-phenyl C61 butyric acid methyl ester (PCBM) as well as a nanocrystalline solution-synthesized zinc oxide (ZnO) nanoparticle (NP) film as the electron-transport layer (ETL). By using solution-processable ZnO crystalline NPs as ETL, we can eliminate the typical high temperature processing/annealing step, which is widely adopted in the conventional ZnO ETL fabrication process via the sol-gel method. Such highly crystalline ZnO NP films can enhance charge collection at the electrodes. It is also found that inverted OSCs exhibit greater air stability and lifetime performance compared to the OSC employing the normal structure. PMID- 23646865 TI - Theoretical examination of O((1)D) insertion reactions to form methanediol, methoxymethanol, and aminomethanol. AB - A computational study of O((1)D) insertion reactions with methanol (CH3OH), dimethyl ether (CH3OCH3), and methyl amine (CH3NH2) was performed to guide laboratory investigations of the insertion product molecules methanediol (HOCH2OH), methoxymethanol (CH3OCH2OH), and aminomethanol (HOCH2NH2), respectively. The minimum energy and higher energy conformer geometries of the products were determined at the MP2/aug-cc-pVTZ level of theory, and CCSD(T)/aug cc-pVTZ calculations were performed on the reactants, products, and transitions states to examine the insertion reaction energetics. Torsional barriers for internal motion in methanediol, methoxymethanol, and aminomethanol were also determined. It was found that O((1)D) insertion into the C-H bond was the most energetically favored reaction pathway, proceeding through a direct and barrierless insertion mechanism. The pathways of O((1)D) insertion into N-H or O H bonds are also possible, though these reactions are less energetically favored, as they proceed through an association product intermediate before proceeding to the insertion products. Predictions are presented for the pure rotational spectra for the methanediol, methoxymethanol, and aminomethanol products based on the determined molecular parameters. These results provide an excellent starting point to guide laboratory spectral studies of the products. PMID- 23646866 TI - A randomized controlled trial of group cognitive behavioral therapy for Chinese breast cancer patients with major depression. AB - BACKGROUND: This study aims to evaluate the effects of Group Cognitive Behavioral Therapy (GCBT) in treating major depression in Chinese women with breast cancer. METHODS: Sixty-two breast cancer patients diagnosed with major depression were randomly assigned to GCBT group (N = 31) or a waiting list control group provided with an educational booklet (N = 31). The primary outcome measure was the 17-Item Hamilton Depression Rating Scale (17-HAMD). The second outcome measures were Self Rating Anxiety Scale, Functional Assessment of Cancer Therapy - Breast and Self Esteem Scale (SES). Assessments were carried out at completion of the study and six-month afterwards. RESULTS: Patients in the GCBT group had a significant reduction in the 17-HAMD mean score by 9 points (p < 0.001), more than any reduction among patients in the control group from baseline to the end of therapy and a significant 7 points (p < 0.001) more reduction from baseline to six-month follow-up. GCBT also yielded significantly greater improvement than the control group with regard to quality of life (QoL; p < 0.01) and self-esteem (p < 0.05). No significant differences were found between groups on improving anxiety (p > 0.05). CONCLUSION: The results of this trial suggest that GCBT is effective for treating major depression, as well as for improving QoL and self-esteem in breast cancer patients. TRIAL REGISTRATION: Chictr.org ChiCTR-TRC-11001689. PMID- 23646867 TI - Dynamic responses of Bacteroides thetaiotaomicron during growth on glycan mixtures. AB - Bacteroides thetaiotaomicron (Bt) is a human colonic symbiont that degrades many different complex carbohydrates (glycans), the identities and amounts of which are likely to change frequently and abruptly from meal-to-meal. To understand how this organism reacts to dynamic growth conditions, we challenged it with a series of different glycan mixtures and measured responses involved in glycan catabolism. Our results demonstrate that individual Bt cells can simultaneously respond to multiple glycans and that responses to new glycans are extremely rapid. The presence of alternative carbohydrates does not alter response kinetics, but reduces expression of some glycan utilization genes as well as the cell's sensitivity to glycans that are present in lower concentration. Growth in a mixture containing 12 different glycans revealed that Bt preferentially uses some before others. This metabolic hierarchy is not changed by prior exposure to lower priority glycans because re-introducing high priority substrates late in culture re-initiates repression of genes involved in degrading those with lower priority. At least some carbohydrate prioritization effects occur at the level of monosaccharide recognition. Our results provide insight into how a bacterial glycan generalist modifies its responses in dynamic glycan environments and provide essential knowledge to interpret related metabolic behaviour in vivo. PMID- 23646868 TI - Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients. AB - BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease characterized by malignant proliferation of a contingent blastic plasmacytoid dendritic cell. This rare entity is recognized mostly by cutaneous spreading, or not having a leukaemic component. The prognosis is very poor. OBJECTIVES: To study a large cohort of 90 patients with BPDCN, to define additional symptoms to form a correct diagnosis earlier, and to manage such patients accordingly. METHODS: We retrospectively reviewed BPDCN cases registered in the French Study Group on Cutaneous Lymphoma database between November 1995 and January 2012. Ninety patients were studied. Demographic data, clinical presentation, initial staging and outcome were recorded. RESULTS: The group contained 62 male and 28 female patients (sex ratio 2.2). Their ages ranged from 8 to 103 years at the time of diagnosis (mean 67.2 years). Three major different clinical presentations were identified. Sixty-six patients (73%) presented with nodular lesions only, 11 patients (12%) with 'bruise-like' patches and 13 (14%) with disseminated lesions (patches and nodules). Mucosal lesions were seen in five patients (6%). The median survival in patients with BPDCN was 12 months. CONCLUSIONS: We here distinguish three different clinical presentations of BPDCN. A nodular pattern is a more common feature than the originally reported 'bruise like' pattern. Despite the fact that BPDCN may initially appear as a localized skin tumour, aggressive management including allogeneic bone marrow transplantation should be considered immediately, as it is currently the only option associated with long-term survival. PMID- 23646872 TI - Rapid heating of Alaska pollock and chicken breast myofibrillar proteins as affecting gel rheological properties. AB - Surimi seafoods (fish/poikilotherm protein) in the U.S.A. are typically cooked rapidly to 90+ degrees C, while comminuted products made from land animals (meat/homeotherm protein) are purposely cooked much more slowly, and to lower endpoint temperatures (near 70 degrees C). We studied heating rate (0.5, 25, or 90 degrees C/min) and endpoint temperature (45 to 90 degrees C) effects on rheological properties (fracture, small strain) of washed myofibril gels derived from fish (Alaska pollock) compared with chicken breast at a common pH (6.75). This was contrasted with published data on gelation kinetics of chicken myosin over the same temperature range. Heating rate had no effect on fracture properties of fish gels but slow heating did yield somewhat stronger, but not more deformable, chicken gels. Maximum gel strength by rapid heating could be achieved within 5 min holding after less than 1 min heating time. Dynamic testing by small strain revealed poor correspondence of the present data to that published for gelling response of chicken breast myosin in the same temperature range. The common practice of reporting small-strain rheological parameters measured at the endpoint temperature was also shown to be misleading, since upon cooling, there was much less difference in rigidity between rapidly and slowly heated gels for either species. PMID- 23646873 TI - Development and validation of the 21-item children's vision for living scale (CVLS) by Rasch analysis. AB - BACKGROUND: The aim was to develop and validate an instrument called the 'Children's Vision for Living Scale' (CVLS) for the assessment of vision-related quality of life in Saudi Arabian children with and without amblyopia. METHODS: A 43-item child self-report questionnaire was initially developed based on interviews with children with amblyopia, their parents and eye-care professionals, and a literature review. Following a process that involved the removal of redundant items, 28 items remained and were piloted on children aged five to 12 years with and without amblyopia (n = 48 amblyopic, n = 53 non amblyopic) living in Saudi Arabia. Rasch analysis was applied to determine whether the 28-item questionnaire fitted the Rasch model. Rasch analysis was used to assess the validity and reliability of the questionnaire. Principal components analysis (PCA) was used to check dimensionality. A 21-item questionnaire resulting from this process was administered in children with (n = 81) and without (n = 82) amblyopia in Saudi Arabia for further validation. RESULTS: The final 21-item questionnaire had good validity and reliability as demonstrated by person separation of 2.02, person reliability of 0.80 (mean square and standard deviation: infit = 1.01 +/- 0.39; outfit = 1.01 +/- 0.40) and item reliability of 0.93 (item infit range = 1.33 to 0.78; item outfit range = 0.78 to 1.30). The mean difference between person and item scores of 0.33 +/- 0.53 logits (scale range, 2 to -2) indicates that the items are well targeted to the populations. The PCA (dimensionality measures) shows the percentage of variance explained by measures equal to 26.4 per cent (modelled 26.9 per cent) and an eigenvalue of the first contrast of 2.5, which demonstrated good stability. CONCLUSION: The 21-item CVLS is a valid uni-dimensional child self-report instrument for the assessment of the impact of amblyopia on vision-related quality of life in children with and without amblyopia living in Saudi Arabia. PMID- 23646874 TI - Ramoplanin imaging conjugates--synthesis and evaluation. AB - In a previous study we found that fluorescence-marked vancomycin--a glycopeptide antibiotic--is taken up into human tumor cells. To expand on these investigations we now used the lipoglycodepsipeptide antibiotic ramoplanin. Compared to vancomycin it is not only a bigger molecule, but it also has two potential binding sites for coupling to the imaging agents. Three different ramoplanin imaging conjugates were synthesized, two used for fluorescence imaging and one for magnetic resonance imaging. The two fluorescent dyes used in confocal laser scanning microscopy (CLSM) and fluorescence activated cell sorting (FACS) were fluorescein isothiocyanate (FITC) and rhodamine isothiocyanate (RITC). The third was the magnetic resonance imaging (MRI) contrast agent gadolinium-1, 4, 7, 10 tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (GdDOTA). The uptake of ramoplanin conjugates, their specificity for different cell lines and the accessibility of the conjugates by imaging methods were evaluated on 8 human cell lines (two benign, six malignant) by CLSM, FACS and MRI experiments. Cytotoxicity of the ramoplanin conjugates was determined in the FACS experiments with the propidium iodide and Annexin-V-Fluos indicating any disruption in the cell membranes. Cytoplasmic uptake of the ramoplanin conjugates was observed in confocal laser scanning images and was measured using FACS and MRI experiments. Compared to the vancomycin conjugates the ramoplanin conjugates showed much weaker and slower uptake. Additionally, uptake of the ramoplanin conjugates led to strong membrane disruption and cell death. PMID- 23646876 TI - Magic angle spinning NMR structure determination of proteins from pseudocontact shifts. AB - Magic angle spinning solid-state NMR is a unique technique to study atomic resolution structure of biomacromolecules which resist crystallization or are too large to study by solution NMR techniques. However, difficulties in obtaining sufficient number of long-range distance restraints using dipolar coupling based spectra hamper the process of structure determination of proteins in solid-state NMR. In this study it is shown that high-resolution structure of proteins in solid phase can be determined without the use of traditional dipolar-dipolar coupling based distance restraints by combining the measurements of pseudocontact shifts (PCSs) with Rosetta calculations. The PCSs were generated by chelating exogenous paramagnetic metal ions to a tag 4-mercaptomethyl-dipicolinic acid, which is covalently attached to different residue sites in a 56-residue immunoglobulin-binding domain of protein G (GB1). The long-range structural restraints with metal-nucleus distance of up to ~20 A are quantitatively extracted from experimentally observed PCSs, and these are in good agreement with the distances back-calculated using an X-ray structure model. Moreover, we demonstrate that using several paramagnetic ions with varied paramagnetic susceptibilities as well as the introduction of paramagnetic labels at different sites can dramatically increase the number of long-range restraints and cover different regions of the protein. The structure generated from solid-state NMR PCSs restraints combined with Rosetta calculations has 0.7 A root-mean-square deviation relative to X-ray structure. PMID- 23646877 TI - Synthesis of uniform CdS nanospheres/graphene hybrid nanocomposites and their application as visible light photocatalyst for selective reduction of nitro organics in water. AB - We report the self-assembly of uniform CdS nanospheres/graphene (CdS NSPs/GR) hybrid nanocomposites via electrostatic interaction of positively charged CdS nanospheres (CdS NSPs) with negatively charged graphene oxide (GO), followed by GO reduction via a hydrothermal treatment. During this facile two-step wet chemistry process, reduced graphene oxide (RGO, also called GR) and the intimate interfacial contact between CdS NSPs and the GR sheets are achieved. Importantly, the CdS NSPs/GR nanocomposites exhibit a much higher photocatalytic performance than bare CdS NSPs toward selective reduction of nitro organics to corresponding amino organics under visible light irradiation. The superior photocatalytic performance of the CdS NSPs/GR nanocomposites can be attributed to the intimate interfacial contact between CdS NSPs and the GR sheets, which would maximize the excellent electron conductivity and mobility of GR that in turn markedly contributes to improving the fate and transfer of photogenerated charge carriers from CdS NSPs under visible light irradiation. Moreover, the photocorrosion of CdS and the photodegradation of GR can be efficiently inhibited. The excellent reusability of the CdS NSPs/GR nanocomposites can be attributed to the synergetic effect of the introduction of GR into the matrix of CdS NSPs and the addition of ammonium formate as quencher for photogenerated holes. It is hoped that our current work could promote us to efficiently harness such a simple and efficient self-assembly strategy to synthesize GR-based semiconductor composites with controlled morphology and, more significantly, widen the application of CdS/GR nanocomposite photocatalysts and offer new inroads into exploration and utilization of GR-based semiconductor nanocomposites as visible light photocatalysts for selective organic transformations. PMID- 23646875 TI - Differential coordination demands in Fe versus Mn water-soluble cationic metalloporphyrins translate into remarkably different aqueous redox chemistry and biology. AB - The different biological behavior of cationic Fe and Mn pyridylporphyrins in Escherichia coli and mouse studies prompted us to revisit and compare their chemistry. For that purpose, the series of ortho and meta isomers of Fe(III) meso tetrakis-N-alkylpyridylporphyrins, alkyl being methyl to n-octyl, were synthesized and characterized by elemental analysis, UV/vis spectroscopy, mass spectrometry, lipophilicity, protonation equilibria of axial waters, metal centered reduction potential, E(1/2) for M(III)P/M(II)P redox couple (M = Fe, Mn, P = porphyrin), kcat for the catalysis of O2(*-) dismutation, stability toward peroxide-driven porphyrin oxidative degradation (produced in the catalysis of ascorbate oxidation by MP), ability to affect growth of SOD-deficient E. coli, and toxicity to mice. Electron-deficiency of the metal site is modulated by the porphyrin ligand, which renders Fe(III) porphyrins >=5 orders of magnitude more acidic than the analogous Mn(III) porphyrins, as revealed by the pKa1 of axially coordinated waters. The 5 log units difference in the acidity between the Mn and Fe sites in porphyrin translates into the predominance of tetracationic (OH)(H2O)FeP complexes relative to pentacationic (H2O)2MnP species at pH ~7.8. This is additionally evidenced in large differences in the E(1/2) values of M(III)P/M(II)P redox couples. The presence of hydroxo ligand labilizes trans axial water which results in higher reactivity of Fe relative to Mn center. The differences in the catalysis of O2(*-) dismutation (log kcat) between Fe and Mn porphyrins is modest, 2.5-5-fold, due to predominantly outer-sphere, with partial inner-sphere character of two reaction steps. However, the rate constant for the inner-sphere H2O2-based porphyrin oxidative degradation is 18-fold larger for (OH)(H2O)FeP than for (H2O)2MnP. The in vivo consequences of the differences between the Fe and Mn porphyrins were best demonstrated in SOD-deficient E. coli growth. On the basis of fairly similar log kcat(O2(*-)) values, a very similar effect on the growth of SOD-deficient E. coli was anticipated by both metalloporphyrins. Yet, while (H2O)2MnTE-2-PyP(5+) was fully efficacious at >=20 MUM, the Fe analogue (OH)(H2O)FeTE-2-PyP(4+) supported SOD-deficient E. coli growth at as much as 200-fold lower doses in the range of 0.1-1 MUM. Moreover the pattern of SOD-deficient E. coli growth was different with Mn and Fe porphyrins. Such results suggested a different mode of action of these metalloporphyrins. Further exploration demonstrated that (1) 0.1 MUM (OH)(H2O)FeTE-2-PyP(4+) provided similar growth stimulation as the 0.1 MUM Fe salt, while the 20 MUM Mn salt provides no protection to E. coli; and (2) 1 MUM Fe porphyrin is fully degraded by 12 h in E. coli cytosol and growth medium, while Mn porphyrin is not. Stimulation of the aerobic growth of SOD-deficient E. coli by the Fe porphyrin is therefore due to iron acquisition. Our data suggest that in vivo, redox-driven degradation of Fe porphyrins resulting in Fe release plays a major role in their biological action. Possibly, iron reconstitutes enzymes bearing [4Fe-4S] clusters as active sites. Under the same experimental conditions, (OH)(H2O)FePs do not cause mouse arterial hypotension, whereas (H2O)2MnPs do, which greatly limits the application of Mn porphyrins in vivo. PMID- 23646878 TI - Time-resolved fluorescence studies of fullerene derivatives. AB - Fullerene (nano-C60) and its water-soluble derivatives have several clinical applications including use as a drug carrier to bypass the blood-ocular and blood brain barriers. However, in vitro and in vivo detection of these nanomaterials is limited by their very low fluorescence quantum yield. The accumulation of fullerene and its derivatives in cells is particularly difficult to measure using standard fluorescence microscopy because their fluorescence is barely detectable in aqueous media. We have developed a time-correlated single-photon counting apparatus with which we were not only able to detect the fluorescence of fullerene and its derivatives in water but could also measure fluorescence temporal decays and determine lifetimes in the range of tens of picoseconds. The compounds studied in this report are C60 (fullerene), the partially hydrogenated hydride C60H36, a monomeric cyclodextrin complexed fullerene [(gamma-CyD)2/C60], and C60(OH)24 (fullerol). In addition, we examined the effect of aggregation on photophysical properties and identified a very short lifetime component belonging to the fluorescence decay of monomeric fullerene, which is lost with increasing aggregation. These data will help to design nanoparticles that have the appropriate structural and photophysical properties to ultimately be of use in a clinical setting. PMID- 23646879 TI - Tunable electrical memory characteristics using polyimide:polycyclic aromatic compound blends on flexible substrates. AB - Resistance switching memory devices with the configuration of poly(ethylene naphthalate)(PEN)/Al/polyimide (PI) blend/Al are reported. The active layers of the PI blend films were prepared from different compositions of poly[4,4'-diamino 4"-methyltriphenylamine-hexafluoroisopropylidenediphthalimide] (PI(AMTPA)) and polycyclic aromatic compounds (coronene or N,N-bis[4-(2-octyldodecyloxy)phenyl] 3,4,9,10-perylenetetracarboxylic diimide (PDI-DO)). The additives of large pi conjugated polycyclic compounds can stabilize the charge transfer complex induced by the applied electric field. Thus, the memory device characteristic changes from the volatile to nonvolatile behavior of flash and write-once-read-many times (WORM) as the additive contents increase in both blend systems. The main differences between these two blend systems are the threshold voltage values and the additive content to change the memory behavior. Due to the stronger accepting ability and higher electron affinity of PDI-DO than those of coronene, the PI(AMTPA):PDI-DO blend based memory devices show a smaller threshold voltage and change the memory behavior in a smaller additive content. Besides, the memory devices fabricated on a flexible PEN substrate exhibit an excellent durability upon the bending conditions. These tunable memory performances of the developed PI/polycyclic aromatic compound blends are advantageous for future advanced memory device applications. PMID- 23646880 TI - Structural elucidation of the lignins from stems and foliage of Arundo donax Linn. AB - As one of the potential energy crops, Arundo donax Linn. is a renewable source for the production of biofuels and bioproducts. In the present study, milled wood lignin (MWL) and alkaline lignin (AL) from stems and foliage of A. donax were isolated and characterized by FT-IR spectroscopy, UV spectroscopy, GPC, 31P NMR, 2D HSQC NMR, and DFRC. The results indicated that both stem and foliage lignins were HGS type lignins. The semiquantitative HSQC spectra analysis demonstrated a predominance of beta-O-4' aryl ether linkages (71-82%), followed by beta-beta', beta-5', beta-1', and alpha,beta-diaryl ethers linkages in the lignins. Compared to stem lignins, foliage lignins had less beta-O-4' alkyl-aryl ethers, lower weight-average molecular weight, less phenolic OH, more H units, and lower S/G ratio. Moreover, tricin was found to incorporate into the foliage lignins (higher content of condensed G units) in significant amounts and might be alkaline stable. PMID- 23646881 TI - Structural characterization of amorphous calcium carbonate-binding protein: an insight into the mechanism of amorphous calcium carbonate formation. AB - ACC (amorphous calcium carbonate) plays an important role in biomineralization process for its function as a precursor for calcium carbonate biominerals. However, it is unclear how biomacromolecules regulate the formation of ACC precursor in vivo. In the present study, we used biochemical experiments coupled with bioinformatics approaches to explore the mechanisms of ACC formation controlled by ACCBP (ACC-binding protein). Size-exclusion chromatography, chemical cross-linking experiments and negative staining electron microscopy reveal that ACCBP is a decamer composed of two adjacent pentamers. Sequence analyses and fluorescence quenching results indicate that ACCBP contains two Ca2+ binding sites. The results of in vitro crystallization experiments suggest that one Ca2+-binding site is critical for ACC formation and the other site affects the ACC induction efficiency. Homology modelling demonstrates that the Ca2+ binding sites of pentameric ACCBP are arranged in a 5-fold symmetry, which is the structural basis for ACC formation. To the best of our knowledge, this is the first report on the structural basis for protein-induced ACC formation and it will significantly improve our understanding of the amorphous precursor pathway. PMID- 23646882 TI - Selective synthesis of 1,2-cis-alpha-glycosides without directing groups. Application to iterative oligosaccharide synthesis. AB - A method for the highly selective synthesis of 1,2-cis-alpha-linked glycosides that does not require the use of the specialized protecting group patterns normally employed to control diastereoselectivity is described. Thioglycoside acceptors can be used, permitting iterative oligosaccharide synthesis. The approach eliminates the need for lengthy syntheses of monosaccharides possessing highly specialized and unconventional protecting group patterns. PMID- 23646883 TI - The emerging therapeutic role of antibody mixtures. AB - A body of evidence suggests that a mixture of therapeutic monoclonal antibodies (mAbs) may be better than a single antibody. Several strategies have been developed to achieve multiple targeting, including the administration of two or more mAbs to the patient, bispecific antibodies and antibody mixtures. Recently, new antibody technologies based on a diverse array of antibodies binding to several different epitopes on any given antigen or antigens have been developed. One of the most promising is the SympressTM manufacturing technology, which allows the production of an antibody mixture in just one bioreactor as a single drug substance. Recombinant antibody mixtures may be applicable to therapy of neoplastic, autoimmune and infectious diseases. PMID- 23646884 TI - Cs2GeB4O9: a new second-order nonlinear-optical crystal. AB - A new alkali-metal borogermanate with noncentrosymmetric structure, namely, Cs2GeB4O9, has been discovered, and a large crystal with dimensions of 20 * 16 * 8 mm(3) has been grown by a high-temperature top-seeded solution method using Cs2O-B2O3 as a flux. The compound crystallizes in the tetragonal space group I4 with a = b = 6.8063(2) A, c = 9.9523(7) A, V = 461.05(4) A(3), and Z = 2. It features a three-dimensional anionic open framework based on GeO4 tetrahedra and B4O9 clusters that are interconnected via corner-sharing, forming one-dimensional channels of nine-/ten-membered rings along the a and b axes, which are occupied by Cs(+) cations. Cs2GeB4O9 exhibits a very high thermal stability with a melting point of 849 degrees C, and it possesses a short-wavelength absorption edge onset at 198 nm determined by UV-vis transmission spectroscopy measurements on a slab of polished crystal. Powder second-harmonic generation (SHG) measurement on sieved crystals reveals that Cs2GeB4O9 is a type I phase-matchable material with a strong SHG response of about 2.8 * KH2PO4. The preliminary investigation indicates that Cs2GeB4O9 is a new promising second-order nonlinear-optical crystalline material. PMID- 23646885 TI - Nostalgia: The bittersweet history of a psychological concept. AB - The concept of nostalgia has changed substantially both denotatively and connotatively over the span of its 300-year history. This article traces the evolution of the concept from its origins as a medical disease to its contemporary understanding as a psychological construct. The difficulty of tracing a construct through history is highlighted. Attention is paid to roles played first by the medical context, and then by the psychiatric, psychoanalytic, and psychological approaches. Emphasis is given to shifts in the designation of nostalgic valence from bitter to sweet to bittersweet, and the processes of semantic drift and depathologization are explored. Because the sense of nostalgia was constructed and reconstructed within social, cultural, and historical contexts, its meaning changed along with the words used to describe and connect it to other entities. Nostalgia's past illustrates the influence of language, social-cultural context, and discipline perspectives on how a construct is defined, researched, and applied. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23646888 TI - Influence of a single physical exercise class on mood states of pregnant women. AB - The aim of the research was to define the influence of a single physical exercise class on mood states of pregnant women and to establish the socio-demographic and personality predictors of mood changes. The sample was comprised of a total of 109 pregnant women aged 19-37 years. Of the group, 62 women participated in physical exercise for pregnant women (the experimental group) and 47 women participated in traditional childbirth education classes (the control group). Emotional states were assessed with the UWIST Mood Adjective Checklist; personality traits were measured with the NEO-FFI, LOT-R and STAI questionnaires. Socio-demographic data were collected with a survey developed by the authors. A single physical exercise class improved the emotional state of pregnant women significantly more than a traditional childbirth education class. Within the experimental group, a significant improvement of mood was observed in all dimensions, while in the control group only hedonic tone increased. Greater improvements in mood can be expected in a group of women who are younger, less optimistic, and who evaluate their health better but physical fitness worse. As a single session of exercise helps improve the mood of pregnant women, this may be an effective strategy to prevent the deterioration of mood state during pregnancy. PMID- 23646886 TI - Post-transcriptional regulation of cystic fibrosis transmembrane conductance regulator expression and function by microRNAs. AB - MicroRNAs (miRNAs) are increasingly recognized as important posttranscriptional regulators of gene expression, and changes in their actions can contribute to disease states. Little is understood regarding miRNA functions in the airway epithelium under normal or diseased conditions. We profiled miRNA expression in well-differentiated primary cultures of human cystic fibrosis (CF) and non-CF airway epithelia, and discovered that miR-509-3p and miR-494 concentrations were increased in CF epithelia. Human non-CF airway epithelia, transfected with the mimics of miR-509-3p or miR-494, showed decreased cystic fibrosis transmembrane conductance regulator (CFTR) expression, whereas their respective anti-miRs exerted the opposite effect. Interestingly, the two miRNAs acted cooperatively in regulating CFTR expression. Upon infecting non-CF airway epithelial cells with Staphylococcus aureus, or upon stimulating them with the proinflammatory cytokines TNF-alpha or IL-1beta, we observed an increased expression of both miRNAs and a concurrent decrease in CFTR expression and function, suggesting that inflammatory mediators may regulate these miRNAs. Transfecting epithelia with anti-miRs for miR-509-3p and miR-494, or inhibiting NF-kappaB signaling before stimulating cells with TNFalpha or IL-1beta, suppressed these responses, suggesting that the expression of both miRNAs was responsive to NF-kappaB signaling. Thus, miR-509-3p and miR-494 are dynamic regulators of CFTR abundance and function in normal, non-CF airway epithelia. PMID- 23646887 TI - Promoting resilience among parents and caregivers of children with cancer. AB - BACKGROUND: Promoting resilience is an aspect of psychosocial care that affects patient and whole-family well-being. There is little consensus about how to define or promote resilience during and after pediatric cancer. OBJECTIVES: The aims of this study were (1) to review the resilience literature in pediatric cancer settings; (2) to qualitatively ascertain caregiver-reported perceptions of resilience; and (3) to develop an integrative model of fixed and mutable factors of resilience among family members of children with cancer, with the goal of enabling better study and promotion of resilience among pediatric cancer families. METHODS: The study entailed qualitative analysis of small group interviews with eighteen bereaved parents and family members of children with cancer treated at Seattle Children's Hospital. Small-group interviews were conducted with members of each bereaved family. Participant statements were coded for thematic analysis. An integrative, comprehensive framework was then developed. RESULTS: Caregivers' personal appraisals of the cancer experience and their child's legacy shape their definitions of resilience. Described factors of resilience include baseline characteristics (i.e., inherent traits, prior expectations of cancer), processes that evolve over time (i.e., coping strategies, social support, provider interactions), and psychosocial outcomes (i.e., post-traumatic growth and lack of psychological distress). These elements were used to develop a testable model of resilience among family members of children with cancer. CONCLUSIONS: Resilience is a complex construct that may be modifiable. Once validated, the proposed framework will not only serve as a model for clinicians, but may also facilitate the development of interventions aimed at promoting resilience in family members of children with cancer. PMID- 23646889 TI - Non-uniform velocity of homogeneous DNA in a uniform electric field: consequence of electric-field-induced slow dissociation of highly stable DNA-counterion complexes. AB - Identical molecules move with identical velocities when placed in a uniform electric field within a uniform electrolyte. Here we report that homogeneous DNA does not obey this fundamental rule. While most DNA moves with similar velocities, a fraction of DNA moves with velocities that vary within a multiple fold range. The size of this irregular fraction increases several orders of magnitude when exogenous counterions are added to DNA. The irregular fraction decreases several orders of magnitude when DNA counterions are removed by dialysis against deionized water in the presence of a strong electric field (0.6 kV/cm). Dialysis without the field is ineffective in decreasing the size of irregular fraction. These results suggest that (i) DNA can form very stable complexes with counterions, (ii) these complexes can be dissociated by an electric field, and (iii) the observed non-uniform velocity of DNA is caused by electric-field-induced slow dissociation of these stable complexes. Our findings help to better understand a fundamental property of DNA: its interaction with counterions. In addition, these findings suggest a practical way of making electromigration of DNA more uniform: removal of strongly bound DNA counterions by electro-dialysis against deionized water. PMID- 23646890 TI - Effect of coil-globule transition on the single-chain crystallization. AB - The folding process of a single chain including coil-globule transition and crystallization has been investigated through dynamic Monte Carlo simulations. The results based upon ensemble averaging illustrated three distinct states: coil, molten globule, and globule states. Furthermore, the crystallization process from these collapsed states demonstrated various characteristics and it also verified the thermodynamic partitions. The isothermal crystallization in the three states showed the folding rates, and the final crystallite morphologies strongly depended on the collapsed states. Especially, the onset temperature of crystallization in the intermediate molten globule state demonstrated the strongest sensitivity to the solvent qualities in the three different states. Moreover, the crystallization in this intermediate state illustrated a two-step folding mechanism with the prior dense core serving as a precursor to induce the subsequent crystallization. Our observations would help in understanding the thermodynamics and kinetics of phase transition of a single macromolecule. Possible relations to the protein folding were also discussed. PMID- 23646891 TI - Trends and associated factors in prevalence of dental trauma in Latin America and Caribbean: a systematic review and meta-analysis. AB - OBJECTIVES: This study aimed to perform a systematic review on the prevalence of, and trends in, dental trauma in permanent teeth in 'Latin America and Caribbean' region and possible factors associated with this injury. METHODS: Literature search was carried out, in PubMed database up to 07 July 2011, for articles written in Portuguese, Spanish, or English reporting on dental trauma prevalence in the Latin American and Caribbean countries. Meta-analyses were undertaken by using random effects modeling to satisfy the purposes of this review. Pooled estimates were calculated with a confidence interval of 95% (95% CI) both for prevalence and odds ratios (OR). RESULTS: This online searching strategy collected and listed 2436 articles on this topic. After evaluating their titles and abstracts, only 24 were finally selected for complete review and data collection. All studies had been performed during adolescence, mostly in 12-year old adolescents. The pooled prevalence of dental trauma in permanent teeth was 18.6%. Positive summary association of dental trauma with boys (pooled OR = 1.72; 95% CI: 1.57-1.89), inadequate lip coverage (pooled OR = 2.26; 95% CI: 1.45 3.52), and increased overjet (>5 mm) (pooled OR = 1.98; 95% CI: 1.61-2.44) were observed across all meta-analysis models. Differences in estimation could be observed when different criteria were used for evaluating dental trauma. On the other hand, prevalence of dental trauma did not tend to show sudden changes over time, despite criteria used. Prevalence of dental trauma after 2000s tended to decrease over time. CONCLUSIONS: Approximately 15-20% of the adolescents in Latin American and Caribbean countries have shown some type of dental trauma in permanent teeth, and it seems there is a trend of decreasing prevalence of dental trauma in the studied areas of this region. Boys, adolescents presenting inadequate lip coverage, or an increased overjet greater than 5 mm are more likely to have traumatic dental injuries. PMID- 23646892 TI - Chemical modification produces species-specific changes in cucurbitacin antifeedant effect. AB - Cucurbitacins are secondary metabolites that mediate insect plant interactions not only as allomones against generalists but also as kairomones for specialist herbivores. This study was undertaken to identify the potential of cucurbitacin derivatives as insect antifeedant agents. The antifeedant capacity against a Cucurbitaceae specialist [ Epilachna paenulata (Coleoptera: Coccinellidae)] and a polyphagous insect [ Pseudaletia adultera (Lepidoptera: Noctuidae)] was evaluated in preference tests in which the insects were given a choice between food plants either treated with the cucurbitacin derivatives or treated with the solvent. The activity was found not to be related to the basic cucurbitacin skeleton, as only 15 of the 28 tested cucurbitacin derivatives were active. Only one of the tested compounds was phagostimulant to the specialist insect (the hemissuccinate of 16 oxo-dihydrocucurbitacin B derivative), while all other active derivatives were deterrent against one of the insects (13 compounds) or both of them (3 compounds). Changes in ring A of the cucurbitacins, as well as in the side chain, modified the activity. As a general trend, when chemical modifications of the basic structure produced a change in activity, the response was opposite in both insects used as biodetectors, indicating that a selective variation in the activity may be achieved by chemical modifications of the cucurbitacin skeleton. PMID- 23646893 TI - Consumers of 4-chloro-2-methylphenoxyacetic acid from agricultural soil and drilosphere harbor cadA, r/sdpA, and tfdA-like gene encoding oxygenases. AB - Microbial degradation of 2-methyl-4-chlorophenoxyacetic acid (MCPA) in soil is enhanced by earthworms and initiated by tfdA-like, cadA and r/sdpA gene encoding oxygenases. Copy numbers of such genes increased during MCPA degradation in soil, and MCPA stimulated transcription of tfdA-like and r/sdpA genes up to 4*. Transcription of cadA was detected in the presence of MCPA only. DNA stable isotope probing after consumption of 0.6-0.8 mg 13C-MCPA gdw -1 in oxic microcosms indicated diverse labeled oxygenase genes in bulk soil, burrow walls, and cast. 9, 6, and 3 operational taxonomic units of tfdA-like, cadA, and r/sdpA genes, respectively, were labeled and affiliated with group 2 Alphaproteobacteria including Bradyrhizobia and group 1 class III Betaproteobacteria. New genes encoding putative MCPA degrading oxygenases were identified. Diversity of labeled OTUs tended to be lower for cast than for bulk soil. The collective data indicate (1) hitherto unknown active MCPA degraders and/or oxygenase genes in soil; (2) that multiple oxygenases are associated with MCPA degradation in soil at the same time; (3) that earthworms impact the capability of MCPA degraders in soil to respond to MCPA; and (4) the collective data enable a more in-depth analysis of MCPA degrader communities in soil by future structural gene-based experimental strategies. PMID- 23646894 TI - O-GlcNAcylation and p50/p105 binding of c-Rel are dynamically regulated by LPS and glucosamine in BV2 microglia cells. AB - BACKGROUND AND PURPOSE: Previously, we demonstrated that glucosamine (GlcN) exerts a suppressive effect on LPS-induced inducible NOS (iNOS) through the inhibition of NF-kappaB activation in BV2 mouse microglial cells. The purpose of the present study was to examine the mechanisms by which GlcN inhibits NF-kappaB activation. EXPERIMENTAL APPROACH: BV2 cells were stimulated with LPS with or without GlcN. NF-kappaB/c-Rel activities were studied by EMSA, nuclear translocation, reporter assay or chromatin immunoprecipitation. Wheat germ agglutinin precipitation or galactosyltransferase assay were used to measure O linked N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) of c-Rel. Protein-protein interactions were examined by co-immunoprecipitation. KEY RESULTS: LPS stimulated the activation of c-Rel, increased the O-GlcNAcylation of c-Rel and enhanced the binding of c-Rel to the NF-kappaB site in the iNOS promoter; GlcN attenuated these effects of LPS. O-GlcNAcylation of both nuclear and cytosolic forms of c-Rel was increased by LPS and reduced by GlcN. LPS increased the interaction of c-Rel with O-GlcNAc transferase (OGT) and p50/p105, and GlcN suppressed these interactions. Knockdown of OGT reduced the c-Rel O GlcNAcylation and c-Rel-p50 interaction in response to LPS, but did not affect either the binding of c-Rel to the iNOS promoter or the transcriptional activity of c-Rel. CONCLUSIONS AND IMPLICATIONS: In BV2 microglial cells, the anti inflammatory effect of GlcN is mediated by prevention of the prolonged activation of transcription factors, c-Rel and NF-kappaB. Further clarification of the mechanism by which GlcN exerts this effect will facilitate the development of pharmacological strategies for preventing excessive NO formation when targeting inflammatory diseases of the periphery or CNS. PMID- 23646896 TI - Large-scale analysis of peptide sequence variants: the case for high-field asymmetric waveform ion mobility spectrometry. AB - Large scale analysis of proteins by mass spectrometry is becoming increasingly routine; however, the presence of peptide isomers remains a significant challenge for both identification and quantitation in proteomics. Classes of isomers include sequence inversions, structural isomers, and localization variants. In many cases, liquid chromatography is inadequate for separation of peptide isomers. The resulting tandem mass spectra are composite, containing fragments from multiple precursor ions. The benefits of high-field asymmetric waveform ion mobility spectrometry (FAIMS) for proteomics have been demonstrated by a number of groups, but previously work has focused on extending proteome coverage generally. Here, we present a systematic study of the benefits of FAIMS for a key challenge in proteomics, that of peptide isomers. We have applied FAIMS to the analysis of a phosphopeptide library comprising the sequences GPSGXVpSXAQLX(K/R) and SXPFKXpSPLXFG(K/R), where X = ADEFGLSTVY. The library has defined limits enabling us to make valid conclusions regarding FAIMS performance. The library contains numerous sequence inversions and structural isomers. In addition, there are large numbers of theoretical localization variants, allowing false localization rates to be determined. The FAIMS approach is compared with reversed phase liquid chromatography and strong cation exchange chromatography. The FAIMS approach identified 35% of the peptide library, whereas LC-MS/MS alone identified 8% and LC-MS/MS with strong cation exchange chromatography prefractionation identified 17.3% of the library. PMID- 23646895 TI - Integrated stress response of Escherichia coli to methylglyoxal: transcriptional readthrough from the nemRA operon enhances protection through increased expression of glyoxalase I. AB - Methylglyoxal (MG) elicits activation of K(+) efflux systems to protect cells against the toxicity of the electrophile. ChIP-chip targeting RNA polymerase, supported by a range of other biochemical measurements and mutant creation, was used to identify genes transcribed in response to MG and which complement this rapid response. The SOS DNA repair regulon is induced at cytotoxic levels of MG, even when exposure to MG is transient. Glyoxalase I alone among the core MG protective systems is induced in response to MG exposure. Increased expression is an indirect consequence of induction of the upstream nemRA operon, encoding an enzyme system that itself does not contribute to MG detoxification. Moreover, this induction, via nemRA only occurs when cells are exposed to growth inhibitory concentrations of MG. We show that the kdpFABCDE genes are induced and that this expression occurs as a result of depletion of cytoplasmic K(+) consequent upon activation of the KefGB K(+) efflux system. Finally, our analysis suggests that the transcriptional changes in response to MG are a culmination of the damage to DNA and proteins, but that some integrate specific functions, such as DNA repair, to augment the allosteric activation of the main protective system, KefGB. PMID- 23646897 TI - Cserjesi et al. reply. PMID- 23646898 TI - Core binding factor acute myeloid leukemia: the impact of age, leukocyte count, molecular findings, and minimal residual disease. AB - PURPOSE: Most patients with acute myeloid leukemia (AML) and genetic rearrangements involving the core binding factor (CBF) have favorable prognosis. In contrast, a minority of them still have a high risk of leukemia recurrence. This study investigated the adverse features of CBF AML that could justify investigational therapeutic approaches. PATIENTS AND METHODS: One hundred and fifty patients (median age 42 yr, range 16-69) with CBF AML (RUNX1-RUNX1T1 n = 74; CBFB-MYH11 n = 76) were prospectively enrolled into two consecutive CETLAM protocols at 19 Spanish institutions. Main clinic and biologic parameters were analyzed in the whole series. In non-selected cases with available DNA samples, the impact of molecular characterization and minimal residual disease (MRD) was also studied. RESULTS: Overall, complete remission (CR) rate was 89% (94% in <=50 yr old and 72% in >50 yr, P = 0.002). At 5 yr, cumulative incidence of relapse (CIR) was 26 +/- 1%, disease-free survival (DFS) 62 +/- 6%, and overall survival (OS) 66 +/- 4%. In multivariate analyses, leukocyte count above 20 * 10(9) /L, BAALC over-expression, and high copy numbers of RUNX1-RUNXT1 or CBFB-MYH11 after induction chemotherapy (CT) led to increased relapse rate. Regarding OS, age >50 yr, leukocyte count above 20 * 10(9) /L, and increased MN1 expression were adverse features. CONCLUSION: Age, leukocyte counts, BAALC, and MN1 gene expressions as well as high copy numbers of RUNX1-RUNXT1 or CBFB-MYH11 after induction chemotherapy are useful tools to predict the outcome and should be considered for risk-adapted therapy. PMID- 23646899 TI - Involvement of alpha2-antiplasmin in dendritic growth of hippocampal neurons. AB - The alpha2-Antiplasmin (alpha2AP) protein is known as a principal physiological inhibitor of plasmin, but we previously demonstrated that it acts as a regulatory factor for cellular functions independent of plasmin. alpha2AP is highly expressed in the hippocampus, suggesting a potential role for alpha2AP in hippocampal neuronal functions. However, the role for alpha2AP was unclear. This study is the first to investigate the involvement of alpha2AP in the dendritic growth of hippocampal neurons. The expression of microtubule-associated protein 2, which contributes to neurite initiation and neuronal growth, was lower in the neurons from alpha2AP-/- mice than in the neurons from alpha2AP+/+ mice. Exogenous treatment with alpha2AP enhanced the microtubule-associated protein 2 expression, dendritic growth and filopodia formation in the neurons. This study also elucidated the mechanism underlying the alpha2AP-induced dendritic growth. Aprotinin, another plasmin inhibitor, had little effect on the dendritic growth of neurons, and alpha2AP induced its expression in the neurons from plaminogen-/- mice. The activation of p38 MAPK was involved in the alpha2AP-induced dendritic growth. Therefore, our findings suggest that alpha2AP induces dendritic growth in hippocampal neurons through p38 MAPK activation, independent of plasmin, providing new insights into the role of alpha2AP in the CNS. PMID- 23646901 TI - Early skin testing is effective for diagnosis of hypersensitivity reactions occurring during anesthesia. AB - Allergic skin tests have to be performed 4-6 weeks after an allergic anesthetic reaction. Patients with allergic reactions during anesthesia were prospectively included (n = 44). Skin tests were performed in two stages: (i) Stage 1 (S1), 0-4 days after the reaction; and (ii) Stage 2 (S2), 4-8 weeks after. Five (11.5%) surgical procedures were suspended due to the reaction. Positive skin tests were obtained in 25/44 patients (57%). Allergic diagnosis was carried out at S1 in 15/25 (60%) and at S2 in 10/25 (40%). Three patients resulted positive only in S1. Overall agreement among S1 and S2 skin tests was 70.45%. The kappa statistic was 0.41 (P-value = 0.002). Odds ratio of obtaining a false negative in S1 (compared with S2) was 3.33. Early allergological study is useful, could minimize false negatives, but should be considered as a complement to late skin tests. PMID- 23646900 TI - A highly stereoselective addition of lithiated ynamides to Ellman-Davis chiral N tert-butanesulfinyl imines. AB - A highly diastereoselective addition of lithiated ynamides to Ellman-Davis chiral imines is described. While additions of N-sulfonyl ynamides are highly stereoselective even without Lewis acids, the use of BF3-OEt2 completely reversed the stereoselectivity. In addition, oxazolidinone-substituted ynamides behaved differently and functioned better with BF3-OEt2, and the chirality of the oxazolidinone ring exerts no impact on the selectivity. PMID- 23646902 TI - Successful use of a donor heart with quadricuspid aortic valve for orthotopic heart transplantation. AB - Quadricuspid aortic valve (QAV) is a rare congenital anomaly of the aortic valve. We describe transplanting a donor heart with a QAV with successful mid-term outcome. PMID- 23646903 TI - Minimal functional domains of paralogues hnRNP L and hnRNP LL exhibit mechanistic differences in exonic splicing repression. AB - Understanding functional distinctions between related splicing regulatory proteins is critical to deciphering tissue-specific control of alternative splicing. The hnRNP (heterogeneous nuclear ribonucleoprotein) L and hnRNP LL (hnRNP L-like) proteins are paralogues that have overlapping, but distinct, expression patterns and functional consequences. These two proteins share high sequence similarity in their RRMs (RNA-recognition motifs), but diverge in regions outside of the RRMs. In the present study, we use an MS2-tethering assay to delineate the minimal domains of hnRNP L and hnRNP LL which are required for repressing exon inclusion. We demonstrate that for both proteins, regions outside the RRMs, the N-terminal region, and a linker sequence between RRMs 2 and 3, are necessary for exon repression, but are only sufficient for repression in the case of hnRNP LL. In addition, both proteins require at least one RRM for maximal repression. Notably, we demonstrate that the region encompassing RRMs 1 and 2 of hnRNP LL imparts a second silencing activity not observed for hnRNP L. This additional functional component of hnRNP LL is consistent with the fact that the full-length hnRNP LL has a greater silencing activity than hnRNP L. Thus the results of the present study provide important insight into the functional and mechanistic variations that can exist between two highly related hnRNP proteins. PMID- 23646904 TI - A service evaluation of the Eczema Education Programme: an analysis of child, parent and service impact outcomes. AB - BACKGROUND: The systematic support of parents of children with eczema is essential in effective disease management. The few existing support models have a limited evidence base. This paper reports the outcome-orientated service evaluation of an original, extensive, social learning-theory based, nurse-led Eczema Education Programme (EEP). OBJECTIVES: To evaluate the EEP using specified child and parental outcomes and service impact data. METHODS: From a sample of 257 parent-child dyads attending the EEP, a pretest-post-test design evaluated its child impact using health-related quality of life measures (Infants' Dermatitis Quality of Life index, which includes a small dermatitis severity element, and Children's Dermatology Life Quality Index), severity measures (Patient Orientated Eczema Measure), a new parental measure (Parental Self Efficacy in Eczema Care Index) and service impact data based on general practitioner (GP) attendance patterns pre- and postintervention. RESULTS: Statistically significant impacts were observed on infant quality of life (P < 0.001), child quality of life (P = 0.027), disease severity (P < 0.001) and parental self-efficacy (P < 0.001). Improvements in child quality of life, parental efficacy and service impact were also evident from qualitative data. The cumulative total of all GP visits for selected participants post-EEP reduced by 62%. CONCLUSIONS: The EEP appears to be an effective model of delivering structured education to parents of children with eczema, and one generalizable to other multiethnic metropolitan populations. As a noncontrolled study, this rigorous service evaluation highlights the model's significance and the case for an evaluative multicentre randomized controlled trial of this educational intervention to inform a nurse-led programme of care. PMID- 23646905 TI - Osteoporosis screening: the long wait for change. PMID- 23646907 TI - Photosensitizing effects of nanometer TiO2 on chlorothalonil photodegradation in aqueous solution and on the surface of pepper. AB - The present study examined the effects of anatase nanometer TiO2 on photochemical degradation of chlorothalonil in aqueous solution and on the plant surface. Results showed that nanometer TiO2 exhibited a strong photosensitizing effect on the degradation of chlorothalonil both in aqueous solution and on the surface of green pepper. The photosensitization rate was the highest in the sunlight compared to illumination under high-pressure mercury and UV lamps. Use of distinct hydroxyl radical scavengers indicated that nanometer TiO2 acted by producing hydroxyl radicals with strong oxidizing capacity. Notably, nanometer TiO2 facilitated complete photodegradation of chlorothalonil with no detectable accumulation of the intermediate chlorothalonil-4-hydroxy. Nanometer TiO2 was also active on the surface of green pepper under natural sunlight both inside and outside of plastic greenhouse. These results together suggest that nanometer TiO2 can be used as a photosensitizer to accelerate degradation of the pesticides under greenhouse conditions. PMID- 23646906 TI - Disparities in women's health across a generation: a mother-daughter comparison. AB - BACKGROUND: The U.S. Centers for Disease Control and Prevention has set national goals to eliminate health disparities by race, sex, and socioeconomic status. Progress in meeting these goals has been mixed. This paper provides a different view on the evolving health of U.S. women by examining a sample of daughters and their mothers. METHODS: The aim was to determine if the health risk profiles of daughters (born 1975-1992) were different from their mothers (born 1957-1964) measured when both were between the ages of 17 and 24 years. The U.S.-based National Longitudinal Survey of Youth 1979 and associated Children and Young Adult Surveys were used. The sample was 2411 non-Hispanic white and African American girls born to 1701 mothers. Outcomes were height, weight, body mass index (BMI), age of menarche, and self-reported health. RESULTS: In both races, daughters were taller but entered adulthood at greater risk for the development of chronic illness than their mothers. Racial differences were greater in the daughters' generation than in the mothers'. Whites in both generations experienced educational differences in health based upon the mother's educational level, with fewer years of maternal education associated with poorer health. African Americans of both generations experienced differences by maternal education in self-reported health. However, when African American daughters were compared with their mothers, daughters born to college educated women gained more weight and had higher BMI and earlier menarche than did daughters born to high school dropouts. CONCLUSION: Health deterioration across generations in both races suggests that much work is needed to meet Healthy People 2020 goals of health equity. PMID- 23646908 TI - Care at the end-of-life: one chance to get it right. PMID- 23646910 TI - Very-high-dose methadone with minimal toxicity and inadequate pain control in a hospice patient with cancer. AB - A case is reported of a 48-year-old Caucasian male who was admitted to hospice care with metastatic cancer of the larynx. The patient required very high methadone doses and experienced little opioid toxicity. The pharmacodynamics and pharmacokinetics of methadone are discussed in the context of this patient experience. PMID- 23646911 TI - Do vicinal disulfide bridges mediate functionally important redox transformations in proteins? AB - Vicinal disulfide bridges, in which a disulfide bond is formed between adjacent cysteine residues, constitute an unusual but expanding class of potential allosteric disulfides. Although vicinal disulfide rings (VDRs) are relatively uncommon, they have proven to be functionally critical in almost all proteins in which they have been discovered. However, it has proved difficult to test whether these sterically constrained disulfides participate in functionally important redox transformations. We demonstrate that chemical replacement of VDRs with dicarba or diselenide bridges can be used to assess whether VDRs function as allosteric disulfides. Our approach leads to the hypothesis that not all VDRs participate in functionally important redox reactions. PMID- 23646912 TI - mCSF1, a nucleus-encoded CRM protein required for the processing of many mitochondrial introns, is involved in the biogenesis of respiratory complexes I and IV in Arabidopsis. AB - The coding regions of many mitochondrial genes in plants are interrupted by intervening sequences that are classified as group II introns. Their splicing is essential for the expression of the genes they interrupt and hence for respiratory function, and is facilitated by various protein cofactors. Despite the importance of these cofactors, only a few of them have been characterized. CRS1-YhbY domain (CRM) is a recently recognized RNA-binding domain that is present in several characterized splicing factors in plant chloroplasts. The Arabidopsis genome encodes 16 CRM proteins, but these are largely uncharacterized. Here, we analyzed the intracellular location of one of these hypothetical proteins in Arabidopsis, mitochondrial CAF-like splicing factor 1 (mCSF1; At4 g31010), and analyzed the growth phenotypes and organellar activities associated with mcsf1 mutants in plants. Our data indicated that mCSF1 resides within mitochondria and its functions are essential during embryogenesis. Mutant plants with reduced mCSF1 displayed inhibited germination and retarded growth phenotypes that were tightly associated with reduced complex I and IV activities. Analogously to the functions of plastid-localized CRM proteins, analysis of the RNA profiles in wildtype and mcsf1 plants showed that mCSF1 acts in the splicing of many of the group II intron RNAs in Arabidopsis mitochondria. PMID- 23646913 TI - Multistep targeted nano drug delivery system aiming at leukemic stem cells and minimal residual disease. AB - Refractory leukemia remains the most common therapeutic problem in clinical treatment of leukemia. The key therapy of refractory leukemia is to kill, thoroughly, the minimal residual disease and leukemia stem cells in the highly vascularized red marrow areas. In this study, two new conjugates, alendronate polyethylene glycol (100) monostearate and folate-polyethylene glycol (100) monostearate, were synthesized to develop a multistep targeting nanostructured lipid carriers by enhancing drug transport to the high bone turnover areas adjacent to the red marrow and targeting the minimal residual disease and leukemia stem cells. This dual targeting system demonstrated a great binding affinity to hydroxyapatite, a model component of bone minerals, and higher cell uptake (in the form of carriers but not drug) and cytotoxicity in the K562 cell line, a leukemia cell line with overexpressed folate receptors, were observed in vitro compared to unmodified carriers, especially when the cells were pretreated and the receptors were up-regulated by all-trans retinoic acid. The comodel test of K562 cells and HA showed that this dual targeting system could desorb from bone surface and be taken up by leukemia cells. For the in vivo study, this dual targeting system exhibited a significant increase in plasma half-life and could specifically accumulate in the bone tissue of rats or mice after intravenous injection. Ex vivo imaging of mice femurs and confocal laser scanning microscope imaging of mice femur slices further confirmed that this dual targeting system could favorably deposit to the osteoblast-enriched areas of high bone turnover in regions of trabecular bone surrounded by red marrow. In vivo antitumor activity in K562/BALB/c-nu leukemia mice showed that the treatment of this dual targeting system significantly reduced the white blood cell (WBC) number in peripheral blood and bone marrow to the normal level. In conclusion, this dual targeting system could precisely target to the regions where the minimal residual disease and leukemia stem cells are located and then be specifically uptaken in large amounts, which is a valuable target for refractory leukemia therapy. PMID- 23646915 TI - Recombinant hormones in osteoporosis. AB - INTRODUCTION: For the last 10 years, bone anabolic therapy with the recombinant human parathyroid hormone (rhPTH) analogue, teriparatide (rhPTH[1 - 34]), or full length rhPTH(1 - 84) has been an option in the treatment of osteoporosis. Both drugs are given as a daily subcutaneous injection. In the USA, only teriparatide is marketed. AREAS COVERED: Mechanisms of action by which rhPTH induces bone anabolic effects includes changes in bone remodeling, geometry and mineral density. Data from randomized controlled trials on anti-fracture efficacy are reviewed as well as results from a number of recent studies on administration less than once-a-day or intermittent-/cyclic-therapy. Treatment effects are compared with those of anti-resorptive agents. EXPERT OPINION: In terms of anti fracture efficacy, treatment with rhPTH is not superior to treatment with potent anti-resorptive agents. However, while the process by which osteoporosis emerges is arrested in response to anti-resorptives, rhPTH acts as a bone anabolic with reversal of the process. Although this mechanism of action seems favorable, the use of rhPTH is limited by a much higher cost than that of anti-resorptive agents. As long as a superior anti-fracture efficacy has not been proven, rhPTH should be confined to patients with severe spinal osteoporosis, including patients in whom treatment with an anti-resorptive has failed. PMID- 23646914 TI - Imaging DNA with fluorochrome bearing metals. AB - Molecules that fluoresce upon binding DNA are widely used in assaying and visualizing DNA in cells and tissues. However, using light to visualize DNA in animals is limited by the attenuation of light transmission by biological tissues. Moreover, it is now clear that DNA is an important mediator of dead cell clearance, coagulation reactions, and an immunogen in autoimmune lupus. Attaching metals (e.g., superparamagnetic nanoparticles, gadolinium ions, radioactive metal ions) to DNA-binding fluorochromes provides a way of imaging DNA in whole animals, and potentially humans, without light. Imaging metal-bearing, DNA binding fluorochromes and their target DNA by magnetic resonance imaging may shed light on the many key roles of DNA in health and disease beyond the storage of genetic information. PMID- 23646916 TI - The dynamic interaction between eyewitnesses and interviewers: the impact of differences in perspective on memory reports and interviewer behavior. AB - Despite myriad possible differences in perspectives brought to an investigative interview by eyewitnesses and interviewers, little is known about how such differences might affect eyewitness memory reports or interviewer behavior. Two experiments tested the impact of such differences in a dynamic interaction paradigm in which participants served as eyewitnesses and interviewers. In Experiment 1 (N = 38 pairs), reporting goals for eyewitnesses and interviewers were manipulated in a factorial design, with participants instructed to provide or obtain either as much information as possible or only accurate information. Matching interviewer-interviewee instructions promoted accurate reporting, regardless of the actual content of the instructions. In Experiment 2 (N = 45 pairs), access to information about corroborating eyewitness identifications was manipulated in a factorial design. Corroborating information affected interviewers, but not eyewitnesses. When interviewers did not have access to corroborating information, they provided more negative feedback, and there was a trend toward interrupting more and asking more yes/no questions. These experiments indicate that differences in perspective can have effects on both the content of a witness's report and the behavior of an interviewer. The potential for differences in perspective should be considered in research on protocols intended to maximize eyewitness report accuracy. PMID- 23646918 TI - Attitudes regarding life sentences for juvenile offenders. AB - Twice in recent years, the U.S. Supreme Court has considered the constitutionality of life sentences without the possibility of parole (LWOP) for juvenile offenders. Given the public nature of this issue, there is scant information on beliefs about imposing LWOP on juveniles. Attitudes on related issues suggest two possibilities. On the one hand, because public opinion regarding juvenile offenders has become somewhat less punitive recently, LWOP may be viewed as excessively harsh punishment. On the other hand, portrayal of some juvenile offenders as superpredators suggests that LWOP may still have public support. We used survey methodology and the unique "ninth justice paradigm" to examine how an offender's age influences beliefs about the appropriateness of LWOP, and the relationship between those beliefs and punishment-related ideologies. Results showed that, except in the case of murder, the majority of respondents disfavored imposing LWOP on juveniles, though a subset approved broad use of LWOP even for young offenders. In fact, after removing from consideration those who oppose LWOP under any circumstances, youthfulness of the offender has little impact on the beliefs about the types of crimes in which LWOP should be imposed (Study 1) or the mean sentence lengths imposed on juvenile offenders (Study 2). Respondents' punishment goals influenced their attitudes, as did beliefs about the likelihood of rehabilitation and reform. Harsh judgments of juveniles who commit serious crimes may result from dispositional attributions of youthful offenders as irredeemable. PMID- 23646917 TI - PTSD symptoms and family versus stranger violence in Iraq and Afghanistan veterans. AB - As a diagnosis, posttraumatic stress disorder (PTSD) has been associated with violence committed by veterans in many studies; however, a potential link to specific PTSD symptoms has received relatively less attention. This paper examines the relationship between PTSD symptoms and different types of violent behavior in Iraq and Afghanistan veterans. Participants were randomly sampled from a roster of all separated U.S. military service members or national guard/reservists who served after September 11, 2001. Data were collected at baseline and 1-year follow-up from a national sample of N = 1,090 veterans, from 50 states and all military branches. Of these veterans, 13% reported aggression toward a family member and 9% toward a stranger during the 1-year study period. Anger symptoms at baseline predicted higher odds of family violence at follow-up, both severe (OR = 1.30, CI [1.13, 1.48], p < .0001) and any (OR = 1.28, CI [1.19, 1.37], p < .0001). PTSD flashback symptoms at baseline predicted higher odds of stranger violence at follow-up, both severe (OR = 1.26, CI [1.11, 1.42], p < .0001) and any (OR = 1.16, CI [1.05, 1.28], p = .0029). Analyses revealed that males were more likely to engage in stranger violence, whereas females were more likely to endorse aggression in the family context. The results provide limited support to the hypothesis that PTSD "flashbacks" in veterans are linked to violence. The differing multivariate models illustrate distinct veteran characteristics associated with specific types of violence. PMID- 23646919 TI - Reward-biased risk appraisal and its relation to juvenile versus adult crime. AB - To what extent is criminal behavior in adolescence attributable to risk appraisal? Using two large cross-sectional samples (N = 929, age range: 10-30 years; and N = 1,357, age range: 12-24 years), we examine whether (a) reward bias in risk appraisal is more prominent in adolescence and (b) the association between risk appraisal and criminal behavior is stronger during adolescence than at other ages. In Study 1, criminal behavior was self-reported; in Study 2, it was defined by involvement with the court. Perceived chances of a negative outcome, seriousness of consequences, and benefits versus costs of various risky activities were assessed to gauge reward bias in risk appraisal. The findings indicate that reward bias is elevated during the adolescence years. Also, risk appraisal bears a stronger relation to self-reported crime in middle adolescence and to official law-breaking behavior in early adolescence than at other ages. The findings are consistent with a dual-systems model of adolescent development and align with recent U.S. Supreme Court decisions addressing juvenile offenders' culpability. PMID- 23646921 TI - Transplantation KCNMA1 modified bone marrow-mesenchymal stem cell therapy for diabetes mellitus-induced erectile dysfunction. AB - This study assessed the effect of KCNMA1 transfected bone marrow-mesenchymal stem cells (BM-MSCs) on the improvement of erectile function in diabetic rats. Sixty male Sprague-Dawley rats were injected with streptozotocin (STZ) and screened with apomorphine (APO) to establish diabetes mellitus-induced erectile dysfunction (DMED). DMED rats were randomly divided into four groups: rats in each group underwent intracavernous injection with either phosphate buffer solution (DMED+PBS), nontransfected MSCs (DMED+MSCs), empty vector transfected MSCs (DMED+null-MSCs) or KCNMA1 transfected MSCs (DMED+KCNMA1-MSCs). Before injection, high levels of KCNMA1 expression were confirmed in KCNMA1-MSCs using RT-PCR and Western blotting. The lentivirus transfected MSCs maintained their potential for multidirectional differentiation. Four weeks after injection, erectile function was ascertained by measuring intracavernous pressure (ICP). Penile tissues were collected for immunohistochemical analysis. The expression of KCNMA1 in the corpus cavernosum was increased, and the DMED+KCNMA1-MSCs group displayed a significant improvement of erectile function. We concluded that KCNMA1 was able to enhance the positive effect of MSCs in the treatment of diabetes-associated erectile dysfunction. PMID- 23646920 TI - RemA is a DNA-binding protein that activates biofilm matrix gene expression in Bacillus subtilis. AB - Biofilm formation in Bacillus subtilis requires expression of the eps and tapA sipW-tasA operons to synthesize the extracellular matrix components, extracellular polysaccharide and TasA amyloid proteins, respectively. Expression of both operons is inhibited by the DNA-binding protein master regulator of biofilm formation SinR and activated by the protein RemA. Here we show that RemA is a DNA-binding protein that binds to multiple sites upstream of the promoters of both operons and is both necessary and sufficient for transcriptional activation in vivo and in vitro. We further show that SinR negatively regulates eps operon expression by occluding RemA binding and thus for the P(eps) promoter SinR functions as an anti-activator. Finally, transcriptional profiling indicated that RemA was primarily a regulator of the extracellular matrix genes, but it also activated genes involved in osmoprotection, leading to the identification of another direct target, the opuA operon. PMID- 23646922 TI - Surface composition tuning of Au-Pt bimetallic nanoparticles for enhanced carbon monoxide and methanol electro-oxidation. AB - The ability to direct bimetallic nanoparticles to express desirable surface composition is a crucial step toward effective heterogeneous catalysis, sensing, and bionanotechnology applications. Here we report surface composition tuning of bimetallic Au-Pt electrocatalysts for carbon monoxide and methanol oxidation reactions. We establish a direct correlation between the surface composition of Au-Pt nanoparticles and their catalytic activities. We find that the intrinsic activities of Au-Pt nanoparticles with the same bulk composition of Au0.5Pt0.5 can be enhanced by orders of magnitude by simply controlling the surface composition. We attribute this enhancement to the weakened CO binding on Pt in discrete Pt or Pt-rich clusters surrounded by surface Au atoms. Our finding demonstrates the importance of surface composition control at the nanoscale in harnessing the true electrocatalytic potential of bimetallic nanoparticles and opens up strategies for the development of highly active bimetallic nanoparticles for electrochemical energy conversion. PMID- 23646924 TI - Thermally controlled decarboxylative [4 + 2] cycloaddition between alkoxyoxazoles and acrylic acid: expedient access to 3-hydroxypyridines. AB - A modified Kondrat'eva cycloaddition involving an unprecedented thermally controlled metal-free decarboxylative aromatization affords an expedient access to natural 3-hydroxypyridine/piperidine systems. PMID- 23646923 TI - Activation of NF-kappaB after chronic ethanol intake and haemorrhagic shock/resuscitation in mice. AB - BACKGROUND AND PURPOSE: Chronic ethanol abuse and haemorrhagic shock are major causes of global mortality and, separately, induce profound hepato- and immune toxic effects via activation of NF-kappaB. Here, we assessed the effects of chronic ethanol intake upon the pathophysiological derangements after haemorrhagic shock with subsequent resuscitation (H/R), with particular attention to the contribution of NF-kappaB. EXPERIMENTAL APPROACH: Transgenic NF kappaB(EGFP) mice, expressing the enhanced green fluorescent protein (EGFP) under the transcriptional control of NF-kappaB cis-elements were fed a Lieber-DeCarli diet containing ethanol (EtOH-diet) or an isocaloric control diet for 4 weeks and were then pairwise subjected to H/R. Liver tissues and peripheral blood were sampled at 2 or 24 h after H/R. Cytokines in blood and tissue and leukocyte activation (as CD11b expression) were measured, along with EGFP as a marker of NF kappaB activation. KEY RESULTS: The EtOH-diet increased mortality at 24 h after H/R and elevated liver injury, associated with an up-regulation of NF-kappaB dependent genes and IL-6 release; it also increased production of NF-kappaB driven intercellular adhesion molecule 1 (ICAM-1) and EGFP in liver tissue. At 2h after the H/R procedure in ethanol-fed mice we observed the highest proportion of NF-kappaB activated non-parenchymal cells and an NF-kappaB-dependent increase in polymorphonuclear leukocyte CD11b expression. CONCLUSIONS AND IMPLICATIONS: The EtOH-diet exacerbated liver injury after H/R, accompanying an overwhelming hepatic and systemic immune response. Our findings contribute to evidence implicating NF-kappaB as a key player in the orchestration of the immune response in haemorrhagic shock patients with a history of chronic ethanol abuse. PMID- 23646925 TI - Neonatal neuroimaging predicts recruitment of contralesional corticospinal tracts following perinatal brain injury. AB - AIM: Unilateral perinatal brain injury may result in recruitment of ipsilateral projections originating in the unaffected hemisphere and development of unilateral spastic cerebral palsy (USCP). The aim of this study was to assess the predictive value of neonatal neuroimaging following perinatal brain injury for recruitment of ipsilateral corticospinal tracts. METHOD: Neonatal magnetic resonance imaging (MRI) and cranial ultrasound scans of 37 children (20 males, 17 females; median [range] gestational age 36 wks(+4) [26(+6) -42wks(+5) ] and birthweight 2312 g ([770-5230g]) with unilateral perinatal arterial ischaemic stroke (n=23) or periventricular haemorrhagic infarction (n=14) were reviewed and scored for involvement of the corticospinal trajectory. Hand function was assessed using the Assisting Hand Assessment (AHA) and transcranial magnetic stimulation (TMS) was performed (age range 7y 4mo-18y and 7mo) to determine the type of cortical motor organization (normal, mixed or ipsilateral). Neuroimaging scores were used to predict TMS patterns. RESULTS: Eighteen children developed USCP with ipsilateral corticospinal tract projections in 13 children (eight mixed, five ipsilateral). AHA scores decreased with increased ipsilateral projections. Asymmetry of the corticospinal tracts seen on neonatal MRI was predictive of development of USCP and recruitment of ipsilateral tracts (positive and negative predictive value of 73% and 91%). INTERPRETATION: Neonatal neuroimaging can predict recruitment of ipsilateral corticospinal tracts. Early knowledge of the expected pattern of cortical motor organization will allow early identification of children eligible for early therapy. PMID- 23646926 TI - Cleavage of GSK-3beta by calpain counteracts the inhibitory effect of Ser9 phosphorylation on GSK-3beta activity induced by H2O2. AB - Glycogen synthase kinase-3 beta (GSK-3beta) dysfunction may play an essential role in the pathogenesis of psychiatric, metabolic, neurodegenerative diseases, in which oxidative stress exists concurrently. Some studies have shown that GSK 3beta activity is up-regulated under oxidative stress. This study evaluated how oxidative stress regulates GSK-3beta activity in human embryonic kidney 293 (HEK293)/Tau cells treated with hydrogen peroxide (H2O2). Here, we show that H2O2 induced an obvious increase of GSK-3beta activity. Surprisingly, H2O2 dramatically increased phosphorylation of GSK-3beta at Ser9, an inactive form of GSK-3beta,while there were no changes of phosphorylation of GSK-3beta at Tyr216. Moreover, H2O2 led to a transient [Ca2+](i) elevation, and simultaneously increased the truncation of GSK-3beta into two fragments of 40 kDa and 30 kDa, whereas inhibition of calpain decreased the truncation and recovered the activity of GSK-3beta. Furthermore, tau was hyperphosphorylated at Ser396, Ser404, and Thr231, three most common GSK-3beta targeted sites after 100 MUM H2O2 administration in HEK293/Tau cells, whereas inhibition of calpain blocked the tau phosphorylation. In addition, we found that there were no obvious changes of Cyclin-dependent kinase 5 (CDK5) expression (responsible for tau phosphorylation) and of p35 cleavage, the regulatory subunit of CDK5 in H2O2-treated HEK293/Tau cells. In conclusion, Ca2+-dependent calpain activation leads to GSK-3beta truncation, which counteracts the inhibitory effect of Ser9 phosphorylation, up regulates GSK-3beta activity, and phosphorylates tau in H2O2-treated HEK293/Tau cells. PMID- 23646927 TI - Bone marrow cell transcripts from Fanconi anaemia patients reveal in vivo alterations in mitochondrial, redox and DNA repair pathways. AB - Fanconi anaemia (FA) is a genetic cancer predisposition disorder associated with cytogenetic instability, bone marrow failure and a pleiotropic cellular phenotype, including low thresholds of responses to oxidative stress, cross linking agents and selected cytokines. This study was aimed at defining the scope of abnormalities in gene expression using the publicly available FA Transcriptome Consortium (FTC) database (Gene Expression Omnibus, 2009 and publicly available as GSE16334). We evaluated the data set that included transcriptomal analyses on RNA obtained from low-density bone marrow cells (BMC) from 20 patients with FA and 11 healthy volunteers, by seeking to identify changes in expression of over 22,000 genes, including a set of genes involved in: (i) bioenergetic pathways; (ii) antioxidant activities; (iii) response to stress and metal-chelating proteins; (iv) inflammation-related cytokines and (v) DNA repair. Ontological analysis of genes expressed at magnitudes of 1.5-fold or greater demonstrated significant suppression of genes in the categories of (i) energy metabolism; (ii) antioxidant activities; and (iii) stress and chelating proteins. Enhanced expression was found for 16 of 26 genes encoding inflammatory cytokines. A set of 20 of 21 transcripts for DNA repair activities were down-regulated; four of these transcripts related to type II topoisomerase. The data provide evidence for alterations in gene regulation of bioenergetic activities, redox-related activities, stress and metal-chelating proteins, and of some selected DNA repair activities in patients with FA. PMID- 23646928 TI - The effect of vaccination, ploidy and smolt production regime on pathological melanin depositions in muscle tissue of Atlantic salmon, Salmo salar L. AB - The presence of melanin in muscle fillets of farmed salmon represents a considerable quality problem for the salmon industry with major economic concerns. In this study, we have examined the presence of abnormal pigmentation in vaccinated versus unvaccinated Atlantic salmon, Salmo salar L., and evaluated possible differences between diploid and triploid fish. Furthermore, the impact of the smolt production regime at ambient (4.5 degrees C) versus elevated temperature (16 degrees C) was investigated. Pigmented muscle spots were analysed for the expression of genes involved in melanization (tyrosinase gene family) and immune-related response in addition to morphological investigations. The proportion of fish with intramuscular melanin deposits was not significantly different between vaccinated and unvaccinated fish, regardless of ploidy. However, an interaction between vaccination and smolt regime was shown, where smoltification at elevated temperature after vaccination increased the number of affected individuals compared with vaccination followed by simulated natural smoltification. Furthermore, there were overall more fish with melanin spots amongst the triploids compared with their diploid counterparts. Transcription of the tyrosinase gene family confirmed an onsite melanogenesis in all pigment spots. The histological examination and the expression of the immune-related genes revealed a chronic polyphasic myopathy that was not affected by vaccination, ploidy or smolt production regime. PMID- 23646929 TI - Exploring the scope of a novel ligand class: synthesis and catalytic examination of metal complexes with 'normal' 1,2,3-triazolylidene ligands. AB - Using new 'normal'-substituted 1,2,3-triazolylidene silver compounds as starting materials allowed for preparation of a series of molybdenum, ruthenium, rhodium, and palladium transition metal complexes bound to the new 1,2,3-triazolylidene ligand system. In this work, the first triazolylidene Mo compound is presented as well as the first structural investigation of a silver complex with a monodentate 1,2,3-triazolylidene. Furthermore, the triazolylidene Pd complex and the Mo complex were tested as precatalysts in Suzuki-Miyaura coupling and epoxidation catalysis, respectively. PMID- 23646930 TI - Nuclear MMP-9 role in the regulation of rat skeletal myoblasts proliferation. AB - BACKGROUND INFORMATION: Matrix metalloproteinases (MMPs) are the key enzymes responsible for the remodelling of extracellular matrix. Two of them, namely MMP 2 and MMP-9 (gelatinases A and B, respectively), are expressed in skeletal muscles and are involved in their regeneration after the injury. Although MMPs are primarily known to act extracellularly, recent studies have shown that some of them are also found within the cell. In this study, we examine intracellular localisation of gelatinases during myoblasts differentiation in vitro, focussing the impact of MMPs inhibition on the myoblasts proliferation and function. RESULTS: We show that MMP-9 localises within the S-phase nuclei of in vitro differentiating myoblasts. The inhibition of MMPs activity achieved by either doxycycline (a non-competitive inhibitor of collagenases), TIMP-1 (tissue inhibitor of metalloproteinases 1) or neutralising anti-MMP-9 antibody affects nuclear localisation of this gelatinase, and impacts at myoblasts proliferation. CONCLUSIONS: During myoblasts differentiation, MMP-9 that is localised in nuclei might be involved in the processes regulating cell cycle progression. PMID- 23646931 TI - Spatial distributions of inorganic elements in honeybees (Apis mellifera L.) and possible relationships to dietary habits and surrounding environmental pollutants. AB - In this study, the laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) was adopted to determine the distribution of inorganic elements, including Ca, Cu, Fe, Mg, Mn, S, P, Pb, and Zn, in honeybees (Apis melifera L.). Two features are particularly noteworthy. First, it was found there is a significant amount of Fe located at the fringe of the abdomen in worker bees; ultrasonic imaging, scanning electron microscopy, and magnetic resonance imaging revealed that it arose from magnetic Fe-bearing nanoparticles (NPs) having an average diameter of approximately 40 nm. Interestingly, only worker bees contained these magnetic Fe-bearing NPs; no similar features appeared in larvae, pupae, wasps, or drones. Second, a detectable amount of Pb accumulated particularly in the alimentary canals of worker bees. Again, no detectable amounts of Pb in larvae, pupae, drones, or wasps, yet a level of 0.24 +/- 0.05 mg/kg of Pb in pollen; therefore, the diet appears to be the primary pathway for environmental pollutants entering the honeybees' food chain. PMID- 23646932 TI - Indocyanine green-augmented diode laser therapy vs. long-pulsed Nd:YAG (1064 nm) laser treatment of telangiectatic leg veins: a randomized controlled trial. AB - BACKGROUND: Telangiectatic leg veins (TLV) represent a common cosmetic problem. Near infrared lasers have been widely used in treatment because of their deeper penetration into the dermis, but with varying degrees of success, particularly because of different vessel diameters. Indocyanine green (ICG)-augmented diode laser treatment (ICG+DL) may present an alternative treatment option. OBJECTIVES: This trial evaluates the efficacy of ICG+DL in the treatment of TLV and compares the safety and efficacy of therapy with the standard treatment, the long-pulsed neodymium-doped yttrium aluminium garnet (Nd:YAG) laser. METHODS: In a prospective randomized controlled clinical trial, 29 study participants with TLV were treated with a Nd:YAG laser (lambdaem = 1064 nm, 160-240 J cm(-2) , 65-ms pulse duration, 5-mm spot size) and ICG+DL (lambdaem = 810 nm, 60-110 J cm(-2) , 48-87-ms pulse duration, 6-mm spot size; total ICG dose 4 mg kg(-1) ) in a side by-side comparison in one single treatment setting that included histological examination in four participants. Two blinded investigators and the participants assessed clearance rate, cosmetic appearance and adverse events up to 3 months after treatment. RESULTS: According to both the investigators' and participants' assessment, clearance rates were significantly better after ICG+DL therapy than after Nd:YAG laser treatment (P < 0.05). On a 10-point scale indicating pain during treatment, participants rated ICG+DL therapy to be more painful (6.1 +/- 2.0) than Nd:YAG laser (5.4 +/- 2.0). CONCLUSIONS: ICG+DL therapy represents a new and promising treatment modality for TLV, with high clearance rates and a very good cosmetic outcome after one single treatment session. PMID- 23646933 TI - Testing decision rules for categorizing species' extinction risk to help develop quantitative listing criteria for the U.S. Endangered Species Act. AB - Lack of guidance for interpreting the definitions of endangered and threatened in the U.S. Endangered Species Act (ESA) has resulted in case-by-case decision making leaving the process vulnerable to being considered arbitrary or capricious. Adopting quantitative decision rules would remedy this but requires the agency to specify the relative urgency concerning extinction events over time, cutoff risk values corresponding to different levels of protection, and the importance given to different types of listing errors. We tested the performance of 3 sets of decision rules that use alternative functions for weighting the relative urgency of future extinction events: a threshold rule set, which uses a decision rule of x% probability of extinction over y years; a concave rule set, where the relative importance of future extinction events declines exponentially over time; and a shoulder rule set that uses a sigmoid shape function, where relative importance declines slowly at first and then more rapidly. We obtained decision cutoffs by interviewing several biologists and then emulated the listing process with simulations that covered a range of extinction risks typical of ESA listing decisions. We evaluated performance of the decision rules under different data quantities and qualities on the basis of the relative importance of misclassification errors. Although there was little difference between the performance of alternative decision rules for correct listings, the distribution of misclassifications differed depending on the function used. Misclassifications for the threshold and concave listing criteria resulted in more overprotection errors, particularly as uncertainty increased, whereas errors for the shoulder listing criteria were more symmetrical. We developed and tested the framework for quantitative decision rules for listing species under the U.S. ESA. If policy values can be agreed on, use of this framework would improve the implementation of the ESA by increasing transparency and consistency. PMID- 23646934 TI - Polysulfides link H2S to protein thiol oxidation. AB - AIMS: Hydrogen sulfide (H2S) is suggested to act as a gaseous signaling molecule in a variety of physiological processes. Its molecular mechanism of action was proposed to involve protein S-sulfhydration, that is, conversion of cysteinyl thiolates (Cys-S(-)) to persulfides (Cys-S-S(-)). A central and unresolved question is how H2S-that is, a molecule with sulfur in its lowest possible oxidation state (-2)-can lead to oxidative thiol modifications. RESULTS: Using the lipid phosphatase PTEN as a model protein, we find that the "H2S donor" sodium hydrosulfide (NaHS) leads to very rapid reversible oxidation of the enzyme in vitro. We identify polysulfides formed in NaHS solutions as the oxidizing species, and present evidence that sulfane sulfur is added to the active site cysteine. Polysulfide-mediated oxidation of PTEN was induced by all "H2S donors" tested, including sodium sulfide (Na2S), gaseous H2S, and morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate (GYY4137). Moreover, we show that polysulfides formed in H2S solutions readily modify PTEN inside intact cells. INNOVATION: Our results shed light on the previously unresolved question of how H2S leads to protein thiol oxidation, and suggest that polysulfides formed in solutions of H2S mediate this process. CONCLUSION: This study suggests that the effects that have been attributed to H2S in previous reports may in fact have been mediated by polysulfides. It also supports the notion that sulfane sulfur rather than sulfide is the actual in vivo agent of H2S signaling. PMID- 23646935 TI - N/S-heterocyclic contaminant removal from fuels by the mesoporous metal-organic framework MIL-100: the role of the metal ion. AB - The influence of the metal ion in the mesoporous metal trimesate MIL-100(Al(3+), Cr(3+), Fe(3+), V(3+)) on the adsorptive removal of N/S-heterocyclic molecules from fuels has been investigated by combining isotherms for adsorption from a model fuel solution with microcalorimetric and IR spectroscopic characterizations. The results show a clear influence of the different metals (Al, Fe, Cr, V) on the affinity for the heterocyclic compounds, on the integral adsorption enthalpies, and on the uptake capacities. Among several factors, the availability of coordinatively unsaturated sites and the presence of basic sites next to the coordinative vacancies are important factors contributing to the observed affinity differences for N-heterocyclic compounds. These trends were deduced from IR spectroscopic observation of adsorbed indole molecules, which can be chemisorbed coordinatively or by formation of hydrogen bonded species. On the basis of our results we are able to propose an optimized adsorbent for the deep and selective removal of nitrogen contaminants out of fuel feeds, namely MIL 100(V). PMID- 23646937 TI - Effects of the delay and duration of self-generated wind on behavioral compensation in unilaterally cercus-ablated crickets, Gryllus bimaculatus. AB - The effects of the delay and duration of wind self-generated during walking on the compensational recovery of escape direction were investigated in unilaterally cercus-ablated crickets, Gryllus bimaculatus. Artificial self-generated winds (self-stimulations; hereafter, SSts) from a nozzle set in front of a cricket placed on a styrofoam ball for stationary walking were used for training after unilateral cercus ablation. The delay and duration of artificial SSts were separately controlled. When the stimulus duration was fixed to 100 msec, the crickets trained with artificial SSts of 1000 msec delay showed a compensational recovery of the escape direction. However, no such compensational recovery was observed in crickets trained with artificial SSts of 1200, 1500, and 2000 msec delays. The relationship between the delay and duration of artificial SSts for compensational recovery was investigated. An artificial SSt with a longer delay required a longer-duration air current to cause a recovery of the escape direction. In contrast, an artificial SSt with a shorter delay was effective even when the duration was short. On the basis of the results obtained in the present study, we propose a hypothesis to explain the initial step for the compensation, that is, how the delay and duration of SSts are traded in terms of the compensational recovery of the escape direction. PMID- 23646938 TI - Diverse susceptibility of Galleria mellonella humoral immune response factors to the exoproteinase activity of entomopathogenic and clinical strains of Pseudomonas aeruginosa. AB - We investigated the effects of extracellular proteinases of two Pseudomonas aeruginosa clinical isolates on the essential humoral immune response parameters in hemolymph of the insect model organism Galleria mellonella in vitro. Two culture media, rich LB and minimal M9, known to induce synthesis of different sets of proteinases secreted by P. aeruginosa were used. Changes in lysozyme, antibacterial and antifungal activities, as well as protein and peptide patterns in hemolymph treated with proteolytic fractions were evaluated. The effect of the proteolytic fractions on the apoLp-III level in hemolymph was determined by immunoblotting with antibodies against G. mellonella apolipophorin III (apoLp III). We found that apoLp-III is hardly degraded by the proteinases of the proteolytic fractions of both clinical P. aeruginosa strains, in contrast to the high susceptibility of the protein to the proteinases of the entomopathogenic strain. The detected differences, together with the changes in the hemolymph protein and peptide patterns caused by the studied fractions, reflected the distinct composition of secreted proteinases of the entomopathogenic P. aeruginosa strain and the clinical strains tested. Our results also suggest the involvement of alkaline protease, the main proteinase of proteolytic fractions of P. aeruginosa grown in minimal medium, in the degradation of G. mellonella antimicrobial factors, such as lysozyme, antibacterial polypeptides, and proteins with antifungal activity. The diverse effects of the P. aeruginosa proteolytic fractions studied on the parameters of G. mellonella immune response indicate that this model insect may be useful in the analysis of the virulence factors of different P. aeruginosa strains. PMID- 23646936 TI - Conflicting roles for a cell surface modification in Salmonella. AB - Chemical modifications of components of the bacterial cell envelope can enhance resistance to antimicrobial agents. Why then are such modifications produced only under specific conditions? Here, we address this question by examining the role of regulated variations in O-antigen length in the lipopolysaccharide (LPS), a glycolipid that forms most of the outer leaflet of the outer membrane in Gram negative bacteria. We determined that activation of the PmrA/PmrB two-component system, which is the major regulator of LPS alterations in Salmonella enterica serovar Typhimurium, impaired growth of Salmonella in bile. This growth defect required the PmrA-activated gene wzz(st), which encodes the protein that determines long O-antigen chain length and confers resistance to complement mediated killing. By contrast, this growth defect did not require the wzz(fepE) gene, which controls production of very long O-antigen, or other PmrA-activated genes that mediate modifications of lipid A or core regions of the LPS. Additionally, we establish that long O-antigen inhibits growth in bile only in the presence of enterobacterial common antigen, an outer-membrane glycolipid that contributes to bile resistance. Our results suggest that Salmonella regulates the proportion of long O-antigen in its LPS to respond to the different conditions it faces during infection. PMID- 23646939 TI - Brief hypo-osmotic shock causes test cell death, prevents neurula rotation, and disrupts left-right asymmetry in Ciona intestinalis. AB - Ascidian Ciona intestinalis tadpole larvae exhibit left-right asymmetry. The photoreceptors are situated on the right side of the sensory vesicle, and the tail curls along the left side of the trunk within the chorion. In tailbud embryos, the Ci-pitx gene is expressed in the left-side epidermis. It was previously reported that embryos generated from naked eggs, which lack the chorionic membrane and accessory cells (follicle cells attached to the outside of the chorion and test cells covering the inner surface of the chorion), show bilateral expression of Ci-pitx. This suggested that the chorion or accessory cells are needed for generation of asymmetry. Here, we show that a brief treatment with 60% artificial seawater (ASW) before, but not after, the neurula stage results in bilateral expression of Ci-pitx in the chorion of tailbud embryos, loss of follicle cells, and randomization of both the direction of tail curling and the locations of photoreceptors in larvae. This treatment also impaired the transient counterclockwise rotation within the chorion at the neurula stage. Nearly all test cells in the chorion died following 60% ASW treatment. These results suggest that dead test cells blocked the neural rotation and impaired left-right asymmetry. We also showed that tailbud embryos and larvae generated from defolliculated eggs produced by 80% ASW treatment, in which the test cells were alive, showed normal left-right asymmetry, suggesting that the follicle cells were not essential for asymmetric morphogenesis. PMID- 23646940 TI - Relationship between two androgenetic clam species, Corbicula leana and Corbicula fluminea, inferred from mitochondrial cytochrome b and nuclear 28S rRNA markers. AB - Two shell color types, yellow (type I) and brown (type II), of hermaphrodite Corbicula fluminea clams from Ritto, Shiga Prefecture, Japan, are sympatric with both male and hermaphrodite Corbicula leana. In the present study, the mitochondrial DNA (mtDNA) cytochrome b and nuclear 28S rRNA genes of C. fluminea were sequenced to construct a haplotype network in order to investigate the genetic relationship with C. leana. Ninety C. fluminea samples revealed only two cytb haplotypes; the majority (97.8%) were CB7, while the remainder were CB1. In C. leana, only CB1 was detected in hermaphrodites, but both CB1 and CB7 were detected in males. Nuclear 28S rRNA haplotypes of C. fluminea type I individuals were divergent from those of hermaphrodite C. leana. However, C. fluminea type I clams shared haplotypes with male C. leana individuals, whereas C. fluminea type II individuals shared haplotypes with both hermaphrodite and male C. leana samples. These results suggest that it may be difficult to define a clear genetic border between these species. PMID- 23646941 TI - Diversity in the matrix structure of eggshells in the Testudines (Reptilia). AB - The eggshells of 56 chelonians were examined by electron microscopy and X-ray diffractometry. They were classified into six types in terms of the matrix structure of their calcareous layer; type I was composed of a thin calcareous layer with minerals in an amorphous structure; type II with shell units composed of mammillary cores calcified with aragonite crystals; type III with shell units composed of mammillary cores, plus a single palisade layer also calcified with aragonite crystals, and with each shell unit separated; type IV with shell units the same as type III, but tightly packed together; type V with shell units composed of mammillary cores plus two palisade layers; and type VI with a cuticle layer calcified with calcite crystals over the same structure as that of type V. X-ray diffraction analyses at the outer surface of eggshells showed a gradual change in crystal disposition from the random disposition of type II to the single direction-oriented disposition of type V. The shell height was approximately parallel to the development of the palisade-layer matrix. The limiting membrane of all eggshell types was perforated with canals and that of type I was partially missing. Type I had a parchment shell, types II and III had a pliable shell (some were rigid) and types IV to VI had rigid shells. The present study showed that the hardness of eggshells can be determined by the composition of the shell matrices, as shell matrices are the framework for mineralization. PMID- 23646942 TI - The fishermen were right: experimental evidence for tributary refuge hypothesis during floods. AB - Fishermen often anecdotally report an unexpected increase of fish caught in small tributary streams during floods, presumably due to refuge-seeking behavior from the main stem. From a population perspective, this implies the significance of refuge habitats and connectivity for population viability against natural disturbances. Despite the plausibility, however, surprisingly few studies have examined the tributary refuge hypothesis, mainly due to the difficulty in field survey during floods. Here, we made use of a large-scale controlled flood to assess whether fishes move into tributaries during flooding in the main stem. A planned water release from the Satsunai River Dam located on Hokkaido Island in Japan rapidly increased the main stem discharge by more than 20-fold. Before, during, and after flooding censuses in four tributaries provided evidence of the refuge-seeking behavior of fishes from the main stem. For example, more than 10 Dolly Varden char, a salmonid fish, were caught in a tributary during the flood, even though almost no individuals were captured before or after the flood. The fish responded immediately to the flooding, suggesting the need for studies during disturbances. In addition, the likelihood of refuge movements varied among tributaries, suggesting the importance of local environmental differences between tributary and the main stem habitats. This is the first study to experimentally confirm the tributary refuge hypothesis, and underscores the roles of habitat diversity and connectivity during disturbances, even though some habitats are not used during normal conditions. PMID- 23646943 TI - Divergence of scent pheromones in allopatric populations of Acanthodactylus boskianus (Squamata: Lacertidae). AB - The evolutionary phenomena associated with divergence in chemical signals between populations of the same species help to understand the process of speciation. Animals detect and react to semiochemicals and pheromones used in communication. Comparison between populations of the same species that are geographically isolated from one another allows us to determine the genetic or environmental factors responsible for chemical differentiation. Acanthodactylus boskianus from the east and west of Egypt were used as an example to compare the geographical diversity in chemical fingerprints of this species' femoral gland secretions and its phylogeography. Chemical analysis via GC-MS showed that the two geographically distinct populations' odor fingerprints are quantitatively different despite sharing the same components of the secretions. Phylogenetic analysis showed that the eastern and western Egyptian populations are genetically distinct and that chemical divergence of these lizards' odor profiles may be an example of signal evolution. PMID- 23646944 TI - Microhabitat use by Hyla japonica and Pelophylax porosa brevipoda at Levees in rice paddy areas of Japan. AB - In Japan, rice paddies have acted as substitute habitats for pond-breeding frogs. However, frog populations are declining due to the loss of habitat and environmental changes in rice paddy areas. Frogs need both aquatic and terrestrial habitats to complete their life history; in rice paddy areas, levees that surround rice paddies provide terrestrial habitats for basking, foraging, and shelter from predators. Studying microhabitat use at levees is important to elucidating the ecological roles of levees and to properly managing them to support frog populations. In this study, we conducted surveys in lowland modernized rice paddy areas in Shiga Prefecture in which a common species, Hyla japonica, and an endangered species, Pelophylax porosa brevipoda, were found. We captured frogs at levees and recorded environmental factors related to levee vegetation, rice paddy conditions, and weather. We constructed generalized linear mixed models to examine the effects of environmental factors on juvenile and adult H. japonica and on small and large juveniles, females, and males of P. p. brevipoda. Our results showed distinct microhabitat uses at levees in different species, sexes, and body sizes. In general, abundance was high at levees with vegetation that provided shelter. The water depth in rice paddies negatively influenced juvenile H. japonica and large juvenile and small female P. p. brevipoda, and positively influenced small male P. p. brevipoda. The maintenance of a mosaic structure of levees was important not only to support frog populations but also to maintain frog diversity in the area. PMID- 23646945 TI - Effects of Evans Blue and amiloride on anti-diuretic hormone (ADH)-induced sodium transport across frog (Rana hexadactyla) skin. AB - The epithelial sodium channel (ENaC) has four subunits, namely alpha (alpha), beta (beta), gamma (gamma) and delta (delta). The functional ENaC is formed by the combination of either alphabetagamma or deltabetagamma subunits. The aim of the present study is to determine the combination of ENaC subunits predominant on the apical side of the frog skin, and the effect of ADH on sodium transport though these two ENaCs subunit combinations. The ventral abdominal skin of the frog, Rana hexadactyla was mounted in an Ussing-type chamber. The voltage-clamp method was performed to measure the ionic transport across the frog skin with normal Ringer solution (NR) on both sides. Evans blue (300 uM) and amiloride (100 uM) were added to the NR on the apical side and ADH (40 nM) was added on the serosal side. Statistical significance was analyzed by Student's paired t-test and repeated-measures ANOVA, P < 0.05 was considered significant. This study suggests that the ENaC of the frog skin consist of both alphabetagamma and deltabetagamma subunit combinations on the apical side. Though both types of subunit combination are present, the alphabetagamma type was found to be more common than deltabetagamma. ADH increases the sodium transport across the frog skin. The effect of ADH on sodium transport is achieved through the combination of delta-subunits, not through the combination of a-subunits in the skin of Pana hexadactyla. PMID- 23646946 TI - Molecular barcoding of an atypical cyprinid population assessed by cytochrome B gene sequencing. AB - A fish population of the carp family Cyprinidae with atypical phenotypic characteristics was observed in one of the main catchments of the Pollino National Park, a valuable, protected area in southern Italy. In this area, the Italian roach Rutilus rubilio (Bonaparte, 1837), a native endemic fish of Tyrrhenean regions, has been introduced in sympatric conditions with Squalius squalus (Bonaparte, 1837) and Telestes muticellus (Bonaparte, 1837). A molecular investigation was carried out to assess the genetic identity of the population with a view to conservation. Direct sequencing of a cytochrome b gene fragment was performed based on 30 individuals of cyprinid fish with atypical phenotype, in addition to 30 S. squalus, 10 T. muticellus, and 30 R. rubilio pure individuals collected in different Italian regions, which served as reference samples. Multiple sequence alignments demonstrated that 50% of atypical-cyprinid haplotypes were maternally inherited from either S. squalus or R. rubilio. No contribution by T. muticellus was determined. Our results indicate an intergeneric hybridization event between S. squalus and R. rubilio, as a consequence of trans-introduction activities of alien species. PMID- 23646947 TI - Neostygarctus lovedeluxe n. sp. from the Miyako Islands, Japan: the first record of Neostygarctidae (Heterotardigrada: Arthrotardigrada) from the Pacific. AB - A new species of the previously monospecific marine tardigrade family Neostygarctidae is described. Neostygarctus lovedeluxe n. sp. was found from a submarine cave in Miyako Islands, Japan. This is the first record of Neostygarctidae from the Pacific. The new species is easily distinguished from the previously known N. acanthophorus by its number of dorsal spines, as N. lovedeluxe has two spines each on the three dorsal body plates in contrast to one in N. acanthophorus. Furthermore the morphology of the two clawed juvenile is reported for the first time in Neostygarctidae, providing new insights into the common sequence in some ontogenic traits. PMID- 23646948 TI - Endogenous-peptide-dependent alloreactivity: new scientific insights and clinical implications. AB - T-cell alloreactivity is generated via immune responsiveness directed against allogeneic (allo) human leucocyte antigen (HLA) molecules. Whilst the alloresponse is of extraordinary potency and frequency, it has often been assumed to be less peptide-specific than conventional T-cell reactivity. Recently, several human studies have shown that both alloreactive CD8(+) and CD4(+) T cells exhibit exquisite allo-HLA and endogenous peptide specificity that has also underpinned tissue-specific allorecognition. In this review, we summarize former and recent scientific evidence in support of endogenous peptide (self-peptide) dependence of T-cell alloreactivity. The clinical implications of these findings will be discussed in the context of both solid organ transplantation and haematopoietic stem cell transplantation (HSCT). Insights into the understanding of the molecular basis of T-cell allorecognition will probably translate into improved allograft survival outcomes, lower frequencies of graft vs host disease and could potentially be exploited for selective graft vs leukaemia effect to improve clinical outcomes following HSCT. PMID- 23646949 TI - Peptide-binding motifs and characteristics for HLA -B*13:01 molecule. AB - Trichloroethylene (TCE)-induced hypersensitivity dermatitis is one of the critical occupational diseases among workers in China. Our previous studies have identified a strong linkage between the disease and the HLA-B*13:01 allele. In this study, we searched for peptides bound to the HLA-B*13:01 molecule; 57 HLA B*13:01-bound peptides in total were identified and 54 peptides were used to calculate frequency of amino acid residues to obtain binding motifs of HLA B*13:01 molecule. The results showed P2, P3, and P9 were the primary binding anchor positions with the dominant anchor motifs of L, Q at P2, L at P9, D at P3. HLA-B*13:01-bound peptides were identified for the first time in our research, the results of which could contribute to the human leukocyte antigen (HLA) binding peptides database. PMID- 23646950 TI - The novel allele HLA-A*02:145 differs from HLA-A*02:01:01 by a single amino acid exchange at position 153 from alanine to valine. AB - HLA-A*02:145 differs from HLA-A*02:02:01:01 by the amino acid exchange at position 153 Ala changes to Val. PMID- 23646951 TI - A novel HLA-A*02 allele, HLA-A*02:129. AB - HLA-A*02:129 differs from HLA-A*02:87 exon 2 at nt 25, nt 29, nt 167 T, nt 184 and nt 192. PMID- 23646952 TI - A novel HLA-A null allele (A*02:395N) with stop codon in exon 2 generated by single nucleotide exchange. AB - The new HLA-A*02:395N allele differs from A*02:01:01 at one nucleotide position in the exon 2. PMID- 23646953 TI - A novel allele, HLA-A*03:01:09, identified by sequence-based typing in a Chinese individual. AB - We describe the identification of a novel allele HLA-A*03:01:09 in a Chinese individual. PMID- 23646954 TI - A novel HLA-A allele, A*66:17 was revealed in a family of a leukemia patient during high-resolution HLA typing. AB - HLA -A*66:17, presented here, shows a single-nucleotide polymorphism in exon 4 in comparison to A*66:01. PMID- 23646955 TI - Identification of the novel HLA-B*50:18 allele variant in an Italian unrelated bone marrow donor. AB - The HLA-B*50:18 allele differs from the closest related B*50:01:01 by one nucleotide substitution at position 454 in exon 3. PMID- 23646956 TI - The novel allele HLA-DQB1*06:01:04 differs from HLA-DQB1*06:01:01 by a single synonymous nucleotide exchange. AB - HLA-DQB1*06:01:04 differs from HLA-DQB1*06:01:01 by the nucleotide exchange at position 156 (G >C) without an amino exchange. PMID- 23646957 TI - Nomenclature for factors of the HLA system, update January 2013. PMID- 23646958 TI - Nomenclature for factors of the HLA system, update February 2013. PMID- 23646959 TI - Nomenclature for factors of the HLA system, update March 2013. PMID- 23646961 TI - The puzzle(s) of pharmacoresistant epilepsy. AB - Despite the availability of >25 antiepileptic drugs, 30% of people with epilepsy do not respond to conventional agents, exhibiting pharmacoresistance (PR)--a high percentage that has not changed significantly in decades. This is not surprising given that all current pharmaceutical agents merely reduce the incidence of seizures ("antiictogenic"); they do not interfere with the natural history of epilepsy and are therefore not antiepileptogenic. The two prevailing hypotheses of pharmacoresistance, the target hypothesis and the transporter hypothesis, can only partially explain the complexity and the diversity of PR. It is a neuropharmacologic priority that we change our approach to understanding PR. Herein we suggest the need to regard PR as a complex puzzle in which the target and transporter hypotheses represent a very small piece of the whole. Indeed, we do not even know if this piece of the whole is epiphenomenal or neurobiologically causal. To grasp the whole, we need to constantly gather information (look around for other pieces) from other perspectives and insights coming from clinical, epidemiologic, neuroradiologic, genetic, and other data. A recent research workshop on PR, the 2nd Halifax International Epilepsy Conference & Retreat, chose this eclectic and all-encompassing approach. The participants were fully aware that their diverse contributions represent only still-fragmented pieces of this frustrating but clinically important puzzle. PMID- 23646962 TI - Road to refractory epilepsy: the Glasgow story. AB - This short article reviews 30 years of prospective observations on outcomes relevant to an expanding cohort of adolescent and adult patients with newly diagnosed epilepsy, who received their first antiepileptic drug (AED) and subsequent long-term follow-up at the Epilepsy Unit at the Western Infirmary in Glasgow, United Kingdom. Despite the fact that the overall prognosis has slowly improved over this time, >30% of the patients remain uncontrolled despite the introduction of a range of new AEDs, some with unique mechanisms of action, over the last 20 years. Most patients followed a constant course (59% controlled, 25% refractory), which could usually be predicted early. The remaining 16% fluctuated between periods of remission and relapse. The likelihood of seizure freedom declined with successive drug regimens, most markedly from the first to the third. A number of factors predicting poorer outcomes have been identified, particularly high pretreatment seizure density and concomitant psychiatric comorbidities. Novel approaches to identifying and treating the processes underpinning the generation and propagation of seizures are required if the current rather disappointing scenario is to be substantially improved. PMID- 23646963 TI - Definition of drug-resistant epilepsy: is it evidence based? AB - Clinical case definitions are the cornerstone of clinical communication and of clinical and epidemiologic research. The ramifications of establishing a case definition are extensive, including potentially large changes in epidemiologic estimates of frequency, and decisions for clinical management. Yet, defining a condition entails numerous challenges such as defining the scope and purpose, incorporating the strongest evidence base with clinical expertise, accounting for patients' values, and considering impact on care. The clinical case definition of drug-resistant epilepsy, in addition, must address what constitutes an adequate intervention for an individual drug, what are the outcomes of relevance, what period of observation is sufficient to determine success or failure, how many medications should be tried, whether seizure frequency should play a role, and what is the role of side effects and tolerability. On the other hand, the principles of evidence-based medicine (EBM) aim at providing a systematic approach to incorporating the best available evidence into the process of clinical decision for individual patients. The case definition of drug-resistant epilepsy proposed by the the International League Against Epilepsy (ILAE) in 2009 is evaluated in terms of the principles of EBM as well as the stated goals of the authors of the definition. PMID- 23646964 TI - The enigma of placebo effects in drug-refractory epilepsies. AB - Placebo effects in the therapy of epilepsy were already known before the introduction of effective antiepileptic drugs (AEDs). They have physiologic correlates, and are even stronger in other neurologic disorders such as pain. Placebo effects in epilepsy have many facets. Our understanding of this phenomenon has increased in the last two decades: placebo effects are stronger in children than in adults, and may be culture- and setting-dependent; and impressive placebo effects occur in animals with epilepsy as well. More research is needed to fully elucidate the mechanism of placebo effects in epilepsy care, particularly as we go forth with studies addressing the issue of pharmacoresistance. PMID- 23646960 TI - Enhanced endothelin receptor type B-mediated vasodilation and underlying [Ca2+]i in mesenteric microvessels of pregnant rats. AB - BACKGROUND AND PURPOSE: Normal pregnancy is associated with decreased vascular resistance and increased release of vasodilators. Endothelin-1 (ET-1) causes vasoconstriction via endothelin receptor type A (ET(A)R), but could activate ET(B)R in the endothelium and release vasodilator substances. However, the roles of ET(B)R in the regulation of vascular function during pregnancy and the vascular mediators involved are unclear. EXPERIMENTAL APPROACH: Pressurized mesenteric microvessels from pregnant and virgin Sprague-Dawley rats were loaded with fura-2/AM for simultaneous measurement of diameter and [Ca2+]i. KEY RESULTS: High KCl (51 mM) and phenylephrine (PHE) caused increases in vasoconstriction and [Ca2+]i that were similar in pregnant and virgin rats. ET-1 caused vasoconstriction that was less in pregnant than virgin rats, with small increases in [Ca2+]i. Pretreatment with the ET(B)R antagonist BQ-788 caused greater enhancement of ET-1-induced vasoconstriction in pregnant rats. ACh caused endothelium-dependent relaxation and decreased [Ca2+]i, and was more potent in pregnant than in virgin rats. ET-1 + ET(A)R antagonist BQ-123, and the ET(B)R agonists sarafotoxin 6c (S6c) and IRL-1620 caused greater vasodilation in pregnant than in virgin rats with no changes in [Ca2+]i, suggesting up-regulated ET(B)R-mediated relaxation pathways. ACh-, S6c- and IRL-1620-induced relaxation was reduced by the NO synthase inhibitor Nomega-nitro-L-arginine methyl ester, and abolished by tetraethylammonium or endothelium removal. Western blots revealed greater amount of ET(B)R in intact microvessels of pregnant than virgin rats, but reduced levels in endothelium-denuded microvessels, supporting a role of endothelial ET(B)R. CONCLUSIONS AND IMPLICATIONS: The enhanced ET(B)R-mediated microvascular relaxation may contribute to the decreased vasoconstriction and vascular resistance during pregnancy. PMID- 23646965 TI - Opportunity gained, opportunity lost: treating pharmacoresistant epilepsy in children. AB - Childhood is a vulnerable time--developmentally, socially, and cognitively. Any disruption may have long-standing effects on the attainment of critical developmental milestones. The impact of ongoing seizures and epilepsy in children is significant and may result in cognitive delay, poorer educational outcomes, and lower employment rates in adulthood. The early recognition, intervention, and treatment of evolving pharmacoresistant epilepsy in children presents a unique opportunities for health care practitioners. Seizure freedom is the ultimate epilepsy treatment goal, given the broad and long-standing effects of seizures in childhood. However, even when we believe the chance of seizure freedom is low, we should not let the perceived unlikelihood of that goal limit the treatments we offer. All children with pharmacoresistant epilepsy should be evaluated at a comprehensive pediatric epilepsy center. Failing to offer state-of-the-art treatments to these children only increases the burden of epilepsy on children and their families. PMID- 23646966 TI - Predicting pharmacoresistance in pediatric epilepsy. AB - Approximately 20% of children with epilepsy will be pharmacoresistant. The impact of intractable epilepsy extends far beyond just the seizures to result in intellectual disability, psychiatric comorbidity, physical injury, sudden unexpected death in epilepsy (SUDEP), and poor quality of life. Various predictors of pharmacoresistance have been identified; however, accurate prediction is still challenging. Population-based epidemiologic studies show that the majority of children who develop pharmacoresistance do so relatively early in the course of their epilepsy. However, approximately one third of children who initially appear pharmacoresistant in the first few years after epilepsy onset will ultimately achieve seizure freedom without surgery. The most significant predictor that early pharmacoresistance will not remit is the presence of a neuroimaging abnormality. Such children should be strongly considered for surgical evaluation. PMID- 23646967 TI - Prevention of sudden unexpected death in epilepsy: a realistic goal? AB - Sudden unexpected death in epilepsy (SUDEP) represents one of the most severe consequences of drug-resistant epilepsy, for which no evidence-based prevention is available. Development of effective prevention will depend on the following: (1) better understanding of the pathophysiology of SUDEP to define the most appropriate targets of intervention, and (2) identification of risk factors for SUDEP that would allow for the design of feasible clinical trials to test targeted interventions in high-risk populations. The most important known risk factor is the occurrence and frequency of generalized tonic-clonic seizure (GTCS), a seizure type that triggers the majority of witnessed SUDEP. Therefore, one likely way to prevent SUDEP is to minimize the risk of GTCS with optimal medical management and patient education. However, whether one might prevent SUDEP in patients with refractory epilepsy by using more frequent review of antiepileptic treatment and earlier referral for presurgical evaluation, remains to be seen. Another hypothetical strategy to prevent SUDEP is to reduce the risk of GTCS-induced postictal respiratory distress. This might be achieved by using lattice pillow, providing nocturnal supervision, reinforcing interictal serotoninergic tone, and lowering opiate- or adenosine-induced postictal brainstem depression. Promising interventions can be tested first on surrogate markers, such as postictal hypoxia in epilepsy monitoring units (EMUs), before SUDEP trials can be implemented. EMU safety should also be improved to avoid SUDEP occurrence in that setting. Finally, the development of ambulatory SUDEP prevention devices should be encouraged but raises a number of unsolved issues. PMID- 23646968 TI - Animal and human data: where are our concepts for drug-resistant epilepsy going? AB - Drug-resistant epilepsy remains a challenge in the therapeutic management of patients with epilepsy. Identification of factors contributing to drug resistance might render a basis for the development of novel therapeutic approaches, for the reorganization of screening programs in drug development, and for the design of personalized treatment concepts. Therefore, experimental and clinical studies need to link efforts and collaborate in order to elucidate drug-resistance mechanisms, to define the relative clinical relevance of selected mechanisms, and to develop and validate novel therapeutic concepts in overcoming resistance. PMID- 23646969 TI - The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs. AB - Pharmacoresistance to antiepileptic drugs (AEDs) is a barrier to seizure freedom for many persons with epilepsy. For nearly two decades, pharmacoresistance has been framed in terms of factors affecting the access of AEDs to their molecular targets in the brain or the actions of the drugs on these targets. Shortcomings in this prevailing view led to the formulation of the intrinsic severity hypothesis of pharmacoresistance to AEDs, which is based on the recognition that there are neurobiologic factors that confer phenotypic variation among individuals with etiologically similar forms of epilepsy and postulates that more severe epilepsy is more difficult to treat with AEDs. In recent years, progress has been made identifying potential genetic mechanisms of variation in epilepsy severity, including subclinical mutations in ion channels that increase or reduce epilepsy severity in mice. Efforts are underway to identify clinically important genetic modifiers. If it can be demonstrated that such severity factors play a role in pharmacoresistance, treatments could be devised to reverse severity mechanisms. By overcoming pharmacoresistance, this new approach to epilepsy therapy may allow drug refractory patients to achieve seizure freedom without side effects. PMID- 23646970 TI - The methylation hypothesis of pharmacoresistance in epilepsy. AB - Seizures cannot be medically controlled in approximately 40% of people with epilepsy. Although we are beginning to understand how to better treat certain seizure types, we still do not know the regulatory events that determine antiepileptic drug resistance. Proposed pathoetiologic mechanisms include altered expression of drug targets (i.e., receptor or ion channel modifications), endothelial drug transporter activation (i.e., increasing drug clearance), or intrinsic severity factors. The latter hypothesis results from an often confirmed clinical observation, that seizure severity is a reliable predictor for the development of pharmacoresistance (PR) in epilepsy. Herein, we propose, that genome modifications that do not involve changes to the DNA sequence per se (i.e., epigenetic changes) could confer PR in patients with epilepsy. Seizures cause excessive neuronal membrane depolarization, which can influence the cellular nucleus; we thus hypothesize that seizures can mediate epigenetic modifications that result in persistent genomic methylation, histone density, and posttranslational modifications, as well as noncoding RNA-based changes. Although experimental evidence is lacking in epilepsy, such mechanisms are well characterized in cancer, either as a result of anticancer drugs themselves or cancer-related intrinsic signals (i.e., noncoding RNAs). We suggest that similar mechanisms also play a role in PR epilepsies. Addressing such epigenetic mechanisms may be a successful strategy to increase the brain's sensitivity to antiepileptic drugs and may even act as disease-modifying treatment. PMID- 23646971 TI - Value of autoantibodies for prediction of treatment response in patients with autoimmune epilepsy: review of the literature and suggestions for clinical management. AB - The detection of antineural autoantibodies in patients with epilepsy has led to the new concept of "autoimmune epilepsy." A particularly important implication is that knowledge of the antigenic target of the underlying antibody permits prognostic estimates. Patients with antibodies to the potassium channel complex (mostly to its leucine-rich glioma inactivated 1 [LGI1] component) have a high chance of becoming seizure free within days to months upon immunotherapy but less so with antiepileptic drug (AED) treatment alone. Seizures in the setting of antibodies to the N-methyl-d-aspartate receptor also have a high likelihood to remit, again especially with rapid institution of immunotherapy. In contrast to these antibodies to neuronal surface molecules, antibodies directed to intracellular antigens (onconeural antibodies, antibodies to glutamic acid decarboxylase) portend a low likelihood of seizure remission, regardless of the treatments chosen. These outcome differences are probably related to the underlying pathophysiology--with largely reversible functional effects of antibodies to surface antigens and irreversible destructive sequelae (probably caused by T cells) in patients with antibodies to intracellular antigens. With ongoing experience with these conditions, clinical and paraclinical clues to the diagnosis of autoimmune epilepsies are emerging. PMID- 23646972 TI - Design of innovative therapeutics for pharmacoresistant epilepsy: challenges and needs. AB - Effective therapy for pharmacoresistant epilepsy is an unmet clinical need. Pharmacologically, there are two logical approaches: super-antiictogenic drugs (SAIDs) or antiepileptogenic agents. However, can either of these agents be successfully designed and developed? Designing SAIDs or antiepileptogenics will require applying the techniques of twenty-first century drug design to this ancient "sacred disease." Before this task can be effectively realized, five fundamental needs will first have to be addressed: need for antiepileptogenic drug targets, need for druggable targets for SAIDs, need for new drug molecule platforms, need for new and relevant animal models, and need for innovative funding strategies. PMID- 23646975 TI - Multimodal neuroimaging: potential biomarkers for response to antiepileptic drugs? AB - Neuroimaging techniques in epilepsy are used widely for definition of the epileptogenic lesion and surgical decision. However, its applications extend to the knowledge of epileptic mechanisms and include the identification of prognostic features that can help our decisions on the appropriate type of treatment on an individual basis. Structural neuroimaging may be able to identify patients more likely to respond to antiepileptic drug (AED) treatment and also patients who are better candidates for earlier surgical treatment. In the past decades, quantitative analyses have also improved our knowledge about epileptogenic lesions and networks as well as the following prognoses: seizure control, cognitive outcome, and comorbidities. New advanced neuroimaging techniques such as functional magnetic resonance imaging (MRI) and the development biotracers that could be associated with inflammation and specific genetic patterns will add further knowledge to the development of epilepsy treatments. PMID- 23646973 TI - EEG abnormalities as a biomarker for cognitive comorbidities in pharmacoresistant epilepsy. AB - Cognitive impairment is a common and often devastating comorbidity of pharmacoresistent epilepsy. The cognitive comorbidity can be both chronic, primarily due to the underlying etiology of the epilepsy, and dynamic or evolving because of recurrent seizures or interictal spikes. There is now considerable evidence that interictal spikes can contribute to cognitive impairment. Interictal spikes in both rodents and humans result in transient impairment of memory retrieval, whereas in immature animals, interictal spikes can result in long-term adverse effects on brain development. Interictal spikes therefore contribute to the cognitive impairment in the pharmacoresistant epilepsies. Effective treatment of pharmacoresistant epilepsy needs to target not only the overt seizures but interictal electroencephalography (EEG) abnormalities as well. PMID- 23646974 TI - Is routine electroencephalography (EEG) a useful biomarker for pharmacoresistant epilepsy? AB - People with seizure disorders who have been treated at the Kork Epilepsy Center over a prolonged time period and who thus provide data concerning the chronic course of epilepsy were investigated in order to address the potential role of electroencephalography (EEG) as a biomarker for pharmacoresistant epilepsy. Clinical course and the corresponding findings from their first recorded EEG, their first EEG following appropriate treatment, and their last EEG were compared. Furthermore, we investigated if interictal epileptiform discharges (IEDs) differ in amplitude and morphology if recorded in long-term seizure-free patients. The early cessation of IEDs was a relatively good marker for a good prognosis, especially in idiopathic generalized epilepsies. However, persistent IEDs had no major impact on the long-term prognosis. We found no differences between IEDs in seizure-free patients or patients with ongoing seizures. Therefore, in our hands, routine EEG was not an appropriate biomarker for the prediction of pharmacoresistant epilepsy. Additional factors such as etiology and pathophysiology also need to be considered. PMID- 23646976 TI - Can we develop pathology-specific MRI contrast for "MR-negative" epilepsy? AB - Recent improvements in magnetic resonance imaging (MRI) hardware, software, and analysis routines are helping to put cases of "MR-negative" epilepsy on the decline. However, most standard-of-care MRI relies on careful manipulation and presentation of T1, T2, and diffusion-weighted contrast, which characterize the behavior of water in "bulk" tissue rather than providing pathology-specific contrast. Research efforts in MR physics continue to identify and develop novel theory, and methods such as diffusional kurtosis imaging (DKI) and temporal diffusion spectroscopy that can better characterize tissue substructure, and chemical exchange saturation transfer (CEST) that can target underlying biochemical processes. The potential role of each technique in targeting pathologies implicated in "MR-negative" epilepsy is outlined herein. PMID- 23646977 TI - A conceptual framework for the use of neuroimaging to study and predict pharmacoresistance in epilepsy. AB - Twenty percent to 49% of newly treated patients with epilepsy will develop pharmacoresistance (PR). The mechanisms leading to PR are unclear. There is currently no unifying theory to explain the variety of presentations of PR and the diversity of potential contributing factors. Etiology of seizures seems to play a critical role in at least a subset of PR. Many magnetic resonance imaging (MRI) studies in the advanced stages of epilepsy suggest a strong association between lesions such as hippocampal sclerosis and focal cortical dysplasia and PR. Unfortunately, almost all of these studies are cross-sectional and retrospective. There is a need for a new perspective on the role of preexisting lesions in the evolution of epilepsy and PR. We propose in this article to study a unique population of drug-naive patients with either first seizure or new-onset epilepsy longitudinally with advanced MRI imaging techniques, including magnetic resonance spectroscopy and diffusion tensor imaging. We hope to be able to monitor imaging findings and the development of PR early in the course of the disease in a subset of these patients with temporal lobe epilepsy (TLE). Our goal is to understand the pathogenesis of PR, to dissect changes associated with the development of PR from changes associated with chronic seizures and medication, and ultimately to predict PR at the onset of disease. PMID- 23646978 TI - Pharmacoresistant epilepsy: unmet needs in solving the puzzle(s). AB - Pharmacoresistant epilepsy is a significant medical problem. The 2nd Halifax International Epilepsy Conference & Retreat identified crucial needs, which if successfully addressed, will aid in paving the way to improved lives for people with pharmacoresistant epilepsy. These are needs: (1) for an evidence-based and dynamic definition of pharmacoresistant epilepsy; (2) for a comprehensive description of the natural history of pharmacoresistant epilepsy; (3) for a comprehensive description of the complications and comorbidities of pharmacoresistant epilepsy; (4) for a rigorous delineation of the epidemiology and socioeconomic impact of pharmacoresistant epilepsy; (5) for clinically meaningful diagnostic and prognostic physiologically based electroencephalography (EEG) biomarkers; (6) for clinically meaningful diagnostic and prognostic anatomically based (MRI Imaging) biomarkers; (7) for biomolecular/biochemical mechanistic understanding of etiopathogenesis for pharmacoresistant epilepsy; (8) for representative animal models of pharmacoresistant epilepsy; (9) for new and effective drugs or other novel treatments for pharmacoresistant epilepsy; and (10) to promote continuing research and research funding targeting pharmacoresistant epilepsy. PMID- 23646979 TI - Advances in the development of hybrid anticancer drugs. AB - INTRODUCTION: Hybrid anticancer drugs are of great therapeutic interests as they can potentially overcome most of the pharmacokinetic drawbacks encountered when using conventional anticancer drugs. In fact, the future of hybrid anticancer drugs is very bright for the discovery of highly potent and selective molecules that triggers two or more cytocidal pharmacological mechanisms of action acting in synergy to inhibit cancer tumor growth. AREAS COVERED: This review represents the most advanced and recent data in the field of hybrid anticancer agents covering mainly the past 5 years of research. It also accounts for other significant reviews already published on the topic of anticancer hybrids. The review showcases the research that is at the leading edge of hybrid anticancer drug discovery. The main areas covered by the present review are: DNA alkylating agent hybrids (e.g., platinum(II), nitrogen mustard, etc.), vitamin-D receptor, agonist-histone deacetylase inhibitors, combi-molecule therapies and other types of hybrid anticancer agents. EXPERT OPINION: The current development in the field describes strategies that have never been used before for the design of hybrid anticancer drugs. The information currently available and described in this section allows us to identify the main parameters required to design such molecules. It also provides a clear view of the future directions that must be explored for the successful development and discovery of useful hybrid anticancer drugs. PMID- 23646981 TI - Effects of bone morphogenetic protein-6 on periodontal wound healing/regeneration in supraalveolar periodontal defects in dogs. AB - OBJECTIVE: Application of a synthetic BMP-6 polypeptide in a rat periodontal fenestration defect model enhanced periodontal wound healing/regeneration including new bone and cementum formation. The purpose of this study was to translate the relevance of these initial observations into a discriminating large animal model. METHODS: Critical-size (4-5 mm) supraalveolar periodontal defects were created at the 2(nd) and 3(rd) mandibular premolar teeth in 11 Beagle dogs. Experimental sites received BMP-6 at 0.25, 1.0 and 2.0 mg/ml soak-loaded onto an absorbable collagen sponge (ACS) carrier or ACS alone (control) each condition repeated in four jaw quadrants. The animals were euthanized at 8 weeks when block biopsies were collected and processed for histologic/histometric analysis. RESULTS: BMP-6 at 0.25, 1.0 and 2.0 mg/ml soak-loaded onto the ACS yielded significantly enhanced new bone (0.99 +/- 0.07 versus 0.23 +/- 0.13 mm/BMP-6 at 0.25 mg/ml) and cementum (2.45 +/- 0.54 versus 0.73 +/- 0.15 mm/BMP-6 at 0.25 mg/ml) formation including a functionally oriented periodontal ligament compared with control (p < 0.05). A significant inverse linear association between BMP-6 dose and new bone (beta = -0.21 +/- 0.09 mm, p = 0.016) and cementum height (beta = -0.34 +/- 0.15 mm, p = 0.023) was observed. Minimal root resorption was observed without significant differences between groups. Ankylosis was not observed for any of the experimental groups. CONCLUSIONS: Surgical application of BMP-6/ACS onto critical-size supraalveolar defects enhanced periodontal wound healing/regeneration, in particular cementogenesis including a functionally oriented periodontal ligament; the low BMP-6 0.25 mg/ml concentration apparently providing the most effective dose. PMID- 23646980 TI - P2X7 receptor-induced death of motor neurons by a peroxynitrite/FAS-dependent pathway. AB - The P2X7 receptor/channel responds to extracellular ATP and is associated with neuronal death and neuroinflammation in spinal cord injury and amyotrophic lateral sclerosis. Whether activation of P2X7 directly causes motor neuron death is unknown. We found that cultured motor neurons isolated from embryonic rat spinal cord express P2X7 and underwent caspase-dependent apoptosis when exposed to exceptionally low concentrations of the P2X7 agonist 2'(3')-O-(4 Benzoylbenzoyl)-ATP. The P2X7 inhibitors BBG, oATP, and KN-62 prevented 2'(3')-O (4-Benzoylbenzoyl)-ATP-induced motor neuron death. The endogenous P2X7 agonist ATP induced motor neuron death at low concentrations (1-100 MUM). High concentrations of ATP (1 mM) paradoxically became protective due to degradation in the culture media to produce adenosine and activate adenosine receptors. P2X7 induced motor neuron death was dependent on neuronal nitric oxide synthase mediated production of peroxynitrite, p38 activation, and autocrine FAS signaling. Taken together, our results indicate that motor neurons are highly sensitive to P2X7 activation, which triggers apoptosis by activation of the well established peroxynitrite/FAS death pathway in motor neurons. PMID- 23646982 TI - Stored carbon partly fuels fine-root respiration but is not used for production of new fine roots. AB - The relative use of new photosynthate compared to stored carbon (C) for the production and maintenance of fine roots, and the rate of C turnover in heterogeneous fine-root populations, are poorly understood. We followed the relaxation of a (13)C tracer in fine roots in a Liquidambar styraciflua plantation at the conclusion of a free-air CO(2) enrichment experiment. Goals included quantifying the relative fractions of new photosynthate vs stored C used in root growth and root respiration, as well as the turnover rate of fine-root C fixed during [CO(2)] fumigation. New fine-root growth was largely from recent photosynthate, while nearly one-quarter of respired C was from a storage pool. Changes in the isotopic composition of the fine-root population over two full growing seasons indicated heterogeneous C pools; < 10% of root C had a residence time < 3 months, while a majority of root C had a residence time > 2 yr. Compared to a one-pool model, a two-pool model for C turnover in fine roots (with 5 and 0.37 yr(-1) turnover times) doubles the fine-root contribution to forest NPP (9 13%) and supports the 50% root-to-soil transfer rate often used in models. PMID- 23646983 TI - Magnesium-tartramide complex mediated asymmetric Strecker-type reaction of nitrones using cyanohydrin. AB - An asymmetric Strecker-type reaction of nitrones using acetone cyanohydrin as a source of HCN has been realized. A magnesium-tartramide complex, generated from (R,R)-2,3-dihydroxy-1,4-di(pyrrolidin-1-yl)-butane-1,4-dione and MeMgBr, promoted transcyanation from the bromomagnesium salt of the cyanohydrin, in the presence of a catalytic amount of DBU, to afford the corresponding optically active (S) alpha-amino nitrile derivatives. The reaction was applicable to various nitrones giving high-to-excellent enantioselectivities. PMID- 23646984 TI - Expression of flavonoid 3',5'-hydroxylase and acetolactate synthase genes in transgenic carnation: assessing the safety of a nonfood plant. AB - For 16 years, genetically modified flowers of carnation ( Dianthus caryophyllus ) have been sold to the floristry industry. The transgenic carnation carries a herbicide tolerance gene (a mutant gene encoding acetolactate synthase (ALS)) and has been modified to produce delphinidin-based anthocyanins in flowers, which conventionally bred carnation cannot produce. The modified flower color has been achieved by introduction of a gene encoding flavonoid 3',5'-hydroxylase (F3'5'H). Transgenic carnation flowers are produced in South America and are primarily distributed to North America, Europe, and Japan. Although a nonfood crop, the release of the genetically modified carnation varieties required an environmental risk impact assessment and an assessment of the potential for any increased risk of harm to human or animal health compared to conventionally bred carnation. The results of the health safety assessment and the experimental studies that accompanied them are described in this review. The conclusion from the assessments has been that the release of genetically modified carnation varieties which express F3'5'H and ALS genes and which accumulate delphinidin-based anthocyanins do not pose an increased risk of harm to human or animal health. PMID- 23646985 TI - Sixteen-year comparisons of parent-reported emotional and behaviour problems and competencies in Norwegian children aged 7-9 years. AB - BACKGROUND: Studies about changes in the prevalence of emotional and behaviour problems across time are lacking, especially among younger children. AIM: To determine if the level of parent-reported emotional and behaviour problems and competencies in young Norwegian school children had changed across a 16-year time interval. METHODS: We compared parent reports obtained by the Child Behavior Checklist in two samples of children aged 7-9 years from the general population assessed in 1991 and 2007. RESULTS: The results demonstrated overall stability or slight decreases of emotional and behaviour problems and a significant increase in competencies, mainly due to increased activity and social competence scores in the 2007 sample. Boys obtained higher scores than girls in Total Problems, Externalizing and Attention problems at both time points and there was a high stability of the rank order of items. CONCLUSIONS: The findings suggest stability in child emotional and behaviour problems, and an increase of competencies across the period. PMID- 23646986 TI - Syntheses, structures, and magnetic properties of acetato- and diphenolato bridged 3d-4f binuclear complexes [M(3-MeOsaltn)(MeOH)x(ac)Ln(hfac)2] (M = Zn(II), Cu(II), Ni(II), Co(II); Ln = La(III), Gd(III), Tb(III), Dy(III); 3 MeOsaltn = N,N'-bis(3-methoxy-2-oxybenzylidene)-1,3-propanediaminato; ac = acetato; hfac = hexafluoroacetylacetonato; x = 0 or 1). AB - A series of 3d-4f binuclear complexes, [M(3-MeOsaltn)(MeOH)x(ac)Ln(hfac)2] (x = 0 for M = Cu(II), Zn(II); x = 1 for M = Co(II), Ni(II); Ln = Gd(III), Tb(III), Dy(III), La(III)), have been synthesized and characterized, where 3-MeOsaltn, ac, and hfac denote N,N'-bis(3-methoxy-2-oxybenzylidene)-1,3-propanediaminato, acetato, and hexafluoroacetylacetonato, respectively. The X-ray analyses demonstrated that all the complexes have an acetato- and diphenolato-bridged M(II)-Ln(III) binuclear structure. The Cu(II)-Ln(III) and Zn(II)-Ln(III) complexes are crystallized in an isomorphous triclinic space group P1, where the Cu(II) or Zn(II) ion has square pyramidal coordination geometry with N2O2 donor atoms of 3-MeOsaltn at the equatorial coordination sites and one oxygen atom of the bridging acetato ion at the axial site. The Co(II)-Ln(III) and Ni(II)-Ln(III) complexes are crystallized in an isomorphous monoclinic space group P2(1)/c, where the Co(II) or Ni(II) ion at the high-spin state has an octahedral coordination environment with N2O2 donor atoms of 3-MeOsaltn at the equatorial sites, and one oxygen atom of the bridged acetato and a methanol oxygen atom at the two axial sites. Each Ln(III) ion for all the complexes is coordinated by four oxygen atoms of two phenolato and two methoxy oxygen atoms of "ligand complex" M(3-MeOsaltn), four oxygen atoms of two hfac(-), and one oxygen atom of the bridging acetato ion; thus, the coordination number is nine. The temperature dependent magnetic susceptibilities from 1.9 to 300 K and the field-dependent magnetization up to 5 T at 1.9 K were measured. Due to the important orbital contributions of the Ln(III) (Tb(III), Dy(III)) and to a lesser extent the M(II) (Ni(II), Co(II)) components, the magnetic interaction between M(II) and Ln(III) ions were investigated by an empirical approach based on a comparison of the magnetic properties of the M(II)-Ln(III), Zn(II)-Ln(III), and M(II)-La(III) complexes. The differences of chi(M)T and M(H) values for the M(II)-Ln(III), Zn(II)-Ln(III) and those for the M(II)-La(III) complexes, that is, Delta(T) = (chi(M)T)(MLn) - (chi(M)T)(ZnLn) - (chi(M)T)(MLa) = J(MLn)(T) and Delta(H) = M(MLn)(H) - M(ZnLn)(H) - M(MLa)(H) = J(MLn)(H), give the information of 3d-4f magnetic interaction. The magnetic interactions are ferromagnetic if M(II) = (Cu(II), Ni(II), and Co(II)) and Ln = (Gd(III), Tb(III), and Dy(III)). The magnitudes of the ferromagnetic interaction, J(MLn)(T) and J(MLn)(H), are in the order Cu(II)-Gd(III) > Cu(II)-Dy(III) > Cu(II)-Tb(III), while those are in the order of M(II)-Gd(III) ~ M(II)-Tb(III) > M(II)-Dy(III) for M(II) = Ni(II) and Co(II). Alternating current (ac) susceptibility measurements demonstrated that the Ni(II)-Tb(III) and Co(II)-Tb(III) complexes showed out-of-phase signal with frequency-dependence and the Ni(II)-Dy(III) and Co(II)-Dy(III) complexes showed small frequency-dependence. The energy barrier for the spin flipping was estimated from the Arrhenius plot to be 14.9(6) and 17.0(4) K for the Ni(II) Tb(III) and Co(II)-Tb(III) complexes, respectively, under a dc bias field of 1000 Oe. PMID- 23646987 TI - Highly uniform platinum icosahedra made by hot injection-assisted GRAILS method. AB - Highly uniform Pt icosahedral nanocrystals with an edge length of 8.8 nm were synthesized in nonhydrolytic systems using the hot injection-assisted GRAILS (gas reducing agent in liquid solution) method. The results show the key factors for the shape control include fast nucleation, kinetically controlled growth, and protection from oxidation by air. The effect of oxygen molecules on the Pt morphology was experimentally confirmed based on the study of shape evolution of icosahedral crystals upon exposure to oxygen gas. The Pt icosahedral catalysts obtained had an area-specific activity of 0.83 mA/cm(2) Pt, four times that of 0.20 mA/cm(2) Pt for typical Pt/C catalysts, in an oxygen reduction reaction (ORR). PMID- 23646988 TI - Reliability estimation in a multilevel confirmatory factor analysis framework. AB - Scales with varying degrees of measurement reliability are often used in the context of multistage sampling, where variance exists at multiple levels of analysis (e.g., individual and group). Because methodological guidance on assessing and reporting reliability at multiple levels of analysis is currently lacking, we discuss the importance of examining level-specific reliability. We present a simulation study and an applied example showing different methods for estimating multilevel reliability using multilevel confirmatory factor analysis and provide supporting Mplus program code. We conclude that (a) single-level estimates will not reflect a scale's actual reliability unless reliability is identical at each level of analysis, (b) 2-level alpha and composite reliability (omega) perform relatively well in most settings, (c) estimates of maximal reliability (H) were more biased when estimated using multilevel data than either alpha or omega, and (d) small cluster size can lead to overestimates of reliability at the between level of analysis. We also show that Monte Carlo confidence intervals and Bayesian credible intervals closely reflect the sampling distribution of reliability estimates under most conditions. We discuss the estimation of credible intervals using Mplus and provide R code for computing Monte Carlo confidence intervals. PMID- 23646989 TI - Error, power, and cluster separation rates of pairwise multiple testing procedures. AB - In comparing multiple treatments, 2 error rates that have been studied extensively are the familywise and false discovery rates. Different methods are used to control each of these rates. Yet, it is rare to find studies that compare the same methods on both of these rates, and also on the per-family error rate, the expected number of false rejections. Although the per-family error rate and the familywise error rate are similar in most applications when the latter is controlled at a conventional low level (e.g., .05), the 2 measures can diverge considerably with methods that control the false discovery rate at that same level. Furthermore, we shall consider both rejections of true hypotheses (Type I errors) and rejections of false hypotheses where the observed outcomes are in the incorrect direction (Type III errors). We point out that power estimates based on the number of correct rejections do not consider the pattern of those rejections, which is important in interpreting the total outcome. The present study introduces measures of interpretability based on the pattern of separation of treatments into nonoverlapping sets and compares methods on these measures. In general, range-based (configural) methods are more likely to obtain interpretable patterns based on treatment separation than individual p-value-based measures. Recommendations for practice based on these results are given in the article. Although the article is complex, these recommendations can be understood without the necessity for detailed perusal of the supporting material. PMID- 23646990 TI - Reversed item bias: an integrative model. AB - In the recent methodological literature, various models have been proposed to account for the phenomenon that reversed items (defined as items for which respondents' scores have to be recoded in order to make the direction of keying consistent across all items) tend to lead to problematic responses. In this article we propose an integrative conceptualization of three important sources of reversed item method bias (acquiescence, careless responding, and confirmation bias) and specify a multisample confirmatory factor analysis model with 2 method factors to empirically test the hypothesized mechanisms, using explicit measures of acquiescence and carelessness and experimentally manipulated versions of a questionnaire that varies 3 item arrangements and the keying direction of the first item measuring the focal construct. We explain the mechanisms, review prior attempts to model reversed item bias, present our new model, and apply it to responses to a 4-item self-esteem scale (N = 306) and the 6-item Revised Life Orientation Test (N = 595). Based on the literature review and the empirical results, we formulate recommendations on how to use reversed items in questionnaires. PMID- 23646991 TI - A method for efficiently sampling from distributions with correlated dimensions. AB - Bayesian estimation has played a pivotal role in the understanding of individual differences. However, for many models in psychology, Bayesian estimation of model parameters can be difficult. One reason for this difficulty is that conventional sampling algorithms, such as Markov chain Monte Carlo (MCMC), can be inefficient and impractical when little is known about the target distribution--particularly the target distribution's covariance structure. In this article, we highlight some reasons for this inefficiency and advocate the use of a population MCMC algorithm, called differential evolution Markov chain Monte Carlo (DE-MCMC), as a means of efficient proposal generation. We demonstrate in a simulation study that the performance of the DE-MCMC algorithm is unaffected by the correlation of the target distribution, whereas conventional MCMC performs substantially worse as the correlation increases. We then show that the DE-MCMC algorithm can be used to efficiently fit a hierarchical version of the linear ballistic accumulator model to response time data, which has proven to be a difficult task when conventional MCMC is used. PMID- 23646992 TI - Coupled latent differential equation with moderators: simulation and application. AB - Latent differential equations (LDE) use differential equations to analyze time series data. Because of the recent development of this technique, some issues critical to running an LDE model remain. In this article, the authors provide solutions to some of these issues and recommend a step-by-step procedure demonstrated on a set of empirical data, which models the interaction between ovarian hormone cycles and emotional eating. Results indicated that emotional eating is self-regulated. For instance, when people do more emotional eating than normal, they will subsequently tend to decrease their emotional eating behavior. In addition, a sudden increase will produce a stronger tendency to decrease than will a slow increase. We also found that emotional eating is coupled with the cycle of the ovarian hormone estradiol, and the peak of emotional eating occurs after the peak of estradiol. The self-reported average level of negative affect moderates the frequency of eating regulation and the coupling strength between eating and estradiol. Thus, people with a higher average level of negative affect tend to fluctuate faster in emotional eating, and their eating behavior is more strongly coupled with the hormone estradiol. Permutation tests on these empirical data supported the reliability of using LDE models to detect self-regulation and a coupling effect between two regulatory behaviors. PMID- 23646993 TI - Circulating mitotic figures in a patient with dual infection by Epstein-Barr virus and cytomegalovirus. PMID- 23646994 TI - Solvent effect on the Stokes shift and on the nonfluorescent decay of the daidzein molecular system. AB - The flavonoids have been the target of several experimental works due to its influence in the human health as antioxidant elements. The fluorescence properties of these compounds have been widely studied due to the large Stokes shifts experimentally observed and the variety of processes that lead to the fluorescence. In the present work the role of the solvent in the large Stokes shift experimentally observed in the daidzein molecular system in water is theoretically studied. Also studied is the nonfluorescent decay mechanism in a polar aprotic solvent like acetonitrile. The solvent effect in the ground and in the low-lying excited electronic states is taken into account by using the sequential-QM/MM methodology. Excited state properties like equilibrium geometries and transition energies were studied by using multiconfigurational calculations, CASSCF and CASPT2. The excited electronic state responsible for the fluorescence spectrum in water was identified, and the large Stokes shift seems to be the result of the large interaction of the system in this electronic state with the solvent. On the other hand, spin-orbit coupling calculations, between the singlet and triplet electronic states, indicate favorable conditions for intersystem crossing, in agreement with the experimental result of nonfluorescence observation. PMID- 23646995 TI - Dermatitis artefacta and artefactual skin disease: the need for a psychodermatology multidisciplinary team to treat a difficult condition. AB - BACKGROUND: Dermatitis artefacta (DA) is a factitious skin disorder caused by the deliberate production of skin lesions by patients with a history of underlying psychological problems. The patient may not be fully aware of this, and the true extent of this disorder, especially in children, is currently unknown. Management of these patients is challenging as many fail to engage effectively with their dermatologist. OBJECTIVES: To explore the various clinical presentations and strategies employed to treat DA in our local population, and note outcomes in order to evaluate effectiveness of our management. METHODS: A retrospective case note review was conducted of 28 patients attending the regional psychodermatology clinic at the Royal London Hospital from January 2003 to December 2011. RESULTS: Out of 28 patients identified with DA, the majority of patients were female, and the most frequent sites for skin lesions were the face and upper body. Anxiety, depression and personality disorders were common underlying psychiatric diagnoses. Ninety-three per cent of patients were successfully managed (i.e. the DA resolved or was in remission at the time of writing) in our combined psychodermatology clinic by a multidisciplinary psychocutaneous medicine team. Thirty-two per cent of our cases were children (aged < 16 years) and one of these was referred to local child protection services; 46% of patients had a concomitant mental health disease at the time of presentation with DA. CONCLUSIONS: A multidisciplinary psychocutaneous team is important in this condition particularly as the patient is likely to require psychological intervention (to facilitate the resolution of the precipitant), in addition to dermatological (to make the diagnosis and, importantly, to exclude organic disease) and psychiatric (to manage concomitant psychiatric disease) input. Our findings indicate that our model of a psychodermatology multidisciplinary team will achieve greater successful treatment of patients with DA and we are the first to describe this important service in the U.K. PMID- 23646996 TI - Identification and characterization of 2-naphthoyl-coenzyme A reductase, the prototype of a novel class of dearomatizing reductases. AB - The enzymatic dearomatization of aromatic ring systems by reduction represents a highly challenging redox reaction in biology and plays a key role in the degradation of aromatic compounds under anoxic conditions. In anaerobic bacteria, most monocyclic aromatic growth substrates are converted to benzoyl-coenzyme A (CoA), which is then dearomatized to a conjugated dienoyl-CoA by ATP-dependent or -independent benzoyl-CoA reductases. It was unresolved whether or not related enzymes are involved in the anaerobic degradation of environmentally relevant polycyclic aromatic hydrocarbons (PAHs). In this work, a previously unknown dearomatizing 2-naphthoyl-CoA reductase was purified from extracts of the naphthalene-degrading, sulphidogenic enrichment culture N47. The oxygen-tolerant enzyme dearomatized the non-activated ring of 2-naphthoyl-CoA by a four-electron reduction to 5,6,7,8-tetrahydro-2-naphthoyl-CoA. The dimeric 150 kDa enzyme complex was composed of a 72 kDa subunit showing sequence similarity to members of the flavin-containing 'old yellow enzyme' family. NCR contained FAD, FMN, and an iron-sulphur cluster as cofactors. Extracts of Escherichia coli expressing the encoding gene catalysed 2-naphthoyl-CoA reduction. The identified NCR is a prototypical enzyme of a previously unknown class of dearomatizing arylcarboxyl CoA reductases that are involved in anaerobic PAH degradation; it fundamentally differs from known benzoyl-CoA reductases. PMID- 23646997 TI - Virtual garden computer program for use in exploring the elements of biodiversity people want in cities. AB - Urban ecology is emerging as an integrative science that explores the interactions of people and biodiversity in cities. Interdisciplinary research requires the creation of new tools that allow the investigation of relations between people and biodiversity. It has been established that access to green spaces or nature benefits city dwellers, but the role of species diversity in providing psychological benefits remains poorly studied. We developed a user friendly 3-dimensional computer program (Virtual Garden [www.tinyurl.com/3DVirtualGarden]) that allows people to design their own public or private green spaces with 95 biotic and abiotic features. Virtual Garden allows researchers to explore what elements of biodiversity people would like to have in their nearby green spaces while accounting for other functions that people value in urban green spaces. In 2011, 732 participants used our Virtual Garden program to design their ideal small public garden. On average gardens contained 5 different animals, 8 flowers, and 5 woody plant species. Although the mathematical distribution of flower and woody plant richness (i.e., number of species per garden) appeared to be similar to what would be expected by random selection of features, 30% of participants did not place any animal species in their gardens. Among those who placed animals in their gardens, 94% selected colorful species (e.g., ladybug [Coccinella septempunctata], Great Tit [Parus major], and goldfish), 53% selected herptiles or large mammals, and 67% selected non-native species. Older participants with a higher level of education and participants with a greater concern for nature designed gardens with relatively higher species richness and more native species. If cities are to be planned for the mutual benefit of people and biodiversity and to provide people meaningful experiences with urban nature, it is important to investigate people's relations with biodiversity further. Virtual Garden offers a standardized tool with which to explore these relations in different environments, cultures, and countries. It can also be used by stakeholders (e.g., city planners) to consider people's opinions of local design. PMID- 23646999 TI - Effective mercury sorption by thiol-laced metal-organic frameworks: in strong acid and the vapor phase. AB - Free-standing, accessible thiol (-SH) functions have been installed in robust, porous coordination networks to provide wide-ranging reactivities and properties in the solid state. The frameworks were assembled by reacting ZrCl4 or AlCl3 with 2,5-dimercapto-1,4-benzenedicarboxylic acid (H2DMBD), which features the hard carboxyl and soft thiol functions. The resultant Zr-DMBD and Al-DMBD frameworks exhibit the UiO-66 and CAU-1 topologies, respectively, with the carboxyl bonded to the hard Zr(IV) or Al(III) center and the thiol groups decorating the pores. The thiol-laced Zr-DMBD crystals lower the Hg(II) concentration in water below 0.01 ppm and effectively take up Hg from the vapor phase. The Zr-DMBD solid also features a nearly white photoluminescence that is distinctly quenched after Hg uptake. The carboxyl/thiol combination thus illustrates the wider applicability of the hard-and-soft strategy for functional frameworks. PMID- 23647002 TI - Directed ortho-lithiation of aminophosphazenes: an efficient route to the stereoselective synthesis of P-chiral compounds. AB - Ortho-directed lithiation of P,P-diphenylaminophosphazenes followed by electrophilic quench is described as an efficient process for synthesizing P chiral ortho-functionalized derivatives in high yields and diastereoselectivities. The method allows the tunable preparation of structurally diverse enantiopure P-chiral compounds including phosphinic and phosphinothioic amides, phosphinic esters, phosphine oxides, and o-aminophosphines. PMID- 23647001 TI - The role of tetrahydrobiopterin and catecholamines in the developmental regulation of tyrosine hydroxylase level in the brain. AB - Tyrosine hydroxylase (TH) is a rate-limiting enzyme for dopamine synthesis and requires tetrahydrobiopterin (BH4) as an essential cofactor. BH4 deficiency leads to the loss of TH protein in the brain, although the underlying mechanism is poorly understood. To give insight into the role of BH4 in the developmental regulation of TH protein level, in this study, we investigated the effects of acute and subchronic administrations of BH4 or dopa on the TH protein content in BH4-deficient mice lacking sepiapterin reductase. We found that BH4 administration persistently elevated the BH4 and dopamine levels in the brain and fully restored the loss of TH protein caused by the BH4 deficiency in infants. On the other hand, dopa administration less persistently increased the dopamine content and only partially but significantly restored the TH protein level in infant BH4-deficient mice. We also found that the effects of BH4 or dopa administration on the TH protein content were attenuated in young adulthood. Our data demonstrate that BH4 and catecholamines are required for the post-natal augmentation of TH protein in the brain, and suggest that BH4 availability in early post-natal period is critical for the developmental regulation of TH protein level. PMID- 23647000 TI - APOE epsilon4, Alzheimer's disease pathology, cerebrovascular disease, and cognitive change over the years prior to death. AB - The goal of this study was to examine the association of the APOE epsilon4 allele with the late-life cognitive trajectory and test the hypothesis that the association of epsilon4 with cognitive decline is explained by Alzheimer's disease (AD) neuropathology. Participants (N = 581) came from 2 longitudinal clinical-pathologic studies of aging and dementia, the Religious Orders Study (ROS) and the Memory and Aging Project (MAP). Longitudinal measures of cognition were derived from detailed annual neuropsychological testing. Uniform neuropathologic evaluations provided quantitative measures of AD pathology, chronic cerebral infarctions, and Lewy bodies. Participants with 1 or more copies of the epsilon4 allele (epsilon2/4 excluded) were considered epsilon4 carriers. Random change point models were applied to examine the association of the epsilon4 allele with onset of terminal decline as well as preterminal and terminal slopes. On average, the onset of terminal decline occurred around 3 years before death, and the rate of terminal decline was eightfold faster than the preterminal decline. The presence of the epsilon4 allele was associated with an earlier onset of terminal decline and faster rates of decline before and after its onset. After adjusting for AD pathology, the epsilon4 allele was no longer associated with onset of terminal decline or preterminal slope, and the association with terminal slope became marginal. The APOE epsilon4 allele is an important determinant of late-life change in cognition, including terminal decline, and works primarily through AD pathology. PMID- 23647003 TI - Development of serum iron as a biological dosimeter in mice. AB - Even though serum iron is a commonly used parameter in iron metabolism, it has not yet been applied for biological dosimetry purpose. A new biological dosimeter based on serum iron has been developed in this work. Serum iron levels in mice subjected to gamma rays from a (60)Co source were detected with the use of ferrous. The doses are from 0.2-7 Gy with a dose rate of 0.2 Gy/min. The results demonstrate that serum iron level increases with increasing dose. The detection limit based on serum iron has a lower limit of dose detection of about 0.5 Gy and the maximal increase of serum iron observed is maintained 4 h after gamma irradiation. Therefore the best suggested time for blood collection is within 4 h after gamma irradiation. Two dose-response relationships were observed with both according to degrees of the increase of serum iron levels and different intervals after gamma irradiation. The first is a linear relationship of y = 0.98x + 6.76 (r = 0.98) obtained 10 min after gamma irradiation; the second is the linear quadratic relationship of y = -0.07x(2) + 1.02x + 6.45 (r = 0.99) obtained 7 days after gamma irradiation. The absorbed doses of mice estimated with the use of both these two dose-response relationships were close to the actual dose of 1 Gy. It is concluded that serum iron is a quick, simple and sensitive biomarker for early assessment of the absorbed dose of mice. PMID- 23647004 TI - Integration of Monte Carlo simulations with PFGE experimental data yields constant RBE of 2.3 for DNA double-strand break induction by nitrogen ions between 125 and 225 keV/MUm LET. AB - The number of small radiation-induced DNA fragments can be heavily underestimated when determined from measurements of DNA mass fractions by gel electrophoresis, leading to a consequent underestimation of the initial DNA damage induction. In this study we reanalyzed the experimental results for DNA fragmentation and DNA double-strand break (DSB) yields in human fibroblasts irradiated with gamma rays and nitrogen ion beams with linear energy transfer (LET) equal to 80, 125, 175 and 225 keV/MUm, originally measured by Hoglund et al. (Radiat Res 155, 818-825, 2001 and Int J Radiat Biol 76, 539-547, 2000). In that study the authors converted the measured distributions of fragment masses into DNA fragment distributions using mid-range values of the measured fragment length intervals, in particular they assumed fragments with lengths in the interval of 0-48 kbp had the mid-range value of 24 kbp. However, our recent detailed simulations with the Monte Carlo code PARTRAC, while reasonably in agreement with the mass distributions, indicate significantly increased yields of very short fragments by high-LET radiation, so that the actual average fragment lengths, in the interval 0-48 kbp, 2.4 kbp for 225 keV/MUm nitrogen ions were much shorter than the assumed mid-range value of 24 kbp. When the measured distributions of fragment masses are converted into fragment distributions using the average fragment lengths calculated by PARTRAC, significantly higher yields of DSB related to short fragments were obtained and resulted in a constant relative biological effectiveness (RBE) for DSB induction yield of 2.3 for nitrogen ions at 125-225 keV/MUm LET. The previously reported downward trend of the RBE values over this LET range for DSB induction appears to be an artifact of an inadequate average fragment length in the smallest interval. PMID- 23647005 TI - Sequential transformation of mesenchymal stem cells is associated with increased radiosensitivity and reduced DNA repair capacity. AB - We used sequentially transformed mesenchymal stem cells to investigate how the events that lead to tumorigenicity influence the cellular response to radiation. Bone marrow derived SH2(+), SH4(+), Stro-1(+) mesenchymal stem cells (MSC) were transformed stepwise by retroviral transfection of hTERT, HPV-16 E6 and E7, SV40 small T antigen and oncogenic H-ras. Cells at three different stages of transformation were irradiated and compared using assays for cytotoxicity, apoptosis, DNA double-strand break (DSB) repair and checkpoint signaling. The effects of inhibition of cell cycle checkpoint signaling on radiosensitivity were investigated using RNA interference. During stepwise transformation, specifically after HPV-16 E6 and E7 transduction, MSCs became more sensitive to radiation. This was associated with increased residual DNA DSB at 24 h and increased apoptosis. Enhanced checkpoint signaling occurred during transformation and there was a differential effect of checkpoint targeting in cells at different stages; Chk1 knockdown enhanced radiosensitivity in all cells while Chk2 knockdown only affected non-transformed cells. These data show that transformation of MSC is associated with a reduction in DNA DSB repair capacity and increased radiosensitivity. Up-regulation of checkpoint signaling does not overcome this and the effect of checkpoint inhibition may change with transformation status. PMID- 23647006 TI - Indications and safety of proton pump inhibitor drug use in patients with cancer. AB - INTRODUCTION: Although the exact prevalence of proton pump inhibitor (PPI) use in cancer patients is not known, it is generally perceived to be widespread. PPIs are generally well tolerated and carry an excellent safety profile. However, increasing and longer term PPI use has raised concerns about the risk of pneumonia, bone fractures and enteric infections, and a possible interaction with clopidogrel that could increase the risk of cardiovascular events. AREAS COVERED: We conducted a PubMed search of English language articles addressing the safety and adverse events associated with PPI use with particular emphasis in cancer patients. EXPERT OPINION: PPIs, frequently used in cancer patients, are generally well tolerated and carry an excellent safety profile. PPI-induced acid suppression may increase the risk of Clostridium difficile or other enteric infections, nutritional deficiencies and community acquired pneumonia, all particularly important in cancer patients. The indications for PPI use in cancer patients should be carefully reviewed prior to use. PMID- 23647007 TI - Dimensional alterations of extraction sites after different alveolar ridge preservation techniques - a volumetric study. AB - OBJECTIVES: The aim of this randomized controlled clinical study was to assess soft tissue contour changes after different alveolar ridge preservation procedures. MATERIAL AND METHODS: Following tooth extraction, 30 patients were randomly assigned to the following treatments (Tx) - Tx 1: xenogenic bone substitute (pre-hydrated collagenated cortico-cancellous porcine bone) and free gingival graft; Tx 2: free gingival graft alone; Tx 3: xenogenic bone substitute; Tx 4: no further treatment (control). Impressions were obtained before tooth extraction (baseline) and 4 months after surgery. Cast models were optically scanned, digitally superimposed and horizontal measurements of the contour alterations between time points were performed using digital imaging analysis. RESULTS: All groups displayed contour shrinkage at the buccal aspect ranging from a mean horizontal reduction of -0.8 +/- 0.5 mm (Tx 1) to -2.3 +/- 1.1 mm (control). Statistically significant differences were found between Tx 1 and Tx 4 as well as Tx 2 and Tx 4. A significant positive influence of the free gingival graft on the maintenance of the ridge width was recorded (p < 0.001). CONCLUSION: In this study, alveolar ridge preservation techniques were not able to entirely compensate for alveolar ridge reduction. Covering the orifice of the extraction socket with a free gingival tissue graft seems to have the potential to limit but not avoid the post-operative external contour shrinkage based on optical scans. PMID- 23647008 TI - Freezing as an intervention to reduce the numbers of campylobacters isolated from chicken livers. AB - The aims of this study were (i) to determine the prevalence and numbers of campylobacters in 63 samples of raw livers purchased at retail across the UK and (ii) to investigate whether the freezing of chicken livers contaminated with Campylobacter was a reliable method for decontamination. Chicken livers naturally contaminated with campylobacters were subjected to freezing at -15 and -25 degrees C for one day and 7 days. Numbers of campylobacters on the livers were determined immediately before and after a 24-h or 7-days freeze treatment and daily during 3 days post-thaw refrigerated storage. Freezing for 24 h at -25 degrees C can reduce numbers of Campylobacter by up to 2 log10 CFU g(-1). Freezing the livers for 24 h at -25 degrees C, thawing overnight in a fridge set to 4 degrees C and refreezing for another 24 h at -25 degrees C reduced the numbers of campylobacters by up to three logs. Reduction in the numbers of campylobacters was significantly greater following a second freeze treatment compared with a single freeze treatment. PMID- 23647009 TI - Matrix metalloproteinase, vitamin A and methylprednisolone effects on experimentally induced amyloid arthropathy. AB - We evaluated the role of some matrix metalloproteinases (MMPs) in enhancing the effect of vitamin A and the inhibiting effect of methylprednisolone on amyloid arthropathy in brown layer chicks. We used 100 one-day-old Isa brown layer chicks. The chicks were allocated to one of four groups as follows: negative control group (I), vitamin A group (II), positive control group (III) and methylprednisolone group (IV). Amyloid arthropathy was induced by injections of complete Freund's adjuvant into the left intertarsal joints of the chicks. Serum vitamin A and tissue MMP (MMP-1, MMP-2, MMP-9) levels were measured and differences among the groups were investigated. Serum vitamin A rates (MUg/dl) were: 63.57 +/- 4.10, 47.13 +/- 10.62, 53.26 +/- 10.79, 98.48 +/- 8.20 in groups I, II, III and IV, respectively (p < 0.001). MMP-1, MMP-2 and MMP-9 levels were evaluated in tissues from the chickens with amyloid arthropathy. Methylprednisolone significantly suppressed the release of MMP-1 and MMP-2, and increased the release of MMP-9 in birds with amyloid arthropathy. In addition, vitamin A significantly increased the release of MMP-1, MMP-2 and MMP-9. PMID- 23647011 TI - Age and gender related changes in hematological parameters of thoroughbred foals. AB - Hematological and biochemical profiles commonly are required in equine medicine. We studied hematological parameters including red blood cells (RBC), white blood cells (WBC), hemoglobin (Hb), hematocrit (PCV), differential leukocyte counts, mean cell volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) in thoroughbred foals at different ages and for both sexes. Sixty healthy thoroughbred foals, 1 day, 3 days and 1 year old were used. Each age group consisted of 10 male and 10 female animals. We found significant differences related to age in RBC values of females, PCV, MCV values of males, WBC, neutrophil percentages, lymphocyte percentages, monocyte percentages of females, and eosinophil percentages and basophil percentages. Significant differences related to gender were found only with regard to PCV at 1 year and WBC at 1 day. The hematological parameters of thoroughbred foals up to one year old may be useful for evaluating and monitoring the health of these animals. PMID- 23647012 TI - The Allium test: injection of test compounds into the bulb. AB - We developed three methods for injecting substances into the bulb of Allium: (1) direct injection, (2) injection through the open space in the bulb after the removal of the upper half of the bulb, and (3) through a special "tunnel" cut in the bulb. Water (control) and solutions of methotrexate and copper sulfate were injected into bulbs and the dynamics of root growth were measured. We found that 2.2 mM methotrexate and 100 mM copper sulfate inhibit root growth. Injection through the "tunnel" was the most effective method. Cytological analysis showed that methotrexate inhibited mitotic activity completely in the root apical meristem and copper sulfate induced swelling of cells in the root meristem. PMID- 23647010 TI - Clinical implications of microRNAs in cancer. AB - MicroRNAs (miRNAs) are endogenously produced non-coding RNAs that serve as micromanagers by negatively regulating gene expression. MiRNAs are implicated in several biological pathways including development of neoplasia. Because altered miRNA expression is implicated in the pathobiology of various cancers, these molecules serve as potential therapeutic targets. Using miRNA mimics to restore levels of aberrantly down-regulated miRNAs or miRNA inhibitors to inactivate over expressed miRNAs shows promise as the next generation of therapeutic strategies. Manipulation of miRNAs offers an alternative therapeutic approach for chemo- and radiation-resistant tumors. Similarly, miRNA expression patterns can be used for diagnosis and to predict prognosis and efficacy of therapy. We present here an overview of how miRNAs affect cancers, how they may be used as biomarkers, and the clinical implications of miRNAs in cancer. PMID- 23647013 TI - Magnetic interactions mediated by diamagnetic cations in [Mn18M] (M = Sr2+, Y3+, Cd2+, and Lu3+) coordination clusters. AB - We previously reported how the synthesis of [Mn(III)12Mn(II)7(MU4-O)8(MU3-eta(1) N3)8(HL(1))12(MeCN)6]Cl2.10MeOH.MeCN (1), which has a Mn19 core corresponding to two supertetrahedral {Mn(II)4Mn(III)6} units sharing a common Mn(II) vertex, can be modified such that the central octacoordinate Mn(II) ion can be replaced by metal ions more likely to favor this coordination geometry such as Dy(III) as exemplified in the compound [Mn(III)12Mn(II)6Dy(III)(MU4-O)8(MU3-Cl)6.5(MU3 N3)1.5(HL)12(MeOH)6]Cl3.25MeOH (2). Here, we report a systematic survey of the effects of incorporating various diamagnetic metal ions M(n+) into this central position. We chose diamagnetic ions with electron configurations with fully occupied or completely empty frontier orbitals in order to gauge the effect on the overall magnetic behavior. The syntheses, structures, and magnetic properties of the heterometallic aggregates [Mn(III)12Mn(II)6Sr(II)(MU4-O)8(MU3-eta(1) N3)7.5(MU3-eta(1)-Cl)0.5(HL(1))12(MeCN)6]Cl2.15MeOH (3), [Mn(III)12Mn(II)6Y(III)(MU4-O)8(MU3-eta(1)-N3)8(HL(1))12(MeCN)6](NO3)3.11MeOH (4), [Mn(III)12Mn(II)6Cd(II)(MU4-O)8(MU3-eta(1)-N3)6.8(MU3-eta(1) Cl)1.2(HL(1))12(MeCN)6](CdCl4)0.25Cl1.5.14.5MeOH (5), and [Mn(III)12Mn(II)6Lu(III)(MU4-O)8(MU3-eta(1)-N3)6.5(MU3-eta(1) Cl)1.5(HL(2))12(MeCN)6]Cl3.3H2O.7MeOH.MeCN (6) (H3L(1) = 2,6-bis(hydroxymethyl)-4 methylphenol, H3L(2) = 2,6-bis(hydroxymethyl)-4-fluorophenol) are reported. The aggregates were prepared in one-pot self-assembly reactions of H3L(1) (or H3L(2)), MnCl2.4H2O or Mn(NO3)2.4H2O, NaOAc.3H2O or Et3N, and NaN3 in the presence of the appropriate diamagnetic metal salt in MeCN/MeOH mixtures. Compounds 3-6 crystallize isotypically to 1 in the trigonal space group R3 with Z = 3. The effects on the magnetic properties were investigated, paying attention to the presence of any weak coupling mediated by the diamagnetic cations between the two {Mn(II)3Mn(III)6} S = 39/2 subunits. In the Cd(2+) compound 5, the two {Mn(II)3Mn(III)6} units are magnetically isolated. In 3, 4, and 6, the diamagnetic Sr(2+), Y(3+), and Lu(3+) cations mediate weak antiferromagnetic interactions between the two {Mn(II)3Mn(III)6} subunits. DFT calculations show that the inter-{Mn(II)3Mn(III)6} interactions in the Mn18M systems are attributable to the electronic structure of the central diamagnetic cation, with systems containing trivalent central cations showing stronger antiferromagnetic interactions than those with isoelectronic divalent cations. PMID- 23647014 TI - Characterization of gene expression endpoints during postembryonic development of the northern green frog (Rana clamitans melanota). AB - Postembryonic development of a larval tadpole into a juvenile frog involves the coordinated action of thyroid hormone (TH) across a diversity of tissues. Changes in the frog transcriptome represent a highly sensitive endpoint in the detection of developmental progression, and for the identification of environmental chemical contaminants that possess endocrine disruptive properties. Unfortunately, in contrast with their vital role as sentinels of environmental change, few gene expression tools currently exist for the majority of native North American frog species. We have isolated seven expressed gene sequences from the Northern green frog (Rana clamitans melanota) that encode proteins associated with TH-mediated postembryonic development and global stress response, and established a quantitative real-time polymerase chain reaction (qPCR) assay. We also obtained three additional species-specific gene sequences that functioned in the normalization of the expression data. Alterations in mRNA abundance profiles were identified in up to eight tissues during R. clamitans postembryonic development, and following exogenous administration of TH to premetamorphic tadpoles. Our results characterize tissue distribution and sensitivity to TH of select mRNA of a common North American frog species and support the potential use of this qPCR assay in identification of the presence of chemical agents in aquatic environments that modulate TH action. PMID- 23647016 TI - Significant spatial aggregation and fine-scale genetic structure in the homosporous fern Cyrtomium falcatum (Dryopteridaceae). AB - Spores of homosporous ferns are small, wind-borne and thus have the potential for long-distance dispersal. This common perception has led to a prediction of near random spatial genetic structure within fern populations. Spore dispersal and spore bank studies, however, indicate that most spores fall close to the maternal plant (< 5 m), supporting a prediction of significant fine-scale genetic structure (FSGS) within populations. To determine which of these two hypotheses is more likely to occur in nature, we measured inbreeding and quantified the spatial distribution of individuals and allozyme-based genotypes using spatial autocorrelation methods within four populations of the fern Cyrtomium falcatum in southern South Korea. Inbreeding levels were low, and all populations exhibited significant aggregation of individuals and strong FSGS. The present results support the second hypothesis, and the substantial FSGS in C. falcatum could reflect the unique features of most homosporous ferns (outcrossing mating systems that lead a majority of spores to occur at short distances and a very limited dispersal distance of male gametes). Although fern spores are physically analogous to orchid seeds, the intensity of FSGS exhibited in C. falcatum is four times stronger than that in 16 terrestrial orchid species. PMID- 23647017 TI - The loss of virulence of histone H1 overexpressing Leishmania donovani parasites is directly associated with a reduction of HSP83 rate of translation. AB - Overexpression of Leishmania histone H1 (LeishH1) was previously found to cause a promastigote-to-amastigote differentiation handicap, deregulation of cell-cycle progression, and loss of parasite infectivity. The aim of this study was to identify changes in the proteome of LeishH1 overexpressing parasites associated with the avirulent phenotype observed. 2D-gel electrophoresis analysis revealed only a small protein subset of differentially expressed proteins in the LeishH1 overexpressing promastigotes. Among these was the chaperone HSP83, known for its protective role in Leishmania drug-induced apoptosis, which displayed lower translational rates. To investigate if the lower expression levels of HSP83 are associated with the differentiation handicap, we assayed the thermostability of parasites by subjecting them to heat-shock (25 degrees C->37 degrees C), a natural stress-factor occurring during stage differentiation. Heat-shock promoted apoptosis to a greater extent in the LeishH1 overexpressing parasites. Interestingly, these parasites were not only more sensitive to heat-shock but also to drug-induced [Sb(III)] cell-death. In addition, the restoration of HSP83 levels re-established drug resistance, and restored infectivity to LeishH1 overexpressing parasites in the murine J774 macrophage model. Overall, this study suggests that LeishH1 levels are critical for the parasite's stress-induced adaptation within the mammalian host, and highlights the cross-talk between pathways involved in drug resistance, apoptosis and virulence. PMID- 23647015 TI - Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. AB - BACKGROUND AND PURPOSE: Thioredoxin-interacting protein (TXNIP), a regulator of cellular oxidative stress, has been associated with activation of NOD-like receptor 3 (NLRP3) inflammasome, inflammation and lipid metabolism, suggesting it has a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in diabetes. In this study we investigated whether TXNIP is involved in type 1 diabetes-associated NAFLD and whether antioxidants, quercetin and allopurinol, alleviate NAFLD by targeting TXNIP. EXPERIMENTAL APPROACH: Diabetes was induced in male Sprague-Dawley rats by a single i.p. injection of 55 mg . kg-1 streptozotocin. Quercetin and allopurinol were given p.o. to diabetic rats for 7 weeks. Hepatic function, oxidative stress, inflammation and lipid levels were determined. Rat BRL-3A and human HepG2 cells were exposed to high glucose (30 mM) in the presence and absence of antioxidants, TXNIP siRNA transfection or caspase 1 inhibitor, Ac-YVAD-CMK. KEY RESULTS: Quercetin and allopurinol significantly inhibited the TXNIP overexpression, activation of NLRP3 inflammasome, down regulation of PPARalpha and up-regulation of sterol regulatory element binding protein-1c (SREBP-1c), SREBP-2, fatty acid synthase and liver X receptor alpha, as well as elevation of ROS and IL-1beta in diabetic rat liver. These effects were confirmed in hepatocytes in vitro and it was further shown that TXNIP down regulation contributed to the suppression of NLRP3 inflammasome activation, inflammation and changes in PPARalpha and SREBPs. CONCLUSIONS AND IMPLICATIONS: Inhibition of hepatic TXNIP by quercetin and allopurinol contributes to the reduction in liver inflammation and lipid accumulation under hyperglycaemic conditions. The targeting of hepatic TXNIP by quercetin and allopurinol may have therapeutic implications for prevention of type 1 diabetes-associated NAFLD. PMID- 23647018 TI - Evaluation of bamboo shoot peptide preparation with angiotensin converting enzyme inhibitory and antioxidant abilities from byproducts of canned bamboo shoots. AB - In this paper, aqueous extract fractions from byproducts of the processing of canned bamboo shoots, including boiled water, filled liquid, and squeezed juice, were obtained by 5 kDa molecular cutoff membranes and marcoporous resin DA201-C treatment. The enriched bamboo shoot angiotensin converting enzyme (ACE) inhibitory peptide preparation fraction (called BSP for short) was extracted with ethyl acetate and n-butanol. The ethyl acetate fraction and n-butanol fraction exhibited higher antioxidant capacities than the leaving water fraction (BSML), which was attributed to the higher phenolic acid and flavonoid content of both fractions, while BSML exhibited the strongest ACE inhibitory activity. Sephadex G 15 gel filtration and semipreparative high-performance liquid chromatography were used for further purification of bamboo shoot ACE inhibitory peptide from BSML. Asp-Tyr was identified as the key active component by ultra-high-performance liquid chromatography and electrospray ionization tandem mass spectrometry. A short-term antihypertensive assay stated that both Asp-Tyr [10 mg day(-1) (kg of body weight)(-1)] and BSP [50 mg day(-1) (kg of body weight)(-1)] could significantly reduce the systolic blood pressure of spontaneously hypertensive rats (3-6 h). This study provides further examples of utilization of byproducts from the processing of canned bamboo shoots for the prevention of hypertension and attenuation of oxidative stress. PMID- 23647020 TI - Differences in the distribution of cytogenetic subtypes between multiple myeloma patients with and without a family history of monoclonal gammopathy and multiple myeloma. AB - We previously reported an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of MGUS and multiple myeloma patients. Here, we examine whether primary cytogenetic categories of myeloma differ between patients with and without a family history of MGUS or myeloma. We studied 201 myeloma patients with available data on family history and molecular cytogenetic classification. Myeloma with trisomies was more common in probands who had an affected first-degree relative with MGUS or myeloma compared with those without a family history (46.9% vs. 33.5%, P = 0.125); however, the difference was not statistically significant. Additional studies on the cytogenetic types of myeloma associated with familial tendency are needed. PMID- 23647019 TI - APP+, a fluorescent analogue of the neurotoxin MPP+, is a marker of catecholamine neurons in brain tissue, but not a fluorescent false neurotransmitter. AB - We have previously introduced fluorescent false neurotransmitters (FFNs) as optical reporters that enable visualization of individual dopaminergic presynaptic terminals and their activity in the brain. In this context, we examined the fluorescent pyridinium dye 4-(4-dimethylamino)phenyl-1 methylpyridinium (APP+), a fluorescent analogue of the dopaminergic neurotoxin MPP+, in acute mouse brain tissue. APP+ is a substrate for the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), and as such represented a candidate for the development of new FFN probes. Here we report that APP+ labels cell bodies of catecholaminergic neurons in the midbrain in a DAT- and NET-dependent manner, as well as fine dopaminergic axonal processes in the dorsal striatum. APP+ destaining from presynaptic terminals in the dorsal striatum was also examined under the conditions inducing depolarization and exocytotic neurotransmitter release. Application of KCl led to a small but significant degree of destaining (approximately 15% compared to control), which stands in contrast to a nearly complete destaining of the new generation FFN agent, FFN102. Electrical stimulation of brain slices at 10 Hz afforded no significant change in the APP+ signal. These results indicate that the majority of the APP+ signal in axonal processes originates from labeled organelles including mitochondria, whereas only a minor component of the APP+ signal represents the releasable synaptic vesicular pool. These results also show that APP+ may serve as a useful probe for identifying catecholaminergic innervations in the brain, although it is a poor candidate for the development of FFNs. PMID- 23647021 TI - Simultaneous EEG and fMRI recordings (EEG-fMRI) in children with epilepsy. AB - By combining electroencephalography (EEG) with functional magnetic resonance imaging (fMRI) it is possible to describe blood oxygenation level-dependent (BOLD) signal changes related to EEG patterns. This way, EEG-pattern-associated networks of hemodynamic changes can be detected anywhere in the brain with good spatial resolution. This review summarizes EEG-fMRI studies that have been performed in children with epilepsy. EEG-fMRI studies in focal epilepsy (structural and nonlesional cases, benign epilepsy with centrotemporal spikes), generalized epilepsy (especially absence epilepsy), and epileptic encephalopathies (West syndrome, Lennox-Gastaut syndrome, continuous spike and waves during slow sleep, and Dravet syndrome) are presented. Although EEG-fMRI was applied mainly to localize the region presumably generating focal interictal discharges in focal epilepsies, EEG-fMRI identified underlying networks in patients with generalized epilepsies and thereby contributed to a better understanding of these epilepsies. In epileptic encephalopathies a specific fingerprint of hemodynamic changes associated with the particular syndrome was detected. The value of the EEG-fMRI technique for diagnosis and investigation of pathogenetic mechanisms of different forms of epilepsy is discussed. PMID- 23647023 TI - Effect of van der Waals interaction on the geometric and electronic properties of DNA nucleosides adsorbed on Cu(111) surface: a DFT study. AB - The geometrical properties and electronic structure of DNA nucleosides (deoxyadenosine, thymidine, deoxyguanosine, deoxycytidine) adsorbed on a metallic surface of Cu(111) are determined using density functional theory computations. In order to assess the effect of the long-range interaction upon the results of the DFT simulations, we compare the results of a standard GGA exchange correlation functional with those produced by the newly developed van der Waals exchange-correlation functional. The most striking difference between the two sets of results occurs for the adsorption energies: standard functional predicts values representing about 30% of those obtained when van der Waals interaction is taken into account. The standard GGA functional favors slightly tilted orientation of the DNA bases with respect to the surface, while the inclusion of the van der Waals effect leads to an almost parallel orientation of the bases with the surface. On the other hand, the position of the sugar pucker is less influenced by the type of the exchange-correlation used. According to our studies, in the presence of long-range interactions, the molecule-surface charge transfer is qualitatively affected. Standard functional predicts a decrease of the electronic population of the adsorbate, while the presence of long-range interaction leads to an opposite effect. PMID- 23647024 TI - Trophic flexibility and the persistence of understory birds in intensively logged rainforest. AB - Effects of logging on species composition in tropical rainforests are well known but may fail to reveal key changes in species interactions. We used nitrogen stable-isotope analysis of 73 species of understory birds to quantify trophic responses to repeated intensive logging of rainforest in northern Borneo and to test 4 hypotheses: logging has significant effects on trophic positions and trophic-niche widths of species, and the persistence of species in degraded forest is related to their trophic positions and trophic-niche widths in primary forest. Species fed from higher up the food chain and had narrower trophic-niche widths in degraded forest. Species with narrow trophic-niche widths in primary forest were less likely to persist after logging, a result that indicates a higher vulnerability of dietary specialists to local extinction following habitat disturbance. Persistence of species in degraded forest was not related to a species' trophic position. These results indicate changes in trophic organization that were not apparent from changes in species composition and highlight the importance of focusing on trophic flexibility over the prevailing emphasis on membership of static feeding guilds. Our results thus support the notion that alterations to trophic organization and interactions within tropical forests may be a pervasive and functionally important hidden effect of forest degradation. PMID- 23647022 TI - Distribution of MC1R variants among melanoma subtypes: p.R163Q is associated with lentigo maligna melanoma in a Mediterranean population. AB - BACKGROUND: Cutaneous melanoma tumour is classified into clinicohistopathological subtypes that may be associated with different genetic and host factors. Variation in the MC1R gene is one of the main factors of risk variation in sporadic melanoma. The relationship between MC1R variants and the risk of developing a specific subtype of melanoma has not been previously explored. OBJECTIVES: To analyse whether certain MC1R variants are associated with particular melanoma subtypes with specific clinicohistopathological features. METHODS: An association study was performed between MC1R gene variants and clinicopathological subtypes of primary melanoma derived from 1679 patients. RESULTS: We detected 53 MC1R variants (11 synonymous and 42 nonsynonymous). Recurrent nonsynonymous variants were p.V60L (30.0%), p.V92M (11.7%), p.D294H (9.4%), p.R151C (8.8%), p.R160W (6.2%), p.R163Q (4.2%) p.R142H (3.3%), p.I155T (3.8%), p.V122M (1.5%) and p.D84E (1.0%). Melanoma subtypes showed differences in the total number of MC1R variants (P = 0.028) and the number of red hair colour variants (P = 0.035). Furthermore, an association between p.R163Q and lentigo maligna melanoma was detected under a dominant model of heritance (odds ratio 2.16, 95% confidence interval 1.07-4.37; P = 0.044). No association was found between p.R163Q and Fitzpatrick skin phototype, eye colour or skin colour, indicating that the association was independent of the role of MC1R in pigmentation. No association was observed between MC1R polymorphisms and other melanoma subtypes. CONCLUSIONS: Our findings suggest that certain MC1R variants could increase melanoma risk due to their impact on pathways other than pigmentation, and may therefore be linked to specific melanoma subtypes. PMID- 23647025 TI - Complete chorion-amnion separation presenting as a stuck fetus. PMID- 23647026 TI - Convenient detection of Pd(II) by a metal-organic framework with sulfur and olefin functions. AB - A highly specific, distinct color change in the crystals of a metal-organic framework with pendant allyl thioether units in response to Pd species was discovered. The color change (from light yellow to orange/brick red) can be triggered by Pd species at concentrations of a few parts per million and points to the potential use of these crystals in colorimetric detection and quantification of Pd(II) ions. The swift color change is likely due to the combined effects of the multiple functions built into the porous framework: the carboxyl groups for bonding with Zn(II) ions to assemble the host network and the thioether and alkene functions for effective uptake of the Pd(II) analytes (e.g., via the alkene-Pd interaction). The resultant loading of Pd (and other noble metal) species into the porous solid also offers rich potential for catalysis applications, and the alkene side chains are amenable to wide-ranging chemical transformations (e.g., bromination and polymerization), enabling further functionalization of the porous networks. PMID- 23647027 TI - Lycospidine A, a new type of Lycopodium alkaloid from Lycopodium complanatum. AB - Lycospidine A (1), the first example of a Lycopodium alkaloid which contains an unprecedented five-membered A ring, was isolated from Lycopodium complanatum. The unique five-membered A ring in 1 indicates that carbons 2-5 in 1 are presumably derived from proline instead of the lysine biosynthetically, which suggests that 1 represent a new class of Lycopodium alkaloid. In addition, the unique structural feature and biosynthetic origin of 1 shed new insight into the structural diversity of Lycopodium alkaloid analogue libraries potentially accessible by engineered biosynthesis. PMID- 23647029 TI - Chondroid syringoma (mixed tumor) with tyrosine crystals. PMID- 23647030 TI - Elasticity. PMID- 23647032 TI - The Intolerance of Uncertainty Scale for Children (IUSC): discriminating principal anxiety diagnoses and severity. AB - The specific relationship of intolerance of uncertainty (IU) to generalized anxiety disorder (GAD) in youth was examined by evaluating the ability of the Intolerance of Uncertainty Scale for Children (IUSC) to discriminate among principal anxiety disorder diagnoses. Analyses examined parent, child, and composite reports of principal anxiety diagnoses in youth aged 7 to 17 years. Results indicate that higher IU scores are associated with GAD by the composite diagnostic. Additionally, the IUSC significantly predicted child-reported anxiety severity. This relationship was not moderated by diagnostic group. The results indicate that IUSC scores are particularly associated with GAD, as well as with more severe child-reported anxiety symptoms. PMID- 23647033 TI - Development and validation of the Alcohol Myopia Scale. AB - Alcohol myopia theory conceptualizes the ability of alcohol to narrow attention and how this demand on mental resources produces the impairments of self inflation, relief, and excess. The current research was designed to develop and validate a scale based on this framework. People who were alcohol users rated items representing myopic experiences arising from drinking episodes in the past month. In Study 1 (N = 260), the preliminary 3-factor structure was supported by exploratory factor analysis. In Study 2 (N = 289), the 3-factor structure was substantiated with confirmatory factor analysis, and it was superior in fit to an empirically indefensible 1-factor structure. The final 14-item scale was evaluated with internal consistency reliability, discriminant validity, convergent validity, criterion validity, and incremental validity. The alcohol myopia scale (AMS) illuminates conceptual underpinnings of this theory and yields insights for understanding the tunnel vision that arises from intoxication. PMID- 23647031 TI - Distinguishing primary and secondary variants of callous-unemotional traits among adolescents in a clinic-referred sample. AB - The current study used model-based cluster analyses to determine if there are 2 distinct variants of adolescents (ages 11-18) high on callous-unemotional (CU) traits that differ on their level of anxiety and history of trauma. The sample (n = 272) consisted of clinic-referred youths who were primarily African American (90%) and who came from low-income families. Consistent with hypotheses, 3 clusters emerged, including a group low on CU traits, as well as 2 groups high on CU traits that differed in their level of anxiety and past trauma. Consistent with past research on incarcerated adults and adolescents, the group high on anxiety (i.e., secondary variant) was more likely to have histories of abuse and had higher levels of impulsivity, externalizing behaviors, aggression, and behavioral activation. In contrast, the group low on anxiety (i.e., primary variant) scored lower on a measure of behavioral inhibition. On measures of impulsivity and externalizing behavior, the higher scores for the secondary cluster were found only for self-report measures, not on parent-report measures. Youths in the primary cluster also were perceived as less credible reporters than youths in the secondary cluster (i.e., secondary variant) or cluster low on CU traits. These reporter and credibility differences suggest that adolescents within the primary variant may underreport their level of behavioral disturbance, which has important assessment implications. PMID- 23647034 TI - The psychometric properties of the Readiness and Motivation Questionnaire: a symptom-specific measure of readiness for change in the eating disorders. AB - Readiness for change, as assessed by the readiness and motivation interview (RMI), predicts a number of clinical outcome variables in eating disorders including enrollment in intensive treatment, symptom change, dropout, and relapse. Although clinically useful, the training and administration of the RMI is time consuming. The purpose of this research was to (a) develop a self-report, symptom-specific version of the RMI, the readiness and motivation questionnaire (RMQ), that can be used to assess readiness for change across all eating disorder diagnoses and (b) establish its psychometric properties. The RMQ provides stage of change, internality, and confidence scores for each of 4 eating disorder symptom domains (restriction, bingeing, and cognitive and compensatory behaviors). Individuals (N = 244) with current eating disorder diagnoses completed the RMQ and measures of convergent, discriminant, and criterion validity. Similar to the RMI scores, readiness scores on the RMQ differed according to symptom domain. Regarding criterion validity, RMQ scores were significantly associated with ratings of anticipated difficulty of recovery activities and completion of recovery activities. The RMQ contributed significant unique variance to anticipated difficulty of recovery activities, beyond those accounted for by the RMI and a questionnaire measure of global readiness. The RMQ is thus an acceptable alternative to the RMI, providing global and domain specific readiness information when time or cost prohibits use of an interview. PMID- 23647035 TI - Passion: Does one scale fit all? Construct validity of two-factor passion scale and psychometric invariance over different activities and languages. AB - The passion scale, based on the dualistic model of passion, measures 2 distinct types of passion: Harmonious and obsessive passions are predictive of adaptive and less adaptive outcomes, respectively. In a substantive-methodological synergy, we evaluate the construct validity (factor structure, reliability, convergent and discriminant validity) of Passion Scale responses (N = 3,571). The exploratory structural equation model fit to the data was substantially better than the confirmatory factor analysis solution, and resulted in better differentiated (less correlated) factors. Results from a 13-model taxonomy of measurement invariance supported complete invariance (factor loadings, factor correlations, item uniquenesses, item intercepts, and latent means) over language (French vs. English; the instrument was originally devised in French, then translated into English) and gender. Strong measurement partial invariance over 5 passion activity groups (leisure, sport, social, work, education) indicates that the same set of items is appropriate for assessing passion across a wide variety of activities--a previously untested, implicit assumption that greatly enhances practical utility. Support was found for the convergent and discriminant validity of the harmonious and obsessive passion scales, based on a set of validity correlates: life satisfaction, rumination, conflict, time investment, activity liking and valuation, and perceiving the activity as a passion. PMID- 23647036 TI - The Subjective Effects of Alcohol Scale: development and psychometric evaluation of a novel assessment tool for measuring subjective response to alcohol. AB - Three decades of research demonstrate that individual differences in subjective response (SR) to acute alcohol effects predict heavy drinking and alcohol-related problems. However, the SR patterns conferring the greatest risk remain under debate. Morean and Corbin (2010) highlighted that extant SR measures commonly have limitations within the following areas: assessment of a comprehensive range of effects, assessment of effects over the complete course of a drinking episode, and/or psychometric validation. Furthermore, the consistent pairing of certain SR measures and theoretical models has made integration of findings difficult. To address these issues, we developed the Subjective Effects of Alcohol Scale (SEAS), a novel, psychometrically sound SR measure for use in alcohol administration studies. Pilot data ensured that the SEAS comprised a comprehensive range of effects that varied in terms of valence and arousal and were perceived as plausible effects of drinking. For validation purposes, the SEAS was included in a 2-site, placebo-controlled, alcohol administration study (N = 215). Exploratory and confirmatory factor analyses identified a 14-item, 4 factor model categorizing effects into affective quadrants (high/low arousal positive; high/low arousal negative). SEAS scores evidenced the following: (a) scalar measurement invariance by limb of the blood alcohol curve (BAC) and beverage condition; (b) good internal consistency; (c) convergence/divergence with extant SR measures, alcohol expectancies, and alcohol use; and (d) concurrent/incremental utility in accounting for alcohol-related outcomes, highlighting the novel high arousal negative and low arousal. PMID- 23647037 TI - Psychometric properties of the functions and addictive features scales of the Ottawa Self-Injury Inventory: a preliminary investigation using a university sample. AB - Nonsuicidal self-injury (NSSI) is an issue primarily of concern in adolescents and young adults. Thus far, no single NSSI self-report measure offers a fully comprehensive assessment of NSSI, particularly including measurement of both its functions and potential addictive features. The Ottawa Self-Injury Inventory (OSI) permits simultaneous assessment of both these characteristics; the current study examined the psychometric properties of this measure in a sample of 149 young adults in a university student sample (82.6% girls, Mage = 19.43 years). Exploratory factor analyses revealed 4 functions factors (internal emotion regulation, social influence, external emotion regulation, and sensation seeking) and a single addictive features factor. Convergent evidence for the functions factor scores was demonstrated through significant correlations with an existing measure of NSSI functions and indicators of psychological well-being, risky behaviors, and context and frequency of NSSI behaviors. Convergent evidence was also shown for the addictive features scores, through associations with NSSI frequency, feeling relieved following NSSI, and inability to resist NSSI urges. Additional comment is made regarding the potential for addictive features of NSSI to be both negatively and positively reinforcing. Results show preliminary psychometric support for the OSI as a valid and reliable assessment tool to be used in both research and clinical contexts. The OSI can provide important information for case formulation and treatment planning, given the comprehensive and all-inclusive nature of its assessment capacities. PMID- 23647038 TI - Development and validation of the revised Identity Style Inventory (ISI-5): factor structure, reliability, and validity. AB - Identity processing style refers to differences in how individuals process identity-relevant information as they engage or manage to avoid the challenges of constructing, maintaining, and/or reconstructing a sense of identity. The third version of the Identity Style Inventory (Berzonsky, 1992b) has been used to operationally define identity styles in most empirical investigations. The objective of the present series of studies was the development and validation of a new revised measure of identity processing style: Identity Style Inventory Version 5 (ISI-5). Initially a pool of 39 generic items was generated that highlighted the processing of identity-relevant information on content-neutral issues such as personal values, goals, problems, and the like. Three style scales were identified by Exploratory Factor Analysis: A 9-item Informational-style scale; a 9-item Normative-style scale; and a 9-item Diffuse-avoidant style scale. Confirmatory factor analysis on an independent sample indicated that this 3 factor solution provided the best fit. Results from 5 studies provided evidence for the psychometric properties of the scales. Scores on the 3 style scales demonstrated good test-retest reliability and internal consistency. Theoretically predicted correlations between the ISI-5 scale scores and performance on measures of identity status, content, and commitment, and measures of rational and automatic processing provided evidence for their convergent and discriminant validity. It is concluded that the scales should be useful for researchers interested in investigating individual differences in identity processing style. Limitations and directions for future research are considered. PMID- 23647039 TI - Predictive validity of adult risk assessment tools with juveniles who offended sexually. AB - An often-held assumption in the area of sexual recidivism risk assessment is that different tools should be used for adults and juveniles. This assumption is driven either by the observation that adolescents tend to be in a constant state of flux in the areas of development, education, and social structure or by the fact that the judicial system recognizes that juveniles and adults are different. Though the assumption is plausible, it is largely untested. The present study addressed this issue by scoring 2 adult sexual offender risk assessment tools, the Minnesota Sex Offender Screening Tool-Revised and the Static-99, on an exhaustive sample (N = 636) of juveniles who had sexually offended (JSOs) in Utah. For comparison, 2 tools designed for JSOs were also scored: the Juvenile Sex Offender Assessment Protocol-II and the Juvenile Risk Assessment Scale. Recidivism data were collected for 2 time periods: before age 18 (sexual, violent, any recidivism) and from age 18 to the year 2004 (sexual). The adult actuarial risk assessment tools predicted all types of juvenile recidivism significantly and at approximately the same level of accuracy as juvenile specific tools. However, the accuracy of longer term predictions of adult sexual recidivism across all 4 tools was substantially lower than the accuracy achieved in predicting juvenile sexual recidivism, with 2 of the tools producing nonsignificant results, documenting the greater difficulty in making longer term predictions on the basis of adolescent behavior. PMID- 23647040 TI - Validation of and revision to the VRAG and SORAG: the Violence Risk Appraisal Guide-Revised (VRAG-R). AB - The violence risk appraisal guide (VRAG) was developed in the early 1990s, and approximately 60 replications around the world have shown its utility for the appraisal of violence risk among correctional and psychiatric populations. At the same time, authorities (e.g., Dawes, Faust, & Meehl, 1989) have argued that tools should be periodically evaluated to see if they need to be revised. In the present study, we evaluated the accuracy of the VRAG in a sample of 1,261 offenders, fewer than half of whom were participants in the development sample, then developed and validated a revised and easier-to-score instrument (the VRAG R). We examined the accuracy of both instruments over fixed durations of opportunity ranging from 6 months to 49 years and examined outcome measures pertaining to the overall number, severity, and imminence of violent recidivism. Both instruments were found to predict dichotomous violent recidivism overall and at various fixed follow-ups with high levels of predictive accuracy (receiver operating characteristic areas of approximately .75) and to significantly predict other violent outcomes. PMID- 23647041 TI - Psychometric properties of the Wender-Reimherr Adult Attention Deficit Disorder Scale. AB - The Wender-Reimherr adult attention deficit disorder scale (WRAADDS; Wender, 1995) is a clinician-rated scale based on the Utah Criteria for attention deficit/hyperactivity disorder (ADHD) in adults. It assesses ADHD symptom severity across 7 domains: attention difficulties, hyperactivity/restlessness, temper, affective lability, emotional over-reactivity, disorganization, and impulsivity. The normative sample consisted of 120 males and females ages 20-49 with no personal or family history of ADHD. Patients with ADHD met Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000) criteria, included males and females ages 20-60, and came from 5 clinical trials. Measures of reliability (test-retest r = .96; interrater r = .75) and internal consistency (Cronbach's alpha = 0.78) were acceptable. The WRAADDS correlated with the Conners' Adult ADHD Rating Scale (CAARS; Conners, Erhardt, & Sparrow, 1999) total scores (r = .501, p < .001). WRAADDS hyperactivity + impulsivity correlated with the CAARS hyperactivity/impulsivity (r = .601, p < .001), and WRAADDS attention + disorganization correlated with the CAARS inattention (r = .430, p < .001). Discriminate validity (adults with vs. without ADHD) was significant for all domains (p < .001). Factor analysis yielded a 2-factor solution accounting for 58% of the variance, one containing the emotional dimensions and the second containing attention and disorganization. Hyperactivity/restlessness and impulsivity were split between both factors. Changes in response to treatment for the WRAADDS and CAARS were highly correlated (p < .001). These psychometric data support continued use of the WRAADDS in adults with ADHD. PMID- 23647042 TI - Incremental criterion validity of WAIS-IV factor index scores: relationships with WIAT-II and WIAT-III subtest and composite scores. AB - The present study examined the incremental validity of Wechsler Adult Intelligence Scale-4th Edition (WAIS-IV; Wechsler, 2008a) factor index scores in predicting academic achievement on the Wechsler Individual Achievement Test-2nd Edition (WIAT-II; Psychological Corporation, 2002a) and on the Wechsler Individual Achievement Test-3rd Edition (WIAT-III; Wechsler, 2009a) beyond that predicted by the WAIS-IV Full Scale IQ (FSIQ). As with previous intelligence test incremental validity studies, the WAIS-IV FSIQ accounted for statistically significant and generally large portions of WIAT-II and WIAT-III subtest and composite score variance. WAIS-IV factor index scores combined to provide statistically significant increments in variance accounted for in most WIAT-II and WIAT-III subtest and composite scores over and above the FSIQ score; however, the effect sizes ranged from trivial to medium as observed in investigations with other intelligence tests (i.e., Glutting, Watkins, Konold, & McDermott, 2006; Youngstrom, Kogos, & Glutting, 1999). Individually, the WAIS-IV factor index scores provided trivial to small unique contributions to predicting WIAT-II and WIAT-III scores. This finding indicated that the FSIQ should retain primacy and greatest interpretive weight in WAIS-IV interpretation, as previously indicated by WAIS-IV subtest variance partitions form hierarchical exploratory factor analyses (Canivez & Watkins, 2010a, 2012b). PMID- 23647043 TI - Assessment of self-harm risk using implicit thoughts. AB - Assessing for the risk of self-harm in acute care is a difficult task, and more information on pertinent risk factors is needed to inform clinical practice. This study examined the relationship of 6 forms of implicit cognition about death, suicide, and self-harm with the occurrence of self-harm in the future. We then attempted to develop a model using these measures of implicit cognition along with other psychometric tests and clinical risk factors. We conducted a prospective cohort of 107 patients (age > 17 years) with a baseline assessment that included 6 implicit association tests that assessed thoughts of death, suicide, and self-harm. Psychometric questionnaires were also completed by the patients, and these included the Beck Hopelessness Scale (Beck, Weissman, Lester, & Trexler, 1974), Barratt impulsiveness scale (Patton, Stanford, & Barratt, 1995), brief symptom inventory (Derogatis & Melisaratos, 1983), CAGE questionnaire for alcoholism (Ewing, 1984), and the drug abuse screening test 10 (Skinner, 1982). Medical and demographic information was also obtained for patients as potential confounders or useful covariables. The outcome measure was the occurrence of self-harm within 3 months. Implicit associations with death versus life as a predictor added significantly (odds ratio = 5.1, 95% confidence interval [1.3, 20.3]) to a multivariable model. The model had 96.6% sensitivity and 53.9% specificity with a high cutoff, or 58.6% sensitivity and 96.2% specificity with a low cutoff. This scale shows promise for screening emergency department patients with mental health presentations who may be at risk for future self-harm or suicide. PMID- 23647044 TI - The Five-Factor Narcissism Inventory (FFNI): a test of the convergent, discriminant, and incremental validity of FFNI scores in clinical and community samples. AB - The five-factor narcissism inventory (FFNI) is a new self-report measure that was developed to assess traits associated with narcissistic personality disorder (NPD), as well as grandiose and vulnerable narcissism from a five-factor model (FFM) perspective. In the current study, the FFNI was examined in relation to Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM IV; American Psychiatric Association, 2000) NPD, DSM-5 (http://www.dsm5.org) NPD traits, grandiose narcissism, and vulnerable narcissism in both community (N = 287) and clinical samples (N = 98). Across the samples, the FFNI scales manifested good convergent and discriminant validity such that FFNI scales derived from FFM neuroticism were primarily related to vulnerable narcissism scores, scales derived from FFM extraversion were primarily related to grandiose scores, and FFNI scales derived from FFM agreeableness were related to both narcissism dimensions, as well as the DSM-IV and DSM-5 NPD scores. The FFNI grandiose and vulnerable narcissism composites also demonstrated incremental validity in the statistical prediction of these scores, above and beyond existing measures of DSM NPD, grandiose narcissism, and vulnerable narcissism, respectively. The FFNI is a promising measure that provides a comprehensive assessment of narcissistic pathology while maintaining ties to the significant general personality literature on the FFM. PMID- 23647045 TI - Comparing countdown- and IRT-based approaches to computerized adaptive personality testing. AB - Computerized adaptive testing (CAT) is an emerging technology in the personality assessment literature given the greater efficiency it affords compared with traditional methods. However, few studies have directly compared the efficiency and validity of 2 competing methods for personality CAT: (a) methods based on item response theory (IRT-CAT) versus (b) methods based on the countdown method (CM-CAT). To that end, we conducted real-data simulations with previously collected responses (N = 8,690) to the Schedule for Nonadaptive and Adaptive Personality (SNAP). Three CAT algorithms (IRT-CAT, IRT-CAT with 5-item minimum, CM-CAT) were evaluated for item savings, classification accuracy, and convergent/discriminant validity. All CATs yielded lower classification accuracy and validity than traditional testing but required 18%-86% fewer items. Ultimately, the IRT-CAT, with minimum 5-item requirement, struck the most ideal balance of highest item savings, and generally fewer costs to validity and accuracy. These results confirm findings regarding item savings trends from previous CAT studies. In addition, this study provides a model for how the validity and precision of CATs may be compared across personality assessments. PMID- 23647046 TI - A brief form of the Affective Neuroscience Personality Scales. AB - The Affective Neuroscience Personality Scales (ANPS) were developed to measure behavioral traits related to 6 affective neurobiological systems (play, seek, care, fear, anger, and sadness). However, the ANPS has a number of problems, including an ill-defined factor structure, overly long scales, and items that are poorly worded, ambiguous, and of questionable content validity. To address these issues, we constructed an improved short form of the ANPS--the Brief ANPS (BANPS). Three studies demonstrated that the 33-item BANPS has a clear and coherent factor structure, relatively high reliabilities (for short scales), and theoretically meaningful correlations with a wide range of external criteria, supporting its convergent and discriminant validity. Unlike typical short-form scales, the BANPS improves upon the psychometric properties of the long form, and we recommend its use in all research contexts. PMID- 23647047 TI - Multilevel confirmatory ordinal factor analysis of the Life Skills Profile-16. AB - The aim of this study was to assess the factor structure of the Life skills profile-16 (LSP-16; Buckingham, Burgess, Solomon, Pirkis, & Eagar, 1998a, 1998b) with a view to meeting the assumption of statistical independence that is at significant risk of violation due to the dependency introduced to the data by pooling numerous ratings made by the same observers across independent patients. The sample consisted of 20,181 outpatients rated by 2,071 clinicians employed within 54 mental health organizations within the New South Wales public adult mental health service. To estimate the extent to which the item scores were contaminated with rater-level intraclass correlations (ICC), I fit 16 3-level multinominal ordered proportional odds intercept only models that revealed large ICCs associated with Level 2 (the rater of the LSP-16) demonstrating that a multilevel analysis was required. A multilevel confirmatory factor analysis (M CFA) using robust weighted least squares (B. O. Muthen, du Toit, & Spisic, 1997) with polychoric correlation was used to test the fit of 2 measurement models that were hypothesized a priori. The 2 models failed to provide an acceptable fit to the sample data and within- and between-level CFAs were used to inform revisions to the 4-factor model. A 15-item version of the LSP was developed, which provided an improved approximate fit in an M-CFA. Limitations of these findings are discussed. PMID- 23647048 TI - Comparing two forms of a childhood perspective-taking measure using CFA and IRT. AB - Deficits in perspective-taking ability have been linked to social problems associated with disorders such as autism spectrum disorders (ASD) and conduct disorder. Even subtle deficits in perspective-taking are related to social adjustment and moral development. A common measure of perspective-taking abilities in children is the "Reading the Mind in the Eyes Task" ("Eyes task"; Baron-Cohen, Wheelwright, Spong, Scahill, & Lawson, 2001). The Eyes task was primarily developed for use in identifying individuals with ASDs, while its function with nonclinical populations has not been clearly addressed. Additionally, it is unknown whether the Eyes task can be used to measure specific deficits or abilities in the cognitive or emotional components of perspective taking. In this article we assessed the structure and function of the Eyes task and an open ended or generative format of the same task (Generative Eyes Task; GET) found to measure emotional perspective-taking specifically. Confirmatory factor analyses found the traditional Eyes task to have the assumed single factor structure, while the GET has a clear 2-factor structure corresponding to emotionally valenced or neutral items. The Eyes task and the GET were also compared using item response theory. The Eyes task provided the most measurement accuracy at 2 standard deviations below the mean making it most accurate for populations with severe deficits, while the GET was most accurate at the mean level of perspective-taking. Based on these analyses, we conclude that the GET is more appropriate for use in nonclinical populations and when emotional perspective-taking abilities are of interest. PMID- 23647049 TI - Secondary trauma self-efficacy: concept and its measurement. AB - The Secondary Trauma Self-Efficacy (STSE) Scale was developed and psychometrically evaluated in 2 studies targeting populations indirectly exposed to traumatic events through work with traumatized clients. Study 1 enrolled behavioral health professionals (n = 247) providing trauma therapy for military clients in the United States. Study 2 investigated characteristics of the STSE Scale among health care and social workers (n(T1) = 306, nT2 = 193) providing services for trauma victims and survivors in Poland. Rooted in social cognitive theory, the 7-item STSE Scale is used to evaluate perceived ability to cope with the challenging demands resulting from work with traumatized clients and perceived ability to deal with the secondary traumatic stress symptoms. In both studies, exploratory and confirmatory factor analysis showed unidimensionality of the scale. The results indicated good internal consistency of the STSE Scale and its stability over time. STSE correlated highly or moderately with secondary traumatic stress symptoms. Comparatively, associations between STSE and perceived social support, secondary traumatic growth, and negative beliefs about the world and self were either moderate or low. The STSE factor structure and pattern of correlations with the validity measures were invariant across the 2 studies, which indicated that the STSE Scale may be a culturally unbiased instrument. PMID- 23647050 TI - Lactadherin/MFG-E8 is essential for microglia-mediated neuronal loss and phagoptosis induced by amyloid beta. AB - Nanomolar beta-amyloid peptide (Abeta) can induce neuronal loss in culture by activating microglia to phagocytose neurons. We report here that this neuronal loss is mediated by the bridging protein lactadherin/milk-fat globule epidermal growth factor-like factor 8 (MFG-E8), which is released by Abeta-activated microglia, binds to co-cultured neurons and opsonizes neurons for phagocytosis by microglia. Abeta stimulated microglial phagocytosis, but did not opsonize neurons for phagocytosis. Abeta (250 nM) induced delayed neuronal loss in mixed glial neuronal mouse cultures that required microglia and occurred without increasing neuronal apoptosis or necrosis. This neuronal death/loss was prevented by antibodies to MFG-E8 and was absent in cultures from Mfge8 knockout mice (leaving viable neurons), but was reconstituted by addition of recombinant MFG-E8. Thus, nanomolar Abeta caused neuronal death by inducing microglia to phagocytose otherwise viable neurons via MFG-E8. The direct neurotoxicity of micromolar Abeta was not affected by MFG-E8. The essential role of MFG-E8 in Abeta-induced phagoptosis, suggests this bridging protein as a potential therapeutic target to prevent neuronal loss in Alzheimer's disease. PMID- 23647052 TI - Intractable headache after excision of an acoustic neuroma treated by stent revascularisation of the sigmoid sinus. AB - A 47 year old man developed severe headaches after resection of an acoustic neuroma ipsilateral to non dominant venous drainage. CSF pressures were normal but imaging studies showed acquired, severe narrowing of the sigmoid sinus where it traversed the surgical defect. Stenting the sinus gave a lasting clinical improvement. PMID- 23647053 TI - Detection of signatures of selective sweeps in the Blonde d'Aquitaine cattle breed. AB - Identifying recent positive selection signatures in domesticated animals could provide information on genome response to strong directional selection from domestication and artificial selection and therefore could help in identifying mutations responsible for improved traits. We used genotyping data generated using Illumina's BovineSNP50 Genotyping BeadChips to identify selection signatures in the Blonde d'Aquitaine breed, a well-muscled French beef breed. For this purpose, we employed a hidden Markov model-based test, which detects selection by studying local variations in the allele frequency spectrum along the genome, within a single population. Three regions containing selective sweeps were identified. Annotation of genes located within these regions revealed interesting candidate genes. For example, myostatin (also known as GDF8), a known muscle growth factor inhibitor, is located within the selection signature region found on chromosome 2. In addition, we have identified chromosomal regions that show some evidence of selection within QTL regions for economically important traits. The results of this study could help to better understand the mechanisms related to the selection of the Blonde d'Aquitaine breed. PMID- 23647051 TI - Cyclin-dependent kinase inhibitor therapy for hematologic malignancies. AB - INTRODUCTION: Cyclin-dependent kinases (CDKs) regulate cell cycle progression. Certain CDKs (e.g., CDK7, CDK9) also control cellular transcription. Consequently, CDKs represent attractive targets for anticancer drug development, as their aberrant expression is common in diverse malignancies, and CDK inhibition can trigger apoptosis. CDK inhibition may be particularly successful in hematologic malignancies, which are more sensitive to inhibition of cell cycling and apoptosis induction. AREAS COVERED: A number of CDK inhibitors, ranging from pan-CDK inhibitors such as flavopiridol (alvocidib) to highly selective inhibitors of specific CDKs (e.g., CDK4/6), such as PD0332991, that are currently in various phases of development, are profiled in this review. Flavopiridol induces cell cycle arrest, and globally represses transcription via CDK9 inhibition. The latter may represent its major mechanism of action via down regulation of multiple short-lived proteins. In early phase trials, flavopiridol has shown encouraging efficacy across a wide spectrum of hematologic malignancies. Early results with dinaciclib and PD0332991 also appear promising. EXPERT OPINION: In general, the antitumor efficacy of CDK inhibitor monotherapy is modest, and rational combinations are being explored, including those involving other targeted agents. While selective CDK4/6 inhibition might be effective against certain malignancies, broad-spectrum CDK inhibition will likely be required for most cancers. PMID- 23647055 TI - CdS/CdSe core-shell nanorod arrays: energy level alignment and enhanced photoelectrochemical performance. AB - Novel CdS/CdSe core-shell nanorod arrays were fabricated by a chemical bath deposition of CdSe on hydrothermally synthesized CdS nanorods. The CdS rods were hexagonal phase faced and the top of the rod was subulate. After the chemical bath deposition approach, CdS nanorod arrays were encapsulated by a uniform CdSe layer resulting enhanced absorbance and extended absorption edges of the films. A tandem structure of the energy bands of CdS/CdSe was also formed as a result of the Fermi level alignment, which is a benefit to the efficient separation of photogenerated charges. CdS/CdSe core-shell arrays gave a maximum photocurrent of 5.3 mA/cm(2), which was 4 and 11 times as large as bare CdS and CdSe, respectively. PMID- 23647056 TI - Base-catalyzed cyclization of N-sulfonyl propargylamides to sulfonylmethyl substituted oxazoles via sulfonyl migration. AB - The reaction of N-sulfonyl propargylamides in the presence of a base catalyst selectively affords 5-sulfonylmethyl oxazoles via 1,4-sulfonyl migration. Allenes have been established as the key intermediates. Experimental evidence has been provided to support a two-step mechanism in the cyclization. PMID- 23647054 TI - A review of age-related dehydroepiandrosterone decline and its association with well-known geriatric syndromes: is treatment beneficial? AB - Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abundant steroids in humans. DHEA levels fall with age in men and women, reaching values sometimes as low as 10%-20% of those encountered in young individuals. This age related decrease suggests an "adrenopause" phenomenon. Studies point toward several potential roles of DHEA, mainly through its hormonal end products, making this decline clinically relevant. Unfortunately, even if positive effects of DHEA on muscle, bone, cardiovascular disease, and sexual function seem rather robust, extremely few studies are large enough and/or long enough for conclusions regarding its effects on aging. Moreover, because it has been publically presented as a "fountain of youth" equivalent, over-the-counter preparations lacking pharmacokinetic and pharmacodynamic data are widely used worldwide. Conceptually, supplementing a pre-hormone is extremely interesting, because it would permit the human organism to adequately use it throughout long periods, increasing or decreasing end products according to his needs. Nevertheless, data on the safety profile of long-term DHEA supplementation are still lacking. In this article, we examine the potential relation between low DHEA levels and well known age-related diseases, such as sarcopenia, osteoporosis, dementia, sexual disorders, and cardiovascular disease. We also review risks and benefits of existing protocols of DHEA supplementation. PMID- 23647057 TI - An on-chip, multichannel droplet sorter using standing surface acoustic waves. AB - The emerging field of droplet microfluidics requires effective on-chip handling and sorting of droplets. In this work, we demonstrate a microfluidic device that is capable of sorting picoliter water-in-oil droplets into multiple outputs using standing surface acoustic waves (SSAW). This device integrates a single-layer microfluidic channel with interdigital transducers (IDTs) to achieve on-chip droplet generation and sorting. Within the SSAW field, water-in-oil droplets experience an acoustic radiation force and are pushed toward the acoustic pressure node. As a result, by tuning the frequency of the SSAW excitation, the position of the pressure nodes can be changed and droplets can be sorted to different outlets at rates up to 222 droplets s(-1). With its advantages in simplicity, controllability, versatility, noninvasiveness, and capability to be integrated with other on-chip components such as droplet manipulation and optical detection units, the technique presented here could be valuable for the development of droplet-based micro total analysis systems (MUTAS). PMID- 23647058 TI - Implication of higher BAALC expression in combination with other gene mutations in adult cytogenetically normal acute myeloid leukemia. AB - Data for 125 patients with cytogenetically normal acute myeloid leukemia (CN-AML) regarding BAALC and combinatorial molecular markers at diagnosis were evaluated. Fewer patients with higher BAALC expression at diagnosis achieved a complete remission (CR) (49.2 vs. 75.8%, p = 0.002) after the first cycle of chemotherapy, and there were more primary refractory cases (37.3 vs. 18.2%, p = 0.017). In a combinatorial analysis, FLT3-ITD-positive patients with higher BAALC showed more refractoriness and the worst overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p < 0.001) in CN-AML. When NPM1-mutated CN-AML was combined with either FLT3-ITD mutation or higher BAALC expression, both OS (p = 0.043) and DFS (p = 0.008) were worse; when combined with both, it showed the worst OS (p < 0.001) and DFS (p = 0.004). Higher BAALC expression and FLT3-ITD mutation, both individually and in combination, were associated with worse survival outcomes in CN-AML, and this was also applicable in NPM1-mutated CN-AML, known as a favorable risk group. PMID- 23647059 TI - Importance of donor ethnicity/race matching in unrelated adult and cord blood allogeneic hematopoietic cell transplant. AB - Donor race matching (both recipient and donor belonging to the same race) might be a factor in outcomes of donor allogeneic hematopoietic cell transplant (alloHCT). A total of 858 patients who underwent umbilical cord blood (UCB) (475 patients: 202 double UCB and 273 single UCB) or unrelated donor (URD) (383 patients) alloHCT between January 1995 and December 2010 were studied. Most patients were Caucasian (87%), followed by Asians (4%), African Americans (3%), Hispanics (3%), mixed race (3%) and American Indians (< 1%). Caucasians constituted 88% of the donor grafts; Caucasians were the most common race of the donor grafts among all races except for Asians. As a result, Caucasians were much more likely to have a race-matched donor than ethnic minorities (91% vs. 33%, p < 0.01). Donor race matching did not affect non-relapse mortality, relapse, acute or chronic graft-versus-host disease or overall survival. Acknowledging the limitations of this study (mainly, self-reported race information and small number of ethnic minorities), at present there are no data supporting that donor race should be considered a factor in donor selection. PMID- 23647060 TI - Candidate gene association studies and risk of chronic lymphocytic leukemia: a systematic review and meta-analysis. AB - To evaluate the contribution of association studies of candidate polymorphisms to inherited predisposition to chronic lymphocytic leukemia (CLL), we conducted a systematic review and meta-analysis of published case-control studies. We identified 36 studies which reported on polymorphic variation in 19 genes and CLL risk. Out of the 23 polymorphic variants, significant associations (p < 0.05) were seen in pooled analyses for only four variants: MDR1, rs1045642; LTA, rs2239704; CD38, rs6449182; and IFNGR1, rs4896243. These findings should be interpreted cautiously, as the estimated false positive report probabilities (FPRPs) for each association were not noteworthy (i.e. FPRP > 0.2). While studies of candidate polymorphisms may be an attractive means of identifying risk factors for CLL, the limited power of published studies to demonstrate statistically significant associations makes it essential that future analyses be based on sample sizes well-powered to identify variants having modest effects on CLL risk. PMID- 23647061 TI - Successful use of very low dose subcutaneous decitabine to treat high-risk myelofibrosis with Sweet syndrome that was refractory to 5-azacitidine. PMID- 23647062 TI - Bortezomib down-modulates the survival factor interferon regulatory factor 4 in Hodgkin lymphoma cell lines and decreases the protective activity of Hodgkin lymphoma-associated fibroblasts. AB - Bortezomib is a proteasome inhibitor active in classical Hodgkin lymphoma (cHL) cell lines, but poorly active in the clinic when used as a single agent, suggesting that the microenvironment could protect from drug efficacy. Therefore, we investigated the effects of bortezomib activity in the presence of HL associated fibroblasts (HL-AFs) and sCD40L. We found that co-cultivation with human HL-AFs or the addition of sCD40L during bortezomib treatment protected cHL cells from apoptosis and cytotoxicity and rescued the down-regulation of the survival factor interferon regulatory factor 4 (IRF4). In contrast, bortezomib treatment before co-cultivation with HL-AFs inhibited in a dose-dependent manner cHL cell adhesion to HL-AFs and completely overcame HL-AF protection against drug activity. Consistently, we found that bortezomib treatment down-regulated the surface expression of CD49d and CD44, which mediate the adhesion of cHL cells to HL-AFs, and of CD54 and CD40, which mediate the adhesion to CD40L+ rosetting T cells. These preclinical findings suggest that the low in vivo activity of bortezomib as a single agent may be due to a protective influence of the microenvironment. However, inclusion of bortezomib in the cHL drug regimen, by reducing IRF4 expression and interactions with the microenvironment, could increase the efficacy of current chemotherapeutic treatment of relapsed/refractory cHL. PMID- 23647064 TI - Features and outcomes of diffuse large B-cell lymphoma of the thyroid in a large contemporary cohort. AB - Among 42 133 cases of diffuse large B-cell lymphoma (DLBCL) registered at the Surveillance, Epidemiology and End Results (SEER) database between 2001 and 2009, we found 487 cases (1.2%) of thyroid DLBCL. Patients were predominantly female, older and less likely to present with advanced disease than their counterparts with DLBCL of another extranodal or nodal site. Survival was superior for patients with thyroid DLBCL, even when adjusted for patient characteristics and stage. Among the 411 patients with stage I/II disease (84%), 351 had available information regarding surgical resection and radiation and at least 4 months of follow-up. Risk of death was higher for subjects who did not receive resection or radiation (hazard ratio = 2.63, 95% confidence interval 1.43-4.85), but not affected by the omission of one of these therapeutic modalities. The use of surgery or radiation may add to systemic treatment and improve survival of patients with stages I/II thyroid DLBCL. PMID- 23647063 TI - Anemia in diffuse large B-cell non-Hodgkin lymphoma: the role of interleukin-6, hepcidin and erythropoietin. AB - Anemia is a frequent sign in patients with diffuse large B-cell lymphoma (DLBCL) at diagnosis. We determined erythropoietin, hepcidin and interleukin-6 (IL-6) in plasma samples of 53 patients with DLBCL. The majority of patients (40/53, 75%) showed defective endogenous erythropoietin production, in particular when anemia was present (p = 0.01). Hepcidin plasma levels were significantly higher in patients compared to controls (p = 0.006), particularly in those with characteristics associated with a more active disease, including elevated lactate dehydrogenase (LDH) (p = 0.0004), B-symptoms (p = 0.07) and an age-adjusted international prognostic index (IPI) score > 1 (p = 0.01). Hepcidin levels correlated strongly to ferritin (r = 0.77, p < 0.0001) and weakly to IL-6 concentrations (r = 0.30, p = 0.03), but not to hemoglobin values. IL-6 inversely correlated to hemoglobin values in both univariate and multivariate analysis (p = 0.04), including hepcidin and erythropoietin as variables. Our findings suggest that elevated hepcidin levels and inadequate erythropoietin response are frequent in DLBCL, but elevated IL-6 plays the major role for the development of anemia. PMID- 23647066 TI - Phytochemical profiles and antioxidant activity of adlay varieties. AB - Consumption of whole grains has been associated with reduced risk of developing major chronic diseases. These health benefits have been attributed in part to their unique phytochemicals. Little is known about the complete profiles of phytochemicals and antioxidant activities of different adlay varieties. The objectives of this study were to determine the phytochemicals profiles of the three adlay varieties, including both free and bound of total phenolics and total flavonoids, and to determine the total antioxidant activity of adlay. The free, bound, and total phenolic contents of adlay samples ranged from 31.23 to 45.19 mg of gallic acid equiv/100 g of sample, from 28.07 to 30.86 mg of gallic acid equiv/100 g of sample, and from 59.30 to 76.04 mg of gallic acid equiv/100 g of sample, respectively. On average, the bound phenolics contributed 45.3% of total phenolic content of the adlay varieties analyzed. The free, bound, and total flavonoid contents of adlay samples ranged from 6.21 to 18.24 mg of catechin equiv/100 g, from 18.68 to 35.27 mg of catechin equiv/100 g, and from 24.88 to 52.86 mg of catechin equiv/100 g, respectively. The average values of bound flavonoids contributed 71.1% of total flavonoids of the adlay varieties analyzed. The percentage contribution of flavonoid content to phenolic content of free, bound, and total ranged from 11.6 to 35.2%, from 50.5 to 66.8%, and from 24.6 to 50.5%. The free, bound, and total oxygen radical absorbance capacity (ORAC) values of adlay samples ranged from 231.9 to 316.6 mg of Trolox equiv/100 g, from 209.0 to 351.4 mg of Trolox equiv/100 g, and from 440.9 to 668.0 mg of Trolox equiv/100 g, respectively. The average ORAC values of bound phytochemicals contributed 48.1% of total antioxidant activity of the adlay varieties analyzed. The content of total polyphenol and the antioxidant capacity are obviously different among different species. Liaoning 5 adlay and Longyi 1 adlay are significantly better than Guizhou heigu adlay. The adlay extracts have obvious proliferate inhibition on human liver cancer cells, and substantially in the experimental concentration range, the adlay sample itself has no cytotoxicity. Knowing the phytochemical profiles and antioxidant activity of adlay gives insights to its potential application to promote health. PMID- 23647065 TI - Activation of adenosine A(2A) receptor reduces osteoclast formation via PKA- and ERK1/2-mediated suppression of NFkappaB nuclear translocation. AB - BACKGROUND AND PURPOSE: We previously reported that adenosine, acting at adenosine A(2A) receptors (A(2A)R), inhibits osteoclast (OC) differentiation in vitro (A(2A)R activation OC formation reduces by half) and in vivo. For a better understanding how adenosine A(2A)R stimulation regulates OC differentiation, we dissected the signalling pathways involved in A(2A)R signalling. EXPERIMENTAL APPROACH: OC differentiation was studied as TRAP+ multinucleated cells following M-CSF/RANKL stimulation of either primary murine bone marrow cells or the murine macrophage line, RAW264.7, in presence/absence of the A(2A)R agonist CGS21680, the A(2A)R antagonist ZM241385, PKA activators (8-Cl-cAMP 100 nM, 6-Bnz-cAMP) and the PKA inhibitor (PKI). cAMP was quantitated by EIA and PKA activity assays were carried out. Signalling events were studied in PKA knockdown (lentiviral shRNA for PKA) RAW264.7 cells (scrambled shRNA as control). OC marker expression was studied by RT-PCR. KEY RESULTS: A(2A)R stimulation increased cAMP and PKA activity which and were reversed by addition of ZM241385. The direct PKA stimuli 8-Cl-cAMP and 6-Bnz-cAMP inhibited OC maturation whereas PKI increased OC differentiation. A(2A)R stimulation inhibited p50/p105 NFkappaB nuclear translocation in control but not in PKA KO cells. A(2A)R stimulation activated ERK1/2 by a PKA-dependent mechanism, an effect reversed by ZM241385, but not p38 and JNK activation. A(2A)R stimulation inhibited OC expression of differentiation markers by a PKA-mechanism. CONCLUSIONS AND IMPLICATIONS: A(2A)R activation inhibits OC differentiation and regulates bone turnover via PKA-dependent inhibition of NFkappaB nuclear translocation, suggesting a mechanism by which adenosine could target bone destruction in inflammatory diseases like rheumatoid arthritis. PMID- 23647067 TI - Human beta-defensin-2 as a marker for disease severity and skin barrier properties in atopic dermatitis. AB - BACKGROUND: Skin infections related to disrupted antimicrobial defence are a common problem in atopic dermatitis (AD). Altered levels of antimicrobial peptides, including human beta-defensin (hBD)-2, have been reported in AD skin, and a link to impaired barrier function has been suggested. OBJECTIVES: To study hBD-2 in relation to skin barrier function in patients with AD and controls, and to study hBD-2 in relation to disease severity. METHODS: Twenty-five patients with AD and 11 controls were enrolled. hBD-2 peptide concentration was determined in stratum corneum samples collected by a minimally invasive tape-stripping method. Disease severity was assessed by SCORing Atopic Dermatitis (SCORAD), and skin barrier function was evaluated by measurement of transepidermal water loss (TEWL) and skin pH. Patients with AD were characterized according to filaggrin mutations. RESULTS: hBD-2 concentrations in the stratum corneum were found to differ between lesional and nonlesional AD skin and controls, with the highest values in lesional skin (P < 0.001). SCORAD and TEWL were significantly increased in participants with measureable hBD-2 (P < 0.018 and P < 0.007, respectively). Significant correlations between hBD-2 in lesional skin, and TEWL and SCORAD were observed (R = 0.55 and R = 0.44, respectively). No correlations with skin pH were found. hBD-2 was not found to relate to filaggrin mutations. CONCLUSIONS: A significant correlation was found between hBD-2, disturbed skin barrier function and disease severity. The minimally invasive skin sample technique enables evaluation of the stratum corneum and its proteins over time and provides the possibility of relating these findings to treatment, infections and physiological variations. PMID- 23647069 TI - Unified changes in cell size permit coordinated leaf evolution. AB - The processes by which the functions of interdependent tissues are coordinated as lineages diversify are poorly understood. Here, we examine evolutionary coordination of vascular, epidermal and cortical leaf tissues in the anatomically, ecologically and morphologically diverse woody plant family Proteaceae. We found that, across the phylogenetic range of Proteaceae, the sizes of guard, epidermal, palisade and xylem cells were positively correlated with each other but negatively associated with vein and stomatal densities. The link between venation and stomata resulted in a highly efficient match between potential maximum water loss (determined by stomatal conductance) and the leaf vascular system's capacity to replace that water. This important linkage is likely to be driven by stomatal size, because spatial limits in the packing of stomata onto the leaf surface apparently constrain the maximum size and density of stomata. We conclude that unified evolutionary changes in cell sizes of independent tissues, possibly mediated by changes in genome size, provide a means of substantially modifying leaf function while maintaining important functional links between leaf tissues. Our data also imply the presence of alternative evolutionary strategies involving cellular miniaturization during radiation into closed forest, and cell size increase in open habitats. PMID- 23647068 TI - Identification of ClpP substrates in Caulobacter crescentus reveals a role for regulated proteolysis in bacterial development. AB - Energy-dependent proteases ensure the timely removal of unwanted proteins in a highly selective fashion. In Caulobacter crescentus, protein degradation by the ClpXP protease is critical for cell cycle progression; however, only a handful of substrates are currently known. Here, we use a trapping approach to identify putative substrates of the ClpP associated proteases in C. crescentus. Biochemical validation of several of these targets reveals specific protease recognition motifs and suggests a need for ClpXP-specific degradation beyond degradation of known cell cycle regulators. We focus on a particular instance of regulated proteolysis in Caulobacter by exploring the role of ClpXP in degrading the stalk synthesis transcription factor TacA. We show that TacA degradation is controlled during the cell cycle dependent on the ClpXP regulator CpdR and that stabilization of TacA increases degradation of another ClpXP substrate, CtrA, while restoring deficiencies associated with prolific CpdR activity. Together, our work reveals a number of new validated ClpXP substrates, clarifies rules of protease substrate selection, and demonstrates how regulated protein degradation is critical for Caulobacter development and cell cycle progression. PMID- 23647070 TI - Engineered absorption enhancement and induced transparency in coupled molecular and plasmonic resonator systems. AB - Coupled plasmonic resonators have become the subject of significant research interest in recent years as they provide a route to dramatically enhanced light matter interactions. Often, the design of these coupled mode systems draws intuition and inspiration from analogies to atomic and molecular physics systems. In particular, they have been shown to mimic quantum interference effects, such as electromagnetically induced transparency (EIT) and Fano resonances. This analogy also been used to describe the surface-enhanced absorption effect where a plasmonic resonance is coupled to a weak molecular resonance. These important phenomena are typically described using simple driven harmonic (or linear) oscillators (i.e., mass-on-a-spring) coupled to each other. In this work, we demonstrate the importance of an essential interdependence between the rate at which the system can be driven by an external field and its damping rate through radiative loss. This link is required in systems exhibiting time-reversal symmetry and energy conservation. Not only does it ensure an accurate and physically consistent description of resonant systems but leads directly to interesting new effects. Significantly, we demonstrate this dependence to predict a transition between EIT and electromagnetically induced absorption that is solely a function of the ratio of the radiative to intrinsic loss rates in coupled resonator systems. Leveraging the temporal coupled mode theory, we introduce a unique and intuitive picture that accurately describes these effects in coupled plasmonic/molecular and fully plasmonic systems. We demonstrate our approach's key features and advantages analytically as well as experimentally through surface-enhanced absorption spectroscopy and plasmonic metamaterial applications. PMID- 23647071 TI - Preparation and exceptional lithium anodic performance of porous carbon-coated ZnO quantum dots derived from a metal-organic framework. AB - Hierarchically porous carbon-coated ZnO quantum dots (QDs) (~3.5 nm) were synthesized by a one-step controlled pyrolysis of the metal-organic framework IRMOF-1. We have demonstrated a scalable and facile synthesis of carbon-coated ZnO QDs without agglomeration by structural reorganization. This unique microstructure exhibits outstanding electrochemical performance (capacity, cyclability, and rate capability) when evaluated as an anode material for lithium ion batteries. PMID- 23647073 TI - Effect of planning for connectivity on linear reserve networks. AB - Although the concept of connectivity is decades old, it remains poorly understood and defined, and some argue that habitat quality and area should take precedence in conservation planning instead. However, fragmented landscapes are often characterized by linear features that are inherently connected, such as streams and hedgerows. For these, both representation and connectivity targets may be met with little effect on the cost, area, or quality of the reserve network. We assessed how connectivity approaches affect planning outcomes for linear habitat networks by using the stock-route network of Australia as a case study. With the objective of representing vegetation communities across the network at a minimal cost, we ran scenarios with a range of representation targets (10%, 30%, 50%, and 70%) and used 3 approaches to account for connectivity (boundary length modifier, Euclidean distance, and landscape-value [LV]). We found that decisions regarding the target and connectivity approach used affected the spatial allocation of reserve systems. At targets >=50%, networks designed with the Euclidean distance and LV approaches consisted of a greater number of small reserves. Hence, by maximizing both representation and connectivity, these networks compromised on larger contiguous areas. However, targets this high are rarely used in real-world conservation planning. Approaches for incorporating connectivity into the planning of linear reserve networks that account for both the spatial arrangement of reserves and the characteristics of the intervening matrix highlight important sections that link the landscape and that may otherwise be overlooked. PMID- 23647074 TI - HPV-genotypes in high-grade intraepithelial cervical lesions in Danish women. AB - OBJECTIVE: A study was undertaken to assess the distribution of high-risk HPV genotypes in high-grade cervical intraepithelial neoplastic lesions in Danish women. DESIGN: Observational, cross-sectional. SETTING: Danish data from a multi centre study undertaken in 13 European countries. POPULATION: 290 archived fixed biopsies with high-grade cervical lesions from the Departments of Pathology at the University Hospitals in Hvidovre and Odense, Denmark. METHODS: Relevant histological samples were anonymized and shipped to a central laboratory for histopathology review and PCR-testing for HPV-DNA. A standardised HPV-test methodology was utilised to enable comparison of HPV-genotype distribution. RESULTS: Of 290 Danish cervical samples, 276 were evaluated as histologically adequate and all of these were HPV-positive (HPV+). Of the HPV+ samples 77.9% were diagnosed with a single HPV-type, with cervical intraepithelial neoplasia (CIN)3 diagnosed in 82.3% and CIN2, CIN2/3, adenocarcinoma in situ (AIS) and AIS+ other high-grade lesion diagnosed in the remaining 17.7%. The most prevalent HPV types were: HPV16 (54.0%), HPV33 (13.5%), HPV31 (10.7%), HPV18 (7.9%) and HPV52 (4.7%). Of the HPV+ samples, 21.4% were diagnosed with multiple HPV-types, with CIN3 diagnosed in 79.6% and CIN2, CIN2/3, AIS and AIS+ other high-grade lesion diagnosed in the remaining 20.4%. The most prevalent HPV-types were: HPV16 (49.2%), HPV31 (30.5%), HPV52 (27.1%), HPV51 (20.3%), HPV18 (16.9%), HPV33 (13.6%), HPV45 (11.9%), with 0.7% unknown types. CONCLUSIONS: HPV16 and HPV18 were detected in approximately 75% of high-grade intraepithelial cervical lesions in a Danish population (single or multiple infections); these two genotypes are considered causative in at least 61.9% of the high-grade intraepithelial lesions (single infection). PMID- 23647075 TI - Negative interpersonal events mediate the relation between borderline features and aggressive behavior: findings from a nonclinical sample of undergraduate women. AB - Interpersonal dysfunction and aggression are features that are frequently found in individuals with borderline personality disorder (BPD); however, few studies have examined the possible causal relationship between aggressive actions and interpersonal problems. In a nonclinical sample of 98 women with a range of BPD features, the present study examined the prospective relationship between aggressive behaviors and negative interpersonal events using a weekly diary method. Results showed that higher BPD symptoms were related to higher aggression and more negative interpersonal events. Furthermore, the aggressive acts endorsed among women with more BPD features were more likely the effect, rather than the cause, of the negative interpersonal events they experienced. Implications for interventions targeting aggression among women with elevated BPD features and suggestions for future research are discussed. PMID- 23647072 TI - Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. AB - PURPOSE: The management of epilepsy in children is particularly challenging when seizures are resistant to antiepileptic medications, or undergo many changes in seizure type over time, or have comorbid cognitive, behavioral, or motor deficits. Despite efforts to classify such epilepsies based on clinical and electroencephalographic criteria, many children never receive a definitive etiologic diagnosis. Whole exome sequencing (WES) is proving to be a highly effective method for identifying de novo variants that cause neurologic disorders, especially those associated with abnormal brain development. Herein we explore the utility of WES for identifying candidate causal de novo variants in a cohort of children with heterogeneous sporadic epilepsies without etiologic diagnoses. METHODS: We performed WES (mean coverage approximately 40*) on 10 trios comprised of unaffected parents and a child with sporadic epilepsy characterized by difficult-to-control seizures and some combination of developmental delay, epileptic encephalopathy, autistic features, cognitive impairment, or motor deficits. Sequence processing and variant calling were performed using standard bioinformatics tools. A custom filtering system was used to prioritize de novo variants of possible functional significance for validation by Sanger sequencing. KEY FINDINGS: In 9 of 10 probands, we identified one or more de novo variants predicted to alter protein function, for a total of 15. Four probands had de novo mutations in genes previously shown to harbor heterozygous mutations in patients with severe, early onset epilepsies (two in SCN1A, and one each in CDKL5 and EEF1A2). In three children, the de novo variants were in genes with functional roles that are plausibly relevant to epilepsy (KCNH5, CLCN4, and ARHGEF15). The variant in KCNH5 alters one of the highly conserved arginine residues of the voltage sensor of the encoded voltage-gated potassium channel. In vitro analyses using cell-based assays revealed that the CLCN4 mutation greatly impaired ion transport by the ClC-4 2Cl(-) /H(+) exchanger and that the mutation in ARHGEF15 reduced GEF exchange activity of the gene product, Ephexin5, by about 50%. Of interest, these seven probands all presented with seizures within the first 6 months of life, and six of these have intractable seizures. SIGNIFICANCE: The finding that 7 of 10 children carried de novo mutations in genes of known or plausible clinical significance to neuronal excitability suggests that WES will be of use for the molecular genetic diagnosis of sporadic epilepsies in children, especially when seizures are of early onset and difficult to control. PMID- 23647076 TI - Insulin-like growth factor II mRNA-binding protein 3 expression promotes tumor formation and invasion and predicts poor prognosis in oral squamous cell carcinoma. AB - BACKGROUND: Insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3), an oncofetal RNA-binding protein, has been implicated in the enhancement of proliferation and invasion in various cancers. This study aimed to investigate the clinical significance and functional role of IGF2BP3 expression in oral squamous cell carcinoma (OSCC). METHODS: IGF2BP3 expression in 93 OSCC patients was investigated using immunohistochemical staining and correlated with clinical parameters and patients' survival. The effect of IGF2BP3 on cell invasion ability was evaluated by RNA interference in OSCC cell line. RESULTS: High expression of IGF2BP3 in OSCC was significantly correlated with large tumor size and lymph node metastasis. Kaplan-Meier analysis revealed that oral cancer patients with high IGF2BP3 expression had a significantly lower 5-year survival (P = 0.0017). Multivariate analysis of clinical samples demonstrated IGF2BP3 to be an independent prognosis factor (P = 0.003). Moreover, the IGF2BP3 shRNA significantly suppressed the invasion ability of OSCC in vitro, and the knockdown of endogenous IGF2BP3 expression also inhibited tumor formation in vivo. CONCLUSIONS: IGF2BP3 enhances cell invasion ability and tumorigenicity in human OSCC in vitro and in vivo. IGF2BP3 is an independent prognostic factor in patients with OSCC. Targeting of IGF2BP3 could potentially suppress the tumor growth and metastasis to improve the outcome of patients with OSCC. PMID- 23647077 TI - Dissecting aneurysm at the A1 segment of the anterior cerebral artery presenting as visual loss and visual field defect. AB - Intracranial dissecting aneurysms mainly occur in the territory of the vertebrobasilar system. Dissecting aneurysms confined to the anterior cerebral artery are rare, and the presentations are usually of either subarachnoid hemorrhage or cerebral infarction. Here, we report a unique case of a dissecting aneurysm of the anterior cerebral artery presenting as a visual field defect. After surgical decompression, visual symptoms recovered. PMID- 23647078 TI - A new modified speculum guided single nostril technique for endoscopic transnasal transsphenoidal surgery: an analysis of nasal complications. AB - Abstract The endoscopic transnasal, transsphenoidal surgical technique for pituitary tumour excision has generally been regarded as a less invasive technique, ranging from single nostril to dual nostril techniques. We propose a single nostril technique using a modified nasal speculum as a preferred technique. We initially reviewed 25 patients who underwent pituitary tumour excision, via endoscopic transnasal transsphenoidal surgery, using this new modified speculum-guided single nostril technique. The results show shorter operation time with reduced intra- and post-operative nasal soft tissue injuries and complications. PMID- 23647079 TI - A novel c.-274C>G polymorphism in bovine SIRT1 gene contributes to diminished promoter activity and is associated with increased body size. AB - SIRT1, a mammalian homologue for yeast silent information regulator 2 (SIR2), is a NAD(+) -dependent deacetylase that belongs to the class III histone deacetylases. It plays an important role in diverse cellular processes, including stress resistance, mitochondrial function, suppression of inflammation and DNA repair. In this study, we screened and identified a novel polymorphism (c. 274C>G) in the SIRT1 promoter region. In silico prediction reveals that this SNP is in the core of cell cycle-dependent element (CDE)-binding motif. Interestingly, the G allele abolished a CDE-binding site, which suggested its functional significance. In the luciferase assay system, we found that the G allele-containing construct displayed a strikingly lower promoter activity compared with the C allele, which may downregulate SIRT1 expression levels. Additionally, we observed a significant association between the c.-274C>G polymorphism and growth traits in Nanyang cattle, suggesting that anomalous transcription factor-based repression of SIRT1 may increase bovine fat mass and body size. PMID- 23647080 TI - Enantioselective synthesis of alpha-tri- and alpha-tetrasubstituted allylsilanes by copper-catalyzed asymmetric allylic substitution of allyl phosphates with silylboronates. AB - A copper/N-heterocyclic carbene-catalyzed asymmetric allylic substitution of allyl phosphates with a silylboronate has been developed to give highly enantioenriched allylsilanes. High regioselectivity has been achieved by employing NaOH as the base, and this catalyst system is effective for both gamma mono- and disubstituted allyl phosphates. PMID- 23647081 TI - Ruxolitinib in clinical practice for therapy of myelofibrosis: single USA center experience following Food and Drug Administration approval. PMID- 23647083 TI - Mass trees: a new phylogenetic approach and algorithm to chart evolutionary history with mass spectrometry. AB - A new phylogenetics approach and algorithm with which to chart the evolutionary history of organisms is presented. It utilizes mass spectral data produced from the proteolytic digestion of proteins, rather than partial or complete gene or translated gene sequences. The concept and validity of the approach is demonstrated herein using both theoretical and experimental mass data, together with the translated gene sequences of the hemagglutinin protein of the influenza virus. A comparison of the mass trees with conventional sequenced-based phylogenetic trees, using two separate tree comparison algorithms, reveals a high degree of similarity and congruence among the trees. Given that the mass map data can be generated more rapidly than gene sequences, even when next generation parallel sequencing is employed, mass trees offer new opportunities and advantages for phylogenetic analysis. PMID- 23647082 TI - Behavioral and physiological responses of female prairie voles (Microtus ochrogaster) to various stressful conditions. AB - Stressful life events elicit hypothalamic-pituitary-adrenal (HPA) axis activation, which may alter psychological states or behavioral routines. Therefore, the current study focused on the HPA axis response to better understand such manifestations in female prairie voles (Microtus ochrogaster). In Experiment 1, females were stressed for 1 h via one of the four stressors: exposure to a novel environment, immobilization ("plastic mesh"), brief social defeat, or prolonged social defeat. Following a 30-min recovery, the females received a 5-min elevated plus maze (EPM) test and, subsequently, blood was collected to measure plasma corticosterone concentrations. Only immobilization stress induced an anxiety-like behavioral response in the EPM test and elevated plasma corticosterone levels compared to the control groups. Corticosterone concentrations were also significantly elevated following exposure to prolonged social defeat compared to the control conditions, but not after novel environment stress or short social defeat. In Experiment 2, females were exposed to immobilization stress over 1, 3, or 7 days in a daily (predictable; pIMO) or irregular (unpredictable; uIMO) schedule. The biobehavioral stress response in females exposed to pIMO for 3 or 7 days did not differ significantly from controls, suggesting these females habituated. By comparison, females exposed to uIMO over 3 or 7 days did not habituate behaviorally or physiologically, even producing augmented corticosterone levels. In both experiments, positive correlations were found between corticosterone levels and anxiety-like behaviors in the EPM test. Together, our data suggest that the stress response by female prairie voles is dependent on stress intensity, source, previous experience, and predictability. Furthermore, the HPA axis response, as evident by corticosterone levels, is associated with the impact that these factors have on behavioral routine. PMID- 23647084 TI - Physiological and metabolic consequences of autophagy deficiency for the management of nitrogen and protein resources in Arabidopsis leaves depending on nitrate availability. AB - Autophagy is present at a basal level in all plant tissues and is induced during leaf ageing and in response to nitrogen (N) starvation. Nitrogen remobilization from the rosette to the seeds is impaired in autophagy mutants. This report focuses on the role of autophagy in leaf N management and proteolysis during plant ageing. Metabolites, enzyme activities and protein contents were monitored in several autophagy-defective (atg) Arabidopsis mutants grown under low and high nitrate conditions. Results showed that carbon (C) and N statuses were affected in atg mutants before any senescence symptoms appeared. atg mutants accumulated larger amounts of ammonium, amino acids and proteins than wild type, and were depleted in sugars. Over-accumulation of proteins in atg mutants was selective and occurred despite higher endopeptidase and carboxypeptidase activities. Specific over-accumulation of the ribosomal proteins S6 and L13 subunits, and of catalase and glutamate dehydrogenase proteins was observed. atg mutants also accumulated peptides putatively identified as degradation products of the Rubisco large subunit and glutamine synthetase 2 (GS2). Incomplete chloroplast protein degradation resulting from autophagy defects could explain the higher N concentrations measured in atg rosettes and defects in N remobilization. It is concluded that autophagy controls C : N status and protein content in leaves of Arabidopsis. PMID- 23647085 TI - Green asparagus (Asparagus officinalis) prevented hypertension by an inhibitory effect on angiotensin-converting enzyme activity in the kidney of spontaneously hypertensive rats. AB - Green asparagus (Asparagus officinalis) is known to be rich in functional components. In the present study, spontaneously hypertensive rats (SHR) were used to clarify whether green asparagus prevents hypertension by inhibition of angiotensin-converting enzyme (ACE) activity. Six-week-old male SHR were fed a diet with (AD group) or without (ND group) 5% asparagus for 10 weeks. Systolic blood pressure (SBP) (AD: 159 +/- 4.8 mmHg, ND: 192 +/- 14.7 mmHg), urinary protein excretion/creatinine excretion, and ACE activity in the kidney were significantly lower in the AD group compared with the ND group. Creatinine clearance was significantly higher in the AD group compared with the ND group. In addition, ACE inhibitory activity was observed in a boiling water extract of asparagus. The ACE inhibitor purified and isolated from asparagus was identified as 2"-hydroxynicotianamine. In conclusion, 2"-hydroxynicotianamine in asparagus may be one of the factors inhibiting ACE activity in the kidney, thus preventing hypertension and preserving renal function. PMID- 23647086 TI - Time course of early histopathological lung changes in an ovine model of acute lung injury and pulmonary infection. AB - Large animal models are valuable tools in biological and medical lung research. Despite the existence of established large animal models, the scientific progress requires more detailed description and expansion of established methods. Previously, we established an ovine model of acute lung injury and subsequent bacterial instillation into the lungs. The current study was designed to assess the time course of early lung histopathological alterations in a large animal model. Injury was induced by smoke inhalation and instillation of live Pseudomonas aeruginosa into the lungs. After 4, 8, 12, 18, and 24 hours, respectively, lung tissue was harvested and histopathological changes were evaluated (n = 4 each). Additional four sheep received no injury and only lung tissue was taken. In injured animals, bronchial obstruction score increased over time and was significantly elevated from 12 to 24 hours (P < .05 versus no injury). Inflammation score was significantly increased at 12 and 18 hours (P < .05 versus no injury). Hemorrhage score was increased at 8 and 12 hours (P < .05 versus no injury). Alveolar edema score was significantly higher in injured sheep at 8, 18, and 24 hours (P < .05 each versus no injury). In conclusion, bronchial obstruction and alveolar edema scores significantly increased over time and reached a plateau, while both inflammation and hemorrhage scores were transiently increased peaking around the 12-hour time point. This information improves the understanding of lung histopathological alterations following acute lung injury and pulmonary infection and may help optimizing the timing of study interventions and evaluation time points in future experiments with this model. PMID- 23647087 TI - Expression pattern of GSTP1 and GSTA1 in the pathogenesis of asthma. AB - Reactive oxygen species (ROS) are known aggravating factors for airway inflammation in asthma. Glutathione S-transferases (GSTs) detoxify ROS and toxic compounds in environmental exposures. However, little is known about the regulation of GST and expression of GST subtypes in asthma. The aim of this study was to evaluate how GSTs are regulated in asthma. We observed total GST activity and expression of GST subtypes in murine asthma models and GST expressions in induced sputum cells of asthmatics. Total GST activity was increased in BAL fluids of OVA-treated murine asthma model. GSTP and GSTA are highly expressed in peribronchiolar mononuclear inflammatory cells and epithelial cells in OVA treated mice. GSTM are expressed in epithelial cells in both OVA and PBS-treated groups. GSTP1 mRNA expression was increased in the lung of OVA-treated mice compared with PBS-treated mice. GSTA1, GSTM1, and GSTT1 mRNA expressions were not different between both groups. GSTA1 mRNA expression was increased in induced sputum cells of asthmatics compared with healthy controls. GSTP1, GSTM1, and GSTT1 mRNA expressions were not different between asthmatics and healthy controls. In asthmatics, GSTP1 and GSTA1 mRNA expressions were higher in induced sputum cells of asthmatics with PC20 <= 4 mg/ml than those with PC20 > 4 mg/ml. GSTM1 and GSTT1 mRNA expressions were not different between two groups. These findings suggest that GSTs are upregulated in the airways of asthmatics in response to increased oxidative stress. GSTP and GSTA are thought to play an important role in protecting the airways of asthmatics compared with GSTM and GSTT. PMID- 23647088 TI - Moderate hypothermia attenuates oxidative stress injuries in alveolar epithelial A549 cells. AB - Reactive oxygen species (ROS) are generally involved in lung inflammation and acute lung injury. We investigated the effects of hypothermia on ROS-induced cell damage in human alveolar type II cells. A549 cells were exposed to H2O2 and cultured at different temperatures, namely, normthermia (37 degrees C), mild hypothermia (34 degrees C), or moderate hypothermia (32 degrees C). Cell damage was measured using various assays. The biochemical studies demonstrated a significant increase in apoptosis and intracellular ROS at 32 degrees C in uninjured A549 cells. After exposure to H2O2, a marked decrease in cell viability (<50%) was demonstrated, and this was significantly ameliorated upon culture at 32 degrees C. Significantly intracellular damage was found to affect the 24-hour H2O2-exposed cells in 37 degrees C (P < .05), including an increase in apoptosis and necrosis, intracellular ROS, caspase-3 activity, HMGB1 protein expression, and some alterations to the cell cycle. On hypothermic treatment, the 24-hour H2O2-induced caspase-3 activation was significantly suppressed in cells cultured at both 32 degrees C and 34 degrees C (P < .05 versus 37 degrees C). The cell cycle changes in 24-hour H2O2-exposed cells were significantly diminished when the cells were cultured in 32 degrees C (P < .05 versus 37 degrees C). However, these intracellular alterations were not seen in 6-hour H2O2-exposed cells. We concluded that moderate hypothermia (32 degrees C) of alveolar epithelial A549 cells seems to provide protection against H2O2-induced 24-hour oxidative stress by attenuating cell death and intracellular damage. However, moderate hypothermia might cause minor damage to uninjured cells, so the use of hypothermic treatment needs to be judiciously applied. PMID- 23647089 TI - CuTe nanocrystals: shape and size control, plasmonic properties, and use as SERS probes and photothermal agents. AB - We report a procedure to prepare highly monodisperse copper telluride nanocubes, nanoplates, and nanorods. The procedure is based on the reaction of a copper salt with trioctylphosphine telluride in the presence of lithium bis(trimethylsilyl)amide and oleylamine. CuTe nanocrystals display a strong near infrared optical absorption associated with localized surface plasmon resonances. We exploit this plasmon resonance for the design of surface-enhanced Raman scattering sensors for unconventional optical probes. Furthermore, we also report here our preliminary analysis of the use of CuTe nanocrystals as cytotoxic and photothermal agents. PMID- 23647090 TI - Effects of road mortality and mitigation measures on amphibian populations. AB - Road mortality is a widely recognized but rarely quantified threat to the viability of amphibian populations. The global extent of the problem is substantial and factors affecting the number of animals killed on highways include life-history traits and landscape features. Secondary effects include genetic isolation due to roads acting as barriers to migration. Long-term effects of roads on population dynamics are often severe and mitigation methods include volunteer rescues and under-road tunnels. Despite the development of methods that reduce road kill in specific locations, especially under-road tunnels and culverts, there is scant evidence that such measures will protect populations over the long term. There also seems little likelihood that funding will be forthcoming to ameliorate the problem at the scale necessary to prevent further population declines. PMID- 23647091 TI - The natural history of actinic keratosis: a systematic review. AB - Knowledge about the development of untreated actinic keratosis (AK) and risk of progression into squamous cell carcinoma (SCC) is important. Therefore, we set out to synthesize primary data on the natural history of AK. We carried out a systematic literature search (Medline, Medline in Process, Embase, Cochrane) of studies on the natural course of AK, regarding (i) progression and regression rates per lesion-year, (ii) changes in total lesion counts over time, and (iii) spontaneous field regression and recurrence rates, taking into account studies on participants without immunosuppression and history of skin cancer, immunosuppressed patients and participants with a history of skin cancer and sunscreen use. Twenty-four eligible studies were identified providing data on at least one of the outcomes. Progression rates of AK to SCC ranged from 0% to 0.075% per lesion-year, with a risk of up to 0.53% per lesion in patients with prior history of nonmelanoma skin cancer. Rates of regression of single lesions ranged between 15% and 63% after 1 year. The data available on recurrence rates of single lesions 1 year after regression indicate a recurrence rate of 15-53%. Data on the relative change of total AK count over time are heterogeneous, and range from -53% to +99.1%. Spontaneous complete field regression rates range from 0% to 21%, with recurrences in 57%. In general, the available data are limited. Important methodological limitations apply. Currently, no reliable estimates concerning the frequency of AK developing into invasive carcinoma can be given, and further studies are needed. PMID- 23647092 TI - Automated measurement of office, home and ambulatory blood pressure in atrial fibrillation. AB - 1. Hypertension and atrial fibrillation (AF) often coexist and are strong risk factors for stroke. Current guidelines for blood pressure (BP) measurement in AF recommend repeated measurements using the auscultatory method, whereas the accuracy of the automated devices is regarded as questionable. This review presents the current evidence on the feasibility and accuracy of automated BP measurement in the presence of AF and the potential for automated detection of undiagnosed AF during such measurements. 2. Studies evaluating the use of automated BP monitors in AF are limited and have significant heterogeneity in methodology and protocols. Overall, the oscillometric method is feasible for static (office or home) and ambulatory use and appears to be more accurate for systolic than diastolic BP measurement. 3. Given that systolic hypertension is particularly common and important in the elderly, the automated BP measurement method may be acceptable for self-home and ambulatory monitoring, but not for professional office or clinic measurement. 4. An embedded algorithm for the detection of asymptomatic AF during routine automated BP measurement with high diagnostic accuracy has been developed and appears to be a useful screening tool for elderly hypertensives. PMID- 23647093 TI - Modafinil alone and in combination with low dose amphetamine does not establish conditioned place preference in male Sprague-Dawley rats. AB - Modafinil is a novel wake-promoting drug with FDA approval for the treatment of narcolepsy, shift work sleep disorder, and sleep apnea. It is also prescribed for many off-label uses such as ADHD and it is currently being assessed as a treatment for psychostimulant dependence. Previous research assessing the abuse liability of modafinil in animals and humans suggests it is less potent and has a low abuse potential compared to traditional psychomotor stimulants. However, modafinil has not been carefully assessed in combination with other psychostimulant drugs. The current study used an unbiased place conditioning procedure simultaneously with locomotor screening procedures to assess the combined behavioral effects of modafinil and d-amphetamine in adult male Sprague Dawley rats. Eight 30-min conditioning trials were conducted in a 2 compartment apparatus with distinct visual and tactile cues. Drug and vehicle conditioning trials were alternated with 1 trial per day separated by 24 hr. On drug conditioning trials, rats were administered either modafinil (64 mg/kg, i.g.), d amphetamine (0.3 or 2.0 mg/kg, s.c.), a combination of modafinil (64 mg/kg) and d amphetamine (0.3 mg/kg), or vehicle injections. On vehicle conditioning trials, all groups received vehicle injections. Preference for either compartment was assessed by recording time spent in each compartment during a 15-min test conducted 24 hr after the last conditioning trial. Results indicated that this low oral dose of modafinil did not significantly increase locomotor activity or establish conditioned place preference (CPP). Moreover, modafinil did not significantly alter the hyperlocomotor or CPP effects of d-amphetamine. To confirm that modafinil is behaviorally active at this low oral dose, a separate assessment of horizontal and vertical activity was conducted with male Sprague Dawley rats in an open field apparatus. Results confirmed that modafinil increased locomotor activity relative to vehicle, with increases in vertical activity especially prominent, a measure that was not assessed in place conditioning trials. Although the current results predict a low abuse liability with concurrent use of modafinil and d-amphetamine, additional research with higher dose combinations may be warranted before ruling out the possibility that these drugs could have additive or synergistic effects. PMID- 23647094 TI - Nicotine levels after IV nicotine and cigarette smoking in men. AB - There has been considerable interest in the pharmacodynamics and pharmacokinetics of nicotine and the influence of different routes of administration. However, these variables are often examined in separate studies, and there is less information about the temporal relation between subjective reports and plasma nicotine levels. This study examined the time course and magnitude of plasma nicotine levels and reports of subjective "high" in nicotine-dependent men after 12 or more hrs of abstinence. The effects of two doses of IV nicotine and two doses of nicotine from cigarette smoking were compared, and samples were collected at 2-min intervals. Plasma nicotine levels after smoking a high nicotine cigarette were significantly greater than after either dose of IV nicotine (p < .001). However, Visual Analog Scale (VAS) ratings of "high" after both doses of IV nicotine and smoking a high-nicotine cigarette did not differ significantly, and followed a similar time course. After smoking a low-nicotine cigarette, VAS ratings of "high" were significantly lower than after either IV nicotine dose or smoking a high-nicotine cigarette (p < .001). Peak levels of "high" were reported within 2 min after IV nicotine administration and the onset of cigarette smoking. Then "high" ratings abruptly decreased, while plasma nicotine rose to peak levels within 4 to 6 min after IV nicotine and 12 to 14 min during cigarette smoking. Plasma nicotine levels did not appear to determine the magnitude or time course of subjective effects under these conditions. PMID- 23647095 TI - Nicotine stimulus expectancy differentially affects reaction time in healthy nonsmokers and smokers depending on sex: a pilot study. AB - Effects of nicotine on neurocognitive performance have been shown but are influenced by nonpharmacological expectancies in smokers, whereas there is little knowledge about expectancy effects in nonsmokers. A half balanced placebo design provides no drug but only placebo and tests the effects of expectations elicited by the information that nicotine was given. Sixty-four healthy participants balanced for smoking status and sex were told that a chewing gum may contain either nicotine or is a placebo in a double-blinded and randomized fashion. One hour later and immediately before neurocognitive function testing (Parametric Go/No-Go task) they were informed--balanced for smoking status and sex--that they belong to the nicotine or to the placebo group. Reaction times of Go responses (RT) and the number of false No-Go responses were analyzed. A significant interaction of all three factors (information, smoking status, sex) was found, indicating that the information to have received nicotine compared with placebo shortened RTs in female smokers but increased it in female nonsmokers, whereas results in men are in part reversed. No effects on No-Go errors were found, and beliefs about nicotine effects had no influence on results. Therefore, the known effects of nicotine on RTs could be influenced by stimulus expectancy not only in smokers but also in nonsmokers. Furthermore, previous results on sex-specific responsiveness to nicotine instructions are supported. PMID- 23647096 TI - ORM-10103, a novel specific inhibitor of the Na+/Ca2+ exchanger, decreases early and delayed afterdepolarizations in the canine heart. AB - BACKGROUND AND PURPOSE: At present there are no small molecule inhibitors that show strong selectivity for the Na(+) /Ca(2+) exchanger (NCX). Hence, we studied the electrophysiological effects of acute administration of ORM-10103, a new NCX inhibitor, on the NCX and L-type Ca(2+) currents and on the formation of early and delayed afterdepolarizations. EXPERIMENTAL APPROACH: Ion currents were recorded by using a voltage clamp technique in canine single ventricular cells, and action potentials were obtained from canine and guinea pig ventricular preparations with the use of microelectrodes. KEY RESULTS: ORM-10103 significantly reduced both the inward and outward NCX currents. Even at a high concentration (10 MUM), ORM-10103 did not significantly change the L-type Ca(2+) current or the maximum rate of depolarization (dV/dtmax ), indicative of the fast inward Na(+) current. At 10 MUM ORM-10103 did not affect the amplitude or the dV/dtmax of the slow response action potentials recorded from guinea pig papillary muscles, which suggests it had no effect on the L-type Ca(2+) current. ORM-10103 did not influence the Na(+) /K(+) pump or the main K(+) currents of canine ventricular myocytes, except the rapid delayed rectifier K(+) current, which was slightly diminished by the drug at 3 MUM. The amplitudes of pharmacologically- induced early and delayed afterdepolarizations were significantly decreased by ORM-10103 (3 and 10 MUM) in a concentration-dependent manner. CONCLUSIONS AND IMPLICATIONS: ORM-10103 is a selective inhibitor of the NCX current and can abolish triggered arrhythmias. Hence, it has the potential to be used to prevent arrhythmogenic events. PMID- 23647097 TI - Re-evaluation of common paradigms regarding the clinical appearance of oral mucosal malignancies. AB - PURPOSE: To evaluate the clinical appearance and rate of ulceration of oral mucosal malignancies, and to investigate the accuracy of clinical provisional diagnoses. METHODS: A 10-year retrospective analysis, which included diagnostic biopsies of malignant tumors of the oral mucosa. The clinical provisional diagnoses were compared with final diagnoses. RESULTS: Two hundred and twenty seven oral mucosal malignant tumors were included. Squamous cell carcinoma and its variants accounted for the majority (78%) of all malignant tumors. The most common clinical presentations were non-ulcerated (59.7%) and ulcerated masses (20.4%). Only 11.9% presented as indurate ulcers. The highest ulceration rate of all malignancies was recorded for SCC, with only about half of SCC and its variants ulcerated at the time of biopsy. 31.1% of all malignancies were not clinically suspected to be malignant and did not even include a request to rule out malignancy. There was a better agreement between the clinical provisional diagnoses and microscopic diagnoses in the SCC group than in other types of malignancy (P < 0.001). CONCLUSION: Within this study sample, non-ulcerated masses rather than indurate ulcers are the most common clinical appearance of oral mucosal malignancies, and even for SCC, that showed the highest ulceration rate at presentation, half were non-ulcerated. Approximately, one-third of oral mucosal malignancies were not suspected to be malignant prior to biopsy. Thus, the level of suspicion currently reserved for mucosal ulcers and ulcerated masses should also be applied to non-ulcerated oral mucosal masses. PMID- 23647098 TI - Superprotonic conductivity in a highly oriented crystalline metal-organic framework nanofilm. AB - The electrical properties of a highly oriented crystalline MOF nanofilm were studied. This nanofilm has low activation energy and a proton conductivity that is among the highest value reported for MOF materials. The study uncovered the reasons for the excellent performance of this nanofilm and revealed a new pathway for proton transport in MOF materials; besides the channels inside a MOF, the surface of the MOF nanocrystal can also dominate proton transport. PMID- 23647100 TI - A SAXS study of aggregation in the synergistic TBP-HDBP solvent extraction system. AB - The macroscopic phase behaviors of a solvent system containing two extractants, tri-n-butyl phosphate (TBP) and di-n-butyl phosphoric acid (HDBP) in n-dodecane, were investigated through use of liquid-liquid extraction and small-angle X-ray scattering (SAXS) experiments. Five organic solutions, each containing a total extractant concentration (TBP + HDBP) of 1 M in varying molar ratios (0, 0.25, 0.5, 0.75, and 1.0 [TBP]:[TBP + HDBP]), were contacted with 0.2 M HNO3 aqueous solutions without and with dysprosium(III) at a concentration of 10(-4) M. An enhancement of the extraction of Dy(3+)--due to effects of synergism arising from the binary combination of extractants--was observed. SAXS data were collected for all solution compositions from 0 to 1 mol-fraction end ratios of TBP after contact with the acidic aqueous solutions both in the absence and presence of Dy as well as for the organic phases before aqueous contact. In the precontacted solutions, no notable changes in the SAXS data were observed upon combining the extractants so that the scattering intensity (I) measured at zero angle (Q = 0 A( 1))--parameter I(0)--the experimental radius of gyration (R(g)), and the maximum linear extent (MLE) of the extractant aggregates were arithmetic averages of the two end members, 1 M HDBP, on the one hand, and 1 M TBP, on the other. In contrast, after contact with the aqueous phases with and without Dy(3+), a significant reorganization occurs with larger aggregates apparent in the extractant mixtures and smaller in the two end member solutions. In particular, the maximum values of the metrical parameters (I(0), R(g), and MLE) correlate with the apparent optimal synergistic extraction mole ratio of 0.25. The SAXS data were further analyzed using the recently developed generalized indirect Fourier transformation (GIFT) method to provide pair-distance distribution functions with real-space information on aggregate morphology. Before aqueous contact, the organic phases show a systematically varying response from globular like reverse micelles in the case of 1 M TBP to rod-shaped architectures in the case of 1 M HDBP. After aqueous contact, the aggregate morphologies of the mixed extractant systems are not simple linear combinations of those for the two end members. Rather, they have larger and more elongated structures, showing sharp discontinuities in the metrics of the aggregate entities that are coincident with the synergistic extraction mixture for Dy(3+). The results in this initial study suggest a supramolecular, micellization aspect to synergism that remains underexplored and warrants further investigation, especially as it concerns the contemporary relevance to decades-old process chemistry and practices for high throughput separations systems. PMID- 23647099 TI - Potential for unreliable interpretation of EEG recorded with microelectrodes. AB - PURPOSE: Recent studies in epilepsy, cognition, and brain machine interfaces have shown the utility of recording intracranial electroencephalography (iEEG) with greater spatial resolution. Many of these studies utilize microelectrodes connected to specialized amplifiers that are optimized for such recordings. We recently measured the impedances of several commercial microelectrodes and demonstrated that they will distort iEEG signals if connected to clinical EEG amplifiers commonly used in most centers. In this study we demonstrate the clinical implications of this effect and identify some of the potential difficulties in using microelectrodes. METHODS: Human iEEG data were digitally filtered to simulate the signal recorded by a hybrid grid (two macroelectrodes and eight microelectrodes) connected to a standard EEG amplifier. The filtered iEEG data were read by three trained epileptologists, and high frequency oscillations (HFOs) were detected with a well-known algorithm. The filtering method was verified experimentally by recording an injected EEG signal in a saline bath with the same physical acquisition system used to generate the model. Several electrodes underwent scanning electron microscopy (SEM). KEY FINDINGS: Macroelectrode recordings were unaltered compared to the source iEEG signal, but microelectrodes attenuated low frequencies. The attenuated signals were difficult to interpret: all three clinicians changed their clinical scoring of slowing and seizures when presented with the same data recorded on different sized electrodes. The HFO detection algorithm was oversensitive with microelectrodes, classifying many more HFOs than when the same data were recorded with macroelectrodes. In addition, during experimental recordings the microelectrodes produced much greater noise as well as large baseline fluctuations, creating sharply contoured transients, and superimposed "false" HFOs. SEM of these microelectrodes demonstrated marked variability in exposed electrode surface area, lead fractures, and sharp edges. SIGNIFICANCE: Microelectrodes should not be used with low impedance (<1 GOmega) amplifiers due to severe signal attenuation and variability that changes clinical interpretations. The current method of preparing microelectrodes can leave sharp edges and nonuniform amounts of exposed wire. Even when recorded with higher impedance amplifiers, microelectrode data are highly prone to artifacts that are difficult to interpret. Great care must be taken when analyzing iEEG from high impedance microelectrodes. PMID- 23647101 TI - Isotopic composition of transpiration and rates of change in leaf water isotopologue storage in response to environmental variables. AB - During daylight hours, the isotope composition of leaf water generally approximates steady-state leaf water isotope enrichment model predictions. However, until very recently there was little direct confirmation that isotopic steady-state (ISS) transpiration in fact exists. Using isotope ratio infrared spectroscopy (IRIS) and leaf gas exchange systems we evaluated the isotope composition of transpiration and the rate of change in leaf water isotopologue storage (isostorage) when leaves were exposed to variable environments. In doing so, we developed a method for controlling the absolute humidity entering the gas exchange cuvette for a wide range of concentrations without changing the isotope composition of water vapour. The measurement system allowed estimation of (18)O enrichment both at the evaporation site and for bulk leaf water, in the steady state and the non-steady state. We show that non-steady-state effects dominate the transpiration isoflux even when leaves are at physiological steady state. Our results suggest that a variable environment likely prevents ISS transpiration from being achieved and that this effect may be exacerbated by lengthy leaf water turnover times due to high leaf water contents. PMID- 23647102 TI - Minocycline reduces remyelination by suppressing ciliary neurotrophic factor expression after cuprizone-induced demyelination. AB - Remyelination is disrupted in demyelinating diseases such as multiple sclerosis, but the underlying pathogenetic mechanisms are unclear. In this study, we employed the murine cuprizone model of demyelination, in which remyelination occurs after removal of the toxin from the diet, to examine the cellular and molecular changes during demyelination and remyelination. Microglia accumulated in the corpus callosum during weeks 2-4 of the cuprizone diet, and these cells remained activated 2 weeks after the change to the normal diet. To examine the role of microglia in remyelination, mice were treated with minocycline to inactivate these cells after cuprizone-induced demyelination. Minocycline treatment reduced the number of CC1-positive oligodendrocytes, as well as levels of myelin basic protein (MBP) and CNPase in the remyelination phase. The expression of CNTF mRNA in the corpus callosum increased after 4 weeks on the cuprizone diet and remained high 2 weeks after the change to the normal diet. Minocycline suppressed CNTF expression during the remyelination phase on the normal diet. Primary culture experiments showed that CNTF was produced by microglia in addition to astrocytes. In vitro, CNTF directly affected the differentiation of oligodendrocytic cells. These findings suggest that minocycline reduces remyelination by suppressing CNTF expression by microglia after cuprizone-induced demyelination. PMID- 23647103 TI - Horror diagnosticus psychiatricus--the fear of expanding nosologies and overdiagnosis in psychiatry. PMID- 23647104 TI - The ferrous iron transporter FtrABCD is required for the virulence of Brucella abortus 2308 in mice. AB - Iron transport has been linked to the virulence of Brucella strains in both natural and experimental hosts. The genes designated BAB2_0837-0840 in the Brucella abortus 2308 genome sequence are predicted to encode a CupII-type ferrous iron transporter homologous to the FtrABCD transporter recently described in Bordetella. To study the role of the Brucella FtrABCD in iron transport, an isogenic ftrA mutant was constructed from B. abortus 2308. Compared with the parental strain, the B. abortus ftrA mutant displays a decreased capacity to use non-haem iron sources in vitro, a growth defect in a low iron medium that is enhanced at pH 6, and studies employing radiolabelled FeCl3 confirmed that FtrABCD transports ferrous iron. Transcription of the ftrA gene is induced in B. abortus 2308 in response to iron deprivation and exposure to acid pH, and similar to other Brucella iron acquisition genes that have been examined the iron responsiveness of ftrA is dependent upon the iron response regulator Irr. The B. abortus ftrA mutant exhibits significant attenuation in both cultured murine macrophages and experimentally infected mice, supporting the proposition that ferrous iron is a critical iron source for these bacteria in the mammalian host. PMID- 23647106 TI - Simple atmospheric hydrogen/deuterium exchange method for enumeration of labile hydrogens by electrospray ionization mass spectrometry. AB - A simple method for hydrogen/deuterium exchange in a standard electrospray (ESI) ionization source is presented. In this method, a D2O droplet is placed between the ESI needle and the entrance of the mass spectrometer and thus saturation of the atmosphere with deuterated vapor in the ESI region is achieved. It was shown that full exchange of up to 23 labile acidic hydrogens with a minimal back exchange with the surrounding atmospheric water can be performed by this method. PMID- 23647105 TI - Case-control study and mRNA expression analysis reveal the MyD88 gene is associated with digestive disorders in rabbit. AB - As in humans, significant associations between Toll-like receptor 4 (TLR4) and digestive disorders have been identified in rabbit and dog. However, as an essential adaptor downstream of TLR4, the genetic variation of myeloid differentiating factor 88 (MyD88) and its association with digestive disorders have remained unknown. In this study, we detected 10 single nucleotide polymorphisms (SNPs) in the entire genomic region of rabbit MyD88. The genetic variation in susceptibility to digestive disorders for the only coding SNP (synonymous c.699T>C) was studied in Yaan (183 cases and 142 controls) and Chengdu populations (145 cases and 140 controls). A case-control association study revealed that individuals with the C allele had significant protection against digestive disorders in the Yaan population (OR = 0.71; 95% CI, 0.51-0.99; P < 0.05), the Chengdu population (OR = 0.55; 95% CI, 0.39-0.78; P < 0.01) and for joint analysis (OR = 0.62; 95% CI, 0.49-0.79; P < 0.01). We also experimentally induced digestive disorders by feeding a fiber-deficient diet and found that increased susceptibility was significantly associated with higher MyD88 mRNA expression (P < 0.05). The lowest MyD88 mRNA expression was observed in individuals carrying the protective CC genotype. These results suggest that MyD88 is one of the most plausible candidate genes in relation to digestive disorders in rabbit. Further studies are required to explore the biological implications of MyD88 in the pathogenesis of digestive disorders. PMID- 23647107 TI - Chemical fingerprinting of naphthenic acids and oil sands process waters-A review of analytical methods for environmental samples. AB - This article provides a review of the routine methods currently utilized for total naphthenic acid analyses. There is a growing need to develop chemical methods that can selectively distinguish compounds found within industrially derived oil sands process affected waters (OSPW) from those derived from the natural weathering of oil sands deposits. Attention is thus given to the characterization of other OSPW components such as oil sands polar organic compounds, PAHs, and heavy metals along with characterization of chemical additives such as polyacrylamide polymers and trace levels of boron species. Environmental samples discussed cover the following matrices: OSPW containments, on-lease interceptor well systems, on- and off-lease groundwater, and river and lake surface waters. There are diverse ranges of methods available for analyses of total naphthenic acids. However, there is a need for inter-laboratory studies to compare their accuracy and precision for routine analyses. Recent advances in high- and medium-resolution mass spectrometry, concomitant with comprehensive mass spectrometry techniques following multi-dimensional chromatography or ion mobility separations, have allowed for the speciation of monocarboxylic naphthenic acids along with a wide range of other species including humics. The distributions of oil sands polar organic compounds, particularly the sulphur containing species (i.e., OxS and OxS2) may allow for distinguishing sources of OSPW. The ratios of oxygen- (i.e., Ox) and nitrogen-containing species (i.e., NOx, and N2Ox) are useful for differentiating organic components derived from OSPW from natural components found within receiving waters. Synchronous fluorescence spectroscopy also provides a powerful screening technique capable of quickly detecting the presence of aromatic organic acids contained within oil sands naphthenic acid mixtures. Synchronous fluorescence spectroscopy provides diagnostic profiles for OSPW and potentially impacted groundwater that can be compared against reference groundwater and surface water samples. Novel applications of X-ray absorption near edge spectroscopy (XANES) are emerging for speciation of sulphur-containing species (both organic and inorganic components) as well as industrially derived boron-containing species. There is strong potential for an environmental forensics application of XANES for chemical fingerprinting of weathered sulphur-containing species and industrial additives in OSPW. PMID- 23647108 TI - The Dutch dominant perspective on water: risks and opportunities involved. AB - To implement or continue water management strategies social support is needed. Social support highly depends on people's perspectives on water. However, these perspectives are not static and may change over time leading to changes in social support for strategies. Therefore, sustainable water management strategies should be robust. Robust strategies are able to cope with changing social and environmental developments. Lacking robustness runs the risk of losing social support, which may force policymakers into sudden or expensive measures. We use the Perspectives Method to analyze the present Dutch policy perspective and the dominant perspective on water among Dutch water professionals, by respectively studying the Dutch Delta report and questionnaire outputs and distinguishing between Hierarchical, Egalitarian, Individualistic and Fatalistic perspectives. A comparison between the policy and professional perspective shows similarities and differences. Topics regarding drought, water supply, and waters' relation to spatial planning need serious reconsideration to guarantee enough present and future social support to implement the measures suggested in the policy report. PMID- 23647109 TI - A survey of Canadian mechanical pulp and paper mill effluents: insights concerning the potential to affect fish reproduction. AB - Building on breakthroughs recently made at kraft mills, a survey of mechanical pulp and paper mill effluents was undertaken to gain insights concerning potential effects on fish reproduction. Effluents from seven Canadian mills were characterized chemically for conventional parameters such as biochemical oxygen demand (BOD) and total suspended solids (TSS). Each sample was further subjected to solvent extraction followed by gas chromatographic separation for the determination of resin/fatty acids and for the estimation of a gas chromatography (GC) profile index. Each mill effluent was assessed for the potential to affect fish reproduction in the laboratory using a five day adult fathead minnow (Pimephales promelas) egg production bioassay with exposures to 100% effluent. The seven effluents were found to have substantial variation both in terms of chemical characterization and effects on fish reproduction. Temporal variations were also noted in effluent quality at mills sampled on different occasions. Similar to what has been observed for kraft mills, a general trend of greater reductions in egg production caused by effluents with greater BOD concentrations and GC profile indices was noted. Effluents with BOD > 25 mg/L and GC Profile indices >5.0 caused a complete cessation of egg production. At the same time, about half of the total effluents sampled had BOD < 25 mg/L and GC profile indices <5.0 and caused no significant effects on egg production, suggesting these values may be useful as effluent quality targets for mechanical pulp and paper mills. However, 3 out of 14 effluents sampled had BOD < 25 mg/L and GC profile indices <5.0 and caused significant reductions in egg production. The reason(s) for reproductive effects caused by such effluents is presently unclear. The effluent quality parameters considered in this study may require further refinement to address their utility in predicting the adverse reproductive effects induced by effluents from mechanical pulp and paper mills. PMID- 23647110 TI - Occurrence and distribution of polycyclic aromatic hydrocarbons in surface water of the Raba River, Hungary. AB - The objective of this study was to investigate the concentration level and distribution of polycyclic aromatic hydrocarbons (PAHs) in surface water of the Raba River; the largest Danube tributary in Hungary. A total of 54 water samples were collected in the period of 2008-2011 and analysed for PAHs by gas chromatography-mass spectrometry (GC/MS) method. The total PAH concentrations (sum of the concentrations of 17 individual PAH compounds) ranged from 41 to 437 ng/L with the mean value of 111 +/- 69.4 ng/L. Phenanthrene and naphthalene were the dominant species in the surface water. Using TEF approaches on the mean concentration PAH data, benzo[a]pyrene and dibenz[ah]anthracene contributed the highest carcinogenic exposure equivalent. A selected number of concentration ratios of specific PAH compounds were calculated to evaluate the possible sources of PAH contamination. The ratios reflected a pattern of pyrogenic input as a major source of PAHs. The comparison of the total PAH concentrations observed for Raba River with other surface waters of the world confirmed that the Raba River could not be regarded as a contaminated river according to the levels of PAHs. PMID- 23647111 TI - Toxicological profiles assessment of the water and sediments from the Krivaja and Jegricka Rivers, Serbia. AB - This study utilizes a combinatorial bio/chemical approach to assess the toxicological profiles of organic pollutants in water and sediment samples from two watercourses that are under significant anthropogenic pressure-the Krivaja and Jegricka rivers in Serbia. Sample preparation by solid-phase extraction and silica-gel fractionation followed by GC/MS analysis, allowed the tentative identification of a variety of non-target contaminants, divided into non-polar, medium-polar and polar fractions. The instrumental analysis revealed slightly different toxicological profiles for the water and sediment from both rivers, and confirmed the presence of various classes of organic contaminants, from non-polar hydrocarbons, to more polar compounds such as aldehydes, ketones and phenols. Polycyclic aromatic hydrocarbons and pesticides were identified, but below toxicologically relevant concentrations. The results of bioanalyses on H4IIE and PLHC-1 cells indicated that cytotoxic potential was pronounced in Jegricka water and sediment samples, and CYP1A inducing potential was observed in both Krivaja and Jegricka sediment samples, although they did not reflect high levels of contamination. Based on the overall data, the sediments of the Krivaja and Jegricka rivers are a more toxicologically relevant matrix than the water. PMID- 23647112 TI - Behavior of Typha angustifolia L. in a free water surface constructed wetlands for the treatment of swine wastewater. AB - The objective of this study was to evaluate the behavior of Typha angustifolia L. in nitrogen retention in a Free Water Surface Constructed Wetland (FWS) for the swine wastewater treatment over a three-year operating period. Results show that the behavior of Typha angustifolia L. in a FWS for treatment of swine wastewater is affected by nitrogen concentration, seasonal variation and plant establishment in the system. Indeed, the application of Nitrogen Loading Rates (NLR) between 7.1-14.3 kg TN/ha.d removes 40% of Total Nitrogen (TN), where the maximum removal (20-40%) takes place in the spring-summer seasons. However, concentrations higher than 120.3 mg NH4 (+)-N/L significantly decrease (P = 0.004) diametrical growth by 55%. However, it was possible to estimate that NLR >14.3 kg TN/ha.d increased biomass production and plant uptake in Typha angustifolia L. during the period analyzed. Additionally, aboveground biomass values were between 1.509.6-2.874.0 g/m(2) and nitrogen uptake 27.4-40.8 g/m(2), where this last value represents 29% of the TN applied during the study. Finally, the TN accumulation in sediments represents less than 2% of the TN incorporated during this period. These results show that an increase of 50% of the TN in sediments increases plant abundance in 73%, which is related to the mineralization processes favored in the system during the last year of operation. PMID- 23647113 TI - The simultaneous removal of calcium, magnesium and chloride ions from industrial wastewater using magnesium-aluminum oxide. AB - In this article, a method for simultaneous removal of calcium, magnesium and chloride by using Mg0.80Al0.20O1.10 as a Magnesium-Aluminum oxide (Mg-Al oxide) was investigated. Mg-Al oxide obtained by thermal decomposition of the Mg-Al layered double hydroxide (Mg-Al LDH). The synthesized Mg-Al oxide were characterized with respect to nitrogen physicosorption, X-ray diffraction (XRD) and field emission scan electron microscopy (FESEM) morphology. Due to high anion exchange capacity of Mg-Al oxide, it was employed in simultaneously removal of Cl(-), Mg(+2) and Ca(+2) from distiller waste of a sodium carbonate production factory. For this purpose, experiments were designed to evaluate the effects of quantity of Mg-Al oxide, temperature and time on the removal process. The removal of Cl(-), Mg(+2) and Ca(+2) from wastewater was found 93.9%, 93.74% and 93.25% at 60 degrees C after 0.5 h, respectively. Results showed that the removal of Cl(-), Mg(+2) and Ca(+2) by Mg-Al oxide increased with increasing temperature, time and Mg-Al oxide quantity. PMID- 23647114 TI - Speciation of heavy metals in water and sediments of an urban lake system. AB - The speciation pattern of heavy metals namely chromium, nickel, copper and lead in water and sediments of an urban lake system of high ecological significance was studied. The total available metal (dissolved) in water follows the sequence Ni>Cr>Pb>Cu. However, a different pattern Pb>Cu>Ni>Cr is observed for total available metal (metal in non-residual phases) in sediments. Significant spatial variations are observed in different geochemical forms of the metals as indicated by two-way ANOVA. This is attributed to localized anthropogenic activities. The anthropogenic parameters of water not only show statistically significant correlations among themselves but also positively correlate with the particulate forms of Cr, Cu and Pb. The total available forms of copper and lead correlate with the organic content of the sediments. Principal component analysis (PCA) separates the metals into three groups: I (Cr); II (Ni); III (Cu and Pb). The polluted sites were identified using hierarchical cluster analysis. Risk assessment code (RAC) analysis indicates low to medium risk due to Cr at most of the sites. However, Ni, Cu and Pb pose medium to high risk. But Pb at a few sites presents very high risk (RAC > 50%). PMID- 23647115 TI - Treatment of colored and real industrial effluents through electrocoagulation using solar energy. AB - This study was undertaken to investigate the removal of Acid Orange 2 (sodium 4 [(2E)-2-(2-oxonaphthalen-1-ylidene) hydrazinyl] benzenesulfonate) and Reactive Blue 19 (2-Anthracenesulfonicacid,1-amino-9,10-dihydro-9,10-dioxo-4-[[3-[[2 (sulfooxy) ethyl] sulfonyl] phenyl] amino]-,sodium salt (1:2)) from synthesized and real effluents through electrocoagulation using solar cells for the purpose of improving economic efficiency of the process. The impact of a number of key operating parameters was explored including current density, anode type, temperature, pH, and electrolyte concentration. The current density of 45 Am(-2) proved to be the optimum level for both dyes. The same optimum alternatives were found for the other parameters in both cases: iron anode, a temperature level of 25 degrees C, a pH of 7, and an electrolyte concentration of 15 mg L(-1). Both effluent samples were subjected to COD (chemical oxygen demand) and TOC (total organic carbon) tests. Cost analysis was performed for the treatment process. PMID- 23647116 TI - Probabilistic health risk assessment of polycyclic aromatic hydrocarbons and polychlorinated biphenyls in urban soils from a tropical city of India. AB - Distribution of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) in urban soils, and their risk for humans was evaluated and presented in this article. The average concentration of ?16PAHs, ?carcinogenic PAHs, ?28PCBs and ?dioxin-like PCBs was 631.6 +/- 244.5 MUg kg(-1), 568.8 +/- 238.8 MUg kg(-1), 11.57 +/- 2.00 MUg kg(-1) and 2.58 +/- 0.34 MUg kg(-1), respectively. Environmental and human health risk assessment parameters such as benzo(a)pyrene total potency equivalent (BaP TPE), index of additive cancer risk (IACR), life time average daily dose (LADD) and incremental lifetime cancer risk (ILCR) have been estimated and discussed. The average benzo(a)pyrene total potency equivalent (BaP TPE) estimate was 0.194 mg kg(-1) and ranging between 8.9*10(-4) to 0.87 mg kg(-1). The incremental life time cancer risk (ILCR) of PAHs through soil ingestion for adults and children was estimated as 8.1*10(-6) and 4.2*10(-5), respectively. However, the cancer risk (ILCR) from non-dioxin like PCBs and dioxin-like PCBs for adults and children ranged between 3.31*10(-8) to 1.741*10(-7) and 1.46*10(-5) to 7.56*10(-5), respectively. These estimated risks were lower than acceptable limits, based on incremental cancer risk from soil exposure. Overall, index of additive cancer risk (IACR) and hazard quotient (HQ) for PAHs and PCBs was lower than safe limit of 1, indicating no environmental and human health risk from PAHs and PCBs in this area of study. PMID- 23647117 TI - Ozone photolysis of paracetamol in aqueous solution. AB - The degradation of a paracetamol (N-acetil-para-aminofenol) aqueous solution (C (0) P = 5 mmol L(-1)) is studied in a bench-scale setup by means of simple ozonation (O3) and ozonation catalyzed with UV light (O3/UV) in order to quantify the influence of UV light on the degradation process. The results have shown that under the adopted experimental conditions (25 degrees C, applied ozone dose = 9.8 mg L(-1) and gas flow rate of 20 L h(-1)) both oxidative systems are capable of removing the substrate with mineralization degrees up to 51% for ozonation and 53% for O3/UV. HPICE chromatography allowed the detection of nitrate ions and maleic and oxalic acids as ultimate carboxylic acids. The experimental data have been interpreted through 5 indicators: the conversion of paracetamol (XP ), the conversion degree of TOC (XTOC ), the apparent rate constant (kap ), the Hatta number (Ha) and the enhancement factor (E). The main advantage of photo-ozonation compared to simple ozonation was a more advanced conversion (79% vs. 92% after 90 min). The paracetamol decay follows a pseudo-first-order reaction with a superior rate constant (higher by 54%) for the UV catalyzed system in comparison with direct ozonation. Mineralization is slightly accelerated (+4%) in the O3/UV system, due to the additional production of hydroxyl radicals induced by the UV light and a higher Hatta number (+24%). Nevertheless, the process was still in the slow reaction kinetic regime (Ha < 0.3), and the enhancement factor was not significantly increased. The results are useful for the design and scale-up of the gas-liquid processes. PMID- 23647118 TI - Adsorption of As(III), As(V) and dimethylarsinic acid onto synthesized lepidocrocite. AB - The trapping of arsenic by zero valent iron is strongly dependant on iron by products. Among these, lepidocrite has been scarcely studied. In this work, we studied the adsorption of two inorganic (As(III), As(V)) and one organic (dimethylarsinic acid, DMA) arsenic species onto lepidocrocite. pH influence was considered in the range 5 to 9, which corresponds to natural water pH. Langmuir model was used to simulate As adsorption isotherms. Our results showed that lepidocrocite offers high adsorption capacities: up to 0,25, 0,41 and 1 mol for As(V), DMA and As(III) could be respectively trapped per kilogram of zero-valent iron. pH influence varied from one arsenic species to another: increasing pH improve As(III) and DMA sorption whereas it has a very low effect on As(V) sorption. PMID- 23647119 TI - Involvement of extracellular and intracellular enzymes of Ceriporia sp. ZLY-2010 for biodegradation of polychlorinated biphenyls (PCBs). AB - This study examined the interrelation between the biodegradation of polychlorinated biphenyls (PCBs) by Ceriporia sp. ZLY-2010 and its fungal enzyme systems. The degradation rates of Aroclor 1254 and 1260 were 29.01% on day 5 and 36.80% on day 10, respectively. MnP (Manganese dependent peroxidase) and laccase activities showed the greatest increases in the samples containing Aroclors, indicating that extracellular enzymes of Ceriporia sp. ZLY-2010 were affected by the addition of Aroclors. However, the relationship between the biodegradation rate and extracellular enzymes might be obscured by the complexity of the biodegradation process. Cytochrome P450 monooxygenase was inhibited and the biodegradation rate of the Aroclor decreased by adding the inhibitor 1 aminobenzotriazole. Two-dimensional gel electrophoresis showed that intracellular enzymes play a significant role in the biodegradation of Aroclor. Complex extracellular and intracellular enzyme systems in Ceriporia sp. ZLY-2010 play an important role in degrading PCBs. Physiological changes of Ceriporia sp. ZLY-2010 caused by PCBs appeared to affect biodegradation of PCBs. However, it is necessary to further study the unidentified enzymes related to the biodegradation of Aroclor. PMID- 23647120 TI - The impact of lead and cadmium on selected motility, prooxidant and antioxidant parameters of bovine seminal plasma and spermatozoa. AB - The aim of this study was to investigate the effects of lead (Pb) and cadmium (Cd) content on basic motility characteristics (motility-MOT, progressive motility-PROG) as well as selected markers of the prooxidant-antioxidant balance (catalase-CAT, glutathione-GSH, malondialdehyde-MDA) in bovine seminal plasma and spermatozoa. Twenty five semen samples were collected from breeding bulls and used in the study. Motility analysis was carried out using the Computer Assisted Sperm Analysis (CASA) system. The samples were centrifuged, fractions of seminal plasma and spermatozoa were separated, lysates were prepared from the sperm cell fractions. Pb and Cd concentrations were determined by the voltametric method (ASV), antioxidants and MDA were analyzed by UV/Vis spectrophotometry. The analysis showed that the average concentration of Pb in the seminal plasma was 0.23 +/- 0.02 MUg/mL, while its amount in the sperm cells was significantly higher (0.41 +/- 0.07 MUg/mL; P < 0.05). The average Cd content in bovine seminal fractions was similar and non-significant: 0.09 +/- 0.01 MUg/mL in the seminal plasma and 0.11 +/- 0.01 MUg/mL in spermatozoa (P > 0.05). The correlation analysis revealed that both heavy metals were significantly negatively correlated with MOT and PROG (P < 0.05; P < 0.01; P < 0.001), CAT (P < 0.05; P < 0.01) as well as GSH (P < 0.05; P < 0.01) but significantly positively associated with MDA as the marker of lipid peroxidation (P < 0.05; P < 0.01). Moreover the samples were categorized in three quality groups (Excellent, Good, Moderate) according to their motility values. The lowest Pb, Cd and MDA concentrations but the best antioxidant characteristics were found in samples of the best quality, moderate quality samples exhibited the highest Pb, Cd and MDA content together with the worst antioxidant capacity. This study demonstrates that Pb and Cd are serious toxic elements, which are able to increase the risk of seminal oxidative stress development and a subsequent decrease of male fertility. PMID- 23647121 TI - Influence of the type and source of inoculum on the start-up of anammox sequencing batch reactors (SBRs). AB - Anammox (anaerobic ammonium oxidation) is an attractive option for the treatment of wastewaters with a low carbon/nitrogen ratio. This is due to its low operating costs when compared to the classical nitrification-denitrification processes. However, one of the main disadvantages of the Anammox process is slow biomass growth, meaning a relatively slow reactor start-up. This becomes even more complicated when Anammox microorganisms are not present in the inoculum. Four inocula were studied for the start-up of Anammox sequencing batch reactors (SBRs) 2 L in volume agitated at 100 rpm, one of them using zeolite as a microbial support. Two inocula were taken from UASB reactors and two from aerobic reactors (activated sludge and SBR). The Anammox SBRs studied were operated at 36 +/- 0.5 degrees C. The results showed that the only inoculum that enabled the enrichment of the Anammox biomass came from an activated sludge plant treating wastewaters from a poultry slaughterhouse. This plant was designed for organic matter degradation and nitrogen removal (nitrification). This could explain the presence of Anammox microorganisms. This SBR operated without zeolite and achieved nitrite and ammonium removals of 96.3% and 68.4% respectively, at a nitrogen loading rate (NLR) of 0.1 kg N/m(3)/d in both cases. The lower ammonium removal was due to the fact that a sub-stoichiometric amount of nitrite (1 molar ratio) was fed. The specific Anammox activity (SAA) achieved was 0.18 g N/g VSS/d. PMID- 23647122 TI - Caffeoylquinic acid-rich purple sweet potato extract, with or without anthocyanin, imparts neuroprotection and contributes to the improvement of spatial learning and memory of SAMP8 mouse. AB - The effects of caffeoylquinic acid (CQA)-rich purple sweet potato (PSP) extract, with (PSPEa) or without (PSPEb) anthocyanin, on the improvement of spatial learning and memory of senescence-accelerated prone mouse strain (SAMP) 8 was determined. SAMP8 was treated with 20 mg/kg/day of PSPEa or PSPEb for 30 days. The effect on spatial learning and memory and the molecular mechanism of this effect were determined in vivo (SAMP8) and in vitro (SH-SY5Y cells). PSPEa or PSPEb reduced the escape latency time of SAMP8 by 17.0 +/- 8.0 and 14.2 +/- 5.8 s (P < 0.01), respectively. PSPEa administration induced an overexpression of antioxidant-, energy metabolism-, and neuronal plasticity-related proteins in the brain of SAMP8. Additionally, PSPEa and PSPEb increased the cell viability by 141.6 and 133% as compared to Abeta1-42-treated cells. These findings suggest that PSP rich in CQA derivatives with or without anthocyanidine had a neuroprotective effect on mouse brain and can improve the spatial learning and memory of SAMP8. PMID- 23647123 TI - Multilevel models from biology to psychology: mission impossible? AB - Systematic efforts are underway to address major flaws in the current diagnostic taxonomy of mental disorders, fostering hope that a new nosology might be based on brain biology. The National Institute of Mental Health Research Domains Criteria (RDoC) initiative aims to redefine mental illness leveraging information that spans molecular to behavioral levels of analysis. Major effort is still needed to forge multilevel conceptual and measurement models capable of representing knowledge within and across these levels. The development of such models may help refine and share complex hypotheses, and reduce the risk of replacing the current taxonomy with dimensions and/or categories that manifest little incremental biological validity. To create useful models we need to define concepts, relations among concepts, and links to supporting evidence. Some methods already enable representation of concepts and measures at the levels of behavioral and basic biological processes, but a major gap at the level of neural circuitry must be bridged to link basic biological and behavioral levels. We provide a schematic framework, using as an example the representation of selected "working memory" concepts and evidence across multiple levels of analysis as these have been described in the RDoC Workshops. This example illustrates multiple challenges and some possible solutions that may help clarify the aims of individual research projects and enable integration of diverse efforts on RDoC and related initiatives. PMID- 23647125 TI - Ventricular repolarization in a rat model of global heart failure. AB - Isoproterenol in high doses induces infarction-like myocardial damage and structural and functional remodelling of the ventricular myocardium. The purpose of the present study was to investigate ventricular repolarization in a rat model of isoproterenol-induced heart failure. Isoproterenol was administered twice to female Wistar rats (170 mg/kg, s.c., 24 h apart). Four weeks after the injections, cardiac output was measured and unipolar epicardial ventricular electrograms were recorded in situ. Activation-recovery intervals were calculated to assess repolarization. Histological examination of the heart ventricles was also performed. Heart failure in rats treated with isoproterenol was indicated by myocardial histopathological damage and reduced cardiac output. In rats with heart failure, the regional differences in activation-recovery interval prolongation over the ventricular epicardium resulted in increasing heterogeneity in the activation-recovery interval distribution and increasing repolarization heterogeneity of the ventricular subepicardium. Myocardial damage and haemodynamic changes in heart failure induced by isoproterenol were accompanied by significant changes in ventricular repolarization, which were not associated with myocardial hypertrophy. PMID- 23647124 TI - Daily patterns of anxiety in anorexia nervosa: associations with eating disorder behaviors in the natural environment. AB - The role of anxiety has been emphasized in etiological/maintenance models of anorexia nervosa. This study identified daily patterns of anxiety in anorexia nervosa and examined the likelihood of the occurrence of eating disorder behaviors in each trajectory, the daily temporal distribution of eating disorder behaviors in each trajectory, and the extent to which the tendency to exhibit particular anxiety trajectories was associated with baseline diagnostic and trait level personality variables. Women with full or subthreshold anorexia nervosa (N = 118) completed a 2-week ecological momentary assessment (EMA) protocol during which they reported on a variety of behavioral and affective variables, including anxiety and eating disorder behaviors. Using latent growth mixture modeling to classify EMA days (N = 1,526) based on anxiety ratings, we identified 7 distinct daily anxiety trajectories. Overall differences between trajectories were found for rates of binge eating, self-induced vomiting, body checking, skipping meals, and dietary restriction. Furthermore, distinct daily temporal distributions of eating disorder behaviors were found across the trajectories, with peaks in the probability of behaviors frequently coinciding with high levels of anxiety. Finally, traits of personality pathology (affective lability, self-harm, social avoidance, and oppositionality) and the presence of a co-occurring mood disorder were found to be associated with the tendency to experience particular daily anxiety trajectories (e.g., stable high anxiety). Findings support the presence of within-person variability in daily anxiety patterns in anorexia nervosa and also provide evidence for an association between these anxiety patterns and eating disorder behaviors. PMID- 23647126 TI - Proteomic analysis of temperature dependent extracellular proteins from Aspergillus fumigatus grown under solid-state culture condition. AB - Fungal species of the genus Aspergillus are filamentous ubiquitous saprophytes that play a major role in lignocellulosic biomass recycling and also are considered as cell factories for the production of organic acids, pharmaceuticals, and industrially important enzymes. Analysis of extracellular secreted biomass degrading enzymes using complex lignocellulosic biomass as a substrate by solid-state fermentation could be a more practical approach to evaluate application of the enzymes for lignocellulosic biorefinery. This study isolated a fungal strain from compost, identified as Aspergillus fumigatus, and further analyzed it for lignocellulolytic enzymes at different temperatures using label free quantitative proteomics. The profile of secretome composition discovered cellulases, hemicellulases, lignin degrading proteins, peptidases and proteases, and transport and hypothetical proteins; while protein abundances and further their hierarchical clustering analysis revealed temperature dependent expression of these enzymes during solid-state fermentation of sawdust. The enzyme activities and protein abundances as determined by exponentially modified protein abundance index (emPAI) indicated the maximum activities at the range of 40-50 degrees C, demonstrating the thermophilic nature of the isolate A. fumigatus LF9. Characterization of the thermostability of secretome suggested the potential of the isolated fungal strain in the production of thermophilic biomass degrading enzymes for industrial application. PMID- 23647127 TI - Analysis of saliva samples from oncological patients treated with 5-fluorouracil and leucovorin calcium by scanning electron microscopy with energy dispersive system. AB - This work presents a chemical and morphological analysis of samples of saliva taken from patients who were under treatment with intravenous chemotherapy with 5 fluorouracil and leucovorin calcium. Samples of saliva were extracted from fifteen patients during the three stages of the treatment: The initial stage (previous to the chemotherapy), the intermediate stage (during the chemotherapy), and the final stage (twenty-one days after finishing the treatment). An amount of 50 MUl was collected in each visit. Chemical contrast images were taken by means of scanning electron microscopy, and X-ray characteristic spectra were obtained from all the studied samples by using an energy dispersive system from all the studied samples. Images that correspond to the intermediate stage showed important differences with respect to the initial and final stages. In addition, X-ray spectra provided information about the present elements in saliva and their relative abundance allowed us to determine variations in the chemical composition. The backscattered electron images and X-ray spectra from the intermediate stage showed clusters of crystals with fluorine content higher than those obtained in initial and final stages. This fact probably indicates the passage of metabolites of 5-fluorouracil and leucovorin calcium from the plasma to the oral cavity. This finding enhances the hypothesis proposed by other authors about the secondary effects of the drugs on the stomatognathic system such as oral mucositis, dysgeusia, and xerostomia with or without hyposalivation. PMID- 23647128 TI - Not to lose sight of the bigger picture: the case of therapeutic communities (TC) research in closed settings in Thailand. PMID- 23647129 TI - Religious coping, spirituality, and substance use and abuse among youth in high risk communities in San Salvador, El Salvador. AB - Little is known about the relationship between religious coping, spirituality, and substance use in developing nations such as El Salvador. Collected in 2011, the sample consists of 290 high-risk and gang-involved adolescents (11-17 years) and young adults (18-25 years) in San Salvador, El Salvador. Structural equation modeling and logistic regression are employed to examine the associations between the Measure of Religious Coping (RCOPE), the Intrinsic Spirituality Scale, and substance use and abuse. Results suggest that spirituality and, to a far lesser degree, religious coping may serve to protect for substance use and abuse among this high-risk population of Salvadoran youth. PMID- 23647131 TI - Advances in the understanding of retinal drug disposition and the role of blood ocular barrier transporters. AB - INTRODUCTION: The blood-retinal barrier (BRB) is required for proper vision and controls exchange of nutrients with the choroidal vessels. This barrier serves as a selective partition between the retina and the circulation, and to maintain the specialized environment of the neural retina with a high degree of control of solute and fluid permeability. AREAS COVERED: The authors review the understanding of retinal drug disposition. The article highlights the routes of ocular drug delivery, and discusses the newest pharmaceutical ophthalmic formulations. Furthermore, the article focuses on drug transporters that are expressed in the corneal epithelium and BRB (ATP-binding cassette and solute carrier superfamilies). These transporters play essential roles in mediating the biodisponibility of drugs in the anterior and posterior chambers of the eye. Finally, the article reviews the ocular complications that are caused by intravitreal injections. EXPERT OPINION: Intraocular drug delivery is the only mode that currently directly broaches the BRB and thereby attains the highest peak intravitreal or intraretinal drug concentration. There is an urgent need for the development of optimal and efficient drug delivery systems. PMID- 23647130 TI - Losartan protects liver against ischaemia/reperfusion injury through PPAR-gamma activation and receptor for advanced glycation end-products down-regulation. AB - BACKGROUND AND PURPOSE: PPAR-gamma has been reported to be a protective regulator in ischaemia/reperfusion (I/R) injury. The receptor for advanced glycation end products (RAGE) plays a major role in the innate immune response, and its expression is associated with PPAR-gamma activation. Several angiotensin receptor blockers possess partial agonist activities towards PPAR-gamma. Therefore, this study investigated the action of losartan, particularly with regard to PPAR-gamma activation and RAGE signalling pathways during hepatic I/R. EXPERIMENTAL APPROACH: Mice were subjected to 60 min of ischaemia followed by 6 h of reperfusion. Losartan (0.1, 1, 3 and 10 mg . kg-1) was administered 1 h prior to ischaemia and immediately before reperfusion. GW9662, a PPAR-gamma antagonist, was administered 30 min prior to first pretreatment with losartan. KEY RESULTS: Losartan enhanced the DNA-binding activity of PPAR-gamma in I/R. Losartan attenuated the increased serum alanine aminotransferase activity, TNF-alpha and IL-6 levels, and nuclear concentrations of NF-kappaB in I/R. GW9662 reversed these beneficial effects. Losartan caused a decrease in apoptosis as assessed by TUNEL assay, in release of cytochrome c and in cleavage of caspase-3, and these effects were abolished by GW9662 administration. Losartan attenuated not only I/R induced RAGE overexpression, but also its downstream early growth response protein-1-dependent macrophage inflammatory protein 2 level; phosphorylation of p38, ERK and JNK; and subsequent c-Jun phosphorylation. GW9662 reversed these effects of losartan administration. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that losartan ameliorates I/R-induced liver damage through PPAR-gamma activation and down-regulation of the RAGE signalling pathway. PMID- 23647132 TI - Antipsychotic drug-treated patients best suited for metformin therapy. Reply. PMID- 23647134 TI - Sodium oxybate-induced psychosis and suicide attempt in an 18-year-old girl. PMID- 23647133 TI - The association of a novel haplotype in the dopamine transporter with preschool age posttraumatic stress disorder. AB - OBJECTIVE: Significant evidence supports a genetic contribution to the development of posttraumatic stress disorder (PTSD). Three previous studies have demonstrated an association between PTSD and the nine repeat allele of the 3' untranslated region (3'UTR) variable number tandem repeat (VNTR) in the dopamine transporter (DAT, rs28363170). Recently a novel, functionally significant C/T single-nucleotide polymorphism (SNP) in the 3'UTR (rs27072) with putative interactions with the 3'VNTR, has been identified. To provide enhanced support for the role of DAT and striatal dopamine regulation in the development of PTSD, this study examined the impact of a haplotype defined by the C allele of rs27072 and the nine repeat allele of the 3'VNTR on PTSD diagnosis in young trauma exposed children. METHODS: DAT haplotypes were determined in 150 trauma-exposed 3 6 year-old children. PTSD was assessed with a semistructured interview. After excluding double heterozygotes, analysis was performed on 143 total subjects. Haplotype was examined in relation to categorical and continuous measures of PTSD, controlling for trauma type and race. Additional analysis within the two largest race categories was performed, as other means of controlling for ethnic stratification were not available. RESULTS: The number of haplotypes (0, 1, or 2) defined by the presence of the nine repeat allele of rs28363170 (VNTR in the 3'UTR) and the C allele of rs27072 (SNP in the 3'UTR) was significantly associated with both the diagnosis of PTSD and total PTSD symptoms. Specifically, children with one or two copies of the haplotype had significantly more PTSD symptoms and were more likely to be diagnosed with PTSD than were children without this haplotype. CONCLUSIONS: These findings extend previous findings associating genetic variation in the DAT with PTSD. The association of a haplotype in DAT with PTSD provides incremental traction for a model of genetic vulnerability to PTSD, a specific underlying mechanism implicating striatal dopamine regulation, and insight into potential future personalized interventions. PMID- 23647135 TI - Prolactin serum concentrations during aripiprazole treatment in youth. AB - OBJECTIVE: This study aimed to: document the extent of the reduction of serum prolactin (PRL) levels induced by aripiprazole (ARI) treatment in children and adolescents, compare this effect by age group, and shed light on this phenomenon. METHODS: PRL serum levels in unmedicated subjects were compared to those in subjects treated with aripiprazole to calculate the rate of subnormal PRL levels during aripiprazole treatment. Next, a literature search was performed to better understand the effects of dopaminergic drugs on PRL levels by age group. RESULTS: Sixty percent of those treated with aripiprazole exhibited subnormal PRL serum levels versus 8% of unmedicated subjects. The rate of PRL subnormality in response to aripiprazole was half as frequent in adolescents and was minimal in adults. The drug-induced reduction of PRL serum levels became more prominent with increasing doses of aripiprazole and with an increased treatment duration. CONCLUSIONS: With the increasing use of aripiprazole in the United States population, it is important that future research be conducted to explore the potential sequelae of subnormal PRL serum levels in children and adolescents. PMID- 23647137 TI - Depression persistence and serotonin transporter genotype in adolescents under usual care conditions. AB - OBJECTIVES: Polymorphisms of the serotonin transporter (SERT) gene have been shown to influence the risk for depression. The goal of this study was to investigate a possible effect of SERT polymorphisms on severity and course of depression symptoms in a community sample of adolescents. METHODS: Community dwelling adolescents (n=192) ages 13-17 years, who were at risk for depression, were followed for a period of 6 months. Subjects donated a saliva sample for genotyping of the 5-HTTLPR and STin2 VNTR polymorphisms of SERT. RESULTS: We found no associations between SERT genotype and severity of depressive symptoms at baseline. Depression symptom severity markedly decreased over time. For 5 HTTLPR, we observed a significant interaction between time and genotype, indicating the possibility that heterozygote genotype carriers (s/l) might experience a greater reduction in depression symptoms over time compared with adolescents with the 5-HTTLPR l/l genotype. CONCLUSIONS: Our study shows that for most community-dwelling adolescents, depressive symptoms decrease over time. A possible interaction effect of time and SERT genotype will require confirmation in larger studies. PMID- 23647138 TI - Periodic fever and hyperimmunoglobulin D syndrome in a boy with pediatric autoimmune neuropsychiatric disorders associated with group A beta-Hemolytic streptococcus. PMID- 23647136 TI - Frequency, characteristics and management of adolescent inpatient aggression. AB - BACKGROUND: Inpatient aggression is a serious challenge in pediatric psychiatry. METHODS: A chart review study in adolescent psychiatric inpatients consecutively admitted over 24 months was conducted, to describe aggressive events requiring an intervention (AERI) and to characterize their management. AERIs were identified based on specific institutional event forms and/or documentation of as-needed (STAT/PRN) medication administration for aggression, both recorded by nursing staff. RESULTS: Among 408 adolescent inpatients (age: 15.2+/-1.6 years, 43.9% male), 1349 AERIs were recorded, with >=1 AERI occurring in 28.4% (n=116; AERI+). However, the frequency of AERIs was highly skewed (median 4, range: 1-258). In a logistical regression model, the primary diagnosis at discharge of disruptive behavior disorders and bipolar disorders, history of previous inpatient treatment, length of hospitalization, and absence of a specific precipitant prior to admission were significantly associated with AERIs (R(2)=0.32; p<0.0001). The first line treatment of patients with AERIs (AERI+) was pharmacological in nature (95.6%). Seclusion or restraint (SRU) was used at least once in 59.4% of the AERI+ subgroup (i.e., in 16.9% of all patients; median within-group SRU frequency: 3). Treatment and discharge characteristics indicated a poorer prognosis in the AERI+ (discharge to residential care AERI+: 22.8%, AERI-: 5.6%, p<0.001) and a greater need for psychotropic polypharmacy (median number of psychotropic medications AERI+: 2; AERI-: 1, p<0.001). CONCLUSIONS: Despite high rates of pharmacological interventions, SRU continue to be used in adolescent inpatient care. As both of these approaches lack a clear evidence base, and as adolescents with clinically significant inpatient aggression have increased illness acuity/severity and service needs, structured research into the most appropriate inpatient aggression management is sorely needed. PMID- 23647139 TI - Plate size does not affect perception of food portion size. AB - BACKGROUND: Evidences have suggested that larger utensils may provoke 'size contrast illusions', influencing the perceived volume and food consumption. OBJECTIVE: To analyse the influence of plate size on the visual estimate of food portion size. METHODS: Two 400 g portions of pasta with tomato sauce were presented on two plates of different diameters (24.0 and 9.0 cm). Each participant visually estimated on an individual basis the quantities of the pasta portions (g) present on each plate. In addition, each subject classified the size of the portions on each plate as 'small', 'medium' and 'large'. The mean estimates of the amount of pasta on each plate were compared by the nonparametric Mann-Whitney. The differences in the frequencies of portion classifications between plates were evaluated by the chi-squared test. RESULTS: Forty-eight students (average 25.8 +/- 8.9 years) participated in the study. There was no difference in the median amount of pasta estimated for the large and small plates (150 g; range 50-500 and 115 g; range 40-500 g, respectively). The classification of the portion size as 'large' was reported by a significantly greater number of persons when they evaluated the amount of pasta arranged on the large plate compared to the small plate (47.9 versus 22.9%, respectively; P = 0.018). CONCLUSION: The size of the plate did not influence the estimate of food portions, even though it did influence the classification of portion size. PMID- 23647141 TI - Controlled synthesis and transfer of large-area WS2 sheets: from single layer to few layers. AB - The isolation of few-layered transition metal dichalcogenides has mainly been performed by mechanical and chemical exfoliation with very low yields. In this account, a controlled thermal reduction-sulfurization method is used to synthesize large-area (~1 cm(2)) WS2 sheets with thicknesses ranging from monolayers to a few layers. During synthesis, WOx thin films are first deposited on Si/SiO2 substrates, which are then sulfurized (under vacuum) at high temperatures (750-950 degrees C). An efficient route to transfer the synthesized WS2 films onto different substrates such as quartz and transmission electron microscopy (TEM) grids has been satisfactorily developed using concentrated HF. Samples with different thicknesses have been analyzed by Raman spectroscopy and TEM, and their photoluminescence properties have been evaluated. We demonstrated the presence of single-, bi-, and few-layered WS2 on as-grown samples. It is well known that the electronic structure of these materials is very sensitive to the number of layers, ranging from indirect band gap semiconductor in the bulk phase to direct band gap semiconductor in monolayers. This method has also proved successful in the synthesis of heterogeneous systems of MoS2 and WS2 layers, thus shedding light on the controlled production of heterolayered devices from transition metal chalcogenides. PMID- 23647140 TI - The mechanism of ORFH79 suppression with the artificial restorer fertility gene Mt-GRP162. AB - The restoration fertility complex (RFC) was previously identified in Honglian (HL)-cytoplasmic male sterility (CMS) rice (Oryza sativa), and glycine-rich protein 162 (GRP162) is responsible for binding to the CMS-associated transcript atp6-orfH79. Here, we engineered a recombinant GRP162 containing the mitochondrial transit peptide, termed Mt-GRP162, as an artificial restorer of fertility (Rf) gene. Mt-GRP162 was confirmed to bind to CMS-associated RNA and to localize to the mitochondria. The transgenic plants showed restored fertility with partially functional pollen. We found that the expression of ORFH79 decreased in transgenic plants, while the expression of atp6-orfH79 was not changed. These findings indicate that Mt-GRP162 restores fertility by suppressing the expression of the cytotoxic protein ORFH79 at the post-transcriptional level rather than via the cleavage of atp6-orfH79 in the presence of RFC. These findings contribute to our understanding of the mechanisms of restoration through diverse pathways. PMID- 23647142 TI - Confirmation and fine-mapping of clinical mastitis and somatic cell score QTL in Nordic Holstein cattle. AB - A genome-wide association study of 2098 progeny-tested Nordic Holstein bulls genotyped for 36 387 SNPs on 29 autosomes was conducted to confirm and fine-map quantitative trait loci (QTL) for mastitis traits identified earlier using linkage analysis with sparse microsatellite markers in the same population. We used linear mixed model analysis where a polygenic genetic effect was fitted as a random effect and single SNPs were successively included as fixed effects in the model. We detected 143 SNP-by-trait significant associations (P < 0.0001) on 20 chromosomes affecting mastitis-related traits. Among them, 21 SNP-by-trait combinations exceeded the genome-wide significant threshold. For 12 chromosomes, both the present association study and the previous linkage study detected QTL, and of these, six were in the same chromosomal locations. Strong associations of SNPs with mastitis traits were observed on bovine autosomes 6, 13, 14 and 20. Possible candidate genes for these QTL were identified. Identification of SNPs in linkage disequilibrium with QTL will enable marker-based selection for mastitis resistance. The candidate genes identified should be further studied to detect candidate polymorphisms underlying these QTL. PMID- 23647143 TI - Combustion of hydrotreated vegetable oil and jatropha methyl ester in a heavy duty engine: emissions and bacterial mutagenicity. AB - Research on renewable fuels has to assess possible adverse health and ecological risks as well as conflicts with global food supply. This investigation compares the two newly developed biogenic diesel fuels hydrotreated vegetable oil (HVO) and jatropha methyl ester (JME) with fossil diesel fuel (DF) and rapeseed methyl ester (RME) for their emissions and bacterial mutagenic effects. Samples of exhaust constituents were compared after combustion in a Euro III heavy duty diesel engine. Regulated emissions were analyzed as well as particle size and number distributions, carbonyls, polycyclic aromatic hydrocarbons (PAHs), and bacterial mutagenicity of the exhausts. Combustion of RME and JME resulted in lower particulate matter (PM) compared to DF and HVO. Particle numbers were about 1 order of magnitude lower for RME and JME. However, nitrogen oxides (NOX) of RME and JME exceeded the Euro III limit value of 5.0 g/kWh, while HVO combustion produced the smallest amount of NOX. RME produced the lowest emissions of hydrocarbons (HC) and carbon monoxide (CO) followed by JME. Formaldehyde, acetaldehyde, acrolein, and several other carbonyls were found in the emissions of all investigated fuels. PAH emissions and mutagenicity of the exhausts were generally low, with HVO revealing the smallest number of mutations and lowest PAH emissions. Each fuel showed certain advantages or disadvantages. As proven before, both biodiesel fuels produced increased NOX emissions compared to DF. HVO showed significant toxicological advantages over all other fuels. Since jatropha oil is nonedible and grows in arid regions, JME may help to avoid conflicts with the food supply worldwide. Hydrogenated jatropha oil should now be investigated if it combines the benefits of both new fuels. PMID- 23647144 TI - Perceived social support for diet and exercise among persons with serious mental illness enrolled in a healthy lifestyle intervention. AB - OBJECTIVE: There is a lack of research on social support for health behavior change among persons with serious mental illness who face disproportionate morbidity and premature death due to cardiovascular disease. This study examined social contact and the demographic, health and clinical characteristics associated with perceived social support for diet and exercise among persons living with serious mental illness enrolled in a healthy lifestyle intervention. METHOD: Baseline data from two ongoing studies of the In SHAPE healthy lifestyle intervention for persons with serious mental illness were included in this analysis (N = 158). Cross-sectional analyses examined social contact and correlates of both negative and positive experiences of social support for diet and exercise. Multiple linear regression was used to assess the relationship between demographic characteristics, symptoms, health, and social support. RESULTS: The majority (80.3%) of participants reported face-to-face contact at least twice monthly with a family member or friend. Readiness to change physical activity was associated with greater criticism from family for exercise behaviors, r(64) = .29, p < .05. Depressive symptoms (beta = .30, p < .01) were significantly associated with more unhealthy family eating environments while controlling for the amount of family contact (beta = .27, p < .01), while readiness to change dietary portion size (beta = .34, p < .01) was associated with encouragement for healthy eating from friends. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Participants had regular contact with significant others who were a source of both positive and negative support for healthy eating and exercise. Engaging natural supports in supporting healthy behaviors may help persons with serious mental illness initiate and maintain lifestyle change. PMID- 23647145 TI - Recovery of people with psychiatric disabilities living in the community and associated factors. AB - OBJECTIVE: Consumer-oriented recovery has been discussed for more than two decades in the mental health field. Although there some qualitative recovery studies have shown important findings, few quantitative studies of this concept currently exist. This study examined the relationship between recovery and associated social-environmental and individual factors. METHOD: A total of 159 people with psychiatric disabilities receiving services from a large community mental health agency participated in the study. Participants completed a self report survey that assessed individual recovery status, social support, perceived recovery-oriented service quality, psychiatric symptoms, and demographics. One hundred twenty-four surveys were analyzed. Hierarchical multiple regression analysis was conducted to examine the relationship between recovery and associated factors. RESULTS: Social support and perceived recovery-oriented service quality had significant positive relationships with recovery; psychiatric symptoms had a significant negative relationship with recovery. The final regression model accounted for 58% of the variance in recovery, F(9, 114) = 17.72, p < .001. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Social-environmental factors play an important role in people's recovery, even after taking into account psychiatric symptoms. Namely, people with psychiatric disabilities can pursue recovery with symptoms as long as they receive appropriate support and services. Mental health professionals should provide services adhering to recovery principles in order to help their clients achieve personal recovery. PMID- 23647146 TI - Evaluating the effects of NAMI's consumer presentation program, In Our Own Voice. AB - OBJECTIVE: Misperceptions about individuals with mental illness and their ability to recover and live productive lives are common. Consumer presentation programs, such as NAMI's (National Alliance on Mental Illness) In Our Own Voice (IOOV), employ psychoeducation and direct contact to help correct misperceptions and offer encouraging messages about recovery for those with and without mental illness. Prior research on IOOV has been limited to student samples in artificial settings. This study was designed to understand audience members' responses to IOOV in natural settings. METHOD: IOOV audience evaluations collected from two NAMI affiliates in 2009 were analyzed (n = 599). A mixed methods approach was used to explore (a) overall responses to the program, (b) whether the program satisfied program goals for audience members, and (c) differences between consumer and nonconsumer responses. RESULTS: The majority of viewers responded very positively. Qualitative responses suggested that the program is meeting NAMI's goals for audience members: educating the public and offering a hope inspiring message of recovery. The program's effects generalized across consumers and nonconsumers with few differences. Nonconsumers were more likely to report that the program was educational, offered hope, and delivered a message of recovery; only the first difference remained when controlling for students. Consumers were more likely to report personally relating to presenters. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: IOOV, as performed in the field, appears to provide educational and inspiring recovery-oriented programming freely available to the public. PMID- 23647147 TI - Ictal-onset localization through connectivity analysis of intracranial EEG signals in patients with refractory epilepsy. AB - PURPOSE: Fifteen percent to 25% of patients with refractory epilepsy require invasive video-electroencephalography (EEG) monitoring (IVEM) to precisely delineate the ictal-onset zone. This delineation based on the recorded intracranial EEG (iEEG) signals occurs visually by the epileptologist and is therefore prone to human mistakes. The purpose of this study is to investigate whether effective connectivity analysis of intracranially recorded EEG during seizures provides an objective method to localize the ictal-onset zone. METHODS: In this study data were analyzed from eight patients who underwent IVEM at Ghent University Hospital in Belgium. All patients had a focal ictal onset and were seizure-free following resective surgery. The effective connectivity pattern was calculated during the first 20 s of ictal rhythmic iEEG activity. The out-degree, which is reflective of the number of outgoing connections, was calculated for each electrode contact for every single seizure during these 20 s. The seizure specific out-degrees were summed per patient to obtain the total out-degree. The electrode contact with the highest total out-degree was considered indicative of localization of the ictal-onset zone. This result was compared to the conclusion of the visual analysis of the epileptologist and the resected brain region segmented from postoperative magnetic resonance imaging (MRI). KEY FINDINGS: In all eight patients the electrode contact with the highest total out-degree was among the contacts identified by the epileptologist as the ictal onset. This contact, that we named "the driver," always laid within the resected brain region. Furthermore, the patient-specific connectivity patterns were consistent over the majority of seizures. SIGNIFICANCE: In this study we demonstrated the feasibility of correctly localizing the ictal-onset zone from iEEG recordings by using effective connectivity analysis during the first 20 s of ictal rhythmic iEEG activity. PMID- 23647149 TI - Celebrating the 75th anniversary of the ACS Division of Analytical Chemistry: a special collection of the most highly cited analytical chemistry papers published between 1938 and 2012. PMID- 23647148 TI - Distinct intrinsic and synaptic properties of pre-sympathetic and pre parasympathetic output neurons in Barrington's nucleus. AB - Barrington's nucleus (BN), commonly known as the pontine micturition center, controls micturition and other visceral functions through projections to the spinal cord. In this study, we developed a rat brain slice preparation to determine the intrinsic and synaptic mechanisms regulating pre-sympathetic output (PSO) and pre-parasympathetic output (PPO) neurons in the BN using patch-clamp recordings. The PSO and PPO neurons were retrogradely labeled by injecting fluorescent tracers into the intermediolateral region of the spinal cord at T13 L1 and S1-S2 levels, respectively. There were significantly more PPO than PSO neurons within the BN. The basal activity and membrane potential were significantly lower in PPO than in PSO neurons, and A-type K(+) currents were significantly larger in PPO than in PSO neurons. Blocking A-type K(+) channels increased the excitability more in PPO than in PSO neurons. Stimulting MU-opioid receptors inhibited firing in both PPO and PSO neurons. The glutamatergic EPSC frequency was much lower, whereas the glycinergic IPSC frequency was much higher, in PPO than in PSO neurons. Although blocking GABAA receptors increased the excitability of both PSO and PPO neurons, blocking glycine receptors increased the firing activity of PPO neurons only. Furthermore, blocking ionotropic glutamate receptors decreased the excitability of PSO neurons but paradoxically increased the firing activity of PPO neurons by reducing glycinergic input. Our findings indicate that the membrane and synaptic properties of PSO and PPO neurons in the BN are distinctly different. This information improves our understanding of the neural circuitry and central mechanisms regulating the bladder and other visceral organs. PMID- 23647150 TI - Identification of sinensetin metabolites in rat urine by an isotope-labeling method and ultrahigh-performance liquid chromatography-electrospray ionization mass spectrometry. AB - Sinensetin (SIN), one of the major polymethoxyflavones (PMFs) contained mainly in the citrus peels, has been reported to possess various bioactivities, including antifungal, antimutagenic, anticancer, and anti-inflammatory activities. Although the biotransformation of SIN in fungi and insects has been reported, the information about the metabolism of SIN in mammals is still unclear. In this study, formation of SIN metabolites in rats was investigated. Four isotope labeled SINs ([4'-D3]SIN, [3'-D3]SIN, [5-D3]SIN, and [6-D3]SIN) were synthesized and administered to rat. The urine samples were collected and main metabolites were monitored by ultrahigh-performance liquid chromatography-electrospray ionization mass spectrometry. The administered compound and four SIN metabolites were detected in rat urine. These metabolites were identified as 4'-hydroxy 5,6,7,3'-tetramethoxyflavone, 5-hydroxy-6,7,3',4'-tetramethoxyflavone, 6-hydroxy 5,7,3',4'-tetramethoxyflavone, and 7-hydroxy-5,6,3',4'-tetramethoxyflavone sulfate. PMID- 23647152 TI - Breaking the cycle of desire: Mindfulness and executive control weaken the relation between an implicit measure of alcohol valence and preoccupation with alcohol-related thoughts. AB - Stimuli with strong affective valence capture attention. This can impede the self regulation of impulses. That is, preoccupation with a tempting stimulus such as alcohol may lead to a continued activation of automatic affective responses to that stimulus, increasing the likelihood of approach and consumption. Self regulation may, thus, benefit from variables that weaken the relation between salient stimuli and cognitive preoccupation with those stimuli. Recent research shows that mindfulness and executive control reduce the link between automatic affective responses to alcohol and alcohol consumption. In this study, the authors examined whether mindfulness and executive control may similarly decouple the relation between automatic affective responses and difficulty in disengaging attention from alcohol-related thoughts. Participants completed measures of trait mindfulness, executive control (a working memory task), automatic alcohol-valence associations, and preoccupation with alcohol-related thoughts. Results showed that (a) both trait mindfulness and executive control are inversely related with alcohol preoccupation, and (b) both mindfulness and executive control weaken a positive relation between automatic alcohol-valence associations and alcohol preoccupation. PMID- 23647151 TI - Gender differences in relationships among PTSD severity, drinking motives, and alcohol use in a comorbid alcohol dependence and PTSD sample. AB - Alcohol dependence (AD) and posttraumatic stress disorder (PTSD) are highly prevalent and comorbid conditions associated with a significant level of impairment. Little systematic study has focused on gender differences specific to individuals with both AD and PTSD. The current study examined gender-specific associations between PTSD symptom severity, drinking to cope (i.e., reduce negative affect), drinking for enhancement (i.e., increase positive affect), and average alcohol use in a clinical sample of men (n = 46) and women (n = 46) with comorbid AD and PTSD. Results indicated that PTSD symptoms were highly associated with drinking-to-cope motives for both men and women, but with greater drinking for enhancement motives for men only. Enhancement motives were positively associated with average alcohol quantity for both men and women, but coping motives were significantly associated with average alcohol quantity for women only. These findings suggest that for individuals with comorbid AD and PTSD, interventions that focus on reducing PTSD symptoms are likely to lower coping motives for both genders, and targeting coping motives is likely to result in decreased drinking for women but not for men, whereas targeting enhancement motives is likely to lead to reduced drinking for both genders. PMID- 23647153 TI - Perceptions of relative risk of disease and addiction from cigarettes and snus. AB - The public is largely unaware of the lower global risk associated with snus compared with that of cigarettes, but little is known of perceptions of relative risks for specific diseases. Inveterate, daily, and nondaily smokers' perceptions of the relative snus/cigarette risk of cardiovascular disease, and of cancer of the lung, stomach, and oral cavity, and perceptions among smokers, snus users, and dual users of the relative risk of nicotine addiction, was studied in a pooled sample from annual national surveys (2008-2011) performed by Statistics Norway. The total sample included 2,661 ever smokers and snus users aged 15-79 years old. Fifty-three percent were men, and the average age was 46.1 year. Compared with medical consensus, all smoker groups overestimated the relative risks of diseases from snus use, and inveterate smokers overestimated them significantly more than other groups. For all diseases except lung cancer, the majority of smokers thought snus users were running a higher or equal risk. For lung cancer, 22% believed that snus use gave a higher or equal risk. Smokers, snus users, and dual users tended to think that snus and cigarettes were equally addictive products, while a somewhat higher proportion of those who had quit both products thought that cigarettes were more addictive. Increased knowledge of the relative health risks might give smokers an incitement to switch to snus and prompt current dual users to stop smoking completely. Awareness could be improved by tailoring information at targeted groups, for example via the health care system. PMID- 23647155 TI - Alcohol-related memory associations in positive and negative affect situations: drinking motives, working memory capacity, and prospective drinking. AB - Although studies on explicit alcohol cognitions have identified positive and negative reinforcing drinking motives that are differentially related to drinking indices, such a distinction has received less attention in studies on implicit cognitions. An alcohol-related Word-Sentence Association Task was used to assess implicit alcohol-related memory associations in positive and negative affect situations in 92 participants. Results revealed that enhancement motives were specifically associated with the endorsement of alcohol words in positive affect situations and coping motives were associated with the endorsement of alcohol words in negative affect situations. Furthermore, alcohol associations in positive affect situations predicted prospective alcohol use and number of binges, depending on levels of working memory capacity. The current findings shed more light on the underpinnings of alcohol use and suggest that implicit memory processes and working memory capacity might be important targets for intervention. PMID- 23647154 TI - Daily mood-drinking slopes as predictors: a new take on drinking motives and related outcomes. AB - Motivational models of alcohol consumption have articulated the manner in which positive and negative experiences motivate drinking in unique social contexts (e.g., M. L. Cooper, M. R. Frone, M. Russell & P. Mudar, 1995, Drinking to regulate positive and negative emotions: A motivational model of alcohol use, Journal of Personality and Social Psychology, Vol. 69, pp. 990-1005). Daily process methodology, in which daily events, moods, and drinking behaviors are reported daily or multiple times per day, has been used to examine behavioral patterns that are consistent with discrete motivations. We advance the notion that repeated patterns of drinking in various social contexts as a function of positive or negative mood increases can provide evidence of individual-level if then drinking signatures, which in turn can predict drinking-related outcomes. The purpose of this study was to examine the utility of slopes to predict longer term drinking motivations and alcohol problems by employing a daily-process study of nonclinical moderate alcohol drinkers (N = 47; 49% women). Participants responded to thrice daily interviews administered via handheld computer for 30 days, followed by a longitudinal telephone survey for 12 months. Participants' daily mood-drinking relationships were extracted from hierarchical linear modeling and employed as predictors of 12-month outcomes in multiple regression analyses. Daily mood-drinking patterns demonstrated significant variability across persons, such that moderate drinkers could be reliably differentiated based on those patterns in terms of distinct drinking-related outcomes. Among the results, negative-mood-solitary-drinking slopes were associated with lower subsequent coping motives but positive-mood-solitary-drinking slopes were predictive of higher coping and lower social motives. Conversely, positive-mood social-drinking associations were predictive of higher enhancement motives and brief Michigan Alcoholism Screening Test scores. Results are interpreted in light of motivational models of consumption. PMID- 23647156 TI - Daily use of protective behavioral strategies and alcohol-related outcomes among college students. AB - The purpose of the present study was to examine associations between use of protective behavioral strategies (PBS) and alcohol-related outcomes (alcohol consumption, negative alcohol consequences, and positive alcohol consequences) using a daily diary approach. This approach is less affected by retrospective memory biases than typical self-reports of alcohol-related variables and allows the examination of both between-subjects and within-person effects. Using hierarchical linear modeling of data from 40 subjects who completed daily dairies for up to 15 days, we found significant within-person variation in PBS use over time, and each type of PBS had unique relationships with alcohol-related outcomes. For example, within-person variation in Serious Harm Reduction, one form of PBS, predicted increased daily alcohol use, negative consequences, and positive consequences. Our findings suggest the importance of intensive longitudinal methods to examine both between-subjects and within-subjects effects of PBS use and alcohol-related outcomes. PMID- 23647158 TI - Identifying indicators of harmful and problem gambling in a Canadian sample through receiver operating characteristic analysis. AB - Many gamblers would prefer to reduce gambling on their own rather than to adopt an abstinence approach within the context of a gambling treatment program. Yet responsible gambling guidelines lack quantifiable markers to guide gamblers in wagering safely. To address these issues, the current investigation implemented receiver operating characteristic (ROC) analysis to identify behavioral indicators of harmful and problem gambling. Gambling involvement was assessed in 503 participants (275 psychiatric outpatients and 228 community gamblers) with the Canadian Problem Gambling Index. Overall gambling frequency, duration, and expenditure were able to distinguish harmful and problematic gambling at a moderate level. Indicators of harmful gambling were generated for engagement in specific gambling activities: frequency of tickets and casino; duration of bingo, casino, and investments; and expenditures on bingo, casino, sports betting, games of skill, and investments. Indicators of problem gambling were similarly produced for frequency of tickets and casino, and expenditures on bingo, casino, games of skill, and investments. Logistic regression analyses revealed that overall gambling frequency uniquely predicted the presence of harmful and problem gambling. Furthermore, frequency indicators for tickets and casino uniquely predicted the presence of both harmful and problem gambling. Together, these findings contribute to the development of an empirically based method enabling the minimization of harmful or problem gambling through self-control rather than abstinence. PMID- 23647157 TI - Externalizing behavior problems among polydrug cocaine-exposed children: Indirect pathways via maternal harshness and self-regulation in early childhood. AB - This study examined direct and indirect associations between prenatal cocaine exposure (CE) and children's externalizing problems in kindergarten via higher maternal harshness and lower self-regulation in early childhood. Other environmental risk variables, such as child exposure to community violence and experience of hunger, were used as additional predictors. The sample consisted of 216 mother-infant dyads recruited at delivery from local area hospitals (116 cocaine-exposed, 100 nonexposed). Maternal harshness was coded from observations of mother-toddler interactions at 2 years of age, and children's self-regulation was measured at 3 years of age using several laboratory paradigms. Maternal reports of externalizing behavior problems were obtained at both time points and at kindergarten. Teacher reports were obtained and classroom observations of externalizing behaviors were conducted in the kindergarten classroom. Results indicated significant indirect associations between CE and maternal reports of externalizing problems via higher maternal harshness at 2 years and higher externalizing problems at 3 years of child age. A second indirect path from CE to externalizing problems in the school setting via higher maternal harshness at 2 years and lower self-regulation at 3 years was also significant. There were significant associations between community violence exposure and maternal reports of externalizing problems, and between hunger and externalizing problems in the school setting. Results highlight the role of parenting and self-regulation in early childhood as critical process variables in the indirect association between CE and externalizing behavior problems in kindergarten. PMID- 23647159 TI - A fully integrated nanosystem of semiconductor nanowires for direct solar water splitting. AB - Artificial photosynthesis, the biomimetic approach to converting sunlight's energy directly into chemical fuels, aims to imitate nature by using an integrated system of nanostructures, each of which plays a specific role in the sunlight-to-fuel conversion process. Here we describe a fully integrated system of nanoscale photoelectrodes assembled from inorganic nanowires for direct solar water splitting. Similar to the photosynthetic system in a chloroplast, the artificial photosynthetic system comprises two semiconductor light absorbers with large surface area, an interfacial layer for charge transport, and spatially separated cocatalysts to facilitate the water reduction and oxidation. Under simulated sunlight, a 0.12% solar-to-fuel conversion efficiency is achieved, which is comparable to that of natural photosynthesis. The result demonstrates the possibility of integrating material components into a functional system that mimics the nanoscopic integration in chloroplasts. It also provides a conceptual blueprint of modular design that allows incorporation of newly discovered components for improved performance. PMID- 23647161 TI - Non-invasive cardiovascular profiling using combined electrocardiogram-Doppler ultrasonography and impedance cardiography: An experimental approach. AB - In the present study, the feasibility of cardiovascular profiling using both combined electrocardiogram (ECG)-Doppler ultrasonography and impedance cardiography (ICG) was evaluated. Fourteen non-pregnant healthy women received 500 mL saline solution (NaCl 0.9% at 999 mL/h) intravenously by steady state infusion. Before and after this acute volume loading, we measured orthostatic challenged cardiac and arterial characteristics using ICG and assessed venous characteristics by combined ECG-Doppler before and during the Valsalva manoeuvre. Changes are expressed as the mean +/- SEM and were evaluated by the one-sample Wilcoxon signed-rank test. After volume loading, the observed fall in stroke volume after postural change from supine to standing decreased (-14 +/- 3 vs -23 +/- 2%; P = 0.011). Hepatic A wave velocity increased 63 +/- 28% after volume loading (P = 0.007) and decreased during the Valsalva manoeuvre (-205 +/- 21%; P = 0.001). Volume loading raised the thoracic fluid content index in both the supine and standing positions (7 +/- 2% and 10 +/- 1%, respectively; P <= 0.014). Combined ECG-Doppler ultrasonography and ICG enables the non-invasive identification of concomitant haemodynamic changes at the level of the heart, the arterial bed and the venous compartment. Our data support the view that non invasive cardiovascular profiling is feasible, which seems particularly useful for the evaluation of patients who are not critically ill, such as pregnant women. PMID- 23647162 TI - Noma (cancrum oris) in the South African context. AB - Noma (cancrum oris) is a destructive necrotising disease affecting orofacial tissues predominantly of malnourished young children. It is characterised by a rapid acute onset which usually starts in the mouth, spreads intra-orally destroying soft tissue and bone and progresses to perforate the facial skin, causing disfigurement. Polybacterial anaerobic infection is critical too, but is not alone sufficient for the initiation of noma. Cofactors, first and foremost malnutrition, but also systemic viral and bacterial infections are crucial to the development of noma. A patient with necrotising stomatitis or noma must be admitted to hospital for antibiotic treatment, fluid and electrolytes as well as nutritional supplementation and general supportive treatment. The epidemiology of noma in the South African population is unknown, and the clinicopathological features are poorly characterised. Although worldwide there is no evidence that HIV infection is a strong risk factor for noma, HIV infection may play a substantial role in the pathogenesis of noma in South Africa. PMID- 23647160 TI - Genome wide proteomics of ERBB2 and EGFR and other oncogenic pathways in inflammatory breast cancer. AB - In this study we selected three breast cancer cell lines (SKBR3, SUM149 and SUM190) with different oncogene expression levels involved in ERBB2 and EGFR signaling pathways as a model system for the evaluation of selective integration of subsets of transcriptomic and proteomic data. We assessed the oncogene status with reads per kilobase per million mapped reads (RPKM) values for ERBB2 (14.4, 400, and 300 for SUM149, SUM190, and SKBR3, respectively) and for EGFR (60.1, not detected, and 1.4 for the same 3 cell lines). We then used RNA-Seq data to identify those oncogenes with significant transcript levels in these cell lines (total 31) and interrogated the corresponding proteomics data sets for proteins with significant interaction values with these oncogenes. The number of observed interactors for each oncogene showed a significant range, e.g., 4.2% (JAK1) to 27.3% (MYC). The percentage is measured as a fraction of the total protein interactions in a given data set vs total interactors for that oncogene in STRING (Search Tool for the Retrieval of Interacting Genes/Proteins, version 9.0) and I2D (Interologous Interaction Database, version 1.95). This approach allowed us to focus on 4 main oncogenes, ERBB2, EGFR, MYC, and GRB2, for pathway analysis. We used bioinformatics sites GeneGo, PathwayCommons and NCI receptor signaling networks to identify pathways that contained the four main oncogenes and had good coverage in the transcriptomic and proteomic data sets as well as a significant number of oncogene interactors. The four pathways identified were ERBB signaling, EGFR1 signaling, integrin outside-in signaling, and validated targets of C-MYC transcriptional activation. The greater dynamic range of the RNA-Seq values allowed the use of transcript ratios to correlate observed protein values with the relative levels of the ERBB2 and EGFR transcripts in each of the four pathways. This provided us with potential proteomic signatures for the SUM149 and 190 cell lines, growth factor receptor-bound protein 7 (GRB7), Crk-like protein (CRKL) and Catenin delta-1 (CTNND1) for ERBB signaling; caveolin 1 (CAV1), plectin (PLEC) for EGFR signaling; filamin A (FLNA) and actinin alpha1 (ACTN1) (associated with high levels of EGFR transcript) for integrin signalings; branched chain amino-acid transaminase 1 (BCAT1), carbamoyl-phosphate synthetase (CAD), nucleolin (NCL) (high levels of EGFR transcript); transferrin receptor (TFRC), metadherin (MTDH) (high levels of ERBB2 transcript) for MYC signaling; S100-A2 protein (S100A2), caveolin 1 (CAV1), Serpin B5 (SERPINB5), stratifin (SFN), PYD and CARD domain containing (PYCARD), and EPH receptor A2 (EPHA2) for PI3K signaling, p53 subpathway. Future studies of inflammatory breast cancer (IBC), from which the cell lines were derived, will be used to explore the significance of these observations. PMID- 23647163 TI - COP1 re-accumulates in the nucleus under shade. AB - Shade-avoider plants typically respond to shade-light signals by increasing the rate of stem growth. CONSTITTUTIVE PHOTOMORPHOGENESIS 1 (COP1) is an E3 ligase involved in the ubiquitin labelling of proteins targeted for degradation. In dark grown seedlings, COP1 accumulates in the nucleus and light exposure causes COP1 migration to the cytosol. Here, we show that in Arabidopsis thaliana, COP1 accumulates in the nucleus under natural or simulated shade, despite the presence of far-red light. In plants grown under white light, the transfer to shade-light conditions triggers an unexpectedly rapid re-accumulation of COP1 in the nucleus. The partial simulation of shade by lowering either blue or red light levels (maintaining far-red light) caused COP1 nuclear re-accumulation. Hypocotyl growth of wild-type seedlings is more sensitive to afternoon shade than to morning shade. A residual response to shade was observed in the cop1 mutant background, but these seedlings showed inverted sensitivity as they responded to morning shade and not to afternoon shade. COP1 overexpression exaggerated the wild-type pattern by enhancing afternoon sensitivity and making morning shade inhibitory of growth. COP1 nuclear re-accumulation also responded more strongly to afternoon shade than to morning shade. These results are consistent with a signalling role of COP1 in shade avoidance. We propose a function of COP1 in setting the daily patterns of sensitivity to shade in the fluctuating light environments of plant canopies. PMID- 23647164 TI - Use of experimental translocations of Allegheny woodrat to decipher causal agents of decline. AB - Translocations are an important tool for wildlife conservation, although progress in the field of reintroduction biology has been hindered by the ad hoc and opportunistic nature of many translocations. We used an experimental translocation to elucidate the role of raccoon roundworm (Baylisascaris procyonis) and inbreeding depression in the decline of the Allegheny woodrat (Neotoma magister), an endangered species. We translocated woodrats from genetically diverse populations in the core of the species range to 4 previously occupied sites (reintroductions) and 2 sites supporting genetically depauperate populations (reinforcements) in Indiana (U.S.A.). In 2 reintroduction sites and 1 reinforcement site, we distributed anthelmintic baits to passively deworm raccoons and reduce the risk of woodrat exposure to roundworms. The remaining sites served as controls. We used raccoon latrine surveys and fecal flotation to monitor temporal variability in roundworm prevalence and effect of treatment. We used live trapping and microsatellite genotyping to monitor the demographic and genetic response of translocated populations over the following 54 months. At the conclusion of the study, 4 of 6 translocations were successfully maintaining abundance through local recruitment. The distribution of anthelmintic baits reduced levels of roundworm contamination, but levels of contamination were also low in 2 of 3 control sites. Reintroductions failed at control sites, one of which was due to high roundworm exposure. The other failed control reintroduction was likely attributable to demographic stochasticity and limited reproductive potential following initial mortality within the first 4 months. In both control and treatment reinforcements, increases in both allelic richness and heterozygosity were accompanied by increases in abundance, which is suggestive of genetic rescue. Our results demonstrate that mitigation of roundworm exposure through the distribution of anthelmintic baits can facilitate woodrat recovery and that diversity within genetically depauperate populations can be restored through the introduction of a limited number of individuals. PMID- 23647165 TI - Assessing the invariance of smoking-related self-efficacy, beliefs, and intention among high school current smokers. AB - Measures of correlates of youth smoking should be invariant. We examined the measurement invariance of smoking-related self-efficacy, beliefs, and intention across gender, race (White vs. Black), ethnicity (non-Hispanic vs. Hispanic), and grade level (9th/10th vs. 11th/12th grade) for 2767 high school current smokers. Strong factorial invariance was found in the factors across gender (NNFI:0.959; CFI:0.959; RMSEA:0.085), grade (NNFI:0.962; CFI:0.962; RMSEA: 0.079), race (NNFI: 0.967; CFI: 0.967; RMSEA: 0.074), and ethnicity (NNFI: 0.965; CFI: 0.965; RMSEA: 0.078). Smoking-related self-efficacy, beliefs, and intention measures may be confidently used to understand attitudinal differences across gender, race, ethnicity, and grade level for youth smokers. PMID- 23647166 TI - Reducing service and substance use among frequent service users: a brief report from the Toronto Community Addictions Team. AB - The Toronto Community Addictions Team (TCAT) is an intensive case management intervention designed to serve people with addictions who are frequent service users, thus addressing a health system priority. Questionnaires given to 65 participants at baseline, 3 months, and 6 months and semi-structured interviews of 10 program participants explored participants' outcomes and experiences with the program. Qualitative findings, analyzed using thematic content analysis, suggest that participants value the program's commitment to harm reduction, financial trusteeship, and recovery orientation. Quantitative findings from paired t-tests reveal that participants improved in community functioning and decreased days of problematic substance use and money spent on alcohol and drugs as early as 3 months after program participation. Future research should used a controlled design and explore predictors of positive outcomes in this vulnerable population. PMID- 23647167 TI - A critical systematic review of alcohol-related outcome expectancies. AB - To assess the validity of the research into alcohol-related outcome expectancies a systematic review of 80 articles published between 1970 and 2013 was conducted. Participant gender, age, and contextual influences are highlighted as possible causes of the observed variations in research findings. There is a need for fuller consideration of the influences of demographics and environmental and social contexts on research findings. It is recommended that alcohol intake measures should be standardized to a greater degree in future research. Contextual influences on expectancies also require extensive future investigation to increase the validity of research and improve alcohol-related interventions. PMID- 23647168 TI - Barriers to medical provider support for prescription naloxone as overdose antidote for lay responders. AB - Poisonings are the leading cause of adult injury death in the United States. Over 12 weeks in 2011, 143 key informant interviews were conducted using a structured interview guide in three study sites in New England. This analysis focuses on the 24 interviews with emergency department providers, substance use treatment providers, pain specialists, and generalist/family medicine practitioners. Using an iterative coding process, we analyzed statements regarding support and concern about naloxone prescription for pain patients and drug users. The study's implications and limitations are discussed and future research suggested. The Centers for Disease Control and Prevention funded this study. PMID- 23647170 TI - Genital and anorectal mucosal melanoma is associated with cutaneous melanoma in patients and in families. AB - BACKGROUND: Genital and anorectal mucosal melanomas (GAMMs) are rare compared with cutaneous melanoma (CM). Many epidemiological and genetic studies have been carried out on CM. In contrast, the genetic and environmental risk factors for GAMM have been poorly documented up to now. OBJECTIVES: To compare the distribution of pigmentation and naevus phenotypes, sun exposure and family history of melanoma between patients with GAMM and CM. METHODS: We compared two series of patients, 81 with GAMM and 293 with CM. RESULTS: Patients with GAMM and CM did not show significant differences for phenotypic risk factors. However, patients with GAMM tended to display red hair (11% vs. 5.5%, P = 0.08) and a poor tanning ability (22% vs. 13.3%, P = 0.06) at a higher frequency than patients with CM. A family history of melanoma was significantly more frequent with GAMM than with CM (18% vs. 7.5%, P = 0.005). Apart from the GAMM index case, affected relatives had CM except in one family. The frequency of multiple primary melanomas (MPMs) was similar in the GAMM and CM series (6% vs. 5.3%, P = 0.43). All patients with GAMM and MPM had only one GAMM primary, while the other primary was cutaneous. No CDKN2A germline mutation was detected in patients with GAMM. CONCLUSIONS: This study shows that GAMM and CM may occur in the same patient, and GAMM may develop in a familial setting. The association of both GAMM and CM in patients and families suggests shared genetic factors by these two types of melanoma. PMID- 23647171 TI - Bomb calorimetry, the gold standard for assessment of intestinal absorption capacity: normative values in healthy ambulant adults. AB - BACKGROUND: Intestinal absorption capacity is considered to be the best method for assessing overall digestive intestinal function. Earlier reference values for intestinal function in healthy Dutch adults were based on a study that was conducted in an inpatient metabolic unit setting in a relatively small series. The present study aimed to readdress and describe the intestinal absorption capacity of healthy adults, who were consuming their usual (Western European) food and beverage diet, in a standard ambulatory setting. METHODS: Twenty-three healthy subjects (aged 22-60 years) were included in the analyses. Nutritional intake (energy and macronutrients) was determined with a 4-day nutritional diary. Subsequently, mean faecal losses of energy (by bomb calorimetry), fat, protein and carbohydrate were determined following a 3-day faecal collection. Finally, intestinal absorption capacity was calculated from the differences between intake and losses. RESULTS: Mean (SD) daily faeces production was 141 (49) g (29% dry weight), containing 891 (276) kJ [10.7 (1.3) kJ g(-1) wet faeces; 22.6 (2.5) kJ g(-1) dry faeces], 5.2 (2.2) g fat, 10.0 (3.8) g protein and 29.7 (11.7) g carbohydrates. Mean (SD) intestinal absorption capacity of healthy subjects was 89.4% (3.8%) for energy, 92.5% (3.7%) for fat, 86.9% (6.4%) for protein and 87.3% (6.6%) for carbohydrates. CONCLUSIONS: The present study provides normative values for both stool nutrient composition and intestinal energy and macronutrient absorption in healthy adults on a regular Dutch diet in an ambulatory setting. Intestinal energy absorption was found to be approximately 90%. PMID- 23647172 TI - Relationship between oral health and frailty in community-dwelling elderly individuals in Brazil. AB - OBJECTIVES: To test the hypothesis that clinical oral health conditions are associated with frailty independent of socioeconomic and general health status. DESIGN: Cross-sectional. SETTING: Population-based cohort study of health, well being, and aging. PARTICIPANTS: One thousand three hundred seventy-four community dwelling individuals representing 998,528 individuals aged 60 and older in the city of Sao Paulo, Brazil. MEASUREMENTS: Frailty was defined on the basis of five characteristics: weight loss, weakness, slowness, exhaustion, and low level of physical activity. Participants with three or more characteristics were classified as frail, with one or two as prefrail, and with zero as nonfrail. Oral health measures were number of teeth, use of dental prostheses, need for dental prostheses, presence of decayed teeth, clinical attachment loss of 4 mm or greater, and periodontal pocket of 4 mm or greater. Data on sociodemographic (age, sex, and schooling) and general health (number of self-reported chronic diseases and smoking status) data were assessed. RESULTS: The prevalence of frailty was 8.5%, with 50.8% considered nonfrail. Elderly individuals with a need for dental prostheses were significantly more likely to be prefrail and frail. Participants with 20 or more teeth had a lower chance of being frail than edentulous individuals. CONCLUSION: The need for dental prostheses was significantly associated with frailty, independent of socioeconomic and general health status. PMID- 23647169 TI - The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. AB - Understanding the neurochemical basis for cognitive function is one of the major goals of neuroscience, with a potential impact on the diagnosis, prevention and treatment of a range of psychiatric and neurological disorders. In this review, the focus will be on a biochemical pathway that remains under-recognized in its implications for brain function, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition - glutamate and acetylcholine. Since this pathway - the kynurenine pathway of tryptophan metabolism - is induced by immunological activation and stress, it also stands in a unique position to mediate the effects of environmental factors on cognition and behaviour. Targeting the pathway for new drug development could, therefore, be of value not only for the treatment of existing psychiatric conditions, but also for preventing the development of cognitive disorders in response to environmental pressures. PMID- 23647174 TI - Coaxial Ni(x)Co(2x)(OH)(6x)/TiN nanotube arrays as supercapacitor electrodes. AB - NixCo2x(OH)6x, as a precursor of intensively studied NiCo2O4, has been directly deposited into self-standing titanium nitride nanotube array (TiN NTA) grid monolithic supports to form a coaxial nanostructured electrode for supercapacitors. With TiN NTA substrates providing a large surface area, fast electron transport, and enhanced structure stability, this NixCo2x(OH)6x/TiN electrode exhibits superior pseudocapacitive performance with a high specific capacitance of 2543 F g(-1) at 5 mV s(-1), remarkable rate performance of 660 F g(-1) even at 500 mV s(-1), and promising cycle performance (about 6.25% capacitance loss for 5000 cycles). Interestingly, the NixCo2x(OH)6x/TiN NTA electrode outperforms the NiCo2O4/TiN NTA electrode, indicating that this self standing NixCo2x(OH)6x/TiN NTA monolith is a promising candidate for high performance supercapacitor applications. PMID- 23647173 TI - The use of imaging to detect schistosomes and diagnose schistosomiasis. AB - Several imaging modalities have been employed to examine schistosomes and monitor schistosome-induced pathology. Ultrasound is a noninvasive imaging method that has long been used in the laboratory and in the field to evaluate pathological changes, notably fibrosis, that arise as a consequence of the host response to schistosome eggs lodging in a variety of tissues. Ultrasonography has been widely used to monitor changes in the extent of fibrosis and in spleen/liver enlargement following chemotherapeutic treatment for schistosomiasis. Imaging methods to monitor schistosomes themselves in vivo (as opposed to detecting schistosome induced pathology) include positron emission tomography and fluorescence molecular tomography. Both approaches rely on schistosome uptake of tracers that are introduced into infected animals and that can be detected externally. These methods have been used to successfully detect schistosomes in vivo and to monitor their elimination following chemotherapeutic treatment. Direct monitoring of live schistosomes in vivo has been achieved using intravital microscopy, when the infected tissues of anaesthetized animals are exposed. Finally, schistosome eggs have been visualized by confocal laser scanning microscopy in infected mice as well as in a human patient with schistosomiasis hematobium. Further advances in imaging technologies seem likely to provide greater insight into disease progression and into the biology of schistosomes in the most relevant setting within a live animal. PMID- 23647175 TI - Photoreduction of azaoxoisoaporphines by amines: laser flash and steady-state photolysis and pulse radiolysis studies. AB - Photoreduction of 7H-benzo[e]perimidin-7-one (3-AOIA, A1) and its 2-methyl derivative (2-Me-3-AOIA, A2) by non-H-donating amines (1,4 diazabicyclo[2.2.2]octane [DABCO]; 2,2,6,6-tetramethylpiperidine [TMP]), and a hydrogen-donating amine (triethylamine [TEA]), has been studied in deaerated neat acetonitrile solutions using laser flash photolysis (LFP) and steady-state photolysis. The triplet excited states of A1 and A2 were characterized by a strong absorption band with lambdamax = 440 nm and lifetimes of 20 and 27 MUs respectively. In the presence of tertiary amines, both triplet excited states were quenched with rate constants close to the diffusional limit (kq ranged between 10(9) and 10(10) M(-1) s(-1)). The transient absorption spectra observed after quenching with DABCO and TMP were characterized by maxima located at 460 nm and broad shoulders in the range of 500-600 nm. These transient species are attributed to solvent-separated radical ion pairs and/or to isolated radical anions. In the presence of TEA, these transients undergo proton transfer, leading to the neutral hydrogenated radicals, protonated over the N1- and O-atoms. Transient absorption spectra of these transients were characterized by maxima located at 400 and 520 nm and 430 nm respectively. Additional support for these spectral assignments was provided by pulse radiolysis (PR) experiments in acetonitrile and 2-propanol solutions. PMID- 23647176 TI - Social mindfulness: skill and will to navigate the social world. AB - Although one may not always see it, social life often involves choices that make people act in ways that are mindful of others or not. We adopt an interdependence theoretical approach to the novel concept of social mindfulness, which we conceptualize in terms of other-regarding choices involving both skill (to see it, e.g., theory of mind, perspective taking) and will (to do it, e.g., empathic concern, prosocial orientation) to act mindfully toward another person's control over outcomes. We operationalized social mindfulness in a new social decision making paradigm that focuses on leaving or limiting choice options for others that we tested across 7 studies. Studies 1a through 1c showed that people with other-oriented mindsets left interdependent others more choice than people with self-oriented and/or unspecified mindsets. Studies 2a and 2b revealed that people developed more favorable judgments of a socially mindful than of a socially unmindful person. Study 3 revealed that unknown others with trustworthy (vs. untrustworthy) faces were met with more social mindfulness. Study 4 revealed that social mindfulness could be traced in personality by being positively related to Honesty-Humility and Agreeableness (HEXACO Personality Inventory-Revised) as well as to Empathy (Interpersonal Reactivity Index) and a prosocial value orientation (SVO). Together, these studies contribute to explaining how social mindfulness can help people to navigate the social world by aiming to maximize other people's control over their situational outcomes. PMID- 23647177 TI - Mosquito and West Nile virus surveillance in northeast Montana, U.S.A., 2005 and 2006. AB - Mosquito and West Nile virus (WNV) surveillance was conducted on a national wildlife refuge in northeast Montana in 2005 and 2006, during which outbreaks of WNV in a colony of American white pelicans (Pelecanus erythrorhynchos Gmelin) (Pelecaniformes: Pelecanidae) resulted in juvenile mortality rates of ~ 31%. Both years, floodwater species Ochlerotatus dorsalis (Meigen) (Diptera: Culicidae), Aedes vexans (Meigen) (Diptera: Culicidae) and Ochlerotatus flavescens (Muller) (Diptera: Culicidae) comprised 78% of the total collection and heightened host seeking activity was observed from mid-June to mid-July. Culex tarsalis Coquillett (Diptera: Culicidae) was most active from mid-July to mid-August and comprised 18% of the collection in 2005 and 20% in 2006. However, fewer than 10% of the Cx. tarsalis females collected in 2006 were obtained adjacent to the pelicans' nesting grounds. Minimum infection rates per 1000 Cx. tarsalis tested for WNV were 1.36 in 2005 and 1.41 in 2006. All pools in which WNV was detected in 2006 were composed of females collected 10 km from the nesting grounds. Substantial juvenile pelican mortality in 2006 despite reductions in the population of the primary vector and in mosquito infection rates near the colony suggests that the methods used to detect the introduction of WNV were too coarse and that amplification of the virus within the colony may reflect causes other than mosquito infection. PMID- 23647178 TI - The effect of keel fractures on egg production, feed and water consumption in individual laying hens. AB - The impact of keel bone fractures on egg production, egg weight and feed and water consumption in individual laying hens. A total of 165 Lohmann brown laying hens were obtained from a commercial farm that consisted of 105 with keel fractures and 60 without keel fractures. 2. After a 4-d period of acclimatisation, hens were individually housed and provided with ad libitum food and water for a 24-h period. The number of eggs laid, egg weight, feed and water consumption during this period were recorded. Keel bone strength was also assessed. 3. Hens free from keel fractures laid more eggs (91.7% vs. 84.9%) of significantly heavier weight (61.9 g vs. 60.2 g), ate less feed (139 g vs. 151 g) and drank less water (212 ml vs. 237 ml) than hens with fractures. 4. There was a significant positive association between keel fracture severity and water consumption, and a significant negative association between keel fracture severity and egg weight and keel bone strength. 5. This small-scale study on individual birds shows that keel bone fractures may have an impact on the economics of egg production. PMID- 23647179 TI - Genetic polymorphism of the CAPN1 gene is associated with meat quality traits in Japanese quail. AB - 1. The objective of the study was to investigate the polymorphisms in two regions of the calpain 1 (CAPN1) gene and their association with breast and thigh meat quality in Japanese quail (ultimate pH (pHu), lightness, redness, yellowness, drip loss, thawing-cooking loss, water holding capacity and shear force, SF). 2. Blood samples were collected randomly from 100 birds and DNA was extracted using a commercial kit. Genotypes were determined by PCR amplification followed by single-strand conformation polymorphism (SSCP) analysis. The effect of CAPN1 genotypes on meat quality traits were analysed using a general linear model (GLM) procedure. 3. Genotypes of the CAPN1 gene in the first region (217-bp) analysed were significantly associated with yellowness and SF. The TT genotype showed significantly higher yellowness and lower shear force (more tenderness) than CT and CC genotypes. Genotypes of the second region of the gene (intron 4, 800-bp) were significantly associated with pHu, redness and SF of the breast meat. The BB genotype showed significantly lower pHu and redness and higher SF (lower tenderness) than other genotypes. 4. Information on polymorphisms of the CAPN1 gene will eventually provide useful information for improving meat quality of Japanese quail through marker-assisted selection. PMID- 23647180 TI - Microstructure, texture and colour development during crust formation on whole muscle chicken fillets. AB - 1. The development of crust during a 22-min period was evaluated in an oven, and in previously cooked-in-bag products (no crust) placed in an oven for 10 min. The oven-roasted products started to develop a thin (2-4 MUm) crust layer after 4 min. At that point, the colour of the fillets turned white but no browning was observed. As roasting time increased, crust thickness and shear force increased, the product turned brown and eventually black at certain spots. 2. Light microscopy revealed the shrinking of muscle fibres close to the surface, as they also lost water. At a certain point, tears between the different layers started to appear. The inner muscle fibres also progressively shrank and the spaces between them increased. Microscopy of cook-in-bag products revealed no crust formation during heating. Upon moving to the oven, crust started to form but was much faster compared with the other products. 3. Cook-in-the-bag samples showed a higher rate of cook loss during the first 12 min (to internal 70 degrees C) compared with oven heating. This could have been due to the fast heating rate in water and/or no crust formation. 4. White colour was fully formed on water-cooked fillets within 2 min (L* = 83), while it was gradually forming on oven-roasted samples (max L* of 79 after 12 min). 5. Shear force measurements showed an increase in both treatments up to 18 min, with a decrease thereafter (when dry crust started to crack). PMID- 23647181 TI - Growth, carcase and meat traits and gene expression in chickens divergently selected for intramuscular fat content. AB - 1. Changes resulting from divergent selection after 5 generations for intramuscular fat (IMF) content in breast muscle in a population of purebred Beijing-You chickens were investigated. Female chickens from lines selected-up (UL) and selected-down (DL) for 5 generations and random-bred controls (CL) were studied at 120 d of age. 2. In the UL, IMF in breast muscle (4.65%) was 1.38 times that in the DL (3.36%). The IMF content in leg muscle was also higher in UL compared to DL. 3. There were significant differences in growth, carcase traits and meat quality between the two selected lines. However, ultimate pH (pHu) was lower and lightness (L*) and yellowness (b*) were higher in breast muscles of UL birds compared to DL birds. Similar trends for pHu and L* value between UL and DL were observed in leg muscle. 4. Significant mRNA expression differences of the heart fatty acid-binding protein (H-FABP) gene between UL and DL were observed in breast muscle, and a negative correlation between expression of mRNA and IMF% in breast and leg muscles pointed to H-FABP as a potential selection candidate gene. PMID- 23647182 TI - Effects of dietary enrichment with n-3 fatty acids on the quality of raw and processed breast meat of high and low growth rate chickens. AB - 1. The enrichment of raw poultry meat with n-3 fatty acids (n-3 FA) has been investigated in detail, particularly in high growth rate genotype standard broiler chickens, whereas low growth rate genotype Label Rouge chickens have received less attention. With the increased development of processed poultry products, it is necessary to ensure that the nutritional and sensory quality of meat enriched with n-3 FA is not affected by processing. 2. Two experiments were undertaken for this purpose. In the first experiment, 696 male Ross 708 chickens were reared under standard conditions, and in the second, 750 male JA 657 chickens were reared under Label Rouge conditions. All birds received the same starting and growing diets containing palm and soya oils in each experiment. Birds were distributed into three groups from 21 or 57 d of age for standard and Label Rouge chickens, respectively, and given a control, linseed oil or extruded linseed diet. Diets were also supplemented with vitamin E (100-200 mg/kg). Birds were slaughtered at 56 or 84 d of age for standard and Label Rouge chickens, respectively. A total amount of 60 kg of breast meat from each group was processed into white cured-cooked meat. 3. The dietary treatment had no effect on the growth performance of chickens or meat yield. The use of extruded linseed or linseed oil only decreased the carcass fatness of the standard chickens but had no effect on the carcass fatness of Label Rouge chickens. The nutritional quality of raw and cured-cooked meat was improved (increased concentration of n-3 FA), whereas the technological quality of the meat (pH, juice loss after cold storage, susceptibility to oxidation, colour, processing yield and shear force value) and sensory quality of the processed products were not or slightly affected. 4. Linked to lower breast yield, to lower lipid content in breast meat and to higher slaughter age, Label Rouge chickens seemed to be less efficient for n-3 FA deposition in breast muscles than standard chickens. PMID- 23647183 TI - Metabolic and hormonal responses of growing modern meat-type chickens to fasting. AB - 1. The present study compared the effects of fasting on circulating concentrations of glucose, insulin and glucagon in male and female modern meat type chickens (Ross 708) at three ages (19 d, 33 d and 47 d). 2. Plasma concentrations of glucose were reduced by fasting with reductions of 24.9% (19-d old), 22.6% (33-d-old) and 17.9% (47-d-old) in broiler chickens fasted for 12 h. 3. Plasma concentrations of insulin decreased with fasting. For instance, circulating concentrations of insulin declined after 6 h of fasting by 45.7%, 54.7% and 50.0%, respectively, in 19-d-old, 33-d-old and 47-d-old broiler chickens. 4. Plasma concentrations of glucagon were increased by fasting. Plasma concentrations of glucagon were elevated by 3.79% (19-d-old), 3.51% (33-d-old) and 3.79% (47-d-old) with 6 h of fasting and remained elevated with 12 h, 18 h and 24 h of fasting. PMID- 23647184 TI - Effect of a novel microbial phytase on production performance and tibia mineral concentration in broiler chickens given low-calcium diets. AB - 1. In a 42-d feeding trial, 264 one-d-old, as hatched, Cobb 400 broiler chickens (6 pens per group, n = 11 per pen in a 2 * 2 factorial arrangement) were fed on two concentrations of dietary calcium (Ca) (9.0 and 7.5 g/kg in starter, 7.5 and 6 g/kg in grower phases) and supplemental phytase (0 and 500 U/kg diet). 2. During d 0-21, the high Ca + phytase diet improved body weight. During d 0-42, feed intake was increased by the low Ca diet and decreased by phytase supplementation. Feed conversion ratio during d 0-21 was improved by the high Ca + phytase diet. 3. At d 42, Ca in duodenal digesta was reduced by low dietary Ca and supplemental phytase. High dietary Ca reduced P in duodenal and jejunal digesta. Phytase reduced digesta P and increased serum P concentration. 4. Relative tibia length decreased with low dietary Ca and increased with phytase. The robusticity index of tibia was improved by the low Ca diet and phytase supplementation. Phytase supplementation increased tibia ash and concentrations of Ca, magnesium (Mg), manganese (Mn), copper (Cu), zinc (Zn) and iron (Fe) in tibia. The low Ca diet increased Mg, Mn and Fe and reduced Cu and Zn in tibia. 5. It was concluded that 7.5 g Ca/kg during weeks 0-3 and 6 g Ca/kg during weeks 3-6 sustained broiler performance and bone ash, while phytase supplementation facilitated tibia mineralisation, particularly during the grower phase. PMID- 23647185 TI - Effects of single or combined dietary supplementation of beta-glucan and kefir on growth performance, blood characteristics and meat quality in broilers. AB - 1. This study was conducted to evaluate the effects of dietary beta-glucan and kefir (a fermented milk product) on growth performance, blood profiles, relative organ weight and meat quality in broilers. 2. A total of 375 day-of-hatch mixed sex ROSS 308 broilers (BW of 46 +/- 0.1 g) were used in a 5-week experiment and randomly allotted to one of the following dietary treatments: (1) NC, basal diet; (2) PC, basal diet + 40 mg/kg of avilamycin; (3) B, NC + 0.1% beta-glucan; (4) K, NC + 0.1% kefir; (5) BK, NC + 0.1% beta-glucan + 0.1% kefir. 3. During weeks 0-3, broilers in B, K and BK treatments had higher body weight gain (BWG) than those in NC treatment. During weeks 4-5, BK treatment had a higher BWG than NC treatment. Overall, broilers given PC, K and BK diets had higher BWG than those given NC diet. The feed efficiency ratio (FCR) was improved by PC treatment. 4. Relative liver weight was increased by B treatment, whereas the relative weight of breast meat and gizzard was higher in BK group than that in NC group. Broilers given PC, B and BK diets had greater breast meat redness value and reduced drip loss at d 5 and d 7. The cooking loss was also reduced by B and BK treatments compared with NC treatment. 5. In conclusion, the results suggested that inclusion of 0.1% beta-glucan and 0.1% kefir, either individually or combined, would improve growth performance and benefit meat quality in broiler chickens. PMID- 23647186 TI - Effect of intermittent feeding, structural components and phytase on performance and behaviour of broiler chickens. AB - 1. Two experiments were conducted to study the effect of intermittent feeding on performance and the efficacy of an exogenous phytase, and to assess whether intermittent feeding changed the activity pattern of broiler chickens. 2. Broiler chickens were given, either ad libitum or intermittently, a phosphorus deficient pelleted diet containing either coarsely or finely ground oat hulls and either no enzyme or a phytase added from 10 d of age, in a 2 * 2 * 2 factorial arrangement. Ad libitum feeding consisted of continuous access to feed in a room with 18 h of light and 6 h of complete darkness, whereas birds on intermittent feeding had restricted access to feed from 7 d of age, with 4 1-h feeding bouts/d and one 2-h feeding bout/d from d 14. 3. Performance, characteristics of the anterior digestive tract and phosphorus retention were assessed in experiment 1, while in experiment 2, birds were observed during 4-h periods to quantify different behaviours. 4. Intermittent feeding and phytase improved performance, but intermittent feeding did not improve the efficacy of the enzyme added. Ad libitum fed broiler chickens ate and drank on average twice per hour, and spent close to three-quarters of their time resting. Apart from an increased standing and feed searching activity for intermittently fed birds compared to ad libitum fed birds during the last hour before feed was presented, no differences in activity was detected. 5. It was concluded that broiler chickens quickly adapt to intermittent feeding without reduction in final body weight and with improvements in feed efficiency, but without improving the efficacy of dietary phytase. Only small changes occur in the behaviour of intermittently fed birds compared to ad libitum fed birds. PMID- 23647187 TI - Effects of dietary rosemary and oregano volatile oil mixture on quail performance, egg traits and egg oxidative stability. AB - 1. This study was conducted to determine the effects of volatile oil mixture on quail laying performance, egg traits and egg malondialdehyde (MDA) concentration. 2. A total of 260 Pharaoh quails (Coturnix coturnix Pharaoh) aged 6 weeks were equally divided into 5 groups of 65 (4 replicates of 13 quails each). The mixture of diets was as follows: a control treatment with 0 mg volatile oil/kg of diet; (1) 200 mg/kg rosemary volatile oil; (2) 200 mg/kg oregano volatile oil; (3) 40 mg/kg rosemary volatile oil plus 160 mg/kg oregano volatile oil (ratio 20:80) and (4) 160 mg/kg rosemary volatile oil plus 40 mg/kg oregano volatile oil (ratio 80:20). The diets were prepared fresh for each treatment. The experimental period lasted 10 weeks. 3. At the end of the experiment, there were no significant differences amongst the groups in body weight, egg weight, egg mass, egg shape index, Haugh unit, egg shell thickness or egg shell-breaking strength. 4. Diets containing rosemary volatile oil increased the egg production significantly. Feed intake significantly increased in the groups containing volatile oil mixture (groups 4 and 5). The inclusion of rosemary volatile oil at 200 mg/kg improved feed efficiency. 5. Egg albumen and egg yolk index values showed significant increases in the group given diets containing rosemary volatile oil. Egg yolk colour became darker with the addition of rosemary and oregano volatile oil. The treatment group had lower egg yolk MDA concentration than the control group. 6. It is concluded that, alone or in combination, rosemary and oregano volatile oil can be used in quail diets without adverse effects on the measured parameters. Inclusion of rosemary and oregano volatile oil in quail diets enhanced the antioxidant status of eggs. PMID- 23647188 TI - Comparison of gene expression profiles of the jejunum of broilers supplemented with a yeast cell wall-derived mannan oligosaccharide versus bacitractin methylene disalicylate. AB - 1. The addition of yeast cell wall (YCW) mannan fractions or low concentrations of antibiotics to the diet of broilers positively affects gut health by improving intestinal cell morphology and improves feed efficiency and performance; however the exact mechanisms are unclear. Based on these production responses, the objective of this study was to compare the effects of supplementing YCW and bacitracin methylene disalicylate (BMD) in the diet on mRNA levels in the jejunum of 6-week-old broilers. 2. Dietary treatments were a maize-soya control diet and the control diet with the addition of YCW or BMD. Birds (n = 7) from each dietary treatment were randomly selected and killed at d 42. Whole jejunum (with serosa) samples were collected for RNA isolation. Gene expression analysis was performed using the AffymetrixGeneChip Chicken Genome Array (Santa Clara, CA, USA). 3. Supplementation with YCW resulted in 928 genes that were significantly changed (456 down-regulated, 472 up-regulated) and supplementation with BMD resulted in 857 genes that significantly changed (408 down-regulated, 449 up-regulated). In addition, 316 genes were significantly changed by both YCW and BMD (146 down regulated, 170 up-regulated). 4. BMD increased the expression of genes involved in lipid and carbohydrate metabolism and decreased expression of genes associated with T-helper cell pathways. Gene expression profiles from birds fed on diets containing YCW showed changes on a genomic level that correspond to slower gut cell turnover and therefore increased energy preservation for growth. 5. In conclusion, supplementation with BMD or YCW had similar influences on the number of differentially expressed genes in the jejunum. Biological functions common to both YCW and BMD with positive activation scores included antiviral response and antimicrobial response. Genes that were affected by BMD or YCW classified into both different and common biological functions and pathways related to improved metabolism and health in the jejunum. PMID- 23647189 TI - Immune-modulatory effects of dietary Saccharomyces cerevisiae cell wall in broiler chickens inoculated with Escherichia coli lipopolysaccharide. AB - 1. An experiment was conducted to study the effect of yeast (Saccharomyces cerevisiae) cell wall (YCW) supplemented in diets of broiler chickens challenged with Escherichia coli lipopolysaccharide (LPS). 2. One-day-old broiler chicks were randomly distributed into 24 cages (6 replicate cages; 8 birds/cage) and were inoculated with 0 or 1 mg/kg body weight E. coli-LPS (d 4 and 9) and 0 or 500 mg YCW/kg feed, resulting in a 2 * 2 factorial arrangement of treatments. Experimental diets did not include coccidiostats, in-feed antibiotics or enzymes. 3. On d 21, the inoculation of E. coli-LPS reduced weight gain and feed intake and increased feed conversion ratio (FCR) of birds, an effect maintained until 28 d. In contrast, chickens given diets with YCW improved the FCR at both 21 and 28 d of age. 4. E. coli-LPS challenge reduced the relative weight of bursa of Fabricius, except when chickens were given YCW, which resulted in an interaction. Supplementation of broiler diets with YCW exacerbated the cellular immune response as measured by the delayed cutaneous hypersensitivity response test. 5. The results of this study suggested a benefit on feed efficiency when YCW was added to diets fed to broiler chickens challenged with E. coli-LPS. Part of the mode of action of YCW might be related to better maintenance of immune status in response to microbial challenge. PMID- 23647190 TI - The phytoestrogen daidzein may affect reproductive performance of Zhedong White geese by regulating gene mRNA levels in the HPG axis. AB - 1. The effect of daidzein, a naturally occurring phytoestrogen, on the reproductive performance of 120 female Zhedong White geese was determined. The geese were divided into 4 groups which were fed on diets containing 0 (Control), 10 (Da1), 20 (Da2) and 30 (Da3) mg daidzein per kg diet. Egg production and weight, fertility and hatchability rates, concentrations of estradiol (E2), triiodothyronine (T3), progesterone (P4), thyroxine (T4) and growth hormone (GH) in serum, and mRNA levels of gonadotropin releasing hormone (GnRH), beta-follicle stimulating hormone (FSHbeta), follicle stimulating hormone receptor (FSHR), oestrogen receptor1 (ESR1), oestrogen receptor2 (ESR2), prolactin (PRL), prolactin receptor (PRLR), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the hypothalamus-pituitary-gonadal axis (HPGA) were measured. 2. Daidzein increased egg weight and fertility but had no detectable effect on egg production and hatchability. 3. Daidzein affected serum P4 and GH concentrations and T4 rhythm, up-regulated GnRH mRNA and PRLR mRNA levels in the hypothalamus, down regulated PRLR mRNA in the hypothalamus, PRL mRNA in the pituitary, and ESR2 mRNA levels in the ovary, respectively. The mRNA rhythms of PRLR in the hypothalamus, PRL, PRLR and FSHbeta in the pituitary, FSHR, ESR1 and ESR2 in the ovary were significantly changed in the Da2 group. 4. It is suggested that an appropriate dose of daidzein might improve reproductive performance by affecting serum hormone concentrations and rhythms and regulating gene mRNA levels in the HPGA of female Zhedong White geese. PMID- 23647191 TI - In vitro initiation of the acrosome reaction in the emu (Dromaius novaehollandiae). AB - 1. An assessment of the efficiency of the acrosome reaction (AR) provides an important predictor of the fertilizing potential of semen and for diagnosis of the causes of infertility. A standardized protocol was therefore developed for initiation of the acrosome reaction in emu spermatozoa in vitro, and the role of CaCl2 or perivitelline membrane (PVM) proteins in determining the outcome of the reaction was investigated. 2. The acrosome reaction (assessed by FITC-PNA) was successfully induced in live spermatozoa by incubation for 2 min in NaCl-TES medium supplemented with 5 mM CaCl2. The maximum response was 32% live acrosome reacted spermatozoa (LAR) achieved after 10 min incubation. 3. Compared to the outcome with 5 mM CaCl2 or PVM protein alone, the response was significantly better with a combination of PVM protein and CaCl2. 4. A significant variation in the percentage of LAR spermatozoa among individual males was observed. No treatment affected the percentage of dead acrosome-reacted spermatozoa. 5. The results emphasize the important role played by both PVM proteins and Ca(2+) in the in vitro initiation of the acrosome reaction. PMID- 23647192 TI - Comparisons of egg quality traits, egg weight loss and hatchability between striped and normal duck eggs. AB - 1. The egg quality of striped and normal duck eggs was compared to determine why striped eggs show decreased hatchability. A total of 430 eggs, obtained from a Pekin duck breeder flock aged 50-65 wks, were used in three experiments. The eggs were weighed and assigned randomly to measure egg quality traits, egg weight (EW) loss and hatchability during incubation. 2. There were no significant differences between egg types in terms of egg shape index, eggshell strength and thickness, albumen height, Haugh unit, yolk colour, weight of the eggshell with or without membranes, calcium, phosphorus, copper and manganese contents in the eggshell (with the inner and outer membranes or without the inner membrane), albumen weight, dry matter of albumen, crude protein (CP) of thick albumen and pH of the thick albumen. 3. The weight of eggshells with membranes, weight of thick albumen and CP of thin albumen in striped eggs were lower than those in normal eggs. 4. The thin albumen in striped eggs was heavier than that in normal eggs. The pH of the thin albumin in striped egg was significantly higher than that in normal eggs. 5. There were no significant differences in EW loss during incubation or duckling weight between striped and normal eggs. However, the hatchability of striped eggs was lower. 6. The lower weight of the eggshell inner membrane and thick albumen, lower CP content and higher pH in the thin albumen of striped eggs might contribute to lower hatchability. PMID- 23647193 TI - Plumping fluid added to storage medium increases twofold the functional life span of fowl spermatozoa in vitro at 4 degrees C. AB - 1. The objective of this study was to examine whether addition of plumping fluid (PF) to Lake's solution (LS) for storage of fowl spermatozoa in vitro at 4 degrees C can prolong survival and improve the quality of spermatozoa. 2. In experiment 1, aliquots of spermatozoa were stored in vitro in LS alone and LS containing 10%, 25%, 50% and 75% (v:v) PF for 0.5, 24, 48, 72, 96 and 120 h at 4 degrees C. After the end of each storage period, spermatozoa were evaluated for their viability, mobility and penetrability. Viability was determined using SYBR 14 and propidium iodide (PI) staining. Mobility was assessed using an Accudenz assay. Penetrability was assessed using spermatozoa-inner perivitelline layer (IPL) interaction assay. 3. In experiment 2, aliquots of spermatozoa were stored in vitro in LS alone and LS containing 25% and 50% (v:v) PF for 0.5, 24, 48 and 72 h at 4 degrees C, and then fertility of the spermatozoa was evaluated using intravaginal artificial insemination (AI) in hens. 4. Storage of spermatozoa in LS alone resulted in loss of viability, mobility, penetrability and fertility within 48 h. In contrast, no loss of viability and penetrability was observed for the spermatozoa stored for 48, 96, 72 and 48 h in LS containing 10%, 25%, 50% and 75% (v:v) PF, respectively. In particular, fertilising capacity was not lost for the spermatozoa stored in the presence of 25% or 50% PF in LS for 48 and 24 h, respectively. 5. In conclusion, these findings demonstrated that in vitro exposure of fowl spermatozoa to PF during hypothermic storage in LS prolonged spermatozoa survival. A 25% (v:v) level of inclusion of PF in LS may be effective for the improvement of viability, penetrability and fertilising ability of the stored spermatozoa. PMID- 23647194 TI - Time-frequency mapping of the rhythmic limb movements distinguishes convulsive epileptic from psychogenic nonepileptic seizures. AB - PURPOSE: A definite diagnosis of psychogenic nonepileptic seizures (PNES) usually requires in-patient video-electroencephalography (EEG) monitoring. Previous research has shown that convulsive psychogenic nonepileptic seizures (PNES) demonstrate a characteristic pattern of rhythmic movement artifact on the EEG. Herein we sought to examine the potential for time-frequency mapping of data from a movement-recording device (accelerometer) worn on the wrist as a diagnostic tool to differentiate between convulsive epileptic seizures and PNES. METHODS: Time-frequency mapping was performed on accelerometer traces obtained during 56 convulsive seizure-like events from 35 patients recorded during in-patient video EEG monitoring. Twenty-six patients had PNES, eight had epileptic seizures, and one had both seizure types. The time-frequency maps were derived from fast Fourier transformations to determine the dominant frequency for sequential 2.56-s blocks for the course of each event. KEY FINDINGS: The coefficient of variation (CoV) of limb movement frequency for the PNES events was less than for the epileptic seizure events (median, 17.18% vs. 52.23%; p < 0.001). A blinded review of the time-frequency maps by an epileptologist was accurate in differentiating between the event types, that is, 38 (92.7%) of 41 and 6 (75%) of 8 nonepileptic and epileptic seizures, respectively, were diagnosed correctly, with seven events classified as "nondiagnostic." Using a CoV cutoff score of 32% resulted in similar classification accuracy, with 42 (93%) of 45 PNES and 10 (91%) of 11 epileptic seizure events correctly diagnosed. SIGNIFICANCE: Time-frequency analysis of data from a wristband movement monitor could be utilized as a diagnostic tool to differentiate between epileptic and nonepileptic convulsive seizure-like events. PMID- 23647196 TI - Superhydrophobic surfaces engineered using diatomaceous earth. AB - We present a simple method to prepare superhydrophobic surfaces using siliceous exoskeleton of diatoms, a widespread group of algae. This makes diatomaceous earth an accessible and cheap natural material. A micro/nanoscale hierarchical topography was achieved by coating a glass surface with diatomaceous earth, giving rise to a superhydrophilic surface. Superhydrophobic surfaces were obtained by a further surface chemical modification through fluorosilanization. The wettability of the superhydrophobic surface can be modified by Argon plasma treatment in a controlled way by exposure time variation. The chemical surface modification by fluorosilanization and posterior fluorinated SH surface modification by plasma treatment was analyzed by XPS. Using appropriated hollowed masks only specific areas on the surface were exposed to plasma permitting to pattern hydrophilic features with different geometries on the superhydrophobic surface. We showed that the present strategy can be also applied in other substrates, including thermoplastics, enlarging the potential applicability of the resulting surfaces. PMID- 23647195 TI - Diethylmaleate and iodoacetate in combination caused profound cell death in astrocytes. AB - Energy failure and oxidative stress have been implicated in the pathogenesis of ischemia. Here, we report a potential link between cytosolic phospholipase A2 (cPLA2) activation and energy failure/oxidative stress-induced astrocyte damage involving reactive oxygen species (ROS), protein kinase C-alpha (PKC-alpha), Src, Raf, and extracellular signal-regulated kinase (ERK) signaling and concurrent elevation of endogenous chelatable zinc. Energy failure and oxidative stress were produced by treating astrocytes with glycolytic inhibitor iodoacetate and glutathione chelator diethylmaleate, respectively. Diethylmaleate and iodoacetate in combination caused augmented damage to astrocytes in a time- and concentration dependent manner. The cell death caused by diethylmaleate/iodoacetate was accompanied by increased ROS generation, PKC-alpha membrane translocation, Src, Raf, ERK, and cPLA2 phosphorylation. Pharmacological studies revealed that these activations all contributed to diethylmaleate/iodoacetate-induced astrocyte death. Intriguingly, the mobilization of endogenous chelatable zinc was observed in diethylmaleate/iodoacetate-treated astrocytes. Zinc appears to act as a downstream mediator in response to diethylmaleate/iodoacetate treatment because of the attenuating effects of its chelator N,N,N',N'-tetrakis(2 pyridylmethyl)ethylenediamine. These observations indicate that ROS/PKC-alpha, Src/Raf/ERK signaling and cPLA2 are active participants in diethylmaleate/iodoacetate-induced astrocyte death and contribute to a vicious cycle between the depletion of ATP/glutathione and the mobilization of chelatable zinc as critical upstream effectors in initiating cytotoxic cascades. PMID- 23647197 TI - Establishment of odontoblastic cells, which indicate odontoblast features both in vivo and in vitro. AB - Tooth tissue engineering offers very attractive perspectives for elaboration of regenerative treatments, which enables to cure tooth loss and restore quality of life of the patients. To elaborate such treatment, isolation and culture of dental pulp cell must be achieved as a key element. In this article, we report the establishment of a stable cell line from GFP transgenic rat dental pulp, named TGC (Tooth Matrix-forming, GFP Rat-derived Cell). TGCs have exhibited odontoblastic feature both in vitro and in vivo. In vitro, TGC exposed to osteogenic medium demonstrated collagen fiber synthesis with matrix vesicle and mineralization and formed a sheet-like substrate on the cell culture dish. Increased ALP activity and elevated transcription level of various genes involved in calcification and dentin formation were also observed. In vivo, transplanted TGC in SCID mice with beta-TCP particles formed dentin-like and pulp-like structure with lining odontoblast. Notably, even after up to 80 passages, TGCs retain their morphological features and differentiation ability. To our knowledge, this is the first report of a dental pulp-derived cell with such stable odontoblastic characteristics. TGC could be a very useful model for further study on dental pulp cell. PMID- 23647198 TI - Time scales for gas-particle partitioning equilibration of secondary organic aerosol formed from alpha-pinene ozonolysis. AB - Most chemical transport models assume instantaneous equilibrium to represent gas particle partitioning of semivolatile organic aerosol. This approach has been challenged by recent studies suggesting that secondary organic aerosol (SOA) cannot reach equilibrium within atmospheric time scales. The emergent hypothesis is that gas-particle partitioning rates are limited by diffusion within the condensed phase, which is thought to be "glassy." Here, we investigate the equilibration time scales of SOA formed from alpha-pinene ozonolysis by measuring the dynamic response to a modest step-change in temperature. Upon heating, equilibrium is disturbed, and the particles evaporate to restore equilibrium at the new temperature, which is attained when evaporation ceases. The SOA was formed at 10 degrees C and then heated to near room temperature (30 degrees C) so that the phase state (viscosity) of the condensed-phase after heating is similar to how it would be in the atmosphere. Experiments were performed in both a thermodenuder, with SOA loading of 350 MUg/m(3), and in a smog chamber, with SOA loading of 2-12 MUg/m(3). Both experiments show, contrary to previous findings, that the SOA achieves equilibrium with dynamic responses consistent with a mass accommodation coefficient of order 0.1. For typical atmospheric conditions, this translates into equilibration time scales on the order of minutes to tens of minutes, supporting the use of equilibrium partitioning in chemical transport models. PMID- 23647199 TI - Coherent and broadband enhanced optical absorption in graphene. AB - We experimentally demonstrate a broadband enhancement of the light absorption in graphene over the whole visible spectrum. This enhanced absorption is obtained in a multilayer structure by using an Attenuated Total Reflectance (ATR) configuration and it is explained in terms of coherent absorption arising from interference and dissipation. The interference mechanism leading to the phenomenon of coherent absorption allows for its precise control by varying the refractive index and/or thickness of the medium surrounding the graphene. PMID- 23647202 TI - Vulnerability and resilience. PMID- 23647200 TI - Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two-state and operational models. AB - Two-state and operational models of both agonism and allosterism are compared to identify and characterize common pharmacological parameters. To account for the receptor-dependent basal response, constitutive receptor activity is considered in the operational models. By arranging two-state models as the fraction of active receptors and operational models as the fractional response relative to the maximum effect of the system, a one-by-one correspondence between parameters is found. The comparative analysis allows a better understanding of complex allosteric interactions. In particular, the inclusion of constitutive receptor activity in the operational model of allosterism allows the characterization of modulators able to lower the basal response of the system; that is, allosteric modulators with negative intrinsic efficacy. Theoretical simulations and overall goodness of fit of the models to simulated data suggest that it is feasible to apply the models to experimental data and constitute one step forward in receptor theory formalism. PMID- 23647203 TI - Response. PMID- 23647204 TI - Response to "The necessity for longitudinal studies in risk perception research". PMID- 23647205 TI - Identification of host proteins involved in Japanese encephalitis virus infection by quantitative proteomics analysis. AB - Japanese encephalitis virus (JEV) enters host cells via receptor-mediated endocytosis and replicates in the cytoplasm of infected cells. To study virus host cell interactions, we performed a SILAC-based quantitative proteomics study of JEV-infected HeLa cells using a subcellular fractionation strategy. We identified 158 host proteins as differentially regulated by JEV (defined as exhibiting a greater than 1.5-fold change in protein abundance upon JEV infection). The mass spectrometry quantitation data for selected proteins were validated by Western blot and immunofluorescence confocal microscopy. Bioinformatics analyses were used to generate JEV-regulated host response networks consisting of regulated proteins, which included 35 proteins that were newly added based on the results of this study. The JEV infection-induced host response was found to be coordinated primarily through the immune response process, the ubiquitin-proteasome system (UPS), the intracellular membrane system, and lipid metabolism-related proteins. Protein functional studies of selected host proteins using RNA interference-based techniques were carried out in HeLa cells infected with an attenuated or a highly virulent strain of JEV. We demonstrated that the knockdown of interferon-induced transmembrane protein 3 (IFITM3), Ran-binding protein 2 (RANBP2), sterile alpha motif domain-containing protein 9 (SAMD9) and vesicle-associated membrane protein 8 (VAMP8) significantly increased JEV replication. The results presented here not only promote a better understanding of the host response to JEV infection but also highlight multiple potential targets for the development of antiviral agents. PMID- 23647206 TI - Survival rate of antitumour necrosis factor-alpha treatments for psoriasis in routine dermatological practice: a multicentre observational study. AB - BACKGROUND: Adherence is an overall marker of treatment success, and it depends on multiple factors including efficacy and safety. Despite the wide use of tumour necrosis factor (TNF)-alpha blockers in the treatment of plaque-type psoriasis, few data regarding treatment adherence in routine clinical practice are available. OBJECTIVES: To estimate the long-term survival rate of anti-TNF-alpha therapy in a cohort of patients with psoriasis in routine clinical practice; to evaluate the reasons for and predictors of treatment discontinuation. METHODS: The Outcome and Survival rate Concerning Anti-TNF Routine treatment (OSCAR) study was based on a retrospective analysis to estimate the long-term survival rate of the first anti-TNF-alpha treatment in patients with psoriasis, from three Italian academic referral centres. Adult patients (n = 650) with plaque psoriasis treated with a first course of adalimumab, etanercept or infliximab for >= 3 months were included. RESULTS: Global adherence to anti-TNF-alpha treatments after 28.9 +/- 15.4 months (867 +/- 462 days) of observation was 72.6%. Etanercept showed a longer survival (mean 51.4 months, 1565 days; P < 0.001) compared with infliximab (36.8 months, 1120 days) and adalimumab (34.7 months, 1056 days). Treatment discontinuation due to primary and secondary inefficacy was observed in 5.2% and 14.5% of patients, respectively, whereas discontinuation due to adverse events was reported in 29 subjects (4.5%). Independent predictors of treatment withdrawal were female gender [hazards ratio (HR) 1.3], treatment with adalimumab or infliximab compared with etanercept (HR 2.7 and 1.7, respectively), and the concomitant use of traditional systemic treatment, as a rescue therapy, compared with monotherapy (HR 1.9). CONCLUSIONS: Overall survival of anti-TNF-alpha agents in psoriasis is elevated, with drug discontinuation mostly due to inefficacy. Etanercept showed a longer adherence compared with adalimumab and infliximab. PMID- 23647207 TI - The current status of the use of palonosetron. AB - Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in the quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. Palonosetron, a second-generation 5-hydroxytryptamine 3 (5 HT3) receptor antagonist, has antiemetic activity at both central and gastrointestinal sites. In comparison to the first-generation 5-HT3 receptor antagonists, it has a higher potency, a significantly longer half-life, and a different molecular interaction with 5-HT3 receptors. Palonosetron has been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. Compared to the first generation 5-HT3 receptor antagonists, palonosetron in combination with dexamethasone has demonstrated better control of delayed CINV in patients receiving highly emetogenic chemotherapy and had a similar safety profile. Due to its efficacy in controlling both acute and delayed CINV, palonosetron may be very effective in the clinical settings of multiple-day chemotherapy and bone marrow transplantation. PMID- 23647208 TI - The relational antecedents of voice targeted at different leaders. AB - We investigated how employees can, simultaneously, speak up to leaders at different levels of the organizational hierarchy. In particular, we examined 2 targets of employees' upward voice on work-related issues: the direct leader (i.e., the supervisor) and the skip-level leader (i.e., supervisor's boss). Drawing on emerging research on the socially embedded nature of leader-member exchanges and using data from 237 employees and their direct and skip-level leaders, we found that the choice of a particular leader as a target was affected by the quality of the dyadic relationship between that leader and the employee. Further, the association between voice to the direct leader and the quality of the employee's relationship with the direct leader was more positive when the relationship between the direct leader and the skip-level leader was stronger. By contrast, the association between voice to the skip-level leader and the quality of the employee's relationship with the skip-level leader was more positive when the relationship between the direct leader and the skip-level leader was weaker. The implications of these findings are discussed. PMID- 23647209 TI - Joint influences of individual and work unit abusive supervision on ethical intentions and behaviors: a moderated mediation model. AB - We develop and test a model based on social cognitive theory (Bandura, 1991) that links abusive supervision to followers' ethical intentions and behaviors. Results from a sample of 2,572 military members show that abusive supervision was negatively related to followers' moral courage and their identification with the organization's core values. In addition, work unit contexts with varying degrees of abusive supervision, reflected by the average level of abusive supervision reported by unit members, moderated relationships between the level of abusive supervision personally experienced by individuals and both their moral courage and their identification with organizational values. Moral courage and identification with organizational values accounted for the relationship between abusive supervision and followers' ethical intentions and unethical behaviors. These findings suggest that abusive supervision may undermine moral agency and that being personally abused is not required for abusive supervision to negatively influence ethical outcomes. PMID- 23647210 TI - Temporary site selection and decision-making methods: a case study of Tehran, Iran. AB - Decisions on selecting an appropriate site for temporary shelter used to be taken in a limited amount of time after a disaster. The need for a systematic method in this area inspired the MADM (multi-attribute decision making) for complex disaster management decisions. This research proposes a model for appropriate and systematic site selection for temporary shelters, before an earthquake, using a geographical information system and MADM based on an earthquake damage assessment. After the effective criteria for site selection of temporary shelters are determined, the geographical layers of these criteria are prepared for Municipal District No.1 of Greater Tehran, the capital of Iran. Given these attributes and the required shelter area (415-610 hectares), 14 zones are proposed initially. Various MADM methods are used for the final selection. The mean of the aggregated ranking results are determined, and 10 of the 14 initial zones are ranked. PMID- 23647211 TI - A single sample method for estimating glomerular filtration rate in cats. AB - BACKGROUND: Validated methods of estimating glomerular filtration rate (GFR) in cats requiring only a limited number of samples are desirable. HYPOTHESIS/OBJECTIVES: To test a single sample method of determining GFR in cats. ANIMALS: The validation population (group 1) consisted of 89 client-owned cats (73 nonazotemic and 16 azotemic). A separate population of 18 healthy nonazotemic cats (group 2) was used to test the methods. METHODS: Glomerular filtration rate was determined in group 1 using corrected slope-intercept iohexol clearance. Single sample clearance was determined using the Jacobsson and modified Jacobsson methods and validated against slope-intercept clearance. Extracellular fluid volume (ECFV) was determined from slope-intercept clearance with correction for the 1 compartment assumption and by deriving a prediction formula for ECFV (ECFV Predicted ) based on the body weight. The optimal single sample method was tested in group 2. RESULTS: A blood sample at 180 minutes and ECFV Predicted were optimal for single sample clearance. Mean +/- SD GFR in group 1 determined using the Jacobsson and modified Jacobsson formulae was 1.78 +/- 0.70 and 1.65 +/- 0.60 mL/min/kg, respectively. When tested in group 2, the Jacobsson method overestimated multisample clearance. The modified Jacobsson method (mean +/- SD 2.22 +/- 0.34 mL/min/kg) was in agreement with multisample clearance (mean +/- SD 2.19 +/- 0.34 mL/min/kg). CONCLUSIONS AND CLINICAL IMPORTANCE: The modified Jacobsson method provides accurate estimation of iohexol clearance in cats, from a single sample collected at 180 minutes postinjection and using a formula based on the body weight to predict ECFV. Further validation of the formula in patients with very high or very low GFR is required. PMID- 23647212 TI - Study of the mode and efficiency of DNA binding in the damage induced by photoactivated water soluble porphyrins. AB - We have investigated the DNA binding interactions and in vitro photoactivated DNA damage induced by a neutral water soluble porphyrin derivative 5,10,15,20 tetrakis(2,4,6-trihydroxyphenyl)porphyrin (TTHPP) and its zinc derivative 5,10,15,20-tetrakis(2,4,6-trihydroxyphenyl)porphyrinato zinc(II) (Zn-TTHPP) upon visible light irradiation through various spectroscopic techniques and employing repair endonucleases. These porphyrin derivatives exhibited high affinity toward DNA through groove binding interactions as evidenced through the UV-vis absorption, emission, circular dichroism spectral and viscosity changes. Interestingly, the free base porphyrin derivative, TTHPP generated efficient singlet oxygen mediated DNA damage sensitive to formamidopyrimidine-DNA glycosylase (Fpg protein), when compared with its metal derivative and to the well-known photosensitizer, hematoporphyrin. These results provide direct evidence for the role of DNA binding mode as well as extent of interactions with DNA in the efficiency of photoactivated DNA damage induced by the neutral porphyrins, which are believed to be the ideal candidates for photodynamic therapeutic applications. PMID- 23647213 TI - Associations between vitamin D and self-reported respiratory disease in older people from a nationally representative population survey. AB - OBJECTIVES: To investigate the association between serum 25-hydroxy vitamin D (25(OH)D) concentrations and respiratory diseases in older people. DESIGN: Cross sectional, nationally representative sample. SETTING: Community. PARTICIPANTS: Two thousand seventy noninstitutionalized adults aged 65 and older taking part in the Health Survey for England 2005. MEASUREMENTS: Serum 25(OH)D levels, self reported long-term respiratory tract diseases, and covariates (age, sex, social class, season of examination, use of vitamin supplements, and physical health status). RESULTS: Participants with severe deficiency (25(OH)D < 35 nmol/L) had more than twice the risk of respiratory disease than those in the highest quartile of 25(OH)D status (>64 nmol/L), and those with moderate deficiency (second quartile: 25(OH)D 35-48.9 nmol/L) had 1.75 times greater odds of respiratory diseases, even after adjustment with covariates. Adjusted analysis showed that those in the third quartile (25(OH)D 49.0 to 63.9 nmol/L) also had a greater risk of respiratory disease (odds ratio = 1.63, 95% confidence interval = 1.04-2.57). CONCLUSION: Low serum 25(OH)D concentrations are associated with respiratory disease. Ensuring adequate 25(OH)D levels is of public health importance for older populations living in northern latitudes and may be an effective way to prevent concurrent respiratory infections and related complications in older people. Further studies are required to investigate whether vitamin D supplementation may reduce the incidence and exacerbations of respiratory disease. PMID- 23647214 TI - External cervical resorption: an analysis using cone beam and microfocus computed tomography and scanning electron microscopy. AB - AIM: To provide a three-dimensional representation of external cervical resorption (ECR) with microscopy, stereo microscopy, cone beam computed tomography (CT), microfocus CT and scanning electron microscopy (SEM). SUMMARY: External cervical resorption is an aggressive form of root resorption, leading to a loss of dental hard tissues. This is due to clastic action, activated by a damage of the covering cementum and stimulated probably by infection. Clinically, it is a challenging situation as it is characterized by a late symptomatology. This is due to the pericanalar protection from a resorption-resistant sheet, composed of pre-dentine and surrounding dentine. The clastic activity is often associated with an attempt to repair, seen by the formation of osteoid tissue. KEY LEARNING POINTS: Cone beam CT is extremely useful in the diagnoses and treatment planning of ECR. SEM analyses provide a better insight into the activity of osteoclasts. The root canal is surrounded by a layer of dentine that is resistant to resorption. PMID- 23647215 TI - Cytoskeleton-dependent endomembrane organization in plant cells: an emerging role for microtubules. AB - Movement of secretory organelles is a fascinating yet largely mysterious feature of eukaryotic cells. Microtubule-based endomembrane and organelle motility utilizing the motor proteins dynein and kinesin is commonplace in animal cells. In contrast, it has been long accepted that intracellular motility in plant cells is predominantly driven by myosin motors dragging organelles and endomembrane bounded cargo along actin filament bundles. Consistent with this, defects in the acto-myosin cytoskeleton compromise plant growth and development. Recent findings, however, challenge the actin-centric view of the motility of critical secretory organelles and distribution of associated protein machinery. In this review, we provide an overview of the current knowledge on actin-mediated organelle movement within the secretory pathway of plant cells, and report on recent and exciting findings that support a critical role of microtubules in plant cell development, in fine-tuning the positioning of Golgi stacks, as well as their involvement in cellulose synthesis and auxin polar transport. These emerging aspects of the biology of microtubules highlight adaptations of an ancestral machinery that plants have specifically evolved to support the functioning of the acto-myosin cytoskeleton, and mark new trends in our global appreciation of the complexity of organelle movement within the plant secretory pathway. PMID- 23647217 TI - Which optimal protein intake in maintenance dialysis patients? PMID- 23647218 TI - Examination with next-generation sequencing technology of the bacterial microbiota in bronchoalveolar lavage samples after traumatic injury. AB - BACKGROUND: We examined the microbiota of bronchoalveolar lavage (BAL) samples with next-generation sequencing (NGS) technology to determine whether its results correlate with those of standard culture methods or affect patient outcome or both. METHODS: We collected BAL samples in the surgical intensive care unit (SICU) as part of the standard of care for intubated individuals who had a Clinical Pulmonary Infection Score (CPIS)>=6 points. A portion of the BAL fluid was sequenced for the 16S region of ribosomal deoxyribonucleic acid (rDNA) with the Roche 454 FLX Titanium sequencer. Sequences were analyzed through a data analysis pipeline to identify the appropriate taxonomic designation (~species) of each 16s sequence. The bacterial microbiota of each BAL sample was compared with the bacteria identified in the sample through standard culture methods. Correlations between the taxonomic diversity of the microbiota and clinical outcome were examined through linear regression and Pearson correlation. RESULTS: Bronchoalveolar lavage samples from 12 individuals in the SICU who had a CPIS>=6 points were examined through 454 pyrosequencing. The number of phylotypes (~species) in the samples ranged from 15 to 129. The number of phyla in the BAL samples ranged from 3 to 14. There was little correlation between the bacteria identified by NGS and those identified with standard culture methods. The same predominant bacterial strain was identified by both culture and sequencing in only a single sample. The correlation between patient days on a ventilator and the number of species in BAL samples was significant (r=0.7435, p=0.0056; r2=0.5528). CONCLUSIONS: Increasing diversity of the bacterial microbiota in BAL samples correlates with the duration of mechanical ventilation. Bacteria identified through standard culture methods were not well correlated with the findings of NGS. PMID- 23647219 TI - Initial outcome after selective intraarterial radionuclide therapy with yttrium 90 microspheres as salvage therapy for unresectable metastatic liver disease. AB - PURPOSE: The aim of the study was to retrospectively evaluate the potential benefit on survival outcomes of selective intraarterial radionuclide therapy (SIRT) with Yttrium-90 microspheres as a salvage therapy in liver metastasis of different tumors. MATERIAL AND METHODS: Sixty-one patients who had unresectable liver metastases from colorectal carcinoma (n=23), neuroendocrine tumor (NET; n=12), cholangiocarcinoma (n=9), and others (n=17) received yttrium-90 microspheres. All patients were treated in a salvage setting with an 11-month mean follow-up. Early metabolic treatment response was evaluated by 18F Fluorodeoxyglucose positron emission tomography (FDG PET-CT) in the sixth week after treatment. RESULTS: Of the 61 patients, 32 were alive at the end of the study; median overall survival (OS) was 17.0 +/- 2.5 months (95% confidence interval: 11.9-22.0). A subset analysis of colorectal and noncolorectal groups demonstrated median OS rates of 14.0 +/- 5.8 and 17.0 +/- 4.8 months, respectively (p=0.543). The mean OS for patients with NET and cholangiocarcinoma was 29.0 +/- 3.1 months and 17.7 +/- 3.2 months, respectively (p=0.010). According to the early metabolic treatment response, the mean OS of responder and nonresponder groups was 32.0 +/- 5.6 months and 11.4 +/- 2.1 months, respectively (p=0.054). Eastern Cooperative Oncology Group performance status <1 (p=0.018) and chemotherapy-naive patients (p=0.008) showed significant correlation with survival. CONCLUSION: SIRT is an effective treatment option for patients with metastatic liver disease in a salvage setting with acceptable toxicity. PMID- 23647220 TI - Epilepsy informatics and an ontology-driven infrastructure for large database research and patient care in epilepsy. AB - The epilepsy community increasingly recognizes the need for a modern classification system that can also be easily integrated with effective informatics tools. The 2010 reports by the United States President's Council of Advisors on Science and Technology (PCAST) identified informatics as a critical resource to improve quality of patient care, drive clinical research, and reduce the cost of health services. An effective informatics infrastructure for epilepsy, which is underpinned by a formal knowledge model or ontology, can leverage an ever increasing amount of multimodal data to improve (1) clinical decision support, (2) access to information for patients and their families, (3) easier data sharing, and (4) accelerate secondary use of clinical data. Modeling the recommendations of the International League Against Epilepsy (ILAE) classification system in the form of an epilepsy domain ontology is essential for consistent use of terminology in a variety of applications, including electronic health records systems and clinical applications. In this review, we discuss the data management issues in epilepsy and explore the benefits of an ontology-driven informatics infrastructure and its role in adoption of a "data-driven" paradigm in epilepsy research. PMID- 23647221 TI - Influence of Implant transmucosal design on early peri-implant tissue responses in beagle dogs. AB - OBJECTIVES: This study was undertaken to evaluate the influences of concave, machined and concave-roughened profiles of transmucosal implant designs on early peri-implant tissue responses. MATERIALS AND METHODS: Implants were used and classified by transmucosal profile and surface type as straight-machined implants (SM), concave-machined implants (CM), or concave-roughened implants (CR). A total of 30 implants (10 per each type) with matching transmucosal profiles were placed directly on alveolar crests in randomized order in the edentulous mandibular ridges of three beagle dogs. Healing abutments were connected 4 weeks after implant placement, and prostheses were connected 8 weeks after implant placement and functionally loaded. All animals were sacrificed at 16 weeks. Peri-apical radiographs were obtained and measured to evaluate peri-implant marginal bone levels. Histological specimens were prepared to measure bone resorption, connective tissue contact, epithelial tissue height, biological width, and length of implant-abutment junction to the apical portion of junctional epithelium. RESULTS: Radiographic and histometric analysis showed that least bone resorption occurred around CM implants and greatest bone resorption around SM implants (P < 0.05). Histometric analysis showed that highest connective tissue attachment and shortest biological width had formed around CM implants. CONCLUSION: Concave machined profiled implants with a transmucosal design may induce less bone resorption and better connective tissue attachment around implants than the straight-machined profiled implants during the early healing phase. PMID- 23647222 TI - The mood stabilizer valproate activates human FGF1 gene promoter through inhibiting HDAC and GSK-3 activities. AB - Valproic acid (VPA) is the primary mood-stabilizing drug to exert neuroprotective effects and to treat bipolar disorder in clinic. Fibroblast growth factor 1 (FGF1) has been shown to regulate cell proliferation, cell division, and neurogenesis. Human FGF1 gene 1B promoter (-540 to +31)-driven green fluorescence (F1BGFP) has been shown to recapitulate endogenous FGF1 gene expression and facilitates the isolation of neural stem/progenitor cells (NSPCs) from developing and adult mouse brains. In this study, we provide several lines of evidence to demonstrate the underlying mechanisms of VPA in activating FGF-1B promoter activity: (i) VPA significantly increased the FGF-1B mRNA expression and the percentage of F1BGFP(+) cells; (ii) the increase of F1BGFP expression by VPA involves changes of regulatory factor X (RFX) 1-3 transcriptional complexes and the increase of histone H3 acetylation on the 18-bp cis-element of FGF-1B promoter; (iii) treatments of other histone deacetylases (HDAC) inhibitors, sodium butyrate and trichostatin A, significantly increased the expression levels of FGF-1B, RFX2, and RFX3 transcripts; (iv) treatments of glycogen synthase kinase 3 (GSK-3) inhibitor, lithium, or GSK-3 siRNAs also significantly activated FGF-1B promoter; (v) VPA specifically enhanced neuronal differentiation in F1BGFP(+) embryonic stem cells and NSPCs rather than GFP(-) cells. This study suggested, for the first time, that VPA activates human FGF1 gene promoter through inhibiting HDAC and GSK-3 activities. PMID- 23647224 TI - Flexible asymmetric supercapacitors based upon Co9S8 nanorod//Co3O4@RuO2 nanosheet arrays on carbon cloth. AB - We have successfully fabricated flexible asymmetric supercapacitors (ASCs) based on acicular Co9S8 nanorod arrays as positive materials and Co3O4@RuO2 nanosheet arrays as negative materials on woven carbon fabrics. Co9S8 nanorod arrays were synthesized by a hydrothermal sulfuration treatment of acicular Co3O4 nanorod arrays, while the RuO2 was directly deposited on the Co3O4 nanorod arrays. Carbon cloth was selected as both the substrate and the current collector for its good conductivity, high flexibility, good physical strength, and lightweight architecture. Both aqueous KOH solutions and polyvinyl alcohol (PVA)/KOH were employed as electrolyte for electrochemical measurements. The as-fabricated ASCs can be cycled reversibly in the range of 0-1.6 V and exhibit superior electrochemical performance with an energy density of 1.21 mWh/cm(3) at a power density of 13.29 W/cm(3) in aqueous electrolyte and an energy density of 1.44 mWh/cm(3) at the power density of 0.89 W/cm(3) in solid-state electrolyte, which are almost 10-fold higher than those reported in early ASC work. Moreover, they present excellent cycling performance at multirate currents and large currents after thousands of cycles. The high-performance nanostructured ASCs have significant potential applications in portable electronics and electrical vehicles. PMID- 23647225 TI - The therapeutic goals of essential thrombocythemia under the clouds of over treatment and under-treatment. AB - INTRODUCTION: Therapeutic stratification after the accurate essential thrombocythemia (ET) diagnosis is made based on the medical history (age, previous thrombosis), clinical assessments (cardiovascular [CV] risk factors, comorbidities, systemic diseases), laboratory examinations (leukocytosis, extreme thrombocytosis, anemia) and if available further sophistical analyses (CD34 count, JAK2V617F homozygosity, and mutant allele burden). AREAS COVERED: Current conventional therapeutic tools for reaching those goals are observation, low-dose aspirin, hydroxyurea, anegrelide and interferon alpha. Those treatment modalities are used alone or in combination to get the therapeutic goals in ET patients. The ET literature search was made in PubMed with particular focus on the clinical trials, recommendations, guidelines and expert opinions. EXPERT OPINION: The most important step for the therapeutic decision of ET in the clinic is the risk assessments. Clinical decision making starts with the detection of the age and the prior thrombosis history of the ET patient. Treatment goals in ET are to avoid thrombosis and bleeding, to treat ET-related symptoms, improve quality of life and to minimize risk of malignant transformation and/or post-ET myelofibrosis. PMID- 23647223 TI - Reading angles in maps. AB - Preschool children can navigate by simple geometric maps of the environment, but the nature of the geometric relations they use in map reading remains unclear. Here, children were tested specifically on their sensitivity to angle. Forty eight children (age 47:15-53:30 months) were presented with fragments of geometric maps, in which angle sections appeared without any relevant length or distance information. Children were able to read these map fragments and compare two-dimensional to three-dimensional angles. However, this ability appeared both variable and fragile among the youngest children of the sample. These findings suggest that 4-year-old children begin to form an abstract concept of angle that applies both to two-dimensional and three-dimensional displays and that serves to interpret novel spatial symbols. PMID- 23647226 TI - Comparison of the kinetics of electron transfer in the diffusion limit for the singlet and triplet quenching of eosin Y by quinones. AB - Electron transfer (ET) rate constants were determined by means of lifetime measurements for the fluorescence quenching and by laser flash photolysis for the triplet quenching of the dye eosin Y by benzoquinones in acetonitrile. The results represent a new aspect of the dependence of the rate constants with the driving force in the diffusion limit region. That is, the rate constants for singlet quenching in the highly negative region of DeltaGet do not decrease as predicted by Marcus theory, but rather show a small positive dependence on the driving force. However, it is found that, in the same free energy range, the triplet rate constants are lower than those for the singlet process. They also increase with the exergonicity of the reaction, but the dependence with DeltaGet is less marked than that found for the singlet reaction. Even at a Gibbs energy change of -1.0 eV the triplet quenching rate constants do not reach the theoretical diffusion limit. The results are analyzed using the current theories for diffusion-mediated ET reactions. PMID- 23647227 TI - The presence of diatom algae in a tracheal wash from a German Wirehaired Pointer with aspiration pneumonia. AB - A 7-year-old spayed female German Wirehaired Pointer was presented with difficulty breathing after being found seizing in a water-filled drainage ditch while out hunting. Aspirates from a tracheal wash contained numerous degenerate neutrophils, fewer macrophages, some of which contained basophilic debris, low numbers of extracellular diatoms, and a single intracellular short bacterial rod. As the dog continued to clinically decline and could not be weaned from oxygen support, the owners chose euthanasia. The major necropsy finding was a severe granulomatous bronchopneumonia that was likely due to aspiration of foreign material based on the microscopic presence of plant-like material, bi-refringent crystalline material, non-cellular debris, and occasional fungal structures. Diatoms are a class of algae that live primarily in water. Diatom analysis has been used, with some controversy, in human forensics to assist in documenting drowning as the cause of death. In this case, given the clinical history, the presence of diatoms and inflammation in the tracheal wash were interpreted as a likely result of the aspiration of surface water. To our knowledge, this is the first reported case of diatoms observed in a cytologic specimen in a nonhuman mammal with aspiration pneumonia. PMID- 23647228 TI - Flocculation of Microcystis aeruginosa using modified larch tannin. AB - To flocculate the cyanobacterium Microcystis aeruginosa from water, larch tannin, a natural polymer, was modified by Mannich reaction to obtain a flocculant, named A-TN, which was then quaternized to yield another flocculant, named Q-TN. A-TN and Q-TN were characterized by Fourier transform infrared spectra (FTIR) and zeta potential analysis. The effects of the flocculation parameters, e.g., dosage, pH, cell density, culture time, and extracellular organic materials, were studied. The results showed that Q-TN was effective under a wider range of pH values than A-TN and could work under a pH of 9.0, whereas A-TN could work only under a pH of 7.0. For algal samples with densities from 1 * 10(8) to 5 * 10(9) cells/L, the optimum dosages of Q-TN to achieve more than 90% removal efficiency ranged from 0.5 to 20 mg/L, and the optimum dosages had a good linear relationship with cell density. Furthermore, the required dosage of Q-TN clearly increased along with the algae culture time, most of which was consumed by the extracellular organic materials (EOM) excreted from the cells. The spectra of the three-dimensional excitation-emission matrix showed that 100% of simple aromatic proteins and 78.8% of protein-like substances in the EOM could be removed by Q-TN. However, Q-TN was less effective in humic/fulvic-like substance flocculation. Q-TN functioned to settle the algae cells and a large amount of their metabolites effectively. PMID- 23647229 TI - Risk factors of polysensitization to contact allergens. AB - BACKGROUND: 'Polysensitization' (PS) is usually defined as contact sensitization to three or more unrelated haptens of the baseline patch test series. Despite PS being an important clinical phenotype indicating increased susceptibility to contact allergy, statistical approaches to analyse PS have hitherto been preliminary. OBJECTIVES: To apply an appropriate regression model for count data, namely, negative binomial hurdle regression, to a large set of clinical patch test data with the aim of estimating PS risk in more detail than previously achieved. METHODS: The detailed information provided by the hurdle model includes a separate estimation of an 'increment factor' quantifying the likelihood of further positive reactions, i.e. PS. Clinical data of 126 878 patients patch tested by departments comprising the IVDK (Information Network of Departments of Dermatology) network (www.ivdk.org) between 1995 and 2010 were included. RESULTS: Regarding anatomical sites as exposure (surrogate), the axillae and the feet were found to be strong PS risk factors. Moreover, age was a strong PS risk factor, and less so, female sex. In comparison, atopic eczema and occupational dermatitis were less important risk factors. Single allergens contributed to PS to a varying extent. CONCLUSIONS: The data presented point to some, very likely exposure related, risk factors which need to be considered in future PS research, e.g. addressing the genetic basis for PS. PMID- 23647230 TI - Structural basis for the mutation-induced dysfunction of human CYP2J2: a computational study. AB - Arachidonic acid is an essential fatty acid in cells, acting as a key inflammatory intermediate in inflammatory reactions. In cardiac tissues, CYP2J2 can adopt arachidonic acid as a major substrate to produce epoxyeicosatrienoic acids (EETs), which can protect endothelial cells from ischemic or hypoxic injuries and have been implicated in the pathogenesis of coronary artery disease and hypertension. However, some CYP2J2 polymorphisms, i.e., T143A and N404Y, significantly reduce the metabolism of arachidonic acid. Lacking experimental structural data for CYP2J2, the detailed mechanism for the mutation-induced dysfunction in the metabolism of arachidonic acid is still unknown. In the current study, three-dimensional structural models of the wild-type CYP2J2 and two mutants (T143A and N404Y) were constructed by a coordinate reconstruction approach and ab initio modeling using CYP2R1 as a template. The structural analysis of the computational models showed that the wild-type CYP2J2 exhibited a typical CYP fold with 12 alpha-helices and three beta-sheets on one side and with the heme group buried deeply inside the core. Due to the small and hydrophobic side-chain, T143A mutation could destabilize the C helix, further placing the water access channel in a closed state to prevent the escape of the produced water molecules during the catalytic processes. N404Y mutation could reposition the side-chain of Leu(378), making it no longer form a hydrogen bond with the carboxyl group of arachidonic acid. However, this hydrogen bond was essential for substrate recognition and positioning in a correct orientation. PMID- 23647231 TI - Chronic kidney disease in dogs in UK veterinary practices: prevalence, risk factors, and survival. AB - BACKGROUND: The prevalence for chronic kidney disease (CKD) in dogs varies widely (0.05-3.74%). Identified risk factors include advancing age, specific breeds, small body size, and periodontal disease. HYPOTHESIS/OBJECTIVES: To estimate the prevalence and identify risk factors associated with CKD diagnosis and survival in dogs. Purebred dogs were hypothesized to have higher CKD risk and poorer survival characteristics than crossbred dogs. ANIMALS: A merged clinical database of 107,214 dogs attending 89 UK veterinary practices over a 2-year period (January 2010-December 2011). METHODS: A longitudinal study design estimated the apparent prevalence (AP) whereas the true prevalence (TP) was estimated using Bayesian analysis. A nested case-control study design evaluated risk factors. Survival analysis used the Kaplan-Meier survival curve method and multivariable Cox proportional hazards regression modeling. RESULTS: The CKD AP was 0.21% (95% CI: 0.19-0.24%) and TP was 0.37% (95% posterior credibility interval 0.02-1.44%). Significant risk factors included increasing age, being insured, and certain breeds (Cocker Spaniel, Cavalier King Charles Spaniel). Cardiac disease was a significant comorbid disorder. Significant clinical signs included halitosis, weight loss, polyuria/polydipsia, urinary incontinence, vomiting, decreased appetite, lethargy, and diarrhea. The median survival time from diagnosis was 226 days (95% CI 112-326 days). International Renal Interest Society stage and blood urea nitrogen concentration at diagnosis were significantly associated with hazard of death due to CKD. CONCLUSIONS AND CLINICAL IMPORTANCE: Chronic kidney disease compromises dog welfare. Increased awareness of CKD risk factors and association of blood biochemistry results with survival time should facilitate diagnosis and optimize case management to improve animal survival and welfare. PMID- 23647232 TI - Can theories of animal discrimination explain perceptual learning in humans? AB - We present a review of recent studies of perceptual learning conducted with nonhuman animals. The focus of this research has been to elucidate the mechanisms by which mere exposure to a pair of similar stimuli can increase the ease with which those stimuli are discriminated. These studies establish an important role for 2 mechanisms, one involving inhibitory associations between the unique features of the stimuli, the other involving a long-term habituation process that enhances the relative salience of these features. We then examine recent work investigating equivalent perceptual learning procedures with human participants. Our aim is to determine the extent to which the phenomena exhibited by people are susceptible to explanation in terms of the mechanisms revealed by the animal studies. Although we find no evidence that associative inhibition contributes to the perceptual learning effect in humans, initial detection of unique features (those that allow discrimination between 2 similar stimuli) appears to depend on an habituation process. Once the unique features have been detected, a tendency to attend to those features and to learn about their properties enhances subsequent discrimination. We conclude that the effects obtained with humans engage mechanisms additional to those seen in animals but argue that, for the most part, these have their basis in learning processes that are common to animals and people. In a final section, we discuss some implications of this analysis of perceptual learning for other aspects of experimental psychology and consider some potential applications. PMID- 23647234 TI - Effect of several bleaching agents on teeth stained with a resin-based sealer. AB - AIM: To evaluate the effect of peroxide-based bleaching agents on teeth stained with AH26 sealer (Dentsply De Trey, Konstanz, Germany), using digital images and computer analysis. METHODOLOGY: Thirty-five maxillary central incisors were root filled, and the internal walls of the access cavity were coated with AH26 sealer. Internal bleaching commenced 4 months after the root fillings. In three experimental groups (n = 10), the teeth were bleached for 21 days using 45% carbamide peroxide (CP) gel, 45% sodium perborate + carbamide peroxide (SP + CP) or sodium perborate + distilled water (SP + W). No bleaching was undertaken in the control group. Digital images of each specimen were made before treatment, 4 months after endodontic treatment and 2 weeks after bleaching. Colour differences (?E) were calculated by determining L*a*b* values using digital images and imaging software. Differences between the original colour and sealer-stained teeth, between sealer-stained and bleached teeth and between original colour and bleached teeth were calculated. Data were analysed using one-way anova and Duncan tests (alpha = 0.05). RESULTS: Colour differences between baseline and sealer staining were in the range of 8.1-9.9, but differences between the groups were not significant. After bleaching, the degree of lightening was essentially identical for the carbamide peroxide and sodium perborate + carbamide peroxide groups, but was significantly greater (P < 0.05) in these two groups than in the sodium perborate + water group. CONCLUSION: For bleaching AH26 sealer-stained teeth, carbamide peroxide gel and carbamide peroxide gel mixed with sodium perborate were equally effective and significantly better than sodium perborate mixed with water. PMID- 23647233 TI - Mild physical impairment predicts future diagnosis of dementia of the Alzheimer's type. AB - OBJECTIVES: To determine whether mildly impaired physical function (based on performance-based assessment) is associated with development of dementia of the Alzheimer's type (DAT) in cognitively normal older adults. DESIGN: Longitudinal, observational study with yearly assessments of physical and cognitive function. Mean follow-up was 5 years. SETTING: Knight Alzheimer's Disease Research Center at Washington University, St. Louis, Missouri. PARTICIPANTS: Four hundred thirty five cognitively normal adults aged 60 and older participating in longitudinal studies of aging. MEASUREMENTS: Survival analyses were used to examine whether scores on the 9-item Physical Performance Test (PPT) predicted time to DAT diagnosis. Cox proportional hazards models were used to examine associations between PPT total scores and time to cognitive impairment and DAT; as well as the association between time and these events, adjusting for and simultaneously testing the effects of age, sex, education, and presence of one or more apolipoprotein (APOE) epsilon4 alleles. RESULTS: During the follow-up period, 81 participants developed DAT. Participants diagnosed with DAT were older (81.0 vs 74.2, P = .001) and had worse performance on the PPT (25.5 vs 28.1, P = .009) than those who remained cognitively normal. Time to DAT diagnosis was associated with PPT total score (hazard ratio (HR) = 0.89, 95% confidence interval (CI) = 0.86-0.93, P < .001) such that time to DAT diagnosis was longer for participants with higher physical performance scores. In the adjusted analysis, PPT score significantly predicted time to DAT diagnosis (HR = 0.94, 95% CI = 0.89-0.99, P = .02). CONCLUSION: Mild physical impairment in cognitively normal older adults is associated with subsequent development of DAT. Although the physical impairment may be sufficiently mild that it is recognized only using performance-based assessments, its presence may predate clinically detectable cognitive decline. PMID- 23647235 TI - Detection and knockdown of microRNA-34a using thioacetamido nucleic acid. AB - Thioacetamido nucleic acids (TANA) contain a backbone modification of dinucleotides consisting of a 5-atom amide linker N3'-COCH2-S-CH2 at thymidine or thymidine-cytidine dimer blocks. Here, the chemical synthesis of the TANA linked 5-methyl-cytidine-cytidine ((Me)cc) dimer block and its incorporation into the DNA sequence, complementary to human microRNA 34 (miR-34) is described. Further, for the first time, we demonstrate the biological applications of TANA modified oligonucleotides in detection and intracellular knockdown of a cancer related microRNA in comparison with DNA containing locked nucleic acid (LNA) and 2'-O methyl modifications. The human microRNA miR-34 is a pro-apoptotic microRNA under the transcriptional control of protein 53 (p53). It gets expressed in response to DNA damage and regulates several cell cycle and apoptosis related targets. Here, we show that the TANA modified antisense oligonucleotide binds specifically to miR-34a, allowing its detection using primer extension. We also show that, using the TANA modified antisense oligonucleotide against miR-34a, intracellular levels of miR-34 can be reduced, and consequently, the expression of its target oncogene V-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN) is enhanced. Further, we assessed the toxicity and serum stability of the oligonucleotide to conclude that it is suitable for detection and modulation of the vital biomarker and tumor suppressor microRNA. PMID- 23647236 TI - Downregulation of multiple CDK inhibitor ICK/KRP genes upregulates the E2F pathway and increases cell proliferation, and organ and seed sizes in Arabidopsis. AB - The ICK/KRP cyclin-dependent kinase (CDK) inhibitors are important plant cell cycle factors sharing only limited similarity with the metazoan CIP/KIP family of CDK inhibitors. Little is known about the specific functions of different ICK/KRP genes in planta. In this study, we created double and multiple mutants from five single Arabidopsis ICK/KRP T-DNA mutants, and used a set of 20 lines for the functional investigation of the important gene family. There were gradual increases in CDK activity from single to multiple mutants, indicating that ICK/KRPs act as CDK inhibitors under normal physiological conditions in plants. Whereas lower-order mutants showed no morphological phenotypes, the ick1 ick2 ick6 ick7 and ick1 ick2 ick5 ick6 ick7 mutants had a slightly altered leaf shape. The quintuple mutant had larger cotyledons, leaves, petals and seeds than the wild-type control. At the cellular level, the ICK/KRP mutants had more but smaller cells in all the organs examined. These phenotypic effects became more apparent as more ICK/KRPs were downregulated, suggesting that to a large extent ICK/KRPs function in plants redundantly in a dosage-dependent manner. Analyses also revealed increased expression of E2F-dependent genes, and elevated RBR1 as well as an increased level of phospho-RBB1 protein in the quintuple mutant. Thus, downregulation of multiple ICK/KRP genes increases CDK activity, upregulates the E2F pathway and stimulates cell proliferation, resulting in increased cell numbers, and larger organs and seeds. PMID- 23647237 TI - Retrospective success and survival rates of dental implants placed with simultaneous bone augmentation in partially edentulous patients. AB - AIM: The aim of this study was to assess the success and survival rate of dental implants placed with simultaneous hard tissue grafting. MATERIAL AND METHODS: All patients treated in Royal Dental Hospital of Melbourne who had implant placement with and without guided bone regeneration (GBR) procedures were identified. Seventy-three attended a follow-up appointment. These patients were examined recording probing depth, bleeding on probing, plaque accumulation and radiographic bone loss by one examiner. Clinical and radiographic findings were compared in grafted and non-grafted groups and also analysed for years in function. RESULTS: Approximately 50% of implants were placed simultaneous guided bone regeneration technique. In the majority of cases, defects were filled by deproteinized bovine bone mineral and covered with collagen membrane. The range of time in function was 20-88 months with a mean 34.8 (+/-1.7). Seventy-nine per cent of the implants placed in anterior maxilla were placed with GBR, while only 18% in posterior mandible needed grafting procedure. The cumulative implant survival rates at the time of examination was 97.95% for both GBR and non-GBR group. The mean PPD, BOP, and Plaque index were not statistically significantly different in GBR vs. non-GBR groups two to seven years in function. However, bone loss is significantly less in GBR group 2-7 years after function. The overall success rate was around 90% after 2-7 years in function with the GBR group slightly less than the non-GBR group, but not statistically significant. CONCLUSIONS: For the subjects included in this retrospective study, the data demonstrate that GBR is a predictable procedure. The survival and success rates of the implants inserted with simultaneous GBR were similar, if slightly lower, to the non-grafted implants. PMID- 23647238 TI - Effects of molecular structure of polyphenols on their noncovalent interactions with oat beta-glucan. AB - Few data were available on the interactions between polyphenols and polysaccharides. The effects of the chemical structure of polyphenols on their interactions with oat beta-glucan were analyzed. Ultrafiltration was applied to determine the adsorption capacities of polyphenols into oat beta-glucan. Hydroxylation favored the adsorption of flavonoids with three or fewer hydroxyl groups but deteriorated those with four or more hydroxyl groups. Among flavonoid isomers, the adsorption capacities increased in the order flavonol > flvaone > flavanone > isoflavone. Glycosylation exerted complicated influences on the adsorption capacities of flavonoids into oat beta-glucan. In most cases, methylation and methoxylation of phenolic acids lowered their adsorption capacities into oat beta-glucan. Esterification of gallic acid weakened its adsorption capacity into oat beta-glucan, whereas o-coumaric acid presented higher adsorption capacity into oat beta-glucan than p- and m-coumaric acids. Galloylation improved the adsorption capacities of catechins into oat beta glucan. PMID- 23647239 TI - Ten-year changes in positive and negative marker food, fruit, vegetables, and salad intake in 9-10 year olds: SportsLinx 2000-2001 to 2010-2011. AB - BACKGROUND: To investigate changes in intakes of 'negative' and 'positive' foods, fruit, vegetables, and salad in serial cohorts of 9-10-year-old children from 2000-2001 to 2010-2011. METHODS: For this serial, cross-sectional study, children in school year 5 (9-10 years of age) completed the SportsLinx Lifestyles Survey [n = 30,239 (15,336 boys and 14,903 girls)]. Changes in positive and negative food scores, and the proportion of boys and girls reportedly consuming fruit, vegetables and salad on the previous day to surveying, were investigated annually from 2000 to 2011. RESULTS: The consumption of negative foods declined and positive foods increased significantly compared to baseline. Positive changes in fruit, vegetables and salad consumption were observed over time, with the most recent cohort more likely to consume fruit, vegetables and salad compared to the 2000-2001 baseline. Girls displayed more favourable positive and negative food scores and were more likely to consume fruit, salad and vegetables across several study years compared to boys. CONCLUSIONS: The consumption of negative and positive foods, fruit, vegetables, and salad has improved over the last 10 years. In addition, girls appear to have better positive and negative food scores, and were more likely to consume fruit, vegetables and salad, across a number of study years or cohorts compared to boys. These encouraging findings suggest that children's food intake has improved since 2000. Furthermore, the data indicate that boys and girls may require separate or different healthy eating messages to further improve food intake. PMID- 23647240 TI - Identifying the active site in nitrogen-doped graphene for the VO2+/VO2(+) redox reaction. AB - Nitrogen-doped graphene sheets (NGS), synthesized by annealing graphite oxide (GO) with urea at 700-1050 degrees C, were studied as positive electrodes in a vanadium redox flow battery. The NGS, in particular annealed at 900 degrees C, exhibited excellent catalytic performance in terms of electron transfer (ET) resistance (4.74 +/- 0.51 and 7.27 +/- 0.42 Omega for the anodic process and cathodic process, respectively) and reversibility (DeltaE = 100 mV, Ipa/Ipc = 1.38 at a scan rate of 50 mV s(-1)). Detailed research confirms that not the nitrogen doping level but the nitrogen type in the graphene sheets determines the catalytic activity. Among four types of nitrogen species doped into the graphene lattice including pyridinic-N, pyrrolic-N, quaternary nitrogen, and oxidic-N, quaternary nitrogen is verified as a catalytic active center for the [VO](2+)/[VO2](+) couple reaction. A mechanism is proposed to explain the electrocatalytic performance of NGS for the [VO](2+)/[VO2](+) couple reaction. The possible formation of a N-V transitional bonding state, which facilitates the ET between the outer electrode and reactant ions, is a key step for its high catalytic activity. PMID- 23647242 TI - Preservice teacher attitudes toward gay and lesbian parents. AB - Gay and lesbian parents are raising an increasing number of children, but little is known about how these parents are viewed by school personnel. In this study, preservice teacher attitudes toward gay and lesbian parents were assessed using implicit, explicit, behavioral, and behavioroid measures. Implicit measures indicate that participants rated same-gender targets more negatively than they rated heterosexual targets, and they rated targets of gay men more negatively than they rated lesbians; however, response patterns varied by participant sex. Furthermore, implicit measures of sexual prejudice generally correlated with explicit and behavioroid measures. The implications of these findings are discussed. PMID- 23647243 TI - School experiences of early adolescent Latinos/as at risk for emotional and behavioral disorders. AB - Previous research has shown that Latino/a middle school students exhibiting emotional or behavioral disturbance are at risk for undesirable academic outcomes. The purpose of this study was to understand the perceptions and experiences of at-risk Latino/a students to identify ways to improve interventions targeted to promote their academic retention and success. Participants included 11 Latino/a students between the ages of 11 and 13 years, 8 males and 3 females, who were screened as being at risk for behavior disorders using the Systematic Screening for Behavior Disorders (SSBD). These students shared their perceptions and experiences of schooling during in-depth qualitative interviews. Interpretative phenomenological analysis (IPA) was used to understand how these students made sense of their school experiences. Students' descriptions tended to be contextualized within relationships with peers, teachers, and family members. Many students shared experiences of being the target of overt racism and microaggressions from peers. Students believed they were more likely to be successful in school when teachers displayed flexibility with deadlines, provided extra help, and communicated a sense of warmth and caring. The data from this study suggested that school psychologists can benefit from attending to at-risk students' perceptions, which, in the context of this study, would require facilitating an inclusive school climate, fostering effective teacher and student relationships, and facilitating parent-teacher relationships during the difficult transition from elementary to middle school. PMID- 23647241 TI - Learning from their own actions: the unique effect of producing actions on infants' action understanding. AB - Prior research suggests that infants' action production affects their action understanding, but little is known about the aspects of motor experience that render these effects. In Study 1, the relative contributions of self-produced (n = 30) and observational (n = 30) action experience on 3-month-old infants' action understanding was assessed using a visual habituation paradigm. In Study 2, generalization of training to a new context was examined (n = 30). Results revealed a unique effect of active over observational experience. Furthermore, findings suggest that benefits of trained actions do not generalize broadly, at least following brief training. PMID- 23647244 TI - Targeting cAMP in chronic lymphocytic leukemia: a pathway-dependent approach for the treatment of leukemia and lymphoma. AB - INTRODUCTION: Cyclic AMP (cAMP) promotes growth arrest and/or apoptosis of various types of lymphoma, in particular chronic lymphocytic leukemia (CLL). These responses have spurred the interest in developing agents that increase cAMP to treat such malignancies and to identify mechanisms of the responses. AREAS COVERED: The murine T-lymphoma cell line S49, has provided an important, pioneering model to define mechanisms of cAMP-mediated lymphoid cell death. Studies with S49 cells demonstrated that cAMP, acting via protein kinase A (PKA), is pro-apoptotic through a mitochondria-dependent pathway and identified cAMP/PKA regulated targets involved in apoptosis. Akin to such findings, cAMP promotes apoptosis via PKA of cells from patients with CLL. Analysis of mediators of cAMP accumulation and cAMP-promoted apoptosis in CLL cells has revealed approaches to increase cAMP and engage its pro-apoptotic action. EXPERT OPINION: This 'pathway approach' targeted to cAMP has identified GPCR agonists/antagonists, AC activators (e.g., AC7), PDE inhibitors (e.g., PDE7B) and/or activators or inhibitors of downstream mediators (PKA and Epac, respectively), which might be utilized therapeutically in CLL. Therapy directed at such targets may prove to be clinically useful and may also provide a proof-of-principle of the utility of targeting cAMP signaling in other types of cancer. PMID- 23647245 TI - High thermoelectric performance via hierarchical compositionally alloyed nanostructures. AB - Previous efforts to enhance thermoelectric performance have primarily focused on reduction in lattice thermal conductivity caused by broad-based phonon scattering across multiple length scales. Herein, we demonstrate a design strategy which provides for simultaneous improvement of electrical and thermal properties of p type PbSe and leads to ZT ~ 1.6 at 923 K, the highest ever reported for a tellurium-free chalcogenide. Our strategy goes beyond the recent ideas of reducing thermal conductivity by adding two key new theory-guided concepts in engineering, both electronic structure and band alignment across nanostructure matrix interface. Utilizing density functional theory for calculations of valence band energy levels of nanoscale precipitates of CdS, CdSe, ZnS, and ZnSe, we infer favorable valence band alignments between PbSe and compositionally alloyed nanostructures of CdS1-xSex/ZnS1-xSex. Then by alloying Cd on the cation sublattice of PbSe, we tailor the electronic structure of its two valence bands (light hole L and heavy hole Sigma) to move closer in energy, thereby enabling the enhancement of the Seebeck coefficients and the power factor. PMID- 23647246 TI - Three-dimensional localization versus fluoroscopically only guided ablations: a meta-analysis. AB - OBJECTIVES: Data regarding efficacy and safety of three-dimensional localization systems (3D) are limited. We performed a meta-analysis of randomized trials comparing combined fluoroscopy- and 3D guided to fluoroscopically-only guided procedures. DESIGN: A systematic search was performed using multiple databases between 1990 and 2010. Outcomes were acute and long-term success, ablation, procedure and fluoroscopic times, radiation dose (RD), and complications. RESULTS: Thirteen studies involving 1292 patients were identified. 3D were tested against fluoroscopic guidance in 666 patients for supraventricular tachycardia (SVT), atrial flutter (AFL), atrial fibrillation (AF), and ventricular tachycardia (VT). Acute and long-term freedom from arrhythmia was not significantly different between 3D and control for AFL (acute success, 97% vs. 93%, p = 0.57; chronic success, 93% vs. 96%, p = 0.90) or for SVT (acute success, 94% vs. 100%, p = 0.36; chronic success, 88% vs. 88%, p = 0.80). A shorter fluoroscopic time was achieved with 3D in AFL (p < 0.001) and in SVT (p = 0.002). RD was significantly less for both AFL (p = 0.002) and SVT (p = 0.01). Ablation and procedure time and complications were not statistically different. CONCLUSIONS: Success, procedure time, and complications were similar between fluoroscopy- and 3D-guided ablations. Fluoroscopic time and RD were significantly reduced for ablation of AFL and SVT with 3D. PMID- 23647247 TI - Mechanical properties evolution of a PLGA-PLCL composite scaffold for ligament tissue engineering under static and cyclic traction-torsion in vitro culture conditions. AB - This study aims to investigate the in vitro degradation of a poly(L-lactic-co glycolic acid)-poly(L-lactic-co-epsilon-caprolactone) (PLGA-PLCL) composite scaffold's mechanical properties under static culture condition and 2 h period per day of traction-torsion cyclic culture conditions of simultaneous 10% uniaxial strain and 90 degrees of torsion cycles at 0.33 Hz. Scaffolds were cultured in static conditions, during 28 days, with or without cell seeded or under dynamic conditions during 14 days in a bioreactor. Scaffolds' biocompatibility and proliferation were investigated with Alamar Blue tests and cell nuclei staining. Scaffolds' mechanical properties were tested during degradation by uniaxial traction test. The PLGA-PLCL composite scaffold showed a good cytocompatibility and a high degree of colonization in static conditions. Mechanical tests showed a competition between two process of degradation which have been associated to hydrolytic and enzymatic degradation for the reinforce yarn in poly(L-lactic-co-glycolic acid) (PLGA). The enzymatic degradation led to a decrease effect on mechanical properties of cell-seeded scaffolds during the 21st days, but the hydrolytic degradation was preponderant at day 28. In conclusion, the structure of this scaffold is adapted to culture in terms of biocompatibility and cell orientation (microfiber) but must be improved by delaying the degradation of it reinforce structure in PLGA. PMID- 23647248 TI - Investigating polymer thiolation in gene delivery. AB - Thiolated polymers containing disulfide linkages are commonly researched in gene delivery with the assumption that the thiolated complexes form disulfide bonds. This study investigates the extent of disulfide linking in a thiol-containing polymer and determines the impact that free thiols have on the polymer's delivery potential. A fluorescent cationic polymer containing thiol pendant chains was prepared from poly(allylamine) and 2-iminothiolate (Traut's reagent). Polymer fluorescence was determined by UV plate readings and fluorescent microscopy. Transfection efficiency and cytotoxicity were assessed in MCF-7 breast cancer cells. Results show that thiolated polymers exhibited fluorescence at ex/em ~595/620. Fluorescent measurements, microscopy imaging, and DNA electrophoresis show that thiolated polymers are not internalized by cells in a culture, yet, they bind to the cell surface, perhaps valuable for applications requiring cell adhesion. PMID- 23647249 TI - Combined use of spinal cord-mimicking partition type scaffold architecture and neurotrophin-3 for surgical repair of completely transected spinal cord in rats. AB - A body of evidence has suggested that tissue-engineered nerve grafts hold promise for the surgical repair of spinal cord injuries. In this study, a novel nerve graft was prepared to be implantated into a 5 mm gap which was caused by a complete transection of the rat spinal cord. The graft was featured by incorporation of neurotrophin-3 into a chitosan-based tube scaffold with a spinal cord-mimicking, partition-type architecture, which was prepared based on the morphometric insights of normal spinal cord anatomy. A set of behavioral, functional, and histological examinations were carried out to evaluate the repair. Results from Basso, Beattie, and Bresnahan tests, motor evoked potential measurements, anterograde tracing, and histological analyses suggested that the combined application of chitosan as the scaffold biomaterial, a spinal cord mimicking partition-type as the scaffold architecture, and neurotrophin-3 (NT-3) as the bioactive component might probably create synergetic promotion on spinal cord regeneration. This composite nerve graft yielded significantly better results in axonal regeneration and function restoration as compared to its scaffold alone or other types of hollow tube scaffold alone. PMID- 23647250 TI - Novel light-curable materials containing experimental bioactive micro-fillers remineralise mineral-depleted bonded-dentine interfaces. AB - This study aimed at evaluating the therapeutic remineralising effects of innovative light-curable materials (LCMs) containing two experimental calcium silicate-based micro-fillers (TCS) modified with beta-TCP only or beta-TCP, zinc oxide (ZnO)/polyacrylic acid (PAA) on mineral-depleted bonded-dentine interfaces in simulated body fluids (SBFS). Three experimental LCMs were formulated: (1) resin A, containing a beta-TCP-modified TCS (betaTCS) micro-filler; (2) resin B, containing a polycarboxylated beta-TCP/ZnO-modified TCS (betaZn-TCS) micro filler; and 3) resin C, containing no filler (control). Acid-etched (35% H3PO4) dentine specimens were bonded using the three LCMs and submitted to atomic force microscope (AFM)/nano-indentation analysis to evaluate the modulus of elasticity (Ei) and hardness (Hi) across the interface after SBFS storage (24 h/1 m/3 m). The ultramorphology and micropermeability of the resin-dentine interface were evaluated using confocal laser microscopy. Resin-dentine sticks were created and submitted to microtensile bond strength (MUTBS) test (SBFS: 24 h/3 m). Scanning electron microscopy (SEM) was performed after de-bonding. The LCMs containing the experimental bioactive micro-fillers reduced the micropermeability and induced a significant increase of the Ei and Hi along the bonding interface. The specimens created using the resin B (betaZn-TCS) attained the highest MUTBS values both after 24 h and 3 m of SBFS storage. In conclusion, the innovative bioactive light curable materials tested in this study are able to induce a therapeutic remineralising effect on the nano-mechanical properties and on the sealing ability of mineral-depleted resin-dentine interfaces. The contemporary idea of minimally invasive operative treatment, where therapeutic restorations are performed to combat the carious process and remineralise the dental hard tissues, may be satisfied by using such resin-base systems, containing betaTCS or betaZn TCS bioactive micro-fillers. PMID- 23647251 TI - Design and physicochemical characterization of poly(amidoamine) nanoparticles and the toxicological evaluation in human endothelial cells: applications to peptide delivery to the brain. AB - In this study, we investigated nanoparticles formulated by self-assembly of a biodegradable poly(amidoamine) (PAA) and a fluorescently labeled peptide, in their capacity to internalize in endothelial cells and deliver the peptide, with possible applications for brain drug delivery. The nanoparticles were characterized in terms of size, surface charge, and loading efficiency, and were applied on human cerebral microvascular endothelial cells (hCMEC/D3) and human umbilical vein endothelial cells (Huvec) cells. Cell-internalization and cytotoxicity experiments showed that the PAA-based nanocomplexes were essentially nontoxic, and the peptide was successfully internalized into cells. The results indicate that these PAAs have an excellent property as nontoxic carriers for intracellular protein and peptide delivery, and provide opportunities for novel applications in the delivery of peptides to endothelial cells of the brain. PMID- 23647252 TI - Preparation and characterization of electrospun PLGA/gelatin nanofibers as a drug delivery system by emulsion electrospinning. AB - Novel biocompatible poly(lactide-co-glycolide) (PLGA) nanofiber mats with favorable biocompatibility and good mechanical strength were prepared, which could serve as an innovative type of tissue engineering scaffold or an ideal controllable drug delivery system. Both hydrophobic and hydrophilic drugs, Cefradine and 5-fluorouracil were successfully loaded into PLGA nanofiber mats by emulsion electrospinning. The natural bioactive protein gelatin (GE) was incorporated into the nanofiber mats to improve the surface properties of the materials for cell adhesion. Nanofibrous scaffolds were characterized by scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, contact angle and tensile measurements. Emulsion electrospun fibers with GE had perfect hydrophilic and good mechanical property. The in vitro release test showed thedrugs released from emulsion electrospun fibers, which achieved lower burst release. The cells cytotoxicity experiment indicated that emulsion electrospun fibers were less toxic and tended to promote fibroblasts cells attachment and proliferation, which implied that the electrospun fibers had promising potential application in tissue engineering or drug delivery. PMID- 23647253 TI - Synthesis and cytotoxicity of brefeldin A conjugated monomethoxy-poly(ethylene glycol)-b-poly(L-lactide) polymeric micelles. AB - A diblock copolymer of monomethoxy-poly(ethylene glycol)-b-poly(L-lactide) (MePEG PLLA)/brefeldin A (BFA) conjugate was synthesized by the reaction of carboxyl terminated copolymer MePEG-PLLA with BFA in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. The conjugation efficiency was found to be 95%. Its structure was confirmed by (1)H nuclear magnetic resonance and gel permeation chromatography. The MePEG-PLLA/BFA conjugate could self-assemble into micelles in aqueous solutions with a low critical micelle concentration of 1.8 * 10(-3 )g/L. Dynamic light scattering and transmission electron microscopy analyses of the MePEG-PLLA/BFA micelles revealed their spherical structure with an average diameter of 120 nm. The release profiles of BFA in PBS were measured by high performance liquid chromatography (HPLC), demonstrating that the controlled release of BFA can be gained for long time. The in vitro antitumor activity of the conjugate micelles against human liver carcinoma HepG2 cells was evaluated by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyl tetrazolium bromide method, and the results showed that BFA can be released from the conjugate micelles without losing cytotoxicity. PMID- 23647254 TI - Chitosan/gelatin porous scaffolds containing hyaluronic acid and heparan sulfate for neural tissue engineering. AB - The novel chitosan (Cs)/gelatin (Gel) porous scaffolds containing hyaluronic acid (HA) and heparan sulfate (HS) were fabricated via freeze-drying technique, and their physicochemical characteristics including pore size, porosity, water absorption, and in vitro degradation and biocompatibility were investigated. It was demonstrated that the Cs/Gel/HA/HS composite scaffolds had highly homogeneous and interconnected pores with porosity above 96% and average pore size ranging from 90 to 140 MUm and a controllable degradation rate. The scanning electron microscopic images, cell viability assay, and fluorescence microscopy observation revealed that the presence of HA and HS in the scaffolds significantly promoted initial neural stem and progenitor cells (NS/PCs) adhesion and supported long time growth in three-dimensional environment. Moreover, NS/PCs also maintained mutilineage differentiation potentials with enhanced neuronal differentiation upon induction in the Cs/Gel/HA/HS composite scaffolds in relation to Cs/Gel scaffolds. These results indicated that the Cs/Gel/HA/HS composite scaffolds were suitable for neural cells' adhesion, survival, and growth and could offer new and important options for neural tissue engineering applications. PMID- 23647255 TI - Wound dressing composed of hyaluronic acid and collagen containing EGF or bFGF: comparative culture study. AB - We developed a novel wound dressing composed of a hyaluronic acid (HA) and collagen (Col) spongy sheet containing epidermal growth factor (EGF) or basic fibrolast growth factor (bFGF) by freeze-drying method (EGF-wound dressing or bFGF-wound dressing, respectively). A wound dressing without any growth factor was prepared as a control in a similar manner as above (C-wound dressing). Intermolecular cross-linkage between Col molecules was induced by UV irradiation. The release behavior of free HA from the wound dressing was investigated using a C-wound dressing. The weight of C-wound dressing after 1 day, 3, 5, and 7 days of incubation on top of a Col gel sheet at the air-water interface (wound surface model) was 55, 36, 30, and 19% of the original weight, respectively. Most free HA and a part of Col was released from the cross-linked Col network in the wound dressing during incubation, as the original Col content in the wound dressing was 33%. Next, fibroblast proliferation was assessed in conventional culture medium preconditioned by immersion of a piece of C-, EGF-, or bFGF-wound dressing, i.e. C-conditioned medium, EGF-conditioned medium, or bFGF-conditioned medium. Cell proliferation in C-conditioned medium increased to approximately the same level as that in conventional medium. Cell proliferation in EGF- and bFGF-conditioned medium was 1.9 times and 2.6 times greater than that in conventional medium after 7 days of cultivation, respectively. Finally, cytokine production of fibroblasts was assessed in a wound surface model using a fibroblast-incorporating Col gel sheet (cultured dermal substitute [CDS]). CDS was elevated to the air-medium interface, on which each wound dressing was placed and cultured for 7 days. Fibroblasts in CDS covered with EGF-wound dressing released 3.6 times more vascular endothelial growth factor (VEGF) and 4.6 times more hepatocyte growth factor (HGF) when compared with the C-wound dressing. Fibroblasts in CDS covered with bFGF-wound dressing released 10.2 times more VEGF and 6.3 times more HGF when compared with the C-wound dressing. This finding indicates that bFGF-wound dressing can facilitate more effectively the VEGF and FGF production compared with EGF-wound dressing. PMID- 23647256 TI - Visible-light photochemical activity of heterostructured core-shell materials composed of selected ternary titanates and ferrites coated by tiO2. AB - Heterostructured photocatalysts comprised of microcrystalline (mc-) cores and nanostructured (ns-) shells were prepared by the sol-gel method. The ability of titania-coated ATiO3 (A = Fe, Pb) and AFeO3 (A = Bi, La, Y) catalysts to degrade methylene blue in visible light (lambda > 420 nm) was compared. The catalysts with the titanate cores had enhanced photocatalytic activities for methylene blue degradation compared to their components alone, whereas the catalysts with ferrite cores did not. The temperature at which the ns-titania shell is crystallized influences the photocatalytic dye degradation. mc-FeTiO3/ns-TiO2 annealed at 500 degrees C shows the highest reaction rate. Fe-doped TiO2, which absorbs visible light, did not show enhanced photocatalytic activity for methylene blue degradation. This result indicates that iron contamination is not a decisive factor in the reduced reactivity of the titania coated ferrite catalysts. The higher reactivity of materials with the titanate cores suggests that photogenerated charge carriers are more easily transported across the titanate-titanate interface than the ferrite-titanate interface and this provides guidance for materials selection in composite catalyst design. PMID- 23647257 TI - In situ synthesis and characterization of nano ZnO on wool: influence of nano photo reactor on wool properties. AB - This study has been carried out to synthesize nano ZnO on wool fabric and also to investigate influences of nano photo reactors on wool fabric characteristics. Zinc acetate has been used as a precursor and the synthesis process has been done in water and water/ethanol media. The treated wool fabrics were heated at 80 degrees C for 10 h to dehydrate Zn(OH)2 obtaining ZnO. The fabric samples were then subjected to daylight for 7 days to examine the influence of nano ZnO photo reactor on the fabric properties. SEM images revealed the embedding of ZnO nanoparticles on the fabrics and X-ray diffraction verified the nanoparticles composition. The Yellowness Index (YI) of the fabrics was measured with Color Eye XTH that has been reduced with increasing pH, Zn(CH3COO)2 concentration, ethanol and heating. The lower water contact angle and time of water absorption confirmed higher hydrophilic properties of the treated fabrics. Interestingly, a higher tensile strength obtained on the wool fabrics proved the interaction of ZnO with protein chains of wool, which was verified through lower alkali solubility of treated fabric with nano ZnO and confirmed more benefits of the in situ synthesis process. PMID- 23647259 TI - Validation of the IDS Octeia ELISA for the determination of insulin-like growth factor 1 in equine serum and tendon tissue extracts. AB - BACKGROUND: Insulin-like growth factor (IGF-1) is an important mediator of tissue repair in horses. OBJECTIVES: The aim of the study was to evaluate whether IGF-1 could be measured reliably in equine serum and tendon tissue extracts, using an IGF-1 ELISA kit developed for human serum and plasma. METHODS: A glycyl-glycine pretreatment protocol of samples was compared with the pretreatment procedure recommended by the manufacturer. Intra- and inter-assay imprecision were evaluated by repeated measurements of equine serum pools. Assay inaccuracy was determined based on the linearity of serially diluted equine serum samples and tendon tissue extracts. The recovery of IGF-1 was evaluated in serum and tendon tissue extracts spiked with known amounts of IGF-1. RESULTS: The range of IGF-1 released using the manufacturer's pretreatment was between 23% and 56% of the amount released using the gly-gly pretreatment in different equine samples. In serum pools with low, intermediate, and high IGF-1 concentrations, intra-assay imprecision was 4.0%, 4.0%, and 3.1%, respectively, and inter-assay imprecision was 13.9%, 7.3%, and 12.8%, respectively. The recovery of serially diluted serum was 96 +/- 3% when diluted with serum, and 72 +/- 15% when diluted with PBS. The recovery after dilution was 108 +/- 17% in tendon tissue extracts. Recovery from serum spiked with a fixed amount of IGF-1 was 101 +/- 5% and 99 +/- 7% from tendon tissue samples. CONCLUSIONS: The IDS Octeia IGF-1 ELISA kit can be used for measuring IGF-1 in equine serum and tendon tissue extract after pretreatment with glycyl-glycine. PMID- 23647258 TI - Metabolic syndrome and hemoglobin levels in elderly adults: the Invecchiare in Chianti Study. AB - OBJECTIVES: To assess the association between metabolic syndrome (MetS) and hemoglobin levels in older adults. DESIGN: The Invecchiare in Chianti (InCHIANTI) Study, a cohort study with a 6-year follow-up. SETTING: Tuscany, Italy. PARTICIPANTS: Adults aged 65 and older (N = 1,036). MEASUREMENTS: MetS was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The adjusted association between baseline hemoglobin and MetS was assessed using multivariable linear regression with hemoglobin as a continuous variable and using logistic regression with median hemoglobin level as the reference. Logistic regression was also performed with any incident decline in hemoglobin levels as the dependent variable. RESULTS: MetS was diagnosed in 263 (25%) participants. At baseline, MetS was associated with higher hemoglobin levels (B = 0.18, 95% confidence interval (CI) = 0.03-0.33, P = .02) and with hemoglobin levels above the median value (odds ratio (OR) = 1.65, 95% CI = 1.17 2.32, P = .004) after adjusting. After 6 years, MetS was associated with lower adjusted probability of lower hemoglobin levels (OR = 0.34, 95% CI = 0.15-0.79, P = .012) but only in the oldest tertile of participants. CONCLUSION: MetS is associated with higher hemoglobin levels in older subjects and with lower probability of hemoglobin loss over 6 years in those in the oldest age group. PMID- 23647260 TI - Contaminants at the sediment-water interface: implications for environmental impact assessment and effects monitoring. AB - Many contaminants in aquatic environments are associated with loosely packed aggregates of particulate material called flocs. Flocculation allows contaminants to accumulate at the sediment-water interface and it packages them in a form that is readily available for ingestion by filter feeding organisms. Unfortunately, most samplers being used for environmental assessment and monitoring suspend this material on impact and fail to sample this critical component of the seabed. In this study we use a slo-corer to collect seabed samples with an undisturbed surface layer and a Gust microcosm erosion chamber to erode the surface of the cores at increasing shear stresses. Results from two different sites, one impacted by tailings from historic gold mining and the other by open-pen salmon aquaculture, showed the levels of metals suspended at stresses below 0.24 Pa were greater than in the underlying sediment. Sampling this highly mobile surface layer is critical for determining the total contaminant load in bottom sediments and, more importantly, this layer represents the most readily available material for suspension. The loss of this layer during sampling could lead to inaccurate measurements of contaminant levels during environmental assessment and effects monitoring. A re-evaluation of the ISO standard for bottom sediment sampling is recommended. PMID- 23647261 TI - Frontal fibrosing alopecia: a clinical review of 20 black patients from South Africa. PMID- 23647262 TI - Computational investigations on base-catalyzed diaryl ether formation. AB - We report investigations with the dispersion-corrected B3LYP density functional method on mechanisms and energetics for reactions of group I metal phenoxides with halobenzenes as models for polyether formation. Calculated barriers for ether formation from para-substituted fluorobenzenes are well correlated with the electron-donating or -withdrawing properties of the substituent at the para position. These trends have also been explained with the distortion/interaction energy theory model which show that the major component of the activation energy is the energy required to distort the arylfluoride reactant into the geometry that it adopts at the transition state. Resonance-stabilized aryl anion intermediates (Meisenheimer complexes) are predicted to be energetically disfavored in reactions involving fluorobenzenes with a single electron withdrawing group at the para position of the arene, but are formed when the fluorobenzenes are very electron-deficient, or when chelating substituents at the ortho position of the aryl ring are capable of binding with the metal cation, or both. Our results suggest that the presence of the metal cation does not increase the rate of reaction, but plays an important role in these reactions by binding the fluoride or nitrite leaving group and facilitating displacement. We have found that the barrier to reaction decreases as the size of the metal cation increases among a series of group I metal phenoxides due to the fact that the phenoxide becomes less distorted in the transition state as the size of the metal increases. PMID- 23647263 TI - Genome-wide transcript analysis of early maize leaf development reveals gene cohorts associated with the differentiation of C4 Kranz anatomy. AB - Photosynthesis underpins the viability of most ecosystems, with C4 plants that exhibit 'Kranz' anatomy being the most efficient primary producers. Kranz anatomy is characterized by closely spaced veins that are encircled by two morphologically distinct photosynthetic cell types. Although Kranz anatomy evolved multiple times, the underlying genetic mechanisms remain largely elusive, with only the maize scarecrow gene so far implicated in Kranz patterning. To provide a broader insight into the regulation of Kranz differentiation, we performed a genome-wide comparative analysis of developmental trajectories in Kranz (foliar leaf blade) and non-Kranz (husk leaf sheath) leaves of the C4 plant maize. Using profile classification of gene expression in early leaf primordia, we identified cohorts of genes associated with procambium initiation and vascular patterning. In addition, we used supervised classification criteria inferred from anatomical and developmental analyses of five developmental stages to identify candidate regulators of cell-type specification. Our analysis supports the suggestion that Kranz anatomy is patterned, at least in part, by a SCARECROW/SHORTROOT regulatory network, and suggests likely components of that network. Furthermore, the data imply a role for additional pathways in the development of Kranz leaves. PMID- 23647264 TI - Mental spatial transformations in 14- and 16-month-old infants: effects of action and observational experience. AB - Infants' ability to mentally track the orientation of an object during a hidden rotation was investigated (N = 28 in each experiment). A toy on a turntable was fully covered and then rotated 90 degrees . When revealed, the toy had turned with the turntable (probable event), remained at its starting orientation (improbable event in Experiment 1), or turned to the opposite side (improbable event in Experiment 2). Results demonstrated a developmental progression between 14 and 16 months of age in infants' sensitivity to spatial object relations and their ability to track the orientation of an object during hidden rotation. Experiment 3 showed that 14-month-olds' performance improved with hands-on training, highlighting the role of action experience in cognitive development. PMID- 23647265 TI - A comparison of hepatic sonographic features and histopathologic diagnosis in canine liver disease: 138 cases. AB - BACKGROUND: Ultrasound examination is commonly used in the diagnostic evaluation of liver disease in dogs. HYPOTHESIS/OBJECTIVES: To determine if hepatic sonographic features were predictive of findings on liver histopathology. We hypothesized that there would be a relationship between sonographic features and the category of liver disease based on histologic assessment. ANIMALS: One hundred and thirty-eight dogs in which the liver was evaluated by both abdominal ultrasound examination and histopathologic examination. Twenty-five dogs were included in each of the following categories based on histopathology: normal, degenerative, vascular, inflammatory, and neoplasia. Thirteen dogs had nodular regeneration. METHODS: Retrospective study. Medical records of dogs from 2005 to 2010 were searched for cases in which the liver was evaluated by abdominal ultrasound examination as well as by histopathology. After independent evaluation of ultrasound images, the recorded sonographic features were analyzed to identify abnormalities associated with each histopathologic diagnosis or degree of fibrosis. RESULTS: Sixty-four percent of sonographically unremarkable livers had histologic abnormalities. Both microhepatia and the identification of abnormal vasculature were significantly associated with a histopathologic diagnosis of vascular disease. Hepatic masses were significantly associated with a diagnosis of neoplasia. Dilated common bile duct and thickened gall bladder wall were significantly associated with hepatitis. There were no sonographic findings consistently present with hepatic fibrosis. CONCLUSION AND CLINICAL IMPORTANCE: Although some ultrasonographic findings, including masses, microhepatia, anomalous veins, and biliary changes, are associated with specific histopathologic abnormalities, sonographic findings are inconsistently detected in many disorders. Overall, hepatic ultrasonographic abnormalities have substantial limitations in predicting the underlying disease. PMID- 23647266 TI - Increasing the efficiency of ligands for FK506-binding protein 51 by conformational control. AB - The design of efficient ligands remains a key challenge in drug discovery. In the quest for lead-like ligands for the FK506-binding protein 51 (FKBP51), we designed two new classes of bicyclic sulfonamides to probe the contribution of conformational energy in these ligands. The [4.3.1] scaffold had consistently higher affinity compared to the [3.3.1] or monocyclic scaffolds, which could be attributed to better preorganization of two key recognition motifs. Surprisingly, the binding of the rigid [4.3.1] scaffold was enthalpy-driven and entropically disfavored compared to the flexible analogues. Cocrystal structures at atomic resolution revealed that the sulfonamide nitrogen in the bicyclic scaffolds can accept an unusual hydrogen bond from Tyr(113) that mimics the putative FKBP transition state. This resulted in the first lead-like, functionally active ligand for FKBP51. Our work exemplifies how atom-efficient ligands can be achieved by careful conformational control even in very open and thus difficult binding sites such as FKBP51. PMID- 23647267 TI - Prospects and challenges: inhalation delivery systems. PMID- 23647268 TI - Monoclonal antibody-fluorescent probe conjugates for in vivo target-specific cancer imaging: toward clinical translation. PMID- 23647270 TI - Industry Update: the latest developments in therapeutic delivery. AB - The present industry update covers the period 2-28 February 2013, with information sourced from company press releases, regulatory and patent agencies, as well as from scientific literature. With the US presidential inauguration in January, the inevitable 'fiscal cliff' and with the healthcare reform taking shape, there are many challenges ahead for the world's largest healthcare market. Healthcare providers are preparing for the 'accountable care organizations' paradigm shift and it has been reported that the pharmaceutical industry is low in public perception; only 'for-profit' health insurers rank lower according to a survey recently published. Although in 2012 one could still observe a decline in the overall number of drug delivery partnering deals announced, there has been a slight recovery, thus, meaning a repeat of the lows of 2011 have not been witnessed. The experts expect a reversed trend in 2013 as larger companies seek to refill pipelines with new candidates and drug-delivery solutions. There is a lot of emphasis on altered oral delivery profiles to provide patient compliance. This is indicated by the recent licensing deals, such as that between Radius Health Inc. and 3M, TissueGen and Biomedical Structures, and new financing rounds of companies, such as SKL, Catalent and BioActiva. Injectable technology, including needle-free delivery, continues to be prevalent in deals, such as those between Clearside and Kala until compelling alternatives to the delivery of biologicals are available. Alternative routes of administration, such as nasal, buccal (Kala), sublingual (Stallergenes) see growing interest; however, bioavailability and reproducible dosing will continue to be a challenge in the foreseeable future. PMID- 23647271 TI - Interview with Vladimir P Torchilin: liposomal carriers for drug delivery. AB - Vladimir P Torchilin is a University Distinguished Professor and Director at the Center for Pharmaceutical Biotechnology and Nanomedicine at the School of Pharmacy, Northeastern University (MA, USA). He has published over 350 original research papers and among many other awards was the recent recipient of the 2012 Bangham Award, for his contributions to the study of liposomes. Professor Torchilin spoke to Therapeutic Delivery about the progress and challenges of the field of liposomal carriers for drug delivery as well as his own career in science to date. Interview conducted by James Potticary, Assistant Commissioning Editor. PMID- 23647272 TI - Research spotlight: microbubbles for therapeutic delivery. AB - Systemic injection of chemotherapy agents for treating cancer can cause severe side effects for the patient, as well as being a relatively inefficient use of expensive and highly toxic drugs. The area of targeted drug delivery in which drugs are delivered utilizing a specialized carrier directly to the cancerous tumor via immuno-recognition has gained much interest in recent years. Such an approach reduces the side effects of systemic injection and also provides a localized, high-concentration treatment directly to the cancer. Our group at the University of Leeds (Leeds, UK) is developing therapeutic microbubbles that double as both agents for contrast-enhanced ultrasound imaging and drug-delivery vehicles that are targeted to specific cancer cell receptors. Ultimately, a large amplitude sound wave will be used to destroy the bubbles and trigger release of the drug at the targeted tumor. Theranostic microbubbles are a simple and versatile drug-delivery technique that could potentially improve cancer treatment, both in terms of patient experience and overall drug efficiency. Importantly, they offer new ways of delivering hydrophobic drugs, which have traditionally been difficult to deliver efficiently. PMID- 23647273 TI - Transdermal delivery of methotrexate for pediatrics using silicon microneedles. AB - BACKGROUND: The objective of this work was to study transdermal delivery of methotrexate using silicon microneedles and simulate plasma concentrations using a population pharmacokinetic model. RESULTS: Characterization of silicon microneedles was carried out by scanning electron microscopy, transepidermal water loss, methylene blue staining, calcein imaging, pore permeability index and confocal microscopy, which confirmed the formation of microchannels. In vitro permeation studies were performed to study the enhancement in transdermal delivery following microporation. CONCLUSION: Simulation data demonstrated that with 16, 64, 128 and 192 microneedles, mean plasma concentrations of 0.3, 1.4, 2.8 and 4.2 ng/ml, respectively, can be achieved. Thus, therapeutically relevant doses could be delivered in pediatrics by increasing the number of microneedles and patch area. PMID- 23647274 TI - Poly[LA-(Glc-Leu)] copolymer as a carrier for ocular delivery of ciprofloxacin: formulation, characterization and in vivo biocompatibility study. AB - BACKGROUND: Ciprofloxacin hydrochloride-encapsulated poly[LA-(Glc-Leu)] copolymeric nanoparticles were prepared to provide sustained release and ameliorate shortcomings associated with eye drops. METHODS: Poly[LA-(Glc-Leu)] copolymer was synthesized by ring opening copolymerization of l-lactide with a cyclodepsipetide. Ciprofloxacin hydrochloride-loaded polymeric nanoparticles were prepared by double emulsification-solvent evaporation technique with emphasis on optimization of different process and formulation variables. RESULTS: Optimized formulation showed encapsulation efficiency of approximately 63.08 +/- 5.88% and a positive zeta potential of +17.46 mV. Scanning electron microscope study revealed the spherical shape of the nanoparticles with a particle size 300-400 nm. In vitro drug-release studies showed sustained release for 24 h with biphasic release pattern. In vivo ocular tolerability study in rabbits demonstrated no signs of toxicity or irritation parallel to the results obtained with the marketed formulation. CONCLUSION: Poly[LA-(Glc-Leu)] copolymer can be used as an efficient carrier for nanoparticle preparation of ciprofloxacin. PMID- 23647275 TI - Alkylsaccharides: circumventing oxidative damage to biotherapeutics caused by polyoxyethylene-based surfactants. AB - Polysorbates and other polyoxyethylene-based surfactants are incorporated into most biotherapeutics to prevent protein aggregation in order to minimize loss of efficacy, induction of unwanted immunogenicity, altered pharmacokinetics and reduced shelf life. While they are effective in initially preventing protein aggregation, they contain ether linkages (within polyoxyethylene moieties) and in the case of polysorbate 80 unsaturated alkyl chains that spontaneously and rapidly auto-oxidize in aqueous solution to protein-damaging peroxides, epoxy acids and reactive aldehydes, including formaldehyde and acetaldehyde. Oxidative damage induces unwanted immunogenicity and in some instances promotes re aggregation. Immunogenicity of biotherapeutics is a serious and growing concern for the US FDA and European Medicines Agency and will have significant and growing impact on the development and regulatory approval of both biosimilar and new innovator biotherapeutics. PMID- 23647276 TI - Therapeutic potential of cell-penetrating peptides. AB - The ability of cell-penetrating peptides to cross plasma membranes has been used for various applications, including the delivery of bioactive molecules to inhibit disease-producing cellular mechanisms. Selective drug delivery into target cells improves drug distribution and decreases dosing and toxicity. In this review, the authors outline the main challenges in the field, namely clarification of mechanisms of entry into cells, as well as current and future perspectives regarding cell-penetrating peptides application for human therapeutics. Here, the authors discuss some of the factors that influence efficacy of delivery and review the current status of preclinical studies and clinical trials involving the use of cell-penetrating peptide-mediated delivery of therapeutics. PMID- 23647277 TI - Strategies for enhanced peptide and protein delivery. AB - Recent advances in the fields of molecular biology and biotechnology have allowed for the large-scale production and subsequent exploitation of the therapeutic potential of protein- and peptide-based drugs. The facilitation of delivery of this class of drugs must be tailored to meet the requirements and often the limitations dictated by the route of delivery chosen. The aim of this review is to comprehensively discuss several routes of drug delivery, detailing the uses and exploitation of each, from origins to present day approaches. Specific reference is made to the compatibility or incompatibility of each approach in the facilitation of the delivery of drugs of protein origin. Additionally, the physiological nature of the delivery route and the inherent physiological obstacles that must be considered when determining the most suitable approach to drug design and delivery enhancement are also addressed. Examples of novel protein-based drug designs and delivery methodologies that illustrate such enhancement strategies are explored. PMID- 23647278 TI - Immunotherapeutic approaches in prion disease: progress, challenges and potential directions. AB - Therapeutic trials utilizing animal models of prion disease have explored a variety of compounds and a number of approaches with varying success, including several immunotherapeutic strategies, such as passive immunization through the delivery of viruses carrying nucleic acid inserts encoding prion protein-specific immunoglobulin. Targeted, organ-specific cellular production of therapeutic proteins is a relatively unexplored approach in the treatment of neurodegeneration despite many successful experimental outcomes in animal models and human trials of other diseases of the CNS. Emphasizing studies utilizing mouse models of disease, this review outlines developments and limitations of immunological approaches to the treatment of prion diseases. In addition, the authors discuss the potential of an experimental therapeutic strategy, utilizing hybridoma cells injected directly into the CNS to establish long-term production of anti-prion antibodies in vivo within the organ associated with the greatest pathogenic change in prion disease, the brain. PMID- 23647279 TI - Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells. AB - The potential use of many promising novel drugs is limited by their inability to specifically reach their site of action after intravenous administration, without secondary effects on healthy tissues. In order to remediate this problem, the protein transferrin (Tf) has been extensively studied as a targeting molecule for the transport of drug and gene delivery systems to the brain and cancer cells. A wide range of delivery approaches have been developed to target the Tf receptor and they have already improved the specific delivery of Tf-bearing therapeutic agents to their site of action. This review provides a summary of the numerous delivery strategies used to target the Tf receptor and focuses on recent therapeutic advances. PMID- 23647281 TI - A randomized clinical trial comparing an acceptance-based behavior therapy to applied relaxation for generalized anxiety disorder. AB - OBJECTIVE: To examine whether an empirically and theoretically derived treatment combining mindfulness- and acceptance-based strategies with behavioral approaches would improve outcomes in generalized anxiety disorder (GAD) over an empirically supported treatment. METHOD: This trial randomized 81 individuals (65.4% female, 80.2% identified as White, average age 32.92) diagnosed with GAD to receive 16 sessions of either an acceptance-based behavior therapy (ABBT) or applied relaxation (AR). Assessments at pretreatment, posttreatment, and 6-month follow up included the following primary outcome measures: GAD clinician severity rating, Structured Interview Guide for the Hamilton Anxiety Rating Scale, Penn State Worry Questionnaire, Depression Anxiety Stress Scale, and the State-Trait Anxiety Inventory. Secondary outcomes included the Beck Depression Inventory-II, Quality of Life Inventory, and number of comorbid diagnoses. RESULTS: Mixed effect regression models showed significant, large effects for time for all primary outcome measures (ds = 1.27 to 1.61) but nonsignificant, small effects for condition and Condition * Time (ds = 0.002 to 0.20), indicating that clients in the 2 treatments improved comparably over treatment. For secondary outcomes, time was significant (ds = 0.74 to 1.38), but condition and Condition * Time effects were not (ds = 0.004 to 0.31). No significant differences emerged over follow-up (ds = 0.03 to 0.39), indicating maintenance of gains. Between 63.3 and 80.0% of clients in ABBT and 60.6 and 78.8% of clients in AR experienced clinically significant change across 5 calculations of change at posttreatment and follow-up. CONCLUSION: ABBT is a viable alternative for treating GAD. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23647282 TI - Convergent and incremental predictive validity of clinician, self-report, and structured interview diagnoses for personality disorders over 5 years. AB - OBJECTIVE: Research has demonstrated poor agreement between clinician-assigned personality disorder (PD) diagnoses and those generated by self-report questionnaires and semistructured diagnostic interviews. No research has compared prospectively the predictive validity of these methods. We investigated the convergence of these 3 diagnostic methods and tested their relative and incremental validity in predicting independent, multimethod assessments of psychosocial functioning performed prospectively over 5 years. METHOD: Participants were 320 patients in the Collaborative Longitudinal Personality Disorders Study diagnosed with PDs by therapist, self-report, and semistructured interview at baseline. We examined the relative incremental validity of therapists' naturalistic ratings relative to these other diagnostic methods for predicting psychosocial functioning at 5-year follow-up. RESULTS: Hierarchical linear regression analyses revealed that both the self-report questionnaire and semistructured interview PD diagnoses had significant incremental predictive validity over the PD diagnoses assigned by a treating clinician. Although, in some cases, the clinicians' ratings for individual PDs did have validity for predicting subsequent functioning, they did not generally provide incremental prediction beyond the other methods. These findings remained robust in a series of analyses restricted to a subsample of therapist ratings based on clinical contact of 1 year or greater. CONCLUSIONS: These results from a large clinical sample echo previous research documenting limited agreement between clinicians' naturalistic PD diagnoses and those from self-report and semistructured interview methods. They extend prior work by providing the first evidence about the relative predictive validity of these different methods. Our findings challenge the validity of naturalistic PD diagnoses and suggest the use of structured diagnostic instruments. PMID- 23647283 TI - Race/ethnicity, education, and treatment parameters as moderators and predictors of outcome in binge eating disorder. AB - OBJECTIVE: Binge eating disorder (BED) is prevalent among individuals from minority racial/ethnic groups and among individuals with lower levels of education, yet the efficacy of psychosocial treatments for these groups has not been examined in adequately powered analyses. This study investigated the relative variance in treatment retention and posttreatment symptom levels accounted for by demographic, clinical, and treatment variables as moderators and predictors of outcome. METHOD: Data were aggregated from 11 randomized, controlled trials of psychosocial treatments for BED conducted at treatment sites across the United States. Participants were N = 1,073 individuals meeting criteria for BED including n = 946 Caucasian, n = 79 African American, and n = 48 Hispanic/Latino participants. Approximately 86% had some higher education; 85% were female. Multilevel regression analyses examined moderators and predictors of treatment retention, Eating Disorder Examination (EDE) global score, frequency of objective bulimic episodes (OBEs), and OBE remission. RESULTS: Moderator analyses of race/ethnicity and education were nonsignificant. Predictor analyses revealed African Americans were more likely to drop out of treatment than Caucasians, and lower level of education predicted greater posttreatment OBEs. African Americans showed a small but significantly greater reduction in EDE global score relative to Caucasians. Self-help treatment administered in a group showed negative outcomes relative to other treatment types, and longer treatment was associated with better outcome. CONCLUSIONS: Observed lower treatment retention among African Americans and lesser treatment effects for individuals with lower levels of educational attainment are serious issues requiring attention. Reduced benefit was observed for shorter treatment length and self-help administered in groups. PMID- 23647284 TI - The temporal association between substance use and intimate partner violence among women arrested for domestic violence. AB - OBJECTIVE: There is a paucity of research on the temporal association between substance use and intimate partner violence (IPV) perpetration and victimization, especially among women arrested for domestic violence. The current study examined whether the probability of IPV perpetration and victimization increases following alcohol or drug use relative to days of no use among women arrested for domestic violence. METHOD: Women arrested for domestic violence and court referred to batterer intervention programs who met criteria for hazardous drinking participated in the current study (N = 105). Women who reported drinking 4 or more drinks on 1 occasion at least once per month for the past 6 months were considered hazardous drinkers. Violence and substance use were assessed with the Timeline Followback Interviews for substance use and IPV. RESULTS: Women were more likely to perpetrate physical violence on a drinking day (OR = 10.58; 95% CI [5.38, 20.79]) and on a heavy drinking day (OR = 12.81; 95% CI [8.10, 33.57]), relative to a nondrinking day. Women were more likely to be victimized by physical violence on a drinking day (OR = 5.22; 95% CI [2.79, 9.77]) and on a heavy drinking day (OR = 6.16; 95% CI [3.25, 11.68]), relative to a nondrinking day. They were more likely to be victims of sexual coercion (OR = 6.06; 95% CI [1.19, 30.80]) on a cocaine use day relative to a nonuse day. CONCLUSIONS: Alcohol use was temporally associated with physical violence perpetration and victimization, and cocaine use was temporally associated with sexual coercion victimization, suggesting that substance use should be targeted in batterer intervention programs for women. PMID- 23647285 TI - Pretreatment anxiety predicts patterns of change in cognitive behavioral therapy and medications for depression. AB - OBJECTIVE: Some studies report that initial anxiety is associated with equivocal or negative effects in depression treatment. In contrast, at least 4 studies of cognitive behavioral therapy (CBT) report that anxiety predicts greater or more rapid change in depression. Further exploration is needed to clarify the relationship between initial anxiety and depression change. Questions include the relationship between anxiety and patterns of change and time to relapse, as well as the specificity effects to CBT. METHOD: The study assessed the relation of Beck Anxiety Inventory anxiety scores to early rapid change and overall change in Beck Depression Inventory-II depression scores during acute depression treatment. Participants were 178 individuals enrolled in a randomized controlled trial of CBT versus antidepressant medications (ADMs) for moderate to severe depression. They were 58% female and 83% Caucasian, with an average age of 40 (SD = 11.5). Thirty-four percent (34%) were married or cohabitating. Hierarchical linear models, including quadratic growth parameters, were used to model change. The relation of anxiety to the probability of posttreatment relapse was also examined. RESULTS: Findings indicate that higher levels of anxiety predict early rapid change, but not overall change, in both CBT and ADM. However, patients with higher levels of intake anxiety evidenced increased risk for relapse after CBT. CONCLUSIONS: Early rapid change predicted by anxiety occurs across different treatment conditions, but this early rapid response is not indicative of positive overall outcome in all cases. These findings might indicate that anxiety predicts a response to nonspecific "common factors" of treatment. PMID- 23647287 TI - The promise of digital (mobile) health in cancer prevention and treatment. PMID- 23647286 TI - Influence of powder-to-water ratio on radiopacity, setting time, pH, calcium ion release and a micro-CT volumetric solubility of white mineral trioxide aggregate. AB - AIM: To evaluate the radiopacity, setting time, pH level, calcium ion release and solubility of white mineral trioxide aggregate (MTA; Angelus, Londrina, Pr, Brazil) with different powder-to-water ratios. METHODOLOGY: Three MTA groups were prepared using 4 : 1, 3 : 1 and 2 : 1 powder-to-water ratios. For the radiopacity analysis, the 10 * 1 mm specimens were arranged on occlusal films with a cylinder of dentine and an aluminium stepwedge. The digitized radiographs were evaluated with Digora 1.51 software to determine the radiographic density. The setting time test was performed according to the American Society for Testing and Materials 266/08 standard specifications, but the specimens were made according to International Organization for Standardization 6876:2001. Thirty acrylic teeth with root-end filling material were immersed in ultrapure water for measurement of pH level and calcium ion release (atomic absorption spectrophotometer) at 3, 24, 72 and 168 h. In the solubility test, the root-end fillings of 30 acrylic teeth were scanned twice by a Micro-CT, before and after immersion in ultrapure water for 168 h. Digital data were reconstructed, and the volume (mm(3) ) of the samples was obtained using CTan software (CTan v1.11.10.0, SkyScan). The data were statistically analysed by the anova, Tukey, Kruskal-Wallis and Dunn's tests. RESULTS: The radiopacity was higher (P < 0.05) when the 4 : 1 proportion was utilized. The setting time was longer, and the pH level and calcium ion release were higher (P < 0.05) with a greater volume of water. The group with more water (2 : 1) had significantly (P < 0.05) more material volume loss (6.46%) compared with the other groups. CONCLUSIONS: The ratio of powder/water significantly interfered with the physical and chemical properties of white MTA Angelus. PMID- 23647288 TI - Is there an optimal treatment sequencing strategy for metastatic castration resistant prostate cancer? PMID- 23647289 TI - Immunotherapy in lung cancer: the potential of cancer stem cells in future therapies. PMID- 23647290 TI - Boswellic acid and its inhibitory effect on tumor growth in systemic malignancies: an emerging concept in oncology. PMID- 23647292 TI - Zoledronic acid to prevent and treat cancer metastasis: new prospects for an old drug. AB - Zoledronic acid (zoledronate, ZometaTM; Novartis Pharmaceuticals, Basel, Switzerland) is a nitrogen-containing bisphosphonate. Zoledronate rapidly binds to bone mineral where it is then ingested by osteoclasts. Once internalized, zoledronate inhibits the mevalonate pathway, which stops osteoclast function, and thus slows bone resorption. Zoledronate is approved for the prevention of skeletal morbidity in metastatic bone disease from solid tumors and multiple myeloma. Zoledronate is also recommended as an option for the treatment of cancer therapy-induced bone loss. In recent large Phase III studies in early breast cancer, zoledronate reduced both local and distant recurrences in women with induced or established natural menopause. Postulated mechanisms underlying the anticancer properties of zoledronate include antiangiogenic and immunomodulatory effects. A clearer understanding of these mechanisms will enable the full potential of zoledronate to be realized. PMID- 23647293 TI - From trial highlights to clinical context: putting American Society of Clinical Oncology gastrointestinal news into practice. AB - Celebrating its tenth anniversary, the Gastrointestinal Cancers Symposium is a world class, international conference focused on research and multidisciplinary management of digestive tract malignancies, co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, the American Gastroenterological Association Institute and the Society of Surgical Oncology. This premium meeting was held from 24 to 26 January 2013 in San Francisco (CA, USA) and, in line with its principal mission, it sought to globally embrace prevention, screening, diagnostics, translational research and multimodal treatment, moving on three major anatomic tracks (upper gastrointestinal cancers, pancreatic/hepatobiliary tumors and colorectal malignancies). Over 2000 healthcare professionals gathered at this valuable 3day scientific event, which included plenary educational sessions and oral presentations of the top-rated abstracts, as well as the exposition of nearly 600 posters. This short article offers a summarized opinion-based overview of the most significant studies presented at the meeting that are likely to impact on clinical practice as well as new drug development, as best exemplified by the three most important messages of the whole meeting: the value of nanoparticle albumin-bound paclitaxel in metastatic pancreatic cancer; that of ramucirumab in second-line gastric cancer; and that of capecitabine and bevacizumab in elderly advanced colorectal cancer patients. PMID- 23647294 TI - New molecular insights in tobacco-induced lung cancer. AB - We know that cigarette smoking is a leading preventable cause of carcinogenesis in lung cancer. Cigarette smoke is a mixture of more than 5000 chemical compounds, among which more than 60 are recognized to have a specific carcinogenic potential. Carcinogens and their metabolites (i.e., N-nitrosamines and polycyclic aromatic hydrocarbons) can activate multiple pathways, contributing to lung cell transformation in different ways. Nicotine, originally thought only to be responsible for tobacco addiction, is also involved in tumor promotion and progression with antiapoptotic and indirect mitogenic properties. Lung nodules are frequent in smokers and can be transformed into malignant tumors depending on persistent smoking status. Even if detailed mechanisms underlying tobacco-induced cancerogenesis are not completely elucidated, this report collects the emergent body of knowledge in order to simplify the extremely complex framework that links smoking exposure to lung cancer. PMID- 23647295 TI - The electromagnetic spectrum: current and future applications in oncology. AB - The electromagnetic spectrum is composed of waves of various energies that interact with matter. When focused upon and directed at tumors, these energy sources can be employed as a means of lesion ablation. While the use of x-rays is widely known in this regard, a growing body of evidence shows that other members of this family can also achieve oncologic success. This article will review therapeutic application of the electromagnetic spectrum in current interventions and potential future applications. PMID- 23647296 TI - Radiotherapy in the management of prostate cancer after radical prostatectomy. AB - The choice of treatment options for prostate cancer patients who have undergone radical prostatectomy depends on their risk profile, which is determined by the tumor node metastasis (TNM) status, histopathologic findings, and the pre- and post-radical prostatectomy PSA characteristics. The results of large clinical studies with a 10-year follow-up or more are the backbone of predictive models for risk estimates that incorporate these criteria and also for guideline recommendations. For low-to-intermediate-risk prostate cancer patients and older patients, observation with--in case of biochemical recurrence--early salvage radiotherapy can be advised after R0 resection, thus, avoiding overtreatment. After R1 resection, adjuvant radiotherapy should be considered. Patients with two or more positive lymph nodes and/or with distant metastasis may benefit from adjuvant hormone deprivation therapy. Beyond this rough outline, detailed analysis of subgroups is still required (and ongoing) to enable individually optimized treatment. PMID- 23647297 TI - New prospects for drug development: the hedgehog pathway revealed. Focus on hematologic malignancies. AB - The hedgehog (Hh) pathway is a critical regulator of vertebrate embryonic development and is involved in the function of processes such as stem cell maintenance and differentiation, tissue polarity and cell proliferation. Given how critical these functions are, it is not surprising that mutations in Hh pathway components are often implicated in the tumorigenesis of a variety of human cancers. Promotion of tumor growth has recently been shown by activated Hh signaling in the tumor itself, as well as by pathway activation within surrounding cells comprising the tumor microenvironment. Targeted disruption of various Hh pathway proteins has been successfully employed as an anticancer strategy with several synthetic Hh antagonists now available. Here, the molecular basis of Hh signaling, the therapeutic rationales for targeting this pathway and the current status of Hh pathway inhibitors in the clinic are reviewed. PMID- 23647298 TI - Rare mutations in non-small-cell lung cancer. AB - In the last decade, new insights in molecular biology have changed the therapeutic landscape of non-small-cell lung cancer. Since 2004, when activating mutations of the EGFR were firstly identified, several genetic aberrations have been discovered, mainly in adenocarcinoma. EGFR mutations are a relatively frequent event in non-small-cell lung cancer, generally consisting of exon 19 deletion or exon 21 substitution. In adenocarcinoma, additional rare mutations are detectable in the EGFR gene, as well as in other genes, including ALK, ROS1, RET, HER2 and BRAF. Recent studies in squamous cell carcinoma identified TP53 as the most frequent mutation, followed by additional more rare mutations, including PI3KCA, PTEN, DDR2 and FGFR. The aim of the present review is to analyze the potential prognostic and predictive role of rare mutations. PMID- 23647299 TI - Molecular networks in melanoma invasion and metastasis. AB - Metastatic melanoma accounts for approximately 80% of skin cancer-related deaths. Up to now there has been no effective treatment for stage IV melanoma patients due to the complexity and dissemination potential of this disease. Melanomas are heterogeneous tumors in which conventional therapies fail to improve overall survival. Targeted therapies are being developed, but the final outcome can be hampered by the incomplete knowledge of the process of melanoma progression. Even if the intracellular pathways are similar, the interaction of the cells with the surrounding environment should be taken into consideration. This article seeks to highlight some of the advances in the understanding of the molecular mechanisms underlying melanoma dissemination. PMID- 23647300 TI - Identification of HOXB8 and KLK11 expression levels as potential biomarkers to predict the effects of FOLFOX4 chemotherapy. AB - AIM: To measure global gene expression in primary advanced colorectal cancer patients who have undergone fluorouracil, leucovorin and oxaliplatin (FOLFOX4) chemotherapy and screen valuable biomarkers to predict the effects of chemotherapy. MATERIALS & METHODS: Samples from primary advanced colorectal cancer patients were collected. The effects of chemotherapy were evaluated, and patients were divided into an experimental group and a control group. Cancerous tissue gene expression profiles were detected by chip technology. Valuable biomarkers were screened by bioinformatic analysis. Immunohistochemical analysis was performed to characterize the pattern of HOXB8 and KLK11 expression. HOXB8 and KLK11 signal probe values were analyzed using receiver operating characteristic analysis. RESULTS: There were differentially expressed genes in the two groups. HOXB8 and KLK11 proteins were observed in the nucleus and on the outside of the cancer cells, respectively. Their prediction accuracies were 79.9 and 76.7%, respectively. CONCLUSION: HOXB8 and KLK11 may be classified as valuable biomarkers, as they can predict the effects of FOLFOX4 chemotherapy in primary advanced colorectal cancer patients. PMID- 23647302 TI - Detection of breast cancer cells in blood samples by immunostaining of the Thomsen-Friedenreich antigen. AB - AIM: Disseminated tumor cells are found in the bone marrow of patients with epithelial carcinoma and are correlated with a poor prognosis of the disease. Their detection is a technical challenge. This report describes a model system for the detection of cancer cells by co-immunostaining of Thomsen-Friedenreich and Her-2 antigens. METHODS & RESULTS: Small numbers of cancer cells from different cancer cell lines were mixed with blood samples of healthy donors. Cytospins were prepared and double immunostaining against Thomsen-Friedenreich antigen and Her-2 was carried out by fluorochrome-coupled antibodies. Quantification of Thomsen-Friedenreich and/or Her-2-positive cells was performed with an epifluorescence microscope. On average, 83% of cancer cells were recovered by this method. CONCLUSION: Immunostaining is a useful method for the detection of cancer cells in blood samples. Results of this model system will be transferred to bone marrow patient samples to prove the benefits for detection of disseminated tumor cells. PMID- 23647301 TI - ALDH7A1 expression is associated with recurrence in patients with surgically resected non-small-cell lung carcinoma. AB - AIM: The purpose of this study was to describe the prognostic significance of ALDH7A1 in surgically treated non-small-cell lung carcinoma. (NSCLC). MATERIALS & METHODS: We immunohistochemically analyzed ALDH7A1 expression in surgically resected NSCLC from 89 patients using a tissue microarray. RESULTS: ALDH7A1 staining was positive in 43 patients and negative in 44 patients, with two tumor sections missing. For stage I NSCLC patients, ALDH7A1 positivity was associated with decreased recurrence-free and overall survival. Multivariate analysis demonstrated that ALDH7A1-expressing NSCLC tumors had a significantly higher incidence of lung cancer recurrence compared with patients with ALDH7A1-negative tumors, although there was no association with overall survival. CONCLUSION: For patients with NSCLC, low ALDH7A1 expression was associated with a decreased incidence of cancer recurrence. Specifically in stage I patients, negative staining for ALDH7A1 was associated with improved recurrence-free and overall survival, suggesting a predictive role in surgically treated patients. PMID- 23647303 TI - Hairy cell leukemia in a patient with situs inversus totalis: an extremely rare combination. AB - Hairy cell leukemia is a rare cancer of the blood. The occurrence of hairy cell leukemia with another very rare genetic disorder makes us question whether it is just a coincidence. This article reports the first case of hairy cell leukemia in a patient with situs inversus totalis in western literature. There have been studies into the pathogenesis of situs inversus totalis that suggest it is caused by the failure of embryonic cells to properly rotate during embryogenesis. On the molecular level, the nodal cilia, which are responsible for embryonic rotation, are built by transport through the KIF3 complex - a kinesin superfamily of molecular motors. The KIF3 complex is also responsible for N-cadherin movement in cells. Furthermore, it is well known that these cell adhesion molecules play an important role in carcinogenesis and its progression. This report attempts to link the rare conditions and propose a possible genetic relationship between the two. PMID- 23647305 TI - Electrorheological fluids based on metallo-supramolecular polyelectrolyte silicate composites. AB - We present an innovative concept for the design of electrorheological fluids (ERF) based on a dispersed phase of rigid-rod-shaped metallo-supramolecular polyelectrolytes (MEPE) intercalated in mesoporous SBA-15 silica. While applying an electric field to this composite dispersed in silicone oil, rheological measurements reveal a strong increase in the storage modulus, indicating the solidification of the fluid. Besides the strong electrorheological effect and the low current densities, we note that the required amount of MEPE is five times lower than in comparable host-guest ERFs. Composites based on mononuclear complexes do not show a comparable electrorheological effect. PMID- 23647306 TI - Large area metal nanowire arrays with tunable sub-20 nm nanogaps. AB - We report a new top-down nanofabrication technology to realize large area metal nanowire (m-NW) arrays with tunable sub-20 nm separation nanogaps without the use of chemical etching or milling of the metal layer. The m-NW array nanofabrication technology is based on a self-regulating metal deposition process that is facilitated by closely spaced and isolated heterogeneous template surfaces that confine the metal deposition into two dimensions, and therefore, electrically isolated parallel arrays of m-NW can be realized with uniform and controllable nanogaps. Au-NW and Ag-NW arrays are presented with high-density ~10(5) NWs cm( 1), variable NW diameters down to ~50 nm, variable nanogaps down to ~5 nm, and very large nanogap length density ~1 km cm(-2). The m-NW arrays are designed and implemented as interdigitated nanoelectrodes for electrochemical applications and as plasmonic substrates where the coupled-mode localized surface plasmon resonance (LSPR) wavelength in the nanogaps between adjacent m-NW dimers can be precisely tuned to match any excitation source in the range from 500 to 1000 nm, thus providing optimal local electromagnetic field enhancement. A spatially averaged (n = 2500) surface-enhanced Raman scattering (SERS) analytical enhancement factor of (1.2 +/- 0.1) * 10(7) is demonstrated from a benzenethiol monolayer chemisorbed on a Au-NW array substrate with LSPR wavelength matched to a He-Ne laser source. PMID- 23647308 TI - Atomic-scale engineering of the electrostatic landscape of semiconductor surfaces. AB - A low-temperature scanning tunneling microscope was used in conjunction with density functional theory calculations to determine the binding sites and charge states of adsorbed Ga and Mn atoms on GaAs(110). To quantify the adatom charge states (both +1e), the Coulomb interaction with an individual Mn acceptor is measured via tunneling spectroscopy and compared with theoretical predictions. Several methods for positioning these charged adatoms are demonstrated, allowing us to engineer the electrostatic landscape of the surface with atomic precision. PMID- 23647307 TI - Effects of macronutrient intake on thigh muscle mass during home-based walking training in middle-aged and older women. AB - We examined whether post-exercise macronutrient supplementation during a 5-month home-based interval walking training (IWT) accelerated exercise-induced increases in skeletal muscle mass and strength in healthy middle-aged and older women. Thirty-five women (41-78 years) were randomly divided into two groups: IWT alone (CNT, n = 18) or IWT plus post-exercise macronutrient (7.6 g protein, 32.5 g carbohydrate, and 4.4 g fat) supplementation (NUT, n = 17). For IWT, all subjects were instructed to repeat five or more sets of 3-min low-intensity walking at 40% peak aerobic capacity (Vo2 peak ), followed by a 3-min high-intensity walking above 70% Vo2 peak per day for 4 or more days per week. We determined Vo2 peak , thigh muscle tissue area by computer tomography, and thigh muscle strength in all subjects before and after IWT. We found that an increase in hamstring muscle tissue area was 2.8 +/- 1.2% in NUT vs -1.0 +/- 0.7% in CNT and that in isometric knee flexion force was 16.3 +/- 3.7% in NUT vs 6.5 +/- 3.0% in CNT; both were significantly higher in NUT than in CNT (both, P < 0.001). Thus, post-exercise macronutrient supplementation enhanced the increases in thigh muscle mass and strength, although partially, in home-based IWT in middle-aged and older women. PMID- 23647309 TI - Arabidopsis plants lacking PsbQ and PsbR subunits of the oxygen-evolving complex show altered PSII super-complex organization and short-term adaptive mechanisms. AB - The oxygen-evolving complex of eukaryotic photosystem II (PSII) consists of four extrinsic subunits, PsbO (33 kDa), PsbP (23 kDa), PsbQ (17 kDa) and PsbR (10 kDa), encoded by seven nuclear genes, PsbO1 (At5g66570), PsbO2 (At3g50820), PsbP1 (At1g06680), PsbP2 (At2g30790), PsbQ1 (At4g21280), PsbQ2 (At4g05180) and PsbR (At1g79040). Using Arabidopsis insertion mutant lines, we show that PsbP1, but not PsbP2, is essential for photoautotrophic growth, whereas plants lacking both forms of PsbQ and/or PsbR show normal growth rates. Complete elimination of PsbQ has a minor effect on PSII function, but plants lacking PsbR or both PsbR and PsbQ are characterized by more pronounced defects in PSII activity. Gene expression and immunoblot analyses indicate that accumulation of each of these proteins is highly dependent on the presence of the others, and is controlled at the post-transcriptional level, whereas PsbO stability appears to be less sensitive to depletion of other subunits of the oxygen-evolving complex. In addition, comparison of levels of the PSII super-complex in wild-type and mutant leaves reveals the importance of the individual subunits of the oxygen-evolving complex for the supramolecular organization of PSII and their influence on the rate of state transitions. PMID- 23647310 TI - The role of attention in motor control. AB - Research on the focus of attention (FOA) in motor control has found a consistent advantage for focusing externally (on the effects of one's actions) compared to focusing internally (on one's body mechanics). However, most of this work has concentrated on movement outcomes, leaving open the question of how external attention changes the movement itself. Somewhat paradoxically, recent research has found that external attention also increases trial-by-trial movement variability. To explain these findings, we propose a theory of attention in motor control, grounded in optimal control theory, wherein variability is minimized along attended aspects of the movement. Internal attention thus reduces variability in individual bodily dimensions (positions and velocities of effectors), whereas external attention minimizes variability in the task outcome. Because the goal of a task defines a dimension in the movement space that is generally oblique to bodily dimensions, external attention should increase correlations among bodily dimensions while allowing their individual variances to grow. The current experiment tests these predictions in a dart-throwing task. External FOA led to more accurate performance and increased variability in the motion of the throwing arm, concomitant with stronger correlations among bodily dimensions (shoulder, elbow, and wrist positions and velocities) in a manner consistent with the task kinematics. These findings indicate a shift in the control policy of the motor system, consistent with the proposed theory. These results suggest an important role of attention as a control parameter in the regulation of the motor system, and more broadly illustrate the importance of cognitive mechanisms in motor behavior. PMID- 23647311 TI - Valuing different human lives. AB - Do people think of the value of all human lives as equivalent irrespective of age? Affirmations of the equal value of all human lives are culturally prominent, yet much evidence points to the fact that the young are often prioritized over the old in life-and-death decision-making contexts. Studies 1-3 aimed to reconcile this tension by showing that although individuals are seen as more equal with respect to negative rights not to be harmed or killed (though not completely equal), they are seen as less equal with respect to positive rights to be aided or saved. Age exerts a large and systematic impact on decisions about who to save and about whose death is more tragic, suggesting that individuals are seen as possessing differing amounts of contingent value. These initial studies also yielded the novel finding that, although children are prioritized over adults, older children are often prioritized over younger children. Study 4 replicated this finding with a think-aloud methodology; the study showed that the preference for older children appears to be driven by their having had more invested in their lives, their better developed social relations, and their greater understanding of death. Studies 5a-5c demonstrated the independent causal effects of each of these variables on judgments of life's value. Finally, in Studies 6 and 7, mediation methods were used to show that older children's more meaningful social relations primarily explain the greater value of older than of younger children. These findings have implications for bioethics and medical policy. PMID- 23647312 TI - Synthesis of tetrasubstituted unsymmetrical 1,4-enediones via copper-promoted autotandem catalysis and air as the oxidant. AB - An efficient procedure has been developed for the preparation of tetrasubstituted unsymmetrical 1,4-enediones via copper-promoted autotandem catalysis and air as the oxidant. Various N-nucleophiles are compatible with this reaction, such as morpholine, piperidine, pyrrolidine, arylamines, pyrazole, imidazole, benzimidazole, and benzotriazole. This reaction also has significant advantages in easily available substrates, atom economy, bond-forming efficiency, and environmental benignity. PMID- 23647313 TI - Interaction of multiwalled carbon nanotubes with supported lipid bilayers and vesicles as model biological membranes. AB - The influence of solution chemistry on the kinetics and reversibility of the deposition of multiwalled carbon nanotubes (MWNTs) on model biological membranes was investigated using a quartz crystal microbalance with dissipation monitoring (QCM-D). Supported lipid bilayers (SLBs) comprised of zwitterionic 1,2-dioleoyl sn-glyero-3-phosphocholine (DOPC), as well as DOPC vesicles, were used as model cell membranes. Under neutral pH conditions, the deposition kinetics of MWNTs on SLBs increased with increasing electrolyte (NaCl and CaCl2) concentrations. In the presence of NaCl, favorable deposition was not achieved even at a concentration of 1 M, which is attributed to the presence of strong repulsive hydration forces due to the highly hydrophilic headgroups of SLBs. Conversely, favorable deposition was observed at CaCl2 concentrations above 0.5 mM when the charge of SLBs was reversed from negative to positive through the binding of Ca(2+) cations to the exposed phosphate headgroups. Favorable nanotube deposition was also observed at pH 2, at which the DOPC SLBs exhibited positive surface charge, since the isoelectric point of DOPC is ca. 4. When MWNTs on SLBs were rinsed with low ionic strength solutions at pH 7.3, only ca. 20% of deposited nanotubes were released, indicating that nanotube deposition was mostly irreversible. The deposition of MWNTs on DOPC vesicles under favorable deposition conditions did not result in any detectable leakage of solution from the vesicles, indicating that MWNTs did not severely disrupt the DOPC bilayers upon attachment. PMID- 23647315 TI - Mobility and microbial activity of allelochemicals in soil. AB - The action of allelochemicals in soil needs their presence in the vicinity of the target plants. Using a soil TLC combined with bioassay approach, the mobility of 10 typical allelochemicals was evaluated. Ferulic, p-hydroxymandelic, p hydroxybenzoic, and vanillic acids always had the lowest mobility (Rf < 0.1), whereas phenolic aldehyde and lactone (vanillin and coumarin) showed the highest mobility (Rf > 0.5). The Rf values of daidzein, 1alpha-angeloyloxycarotol, DIMBOA, and m-tyrosine ranged from 0.24 to 0.32. Binary mixtures of these allelochemicals led to an increase in mobility factors for selected combinations. Phospholipid fatty acid profiling indicated that there were different soil microbial communities in the segments containing allelochemicals residues in the developed TLC soil layer. A difference in microbial community structure occurred between two nitrogenous DIMBOA and m-tyrosine and another eight allelochemicals. The results suggest that the soil activity of allelochemicals on bioassay species and microbial communities depends on their mobility in soil. PMID- 23647314 TI - Optimal blood pressure for cognitive function: findings from an elderly African American cohort study. AB - OBJECTIVES: To report the results from a prospective cohort study on the association between blood pressure (BP) and cognitive function in elderly African Americans. DESIGN: Prospective cohort study conducted from 1997 to 2009. SETTING: Community-based study in Indianapolis. PARTICIPANTS: African Americans aged 65 years or older (N = 3,145). MEASUREMENTS: At each assessment, participant cognitive function was measured using the Community Screening Interview for Dementia. Other measurements included BP, height, weight, education level, antihypertensive medication use, alcohol use, smoking, and history of chronic medical conditions. RESULTS: Longitudinal assessments (n = 5,995) contributed by 2,721 participants with complete independent variables were analyzed using a semiparametric mixed-effects model. Systolic BP (SBP) of approximately 135 mmHg and diastolic BP (DBP) of approximately 80 mmHg were associated with optimal cognitive function after adjusting for other variables (P = .02). Weight loss with body mass index < 30.0 kg/m(2) was significantly related to poorer cognitive performance (P < .001). Older age at first assessment, lower education level; smoking; and history of depression, stroke, and diabetes mellitus were related to worse cognitive function; taking antihypertensive medication and drinking alcohol were associated with better cognitive function. CONCLUSION: High and low BP were associated with poorer cognitive performance. A joint optimal region of SBP and DBP for cognitive function has been identified, which may provide useful clinical information on optimal BP control in cognitive health and lead to better quality of life for elderly adults. PMID- 23647317 TI - Apology. PMID- 23647316 TI - Reciprocal regulation of calcium-/phosphate-regulating hormones in cyclists during the Giro d'Italia 3-week stage race. AB - Calcium and phosphate are essential for cell functions, and their serum concentrations result from the balance between intestinal absorption, bony storage, and urinary excretion. Fibroblast growth factor 23 (FGF23), expressed by osteocytes and osteoblasts, acts in the kidney, leading to hypophosphatemia and low 1,25-dihydroxycholecalciferol synthesis, but suppresses parathyroid function. The aim of this study was to explore the effects of a high-energy demanding cycling race on this bone-kidney-parathyroid axis. We studied nine cyclists during the 2011 Giro d'Italia stage race. Pre-analytical and analytical phases followed academic and anti-doping recommendations. Serum parathyroid hormone (PTH), 25(OH)D, total calcium, inorganic phosphorus, and plasma FGF23 were measured on days -1, 12, and 22 and corrected for changes in plasma volume. Dietary calcium and phosphorus, anthropometric parameters (height, weight, and body mass index) and indexes of metabolic effort (net energy expenditure, power output) were recorded. Dietary calcium and phosphorus intakes were kept at the same levels throughout the race. Twenty-five (OH)D, PTH, and calcium concentrations remained stable. FGF23 increased 50% with a positive correlation with the indexes of metabolic effort and, consequently, phosphorous decreased, although only in the first half. The strong metabolic effort acts on the bone kidney-parathyroid system, and the rise in FGF23 plasma concentration might be aimed at maintaining calcium and phosphorus homeostasis. PMID- 23647318 TI - False-positive PET scan after bone marrow biopsy. PMID- 23647319 TI - Remarkable order of a high-performance polymer. AB - We directly image the rich nanoscale organization of the high performance, n-type polymer poly{[N,N'-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6 diyl]-alt-5,5'-(2,2'-bithiophene)} (P(NDI2OD-T2)) using a combination of high resolution transmission electron microscopy and scanning transmission electron microscopy. We demonstrate that it is possible to spatially resolve "face-on" lamella through the 2.4 nm alkyl stacking distance corresponding to the (100) reflection. The lamella locally transition between ordered and disordered states over a length scale on the order of 10 nm; however, the polymer backbones retain long-range correlations over length-scales approaching a micrometer. Moreover, we frequently observe overlapping structure implying a number of layers may exist throughout the thickness of the film (~20 nm). The results provide a simple picture, a highly ordered lamella nanostructure over nearly the entire film and ordered domains with overlapping layers providing additional interconnectivity, which unifies prior seemingly contradictory conclusions surrounding this remarkable, high-mobility material. PMID- 23647320 TI - Serum alpha1-proteinase inhibitor concentrations in healthy dogs--method validation and determination of reference interval and intra-individual variation. AB - BACKGROUND: A chronic loss of canine alpha1 -proteinase inhibitor (calpha1 -PI) into the gastrointestinal (GI) tract could change the systemic proteinase proteinase inhibitor balance. Serum calpha1 -PI concentrations have not been studied in dogs with well-defined GI diseases. OBJECTIVES: To further evaluate serum calpha1 -PI concentrations in dogs with GI diseases, the objectives of this study were to (1) analytically validate a previously developed fecal calpha1 -PI immunoassay to determine serum concentrations, (2) determine a population-based reference interval (RI) and assess the clinical utility, (3) determine stability of serum calpha1 -PI, (4) determine the intra-individual variation in healthy dogs, and (5) determine the clinically relevant magnitude of change of serum calpha1 -PI. METHODS: Prestudy validation of the (125) I-calpha1 -PI immunoassay included linearity, spiking recovery, and intra- and inter-assay precision. A RI was calculated with samples of healthy dogs. Stability at -20 degrees C was tested on 36 samples. Intra-individual variation was assessed using samples collected from 11 healthy dogs over a 12-week period. RESULTS: The calpha1 -PI radioimmunoassay (RIA) was linear, accurate, precise, and reproducible. Serum calpha1 -PI decreased by 11% after one year at -20 degrees C. Analytical, intra individual, inter-individual, and total variation were 6.4, 9.9, 9.0, and 25.3%, respectively. The RI for serum calpha1 -PI was 732-1802 mg/L (n = 87); there were no differences between sex and age groups. The index of individuality was 1.31. As analytical variation was > 1/2 inter-individual variation, the minimum critical difference was not determined. CONCLUSIONS: The results of this study provide the basis for further evaluating serum calpha1 -PI in dogs with GI disease. Using a population-based RI for serum calpha1 -PI appears to be appropriate. PMID- 23647321 TI - Development of Streptococcus gordonii-specific quantitative real-time polymerase chain reaction primers based on the nucleotide sequence of rpoB. AB - In this study, Streptococcus gordonii-specific quantitative real-time polymerase chain reaction (qPCR) primers, RTSgo-F2/RTSgo-R2, were developed based on the nucleotide sequences of RNA polymerase beta-subunit gene (rpoB). The specificity of the RTSgo-F2/RTSgo-R2 primers was assessed by conventional PCR on 99 strains comprising 63 oral bacterial species, including the type strain and eight clinical isolates of S. gordonii. PCR products were amplified from the genomic DNAs of only S. gordonii strains. The qPCR primers were able to detect as little as 40 fg of S. gordonii genomic DNA at a cycle threshold value of 33. These findings suggest that these qPCR primers detect S. gordonii with high specificity and sensitivity. PMID- 23647322 TI - Use of machine learning methods to reduce predictive error of groundwater models. AB - Quantitative analyses of groundwater flow and transport typically rely on a physically-based model, which is inherently subject to error. Errors in model structure, parameter and data lead to both random and systematic error even in the output of a calibrated model. We develop complementary data-driven models (DDMs) to reduce the predictive error of physically-based groundwater models. Two machine learning techniques, the instance-based weighting and support vector regression, are used to build the DDMs. This approach is illustrated using two real-world case studies of the Republican River Compact Administration model and the Spokane Valley-Rathdrum Prairie model. The two groundwater models have different hydrogeologic settings, parameterization, and calibration methods. In the first case study, cluster analysis is introduced for data preprocessing to make the DDMs more robust and computationally efficient. The DDMs reduce the root mean-square error (RMSE) of the temporal, spatial, and spatiotemporal prediction of piezometric head of the groundwater model by 82%, 60%, and 48%, respectively. In the second case study, the DDMs reduce the RMSE of the temporal prediction of piezometric head of the groundwater model by 77%. It is further demonstrated that the effectiveness of the DDMs depends on the existence and extent of the structure in the error of the physically-based model. PMID- 23647323 TI - Giant electroresistance of super-tetragonal BiFeO3-based ferroelectric tunnel junctions. AB - Ferroelectric tunnel junctions enable a nondestructive readout of the ferroelectric state via a change of resistance induced by switching the ferroelectric polarization. We fabricated submicrometer solid-state ferroelectric tunnel junctions based on a recently discovered polymorph of BiFeO3 with giant axial ratio ("T-phase"). Applying voltage pulses to the junctions leads to the highest resistance changes (OFF/ON ratio >10,000) ever reported with ferroelectric tunnel junctions. Along with the good retention properties, this giant effect reinforces the interest in nonvolatile memories based on ferroelectric tunnel junctions. We also show that the changes in resistance scale with the nucleation and growth of ferroelectric domains in the ultrathin BiFeO3 (imaged by piezoresponse force microscopy), thereby suggesting potential as multilevel memory cells and memristors. PMID- 23647324 TI - Porphyrin-sensitized solar cells: effect of carboxyl anchor group orientation on the cell performance. AB - The effect of the orientation of the porphyrin sensitizer onto the TiO2 surface on the performance of dye-sensitized solar cells (DSSCs) is reported. Free-base and zinc porphyrins bearing a carboxyl anchoring group at the para, meta, or ortho positions of one of the meso-phenyl rings were synthesized for application in Gratzel-type photoelectrochemical cells. The remainder of the meso-phenyl rings was substituted with alkyl chains of different length to visualize any aggregation effects. Absorption and fluorescence studies were performed to characterize and observe spectral coverage of the thirteen newly synthesized porphyrin derivatives. Photoelectrochemical studies were performed after immobilization of porphyrins onto nanocrystalline TiO2 and compared with DSSC constructed using N719 dye as reference. The performance of DSSCs with the porphyrin anchoring at the para or meta position were found to greatly exceed those with the anchoring group in the ortho position. Additionally, cells constructed using zinc porphyrin derivatives outperformed the free-base porphyrin analogs. Better dye regeneration efficiency for the zinc porphyrin derivatives compared to their free-base porphyrin analogs, and for the meta and para derivatives over the ortho derivatives was evaluated from electrochemical impedance spectroscopy studies. Femtosecond transient absorption spectroscopy studies were performed to probe the kinetics of charge injection and charge recombination with respect to the orientation of porphyrin macrocycle on TiO2 surface. The ortho porphyrin derivative with an almost flat orientation to the TiO2 surface revealed fast charge recombination and suggested occurrence of through-space charge transfer. The overall structure-performance trends observed for the present porphyrin DSSCs have been rationalized based on spectral, electrochemical, electrochemical impedance spectroscopy, and transient spectroscopy results. PMID- 23647325 TI - Finally, someone who "gets" me! Multiracial people value others' accuracy about their race. AB - Monoracial people typically encounter correct views about their race from others. Multiracial people, however, encounter different views about their race depending on the situation. As a result, multiracial (but not monoracial) people may regard race as a less visible aspect of the self that they hope others will verify during social interactions. Multiracial people should therefore value others' accuracy about their race more than monoracial people. In Study 1, multiracial and monoracial participants expected to meet a partner who was accurate or confused about their racial backgrounds. Multiracial (but not monoracial) participants reported heightened interest in interacting with an accurate partner. In Study 2, multiracial (but not monoracial) participants perceived accurate partners as more likely than confused partners to fulfill their needs for self-verification during an interaction. Increased expectations for self verification, moreover, explained multiracial (but not monoracial) participants' heightened interest in interacting with accurate partners. The results suggest that multiracial (but not monoracial) people view race as an aspect of the self (like personality traits or values) requiring verification from others during interactions. PMID- 23647326 TI - An introduction to the composition of the Multi-Site University Study of Identity and Culture (MUSIC): a collaborative approach to research and mentorship. AB - The Multi-Site University Study of Identity and Culture (MUSIC) is the product of a research collaboration among faculty members from 30 colleges and universities from across the United States. Using Katz and Martin's (1997, p. 7) definition, the MUSIC research collaboration is "the working together of researchers to achieve the common goals of producing new scientific knowledge." The collaboration involved more than just coauthorship; it served "as a strategy to insert more energy, optimism, creativity and hope into the work of [researchers]" (Conoley & Conoley, 2010, p. 77). The philosophy underlying the MUSIC collaborative was intended to foster natural collaborations among researchers, to provide opportunities for scholarship and mentorship for early career and established researchers, and to support exploration of identity, cultural, and ethnic/racial research ideas by tapping the expertise and interests of the broad MUSIC network of collaborators. In this issue, five research articles present innovative findings from the MUSIC datasets. There are two themes across the articles. Research is emerging about broadening the constructs and measures of acculturation and ethnic identity and their relation to health risk behaviors and psychosocial and mental health outcomes. The second theme is about the relationship of perceived discrimination on behavioral and mental health outcomes among immigrant populations. PMID- 23647327 TI - Where are you from? A validation of the Foreigner Objectification Scale and the psychological correlates of foreigner objectification among Asian Americans and Latinos. AB - Many ethnic minorities in the United States consider themselves to be just as American as their European American counterparts. However, there is a persistent cultural stereotype of ethnic minorities as foreigners (i.e., the perpetual foreigner stereotype) that may be expressed during interpersonal interactions (i.e., foreigner objectification). The goal of the present study was to validate the Foreigner Objectification Scale, a brief self-report measure of perceived foreigner objectification, and to examine the psychological correlates of perceived foreigner objectification. Results indicated that the Foreigner Objectification Scale is structurally (i.e., factor structure) and metrically (i.e., factor loadings) invariant across foreign-born and U.S.-born Asian Americans and Latinos. Scalar (i.e., latent item intercepts) invariance was demonstrated for the two foreign-born groups and the two U.S.-born groups, but not across foreign-born and U.S.-born individuals. Multiple-group structural equation models indicated that, among U.S.-born individuals, perceived foreigner objectification was associated with less life satisfaction and more depressive symptoms, and was indirectly associated with lower self-esteem via identity denial, operationalized as the perception that one is not viewed by others as American. Among foreign-born individuals, perceived foreigner objectification was not significantly associated directly with self-esteem, life satisfaction, or depressive symptoms. However, perceived foreigner objectification was positively associated with identity denial, and identity denial was negatively associated with life satisfaction. This study illustrates the relevance of perceived foreigner objectification to the psychological well-being of U.S.-born Asian Americans and Latinos. PMID- 23647328 TI - A two-factor model of ethnic identity exploration: Implications for identity coherence and well-being. AB - The purpose of this cross-sectional study was to investigate the multidimensional nature of ethnic identity exploration and its relevance for a broader sense of identity and well-being. Participants were 3,637 ethnic minority college students who completed survey measures of ethnic identity exploration, general identity coherence, general identity confusion, and well-being. Consistent with our 3 hypotheses, the results indicated that (a) ethnic identity exploration comprised 2 dimensions, participation and search; (b) participation was positively associated with well-being, whereas search was negatively associated with well being; and (c) identity coherence and identity confusion mediated the associations between participation and search, respectively, and well-being. These findings have important theoretical implications for conceptualization and measurement of ethnic identity exploration and its association with well-being. PMID- 23647329 TI - Testing Jessor's problem behavior theory and syndrome: a nationally representative comparative sample of Latino and African American adolescents. AB - Based on Jessor's problem behavior theory (PBT; R. Jessor, 1987, Problem-behavior theory, psychosocial development, and adolescent problem drinking, British Journal of Addiction, Vol. 82, pp. 331-342), the comparability of a second-order problem behavior model (SPBM) was investigated employing structural equation modeling (SEM) and latent mean differences in problem behavior engagement were examined among racial/ethnic adolescents. Within a span of nearly 25 years, this study represents the first nationally representative sample of Latino and African American adolescents utilized in testing Jessor's PBT and problem behavior syndrome (PBS). Using a sample of 5,831 Latino, African American, and European American adolescents drawn from the National Longitudinal Study of Adolescent Health, a series of invariance tests evidenced support for Jessor's PBT and PBS. Latent mean difference test results evidenced significant differences in problem behaviors (e.g., academic failure [AF], aggression [AG], substance use [SU], and risky sexual activity[RSA]) across racial/ethnic adolescent groups, which could be explained partially by PBS. A discussion of findings, limitations, and recommendations for future research is presented. PMID- 23647330 TI - Racial identity mediates the association between ethnic-racial socialization and depressive symptoms. AB - Ethnic-racial socialization has been positively linked with psychological adjustment; however, the mechanisms underlying this association remain unclear. In this study, the authors examined the mediating role of racial identity in the association between racial socialization and depressive symptoms. Participants were 211 African American young adults (62% female; mean age = 20.73, SD = 1.90) recruited from a predominately White southeastern university. Multivariate mediation analyses revealed an indirect effect of racial pride messages on depressive symptoms through private regard such that individuals who reported receiving more frequent racial pride messages were more likely to feel positively about their race, and, in turn, less likely to report depressive symptoms. Individuals who reported that their parents engaged in more socialization activities (e.g., attending cultural events) were also more likely to feel positively about their race and, in turn, report fewer depressive symptoms. These results suggest that positive feelings about one's race are important considerations in our understanding of the relation between ethnic-racial socialization and youth psychological adjustment. PMID- 23647332 TI - Native American undergraduate students' persistence intentions: a psychosociocultural perspective. AB - Attending to persistence intentions among Native American students enrolled in institutions of higher education is critical, given low retention rates. The purpose of the study was twofold: (a) we developed and examined the psychometric properties of a new measure, the Native American Collective Pursuits of Education (NACOPE), and (b) we explored persistence attitudes among 156 Native American students using Gloria and Rodriguez's (2000) psychosociocultural framework. Pilot data and exploratory analysis supported the psychometric properties of the NACOPE and its use to understand educational experiences for Native American students. Results also supported the prediction of culturally relevant noncognitive variables to persistence intentions. Limitations, directions for future research, and implications for higher education are discussed. PMID- 23647331 TI - Can additive measures add to an intersectional understanding? Experiences of gay and ethnic discrimination among HIV-positive Latino gay men. AB - The current study investigated a methodological question of whether traditional, additive, quantitative data can be used to address intersectional issues, and illustrated such an approach with a sample of 301 HIV-positive, Latino gay men in the United States. Participants were surveyed using A-CASI. Hierarchical logistic set regression investigated the role of sets of variables reflecting demographic characteristics, gender nonconformity, and gay and ethnic discrimination in relation to depression and gay collective identity. Results showed the discrimination set was related to depression and to gay collective identity, as was gender nonconformity. Follow-up logistic regression showed that both types of discrimination were associated with greater depression, but gender nonconformity was not. Gay discrimination and gender nonconformity were positively associated with gay collective identity, whereas ethnic discrimination was negatively associated. Results are discussed in terms of the use of traditional quantitative data as a potential means of understanding intersectional issues, as well as of contributing to knowledge about individuals facing multiple structural inequalities. PMID- 23647334 TI - BiVO4-silica composites containing cobalt phthalocyanine groups: synthesis, characterization and application in photodegradation of 2,4,6-trichlorophenol. AB - BiVO4-silica composites were prepared and grafted with sulfonated cobalt phthalocyanine. The structural and chemical properties including crystalline phase, specific surface area, UV-Visible diffuse reflectance behavior, morphology and photocatalytic activity were investigated. Depending on the silica content and subsequently amounts of loaded phthalocyanine, various catalytic activities were observed. The sample containing nominal 15% silica and grafted with phthalocyanine showed less aggregated form of this organic dye, smaller and nanometric particles, and higher photocatalytic activity in degradation of 2,4,6 trichlorophenol. PMID- 23647335 TI - Botulinum neurotoxin G binds synaptotagmin-II in a mode similar to that of serotype B: tyrosine 1186 and lysine 1191 cause its lower affinity. AB - Botulinum neurotoxins (BoNTs) block neurotransmitter release by proteolyzing SNARE proteins in peripheral nerve terminals. Entry into neurons occurs subsequent to interaction with gangliosides and a synaptic vesicle protein. Isoforms I and II of synaptotagmin were shown to act as protein receptors for two of the seven BoNT serotypes, BoNT/B and BoNT/G, and for mosaic-type BoNT/DC. BoNT/B and BoNT/G exhibit a homologous binding site for synaptotagmin whose interacting part adopts helical structure upon binding to BoNT/B. Whereas the BoNT/B-synaptotagmin-II interaction has been elucidated in molecular detail, corresponding information about BoNT/G is lacking. Here we systematically mutated the synaptotagmin binding site in BoNT/G and performed a comparative binding analysis with mutants of the cell binding subunit of BoNT/B. The results suggest that synaptotagmin takes the same overall orientation in BoNT/B and BoNT/G governed by the strictly conserved central parts of the toxins' binding site. The surrounding nonconserved areas differently contribute to receptor binding. Reciprocal mutations Y1186W and L1191Y increased the level of binding of BoNT/G approximately to the level of BoNT/B affinity, suggesting a similar synaptotagmin bound state. The effects of the mutations were confirmed by studying the activity of correspondingly mutated full-length BoNTs. On the basis of these data, molecular modeling experiments were employed to reveal an atomistic model of BoNT/G-synaptotagmin recognition. These data suggest a reduced length and/or a bend in the C-terminal part of the synaptotagmin helix that forms upon contact with BoNT/G as compared with BoNT/B and are in agreement with the data of the mutational analyses. PMID- 23647336 TI - Distinct response components indicate that binding is the primary cause of response repetition effects. AB - Humans must constantly react to their environments. In many cases, repeating a response results in performance benefits, but sometimes it results in performance costs. This dichotomy is referred to as response repetition effects (RR effects). To understand these effects, we dissociated 2 components of a response: response categories (response meaning) and motor responses (response execution). By doing so, we were able to examine 2 proposed explanations of RR effects. One, the response inhibition account, explains that RR effects are the product of an inhibitory mechanism meant to prevent accidental reexecution of responses and stimulus category repetition priming. The response inhibition account predicts additive effects of response inhibition and stimulus category priming. Another, the binding account, explains that RR effects are the product of interference from automatically retrieved memories of previous events. The binding account predicts an interactive relationship between the transitions of task, response category, and motor response; a partial repetition of trial components (i.e., the task, the response category, and the motor response) will result in interference when compared with repeating all or switching all components. In Experiments 1 and 2, response components were dissociated by using a verification procedure. In Experiment 3, the response components were dissociated by varying the motor response used to indicate each response category. We found an interactive relationship between the transitions of task, response category, and motor response, demonstrating the role of binding in RR effects. In combination with previous results, our results suggest that binding and response inhibition are separable components of RR effects. PMID- 23647337 TI - A diffusion model account of masked versus unmasked priming: are they qualitatively different? AB - In the past decades, hundreds of articles have explored the mechanisms underlying priming. Most researchers assume that masked and unmasked priming are qualitatively different. For masked priming, the effects are often assumed to reflect savings in the encoding of the target stimulus, whereas for unmasked priming, it has been suggested that the effects reflect the familiarity of the prime-target compound cue. In contrast, other researchers have claimed that masked and unmasked priming reflect essentially the same core processes. In this article, we use the diffusion model (R. Ratcliff, 1978, A theory of memory retrieval, Psychological Review, Vol. 85, pp. 59-108) to account for the effects of masked and unmasked priming for identity and associatively related primes. The fits of the model led us to the following conclusion: Masked related primes give a head start to the processing of the target compared with unrelated primes, whereas unmasked priming affects primarily the quality of the lexical information. PMID- 23647338 TI - Thermospermine levels are controlled by an auxin-dependent feedback loop mechanism in Populus xylem. AB - Polyamines are small polycationic amines that are widespread in living organisms. Thermospermine, synthesized by thermospermine synthase ACAULIS5 (ACL5), was recently shown to be an endogenous plant polyamine. Thermospermine is critical for proper vascular development and xylem cell specification, but it is not known how thermospermine homeostasis is controlled in the xylem. We present data in the Populus model system supporting the existence of a negative feedback control of thermospermine levels in stem xylem tissues, the main site of thermospermine biosynthesis. While over-expression of the ACL5 homologue in Populus, POPACAULIS5, resulted in strong up-regulation of ACL5 expression and thermospermine accumulation in leaves, the corresponding levels in the secondary xylem tissues of the stem were similar or lower than those in the wild-type. POPACAULIS5 over-expression had a negative effect on accumulation of indole-3 acetic acid, while exogenous auxin had a positive effect on POPACAULIS5 expression, thus promoting thermospermine accumulation. Further, over-expression of POPACAULIS5 negatively affected expression of the class III homeodomain leucine zipper (HD-Zip III) transcription factor gene PttHB8, a homologue of AtHB8, while up-regulation of PttHB8 positively affected POPACAULIS5 expression. These results indicate that excessive accumulation of thermospermine is prevented by a negative feedback control of POPACAULIS5 transcript levels through suppression of indole-3-acetic acid levels, and that PttHB8 is involved in the control of POPACAULIS5 expression. We propose that this negative feedback loop functions to maintain steady-state levels of thermospermine, which is required for proper xylem development, and that it is dependent on the presence of high concentrations of endogenous indole-3-acetic acid, such as those present in the secondary xylem tissues. PMID- 23647339 TI - Phylogenetic diversity of bacteria isolated from sick dogs using the BAPGM enrichment culture platform. AB - BACKGROUND: Bartonella alpha-Proteobacteria growth medium (BAPGM) enrichment culture has proven useful for documenting Bartonella species infection and has facilitated growth of other fastidious bacteria from human samples. PURPOSE: To report non-Bartonella bacterial isolates obtained from canine samples cultured using BAPGM enrichment culture. ANIMALS: Between 2004 and 2008, 695 specimens from 513 dogs were tested by the NCSU-IPRL using the BAPGM enrichment culture. Over the same period of time, blood samples from 270 dogs were cultured by the NCSU-CML using Bactec-Plus Aerobic/F media. METHODS: BAPGM isolates were characterized using Bartonella genus primers and 16S rDNA primers followed by DNA sequencing. NCSU medical records were retrospectively reviewed. Blood culture results from the NCSU-CML were compared with BAPGM blood culture results. RESULTS: Seventy-nine non-Bartonella isolates were obtained from 69/513 dogs. The most commonly isolated phylum was Proteobacteria (48.1%) with alpha Proteobacteria being the most commonly isolated class. Staphylococcus and Sphingomonas were the most commonly isolated genera. The majority of the remaining isolates were bacteria that are rarely isolated from canine samples. Comparison of NCSU-CML and IPRL (BAPGM) blood culture isolates showed alpha Proteobacteria were isolated more often from BAPGM. CONCLUSIONS AND CLINICAL IMPORTANCE: Use of insect cell culture enrichment medium, such as BAPGM, appears to enhance the growth of alpha-Proteobacteria, but also results in isolation of non-alpha-Proteobacteria from sick dogs. Future studies are needed to elucidate the utility of BAPGM and other "nonconventional" growth media and methods for isolation of fastidious organisms and to determine if these organisms play a causal role in disease development. PMID- 23647340 TI - Clonal relationship of Escherichia coli biofilm producer isolates obtained from mastitic milk. AB - Escherichia coli is capable of producing several virulence factors involved in the pathophysiology of bovine mastitis. Cell surface structures such as flagella, pili, and other outer membrane adhesins are considered essential for biofilm formation on abiotic surfaces. The aim of this study was characterize the molecular profile of E. coli isolates obtained from mastitic milk by using the technique of pulsed-field gel electrophoresis (PFGE) and evaluating results within the pulsetypes formed with the presence of virulence genes involved in biofilm production. Twenty-seven E. coli biofilm-producing isolates were obtained from mastitic milk samples belonging to Brazilian Agricultural Research Corporation; these samples were analyzed by PFGE. We identified 9 (I to IX) different phylogenetic groups with a similarity of 90% and observed the presence of fimA (large subunit of the fimbriae type 1) and csgA gene (large subunit of curli fimbriae) in all isolates. Sixteen isolates had the gene fliC (flagellin). Evaluation of the genetic profile carried out through the PFGE showed that the bacteria do not share the same origin. It was not possible to associate the biofilm production capacity with the presence or absence of related genes. Therefore, strains of environmental mastitis-causing E. coli present different pathotypes. PMID- 23647341 TI - Detection of potential suberinase-encoding genes in Streptomyces scabiei strains and other actinobacteria. AB - Streptomyces scabiei causes common scab, an economically important disease of potato tubers. Some authors have previously suggested that S. scabiei penetration into host plant tissue is facilitated by secretion of esterase enzymes degrading suberin, a lipidic biopolymer of the potato periderm. In the present study, S. scabiei EF-35 showed high esterase activity in suberin-containing media. This strain also exhibited esterase activity in the presence of other biopolymers, such as lignin, cutin, or xylan, but at a much lower level. In an attempt to identify the esterases involved in suberin degradation, translated open reading frames of S. scabiei 87-22 were examined for the presence of protein sequences corresponding to extracellular esterases of S. scabiei FL1 and of the fungus Coprinopsis cinerea VTT D-041011, which have previously been shown to be produced in the presence of suberin. Two putative extracellular suberinase genes, estA and sub1, were identified. The presence of these genes in several actinobacteria was investigated by Southern blot hybridization, and both genes were found in most common-scab-inducing strains. Moreover, reverse transcription - polymerase chain reaction performed with S. scabiei EF-35 showed that estA was expressed in the presence of various biopolymers, including suberin, whereas the sub1 gene appeared to be specifically expressed in the presence of suberin and cutin. PMID- 23647342 TI - Cyclic AMP receptor protein is a repressor of adenylyl cyclase gene cyaA in Yersinia pestis. AB - Yersinia pestis is one of the most dangerous pathogens. The cyclic AMP receptor protein (CRP) is required for the full virulence of Y. pestis, and it acts as a transcriptional regulator to control a large regulon, which includes several virulence-associated genes. The regulatory action of CRP is triggered only by binding to the small molecule cofactor cyclic AMP (cAMP). cAMP is synthesized from adenosine triphosphate by the adenylyl cyclase encoded by cyaA. In the present work, the regulation of crp and cyaA by CRP was investigated by primer extension, LacZ fusion, electrophoretic mobility shift assay, and DNase I footprinting. No transcriptional regulatory association between CRP and its own gene could be detected under the growth conditions tested. In contrast, CRP bound to a DNA site overlapping the core promoter -10 region of cyaA to repress the cyaA transcription. The determination of cellular cAMP levels further verified that CRP negatively controlled cAMP production. Repression of cAMP production by CRP through acting on the cAMP synthesase gene cyaA would represent a mechanism of negative automodulation of cellular CRP function. PMID- 23647343 TI - Biodegradation of cypermethrin by a novel Catellibacterium sp. strain CC-5 isolated from contaminated soil. AB - The bacterial strain CC-5, isolated from contaminated soil and identified as Catellibacterium sp. based on morphology and partial 16S rDNA gene sequence analysis, utilized cypermethrin as its sole carbon source and degraded 97% of 100 mg.L(-1) cypermethrin within 7 days. The optimal degradation conditions were determined to be 30 degrees C and pH 7.0. Degradation was found to follow a first-order model at initial cypermethrin concentrations below 400 mg.L(-1). Strain CC-5 suffered substrate inhibition at high cypermethrin concentrations, and the biodegradation kinetics were successfully described by the Haldane model, with a maximal specific degradation rate of 1.36 day(-1), an inhibition constant of 164.61 mg.L(-1), and a half-saturation constant of 101.12 mg.L(-1). Inoculating cypermethrin-treated soil samples with strain CC-5 resulted in a higher rate of cypermethrin removal than that in noninoculated soil, regardless of whether the soil had previously been sterilized. These results reveal that the bacterial strain may possess potential to be used in bioremediation of pyrethroid contaminated environment. PMID- 23647344 TI - Isolation and characterization of a rare waterborne lytic phage of Salmonella enterica serovar Paratyphi B. AB - A lytic phage of Salmonella serovar Paratyphi B, named phiSPB, was isolated from surface waters of the Pavana River in India. Phage phiSPB is a member of the Podoviridae family and is morphologically similar to the 7-11 phages of the C3 morphotype of tailed phages, characterized by a very long, cigar-shaped head. The head measured approximately 153 * 57 nm, and the tail size was 12 * 7 nm. The phage was stable over a wide range of pH (4-9) and temperature (4-40 degrees C). The adsorption rate constant was 4.7 * 10(-10). Latent and eclipse periods were 10 and 15 min, respectively, and the burst size was 100 plaque-forming units/infected cell after 25 min at 37 degrees C. The phage DNA was 59 kb in size. Ten major proteins were observed on SDS-PAGE, although some of these proteins could be bacterial contaminants. This is the first report of Salmonella enterica subsp. enterica serovar Paratyphi B phage of C3 morphotype from India that has many unique features, such as high replication potential, short replication time, and stability over a wide range of pH and temperature, making it a promising biocontrol agent against the drug-resistant strains of Salmonella Paratyphi B. PMID- 23647345 TI - Diversity of bacterial community during spring phytoplankton blooms in the central Yellow Sea. AB - Bacterial community diversity and the effects of environmental factors on bacterial community composition during 2 spring phytoplankton blooms in the central Yellow Sea were investigated by using denaturing gradient gel electrophoresis (DGGE) and multivariate statistical analysis. The Shannon-Weaver indices (H') of bacterial diversity from samples at station B23 were higher than those at station B20. Cluster analysis based on DGGE band patterns indicated temporal variations of bacterial community at the 2 bloom stations but a vertical distribution pattern only at station B20. The predominant bacterial groups were affiliated with Alphaproteobacteria, Gammaproteobacteria, Cytophaga Flavobacterium-Bacteroides, Deltaproteobacteria, and Actinobacteria. The effects of environmental factors on bacterial community were analyzed by canonical correspondence analysis. Bacterial community structures were significantly affected by silicate at station B20 and by Paralia sulcata and Heterocapsa spp. at station B23. From the results, phytoplankton species composition had a significant effect on bacterial community structure during phytoplankton blooms in the central Yellow Sea. PMID- 23647346 TI - Comparative analysis of induction of osmotic-stress-dependent genes in Vibrio vulnificus exposed to hyper- and hypo-osmotic stress. AB - Vibrio vulnificus, a halophilic pathogenic bacterium of marine environments, encounters changes in salinity in its natural habitat and in the food-processing environment. The comparative response of V. vulnificus to hyperosmotic and hypoosmotic stress in terms of gene expression was investigated. Genes belonging to the proU operon for transport of compatible solutes and compatible solute synthesis were significantly upregulated (3- to 4.7-fold) under hyperosmotic stress. Under hypoosmotic stress, upregulation of genes coding for mechanosensitive channels of small conductance (mscS) was not observed. In hyperosmotic conditions a 2.3-fold decrease in the expression of aqpZ was observed. A 2-fold induction in gyrA was observed in V. vulnificus cells on exposure to hyperosmotic stress. groEL genes, VVA1659 (1.6-fold), and VV3106 (1 fold) were induced in hypoosmotic condition. Results of this study indicate that to manage hyperosmotic stress, V. vulnificus accumulated osmoprotectants through uptake or through endogenous synthesis of compatible solutes. Expression of mscS may not be necessary for immediate protection in cells exposed to hyper- and hypo osmotic stress. Comparative analysis of important osmotic-stress-related genes showed up- or down-regulation of 14 genes in hyperosmotic stress as compared with up- or down-regulation of only 7 genes in hypoosmotic stress, indicating that the cells respond asymmetrically to hyper- and hypo-osmotic stress. PMID- 23647347 TI - Occurrence and population density of Campylobacter jejuni in irrigation ponds on produce farms in the Suwannee River Watershed. AB - Campylobacter spp., especially Campylobacter jejuni, are common causal agents of gastroenteritis globally. Poultry, contaminated water, and fresh produce are considered to be the main sources for infection by this pathogen. In this study, occurrence and population density of C. jejuni from vegetable irrigation ponds in the Suwannee River watershed were investigated and the relationship to environmental factors was analyzed. Two water samples were collected from each of 10 ponds every month from January 2011 to February 2012. Campylobacter jejuni was detected by quantitative real-time PCR. Nine of the 10 ponds were positive for C. jejuni some of the time with an overall prevalence of 19.3%. The highest counts were obtained in spring 2011. Oxidation-reduction potential and total nitrogen concentration were positively correlated (P < 0.05) with mean population and occurrence of C. jejuni, while temperature and dissolved oxygen percent saturation (DO%) were negatively correlated with mean population (P < 0.05). Presence of this pathogen was related to bacterial community composition. No correlations were found between C. jejuni and fecal indicators. Increasing DO% of irrigation water and limiting nitrogen pollution in the ponds are suggested to reduce the contamination risk of C. jejuni in a major fruit and vegetable growing area. PMID- 23647348 TI - Synbiotic administration of canine-derived strain Lactobacillus fermentum CCM 7421 and inulin to healthy dogs. AB - The canine-derived strain Lactobacillus fermentum CCM 7421 has been demonstrated to exert certain health benefits as a probiotic in dogs. Synbiotic combinations are widely used but are rarely studied in dogs. In this study the prebiotic inulin in combination with L. fermentum CCM 7421 was tested for its effects on faecal microbial populations, faecal characteristics, and blood biochemistry in canine experiments. Healthy adult dogs (n = 36) were randomly assigned to 1 of 3 treatment groups (12 dogs/treatment): (i) the control group (C), (ii) the probiotic group (LF group: L. fermentum CCM 7421, 10(8) CFU/mL of Ringer buffer, 0.1 mL/kg of body mass), and (iii) the synbiotic group (LF+I group: L. fermentum CCM 7421 + inulin (I; Raftifeed IPS) added as 1% of diet). The experiment lasted for 7 weeks with a 2-week treatment period. We detected a significant increase of lactic acid bacteria (LF versus C, day 7; LF versus C and LF versus LF+I, days 28 and 49), a decrease of clostridia (LF versus C, day 14), a lower pH value (LF versus LF+I, day 28), and a higher ammonia concentration (LF versus LF+I, days 14 and 49) in faecal samples. The synbiotic LF+I combination did not intensify the probiotic L. fermentum CCM 7421 efficacy, but its slight laxative effect can be useful to prevent constipation, e.g., in senior dogs. PMID- 23647350 TI - Real-time polymerase chain reaction for detection of encapsulated Haemophilus influenzae using degenerate primers to target the capsule transport gene bexA. AB - A real-time polymerase chain reaction assay that uses degenerate primers and a dual-labelled probe was developed to detect the bexA gene of Haemophilus influenzae, including those belonging to non-b serotypes as well as clonal division II strains. This assay is sensitive and specific, detecting 20 copies of the gene, but negative with a variety of bacteria associated with meningitis and bacteremia or septicemia. PMID- 23647351 TI - Population genetics of Haemophilus influenzae serotype a in three Canadian provinces. AB - Haemophilus influenzae serotype a (Hia) is an important pathogen since the introduction of vaccines for control of disease due to serotype b strains. Using a sodC-based polymerase chain reaction, Hia can be divided into 2 phylogenetic divisions, each with their own unique multilocus sequence types. Most Canadian Hia belongs to clonal division I and the ST-23 clonal complex. The recently described hypervirulent clone of ST-4 was found in a single Canadian isolate. Therefore, surveillance of invasive H. influenzae disease should include serotyping to detect Hia and multilocus sequence typing to detect hypervirulent clones. PMID- 23647352 TI - Hemoglobinopathy carrier prevalence in the United Arab Emirates: first analysis of the Dubai Health Authority premarital screening program results. AB - The aim of this study was to determine the prevalence of hemoglobinopathy carriers in United Arab Emirates (UAE) nationals subjected to mandatory premarital screening in Dubai over a 4-year period. Data from UAE nationals who underwent premarital screening by the Dubai Health Authority between January 2007 and December 2010 were collected and analyzed. Premarital screening in Dubai is based on complete blood counts (CBC) and hemoglobin (Hb) high performance liquid chromatography (HPLC). Among the 6,420 UAE nationals screened, 8.5% (n = 545) were suspected to be carriers. The following carrier frequencies were observed: beta-thalassemia (beta-thal), 4.56% (n = 293); Hb S [beta6(A3)Glu->Val, GAG>GTG; HBB: c.20A>T], 2.9% (n = 186); Hb D-Punjab [beta121(GH4)Glu->Gln, GAA>CAA; HBB: c.364G>C], 0.78% (n = 50); Hb Lepore (deltabeta hybrid gene) with an undetermined molecular genotype, 0.17% (n = 11); Hb E [beta26(B8)Glu->Lys, GAG>AAG; HBB: c.79G>A], 0.03% (n = 2); and hereditary persistence of fetal Hb (HPFH), 0.016% (n = 1). Hb E-Hb S and Hb E-beta-thal also occurred at a rate of 0.016% (n = 1) each; and 0.87% (n = 56) subjects were suspected of carrying silent beta-thal. The prevalence of beta-thal trait was consistent with the prevalence published by others in the region. Silent beta-thal is challenging for screening programs, and is expected to arise in populations with a high prevalence of beta-thal carriers. The prevalence of Hb S trait observed in this study was lower than that in other reports for the region. New cases of beta-thal major (beta-TM) still arise because many fertile couples got married before the screening programs were implemented, and pregnancy termination is not widely practiced in the UAE due to religious restraints. Moreover, some couples choose not to have prenatal diagnosis (PND) or pre implantation genetic diagnosis (PGD), even if they are aware of their risk status. The prevalence of beta-thal trait in the UAE is high. This justifies efforts to control the disease by holding regular community awareness and screening programs, performing premarital screening and genetic counseling, and making PND and PGD available to couples who request it. PMID- 23647349 TI - Higher seasonal variation of actinobacterial communities than spatial heterogeneity in the surface sediments of Taihu Lake, China. AB - Much more attention has been paid to the actinobacterial community in soils or water columns of aquatic habitats. However, there are few studies on their composition and diversity in lake sediments. Here, we used denaturing gradient gel electrophoresis and clone libraries of partial 16S rRNA gene to study the spatial variations of actinobacterial communities across 4 seasons in the surface sediments of the shallow, subtropical Taihu Lake. Cluster analysis based on fingerprints showed clear spatiotemporal variations of actinobacterial communities and higher seasonal variation than spatial heterogeneity. Based on clone libraries, this pattern was supported by the principal coordinates analysis in the phylogenetic context and by detrended correspondence analysis on the operational taxonomic unit table. Additionally, phylogenetic analysis showed that the putative freshwater-specific actinobacterial lineages (e.g., acI) were also detected in the lake sediments, which suggests that these subclusters may also adapt to the sediment environments. Summarily, our results suggested that actinobacterial communities of the surface sediments were more affected by seasonal variation than spatial heterogeneity in the intrahabitat of Taihu Lake. PMID- 23647353 TI - Improving carbon nitride photocatalysis by supramolecular preorganization of monomers. AB - Here we report a new and simple synthetic pathway to form ordered, hollow carbon nitride structures, using a cyanuric acid-melamine (CM) complex in ethanol as a starting product. A detailed analysis of the optical and photocatalytic properties shows that optimum hollow carbon nitride structures are formed after 8 h of condensation. For this condensation time, we find a significantly reduced fluorescence intensity and lifetime, indicating the formation of new, nonradiative deactivation pathways, probably involving charge-transfer processes. Enhanced charge transfer is seen as well from a drastic increase of the photocatalytic activity in the degradation of rhodamine B dye, which is shown to proceed via photoinduced hole transfer. Moreover, we show that various CM morphologies can be obtained using different solvents, which leads to diverse ordered carbon nitride architectures. In all cases, the CM-C3N4 structures exhibited superior photocatalytic activity compared to the bulk material. The utilization of CM hydrogen-bonded complexes opens new opportunities for the significant improvement of carbon nitride synthesis, structure, and optical properties toward an efficient photoactive material for catalysis. PMID- 23647354 TI - Selective synthesis of [2]- and [3]catenane tuned by ring size and concentration. AB - The syntheses of [2]- and [3]catenanes by olefin metathesis and oxidative acetylide coupling have been studied in detail. Pseudorotaxanes that were obtained by mixing crown ether and ammonium salts containing two terminal reactive end-groups were converted to [2]- and [3]catenane. Their yields were influenced not only by the chain length of the ammonium salts but also by the concentration of the crown ether and the ammonium salts. The strain energies of [2]catenane were responsible for the formation of [2]catenane. PMID- 23647355 TI - Effects of Head Start REDI on children's outcomes 1 year later in different kindergarten contexts. AB - One year after participating in the Research-based, Developmentally Informed (REDI) intervention or "usual practice" Head Start, the learning and behavioral outcomes of 356 children (17% Hispanic, 25% African American; 54% girls; Mage = 4.59 years at initial assessment) were assessed. In addition, their 202 kindergarten classrooms were evaluated on quality of teacher-student interactions, emphasis on reading instruction, and school-level student achievement. Hierarchical linear analyses revealed that the REDI intervention promoted kindergarten phonemic decoding skills, learning engagement, and competent social problem-solving skills, and reduced aggressive-disruptive behavior. Intervention effects on social competence and inattention were moderated by kindergarten context, with effects strongest when children entered schools with low student achievement. Implications are discussed for developmental models of school readiness and early educational programs. PMID- 23647356 TI - Effectiveness of two intracanal dressings in adult Portuguese patients: a qPCR and anaerobic culture assessment. AB - AIM: To quantify bacterial equivalents before and after chemomechanical preparation using 3% sodium hypochlorite (NaOCl) and intracanal dressing with calcium hydroxide paste (Ca(OH)2 ) or 2% Chlorhexidine digluconate gel (CHX) in necrotic pulps associated or not with apical periodontitis and to further compare this quantification with counts of anaerobic microorganisms. METHODOLOGY: Prospective clinical trial in 69 single-rooted adult teeth (strict inclusion criteria); CHX group: 34; Ca(OH)2 group: 35. Bacteria samples were taken at baseline (S1), after chemomechanical preparation (S2) and after 14 days of intracanal dressing (S3). Bacterial equivalents were assessed by broad-range real time polymerase chain reaction (qPCR), and live viable bacteria measured with conventional anaerobic culture (CFU/mL). Descriptive/inferential analysis was performed with spss vs. 20.0 (alpha = 0.05) using the Kruskal-Wallis, Mann Whitney and chi-squared tests and Spearman's correlation coefficients. RESULTS: Both groups showed a significant decrease between S1 and S2 (Mann-Whitney U-test; P < 0.001) both in qPCR and in culture. In the Ca(OH)2 -group, no variation was observed between S2 and S3 by qPCR and culture. In contrast, the CHX group showed a significant increase from S2 to S3 by both techniques. The two groups were only significantly different in S3 (Mann-Whitney U-test; P <= 0.001), with a worse performance in the CHX group. Again, these results were congruent by both approaches. Data from both approaches correlate reasonably (rS < 0.5). CONCLUSIONS: Infected root canals contained a high bacterial load, and the chemomechanical root canal preparation reduced bacterial equivalents by 99.1% and anaerobic counts by 98.5%. Intracanal dressings were not efficient at reducing bacterial load, but the 14-day intracanal dressing with Ca(OH)2 performed significantly better than CHX, particularly in cases with apical periodontitis. PMID- 23647357 TI - Whey protein hydrolysate augments tendon and muscle hypertrophy independent of resistance exercise contraction mode. AB - In a comparative study, we investigated the effects of maximal eccentric or concentric resistance training combined with whey protein or placebo on muscle and tendon hypertrophy. 22 subjects were allocated into either a high-leucine whey protein hydrolysate + carbohydrate group (WHD) or a carbohydrate group (PLA). Subjects completed 12 weeks maximal knee extensor training with one leg using eccentric contractions and the other using concentric contractions. Before and after training cross-sectional area (CSA) of m. quadriceps and patellar tendon CSA was quantified with magnetic resonance imaging and a isometric strength test was used to assess maximal voluntary contraction (MVC) and rate of force development (RFD). Quadriceps CSA increased by 7.3 +/- 1.0% (P < 0.001) in WHD and 3.4 +/- 0.8% (P < 0.01) in PLA, with a greater increase in WHD compared to PLA (P < 0.01). Proximal patellar tendon CSA increased by 14.9 +/- 3.1% (P < 0.001) and 8.1 +/- 3.2% (P = 0.054) for WHD and PLA, respectively, with a greater increase in WHD compared to PLA (P < 0.05), with no effect of contraction mode. MVC and RFD increased by 15.6 +/- 3.5% (P < 0.001) and 12-63% (P < 0.05), respectively, with no group or contraction mode effects. In conclusion, high leucine whey protein hydrolysate augments muscle and tendon hypertrophy following 12 weeks of resistance training - irrespective of contraction mode. PMID- 23647358 TI - A review of the application of near-infrared spectroscopy for the analysis of potatoes. AB - Potato (Solanum tuberosum L.) is one of the most important crops in the world being considered as a staple food in many developing countries. The potato industry like other vegetable and fruit industries is subject to the current demand of quality products. In order to meet this challenge, the food industry is relying on the adoption of nondestructive and environmentally friendly techniques to determine quality of products. Near-infrared spectroscopy (NIRS) is currently one of the most advanced nondestructive technologies regarding instrumentation and application, and it also complies with the environment requirements as it does not generate emissions or waste. This paper reviews research progress on the analysis of potatoes by NIRS both in terms of determination of constituents and classification according to the different constituents of the tubers. A brief description of the fundamentals of NIRS technology and its advantages over other quality assessment techniques is included. Finally, future prospects of the development of NIRS technology at the industrial level are explored. PMID- 23647359 TI - Design and fabrication of superamphiphobic paper surfaces. AB - Cellulose-based paper remains a vital component of modern day society; however, its use is severely limited in certain applications because of hydrophilic and oleophilic properties. In this manuscript we present a novel method to create superamphiphobic paper by combining the control of fiber size and structure with plasma etching and fluoropolymer deposition. The heterogeneous nature of the paper structure is drastically different from that of artificially created superamphiphobic surfaces. By refining the wood fibers, smaller diameter fibers (fibrils) are created to support fluid droplets. After oxygen plasma etching and deposition of a fluoropolymer film, paper samples are able to support motor oil contact angles of 149 +/- 3 degrees , although these structures readily absorb n hexadecane. Exchange of water in the pulp solution with sec-butanol provides additional control over fiber spacing to create superamphiphobic substrates with contact angles >150 degrees for water, ethylene glycol, motor oil, and n hexadecane. PMID- 23647360 TI - A phenomenological model for particle retention in single, saturated fractures. AB - Fractured aquifers are some of the most poorly characterized subsurface environments despite posing one of the highest risks to the protection of potable groundwater. This research was designed to improve the understanding of the factors affecting particle transport through fractures by developing a phenomenological model based on laboratory-scale transport data. The model presented in this research employed data from over 70 particle tracer tests conducted in single, saturated, variable-aperture fractures that were obtained from the natural environment and fractured in the laboratory or cast from epoxy in the laboratory. The particles employed were Escherichia coli RS2-GFP and microspheres. The tracer experiments were conducted in natural (dolomitic limestone and granite) as well as epoxy replicas of the natural fractures. The multiple linear regression analysis revealed that the most important factors influencing particle retention in fractures are the ratio of the ionic strength of solution to collector charge, the ratio of particle to collector charge, and the ratio of advective to diffusive forces as described by the Peclet number. The model was able to reasonably (R(2) = 0.64) predict the fraction of particles retained; however, it is evident that some factors not accounted for in the model also contributed to retention. This research presents a novel approach to understanding particle transport in fractures, and illustrates the relative importance of various factors affecting the transport mechanisms. The utility of this model lies in the increased understanding of particle transport in fractures, which is extremely useful for directing future research. PMID- 23647362 TI - Computer simulation of fifth generation dendronized polymers: impact of charge on internal organization. AB - The internal organization of a fifth-generation dendronized polymer (PG5) has been investigated by atomistic molecular dynamics simulations in a vacuum. This study reveals an exceptional behavior of PG5 within the homologous series of g generation PGg polymers. Three molecular configurations, which present a heterogeneous distribution of dendrons and an amount of backfolding lower than PG4 and PG6, have been obtained for PG5. The highest stability and closest agreement with available experimental data corresponds to a helical conformation characterized by a pitch of about 30 A, thickness of 105 A, and average density of 0.861 g/cm(3). While small angle neutron scattering studies of PG5 in solution show a constant radial density distribution around the backbone, we here in our vacuum studies find a cylindrical volume element of sharply reduced density reminiscent of a pore. This neutral PG5 was compared with its charged deprotected analogue, dePG5 in water, to see in as much the positive charges in the periphery of this macromolecule would affect its conformational behavior. During deprotection of PG5, the tert-butyloxycarbonyl protected amine groups are converted into ammonium, mimicking the experimental situation during a divergent synthesis procedure. The repulsive interactions among the positively charged ammonium groups are responsible for a huge (~30%) reduction of the average density and a small (~1%) increase of elongation of the helical backbone, which results in a structure with a spongy appearance. Also here, we find a reduced dendron density near the backbone which is compensated for by the pore being filled with water. PMID- 23647361 TI - Light-controlled graphene-elastin composite hydrogel actuators. AB - Hydrogels actuators (HAs) that can reversibly respond to stimuli have applications in diverse fields. However, faster response rates and improved control over actuation timing and location are required to fulfill their potential. To address these criteria, we synthesized near-infrared light-driven HAs by interfacing genetically engineered elastin-like polypeptides with reduced graphene oxide sheets. The resulting nanocomposites exhibited rapid and tunable motions controlled by light position, intensity, and path, including finger-like flexing and crawling. This work demonstrates the ability of rationally designed proteins to be combined with synthetic nanoparticles for the creation of macroscale functional materials. PMID- 23647363 TI - Towards universal wavelength-specific photodegradation rate constants for methyl mercury in humic waters, exemplified by a Boreal lake-wetland gradient. AB - We report experimentally determined first-order rate constants of MeHg photolysis in three waters along a Boreal lake-wetland gradient covering a range of pH (3.8 6.6), concentrations of total organic carbon (TOC 17.5-81 mg L(-1)), total Fe (0.8-2.1 mg L(-1)), specific UV254 nm absorption (3.3-4.2 L mg(-1) m(-1)) and TOC/TON ratios (24-67 g g(-1)). Rate constants determined as a function of incident sunlight (measured as cumulative photon flux of photosynthetically active radiation, PAR) decreased in the order dystrophic lake > dystrophic lake/wetland > riparian wetland. After correction for light attenuation by dissolved natural organic matter (DOM), wavelength-specific (PAR: 400-700 nm, UVA: 320-400 nm and UVB: 280-320 nm) first-order photodegradation rate constants (kpd) determined at the three sites were indistinguishable, with average values (+/- SE) of 0.0023 +/- 0.0002, 0.10 +/- 0.024 and 7.2 +/- 1.3 m(2) E(-1) for kpdPAR, kpdUVA, and kpdUVB, respectively. The relative ratio of kpdPAR, kpdUVA, and kpdUVB was 1:43:3100. Experiments conducted at varying MeHg/TOC ratios confirm previous suggestions that complex formation with organic thiol groups enhances the rate of MeHg photodegradation, as compared to when O and N functional groups are involved in the speciation of MeHg. We suggest that if the photon fluxes of PAR, UVA, and UVB radiation are separately determined and the wavelength-specific light attenuation is corrected for, the first-order rate constants kpdPAR, kpdUVA, and kpdUVB will be universal to waters in which DOM (possibly in concert with Fe) controls the formation of ROS, and the chemical speciation of MeHg is controlled by the complexation with DOM associated thiols. PMID- 23647365 TI - An enantioselective approach to furanoeremophilanes: (+)-9-oxoeuryopsin. AB - An enantioselective total synthesis of the furanoeremophilane sesquiterpene (+)-9 oxoeuryopsin 1 is reported. The synthesis involves as a key step a copper(II) triflate catalyzed tandem asymmetric conjugate addition of AlMe3 to 2-methyl-2 cyclohexen-1-one with the Feringa (S,R,R)-phosphoramidite binaphthol ligand, followed by aldol condensation of the resulting aluminum enolate with 4-methyl-3 furaldehyde 4. This tandem transformation has not been previously reported with a 2-substituted-2-cyclohexen-1-one. Conventional functional group manipulations completed the synthesis. PMID- 23647364 TI - The role of acidemia in maternal binge alcohol-induced alterations in fetal bone functional properties. AB - BACKGROUND: Heavy alcohol consumption during pregnancy negatively impacts the physical growth of the fetus. Although the deleterious effects of alcohol exposure during late gestation on fetal brain development are well documented, little is known about the effect on fetal bone mechanical properties or the underlying mechanisms. The purpose of this study was to investigate the effects of late gestational chronic binge alcohol consumption and alcohol-induced acidemia, a critical regulator of bone health, on functional properties of the fetal skeletal system. METHODS: Suffolk ewes were mated and received intravenous infusions of saline or alcohol (1.75 g/kg) over 1 hour on 3 consecutive days per week followed by 4 days without treatment beginning on gestational day (GD) 109 and concluding on GD 132 (term = 147 days). The acidemia group was exposed to increased inspired fractional concentrations of CO2 to closely mimic the alcohol induced decreases in maternal arterial pH seen in the alcohol group. RESULTS: Fetal femurs and tibias from the alcohol and acidemia groups were ~3 to 7% shorter in length compared with the control groups (p < 0.05). Three-point bending procedure demonstrated that fetal femoral ultimate strength (MPa) for the alcohol group was decreased (p < 0.05) by ~24 and 29%, while the acidemia group exhibited a similar decrease (p < 0.05) of ~32 and 37% compared with the normal control and saline control groups, respectively. Bone extrinsic and intrinsic mechanical properties including maximum breaking force (N) and normalized breaking force (N/kg) of fetal bones from the alcohol and acidemia groups were significantly decreased (p < 0.05) compared with both control groups. CONCLUSIONS: We conclude that late gestational chronic binge alcohol exposure reduces growth and impairs functional properties of the fetal skeletal system and that the repeated episodes of alcohol-induced maternal acidemia may be at least partially responsible for these effects. PMID- 23647366 TI - Amino acid substitution in the active site of DNA polymerase beta explains the energy barrier of the nucleotidyl transfer reaction. AB - DNA polymerase beta (pol beta) is a bifunctional enzyme widely studied for its roles in base excision DNA repair, where one key function is gap-filling DNA synthesis. In spite of significant progress in recent years, the atomic level mechanism of the DNA synthesis reaction has remained poorly understood. Based on crystal structures of pol beta in complex with its substrates and theoretical considerations of amino acids and metals in the active site, we have proposed that a nearby carboxylate group of Asp256 enables the reaction by accepting a proton from the primer O3'group, thus activating O3'as the nucleophile in the reaction path. Here, we tested this proposal by altering the side chain of Asp256 to Glu and then exploring the impact of this conservative change on the reaction. The D256E enzyme is more than 1000-fold less active than the wild-type enzyme, and the crystal structures are subtly different in the active sites of the D256E and wild-type enzymes. Theoretical analysis of DNA synthesis by the D256E enzyme shows that the O3'proton still transfers to the nearby carboxylate of residue 256. However, the electrostatic stabilization and location of the O3' proton transfer during the reaction path are dramatically altered compared with wild type. Surprisingly, this is due to repositioning of the Arg254 side chain in the Glu256 enzyme active site, such that Arg254 is not in position to stabilize the proton transfer from O3'. The theoretical results with the wild-type enzyme indicate an early charge reorganization associated with the O3' proton transfer, and this does not occur in the D256E enzyme. The charge reorganization is mediated by the catalytic magnesium ion in the active site. PMID- 23647367 TI - Clinical and pathological analysis of epidural inflammation in intervertebral disk extrusion in dogs. AB - BACKGROUND: Little is known about the pathologic changes in the epidural space after intervertebral disk (IVD) extrusion in the dog. OBJECTIVES: To analyze the pathology of the epidural inflammatory response, and to search for correlations between this process and clinical findings. METHODS: Clinical data from 105 chondrodystrophic (CD) and nonchondrodystrophic (NCD) dogs with IVD extrusion were recorded. Epidural material from these dogs was examined histopathologically and immunohistochemically. Using statistical analysis, we searched for correlations between severity of epidural inflammation and various clinical and pathologic variables. RESULTS: Most dogs exhibited an epidural inflammatory response, ranging from acute invasion of neutrophils to formation of chronic granulation tissue. The mononuclear inflammatory infiltrates consisted mostly of monocytes and macrophages and only few T and B cells. Surprisingly, chronic inflammatory patterns also were found in animals with an acute clinical history. Severity of the epidural inflammation correlated with degree of the epidural hemorrhage and nucleus pulposus calcification (P = .003 and .040), but not with age, chondrodystrophic phenotype, neurologic grade, back pain, pretreatment, or duration. The degree of inflammation was statistically (P = .021) inversely correlated with the ability to regain ambulation. CONCLUSION AND CLINICAL IMPORTANCE: Epidural inflammation occurs in the majority of dogs with IVD extrusion and may develop long before the onset of clinical signs. Presence of calcified IVD material and hemorrhage in the epidural space may be the triggers of this lesion rather than an adaptive immune response to the nucleus pulposus as suggested in previous studies. Because epidural inflammation may affect outcome, further research is warranted. PMID- 23647369 TI - Real-life effectiveness and tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease: the EMBRACE study. AB - OBJECTIVE: To assess the real-life effectiveness and tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease (AD) in Canada. RESEARCH DESIGN AND METHODS: Eighteen-month observational, prospective, multi-center, open-label study conducted on AD patients with Standardized Mini-Mental State Examination (SMMSE) score of 10-26 and Global Deterioration Scale (GDS) score of 4-6. Patients were treated with the rivastigmine transdermal patch (Exelon patch*) 5 cm2 (4.6 mg/24 hours) or 10 cm2 (9.5 mg/24 hours), once daily. MAIN OUTCOME MEASURES: Primary outcome was change in SMMSE from baseline to 18 months. Secondary outcomes included change in SMMSE at 6 and 12 months and change in GDS, Assessment of Patient Ability (APA-C), Overall Patient Assessment Rating (OPAR), caregiver-reported compliance and treatment satisfaction at 6, 12, and 18 months. RESULTS: Among the 1204 patients enrolled, 969 were included in the ITT analysis. Mean (SD) age was 80.2 (8.00) years, disease duration was 0.6 (1.26) years, 62.0% of patients were women, 80.4% were living in the community, and 69.3% were treatment naive. Mean (SD) baseline SMMSE and GDS scores were 21.8 (3.98) and 4.2 (0.61), respectively. Over 18 months of treatment there were no clinically significant changes in SMMSE and GDS. The majority of patients showed improvement or no change in GDS, APA-C and OPAR over 18 months. The proportion with reported improvement in GDS, APA-C and OPAR was higher than the proportion that deteriorated. Compliance improved from baseline to 18 months and for 88.2% of patients caregivers preferred the transdermal patch to oral medications. CONCLUSIONS: The rivastigmine transdermal patch is effective in maintaining cognitive function over 18 months of treatment in patients with mild-to-moderate AD. The safety profile was comparable to the data in the Canadian product monograph. Lack of a comparator group is a potential limitation of the study. PMID- 23647368 TI - The legacy of early insecurity histories in shaping adolescent adaptation to interparental conflict. AB - This study tested whether the mediational pathway involving interparental conflict, adolescent emotional insecurity, and their psychological problems was altered by their earlier childhood histories of insecurity. Participants included 230 families, with the first of the five measurement occasions occurring when children were in first grade (Mage = 7 years). Results indicated that interparental conflict was associated with increases in adolescent emotional insecurity that, in turn, predicted subsequent increases in their psychological problems. Childhood insecurity predicted adolescent maladjustment 5 years later even after considering contemporaneous family experiences. Moderator findings revealed that adolescents with relatively higher levels of insecurity in childhood evidenced disproportionately greater and reduced levels of insecurity in the context of high and low levels of interparental conflict, respectively. PMID- 23647370 TI - Cardiovascular event rates in atorvastatin patients versus patients switching from atorvastatin to simvastatin. AB - OBJECTIVE: Statin dose, adherence, and cardiovascular (CV) outcomes are important factors when considering switching statin therapies. The objective of the study was to compare CV event rates and risk in managed care patients receiving atorvastatin versus those switched to simvastatin from atorvastatin. METHODS: Patients 18-64 years, with >=3 continuous pharmacy claims for atorvastatin between 1/1/05-11/30/07 and >=12 months pre- and >=3 months post-index continuous eligibility were identified using HealthCore Integrated Research Database (HIRD). Patients were stratified into two cohorts: one continued atorvastatin without interruption and the other switched to simvastatin. Patients were matched 1:10 (continue atorvastatin/switch simvastatin) on five variables, excluding lipid parameters due to limited data availability. Descriptive statistics were reported for sample characteristics. A multivariate Cox proportional hazards model was developed to evaluate adjusted CV risk. RESULTS: In total 73,960 atorvastatin patients and 7396 simvastatin-switch patients were analyzed. The mean age was 54 +/- 7 years (both cohorts). Mean follow-up was 440 days for atorvastatin patients and 237 days for simvastatin-switch patients. Mean dose and therapy duration for atorvastatin was 20 mg and 321 days compared with 33 mg and 195 days for simvastatin-switch, respectively. Of the simvastatin-switch patients, 32% were switched to a less potent simvastatin dose (<2* prior atorvastatin dose). After adjusting for demographic/clinical characteristics, no significant differences were found in CV risk between cohorts. LIMITATIONS: Limitations include use of administrative claims data without lipid level laboratory results data and the length of follow-up which may not have been sufficient to demonstrate significant differences in event rates between groups. CONCLUSION: In this managed care population, no significant differences were found in risk of CV events among patients switching to simvastatin compared to patients continuing atorvastatin. Switched patients may differ from controls for reasons not captured in the database. PMID- 23647371 TI - Fast and efficient molecule detection in localization-based super-resolution microscopy by parallel adaptive histogram equalization. AB - In localization-based super-resolution microscopy, individual fluorescent markers are stochastically photoactivated and subsequently localized within a series of camera frames, yielding a final image with a resolution far beyond the diffraction limit. Yet, before localization can be performed, the subregions within the frames where the individual molecules are present have to be identified-oftentimes in the presence of high background. In this work, we address the importance of reliable molecule identification for the quality of the final reconstructed super-resolution image. We present a fast and robust algorithm (a-livePALM) that vastly improves the molecule detection efficiency while minimizing false assignments that can lead to image artifacts. PMID- 23647372 TI - Variation in the prevalence of sarcopenia and sarcopenic obesity in older adults associated with different research definitions: dual-energy X-ray absorptiometry data from the National Health and Nutrition Examination Survey 1999-2004. AB - OBJECTIVES: To determine the prevalence range for sarcopenic obesity and its relationship with sex, age, and ethnicity. DESIGN: Cross-sectional analysis of a population-based sample. SETTING: Noninstitutionalized persons in the United States participating in the National Health and Nutrition Examination Surveys 1999-2004. PARTICIPANTS: Subsample of 4,984 subjects aged 60 and older with dual energy X-ray absorptiometry body composition data. MEASUREMENTS: Eight definitions of sarcopenic obesity identified from six studies found using a systematic literature review (Baumgartner, Bouchard, Davison, Zoico, Levine, Kim 1,2,3) were applied to the sample. Results were stratified according to sex, age, and ethnicity. RESULTS: Prevalence of sarcopenic obesity ranged from 4.4% to 84.0% in men and from 3.6% to 94.0% in women. Prevalence was higher in men using definitions from Baumgartner (17.9% vs 13.3%, P < .001), Levine (14.2% vs 6.6%, P < .001), and Kim-1 (30.0% vs 9.3%, P < .001); lower for men using the Davison (4.4% vs 11.1%, P < .001) and Kim-2 (83.7% vs 94.0%) definitions; and the same for men and women using the Bouchard (45.3% vs 44.3%, P = .32) and Kim-3 (75.6% vs 77.0%, P = .51) definitions. For all but one definition, sarcopenic obesity increased with each decade and was lower in non-Hispanic blacks than whites. CONCLUSION: Prevalence of sarcopenic obesity in older adults varies up to 26-fold depending on current research definitions. Such a high degree of variability suggests the need to establish consensus criteria that can be reliably applied across clinical and research settings. PMID- 23647373 TI - A phase I first-in-human study with tefinostat - a monocyte/macrophage targeted histone deacetylase inhibitor - in patients with advanced haematological malignancies. AB - Tefinostat (CHR-2845) is a monocyte/macrophage targeted histone deacetylase inhibitor (HDACi). This first-in-human, standard 3 + 3 dose escalating trial of oral, once daily tefinostat was conducted to determine the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tefinostat in relapsed/refractory haematological diseases. Eighteen patients were enrolled at doses of 20-640 mg. Plasma concentrations of tefinostat exceeded those demonstrated to give in vitro anti-proliferative activity. Flow cytometric pharmacodynamic assays demonstrated monocyte-targeted increases in protein acetylation, without corresponding changes in lymphocytes. Dose-limiting toxicities (DLTs) were not observed and dose escalation was halted at 640 mg without identification of the maximum tolerated dose. Drug-related toxicities were largely Common Toxicity Criteria for Adverse Events grade 1/2 and included nausea, anorexia, fatigue, constipation, rash and increased blood creatinine. A patient with chronic monomyelocytic leukaemia achieved a bone marrow response, with no change in peripheral monocytes. An acute myeloid leukaemia type M2 patient showed a >50% decrease in bone marrow blasts and clearance of peripheral blasts. In conclusion, tefinostat produces monocyte targeted HDACi activity and is well tolerated, without the DLTs, e.g. fatigue, diarrhoea, thrombocytopenia, commonly seen with non-targeted HDACi. The early signs of efficacy and absence of significant toxicity warrant further evaluation of tefinostat in larger studies. (clinicaltrials.gov identifier: NCT00820508). PMID- 23647374 TI - Three-dimensional visualization of mixed species biofilm formation together with its substratum. AB - Biofilms, such as dental plaque, are aggregates of microorganisms attached to a surface. Thus, visualization of biofilms together with their attached substrata is important in order to understand details of the interaction between them. However, so far there is limited availability of such techniques. Here, non invasive visualization of biofilm formation with its attached substratum by applying the previously reported technique of continuous-optimizing confocal reflection microscopy (COCRM) is reported. The process of development of oral biofilm together with its substratum was sequentially visualized with COCRM. This study describes a convenient method for visualizing biofilm and its attached surface. PMID- 23647376 TI - Salivary carriage of periodontal pathogens in generalized aggressive periodontitis families. AB - BACKGROUND: Generalized aggressive periodontitis (GAP) is a multifactorial disease that shows a specific microbial profile and a familial aggregation. AIM: This study evaluated the salivary microbial profile of families with a history of GAP and compared them with healthy families. DESIGN: Fifteen families with parents presenting periodontal health and 15 with parents with a history of GAP were selected. Each family had a child aged 6-12 years. Stimulated saliva was collected from all subjects, and Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf), and Aggregatibacter actinomycetemcomitans (Aa) amounts were determined. RESULTS: Children of GAP families showed higher detection of Aa (90%) than children of healthy families (45%) (P < 0.05). Parents with GAP showed a Pg salivary concentration statistically higher than that of healthy parents (P < 0.05).Children of GAP families, however, exhibited similar Pg concentration than healthy children (P > 0.05). Tf amounts did not differ either in parents or in children (P > 0.05) The infection risk calculation indicates that children who have one parent who is positive for Aa have 16.3 times (95% CI 3.1-87.2) more risk of being infected with Aa (P < 0.05) than children from an Aa-negative family. CONCLUSION: It may be concluded that children of parents with aggressive periodontitis have higher levels and higher risk of Aa infection. PMID- 23647375 TI - A new PAX8 mutation causing congenital hypothyroidism in three generations of a family is associated with abnormalities in the urogenital tract. AB - BACKGROUND: Although thyroid dysgenesis is the most common cause of congenital hypothyroidism (CH), its molecular basis remains largely elusive. Indeed, in only a minority of cases with thyroid dysgenesis (2%-3%) was it possible to identify an underlying genetic defect. The objective of this study was to screen the PAX8 gene and the PAX2 gene in a family with six cases of CH spanning three generations and presenting urogenital malformations. Herein, we report a case series and in vitro characterization of the PAX8 gene mutation. METHODS: Investigations were conducted at a tertiary care referral center. The index case was diagnosed to have congenital hypothyroidism at 7 months of age when he presented with severe impairment of suckling, constipation, and poor development. Treatment with levothyroxine corrected the symptoms and was associated with catch up growth. His progeny, including two sons, one daughter, and two granddaughters, were affected by CH, and three of them received the diagnosis at neonatal screening. Ultrasound demonstrated normally located thyroid glands with reduced volumes. Five of the six affected family members, including the index case, had urogenital malformations, including incomplete horseshoe kidney, undescended testicles, hydrocele, and ureterocele. Strabismus was found in three out of six affected patients. No other somatic malformations were found. RESULTS: Direct sequencing of the PAX8 gene revealed a new heterozygous mutation (c.74C > G) in all affected individuals. This mutation leads to substitution of proline with arginine at codon 25 (P25R). Fluorescence microscopy showed that P25R is normally located in the nucleus. In transient transfection studies, this mutation causes reduced transcriptional activation ability when using a luciferase reporter construct under the control of a thyroglobulin promoter. This diminished transactivation ability is due to loss of DNA binding capability as shown in electrophoresis mobility shift assay. The sequencing analysis of the PAX2 gene was normal. CONCLUSIONS: We conclude that this novel PAX8 mutation is responsible for a severe form of dominantly inherited CH. The mutation seems to be associated with abnormalities of the urogenital tract. PMID- 23647377 TI - Overexpression of a R2R3 MYB gene MdSIMYB1 increases tolerance to multiple stresses in transgenic tobacco and apples. AB - MYB transcription factors (TFs) involve in plant abiotic stress tolerance and response in various plant species. In this study, rapid amplification of cDNA ends (RACE) was conducted to isolate the R2R3-MYB TF gene MdSIMYB1 from apples (Malus * domestica). The gene transcripts were abundant in the leaves, flowers and fruits, compared to other organs, and were induced by abiotic stresses and plant hormones. We observed the subcellular localization of an MdSIMYB1-GFP fusion protein in the nucleus. Furthermore, the MdSIMYB1 gene was introduced into the tobacco genome and ectopically expressed in transgenic lines. The results indicate that MdSIMYB1 transgenic tobacco seed germination is insensitive to abscisic acid and NaCl treatment. Additionally, it was found that the ectopic expression of MdSIMYB1 enhanced the tolerance of plants to high salinity, drought and cold tolerance by upregulating the stress-responsive genes NtDREB1A, NtERD10B and NtERD10C. Meanwhile, the transgenic tobacco exhibited robust root growth because of the enhanced expression of the auxin-responsive genes NtIAA4.2, NtIAA4.1 and NtIAA2.5 under stress conditions, which is conducive to stress tolerance. Finally, transgenic apple lines were obtained and tested. Transgenic apple lines that were overexpressing MdSIMYB1 exhibited a higher tolerance to abiotic stress than the wild-type control, but suppression of MdSIMYB1 resulted in lower tolerance. Our results indicate that MdSIMYB1 may be utilized as a target gene for enhancing stress tolerance in important crops. PMID- 23647378 TI - SNARC struggles: Instant control over spatial-numerical associations. AB - [Correction Notice: An Erratum for this article was reported in Vol 39(6) of Journal of Experimental Psychology: Learning, Memory, and Cognition (see record 2013-39107-001). In the article, incorrect values appeared for the number of trials in the experiment (section: Procedure) and for the intercepts of four regression lines (section: Regression Coefficient Analysis). The correct number of trials in the experiment is 16 trials in a training block followed by 10 blocks of 128 trials each. The intercepts for response repetitions amounted to 0.72 ms for the SNARC effect following incongruent trials, and to 51.55ms following congruent trials. For response alternations, the intercepts amounted to 35.39 ms for the SNARC effect following incongruent trials and to 50.88 ms following congruent trials. The conclusions presented in the article are not affected by these mistakes.] Numbers and space are tightly linked-a phenomenon that is referred to as the spatial-numerical association of response codes (SNARC) effect (Dehaene, Bossini, & Giraux, 1993). The present study investigates how quickly and flexibly the behavioral impact of such spatial-numerical associations can be controlled. Participants performed a parity judgment task, and we examined how the SNARC effect is influenced by the preceding congruency between the required response and the target number's spatial association. Results indicate that the SNARC effect is reduced instantly after having experienced a number's spatial association to interfere with responding. This sequential modulation indicates a pronounced flexibility of spatial-numerical associations driven by cognitive control mechanisms. PMID- 23647379 TI - Gradient phonological inconsistency affects vocabulary learning. AB - Learners frequently experience phonologically inconsistent input, such as exposure to multiple accents. Yet, little is known about the consequences of phonological inconsistency for language learning. The current study examines vocabulary acquisition with different degrees of phonological inconsistency, ranging from no inconsistency (e.g., both talkers call a picture /vig/) to mild but detectable inconsistency (e.g., one talker calls a picture a /vig/, and the other calls it a /vIg/), up to extreme inconsistency (e.g., the same picture is both a /vig/ and a /dId?/). Previous studies suggest that learners readily extract consistent phonological patterns, given variable input. However, in Experiment 1, adults acquired phonologically inconsistent vocabularies more slowly than phonologically consistent ones. Experiment 2 examined whether word form inconsistency alone, without phonological competition, was a source of learning difficulty. Even without phonological competition, listeners learned faster in 1 accent than in 2 accents, but they also learned faster in 2 accents (/vig/ = /vIg/) than with completely different labels (/vig/ = /dId?/). Overall, results suggest that learners exposed to multiple accents may experience difficulty learning when 2 forms mismatch by more than 1 phonological feature, plus increased phonological competition due to a greater number of word forms. Implications for learning from variable input are discussed. PMID- 23647380 TI - Whole-language and item-specific control in bilingual language production. AB - The current study investigated the scope of bilingual language control differentiating between whole-language control involving control of an entire lexicon specific to 1 language and lexical-level control involving only a restricted set of recently activated lexical representations. To this end, we tested 60 Dutch-English (Experiment 1) and 64 Chinese-English bilinguals (Experiment 2) on a verbal fluency task in which speakers produced members of letter (or phoneme for Chinese) categories first in 1 language and then members of either (a) the same categories or (b) different categories in their other language. Chinese-English bilinguals also named pictures in both languages. Both bilingual groups showed reduced dominant language fluency after producing exemplars from the same categories in the nondominant language, whereas nondominant language production was not influenced by prior production of words from the same categories in the other language. Chinese-English, but not Dutch English, bilinguals exhibited similar testing order effects for different letter/phoneme categories. In addition, Chinese-English bilinguals who exhibited significant testing order effects in the repeated categories condition of the fluency task exhibited no such effects when naming repeated pictures after a language switch. These results imply multiple levels of inhibitory control in bilingual language production. Testing order effects in the verbal fluency task pinpoint a lexical locus of bilingual control, and the finding of interference effects for some bilinguals even when different categories are tested across languages further implies a whole-language control process, although the ability to exert such global inhibition may only develop for some types of bilinguals. PMID- 23647381 TI - Is vocabulary growth influenced by the relations among words in a language learner's vocabulary? AB - Several recent studies have explored the applicability of the preferential attachment principle to account for vocabulary growth. According to this principle, network growth can be described by a process in which existing nodes recruit new nodes with a probability that is an increasing function of their connectivity within the existing network. The current study combined subjective estimates of the age of acquisition (AoA) and associations among words in a large corpus to estimate the organization of semantic knowledge at multiple points in vocabulary growth. Consistent with previous studies, the number of connections or relations among words followed a power law distribution in which relatively few words were highly connected with other words and most words were connected to relatively few words. In addition, the growth in the number of connections of a word was a linear function of its initial number of connections, and the ratio of connections to any two words was relatively constant over time. Finally, number of connections to known words was a reliable predictor of a word's AoA. All of these findings can be shown to be consistent with the preferential attachment principle. PMID- 23647382 TI - Correlation of total antioxidant capacity with reactive oxygen species (ROS) consumption measured by oxidative conversion. AB - Although both antioxidant capacity and oxidative conversion (hazard) are important in food and bioanalytical chemistry, there is considerable confusion in the literature between the results of these two types of assays. After the generation of ROS in the medium via Fe(III)-H2O2 reaction, attenuation of total oxidative conversion (TOC; as measured by thiobarbituric acid-reactive substances (TBARS) and N,N-dimethyl-p-phenylenediamine (DMPD) assays) was tested for possible correlation with the total antioxidant capacity (TAC; as measured by cupric reducing antioxidant capacity (CUPRAC) and trolox equivalent antioxidant capacity (ABTS/TEAC) assays) of the introduced antioxidant sample. The inverse relationship between oxidative conversion and antioxidant capacity was processed to establish a curvilinear relationship between the absolute values of TAC increments and TOC decrements as a function of added antioxidant concentration. This simple relationship may form a bridge between the two diverse disciplines of medical biochemistry and food analytical chemistry mainly using TOC and TAC results, respectively. PMID- 23647383 TI - Reversible mechanochromism of a luminescent elastomer. AB - A novel mechanochromic elastomer was manufactured by doping bis(benzoxazolyl)stibene (BBS) into a thermoplastic polyurethane. Both solution casting and melt compounding approaches were tried with a range of BBS concentrations, and an optimal concentration of 0.5% was selected to investigate the mechanochromic mechanism in detail. When the blend film was stretched up to 100%, its emission peaks at 475 and 413 nm changed in intensity ratio from 6.3 to 1.8. When it was released, both the film size and emission peaks largely recovered. By a short annealing at 120 degrees C, their full recovery was achieved. Its reversion mechanism was proposed and proved by X-ray diffraction. In comparison to previous mechanochromic materials, this smart elastomer is easy to prepare, highly sensitive to stress, facilely renewable in usage, and totally based on biocompatible materials, having potential applications like stress sensors, intelligent devices, and alarming packages. PMID- 23647385 TI - Suggestions for the diagnosis and elimination of hepatitis E virus in pigs used for xenotransplantation. AB - The hepatitis E virus (HEV) is considered a zoonotic pathogen. In xenotransplantation, given the high prevalence of HEV infection in pigs, the risk of zoonotic transmission from a porcine source is considered high. Currently no clear data are available on how to diagnose and eliminate HEV in herds used for medical purposes and the importance of viral infection at the stage of harvest. In this study, several groups of animals currently used for medical purposes were found RNA positive in both serum and faeces for HEV genotype 3. In addition, viraemia was found in animals up to 3.6 yr of age, which is much longer than originally expected. Herd transmission rates appeared to be significantly lower in animals kept under minimal barrier conditions, compared with those observed for commercial animals, and as expected, segregation of animals at an early age prevented spread of infection. This study makes suggestions to ensure appropriate detection and eradication of HEV from a donor herd to be used for xenotransplantation purposes. PMID- 23647384 TI - Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity. AB - CNS trauma generates a proteolytic imbalance contributing to secondary injury, including axonopathy and neuron degeneration. Kallikrein 6 (Klk6) is a serine protease implicated in neurodegeneration, and here we investigate the role of protease-activated receptors 1 (PAR1) and PAR2 in mediating these effects. First, we demonstrate Klk6 and the prototypical activator of PAR1, thrombin, as well as PAR1 and PAR2, are each elevated in murine experimental traumatic spinal cord injury (SCI) at acute or subacute time points. Recombinant Klk6 triggered extracellular signal-regulated kinase (ERK1/2) signaling in cerebellar granule neurons and in the NSC34 spinal cord motoneuron cell line, in a phosphoinositide 3-kinae and MEK-dependent fashion. Importantly, lipopeptide inhibitors of PAR1 or PAR2, and PAR1 genetic deletion, each reduced Klk6-ERK1/2 activation. In addition, Klk6 and thrombin promoted degeneration of cerebellar neurons and exacerbated glutamate neurotoxicity. Moreover, genetic deletion of PAR1 blocked thrombin-mediated cerebellar neurotoxicity and reduced the neurotoxic effects of Klk6. Klk6 also increased glutamate-mediated Bim signaling, poly-ADP-ribose polymerase cleavage and lactate dehydrogenase release in NSC34 motoneurons and these effects were blocked by PAR1 and PAR2 lipopeptide inhibitors. Taken together, these data point to a novel Klk6-signaling axis in CNS neurons that is mediated by PAR1 and PAR2 and is positioned to contribute to neurodegeneration. PMID- 23647387 TI - Cultural humility: measuring openness to culturally diverse clients. AB - Building on recent theory stressing multicultural orientation, as well as the development of virtues and dispositions associated with multicultural values, we introduce the construct of cultural humility, defined as having an interpersonal stance that is other-oriented rather than self-focused, characterized by respect and lack of superiority toward an individual's cultural background and experience. In 4 studies, we provide evidence for the estimated reliability and construct validity of a client-rated measure of a therapist's cultural humility, and we demonstrate that client perceptions of their therapist's cultural humility are positively associated with developing a strong working alliance. Furthermore, client perceptions of their therapist's cultural humility were positively associated with improvement in therapy, and this relationship was mediated by a strong working alliance. We consider implications for research, practice, and training. PMID- 23647386 TI - Anti-apoptotic effect of microRNA-21 after contusion spinal cord injury in rats. AB - Multiple cellular, molecular, and biochemical changes contribute to the etiology and treatment outcome of contusion spinal cord injury (SCI). Dysregulation of microRNAs (miRNAs) has been found following SCI in recent studies. However, little is known about the functional significance of the unique role of miRNAs in SCI. We analyzed the miRNA expression patterns 1 and 3 days following rat SCI using miRNA microarray. Microarray data revealed that nine miRNAs were upregulated and five miRNAs were downregulated 1 day post-injury, and that three miRNAs were upregulated and five miRNAs were downregulated 3 days post-injury, in the sites of contused when compared with sham rat spinal cords. Because miR-21 was one of the miRNAs being most significantly upregulated, we investigated its function. Knockdown of miR-21 by antagomir-21 led to attenuated recovery in hindlimb motor function, increased lesion size, and decreased tissue sparing in rats. Compared with the negative control group, treatment with antagomir-21 significantly increased apoptosis following SCI. Pro-apoptosis genes Fas ligand (FasL), phosphatase and tensin homolog (PTEN), and programmed cell death protein 4 (PDCD4) were proved to be direct targets of miR-21 in many diseases and cell types. In vivo treatment with antagomir-21 increased the expression of FasL and PTEN, but did not affect PDCD4. These results suggested that miR-21 played an important role in limiting secondary cell death following SCI, and that the protective effects of miR-21 might have been the result of its regulation on pro apoptotic genes. Thus, miR-21 may play an important role in the pathophysiology of SCI. PMID- 23647388 TI - "Leaving before she leaves": considering future family when making career plans. AB - An instrument was developed to measure the extent to which people consider future children and romantic partners when planning for a career (i.e., the PLAN scale). Two independent factor-analytic studies of a total of 726 college women were conducted to assess the factor structure and psychometric properties of this measure. Results suggested that the PLAN represents a general Considering Future Family When Making Career Plans factor and 2 domain-specific factors: Considering Children and Prioritizing and Compromising for Partner. Suggestions for future research and practice using the PLAN scale are provided. PMID- 23647390 TI - Interpersonal microprocesses predict cognitive-emotional processing and the therapeutic alliance in psychotherapy for depression. AB - Interpersonal theories of psychotherapy hypothesize that the success of therapy depends on the therapist's and patient's dominant and affiliative behaviors as well as their interplay (complementarity). This study sought to investigate (a) how in-session interpersonal microprocesses predict postsession evaluations of the therapeutic alliance as well as cognitive-emotional processing and (b) how complementarity develops over the course of a therapy session. Twenty depressed patients were treated at a university-based outpatient clinic with a variant of cognitive therapy. One session was analyzed from each therapy's middle phase using a novel real-time rating procedure (joystick method) to assess the patients' and therapists' affiliative and dominant behaviors as well as their resulting complementarity over the course of the session. The therapeutic alliance and cognitive-emotional processing were assessed by self-reports directly after the respective session. As predicted, more emotional arousal was associated with deviations from complementarity, whereas a positive alliance was related to affiliative patient behavior. Moreover, marginally significant trends suggest that refraining from answering to the pull of patient hostility might benefit both the alliance as well as cognitive-emotional processing. Overall, multilevel growth modeling revealed a significant cubic trend of complementarity over the course of the session. Implications for future research and practice are discussed. PMID- 23647389 TI - Mental illness disclosure in Chinese immigrant communities. AB - Support from social networks is imperative to mental health recovery of persons with mental illness. However, disclosing mental illness may damage a person's participation in networks due to mental illness stigma, especially in Chinese immigrant communities where social networks (the guanxi network) have specific social-cultural significance. This study focused on mental illness disclosure in Chinese immigrant communities in New York City. Fifty-three Chinese psychiatric patients were recruited consecutively from 2 Chinese bilingual psychiatric inpatient units from 2006 to 2010. Two bilingual psychologists interviewed each participant once in a semistructured interview, including 6 questions on mental illness disclosure. Conventional content analysis was applied to conceptualize the phenomenon. Results showed that participants voluntarily disclosed to a circle of people composed primarily of family and relatives. The decisions and strategies to disclose depended on participants' consideration of 3 critical elements of social relationships. Ganqing, affection associated with relationship building, ultimately determined who had the privilege to know. Renqing, the moral code of reciprocal kindness, further influenced disclosure decisions and what participants anticipated as responses to disclosure. Lastly, concerns over preserving face (lian), a construct representing personal and familial dignity, oftentimes prohibited disclosure. Additionally, in this tight-knit network, involuntary disclosure could happen without participants' permission or knowledge. Participants commonly suffered from stigma after disclosure. However, half of our participants reported situations in which they experienced little discriminatory treatment, and some experienced support and care as a result of cultural dynamics. Recommendations for culturally sensitive practice to facilitate mental illness disclosure among Chinese immigrants were discussed. PMID- 23647391 TI - Housing and mobility demands of individual households and their life cycle assessment. AB - Household consumption, apart from governmental consumption, is the main driver of worldwide economy. Attached to each household purchase are economic activities along the preceding supply chain, with the associated resource use and emissions. A method to capture and assess all these resource uses and emissions is life cycle assessment. We developed a model for the life cycle assessment of housing and land-based mobility (excluding air travel) consumption of individual households a small village in Switzerland. Statistical census and dwelling register data are the foundations of the model. In a case study performed on a midsized community, we found a median value of greenhouse gas emissions of 3.12 t CO2 equiv and a mean value of 4.30 t CO2 equiv per capita and year for housing and mobility. Twenty-one percent of the households in the investigated region were responsible for 50% of the total greenhouse gas emissions, meaning that if their emissions could be halved the total emissions of the community would be reduced by 25%. Furthermore, a cluster analysis revealed that driving factors for large environmental footprints are demands of large living area heated by fossil energy carriers, as well as large demands of motorized private transportation. PMID- 23647392 TI - Clinical evaluation and endoscopic classification of bronchomalacia in dogs. AB - BACKGROUND: Little information is available about the association between bronchomalacia and historical or clinicopathologic data. Also, studies applying an endoscopic classification scheme that differentiates between static and dynamic bronchial collapse and based on a scoring system are lacking. OBJECTIVES: To describe the clinical presentation of bronchomalacia in dogs, to classify endoscopic findings, and to evaluate associations among historical, clinicopathologic data, and endoscopic findings. ANIMALS: Fifty-nine client-owned dogs with an endoscopic diagnosis of bronchomalacia. METHODS: In this retrospective study, medical records were analyzed and video documentation was reviewed to assign a score to endoscopic findings. Univariate analysis was performed on categorical variables organized in contingency tables, and a stepwise logistic regression model was used for multivariate analysis. RESULTS: Of the 59 dogs included in the study, 2 were affected by static bronchial collapse (SBC), 35 by dynamic bronchial collapse (DBC), and 22 by both SBC and DBC. The association between SBC and DBC was more frequently seen in the dogs with higher body weight, pulmonary hypertension, a bronchial type of radiographic pattern, and nodularity at endoscopic examination. Thirty-one dogs were presented with tracheomalacia and bronchomalacia; an association emerged between these concurrent disorders in dogs living indoors. Multivariate analysis of the endoscopic scores showed a correlation between DBC severity and cough duration. CONCLUSION AND CLINICAL IMPORTANCE: Results of this study provide evidence for 2 different types of bronchial collapse. Endoscopic scoring scheme has proved to be promising in the bronchomalacia classification, although further evaluation of its applicability in larger canine populations is needed. PMID- 23647393 TI - Diagnosis of rickettsial diseases in dogs and cats. AB - Rickettsial agents, including those in the genera Anaplasma, Ehrlichia, Neorickettsia, and Rickettsia, are important and common vector-borne pathogens of dogs and cats. Disease induced by these organisms ranges from clinically inapparent to severe and potentially fatal. However, laboratory confirmation of a rickettsial etiology can be complicated by a number of factors, including the wide spectrum of disease induced by these organisms, an often low and widely fluctuating level of organism present in infected animals, cross-reactions on serologic and molecular assays, and the presence of co-infections. Correct diagnosis is most likely to be reached when multiple diagnostic strategies, including careful microscopic examination of stained blood films or tissues, both specific and broad serologic tests, and a suite of molecular detection assays, are used in concert. Accurate interpretation of diagnostic tests requires awareness of the likelihood for multiple agents, including novel organisms, to be responsible for the results seen in a given patient. This review provides an overview of current strategies used to diagnose rickettsial infections in dogs and cats. PMID- 23647394 TI - Epi-, epoxy-, and C2-modified bengamides: synthesis and biological evaluation. AB - With the objective of investigating the influence of structural modifications of the polyketide chain of the bengamides upon their antitumoral activities, we targeted the preparation of bengamide E analogues with modification of the stereochemistry at C-2 and at C-3, the substituent at the C-2 position, and the presence of oxirane rings. For the synthesis of these analogues, a new synthetic method for asymmetric epoxidation, developed in our laboratories, was employed utilizing the chiral sulfonium salts 22 and 23. In order to access 2-epi bengamide E from these epoxy amides, a synthetic methodology, developed by Miyashita, allowed an oxirane-ring-opening reaction with a double inversion of the configuration. Alternatively, an aldol reaction provided access to the same analogue in a shorter and more efficient manner. Finally, biological evaluation of all of these bengamide E analogues demonstrated that the polyketide chain is essential for the antitumor activity of these natural products, not being amenable to structural or configurational modifications. PMID- 23647397 TI - Prostacyclin and its analogues in pulmonary artery hypertension: a meta-analysis. AB - OBJECTIVE: Individual studies examining the effects of prostacyclin and its analogues on pulmonary artery hypertension (PAH) have reported controversial results. This study aims to evaluate the efficacy of these agents for PAH by a meta-analysis based on randomized controlled trials (RCTs). RESEARCH DESIGN AND METHODS: We systematically searched Pubmed, MEDLINE, EMBASE, ISI Web of Science, and the Cochrane Library through April 2012. All published RCTs reporting the effects of treatment with prostacyclin or its analogues in PAH were included. Summary statistics were calculated using a random effects model. RESULTS: A total of 14 RCTs with 1606 participants were analyzed. Overall, prostacyclin and its analogues increased 6-minute walk distance (6-MWD) (weighted mean differences [WMD]=18.78 meters, 95% confidence interval [CI]: 11.21 to 26.35; p<0.01) and improved NYHA functional class status (odds ratios [OR]=3.98, 95% CI: 1.70 to 9.34; p=0.001) compared with the control. Moreover, these agents led to statistically significant reductions in mean pulmonary artery pressure (mPAP) (WMD=-4.63 mmHg, 95% CI: -6.81 to -2.44; p<0.01) and pulmonary vascular resistance (PVR) (standardized mean difference [SMD] = -0.69, 95% CI: -0.96 to 0.43; p<0.01). Notably, there were distinct effects on these endpoints observed in pooled subgroup analyses based on agent class (all p for interaction<0.01). In addition, PAH-specific therapy appeared to have superiority over the control in reducing the incidence of all-cause death (OR=0.49, 95% CI: 0.26 to 0.94; p=0.03). However, there existed a substantial publication bias, which appeared to markedly impact the overall result of 6-MWD. CONCLUSIONS: PAH-specific treatment with prostacyclin and its analogues significantly improved exercise capacity, cardiopulmonary hemodynamics, and lowered all-cause mortality in patients with PAH. PMID- 23647395 TI - A novel bioassay for anti-thyrotrophin receptor autoantibodies detects both thyroid-blocking and stimulating activity. AB - Autoantibodies to the thyrotrophin (TSH) receptor (anti-TSHR) are unique, in that they are involved directly in the pathophysiology of certain autoimmune thyroid diseases (AITD). Thyroid-stimulating antibodies (TSAb) act as agonists that activate the thyroid gland and cause Graves' disease. Other anti-TSHR antibodies block TSH and can cause hypothyroidism. Thyroid-blocking antibodies (TBAb) have not been studied as extensively as TSAb. We developed a TBAb bioassay based on a cell line that expresses a chimeric TSHR. The 50% inhibitory concentration of the chimeric Chinese hamster ovary (CHO)-Luc cells was more than five-fold lower compared with the wild-type CHO-Luc cells. We tested the performance of this bioassay using a thyroid-blocking monoclonal antibody K1-70, established an assay cut-off and detected TBAb in 15 of 50 (30%) patients with AITD. Interestingly, the assay detects both TSAb and TBAb and measures the net activity of a mixture of both types of antibodies. There was a high correlation (R(2) 0.9, P < 0.0001) between the results of the TSAb assay and the negative percentage inhibition of the TBAb assay. The TBAb bioassay was approximately 20-fold more sensitive than a commercially available TSHR binding assay (TRAb). In contrast to TRAb, sera with high levels of TBAb activity were able to be diluted several hundred-fold and still exhibit blocking activity above the cut-off level. Thus, this TBAb bioassay provides a useful tool for measuring the activity of anti-TSHR antibodies and may help clinicians to characterize the diverse clinical presentations of patients with AITD. PMID- 23647396 TI - Quatsomes: vesicles formed by self-assembly of sterols and quaternary ammonium surfactants. AB - Thermodynamically stable nanovesicle structures are of high interest for academia and industry in a wide variety of application fields, ranging from preparation of nanomaterials to nanomedicine. Here, we show the ability of quaternary ammonium surfactants and sterols to self-assemble, forming stable amphiphilic bimolecular building-blocks with the appropriate structural characteristics to form in aqueous phases, closed bilayers, named quatsomes, with outstanding stability, with time and temperature. The molecular self-assembling of cholesterol and surfactant cetyltrimethylammonium bromide (CTAB) was studied by quasi-elastic light scattering, cryogenic transmission electron microscopy, turbidity (optical density) measurements, and molecular dynamic simulations with atomistic detail, upon varying the cholesterol-to-surfactant molar ratio. As pure species, CTAB forms micelles and insoluble cholesterol forms crystals in water. However, our molecular dynamic simulations reveal that the synergy between CTAB and cholesterol molecules makes them self-assemble into bimolecular amphiphiles and then into bilayers in the presence of water. These bilayers have the same structure of those formed by double-tailed unimolecular amphiphiles. PMID- 23647398 TI - Achieving recommended low density lipoprotein cholesterol goals and the factors associated with target achievement of hypercholesterolemia patients with rosuvastatin in primary care. AB - OBJECTIVE: Hypercholesterolemia is a major risk factor for cardiovascular disease and requires continuous management. The role of primary physicians in this regard is important, yet the factors associated with successful lipid lowering treatments in primary clinics have not been clearly identified. We aimed to evaluate the rate of successful hypercholesterolemia treatment in Korean primary care, and to identify the factors associated with achieving low density lipoprotein cholesterol (LDL-C) targets. METHODS: We prospectively recruited and retrospectively assessed 1851 Korean patients with hypercholesterolemia who visited family physicians and were prescribed rosuvastatin for the first time. LDL-C lowering targets, defined according to NCEP ATP III guidelines, were evaluated at 6 months after the first prescription. The factors associated with achieving these targets were also assessed. RESULTS: Overall, 87.6% of our participants attained their LDL-C goals. In multiple logistic regression analysis, good adherence to medication was strongly associated with the achievement of target LDL-C levels, whereas higher cardiovascular risk factors including diabetes (in both sexes), low high density lipoprotein, and current smoking status (in males), and hypertension (in females) were related to LDL-C target level failures. CONCLUSION: Our observations of the short period for hypercholesterolemia in Korean primary care has revealed that the rate of achieving target LDL-C levels was high in these patients, whereas patients at higher risk for cardiovascular disease tended to have lower LDL-C achievement outcomes. Primary care physicians should pay more attention to patients showing higher cardiovascular risk and stress the need for good adherence and management regimens in these individuals. PMID- 23647399 TI - Use of the conjugated polyelectrolyte poly{[9,9-bis(6'-N,N,N trimethylammonium)hexyl]fluorene-phenylene} bromide (HTMA-PFP) as a fluorescent membrane marker. AB - The present work explores the potential use of the conjugated cationic polyfluorene {[9,9-bis(6'-N,N,N-trimethylammonium)hexyl]fluorene-phenylene} bromide (HTMA-PFP) as a fluorescent membrane marker. To this end, the interaction of the polyelectrolyte with anionic model membranes has been investigated using different biophysical approaches. High affinity interaction was confirmed through alterations in the fluorescence spectrum of HTMA-PFP and by Forster resonance energy transfer (FRET) analysis. Quenching data indicate that once HTMA-PFP interacts with the membrane, it penetrates in the hydrophobic core embedded in the lipid bilayer where it presents high fluorescence quantum yield and photostability. Leakage experiments and dynamic light scattering (DLS) measurements show that the integrity of the lipid vesicles is maintained after polymer incorporation since no vesicle fusion or decomposition into small fragments is detectable. This conclusion is supported by fluorescence microscopy images, which confirm that polyelectrolyte interacts with the vesicle, labeling the lipid membrane without altering its morphology. Further experiments performed as a function of temperature indicate that the polymer is accommodated in the membrane without inducing significant loss of lipid cooperativity and without altering the packing of lipids within the bilayer. Finally, results show that polyelectrolyte fluorescence is sensitive to the large structural changes taking place in the lipid bilayer at the lipid phase transition. All these results confirm the ability of HTMA-PFP to visualize membrane structures and to monitor membrane processes. PMID- 23647400 TI - Highly potent inhibitors of quorum sensing in Staphylococcus aureus revealed through a systematic synthetic study of the group-III autoinducing peptide. AB - Methods to intercept bacterial quorum sensing (QS) have attracted significant attention as potential anti-infective therapies. Staphylococcus aureus is a major human pathogen that utilizes autoinducing peptide (AIP) signals to mediate QS and thereby regulate virulence. S. aureus strains are categorized into four groups (I IV) according to their AIP signal and cognate extracellular receptor, AgrC. Each group is associated with a certain disease profile, and S. aureus group-III strains are responsible for toxic shock syndrome and have been underestimated in other infections to date. A limited set of non-native AIP analogs have been shown to inhibit AgrC receptors; such compounds represent promising tools to study QS pathways in S. aureus . We seek to expand this set of chemical probes and report herein the first design, synthesis, and biological testing of AIP-III mimetics. A set of non-native peptides was identified that can inhibit all four of the AgrC receptors (I-IV) with picomolar IC50 values in reporter strains. These analogs also blocked hemolysis by wild-type S. aureus group I-IV strains-a virulence trait under the control of QS-at picomolar concentrations. Moreover, four of the lead AgrC inhibitors were capable of attenuating the production of toxic shock syndrome toxin-1 (also under the control of QS) by over 80% at nanomolar concentrations in a wild-type S. aureus group-III strain. These peptides represent, to our knowledge, the most potent synthetic inhibitors of QS in S. aureus known, and constitute new and readily accessible chemical tools for the study of the AgrC system and virulence in this deadly pathogen. PMID- 23647401 TI - Extranodal NK/T-cell lymphoma with leukaemic presentation. PMID- 23647403 TI - Receptor-free poly(phenylenevinylene) fibrous membranes for cation sensing: high sensitivity and good selectivity achieved by choosing the appropriate polymer matrix. AB - Poly(phenylenevinylene)/polyimide (PPV/PI) and poly(phenylenevinylene)/ polymethylmethacrylate (PPV/PMMA) fibrous membranes without any deliberately introduced receptors were prepared as fluorescence sensing materials through electrospinning, followed by thermal treatment. Both of these membranes displayed higher sensitivity toward most cations compared to the corresponding spin-coated films. PPV/PMMA membranes were more sensitive than PPV/PI membranes toward Cu(2+) and Fe(3+). About 4.5 fold of intensity enhancement upon 20 nM of Cu(2+), 80% of quenching upon 20 nM of Fe(3+) with fast response and simple regeneration were realized for PPV/PMMA membrane. The preliminary investigation into the mechanism revealed that the properties of the polymer matrix and thermal treatment of the membrane played important roles in the sensing performance. PMID- 23647402 TI - Thyroid status and 6-year mortality in elderly people living in a mildly iodine deficient area: the aging in the Chianti Area Study. AB - OBJECTIVES: To test the hypothesis that, in older adults, living in a mildly iodine-deficient area, thyroid dysfunction may be associated with mortality independent of potential confounders. DESIGN: Longitudinal. SETTING: Community based. PARTICIPANTS: Nine hundred fifty-one individuals aged 65 and older. MEASUREMENTS: Plasma thyrotropin, free thyroxine, and free triiodothyronine concentrations and demographic features were evaluated in participants of the Invecchiare in Chianti Study aged 65 and older. Participants were classified according to thyroid function test. Kaplan-Meier survival and Cox proportional hazards models adjusted for confounders were used in the analysis. RESULTS: Eight hundred nineteen participants were euthyroid, 83 had subclinical hyperthyroidism (SHyper), and 29 had subclinical hypothyroidism (SHypo). Overt hypo- and hyperthyroidism were found in five and 15 subjects, respectively. During a median of 6 years of follow-up, 210 deaths occurred (22.1%), 98 (46.6%) of which were from cardiovascular causes. Kaplan-Meier analysis revealed higher overall mortality for SHyper (P = .04) than euthyroid subjects. After adjusting for multiple confounders, participants with SHyper (hazard ratio (HR) = 1.65, 95% confidence interval (CI) = 1.02-2.69) had significantly higher all-cause mortality than those with normal thyroid function. No significant association was found between SHyper and cardiovascular mortality. In euthyroid subjects, thyrotropin was found to be predictive of lower risk of all-cause mortality (HR = 0.76, 95% CI = 0.57-0.99). CONCLUSION: SHyper is an independent risk factor for all-cause mortality in older adults. Low to normal circulating thyrotropin should be carefully monitored in elderly euthyroid individuals. PMID- 23647404 TI - Rehabilitation training using complex motor learning rescues deficits in eyeblink classical conditioning in female rats induced by binge-like neonatal alcohol exposure. AB - BACKGROUND: Effective treatments for the behavioral and cognitive deficits in children with fetal alcohol spectrum disorders (FASD) are lacking, and translational approaches using animal models can help develop rational interventions. One such model, binge-like alcohol exposure in neonatal rats during the period of brain development comparable with that of the human third trimester, causes structural and functional damage to the cerebellum and disrupts cerebellar-dependent eyeblink classical conditioning. The eyeblink conditioning deficits first demonstrated in this rat model predicted the similar deficits subsequently demonstrated in children with FASD. METHODS: The current study extends this translational approach by testing the hypothesis that rehabilitation training involving 20 days of training on traversal of an obstacle course (complex motor learning) would ameliorate the deficits on classical conditioning of eyeblink responses produced by the neonatal alcohol exposure. We have previously shown that this training stimulates cerebellar synaptic plasticity and improves alcohol-induced deficits on motor coordination tasks. RESULTS: The current studies found that rehabilitation training significantly attenuated alcohol-induced deficits in acquisition of eyeblink conditioning in females but not in males. These results are consistent with normalization of cerebellar dependent learning, at least in alcohol-exposed females. CONCLUSIONS: These findings extend previous studies in this model suggesting that rehabilitation of adolescents with FASD using training with complex motor learning tasks could be effective in ameliorating functional impairments associated with cerebellar damage. Eyeblink classical conditioning deficits are now well documented in children with FASD and could serve as an evaluation measure to continue to develop therapeutic interventions such as complex motor learning. PMID- 23647405 TI - Aiding nature's organelles: artificial peroxisomes play their role. AB - A major goal in medical research is to develop artificial organelles that can implant in cells to treat pathological conditions or to support the design of artificial cells. Several attempts have been made to encapsulate or entrap enzymes, proteins, or mimics in polymer compartments, but only few of these nanoreactors were active in cells, and none was proven to mimic a specific natural organelle. Here, we show the necessary steps for the development of an artificial organelle mimicking a natural organelle, the peroxisome. The system, based on two enzymes that work in tandem in polymer vesicles, with a membrane rendered permeable by inserted channel proteins was optimized in terms of natural peroxisome properties and function. The uptake, absence of toxicity, and in situ activity in cells exposed to oxidative stress demonstrated that the artificial peroxisomes detoxify superoxide radicals and H2O2 after endosomal escape. Our artificial peroxisome combats oxidative stress in cells, a factor in various pathologies (e.g., arthritis, Parkinson's, cancer, AIDS), and offers a versatile strategy to develop other "cell implants" for cell dysfunction. PMID- 23647406 TI - Impact of Yoga Nidra on menstrual abnormalities in females of reproductive age. AB - OBJECTIVES: The aim of this study was to observe the effect of Yoga Nidra practice on hormone levels in patients who had menstrual irregularities. DESIGN: The study was a randomized controlled trial. SETTINGS/LOCATION: The study was conducted in the Department of Obstetrics and Gynecology at Chhatrapati Sahuji Maharaj Medical University, Uttar Pradesh, Lucknow, India. SUBJECTS were divided randomly into 2 groups-an intervention and a control group, with 75 subjects in each group. Of these subjects, 126 completed the study protocol. SUBJECTS: This study involved 150 subjects with menstrual irregularities; 126 of whom completed the protocol. INTERVENTIONS: The intervention was the practice of Yoga Nidra. The yogic intervention duration was 35-40 minutes/day, five times/week for 6 months. An estimation of hormonal profile was done for both groups at baseline and after 6 months. RESULTS: Thyroid-stimulating hormone (p<0.002), follicle-stimulating hormone (p<0.02), luteinizing hormone (p<0.001), and prolactin (p<0.02) were decreased significantly in the intervention group, compared with the control group. CONCLUSIONS: The present study demonstrated the efficacy of Yoga Nidra on hormone profiles in patients with menstrual irregularities. Yoga Nidra practice was helpful in patients with hormone imbalances, such as dysmenorrhea, oligomenorrhea, menorrhagia, metrorrhagia, and hypomenorrhea. PMID- 23647407 TI - The application of blood flow restriction training into Western medicine: isn't it about time? PMID- 23647408 TI - Effects of electroacupuncture on depression and the production of glial cell line derived neurotrophic factor compared with fluoxetine: a randomized controlled pilot study. AB - BACKGROUND AND OBJECTIVE: Postmortem studies indicate that the number and density of glial cells are reduced in different brain regions of patients with depression. Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the pathogenesis of depressive disorder (DD) and might be a biomarker for damage to nerve cells. In this study, we compared the therapeutic effects of electroacupuncture (EA) and fluoxetine, a serotonin reuptake inhibitor, on DD patients, focusing on the serum level of GDNF. DESIGN: This was a prospective, randomized clinical trial. SETTING: Seventy-five patients with DD from the Department of Acupuncture, Beijing Hospital of Traditional Chinese Medicine, were recruited. INTERVENTION: Twenty patients were treated with acupuncture for 6 weeks on the acupoints of Baihui (DU20) and Zusanli (ST36). Sixteen patients were treated with acupuncture for 6 weeks on the acupoints of Taichong (LR3), Sanyinjiao (SP6), Neiguan (PC6), and Shenmen (HT7), and constituted the electroacupuncture control group. The patients received acupuncture treatment five times per week. Twenty-five patients were treated with oral fluoxetine (20 mg/day) for 6 weeks. OUTCOME MEASURES: All subjects were evaluated by the Hamilton Depression Rating Scale at four time points (0 [baseline], 2, 4, and 6 weeks after treatment). Serum GDNF was quantified in duplicate by enzyme-linked immunosorbent assay (ELISA). RESULTS: EA and fluoxetine had similar curative effects on DD patients. EA had a faster onset of action, better response rate, and better improvement rate than fluoxetine. Both fluoxetine and EA treatment restored the normal concentration of GDNF in the serum of DD patients. CONCLUSION: EA treatment for depression is as effective as a recommended dose of fluoxetine. However, EA demonstrates an advantage in the regulation of the production of GDNF compared with fluoxetine. PMID- 23647409 TI - Ciprofloxacin and rifampin have opposite effects on levothyroxine absorption. AB - BACKGROUND: Levothyroxine (L-T4) absorption varies between individuals, and can be affected by various concomitantly administered drugs. Case reports have indicated an association between cotreatment with ciprofloxacin or rifampin and hypothyroidism in patients on a stable L-T4 dose. METHODS: The effects of two antibiotics on T4 absorption were prospectively assessed in a double-blind, randomized, crossover fashion. Eight healthy volunteers received 1000 MUg L-T4 combined with placebo, ciprofloxacin 750 mg, or rifampin 600 mg as single doses. We measured total plasma thyroxine (T4) concentrations over a 6-hour period after dosing using liquid chromatography-tandem mass spectrometry. For each study arm, areas under the T4 plasma concentration-time curve (T4 AUCs) were compared. RESULTS: Coadministration of ciprofloxacin significantly decreased the T4 AUC by 39% (p = 0.035), while, surprisingly, rifampin significantly increased T4 AUC by 25% (p = 0.003). CONCLUSION: Intestinal absorption of L-T4 is differentially affected by acute coadministration of ciprofloxacin or rifampin. Mechanistic studies focused on intestinal and possibly hepatic thyroid hormone transporters are required to explain the observed drug interactions with L-T4. PMID- 23647410 TI - Directed self-assembly of nanoparticles for nanomotors. AB - We report, for the first time, the design and fabrication of a nanoparticle-based nanomotor system by directly self-assembling nanoparticles onto functional, nanometer-thin lamellae, such as polymer single crystals. Tens of thousands of judiciously selected nanoparticles (gold, iron oxide, and platinum nanoparticles) with sizes ranging from <5 to a few tens of nanometers have been introduced into a single nanomotor via directed self-assembly. The resulting nanomotor realizes functions such as autonomous movement, remote control, and cargo transportation by utilizing the advantages offered by nanoparticles, such as the small size, surface plasmon resonance, catalytic and magnetic properties. Because of the structural and functional versatility of nanoparticles, the facile fabricating procedure, and the potential for mass production, our strategy shows a key step toward the development of next generation multifunctional nanomotors. PMID- 23647411 TI - Development of ideas on channel flow in bedrock in the period 1850-1950. PMID- 23647412 TI - Brucella melitensis 16MDeltahfq attenuation confers protection against wild-type challenge in BALB/c mice. AB - Brucellosis is a globally distributed zoonotic disease that causes animal and human diseases. Although effective, the current Brucella vaccines (Rev.1 and M5 90) have several drawbacks. The first involves residual virulence for animals and humans and the second is the inability to differentiate natural infection from that caused by vaccination. Therefore, Brucella melitensis 16M hfq mutant (16MDeltahfq) was constructed to overcome these drawbacks. Similarly to Rev.1 and M5-90, 16MDeltahfq reduces survival in macrophages and mice and induces strong protective immunity in BALB/c mice. Moreover, these vaccines elicit anti-Brucella specific IgG1 and IgG2a subtype responses and induce secretion of gamma interferon and interleukin-4. The Hfq antigen also allows serological differentiation between infected and vaccinated animals. These results show that 16MDeltahfq is an ideal live attenuated vaccine candidate against virulent Brucella melitensis 16M infection. It will be further evaluated in sheep. PMID- 23647413 TI - Number trumps area for 7-month-old infants. AB - Over the past few decades, there has been extensive debate as to whether humans represent number abstractly and, if so, whether perceptual features of a set such as cumulative surface area or contour length are extracted more readily than number from the external world. Here we show that 7-month-old infants are sensitive to smaller ratio changes in number than cumulative area when each variable is tested separately and that infants prefer to look at number changes compared with area changes when the 2 variables are pitted directly against each other. Our results provide strong evidence that number is a more salient dimension to young infants than cumulative surface area and that infants' ability to discriminate sets on the basis of number is more finely tuned than their ability to discriminate sets on the basis of cumulative surface area. PMID- 23647414 TI - From early attachment to engagement with learning in school: the role of self regulation and persistence. AB - This article presents theoretical arguments and supporting empirical evidence suggesting that attachment experiences in early life may be important in the later development of self-regulation and conscientious behavior. Analyses of data from the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development (NICHD Early Child Care Research Network, 2005; N = 1,149) were conducted to test the association between attachment, measured at 15 and 36 months, and 3 measures of self-regulation (social self-control rated by teachers, task persistence as measured by observers in a series of lab tasks, and a continuous performance test) between Grades 1 and 5. Mediational analyses were also conducted to test whether self-regulation mediates the effect of attachment on children's engagement with learning in the classroom, as measured by direct observation. The results confirmed the hypothesis that attachment would be related to later self-regulation, but only for social self-control, and attentional impulsivity, not task persistence. Furthermore, social self-control at Grade 1 mediated the effect of attachment (at both 15 and 36 months) on school engagement at Grade 5, even when Grade 1 school engagement was statistically controlled. The discussion focuses on the potential importance of early attachment experiences for the development and maintenance of conscientiousness across the lifespan. PMID- 23647415 TI - Moral complexity in middle childhood: children's evaluations of necessary harm. AB - We assessed 5- to 11-year-olds' (N = 76) judgments of straightforward moral transgressions (prototypical harm) as well as their evaluations of complex, hypothetical scenarios in which an actor transgresses in order to prevent injury (necessary harm). The nature of the actor's transgression (psychological or physical harm) varied across participants. Moral judgments and justifications, knowledge of the actor's psychological experience, and their associations were examined. At all ages, children negatively evaluated prototypical harm; judgments of necessary harm became increasingly more forgiving with age as justifications pertaining to the actor's harm decreased. References to the actor's positive actions and children's tendency to coordinate conflicting concerns increased with age, but only when evaluating psychological harm. Across conditions, older children viewed transgressors as holding increasingly more positive attitudes toward their own actions, and this was uniquely associated with more forgiving moral judgments and justifications of necessary but not prototypical harm. Findings are discussed in relation to the emergence of more flexible and nuanced moral evaluations during middle childhood. PMID- 23647416 TI - Deciding in the dark: age differences in intuitive risk judgment. AB - Elevated levels of risky behavior in adolescence may signal developmental change in unconscious appraisal of risk. Yet, prior research examining adolescent risk judgment has used tasks that elicit conscious deliberation. The present study, in contrast, attempts to characterize age differences in (less conscious) intuitive impressions of risk. Participants (N = 282; ages 10-30) were presented with depictions of a range of risky and nonrisky activities. They were given 2.5 s to rate each activity on a continuous scale ranging from "bad idea" (low-risk favorability) to "good idea" (high-risk favorability). A curvilinear pattern was found, such that favorability ratings increased across adolescence and peaked around age 20. These results pose a challenge to developmental models that view early adolescence as the period of greatest predisposition toward risk taking; however, they are fairly consistent with age patterns for actual risk taking, at least with respect to crime, binge drinking, and unwanted pregnancy. PMID- 23647417 TI - Developmental changes in motor control: insights from bimanual coordination. AB - Manual dexterity is known to gradually progress with developmental age. In this study, we evaluate the performance of unimanual and bimanual actions under perturbed and unperturbed conditions in children between 4 and 10 years of age. Behavior was assessed by means of trajectory measurements and degree of bimanual coupling. The results showed that the younger children performed less successfully than the older children in the unimanual and bimanual tasks, with a plateau occurring around the age of 8 years. The SWAN rating scale of inattention and hyperactivity/impulsivity correlated with bimanual behavior at this particular age, suggesting that these traits are predictors of intricate skill performance during a critical developmental phase when significant refinement of control mechanisms occurs. The data furthermore revealed that a rebalancing of the between-hand performance asymmetries enabled superior bimanual coordination patterns in the older children. This suggests that progress in bimanual behavior relies on essential changes in unimanual processing and points to a dynamic interplay of circuitry. Overall, the data highlight a progressive change and integration of control systems due to developmental age with behavioral performance being guided by the existing constraints. PMID- 23647418 TI - Enhancing peer cultures of academic effort and achievement in early adolescence: promotive effects of the SEALS intervention. AB - Peer cultures of effort and achievement influence early adolescents' academic adjustment. A randomized controlled trials design was used to test the extent to which aspects of peer cultures of effort and achievement were enhanced following teachers' participation in the Supporting Early Adolescents' Learning and Social Success (SEALS) intervention. Observational and survey data from teachers (N = 188) and survey data from 6th-graders (N = 2,453) in 36 rural schools across the United States were analyzed. Results indicated that in SEALS versus matched control schools, social prominence was more favorably associated with effort and school valuing, and peer group injunctive norms were more supportive of effort and achievement. Findings indicate that aspects of peer cultures respond to the school context and provide evidence of the efficacy of the SEALS model. PMID- 23647419 TI - Evolutionary conservation of an atypical glucocorticoid-responsive element in the human tyrosine hydroxylase gene. AB - The human tyrosine hydroxylase (hTH) gene has a 42 bp evolutionarily conserved region designated (CR) II at -7.24 kb, which bears 93% homology to the region we earlier identified as containing the glucocorticoid response element, a 7 bp activator protein-1 (AP-1)-like motif in the rat TH gene. We cloned this hTH-CRII region upstream of minimal basal hTH promoter in luciferase (Luc) reporter vector, and tested glucocorticoid responsiveness in human cell lines. Dexamethasone (Dex) stimulated Luc activity of hTH-CRII in HeLa cells, while mifepristone, a glucocorticoid receptor (GR) antagonist, prevented Dex stimulation. Deletion of the 7 bp 5'-TGACTAA at -7243 bp completely abolished the Dex-stimulated Luc activity of hTH-CRII construct. The AP-1 agonist, tetradeconoyl-12,13-phorbol acetate (TPA), also stimulated hTH promoter activity, and Dex and TPA together further accentuated this response. Chromatin immunoprecipitation assays revealed the presence of both GR and AP-1 proteins, especially Jun family members, at this hTH promoter site. Dex did not stimulate hTH promoter activity in a catecholaminergic cell line, which had low endogenous GR levels, but did activate the response when GR was expressed exogenously. Thus, our studies have clearly identified a glucocorticoid-responsive element in a 7 bp AP-1-like motif in the promoter region at -7.24 kb of the human TH gene. PMID- 23647420 TI - Phosphite in sedimentary interstitial water of Lake Taihu, a large eutrophic shallow lake in China. AB - The seasonal occurrence and distribution of phosphite (HPO3(2-), P) in sedimentary interstitial water from Lake Taihu was monitored from 2011 to 2012 to better understand its possible link to P cycle in the eutrophic shallow lake. Phosphite concentrations ranged from < MDL to 14.32 +/- 0.19 MUg P/kg with a mean concentration of 1.58 +/- 0.33 MUg P/kg, which accounts for 5.51% total soluble P (TSP(s)) in surficial sediments (0-20 cm). Spatially, the concentrations of sedimentary phosphite in the lake's northern areas were relatively higher than those in the southern areas. Higher phosphite concentrations were always observed in seriously polluted sites. Generally, phosphite in the deeper layers (20-40 cm and 40-60 cm) showed minor fluctuations compared to that in the surficial sediments, which may be associated with the frequent exchange at the sediment water interface. Phosphite concentrations in surficial or core sediments decreased as spring > autumn > summer > winter. Higher phosphite levels occurred in the areas with lower redox (Eh), higher P contents, and particularly when metal bonded with P to form Al-P(s) and Ca-P(s). Phosphite may be an important media in the P biogeochemical cycle in Lake Taihu and contribute to its internal P transportation. PMID- 23647421 TI - Twenty-first century palliative care: a tale of four nations. AB - Hospice and palliative care development, in terms of availability and services, occur to varying degrees in the developing world. In this paper, the evolution of palliative care practices in four developing nations (Nigeria, Georgia, Ethiopia and Tanzania) is described. By highlighting common problems as well as the unique individual perspectives of each country's practice, this paper aims at increasing global awareness of palliative care in the developing world. While the call for palliative care to become a fundamental human right is sustained, it is also hoped that this article will stimulate a global discussion on the best possible way to encourage the establishment and growth of palliative care services in other developing countries where hitherto it has not been in existence, with policymakers and healthcare professionals taking the lead through the institution of sound national policies to promote and provide palliative care to all citizenry. PMID- 23647422 TI - Surface-enhanced Raman spectroscopy of double-shell hollow nanoparticles: electromagnetic and chemical enhancements. AB - Enhancements of the Raman signal by the newly prepared gold-palladium and gold platinum double-shell hollow nanoparticles were examined and compared with those using gold nanocages (AuNCs). The surface-enhanced Raman spectra (SERS) of thiophenol adsorbed on the surface of AuNCs assembled into a Langmuir-Blodgett monolayer were 10-fold stronger than AuNCs with an inner Pt or Pd shell. The chemical and electromagnetic enhancement mechanisms for these hollow nanoparticles were further proved by comparing the Raman enhancement of nitrothiophenol and nitrotoulene. Nitrothiophenol binds to the surface of the nanoparticles by covalent interaction, and Raman enhancement by both the two mechanisms is possible, while nitrotoulene does not form any chemical bond with the surface of the nanoparticles and hence no chemical enhancement is expected. Based on discrete dipole approximation (DDA) calculations and the experimental SERS results, AuNCs introduced a high electromagnetic enhancement, while the nanocages with inner Pt or Pd shell have a strong chemical enhancement. The optical measurements of the localized surface plasmon resonance (LSPR) of the nanocages with an outer Au shell and an inner Pt or Pd shell were found, experimentally and theoretically, to be broad compared with AuNCs. The possible reason could be due to the decrease of the coherence time of Au oscillated free electrons and fast damping of the plasmon energy. This agreed well with the fact that a Pt or Pd inner nanoshell decreases the electromagnetic field of the outer Au nanoshell while increasing the SERS chemical enhancement. PMID- 23647423 TI - Genetic susceptibility and mechanisms for refractive error. AB - Refractive errors, myopia and hyperopia, are the most common causes of visual impairment worldwide. Recent advances in genetics have been utilized to identify a wealth of genetic loci believed to contain susceptibility genes for refractive error (RE). The current genetic evidence confirms that RE is influenced by both common and rare variants with a significant environmental component. These studies argue that only by combining genetic and environmental knowledge with in vivo measurements of biological states will it be possible to understand the underlying biology of RE that will lead to novel therapeutic targets and accurate genetic predictions. PMID- 23647424 TI - Association of Mn-SOD mutation (c.47T > C) with various POAG clinical indices. AB - BACKGROUND: To investigate whether the c.47T > C mutation in the manganese superoxide dismutase gene (Mn-SOD) is a risk factor for primary open angle glaucoma (POAG) in the Saudi population. MATERIALS AND METHODS: A cohort of 226 unrelated POAG patients and 403 unrelated control subjects from Saudi Arabia were genotyped for a single nucleotide polymorphism (SNP; rs4880; c.47T > C) utilizing Taq-Man(r) assay ID: C_8709053_10. The association between mutant genotypes and various clinical indices important for POAG was also investigated. RESULTS: Among cases, the prevalence of the wildtype genotype (T/T) was 22.1% (50/226), while the heterozygous mutated genotype (T/C) was 50.9% (115/226) and the homozygous mutant genotype (C/C) was 27% (61/226). There were no statistically significant differences between cases and controls in terms of the genotype distribution on both heterozygous mutant (p = 0.916) and homozygous mutant (p = 0.988) genotypes. POAG patients with the mutant genotypes had slightly higher intraocular pressure (IOP) than controls. Additionally, patients with T/C genotype had slight elevation of the cup/disc ratio than the normal group. Additionally, the age at onset of disease showed an increasing trend with severity of mutation where it increases across groups T/T, T/C, and C/C being at [48.9 (+/-16.3), 51.4 (+/ 12.2), and 56.5 (+/-13.9)] respectively and a p value of 0.028 for the C/C genotype. CONCLUSIONS: This mutation could be associated with various clinical indices important for POAG. If similar findings were found in other populations and larger cohorts, then this SNP may be used as a marker for assessing the severity of the disease. PMID- 23647425 TI - Optic disc dysplasia in poland syndrome. AB - PURPOSE: To report optic disc dysplasia in a case of Poland syndrome. DESIGN: Non interventional case report. METHODS: A 2-year-old boy with Poland syndrome was referred for ophthalmic evaluation after abnormal optic discs were found on exam. RESULTS: Physical exam at birth revealed right-sided aplasia of the pectoralis major muscle, symbrachydactyly, hypoplastic scapula, and an abnormal third rib. On dilated examination the optic nerve heads were dysplastic. The findings included multiple cilioretinal vessels, situs inversus, inferotemporal excavation, and surrounding pigmentary disturbances. CONCLUSION: Only one case of optic disc anomaly has been reported in Poland syndrome and was described as morning glory syndrome. The optic discs in our patient do not fit well with other optic disc excavation syndromes but are most reminiscent of those in papillorenal syndrome. As both Poland syndrome and papillorenal syndrome share vascular dysfunction as a possible etiology, this case adds to the literature of vascular dysgenesis in Poland syndrome. PMID- 23647426 TI - Abdominal imaging can misdiagnose submassive hepatic necrosis as cirrhosis in acute liver failure. AB - Patients with acute liver failure (ALF) can be listed status I for liver transplantation (LT) whereas patients with cirrhosis must follow the MELD scoring system. Liver imaging can mistakenly diagnose submassive hepatic necrosis in ALF as cirrhosis. The purpose of our study was to assess the accuracy of ultrasound (US) and computed tomography (CT) in distinguishing cirrhosis from ALF. All patients listed for ALF and transplanted during the study period were included. Controls were age- and gender-matched cirrhotic patients who underwent LT during the same period. Abdominal US or CT scans obtained on all patients were independently reviewed by three blinded abdominal radiologists. Explants from all patients were reviewed by two blinded pathologists, and histological diagnosis was correlated with radiological diagnosis. Forty-one patients with ALF and 42 patients with cirrhosis were analyzed. Univariate and multivariate analyses both revealed overall accuracy of 85% for ultrasound and 93% for CT. US and CT scans both provide high levels of accuracy in terms of discriminating ALF from cirrhosis but measures taken to determine whether a patient has ALF vs. cirrhosis needs to approach 100% accuracy. Thus, imaging studies alone should not definitively diagnosis one etiology of liver failure over the other. PMID- 23647427 TI - Evaluation of a Nutrition Care Process-based audit instrument, the Diet-NCP Audit, for documentation of dietetic care in medical records. AB - Adequate documentation in medical records is important for high-quality health care. Documentation quality is widely studied within nursing, but studies are lacking within dietetic care. The aim of this study was to translate, elaborate and evaluate an audit instrument, based on the four-step Nutrition Care Process model, for documentation of dietetic care in medical records. The audit instrument includes 14 items focused on essential parts of dietetic care and the documentation's clarity and structure. Each item is to be rated 0-1 or 0-2 points, with a maximum total instrument score of 26. A detailed manual was added to facilitate the interpretation and increase the reliability of the instrument. The instrument is based on a similar tool initiated 9 years ago in the United States, which in this study was translated to Swedish and further elaborated. The translated and further elaborated instrument was named Diet-NCP-Audit. Firstly, the content validity of the Diet-NCP-Audit instrument was tested by five experienced dietitians. They rated the relevance and clarity of the included items. After a first rating, minor improvements were made. After the second rating, the Content Validity Indexes were 1.0, and the Clarity Index was 0.98. Secondly, to test the reliability, four dietitians reviewed 20 systematically collected dietetic notes independently using the audit instrument. Before the review, a calibration process was performed. A comparison of the reviews was performed, which resulted in a moderate inter-rater agreement with Krippendorff's alpha = 0.65-0.67. Grouping the audit results in three levels: lower, medium or higher range, a Krippendorff's alpha of 0.74 was considered high reliability. Also, an intra-rater reliability test-retest with a 9 weeks interval, performed by one dietitian, showed strong agreement. To conclude, the evaluated audit instrument had high content validity and moderate to high reliability and can be used in auditing documentation of dietetic care. PMID- 23647428 TI - Xanthates and trithiocarbonates strongly inhibit carbonic anhydrases and show antiglaucoma effects in vivo. AB - Dithiocarbamates (DTCs) were recently discovered as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. A series of xanthates and a trithiocarbonate, structurally related to the DTCs, were prepared by reaction of alcohols/thiols with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of four human (h) isoforms, hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar xanthate/trithiocarbonate inhibitors targeting these CAs were detected. A docking study of some xanthates within the CA II active site showed that these compounds bind in a similar manner with the dithiocarbamates, coordinating monodentately to the Zn(II) ion from the enzyme active site. Several xanthates showed potent intraocular pressure lowering activity in two animal models of glaucoma via the topical administration. Xanthates and thioxanthates represent two novel, promising classes of CA inhibitors. PMID- 23647429 TI - Progesterone and related progestins: potential new health benefits. AB - Progesterone is a steroid hormone that is essential for the regulation of reproductive function. The main physiological roles of this hormone have been widely described. Progesterone and progestins have been approved for a number of indications including the treatment of irregular and anovulatory menstrual cycles and, when combined with estrogen, for contraception, and the prevention of endometrial hyperplasia in postmenopausal hormonal replacement therapy (HRT) regimens. Lack of understanding between the differences in categories of the progestins as well as with the physiological hormone has resulted in considerable controversy surrounding the use of progestins for HRT regimens. Newer evidence suggests that there are distinct differences between the molecules and there is no progestin class effect, with regard to benefits or side-effects. In addition to its role in reproduction, progesterone regulates a number of biologically distinct processes in other tissues, particularly in the nervous system and the vessels. Recently, it has been shown in animal experiments that progesterone and the progestin Nestorone((r)) have positive effects on neuroregeneration and repair of brain damage, as well as myelin repair. The potential benefits of natural progesterone and its related derivatives warrant further investigation. It is hoped that a better understanding of the mechanism of action of progesterone and selected progestins will help in defining better therapies for men and women. PMID- 23647430 TI - Interfacial engineering using mixed protein systems: emulsion-based delivery systems for encapsulation and stabilization of beta-carotene. AB - Emulsion-based delivery systems are needed to encapsulate, protect, and deliver lipophilic bioactive components in the food, personal care, and pharmaceutical industries. The functional performance of these systems can be controlled by engineering the composition and structure of the interfacial layer coating the lipid droplets. In this study, interfacial properties were controlled using two globular proteins with widely differing isoelectric points: lactoferrin (LF: pI ~ 8.5) and beta-lactoglobulin (BLG: pI ~ 5). Oil-in-water emulsions were prepared with different interfacial properties: [LF]-only; [BLG]-only; [LF]-[BLG] (laminated); [BLG]-[LF]-(laminated); and [BLG/LF]-(mixed). The influence of pH, ionic strength, and temperature on the physical stability of beta-carotene enriched emulsions was investigated. [LF]-emulsions were stable to droplet aggregation from pH 2 to 9 (0 mM NaCl), but all other emulsions aggregated at intermediate pH values. [BLG]-emulsions aggregated at high salt levels (>=50 mM NaCl), but all other emulsions were stable (0 to 300 mM NaCl). [BLG/LF]-emulsions were unstable to heating (>=60 degrees C), but all other emulsions were stable (30 to 90 degrees C). Color fading due to beta-carotene degradation occurred relatively quickly in [BLG]-emulsions (37 degrees C) but was considerably lower in all other emulsions, which was attributed to the ability of LF to bind iron or interact with beta-carotene. This study provides useful information for designing emulsion-based delivery systems to encapsulate and protect bioactive lipids, such as carotenoids. PMID- 23647431 TI - Design and synthesis of pyrrolotriazepine derivatives: an experimental and computational study. AB - The pyrrole derivatives having carbonyl groups at the C-2 position were converted to N-propargyl pyrroles. The reaction of those compounds with hydrazine monohydrate resulted in the formation of 5H-pyrrolo[2,1-d][1,2,5]triazepine derivatives. The synthesis of these compounds was accomplished in three steps starting from pyrrole. On the other hand, attempted cyclization of a pyrrole ester substituted with a propargyl group at the nitrogen atom gave, unexpectedly, the six-membered cyclization product, 2-amino-3-methylpyrrolo[1,2-a]pyrazin-1(2H) one as the major product. The expected cyclization product with a seven-membered ring, 4-methyl-2,3-dihydro-1H-pyrrolo[2,1-d][1,2,5]triazepin-1-one was formed as the minor product and was converted quantitatively to the major product. The formation mechanism of the products was investigated, and the results obtained were also supported by theoretical calculations. PMID- 23647432 TI - Functional and structural age-related changes in the scalp skin of Caucasian women. AB - BACKGROUND: Ageing of the skin, being chronological or sun induced is highly documented. Scalp, as a specific skin site, has, however, received little attention. This work attempted to describe functional and structural alterations that occur in scalp skin with ageing. METHODS: Two different age groups (N = 15 each; 30 +/- 3 and 62 +/- 2 y.o. respectively) of Caucasian women participated in the study. Some functional parameters (TEWL, Sebum level, Hydration, T degrees ) were recorded on the vertex part of the scalp, after having cut the hair flat on the scalp surface. Imaging of some structural criteria was carried out using high frequency ultrasound technique and optical coherence tomography on the same scalp site and on the mid-forehead, as a close control skin site. RESULTS: As compared with the younger group, the scalp of older women significantly showed a decreased TEWL and a slightly lower T degrees . The thickness of total skin (epidermis + dermis) increased with age on both scalp and on forehead. The thickness of scalp epidermis decreased with age while not significantly altered on forehead. Pseudoattenuation of ultrasound images increased in the older age group. Other criteria, such as sebum level, stratum corneum hydration, stratum corneum thickness, were not found altered with age. CONCLUSION: With ageing, some few functional and structural changes are observed in the scalp of Caucasian women. Similarities or differences with those previously reported in other skin sites are discussed. PMID- 23647434 TI - Solvothermal one-step synthesis of Ni-Al layered double hydroxide/carbon nanotube/reduced graphene oxide sheet ternary nanocomposite with ultrahigh capacitance for supercapacitors. AB - A Ni-Al layered double hydroxide (LDH), mutil-wall carbon nanotube (CNT), and reduced graphene oxide sheet (GNS) ternary nanocomposite electrode material has been developed by a facile one-step ethanol solvothermal method. The obtained LDH/CNT/GNS composite displayed a three-dimensional (3D) architecture with flowerlike Ni-Al LDH/CNT nanocrystallites gradually self-assembled on GNS nanosheets. GNS was used as building blocks to construct 3D nanostructure, and the LDH/CNT nanoflowers in turn separated the two-dimensional (2D) GNS sheets, which preserved the high surface area of GNSs. Furthermore, the generated porous networks with a narrow pore size distribution in the LDH/CNT/GNS composite were also demonstrated by the N2 adsorption/desorption experiment. Such morphology would be favorable to improve the mass transfer and electrochemical action of the electrode. As supercapacitor electrode material, the LDH/CNT/GNS hybrid exhibited excellent electrochemical performance, including ultrahigh specific capacitance (1562 F/g at 5 mA/cm(2)), excellent rate capability, and long-term cycling performance, which could be a promising energy storage/conversion material for supercapacitor application. PMID- 23647433 TI - Fracture risk in older, long-term survivors of early-stage breast cancer. AB - OBJECTIVES: To examine the effect of breast cancer and its treatment on fracture risk in older breast cancer survivors. DESIGN: A 10-year prospective cohort study beginning 5 years after a diagnosis of breast cancer for survivors and match date for comparison women. SETTING: Six integrated healthcare systems. PARTICIPANTS: Women aged 65 and older (1,286 survivors, 1,286 comparison women, mean age 77.7 in both groups, white, non-Hispanic: survivors, 81.6%; comparison women, 85.2%) who were alive and recurrence free 5 years after a diagnosis of early-stage breast cancer and matched on age, study site, and enrollment year to a comparison cohort without breast cancer. MEASUREMENTS: Cox proportional hazards models were used to estimate the association between fracture risk and survivor-comparison status, adjusting for drugs and risk factors associated with bone health. A subanalysis was used to evaluate the association between tamoxifen exposure and fracture risk. RESULTS: No difference was observed in fracture rates between groups (hazard ratio (HR) = 1.1, 95% confidence interval (CI) = 0.9-1.3). The protective effect of tamoxifen was not statistically significant (HR = 0.9, 95% CI = 0.6-1.2). CONCLUSION: Long-term survivors of early-stage breast cancer diagnosed at age 65 and older are not at greater risk of osteoporotic fractures than age-matched women without breast cancer. There appears to be no long-term protection from fractures with tamoxifen use. PMID- 23647435 TI - Healthcare utilization in medical intensive care unit survivors with alcohol withdrawal. AB - BACKGROUND: Rehospitalization is an important and costly outcome that occurs commonly in several diseases encountered in the medical intensive care unit (ICU). Although alcohol use disorders are present in 40% of ICU survivors and alcohol withdrawal is the most common alcohol-related reason for admission to an ICU, rates and predictors of rehospitalization have not been previously reported in this population. METHODS: We conducted a retrospective cohort study of medical ICU survivors with a primary or secondary discharge diagnosis of alcohol withdrawal using 2 administrative databases. The primary outcome was time to rehospitalization or death. Secondary outcomes included time to first emergency department or urgent care clinic visit in the subset of ICU survivors who were not rehospitalized. Cox proportional hazard models were adjusted for age, gender, race, homelessness, smoking, and payer source. RESULTS: Of 1,178 patients discharged from the medical ICU over the study period, 468 (40%) were readmitted to the hospital and 54 (4%) died within 1 year. Schizophrenia (hazard ratio 2.23, 95% CI 1.57, 3.34, p < 0.001), anxiety disorder (hazard ratio 2.04, 95% CI 1.30, 3.32, p < 0.01), depression (hazard ratio 1.62, 95% CI 1.05, 2.40, p = 0.03), and Deyo comorbidity score >=3 (hazard ratio 1.43, 95% CI 1.09, 1.89, p = 0.01) were significant predictors of time to death or first rehospitalization. Bipolar disorder was associated with time to first emergency department or urgent care clinic visit (hazard ratio 2.03, 95% CI 1.24, 3.62, p < 0.01) in the 656 patients who were alive and not rehospitalized within 1 year. CONCLUSIONS: The presence of a psychiatric comorbidity is a significant predictor of multiple measures of unplanned healthcare utilization in medical ICU survivors with a primary or secondary discharge diagnosis of alcohol withdrawal. This finding highlights the potential importance of targeting longitudinal multidisciplinary care to patients with a dual diagnosis. PMID- 23647436 TI - Management of cytomegalovirus infection in haemopoietic stem cell transplantation. PMID- 23647437 TI - Intracellular drug delivery nanocarriers of glutathione-responsive degradable block copolymers having pendant disulfide linkages. AB - Self-assembled micelles of amphiphilic block copolymers (ABPs) with stimuli responsive degradation (SRD) properties have a great promise as nanotherapeutics exhibiting enhanced release of encapsulated therapeutics into targeted cells. Here, thiol-responsive degradable micelles based on a new ABP consisting of a pendant disulfide-labeled methacrylate polymer block (PHMssEt) and a hydrophilic poly(ethylene oxide) (PEO) block were investigated as effective intracellular nanocarriers of anticancer drugs. In response to glutathione (GSH) as a cellular trigger, the cleavage of pendant disulfide linkages in hydrophobic PHMssEt blocks of micellar cores caused the destabilization of self-assembled micelles due to change in hydrophobic/hydrophilic balance. Such GSH-triggered micellar destabilization changed their size distribution with an appearance of large aggregates and led to enhanced release of encapsulated anticancer drugs. Cell culture results from flow cytometry and confocal laser scanning microscopy for cellular uptake as well as cell viability measurements for high anticancer efficacy suggest that new GSH-responsive degradable PEO-b-PHMssEt micelles offer versatility in multifunctional drug delivery applications. PMID- 23647440 TI - Ethnic Swedish parents' experiences of minority ethnic nurses' cultural competence in Swedish paediatric care. AB - BACKGROUND: Sweden has a population of a little more than 9.4 million. The rapid growth of immigration in Sweden has resulted in an increased number of minority ethnic patients and minority ethnic nurses in the Swedish healthcare system. This also applies to paediatric care. AIM: The purpose of this study was to explore how parents with ethnic Swedish backgrounds experience minority ethnic nurses' cultural competence and the care the nurses provide in a Swedish paediatric care context. METHOD: This exploratory qualitative study is of 14 parents with an ethnic Swedish background whose child was in a ward at a children's hospital in Stockholm County Council. Data were collected using semi-structured interviews to identify parents' perceptions and experiences of minority ethnic nurses' cultural competence. The interviews were analysed by qualitative content analysis. RESULTS: The analyses of the interviews led to four main categories: influence of nurses' ethnicity; significance of cross-cultural communication; cross-cultural skills; and the importance of nursing education. CONCLUSIONS: Nurses' ethnicity did not have much impact on parents' satisfaction with their child's care. The parents attached importance to nurses' language skills and to their adaptation and awareness of Swedish culture. They also attached weight to nurses' professional knowledge and personal attributes. The role of nursing education to increase nurses' cultural awareness was highlighted too. PMID- 23647439 TI - Alternative splicing and retinal degeneration. AB - Alternative splicing is highly regulated in tissue-specific and development specific patterns, and it has been estimated that 15% of disease-causing point mutations affect pre-mRNA splicing. In this review, we consider the cis-acting splice site and trans-acting splicing factor mutations that affect pre-mRNA splicing and contribute to retinal degeneration. Numerous splice site mutations have been identified in retinitis pigmentosa (RP) and various cone-rod dystrophies. Mutations in alternatively spliced retina-specific exons of the widely expressed RPGR and COL2A1 genes lead primarily to X-linked RP and ocular variants of Stickler syndrome, respectively. Furthermore, mutations in general pre-mRNA splicing factors, such as PRPF31, PRPF8, and PRPF3, predominantly cause autosomal dominant RP. These findings suggest an important role for pre-mRNA splicing in retinal homeostasis and the pathogenesis of retinal degenerative diseases. The development of novel therapeutic strategies to modulate aberrant splicing, including small molecule-based therapies, has the potential to lead to new treatments for retinal degenerative diseases. PMID- 23647441 TI - A highly efficient synthetic vector: nonhydrodynamic delivery of DNA to hepatocyte nuclei in vivo. AB - Multifunctional membrane-core nanoparticles, composed of calcium phosphate cores, arginine-rich peptides, cationic and PEGylated lipid membranes, and galactose targeting ligands, have been developed as synthetic vectors for efficient nuclear delivery of plasmid DNA and subsequent gene expression in hepatocytes in vivo. Targeted particles exhibited rapid and extensive hepatic accumulation and were predominantly internalized by hepatocytes, while the inclusion of such peptides in LCP was sufficient to elicit high degrees of nuclear translocation of plasmid DNA. Monocyclic CR8C significantly enhanced in vivo gene expression over 10-fold more than linear CR8C, likely due to a release-favoring mechanism of the DNA/peptide complex. Though 100-fold lower in activity than that achieved via hydrodynamic injection, this formulation presents as a much less invasive alternative. To our knowledge, this is the most effective synthetic vector for liver gene transfer. PMID- 23647443 TI - Synergistic and antagonistic effects of alpha-Amylase and amyloglucosidase on starch digestion. AB - The influence of biomacromolecular physical structure on the kinetics of degradation with exo-acting or a mixture of endo- and exo-acting enzymes was studied using three physical forms of maize and potato starch, amyloglucosidase (exo-acting) and alpha-amylase (endo-acting) as exemplars. For starch in granular form, there was synergism between the enzymes in the production of glucose. In contrast, endo- and exo-acting enzymes showed antagonistic effects in digestion of cooked starches. Antagonism was ascribed to the rapid production of low molecular weight oligomers by alpha-amylase, which are less efficiently digested by amyloglucosidase than polymeric substrates. The rates of digestion of swollen granule ghosts cooked under low shear conditions were slower than starches cooked under high shear conditions that prevent granule ghost formation. There was also an enzyme-resistant fraction present in granule ghosts, in contrast to high shear cooked starches that were fully digested under the conditions used. PMID- 23647442 TI - Laterality and the evolution of the prefronto-cerebellar system in anthropoids. AB - There is extensive evidence for an early vertebrate origin of lateralized motor behavior and of related asymmetries in underlying brain systems. We investigate human lateralized motor functioning in a broad comparative context of evolutionary neural reorganization. We quantify evolutionary trends in the fronto cerebellar system (involved in motor learning) across 46 million years of divergent primate evolution by comparing rates of evolution of prefrontal cortex, frontal motor cortex, and posterior cerebellar hemispheres along individual branches of the primate tree of life. We provide a detailed evolutionary model of the neuroanatomical changes leading to modern human lateralized motor functioning, demonstrating an increased role for the fronto-cerebellar system in the apes dating to their evolutionary divergence from the monkeys (~30 million years ago (Mya)), and a subsequent shift toward an increased role for prefrontal cortex over frontal motor cortex in the fronto-cerebellar system in the Homo-Pan ancestral lineage (~10 Mya) and in the human ancestral lineage (~6 Mya). We discuss these results in the context of cortico-cerebellar functions and their likely role in the evolution of human tool use and speech. PMID- 23647444 TI - Impact of neoadjuvant chemotherapy on survival in breast cancer patients in daily practice: a population-based study. AB - This population-based study aimed to describe the effects of neoadjuvant chemotherapy (NC) on survival in breast cancer (BC) patients in daily practice. BC patients treated with NC followed by surgery and radiotherapy, were retrospectively selected from 1982 to 2005 using the Cote d'Or BC registry. These patients were matched for the baseline AJCC (American Joint Committee on Cancer) stage, age at diagnosis, date of diagnosis and oestrogens receptors status to those who had undergone surgery followed by adjuvant chemotherapy and radiotherapy. The prognostic effect of NC on survival in BC patients was assessed with relative survival (RS) analyses. From 1982 to 2005, 210 patients with BC diagnosed in Cote d'Or were treated with NC followed by surgery and radiotherapy. For these patients, mean age at diagnosis was 50 (SD = 11). The main tumour characteristics were clinical AJCC stage 3 (46%) and an advanced Scarff Bloom and Richardson (SBR) stage (80%). Breast conserving surgery was performed in 84 patients (40%), 151 patients (72%) were treated with anthracyclines as the NC and the 5-year RS rate was 71%. Among these patients, 92 (37%) were matched. In this population, multivariate analyses showed that the use of NC did not independently influence RS: relative excess risk = 0.93 (0.50, 1.71). PMID- 23647445 TI - Randomized, open-label study to evaluate patient-reported outcomes with fingolimod after changing from prior disease-modifying therapy for relapsing multiple sclerosis: EPOC study rationale and design. AB - OBJECTIVE: The study to Evaluate Patient OutComes, Safety, and Tolerability of Fingolimod (EPOC; NCT01216072) aimed to test the hypothesis that therapy change to oral Gilenya (Novartis AG, Stein, Switzerland) (fingolimod) improves patient reported outcomes compared with standard-of-care disease-modifying therapy (DMT) in patients with relapsing multiple sclerosis; safety and tolerability were also assessed. This communication describes the study rationale and design. METHODS: EPOC is a phase 4, open-label, multi-center study conducted in the US and Canada of patients with relapsing forms of multiple sclerosis who are candidates for therapy change. Therapy change eligibility was determined by the treating physician (US patients) or required an inadequate response to or poor tolerance for at least 1 MS therapy (Canadian patients). Patients were randomly assigned in a 3:1 ratio to 6 months of treatment with once-daily oral fingolimod 0.5 mg or standard-of-care DMTs. The primary study end-point was the change from baseline in treatment satisfaction as determined by the global satisfaction sub-scale of the Treatment Satisfaction Questionnaire for Medication. Secondary end-points included changes from baseline in perceived effectiveness and side-effects, and measures of activities of daily living, fatigue, depression, and quality-of-life. A 3-month open-label fingolimod extension was available for patients randomly assigned to the DMT group who successfully completed all study visits. RESULTS: Enrollment has been completed with 1053 patients; the patient population is generally older and has a longer duration of disease compared with populations from phase 3 studies of fingolimod. LIMITATIONS: Inclusion criteria selected for patients with a sub-optimal experience with a previous DMT, limiting the collection of data on therapy change in patients who were satisfied with their previous DMT. CONCLUSIONS: Results of the EPOC study are anticipated in early 2013 and will inform treatment selection by providing patient-centered data on therapy switch to fingolimod or standard-of-care DMTs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01216072. PMID- 23647446 TI - Understanding the effects on HR-QoL of treatment for overactive bladder: a detailed analysis of EQ-5D clinical trial data for mirabegron. AB - BACKGROUND: Analysis of EQ-5D data often focuses on changes in utility, ignoring valuable information from other parts of the instrument. The objective was to explore how the utility index, EQ-5D profile, and EQ-VAS captured change in clinical trials of mirabegron, a new treatment for overactive bladder (OAB). DATA: Data were pooled from three phase III clinical trials that investigated the efficacy and safety of mirabegron vs placebo. Tolterodine ER 4 mg was included as an active control in one study: (1) placebo, mirabegron 50 mg and 100 mg, and tolterodine 4 mg ER; (2) placebo, mirabegron 50 mg and 100 mg; (3) placebo, and mirabegron 25 mg and 50 mg. Data were collected at baseline, week 4, 8, and 12. METHODS: Analyses were performed on full analysis and modified intention to treat (ITT) data sets using UK utilities. Analysis controlled for relevant patient characteristics. Analysis of Covariance identified changes from baseline at each time point in utilities and EQ-VAS. Areas Under the Curve were estimated to summarize inter-temporal differences in effect. EQ-5D profile data were analysed using the Paretian Classification of Health Change. RESULTS: In modified ITT analyses, mirabegron 50 mg was superior to tolterodine 4 mg in changes from baseline utilities after 12 weeks (p < 0.05); similarly, AUC results showed mirabegron 50 mg to be superior to tolterodine (p < 0.05) and placebo (p < 0.05) with the benefit already apparent at 4 weeks (p < 0.05). EQ-VAS more consistently indicated superior outcomes: all three mirabegron doses showed statistically significant greater effectiveness compared to tolterodine at 12 weeks. Individual EQ-5D dimensions and the overall profile showed no significant differences between study arms. CONCLUSION: Mirabegron showed quicker and superior improvement in HR-QoL compared to tolterodine 4 mg ER. A limitation of the study is that EQ-5D was a secondary outcome in the pivotal trials, which were not powered to measure differences on EQ-5D. PMID- 23647447 TI - A longitudinal analysis of costs associated with change in disease activity in systemic lupus erythematosus. AB - OBJECTIVES: To estimate the economic consequences of changes in disease activity on healthcare resource utilization (HRU) and costs. METHODS: A retrospective longitudinal study of systemic lupus erythematosus (SLE) patients receiving care in a regional integrated health delivery system in the US from 01/2004 through 03/2011 was conducted using electronic health records, medical chart reviews, and claims. Eligible patients were >=18 years old, with >=1 rheumatologist-confirmed SLE diagnosis and >=1 eligible rheumatology encounter. Patients were continuously enrolled >=90 days before and >=30 days after the encounters. Charts were manually reviewed to estimate SLEDAI scores. Average unit costs of each medical procedure, facility use, and prescription were estimated from a payer perspective (2011 USD) using a managed care claims database. HRU and costs were calculated for the 30-day period surrounding every SLEDAI score date (10 days before and 19 after). Relationships between HRU/costs and SLEDAI scores were estimated using mixed-effect models. RESULTS: Overall, 178 SLE patients were included; mean age was 50.6 years, 91% were female, and 95.5% Caucasian. Patients had a total of 1343 encounters with SLEDAI scores over an average period of 1035 days. Reductions of SLEDAI scores were associated with reductions in HRU and costs. SLEDAI score reductions of 4-points were associated with reductions of 10% HRU and 14% costs over a 30-day period; reductions of 8-points had associated reductions of 19% HRU and 26% costs; and reductions of 10-points had associated reductions of 23% HRU and 31% costs. Annualized, changes in SLEDAI scores are associated with changes of $2485 (SLEDAI score change: 10-6), $4624 (10-2), and $5579 (10-0), respectively. CONCLUSION: Reductions in disease activity were associated with substantial reductions of HRU and costs. LIMITATIONS: Only short term effects of disease activity change were investigated, disregarding other potential benefits of low disease activity on long-term organ damage prevention or comorbidities. PMID- 23647448 TI - What kinds of website and mobile phone-delivered physical activity and nutrition interventions do middle-aged men want? AB - Within a health context, men in Western societies are a hard-to-reach population who experience higher rates of chronic disease compared with women. Innovative technology-based interventions that specifically target men are needed; however, little is known about how these should be developed for this group. This study aimed to examine opinions and perceptions regarding the use of Internet and mobile phones to improve physical activity and nutrition behaviors for middle aged men. The authors conducted 6 focus groups (n = 30) in Queensland, Australia. Their analyses identified 6 themes: (a) Internet experience, (b) website characteristics, (c) Web 2.0 applications, (d) website features, (e) self monitoring, and (f) mobile phones as delivery method. The outcomes indicate that men support the use of the Internet to improve and self-monitor physical activity and dietary behaviors on the condition that the website-delivered interventions are quick and easy to use, because commitment levels to engage in online tasks are low. Participants also indicated that they were reluctant to use normal mobile phones to change health behaviors, although smartphones were perceived to be more acceptable. This pilot study suggests that there are viable avenues to engage middle-aged men in Internet- or in mobile-delivered health interventions. This study also suggests that to be successful, these interventions need to be tailor-made especially for men, with an emphasis on usability and convenience. A wider quantitative study would bring further support to these findings. PMID- 23647449 TI - Anion exchange resins as a source of nitrosamines and nitrosamine precursors. AB - Anion exchange resins are important tools for the removal of harmful anionic contaminants from drinking water, but their use has been linked to the presence of carcinogenic nitrosamines in treated drinking water. In bench-scale batch and column experiments, anion exchange resins from a large, representative group were investigated as sources of the nitrosamines N-nitrosodimethylamine (NDMA), N nitrosodiethylamine (NDEA), N-nitrosodi-n-propylamine (NDPA), and N-nitrosodi-n butylamine (NDBA) and their precursors. Several resins were found to release high levels (up to >2000 ng/L, orders of magnitude above drinking water regulatory levels) of nitrosamines upon initial rinsing with lab-grade water, with levels subsiding within 50-100 bed volumes of rinsing. Resins released similarly high levels of nitrosamine precursors, with spikes in precursor release triggered by regeneration of resins with sodium chloride or by interruptions in flow resulting in prolonged contact times. Free chlorine or preformed monochloramine in feedwater led to the production of nitrosamines. Resins released different nitrosamines and precursors depending on their functional groups, with some resins releasing as many as three different nitrosamines and their precursors. These findings have significant implications for the pretreatment and appropriate use of anion exchange resins by drinking water utilities and for the production of anion exchange resins by manufacturers. PMID- 23647450 TI - Completely regioselective direct C-H functionalization of benzo[b]thiophenes using a simple heterogeneous catalyst. AB - The first completely selective C3 C-H arylation of benzo[b]thiophenes is reported, demonstrating previously unexploited reactivity of palladium. Benzo[b]thiophenes are coupled with readily available aryl chlorides using a ligand-free, dual catalytic system of heterogeneous Pd/C and CuCl. The reaction is operationally simple and insensitive to air and moisture, and it provides valuable products with complete selectivity. Significant investigations into the nature of the active catalytic species and mechanistic considerations are discussed. PMID- 23647451 TI - Sol-gel-derived silver-nanoparticle-embedded thin film for mass spectrometry based biosensing. AB - A porous silver-nanoparticle (AgNP)-embedded thin film biosensor was produced by the sol-gel method. The thin films were used as matrix-free laser desorption ionization mass spectrometry (LDI-MS) biosensors applicable to several chemical classes. In these experiments, UV laser irradiation (337 nm) of the AgNP facilitates desorption and ionization of a number of peptides, triglycerides, and phospholipids. Preferential ionization of sterols from vesicles composed of olefinic phosphosphatidylcholines is also demonstrated, offering the possibility for a simplified approach for sterol analysis from complex mixtures. The composition of the nanoparticles was confirmed by X-ray photoelectron spectroscopy (XPS) and UV-vis spectroscopy. XPS data revealed a binding energy of 368.2 eV, consistent with the previous assignment of the binding energy for the Ag 3d(5/2) peak from Ag(0) at 368.1 +/- 0.1 eV. The surface morphology of the thin films was studied by field-emission scanning electron microscopy (FE-SEM) and revealed the presence of nanoparticles and the porous nature of the biosensor. PMID- 23647452 TI - Photophysics of xanthone: a quantum chemical perusal. AB - A theoretical analysis of the chromophore xanthone has been carried out in various cases, starting from the isolated molecule and going on to the extremely polar-protic solvated chromophore. In the gas phase, we find that an El-Sayed forbidden channel with a rate constant of kISC = 2 * 10(11) s(-1) is one of the trend-setting factors in the photophysical kinetics. The fluorescence is found to be quenched in the gas phase and polar-aprotic solvents. The analysis of xanthone in aqueous solution supports the delayed fluorescence model, which has been suggested to explain the high fluorescence quantum yield observed in water. Besides, we present a detailed analysis of the photophysics of xanthone in acetonitrile and methanol. PMID- 23647453 TI - Sensorimotor and linguistic information attenuate emotional word processing benefits: an eye-movement study. AB - Recent studies have reported that emotional words are processed faster than neutral words, though emotional benefits may not depend solely on words' emotionality. Drawing on an embodied approach to representation, we examined interactions between emotional, sensorimotor, and linguistic sources of information for target words embedded in sentential contexts. Using eye-movement measures for 43 native English speakers, we observed emotional benefits for negative and positive words and sensorimotor benefits for words high in concreteness, but only when target words were low in frequency. Moreover, emotional words were maximally faster than neutral words when words were low in concreteness (i.e., highly abstract), and sensorimotor benefits occurred only when words were not emotionally charged (i.e., emotionally neutral). Furthermore, emotional and concreteness benefits were attenuated by individual differences that attenuate and amplify emotional and sensorimotor information, respectively. Our results suggest that behavior is functionally modulated by embodied information (i.e., emotional and sensorimotor) when linguistic contributions to representation are not enhanced by high frequency. Furthermore, emotional benefits are maximal when words are not already embodied by sensorimotor contributions to representation (and vice versa). Our work is consistent with recent studies that have suggested that abstract words are grounded in emotional experiences, analogous to how concrete words are grounded in sensorimotor experiences. PMID- 23647454 TI - Red enhances the processing of facial expressions of anger. AB - Emotional expressions convey important social information. Given the social importance of decoding emotions, expressive faces wield great influence on cognition and perception. However, contextual factors also exert a top-down influence on emotion detection, privileging particular expressions over others. The current research investigates how the psychological meaning implied by the color red biases the processing of anger expressions. Red has been shown to carry the meaning of threat and danger, and in two experiments we find that exposure to red enhances the perception and identification of anger. In Experiment 1, the identification of anger, relative to happiness, was facilitated when faces were viewed on a red background. In Experiment 2, the red-anger facilitation effect was replicated and shown to not generalize to another high arousal negative emotion, fear. These results document a novel influence of color on emotion detection processes. PMID- 23647455 TI - The donor line break cannula: effect on the donation process, blood component quality and transfusion microbiology testing of an important new blood bag safety feature. AB - BACKGROUND: The use of blood packs with an integral sampling system can result in anti-coagulant from the main bag reaching the sample pouch via the donor line, causing delayed coagulation of blood samples. In NHS Blood and Transplant, this has prevented the use of serum, the preferred matrix for transfusion microbiology (TM) testing, which has led to an increased false positive rate with ethylenediaminetetraacetic acid (EDTA) plasma. There is also a remote possibility of false negative results owing to sample dilution. Manufacturers have responded by offering packs with a donor line break cannula (DLBC) to prevent these adverse effects. OBJECTIVES: The aims of this study were to assess the impact of DLBC packs on donation, blood component quality and of the potential return to serum for TM testing. METHODS: DLBC packs from three manufacturers were assessed against control packs of the same dimensions and configuration. Donation duration, flow rate, platelet factor 4, prothrombin fragment 1+2, haemolysis and collection and processing incidents were compared. RESULTS: Results indicated no clinically significant adverse effect from the DLBC on the activation state of platelets, the coagulation cascade or increased haemolysis. Donation duration and blood collection and processing incident rates for DLBC packs were not significantly different to controls. CONCLUSIONS: The use of DLBC packs would reduce the complexity of manipulations during blood collection and therefore the likelihood of microbially contaminated donations (incorrect skin core diversion) and false negative TM tests. DLBC packs would enable the use of serum for TM testing with a significant reduction in false positive tests compared to EDTA plasma. PMID- 23647457 TI - Androgen therapy in women, beyond libido. AB - OBJECTIVE: The aim of this review was to summarize the literature regarding the potential role of testosterone therapy for women. METHODS: The author conducted a search of the literature using Medline (Ovid, 1946-present) and PubMed (1966 2013) for English-language studies that included the following search terms: 'testosterone' or 'androgen' combined with 'women', 'therapy' or 'treatment'. RESULTS: Randomized, placebo-controlled trials have consistently shown that transdermal testosterone therapy improves sexual desire, arousal, orgasm frequency and satisfaction in premenopausal and postmenopausal women presenting with sexual desire/arousal problems. No adverse metabolic effects have been observed in these studies. In postmenopausal women, testosterone therapy has also been associated with favorable effects on body composition, bone, cardiovascular function and cognitive performance. CONCLUSIONS: Although androgens have many varied roles, the focus of testosterone therapy for women has been on improving sexual desire. Not only do testosterone effects on sexuality extend beyond libido, but testosterone has other key physiological actions. Issues that urgently need to be addressed include approval of a testosterone formulation that delivers a female dose such that physicians refrain from prescribing compounded testosterone or modifying doses of testosterone formulated for men and regulation of prescription of compounded androgens for women. PMID- 23647456 TI - TRIM13 (RFP2) downregulation decreases tumour cell growth in multiple myeloma through inhibition of NF Kappa B pathway and proteasome activity. AB - Multiple myeloma (MM) is an incurable neoplasm caused by proliferation of malignant plasma cells in the bone marrow (BM). MM is characterized frequently by a complete or partial deletion of chromosome 13q14, seen in more than 50% of patients at diagnosis. Within this deleted region the tripartite motif containing 13 (TRIM13, also termed RFP2) gene product has been proposed to be a tumour suppressor gene (TSG). Here, we show that low expression levels of TRIM13 in MM are associated with chromosome 13q deletion and poor clinical outcome. We present a functional analysis of TRIM13 using a loss-of-function approach, and demonstrate that TRIM13 downregulation decreases tumour cell survival as well as cell cycle progression and proliferation of MM cells. In addition, we provide evidence for the involvement of TRIM13 downregulation in inhibiting the NF kappa B pathway and the activity of the 20S proteasome. Although this data does not support a role of TRIM13 as a TSG, it substantiates important roles of TRIM13 in MM tumour survival and proliferation, underscoring its potential role as a novel target for therapeutic intervention. PMID- 23647458 TI - Human choroid plexus papilloma cells efficiently transport glucose and vitamin C. AB - In vitro and in vivo studies suggest that the basolateral membrane of choroid plexus cells, which is in contact with blood vessels, is involved in the uptake of the reduced form of vitamin C, ascorbic acid (AA), through the sodium-vitamin C cotransporter, (SVCT2). Moreover, very low levels of vitamin C were observed in the brains of SVCT2-null mice. The oxidized form of vitamin C, dehydroascorbic acid (DHA), is incorporated through the facilitative glucose transporters (GLUTs). In this study, the contribution of SVCT2 and GLUT1 to vitamin C uptake in human choroid plexus papilloma (HCPP) cells in culture was examined. Both the functional activity and the kinetic parameters of GLUT1 and SVCT2 in cells isolated from HCPP were observed. Finally, DHA uptake by GLUT1 in choroid plexus cells was assessed in the presence of phorbol-12-myristate-13-acetate (PMA) activated human neutrophils. A marked increase in vitamin C uptake by choroid plexus cells was observed that was associated with superoxide generation and vitamin C oxidation (bystander effect). Thus, vitamin C can be incorporated by epithelial choroid plexus papilloma cells using the basolateral polarization of SVCT2 and GLUT1. This mechanism may be amplified with neutrophil infiltration (inflammation) of choroid plexus tumors. In choroid plexus papilloma cells, the vitamin C transporters SVCT2 and GLUT1 are polarized to the basolateral epithelial membrane, where SVCT2 is essential for AA flux from the blood vessels into the brain. However, neutrophils, attracted by inflammation or the tumor microenvironment, can oxidize extracellular AA to DHA, thereby enabling its uptake through GLUT1. For the first time, we show the in vivo and in vitro basolateral co-distribution of functional SVCT2 and GLUT1 in epithelial cells. We postulate that patients with choroid plexus papillomas may continue to transport vitamin C from the blood to CSF. However, increased transport of oxidized vitamin C could generate pro-oxidative conditions that may help control tumor growth. PMID- 23647459 TI - Avicularin, a plant flavonoid, suppresses lipid accumulation through repression of C/EBPalpha-activated GLUT4-mediated glucose uptake in 3T3-L1 cells. AB - Avicularin (quercetin-3-O-alpha-L-arabinofuranoside) is a plant flavonoid and a quercetin glycoside. In this study, we found that avicularin suppressed the accumulation of intracellular lipids through repression of glucose transporter 4 (GLUT4)-mediated glucose uptake in mouse adipocytic 3T3-L1 cells. Avicularin was highly purified (purity of more than at least 99%) from Taxillus kaempferi (DC.) Danser (Loranthaceae) by high-performance liquid chromatography, and its structure was determined by nuclear magnetic resonance and mass spectrometry. Avicularin decreased the intracellular triglyceride level along with a reduction in the expression of adipogenic genes such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein (C/EBP) alpha, and aP2 (fatty acid binding protein 4). In contrast, avicularin did not affect the expression of lipogenic and lipolytic genes. Interestingly, the expression of the GLUT4 gene was significantly suppressed in an avicularin-concentration-dependent manner. Moreover, the binding of C/EBPalpha to the promoter region of the GLUT4 gene was repressed by adding avicularin to the medium in 3T3-L1 cells, as demonstrated by the results of a chromatin immunoprecipitation assay. These results indicate that avicularin inhibited the accumulation of the intracellular lipids by decreasing C/EBPalpha-activated GLUT4-mediated glucose uptake in adipocytes. PMID- 23647460 TI - A necrotic uterus after a B-Lynch Suture: fertility sparing surgery. PMID- 23647462 TI - Physalin A induces apoptotic cell death and protective autophagy in HT1080 human fibrosarcoma cells. AB - Physalin A (1) is a withanolide isolated from Physalis alkekengi var. franchetii. In this study, the selective growth inhibitory effects on tumor cells induced by 1 were screened, and the mechanism was investigated on 1-induced growth inhibition, including apoptosis and autophagy, in human fibrosarcoma HT1080 cells. Apoptosis induced by 1 in HT1080 cells was associated with up-regulation of caspase-3 and caspase-8 expression. However, there were no significant changes in caspase-9, Bid, Bax, and Bcl-2 expression, indicating that 1-induced apoptosis in HT1080 cells occurs mainly through activation of the death receptor-associated extrinsic apoptotic pathways. Autophagy induced by 1 was found to antagonize apoptosis in HT1080 cells. This effect was enhanced by rapamycin and suppressed by the autophagy inhibitor 3-methyladenine (3MA). Loss of beclin 1 (as an autophagic regulator) function led to similar results to 3MA. However, 1 did not show inhibitory effects on normal human cells (human peripheral blood mononuclear cells). Taken together, these results suggest that 1 may be a promising agent for the treatment of cancer. PMID- 23647463 TI - A smart DNA tetrahedron that isothermally assembles or dissociates in response to the solution pH value changes. AB - This communication reports a DNA tetrahedron whose self-assembly is triggered by an acidic environment. The key element is the formation/dissociation of a short, cytosine (C)-containing, DNA triplex. As the solution pH value oscillates between 5.0 and 8.0, the DNA triplex will form and dissociate that, in turn, leads to assembly or disassembly of the DNA tetrahedron, which has been demonstrated by native polyacrylamide gel electrophoresis (PAGE). We believe that such environment-responsive behavior will be important for potential applications of DNA nanocages such as on-demand drug release. PMID- 23647461 TI - Graft macrosteatosis and time of T-tube removal as risk factors for biliary strictures after liver transplantation. AB - Biliary strictures (BS) remain a significant problem following liver transplantation (LT), representing an important cause of morbidity. The purpose of this follow-up study was to evaluate the incidence and risk factors associated with BS after LT. From 2001 to 2009, 244 consecutive patients underwent LT at our center. Multiple donor and recipient variables were collected for each patient. Exclusion criteria were hepaticojejunostomy, living-donor LT, and follow-up less than three months. We reviewed 177 patients, all of whom underwent an end-to-end choledochocholedochostomy and T-tube placement. BS occurred in 23% of patients. Multivariate analysis revealed that graft macrovesicular steatosis >25% (p = 0.05, OR 3.38) and time of T-tube removal less than six months (p = 0.02, OR 2.53) were independent risk factors for BS. Biliary strictures did not affect patient and graft survival. Donor macrovesicular steatosis represents a risk factor for BS, contributing to liver damage through a reduction in hepatic blood flow. Time of T-tube removal seems to play a role in the development of BS, although it is unclear whether it represents the cause or the consequence of the development of BS. PMID- 23647464 TI - Alternative treatment option for hypopharyngeal cancer: clinical outcomes after conservative laryngeal surgery with partial pharyngectomy. AB - CONCLUSION: The oncological and functional outcomes of hypopharyngeal cancer after conservative laryngeal surgery are fairly acceptable, making this a reasonable initial treatment option for selected patients. OBJECTIVE: The purpose of this study was to assess the clinical outcomes of patients with hypopharyngeal squamous cell carcinoma (SCC) treated with conservative laryngeal surgery with partial pharyngectomy. METHODS: Fifty-eight patients with hypopharyngeal SCC who underwent laryngeal preservation surgery were enrolled. The tumors were classified as cT1 in 5 (8.6%) patients, cT2 in 35 (60.3%), cT3 in 14 (24.1%), and cT4a in 4 (6.9%) patients. RESULTS: Surgical outcomes: 5-year overall and disease specific survival rates were 78% and 77.6%. Recurrent disease developed in 13 patients (22.4%). Multivariate analysis revealed that level VI metastasis confirmed by histopathological analysis, close (< 5 mm) histologic margin, advanced N stage, and posterior pharyngeal wall tumor were independent factors associated with poor disease-specific survival. Functional outcomes: 50 patients (86.2%) could obtain all their nutritional needs orally. Eight patients needed the assistance of a percutaneous endoscopic gastrostomy tube. Oral re alimentation was achieved within a mean of 26.1 days after surgery. Fifty-one patients (87.9%) could be decannulated after a mean of 43.8 days postoperatively. PMID- 23647465 TI - Validity and reliability testing of the Swedish version of Melbourne Decision Making Questionnaire. AB - BACKGROUND: The Melbourne Decision-Making Questionnaire (MDMQ) is an attempt to capture and measure coping strategies that people use. The instrument had not previously been translated into Swedish. The aim of this study was to evaluate validity and reliability of the Swedish version of the MDMQ. METHOD: A Swedish translation was performed and back-translated. A group of five pilot readers evaluated content validity. The translated questionnaire was tested among 735 patients, healthcare workers, healthcare students and teachers. A parallel analysis (PA), exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were performed. RESULT: An initial EFA with a four-factor solution showed a low concordance with the original 22-item four-factor model with a very low Cronbach's alpha in one of the dimensions. However, a second EFA with a three factor solution showed a good model fit for the Swedish translation of the Melbourne Decision-Making Questionnaire (MDMQ-S) with a satisfactory Cronbach's alpha. A CFA showed a goodness of fit after deleting six items. CONCLUSION: After testing the MDMQ-S, we found support for validity and reliability of the instrument. We found the 16-item version of MDMQ-S to be satisfactory concerning the subscales vigilance, procrastination and buck-passing. However, we found no support that the hypervigilance dimension could be measured by the MDMQ-S. PMID- 23647466 TI - Real-time detection of isothermal amplification reactions with thermostable catalytic hairpin assembly. AB - Catalytic hairpin assembly (CHA) is an enzyme-free amplification method that has previously proven useful in amplifying and transducing signals at the terminus of nucleic acid amplification reactions. Here, for the first time, we engineered CHA to be thermostable from 37 to 60 degrees C and in consequence have generalized its application to the real-time detection of isothermal amplification reactions. CHA circuits were designed and optimized for both high- and low-temperature rolling circle amplification (RCA) and strand displacement amplification (SDA). The resulting circuits not only increased the specificity of detection but also improved the sensitivity by as much as 25- to 10000-fold over comparable real time detection methods. These methods have been condensed into a set of general rules for the design of thermostable CHA circuits with high signals and low noise. PMID- 23647467 TI - Factors that affect Pickering emulsions stabilized by graphene oxide. AB - Stable Pickering emulsions were prepared using only graphene oxide (GO) as a stabilizer, and the effects of the type of oil, the sonication time, the GO concentration, the oil/water ratio, and the pH value on the stability, type, and morphology of these emulsions were investigated. In addition, the effects of salt and the extent of GO reduction on emulsion formation and stability were studied and discussed. The average droplet size decreased with sonication time and with GO concentration, and the emulsions tended to achieve good stability at intermediate oil/water ratios and at low pH values. In all solvents, the emulsions were of the oil-in-water type, but interestingly, some water-in-oil-in water (w/o/w) multiple emulsion droplets were also observed with low GO concentrations, low pH values, high oil/water ratios, high salt concentrations, or moderately reduced GO in the benzyl chloride-water system. A Pickering emulsion stabilized by Ag/GO was also prepared, and its catalytic performance for the reduction of 4-nitrophenol was investigated. This research paves the way for the fabrication of graphene-based functional materials with novel nanostructures and microstructures. PMID- 23647469 TI - Antifungal effect of Allium tuberosum, Cinnamomum cassia, and Pogostemon cablin essential oils and their components against population of Aspergillus species. AB - Antifungal activity of Allium tuberosum (AT), Cinnamomum cassia (CC), and Pogostemon cablin (Patchouli, P) essential oils against Aspergillus flavus strains 3.2758 and 3.4408 and Aspergillus oryzae was tested at 2 water activity levels (aw : 0.95 and 0.98). Main components of tested essential oils were: allyl trisulfide 40.05% (AT), cinnamaldehyde 87.23% (CC), and patchouli alcohol 44.52% (P). The minimal inhibitory concentration of the plant essential oils against A. flavus strains 3.2758 and 3.4408 and A. oryzae was 250 ppm (A. tuberosum and C. cassia), whereas Patchouli essential oil inhibited fungi at concentration > 1500 ppm. The essential oils exhibited suppression effect on colony growth at all concentrations (100, 175, and 250 ppm for A. tuberosum; 25, 50, and 75 for C. cassia; 100, 250, and 500 for P. cablin essential oil). Results of the study represent a solution for possible application of essential oil of C. cassia in different food systems due to its strong inhibitory effect against tested Aspergillus species. In real food system (table grapes), C. cassia essential oil exhibited stronger antifungal activity compared to cinnamaldehyde. PMID- 23647470 TI - Providing food for a nation and world: a question of balance. PMID- 23647471 TI - Principal variance component analysis of crop composition data: a case study on herbicide-tolerant cotton. AB - Compositional studies on genetically modified (GM) and non-GM crops have consistently demonstrated that their respective levels of key nutrients and antinutrients are remarkably similar and that other factors such as germplasm and environment contribute more to compositional variability than transgenic breeding. We propose that graphical and statistical approaches that can provide meaningful evaluations of the relative impact of different factors to compositional variability may offer advantages over traditional frequentist testing. A case study on the novel application of principal variance component analysis (PVCA) in a compositional assessment of herbicide-tolerant GM cotton is presented. Results of the traditional analysis of variance approach confirmed the compositional equivalence of the GM and non-GM cotton. The multivariate approach of PVCA provided further information on the impact of location and germplasm on compositional variability relative to GM. PMID- 23647472 TI - Self-directed growth of aligned adenine molecular chains on Si(111)7*7: direct imaging of hydrogen-bond mediated dimers and clusters at room temperature by scanning tunneling microscopy. AB - The early stage of adsorption of adenine on Si(111)7*7 is studied by scanning tunneling microscopy (STM). Bright protrusions are observed in both empty-state and filled-state STM images, indicative of molecular adsorption of adenine through dative bonding. The majority of these bright protrusions appear as dimer pairs formed by hydrogen bonding at the initial adsorption stage. The formation of dative bonds between the substrate and adenine and the feasibility of the H bond mediated dimers are supported by ab initio DFT/B3LYP/6-31G++(d,p) calculations, and are in excellent accord with our recent X-ray photoemission data. Remarkably, these dimers are found to undergo self-organization into aligned superstructures, evidently with common link arrangements, including straight, offset, and zigzag chains, square quartets, double quartets, and other multiple dimer structures. As the exposure of adenine increases, the populations of dimers as well as the self-organized double dimer and other higher-order structures also increase. The end-to-end dimer links are found to be most prominent in the growth of adenine molecular chains, most notably aligned along the Si dimer-wall or [-1 1 0] direction of the 7*7 unit cell. The self-aligned adenine dimer molecular chains offer a natural template for catch-and-release biosensing, lithography, and molecular electronic applications. PMID- 23647473 TI - Genetics of human cataract. AB - The pathogenesis of inherited cataracts of all kinds recapitulates the developmental and cell biology of the lens. Just as each novel mutation provides additional information about the structural or functional biology of the affected gene, each newly identified gene provides insight into the developmental and cellular biology of the lens. The set of genes currently known to be associated with cataract is far from complete, especially for age-related cataract, and there is much additional information to be discovered through further genetic studies. PMID- 23647474 TI - Management of sialorrhoea in motor neuron disease: a survey of current UK practice. AB - Our objective was to better understand UK-wide practice in managing sialorrhoea in motor neuron disease among specialist clinicians. We used a survey of neurologists in the UK with a special interest in motor neuron disease designed to establish clinicians' attitudes towards treatment options and resources for sialorrhoea management. Twenty-three clinicians replied, representing 21 centres. Sixteen centres were specialist MND Care Centres. Clinicians estimated seeing a total of 1391 newly diagnosed patients with MND in 2011. One hundred and ninety three patients were described. Forty-two percent of patients reviewed in clinicians' last clinic had sialorrhoea and 46% of those with sialorrhoea had uncontrolled symptoms. Clinicians' preferred drugs were hyoscine patches, amitriptyline, carbocisteine and botulinum toxin. Botulinum toxin was used in 14 centres. Risk of dysphagia and staff skills were identified as the main barriers to botulinum toxin use. This survey suggests that there may be as many as 1700 patients with MND in the UK who have symptoms of sialorrhoea and that symptoms may be poorly controlled in nearly half. Treatment strategies varied, reflecting the lack of evidence based guidelines. The use of specialist treatments was influenced by local infrastructure. This study highlights the need for further work to develop evidence based guidance. PMID- 23647475 TI - How interpersonal communication mediates the relationship of multichannel communication connections to health-enhancing and health-threatening behaviors. AB - This article examines how everyday media use and interpersonal communication for health information could influence health behaviors beyond intervention or campaign contexts. The authors argue that interpersonal communication works as an independent information channel and mediates the relation between media channels and health behaviors. In addition, the authors investigate whether interpersonal communication differently influences the relation between media connections and health behaviors for more and less educated individuals. Using data from the 2008 Annenberg National Health Communication Survey, the authors show that multiple communication channels for health information encourage health-enhancing behaviors but do not have significant relations with health-threatening behaviors. Interpersonal communication is directly linked to health-enhancing behaviors, but it also mediates the influence of individuals' multichannel media environment on health-enhancing behaviors. The mediating role of interpersonal health communication was only significant for less educated people. In addition, among media channels, television was a more important instigator of health related conversations with family and friends for the less educated group. The theoretical and practical implications of these findings, as well as suggestions for future research directions, are discussed. PMID- 23647478 TI - C1 inhibitor concentrate treatment of multiple laryngeal attacks in a 53-year-old woman with hereditary angioedema. AB - This report describes a woman who experienced a high number of laryngeal hereditary angioedema (HAE) attacks during her participation in the IMPACT2 clinical trial of C1-INH concentrate. A 53-year-old caucasian female with a 31 year history of type 1 HAE experienced 16 laryngeal HAE attacks between 3 August 2006 and 23 February 2010, 15 of which were severe. All laryngeal attacks were successfully treated with C1-INH 20 U/kg, with a median onset of relief of 14 min and median time to complete resolution of symptoms of 20 h, and no need for redosing. The reliable success of C1-INH for these potentially fatal events is reassuring for both patients and prescribers. PMID- 23647479 TI - Visualization of plasma membrane compartmentalization by high-speed quantum dot tracking. AB - In this study, we have imaged plasma membrane molecules labeled with quantum dots in live cells using a conventional wide-field microscope with high spatial precision at sampling frequencies of 1.75 kHz. Many of the resulting single molecule trajectories are sufficiently long (up to several thousand steps) to allow for robust single trajectory analysis. This analysis indicates that a majority of the investigated molecules are transiently confined in nanoscopic compartments with a mean size of (100-150 nm)(2) for a mean duration of 50-100 ms. PMID- 23647480 TI - Large-scale roll-to-roll fabrication of vertically oriented block copolymer thin films. AB - Large-scale roll-to-roll (R2R) fabrication of vertically oriented nanostructures via directed self-assembly of cylindrical block copolymer (c-BCP) thin films is reported. Nearly 100% vertical orientation of cylinders in sub-100 nm c-BCP films under optimized processing via a dynamic sharp temperature gradient field termed Cold Zone Annealing-Sharp or 'CZA-S' is achieved, with successful scale-up on a prototype custom-built 70 ft * 1 ft R2R platform moving at 25 MUm/s, with 9 consecutive CZA units. Static thermal annealing of identical films in a conventional vacuum oven fails to produce comparable results. As a potential for applications, we fabricate high-density silicon oxide nanodot arrays from the CZA S annealed BCP thin film template. PMID- 23647481 TI - The validation and application of the Chinese version of perceived nursing work environment scale. AB - AIMS AND OBJECTIVES: To improve the development of the Chinese version of Perceived Nursing Work Environment (C-PNWE) scale by examination and application and to explore the nurses' perception of their working environment in a hospital. BACKGROUND: The C-PNWE scale was translated and revised from the PNWE scale. The least of perfection is that the development of C-PNWE ignored that the psychometric properties of the PNWE instrument were established of critical care nurses and further application and testing of the PNWE in various patient care settings were recommended. DESIGN: This is a cross-sectional design. Nurses from different departments of a hospital were sampled by convenience sampling and investigated by self-administrated questionnaire. METHODS: Data obtained through questionnaires were analysed by descriptive statistical analyses and profile analyses using the Statistical Package for the Social Sciences (SPSS) Chinese version 17.0 software. RESULTS: The coincident and level profile analyses indicated that these groups can merge into one group, and the profile of measurement result of this merged group would not exhibit flatness. Among six dimensions of C-PNWE scale, the Staffing and Resource Adequacy got the lowest average score. Among 41 items, 'Opportunity for staff nurse to participate in policy decisions' got the lowest mean. CONCLUSIONS: The C-PNWE scale shows good psychometric properties and can be used to explore nurses' perspectives of the nursing practice environment in China. And the situation of nurses' perceived working environment in China needs further study. RELEVANCE TO CLINICAL PRACTICE: Shaping nursing practice environments to promote desired outcomes requires valid and reliable measures to assess practice environments prior to, during and following efforts to implement change. The C-PNWE scale can be a useful measurement tool for administrators to improve the nursing work environment in China. PMID- 23647482 TI - Cost and utilization of healthcare services for hip and knee replacement. AB - OBJECTIVE: Describe resource utilization and costs for total hip replacement (THR) and total knee replacement (TKR) for the 90 days before hospitalization for surgery, the hospital event, and the 90 and 360 days after hospitalization for surgery with emphasis on 90 days after hospitalization. METHODS: A large insurance database was used to identify outpatient and summarized hospital resource use and payments (insurer perspective) for THR and TKR. A second large US database provided hospital details (charge description master level) of inpatient services, costs, and charges (hospital perspective) for a different sample of THR and TKR patients. Included patients were >=45 years old, had no hospitalization record within 1 year before surgery, and THR length of stay (LOS) of 2-8 days or TKR LOS 2-6 days. RESULTS: There were 22 618 THR and 50 686 TKR patients in the insurance database and 81 635 THR and 158 990 TKR in the hospital database. Average age was ~66 years for THR and TKR patients. Median LOS was 4 days (both surgeries). Hospital costs (hospital perspective) were $17 588 in US dollars (USD) and $16 267 (USD) for THR and TKR, respectively. Reimbursement for hospital services (insurer perspective) were $22 967 (USD) and $21 583 (USD) for THR and TKR, respectively. In 90 days post-surgery, THR and TKR total payments were $3827 (USD) and $4237 (USD), respectively. Payments for the first 90 days post-surgery were 57.5% of the 360-day post-period for THR-related payments and 59.9% for TKR-related payments. CONCLUSION: Payers considering use of episode-of care payment models for THR and TKR may wish to concentrate efforts on the 90 days post-discharge. LIMITATIONS: While this study used large samples of subjects, generalisability of the results may be limited since the samples were not randomized samples of THR and TKR patients. It is noteworthy that patients in the hospital sample are not the same as those in the insurer sample. Selection of hip-related and knee-related procedures and associated costs was based on qualitative review. Payers may use different billing codes or aggregate costs differently. PMID- 23647483 TI - The cost-effectiveness of onabotulinumtoxinA for the prophylaxis of headache in adults with chronic migraine in the UK. AB - BACKGROUND: Although chronic migraine is associated with substantial disability and costs, few treatments have been shown to be effective. OnabotulinumtoxinA (Botox, Allergan Inc., Irvine, CA) is the first treatment to be licensed in the UK for the prophylaxis of headaches in adults with chronic migraine. This study aims to evaluate the cost-effectiveness of onabotulinumtoxinA in this indication in the UK. METHODS: A state-transition (Markov) model was developed comparing onabotulinumtoxinA to placebo. Efficacy data and utility values were taken from the pooled Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical trials program (n = 1384). Estimates of resource utilisation were taken from the International Burden of Migraine Study (IBMS), and stopping rules were informed by published medical guidelines and clinical data. This study estimated 2-year discounted costs and quality-adjusted life years (QALYs) from the UK National Health Service perspective. RESULTS: At 2 years, treatment with onabotulinumtoxinA was associated with an increase in costs of L1367 and an increase in QALYs of 0.1 compared to placebo, resulting in an incremental cost effectiveness ratio (ICER) of L15,028. Treatment with onabotulinumtoxinA reduced headache days by an estimated 38 days per year at a cost of L18 per headache day avoided. Sensitivity analysis showed that utility values had the greatest influence on model results. The ICER remained cost-effective at a willingness to pay threshold of L20,000-L30,000/QALY in the majority of scenario analyses as well as in probabilistic sensitivity analysis, where onabotulinumtoxinA was cost effective on 96% of occasions at a threshold of L20,000/QALY and 98% of occasions at L30,000/QALY. CONCLUSION: OnabotulinumtoxinA has been shown to reduce the frequency of headaches in patients with chronic migraine and can be considered a cost-effective use of resources in the UK National Health Service. The uncertainties in the model relate to the extrapolation of clinical data beyond the 56-week trial. PMID- 23647484 TI - Plant invasions across the Northern Hemisphere: a deep-time perspective. AB - Few invasion biologists consider the long-term evolutionary context of an invading organism and its invaded ecosystem. Here, I consider patterns of plant invasions across Eastern North America, Europe, and East/Far East Asia, and explore whether biases in exchanges of plants from each region reflect major selection pressures present within each region since the late Miocene, during which temperate Northern Hemisphere floras diverged taxonomically and ecologically. Although there are many exceptions, the European flora appears enriched in species well adapted to frequent, intense disturbances such as cultivation and grazing; the North American composite (Asteraceae) flora appears particularly well adapted to nutrient-rich meadows and forest openings; and the East Asian flora is enriched in shade-tolerant trees, shrubs, and vines of high forest-invasive potential. I argue that such directionality in invasions across different habitat types supports the notion that some species are preadapted to become invasive as a result of differences in historical selection pressures between regions. PMID- 23647485 TI - Hybrid approach in an acute type B aortic dissection in a female patient after having a renal transplant. AB - This study describes our experiences with a 44-year-old woman who developed acute type B aortic dissection and elected emergency surgery 3 years after a renal transplant. This led to acute ischemia in the right lower extremity. The first stage of surgery was to implant an extra-anatomic (pretracheal) bypass with a GORE-TEX prosthesis from the brachiocephalic trunk to the left common carotid artery. The second stage was implanting a stent graft into the aortic arch that covered the left common carotid artery and the left subclavian artery. The third stage was to insert a stent graft that involved the entire thoracic aorta and proximal segment of the abdominal aorta to the celiac trunk, with the right axillary and left femoral approach. The fourth stage was an extra-anatomic (suprapubic) bypass with the GORE-TEX prosthesis from the left femoral artery to the right femoral artery. Surgery resulted in normal blood supply to the organs and restored renal function. PMID- 23647486 TI - Population pharmacokinetics of ertapenem in juvenile and old rats. AB - Ertapenem is a parenteral broad-spectrum carbapenem active against Gram-negative pathogens, which has been approved for treatment of different infectious situations in adults and children. Favourable pharmacokinetics and pharmacodynamics have been established in young adults. In the elderly, dosing regimen adaptations are not recommended. Nevertheless, pharmacokinetic studies in paediatrics have not been published yet. The aim of this study was to document whether age influenced ertapenem disposition by comparing its pharmacokinetics in three groups of rats. Rats were separated into three groups: very young rats 21 day-old, 10-week-old and 7-month-old rats. A population pharmacokinetic model was built and evaluated, using the NONMEM software. Pharmacokinetic parameters, interindividual variability and residual variability were estimated. The final model was evaluated by a bootstrap procedure and visual predictive check. The ertapenem concentration-time data were best described by a one-compartment model with zero-order input and first-order elimination. Effect of very young and old ages was estimated on central volume and clearance. Model evaluation indicated that the model was robust and parameter estimates were accurate. Central volume was found to be dependent on age and increase with age. Although the dosing regimen was weight adjusted, clearance was found to depend not only on age but also on weight. This study clearly documents changes in ertapenem pharmacokinetics according to group of age. These results suggest that paediatric dosing regimen cannot be directly extrapolated from a pharmacokinetic model in young adults unless it took into account age-induced modifications. PMID- 23647487 TI - Rhazinilam-Leuconolam-Leuconoxine Alkaloids from Leuconotis griffithii. AB - Eight new indole alkaloids (1-8) belonging to the rhazinilam-leuconolam leuconoxine group, in addition to 52 other alkaloids, were isolated from the stem bark extract of Leuconotis griffithii, viz., nor-rhazinicine (1), 5,21 dihydrorhazinilam-N-oxide (2), 3,14-dehydroleuconolam (3), and leuconodines A-E (4-8). The structures of these alkaloids were determined using NMR and MS analyses and in some instances confirmed by X-ray diffraction analyses. Alkaloids 1, 5, and 7 showed only moderate to weak cytotoxicity toward KB cells (IC50 12-18 MUg/mL), while 8 showed moderate activity in reversing MDR in vincristine resistant KB cells. PMID- 23647489 TI - Three-dimensional sonohysterography may replace hysteroscopy for women with perimenopausal bleeding. AB - OBJECTIVE: To investigate whether three-dimensional saline-infusion transvaginal sonohysterography can replace hysteroscopy in the detection of intrauterine lesions in women with perimenopausal bleeding. MATERIALS AND METHODS: This study was carried out at the Department of Obstetrics and Gynecology, Menofyia University Hospital in Egypt. Fifty women who presented with perimenopausal bleeding and fulfilled the inclusion criteria were recruited for the study. Three dimensional sonohysterography was performed followed by hysteroscopy for all women. Results were tabulated and statistically analyzed. The accuracy of both techniques was calculated in terms of sensitivity, specificity, positive and negative predictive values. RESULTS: The mean age of women enrolled was 47.5 +/- 5.61 years and the mean body mass index was 28.13 +/- 2.91 kg/m(2). Three dimensional sonohysterography detected no abnormality in 26 women but hysteroscopy only detected 24 with no abnormality. Compared to hysteroscopy, three-dimensional sonohysterography has sensitivities of 100% and 92% in the detection of endometrial polyps and submucous fibroids, respectively. The specificity of sonohysterography for both lesions was 100%. The sensitivity and specificity for other lesions exceeded 95%. CONCLUSIONS: Three-dimensional sonohysterosonography may be considered as an effective alternative to hysteroscopy in the assessment of the uterine cavity for any woman with perimenopausal bleeding. PMID- 23647490 TI - 'Tolerating violence': a qualitative study into the experience of professionals working within one UK learning disability service. AB - AIMS AND OBJECTIVES: To explore this complexity further, enhancing understanding of professionals' experience of violence and reasons for non-reporting with regard to people with a learning disability. BACKGROUND: This article reports on a qualitative follow-up study to a whole-population survey investigating the under-reporting of violence within one learning disability service. The survey had identified a pronounced level of under-reporting but suggested an unexpected degree of complexity around the issue, which warranted further study. DESIGN: A qualitative research design was employed. METHODS: Semi-structured interviews were conducted with 22 professionals working in learning disability services; data were subsequently transcribed verbatim and subject to stringent thematic analysis. RESULTS: The findings confirmed that the decision to report an incident or not was complicated by professional interpretation of violence. Three themes were produced by the analysis: the reality of violence, change over time and (zero) tolerance. CONCLUSION: The study indicates that both experience of violence and ways of understanding it in relation to learning disability are shared across professional groups, although nurses are both more inured and generally more accepting of it. The study suggests that the relationship between learning disability nurses and service users with a propensity for violence is complicated by issues of professional background and concerns about the pertinence of zero tolerance. RELEVANCE TO CLINICAL PRACTICE: The availability of effective protocols and procedures is important, but services need also to acknowledge the more ambiguous aspects of the therapeutic relationship to fully understand under-reporting of service user violence in the context of learning disability. PMID- 23647491 TI - Arsenic removal with composite iron matrix filters in Bangladesh: a field and laboratory study. AB - The main arsenic mitigation measures in Bangladesh, well-switching and deep tube wells, have reduced As exposure, but water treatment is important where As-free water is not available. Zero-valent iron (ZVI) based SONO household filters, developed in Bangladesh, remove As by corrosion of locally available inexpensive surplus iron and sand filtration in two buckets. We investigated As removal in SONO filters in the field and laboratory, covering a range of typical groundwater concentrations (in mg/L) of As (0.14-0.96), Fe (0-17), P (0-4.4), Ca (45-162), and Mn (0-2.8). Depending on influent Fe(II) concentrations, 20-80% As was removed in the top sand layer, but As removal to safe levels occurred in the ZVI layer of the first bucket. Residual As, Fe, and Mn were removed after re-aeration in the sand of the second bucket. New and over 8-year-old filters removed As to <50 MUg/L and mostly to <10 MUg/L and Mn to <0.2 mg/L. Vertical concentration profiles revealed formation of Fe(II) by corrosion of Fe(0) with O2 and incorporation of As into forming amorphous Fe phases in the composite iron matrix (CIM) of newer filters and predominantly magnetite in older filters. As mass balances indicated that users filtered less than reported volumes of water, pointing to the need for more educational efforts. All tested SONO filters provided safe drinking water without replacement for up to over 8 years of use. PMID- 23647488 TI - Impact of lifetime alcohol use on liver fibrosis in a population of HIV-infected patients with and without hepatitis C coinfection. AB - BACKGROUND: The effect of alcohol on liver disease in HIV infection has not been well characterized. METHODS: We performed a cross-sectional multivariable analysis of the association between lifetime alcohol use and liver fibrosis in a longitudinal cohort of HIV-infected patients with alcohol problems. Liver fibrosis was estimated with 2 noninvasive indices, "FIB-4," which includes platelets, liver enzymes, and age; and aspartate aminotransferase/platelet ratio index ("APRI"), which includes platelets and liver enzymes. FIB-4 <1.45 and APRI <0.5 defined the absence of liver fibrosis. FIB-4 >3.25 and APRI >1.5 defined advanced liver fibrosis. The main independent variable was lifetime alcohol consumption (<150 kg, 150 to 600 kg, >600 kg). RESULTS: Subjects (n = 308) were 73% men, mean age 43 years, 49% with hepatitis C virus (HCV) infection, 60% on antiretroviral therapy, 49% with an HIV RNA load <1,000 copies/ml, and 18.7% with a CD4 count <200 cells/mm(3) . Forty-five percent had lifetime alcohol consumption >600 kg, 32.7% 150 to 600 kg, and 22.3% <150 kg; 33% had current heavy alcohol use, and 69% had >9 years of heavy episodic drinking. Sixty-one percent had absence of liver fibrosis and 10% had advanced liver fibrosis based on FIB-4. In logistic regression analyses, controlling for age, gender, HCV infection, and CD4 count, no association was detected between lifetime alcohol consumption and the absence of liver fibrosis (FIB-4 <1.45) (adjusted odds ratio [AOR] = 1.12 [95% CI: 0.25 to 2.52] for 150 to 600 kg vs. <150 kg; AOR = 1.11 [95% CI: 0.52 to 2.36] for >600 kg vs. <150 kg; global p = 0.95). Additionally, no association was detected between lifetime alcohol use and advanced liver fibrosis (FIB-4 >3.25). Results were similar using APRI, and among those with and without HCV infection. CONCLUSIONS: In this cohort of HIV-infected patients with alcohol problems, we found no significant association between lifetime alcohol consumption and the absence of liver fibrosis or the presence of advanced liver fibrosis, suggesting that alcohol may be less important than other known factors that promote liver fibrosis in this population. PMID- 23647492 TI - Controlling the Type I error rate by using the nonparametric bootstrap when comparing means. AB - Of the several tests for comparing population means, the best known are the ANOVA, Welch, Brown-Forsythe, and James tests. Each performs appropriately only in certain conditions, and none performs well in every setting. Researchers, therefore, have to select the appropriate procedure and run the risk of making a bad selection and, consequently, of erroneous conclusions. It would be desirable to have a test that performs well in any situation and so obviate preliminary analysis of data. We assess and compare several tests for equality of means in a simulation study, including non-parametric bootstrap techniques, finding that the bootstrap ANOVA and bootstrap Brown-Forsythe tests exhibit a similar and exceptionally good behaviour. PMID- 23647493 TI - Anaemia and cognitive performances in the elderly: a systematic review. AB - Anaemia defined as a haemoglobin level <13 g/dl in men and <12 g/dl in women is common in older people and associated with numerous health consequences. The aim of this study was to systematically review all published data from the past 30 years that studied the association between anaemia and cognitive performance in people aged 65 years and over. An English and French Medline and Cochrane Library search ranging from 1979 to 2011 indexed under the Medical Subject Heading (MeSH) terms 'haemoglobin' or 'anaemia' combined with the terms 'dementia' or 'cognition disorders' or 'memory disorders' or 'orientation' or 'executive functions' or 'attention' or 'brain' or 'neuropsychological tests' was performed. Ninety-eight studies were selected. The following specific conditions were excluded: cancer, chronic kidney diseases, chronic heart disease and post-operative cognitive dysfunction. Five observational studies and six prospective cohort studies were included in the final analysis. According to the studies, the number of participants ranged from 302 to 2250 community-dwelling older people aged 55 years or over. Four studies considered the association between haemoglobin concentration and global cognitive functions, another three examined the association between haemoglobin concentration and the incidence of dementia, and four studies evaluated some specific aspects of cognition. A significant positive association was shown between anaemia and global cognitive decline as well as the incidence of dementia. A significant association was also shown between anaemia and executive functions. This systematic review shows a probable association between anaemia and cognitive performances, particularly with executive functions. PMID- 23647494 TI - Monitoring the Internet for emerging psychoactive substances available to Australia. AB - INTRODUCTION AND AIMS: Novel psychoactive substances are increasingly available, both in traditional storefronts and via the Internet. While some use of such substances has been captured in Australian consumer surveys and wastewater analyses, there is little information about the products that are available to Australia via the Internet. DESIGN AND METHODS: Systematic monthly Internet monitoring for emerging psychoactive substances was conducted between July 2011 and July 2012. Webstores identified through searches were examined to determine if they sold stimulant or psychedelic emerging psychoactive substances to Australia. Internet search numbers for these products were examined over time using commercial tools. RESULTS: In 12 months, 43 unique webstores were identified selling to Australia, averaging two new webstores per month; however, two-fifths had closed within six months. Over 200 unique chemically unspecified products sold by purported effect (e.g. 'charge') were identified over 12 months, averaging 10 new products per month. Almost half of these products had disappeared from the market within six months. Eighty-six unique chemically specified products (e.g. methylenedioxypyrovalerone) were identified over 12 months, averaging four new novel substances per month. Once released, these products typically remained available, with almost 90% still available for purchase over a 6-month period. Almost 40 000 searches for these products emanated from Australia per month. DISCUSSION AND CONCLUSION: This market is fast paced as retailers strive to beat both regulatory processes and competitors. Ongoing attention to these markets, incorporating surveillance of both Internet and traditional storefronts, is crucial as several of the substances identified have demonstrated potential for health and neurological harm. PMID- 23647495 TI - Platelet indices in renovascular thrombosis after a renal transplant. PMID- 23647496 TI - Layer by layer assembly of a biocatalytic packaging film: lactase covalently bound to low-density polyethylene. AB - Active packaging is utilized to overcome limitations of traditional processing to enhance the health, safety, economics, and shelf life of foods. Active packaging employs active components to interact with food constituents to give a desired effect. Herein we describe the development of an active package in which lactase is covalently attached to low-density polyethylene (LDPE) for in-package production of lactose-free dairy products. The specific goal of this work is to increase the total protein content loading onto LDPE using layer by layer (LbL) deposition, alternating polyethylenimine, glutaraldehyde (GL), and lactase, to enhance the overall activity of covalently attached lactase. The films were successfully oxidized via ultraviolet light, functionalized with polyethylenimine and glutaraldehyde, and layered with immobilized purified lactase. The total protein content increased with each additional layer of conjugated lactase, the 5 layer sample reaching up to 1.3 MUg/cm2 . However, the increase in total protein did not lend to an increase in overall lactase activity. Calculated apparent Km indicated the affinity of immobilized lactase to substrate remains unchanged when compared to free lactase. Calculated apparent turnover numbers (kcat ) showed with each layer of attached lactase, a decrease in substrate turnover was experienced when compared to free lactase; with a decrease from 128.43 to 4.76 s( 1) for a 5-layer conjugation. Our results indicate that while LbL attachment of lactase to LDPE successfully increases total protein mass of the bulk material, the adverse impact in enzyme efficiency may limit the application of LbL immobilization chemistry for bioactive packaging use. PMID- 23647498 TI - Preparation and reactions of enantiomerically pure alpha-functionalized Grignard reagents. AB - A strategy for the generation of enantiomerically pure alpha-functionalized chiral Grignard reagents is presented. The approach involves the synthesis of alpha-alkoxy and alpha-amino sulfoxides in >=99:1 dr and >=99:1 er via asymmetric deprotonation (s-BuLi/chiral diamine) and trapping with Andersen's sulfinate (menthol derived). Subsequent sulfoxide -> Mg exchange (room temperature, 1 min) and electrophilic trapping delivers a range of enantiomerically pure alpha-alkoxy and alpha-amino substituted products. Using this approach, either enantiomer of products can be accessed in 99:1 er from asymmetric deprotonation protocols without the use of (-)-sparteine as the chiral ligand. Two additional discoveries are noteworthy: (i) for the deprotonation and trapping with Andersen's sulfinate, there is a lack of stereospecificity at sulfur due to attack of a lithiated intermediate onto the alpha-alkoxy and alpha-amino sulfoxides as they form, and (ii) the alpha-alkoxy-substituted Grignard reagent is configurationally stable at room temperature for 30 min. PMID- 23647497 TI - Antihypertensive pharmacotherapy and long-term outcomes in pediatric kidney transplantation. AB - Hypertension (HTN) is common in pediatric recipients following kidney transplantation (KT). We retrospectively assessed the impact of HTN on long-term (>10-yr) outcomes in pediatric KT recipients (aged < 18 yr) at our center. Two hundred and ninety-three pediatric KT recipients (83% living donor [LD]) with graft survival (GS) for >=5 yr were studied. HTN was defined by antihypertensive medication use at five yr post-KT. One hundred and sixty (55%) recipients did not have HTN, and 133 (45%) had HTN at five yr post-KT. There were no differences in actuarial patient survival between cohorts. Actuarial GS at 15 and 20 yr was 68% and 53% for recipients without HTN, and 53% and 33% for recipients with HTN (p = 0.006). Among LD recipients using one antihypertensive, GS at 15 yr was 100% for those using an angiotensin-converting enzyme inhibitor (ACEI) and 44% for those not using an ACEI (p = 0.04). Among these recipients, HTN treated with no ACEI was a significant risk factor for graft failure at >5 yr (hazard ratio [HR] = 2.5, p = 0.02), but HTN treated with an ACEI was not (HR = 0.6, p = 0.7). HTN at five yr post-KT is associated with poorer long-term GS in pediatric recipients, but ACEI therapy may enable better outcomes and should be studied further. PMID- 23647499 TI - Phospholipid-lactose permease interaction as reported by a head-labeled pyrene phosphatidylethanolamine: a FRET study. AB - Forster resonance energy transfer (FRET) measurements were performed in preceding works to study the selectivity between a single-tryptophan mutant of lactose permease (LacY) of Escherichia coli (used as the donor) and phospholipid probes labeled with pyrene at the acyl chain moiety (used as the acceptor). In the present work, we report the results obtained by using the same LacY mutant (W151/C154G) and binary lipid mixtures of phosphatidylethanolamine (PE) differing in the acyl chain composition and 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac (1-glycerol)] (POPG) (3:1 mol/mol) doped with a phospholipid probe labeled with pyrene at the headgroup. The use of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine N-(1-pyrenesulfonyl) ammonium salt (HPyr-PE), which bears two unsaturated acyl chains, enabled the investigation of the specific interaction between LacY and HPyr-PE. The main conclusions raised from our results suggest that (i) for phase separated systems, LacY would be located in fluid domains nominally enriched in POPG, and if a given proportion of PE is present in this phase, it will be mainly located around LacY; and (ii) in the absence of phase separation, LacY is preferentially surrounded by PE and, in particular, seems to be sensitive to the lipid spontaneous curvature. PMID- 23647500 TI - WDR45 mutations define a novel disease entity--static encephalopathy of childhood with neurodegeneration in adulthood. PMID- 23647501 TI - Factors associated with child custody evaluators' recommendations in cases of intimate partner violence. AB - Although child custody evaluations can lead to unsafe outcomes in cases of intimate partner violence (IPV), little is known about factors associated with evaluators' recommendations. In this study of 465 child custody evaluators, we investigated the association between evaluators' beliefs, background, and knowledge and their custody and visitation recommendations in cases involving IPV. We hypothesized that evaluators' belief in false allegations by the mother and their recommendations that perpetrators have custody or unsupervised visits would be positively associated with (a) being a male evaluator, (b) patriarchal norms, (c) not knowing a survivor of IPV, and (d) less knowledge of IPV. In addition, we hypothesized that evaluators' belief in false allegations by mothers would be related to their recommendation that perpetrators have custody or unsupervised visits. Results supported most of the hypothesized relationships. Multivariate analysis revealed that belief variables explained more of the variance in custody-visitation outcomes than demographic and knowledge variables. Implications of the findings for IPV training, evaluator selection, and evaluation guidelines are provided. PMID- 23647503 TI - Oestradiol concentrations are not elevated in obesity-associated hypogonadotrophic hypogonadism. PMID- 23647504 TI - Fibrinolytic therapy of thrombosis in 27 newborns followed-up in neonatal intensive care unit. AB - BACKGROUND AND AIM: We aimed to report newborns with thrombosis and needed fibrinolytic treatment. PATIENTS AND METHODS: This was a retrospective study conducted on 27 newborns with thrombosis followed-up in a neonatal intensive care unit between December 2007 and December 2012. The patients were divided into two groups according to treatment protocol; Group 1 (n = 15): recombinant tissue-type plasminogen activator (r-tPA) and Group 2 (n = 12): streptokinase (STK). The groups were compared in terms of the efficacy and complications of the treatments. RESULTS: In Group 1, flow restoration was complete in nine (60%) patients, partial in two (13.3%), and absent in four (26.7%). In Group 2, flow restoration was complete in seven (58.3%) patients, partial in three (25%), and absent in two (16.0%). The incidence of complete/partial recovery was similar in the groups. There was no difference between the two groups with regard to the duration of thrombus resolution. Fibrinolytic treatment was terminated in seven patients (46.7%) in Group 1, while in three patients (25%) in Group 2 due to the complications. The most common complications were minor or major bleedings. There was no statistically significant difference with regard to all bleedings complications between the two groups (P = .08), although the incidence of skin hemorrhages was higher in Group 1 (P = .007). There was no significant difference between the mortality rates. CONCLUSION: Even though the use of STK is not further recommended because of its potential undesirable side effects in newborns, its efficacy and safety appears to be similar to those of r-tPA. PMID- 23647505 TI - Characteristics of children with non-hodgkin lymphoma associated with primary immune deficiency diseases: descriptions of five patients. AB - BACKGROUND: An increased incidence of non-Hodgkin lymphoma (NHL) has been seen in various primary immune deficiency (PID) cases. The present study aimed to evaluate the clinical characteristics and treatment outcomes of five cases with NHL associated with primary immunodeficiency. METHODS: We retrospectively evaluated five patients with primary immunodeficiency who developed NHL. Two patients had ataxia-telangiectasia (A-T), one patient had common variable immunodeficiency (CVID), one patient had Bloom's Syndrome, and one patient had Wiskott-Aldrich syndrome (WAS). RESULTS: All patients were male (median age, 8 years). Stage distribution was stage III in three patients and stage IV in two patients. Three patients had B-cell lymphoma and two had T-cell lymphoma. Reduced doses of Berlin-Frankfurt-Munster (BFM) and French Society of Pediatric Oncology (SFOP) regimens were used in four patients according to histopathological subtype. The two patients with ataxia and one patient with Bloom's Syndrome died of progressive/relapsed disease at months 5, 19, and 6, respectively. The patient with CVID associated with T-cell lymphoma has been in remission for 7 years. A full-dosage regimen of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was successfully used in the patient with WAS and B-cell lymphoma; he was still in remission after 3 years. CONCLUSION: Primary immunodeficiency diseases are one of the strongest known risk factors for the development of NHL. Management of these patients remains problematic. There is a great need to develop new therapeutic approaches in this group. The use of rituximab in combination with CHOP may provide a promising treatment option for B cell lymphomas associated with immunodeficiency. PMID- 23647506 TI - Allogeneic hematopoietic stem cell transplantation for treatment of Gaucher disease. AB - Ito and Barrett recently reviewed the international experiences with allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of the neuronopathic and non-neuronopathic forms of Gaucher disease (GD). In the present communication, the author adds some updated data on the long-term outcome of allo HSCT for Swedish GD patients with the mean and median follow-up time of 27 years (the longest follow-up of 30 years) and makes comments on some of the authors' statements found in the article. PMID- 23647507 TI - Cerebral radiation necrosis in pediatric patients. AB - Radiation necrosis is a well-described toxicity following radiation therapy in the brain. There is little data regarding the incidence of radiation necrosis in pediatric patients. We retrospectively reviewed our experience with 101 children with solid brain tumors. Radiation necrosis was diagnosed by examination of magnetic resonance imaging. Median follow-up for all patients was 13 months (range 3-51). Radiation necrosis occurred in 5% (5/101) of cases with a median time to onset of 1.2 months. In three of these children, the child was symptomatic, requiring management with steroids and bevacizumab. Radiation necrosis did not correlate with the administration of chemotherapy, age at treatment, or planning treatment volume. Our experience with pediatric patients treated with radiotherapy for solid brain tumor suggests that children may have an increased likelihood to develop radiation necrosis compared to adults. PMID- 23647508 TI - Synthesis of dibenzo[b,f]silepins with a benzoquinolyl ligand. AB - A benzo[h]quinolyl ligand provided pentacoordinate character for silicon in dibenzo[b,f]silepins. Substituents on the silicon center determined both conformations of the dibenzosilepin and luminescence properties in relation to charge transfer. PMID- 23647509 TI - Successful outcome in a dog with neurological and respiratory signs following smoke inhalation. AB - OBJECTIVE: To report the case management of a patient with smoke inhalation complicated by neurological impairment, carboxyhemoglobinemia, acute respiratory distress syndrome (ARDS), upper airway obstruction, aspiration pneumonia, and bacteremia. CASE SUMMARY: A 1.5-year-old male intact Beagle presented shortly after being involved in a household fire. Upon arrival the dog was diagnosed with ARDS and demonstrated acute neurological signs (eg, obtundation and seizures). Treatment included mechanical ventilation, temporary tracheostomy, and intensive supportive care. During hospitalization, the dog suffered multiple complications including prolonged neurological abnormalities, aspiration pneumonia, and bacteremia. The dog recovered over a 16-day period. NEW OR UNIQUE INFORMATION PROVIDED: This is the first description of extensive management of a patient suffering both neurological and respiratory complication due to smoke inhalation, and details the steps that were taken to achieve a successful outcome. PMID- 23647510 TI - Intensive rehabilitation for dementia improved cognitive function and reduced behavioral disturbance in geriatric health service facilities in Japan. AB - AIM: To examine the efficacy of rehabilitation for elderly individuals with dementia at intermediate facilities between hospitals and home, based on the policies for elderly individuals to promote community-based care at home and dehospitalization. METHODS: Participants were older adults with dementia newly admitted to intermediate facilities. A total of 158 in the intervention group who claimed Long-Term Care Insurance for three consecutive months, and 54 in the control group were included in the analysis. The interventions were carried out in a tailor-made manner to meet individual needs. The personal sessions were carried out three times a week for 3 months after admission by physical, occupational or speech therapists. Outcome measures were cognitive tests (Hasegawa Dementia Scale revised [HDS-R] and Mini-Mental State Examination), and observational assessments of dementia severity, activities of daily living (ADL), social activities, behavioral and psychological symptoms of dementia (BPSD) using a short version of the Dementia Disturbance Scale (DBD13), depressive mood, and vitality. RESULTS: Significant improvement in the intervention group was shown in cognitive function measured by HDS-R (interaction F[1, 196] = 5.190, P = 0.024), observational evaluation of dementia severity (F[1,198] = 9.550, P = 0.002) and BPSD (DBD13; F[1,197] = 4.506, P = 0.035). Vitality, social activities, depressive mood and ADL were significantly improved only in the intervention group, although interaction was not significant. CONCLUSIONS: Significant improvement by intervention was shown in multiple domains including cognitive function and BPSD. Cognitive decline and worsening of BPSD are predictors of care burden and hospitalization, thus intensive rehabilitation for dementia was beneficial for both individuals with dementia and their caregivers. PMID- 23647511 TI - Intensive care delirium - effect on memories and health-related quality of life - a follow-up study. AB - AIMS AND OBJECTIVES: To investigate the effects of delirium in the intensive care unit on health-related quality of life, healthcare dependency and memory after discharge and to explore the association between health-related quality of life and memories, patient diaries and intensive care unit follow-up. BACKGROUND: Up to 83% of intensive care unit patients experience delirium. In addition to increased risk of mortality, morbidity and cognitive impairment, the experience itself is unpleasant. A number of studies have focused on memories associated with delirium, but the association between delirium, memories and health-related quality needs further investigation. DESIGN: We used an observational multicentre design with telephone interviews. METHODS: Adult intensive care unit patients (n = 360) were consecutively recruited and interviewed using the intensive care unit Memory Tool one week after intensive care unit. Interviews were repeated after two and six months and supplemented with Short Form-36 and the Barthel Index. RESULTS: Delirium was detected in 60% of the patients in our study, and delirious patients had significantly fewer factual memories and more memories of delusion than nondelirious patients up to six months postintensive care unit discharge. Delirium, memories and intensive care unit diaries with follow-up did not affect health-related quality of life and healthcare dependency. Memories of delusions might have an impact on patients assessed as nondelirious. CONCLUSIONS: More than half of the patients in intensive care unit experience delirium, which is associated with fewer factual memories and more memories of delusions. Short Form 36 might not be sensitive to delirium-related outcomes. Future research should include the development of better assessment tools to determine the long-term consequences of intensive care unit delirium. RELEVANCE TO CLINICAL PRACTICE: We recommend regular assessment to prevent, detect and treat delirium. We also recommend an intensive care unit follow-up programme providing an opportunity for postintensive care unit patients, particularly previously delirious patients, to discuss their memories and experiences with intensive care unit professionals. PMID- 23647512 TI - Improvement in middle cerebral artery structure and endothelial function in stroke-prone spontaneously hypertensive rats after macrophage depletion. AB - BACKGROUND: Inflammation is involved in the pathogenesis of hypertension. Hypertensive animals have an increased number of perivascular macrophages in cerebral arteries. Macrophages might be involved in remodeling of the cerebral vasculature. We hypothesized that peripheral macrophage depletion would improve MCA structure and function in hypertensive rats. METHODS: For macrophage depletion, six-week-old stroke-prone spontaneously hypertensive rats (SHRSP) were treated with CLOD, 10 mL/kg every three or four days, i.p., or vehicle (PBS lipo). MCA structure and function were analyzed by pressure and wire myography. RESULTS: Blood pressure was not affected by CLOD. The number of perivascular CD163-positive cells per microscopic field was reduced in the brain of SHRSP+CLOD. CLOD treatment caused an improvement in endothelium-dependent dilation after intralumenal perfusion of ADP and incubation with Ach. Inhibition of NO production blunted the Ach response, and endothelium-independent dilation was not altered. At an intralumenal pressure of 80 mmHg, MCA from SHRSP+CLOD showed increased lumen diameter, decreased wall thickness, and wall-to-lumen ratio. Cross-sectional area of pial arterioles from SHRSP+CLOD was higher than PBS lipo. CONCLUSIONS: These results suggest that macrophage depletion attenuates MCA remodeling and improves MCA endothelial function in SHRSP. PMID- 23647514 TI - Tool selectivity in left occipitotemporal cortex develops without vision. AB - Previous studies have provided evidence for a tool-selective region in left lateral occipitotemporal cortex (LOTC). This region responds selectively to pictures of tools and to characteristic visual tool motion. The present human fMRI study tested whether visual experience is required for the development of tool-selective responses in left LOTC. Words referring to tools, animals, and nonmanipulable objects were presented auditorily to 14 congenitally blind and 16 sighted participants. Sighted participants additionally viewed pictures of these objects. In whole-brain group analyses, sighted participants showed tool selective activity in left LOTC in both visual and auditory tasks. Importantly, virtually identical tool-selective LOTC activity was found in the congenitally blind group performing the auditory task. Furthermore, both groups showed equally strong tool-selective activity for auditory stimuli in a tool-selective LOTC region defined by the picture-viewing task in the sighted group. Detailed analyses in individual participants showed significant tool-selective LOTC activity in 13 of 14 blind participants and 14 of 16 sighted participants. The strength and anatomical location of this activity were indistinguishable across groups. Finally, both blind and sighted groups showed significant resting state functional connectivity between left LOTC and a bilateral frontoparietal network. Together, these results indicate that tool-selective activity in left LOTC develops without ever having seen a tool or its motion. This finding puts constraints on the possible role that this region could have in tool processing and, more generally, provides new insights into the principles shaping the functional organization of OTC. PMID- 23647515 TI - An empirical reevaluation of absolute pitch: behavioral and electrophysiological measurements. AB - Here, we reevaluated the "two-component" model of absolute pitch (AP) by combining behavioral and electrophysiological measurements. This specific model postulates that AP is driven by a perceptual encoding ability (i.e., pitch memory) plus an associative memory component (i.e., pitch labeling). To test these predictions, during EEG measurements AP and non-AP (NAP) musicians were passively exposed to piano tones (first component of the model) and additionally instructed to judge whether combinations of tones and labels were conceptually associated or not (second component of the model). Auditory-evoked N1/P2 potentials did not reveal differences between the two groups, thus indicating that AP is not necessarily driven by a differential pitch encoding ability at the processing level of the auditory cortex. Otherwise, AP musicians performed the conceptual association task with an order of magnitude better accuracy and shorter RTs than NAP musicians did, this result clearly pointing to distinctive conceptual associations in AP possessors. Most notably, this behavioral superiority was reflected by an increased N400 effect and accompanied by a subsequent late positive component, the latter not being distinguishable in NAP musicians. PMID- 23647513 TI - Vitamin D analogue TX 527 down-regulates the NF-kappaB pathway and controls the proliferation of endothelial cells transformed by Kaposi sarcoma herpesvirus. AB - BACKGROUND AND PURPOSE: The Kaposi sarcoma (KS)-associated herpesvirus GPCR (vGPCR) is a key molecule in the pathogenesis of KS, where it increases NF-kappaB gene expression and activates the NF-kappaB pathway. We investigated whether the less calcemic vitamin D analogue TX 527 inhibited the proliferation of endothelial cells transformed by vGPCR by modulation of the NF-kappaB pathway. EXPERIMENTAL APPROACH: Endothelial cells transformed by vGPCR (SVEC-vGPCR) were treated with TX 527. Proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-5 (3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) and cell cycle by flow cytometry. mRNA and protein levels were measured by real-time quantitative reverse transcriptase-PCR (qRT-PCR) and immunoblot analysis respectively. KEY RESULTS: TX 527, similar to bortezomib (0.5 nM), a proteasome inhibitor that inhibits the activation of NF-kappaB, reduced proliferation and induced G0/G1 cell cycle arrest in SVEC-vGPCR. TX 527 like 1alpha,25(OH)2 D3 , biological active form of vitamin D, decreased the activity of NF-kappaB comparable with the effect of bortezomib. Time-response studies showed that TX 527 significantly decreased NF-kappaB and increased IkappaBalpha mRNA and protein levels. The increase of IkappaBalpha was accompanied by a reduction in p65/NF kappaB translocation to the nucleus. These responses were abolished when vitamin D receptor (VDR) expression was suppressed by stable transfection of shRNA against VDR. In parallel with NF-kappaB inhibition, there was a down-regulation of inflammatory genes such as IL-6, CCL2/MCP and CCL20/MIP3alpha. CONCLUSIONS AND IMPLICATIONS: These results suggest that the anti-proliferative effects of the vitamin D analogue TX 527 in SVEC-vGPCR occur by modulation of the NF-kappaB pathway and are VDR dependent. PMID- 23647516 TI - Different synchronization rules in primary and nonprimary auditory cortex of monkeys. AB - Synchronized neuronal firing in cortex has been implicated in feature binding, attentional selection, and other cognitive processes. This study addressed the question whether different cortical fields are distinct by rules according to which neurons engage in synchronous firing. To this end, we simultaneously recorded the multiunit firing at several sites within the primary and the caudomedial auditory cortical field of anesthetized macaque monkeys, determined their responses to pure tones, and calculated the cross-correlation function of the spontaneous firing of pairs of units. In the primary field, the likelihood of synchronous firing of pairs of units increased with the similarity of their frequency tuning and their response latencies. In the caudomedial field, by contrast, the likelihood of synchronization was highest when pairs of units had an octave and other harmonic relationships and when units had different response latencies. The differences in synchrony of the two fields were not paralleled by differences in distributions of best frequency, bandwidth of tuning curves, and response latency. Our findings suggest that neuronal synchrony in different cortical fields may underlie the establishment of specific relationships between the sound features that are represented by the firing of the neurons and which follow the Gestalt laws of similarity in the primary field and good continuation in the caudomedial field. PMID- 23647517 TI - Interhemispheric communication influences reading behavior. AB - We can read words at an amazing speed, with the left hemisphere taking the burden of the processing in most readers (i.e., over 95% of right-handers and about 75% of left-handers). Yet, it is a long-standing question whether word reading in central vision is possible without information transfer between the left and right hemispheres (LH/RH). Here we show that such communication is required by comparing word naming latencies and eye movement data of people with LH language dominance and a unique sample of healthy RH dominant people. The results reveal that individuals with LH speech dominance name words faster when they are allowed to fixate at the word beginning, whereas RH dominants are faster for fixations toward the end. In text reading, the eyes of LH dominants land more to the left than the eyes of RH dominants, making more information directly available to the dominant hemisphere. We conclude that the traditional view of bilateral projections in central vision is incorrect. In contrast, interhemispheric communication is needed in central vision, and eye movements are adjusted to optimize information uptake. Our findings therefore call into question the explanation of macular sparing in hemianopia based on a bilaterally projecting fovea. In addition, these results are in line with the increase of white matter in the splenium of the corpus callosum when people learn to read. PMID- 23647519 TI - rTMS of medial parieto-occipital cortex interferes with attentional reorienting during attention and reaching tasks. AB - Unexpected changes in the location of a target for an upcoming action require both attentional reorienting and motor planning update. In both macaque and human brain, the medial posterior parietal cortex is involved in both phenomena but its causal role is still unclear. Here we used on-line rTMS over the putative human V6A (pV6A), a reach-related region in the dorsal part of the anterior bank of the parieto-occipital sulcus, during an attention and a reaching task requiring covert shifts of attention and planning of reaching movements toward cued targets in space. We found that rTMS increased RTs to invalidly cued but not to validly cued targets during both the attention and reaching task. Furthermore, we found that rTMS induced a deviation of reaching endpoints toward visual fixation and that this deviation was larger for invalidly cued targets. The results suggest that reorienting signals are used by human pV6A area to rapidly update the current motor plan or the ongoing action when a behaviorally relevant object unexpectedly occurs in an unattended location. The current findings suggest a direct involvement of the action-related dorso-medial visual stream in attentional reorienting and a more specific role of pV6A area in the dynamic, on line control of reaching actions. PMID- 23647518 TI - The neural basis of inhibitory effects of semantic and phonological neighbors in spoken word production. AB - Theories of word production and word recognition generally agree that multiple word candidates are activated during processing. The facilitative and inhibitory effects of these "lexical neighbors" have been studied extensively using behavioral methods and have spurred theoretical development in psycholinguistics, but relatively little is known about the neural basis of these effects and how lesions may affect them. This study used voxel-wise lesion overlap subtraction to examine semantic and phonological neighbor effects in spoken word production following left hemisphere stroke. Increased inhibitory effects of near semantic neighbors were associated with inferior frontal lobe lesions, suggesting impaired selection among strongly activated semantically related candidates. Increased inhibitory effects of phonological neighbors were associated with posterior superior temporal and inferior parietal lobe lesions. In combination with previous studies, these results suggest that such lesions cause phonological-to lexical feedback to more strongly activate phonologically related lexical candidates. The comparison of semantic and phonological neighbor effects and how they are affected by left hemisphere lesions provides new insights into the cognitive dynamics and neural basis of phonological, semantic, and cognitive control processes in spoken word production. PMID- 23647520 TI - Tooth loss in individuals under periodontal maintenance therapy: 5-year prospective study. AB - BACKGROUND AND OBJECTIVE: Tooth loss (TL), one of the most visible results of the evolution of periodontitis, causes physiological and psychological impacts on a patient's life. This prospective study aimed to evaluate the incidence, underlying reasons and influence of risk predictors for the occurrence of TL in a program of periodontal maintenance therapy (PMT) over 5 years. METHODS: The sample comprised 212 individuals diagnosed with chronic moderate-severe periodontitis, who had finished active periodontal treatment, were incorporated in a PMT program. Individuals were divided in to two groups: 96 regular compliers (RC) and 116 irregular compliers (IC). Full-mouth periodontal examination was performed. Social, demographic, behavioral and biological variables of interest were collected at all PMT visits. The effect of risk predictors and confounders for TL, as well as the underlying reasons of TL, were assessed by univariate and multivariate analysis. RESULTS: TL was significantly lower among RC (0.12 teeth lost/year) in comparison to IC (0.36 teeth lost/year; p < 0.01). Individuals that were > 55 years old, males and smokers lost significantly more teeth in both groups (with IC > RC). The number of teeth lost due to periodontal reasons was significantly higher than TL for other reasons in both groups (p < 0.01). The final linear and logistic model for TL included: male gender, smoking, probing depth 4-6 mm in up to 10% of sites and irregular compliance. CONCLUSION: IC individuals undergoing PMT presented higher rates of TL when compared to RC individuals. Findings demonstrated the influence of irregular compliance and the importance of monitoring other risk predictors for TL such as smoking, male gender and severity of probing depth during PMT. PMID- 23647521 TI - Echinocandins in invasive candidiasis. AB - We summarise a recent meeting, sponsored by Pfizer Inc., where experts in Asia shared their clinical experience in managing IC. The echinocandins have demonstrated good activity against non-albicans infections and also azole resistant strains, both preclinically and in recent clinical trials. As well as proving efficacious, echinocandins have a favourable safety profile and are well tolerated, including among inpatient subpopulations, such as transplant recipients and those with renal or hepatic dysfunction. In addition the echinocandins generally have minimal drug-drug interactions, unlike the oral azoles, which have multiple effects on cytochrome P450-mediated drug metabolism. Echinocandins are characterised by a good safety profile, few drug-drug interactions and good susceptibilities. With the increase in potentially azole resistant non-albicans infections, echinocandins may become the first-line treatment of choice for many patients. PMID- 23647522 TI - Dehydroepiandrosterone in women with premature ovarian failure and Hashimoto's thyroiditis. AB - We evaluated dehydroepiandrosterone sulfate (DHEAS) levels in premature ovarian failure (POF) patients with and without Hashimoto's thyroiditis, and the impact of DHEA supplementation on thyroid autoantibodies. In a retrospective case series, we included 67 women with spontaneous POF who received estrogen/gestagen replacement with or without DHEA (30 mg/day) for 3 months. Women who were seropositive for thyroglobulin antibodies and/or thyroperoxidase autoantibodies (n = 30) revealed lower pretherapeutic DHEAS levels (1.2 MUg/ml, range 0.4-2.9 MUg/ml vs. 1.9 MUg/ml, range 0.2-3.9 MUg/ml; p < 0.001). DHEAS showed an inverse correlation with both thyroglobulin antibodies (r = -0.426, p < 0.001) and thyroperoxidase autoantibodies (r = -0.362, p = 0.002). When treated with additional DHEA, significant decreases were found for thyroperoxidase autoantibodies (median 85.0 IU/ml, range 41-600 IU/ml vs. median 51.0 IU/ml, range 20-589 IU/ml; p = 0.005) but not for thyroglobulin antibodies. PMID- 23647523 TI - A qualitative study of hospital patients' understanding of health promotion. AB - AIMS AND OBJECTIVES: To examine hospital patients' understanding of health promotion in Jordan. BACKGROUND: Increasingly, hospital nurses are urged to promote patients' health and meet their needs. Yet, internationally, little is known about how patients themselves understand health promotion, and no Jordanian study has been undertaken in this area. DESIGN: A qualitative design was used. METHODS: Focus group discussions (n = 4) were undertaken with hospital patients. All discussions were digitally recorded, transcribed verbatim and analysed using qualitative thematic analysis. RESULTS: Three images of health promotion emerged. These include health promotion as having adequate health knowledge, economic independency and good environment. It was also found that gender and spirituality affected patients' conceptualisations. CONCLUSIONS: Hospital patients' understanding and expectations of health promotion are complex and go beyond the disease management approach. Therefore, if health promotion is to meet patients' needs and operate at empowerment and socio-economic levels, the images identified in this article should be considered. The study limitations and recommendations for practice and future research are also outlined. RELEVANCE TO CLINICAL PRACTICE: There is a need for a framework of health promotion that integrates patients' beliefs in general and particularly those related to religion and gender roles within the daily philosophy of care. Having achieved this, hospital nurses will be able to deliver culturally competent and wide-reaching health promotion. PMID- 23647525 TI - A 2-year-old with acute abdominal distension and pallor (case presentation). PMID- 23647526 TI - Attention-deficit/hyperactivity disorder increased the risk of injury: a population-based follow-up study. AB - AIM: To explore the frequency and risk for injury among children with Attention deficit/hyperactivity Disorder (ADHD) in Taiwan through a population-based study. METHODS: A total of 3616 subjects aged between four and twelve years diagnosed with ADHD were selected along with a comparison cohort comprising 18 080 subjects. Each subject was individually traced for a three-year period from their index date to identify those subjects who subsequently received a diagnosis of injury. We used stratified Cox proportional hazards regressions to examine the three-year injury-free survival rates between the two cohorts. RESULTS: Of the subjects, the incidence rate of injury during the three-year follow-up period was 7.97 (95% CI = 7.45-8.51) and 5.36 (95% CI = 5.17-5.56) for the study and comparison cohort, respectively. After adjusting for geographic region, the hazard ratio (HR) of injury for subjects with ADHD was 1.64 (95% CI = 1.50-1.79) that of comparison subjects. In addition, we found children with ADHD aged between four and 6 years to demonstrate a greater HR (1.98, 95% CI = 1.72-2.28) than those aged between seven and twelve (HR = 1.46, 95% CI = 1.31-1.63). CONCLUSIONS: Children with ADHD appear to be at a higher risk for injury than children that are not diagnosed with ADHD. PMID- 23647527 TI - A 2-year-old with acute abdominal distension and pallor (discussion and diagnosis). PMID- 23647528 TI - Treating Fragile X syndrome with the diuretic bumetanide: a case report. AB - We report that daily administration of the diuretic NKCC1 chloride co transporter, bumetanide, reduces the severity of autism in a 10-year-old Fragile X boy using CARS, ADOS, ABC, RDEG and RRB before and after treatment. In keeping with extensive clinical use of this diuretic, the only side effect was a small hypokalaemia. A double-blind clinical trial is warranted to test the efficacy of bumetanide in FRX. CONCLUSION: This single case report showed an improvement of the scores of each test used after 3 months of treatment. Double-blind clinical trials are warranted to test the efficacy of bumetanide in FRX. PMID- 23647529 TI - Attitudes of regular injecting drug users towards the legal status of the major illicit drugs. AB - INTRODUCTION AND AIMS: The study aimed to determine injecting drug users' (IDU) attitudes, and correlates of attitudes, towards continued prohibition, decriminalisation or legalisation of the major illicit drugs. DESIGN AND METHODS: This study used structured interview with 300 IDUs who had injected on at least a weekly basis over the preceding 12 months. RESULTS: Methamphetamine was rated the most harmful of the five illicit substances and cannabis the lowest. By far the highest level of support for legislative change was for cannabis, with only 8.7% supporting continued prohibition. While there was majority support for change to the legal status of heroin, the modal position was for decriminalisation. Support for changing the status of the three illicit psychostimulants was low, with the majority believing that methamphetamine (63.3%), cocaine (53.3%) and 3,4 methylenedioxy-N-methylamphetamine (53.3%) should remain illegal. Demographic characteristics were largely unrelated to attitudes. Lower levels of perceived harm were associated with increased likelihood of support for legalisation of all substances. Recent use was positively related to support for both decriminalisation and legality of heroin, but was not associated with views on other substances. Higher lifetime polydrug use was associated with support for the legalisation of heroin, methamphetamine, cocaine and 3,4-methylenedioxy-N methylamphetamine. DISCUSSION AND CONCLUSIONS: IDUs expressed nuanced views on different substances. In policy debates, care should be taken not to speak for IDUs by imputing their beliefs. It is clear that the fact that a group uses illegal drugs does not necessarily imply that they support changes to their legal status. PMID- 23647531 TI - CXCL13 and B-cell activating factor as putative biomarkers in systemic sclerosis. PMID- 23647530 TI - Electronic structural changes of Mn in the oxygen-evolving complex of photosystem II during the catalytic cycle. AB - The oxygen-evolving complex (OEC) in photosystem II (PS II) was studied in the S0 through S3 states using 1s2p resonant inelastic X-ray scattering spectroscopy. The spectral changes of the OEC during the S-state transitions are subtle, indicating that the electrons are strongly delocalized throughout the cluster. The result suggests that, in addition to the Mn ions, ligands are also playing an important role in the redox reactions. A series of Mn(IV) coordination complexes were compared, particularly with the PS II S3 state spectrum to understand its oxidation state. We find strong variations of the electronic structure within the series of Mn(IV) model systems. The spectrum of the S3 state best resembles those of the Mn(IV) complexes Mn3(IV)Ca2 and saplnMn2(IV)(OH)2. The current result emphasizes that the assignment of formal oxidation states alone is not sufficient for understanding the detailed electronic structural changes that govern the catalytic reaction in the OEC. PMID- 23647532 TI - Transcranial color-coded sonography to predict recurrent transient ischaemic attack/stroke. AB - BACKGROUND AND PURPOSE: Patients with transient ischaemic attack (TIA) with a high risk of imminent stroke can be identified with the ABCD(2) score and findings on MRI and CT angiography. The predictive value of transcranial color coded sonography (TCCS) has not been evaluated in this setting. METHODS: A retrospective analysis was conducted of patients consecutively treated for TIA or minor stroke in a TIA clinic within 24 h of symptom onset. Agreement between TCCS and MRI three-dimensional time-of-flight images for the diagnosis of proximal (internal carotid artery, vertebral artery, basilar artery, circle of Willis and main stem of the middle cerebral artery) >50% stenosis or occlusion of the intracranial symptomatic artery was evaluated. The sensitivity, specificity, predictive values and likelihood ratio of TCCS for predicting recurrent TIA/stroke at 7 days were calculated. RESULTS: Of 159 patients with a TIA or minor stroke within the last 24 h, 142 had a readable acoustic temporal bone window (89.3%). TCCS and MRI were performed within 4 h of each other in 116 patients. MRI showed a symptomatic proximal intracranial steno-occlusive lesion in six patients. Agreement between MRI and TCCS was perfect (kappa coefficient = 1). Recurrent TIA/stroke occurred in 10 patients (eight TIA and two minor strokes). All recurrences occurred within 24 h of symptom onset. A symptomatic proximal intracranial steno-occlusive lesion was found on TCCS in 4/10 patients with recurrence and 3/132 patients without recurrence [sensitivity 40%; specificity 97.7%; likelihood ratio 18.1; odds ratio (95% CI) adjusted for ABCD(2) score 31.5 (4.5-218.6)]. CONCLUSION: Our study shows that TCCS can be used to guide triage of patients with TIA. PMID- 23647533 TI - Temporal and behavioral variability in cannabinoid receptor expression in outbred mice submitted to ethanol-induced locomotor sensitization paradigm. AB - BACKGROUND: There is a close relationship between the endocannabinoid system and alcoholism. This study investigated possible differential expression of cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) in an outbred mice strain displaying behavioral variability to ethanol (EtOH)-induced locomotor sensitization. METHODS: Male adult Swiss mice treated chronically with EtOH (2 g/kg, i.p., daily for 21 days) were classified as "EtOH_High" or "EtOH_Low" according to their locomotor activity after the 21st EtOH injection. A control group was similarly injected with saline. Temporal analysis of CB1R and CB2R immunoreactivity was performed in 3 different occasions: (i) at the end of chronic EtOH treatment, (ii) on the fifth day of EtOH withdrawal, and (iii) after EtOH challenge. RESULTS: Overall, no differences were seen between experimental groups regarding the CB1R at the end of acquisition. However, there were decreases in CB2R in the prefrontal cortex and the hippocampus in EtOH_Low mice. On the fifth day of withdrawal, only EtOH_High mice presented increase in CB1R. Nonetheless, CB2R up-regulation was observed in both EtOH_High and EtOH_Low mice. EtOH challenge counteracted CB1R and CBR2 up-regulation, mainly in the EtOH_High, in structures related to emotionality, such as prefrontal cortex, ventral tegmental area, amygdala, striatum, and hippocampus. CONCLUSIONS: There are different patterns of cannabinoid receptor expression during locomotor sensitization paradigm, at both temporal and behavioral perspectives. We hypothesize that CB2R down-regulation might be related to resilience to develop locomotor sensitization, while CB1R up-regulation relates to withdrawal aspects in sensitized mice. PMID- 23647535 TI - Ethical amendments to the Israeli Organ Transplant Law. PMID- 23647534 TI - Neuroanatomical asymmetries and handedness in chimpanzees (Pan troglodytes): a case for continuity in the evolution of hemispheric specialization. AB - Many historical and contemporary theorists have proposed that population-level behavioral and brain asymmetries are unique to humans and evolved as a consequence of human-specific adaptations such as language, tool manufacture and use, and bipedalism. Recent studies in nonhuman animals, notably primates, have begun to challenge this view. Here, I summarize comparative data on neuroanatomical asymmetries in the planum temporale (PT) and inferior frontal gyrus (IFG) of humans and chimpanzees, regions considered the morphological equivalents to Broca's and Wernicke's areas. I also review evidence of population level handedness in captive and wild chimpanzees. When similar methods and landmarks are used to define the PT and IFG, humans and chimpanzees show similar patterns of asymmetry in both cortical regions, though humans show more pronounced directional biases. Similarly, there is good evidence that chimpanzees show population-level handedness, though, again, the expression of handedness is less robust compared to humans. These results stand in contrast to reported claims of significant differences in the distribution of handedness in humans and chimpanzees, and I discuss some possible explanations for the discrepancies in the neuroanatomical and behavioral data. PMID- 23647536 TI - Editorial (hot topic: using cheminformatics for drug and target discovery in medicinal chemistry). PMID- 23647538 TI - The pH-triggered conversion of the PrP(c) to PrP(sc.). AB - Transmissible spongiform encephalopathies (TSEs) are prion protein misfolding diseases that involve the accumulation of an abnormal beta-sheet-rich prion protein aggregated form (PrP(sc)) of the normal alpha- helix-rich prion protein (PrP(c)) within the central nervous system (CNS) and other organs. On account of its large size and insolubility properties, characterization of PrP(c) is quite difficult. A soluble intermediate, called PrP(beta) or beta(o), exhibiting many of the same features as PrP(sc), can be generated using a combination of low pH and/or mild denaturing conditions. Here, we review the current knowledge on the following five issues relevant to the conversion mechanisms of PrP(c) to PrP(sc) : (1) How is the Stability of the Helical Structures in the Native PrP(c) Related to the Primary Structure of the PrP(c) (2) Why the Low pH Solution System is a Ideal Trigger of PrP(c) to PrP(sc) Conversion (3) How are the Structural and Dynamical Characteristics of the alpha-helixrich Intermediates Determined using NMR Data (4) How are the Premolten (PrP(alpha4) and PrP(alphabeta)) and beta Oligomer (PrP(beta)) Intermediates Detected and Assayed, and (5) Can the Disordered N-terminal Domain be folded into the Structural Segment? Particularly, Chou's wenxiang diagram (http://en.wikipedia.org/wiki/Wenxiang_diagram) was introduced for providing an intuitive picture. This review may help to further understand the prion protein misfolding mechanism. PMID- 23647537 TI - Unconventional interaction forces in protein and protein-ligand systems and their impacts to drug design. AB - In drug design and enzyme engineering, the information of interactions between receptors and ligands is crucially important. In many cases, the protein structures and drug-target complex structures are determined by a delicate balance of several weak molecular interaction types. Among these interaction forces several unconventional interactions play important roles, however, less familiar for researchers. The cation-pi interaction is a unique noncovalent interaction only acting between aromatic amino acids and organic cations (protonated amino acids) and inorganic cations (proton and metallic). This article reports new study results in the interaction strength, the behaviors and the structural characters of cation-pi interactions between aromatic amino acids (Phe, Tyr, and Trp) and organic and inorganic cations (Lys(+), Arg(+), H(+), H3O(+), Li(+), Na(+), K(+), Ca(2+), and Zn(2+)) in gas phase and in solutions (water, acetonitrile, and cyclohexane). Systematical research revealed that the cation-pi interactions are point-to-plane (aromatic group) interactions, distance and orientationdependent, and the interaction energies change in a broad range. In gas phase the cation-pi interaction energies between aromatic amino acids (Phe, Tyr, and Trp) and metallic cations (Li(+), Na(+), K(+), Ca(2+), and Zn(2+)) are in the range -12 to -160 kcal/mol, and the interaction energies of protonated amino acids (Arg(+) and Lys(+)) are in the range from -9 to -18 kcal/mol. In solutions the cation-pi energies decrease with the dielectric constant epsilon of solvents. However, in aqueous solution the cation-pi energies of H3O(+) and protonated amino acids are less affected by solvation effects. The applications of unconventional interaction forces in drug design and in protein engineering are introduced. PMID- 23647539 TI - A challenge for medicinal chemistry by the 17beta-hydroxysteroid dehydrogenase superfamily: an integrated biological function and inhibition study. AB - Members of the 17beta-hydroxysteroid dehydrogenase (17beta-HSD) superfamily perform distinct multiple catalyses by the same enzyme, apparently contradictory to the long-held beliefs regarding the high specificity of enzymes. Surprisingly, these multi-catalyses can combine synergistically in vitro and in vivo and their dysfunction may result in the stimulation of breast or prostate cancer. 17beta HSD1 possesses high estrogen activation activity, while its androgen inactivation is significant for decreasing the week concentration of dihydrotestosterone (DHT) in breast cancer cells, an important factor for cell proliferation. 17beta-HSD5 can also carry out multiple catalyses in hormone-dependent cancer cells. In addition to 17beta-HSDs 1 and 5 some other family members possess such dual activity as well, and their inhibition decreases hormone- dependent cancer proliferation. The multi-specificity of 17beta-HSD1 is structurally based on the pseudo-symmetric androgens that can accommodate the narrow enzyme substrate tunnel by both normal and alternative binding. The atypical family member 17beta HSD5 possesses a spacious binding site, which is accessible to several substrates. Expression of 17beta- HSD1 can also control other estrogen-responsive elements such as pS2, and can regulate steroid-hormone receptors. The fundamental involvement of 17beta-HSD1 in catalysis and gene regulation underlies its close relationship to breast cancer, attributable to its long evolutionary process. These observations stimulated detailed study of steroid-converting enzyme inhibition. The most significant efforts in designing 17beta-HSD1 inhibitors in decades have progressed through structure activity relationship studies supported by the availability of both small and protein molecule structures, with the elimination of residual estrogenic activity in the inhibitors. The first non estrogenic inhibitors of 17beta-HSD1 to show activity in vivo (breast cancer animal model) are now reported. PMID- 23647540 TI - Open source software and web services for designing therapeutic molecules. AB - Despite the tremendous progress in the field of drug designing, discovering a new drug molecule is still a challenging task. Drug discovery and development is a costly, time consuming and complex process that requires millions of dollar and 10-15 years to bring new drug molecules in the market. This huge investment and long-term process are attributed to high failure rate, complexity of the problem and strict regulatory rules, in addition to other factors. Given the availability of 'big' data with ever improving computing power, it is now possible to model systems which is expected to provide time and cost effectiveness to drug discovery process. Computer Aided Drug Designing (CADD) has emerged as a fast alternative method to bring down the cost involved in discovering a new drug. In past, numerous computer programs have been developed across the globe to assist the researchers working in the field of drug discovery. Broadly, these programs can be classified in three categories, freeware, shareware and commercial software. In this review, we have described freeware or open-source software that are commonly used for designing therapeutic molecules. Major emphasis will be on software and web services in the field of chemo- or pharmaco-informatics that includes in silico tools used for computing molecular descriptors, inhibitors designing against drug targets, building QSAR models, and ADMET properties. PMID- 23647541 TI - Recent progresses in identifying nuclear receptors and their families. AB - Nuclear receptors (NRs) are members of a large superfamily of evolutionarily related DNA-binding transcription factors. They regulate diverse functions, such as homeostasis, reproduction, development and metabolism. As nuclear receptors bind small molecules that can easily be modified by drug design, and control functions associated with major diseases (e.g. cancer, osteoporosis and diabetes), they are promising pharmacological targets. According to their different action mechanisms or functions, NR superfamily has been classified into seven families: NR1 (thyroid hormone like), NR2 (HNF4-like), NR3 (estrogen like), NR4 (nerve growth factor IB-like), NR5 (fushi tarazu-F1 like), NR6 (germ cell nuclear factor like), and NR0 (knirps or DAX like). With the avalanche of protein sequences generated in the postgenomic age, Scientists are facing the following challenging problems. Given an uncharacterized protein sequence, how can we identify whether it is a nuclear receptor? If it is, what family even subfamily it belongs to? To address these problems, many cheminformatics tools have been developed for nuclear receptor prediction. The current review is mainly focused on this field, including the functions, computational methods and limitations of these tools. PMID- 23647542 TI - Using cheminformatics for the identification of biological functions of small molecules in metabolic pathway. AB - Small molecules are involved in metabolic pathways responsible for many biological activities. Therefore it is essential to study them to uncover the unknown biological function of highly complex living systems. It is a crucial step in modern drug discovery to correctly and effectively discover small molecules' biological function since small molecules are related to many protein functions and biological processes. This paper presents the application of cheminformatics approaches in predicting small molecule's (ligand's) biological function in metabolic pathway. Many examples of success in identification and prediction in the area of small molecule metabolic pathway mapping and small molecule-protein interaction prediction have been discussed. PMID- 23647543 TI - Molecular recognition of human angiotensin-coverting enzyme I (hACE I) and different inhibitors. AB - The human angiontensin-converting enzyme I (hACEI) is a zinc metalloproteinase that hydrolytically cleaves a C-terminal dipeptide from a wide range of peptide substrates, and it plays an important role in regulating blood pressure. MD simulations and interaction energy calculations for docking and crystal structures were performed to investigate the correct conformation of the ACE with enalaprilat and nanopepetide. The analysis of root-mean-squrared fluctuation (RMSF), which is usually applied to measure the mobility and flexibility of the proteins, and dynamic correlation of residues show that the fluctuation pattern of the each two structure of the same ligand is almost the same mode. Hydrogen bond analysis shows that the correct crystal conformation is more stable than a wrong docking conformation. In addition, we are demonstrating that calculating interaction energy between protein and its ligands is an accurate and efficient way to select the correct conformation from docking conformations. PMID- 23647544 TI - Investigation binding patterns of human carboxylesterase I (hCES I) with broad substrates by MD simulations. AB - Human carboxylesterase I (hCES 1) plays an important role in the metabolism and activation of prodrugs, such as, the hydrolysis of a variety of drugs of prodrugs featuring an ester, amide or carbamate function. The bindings of the substrates of different lengths and cocaine to hCES1 at two different binding sites, catalytic site and Z-site, were studies through MD simulations. For each case, the correlation analysis has been performed to explore the binding patterns of a broad range of substrates binding to the hCES1. PMID- 23647545 TI - Sucrose hydrolytic enzymes: old enzymes for new uses as biocatalysts for medical applications. AB - Sucrose hydrolytic enzymes, widely used in a variety of food industries, employ sucrose as a substrate. In addition to their hydrolysis activities, they have other recently discovered characteristics that should make them useful for medical applications. Here, the two enzymes sucrose phosphorylase and invertase are discussed. Sucrose phosphorylase glycosylates non-carbohydrate small molecules and invertase can be used in a portable and personal biosensor to quantify a variety of analytical targets. PMID- 23647546 TI - Metallo-beta-lactamases: structural features, antibiotic recognition, inhibition, and inhibitor design. AB - Owing to their ability in destroying or slowing down the growth of bacteria, antibiotics have been widely used to treat the bacterial infections. However, because of the long-term and irresponsible use of antibiotics, resistance to antibiotics has become a serious problem directly threatening the public health worldwide. To fight against and resist beta- lactam antibiotics, bacteria usually employed beta-lactamases, especially the metallo-beta-lactamases, to hydrolyze the C-N bond of the beta-lactam ring so as to inactivate the antibiotics. In this minireview, we are to summarize the structural features of the metallo-beta lactamases, as well as their antibiotic binding modes and resistance mechanisms, in hopes that the discussion and analysis presented in this paper can stimulate new strategies to overcome the resistance problem and find novel inhibitors against the metallo-beta-lactamases. PMID- 23647547 TI - The local structure and vibrational properties of BaTi2O5 glass revealed by molecular dynamics simulation. AB - Molecular dynamics simulations have been performed to prepare the structural model of BaTi2O5 glass. The total correlation function obtained from the structural model agreed rather well with both the X-ray and neutron diffraction data. We found distorted 4-, 5-, and 6-coordinated Ti atoms whose distortion increases with coordination number. Furthermore, the distorted polyhedra were connected to each other by corner-, edge-, or face-sharing. Using the optimal structural model, the vibrational density of state was calculated, and the origin of the bands of Raman scattering spectrum was investigated. It was revealed that not only symmetric and antisymmetric vibration in one TiOn polyhedron but also stretching, bending, and rocking motions in Ti-O-Ti linkage contributed to the Raman bands above 600 cm(-1), which govern the principal vibration in the glass. These results conclude that a Ti-O-Ti network consisting of various types of TiOn polyhedra certainly exists in BaTi2O5 glass, although the local structure around Ti deviates from the Zachariasen's rule of glass formation. PMID- 23647548 TI - TRAIL-induced miR-146a expression suppresses CXCR4-mediated human breast cancer migration. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising agent for cancer therapy, as this molecule induces apoptosis specifically in various cancer cells. Apart from apoptosis, TRAIL also induces non-apoptotic signals, such as those for autophagy, proliferation and metastasis in cancer cells. In the present study, we report that TRAIL suppressed CXCR4 mediated human breast cancer MDA-MB-231 cell migration by up-regulating miR-146a expression through NF-kappaB. TRAIL receptor 1 (TRAIL-R1, DR4) was highly expressed in TRAIL-treated MDA-MB-231 cells. A neutralization antibody against DR4 specifically blocked TRAIL-induced NF-kappaB activation and miR-146a expression. These results were confirmed in a human breast cancer xenograft mouse model, suggesting that TRAIL significantly enhanced miR-146a expression and suppressed CXCR4 expression, indicating that TRAIL-induced miR-146a up-regulation is negatively associated with CXCR4 expression. These findings suggest that TRAIL induced miR-146a expression suppresses CXCR4-mediated human breast cancer migration, and provide further insight into the non-apoptotic function of TRAIL in the prevention of metastasis as a therapy for breast cancer. PMID- 23647549 TI - Effect of low-dose electron beam irradiation on quality of ground beef patties and raw, intact carcass muscle pieces. AB - The objectives of this study were to determine the effects of a low-dose (<=1 kGy), low-penetration electron beam on the sensory qualities of (1) raw muscle pieces of beef and (2) cooked ground beef patties. Outside flat, inside round, brisket and sirloin muscle pieces were used as models to demonstrate the effect of irradiation on raw beef odor and color, as evaluated by a trained panel. Ground beef patties were also evaluated by a trained panel for tenderness, juiciness, beef flavor, and aroma at 10%, 20%, and 30% levels of fat, containing 0% (control), 10%, 20%, 50%, and 100% irradiated meat. With whole muscle pieces, the color of controls appeared more red (P < 0.05) than irradiated muscles, however, both control and treatments showed a gradual deterioration in color over 14 d aerobic storage at 4 degrees C. Off-aroma intensity of both control and treatments increased with storage time, but by day 14, the treated muscles showed significantly (P < 0.05) less off-aroma than the controls, presumably as a result of a lower microbial load. It was found that a 1 kGy absorbed dose had minimal effects on the sensory properties of intact beef muscle pieces. Irradiation did not have a significant effect (P > 0.05) on any of the sensory attributes of the patties. Low-dose irradiation of beef trim to formulate ground beef appears to be a viable alternative processing approach that does not affect product quality. PMID- 23647550 TI - Modified Taylor Complex Figure: normative data from 290 adults. AB - Data for copying and delayed recall (after a 15-min delay) of the Modified Taylor Complex Figure (MTCF), an alternative form of the Rey-Osterrieth Complex Figure (ROCF), were collected from 290 healthy participants. Normative data are provided. Age and education were significantly correlated with MTCF scores and must be corrected for to interpret results accurately. More specifically, increasing age adversely affected performance, whereas a higher education resulted in a better performance. Twenty-five participants were tested with both complex figures (MTCF and ROCF) in two separate sessions to assess correlation, which proved to be high. The collected data allow using the MTCF as a valid alternative material for testing visual long-term memory avoiding implicit learning that can occur when the same version of the ROCF is used for repeated testing sessions. PMID- 23647552 TI - Live birth in a woman without ovaries after autograft of frozen-thawed ovarian tissue combined with growth factors. AB - Currently, cryopreservation of oocytes, embryos and ovarian tissue is considered the basis of fertility preservation programs for women with cancer and other diseases who are rendered sterile by gonadotoxic drugs or radiation.Numerous studies have confirmed that autograft of frozen-thawed ovarian tissue can restore ovarian function and fertility. A total of twenty-two live births have been reported but we still have to consider this technique as experimental. The main problem is that the implant undergoes ischemia until neoangiogenesis is restored, resulting in significant follicular loss.At the moment, there are numerous publications in different medical fields that publish successful experiences with plasma rich in platelets (PRP) in different clinical situations promoting angiogenesis. Thus, we considered the possibility of using it in the field of ovarian autologous transplantation in order to improve the vascularization of the implant and its quality. For this, both thawed ovarian tissue as practiced pockets on the rear side of the broad ligament which have been placed, have been impregnated with PRP. We can say that the implant treated in this way has had a rapid and successful response.We report a special interesting case because this is the first time that this technique is performed successfully in a woman without ovaries combined with growth factors to promote neoangiogenesis. Obviously, the results of the hormonal response come exclusively from the implanted tissue in these special conditions. PMID- 23647551 TI - Repeated cycles of binge-like ethanol (EtOH)-drinking in male C57BL/6J mice augments subsequent voluntary EtOH intake but not other dependence-like phenotypes. AB - BACKGROUND: Recently, procedures have been developed to model specific facets of human alcohol abuse disorders, including those that model excessive binge-like drinking (i.e., "drinking-in-the-dark," or DID procedures) and excessive dependence-like drinking (i.e., intermittent ethanol [EtOH] vapor exposure). Similar neuropeptide systems modulate excessive EtOH drinking stemming from both procedures, raising the possibility that both paradigms are actually modeling the same phenotypes and triggering the same central neuroplasticity. Therefore, the goal of this present project was to study the effects of a history of binge-like EtOH drinking, using DID procedures, on phenotypes that have previously been described with procedures to model dependence-like drinking. METHODS: Male C57BL/6J mice first experienced 0 to 10 four-day binge-like drinking episodes (3 days of rest between episodes). Beginning 24 hours after the final binge-like drinking session, mice were tested for anxiety-like behaviors (with elevated plus maze [EPM] and open-field locomotor activity tests), ataxia with the rotarod test, and sensitivity to handling-induced convulsions (HICs). One week later, mice began a 40-day 2-bottle (water vs. EtOH) voluntary consumption test with concentration ranging from 10 to 20% (v/v) EtOH. RESULTS: A prior history of binge-like EtOH drinking significantly increased subsequent voluntary EtOH consumption and preference, effects most robust in groups that initially experienced 6 or 10 binge-like drinking episodes and completely absent in mice that experienced 1 binge-like drinking episode. Conversely, a history of binge like EtOH drinking did not influence anxiety-like behaviors, ataxia, or HICs. CONCLUSIONS: Excessive EtOH drinking stemming from DID procedures does not initially induce phenotypes consistent with a dependence-like state. However, the subsequent increases in voluntary EtOH consumption and preference that become more robust following repeated episodes of binge-like EtOH drinking may reflect the early stages of EtOH dependence, suggesting that DID procedures may be ideal for studying the transition to EtOH dependence. PMID- 23647553 TI - Preliminary evaluation of tear production in dogs hospitalized in an intensive care unit. AB - OBJECTIVE: To determine the tear production in dogs admitted to an intensive care unit (ICU). DESIGN: Prospective observational study from November 2010-September 2011. SETTING: Private emergency and referral hospital. ANIMALS: Thirty healthy control dogs and 30 dogs hospitalized in an ICU for treatment of systemic illness without previously diagnosed ophthalmic disorders and no recent history of anesthesia. Enrollment was based on availability of the ophthalmologist within 24 hours of admission to the ICU. INTERVENTIONS: Tear production was measured utilizing Schirmer tear test strips (STT) in healthy control animals as well as in hospitalized canine patients. All patients received an ophthalmic examination by a board-certified veterinary ophthalmologist within 24 hours of admission to the ICU. Lubrication with artificial tear gel every 2-4 hours as needed was implemented after STT was measured. MEASUREMENTS AND MAIN RESULTS: Average tear productions in the control and canine ICU populations were 24.5 mm/min and 13.2 mm/min, respectively. This was found to be statistically significant (P < 0.001). Furthermore, there was a trend toward a decrease in tear production in patients with kidney disease and a trend toward normal tear production in patients with cardiac disease but the sample size was likely too small to enable detection of a statistically significant difference. CONCLUSIONS: This study demonstrates a decrease in tear production in canine ICU patients. While further study is warranted to determine how different diseases impact tear production, these finding support the implementation of frequent ocular lubrication in all ICU patients. PMID- 23647554 TI - Computational design gains momentum in enzyme catalysis engineering. AB - Computational protein design is becoming a powerful tool for tailoring enzymes for specific biotechnological applications. When applied to existing enzymes, computational re-design makes it possible to obtain orders of magnitude improvement in catalytic activity towards a new target substrate. Computational methods also allow the design of completely new active sites that catalyze reactions that are not known to occur in biological systems. If initial designs display modest catalytic activity, which is often the case, this may be improved by iterative cycles of computational design or by follow-up engineering through directed evolution. Compared to established protein engineering methods such as directed evolution and structure-based mutagenesis, computational design allows for much larger jumps in sequence space; for example, by introducing more than a dozen mutations in a single step or by introducing loops that provide new functional interactions. Recent advances in the computational design toolbox, which include new backbone re-design methods and the use of molecular dynamics simulations to better predict the catalytic activity of designed variants, will further enhance the use of computational tools in enzyme engineering. PMID- 23647555 TI - Reasons for poor adherence to antiretroviral therapy postnatally in HIV-1 infected women treated for their own health: experiences from the Mitra Plus study in Tanzania. AB - BACKGROUND: In a study of prevention of mother-to-child transmission of HIV (PMTCT) by triple antiretroviral therapy (ART) in Dar es Salaam, Tanzania (the Mitra Plus study), retrospective viral load testing revealed a high and increasing frequency of detectable viral load during follow-up for two years postnatally in women given continuous ART for their own health suggesting poor adherence. This study explored women's own perceived barriers to adherence to ART post-delivery so as to identify ways to facilitate better drug adherence among women in need of ART for their own health. METHODS: Semi-structured interviews were conducted with 23 of the 48 women who had detectable viral load at 24 months postnatally. Content analysis was used to analyze the data. RESULTS: Most women in the study did not acknowledge poor adherence until confronted with the viral load figures. Then, however, they revealed multiple reasons for failing to adhere. They said that their motivation to take ART decreased once they had protected their children from becoming infected and successfully weaned them. Feeling well for some, and a feeling of hopelessness for others, also decreased motivation to continue ART. The overwhelming demands of everyday life, poverty and lack of empowerment also posed significant barriers to long-term adherence. The need to keep their HIV status a secret and not let anyone see them taking the drugs was another steep barrier. CONCLUSION: Reasons for postnatal failure to adhere by mothers put on ART for life during pregnancy included lack of motivation to continue ART after weaning the child, poverty and stigma. Projects that simultaneously address stigma, poverty and women's lack of empowerment may be necessary for PMTCT and ART to reach their full potential. Our results indicate that the new WHO proposal to start all HIV-infected pregnant women on lifelong ART regardless of CD4 cell count needs to address the challenging realities of women in resource-poor contexts if it is to be successful. PMID- 23647556 TI - Root caries: a periodontal perspective. AB - BACKGROUND AND OBJECTIVE: A prevailing dental problem in the periodontal patient is root caries. Specifically, periodontal involvement often results in root surfaces becoming exposed and at risk for this condition. Periodontal therapy often leads to increased gingival recession as well, and the associated increased root caries risk may compromise the long-term success and survival of periodontally treated teeth.This narrative review will address the topic of root caries in the periodontal patient, focusing on unmet research needs. MATERIAL AND METHODS: The Medline database was searched to identify items dealing with root caries, in terms of clinical features, diagnosis, pathogenic mechanisms and histopathology, as well as epidemiology, focusing then on the relationship between root caries and periodontal disorders. RESULTS: Although there is extensive literature on root caries, consensus is lacking regarding certain aspects, such as diagnostic criteria, prevalence within populations and indisputable risk factors. Advancing age could be an aggravating factor in susceptibility to root caries for the periodontal patient; however, definitive evidence in this regard is still missing. Similarly, full awareness of the increased risk of root caries in patients with periodontal disease or long-term periodontal treatment appears to be still lacking. CONCLUSION: Research regarding root caries in age-specific (elderly) periodontal patients is needed. Improved oral hygiene practices, locally applied preventive measures, good dietary habits and regular dental check-ups are crucial approaches to prevent both periodontal disease progression and root caries. Periodontal patients with root exposure should follow a strict root caries prevention protocol, as an integral component of their periodontal maintenance therapy. PMID- 23647557 TI - Seeing objects through the language glass. AB - Recent streams of research support the Whorfian hypothesis according to which language affects one's perception of the world. However, studies of object categorization in different languages have heavily relied on behavioral measures that are fuzzy and inconsistent. Here, we provide the first electrophysiological evidence for unconscious effects of language terminology on object perception. Whereas English has two words for cup and mug, Spanish labels those two objects with the word "taza." We tested native speakers of Spanish and English in an object detection task using a visual oddball paradigm, while measuring event related brain potentials. The early deviant-related negativity elicited by deviant stimuli was greater in English than in Spanish participants. This effect, which relates to the existence of two labels in English versus one in Spanish, substantiates the neurophysiological evidence that language-specific terminology affects object categorization. PMID- 23647558 TI - Perceptual demand modulates activation of human auditory cortex in response to task-irrelevant sounds. AB - In the visual modality, perceptual demand on a goal-directed task has been shown to modulate the extent to which irrelevant information can be disregarded at a sensory-perceptual stage of processing. In the auditory modality, the effect of perceptual demand on neural representations of task-irrelevant sounds is unclear. We compared simultaneous ERPs and fMRI responses associated with task-irrelevant sounds across parametrically modulated perceptual task demands in a dichotic listening paradigm. Participants performed a signal detection task in one ear (Attend ear) while ignoring task-irrelevant syllable sounds in the other ear (Ignore ear). Results revealed modulation of syllable processing by auditory perceptual demand in an ROI in middle left superior temporal gyrus and in negative ERP activity 130-230 msec post stimulus onset. Increasing the perceptual demand in the Attend ear was associated with a reduced neural response in both fMRI and ERP to task-irrelevant sounds. These findings are in support of a selection model whereby ongoing perceptual demands modulate task-irrelevant sound processing in auditory cortex. PMID- 23647560 TI - ERPs and neural oscillations during volitional suppression of memory retrieval. AB - Although investigations of memory and the dynamics of ERP components and neural oscillations as assessed through EEG have been well utilized, little research into the volitional nature of suppression over memory retrieval have used these methods. Oscillation analyses conducted on the Think/No-Think (TNT) task and volitional suppression of retrieval are of interest to broaden our knowledge of neural oscillations associated not only during successful memory retrieval but also when retrieval is unwanted or suppressed. In the current study, we measured EEG during a TNT task and performed ERP and EEG spectral power band analyses. ERP results replicated other researchers' observations of increases in 500-800 msec parietal effects for items where retrieval was instructed to be elaborated compared with being suppressed. Furthermore, EEG analyses indicated increased alpha (8-12 Hz) and theta (3-8 Hz) oscillations across parietal electrodes for items that were instructed to be suppressed versus those to be elaborated. Additionally, during the second half of the experiment (after repeated attempts at control), increases in theta oscillations were found across both frontal and parietal electrodes for items that were instructed to be suppressed and that were ultimately forgotten versus those ultimately remembered. Increased alpha power for items that were instructed to be suppressed versus elaborated may indicate reductions of retrieval attempts or lack of retrieval success. Increased theta power for items that were instructed to be suppressed versus elaborated may indicate increased or prolonged cognitive control to monitor retrieval events. PMID- 23647559 TI - Perceptual integration for qualitatively different 3-D cues in the human brain. AB - The visual system's flexibility in estimating depth is remarkable: We readily perceive 3-D structure under diverse conditions from the seemingly random dots of a "magic eye" stereogram to the aesthetically beautiful, but obviously flat, canvasses of the Old Masters. Yet, 3-D perception is often enhanced when different cues specify the same depth. This perceptual process is understood as Bayesian inference that improves sensory estimates. Despite considerable behavioral support for this theory, insights into the cortical circuits involved are limited. Moreover, extant work tested quantitatively similar cues, reducing some of the challenges associated with integrating computationally and qualitatively different signals. Here we address this challenge by measuring fMRI responses to depth structures defined by shading, binocular disparity, and their combination. We quantified information about depth configurations (convex "bumps" vs. concave "dimples") in different visual cortical areas using pattern classification analysis. We found that fMRI responses in dorsal visual area V3B/KO were more discriminable when disparity and shading concurrently signaled depth, in line with the predictions of cue integration. Importantly, by relating fMRI and psychophysical tests of integration, we observed a close association between depth judgments and activity in this area. Finally, using a cross-cue transfer test, we found that fMRI responses evoked by one cue afford classification of responses evoked by the other. This reveals a generalized depth representation in dorsal visual cortex that combines qualitatively different information in line with 3-D perception. PMID- 23647561 TI - Androgen levels during adjuvant endocrine therapy in postmenopausal breast cancer patients. AB - OBJECTIVE: To investigate plasma steroid hormone levels in postmenopausal breast cancer patients with and without adjuvant endocrine therapy and in healthy postmenopausal women. METHODS: Steroid hormone levels in postmenopausal breast cancer patients treated with aromatase inhibitors (n = 32) were compared with breast cancer patients treated with tamoxifen (n = 34), breast cancer patients without adjuvant endocrine therapy (n = 15), and healthy postmenopausal women (n = 56). Pregnenolone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11 deoxycortisol, cortisol, cortisone, dehydroepiandrosterone (DHEA), androstenedione, total testosterone, dihydrotestosterone, estrone and estradiol were measured using liquid chromatography-tandem mass spectrometry. Sex hormone binding globulin was measured by solid-phase chemiluminescent immunometric assays, and the free androgen index was calculated. RESULTS: Aromatase inhibitor users did not differ in dihydrotestosterone, total testosterone, androstenedione, DHEA, or free androgen index levels from healthy controls or untreated breast cancer patients. The highest total testosterone levels were found in tamoxifen treated women, who had significantly higher plasma concentrations than both women treated with aromatase inhibitors and breast cancer patients without adjuvant treatment. Concentrations of cortisol and cortisone were significantly greater in aromatase inhibitor users as well as tamoxifen users, in comparison with healthy controls and untreated breast cancer patients. Aromatase inhibitor users had lower estrone and estradiol plasma concentrations than all other groups. CONCLUSION: Adjuvant treatment with aromatase inhibitors or tamoxifen was associated with increased cortisol and cortisone plasma concentrations as well as decreased estradiol concentrations. Androgen levels were elevated in tamoxifen treated women but not in aromatase inhibitor users. PMID- 23647562 TI - Assessing the responsiveness of the Brazilian FIS to treatment for traumatic dental injury. AB - OBJECTIVE: This study aimed to assess the responsiveness of the Brazilian version of the Family Impact Scale (B-FIS) to describe changes in the quality of life (QoL) after treatment for traumatic dental injury (TDI). METHODS: After applying the eligibility criteria, 156 patients from 2 to 14 years old, who were attending a dental trauma center, were selected over an 18-month period. QoL was evaluated at two different appointments: A1 (after TDI) and A2 (after TDI treatment). The B FIS scores were calculated using the additive method. The responsiveness was analyzed by standardized response means (SRMs). RESULTS: Mean B-FIS scores were 12.1 (7.5 SD) and 2.7 (4.4 SD), while the median scores were 12.0 and 2.0, at A1 and A2 (P < 0.01), respectively. The B-FIS responsiveness scores dropped 9.4 points after TDI treatment. The change was observed as a decrease in the impact after TDI treatment, demonstrating a positive reduction in its absolute number as well as an improvement in the family's QoL. The SRM achieved was as follows: 1.2 total scale, 1.1 parental emotions, 0.5 family conflicts, 0.9 parental/family activity, 0.1 financial burden. The B-FIS scores indicated that TDI has significant impact on the family's QoL in A1 and still has impact in A2. The change was observed as a positive decrease in the impact after TDI treatment. CONCLUSIONS: The responsiveness of the FIS (Brazilian version) in detecting the family's change in QoL after TDI treatment was confirmed by SRM. PMID- 23647563 TI - Effect of pH on the in vitro susceptibility of planktonic and biofilm-grown Proteus mirabilis to the quinolone antimicrobials. AB - AIMS: To examine the effect of elevated pH, as reported during urinary catheter infections, on quinolone activity against the urease-producing pathogen Proteus mirabilis. METHODS AND RESULTS: Susceptibility of Pr. mirabilis to nalidixic acid, norfloxacin and ciprofloxacin was examined in media of pH 5 to pH 10 by determination of MICs, MBCs, minimum biofilm eradication concentrations (MBECs) and time-kill assays. Elevation of media pH from 5 to 9 caused a 10-fold decrease in bacteriostatic activity of nalidixic acid and was also associated with loss of the characteristic 'paradoxical' bactericidal activity. Alkaline pH, however, increased both bacteriostatic and bactericidal activities of the two fluoroquinolones tested against both planktonic and biofilm-associated Pr. mirabilis; MBC and MBEC values for ciprofloxacin decreased approx. 6000-fold and 10-fold, respectively, between pH 5 and pH 9. Rates of kill of all three agents were most rapid at pH 7, the optimal pH for bacterial replication. CONCLUSIONS: pH has a pronounced effect on quinolone-mediated killing, which may be attributed to the dependence of cellular uptake on quinolone ionization state. SIGNIFICANCE AND IMPACT OF THE STUDY: These results provide rationale for the use of these agents for Pr. mirabilis eradication in alkaline environments, including urinary catheter infections: the incidence, recurrence and recalcitrance of which pose a significant burden to healthcare providers. PMID- 23647564 TI - Novel imino thioether complexes of platinum(II): synthesis, structural investigation, and biological activity. AB - The reactions of the nitrile complexes cis- and trans-[PtCl2(NCR)2] (R = Me, Et, CH2Ph, Ph) with an excess of ethanethiol, EtSH, in the presence of a catalytic amount of n-BuLi in tetrahydrofuran (THF), afforded in good yield the bis-imino thioether derivatives cis-[PtCl2{E-N(H)?C(SEt)R}2] (R = Me (1), Et (2), CH2Ph (3), Ph (4)) and trans-[PtCl2{E-N(H)?C(SEt)R}2] (R = Me (5), Et (6), CH2Ph (7), Ph (8)). The imino thioether ligands assumed the E configuration corresponding to a cis addition of the thiol to the nitrile triple bond. The spectroscopic properties of these complexes have been reported along with the molecular structures of 1, 2, and 7 as established by X-ray crystallography which indicated that these compounds exhibit square-planar coordination geometry around the platinum center. Four N-H...Cl intermolecular contacts (N-H...Cl ca. 2.5-2.7 A) between each chlorine atom and the N-H proton of the imino thioether ligand gave rise to "dimers" Pt2Cl4L4 (L = imino thioether) formed by two PtCl2L2 units. The cytotoxic properties of these new platinum(II) complexes were evaluated against various human cancer cell lines. Among all derivatives, trans-[PtCl2{E N(H)?C(SEt)CH2Ph}2] showed the greatest in vitro cytotoxic activity being able to decrease cancer cell viability roughly 3-fold more effectively than cisplatin. PMID- 23647565 TI - Determination of the high prevalence of Dual/Mixed- or X4-tropism among HIV type 1 CRF01_AE in Hong Kong by genotyping and phenotyping methods. AB - In Hong Kong, the CCR5 antagonist has recently been introduced into salvage therapy for multiclass drug-resistant HIV-1-infected patients. Coreceptor usage must be determined prior to the usage of the CCR5 antagonist, which does not inhibit X4-tropic viruses. This study aimed to determine the tropism prevalence for HIV-1 subtypes B and CRF01_AE in Hong Kong. In addition, a modified promoter PCR phenotypic assay was used to validate the genotypic tropism prediction on CRF01_AE. One hundred and five subtype B and 98 CRF01_AE antiretroviral-naive patients were recruited for this study. The viral env V3 region isolated from the patients was sequenced and analyzed by Geno2pheno (FPR=5.75% or 10%, Clonal or Clinical), position-specific scoring matrix (WebPSSM, x4r5 subtype B matrix), and the combination of 11/25 and net charge rules. Fifteen concordant and 22 discordant tropism genotyped CRF01_AE samples were further phenotyped by either enhanced sensitivity Trofile assay or an optimized promoter-PCR phenotypic assay. The prevalence of Dual/Mixed- or X4-tropic virus in antiretroviral-naive subtype CRF01_AE was 39.1%, which was significantly higher than subtype B (p<0.05), regardless of the choices of genotypic algorithms. Our phenotypic data proposed that a better genotypic tropism prediction for HIV-1 CRF01_AE would be using both Geno2pheno (FPR=10%, Clonal) and WebPSSM (x4r5 subtype B matrix) algorithms in combination. The sensitivity and specificity for this combination were 88.9% and 89.3%, respectively. The comparatively high prevalence of Dual/Mixed- or X4 tropic virus in CRF01_AE demonstrated the need for special attention to future treatment strategies. PMID- 23647566 TI - Determination of the safe range of graft size mismatch using body surface area index in deceased liver transplantation. AB - In live donor liver transplantation, rigorous standardized criteria for matching of liver volume between donor and recipient have prevented graft loss because of size mismatch. In deceased whole liver transplantation, the safe donor-recipient size mismatch range remains unknown. We developed a multivariate survival model (generalized additive model) to estimate hazard risk of body surface area index (BSAi) for 3-year graft survival using data derived from the national registry database between 2005 and 2010. BSAi was calculated by BSA of donor divided by BSA of recipient. 24 509 patients were included in the analysis. Small-for-size (SFS) grafts with BSAi less than 0.78 had a significant impact on graft dysfunction with progressive increase of hazard risk toward the lowest end and a higher incidence of primary graft nonfunction and vascular thrombosis. Large-for size (LFS) grafts with BSAi greater than 1.24 had a significant impact on graft dysfunction with progressive increase of hazard risk toward the largest end. Our findings suggest that donor grafts with BSAi < 0.78 could be considered 'SFS' and donor grafts with BSAi > 1.24 could be considered 'LFS', with both extremes resulting in decreased graft survival. Therefore, BSAi > 0.78 and <1.24 appears to be a safe range to avoid adverse outcome associated with size mismatch. PMID- 23647567 TI - Quantitative reflection imaging of fixed Aplysia californica pedal ganglion neurons on nanostructured plasmonic crystals. AB - Studies of the interactions between cells and surrounding environment including cell culture surfaces and their responses to distinct chemical and physical cues are essential to understanding the regulation of cell growth, migration, and differentiation. In this work, we demonstrate the capability of a label-free optical imaging technique-surface plasmon resonance (SPR)-to quantitatively investigate the relative thickness of complex biomolecular structures using a nanoimprinted plasmonic crystal and laboratory microscope. Polyelectrolyte films of different thicknesses deposited by layer-by-layer assembly served as the model system to calibrate the reflection contrast response originating from SPRs. The calibrated SPR system allows quantitative analysis of the thicknesses of the interface formed between the cell culture substrate and cellular membrane regions of fixed Aplysia californica pedal ganglion neurons. Bandpass filters were used to isolate spectral regions of reflected light with distinctive image contrast changes. Combining of the data from images acquired using different bandpass filters leads to increase image contrast and sensitivity to topological differences in interface thicknesses. This SPR-based imaging technique is restricted in measurable thickness range (~100-200 nm) due to the limited plasmonic sensing volume, but we complement this technique with an interferometric analysis method. Described here simple reflection imaging techniques show promise as quantitative methods for analyzing surface thicknesses at nanometer scale over large areas in real-time and in physicochemical diverse environments. PMID- 23647568 TI - Impact of blood pressure changes and course on hematoma growth in acute intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: An association between high blood pressure (BP) in acute intracerebral hemorrhage (ICH) and hematoma growth (HG) has not been clearly demonstrated. Therefore, the impact of BP changes and course on HG and clinical outcome in patients with acute ICH was determined. METHODS: In total, 117 consecutive patients with acute (<6 h) supratentorial ICH underwent baseline and 24-h CT scans, CT angiography for the detection of the spot sign and non-invasive BP monitoring at 15-min intervals over the first 24 h. Maximum and minimum BP, maximum BP increase and drop from baseline, and BP variability values from systolic BP (SBP), diastolic BP and mean arterial pressure (MAP) were calculated. SBP and MAP loads were defined as the proportion of readings >180 and >130 mmHg, respectively. HG (>33% or >6 ml), early neurological deterioration (END) and 3 month mortality were recorded. RESULTS: Baseline BP variables were unrelated to either HG or clinical outcome. Conversely, SBP 180-load independently predicted HG (odds ratio 1.05, 95% CI 1.010-1.097, P = 0.016), whilst both SBP 180-load (odds ratio 1.04, 95% CI 1.001-1.076, P = 0.042) and SBP variability (odds ratio 1.2, 95% CI 1.047-1.380, P = 0.009) independently predicted END. Although none of the BP monitoring variables was associated with HG in the spot-sign-positive group, higher maximum BP increases from baseline and higher SBP and MAP loads were significantly related to HG in the spot-sign-negative group. CONCLUSIONS: In patients with acute supratentorial ICH, SBP 180-load independently predicts HG, whilst both SBP 180-load and SBP variability predict END. PMID- 23647571 TI - Anatomic study of full facial and scalp allografts without cutaneous facial scars. AB - Conventional reconstructive procedures for face and scalp reconstruction fall short of aesthetic and functional goals because of the unique quality and quantity of facial and scalp soft tissue. The purpose of this cadaver study was to demonstrate the feasibility of a flap design for full face and scalp composite tissue allotransplantation, without cutaneous facial scars. Six fresh human cadavers were dissected with sagittal scalp and mucosal incisions for full face and scalp harvest without cutaneous facial incisions. Sub-galeal and sub-SMAS dissection allowed for inclusion of the external carotid and internal jugular systems. Time of facial-scalp flap harvesting, length of the arterial and venous pedicles, length of sensory nerves (that were included in the facial flaps) and approximate surface area of the flaps were measured. Three of six flaps were transferred to recipient cadavers and the time of transfer was recorded. As a proof of concept, the external carotid arteries of one of six cadavers was flushed to remove clots and perfused with a radio-opaque latex polymer, Microfil (Flow Tech Inc.), to study flap perfusion by X-ray imaging. In the donor cadaver, the mean harvesting time of the total facial-scalp flap was 105 +/- 19 minutes. The mean length of the supraorbital, infraorbital, mental and great auricular nerves were 1.3 +/- 0.2, 1.3 +/- 0.1, 1.3 +/- 0.1, and 4.8 +/- 0.6 cm, respectively. The mean length of the external carotid artery and external jugular vein were 8.7 +/- 0.3 and 9.2 +/- 0.4 cm, respectively. The approximate area of the harvested flap was 1063 +/- 60 cm(2). In preparation for full face and scalp allotransplantation in humans, this study has demonstrated the feasibility of a full face and scalp flap without visible facial incisions. PMID- 23647569 TI - Impaired vascular KATP function attenuates exercise capacity in obese zucker rats. AB - OBJECTIVE: Obese subjects exhibit decreased exercise capacity (VO2max ). We have shown that vascular KATP channel mediates arteriolar dilation to muscle contraction. We hypothesize that exercise capacity is decreased in obesity due to impaired vascular KATP function. METHODS: The VO2max was measured in LZR and OZR by treadmill running before and following treatment with the KATP blocker glibenclamide i.p. One week later, the spinotrapezius muscle was prepared for in vivo microscopy. Arcade arteriolar diameters were measured following muscle contraction or application of the KATP opener cromakalim before and after glibenclamide application. In additional animals, LZR and OZR were treated with apocynin for five weeks. VO2max and arteriolar dilation experiments were repeated. RESULTS: The OZR exhibited decreased VO2max , functional and cromakalim induced vasodilation as compared with LZR. Glibenclamide had no effect on VO2max and functional vasodilation in OZR, but significantly inhibited responses in LZR. Vascular superoxide levels and NADPH oxidase activity were increased in OZR, but reduced in apocynin-treated OZR. Apocynin increased the VO2max , functional and cromakalim-induced vasodilation in OZR with no effect in LZR. CONCLUSIONS: Exercise capacity is dependent on vascular KATP channel function. The reduced exercise capacity in OZR appears to be due in part to superoxide-mediated impairment in vascular KATP function. PMID- 23647572 TI - Intra-aortic balloon shape change: effects on volume displacement during inflation and deflation. AB - It has been observed that operating the intra-aortic balloon at an angle to the horizontal resulted in a reduction of the volume displaced toward the coronary arteries and compromised afterload reduction. Therefore, the aim of this work is to examine whether changing the current balloon shape, which has not been altered for 40 years, could compensate for the negative hemodynamic effects due to angulation. We tested two tapered balloons, increasing diameter (TID) and decreasing diameter (TDD), and compared the results with those obtained from a standard cylindrical balloon. The balloons were tested in vitro at 60 beats/min and a static pressure of 90 mm Hg. The balloons were operated at four angles (0 degrees , 20 degrees , 30 degrees , 45 degrees ), and the pressure at three locations along the balloon (base, middle, and tip) was also measured. Flow rate upstream of the tip of the balloon was also measured to indicate the flow displaced toward the coronary circulation. The relative volume displaced toward (VUTVi) and suctioned away from (VUTVd) the simulated ascending aorta, during inflation and deflation, respectively, is reduced when a standard cylindrical balloon is operated at an angle to the horizontal. The TDD provided the greatest VUTVi and also produced the largest pulse pressure during deflation. Although the TID provided less VUTVi and VUTVd at smaller angles, it was not markedly affected by the change of angle. According to these results, different balloon shapes analyzed, with comparable volume to that of a cylindrical balloon, produced greater inflation and deflation benefits, at the horizontal and at a range of angles to the horizontal. Further investigations are required to optimize the shape of the tapered balloons to fit into the available physiological space. PMID- 23647574 TI - Quality change of apple slices coated with Aloe vera gel during storage. AB - Fresh-cut apples are easily susceptible to browning and microbial spoilage. In this study, an edible coating prepared from Aloe vera gel containing antibrowning solution was applied to preserve the quality of fresh-cut apples during storage. Fresh-cut apples were treated with both an Aloe vera gel and an Aloe vera gel containing 0.5% cysteine and then stored at 4 degrees C for 16 d. The color, firmness, weight loss, soluble solid content, titratable acidity, microbial analysis, and sensory evaluation were analyzed during storage. Fresh-cut apples coated with the Aloe vera gel showed delayed browning and reduced weight loss and softening compared to the control. The Aloe vera gel coating was also effective in reducing the populations of the total aerobic bacteria and yeast and molds. In particular, Aloe vera gel containing 0.5% cysteine was most effective in delaying browning and the reduction of microbial populations among the treatments. These results suggest that an Aloe vera gel coating can be used for maintaining the quality of fresh-cut apples. PMID- 23647575 TI - Foodborne transmission of bovine spongiform encephalopathy to nonhuman primates. AB - Risk for human exposure to bovine spongiform encephalopathy (BSE)-inducing agent was estimated in a nonhuman primate model. To determine attack rates, incubation times, and molecular signatures, we orally exposed 18 macaques to 1 high dose of brain material from cattle with BSE. Several macaques were euthanized at regular intervals starting at 1 year postinoculation, and others were observed until clinical signs developed. Among those who received >=5 g BSE-inducing agent, attack rates were 100% and prions could be detected in peripheral tissues from 1 year postinoculation onward. The overall median incubation time was 4.6 years (3.7-5.3). However, for 3 macaques orally exposed on multiple occasions, incubation periods were at least 7-10 years. Before clinical signs were noted, we detected a non-type 2B signature, indicating the existence of atypical prion protein during the incubation period. This finding could affect diagnosis of variant Creutzfeldt-Jakob disease in humans and might be relevant for retrospective studies of positive tonsillectomy or appendectomy specimens because time of infection is unknown. PMID- 23647576 TI - Hypersensitivity and desensitization to antineoplastic agents: outcomes of 189 procedures with a new short protocol and novel diagnostic tools assessment. AB - BACKGROUND: Desensitization to antineoplastic agents is becoming a standard of care. Efforts to establish and improve these techniques are being made at many institutions. Our aims are to evaluate a new rapid desensitization protocol designed to be shorter (approximately 4 h) and safer (reducing hazardous drugs exposure risks) and to assess the oxaliplatin-specific immunoglobulin E (IgE) as a novel diagnostic tool. METHODS: Prospective, observational, longitudinal study with patients who, for a 1-year period, suffered reactions to antineoplastic agents and were referred to the Desensitization Program at Ramon y Cajal University Hospital (RCUH). Patients were included or excluded as desensitization candidates after anamnesis, skin testing, risk assessment, and graded challenge. Specific IgE was determined in oxaliplatin-reactive patients. Candidate patients were desensitized using the new RCUH rapid desensitization protocol. RESULTS: Of 189 intravenous rapid desensitizations, 188 were successfully accomplished in the 23 patients who met inclusion criteria for desensitization (of 58 referred patients). No breakthrough reactions occurred in 94% of desensitizations, and most breakthrough reactions were mild. In 10 oxaliplatin-reactive patients, 38 desensitizations were successfully accomplished. Sensitivity for oxaliplatin specific IgE was 38% (0.35UI/l cutoff point) and 54% (0.10UI/l cutoff point); specificity was 100% for both cutoff points. CONCLUSIONS: In the hands of a Desensitization Program, managed by drug desensitization experts, this new protocol has proven an effective therapeutic tool for hypersensitivity to several antineoplastic agents (oxaliplatin, carboplatin, paclitaxel, docetaxel, cyclophosphamide, and rituximab); moreover, it improves safety handling of hazardous drugs. We report the first large series of oxaliplatin desensitizations. Oxaliplatin-specific IgE determination could be helpful. PMID- 23647573 TI - That which does not kill me makes me stronger; combining ERK1/2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance. AB - Oncogenic mutations in RAS or BRAF can drive the inappropriate activation of the ERK1/2. In many cases, tumour cells adapt to become addicted to this deregulated ERK1/2 signalling for their proliferation, providing a therapeutic window for tumour-selective growth inhibition. As a result, inhibition of ERK1/2 signalling by BRAF or MEK1/2 inhibitors is an attractive therapeutic strategy. Indeed, the first BRAF inhibitor, vemurafenib, has now been approved for clinical use, while clinical evaluation of MEK1/2 inhibitors is at an advanced stage. Despite this progress, it is apparent that tumour cells adapt quickly to these new targeted agents so that tumours with acquired resistance can emerge within 6-9 months of primary treatment. One of the major reasons for this is that tumour cells typically respond to BRAF or MEK1/2 inhibitors by undergoing a G1 cell cycle arrest rather than dying. Indeed, although inhibition of ERK1/2 invariably increases the expression of pro-apoptotic BCL2 family proteins, tumour cells undergo minimal apoptosis. This cytostatic response may simply provide the cell with the opportunity to adapt and acquire resistance. Here we discuss recent studies that demonstrate that combination of BRAF or MEK1/2 inhibitors with inhibitors of pro-survival BCL2 proteins is synthetic lethal for ERK1/2-addicted tumour cells. This combination effectively transforms the cytostatic response of BRAF and MEK1/2 inhibitors into a striking apoptotic cell death response. This not only augments the primary efficacy of BRAF and MEK1/2 inhibitors but delays the onset of acquired resistance to these agents, validating their combination in the clinic. LINKED ARTICLES: This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8. PMID- 23647577 TI - Mortality from sudden unexpected death in epilepsy (SUDEP) in a cohort of adults with intellectual disability. AB - BACKGROUND: People with intellectual disability (ID) and epilepsy are more likely to die prematurely than the general population. A significant number of deaths in people with epilepsy may be potentially preventable through better seizure control, regular monitoring and raising awareness among patients and carers. The aim of this project was to study mortality from sudden unexpected death in epilepsy (SUDEP) in adults with ID. METHODS: All adults (>=20 years old) living in Leicester city, Leicestershire and Rutland, UK, with ID between 1993 and 2010 were identified using the Leicestershire Intellectual Disability Register database. People with and without ID who died during the same period were identified using death certificate data from the Office for National Statistics (ONS). Deaths from probable and definite SUDEP were identified. Additional information on adults with ID who had died from probable or definite SUDEP was obtained from case notes and post-mortem reports, where available. Cases of probable and definite SUDEP in adults with ID were compared with the general population using standardised mortality ratios (SMRs). RESULTS: A total of 898 adults with ID had died over the 18-year study period. Of these, 244 deaths (27%) occurred in people with ID who had a diagnosis of epilepsy. Twenty-six people with ID died from probable or definite SUDEP, which was the second most common cause of death among adults with ID and epilepsy. All-cause specific SMRs were 2.2 [95% confidence interval (CI): 2.0-2.4] and 2.8 (95% CI: 2.5-3.1) for men and women with ID respectively. SMRs were 3.2 (95% CI: 2.7-3.8) and 5.6 (95% CI: 4.6 6.7) for men and women with epilepsy and ID respectively. During the same study period, 83 adults without ID had died of probable or definite SUDEP. The SMRs for SUDEP in patients with ID were 37.6 for men (95% CI: 21.9-60.2) and 52.0 for women (95% CI: 23.8-98.8). We found that in the majority of ID cases there was little detailed documentation on the circumstances surrounding deaths, no communication with patients/carers about risk of SUDEP and an absence of post mortem reports or carers' referral for bereavement counselling. CONCLUSION: The authors believe that a comprehensive risk management under a multiagency/multidisciplinary framework should be undertaken for all adults with ID and epilepsy in day-to-day clinical practice to reduce mortality in people with ID. PMID- 23647578 TI - Functional and morphological changes in diabetic macular edema over the course of anti-vascular endothelial growth factor treatment. AB - PURPOSE: To evaluate macular morphology and function in diabetic macular edema (DME) over the course of intravitreal anti-vascular endothelial growth factor (VEGF) treatment with Ranibizumab. METHODS: A consecutive series of 39 study eyes with centre-involving DME were included in this study. In all subjects, best corrected visual acuity (BCVA) according ETDRS protocol, fluorescein angiography (FA), microperimetric macular sensitivity (MP) and Spectral Domain optical coherence tomography (SD-OCT) cross-sectional scans were obtained before treatment and after 3 monthly applied intravitreal Ranibizumab injections. Six different morphological qualities [IS/OS layer integrity, outer nuclear layer (ONL) cysts, ONL cyst size, inner nuclear layer (INL) cysts, blocking phenomenon and subretinal fluid] were graded of each cross-sectional OCT scan before and over the course of treatment by two experienced graders. Correlation analyses between functional and morphological parameters were obtained. RESULTS: Mean BCVA increased from 26 +/- 14 to 33 +/- 13 letters after 3 consecutive monthly applied Ranibizumab injections (p < 0.001). Central retinal thickness (CRT) decreased from 504 +/- 144 to 387 +/- 122 MUm (p < 0.001). Over the course of treatment, IS/OS continuity improved (index: 0.56 +/- 0.52 to 0.43 +/- 0.49, Z = -1.415, p = 0.157), ONL cyst prevalence and size decreased significantly (index: 0.61 +/- 0.44 to 0.56 +/- 0.35, Z = -3.41, p = 0.001 and 1.75 +/- 0.88 to 1.17 +/- 1.05, Z = -4.02, p < 0.001), INL cyst prevalence decreased (index: 0.35 +/- 0.52 to 0.28 +/- 0.52, Z = -1.60, p = 0.109), blocking phenomenon did not change significantly (index: 00.12 +/- 0.16 to 0.13 +/- 0.15, Z = -0.45, p = 0.656) and subretinal fluid almost disappeared (index: 0.10 +/- 0.24 vs. 0.00 +/- 0.01, Z = -2.56, p = 0.011). Correlation analyses revealed highest significant correlations between ONL cyst prevalence and their size and CRT as well as BCVA and MP before treatment and over the course of treatment. CONCLUSIONS: ONL cysts and their size as morphological parameters correlate with retinal function measured with BCVA and microperimetry before and over the course of anti-VEGF therapy with Ranibizumab in patients with DME. PMID- 23647579 TI - Experimental evidence for direct insulator-quantum Hall transition in multi-layer graphene. AB - We have performed magnetotransport measurements on a multi-layer graphene flake. At the crossing magnetic field Bc, an approximately temperature-independent point in the measured longitudinal resistivity rhoxx, which is ascribed to the direct insulator-quantum Hall (I-QH) transition, is observed. By analyzing the amplitudes of the magnetoresistivity oscillations, we are able to measure the quantum mobility MUq of our device. It is found that at the direct I-QH transition, MUqBc ~ 0.37 which is considerably smaller than 1. In contrast, at Bc, rhoxx is close to the Hall resistivity rhoxy, i.e., the classical mobility MUBc is ~ 1. Therefore, our results suggest that different mobilities need to be introduced for the direct I-QH transition observed in multi-layered graphene. Combined with existing experimental results obtained in various material systems, our data obtained on graphene suggest that the direct I-QH transition is a universal effect in 2D. PMID- 23647580 TI - Prospective evaluation of reliability of cone-beam computed tomography in detecting different position of vibroplasty middle ear implants. AB - OBJECTIVES: This study had the following objectives: (i) to determine the accuracy of determination of Vibrant Soundbridge position in the spectrum of typically implanted sites in the middle ear, (ii) to assess interobserver agreement between three observers with different levels of radiology experience and (iii) to determine the suitability of cone-beam computed tomography (CT) to be used as the baseline radiological assessment post implantation, confirm ferromagnetic transducer (FMT) position. DESIGN: Prospective research study. Using four fresh human cadaveric heads, different types of vibroplasty were performed. After each step, cone-beam CT was performed for each of the four cadaveric heads. SETTING: University hospital (ENT and Neuroradiology). PARTICIPANTS: Four fresh cadaveric heads of human donors were operated and analysed by radiological imaging. MAIN OUTCOME MEASURES: There are different ways of coupling an ferromagnetic transducer to the anatomical structures of the middle and inner ear. Possibilities of differentiation between these coupling variants should be presented. RESULTS: The individual reconstruction view was significantly different from a standardised view for each observer (observer 1: P = 0.003; observer 2: P = 0.001; observer 3: P = 0.002) for all coupling variants combined as well as for each individual coupling variant (overall correct diagnosis: 100% versus 60%). Regarding the frequency of correct diagnosis, no significant differences were found between the three observers (P > 0.500) for each individual coupling variant as well as for all coupling variants combined. The worst rates of correct diagnosis were found in the standardised view for incus (42%), stapes (0%) and TORP (17%) vibroplasty. CONCLUSION: Cone-beam CT as a radiological control for Vibrant Soundbridge is safe and adequately sensitive and reliable and is therefore suitable for clinical investigation. The position of the ferromagnetic transducer in the middle ear and the presence or absence of an additional coupler could be determined in this study. Therefore, cone-beam-CT is useful for the assessment of device failure when there has been gross displacement of the ferromagnetic transducer (or smaller displacements in case of a baseline postoperative cone-beam CT). Regarding the quality of imaging, cone beam CT produced accurate results with different observers with widely varying radiological experience. PMID- 23647581 TI - Prevalence and determinants of use of potentially inappropriate medications in elderly inpatients: a prospective study in a tertiary healthcare setting. AB - AIM: To determine the prevalence and predictors of potentially inappropriate medications (PIM) prescribing in elderly inpatients using the modified American Geriatrics Society (AGS) updated Beers criteria 2012 and comparing it with the Beers criteria 2003. METHODS: The prospective observational study was carried out between September 2011 and May 2012 at a public teaching hospital. Elderly inpatients aged >=60 years were included. Multivariate logistic regression analysis was used to determine the predictors of PIM prescribing. RESULTS: The results were based on data of 502 patients; more than half (60%) were males and 66% were aged between 60-69 years with a mean (standard deviation [SD]) of 68 (7) years. Mean (SD) number of diagnoses and medications were three (1) and nine (4), respectively. A total of 81 (16%) patients were prescribed with at least >=1 PIM according to modified AGS updated Beers criteria 2012, compared with 11% according to Beers criteria 2003. On multivariate regression, important predictors for PIM prescribing were found to be age >=80 years (odds ratio [OR] 2.46, 95% confidence interval (CI) 1.27-3.12; P = 0.03), male sex (OR 1.35, 95% CI 1.06-1.84; P = 0.03), more than three diagnoses (OR 2.47, 95% CI 1.59-3.39; P = 0.04), >=6 medications prescribed (OR 1.16, 95% CI 1.02-1.35; P = 0.03) and >=10 days of hospital stay (OR 1.59, 95% CI 1.09-2.31; P = 0.02). CONCLUSIONS: The results show that PIM prescribing is common among hospitalized elderly Indian patients. It is feasible to reduce this practice through the provision of appropriate unbiased information to healthcare professionals. PMID- 23647582 TI - CB1 receptor signaling regulates social anxiety and memory. AB - The endocannabinoid (eCB) system regulates emotion, stress, memory and cognition through the cannabinoid type 1 (CB1 ) receptor. To test the role of CB1 signaling in social anxiety and memory, we utilized a genetic knockout (KO) and a pharmacological approach. Specifically, we assessed the effects of a constitutive KO of CB1 receptors (CB1 KOs) and systemic administration of a CB1 antagonist (AM251; 5 mg/kg) on social anxiety in a social investigation paradigm and social memory in a social discrimination test. Results showed that when compared with wild-type (WT) and vehicle-treated animals, CB1 KOs and WT animals that received an acute dose of AM251 displayed anxiety-like behaviors toward a novel male conspecific. When compared with WT animals, KOs showed both active and passive defensive coping behaviors, i.e. elevated avoidance, freezing and risk-assessment behaviors, all consistent with an anxiety-like profile. Animals that received acute doses of AM251 also showed an anxiety-like profile when compared with vehicle-treated animals, yet did not show an active coping strategy, i.e. changes in risk-assessment behaviors. In the social discrimination test, CB1 KOs and animals that received the CB1 antagonist showed enhanced levels of social memory relative to their respective controls. These results clearly implicate CB1 receptors in the regulation of social anxiety, memory and arousal. The elevated arousal/anxiety resulting from either total CB1 deletion or an acute CB1 blockade may promote enhanced social discrimination/memory. These findings may emphasize the role of the eCB system in anxiety and memory to affect social behavior. PMID- 23647583 TI - To get what we aim for--progress in diversity generation methods. AB - Protein re-engineering by directed evolution has become a standard approach for tailoring enzymes in many fields of science and industry. Advances in screening formats and screening systems are fueling progress and enabling novel directed evolution strategies, despite the fact that the quality of mutant libraries can still be improved significantly. Diversity generation strategies in directed enzyme evolution comprise three options: (a) focused mutagenesis (selected residues are randomized); (b) random mutagenesis (mutations are randomly introduced over the whole gene); and (c) gene recombination (stretches of genes are mixed to chimeras in a random or rational manner). Either format has both advantages and limitations depending on the targeted enzyme and property. The quality of diverse mutant libraries plays a key role in finding improved mutants. In this review, we summarize methodological advancements and novel concepts (since 2009) in diversity generation for all three formats. Advancements are discussed with respect to the state of the art in diversity generation and high throughput screening capabilities, as well as robustness and simplicity in use. Furthermore, limitations and remaining challenges are emphasized 'to get what we aim for' through 'optimal diversity' generation. PMID- 23647584 TI - Written plans: an overlooked mechanism to develop recovery-oriented primary care for depression? AB - There is a global shift to foster patient-centred and recovery-oriented mental health services. This has resulted from the expansion of how the concept of recovery is understood in mental health literature and practice. Recovery is now more than a return to function or reduction in symptoms; it is a subjective, individualised and multi-faceted experience. To date there has not been investigation of how recovery-oriented services can be translated and implemented into the primary mental health care system. This paper presents the results of a survey from a prospective cohort of primary care patients with probable depression about the importance of written plans to recover. The benefits of having a written plan to recover from depression, as outlined by the participants, were analysed using Leximancer software. The findings provide insights into how written plans may be an important mechanism for implementing a recovery-oriented primary mental health care system. We conclude that the benefits of a written plan provide insight into how patients conceptualise recovery. PMID- 23647585 TI - Restorative proctocolectomy in patients with ulcerative colitis: a cross sectional Danish population study on function and quality of life. AB - AIM: The study evaluated function and quality of life (QoL) in all patients having restorative proctocolectomy (RPC) in Denmark for ulcerative colitis (UC) from 1980 to 2010. Inclusion of all patients in one country has never previously been achieved. METHOD: All patients who had had a RPC in Denmark, from the first case in 1980 to the last case in 2010, were studied. A cross-sectional questionnaire survey was performed, and function and QoL were assessed using a standardized questionnaire - the Short-Form 36 (SF36) - and the inflammatory bowel disease questionnaire (IBDQ). RESULTS: The median duration of follow up was 11 (range, 1-30) years. Apart from deaths, pouch failures and research protection, data on function and QoL were obtained from 1047 (85%) of 1229 patients who had a functioning pouch at the time of the investigation. More female patients than male patients experienced urgency (56% vs 44%, P = 0.0021). The median number of bowel movements per 24 h was 7 (range, 1-23) in female patients and 6 (range, 1-20) in male patients (P < 0.001). Pad usage was more frequent among female patients than among male patients (62% vs 38%, P < 0.001). A higher incidence of major incontinence (P = 0.009) and use of pads (P = 0.01) was found among patients who had been operated on 21-30 years previously compared with those operated on 11-20 years previously. The prevalence of urgency was higher in patients who received surgery 0-10 years previously compared with 11-20 years previously (P = 0.009). The total IBDQ score was higher in male patients than in female patients (P < 0.001). Male patients scored higher in five of eight SF36 domains (P < 0.001). CONCLUSION: Female patients had more urgency, a higher frequency of defaecation and higher pad usage. This was associated with a reduced QoL. Nevertheless, RPC resulted in good function and a high degree of satisfaction in most patients. PMID- 23647586 TI - Response letter to "Quality of evidence for multivariate analysis to keep stable estimates". PMID- 23647587 TI - Renal failure after renal sympathetic ablation in a patient with chronic kidney disease--which came first, the chicken or the egg? PMID- 23647588 TI - Presence of desaturated hemoglobin enhances the contribution of blood cells to flow-mediated dilation in subjects with systemic sclerosis. PMID- 23647589 TI - Abnormal left ventricular longitudinal function assessed by echocardiographic and tissue Doppler imaging is a powerful predictor of diastolic dysfunction in hypertensive patients: the SPHERE study. AB - BACKGROUND: Through integrated use of echo-Doppler and tissue Doppler imaging (TDI), it is possible to obtain a comprehensive evaluation of both left ventricular (LV) diastolic and longitudinal functions. In this study, we sought to assess the prevalence of LV diastolic dysfunction (LVDD) and its relation with indices of long-axis function in asymptomatic patients with arterial hypertension. METHODS AND RESULTS: A perspective echo-Doppler study was performed in 1556 consecutive asymptomatic patients with grade 2-to-3 arterial hypertension aged 40-80 years enrolled in the SPHERE (multicenter proSPective study of ecHocardiography in hypERtEnsion) study. All patients had a LV ejection fraction (EF)>=50% and no history of heart failure or coronary artery disease. Advanced LVDD was identified by an average mitral-to-peak early diastolic annular ratio (E/e')>=13. Less than advanced LVDD was identified by: 8=34 ml/m(2). Overall LVDD was present in 286 patients (18%): advanced in 128, less than advanced in 158. LV long-axis function, as assessed by average peak systolic annular velocity (hazard ratio [HR]: 0.54, p<0.0001), mitral E/A ratio (HR: 3.20, p=0.0009), age (HR: 1.05, p=0.0087), body mass index (HR: 1.06, p=0.037), and relative wall thickness (HR: 1.05, p=0.050) were independent predictors of advanced LVDD. LV long-axis function (HR: 0.78, p<0.0001), E/A ratio (HR: 2.35, p=0.0032), LV end-diastolic volume index (HR: 1.04, p=0.0035), and age (HR: 1.03, p=0.018) were independently associated with overall LVDD, with a borderline contribution of LV mass index (HR: 1.01, p=0.062). CONCLUSIONS: An abnormal LV long-axis function was a powerful determinant of any LVDD in asymptomatic patients with arterial hypertension. PMID- 23647590 TI - Use of BVS in a chronic total occlusion with bifurcation lesion. PMID- 23647591 TI - Functional tricuspid regurgitation: an underestimated issue. AB - This review article focuses on functional tricuspid regurgitation (FTR) that has long been a neglected and underestimated entity. FTR is defined as leakage of the tricuspid valve during systole in the presence of structurally normal leaflets and chordae. FTR may be secondary to several heart diseases, more commonly mitral valve disease, pulmonary hypertension, atrial fibrillation, cardiomyopathies, right ventricular dysplasia, and idiopathic annular dilatation. The reported prevalence of moderate or greater FTR is roughly 16%, but it rises up to 89% when considering FTR of any grade. According to the recommendations of the European Association of Echocardiography, two-dimensional transthoracic echocardiography (TTE) is the first-line imaging modality for the assessment of valvular regurgitation, whereas three-dimensional TTE may provide additional information in patients with complex valve lesions. Transesophageal echocardiography may be used when TTE results are inconclusive. The natural history of FTR is unfavorable, even in less than severe tricuspid regurgitation. Data from the literature suggest that moderate or greater FTR is a risk factor for worse survival. In addition, FTR of any grade may worsen over time, which makes it reasonable to consider the correction of FTR at an early stage, preferably at the time of mitral valve surgery. Tricuspid valve annuloplasty is the gold standard surgical treatment for FTR and is associated with a recurrence rate, defined as postoperative moderate or severe FTR, ranging from 2.5 to 5.5% at 1-year follow up. PMID- 23647592 TI - Myocardial bridging, apical ballooning syndrome and myocardial stunning: shall we connect the dots? PMID- 23647593 TI - Diffuse, subendocardial vasculitis. A new entity identified by cardiovascular magnetic resonance and its clinical implications. PMID- 23647594 TI - Ivabradine significantly improves cardiac function in patients with ischemic heart disease: a meta-analysis of randomized controlled trials. PMID- 23647595 TI - Utility of 320 slice mapping CT for adrenal vein sampling in subjects suspected of having primary-aldosteronism compared with digital-subtraction-angiography and selective retrograde CT adrenal venography. PMID- 23647596 TI - Plasma N-terminal pro-brain natriuretic peptide levels predict new-onset atrial fibrillation in patients with acute myocardial infarction. PMID- 23647597 TI - Detection of adrenal veins on selective retrograde CT adrenal venography in comparison with digital subtraction angiography in subjects with established diagnosis of one-sided adrenal aldosterone-producing tumor confirmed by adrenal vein sampling, histopathology and clinical course. AB - PURPOSE: Adrenal vein (AV) sampling (AVS) is the diagnostic gold standard for primary aldosteronism (PA), but right-sided AVS is difficult. We compared detection of AVs by selective retrograde CT adrenal venography (SRCTAV) with digital subtraction angiography (DSA). MATERIALS AND METHODS: Data on 29 subjects (11 males, mean age 55 y) with increased serum aldosterone concentrations (SAC) and a diagnosed right or left aldosterone-producing tumor (APT) by AVS who underwent laparoscopic adrenalectomy were retrospectively analyzed. Before AVS, visualizing AVs was attempted by DSA and SRCTAV (Aquilion). If after the adrenocorticotropic hormone loading test serum cortisol concentration (SCC) from either AV was >200 MUg/dl, AVS was considered successful. If the SAC/SCC ratio for one side was >=4 times higher than the other side, we diagnosed a one-sided APT. RESULTS: Left and right AV, respectively, were visualized in 29 (100%) and 22 subjects (76%) by DSA and 29 (100%) and 28 subjects (97%) by SRCTAV, with right-AV detection significantly higher by SRCTAV (p<0.05). Cannulations were regarded successful in 28 subjects having both AVs observed on SRCTAV but not in the remaining subject whose adrenocortical scintigram was positive, however. Adrenalectomy was performed with a diagnosis of adenoma. Among 28 subjects with successful AVS, histopathological diagnoses included adenoma (25), nodular hyperplasia (2) and normal (1). After adrenalectomy, antihypertensive drug usage in 28 patients was reduced or stopped with decreases in SAC (97%). CONCLUSIONS: Detection of AV was significantly higher by SRCTAV than DSA, especially on the right side, in 29 subjects diagnosed with one-sided APT. PMID- 23647598 TI - The "know your numbers" program in Atahualpa--a pilot study aimed to reduce cardiovascular diseases and stroke burden in rural communities of developing countries. PMID- 23647600 TI - Can anatomy be used as a surrogate for physiology? The IVUS conundrum. PMID- 23647599 TI - Protein-L-isoaspartate (D-aspartate) O-methyltransferase protects cardiomyocytes against hypoxia induced apoptosis through inhibiting proapoptotic kinase Mst1. AB - BACKGROUND: Mammalian sterile 20-like kinase 1 (Mst1) is a mammalian homolog of Hippo kinase from Drosophila and it is a critical component of the Hippo signaling pathway, which regulates a variety of biological processes ranging from cell contact inhibition, organ size control, apoptosis and tumor suppression in mammals. Mst1 plays essential roles in heart disease since its activation causes cardiomyocyte apoptosis and dilated cardiomyopathy. However, the mechanism underlying Mst1 activation in the heart is not known. METHODS AND RESULTS: To identify novel cardiac proteins that may regulate Mst1 activity in the heart under pathophysiological conditions, a yeast two-hybrid screening of a human heart cDNA library with a dominant-negative Mst1 (K59R) mutant used as bait was performed. As a result, protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) was identified as an Mst1-interacting protein. The interaction of PCMT1 with Mst1 was confirmed by co-immunoprecipitation in both co-transfected HEK293 cells and native cardiomyocytes, in which PCMT1 interacted with the kinase domain of Mst1, but not with its C-terminal regulatory domain. Overexpression of PCMT1 did not affect the Mst1 expression, but significantly attenuated the Mst1 activation and its apoptotic effects in response to the hypoxia/reoxygenation induced injury in cardiomyocytes. Indeed, upregulation of PCMT1 by CGP3466B, a compound related to the anti-Parkinson's drug R-(-)-deprenyl with potent antiapoptotic effects, inhibited the hypoxia/reoxygenation induced Mst1 activation and cardiomyocyte apoptosis. CONCLUSIONS: These findings implicate PCMT1 as a novel inhibitor of Mst1 activation in cardiomyocytes and suggest that targeting PCMT1 may prevent myocardial apoptosis through inhibition of Mst1. PMID- 23647601 TI - Health-related quality of life associated with treatment adherence in patients with hypertension: a cross-sectional study. PMID- 23647602 TI - Evaluation of a training course in focused echocardiography for noncardiology house officers. AB - OBJECTIVE: To determine whether a training course in focused echocardiography can improve the proficiency of noncardiology house officers in accurately interpreting cardiovascular disease and echocardiography findings in dogs entering the emergency room setting. DESIGN: Prospective, blinded, educational study. SETTING: University veterinary teaching hospital. STUDY SUBJECTS: House officers underwent training in focused echocardiography. Fifteen dogs, including normal dogs and dogs with stable congenital or acquired cardiac disease, were used as study subjects during the laboratory session. INTERVENTIONS: A 6-hour curriculum on focused echocardiography was developed that included didactic lectures, clinical cases, and hands-on echocardiography. MEASUREMENTS AND MAIN RESULTS: Pre- and postcourse written examinations were administered to participants. House officers attended didactic lectures that were subsequently followed by a hands-on laboratory session and practical examination, which involved performing transthoracic echocardiography on dogs with and without cardiovascular disease. Twenty-one house officers completed the focused echocardiography training course. Written examination scores were 57 +/- 12% before and 75 +/- 10% after training (P < 0.001). Following the course, 97% of participants in the practical examination were able to obtain the correct right parasternal short- or long-axis view. Posttraining, most participants correctly identified pleural effusion (90%) and pericardial effusion (95%) and discriminated normal atrial size from atrial enlargement (86%). However, successful identification of a cardiac mass, volume status, and ability to recognize a poor quality study as nondiagnostic remained relatively low. Most trainees responded that the length of hands-on laboratory training was too abbreviated and that the course should be > 6 hours. CONCLUSION: A focused echocardiography training course improved knowledge and yielded acceptable proficiency in some echocardiographic findings commonly identified in the emergency room. This training course was not able to provide the skills needed for house officers to accurately assess fluid volume status, identify cardiac masses, ventricular enlargement or hypertrophy, and certain cardiac diseases. PMID- 23647603 TI - Partial purification and characterization of chiIO8, a novel antifungal chitinase produced by Bacillus cereus IO8. AB - AIMS: To investigate the distribution of chitinase IO8 in Bacillus cereus strains, the enhancing effects of the chitinase-producing B. cereus strains on biocontrol potential by dual culture assay and in vivo assay against Botrytis cinerea and also the enhancing effects of the chiIO8 on disinfectant properties against seed-borne diseases. Moreover, the application of chiIO8 treatment was also observed to improve the germinative energy. METHODS AND RESULTS: The purification steps included ammonium sulfate precipitation, with columns of DEAE Sepharose anion-exchange chromatography and Sephacryl S-400 high-resolution gel chromatography. The method gave a 5.8-fold increase in the specific activity and had a yield of 17%. The molecular weight of the partially purified chitinase chiIO8 was found to be around 30 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The optimal pH and optimal temperature of the partially purified chitinase were pH 6.5 and 65 degrees C, respectively. The thermostable chitinase still retained the activity after incubation for 100 min at 65 degrees C, and it was increased about 1.25 times than that of the control (before heating) when the enzyme solution heated at 65 degrees C for 60 min. The partially purified chitinase chiIO8 displays a wide inhibitory spectrum towards all phytopathogenic fungi tested. chiIO8 also exhibited effective disinfectant properties against seed-borne diseases. CONCLUSION: The present investigation emphasizes the potential of chitinase-producing micro-organism as promising biocontrol agents of fungal plant pathogens with chitinous cell wall. The novel chitinase chiIO8 proved an efficient, environmentally safe and user-friendly solution. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first investigation devoted exclusively to analyse the distribution of chitinase in B. cereus. It infers that the chitinase produced by B. cereus might play a role in the activity of the biopesticide. PMID- 23647604 TI - Evolving neonatal steroid prescription habits and patient outcomes. AB - AIM: Indications for post-natal steroids among preterm infants are evolving. The objective of this study was to compare steroid use in 2 cohorts 5 years apart and to document the short- and long-term outcomes of our most recent cohort. METHODS: Retrospective chart review of infants born under 28 weeks of gestational age for two cohorts (January 2002-August 2003 and July 2008-March 2010). RESULTS: Two hundred and fourteen infants were included. More infants received steroids in the later cohort (20% vs 35%, p = 0.021) but survival rates did not improve. There was a shift towards hydrocortisone use (<7% vs 76%) and pulmonary indications (36% vs 61% of courses; p = 0.021). Patients died later (8 days vs 30 days; p = 0.02), with a strong correlation between time of death and total dose of steroids (r = 0.91; p = 0.01). Neurodevelopmental outcomes for patients who received steroids for pulmonary indications were inferior to those for the rest of the cohort (severe adverse outcome 26% vs 4.8%, p = 0.03). CONCLUSION: The improvement in short-term respiratory status of ill preterm patients was offset by a disturbing increase in age at death and no improvement in survival rates. PMID- 23647605 TI - Expression of extracellular matrix metalloproteinase inducer glycosylation and caveolin-1 in healthy and inflamed human gingiva. AB - BACKGROUND AND OBJECTIVE: Glycosylated extracellular matrix metalloproteinase inducer (EMMPRIN) is specifically associated with caveolin-1 and influences its ability to induce matrix metalloproteinases (MMPs) production. This study investigated EMMPRIN glycosylation and caveolin-1 expression in healthy and inflamed human gingival tissues, analyzed the relationship between EMMPRIN glycosylation and caveolin-1 expression, and assessed how this interaction influenced MMP-1 production. MATERIAL AND METHODS: Gingival tissues were collected from 10 healthy subjects and 15 chronic periodontitis (chronic periodontitis) subjects. EMMPRIN, caveolin-1 and MMP-1 expressions were analyzed by immunohistochemistry. EMMPRIN and caveolin-1 co-localization was detected by immunofluorescence. EMMPRIN glycosylation, caveolin-1, active MMP-1 and proMMP-1 expression was assessed by Western blot. RESULTS: EMMPRIN was expressed in gingival epithelial cells, inflammatory cells, endothelial and fibroblast-like cells. Strong caveolin-1 immunoreactivity was detected in gingival epithelial and endothelial cells. Double immunofluorescence studies revealed EMMPRIN and caveolin-1 co-localization in gingival epithelium, endothelial and fibroblast like cells. Compared with healthy subjects, the chronic periodontitis group had increased high-glycoform EMMPRIN (HG-EMMPRIN) and active MMP-1 expression (p < 0.05). Active MMP-1 and proMMP-1 protein levels were positively correlated with HG-EMMPRIN levels (p < 0.05). CONCLUSION: EMMPRIN and caveolin-1 colocalize in periodontal tissues. The increased active MMP-1 and proMMP-1 production may be associated with elevated HG-EMMPRIN levels. PMID- 23647607 TI - Head-to-head comparison of the pharmacokinetic profiles of a high-purity factor IX concentrate (AlphaNine(r)) and a recombinant factor IX (BeneFIX(r)) in patients with severe haemophilia B. AB - Head-on comparative studies of factor IX (FIX) concentrates performed under standardized conditions are rarely conducted regardless of being a valuable instrument guiding health care providers towards better informed and cost effective decisions. This study is an extension of a multicentre study that assessed the efficacy, safety and pharmacokinetics (PK) of AlphaNine((r)) in 25 previously treated patients with severe haemophilia B (FIX:C <= 2%). After a washout period >= 7 days following the last PK performed with AlphaNine((r)) after a dose of 65-75 IU kg(-1) , an identical PK study was performed with BeneFIX((r)) on 22 of the same patients. Venous blood samples for analysis were taken at baseline and at 0.25, 0.5, 1, 3, 6, 9, 24, 48, 72 and 74 h post infusion. The outcomes of the comparison of the PK parameters were as follows: Mean (+/- SD) in vivo recovery (IVR) was 1.3 +/- 0.4 IU dL(-1) per IU kg(-1) for AlphaNine((r)) and 1.0 +/- 0.3 IU dL(-1) per IU kg(-1) for BeneFIX((r)) (P < 0.01). Mean terminal half-life, mean residence time, area under the curve, clearance and volume of distribution of BeneFIX((r)) were 36.0 +/- 12.8 h, 39.3 +/- 13.9 h, 1631 +/- 467 IU h dL(-1) , 0.046 +/- 0.01 dL kg(-1) min(-1) and 1.75 +/- 0.52 mL kg(-1) respectively. These values were not significantly different to those observed in AlphaNine((r)), although BeneFIX((r)) displayed higher than expected IVR values and lower than expected clearance values. In conclusion, AlphaNine((r)) showed a comparable half-life, but an IVR significantly higher than that of BeneFIX((r)). This dissimilarity may have implications on dosing requirements for on-demand treatment regimes affecting optimal resource allocation. PMID- 23647608 TI - Neonatal scalp haematoma and necrosis. AB - Birth trauma after prolonged deliveries and instrument-assisted extractions can result in skin lesions and reduced viability of the scalp. In these instances, scalp swellings and haematomas are often also seen. The classification and inter relationship between these conditions might not, however, always be clear. This report describes three cases of neonates with scalp swellings and necrosis. Nomenclature, underlying causes, work up, treatment options, and outcomes are presented and discussed. The first case consisted of a newborn with a subgaleal haematoma and occipital pressure necrosis that healed by secondary intention. In the second case, an infected scalp haematoma led to scarring and alopecia that required secondary reconstruction with tissue expansion. The third neonate suffered from a subgaleal haematoma and a scalp lesion that required split skin grafting and secondary reconstruction with tissue expansion. PMID- 23647609 TI - Hyphenation of supercritical fluid chromatography and two-dimensional gas chromatography-mass spectrometry for group type separations. AB - The Fischer-Tropsch (FT) process produces a variety of compounds over a wide carbon number range and the synthetic crude oil produced by this process is rich in highly valuable olefins and oxygenates, which crude oil only contains at trace levels. The characterization of these products is very challenging even when using comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC*GC-TOF-MS). The separation between cyclic paraffins and olefins is especially difficult since they elute in similar positions on the GC*GC chromatogram and since they have identical molecular masses with indistinguishable fragmentation patterns. Previously, a high performance liquid chromatography (HPLC) fractionation procedure was used prior to GC*GC-TOF-MS analysis to distinguish between alkenes and alkanes, both cyclic and non-cyclic, however, there was co-elution of the solvents used in the HPLC fractionation procedure, and the volatile components in the gasoline sample and the dilution introduced by the off-line fractionation procedure made it very difficult to investigate components present at very low concentrations. The hyphenation of supercritical fluid chromatography (SFC) to GC*GC is less complicated and the removal of the supercritical CO2 can be easily achieved without any loss of the volatile sample components, eliminating the introduction of co-eluting solvents as well as the dilution effect. This paper describes the on-line hyphenation of SFC to a GC*GC system in order to comprehensively characterize the chemical groups (saturates, unsaturates, oxygenates and aromatics) in an FT sample. PMID- 23647606 TI - Histamine H3 receptors, the complex interaction with dopamine and its implications for addiction. AB - Histamine H3 receptors are best known as presynaptic receptors inhibiting the release of histamine, as well as other neurotransmitters including acetylcholine and dopamine. However, in the dorsal and ventral striatum, the vast majority of H3 receptors are actually located postsynaptically on medium sized spiny output neurons. These cells also contain large numbers of dopamine (D1 and D2) receptors and it has been shown that H3 receptors form heterodimers with both D1 and D2 receptors. Thus, the anatomical localization of H3 receptors suggests a complex interaction that could both enhance and inhibit dopaminergic neurotransmission. Dopamine, especially within the striatal complex, plays a crucial role in the development of addiction, both in the initial reinforcing effects of drugs of abuse, as well as in maintenance, relapse and reinstatement of drug taking behaviour. It is, therefore, conceivable that H3 receptors can moderate the development and maintenance of drug addiction. In the present review, we appraise the current literature on the involvement of H3 receptors in drug addiction and try to explain these data within a theoretical framework, as well as provide suggestions for further research. PMID- 23647610 TI - A dynamic multiple reaction monitoring method for the multiple components quantification of complex traditional Chinese medicine preparations: Niuhuang Shangqing pill as an example. AB - It is a challenging task to simultaneously and quantitatively analyze multiple components in DFF [Da-Fu-Fang, namely, complex traditional Chinese medicine (TCM) preparations containing more than ten TCMs] due to their numerous and extreme complex chemical compositions possessing a wide variety of chemical and physical features, and their very low content. Rather than using a conventional mass spectrometry (MS) method with multiple reaction monitoring (MRM), in the current study, this challenge was addressed by using dynamic multiple reaction monitoring (DMRM). Using a DFF, Niuhuang Shangqing pill, which is composed of 19 TCMs, as a model, a rapid (one run in 20min), sensitive [lower limit of detection (LOD) and limit of quantitation (LOQ) were achieved comparable with MRM] and accessible (a standard HPLC/MS/MS instrumentation was employed) MS method was successfully developed for the simultaneous quantification of 41 bioactive components which represented 15 of the 19 medicinal plants. A comparison of LOD and LOQ using MRM and DMRM was made to quantitatively reveal that the latter demonstrated advantages over the former. Meanwhile, a standard operating procedure concerning the development of a new DMRM method was recommended. The MS data were obtained in the positive ion mode with electrospray ionization as the ion source, acetonitrile and water as mobile phase and a Kinetex C18 core-shell column (100mm*2.10mm, 2.6MUm, Phenomenex Inc.) as the analytical column. This method was then applied to 32 batches of samples. It transpired, through principal component analysis and orthogonal partial least squares discriminant analysis, that the consistency of the products was relatively good within one company, but poor among different companies among the 32 samples; one failed to qualify in terms of the Chinese Pharmacopeia. This work illustrated that the proposed DMRM method was particularly suitable for quantifying the trace components in DFF and capable of ensuring the quality of DFF. PMID- 23647611 TI - Computational fluid dynamics study of the optimal design and operating conditions of the segmentation ring used in parallel segmented flow columns. AB - We report on a numerical study wherein we modeled the influence of the segmentation ring used in the recently introduced parallel segmented flow concept. The study reconfirms that the parallel segmented flow concept can indeed improve separation performance of radially heterogeneous beds. It was however also found that the segmentation ring in itself introduces significant flow disturbances. Depending on its thickness and the fraction of the total flow rate going through the central opening, the ring itself can constitute a loss in volumetric variance (sigmav(2)) in the order of a few up to a few tens of MUl(2). Although the ideal flow-split ring would be infinitely thin, it was found that halving the current 0.62mm ring thickness used in literature to 0.31mm would already eliminate most of its negative effect. At the inlet, the optimal central flow rate fraction for a 0.62mm as well as a 0.31mm wide ring in a 4.6mm I.D. column lies in the range of 0.25-0.4. At the outlet, the optimal range is 0.15 0.4. PMID- 23647612 TI - Direct analysis of phthalate ester biomarkers in urine without preconcentration: method validation and monitoring. AB - Phthalates, which are ubiquitous in the environment, are readily metabolized in human bodies to their respective monoesters. These phthalate monoesters are non persistent with short half-lives, which make them the ideal biomarkers of human exposure to phthalates. In this study a direct analysis method without preconcentration was developed and validated for the following phthalate ester metabolites in urine: mono-(2-ethylhexyl) phthalate, mono-(2-ethyl-5 hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl)phthalate, monobenzyl phthalate, mono-isobutylphthalate, mono-n-butyl phthalate and monoethyl phthalate. The recovery of the phthalate ester metabolites varied between 97% and 104%. The intraday precision for the replicate analysis (n=10) of a urine sample did not exceed 5% for most of the compounds. The coefficient of variance amounted to 2-3%. The limit of quantification was set equal to 0.5MUg/L for the majority of the compounds. A comparison between the direct analysis method and a foregoing solid phase extraction (SPE) of the urine sample was made. Finally, the applicability of the direct analysis method was tested in three interlaboratory comparisons. PMID- 23647613 TI - Ion-pair reversed-phase chromatography of short double-stranded deoxyribonucleic acid in silicon micro-pillar array columns: retention model and applications. AB - Separation of double-stranded (ds) DNAs is important in numerous biochemical analyses relevant for clinical applications. A widely used separation technique is high performance liquid chromatography (HPLC), in the variant of ion-pair reversed-phase (IP-RP) chromatography. HPLC can be miniaturized by means of silicon micro-pillar array columns leading to on-chip fast and high resolution dsDNA separation with limited sample quantity. However, theoretical studies of retentive behavior of dsDNA in miniaturized chromatographic columns are hardly available, despite their enormous practical relevance. This paper established a new retention model to describe the size dependent separation of dsDNAs for any characteristic of the linear mobile phase gradient, in analogy to the model used to describe the retention of polymer chains with repeating units in RP HPLC. The model agrees with a large amount of dsDNA retention data, measured using DNA molecules in the size range of 10-400 base pairs in columns with different lengths (2 and 40cm) and different micro-pillar sizes (2 and 2.5MUm in diameter), in various mobile phase gradients. The model is particularly useful in practice, since it requires no numerical solutions and the column-specific fitting parameters (4 or 5) can be determined in a limited number of separation runs. As examples of its applications, the model has been used for the optimization of dsDNA step-gradient separations (5 dsDNAs separated within 8min) and for the determination of the size of dsDNA fragment (with uncertainty of about 2%). These applications are especially relevant for on-chip DNA analysis devices. PMID- 23647614 TI - Liposome-encapsulated hemoglobin ameliorates ischemic stroke in nonhuman primates: longitudinal observation. AB - Liposome-encapsulated hemoglobin (LEH) is protective early after brain ischemia in rats and nonhuman primates, but it remains unclear whether the protection persists and confers any benefits beyond the acute phase of brain ischemia and reperfusion. Ten monkeys underwent middle cerebral artery occlusion, received LEH (2 mL/kg, n = 5) or saline (2 mL/kg, n = 5) 5 min later, and reperfusion 3 h later. Positron emission tomography studies were repeated for the cerebral metabolic rate of O2 (CMRO2 ) as well as glucose (CMRglc) up to 8 days after reperfusion, when the animals were euthanized for morphological studies. There was no difference in O2 metabolism until 3 h after reperfusion, when CMRO2 was significantly better preserved in the cortex, but not in basal ganglia, on Day 0 in LEH-treated monkeys. The extent of cortical infarction (saline 68 +/- 10% vs. LEH 38 +/- 9%, P < 0.05) and CMRO2 (mild suppression: saline 34 +/- 10% vs. LEH 14 +/- 4%, P < 0.05) remained significantly better preserved 8 days later, when CMRglc showed a similar pattern of cortical protection (mild suppression: saline 49 +/- 15% vs. LEH 37 +/- 4%, P < 0.05) in LEH-treated monkeys, together with regained body weight. Somatic weight control, morphological integrity, CMRO2 , and CMRglc were better preserved immediately, as well as 8 days after occlusion and reperfusion of the middle cerebral artery in monkeys receiving LEH early after onset of ischemia. PMID- 23647615 TI - The role of potential mediators in racial inequalities in tooth loss: the Pro Saude study. AB - OBJECTIVE: To assess the relation between race and tooth loss, as well as the influence of socioeconomic factors, health behaviours, routine dental care and self-reported discrimination on this association. METHODS: This is a cross sectional study with data collected from the baseline of the Pro-Saude Study (Rio de Janeiro/Brazil), among 3253 civil servants in 1999-2001. Race was measured as self-reported skin colour (Black/Brown/White). The outcome was self-reported tooth loss, measured in four ordered categories (none/one or few/many/all or almost all). Three mediating pathways were explored between race and tooth loss. The first included self-reported discrimination assessed with a five-item scale. The second pathway included behavioural factors: routine dental care, marital status, smoking and alcohol consumption. The third considered socioeconomic factors: income, education, maternal education and early life poverty. Confounding factors were age and sex. Statistical analyses were carried out with ordinal logistic regression. RESULTS: Absence of all or almost all teeth was reported by 8% of respondents. White individuals comprised 53% of the population, followed by Browns (26%) and Blacks (22%). After adjustment, Blacks had an odds ratio of being in a higher category of missing teeth equal to 1.39 (95% CI 1.12 1.72), and Browns, 1.33 (95% CI 1.10-1.60), when compared to Whites. Age, sex and socioeconomic variables explained most of racial inequalities in tooth loss, while behavioural and discrimination variables contributed very little. Behavioural and socioeconomic variables were associated with tooth loss, while discrimination was not. No statistically significant interactions were found. CONCLUSIONS: There is an association between race and tooth loss that is mainly explained by current and early life socioeconomic variables, but not by behavioural factors and self-reported discrimination. PMID- 23647616 TI - Determinants of lifestyle behavior in type 2 diabetes: results of the 2011 cross sectional survey on living with chronic diseases in Canada. AB - BACKGROUND: Lifestyle behavior modification is an essential component of self management of type 2 diabetes. We evaluated the prevalence of engagement in lifestyle behaviors for management of the disease, as well as the impact of healthcare professional support on these behaviors. METHODS: Self-reported data were available from 2682 adult respondents, age 20 years or older, to the 2011 Survey on Living with Chronic Diseases in Canada's diabetes component. Associations with never engaging in and not sustaining self-management behaviors (of dietary change, weight control, exercise, and smoking cessation) were evaluated using binomial regression models. RESULTS: The prevalence of reported dietary change, weight control/loss, increased exercise and smoking cessation (among those who smoked since being diagnosed) were 89.7%, 72.1%, 69.5%, and 30.6%, respectively. Those who reported not receiving health professional advice in the previous 12 months were more likely to report never engaging in dietary change (RR = 2.7, 95% CI 1.8 - 4.2), exercise (RR = 1.7, 95% CI 1.3 - 2.1), or weight control/loss (RR = 2.2, 95% CI 1.3 - 3.6), but not smoking cessation (RR = 1.0; 95% CI: 0.7 - 1.5). Also, living with diabetes for more than six years was associated with not sustaining dietary change, weight loss and smoking cessation. CONCLUSION: Health professional advice for lifestyle behaviors for type 2 diabetes self-management may support individual actions. Patients living with the disease for more than 6 years may require additional support in sustaining recommended behaviors. PMID- 23647617 TI - The Self-Rating Scale of Self-Directed Learning (SRSSDL): a factor analysis of the Italian version. AB - BACKGROUND: The development of self-directed learning (SDL) is a growing priority among nurses and other health care workers: they need to be prepared in order for their university education to be effective and relevant to their lifelong learning. To learn in a self-directed manner, it is necessary to develop an awareness of one's ability to self-learn and then to implement appropriate and effective strategies; progress must be assessed using validated measurement tools. OBJECTIVES: The aim of this study was to examine the factor structure of the Italian version of the Self-Rating Scale of Self-directed Learning (SRSSDL(Ita)), and to provide evidence of its validity. DESIGN: A cross-sectional design was undertaken. PARTICIPANTS: Given that the instrument is composed of 60 items, a total of 600 to 900 participants were targeted. In addition, according to the theoretical assumption that self-directed learning - as a crucial component of lifelong learning - is a measurable skill that is developed across the individual's professional life, a maximum variation sample was examined. Therefore, 847 participants were involved, including 453 nurses, 141 radiology technicians, 182 nursing students and 68 radiology technician students. METHODS: Principal component analysis and factor analysis were performed. RESULTS: The Italian version of the SRSSDL Scale consists of 40 items composed of eight factors: Awareness (alpha=0.805), Attitudes (alpha=0.778), Motivation (alpha=0.789), Learning Strategies (alpha=0.789), Learning Methods (alpha=0.781), Learning Activities (alpha=0.676), Interpersonal Skills (alpha=0.684), and Constructing Knowledge (alpha=0.732). CONCLUSIONS: The SRSSDLIta consists of 40 items across eight factors. The shorter Italian version might reduce the time needed to complete, thereby making the tool faster and easier to use. PMID- 23647618 TI - Proximal atypical lentigo as a clue to amelanotic melanoma: a novel warning sign in the evaluation of monodactylous onychodystrophy. PMID- 23647619 TI - Neural networks to identify multiple sclerosis with optical coherence tomography. AB - PURPOSE: To compare axonal loss in ganglion cells detected with spectral-domain optical coherence tomography (OCT) in eyes of patients with multiple sclerosis (MS) versus healthy control subjects using an artificial neural network (ANN). To analyse the capability of the ANN technique to improve the detection of retinal nerve fibre layer (RNFL) damage in patients with multiple sclerosis. METHODS: Patients with multiple sclerosis (n = 106) and age-matched healthy subjects (n = 115) were enrolled. The Spectralis OCT system was used to obtain the circumpapillary RNFL thickness in both eyes. The 768 RNFL thickness measurements provided by the Spectralis OCT were performed to obtain thickness measurements from 24 uniformly divided locations around the peripapillary RNFL. The performance of the ANN technique for identifying RNFL loss in patients with multiple sclerosis was evaluated. Receiver-operating characteristic (ROC) curves were used to display the ability of the test to discriminate between MS and healthy eyes in our population. ROC curves obtained using ANN and parameters provided by OCT (mean and 6 sector thicknesses) were compared. RESULTS: The capability of the ANN technique to detect RNFL loss in patients with multiple sclerosis compared with healthy subjects was good. The area under the ROC curve was 0.945. Compared with the OCT-provided parameters, the ANN had the largest area under the ROC curve. CONCLUSIONS: Measurements of RNFL thickness obtained with Spectralis OCT have a good ability to differentiate between healthy and individuals with multiple sclerosis. Based on the area under the ROC curve, the ANN performed better than any single OCT parameter. PMID- 23647620 TI - The cytotoxicity evaluation of magnetic iron oxide nanoparticles on human aortic endothelial cells. AB - One major obstacle for successful application of nanoparticles in medicine is its potential nanotoxicity on the environment and human health. In this study, we evaluated the cytotoxicity effect of dimercaptosuccinic acid-coated iron oxide (DMSA-Fe2O3) using cultured human aortic endothelial cells (HAECs). Our results showed that DMSA-Fe2O3 in the culture medium could be absorbed into HAECs, and dispersed in the cytoplasm. The cytotoxicity effect of DMSA-Fe2O3 on HAECs was dose-dependent, and the concentrations no more than 0.02 mg/ml had little toxic effect which were revealed by tetrazolium dye assay. Meanwhile, the cell injury biomarker, lactate dehydrogenase, was not significantly higher than that from control cells (without DMSA-Fe2O3). However, the endocrine function for endothelin-1 and prostacyclin I-2, as well as the urea transporter function, was altered even without obvious evidence of cell injury in this context. We also showed by real-time PCR analysis that DMSA-Fe2O3 exposure resulted in differential effects on the expressions of pro- and anti-apoptosis genes of HAECs. Meanwhile, it was noted that DMSA-Fe2O3 exposure could activate the expression of genes related to oxidative stress and adhesion molecules, which suggested that inflammatory response might be evoked. Moreover, we demonstrated by in vitro endothelial tube formation that even a small amount of DMSA-Fe2O3 (0.01 and 0.02 mg/ml) could inhibit angiogenesis by the HAECs. Altogether, these results indicate that DMSA-Fe2O3 have some cytotoxicity that may cause side effects on normal endothelial cells. PMID- 23647621 TI - In-silico design of computational nucleic acids for molecular information processing. AB - Within recent years nucleic acids have become a focus of interest for prototype implementations of molecular computing concepts. During the same period the importance of ribonucleic acids as components of the regulatory networks within living cells has increasingly been revealed. Molecular computers are attractive due to their ability to function within a biological system; an application area extraneous to the present information technology paradigm. The existence of natural information processing architectures (predominately exemplified by protein) demonstrates that computing based on physical substrates that are radically different from silicon is feasible. Two key principles underlie molecular level information processing in organisms: conformational dynamics of macromolecules and self-assembly of macromolecules. Nucleic acids support both principles, and moreover computational design of these molecules is practicable. This study demonstrates the simplicity with which one can construct a set of nucleic acid computing units using a new computational protocol. With the new protocol, diverse classes of nucleic acids imitating the complete set of boolean logical operators were constructed. These nucleic acid classes display favourable thermodynamic properties and are significantly similar to the approximation of successful candidates implemented in the laboratory. This new protocol would enable the construction of a network of interconnecting nucleic acids (as a circuit) for molecular information processing. PMID- 23647622 TI - 'It ain't what you do it's the way that you do it': lessons for health care from decommissioning of older people's services. AB - Public sector organisations are facing one of the most difficult financial periods in history and local decision-makers are tasked with making tough rationing decisions. Withdrawing or limiting services is an emotive and complex task and something the National Health Service has always found difficult. Over time, local authorities have gained significant experience in the closure of care homes - an equally complex and controversial issue. Drawing on local knowledge and best practice examples, this article highlights lessons and themes identified by those decommissioning care home services. We believe that such lessons are relevant to those making disinvestment decisions across public sector services, including health-care. The study employed semi-structured interviews with 12 Directors of Adult Social Services who had been highlighted nationally as having extensive experience of home closures. Interviews were conducted over a 2-week period in March 2011. Results from the study found that having local policy guidance that is perceived as fair and reasonable was advocated by those involved in home closures. Many local policies had evolved over time and had often been developed following experiences of home closures (both good and bad). Decisions to close care home services require a combination of strong leadership, clear strategic goals, a fair decision-making process, strong evidence of the need for change and good communication, alongside wider stakeholder engagement and support. The current financial challenge means that public sector organisations need to make tough choices on investment and disinvestment decisions. Any such decisions need to be influenced by what we know constitutes best practice. Sharing lessons and experiences within and between sectors could well inform and develop decision-making practices. PMID- 23647624 TI - Increase in hepatitis A in tourists from Denmark, England, Germany, the Netherlands, Norway and Sweden returning from Egypt, November 2012 to March 2013. PMID- 23647623 TI - Populations at risk for alveolar echinococcosis, France. AB - During 1982-2007, alveolar echinococcosis (AE) was diagnosed in 407 patients in France, a country previously known to register half of all European patients. To better define high-risk groups in France, we conducted a national registry-based study to identify areas where persons were at risk and spatial clusters of cases. We interviewed 180 AE patients about their way of life and compared responses to those of 517 controls. We found that almost all AE patients lived in 22 departements in eastern and central France (relative risk 78.63, 95% CI 52.84 117.02). Classification and regression tree analysis showed that the main risk factor was living in AE-endemic areas. There, most at-risk populations lived in rural settings (odds ratio [OR] 66.67, 95% CI 6.21-464.51 for farmers and OR 6.98, 95% CI 2.88-18.25 for other persons) or gardened in nonrural settings (OR 4.30, 95% CI 1.82-10.91). These findings can help sensitization campaigns focus on specific groups. PMID- 23647625 TI - Ongoing multi-strain food-borne hepatitis A outbreak with frozen berries as suspected vehicle: four Nordic countries affected, October 2012 to April 2013. PMID- 23647626 TI - Severe Seoul hantavirus infection in a pregnant woman, France, October 2012. PMID- 23647628 TI - European Immunization Week 2013 and new ECDC tools to support routine vaccination programmes. PMID- 23647627 TI - Virus-host interactions and the unusual age and sex distribution of human cases of influenza A(H7N9) in China, April 2013. PMID- 23647629 TI - Joint ECDC CNRL and WHO/Europe briefing note on diagnostic preparedness in Europe for detection of avian influenza A(H7N9) viruses. PMID- 23647631 TI - Telomere shortening in human diseases. AB - The discovery of telomeres dates back to the early 20th century. In humans, telomeres are heterochromatic structures with tandem DNA repeats of 5'-TTAGGG-3' at the chromosomal ends. Telomere length varies greatly among species and ranges from 10 to 15 kb in humans. With each cell division, telomeres shorten progressively because of the 'end-replication problem'. Short or dysfunctional telomeres are often recognized as DNA DSBs, triggering cell-cycle arrest and result in cellular senescence or apoptotic cell death. Therefore, telomere shortening serves as an important tumor-suppressive mechanism by limiting cellular proliferative capacity by regulating senescence checkpoint activation. Although telomeres serve as a mitotic clock to cells, they also confer capping on chromosomes, with help from telomere-associated proteins. Over the past decades, many studies of telomere biology have demonstrated that telomeres and telomere associated proteins are implicated in human genetic diseases. In addition, it has become more apparent that accelerated telomere erosion is associated with a myriad of metabolic and inflammatory diseases. Moreover, critically short or unprotected telomeres are likely to form telomeric fusions, leading to genomic instability, the cornerstone for carcinogenesis. In light of these, this minireview summarizes studies on telomeres and telomere-associated proteins in human diseases. Elucidating the roles of telomeres involved in the mechanisms underlying pathogenesis of these diseases may open up new possibilities for novel molecular targets as well as provide important diagnostic and therapeutic implications. PMID- 23647632 TI - Determination of xylazine and 2,6-xylidine in animal tissues by liquid chromatography-tandem mass spectrometry. AB - Xylazine is a potent alpha2-adrenergic agonist used in veterinary medicine for sedation, analgesia, muscle relaxation, and so on. Its residue in animal-derived food may cause the food safety problem. Moreover, the metabolite 2,6-xylidine was reported to be a genotoxic and carcinogenic compound. Therefore, it is necessary to develop a high sensitive method for analyzing xylazine and metabolite residue in animal products. Here, we described a LC-MS/MS method for simultaneous determination of xylazine and 2,6-xylidine in 4 animal tissues: liver, meat, kidney, and fat. The samples were extracted by acetonitrile, and further clean up by hexane. The analysis was performed on a C18 reversed-phase column and API 5000 Triple Quadrupole mass spectrometry with positive electrospray ionization interface operating in the multiple-reaction monitoring mode. For all of the investigated sample matrix, the limit of detection (limit of quantitation) for xylazine and 2,6-xylidine were 0.06 (0.2) and 1.5 (5) MUg/kg, respectively, the recoveries were between 63.5% and 90.8%. The precision was within the range of required criteria for method development. The presented method is sensitive and reproducible, and thus suitable for accurate quantification of xylazine and metabolite residue in animal-derived food products. PMID- 23647633 TI - Airborne olive pollen counts are not representative of exposure to the major olive allergen Ole e 1. AB - Pollen is routinely monitored, but it is unknown whether pollen counts represent allergen exposure. We therefore simultaneously determined olive pollen and Ole e 1 in ambient air in Cordoba, Spain, and Evora, Portugal, using Hirst-type traps for pollen and high-volume cascade impactors for allergen. Pollen from different days released 12-fold different amounts of Ole e 1 per pollen (both locations P < 0.001). Average allergen release from pollen (pollen potency) was much higher in Cordoba (3.9 pg Ole e 1/pollen) than in Evora (0.8 pg Ole e 1/pollen, P = 0.004). Indeed, yearly olive pollen counts in Cordoba were 2.4 times higher than in Evora, but Ole e 1 concentrations were 7.6 times higher. When modeling the origin of the pollen, >40% of Ole e 1 exposure in Evora was explained by high-potency pollen originating from the south of Spain. Thus, olive pollen can vary substantially in allergen release, even though they are morphologically identical. PMID- 23647634 TI - The effect of 1% tropicamide-induced mydriasis and cycloplegia on spherical refraction of the adult horse. AB - OBJECTIVES: To determine the effects of tropicamide 1% on the refractive state of the adult equine globe and identify the most appropriate time period (in relation to mydriasis) to perform streak retinoscopy. ANIMALS STUDIED: Eight university owned mares of various ages and breeds. PROCEDURES: Topical tropicamide 1% was applied to one randomly selected eye from each of the horses to induce mydriasis and cycloplegia. The contralateral eyes served as controls. Streak retinoscopy and pupillometry were performed prior to, and every 5 min after tropicamide 1% installation for 90 min. RESULTS: All values are expressed as mean +/- SD. Both horizontal (2.8 +/- 0.74 mm) and vertical (7.3 +/- 1.29 mm) mean pupil diameters increased significantly (P < 0.04) in the treatment eyes compared with the control eyes (horizontal [0.48 +/- 0.85 mm] and vertical [1.06 +/- 1.31 mm] pupil diameter). No significant differences in the refractive states of the treatment (horizontal: +0.25 +/- 0.43 D and vertical: +0.41 +/- 0.37 D) or control (horizontal: +0.34 +/- 0.39 D and vertical: +0.41 +/- 0.37 D) eyes were identified at any time point. Three of the eight treatment eyes demonstrated blurry or reversing streak reflexes during streak retinoscopy evaluation following the application of topical tropicamide 1%. CONCLUSIONS: While these reflexes did not significantly influence streak retinoscopy results, their presence may subjectively influence a novice retinoscopist's ability to obtain accurate results. Therefore, optimal streak retinoscopy results may be obtained prior to, or 40- to 45-min following the application of topical tropicamide 1%, once near-maximal dilation has been achieved. PMID- 23647635 TI - Effect of a multimodal exercise program on sleep disturbances and instrumental activities of daily living performance on Parkinson's and Alzheimer's disease patients. AB - AIM: To assess the contribution of a multimodal exercise program on the sleep disturbances (SD) and on the performance of instrumental activities daily living (IADL) in patients with clinical diagnosis of Alzheimer's disease (AD) and Parkinson's disease patients (PD). METHODS: A total of 42 consecutive patients (23 training group, 19 control group) with PD and 35 demented patients with AD (19 trained group, 16 control group) were recruited. Participants in both training groups carried out three 1-h sessions per week of a multimodal exercise program for 6 months. The Pfeffer Questionnaire for Instrumental Activities and the Mini-Sleep Questionnaire were used to assess the effects of the program on IADL and SD respectively. RESULTS: Two-way ancova showed interactions in IADL and SD. Significant improvements were observed for these variables in both intervention groups, and maintenance or worsening was observed in control groups. The analysis of effect size showed these improvements. CONCLUSION: The present study results show that a mild to moderate intensity of multimodal physical exercises carried out on a regular basis over 6 months can contribute to reducing IADL deficits and attenuating SD. PMID- 23647636 TI - Sensitivity of Mycobacterium avium subsp paratuberculosis, Escherichia coli and Salmonella enterica serotype Typhimurium to low pH, high organic acids and ensiling. AB - AIMS: To evaluate the persistence of Mycobacterium avium subsp paratuberculosis (Myco. paratuberculosis), Salmonella enterica serotype Typhimurium (Salm.Typhimurium) and a commensal Escherichia coli (E. coli) isolate under the low pH and high organic acid (OA) conditions of ensiling of forages. METHODS AND RESULTS: Decay rates and the time required to obtain a 90% reduction in cell concentration were calculated following (i) exposure to buffered OA (pH 4.0, 5.0, 6.0 or 7.0) (ii) exposure to silage exudates and (iii) survival through ensiling of forage materials. Salm. Typhimurium had higher decay rates in silage exudates (-0.5601 day(-1) ) than did E. coli (-0.1265 day(-1) ), but both exhibited lower decay rates in silage than in OA or silage exudates. Myco. paratuberculosis showed no decrease in silage and decay rates in silage exudates were significantly lower (2-12 times) than for the other two organisms. CONCLUSIONS: Escherichia coli, Salm. Typhimurium and Myco. paratuberculosis exhibit marked differences in response to acidity. All three organisms show acid resistance, but Myco. paratuberculosis in particular, if present in manure and applied to forage grasses, may survive the low pH and high OA of the ensilaging process; silage may therefore be a potential route of infection if ingested by a susceptible animal. SIGNIFICANCE AND IMPACT OF STUDY: This information contributes to the understanding of potential risks associated with silage preservation and contamination of livestock feed with manure-borne pathogens. PMID- 23647637 TI - Suture-button suspensionplasty for thumb carpometacarpal arthritis: a minimum 2 year follow-up. AB - PURPOSE: To retrospectively review the results at a minimum of 2 years of suture button plasty with partial or full trapeziectomy and suture-button suspensionplasty. METHODS: We evaluated 21 patients who received suture-button suspensionplasty at least 2 years after surgery. We measured postoperative pinch strength, grip strength, range of motion, and metacarpal height. All patients also completed the Quick Disabilities of the Arm, Shoulder, and Hand questionnaire. RESULTS: At an average follow-up of 2.8 +/- 0.7 years, the mean Quick Disabilities of the Arm, Shoulder, and Hand score was 10 +/- 9. Pinch and grip strengths were 86% and 89% of the contralateral limb, respectively. Average first trapezial height was 74% of the contralateral trapezial height. There were no major complications. CONCLUSIONS: The favorable results of the suture-button suspensionplasty procedure confirm its usefulness in treating thumb carpometacarpal arthritis with minimal risk of complications, ineffective fixation, or loss of function. Subjective and objective outcomes measures are similar to previously described techniques. The benefit of this technique results from the implanted nature of the suspensionplasty elements that require no time to heal, so rehabilitation is begun as early as 10 days postoperatively. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 23647638 TI - Outcomes of rigid night splinting and activity modification in the treatment of cubital tunnel syndrome. AB - PURPOSE: To prospectively analyze, using validated outcome measures, symptom improvement in patients with mild to moderate cubital tunnel syndrome treated with rigid night splinting and activity modifications. METHODS: Nineteen patients (25 extremities) were enrolled prospectively between August 2009 and January 2011 following a diagnosis of idiopathic cubital tunnel syndrome. Patients were treated with activity modifications as well as a 3-month course of rigid night splinting maintaining 45 degrees of elbow flexion. Treatment failure was defined as progression to operative management. Outcome measures included patient reported splinting compliance as well as the Quick Disabilities of the Arm, Shoulder, and Hand questionnaire and the Short Form-12. Follow-up included a standardized physical examination. Subgroup analysis included an examination of the association between splinting success and ulnar nerve hypermobility. RESULTS: Twenty-four of 25 extremities were available at mean follow-up of 2 years (range, 15-32 mo). Twenty-one of 24 (88%) extremities were successfully treated without surgery. We observed a high compliance rate with the splinting protocol during the 3-month treatment period. Quick Disabilities of the Arm, Shoulder, and Hand scores improved significantly from 29 to 11, Short Form-12 physical component summary score improved significantly from 45 to 54, and Short Form-12 mental component summary score improved significantly from 54 to 62. Average grip strength increased significantly from 32 kg to 35 kg, and ulnar nerve provocative testing resolved in 82% of patients available for follow-up examination. CONCLUSIONS: Rigid night splinting when combined with activity modification appears to be a successful, well-tolerated, and durable treatment modality in the management of cubital tunnel syndrome. We recommend that patients presenting with mild to moderate symptoms consider initial treatment with activity modification and rigid night splinting for 3 months based on a high likelihood of avoiding surgical intervention. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 23647640 TI - Epidemiology of adult acute hand infections at an urban medical center. AB - PURPOSE: To define the current epidemiology of adult acute hand infections in an urban setting, with the aim of helping to improve empiric treatment, as hand infections represent a major source of morbidity and can result in stiffness and, possibly, amputation. METHODS: We performed an electronic medical record search to identify all patients admitted to our urban academic medical center with diagnoses related to open wounds and infections in the hand and fingers over a 6 year period (2005-2010). We recorded demographic data, location of infection, medical comorbidities, and culture data. RESULTS: Of the 2,287 patients admitted with diagnoses related to open wounds and infections in the hand and fingers, 1,507 incision and drainage procedures were performed, which resulted in 458 patients (30%) with culture-positive infections. Wound cultures identified 39 different species of bacteria. Most of these were methicillin-resistant Staphylococcus aureus, which compromised 53% of positive cultures, followed by methicillin-sensitive S aureus in 23% of positive cultures. The cultures were polymicrobial in 19%. History of intravenous drug use or diabetes mellitus was a strong predictor of polymicrobial infection. CONCLUSIONS: Methicillin-resistant Staphylococcus aureus was the most common bacteria cultured from these infections. Empiric antibiotic coverage should routinely cover methicillin resistant S aureus. We noted a higher incidence of polymicrobial infections than previously reported, particularly with intravenous drug use, diabetes, and human bites. Volar hand infections had the highest percentage of positive cultures, whereas paronychia had the lowest percentage. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 23647641 TI - Volar plate position and flexor tendon rupture following distal radius fracture fixation. AB - PURPOSE: To determine whether there were differences between plate position in patients who had postoperative flexor tendon ruptures following volar plate fixation of distal radius fractures and those who did not. METHODS: Three blinded reviewers measured the volar plate prominence and position on the lateral radiographs of 8 patients treated for flexor tendon ruptures and 17 matched control patients without ruptures following distal radius fracture fixation. We graded plate prominence using the Soong grading system, and we measured the distances between the plate and both the volar critical line and the volar rim of the distal radius. RESULTS: A higher Soong grade was associated with flexor tendon rupture. Patients with ruptures had plates that were more prominent volarly and more distal than matched controls without ruptures. Plate prominence projecting greater than 2.0 mm volar to the critical line had a sensitivity of 0.88, a specificity of 0.82, and positive and negative predictive values of 0.70 and 0.93, respectively, for tendon ruptures. Plate position distal to 3.0 mm from the volar rim had a sensitivity of 0.88, a specificity of 0.94, and positive and negative predictive values of 0.88 and 0.94, respectively, for tendon ruptures. CONCLUSIONS: We identified plate positions associated with attritional flexor tendon rupture following distal radius fracture fixation with volar plates. To decrease rupture risk, we recommend considering elective hardware removal after union in symptomatic patients with plate prominence greater than 2.0 mm volar to the critical line or plate position within 3.0 mm of the volar rim. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 23647642 TI - Outcomes of single-stage grip-release reconstruction in tetraplegia. AB - PURPOSE: To evaluate the outcomes of our technique for single-stage grip-release reconstruction and compare it with previous 1- and 2-stage grip reconstructions in tetraplegia. METHODS: A total of 14 patients (16 hands) with tetraplegia underwent a single-stage combination of operations to provide pinch, grip, and release function. We compared the study group with a historical control group of 15 patients (18 hands) who had been treated with staged flexion-extension grip release reconstructions. Both groups were classified as ocular cutaneous 4. Assessment parameters included grip and pinch strength, maximal opening of the first webspace, and Canadian Occupational Performance Measurement. Both groups were rehabilitated with early active mobilization beginning the first day after surgery. RESULTS: Grip strength and opening of the first webspace were significantly greater in the single-stage group than in the comparative group. Pinch strength was not significantly different between groups. On the Canadian Occupational Performance Measurement score, patients belonging to the single stage group were highly satisfied (increase of 3.7 points) and could perform several of their self-selected goals (3.5 points of improvement). CONCLUSIONS: The single-stage grip-release reconstruction provides people who have spinal cord injuries and tetraplegia with improved and reliable grip function; active finger flexion, active thumb flexion, passive thumb extension, and passive interossei function can all be achieved through this procedure. Early active mobilization is particularly important in improving functional outcome after this combination of grip reconstruction procedures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 23647643 TI - Rosacea - S1 guideline. PMID- 23647644 TI - Results of the WIRK prospective, non-interventional observational study of recombinant activated factor VII (rFVIIa) in patients with congenital haemophilia with inhibitors and other bleeding disorders. AB - Recombinant activated factor VII (rFVIIa) has been available for the treatment of acute bleeding and for prevention of bleeding during surgery and invasive procedures in patients with congenital haemophilia with inhibitors (CHwI) and acquired haemophilia since 1996. The study objective was to assess the efficacy and safety of rFVIIa in patients with CHwI, acquired haemophilia, congenital FVII deficiency and Glanzmann's thrombasthenia, in a real-life clinical setting. There were no specific inclusion or exclusion criteria; participation was offered to all German haemophilia centres known to use rFVIIa to treat patients with the above indications. Data on rFVIIa use and efficacy for the treatment of acute bleeding episodes and invasive procedures were recorded. Adverse drug reactions and recurrent bleeding episodes were also monitored. In total, 64 patients (50.0% women) received rFVIIa treatment. Patients experienced 281 evaluable bleeding episodes and underwent 44 invasive procedures. In 252 of 281 (89.7%) bleeding episodes, a stop (66.5%) or a significant reduction (23.1%) in bleeding was observed. No bleeding complications were reported for 42 of 44 (95.5%) invasive procedures covered with rFVIIa. A clear positive association was observed between early initiation of rFVIIa treatment for acute bleeding and efficacy. The total cumulative dose and number of injections were 468.3 +/- 545.8 MUg kg(-1) and 3.6 +/- 4.6 respectively. No drug-related adverse events were reported. rFVIIa use in Germany provided effective haemostatic cover without associated adverse events in the management of acute bleeds and invasive procedures across a range of bleeding disorders. PMID- 23647646 TI - The hierarchical structure and construct validity of the PID-5 trait measure in adolescence. AB - The DSM-5 may be the first edition that enables a developmental perspective on personality disorders because of its proposal to include a trait assessment in the Axis II section. The current study explores the reliability, structure, and construct validity of the Personality Inventory for DSM-5 (PID-5; Krueger, Derringer, Markon, Watson, & Skodol, 2012) in adolescents, a measure that assesses the proposed DSM-5 traits. A community sample of Flemish adolescents (N = 434; 44.7% male) provided self-reports on the PID-5 and the Dimensional Personality Symptom Itempool (DIPSI; De Clercq, De Fruyt, Van Leeuwen, & Mervielde, 2006). Results indicate an acceptable reliability for the majority of the PID-5 facets and a tendency toward structural convergence of the adolescent PID-5 structure with the adult proposal. Convergent validity with age-specific facets of personality pathology was generally supported, but discriminant validity appeared to be low. Beyond the findings that support the applicability of the PID-5 in adolescents, developmental issues may be responsible for specific differences in the adolescent PID-5 structure, the rather poor discriminant validity of the PID-5, and the lower reliability of a small number of PID-5 facets. These results indicate that further research on the validity of the PID-5 in younger age groups is required. PMID- 23647639 TI - How surgeons make decisions when the evidence is inconclusive. AB - PURPOSE: To address the factors that surgeons use to decide between 2 options for treatment when the evidence is inconclusive. METHODS: We tested the null hypothesis that the factors surgeons use do not vary by training, demographics, and practice. A total of 337 surgeons rated the importance of 7 factors when deciding between treatment and following the natural history of the disease and 12 factors when deciding between 2 operative treatments using a 5-point Likert scale between "very important" and "very unimportant." RESULTS: According to the percentages of statements rated very important or somewhat important, the most popular factors influencing recommendations when evidence is inconclusive between treatment and following the natural course of the illness were "works in my hands," "familiarity with the treatment," and "what my mentor taught me." The most important factors when evidence shows no difference between 2 surgeries were "fewer complications," "quicker recovery," "burns fewer bridges," "works in my hands" and "familiarity with the procedure." Europeans rated "works in my hands" and "cheapest/most resourceful" of significantly greater importance and "what others are doing," "highest reimbursement," and "shorter procedure" of significantly lower importance than surgeons in the United States. Observers with fewer than 10 years in independent practice rated "what my mentor taught me," "what others are doing" and "highest reimbursement" of significantly lower importance compared to observers with 10 or more years in independent practice. CONCLUSIONS: Surgeons deciding between 2 treatment options, when the evidence is inconclusive, fall back to factors that relate to their perspective and reflect their culture and circumstances, more so than factors related to the patient's perspective, although this may be different for younger surgeons. CLINICAL RELEVANCE: Hand surgeons might benefit from consensus fallback preferences when evidence is inconclusive. It is possible that falling back to personal comfort makes us vulnerable to unhelpful commercial and societal influences. PMID- 23647648 TI - Usefulness of omalizumab in ten patients with severe occupational asthma. AB - BACKGROUND: The management of severe occupational asthma (OA) remains problematic and new alternative treatments providing better disease control are required, ideally enabling affected individuals to remain in their job. METHODS: Ten patients with severe uncontrolled OA were treated with the monoclonal anti-IgE antibody omalizumab. In six cases the causative agent was a high molecular weight (HMW) compound and in four cases it was a low molecular weight (LMW) chemical. All of the patients had well documented OA despite workplace adjustments. RESULTS: During treatment, nine patients exhibited a lower rate of asthma exacerbations and used less oral or inhaled corticosteroids. Seven patients were able to continue working at the same workplace as before treatment. CONCLUSION: We have demonstrated that omalizumab is a potential treatment for severe uncontrolled OA and enabled seven of the ten patients in the study to remain in their job. PMID- 23647647 TI - Depression, antidepressant medications, and risk of Clostridium difficile infection. AB - BACKGROUND: An ancillary finding in previous research has suggested that the use of antidepressant medications increases the risk of developing Clostridium difficile infection (CDI). Our objective was to evaluate whether depression or the use of anti-depressants altered the risk of developing CDI, using two distinct datasets and study designs. METHODS: In Study 1, we conducted a longitudinal investigation of a nationally representative sample of older Americans (n = 16,781), linking data from biennial interviews to physician and emergency department visits, stays in hospital and skilled nursing facilities, home health visits, and other outpatient visits. In Study 2, we completed a clinical investigation of hospitalized adults who were tested for C. difficile (n = 4047), with cases testing positive and controls testing negative. Antidepressant medication use prior to testing was ascertained. RESULTS: The population-based rate of CDI in older Americans was 282.9/100,000 person-years (95% confidence interval (CI)) 226.3 to 339.5) for individuals with depression and 197.1/100,000 person-years for those without depression (95% CI 168.0 to 226.1). The odds of CDI were 36% greater in persons with major depression (95% CI 1.06 to 1.74), 35% greater in individuals with depressive disorders (95% CI 1.05 to 1.73), 54% greater in those who were widowed (95% CI 1.21 to 1.95), and 25% lower in adults who did not live alone (95% CI 0.62 to 0.92). Self-reports of feeling sad or having emotional, nervous or psychiatric problems at baseline were also associated with the later development of CDI. Use of certain antidepressant medications during hospitalization was associated with altered risk of CDI. CONCLUSIONS: Adults with depression and who take specific anti-depressants seem to be more likely to develop CDI. Older adults who are widowed or who live alone are also at greater risk of CDI. PMID- 23647645 TI - Different prognosis in hospitalized patients with influenza one season after the pandemic H1N1 influenza of 2009-2010 in Spain. AB - BACKGROUND: The present report compares prognosis in hospitalized cases with the H1N1 pandemic virus in two seasons. METHODS: Two series of hospitalized patients with laboratory-confirmed H1N1 pandemic influenza have been compared: 813 in the season 2009-2010 and 707 in the season 2010-2011. A detailed history of variables preceding hospital admission and during hospitalization was obtained by interview and clinical charts. A combined endpoint of death admission to intensive care was used as outcome due to the low number of deaths. Logistic regression was applied in the analysis for adverse outcome. RESULTS: Patients of the second season had different characteristics than in the first one (older, more underlying conditions, more malfunctioning organs and more symptoms). Patients with H1N1 pandemic virus when hospitalized were more frequently directly admitted to ICU during the 2010-2011 season than in the previous season (RR=2.10; 95% confidence intervals CI, 1.55-2.85), as a consequence of a higher presence of sepsis and respiratory distress. These patients also showed during hospitalization a higher risk of ICU admission or death (RR=3.22, 95% CI, 2.15-4.83). After adjusting for the differences in risk factors of adverse outcome, patients in the second season showed a higher risk of ICU admission and/or in-hospital death odds ratio (OR=3.77, 95% CI, 2.30-6.18). CONCLUSION: Hospitalized patients with H1N1 pandemic influenza during the second season were more severely affected at hospital admission and showed a worse prognosis than in previous season, independently of the differences found at hospital admission. PMID- 23647649 TI - Three-dimensional remodeling of young Asian women's faces using 20-mg/ml smooth, highly cohesive, viscous hyaluronic acid fillers: a retrospective study of 320 patients. AB - BACKGROUND: Because Asian faces are generally flatter than Caucasian faces, Asian women are increasingly requesting facial volume enhancement. OBJECTIVE: To clarify the effectiveness and safety of a volumizing treatment using 20-mg/mL smooth, highly cohesive, viscous hyaluronic acid fillers in young Asian women. MATERIALS AND METHODS: We retrospectively reviewed 320 patients who had been treated with this filler from March 2010 to February 2012. The filler was injected in the shape of a diamond to the glabella, both malar eminences, and chin. Overall, 4 to 6 mL of filler was sufficient to enhance the volume of a face in young Asian women. Both the physicians and patients rated effectiveness on the Global Aesthetic Improvement Scale at week 4. Need for touch-up and any adverse events were also evaluated. RESULTS: Most patients were very satisfied with this volumizing procedure, and there were no major complications. CONCLUSION: The 20 mg/mL smooth, highly cohesive, viscous hyaluronic acid filler is an effective, well-tolerated treatment option in young Asian women wishing for a more-three dimensional profile. PMID- 23647650 TI - A novel quinoline derivative that inhibits mycobacterial FtsZ. AB - High throughput phenotypic screening of large commercially available libraries through two NIH programs has produced thousands of potentially interesting hits for further development as antitubercular agents. Unfortunately, these screens do not supply target information, and further follow up target identification is required to allow optimal rational design and development of highly active and selective clinical candidates. Cheminformatic analysis of the quinoline and quinazoline hits from these HTS screens suggested a hypothesis that certain compounds in these two classes may target the mycobacterial tubulin homolog, FtsZ. In this brief communication, activity of a lead quinoline against the target FtsZ from Mycobacterium tuberculosis (Mtb) is confirmed as well as good in vitro whole cell antibacterial activity against Mtb H37Rv. The identification of a putative target of this highly tractable pharmacophore should help medicinal chemists interested in targeting FtsZ and cell division develop a rational design program to optimize this activity toward a novel drug candidate. PMID- 23647651 TI - A pilot functional MRI study of the effects of prefrontal rTMS on pain perception. AB - OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has been shown to effectively treat depression, and its potential value in pain management is emphasized by recent studies. Transcranial magnetic stimulation (TMS)-evoked activity in the prefrontal cortex may be associated with corticolimbic inhibitory circuits capable of decreasing pain perception. The present exploratory pilot study used functional magnetic resonance imaging (fMRI) to examine the effects of left prefrontal rTMS on brain activity and pain perception. DESIGN AND INTERVENTION: Twenty-three healthy adults with no history of depression or chronic pain underwent an 8-minute thermal pain protocol with fMRI before and after a single rTMS session. Participants received 15 minutes of either real (N = 12) or sham (N = 11) 10 Hz rTMS over the left prefrontal cortex (110% of resting motor threshold; 5 seconds on, 10 seconds off). RESULTS: TMS was associated with a 13.30% decrease in pain ratings, while sham was associated with an 8.61% decrease (P = 0.04). TMS was uniquely associated with increased activity in the posterior cingulate gyrus, precuneous, right superior frontal gyrus, right insula, and bilateral postcentral gyrus. Activity in the right superior prefrontal gyrus was negatively correlated with pain ratings (r = -0.65, P = 0.02) in the real TMS group. CONCLUSIONS: Findings suggest that prefrontal rTMS may be capable of activating inhibitory circuits involved with pain reduction. PMID- 23647652 TI - Distribution and genetic variation of Amblyomma triste (Acari: Ixodidae) in Argentina. AB - A study was conducted to investigate the distribution of Amblyomma triste in Argentina under the hypothesis that this tick prevails in riparian localities along the Parana River and adjacent humid environments from 34 degrees 30' S to 25 degrees 20' S, approximately. Ticks were collected from mammals and vegetation in those environments from November 2008 to October 2012. Additionally, genetic variation was tested from Argentinean, Brazilian, Chilean, and Uruguayan populations of A. triste by comparing sequences of 16S rDNA mitochondrial gene. The hypothesis was not confirmed because A. triste were collected at 36 degrees 16' S, well beyond the southern limit predicted, and the distribution along the banks of the Parana River was not continuous. The northernmost population of A. triste within Argentina was found at 25 degrees 42' S. Still undetermined abiotic factors and plant communities may play a role in modulating the abundance of A. triste because host availability does not appear to be a restriction factor. The genetic variation among A. triste populations from Argentina, Brazil, and Uruguay indicates that they belong to a unique taxon that is considered bona fide A. triste (type locality Montevideo, Uruguay) while it is unclear if the Chilean population of A. triste is conspecific with the other populations investigated in this study. It would be of importance to compare those genetically homogeneous populations with other populations of alleged A. triste, especially populations established in the Nearctic Zoogeographic Region in Mexico and USA. PMID- 23647653 TI - False positive detection of peanut residue in liquid caramel coloring using commercial ELISA kits. AB - Initial food industry testing in our laboratory using enzyme-linked immunosorbent assay (ELISA) methods indicated that the darkest caramel color (class IV) unexpectedly contained traces of peanut protein, a potential undeclared allergen issue. Caramel production centers on the heating of sugars, often glucose, under controlled heat and chemical processing conditions with other ingredients including ammonia, sulfite, and/or alkali salts. These ingredients should not contain any traces of peanut residue. We sought to determine the reliability of commercially available peanut allergen ELISA methods for detection of apparent peanut residue in caramel coloring. Caramel color samples of classes I, II, III, and IV were obtained from 2 commercial suppliers and tested using 6 commercially available quantitative and qualitative peanut ELISA kits. Five lots of class IV caramel color were spiked with a known concentration of peanut protein from light roasted peanut flour to assess recovery of peanut residue using a spike and recovery protocol with either 15 ppm or 100 ppm peanut protein on a kit-specific basis. A false positive detection of peanut protein was found in class IV caramel colors with a range of 1.2 to 17.6 parts per million recovered in both spiked and unspiked liquid caramel color samples. ELISA kit spike/recovery results indicate that false negative results might also be obtained if peanut contamination were ever to actually exist in class IV caramel color. Manufacturers of peanut-free products often test all ingredients for peanut allergen residues using commercial ELISA kits. ELISA methods are not reliable for the detection of peanut in class IV caramel ingredients and their use is not recommended with this matrix. PMID- 23647655 TI - Obstacle crossing in Parkinson's disease: mediolateral sway of the centre of mass during level-ground walking and obstacle crossing. AB - BACKGROUND: Falls are common in idiopathic Parkinson's disease (PD) and frequently occur when walking and crossing obstacles. OBJECTIVE: To determine whether people with mild to moderately severe PD have abnormal centre of mass (CoM) motion in response to the perturbations of level-ground walking and obstacle crossing. METHOD: Mediolateral excursion and velocity of the CoM were measured using three-dimensional motion analysis and force platforms in 20 people with mild to moderately severe PD at the peak dose of their PD medication, and 20 age and sex matched healthy control participants. RESULTS: People with PD had greater sideways sway than healthy older adults when walking, particularly when walking over obstacles. People with PD also maintained their CoM more medial to their stance foot throughout the swing phase of gait compared to controls. The severity of motor symptoms in people with PD, measured using the UPDRS-III, was associated with faster sideways CoM motion but not increased CoM excursions. CONCLUSIONS: Environmental hazards, such as ground-based obstacles, may accentuate postural instability in people with PD. Increased mediolateral sway might be due to impaired postural responses or kinematic compensations to increase foot clearance. Fall prevention programs could benefit from inclusion of components educating people with PD about the risks associated with obstacle crossing when walking. PMID- 23647654 TI - Improving quality of care for persons with diabetes: an overview of systematic reviews - what does the evidence tell us? AB - BACKGROUND: Ensuring high quality care for persons with diabetes remains a challenge for healthcare systems globally with consistent evidence of suboptimal care and outcomes. There is increasing interest in quality improvement strategies to improve diabetes management as reflected by a growing number of systematic reviews. These reviews are of varying quality and dispersed across many sources. In this paper, we present an overview of systematic reviews evaluating the impact of interventions to improve the quality of diabetes care. METHODS: We searched for systematic reviews evaluating the effectiveness of any intervention intended to improve intermediate patient outcomes and process of care measures for patients with any type of diabetes. Two reviewers independently screened search results, appraised each systematic review using AMSTAR and extracted data from high quality reviews (AMSTAR score >= 5). Within reviews, we used vote counting by direction of effect to report the number of studies favouring an intervention for each outcome. We produced summaries of results for each intervention category. RESULTS: We identified 125 reviews of varying methodological quality and summarised key findings from 50 high quality reviews. We categorised reviews by quality improvement intervention. Eight reviews were broad based (involving a variety of strategies). Other reviews considered: patient education and support (n = 21), telemedicine (n = 10), provider role changes (n = 7), and organisational changes (n = 4). Reviews reported intermediate patient outcomes (e.g. glycaemic control) (n = 49) and process of care outcomes (n = 9). There was evidence of considerable overlap of included studies between reviews. CONCLUSIONS: There is consistent evidence from high quality systematic reviews that patient education and support, provider role changes, and telemedicine are associated with improvements in glycaemic and vascular risk factor control in patients. There is less evidence about the impact of quality improvement interventions on other key process measures such as screening patients for diabetic complications. This paper provides decision makers with a comprehensive overview of evidence from high quality systematic reviews about the effects of quality improvement interventions on improving diabetes care. PMID- 23647656 TI - Pathogenesis of epiphyseal osteochondrosis. AB - Osteochondrosis (OC) of the articular epiphyseal cartilage complex (AECC) is a developmental disease that is present in the first weeks of life. It is characterized by focal chondronecrosis and retention of growth cartilage due to failure of endochondral ossification. Fissures may extend from the lesion through the overlying articular cartilage to create a cartilage flap and an osteochondral fragment. This articular form is known as osteochondritis dissecans (OCD). There have been many hypotheses about the etiopathogenesis of OC of the AECC including, amongst others, ischemia of growth cartilage or altered cartilage type II collagen metabolism. The ischemia theory proposes that necrosis of the vessels in the cartilage canals of the sub-articular growth cartilage leads to necrosis of chondrocytes and retention of necrotic cartilage. Several studies have measured biomarkers in serum and synovial fluid to demonstrate a consistent increase in type II collagen synthesis in young animals of different species. Although these changes could represent lesion reparative events, there is no comparable increase in the synthesis of cartilage matrix proteoglycan molecule. It is therefore speculated that an altered type II collagen metabolism may be involved in the early changes associated with OC. Further studies of OC susceptible animals in utero and the first weeks of life are required to elucidate the cause of vessel necrosis and the exact role of type II collagen structure and metabolism in OC. PMID- 23647657 TI - Antiarrhythmic effect of ranolazine in combination with class III drugs in an experimental whole-heart model of atrial fibrillation. AB - BACKGROUND: Ranolazine is evaluated for antiarrhythmic therapy of atrial fibrillation (AF). The electrophysiologic mechanisms of ranolazine in combination with class III drugs were studied in an isolated whole-heart model of stretch related AF. METHODS AND RESULTS: Thirty rabbits were fed with amiodarone (50 mg/kg/day, n = 10), dronedarone (50 mg/kg/day, n = 10), or placebo (n = 10) for 6 weeks. Subsequently, in isolated hearts, AF was induced by high-rate atrial pacing and acute atrial dilatation. In placebo-treated hearts, d,l-sotalol (50 MUM) was acutely administered. Ranolazine (10 MUM) was additionally infused in all groups. Chronic amiodarone (+26 +/- 7 ms, P < 0.05) or dronedarone (+22 +/- 4 ms, P < 0.05) as well as acute application of d,l-sotalol (+20 +/- 3 ms, P < 0.05) increased atrial action potential duration (aAPD90 ). Additional treatment with ranolazine did not significantly change aAPD90 (P = ns). Class III drugs did not affect interatrial conduction time, while ranolazine significantly increased it (amiodarone group: +15 +/- 3 ms, dronedarone group: +11 +/- 3 ms, sotalol group: +15 +/- 6 ms; P < 0.05 each). Ranolazine led to an additional increase in atrial effective refractory period (aERP), thus leading to an enhanced atrial postrepolarization refractoriness (aPRR, +17 +/- 6 ms, +21 +/- 4 ms and +16 +/- 8 ms, P < 0.05, respectively). Acute atrial dilatation increased AF incidence compared with baseline. Amiodarone-pretreated hearts showed a lower incidence of AF. Additional infusion of ranolazine further diminished AF. Dronedarone or acute infusion of sotalol did not significantly suppress AF, while additional treatment with ranolazine in these groups also reduced AF incidence. CONCLUSION: In this study, ranolazine on top of class III antiarrhythmic therapy had a beneficial effect. The increase in interatrial conduction time and marked atrial aPRR suppressed AF. These results shed further light on a potential therapeutic benefit of ranolazine on top of conventional antiarrhythmic therapy for rhythm control in AF. PMID- 23647658 TI - The over time development of chronic illness self-management patterns: a longitudinal qualitative study. AB - BACKGROUND: There currently exists a vast amount of literature concerning chronic illness self-management, however the developmental patterns and sustainability of self-management over time remain largely unknown. This paper aims to describe the patterns by which different chronic illness self-management behaviors develop and are maintained over time. METHOD: Twenty-one individuals newly diagnosed with chronic illnesses (e.g., diabetes, rheumatism, ischemic heart disease, multiple sclerosis, chronic renal disease, inflammatory bowel disease) were repeatedly interviewed over two-and-a-half years. The interviews were conducted in Sweden from 2006 to 2008. A total of 81 narrative interviews were analyzed with an interpretive description approach. RESULTS: The participants' self-management behaviors could be described in four different developmental patterns: consistent, episodic, on demand, and transitional. The developmental patterns were related to specific self-management behaviors. Most participants took long term medications in a consistent pattern, whereas exercise was often performed according to an episodic pattern. Participants managed health crises (e.g., angina, pain episodes) according to an on demand pattern and everyday changes due to illness (e.g., adaptation of work and household activities) according to a transitional pattern. All of the participants used more than one self-management pattern. CONCLUSION: The findings show that self-management does not develop as one uniform pattern. Instead different self-management behaviors are enacted in different patterns. Therefore, it is likely that self-management activities require support strategies tailored to each behavior's developmental pattern. PMID- 23647660 TI - A scoping review of personalisation in the UK: approaches to social work and people with learning disabilities. AB - There have been rapid developments in personalisation of health and social care in the UK over the past 5 years to develop a more flexible model of provision based upon greater choice and control for service users. This has been important for people with learning disabilities who are often dependent on others such as social workers to support their autonomy and independence. This article discusses a study carried out to explore the impact of personalisation on people with learning disabilities and the role of social workers to support this. A scoping review of the UK literature from 1996 to 2011 was conducted. It was found that there has not been a significant amount of empirical research in this area. Some studies, such as reports by InControl, have suggested that when implemented well, personalisation can have a positive impact on the lives of people with learning disabilities. Other literature highlighted the limitations and critiques of personalisation. Without the right support to manage budgets and autonomy, people with learning disabilities could be left vulnerable. In respect of the social workers, the finding of the review was that there was a lack of guidance on how to implement personalisation and a perceived threat to their traditional practice role, resulting in barriers to implementation. Although the literature emphasises the need for choice, control and autonomy in personalisation, the conclusion of this study is that more research needs to be carried out into how professional roles fit into and can support this process. PMID- 23647661 TI - A simple and novel method for GII norovirus genome clone with generic primers. AB - AIMS: This study aims to establish a novel method for cloning GII norovirus genome using generic primers rationally designed based on multiple alignments of 96 GII norovirus genome sequences. METHODS AND RESULTS: Based on conservative analysis of 96 GII norovirus genome sequences available in GenBank, three fragments encompassing the full-length genome were rationally designed. Fragments A, B and C were amplified by primers N1F/N2819R, N2689F/COG2R and COG2F/adaptor, respectively. Meanwhile, the sensitivity of the novel primers was evaluated, which could achieve 10(1) RTPCRU, as determined by the common detection primer pair JV12/JV13. The availability of the novel protocol was verified by sequencing two norovirus strains with different genotypes. CONCLUSIONS: Primers for GII norovirus genome clone were rationally designed, and a novel GII genome clone method was established. SIGNIFICANCE AND IMPACT OF THE STUDY: The three-fragment cloning method can be used as a universal tool to collect information on the genome of norovirus strains for future evolution and antivirus studies. PMID- 23647659 TI - World Health Organization International Standard to harmonize assays for detection of hepatitis E virus RNA. AB - Nucleic acid amplification technique-based assays are a primary method for the detection of acute hepatitis E virus (HEV) infection, but assay sensitivity can vary widely. To improve interlaboratory results for the detection and quantification of HEV RNA, a candidate World Health Organization (WHO) International Standard (IS) strain was evaluated in a collaborative study involving 23 laboratories from 10 countries. The IS, code number 6329/10, was formulated by using a genotype 3a HEV strain from a blood donation, diluted in pooled human plasma and lyophilized. A Japanese national standard, representing a genotype 3b HEV strain, was prepared and evaluated in parallel. The potencies of the standards were determined by qualitative and quantitative assays. Assay variability was substantially reduced when HEV RNA concentrations were expressed relative to the IS. Thus, WHO has established 6329/10 as the IS for HEV RNA, with a unitage of 250,000 International Units per milliliter. PMID- 23647662 TI - Rethinking the nature of fibrolamellar bone: an integrative biological revision of sauropod plexiform bone formation. AB - We present novel findings on sauropod bone histology that cast doubt on general palaeohistological concepts concerning the true nature of woven bone in primary cortical bone and its role in the rapid growth and giant body sizes of sauropod dinosaurs. By preparing and investigating longitudinal thin sections of sauropod long bones, of which transverse thin sections were published previously, we found that the amount of woven bone in the primary complex has been largely overestimated. Using comparative cellular and light-extinction characteristics in the two section planes, we revealed that the majority of the bony lamina consists of longitudinally organized primary bone, whereas woven bone is usually represented only by a layer a few cells thin in the laminae. Previous arguments on sauropod biology, which have been based on the overestimated amount, misinterpreted formation process and misjudged role of woven bone in the plexiform bone formation of sauropod dinosaurs, are thereby rejected. To explain the observed pattern in fossil bones, we review the most recent advances in bone biology concerning bone formation processes at the cellular and tissue levels. Differentiation between static and dynamic osteogenesis (SO and DO) and the revealed characteristics of SO- versus DO-derived bone tissues shed light on several questions raised by our palaeohistological results and permit identification of these bone tissues in fossils with high confidence. By presenting the methods generally used for investigating fossil bones, we show that the major cause of overestimation of the amount of woven bone in previous palaeohistological studies is the almost exclusive usage of transverse sections. In these sections, cells and crystallites of the longitudinally organized primary bone are cut transversely, thus cells appear rounded and crystallites remain dark under crossed plane polarizers, thereby giving the false impression of woven bone. In order to avoid further confusion in palaeohistological studies, we introduce new osteohistological terms as well as revise widely used but incorrect terminology. To infer the role of woven bone in the bone formation of fast growing tetrapods, we review some aspects of the interrelationships between the vascularity of bone tissues, basal metabolic rate, body size and growth rate. By putting our findings into the context of osteogenesis, we provide a new model for the diametrical limb bone growth of sauropods and present new implications for the evolution of fast growth in vertebrates. Since biomechanical studies of bone tissues suggest that predominant collagen fibre orientation (CFO) is controlled by endogenous, functional and perhaps phylogenetic factors, the relationship between CFO and bone growth rate as defined by Amprino's rule, which has been the basis for the biological interpretation of several osteohistological features, must be revised. Our findings draw attention to the urgent need for revising widely accepted basic concepts of palaeohistological studies, and for a more integrative approach to bone formation, biomechanics and bone microstructural features of extant and extinct vertebrates to infer life history traits of long extinct, iconic animals like dinosaurs. PMID- 23647663 TI - Exclusively membrane-inserted state of an uncleavable Tat precursor protein suggests lateral transfer into the bilayer from the translocon. AB - In bacteria, the export of proteins by the twin-arginine translocase (Tat) pathway is directed by cleavable N-terminal signal peptides. We studied the relationship between transport and maturation using a substrate, YedY, that contains an Ala > Leu substitution at the -1 position of the signal peptide. This blocks maturation and leads to the accumulation of a membrane-bound precursor form with the mature domain exposed to the periplasm. Its accumulation does not block transport of other Tat substrates, indicating that exit from the translocation channel has taken place, and the precursor protein is fir mLy integrated into the membrane bilayer. The membrane-integrated nature of the precursor, and complete absence of precursor protein in the periplasm, strongly suggest that the precursor has undergone lateral transfer into the bilayer during translocation. We propose that subsequent proteolytic processing releases the mature protein into the periplasm. A delay in processing results in an inhibition of cell growth, emphasizing a requirement for efficient maturation of Tat substrates. PMID- 23647664 TI - The caligid life cycle: new evidence from Lepeophtheirus elegans reconciles the cycles of Caligus and Lepeophtheirus (Copepoda: Caligidae). AB - The developmental stages of the sea louse Lepeophtheirus elegans (Copepoda: Caligidae) are described from material collected from marine ranched Korean rockfish, Sebastes schlegelii. In L. elegans, setal number on the proximal segment of the antennule increases from 3 in the copepodid to 27 in the adult. Using the number of setae as a stage marker supports the inference that the post naupliar phase of the life cycle comprises six stages: copepodid, chalimus I, chalimus II, pre-adult I, pre-adult II, and the adult. We observed variation in body length in both of the chalimus stages which we consider represents an early expression of sexual size dimorphism. We interpret the larger specimens of chalimus I as putative females, and the smaller as putative males; similarly with chalimus II, larger specimens are putative females and the smaller are males. Two patterns of life cycle are currently recognized within the Caligidae but the evidence presented here reconciles the two. We conclude that the typical caligid life cycle comprises only eight stages: two naupliar, one copepodid, and four chalimus stages preceding the adult in Caligus, but with the four chalimus stages represented by two chalimus and two pre-adult stages in Lepeophtheirus. This is a profound change with significant implications for the aquaculture industry, given that lice monitoring protocols include counts of chalimus stages and use temperature to predict when they will moult into the more pathogenic, mobile pre adults. Lice management strategies must be tailored to the precise life cycle of the parasite. PMID- 23647665 TI - Predicting clinical instability of older patients in post-acute care units: a nationwide cohort study. AB - AIM: Although patients admitted to post-acute care (PAC) units are usually clinically stable, unexpected medical conditions requiring acute ward readmissions still occur and can jeopardize the clinical effectiveness of PAC services. The main purpose of the present study was to evaluate predictive factors for clinical instability of patients in PAC units to improve the quality of PAC services. METHODS: This was a nationwide multicenter cohort study that recruited patients from five PAC units in Taiwan between July 2007 and June 2009. All patients received the comprehensive geriatric assessment (CGA) within 72 h of PAC unit admissions. Conditions requiring acute ward re-admissions from PAC units were defined as clinical instability. Causes of clinical instability for all patients and data of CGA were collected for analysis. RESULTS: Of 918 enrolled participants, 119 (12.9%) experienced acute ward readmissions, including 106 (89.1%) admissions related to medical conditions and 13 (10.9%) for surgical causes. Common conditions included diseases of the respiratory system (n = 32, 26.9%), genitourinary system (n = 24, 20.2%) and digestive system (n = 14, 11.8%). Surgical conditions, mainly fractures and dislocation of upper limbs, were significantly more likely to occur later (P = 0.05) in the PAC unit admissions than medical conditions. Compared with the non-readmission group, the readmission group was leaner (mean body mass index 21.1 +/- 2.8 vs 22.0 +/- 3.8 kg/m(2) , P = 0.007), having poorer functional status (mean Barthel Index 41.0 +/ 19.4 vs 45.4 +/- 20.3, P = 0.02; mean IADL: 1.3 +/- 1.6 vs 1.7 +/- 1.8, P = 0.016), poorer cognitive function (mean Mini-Mental State Examination: 16.8 +/- 6.4 vs 18.3 +/- 6.4, P = 0.022), poorer ambulation (mean Timed Up & Go test 32.7 +/- 18.7 vs 26.6 +/- 11.7 s, P = 0.039) and poorer nutritional status (mean Mini Nutrition Assessment 13.3 +/- 5.7 vs 15.4 +/- 5.8, P < 0.001), but similar in depression status (mean Geriatric Depression Score 3.7 +/- 3.3 vs 3.4 +/- 2.8, P = 0.247). In multivariate logistical regression model, lower Mini-Mental State Examination score was the only independent predictor for clinical instability (odds ratio 3.8, 95% confidence interval 1.348-10.870, P = 0.012). CONCLUSION: Approximately 13% of PAC patients might experience acute ward readmissions, and nearly 90% of them are caused by medical conditions. Poor cognitive function is a significant predictive factor for clinical instability in PAC, which deserves more clinical attention for all PAC patients. PMID- 23647666 TI - Total knee arthroplasty in haemophilic arthropathy with severe flexion deformity and HIV-TB co-infection: a case report. PMID- 23647667 TI - High level of susceptibility to human TRIM5alpha conferred by HIV-2 capsid sequences. AB - BACKGROUND: HIV-2, which was transmitted to humans from a distant primate species (sooty mangabey), differs remarkably from HIV-1 in its infectivity, transmissibility and pathogenicity. We have tested the possibility that a greater susceptibility of HIV-2 capsid (CA) to the human restriction factor TRIM5alpha (hTRIM5alpha) could contribute to these differences. RESULTS: We constructed recombinant clones expressing CA from a variety of HIV-2 viruses in the context of HIV-1 NL4-3-luciferase. CA sequences were amplified from the plasma of HIV-2 infected patients, including 8 subtype A and 7 subtype B viruses. CA from 6 non epidemic HIV-2 subtypes, 3 HIV-2 CRF01_AB recombinants and 4 SIVsmm viruses were also tested. Susceptibility to hTRIM5alpha was measured by comparing single-cycle infectivity in human target cells expressing hTRIM5alpha to that measured in cells in which hTRIM5alpha activity was inhibited by overexpression of hTRIM5gamma.The insertion of HIV-2 CA sequences in the context of HIV-1 did not affect expression and maturation of the HIV-2 CA protein. The level of susceptibility hTRIM5alpha expressed by viruses carrying HIV-2 CA sequences was up to 9-fold higher than that of HIV-1 NL4-3 and markedly higher than a panel of primary HIV-1 CA sequences. This phenotype was found both for viruses carrying CA from primary HIV-2 sequences and viruses carrying CA from laboratory-adapted HIV 2 clones. High hTRIM5alpha susceptibility was found in all HIV-2 subtypes. In this series of viruses, susceptibility to hTRIM5alpha was not significantly affected by the presence of a proline at position 119 or by the number of prolines at positions 119, 159 or 178 in HIV-2 CA. No significant correlation was found between HIV-2 viremia and sensitivity to hTRIM5alpha. CONCLUSIONS: HIV-2 capsid sequences expressed high levels of susceptibility to hTRIM5alpha. This property, common to all HIV-2 sequences tested, may contribute in part to the lower replication and pathogenicity of this virus in humans. PMID- 23647668 TI - Insurance disparities in the outcomes of spinal cord stimulation surgery. AB - OBJECTIVES: The Affordable Care Act aims to expand health insurance and to help narrow existing health care disparities. Medicaid patients have previously been noted to be at an increased risk for impaired access to health care, delayed medical treatment, and the receipt of substandard care. Conversely, those with commercial insurance may be subject to overtreatment. The goal of this study was to evaluate how Medicaid versus commercial insurance status affects outcomes following spinal cord stimulation (SCS) surgery. MATERIALS AND METHODS: A retrospective cohort study of 13,774 patients underwent either percutaneous or paddle permanent SCS implantation, selected from the Thomson Reuter's MarketScan database between 2000 and 2009. Patients were characterized by age at initial procedure, gender, baseline comorbidity burden, procedure-associated diagnosis code, follow-up, and type of insurance (Medicaid vs. commercial insurance). Outcome measures included probability of reoperation, timing and type of reoperation, presence of postoperative complications (immediate, 30 days, and 90 days), and overall utilization of health resources postoperatively. Multivariate analysis was performed comparing the relative effect of insurance status on outcomes following initial surgery. RESULTS: Medicaid patients had greater healthcare resource utilization as measured by medications prescribed, emergency department visits, and length of stay; however, commercially insured patients had significantly higher overall costs ($110,908 vs. $64,644, p < 0.0001). Commercial and Medicaid patients did not significantly differ in their complication rates during the index hospitalization or at 30 days or 90 days postoperatively. The group were also not significantly different in their two-year reoperation rates (7.32% vs. 5.06%, p = 0.0513). CONCLUSIONS: There are substantial insurance disparities that affect healthcare utilization and overall cost following SCS. Efforts for national healthcare reform should examine system factors that will reduce socioeconomic disparities in outcomes following SCS. PMID- 23647669 TI - Low-birthweight rates higher among Bangladeshi neonates measured during active birth surveillance compared to national survey data. AB - Birth size is an important gauge of fetal and neonatal health. Birth size measurements were collected within 72 h of life for 16 290 live born, singleton infants in rural Bangladesh from 2004 to 2007. Gestational age was calculated based on the date of last menstrual period. Newborns were classified as small-for gestational age (SGA) based on a birthweight below the 10th percentile for gestational age, using three sets of US reference data. Birth size distributions were explored based on raw values as well as after z-score standardisation in reference to World Health Organization (WHO) 2006 growth standards. Mean (SD) birthweight (g), length (cm) and head circumference (cm) measurements, completed within [median (25th, 75th percentile)] 15 (8, 23) h of life, were 2433 (425), 46.4 (2.4) and 32.4 (1.6), respectively. Twenty-two per cent were born preterm. Over one-half (55.3%) of infants were born low birthweight; 46.6%, 37.0% and 33.6% had a weight, length and head circumference below -2 z-scores of the WHO growth standard at birth; and 70.9%, 72.2% and 59.8% were SGA for weight based on Alexander et al., Oken et al. and Olsen et al. references, respectively. Infants in this typical rural Bangladesh setting were commonly born small, reflecting a high burden of fetal growth restriction and preterm birth. Our findings, produced by active birth surveillance, suggest that low birthweight is far more common than suggested by cross-sectional survey estimates. Interventions that improve fetal growth during pregnancy may have the largest impact on reducing SGA rates. PMID- 23647670 TI - Treatment with telbivudine for fulminant hepatitis B. PMID- 23647671 TI - Autophagy and cancer: taking the 'toxic' out of cytotoxics. AB - OBJECTIVES: Autophagy is the catabolic process that facilitates the degradation of proteins and organelles into recyclable nutrients for use by the cell. This article will review current literature to support the hypothesis that autophagy is pivotal in cancer progression and survival and provides some rationale behind the notion that autophagy can be a target for future cancer therapy. KEY FINDINGS: For the most part, autophagy is pro-cancerous in that it enables the affected cell to meet its nutritional requirements in hypoxic and cytotoxic environments (mainly due to chemotherapy), thus facilitating continued growth and proliferation of tumour cells. As such, it is reasonable to perceive autophagy as a mechanistic target for cancer therapy. However, the challenge to date has been the complexity of the mechanisms involved and the identification of key regulators of autophagy. This has been further complicated by the inherent variation between different cancer cell lines. SUMMARY: Better understanding of the role and mechanisms of autophagy in cancer, with a prelude to ways of exploiting this knowledge, may lead to better chemotherapeutic management of patients suffering from this currently incurable disease. PMID- 23647672 TI - Antimicrobial activity of newly synthesized methylsulfanyl-triazoloquinazoline derivatives. AB - OBJECTIVE: The aim of this research was to study and evaluate the antimicrobial activity of a novel 2-methylsulfanyl-[1,2,4]triazolo[1,5-a]quinazoline and its derivatives. Antibacterial activity of the target compounds was tested against a variety of species of Gram-positive bacteria such as Staphylococcus aureus ATCC 29213, Bacillus subtilis ATCC6633, and Gram-negative bacteria such as Pseudomonas aeruginosa ATCC27953 and Escherichia coli ATCC 25922. In addition some yeast and fungi, Candida albicans NRRL Y-477 and Aspergillus niger, respectively, were screened. METHODS: Antimicrobial tests were carried out by the agar well diffusion method, using 100 MUl of suspension containing 1 * 10(8) CFU/ml of pathological tested bacteria, 1 * 10(6) CFU/ml of yeast, and 1 * 10(4) spore/ml of fungi spread on nutrient agar (NA), Sabourand dextrose agar (SDA), and potato dextrose agar (PDA), respectively. KEY FINDINGS: The minimum inhibitory concentration (MIC) of the tested compounds was determined using the broth double dilution method (serially diluted technique) in proper nutrient. For comparison, ciprofloxacin and ketoconazole were used as antibacterial and antifungal reference drugs, respectively. Compounds 6, 9, 13, 14, and 11 were found to have the highest broad-spectrum antibacterial activity against S. aureus ATCC 29213, B. subtilis ATCC6633 and Gram-negative bacteria such as P. aeruginosa ATCC27953 and E. coli ATCC 25922 with MIC values of 6.25 and 12.50 MUg/ml. CONCLUSIONS: It was clear that many of the synthesized compounds exhibited good antimicrobial activity. This study has revealed that compounds 6, 9, 13, 14, and 11 have been disclosed as moderate antimicrobial agents. These compounds could be useful as templates for further development through modification or derivatization to design more potent antimicrobial agents. PMID- 23647673 TI - Effect of storage conditions on the stability of beta-lapachone in solid state and in solution. AB - OBJECTIVES: In this work, the effects of several technological factors on the stability of beta-lapachone (betaLAP) in solution and in the solid state were investigated. METHODS: The effects of relative humidity and light on the stability of betaLAP in the solid state were studied. Samples were characterized by liquid chromatography, thermal analysis, X-ray powder diffraction and optical microscopy. In solution, the effects of light conditions and additives (cyclodextrins) were also evaluated. Molecular modelling was used to support the degradation mechanism involved. Additionally, the pH stability profile of betaLAP was established. KEY FINDINGS: The synergism of relative humidity and light promoted degradation of betaLAP in the solid state, with important consequences for the physical and chemical characteristics of the drug after storage. Random methyl-beta-cyclodextrin was able to protect the drug against the hydrolytic process in darkness. However, it accelerated the drug decomposition by photolysis in light conditions. According to the pH stability profile, betaLAP undergoes an alkaline hydrolysis, its maximum stability pH being over the range 2-4. CONCLUSIONS: These studies provide useful information regarding the optimal storage conditions and formulations of betaLAP. PMID- 23647674 TI - Enhanced brain targeting of curcumin by intranasal administration of a thermosensitive poloxamer hydrogel. AB - OBJECTIVES: The aim of this study was to develop a curcumin intranasal thermosensitive hydrogel and to improve its brain targeting efficiency. METHODS: The hydrogel gelation temperature, gelation time, drug release and mucociliary toxicity characteristics as well as the nose-to-brain transport in the rat model were evaluated. KEY FINDINGS: The developed nasal hydrogel, composed of Pluronic F127 and Poloxamer 188, had shorter gelation time, longer mucociliary transport time and produced prolonged curcumin retention in the rat nasal cavity at body temperature. The hydrogel release mechanism was diffusion-controlled drug release, evaluated by the dialysis membrane method, but dissolution-controlled release when evaluated by the membraneless method. A mucociliary toxicity study revealed that the hydrogel maintained nasal mucosal integrity until 14 days after application. The drug-targeting efficiencies for the drug in the cerebrum, cerebellum, hippocampus and olfactory bulb after intranasal administration of the curcumin hydrogel were 1.82, 2.05, 2.07 and 1.51 times that after intravenous administration of the curcumin solution injection, respectively, indicating that the hydrogel significantly increased the distribution of curcumin into the rat brain tissue, especially into the cerebellum and hippocampus. CONCLUSIONS: A thermosensitive curcumin nasal gel was developed with favourable gelation, release properties, biological safety and enhanced brain-uptake efficiency. PMID- 23647675 TI - Cutaneous delivery of alpha-tocopherol and lipoic acid using microemulsions: influence of composition and charge. AB - OBJECTIVES: To assess whether the composition and charge of microemulsions affect their ability to simultaneously deliver alpha-tocopherol and lipoic acid into viable skin layers. METHODS: alpha-Tocopherol and lipoic acid were added (1.1 and 0.5% w/w, respectively) to decylglucoside-based microemulsions containing mono dicaprylin. Microemulsions containing surfactant : oil : water (w/w/w) at 60 : 30 : 10 (ME-O) and 46 : 23 : 31 (ME-W), as well as a cationic form of ME-W containing 1% phytosphingosine (ME-Wphy) were characterized, and their ability to disrupt the skin barrier and deliver the antioxidants in vitro in the skin was evaluated. Antioxidant activity in ME-Wphy-treated skin was assessed using the thiobarbituric acid-reactive substances (TBARS) assay. KEY FINDINGS: The internal phase diameters of microemulsions ranged between 42 and 55 nm; phytosphingosine addition and pH adjustment to 5.0 increased zeta potential from -4.3 to +29.1 mV. ME-O displayed w/o structure, whereas ME-W and ME-Wphy were consistent with o/w. Microemulsions affected skin electrical resistance and transepidermal water loss, but did not affect lipoic acid penetration. alpha-Tocopherol delivery increased following the order ME-O < ME-W < ME-Wphy. ME-Wphy presented suitable short-term stability. The antioxidants delivered by ME-Wphy decreased TBARS cutaneous levels. CONCLUSIONS: Even though microemulsion structure only affected tocopherol penetration, delivered levels of both antioxidants were sufficient for a decrease in TBARS, supporting their use for enhanced protection. PMID- 23647676 TI - Protein-coated nanoparticles embedded in films as delivery platforms. AB - OBJECTIVES: This work aimed to evaluate the performance of nanoparticle-loaded films based on matrices of polymethacrylates and hydroxypropylmethylcellulose (HPMC) intended for delivery of macromolecules. METHODS: Lysozyme (Lys)-loaded nanoparticles were manufactured by antisolvent co-precipitation. After size, loading efficiency and stability characterization, the selected batch of particles was further formulated into films. Films were characterized for mechanical properties, mucoadhesion, Lys release and activity after manufacture. KEY FINDINGS: We found that protein-coated nanoparticles could be obtained in USP phosphate buffer pH 6.8. Particles obtained at pH 6.8 had a z-average of 347.2 nm, a zeta-potential of 21.9 mV and 99.2% remaining activity after manufacture. This formulation was further studied for its application in films for buccal delivery. Films loaded with nanoparticles that contained Eudragit RLPO (ERL) exhibited excellent mechanical and mucoadhesive properties. Due to its higher water-swelling and solubility compared with ERL, the use of HPMC allowed us to tailor the release of Lys from films. The formulation composed of equal amounts of ERL and HPMC revealed a sustained release over 4 h, with Lys remaining fully active at the end of the study. CONCLUSIONS: Mucoadhesive films containing protein-coated nanoparticles are promising carriers for the buccal delivery of proteins and peptides in a stable form. PMID- 23647677 TI - Enhanced dissolution and oral bioavailability of tanshinone IIA base by solid dispersion system with low-molecular-weight chitosan. AB - OBJECTIVES: The aim of this study is to improve the dissolution and oral bioavailability of tanshinone IIA (TAN). METHODS: Solid dispersions of TAN with low-molecular-weight chitosan (LMC) were prepared and the in-vitro dissolution and in-vivo performance were evaluated. KEY FINDINGS: At 1 h, the extent of dissolution of TAN from the LMC-TAN system (weight ratio 9 : 1) increased about 368.2% compared with the pure drug. Increasing the LMC content from 9 : 1 to 12 : 1 in this system did not significantly increase the rate and the extent of dissolution. Differential scanning calorimetry, X-ray diffraction and scanning electron microscopy demonstrated the formation of amorphous tanshinone IIA and the absence of crystallinity in the solid dispersion. Fourier transform infrared spectroscopy revealed that there was no interaction between drug and carrier. In vivo test showed that LMC-TAN solid dispersion system presented significantly larger AUC0-t , which was 0.67 times that of physical mixtures and 1.17 times that of TAN. Additionally, the solid dispersion generated obviously higher Cmax and shortened Tmax compared with TAN and physical mixtures. CONCLUSIONS: In conclusion, the LMC -based solid dispersions could achieve complete dissolution, accelerated absorption rate and superior oral bioavailability. PMID- 23647678 TI - Relaxant effect of chloroquine in rat ileum: possible involvement of nitric oxide and BKCa. AB - OBJECTIVES: Bitter perception has a particularly important role in host defence. However, to date, direct effects of bitter compounds on small intestinal motility have not been shown. This study investigated the effects of bitter compounds on the spontaneous contraction of longitudinal smooth muscle strips of rat ileum. METHODS: Isolated longitudinal smooth muscle strips of rat ileum were used for tension recording in vitro. Immunofluorescence staining was used to identify the localization of TAS2R10 receptors. KEY FINDINGS: The spontaneous contraction of rat ileum was decreased after chloroquine administration. Other bitter compounds, such as quinine, denatonium and saccharin, exhibited similar effects. Chloroquine induced relaxation was not blocked by tetrodotoxin, but was partially reversed by the nitric oxide synthase inhibitor L-NAME or the large conductance Ca(2+) activated K(+) (BKCa) channel antagonist iberiotoxin. By surgically removing the small intestinal mucosa or bathing in Ca(2+) -free Krebs solution, the chloroquine-induced relaxation was largely attenuated. The immunofluorescence staining showed that TAS2R10 receptors were expressed in rat ileum. CONCLUSIONS: The results indicate that bitter receptor agonists induce relaxation of longitudinal smooth muscle strips of rat ileum, which is mediated by nitric oxide and BKCa channels. PMID- 23647679 TI - Retaining cytotoxic activity of anthrapyridone CO1 against multidrug resistant cells is related to the ability to induce concomitantly apoptosis and lysosomal death of leukaemia HL60/VINC and HL60/DOX cells. AB - OBJECTIVES: The effect of anthrapyridone compound CO1 retaining cytotoxic activity against multidrug resistant (MDR) tumour cells on inducing cell death of the sensitive leukaemia HL60 cell line and its MDR sublines (HL60/VINC and HL60/DOX) was examined. METHODS: The effects of CO1 and the reference compound doxorubicin (DOX) on examined cells were analysed by studying their cytotoxicity, drug intracellular accumulation, cell cycle distribution, caspase-3 and caspase-8 activity, Fas expression and lysosomal integrity. KEY FINDINGS: CO1 was much less effective at influencing the cell cycle of examined cells than DOX a well-known antitumour drug targeting cellular DNA and causing G2/M checkpoint arrest. CO1 caused much less pronounced appearance of the sub-G1 population and oligonucleosomal DNA fragmentation, characteristic of apoptosis, compared with DOX. Significantly lower caspase-3 and caspase-8 activity was also observed in the response of these cells to CO1 compared with DOX treatment. CO1 did not change the expression of the Fas death receptor, characteristic of apoptotic pathways, on the surface of studied cells. Interestingly, the results showed that CO1 caused lysosomal membrane permeability (LMP) of the cells, whereas DOX did not perturb the lysosomal integrity of the studied cells. CONCLUSIONS: The results suggest that CO1 could induce LMP-mediated cell death as a main lethal effect in a caspase-independent fashion. PMID- 23647680 TI - Prophylactic effects of methyl-3-O-methyl gallate against sodium fluoride-induced oxidative stress in erythrocytes in vivo. AB - OBJECTIVES: The purpose of this study was to demonstrate the effect of methyl-3-O methyl gallate (M3OMG), a rare polyphenolic natural product with a potent in vitro antioxidant effect, against sodium fluoride (NaF)-induced oxidative stress in rat erythrocytes in vivo. METHODS: Male Wistar rats were treated daily with either M3OMG (10 and 20 mg/kg) obtained through synthesis, vitamin C (10 mg/kg) or vehicle intraperitoneally for 7 days. Oxidative stress was then induced by exposing animals to NaF (600 ppm) through drinking water for 7 days. At the end of intoxication period, rats were killed and erythrocytes isolated. The activity of antioxidant enzymes (catalase and superoxide dismutase) and levels of reduced glutathione and thiobarbituric acid reactive substances were measured in erythrocyte haemolysates. RESULTS: NaF intoxication resulted in a 1.9-fold increase in erythrocyte lipid peroxidation associated with significant (P < 0.001) depletion of reduced glutathione level. Superoxide dismutase and catalase activity was suppressed by NaF treatment by 3.069 and 2.3 fold when compared with untreated control groups. Pretreatment of rats with M3OMG or vitamin C afforded protection against NaF-induced oxidative stress as assessed through the measured oxidant/antioxidant markers. CONCLUSION: This finding provided in-vivo evidence for the therapeutic potential of M3OMG in combating fluoride-induced oxidative damage in cellular systems. PMID- 23647681 TI - Evidence for regulation of UDP-glucuronosyltransferase (UGT) 1A1 protein expression and activity via DNA methylation in healthy human livers. AB - OBJECTIVES: Interindividual variability in glucuronidation of bilirubin and drugs by UDP-glucuronosyltransferase 1A1 (UGT1A1) is considerable and only partially explained by genetic polymorphisms and enzyme inducers. Here we determined whether a well-known epigenetic modification, cytosine methylation, explains a proportion of this variability in human liver. METHODS: UGT1A1 phenotypes, including UGT1A1 protein and bilirubin glucuronidation, and UGT1A1*28 genotype were determined using a human liver bank (n = 46). Methylation levels were quantified at 5 CpG sites associated with known transcription factor response elements in the UGT1A1 promoter and distal enhancer, as well as a CpG-rich island 1.5 kb further upstream. KEY FINDINGS: Individual CpG sites showed considerable methylation variability between livers, ranging from 10- to 29-fold variation with average methylation levels from 25 to 41%. Multivariate regression analysis identified *28/*28 genotype, -4 CpG site methylation and alcohol history as significant predictors of UGT1A1 protein content. Exclusion of livers with *28/*28 genotype or alcohol history revealed positive correlations of -4 CpG methylation with bilirubin glucuronidation (R = 0.73, P < 0.00001) and UGT1A1 protein content (R = 0.54, P = 0.008). CONCLUSION: These results suggest that differential methylation of the -4 CpG site located within a known USF response element may explain a proportion of interindividual variability in hepatic glucuronidation by UGT1A1. PMID- 23647682 TI - Aegle marmelos Correa leaf extract prevents secondary complications in streptozotocin-induced diabetic rats and demonstration of limonene as a potent antiglycating agent. AB - OBJECTIVES: To study the antiglycating, antidiabetic and antioxidant properties of Aegle marmelos Correa leaf extract and identify the bioactive constituent. METHODS: The effect of the chloroform extract of Aegle marmelos Correa was studied in streptozotocin-induced diabetic rats through evaluation of biochemical parameters. Antiglycation activity was assessed in vitro through measurement of total and specific advanced glycation end products, protein carbonyl formation and collagen solubility tests. Antioxidant potential was evaluated using the ferric-reducing antioxidant power assay and 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) assays. Identification of the bioactive component was attempted through silica gel column chromatography and GC-MS analysis. RESULTS: In-vivo studies for 60 days revealed that the extract prevented kidney damage and other secondary complications. The chloroform extract at 16 MUg could inhibit protein glycation by 44.33% and pentosidine formation by 59.31%, and could effectively inhibit protein carbonyl formation. It could scavenge DPPH radicals up to 85.26% (IC50: 26 MUg). Bio-guided fractionation revealed limonene as the bioactive component, which could account for the antiglycating activity shown by the chloroform extract. CONCLUSION: The chloroform extract of Aegle marmelos demonstrated antidiabetic antiglycating and antioxidant activity, effectively preventing kidney damage and establishment of cataracts. Limonene is reported for the first time as possessing potent antiglycating activity and is non-toxic at the concentration used. PMID- 23647683 TI - Anti-inflammatory effect of hexane fraction from Myagropsis myagroides ethanolic extract in lipopolysaccharide-stimulated BV-2 microglial cells. AB - OBJECTIVES: Microglial activation has been implicated in neurological disorders for its inflammatory and neurotrophic effects. We investigated the anti inflammatory effect of the hexane fraction from Myagropsis myagroides (Mertens ex Turner) Fensholt ethanolic extract and its underlying molecular mechanism in lipopolysaccharide-stimulated microglia. METHODS: Various solvent fractions prepared from the ethanolic extract of M. myagroides were analysed for total phenolic content, 2,2-diphenyl-1-picrylhydrazyl radical-scavenging activity and inhibitory effect on nitric oxide (NO) production in activated BV-2 microglia. We measured prostaglandin E2 (PGE2 ) and pro-inflammatory cytokine levels by enzyme linked immunosorbent assay. Expression of inflammatory enzymes was analysed by Western blot. Nuclear translocation and activation of nuclear factor-kappaB (NF kappaB) were determined by immunofluorescence and reporter gene assay, respectively. KEY FINDINGS: Among the fractions, the hexane fraction (MMH), rich in fatty acid, showed the highest inhibitory activity on NO generation. Pretreatment with MMH decreased mRNA and protein levels of inducible NO synthase and cyclooxygenase-2, resulting in a decrease in NO and PGE2 in LPS-stimulated BV 2 cells. Furthermore, MMH inhibited the production of inducible pro-inflammatory cytokines at their transcriptional level via inactivation of NF-kappaB. MMH inhibited the activation of extracellular signal-regulated kinase and c-Jun N terminal kinase. CONCLUSIONS: These results indicate that MMH has a strong anti inflammatory activity in LPS-stimulated microglia, suggesting that MMH can be used as a therapeutic agent against neuroinflammatory diseases. PMID- 23647684 TI - Downregulation of beta1 -adrenergic receptors in rat C6 glioblastoma cells by hyperforin and hyperoside from St John's wort. AB - OBJECTIVES: While the use of St John's wort extracts as treatment for mild to moderate depression is well established the mode of action is still under investigation. Individual constituents of St John's wort extract were tested for possible effects on the beta1 AR density and a subsequent change in downstream signalling in rat C6 glioblastoma cells. METHODS: The effect of compounds from St John's wort extract on the downregulation of beta1 -adrenergic receptor-GFP fusion proteins (beta1 AR-green fluorescent protein (GFP)) of transfected rat C6 gliobastoma cells (C6-beta1 AR-GFP) was investigated by means of confocal laser scanning microscopy (LSM). The influence on the lateral mobility of beta1 AR-GFP in C6-beta1 AR-GFP was investigated by fluorescence correlation spectroscopy. The formation of second messenger was determined by c-AMP-assay. KEY FINDINGS: Confocal LSM revealed that pretreatment of cells with 1 MUm of hyperforin and hyperoside for 6 days, respectively, led to an internalization of beta1 AR-GFP under non-stimulating conditions. Observation by fluorescence correlation spectroscopy showed two diffusion time constants for control cells, with taudiff1 = 0.78 +/- 0.18 ms and taudiff2 = 122.53 +/- 69.41 ms, similarly distributed. Pretreatment with 1 MUm hyperforin or 1 MUm hyperoside for 3 days did not alter the taudiff values but decreased the fraction of taudiff1 whereas the fraction of taudiff2 increased significantly. An elevated level of beta1 AR-GFP with hindered lateral mobility was in line with beta1 AR-GFP internalization induced by hyperforin and hyperoside, respectively. A reduced beta1 -adrenergic responsiveness was assumed for C6 gliobastoma cells after pretreatment for 6 days with 1 MUm of both hyperforin and hyperoside, which was confirmed by decreased cAMP formation of about 10% and 5% under non-stimulating conditions. Decrease in cAMP formation by 23% for hyperforin and 15% for hyperoside was more pronounced after stimulation with 10 MUm dobutamine for 30 min. CONCLUSIONS: The treatment of C6 gliobastoma cells with hyperforin and hyperoside results in a reduced beta1 AR density in the plasma membrane and a subsequent reduced downstream signalling. PMID- 23647685 TI - Hepatosteatosis and hepatic insulin resistance are blunted by argirein, an anti inflammatory agent, through normalizing endoplasmic reticulum stress and apoptosis in diabetic liver. AB - OBJECTIVES: Insulin resistance represents a mechanism underlying defect metabolism of carbohydrate and lipid linked to inflammatory reactions in diabetic liver. We hypothesized that the changes may be secondary to endoplasmic reticulum (ER) stress, which could be alleviated by either argirein or valsartan. METHODS: Hepatosteatosis in diabetic liver was induced in rats fed with a high-fat diet (HFD) for 12 weeks combined with a single low dose of streptozotocin (STZ 35 mg/kg, ip). Interventions (mg/kg/d, po)with either argirein (50, 100 and 200) or valsartan (12) were conducted in the last 4 weeks. KEY FINDINGS: In diabetic liver fat was significantly accumulated in association with elevated hepatic glucose, serum insulin and homeostasis model assessment of insulin resistance value. Downregulated glucose transporter 4, insulin receptor substrate-1 and leptin receptor (P < 0.01) were found relative to normal, where DNA ladder, downregulated B cell lymphoma/leukemia-2, upregulated B cell lymphoma/leukemia-2 Associated X protein and upregulated ER stress chaperones such as Bip/GRP78 (also known as Binding Protein, BiP), PKR-like ER kinase (PERK), p-PERK/PERK and C/EBP homologous protein were significant. These abnormalities were significantly ameliorated by argirein and valsartan. CONCLUSIONS: Hepatosteatosis induced by HFD/low STZ manifests insulin resistance and apoptosis, linked to an entity of low-grade inflammation due to activated ER stress sensors. With anti-inflammatory activity either argirein or valsartan blunts hepatosteatosis through normalizing ER stress and apoptosis in the diabetic liver. PMID- 23647687 TI - Intensive care and non-invasive mechanical ventilation in kyphoscoliosis: are new perspectives still needed? AB - Non-invasive ventilation (NIV) assists breathing and thus improves oxygenation in patients with Kyphoscoliosis. The benefits of short- and long-term intermittent nocturnal in such patients have been reported previously (improvement of vital capacity, total lung capacity, muscle strength, daytime oxygenation, exercise capacity, and pulmonary hypertension). We review this important study reporting patients with kyphoscoliosis and acute respiratory failure along with their long term outcomes. We believe that this letter may provide important information regarding the prognosis and efficacy of NIV. PMID- 23647686 TI - The positive inotropic effect of the ethyl acetate fraction from Erythrina velutina leaves on the mammalian myocardium: the role of adrenergic receptors. AB - OBJECTIVES: We studied the effects of ethyl acetate fraction (EAcF) obtained from Erythrina velutina leaves on mammalian myocardium. METHODS: The effect of EAcF on the contractility was studied using guinea-pig left atria mounted in a tissue bath (Tyrode's solution, 29 degrees C, 95% CO2 , 5% O2 ) and electrically stimulated (1 Hz). Concentration-response curves of EAcF were obtained in the presence of propranolol (1 MUm), nifedipine (1 MUm) and in reserpinized animals (5 mg/kg). The involvement of l-type calcium current (ICa,L ) on the EAcF effect was observed in cardiomyocytes of mice assessed using patch-clamp technique. KEY FINDINGS: EAcF (550 MUg/ml) had a positive inotropic effect, increasing the atrial force by 164% (EC50 = 157 +/- 44 MUg/ml, n = 6), but it was less potent than isoproterenol (EC50 = 0.0036 +/- 0.0019 MUg/ml, n = 8). The response evoked by EAcF was abolished by propranolol or nifedipine. Reserpine did not alter the inotropic response of EAcF. Furthermore, an enhancement of the ICa,L peak (31.2%) with EAcF was observed. Chemical analysis of EAcF revealed the presence of at least 10 different flavonoid glycoside derivatives. Two were identified as vicenin II and isorhoifolin. CONCLUSIONS: We conclude that EAcF increases the cardiac contractile force by increasing the l-type calcium current and activating the adrenergic receptor pathway. PMID- 23647689 TI - Improving pain practices through core competencies. PMID- 23647688 TI - Patient preferences for adherence to treatment for osteoarthritis: the MEdication Decisions in Osteoarthritis Study (MEDOS). AB - BACKGROUND: Often affecting knee joints, osteoarthritis (OA) is the most common type of arthritis and by 2020 is predicted to become the fourth leading cause of disability globally. Without cure, medication management is symptomatic, mostly with simple analgesics such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), and glucosamine sulfate. Adherence to arthritis medications is generally low. Intentional non-adherence, that is deliberate decision-making about the use of analgesics, occurs in OA patients. To date, a limited number of studies have explored medication-taking decisions in people with OA nor the extent to which individuals' trade off one treatment factor for another in their decision-making using quantitative techniques. This study aimed to estimate the relative influence of medication-related factors and respondent characteristics on decisions to continue medications among people with symptomatic OA. METHODS: A discrete choice experiment (DCE) was conducted among participants attending end of-study visits in the Long-term Evaluation of Glucosamine Sulfate (LEGS) study (ClinicalTrials.gov ID: NCT00513422). The paper-based survey was used to estimate the relative importance of seven medication specific factors (pain efficacy, mode of action, dose frequency, treatment schedule, side effects, prescription, and out-of-pocket costs) and respondent characteristics on decisions to continue medications. RESULTS: 188 (response rate 37%) completed surveys were returned. Four of the seven medication factors (side effects, out-of-pocket costs, mode of action, treatment schedule) had a significant effect on the choice to continue medication; patient characteristics did not. Assuming equivalent pain efficacy and disease-modifying properties for glucosamine, the positive relative likelihood of continuing with sustained-release acetaminophen was equivalent to glucosamine. By contrast, the negative relative likelihood of NSAID continuation was mostly driven by the side effect profile. The predicted probability of continuing with glucosamine decreased with increasing out-of-pocket costs. CONCLUSIONS: This study has characterised the complexity of medication-taking decisions that potentially underpin intentional non-adherent behaviour for people with symptomatic OA. In particular, medication risks and cost were important and ought to be borne into considerations in interpreting clinical trial evidence for practice. Ultimately addressing these factors may be the way forward to realising the full potential of health and economic benefits from the efficacious and safe use of OA medications. PMID- 23647690 TI - Presence of virulence genes, adhesion and invasion of Arcobacter butzleri. AB - AIMS: The pathogenic potential of Arcobacter butzleri isolates was investigated by detecting the presence of putative virulence genes and analysing the adhesive and invasive capabilities in cell cultures of human cell lines. METHODS AND RESULTS: The presence of ten putative virulence genes in 52 A. butzleri isolates was determined by PCR. The genes ciaB, mviN, pldA, tlyA, cj1349 and cadF were detected in all, whilst irgA (15%), iroE (60%), hecB (44%) and hecA (13%) were detected only in few A. butzleri isolates. On HT-29 cells, four of six isolates adhered to and three of them were able to invade, whilst all six isolates adhered to and invaded Caco-2 cells with higher degrees. The genes ciaB, cadF and cj1349 of all six isolates were sequenced, but no considerable changes of the amino acids in putative functional domains were observed. CONCLUSION: Selected A. butzleri isolates adhere to and invade HT-29 and Caco-2 cells, which emphasize their human pathogenic potential. The efficiency of invasion depends on the eukaryotic cell line and individual bacterial strain used. We could not show any functional correlation between the amino acid sequence of CadF, CiaB or Cj1349 and the adhesive and invasive phenotype. SIGNIFICANCE AND IMPACT OF THE STUDY: We have shown that some A. butzleri strains invade various cell lines. This underlines their pathogenic potential and hints at their relevance in human disease. PMID- 23647691 TI - Interaction forces between silica surfaces in cationic surfactant solutions: an atomic force microscopy study. AB - The interaction forces between silicon oxide surfaces in the presence of surfactant solutions were studied. Based on the qualitative and quantitative analysis of these interaction forces the correlation with the structure of the aggregates on the surfaces is analyzed. A colloidal probe atomic force microscope (AFM) was used to measure the forces between two colloidal silica particles and between a colloidal particle and a silicon wafer in the presence of hexadecyltrimethylammonium bromide (CTAB) at concentrations between 0.005 mM and 1.2 mM. Different interaction forces were obtained for the silica particle-silica particle system when compared to those for the silica particle-silicon wafer system for the same studied concentration. This indicates that the silica particles and the silicon wafer have different aggregate morphologies on their surfaces. The point of zero charge (pzc) was obtained at 0.05 mM CTAB concentration for the silica particles and at 0.3mM for the silica particle silicon wafer system. This indicates a higher charge at the silicon wafer than at the silica particles. The observed long range attractions are explained by nanobubbles present at the silicon oxide surfaces and/or by attractive electrostatic interactions between the surfaces, induced by oppositely charged patches at the opposing Si oxide surfaces. PMID- 23647692 TI - Nanomechanics of surface DNA switches probed by captive contact angle. AB - Self-assembled monolayers of Thrombin Binding Aptamers (TBA) were prepared on gold surfaces with typical surface densities of close-packed ssDNA (4*10(12) and 8*10(12)molecules/cm(2)). CONtact Angle MOlecular REcognition (CONAMORE) in captive bubble geometry was then assessed to scan the surface work triggered by TBAs when switching from the elongated to the G-quadruplex conformation upon binding with Na(+) or K(+) cations. We found Na(+) and K(+) could induce comparable linear to G-quadruplex strokes, and resulted in values for surface work of ~-70 pN nm/molecule (~18 kBT). The strokes change the in-plane van der Waals and weak electrostatic interactions and accumulate to result in macroscopic surface work. Micro- to macroscopic translation strongly depends on the nature of the cation and TBA surface density. In particular, the K(+) stimulus triggers a macroscopic surface work of -2.2+/-0.2 and -5.3+/-0.2 mN/m for low and high packed monolayers, respectively, while Na(+) triggers up to -6.7+/-1.0 mN/m in the highly packed monolayer, but creates negligible work for the low packed monolayer. These results show that CONAMORE can contribute important information for the development of devices based on DNA switches, and ultimately help address some of the open challenges for DNA-based nanomachinery. PMID- 23647693 TI - Recent advances in designing superhydrophobic surfaces. AB - The interest in superhydrophobic surfaces has grown exponentially over recent decades. Since the lotus leaf dual hierarchical structure was discovered, researchers have investigated the foundations of self-cleaning behavior. Generally, surface micro/nanostructuring combined with low surface energy of materials leads to extreme anti-wetting properties. The great number of papers on this subject attests the efforts of scientists in mimicking nature to generate superhydrophobicity. Besides the thirst for knowledge, scientists have been driven by the many possible industrial applications of superhydrophobic materials in several fields. Many methods and techniques have been developed to fabricate superhydrophobic surfaces, and the aim of this paper is to review the recent progresses in preparing manmade superhydrophobic surfaces. PMID- 23647694 TI - Construction of efficient CdS-TiO2 heterojunction for enhanced photocurrent, photostability, and photoelectron lifetimes. AB - The photoefficiency of CdS/TiO2 electrodes can be enhanced by employing efficient method of CdS sensitization from which, the contact area, thickness of CdS layer, and the recombination of photoelectrons with electrolyte can be controlled. Here, we demonstrate a simple solvothermal approach of CdS quantum dots (QDs) sensitization on TiO2 nanoparticle (NP) film coated on FTO. Our new approach prevents the clogging of CdS QDs and promotes uniform deposition of QDs throughout the mesoporous TiO2 NP film. The sensitization of CdS can be controlled by the reaction time and the concentration of the precursors. The solvothermally sensitized photoanodes exhibit enhanced photocurrents and fill factors and improved photostability in aqueous solution compared to the one prepared by a conventional SILAR method. Open-circuit potential decay measurement under shutting off illumination shows that the lifetime of photoelectron is extended with solvothermally prepared CdS layer, indicating efficient suppression of recombination of the accumulated electron in TiO2 to the electrolyte. This methodology can be applied in making more efficient heterojunctions consisting of CdS and other wide band gap oxide semiconductors which could improve charge separation and mitigate charge recombination for photoelectrochemical applications. PMID- 23647695 TI - [Antioxidant and anti-inflammatory activities of Moroccan Erica arborea L]. AB - AIM: The present study was carried out to evaluate the antioxidant and anti inflammatory capacity, and acute toxicity of Moroccan Erica arborea leaves. METHODS: Antioxidant capacity was assessed by diphenyle-picryl-hydrazyl (DPPH), phosphomolybdate (PPM) and ferric reducing antioxidant power (FRAP) tests and anti-inflammatory capacity was evaluated by hind paw oedema model using carrageenan-induced inflammation in rat. The acute toxicity was evaluated using mice. RESULTS: Acute toxicity of ethanolic extract of E. arborea showed no sign of toxicity at dose of 5 g/kg B.W. Our extracts have important antioxidant properties. The efficient concentration of the ethanolic extract (10.22 MUg/ml) required for decreasing initial DPPH concentration by 50% was comparable to that of standard solution butyl-hydroxy-toluene (BHT) (8.87 MUg/ml). The administration of ethanolic extract at doses of 200 and 400mg/kg B.W. was able to prevent plantar oedema and exhibited a significant inhibition against carrageenan induced inflammation when compared to the control group (NaCl 0.9%) but comparable to those of diclofenac (reference drug). CONCLUSIONS: Our results show that the leaves of E. arborea may contain some bioactive compounds which are responsible for the antioxidant and anti-inflammatory activities observed here. Our finding may indicate the possibility of using the extracts of this plant to prevent the antioxidant and inflammatory processes. PMID- 23647696 TI - [Potential role of the angiogenic factor "EG-VEGF" in gestational trophoblastic diseases]. AB - Gestational trophoblastic disease (MGT) includes a wide spectrum of pathologies of the placenta, ranging from benign precancerous lesions, with gestational trophoblastic tumors. Metastases are the leading causes of death as a result of this tumor. They represent a major problem for obstetrics and for the public health system. To date, there is no predictor of the progression of molar pregnancies to gestational trophoblastic tumor (GTT). Only an unfavorable plasma hCG monitoring after evacuation of hydatidiform mole is used to diagnose a TTG. The causes of the development of this cancer are still poorly understood. Increasing data in the literature suggests a close association between the development of this tumor and poor placental vascularization during the first trimester of pregnancy. The development of the human placenta depends on a coordination between the trophoblast and endothelial cells. A disruption in the expression of angiogenic factors could contribute to uterine or extra-uterine tissue invasion by extravillous trophoblast, contributing to the development of TTG. This review sheds lights on the phenomenon of angiogenesis during normal and abnormal placentation, especially during the MGT and reports preliminary finding concerning, the variability of expression of "Endocrine Gland-Derived Vascular Endothelial Growth Factor" (EG-VEGF), a specific placental angiogenic factor, in normal and molar placentas, and the potential role of differentiated expressions of the main placental angiogenic factors in the scalability of hydatidiform moles towards a recovery or towards the development of gestational trophoblastic tumor. Deciphering the mechanisms by which the angiogenic factor influences these processes will help understand the pathophysiology of MGT and to create opportunities for early diagnosis and treatment of the latter. PMID- 23647697 TI - The therapeutic role of oral tolerance in dextran sulfate sodium-induced colitis via Th1-Th2 balance and gammadelta T cells. AB - OBJECTIVE: To evaluate the state of oral tolerance and its therapeutic role in mice with dextran sulfate sodium (DSS)-induced colitis. METHODS: Delayed-type hypersensitivity (DTH) was determined 7 and 14 days after DSS-induced colitis and control mice. Disease activity index (DAI) score and colonic histopathological score were measured 7 days after colonic extracted protein (CEP) or bovine serum albumin (BSA) (control) was administrated, with the evaluation of Th1-Th2 balance in the spleen, Peyer's patch and gammadelta T cells in intraepithelial lymphocytes and lamina proper lymphocytes in the intestine. RESULTS: After fed with 250 MUg ovalbumin oral tolerance was induced in 7 days in both DSS-induced colitis and control mice, while oral tolerance persisted in the control mice but vanished in DSS-induced colitis 14 days after ovalbumin challenge. DAI and colonic histopathological scores were decreased significantly after the ingestion of CEP (controlled by BSA) in DSS-induced colitis with significant reduction of Th1 and the ratio of Th1 to Th2 in Peyer's patch as well as the gammadelta T cells in lamina proper lymphocytes in the intestine. No significant difference in Th1-Th2 balance in the spleen and gammadelta T cells in intraepithelial lymphocytes in the intestine were observed. CONCLUSIONS: There is a defect in oral tolerance at day 7 in DSS-induced colitis. If taken orally, CEP may have a protective role in DSS-induced colitis, which may be related to the deflection from Th1 to Th2 in Peyer's patch and the reduction of gammadelta T cells in lamina proper lymphocytes in the intestine. PMID- 23647698 TI - Marker-free genetic engineering of the chloroplast in the green microalga Chlamydomonas reinhardtii. AB - The work applied a transgene expression method based on the replacement of an inactive rbcL gene as the selection marker in Chlamydomonas reinhardtii chloroplasts. The native rbcL gene in strain CC2653 has a point mutation that causes early translation termination, thus resulting in a photosynthesis mutant. Recovery of rbcL function for selection is offered along with the heterologous expression of the alcohol dehydrogenase ADH1 gene from Saccharomyces cerevisiae in the Chlamydomonas chloroplast. The CrCpADH1 gene was inserted via double homologous recombination in the psaB-rbcL chloroplast intergenic region of recipient strain CC2653, using the psaB and rbcL gene sequences for the double homologous recombination. This transformation conferred a functional rbcL gene and expression of the CrCpADH1 transgene in the recipient strain. This method alleviated the need to use antibiotics for selection, resulting in a negligible number of false positives during screening, and attaining a transformation efficiency greater than 90%. The approach also ensured segregation of chloroplast DNA copies, so as to achieve homoplasmy of the transformant chloroplast DNA, with a concomitant elimination of recipient strain Cp DNA. High levels of steady-state CrCpADH1 transcripts were detected in the homoplasmic transformants. However, CrCpADH1 protein levels were attenuated under continuous illumination growth conditions due to oxygen accumulation in the cells. Under conditions of low oxygen partial pressure, or anoxia, accumulation of CrCpADH1 protein in the cells and ethanol in the growth medium was observed. A metabolic pathway for ethanol production is proposed in Chlamydomonas, mediated by the chloroplast-localized CrCpADH1 transgenic enzyme. PMID- 23647699 TI - Graduated driver license nighttime compliance in U.S. teen drivers involved in fatal motor vehicle crashes. AB - BACKGROUND: Examination of teen driver compliance with graduated driver licensing (GDL) laws could be instrumental in identifying factors associated with persistently high motor vehicle mortality rates. METHODS: Fatality analysis reporting system (FARS) data from the years 2006 to 2009 were used in this nation wide cross-sectional study of drivers covered by a state nighttime GDL law (n=3492). A new definition of weekend, based on the school night in relation to the teenage social landscape, redefined Friday night as a weekend night and Sunday night as a weekday/school night and compared it to previous weekend definitions. Multiple logistic regression was used to examine independent effects of demographic, behavioral, environmental, contextual, and other factors on compliance with nighttime GDL laws. All analyses were performed in Stata version 11. RESULTS: Given coverage under nighttime GDL laws, drivers aged 15-17 years were non-compliant in 14.9% of the fatal MVCs in which they were involved, and nearly one-fifth (18.8%) of all fatalities aged 15-17 years were associated with non-compliance. Mortality risk was 10% higher using a revised social (school night) versus traditional (Sat-Sun) weekend definitions. In multivariable analysis, drivers non-compliant with nighttime GDL laws were more likely to be drinking (OR=4.97, 3.85-6.40), unbelted (OR=1.58, 1.25-1.99), driving on the weekend (OR=1.82, 1.47-2.24), and killed (OR=1.31, 1.04-1.65). CONCLUSION: GDL non-compliance contributes to teen motor vehicle mortality. Legislative and enforcement efforts targeting non-school night driving, seatbelt nonuse and alcohol have potential to further reduce teen driving mortality. PMID- 23647700 TI - Paediatric spinal fusion surgery and the transition to home-based care: provider expectations and carer experiences. AB - There are more than 12 million children with special healthcare needs (CSHCNs) in the United States, many of whom require specialised health-care to treat chronic physical and developmental conditions. This study is a qualitative investigation of programme, surgical and at-home recovery experiences among CSHCNs and their family carers who participated in a spine surgical care programme at a paediatric hospital in the Western United States. The programme is designed to manage increased surgical risk and the transition of care from hospital to home for children with severe scoliosis undergoing spinal fusion surgery. We conducted 30 semi-structured in-depth interviews with 14 surgical team members and 16 family carers of children who had programme evaluations and spinal surgeries in 2006. Data were collected in 2008 and 2009 in hospital or at home locations to gather programme participation feedback from families and inform the adequacy of programme support to families during at-home recovery. Data were analysed by reflexive team and content analysis methodologies. Results showed the programme was effective at improving preoperative surgical evaluation and helping families to anticipate some aspects of the surgical experience and hospital discharge. However, the impact of spinal fusion surgery and the subsequent transition to home-based care was profoundly emotional for patients and their carers. Our data indicate that programme providers underestimated the extent of emotional trauma experienced by patients and families, particularly during the at-home recovery process. The data also suggest meaningful differences in providers' and carers' expectations for surgery. Carers' disappointment with their recovery experiences and the perceived lack of post-discharge support impacted their interpretations of and perspectives on their surgical experience. Implications of this research for surgical care programmes include the need for assessment and provision of support for physical, social, and emotional burdens experienced by patients and carers at pre-surgical, surgical and at-home recovery phases. PMID- 23647701 TI - Neurologist consistency in interpreting information provided by an interactive visualization software for deep brain stimulation postoperative programming assistance. AB - INTRODUCTION: Postoperative programming in deep brain stimulation (DBS) therapy for movement disorders can be challenging and time consuming. Providing the neurologist with tools to visualize the electrode location relative to the patient's anatomy along with models of tissue activation and statistical data can therefore be very helpful. In this study, we evaluate the consistency between neurologists in interpreting and using such information provided by our DBS programming assistance software. METHODS: Five neurologists experienced in DBS programming were each given a dataset of 29 leads implanted in 17 patients. For each patient, probabilistic maps of stimulation response, anatomical images, models of tissue activation volumes, and electrode positions were presented inside a software framework called CRAnialVault Explorer (CRAVE) developed in house. Consistency between neurologists in optimal contact selection using the software was measured. RESULTS: With only the efficacy map, the average consistency among the five neurologists with respect to the mode and mean of their selections was 97% and 95%, respectively, while these numbers were 93% and 89%, respectively, when both efficacy and an adverse effect map were used simultaneously. Fleiss' kappa statistic also showed very strong agreement among the neurologists (0.87 when using one map and 0.72 when using two maps). CONCLUSION: Our five neurologists demonstrated high consistency in interpreting information provided by the CRAVE interactive visualization software for DBS postoperative programming assistance. Three of our five neurologists had no prior experience with the software, which suggests that the software has a short learning curve and contact selection is not dependent on familiarity with the program tools. PMID- 23647702 TI - Reducing risk in maternity by optimising teamwork and leadership: an evidence based approach to save mothers and babies. AB - Poor teamwork results in preventable morbidity and mortality for mothers and babies. Suboptimal communication and lack of leadership cost not only lives but also money that is diverted from clinical care to insurance and litigation. Avoidable harm is usually not the result of staff failing their duty of care, it is the result of poor training failing hard-worked staff. A few simple teamwork and leadership behaviours can make a huge difference to outcome and experience for women and their companions, yet they are often missing from maternity care. Recent research has identified the problems and solutions, including the best way to train maternity teams to make a palpable difference. We describe simple yet evidence-based methods to improve teams and leaders. PMID- 23647703 TI - Surgical impact of an inferior right hepatic vein on right anterior sectionectomy and right posterior sectionectomy. AB - BACKGROUND: In hepatocellular carcinoma, anatomical resection is important because of portal spread. In right anterior sectionectomy (RAS) and right posterior sectionectomy (RPS), the right hepatic vein (RHV) may not correspond with the intersectional plane if an inferior RHV (IRHV) is present. The aim of this study was to evaluate the influence of the IRHV on the exposure of the RHV retrospectively. METHODS: One hundred ninety-one patients underwent RAS or RPS by the Glissonean pedicle transection method. The calibres of the RHV and IRHV were measured and assessed the extent of exposure of RHV. RESULTS: One hundred seventeen patients underwent RAS and 74 underwent RPS. The calibre of the RHV averaged 8.0 mm and that of the IRHV, 6.2 mm. Exposure of the RHV was divided into three groups: no exposure 31 (16.2%) (with IRHV, 20 patients; without IRHV, 11 patients), upper half exposure 49 (25.7%; with IRHV, 24; without IRHV, 25) and full exposure 111 (58.1%) (with IRHV, 16; without IRHV, 95). The effect of the IRHV on exposure of the RHV was substantial (P < 0.001). CONCLUSIONS: The IRHV can affect the course of the RHV and its exposure. Therefore, in RAS and RPS, it is important to evaluate the existence of the IRHV. PMID- 23647704 TI - Results from a large multinational clinical trial (guardianTM1) using prophylactic treatment with turoctocog alfa in adolescent and adult patients with severe haemophilia A: safety and efficacy. AB - Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open-label, non controlled trial investigated the safety and efficacy of turoctocog alfa, a new rFVIII product. The primary objective was to evaluate safety. A total of 150 patients (24 adolescents and 126 adults) with severe haemophilia A (FVIII activity <= 1%), with at least 150 exposure days (EDs) to any FVIII product and no history of inhibitors were enrolled, and 146 patients (97%) completed the trial. All patients received prophylaxis with turoctocog alfa for approximately 6 months and had a mean of 85 EDs during the trial. None of the patients developed FVIII inhibitors, there were no indications of early FVIII inhibitor development and no safety concerns were identified. A total of 225 adverse events were reported in 100 (67%) patients, with the most common being events associated with dosing procedures, headaches, and nasopharyngitis. A total of 499 bleeding episodes were reported during the trial, the majority (89%) were controlled with 1-2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as 'excellent' or 'good' haemostatic response) for treatment of bleeding episodes was 81%. The overall median annualized bleeding rate was 3.7 (interquartile range: 8.7) bleeds/patient/year. In conclusion, turoctocog alfa provides a new, safe and effective alternative for prophylaxis and treatment of bleeding episodes in patients with haemophilia A. PMID- 23647705 TI - Predicting the effect of anthelmintic treatment on milk production of dairy cattle in Canada using an Ostertagia ostertagi ELISA from individual milk samples. AB - Gastrointestinal nematodes, such as Ostertagia ostertagi and several species of Cooperia, are ubiquitous in temperate climates and have been shown to have detrimental effects on production in adult dairy cattle. A published meta analysis demonstrated that overall, producers lose approximately 0.35 kg of milk per parasitized cow per day. Enzyme-linked immunosorbent assays (ELISAs) have the ability to quantify nematode infections in cattle, and thus, could be used to estimate the amount of milk production loss due to differing levels of parasitism at the individual cow level. ELISA results from individual cow milk samples were used to predict milk production response following a randomized anthelmintic treatment in a large field trial. To increase statistical power, the data collected from this field trial was pooled with data from two other published field trials to form an individual patient data meta-analysis (IPDMA). The ability to predict the effect of anthelmintic treatment on milk production depends on the level of parasitism quantified by an ELISA measuring milk antibodies against O. ostertagi, and reported as optical density ratios (ODRs). Therefore, the estimates from the interaction between ODR and treatment on milk production were used to determine how well the ODR predicted the response of the treatment. It was anticipated that the relationship between milk production and ODR was unlikely to be linear, so fractional polynomials were applied to the continuous ODR values. The interaction in the field trial showed a trend (p=0.138) toward a beneficial treatment effect when the individual ODR values, measured in late lactation and using Svanovir((r)), were greater than 0.12. When individual data from two other similar studies were included in an IPDMA, the interaction terms became statistically significant (p=0.009) indicating that there is a beneficial treatment effect when ODR values are slightly elevated. A graph was used to demonstrate the treatment effect (the estimated difference of kg/cow/day of milk yield between the treated and placebo cows), with 95% confidence intervals, as the ODR values increase. It is important to note that the methods of quantifying the ODR values differed between the three studies in the IPDMA, therefore some caution should be used when using these final estimated values. However, the shape and magnitude of the treatment effects, as well as the other fixed model estimates, were very similar between the field trial and the IPDMA suggesting that any bias would likely be minimal. PMID- 23647706 TI - The Munich Anatomical Institute under National Socialism. First results and prospective tasks of an ongoing research project. AB - While research into the history of German anatomy under National Socialist rule has increased during the last decade, the story of one of the most important anatomical institutes of the time, the Anatomische Anstalt Munich, has not yet been explored. This study presents the results of an ongoing, cooperative research project at the universities of Halle and Munich and focuses on the history of the institution, its personnel and organization, and its interactions with the National Socialist regime. It reveals continuity and disruption within the institute following Munich anatomists' involvement with the regime's policies and ideology as well as their becoming victims to these policies. Also documented is the manner in which the Munich anatomy benefited from the massive increase in executions, especially during the Second World War, by receiving and using the bodies of prisoners executed at the Stadelheim prison in Munich for scientific purposes. Finally, an outlook is presented regarding planned research aiming to fully understand the history of the Anatomische Anstalt during National Socialism. PMID- 23647707 TI - Early infantile cardiomyopathy and liver disease: a multisystemic disorder caused by congenital lipodystrophy. AB - Congenital generalized lipodystrophy is a rare inherited multisystemic disorder associated with disturbances of adipocyte functions. We report a young boy presenting at age 1 month with liver disease and severe hypertrophic cardiomyopathy. Despite this multisystemic involvement and contrasting with a cachectic appearance, the anthropometric parameters showed marked overgrowth (+4 DS), leading to diagnosis of congenital lipodystrophy, which was confirmed by the presence of the new homozygous c.259C>T (p.Gln87*) mutation in the AGPAT2 gene. Early infantile cardiomyopathy should be considered as a specific endophenotype in Berardinelli-Seip Congenital Lipodystrophy syndrome. PMID- 23647708 TI - Palatal tremor as a manifestation of epilepsia partialis continua caused by acute precentral gyral infarction. AB - We describe a patient with palatal tremor (PT) as a manifestation of focal seizure caused by acute cortical infarction. Brain MRI showed acute infarction in the left precentral gyrus without evidence of brainstem lesions or hypertrophy of the inferior olivary nucleus. We discuss the differences between our patient and previous reports of symptomatic PT and the mechanisms involved in the development of PT associated with cortical lesions. PMID- 23647709 TI - Methotrexate-induced myelopathy mimicking subacute combined degeneration of the spinal cord. AB - Methotrexate (MTX), a folate antagonist, is widely used to treat hematological malignancies. Although it is known to cause myelopathy, little is known about the pathophysiology and natural history of this myelopathy. We describe a 42-year-old woman with acute lymphoblastic leukemia who was treated with chemotherapy consisting of intrathecal MTX who developed a progressive myelopathy. The myelopathy mimicked, radiologically, subacute combined degeneration (SACD) of the spinal cord. This myelopathy mimicking SACD could be explained by the folate antagonism of MTX. The progressive clinical signs and serial MRI in this patient further our understanding of the natural progression of this myelopathy. PMID- 23647710 TI - Percutaneous kyphoplasty in the treatment of painful osteoblastic metastatic spinal lesions. AB - Percutaneous kyphoplasty (PKP) represents a powerful tool in the management of oncology patients who suffer from painful osteolytic spinal lesions, due to the minimally invasive nature of the procedure. However, there have been few reports on the role of PKP in the treatment of osteoblastic metastatic spinal lesions. We report our experience of the treatment of six patients with painful osteoblastic metastatic spinal lesions using PKP. Immediate relief of pain and improvement of functional status were achieved in all of them without PKP-related complications, which may encourage more studies of PKP in the palliative treatment of patients with painful osteoblastic metastatic spinal lesions. PMID- 23647711 TI - Observational research: an integral part of enhancing diabetes management in south-east Asia. PMID- 23647712 TI - Safety and effectiveness of insulin detemir in type 2 diabetes: results from the ASEAN cohort of the A1chieve study. AB - AIM: To determine the safety and effectiveness of insulin detemir (IDet) in type 2 diabetes patients from the ASEAN cohort of the A1chieve study. METHODS: Patients from Indonesia, Malaysia, Philippines and Singapore prescribed IDet at the discretion of their physicians were included. The primary outcome was the incidence of serious adverse drug reactions including major hypoglycaemia over 24 weeks. Secondary endpoints included changes in the frequency of hypoglycaemia, serious adverse events and effectiveness assessments. RESULTS: This sub-analysis included 1540 patients (insulin-naive, 1239; insulin-experienced, 301) with mean age +/- SD 56.4 +/- 10.9 years, BMI 25.4 +/- 4.6 kg/m(2) and diabetes duration 6.9 +/- 5.3 years. Insulin-naive patients received a baseline IDet dose of 0.24 +/- 0.11 U/kg titrated up to 0.37 +/- 0.21 U/kg by Week 24. The pre-study insulin dose in insulin-experienced patients was 0.41 +/- 0.25 U/kg and baseline IDet dose was 0.31 +/- 0.24 U/kg titrated up to 0.40 +/- 0.20 U/kg by Week 24. Overall hypoglycaemia decreased from 1.73 to 0.46 events/patient-year from baseline to Week 24 (change in proportion of patients affected, p < 0.0001). At Week 24, 1 major hypoglycaemic event was reported in 1 insulin-experienced patient. IDet significantly improved glucose control (p < 0.001) at Week 24. The lipid profile and systolic blood pressure improved (p < 0.001) and body weight did not change significantly. Quality of life was positively impacted (p < 0.001). CONCLUSION: IDet was well-tolerated and improved glycaemic control without increasing the risk of hypoglycaemia or weight gain. PMID- 23647713 TI - Safety and effectiveness of insulin aspart in type 2 diabetic patients: results from the ASEAN cohort of the A1chieve study. AB - AIM: To examine the clinical safety and effectiveness of insulin aspart (IAsp) therapy in type 2 diabetes (T2D) patients from the ASEAN cohort of the international, 24-week, non-interventional A1chieve study. METHODS: T2D patients from Indonesia, Malaysia, Philippines and Singapore, who started IAsp therapy with or without oral glucose-lowering drugs, were included. The primary endpoint was the incidence of serious adverse drug reactions (SADRs), including major hypoglycaemic events. Secondary endpoints included hypoglycaemia, glycated haemoglobin A1c [HbA1c], fasting plasma glucose [FPG], postprandial plasma glucose [PPPG], systolic blood pressure [SBP], body weight and lipids. Quality of life (QoL) was assessed using the EQ-5D questionnaire. RESULTS: Overall, 312 T2D patients (222 insulin-naive and 90 insulin-experienced) with a mean +/- SD age of 56.6 +/- 11.2 years, BMI of 24.2 +/- 3.9 kg/m(2) and diabetes duration of 7.0 +/- 5.7 years were included. The mean daily IAsp dose was 0.51 +/- 0.31 U/kg at baseline titrated up to 0.60 +/- 0.29 U/kg at Week 24. No SADRs or major hypoglycaemic events were reported in the entire subgroup. The proportion of patients who reported overall hypoglycaemia decreased from baseline to Week 24 (7.1% vs. 0.3%, p < 0.0001). The mean HbA1c improved from 9.5 +/- 1.6% at baseline to 7.6 +/- 1.3% after 24 weeks (p < 0.001). The mean FPG, post-breakfast PPPG and SBP also improved (p < 0.001). Health-related QoL scores increased in the entire subgroup (mean increase: 9.8 +/- 14.6 points, p < 0.001). CONCLUSIONS: Starting IAsp therapy was well-tolerated and was associated with significantly improved overall glycaemic control in the ASEAN cohort. PMID- 23647714 TI - Switching from biphasic human insulin to biphasic insulin aspart 30 in type 2 diabetes: results from the ASEAN subgroup of the A1chieve study. AB - AIM: To evaluate the safety and effectiveness of biphasic insulin aspart 30 (BIAsp 30) in ASEAN type 2 diabetes (T2D) patients switched from biphasic human insulin (BHI) in the non-interventional 24-week A1chieve study. METHODS: Indonesian, Malaysian, Filipino and Singaporean patients switched from BHI to BIAsp 30 at their physicians' discretion were included. The incidence of serious adverse drug reactions (SADRs), including major hypoglycaemia was the primary endpoint. Changes in hypoglycaemia, glycated haemoglobin A1c (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), lipids, body weight and systolic blood pressure were also evaluated. Quality of life (QoL) was measured using the EQ-5D questionnaire. RESULTS: For the 465 patients included (mean +/- SD age: 56 +/- 10.3 years, diabetes duration: 9.7 +/- 7.1 years, baseline HbA1c: 9.4 +/- 1.8%), the mean pre-study BHI dose was 0.62 +/- 0.28 IU/kg and 63.4% were dosing BHI twice daily (bid). The mean baseline BIAsp 30 dose was 0.65 +/- 0.27 U/kg, titrated up to 0.71 +/- 0.28 U/kg over 24 weeks, and most patients continued bid dosing. No SADRs or major hypoglycaemic episodes were reported. The proportion of patients reporting overall hypoglycaemia decreased significantly from 10.8% at baseline to 3.4% at Week 24 (p < 0.0001). Significant improvements in glycaemic control were noted (HbA1c: -1.4 +/- 1.7%, FPG: -56.7 +/- 72.5 mg/dL, post-breakfast PPPG: -84.8 +/- 82.8 mg/dL, p < 0.001). Mean QoL improved by +6.6 +/- 14.6 points (p < 0.001). CONCLUSION: BIAsp 30 was well-tolerated and significantly increased glycaemic control in this ASEAN subgroup poorly controlled on BHI. PMID- 23647715 TI - Safety and effectiveness of biphasic insulin aspart 30 in type 2 diabetes: results from the ASEAN cohort of the A1chieve study. AB - AIM: To determine the safety and effectiveness of biphasic insulin aspart 30 (BIAsp 30) in the ASEAN cohort of the A1chieve study. METHODS: Type 2 diabetes patients from Indonesia, Malaysia, Philippines and Singapore prescribed BIAsp 30 therapy were included. The primary outcome was evaluation of serious adverse drug reactions including major hypoglycaemia over 24 weeks. Secondary outcomes were changes in hypoglycaemic events, serious adverse events (SAEs) and effectiveness parameters. RESULTS: This sub-analysis included 2798 patients (insulin-naive, 1903; insulin-experienced, 895) with mean age +/- SD, 55.3 +/- 10.8 years, BMI, 24.9 +/- 4.6 kg/m(2) and diabetes duration, 7.5 +/- 5.9 years. Baseline HbA1c in the entire cohort was poor (9.9%, 85 mmol/mol). A total of 15 SAEs were reported in 7 insulin-experienced patients (1 moderate event was related to BIAsp 30). Overall hypoglycaemia at Week 24 was 0.88 events/patient-year compared to 1.71 events/patient-year reported at baseline (change in proportion of patients affected, p < 0.0001). No major hypoglycaemia was reported at Week 24. BIAsp 30 significantly improved glucose control (HbA1c, fasting plasma glucose and postprandial plasma glucose, p < 0.001) at Week 24. The proportion of patients achieving HbA1c <7.0% at Week 24 was 35.3% compared to 3.5% at baseline. The lipid profile and systolic blood pressure also improved significantly (p < 0.001). Quality of life was positively impacted (mean change in visual analogue scores from EQ-5D = 10.6 +/- 13.8 points, p < 0.001). CONCLUSION: BIAsp 30 was well-tolerated and improved glucose control while decreasing the risk of hypoglycaemia. PMID- 23647716 TI - Safety and effectiveness of biphasic insulin aspart 30 in a Bangladeshi subgroup of type 2 diabetic patients switched from biphasic human insulin 30: a sub analysis of the A1chieve study. AB - AIM: To determine the safety and effectiveness of biphasic insulin aspart 30 (BIAsp 30) therapy in Bangladeshi type 2 diabetes (T2D) patients switched from biphasic human insulin (BHI) as a sub-analysis of the A1chieve study. METHODS: Bangladeshi patients switched from BHI to BIAsp 30 at the discretion of their physicians were included. The primary outcome was the incidence of serious adverse drug reactions (SADRs), including major hypoglycaemia. Secondary outcomes comprised changes from baseline to Week 24 in the number of hypoglycaemic events, glycated haemoglobin A1c (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), systolic blood pressure and body weight. Quality of life (QoL) was evaluated at baseline and Week 24 using the EQ-5D questionnaire. RESULTS: A total of 82 patients (mean age +/- SD: 52.3 +/- 12.2 years; body mass index: 25.6 +/- 3.3 kg/m(2)) with a mean diabetes duration of 9.5 +/- 5.5 years and mean duration on insulin of 2.5 +/- 2.4 years were included. The mean BIAsp 30 dose was 0.49 +/- 0.20 U/kg at baseline and 0.47 +/- 0.17 U/kg at Week 24. No SADRs were reported. No events of hypoglycaemia (overall, major, minor or nocturnal) were reported at Week 24. Mean HbA1c, FPG and PPPG levels improved by 2.5 +/- 1.3%, -65.0 +/- 31.8 mg/dL and -119.3 +/- 48.7 mg/dL, respectively, over 24 weeks. QoL also improved (mean change from baseline: +28.5 +/- 12.9 points). CONCLUSION: Switching from BHI to BIAsp 30 therapy improved blood glucose control and was well-tolerated in this Bangladeshi subgroup. PMID- 23647717 TI - Safety and effectiveness of biphasic insulin aspart 30 in type 2 diabetes patients switched from biphasic human insulin 30: results from the Filipino cohort of the A1chieve study. AB - AIM: To evaluate the safety and effectiveness of biphasic insulin aspart 30 (BIAsp 30) in Filipino patients with type 2 diabetes previously treated with biphasic human insulin 30 (BHI 30). METHODS: Safety and effectiveness outcomes were measured in all patients switching from BHI 30 to BIAsp 30 in the Filipino cohort of the 24-week, multinational, prospective, non-interventional A1chieve study. RESULTS: A total of 111 Filipino patients (mean age +/- SD, 57.4 +/- 12.8 years; BMI, 25.8 +/- 5.6 kg/m(2)) with mean diabetes duration of 9.9 +/- 7.1 years switched therapy from BHI 30 to BIAsp 30. The mean pre-study BHI 30 dose was 0.65 +/- 0.28 IU/kg and the baseline BIAsp 30 dose was 0.65 +/- 0.26 U/kg titrated up to 0.70 +/- 0.26 U/kg by Week 24. No serious adverse drug reactions were reported. Overall hypoglycaemia was reduced from 5.62 to 1.98 events/patient year. Minor and nocturnal hypoglycaemia decreased and no major hypoglycaemia was reported at Week 24. Glucose control improved from baseline to Week 24 (HbA1c, 2.2 +/- 2.1% [24 +/- 23 mmol/mol]; FPG, -72.0 +/- 71.8 mg/dL; PPPG, -145.5 +/- 125.4 mg/dL). A total of 24 patients achieved HbA1c levels <7.0% at Week 24 compared to 6 patients reporting this target at baseline. Quality of life was positively impacted at Week 24 (change in visual analogue scores, 15.3 +/- 16.9 points). CONCLUSION: Switching from BHI 30 to BIAsp 30 improved glycaemic control without increasing the risk of hypoglycaemia. PMID- 23647718 TI - Clinical safety and effectiveness of biphasic insulin aspart 30 in type 2 diabetes patients switched from biphasic human insulin 30: results from the Indonesian cohort of the A1chieve study. AB - AIM: To evaluate the safety and effectiveness of biphasic insulin aspart 30 (BIAsp 30) in Indonesian type 2 diabetes patients switched from biphasic human insulin 30 (BHI 30) as a sub-analysis of the A1chieve study. METHODS: Clinical safety and effectiveness over 24 weeks was evaluated in Indonesian patients who switched from BHI 30 to BIAsp 30 at the discretion of their physician. RESULTS: A total of 244 patients with mean age +/- SD 55.6 +/- 9.5 years, BMI 24.6 +/- 3.8 kg/m(2), and mean diabetes duration 7.8 +/- 5.7 years were included. The mean pre study BHI 30 dose was 0.56 +/- 0.25 IU/kg and the baseline BIAsp 30 dose was 0.60 +/- 0.26 U/kg titrated up to 0.65 +/- 0.25 U/kg by Week 24. No serious adverse drug reactions were reported throughout the study. Overall hypoglycaemia decreased from 2.18 to 0.06 events/patient-year with a significant decrease in the proportion of patients affected (p < 0.0001). No nocturnal or major hypoglycaemia was reported at Week 24. HbA1c improved from 8.8 +/- 1.2% at baseline to 7.3 +/- 0.8% at Week 24. A total of 45 patients achieved HbA1c <7.0% as compared to 5 patients with HbA1c <7.0% at baseline. FPG and PPPG improved significantly after 24 weeks (p < 0.001). Quality of life was positively impacted (change in visual analogue scores, 3.0 +/- 11.6 points, p < 0.001). CONCLUSION: Switching from BHI 30 to BIAsp 30 in this Indonesian cohort was well-tolerated and improved glycaemic control with a decreased risk of hypoglycaemia. PMID- 23647719 TI - Clinical experience with insulin detemir: results from the Indonesian cohort of the international A1chieve study. AB - AIM: To determine the safety and efficacy of insulin detemir in Indonesian patients with type 2 diabetes (T2D) as a sub-analysis of the 24-week, prospective, multinational, non-interventional A1chieve study. METHODS: This study included 477 Indonesian T2D patients starting insulin detemir at the discretion of their physicians. Safety and efficacy was measured in routine clinical practice at baseline, interim (around 12 weeks from baseline) and final (around 24 weeks from baseline) visit. RESULTS: At baseline the mean age, duration of diabetes and mean BMI were 55.3 +/- 8.5 years, 5.9 +/- 4.0 years and 24 +/- 3.6 kg/m(2), respectively. Of these patients, 78% were insulin-naive and 22% were prior insulin users. Glycaemic control was poor at baseline. After 24 weeks, significant reductions were observed in mean HbA1c (2.2%, p < 0.001), fasting plasma glucose (90.0 mg/dL, p < 0.001) and postprandial plasma glucose (115.4 mg/dL, p < 0.001) levels, in the entire cohort. Similar significant reductions were also seen in insulin-naive patients and prior insulin users. In the entire cohort, 32.5% patients achieved HbA1c levels <7.0% while 32.0% insulin naive patients and 33.9% prior insulin users achieved this target after 24 weeks. No hypoglycaemic events were reported in the entire cohort. Modest increase in body weight was noted in the insulin-naive group, while mean body weight decreased in prior insulin users after 24 weeks of insulin detemir therapy. CONCLUSION: This sub-analysis suggests that insulin detemir can be a safe and effective option for initiating insulin therapy in people with T2D in Indonesia. PMID- 23647720 TI - Clinical experience with BIAsp 30: results from the Indonesian cohort of the international A1chieve study. AB - AIM: To evaluate the safety and effectiveness of biphasic insulin aspart 30 (BIAsp 30) in Indonesian patients with type 2 diabetes (T2D) as part of the 24 week, international, prospective, non-interventional A1chieve study. METHODS: Indonesian patients who started BIAsp 30 were included. Safety and efficacy was measured as part of routine clinical practice at baseline, Week 12 and Week 24. RESULTS: Overall, 1324 patients having a mean +/- SD age, duration of diabetes and body mass index of 55.2 +/- 9.9 yrs, 6.8 +/- 5.2 yrs and 24.1 +/- 3.6 kg/m(2), respectively, were enrolled. 67% of patients were insulin-naive and 33% were prior insulin users. Glycaemic control was poor at baseline. After 24 weeks, significant reductions from baseline were observed in the mean glycated haemoglobin A1c (HbA1c) (-2.6%), fasting plasma glucose (-93.8 mg/dL) and postprandial plasma glucose (-134.8 mg/dL) levels in the entire cohort (p < 0.001). Significant reductions were also seen in insulin-naive patients and prior insulin users. At Week 24, 29.9% of patients in the entire cohort achieved target HbA1c level of <7.0%, while 26.7% and 39.2% achieved this target among insulin naive patients and prior insulin users, respectively. The proportion of patients reporting overall hypoglycaemia significantly decreased in the entire cohort after 24 weeks of BIAsp 30 therapy. A small significant increase in body weight was noted in the entire cohort, insulin-naive patients and prior insulin users. CONCLUSION: The current study suggests that BIAsp 30 can be considered as a safe and effective option for initiating as well as intensifying insulin therapy in Indonesian patients with T2D. PMID- 23647721 TI - Cost analysis of glatiramer acetate vs. fingolimod for the treatment of patients with relapsing-remitting multiple sclerosis in Spain. AB - BACKGROUND: Fingolimod is an innovative drug with a significant budget impact in the treatment of MS in Spain. The aim of this study was to calculate the direct cost comparison of glatiramer acetate and fingolimod for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS) in Spain. METHODS: A cost analysis model was developed to compare glatiramer acetate and fingolimod, based on a 1-year time horizon. In addition to the pharmacological costs, resource use was estimated for glatiramer acetate (1 hour of training with nursing staff in self-injection techniques for subcutaneous administration) and fingolimod (vaccination for varicella-zoster virus in 5% of patients, 3 complete blood counts per year, 3 ophthalmology visits for prevention of macular edema, 3 transaminase tests to monitor liver function, and cardiovascular monitoring consisting of 1 ECG before the first fingolimod dose and at 6 hours; 1 day outpatients-hospital visit for cardiological monitoring during 6 hours on the day of the first fingolimod dose, with follow-up of blood pressure and heart rate every hour). The pharmacological costs were calculated based on the ex-factory price of the drugs evaluated, using the doses recommended in the respective Summary of Products Characteristics (SmPC). Total invoicing volume was discounted by 7.5%, as laid down in Spanish Royal Decree 8/2010. Unit costs were obtained from the e-Salud database and the drug catalog. Costs in the model are expressed in ?2012. RESULTS: The cost of annual treatment was ?9,439.42 for glatiramer acetate and ?19,602.18 for fingolimod, yielding a cost difference of ?10,162.76. Assuming a fixed budget of ?100,000.00, approximately 10 patients could be treated with glatiramer acetate, compared to 5 with fingolimod. CONCLUSIONS: Fingolimod therapy requires twice the investment as glatiramer acetate. PMID- 23647722 TI - Love thy neighbour: facilitation through an alternative signalling modality in plants. AB - BACKGROUND: Both competitive and facilitative interactions between species play a fundamental role in shaping natural communities. A recent study showed that competitive interactions between plants can be mediated by some alternative signalling channel, extending beyond those channels studied so far (i.e. chemicals, contact and light). Here, we tested whether such alternative pathway also enables facilitative interactions between neighbouring plant species. Specifically, we examined whether the presence of a 'good' neighbouring plant like basil positively influenced the germination of chilli seeds when all known signals were blocked. For this purpose, we used a custom-designed experimental set-up that prevented above- and below-ground contact and blocked chemical and light-mediated signals normally exchange by plants. RESULTS: We found that seed germination was positively enhanced by the presence of a 'good' neighbour, even when the known signalling modalities were blocked, indicating that light, touch or chemical signals may not be indispensible for different plant species to sense each other's presence. CONCLUSIONS: We propose that this alternative signalling modality operates as a general indicator of the presence of heterospecifics, enabling seeds to detect and identify a neighbour prior to engaging in a more finely-tuned, but potentially more costly, response. PMID- 23647724 TI - Highly sensitive serological methods for detecting tomato yellow leaf curl virus in tomato plants and whiteflies. AB - BACKGROUND: Tomato yellow leaf curl virus (TYLCV) is a member of the genus Begomovirus in the family Geminiviridae, which causes severe losses in tomato production in tropic and subtropic regions. METHODS: The purified TYLCV virions were used as the immunogen to produce monoclonal antibodies (MAbs) using the hybridoma technology. MAb-based dot enzyme-linked immunosorbent assay (dot-ELISA) and direct tissue blot immunoassay (DTBIA) were developed for sensitive, simple, and rapid detection of TYLCV in field tomato and whitefly (Bemisia tabaci) samples collected from TYLCV prevalent provinces in China. RESULTS: Using the hybridoma technology, six murine MAbs (1C4, 8D10, 6E3, 2F2, 3F4 and 4G3) against TYLCV were prepared. Using the MAb 1C4, dot-ELISA and DTBIA were then established for detecting TYLCV in field tomato and whitefly samples collected from TYLCV prevalent provinces in China. The dot-ELISA could detect TYLCV in infected tissue crude extract diluted at 1:5,120 (w/v, g mL-1), and in viruliferous whitefly homogenate diluted at 1:128 (individual whitefly/MUL), respectively. Field tomato samples (n=487) and whitefly samples (n=110) from TYLCV prevalent districts in China were screened for the presence of TYLCV using the two developed methods, and the results were further confirmed by PCR and nucleotide sequencing. The survey revealed that TYLCV is widespread on tomato plants in Zhejiang, Shandong and Henan provinces in China. CONCLUSIONS: The developed dot-ELISA is very suitable for the routine detection of TYLCV in field tomato and whitefly samples, and the DTBIA is more suitable for the routine detection of TYLCV in large-scale tomato plant samples collected from TYLCV prevalent areas. PMID- 23647723 TI - Nutraceuticals and chemotherapy induced peripheral neuropathy (CIPN): a systematic review. AB - Chemotherapy induced peripheral neuropathy [CIPN] is a common significant and debilitating side effect resulting from the administration of neurotoxic chemotherapeutic agents. These pharmaco-chemotherapeutics can include taxanes, vinca alkaloids and others. Moderate to severe CIPN significantly decreases the quality of life and physical abilities of cancer patients and current pharmacotherapy for CIPN e.g. Amifostine and antidepressants have had limited efficacy and may themselves induce adverse side effects. To determine the potential use of nutraceuticals i.e. vitamin E, acetyl-L-carnitine, glutamine, glutathione, vitamin B6, omega-3 fatty acids, magnesium, calcium, alpha lipoic acid and n-acetyl cysteine as adjuvants in cancer treatments a systematic literature review was conducted. Revised clinical studies comprised of randomized clinical trials that investigated the anti-CIPN effect of nutraceuticals as the adjuvant intervention in patients administered chemotherapy. Twenty-four studies were assessed on methodological quality and limitations identified. Studies were mixed in their recommendations for nutraceuticals. Currently no agent has shown solid beneficial evidence to be recommended for the treatment or prophylaxis of CIPN. The standard of care for CIPN includes dose reduction and/or discontinuation of chemotherapy treatment. The management of CIPN remains an important challenge and future studies are warranted before recommendations for the use of supplements can be made. PMID- 23647725 TI - Effect of zinc intake on serum/plasma zinc status in infants: a meta-analysis. AB - A systematic review and meta-analysis of available randomised controlled trials (RCTs) was conducted to evaluate the effect of zinc (Zn) intake on serum/plasma Zn status in infants. Out of 5500 studies identified through electronic searches and reference lists, 13 RCTs were selected after applying the exclusion/inclusion criteria. The influence of Zn intake on serum/plasma Zn concentration was considered in the overall meta-analysis. Other variables were also taken into account as possible effect modifiers: doses of Zn intake, intervention duration, nutritional status and risk of bias. The pooled beta of status was 0.09 [confidence interval (CI) 0.05 to 0.12]. However, a substantial heterogeneity was present in the analyses (I(2) = 98%; P = 0.00001). When we performed a meta regression, the effect of Zn intake on serum/plasma Zn status changed depending on the duration of the intervention, the dose of supplementation and the nutritional situation (P ANCOVA = 0.054; <0.001 and <0.007, respectively). After stratifying the sample according to the effect modifiers, the results by duration of intervention showed a positive effect when Zn intake was provided during medium and long periods of time (4-20 weeks and >20 weeks). A positive effect was also seen when doses ranged from 8.1 to 12 mg day(-1). In all cases, the pooled beta showed high evidence of heterogeneity. Zn supplementation increases serum/plasma Zn status in infants, although high evidence of heterogeneity was found. Further standardised research is urgently needed to reach evidence-based conclusions to clarify the role of Zn supplementation upon infant serum/plasma Zn status, particularly in Europe. PMID- 23647726 TI - The relations of obesity indicators and early metabolic disturbance with upper extremity pain. AB - OBJECTIVES: To determine whether signs of metabolic disturbance and especially visceral obesity are associated with upper extremity pain. DESIGN: Cohort study. SUBJECTS: One hundred and seventy-seven workers (154 women, 23 men; age 20-64 years, mean 45) seeking medical advice in the occupational health service for incipient upper extremity disorders were included. MEASURES: Weight, height, waist circumference, and hip circumference were measured. Visceral and liver fat content and carotid artery intima-media thickness were estimated with ultrasound. Pain intensity and pain interference with sleep were assessed with visual analog scales at baseline and after 2, 8, 12, 52, and 104 weeks follow-up. Generalized estimating equation approach was used to analyze the repeated measures data. RESULTS: All obesity indicators were associated with both pain intensity and pain interference with sleep. Visceral fat thickness was the strongest predictor of pain intensity and pain interference with sleep. Carotid intima-media thickness was neither associated with pain intensity nor with pain interference with sleep. CONCLUSIONS: Visceral obesity seems to be a risk factor for upper extremity pain. Further studies are needed to elucidate the underlying mechanisms and to clarify whether weight loss can be helpful in pain management. PMID- 23647727 TI - Successful transendoscopic oesophageal mass ablation in two dogs with Spirocerca lupi associated oesophageal sarcoma. AB - This report describes two cases of oesophageal tumours managed by transendoscopic neodymium:yttrium-aluminum-garnet laser ablation and polypectomy snare electrocautery. In each dog oesophagoscopy revealed caudal oesophageal masses, suspected to be Spirocerca lupi-induced oesophageal neoplasia. To resect the masses, transendoscopic neodymium:yttrium-aluminum-garnet laser ablation was used in the first case and polypectomy snare electrocautery in the second. Recovery was uneventful. Histopathology was consistent with oesophageal fibrosarcoma and osteosarcoma in each case, respectively. Follow-up oesophagoscopy revealed apparently healthy oesophageal tissue except for focal scar tissue in the first case. Transendoscopic laser ablation and polypectomy snare electrocautery is a potential non-invasive, cost effective alternative for surgical oesophageal mass resection. PMID- 23647729 TI - Neighborhood socioeconomic characteristics, the retail environment, and alcohol consumption: a multilevel analysis. AB - BACKGROUND: The neighborhoods where people live can influence their drinking behavior. We hypothesized that living in a neighborhood with lower median income, higher alcohol outlet density, and only liquor stores and no grocery stores would be associated with higher alcohol consumption after adjusting for individual demographic and lifestyle factors. METHODS: We used two self-report measures to assess alcohol consumption in a sample of 9959 adults living in a large Midwestern county: volume of alcohol consumed (count) and binge drinking (5 or more drinks vs.<5 drinks). We measured census tract median annual household income based on U.S. Census data. Alcohol outlet density was measured using the number of liquor stores divided by the census tract roadway miles. The mix of liquor and food stores in census tracts was assessed using a categorical variable based on the number of liquor and number of food stores using data from InfoUSA. Weighted hierarchical linear and Poisson regression were used to test our study hypothesis. RESULTS: Retail mix was associated with binge drinking. Individuals living in census tracts with only liquor stores had a 46% higher risk of binge drinking than individuals living in census tracts with food stores only after controlling for demographic and lifestyle factors. CONCLUSION: Census tract characteristics such as retail mix may partly explain variability in drinking behavior. Future research should explore the mix of stores, not just the over concentration of liquor stores in census tracts. PMID- 23647728 TI - Factor structure of PTSD symptoms in opioid-dependent patients rating their overall trauma history. AB - BACKGROUND: The current standard for posttraumatic stress disorder (PTSD) diagnosis is a 3-factor model (re-experiencing, avoidance, and hyperarousal). Two 4-factor models of PTSD, the emotional numbing model (re-experiencing, avoidance, emotional numbing, and hyperarousal) and the dysphoria model (re-experiencing, avoidance, dysphoria, and hyperarousal), have considerable empirical support in the extant literature. However, a newer 5-factor model of PTSD has been introduced that is receiving interest. The 5-factor model differs from the four factor models in its placement of three symptoms (irritability, sleep disturbance, and concentration difficulties) into a separate cluster termed dysphoric arousal. We empirically compared the theoretical factor structures of 3 , 4-, and 5-factor models of PTSD symptoms to find the best fitting model in a sample of opioid-dependent hospitalized patients. METHODS: Confirmatory factor analyses were conducted on the 17 self-reported PTSD symptoms of the Posttraumatic Checklist - Civilian Version (PCL-C) in a sample of 151 men and women with opioid dependence. RESULTS: Both four-factor models fit the observed data better than the three-factor model of PTSD; the dysphoria model was preferred to the emotional numbing model in this sample. The recently introduced five-factor model fit the observed data better than either four factor model. CONCLUSIONS: PTSD is a heterogeneous disorder comprised of symptoms of re experiencing, avoidance, numbing, and dysphoria. Three symptoms, irritability, sleep disturbance, and concentration difficulties, may represent a unique latent construct separate from these four symptom clusters in opioid-dependent populations who have experienced traumatic events. PMID- 23647730 TI - Public health strategies for prevention and control of HSV-2 in persons who use drugs in the United States. AB - BACKGROUND: Herpes simplex virus type 2 (HSV-2) affects HIV acquisition, transmission, and disease progression. Effective medications for genital herpes and for HIV/AIDS exist. Parenteral transmission of HIV among persons who inject drugs is decreasing. Reducing sexual transmission of HIV and HSV-2 among persons who use drugs (PWUD; i.e., heroin, cocaine, "speedball", crack, methamphetamine through injection or non-injection) necessitates relevant services. METHODS: We reviewed HSV-2 sero-epidemiology and HSV-2/HIV associations in U.S.-based studies with PWUD and the general literature on HSV-2 prevention and treatment published between 1995 and 2012. We used the 6-factor Kass framework to assess relevant HSV 2 public health strategies and services in terms of their goals and effectiveness; identification of, and minimization of burdens and concerns; fair implementation; and fair balancing of benefits, burdens, and concerns. RESULTS: Eleven studies provided HSV-2 serologic test results. High HSV-2 sero-prevalence (range across studies 38-75%) and higher sero-prevalence in HIV-infected PWUD (97 100% in females; 61-74% in males) were reported. Public health strategies for HSV 2 prevention and control in PWUD can include screening or testing; knowledge of HSV-2 status and partner disclosure; education, counseling, and psychosocial risk reduction interventions; treatment for genital herpes; and HIV antiretroviral medications for HSV-2/HIV co-infected PWUD. CONCLUSIONS: HSV-2 sero-prevalence is high among PWUD, necessitating research on development and implementation of science-based public health interventions for HSV-2 infection and HSV-2/HIV co infections, including research on effectiveness and cost-effectiveness of such interventions, to inform development and implementation of services for PWUD. PMID- 23647731 TI - The role of depression and social support in non-fatal drug overdose among a cohort of injection drug users in a Canadian setting. AB - OBJECTIVES: Non-fatal overdose remains a significant source of morbidity among people who inject drugs (IDU). Although depression and social support are important in shaping the health of IDU, little is known about the relationship between these factors and overdose. Therefore, we sought to determine whether depressive symptoms and social support predicted non-fatal overdose among IDU in a Canadian setting. METHODS: Data were derived from three prospective cohorts of people who use drugs: the Vancouver Injection Drug Users Study (VIDUS), the ACCESS Cohort, and the At-Risk Youth Study (ARYS). Multilevel modeling was used to determine if depression and social support were significant predictors of non fatal overdose across time. Analyses were stratified by sex. RESULTS: There were 1931 participants included in this analysis, including 653 (33.8%) females and 69 (3.6%) youth 20 years old or younger. Depressed men (adjusted odds ratio [AOR]=1.53, 95% confidence intervals [CI]=1.25, 1.87) and women (adjusted odds ratio [AOR]=2.23, 95% confidence intervals [CI]=1.65, 3.00) were more likely to experience a non-fatal overdose. Further, among women, those who reported having 3 or more persons they could rely upon for social support were less likely to experience a non-fatal overdose (AOR=0.54, 95% CI 0.31, 0.93). CONCLUSION: Although depression was a significant predictor of non-fatal drug overdose, social support was a significant predictor among women only. Possible strategies to prevent non-fatal overdose may include identifying IDU experiencing severe depressive symptoms and providing targeted mental health treatments and mobilizing interpersonal social support among IDU, especially among women. PMID- 23647732 TI - Targeting surveillance for zoonotic virus discovery. AB - We analyzed a database of mammal-virus associations to ask whether surveillance targeting diseased animals is the best strategy to identify potentially zoonotic pathogens. Although a mixed healthy and diseased animal surveillance strategy is generally best, surveillance of apparently healthy animals would likely maximize zoonotic virus discovery potential for bats and rodents. PMID- 23647733 TI - The first steps on the path toward genomic predictors of behavioral therapy for posttraumatic stress disorder. PMID- 23647734 TI - Threat-related attention bias in the early stages of cognitive-behavior therapy action for panic disorder. PMID- 23647735 TI - Fear and anxiety take a double hit from vagal nerve stimulation. PMID- 23647736 TI - Cell counting of body fluids: comparison between three automated haematology analysers and the manual microscope method. AB - INTRODUCTION: Haematological analysis of body fluids (BF) specimens can provide clinicians with valuable diagnostic information because it can indicate one of several serious medical conditions. Although up to now the microscopic counting and the differentiation of WBC in a BF smear have been used as a reference. The introduction of semiautomated and automated methods of analysis has reduced interoperator variability and improved turnaround time and precision. The aim of our study was to evaluate the accuracy and the correlation between the three methods and with the reference method. METHODS: We examined 110 body fluid samples. Total counting of each sample has been conducted with all systems: Pentra DX120, ADVIA 2120 and XE-2100 and the manual method. RESULTS: We found statistically significant correlation between the data obtained in the ascitic and pleuric liquid but not in the cerebrospinal fluid. CONCLUSION: The introduction of automated method for BF analysis is more and more useful in the routine job of a laboratory analysis. It is therefore very important to evaluate the performance of the different automated haematology technologies, because there is a lack of literature in this field. The comparison between the Pentra DX 120, the other technologies and the manual counting showed instrumental overlapping capabilities. PMID- 23647737 TI - Simplified negative pressure wound therapy: clinical evaluation of an ultraportable, no-canister system. AB - The aim of this study was to evaluate a prototype negative pressure wound therapy (NPWT) system that has been developed to simplify NPWT for wounds at the lower end of the acuity scale. The new device has a single preset pressure of -80 mmHg, is single use and operates without an exudate canister. The disposable NPWT system (PICOTM) was tested in a prospective, non-comparative, multicentre clinical trial to assess device functionality and clinical acceptance. Twenty patients were recruited for a maximum treatment period of 14 days. The NPWT devices were fitted with data log chips to enable longitudinal assessment of negative pressure and leak rates during therapy. Sixteen (80%) patients had closed surgical wounds, two (10%) patients had traumatic wounds and two (10%) patients received meshed split thickness skin grafts. The mean study duration was 10.7 days (range: 5-14 days) and the mean dressing wear time per individual patient was 4.6 days (range: 2-11). Fifty-five percent of wounds had closed by the end of the 14-day study or earlier, with a further 40% of wounds progressing to closure. Real-time pressure monitoring showed continuous delivery of NPWT. Three cases are discussed representing different wound locations and different patient factors that can increase the risk of post-surgical complications. Clinical studies of the disposable NPWT system confirmed the ability of the simplified single-use device to function consistently over the expected wear time. The anticipated reduced costs, ease of use and increased mobility of patients using this system may enable NPWT benefits to be available to a greater proportion of patients. PMID- 23647739 TI - Shifting the balance of care? A qualitative study of policy implementation in community nursing. AB - AIM: This qualitative study examined the interaction between policy implementation and service organisation and delivery for community nursing services. BACKGROUND: Leadership in nursing is at the fore front of the policy agenda for shifting the balance of care from hospitals to the community setting and for improving the quality of healthcare services. Yet, little is known about the implementation of policy within the community setting. METHOD: A qualitative, interpretive analysis including semi-structured interviews with nurse leaders (n = 12) and community nurses (n = 27) and three focus groups (n = 13) with community nurses (Total N = 39) in three Health Boards in Scotland. RESULTS: Policy implementation is not adequately integrated between primary and secondary care service at the point of care delivery. The 'top down approach' to policy implementation for shifting the balance of care is currently at odds with the grass roots service organisation and delivery in the community setting. CONCLUSIONS: The aspirations of integrated, collaborative health and social care require more clinicians working at the frontline in both primary and secondary care to value more the work of colleagues in the different sectors. IMPLICATION FOR NURSING MANAGEMENT: The current 'top down approach' to policy implementation encourages resistance in the frontline community nurses rather than commitment. A more 'bottom up' integrated approach to policy implementation is therefore required. PMID- 23647738 TI - A multicenter randomized phase IIb efficacy study of Vx-001, a peptide-based cancer vaccine as maintenance treatment in advanced non-small-cell lung cancer: treatment rationale and protocol dynamics. AB - We present the treatment rationale and study design of a multicenter, open-label, randomized, 2-arm, phase IIb study. Patients with stage IV or recurrent stage I to III non-small-cell lung cancer (NSCLC) whose disease does not progress after 4 cycles of first-line platinum-based chemotherapy will be randomized in a 1:1 ratio to 1 of 2 study arms. Patients will receive the cancer vaccine Vx-001 + Montanide ISA51 VG (Seppic, Paris, France) adjuvant subcutaneously, at a dose of 2 mg, or placebo + Montanide ISA51 VG adjuvant subcutaneously. The vaccination protocol comprises 2 injections with the TYR-Vx001 or placebo (1 at day 0 and another at week 3) and 4 injections with the ARG-Vx001 or placebo, at weeks 6, 9, 12, and 15. After the treatment assessment at week 18, patients will receive the ARG-Vx001 or placebo every 12 weeks starting from week 27 until disease progression, unacceptable toxicity, withdrawal of informed consent, or death. The primary end point of this study is the survival rate at 12 months. Secondary end points include time-to-event comparison of overall survival and comparison of time to treatment failure. Exploratory objectives include comparison of disease control rate after the end of subsequent second-line treatments, comparisons of vaccine immune responses, comparison of survival rate at 12 months in patients with vaccine-induced immune response detected after the second and sixth injections, identification of biomarkers on lymphocytes and on tumors, and comparison of safety and tolerability. PMID- 23647740 TI - [Work environment and patient safety: data comparison between Seneca and RN4CAST projects]. AB - OBJECTIVE: To analyze the relationship between the work environment and burnout of nurses and the quality of care for patient safety at the Spanish National Health System Hospitals included in SENECA and RN4CAST studies. METHOD: Descriptive study with a secondary analysis that compares data of 984 patient records, 1469 patient, and 1886 professional surveys from SENECA project, with 2139 nurses' surveys from RN4CAST study, in 24 hospitals. Adverse events data related to care, and patient's and professional's perception of safety were compared with work environment (measured by the Nursing Work Index) and burnout (measured by Maslach Burnout Inventory). RESULTS: There was a statistically significant relation of pain with "Staffing and resource adequacy" (r=-0,435, p=0,03) and nosocomial infection with "Nursing foundations for quality of care" (r=-0,424; p=0,04) and "Nurse participation in hospital affairs" (r=-0,516, p=0,01) of the Nursing Work Index. The hospital classification obtained from the Nursing Work Index was associated with the patients' perception of safety (r=0,66, p<0,01). Professionals' perception of participation in patient safety issues was associated with the five factors of the Nursing Work Index (r ? [|0,41|-|0,78 |], p<0,046) and with Maslach emotional exhaustion (r=-0,518, p=0,01). CONCLUSIONS: The organizations that foster a supportive work environment will have patients that perceive safer care. In addition, proper resource management could decrease the occurrence of adverse events such as pain. PMID- 23647741 TI - Women's experiences with information provision and deciding about fertility preservation in the Netherlands: 'satisfaction in general, but unmet needs'. AB - OBJECTIVE: It is not well-known how women receiving counselling consultation about fertility preservation (FP) in the Netherlands perceive the information provision about and referral for FP in the oncology setting. The aim of this study was to qualitatively explore women's experiences with the (process of) information provision about the gonadotoxic effects of cancer treatment and about FP and the decision-making process and to obtain their recommendation for improvements. METHODS: Semi-structured interviews with female patients with cancer who had received a counselling consultation on FP (at 18-40 years of age). RESULTS: Thirty-four interviews were held (response rate 64%). Information provision was considered to be important. Overall, women were satisfied with the timing and the content of the information, but women were less positive about the need to be assertive to get information, and the multiplicity of decisions and actions to be carried out in a very short time frame. CONCLUSIONS: Information provision on gonadotoxic effects of cancer treatment and about FP was overall deemed sufficient, timely and important. Women recommended standardization of the information provision, improvement of communication among clinicians and medical centres, and availability of FP-specific patient information materials to improve future information provision processes. PMID- 23647742 TI - Iterative rank-order normalization of gene expression microarray data. AB - BACKGROUND: Many gene expression normalization algorithms exist for Affymetrix GeneChip microarrays. The most popular of these is RMA, primarily due to the precision and low noise produced during the process. A significant strength of this and similar approaches is the use of the entire set of arrays during both normalization and model-based estimation of signal. However, this leads to differing estimates of expression based on the starting set of arrays, and estimates can change when a single, additional chip is added to the set. Additionally, outlier chips can impact the signals of other arrays, and can themselves be skewed by the majority of the population. RESULTS: We developed an approach, termed IRON, which uses the best-performing techniques from each of several popular processing methods while retaining the ability to incrementally renormalize data without altering previously normalized expression. This combination of approaches results in a method that performs comparably to existing approaches on artificial benchmark datasets (i.e. spike-in) and demonstrates promising improvements in segregating true signals within biologically complex experiments. CONCLUSIONS: By combining approaches from existing normalization techniques, the IRON method offers several advantages. First, IRON normalization occurs pair-wise, thereby avoiding the need for all chips to be normalized together, which can be important for large data analyses. Secondly, the technique does not require similarity in signal distribution across chips for normalization, which can be important for maintaining biologically relevant differences in a heterogeneous background. Lastly, IRON introduces fewer post-processing artifacts, particularly in data whose behavior violates common assumptions. Thus, the IRON method provides a practical solution to common needs of expression analysis. A software implementation of IRON is available at [http://gene.moffitt.org/libaffy/]. PMID- 23647743 TI - A method for rapid production of heteromultimeric protein complexes in plants: assembly of protective bluetongue virus-like particles. AB - Plant expression systems based on nonreplicating virus-based vectors can be used for the simultaneous expression of multiple genes within the same cell. They therefore have great potential for the production of heteromultimeric protein complexes. This work describes the efficient plant-based production and assembly of Bluetongue virus-like particles (VLPs), requiring the simultaneous expression of four distinct proteins in varying amounts. Such particles have the potential to serve as a safe and effective vaccine against Bluetongue virus (BTV), which causes high mortality rates in ruminants and thus has a severe effect on the livestock trade. Here, VLPs produced and assembled in Nicotiana benthamiana using the cowpea mosaic virus-based HyperTrans (CPMV-HT) and associated pEAQ plant transient expression vector system were shown to elicit a strong antibody response in sheep. Furthermore, they provided protective immunity against a challenge with a South African BTV-8 field isolate. The results show that transient expression can be used to produce immunologically relevant complex heteromultimeric structures in plants in a matter of days. The results have implications beyond the realm of veterinary vaccines and could be applied to the production of VLPs for human use or the coexpression of multiple enzymes for the manipulation of metabolic pathways. PMID- 23647745 TI - The effect of sacral neuromodulation on anticholinergic use and expenditures in a privately insured population. AB - OBJECTIVES: Sacral neuromodulation is Food and Drug Administration approved for many types of voiding dysfunction. Goals of treatment often include cessation of anticholinergic therapy. With the goal of understanding the impact of sacral neuromodulation on anticholinergic use, we analyzed patterns of care using a national claims-based dataset. MATERIALS AND METHODS: The Ingenix (i3) data base contains insurance claims, including utilization and cost data, for 75 large employers. De-identified patients who underwent sacral neuromodulation between 2002 and 2007 were identified by the unique current procedural terminology-4 procedure code for pulse generator implantation, code 64590. The number and costs of anticholinergic prescriptions were compared before and after treatment. RESULTS: There were 266 percutaneous and 794 two-staged procedures performed from 2002 to 2007 in the i3 dataset. A total of 484 pulse generator implantations were performed, representing 46% of the test procedures. During the year prior to pulse generator placement, each patient purchased an average of 2.1 prescriptions for an anticholinergic agent (SD 3.5). During the year after neuromodulation, each patient purchased an average of 1.0 prescription (SD 2.3, p < 0.0001 by t test). Prescription charges were $241.31 per patient before and $103.52 after neuromodulation, a statistically significant cost difference (p < 0.0001 by t test). During the year before the procedure, 50% of patients filled anticholinergic prescriptions. This decreased to 23% after the procedure (p < 0.0001 by chi-square test). CONCLUSIONS: Sacral neuromodulation was associated with a significant decrease in the use of anticholinergic medication. Cost effectiveness analyses that take into account patient quality-adjusted life years are needed to determine the true cost-benefit ratio of sacral neuromodulation. PMID- 23647746 TI - Protective effects of curcumin supplementation on intestinal ischemia reperfusion injury. AB - The aim of this study was to investigate the effects curcumin on inflammation and oxidative stress markers in the intestinal ischemia reperfusion (IIR) injury induced rats. Rats were divided into four groups: sham (S), intestinal IR (IIR), curcumin plus sham (CS), and curcumin plus intestinal IR (CIIR). Curcumin was given 200 mg kg-1 for 20 days. IIR was produced by 45 min of intestinal ischemia followed by a 120 min of reperfusion. Although interleukin-6 levels tended to increase in IIR group tumor necrosis factor-alpha levels were not different. Intestinal myeloperoxidase activity in CS group was lower than IIR group. In intestine and heart tissues, malondialdehyde levels in CS and CIIR groups were lower than S and IIR groups. Superoxide dismutase activity in CIIR group was higher than IIR group in intestine and lung tissues. Curcumin has a protective role against ischemia reperfusion injury. PMID- 23647747 TI - Identification of a homozygous Cys410Ser mutation in the von Willebrand factor D2 domain causing type 2A(IIC) von Willebrand disease phenotype in an Iranian patient. PMID- 23647748 TI - Reirradiation and stereotactic radiotherapy for tumors in the lung: dose summation and toxicity. AB - PURPOSE: To assess the accumulated dose and the toxicity after reirradiation for tumors in the lung using non-rigid registration. MATERIAL AND METHODS: Twenty patients with a tumor in the lung were reirradiated with or after stereotactic radiotherapy. The summed dose distribution was calculated using non-rigid registration. All doses were recalculated to an equivalent dose of 2 Gy per fraction (EQD2). The median follow-up time was 12 months (range 2-52). RESULTS: The median Dmax of the lung in the summed plans was 363 Gy3 (range 123-590). The median accumulated V20 of the lungs was 15.2%. Seven patients had in the heart and the trachea an accumulated dose >=70 Gy3, with a median D(max) of the heart of 115 Gy3 and 89 Gy3 for the trachea. Eight patients had in the esophagus an accumulated dose >=70 Gy3, with a median accumulated dose of 85 Gy3. No grade 3-5 toxicity was observed. CONCLUSION: Reirradiation of the lung with or after stereotactic radiotherapy is feasible to a median Dmax of 363 Gy3 to the lung, as low toxicity was observed. PMID- 23647749 TI - Prognostic parameters for acute esophagus toxicity in intensity modulated radiotherapy and concurrent chemotherapy for locally advanced non-small cell lung cancer. AB - BACKGROUND AND PURPOSE: The aim of this study was to correlate clinical and dosimetric variables with acute esophageal toxicity (AET) following Intensity Modulated Radiotherapy (IMRT) with concurrent chemotherapy for locally advanced non-small cell lung cancer (NSCLC). In addition, timeline of AET was reported. MATERIAL AND METHODS: 153 patients with locally advanced NSCLC treated with 66 Gy/2.75 Gy/24 fractions of radiotherapy and concurrent daily low dose cisplatin were selected. Medical records and treatments of these patients were retrospectively reviewed. Maximum AET grade >=2 and maximum grade 3 were the endpoints of this study. Dates for onset, maximum and recovery (to baseline) of AET were reported. Univariate and multivariate analysis were applied to correlate clinical, tumor, dosimetric and chemotherapy dose variables to AET grade >=2 and grade 3. RESULTS: AET grade 2 occurred in 37% and grade 3 in 20% of the patients. The median onset of AET was around day 15 for all grades. The median onset of the maximum grade was day 30 for both grades 2 and 3. The median duration was 43 days for grade 1, 50 days for grade 2 and >80 days for grade 3. Of the grade 3 AET patients, 48% recovered within 3 months. Esophagus V50, ethnic background, and the number of cisplatin administrations were significantly correlated with grade 3 AET. CONCLUSIONS: For NSCLC patients treated with concurrent chemotherapy and IMRT A higher number of cisplatin administrations, non-Caucasian background and higher V50oes were associated with grade 3 AET. The median onset of AET grade 3 is 15 days after the start of treatment, maximized at day 30, with a median duration of >80 days. PMID- 23647750 TI - Prostate stereotactic ablative body radiotherapy using a standard linear accelerator: toxicity, biochemical, and pathological outcomes. AB - BACKGROUND AND PURPOSE: Biological dose escalation through stereotactic ablative radiotherapy (SABR) holds promise of improved patient convenience, system capacity and tumor control with decreased cost and side effects. The objectives are to report the toxicities, biochemical and pathologic outcomes of this prospective study. MATERIALS AND METHODS: A phase I/II study was performed where low risk localized prostate cancer received SABR 35 Gy in 5 fractions, once weekly on standard linear accelerators. Common Terminology Criteria for Adverse Events v3.0 and Radiation Therapy Oncology Group late morbidity scores were used to assess acute and late toxicities, respectively. Biochemical control (BC) was defined by the Phoenix definition. RESULTS: As of May 2012, 84 patients have completed treatment with a median follow-up of 55 months (range 13-68 months). Median age was 67 years and median PSA was 5.3 ng/ml. The following toxicities were observed: acute grade 3+: 0% gastrointestinal (GI), 1% genitourinary (GU), 0% fatigue; late grade 3+: 1% GI, 1% GU. Ninety-six percent were biopsy negative post-treatment. The 5-year BC was 98%. CONCLUSIONS: This novel technique employing standard linear accelerators to deliver an extreme hypofractionated schedule of radiotherapy is feasible, well tolerated and shows excellent pathologic and biochemical control. PMID- 23647751 TI - Intensity modulated proton therapy for postmastectomy radiation of bilateral implant reconstructed breasts: a treatment planning study. AB - BACKGROUND AND PURPOSE: Delivery of post-mastectomy radiation (PMRT) in women with bilateral implants represents a technical challenge, particularly when attempting to cover regional lymph nodes. Intensity modulated proton therapy (IMPT) holds the potential to improve dose delivery and spare non-target tissues. The purpose of this study was to compare IMPT to three-dimensional (3D) conformal radiation following bilateral mastectomy and reconstruction. MATERIALS AND METHODS: Ten IMPT, 3D conformal photon/electron (P/E), and 3D photon (wide tangent) plans were created for 5 patients with breast cancer, all of whom had bilateral breast implants. Using RTOG guidelines, a physician delineated contours for both target volumes and organs-at-risk. Plans were designed to achieve 95% coverage of all targets (chest wall, IMN, SCV, axilla) to a dose of 50.4 Gy or Gy (RBE) while maximally sparing organs-at-risk. RESULTS: IMPT plans conferred similar target volume coverage with enhanced homogeneity. Both mean heart and lung doses using IMPT were significantly decreased compared to both P/E and wide tangent planning. CONCLUSIONS: IMPT provides improved homogeneity to the chest wall and regional lymphatics in the post-mastectomy setting with improved sparing of surrounding normal structures for woman with reconstructed breasts. IMPT may enable women with mastectomy to undergo radiation therapy without the need for delay in breast reconstruction. PMID- 23647752 TI - Plan of the day selection for online image-guided adaptive post-prostatectomy radiotherapy. AB - PURPOSE: To compare the cone-beam CT (CBCT) soft tissue localization disparity between radiation oncologists (RO) and radiation therapy technologists (RTT) in a novel online protocol of image-guided adaptive radiotherapy to the postoperative prostate bed. METHOD: Using the planning CT and pre-treatment CBCTs from the first week of radiotherapy, four adaptive plans of different sizes were derived for each of eight post-prostatectomy patients. Four ROs collectively defined the reference answer, i.e. the plan of the day and isocentre correction for 40 CBCTs taken in weeks 2-6 of treatment for each patient. RTTs were randomly assigned five of these CBCTs; and asked to record their plan of the day selection and isocentre correction. RTT selection and reference answers were compared. The distance between the RTT selection and the reference answer was calculated. RESULTS: A total of 33 RTTs took part in this study. The average difference in CTV volume (reference answer-RTT selection) was 1.32 cm(3) (SD 29 cm(3)) overall. The average difference between reference answer and RTT isocentre coordinates was SI 1mm (SD 4.8mm), LR 1.1mm (SD 4.0mm) and AP -0.2mm (SD 3.9 mm). Distance of superior 8mm, inferior 6mm, left 4mm, right 2mm, anterior 6mm and posterior 6mm covered 100% of the CTV in 90% of fractions. CONCLUSION: The difference between RTT and RO selection of adaptive volumes is small and can be accounted for in a clinically acceptable CTV to PTV margin. Adaptive post-prostatectomy radiotherapy is feasible, in the setting of an academic center although at the moment, we have insufficient evidence to suggest that margins can yet be reduced with IGART with the current protocol. PMID- 23647753 TI - Phase I trial of the combination of the Akt inhibitor nelfinavir and chemoradiation for locally advanced rectal cancer. AB - PURPOSE: To investigate the toxicity of nelfinavir, administered during preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer. MATERIAL AND METHODS: Twelve patients were treated with chemoradiotherapy to 50.4 Gy combined with capecitabine 825 mg/m(2) BID. Three dose levels (DL) of nelfinavir were tested: 750 mg BID (DL1), 1250 mg BID (DL2) and an intermediate level of 1000 mg BID (DL3). Surgery was performed between 8 and 10 weeks after completion of CRT. Primary endpoint was dose-limiting toxicity (DLT), defined as any grade 3 or higher non-hematological or grade 4 or higher hematological toxicity. RESULTS: Eleven patients could be analyzed: 5 were treated in DL1, 3 in DL2 and 3 in DL3. The first 3 patients in DL1 did not develop a DLT. In DL2 one patient developed gr 3 diarrhea, 1 patient had gr 3 transaminase elevation and 1 patient had a gr 3 cholangitis with unknown cause. An intermediate dose level was tested in DL3. In this group 2 patients developed gr 3 diarrhea and 1 patient gr 3 transaminase elevation and gr 4 post-operative wound complication. Three patients achieved a pathological complete response (pCR). CONCLUSIONS: Nelfinavir 750 mg BID was defined as the recommended phase II dose in combination with capecitabine and 50.4 Gy pre-operative radiotherapy in rectal cancer. First tumor response evaluations are promising, but a further phase II study is needed to get more information about efficacy of this treatment regimen. PMID- 23647754 TI - Risk of endocrine pancreatic insufficiency in patients receiving adjuvant chemoradiation for resected gastric cancer. AB - BACKGROUND: Adjuvant radiotherapy combined with 5-fluorouracil based chemotherapy has become the new standard after curative resection in high risk gastric cancer. Beside many complications due to surgery, the addition of chemotherapy and radiotherapy as adjuvant treatment may lead to both acute and late toxicities. Pancreatic tissue irradiation during this adjuvant treatment because of incidental and unavoidable inclusion of the organ within the radiation field may affect exocrine and endocrine functions of the organ. MATERIALS AND METHODS: Fifty-three patients with gastric adenocarcinoma were evaluated for adjuvant chemoradiotherapy after surgery. While 37 out of 53 patients were treated postoperatively due to either serosal or adjacent organ or lymph node involvement, 16 patients without these risk factors were followed up regularly without any additional treatment and they served as the control group. Fasting blood glucose (FBG), hemoglobin A1c (HBA1c), insulin and C-peptide levels were measured in the control and study groups after the surgery and 6 months and 1 year later. RESULTS: At the baseline there was no difference in FBG, HbA1c, C peptide and insulin levels between the control and the study groups. At the end of the study there was a statistically significant decline in insulin and C peptide levels in the study group, (7.5 +/- 6.0 vs 4.5 +/- 4.4 IU/L, p: 0.002 and 2.3 +/- 0.9 vs 1.56 +/- 0.9 ng/ml, p: 0.001) respectively. CONCLUSIONS: Adjuvant radiotherapy in gastric cancer leads to a decrease in beta cell function and insulin secretion capacity of the pancreas with possible diabetes risk. Radiation induced pancreatic injury and late effects of radiation on normal pancreatic tissue are unknown, but pancreas is more sensitive to radiation than known. This organ should be studied extensively in order to determine the tolerance doses and it should be contoured during abdominal radiotherapy planning as an organ at risk. PMID- 23647755 TI - A treatment planning comparison of four target volume contouring guidelines for locally advanced pancreatic cancer radiotherapy. AB - BACKGROUND AND PURPOSE: Contouring of target volumes varies significantly in radiotherapy of pancreatic ductal adenocarcinoma (PDAC). There is a lack of consensus as to whether elective lymph nodes (eLN's) should be included or not in the planning target volume (PTV). In the present study we analyzed the dosimetric coverage of the eLN's and organs at risk (OAR) by comparing four different contouring guidelines. METHODS AND MATERIALS: PTVs were delineated with (Oxford and RTOG guidelines) or without (Michigan and SCALOP guidelines) including the eLNs in eleven patients with PDAC. eLNs included the peripancreatic, paraaortic, paracaval, celiac trunk, superior mesenteric and portal vein clinical target volumes (CTVs). A 3D-CRT plan (50.40 Gy in 28 fractions) was performed to analyze and compare the dosimetric coverage of all eLNs and OAR between the 4 contouring guidelines. RESULTS: The size of Oxford and RTOG PTVs was comparable and significantly larger than the SCALOP and Michigan PTVs. Interestingly the eLNs received a significant amount of incidental dose irradiation by PTV-based plans that only aimed to treat the tumor without the eLNs. The dosimetric coverage of eLN presented a large variability according to the respective contouring methods. The difference in the size of the 4 PTVs was reflected to the dose distribution at the OAR. CONCLUSIONS: Our study provides important information regarding the impact of different contouring guidelines on the dose distribution to the eLNs and the OAR in patients with locally advanced PDAC treated with radiotherapy. PMID- 23647756 TI - Radiotherapy with rectangular fields is associated with fewer clinical failures than conformal fields in the high-risk prostate cancer subgroup: results from a randomized trial. AB - OBJECTIVE: High-risk prostate cancer patients are at risk for subclinical disease and micro-metastasis at the time of treatment. Nowadays, tight margins reduce dose to periprostatic areas compared to earlier techniques. We investigated whether rectangular fields were associated with fewer failures compared to conformal fields (with lower extraprostatic dose). METHODS: We selected 164 high risk patients from the trial population of 266 T1-T4N0M0 patients, randomized between rectangular (n=79) and conformal fields (n=85). Prescribed dose was 66 Gy to the prostate and seminal vesicles plus 15 mm margin. We compared clinical failure rates (in- and excluding local failures), between both arms. Dose differences around the prostate were calculated based on an inter-patient mapping method. RESULTS: Median follow-up was 34 months. There were 9 clinical failures in the rectangular arm versus 24 in the conformal arm (p=0.012). Number of failures outside the prostate was 7 and 19, respectively (p=0.025). We observed average dose differences of 5-35 Gy between the arms in the regions around the prostate. CONCLUSIONS: We found a significantly lower risk of early tumor progression for patients treated with rectangular fields. Treatment failure can probably in part be prevented by irradiation of areas suspected of subclinical disease in high-risk prostate cancer. PMID- 23647757 TI - The radiosensitization effect of titanate nanotubes as a new tool in radiation therapy for glioblastoma: a proof-of-concept. AB - BACKGROUND AND PURPOSE: One of the new challenges to improve radiotherapy is to increase the ionizing effect by using nanoparticles. The interest of titanate nanotubes (TiONts) associated with radiotherapy was evaluated in two human glioblastoma cell lines (SNB-19 and U87MG). MATERIALS AND METHODS: Titanate nanotubes were synthetized by the hydrothermal treatment of titanium dioxide powder in a strongly basic NaOH solution. The cytotoxicity of TiONts was evaluated on SNB-19 and U87MG cell lines by cell proliferation assay. The internalization of TiONts was studied using Transmission Electron Microscopy (TEM). Finally, the effect of TiONts on cell radiosensitivity was evaluated using clonogenic assay. Cell cycle distribution was evaluated by flow cytometry after DNA labeling. DNA double-stranded breaks were evaluated using gammaH2AX labeling. RESULTS: Cells internalized TiONts through the possible combination of endocytosis and diffusion with no cytotoxicity. Clonogenic assays showed that cell lines incubated with TiONts were radiosensitized with a decrease in the SF2 parameter for both SNB-19 and U87MG cells. TiONts decreased DNA repair efficiency after irradiation and amplified G2/M cell-cycle arrest. CONCLUSION: Our results indicated that further development of TiONts might provide a new useful tool for research and clinical therapy in the field of oncology. PMID- 23647758 TI - Accelerated partial breast irradiation with interstitial brachytherapy as second conservative treatment for ipsilateral breast tumour recurrence: multicentric study of the GEC-ESTRO Breast Cancer Working Group. AB - PURPOSE: To analyse the clinical outcome after salvage lumpectomy and multi catheter brachytherapy (MCB) for ipsilateral breast tumour recurrence (IBTR). MATERIAL AND METHODS: Between 09/00 and 09/10, 217 patients presenting an IBTR underwent lumpectomy and MCB (low, pulsed, or high-dose rate). Survival rates without second local recurrence (2nd LR), distant metastasis (DM), and overall survival (OS) were analysed as well as late effects and cosmetic results. Univariate and multivariate analyses (MVA) based on IBTR data were performed to find prognostic factors for 2nd LR, DM, and OS. RESULTS: Median follow-up after the IBTR was 3.9 years [range: 1.1-10.3]. Five and 10-year actuarial 2nd LR rates were 5.6% [range: 1.5-9.5] and 7.2% [range: 2.1-12.1], respectively. Five and 10 year actuarial DM rates were 9.6% [range: 5.7-15.2] and 19.1% [range: 7.8-28.3], respectively. Five and 10-year actuarial OS rates were 88.7% [range: 83.1-94.8] and 76.4% [range: 66.9-87.3], respectively. In MVA, histological grade was prognostic factor for 2nd LR (p=0.008) and OS (p=0.02); while tumour size was prognostic factor for DM (p=0.03). G3-4 complication rate was 11%. Excellent/good cosmetic result was achieved in 85%. CONCLUSION: This study suggests that in case of IBTR, lumpectomy plus MCB is feasible and effective in preventing 2nd LR with an OS rate at least equivalent to those achieved with salvage mastectomy. PMID- 23647759 TI - Implementation and initial clinical experience of offline PET/CT-based verification of scanned carbon ion treatment. AB - BACKGROUND AND PURPOSE: We report on the implementation of offline PET/CT-based treatment verification at the Heidelberg Ion Beam Therapy Centre (HIT) and present first clinical cases for post-activation measurements after scanned carbon ion irradiation. Key ingredient of this in-vivo treatment verification is the comparison of irradiation-induced patient activation measured by a PET scanner with a prediction simulated by means of Monte Carlo techniques. MATERIAL AND METHODS: At HIT, a commercial full-ring PET/CT scanner has been installed in close vicinity to the treatment rooms. After selected irradiation fractions, the patient either walks to the scanner for acquisition of the activation data or is transported using a shuttle system. The expected activity distribution is obtained from the production of beta(+)-active isotopes simulated by the FLUKA code on the basis of the patient-specific treatment plan, post-processed considering the time course of the respective treatment fraction, the estimated biological washout of the induced activity and a simplified model of the imaging process. RESULTS: We present four patients with different indications of head, head/neck, liver and pelvic tumours. A clear correlation between the measured PET signal and the simulated activity pattern is observed for all patients, thus supporting a proper treatment delivery. In the case of a pelvic tumour patient it was possible to detect minor treatment delivery inaccuracies. CONCLUSIONS: The initial clinical experience proves the feasibility of the implemented strategy for offline confirmation of scanned carbon ion irradiation and therefore constitutes a first step towards a comprehensive PET/CT-based treatment verification in the clinical routine at HIT. PMID- 23647760 TI - Three-phase adaptive dose-painting-by-numbers for head-and-neck cancer: initial results of the phase I clinical trial. AB - PURPOSE: To evaluate feasibility of using deformable image co-registration in three-phase adaptive dose-painting-by-numbers (DPBN) for head-and-neck cancer and to report dosimetrical data and preliminary clinical results. MATERIAL AND METHODS: Between November 2010 and October 2011, 10 patients with non-metastatic head-and-neck cancer enrolled in this phase I clinical trial where treatment was adapted every ten fractions. Each patient was treated with three DPBN plans based on: a pretreatment 18[F]-FDG-PET scan (phase I: fractions 1-10), a per-treatment 18[F]-FDG-PET/CT scan acquired after 8 fractions (phase II: fractions 11-20) and a per-treatment 18[F]-FDG-PET/CT scan acquired after 18 fractions (phase III: fractions 21-30). A median prescription dose to the dose-painted target was 70.2 Gy (fractions 1-30) and to elective neck was 40 Gy (fractions 1-20). Deformable image co-registration was used for automatic region-of-interest propagation and dose summation of the three treatment plans. RESULTS: All patients (all men, median age 68, range 48-74 years) completed treatment without any break or acute G>=4 toxicity. Target volume reductions (mean (range)) between pre-treatment CT and CT on the last day of treatment were 72.3% (57.9-98.4) and 46.3% (11.0-73.1) for GTV and PTV(high_dose), respectively. Acute G3 toxicity was limited to dysphagia in 3/10 patients and mucositis in 2/10 patients; none of the patients lost >=20% weight. At median follow-up of 13, range 7-22 months, 9 patients did not have evidence of disease. CONCLUSIONS: Three-phase adaptive 18[F]-FDG-PET guided dose painting by numbers using currently available tools is feasible. Irradiation of smaller target volumes might have contributed to mild acute toxicity with no measurable decrease in tumor response. PMID- 23647761 TI - Palliative brachytherapy with or without primary stent placement in patients with oesophageal cancer, a randomised phase III trial. AB - PURPOSE: To investigate whether a combination of self-expanding metal stent (SEMS) and brachytherapy provided more rapid and prolonged effect on dysphagia without increased pain compared to brachytherapy alone in patients with incurable oesophageal cancer. METHODS: 41 Patients were randomised to SEMS followed by brachytherapy, 8 Gy*3 (n=21) or brachytherapy alone, 8 Gy*3 (n=20). Change in dysphagia and pain three and seven weeks after randomisation (FU1 and FU2) was assessed by patient-reported outcome. Dysphagia, other symptoms and health related quality of life were assessed every four weeks thereafter. The study was closed before the estimated patient-number was reached due to slow recruitment. RESULTS: Patients receiving SEMS followed by brachytherapy had significantly improved dysphagia at FU1 compared to patients receiving brachytherapy alone (n=35). Difference in pain was not observed. At FU2, patients in both arms (n=21) had less dysphagia. Four patients in the combined treatment arm experienced manageable complications, no complications occurred after brachytherapy alone. CONCLUSION: For the relief of dysphagia, SEMS followed by brachytherapy is preferable and safe for patients in need of immediate alleviation, while brachytherapy with or without preceding SEMS provides relief within a few weeks after treatment. PMID- 23647763 TI - School reports: at least his education didn't go to his head. PMID- 23647764 TI - ASCIA guidelines for prevention of anaphylaxis in schools, pre-schools and childcare: 2012 update. AB - Appropriate management and prevention of anaphylaxis in the school, pre-school and childcare settings requires advanced planning and communication. The Australasian Society of Clinical Immunology and Allergy has developed Guidelines for Prevention of Anaphylaxis in Schools, Pre-schools and Childcare to assist school, pre-school and childcare staff in appropriate implementation of risk minimisation strategies. Risk-minimisation strategies recommended take into consideration the needs of the allergic child; effectiveness of measures; stresses on parents and staff, the allergic child and their peers; and the implications of the recommended risk-minimisation strategies. These Guidelines address risk-minimisation strategies for food, insect and medication allergies; however, the majority of strategies relate to food allergy due to the higher risk of exposure in these settings. Training in recognition of allergic symptoms (including anaphylaxis), appropriate response and treatment, as well as how to prevent exposure to known allergens are essential for effective anaphylaxis management in the school, pre-school and childcare settings. PMID- 23647762 TI - Evaluation of the cytotoxicity, mutagenicity and antimutagenicity of a natural antidepressant, Hypericum perforatum L. (St. John's wort), on vegetal and animal test systems. AB - BACKGROUND: St. John's wort (Hypericum perforatum L.) is an herbaceous plant that is native to Europe, West Asia and North Africa and that is recognized and used worldwide for the treatment of mild and moderate depression. It also has been shown to be therapeutic for the treatment of burns, bruises and swelling and can be used for its wound healing, antiviral, antimicrobial, antioxidant, analgesic, hepato-protective and anxiolytic properties. The aim of this study was to evaluate the potential cytotoxic, mutagenic and antimutagenic action of H. Perforatum. METHODS: Meristematic cells were used as the test system for Allium cepa L., and bone marrow cells from Rattus norvegicus, ex vivo, were used to calculate the mitotic index and the percentage of chromosomal aberration. Statistical analysis was performed using the chi-square test. RESULTS: This medicinal plant had no cytotoxic potential in the vegetal test system evaluated. In the animal test system, none of the acute treatments, including intraperitoneal gavage and subchronic gavage, were cytotoxic or mutagenic. Moreover, this plant presented antimutagenic activity against the clastogenic action of cyclophosphamide, as confirmed in pre-treatment (76% reduction in damage), simultaneous treatment (95%) and post-treatment (97%). CONCLUSIONS: Thus, the results of this study suggest that the administration of H. perforatum, especially by gavage similar to oral consumption used by humans, is safe and with beneficial antimutagenic potential. PMID- 23647765 TI - Montelukast can reduce the severity and extent of atopic dermatitis. PMID- 23647770 TI - A boy with radiopacities on his abdominal X-ray. PMID- 23647771 TI - Reactive pituitary hyperplasia associated with paediatric primary hypothyroidism. PMID- 23647772 TI - Antenatal counselling: documentation and recall. PMID- 23647773 TI - Pulmonary embolus in a haemophilia patient. PMID- 23647774 TI - Preclinical radiation dosimetry for the novel SV2A radiotracer [18F]UCB-H. AB - BACKGROUND: [18F]UCB-H was developed as a novel radiotracer with a high affinity for synaptic vesicle protein 2A, the binding site for the antiepileptic levetiracetam. The objectives of this study were to evaluate the radiation dosimetry of [18F]UCB-H in a preclinical trial and to determine the maximum injectable dose according to guidelines for human biomedical research. The radiation dosimetry was derived by organ harvesting and dynamic micro positron emission tomography (PET) imaging in mice, and the results of both methods were compared. METHODS: Twenty-four male C57BL-6 mice were injected with 6.96 +/- 0.81 MBq of [18F]UCB-H, and the biodistribution was determined by organ harvesting at 2, 5, 10, 30, 60, and 120 min (n = 4 for each time point). Dynamic microPET imaging was performed on five male C57BL-6 mice after the injection of 9.19 +/- 3.40 MBq of [18F]UCB-H. A theoretical dynamic bladder model was applied to simulate urinary excretion. Human radiation dose estimates were derived from animal data using the International Commission on Radiological Protection 103 tissue weighting factors. RESULTS: Based on organ harvesting, the urinary bladder wall, liver and brain received the highest radiation dose with a resulting effective dose of 1.88E-02 mSv/MBq. Based on dynamic imaging an effective dose of 1.86E-02 mSv/MBq was calculated, with the urinary bladder wall and liver (brain was not in the imaging field of view) receiving the highest radiation. CONCLUSIONS: This first preclinical dosimetry study of [18F]UCB-H showed that the tracer meets the standard criteria for radiation exposure in clinical studies. The dose-limiting organ based on US Food and Drug Administration (FDA) and European guidelines was the urinary bladder wall for FDA and the effective dose for Europe with a maximum injectable single dose of approximately 325 MBq was calculated. Although microPET imaging showed significant deviations from organ harvesting, the Pearson's correlation coefficient between radiation dosimetry derived by either method was 0.9666. PMID- 23647775 TI - Atopic diathesis in patients with Kawasaki disease. AB - OBJECTIVE: To determine the association between Kawasaki disease (KD) and atopic diathesis (atopic dermatitis [AD], allergic rhinitis, and asthma) in children younger than 5 years of age. STUDY DESIGN: In this nationwide study, we aimed to analyze the association and temporal relationship between KD and atopic diathesis. Data were obtained from the National Health Insurance Research Database of Taiwan from 1997 to 2010. In total, 200 patients with KD younger than 5 years of age and 800 age- and sex-matched control subjects were enrolled. RESULTS: In the whole study population, an increased risk of any concomitant atopic diseases was observed in patients with KD (OR 1.61, 95% CI 1.15-2.26). The risk of AD was increased in male patients between 1 and 5 years of age (OR 3.02, 95% CI 1.22-7.50). More than 60% of the patients developed atopic diseases after the diagnosis of KD. CONCLUSION: There appears to be an association between KD and risk of AD. Most of the atopic diseases occurred after the episode of KD. PMID- 23647776 TI - Accuracy of the unified approach in maternally influenced traits--illustrated by a simulation study in the honey bee (Apis mellifera). AB - BACKGROUND: The honey bee is an economically important species. With a rapid decline of the honey bee population, it is necessary to implement an improved genetic evaluation methodology. In this study, we investigated the applicability of the unified approach and its impact on the accuracy of estimation of breeding values for maternally influenced traits on a simulated dataset for the honey bee. Due to the limitation to the number of individuals that can be genotyped in a honey bee population, the unified approach can be an efficient strategy to increase the genetic gain and to provide a more accurate estimation of breeding values. We calculated the accuracy of estimated breeding values for two evaluation approaches, the unified approach and the traditional pedigree based approach. We analyzed the effects of different heritabilities as well as genetic correlation between direct and maternal effects on the accuracy of estimation of direct, maternal and overall breeding values (sum of maternal and direct breeding values). The genetic and reproductive biology of the honey bee was accounted for by taking into consideration characteristics such as colony structure, uncertain paternity, overlapping generations and polyandry. In addition, we used a modified numerator relationship matrix and a realistic genome for the honey bee. RESULTS: For all values of heritability and correlation, the accuracy of overall estimated breeding values increased significantly with the unified approach. The increase in accuracy was always higher for the case when there was no correlation as compared to the case where a negative correlation existed between maternal and direct effects. CONCLUSIONS: Our study shows that the unified approach is a useful methodology for genetic evaluation in honey bees, and can contribute immensely to the improvement of traits of apicultural interest such as resistance to Varroa or production and behavioural traits. In particular, the study is of great interest for cases where negative correlation between maternal and direct effects and uncertain paternity exist, thus, is of relevance for other species as well. The study also provides an important framework for simulating genomic and pedigree datasets that will prove to be helpful for future studies. PMID- 23647777 TI - The effect of introducing IGRA to screen French healthcare workers for tuberculosis and potential conclusions for the work organisation. AB - INTRODUCTION: In France, pre-employment screening for tuberculosis (TB) is performed for healthcare workers (HCW). Screening is repeated when exposure to TB patients or infectious material occurs. The results of these TB screenings were analysed in a retrospective analysis. METHOD: Tuberculin skin tests (TST) and interferon-gamma release assays (QuantiFERON(r) Gold In-Tube - QFT) were used to perform the TB screenings. The screening results of 637 HCWs on whom QFT was performed were taken from the records of the University Hospital of Nantes. RESULTS: In three (0.5%) HCW, the QFT was indeterminate. In 22.2%, the QFT was positive. A second QFT was performed in 118 HCWs. The reversion rate was 42% (5 out of 17). The conversion rate was 6% (6 out of 98). A TST was performed on 466 (73.5%) of the HCWs. Results for TST > 10 mm were 77.4%. In those with a TST < 10 mm, QFT was positive in 14% and in those with a TST >= 10 mm, QFT was positive in 26.7%. Depending on the definition for conversion in the QFT, the annual attack rate was 4.1% or 7.3%. X-ray and pneumology consultation was based on positive QFT rather than TST alone (52 out of 56). No active TB was detected. CONCLUSION: The TST overestimated the prevalence of LTBI in this cohort. The decision about X ray and consultation regarding preventive treatment should be based on the QFT rather than the TST results. The high reversion rate should be taken into consideration when consulting with HCWs regarding preventive treatment. The high conversion rate seems to indicate that preventive measures such as wearing masks should be improved. PMID- 23647778 TI - Polypharmacy and mortality among nursing home residents with advanced cognitive impairment: results from the SHELTER study. AB - INTRODUCTION: Older adults with advanced cognitive impairment have a limited life expectancy and the use of multiple drugs is of questionable benefit in this population. The aim of the present study was to assess if, in a sample of nursing home (NH) residents with advanced cognitive impairment, the effect of polypharmacy on mortality differs depending on estimated life expectancy. METHODS: Data were from the Services and Health for Elderly in Long TERm care (SHELTER) project, a study collecting information on residents admitted to 57 NHs in 8 European countries. Polypharmacy was defined as the concomitant use of 10 or more drugs. Limited life expectancy was estimated based on an Advanced Dementia Prognostic Tool (ADEPT) score of 13.5 or more. A Cognitive Performance Scale score of 5 or more was used to define advanced cognitive impairment. Participants were followed for 1 year. RESULTS: Mean age of 822 residents with advanced cognitive impairment entering the study was 84.6 (SD 8.0) years, and 630 (86.6%) were women. Overall, 123 participants (15.0%) had an ADEPT score of 13.5 or more (indicating limited life expectancy) and 114 (13.9%) were on polypharmacy. Relative to residents with ADEPT score less than 13.5, those with ADEPT score of 13.5 or higher had a lower use of benzodiazepines, antidementia drugs, and statins but a higher use of beta-blockers, digoxin, and antibiotics. Polypharmacy was associated with increased mortality among residents with ADEPT score of 13.5 or more (adjusted hazard ratio [HR] 2.19, 95% confidence interval [CI]: 1.15 4.17), but not among those with ADEPT score less than 13.5 (adjusted HR 1.10, 95% CI: 0.71-1.71). DISCUSSION: Polypharmacy is associated with increased mortality in NH residents with advanced cognitive impairment at the end of life. CONCLUSION: These findings underline the need to assess life expectancy in older adults to improve the prescribing process and to simplify drug regimens. PMID- 23647779 TI - Interdisciplinary interventions and teams are good...can we move beyond that? PMID- 23647780 TI - Hypogonadism, testosterone, and nursing home residents. PMID- 23647781 TI - Inpatients' expectations and experiences of hospital pharmacy services: qualitative study. AB - INTRODUCTION: Hospital pharmacists' have traditionally focused on the manufacture and supply of medicines. However, the increasing complexity and range of medicines and a greater awareness of medication errors has facilitated a change towards a patient-centred role. Given this movement, it is surprising that a search of the published literature shows very little research that evaluated patients' views of hospital-based pharmacy services. OBJECTIVE: To explore inpatients' expectations and experiences of hospital-based pharmacy services. STUDY SETTING AND DESIGN: Face-to-face semi-structured interviews with inpatients admitted to acute medical wards of three NHS general hospitals. PRINCIPAL FINDINGS: Seventy-four inpatients were interviewed: 37 were male with average age 73 years (age range of 19-86 years). The predominate number of participants (62/74, 84%) being in the 65-80 years of age group. Thematic analysis of the data was driven by three themes; patients' expectations of the pharmacist's involvement in their treatment and care, the patients' experiences of any interaction that may have taken place and the patients' evaluation of their interaction with the pharmacist. CONCLUSIONS: There was a dichotomy of expectations and opinions from patients about the role of hospital pharmacists and the services being provided. As pharmacists' roles are developing towards a patient-orientated model in which pharmacists have direct contact with patients and their care, it is important to ensure that patients are aware of these developments to help them maximize the benefit they derive from their country's health-care system. PMID- 23647782 TI - What is health? AB - Classical medical research is disease focused and still defines health as absence of disease. Languages, however, associate a positive concept of wholeness with health as does the WHO health definition. Newer medical health definitions emphasize the capacity to adapt to changing external and internal circumstances. The results of the 2010 Global Burden of Disease study provides keys for a quantifiable health metrics by developing statistical tools calculating healthy life expectancy. Of central social and economic importance is the question whether healthy ageing can be achieved. This concept hinges on theories on the biological basis of lifespan determination and whether negligible senescence and the compression of morbidity can be achieved in human societies. Since the health impact of the human gut microbiome is currently a topical research area, microbiologists should be aware of the problems in defining health. PMID- 23647783 TI - Correlation of selection scores with subsequent assessment scores during surgical training. AB - BACKGROUND: Determining admission criteria to select candidates most likely to succeed in surgical training in Australia and New Zealand has been an imprecise art with little empirical evidence informing decisions. Selection to the Royal Australasian College of Surgeons' Surgical Education and Training programme is based entirely on applicants' performance in structured curriculum vitae (CV), referees' reports and interviews. This retrospective review compared General Surgery (GS) trainees' performance in selection with subsequent performance in assessments during training. METHODS: Data from three cohorts of GS trainees were sourced. Scores for four selection items were compared with scores from six training assessments. Interrelationships within each of the sets of selection and assessment variables were determined. RESULTS: A single significant relationship was found between scores on the three selection tools. High scores in the CV did not correlate with higher scores in any subsequent assessments. The structured referee report score, multi-station interview score and total selection score all correlated with performance in subsequent work-based assessments and examinations. Direct observation of procedural skills (DOPS) scores appear to reflect increasing acquisition of operative skills. Performance in mini clinical examinations (Mini-CEX) was variable, perhaps reflecting limitations of this assessment. Candidates who perform well in one examination tend to perform well in all three examinations. CONCLUSIONS: No selection tool demonstrated strong relationships with scores in all subsequent assessments; however referee reports, multi-station interviews and total selection scores are indicators for performance in particular assessments. This may engender confidence that candidates admitted into the GS training programme are likely to progress successfully through the programme. PMID- 23647785 TI - Tapentadol analgesic interaction with clonidine. PMID- 23647784 TI - Considerations in developing lipid-based nutrient supplements for prevention of undernutrition: experience from the International Lipid-Based Nutrient Supplements (iLiNS) Project. AB - The International Lipid-Based Nutrient Supplements (iLiNS) Project began in 2009 with the goal of contributing to the evidence base regarding the potential of lipid-based nutrient supplements (LNS) to prevent undernutrition in vulnerable populations. The first project objective was the development of acceptable LNS products for infants 6-24 months and for pregnant and lactating women, for use in studies in three countries (Burkina Faso, Ghana and Malawi). This paper shares the rationale for a series of decisions in supplement formulation and design, including those related to ration size, ingredients, nutrient content, safety and quality, and packaging. Most iLiNS supplements have a daily ration size of 20 g and are intended for home fortification of local diets. For infants, this ration size is designed to avoid displacement of breast milk and to allow for dietary diversity including any locally available and accessible nutrient-dense foods. Selection of ingredients depends on acceptability of flavour, micronutrient, anti nutrient and essential fatty acid contents. The nutrient content of LNS designed to prevent undernutrition reflects the likelihood that in many resource-poor settings, diets of the most nutritionally vulnerable individuals (infants, young children, and pregnant and lactating women) are likely to be deficient in multiple micronutrients and, possibly, in essential fatty acids. During ingredient procurement and LNS production, safety and quality control procedures are required to prevent contamination with toxins or pathogens and to ensure that the product remains stable and palatable over time. Packaging design decisions must include consideration of product protection, stability, convenience and portion control. PMID- 23647786 TI - Campylobacter coli outbreak in men who have sex with men, Quebec, Canada, 2010 2011. AB - During September 2010-November 2011, a cluster of erythromycin-susceptible, tetracycline- and ciprofloxacin-resistant Campylobacter coli pulsovar 1 infections was documented, involving 10 case-patients, in Montreal, Quebec, Canada. The findings suggested sexual transmission of an enteric infection among men who have sex with men. PMID- 23647787 TI - Pyogenic granuloma satellite of deep infection: tuberculous osteitis. PMID- 23647788 TI - Beyond pregnancy--the neglected burden of mortality in young women of reproductive age in Bangladesh: a prospective cohort study. AB - OBJECTIVE: To describe proportionate mortality and causes of death unrelated to pregnancy. DESIGN: Prospective cohort study. SETTING: Rural northwest Bangladesh. POPULATION: A cohort of 133,617 married women of reproductive age. METHODS: Verbal autopsies were conducted for women who died whilst under surveillance in the cohort trial. Physician-assigned causes of death based on verbal autopsies were used to categorise deaths. MAIN OUTCOME MEASURES: The proportion of deaths due to non-communicable diseases, infectious diseases, injury or pregnancy. RESULTS: Of the 1107 deaths occurring among women between 2001 and 2007, 48% were attributed to non-communicable diseases, 22% to pregnancy, 17% to infections, 9% to injury and 4% to other causes. CONCLUSIONS: Although focus on pregnancy related mortality remains important, more attention is warranted on non communicable diseases among women of reproductive age. PMID- 23647789 TI - Outcomes of percutaneous and paddle lead implantation for spinal cord stimulation: a comparative analysis of complications, reoperation rates, and health-care costs. AB - OBJECTIVES: Spinal cord stimulation (SCS) is a well-established modality for the treatment of chronic pain, and can utilize percutaneous or paddle leads. While percutaneous leads are less invasive, they have been shown to have higher lead migration rates. In this study, we compared the long-term outcomes and health care costs associated with paddle and percutaneous lead implantation. MATERIALS AND METHODS: We utilized the MarketScan data base to examine patients who underwent percutaneous or paddle lead SCS system implantation from 2000 to 2009. Outcomes including complications, reoperation rates, and health-care costs were evaluated in propensity score matched cohorts using univariate and multivariate analyses. RESULTS: The study cohort was comprised of 13,774 patients. At 90 days following the initial procedure, patients in the SCS paddle group were more likely to develop a postoperative complication than patients receiving percutaneous systems (3.4% vs. 2.2%, p = 0.0005). Two-year (6.3% vs. 3.5%, p = 0.0056) and long-term (five+ years) (22.9% vs. 8.5%, p < 0.0008) reoperation rates were significantly higher in those with percutaneous lead systems. However, long-term health-care costs were similar for those receiving paddle and percutaneous leads ($169,768 vs. $186,139, p = 0.30). CONCLUSIONS: While the implantation of paddle leads is associated with slightly higher initial postoperative complications, these leads are associated with significantly lower long-term reoperation rates. Nonetheless, long-term health-care costs are similar between paddle and percutaneous leads. Additional improvements in SCS technologies that address the shortcomings of current systems are needed to reduce the risk of reoperation due to hardware failure. Further study is required to evaluate the efficacy of newer percutaneous and paddle SCS systems and examine their comparative outcomes. PMID- 23647790 TI - Efficacy of allergen-specific immunotherapy for atopic dermatitis: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Allergen-specific immunotherapy (allergen-SIT) is the only treatment directed at the cause of IgE-mediated allergic diseases. However, there is controversy over the use of SIT for patients with atopic dermatitis. OBJECTIVE: We performed a systematic review and meta-analysis to assess the efficacy of SIT for patients with atopic dermatitis. METHODS: We performed manual searches of reference lists and computerized searches of the MEDLINE, EMBASE, CINAHL, Web of Science, and Cochrane databases (through December 10, 2012) for randomized controlled trials that compared SIT with placebo for patients with atopic dermatitis. The outcome of interest was a dichotomous variable, in terms of treatment success; a meta-analysis was performed by using a random-effects analysis. Subgroup analyses were carried out to evaluate the effects of long-term treatment (more than 1 year), SIT for severe atopic dermatitis, SIT for children, and subcutaneous and sublingual administration of immunotherapy. RESULTS: We analyzed 8 randomized controlled trials that comprised a total of 385 subjects. We found that SIT has a significant positive effect on atopic dermatitis (odds ratio [OR], 5.35; 95% CI, 1.61-17.77; number needed to treat, 3; 95% CI, 2-9). SIT also showed significant efficacy in long-term treatment (OR, 6.42; 95% CI, 1.50-27.52) for patients with severe atopic dermatitis (OR, 3.13; 95% CI, 1.31 7.48), and when administered subcutaneously (OR, 4.27; 95% CI, 1.36-13.39). CONCLUSIONS: A meta-analysis provides moderate-level evidence for the efficacy of SIT against atopic dermatitis. However, these findings are based on an analysis of a small number of randomized controlled trials, with considerable heterogeneity among trials. PMID- 23647791 TI - Exercise-induced normalization of right precordial negative T waves in arrhythmogenic right ventricular cardiomyopathy. AB - Negative T waves (NTWs) in right precordial leads (V1 to V3) may be observed on the electrocardiogram (ECG) of healthy subjects but can also represent the hallmark of an underlying arrhythmogenic right ventricular cardiomyopathy (ARVC). It has been a consistent observation that NTWs usually become upright with exercise in healthy subjects without underlying heart disease. No systematic study has evaluated exercise-induced changes of NTWs in ARVC. We assessed the prevalence and relation to the clinical phenotype of exercise-induced right precordial NTWs changes in 35 patients with ARVC (19 men, mean age 22.2 +/- 6.2 years). Forty-one healthy subjects with right precordial NTWs served as controls. At peak of exercise (mean power 149 +/- 43 W, mean heart rate 83.6 +/- 12.6% of target), NTWs persisted in 3 patients with ARVC (9%), completely normalized in 12 (34%), and partially reverted in 20 (57%). Patients with ARVC with or without NTWs normalization showed a similar clinical phenotype. The overall prevalence of right precordial T waves changes during exercise (normalization plus partial reversal) did not differ between patients with ARVC and controls (92% vs 88%, p = 1.0), whereas there was a statistically nonsignificant trend toward a greater prevalence of complete normalization in controls (56% vs 34%, p = 0.06). In conclusion, our study demonstrated that right precordial NTWs partially or completely revert with exercise in most patients with ARVC, and NTWs normalization is unrelated to the clinical phenotype. Exercise-induced NTWs changes are inaccurate in differentiating between ARVC patients and benign repolarization abnormalities. PMID- 23647792 TI - Joint associations of alcohol consumption and physical activity with all-cause and cardiovascular mortality. AB - Individual associations of alcohol consumption and physical activity with cardiovascular disease are relatively established, but the joint associations are not clear. Therefore, the aim of this study was to examine prospectively the joint associations between alcohol consumption and physical activity with cardiovascular mortality (CVM) and all-cause mortality. Four population-based studies in the United Kingdom were included, the 1997 and 1998 Health Surveys for England and the 1998 and 2003 Scottish Health Surveys. In men and women, respectively, low physical activity was defined as 0.1 to 5 and 0.1 to 4 MET hours/week and high physical activity as >=5 and >=4 MET-hours/week. Moderate or moderately high alcohol intake was defined as >0 to 35 and >0 to 21 units/week and high levels of alcohol intake as >35 and >21 units/week. In total, there were 17,410 adults without prevalent cardiovascular diseases and complete data on alcohol and physical activity (43% men, median age 55 years). During a median follow-up period of 9.7 years, 2,204 adults (12.7%) died, 638 (3.7%) with CVM. Cox proportional-hazards models were adjusted for potential confounders such as marital status, social class, education, ethnicity, and longstanding illness. In the joint associations analysis, low activity combined with high levels of alcohol (CVM: hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.28 to 2.96, p = 0.002; all-cause mortality: HR 1.64, 95% CI 1.32 to 2.03, p <0.001) and low activity combined with no alcohol (CVM: HR 1.93, 95% CI 1.35 to 2.76, p <0.001; all-cause mortality: HR 1.50, 95% CI 1.24 to 1.81, p <0.001) were linked to the highest risk, compared with moderate drinking and higher levels of physical activity. Within each given alcohol group, low activity was linked to increased CVM risk (e.g., HR 1.48, 95% CI 1.08 to 2.03, p = 0.014, for the moderate drinking group), but in the presence of high physical activity, high alcohol intake was not linked to increased CVM risk (HR 1.32, 95% CI 0.52 to 3.34, p = 0.555). In conclusion, high levels of drinking and low physical activity appear to increase the risk for cardiovascular and all-cause mortality, although these data suggest that physical activity levels are more important. PMID- 23647794 TI - Effect of dabigatran on referrals to and switching from warfarin in two academic anticoagulation management services. AB - Dabigatran was expected to replace warfarin for stroke prevention in patients with nonvalvular atrial fibrillation (AF) who are warfarin naive, difficult to maintain in therapeutic range, or at risk of warfarin-related bleeding complications. We hypothesized that the number of patients with nonvalvular AF referred to Anticoagulation Management Services would decrease sharply and that most would switch from warfarin to dabigatran. We evaluated the number of patients with nonvalvular AF referred to 2 large services, Anticoagulation Management Service 1 and Anticoagulation Management Service 2, 12 months before and after market entry of dabigatran. We also evaluated the number of patients who switched from warfarin to dabigatran. Anticoagulation Management Service 1 follows 1,225 patients with nonvalvular AF with mean CHADS2 and CHA2DS2-VASc scores of 2.0 and 3.5, respectively. Anticoagulation Management Service 2 follows 1,137 patients with nonvalvular AF with mean CHADS2 and CHA2DS2-VASc scores of 2.0 and 3.3, respectively. In the 12 months preceding market entry of dabigatran, patients with nonvalvular AF constituted 537 (31.4%) of the referrals sent to Anticoagulation Management Service 1 and increased to 793 (32.3%) in the following 12 months. For Anticoagulation Management Service 2, patients with nonvalvular AF constituted 617 (30.7%) of referrals before market entry of dabigatran and decreased to 495 (25.2%) of referrals. Eighty-one patients (6.6%) from Anticoagulation Management Service 1 and 44 (3.9%) from Anticoagulation Management Service 2 have switched from warfarin to dabigatran. The frequency of initial prescription of dabigatran for stroke prevention in AF and the frequency of transition from warfarin to dabigatran have been less than expected. PMID- 23647795 TI - AM bundle controls the anterior-posterior and rotational stability to a greater extent than the PL bundle - a cadaver study. AB - BACKGROUND: The purpose of this study was to evaluate the influence of both bundles of the anterior cruciate ligament (ACL) on knee stability, anterior posterior translation (APT) and internal (IR) and external (ER) rotation in cadaveric knees using a computer navigation system. METHODS: The APT, IR, and ER of the knees were recorded in the intact condition, the anterolateral bundle (AM) or the posterolateral bundle (PL) deficit condition and in the ACL-deficient condition. The KT-1000 arthrometer was used for APT evaluation. The measurement of rotational movements was done using a rollimeter. All tests were performed at 30 degrees , 60 degrees and 90 degrees of flexion. RESULTS: At 30 degrees of flexion: In the intact knee APT was 5.8mm, IR 12.1 degrees , ER 10.1 degrees . After the AM was cut, the APT increased to 9.1mm, IR to 13.9 degrees and ER to 12.6 degrees . After the PL was cut, the APT was 6.4mm, IR 13.1 degrees and ER 10.6 degrees . After the AM and PL were cut, the APT was 10.8mm, IR 15.7 degrees and the ER was 12.9 degrees on average. CONCLUSIONS: The AM has a greater impact on the APT than the PL in all knee joint flexion angles. The PL does not resist the rotational stability more than the AM. The rotational stability is better controlled by both bundles of ACL as compared to one bundle of the ACL. CLINICAL RELEVANCE: This study acknowledges the fact that the both bundles of the ACL are importants for AP and rotational stability of the knee joint. PMID- 23647796 TI - Proximal superficial femoral artery occlusion, collateral vessels, and walking performance in peripheral artery disease. AB - OBJECTIVES: We studied associations of magnetic resonance imaging (MRI)-measured superficial femoral artery (SFA) occlusions with functional performance, leg symptoms, and collateral vessel number in peripheral artery disease (PAD). We studied associations of collateral vessel number with functional performance in PAD. BACKGROUND: Associations of MRI-detected SFA occlusion and collateral vessel number with functional performance among individuals with PAD have not been reported. METHODS: A total of 457 participants with an ankle brachial index (ABI) <1.00 had MRI measurement of the proximal SFA with 12 consecutive 2.5-MUm cross sectional images. An occluded SFA was defined as an SFA in which at least 1 segment was occluded. A nonoccluded SFA was defined as absence of any occluded slices. Collateral vessels were visualized with magnetic resonance angiography. Lower extremity functional performance was measured with the 6-min walk, 4-m walking velocity at usual and fastest pace, and the Short Physical Performance Battery (SPPB) (0 to 12 scale, 12 = best). RESULTS: Adjusting for age, sex, race, comorbidities, and other confounders, the presence of an SFA occlusion was associated with poorer 6-min walk performance (1,031 vs. 1,169 feet, p = 0.006), slower fast-paced walking velocity (1.15 vs. 1.22 m/s, p = 0.042), and lower SPPB score (9.07 vs. 9.75, p = 0.038) compared with the absence of an SFA occlusion. More numerous collateral vessels were associated with better 6-min walk performance (0 to 3 collaterals-1,064 feet, 4 to 7 collaterals-1,165 feet, >=8 collaterals-1,246 feet, p trend = 0.007), faster usual-paced walking speed (0 to 3 collaterals-0.84 m/s, 4 to 7 collaterals-0.88 m/s, >=8 collaterals-0.91 m/s, p trend = 0.029), and faster rapid-paced walking speed (0 to 3 collaterals-1.17 m/s, 4 to 7 collaterals-1.22 m/s, >=8 collaterals-1.29 m/s, p trend = 0.002), adjusting for age, sex, race, comorbidities, ABI, and other confounders. CONCLUSIONS: Among PAD participants, MRI-visualized occlusions in the proximal SFA are associated with poorer functional performance, whereas more numerous collaterals are associated with better functional performance. (Magnetic Resonance Imaging to Identify Characteristics of Plaque Build-Up in People With Peripheral Arterial Disease; NCT00520312). PMID- 23647798 TI - Consequences of delayed therapy for sports-related bleeds in patients with mild to-moderate haemophilia and type 3 von Willebrand's disease not on prophylaxis. PMID- 23647797 TI - A roadmap of cell-type specific gene expression during sequential stages of the arbuscular mycorrhiza symbiosis. AB - BACKGROUND: About 80% of today's land plants are able to establish an arbuscular mycorrhizal (AM) symbiosis with Glomeromycota fungi to improve their access to nutrients and water in the soil. On the molecular level, the development of AM symbioses is only partly understood, due to the asynchronous development of the microsymbionts in the host roots. Although many genes specifically activated during fungal colonization have been identified, genome-wide information on the exact place and time point of their activation remains limited. RESULTS: In this study, we relied on a combination of laser-microdissection and the use of Medicago GeneChips to perform a genome-wide analysis of transcription patterns in defined cell-types of Medicago truncatula roots mycorrhized with Glomus intraradices. To cover major stages of AM development, we harvested cells at 5-6 and at 21 days post inoculation (dpi). Early developmental stages of the AM symbiosis were analysed by monitoring gene expression in appressorial and non appressorial areas from roots harbouring infection units at 5-6 dpi. Here, the use of laser-microdissection for the first time enabled the targeted harvest of those sites, where fungal hyphae first penetrate the root. Circumventing contamination with developing arbuscules, we were able to specifically detect gene expression related to early infection events. To cover the late stages of AM formation, we studied arbusculated cells, cortical cells colonized by intraradical hyphae, and epidermal cells from mature mycorrhizal roots at 21 dpi. Taken together, the cell-specific expression patterns of 18014 genes were revealed, including 1392 genes whose transcription was influenced by mycorrhizal colonization at different stages, namely the pre-contact phase, the infection of roots via fungal appressoria, the subsequent colonization of the cortex by fungal hyphae, and finally the formation of arbuscules. Our cellular expression patterns identified distinct groups of AM-activated genes governing the sequential reprogramming of host roots towards an accommodation of microsymbionts, including 42 AM-activated transcription factor genes. CONCLUSIONS: Our genome-wide analysis provides novel information on the cell-specific activity of AM-activated genes during both early and late stages of AM development, together revealing the road map of fine-tuned adjustments of transcript accumulation within root tissues during AM fungal colonization. PMID- 23647799 TI - A systematic approach to the planning, implementation, monitoring, and evaluation of integrated health services. AB - BACKGROUND: Because of the current emphasis and enthusiasm focused on integration of health systems, there is a risk of piling resources into integrated strategies without the necessary systems in place to monitor their progress adequately or to measure impact, and to learn from these efforts. The rush to intervene without adequate monitoring and evaluation will continue to result in a weak evidence base for decision making and resource allocation. Program planning and implementation are inextricability linked to monitoring and evaluation. Country level guidance is needed to identify country-specific integrated strategies, thereby increasing country ownership. DISCUSSION: This paper focuses on integrated health services but takes into account how health services are influenced by the health system, managed by programs, and made up of interventions. We apply the principles in existing comprehensive monitoring and evaluation (M&E) frameworks in order to outline a systematic approach to the M&E of integration for the country level. The approach is grounded by first defining the country-specific health challenges that integration is intended to affect. Priority points of contact for care can directly influence health, and essential packages of integration for all major client presentations need to be defined. Logic models are necessary to outline the plausible causal pathways and define the inputs, roles and responsibilities, indicators, and data sources across the health system. Finally, we recommend improvements to the health information system and in data use to ensure that data are available to inform decisions, because changes in the M&E function to make it more integrated will also facilitate integration in the service delivery, planning, and governance components. SUMMARY: This approach described in the paper is the ideal, but its application at the country level can help reveal gaps and guide decisions related to what health services to prioritize for integration, help plan for how to strengthen systems to support health services, and ultimately establish an evidence base to inform investments in health care. More experience is needed to understand if the approach is feasible; similarly, more emphasis is needed on documenting the process of designing and implemented integrated interventions at the national level. PMID- 23647800 TI - Tacrolimus fails to regulate collagen expression in dermal fibroblasts. AB - BACKGROUND: The purpose of this study was to investigate the effects of tacrolimus on human fibroblasts derived from unwounded skin, hypertrophic scars (HTS), and keloids. We hypothesized that tacrolimus, a potent anti-inflammatory and immunosuppressant drug known to attenuate solid organ transplant fibrosis, would block collagen expression in human dermal fibroblasts. METHODS: We performed genomewide microarray analysis on human dermal fibroblasts treated with tacrolimus in vitro. We used principal component analysis and hierarchical clustering to identify targets regulated by tacrolimus. We performed quantitative polymerase chain reaction to validate the effect of tacrolimus on collagen 1 and 3 expression. RESULTS: We identified 62, 136, and 185 gene probes on microarray analysis that were significantly regulated (P < 0.05) by tacrolimus in normal, HTS, and keloid fibroblasts, respectively. Collagen pathways were not blocked after tacrolimus exposure in any of the fibroblast groups; we validated these findings using quantitative polymerase chain reaction for collagen 1 and 3. Microarray gene expression of NME/NM23 nucleoside diphosphate kinase 1 and heterogeneous nuclear ribonucleoprotein H3-2H9 were significantly downregulated (P < 0.05) by tacrolimus in both HTS and keloid fibroblast populations but not normal fibroblasts. CONCLUSIONS: Tacrolimus does not modulate the expression of collagen 1 or 3 in human dermal fibroblasts in vitro. Microarray gene expression of NME/NM23 nucleoside diphosphate kinase 1 and heterogeneous nuclear ribonucleoprotein H3-2H9 are blocked by tacrolimus in pathologic fibroblasts but not normal fibroblasts, and may represent novel genes underlying HTS and keloid pathogenesis. Tacrolimus-based anti-fibrotics might prove more effective if non fibroblast populations such as inflammatory cells and keratinocytes are targeted. PMID- 23647801 TI - Extracorporeal membrane oxygenation for resuscitation of deceased cardiac donor livers for hepatocyte isolation. AB - BACKGROUND: Deceased cardiac donors (DCDs) have become a useful source of organs for liver transplantation; nevertheless, there are concerns about the longevity of these grafts. The aim of this study was to evaluate the use of extracorporeal membrane oxygenation (ECMO) to resuscitate DCD porcine livers as a preclinical model using hepatocyte isolation and viability as a marker to assess whole-graft preservation. MATERIALS AND METHODS: We randomized Landrace pigs into three groups after cardiac death and 30 min of warm ischemia: group 1, peritoneal cooling with intravascular cooling for 2 h; group 2, ECMO for 2 h; and group 3, control (conventional intravascular cooling and retrieval). We then reperfused group 1 and 2 livers for 2 h on an ex vivo reperfusion circuit and isolated hepatocytes. RESULTS: After reperfusion, hepatocyte viability was significantly improved in the ECMO group compared to the cooling groups, as measured by trypan blue, methylthiazolyldiphenyl-tetrazolium bromide, and seeding efficiency. Glycogen and reduced glutathione content were significantly used in the ECMO group both before and after reperfusion compared with group 2. The adenosine diphosphate:adenosine triphosphate ratio showed an improved trend (lower) in the ECMO group compared with the cooling group but did not reach statistical significance either before or after reperfusion. CONCLUSIONS: This preclinical study suggests that ECMO is a viable technique for liver preservation that gives an improved yield of hepatocytes when isolated from a DCD liver, suggesting improved liver preservation. PMID- 23647802 TI - Expression of intestinal CD40 after experimental traumatic brain injury in rats. AB - BACKGROUND: Nuclear factor kappa B (NF-kappaB) has been shown to be activated in the intestine after traumatic brain injury (TBI), and results in gastrointestinal mucosal injury. In addition, CD40 has a major role in the activation of NF-kappaB and is up-regulated in inflammatory bowel disease. However, we found no study in the literature investigating the intestinal expression of CD40 after TBI. Hence, we designed the current study to explore the intestinal expression pattern of CD40 after TBI in rats. We hypothesized that CD40 could mediate inflammation and ultimately contribute to acute intestinal mucosal injury after TBI. METHODS: We randomly divided rats into control and TBI groups at 3, 6, 12, 24, and 72 h, respectively. We assessed the expression of CD40 by quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemical study, and detected the levels of tumor necrosis factor-alpha (TNF-alpha), intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) by enzyme-linked immunosorbent assay. RESULTS: The mRNA and protein levels of -CD40 increased by 3 and 6 h, peaked at 6 and 12 h, and remained elevated until 24 and 72 h post-injury, respectively. Levels of TNF-alpha, VCAM-1, and ICAM-1 also markedly increased in jejunum tissue after TBI. Interestingly, there was a positive relationship between the expression of CD40 and that of TNF-alpha, VCAM 1, and ICAM-1. CONCLUSIONS: CD40 could be markedly elevated in intestine after TBI in rats, and it might have an important role in the pathogenesis of acute intestinal mucosal injury mediated by inflammatory response. PMID- 23647803 TI - The prevalence of Hirschsprung disease in premature infants after suction rectal biopsy. AB - BACKGROUND: The prevalence of Hirschsprung disease (HD) in the premature infant population is not well documented. However, delayed passage of stool is common in premature infants, and suction rectal biopsy (SRB) is often used to evaluate for HD in this population. The use of SRB is unknown. Therefore, we evaluated the role of SRB in premature infants with abnormal stooling patterns. METHODS: After Institutional Review Board approval, a retrospective study was conducted on all infants having an SRB performed to exclude HD from January 2000 to December 2010. Infants were divided into two groups according to gestational age (premature < 37 wk; term >= 37 wk). Demographics, diagnosis, treatments, and outcomes were collected. A subset analysis was performed on patients diagnosed with HD. RESULTS: Two hundred sixty-nine infants were identified (113 premature and 156 term). Six premature infants (5.3%) and 79 term infants (50.6%) were found to have HD (P < 0.01). As expected, gestational age was significantly different between groups (31.7 versus 38.9 wk, P < 0.01) (Table 1). Premature infants were less likely to have prenatal care (35% versus 55%, P < 0.01) and had longer lengths of hospital stay (45.6 versus 17.6 d, P < 0.01). The most common location of aganglionosis was rectosigmoid in both groups (group 1, 50%; group 2, 33%, P = 0.7). CONCLUSIONS: HD occurs significantly less often in premature infants than in term infants. Alternative diagnoses should be investigated in this population when delayed stooling patterns are encountered. SRB should be used more selectively in this group. PMID- 23647804 TI - Cognitive training for improving executive function in chemotherapy-treated breast cancer survivors. AB - BACKGROUND: A majority of breast cancer (BC) survivors, particularly those treated with chemotherapy, experience long-term cognitive deficits that significantly reduce quality of life. Among the cognitive domains most commonly affected include executive functions (EF), such as working memory, cognitive flexibility, multitasking, planning, and attention. Previous studies in other populations have shown that cognitive training, a behavioral method for treating cognitive deficits, can result in significant improvements in a number of cognitive skills, including EF. MATERIALS AND METHODS: In this study, we conducted a randomized controlled trial to investigate the feasibility and preliminary effectiveness of a novel, online EF training program in long-term BC survivors. A total of 41 BC survivors (21 active, 20 wait list) completed the 48 session training program over 12 weeks. The participants were, on average, 6 years after therapy. RESULTS: Cognitive training led to significant improvements in cognitive flexibility, verbal fluency and processing speed, with marginally significant downstream improvements in verbal memory as assessed via standardized measures. Self-ratings of EF skills, including planning, organizing, and task monitoring, also were improved in the active group compared with the wait list group. CONCLUSIONS: Our findings suggest that EF skills may be improved even in long-term survivors by using a computerized, home-based intervention program. These improvements may potentially include subjective EF skills, which suggest a transfer of the training program to real-world behaviors. PMID- 23647805 TI - Opting out of dialysis - Exploring patients' decisions to forego dialysis in favour of conservative non-dialytic management for end-stage renal disease. AB - BACKGROUND: Dialysis prolongs the life of people with end-stage renal disease (ESRD), but for patients who are elderly and suffer multiple comorbid illnesses the benefits of dialysis may be outweighed by its negative consequences. Non dialytic conservative management has therefore become an alternative treatment route, yet little is known on patients' experience with choosing end-of-life treatment. AIMS: To gain insight into the decision-making process leading to opting out of dialysis and the experience with conservative non-dialytic management from the patients' perspective. DESIGN: Qualitative study using semi structured interviews. Interpretative phenomenological analysis was undertaken as the framework for data analysis. SETTING/PARTICIPANTS: N = 9 ESRD participants who have taken the decision to forego dialysis were recruited from the advanced care programme under the National Healthcare Group, Singapore. RESULTS: Participants discussed life since ESRD diagnosis, and the personal and contextual factors that led them to choose conservative management. The perceived physical and financial burden of dialysis both for the individual but most importantly for their family, uncertainty over likely gains over risks which were fuelled by communication of negative dialysis stories of others, coupled with sense of life completion and achievement led them to refuse dialysis. All participants took ownership of their decision despite contrary advice by doctors and were content with their decision and current management. CONCLUSIONS: Study highlights the factors driving patients' decisions for conservative non-dialytic management over dialysis to allow medical professionals to offer appropriate support to patients through their decision-making process and in caring them for the rest of their lives. PMID- 23647806 TI - Advances in sex determination in bats and its utility in wind-wildlife studies. AB - We developed a simple and reliable genetic method to determine sex in bats from the Vespertilionidae and Molossidae families. Polymerase chain reaction was used to amplify a portion of the introns within the zinc-finger-X (Zfx) and zinc finger-Y (Zfy) genes. We designed primers to produce size variation between the Zfx and Zfy products that could be visualized using gel electrophoresis. Using an example from our wind-wildlife research, we show how sex data generated using this method are superior to sex data based on external morphology. Our method allows for the generation of sex data across a wide range of bats that can be used to address key questions in wildlife forensics, behavioural ecology, conservation and evolutionary biology. PMID- 23647807 TI - Estimation of change of bone structures after total hip replacement using bone remodeling simulation. AB - BACKGROUND: The principal cause of femoral stem failure is the loosening of the total hip replacement due to bone resorption in the vicinity of the prosthesis (stress shielding). Bone rebuilds its structure continuously according to the daily mechanical stimuli. Therefore, surgical intervention alters the mechanical condition of bone severely. In this study, we propose a method to predict the change of bone structure after total hip replacement using bone remodeling simulation. METHOD: The bone-stem complex structure model after total hip replacement was reconstructed based on CT-images used for preoperative planning by orthopedic experts. The bone remodeling simulation was conducted under the daily loading condition using our previous remodeling model, and the average equivalent stresses in the Gruen zone were evaluated. FINDINGS: The predicted bone loss relevant to stress shielding was consistent to follow-up clinical data. Moreover, the remodeling simulation when using the stems of different size for the same patient could detect the size-dependent change of stress in the Gruen zone. In particular, the zone under the neck of the stem showed significant changes of stress and large bone loss, accompanying the risk of loosening or fracture. INTERPRETATIONS: Prediction of bone structure changes after total hip replacement gives us significant information for longevity of prosthesis. Simulation results showed that the present computational framework could be considered to have potential in preoperative planning of total hip replacement. PMID- 23647808 TI - Liver surgery in the multidisciplinary management of gastrointestinal stromal tumour. AB - INTRODUCTION: After the introduction of tyrosine kinase inhibitors (TKIs), the role of surgical resection in treating liver metastasis from gastrointestinal stromal tumour (GIST) is unclear. In this study, we evaluated the outcome of patients treated with TKIs followed by surgery for metastatic GIST. METHODS: Eleven patients underwent liver resection after downsizing TKIs therapy for metastatic GIST from 2006 until 2010 were reviewed. RESULTS: One and two-year overall survival rates were 80.8 and 70.7%. All patients with an initially resectable tumour were still alive without recurrence. Patients operated on clinical response had a better outcome (1- and 2-year overall survival (OS) rate 100%) than those operated on disease progression (1- and 2-year OS rates 60 and 40%; P = 0.043). No deaths were observed among patients who achieved an R0 resection (R0 versus R1/R2, P = 0.001). DISCUSSION: R0 resection and clinical response to TKI are predictor of survival. Surgical resection should be performed as soon as feasible in responding patients. In poor responders, surgery may not add any survival benefit, except in localized progressive disease. In resectable metastatic liver disease, preoperative TKIs or upfront surgery followed by adjuvant therapy could be considered. Larger studies are needed to determine the optimum approach in patients with metastatic GIST. PMID- 23647809 TI - Delayed diagnosis of chronic Q fever and cardiac valve surgery. AB - Untreated chronic Q fever causes a high number of complications and deaths. We present cases of chronic Q fever that were not diagnosed until after the patients underwent cardiac valve surgery. In epidemic areas, Q fever screening of valve surgery patients secures early initiation of treatment and can prevent illness and death. PMID- 23647810 TI - Juvenile idiopathic arthritis in the new world of biologics. AB - Juvenile idiopathic arthritis results in significant pain and disability in both children and adults. Advances in treatment resulting in improved long-term outcomes have occurred; however, an emphasis on early and aggressive diagnosis and management hopes to improve outcomes further. Juvenile idiopathic arthritis remains a clinical diagnosis of exclusion, but further research may delineate biological markers associated with the disease and its subtypes. Therapy for patients includes intra-articular steroid injections, disease modifying agents such as methotrexate and biological agents. Biological agents have provided exciting new therapeutic options in the last decade; however, long-term side effects of modulating the immune system are not yet fully understood. Systemic steroids may also be required but their long-term use is avoided. Uveitis needs to be screened for in all of those with the diagnosis. Multidisciplinary team care is required in managing these young people. PMID- 23647811 TI - Unsaturated fatty acids differ between hepatic colorectal metastases and liver tissue without tumour in humans: results from a randomised controlled trial of intravenous eicosapentaenoic and docosahexaenoic acids. AB - INTRODUCTION: Mediators derived from the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid oxidation have been shown to have tumour promoting effects in experimental models, while n-3 PUFAs are thought to be protective. Here we report fatty acid concentrations in hepatic colorectal metastases compared to liver tissue without tumour in humans. METHODS: Twenty patients with colorectal liver metastasis were randomized to receive a 72 h infusion of parenteral nutrition with or without n-3 PUFAs. Histological samples from liver metastases and liver tissue without tumour were obtained from 15 patients at the time of their subsequent liver resection (mean 8 days (range 4-12) post-infusion) and the fatty acid composition determined by gas chromatography. RESULTS: There were no significant differences in fatty acid composition between the two intervention groups. When data from all patients were combined, liver tissue without tumour had a higher content of both n-3 and n-6 PUFAs and a lower content of oleic acid and total n-9 fatty acids compared with tumour tissue (p<0.0001, 0.0002,<0.0001 and <0.0001, respectively). The n-6/n-3 PUFA ratio was found to be higher in tumour tissue than tissue without tumour (p<0.0001). CONCLUSIONS: Hepatic colorectal adenocarcinoma metastases have a higher content of n-9 fatty acids and a lower content of n-6 and n-3 PUFAs than liver tissue without tumour. PMID- 23647812 TI - Association between gestational diabetes mellitus and subsequent overactive bladder among premenopausal female twins. AB - OBJECTIVE: To investigate the association between a history of gestational diabetes mellitus (GDM) and overactive bladder (OAB) in women of premenopausal age. DESIGN: Population-based study. SETTING: The Swedish Twin Register. POPULATION: In 2005, a total of 14 094 female twins born between 1959 and 1985 in the Swedish Twin Registry participated in a comprehensive survey on common exposures and complex diseases. Structured questions provided information on GDM and OAB. The present study was designed as a cross-sectional analysis including all women in the cohort having given birth before 2005 (n = 7855). METHODS: A logistic regression model based on generalised estimating equations was used to derive odds ratios (ORs). MAIN OUTCOME MEASURE: The association between a history of GDM and OAB was estimated using ORs with 95% confidence intervals (CIs). RESULTS: The prevalence of OAB in women with a history of GDM was 19.1% compared with 10.7% in women without GDM. This corresponded to a two-fold increased odds of OAB in women with a history of gestational diabetes (OR 2.13, 95% CI 1.48 3.05). After adjusting the analysis for age, body mass index, parity, smoking, and diabetes mellitus, having had GDM was associated with doubled odds of OAB (OR 1.88, 95% CI 1.26-2.80). CONCLUSIONS: A history of GDM was positively associated with OAB among women of premenopausal age. The association does not seem to be mediated by body mass index or type-I or type-II diabetes mellitus. PMID- 23647813 TI - Catastrophic failure of a Boston Scientific Artisan spinal cord stimulator. PMID- 23647814 TI - Oral immunization with an attenuated Salmonella Gallinarum mutant as a fowl typhoid vaccine with a live adjuvant strain secreting the B subunit of Escherichia coli heat-labile enterotoxin. AB - BACKGROUND: The Salmonella Gallinarum (SG) lon/cpxR deletion mutant JOL916 was developed as a live vaccine candidate for fowl typhoid (FT), and a SG mutant secreting an Escherichia coli heat-labile enterotoxin B subunit (LTB), designated JOL1229, was recently constructed as an adjuvant strain for oral vaccination against FT. In this study, we evaluated the immunogenicity and protective properties of the SG mutant JOL916 and the LTB adjuvant strain JOL1229 in order to establish a prime and boost immunization strategy for each strain. In addition, we compared the increase in body weight, the immunogenicity, the egg production rates, and the bacteriological egg contamination of these strains with those of SG 9R, a widely used commercial vaccine. RESULTS: Plasma IgG, intestinal secretory IgA (sIgA), and cell-mediated responses were significantly induced after a boost inoculation with a mixture of JOL916 and JOL1229, and significant reductions in the mortality of chickens challenged with a wild-type SG strain were observed in the immunized groups. There were no significant differences in increases in body weight, cell-mediated immune responses, or systemic IgG responses between our vaccine mixture and the SG 9R vaccine groups. However, there was a significant elevation in intestinal sIgA in chickens immunized with our mixture at 3 weeks post-prime-immunization and at 3 weeks post-boost immunization, while sIgA levels in SG 9R-immunized chickens were not significantly elevated compared to the control. In addition, the SG strain was not detected in the eggs of chickens immunized with our mixture. CONCLUSION: Our results suggest that immunization with the LTB-adjuvant strain JOL1229 can significantly increase the immune response, and provide efficient protection against FT with no side effects on body weight, egg production, or egg contamination. PMID- 23647815 TI - Acute pain control challenges with buprenorphine/naloxone therapy in a patient with compartment syndrome secondary to McArdle's disease: a case report and review. AB - OBJECTIVE: We report the first case of non-iatrogentic exertional rhabdomyolysis leading to acute compartment syndrome in a patient with McArdle's disease. We describe considerations of concurrent buprenorphine/naloxone therapy during episodes of severe acute pain. DESIGN: Case report. CASE PRESENTATION: A 50-year old male with a history of McArdle's disease, taking buprenorphine/naloxone for chronic pain and opioid dependence, presented to the Emergency Department with severe bilateral anterior thigh pain. Over the following 8 hours, he was given a total of 12 mg of intravenous hydromorphone with minimal pain relief. The decision was made to initiate patient-controlled analgesia (PCA) with hydromorphone started at 0.5 mg as needed with a 15-minute lockout. Subsequently, the patient's anterior thighs were found to be extremely tense. His creatine kinase level rose to 198,688 units/L and compartment pressures were greater than 90 mm Hg bilaterally. The patient was taken for emergent bilateral fasciotomies. The hydromorphone PCA was increased to 0.8 mg as needed with a 15-minute lockout and a basal rate of 0.5 mg/h. The patient's reported pain plateaued at 3/10 intensity 2 days after surgery, and he was transitioned to oxycodone and hydrocodone/acetaminophen. He followed up with his pain management physician 2 months later who restarted suboxone and a buphrenorphine transdermal patch. DISCUSSION: Buprenorphine/naloxone is being prescribed off-label with increasing frequency for pain management in patients with or without a history of opioid abuse. Severe acute pain is more difficult to control with opioid analgesics in patients taking buprenorphine/naloxone, requiring higher than usual doses. If buprenorphine/naloxone is discontinued to better treat acute pain with other opioids, monitoring for overdose must take place for at least 72 hours. PMID- 23647816 TI - Leptospirosis in horses. AB - Leptospirosis in horses has been considered a relatively uncommon infection. However, recent data suggest that the infection is widespread, with the incidence and infecting serovars varying considerably in different geographical regions. The majority of infections remain asymptomatic. Clinical signs in equine leptospirosis resemble those seen in other animal species. However, leptospirosis as a cause of acute respiratory distress is becoming more frequently recognised. A particular feature of equine leptospirosis is post infection recurrent uveitis (moon blindness or periodic ophthalmia), which appears to be mediated by autoimmune mechanisms involving cross reactivity between ocular tissues and leptospiral membrane proteins. There are no leptospiral vaccines licensed for use in horses, with no prospect for any becoming available in the foreseeable future. Accordingly, prevention of equine leptospirosis must rely on good hygiene practices, minimisation of rodent contact, and vaccination of other species of production and companion animals. PMID- 23647817 TI - [Prevalence of genotype-specific HPV infection among women in France: implications for screening and vaccination]. AB - OBJECTIVES: To assess human papillomavirus (HPV) prevalence and genotype distribution by age and cervical cytology/histology status among women undergoing routine gynecological examinations, and to discuss the possible impact on preventive strategies. PATIENTS AND METHODS: Liquid-based cytology (LBC) samples were tested for HPV DNA, mRNA, and HPV genotypes. Women with ASC-US+ and/or at least one positive HPV test were referred to colposcopy. Those with normal colposcopy results had biopsies taken at the 6 and 12 o'clock positions of the normal transformation zone. RESULTS: Of the 5002 women, 515 (10.3 %) were less than 25 and 4487 (89.7 %) were 25 years old or more. Overall HPV prevalence was 10.1 % to 16.1 % depending on the assay. HPV prevalence increased with the cytological and histological severity of cervical lesions. Prevalence of HPV 16/18 was 5.2 % and 2.7 % in women less than 25 and 25 years old or more, respectively. HPV 16 was the type most strongly associated with a diagnosis of CIN3+ (odds ratio=11.64 versus HPV 16 absent, P<0.001). A high proportion of high grade cervical lesions (60.6 % of genotyping assay-positive CIN2+) were associated with HPV types 31, 33, 45, 52, or 58. DISCUSSION ET CONCLUSION: These data indicate that almost all young women could benefit from HPV prophylactic vaccination, but confirm the need for continued cervical screening and highlight the need for future vaccines to target a wider range of HPV types. PMID- 23647818 TI - [Professional liability insurance of the resident in gynecology-obstetric: is it still possible to have safety private practice in France?]. PMID- 23647819 TI - [2013 annual meeting of the International Society for the Study of Women's Sexual Health (ISSWSH), 28 February-3 March 2013, New Orleans, Louisiana, USA. State of pharmacologial research in Women's Sexual Medicine: From testosterone to bremelatonide]. PMID- 23647820 TI - [Para-aortic lymphadectomy in question...]. PMID- 23647821 TI - Peanut-based ready-to-use therapeutic food: how acceptable and tolerated is it among malnourished pregnant and lactating women in Bangladesh? AB - Within a Medecins Sans Frontieres's nutrition programme in Kamrangirchar slum, Dhaka, Bangladesh this study was conducted to assess the acceptability of a peanut-based ready-to-use therapeutic food (RUTF) - Plumpy'nut((r)) (PPN) among malnourished pregnant and lactating women (PLW). This was a cross-sectional survey using semi-structure questionnaire that included all PLW admitted in the nutrition programme, who were either malnourished or at risk of malnutrition and who had received PPN for at least 4 weeks. A total of 248 women were interviewed of whom 99.6% were at risk of malnutrition. Overall, 212 (85%) perceived a therapeutic benefit. Despite this finding, 193 (78%) women found PPN unacceptable, of whom 12 (5%) completely rejected it after 4 weeks of intake. Reasons for unacceptability included undesirable taste (60%) and unwelcome smell (43%) - more than half of the latter was due to the peanut-based smell. Overall, 39% attributed side effects to PPN intake including nausea, vomiting, diarrhoea, abdominal distension and pain. Nearly 80% of women felt a need to improve PPN - 82% desiring a change in taste and 48% desiring a change in smell. Overall, only 146 (59%) understood the illustrated instructions on the package. Despite a perceived beneficial therapeutic effect, only two in 10 women found PPN acceptable for nutritional rehabilitation. We urge nutritional agencies and manufacturers to intensify their efforts towards developing more RUTF alternatives that have improved palatability and smell for adults and that have adequate therapeutic contents for treating malnourished PLW in Bangladesh. PMID- 23647822 TI - Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. AB - Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side effects due to non-specific cysteine modification. PMID- 23647823 TI - Dieckol, a SARS-CoV 3CL(pro) inhibitor, isolated from the edible brown algae Ecklonia cava. AB - SARS-CoV 3CL(pro) plays an important role in viral replication. In this study, we performed a biological evaluation on nine phlorotannins isolated from the edible brown algae Ecklonia cava. The nine isolated phlorotannins (1-9), except phloroglucinol (1), possessed SARS-CoV 3CL(pro) inhibitory activities in a dose dependently and competitive manner. Of these phlorotannins (1-9), two eckol groups with a diphenyl ether linked dieckol (8) showed the most potent SARS-CoV 3CL(pro) trans/cis-cleavage inhibitory effects (IC(50)s = 2.7 and 68.1 MUM, respectively). This is the first report of a (8) phlorotannin chemotype significantly blocking the cleavage of SARS-CoV 3CL(pro) in a cell-based assay with no toxicity. Furthermore, dieckol (8) exhibited a high association rate in the SPR sensorgram and formed extremely strong hydrogen bonds to the catalytic dyad (Cys145 and His41) of the SARS-CoV 3CL(pro). PMID- 23647824 TI - Design, synthesis, and DNA binding characteristics of a group of orthogonally positioned diamino, N-formamido, pyrrole- and imidazole-containing polyamides. AB - Orthogonally positioned diamino/dicationic polyamides (PAs) have good water solubility and enhanced binding affinity, whilst retaining DNA minor groove and sequence specificity compared to their monoamino/monocationic counterparts. The synthesis and DNA binding properties of the following diamino PAs: f-IPI (3a), f IPP (4), f-PIP (5), and f-PPP (6) are described. P denotes the site where a 1 propylamino group is attached to the N1-position of the heterocycle. Binding of the diamino PAs to DNA was assessed by DNase I footprinting, thermal denaturation, circular dichroism titration, biosensor surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) studies. According to SPR studies, f-IPI (3a) bound more strongly (K(eq)=2.4*10(8) M(-1)) and with comparable sequence selectivity to its cognate sequence 5'-ACGCGT-3' when compared to its monoamino analog f-IPI (1). The binding of f-IPI (3a) to 5' ACGCGT-3' via the stacked dimer motif was balanced between enthalpy and entropy, and that was quite different from the enthalpy-driven binding of its monoamino parent f-IPI (1). f-IPP (4) also bound more strongly to its cognate sequence 5' ATGCAT-3' (K(eq)=7.4*10(6) M(-1)) via the side-by-side stacked motif than its monoamino analog f-IPP (2a). Although f-PPP (6) bound via a 1:1 motif, it bound strongly to its cognate sequence 5'-AAATTT-3' (K(eq)=4.8*10(7) M(-1)), 15-times higher than the binding of its monoamino analog f-PPP (2c), albeit f-PPP bound via the stacked motif. Finally, f-PIP (5) bound to its target sequence 5'-ATCGAT 3' as a stacked dimer and it has the lowest affinity among the diamino PAs tested (Keq <1*10(5) M(-1)). This was about two times lower in affinity than the binding of its monoamino analog f-PIP (2b). The results further demonstrated that the 'core rules' of DNA recognition by monoamino PAs also apply to their diamino analogs. Specifically, PAs that contain a stacked IP core structure bind most strongly (highest binding constants) to their cognate GC doublet, followed by the binding of PAs with a stacked PP structure to two degenerate AT base pairs, and finally the binding of PAs with a PI core to their cognate CG doublet. PMID- 23647825 TI - An epigenetic modifier enhances the production of anti-diabetic and anti inflammatory sesquiterpenoids from Aspergillus sydowii. AB - The addition of a DNA methyltransferase inhibitor, 5-azacytidine, to Aspergillus sydowii fungus culture broth changed its secondary metabolites profile. Analysis of the culture broth extract led to the isolation of three new bisabolane-type sesquiterpenoids: (7S)-(+)-7-O-methylsydonol (1), (7S,11S)-(+)-12-hydroxysydonic acid (2) and 7-deoxy-7,14-didehydrosydonol (3), along with eight known compounds. The isolated compounds were evaluated for their anti-diabetic and anti inflammatory activities. Among the isolates, (S)-(+)-sydonol (4) did not only potentiate insulin-stimulated glucose consumption but also prevented lipid accumulation in 3T3-L1 adipocytes. Additionally, (S)-(+)-sydonol (4) exhibited significant anti-inflammatory activity through inhibiting superoxide anion generation and elastase release by fMLP/CB-induced human neutrophils. This is the first report on isolating a secondary metabolite with anti-diabetic and anti inflammatory activities from microorganisms. PMID- 23647826 TI - Not just simple degenerative disc disease (alkaptonuria). PMID- 23647827 TI - Comparison between the accuracy of percutaneous and open pedicle screw fixations in lumbosacral fusion. AB - BACKGROUND CONTEXT: In pedicle screw fixation, accurate insertion is essential to avoid neurological injury or weak stability. The percutaneous pedicle screw system was developed for minimally invasive spine surgery, and its safety has already been reported. However, the accuracy of percutaneous pedicle screw fixation (PPF) has not been compared with that of the open system to date. PURPOSE: To compare the accuracy of PPF with that of open pedicle screw fixation (open PF) and to investigate the risk factors associated with pedicle wall penetration. STUDY DESIGN/SETTING: A retrospective case series. PATIENT SAMPLE: The study group included 237 patients who underwent posterior pedicle screw fixation between January 2008 and October 2010 at a single institute with a total of 1,056 pedicle screw fixations completed. One hundred and twenty-six patients with 558 screws underwent open PF and 111 patients with 498 screws underwent PPF. OUTCOME MEASURES: Postoperative computerized tomography, including sagittal and coronal reformatted images. METHODS: Consecutive surgeries with either conventional open PF or PPF for anterior lumbar interbody fusion or transforaminal lumbar interbody fusion were performed. The open pedicle screw employed was from the WSH system (Winova, Seoul, Korea), and the two percutaneous pedicle screw systems were the Sextant (Medtronics, Minneapolis, MN, USA) and the Viper systems (DePuy Spine, Raynham, MA, USA). Computed tomography images were evaluated to determine pedicle wall penetration after operation. Severity was classified as mild (<3 mm), moderate (3-6 mm), and severe (>=6 mm), and the direction was assessed as medial, lateral, inferior, and superior. RESULTS: Pedicle wall penetration occurred in 75 patients (13.4%) in the open PF group and 71 patients (14.3%) in the PPF group and was not statistically different between the groups (p=.695). Assessment of the severity of the pedicle wall penetration revealed that minor penetration was the most common (open PF group, 9.7%; PPF group, 10.6%), although the distribution of the degree of severity was not statistically different between the groups (p=.863). A relatively higher incidence of lateral penetration was observed in the open PF group (66.7% vs. 43.7%), whereas medial, superior, and inferior penetrations were higher in the PPF group (p=.033). Other parameters such as age, sex, surgical method, and surgeon factors did not influence the penetration rate, but bone mineral densitometry negatively correlated with the penetration. CONCLUSIONS: Pedicle wall penetration during screw fixation was not different between the open PF and PPF groups. The lateral, paraspinal, muscle-splitting approach seems to lessen medial wall penetration, especially in the S1 vertebra. Distribution of the direction of penetration differs between the groups, with lateral wall penetration being more prominent in the open PF group. Careful placement of pedicle screws is necessary for a stronger construct because of the high incidence of penetration. PMID- 23647828 TI - Data coverage of a cancer registry in southern Iran before and after implementation of a population-based reporting system: a 10-year trend study. AB - BACKGROUND: Cancer registries help to decrease the burden of cancers by collecting accurate and complete data. We aimed to measure the completeness of coverage of information recorded between 2000 and 2009 in a cancer registry program in Fars province, southern Iran. METHODS: The cancer registry program run by Shiraz University of Medical Sciences was investigated in two periods: pathology-based data from 2000 to 2007 and population-based data from 2007 to 2009. Completeness of yearly coverage was measured as the number of reported cases of cancer in each year divided by estimated cases based on 107.3 new cases per 100 000 individuals. The percentage of complete data registration (patient's name, age, gender, address, phone number and father's name) and correct cancer encoding was calculated for each year and compared to the maximum acceptable error rate for each item. RESULTS: A total of 29 277 non-duplicate cancer records were studied. Completeness of coverage varied from 22.68% in 2000 to 118.7% in 2008. Deficiencies in patients' demographic data were highest for name in 2002 (0.09%), age in 2006 (2.36%), gender in 2001 (0.06%) and father's name in 2001 (52.5%). Incomplete address (99.7%) and missing phone number (100%) were most frequent in 2000, and deficiencies in encoding information were highest in 2008 (6.36%). CONCLUSIONS: The cancer registry program in Fars province (southern Iran) was considered satisfactory in terms of completeness of coverage and information about age. However, it was deficient in recording patients' phone number and address, and father's name. The error level for cancer encoding was unacceptably high. Enhancing hardware and software resources, education and motivation in all public and private sectors involved in the cancer registry program, and greater attention to epidemiological research are needed to increase the quality of the cancer registry program, including its completeness. PMID- 23647829 TI - Evaluation of the potency of two novel bispyridinium oximes (K456, K458) in comparison with oxime K203 and trimedoxime to counteract tabun-induced neurotoxicity in rats. AB - The ability of two newly developed bispyridinium oximes (K456, K458) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with oxime K203 and trimedoxime using the functional observational battery. The neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (200 MUg/kg i.m.; 85% of LD50 value) were evaluated. Tabun induced neurotoxicity was monitored by the functional observational battery and automatic measurement of motor activity at 2 hr after tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun poisoned rats to survive till the end of experiment. Both newly developed oximes (K456, K458) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease tabun-induced acute neurotoxicity was slightly higher than that of trimedoxime and oxime K203, but the difference in neuroprotective efficacy among all oximes studied is not large enough to make a decision about replacement of commonly used oximes (especially trimedoxime and obidoxime) in the treatment of acute tabun poisonings. PMID- 23647831 TI - Interleukin-1beta induces tumor necrosis factor-alpha secretion from rat hepatocytes. AB - AIM: Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine involved in various inflammatory diseases. The only production of TNF-alpha in the liver is thought to be from hepatic macrophages known as Kupffer cells, predominantly in response to bacterial lipopolysaccharide (LPS). METHODS: Primary cultured rat hepatocytes were used to analyze TNF-alpha expression in response to the pro inflammatory cytokine, interleukin-1beta (IL-1beta). Livers of rats subjected to LPS-induced endotoxemia were analyzed. RESULTS: Immunocytochemistry and enzyme linked immunosorbent assays demonstrated that IL-1beta-treated rat hepatocytes secreted TNF-alpha, and RNA analyses indicated that TNF-alpha mRNA was induced specifically by IL-1beta. Northern blot analysis showed that not only mRNA, but also a natural antisense transcript (asRNA), was transcribed from the rat Tnf gene in IL-1beta-treated hepatocytes. TNF-alpha was detected in the hepatocytes of LPS-treated rats. Both TNF-alpha mRNA and asRNA were expressed in the hepatocytes of LPS-treated rats, human hepatocellular carcinoma and human monocyte/macrophage cells. To disrupt the interaction between TNF-alpha asRNA and TNF-alpha mRNA, sense oligonucleotides corresponding to TNF-alpha mRNA were introduced into rat hepatocytes resulting in significantly increased levels of TNF-alpha mRNA. One of these sense oligonucleotides increased a half-life of TNF alpha mRNA, suggesting that the TNF-alpha asRNA may reduce the stability of TNF alpha mRNA. CONCLUSION: IL-1beta-stimulated rat hepatocytes are a newly identified source of TNF-alpha in the liver. TNF-alpha mRNA and asRNA are expressed in rats and humans, and the TNF-alpha asRNA reduces the stability of the TNF-alpha mRNA. Hepatocytes and TNF-alpha asRNA may be therapeutic targets to regulate levels of TNF-alpha mRNA. PMID- 23647830 TI - Evolutionary relationships of ATP-Binding Cassette (ABC) uptake porters. AB - BACKGROUND: The ATP-Binding Cassette (ABC) functional superfamily includes integral transmembrane exporters that have evolved three times independently, forming three families termed ABC1, ABC2 and ABC3, upon which monophyletic ATPases have been superimposed for energy-coupling purposes [e.g., J Membr Biol 231(1):1-10, 2009]. The goal of the work reported in this communication was to understand how the integral membrane constituents of ABC uptake transporters with different numbers of predicted or established transmembrane segments (TMSs) evolved. In a few cases, high resolution 3-dimensional structures were available, and in these cases, their structures plus primary sequence analyses allowed us to predict evolutionary pathways of origin. RESULTS: All of the 35 currently recognized families of ABC uptake proteins except for one (family 21) were shown to be homologous using quantitative statistical methods. These methods involved using established programs that compare native protein sequences with each other, after having compared each sequence with thousands of its own shuffled sequences, to gain evidence for homology. Topological analyses suggested that these porters contain numbers of TMSs ranging from four or five to twenty. Intragenic duplication events occurred multiple times during the evolution of these porters. They originated from a simple primordial protein containing 3 TMSs which duplicated to 6 TMSs, and then produced porters of the various topologies via insertions, deletions and further duplications. Except for family 21 which proved to be related to ABC1 exporters, they are all related to members of the previously identified ABC2 exporter family. Duplications that occurred in addition to the primordial 3 -> 6 duplication included 5 -> 10, 6 -> 12 and 10 -> 20 TMSs. In one case, protein topologies were uncertain as different programs gave discrepant predictions. It could not be concluded with certainty whether a 4 TMS ancestral protein or a 5 TMS ancestral protein duplicated to give an 8 or a 10 TMS protein. Evidence is presented suggesting but not proving that the 2TMS repeat unit in ABC1 porters derived from the two central TMSs of ABC2 porters. These results provide structural information and plausible evolutionary pathways for the appearance of most integral membrane constituents of ABC uptake transport systems. CONCLUSIONS: Almost all integral membrane uptake porters of the ABC superfamily belong to the ABC2 family, previously established for exporters. Most of these proteins can have 5, 6, 10, 12 or 20 TMSs per polypeptide chain. Evolutionary pathways for their appearance are proposed. PMID- 23647832 TI - Laparoscopy and peritoneal cytology: important prognostic tools to guide treatment selection in gastric adenocarcinoma. AB - BACKGROUND: Previous studies have suggested that patients with occult peritoneal metastases not seen on preoperative imaging have poor prognosis. In this study, we aim to evaluate the utility and impact of staging laparoscopy and peritoneal cytology in patients with gastric adenocarcinoma. METHODS: A retrospective analysis of patients with gastric adenocarcinoma managed at two major metropolitan hospitals in Melbourne, Australia, between January 1999 and July 2010 was undertaken. The main outcome measures were the number of patients in whom laparoscopy and/or peritoneal cytology changed treatment intent, and the overall survival of patients with occult metastases detected by laparoscopy/cytology. RESULTS: Staging laparoscopy as an independent procedure was performed in 74.3% (148/199) of patients who had neither unequivocal metastases (M1) on preoperative imaging nor early T1 disease on endoscopic ultrasound. Laparoscopy/cytology detected occult metastases in 38 (25.6%) patients (27 macroscopic M1 and 11 microscopic M1 with positive peritoneal cytology only), leading to change in the treatment intent in 37 cases. The median overall survivals of patients with metastatic disease detected at staging laparoscopy (8.3 months, 95% confidence interval (CI) 5.4-16.5) or on peritoneal cytology (4.9 months, 95% CI 4.2-48) were as poor as those with M1 disease seen on preoperative imaging (6.7 months, 95% CI 4.2-8.9), P = 0.97. CONCLUSIONS: Laparoscopy and peritoneal cytology add incremental value to modern imaging in the staging of gastric adenocarcinomas by detecting occult metastatic disease. Their utility needs to be optimized to allow better treatment selection for gastric cancer patients. PMID- 23647833 TI - The effectiveness of voluntary modifications of gait pattern to reduce the knee adduction moment. AB - It has been suggested to use gait modifications in the retraining of patients with knee osteoarthritis (OA), in order to reduce the external knee adduction moment (KAdM). This study focused on the effect of walking speed, foot position and trunk sway, and on the 3D knee moments. Gait analyses of fourteen healthy volunteers were performed in a gait laboratory. Subjects walked at three different speeds in their normal gait pattern, as well as with toe-in and toe-out gait and with medio-lateral trunk sway at a self-selected speed. Fast walking speed increased the KAdM (17-30%) and flexion moment (32%). A slower walking speed did not decrease the KAdM. Toe-in mainly decreased the KAdM (45%) and the transverse moment (38%) during early stance. Toe-out decreased the KAdM during late stance (56%), but increased the KAdM during early stance and midstance (21 24%), due to decreased endorotation of the hip with knee flexion. Trunk sway decreased the KAdM during early stance and midstance (31-33%). Gait modifications mainly affected the KAdM, but changes in sagittal and transverse knee moments and kinematics were also observed. This indicates that, when estimating knee load, taking only the frontal plane kinetics into consideration may lead to erroneous simplifications. No conclusive beneficial effects were found in any of the gait modifications throughout the entire stance phase. PMID- 23647835 TI - Adherence to national diet and physical activity objectives among active duty military personnel: what are the implications? PMID- 23647834 TI - Eating patterns and leisure-time exercise among active duty military personnel: comparison to the Healthy People objectives. AB - OBJECTIVE: To assess whether active duty military personnel meet Healthy People 2010 objectives for physical activity and fruit, vegetable, and whole-grain intake; the relationship of select demographic characteristics, lifestyle factors (eg, smoking), and eating patterns (eg, frequency and location of meals) on achieving diet and exercise-related Healthy People 2010 objectives; and the relationship of eating patterns to self-reported weight gain. METHODS: Secondary data from 15,747 participants in the 2005 Department of Defense Health Related Behaviors Survey was analyzed. RESULTS: More than 57% of respondents met the Healthy People 2010 guidelines for moderate or vigorous leisure exercise but only 3% reported eating fruit (once), vegetables (3 times), and whole grains (3 times) daily. Individuals who reported gaining weight during the previous year were more likely to skip breakfast and eat at, or from, a restaurant >=2 times per week compared with those who did not gain weight (P<0.001). Regression analysis indicated that women were more likely to eat fruits (odds ratio [OR] 1.25) and vegetables (OR 1.20) and less likely than men to eat whole grains (OR 0.76) or engage in moderate or vigorous exercise (OR 0.71). Military personnel who skipped breakfast >=2 times per week (OR 0.45) or ate at a restaurant/takeout food (OR 0.54) >=2 times per week were significantly less likely to meet Healthy People 2010 guidelines for food intake (defined as achieving a daily intake of one or more fruits, three or more vegetables, and three or more servings of whole grains) and exercise (OR 0.88 and 0.82, respectively). CONCLUSIONS: Although the majority of military personnel met guidelines for physical activity, their intake of fruits, vegetables, and whole grains was suboptimal. Skipping breakfast and eating at, or from, restaurants were risk factors for poor nutrient intake and associated with weight gain. These data suggest that skipping breakfast and eating out deter achieving Healthy People 2010 objectives and provide targets for military programs to promote achieving these objectives. PMID- 23647837 TI - Triple coronary artery bypass graft surgery in a patient with factor VII deficiency: a case report. PMID- 23647836 TI - Trends in relative mortality between Hispanic and non-Hispanic whites initiating dialysis: a retrospective study of the US Renal Data System. AB - BACKGROUND: Hispanic patients undergoing long-term dialysis experience better survival compared with non-Hispanic whites. It is unknown whether this association differs by age, has changed over time, or is due to differential access to kidney transplantation. STUDY DESIGN: National retrospective cohort study. SETTING & PARTICIPANTS: Using the US Renal Data System, we identified 615,618 white patients 18 years or older who initiated dialysis therapy between January 1, 1995, and December 31, 2007. PREDICTORS: Hispanic ethnicity (vs non Hispanic whites), year of end-stage renal disease incidence, age (as potential effect modifier). OUTCOMES: All-cause and cause-specific mortality. RESULTS: We found that Hispanics initiating dialysis therapy experienced lower mortality, but age modified this association (P < 0.001). Compared with non-Hispanic whites, mortality in Hispanics was 33% lower at ages 18-39 years (adjusted cause-specific HR [HRcs], 0.67; 95% CI, 0.64-0.71) and 40-59 years (HRcs, 0.67; 95% CI, 0.66 0.68), 19% lower at ages 60-79 years (HRcs, 0.81; 95% CI, 0.80-0.82), and 6% lower at 80 years or older (HRcs, 0.94; 95% CI, 0.91-0.97). Accounting for the differential rates of kidney transplantation, the associations were attenuated markedly in the younger age strata; the survival benefit for Hispanics was reduced from 33% to 10% at ages 18-39 years (adjusted subdistribution-specific HR [HRsd], 0.90; 95% CI, 0.85-0.94) and from 33% to 19% among those aged 40-59 years (HRsd, 0.81; 95% CI, 0.80-0.83). LIMITATIONS: Inability to analyze Hispanic subgroups that may experience heterogeneous mortality outcomes. CONCLUSIONS: Overall, Hispanics experienced lower mortality, but differential access to kidney transplantation was responsible for much of the apparent survival benefit noted in younger Hispanics. PMID- 23647838 TI - How to avoid Twiddler's syndrome in deep brain stimulation for dystonia? PMID- 23647839 TI - Fosphenytoin induced transient pendular nystagmus. AB - Pendular nystagmus was seen after intravenous infusion of fosphenytoin for the treatment of breakthrough seizure. The oscillations were conjugate, quasi sinusoidal, and regular. The nystagmus was resolved within 12h. Phenytoin is known to cause conduction slowing. Such delays in the feedback between the cerebellum and the oculomotor neural integrator may cause instability of the integrator. An improvement in the conduction delay following post-ictal recovery may resolve the pendular nystagmus. PMID- 23647841 TI - Elevated fasting glucose levels within normal range are associated with an increased risk of metabolic syndrome in older women. AB - OBJECTIVE: The prevalence of cardiovascular disease (CVD) and metabolic syndrome (MetS) increases with increasing fasting plasma glucose (FPG) levels in an elderly population with pre-diabetes or diabetes. However, it remains unknown whether the relationship between elevated FPG and increased risks of MetS exists in older women with normoglycemia (FPG<100mg/dL). Therefore, the present study was conducted to fill the lack of information in that area. MATERIALS AND METHODS: We included 6505 apparently healthy women, aged 65years and older, with normoglycemia who participated in routine health checkups at health screening centers in Taiwan. Components of MetS (FPG, waist circumference (WC), high density lipoprotein cholesterol (HDL-C), triglycerides, and systolic/diastolic blood pressure), body mass index (BMI), low-density lipoprotein cholesterol (LDL C), total cholesterol, and percentage body fat (PBF) were examined in all subjects. RESULTS: Subjects were sub-grouped by FPG levels (<90mg/dL, 91-95mg/dL and >95mg/dL for group 1, group 2 and group 3, respectively). Subjects in group 2 and group 3 were 1.22-fold (P=0.017) and 1.25-fold (P=0.007) more likely to have MetS compared with those in group 1. Age, WC, BMI, PBF, systolic and diastolic blood pressure, total cholesterol, triglycerides, and HDL-C were significantly correlated with FPG, whereas HDL-C was negatively correlated with FPG. In a multivariate stepwise regression analysis, PBF, LDL-C, triglycerides, and age were significantly and independently associated with FPG. CONCLUSION: Among older women, the risk of MetS was significantly associated with elevated FPG even for subjects with normal FPG. Lifestyle interventions for reducing PBF and controlling dyslipidemia could help reduce the risk of MetS in this population. PMID- 23647840 TI - Direct and indirect cost burden associated with multiple sclerosis relapses: excess costs of persons with MS and their spouse caregivers. AB - BACKGROUND: MS relapses are unpredictable and can be concerning to patients and their caregivers. OBJECTIVE: To assess the direct and indirect cost burden associated with relapses of different severities in MS patients and with MS relapse frequency on spouse caregivers. METHODS: Using a U.S. insurance claims and employee disability database (1999-2011), we studied adult MS patients (ICD-9 CM: 340.x) and their spouse caregivers. A previously published algorithm to identify relapses was used to stratify: (1) MS patients into cohorts of no, low/moderate, and high severity relapse based on the most severe relapse within one year of follow-up (if any); (2) caregivers into cohorts of no, less, and more frequent relapses based on the overall frequency of relapses of their spouse. Adjusted cost differences and 95% confidence intervals evaluating the yearly incremental costs at 12 months of follow-up (MS patients) and overall (caregivers) associated with relapses are reported. RESULTS: Among the 9421 MS patients (N: no relapse=7686; low/moderate severity relapse=1220; high severity relapse=515) identified, both relapse cohorts incurred significantly higher annual incremental direct costs than the no relapse cohort (low/moderate severity=$8269 [6565-10,115]; high severity=$24,180 [20,263-28,482]) and indirect costs (low/moderate severity=$1429 [759-2147]; high severity=$2714 [1468-4035]). More frequent relapses versus no relapse also translated into a significantly greater cost burden for caregivers (direct+indirect=$1725 [376-2885]) but less frequent relapses did not. CONCLUSIONS: Relapse severity was significantly and increasingly associated with greater direct and indirect costs in MS patients. More frequent relapses also translated into a significant cost burden in spouse caregivers. PMID- 23647842 TI - Air particulate matter and cardiovascular disease: a narrative review. AB - Consistent evidences from both epidemiological and experimental studies have demonstrated that short- and long-term exposure to particulate matter (PM), in particular to the finest particles (i.e. airborne PM with aerodynamic diameter less than 2.5 MUm, PM2.5), is associated with cardiovascular morbidity and mortality. PM concentration has been linked with several clinical manifestations of cardiovascular diseases (CVD), including myocardial infarction, stroke, heart failure, arrhythmias, and venous thromboembolism. Noteworthy, some groups of subjects, like elderly, diabetics, or those with known coronary artery disease, appear specifically susceptible to the harmful effects triggered by PM exposure. Although the PM-related risk for a single individual appears relatively low, the PM-related population attributable risk is impressive. Recent studies indicate that the PM-CVD relationship is likely more complex than a mere quantitative association between overall PM concentration and disease risk. Indeed, the biological effects of PM may vary in function of both the aerodynamic diameter and the chemical composition. Moreover, it has been shown that the influence of air pollution on health is not limited to PM. Indeed, other gaseous pollutants may play an independent role in CVD, suggesting the need to develop multi pollutant preventive approaches. Causality has been recently strongly supported by observations showing reduced CVD mortality after coordinated community policies resulting in lowering PM exposure at population level. An in-depth knowledge on the heterogeneous sources, chemical compounds, and biological effects of PM may help to propose more accurate and clinically effective recommendations for this important and modifiable factor contributing to CVD burden. PMID- 23647844 TI - Nanomechanical analysis of pigmented human melanoma cells. AB - Based on hitherto measurements of elasticity of various cells in vitro and ex vivo, cancer cells are generally believed to be much softer than their normal counterparts. In spite of significant research efforts on the elasticity of cancer cells, only few studies were undertaken with melanoma cells. However, there are no reports concerning pigmented melanoma cells. Here, we report for the first time on the elasticity of pigmented human melanoma cells. The obtained data show that melanin significantly increases the stiffness of pigmented melanoma cells and that the effect depends on the amount of melanin inside the cells. The dramatic impact of melanin on the nanomechanical properties of cells puts into question widely accepted paradigm about all cancer cells being softer than their normal counterparts. Our findings reveal significant limitations of the nanodiagnosis approach for melanoma and contribute to better understanding of cell elasticity. PMID- 23647843 TI - Cyclic [G(2',5')pA(3',5')p] is the metazoan second messenger produced by DNA activated cyclic GMP-AMP synthase. AB - Recent studies identified cyclic GMP-AMP (cGAMP) as a metazoan second messenger triggering an interferon response. cGAMP is generated from GTP and ATP by cytoplasmic dsDNA sensor cGAMP synthase (cGAS). We combined structural, chemical, biochemical, and cellular assays to demonstrate that this second messenger contains G(2',5')pA and A(3',5')pG phosphodiester linkages, designated c[G(2',5')pA(3',5')p]. We show that, upon dsDNA binding, cGAS is activated through conformational transitions, resulting in formation of a catalytically competent and accessible nucleotide-binding pocket for generation of c[G(2',5')pA(3',5')p]. We demonstrate that cyclization occurs in a stepwise manner through initial generation of 5'-pppG(2',5')pA prior to cyclization to c[G(2',5')pA(3',5')p], with the latter positioned precisely in the catalytic pocket. Mutants of cGAS dsDNA-binding or catalytic pocket residues exhibit reduced or abrogated activity. Our studies have identified c[G(2',5')pA(3',5')p] as a founding member of a family of metazoan 2',5'-containing cyclic heterodinucleotide second messengers distinct from bacterial 3',5' cyclic dinucleotides. PMID- 23647846 TI - Alpha-ray spectrometry at high temperature by using a compound semiconductor detector. AB - The use of conventional radiation detectors in harsh environments is limited by radiation damage to detector materials and by temperature constraints. We fabricated a wide-band gap semiconductor radiation detector based on silicon carbide. All the detector components were considered for an application in a high temperature environment like a nuclear reactor core. The radiation response, especially to alpha particles, was measured using an (241)Am source at variable operating voltages at room temperature in the air. The temperature on detector was controlled from 30 degrees C to 250 degrees C. The alpha-particle spectra were measured at zero bias operation. Even though the detector is operated at high temperature, the energy resolution as a function of temperature is almost constant within 3.5% deviation. PMID- 23647845 TI - Prevalence of tuberculosis in pigs slaughtered at two abattoirs in Ethiopia and molecular characterization of Mycobacterium tuberculosis isolated from tuberculous-like lesions in pigs. AB - BACKGROUND: Tuberculosis (TB) is an infectious, granulomatous disease caused by acid-fast bacilli of the genus Mycobacterium. The disease affects practically all species of vertebrates. Although mammalian tuberculosis has been nearly controlled in many developed countries, it is still a serious problem in humans and domestic animals including pigs in developing countries. In Ethiopia, the prevalence of TB in pigs is not known. Therefore, this study was designed to estimate the prevalence of TB in pigs in central Ethiopia and to characterize the causative agents using molecular techniques. RESULTS: The estimated prevalence of TB was 5.8% (49/841). Age and origin of pigs were significantly associated (P<0.001) with the prevalence. In contrast, an association of sex, floor type and water source with the prevalence could not be shown. Culture positivity was confirmed in 30.6% (15/49) of the tuberculous-like lesions. Of the 15 isolates, 12 were acid fast positive while five of the latter were confirmed by multiplex PCR as members of the M. tuberculosis complex. Speciation of the five isolates further confirmed that they were M. tuberculosis, belonging to SIT1088 (two isolates) and SIT1195 (one isolate). The remaining two isolates belong to an identical spoligotype, the pattern of which was not found in the spoligotype database (SpolDB4). CONCLUSIONS: The isolation of M. tuberculosis from pigs suggests a possible risk of transmission between humans and pigs. Hence, establishing feasible control methods is required. PMID- 23647847 TI - ISO standards on test methods for water radioactivity monitoring. AB - Water is vital to humans and each of us needs at least 1.5L of safe water a day to drink. Beginning as long ago as 1958 the World Health Organization (WHO) has published guidelines to help ensure water is safe to drink. Focused from the start on monitoring radionuclides in water, and continually cooperating with WHO, the International Standardization Organization (ISO) has been publishing standards on radioactivity test methods since 1978. As reliable, comparable and 'fit for purpose' results are an essential requirement for any public health decision based on radioactivity measurements, international standards of tested and validated radionuclide test methods are an important tool for production of such measurements. This paper presents the ISO standards already published that could be used as normative references by testing laboratories in charge of radioactivity monitoring of drinking water as well as those currently under drafting and the prospect of standardized fast test methods in response to a nuclear accident. PMID- 23647848 TI - Forced-air warming in infants and children. PMID- 23647849 TI - Hypospadias surgery and locoregional anesthesia. PMID- 23647850 TI - Metatarsus adductus: development of a non-surgical treatment pathway. AB - Metatarsus adductus (MA) occurs in one to two cases per 1000 births and is the most common congenital foot deformity in newborns. The appearance is that of a curved or adducted forefoot with a normal hindfoot. A systematic literature review was conducted to answer the following question: For a child who presents with MA, what is the most evidence-based conservative treatment option? Thirteen articles were reviewed using the National Health and Medical Research Council levels of evidence and guidelines for clinical practice. Conservative treatment options reported on included the following: no treatment, stretching, splinting, serial casting, sitting and sleeping positions and footwear/orthotics. There was strong evidence supporting no treatment in the case of flexible MA. Some limited evidence was found for the treatment of semi-rigid MA. Clinicians should use these recommendations together with clinical experience when advising parents on treatment of MA. PMID- 23647851 TI - Genetic characterization of a core collection of flax (Linum usitatissimum L.) suitable for association mapping studies and evidence of divergent selection between fiber and linseed types. AB - BACKGROUND: Flax is valued for its fiber, seed oil and nutraceuticals. Recently, the fiber industry has invested in the development of products made from linseed stems, making it a dual purpose crop. Simultaneous targeting of genomic regions controlling stem fiber and seed quality traits could enable the development of dual purpose cultivars. However, the genetic diversity, population structure and linkage disequilibrium (LD) patterns necessary for association mapping (AM) have not yet been assessed in flax because genomic resources have only recently been developed. We characterized 407 globally distributed flax accessions using 448 microsatellite markers. The data was analyzed to assess the suitability of this core collection for AM. Genomic scans to identify candidate genes selected during the divergent breeding process of fiber flax and linseed were conducted using the whole genome shotgun sequence of flax. RESULTS: Combined genetic structure analysis assigned all accessions to two major groups with six sub-groups. Population differentiation was weak between the major groups (F(ST) = 0.094) and for most of the pairwise comparisons among sub-groups. The molecular coancestry analysis indicated weak relatedness (mean = 0.287) for most individual pairs. Abundant genetic diversity was observed in the total panel (5.32 alleles per locus), and some sub-groups showed a high proportion of private alleles. The average genome-wide LD (r2) was 0.036, with a relatively fast decay of 1.5 cM. Genomic scans between fiber flax and linseed identified candidate genes involved in cell-wall biogenesis/modification, xylem identity and fatty acid biosynthesis congruent with genes previously identified in flax and other plant species. CONCLUSIONS: Based on the abundant genetic diversity, weak population structure and relatedness and relatively fast LD decay, we concluded that this core collection is suitable for AM studies targeting multiple agronomic and quality traits aiming at the improvement of flax as a true dual purpose crop. Our genomic scans provide the first insights into candidate regions affected by divergent selection in flax. In combination with AM, genomic scans have the ability to increase the power to detect loci influencing complex traits. PMID- 23647852 TI - Impact of loop electrosurgical excision procedure for cervical intraepithelial neoplasia on HIV-1 genital shedding: a prospective cohort study. AB - OBJECTIVE: We sought to examine the impact of the loop electrosurgical excision procedure (LEEP) on the rate and magnitude of HIV-1 genital shedding among women undergoing treatment for cervical intraepithelial neoplasia 2/3 (CIN2/3). DESIGN: Prospective cohort study. POPULATION: Women infected with HIV-1 undergoing LEEP for CIN2/3 in Kisumu, Kenya. METHODS: Participants underwent specimen collection for HIV-1 RNA prior to LEEP and at 1, 2, 4, 6, 10, and 14 weeks post-LEEP. HIV-1 viral load was measured in cervical and plasma specimens using commercial real time polymerase chain reaction (PCR) assays, to a lower limit of detection of 40 copies per specimen. MAIN OUTCOME MEASURES: Presence and magnitude of HIV-1 RNA (copies per specimen or cps) in post-LEEP specimens, compared with baseline. RESULTS: Among women on highly active antiretroviral therapy (HAART), we found a statistically significant increase in cervical HIV-1 RNA concentration at week 2, with a mean increase of 0.43 log10 cps (95% CI 0.03-0.82) from baseline. Similarly, among women not receiving HAART, we found a statistically significant increase in HIV-1 shedding at week 2 (1.26 log10 cps, 95% CI 0.79-1.74). No other statistically significant increase in concentration or detection of cervical HIV 1 RNA at any of the remaining study visits were noted. CONCLUSIONS: In women infected with HIV undergoing LEEP, an increase in genital HIV shedding was observed at 2 but not at 4 weeks post-procedure. The current recommendation for women to abstain from vaginal intercourse for 4 weeks seems adequate to reduce the theoretical increased risk of HIV transmission following LEEP. PMID- 23647853 TI - Treatment of tularemia in patient with chronic graft-versus-host disease. AB - We describe a case of human tularemia caused by Francisella tularensis subsp. holarctica in a stem cell transplant recipient with chronic graft-versus-host disease who was receiving levofloxacin prophylaxis. The infection was characterized by pneumonia with septic complications. The patient was successfully treated with doxycycline. PMID- 23647854 TI - Kinetic analyses of trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid transport in Xenopus laevis oocytes expressing human ASCT2 and SNAT2. AB - INTRODUCTION: Trans-1-amino-3-[(18)F]fluorocyclobutanecarboxylic acid (anti [(18)F]FACBC) is a promising amino acid positron emission tomography (PET) radiotracer for visualizing prostate cancer. We previously showed that anti-FACBC is transported by amino acid transporters, especially by alanine-serine-cysteine transporter 2 (ASCT2), which is associated with tumor growth. We studied this affinity to assess the mechanism of anti-FACBC transport in prostate cancer cells. METHODS: Kinetic assays for trans-1-amino-3-fluoro-[1 (14)C]cyclobutanecarboxylic acid ([(14)C]FACBC) were performed in Xenopus laevis oocytes over-expressing either ASCT2 or sodium-coupled neutral amino acid transporter 2 (SNAT2), both of which are highly expressed in prostate cancer cells. We also examined the kinetics of [(14)C]FACBC uptake using mammalian cell lines over-expressing system L amino acid transporter 1 or 2 (LAT1 or LAT2). Results: ASCT2 and SNAT2 transported [14C]FACBC with Michaelis-Menten kinetics Km values of 96.7 +/- 45.2 MUM and 196.5 +/- 19.7 MUM, respectively. [correted]. LAT1 and LAT2 transported [(14)C]FACBC with Michaelis-Menten Km values of 230.4 +/- 184.5 MUM and 738.5 +/- 87.6 MUM, respectively. CONCLUSIONS: Both ASCT2 and SNAT2 recognize anti-FACBC as a substrate. Anti-FACBC has higher affinity for ASCT2 than for SNAT2, LAT1, or LAT2. The ASCT2-preferential transport of anti [(18)F]FACBC in cancer cells could be used for more effective prostate cancer imaging. PMID- 23647855 TI - Treatment development: can we find a better way? AB - The present paper argues that traditional approaches to treatment development, including a technological approach, a stage model, and existing inductive approaches such as functional analysis are inadequate in various ways. Treatment developing needs to focus more on theoretical development, practicality, and the fit with clients and practitioners. We argue that progress requires greater philosophical clarity, and steps to ensure a connection between philosophy of science assumptions and an analytic agenda which fits naturally with applied psychology. Theoretical progress requires distinguishing between clinical and basic models and harmonizing their relationship, and more focus on the manipulable context of action. Applied psychology needs to join in a common cause with basic psychology in domains of mutual interest, and develop basic analyses and mid-level terms that can be both scientifically progressive and clinically useful. Issues of practicality, capacity for dissemination, and public health impact need to be considered at the beginning and throughout treatment development. Issues of effectiveness, change processes, mediation, moderation, training, active components, and similar issues should be part of the evaluation system from the beginning. It is time to create a more coherent approach to treatment innovation. PMID- 23647856 TI - Why many clinical psychologists are resistant to evidence-based practice: root causes and constructive remedies. AB - Psychotherapists are taught that when a client expresses resistance repeatedly, they must understand and address its underlying sources. Yet proponents of evidence-based practice (EBP) have routinely ignored the root causes of many clinical psychologists' reservations concerning the use of scientific evidence to inform clinical practice. As a consequence, much of the resistance to EBP persists, potentially widening the already large scientist-practitioner gap. Following a review of survey data on psychologists' attitudes toward EBP, we examine six sources underpinning resistance toward EBP in clinical psychology and allied domains: (a) naive realism, which can lead clinicians to conclude erroneously that client change is due to an intervention itself rather than to a host of competing explanations; (b) deep-seated misconceptions regarding human nature (e.g., mistaken beliefs regarding the causal primacy of early experiences) that can hinder the adoption of evidence-based treatments; (c) statistical misunderstandings regarding the application of group probabilities to individuals; (d) erroneous apportioning of the burden of proof on skeptics rather than proponents of untested therapies; (e) widespread mischaracterizations of what EBP entails; and (f) pragmatic, educational, and attitudinal obstacles, such as the discomfort of many practitioners with evaluating the increasingly technical psychotherapy outcome literature. We advance educational proposals for articulating the importance of EBP to the forthcoming generation of clinical practitioners and researchers, and constructive remedies for addressing clinical psychologists' objections to EBP. PMID- 23647858 TI - Primary cardiac synovial sarcoma. AB - Primary cardiac synovial sarcoma is an extremely rare entity. The clinical and pathologic characteristics are still poorly understood, and prognostic factors influencing overall survival are still unknown. In the present study, all characteristics of reported patients, including sex, age, clinical presentations, laboratory tests, electrocardiogram, imaging findings, pathology, location, therapy, and follow-up were carefully reviewed and survival analysis was performed. The present study has summarized some key features and may provide an effective consultation for the diagnosis and treatment of the tumor. PMID- 23647857 TI - Blood transfusion and infection after cardiac surgery. AB - Cardiac surgery is the largest consumer of blood products in medicine; although believed life saving, transfusion carries substantial adverse risks. This study characterizes the relationship between transfusion and risk of major infection after cardiac surgery. In all, 5,158 adults were prospectively enrolled to assess infections after cardiac surgery. The most common procedures were isolated coronary artery bypass graft surgery (31%) and isolated valve surgery (30%); 19% were reoperations. Infections were adjudicated by independent infectious disease experts. Multivariable Cox modeling was used to assess the independent effect of blood and platelet transfusions on major infections within 60 +/- 5 days of surgery. Red blood cells (RBC) and platelets were transfused in 48% and 31% of patients, respectively. Each RBC unit transfused was associated with a 29% increase in crude risk of major infection (p < 0.001). Among RBC recipients, the most common infections were pneumonia (3.6%) and bloodstream infections (2%). Risk factors for infection included postoperative RBC units transfused, longer duration of surgery, and transplant or ventricular assist device implantation, in addition to chronic obstructive pulmonary disease, heart failure, and elevated preoperative creatinine. Platelet transfusion decreased the risk of infection (p = 0.02). Greater attention to management practices that limit RBC use, including cell salvage, small priming volumes, vacuum-assisted venous return with rapid autologous priming, and ultrafiltration, and preoperative and intraoperative measures to elevate hematocrit could potentially reduce occurrence of major postoperative infections. PMID- 23647860 TI - Heterogeneity of lung volume reduction surgery outcomes in patients selected by use of evidence-based criteria. AB - BACKGROUND: Despite its benefit, lung volume reduction surgery (LVRS) is underused, partially because of the heterogeneous responses and lack of recent outcomes data. METHODS: Data from 59 consecutive emphysema patients who underwent LVRS were analyzed. The proportion of patients responding based on 6-minute walk distance (6-MWD), exercise capacity (watts), and forced expiratory volume in 1 second (FEV1) were calculated. Baseline variables were correlated with improvements in 6-MWD, maximal watts, and FEV1. RESULTS: Eighty-eight percent of patients responded to LVRS, with a higher proportion of FEV1 and 6-MWD responders in our cohort compared with similar patients from the National Emphysema Treatment Trial. Significant associations existed between lower baseline 6-MWD and increased 6-MWD after operation (r = -0.423), more extensive emphysema and increased FEV1 (r = 0.491), and hyperinflation and increased maximal watts (r = 0.438). The probability of survival was 0.93 at 90 days, 0.90 at 1 year, and 0.80 (3 years). The lowest exercise group (<20 watts on baseline testing) had an increased risk for death (RR 13.3, p = 0.001). CONCLUSIONS: There were durable improvements in FEV1 and exercise capacity in patients meeting the National Emphysema Treatment Trial criteria. Survival was comparable to that in similar patients from the National Emphysema Treatment Trial; response rates were higher in our cohort for FEV1 and 6-MWD. Those with lower 6-MWD, more emphysema, and more hyperinflation at baseline were most likely to respond to LVRS. Those with lowest exercise capacity at baseline may have a higher risk of death after LVRS. PMID- 23647859 TI - Completion pneumonectomy: outcomes for benign and malignant indications. AB - BACKGROUND: Past series have identified completion pneumonectomy (CP) as a high risk operation. We evaluated factors affecting outcomes of CP with a selective approach to offering this operation. METHODS: We analyzed a prospective institutional database and abstracted information on patients undergoing pneumonectomy. Patients undergoing CP were compared with those undergoing primary pneumonectomy (PP). RESULTS: Between January 2000 and February 2011, 211 patients underwent pneumonectomy, of which 35 (17%) were CPs. Ten of 35 (29%) CPs were for benign disease and 25 of 35 (71%) for cancer. Major perioperative morbidity was seen in 21 of 35 (60%) with 4 (11%) perioperative deaths. In univariate analysis, postoperative bronchopleural fistula (p = 0.05) and benign diagnosis (p = 0.07) tended to be associated with perioperative mortality. All 10 patients undergoing CP for benign disease developed a major complication compared with 11 of 25 (44%) with malignancy, p = 0.002. A bronchopleural fistula (4 of 35, 11%) was more likely to occur in patients undergoing CP shortly after the primary operation (interval between lobectomy and CP; 0.28 vs 4.5 years; p = 0.018) with a trend toward a benign indication for operation (p = 0.07). Median survival after CP for benign and malignant indications was 24.3 months and 36.5 months, respectively. Comparing CP patients to those undergoing PP (n = 176), CP patients were more likely to undergo an operation for benign disease (10 of 35, 29% vs 14 of 176, 8%, p = 0.001). Perioperative mortality for PP was 10 of 176 (5.7%), and was statistically similar to CP (11%). CONCLUSIONS: Despite a selective approach, CP remains a morbid operation, particularly for benign indications. Rigorous preoperative optimization, ruling out contraindications to operation and attention to technical detail, are recommended. PMID- 23647861 TI - Performing coronary artery bypass grafting off-pump may compromise long-term survival in a veteran population. AB - BACKGROUND: There are ample data regarding the short-term outcomes of on-pump and off-pump coronary artery bypass grafting (CABG), but little is known about the long-term survival associated with these approaches. METHODS: Using the Veterans Affairs (VA) Continuous Improvement in Cardiac Surgery Program, we identified all VA patients (n = 65,097) who underwent primary isolated CABG from October 1997 to April 2011. The primary outcome measure was all-cause mortality. Age, 17 preoperative risk factors, and year of operation were used to calculate propensity scores for each patient. A greedy-match algorithm using the propensity scores matched 8,911 off-pump with 26,733 on-pump patients. Survival functions were estimated by the Kaplan-Meier method and compared by using the log-rank test. RESULTS: In the complete cohort, off-pump was used in 11,629 of 65,097 (17.9%) operations. For the matched cohort, the median follow-up was 6.7 years (interquartile range, 3.72 to 9.35 years). Risk-adjusted mortality did not differ significantly between the off-pump and on-pump groups at 1 year (4.67% vs 4.78%; risk ratio [RR], 0.98; 95% confidence interval [CI], 0.88 to 1.09) or 3 years (9.21% vs 8.89%; RR, 1.04; 95% CI, 0.96 to 1.12). However, risk-adjusted mortality was higher in the off-pump group at 5 years (14.47% vs 13.45%; RR, 1.08; 95% CI 1.02 to 1.15) and 10 years (25.18% vs 23.57%; RR, 1.07; 95% CI, 1.03 to 1.12). Overall, the hazard ratio for off-pump vs on-pump was 1.06 (95% CI, 1.00 to 1.13; p = 0.04). CONCLUSIONS: Off-pump CABG may be associated with decreased long-term survival. Further studies are needed to identify the reasons behind this finding. PMID- 23647862 TI - A statistical finite element model of the knee accounting for shape and alignment variability. AB - By characterizing anatomical differences in size and shape between subjects, statistical shape models enable population-based evaluations in biomechanics. Statistical models have largely focused on individual bones with application to implant sizing, bone fracture and osteoarthritis; however, in joint mechanics applications, the statistical models must consider the geometry of multiple structures of a joint and their relative position. Accordingly, the objectives of this study were to develop a statistical shape and alignment modeling (SSAM) approach to characterize the intersubject variability in bone morphology and alignment for the structures of the knee, to demonstrate the statistical model's ability to describe variability in a training set and to generate realistic instances for use in finite element evaluation of joint mechanics. The statistical model included representations of the bone and cartilage for the femur, tibia and patella from magnetic resonance images and relative alignment of the structures at a known, loaded position in an experimental knee simulator for a training set of 20 specimens. The statistical model described relationships or modes of variation in shape and relative alignment of the knee structures. By generating new 'virtual subjects' with physiologically realistic knee anatomy, the modeling approach can efficiently perform investigations into joint mechanics and implant design which benefit from population-based considerations. PMID- 23647863 TI - Validation of multiple subject-specific finite element models of unicompartmental knee replacement. AB - Accurate computer modelling of the fixation of unicompartmental knee replacements (UKRs) is a valuable design tool. However, models must be validated with in vitro mechanical tests to have confidence in the results. Ten fresh-frozen cadaveric knees with differing bone densities were CT-scanned to obtain geometry and bone density data, then implanted with cementless medial Oxford UKRs by an orthopaedic surgeon. Five strain gauge rosettes were attached to the tibia and femur of each knee and the bone constructs were mechanically tested. They were re-tested following implanting the cemented versions of the implants. Finite element models of four UKR tibiae and femora were developed. Sensitivity assessments and convergence studies were conducted to optimise modelling parameters. The cemented UKR pooled R(2) values for predicted versus measured bone strains were 0.85 and 0.92 for the tibia and femur respectively. The cementless UKR pooled R(2) values were slightly lower at 0.62 and 0.73 which may have been due to the irregularity of bone resections. The correlation of the results was attributed partly to the improved material property prediction method used in this project. This study is the first to validate multiple UKR tibiae and femora for bone strain across a range of specimen bone densities. PMID- 23647864 TI - An electronic nose discriminates exhaled breath of patients with untreated pulmonary sarcoidosis from controls. AB - BACKGROUND: Sarcoidosis is a systemic granulomatous disease of unknown cause that affects the lungs in over 90% of cases. Breath analysis by electronic nose technology provides exhaled molecular profiles that have potential in the diagnosis of several respiratory diseases. OBJECTIVES: We hypothesized that exhaled molecular profiling may distinguish well-characterized patients with sarcoidosis from controls. To that end we performed electronic nose measurements in untreated and treated sarcoidosis patients and in healthy controls. METHODS: 31 sarcoidosis patients (11 patients with untreated pulmonary sarcoidosis [age: 48.4 +/- 9.0], 20 patients with treated pulmonary sarcoidosis [age: 49.7 +/- 7.9]) and 25 healthy controls (age: 39.6 +/- 14.1) participated in a cross sectional study. Exhaled breath was collected twice using a Tedlar bag by a standardized method. Both bags were then sampled by an electronic nose (Cyranose C320), resulting in duplicate data. Statistical analysis on sensor responses was performed off-line by principal components (PC) analyses, discriminant analysis and ROC curves. RESULTS: Breathprints from patients with untreated pulmonary sarcoidosis were discriminated from healthy controls (CVA: 83.3%; AUC 0.825). Repeated measurements confirmed those results. Patients with untreated and treated sarcoidosis could be less well discriminated (CVA 74.2%), whereas the treated sarcoidosis group was undistinguishable from controls (CVA 66.7%) CONCLUSION: Untreated patients with active sarcoidosis can be discriminated from healthy controls. This suggests that exhaled breath analysis has potential for diagnosis and/or monitoring of sarcoidosis. PMID- 23647865 TI - Diversity selection of compounds based on 'protein affinity fingerprints' improves sampling of bioactive chemical space. AB - Diversity selection is a frequently applied strategy for assembling high throughput screening libraries, making the assumption that a diverse compound set increases chances of finding bioactive molecules. Based on previous work on experimental 'affinity fingerprints', in this study, a novel diversity selection method is benchmarked that utilizes predicted bioactivity profiles as descriptors. Compounds were selected based on their predicted activity against half of the targets (training set), and diversity was assessed based on coverage of the remaining (test set) targets. Simultaneously, fingerprint-based diversity selection was performed. An original version of the method exhibited on average 5% and an improved version on average 10% increase in target space coverage compared with the fingerprint-based methods. As a typical case, bioactivity-based selection of 231 compounds (2%) from a particular data set ('Cutoff-40') resulted in 47.0% and 50.1% coverage, while fingerprint-based selection only achieved 38.4% target coverage for the same subset size. In conclusion, the novel bioactivity-based selection method outperformed the fingerprint-based method in sampling bioactive chemical space on the data sets considered. The structures retrieved were structurally more acceptable to medicinal chemists while at the same time being more lipophilic, hence bioactivity-based diversity selection of compounds would best be combined with physicochemical property filters in practice. PMID- 23647866 TI - Prevalence of high-risk human papilloma virus among women with hepatitis C virus before liver transplantation. AB - BACKGROUND: We sought to assess the prevalence and risk factors for high-risk human papillomavirus (HPV) infection among female liver transplant (LT) candidates. Traditional health screening before LT listing has included Pap smear and is typically carried out by the patient's local provider. The prevalence of high-risk HPV in this population has not been studied. METHODS: With Institutional Review Board approval, 62 LT candidates received a liquid-based Pap smear with high-risk HPV testing as part of their pre-transplant evaluation by a single provider. Clinical variables included age, ethnicity, insurance status, prior Pap smear, and HPV results, HPV risk factors including age of first intercourse, number of lifetime partners, last sexual activity, smoking, birth control pill use, history of sexually transmitted infections, human immunodeficiency virus status, immunosuppressive medication, medical diagnoses, prescribed medications, and history of hepatitis A, B, C, or D. RESULTS: The 62 women had a median age of 56 years, and 39% had high-risk behavior known to be associated with HPV. Ten of 62 patients (16.1%) had high-risk HPV at baseline screening, 5 of whom had atypical cytology. All of the patients who were positive for high-risk HPV had an etiology of hepatitis C virus (HCV) as the underlying cause of liver disease, with the majority (90%) having no history of high-risk behavior for HPV. In contrast, all patients with high-risk behavior who were HCV negative were HPV negative. Fisher's exact test demonstrated a statistically significant relationship between HPV and HCV; odds ratio = 24.4, 95% confidence interval, 1.4, 438.7, P-value = 0.0013. None of the other potential risk factors were associated with HPV in this cohort. CONCLUSIONS: In this study, we provide evidence of a strong association between HCV and HPV in LT candidates, which has not been previously reported. HPV positivity was observed in non-sexually active women, suggesting a reactivation of dormant HPV. An association between hepatitis C and high-risk HPV could involve impairment of T-cell function by hepatitis C. These data support close surveillance in women's health screening for LT candidates. Further studies to characterize immune responses in these patients will be in order. PMID- 23647868 TI - Strategic leadership: setting priorities. PMID- 23647867 TI - Estimating postmortem interval using RNA degradation and morphological changes in tooth pulp. AB - The accurate determination of time since death, or postmortem interval (PMI), can be critical in the investigation of suspicious deaths. Knowing when a suspicious death occurred can limit the number of potential suspects to those without a viable alibi for the time of the crime. The forensic techniques currently employed to determine PMI: pathology, entomology, and anthropology, are accurate over different time periods following death. A large gap in time exists between the capabilities of forensic entomology and traditional anthropology, leaving a period in which PMI is difficult to estimate. In this study, time-dependent differences in RNA decay rates were examined to extend the time frame over which early PMI estimates can be made. Comparing the decay rates of a large, labile segment of beta-actin RNA and a smaller, more stable, non-overlapping segment of the same RNA from tooth pulp, we were able to estimate PMI values of pigs buried within a shallow grave for up to 84 days. This compares favorably to an estimate of PMI using insect data. Full skeletonization and loss of insect activity was observed by day 28 of our study. In addition to differences in RNA decay rates, morphological changes were observed in the pulp as it aged postmortem. To provide a quantitative measure of progressive color changes, analysis of digital photographs of each tooth's pulp were used to construct a simple colorimetric assay. This assay was then used to cluster ages of pulp samples by color. The two assays, used in combination with one another, can create a more precise estimate of PMI. The potential advantages of this molecular means of estimating PMI include extending the time frame for such estimates, is applicable to samples collected worldwide (no specialized knowledge of local insect fauna is required), is relatively fast, and inexpensive. PMID- 23647869 TI - The Radiology Resident iPad Toolbox: an educational and clinical tool for radiology residents. AB - Tablet computing and mobile resources are the hot topics in technology today, with that interest spilling into the medical field. To improve resident education, a fully configured iPad, referred to as the "Radiology Resident iPad Toolbox," was created and implemented at the University of Colorado. The goal was to create a portable device with comprehensive educational, clinical, and communication tools that would contain all necessary resources for an entire 4 year radiology residency. The device was distributed to a total of 34 radiology residents (8 first-year residents, 8 second-year residents, 9 third-year residents, and 9 fourth-year residents). This article describes the process used to develop and deploy the device, provides a distillation of useful applications and resources decided upon after extensive evaluation, and assesses the impact this device had on resident education. The Radiology Resident iPad Toolbox is a cost-effective, portable, educational instrument that has increased studying efficiency; improved access to study materials such as books, radiology cases, lectures, and web-based resources; and increased interactivity in educational conferences and lectures through the use of audience-response software, with questions geared toward the new ABR board format. This preconfigured tablet fully embraces the technology shift into mobile computing and represents a paradigm shift in educational strategy. PMID- 23647870 TI - Adopting pain management competencies. PMID- 23647871 TI - Assessment of drug use pattern using WHO prescribing indicators at Hawassa University Teaching and Referral Hospital, south Ethiopia: a cross-sectional study. AB - BACKGROUND: To promote rational drug use in developing countries, it is important to assess drug use pattern using the World Health Organization (WHO) drug use indicators. The aim of this study was to assess the drug prescription patterns at the Medical Outpatient Pharmacy of Hawassa University Teaching and Referral Hospital, using some of the WHO core drug use indicators. METHODS: A descriptive, quantitative, and cross-sectional survey was conducted to determine the current prescribing practices at Hawassa University Teaching and Referral Hospital. The sample was selected using systematic random sampling. 1290 patient encounters were reviewed retrospectively for a 2-year period from September 2007 to September 2009. Data were collected from prescriptions and Prescription registration books retained in the pharmacy. RESULT: The average number of drugs prescribed per encounter or mean was 1.9 (SD 0.91) with a range between 1 and 4. The percentage of encounters in which an antibiotic or injection was prescribed was 58.1% (n = 749) and 38.1% (n = 491), respectively. The Percentage of drugs prescribed by generic name and from an essential drug list was 98.7% (n=2419) and 96.6% (n=2367), respectively. The most commonly prescribed forms of antibiotics were amoxicillin (16.4%), ampicillin (15%), gentamicin (14.9%) and chloramphenicol (11.6%). On the other hand, the most commonly prescribed injections were ampicillin (21.4%), cloxacillin (13.4%), crystalline penicillin (12.4%), ceftriaxon (9.8%) gentamicin (9.8%), diclofenac (9.4%), chloramphenicol 41 (8.4%) and furosemide 25 (5.1%). CONCLUSION: On the basis of the finding of this study, the prescribing practices for antibiotic and injection shows deviation from the standard recommended by WHO. These two commonly overused and costly forms of drug therapy need to be regulated closely. Drug use evaluation should be done for some of the antibiotics to check whether they were appropriately prescribed or not. On the other hand, polypharmacy, generic prescribing and prescribing from EDL were not found to be a problem in this study. Teaching hospitals have a special responsibility to society to promote rational prescribing by their staff and, through them, the future generations of doctors. PMID- 23647873 TI - An update on Kawasaki disease II: clinical features, diagnosis, treatment and outcomes. AB - This is the second of two updates on Kawasaki disease. The first review focused on epidemiology and aetio-pathogenesis. Here, we review the clinical features and diagnosis of Kawasaki disease, as well as recent evidence on treatment, follow-up and cardiovascular outcomes. PMID- 23647874 TI - Medicines use reviews: a potential resource or lost opportunity for general practice? AB - BACKGROUND: Patient non-adherence to medicines represents a significant waste of health resource and lost opportunity for health gain. Medicine management services are a key health policy strategy to encourage patients to take medicines as they are prescribed. One such service is the English Medicines Use Review (MUR) which is an NHS-funded community pharmacy service involving a patient pharmacist consultation aiming to improve patients' knowledge of medicines and their use. To date the evidence for MURs to improve patient health outcomes is equivocal and GPs are reported to be sceptical about the value of the service. This paper presents the patient's perspective of the MUR service and focuses on the importance of GP-pharmacist collaboration for patient care. Suggestions on how MURs may have value to GPs through the delivery of increased patient benefit are discussed. METHOD: A qualitative study involving ten weeks of ethnographic observations in two English community pharmacies. Observations were made of all pharmacy activities including patient-pharmacist MUR consultations. Subsequent interviews with these patients were conducted to explore their experience of the service. Interviews with the pharmacy staff were conducted after the period of observations. A thematic approach was used to analyse the data. RESULTS: Fifty four patients agreed to have their MUR observed of which thirty-four were interviewed. Seventeen pharmacy staff were also interviewed. Patients reported positive views about MURs. However, there was little evidence suggesting that pharmacists and GPs were working collaboratively or communicating outcomes resulting from MURs. MURs were conducted in isolation from other aspects of patient care. Patients considered GPs to have authority over medicines making a few wary that MURs had the potential to cause tensions between these professionals and possibly adversely affect their own relationship with their doctor. CONCLUSIONS: This study reveals the potential for effective GP-pharmacist collaboration to improve the capacity of the MUR service to support patient medicine taking. Closer collaboration between GPs and pharmacists could potentially improve patients' use of medicines and associated health care outcomes. The current lack of such collaboration constitutes a missed opportunity for pharmacists and GPs to work together with patients to improve effective prescribing and optimise patient use of medicines. PMID- 23647875 TI - Development and characterization of a clinically relevant mouse model of melanoma brain metastasis. PMID- 23647876 TI - Oral myiasis--a case report. AB - Myiasis, a term introduced by William Hope in 1840, refers to the invasion of tissues and organs of animals and human wounds and certain body cavities by the dipteran larvae, which manifests as subcutaneous furunculoid or boil-like lesions. Oral myiasis is a rare pathology and a risk to the patient's life. A higher incidence is seen in rural areas, affecting the tropical and subtropical zones of Africa and America. It can be secondary to medical or anatomic conditions, such as cancrum oris, neglected mandibular fracture, cerebral palsy, mouth breathing, anterior open bite, incompetent lips, and use of mechanical ventilation. Myiasis also has been described after tooth extraction. All these conditions more easily allow the infestation of human tissues. Myiasis affecting the orodental complex is rare. This case report describes oral myiasis in a 25 year-old male patient who was a gardener by profession. The lesion was treated with turpentine oil, which forced the larvae out, and irrigated with normal saline solution. PMID- 23647877 TI - Multiple-parameter evaluation demonstrates low donor-site morbidity after submental flap harvesting. AB - PURPOSE: The objective of this study was to implement a scoring system to analyze the authors' experience of donor-site morbidity after harvesting a submental flap for the reconstruction of surgical defects at the head and neck region after oncologic resection. MATERIALS AND METHODS: A retrospective case series study was conducted of patients who underwent reconstruction with a submental flap at the Tri-Service General Hospital (Taipei, Taiwan) from 2008 through 2012. Five parameters representing donor-site morbidity (whistling, smiling, neck extension, beard change, and esthetic outcome) were evaluated with a scoring system developed by a blinded panel of 2 clinicians and the patients. Scores were analyzed and compared between patient subgroups. RESULTS: Twenty-two patients (20 men and 2 women; mean age, 56 yr) underwent reconstruction with a submental flap after head and neck tumor ablation. Primary lesion sites included the oral cavity (13 patients), pharynx (6 patients), larynx (1 patient), neck (1 patient), and sinus (1 patient). The means of all 5 parameters evaluated were higher than 8 on a scale of 0 to 9 (whistling, 8.7; smiling, 8.7; beard change, 8.9; neck extension, 8.2; esthetic outcome, 8.2), showing that submental flap harvesting led to low donor-site morbidity. CONCLUSIONS: Donor-site morbidity after submental flap harvesting was evaluated with a scoring system measuring 5 parameters, namely whistling, smiling, beard change, neck extension, and esthetic outcome. In general, donor-site morbidity was very low. This implemented system and these findings will be helpful in future reconstructive surgical planning and management. PMID- 23647878 TI - Odontogenic infection due to Aerococcus viridans: a case report. PMID- 23647879 TI - Predictors of mortality in cirrhotic patients undergoing extrahepatic surgery: comparison of Child-Turcotte-Pugh and model for end-stage liver disease-based indices. AB - BACKGROUND: Underlying liver cirrhosis is associated with high morbidity and mortality after surgery. Previous studies have reported conflicting results about the value of Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores as predictors of post-operative mortality. This study was designed to compare the capacities of CTP, MELD and MELD-based indices in predicting mortality for patients with liver cirrhosis who underwent elective extrahepatic surgery. METHODS: The medical records of 79 patients with liver cirrhosis who underwent elective extrahepatic surgery under general anaesthesia from December 2000 to December 2009 were reviewed retrospectively. RESULTS: The median follow up period was 21 months, and the mortality rate was 24.1% (n = 19). Among the 19 mortalities, nine (11.4%) occurred while the patient was hospitalized after surgery. Intraoperative transfusion amount (>=700 mL; odds ratio 6.294, P = 0.004) and the integrated MELD score (>=34; odds ratio 6.654, P = 0.007) were significantly correlated with post-operative mortality. CTP score (hazard ratio 1.575, P = 0.012) was significantly correlated with overall mortality. CONCLUSIONS: Integrated MELD may be a more accurate predictor of operative mortality in cirrhotic patients undergoing extrahepatic surgery than CTP and other MELD-Na based indices. However, overall mortality may be reflected more accurately by CTP score. Further large-scale study will be needed to validate this result. PMID- 23647880 TI - Incidence, clinical characteristics and 30-day mortality of enterococcal bacteraemia in Denmark 2006-2009: a population-based cohort study. AB - Enterococci currently account for approximately 10% of all bacteraemias, reflecting remarkable changes in their epidemiology. However, population-based data of enterococcal bacteraemia are scarce. A population-based cohort study comprised all patients with a first episode of Enterococcus faecalis or Enterococcus faecium bacteraemia in two Danish regions during 2006-2009. We used data collected prospectively during clinical microbiological counselling and hospital registry data. We determined the incidence of mono- and polymicrobial bacteraemia and assessed clinical and microbiological characteristics as predictors of 30-day mortality in monomicrobial bacteraemia by logistic regression analysis. We identified 1145 bacteraemic patients, 700 (61%) of whom had monomicrobial bacteraemia. The incidence was 19.6/100 000 person-years (13.0/100 000 person-years for E. faecalis and 6.6/100 000 person-years for E. faecium). The majority of bacteraemias were hospital-acquired (E. faecalis, 45.7%; E. faecium, 85.2%). Urinary tract and intra-abdominal infections were the predominant foci for the two species, respectively. Infective endocarditis (IE) accounted for 25% of patients with community-acquired E. faecalis bacteraemia. Thirty-day mortality was 21.4% in patients with E. faecalis and 34.6% in patients with E. faecium. Predictors of 30-day mortality included age, co-morbidity and hospital-acquired bacteraemia. In addition, intra-abdominal infection, unknown focus and high-level gentamicin resistance were predictors of mortality in E. faecalis patients. E. faecium was associated with increased risk of mortality compared with E. faecalis. The study emphasizes the importance of enterococci both in terms of incidence and prognosis. The frequency of IE in patients with E. faecalis bacteraemia emphasizes the importance of echocardiography, especially in community-acquired cases. PMID- 23647881 TI - Effect of induced ruminal acidosis on blood variables in heifers. AB - BACKGROUND: Ruminal acidosis is responsible for the onset of different pathologies in dairy and feedlot cattle, but there are major difficulties in the diagnosis. This study modelled the data obtained from various blood variables to identify those that could indicate the severity of ruminal acidosis. Six heifers were fed three experimental rations throughout three periods. The diets were characterised by different starch levels: high starch (HS), medium starch (MS) and low starch, as the control diet (CT). Ruminal pH values were continuously measured using wireless sensors and compared with pH measurements obtained by rumenocentesis. Blood samples were analysed for complete blood count, biochemical profile, venous blood gas, blood lipopolysaccharide (LPS) and LPS-binding proteins (LBP). RESULTS: The regression coefficient comparing the ruminal pH values, obtained using the two methods, was 0.56 (P = 0.040). Feeding the CT, MS and HS led to differences in the time spent below the 5.8, 5.5 and 5.0 pH thresholds and in several variables, including dry matter intake (7.7 vs. 6.9 vs. 5.1 kg/d; P = 0.002), ruminal nadir pH (5.69 vs. 5.47 vs. 5.44; P = 0.042), mean ruminal pH (6.50 vs. 6.34 vs. 6.31; P = 0.012), haemoglobin level (11.1 vs. 10.9 vs. 11.4 g/dL; P = 0.010), platelet count (506 vs. 481 vs. 601; P = 0.008), HCO3( ) (31.8 vs. 31.3 vs. 30.6 mmol/L; P = 0.071) and LBP (5.9 vs. 9.5 vs. 10.5 MUg/mL; P < 0.001). A canonical discriminant analysis (CDA) was used to classify the animals into four ruminal pH classes (normal, risk of acidosis, subacute ruminal acidosis and acute ruminal acidosis) using haemoglobin, mean platelet volume, beta-hydroxybutyrate, glucose and reduced haemoglobin. CONCLUSIONS: Although additional studies are necessary to confirm the reliability of these discriminant functions, the use of plasma variables in a multifactorial model appeared to be useful for the evaluation of ruminal acidosis severity. PMID- 23647882 TI - Acute coronary syndromes in older adults: a review of literature. AB - INTRODUCTION: Acute coronary syndromes (ACS) are the leading cause of death in older adults, aged 65 years or older. The clinical presentation varies, and the absence of chest pain may occur. Our purpose was to synthesize the published literature (2000-2012) to (1) examine the initial ED presentation of older adults with confirmed ACS, (2) identify knowledge gaps, (3) determine whether gender differences exist in the presentation of ACS, and (4) describe recommendations for practice and research. METHODS: A systematic review was conducted from September 2000 to September 2012. RESULTS: The review suggests that older adults with ACS report chest pain more commonly when arriving to the emergency department. Older adults have higher in-hospital mortality rates than adults aged younger than 65 years. However, older adults reporting an absence of chest pain on arrival are twice as likely to die compared with older adults with chest pain. With regard to gender differences, we note that men are more likely to present with chest pain whereas women are more likely to present with nausea. Women have higher in-hospital mortality rates both with and without chest pain presentation. Delay in time to arrival, as well as delay to primary percutaneous intervention, is reported for older adults with and without chest pain. DISCUSSION: Older adults with ACS are at risk for higher mortality rates and delays in time to treatment modalities. Early recognition of symptoms suggestive of ACS by the emergency triage nurse can improve patient outcomes. PMID- 23647883 TI - Scrub typhus outbreak, northern Thailand, 2006-2007. AB - During a scrub typhus outbreak investigation in Thailand, 4 isolates of O. tsutsugamushi were obtained and established in culture. Phylogenetic analysis based on the 56-kDa type-specific antigen gene demonstrated that the isolates fell into 4 genetic clusters, 3 of which had been previously reported and 1 that represents a new genotype. PMID- 23647884 TI - Cost and resource implications with serum angiogenic factor estimation in the triage of pre-eclampsia. AB - OBJECTIVES: To analyse the economic and resource implications of using plasma soluble fms-like tyrosine kinase-1 s(Flt1) and placenta growth factor (PlGF) measurements in pre-eclampsia evaluation and management. DESIGN: Retrospective cost analysis of our prospective cohort study. SETTING: Boston, Massachusetts (USA). POPULATION: Women (n = 176) presenting to the hospital at <34 weeks of gestation for evaluation of possible pre-eclampsia during 2009-10. Cases without complete cost or outcome data (n = 9) and re-enrolments (n = 18) were excluded. METHODS: Modelled comparisons between the standard approach (combination of blood pressure, urinary protein excretion, alanine aminotransferase and platelet counts) and a novel approach (ratio of plasma sFlt1 and PlGF) using actual hospital data converted to 2012 US dollars in accordance with the Centers for Medicare and Medicaid Services. MAIN OUTCOME MEASURES: Direct 2-week costs and resource use by groups having true or false positive and negative test results for adverse outcomes according to approach. RESULTS: The improved specificity of the novel approach decreased the proportion of women falsely labelled as test positive from 42.3% (34.4-50.2%) to 4.0% (0.85-7.15%) and increased the proportion correctly labelled as test-negative from 23.5% (16.7-30.3%) to 61.7% (53.9-69.5%). This could potentially reduce average per-patient costs by $1215. Substantial quantities of resources [47.2% (35.7-58.7%) of antenatal admissions and 72.5% (68.0-77.0%) of tests for fetal wellbeing] were unnecessarily used for women who were truly negative. A proportion of iatrogenic preterm deliveries among women with negative results was potentially avoidable representing further cost and resource savings. CONCLUSIONS: Clinical use of the plasma sFlt1 and PlGF ratio improves risk stratification among women presenting for pre-eclampsia evaluation and has the potential to reduce costs and resource use. PMID- 23647885 TI - Low and moderate photosynthetically active radiation affects the flavonol glycosides and hydroxycinnamic acid derivatives in kale (Brassica oleracea var. sabellica) dependent on two low temperatures. AB - Kale (Brassica oleracea var. sabellica) contains a large number of naturally occurring structurally different non-acylated and acylated flavonol glycosides as well as hydroxycinnamic acid derivatives. The objective of this study was to determine the effect of low and moderate photosynthetic active radiation (PAR) and how these levels interact with low temperature in these phenolic compounds. Juvenile kale plants were treated with PAR levels from 200 to 800 MUmol m(-2) s( 1) at 5 and 10 degrees C under defined conditions in climate chambers. Of the investigated 20 compounds, 11 and 17 compounds were influenced by PAR and temperature, respectively. In addition, an interaction between PAR and temperature was found for eight compounds. The response of the phenolic compounds to PAR was structure-dependent. While quercetin triglycosides increased with higher PAR at 5 and 10 degrees C, the kaempferol triglycosides exhibited the highest concentrations at 400 MUmol m(-2) s(-1). In contrast, kaempferol diglycosides exhibited the highest concentrations at increased PAR levels of 600 and 800 MUmol m(-2) s(-1) at 10 degrees C. However, key genes of flavonol biosynthesis were influenced by temperature but remained unaffected by PAR. Furthermore, there was no interaction between the PAR level and the low temperature in the response of hydroxycinnamic acid derivatives in kale with the exception of caffeoylquinic acid, which decreased with higher PAR levels of 600 and 800 MUmol m(-2) s(-1) and at a lower temperature. In conclusion, PAR and its interaction with temperature could be a suitable tool for modifying the profile of phenolic compounds. PMID- 23647886 TI - Muscle fatigue based evaluation of bicycle design. AB - Bicycling posture leads to considerable discomfort and a variety of chronic injuries. This necessitates a proper bicycle design to avoid injuries and thereby enhance rider comfort. The objective of this study was to investigate the muscle activity during cycling on three different bicycle designs, i.e., rigid frame (RF), suspension (SU) and sports (SP) using surface electromyography (sEMG). Twelve male volunteers participated in this study. sEMG signals were acquired bilaterally from extensor carpi radialis (ECR), trapezius medial (TM), latissimus dorsi medial (LDM) and erector spinae (ES), during 30 min of cycling on each bicycle and after cycling. Time domain (RMS) and frequency domain (MPF) parameters were extracted from acquired sEMG signals. From the sEMG study, it was found that the fatigue in right LDM and ES were significantly (p < 0.05) higher in SP bicycle. This was corroborated by a psychophysical assessment based on RBG pain scale. The study also showed that there was a significantly lesser fatigue with the SU bicycle than the RF and SP bicycles. PMID- 23647887 TI - Improving meat cutters' work: changes and effects following an intervention. AB - Meat cutters face higher risks of injury and musculoskeletal problems than most other occupational groups. The aims of this paper were to describe ergonomics changes implemented in three meat cutting plants and to evaluate effects related to ergonomics on the individual meat cutters and their work. Data was collected by interviews, observations, document studies and a questionnaire (n = 247), as a post intervention study. The changes implemented consisted of reducing knife work to a maximum of 6 h per day and introducing a job rotation scheme with work periods of equal length. Tasks other than traditional meat cutting were added. A competence development plan for each meat cutter and easy adjustment of workplace height were introduced. The questionnaire showed a reduction in perceived physical work load. In general, the changes were perceived positively. Figures from the company showed a positive trend for injuries and sick leave. PMID- 23647888 TI - Antioxidant system response is modified by dietary fat in adipose tissue of metabolic syndrome patients. AB - Metabolic syndrome (MetS) is associated with high oxidative stress, which is caused by an increased expression of NADPH-oxidase and a decreased expression of antioxidant enzymes in the adipose tissue. Our aim was to evaluate whether the quality and quantity of dietary fat can modify that process. A randomized, controlled trial conducted within the LIPGENE study assigned MetS patients to one of four diets for 12 wk each: (i) high-saturated fatty acid (HSFA), (ii) high monounsaturated fatty acid (HMUFA), (iii) and (iv) two low-fat, high-complex carbohydrate diet supplemented with n-3 polyunsaturated fatty acids (LFHCC n3), or placebo (LFHCC). A fat challenge reflecting the same fatty acid composition as the original diets was conducted post-intervention. The intake of an HSFA meal induced a higher postprandial increase in gp91phox and p67phox mRNA levels than after the intake of HMUFA, LFHCC and LFHCC n-3 meals (all p-values<0.05). The postprandial decrease in CAT, GPXs and TXNRD1 mRNA levels after the HSFA meal intake was higher than after the intake of HMUFA, LFHCC and LFHCC n-3 meals (all p-values<0.05). The intake of an HSFA meal induced a higher postprandial increase in KEAP1 mRNA levels than after the consumption of the HMUFA (P=.007) and LFHCC n 3 (P=.001) meals. Our study demonstrated that monounsaturated fat consumption reduces oxidative stress as compared to saturated fat by inducing higher postprandial antioxidant response in adipose tissue, and thus, replacing SFA for MUFA may be an effective dietary strategy to reduce the oxidative stress in MetS patients and its pathophysiological consequences. PMID- 23647889 TI - Effects of a yoga intervention on lipid profiles of diabetes patients with dyslipidemia. AB - OBJECTIVE: The present study was conducted to assess the effectiveness of yoga in the management of dyslipidemia in patients of type 2 diabetes mellitus. METHODS: This randomized parallel study was carried out in Medical College Trivandrum, Kerala, India. Hundred type 2 diabetics with dyslipidemia were randomized into control and yoga groups. The control group was prescribed oral hypoglycemic drugs. The yoga group practiced yoga daily for 1 h duration along with oral hypoglycemic drugs for 3 months. The lipid profiles of both the groups were compared at the start and at the end of 3 months. RESULTS: After intervention with yoga for a period of 3 months the study group showed a decrease in total cholesterol, triglycerides and LDL, with an improvement in HDL. CONCLUSION: Yoga, being a lifestyle incorporating exercise and stress management training, targets the elevated lipid levels in patients with diabetes through integrated approaches. PMID- 23647890 TI - Yoga - an ancient solution to a modern epidemic. Ready for prime time? PMID- 23647891 TI - Comparison of diagnostic utilities of ankle-brachial index and carotid intima media thickness as surrogate markers of significant coronary atherosclerosis in Indians. AB - AIM: We aimed to compare Ankle-brachial index (ABI) and Carotid intima-media thickness (CIMT) as surrogate markers of significant coronary atherosclerosis in South Indians with coronary artery disease (CAD). METHODS AND RESULTS: There were two groups: CAD group (n = 59) and Control group (n = 55). Mean ABI (0.82 +/- 0.06 vs. 1.16 +/- 0.11, p < 0.0001) and mean CIMT (0.74 +/- 0.22 mm vs. 0.45 +/- 0.09 mm, p < 0.0001) were statistically different between two groups. ABI < 0.9 (sensitivity: 91.53%, specificity: 100%) and CIMT > 0.63 mm (sensitivity: 61.02%, specificity: 98.18%) implied significant CAD. ABI and CIMT were negatively correlated to one another. With increasing severity of CAD, ABI decreased but CIMT increased. CONCLUSION: ABI and CIMT are simple noninvasive tools providing insight into coronary atherosclerosis. They can be done at bedside and easily repeated than coronary angiography. ABI < 0.9 is a better surrogate marker of significant coronary atherosclerosis than CIMT > 0.63 mm in South Indians with CAD. PMID- 23647892 TI - Coronary sinus filling time: a novel method to assess microcirculatory function in patients with angina and normal coronaries. AB - OBJECTIVE: Dysfunction of the coronary microcirculation is considered as one of the factors responsible for symptoms and abnormal stress tests in patients with angina and normal coronaries (syndrome X). We sought to evaluate the usefulness of coronary sinus filling time (CSFT) to assess coronary microcirculation in this group of patients. METHODS: We compared the CSFT of patients having definite angina or atypical angina with positive treadmill electrocardiography test (angina group), with that of patients undergoing coronary angiogram (CAG) prior to balloon mitral valvuloplasty (control group). During CAG, coronary sinus was visualized in appropriate views and CSFT in seconds was derived from frame count. Thrombolysis In Myocardial Infarction (TIMI) flow grade, corrected TIMI (cTIMI) frame count, TIMI Myocardial Perfusion grade (TMP) were assessed. RESULTS: There were 41 patients in angina group and 16 in control group. Among the angina group 68.8% were females as against 81.8% in the control group. 87.8% (n = 36) had typical angina. Mean CSFT was 4.25 +/- 0.72 s and 3.46 +/- 0.99 s in the angina group and control group respectively (p = 0.001). No significant differences were found between the groups with respect to TMP (p = 0.68) & cTIMI frame count (p = 0.22). CONCLUSION: CSFT is a simple method to assess the transit time through coronary microcirculation. CSFT was significantly delayed in patients with angina and normal coronaries. TMP and cTIMI frame count were not significantly different between groups. PMID- 23647893 TI - Fractional flow reserve: intracoronary versus intravenous adenosine induced maximal coronary hyperemia. AB - BACKGROUND: Fractional Flow Reserve (FFR), a measure of coronary stenosis severity is based on the achievement of maximal hyperemia of coronary microcirculation. The most widely used pharmacological agent is adenosine which is administered either by intra coronary or intra venous routes. IV route is time consuming, has more side effects and expensive. This study is undertaken to compare the two routes of administration. METHODS: FFR was assessed in 50 patients with 56 intermediate focal lesions using both IV and intracoronary (IC) adenosine. FFR was calculated as the ratio of the distal coronary pressure to the aortic pressure at maximal hyperemia. RESULTS: A total of 25 left anterior descending, 8 right, 21 circumflex, and 2 left main coronary arteries were evaluated. The mean percent stenosis was 63.91 +/- 13.13 SD and, the mean FFR was 0.831 +/- 0.0738 SD for IV and 0.832 +/- 0.0707 SD for IC adenosine. There was a strong and linear correlation between 2 sets of observations with IV dose and IC adenosine dose (R = 0.964, y = 0.065 + 0.923x; p < 0.001) (y = IV dose, x = IC dose). The agreement between the two sets of measurements was also high, with a mean difference of: 0.001 +/- 0.0197. The changes in heart rate and blood pressure were significantly higher in IV adenosine group. Different incremental doses were well tolerated, with fewer systemic adverse events with IC adenosine. Transient AV blocks were observed with both IV and IC adenosine. CONCLUSIONS: This study suggests that IC adenosine is equivalent to IV infusion for the determination of FFR. The administration of IC adenosine is easy to use, cost effective, safe and associated with fewer systemic events. PMID- 23647894 TI - Comparative assessment of platelet GpIIb/IIIa receptor occupancy ratio with Eptifibatide/Tirofiban in patients presenting with ACS and undergoing PCI. AB - BACKGROUND: The level of platelet inhibition by a Glycoprotein IIb/IIIa (GpIIb/IIIa) antagonist therapy necessary to minimize thrombotic complications in patients undergoing percutaneous coronary intervention (PCI) is a subject of debate. The degree of platelet inhibition obtained 10 min after start of GpIIb/IIIa antagonist therapy predicts adverse events after PCI. The aim of this study was to look at platelet inhibition and to compare platelet GpIIb/IIIa receptors occupancy ratio (GpRO) with Eptifibatide and Tirofiban using various dose regimens and correlate with 30-day clinical outcomes in patients presenting with high-risk acute coronary syndromes (ACS) and undergoing PCI. METHODS: The patients were divided into four sub groups: (1) Eptifibatide two intracoronary bolus (180 MUg/kg) alone (E(B)); or (2) two intravenous bolus (180 MUg/kg) followed by infusion at 2 MUg/kg/min for 24 h (E(B + Inf)); and (3) Tirofiban standard bolus dose (0.4 MUg/kg) over 30 min followed by infusion at 0.1 MUg/kg/min (T(Std)); or (4) at ADVANCE dose bolus (25 MUg/kg) over 3 min, followed by infusion at 0.1 MUg/kg/min (T(Adv)). Number of GpIIb/IIIa receptors was assessed by flow cytometry at baseline and 10 min after the bolus and percentage of free receptors was determined to calculate the GpRO. Patients were followed for 30 days for any major adverse cardiac events (MACE). RESULTS: 200 consecutive patients (including 74% with ST-elevation ACS) were enrolled. GpRO in groups E(B) (n = 48) and E(B + Inf) (n = 44) were 62.7% +/- 27.2% and 61.4% +/- 6.1% respectively while in the groups T(Std) (n = 96) and T(Adv) (n = 12) groups were 35.1% +/- 17.74% and 68.8% +/- 27.3% respectively. The GpRO was similar in E(B), E(B + Inf) and T(Adv) groups and was significantly higher than T(Std) group (p < 0.0001). The 30-day MACE rates in E(B) (4.2%), E(B + Inf) (4.5%) and T(Adv) (4.2%) were significantly lower than T(Std) group (12.5%) (p < 0.01). CONCLUSIONS: Standard dose Tirofiban results in significantly lower rates of GpIIb/IIIa receptor occupancy ratio and this correlated with higher incidence of 30-day MACE in high-risk ACS patients undergoing PCI. PMID- 23647896 TI - Oral flecainide is effective in management of refractory tachycardia in infants. AB - BACKGROUND: Propranolol and digoxin have been used as first line drugs for treatment of supraventricular tachycardia (SVT) in infants. Flecainide and other drugs have been effective as a second line treatment for controlling refractory SVT. MATERIAL AND METHODS: This is a prospective study without randomization and control. The inclusion criteria were: infants (<=12 months) with tachyarrhythmia who failed to respond to first line drugs. Patients having post-surgical arrhythmias were excluded from the study. RESULTS: A total of 8 infants were treated with flecainide for refractory tachyarrhythmia's. Diagnosis on electrocardiogram (ECG) was atrioventricular reentry tachycardia (AVRT) in 5, atrial ectopic tachycardia (AET) in 2, a combination of AVRT and atrioventricular nodal reentry tachycardia (AVNRT) in 1. All patients had failed trial of antiarrhythmic drugs prior to presentation: digoxin and propranolol in 7, amiodarone in 3, cardioversion in 1. Flecainide (80-130 mg/m(2) orally) resulted in termination of the tachycardia in all 8 patients. Acute pharmacological termination of arrhythmia occurred with oral flecainide loading in 1 and temporarily with intravenous esmolol loading in 1 patient. Adjuvant therapy in form of propranolol was used in 5 and digoxin in 2. There were no side effects noted. Four episodes of recurrence were noted in 3 patients over 2 years, all of which responded to dose increase. Mean follow up time is 24.75 months. CONCLUSION: This small case series indicates that flecainide is an effective antiarrhythmic agent, free of side effects and when used orally is capable of terminating and controlling relatively resistant supraventricular tachycardia in children. PMID- 23647895 TI - Polymorphisms of MDR1, CYP2C19 and P2Y12 genes in Indian population: effects on clopidogrel response. AB - AIMS/OBJECTIVE: Influence of genetic variations on the response of clopidogrel, an antiplatelet drug is implicated. In the present study, the prevalence of single nucleotide polymorphisms of MDR1 (C3435T), CYP2C19 [CYP2C19*2 CYP2C19*3, CYP2C19*17] and P2Y12 (i-T744C) in Indian population and their effects on clopidogrel response was analyzed. METHODS AND RESULTS: To analyze the prevalence of polymorphisms, 102 healthy individuals were recruited. Clopidogrel response was assessed by ADP induced platelet aggregation in clopidogrel naive acute myocardial infarction (AMI) patients (n = 26) screened from 100 AMI cases, before loading dose of 300 mg, at 24 h before next dose and 6 days after on 75 mg per day and platelet aggregation inhibition (PAI) was calculated between these time intervals. Genotyping was carried out by PCR-based restriction enzyme digestion method for C3435T of MDR1 and i-T744C of P2Y12, by multiplex PCR for CYP2C19*2 (G681A) and CYP2C19*3 (G636A) and by nested PCR for CYP2C19*17 (C806T). The effect of the above mentioned genetic variations on PAI was analyzed. Variant allele of CYP2C19*3 was not observed while the prevalence of 3435T of MDR1 (0.524), CYP2C19*2 (681A, 0.352); i-744C of P2Y12 (0.088), as well as wild type allele CYP2C19*17 (C806, 0.897) associated with decrease clopidogrel response were observed. Trend toward poor response to clopidogrel was observed at 24 h with the variant genotypes of CYP2C19*2 and i-T744C of P2Y12 as compared to wild type. CONCLUSION: The present study did show a trend toward impaired response of clopidogrel to inhibit platelet aggregation with variant genotypes of CYP2C19*2 and iT744C of P2Y12 compared to respective wild type genotype at 24 h. PMID- 23647897 TI - Fragmented narrow QRS complex: predictor of left ventricular dyssynchrony in non ischemic dilated cardiomyopathy. AB - BACKGROUND: Cardiac resynchronization therapy is an important therapeutic modality in drug refractory symptomatic patients of heart failure with wide QRS (>=120 ms) on electrocardiogram. However, wide QRS (considered as a marker of electrical dyssynchrony) occurs in only 30% of heart failure patients, making majority of drug refractory heart failure patients ineligible for resynchronization therapy. Significant numbers of patients with narrow QRS have echocardiographic evidence of left ventricular dyssynchrony. However, there is sparse data about additional features on the surface ECG which can predict intraventricular dyssynchrony. This study was undertaken to assess the utility of fragmented narrow QRS complex to predict significant intraventricular dyssynchrony in symptomatic patients of non-ischemic dilated cardiomyopathy. METHOD: 100 symptomatic patients of non-ischemic dilated cardiomyopathy with narrow QRS complexes (50 each with fragmented and normal QRS) were recruited. Tissue Doppler imaging was used to assess intraventricular dyssynchrony as per 'Yu index'. RESULTS: 78% patients (n = 39) in fQRS complex group and 14% (n = 7) in normal QRS complex group had significant intraventricular dyssynchrony (chi(2) = 20.61; p < 0.000005). fQRS complexes had 84.78% sensitivity, 79.62% specificity, a positive predictive value of 78% and negative predictive value of 86% to detect intraventricular dyssynchrony. fQRS also had sensitivity and specificity of 93% and 90% respectively to localize the dyssynchronous segment. CONCLUSION: fQRS is a marker of electrical dyssynchrony, which results in significant intraventricular dyssynchrony in patients of non-ischemic dilated cardiomyopathy and a narrow QRS interval. fQRS localizes the dyssynchronous segment and might be useful in identifying patients who can benefit from cardiac resynchronization therapy. PMID- 23647898 TI - Association between erectile dysfunction and coronary artery disease and its severity. AB - BACKGROUND/AIMS: To investigate the prevalence of erectile dysfunction (ED) in patients with coronary artery disease (CAD), its relationship between the severity of ED and the extent of coronary vessel involvement and to register the mean time interval between them. METHODS: 240 patients with CAD divided into three age-matched groups: Group 1 (n = 60), ACS with one-vessel disease (1VD); group 2 (n = 60), ACS with 2,3VD; group 3 (n = 60), CSA. Control group (C, n = 60) was composed of patients with suspected CAD who were found to have entirely normal coronary arteries by angiography. ED as any value <26 according to the Gensini's scores and according to the International Index of Erectile Function (IIEF). RESULTS: ED prevalence was 76%. ED prevalence was lower in G1 vs. G3 (22 vs.65%). G2 ED rate [55%, P < 0.0001] IIEF = 24 (17-29) & Gensini's scores-21 (12.5-32) were significantly different from G1 and similar to G3, ED in ACS differs according to the extent of CAD. G3 patients who had ED symptoms prior to CAD symptoms and time interval between ED and CAD symptom onset in CCS according to number of vessels. Onset of sexual dysfunction occurred before CAD onset with a mean time interval of 24 m [12-36]. CONCLUSION: Early diagnosis of ED, cardiovascular assessment and aggressive treatment of cardiovascular risk factors might have contributed to prevent the acute events of this patient. Patients should be systematically screened for ED as a part of periodic examination programs. This would lead to early detection of modifiable vascular risk factors, or already existing vascular disease and to prevent ED and vascular disease progression through pharmacological and life style modifications. PMID- 23647899 TI - "On" or "Off" pump coronary artery bypass grafting - is the last word out? PMID- 23647900 TI - Absent pulmonary valve syndrome with tetralogy of Fallot detected at an early gestational age of 27 weeks - a case report. AB - OBJECTIVE: Absent pulmonary valve syndrome (APVS) is a rare congenital anomaly, usually seen in association with a ventricular septal defect. It has been reported to occur in 3-6% of cases of tetralogy of Fallot (TOF). In this case report we discuss a case of absent pulmonary valve syndrome with tetralogy of Fallot that was detected in utero by fetal echocardiography at 27 weeks of gestation. CASE: A 20-year-old pregnant woman at 27 weeks of gestation referred to our Institute. She has no consanguineous history. We diagnosed the case as tetralogy of Fallot with absent pulmonary valves in fetal echocardiographic study. CONCLUSION: We conclude that when a paracardiac cystic, pulsatile lesion with dilated pulmonary arteries are seen in the fetus in utero then other features associated with the syndrome, such as TOF and the presence or absence of the ductus arteriosus should be looked for. In our case there was no ductus arteriosus. PMID- 23647901 TI - Intravascular ultrasound-guided revascularization of a chronically occluded left main coronary artery. AB - We describe a case of a left main coronary artery (LMCA) chronic total occlusion (CTO), which we elected to treat through percutaneous coronary intervention (PCI). In this case report, we briefly review the prevalence of LMCA CTO, discuss the feasibility of PCI versus surgical revascularization and highlight the importance of intravascular ultrasound in the guidance of these complex procedures. PMID- 23647902 TI - Constrictive pericarditis following coronary artery bypass grafting. AB - Constrictive pericarditis following Coronary Artery Bypass Surgery is an uncommon disorder. We report a patient who developed constrictive pericarditis after Coronary Artery Bypass Grafting. After an unsuccessful trial of medical management and pericardial tapping, he underwent pericardiectomy via a left posterolateral thoracotomy. PMID- 23647903 TI - Stepwise evaluation of left to right shunts by echocardiography. PMID- 23647904 TI - Nodal and infranodal atrioventricular conduction block: electrophysiological basis to correlate the ECG findings. AB - A 68-year-old woman with a history of dilated non-ischemic cardiomyopathy presented with syncope. The index ECG showed sinus rhythm with left bundle branch block. On telemetry episodes of sinus rhythm with narrower QRS complexes conduced in 2:1 pattern were noted. Invasive electrophysiological study was performed to determine cause of syncope. Normal conduction up to the AV node with an AH interval of 79 ms (normal = 55-125 ms) was observed. However, every alternate sinus beat was blocked after the inscription of His deflection (infra-Hisian block). The narrow beats conducted through the His bundle with HV intervals of 54 ms (normal = 35-55 ms). When 1:1 conduction resumed further abnormality of the His-Purkinje conduction system became evident with a QRS morphology that of an LBBB and prolongation of HV interval (HV = 96 ms). Criteria to differentiate nodal versus infranodal block based on electrophysiological properties of the nodal and infranodal system are discussed. PMID- 23647905 TI - Characterization of lipid profile in coronary heart disease patients in Sudan. PMID- 23647906 TI - Association between blood glucose level and in-hospital mortality in patients with acute myocardial infarction. PMID- 23647907 TI - Evaluating the impact of pre-transplant desensitization utilizing a plasmapheresis and low-dose intravenous immunoglobulin protocol on BK viremia in renal transplant recipients. AB - BACKGROUND: A correlation exists between polyomavirus BK (BKV) viremia in renal transplant recipients (RTR) and the degree of immunosuppression. However, the impact of pre-transplant desensitization on the incidence of BKV viremia is unknown. METHODS: This retrospective study evaluated living-donor RTR between January 2004 and December 2008 receiving routine BKV viral load monitoring. Patients were divided into those who underwent pre-transplant desensitization (n = 20) and those who did not (n = 71). The primary endpoint was the incidence of BKV viremia at 1 year post transplant. RESULTS: All demographic data were similar, except for more female patients (65% vs. 36.6%; P = 0.0392) in the desensitized group. More desensitized patients had a previous transplant (75% vs. 12.7%; P < 0.0001) and were more likely to be induced with basiliximab (75% vs. 35.2%; P = 0.0021). Following transplantation, antibody-mediated rejection (AMR) rates were highest in the desensitized group (55% vs. 1.4%; P < 0.0001). The incidence of BKV viremia at 1 year post transplant was significantly higher in desensitized patients (45% vs. 19.7%; P = 0.0385). Desensitization was also associated with a higher prevalence of BKV viremia at any time post transplant (50% vs. 22.5%; P = 0.0245), polyomavirus-associated nephropathy (20% vs. 2.8%; P = 0.0198) and BKV-related allograft loss (10% vs. 0%; P = 0.0464). Also of note, in a subgroup analysis of only our desensitized patients, it did not appear that development of AMR significantly impacted the incidence of BKV viremia in these individuals. CONCLUSIONS: This analysis reveals that pre-transplant desensitization significantly increases the risk for BKV viremia and nephropathy. PMID- 23647908 TI - The lactase persistence genotype is associated with body mass index and dairy consumption in the D.E.S.I.R. study. AB - OBJECTIVE: The T allele of a functional polymorphism (rs4988235: LCT-13910 C>T), close to the lactase gene, correlates with lactase persistence (LP) in adults. The LP genotype (TT+TC) has been associated with a higher BMI in European populations in cross-sectional studies. In the French D.E.S.I.R. cohort, a high consumption of dairy products was associated with a lower body weight gain over 9 years, and with a lower incidence of high plasma glucose levels and/or the metabolic syndrome. Our aim was to test in this study, the association of rs4988235 with BMI and related metabolic diseases, in interaction with dairy product consumption. METHODS: Among 5212 subjects from D.E.S.I.R., 3575 Caucasians born in mainland France were genotyped and followed over 9years. RESULTS: Those with the LP genotype (frequency: 78.5%) had a higher dairy product consumption, at inclusion and at year-9 (P<0.001). They also had a higher BMI at both time points (difference=0.3kg/m(2), P=0.05), but this effect was restricted to medium/high dairy product consumers (difference=0.5kg/m(2), P=0.006). This genotype was also associated with the metabolic syndrome (IDF definition), but this association disappeared after adjustment for BMI. In the whole population, the C allele was associated with a higher prevalence of impaired fasting glycemia and/or type 2 diabetes. CONCLUSIONS: The lactase persistence genotype was shown to be associated with a higher BMI in a longitudinal study, mainly in those consuming high amounts of dairy products. The association of the C allele, responsible for lactase non-persistence, with the risk of hyperglycemia needs to be replicated. PMID- 23647909 TI - Computational identification of a new binding site in influenza virus hemagglutinin for membrane fusion inhibitors. AB - The influenza virus hemagglutinin is a potential drug target for antivirus treatment. A variety of membrane fusion inhibitors targeting hemagglutinin have been discovered, but the binding sites and modes, important for understanding membrane fusion and rational drug design, have not yet been elucidated. In this article, we investigated the possible hemagglutinin binding sites for the current membrane fusion inhibitors. Four possible binding pockets (Pocket A, B, C, and D) at the stalk region of hemagglutinin were detected and defined using the CAVITY program. Most of the current membrane fusion inhibitors were reported to bind to Pocket C by amino acid mutation experiments and molecular modeling simulation. However, our binding site prediction suggested that Pocket A is the best ligand binding site other than Pocket C. Using a specific computational protocol combining molecular docking, three-dimensional QSAR, and receptor mimicking, we further found that Pocket A is the putative binding site for a series of membrane fusion inhibitors (1-phenyl-cycloalkane carbamides). This is further proven by the antiviral spectrum of the inhibitors. This protocol for the identification of ligand binding sites in influenza hemagglutinin is also applicable for the analysis of other protein targets with no explicit binding information. PMID- 23647910 TI - Medical marijuana: a viable tool in the armamentaria of physicians treating chronic pain? A case study and commentary. PMID- 23647911 TI - Histopathological atlas and proposed classification for melanocytic lesions in Tyr::NRas(Q61K) ; Cdkn2a(-/-) transgenic mice. PMID- 23647912 TI - Editorial comment. PMID- 23647913 TI - Editorial comment. PMID- 23647914 TI - Effects of 3 months of short sessions of controlled whole body vibrations on the risk of falls among nursing home residents. AB - BACKGROUND: Fatigue, lack of motivation and low compliance can be observed in nursing home residents during the practice of physical activity. Because exercises should not be too vigorous, whole body vibration could potentially be an effective alternative. The objective of this randomized controlled trial was to assess the impact of 3-month training by whole body vibration on the risk of falls among nursing home residents. METHODS: Patients were randomized into two groups: the whole body vibration group which received 3 training sessions every week composed of 5 series of only 15 seconds of vibrations at 30 Hz frequency and a control group with normal daily life for the whole study period. The impact of this training on the risk of falls was assessed blindly by three tests: the Tinetti Test, the Timed Up and Go test and a quantitative evaluation of a 10 second walk performed with a tri-axial accelerometer. RESULTS: 62 subjects (47 women and 15 men; mean age 83.2 +/- 7.99 years) were recruited for the study. No significant change in the studied parameters was observed between the treated (n=31) and the control group (n=31) after 3 months of training by controlled whole-body-vibrations. Actually, the Tinetti test increased of + 0.93 +/- 3.14 points in the treated group against + 0.88 +/- 2.33 points in the control group (p = 0.89 when adjusted). The Timed Up and Go test showed a median evolution of - 1.14 (- 4.75-3.73) seconds in the treated group against + 0.41 (- 3.57- 2.41) seconds in the control group (p = 0.06). For the quantitative evaluation of the walk, no significant change was observed between the treated and the control group in single task as well as in dual task conditions. CONCLUSIONS: The whole body vibration training performed with the exposition settings such as those used in this research was feasible but seems to have no impact on the risk of falls among nursing home residents. Further investigations, in which, for example, the exposure parameters would be changed, seem necessary. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: NCT01759680. PMID- 23647915 TI - Intracellular trafficking and secretion of inflammatory cytokines. AB - The secretion of cytokines by immune cells plays a significant role in determining the course of an inflammatory response. The levels and timing of each cytokine released are critical for mounting an effective but confined response, whereas excessive or dysregulated inflammation contributes to many diseases. Cytokines are both culprits and targets for effective treatments in some diseases. The multiple points and mechanisms that have evolved for cellular control of cytokine secretion highlight the potency of these mediators and the fine tuning required to manage inflammation. Cytokine production in cells is regulated by cell signaling, and at mRNA and protein synthesis levels. Thereafter, the intracellular transport pathways and molecular trafficking machinery have intricate and essential roles in dictating the release and activity of cytokines. The trafficking machinery and secretory (exocytic) pathways are complex and highly regulated in many cells, involving specialized membranes, molecules and organelles that enable these cells to deliver cytokines to often-distinct areas of the cell surface, in a timely manner. This review provides an overview of secretory pathways - both conventional and unconventional - and key families of trafficking machinery. The prevailing knowledge about the trafficking and secretion of a number of individual cytokines is also summarized. In conclusion, we present emerging concepts about the functional plasticity of secretory pathways and their modulation for controlling cytokines and inflammation. PMID- 23647916 TI - Role of cerebral ultrasound and magnetic resonance imaging in newborns with congenital cytomegalovirus infection. AB - PURPOSE: To assess the diagnostic and prognostic value of cerebral magnetic resonance imaging (cMRI) in comparison with that of cerebral ultrasound (cUS) in predicting neurodevelopmental outcome in newborns with congenital cytomegalovirus (CMV) infection. METHODS: Forty CMV-congenitally infected newborns underwent cUS and cMRI within the first month of life. Clinical course, laboratory findings, visual/hearing function and neurodevelopmental outcome were documented. RESULTS: Thirty newborns showed normal cMRI, cUS and hearing/visual function in the first month of life; none showed CMV-related abnormalities at follow-up. Six newborns showed pathological cMRI and cUS findings (pseudocystis, ventriculomegaly, calcifications, cerebellar hypoplasia) but cMRI provided additional information (white matter abnormalities in three cases, lissencephaly/polymicrogyria in one and a cyst of the temporal lobe in another one); cerebral calcifications were detected in 3/6 infants by cUS but only in 2/6 by cMRI. Four of these 6 infants showed severe neurodevelopmental impairment and five showed deafness during follow-up. Three newborns had a normal cUS, but cMRI documented white matter abnormalities and in one case also cerebellar hypoplasia; all showed neurodevelopmental impairment and two were deaf at follow-up. One more newborn showed normal cUS and cMRI, but brainstem auditory evoked responses were abnormal; psychomotor development was normal at follow-up. CONCLUSIONS: Compared with cUS, cMRI disclosed additional pathological findings in CMV-congenitally infected newborns. cUS is a readily available screening tool useful in the identification of infected newborns with major cerebral involvement. Further studies with a larger sample size are needed to determine the prognostic role of MRI, particularly regarding isolated white matter lesions. PMID- 23647917 TI - The ominous sequence in patients with tuberous sclerosis complex. AB - BACKGROUND: The clinical phenotypes and their severity in patients with tuberous sclerosis complex can be quite variable and are sometimes never determined simply by the primary mutation. These make clinically selecting appropriate treatments and predicting disease outcome difficult. In this report, the prognostic ominous sequence was evaluated in association with clinical manifestations and gene mutations. METHODS: The patients were classified by each renal lesion of angiomyolipomas and polycystic disease. The other clinical manifestations and outcomes of epilepsy, mental retardation, facial angiofibromas, subependymal giant cell astrocytoma, cortical tubers were reviewed and each gene mutations were analyzed in seven unrelated patients. RESULTS: Two patients with multiple and large proliferative renal angiomyolipoma showed poor clinical outcome than the patients with other renal lesions. These patients presented with progressively proliferative facial angiofibroma, West syndrome, Lennox-Gastaut syndrome, severe mental retardation, subependymal giant cell astrocytoma and they were affected by TSC2 gene mutations. CONCLUSION: The sequence of progressively proliferative renal angiomyolipoma, facial angiofibroma, West syndrome and TSC2 gene mutations might be prognostic ominous factors. PMID- 23647918 TI - The efficacy of gabapentin in children of partial seizures and the blood levels. AB - AIM: To evaluate the long-term efficacy of gabapentin (GBP) and usefulness of measurement of the blood level for the observation of patients that have partial seizures. METHODS: Thirty patients (20 effective cases and 10 ineffective cases) treated with GBP for the localization related epilepsy had their peak blood levels of GBP. The levels were measured seven time points, one, 6, 12, 18, 24, 30, and 36month after the start of medication. The efficacy of GBP was evaluated at one month after the initiation of medication and every year for 3years, based on the R Ratio and the degree of improvement for the paroxysmal strength and length. RESULTS: GBP levels were higher in the effective cases than the levels in the ineffective cases 6months after and 1year after the initiation of medication (p<0.05). The level 6months after the start in the effective cases was 5.429+/ 2.384MUg/ml (mean+/-SD), and 5.837+/-3.217MUg/ml after 1year. The cases that were effective for 1year maintained approximately the same efficacy for 3years after the initiation of medication, but there was no correlation between the level and the R Ratio, paroxysmal strength and length. CONCLUSIONS: No precise definition of the therapeutic range was recognized because of no correlation between GBP level and the improvement of clinical manifestations. We recommend the GBP optimal range that is established the range within 3-8MUg/ml (mean; 5MUg/ml) as therapeutic target without the side effect. PMID- 23647919 TI - Sequences of multiple bacterial genomes and a Chlamydia trachomatis genotype from direct sequencing of DNA derived from a vaginal swab diagnostic specimen. AB - Ultra-deep Illumina sequencing was performed on whole genome amplified DNA derived from a Chlamydia trachomatis-positive vaginal swab. Alignment of reads with reference genomes allowed robust SNP identification from the C. trachomatis chromosome and plasmid. This revealed that the C. trachomatis in the specimen was very closely related to the sequenced urogenital, serovar F, clade T1 isolate F SW4. In addition, high genome-wide coverage was obtained for Prevotella melaninogenica, Gardnerella vaginalis, Clostridiales genomosp. BVAB3 and Mycoplasma hominis. This illustrates the potential of metagenome data to provide high resolution bacterial typing data from multiple taxa in a diagnostic specimen. PMID- 23647920 TI - Patterns of failure in patients with locally advanced rectal cancer receiving pre operative or post-operative chemoradiotherapy. AB - BACKGROUND: We investigated patterns of failure in patients with locally advanced rectal cancer (LARC) according to chemoradiotherapy (CRT) timing: pre-operative versus post-operative. Also, patterns of failure, particularly distant metastasis (DM), were analyzed according to tumor location within the rectum. METHODS: In total, 872 patients with LARC who had undergone concurrent CRT and radical surgery between 2001 and 2007 were analyzed retrospectively. Concurrent CRT was administered pre-operatively (cT3-4) or post-operatively (pT3-4 or pN+) in 550 (63.1%) and 322 (36.9%) patients, respectively. Median follow-up period was 86 (range, 12-133) months for 673 living patients. Local recurrence (LR) was defined as any disease recurrence within the pelvis, and any failure outside the pelvis was classified as a DM. Only the first site of recurrence was scored. RESULTS: In total, 226 (25.9%) patients developed disease recurrence. In the pre-operative CRT group, the incidences of isolated LR, combined LR and DM, and isolated DM were 17, 21, and 89 patients, respectively. In the post-operative CRT group, these incidences were 8, 15, and 76 patients, respectively. LR within 2 years constituted 44.7% and 60.9% of all LRs in the pre-operative and post-operative CRT groups, respectively. Late (> 5 years) LR comprised 13.2% and 4.3% of all LRs in the pre-operative and post-operative CRT groups, respectively. The lung was the most common DM site (108/249, 43.4%). Lung or para-aortic lymph node metastasis developed more commonly from low-to-mid rectal tumors while liver metastasis developed more commonly from upper rectal tumors. Lung metastasis occurred later than liver metastasis (n = 54; 22.6 +/- 15.6 vs. 17.4 +/- 12.1 months; P = 0.035). CONCLUSIONS: This study showed that LARC patients receiving pre-operative CRT tended to develop late LR more often than those receiving post operative CRT. Further extended follow-up than is conventional may be necessary in LARC patients who are managed with optimized multimodal treatments, and the follow-up strategy may need to be individualized according to tumor location within the rectum. PMID- 23647921 TI - Effects of phosphorus starvation versus limitation on the marine cyanobacterium Prochlorococcus MED4 II: gene expression. AB - Phosphorus (P) availability drives niche differentiation in the most abundant phytoplankter in the oceans, the marine cyanobacterium Prochlorococcus. We compared the molecular response of Prochlorococcus strain MED4 to P starvation in batch culture to P-limited growth in chemostat culture. We also identified an outer membrane porin, PMM0709, which may allow transport of organic phosphorous compounds, rather than phosphate as previously suggested. The expression of three P uptake genes, pstS, the high-affinity phosphate-binding component of the phosphate transporter, phoA, an alkaline phosphatase, and porin PMM0709, were strongly upregulated (between 10- and 700-fold) under both P starvation and limitation. pstS exhibits high basal expression under P-replete conditions and is likely necessary for P uptake regardless of P availability. A P-stress regulatory gene, ptrA, was upregulated in response to both P starvation and limitation although a second regulatory gene, phoB, was not. Elevated expression levels (> 10-fold) of phoR, a P-sensing histidine kinase, were only observed under conditions of P limitation. We suggest Prochlorococcus in P-limited systems are physiologically distinct from cells subjected to abrupt P depletion. Detection of expression of both pstS and phoR in field populations will enable discernment of the present P status of Prochlorococcus in the oligotrophic oceans. PMID- 23647922 TI - Integrating HIV care into nurse-led primary health care services in South Africa: a synthesis of three linked qualitative studies. AB - BACKGROUND: The integration of HIV care into primary care services is one of the strategies proposed to increase access to treatment for people living with HIV/AIDS in high HIV burden countries. However, how best to do this is poorly understood. This study documents different factors influencing models of integration within clinics. METHODS: Using methods based on the meta-ethnographic approach, we synthesised the findings from three qualitative studies of the factors that influenced integration of HIV care into all consultations in primary care. The studies were conducted amongst staff and patients in South Africa during a randomised trial of nurse initiation of antiretroviral therapy (ART) and integration of HIV care into primary care services - the Streamlining Tasks and Roles to Expand Treatment and Care for HIV (STRETCH) trial. Themes from each study were identified and translated into each other to develop categories and sub-categories and then to inform higher level interpretations of the synthesised data. RESULTS: Clinics varied as to how HIV care was integrated. Existing administration systems, workload and support staff shortages tended to hinder integration. Nurses' wanted to be involved in providing HIV care and yet also expressed preferences for developing expertise in certain areas and for establishing good nurse patient relationships by specialising in certain services. Patients, in turn, were concerned about the stigma of separate HIV services and yet preferred to be seen by nurses with expertise in HIV care. These factors had conflicting effects on efforts to integrate HIV care. CONCLUSION: Local clinic factors and nurse and patient preferences in relation to care delivery should be taken into account in programmes to integrate HIV care into primary care services. The integration of medical records, monitoring and reporting systems would support clinic based efforts to integrate HIV care into primary care services. PMID- 23647923 TI - Linking geology, fluid chemistry, and microbial activity of basalt- and ultramafic-hosted deep-sea hydrothermal vent environments. AB - Hydrothermal fluids passing through basaltic rocks along mid-ocean ridges are known to be enriched in sulfide, while those circulating through ultramafic mantle rocks are typically elevated in hydrogen. Therefore, it has been estimated that the maximum energy in basalt-hosted systems is available through sulfide oxidation and in ultramafic-hosted systems through hydrogen oxidation. Furthermore, thermodynamic models suggest that the greatest biomass potential arises from sulfide oxidation in basalt-hosted and from hydrogen oxidation in ultramafic-hosted systems. We tested these predictions by measuring biological sulfide and hydrogen removal and subsequent autotrophic CO2 fixation in chemically distinct hydrothermal fluids from basalt-hosted and ultramafic-hosted vents. We found a large potential of microbial hydrogen oxidation in naturally hydrogen-rich (ultramafic-hosted) but also in naturally hydrogen-poor (basalt hosted) hydrothermal fluids. Moreover, hydrogen oxidation-based primary production proved to be highly attractive under our incubation conditions regardless whether hydrothermal fluids from ultramafic-hosted or basalt-hosted sites were used. Site-specific hydrogen and sulfide availability alone did not appear to determine whether hydrogen or sulfide oxidation provides the energy for primary production by the free-living microbes in the tested hydrothermal fluids. This suggests that more complex features (e.g., a combination of oxygen, temperature, biological interactions) may play a role for determining which energy source is preferably used in chemically distinct hydrothermal vent biotopes. PMID- 23647925 TI - Keeping the focus on safer practices: a safer practices lens. PMID- 23647924 TI - "Everything that looks good ain't good!": perspectives on urban redevelopment among persons with a history of injection drug use in Baltimore, Maryland. AB - BACKGROUND: While urban redevelopment is intended to ameliorate urban decay, some studies demonstrate that it can negatively impact some residents. Few studies have considered its impact on persons with a history of drug use. METHODS: A convenience sample of 25 current or former injection drug users from Baltimore, Maryland, enrolled in the AIDS Linked to the Intravenous Experience study, and reporting residence in or bordering a redeveloping neighborhood participated in 1 2 semi-structured in-depth interviews from July, 2011 to February, 2012. Interviews explored personal experiences with redevelopment and perceptions of community-wide impact. Data were analyzed using the constant comparison method. RESULTS: Respondents rarely described urban redevelopment as solely negative or positive. Revitalization and increased security in the redeveloping area were reported as positive consequences. Negative consequences included the lack of redevelopment-related employment opportunities, disruption of social ties, and housing instability among relocated residents. Respondents also said that urban redevelopment led to the displacement of drug markets to adjacent neighborhoods and outlying counties. Residential relocation and displacement of drug markets were reported as beneficial for persons in contemplative and later stages of recovery. CONCLUSION: These findings support a holistic approach to urban redevelopment that increases access to employment opportunities and affordable housing, and ensures equitable coverage of public services such as law enforcement. PMID- 23647926 TI - Detecting Rickettsia parkeri infection from eschar swab specimens. AB - The typical clinical presentation of several spotted fever group Rickettsia infections includes eschars. Clinical diagnosis of the condition is usually made by analysis of blood samples. We describe a more sensitive, noninvasive means of obtaining a sample for diagnosis by using an eschar swab specimen from patients infected with Rickettsia parkeri. PMID- 23647927 TI - [Stroke prevention in patients with nonvalvular atrial fibrillation.What's new?]. PMID- 23647928 TI - [The change of paradigm in stroke prevention in atrial fibrillation. Challenges and emerging opportunities for the family physician]. AB - Atrial fibrillation (AF), is the most prevalent sustained arrhythmia in general population, affecting up to 10% in patients of advanced age. AF doubles overall mortality and increases up to 5-6 times the risk of stroke, which have the characteristic of being particularly harmful. The basis of treatment on AF are the rhythm or rate control and the prevention of thromboembolism. For the latter purpose the treatments that have been most effective are oral anticoagulants. For decades and until just a few years ago, the only oral drugs available for this purpose have been the anti-vitamin K, mainly represented in our country by acenocoumarol and lesser extent by warfarin. These drugs have been shown to reduce strokes and mortality compared to placebo and with antiplatelet drugs, so have been and continue to be the standard treatment and the comparator for all antithrombotic drugs in patients with AF. The variability in the therapeutic response, their food and drugs interactions and their narrow therapeutic window that entail the need to frequently monitoring, has led to look for new drugs that, at least maintaining their advantages, where able to avoid some of the drawbacks. Currently we have a number of new drugs that meet these premises, although they have the disadvantage of a higher direct cost. The arrival of these new oral anticoagulants (NOAC) make necessary to know them well, reach a consensus for a correct use and to make changes in the clinical management of these patients when they are used. In this article we review the indications and way of use of the different options (classics and news) of antithrombotic therapy in patients with AF, the situation of anticoagulated patients in our country, the characteristics of the NOAC, its recommendations for use and the challenges to that are subjected family physicians regarding these changes. PMID- 23647929 TI - [Atrial fibrillation: from detection to treatment. Role of the family physician, cardiologist and other specialists. New models of clinical management]. AB - The prevalence of atrial fibrillation (AF) in adults in Spain is estimated to be 4.4% of the population aged 40 years or more, corresponding to a mean of 30 to 40 patients per family physician. The importance of this common arrhythmia lies, above all, in its close association with stroke and other systemic embolisms, among other possible complications. Diagnosis of AF is based on electrocardiographic recording and can consequently be made by the family physician, who should make an overall assessment of the patient's health, including risk factors, comorbidity and type of AF and evaluate embolic and hemorrhagic risk. The decision to prescribe anticoagulation therapy or not should be taken promptly and should be based on the patient's embolic risk and not on the type of arrhythmia. In addition, the family physician, together with the treating cardiologist, should decide on the most appropriate therapeutic strategy for each individual patient: a rhythm control strategy (attempting to recover and maintain sinus rhythm) or a rate control strategy (maintaining heart rate within acceptable limits). Antithrombotic treatment should form part of both strategies, since stroke is the most serious and common complication of AF and also has the greatest effects on morbidity and mortality. Moreover, cardioembolic strokes (accounting for one out of every four strokes) are especially devastating, with the highest fatality, hospital and social resource use, and associated disability. Control of AF and particularly stroke prevention with adequate anticoagulation should be carried out mainly in primary care. Nevertheless, multidisciplinary management is required in most patients, which requires effective coordination between primary and specialized care, especially cardiology, hematology and neurology (in patients who have already had a stroke). PMID- 23647932 TI - Influence of a bioceramic root end material and mineral trioxide aggregates on fibroblasts and osteoblasts. AB - OBJECTIVE: The biocompatibility of materials used in endodontic treatment is of high importance, because they can come in contact with periradicular tissues and there is a risk of possible systemic toxicity. The aim of the present study was to investigate the in vitro reaction to a bioceramic based root end material in comparison to mineral trioxide aggregates (MTA) as the established gold standard. DESIGN: The root end materials grey MTA Angelus (GMTA), white MTA Angelus (WMTA), ProRoot MTA, and EndoSequence Root Repair Material (ERRM) were incubated with human periodontal ligament fibroblasts and osteoblasts (10(4)cells/ml) for up to 96h. Cell proliferation (RFU) was determined by means of the Alamar Blue assay. In addition, fluorescence staining was carried out to visually monitor cell growth and morphology. RESULTS: For most of the observational time period of up to 96h, there was no statistically significant difference between the proliferation rates of the control cells and those in contact with ERRM. In contrast, the mineral trioxide based materials caused from 24 to 96h significantly lower proliferation rates in comparison to the controls (p<0.001). For proliferation rates of cells in contact with MTAs and ERRM significant differences were observed throughout the whole observation time for the osteoblasts, but only up to 24h for the human periodontal ligament fibroblasts. CONCLUSION: Within the limits of this study the results suggest that the bioceramic root end material is biocompatible, but needs to be investigated in clinical studies before it can be recommended as retrograde sealer in endodontic practice. PMID- 23647933 TI - Dronedarone's inhibition of If current is the primary mechanism responsible for its bradycardic effect. AB - INTRODUCTION: The mechanism(s) whereby dronedarone reduces sinus rate are not well understood, although L-type calcium channel antagonism, beta-adrenergic blockade, and inhibition of If are plausible. METHODS AND RESULTS: In anesthetized pigs, we compared the effects of dronedarone to the prototypical If inhibitor, ivabradine, and the L-type calcium channel antagonist diltiazem on heart rate, mean arterial blood pressure (MAP), and contractility. Dronedarone's effects on the phenylephrine-induced rise in MAP and on the chronotropic response to isoproterenol were also investigated. Cumulative doses of dronedarone (0.5 mg/kg, i.v., and 5.0 mg/kg, i.v.; plasma level: 80 +/- 16.1 nM) progressively reduced heart rate (P < 0.02) without changes in MAP or contractility as assessed by LV dP/dt (N = 6). Ivabradine (0.5 mg/kg, i.v.) similarly reduced heart rate (P < 0.01) without change in MAP (N = 6). Diltiazem (0.8 mg/kg, i.v.) reduced heart rate and MAP and decreased contractility (N = 6). Dronedarone blunted phenylephrine's alpha-receptor-mediated increase in MAP but did not alter the marked beta-adrenergic receptor (BAR)-mediated increase in heart rate induced by isoproterenol. When dronedarone injection was preceded by ivabradine, no further decrease in heart rate or change in MAP was observed (N = 6). CONCLUSIONS: Dronedarone reduced heart rate without affecting MAP or contractility, effects that differ from L-type calcium channel blockade. Dronedarone did not antagonize BAR stimulation, and its heart-rate lowering effects were eliminated by prior administration of ivabradine. Thus, dronedarone's bradycardic action is likely due to inhibition of If and not to blockade of either L-type calcium channels or BAR. PMID- 23647931 TI - The pancreatic beta cell and type 1 diabetes: innocent bystander or active participant? AB - Type 1 diabetes mellitus (T1DM) is a chronic disease resulting from destruction of insulin-producing pancreatic beta cells. Genetic and environmental factors contribute to T1DM onset. Use of high-throughput DNA sequencing has allowed geneticists to perform genome-wide association studies (GWAS) to identify novel gene loci associated with T1DM. Interestingly, >50% of these genes encode products that are expressed in beta cells. These studies, coupled with emerging molecular evidence that beta cells are impaired by gain-of-function or loss-of function of these loci, suggest an active role for the beta cell in eliciting its own demise. Although immune dysregulation plays a vital role in T1DM pathogenesis, understanding the mechanisms contributing to beta cell failure may lead to new strategies to preserve or improve beta cell function in patients with T1DM. PMID- 23647930 TI - Cracking the O-GlcNAc code in metabolism. AB - Nuclear, cytoplasmic, and mitochondrial proteins are extensively modified by O linked beta-N-acetylglucosamine (O-GlcNAc) moieties. This sugar modification regulates fundamental cellular processes in response to diverse nutritional and hormonal cues. The enzymes O-GlcNAc transferase (OGT) and O-linked beta-N acetylglucosaminase (O-GlcNAcase) mediate the addition and removal of O-GlcNAc, respectively. Aberrant O-GlcNAcylation has been implicated in a plethora of human diseases, including diabetes, cancer, aging, cardiovascular disease, and neurodegenerative disease. Because metabolic dysregulation is a vital component of these diseases, unraveling the roles of O-GlcNAc in metabolism is of emerging importance. Here, we review the current understanding of the functions of O GlcNAc in cell signaling and gene transcription involved in metabolism, and focus on its relevance to diabetes, cancer, circadian rhythm, and mitochondrial function. PMID- 23647934 TI - Radiofrequency catheter ablation of intractable ventricular tachycardia in an infant following arterial switch operation. AB - A full-term male neonate presented with cyanosis upon delivery and was subsequently diagnosed with d-transposition of the great arteries, ventricular septal defect, and restrictive atrial septal defect. Following initiation of intravenous prostaglandins and balloon atrial septostomy, an arterial switch operation was performed on day 3 of life. The postoperative course was complicated by intractable ventricular tachycardia that was refractory to lidocaine, amiodarone, esmolol, fosphenytoin, and mexiletine drug therapy. Ventricular tachycardia was suppressed with overdrive atrial pacing but recurred upon discontinuation. Seven weeks postoperatively, radiofrequency catheter ablation was performed due to hemodynamically compromising persistent ventricular tachycardia refractory to medical therapy. The ventricular tachycardia was localized to the inferior-lateral right ventricular outlet septum. The procedure was successful without complications or recurrence. Antiarrhythmics were discontinued after the ablation procedure. Seven days after the ablation, a different, slower fascicular rhythm was noted to compete with the infant's sinus rhythm. This was consistent with the preablation amiodarone having reached subtherapeutic levels given its very long half-life. The patient was restarted on oral beta blockers and amiodarone. The patient was subsequently discharged home in predominantly sinus rhythm with intermittent fascicular rhythm. PMID- 23647935 TI - [Smoking among women in Africa]. PMID- 23647936 TI - [Hospital information system performance for road traffic accidents analysis in a hospital recruitment based area]. AB - BACKGROUND: Road traffic accidents in France are mainly analyzed through reports completed by the security forces (police and gendarmerie). But the hospital information systems can also identify road traffic accidents via specific documentary codes of the International Classification of Diseases (ICD-10). The aim of this study was therefore to determine whether hospital stays consecutive to road traffic accident were truly identified by these documentary codes in a facility that collects data routinely and to study the consistency of results from hospital information systems and from security forces during the 2002-2008 period. METHODS: We retrieved all patients for whom a documentary code for road traffic accident was entered in 2002-2008. We manually checked the concordance of documentary code for road traffic accident and trauma origin in 350 patient files. The number of accidents in the Grenoble area was then inferred by combining with hospitalization regional data and compared to the number of persons injured by traffic accidents declared by the security force. RESULTS: These hospital information systems successfully report road traffic accidents with 96% sensitivity (95%CI: [92%, 100%]) and 97% specificity (95%CI: [95%, 99%]). The decrease in road traffic accidents observed was significantly less than that observed was significantly lower than that observed in the data from the security force (45% for security force data against 27% for hospital data). CONCLUSION: Overall, this study shows that hospital information systems are a powerful tool for studying road traffic accidents morbidity in hospital and are complementary to security force data. PMID- 23647937 TI - Measuring social inequalities in cause-specific mortality in France: comparison between linked and unlinked approaches. AB - BACKGROUND: Monitoring the time trends in socioeconomic inequalities in mortality by cause is a key public health issue. The aim of this study was to compare methods to measure social inequalities in cause-specific mortality in the French population aged 25-55 years. More specifically, it compares bias and precision related to the use of occupational class declared at the last census (linked data) to the one declared at the time of death on the death certificate (unlinked data). METHODS: We used a representative sample of 1% of the French population. Causes of death were obtained by direct linkage with the French national death registry. Occupational class was classified into eight categories. Taking professionals and managers as the reference, relative risks of mortality by cause and their 95% confidence intervals were estimated using Poisson models for the 1983-1989, 1991-1997, and 2000-2006 periods. The relative risks were calculated with both linked data and exhaustive unlinked data. RESULTS: Over the 2000-2006 period, occupational classes declared at census and on the death certificate were consistent for half of the deaths. Relative risks for manual workers were found to be similar between the two approaches over the 1983-1989 and 1991-1997 periods, and higher for the unlinked approach over the 2000-2006 period. Over the latter period, the order and magnitude of relative risks varied similarly by occupational class and cause of death for both approaches. Confidence intervals obtained from linked data were wide. CONCLUSION: Occupational class derived from the death certificate must be used with caution as a measure for epidemiological purposes and the available linked data do not allow accurate estimates of social inequalities in cause-specific mortality. Other solutions should be considered in order to improve the follow-up of social inequalities in mortality. This would require the collection of educational level on the death certificate or the linkage of the cause of death database with other exhaustive and informative databases. PMID- 23647938 TI - [Excessive daytime sleepiness. An epidemiological study based on a "sleep/breathing" questionnaire]. AB - BACKGROUND: A field survey used a "sleep-breathing" questionnaire to estimate the prevalence of the excessive daytime sleepiness in a sample of middle-aged males. METHODS: Eight hundred and fifty men aged 22 to 66 years agreed to answer a questionnaire and have anthropometric measurements. To the question on excessive daytime sleepiness, 90 subjects (10.8%) responded "often" or "almost always"; 740 gave a negative answer. RESULTS: The sleepy subjects were older and had a higher "central" weight. All the sleep-disturbed breathing symptoms and those suggesting sleep disturbances were more frequent in sleepy subjects. Sleepiness was significantly associated with sleep apnea and chronic bronchitis. Logistic regression identified six items independently associated with daytime sleepiness; there were three indirect indicators of sleepiness, age, a history of chronic bronchitis and disruptive movements during sleep. CONCLUSIONS: This epidemiologic study in a sample of active middle-aged males confirms the association of daytime sleepiness with a series of respiratory and non-respiratory sleep disturbances. The original findings are the role of a "central" obesity, the association with nightmares, and the role of chronic bronchitis as a determinant of daytime sleepiness. PMID- 23647939 TI - Prevention of obesity and diabetes in childbearing women. AB - Obesity and diabetes have become pandemic in the United States, with more than one-third of the US population obese and 8.3% of the population affected by diabetes. Efforts to prevent type 2 diabetes focus primarily on healthy eating and physical activity. In particular, women from at-risk racial and ethnic groups and those who have experienced gestational diabetes are at high risk for developing type 2 diabetes. Achieving a healthy weight prior to conception, staying within weight gain guidelines during pregnancy, and losing accumulated pregnancy weight postpartum are key prevention factors. Maintaining a healthy weight in the long-term is a challenge. Behavioral psychology and coaching techniques are presented in this article that can be useful in sustaining behaviors that promote a healthy weight. PMID- 23647940 TI - A gap in disease-specific survival between younger and older adults with de novo metastatic renal cell carcinoma: results of a SEER database analysis. AB - BACKGROUND: Consistent with other data sets, our own institutional series suggests that survival in patients aged >= 75 years with metastatic renal cell carcinoma (mRCC) is inferior to that in patients < 75 years. We sought to confirm these trends through exploration of the Surveillance, Epidemiology and End Results (SEER) registry. PATIENTS AND METHODS: We assessed disease-specific survival (DSS) in 6204 patients with clear cell, papillary, or chromophobe mRCC diagnosed between 1992 and 2009, with the a priori hypothesis that DSS was shorter in patients aged >= 75 years. Analyses were further stratified by the period of diagnosis, either between 1992 and 2004 (the "cytokine era") or 2005 to 2009 (the "targeted therapy" era). Univariate and multivariate analyses were conducted to determine the association between clinicopathologic characteristics and DSS. RESULTS: DSS was shorter in patients aged >= 75 years than in patients aged < 75 years (9 vs. 16 months; P < .0001). In patients 18 to 74 years, DSS was superior in the targeted therapy era compared with the cytokine era (P < .0001). However, in patients >= 75 years, no difference in DSS was noted between these periods (P = .90). On multivariate analysis, age >= 75 years, female sex, diagnosis during the cytokine era, node-positive disease, and absence of cytoreductive nephrectomy were independently associated with DSS. CONCLUSION: DSS appears to be inferior in older adults with mRCC (specifically, patients aged >= 75 years). Furthermore, in contrast to their younger counterparts, no improvement in DSS was seen in older adults in the transition from the cytokine era to the targeted therapy era. PMID- 23647941 TI - Prostate cancer detection by using digital rectal examination: contemporary practice patterns in the United States. AB - BACKGROUND: Digital rectal examination (DRE) may play an important role as a secondary method of prostate cancer detection if prostate-specific antigen (PSA) screening decreases. Current practice patterns in the use of DRE are not well defined, and potential variations in its use among different subgroups of men are unclear. MATERIALS AND METHODS: The Behavioral Risk Factor Surveillance System was examined for the year 2010. All men aged 40 years old or older were asked if they ever had a rectal examination to check their prostate and the date of their last examination. Men who reported having had a DRE within the past 12 months were considered up to date. The proportion of men who reported having had a DRE and independent demographic and socioeconomic predictors for having had a DRE were determined. RESULTS: A total of 110,661 respondents were included: 72.2% of respondents reported ever having had a DRE; 36.8% had had a DRE within the past year, and 49.7% within the past 2 years. On multivariate analysis for reporting having an up-to-date DRE, older men, those with higher body mass index, and those of black race were more likely to have an up-to-date DRE. Asian or Hispanic race, divorced or widowed marital status, lower education, lower income, and lack of health insurance were independently associated with being less likely to have an up-to-date DRE. CONCLUSIONS: Of American men, 36.8% reported having an up-to-date DRE within the past year and 49.7% of men within the past 2 years. Demographic and socioeconomic characteristics were strongly associated with the likelihood of having an up-to-date DRE. PMID- 23647942 TI - Stability of stored samples for assays of glycated albumin. PMID- 23647943 TI - Added value of novel circulating and genetic biomarkers in type 2 diabetes prediction: a systematic review. AB - AIMS: To provide a systematic overview of the added value of novel circulating and genetic biomarkers in predicting type 2 diabetes (T2DM). METHODS: We searched MEDLINE and EMBASE (January 2000 to September 2012) for studies that reported a measure of improvement in the performance of T2DM risk prediction models subsequent to adding novel biomarkers to traditional risk factors. We extracted data on study methods and metrics of incremental predictive value of novel biomarkers. RESULTS: We included 34 publications from 30 studies. All studies reported a change in the area under the receiver-operating characteristic curve, which was modest, ranging from -0.004 to 0.1, with claims of statistically significant improvements in eleven studies. The net reclassification index was evaluated in 11 studies, and ranged from -2.2% to 10.2% after inclusion of genetic markers in six studies (statistically significant in two cases), and from -0.5% to 27.5% after inclusion of non-genetic markers in five studies (non significant in two studies). The integrated discrimination index (0-2.04) was reported in eight studies, being statistically significant in five of these. CONCLUSIONS: Currently known novel circulating and genetic biomarkers do not substantially improve T2DM risk prediction above and beyond the ability of traditional risk factors. PMID- 23647944 TI - Early vitreoretinal surgery on vascularly active stage 4 retinopathy of prematurity through the preoperative intravitreal bevacizumab injection. AB - PURPOSE: To evaluate the effect of early vitreoretinal surgery on vascularly active stage 4 ROP through the preoperative use of intravitreal bevacizumab. METHODS: This was a retrospective study. Eighteen patients with vascularly active stage 4 ROP who underwent primary vitrectomy from April 2007 to March 2010 were enrolled. Twelve eyes from eight patients received one-time intravitreal injection of 0.625 mg bevacizumab 7 days prior to vitrectomy (bevacizumab group), and 11 eyes from 10 patients underwent the surgical procedure without bevacizumab (control group). Demographical information of all patients was recorded. The patients were followed up for 12-36 months after the surgery. The postmenstrual age at vitrectomy, surgical procedure, anatomical and visual outcome, adverse effects and surgical complications were compared. RESULTS: There was no statistically significant difference between the two groups in gender, birthweight and gestational age. The bevacizumab group showed remarkable regression of vascular activity after the injection. The mean postmenstrual age at the time of vitrectomy was significantly earlier in the bevacizumab group (40 versus 47 weeks, p = 0.002) compared with the controls. The mean surgery time was shorter in the bevacizumab group (74.81 versus 101.70 min, bevacizumab group versus control, p = 0.002). At the final follow-up, all patients in the bevacizumab group achieved anatomical retinal attachment, compared with 70% in the control group. Eighty-eight per cent patients in the bevacizumab group obtained pattern vision, while it was 30% in the control group (p = 0.015). CONCLUSION: Intravitreal bevacizumab administrated prior to vitrectomy effectively reduced active neovascularization in vascularly active stage 4 ROP patients, thus advancing the timing of vitrectomy and facilitating pars plicata vitrectomy (PPV). PMID- 23647945 TI - No effect of antifungal compounds on functional properties of human antifungal T helper type 1 cells. AB - Despite the availability of new antifungal compounds, invasive fungal disease is associated with a high mortality in hematopoietic stem cell transplant (HSCT) recipients. A growing body of evidence suggests that T lymphocytes from the T helper type 1 (TH 1) play an important role in the antifungal host defense, and preliminary data indicate a potential benefit of infusing donor-derived antifungal TH 1 cells to HSCT patients suffering from invasive fungal disease. Unfortunately, it is unclear to date whether the function of these cells is affected by concomitantly administered antifungal agents. We therefore analyzed the effects of various concentrations of commonly used antifungal compounds such as amphotericin B, caspofungin, fluconazole, voriconazole, and posaconazole on the functional properties of cultivated human antifungal TH 1 cells. None of the antifungal compounds tested significantly influenced the secretion of interferon gamma and tumor necrosis factor-alpha, and only posaconazole at high concentrations slightly decreased proliferation of antifungal TH 1 cells. Our data indicate that the antifungal agents tested do not significantly affect the functional properties of antifungal TH 1 cells and can therefore be concomitantly administered. PMID- 23647946 TI - Cancer: a "stem-cell" disease? AB - BACKGROUND: Nowadays, we believe that cancer is a genetic disease. We focus on the genetic targets and epigenetic changes in a tumor. Remarkably, many crucial signal pathways in a malignant cell involve "stem-ness" genes. The prevalence of stem-ness in cancer suggests that cancer has a stem-cell origin and is a stem cell disease. PRESENTATION OF THE HYPOTHESIS: The observation that many innate stem-ness properties are easily interchangeable with malignant hallmarks needs to be further elucidated. There appears to be a malignant potential in every stem cell and a stem cell potential in every malignant cell. I hypothesize that cancer is a stem-cell disease rather than a genetic disease. TESTING THE HYPOTHESIS: We will use homeobox genes to endow a certain progenitor cell with specific stem ness properties and confer different stem-cell phenotypes to the particular cell type in a hierarchical manner. We will demonstrate that an earlier homeobox gene plus a genetic defect (such as Pten loss) tend to form a more virulent tumor, while a later homeobox gene plus the same genetic defect tend to express a more indolent phenotype. Importantly, we will show that in clinically relevant cancer subtypes, those with worse clinical outcomes may paradoxically harbor fewer genetic mutations than those with better outcomes do. IMPLICATIONS OF THE HYPOTHESIS: The recognition that cancer is a stem-cell disease will instigate major paradigm shifts in our basic understanding of cancer. Many fundamental principles of oncology, such as multistep carcinogenesis, need to be reconciled. The realization that cancer is a stem-cell disease will also have profound clinical implications on personalized care. Many aspects of our current clinical trials need to be reevaluated. PMID- 23647947 TI - The presence of old pulmonary tuberculosis is an independent prognostic factor for squamous cell lung cancer survival. AB - BACKGROUND: Pulmonary tuberculosis (TB) is associated with an increased risk of lung cancer. Our study investigated whether the coexistence of an old pulmonary TB lesion is an independent prognostic factor for lung cancer survival in Chinese non-small cell lung cancer patients. METHODS: We performed a retrospective review of 782 non-small cell lung cancer patients who underwent surgical resection as their primary treatment in 2006 and were followed for 5 years. The associations between lung cancer survival and the presence of old pulmonary TB lesions were assessed using Cox's proportional hazard regression analysis adjusted for WHO performance status (PS), age, sex, smoking-status, tumor stage, and surgical approach. RESULTS: Sixty-four of the patients had old pulmonary TB lesions. The median survival of squamous cell carcinoma patients with TB was significantly shorter than that of patients without TB (1.7 vs. 3.4 years, p < 0.01). The presence of an old pulmonary TB lesion is an independent predictor of poor survival with a hazard ratio (HR) of 1.72 (95% CI, 1.12-2.64) in the subgroup of squamous cell carcinoma patients studied. CONCLUSION: The presence of an old pulmonary TB lesion may be an important prognostic factor for predicting the survival of squamous cell carcinoma patients. PMID- 23647948 TI - Prevalence and spread of extended-spectrum beta-lactamase-producing Enterobacteriaceae in Ngaoundere, Cameroon. AB - During April 2010 and June 2010, 334 Enterobacteriaceae isolates from 590 participants (outpatients, inpatients, inpatient carers, hospital workers and members of their households) were collected from faecal samples. Based on beta lactamase pattern, origin of strains and the relationship between participants, 44 isolates of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae were selected from 44 participants (in Ngaoundere Protestant Hospital and Ngaoundere Regional Hospital, Cameroon). To determine the relatedness of bacterial strains, these isolates were fingerprinted using the automated, repetitive-sequenced-based PCR-based DiversiLab system. Subsequently, E. coli isolates that had undergone DiversiLab analysis were examined with respect to their phylogenetic group and detection of the ST131 clone to shed light on the epidemiology of these isolates in the Ngaoundere hospitals. The prevalence of faecal carriage of ESBL-producing Enterobacteriaceae among the study participants was 54.06%. According to participant groups, the prevalence of faecal carriage was also high (outpatients 45%; inpatients 67%; inpatient carers 57%; hospital workers 44%; and members of their households 46%). Analysis of the molecular epidemiology of ESBL-producing E. coli and K. pneumoniae showed a close relationship of the isolates between related and non-related individuals. In addition, DiversiLab results of E. coli identified four related isolates (4/22) from cluster III belonging to the epidemiologically important clone ST131. Our results highlight the importance of outpatients, inpatients, their carers, hospital workers and their families as reservoirs of ESBL-producing Enterobacteriaceae. PMID- 23647949 TI - Older adults are mobile too!Identifying the barriers and facilitators to older adults' use of mHealth for pain management. AB - BACKGROUND: Mobile health (mHealth) is a rapidly emerging field with the potential to assist older adults in the management of chronic pain (CP) through enhanced communication with providers, monitoring treatment-related side effects and pain levels, and increased access to pain care resources. Little is currently known, however, about older adults' attitudes and perceptions of mHealth or perceived barriers and facilitators to using mHealth tools to improve pain management. METHODS: We conducted six focus groups comprised of 41 diverse older adults (>=60 years of age) with CP. Participants were recruited from one primary care practice and two multiservice senior community day-visit centers located in New York City that serve older adults in their surrounding neighborhoods. Focus group discussions were recorded and transcribed, and transcriptions were analyzed using direct content analysis to identify and quantify themes. RESULTS: Focus group discussions generated 38 individual themes pertaining to the use of mHealth to help manage pain and pain medications. Participants had low prior use of mHealth (5% of participants), but the vast majority (85%) were highly willing to try the devices. Participants reported that mHealth devices might help them reach their healthcare provider more expeditiously (27%), as well as help to monitor for falls and other adverse events in the home (15%). Barriers to device use included concerns about the cost (42%) and a lack of familiarity with the technology (32%). Facilitators to device use included training prior to device use (61%) and tailoring devices to the functional needs of older adults (34%). CONCLUSIONS: This study suggests that older adults with CP are interested and willing to use mHealth to assist in the management of pain. Participants in our study reported important barriers that medical professionals, researchers, and mHealth developers should address to help facilitate the development and evaluation of age-appropriate, and function-appropriate, mHealth devices for older persons with CP. PMID- 23647950 TI - Evaluation of Solvita compost stability and maturity tests for assessment of quality of end-products from mixed latrine style compost toilets. AB - It is challenging and expensive to monitor and test decentralized composting toilet systems, yet critical to prevent the mismanagement of potentially harmful and pathogenic end-product. Recent studies indicate that mixed latrine composting toilets can be inhibited by high ammonia content, a product of urea hydrolysis. Urine-diverting vermicomposting toilets are better able to accomplish the goals of remote site human waste management by facilitating the consumption of fecal matter by earthworms, which are highly sensitive to ammonia. The reliability of Solvita compost stability and maturity tests were evaluated as a means of determining feedstock suitability for vermicomposting (ammonia) and end-product stability/completeness (carbon dioxide). A significant linear regression between Solvita ammonia and free ammonia gas was found. Solvita ranking of maturity did not correspond to ranking assigned by ammonium:nitrate standards. Solvita ammonia values 4 and 5 contained ammonia levels below earthworm toxicity limits in 80% and 100% of samples respectively indicative of their use in evaluating feedstock suitability for vermicomposting. Solvita stability tests did not correlate with carbon dioxide evolution tests nor ranking of stability by the same test, presumably due to in situ inhibition of decomposition and microbial respiration by ammonia which were reported by the Solvita CO2 test as having high stability values. PMID- 23647951 TI - Dynamic of functional microbial groups during mesophilic composting of agro industrial wastes and free-living (N2)-fixing bacteria application. AB - Although several reports are available concerning the composition and dynamics of the microflora during the composting of municipal solid wastes, little is known about the microbial diversity during the composting of agro-industrial refuse. For this reason, the first parts of this study included the quantification of microbial generic groups and of the main functional groups of C and N cycle during composting of agro-industrial refuse. After a generalized decrease observed during the initial phases, a new bacterial growth was observed in the final phase of the process. Ammonifiers and (N2)-fixing aerobic groups predominated outside of the piles whereas, nitrate-reducing group increased inside the piles during the first 23days of composting. Ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB), showed an opposite trend of growth since ammonia oxidation decreased with the increase of the nitrite oxidation activity. Pectinolytics, amylolytics and aerobic cellulolytic were present in greater quantities and showed an upward trend in both the internal and external part of the heaps. Several free-living (N2)-fixing bacteria were molecularly identify as belonging especially to uncommon genera of nitrogen fixing bacteria as Stenotrophomonas, Xanthomonas, Pseudomonas, Klebsiella, Alcaligenes, Achromobacter and Caulobacter. They were investigated for their ability to fix atmospheric nitrogen to employ as improvers of quality of compost. Some strains of Azotobacter chrococcum and Azotobacter salinestris were also tested. When different diazotrophic bacterial species were added in compost, the increase of total N ranged from 16% to 27% depending on the selected microbial strain being used. Such microorganisms may be used alone or in mixtures to provide an allocation of plant growth promoting rhizobacteria in soil. PMID- 23647952 TI - Phage display antibodies for diagnostic applications. AB - With major developments in molecular biology, numerous display technologies have been successfully introduced for recombinant antibody production. Even so, phage display still remains the gold standard for recombinant antibody production. Its success is mainly attributed to the robust nature of phage particles allowing for automation and adaptation to modifications. The generation of monospecific binders provides a vital tool for diagnostics at a lower cost and higher efficiency. The flexibility to modify recombinant antibodies allows great applicability to various platforms for use. This review presents phage display technology, application and modifications of recombinant antibodies for diagnostics. PMID- 23647953 TI - Virus-neutralizing antibodies to hepatitis C virus. AB - For a long time, the lack of an appropriate cell culture system has hampered the study of neutralizing antibody responses against hepatitis C virus (HCV). However, the last decade has seen the development of several model systems that have significantly advanced our understanding of viral entry and antibody neutralization. Studies of acutely infected patients suggest that a strong and early production of neutralizing antibodies may contribute to control the virus during the acute phase of HCV infection and facilitate viral elimination by cellular immune responses. It also emerges that the early antibody response mainly targets hypervariable region 1 (HVR1) of the envelope glycoprotein E2. This host response can lead to viral escape from neutralization by rapid amino acid changes in this hypervariable region. In contrast, cross-reactive neutralizing antibodies seem to appear later during HCV infection, and several mechanisms contribute to reduce their accessibility to their cognate epitopes. These include the masking of major conserved neutralizing epitopes by HVR1, specific N-linked glycans and the lipid moiety of the viral particle. Other potential mechanisms of evasion from the neutralizing antibody response include a modulation by high-density lipoproteins and interfering antibodies as well as the capacity of the virus to be transferred by cell-to-cell contacts. Finally, the recent identification of several highly conserved neutralizing epitopes provides some opportunities for the design and development of vaccine candidates that elicit a protective humoral immune response. PMID- 23647954 TI - IL-28B polymorphisms and the response to antiviral therapy in HCV genotype 2 and 3 varies by ethnicity: a meta-analysis. AB - Studies of IL-28B genotype in patients with hepatitis C virus (HCV) genotype 2/3 infection have yielded conflicting results. The aim of this meta-analysis was to obtain a pooled odds ratio (OR) of the impact of IL-28B genotype on achieving sustained virologic response (SVR) in patients with HCV genotype 2/3 infection treated with pegIFN and ribavirin. A meta-analysis with a random effects model was performed, and study heterogeneity and publication bias were assessed. Forty three percent of the Caucasians (11 studies) and 86% of Asians (five studies) had the favourable IL-28B genotype. In Caucasians, the pooled OR of SVR with the favourable IL-28B genotype was 1.36 (95%CI: 0.98-1.88, P = 0.07) in all patients and 1.55 (95%CI: 1.10-2.18, P = 0.01) in patients treated with pegIFN and ribavirin for >=24 weeks. In Asians, the pooled OR of SVR in patients with the favourable IL-28B genotype was 1.99 (95%CI: 0.94-4.25, P = 0.07). The favourable IL-28B genotype was also significantly associated with rapid virologic response (RVR) in both groups (Caucasians: OR: 1.82, 95%CI: 1.12-2.96, P = 0.02; Asians: 2.39, 95%CI: 1.39-4.11, P = 0.002), as well as the likelihood of an SVR in a subgroup of 350 Caucasian patients without an RVR (OR: 3.29, 95%CI: 1.67-6.51, P = 0.001). The favourable IL-28B genotype is a statistically significant predictor of SVR and RVR in Caucasian patients treated with pegIFN and ribavirin for 24 weeks. In contrast, the favourable IL-28B genotype is associated with RVR, but not SVR in Asian HCV genotype 2 patients. PMID- 23647955 TI - Induction of interferon-lambda contributes to Toll-like receptor-3-activated hepatic stellate cell-mediated hepatitis C virus inhibition in hepatocytes. AB - There is limited information about the role of hepatic stellate cells (HSC) in liver innate immunity against hepatitis C virus (HCV). We thus examined whether HSC can produce antiviral factors that inhibit HCV replication in human hepatocytes. HSC expressed functional Toll-like receptor 3 (TLR-3), which could be activated by its ligand, polyinosine-polycytidylic acid (poly I:C), leading to the induction of interferon-lambda (IFN-lambda) at both mRNA and protein levels. TLR-3 signalling of HSC also induced the expression of IFN regulatory factor 7 (IRF-7), a key regulator of IFN signalling pathway. When HCV JFH-1-infected Huh7 cells were co-cultured with HSC activated with poly I:C or incubated in media conditioned with supernatant (SN) from poly I:C-activated HSC, HCV replication was significantly suppressed. This HSC SN action on HCV inhibition was mediated through IFN-lambda, which was evidenced by the observation that antibody to IFN lambda receptors could neutralize the HSC-mediated anti-HCV effect. The role of IFN-lambda in HSC-mediated anti-HCV activity is further supported by the observation that HSC SN treatment induced the expression of IRF-7 and IFN stimulated genes (ISGs), OAS-1 and MxA in HCV-infected Huh7 cells. These observations indicate that HSC may be a key regulatory bystander, participating in liver innate immunity against HCV infection using an IFN-lambda-dependent mechanism. PMID- 23647956 TI - Analysis of genotype 2 and 3 hepatitis C virus variants in patients treated with telaprevir demonstrates a consistent resistance profile across genotypes. AB - Study C209 evaluated the activity of telaprevir in treatment-naive patients with genotypes 2 or 3 (G2, G3) hepatitis C virus (HCV) infection. Telaprevir monotherapy showed potent activity against HCV G2, but limited activity against G3. This analysis was performed to characterize HCV viral variants emerging during telaprevir-based treatment of G2/G3 HCV-infected patients. Patients were randomized to receive 2 weeks of treatment with telaprevir (telaprevir monotherapy), telaprevir plus peginterferon alfa-2a and ribavirin (triple therapy), or placebo plus peginterferon alfa-2a and ribavirin (control), followed by 22-24 weeks of peginterferon/ribavirin alone. Viral breakthrough was defined as an increase >1 log10 in HCV RNA from nadir, or HCV RNA >100 IU/mL in patients previously reaching <25 IU/mL. Twenty-three patients (47%) had G2 and 26 (53%) had G3 HCV. Viral breakthrough occurred during the initial 2-week treatment phase in six G2 patients (66.7%; subtypes 2, 2a and 2b) and three G3 patients (37.5%; all subtype 3a), all in the telaprevir monotherapy arm. Four breakthrough patients (three G2, one G3) subsequently achieved sustained virologic response (SVR). In all patients with breakthrough and available sequence data, mutations associated with reduced susceptibility to telaprevir in genotype 1 (G1) HCV were observed. No novel G2/G3-specific mutations were associated with telaprevir resistance. The telaprevir resistance profile appeared consistent across HCV genotypes 1, 2 and 3. Although viral breakthrough with resistance occurred in patients receiving telaprevir monotherapy, half of these patients achieved an SVR upon addition of peginterferon/ribavirin highlighting the importance of combination therapy. PMID- 23647957 TI - Anti-inflammatory cytokines, pro-fibrogenic chemokines and persistence of acute HCV infection. AB - Chemokines and cytokines play a vital role in directing and regulating immune responses to viral infections. Persistent hepatitis C virus (HCV) infection is characterized by the loss of anti-HCV cellular immune responses, while control of HCV infection is associated with maintenance of anti-HCV cellular immune responses. To determine whether plasma concentrations of 19 chemokines and cytokines controlling T-cell trafficking and function differed based on infection outcome, we compared them in at-risk subjects followed prospectively for HCV infection. Levels were compared over time in subjects who controlled HCV infection (Clearance) and subjects who developed persistent HCV infection (Persistence) at two time points during acute infection: (i) first viraemic sample (initial viraemia) and (ii) last viraemic sample in Clearance subjects and time-matched samples in Persistence subjects. At initial viraemia, increased pro inflammatory tumour necrosis factor alpha (TNFalpha) plasma concentrations were observed in the Clearance group, while the plasma levels of anti-inflammatory interleukin (IL)-2, IL-10 and IL-13 were higher in the Persistence group. IL-13 was positively correlated with IL-2 and IL-10 at initial viraemia in the Persistence group. At the time of last viraemia, plasma levels of eotaxin, macrophage chemoattractant protein-4 (MCP-4), IL-5 and IL-10 were higher in the Persistence group and IL-10 and IL-5 levels were positively correlated. Collectively, these results suggest that the development of persistent infection is associated with an anti-inflammatory and pro-fibrogenic chemokine and cytokine profile that is evident at the onset of infection and maintained throughout acute infection. PMID- 23647958 TI - The presence of resistance mutations to protease and polymerase inhibitors in Hepatitis C virus sequences from the Los Alamos databank. AB - Several new direct-acting antiviral (DAA) drugs are in development for chronic hepatitis C viral (HCV) infection, and NS3-NS4A serine protease and the NS5B RNA dependent RNA polymerase have been the major targets. HCV variants displaying drug-resistant phenotypes have been observed both in vitro and during clinical trials. Our aim was to characterize amino acid changes at positions previously associated with resistance in protease (NS3) and polymerase (NS5B) regions from treatment-naive HCV patients infected with genotypes 1a, 1b and 3a. All 1383 NS3 protease sequences (genotype 1a = 680, 1b = 498 and 3a = 205) and 806 NS5B polymerase sequences (genotypes 1a = 471, 1b = 329, 3a = 6) were collected from Los Alamos databank. Genotype 3a protease sequences showed the typical low-level resistance mutation V36L. NS3 sequences from other genotypes presented mutations on positions 36, 39, 41, 43, 54, 80, 109, 155 and 168 in a frequency lower than 2%, except for the mutation Q80R found in 35% of genotype 1a isolates. Polymerase sequences from genotype 3a patients showed five typical mutations: L419I, I424V, I482L, V499A and S556G. Two positions presented high polymorphism in the NS5B region from genotype 1a (V499A) and genotype 1b (C316N) subjects. Our results demonstrated a natural profile of genotype 3a that can be associated with the pre existence of HCV variants resistant to first-generation protease inhibitors and to non-nucleoside polymerase inhibitors. Likewise, genotype 1b isolates and genotype 1a sequences exhibited pre-existing mutations associated with resistance to Palm II and Thumb I polymerase inhibitors, respectively. PMID- 23647959 TI - Quantification of hepatitis B surface antigen and E antigen: correlation between Elecsys and architect assays. AB - Quantification of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and their change model during treatment are emerging as a useful tool for assessing the outcome of hepatitis B virus (HBV) infection and predicting the efficacy of antiviral therapy. The aim of this study was to compare the performance of the Elecsys and Architect assays for HBsAg and HBeAg quantification. Quantification of HBsAg and HBeAg, determined by these two assays, were assessed in 1292 sera from patients with chronic hepatitis B(CHB). HBeAg quantification in serum was performed by calibrating the results through HBeAg Paul-Ehrlich international (PEI) reference standard. The HBV genotype was determined by direct sequencing and phylogenetic analysis. Of 1292 samples, the distribution of genotype was 514 (39.78%) genotype B, 776 (60.06%) genotype C, 2 (0.16%) genotype D. The results of HBsAg and HBeAg quantification between the Architect and Elecsys assays were significantly correlated (HBsAg: r = 0.939; HBeAg: r = 0.987), independent of HBV genotype and treatment phase. The mean differences between the two methods (the log10 [Elecsys] - the log10 [Architect]) were 0.075 log10 IU/mL and -0.149 log10 PE IU/mL in quantifying HBsAg and HBeAg, respectively. This study demonstrates a high correlation between the Elecsys and the Architect assays in quantifying HBsAg and HBeAg, regardless of HBV genotype. Both the two assays can be used to monitor the HBsAg and HBeAg levels in patients with chronic hepatitis B. PMID- 23647960 TI - DNA methylation patterns of peroxisome proliferator-activated receptor gamma gene associated with liver fibrosis and inflammation in chronic hepatitis B. AB - Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor that regulates gene expression of inflammatory mediators in liver injury. Hepatitis B virus (HBV) suppresses the PPAR gamma-mediated transactivation in liver cancerous cell lines. However, the role of PPAR gamma in patients with chronic HBV infection has not fully demonstrated. Our present study was firstly to determine the clinical relevance of peripheral PPAR gamma mRNA levels in chronic hepatitis B (CHB) patients, and then, the DNA methylation of PPAR gamma promoter was investigated. Peripheral blood mononuclear cells (PBMCs) were isolated from 91 CHB patients and 18 healthy controls. The mRNA level of PPAR gamma was determined by quantitative real-time PCR; meanwhile, the CpG island methylation was assessed by methylation-specific PCR. CHB patients showed significantly lower mRNA level of PPAR gamma than healthy controls (P = 0.005). The mRNA level was decreased in HBV-DNA-positive group than HBV-DNA-negative group (P = 0.041). Interaction analysis demonstrated that the DNA methylation pattern was responsible for the suppression of peripheral PPAR gamma transcription in CHB patients (P = 0.003). Furthermore, the hypermethylation of PPAR gamma gene promoter was significantly associated with liver inflammation and fibrosis in CHB. In conclusion, DNA methylation patterns were responsible for the decreased mRNA level of peripheral PPAR gamma in CHB patients. Liver inflammation and fibrosis were found to be associated with hypermethylation of PPAR gamma promoter. PMID- 23647961 TI - Identification of HEV in symptom-free migrants and environmental samples in Italy. AB - Hepatitis E virus (HEV) is considered an emerging pathogen in industrialized countries. The occurrence of HEV genotypes in samples of faeces from asymptomatic migrants arriving on the coasts of South Italy and environmental samples was investigated. Analyses of sequences were used to compare human and environmental genotypes. A total of 40 stool specimens, 12 samples of untreated urban sewage, 12 samples of treated urban sewage and 12 samples of surface water were analysed. Viruses were concentrated from water samples by the tangential flow ultrafiltration technique. The presence of HEV RNA was detected by nested RT-PCR. Viral isolates were sequenced and phylogenetically characterized. Two (5%) of the 40 faecal samples tested were found to be positive for HEV RNA (G1 and G3 genotypes). The virus was detected in 25% (3/12) of the untreated sewage samples and 25% (3/12) of the surface water samples: all isolates belonged to G3 genotype. None of the treated sewage samples were found to be HEV RNA positive. The virus was detected in the faeces of two asymptomatic subjects, suggesting a potential role for symptom-free HEV carriers as a human reservoir. G3 HEV strains were detected in the untreated sewage, as observed in similar studies conducted in other European countries but differing from another study conducted in Italy recently. Moreover, our results show the first case of HEV isolated from fresh surface waters. PMID- 23647962 TI - Maternal HBsAg status and infant size: the importance of viral load and HBsAg quantification. PMID- 23647963 TI - Community structure of soil phototrophs along environmental gradients in arid Himalaya. AB - The well-developed biological soil crusts cover up to 40% of the soil surface in the alpine and subnival zones of the Tibetan Plateau, accounting for a vast area of Asia. We investigated the diversity and biomass of the phototrophic part (Cyanobacteria) of the microbial community inhabiting biological soil crusts and uncrusted soils in their surroundings on the elevation gradient of 5200-5900 m a.s.l. The influence of soil physico-chemical properties on phototrophs was studied. The ability of high-altitude phototrophs to fix molecular nitrogen was also determined under laboratory conditions. The biological soil crust phototroph community did not differ from that living in uncrusted soil in terms of the species composition, but the biomass is three-to-five times higher. An increasing trend in the cyanobacterial biomass from the biological soil crusts with elevation was observed, with the genera Nostoc spp., Microcoleus vaginatus and Phormidium spp. contributing to this increase. Based on the laboratory experiments, the highest nitrogenase activity was recorded in the middle elevations, and the rate of nitrogen fixation was not correlated with the cyanobacterial biomass. PMID- 23647964 TI - Mesenchymal stem cell transplantation mitigates electrophysiological remodeling in a rat model of myocardial infarction. AB - INTRODUCTION: Transplantation of mesenchymal stem cells (MSCs) has shown therapeutic potential for cardiovascular diseases, but the electrophysiological implications are not understood. The purpose of this study was to evaluate the impact of MSC transplantation on adverse electrophysiological remodeling in the heart following myocardial infarction (MI). METHODS AND RESULTS: Three weeks after coronary ligation to induce MI in rats, MSCs or culture medium were directly injected into each infarct. One to two weeks later, hearts were excised, Langendorff-perfused, and optically mapped using the potentiometric fluorescent dye Di-4-ANEPPS. Quantitative real-time PCR was also performed to assess gene expression. Optical mapping showed that post-MI reduction in conduction velocity (from 0.70 +/- 0.04 m/s in 12 normal controls to 0.47 +/- 0.02 m/s in 11 infarcted hearts, P < 0.05) was attenuated with MSC transplantation (0.65 +/- 0.04 m/s, n = 18, P < 0.05). Electrophysiological changes correlated with higher vascular density and better-preserved ventricular geometry in MSC-transplanted hearts. A number of ion channel genes showed changes in RNA expression following infarction. In particular, the expression of Kir2.1, which mediates the inward rectifier potassium current, I(K1), was reduced in infarcted tissues (n = 7) to 13.8 +/- 3.7% of normal controls, and this post-MI reduction was attenuated with MSC transplantation (44.4 +/- 11.2%, n = 7, P < 0.05). CONCLUSION: In addition to promoting angiogenesis and limiting adverse structural remodeling in infarcted hearts, MSC transplantation also alters ion channel expression and mitigates electrophysiological remodeling. Further understanding of the electrophysiological impact of MSC transplantation to the heart may lead to the development of cell-based therapies for post-MI arrhythmias. PMID- 23647965 TI - Evaluation of interferon-gamma release assay in the diagnosis of osteoarticular tuberculosis. AB - The aim of this study was to assess the value of interferon-gamma (IFN-gamma) release assay (IGRA) (T-SPOT.TB) for patients with suspected osteoarticular tuberculosis (TB) in comparison with conventional and molecular methods. Of 145 patients with suspected osteoarticular TB, recruited from Beijing Chest Hospital between July 2011 and June 2012, 86 (59.3%)had osteoarticular TB (26 with culture confirmed TB, 60 with probable TB), 24 (16.6%) were not having active TB. The remaining 17 (11.7%) inconclusive TB and 18 (12.4%) possible TB were excluded from final analysis. In addition to conventional tests and molecular method, T SPOT.TB assay using peripheral blood mononuclear cells to examine IFN-gamma response to early secretory antigenic target 6 and culture filtrate protein 10 was also performed. The sensitivity and specificity for T-SPOT.TB assay were 94.2% and 70.8%, respectively. A statistically significant difference in sensitivity was found between T-SPOT.TB assay (94.2%) and other tests (acid-fast bacilli smear (19.7%), culture (34.2%), real-time PCR (36.8%); P < 0.01, respectively). These results suggested that the IGRA assay could provide useful aids in the diagnosis of osteoarticular TB. PMID- 23647967 TI - Feeding dysfunction in single ventricle patients with feeding disorder. AB - PURPOSE: To determine whether caregivers of children with single ventricle heart defects identified as having feeding disorder will report more frequent feeding dysfunction, or maladaptive mealtime behavior and/or interactions, when compared with reference populations. METHODS: As part of routine evaluation, parents of children evaluated at the Feeding, Swallowing, and Nutrition Center at the Children's Hospital of Wisconsin completed previously validated questionnaires to assess feeding dysfunction and parental stress. Parental responses for single ventricle patients were compared with all other children evaluated with a feeding disorder. RESULTS: Questionnaires were completed in eight patients with single ventricle heart defects. The mean age was 36 +/- 23 months, with five females (63%). Mean weight-for-age z-score was -1.4 +/- 0.9. Compared with noncardiac feeding clinic children, there was more reported child resistance to eating (83 +/- 15% vs. 44 +/- 2%; P = .05). Single ventricle parents were more likely to report distress (50 +/- 18% vs. 21 +/- 2%; P = .04) and a difficult child (63 +/- 17% vs. 31 +/- 2%; P = .05). There was also more defensive responding among parents of single ventricle children (63 +/- 17% vs. 29 +/- 2%; P = .04). CONCLUSION: Single ventricle patients evaluated for disordered feeding more frequently showed resistance to eating and parental distress than noncardiac feeding clinic patients. Parents of these children underestimated the degree of feeding difficulty by defensive responding and had more parental distress. These findings suggest that feeding dysfunction can contribute to longer-term feeding and growth problems in single ventricle patients with feeding disorder. PMID- 23647968 TI - Multidisciplinary collaborative development of a plain-language prenatal education book. AB - During pregnancy, women actively seek out health information that promotes the well-being of themselves and their fetuses. For those with health literacy challenges, access to understandable health information can be difficult. Written information, in particular, needs to be readable and usable by the women served. Plain language is an essential component of effective health education material. In an effort to create standardized prenatal education materials for a diverse population of childbearing women, Boston Medical Center's midwifery service led a multidisciplinary initiative to develop a comprehensive plain-language prenatal education book. Midwives, obstetricians, family physicians, nurses, and community doulas contributed to the content of the book; art students provided graphic design skills; and a literacy consultant assisted in the wording and layout. The Hey Mama! book provides women with woman-centered, readable, comprehensive information about pregnancy, labor, postpartum, and newborn care. PMID- 23647970 TI - Potential of industrial biotechnology with cyanobacteria and eukaryotic microalgae. AB - Both cyanobacteria and eukaryotic microalgae are promising organisms for sustainable production of bulk products such as food, feed, materials, chemicals and fuels. In this review we will summarize the potential and current biotechnological developments. Cyanobacteria are promising host organisms for the production of small molecules that can be secreted such as ethanol, butanol, fatty acids and other organic acids. Eukaryotic microalgae are interesting for products for which cellular storage is important such as proteins, lipids, starch and alkanes. For the development of new and promising lines of production, strains of both cyanobacteria and eukaryotic microalgae have to be improved. Transformation systems have been much better developed in cyanobacteria. However, several products would be preferably produced with eukaryotic microalgae. In the case of cyanobacteria a synthetic-systems biology approach has a great potential to exploit cyanobacteria as cell factories. For eukaryotic microalgae transformation systems need to be further developed. A promising strategy is transformation of heterologous (prokaryotic and eukaryotic) genes in established eukaryotic hosts such as Chlamydomonas reinhardtii. Experimental outdoor pilots under containment for the production of genetically modified cyanobacteria and microalgae are in progress. For full scale production risks of release of genetically modified organisms need to be assessed. PMID- 23647969 TI - Ivermectin to reduce malaria transmission: a research agenda for a promising new tool for elimination. AB - BACKGROUND: The heterogeneity of malaria transmission makes widespread elimination a difficult goal to achieve. Most of the current vector control measures insufficiently target outdoor transmission. Also, insecticide resistance threatens to diminish the efficacy of the most prevalent measures, indoor residual spray and insecticide treated nets. Innovative approaches are needed. The use of endectocides, such as ivermectin, could be an important new addition to the toolbox of anti-malarial measures. Ivermectin effectively targets outdoor transmission, has a novel mechanism of action that could circumvent resistance and might be distributed over the channels already in place for the control of onchocerciasis and lymphatic filariasis. METHODS: The previous works involving ivermectin and Anopheles vectors are reviewed and summarized. A review of ivermectin's safety profile is also provided. Finally three definitive clinical trials are described in detail and proposed as the evidence needed for implementation. Several smaller and specific supportive studies are also proposed. CONCLUSIONS: The use of ivermectin solves many challenges identified for future vector control strategies. It is an effective and safe endectocide that was approved for human use more than 25 years ago. Recent studies suggest it might become an effective and complementary strategy in malaria elimination and eradication efforts; however, intensive research will be needed to make this a reality. PMID- 23647971 TI - Quantitative approaches to uncover physical mechanisms of tissue morphogenesis. AB - Morphogenesis, the creation of tissue and organ architecture, is a series of complex and dynamic processes driven by genetic programs, microenvironmental cues, and intercellular interactions. Elucidating the physical mechanisms that generate tissue form is key to understanding development, disease, and the strategies needed for regenerative therapies. Advancements in imaging technologies, genetic recombination techniques, laser ablation, and microfabricated tissue models have enabled quantitative descriptions of the cellular motions and tissue deformations and stresses with unprecedented temporal and spatial resolution. Using these data synergistically with increasingly more sophisticated physical, mathematical, and computational models will unveil the physical mechanisms that drive morphogenesis. PMID- 23647972 TI - Engineering the matrix microenvironment for cell delivery and engraftment for tissue repair. AB - Cell-based therapies represent promising strategies for tissue repair, particularly in cases in which host cells, due to disease, age, or excessive trauma, are unable to repair the defect or deficiency alone, even with additional delivered therapeutics. Current cell therapies fail to address long-term engraftment or delivery timing and location and result in modest improvements with long term engraftment rates of less than 1%. In many cell therapy applications, an appropriate carrier must be used to deliver transplanted cells and promote cell engraftment and function for a successful outcome by providing the appropriate microenvironment for the interactions between transplanted and host cells. This review highlights important considerations for engineering the microenvironment for cell delivery and engraftment in tissue repair. PMID- 23647973 TI - Contaminated ventilator air flow sensor linked to Bacillus cereus colonization of newborns. AB - We investigated Bacillus cereus-positive tracheal aspirates from infants on ventilators in a neonatal intensive care unit. Multilocus sequence typing determined a genetic match between strains isolated from samples from a case patient and from the air flow sensor in the ventilator. Changing the sterilization method for sensors to steam autoclaving stopped transmission. PMID- 23647974 TI - Core sediment bacteria drive community response to anthropogenic contamination over multiple environmental gradients. AB - In this study, 454 pyrosequencing of the 16S rRNA gene was used to investigate sediment bacterial community response to contaminant disturbance across six estuaries with differing levels of 'modification'. We observed a significant influence of metal and polycyclic aromatic hydrocarbon contaminants in shaping bacterial community composition, structure and diversity, with metals being the more influential contaminant. An abundant and pervasive 'core' set of bacteria found in every sample were largely responsible for mediating community response to contamination. These 13 core operational taxonomic units were mostly comprised of Gamma-, Delta-, Alphaproteobacteria and Acidobacteria. Sediment silt and metals together explained the most variation in bacterial community composition (19.7%). Following this strong contaminant signature, salinity and temperature represented important environmental variables predicting 10.9% of community variation. While overall network connectivity measures supported the idea of an inherently diverse soil microbiome with some degree of functional redundancy, lower values observed in contaminated sediments indicate potential structural perturbations in the community from fracturing or loss of bacterial associations. The large number of unclassified sequences obtained in this study contribute to improving our understanding of environmentally relevant strains in relation to anthropogenic contamination, which have been overlooked in laboratory studies. PMID- 23647976 TI - Modified nasal dermoplasty technique for treatment of recurrent polyposis: preliminary results. AB - OBJECTIVE: To present and evaluate the use of nasal dermoplasty for control of recurrent nasal polyps. STUDY DESIGN: Prospective case series. METHOD: The mucosa of the fovea ethmoidalis and the lamina papyracea was replaced by a split thickness skin graft. The follow-up period ranged from 2 to 12 months. RESULTS: Five patients underwent nasal dermoplasty for recurrent nasal polyposis. In three cases, the graft uptake was successful. Post-operatively, four patients reported they were in better condition than at the same interval after their previous operation. Recurrence of polyps was noted in all patients but not in the grafted areas. CONCLUSION: In this study, there was a high prevalence of successful graft uptake following nasal dermoplasty. This technique may have potential for the control of recurrent nasal polyps. Although it is demanding and time-consuming, it may reduce the need for multiple operations. Further research is justified to establish its efficacy. PMID- 23647975 TI - PTSD risk associated with a functional DRD2 polymorphism in heroin-dependent cases and controls is limited to amphetamine-dependent individuals. AB - Posttraumatic stress disorder (PTSD), a pathologic response to severe stress, is a common co-morbid disorder in substance-dependent individuals. Evidence from twin studies suggests that PTSD is moderately heritable. Genetic association studies to date have reported a limited number of replicated findings. We conducted a candidate gene association study in trauma-exposed individuals within the Comorbidity and Trauma Study's sample (1343 heroin-dependent cases and 406 controls from economically disadvantaged neighborhoods). After data cleaning, the 1430 single nucleotide polymorphisms (SNPs) retained for analyses provided coverage of 72 candidate genes and included additional SNPs for which association was previously reported as well as 30 ancestry-informative markers. We found a functional DRD2 promoter polymorphism (rs12364283) to be most highly associated with PTSD liability [odds ratio (OR) 1.65 (1.27-2.15); P = 1.58 * 10(-4) ]; however, this association was not significant, with a stringent Bonferroni correction for multiple comparisons. The top hits include SNPs from other dopaminergic system genes: DRD2 DRD3, TH and DBH. Additional analyses revealed that the association involving rs12364283 is largely limited to amphetamine dependent individuals. Substantial risk is observed in amphetamine-dependent individuals, with at least one copy of this SNP [OR 2.86 (1.92-4.27); P = 2.6 * 10(-7) ]. Further analyses do not support extensive mediation of PTSD risk via self-reported impulsivity (BIS total score). These findings suggest roles for impairment in inhibitory control in the pathophysiology of PTSD and raise questions about stimulant use in certain populations (e.g. those in combat). PMID- 23647977 TI - A narrative review of factors influencing detection and treatment of depression in Vietnam. AB - Depression is among the most common psychiatric conditions in primary health care, and constitutes an important part of the global disease burden. However, it is difficult to obtain comparable data on depression worldwide and models for treatment and intervention need to be locally adapted. We conducted a narrative review of research literature on factors that influence depression screening, diagnosis and treatment among the Vietnamese population. This explorative approach included studies describing: a) culturally or contextually specific risk factors for depression; b) any depression treatment seeking or treatment acceptability/adherence aspects or; c) depression screening among Vietnamese patients. We searched the PubMed and Cinahl databases, as well as relevant Vietnamese peer-reviewed journals and this produced 20 articles that were included in the review. Our findings indicate the importance of considering somatic symptoms when screening for depression in Vietnam as well as the use of culturally adapted and dimensional screening instruments. Our study confirms that depression reflects chronic social adversity, and thus an approach to mental health management that focuses solely on individual pathology will fail to address its important social causes. Further studies should elucidate whether neurasthenia is a commonly used illness label among Vietnamese patients that coincides with depression. The tendency among Vietnamese to seek traditional Vietnamese medicine and meditation practice when experiencing emotional distress was supported by our findings. PMID- 23647978 TI - Performance of the Framingham risk score in patients receiving hemodialysis. AB - AIM: The Framingham Risk Score (FRS), calculated by considering conventional risk factors of cardiovascular diseases, was developed to predict coronary heart disease in various populations. However, reverse epidemiology has been raised concerning these risk factors in predicting high cardiovascular mortality in hemodialysis patients. Our objectives are to determine whether FRS is associated with overall and cardiovascular mortality and the role of new risk markers when they were added to a FRS model in hemodialysis patients. METHODS: This study enrolled 201 hemodialysis patients aged 20-80 years old. The FRS is used to identify individuals categorized as low (<6% 10-year risk), intermediate (6-20% risk) or high risk (>20% risk). Medical records were reviewed to collect clinical information. Data of ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) were obtained by an ABI-form device. RESULTS: The mean follow-up period was 4.4 +/- 1.5 years. Intermediate risk predicted overall hazard ratio (HR) (2.157, P = 0.039) and cardiovascular mortality (HR= 5.023; P = 0.004) versus low risk, but 'high' risk did not. High risk (vs low risk) predicted cardiovascular events (HR = 2.458, P = 0.05). Besides, the addition of ABI < 0.9 (P = 0.021) and baPWV (P = 0.014) to a FRS model significantly improved the predictive value for overall mortality. CONCLUSION: In hemodialysis patients, intermediate risk but not high risk categorization by FRS predicted overall and cardiovascular mortality, and high risk predicted cardiovascular events. ABI < 0.9 and baPWV provided additional predictive values for overall mortality. Future study is needed to develop hemodialysis-specific equations and assess whether risk refinement using ABI < 0.9 and baPWV leads to a meaningful change in clinical outcomes. PMID- 23647979 TI - Periprocedural dabigatran in atrial fibrillation ablation: a new kid on the block. PMID- 23647981 TI - Exploring telemonitoring and self-management by patients with chronic obstructive pulmonary disease: a qualitative study embedded in a randomized controlled trial. AB - OBJECTIVE: To explore patient and professional views on self-management in the context of telemonitoring in chronic obstructive pulmonary disease (COPD). METHODS: Semi-structured interviews with patients with COPD and healthcare professionals participating in a randomized controlled trial of telemonitoring in Lothian, Scotland, explored experiences of using telemonitoring, and dynamics in patient-practitioner relationships. Transcribed data were analyzed using the Framework approach. RESULTS: 38 patients (mean age 67.5 years) and 32 professionals provided 70 interviews. Patients considered that telemonitoring empowered self-management by enhancing their understanding of COPD and providing additional justification for their decisions to adjust treatment or seek professional advice. Professionals discussed telemonitoring as promoting compliance with medical advice and encouraged patients to exercise personal responsibility within clinical parameters, but expressed concerns about promoting the sick role and creating dependence on telemonitoring. CONCLUSION: Telemonitoring assisted many patients to embrace greater responsibility for their health but the model of service provision remained clinician-centered. A medical model of 'compliant self-management' may paradoxically have promoted dependence on professionals. PRACTICE IMPLICATIONS: Patients and professionals shared responsibility for meeting the central objective of prompt management of exacerbations of COPD. Care is needed, however, to minimize the risk in some patients, of telemonitoring increasing dependence on practitioner support. PMID- 23647980 TI - Bridging the transition from cancer patient to survivor: pilot study results of the Cancer Survivor Telephone Education and Personal Support (C-STEPS) program. AB - OBJECTIVE: To develop a feasibility study of a theory-driven telephone counseling program to enhance psychosocial and physical well-being for cancer survivors after treatment. METHODS: Participants (n=66) were recruited from two Colorado hospitals with self-administered questionnaires at baseline and two weeks post intervention. The one group, intervention only design included up to six thematic telephone counseling sessions over three months. Topics included nutrition, physical activity, stress management, and medical follow-up. Primary outcomes were cancer-specific distress, self-reported fruit and vegetable consumption and physical activity. RESULTS: Of 66 subjects, 46 completed at least one counseling module and the follow-up assessment (70% retention rate). Mean satisfaction was 9 out of 10, and all participants would recommend C-STEPS to other survivors. Cancer-specific distress (Impact of Event Scale - Intrusion subscale) decreased for entire study population (p<0.001) and stress management session participants (p<0.001). Fruit and vegetable consumption increased for nutrition and exercise session participants (p=0.02) and the entire sample (p=NS). Physical activity increased in the entire group (p=0.006) and for nutrition and exercise session participants (p=0.01). CONCLUSION AND PRACTICE IMPLICATIONS: C-STEPS is a feasible telephone counseling program that transcends geographic barriers, demonstrating the potential to decrease distress and promote coping and healthy lifestyles among cancer survivors. PMID- 23647982 TI - Motivational interviewing by HIV care providers is associated with patient intentions to reduce unsafe sexual behavior. AB - OBJECTIVE: Motivational interviewing (MI) can promote behavior change, but HIV care providers rarely have training in MI. Little is known about the use of MI consistent behavior among untrained providers. This study examines the prevalence of such behaviors and their association with patient intentions to reduce high risk sexual behavior. METHODS: Audio-recorded visits between HIV-infected patients and their healthcare providers were searched for counseling dialog regarding sexual behavior. The association of providers' MI-consistence with patients' statements about behavior change was assessed. RESULTS: Of 417 total encounters, 27 met inclusion criteria. The odds of patient commitment to change were higher when providers used more reflections (p=0.017), used more MI consistent utterances (p=0.044), demonstrated more empathy (p=0.049), and spent more time discussing sexual behavior (p=0.023). Patients gave more statements in favor of change (change talk) when providers used more reflections (p<0.001) and more empathy (p<0.001), even after adjusting for length of relevant dialog. CONCLUSION: Untrained HIV providers do not consistently use MI techniques when counseling patients about sexual risk reduction. However, when they do, their patients are more likely to express intentions to reduce sexual risk behavior. PRACTICE IMPLICATIONS: MI holds promise as one strategy to reduce transmission of HIV and other sexually transmitted infections. PMID- 23647983 TI - Allosteric inhibition of HIV-1 integrase activity. AB - HIV-1 integrase is an important therapeutic target in the fight against HIV/AIDS. Integrase strand transfer inhibitors (INSTIs), which target the enzyme active site, have witnessed clinical success over the past 5 years, but the generation of drug resistance poses challenges to INSTI-based therapies moving forward. Integrase is a dynamic protein, and its ordered multimerization is critical to enzyme activity. The integrase tetramer, bound to viral DNA, interacts with host LEDGF/p75 protein to tether integration to active genes. Allosteric integrase inhibitors (ALLINIs) that compete with LEDGF/p75 for binding to integrase disrupt integrase assembly with viral DNA and allosterically inhibit enzyme function. ALLINIs display steep dose response curves and synergize with INSTIs ex vivo, highlighting this novel inhibitor class for clinical development. PMID- 23647984 TI - Targeting the untargetable: recent advances in the selective chemical modulation of protein phosphatase-1 activity. AB - Protein phosphatase-1 (PP1) has long been neglected as a potential drug target owing to its misinterpreted unselective nature. However, growing evidence demonstrates that PP1 is highly selective in complex with regulatory proteins at the holoenzyme level, each of which is involved in different essential cellular signaling events. Here we summarize promising approaches to specifically activate or inhibit PP1 activity, and discuss remaining challenges and potential solutions. The summarized chemical tools pave the way for a better understanding of PP1's role in signaling networks, and the effects resulting from their application suggest their potential as future therapeutic candidates. PMID- 23647986 TI - Periprocedural antiplatelet therapy: recommendations for standardized reporting in patients on antiplatelet therapy: communication from the SSC of the ISTH. PMID- 23647985 TI - Targeting unfolded protein response signaling pathways to ameliorate protein misfolding diseases. AB - Protein homeostasis (or proteostasis) within the endoplasmic reticulum (ER) is regulated by the unfolded protein response (UPR). The UPR consists of three integrated signaling pathways activated by the accumulation of misfolded proteins within the ER lumen. Activation of the UPR alters ER proteostasis through translational attenuation of new protein synthesis and transcriptional remodeling of ER proteostasis pathways, providing a mechanism to adapt ER proteostasis in response to cellular stress. The capacity of the UPR to alter ER proteostasis suggests that exogenous manipulation of UPR signaling pathways offers therapeutic promise to alter the fate of pathologic proteins associated with human protein misfolding diseases. Here, we discuss the therapeutic potential of exogenous UPR activation to treat human disease and highlight specific small molecule approaches for regulating UPR signaling that could be beneficial to treat protein misfolding diseases. PMID- 23647987 TI - Moderate water stress causes different stomatal and non-stomatal changes in the photosynthetic functioning of Phaseolus vulgaris L. genotypes. AB - The impact of moderate water deficit on the photosynthetic apparatus of three Phaseolus vulgaris L. cultivars, Plovdiv 10 (P10), Dobrudjanski Ran (DR) and Prelom (Prel), was investigated. Water shortage had less impact on leaf hydration, RWC (predawn and midday) and predawn water potential in Prel. RWC and Psi(p) were more reduced in P10, while there was no osmotic adjustment in any cultivar. Although drought drastically reduced stomatal opening in P10 and DR, reduced A(max) indicated non-stomatal limitations that contributed to the negligible P(n). These limitations were on potential thylakoid electron transport rates of PSI and II, pointing to photosystem functioning as a major limiting step in photosynthesis. This agrees with decreases in actual photochemical efficiency of PSII (F(v)'/F(m)'), quantum yield of photosynthetic non-cyclic electron transport (phi(e)) and energy-driven photochemical events (q(P)), although the impact on these parameters would also include down-regulation processes. When compared to DR, Prel retained a higher functional state of the photosynthetic machinery, justifying reduced need for photoprotective mechanisms (non photochemical quenching, zeaxanthin, lutein, beta-carotene) and maintenance of the balance between energy capture and dissipative pigments. The highest increases in fructose, glucose, arabinose and sorbitol in Prel might be related to tolerance to a lower oxidative state. All cultivars had reduced A(max) due to daytime stomatal closure in well-watered conditions. Under moderate drought, Prel had highest tolerance, higher leaf hydration and maintenance of important photochemical use of energy. However, water shortage caused appreciable non stomatal limitations to photosynthesis linked to regulation/imbalance at the metabolic level (and growth) in all cultivars. This included damage, as reflected in decreased potential photosystem functioning, pointing to higher sensitivity of photosynthesis to drought than is commonly assumed. PMID- 23647989 TI - Choroidal vessel diameter in central serous chorioretinopathy. AB - PURPOSE: To measure the hyporeflective lumen in the choroid of patients with central serous choroidopathy (CSC) and to compare the diameter with that of a control group. METHODS: The prospective comparative observational clinical study included patients with unilateral CSC and a control group of normal subjects, matched in age, gender and refractive error with the study group. Subfoveal choroidal thickness (SFCT) and the largest diameter of choroidal hyporeflective lumen as surrogates for the choroidal vessels were measured by enhanced depth imaging optical coherence tomography (OCT). RESULTS: The study group included 15 Chinese patients and the control group 15 control subjects. Mean SFCT was significantly (p = 0.04) larger in the affected eyes (455 +/- 73 MUm) than in the contralateral unaffected eyes (387 +/- 94 MUm), in which it was significantly (p = 0.005) larger than in the control group (289 +/- 71 MUm). In a parallel manner, the mean diameter of the largest hyporeflective lumen was larger, but not significantly larger (p = 0.18) in the affected eyes (305 +/- 101 MUm) than in the in the contralateral unaffected eyes (251 +/- 98 MUm), in which it was significantly (p = 0.001) larger than in the control group (140 +/- 40 MUm). Largest vessel diameter was significantly (p < 0.001; correlation coefficient: 0.73) correlated with the thickness of the total choroid. CONCLUSIONS: In patients with CSC, the affected eyes show larger hyporeflective lumen than the contralateral clinically unaffected eyes and significantly larger than normal control eyes. Assuming these hyporeflective lumens to be choroidal vessels, macular swelling in CSC is markedly associated with vascular engorgement. As also the clinically unaffected eyes showed macular choroidal significant swelling, CSC may have a systemic component with usually asymmetric ocular involvement. PMID- 23647988 TI - Lower amygdala volume in men is associated with childhood aggression, early psychopathic traits, and future violence. AB - BACKGROUND: Reduced amygdala volume has been implicated in the development of severe and persistent aggression and the development of psychopathic personality. With longitudinal data, the current study examined whether male subjects with lower amygdala volume have a history of aggression and psychopathic features dating back to childhood and are at increased risk for engaging in future aggression/violence. METHODS: Participants were selected from a longitudinal study of 503 male subjects initially recruited when they were in the first grade in 1986-1987. At age 26, a subsample of 56 men with varying histories of violence was recruited for a neuroimaging substudy. Automated segmentation was used to index individual differences in amygdala volume. Analyses examined the association between amygdala volume and levels of aggression and psychopathic features of participants measured in childhood and adolescence. Analyses also examined whether amygdala volume was associated with violence and psychopathic traits assessed at a 3-year follow-up. RESULTS: Men with lower amygdala volume exhibited higher levels of aggression and psychopathic features from childhood to adulthood. Lower amygdala volume was also associated with aggression, violence, and psychopathic traits at a 3-year follow-up, even after controlling for earlier levels of these features. All effects remained after accounting for several potential confounds. CONCLUSIONS: This represents the first prospective study to demonstrate that men with lower amygdala volume have a longstanding history of aggression and psychopathic features and are at increased risk for committing future violence. Studies should further examine whether specific amygdala abnormalities might be a useful biomarker for severe and persistent aggression. PMID- 23647990 TI - Passion. PMID- 23647991 TI - What are you going to do? PMID- 23647992 TI - Withholding cardiopulmonary resuscitation - at the crossroads of compassion and corporate policy. PMID- 23647993 TI - Emergency nursing review questions: May 2013. PMID- 23647994 TI - Enhancing ED triage to accommodate the special needs of geriatric patients. PMID- 23647995 TI - Weigh children in kilograms only! Response. PMID- 23647996 TI - Weigh children in kilograms only! PMID- 23647997 TI - How much do ED patients know about medication prescribed for them on discharge? A pilot study in Turkey. AB - INTRODUCTION: Hospital emergency departments provide health care to patients with various ailments and illnesses. If necessary, doctors write prescriptions for patients who visit emergency departments for their use after discharge from hospitals. It is important to inform patients about their prescribed medications because compliance with the prescription plays an important role in the success of the treatment. If a patient must use more than one medication, this might result in negative drug interactions. These undesirable developments may adversely affect the treatment process and cause many unplanned patient visits to emergency departments. This study was carried out to determine patient knowledge as related to the names, dosage, frequency, purpose and course of medications given on discharge from emergency departments. METHODS: Study subjects were patients who came to the emergency department between the hours of 8 am and 8 pm during a period of 1 month. Data were collected through use of a questionnaire. RESULTS: In this study, it was found that 37% of the patients (37 patients) had no knowledge at all about the prescribed medications; however, out of 63 patients, 61.9% had knowledge of when to take the medications, 57.1% knew the purpose of the particular medications, and 52.3% were aware of the appropriate dosage. Furthermore, 31.7% knew the name of the medications and 25.3% knew something about their prescribed course. CONCLUSION: Upon discharge from emergency departments, patients should be fully and properly informed about their prescribed medications through a written document. Providing patients with information concerning the correct use of their prescribed medications enables them to use the medications appropriately, thereby increasing not only their satisfaction but also their compliance with the treatment plan. As a result, this vital information may help to decrease rehospitalizations. PMID- 23647998 TI - Emergency nursing review questions: May 2013 online only. PMID- 23647999 TI - Prophylactic peritoneal dialysis following cardiopulmonary bypass in children is associated with decreased inflammation and improved clinical outcomes. AB - OBJECTIVE: To investigate impact of prophylactic peritoneal dialysis (PD) on clinical outcomes and inflammatory cytokines in children following cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective before-and-after nonrandomized cohort study. SETTING: Pediatric cardiovascular intensive care unit in tertiary hospital. PATIENTS: Fifty-two consecutive neonates and infants at high risk for postoperative fluid overload following cardiopulmonary bypass. All had PD catheters placed during primary cardiac surgery. INTERVENTION: Initial 27 patients were managed with passive peritoneal drainage and diuretics (controls). Following 25 patients were started on prophylactic PD in immediate postoperative period and managed per PD protocol (+PD). OUTCOME MEASURES: Cumulative fluid balance, indices of disease severity, and clinical outcomes were prospectively collected. Plasma interleukin-6 and interleukin-8 were measured immediately before-and-after cardiopulmonary bypass and at 24 and 48 hours post cardiopulmonary bypass. RESULTS: Demographics, diagnoses, and intraoperative variables were similar. Median net fluid balance was more negative in +PD at 24 hours, -24 mL/kg (interquartile range: -62, 11) vs. +18 mL/kg (interquartile range: -26, 11), P = .003, and 48 hours, -88 mL/kg (interquartile range: -132, 54) vs. -46 mL/kg (interquartile range: -84, -12), P = .004. +PD had median 55 mL/kg less fluid intake at 24 hours, P = .058. Peritoneal drain, urine, and chest tube output were comparable over first 24 hours. Mean inotrope score was lower in +PD at 24 hours. +PD had earlier sternal closure--24 hours (interquartile range: 20, 40) vs. 63 hours (interquartile range: 44, 72), P < .001--and a trend toward shorter duration of mechanical ventilation--71 hours (interquartile range: 49, 135) vs. 125 hours (interquartile range: 70, 195), P = .10. +PD experienced lower serum concentrations of interleukin-6 and interleukin-8 at 24 hours. CONCLUSIONS: Prophylactic PD is associated with greater net negative fluid balance, decreased inotrope requirements, and lower serum concentrations of inflammatory cytokines in the early postoperative period. PMID- 23648000 TI - Comparison study of the partial-breast irradiation techniques: dosimetric analysis of three-dimensional conformal radiation therapy, electron beam therapy, and helical tomotherapy depending on various tumor locations. AB - The partial-breast irradiation (PBI) technique, an alternative to whole-breast irradiation, is a beam delivery method that uses a limited range of treatment volume. The present study was designed to determine the optimal PBI treatment modalities for 8 different tumor locations. Treatment planning was performed on computed tomography (CT) data sets of 6 patients who had received lumpectomy treatments. Tumor locations were classified into 8 subsections according to breast quadrant and depth. Three-dimensional conformal radiation therapy (3D CRT), electron beam therapy (ET), and helical tomotherapy (H-TOMO) were utilized to evaluate the dosimetric effect for each tumor location. Conformation number (CN), radical dose homogeneity index (rDHI), and dose delivered to healthy tissue were estimated. The Kruskal-Wallis, Mann-Whitney U, and Bonferroni tests were used for statistical analysis. The ET approach showed good sparing effects and acceptable target coverage for the lower inner quadrant-superficial (LIQ-S) and lower inner quadrant-deep (LIQ-D) locations. The H-TOMO method was the least effective technique as no evaluation index achieved superiority for all tumor locations except CN. The ET method is advisable for treating LIQ-S and LIQ-D tumors, as opposed to 3D-CRT or H-TOMO, because of acceptable target coverage and much lower dose applied to surrounding tissue. PMID- 23648001 TI - A binary-based approach for detecting irregularly shaped clusters. AB - BACKGROUND: There are many applications for spatial cluster detection and more detection methods have been proposed in recent years. Most cluster detection methods are efficient in detecting circular (or circular-like) clusters, but the methods which can detect irregular-shaped clusters usually require a lot of computing time. METHODS: We propose a new spatial detection algorithm for lattice data. The proposed method can be separated into two stages: the first stage determines the significant cells with unusual occurrences (i.e., individual clustering) by applying the Choynowski's test, and the second stage determines if there are clusters based on the information of the first stage by a binomial approximate method. We first use computer simulation to evaluate the performance of the proposed method and compare it with the scan statistics. Furthermore, we take the Taiwan Cancer data in 2000 to illustrate the detection results of the scan statistics and the proposed method. RESULTS: The simulation results support using the proposed method when the population sizes are large and the study regions are irregular. However, in general, the scan statistics still have better power in detecting clusters, especially when the population sizes are not large. For the analysis of cancer data, the scan statistics tend to spot more clusters, and the clusters' shapes are close to circular (or elliptic). On the other hand, the proposed methods only find one cluster and cannot detect small-sized clusters. CONCLUSIONS: In brief, the proposed methods can detect both circular and non-circular clusters well when the significant cells are correctly detected by the Choynowski's method. In addition, the binomial-based method can handle the problem of multiple testing and save the computing time. On the other hand, both the circular and elliptical scan statistics have good power in detecting clusters, but tend to detect more clusters and have lower accuracy in detecting non-circular clusters. PMID- 23648002 TI - Professor Meinhart H. Zenk: keeping the legacy alive. PMID- 23648003 TI - Low serum total nitrite and nitrate levels in severe leptospirosis. AB - BACKGROUND: The relationship between inducible nitric oxide synthatase activity and disease severity in leptospirosis is unclear. Nitric oxide is converted to nitrites and nitrates, thus nitrite and nitrate levels (NOx) in serum are considered surrogate markers for nitric oxide. NOx are excreted through the kidneys, and elimination is diminished in renal impairment. We assessed the correlation of NOx with disease severity in patients with leptospirosis, compared with healthy controls and non-leptospirosis fever patients. METHODS: All patients admitted over a two-month period to the National Hospital, Colombo, Sri Lanka with a clinical picture suggestive of leptospirosis were included. Leptospirosis was confirmed by the microscopic agglutination test (titre >= 400). Severe leptospirosis was defined by the presence of two or more of the following criteria: jaundice (bilirubin> 51.3 MUmol/l), oliguria (urine output < 400 ml/day), serum creatinine> 133 MUmol/l or blood urea > 25.5 mmol/l, or the presence of organ dysfunction. Non-leptospirosis fever patients and healthy volunteers were used as control groups. NOx levels were measured using a modified Griess reaction. RESULTS: Forty patients were confirmed as having leptospirosis and 26 of them had severe disease. NOx levels were significantly higher in confirmed leptospirosis patients compared to healthy controls, MAT equivocal patients and non-leptospirosis fever patients (p<0.001). NOx concentrations were also significantly higher in patients with severe compared to mild leptospirosis (p<0.001). Once NOx levels were corrected for renal function, by using the ratio NOx/creatinine, NOx levels were actually significantly lower in patients with severe disease compared to other patients, and values were similar to those of healthy controls. CONCLUSIONS: We postulate that high NOx levels may be protective against severe leptospirosis, and that finding low NOx levels (when corrected for renal function) in patients with leptospirosis may predict the development of severe disease and organ dysfunction. PMID- 23648004 TI - Mycobacterium avium subspecies paratuberculosis is widely distributed in British soils and waters: implications for animal and human health. AB - In the first comprehensive geographical survey of distribution in Great Britain, Mycobacterium avium ssp. paratuberculosis (MAP) was detected in 115 of 1092 (10.5%) soil cores, in the range of 5 * 10(2) to 3 * 10(6) MAP cell equivalents (CE) g(-1) wet weight soil with the majority of the positive PCR reactions (n = 75; 65%) occurring around the limit of detection (500-5000 CE g(-1) wet weight soil). The distribution of MAP significantly increased from North to South and was significantly correlated with increasing cattle numbers over the same longitudinal axis. Similarly MAP occurrence significantly increased towards easterly latitudes although none of the parameters measured were associated. Comparisons of land use indicated that MAP was widely distributed in both farming and non-farming areas. Soil core samples taken from the rivers Wyre and Douglas catchments (Lancashire, UK) and river Tywi (South Wales) were negative for MAP. However, river monitoring showed a consistent presence of MAPs throughout those catchments over a 6-month period. We concluded that MAP is widely distributed within and outside the confines of the farming environment; its geographical distribution is wider than originally anticipated and; monitoring rivers describes the MAP status of catchment better than individual soil samples. PMID- 23648005 TI - Rapid, transient potentiation of dendritic spines in context-induced relapse to cocaine seeking. AB - Addiction to cocaine produces long-lasting, stable changes in brain synaptic physiology that might contribute to the vulnerability to relapse. In humans, exposure to environmental contexts previously paired with drug use precipitates relapse, but the neurobiological mechanisms mediating this process are unknown. Initiation of cocaine relapse via re-exposure to a drug-associated context elicited reinstatement of cocaine seeking as well as rapid, transient synaptic plasticity in the nucleus accumbens core (NAcore), measured as an increase in dendritic spine diameter. These results show that rapid context-evoked synaptic potentiation in the NAcore may underpin relapse to cocaine use. PMID- 23648006 TI - Trends in epistaxis embolization in the United States: a study of the Nationwide Inpatient Sample 2003-2010. AB - PURPOSE: Endovascular embolization has emerged as a viable adjunct and alternative to surgical ligation in selected cases of epistaxis refractory to nasal packing. A large administrative database was used to study outcomes, complications, and trends in utilization of surgical and endovascular treatments for epistaxis. MATERIALS AND METHODS: With the Nationwide Inpatient Sample from 2003 to 2010, patients with a primary diagnosis of epistaxis undergoing surgical ligation and/or endovascular embolization were identified. Trends in the use of these procedures from 2003 to 2010 were examined. Three groups of patients were defined: those who underwent (i) surgical ligation, (ii) endovascular embolization, or (iii) both. Demographic variables, comorbidities, and outcomes were compared across groups. RESULTS: Among a total of 69,410 patients identified, 64,289 (92.6%) underwent surgical ligation alone for epistaxis, 4,440 (6.4%) underwent endovascular embolization alone, and 681 (1.0%) underwent both treatments. Use of endovascular embolization for epistaxis increased from 2.8% of cases in 2003 to 10.7% of cases in 2010 (P<.0001). Patients who underwent endovascular embolization had similar mortality rates as those who underwent surgical ligation (2.1% [93 of 4,440] vs 2.1% [1,328 of 64,289]; P = .89). Endovascular embolization was associated with significantly higher rates of stroke (0.9% [41 of 4,440] vs 0.1% [34/64,289]; P<.0001) and hematoma (1.9% [83 of 4,440] vs 0.4% [239 of 64,289]; P<.0001). CONCLUSIONS: Use of endovascular embolization for treatment of epistaxis increased significantly between 2003 and 2010. Patients who underwent endovascular embolization had similar mortality rates but higher stroke rates compared with those who underwent surgical ligation. PMID- 23648007 TI - Are cuffed peripherally inserted central catheters superior to uncuffed peripherally inserted central catheters? A retrospective review in a tertiary pediatric center. AB - PURPOSE: To assess the use of cuffed peripherally inserted central catheters (PICCs) compared with uncuffed PICCs in children with respect to their ability to provide access until the end of therapy. MATERIALS AND METHODS: A retrospective review of PICCs inserted between January 2007 and December 2008 was conducted. Data collected from electronic records included patient age, referring service, clinical diagnosis, inserting team (pediatric interventional radiologists or neonatal intensive care unit [NICU] nurse-led PICC team), insertion site, dates of insertion and removal, reasons for removal, and need for a new catheter insertion. A separate subset analysis of the NICU population was performed. Primary outcome measured was the ability of the PICCs to provide access until the end of therapy. RESULTS: Cuffed PICCs (n = 1,201) were significantly more likely to provide access until the end of therapy than uncuffed PICCs (n = 303) (P = .0002). Catheter removal before reaching the end of therapy with requirement of placement of a new PICC occurred in 26% (n = 311) of cuffed PICCs and 38% (n = 114) of uncuffed PICCs. Uncuffed PICCs had a significantly higher incidence of infections per 1,000 catheter days (P = .023), malposition (P = .023), and thrombus formation (P = .022). In the NICU subset analysis, cuffed PICCs had a higher chance of reaching end of therapy, but this was not statistically significant. CONCLUSIONS: In this pediatric population, cuffed PICCs were more likely to provide access until the end of therapy. Cuffed PICCs were associated with lower rates of catheter infection, malposition, and thrombosis than uncuffed PICCs. PMID- 23648008 TI - Advanced care planning discussions with adolescents and young adults with cancer. PMID- 23648009 TI - Diabetic peripheral neuropathy in youth. PMID- 23648010 TI - Endometrial CD16(+) and CD16(-) NK cell count in fertility and unexplained infertility. AB - PROBLEM: Peripheral counts of CD16(+ ) NK cells have been well characterized in reproductive failure. However, not enough case-control clinical studies have been conducted to establish normal or abnormal CD16(+/-) values in the endometrium. METHOD OF STUDY: Peripheral and endometrial NK cell counts by FACS, IL-6, and VEGF cytokines levels by ELISA were characterized in fertile women and unexplained infertility patients with implantation failures (UI-IF) during implantation window. ROC and correlation analysis were performed. RESULTS: Receiver Operating Characteristic(ROC) analysis revealed endometrial CD16(+ ) NK cells, IL-6, and VEGF as good diagnostic parameters for unexplained infertility. Almost half of UI-FI patients showed increased total and CD16(+ ) NK cell counts correlating with decreased levels of endometrial IL-6 and VEGF. No correlation was found with peripheral blood values. CONCLUSION: Increased CD16(+ ) NK cells were associated with IL-6 and VEGF deficiency in a high proportion of UI-IF patients. Testing for these immunomarkers could be a potential tool in infertility diagnosis. PMID- 23648011 TI - Baseline characteristics of European and non-European adult patients with attention deficit hyperactivity disorder participating in a placebo-controlled, randomized treatment study with atomoxetine. AB - BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) often presents as an impairing lifelong condition in adults; yet it is currently underdiagnosed and undertreated in many European countries. This analysis examines the characteristics of adult patients with ADHD in a European (EUR) and non-European (NE) patient population. METHODS: Baseline data from the open-label treatment period of a randomized trial of atomoxetine in adult patients with ADHD (N=2017; EUR, n=1217; NE, n=800) were examined. All patients who were enrolled were included in the baseline analyses. RESULTS: The demographics for patients in the EUR and NE groups were comparable. Patients in the EUR group had a somewhat lower percentage of prior exposure to psychostimulants compared with the NE group (32.7% vs. 38.9%, p=.0049). Scores on the Conners' Adult ADHD Rating Scale Investigator Rated: Screening Version with adult ADHD prompts (18-item total, inattentive and hyperactive/impulsive subscales, and index) were comparable. The adult ADHD Quality of Life-Life Outlook and Life Productivity domain scores were significantly different between groups (p<=.0004). The EuroQol-5 Dimension United Kingdom and United States population-based index scores and Health State score were comparable between groups. CONCLUSIONS: Adults with ADHD in Europe present similar demographics and baseline characteristics to those outside Europe and hence, study results outside Europe may be generalizable to patients in Europe. TRIAL REGISTRATION: Clinicaltrials.gov, NCT00700427. PMID- 23648012 TI - Implications of dengue outbreaks for blood supply, Australia. AB - Dengue outbreaks have increased in size and frequency in Australia, and transfusion-transmitted dengue poses a risk to transfusion safety. Using whole blood samples collected during the large 2008-2009 dengue epidemic, we estimated the risk for a dengue-infectious blood donation as ~1 in 7,146 (range 2,218 50,021). PMID- 23648013 TI - [Analgesia for labour and delivery in a parturient with paramytonia congenita]. AB - A patient presenting with paramyotonia congenita (Eulenburg's paramyotonia) was seen at the preanaesthetic visit during pregnancy. The underlying disease was known for years. Analysis of the literature and advice taken from specialists emphasized the safe use of regional anaesthesia and analgesia which was indeed used for labour and delivery without any complication. By contrast, the limited information available on the use of general anaesthesia suggests the risks associated with the use of succinylcholine and possibly with halogenated agents. Additional and useful factors that may limit the occurrence of myotonic crises such as maintenance of normal temperature and plasma potassium concentration, should be undertaken simultaneously. PMID- 23648014 TI - Adult stem cells for chronic lung diseases. AB - Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are chronic, progressive and lethal lung diseases. The incidence of IPF and COPD increases with age, independent of exposure to common environmental risk factors. At present, there is limited understanding of the relationship between ageing and the development of chronic lung diseases. One hypothesis is that chronic injury drives to exhaustion the local and systemic repair responses in the lung. These changes are accentuated during ageing where there is a progressive accumulation of senescent cells. Recently, stem cells have emerged as a critical reparative mechanism for lung injury. In this review, we discuss the repair response of bone marrow-derived mesenchymal stem cells (B-MSC) after lung injury and how their function is affected by ageing. Our own work has demonstrated a protective role of B-MSC in several animal models of acute and chronic lung injury. We recently demonstrated the association, using animal models, between age and an increase in the susceptibility to develop severe injury and fibrosis. At the same time, we have identified functional differences between B-MSC isolated from young and old animals. Further studies are required to understand the functional impairment of ageing B-MSC, ultimately leading to a rapid stem cell depletion or fatigue, interfering with their ability to play a protective role in lung injury. The elucidation of these events will help in the development of rational and new therapeutic strategies for COPD and IPF. PMID- 23648015 TI - Alternative pre-mRNA splicing in neurons: growing up and extending its reach. AB - Alternative pre-mRNA splicing determines the protein output of most neuronally expressed genes. Many examples have been described of protein function being modulated by coding changes in different mRNA isoforms. Several recent studies demonstrate that, through the coupling of splicing to other processes of mRNA metabolism, alternative splicing can also act as an on/off switch for gene expression. Other regulated splicing events may determine how an mRNA is utilized in its later cytoplasmic life by changing its localization or translation. These studies make clear that the multiple steps of post-transcriptional gene regulation are strongly linked. Together, these regulatory process play key roles in all aspects of the cell biology of neurons, from their initial differentiation, to their choice of connections, and finally to their function with mature circuits. PMID- 23648016 TI - Incidence of venous thromboembolism after elective knee arthroscopic surgery: a historical cohort study. AB - BACKGROUND: The incidence of symptomatic venous thromboembolism (VTE) after knee arthroscopy is uncertain. OBJECTIVES: To estimate the incidence of symptomatic VTE after arthroscopic knee surgery. METHODS: In a population-based historical cohort study, all Olmsted County, MN, USA, residents undergoing a first arthroscopic knee surgery during the 18-year period of 1988-2005 were followed for incident deep venous thrombosis or pulmonary embolism. The cumulative incidence of VTE after knee arthroscopy was determined using the Kaplan-Meier product limit estimator. Patient age at surgery, sex, calendar year of surgery, body mass index, anesthesia characteristics, and hospitalization were tested as potential predictors of VTE using Cox proportional hazards modeling, both univariately and adjusted for age and sex. RESULTS: Among 4833 Olmsted County residents with knee arthroscopy, 18 developed postoperative VTE, all within the first 6 weeks after surgery. The cumulative incidence rates of symptomatic VTE at 7, 14, and 35 days were 0.2%, 0.3%, and 0.4%, respectively. The hazard for postoperative VTE was significantly increased for older patient age (hazard ratio = 1.34 for each 10-year increase in patient age; P = 0.03) and hospitalization either before or after knee arthroscopy (hazard ratio = 14.1; P < 0.001). CONCLUSIONS: The incidence of symptomatic VTE after arthroscopic knee surgery is very low. Older age and hospitalization are associated with increased risk. Routine prophylaxis to prevent symptomatic VTE is likely not needed in this patient population. PMID- 23648018 TI - Sudden cardiac arrest in a young patient with hypertrophic cardiomyopathy and zero canonical risk factors: the inherent limitations of risk stratification in hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy is the most common heritable cardiovascular disease and a common cause of sudden cardiac death (SCD) in young adolescents and athletes. Clinical risk stratification for SCD is predicated on the presence of established risk factors; however, this assessment is far from perfect. Herein, we present a 16-year-old male who was resuscitated successfully from his sentinel event of out-of-hospital cardiac arrest. Prior to this event, he was asymptomatic and lacked all traditional SCD-predisposing risk factors for hypertrophic cardiomyopathy. PMID- 23648017 TI - Atorvastatin inhibits RhoC function and limits head and neck cancer metastasis. AB - OBJECTIVE: RhoC oncogene is a well characterized marker of metastasis in a majority of invasive cancers, including HNSCC. Elevated RhoC expression has been found to be associated with distant metastasis. Statins are a class of drugs that are used to reduce cholesterol levels by inhibiting HMG-CoA reductase activity which in turns prevents mevalonate synthesis, which is a precursor for synthesis of cholesterol and prenylation. Interestingly, the proper function of Rho proteins depends on prenylation. Significantly, it has been reported that metastasis in human melanoma can be reduced by atorvastatin which inhibits RhoC activity by preventing its geranylgeranylation. Given that RhoC is a key oncogene involved in metastasis, we hypothesized Atorvastatin can reduce head and neck metastasis by inhibiting RhoC activity. METHODS: In vitro and in vivo studies were carried out to evaluate the ability of Atorvastatin to inhibit RhoC function and HNSCC metastasis. Cell motility, proliferation, cell invasion, and colony formation assays were performed according to the standard protocols. RESULTS: Atorvastatin treatment significantly reduced the active form of RhoC in vitro and diminished cell motility, invasion, proliferation and colony formation. Importantly, we observed a significant decrease in p-ERK1/2 and p-STAT3 in Atorvastatin treated cell lines. In vivo experiments revealed inhibition of angiogenesis and lung metastases with Atorvastatin therapy. CONCLUSIONS: This study is the first of its kind to establish a potential role of Atorvastatin in head and neck cancer therapy. These findings suggest that Atorvastatin can be a potential low risk adjuvant therapy to minimize metastases in aggressive forms of HNSCC. PMID- 23648020 TI - Antitumor activity of a polysaccharide from Pleurotus eryngii on mice bearing renal cancer. AB - One water-soluble polysaccharide (PEPw), with an average molecular weight of 2.5*10(4)Da, was isolated from the fruiting bodies of Pleurotus eryngii and subjected to composition analysis and evaluated for the antitumor and immunomodulatory activity. PEPw was composed of arabinose, mannose and galactose in a molar ratio of 1.2:2.3:6.2 and had a backbone mainly consisting of 1,6 linked-Galp, 1,2,6-linked-Galp and 1,4-linked-Manp residues, which was occasionally terminated with terminal-Araf attached to O-2 of 1,2,6-linked-Galp residue. The animal experiment results showed that PEPw significantly increased relative thymus and spleen indices, promoted the spleen lymphocytes proliferation induced by ConA or LPS, elevated the activities of NK cell and CTL in spleen, and increased the serum concentration of TNF-alpha and IL-2 in Renca tumor-bearing mice. As a result, the tumor growth was significantly inhibited by PEPw treatment at the doses of 50, 100 and 200mg/kg in a dose-dependent manner. These data indicated that the anti-tumor activity of PEPw may be related to the activation of the immune response in tumor-bearing mice. PMID- 23648019 TI - Reprogramming of the HepG2 genome by long interspersed nuclear element-1. AB - Long Interspersed Nuclear Element-1 (LINE-1 or L1) is an autonomous, mobile element within the human genome that transposes via a "copy and paste" mechanism and relies upon L1-encoded endonuclease and reverse transcriptase (RT) activities to compromise genome integrity. L1 has been implicated in various forms of cancer, but its role in the regulation of the oncogenic phenotype is not understood. The present studies were conducted to evaluate mechanisms of genetic regulatory control in HepG2 cells by human L1, or a D702Y mutant deficient in RT activity, and their influence on cellular phenotype. Forced expression of synthetic L1 ORF1p and ORF2p was associated with formation of cytoplasmic foci and minor association with the nuclear compartment. While de novo L1 mobilizations were only identified in cells expressing wild type L1, and were absent in the D702Y mutant, changes in gene expression profiles involved RT dependent as well as RT independent mechanisms. Synthetic L1 altered the expression of 24 in silico predicted genetic targets; ten of which showed RT dependence, ten RT-independence, and four reciprocal regulatory control by both wild type and RT mutant. Of five targets examined, only VCAM1 and PTPRB colocalized with newly retrotransposed wild type L1. Biological discretization to partition patterns of gene expression into unique frequencies identified adhesion, inflammation, and cellular metabolism as key processes targeted for molecular interference with disruption of epithelial-to-mesenchymal programming seen irrespective of the RT phenotype. These findings establish L1 as a key regulator of genome plasticity and EMT via mechanisms independent of RT activity. PMID- 23648021 TI - Thermal characterization and detailed kinetic analysis of Cassava starch thermo oxidative degradation. AB - Detailed kinetic analysis of Cassava starch thermo-oxidative degradation was performed, using thermogravimetric analysis (TGA) and derivative thermogravimetry (DTG) at four different heating rates. It was found that degradation process is very complex, as identified through continuous change of apparent activation energy with degree of degradation. It was established that process proceeds through three main degradation stages with one additional sub-stage attached to the second degradation stage, which was detected by appearance of "shoulder" on DTG curves. It was found that most important degradation stage can be described by "lumped" model, which implies that free radicals simultaneously attack both linear and branched molecular forms of the starch. This is characterized by an unusually high value of obtained reaction order (n=3.49). Application of nonlinear least squares method was confirmed the reliability of evaluated kinetic parameters and function of reaction mechanism, which were derived on the basis of other kinetic methods. PMID- 23648022 TI - Highly stretchable nanoalginate based polyurethane elastomers. AB - Highly stretchable elastomeric samples based on cationic polyurethane dispersions sodium alginate nanoparticles (CPUD/SA) were prepared by the solution blending of sodium alginate and aqueous polyurethane dispersions. CPUDs were synthesized by step growth polymerization technique using N-methyldiethanolamine (MDEA) as a source of cationic emulsifier. The chemical structure and thermal-mechanical properties of these systems were characterized using FTIR and DMTA, respectively. The presence of nanoalginate particles including nanobead and nanorod particles were proved by SEM and EDX. It was observed that thermal properties of composites increased with increasing SA content. All prepared samples were known as thermoplastic-elastomers with high percentages of elongation. Excellent compatibility of prepared nanocomposites was proved by the DMTA data. PMID- 23648023 TI - Associating and rheological behaviors of fluorinated cationic guar gum in aqueous solutions. AB - The fluorinated cationic guar gum (FCGG) was prepared with cationic guar gum (CGG) and fluorinated reactive monomer (FAM). FAM was synthesized from isophorone diisocyanate and 2,2,3,4,4,4-hexafluoro-1-butanol. The molecular structure, associating and rheological behaviors of FCGG were studied by the FT-IR, (19)F NMR, X-ray diffraction, dynamic rheometer and fluorescence spectroscopy, respectively. The results show that FAM is successfully incorporated into CGG. With the increased degree of substitution (DS), the crystallinity is reduced from 3.01 to 0.67% and the characteristic relaxation time is changed significantly from 0.10 to 3.3s. At low shear rates (<20s(-1)), the viscosity of FCGG solution increases with the increase of shear rates. The bigger the DS, the higher the apparent viscosity. The viscosity retention factor of FCGG can reach 126.97% at 30 degrees C and 51.33% at 60 degrees C, respectively. The data indicate that FCGG has much better heat resistance. PMID- 23648024 TI - Optimizing conditions of polysaccharide extraction from Shiitake mushroom using response surface methodology and its regulating lipid metabolism. AB - Process conditions (extraction time, extraction temperature, water/solid ratio and incubation time) of Shiitake mushroom polysaccharides (SMP) were optimized by conducting experiments at three different levels using the response surface method (RSM). A second-order polynomial response surface equation was developed indicating the effect of variables on polysaccharides yield. Contour maps generated using the response surface equation showed that all the experimental variables significantly affected the yield. The effect of SMP on oxidative damage in mice fed by high cholesterol diet (HCD) was done in vivo. Results showed that SMP can decreased serum total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-c) levels, and increased high density lipoprotein (HDL-c) levels in HCD mice. Treatment with SMP reduced blood, liver lipid peroxidation level and increased antioxidant enzymes activities. Thus it can be concluded that SMP can improve lipid metabolism and decreased oxidative damage in HCD mice. PMID- 23648025 TI - Phase composition and interface of starch-gelatin blends studied by synchrotron FTIR micro-spectroscopy. AB - The well recognized complex issue of compatibility between starch and gelatin was investigated based on their interface and phase composition using synchrotron FTIR micro-spectroscope. A high amylose (80%) corn starch grafted with flexible and hydrophilic hydroxpropyl groups and plasticized by poly(ethylene glycol) (PEG) was used in this work. The FTIR beam focused on a 5 MUm*5 MUm detection region and the micro-spectroscope was scanned across the gelatin-starch interface. It was found that there was about a 20 MUm thickness layer where gelatin and starch were in co-existence, indicating that gelatin and starch are compatible to a certain degree in this system. The ratio of the areas of the saccharide CO bands (1180-953 cm(-1)) and the amide I and II bands (1750-1483 cm( 1)) was used to monitor the relative distributions of the two components of the blends. FTIR 2 and 3-dimensional maps indicated that gelatin constituted the continuous phase up to 80% of starch content. The PEG was homogeneously distributed in both gelatin and starch phases, and blurred the interface between gelatin and starch in the chemical maps, indicating that PEG acted not only as a plasticizer but as a compatibilizer for the gelatin-starch blends. PMID- 23648026 TI - Dry powder preparation of inulin fructotransferase from Arthrobacter aurescens SK 8.001 fermented liquor. AB - Difructosan anhydrides III (DFA III) are usually obtained by inulin conversion with inulin fructotransferase (IFTase). IFTase liquor is difficult to store for a long time, which could greatly restrict its application and DFA III production. To meet DFA III scale-up preparation, this work was explored to research dry powder preparation of IFTase from Arthrobacter aurescens SK 8.001 fermented liquor by ultrafiltration concentration, ammonium sulfate precipitation and freeze drying. IFTase powder (10.2g) was obtained from IFTase precipitation (126.4 g) and its specific activity determined was 16.4 U/mg. Dry powder of IFTase could maintain over 120 days at different temperatures. These results showed that it is easy to scale up DFA III preparation for industrial capacity. PMID- 23648027 TI - A robust and universal NMR method for the compositional analysis of polysaccharides. AB - A method is presented for the detailed and accurate quantitative determination of the monomeric composition of polysaccharides. The method is a modification of the well-known Saeman hydrolysis in combination with 600 MHz (1)H NMR quantification. Experimental conditions for this two-step hydrolysis have been optimized for cellulose and hemicelluloses, and the method has been applied to several other polysaccharides as well. It is shown that even very resistant polysaccharides are hydrolyzed completely, while at the same time degradation of monosaccharides is kept at a minimum. The degradation of monosacharides is corrected for by subjecting a standard mixture represented in the polymer to the same conditions. This correction results in a very accurate and reproducible method with relative deviations down to 1%. It is shown that the duration of hydrolysis and the concentration of sulfuric acid in the second hydrolysis step are the most important factors to determine the reliability of the results. PMID- 23648028 TI - Thermoplastic starch films reinforced with talc nanoparticles. AB - Nanocomposite films of thermoplastic corn starch (TPS) with talc particles were obtained by thermo-compression in order to study the effect of filler on structure, optical, and thermal properties. Talc increased the films rigid phase, thus their cross-sections resulted more irregular. Talc preferential orientation within matrix and good compatibility between particles and TPS was observed by SEM. Slight crystalline structure changes in TPS matrix were measured by XRD and DSC, due to talc nucleating effect. Randomly dispersed talc nanoagglomerates and individual platelets were assessed by TEM. Laminar morphology and nano-sized particles allowed that nanocomposite films were optically transparent. TPS-talc films resulted heterogeneous materials, presenting domains rich in glycerol and others rich in starch. Talc incorporation higher than 3%, w/w increased softening resistance of the nanocomposites as stated by DMA. Relaxation temperatures of glycerol-rich phase shifted to higher values since talc reduces the mobility of starch chains. PMID- 23648029 TI - Cellulase immobilization onto the reversibly soluble methacrylate copolymer for denim washing. AB - Cellulase treatment of denim fabrics is an environmentally friendly way for producing desired worn look. In this work, the enzymatic treatments of the denim fabrics, i.e., bio-washing, using native cellulase and cellulase immobilized with reversibly soluble copolymer (Eudragit S-100), immobilized-cellulase, have been investigated. According to the analyses of the lightness (CIE L value), color strength (K/S value) and color variations, at a cellulase concentration level of 6% o.w.f., the denim fabrics treated with the immobilized cellulase showed decoloration and color effect close to the native cellulase. However, the immobilized cellulase treatment of the denim fabrics showed lower weight loss and considerably higher tensile strength than those treated with the native cellulase. Both the native and immobilized cellulases improved the crystalline indice and the apparent crystallite size of the fiber sample compared with the control ones. The amorphous portion of the cellulose suffered more hydrolysis by the native cellulase than the immobilized cellulase. Scanning electron microscope pictures (SEM) and digital pictures further indicated that the immobilized cellulase can efficiently remove indigo dyestuffs on the surfaces of the denim fabrics without the problem of excessive damage to the fibers. PMID- 23648030 TI - Comparative study of processing methods for starch/gelatin films. AB - In this work, the influence of processing methods on the properties of starch/gelatin films plasticized with glycerol and sorbitol is reported. Four different processing techniques: casting; pressing; pressing followed by blowing and extrusion followed by blowing were evaluated. Bioplastics prepared by casting were homogeneous and transparent with lower opacity and water vapor permeability (WVP) values when compared to films prepared by other techniques. Among the cast films studied, those with 3% lipophilic starch, in 1:1 proportions and plasticized with sorbitol, showed lower WVP values and higher tensile strength (TS). Films obtained by pressing and blowing showed little expansion during blow, had cracks in the surface, low TS and higher WVP. These films were the only samples to show crystallinity as determined by thermal analysis and X-ray diffraction. In conclusion, different processing techniques have significantly affected the properties of these films. PMID- 23648031 TI - Enzyme catalyzed cross-linking of spruce galactoglucomannan improves its applicability in barrier films. AB - Hemicelluloses are one of the main constituents of plant cell walls and thereby one of the most abundant biopolymers on earth. They can be obtained as by products from different wood based processes, most importantly from the mechanical pulping. Hemicelluloses have interesting properties in e.g. barrier film applications. However, their relatively low molecular weight after isolation and co-extraction with lignin has limited their use. In this work, we present a novel technique for increasing the molecular weight of different wood hemicelluloses from mechanical pulping process waters as well as from pre hydrolysis extracts. This is achieved by enzyme-catalyzed cross-linking of aromatic moieties bound to the hemicelluloses. The cross-linking treatment resulted in significantly improved mechanical properties in barrier films made with spruce galactoglucomannan. To our knowledge, this is the first time that wood hemicelluloses have been cross-linked by utilizing the bound aromatic moieties and creates new possibilities for utilizing this raw material source. PMID- 23648032 TI - Unexplored possibilities of all-polysaccharide composites. AB - Composites made solely from polysaccharides are mostly ecological because they can degrade without leaving behind ecologically harmful residues, in contrast to composites which contain synthetic polymers. Herein, the following groups of all polysaccharide composites (APCs) are discussed: an all-cellulose group that includes cotton composites, cellulose combined with other polysaccharides, as well as those based on chitin/chitosan, heparin, hyaluronan, xylan, glucomannan, pectin, xyloglucan, arabinan, starch, carrageenan, alginate, galactan as one of the components in combination with other polysaccharides. They can be used in medical, paper, food, packing, textile, electronic, mechanical engineering and other applications. The composites were tested for absorptivity, biodegradability, crystallinity, rheology, and mechanical, optical, separation, gelling, pasting, film-forming, adhesive, antimicrobial properties, as well as water vapor permeability, water repellency, dye uptake, and fire-retardancy. Except for food applications, composites based on more than two types of polysaccharides have rarely been used and many possible combinations remain unexplored. PMID- 23648033 TI - Coelectrospinning of chitosan/alginate fibers by dual-jet system for modulating material surfaces. AB - Chitosan and alginate are two frequently used biomaterials for tissue engineering. In this study, electrospinning technique was applied for their nanofiber fabrications to mimic extracellular environment (ECM). Polyethylene oxide (PEO) was applied to increase viscosities of polymer solutions to obtain nanofibers with appropriate morphologies. To modulate surface properties, a dual jet system was developed to coelectrospin chitosan and alginate nanofibers on one substrate. Because the deposition rates of electrospun fibers linearly correlated to the perfusion rates of polymer solutions, the composition ratios of nanofibers were thus manipulated, which determined both the chemical properties and hydrophobicity of fibrous mats. In vitro cell culture results suggested that the cell morphology highly depended on the fiber composition, and the composite nanofibers demonstrated higher biocompatibility than that on pure fibers. Finally, the degradation of alginate fibers was controlled by the crosslinking process. Reducing calcium ions resulted in partial fiber degradation, by which the composition ratios of nanofibers varied with time. This dynamically changed environment performed a promising property to improve viability of surface cells. Through this tunable system, surface properties of scaffolds can be finely adjusted to benefit tissue engineering applications. PMID- 23648034 TI - Cellulose nanobiocomposites with reinforcement of boron nitride: study of thermal, oxygen barrier and chemical resistant properties. AB - A series of cellulose based nanobiocomposites (cellulose/BN) were prepared with incorporation of various percentage of nano boron nitride (BN). The interaction between cellulose and boron nitride was studied by Fourier transform infrared spectroscopy (FTIR). The structure of cellulose/BN nanobiocomposites was investigated by XRD, FESEM, and HRTEM. It was observed that the boron nitride nanoparticles were dispersed within cellulose matrix due to intercalation and partial exfoliation. The quantitative identification of nanobiocomposites was investigated by selected area electron diffraction (SAED). Thermal stabilities of the prepared nanobiocomposites were measured by thermo gravimetric analysis (TGA) and it was found that thermal stability of the nanobiocomposites was higher than the virgin cellulose. The oxygen barrier property of cellulose/BN nanobiocomposites was measured using a gas permeameter and a substantial reduction in oxygen permeability due to increase in boron nitride loading was observed. Further it was noticed that the chemical resistance of the nanobiocomposites was more than the virgin cellulose. Hence, the prepared nanobiocomposite may be widely used for insulating and temperature resistant packaging materials. PMID- 23648035 TI - Preparation and characterization of inclusion complexes formed between baicalein and cyclodextrins. AB - This study investigates the solubility of baicalein (Ba) with the addition of modified cyclodextrins using phase solubility method. The solubility of Ba in the presence of natural (alpha-, beta-, and gamma-) cyclodextrins and its derivatives, namely, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and (2,6-di-O methyl)-beta-cyclodextrin (DM-beta-CD), was higher than that of free Ba. In particular, the stability constant of inclusion complex with DM-beta-CD was 13672.67l mol(-1), which was the highest among the examined cyclodextrins. The inclusion complexes of Ba and DM-beta-CD were prepared via freeze-drying method, which were both characterized in the solution and solid state by UV-vis spectroscopy, differential scanning calorimetry (DSC), proton nuclear magnetic resonance ((1)H NMR), scanning electron microscopy (SEM), and X-ray powder diffractometry (XRPD). The UV-vis, DSC, (1)H NMR, SEM, and XRPD results proved the formation of inclusion complex between Ba and DM-beta-CD. Furthermore, the dissolution rate and thermal stability of the inclusion complex were significantly enhanced compared with the pure drug. Therefore, using DM-beta-CD can effectively improve the solubility and thermal stability of free Ba, which is a promising approach to promote its clinical application. PMID- 23648036 TI - Biological and physicochemical properties of two polysaccharides from the mycelia of Grifola umbellate. AB - In the present study, we firstly reported the antioxidant, antitumor and immunomodulatory effects of two polysaccharides (GUMP-1-1 and GUMP-1-2) isolated from Grifola umbellata mycelia. Chemical analysis indicated that two polysaccharide fractions contained different content of neutral sugar, uronic acid and protein, as well as varying monosaccharide compositions and average molecular weight. We found that they could significantly inhibit the growth of H22 implanted tumor and enhance the spleen index and splenocyte proliferation of H22 tumor-bearing mice. In addition, GUMP-1-2 had the stronger free radicals scavenging and ferrous ion chelating abilities than GUMP-1-1 in vitro. These results indicated that antitumor activity of two purified polysaccharides might be achieved by improving immune response and the different chemical composition and average molecular weight could affect their antitumor, antioxidant and immunomodulatory activities. PMID- 23648037 TI - Characterization and optimization of production of exopolysaccharide from Chlamydomonas reinhardtii. AB - Chlamydomonas reinhardtii strain RAC was isolated based on its ability to secrete large amount of exopolysaccharide (EPS). The purified EPS had a molecular weight of 2.25*10(5)Da, and showed fibrillar structure with surfaces having sheet-like appearance. Chemical analysis showed the presence of galacturonic acid, ribose, arabinose, xylose, glucose, galactose and rhamnose sugars. The production of EPS was optimized by the classical one-at-a-time approach and Plackett-Burman design, followed by response surface methodology. The resulting response surface model was statistically significant (p<0.5) and predicted maximum EPS production of 628 mg/L. The optimum production medium consisted of CaCl2 - 74, NaNO3 - 422, K2HPO4 10 and MgSO4 - 200mg/L with a pH 7. The EPS showed significant antioxidant activity, which can have several industrial applications. This is the first report on characterization and production of EPS from a Chlamydomonas strain isolated from India. Its differences from the earlier reported EPS are discussed. PMID- 23648038 TI - Amylopectin grafted with poly (acrylic acid): development and application of a high performance flocculant. AB - In recent years, wastewater treatment, especially for wastewaters which are not suitably recycled by conventional or normal biological processes, is getting more importance. Of late, natural biopolymer based flocculants are extensively used for wastewater treatment because of low cost, environment-friendly and easily availablility from reproducible farm and forest resources. This article introduces the development of a natural polymer based flocculant [amylopectin grafted with poly (acrylic acid) - AP-g-PAA] for treatment of synthetic effluent as well as mining industry wastewater. The graft copolymer based flocculants have been developed under optimum conditions and characterized using viscometry, (13)C NMR, SEM, TGA, rheological characteristics, determination of hydrodynamic radius and CHN analysis. The flocculation characteristics of grafted and ungrafted polysaccharide have been evaluated in synthetic effluents (as Fe-ore, kaolin, Mn ore suspensions) as well as in mining industry wastewater. PMID- 23648039 TI - Hydrogel, aerogel and film of cellulose nanofibrils functionalized with silver nanoparticles. AB - In this work, we describe hydrogels, aerogels and films of nanofibrillated cellulose (NFC) functionalized with metal nanoparticles using silver as an example. The TEMPO process used to produce NFC generates negatively charged surface carboxylate groups that provide high binding capability to transition metal species such as Ag(+). The gelation of NFC triggered by transition monovalent metal ions was revealed for the first time. The interaction was utilized to bind Ag(+) on the NFC surface and simultaneously induce formation of NFC-Ag(+) hydrogels, where Ag(+) was slowly reduced to Ag nanoparticles by hydroxyl groups on NFC without additional reducing agent. The NFC-Ag(+) hydrogel was initiated by strong association of carboxylate groups on NFC with Ag(+) and sufficient NFC surface charge reduction. The stiff hydrogel has a storage modulus leveled off at a plateau value of ~6800Pa. Porous aerogels and flat thin films comprising a continuous matrix of NFC were decorated with Ag nanoparticles through freeze-drying or solution-casting of NFC-Ag(+) dispersions with low contents of Ag(+), respectively, followed by UV reduction. The presence of Ag species on NFC reduced coalescence of nanofibrils in the film formation as revealed from AFM phase images. PMID- 23648040 TI - Multifunctional finishing of cotton fabrics with 3,3',4,4'-benzophenone tetracarboxylic dianhydride: reaction mechanism. AB - Aqueous solutions of 3,3',4,4'-benzophenone tetracarboxylic dianhydride (BPTCD) were successfully employed in treatment of cotton fabrics to bring multiple functions onto the cotton cellulose. The overall reaction mechanism of the chemical finishing process was investigated. Results revealed that the dianhydride groups of BPTCD were hydrolyzed to tetracarboxylic acid groups, and the acid could directly react with hydroxyl groups on cellulose under the catalyst sodium hypophosphite to form ester bonds. Such a mechanism is different from the mostly recognized formation of anhydride from polycarboxylic acid and then esterification between the anhydride with hydroxyl groups. FTIR, DSC and thermogravimetric analyzer (TGA) were employed in the analysis of the reactions, respectively. PMID- 23648041 TI - Effect of cellulose whisker content on the properties of poly(ethylene-co-vinyl acetate)/cellulose composites. AB - The reinforcing effect of cellulose whiskers, produced from banana waste fibres, has been investigated using poly(ethylene-co-vinyl acetate) [EVA]/cellulose whisker composites. Cellulose whiskers, approximately 300 nm long and 30 nm wide, were obtained via a sulphuric acid hydrolysis method. The effects of the cellulose whisker loading on the thermal properties, mechanical properties and on the morphological features of the composites have been investigated. EVA copolymer with a vinyl acetate segment content of 40% has been used for composite fabrication. The developed composites showed superior thermal and mechanical properties relative to that of the EVA copolymer alone. Three theoretical models, namely the Halpin-Tsai model, the Kerner model and the Nicolais-Narkis model have been employed to provide a basis for the comparison of the results with the observations from the tensile investigations. PMID- 23648042 TI - Dipsacus asperoides polysaccharide induces apoptosis in osteosarcoma cells by modulating the PI3K/Akt pathway. AB - An alkaline extractable and water-soluble polysaccharide (ADAPW), with an average molecular weight of 16kDa, was purified from the alkaline extraction of the roots of Dipsacus asperoides. Monosaccharide component analysis indicated that ADAPW was composed of glucose, rhamnose, arabinose and mannose in a molar ratio of 8.54:1.83:1.04:0.42. This study aimed to investigate the effect of ADAPW on the viability of human osteosarcoma cell line HOS cells, and explore the possible mechanisms. The results revealed that ADAPW inhibited the proliferation of HOS cells in a dose-dependent manner by inducing apoptosis. Furthermore, treatment with ADAPW caused a loss of mitochondrial membrane potential and accumulation of reactive oxygen species (ROS). In addition, Western blot analysis demonstrated that ADAPW down-regulated the protein expressions of PI3K and phosphorylated Akt (pAkt) in HOS cells. Taken together, induction of apoptosis on HOS cells by ADAPW was mainly associated with ROS production, mitochondrial dysfunction, and inhibition of PI3K/Akt signaling pathway. So this finding suggests that ADAPW may be potentially effective in cancer prevention against human osteosarcoma. PMID- 23648043 TI - Copper toxicity in Chinese cabbage is not influenced by plant sulphur status, but affects sulphur metabolism-related gene expression and the suggested regulatory metabolites. AB - The toxicity of high copper (Cu) concentrations in the root environment of Chinese cabbage (Brassica pekinensis) was little influenced by the sulphur nutritional status of the plant. However, Cu toxicity removed the correlation between sulphur metabolism-related gene expression and the suggested regulatory metabolites. At high tissue Cu levels, there was no relation between sulphur metabolite levels viz. total sulphur, sulphate and water-soluble non-protein thiols, and the expression and activity of sulphate transporters and expression of APS reductase under sulphate-sufficient or-deprived conditions, in the presence or absence of H2 S. This indicated that the regulatory signal transduction pathway of sulphate transporters was overruled or by-passed upon exposure to elevated Cu concentrations. PMID- 23648044 TI - [Validation of abdominal wound dehiscence's risk model]. AB - INTRODUCTION: The aim of this study is to determine the usefulness of the risk model developed by van Ramshorst et al., and a modification of the same, to predict the abdominal wound dehiscence's risk in patients who underwent midline laparotomy incisions. MATERIALS AND METHODS: Observational longitudinal retrospective study. SAMPLE: Patients who underwent midline laparotomy incisions in the General and Digestive Surgery Department of the Sabadell's Hospital-Parc Tauli's Health and University Corporation-Barcelona, between January 1, 2010 and June 30, 2010. Dependent variable: Abdominal wound dehiscence. INDEPENDENT VARIABLES: Global risk score, preoperative risk score (postoperative variables were excluded), global and preoperative probabilities of developing abdominal wound dehiscence. RESULTS: SAMPLE: 176 patients. Patients with abdominal wound dehiscence: 15 (8.5%). The global risk score of abdominal wound dehiscence group (mean: 4.97; IC 95%: 4.15-5.79) was better than the global risk score of No abdominal wound dehiscence group (mean: 3.41; IC 95%: 3.20-3.62). This difference is statistically significant (P<.001). The preoperative risk score of abdominal wound dehiscence group (mean: 3.27; IC 95%: 2.69-3.84) was better than the preoperative risk score of No abdominal wound dehiscence group (mean: 2.77; IC 95%: 2.64-2.89), also a statistically significant difference (P<.05). The global risk score (area under the ROC curve: 0.79) has better accuracy than the preoperative risk score (area under the ROC curve: 0.64). CONCLUSION: The risk model developed by van Ramshorst et al. to predict the abdominal wound dehiscence's risk in the preoperative phase has a limited usefulness. Additional refinements in the preoperative risk score are needed to improve its accuracy. PMID- 23648045 TI - Understanding the human immune system in the 21st century: the Human Immunology Project Consortium. PMID- 23648046 TI - The effect of tube length on postoperative outcome after glaucoma drainage implant surgery. PMID- 23648047 TI - Public health: passing interest or core business? PMID- 23648048 TI - Associations of neighborhood characteristics with active park use: an observational study in two cities in the USA and Belgium. AB - BACKGROUND: Public parks can be an important setting for physical activity promotion, but to increase park use and the activity levels of park users, the crucial attributes related to active park use need to be defined. Not only user characteristics and structural park attributes, but also characteristics of the surrounding neighborhood are important to examine. Furthermore, internationally comparable studies are needed, to find out if similar intervention strategies might be effective worldwide. The main aim of this study was to examine whether the overall number of park visitors and their activity levels depend on study site, neighborhood walkability and neighborhood income. METHODS: Data were collected in 20 parks in Ghent, Belgium and San Diego, USA. Two trained observers systematically coded park characteristics using the Environmental Assessment of Public Recreation Spaces (EAPRS) tool, and park user characteristics using the System for Observing Play and recreation in Communities (SOPARC) tool. Multilevel multiple regression models were conducted in MLwiN 2.25. RESULTS: In San Diego parks, activity levels of park visitors and number of vigorously active visitors were higher than in Ghent, while the number of visitors walking and the overall number of park visitors were lower. Neighborhood walkability was positively associated with the overall number of visitors, the number of visitors walking, number of sedentary visitors and mean activity levels of visitors. Neighborhood income was positively associated with the overall number of visitors, but negatively with the number of visitors being vigorously active. CONCLUSIONS: Neighborhood characteristics are important to explain park use. Neighborhood walkability-related attributes should be taken into account when promoting the use of existing parks or creating new parks. Because no strong differences were found between parks in high- and low-income neighborhoods, it seems that promoting park use might be a promising strategy to increase physical activity in low-income populations, known to be at higher risk for overweight and obesity. PMID- 23648049 TI - Association of frailty with body composition among patients on hemodialysis. AB - Although sarcopenia is thought to underlie the manifestations of frailty, association of frailty with measures of body composition is underinvestigated. METHODS: Eighty hemodialysis patients were included in the study. Performance based frailty (PbF) used gait speed over 20 feet and 5 sit-to-stand (1 point each for lowest quintile) for the physical components of the frailty phenotype plus exhaustion (Short Form-36 [SF-36] vitality score <55) and physical activity (lowest quintile of weekly kcal energy expenditure on leisure activity on the Physical Activity Scale for the Elderly questionnaire; 1 point). Function-based frailty (FbF) defined by questionnaire measures of physical functioning (SF-36 Physical Function score <75; 1 point), exhaustion, and physical activity as for PbF. A score of 2 or greater was defined as frail. Outcomes related to muscle size included muscle area of the contractile tissue of the anterior tibialis and quadriceps muscles using magnetic resonance imaging, phase angle using bioimpedance analysis, lean body mass using dual energy X-ray absorptiometry, and body mass index (BMI). Linear regression was used to analyze associations between frailty and muscle size, with and without sex and age covariates. RESULTS: Fifty nine percent of individuals met PbF criteria, 63% met FbF criteria, and 55% met both. In univariate analysis, PbF and FbF were associated with smaller muscle area of the quadriceps, smaller phase angle, and higher BMI. Associations remained significant for the quadriceps after adjustment for age and sex. The magnitude of association of PbF with quadriceps muscle area was greater than 10 years of age (-30.3 cm(2)P = .02 vs. -6.6 cm(2)P < .0001) in multivariate analysis. There was no significant association between either measure of frailty and other measures of body composition after adjustment for age and sex. CONCLUSION: Frailty was associated with measurements related to muscle size in a population of individuals with chronic kidney disease, a known contributor to muscle wasting. PMID- 23648050 TI - GREMET: an integrative tool for the prediction of mutation effects on gene regulation. AB - The identification of thousands of mutations yearly has put new challenges to researchers who are interested in fast and effective annotation as well as the prediction of potential implications to the gene regulation mechanisms. This work presents an integrative tool, called GREMET, for the prediction of alterations in gene splicing regulation inferred by mutations of the human genome. GREMET supports the characterization of mutations either single-point or indels with respect to their effect on the splicing potential of the neighboring sequences and the binding strength of auxiliary cis-acting splicing enhancers. In addition, GREMET identifies possible consequences of mutations on the DNA methylation through the disruption or creation of CpG sequences. Besides locus-specific mutations, GREMET performs the analyses on newly identified mutations and provides an easy-to-use Web interface helping researchers to save time in routine mutation analyses. GREMET is freely accessible at: http://kedip.med.auth.gr/biotools/gremet/. PMID- 23648051 TI - Novel lyssavirus in bat, Spain. AB - A new tentative lyssavirus, Lleida bat lyssavirus, was found in a bent-winged bat (Miniopterus schreibersii) in Spain. It does not belong to phylogroups I or II, and it seems to be more closely related to the West Causasian bat virus, and especially to the Ikoma lyssavirus. PMID- 23648052 TI - Resistance to essential oils affects survival of Salmonella enterica serovars in growing and harvested basil. AB - The number of outbreaks of food-borne illness associated with consumption of fresh products has increased. A recent and noteworthy outbreak occurred in 2007. Basil contaminated with Salmonella enterica serovar Senftenberg was the source of this outbreak. Since basil produces high levels of antibacterial compounds the aim of this study was to investigate if the emerging outbreak reflects ecological changes that occurred as a result of development of resistance to ingredients of the basil oil. We irrigated basil plants with contaminated water containing two Salmonella serovars, Typhimurium and Senftenberg, and showed that Salmonella can survive on the basil plants for at least 100 days. S. Senftenberg counts in the phyllosphere were significantly higher than S. Typhimurium, moreover, S. Senftenberg was able to grow on stored harvested basil leaves. Susceptibility experiments demonstrated that S. Senftenberg is more resistant to basil oil and to its antimicrobial constituents: linalool, estragole and eugenol. This may indicate that S. Senftenberg had adapted to the basil environment by developing resistance to the basil oil. The emergence of resistant pathogens has a significant potential to change the ecology, and opens the way for pathogens to survive in new niches in the environment such as basil and other plants. PMID- 23648054 TI - Metastasis-related miR-185 is a potential prognostic biomarker for hepatocellular carcinoma in early stage. AB - We previously reported that miR-185 is associated with hepatocellular carcinoma (HCC) venous metastasis analysed by miRNA-array profile. The aim of this study is to further investigate the clinicopathological significance and prognostic value of miR-185 in early stage HCC. We classified 95 patients with early stage HCC into treated recurrence group (TR) and none treated recurrence group (NTR), and detected the miR-185 expression levels in TR and NTR groups. We found that low miR-185 expression correlated with more tumor recurrence (37/46), while high miR 185 level led to lower recurrence rate (17/49) (P<0.05). There was no direct relationship between miR-185 and clinicopathological features, including age, gender, ALT, AFP, liver cirrhosis, tumor size, tumor encapsulation, tumor differentiation (P>0.05). Kaplan-Meier analysis showed that low miR-185 group had a remarkable lower survival rate and shorter time to recurrence than high miR-185 group (P<0.05). Univariate and multivariate analysis, using Cox's proportional hazards model, also indicated that low miR-185 expression was a sensitive prognostic factor for survival and recurrence in early stage HCC (P<0.05). We upregulated or downregulated miR-185 expression by transfected miR-185 mimics or inhibitor into HCC cell lines, and observed the influence of miR-185 on HCC cells in vitro. Our results manifested that miR-185 could suppress the tumor cell growth and invasive ability (P<0.05). Therefore, miR-185 might be an effective and sensitive biomarker of HCC in early stage, and the upregulation of miR-185 might be considered to be a potentially important molecular treatment strategy for patients with HCC. PMID- 23648053 TI - Specific inhibition of PI3K p110delta inhibits CSF-1-induced macrophage spreading and invasive capacity. AB - Colony stimulating factor-1 (CSF-1) stimulates mononuclear phagocytic cell survival, growth and differentiation into macrophages through activation and autophosphorylation of the CSF-1 receptor (CSF-1R). We have previously demonstrated that CSF-1-induced phosphorylation of Y721 (pY721) in the receptor kinase insert triggers its association with the p85 regulatory subunit of phosphoinositide 3'-kinase (PI3K). Binding of p85 PI3K to the CSF-1R pY721 motif activates the associated p110 PI3K catalytic subunit and stimulates spreading and motility in macrophages and enhancement of tumor cell invasion. Here we show that pY721-based signaling is necessary for CSF-1-stimulated PtdIns(3,4,5)P production. While primary bone marrow-derived macrophages and the immortalized bone marrow-derived macrophage cell line M-/-.WT express all three class IA PI3K isoforms, p110delta predominates in the cell line. Treatment with p110delta specific inhibitors demonstrates that the hematopoietically enriched isoform, p110delta, mediates CSF-1-regulated spreading and invasion in macrophages. Thus GS-1101, a potent and selective p110delta inhibitor, may have therapeutic potential by targeting the infiltrative capacity of tumor-associated macrophages that is critical for their enhancement of tumor invasion and metastasis. PMID- 23648056 TI - Efficacy of ultrasound-guided transversus abdominis plane blocks for post cesarean delivery analgesia: a double-blind, dose-comparison, placebo-controlled randomized trial. AB - BACKGROUND: The analgesic benefit of TAP (transversus abdominis plane) blocks for cesarean delivery pain remains controversial. We compared the analgesic efficacy of two doses of local anesthetic for TAP blocks after cesarean delivery. METHODS: Sixty women having cesarean delivery under spinal anesthesia were randomized to receive ultrasound-guided TAP blocks using either high-dose ropivacaine (3mg/kg), low-dose ropivacaine (1.5mg/kg) or placebo. Patients received intrathecal 0.75% bupivacaine 10-12mg, fentanyl 10MUg and morphine 150MUg and standard multimodal analgesia. The primary outcome was the difference in pain with movement using a numeric rating scale at 24h. Other outcomes included time to first request for analgesia, pain scores at 6, 12, 36, 48h and at 6 and 12weeks, opioid consumption, adverse effects, quality of recovery, and satisfaction. RESULTS: There were no differences between groups in the primary outcome. Mean +/- SD pain scores (0-10) with movement at 24h were: high-dose ropivacaine 3.6+/-1.5, low dose ropivacaine 4.6+/-2.1 and placebo 4.1+/-1.7. With respect to secondary outcomes, the mean +/- SD pain scores at 6h were lower in the high-dose group 2.0+/-1.8 compared to the low-dose 3.4+/-2.7 and placebo groups 4.2+/-2.0 (P=0.009). Pain scores at 12h were also lower in the high-dose group 2.2+/-2.0 compared to the low-dose group 4.1+/-2.7 and placebo group 4.0+/-1.3 (P=0.011). There was no difference in other outcomes between groups. CONCLUSIONS: Neither high- or low-dose TAP blocks as part of a multimodal analgesia regimen including intrathecal morphine improved pain scores with movement at 24h after cesarean delivery when compared to placebo TAP blocks. High-dose TAP blocks may improve pain scores up to 12h after cesarean delivery. PMID- 23648055 TI - Magnetic resonance imaging zygapophyseal joint space changes (gapping) in low back pain patients following spinal manipulation and side-posture positioning: a randomized controlled mechanisms trial with blinding. AB - OBJECTIVE: The purpose of this study was to quantify lumbar zygapophyseal (Z) joint space separation (gapping) in low back pain (LBP) subjects after spinal manipulative therapy (SMT) or side-posture positioning (SPP). METHODS: This was a controlled mechanisms trial with randomization and blinding. Acute LBP subjects (N = 112; four n = 28 magnetic resonance imaging [MRI] protocol groups) had 2 MRI appointments (initial enrollment and after 2 weeks of chiropractic treatment, receiving 2 MRI scans of the L4/L5 and L5/S1 Z joints at each MRI appointment. After the first MRI scan of each appointment, subjects were randomized (initial enrollment appointment) or assigned (after 2 weeks of chiropractic treatment appointment) into SPP (nonmanipulation), SMT (manipulation), or control MRI protocol groups. After SPP or SMT, a second MRI was taken. The central anterior posterior joint space was measured. Difference between most painful side anterior posterior measurements taken postintervention and preintervention was the Z joint "gapping difference." Gapping differences were compared (analysis of variance) among protocol groups. Secondary measures of pain (visual analog scale, verbal numeric pain rating scale) and function (Bournemouth questionnaire) were assessed. RESULTS: Gapping differences were significant at the first (adjusted, P = .009; SPP, 0.66 +/- 0.48 mm; SMT, 0.23 +/- 0.86; control, 0.18 +/- 0.71) and second (adjusted, P = .0005; SPP, 0.65 +/- 0.92 mm; SMT, 0.89 +/- 0.71; control, 0.35 +/- 0.32) MRI appointments. Verbal numeric pain rating scale differences were significant at first MRI appointment (P = .04) with SMT showing the greatest improvement. Visual analog scale and Bournemouth questionnaire improved after 2 weeks of care in all groups (both P < .0001). CONCLUSIONS: Side-posture positioning showed greatest gapping at baseline. After 2 weeks, SMT resulted in greatest gapping. Side-posture positioning appeared to have additive therapeutic benefit to SMT. PMID- 23648057 TI - Bronchospasm following ergometrine in a non-asthmatic patient. PMID- 23648058 TI - An unusual case of haemorrhage. PMID- 23648059 TI - Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1. AB - The contribution that oxidative damage to DNA and/or RNA makes to the aging process remains undefined. In this study, we used the hMTH1-Tg mouse model to investigate how oxidative damage to nucleic acids affects aging. hMTH1-Tg mice express high levels of the hMTH1 hydrolase that degrades 8-oxodGTP and 8-oxoGTP and excludes 8-oxoguanine from both DNA and RNA. Compared to wild-type animals, hMTH1-overexpressing mice have significantly lower steady-state levels of 8 oxoguanine in both nuclear and mitochondrial DNA of several organs, including the brain. hMTH1 overexpression prevents the age-dependent accumulation of DNA 8 oxoguanine that occurs in wild-type mice. These lower levels of oxidized guanines are associated with increased longevity and hMTH1-Tg animals live significantly longer than their wild-type littermates. Neither lipid oxidation nor overall antioxidant status is significantly affected by hMTH1 overexpression. At the cellular level, neurospheres derived from adult hMTH1-Tg neural progenitor cells display increased proliferative capacity and primary fibroblasts from hMTH1-Tg embryos do not undergo overt senescence in vitro. The significantly lower levels of oxidized DNA/RNA in transgenic animals are associated with behavioral changes. These mice show reduced anxiety and enhanced investigation of environmental and social cues. Longevity conferred by overexpression of a single nucleotide hydrolase in hMTH1-Tg animals is an example of lifespan extension associated with healthy aging. It provides a link between aging and oxidative damage to nucleic acids. PMID- 23648060 TI - Buprenorphine. PMID- 23648061 TI - "Safari ni taabu": research and curriculum development as an instrument for greater understanding of spirituality and love in health sciences--humanistic personal and professional notes on a journey in Africa. PMID- 23648063 TI - Dieselzymes: development of a stable and methanol tolerant lipase for biodiesel production by directed evolution. AB - BACKGROUND: Biodiesels are methyl esters of fatty acids that are usually produced by base catalyzed transesterification of triacylglyerol with methanol. Some lipase enzymes are effective catalysts for biodiesel synthesis and have many potential advantages over traditional base or acid catalyzed transesterification. Natural lipases are often rapidly inactivated by the high methanol concentrations used for biodiesel synthesis, however, limiting their practical use. The lipase from Proteus mirabilis is a particularly promising catalyst for biodiesel synthesis as it produces high yields of methyl esters even in the presence of large amounts of water and expresses very well in Escherichia coli. However, since the Proteus mirabilis lipase is only moderately stable and methanol tolerant, these properties need to be improved before the enzyme can be used industrially. RESULTS: We employed directed evolution, resulting in a Proteus mirabilis lipase variant with 13 mutations, which we call Dieselzyme 4. Dieselzyme 4 has greatly improved thermal stability, with a 30-fold increase in the half-inactivation time at 50 degrees C relative to the wild-type enzyme. The evolved enzyme also has dramatically increased methanol tolerance, showing a 50 fold longer half-inactivation time in 50% aqueous methanol. The immobilized Dieselzyme 4 enzyme retains the ability to synthesize biodiesel and has improved longevity over wild-type or the industrially used Brukholderia cepacia lipase during many cycles of biodiesel synthesis. A crystal structure of Dieselzyme 4 reveals additional hydrogen bonds and salt bridges in Dieselzyme 4 compared to the wild-type enzyme, suggesting that polar interactions may become particularly stabilizing in the reduced dielectric environment of the oil and methanol mixture used for biodiesel synthesis. CONCLUSIONS: Directed evolution was used to produce a stable lipase, Dieselzyme 4, which could be immobilized and re-used for biodiesel synthesis. Dieselzyme 4 outperforms the industrially used lipase from Burkholderia cepacia and provides a platform for still further evolution of desirable biodiesel production properties. PMID- 23648064 TI - The clinical impact of chromosomal rearrangements with breakpoints upstream of the SOX9 gene: two novel de novo balanced translocations associated with acampomelic campomelic dysplasia. AB - BACKGROUND: The association of balanced rearrangements with breakpoints near SOX9 [SRY (sex determining region Y)-box 9] with skeletal abnormalities has been ascribed to the presumptive altering of SOX9 expression by the direct disruption of regulatory elements, their separation from SOX9 or the effect of juxtaposed sequences. CASE PRESENTATION: We report on two sporadic apparently balanced translocations, t(7;17)(p13;q24) and t(17;20)(q24.3;q11.2), whose carriers have skeletal abnormalities that led to the diagnosis of acampomelic campomelic dysplasia (ACD; MIM 114290). No pathogenic chromosomal imbalances were detected by a-CGH. The chromosome 17 breakpoints were mapped, respectively, 917-855 kb and 601-585 kb upstream of the SOX9 gene. A distal cluster of balanced rearrangements breakpoints on chromosome 17 associated with SOX9-related skeletal disorders has been mapped to a segment 932-789 kb upstream of SOX9. In this cluster, the breakpoint of the herein described t(17;20) is the most telomeric to SOX9, thus allowing the redefining of the telomeric boundary of the distal breakpoint cluster region related to skeletal disorders to 601-585 kb upstream of SOX9. Although both patients have skeletal abnormalities, the t(7;17) carrier presents with relatively mild clinical features, whereas the t(17;20) was detected in a boy with severe broncheomalacia, depending on mechanical ventilation. Balanced and unbalanced rearrangements associated with disorders of sex determination led to the mapping of a regulatory region of SOX9 function on testicular differentiation to a 517-595 kb interval upstream of SOX9, in addition to TESCO (Testis-specific enhancer of SOX9 core). As the carrier of t(17;20) has an XY sex chromosome constitution and normal male development for his age, the segment of chromosome 17 distal to the translocation breakpoint should contain the regulatory elements for normal testis development. CONCLUSIONS: These two novel translocations illustrate the clinical variability in carriers of balanced translocations with breakpoints near SOX9. The translocation t(17;20) breakpoint provides further evidence for an additional testis-specific SOX9 enhancer 517 to 595 kb upstream of the SOX9 gene. PMID- 23648065 TI - Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. AB - Chemotherapeutic agents are notoriously known to have a narrow therapeutic range that often results in life-threatening toxicity. Hence, it is clinically important to identify the patients who are at high risk for severe toxicity to certain chemotherapy through a pharmacogenomics approach. In this study, we carried out multiple genome-wide association studies (GWAS) of 13 122 cancer patients who received different chemotherapy regimens, including cyclophosphamide and platinum-based (cisplatin and carboplatin), anthracycline-based (doxorubicin and epirubicin), and antimetabolite-based (5-fluorouracil and gemcitabine) treatment, antimicrotubule agents (paclitaxel and docetaxel), and topoisomerase inhibitors (camptothecin and etoposide), as well as combination therapy with paclitaxel and carboplatin, to identify genetic variants that are associated with the risk of severe neutropenia/leucopenia in the Japanese population. In addition, we used a weighted genetic risk scoring system to evaluate the cumulative effects of the suggestive genetic variants identified from GWAS in order to predict the risk levels of individuals who carry multiple risk alleles. Although we failed to identify genetic variants that surpassed the genome-wide significance level (P < 5.0 * 10(-8) ) through GWAS, probably due to insufficient statistical power and complex clinical features, we were able to shortlist some of the suggestive associated loci. The current study is at the relatively preliminary stage, but does highlight the complexity and problematic issues associated with retrospective pharmacogenomics studies. However, we hope that verification of these genetic variants through local and international collaborations could improve the clinical outcome for cancer patients. PMID- 23648066 TI - Poor reporting quality of key Randomization and Allocation Concealment details is still prevalent among published RCTs in 2011: a review. AB - RATIONALE, AIMS AND OBJECTIVES: Randomized controlled trials (RCTs) are powerful tools; it is essential that these trials are not only conducted rigorously, but reported accurately. The aim of this paper was to describe the reporting quality among a set of RCTs published in 2011 on methodological details essential to judging the adequacy of allocation concealment methods employed. METHODS: Medline was searched using the Ovid platform to identify all those RCTs published in January 2011 in core clinical journals. Methodological details in relation to allocation concealment were extracted from the identified RCTs to allow the reporting quality to be assessed. If the information was not available in the paper the corresponding author was contacted. RESULTS: Eighty-five papers were identified, 74% (n = 63) endorsed the CONSORT statement. 73% (n = 62) required the author to be contacted for further information. Sequence generation methods were ascertained in 74% of trials, allocation concealment method in 41%, details of who recruited participants and who generated the randomization sequence in 38%. CONCLUSIONS: There is evidence to suggest that in 2011 key methodological information relating to allocation concealment is still not reported well in RCTs. Authors and journal editors need to ensure explicit and clear methods are reported in RCTs published. PMID- 23648067 TI - On the relationship between retrospective childhood ADHD symptoms and adult BPD features: the mediating role of action-oriented personality traits. AB - A number of studies have reported data suggestive of a significant association between ADHD and BPD, nevertheless, the nature of this relation has not been fully understood yet. In our study, we tried to evaluate if the relationship between retrospectively assessed ADHD symptoms and adult BPD features could mediated by selected temperament/personality traits. Four hundred forty-seven in- and outpatients consecutively admitted to the Clinical Psychology and Psychotherapy Unit of the Scientific Institute H San Raffaele of Milan, Italy, were administered the Italian versions of the following instruments: Structured Clinical Interview for DSM-IV Axis II Personality Disorders, Version 2.0 (SCID II), Wender Utah Rating Scale (WURS), Temperament and Character Inventory-Revised (TCI-R), Barratt Impulsiveness Scale-11 (BIS-11), and Aggression Questionnaire (AQ). Our mediation analyses showed that the combination of impulsivity, aggression, novelty seeking, and juvenile conduct problems completely mediate the relationship between retrospectively assessed ADHD symptoms and current BPD features. PMID- 23648068 TI - Towards standardization of clot waveform analysis and recommendations for its clinical applications. PMID- 23648069 TI - Tuberculosis exposure among evacuees at a shelter after earthquake, Japan, 2011. AB - Tuberculosis was diagnosed in a person who had stayed in a shelter after the 2011 Great East Japan Earthquake. A contact investigation showed that the prevalence of latent tuberculosis infection among other evacuees at the shelter was 20%. Our report underscores the importance of tuberculosis prevention and control after natural disasters. PMID- 23648070 TI - Feasibility of multifocal intra-ocular lens exchange and conversion to the bag-in the-lens implantation. AB - PURPOSE: Our purpose was to evaluate the surgical outcome after intra-ocular lens exchange in patients who presented impairing visual complaints after primary multifocal intra-ocular lens (MIOL) implantation. In particular, the study was undertaken to look at the number of eyes that could be equipped with the bag-in the-lens (BIL) IOL after MIOL exchange. METHODS: This series consisted of 30 eyes of 21 consecutive patients scheduled for MIOL exchange. In 15 out of the 30 eyes, IOL misalignment was measured on slit lamp anterior segment photo's after defining the mathematical centres of the IOL optic, pupil and limbus. RESULTS: Diffractive MIOL was more frequently explanted (25; 83%) when compared with refractive MIOL (4; 13%) and progressive optic IOL (1; 4%). In 21 out of the 30 eyes (70%) a bag-in-the-lens could be implanted. In 7 out of the 30 eyes (23%), the capsule was not considered sufficiently stable to accommodate an IOL. An iris fixated IOL or a sulcus-fixated IOL was then implanted. In 2 out of the 30 eyes (6%) the remaining capsular bag could accommodate a traditional lens-in-the-bag only. Eyes that underwent Nd:YAG laser capsulotomy prior to the MIOL exchange needed anterior vitrectomy peroperatively (11 eyes; 37%). Visual acuity improved postoperatively in 13 out of the 30 eyes and remained stable in 17 out of the 30 eyes. CONCLUSIONS: Since the BIL technique requires a very well-preserved capsular bag for the purpose of the IOL implantation, the success rate of BIL implantation after MIOL is a good indicator to evaluate the degree of difficulty to exchange MIOL. PMID- 23648071 TI - Multimodal integration of fNIRS, fMRI and EEG neuroimaging. PMID- 23648072 TI - Free drugs in clinical trials and their potential cost saving impact on the National Health Service: a retrospective cost analysis in Italy. AB - BACKGROUND: The cost of new anti-cancer drugs has dramatically increased in recent years, and countermeasures are required in order to limit pharmaceutical expenses. Sponsored clinical trials that provide drugs free of charge may be a useful tool in order to reduce drug costs. The aim of this analysis is to evaluate the effect of clinical trials on pharmaceutical expenditure savings. METHODS: We evaluated the cost of drugs administered in clinical practice and in clinical trials (considering only the standard regimens that were administered also in clinical practice) in 2010 at the Lung Cancer Unit of the National Institute for Cancer Research in Genoa, Italy. The cost of drugs was calculated on the price charged at our Institute in 2010. The supposed cost of experimental treatment replacing standard therapy was converted in the cost of the treatments that would have been chosen in clinical practice, considering histology, line of treatment and number of administered cycles. RESULTS: From 1/1/2010 to 12/31/2010, 196 patients affected by lung cancer or pleural mesothelioma were treated. 152 patients (78%) received treatment in clinical practice or in non sponsored trials (18 patients in 4 trials), while 44 (22%) were treated in one of the 12 sponsored clinical trials recruiting in 2010. Globally, 606 cycles of treatment would have been administered to patients, of which 436 (72%) were administered in clinical practice or in non-sponsored trials and 170 (28%) were administered in pharmaceutical company sponsored clinical trials. The overall cost of those anti-neoplastic drugs, based on the prices charged at our Institute in 2010, was ?799 803. The cost of drugs administered in clinical practice or in non-sponsored trials was ?556 649 (70%), whereas the cost of standard drugs administered in clinical trials was ?243 154 (30%). The grants provided by pharmaceutical companies were evaluated and amounted to ?235 965. CONCLUSIONS: The participation in sponsored clinical trials in which drugs are provided free of charge offers substantial cost savings for the National Health Service; moreover, the grants received for each enrolled patient produced additional income. PMID- 23648073 TI - Right pulmonary artery obstruction is a long-term complication of aortopulmonary window repair. AB - The early outcomes of transaortic patch repair closure for aortopulmonary window are satisfactory, but the lifelong fate of the aorta and pulmonary artery remains unknown. We describe a 40-year-old patient with right pulmonary artery occlusion accompanied by aneurysmal dilation of the ascending aorta 38 years after transaortic repair of an aortopulmonary window. Operative findings revealed patch shrinkage and thrombotic occlusion of the right pulmonary artery. The dilated ascending aorta firmly adhered to the right pulmonary artery. After pulmonary artery thrombectomy, the right pulmonary artery was reconstructed and the dilated ascending aorta was replaced. PMID- 23648074 TI - Auxin transport during root gravitropism: transporters and techniques. AB - Root gravitropism is a complex, plant-specific process allowing roots to grow downward into the soil. Polar auxin transport and redistribution are essential for root gravitropism. Here we summarise our current understanding of underlying molecular mechanisms and involved transporters that establish, maintain and redirect intercellular auxin gradients as the driving force for root gravitropism. We evaluate the genetic, biochemical and cell biological approaches presently used for the analysis of auxin redistribution and the quantification of auxin fluxes. Finally, we also discuss new tools that provide a higher spatial or temporal resolution and our technical needs for future gravitropism studies. PMID- 23648075 TI - Changes in plasma and erythrocyte omega-6 and omega-3 fatty acids in response to intravenous supply of omega-3 fatty acids in patients with hepatic colorectal metastases. AB - BACKGROUND: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are functionally the most important omega-3 polyunsaturated fatty acids (PUFAs). Oral supply of these fatty acids increases their levels in plasma and cell membranes, often at the expense of the omega-6 PUFAs arachidonic acid (ARA) and linoleic acid. This results in an altered pattern of lipid mediator production to one which is less pro-inflammatory. We investigated whether short term intravenous supply of omega-3 PUFAs could change the levels of EPA, DHA, ARA and linoleic acid in plasma and erythrocytes in patients with hepatic colorectal metastases. METHODS: Twenty patients were randomised to receive a 72 hour infusion of total parenteral nutrition with (treatment group) or without (control group) omega-3 PUFAs. EPA, DHA, ARA and linoleic acid were measured in plasma phosphatidylcholine (PC) and erythrocytes at several times points up to the end of infusion and 5 to 12 days (mean 9 days) after stopping the infusion. RESULTS: The treatment group showed increases in plasma PC EPA and DHA and erythrocyte EPA and decreases in plasma PC and erythrocyte linoleic acid, with effects most evident late in the infusion period. Plasma PC and erythrocyte EPA and linoleic acid all returned to baseline levels after the 5-12 day washout. Plasma PC DHA remained elevated above baseline after washout. CONCLUSIONS: Intravenous supply of omega-3 PUFAs results in a rapid increase of EPA and DHA in plasma PC and of EPA in erythrocytes. These findings suggest that infusion of omega-3 PUFAs could be used to induce a rapid effect especially in targeting inflammation. PMID- 23648076 TI - Endogenous plasma coenzyme Q10 concentration does not correlate with plasma total antioxidant capacity level in healthy untrained horses. AB - Coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial electron transport pathway, and is also the only known endogenously synthesized lipid soluble antioxidant. The aim of the present study was to determine, for the first time, endogenous plasma CoQ10 concentration and its correlation with plasma total antioxidant capacity (TAC) and serum total cholesterol (TC) in a population of healthy untrained horses. Thirty-one horses were included in the study. Plasma CoQ10 concentration ranged from 0.380 to 2.090 mg/L, which is in general agreement with plasma CoQ10 concentration in humans. The study demonstrated no significant correlation between plasma CoQ10 and TAC, which indicates that CoQ10 does not contribute to the TAC of equine plasma significantly. In contrast to humans, no significant correlation was found between CoQ10 and TC in investigated horses. The results warrant further studies on CoQ10 supplementation in healthy untrained horses and subsequent determination of correlations between CoQ10 and TAC. PMID- 23648077 TI - First detection and molecular diversity of Brazilian bovine torovirus (BToV) strains from young and adult cattle. AB - Bovine torovirus (BToV) is an established enteric pathogen of cattle, but its occurrence in Brazilian cattle had not been reported until now. This article describes a survey on BToV in Brazil carried out on 80 fecal samples from diarrheic young and adult cattle, using a nested-RT-PCR targeting the nucleocapsid (N) gene. BToV was detected in 6.25% (5/80) of stool samples from three different geographic regions. Sequences analysis showed that Brazilian BToVs have a high degree of identity with European and Japanese BToVs and a lower degree of identity with North American Breda 1 strain. These results show that, albeit its low frequency and the scarce number of research on the field, BToV is still present amongst cattle populations. PMID- 23648078 TI - Bacteriology of septic arthritis at a regional hospital in Southern Taiwan. PMID- 23648079 TI - A bundled approach to reduce methicillin-resistant Staphylococcus aureus infections in a system of community hospitals. AB - Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a significant challenge to U.S. healthcare facilities, but there has been limited study of initiatives to reduce infection and increase patient safety in community hospitals. To address this need, a multifaceted program for MRSA infection prevention was developed for implementation in 159 acute care facilities. This program featured five distinct tools-active MRSA surveillance of high-risk patients, enhanced barrier precautions, compulsive hand hygiene, disinfection and cleaning, and executive champions and patient empowerment-and was implemented during 1Q-2Q 2007. Postintervention (3Q 2007-2Q 2008), 10.2% of patients with high-risk for infection or complications due to MRSA had nasal colonization. Volume of disposable gown and alcohol-based hand sanitizer use increased substantially following program implementation. Self-reported rates, based on NHSN definitions, of healthcare-associated central line-associated bloodstream infections and ventilator-associated pneumonia due to MRSA decreased 39% (p < .001) and 54% (p < .001), respectively. Infection rates continued to decrease during the follow-up period (1Q-4Q 2009). This sustained improvement demonstrates that reducing healthcare-associated MRSA infections in a large number of diverse facilities is possible and that a "bundled" approach that translates science into clinical and executive performance expectations may aid in overcoming traditional barriers to implementation. PMID- 23648080 TI - ADP-receptor inhibitors in the perioperative period: the good, the bad, and the ugly. PMID- 23648081 TI - Intravenous flurbiprofen axetil can stabilize the hemodynamic instability due to mesenteric traction syndrome--evaluation with continuous measurement of the systemic vascular resistance index using a FloTrac(r) sensor. AB - OBJECTIVE: Evaluation of the stabilizing effect of intravenous flurbiprofen axetil against hemodynamic instability due to mesenteric traction syndrome (MTS) by continuous measurement of systemic vascular resistance index (SVRI) using a FloTrac((r)) sensor was evaluated. DESIGN: Prospective randomized trial. SETTING: A single-center study performed in an educational hospital. PARTICIPANTS: Two prospective studies were carried out, each with 40 patients scheduled for elective open abdominal surgery. INTERVENTION: Twenty patients received 50 mg of flurbiprofen axetil after the recognition of MTS by the anesthesiologist (group FT). The remaining patients served as controls (groups CP and CT). MEASUREMENTS AND MAIN RESULTS: SVRI data was collected every 20 seconds for 1 hour after starting the laparotomy. The average SVRI prior to skin incision was taken as the baseline. Following 3 values were devised to evaluate MTS: the S-value (sum total of changes in SVRI from baseline), the T-value (period during which SVRI remained 20% or more below baseline), and the M-value (maximum change in SVRI from baseline). In group FP, decrease in SVRI was smaller than in group CP, and statistical differences in the 3 values were found. In group FT, SVRI recovered earlier than in group CT, and statistical differences were found in S-value and T value. However, the M-value had no statistical differences. CONCLUSIONS: Intravenous flurbiprofen axetil can stabilize the hemodynamic instability due to MTS. PMID- 23648082 TI - Neurocognitive outcomes of cardiac surgery. PMID- 23648083 TI - Special issue: Catalytic mechanisms by biological systems--introduction. AB - Research on enzyme mechanisms is advancing knowledge of the chemistry and biochemistry of catalytic mechanisms by biological systems. The structural dynamical properties of enzymes are of key importance. Advanced methodological approaches and new insights into enzyme functioning, and new emerging approaches for the redesign/design of enzymes or artificial biocatalysts, were discussed at the EMBO conference on Catalytic Mechanisms by Biological Systems. PMID- 23648084 TI - Swiss flag or Red Cross emblem: why the confusion? PMID- 23648085 TI - Neural circuits and motivational processes for hunger. AB - How does an organism's internal state direct its actions? At one moment an animal forages for food with acrobatic feats such as tree climbing and jumping between branches. At another time, it travels along the ground to find water or a mate, exposing itself to predators along the way. These behaviors are costly in terms of energy or physical risk, and the likelihood of performing one set of actions relative to another is strongly modulated by internal state. For example, an animal in energy deficit searches for food and a dehydrated animal looks for water. The crosstalk between physiological state and motivational processes influences behavioral intensity and intent, but the underlying neural circuits are poorly understood. Molecular genetics along with optogenetic and pharmacogenetic tools for perturbing neuron function have enabled cell type selective dissection of circuits that mediate behavioral responses to physiological state changes. Here, we review recent progress into neural circuit analysis of hunger in the mouse by focusing on a starvation-sensitive neuron population in the hypothalamus that is sufficient to promote voracious eating. We also consider research into the motivational processes that are thought to underlie hunger in order to outline considerations for bridging the gap between homeostatic and motivational neural circuits. PMID- 23648087 TI - Characterization of a short isoform of the kidney protein podocin in human kidney. AB - BACKGROUND: Steroid resistant nephrotic syndrome is a severe hereditary disease often caused by mutations in the NPHS2 gene. This gene encodes the lipid binding protein podocin which localizes to the slit diaphragm of podocytes and is essential for the maintenance of an intact glomerular filtration barrier. Podocin is a hairpin-like membrane-associated protein that multimerizes to recruit lipids of the plasma membrane. Recent evidence suggested that podocin may exist in a canonical, well-studied large isoform and an ill-defined short isoform. Conclusive proof of the presence of this new podocin protein in the human system is still lacking. METHODS: We used database analyses to identify organisms for which an alternative splice variant has been annotated. Mass spectrometry was employed to prove the presence of the shorter isoform of podocin in human kidney lysates. Immunofluorescence, sucrose density gradient fractionation and PNGase-F assays were used to characterize this short isoform of human podocin. RESULTS: Mass spectrometry revealed the existence of the short isoform of human podocin on protein level. We cloned the coding sequence from a human kidney cDNA library and showed that the expressed short variant was retained in the endoplasmic reticulum while still associating with detergent-resistant membrane fractions in sucrose gradient density centrifugation. The protein is partially N-glycosylated which implies the presence of a transmembranous form of the short isoform. CONCLUSIONS: A second isoform of human podocin is expressed in the kidney. This isoform lacks part of the PHB domain. It can be detected on protein level. Distinct subcellular localization suggests a physiological role for this isoform which may be different from the well-studied canonical variant. Possibly, the short isoform influences lipid and protein composition of the slit diaphragm complex by sequestration of lipid and protein interactors into the endoplasmic reticulum. PMID- 23648088 TI - Elucidating the microbial resuscitation cascade in biological soil crusts following a simulated rain event. AB - Biological soil crusts (biocrusts) are photosynthetic mats formed through an association of prokaryotic and eukaryotic microorganisms with soil particles. Biocrusts are found in virtually any terrestrial ecosystem where vascular plant coverage is abiotically limited, with drylands comprising the primary habitat for them. We studied the dynamics of the active bacterial community in two biocrusts from an arid and a hyperarid region in the Negev Desert, Israel, under light-oxic and dark-anoxic incubation conditions after simulated rainfall. We used H2(18)O for hydrating the crusts and analysed the bacterial community in the upper and lower parts of the biocrust using an RNA-stable isotope probing approach coupled with 454-pyrosequencing. In both biocrusts, two distinct bacterial communities developed under each incubation condition. The active anaerobic communities were initially dominated by members of the order Bacillales which were later replaced by Clostridiales. The aerobic communities on the other hand were dominated by Sphingobacteriales and several Alphaproteobacteria (Rhizobiales, Rhodobacterales, Rhodospirillales and Rubrobacteriales). Actinomycetales were the dominant bacterial order in the dry crusts but quickly collapsed and accounted for < 1% of the community by the end of the incubation. Our study shows that biocrusts host a diverse community whose members display complex interactions as they resuscitate from dormancy. PMID- 23648086 TI - Translational approach to develop novel medications on alcohol addiction: focus on neuropeptides. AB - Research on alcohol and drug dependence has shown that the development of addiction depends on a complex interplay of psychological factors, genetic or epigenetic predisposing factors, and neurobiological adaptations induced by drug consumption. A greater understanding of the mechanisms leading to alcohol abuse will allow researchers to identify genetic variation that corresponds to a specific biological vulnerability to addiction, thus defining robust endophenotypes that might help deconstruct these complex syndromes into more tractable components. To this end, it is critical to develop a translational framework that links alterations at the molecular level, to changes in neuronal function, and ultimately to changes at the behavioral and clinical levels. Translational phenotypes can be identified by the combination of animal and human studies designed to elucidate the neurofunctional, anatomical and pharmacological mechanisms underlying the etiology of alcohol addiction. The present article offers an overview of medication development in alcoholism with a focus on the critical aspect of translational research. Moreover, significant examples of promising targets from neuropeptidergic systems, namely nociceptin/orphanin FQ and neuropeptide S are given. PMID- 23648089 TI - Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive. AB - Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, extends the life span of yeast, worms, flies, and mice. Interventions that promote longevity are often correlated with increased insulin sensitivity, and it therefore is surprising that chronic rapamycin treatment of mice, rats, and humans is associated with insulin resistance (J Am Soc Nephrol., 19, 2008, 1411; Diabetes, 00, 2010, 00; Science, 335, 2012, 1638). We examined the effect of dietary rapamycin treatment on glucose homeostasis and insulin resistance in the genetically heterogeneous HET3 mouse strain, a strain in which dietary rapamycin robustly extends mean and maximum life span. We find that rapamycin treatment leads to glucose intolerance in both young and old HET3 mice, but in contrast to the previously reported effect of injected rapamycin in C57BL/6 mice, HET3 mice treated with dietary rapamycin responded normally in an insulin tolerance test. To gauge the overall consequences of rapamycin treatment on average blood glucose levels, we measured HBA1c. Dietary rapamycin increased HBA1c over the first 3 weeks of treatment in young animals, but the effect was lost by 3 months, and no effect was detected in older animals. Our results demonstrate that the extended life span of HET3 mice on a rapamycin diet occurs in the absence of major changes in insulin sensitivity and highlight the importance of strain background and delivery method in testing effects of longevity interventions. PMID- 23648090 TI - Soluble interleukin-6 receptor is a serum biomarker for the response of esophageal carcinoma to neoadjuvant chemoradiotherapy. AB - Preoperative chemoradiotherapy has been shown to improve the outcome of patients with esophageal cancer, but because response to this therapy varies, it is desirable to identify in advance individuals who would be unlikely to benefit, in order to avoid unnecessary adverse drug effects. The serum profiles of 84 cytokines and related proteins were determined in 37 patients with esophageal squamous cell carcinoma who received identical neoadjuvant preoperative chemoradiotherapy regimens and underwent surgical resection. Histological response to this therapy was assessed in surgically resected specimens. The serum soluble interleukin-6 receptor (sIL6R) level was significantly higher in 30 patients who failed to achieve a histological complete response (P = 0.005). Multivariate analysis revealed that the increased level of sIL6R was one of several significant independent predictors of an unfavorable outcome (hazard ratio, 2.87; P = 0.017). The increased level of this cytokine in patients who did not obtain a complete response was reproducibly observed in an independent cohort of 34 patients. Esophageal squamous cell carcinoma patients with an increased serum level of sIL6R are predicted to respond poorly to preoperative chemoradiotherapy, therefore, their exclusion from this treatment may be considered. Persistent systemic inflammation is implicated as a possible mechanism of resistance to this therapy. PMID- 23648091 TI - Chest pain with elevated troponin assay in adolescents. AB - OBJECTIVE: We sought to describe the evaluation, treatment, and follow-up of adolescents who presented to a single institution with chest pain and an elevated troponin I value in the absence of typical symptoms of pericarditis or myocarditis. Materials and methods We performed a retrospective review of patients in the age group of 10-18 years of age with no history of significant heart disease admitted to our institution from 2000 to 2010 after presenting with chest pain and an elevated troponin I value. RESULTS: A total of 16 patients were identified with a median age of 16.5 years (range 11.2-17.8 years). Of these 13 (81%) were male and 10 (63%) showed evidence of localised ST elevations on electrocardiogram. The median peak troponin I level was 17.8 nanograms per millilitre (range 0.89-227, normal less than 0.4). There were eight patients (50%) with a diagnosis of coronary vasospasm, three patients (20%) with atypical myopericarditis, one patient with coronary anomaly, one patient with hypercoagulable disorder, and one patient with prolonged supraventricular tachycardia. In two patients, no definitive diagnosis was made. There was one patient who needed catheter-based intervention, which involved stenting of a coronary artery after a procedure-related complication. CONCLUSIONS: In our cohort of adolescents without history of significant cardiac disease, chest pain and elevated troponin I levels were attributed to a variety of causes. Although coronary vasospasm and atypical myopericarditis were seen most commonly, coronary anomaly was identified in one case. Magnetic resonance imaging proved a useful diagnostic tool to assess coronary artery anatomy and myocardial changes suggestive of myocarditis. On the basis of these results and a review of the literature, a general evaluation algorithm is presented. PMID- 23648092 TI - Allocation concealment: a methodological review. AB - RATIONALE, AIMS AND OBJECTIVES: The accurate reporting of the trial methodology and results is essential for accurate judgement on the quality of the research. This review aims to assess the impact of the adequacy of allocation concealment on treatment effect estimates. METHODS: A search was performed in MEDLINE (via the Ovid platform) to identify all randomized controlled trials (RCTs) indexed in January 2011 within its set of 'core clinical journals'. Meta-regression was undertaken on a subset of two arm trials to quantify the association between adequacy of allocation concealment and effect size. RESULTS: Adequate allocation concealment methods were used in 27% (n = 23) of included trials. There was insufficient information given in 68% (n = 58) of trials to make a judgement on allocation concealment. Meta-regression showed that there was a trend, not statistically significant, towards a smaller effect size between adequacy of allocation concealment and effect sizes. CONCLUSION: This review highlighted that research needs to be reported to a higher standard and there are many trials reporting poor methods of allocation concealment within the small sample of trials included in this review. PMID- 23648093 TI - Bio-inspired citrate-functionalized apatite thin films crystallized on Ti-6Al-4V implants pre-coated with corrosion resistant layers. AB - In this paper the crystallization of a bioinspired citrate-functionalized apatite (cit-Ap) thin film (thickness about 2MUm) on Ti-6Al-4V supports pre-coated with bioactive and corrosion resistant buffer layer of silicon nitride (Si3N4), silicon carbide (SiC) or titanium nitride (TiN) is reported. The apatitic coatings were produced by a new coating technique based on the induction heating of the implants immersed in a flowing calcium-citrate-phosphate solution at pH11. The influence of the buffer layers and the surface roughness of the substrate on the chemical-physical features and adhesion of the cit-Ap films were investigated. The best plasticity, compactness and adherence properties have been found in the Ap layer grown on Si3N4, followed by the Ap grown on SiC and TiN, respectively. The adhesion property was likely related to the roughness of the buffered substrates, whereas the compactness and plasticity were closely related to the operating conditions during the Ap crystallization (flow rate of the solution and increase of temperature) rather than to the nature of the buffer layer. PMID- 23648094 TI - [Clot in right atrium seen in transthoracic ultrasound in a patient with intraoperative cardiorespiratory arrest]. PMID- 23648095 TI - Identification and characterization of alpha1 -antitrypsin in fibrin clots. AB - BACKGROUND AND OBJECTIVES: Preliminary studies indicated that alpha1 -antitrypsin (A1AT) is the most abundant protein that is non-covalently bound to fibrin clots prepared from plasma. The aim of this study was to identify and characterize fibrin(ogen)-bound A1AT. METHODS AND RESULTS: Plasma clots were prepared and extensively washed with saline. Clot-bound A1AT could only be extracted using denaturing agents such as urea, thiourea or SDS, pointing to an apparently strong association. Purified fibrinogen, but still containing A1AT as a contaminant, was gel filtered, which showed that the A1AT was bound to fibrinogen. A specific ELISA detected the presence of A1AT-fibrinogen complexes in both purified fibrinogen and pooled normal plasma. Finally, fibrin(ogen)-Sepharose chromatography indicated that A1AT purified from plasma contained a small fraction of fibrin(ogen)-binding A1AT. To study the inhibitory activity of fibrin(ogen)-bound A1AT, both fibrinogen containing A1AT and washed plasma clots were incubated with increasing amounts of elastase. SDS-PAGE and Western blotting showed under both conditions the generation of the A1AT-elastase complex as well as cleaved A1AT. The inhibitory activity of fibrin(ogen)-bound A1AT was also demonstrated by measuring elastase-induced lysis of fibrin clots. CONCLUSION: Fibrin clots contain strongly bound A1AT, which is functionally active as a serine protease inhibitor (serpin). This A1AT might play a role in the local regulation of proteases involved in coagulation or fibrinolysis and represent a novel link between the inflammatory and hemostatic systems. PMID- 23648096 TI - Migraine and vascular risk factors in the elderly. AB - AIM: The association between migraine and cerebrovascular disease is well documented in younger migraine patients, especially those with aura. Prevalence estimates of vascular risk factors among elderly migraine sufferers are lacking. The present study was designed to estimate the prevalence of vascular risk factors in the elderly population with late onset of migraine without aura. METHODS: The medical records of 163 patients aged 50 years and older suffering from migraine without aura were assessed for vascular risk factors, including hypertension, elevated serum lipid levels, diabetes mellitus and cardiovascular disease. Prevalence was estimated and compared with age- and sex-matched vascular risk factor estimates for the general population extracted from the 2003-2004 Israeli National Health Interview Survey, and to a group of patients matched by age suffering from migraine with aura. RESULTS: Among women with migraine without aura, hypertension, hyperlipidemia and diabetes mellitus were significantly less prevalent than among women without migraine without aura. Prevalence estimates for vascular risk factors did not differ by migraine among males. The group of older patients suffering from migraine with aura showed a higher incidence of vascular risk factors in respect to the group of migraine patients without aura. CONCLUSIONS: The findings of the present study might have an important clinical relevance, suggesting another pathophysiological process in respect to patients suffering from migraine with aura, and this evidence might have different therapeutic implications. PMID- 23648097 TI - Expression of insulin-like growth factor 1 receptor in rat retina following optic nerve injury. AB - PURPOSE: To investigate the apoptosis in retinal ganglion cells (RGCs) and insulin-like growth factor 1 receptor (IGF-1R) in the retina following optic nerve crush. METHODS: Healthy Wistar rats (N = 70) were divided into two groups: a normal control group and an optic nerve injury group. Immunohistochemistry and flow cytometry were performed to detect the expression of IGF-1R and to measure the apoptosis of RGCs, respectively. RESULTS: Immunohistochemistry revealed that at 1 hr after optic nerve injury, IGF-1R immunoreactivity began to increase and reached a maximal level at 24 hr (p < 0.05), where it remained elevated up to 14 days after injury. RGC apoptosis in the normal control group was 0.53%, while the apoptosis rate in the optic nerve injury group increased over time. The apoptosis rate in the optic nerve injury group was 1.4% at 1 hr, 4.4% at 6 hr, 5.2% at 12 hr and reached a maximal level (8.5%) at 24 hr. Subsequently, the rate declined to 1.9% 7 days after injury and 0.9% 2 weeks after injury. CONCLUSION: The IGF-1R immunereactivity in the retina increased after optic nerve injury. IGF-1R may regulate the apoptosis and regeneration of RGCs at different stages after optic nerve injury. PMID- 23648098 TI - Genetic analysis of primaquine tolerance in a patient with relapsing vivax malaria. AB - Patients with Plasmodium vivax malaria are treated with primaquine to prevent relapse infections. We report primaquine failure in a patient with 3 relapses without any possibility of re-infection. Using whole genome sequencing of the relapsing parasite isolates, we identified single nucleotide variants as candidate molecular markers of resistance. PMID- 23648099 TI - Leptin and resistin in overweight patients with and without asthma. AB - BACKGROUND: Excess body mass increases the risk of development of asthmatic symptoms and their severity and decreases the treatment effectiveness. One of the hypotheses explaining the link between the two diseases concerns the adipokines, hormones produced by adipose tissue with a proinflammatory character. The aim of this study was to compare the levels of the adipokines (leptin and resistin) between overweight asthmatic patients, asthmatic patients with normal weight and overweight patients without asthma. METHODS: 80 peripheral blood samples were collected from patients and blood serum extracted. Three groups were selected: overweight asthmatic patients (BMI>=25), overweight patients without asthma and asthmatic patients with normal weight (BMI<25). Waist circumference of the patients was measured (cut-off points were 80cm for women and over 94cm for men) and a skin prick test performed. Comparison of adipokine concentration between the 3 groups was made and association between these concentrations and the measurements was performed. RESULTS: Although the concentrations of both adipokines were slightly higher for overweight asthmatic patients compared to overweight healthy patients, these differences were not significant. A significant association was found between leptin concentration and both BMI (p<0.01) and waist circumference (p<0.01). A difference for this cytokine was also found between asthmatic and non-asthmatic female patients (p<0.05). CONCLUSIONS: As expected overweight patients with BMI>=25 and patients with increased waist circumference showed higher leptin levels. We suggest that the studied cytokines, with a stronger indication for leptin, can elicit asthmatic inflammation in obese phenotype of asthma that affects more frequently women. PMID- 23648100 TI - Separation of the four most important latex allergens from latex gloves: a potential tool for diagnosis and immunotherapy purposes. PMID- 23648101 TI - Ascaris lumbricoides infection in urban schoolchildren: specific IgE and IL-10 production. AB - BACKGROUND: Helminth infections and allergies are diseases with intense Th2 lymphocytes participation and characterised by a high IgE and Interleukin-(IL) IL 4, IL-5 production and eosinophilia. However, helminths also induce IL-10 production, which may alter the outcome of allergic diseases in infected patients. OBJECTIVE: This experimental study analyses the relationship between IL 10 production by cell culture from geohelminth infected and non-infected children and specific IgE to Ascaris lumbricoides (Asc) or Blomia tropicalis (BT). METHODS: IL-10 content in supernatant from peripheral blood mononuclear cell culture from nine helminth infected and eleven non-infected patients was determined by ELISA after in vitro stimulation with Asc or BT extracts. RESULTS: A positive association was observed between total IgE levels and anti-Ascaris and anti-Blomia tropicalis specific IgE, independent of infection status. For both helminth-infected and non-infected groups, there was no difference in IL-10 production in response to Asc extract, even though anti-Ascaris IgE levels were higher in the latter group. In response to BT stimulus, a lower production of IL 10 by the geohelminth-infected group was observed, but with no relationship between IL-10 production and specific IgE to BT. CONCLUSION: The results suggest that anti-Ascaris IgE in non-infected patients may be associated to a resistance to parasites. Levels of specific IgE to parasite antigens or B. tropicalis allergen were not impaired by IL-10 production in children from an urban area in which geohelminthiasis is endemic. PMID- 23648102 TI - Metabolic engineering for the production of polyunsaturated fatty acids by oleaginous fungus Mortierella alpina 1S-4. AB - Researches related with the application of functional lipids such as polyunsaturated fatty acids (PUFAs) have been conducted in various fields with a view to health and dietary requirements. Novel rich sources other than known natural sources such as plant seeds and fish oils are required for increasing demands of PUFAs. The filamentous fungus Mortierella alpina 1S-4 produces triacylglycerols rich in arachidonic acid, i.e., ones reaching 20 g/l in concentration and containing 30-70% arachidonic acid as total fatty acids. Various mutants derived from M. alpina 1S-4 have led to the production of oils containing various PUFAs. Molecular breeding of M. alpina strains by means of manipulation of the genes involved in PUFA biosynthesis facilitates improvement of PUFA productivity and elucidation of the functions of their enzymes. This review describes practical PUFA production through mutant breeding, functional analyses of the genes of the enzymes involved in PUFA biosynthesis, and recent advances in unique PUFA production through molecular breeding. PMID- 23648103 TI - TK1656, a thermostable l-asparaginase from Thermococcus kodakaraensis, exhibiting highest ever reported enzyme activity. AB - Two L-asparaginase homologs, TK1656 and TK2246, have been found in the genome of Thermococcus kodakaraensis. The gene encoding TK1656 consists of 984 nucleotides corresponding to a polypeptide of 328 amino acids. To examine the properties of TK1656, the structural gene was cloned, expressed in Escherichia coli and the purified gene product was characterized. TK1656 exhibited high asparaginase activity (2350 U mg-1) but no glutaminase activity. The enzyme also displayed the D-asparaginase activity but 50% to that of L-asparaginase. The highest activity was observed at 85 degrees C and pH 9.5. TK1656 catalyzed the conversion of L asparagine to L-aspartatic acid and ammonia following Michaelise-Menten kinetics with a K(m) and V(max) values of 5.5 mM and 3300 mmol min-1 mg-1, respectively. The activation energy from the linear Arrhenius plot was found to be 58 kJ mol-1. Unfolding studies suggested that urea could not induce complete unfolding and inactivation of TK1656 even at a concentration 8 M; however, in the presence of 4 M guanidine hydrochloride enzyme structure was unfolded with complete loss of enzyme activity. PMID- 23648104 TI - Investigation of the physiological response to oxygen limited process conditions of Pichia pastoris Mut(+) strain using a two-compartment scale-down system. AB - Inhomogeneities in production-scale bioreactors influence microbial growth and product quality due to insufficient mixing and mass transfer. For this reason, lots of efforts are being made to investigate the effects of gradients that impose stress in large-scale reactors in laboratory scale. We have implemented a scale-down model which allows separating a homogeneous part, a stirred tank reactor (STR), and a plug flow reactor (PFR) which mimics the inhomogeneous regimes of the large-scale fermenters. This scale-down model shows solutions to trigger oxygen limited conditions in the PFR part of the scale-down setup for physiological analysis. The goal of the study was to investigate the scale-up relevant physiological responses of Pichia pastoris strain to oxygen limited process conditions in the above mentioned two-compartment bioreactor setup. Experimental results with non-induced cultures show that the specific growth rate significantly decreased with increasing the exposure time to oxygen limitation. In parallel more by-products were produced. Examining physiological scalable key parameters, multivariate data analyses solely using on-line data revealed that different exposures to the oxygen limitation significantly affected the culture performance. This work with the small scale-downs setup reflects new approaches for a valuable process development tool for accelerating strain characterization or for verifying CFD simulations of large-scale bioreactors. As a novel methodological achievement, the combination of the two-compartment scale-down system with the proposed multivariate techniques of solely using on-line data is a valuable tool for recognition of stress effects on the culture performance for physiological bioprocess scale-up issues. PMID- 23648105 TI - Electrochemical disinfection of fish pathogens in seawater without the production of a lethal concentration of chlorine using a flow reactor. AB - An electrochemical disinfection system employing a honeycombed platinum coated titanium electrode was developed for the disinfection of seawater. Cell suspensions (2 l, 103 cells/ml) of the fish pathogens, Vibrio alginolyticus, Edwardsiella tarda, Lactococcus garvieae and Vibrio anguillarum were circulated in a reactor equipped with 10 sets of these electrodes at a flow rate of 200 ml/min with an applied potential of 1.0 V vs. Ag/AgCl reference electrode. The circulated cells were completely disinfected after 3 h of treatment, whereas free residual chlorine generated due to seawater electrolysis was below 0.1 ppm. In addition, a diphenyl-1-pyrenylphosphine fluorescent assay revealed that lipid peroxidation in the cell membranes of disinfected bacteria was induced probably by reactive oxygen species generated during electrochemical treatment. PMID- 23648106 TI - Fibrosis in hepatitis C patients predicts complications after elective total joint arthroplasty. AB - Effects of Hepatitis C on total hip (THA) and total knee arthroplasty (TKA) outcomes are poorly understood. Seventy-two hepatitis C patients underwent 77 primary THA or TKA and were retrospectively identified, stratified by fibrosis and thrombocytopenia and compared to matched controls. Overall, Hepatitis C and control patients had similar outcomes. After TKA, fibrotic hepatitis C patients demonstrated a greater average hemoglobin drop than non-fibrotic hepatitis C patients (4.9 versus 3.8, P=0.023), greater deep infection rate (21% versus 0%, P=0.047), and rate of cellulitis (21% versus 0%, P=0.047). Thrombocytopenia showed a trend toward greater infections. Prior to fibrosis, Hepatitis C patients appear to be at no increased risk of complication after joint arthroplasty. Evaluation of fibrosis may predict poor outcome in Hepatitis C patients. PMID- 23648107 TI - Custom-made cement-linked mega prostheses: a salvage solution for complex periprosthetic femoral fractures. AB - Periprosthetic femoral fractures with long stem implants, poor bone stock and loosening pose a considerable surgical challenge. We describe a reconstruction technique using a custom-made mega-prosthesis, cement-linked to the femoral stem of a well-fixed existing implant. Clinical and radiological outcomes were assessed at our tertiary referral centre. There were 15 patients with a periprosthetic femoral fracture: 5 proximal and 10 distal femoral arthroplasties linked to existing femoral stems. The survival rate was 93.3% at a mean follow-up of 5.3 years (0.5-19.3) with 1 revision. We present a salvage technique with good intermediate-term outcomes for highly selected patients with complex periprosthetic femoral fractures, as another option to conventional fixation methods. Specifically, it allows immediate weight bearing and avoids some of the morbidity of total femoral arthroplasty or amputation. PMID- 23648108 TI - "Never reflected anywhere": body image among ethnoracialized gay and bisexual men. AB - A growing body of literature has highlighted the increased prevalence of body image concerns and associations with health outcomes among gay and bisexual men (GBM). Little research, however, has examined the link between body image and social oppression for ethnoracialized GBM. Using an intersectionality lens and qualitative inductive analysis, data were collected through focus groups and interviews with GBM (n=61) who identify with one of four ethnoracial groups (Black, East/Southeast Asian, South Asian, Latino/Brazilian). Three main themes emerged: (1) body image idealization in gay/bisexual male culture, (2) negotiating a racialized body image, and (3) negotiating the impact of body image on relationship with self and others. The study results highlighted how multiple forms of oppression (e.g., racism, sexism) intersected with one another to impact the body image and overall well-being among ethnoracialized GBM. PMID- 23648109 TI - Structure-activity relationships of analogs of 3,4,5-trimethylfuran-2(5H)-one with germination inhibitory activities. AB - Smoke-derived butenolide compounds have, in recent years, been shown to be important germination signaling molecules, which also affect seedling growth. The butenolide 3,4,5-trimethylfuran-2(5H)-one was previously isolated from plant derived smoke and was found to significantly reduce the effect on germination by the highly active promotor karrikinolide (KAR1, 3-methyl-2H-furo[2,3-c]pyran-2 one), another smoke-derived compound. In this study, 11 analogs of 3,4,5 trimethylfuran-2(5H)-one were synthesized and their effect on the germination of light-sensitive 'Grand Rapids' lettuce seeds (Lactua sativa cv. 'Grand Rapids') were evaluated. A concentration series (1mM-1MUM) of the analogs were tested alone, or in combination with 0.01MUM KAR1. Only two compounds were found to reduce the germination promotory effect of 0.01MUM KAR1 in a similar manner as observed with 3,4,5-trimethylfuran-2(5H)-one, with activity ranging from 1mM to 10MUM. Four compounds were found to have inhibitory activity at 1mM and 100MUM. The retention of activity by some of the analogs may be useful for designing novel compounds with improved activity. Furthermore, understanding the structure activity relationships of these compounds may be helpful in synthesizing molecular probes that can be used to further investigate the mechanism of action of these compounds in regulating seed germination. PMID- 23648110 TI - Elicitation of galanthamine biosynthesis by Leucojum aestivum liquid shoot cultures. AB - The effects of methyl jasmonate and jasmonic acid on galanthamine production, phenolic acid content and growth of Leucojum aestivum L. shoot culture, cultivated in submerged conditions were investigated. The best time-point for addition of elicitors was during the exponential phase of the culture growth. The maximal contents of galanthamine and lycorine (226.9 MUg/flask and 491.4 MUg/flask, 1.36 and 1.67-fold higher compared to the control, respectively) were achieved after elicitation with jasmonic acid, whereas the elicitation with methyl jasmonte resulted in maximal accumulation of phenolic acids. It was demonstrated that the boosting effect of jasmonic acid on Amaryllidacea alkaloid biosynthesis was due to induction of the activity of tyrosine decarboxylase, whereas methyl jasmonate stimulates the biosynthesis of phenolic acids by inducing mainly the activity of phenylalanine ammonia-lyase. PMID- 23648111 TI - Zinc-induced modulation of SRSF6 activity alters Bim splicing to promote generation of the most potent apoptotic isoform BimS. AB - Bim is a member of the pro-apoptotic BH3-only Bcl-2 family of proteins. Bim gene undergoes alternative splicing to produce three predominant splicing variants (BimEL, BimL and BimS). The smallest variant BimS is the most potent inducer of apoptosis. Zinc (Zn(2+)) has been reported to stimulate apoptosis in various cell types. In this study, we examined whether Zn(2+) affects the expression of Bim in human neuroblastoma SH-SY5Y cells. Zn(2+) triggered alterations in Bim splicing and induced preferential generation of BimS, but not BimEL and BimL, in a dose- and time-dependent manner. Other metals (cadmium, cobalt and copper) and stresses (oxidative, endoplasmic reticulum and genotoxic stresses) had little or no effect on the expression of BimS. To address the mechanism of Zn(2+)-induced preferential generation of BimS, which lacks exon 4, we developed a Bim mini-gene construct. Deletion analysis using the Bim mini-gene revealed that predicted binding sites of the SR protein SRSF6, also known as SRp55, are located in the intronic region adjacent to exon 4. We also found that mutations in the predicted SRSF6-binding sites abolished generation of BimS mRNA from the mutated Bim mini gene. In addition, a UV cross-linking assay followed by Western blotting showed that SRSF6 directly bound to the predicted binding site and Zn(2+) suppressed this binding. Moreover, Zn(2+) stimulated SRSF6 hyper-phosphorylation. TG003, a cdc2-like kinase inhibitor, partially prevented Zn(2+)-induced generation of BimS and SRSF6 hyper-phosphorylation. Taken together, our findings suggest that Zn(2+) inhibits the activity of SRSF6 and promotes elimination of exon 4, leading to preferential generation of BimS. PMID- 23648113 TI - Outcome of infants with unrepaired heart disease admitted to the pediatric intensive care unit: single-center developing country perspective. AB - OBJECTIVE: Congenital heart disease (CHD) has an incidence of ~0.8-1%. Outcome of previously diagnosed CHD patients awaiting surgery (either correction or palliation) in a developing country setting is unknown. We strive to determine the outcome of patients with CHD awaiting surgery who present to pediatric intensive care unit (PICU) setting with an acute illness. DESIGN: Retrospective cross-sectional chart review. SETTING: Pediatric intensive care unit of The Aga Khan University Hospital, Karachi, Pakistan. PATIENT: Medical records of infants (1-12 months) with CHD awaiting surgery presenting to the PICU with an acute illness between January 2009 and June 2012 were included. Newly diagnosed CHD patients, those not requiring PICU admission, and those transferred to another hospital were excluded. RESULTS: A total of 34 infants met the inclusion criteria. Median age at presentation was 5 months. Seventy-four percent of the infants had CHD lesion characterized by increased pulmonary blood flow (shunt lesions). Though none of the patients met the strict criteria for sepsis or pneumonia, 74% were admitted with a diagnosis of pneumonia or sepsis. Only 15% of patient had congestive heart failure as an admitting diagnosis. Oxygen therapy was given to 94% of these patients. Fifty-nine percent of these patients expired during the admission, 95% of those expired had multiorgan dysfunction. CONCLUSION: Patients with CHD awaiting surgery and who admitted to the PICU with acute illness are at high risk for mortality. Stringent criteria to diagnose pneumonia or sepsis should be used in these patients. PMID- 23648112 TI - Assessing the quality of life of health-referred children and adolescents with short stature: development and psychometric testing of the QoLISSY instrument. AB - BACKGROUND: When evaluating the outcomes of treatment in paediatric endocrinology, the health-related quality of life (HrQoL) of the child is to be taken into consideration. Since few self-reported HrQoL instruments exist for children with diagnosed short stature (dSS), the objective of this study was to develop and psychometrically test a targeted HrQoL instrument for use in multinational clinical research. METHODS: The target population were short stature (height<-2 SDS) children and adolescents (age 8-12 and 13-18 years) with a diagnosis of growth hormone deficiency (GHD) or idiopathic short stature (ISS), differing in growth hormone treatment status. Focus group discussions for concept and item generation, piloting of the questionnaire with cognitive debriefing, and instrument field testing with a retest were conducted simultaneously in five countries. After qualitative and preliminary quantitative analyses, psychometric testing of field test data in terms of reliability and validity including confirmatory factor analyses (CFA) was performed. RESULTS: Following item generation from focus group discussions, 124 items were included in a pilot test with a cognitive debriefing exercise providing preliminary feedback on item and domain operating characteristics. A field test with 268 participants showed high internal consistency reliabilities (alpha 0.82-0.95), good correlations with generic measures (up to r=.58), significant known group differences (e.g. in height: F=32, df 244, p<0.001) and an acceptable CFA model fit suggesting construct validity of the three-domain core structure with 22 items, supplemented by three mediator domains with 28 items. CONCLUSIONS: The QoLISSY questionnaire is a promising step forward in assessing the impact of dSS on HrQoL. It is based on items generated from the subjective experience of short stature children referred for endocrine investigation, is validated for use in five languages and it is easy to administer in clinical and research settings. PMID- 23648114 TI - Anaerobic digestion in municipal solid waste management: part of an integrated, holistic and sustainable solution. PMID- 23648117 TI - Genetic testing for hearing loss in the United States should include deletion/duplication analysis for the deafness/infertility locus at 15q15.3. AB - BACKGROUND: Hearing loss is the most common birth defect and the most prevalent sensorineural disorder in developed countries. More than 50% of prelingual deafness is genetic, most often autosomal recessive and nonsyndromic, of which 50% can be attributed to the disorder DFNB1, caused by mutations in GJB2 and GJB6. Sensorineural hearing loss and male infertility (Deafness-Infertility Syndrome; DIS) is a contiguous gene deletion syndrome resulting from homozygous deletion of the CATSPER2 and STRC genes on chromosome 15q15.3. Females with DIS have only hearing loss and are fertile. Until recently this syndrome has only been described in three consanguineous families and 2 nonconsanguineous families. RESULTS: We recently indentified a patient with hearing loss and macrocephaly who was found to be homozygous for this deletion. Her nonconsanguineous parents are both carriers. We examined our database of patients tested by array CGH and determined that just over 1% of our patients are heterozygous for this deletion. If this number is representative of the general population, this implies a 1% carrier frequency and prevalence of DIS of 1 in 40,000 individuals. CONCLUSION: We propose that DIS is a greatly under-diagnosed cause of deafness and should be considered in children with hearing loss. Likewise, current molecular genetic testing panels for hearing loss in the United States should be expanded to include deletion/duplication analysis of this region. PMID- 23648118 TI - Ecological differentiation of cryptic species within an asexual protist morphospecies: a case study of filamentous green alga Klebsormidium (Streptophyta). AB - Taxa of microbial eukaryotes defined on morphological basis display a large degree of genetic diversity, implying the existence of numerous cryptic species. However, it has been postulated that genetic diversity merely mirrors accumulation of neutral mutations. As a case taxon to study cryptic diversity in protists, we used a widely distributed filamentous genus, Klebsormidium, specifically the lineage E (K. flaccidum/K. nitens complex) containing a number of morphologically similar strains. Fourteen clades were recognized in the phylogenetic analysis based on a concatenated ITS rDNA + rbcL data set of more than 70 strains. The results of inferred character evolution indicated the existence of phylogenetic signal in at least two phenotypic characters (production of hydro-repellent filaments and morphology of zoosporangia). Moreover, the lineages recovered exhibited strong ecological preferences to one of the three habitat types: natural subaerial substrata, artificial subaerial substrata, and aquatic habitats. We interpret these results as evidence of existence of a high number of cryptic species within the single morphospecies. We consider that the permanent existence of genetically and ecologically well defined cryptic species is enabled by the mechanism of selective sweep. PMID- 23648119 TI - Diagnosis, prognosis and treatment of patients with gastrointestinal stromal tumour (GIST) and germline mutation of KIT exon 13. AB - BACKGROUND: The demonstration of the role of activating mutations of KIT or PDGFRA and the development of targeted therapies have modified the prognosis of patients with gastrointestinal stromal tumours (GISTs). Identification of kindreds with KIT or PDGFRA germline mutation raised new questions, especially regarding the diagnosis, management, monitoring and treatment of these patients. METHODS: We identified index patients of three different families with a KIT exon 13 germline mutation. Pedigree of GIST kindred was assessed in oncogenetic consultation, and medical records were reviewed. Efficacy of imatinib in GISTs with KIT exon 13 was evaluated and compared with published data. RESULTS: All KIT germline mutations were p.K642E. Twenty affected patients were identified in the three families. GISTs were multiple and occurred before 45years in all but one case. All resected tumours were of spindle cell histology, CD117 positive, and had low or intermediate risk of relapse. Lentigines involving the palms and soles were detected in four patients, and three patients had motrice dysphagia. Nine affected patients died of their disease, all but one before 65years. Affected patients were most often symptomatic and required iterative surgical resections. Imatinib was efficient in GISTs with p.K642E mutation with a disease control rate superior to 90% whatever the sporadic or inherited origin of the tumour. CONCLUSIONS: We propose a regular screening of kindreds who have germline mutation. Treatment with imatinib should be considered for those with symptomatic tumour, larger than 3cm and/or growing rapidly. PMID- 23648121 TI - Percutaneous hepatic venous stenting for menorrhagia in Budd-Chiari syndrome. PMID- 23648122 TI - Tumor associated macrophage expressing CD204 is associated with tumor aggressiveness of esophageal squamous cell carcinoma. AB - Tumor associated macrophages (TAMs) are the most abundant cancer stromal cells educated by tumor microenvironment to acquire trophic functions facilitating angiogenesis, matrix breakdown and cancer cell motility. Tumor associated macrophages have anti-inflammatory properties or "alternatively" activated (M2) phenotype expressing CD204 and/or CD163. To know the role of TAMs in the growth and progression of esophageal squamous cell carcinomas (ESCCs), we calculated intratumoral CD204, CD163 or CD68 expressing macrophage count (MphiC) and CD34 positive microvessel density (MVD) by immunohistochemistry in 70 cases of surgically resected ESCCs and compared them with the clinicopathological factors and prognosis of patients. MphiC had positive linear association with MVD. High CD204(+) MphiC were significantly correlated with more malignant phenotypes including depth of tumor invasion, lymph and blood vessel invasion, lymph node metastasis as well as clinical stages. On the other hand, CD163(+) MphiC did not associate with these clinicopathological factors with the exception of depth of tumor invasion and blood vessel invasion. Patients with high CD204(+) MphiC ESCCs showed poor disease-free survival (P = 0.021). Conditioned media of five ESCC cell lines (TE-8, -9, -10, -11 and -15) induced mRNA as well as protein expression of CD204 but not of CD163 with upregulation of vascular endothelial growth factor-A mRNA in TPA treated human acute monocytic leukemia cell line THP 1. These results overall indicate that CD204 is a useful marker for TAMs contributing to the angiogenesis, progression and prognosis of ESCCs whose specific tumor microenvironment may educate macrophages to be CD204(+) M2 TAMs. PMID- 23648120 TI - Surgery and risk for multiple sclerosis: a systematic review and meta-analysis of case-control studies. AB - BACKGROUND: Although the precise etiology of multiple sclerosis is largely unknown, there is some speculation that a prior history of surgery may be associated with the subsequent risk for developing the disease. Therefore, we aimed to examine surgery as a risk factor for the diagnosis of multiple sclerosis. METHODS: We searched for observational studies that evaluated the risk for developing multiple sclerosis after surgery that occurred in childhood (<= 20 years of age) or "premorbid" (> 20 years of age). We specifically included surgeries classified as: tonsillectomy, appendectomy, adenoidectomy, or "surgery". We performed a systematic review and meta-analyses and calculated odds ratios (OR) and their 95% confidence intervals (CIs) using a random effects model. RESULTS: We identified 33 case-control studies, involving 27,373 multiple sclerosis cases and 211,756 controls. There was a statistically significant association between tonsillectomy (OR = 1.32, 95% CI 1.08-1.61; 12 studies, I(2) = 44%) and appendectomy (OR = 1.16, 95% CI 1.01-1.34; 7 studies, I(2) = 0%) in individual's <= 20 years of age and the subsequent risk for developing multiple sclerosis. There was no statistically significant association between risk for multiple sclerosis and tonsillectomy occurring after age 20 (OR = 1.20, 95% CI 0.94-1.53; 9 studies, I(2) = 32%), in those with appendectomy at > 20 years (OR = 1.26, 95% CI 0.92-1.72; 5 studies, I(2) = 46%), and in those with adenoidectomy at <= 20 years of age (OR = 1.06, 95% CI 0.68-1.68; 3 studies, I(2) = 35%). The combined OR of 15 studies (N = 2,380) looking at "surgery" before multiple sclerosis diagnosis was not statistically significant (OR = 1.19, 95% CI 0.83 1.70; I(2) = 71%). CONCLUSIONS: We found a small but statistically significant and clinically important increased risk for developing multiple sclerosis, in those with tonsillectomy and appendectomy at <= 20 years of age. There was no convincing evidence to support the association of other surgeries and the risk for multiple sclerosis. Well-designed prospective etiological studies, pertaining to the risk for developing multiple sclerosis, ought to be conducted and should include the examination of various surgeries as risk factors. PMID- 23648123 TI - A naive approach for deriving scoring systems to support clinical decision making. AB - RATIONALE, AIMS AND OBJECTIVES: Scoring systems are frequently proposed in medicine to summarize a set of qualitative and quantitative items by means of a numeric score. Their design often requires modelling ability and subjective judgments. This can make it difficult to adapt a scoring system to a clinical setting different from that in which the system was developed. The objective of this study was to discuss an approach to derive scoring systems, which can be easily modified and matched to any scenario. METHODS: A naive Bayes approach was used to develop a scoring system that is completely defined by descriptive tables obtained by frequency counts from the training set. The approach was implemented to build a locally customized scoring system for planning transfusion requirements after cardiac surgery. The performance of this system was evaluated and compared with that of a logistic regression model designed using the same predictors. The working sample was a set of 3182 consecutive patients undergoing cardiac surgery at the University Hospital of Siena, Italy. RESULTS: The area under the receiver operating characteristic curve was equal to 0.811 and 0.824 for the scoring system and for the logistic regression model, respectively. This result proves that this global index of discrimination capacity was virtually identical and very good for both models. The values of sensitivity, specificity and overall correct-classification percentage obtained by the leave-one-out method were practically the same for the two models (73.9% versus 75.3%). CONCLUSIONS: An easy-fitting and trustworthy scoring system can be directly developed using a naive Bayes approach. The simplicity of its design allows the system to be customized to any specific institution and updated regularly. This aspect has important practical implications because it can encourage the use of scoring systems among clinicians, enabling their performance to be properly assessed in a wider clinical context. PMID- 23648124 TI - Imagining sisyphus happy. PMID- 23648125 TI - Clinical trials with ... drugs? Based on 2 projects in Alzheimer's disease and malaria. AB - The biomedical research act (BRA) regulates clinical research in humans, but not that related to clinical trials with medicinal products. This article describes the scientific and regulatory foundations supporting 2 projects which could be observed as clinical trials, can follow the BRA requirements. One is a positron emission tomography study with radiopharmaceutical to determine the presence of amyloid-beta protein deposition in certain areas of the brain of cognitively healthy adults. The other is a study on controlled malaria infection in healthy volunteers using the inoculation of aseptic, purified and cryopreserved Plasmodium falciparum sporozoites. Since in both studies subjects undergo invasive procedures, the BRA requires the approval of the study by the relevant regional health authorities. These 2 studies have been the first ones that have used this regulatory procedure in Catalonia. PMID- 23648126 TI - Does pupil dilation influence subfoveal choroidal laser Doppler flowmetry? AB - PURPOSE: The aim of this study was to assess (i) whether pupil dilation with tropicamide influences subfoveal choroidal blood flow, as assessed by continuous laser Doppler flowmetry (LDF) and (ii) if this is the case, whether the effect is due to a haemodynamic response of the drug-induced dilation. METHODS: Following the instillation of one drop of 1% tropicamide in one eye of 18 healthy, nonsmoking volunteers (age 20-25 years), the subfoveal choroidal LDF parameters (Vel, Vol and ChBF) were recorded during 30 min, at 3-min intervals under two paradigms: through an artificial pupil (4 mm diameter) placed in front of the cornea (P1) and without this artificial pupil (P2). RESULTS: Tropicamide increased the pupil diameter from 3.3 +/- 0.4 mm (mean +/- SD) to 8.3 +/- .4 mm. Full dilation was reached at ~24 min. During this period of time, linear regression analysis demonstrated that none of the LDF parameters varied significantly (p > 0.05), either under P1 or P2. Based on a group of 12 subjects, the smallest (%) change in the mean value of ChBF (ChBFm ) that would be detectable (sensitivity of the method, S) was found to be 2% for P1 and 6% for P2. The average coefficient of variation of ChBFm based on eight measurements during dilation was greater for P2 than for P1 by a factor of approximately 2. CONCLUSION: Tropicamide had no significant influence on the subfoveal choroidal LDF parameters measured by continuous LDF during pupil dilation. Furthermore, pupil dilation did not affect ChBFm by more than the calculated minimum percentage change of 6% detectable with our method. PMID- 23648127 TI - [Ischemic stroke following a scorpion sting]. AB - Scorpion envenomation is caused by an accidental scorpion sting. In its severe form, it involves life-threatening respiratory or cardiac damage; it may also cause the neurological severity of systemic manifestations. We report the case of a young 35-year-old woman stung by an Androctonus mauretanicus scorpion, who developed impaired consciousness, hemiplegia and respiratory distress. At admission, the brain computed tomography showed a hypodense area in the right parietal region; the chest radiograph revealed a bilateral alveolar syndrome. Troponin was elevated and hemostasis disorders were present. The clinical course was remarkable: cardiogenic shock with multiple organ failure followed by death on day 3. This case illustrates a rare complication of scorpion envenomation: ischemic stroke due to an undetermined mechanism, which in addition to the cardiac and respiratory injuries, led to the serious complications and fatal outcome. PMID- 23648128 TI - Measurement structure of the caregiver burden scale: findings from a national community survey in Taiwan. AB - AIM: There is no appropriate understanding of community family caregiver burden. The object of the present study was to evaluate the measurement structure of a caregiver burden scale from a nationally representative Taiwanese community sample. METHODS: Data from nationally representative subjects completing face-to face interviews on caregiver burden were analyzed. A total of 9020 primary adult family caregivers were enrolled. All of the valid respondents were equally divided into three subsamples. The first sample was used to explore the factor structure of burden scale. The second sample was used to validate the factor structure. The third sample was used to verify the adequacy and stability of the factor structures developed in the former steps. RESULTS: A total of 8826 valid data were included for analysis. Exploratory and confirmatory factor analysis identified the four-factor, 15-item Caregiver Burden Scale (CBS-15) in the present study. The extracted four factors were predominantly accounted for by the items measuring "burden of time," "relational burden," "financial burden" and "emotional burden". All the goodness-of-fit indices reported for this model were acceptable. CONCLUSION: The present study supports the usefulness of the CBS-15 as a tool to understand the measurement structure of burden in a nationally representative Taiwanese community family caregivers sample. The CBS-15 can be used to identify community caregiver needs. PMID- 23648129 TI - Vitamin D receptor Fok I polymorphism is associated with low bone mineral density in postmenopausal women: a meta-analysis focused on populations in Asian countries. AB - OBJECTIVE: To explore the associations between vitamin D receptor (VDR) gene polymorphisms (including Fok I, Bsm I and Apa I) and bone mineral density (BMD) in postmenopausal Asian women. STUDY DESIGN: Databases of Medline, Embase and Wangfang were retrieved to identify eligible studies, with update to 1st February 2012. Standardized mean difference (SMD) and 95% confidence intervals were calculated by using fixed- or random-effect model. Best genetic comparison model was determined by using the Thakkinstian method. RESULTS: A total of 14 studies with 3243 healthy postmenopausal Asian women were included in this meta-analysis. Overall, pooled analyses indicated that the f allele of VDR Fok I was significantly associated with decreased BMD in the lumbar spine (ff vs. FF: SMD (95% CI): -0.87 (-1.38, -0.35); P=0.001 for lumbar spine; -0.43 (-0.93, 0.06), P=0.086 for femoral neck). In contrast, we did not observe overall associations between VDR Bsm I and Apa I polymorphisms and BMD in either lumbar spine or femoral neck (Bsm I bb vs. BB: SMD (95% CI): 0.61 (-1.30, 2.53), P=0.531 for lumbar spine; Apa I aa vs. AA: SMD (95% CI): 0.66 (-0.16, 1.48), P=0.113 for lumbar spine). When subgroup analyses were conducted according to countries, Indians carrying the VDR Fok I ff genotype were at risk of low BMD at lumbar spine (ff vs. FF: SMD (95% CI): -0.57 (-0.85, -0.29), P<0.001). Sensitivity analyses indicated that no single study had substantial influence on all combined analyses. In addition, no publication bias was identified. CONCLUSIONS: This meta analysis indicated that VDR Fok I, rather than Bsm I and Apa I polymorphisms, is associated with bone mineral density in postmenopausal Asian women (especially for Indian women), and can probably be used with other genetic markers together to identify individuals at high risk of osteoporosis. PMID- 23648130 TI - Broken Grafenberg ring incarcerated in para-ureteral space: a rare case of retained IUD accompanied pregnancy. PMID- 23648131 TI - Next-generation sequencing study finds an excess of rare, coding single nucleotide variants of ADAMTS13 in patients with deep vein thrombosis. AB - BACKGROUND: The considerable genetic predisposition to deep vein thrombosis (DVT) is only partially accounted for by known genetic risk variants. Rare single nucleotide variants (SNVs) of the coding areas of hemostatic genes may explain part of this missing heritability. The ADAMTS13 and VWF genes encode two interconnected proteins with fundamental hemostatic functions, the disruption of which may result in thrombosis. OBJECTIVES: To study the distribution and burden of rare coding SNVs of ADAMTS13 and VWF found by sequencing in cases and controls of DVT. PATIENTS/METHODS: The protein-coding areas of 186 hemostatic/proinflammatory genes were sequenced by next-generation technology in 94 thrombophilia-negative patients with DVT and 98 controls. Gene-specific information on ADAMTS13 and VWF was used to study the association between DVT and rare coding SNVs of the two genes. RESULTS: More than 70 billion base pairs of raw sequence data were produced to sequence the 700-kb target area with a median redundancy of * 45 in 192 individuals. Most of the 4366 SNVs identified were rare and non-synonymous, indicating pathogenetic potential. Rare (frequency of < 1%) and low-frequency (< 5%) coding SNVs of ADAMTS13 were associated with DVT (prevalence 17% vs. 4%; odds ratio [OR] 4.8 and 95% confidence interval [CI] 1.6 15.0 for rare coding; prevalence 36% vs. 23%, OR 1.9 and 95% CI 1.0-3.5 for low frequency coding). Patients with rare coding SNVs of ADAMTS13 had lower plasma levels of ADAMTS-13 activity than patients without them. SNVs of VWF were not associated with DVT. CONCLUSIONS: We found an excess of rare coding SNVs of the ADAMTS13 gene in patients with DVT. PMID- 23648132 TI - The formation and sequestration of heterochromatin during development: delivered on 7 September 2012 at the 37th FEBS Congress in Sevilla, Spain. AB - Chromatin is not randomly positioned in the nucleus, but is distributed in subdomains based on its degree of compaction and transcriptional status. Recent studies have shed light on the logic of chromatin distribution, showing that tissue-specific promoters drive distinct patterns of gene positioning during cell type differentiation. In addition, the sequestration of heterochromatin at the nuclear envelope has been found to depend on lamin and lamin-associated proteins. On the chromatin side, H3K9 monomethylation, dimethylation and trimethylation were shown to be the critical signals for perinuclear anchoring in worm embryonic nuclei. Downregulation of an equivalent histone methyltransferase, G9a, in human cells has a similar effect. In worms, the sequestration of the terminal methyltransferase by repressed chromatin may facilitate the propagation of a heterochromatin compartment, much as the sequestration of the silent information regulatory complex does at telomeric foci in budding yeast. These results argue for conserved logic in eukaryotic nuclear organization. PMID- 23648133 TI - Impact of early adolescent anxiety disorders on self-esteem development from adolescence to young adulthood. AB - PURPOSE: To examine the association between early adolescent anxiety disorders and self-esteem development from early adolescence through young adulthood. METHODS: Self-esteem was measured at mean ages 13, 16, and 22 for 821 participants from the Children in the Community Study, a population-based longitudinal cohort. Anxiety disorders were measured at mean age 13 years. Multilevel growth models were employed to analyze the change in self-esteem from early adolescence to young adulthood and to evaluate whether adolescent anxiety disorders predict both average and slope of self-esteem development. RESULTS: Self-esteem increased during adolescence and continued to increase in young adulthood. Girls had lower average self-esteem than boys, but this difference disappeared when examining the effect of anxiety. Adolescents with anxiety disorder had lower self-esteem, on average, compared with healthy adolescents (effect size [ES] = -.35, p < .01). Social phobia was found to have the greatest relative impact on average self-esteem (ES = -.30, p < .01), followed by overanxious disorder (ES = -.17, p < .05), and simple phobia (ES = -.17, p < .05). Obsessive compulsive-disorder (OCD) predicted a significant decline in self esteem from adolescence to young adulthood (beta = -.1, p < .05). Separation anxiety disorder was not found to have any significant impact on self-esteem development. CONCLUSIONS: All but one of the assessed adolescent anxiety disorders were related to lower self-esteem, with social phobia having the greatest impact. OCD predicted a decline in self-esteem trajectory with age. The importance of raising self-esteem in adolescents with anxiety and other mental disorders is discussed. PMID- 23648134 TI - [Viral retinitis following intravitreal triamcinolone injection]. AB - Necrotizing viral retinitis is associated with infection by the Herpes family of viruses, especially herpes simplex virus (HSV), varicella zoster virus (VZV) and occasionally cytomegalovirus (CMV). When the diagnosis is suspected clinically, antiviral therapy must be instituted immediately. We report the case of a patient presenting with necrotizing viral retinitis 3 months following intravitreal injection of triamcinolone acetonide for diabetic macular edema. Fluorescein angiography demonstrated a superior temporal occlusive vasculitis. A diagnostic anterior chamber paracentesis was performed to obtain deoxyribo-nucleic acid (DNA) for a polymerase chain reaction (PCR) test for viral retinitis. PCR was positive for CMV. The patient was placed on intravenous ganciclovir. CMV retinitis is exceedingly rare in immunocompetent patients; however, it remains the most common cause of posterior uveitis in immunocompromised patients. The incidence of this entity remains unknown. Local immunosuppression, the dose and the frequency of injections may explain the occurrence of this severe retinitis. PMID- 23648136 TI - HIV among women and children in Pakistan. AB - The HIV epidemic in Pakistan has now transmitted to female spouses of HIV positive injection drug users (IDUs) and bisexual men, and to preadolescent children through vertical transmission. Owing to sociocultural barriers, HIV infected pregnant women and children do not have optimum access to treatment, hindering the prevention of HIV transmission. PMID- 23648135 TI - Upregulation of ATF3 inhibits expression of the pro-inflammatory cytokine IL-6 during Neisseria gonorrhoeae infection. AB - Neisseria gonorrhoeae regulates the expression of epithelial cell genes, activates cytoprotective pathways in the infected cell and protects it from apoptosis. Many of these responses are enhanced by the Type IV pilus (Tfp). We tested the hypothesis that N. gonorrhoeae modulates the innate immune response by inducing expression of ATF3, a transcription factor that negatively regulates the expression of many cytokine genes. We further determined whether Tfp are involved in these events. We found that N. gonorrhoeae induces ATF3 expression in mucosal epithelial cells through activation of mitogen-activated protein kinases. Maximal ATF3 expression requires Tfp retraction. Knocking down endogenous levels of ATF3 results in higher levels of IL-6 transcript. Our findings strongly suggest that ATF3 is involved in suppressing cytokine expression during gonococcal infection. We propose a model for the role of ATF3 in the context of N. gonorrhoeae infection. PMID- 23648137 TI - Does changing from a first generation antipsychotic (perphenazin) to a second generation antipsychotic (risperidone) alter brain activation and motor activity? A case report. AB - BACKGROUND: In patients with schizophrenia, altered brain activation and motor activity levels are central features, reflecting cognitive impairments and negative symptoms, respectively. Newer studies using nonlinear methods have addressed the severe disturbances in neurocognitive functioning that is regarded as one of the core features of schizophrenia. Our aim was to compare brain activation and motor activity in a patient during pharmacological treatment that was switched from a first- to a second-generation antipsychotic drug. We hypothesised that this change of medication would increase level of responding in both measures. CASE PRESENTATION: We present the case of a 53-year-old male with onset of severe mental illness in adolescence, ICD-10 diagnosed as schizophrenia of paranoid type, chronic form. We compared brain activation and motor activity in this patient during pharmacological treatment with a first-generation (perphenazin), and later switched to a second-generation (risperidone) antipsychotic drug. We used functional magnetic resonance imaging (fMRI) to measure brain activation and wrist worn actigraphy to measure motor activity. CONCLUSION: Our study showed that brain activation decreased in areas critical for cognitive functioning in this patient, when changing from a first to a second generation antipsychotic drug. However the mean motor activity level was unchanged, although risperidone reduced variability, particularly short-term variability from minute to minute. Compared to the results from previous studies, the present findings indicate that changing to a second-generation antipsychotic alters variability measures towards that seen in a control group, but with reduced brain activation, which was an unexpected finding. PMID- 23648138 TI - Special issue on the Challenges in Environmental Science and Engineering, CESE 2012: September 9-13, 2012, Melbourne, Australia. PMID- 23648139 TI - Nuclear beta-catenin accumulation is associated with increased expression of Nanog protein and predicts poor prognosis of non-small cell lung cancer. AB - BACKGROUND: Although the prognostic roles of beta-catenin expression in non-small cell lung cancer (NSCLC) have been reported in several immunohistochemical (IHC) studies, the results were not consistent because some studies lack sufficient number of the positive cases or did not evaluate the subcellular localization features of the protein. METHOD: In this study, we have evaluated the expression levels and subcellular localization of beta-catenin and Nanog proteins IHC staining in tissue specimens from 309 patients with NSCLC, and explored their association with clinicopathological features and patient outcome. RESULTS: We showed that patients with negative expression of membranous beta-catenin had a trend towards shorter survival (p=0.064) than those with positive expression. In contrast to previous studies, we found that increased expression of either cytoplasmic or nuclear beta-catenin was strongly associated with poor prognosis and was an independent prognosticator for overall survival (p <0.01). We further found that NSCLC cells frequently exhibited an abundance of nuclear Nanog protein which was significantly correlated with nuclear beta-catenin expression (p <0.01) and poor prognosis (p <0.01). Interestingly, immunofluorescent staining results revealed that increased expression of Nanog and nuclear translocation of beta catenin occurred concomitantly in response to epidermal growth factor receptor(EGFR) signaling in A549 and H23 cells. Furthermore, western blot analysis show that nuclear beta-catenin rather than cytoplasmic beta-catenin expression in the A549 and H23 cells can be enhanced by adding EGF, Nanog expression in the A549 and H23 cells with knockdown of beta-catenin can not be obviously enhanced by adding EGF. CONCLUSION: We propose that evaluation of subcellular localization of beta-catenin and Nanog expression is of clinical significance for patients with NSCLC. PMID- 23648140 TI - Knowledge and attitudes of anesthesia providers about noncardiac surgery in adults with congenital heart disease. AB - OBJECTIVE: To examine the knowledge and attitudes of anesthesia providers in relation to the care of adult congenital heart disease (ACHD) patients presenting for noncardiac surgery. DESIGN/SETTING: A novel survey was designed and administered to 168 anesthesiologists across a single academic department in a range of practice environments. INTERVENTIONS: None. OUTCOME MEASURES: Survey responses, including true/false, multiple choice, and Likert scale questions. RESULTS: A total of 118 anesthesiologists (response rate = 70%) completed the survey. Knowledge scores ranged from 0 to 19 (median [interquartile range] = 7 [5 13]) out of a possible maximum of 20. Total knowledge scores differed significantly by fellowship background (P = .004), with higher scores in those with cardiac (11 [7-15], P = .005) and pediatric (12 [6-15], P = .001) fellowship training, but not in those with critical care, obstetric, regional, or pain management training. Scores also differed by frequency of providing care for cardiopulmonary bypass cases and frequency of providing care for patients under 2 years of age (P < .001 for both), but not by gender or years removed from residency. Respondents reported only moderate levels of comfort with a range of questions about providing perioperative or obstetric care to ACHD patients, with decreasing levels of comfort reported in patients with more complex lesions. CONCLUSIONS: Within the context of the limitations of a single-institution survey design, the low levels of knowledge and comfort we observed suggest that providers may benefit from improved training and protocols for ensuring adequate preparedness for the care of ACHD patients. PMID- 23648142 TI - Asking the right questions to find the keys to wound healing. PMID- 23648144 TI - Mechanistic / mammalian target protein of rapamycin signaling in hematopoietic stem cells and leukemia. AB - Mechanistic/mammalian target protein of rapamycin (mTOR) is an evolutionarily conserved kinase that plays a critical role in sensing and responding to environmental determinants such as nutrient availability, energy sufficiency, stress, and growth factor concentration. mTOR participates in two complexes, designated mTOR complex 1 (mTORC1) and 2 (mTORC2), both of which phosphorylate multiple substrates. Recent studies have revealed that the fine-tuning activity of mTOR complexes contributes to both maintenance of hematopoietic stem cells (HSCs) and suppression of leukemogenesis. Dysregulation of mTORC1 activity results in impaired HSC homeostasis. Abnormalities of mTOR signaling are observed in many patients with leukemia and genetic studies clearly show that the leukemogenesis associated with Pten deficiency involves both mTORC1 and mTORC2. Although the several mTOR inhibitors have been developed for cancer therapy, effectiveness of the inhibitors for eradication of leukemia stem cells (LSCs) is unknown. Advances in understanding of how mTOR signaling is involved in mechanisms of normal HSC and LSC homeostasis may lead to novel therapeutic approaches that can successfully eradicate leukemia. PMID- 23648141 TI - Loss of exon 4 in a human T-cell factor-4 isoform promotes hepatic tumourigenicity. AB - BACKGROUND: T-cell factor (TCF) proteins represent key transcription factors that activate Wnt/beta-catenin signalling. We have reported that a pair of TCF-4 isoforms (TCF-4C and TCF-4D) exhibit differential TCF transcriptional activity in hepatocellular carcinoma (HCC) cells, although their structure differs by only the presence (TCF-4D) or absence (TCF-4C) of exon 4. AIM: To demonstrate a regulatory role of exon 4 in HCC development. METHODS: TCF-4C and TCF-4D expression profiles were examined in 27 pairs of human HCC and adjacent liver tissues. The functional role of the TCF-4 isoforms was evaluated in OUMS-29 (an immortalized hepatocyte-derived) and HAK-1A (a well-differentiated HCC) cell lines using stable clones overexpressing the TCF-4 isoforms. RESULTS: TCF-4C was significantly upregulated in HCC tissues compared with corresponding peritumour and normal liver tissues; in contrast, there was no difference in TCF-4D expression. TCF-4C clones derived from both cell lines exhibited increased TCF activity, Wnt-responsive target genes, cell proliferation, cell cycle progression and resistance to chemotherapeutic drugs compared with TCF-4D clones. Capability of cell migration and colony formation was significantly higher in TCF-4C than TCF-4D clones. In a nude mice xenograft model, the HAK-1A-derived TCF-4C clone rapidly developed tumours compared with the TCF-4D clone. TCF-4C clone-derived tumours exhibited upregulation of Wnt-responsive target genes compared with the slow developing and small TCF-4D-derived tumours. CONCLUSION: These results demonstrate that the TCF-4C isoform lacking exon 4 is associated with a malignant phenotype compared with the exon 4-harbouring TCF-4D isoform, indicating that exon 4 of TCF-4 plays a prominent role in HCC development. PMID- 23648145 TI - Diabetes is a strong predictor of mortality during tuberculosis treatment: a prospective cohort study among tuberculosis patients from Mwanza, Tanzania. AB - OBJECTIVE: Strong evidence suggests diabetes may be associated with tuberculosis (TB) and could influence TB treatment outcomes. We assessed the role of diabetes on sputum culture conversion and mortality among patients undergoing TB treatment. METHODS: A total of 1250 Tanzanian TB patients were followed prospectively during TB treatment with sputum culture after 2 and 5 months. Survival status was assessed at least 1 year after initiation of treatment. At baseline, all participants underwent testing for diabetes and HIV, and the serum concentration of the acute phase reactant alpha-1 glycoprotein (AGP) was determined. RESULTS: There were no differences between participants with and without diabetes regarding the proportion of positive cultures at 2 (3.8% vs. 5.8%) and 5 (1.3% vs. 0.9%) months (P > 0.46). However, among patients with a positive TB culture, relatively more patients with diabetes died before the 5 month follow-up. Within the initial 100 days of TB treatment, diabetes was associated with a fivefold increased risk of mortality (RR 5.09, 95% CI 2.36; 11.02, P < 0.001) among HIV uninfected, and a twofold increase among HIV co infected patient (RR 2.33 95% CI 1.20; 4.53, P = 0.012), while diabetes was not associated with long-term mortality. Further adjustment with AGP did not change the estimates. CONCLUSION: Diabetes considerably increases risk of early mortality during TB treatment. The effect may not be explained by increased severity of TB, but could be due to impaired TB treatment response. Research is needed to clarify the mechanism and to assess whether glycaemic control improves survival. PMID- 23648146 TI - Neuroimaging of rapid eye movement sleep behavior disorder: transcranial ultrasound, single-photon emission computed tomography, and positron emission tomography scan data. AB - Idiopathic rapid eye movement sleep behavior disorder (iRBD), which typically develops in middle-aged individuals or later and progresses chronically, is a common clinical manifestation of Lewy body-related syndrome. It is important that combinations of neuroimaging markers in iRBD are considered for the purpose of diagnosing neurodegenerative diseases such as Parkinson disease (PD), dementia with Lewy body disease (DLB), or multiple system atrophy (MSA) at an early stage. Important advances have been made in the diagnosis of PD or DLB using imaging methods such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scans or transcranial B-mode ultrasonography (TCS). These methods are important in clinical research, in which the identification of biomarkers for iRBD offers diagnostic opportunities and points the way to new therapeutic strategies. This review focuses on neuroimaging studies of rapid eye movement sleep behavior disorder (RBD) patients using techniques such as TCS, SPECT, and PET scans. PMID- 23648147 TI - Borrelia recurrentis in head lice, Ethiopia. AB - Since the 1800s, the only known vector of Borrelia recurrentis has been the body louse. In 2011, we found B. recurrentis DNA in 23% of head lice from patients with louse-borne relapsing fever in Ethiopia. Whether head lice can transmit these bacteria from one person to another remains to be determined. PMID- 23648149 TI - Lymphadenectomy for bladder cancer at the time of radical cystectomy. AB - CONTEXT: Although the importance of lymphadenectomy during radical cystectomy (RC) in high-risk non-muscle-invasive and muscle-invasive bladder cancer (BCa) is well accepted, the optimal extent of lymphadenectomy, number of lymph nodes (LNs) to be retrieved, and prognostic and therapeutic role of lymphadenectomy remain debated issues. OBJECTIVE: In this review, we summarize the existing data on the value of lymphadenectomy for staging and outcome of BCa patients undergoing RC and lymphadenectomy. EVIDENCE ACQUISITION: A systematic Medline/PubMed literature search of peer-reviewed scientific articles published from 1998 and 2012, concerning the role of lymphadenectomy in BCa patients, was carried out. The terms and permutations used were lymphadenectomy, bladder cancer/carcinoma, urothelial carcinomas, radical cystectomy, lymph node metastasis, lymph node dissection, bladder, recurrence, and survival. Selective older articles were included. EVIDENCE SYNTHESIS: Bilateral pelvic lymphadenectomy is an integral part of RC for BCa. The literature regarding the role of lymphadenectomy in BCa patients in general is retrospective, nonstandardized, and of low-level quality in regard to evidence. Prospective randomized trials designed to define the optimal template of lymphadenectomy and its impact on oncologic outcome are advocated. Some of these studies are ongoing, and their completion and analyses are necessary to resolve controversies. CONCLUSIONS: Many consistent and concordant observations, although of low level of evidence, document that the extent of lymphadenectomy may influence disease-free survival after RC independent of the status of LNs and the pathologic stage of BCa. Lymphadenectomy standardization at the time of RC to create evidence-based guidelines is essential for further improvement of surgical quality and BCa patient survival. PMID- 23648150 TI - Thickness and fit of mouthguards according to heating methods. AB - The purpose of this study was to examine the difference in the thickness and fit of mouthguards made by four different heating methods of the mouthguard sheet material. A Sports Mouthguard((r)) of 3.8-mm thickness was used in this study. Four heating methods were performed. In one method, the sheet was heated only one side. In the other methods, one side of the sheet was heated first until the center of the sheet was displaced by 0.5 cm, 1.0 cm, and 1.5 cm from the baseline, and then turned upside down and heated. The sheets were adapted using a vacuum former when the heated sheets hung 1.5 cm from the baseline. We measured the thickness and fit of the mouthguard at the areas of the central incisor and first molar. The difference in thickness at the central incisor and first molar regions was analyzed by two-way anova. The difference in fit with different heating methods was analyzed by one-way anova. The results showed that the thickness of the mouthguard differed in the central incisor and first molar areas (P < 0.01 or P < 0.05), but not with the heating methods. The fit of the mouthguard at the central incisor and first molar areas was significantly different among the heating methods (P < 0.01 and P < 0.05). These results suggested that the fit of the mouthguard was superior when the heated surface of the sheet contacted the surface of the working model. This finding may help to fabricate accurate mouthguards. PMID- 23648148 TI - Odontogenic ameloblast-associated protein (ODAM) inhibits growth and migration of human melanoma cells and elicits PTEN elevation and inactivation of PI3K/AKT signaling. AB - BACKGROUND: The Odontogenic Ameloblast-associated Protein (ODAM) is expressed in a wide range of normal epithelial, and neoplastic tissues, and we have posited that ODAM serves as a novel prognostic biomarker for breast cancer and melanoma. Transfection of ODAM into breast cancer cells yields suppression of cellular growth, motility, and in vivo tumorigenicity. Herein we have extended these studies to the effects of ODAM on cultured melanoma cell lines. METHODS: The A375 and C8161 melanoma cell lines were stably transfected with ODAM and assayed for properties associated with tumorigenicity including cell growth, motility, and extracellular matrix adhesion. In addition, ODAM-transfected cells were assayed for signal transduction via AKT which promotes cell proliferation and survival in many neoplasms. RESULTS: ODAM expression in A375 and C8161 cells strongly inhibited cell growth and motility in vitro, increased cell adhesion to extracellular matrix, and yielded significant cytoskeletal/morphologic rearrangement. Furthermore, AKT activity was downregulated by ODAM expression while an increase was noted in expression of the PTEN (phosphatase and tensin homolog on chromosome 10) tumor suppressor gene, an antagonist of AKT activation. Increased PTEN in ODAM-expressing cells was associated with increases in PTEN mRNA levels and de novo protein synthesis. Silencing of PTEN expression yielded recovery of AKT activity in ODAM-expressing melanoma cells. Similar PTEN elevation and inhibition of AKT by ODAM was observed in MDA-MB-231 breast cancer cells while ODAM expression had no effect in PTEN-deficient BT-549 breast cancer cells. CONCLUSIONS: The apparent anti-neoplastic effects of ODAM in cultured melanoma and breast cancer cells are associated with increased PTEN expression, and suppression of AKT activity. This association should serve to clarify the clinical import of ODAM expression and any role it may serve as an indicator of tumor behavior. PMID- 23648151 TI - [Translational medicine and cardiopulmonary resuscitation]. PMID- 23648152 TI - [Establishing a novel transabdominal cardiopulmonary resuscitation maneuver]. PMID- 23648153 TI - [Pay attention to cerebral protection after cardiopulmonary resuscitation in children]. PMID- 23648154 TI - [Reproducing and evaluating a rabbit model of multiple organ dysfunction syndrome after cardiopulmonary resuscitation resulted from asphyxia]. AB - OBJECTIVE: To evaluate the reproduction of a model of post resuscitation multiple organ dysfunction syndrome (PR-MODS) after cardiac arrest (CA) in rabbit, in order to provide new methods for post-CA treatment. METHODS: Thirty-five rabbits were randomly divided into three groups, the sham group (n=5), the 7-minute asphyxia group (n=15), and the 8-minute asphyxia group (n=15). The asphyxia CA model was reproduced with tracheal occlusion. After cardiopulmonary resuscitation (CPR), the ratio of recovery of spontaneous circulation (ROSC), the mortality at different time points and the incidence of systemic inflammatory response syndrome (SIRS) were observed in two asphyxia groups. Creatine kinase isoenzyme (CK-MB), alanine aminotransferase (ALT), creatinine (Cr), glucose (Glu) and arterial partial pressure of oxygen (PaO2) levels in blood were measured in the two asphyxia groups before CPR and 12, 24 and 48 hours after ROSC. The survived rabbits were euthanized at 48 hours after ROSC, and heart, brain, lung, kidney, liver, and intestine were harvested for pathological examination using light microscope. PR-MODS after CA was defined based on the function of main organs and their pathological changes. RESULTS: (1) The incidence of ROSC was 100.0% in 7 minute asphyxia group and 86.7% in 8-minute asphyxia group respectively (P>0.05). The 6-hour mortality in 8-minute asphyxia group was significantly higher than that in 7-minute asphyxia group (46.7% vs. 6.7%, P<0.05), and the mortality of 8 minute asphyxia group at 12 - 48 hours was slightly higher compared with that of 7-minute asphyxia group (all P>0.05). (2) There was a variety of organ dysfunctions in survived rabbits after ROSC, including chemosis, respiratory distress, hypotension, abdominal distension, weakened or disappearance of bowel peristalsis and oliguria. (3) There was no SIRS or associated changes in major organ function in the sham group. SIRS was observed at 12 - 24 hours after ROSC in the two asphyxia groups. CK-MB was increased significantly at 12 hours after ROSC compared with that before asphyxia (7-minute asphyxia group: 786.88+/-211.84 U/L vs. 468.20+/-149.45 U/L, 8-minute asphyxia group: 894.88+/-248.80 U/L vs. 462.11+/-115.15 U/L, both P<0.05), ALT, Cr and Glu were elevated obviously at 24 hours after ROSC (7-minute asphyxia group ALT: 174.25+/-36.28 U/L vs. 50.27+/ 9.37 U/L, Cr: 144.25+/-41.64 MUmol/L vs. 67.71+/-16.47 MUmol/L, Glu: 11.21+/-1.14 mmol/L vs. 5.59+/-1.10 mmol/L; 8-minute asphyxia group ALT: 205.50+/-10.61 U/L vs. 51.13+/-10.37 U/L, Cr: 230.50+/-88.39 MUmol/L vs. 65.93+/-13.81 MUmol/L, Glu: 11.55+/-0.35 mmol/L vs. 6.41+/-1.23 mmol/L, all P<0.05), and PaO2 was lowered significantly at 48 hours after ROSC (7-minute asphyxia group: 5.03+/-0.73 kPa vs. 9.07+/-1.03 kPa, P<0.05). (4) There were pathological changes in major organ in the survived rabbits at 48 hours after ROSC (only 4 rabbits survived in 7 minute asphyxia group), including infiltration of inflammatory cells, partial cellular degeneration, edema, necrosis and tissue bleeding in major organs. CONCLUSION: If the SIRS and dysfunction of two or more organ were defined in animals after ROSC, the signs, biochemical markers and nonspecific pathological changes could be accepted to evaluate the PR-MODS. PMID- 23648155 TI - [Influence on kidney after resuscitation of heart arrest due to hypothermia induced by 4 centigrade normal saline in pig]. AB - OBJECTIVE: To assess the effects of hypothermia state induced by 4 centigrade normal saline (NS) on kidney after successful cardiopulmonary resuscitation (CPR) in pig. METHODS: After the induction of a 4-minute ventricular fibrillation (VF) in pigs, standard CPR was performed, and then the surviving pigs were divided into two groups: hypothermia group (n=5) with 4 centigrade NS continuous infusion at the speed of 1.33 ml*kg(-1)*min(-1) for 22 minutes, and then the speed was slowed down to 10 ml*kg(-1)*min(-1) and maintaining for 4 hours; the normal temperature group (n=5) with infusion of NS of normal temperature with the same speed as that of the hypothermia group. The hemodynamic parameters and oxygen metabolism were monitored before CA and also at different time points after recovery of spontaneous circulation (ROSC). Blood samples were collected to determine the serum urea nitrogen (BUN) and creatinine (Cr). The animals were sacrificed, and the kidneys were collected to determine the ATPase activity, as well as the histological changes with both light and electron microscopy at 24 hours after ROSC. RESULTS: Continuous infusion of 4 centigrade NS could lower the central temperature by no more than 1.5 centigrade, with a little lowering of cardiac output, without obvious changes in heart rate, mean arterial pressure and coronary perfusion pressure, but the oxygen extraction rate was decreased compared with that of the normal temperature group. Serum BUN and Cr at 2 hours and 4 hours of ROSC in the normal temperature group were higher than those before CA (BUN: 3.80+/-0.79 mmol/L, 4.12+/-0.85 mmol/L vs. 3.11+/-0.48 mmol/L; Cr: 94.43+/-18.25 MUmol/L, 94.15+/-14.03 MUmol/L vs. 79.70+/-16.03 MUmol/L, all P<0.05), and the levels in hypothermia group showed no significant changes compared with those of normal temperature group. The activities of renal Na (+) K(+)-ATPase and Ca(2+)-ATPase at 24 hours after ROSC in the hypothermia group were lower than those in the normal temperature group, but without significant difference (1.278+/-0.664 MUmol*mg(-1)*h(-1) vs. 3.190+/-0.789 MUmol*mg(-1)*h( 1), 1.727+/-0.772 MUmol*mg(-1)*h(-1) vs. 2.630+/-0.816 MUmol*mg(-1)*h(-1), both P>0.05). Compared with the normal temperature group, there were less cellular edema, necrosis and inflammatory cells infiltration in the hypothermia group, and the mitochondria appeared normal. CONCLUSION: 4 centigrade NS continuous infusion after CPR could quickly create a hypothermia state, and the hemodynamics and oxygen metabolism were maintained, thus protecting the kidney. PMID- 23648156 TI - [The effects of CDP-Choline on the improvement of the successful rate of cardiopulmonary resuscitation and post-resuscitation cardiac function]. AB - OBJECTIVE: To investigate the effects of CDP-Choline on the improvement of recovery of spontaneous circulation (ROSC) and protection against myocardial injury in cardiopulmonary resuscitation (CPR). METHODS: Sprague-Dawley (SD) rats were randomized into four groups: control group (n=5, no asphyxia), model group (n=10), adrenaline group (n=10) and CDP-Choline group (n=10). Cardiac arrest (CA) was induced by asphyxia, and then CPR was initiated. Drugs were administered at 5 minutes before CPR and at the initiation of CPR. Equal amount of normal saline was given in the control group and the model group. The hemodynamic parameters were monitored during CPR and after ROSC. After 2 hours, the myocardial tissue of the rats was harvested to assess the degree of ischemia/reperfusion (I/R) injury by measuring ATPase activity, superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. RESULTS: Compared with the model group, the rate of ROSC was significantly elevated (90%, 80% vs. 20%, both P<0.01) in the CDP Choline group and the adrenaline group, the time of achieving ROSC was shorter (53+/-10 s, 55+/-9 s vs. 95+/-7 s, both P<0.01), and the heart rate (HR) and mean arterial pressure (MAP) at 2 hours after CPR were higher (HR: 222.78+/-41.55 bpm, 167.75+/-11.76 bpm vs. 131.50+/-0.70 bpm; MAP: 36.53+/-8.69 mm Hg, 39.30+/-6.45 mm Hg vs. 30.19+/-5.15 mm Hg, all P<0.01). The cardiac function [the maximal rate of left ventricular pressure increase/decline (+/-dp/dt max)] in the CDP-Choline group was gradually stabilized and significantly higher than that in the model and the adrenaline groups. The cardiac function in the adrenaline group was higher than that of the model group, but it was in a tendency of lowering. Compared with the model group and the adrenaline group, the reduction of Na(+) K(+)-ATPase and SOD activity were significantly increased in the CDP-Choline group (Na(+)-K(+)-ATPase: 7.35+/-0.20 MUmol*mg(-1)*h(-1) vs. 5.11+/-0.69 MUmol*mg(-1)*h(-1), 4.70+/-0.41 MUmol*mg(-1)*h(-1); SOD activity: 320.65+/-47.25 U/mg vs. 225.79+/-24.64 U/mg, 253.67+/-12.00 U/mg, all P<0.01), and myocardial MDA content in the CDP-Choline group was significantly lower than that in the model group and the adrenaline group (8.19+/-1.64 mmol/mg vs. 16.59+/-1.27 mmol/mg, 14.65+/-0.93 mmol/mg, both P<0.01) . There was no significant difference in the measured parameters between the CDP-Choline group and the control group, and also between the model group and the adrenaline group. CONCLUSION: CDP Choline has the effect on improvement of the successful rate of CPR, and it shows an obvious myocardial protection against I/R compared with adrenaline. PMID- 23648157 TI - [The influence of hypertensive perfusion on ultrastructure of gastrointestinal tissue and enzymology of pigs after cardiopulmonary resuscitation]. AB - OBJECTIVE: To study ultrastructure of gastrointestinal tissue and enzymology in pigs after cardiopulmonary resuscitation (CPR) in conditions of hypertensive perfusion. METHODS: Sixteen experimental pigs were induced ventricular fibrillation (VF) by direct current shock. CPR was conducted 4 minutes after VF, and 10 pigs were successfully resuscitated. These 10 pigs were divided into control group (n=5) and hypertensive perfusion group (n=5) through random number table method. Norepinephrine was administered to maintain the mean arterial pressure (MAP) at 130% of the baseline in the hypertensive perfusion group. Serum diamine oxidase (DAO) and gastrointestinal ATPase level were determined, and gastrointestinal mucosa damages were examined with light microscope, and mitochondria injury was observed by electric microscope 24 hours after recovery of spontaneous circulation (ROSC). RESULTS: The serum DAO level showed a significant increase at 2 hours and 4 hours after ROSC in hypertensive perfusion group and control group compared with baseline (hypertensive perfusion group: 15.66+/-2.24 U, 15.76+/-0.95 U vs. 8.38+/-0.70 U, control group: 14.87+/-1.34 U, 13.85+/-0.52 U vs. 9.92+/-0.78 U, all P<0.05), but when the individual value was compared between two groups, no significant difference was found. The Na(+)-K(+) ATPase and Ca(2+)-ATPase of gastric tissue showed significant increase in the hypertensive perfusion group compared with the control group at 24 hours after ROSC (Na(+)-K(+)-ATPase: 6.07+/-1.49 MUmol*mg(-1)*h(-1) vs. 2.89+/-1.48 MUmol*mg( 1)*h(-1), Ca(2+)-ATPase: 7.67+/-1.86 MUmol*mg(-1)*h(-1) vs. 3.07+/-1.50 MUmol*mg( 1)*h(-1), both P<0.05). There was no significant difference in ATPase activity of intestinal tissue between the two groups. Gastrointestinal mucosa damages and mitochondrial injury in the hypertensive perfusion group were less obviously than in the control group. CONCLUSIONS: Gastrointestinal function injury, abnormal energy metabolism, increased serum DAO levels, destruction of intestinal microvilli were found after CPR. Hypertensive perfusion could improve cell energy metabolism, reduce the mucosal injury, and protect the digestive tract from injury due to CPR. PMID- 23648159 TI - [The evaluation of cerebral function by diffusion weighted imaging after norepinephrine-induced hypertensive perfusion therapy in pig model of cardiac arrest]. AB - OBJECTIVE: To evaluate the changes in cerebral function of pigs with cardiac arrest (CA) after recovery of spontaneous circulation (ROSC) after hypertension perfusion therapy induced by norepinephrine (NE). METHODS: Ventricular fibrillation (VF) was induced by electrical stimulation, and standard cardiopulmonary resuscitation (CPR) was performed after VF for 4 minutes. The pigs with successful ROSC were randomly divided into two group, each n=5. The pigs in the hypertensive reperfusion group were given with NE immediately to maintain the mean arterial pressure (MAP) at 130% before VF for 4 hours; MAP of the pigs in normal reperfusion group was maintained for 4 hours as baseline. The changes in hemodynamics were observed for 4 hours in both groups. Cerebral cortex was scanned with diffusion weighted imaging (DWI) before VF and 1 hour and 3 hours after ROSC, and the dynamic changes in brain functional imaging were observed. Twenty-four hours after ROSC, brain biopsy were collected and examined after hematoxylin and eosin staining (HE). RESULTS: Compared with the normal reperfusion group, heart rate (HR), MAP, cardiac output (CO) and coronary perfusion pressure (CPP) in the hypertensive reperfusion group showed a tendency to increase (ROSC 30 minutes HR: 167+/-8 bpm vs. 140+/-15 bpm, ROSC 1 hour MAP: 131+/-9 mm Hg vs. 108+/-10 mm Hg, ROSC 1 hour CO: 4.9+/-0.1 L/min vs. 3.4+/-0.5 L/min, ROSC 2 hours CPP: 118+/-12 mm Hg vs. 88+/-1 mm Hg, P<0.05 or P<0.01). There was no obvious abnormality as shown by DWI before and after resuscitation, and the apparent diffusion coefficient (ADC) showed a tendency to decrease after resuscitation in both groups. The ADC in the normal reperfusion group was decreased more than that in the hypertensive reperfusion. Pathological study showed that the protective effect of the hypertensive reperfusion on brain tissue was better than that of the normal reperfusion group. CONCLUSION: Hypertensive reperfusion can produce hemodynamic changes, and an increase in cerebral blood flow, thus it produces a protective effect on brain to promote the recovery of neurological function in pigs with CA after resuscitation. PMID- 23648158 TI - [Protective effect of anisodamine against myocardial cell apoptosis through mitochondria impairment in cardiac arrest in pigs]. AB - OBJECTIVE: To investigate the protective effect of anisodamine on myocardial mitochondrial damage in cardiac arrest (CA) in pigs. METHODS: Twenty-three male pigs were randomly divided into three groups, epinephrine group (n=9), anisodamine group (n=9) and control group (n=5). CA following ventricular fibrillation (VF) was induced by alternating current. The blood samples were collected before CA, 8 minutes after CA and instantly after recovery of spontaneous circulation (ROSC), and 30 minutes and 24 hours later. Hearts were obtained at 24 hours after ROSC. The changes in Cytochrome C (Cyt C) and caspase 3 in plasma and myocardium were analyzed by enzyme-linked immunosorbent assay (ELISA). The myocardial specimens were observed by transmission electron microscopy for ultrastructural changes, and apoptosis was assessed with Hoechst 33258 staining. RESULTS: The ROSC rate of the anisodamine group was elevated by 22.22% compared with the epinephrine group (77.78% vs. 55.56%, P>0.05). All animals with resumption of ROSC survived up to 24 hours. The plasma contents of Cyt C and caspase-3 in the epinephrine group and the anisodamine group gradually increased after ROSC, and were significantly higher than those in the control group. But the plasma Cyt C level in the anisodamine group was lower than that in the epinephrine group at 30 minutes and 24 hours after ROSC (48.68+/-19.50 nmol/L vs. 77.51+/-29.87 nmol/L, 48.98+/-20.26 nmol/L vs. 82.11+/-25.09 nmol/L, both P<0.05). There was no significant difference in protein contents of both Cyt C and caspase-3 in plasma and myocardium between two resuscitate groups. Both epinephrine and anisodamine could mitigate cardiac mitochondrial damage after CA, but the anisodamine showed better effect. The myocardium apoptosis ratio in the anisodamine group was lower than that of the epinephrine group [(0.15+/-0.04)% vs. (0.37+/-0.04)%, P<0.01]. CONCLUSION: By decreasing the protein content of Cyt C, and reducing the extent of damage to myocardial mitochondria, anisodamine can protect the myocardial ultrastructure, and restrain the mitochondria-induced cell apoptosis after resuscitation. PMID- 23648160 TI - [The impact of interrupted abdominal aorta compression on resuscitation effects of cardiac arrest rabbit]. AB - OBJECTIVE: To determine whether interrupted abdominal aorta compression cardiopulmonary resuscitation (IAAC-CPR), as a new cardiopulmonary resuscitation (CPR) method, can improve resuscitation effects on rabbits with cardiac arrest (CA). METHODS: Twenty-eight New Zealand rabbits were randomly divided into two groups in equal number (n=14), and they were resuscitated either by standard CPR (STD-CPR, external chest compression) or by IAAC-CPR (abdominal aorta compression at intermission of external chest compression). CA model was reproduced by injection of iced-potassium chloride, and it was maintained for 3 minutes before resuscitation. Electrocardiogram (ECG), hemodynamic indexes were monitored continuously. Aortic systolic pressure and right atrial pressure at baseline and during resuscitation were recorded. Mean arterial pressure (MAP), coronary perfusion pressure (CPP) and recovery of spontaneous circulation (ROSC) indexes were compared between two groups. RESULTS: Compared with STD-CPR group, MAP within 2 minutes of resuscitation (without drugs intervention) in the IAAC-CPR group was significantly increased (30 s: 46.0+/-12.6 mm Hg vs. 30.0+/-12.2 mm Hg, 60 s: 57.0+/-15.6 mm Hg vs. 31.9+/-9.7 mm Hg, 90 s: 61.9+/-14.4 mm Hg vs. 36.0+/ 9.8 mm Hg, 120 s: 63.1+/-12.6 mm Hg vs. 37.8+/-11.1 mm Hg, all P<0.05), and CPP was also significantly increased (30 s: 29.9+/-17.4 mm Hg vs. 14.1+/-11.0 mm Hg, 60 s: 43.1+/-22.4 mm Hg vs. 14.3+/-9.8 mm Hg, 90 s: 46.7+/-20.1 mm Hg vs. 15.9+/ 7.7 mm Hg, 120 s: 50.5+/-21.0 mm Hg vs. 17.3+/-9.9 mm Hg, all P<0.05), the time of ROSC was earlier (212.1+/-43.4 s vs. 307.3+/-51.2 s, P<0.05), and successful resuscitation rate was significantly higher (85.7% vs. 42.8%, P<0.05). However, there were no statistical differences in ROSC rate and the survivor rate at 24 hours and 48 hours between the two groups, though they were increased. No abdominal organs injury was found in all animals by postmortem study. CONCLUSION: Abdominal aorta compression in the intermittent period of chest compression (IAAC CPR) increases MAP, CPP and the successful rate of resuscitation, thus improves the outcome. PMID- 23648161 TI - [The effect of ventricular fibrillation time and NYHA classification on defibrillation in intensive care unit patients]. AB - OBJECTIVE: To investigate whether the sequence of defibrillation (DF) and cardiopulmonary resuscitation (CPR), duration of ventricular fibrillation (VF), and New York Heart Association (NYHA) classification would affect DF result in intensive care unit. METHODS: Ninety-three cases needing instantaneous DF were divided into three groups according to VF lasting time: <4 minute group (n=53), 4 - 8 minute group (n=24), >8 minute group (n=16), and each group was randomly divided into two sub-groups according to time sequence: the prior DF group or the prior CPR for five cycles followed by DF group (prior CPR group). The effect of VF time, the sequence of DF and CPR, and NYHA classification on success rate of DF were observed. RESULTS: With prolonging VF time, success rate of DF obviously lowered [success rate of DF for VF<4 minute, 4 - 8 minute, and >8 minute groups were 83.0% (44/53), 62.5% (15/24), and 25.0% (4/16), respectively, all P<0.01]. When VF time lasted less than 4 minutes, success rate of DF in the prior DF group was obviously higher than that in the prior CPR group [88.9% (24/27) vs. 76.9% (20/26), P<0.05]. When VF time lasted for 4 - 8 minutes, the prior DF group had slightly higher success rate of DF compared with the prior CPR group [66.7% (8/12) vs. 58.3% (7/12), P=0.09]. When VF time lasted longer than 8 minutes, the success rate of DF in the prior CPR group was obviously higher than that in the prior DF group [37.5% (3/8) vs. 12.5% (1/8), P<0.01]. The success rate of DF was lowered in higher NYHA classification [success rate of DF for NYHA classification I-IV was 96.4% (27/28), 80.0% (20/25), 47.8% (11/23), 29.4% (5/17), respectively, P<0.05 or P<0.01]. CONCLUSIONS: VF lasting time and NYHA classification are key factors to success rate of DF, and the choice of sequence of DF and CPR depends on the lasting time of VF. For cases with the high NYHA classification, we should make some judgement beforehand and prepare some preventive measures. PMID- 23648162 TI - [Study of setting of ventilator volume tidal and airway pressure alarm threshold with continuous extra-sternum heart compression in cardiopulmonary resuscitation]. AB - OBJECTIVE: To investigate the setting of ventilator volume tidal (VT) and airway pressure alarm threshold during cardiopulmonary resuscitation (CPR) by continuous extra-sternum heart compression. METHODS: Forty cases with respiration and cardiac arrest in the department of critical care medicine were randomly divided into low VT ventilation group and conventional VT group. Both groups were given the volume control mode. In the low VT ventilation group, VT was set on 6 - 7 ml/kg, and high pressure alarm threshold was adjusted to 60 cm H2O by the conventional 40 cm H2O during CPR. In the conventional VT group, VT and high pressure alarm threshold were set at 8 - 12 ml/kg and 40 cm H2O, respectively. Real-time actual VT, peak inspiratory pressure (PIP), and arterial blood gas test, blood lactic acid at 10 minutes and 30 minutes after CPR were observed. RESULTS: At 10 minutes after CPR, in the low VT ventilation group, arterial blood pH, arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), HCO3(-), arterial oxygen saturation (SaO2) and blood lactic acid were better as compared with those in the conventional VT ventilation group (pH: 7.21+/-0.09 vs. 7.13+/-0.07, PaO2: 45.35+/-5.92 mm Hg vs. 40.70+/-4.70 mm Hg, PaCO2: 57.10+/-7.59 mm Hg vs. 61.60+/-5.47 mm Hg, HCO3(-): 18.50+/-3.50 mmol/L vs. 14.75+/-2.65 mmol/L, SaO2: 0.796+/-0.069 vs. 0.699+/-0.066, blood lactic acid: 7.07+/-1.60 mmol/L vs. 8.13+/-1.56 mmol/L, all P<0.05). The success rate of resuscitation in the low VT ventilation group was higher than that of the conventional VT ventilation group (45% vs. 15%, P<0.05), and PIP (cm H2O) of low VT ventilation group was lower than that of the conventional VT group (37.25+/ 7.99 cm H2O vs. 42.70+/-7.40 cm H2O, P<0.05). In all the patients in both groups barotrauma did not occur. CONCLUSION: The strategy of low ventilator VT (6 - 7 ml/kg) with appropriate elevation of airway pressure alarm threshold was better than that of conventional ventilation setting, with no increase in incidence of barotraumas during CPR. PMID- 23648163 TI - [Effect of ulinastatin on improving inflammatory response and myocardial and lung tissue injury after cardiopulmonary resuscitation in pigs]. AB - OBJECTIVE: To evaluate the effects of ulinastatin (UTI) on improving inflammatory response and myocardial and lung tissue injury after cardiopulmonary resuscitation (CPR) in porcine model. METHODS: Ventricular fibrillation (VF) was induced in 20 female pigs by programmed stimulation method. CPR was begun 8 minutes after VF. Pigs with recovery of spontaneous circulation (ROSC) were randomly divided into two groups: group UTI, UTI was given immediately after resuscitation, with 100 kU dissolved in 5 ml of normal saline by slow intravenous injection every 3 hours, up to 24 hours after resuscitation. In control group, 5 ml of normal saline was given with same delivery time and frequency as that in the UTI group. Before VF, immediately after ROSC, 3 hours, 12 hours and 24 hours after ROSC, samples of venous blood were collected for examination of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), using the enzyme-linked immunospecific assay (ELISA) method. The pigs were sacrificed at 24 hours after ROSC for myocardium and lung pathological and ultrastructural examinations. RESULTS: Among a total of 20 domestic pigs, 15 pigs were successfully resuscitated after 8-minute VF. Eight pigs in UTI group and 7 pigs in control group survived for 24 hours. Pro-inflammatory factors of the both groups were increased gradually after ROSC. Levels of TNF-alpha, IL-1beta, ICAM-1 and VCAM-1 were not significant different between UTI and control groups before VF and immediately after ROSC. But TNF-alpha and IL-1beta levels were significantly lower in the UTI group than those of the control group beginning from 3 hours after ROSC (TNF-alpha: 28.79+/-9.49 ng/L vs. 44.01+/-17.01 ng/L, IL 1beta: 153.50+/-67.47 ng/L vs. 252.09+/-80.41 ng/L, both P<0.05); ICAM-1 and VCAM 1 levels were significantly lower in the UTI group than those of the control group from 12 hours after ROSC (ICAM-1: 11.05+/-5.11 MUg/L vs. 17.09+/-5.69 MUg/L, VCAM-1: 11.17+/-4.75 MUg/L vs. 16.62+/-4.63 MUg/L, both P<0.05). The myocardium and lung injuries at 24 hours after ROSC were significantly milder in UTI group than that of the control group. CONCLUSION: UTI can significantly reduce the pro-inflammatory reaction and the extent of myocardial and lung tissue injury after resuscitation. PMID- 23648164 TI - [Cause analysis of prolonged intensive care unit stay after coronary artery bypass grafting]. AB - OBJECTIVE: To investigate the risk factors of prolonged intensive care unit (ICU) stay following coronary artery bypass grafting (CABG), and to provide a reference for effective control measure. METHODS: A retrospective study was conducted. All data of patients with post CABG admitted to the Department of Critical Care Medicine of the First People's Hospital in Yichang from January 2008 to January 2012 were retrospectively analyzed. The CABG patients staying in ICU more than 3 days served as observation group, and the patients staying in ICU less than 3 days were the control group. Potential risk factors in both groups were compared, and multivariable non-condition logistic regressions analysis was adopted to determine the independent risk factors which resulted in prolonged stay in ICU after CABG. RESULTS: Sixty-eight patients underwent CABG were analyzed retrospectively. Twenty-four cases (35.29%) had prolonged stay in ICU after CABG. Univariate analysis showed that the risk factors of prolonged stay in ICU after CABG were low cardiac output, arrhythmia, postoperative respiratory failure, postoperative acute renal failure, emergency operation, and left atrial inner diameter. The multivariable logistic regression analysis showed that the independent risk factor of prolonged stay in ICU after CABG was the postoperative respiratory failure [odds ratio (OR)=6.856, 95% confidence interval (95%CI) 1.322 - 35.559, P<0.05]. CONCLUSIONS: The independent risk factor of prolonged stay in ICU after CABG was postoperative respiratory failure. By monitoring the risk factors, duration of stay in ICU after CABG can be decreased. PMID- 23648165 TI - [The tendency of changes in blood oxygen saturation and arrhythmia: a clinical report of 500 cases]. AB - OBJECTIVE: To observe the correlation of duration of hypoxia and degree of arrhythmia in patients with and without past history of cardiac disease, in order to provide a warning value supplied by pulse oxygen saturation (SpO2) monitoring for clinical surveillance. METHODS: A prospective study was conducted. Patients with arrhythmia induced solely by hypoxia were included, and they were grouped into cardiac diseases group (n=487) and non-cardiac diseases group (n=13) according to whether or not they had cardiac diseases. Both groups were undergoing mechanical ventilation, and the real time monitoring of electrocardiogram (ECG) and the SpO2 were monitored. The types of arrhythmia and duration and severity of hypoxia were observed. The method of logistic regression was conducted to find the affecting factors of arrhythmia. RESULTS: There were significant differences in SpO2 (0.82+/-0.12 vs. 0.50+/-0.10) and duration of arrhythmia (2.55+/-1.02 minutes vs. 17.13+/-1.45 minutes) between the cardiac disease group and the non-cardiac disease group (both P<0.01). The multifactor logistic regression analysis on the affecting factors in patients with cardiac arrhythmia indicated that cough during sputum suction [odds ratio (OR)=3.078, 95% confidence interval (95%CI) 1.756 - 6.235], long duration of tracheal intubation (OR=0.267, 95%CI 0.122 - 0.573), over anesthesia (OR=2.541, 95%CI 1.039 - 6.615), inadequate tidal volume (OR=4.360, 95%CI 2.187 - 9.443), low respiratory frequency (OR=0.297, 95%CI 0.069 - 1.113) were all risk factors of arrhythmia (P<0.05 or P<0.01). CONCLUSIONS: The hypoxemia (lowering of SpO2) is the independent risk factor leading to arrhythmia. Healthy heart can tolerate hypoxia better, and the SpO2 warning value is <=0.60. Compared with the non-cardiac disease group, patients in cardiac disease group has significantly lower toleration ability against hypoxia, and its SpO2 warning value is lower than 0.95. PMID- 23648166 TI - [The use of Charlson weighted index of comorbidities scoring system to evaluate the impact of original diseases for prognosis in intensive care unit patients]. AB - OBJECTIVE: To investigate the efficiency of original diseases by the Charlson weighted index of comorbidities (WIC) in predicting 28-day mortality in patients with critical illnesses in intensive care unit (ICU). METHODS: A single-center retrospective analysis of clinical data of 406 patients admitted between January 2009 and October 2011 to Shanghai Changzheng Hospital was conducted. The patients were divided into non-survivor group (n=104) and survivor group (n=302) according to 28-day outcome. The data were recorded, and the WIC and the acute physiology and chronic health evaluation II (APACHEII) score were calculated. Logistic regression analysis was used to determine the independent predictors for 28-day mortality. RESULTS: Compared with survivors, the average age, WIC and APACHEII scores, severe sepsis, pneumonia, and multiple injuries were higher in non survivors. The univariate analysis showed that age, the WIC score, APACHEII score, pneumonia, multiple injuries and severe sepsis were related with patients' 28-day prognosis. The multivariate logistic regression revealed that 28-day prognosis depended significantly on WIC score [odds ratio (OR)=1.538, 95% confidence interval (95%CI) 1.265 - 1.869, P=0.000], APACHEII score (OR=1.193, 95%CI 1.137 - 1.252, P=0.000), pneumonia (OR=0.546, 95%CI 0.304 - 0.982, P=0.043), and severe sepsis (OR=0.178, 95%CI 0.098 - 0.323, P=0.000). The area under the receiver operating characteristics curve (ROC curve) in predicting mortality was 0.657 (0.592 - 0.722) for the WIC score, 0.790 (0.739 - 0.841) for APACHEII score and 0.821 (0.772 - 0.869) for their combination. CONCLUSION: The WIC scoring system can be a good evaluation method for 28-day prognosis in ICU patients. PMID- 23648167 TI - [Effects of anisodamine on end-tidal pressure of carbon dioxide and cardiopulmonary resuscitation result in swine with cardiac arrest]. PMID- 23648168 TI - [An investigation into the recognition of cardiopulmonary resuscitation of students in a university]. PMID- 23648169 TI - [Mild hypothermia after cardiopulmonary resuscitation]. PMID- 23648170 TI - Tankyrases as drug targets. AB - Tankyrase 1 and tankyrase 2 are poly(ADP-ribosyl)ases that are distinguishable from other members of the enzyme family by the structural features of the catalytic domain, and the presence of a sterile alpha-motif multimerization domain and an ankyrin repeat protein-interaction domain. Tankyrases are implicated in a multitude of cellular functions, including telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, Wnt beta-catenin signaling, and viral replication. In these processes, tankyrases interact with target proteins, catalyze poly(ADP-ribosyl)ation, and regulate protein interactions and stability. The proposed roles of tankyrases in disease relevant cellular processes have made them attractive drug targets. Recently, several inhibitors have been identified. The selectivity and potency of these small molecules can be rationalized by how they fit within the NAD(+)-binding groove of the catalytic domain. Some molecules bind to the nicotinamide subsite, such as generic diphtheria toxin-like ADP-ribosyltransferase inhibitors, whereas others bind to a distinct adenosine subsite that diverges from other diphtheria toxin-like ADP-ribosyltransferases and confers specificity. A highly potent dual site inhibitor is also available. Within the last few years, tankyrase inhibitors have proved to be useful chemical probes and potential lead compounds, especially for specific cancers. PMID- 23648171 TI - An adaptive neuromorphic model of ocular dominance map using floating gate 'synapse'. AB - A novel analogue CMOS design of a cortical cell, that computes weighted sum of inputs, is presented. The cell's feedback regime exploits the adaptation dynamics of floating gate pFET 'synapse' to perform competitive learning amongst input weights as time-staggered winner take all. A learning rate parameter regulates adaptation time and a bias enforces resource limitation by restricting the number of input branches and winners in a competition. When learning ends, the cell's response favours one input pattern over others to exhibit feature selectivity. Embedded in a 2-D RC grid, these feature selective cells are capable of performing a symmetry breaking pattern formation, observed in some reaction diffusion models of cortical feature map formation, e.g. ocular dominance. Close similarity with biological networks in terms of adaptability and long term memory indicates that the cell's design is ideally suited for analogue VLSI implementation of Self-Organizing Feature Map (SOFM) models of cortical feature maps. PMID- 23648172 TI - Ascorbate enhances elastin synthesis in 3D tissue-engineered pulmonary fibroblasts constructs. AB - Extracellular matrix remodeling is a continuous process that is critical to maintaining tissue homeostasis, and alterations in this process have been implicated in chronic diseases such as atherosclerosis, lung fibrosis, and emphysema. Collagen and elastin are subject to ascorbate-dependent hydroxylation. While this post-translational modification in collagen is critical for function, the role of hydroxylation of elastin is not well understood. A number of studies have indicated that ascorbate leads to reduced elastin synthesis. However, these studies were limited to analysis of cells grown under traditional 2D tissue culture conditions. To investigate this process we evaluated elastin and collagen synthesis in primary rat neonatal pulmonary fibroblasts in response to ascorbate treatment in traditional 2D culture and within 3D cross-linked gelatin matrices (Gelfoam). We observed little change in elastin or collagen biosynthesis in standard 2D cultures treated with ascorbate, yet observed a dramatic increase in elastin protein and mRNA levels in response to ascorbate in 3D cell-Gelfoam constructs. These data suggest that the cell-ECM architecture dictates pulmonary cell response to ascorbate, and that approaches aimed toward stimulating ECM repair or engineering functional cell-derived matrices should consider all aspects of the cellular environment. PMID- 23648174 TI - A comparison in independent nurse prescribing and patient group directions by nurse practitioners in the emergency department: a cross sectional review. AB - AIM: To explore nurse prescribing in an emergency department using patient group directions versus independent nurse prescribing. BACKGROUND: Patient group directions allow restricted access to medication in unselected patients using pre set criteria. Independent nurse prescribing is a flexible method of medication provision. Limited data exists on the application of either method in clinical practice. METHODS: Exploration of patient group directions and independent nurse prescribing application in an emergency department using 617 nurse practitioners' clinical notes; 235 and 382 respectively. Patient attendances from 01/07/2009 to 30/06/2010 were randomly sampled. Prescribing frequency; range of medications and diagnoses; independent episode completion and prescribing safety was explored. RESULTS: Statistical difference exists in prescribing frequency between the independent nurse prescribers (51.6%, n = 197) and patient group directions (32.3%, n = 76). Appropriate medication given by 99.7% (n = 381) of independent nurse prescribers, with 1 contraindicated drug provided. The limitations of patient group directions was highlighted in 11.8% (n = 9) of cases, however all drugs given were appropriate for the diagnosis. No statistical difference in independent episode completion. CONCLUSIONS: Nurses provide appropriate medication in an emergency department. Patients being managed by nurse prescribers were more likely to receive medication. Further investigation is required to justify this. PMID- 23648173 TI - Evaluation of the effects of electrical stimulation on cartilage repair in adult male rats. AB - This study describes the organization of mature hyaline xiphoid cartilage during repair in animals submitted to electrical current stimulation. Twenty male Wistar rats, 90 days old, were divided into a control group (CG) and a treated group (TG). A cylindrical full-thickness cartilage defects were created with a 3-mm punch in anesthetized animals. After 24h, TG received daily applications of a continuous electrical current (1Hz/20MUA) for 5min. The animals were sacrificed after 7, 21 and 35 days for structural analysis. In CG, the repair tissue presented fibrous characteristics, with fibroblastic cells being infiltrated and permeated by blood vessels. Basophilic foci of cartilage tissue were observed on day 35. In TG, the repair tissue also presented fibrous characteristics, but a larger number of thick collagen fibers were seen on day 21. A large number of cartilaginous nests were observed on day 35. Cell numbers were significantly higher in TG. Calcification points were detected in TG on day 35. There was no difference in elastic fibers between groups. Ultrastructural analysis revealed the presence of chondrocyte-like cells in CG at all time points, but only on days 21 and 35 in TG. The amount of cuprolinic blue-stained proteoglycans was higher in TG on day 35. Microcurrent stimulation accelerates the repair process in non articular hyaline cartilage. PMID- 23648176 TI - Ocular manifestations and visual functions in patients with Fanconi anaemia. AB - PURPOSE: Fanconi anaemia (FA) is a multisystemic disorder with ocular implications. This study aims to describe visual function, ocular characteristics and visual processing skills in patients with FA after haematopoietic stem cell transplantation. METHODS: Ten patients with FA, ages 8-17 years, underwent ophthalmological examinations, corneal, periocular and fundus photography, visual evoked potentials (VEPs), visual fields and ocular motor and visual processing information tests. RESULTS: Best-corrected decimal visual acuity was >=0.65 in all 20 eyes. Microcornea was present in 18 of 18 eyes, short axial lengths in six of six eyes, steep corneal curvatures in four of six eyes, ptosis in 14 of 16 eyes, short palpebral fissures in 15 of 16 eyes and hypotelorism in three of seven patients. Optic disc areas were smaller in patients with FA compared to controls (p = 0.0003 right, p = 0.0003 left eye). Visual fields were abnormal in 4 of 18 eyes, while VEP was abnormal in 1 of 20 eyes. Eight patients had ocular motor dysfunction, while nine of 10 patients showed delay in visual processing skills. CONCLUSION: Patients with FA can present with microcornea, microphthalmia, ptosis, steep corneal curvatures, small optic discs, ptosis and delay in visual processing skills. Detailed ophthalmological and visual processing skills assessments and developmental investigations are important to detect impairments and facilitate appropriate support. PMID- 23648175 TI - A novel pair of inducible expression vectors for use in Methylobacterium extorquens. AB - BACKGROUND: Due to the ever increasing use of diverse microbial taxa in basic research and industrial settings, there is a growing need for genetic tools to alter the physiology of these organisms. In particular, there is a dearth of inducible expression systems available for bacteria outside commonly used gamma proteobacteria, such as Escherichia coli or Pseudomonas species. To this end, we have sought to develop a pair of inducible expression vectors for use in the alpha-proteobacterium Methylobacterium extorquens, a model methylotroph. FINDINGS: We found that the P(R) promoter from rhizobial phage 16-3 was active in M. extorquens and engineered the promoter to be inducible by either p-isopropyl benzoate (cumate) or anhydrotetracycline. These hybrid promoters, P(R/cmtO) and P(R/tetO), were found to have high levels of expression in M. extorquens with a regulatory range of 10-fold and 30-fold, respectively. Compared to an existing cumate-inducible (10-fold range), high-level expression system for M. extorquens, P(R/cmtO) and P(R/tetO) have 33% of the maximal activity but were able to repress gene expression 3 and 8-fold greater, respectively. Both promoters were observed to exhibit homogeneous, titratable activation dynamics rather than on-off, switch like behavior. The utility of these promoters was further demonstrated by complementing loss of function of ftfL--essential for growth on methanol--where we show P(R/tetO) is capable of not only fully complementing function but also producing a conditional null phenotype. These promoters have been incorporated into a broad-host-range backbone allowing for potential use in a variety of bacterial hosts. CONCLUSIONS: We have developed two novel expression systems for use in M. extorquens. The expression range of these vectors should allow for increased ability to explore cellular physiology in M. extorquens. Further, the P(R/tetO) promoter is capable of producing conditional null phenotypes, previously unattainable in M. extorquens. As both expression systems rely on the use of membrane permeable inducers, we suspect these expression vectors will be useful for ectopic gene expression in numerous proteobacteria. PMID- 23648177 TI - Have we improved use of medicines in developing and transitional countries and do we know how to? Two decades of evidence. AB - OBJECTIVE: To assess progress in improving use of medicines in developing and transitional countries by reviewing empirical evidence, 1990-2009, concerning patterns of primary care medicine use and intervention effects. METHODS: We extracted data on medicines use, study setting, methodology and interventions from published and unpublished studies on primary care medicine use. We calculated the medians of six medicines use indicators by study year, country income level, geographic region, facility ownership and prescriber type. To estimate intervention impacts, we calculated greatest positive (GES) and median effect sizes (MES) from studies meeting accepted design criteria. RESULTS: Our review comprises 900 studies conducted in 104 countries, reporting data on 1033 study groups from public (62%), and private (mostly for profit) facilities (26%), and households. The proportion of treatment according to standard treatment guidelines was 40% in public and <30% in private-for-profit sector facilities. Most indicators showed suboptimal use and little progress over time: Average number of medicines prescribed per patient increased from 2.1 to 2.8 and the percentage of patients receiving antibiotics from 45% to 54%. Of 405 (39%) studies reporting on interventions, 110 (27%) used adequate study design and were further analysed. Multicomponent interventions had larger effects than single component ones. Median GES was 40% for provider and consumer education with supervision, 17% for provider education alone and 8% for distribution of printed education materials alone. Median MES showed more modest improvements. CONCLUSIONS: Inappropriate medicine use remains a serious global problem. PMID- 23648178 TI - Quantitative insights into actin rearrangements and bacterial target site selection from Salmonella Typhimurium infection of micropatterned cells. AB - Reorganization of the host cell actin cytoskeleton is crucial during pathogen invasion. We established micropatterned cells as a standardized infection model for cell invasion to quantitatively study actin rearrangements triggered by Salmonella Typhimurium (S. Tm). Micropatterns of extracellular matrix proteins force cells to adopt a reproducible shape avoiding strong cell-to-cell variations, a major limitation in classical cell culture conditions. S. Tm induced F-actin-rich ruffles and invaded micropatterned cells similar to unconstrained cells. Yet, standardized conditions allowed fast and unbiased comparison of cellular changes triggered by the SipA and SopE bacterial effector proteins. Intensity measurements in defined regions revealed that the content of pre-existing F-actin remained unchanged during infection, suggesting that newly polymerized F-actin in bacteria-triggered ruffles originates from the G-actin pool. Analysing bacterial target sites, we found that bacteria did not show any preferences for the local actin cytoskeleton specificities. Rather, invasion was constrained to a specific 'cell height', due to flagella-mediated near-surface swimming. We found that invasion sites were similar to bacterial binding sites, indicating that S. Tm can induce a permissive invasion site wherever it binds. As micropatterned cells can be infected by many different pathogens they represent a valuable new tool for quantitative analysis of host-pathogen interactions. PMID- 23648179 TI - Retrospective analysis of clinical findings and outcome of cats with suspected rattlesnake envenomation in Southern California: 18 cases (2007-2010). AB - OBJECTIVE: To evaluate treatment and survival rates of cats with suspected rattlesnake envenomation. DESIGN: Retrospective study. SETTING: Veterinary emergency referral hospital in Southern California. ANIMALS: Client-owned animals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighteen cats were treated for suspected rattlesnake envenomation between January 2007 and August 2010. There were 3 fatalities and 15 cats survived (16% mortality rate). Two cases developed pelvic limb paresis 3-4 days post envenomation. There were no apparent adverse reactions to treatment with antivenom. CONCLUSIONS: Cats are presented infrequently for treatment of envenomation compared to dogs. Envenomation in cats should be treated according to guidelines established for people and dogs and administration of antivenom does not appear to be associated with adverse events. The mortality rate in this study was found to be 16%, which is higher than the mortality rate reported for dogs suspected of rattlesnake envenomation in a similar region (4.1%). Pelvic limb paresis may develop 3-4 days post envenomation but can resolve within 24 hours. PMID- 23648180 TI - Synthesis and preliminary evaluation steroidal antiestrogen-geldanamycin conjugates. AB - Three novel steroidal antiestrogen-geldanamycin conjugates were prepared using a convergent strategy. The antiestrogenic component utilized the 11beta-(4 functionalized-oxyphenyl) estradiol scaffold, while the geldanamycin component was derived by replacement of the 17-methoxy group with an appropriately functionalized amine. Ligation was achieved in high yield using azide alkyne cyclization reactions. Evaluation of the products against two breast cancer cell lines indicated that the conjugates retained significant antiproliferative activity. PMID- 23648181 TI - Discovery and optimization of arylsulfonyl 3-(pyridin-2-yloxy)anilines as novel GPR119 agonists. AB - We describe the discovery of a series of arylsulfonyl 3-(pyridin-2-yloxy)anilines as GPR119 agonists derived from compound 1. Replacement of the three methyl groups in 1 with metabolically stable moieties led to the identification of compound 34, a potent and efficacious GPR119 agonist with improved pharmacokinetic (PK) properties. PMID- 23648182 TI - The use of virtual screening and differential scanning fluorimetry for the rapid identification of fragments active against MEK1. AB - We report the analysis of an in-house fragment screening campaign for the oncology target MEK1. The application of virtual screening (VS) as a primary fragment screening approach, followed by biophysical validation using differential screening fluorimetry (DSF), with resultant binding mode determination by X-ray crystallography (X-ray), is presented as the most time and cost-effective combination of in silico and in vitro methods to identify fragments. We demonstrate the effectiveness of the VS-DSF workflow for the early identification of fragments to both 'jump-start' the drug discovery project and to complement biochemical screening data. PMID- 23648183 TI - Birth-death branching models. Application to African elephant populations. AB - Branching models have a long history of biological applications, particularly in population dynamics. In this work, our interest is the development of mathematical models to describe the demographic dynamics of socially structured animal populations, focusing our attention on lineages, usually matrilines, as the basic structure in the population. Significant efforts have been made to develop models based on the assumption that all individuals behave identically with respect to reproduction. However, the reproduction phase has a large random component that involves not only demographic but also environmental factors that change across range distribution of species. In the present work, we introduce new classes of birth-death branching models which take such factors into account. We assume that both, the offspring probability distribution and the death probabilities may be different in each generation, changing either predictably or unpredictably in relation to habitat features. We consider the genealogical tree generated by observation of the process until a pre-set generation. We determine the probability distributions of the random variables representing the number of dead or living individuals having at least one ancestor alive, living individuals whose ancestors are all dead, and dead individuals whose ancestors are all dead, explicitly obtaining their principal moments. Also, we derive the probability distributions corresponding to the partial and total numbers of such biological variables, obtaining in particular the distribution of the total number of matriarchs in the genealogical tree. We apply the proposed models to describe the demographic dynamics of African elephant populations living in different habitats. PMID- 23648184 TI - Synaptotagmins 1 and 2 as mediators of rapid exocytosis at nerve terminals: the dyad hypothesis. AB - The dyad model was developed to explain the extremely rapid kinetics of synaptic vesicle exocytosis. In contrast to most hypotheses which invoke interactions among synaptotagmins, SNAREs and other regulatory molecules, the dyad model features a quartet of synaptotagmins arrayed at the synaptic vesicle-plasma membrane interface. Ca(2+)-triggered movements of these synaptotagmins initiate a sequence of events culminating in the fusion of the vesicular and plasma membranes. The relative simplicity of this model and its amenability to empirical testing provide a useful template for future investigations of the molecular events underlying the exocytotic cascade. PMID- 23648185 TI - Minimal autocatalytic networks. AB - Self-sustaining autocatalytic chemical networks represent a necessary, though not sufficient condition for the emergence of early living systems. These networks have been formalised and investigated within the framework of RAF theory, which has led to a number of insights and results concerning the likelihood of such networks forming. In this paper, we extend this analysis by focussing on how small autocatalytic networks are likely to be when they first emerge. First we show that simulations are unlikely to settle this question, by establishing that the problem of finding a smallest RAF within a catalytic reaction system is NP hard. However, irreducible RAFs (irrRAFs) can be constructed in polynomial time, and we show it is possible to determine in polynomial time whether a bounded size set of these irrRAFs contain the smallest RAFs within a system. Moreover, we derive rigorous bounds on the sizes of small RAFs and use simulations to sample irrRAFs under the binary polymer model. We then apply mathematical arguments to prove a new result suggested by those simulations: at the transition catalysis level at which RAFs first form in this model, small RAFs are unlikely to be present. We also investigate further the relationship between RAFs and another formal approach to self-sustaining and closed chemical networks, namely chemical organisation theory (COT). PMID- 23648186 TI - Modelling wild-domestic interbreeding: how selection on a quantitative trait affects gene flow at a neutral locus. AB - Interbreeding between domesticated individuals and their wild conspecifics occurs in a range of species. The rate of gene flow into the wild population, estimated using genetic markers, is often smaller than the fraction of immigrants, as immigrants and their descendants generally have lower relative fitness. Here the difference between one-way migration rate and gene flow (effective migration rate) is explored using quantitative genetic simulations. We model a trait undergoing stabilizing selection in the recipient population, influenced by an infinite number of loci, each with small effect. Immigrants have suboptimal trait values, and differ in allele frequency at an unlinked neutral marker locus. We derive an analytical approximation for the effective migration rate, and show that in the limiting case of low migration rates, the ratio between effective and actual migration rate approximately equals the ratio between mean fitness of immigrants and in the admixed population. This ignores indirect selection on the marker locus within the admixed population due to covariance with the trait value, which may be substantial when the genetic difference between the populations is large. For higher migration rates, the gene flow/migration ratio rises with increasing migration rate, inflating the rate of gene flow. PMID- 23648187 TI - On the evolution of intergenerational division of labor, menopause and transfers among adults and offspring. AB - We explain how upward transfers from adult children to their elderly parents might evolve as an interrelated feature of a deepening intergenerational division of labor. Humans have a particularly long period of juvenile dependence requiring both food and care time provided mainly by younger and older adults. We suggest that the division of labor evolves to exploit comparative advantage between young and old adults in fertility, childcare and foraging. Eventually the evolving division of labor reaches a limit when the grandmother's fertility reaches zero (menopause). Continuing, it may hit another limit when the grandmother's foraging time has been reduced to her subsistence needs. Further specialization can occur only with food transfers to the grandmother, enabling her to reduce her foraging time to concentrate on additional childcare. We prove that this outcome can arise only after menopause has evolved. We describe the conditions necessary for both group selection (comparative steady state reproductive fitness) and individual selection (successful invasion by a mutation), and interpret these conditions in terms of comparative advantages. PMID- 23648188 TI - Direct plant-predator interactions as determinants of food chain dynamics. AB - Predator-prey interactions play out in a physical matrix defined at least to some extent by the quantity and architecture of plants. Ambush predators for instance might more effectively encounter and capture prey in thick vegetation than in thin, open vegetation with good visibility. Yet these vegetation attributes are themselves potentially influenced by the intensity of herbivory, which in turn reflects the magnitude of predation. This intertwining of trophic interactions and basal biomass leads to a largely unexplored feedback in food chain dynamics. In this paper, we examine a number of extensions of standard predator-prey and food chain models that incorporate this kind of "bottom-up" influence on trophic interactions. Even simple models reveal a range of interesting behaviors. For instance, vegetation-dependent attack rates can generate alternative stable states, in one of which the predator effectively limits herbivores to low numbers, freeing plants of substantial regulation by herbivory, and in the other of which the predator is either absent, or present as an ineffective top trophic level. This can occur both in models in which the top predator is a specialist, completely dependent upon the herbivore, and in models in which the top predator is a generalist, inflicting mortality upon the focal prey species, but itself sustained in numbers by alternative prey. Another possibility is that the feedback between basal biomass and attack rates destabilizes the trophic interactions, leading to sustained oscillations in food chains. Comparable effects can arise if handling times depend upon vegetation biomass. These models illustrate the rich complexity of effects that can arise even in relatively simple community models, once one takes into account the range of potential feedback effects that are potentially present. PMID- 23648189 TI - Stromal cell derived factor-1alpha protects stem cell derived insulin-producing cells from glucotoxicity under high glucose conditions in-vitro and ameliorates drug induced diabetes in rats. AB - BACKGROUND: Diabetes mellitus is affecting more than 300 million people worldwide. Current treatment strategies cannot prevent secondary complications. Stem cells due to their regenerative power have long been the attractive target for the cell-based therapies. Mesenchymal stem cells (MSCs) possess the ability to differentiate into several cell types and to escape immune recognition in vitro. MSCs can be differentiated into insulin-producing cells (IPCs) and could be an exciting therapy for diabetes but problems like poor engraftment and survivability need to be confronted. It was hypothesized that stromal cell derived factor- 1alpha (SDF-1alpha) will enhance therapeutic potential of stem cell derived IPCs by increasing their survival and proliferation rate. METHODS: Novel culture conditions were developed to differentiate bone marrow derived mesenchymal stem cells (BMSCs) into IPCs by using endocrine differentiation inducers and growth factors via a three stage protocol. In order to enhance their therapeutic potential, we preconditioned IPCs with SDF-1alpha. RESULTS: Our results showed that SDF-1alpha increases survival and proliferation of IPCs and protects them from glucotoxicity under high glucose conditions in vitro. SDF 1alpha also enhances the glucose responsive insulin secretion in IPCs in vitro. SDF-1alpha preconditioning reverses hyperglycemia and increase serum insulin in drug induced diabetic rats. CONCLUSIONS: The differentiation of BMSCs into IPCs and enhancement of their therapeutic potential by SDF-1alpha preconditioning may contribute to cell based therapies for diabetes. PMID- 23648191 TI - Molecular factors involved in the control of muscle mass during hypoxia-exposure: the main hypotheses are revisited. PMID- 23648190 TI - Characterization of clinical photosensitivity in cutaneous lupus erythematosus. AB - BACKGROUND: Photosensitivity (PS) in lupus erythematosus (LE) is frequently determined by patient report. OBJECTIVE: We sought to characterize self-reported PS in cutaneous LE (CLE). METHODS: The PS survey was used to classify subject responses into 5 phenotypes: direct sun-induced CLE flare (directCLE); general exacerbation of CLE (genCLE); polymorphic light eruption-like reactions (genSkin); general pruritus/paresthesias (genRxn); and sun-induced systemic symptoms (genSys). In all, 91 subjects with CLE alone or with CLE and systemic LE were interviewed. RESULTS: In all, 81% ascribed to 1 or more PS phenotypes. CLE specific reactions (direct sun-induced CLE flare or general exacerbation of CLE) were reported by 86% of photosensitive subjects. Higher CLE disease activity (measured by CLE Disease Area and Severity Index activity scores) was suggestive of direct sun-induced CLE flare reactions (P = .09). In all, 60% of photosensitive subjects described CLE-nonspecific reactions: polymorphic light eruption-like rash and general pruritus/paresthesias. These phenotypes often co occurred with CLE-specific reactions and were predicted by more systemic disease activity as measured by Physicians Global Assessment (PGA) scores in regression analyses (genSkin, P = .02) and (genRxn, P = .05). In all, 36% of subjects reported systemic reactions and higher PGA scores were predictive of the sun induced systemic symptoms phenotype (P = .02); a diagnosis of systemic LE was not (P = .14). LIMITATIONS: PS was inferred from patient report and not directly observed. CONCLUSIONS: Characterization of self-reported PS in LE reveals that patients experience combinations of CLE-specific, CLE-nonspecific, and systemic reactions to sunlight. Sun-induced CLE flares are associated with more active CLE disease. Polymorphic light eruption-like, generalized pruritus/paresthesias, and systemic reactions are associated with more active systemic disease. Recognition of PS phenotypes will permit improved definitions of clinical PS and allow for more precise investigation into its pathophysiology. PMID- 23648192 TI - What clinical differences distinguish depressed teens with and without comorbid externalizing problems? AB - OBJECTIVE: This study examined differences in co-occurring symptoms, psychosocial correlates, health care utilization and functional impairment in youth who screened positive for depression, stratified by whether or not they also self reported externalizing problems. METHODS: The AdoleSCent Health Study examined a random sample of youth ages 13-17 enrolled in a health care system. A total of 2291 youth (60.7% of the eligible sample) completed a brief depression screen: the two-item Patient Health Questionnaire. The current analyses focus on a subset of youth (n=113) who had a follow-up interview and screened positive for possible depression on the Patient Health Questionnaire 9 using a cutoff score of 11 or higher [1]. Youth were categorized as having externalizing behavior if their score was >= 7 on the Pediatric Symptom Checklist (PSC) externalizing scale [2,3]. chi(2) tests and Wilcoxon rank sum tests were used to compare groups. RESULTS: Differences between groups included that youth with depression and externalizing symptoms had a higher rate of obesity and had higher self-reported functional impairment than youth with depression symptoms alone. CONCLUSIONS: Adding screening for externalizing problems to existing recommendations for depression screening may help primary care providers to identify a high-risk depressed group of youth for referral to mental health services. PMID- 23648194 TI - Platelet rich plasma. PMID- 23648193 TI - The screen for cognitive impairment in psychiatry: diagnostic-specific standardization in psychiatric ill patients. AB - BACKGROUND: The Screen for Cognitive Impairment in Psychiatry (SCIP) is a simple and easy to administer scale developed for screening cognitive deficits. This study presents the diagnostic-specific standardization data for this scale in a sample of schizophrenia and bipolar I disorder patients. METHODS: Patients between 18 and 55 years who are in a stable phase of the disease, diagnosed with schizophrenia, schizoaffective disorder, schizophreniform disorder, or bipolar I disorder were enrolled in this study. RESULTS: The SCIP-S was administered to 514 patients (57.9% male), divided into two age groups (18-39 and 40-55 years) and two educational level groups (less than and secondary or higher education). The performance of the patients on the SCIP-S is described and the transformed scores for each SCIP-S subtest, as well as the total score on the instrument, are presented as a percentile, z-score, T-scores, and IQ quotient. CONCLUSIONS: We present the first jointly developed benchmarks for a cognitive screening test exploring functional psychosis (schizophrenia and bipolar disorder), which provide increased information about patient's cognitive abilities. Having guidelines for interpreting SCIP-S scores represents a step forward in the clinical utility of this instrument and adds valuable information for its use. PMID- 23648195 TI - Growth factor content in PRP and their applicability in medicine. AB - This paper reviews available reports on the advantages and possibilities of clinical use of platelet-rich plasma preparations, with particular emphasis on platelet growth factors. Platelets, an important reservoir of growth factors in the body, play an important role in many processes such as coagulation, immune response, angiogenesis and the healing of damaged tissues. Numerous proteins are contained in the alpha-granules of platelets: platelet-derived growth factor (PDGF), transforming growth factor (TGF), platelet factor interleukin (IL), platelet-derived angiogenesis factor (PDAF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor IGF and fibronectin. The development of methods and systems for blood and cell sorting (e.g. CAPSS - compact advanced platelet sequestration system Elektromedics 500, PCCS - platelet concentrate collection system Curasan) have made it possible to obtain significant concentrations of platelets (even by 338 percent) and high concentrations of growth factors, in a form of sterile mass that can be used immediately for clinical purposes. Platelet-rich plasma (PRP; autologous platelet rich plasma - APRP) are platelet concentrates made of autogenous blood with a high number of platelets in a small volume of plasma. The clinical efficacy of platelet concentrates depends mainly on the number of platelets and the concentration of their growth factors, which act as transmitters in most processes in tissues, particularly in healing where they are responsible for proliferation, differentiation, chemotaxis and tissue morphogenesis. They operate as part of autocrine, paracrine and endocrine mechanisms. Growth factors derived from centrifuged blood were first used in patients with chronic skin ulcers. The clinical use of PRP for a wide variety of applications has been reported mostly in oral and maxillo-facial surgery, orthopedic surgery, treatment of soft tissue diseases and injuries, treatment of burns, hard-to-heal wounds, tissue engineering and implantology. PMID- 23648196 TI - Platelet lipidomic. AB - Lipids account for 16-19 percent dry platelet matter and includes 65 percent phospholipids, 25 percent neutral lipids and about 8 percent glycosphingolipids. The cell membrane that surrounds platelets is a bilayer that contains different types phospholipids symmetrically distributed in resting platelets, such as phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylcholine, and sphingomyelin. The collapse of lipid asymmetry is exposure of phosphatidylserine in the external leaflet of the plasma bilayer, where it is known to serve at least two major functions: providing a platform for development of the blood coagulation cascade and presenting the signal that induces phagocytosis of apoptotic cells. During activation, this asymmetrical distribution becomes disrupted, and PS and PE become exposed on the cell surface. The transbilayer movement of phosphatidylserine is responsible for the platelet procoagulant activity. Exposure of phosphatidylserine is a flag for macrophage recognition and clearance from the circulation. Platelets, stored at room temperature for transfusion for more than 5 days, undergo changes collectively known as platelet storage lesions. Thus, the platelet lipid composition and its possible modifications over time are crucial for efficacy of platelet rich plasma therapy. Moreover, a number of substances derived from lipids are contained into platelets. Eicosanoids are lipid signaling mediators generated by the action of lipoxygenase and include prostaglandins, thromboxane A2, 12 hydroxyeicosatetraenoic acid. Isoprostanes have a chemical structure similar to this of prostanoids, but are differently produced into the particle, and are ligands for prostaglandins receptors, exhibiting biological activity like thromboxane A2. Endocannabinoids are derivatives from arachidonic acid which could reduce local pain. Phospholipids growth factors (sphingolipids, lysophosphatidic acid, platelet-activating factor) are involved in tissue regenerating process. Finally, a warning concerning the atherogenic role of platelets, although it should not be exerted in a local therapy, is mentioned. The lipid content of plaletets must be taken into account when these particles are concentrated and used for a local therapy, while the different categories of lipid derivatives could improve or affect the quality of the product. PMID- 23648197 TI - Platelet rich plasma therapy: inflammatory molecules involved in tissue healing. AB - Inflammation represents a fundamental aspect of the healing process. Besides their primary role in hemostasis, platelets play an active role in the immunological and inflammatory aspect of tissue healing. Indeed , they can be directly involved in the inflammatory response by the production and release of several inflammatory mediators, including a variety of cytokines, such as TGF beta, IL-1 beta, CD40L, and chemokines, such as CXCL7, CXCL4, CXCL4L1, CCl5, CXCL1, CXCL8, CXCL5, CXCL12, CCL2, CCL3. Platelet are not only a source of several chemokine involved in the inflammatory response and tissue healing, but they also express chemokine receptors, in particular CCR1 CCR3 CCR4 and CXCR4, thus being able to being able to regulate the inflammatory response associated to the healing process. However, this local inflammation must be taken under control, and platelets can prevent the excess of leukocytes recruitment by anti inflammatory cytokines, such as TGF-beta. For this biological properties of platelets, platelet rich plasma therapy (PRP) is considered an innovative and promising approach that has been extended to many field of medicine, ranging from non-union defects, bone fractures, spinal fusion, bone implant and osteointegration, joint arthroplasty, to the treatment of several traumatic or degenerative pathologies of tendons, cartilage and ligaments. PMID- 23648198 TI - Microbicidal properties of Leukocyte- and Platelet-Rich Plasma/Fibrin (L-PRP/L PRF): new perspectives. AB - Platelets, as main actors of the first stage of the healing process, play an important role in tissue repair. Their granules contain many active substances, particularly over 30 growth factors with significant effects on the resident cells at the site of injury, such as mesenchymal stem cells, chondrocytes, fibroblasts, osteoblasts. This potential may be increased by the concentration of the platelets, using platelet-rich plasma/fibrin products. In the four families of platelet concentrates, 2 families contain also significant concentrations of leukocytes: L-PRP (Leukocyte- and Platelet-Rich Plasma) and L-PRF (Leukocyte- and Platelet-Rich Fibrin). Inductive properties of platelet concentrates were widely described. However, they present also antimicrobial effects. The antibacterial effects of L-PRP were highlighted in only a few in vitro studies. Strong activity comparable to gentamicin and oxacillin for L-PRP against methicillin susceptible Staphylococcus aureus (MSSA) was already demonstrated. L-PRP also inhibited the growth of methicillin resistant Staphylococcus aureus (MRSA) and Escherichia coli. Some authors also reported clinical observations about the reduction of infections and the induction of healing processes after the use of platelet concentrates in cardiac, orthopaedic, oral and maxillofacial surgery. However, very little is yet known about the antibacterial effects of these concentrates. In this manuscript, the current data about the antimicrobial agents and cells present in the platelet-rich plasma/fibrin are highlighted and discussed, in order to introduce this new key chapter of the platelet concentrate technology history. PMID- 23648199 TI - Applications and limits of platelet-rich plasma in sports related injuries. AB - Platelet-rich plasma (PRP) is a promising alternative approach based on the efficacy of autologous growth factors to accelerate tissue healing, allowing a fast recovery after muscles, ligaments, tendon or cartilage lesions. This literature review begin focusing on the role of platelets growth factors in these tissue healing and on the available preparation methods for PRP. Moreover we consider the in vitro and in vivo study on PRP, some of the most important therapeutic applications and limitations. Although several preclinical studies show promising results, clinical studies still show controversial results. Further studies are required to define the efficacy and to specify the way of using PRP in the orthopaedic practice. PMID- 23648200 TI - The use of autologous platelet and plasma products in salvage neck dissections: a prospective clinical study evaluating early and late wound healing. AB - OBJECTIVES: To evaluate the effect of autologous platelet and plasma adhesives (APA) on postoperative drainage and soft-tissue fibrosis following neck dissections. DESIGN: This was a blinded comparative prospective cohort study done as two parts: part one evaluated early post-surgical outcomes and part two evaluated late tissue fibrosis. METHOD: Salvage neck dissections were stratified into two groups based on severity of prior treatment. High risk patients were defined as those who had previously undergone chemoradiation therapy and autologous platelet adhesives were administered to the surgical wound intraoperatively. The low risk group consisted of patients undergoing salvage neck dissections following radiation only and acted as controls. Part one evaluated postsurgical wound drainage as the primary outcome as well as length of hospital stay and complications. Part two evaluated late postoperative tissue fibrosis by comparing neck skin using the Cutometer. R2 and F0 were the specific Cutometer parameters for quantifying the viscoelastic properties of the skin. RESULTS: Postoperative wound drainage was significantly less (253.7 vs. 345.8) in the autologous platelet adhesive group as compared to the control group (p less than 0.03). Length of stay in the APA group versus the control group was 3.13 and 3.86 days respectively (p less than 0.004). Both R2 and F0 measurements showed improved viscoelastic properties of the skin in the APA group (R2 p less than 0.05, F0 p less than 0.05). CONCLUSIONS: APA application following salvage neck dissections may reduce early postperative wound drainage and improve long-term skin quality. PMID- 23648202 TI - [Optical coherence tomography. Bases and applications of a new intravascular imaging technique]. AB - Coronary angiography is the reference technique for the diagnosis of coronary disease. However, the majority of acute coronary syndromes involve angiographically non-significant lesions. It is also the technique of choice for guiding the implantation of endovascular prostheses and their later monitoring. Optical coherence tomography is an interferometric imaging technique that penetrates tissue approximately 2-3mm and provides axial and lateral resolution. It is able to distinguish different tissue types, such as fibrous, lipid-rich, necrotic, or calcified tissue. Optical coherence tomography is able to recognize a variety of features of atherosclerotic plaques that have been associated with rapid lesion progression and clinical events, such as thin cap fibroatheroma, fibrous cap thickness, dense macrophage infiltration, and thrombus formation. Currently, there is growing interest in the value of optical coherence tomography in the area of coronary intervention, where the technique offers significant advantages over more widespread intravascular diagnostic techniques such as intravascular ultrasound. Its higher resolution permits to recognize periprocedural complications, such as microdissection of the coronary artery, stent malapposition, and neointimal hyperplasia, making this tool one of the most promising techniques in the intravascular diagnosis. PMID- 23648201 TI - Treatment of knee chondropathy with platelet rich plasma. Preliminary results at 6 months of follow-up with only one injection. AB - Application of new biological treatments in orthopaedics is controversial nowadays. Surgeons and practitioners know how difficult can be to choose a solution for chondral injuries. Joint damages are from little contusions, osteochondral fractures, avascular necrosis, osteochondritis and degenerative processes like osteoarthritis and rheumatisms. All mentioned have a common problem: the lack of regenerating hyaline cartilage by themselves. Recently, PRP have been used to treat early moderate chondropathies. Here we show the preliminary results of 30 patients affected by chondropathy of the knee after 6 months treated with a single intrarticular injection of PRP. Thirty patients, 18 65 years old, with a diagnosis of I to III Outerbridge chondropathy in the knee, pain for more than 3 months following conservative treatment and no bone axial defect, were treated with one intraarticular injection of PRP (GPS mini set, BIOMET), after written consent and Ethic and Legal Committee approval. VAS and KOOS scores were evaluated before PRP injection and at 1, 3 and 6 months after the treatment. ANOVA with repeated measures using the SPSS showed significantly better results in term of KOOS and VAS scores at 1, 3 and 6 months respect to the pre-injection value (p less than 0,05) We think that PRP treatment is a promising alternative for the treatment of knee chondropathy; however its efficacy has to be demonstrated with more clinical works, with longer follow up and with greater number of patients, even with controlled and randomized trials. In our study only one injection of PRP has been able to allow a clinical improvement, suggesting the possibility to avoid multiple injections protocols, and consequently reducing the health expenses. Until the efficacy of PRP will not be definitely demonstrated, surgeon should be very prudent in indications. PMID- 23648204 TI - Analysis of 49 autosomal SNPs in three ethnic groups from Iran: Persians, Lurs and Kurds. AB - A total number of 149 individuals from Iran (Persians, Lurs and Kurds) were analyzed for 49 autosomal SNPs using PCR, SBE and capillary electrophoresis. No deviation from Hardy-Weinberg expectations was observed. One SNP pair (rs1015250 rs251934) showed significant linkage disequilibrium in Kurds. However, this was most likely due to chance. High intrapopulation variability and no significant population structure were observed among the three ethnic groups from Iran. Pairwise FST values obtained from the mean numbers of pairwise differences between SNP profiles were calculated for Persians, Lurs, Kurds and eighteen other worldwide populations. For each of the three Iranian ethnic groups, the lowest FST values calculated between an Iranian and non-Iranian populations were observed between Iranians and populations in Iraq and Turkey. The three Iranian ethnic groups grouped together with other West Asian populations in the MDS plot drawn from the FST values. Statistical parameters of forensic interest calculated for the Iranian ethnic groups showed values of the same order of magnitudes as those obtained for Asians. The mean match probability calculated for the 49 SNPs ranged from 1.7x10(-18) for Kurds to 1.3x10(-19) for Persians. Despite the low level of genetic structure observed among Persians, Lurs and Kurds, a single autosomal SNP database should be used with care when extending its forensic application to other Iranian ethnic groups. PMID- 23648203 TI - Spatio-temporal analysis to identify determinants of Oncomelania hupensis infection with Schistosoma japonicum in Jiangsu province, China. AB - BACKGROUND: With the successful implementation of integrated measures for schistosomiasis japonica control, Jiangsu province has reached low-endemicity status. However, infected Oncomelania hupensis snails could still be found in certain locations along the Yangtze river until 2009, and there is concern that they might spread again, resulting in the possible re-emergence of infections among people and domestic animals alike. In order to establish a robust surveillance system that is able to detect the spread of infected snails at an early stage, sensitive and reliable methods to identify risk factors for the establishment of infected snails need to be developed. METHODS: A total of 107 villages reporting the persistent presence of infected snails were selected. Relevant data on the distribution of infected snails, and human and livestock infection status information for the years 2003 to 2008 were collected. Spatio temporal pattern analysis including spatial autocorrelation, directional distribution and spatial error models were carried out to explore spatial correlations between infected snails and selected explanatory factors. RESULTS: The area where infected snails were found, as well as their density, decreased significantly between 2003 and 2008. Changes in human and livestock prevalences were less pronounced. Three statistically significant spatial autocorrelations for infected snails were identified. (i) The Moran's I of infected snails increased from 2004 to 2007, with the snail density increasing and the area with infected snails decreasing. (ii) The standard deviations of ellipses around infected snails were decreasing and the central points of the ellipses moved from West to East. (iii) The spatial error models indicated no significant correlation between the density of infected snails and selected risk factors. CONCLUSIONS: We conclude that the contribution of local infection sources including humans and livestock to the distribution of infected snails might be relatively small and that snail control may limit infected snails to increasingly small areas ecologically most suitable for transmission. We provide a method to identify these areas and risk factors for persistent infected snail presence through spatio-temporal analysis, and a suggested framework, which could assist in designing evidence based control strategies for schistosomiasis japonica elimination. PMID- 23648205 TI - Pediatric cardiac transplantation using hearts previously refused for quality: a single center experience. AB - Pediatric donor hearts are regularly refused for donor quality with limited evidence as to which donor parameters are predictive of poor outcomes. We compare outcomes of recipients receiving hearts previously refused by other institutions for quality with the outcomes of recipients of primarily offered hearts. Data for recipients aged <=18 and their donors were obtained. Specific UNOS refusal codes were used to place recipients into refusal and nonrefusal groups; demographics, morbidity and mortality were compared. Kaplan-Meier analysis with log-rank test was used to determine differences in graft survival. A multivariable Cox proportional hazards model was constructed to determine independent risk factors for postoperative mortality. From July 1, 2000 to April 30, 2011, 182 recipients were transplanted and included for analysis. One hundred thirty received a primarily offered heart; 52 received a refused heart. No difference in postoperative complications or graft survival between the two groups (p = 0.190) was found. Prior refusal was not an independent risk factor for recipient mortality. Analysis of this large pediatric cohort examining outcomes with quality-refused hearts shows that in-hospital morbidity and long-term mortality for recipients of quality-refused hearts are no different than recipients of primarily offered hearts, suggesting that donor hearts previously refused for quality are not necessarily unsuitable for transplant and often show excellent outcomes. PMID- 23648206 TI - Membrane dynamics in physiology and disease. PMID- 23648207 TI - Constriction of porcine retinal arterioles induced by endothelin-1 and the thromboxane analogue U46619 in vitro decreases with increasing vascular branching level. AB - PURPOSE: The retinal blood flow depends on the diameter of retinal arterioles, but diameter changes in these vessels have hitherto only been assessed in vessels larger than approximately 100 MUm. Therefore, a new method was developed for studying diameter changes along the vascular tree of arterioles in whole perfused segments of porcine retinas, and the effect of known vasoconstrictors on the diameter of retinal arterioles at different branching levels were studied. METHODS: Thirty-four whole-mounted porcine retinas were placed in a specially designed tissue chamber. On the basis of video recordings through an inverted microscope, the diameter of retinal arterioles was measured at five different branching levels before and after addition of a high potassium concentration, or increasing concentrations of endothelin-1, the prostaglandin analogue U46619, noradrenaline or none (time controls). RESULTS: The baseline diameter ranged from 136 MUm (95% CI 132-140 MUm) for 1st order arterioles to 33 MUm (95% CI 21-44 MUm) for 5th order arterioles. In 1st order arterioles, endothelin produced 56.6% (95% CI 47.6-64.0) and U46619 14.6% (95% CI 5.7-22.6) relative constriction compared with baseline, which for both compounds decreased significantly with increasing branching level (p<0.0001 and p<0.0001, respectively). The change in diameter during addition of noradrenaline did not differ significantly from the time controls (p=0.07). CONCLUSIONS: The effect of retinal vasoconstrictors differs among larger and smaller arterioles. The study highlights the need for investigating diameter regulation in smaller retinal arterioles as a basis for understanding normal and pathological changes in retinal blood flow. PMID- 23648208 TI - Comparison of a gel column blood typing method and a point-of-care cartridge for dog erythrocyte antigen 1.1. AB - BACKGROUND: Blood typing for the presence of Dog Erythrocyte Antigen (DEA) 1.1 is recommended in all donor and recipient dogs prior to transfusion of blood products. The objective of this study was to determine if a point-of-care DEA 1.1 blood typing cartridge could be used in place of the gel column typing method. STUDY DESIGN: Detection of DEA 1.1 was performed using a laboratory-based gel column method and a point-of-care cartridge. A convenience sample of 30 healthy blood donors, 13 dogs with immune-mediated hemolytic anemia (IMHA) (3 of which had concurrent immune-mediated thrombocytopenia [IMT]), and 44 dogs with other diseases was included in the study. KEY FINDINGS: Agreement was observed between the tests for normal dogs and dogs with nonimmune-mediated disease in 74/74 cases. Two dogs in the IMHA group had indeterminate gel column blood typing results; 1 dog in this group had a negative gel column test result but a positive cartridge test result. SIGNIFICANCE: There was good agreement between the 2 methods for normal dogs and dogs with nonimmune-mediated disease. Blood typing methods in dogs with IMHA should be further investigated. PMID- 23648209 TI - Severe fever with thrombocytopenia syndrome virus among domesticated animals, China. AB - To investigate the infections of severe fever with thrombocytopenia syndrome virus (SFTSV) in domesticated animals, we sampled a total of 3,039 animals in 2 counties in Shandong Province, People's Republic of China, from April to November 2011. SFTSV-specific antibodies were detected in 328 (69.5%) of 472 sheep, 509 (60.5%) of 842 cattle, 136 (37.9%) of 359 dogs, 26 (3.1%) of 839 pigs, and 250 (47.4%) of 527 chickens. SFTSV RNA was detected in all sampled animal species, but the prevalence was low, ranging from 1.7% to 5.3%. A cohort study in 38 sheep was conducted to determine when seroconversion to SFTSV occured. SFTSVs were isolated from sheep, cattle, and dogs and shared >95% sequence homology with human isolates from the same disease-endemic regions. These findings demonstrate that natural infections of SFTSV occur in several domesticated animal hosts in disease-endemic areas and that the virus has a wide host range. PMID- 23648210 TI - Ultrasonic evaluation of microwave-induced thermal lesions based on wavelet analysis of mean scatterer spacing. AB - The microwave ablation has become an important manner for tumor treatment. In this paper, we proposed a new method for evaluation of microwave-induced thermal lesions using the wavelet analysis of the mean scatterer spacing (MSS). First, the ultrasonic radiofrequency (RF) data of normal and coagulated porcine liver tissues was collected through the temperature-controlled water bath heating experiments. The convex array ultrasound probe with a center frequency of 3.5 MHz was used. Second, the wavelet analysis was used to compute the MSS of normal and coagulated porcine liver tissues, respectively. Finally, the microwave-induced thermal lesions were detected based on the differences in the MSS between normal tissues and thermal lesions. Eighteen cases of microwave ablation experiments and 20 cases of water bath heating experiments were conducted on fresh porcine liver samples. The MSS of normal porcine liver tissues was 1.15+/-0.12 mm, and the MSS of coagulated porcine liver tissues was 0.93+/-0.07 mm. Six cases of thermal lesions were compared between the MSS-detected area and the caliper-measured area, and the MSS-detected area had an error of (13.55+/-5.29) %. The experimental results indicated that the proposed method could be used in preliminary detection and evaluation of microwave-induced thermal lesions. PMID- 23648211 TI - Application of arbitrary pulse width and position trains for the correlation sidelobes reduction for narrowband transducers. AB - Novel excitation technique is suggested which allows to reduce the correlation function sidelobes in case of narrowband channel. Application is planned for time of flight estimation using air coupled narrowband transducers. Time of flight is estimated by using the correlation function peak position. Narrowband signal has high level of correlation function sidelobes and therefore large signal to noise ratio cannot be fully exploited. Our investigation aimed to reduce the sidelobes by optimizing the signal. Novelty of the approach is that trains of arbitrary width and position square pulses are used. Such signals are easy to generate and to simulate in digital domain. The excitation signal spectrum was allowed to span beyond the passband, improving the envelope bandwidth in such way. The signal energy loss is caused by the attenuation of the out-of-band portion of the signal. Optimal balance between the energy loss and the sidelobes reduction had to be found. To predict the signal performance, the AC response of the transmission channel was measured and then used in simulation to predict the candidate signal's performance: the expected sidelobes' level and the energy. Monte Carlo technique was used to generate the candidate signals' parameters for the simulation. The relative noise margin was suggested as optimum criteria to balance the loss of the energy and the sidelobes reduction. Performance of the optimal signals obtained in simulation was verified experimentally. It was concluded that reduction of the sidelobes' is possible even for narrowband channel if some energy loss can be tolerated. An increase of 40% in relative noise margin, compared to the same length CW burst signals was achieved. PMID- 23648212 TI - Amplitude modulated chirp excitation to reduce grating lobes and maintain ultrasound intensity at the focus of an array. AB - During application of high intensity focused ultrasound (HIFU) with therapy arrays, the existence of grating lobes can cause heating at unintended tissue regions. Therefore, the reduction of grating lobes in therapeutic arrays is an important goal. One way to reduce the grating lobes in therapy arrays is to excite the arrays with broadband signals (defined here as >10% fractional bandwidth). To achieve a reduction in grating lobe levels in an ultrasonic array, coded waveforms can be utilized that reduce the grating lobe levels while maintaining the spatial peak temporal average intensity. In this study, a 5-MHz, 9-element, 1.25 mm inter-elemental spacing linear array was excited by a sinusoidal waveform, a conventional linear chirp, and a modified linear chirp. Both chirps spanned the -3-dB bandwidth of the transducer. The conventional chirp was a broadband signal with a linear sweep of frequencies between 2.5 and 7.5 MHz, with all frequency components excited with equal amplitude. The modified chirp signal also swept the frequencies between 2.5 and 7.5 MHz, but the amplitude was weighted such that the edges (low and high frequencies of the band) were excited with more energy than the center of the band. In simulations, the field patterns for the sinusoidal, conventional chirp and modified chirp excitations were produced from the array using Field II and compared. For experiments, the beam pattern from a 5-MHz single-element transducer was mapped using a hydrophone for the sinusoidal, conventional chirp and modified chirp excitation. Each field from the transducer was repeated and summed to produce a field from an array of 9 elements. The difference in the time averaged intensity (in dB) in the main lobe and grating lobes were estimated for each excitation and compared. The results demonstrated that the chirp signals resulted in decreases in grating lobe levels compared to the main lobe, i.e. 10 dB down for focusing and 6 dB down for focusing and steering. A further 1 dB decrease in grating lobe levels was observed for the modified chirp excitation compared to the conventional chirp excitation, which corresponds to ~21% reduction in energy deposition at the grating lobe location. PMID- 23648213 TI - Effect of valproic acid on survival and neurologic outcomes in an asphyxial cardiac arrest model of rats. AB - AIM OF THE STUDY: Valproic acid (VPA) has been known to reduce neuronal injury, has anti-inflammatory and anti-apoptotic effects as a histone deacetylase (HDAC) inhibitor. Thus, this study was performed to investigate the effects of VPA on survival and neurological outcomes in an asphyxial cardiac arrest model of rats. METHODS: Male Sprague-Dawley rats were subjected to asphyxial cardiac arrest. For survival study, rats were subjected to 450s of asphyxial cardiac arrest. Cardiopulmonary resuscitation (CPR) was performed and then rats were blindly allocated to one of two groups (control group, n=10; VPA group, n=10). Valproic acid (300mgkg(-1)) or vehicle (normal saline) was administered via tail vein immediately after return of spontaneous circulation (ROSC) and observed for 72h. For neurological outcome study, rats (n=7 for each group) were subjected to same experimental procedures except duration of cardiac arrest of 360s. Neurological deficit scale (NDS) score was measured every 24h after ROSC for 72h and was ranged from 0 (brain dead) to 80 (normal). Brain tissues were harvested at 72h for evaluation of apoptotic injury and acetylation status of histone H3. RESULTS: In survival study, 2 rats in VPA group were excluded because cardiac arrest was not achieved in predetermined time. Thus, 10 rats were allocated to control group and 8 rats were allocated to VPA group. The survival rates at 72h after cardiac arrest were significantly higher in VPA group than in control group (6/8 in VPA group, 3/10 rats in control group; log rank test, p<0.05). In neurological outcome study, all rats survived for 72h and NDS at 72h were significantly higher in VPA group than in control group (p<0.05). In brain tissues, expressions of acetylated histone H3 were not significantly different. However, expressions of cleaved caspase-3 were significantly lower in VPA group than in control group (p<0.05). CONCLUSION: VPA increased survival rates and improved neurologic outcome in asphyxial cardiac arrest model of rats while decreasing expressions of cleaved caspase-3. PMID- 23648214 TI - Prognostication of coma after cardiac arrest: think positive. PMID- 23648215 TI - Performance of the i-gelTM during pre-hospital cardiopulmonary resuscitation. AB - BACKGROUND: Current cardiopulmonary resuscitation (CPR) guidelines recommend airway management and ventilation whilst minimising interruptions to chest compressions. We have assessed i-gelTM use during CPR. METHODS: In an observational study of i-gelTM use during CPR we assessed the ease of i-gelTM insertion, adequacy of ventilation, the presence of a leak during ventilation, and whether ventilation was possible without interrupting chest compressions. RESULTS: We analysed i-gelTM insertion by paramedics (n=63) and emergency physicians (n=7) in 70 pre-hospital CPR attempts. There was a 90% first attempt insertion success rate, 7% on the second attempt, and 3% on the third attempt. Insertion was reported as easy in 80% (n=56), moderately difficult in 16% (n=11), and difficult in 4% (n=3). Providers reported no leak on ventilation in 80% (n=56), a moderate leak in 17% (n=12), and a major leak with no chest rise in 3% (n=2). There was a significant association between ease of insertion and the quality of the seal (r=0.99, p=0.02). The i-gelTM enabled continuous chest compressions without pauses for ventilation in 74% (n=52) of CPR attempts. There was no difference in the incidence of leaks on ventilation between patients having continuous chest compressions and patients who had pauses in chest compressions for ventilation (83% versus 72%, p=0.33, 95% CI [-0.1282, 0.4037]). Ventilation during CPR was adequate during 96% of all CPR attempts. CONCLUSIONS: The i-gelTM is an easy supraglottic airway device to insert and enables adequate ventilation during CPR. PMID- 23648216 TI - Advances in electronic surveillance for healthcare-associated infections in the 21st Century: a systematic review. AB - BACKGROUND: Traditional methodologies for healthcare-associated infection (HCAI) surveillance can be resource intensive and time consuming. As a consequence, surveillance is often limited to specific organisms or conditions. Various electronic databases exist within the healthcare setting and may be utilized to perform HCAI surveillance. AIM: To assess the utility of electronic surveillance systems for monitoring and detecting HCAI. METHODS: A systematic review of published literature on surveillance of HCAI was performed. Databases were searched for studies published between January 2000 and December 2011. Search terms were divided into infection, surveillance and data management terms, and combined using Boolean operators. Studies were included for review if they demonstrated or proposed the use of electronic systems for HCAI surveillance. FINDINGS: In total, 44 studies met the inclusion criteria. For the majority of studies, emphasis was on the linkage of electronic databases to provide automated methods for monitoring infections in specific clinical settings. Twenty-one studies assessed the performance of their method with traditional surveillance methodologies or a manual reference method. Where sensitivity and specificity were calculated, these varied depending on the organism or condition being surveyed and the data sources employed. CONCLUSIONS: The implementation of electronic surveillance was found to be feasible in many settings, with several systems fully integrated into hospital information systems and routine surveillance practices. The results of this review suggest that electronic surveillance systems should be developed to maximize the efficacy of abundant electronic data sources existing within hospitals. PMID- 23648217 TI - Statistical methodological issues in mapping historical schistosomiasis survey data. AB - For schistosomiasis and other neglected tropical diseases for which resources for control are still limited, model-based maps are needed for prioritising spatial targeting of control interventions and surveillance of control programmes. Bayesian geostatistical modelling has been widely and effectively used to generate smooth empirical risk maps. In this paper, we review important issues related to the modelling of schistosomiasis risk, including Bayesian computation of large datasets, heterogeneity of historical survey data, stationary and isotropy assumptions and novel approaches for Bayesian geostatistical variable selection. We provide an example of advanced Bayesian geostatistical variable selection based on historical prevalence data of Schistosoma mansoni in Cote d'Ivoire. We include a "parameter expanded normal mixture of inverse-gamma" prior for the regression coefficients, which in turn allows selection of blocks of covariates, particularly categorical variables. The implemented Bayesian geostatistical variable selection provided a rigorous approach for the selection of predictors within a Bayesian geostatistical framework, identified the most important predictors of S. mansoni infection risk and led to a more parsimonious model compared to traditional selection approaches that ignore the spatial structure in the data. In conclusion, statistical advances in Bayesian geostatistical modelling offer unique opportunities to account for important inherent characteristics of the Schistosoma infection, and hence Bayesian geostatistical models can guide the spatial targeting of control interventions. PMID- 23648218 TI - Molecular characterization of mosquitocidal Bacillus sphaericus isolated from Tamil Nadu, India. AB - Forty-two Bacillus sphaericus strains were isolated from soil around Tamil Nadu, India. The phylogenetic relationship among the B. sphaericus isolates was analysed by REP-PCR and multiplex PCR was performed for the detection of mosquito larvicidal genes binA, binB, mtx1, mtx2 and mtx3 in B. sphaericus isolates. According to the REP-PCR band pattern, B. sphaericus isolates were divided into group A comprising I-XI clusters and group B comprising cluster XII. Three of the isolates BSTN01, 23 and 24 were gathered under cluster XII showed a high level of larvicidal activity against Culex quinquefasciatus and Anopheles stephensi, the other 39 isolates grouped under I-XI clusters were non-toxic or weak or moderately toxic to mosquito larvae. Even though BSTN23 and 24 were isolated from the same location and both contained all the five mosquito larvicidal genes, their intraspecies difference was clearly elucidated by REP-PCR analysis. Among high toxic isolates, BSTN23 and 24 were observed to contain all the five toxin genes and BSTN01 showed the presence of binary toxin and Mtx1 toxin genes. The isolates BSTN02, 03, 07, 14, 16, 19, 20, 21, 25, 31, 36 and 39 were found to contain mtx1 gene with combination of mtx2 and/or mtx3 showed moderate or low toxicity against mosquito larvae. binA, binB and mtx1 genes were not present in non-toxic isolates. The present study revealed the genetic heterogeneity between both toxic and non-toxic isolates and indicates that there is a good correlation between the presence of toxin genes and toxicity of the strains. These techniques could be developed in screening of novel highly toxic B. sphaericus strains from environment without bioassay on mosquito larvae. PMID- 23648220 TI - The physiological response of protease inhibition in dystrophic muscle. AB - Duchenne muscular dystrophy (DMD) is caused by the production of a non-functional dystrophin gene product and a failure to accumulate functional dystrophin protein in muscle cells. This leads to membrane instability, loss of Ca(2+) homoeostasis and widespread cellular injury. Associated with these changes are increased protease activities in a variety of proteolytic systems. As such, there have been numerous investigations directed towards determining the therapeutic potential of protease inhibition. In this review, evidence from genetic and/or pharmacological inhibition of proteases as a treatment strategy for DMD is systematically evaluated. Specifically, we review the potential roles of calpain, proteasome, caspase, matrix metalloproteinase and serine protease inhibition as therapeutic approaches for DMD. We conclude that despite early results to the contrary, inhibition of calpain proteases is unlikely to be successful. Conversely, evidence suggests that inhibition of proteasome, matrix metalloproteinases and serine proteases does appear to decrease disease severity. An important caveat to these conclusions, however, is that the fundamental cause of DMD, dystrophin deficiency, is not corrected by this strategy. Hence, this should not be viewed as a cure, but rather, protease inhibitors should be considered for inclusion in a therapeutic cocktail. Physiological Relevance. Selective modulation of protease activity has the potential to profoundly change intracellular physiology resulting in a possible treatment for DMD. However, alteration of protease activities could also lead to worsening of disease progression by promoting the accumulation of substrates in the cell. The balance of benefit and potential damage caused by protease inhibition in human DMD patients is largely unexplored. PMID- 23648219 TI - Protocol: does sodium nitrite administration reduce ischaemia-reperfusion injury in patients presenting with acute ST segment elevation myocardial infarction? Nitrites in acute myocardial infarction (NIAMI). AB - BACKGROUND: Whilst advances in reperfusion therapies have reduced early mortality from acute myocardial infarction, heart failure remains a common complication, and may develop very early or long after the acute event. Reperfusion itself leads to further tissue damage, a process described as ischaemia-reperfusion injury (IRI), which contributes up to 50% of the final infarct size. In experimental models nitrite administration potently protects against IRI in several organs, including the heart. In the current study we investigate whether intravenous sodium nitrite administration immediately prior to percutaneous coronary intervention (PCI) in patients with acute ST segment elevation myocardial infarction will reduce myocardial infarct size. This is a phase II, randomised, placebo-controlled, double-blinded and multicentre trial. METHODS AND OUTCOMES: The aim of this trial is to determine whether a 5 minute systemic injection of sodium nitrite, administered immediately before opening of the infarct related artery, results in significant reduction of IRI in patients with first acute ST elevation myocardial infarction (MI). The primary clinical end point is the difference in infarct size between sodium nitrite and placebo groups measured using cardiovascular magnetic resonance imaging (CMR) performed at 6-8 days following the AMI and corrected for area at risk (AAR) using the endocardial surface area technique. Secondary end points include (i) plasma creatine kinase and Troponin I measured in blood samples taken pre-injection of the study medication and over the following 72 hours; (ii) infarct size at six months; (iii) Infarct size corrected for AAR measured at 6-8 days using T2 weighted triple inversion recovery (T2-W SPAIR or STIR) CMR imaging; (iv) Left ventricular (LV) ejection fraction measured by CMR at 6-8 days and six months following injection of the study medication; and (v) LV end systolic volume index at 6-8 days and six months. FUNDING, ETHICS AND REGULATORY APPROVALS: This study is funded by a grant from the UK Medical Research Council. This protocol is approved by the Scotland A Research Ethics Committee and has also received clinical trial authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) (EudraCT number: 2010-023571-26). TRIAL REGISTRATION: ClinicalTrials.gov: NCT01388504 and Current Controlled Trials: ISRCTN57596739. PMID- 23648221 TI - Physical activity, leisure-time screen use and depression among children and young adolescents. AB - OBJECTIVES: Adolescent mental disorders remain a relatively neglected area of research, despite evidence that these conditions affect youth disproportionately. We examined associations between physical activity, leisure-time screen use and depressive symptoms among Australian children and adolescents. DESIGN: Large cross-sectional observational study. METHODS: Self-reported physical activity and leisure-time screen behaviours, and depressive symptoms using the Short Mood and Feeling Questionnaire were assessed in 8256 students aged 10-16 years (mean age=11.5 years, SD=0.8). RESULTS: Thirty three percent of the sample reported moderate to high depressive symptoms, with rates higher among females (OR=1.18; 95% CI: 1.02, 1.36; p=0.001). Increased opportunities to be active at school outside class (OR=0.70; 0.58, 0.85; p<0.001), being active in physical education classes (OR=0.77; 0.69, 0.86; p<0.001), greater involvement in sports teams at school (OR=0.77; 0.67, 0.88; p<0.001) and outside of school (OR=0.84; 0.73, 0.96; p=0.01) were all independently associated with lower odds for depressive symptoms. Meeting recommended guidelines for physical activity (OR=0.62; 0.44, 0.88; p=0.007) and, for 12-14 year olds, leisure-time screen use (OR=0.77; 0.59, 0.99; p=0.04) were also independently associated with lower odds for depressive symptoms. CONCLUSIONS: Higher levels of physical activity among children and young adolescents, and lower levels of leisure-time screen use among young adolescents, are associated with lower depressive symptoms. Longitudinal studies are needed to understand the causal relationships between these variables. PMID- 23648222 TI - Efficacy and safety of photodynamic therapy for recurrent, high grade nonmuscle invasive bladder cancer refractory or intolerant to bacille Calmette-Guerin immunotherapy. AB - PURPOSE: We evaluated the effectiveness of photodynamic therapy using Radachlorin in patients with high grade, nonmuscle invasive bladder cancer refractory or intolerant to bacillus Calmette-Guerin therapy who refused radical cystectomy. MATERIALS AND METHODS: Between July 2009 and December 2011 photodynamic therapy was performed in 22 men and 12 women. Radachlorin (0.5 to 0.6 mg/kg) was injected intravenously 2 to 3 hours before photodynamic therapy. After complete transurethral resection, a diffuser using a 22Fr cystoscope was placed in the bladder for irradiation with a 662 nm laser. Output beam power was adjusted to 1.8 W and the light dose was 15 J/cm(2). Photodynamic therapy was performed for 16 to 30 minutes. Recurrence after photodynamic therapy was followed by regular cystoscopy at 1, 2 and 3 months, and at 3-month intervals thereafter for up to 2.8 years. Efficacy was assessed by cystoscopy, cytology and histology, and defined as the number of patients who were tumor free after initial photodynamic therapy. RESULTS: Mean +/- SD patient age was 62.94 +/- 8.71 years. Average followup was 26.74 +/- 6.34 months (median 28.12). As the primary efficacy outcome, the recurrence-free rate was 90.9% at 12 months, 64.4% at 24 months and 60.1% at 30 months. As the secondary efficacy outcome, there was no statistical difference in mass size, carcinoma in situ, number of previous bacillus Calmette Guerin administrations, number of transurethral bladder resections or tumor multiplicity on Kaplan-Meier analysis (each p >0.05). No evidence of severe adverse effects was detected after photodynamic therapy. CONCLUSIONS: Photodynamic therapy with Radachlorin is a safe, effective treatment for nonmuscle invasive bladder cancer refractory or intolerant to bacillus Calmette Guerin therapy in select patients. PMID- 23648223 TI - Identifying appropriate patients for early salvage radiotherapy after prostatectomy. AB - PURPOSE: It remains unclear whether relapsed prostate specific antigen at postprostatectomy salvage radiotherapy impacts outcomes as long it is 1.0 ng/ml or less. MATERIALS AND METHODS: We performed a retrospective cohort study of 197 patients treated with salvage radiotherapy in the setting of detectable relapsed prostate specific antigen 1.0 ng/ml or less. Patients were excluded from analysis if they had lymph node involvement or received androgen deprivation therapy. Freedom from prostate specific antigen progression after salvage radiotherapy was analyzed by a Cox regression model. RESULTS: Median relapsed prostate specific antigen was 0.33 ng/ml (range 0.07 to 1.0). There was 86% freedom from prostate specific antigen progression at a median followup of 52 months. Relapsed prostate specific antigen (HR 1.9, p = 0.004), Gleason score 8-10 (HR 5.2, p <0.001) and negative margin status (HR 2.0, p = 0.02) were independently associated with an increased risk of prostate specific antigen progression after salvage radiotherapy. We identified interaction between relapsed prostate specific antigen and Gleason score (p = 0.04) but not margin status. A significant association was noted between higher relapsed prostate specific antigen and prostate specific antigen progression after salvage radiotherapy in patients with Gleason score 8-10 but not 7 or less. In patients with Gleason score 8-10 the rate of freedom from prostate specific antigen progression at 53 months was 77% vs 26% when salvage radiotherapy was initiated at a relapsed prostate specific antigen of 0.33 or less vs 0.34 to 1.0 ng/ml (log rank p = 0.003). CONCLUSIONS: Different relapsed prostate specific antigen thresholds for unsuccessful salvage radiotherapy may exist based on Gleason score. These data suggest that patients with Gleason score 8-10 should be offered salvage radiotherapy at the earliest detectable relapsed prostate specific antigen, even 0.33 ng/ml or less. Those with Gleason score 7 or less may have the opportunity to be followed with serial prostate specific antigen measurements to improve risk stratification, and delay and/or avoid the potential toxicity of salvage radiotherapy. PMID- 23648224 TI - Adamantane and neuraminidase inhibitor resistance among circulating human influenza A viruses in Cuba during 2006-2010. PMID- 23648225 TI - Physical activity in older people: a systematic review. AB - BACKGROUND: Physical activity (PA) in older people is critically important in the prevention of disease, maintenance of independence and improvement of quality of life. Little is known about the physical activity of the older adults or their compliance with current physical activity guidelines. METHODS: A systematic literature search of the published literature was conducted. Included were published reports of original research that independently reported: the PA level of non-institutional older adults (aged 60 years and over); and the proportion of older adults in the different samples who met PA recommendations or guidelines. The review was restricted to studies published since 2000 to provide a current picture of older adults' PA levels. RESULTS: Fifty three papers were included in the review. The percentage of older adults meeting recommended physical activity ranged from 2.4 - 83.0% across the studies. Definitions of "recommended" physical activity in older adults varied across the studies as did approaches to measurement which posed methodological challenges to data analysis. Older age groups were less likely than the reference group to be regularly active, and women were less likely than men to achieve regular physical activity, especially leisure time physical activity, when measured by both subjective and objective criteria. CONCLUSION: The review highlights the need for studies which recruit representative random samples of community based older people and employ validated measurement methods consistently to enable comparison of PA levels over time and between countries. PMID- 23648226 TI - University student depression inventory (USDI): confirmatory factor analysis and review of psychometric properties. AB - BACKGROUND: The 30-item USDI is a self-report measure that assesses depressive symptoms among university students. It consists of three correlated three factors: lethargy, cognitive-emotional and academic motivation. The current research used confirmatory factor analysis to asses construct validity and determine whether the original factor structure would be replicated in a different sample. Psychometric properties were also examined. METHOD: Participants were 1148 students (mean age 22.84 years, SD=6.85) across all faculties from a large Australian metropolitan university. Students completed a questionnaire comprising of the USDI, the depression anxiety stress scale (DASS) and Life Satisfaction Scale (LSS). RESULTS: The three correlated factor model was shown to be an acceptable fit to the data, indicating sound construct validity. Internal consistency of the scale was also demonstrated to be sound, with high Cronbach alpha values. Temporal stability of the scale was also shown to be strong through test-retest analysis. Finally, concurrent and discriminant validity was examined with correlations between the USDI and DASS subscales as well as the LSS, with sound results further supporting the construct validity of the scale. Cut-off points were also developed to aid total score interpretation. LIMITATIONS: Response rates are unclear. In addition, the representativeness of the sample could be improved potentially through targeted recruitment (i.e. reviewing the online sample statistics during data collection, examining the representativeness trends and addressing particular faculties within the university that were underrepresented). CONCLUSIONS: The USDI provides a valid and reliable method of assessing depressive symptoms found among university students. PMID- 23648227 TI - Association between major depressive disorder and the norepinephrine transporter polymorphisms T-182C and G1287A: a meta-analysis. AB - BACKGROUND: Previous studies have implicated norepinephrine transporter (NET) gene polymorphisms in the etiology of major depressive disorder (MDD). Recently, two single nucleotide NET polymorphisms, T-182C (rs2242446) in the promoter region and G1287A (rs5569) in exon 9, were found to be associated with MDD in different populations. However, inconsistent and inconclusive results have also been obtained. METHODS: In this study, we examined whether rs2242446 and rs5569 genetic variants are related to the etiology of MDD using a meta-analysis. Relevant case-control studies were retrieved by database searching and selected according to established inclusion criteria. RESULTS: Eight articles were identified that tested the relationship between the NET T-182C and/or G1287A polymorphism and MDD. Statistical analyses revealed no significant association between these polymorphisms and MDD (OR=1.23, 95% CI=0.77-1.97, P=0.38 for T 182C; OR=1.00, 95% CI=0.78-1.29, P=0.99 for G1287A). LIMITATIONS: The results must be treated with caution because of the small sample sizes of several included studies. CONCLUSIONS: Our findings suggest that the NET T-182C and G1287A polymorphisms are not susceptibility factors for MDD. PMID- 23648228 TI - Commentary on 'Systematic review and meta-analysis of the retroperitoneal versus the transperitoneal approach to the abdominal aorta'. PMID- 23648229 TI - CREST: the twilight zone between (mis)interpretation and deception. PMID- 23648231 TI - Portal vein thrombosis after colectomy for ulcerative colitis: two case reports and proposed novel pathophysiology for this association. PMID- 23648230 TI - Altitudinal variation in haemosporidian parasite distribution in great tit populations. AB - BACKGROUND: One of the major issues concerning disease ecology and conservation is knowledge of the factors that influence the distribution of parasites and consequently disease outbreaks. This study aimed to investigate avian haemosporidian composition and the distribution of these parasites in three altitudinally separated great tit (Parus major) populations in western Switzerland over a three-year period. The objectives were to determine the lineage diversity of parasites occuring across the study populations and to investigate whether altitudinal gradients govern the distribution of haemosporidian parasites by lineage. METHODS: In this study molecular approaches (PCR and sequencing) were used to detect avian blood parasites (Plasmodium sp., Haemoproteus sp. and Leucocytozoon sp.) in populations of adult great tits caught on their nests during three consecutive breeding seasons. RESULTS: High levels of parasite prevalence (88-96%) were found across all of the study populations with no significant altitude effect. Altitude did, however, govern the distribution of parasites belonging to different genera, with Plasmodium parasites being more prevalent at lower altitudes, Leucocytozoon parasites more at high altitude and Haemoproteus parasite prevalence increasing with altitude. A total of 27 haemosporidian parasite lineages were recorded across all study sites, with diversity showing a positive correlation to altitude. Parasites belonging to lineage SGS1 (P. relictum) and PARUS4 and PARUS19 (Leucocytozoon sp.) dominated lower altitudes. SW2 (P. polare) was the second most prevalent lineage of parasite detected overall and these parasites were responsible for 68% of infections at intermediate altitude, but were only documented at this one study site. CONCLUSIONS: Avian haemosporidian parasites are not homogeneously distributed across host populations, but differ by altitude. This difference is most probably brought about by environmental factors influencing vector prevalence and distribution. The high occurrence of co-infection by different genera of parasites might have pronounced effects on host fitness and should consequently be investigated more rigorously. PMID- 23648232 TI - Lentivirus restriction by diverse primate APOBEC3A proteins. AB - Rhesus macaque APOBEC3A (rhA3A) is capable of restricting both simian-human immunodeficiency virus (SHIVDeltavif) and human immunodeficiency virus (HIV 1Deltavif) to a greater extent than hA3A. We constructed chimeric A3A proteins to define the domains required for differential lentivirus restriction. Substitution of amino acids 25-33 from rhA3A into hA3A was sufficient to restrict HIVDeltavif to levels similar to rhA3A restriction of SHIVDeltavif. We tested if differential lentivirus restriction is conserved between A3A from Old World monkey and hominid lineages. A3A from African green monkey restricted SHIVDeltavif but not HIV 1Deltavif and colobus monkey A3A restricted both wild type and SHIVDeltavif and HIV-1Deltavif. In contrast, the gibbon ape A3A restricted neither SHIVDeltavif nor HIV-1Deltavif. Restriction of SHIVDeltavif and HIV-1Deltavif by New World monkey A3A proteins was not conserved as the A3A from the squirrel monkey but not the northern owl monkey restricted SHIVDeltavif. Finally, the colobus A3A protein appears to restrict by a novel post-entry mechanism. PMID- 23648233 TI - Mapping the telomere integrated genome of human herpesvirus 6A and 6B. AB - Human herpesvirus 6B (HHV-6B) is the causative agent of roseola infantum. HHV-6A and 6B can reactivate in immunosuppressed individuals and are linked with severe inflammatory response, organ rejection and central nervous system diseases. About 0.85% of the US and UK population carries an integrated HHV-6 genome in all nucleated cells through germline transmission. We have previously reported that the HHV-6A genome integrated in telomeres of patients suffering from neurological dysfunction and also in telomeres of tissue culture cells. We now report that HHV 6B also integrates in telomeres during latency. Detailed mapping of the integrated viral genomes demonstrates that a single HHV-6 genome integrates and telomere repeats join the left end of the integrated viral genome. When HEK-293 cells carrying integrated HHV-6A were exposed to the histone deacetylase inhibitor Trichostatin A, circularization and/or formation of concatamers were detected and this assay could be used to distinguish between lytic replication and latency. PMID- 23648234 TI - Transmission of Mycobacterium tuberculosis Beijing Strains, Alberta, Canada, 1991 2007. AB - Beijing strains are speculated to have a selective advantage over other Mycobacterium tuberculosis strains because of increased transmissibility and virulence. In Alberta, a province of Canada that receives a large number of immigrants, we conducted a population-based study to determine whether Beijing strains were associated with increased transmission leading to disease compared with non-Beijing strains. Beijing strains accounted for 258 (19%) of 1,379 pulmonary tuberculosis cases in 1991-2007; overall, 21% of Beijing cases and 37% of non-Beijing cases were associated with transmission clusters. Beijing index cases had significantly fewer secondary cases within 2 years than did non-Beijing cases, but this difference disappeared after adjustment for demographic characteristics, infectiousness, and M. tuberculosis lineage. In a province that has effective tuberculosis control, transmission of Beijing strains posed no more of a public health threat than did non-Beijing strains. PMID- 23648235 TI - Pretransplant immunosuppression followed by reduced-toxicity conditioning and stem cell transplantation in high-risk thalassemia: a safe approach to disease control. AB - Patients with class 3 thalassemia with high-risk features for adverse events after high-dose chemotherapy with hematopoietic stem cell transplantation (HSCT) are difficult to treat, tending to either suffer serious toxicity or fail to establish stable graft function. We performed HSCT in 18 such patients age >=7 years and hepatomegaly using a novel approach with pretransplant immunosuppression followed by a myeloablative reduced-toxicity conditioning regimen (fludarabine and i.v. busulfan [Flu-IV Bu]) and then HSCT. The median patient age was 14 years (range, 10 to 18 years). Before the Flu-IV Bu + antithymocyte globulin conditioning regimen, all patients received 1 to 2 cycles of pretransplant immunosuppression with fludarabine and dexamethasone. Thirteen patients received a related donor graft, and 5 received an unrelated donor graft. An initial prompt engraftment of donor cells with full donor chimerism was observed in all 18 patients, but 2 patients developed secondary mixed chimerism that necessitated withdrawal of immunosuppression to achieve full donor chimerism. Two patients (11%) had acute grade III-IV graft-versus-host disease, and 5 patients had limited chronic graft-versus-host disease. The only treatment related mortality was from infection, and with a median follow-up of 42 months (range, 4 to 75), the 5-year overall survival and thalassemia-free survival were 89%. We conclude that this novel sequential immunoablative pretransplantation conditioning program is safe and effective for patients with high-risk class 3 thalassemia exhibiting additional comorbidities. PMID- 23648236 TI - Nelarabine for T cell acute lymphoblastic leukemia relapsing after allogeneic hematopoietic stem cell transplantation: an opportunity to improve survival. AB - T-ALL relapsing after allogeneic stem cell transplantation is unusual but classically associated with poor outcome. Recently, encouraging results have been reported with Nelarabine in relapse or refractory cases. On behalf of the Group of Research in Adult ALL (GRAALL), we conducted a retrospective analysis of patients receiving Nelarabine following relapse after transplantation. Eleven patients received Nelarabine as salvage therapy in this situation. Most of them were transplanted in first Complete Remission (CR), and received a myeloablative conditioning regimen in 7 cases. Relapse occurred with a median time of 199 days. Nelarabine was given at 1.5 g/m(2)/day (Day 1, D3, D5) alone (N = 5) or in association (N = 6). The overall hematological response rate was 81%. Neurologic toxicity represents the main adverse event (N = 4), mainly grade I-II. Event free survival and overall survival at 1 year were 70 and 90% respectively. Nelarabine is a valuable option for salvage therapy in T-cell acute lymphoblastic leukemia relapsing after transplantation. PMID- 23648238 TI - Qualitative research in organ transplantation: recent contributions to clinical care and policy. AB - Qualitative studies remain relatively uncommon in the transplant literature but are an important approach contributing unique strengths in some areas of research. With the increased focus on patient-centered research and decision making, it is timely to review qualitative research in the context of transplantation. While quantitative research addresses questions about the effectiveness of interventions or associations between risk factors and outcomes, qualitative research has an equal and complementary role in providing understanding about people's behaviors, attitudes, and values. Qualitative research has provided insights into some of the important but elusive questions in transplantation, including the sources of barriers to organ donation and inequities in access to transplantation, nonadherence to immunosuppressive regimens, and complex psychosocial outcomes. This review highlights recent contributions of qualitative research to transplantation practice and policy, and identifies key principles to guide qualitative research appraisal. PMID- 23648237 TI - A phase I study of CPX-351 in combination with busulfan and fludarabine conditioning and allogeneic stem cell transplantation in adult patients with refractory acute leukemia. AB - This phase I study evaluated the maximal tolerated dose of CPX-351 when administered sequentially with allogeneic hematopoietic stem cell transplantation (HSCT) in patients with refractory acute leukemia. CPX-351 is a novel liposomal formulation that combines cytosine arabinoside (ara-c) and daunorubicin in a fixed molar ratio of 5:1. Patients in cohorts of 3 were treated with CPX-351 followed by fludarabine and busulfan (Bu/Flu) conditioning at 4-week (schedule A) or 3-week (schedule B) intervals. CPX-351 doses were escalated in 20-U/m(2) increments starting at 60 U/m(2) for 3 doses. Of the 36 patients enrolled, 29 were able to undergo HSCT, and the other 7 (the majority on schedule A) did not proceed to HSCT because of rapid disease progression. The maximal tolerated dose of CPX-351 was not reached at the 120 U/m(2) * 3 dose level. All 29 patients who proceeded to HSCT demonstrated adequate neutrophil and platelet engraftment. The median follow-up on the study for all 36 patients was 205 days (range, 20 to 996 days). The 1-year cumulative incidence of relapse for the 36 patients was 60.1% (95% confidence interval [CI], 43.4% to 77.3%), and that of nonrelapse mortality was 23.8% (95% CI, 10.9% to 47.4%). The 1-year overall survival and leukemia-free survival were 37% (95% CI, 21% to 53%) and 27% (95% CI, 13% to 43%), respectively. Our data suggest that a phase II trial should incorporate CPX-351 120 U/m(2) * 3 dosing on schedule B. Patients with good performance status and those who achieve effective cytoreduction from CPX-351 derived the greatest benefit. PMID- 23648240 TI - [Study on the relationship between child abuse, parent-child separation in childhood and the aggressive behavior in adolescence among 1417 junior high school students]. AB - OBJECTIVE: To explore the relationship between aggressive behaviors, parent-child separation and experience of childhood abuse among junior high school students. METHODS: A total of 1417 students in ordinary junior high schools from 3 townships in Huoshan, Anhui were involved in this study. Self-made questionnaire was used to estimate aggressive behaviors, parent-child separation in childhood, child abuse and social demographic information of the students under this study. RESULTS: Related scores (2.52 +/- 0.78) on physical aggression in boys was higher than in girls (2.29 +/- 0.79) while the scores related to anger (2.60 +/- 0.82) and hostility (2.58 +/- 0.80) in girls, were higher than those in boys (2.41 +/- 0.75, 2.47 +/- 0.78), all with statistically significant differences (P < 0.05). Scores related to different types of aggressive behaviors and the scores in total, were higher in students from the senior class (P < 0.001). Scores on items as verbal aggression, hostility and in total, were higher in those adolescents which had undergone maternal-child separation during their childhood (P < 0.05). Scores on hostility and in total, were higher in those adolescents which had suffered from father-child separation during their childhood (P < 0.05). Scores related to anger, hostility and in total, were higher in those adolescents which had undergone both parent-child separation when they were much younger (P < 0.05). Students who had suffered from various types of repeated abuse showed higher scores in various types of aggressive behaviors and in total, than those who did not have the same experience. Most of the differences among groups were statistically significant (P < 0.05). CONCLUSION: Students that suffered parent child separation in their earlier childhood and with repeated experiences of abuse in childhood appeared to be risk factors causing aggressive behaviors to develop during the age of adolescence. PMID- 23648239 TI - [Relationship between folic acid supplements during peri-conceptional period and the adverse pregnancy outcomes: a cohort study]. AB - OBJECTIVE: To examine the association between folic acid supplements during peri conception and the related adverse birth outcome. METHODS: Pregnant women who received first prenatal care at 4 municipal-level medical institutions in Maanshan, from Oct. 2008 to Oct. 2010 were selected as the target population. All participants were asked to complete a self-administered questionnaire which including data on demographic characteristics, interval, complications and frequency of taking folic acid etc., during pregnancy. The follow-up-records after delivery would include factors as: fetal weight, height, circumference of head, chest circumference of the neonates. Finally, 4448 valid questionnaires were gathered, including 190 premature, 147 small for gestational age and 104 low birth weight babies. Descriptive statistics and logistic regression models were used for data analysis. RESULTS: Data showed that the weight, height and head circumference of the fetal at birth among pregnant women who had taken supplementary standard folic acid during peri-conception period or only during the first trimester, were all better than those pregnant women who had not taken the standard folic acid supplements. After adjustment for potential confounders as gestational weeks, maternal age, mather's education level, results from the logistic regression showed that intake of standard folic acid supplements appeared a protective factor for those babies who were smaller than the gestational age (RR = 0.45, 95%CI: 0.24 - 0.86), at premature delivery (RR = 0.52, 95%CI: 0.32 - 0.87) or with low birth weight (RR = 0.39, 95%CI: 0.19 - 0.80). However, data from this study showed that provision of folic acid supplements to the pre-pregnant or at first trimester alone did not make obvious impact on those babies as prematured, small for gestational age and at low birth weight. CONCLUSION: Standardized provision of folic acid supplements during peri conceptional period could improve the outcomes of birth. PMID- 23648241 TI - [HIV sero-conversion rate and risk factors among HIV discordant couples in Zhumadian city, Henan province]. AB - OBJECTIVE: To analyze the sero-conversion rate and risk factors among HIV discordant couples in Zhumadian. METHODS: Sero-discordant couples had been followed up during 2006 - 2011. Information were collected from the National Comprehensive HIV/AIDS Information Management System and the HIV discordant couples Follow-up Management Information System including demographic characteristics of sero-negative spouses, the characteristics of infection and antiretroviral therapy information of index spouses, marital sexual behavior and social support etc., on a biannual basis. Blood specimens of sero-negative spouses were also collected and tested. Cox proportional-hazard model was used to analyze the related risk factors on HIV sero-conversion. RESULTS: Among 4813 sero discordant couples, 127 HIV sero-conversion spouses were identified, with a total sero-conversion rate as 0.63 per 100 person-years. The one-year sero-conversion rate in 2006 - 2011 ranged from 0.29 to 1.28 per 100 person-years. Factors that associated with increased risk of HIV sero-conversion were: sero-negative spouses with lower education level (RR = 1.50, 95%CI: 1.02 - 2.21, P = 0.04), index spouses not received ART (RR = 3.16, 95%CI: 2.20 - 4.56, P < 0.01) and last recorded CD4(+) cell counts as < 200 cells per ul (RR = 2.11, 95%CI: 1.40 - 3.19, P < 0.01), marital sexual contacts in the past 6 months with frequency of >= 4 times per month (RR = 4.27, 95%CI: 2.89 - 6.30, P < 0.01) but never used condoms (RR = 6.40, 95%CI: 3.67 - 11.17, P < 0.01), couples had not received any financial support and care assistance in the past 6 months (RR = 4.75, 95%CI: 2.34 - 9.64, P < 0.01). CONCLUSION: During 2006 - 2011, the sero-conversion rate among sero-negative spouses in Zhumadian had been stabilized and the rate was lower than it was in the last years. The increase of ART acceptance and its adherence and social support should be improved and focused on the follow-up management towards the serodiscordant couples. PMID- 23648242 TI - [Study on the rates of infection and spontaneous clearance on HCV among HIV infected men who have sex with men in China]. AB - OBJECTIVE: The aim of this study was to understand the rates of infection and spontaneous clearance on hepatitis C virus (HCV) among HIV-infected men who have sex with men (MSM) in China. METHODS: HIV-infected MSM from Shenyang, Beijing, Changsha and Kunming were selected to take the HCV antibody and HVC-RNA tests, and then classified into 'under recovery (RNA-/Ab+) ' or being chronic (RNA+/Ab+). Information on demography, CD4(+) T cell, HIV viral load and liver biochemical indicators were also collected. RESULTS: In 513 HIV-infected MSM, the positive rate of HCV antibody was 1.94% (10/513) and the positive rate of HVC-RNA was 0.77% (4/513). Five patients showed clearance of HVC-RNA, spontaneously. These 5 patients had low levels of both alanine transaminase (ALT) and aspartate aminotransferase (AST), and with high level of CD4(+) T cells, when compared to those who were not able to clear the HVC-RNA. CONCLUSION: Currently, the HCV infection rate was still at quite low level among the HIV-infected MSM in China. Dynamic of HIV/HCV co-infection should be monitored so as to develop suitable strategy on prevention and treatment among this population, in China. PMID- 23648243 TI - [Comparative analysis on both high risk behaviours, infection of HIV and syphilis between married and unmarried men who have sex with men]. AB - OBJECTIVE: To understand the distribution of marriage status among men who have sex with men (MSM) in the city of Changzhou, and to explore the impact of marriage on AIDS related high risk behaviors and HIV infection in this population. METHODS: Target sampling (snowball sampling) was adopted to carry out a cross-sectional study, and structured questionnaire-based interviews were conducted to collect information on social demography, HIV related high risk behaviors. Blood and urine samples were collected to detect HIV, syphilis, gonorrhea and Chlamydia trachomatis infections. RESULTS: Of the 655 participants, 37.4% were married. Married MSM mostly sought their sexual partners at the public bathing house (61.6%), while unmarried MSM were mainly through bars (33.6%) or internet (31.1%). The proportion of having anal sex with men during the last 6 months was lower in the married group (50.8%) than in the unmarried group (73.3%), (P < 0.001) The percentage of having sex with women in the last 6 months was significantly higher in the married group (68.9%) than that in the unmarried group (33.2%) (P < 0.001), (OR = 4.454, 95%CI: 3.168 - 6.261). The rates of condom use in the last anal sex with men in married and unmarried groups were 71.0% and 77.6%, respectively (P = 0.152). The rate of condom use in the last intercourse with women was significantly lower in the married group (44.0%) than that in the unmarried group (70.4%) (P < 0.001), (OR = 0.331, 95%CI: 0.205 - 0.535). In the sex trade, most of the married MSM would "buy" sex (66.7%), while unmarried MSM would "sell" sex (63.2%) (P < 0.05), (OR = 3.429, 95%CI: 1.255 - 9.366). The percentage of having drugs in the previous year was higher in married group (3.3%) than that in the unmarried group (0.8%) (P < 0.05). In married and unmarried groups, the infection rates of HIV, syphilis, gonorrhea and Chlamydia trachomatis appeared to be (8.6%, 8.6%), (17.1%, 12.3%), (1.6%, 2.4%), and (3.3%, 9.0%), respectively (P > 0.05). CONCLUSION: Marriage seemed to have had limited effects on reducing the high risk behaviors of MSM. Different and multiform interventions should be developed according to the different characteristics of married or unmarried MSM population. PMID- 23648244 TI - [Evaluation on the effect of immunization and safety of live attenuated and inactivated hepatitis A vaccine in China]. AB - OBJECTIVE: To evaluate the safety of both domestic live attenuated and inactivated hepatitis A vaccines, and to provide reference for emergent vaccination after hepatitis A outbreaks. METHODS: 493 children aged 6 - 9 with negative antibody to HAV (produced by Abbott) were randomly divided into four groups as vaccinated with domestic live attenuated hepatitis A vaccine (Group A), domestic inactivated hepatitis A vaccine (Group B), imported inactivated hepatitis A vaccine (Group C) and hepatitis B vaccine (Group D) respectively. Adverse events following the immunization were observed 30 minutes, 24, 48 and 72 hours after the vaccination, under double-blind method. RESULTS: The main AEFIs were: fever, local pain and scleroma but no other severe AEFIs were observed. The rates of AEFIs were 13.95% in Group A, 15.25% in group B, 16.80% in group C and 25.62% in group D, with no statistical differences between these groups (chi(2) = 6.953, P > 0.05). 2 weeks after the vaccination, the positive conversion rates of domestic live attenuated hepatitis A vaccine and domestic inactivated hepatitis A vaccine were 85.0% and 94.59% respectively. The rate of domestic inactivated hepatitis A vaccine reached 100% at 4 weeks after the vaccination. The antibody levels of HAV-IgG of Group A and B in 2, 4 and 12 weeks of vaccination and of Group C were higher than that of Group D. After 12 weeks of vaccination, the antibody level of group B became higher than it was Group C. CONCLUSION: There were no differences on safety among domestic live attenuated hepatitis A vaccine, domestic inactivated hepatitis A vaccine or imported inactivated hepatitis A vaccine under routine or emergency vaccination. All the vaccines showed satisfactory effects. PMID- 23648245 TI - [Association between ameloblastin gene polymorphisms and the susceptibility to dental fluorosis]. AB - OBJECTIVE: To study the distribution of ameloblastin (AMBN) gene polymorphism in coal-fire caused fluorosis (CFCF) in Chongqing municipality and the relationship between AMBN gene polymorphism and the susceptibility to dental fluorosis. METHODS: Under a case-control study, 100 children aged 8 - 12 and 30 adults with dental fluorosis were enrolled in Wushan and Fengjie counties of Chongqing from December 2010 to February 2011. Another 100 children aged 8 - 12 and 30 adults with non-dental fluorosis were chosen as internal control groups together with 50 children and 30 adults without dental fluorosis were selected as external control groups in the non-epidemic area of Yubei district. DNA was extracted from peripheral blood sample of these people. Genotype of AMBN gene 7 extron 538_540delGGA, 10 extron 657A > G and 13 extron 986C > T loci were detected using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: The rates of 7 extron 538_540delGGA loci among case, internal and external control groups were as follows: GGA/GGA-/- 61.2% (74/121), 78.5% (102/130), 74.3% (52/70) ; GGA/-: 24.0% (29/121), 15.4% (20/130), 22.9% (16/70) ; -/-: 14.8% (18/121), 6.1% (8/130), 2.8% (2/70), the difference was statistically significant (chi(2) = 14.353 P < 0.05). The AA appeared to be 86.8% (105/121), 93.1% (121/130), 91.4% (64/70) and AG were 13.2% (16/121), 6.9% (9/130), 8.6% (6/70), with difference not statistically significant (chi(2) = 2.972, P > 0.05). CC appeared as 81.0% (98/121), 90.0% (117/130), 87.1% (61/70) while CT as 19.0% (23/121), 10.0% (13/130), 12.9% (9/70), with difference not statistically significant (chi(2) = 4.319, P > 0.05). In comparing with the two control groups, the frequency of GGA/GGA was decreasing (chi(2) values were 8.957, 3.405, respectively, P < 0.05) while the frequency of -/- was increasing (chi(2) values were 5.134, 6.833, respectively, P < 0.05). RESULTS: from the univariate analysis showed that the individuals who were carrying -/- genotype had an increased risk of suffering from fluorosis (OR values were 2.7, 5.9, respectively, P < 0.05). When compared with the internal control group, the CT genotype of case group showed an increase (chi(2) = 4.139, P < 0.05) while individuals that carrying CT genotype had an increased risk of suffering from fluorosis (OR = 2.1, P < 0.05), in epidemic-area. CONCLUSION: Our results showed that the 7 extron 538_540delGGA and the 13 extron 986C > T loci polymorphism in AMBN gene might serve as the susceptibility factors causing the coal-fired fluorosis. PMID- 23648246 TI - [Disease burden on diabetes in China, 2010]. AB - OBJECTIVE: To estimate the disease burden of diabetes in China, 2010. METHODS: We calculated the disability adjusted life years (DALYs) of diabetes, using data from both the Mortality Surveillance in National Disease Surveillance Points System and the China Chronic Disease Surveillance (2010). We also examined the differences of DALYs by gender, age, urban/rural areas and geographical locations. RESULTS: The overall disease burden of diabetes was 19.12 DALYs per 1000 population. Men (18.30 DALYs per 1000) had a higher DALY rate than in women (19.97 DALYs per 1000). We observed an upside-down "U" relationship between DALY rate and age. Residents aged 15 - 79 years bore most part of disease burden and the burden peaked among population at age from 45 to 60 years (30.39 DALYs per 1000). There was a higher DALY rate seen in the population from the urban areas (17.83 DALYs per 1000) than those from the rural areas (17.03 DALYs per 1000). In order, the burden showed a decrease from the eastern region (22.28 DALYs per 1000), middle region (19.62 DALYs per 1000) to the western region (13.54 DALYs per 1000), in the country. CONCLUSION: China is currently carrying considerable burden caused by diabetes among the population of labor force while inequity of burden was seen among different geographical regions within China. PMID- 23648247 TI - [Dietary patterns of Chinese adults in nine provinces]. AB - OBJECTIVE: To examine and characterize the dietary patterns of Chinese adults in nine provinces. METHODS: The subjects were selected from the 'China Health and Nutrition Survey' within age group of 18 - 70 years old in 2009. 24-hour dietary recall method for 3 consecutive days was used to collect information on food intake. RESULTS: Major dietary patterns of Chinese adults in nine provinces were labeled "rice/pork" in both men and women while "fruit/egg", "beef, mutton/poultry"and "ethnic food/legumes" in men and "fruit/milk", "tubers/grains" in women. Urban or rural life style and related characteristics of the population showed an influence on the dietary pattern (men: beta = -0.153 24, -0.153 24, 0.376 62, 0.148 10, P < 0.01; women: beta = -0.139 43, 0.222 00, -0.308 36, P < 0.01). CONCLUSION: The dietary patterns of Chinese adults varied by sex and "Rice/Pork" had been the typical dietary pattern among the Chinese adults. PMID- 23648248 TI - [Situation on HIV/AIDS epidemics among migrant population in China, 2008 - 2011]. AB - OBJECTIVE: To analyze the HIV/AIDS epidemics situation among migrant population. METHODS: Data on HIV/AIDS cases among mobile population through case reporting system was collected from 2008 to 2011. RESULTS: The number of reported cases on HIV/AIDS among mobile population had been rising, with proportions of the total reported cases increased from 10.2% in 2008, to 18.2% in 2011. Sexual contacts continued to be the major route of transmission. With the increasing proportion of homosexual transmission, HIV/AIDS cases among mobile population moved from high HIV-prevalence areas in the western and central parts to low HIV-prevalence areas in the eastern part of the country. CONCLUSION: In recent years, the number of HIV/AIDS cases among mobile population was increasing in the case reporting system. Data showed that some male rural migrants had been engaged in commercial sex activities that called for more effective intervention measures to be taken to reduce the new HIV/AIDS infections in the migrant population. PMID- 23648249 TI - [Molecular epidemiological study on HIV/AIDS under the follow-up program in Zhejiang province in 2009]. AB - OBJECTIVE: To analyze the molecular epidemiological characteristics on HIV infectors/AIDS patients (HIV/AIDS) under a follow-up program in Zhejiang province in 2009. METHODS: 303 cases were randomly sampled. Information on the cases was collected and followed by genomic DNA extraction. Gag gene fragments were amplified by nested PCR, followed by sequencing and bio-informatic analysis. RESULTS: The rate of success for sequence acquisition was 74.3% (225/303). Distributions of HIV subtypes were as follows: CRF01_AE (58.7%), CRF07_BC (13.8%), CRF08_BC (9.8%), B' (15.1%), C (1.8%), G (0.4%) and unassigned BC (unique recombinant form 0.4%). RESULTS: from the HIV BLAST analysis showed that the sources of strains with the highest homology involved in 10 provinces/municipalities (Liaoning, Guangxi, Yunnan, Henan, etc.) and five other countries (Thailand, Vietnam, India, South Africa and Libya). The CRF01_AE phylogenetic tree was divided into four clusters. The sequences of HIV/AIDS with homosexual transmission showed a gather in cluster 1, and mix with those infected through heterosexual contact. CONCLUSION: Circulating recombinant forms of HIV seemed to play a dominant role in Zhejiang province. Unique recombinant form and new subtype of HIV were found. People living with HIV under homosexual transmission and heterosexual transmission had a trend of interwoven with each other. Increase of both the diversity and complexity of HIV strains were also noticed in Zhejiang province. PMID- 23648251 TI - [Distribution of HIV-1 subtypes in Guangxi Zhuang Autonomous Region, 2008-2009]. AB - OBJECTIVE: To understand the distribution of HIV-1 subtypes in Guangxi Zhuang Autonomous Region. METHODS: 294 participants who were infected by HIV-1 in 2008 - 2009 and residing in 13 cities in Guangxi were enrolled into this study. Epidemiological information showed that heterosexual transmission was the main transmitting route. 1584 bp full length gag gene, 3147 bp full length pol gene and 558 bp env (C2V3) fragments were amplified by using RT-PCR and then directly sequenced. NCBI genotyping tool and Mega 5.03 software were used to determine the HIV subtypes. Simplot and Recombinant HIV-1 Drawing Tool were used for the analysis of recombination. RESULTS: A total of 739 sequences, including 270 gag, 246 pol and 223 env (C2V3), were successfully obtained from 294 plasma specimens. Genotypes of HIV from 272 participants were determined. CRF01_AE was found the dominant (77.6%), followed by CRF08_BC (10.7%) and CRF07_BC (7.4%). 7 unique recombinant forms, 4 subtype B (B') and 1 subtype G were also identified. No significant difference on the distribution of subtypes among different regions and ethnics was found. Among the 7 unknown recombinant forms, 6 strains were mosaic B and/or C fragments with CRF01_AE genome as the backbone, while one strain originated from CRF07_BC and CRF08_BC. CONCLUSION: Currently, CRF01_AE was found the major subtype of HIV epidemic in Guangxi. New recombinant forms with CRF01_AE as backbones had been emerging, which called for serious attention. PMID- 23648250 TI - [Molecular-epidemiological characteristics of HIV-1 isolated from newly diagnosed female subjects in Beijing, 2006 - 2010]. AB - OBJECTIVE: To analyze the molecular-epidemiological characteristics of HIV-1 strains prevailing among female people living with HIV in Beijing. METHODS: Gag gene fragments from the 100 newly diagnosed female HIV-1 infections during 2006 to 2010 in Beijing were amplified, sequenced, and phylogenetically analyzed. RESULTS: Eighty-two HIV-1 gag gene fragments were amplified and analyzed. 1 (1.22%), 1 (1.22%), 3 (3.66%), 23 (28.05%), 8 (9.76%), 2 (2.44%), 1 (1.22%), 18 (21.95%), 3 (3.66%), 1 (1.22%), 14 (17.07%), 4 (4.88%) and 3 (3.66%) individuals were infected with HIV-1 subtypes A1, A2, B, B', C, D, G, H, CRF01_AE, CRF02_AG, CRF07_BC, CRF08_BC and B'/C recombinants respectively. CONCLUSION: The subtypes circulating in female HIV infections in Beijing were more diverse than in male and the proportions of B' and rare subtypes were relatively high. Surveillance programs on HIV-1 genetic diversity should be strengthened. PMID- 23648252 TI - [Virulence genes and pathogenicity of Shigella flexneri Xv isolated in Beijing]. AB - OBJECTIVE: To understand the biochemical characteristics, virulence genes and pathogenicity of Shigella flexneri Xv isolated in Beijing. METHODS: 61 strains of S. flexneri Xv isolated from diarrhea patients in Beijing were systematically determined through biochemical reactions and serological tests. Application of PCR technique in detection of virulence genes on ipaH, sen, virF, ial and pulsed field gel electrophoresis (PFGE) was used to identify the related characteristics and on rat lung slices to determine its pathogenicity. RESULTS: All of the S. flexneri Xv could ferment glucose, mannitol, melibiose and arabinose. Using serum agglutination, we found that the antigen structure was (IV: 7, 8). IpaH, sen, virF and ial that carried rates of virulence genes appeared to be 100%, 81.97%, 75.41% and 80.30%, respectively. Among 61 strains of S. flexneri Xv, the PFGE typing of Shigella bacteria could be divided into 25 belt types while the results from rat lung slices showed inflammatory change of Xv. CONCLUSION: S. flexneri Xv was found that it carried high rate of Shigella virulence genes, exhibiting genetic polymorphism and highly invasive. PMID- 23648253 TI - [Emergence of novel variants of gyrA, parC, qnrS genes in multi-drug resistant Klebsiella caused pneumonia]. AB - OBJECTIVE: To investigate the resistant mechanism of quinolones on multi-drug resistant Klebsiella caused pneumonia (MDR-KPN). METHODS: From August 2008 to May 2010, 47 strains of MDR-KPN were collected from 6 hospitals in Hangzhou and Huzhou in Zhejiang province in China. Drug target genes to quinolones (gyrA, parC) and quinolone-resistance genes mediated by mobile genetic elements [qnrA, qnrB, qnrS, aac (6')-Ib-cr, qepA] were analyzed by PCR and verified by DNA sequencing. RESULTS: Positive results were found in 47 strains of MDR-KPN, 43 strains (91.5%) of gyrA mutation, 40 strains (85.1%) of parC mutation, 3 strains (6.4%) of qnrB2, 1 strain (2.1%) of qnrB 4, 8 strains (17.0%) of qnrS 1, 5 strains (10.6%) of qnrS 4, 2 strains (4.3%) of aac (6')-Ib-cr respectively. Moreover, 5 novel variants of gyrA (GenBank accession number: JN811952, JN811953, JN811954, JN811955, JN811956), 5 novel variants of parC (GenBank accession number: JN817432, JN817433, JN817434, JN817435, JN817436) were also identified. In addition, qnrS4 (GenBank accession number: JN836269) appeared to be the novel variants of qnrS. CONCLUSION: Quinolone-resistance-determining region played a key role on the resistance to quinolones in this group of MDR-KPN, and quinolone resistance genes mediated by mobile genetic elements [qnrB2, qnrB4, qnrS1, qnrS4, aac (6')-Ib-cr] showed positive in some parts of the strains. This was the first report on emergence of qnrS4 in the world. PMID- 23648254 TI - [Effect of temperature on hospital admission among patients with chronic systolic heart failure]. AB - OBJECTIVE: To investigate the effect of temperature on hospital admission among patients with chronic systolic heart failure (CSHF). METHODS: Data regarding in hospital patients with CSHF were gathered from 12 hospitals in Hubei province, between 2000 and 2010. Patients with a history of congenital heart disease and the history of cancer from this series, were excluded. Chi-square (chi(2)) tests and t tests were used for descriptive analysis. Univariate and multivariate logistic regression methods were performed to determinate the risk of hospital admission of every month to compare with the previous one. We used 2-tailed 95% confidence interval (CI), and tests with P < 0.01 to consider the significant levels, statistically. We also used the SPSS 13.0 for Windows, release 15, 2006 (SPSS Inc, Chicago, Ill) for data analyses. RESULTS: (1) 48 964 patients were enrolled in the present study. The numbers of admission increased 18.71%, 13.84%, -21.90%, -34.62%, -21.97%, -3.81%, -2.04%, 10.13%, -17.13%, -0.85%, 21.54% and 42.70% from January to December when compared to the average number of admission. (2) The odds ratios (ORs) (95% CI, P values) of hospital admission in January, February and December were 1.09 (0.96 - 1.23, 0.54), 0.98 (0.84 - 1.10, 0.46) and 0.96 (0.84 - 1.08, 0.59), respectively in females which did not show any significant differences when compared to the number in August. However the ratios were 0.61 (0.54 - 0.69, < 0.01), 0.80 (0.68 - 0.92, < 0.01) and 0.73 (0.64 - 0.83, < 0.01), respectively, in males that showed significant differences when, compared to the figures in August. (3) The OR of admission increased more when temperature got lower for patients with coronary artery disease, hypertension heart disease or rheumatic heart disease, but not with dilated cardiomyopathy. (4) The OR of admission showed a different impact on patients with different occupation, along with the change of temperature. Low or high temperature did not seem to have different effects on the OR of admission in patients who were free lanced or unemployed. CONCLUSION: Temperature seemed to have significant effects on the risk of admission, which related to gender, etiology or occupation. PMID- 23648255 TI - [Relationship between clinical characteristics of lung cancer patients regarding their occupational exposure]. AB - OBJECTIVE: To study the relationship between clinical characteristics of lung cancer patients and their occupational exposure. METHODS: 2110 workers (>= 20 years) who had been engaged in occupation that were exposed to risk factors of lung cancer, were asked to fill in questionnaires which included social demographic characteristics, length of service, smoking history and habits etc. 378 cases with lung cancer admitted in the Tangshan Worker's Hospital were selected and their clinical data including general information, symptoms or signs other than lungs, CT findings, histological type of the tumor, metastasis of tumors etc. were compared between the occupational exposure group and the control group. RESULTS: The rate of lung cancer was 29.43% (621/2110) among the workers with occupational exposure, and in men it was higher than in women (P > 0.05). There were significant differences seen in the rates of lung cancer with different age, smoking history/habits and years of employment among workers having had the histories of occupational exposure (P < 0.01). With CT findings, the rate of obstructive emphysema in the occupational exposure group (36.91%) was higher than in the control group (18.78%), (P < 0.01). Pathologically, squamous cell carcinoma (36.24%) appeared to be higher than it did in the control group (28.38%). The rate of pleural metastasis in the occupational exposure group was 14.09%, while it was 7.42% (P < 0.05) in the control group. CONCLUSION: People, having had occupational exposure, showed an association between the rate of lung cancer and factors as: excessive smoking, advanced age and long histories of occupational exposure. Squamous cell carcinoma with obstructive emphysema and pleural metastasis appeared to be dominantly seen. PMID- 23648256 TI - [Study on the efficacy of quarantine during outbreaks of acute hemorrhagic conjunctivitis outbreaks at schools through the susceptive-infective-quarantine removal model]. AB - To assess the efficacy of quarantine for acute hemorrhagic conjunctivitis (AHC) outbreaks control in schools, by using the Compartment Model. Through combining the characters of both AHC and compartment model, we built a susceptive-infective removal (SIR) model suited for AHC outbreaks control in schools, and then quarantine was added into the model to develop a susceptive-infective-quarantine removal (SIQR) model. An outbreak of AHC in Changsha in 2011 was employed as a sample to assess the effect of quarantine for the prevention and control of AHC. Basic reproduction number (lambda0) of the AHC outbreak without intervention was 6.80, thus the transmission speed of the disease became quite fast. If no intervention had been adopted, almost all the students, faculties and staff members would have been infected within 23 days, and the accumulative cases would become 738, with the total attack rate (TAR) as 99.73%. The peak of the outbreak was at Sep. 11th and the number of new cases was 126 on that day. The efficacy would have been different if quarantine forces had been taken at different time and differently. The bigger and earlier the quarantine force had been adopted, the lower morbidity peak and the smaller TAR would have been appeared, with better efficacy of outbreak control. If the quarantine rate had been taken at the level of 90% on the sixth day, the accumulative case would have been reduced to 132 and the TAR had become 17.84% consequently. Quarantine program could be used as a main intervention approach to be employed for ACH outbreak at schools. PMID- 23648257 TI - [Hepatitis C virus genotypes in China: a systematic review]. AB - OBJECTIVE: To provide information on the geographical distribution of hepatitis C virus (HCV) genotype and subtypes in the Chinese population. METHODS: A comprehensive search was carried out in CHKD (China Hospital Knowledge Database), Wanfang (Chinese), CBMDisc and PubMed databases to identify all the papers being published on HCV genotypes/serotypes and subtypes in China. All studies were grouped according to the sites, period and objects of the studies, to analyse the distribution of HCV genotype. RESULTS: A total of 140 studies were included in this Meta-analysis program, which contained 168 records. We found that the predominate genotypes in China were 1b and 2a subtype, and the distributions of HCV subtypes were different in the western or southern parts of the country. Subtypes 3a, 3b and 6a had been significantly increased along with the decrease of subtypes 1b and 2a. There were various HCV subtypes among injection drug users with subtypes 3a, 3b and 6a found among them. CONCLUSION: The distribution of HCV genotypes and subtypes in the Chinese population had changed significantly. PMID- 23648258 TI - [Meta analysis on the co-infection between Mycobacterium tuberculosis and HIV/AIDS in China]. AB - OBJECTIVE: To understand and estimate the rate of co-infection between Mycobacterium tuberculosis (M. tuberculosis) and the human immunodeficiency virus (HIV). METHODS: Based on the related literature regarding Chinese M. tuberculosis and HIV co-infection being published between 2000 and 2012 in PubMed, China National Knowledge Infrastructure (CNKI), Wan Fang Databases and the Chinese Science & Technology Journal Database (VIP), we extracted related information and applied the generic inverse variance model to estimate the following parameters as: co-infection rate, differences on gender, region and subgroups. We also used the STROBE Statement and observational quality evaluation standard to evaluate the quality of literature, and employed sensitivity analyses to evaluate the impact of research quality. RESULTS: 39 papers were included in this Meta analysis, which contained a total sample size of 168 286. The co-infection rate of HIV in TB patients was 0.86% (95%CI: 0.80% - 0.93%), when using the generic inverse variance model. According to subgroups analyses, at alpha = 0.05 level, men had a higher co-infection rate (1.53%) than women (0.54%) and areas with high infection rate of HIV/AIDS (0.91%) were more commonly seen than low infection rate areas of HIV/AIDS (0.71%) and with significant differences. The co-infection rate of M. tuberculosis in patients infected with HIV was 14.44% (95%CI: 13.62% - 15.30%). Data from subgroup analyses also showed that at the alpha = 0.05 level, the co-infection rates from hospital samples (28.64%) were higher than those from the population samples' (4.74%). The co-infection rate (15.79%) from the western region was higher than that in the Central and Eastern regions (13.88% and 6.47% respectively), with significant differences. After excluding the papers that only met a few items of the STRODE Statement, results of the Meta-analysis were very close to the original results. CONCLUSION: The co-infection rate of both M. tuberculosis and HIV was high in China. Therefore, it was crucial for people and related organizations to pay more attention to this problem of co-infection. PMID- 23648259 TI - [Ecological-geographic landscapes of natural plague foci in China VIII. Typing of natural plague foci]. AB - Since plague is an important natural focus zoonosis, the typing of natural plague foci becomes one of the elements in understanding the nature and developing related prevention program of the disease. Natural foci of plague are composed by four fundamental parts which include Eco-geographical landscape (natural plague foci), hosts, vectors and pathogens (Yersinia pestis) that comprehensively interact through the large temporal scale of evolution. Human activities have had great impact on the foci of natural plague. Based on the published serial research papers, we tried to integrate the knowledge of each factor in natural plague foci and focusing on theoretical aspects, so as to strengthen the prevention and surveillance programs of plague to be extrapolated to other zoonosis. PMID- 23648260 TI - [Application and progress of multilevel models in epidemiological research]. PMID- 23648261 TI - One-pot synthesis of alpha-Fe2O3 nanospheres by solvothermal method. AB - We have successfully prepared alpha-Fe2O3 nanospheres by solvothermal method using 2-butanone and water mixture solvent for the first time, which were about 100 nm in diameter and composed of very small nanoparticles. The as-prepared samples were characterized using X-ray diffraction, scanning electron microscopy, and transmission electron microscopy. The results showed that the product was alpha-Fe2O3 nanosphere, and the temperature was an important factor on the formation of alpha-Fe2O3 nanospheres. PMID- 23648262 TI - Pseudophakic monovision: optimal distribution of refractions. AB - PURPOSE: To determine the optimal distribution of refractions in monofocal, pseudophakic monovision. METHODS: A previously reported mathematical method for describing defocus for a single eye (Acta Ophthalmol, 89, 2011, 111) is expanded to the binocular situation. The binocular distribution of refractions yielding the least defocus over the most extended fixation intervals is identified by mathematical optimization. The results are tested in a group of 22 pseudophakic patients. RESULTS: For the fixation interval 0.25-6.0 m, the optimal refractions are pure spheres of -0.27D for the distance eye and -1.15D for near eye. The mathematically derived defocus structure is confirmed in the clinical series. CONCLUSIONS: The reported mathematical method enables identification of the optimal distribution of refractions over any fixation interval. Monovision with refractions of approximately -0.25 and -1.25D may lead to spectacle independence for distance and intermediate vision. Binocular problems--such as monovision suppression, reduced stereoacuity and binocular inhibition--are likely to be minimal with the suggested anisometropia of 1.0D. This moderate monovision is fully reversible with spectacle correction, as the induced aniseikonia is minimal and it therefore represents a safe alternative to multifocal intraocular lenses (IOLs). PMID- 23648263 TI - Amperometric biosensor based on Prussian Blue nanoparticle-modified screen printed electrode for estimation of glucose-6-phosphate. AB - Glucose-6-phosphate (G6P) plays an important role in carbohydrate metabolism of all living organisms. Compared with the conventional analytical methods available for estimation of G6P, the biosensors having relative simplicity, specificity, low cost, and fast response time are a promising alternative. We have reported a G6P biosensor based on screen-printed electrode using Prussian Blue (PB) nanoparticles and enzymes, glucose-6-phosphate dehydrogenase, and glutathione reductase. The PB nanoparticles acted as a mediator and thereby enhanced the rate of electron transfer in a bienzymatic reaction. The Fourier transform infrared spectroscopy and energy-dispersive X-ray spectroscopy study confirmed the formation of PB, whereas atomic force microscopy revealed that PB nanoparticles were approximately 25 to 30 nm in diameter. Various optimization studies, such as pH, enzyme, and cofactor loading, were conducted to obtain maximum amperometric responses for G6P measurement. The developed G6P biosensor showed a broad linear response in the range of 0.01 to 1.25 mM, with a detection limit of 2.3 MUM and sensitivity of 63.3 MUA/mM at a signal-to-noise ratio of 3 within 15s at an applied working potential of -100 mV. The proposed G6P biosensor also exhibited good stability and excellent anti-interference ability, and it worked well for serum samples. PMID- 23648265 TI - Radical prostatectomy is a reasonable treatment for patients over 70 years of age. AB - OBJECTIVE: To compare the tumor nature and oncological course of patients operated on by radical prostatectomy in three age groups. MATERIAL AND METHOD: From the prospective completion of the data base of our department, we analyzed 1012 patients operated on between 1986 and December 2009. Patients with neo- or adjuvant treatment and those with pre-operative PSA over 50 were excluded. The sample was divided into three groups: younger than 60, 60 to 69 and over 70. The clinical, pathological variables, biochemical course and need for rescue treatment were analyzed. We consider biochemical relapse as when the PSA values reached values greater than 0.4 in two consecutive measurements. Rescue was defined as the need for hormone treatment or radiotherapy. We then made a comparative study, a univariate survival analysis by Kaplan and Meyer Curves and multivariate by Cox's regression. RESULTS: The median follow-up was 55.1 months. Of the 1012 patients included in the study, 317 patients (31.3%) had biochemical progression and 259 (25.6%) required rescue treatment. We observed that the groups with the older age had a significantly higher PSA and higher stages than the rest. No differences were observed in the Gleason score of the surgical specimen or in the state of the surgical margins. Biochemical relapse free survival at 5 years was 72.3% (CI 66.4-78.2) in patients under 60 years, 65.3% (CI 60.6-70.0) for patients under 70 and 62.2% (CI 53.2-71.1) for patients of 70 years or older; P<.05. In the univariate study, age was a factor that was significantly associated to biochemical relapse. However, it loses interest in the multivariate study and PSA, pathological state and Gleason score regain interest. Rescue treatment free survival did not differ by age groups. CONCLUSIONS: In the current study, worse biochemical evolution of patients over 70 was observed. However, this worse biochemical course was conditioned by clinically more aggressive tumors that, in our opinion, justifies the decision made in regards to the surgical approach taken with these patients. PMID- 23648266 TI - Evaluation of single vs. staged mesophilic anaerobic digestion of kitchen waste with and without microwave pretreatment. AB - Effects of single and dual stage (acidogenic-methanogenic) mesophilic anaerobic digestion (AD) of kitchen waste (KW) was evaluated at hydraulic retention times (HRTs) of 20, 15, 12 and 9 d with and without thermal microwave (MW) pretreatment (145 degrees C). Anaerobic acidification in terms of acid accumulation was superior compared to microaerophilic acidification. Maximum anaerobic acidification of KW was determined to occur with an HRT of 2 d which was then selected for the acidification stage. The dual stage AD system fed with untreated KW produced the maximum biogas and volatile solids (VS) stabilization efficiencies at the shortest HRT of 9 d. Conversely, for free liquid resulting from MW pretreatment of KW the two stage reactor at 20 d HRT produced three fold more methane compared with the untreated free liquid control. However, MW pretreatment and AD of the free liquid fraction only, was not a sustainable treatment option. For KW, staging of the AD process had a greater positive impact on waste stabilization and methane yield compared to single stage reactors or MW pretreatment. KW can be characterized as being a readily biodegradable solid waste; concomitantly it is recommended that digester staging without MW pretreatment be employed to maximize methane yield and production. PMID- 23648267 TI - Comparative SWOT analysis of strategic environmental assessment systems in the Middle East and North Africa region. AB - This paper presents a SWOT analysis of SEA systems in the Middle East North Africa region through a comparative examination of the status, application and structure of existing systems based on country-specific legal, institutional and procedural frameworks. The analysis is coupled with the multi-attribute decision making method (MADM) within an analytical framework that involves both performance analysis based on predefined evaluation criteria and countries' self assessment of their SEA system through open-ended surveys. The results show heterogenous status with a general delayed progress characterized by varied levels of weaknesses embedded in the legal and administrative frameworks and poor integration with the decision making process. Capitalizing on available opportunities, the paper highlights measures to enhance the development and enactment of SEA in the region. PMID- 23648268 TI - Examining labelling effects within discrete choice experiments: an application to recreational site choice. AB - Data from a discrete choice experiment aimed at eliciting the demand for recreational walking trails on farmland in Ireland is used to explore whether some respondents reach their choices solely on the basis of the alternative's label. To investigate this, this paper exploits a discrete mixtures approach that also encompasses continuous distributions to reflect the heterogeneity in preferences for the attributes and alternatives. We find evidence that a proportion of respondents choose on the basis of the label only and that differences emerge between rural and urban respondents. We provide a number of alternative explanations for why this may occur. Results highlight a large impact on welfare measures when we accommodate the fact that a proportion of respondents choose on the basis of the label only. PMID- 23648264 TI - Cardiac vagal control and children's adaptive functioning: a meta-analysis. AB - Polyvagal theory has influenced research on the role of cardiac vagal control, indexed by respiratory sinus arrhythmia withdrawal (RSA-W) during challenging states, in children's self-regulation. However, it remains unclear how well RSA-W predicts adaptive functioning (AF) outcomes and whether certain caveats of measuring RSA (e.g., respiration) significantly impact these associations. A meta analysis of 44 studies (n=4996 children) revealed small effect sizes such that greater levels of RSA-W were related to fewer externalizing, internalizing, and cognitive/academic problems. In contrast, RSA-W was differentially related to children's social problems according to sample type (community vs. clinical/at risk). The relations between RSA-W and children's AF outcomes were stronger among studies that co-varied baseline RSA and in Caucasian children (no effect was found for respiration). Children from clinical/at-risk samples displayed lower levels of baseline RSA and RSA-W compared to children from community samples. Theoretical/practical implications for the study of cardiac vagal control are discussed. PMID- 23648269 TI - Characterization of ion currents of murine CD117(pos) stem cells in vitro and their modulation under AT2 R stimulation. AB - AIM: Hematopoietic stem cells, especially CD117(pos) cells, have been found to possess a regenerative potential in various tissues, in particular cardiac muscle. However, the characterization of the relevant ion currents of stem cells prior to implantation lacks documentation. Activation of angiotensin II type 2 receptor (AT2 R) can lead to further cell differentiation and receptor auto expression and might thus influence electrophysiological properties of CD117(pos) stem cells. This study was designed to functionally characterize membrane currents of CD117(pos) cells under normal and AT2 R-stimulated conditions. METHODS: CD117(pos) murine bone marrow stem cells were isolated with MACS technique and stimulated for the AT2 R with angiotensin II and losartan for 3-5 days prior to patch-clamp measurements. RT-PCR was used to determine channel expression. Endothelial properties were analysed with immunocytochemistry and acLDL uptake assay. RESULTS: A well-expressed inward rectifying current (IKir ) was identified in cultured CD117(pos) cells. Furthermore, a ZD 7288 (HCN channel blocker)-sensitive current component was isolated. Voltage-dependent potassium currents and chloride currents were less expressed. A small fraction of cells demonstrated voltage- and time-dependent inward currents. In AT2 R-stimulated cells inward rectifying the hyperpolarization-induced inward currents were slightly attenuated on the translational level but showed increased mRNA expression. Cultured CD117(pos) cells express CD31 and VEGFR-2 and significantly increased the uptake of acLDL. CONCLUSIONS: CD117(pos) cells do not have properties of action potential-generating cells and moderately change their excitability during AT2 R stimulation. Electrophysiological and molecular properties of control and AT2 R-stimulated cells point to a differentiation to vascular endothelial cells. This could increase beneficial vascularization in injured tissues. PMID- 23648270 TI - New pathways to control inflammatory responses in adipose tissue. AB - Obesity is characterized by the presence of chronic inflammation in adipose tissue, particularly in the visceral compartment, that has been causally linked to development of obesity-associated comorbidities. This link can be either direct or indirect, through induction of insulin resistance. This review summarizes recent evidence on potential pharmacological targets of adipose tissue inflammation, with emphasis on mediators that are being studied for intervention in chronic inflammatory diseases and are therefore viable therapeutical candidates. Specifically, we discuss evidence on the role of the inflammasome and its downstream products as a potential target for anti-inflammatory strategies as well as T regulatory (Treg) cells and mediators involved in the resolution phase of inflammation such as resolvins, protectins, annexin A1 (ANXA1) and galectins as potential targets for novel agonist therapies. PMID- 23648271 TI - Targeted cancer immunotherapy. AB - The understanding that the immune system plays a dual role in cancer progression has led to the recent development of targeted immunotherapies. These treatments, which aim to harness the immune system against cancer, include monoclonal antibodies, immune adjuvants, cell-based therapy and vaccines. Although numerous immune-targeted treatment modalities have entered the clinic, most have shown limited efficacy. The intrinsic heterogeneity and genomic instability of the tumor, coupled with immune suppression induced by both the tumor and its microenvironment, remain the main obstacles to the success of these therapies. We believe that the primary objective of the new generation of therapies must be to reinstate immune surveillance against primary and metastatic tumor cells, while inhibiting the immune suppressive microenvironment. Most probably this will be achieved by combining several treatment modalities. This paper will briefly review current immunotherapies and their promise, as well as the obstacles associated with them. PMID- 23648272 TI - Doctors, have you ever heard about sleep disturbance, erectile dysfunction, and epilepsy? PMID- 23648273 TI - Lovastatin and sudden unexpected death in epilepsy: a matter for debate. PMID- 23648274 TI - A more realistic approach, using dynamic stimuli, to test facial emotion recognition impairment in temporal lobe epilepsy. AB - To explore potentially impaired social functioning in patients with mesial temporal lobe epilepsy (MTLE), we evaluated facial emotion recognition (FER) using dynamic facial stimuli. We evaluated FER in 88 patients with MTLE, including 25 posttemporal lobectomy (PTL) patients, when they watched videos of actors expressing the six basic emotions of happiness, sadness, anger, fear, surprise, and disgust. Thirty-two healthy subjects were examined as controls. The relationships between task, performance, and neurophysiological and radiological variables potentially affecting the ability to recognize moving facial emotions were examined by multivariate analysis. Both the patients with MTLE and the PTL subset demonstrated significantly impaired FER compared with healthy controls. Of the six emotions, they showed impaired recognition of sadness, fear, and disgust. Facial emotion recognition was impaired in patients with chronic MTLE, particularly those with bilateral damage. Failure to recognize emotional expressions, particularly fear, disgust, and sadness, may contribute to difficulties in social functioning and relationship building. PMID- 23648275 TI - Trans-middle temporal gyrus selective amygdalohippocampectomy for medically intractable mesial temporal lobe epilepsy in adults: seizure response rates, complications, and neuropsychological outcomes. AB - OBJECTIVE: Selective amygdalohippocampectomy (AHC) has evolved to encompass a variety of techniques to resect the mesial temporal lobe. To date, there have been few large-scale evaluations of trans-middle temporal gyrus selective AHC. The authors examine a large series of patients who have undergone the trans middle temporal gyrus AHC and assess its clinical and neuropsychological impact. METHODS: A series of 76 adult patients underwent selective AHC via the trans middle temporal gyrus approach over a 10-year period, 19 of whom underwent pre- and postoperative neuropsychological evaluations. RESULTS: Favorable seizure response rates were achieved (92% Engel class I or II), with very low surgical morbidity and no mortality. Postoperative neuropsychological assessment revealed a decline in verbal memory for the left AHC group. No postoperative memory decline was identified for the right AHC group, but rather some improvements were noted within this group. CONCLUSIONS: The trans-middle temporal gyrus selective AHC is a safe and effective choice for management of medically refractory epilepsy in adults. PMID- 23648276 TI - Network analysis reveals patterns of antiepileptic drug use in children with medically intractable epilepsy. AB - Network analysis is an emerging tool for the study of complex systems. Antiepileptic drug (AED) polytherapy in children with medically intractable epilepsy may be considered a complex system, given the heterogeneity of drug combinations that are frequently modified according to clinical indications. The current article presents a concise review of network theory and its application to the characterization of AED use in children with refractory epilepsy. Current and previous AEDs prescribed to 27 children with refractory, localization-related epilepsy were recorded, and network theory was applied to identify patterns of drug administration. Of the fifteen unique AEDs prescribed, levetiracetam possessed the highest betweenness centrality within the network. Furthermore, first generation AEDs were often discontinued, while lacosamide and topiramate were most likely to be initiated. We also identified three subnetworks of AEDs that were commonly coadministered. We conclude that network analysis is an effective method to characterize the complexity of AED administration patterns in children with epilepsy with many promising future applications. PMID- 23648277 TI - Impaired language function in generalized epilepsy: inadequate suppression of the default mode network. AB - We aimed to study the effect of a potential default mode network (DMN) dysfunction on language performance in epilepsy. Language dysfunction in focal epilepsy has previously been connected to brain damage in language-associated cortical areas. In this work, we studied generalized epilepsy (GE) without focal brain damage to see if the language function was impaired. We used functional magnetic resonance imaging (fMRI) to investigate if the DMN was involved. Eleven persons with GE and 28 healthy controls were examined with fMRI during a sentence reading task. We demonstrated impaired language function, reduced suppression of DMN, and, specifically, an inadequate suppression of activation in the left anterior temporal lobe and the posterior cingulate cortex, as well as an aberrant activation in the right hippocampal formation. Our results highlight the presence of language decline in people with epilepsy of not only focal but also generalized origin. PMID- 23648278 TI - Nonlinear system identification for prostate cancer and optimality of intermittent androgen suppression therapy. AB - These days prostate cancer is one of the most common types of malignant neoplasm in men. Androgen ablation therapy (hormone therapy) has been shown to be effective for advanced prostate cancer. However, continuous hormone therapy often causes recurrence. This results from the progression of androgen-dependent cancer cells to androgen-independent cancer cells during the continuous hormone therapy. One possible method to prevent the progression to the androgen-independent state is intermittent androgen suppression (IAS) therapy, which ceases dosing intermittently. In this paper, we propose two methods to estimate the dynamics of prostate cancer, and investigate the IAS therapy from the viewpoint of optimality. The two methods that we propose for dynamics estimation are a variational Bayesian method for a piecewise affine (PWA) system and a Gaussian process regression method. We apply the proposed methods to real clinical data and compare their predictive performances. Then, using the estimated dynamics of prostate cancer, we observe how prostate cancer behaves for various dosing schedules. It can be seen that the conventional IAS therapy is a way of imposing high cost for dosing while keeping the prostate cancer in a safe state. We would like to dedicate this paper to the memory of Professor Luigi M. Ricciardi. PMID- 23648279 TI - A pilot study of prospective memory functioning in early breast cancer survivors. AB - AIMS: To evaluate prospective memory (PM) functioning in early breast cancer (BC) survivors and its association with fatigue and depression. METHODS: The Memory for Intention Screening Test, the Center for Epidemiologic Studies Depression Scale and the Functional Assessment of Cancer Therapy-Fatigue subscale were administered to 80 patients and 80 aged-matched healthy controls. RESULTS: Patients performed more poorly than controls on the memory test (p < 0.001) and had a higher rate of impairment (odds ratio = 5.5, p < 0.01). Fatigue mediated the relationship between Group membership and PM performance. CONCLUSIONS: BC survivors exhibited a clear pattern of PM deficit and fatigue was a major contributor to this deficit. This suggests that a common mechanism may be involved in fatigue symptoms and memory disturbances experienced by patients. Further research is needed to evaluate the role of adjuvant therapy in PM deficits and to explore whether interventions targeted at improving fatigue may also improve memory functioning in BC survivors. PMID- 23648280 TI - The morphology of human hyoid bone in relation to sex, age and body proportions. AB - Morphological aspects of the human hyoid bone are, like many other skeletal elements in human body, greatly affected by individual's sex, age and body proportions. Still, the known sex-dependent bimodality of a number of body size characteristics overshadows the true within-group patterns. Given the ambiguity of the causal effects of age, sex and body size upon hyoid morphology the present study puts the relationship between shape of human hyoid bone and body proportions (height and weight) under scrutiny of a morphological study. Using 211 hyoid bones and landmark-based methods of geometric morphometrics, it was shown that the size of hyoid bones correlated positively with measured body dimensions but showed no correlation if the individual's sex was controlled for. For shape variables, our results revealed that hyoid morphology is clearly related to body size as expressed in terms of the height and weight. Yet, the hyoid shape was shown to result primarily from the sex-related bimodal distribution of studied body size descriptors which, in the case of the height dependent model, exhibited opposite trends for males and females. Apart from the global hyoid shape given by spatial arrangements of the greater horns, body size dependency was translated into size and position of the hyoid body. None of the body size characters had any impact on hyoid asymmetry. Ultimately, sexually dimorphic variation was revealed for age-dependent changes in both size and shape of hyoid bones as male hyoids tend to be more susceptible to modifications with age than female bones. PMID- 23648281 TI - Correction of distortions in distressed mothers' ratings of their preschool children's psychopathology. AB - The often-reported low informant agreement about child psychopathology between multiple informants has lead to various suggestions about how to address discrepant ratings. Among the factors that may lower agreement that have been discussed is informant credibility, reliability, or psychopathology, which is of interest in this paper. We tested three different models, namely, the accuracy, the distortion, and an integrated so-called combined model, that conceptualize parental ratings to assess child psychopathology. The data comprise ratings of child psychopathology from multiple informants (mother, therapist and kindergarten teacher) and ratings of maternal psychopathology. The children were patients in a preschool psychiatry unit (N=247). The results from structural equation modeling show that maternal ratings of child psychopathology were biased by maternal psychopathology (distortion model). Based on this statistical background, we suggest a method to adjust biased maternal ratings. We illustrate the maternal bias by comparing the ratings of mother to expert ratings (combined kindergarten teacher and therapist ratings) and show that the correction equation increases the agreement between maternal and expert ratings. We conclude that this approach may help to reduce misclassification of preschool children as 'clinical' on the basis of biased maternal ratings. PMID- 23648282 TI - Theta burst transcranial magnetic stimulation for the treatment of auditory verbal hallucinations: results of a randomized controlled study. AB - One Hertz (1 Hz) repetitive transcranial magnetic stimulation (rTMS) is an effective therapy for auditory verbal hallucinations (AVH). Theta burst protocols (TBS) show longer after-effects. This single-blind, randomized controlled study compared continuous TBS with 1Hz rTMS in a 10-day treatment. Patients were diagnosed with schizophrenia or schizoaffective disorder. TBS demonstrated equal clinical effects compared to 1Hz TMS. PMID- 23648283 TI - Sero-surveillance for surra in cattle using native surface glycoprotein antigen from Trypanosoma evansi. AB - Surra, caused by Trypanosoma evansi affects a wide range of domestic and wild animals in the tropics, taking a huge toll on the already impoverished economy here. In bovines surra normally develops into a chronic infection that is often associated with severe production losses, yet with no distinct clinical signs making its adequate diagnosis vital. Though direct microscopic observation of T. evansi in circulation may be the diagnostic gold standard for surra, it is insensitive and impractical for population prevalence studies, making sero diagnosis the preferred choice for the latter. In this study, we standardize an ELISA with Concanavalin-A (Con-A) affinity purified T. evansi surface glycoprotein antigen and compare its sensitivity and specificity to direct microscopy of stained thin smears and molecular (PCR) diagnostics. The ELISA was then put on field trial for sero-surveillance of cattle for surra in three geographically distinct populations in the Indian subcontinent, to yield an overall sensitivity and specificity of 100% and 89.15% compared to standard stained thin smear examinations and 95.23% and 90.84% compared to blood PCR examinations. PMID- 23648284 TI - Expression of IL-4, IL-10 and IFN-gamma in the liver tissue of cattle that are naturally infected with Fasciola hepatica. AB - The role of interleukin IL-4, IL-10 and interferon gamma cytokines on natural Fasciola hepatica infection was investigated by quantifying the mRNA levels in liver tissue from chronically infected cattle. IL-4 and IL-10 had higher expression relative to interferon gamma in the liver tissue of infected animals when compared with the control group. The higher levels of IL-10 and IL-4 observed in the present study suggest a synergism between these cytokines, as well as involvement in the suppression of TH1 cell responses and a consequent induction of decreased interferon gamma expression in chronic cattle fascioliasis. The cytokine ratios were positively correlated, indicating a predominance of IL-4 in the chronic phase of infection with respect to interferon gamma and IL-10. Interferon gamma was predominant expressed in the controls, suggesting the involvement of IL-10 in modulating the immune response in favor of IL-4 in infected animals. Our results suggest that the TH2 polarized host immune response previously observed in experimental infection may also be responsible for establishing chronic phase and the maintenance of the natural infection of cattle from endemic areas that are in continuous contact with parasite. PMID- 23648285 TI - Influence of forced air volume on water evaporation during sewage sludge bio drying. AB - Mechanical aeration is critical to sewage sludge bio-drying, and the actual water loss caused by aeration can be better understood from investigations of the relationship between aeration and water evaporation from the sewage sludge bio drying pile based on in situ measurements. This study was conducted to investigate the effects of forced air volume on the evaporation of water from a sewage sludge bio-drying pile. Dewatered sewage sludge was bio-dried using control technology for bio-drying, during which time the temperature, superficial air velocity and water evaporation were measured and calculated. The results indicated that the peak air velocity and water evaporation occurred in the thermophilic phase and second temperature-increasing phase, with the highest values of 0.063 +/- 0.027 m s(-1) and 28.9 kg ton(-1) matrix d(-1), respectively, being observed on day 4. Air velocity above the pile during aeration was 43-100% higher than when there was no aeration, and there was a significantly positive correlation between air volume and water evaporation from day 1 to 15. The order of daily means of water evaporation was thermophilic phase > second temperature increasing phase > temperature-increasing phase > cooling phase. Forced aeration controlled the pile temperature and improved evaporation, making it the key factor influencing water loss during the process of sewage sludge bio-drying. PMID- 23648286 TI - Determining the limits of anaerobic co-digestion of thickened waste activated sludge with grease interceptor waste. AB - Anaerobic co-digestion of thickened waste activated sludge (TWAS) with grease interceptor waste (GIW) from a food service establishment was conducted in lab scale semi-continuous digesters. GIW included the entire contents of the grease interceptor (GI) including fat, oil, and grease (FOG), food residuals, and associated wastewater. GIW was added in step increases to identify the maximum methane production and the corresponding threshold input of GIW that led to inhibition of methanogenesis. The experiment was performed at mesophilic conditions (37 degrees C) with a solids retention time (SRT) of 20 days. The highest GIW addition rate achieved without digester failure was 20% (v/v), or 65.5% (w/w) of volatile solids (VS) added, enhancing the methane yield from 0.180 to 0.752 m3(CH4)/kg(VS added), biogas production from 2.2 * 10(-3) to 1.4 * 10( 2) m(3)/d, and methane content from 60.2% to 70.1%. The methane yield of 0.752 m3(CH4)/kg(VS added) is the highest value reported to date for co-digestion of GIW. Stepwise increases in co-substrate addition led to better microbial acclimation and reduced the GIW inhibitory effect. The limit for GIW addition leading to an inhibited digestion process was identified to be between 20 and 40% (v/v) or 65.5 and 83.5% (w/w) of VS added. The results show the significant benefits of anaerobic co-digestion of GIW and the positive impacts of gradual addition of GIW. PMID- 23648287 TI - Effect of IX dosing on polypropylene and PVDF membrane fouling control. AB - The performance of ion exchange (IX) resin for organics removal from wastewater was assessed using advanced characterisation techniques for varying doses of IX. Organic characterisation using liquid chromatography with a photodiode array (PDA) and fluorescence spectroscopy (Method A), and UV254, organic carbon and organic nitrogen detectors (Method B), was undertaken on wastewater before and after magnetic IX treatment. Results showed partial removal of the biopolymer fraction at high IX doses. With increasing concentration of IX, evidence for nitrogen-containing compounds such as proteins and amino acids disappeared from the LC-OND chromatogram, complementary to the fluorescence response. A greater fluorescence response of tryptophan-like proteins (278 nm/343 nm) for low IX concentrations was consistent with aggregation of tryptophan-like compounds into larger aggregates, either by self-aggregation or with polysaccharides. Recycling of IX resin through multiple adsorption steps without regeneration maintained the high level of humics removal but there was no continued removal of biopolymer. Subsequent membrane filtration of the IX treated waters resulted in complex fouling trends. Filtration tests with either polypropylene (PP) or polyvinylidene fluoride (PVDF) membranes showed higher rates of initial fouling following treatment with high IX doses (10 mL/L) compared to filtration of untreated water, while treatment with lower IX doses resulted in decreased fouling rates relative to the untreated water. However, at longer filtration times the rate of fouling of IX treated waters was lower than untreated water and the relative fouling rates corresponded to the amount of biopolymer material in the feed. It was proposed that the mode of fouling changed from pore constriction during the initial filtration period to filter cake build up at longer filtration times. The organic composition strongly influenced the rate of fouling during the initial filtration period due to competitive adsorption processes, while at longer filtration times the rate of fouling appeared to depend upon the amount of biopolymer material in the feed water. PMID- 23648288 TI - Blood vitamin D(3) metabolite concentrations of adult female bearded dragons (Pogona vitticeps) remain stable after ceasing UVb exposure. AB - Vitamin D deficiency can lead to several health problems collectively called metabolic bone disease (MBD). One commonly kept reptile species prone to develop MBD if managed incorrectly is the bearded dragon (Pogona vitticeps). This study aimed to determine the extent to which adult female bearded dragons fed a diet low in vitamin D can use stored vitamin D and its metabolites to maintain plasma 25(OH)D(3) and 1,25(OH)(2)D(3) concentrations after discontinuing UVb exposure. Blood samples of healthy adult female bearded dragons, exposed to UVb radiation for over 6 months were collected (day 0) after which UVb exposure was discontinued for 83 days and blood was collected. Blood plasma was analysed for concentrations of total Ca, total P, ionized Ca, uric acid, 25(OH)D(3) and 1,25(OH)(2)D(3). There was no significant change in plasma 25(OH)D(3) and 1,25(OH)(2)D(3) concentrations during the study. While total Ca and P in whole blood was found to significantly decrease over time (P < 0.0088 and 0.0016, respectively), values were within the reference range. Plasma ionized Ca tended (P = 0.0525) to decrease during the study. Adult female bearded dragons, previously exposed to UVb, are able to maintain blood vitamin D metabolite concentrations when UVb exposure is discontinued for a period of up to 83 days. PMID- 23648289 TI - Olive flounder (Paralichthys olivaceus) cystatin B: cloning, tissue distribution, expression and inhibitory profile of piscine cystatin B. AB - Among the cystatin superfamily, cystatin B, also known as stefin B, is an intracellular inhibitor that regulates the activities of cysteine proteases, such as papain and cathepsins. In this study, the 536 bp cystatin B cDNA (referred to hereafter as PoCystatin B) was cloned from olive flounder (Paralichthys olivaceus) using a combination of the rapid amplification of cDNA ends (RACE) approach and olive flounder cDNA library screening. To determine the tissue distribution of PoCystatin B mRNA, the expression of PoCystatin B in normal and lipopolysaccharide (LPS)-stimulated flounder tissues were compared with that of the inflammatory cytokines interleukin (IL)-1beta, IL-6, and IL-8 by reverse transcription (RT)-polymerase chain reaction (PCR). The results of the RT-PCR analysis revealed ubiquitous PoCystatin B expression in normal and LPS-stimulated tissues. To characterize the enzymatic activity of PoCystatin B protein, recombinant PoCystatin B protein was overexpressed in Escherichia coli BL21(DE3) cells in the pColdTM TF DNA expression vector as a soluble fusion protein of 67 kDa. PoCystatin B inhibited papain cysteine protease, bovine cathepsin B, and fish cathepsins F and X to a greater extent, whereas fish cathepsins L, S, and K were inhibited to a lesser extent. These results indicate that the enzymatic characteristics of the olive flounder cystatin B are similar to those of mammalian cystatin B proteins, and provide a better understanding of the mechanisms of regulation of cathepsins and cystatins in marine organisms. PMID- 23648291 TI - [A new target in non-small cell lung cancer: ROS1 fusion gene]. PMID- 23648290 TI - Mechanistic studies on the synergistic cytotoxicity of the nucleoside analogs gemcitabine and clofarabine in multiple myeloma: relevance of p53 and its clinical implications. AB - Hematopoietic stem cell transplantation (HSCT) is an established treatment for multiple myeloma (MM), a plasma cell malignancy. To identify an improved pretransplant conditioning regimen, we investigated the cytotoxicity of gemcitabine (Gem) and clofarabine (Clo) combinations toward MM cell lines and patient cell samples. A strong synergism of the two nucleoside analogs, when combined at their approximate IC10 concentrations, was observed. This synergism could be partly due to the observed Gem-mediated phosphorylation and activation of deoxycytidine kinase, resulting in enhanced phosphorylation of Gem and Clo. Their cytotoxicity correlated with a robust activation of the DNA damage response pathway. [Gem+Clo] decreased the mitochondrial membrane potential with a concomitant release of proapoptotic factors into the cytoplasm and nucleus and the activation of apoptosis. Exposure of MM cells to [Gem+Clo] also decreased the level of ribosomal RNA (rRNA), which might have resulted in nucleolar stress, as reported previously, and caused a p53-dependent cell death. A reduction by approximately 50% in the cytotoxicity of Gem and Clo was observed in the presence of pifithrin alpha, a p53 inhibitor. Furthermore, MM cell lines with mutant p53 exhibited greater resistance to Gem and Clo, supporting a role for the p53 protein in these cytotoxic responses. Our results provide a rationale for clinical trials incorporating [Gem+Clo] combinations as part of conditioning therapy for high-risk patients with MM undergoing HSCT. PMID- 23648292 TI - [Host glial cell canceration induced by glioma stem cells in GFP/RFP dual fluorescence orthotopic glioma models in nude mice]. AB - OBJECTIVE: During the process of tissue remodeling in human tumor transplantation models, the roles of the inoculated tumor cells and host tissue in tumor progression is still largely unknown. The aim of this study was to investigate the relationships and interactions between these two sides using GFP-RFP double fluorescence tracing technique. METHODS: Red fluorescence protein (RFP) gene was stably transfected into glioma stem cell line SU3, then SU3-RFP cells were transplanted into the brain of athymic nude mice with green fluorescence protein (GFP) expression. After the intracerebral tumors were formed, the relationship and interaction between GFP cells and RFP cells were analyzed. Highly proliferative GFP cells were screened out, and monocloned with micro-pipetting. DNA content assay, chromosome banding and carcinogenicity test of the GFP cells were performed to observe the GFP cells' cancerous phenotype in nude mice. RESULTS: In the transplantable tumor tissue, besides a great quantity of RFP cells, there were still a proportion of GFP cells and GFP/RFP fusion cells. The proportion of RFP cells, GFP cells and GFP/RFP cells were (88.99 +/- 1.46)%, (5.59 +/- 1.00)%, and (4.11 +/- 1.020)%, respectively. Two monoclonal host GFP cells (H1 and H9) were cloned, which demonstrated the properties of immortality, loss of contact inhibition, and ultra-tetraploid when cultured in vitro. Both H1 and H9 cells expressed CNP, a specific marker of oligodendrocytes. The GFP cells also demonstrated 100% tumorigenic rate and high invasive properties in vivo. CONCLUSIONS: In this glioma transplantation model, the transplanted tumor tissues contained not only transplanted glioma stem cells but also cancerous host GFP cells. Our findings offer important clues to further research on the relationships among different members in the tumor microenvironment. PMID- 23648293 TI - [Antitumor effect of baicalin on rat brain glioma]. AB - OBJECTIVE: To investigate the therapeutic mechanism of baicalin on rat brain glioma. METHODS: Deep brain glioma models were established by injection of glioma cell line C6 cells into the brain of Wistar rats. The rats at 7 days after modeling were randomly divided into tumor control group (0.9% NaCl solution 30 mg*kg(-1)*d(-1) gavage)and experimental groups. The experimental rats was divided into 3 groups: low dose group (50 mg*kg(-1)*d(-1)), middle dose group (100 mg*kg( 1)*d(-1)) and high dose group (200 mg*kg(-1)*d(-1)), given the baicalin by gavage. Pathological and electron microscopic changes were observed. The expressions of p53 and Bcl-2 were determined by immunohistochemistry, and the changes of MRI, the average survival time and body weight of the rats in each group after treatments were analyzed. RESULTS: Compared with the control group, the tumor diameter and volume of high dose group rats before sacrifice were significantly reduced (P < 0.01), and the survival time was significantly prolonged (P < 0.01). Immunohistochemistry revealed strong positive expression rate of mutant p53 (84.47 +/- 3.74)% and moderately positive rate (47.28 +/- 2.38)% in the control group, significantly higher than that in the negative group (12.91 +/- 1.07)% (P < 0.01). The positive rate of mutant p53 of the high dose group was (46.42 +/- 2.19)%, significantly lower than that of the control group (84.47 +/- 3.74)% (P < 0.01). The expression rate of Bcl-2 in the control group was strongly positive (86.51 +/- 4.17)% and moderate positive (48.19 +/- 2.11)%, significantly higher than that of the negative group (10.36 +/- 1.43)% (P < 0.01). Electron microscopy revealed that baicalin caused damages of the cell nuclei and organelles in the gliomas. CONCLUSIONS: Baicalin has significant inhibitory effect on glioma in vivo, and its mechanism may be related to cell apoptosis induced by down-regulated expression of mutant p53, but not related with Bcl-2 expression. PMID- 23648294 TI - [Effect of 5-aza-2'-deoxycytidine on growth and methylation of RUNX3 gene in human pancreatic cancer cell line MiaPaca2]. AB - OBJECTIVE: To investigate the effect of demethylating agent 5-aza-2' deoxycytidine (5-Aza-CdR) on the growth of human pancreatic cancer cell line MiaPaca2 and the expression and methylation of tumor suppressor gene RUNX3. METHODS: Human pancreatic cancer cell line MiaPaca2 cells were treated with different concentrations of 5-Aza-CdR. Morphological changes of MiaPaca2 cells were observed by light microscopy. The activity of cell proliferation was analyzed by MTT assay. The changes of RUNX3 mRNA expression were detected by semi quantitative reverse transcription-polymerase chain reaction (RT-PCR). Changes of RUNX3 gene methylation was detected by methylation-specific polymerase chain reaction. RESULTS: MiaPaca2 cells were treated with 2.5, 5, 10 and 20 umo1/L 5 Aza-CdR, respectively. The inhibition rates of MiaPaca2 cells treated for 24 h were (9.17 +/- 2.15)%, (10.75 +/- 2.04)%, (12.57 +/- 1.64)% and (18.70 +/- 1.51)%, respectively. The inhibition rates were (14.94 +/- 1.68)%, (18.60 +/- 1.57)%, (22.84 +/- 1.58)% and (33.24 +/- 1.53)%, respectively, after 48 h treatment; (21.46 +/- 1.60)%, (28.62 +/- 1.72)%, (35.14 +/- 1.64)% and (45.06 +/- 1.47)%, respectively, after 72 h treatment; and (26.35 +/- 1.71)%, (34.48 +/- 1.69)%, (40.05 +/- 1.60)% and (49.99 +/- 1.61)%, respectively, after 96 h treatment. The differences between inhibition rates of each experimental and control groups (0.00 +/- 0.00)% were statistically significant (P < 0.05). At the same time, the inhibition rates of different concentration groups showed significant differences (P < 0.05). At 48 h, 72 h and 96 h, the inhibition rates of each pair concentration groups showed significant differences (P < 0.05). 5 Aza- CdR inhibited the growth of MiaPaca2 cells, and the higher the concentration, the stronger the inhibition after 24 h. 5-Aza-CdR also reversed the methylation status of RUNX3 gene, and restored the expression of RUNX3 mRNA with a dose-effect relationship. CONCLUSIONS: The methylation of RUNX3 gene is significantly related with the occurrence and development of pancreatic cancer, and abnormal methylation of RUNX3 gene may contribute to the loss of RUNX3 mRNA expression. 5-Aza-CdR may effectively cause reversion of RUNX3 methylation, and treatment with 5-Aza-CdR can reactivate the gene expression and inhibit the cell growth. This may provide a new way for diagnosis and treatment of pancreatic cancer. PMID- 23648296 TI - [Screening for EGFR mutations in lung cancer by a novel real-time PCR with double loop probe and Sanger DNA sequencing]. AB - OBJECTIVE: To map the frequency and types of EGFR gene mutations present in lung cancer tissues. To evaluate the clinical applicability of a novel real-time double-loop probe PCR of which the ADx-EGFR kit is based, and to compare its performance with traditional Sanger DNA sequencing in the detection of somatic mutations of tumor genes. METHODS: A total of 208 formalin-fixed paraffin embedded (FFPE) tumor samples were tested. Genomic DNA of the tissue samples was extracted and purified, and subjected to both traditional PCR amplification, Sanger sequencing of EGFR gene in exon 18, 19, 20, 21, and ADx's EGFR mutation detection kit. The mutation rates for EGFR gene in exon 18, 19, 20, 21, as well as the frequency of each mutation detected by the two methods, were analyzed. RESULTS: The traditional Sanger DNA sequencing technique was successfully performed in 196 out of 208 (94.2%) lung cancer samples, and 22 samples (11.2%) showed EGFR gene mutations. ADx-EGFR kit was successfully used in the lung cancers of all of the 208 cases (100.0%), and 40 samples (19.2%) showed mutations. In the lung cancer samples analyzed, mutations were mainly detected in the exon 19 and exon 21 L858R point mutation, i.e. 4.8% (10/208) and 11.6% (23/208) of total mutations, respectively, and the remaining mutations were rare. CONCLUSIONS: The success rate of ADx-EGFR real-time PCR for formalin-fixed and paraffin-embedded tissues samples is significantly higher than that of Sanger sequencing (P < 0.01). There are significant differences between the two methods. ADx-EGFR real-time PCR shows a much higher successful detection rate and mutation rate of lung cancer tissues compared with that of Sanger sequencing. As a result, the real-time PCR with ADx-EGFR kit is proved to have a good clinical applicability and a strong advantage over the traditional Sanger DNA sequencing. It is an effective and reliable tool for clinical screening of somatic gene mutations in tumors. PMID- 23648295 TI - [Effect of silencing AEG-1 with small interfering RNA on the proliferation and cell cycle of gastric carcinoma SGC-7901 cells]. AB - OBJECTIVE: To explore the effect of down-regulation of astrocyte elevated gene-1 (AEG-1) expression on cell proliferation and cell cycle of gastric carcinoma cells, and its possible molecular mechanism. METHODS: Control siRNA and AEG-1 siRNA were transfected into gastric carcinoma SGC-7901 cells. 48 h after transfection, the cells were divided into 3 groups including untransfected, siRNA control and AEG-1 siRNA transfection groups. Expressions of AEG-1 mRNA and protein in the 3 group cells were detected by real-time quantitative PCR and Western blot. The changes of cell proliferation were examined using CCK-8 kit, and the cell cycle distribution was detected by flow cytometry. Finally, expressions of cell proliferation and cell cycle related proteins were detected by Western blot. RESULTS: Real-time quantitative PCR and Western blot demonstrated that compared with the untransfected and siRNA control groups, expressions of AEG-1 mRNA and protein were significantly down-regulated in the AEG-1 siRNA transfection group (P < 0.05), but there was no significant difference between the untransfected and siRNA control groups (P > 0.05). Furthermore, in vivo experiment confirmed a significant down-regulation of AEG-1 protein in the AEG-1 siRNA transfection group (P < 0.05). In addition, AEG-1 siRNA obviously inhibited the proliferation of SGC-7901 cells at different time points after transfection with AEG-1 siRNA. The percentage of cells in G0/G1 phase in the AEG-1 siRNA transfection group [(61.26 +/- 1.25)%] was significantly higher than those in the untransfected group [(46.17 +/- 1.91)%] and siRNA control group [(46.46 +/- 1.96)%], and there was a significant difference between them (all P < 0.001). Furthermore, the result of Western blotting revealed that down-regulation of AEG-1 expression evoked the down-regulation of cdk2 and cyclin D1 expressions and elevation of p21 expression in vitro and in vivo. CONCLUSIONS: The inhibition of cell proliferation and cell cycle arrest mediated by down regulation of AEG-1 expression may be closely associated with the changes of expression of cell cycle related proteins including cdk2, cyclin D1 and p21. PMID- 23648297 TI - [Comparison of full-field digital mammography and digital breast tomosynthesis on assessment of the lesions in dense breast: a preliminary study]. AB - OBJECTIVE: To compare the performance of full-field digital mammography (FFDM) and digital breast tomosynthesis (DBT) in the assessment of the lesions in dense breast, and to estimate the difference in diagnosis of breast disease by FFDM images alone and FFDM plus DBT images. METHODS: According to the breast imaging reporting and data system (BIRADS), 134 patients were selected. The morphology of the lesions shown on FFDM and DBT were evaluated and compared, and the maximum diameter of the lesions was measured. At first, doctors made the diagnosis of a patient by reading FFDM only. Then they made another diagnosis by combining with DBT images of the same patient. The two diagnoses were compared and analyzed according to the pathology results. RESULTS: One hundred and thirty-four patients were included in this study, and all of them were confirmed by histology (65 benign cases, 69 malignant cases). DBT could show more details about the morphology of the lesions, including the border of the masses, spiculation and vessels. The numbers of those signs detected by DBT were 46, 30 and 3, respectively, while only 33 case with circumscribed masses and 14 cases with spiculation were detected by FFDM. Only the difference of spiculation in heterogeneously dense breast detected by DBT and FFDM was statistically significant (P < 0.05). Of the cases with calcifications, DBT images (reconstructed as a 1-mm-thick slice) showed calcifications superior to FFDM in 2 cases, equal to FFDM in 23 cases, and inferior to FFDM in 11 cases. The difference was statistically significant (P < 0.05). But when thickness was changed into 1 cm, the visibility of calcifications in those cases was equal between FFDM and DBT. The maximum diameter of lesions was 2.46 +/- 1.64 cm in DBT image, and 2.58 +/- 1.62 cm in FFDM image, with a significant difference (P < 0.05). Comparing with reading FFDM images only, the accuracy of FFDM combining with DBT was increased from 88.8% to 91.8%. For FFDM, the AUC of ROC was 0.887, while for DBT it was increased to 0.912, with a non-significant difference (P > 0.05). CONCLUSIONS: DBT is superior to FFDM in the morphological characterization and small calcification in the lesions in dense breast. Combining FFDM and DBT improves the accuracy of diagnosis, but the difference is not statistically significant. PMID- 23648298 TI - [Analysis of the factors affecting pathologic complete response to neoadjuvant chemotherapy in breast cancer patients]. AB - OBJECTIVE: To analyze the factors affecting pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer patients. METHODS: A retrospective cohort study was carried out to analyze the clinical data of 141 breast cancer patients treated with neoadjuvant chemotherapy. The factors affecting pCR and the changes of tumor receptor status before and after treatment were analyzed. RESULTS: Among all the 141 patients, 21 patients (14.9%) achieved pCR. The rate of pCR achieved by regimens of anthracycline combined with taxane was higher (16.8%, 19/113) than that by anthracycline-containing regimens (7.1%, 1/14). The dose intensity of anthracycline had a significant correlation with pCR rate (P < 0.05). The pCR rate in the relative dose intensity of taxane >= 0.85 arm was higher than that of < 0.85 arm (P = 0.02). Eighty patients (56.7%) had completed more than 4 cycles of chemotherapy and the median time to achieve pCR was 6 (3 to 10) cycles. The pCR rate had a significant difference between patients < 6 and >= 6 cycles (7.1% vs. 22.5%,P = 0.01). Multivariate analysis showed that tumor size measured by palpation <= 5 cm and >= 6 chemotherapy cycles were significantly related with pCR rate (P < 0.05). In all the 21 pCR patients, the pre-treatment ER(-), PR(-), HER-2(-) statuses were in 14, 14 and 17 patients, respectively. The status of ER, PR, HER-2 of most patients (74.2%, 69.7% and 87.7%, respectively) was not changed after treatment. Among the patients with changes in receptor status, ER changed from negative to positive was in the majority (37.1%, 13/35 vs. 12.9%, 4/31, P < 0.05), and the percentage of changes in PR and HER-2 status had no significant differences. CONCLUSIONS: The regimens of anthracycline combined with taxane can achieve a higher pCR rate. The lymph node and receptor status before therapy have no significant correlation with pCR. Patients who have primary tumor size <= 5 cm, >= 6 chemotherapy cycles and enough dose intensity are easier to achieve pCR. The receptor status before and after therapy should be determined, and according to any positive results, physicians can chose HER-2 targeted therapy and/or endocrine therapy after surgery to benefit the patients. PMID- 23648299 TI - [Cisplatin-based chronotherapy for advanced none-small cell lung cancer: a randomized controlled study]. PMID- 23648300 TI - [Low dose volume histogram analysis of the lungs in prediction of acute radiation pneumonitis in patients with esophageal cancer treated with three-dimensional conformal radiotherapy]. AB - OBJECTIVE: To investigate the predictive value of low dose volume of the lung on acute radiation pneumonitis (RP) in patients with esophageal cancer treated with three-dimensional conformal radiotherapy (3D-CRT) only, and to analyze the relation of comprehensive parameters of the dose-volume V5, V20 and mean lung dose (MLD) with acute RP. METHODS: Two hundred and twenty-two patients with esophageal cancer treated by 3D-CRT have been followed up. The V5-V30 and MLD were calculated from the dose-volume histogram system. The clinical factors and treatment parameters were collected and analyzed. The acute RP was evaluated according to the RTOG toxicity criteria. RESULTS: The acute RP of grade 1, 2, 3 and 4 were observed in 68 (30.6%), 40 (18.0%), 8 (3.6%) and 1 (0.5%) cases, respectively. The univariate analysis of measurement data:The primary tumor length, radiation fields, MLD and lung V5-V30 had a significant relationship with the acute RP. The magnitude of the number of radiation fields, the volume of GTV, MLD and Lung V5-V30 had a significant difference in whether the >= grade 1 and >= grade 2 acute RP developed or not. Binary logistic regression analysis showed that MLD, Lung V5, V20 and V25 were independent risk factors of >= grade 1 acute RP, and the radiation fields, MLD and Lung V5 were independent risk factors of >= grade 2 acute RP. The >= grade 1 and >= grade 2 acute RP were significantly decreased when MLD less than 14 Gy, V5 and V20 were less than 60% and 28%,respectively. When the V20 <= 28%, the acute RP was significantly decreased in V5 <= 60% group. When the MLD was <= 14 Gy, the >= 1 grade acute RP was significantly decreased in the V5 <= 60% group. When the MLD was >14 Gy, the >= grade 2 acute RP was significantly decreased in the V5 <= 60% group. CONCLUSIONS: The low dose volume of the lung is effective in predicting radiation pneumonitis in patients with esophageal cancer treated with 3D-CRT only. The comprehensive parameters combined with V5, V20 and MLD may increase the effect in predicting radiation pneumonitis. PMID- 23648301 TI - [Prognostic analysis of curative surgery for stage IIIA-N2 non-small cell lung cancer]. AB - OBJECTIVE: To investigate the survival and prognostic factors in patients undergoing potentially curative resection of stage IIIA-N2 non-small cell lung cancer. METHODS: Clinical data of eighty-nine patients, who underwent curative operation from January 2003 to April 2007 in the Peking University First Hospital and were pathologically diagnosed as stage IIIA-N2 NSCLC, were reviewed. The patients were followed up until death or the cut-off date. The overall 3-year and 5-year survival rates were calculated, and Cox proportional hazard model was used to determine the clinical and pathological risk factors and evaluate their influence on the survival. RESULTS: The three-year and five-year survival rates were 51.7% and 31.5%, respectively. The univariate Cox regression analysis revealed five significant factors associated with prognosis: the arm of age < 55, T3 stage, lymphovascular invasion (LVI), multiple positive N2 station and the number of positive N2 nodes > 3 were found to be at increased risk of tumor related death, and those risk factors were confirmed especially in the age >= 55 group. Multivariate Cox regression analysis indicated three independent prognostic factors: T3 stage, LVI and multiple positive N2 station. CONCLUSIONS: The results of this preliminary study show that T3 stage, lymphovascular invasion and N2 level (single or multiple station) are associated with the prognosis of stage IIIA-N2 NSCLC patients after potentially curative resection, and the characteristics of age < 55 and the number of positive N2 nodes > 3 may imply worse prognosis. PMID- 23648302 TI - [Prognosis of hepatocellular carcinoma: a study of 832 cases]. AB - OBJECTIVE: To investigate the prognostic factors of hepatocellular carcinoma. METHODS: The purpose of this study was to retrospectively analyze the surgical outcomes of hepatocellular carcinoma (HCC) in 832 patients who underwent hepatic resection between February 2002 and June 2010 in the Cancer Hospital of Chinese Academy of Medical Sciences. Post-resection prognostic factors were assessed using a univariate Kaplan-Meier analysis and a multivariate Cox proportional hazards model. RESULTS: The overall 1-, 3- and 5-year survival rates were 92.0%, 70.2% and 53.6%, respectively. The disease free survival rates (DFS) were 90.2%, 61.5% and 40.5%, respectively. The univariate analysis showed that a better prognosis for overall survival (OS) was associated with asymptomatic presentation, small tumor, single lesion, high-grade histological differentiation, no vascular tumor embolus, negative serum alpha-fetoprotein (AFP), negative serum alkaline phosphatase (ALP), Child-Pugh class A, no ascites, no/mild cirrhosis, new surgical techniques, no blood transfusion, no regional lymph node metastasis, no major vascular invasion, and no extra-hepatic invasion. The multivariate analysis showed that asymptomatic presentation, small tumor, single lesion, no tumor embolus, negative serum alpha-fetoprotein (AFP), no regional lymph node metastasis, no major vascular invasion, no extra-hepatic invasion, no/mild cirrhosis, and surgical techniques are independent factors for a longer overall survival. CONCLUSIONS: The prognosis of HCC after resection is influenced by a number of factors. Therefore, regularly screening and early diagnosis, applying surgical techniques to minimize the liver injury, and preventing the aggravation of cirrhosis are important measures to improve the overall survival of HCC patients. For those patients with high risk factors of recurrence, routine follow-up is one of the best methods to be recommended. PMID- 23648303 TI - [Analysis of the diagnosis, treatment and prognosis in acute obstruction of proximal and distal colorectal cancers]. AB - OBJECTIVE: The study aimed to review the treatment and prognosis of acute obstruction of colorectal cancers and to compare different treatment strategies of those cancers, and to evaluate the risk factors affecting perioperative complications. METHODS: Clinical data of 184 patients with acute obstruction of colorectal cancer undergone operation were analyzed retrospectively. RESULTS: A total of 184 patients with acute obstruction of colorectal cancer was collected in this study, including 58 patients with proximal and 126 patients of distal colorectal cancers. Perioperative death occurred in 2/58 patients (3.4%) with distal colorectal cancer and 6/126 cases (4.8%) of distal colorectal cancer (P > 0.05). The overall perioperative complications in the two groups were not significantly different (P = 0.794). Among the 58 patients with proximal colorectal cancer, one patient underwent colostomy, but among the 126 patients with distal colorectal cancer, 41 patients underwent colostomy, showing a significant difference between the two groups (P = 0.002). ASA scores (grade 3 - 4), elderly age (>= 70 years) and colon perforation peritonitis were independent prognostic factors associated with perioperative mortality and morbidity. Patients in the self-expandable metallic stent (SEMS) group had a significantly shorter hospital stay (25.4 +/- 8.3) d than that in the emergency surgery group (32.8 +/- 16.4) d, (P = 0.039). CONCLUSIONS: Endoscopic stent implantation provides an acceptable modality of palliation for acute proximal large bowel obstruction caused by malignancies. In acute colorectal cancer obstruction, SEMS can provide a minimally invasive management compared with surgical intervention. PMID- 23648304 TI - [Outcome analysis of simultaneous liver resection for synchronous liver metastases from colorectal cancer]. AB - OBJECTIVE: To analyze the outcomes of simultaneous liver resection for patients who have primary colorectal cancer with synchronous hepatic metastases to see if there is any advantage for doing so. METHODS: We retrospectively analyzed the medical records (1999 - 2009) of 53 consecutive patients with synchronously recognized primary colorectal carcinoma and hepatic metastases who underwent simultaneous (40 patients) or two-stage (13 patients) colonic and hepatic resections performed at our hospital. RESULTS: There was no thirty-day mortality in both groups. The two groups had significant differences in mean operation duration [(212.9 +/- 72.3) min vs. (326.5 +/- 140.2) min, P = 0.014], mean blood loss [(337.5 +/- 298.0) ml vs. (594.6 +/- 430.5) ml, P = 0.020], post-operative hospital stay [(16.2 +/- 8.1) day vs. (25.8 +/- 8.5) day, P = 0.001]. The incidence rates of post-operative complications were 25.0% (10/40) and 53.8% (7/13), respectively, in the two groups (P = 0.053). The 1-, 3-, 5-year survival rates in the simultaneous resection group were 95.0%, 57.0% and 37.4%, respectively, with a median overall survival of 40.0 months and median disease free survival of 14.0 months. The 1-, 3-, 5-year survival rates in the two-stage resection group were 92.3%, 58.7% and 36.7%, respectively, with a median overall survival of 38.0 months and median disease-free survival of 13.0 months. There were no significant differences between the two groups in respect of their survivals (P > 0.05). CONCLUSIONS: Simultaneous colectomy and hepatectomy are safe and efficient for colorectal cancer patients who have synchronous colorectal liver metastases, with less complications and blood loss, and shorter hospital stay compared with the two-stage resection. PMID- 23648305 TI - [Neuroendocrine tumors: analysis of 252 cases]. AB - OBJECTIVE: To investigate the epidemiology, diagnosis, and treatment status of neuroendocrine tumors (NETs) in our hospital. METHODS: Medical records of 252 patients with neuroendocrine tumors diagnosed and treated in our hospital from January 1, 2004 to December 31, 2009 were collected and retrospectively reviewed in this study. The clinicopathological data including age of onset, initial symptoms, primary site, pathological conditions (Sny, CgA, Ki-67), disease stage at diagnosis, treatment, and follow up were analyzed. RESULTS: The gender ratio M/F of the 252 cases was 1.9:1, with mean age of 55.2 years, and the high incidence was in age of 60-69 years. The tumors were located in the gastrointestinal tract (117 cases, 46.4%), broncho-pulmonary system (74 cases, 29.4%), other sites (61 cases, 24.2%) and unknown primary site (2 cases, 0.8%). Their first clinical symptoms vary, depending on the primary site. The common symptoms of primary rectal NETs were changes in bowel habits (29.3%) and diarrhea or constipation (17.5%), and most gastric NETs presented epigastric discomfort (86.4%). Most patients (71.4%) were diagnosed with stage I, II, III disease. Among the 252 cases, there were 110 carcinoids (43.7%), 108 neuroendocrine carcinomas (42.9%), 23 atypical carcinoids (9.1%), five neuroendocrine tumors (2.0%), four Merkel cell tumors (1.6%), and two composite carcinoids (0.8%). 206 patients (81.7%) received surgery, 39 (15.5%) received chemotherapy, and 31 cases (12.3%) were treated by palliative radiotherapy. CONCLUSIONS: This single-center retrospective analysis of data demonstrated that males have a higher incidence rate than females. The most common primary sites of NETs are the digestive tract and lungs. The initial symptoms of NETs are different depending on their primary sites. Good prognosis can be achieved in the majority of patients after surgery, chemotherapy and palliative radiotherapy. PMID- 23648306 TI - [Evaluation of the quality of life in patients with breast cancer at different TNM stages after standardized treatment]. AB - OBJECTIVE: To evaluate the quality of life (QOL) in patients with breast cancer at different TNM stages and to estimate the value of EuroQol Five Dimension Indicator (EQ-5D) in measuring QOL among Chinese breast cancer patients. METHODS: A survey with Quality of Life Instruments for Cancer Patients-Breast Cancer (QLICP-BR) and EQ-5D was undertaken in breast cancer patients who had completed their standardized treatment (except for the endocrine treatment) six months ago. Chi-square test, one-way ANOVA, and covariance analysis were used to evaluate the possible factors influencing the QOL of breast cancer patients. Simultaneously, with the results of Quality of Life Instruments for Cancer Patients-General Module (QLICP-GM, which is included in QLICP-BR.) and the total scores of QLICP BR as standard, we conducted Pearson correlation analysis to evaluate the value of EQ-5D. RESULTS: A total of 178 female breast cancer survivors were collected from March 2010 to September 2010. There were 47 cases (26.4%) at stage 0 and I, 81 cases (45.5%) at stage II, and 50 cases (28.1%) at stage III and IV. The total standardized score of QLICP-BR was 72.55 +/- 3.10 in patients at stage 0 and I, 64.09 +/- 2.69 in patients at stage II and 58.21 +/- 3.00 in patients at stage III and IV. The total standardized score of QLICP-BR and social domain of patients at stage 0 and I were higher than patients at stage II (all P < 0.05). The total standardized score of QLICP-BR, specific domain of breast cancer, psychological, social and physical domains of patients at stage 0 and I were higher than patients at stage III and IV (all P < 0.05). Covariance analysis showed that QOL standardized scores were significantly different across TNM stages when age, degree of education, birth place (metropolis or rural), occupation, domestic income, and medical insurance were controlled (P = 0.002). Correlation analysis indicated that EQ-5D has a positive correlation with QLICP GM and QLICP-BR (all P < 0.05). CONCLUSIONS: QOL of patients with early stage breast cancer is better than those at late stage. Early diagnosis and treatment can improve QOL of breast cancer patients. Chinese version of EQ-5D can well detect the differences of QOL among patients with different TNM stages, which can be used for evaluating QOL in Chinese female breast cancer patients. PMID- 23648307 TI - Propafenone blocks human cardiac Kir2.x channels by decreasing the negative electrostatic charge in the cytoplasmic pore. AB - Human cardiac inward rectifier current (IK1) is generated by Kir2.x channels. Inhibition of IK1 could offer a useful antiarrhythmic strategy against fibrillatory arrhythmias. Therefore, elucidation of Kir2.x channels pharmacology, which still remains elusive, is mandatory. We characterized the electrophysiological and molecular basis of the inhibition produced by the antiarrhythmic propafenone of the current generated by Kir2.x channels (IKir2.x) and the IK1 recorded in human atrial myocytes. Wild type and mutated human Kir2.x channels were transiently transfected in CHO and HEK-293 cells. Macroscopic and single-channel currents were recorded using the patch-clamp technique. At concentrations >1MUM propafenone inhibited IKir2.x the order of potency being Kir2.3~IK1>Kir2.2>Kir2.1 channels. Blockade was irrespective of the extracellular K(+) concentration whereas markedly increased when the intracellular K(+) concentration was decreased. Propafenone decreased inward rectification since at potentials positive to the K(+) equilibrium potential propafenone-induced block decreased in a voltage-dependent manner. Importantly, propafenone favored the occurrence of subconductance levels in Kir2.x channels and decreased phosphatidylinositol 4,5-bisphosphate (PIP2)-channel affinity. Blind docking and site-directed mutagenesis experiments demonstrated that propafenone bound Kir2.x channels at the cytoplasmic domain, close to, but not in the pore itself, the binding site involving two conserved Arg residues (residues 228 and 260 in Kir2.1). Our results suggested that propafenone incorporated into the cytoplasmic domain of the channel in such a way that it decreased the net negative charge sensed by K(+) ions and polyamines which, in turn, promotes the appearance of subconductance levels and the decrease of PIP2 affinity of the channels. PMID- 23648308 TI - Pupil shape as viewed along the horizontal visual field. AB - Changes in pupil size and shape are relevant for peripheral imagery by affecting aberrations and how much light enters and/or exits the eye. The purpose of this study is to model the pattern of pupil shape across the complete horizontal visual field and to show how the pattern is influenced by refractive error. Right eyes of 30 participants were dilated with 1% cyclopentolate, and images were captured using a modified COAS-HD aberrometer alignment camera along the horizontal visual field to +/-90 degrees . A two-lens relay system enabled fixation at targets mounted on the wall 3 m from the eye. Participants placed their heads on a rotatable chin rest, and eye rotations were kept to less than 30 degrees . Best-fit elliptical dimensions of pupils were determined. Ratios of minimum to maximum axis diameters were plotted against visual field angle. Participants' data were well fitted by cosine functions with maxima at (-)1 degrees to (-)9 degrees in the temporal visual field and widths 9% to 15% greater than predicted by the cosine of the field angle . Mean functions were 0.99 cos([ + 5.3]/1.121), R(2) 0.99 for the whole group and 0.99 cos([ + 6.2]/1.126), R(2) 0.99 for the 13 emmetropes. The function peak became less temporal and the width became smaller with increase in myopia. Off-axis pupil shape changes are well described by a cosine function that is both decentered by a few degrees and flatter by about 12% than the cosine of the viewing angle, with minor influences of refraction. PMID- 23648310 TI - Transcendental phenomenology and classic grounded theory as mixed data collection methods in a study exploring fetal alcohol spectrum disorder in New Zealand. AB - BACKGROUND: Despite the risk of 'method slurring', researchers have triangulated within a single qualitative study methods that are philosophically incongruent or in a limited context, are congruent, as with hermeneutic phenomenology and constructivist grounded theory. METHODS/MATERIALS: We aimed to make the case that what works best can be to mix two qualitative methods that are philosophically congruent. Thus, we used transcendental phenomenology (TP) and classic grounded theory (CGT) in synergetic sequence to answer our research question. These methods have not previously been used together and one method would not have sufficed. Using the same participant sample, we sought to explore and understand the daily challenges of living with fetal alcohol spectrum disorder (FASD) since no study to date had addressed these issues within New Zealand. Our retrospective exploratory two-phase sequential design was framed by the meta-theory of pragmatism. It mixed qualitative strategies that are ontologically and epistemologically compatible (i.e. TP and CGT are ontologically realist, but epistemologically idealist). They are useful together for the aim of meaningfully studying the lived experiences of purposively selected participants. Empirical data, as secondary results, provide supportive evidence. CONCLUSION: The first paper from this study was published in J Popul Ther Clin Pharmacol Vol 19(1):e41 e50 when the main findings were reported. This second paper gives greater focus to the methodologies employed and data analysis from the second phase. PMID- 23648309 TI - Food allergy: an enigmatic epidemic. AB - Food allergy is a common disease that is rapidly increasing in prevalence for reasons that remain unknown. Current research efforts are focused on understanding the immune basis of food allergy, identifying environmental factors that may contribute to its rising prevalence, and developing immunotherapeutic approaches to establish immune tolerance to foods. Technological advances such as peptide microarray and MHC class II tetramers have begun to provide a comprehensive profile of the immune response to foods. The burgeoning field of mucosal immunology has provided intriguing clues to the role of the diet and the microbiota as risk factors in the development of food allergy. The purpose of this review is to highlight significant gaps in our knowledge that need answers to stem the progression of this disorder that is reaching epidemic proportions. PMID- 23648311 TI - Semi-automated solid phase extraction method for the mass spectrometric quantification of 12 specific metabolites of organophosphorus pesticides, synthetic pyrethroids, and select herbicides in human urine. AB - Organophosphate and pyrethroid insecticides and phenoxyacetic acid herbicides represent important classes of pesticides applied in commercial and residential settings. Interest in assessing the extent of human exposure to these pesticides exists because of their widespread use and their potential adverse health effects. An analytical method for measuring 12 biomarkers of several of these pesticides in urine has been developed. The target analytes were extracted from one milliliter of urine by a semi-automated solid phase extraction technique, separated from each other and from other urinary biomolecules by reversed-phase high performance liquid chromatography, and detected using tandem mass spectrometry with isotope dilution quantitation. This method can be used to measure all the target analytes in one injection with similar repeatability and detection limits of previous methods which required more than one injection. Each step of the procedure was optimized to produce a robust, reproducible, accurate, precise and efficient method. The required selectivity and sensitivity for trace level analysis (e.g., limits of detection below 0.5ng/mL) was achieved using a narrow diameter analytical column, higher than unit mass resolution for certain analytes, and stable isotope labeled internal standards. The method was applied to the analysis of 55 samples collected from adult anonymous donors with no known exposure to the target pesticides. This efficient and cost-effective method is adequate to handle the large number of samples required for national biomonitoring surveys. PMID- 23648312 TI - Telmisartan inhibits AGE-induced podocyte damage and detachment. AB - Advanced glycation end products (AGE) formed at an accelerated rate under diabetes, could cause podocyte apoptosis, thereby being involved in the development and progression of diabetic nephropathy. Renin-angiotensin system (RAS) plays a role in diabetic nephropathy as well. However, it remains unknown whether there exists a pathophysiological crosstalk between the RAS and AGE in podocyte damage in diabetic nephropathy. Therefore, this study investigated the effects of telmisartan, an angiotensin II (Ang II) type 1 receptor (AT1R) blocker on AGE or Ang II-induced podocyte damage in vitro. We further examined here the effects of AGE on AT1R expression levels in podocytes. AGE or Ang II not only increased DNA damage of podocytes which was evaluated by comet assay, but also induced cell detachment, both of which were significantly blocked by the treatment with telmisartan. AGE significantly increased AT1R levels in podocytes, whereas podocyte Ang II production was modestly stimulated by AGE. Telmisartan alone did not affect the release of lactate dehydrogenase from podocytes. Our present study suggests that AGE could induce podocyte DNA damage and detachment partly via stimulation of the Ang II-AT1R axis, thus providing a novel beneficial aspect of telmisartan in diabetic nephropathy. PMID- 23648314 TI - Bilateral testicular dislocation with pelvic ring fracture: a case report and literature review. AB - We report a case of a bilateral testicular dislocation with B1-1 pelvic-ring fracture according to the modified Tile AO classification, in a patient of 62 years. The mechanism of injury was impaction on the tank of a motorcycle. Symphyseal plate fixation using a Pfannenstiel approach was associated to bilateral orchidopexy through scrotal approach. The posterior pelvic ring was stabilized by iliosacral screwing because the left sacroiliac joint was open. The outcome was favorable without disorders of gonadal function. Systematic testicular palpation and careful CT analysis of the genital organs enabled identification and effective management of these rare urinary tract lesions. PMID- 23648313 TI - Adipokines and endothelial dysfunction in obesity WHO degrees III. AB - Obesity is closely associated with the metabolic syndrome (MetS) and subsequent low-grade inflammation links to endothelial dysfunction (ED) and cardiovascular disease. The impact of adipokines on retinal ED is not fully understood, in particular not in severe obesity. The aim of the study was to identify the association of the MetS and prespecified adipokines on retinal ED in obesity WHO degrees III. 92 obese patients (obesity WHO degrees III) were assessed for the MetS (IDF), neck circumference, adipokines and inflammatory markers (hsCRP, TNFalpha, Il-6, MCP-1, sICAM, sVCAM, IGF-BP3, RBP 4 and adiponectin). Retinal ED as determined by the arterio-venous-ratio (AVR) and retinal vessel diameters (CRAE, CRVE) was measured using retinal photographs. Obese subjects with MetS (MetS+ group) differed from the MetS- by neck circumference, fasting plasma glucose, insulin, HOMA-IR, triglycerides and HDL-C. Importantly, IL-6, sICAM and adiponectin were significantly different between groups, while measures of retinal ED showed no differences. Univariate linear regression revealed a significant association between neck circumference and ED for patients with MetS, and a significant association between adiponectin and CRAE for patients without MetS. This study shows that ED in obesity WHO degrees III is independent of MetS or inflammation and that neck circumference has an impact on ED in obesity WHO degrees III. PMID- 23648315 TI - Anatomic and CT scan assessment of Teres Minor: a new index of trophicity. AB - INTRODUCTION: The present study reports the development of a CT assessment protocol for Teres Minor (TM) trophicity. HYPOTHESIS: Quantitative reproductible Terres Minor assessment on CT estimates the influence of muscle trophicity on the clinical and radiological results of palliative treatment of irreparable rotator cuff tear. MATERIALS AND METHOD: An anatomic study of 30 cadaveric shoulders confirmed a constant anatomic relation between Terres Minor and the inferior pole of the glenoid cavity. This landmark was used to develop a novel CT assessment of TM trophicity. RESULTS: The CT assessment showed excellent inter- and intra observer reproductibility. The protocol defines a trophicity index, T2/G (T2 being TM thickness on axial CT slice, and G the maximum glenoid cavity thickness on axial slice), enabling reproductible TM analysis on preoperative arthro-CT. CONCLUSION: The study validated the CT protocol, allowing application in pre- and postoperative assessment of irreparable rotator cuff tear. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 23648316 TI - Efficacy of first metatarsophalangeal joint lateral release in hallux valgus surgery. AB - INTRODUCTION: Lateral release of the sesamoid ligament complex is one of the key step to the surgical treatment of hallux valgus. Although numerous techniques are available to perform this procedure, there is no accepted consensus on the method of choice. The goal of this study was to evaluate the efficacy of sequential release of lateral soft tissue structures for correction of hallux valgus deformity. PATIENTS AND METHODS: This study included 40 patients, mean age 50.9 years old (+/-17.4), with 49 hallux valgus deformities from mechanical causes. The first metatarsophalangeal angle (M1P1), the intermetatarsal angle (M1M2) and the position of the sesamoids in relation to mechanical axis of M (according to the Research Committee of the American Orthopedic Foot and Ankle Society) were determined on preoperative X-rays. During the procedure, lateral release was performed in several steps: sectioning the metatarsosesamoid suspensory ligament then sectioning the phalangeal insertional band (PIB) and complete detachment of the adductor on the fibular sesamoid ligament. We measured the changes in the M1P1 and M1M2 angles during this step-by-step release. RESULTS: The M1P1 angle decreased during each step of release and went from 29.9 degrees to 11.1 degrees (P<0.001). The M1M2 decreased by 1.70 degrees following medial capusolorrhaphy. Simple capsulorrhaphy reduced the hallux valgus deformity by 8.2 degrees (44%). Release of the metatarsosesamoid suspensory ligament resulted in a decrease of 3.9 degrees (or 21% of total release), release of the PIB in a decrease of 5.1 degrees (27%) and complete detachment of the adductor in a decrease of 1.5 degrees (8%). Thirty six percent of the sesamoids were reduced after metatarsosesamoid ligament resection, 56% after PIB release, and 60% after adductor release. DISCUSSION: Lateral soft tissue release is ensured in most cases by sectioning the metatarsosesamoid suspensory ligament and the PIB. Release of the adductor from the fibular sesamoid has a limited effect. CONCLUSION: Lateral soft tissue release should include sectioning the metatarsosesamoid suspensory ligament and detaching the PIB. This release should be enough to correct the deformity without performing any osteotomy in hallux valgus with M1P1<27 degrees and M1M2<10 degrees , as long as a stable medial plane can be obtained. LEVEL OF EVIDENCE: Level IV. PMID- 23648317 TI - Scale dependency of biocapacity and the fallacy of unsustainable development. AB - Area-based information obtained from remote sensing and aerial photography is often used in studies on ecological footprint and sustainability, especially in calculating biocapacity. Given the importance of the modifiable areal unit problem (MAUP; i.e. the scale dependency of area-based information), a comprehensive understanding of how the changes of biocapacity across scales (i.e. the resolution of data) is pivotal for regional sustainable development. Here, we present case studies on the effect of spatial scales on the biocapacity estimated for two typical river basin and watershed in Northwest China. The analysis demonstrated that the area sizes of major land covers and subsequently biocapacity showed strong signals of scale dependency, with minor land covers in the region shrinking while major land covers expanding when using large-grain (low resolution) data. The relationship between land cover sizes and their change ratio across scales was shown to follow a logarithm function. The biocapacity estimated at 10 * 10 km resolution is 10% lower than the one estimated at 1 * 1 km resolution, casting doubts on many regional and global studies which often rely on coarse scale datasets. Our results not only suggest that fine-scale biocapacity estimates can be extrapolated from coarse-scale ones according to the specific scale-dependent patterns of land covers, but also serve as a reminder that conclusions of regional and global un-sustainability derived from low resolution datasets could be a fallacy due to the MAUP. PMID- 23648319 TI - Effects of experimental imperfections on a spin counting experiment. AB - Spin counting NMR is an experimental technique that allows a determination of the size and time evolution of networks of dipolar coupled nuclear spins. This work reports on an average Hamiltonian treatment of two spin counting sequences and compares the efficiency of the two cycles in the presence of flip errors, RF inhomogeneity, phase transients, phase errors, and offset interactions commonly present in NMR experiments. Simulations on small quantum systems performed using the two cycles reveal the effects of pulse imperfections on the resulting multiple quantum spectra, in qualitative agreement with the average Hamiltonian calculations. Experimental results on adamantane are presented, demonstrating differences in the two sequences in the presence of pulse errors. PMID- 23648318 TI - The effects and outcomes of electrolyte disturbances and asphyxia on newborns hearing. AB - OBJECTIVE: To determine the effect of electrolyte disturbances (ED) and asphyxia on infant hearing and hearing outcomes. STUDY DESIGN: We conducted newborn hearing screening with transient evoked otoacoustic emission (TEOAE) test on a large scale (>5000 infants). The effects of ED and asphyxia on infant hearing and hearing outcomes were evaluated. RESULT: The pass rate of TEOAE test was significantly reduced in preterm infants with ED (83.1%, multiple logistic regression analysis: P<0.01) but not in full-term infants with ED (93.6%, P=0.41). However, there was no significant reduction in the pass rate in infants with asphyxia (P=0.85). We further found that hypocalcaemia significantly reduced the pass rate of TEOAE test (86.8%, P<0.01). In the follow-up recheck at 3 months of age, the pass rate remained low (44.4%, P<0.01). CONCLUSION: ED is a high-risk factor for preterm infant hearing. Hypocalcaemia can produce more significant impairment with a low recovery rate. PMID- 23648320 TI - Manual versus automated gamma-H2AX foci analysis across five European laboratories: can this assay be used for rapid biodosimetry in a large scale radiation accident? AB - The identification of severely exposed individuals and reassurance of the 'worried well' are of prime importance for initial triage following a large scale radiation accident. We aim to develop the gamma-H2AX foci assay into a rapid biomarker tool for use in accidents. Here, five laboratories established a standard operating procedure and analysed 100 ex vivo gamma-irradiated, 4 or 24h incubated and overnight-shipped lymphocyte samples from four donors to generate gamma-H2AX reference data, using manual and/or automated foci scoring strategies. In addition to acute, homogeneous exposures to 0, 1, 2 and 4Gy, acute simulated partial body (4Gy to 50% of cells) and protracted exposures (4Gy over 24h) were analysed. Data from all laboratories could be satisfactorily fitted with linear dose response functions. Average yields observed at 4h post exposure were 2-4 times higher than at 24h and varied considerably between laboratories. Automated scoring caused larger uncertainties than manual scoring and was unable to identify partial exposures, which were detectable in manually scored samples due to their overdispersed foci distributions. Protracted exposures were detectable but doses could not be accurately estimated with the gamma-H2AX assay. We conclude that the gamma-H2AX assay may be useful for rapid triage following a recent acute radiation exposure. The potentially higher speed and convenience of automated relative to manual foci scoring needs to be balanced against its compromised accuracy and inability to detect partial body exposures. Regular re calibration or inclusion of reference samples may be necessary to ensure consistent results between laboratories or over long time periods. PMID- 23648321 TI - Telmisartan ameliorates germ cell toxicity in the STZ-induced diabetic rat: studies on possible molecular mechanisms. AB - Testicular damage is a common clinical problem in diabetic individuals that severely affects the quality of life. The present study investigates the possible protective mechanisms of telmisartan, an angiotensin II-receptor antagonist in the germ cell of diabetic rat. Male SD rats were used and randomized into six groups: control, telmisartan control, diabetic control and diabetic group treated with telmisartan at the doses of 3, 6 and 12mg/kg/day, per oral for 4 weeks. Diabetes was induced by injecting a single dose of streptozotocin (STZ), (55mg/kg) dissolved in ice-cold 10mM citrate buffer; pH 4.4 and administered i.p. immediately after preparation to the SD rats. At the end of the study, rats were sacrificed and the levels of nitrite, superoxide, malondialdehyde (MDA), glutathione (reduced and peroxidase) and superoxide dismutase (SOD) were measured. Germ cell toxicity was evaluated by using sperm count, sperm comet assay, histology of testes and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Further to confirm the oxidative and nitrosative damage, immunohistological quantification of 8-oxo-dG (8-oxo-7,8 dihydro-2'-deoxyguanosine) and 3-nitrotyrosine were evaluated respectively. Results showed that telmisartan significantly restored the levels of nitrite, superoxide, malondialdehyde, and glutathione and superoxide dismutase in diabetic testes. Further, telmisartan significantly increased the sperm counts, reduced apoptotic cell death, sperm DNA damage, oxidative and nitrosative damage in diabetic rat. Western blot analysis showed that telmisartan reduced the testicular inflammation and cell death by down-regulating the expression of NF kappaB, IL-6, TNF-alpha, p-ERK1/2, iNOS, caspase-3 and increasing the PPAR-gamma expression. Results clearly indicate that telmisartan significantly reduced the both oxidative and nitrosative stress, inflammation and cell death in diabetic testes. The present results confirmed that telmisartan exhibited beneficial role in the germ cell of diabetic rat. PMID- 23648322 TI - [Ischaemic nephropathy in an octogenarian patient: long-term follow up after percutaneous revascularisation]. PMID- 23648323 TI - Management of high-risk prostate cancer: radiation therapy and hormonal therapy. AB - The prognosis of high-risk prostate cancer is poor with a high mortality rate. The Radiation Therapy Oncology Group (RTOG) has performed dose-escalation studies of external beam radiation therapy (EBRT) and has developed high-precision radiation therapy (RT) methods such as intensity-modulated RT, carbon ion therapy, and proton beam therapy. High-dose rate brachytherapy (HDR-BT) is also studied as an option for high-risk prostate cancer treatment. Past clinical trials have suggested that the local control rate of high-risk prostate cancer improves with total EBRT dose, even for doses > 70 Gy. Several randomized controlled trials, including RTOG 94-06, have shown significantly better prognoses with higher doses (> 75 Gy) than with lower doses (< 70 Gy). A proton beam therapy trial (PROG 95-09) also showed similar results. A phase II clinical trial (National Institute for Radiological Sciences, Japan; trial 9904) showed that carbon ion therapy resulted in very good biochemical recurrence-free survival rates among high-risk prostate cancer patients, demonstrating particle therapy to be a valid treatment option. RTOG 86-10 showed that short-term neo adjuvant hormonal therapy (HT) was inadequate for high-risk prostate cancer but effective for intermediate-risk prostate cancer, whereas RTOG 92-02 and the European Organisation for Research and Treatment of Cancer (EORTC) 22863 showed significant improvements in the prognosis of high-risk groups receiving long-term (> 2 years) HT combined with definitive RT. Further studies are warranted to elucidate optimal irradiation doses, HT treatment durations, and combination therapy schedules. PMID- 23648324 TI - Extraction and clean-up methods for organochlorine pesticides determination in milk. AB - Organochlorine pesticides (OCPs) can cause environmental damage and human health risks since they are lipophilic compounds with high resistance to degradation and long half-lives in humans. As most persistent OCPs have been banned years ago, it is expected to find these compounds at trace levels in environment. Therefore, increasingly sensitive and reliable analytical techniques are required to ensure effective monitoring of these compounds. The aim of this review is to discuss extraction and clean-up methods used to monitor OCP residues in milk, reported in the last 20 years. To carry out this review, an exhaustive bibliographic review was conducted. Despite the disadvantages of conventional extraction and clean-up methods, such as liquid-liquid, solid-phase or Soxhlet extractions, these procedures are still used due to their reliability. New extraction methods, like solid-phase microextraction, matrix solid-phase dispersion or QuEChERS, have not been thoroughly evaluated for OCP determination in milk. Almost all the methodologies analyzed in this review presented good performance characteristics according to the performance acceptability criteria set in SANCO's procedure. Comparison between limits of quantification (LOQ) and detection (LOD), for the reported methodologies, is not always possible due to the heterogeneity of the units. Thus, researchers should take into account an homogenization of LOD and LOQ units, according to the international regulations and MRLs established. Finally, more research is necessary to obtain the ideal methodology for OCPs determination in milk, which comprises the environmentally friendly characteristics of the new techniques and the reliability of the traditional methodologies. PMID- 23648325 TI - Organic compounds in olive mill wastewater and in solutions resulting from hydrothermal carbonization of the wastewater. AB - Organic components in olive mill wastewater (OMW) were analyzed by exhaustive solvent extraction of the lyophilisate followed by pre-chromatographic derivatization techniques and GC/MS-analysis of the extracts. Simple biophenols including tyrosol (Tyr), hydroxytyrosol (OH-Tyr) and homovanillic alcohol as well as complex biophenols including decarbomethoxy ligostride aglycon and decarbomethoxy oleuropein aglycon proved most abundant analytes. Hydroxylated benzoic and cinnamic acids are less abundant, which may indicate a humification process to have occurred. The pattern of organic components obtained from native OMW was compared with that obtained from hydrothermal carbonization (HTC) of the waste product. Former results provided strong evidence that HTC of OMW at 220 degrees C for 14h results in an almost complete hydrolysis of complex aglycons. However, simple biophenols were not decomposed on hydrothermal treatment any further. Phenol and benzenediols as well as low molecular weight organic acids proved most abundant analytes which were generated due to HTC. Similarly to aglycons, lipids including most abundant acylglycerines and less abundant wax esters were subjected almost quantitatively to hydrolysis under hydrothermal conditions. Fatty acids (FAs) released from lipids were further decomposed. The pathways of volatile analytes in both native OMW and aqueous HTC solutions were studied by solventless headspace-Solid Phase Micro Extraction. Basically, a wide array low molecular alcohols and ketones occurring in native OMW survived the HTC process. PMID- 23648326 TI - Distinguishing dissolved organic matter at its origin: size and optical properties of leaf-litter leachates. AB - Dissolved organic matter (DOM) was leached from eight distinct samples of leaves taken from six distinct trees (red maple, bur oak at three times of the year, two sugar maple and two white spruce trees from disparate soil types). Multiple samples were taken over 72-96h of leaching. The size and optical properties of leachates were assessed using asymmetrical flow field-flow fractionation (AF4) coupled to diode-array ultraviolet/visible absorbance and excitation-emission matrix fluorescence detectors (EEM). The fluorescence of unfractionated samples was also analyzed. EEMs were analyzed using parallel factor analysis (PARAFAC) and principal component analysis (PCA) of proportional component loadings. Both the unfractionated and AF4-fractionated leachates had distinct size and optical properties. The 95% confidence ranges for molecular weight distributions were determined as: 210-440Da for spruce, 540-920Da for sugar maple, 630-800Da for spring oak leaves, 930-950Da for senescent oak, 1490-1670 for senescent red maple, and 3430-4270Da for oak leaves that were collected from the ground after spring thaw. In most cases the fluorescence properties of leachates were different for individuals from different soil types and across seasons; however, PCA of PARAFAC loadings revealed that the observed distinctiveness was chiefly species-based. Strong correlations were found between the molecular weight distribution of both unfractionated and fractionated leachates and their principal component loadings (R(2)=0.85 and 0.95, respectively). It is concluded that results support a species-based origin for differences in optical properties. PMID- 23648327 TI - Regeneration of activated carbon saturated with odors by non-thermal plasma. AB - The dielectric barrier discharge (DBD) regeneration process of an activated carbon (AC) saturated with dimethyl sulfide was studied on a laboratory scale. The results showed sustainable high regeneration efficiency (RE) (>90%) in successive regeneration cycles (10 cycles). Energy density, humidity and oxygen content were key factors for DBD system, with optimum conditions of 761JL(-1), 0 1vol% and 5%, respectively. The high efficiency was likely attributed to the improvement of structure and surface properties of AC by DBD. After the first regeneration, surface area, micropore volume and total pore volume of AC increased by 8%, 23% and 15% respectively, while average pore size decreased by 9.5%. The number of carboxylic groups doubled (from 0.22 to 0.48mmolg(-1)) while that of phenolic groups remarkably decreased (from 0.48 to 0.26mmolg(-1)) after successive regeneration cycles, which helped to maintain high RE. The results suggested DBD as a novel, efficient alternative process for odor-saturated AC regeneration. PMID- 23648328 TI - Study of cytotoxic effects of single-walled carbon nanotubes functionalized with different chemical groups on human MCF7 cells. AB - Functionalization is an important technique to increase the solubility and biocompatibility of single-wall carbon nanotubes (SWCNTs). In this study, we investigated the cytotoxicity of four types of SWCNTs functionalized with hydroxyl, amino, carboxyl and polyethyleneglycol on MCF7 cells. These functionalized SWCNTs (f-SWCNTs) have insignificant effects on mitochondrial activity and ROS production in MCF7 cells at all test concentrations. However, explicit results revealed that all the tested f-SWCNTs could cause changes of cell morphology, induce cell membrane damage, decrease cell adhesion, and increase cell apoptosis. Therefore, this study shows the potential side effects of f-SWCNTs accompanying with the increase of dispersibility and stability in environment or serum (to prevent their aggregation), and highlights the need for further research to examine the potential toxicity of f-SWCNTs before they are used in the environmental and biomedical fields. PMID- 23648329 TI - Per- and polyfluoroalkyl substances in selected sewage sludge in Nigeria. AB - Levels of seven major perfluoroalkyl carboxylates (PFCAs) and three perfluoroalkyl sulfonates (PFSAs) were analyzed for the first time in sludge from wastewater treatment plants from Nigeria. Measurements were performed using an analytical methodology using solid-phase extraction (SPE) and ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS-MS). The method detection limit and method quantification limit was 3pg/g and 9.5pg/g for both analytes (PFCAs and PFSAs) respectively. Typical recoveries ranged from 50% to 104% for spiked mass labeled internal standards of 1ng (absolute value) to 1g of sample. All sludge samples taken from industrial, domestic and hospital wastewater treatment plants contained measurable levels of PFASs. Levels of the quantified perfluoroalkyl carboxylates and perfluoroalkyl sulfonates concentrations ranged from 10 to 597 and 14 to 540pg/g, respectively. The concentrations were therefore lower compared to sewage sludge samples reported in other regions in the world. Perfluoroalkyl carboxylates with carbon chain having >=8 fluorinated carbons were detected in the analyzed sewage sludge samples at higher levels compared to carboxylates with <8 fluorinated carbon chain. The measured concentrations indicate that no PFAS point source for the 10 investigated sewage treatment plants existed. Furthermore the low levels in the four municipal sewage treatment plants in Lagos is a first indication that even in an African megacity like Lagos the PFASs release from households are low until now. The highest PFOS level was found in a hospital sewage sludge (539.6pg/g) possibly indicating (minor) release from medical equipment where some are known to contain PFOS. The PFASs in waste water sludge from a brewery warrant further investigations. PMID- 23648330 TI - PCDD/Fs and dioxin-like PCBs in fish species from Lake Victoria, East Africa. AB - Two commercially important fish species, Nile perch (Lates niloticus) and Nile tilapia (Oreochromis niloticus) belonging to different trophic levels were collected from the Napoleon Gulf and Thurston Bay in Lake Victoria. Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (dl-PCBs) were extracted from the fish muscles and livers using the (13)C isotope dilution method, followed by multiple column chromatography clean-up. Analysis was achieved by a high resolution gas chromatography coupled with a high resolution mass spectrometer. The concentrations of analytes ranged from 0.07 to 0.59pgg(-1) fresh weight (fw) and 0.3-19.0pgg(-1) in L. niloticus and 0.06-0.18 and 0.2-15.7pgg(-1) in O. niloticus, for ?PCDD/Fs and ?dl-PCBs, respectively. Differences in congener concentrations were observed between the two fish species and study sites, and this was attributed to differences in feeding habits and trophic levels. World Health Organization-toxic equivalents (WHO-TEQs) were in the range 0.01 0.16pgTEQg(-1) for the PCDD/Fs and 0.001-0.74pgTEQg(-1) for the dl-PCBs. The TEQ values in the present study were lower compared to those of most fish samples reported in literature and were within permissible levels recommended by the European Union, implying that the fish was fit for human consumption. PMID- 23648331 TI - Polybrominated diphenyl ethers in sediment and caged mussels (Elliptio complanata) deployed in the Niagara River. AB - Polybrominated diphenyl ethers (PBDEs) were detected in caged mussels (Elliptio complanata), deployed in the Niagara River for 3weeks in 2003, 2004 and 2006 and in sediment collected from the river and tributaries. The highest concentrations (measured as the sum of 17 BDE congeners) were in mussels deployed within tributaries to the American side of the River (Cayuga Creek: 11.5ngg(-1) wet wt.; Two Mile Creek 9.5ngg(-1); and Gill Creek: 5.8ngg(-1)). In addition to contributions from the atmosphere, each urban tributary has multiple potential sources of PBDEs which include storm sewers, sewage treatment plants and industries located upstream of the sampling sites. Total PBDE concentrations in sediment ranged from 0.25 to 188ngg(-1). In general, mean mussel tissue concentrations were positively correlated with sediment BDE concentrations. Total PBDE concentrations were higher in mussels deployed at most sites in the Tonawanda Channel which is highly industrialised, compared with mussels deployed on the Canadian side of the upper Niagara River where the surrounding area is generally rural. The sum of BDE-47, -99, -100, -153, -154 and -209 contributed between 92% and 96% of the total BDE concentrations in all of the mussel samples. BDE-209 represented between 39% and 100% of the total BDE in sediment samples. BSAFs in mussels ranged from 1 to 18 depending on the sampling station. Ratios of BDE-47/99 and BDE-100/99 and congener patterns in mussels and sediment were suggestive of the penta formulation as the historical source. PMID- 23648332 TI - Xenoestrogenic and dioxin-like activity in blood of East Greenland polar bears (Ursus maritimus). AB - The aims of the project were to (i) extract the lipophilic persistent organic pollutants (POPs) from the blood of 99 East Greenland polar bears and assess the combined mixture effect on the estrogen receptor (ER) and the aryl hydrocarbon receptor (AhR) mediated transactivity; (ii) To evaluate whether the receptor transactivities were associated with selected POP markers, and (iii) compare the receptor transactivities in polar bears with earlier studies on Greenlandic Inuit. Lipophilic POPs were extracted using a combination of solid-phase extraction (SPE) and high performance liquid chromatography (HPLC). ER mediated transactivity was determined using the ER luciferase reporter MVLN cell assay. The extracts were tested alone (XER) and together with 17beta-estradiol (E2) as a physiological mimic (XERcomp). Dioxins and dioxin-like (DL) compounds were extracted by a combination of SPE and the Supelco Dioxin Prep System(r). AhR mediated dioxin-like transactivity was determined using the AhR luciferase reporter Hepa 1.12cR cell assay. Agonistic ER transactivity was elicited by 19% of the samples, and a further increased E2 induced ER response was found for 52%, whereas 17% antagonized the E2 induced ER response. Positive correlations were found in subadult bears between XER and several POP biomarkers. XER and XERcomp correlated positively to each other. A total of 91% of the polar bear blood extracts elicited agonistic AhR transactivity. The AhR-TCDD equivalent (AhR-TEQ) median levels were higher among adult bears compared to subadult bears, but not significantly. PMID- 23648334 TI - Tissue feature-based intra-fractional motion tracking for stereoscopic x-ray image guided radiotherapy. AB - Real-time knowledge of tumor position during radiation therapy is essential to overcome the adverse effect of intra-fractional organ motion. The goal of this work is to develop a tumor tracking strategy by effectively utilizing the inherent image features of stereoscopic x-ray images acquired during dose delivery. In stereoscopic x-ray image guided radiation delivery, two orthogonal x ray images are acquired either simultaneously or sequentially. The essence of markerless tumor tracking is the reliable identification of inherent points with distinct tissue features on each projection image and their association between two images. The identification of the feature points on a planar x-ray image is realized by searching for points with high intensity gradient. The feature points are associated by using the scale invariance features transform descriptor. The performance of the proposed technique is evaluated by using images of a motion phantom and four archived clinical cases acquired using either a CyberKnife equipped with a stereoscopic x-ray imaging system, or a LINAC equipped with an onboard kV imager and an electronic portal imaging device. In the phantom study, the results obtained using the proposed method agree with the measurements to within 2 mm in all three directions. In the clinical study, the mean error is 0.48 +/- 0.46 mm for four patient data with 144 sequential images. In this work, a tissue feature-based tracking method for stereoscopic x-ray image guided radiation therapy is developed. The technique avoids the invasive procedure of fiducial implantation and may greatly facilitate the clinical workflow. PMID- 23648333 TI - Removal and reductive dechlorination of triclosan by Chlorella pyrenoidosa. AB - Triclosan that is widely used as antimicrobial agent has been detected as contaminant in various aquatic environments. In this work, removal and biodegradation of triclosan in water by using a ubiquitous green alga, Chlorella pyrenoidosa was investigated. When C. pyrenoidosa was exposed to a series concentration of triclosan from 100 to 800ngmL(-1), more than 50% of triclosan was eliminated by algal uptake from the culture medium during the first 1h exposure and reached equilibrium after the 6h treatment. In the biodegradation experiments, a removal percentage of 77.2% was obtained after C. pyrenoidosa was cultivated with 800ngmL(-1) triclosan for 96h. A major metabolite from the reductive dechlorination of triclosan was identified by using liquid chromatography coupled with electrospray ionization-mass spectrometry. The ultrastructural morphology of algal cells grown in the presence of triclosan was observed by using transmission electron microscopy and the growth of algal cells was detected. It was found that the trilcosan treatment resulted in the disruption of the chloroplast and the release of organic material into aquatic environment, which indicated that triclosan may affect membrane metabolism. PMID- 23648335 TI - Community-based Men's Sheds: promoting male health, wellbeing and social inclusion in an international context. AB - Males experience greater mortality and morbidity than females in most Western countries. The Australian and Irish National Male Health Policies aim to develop a framework to address this gendered health disparity. Men's Sheds have a distinct community development philosophy and are thus identified in both policies as an ideal location to address social isolation and positively impact the health and wellbeing of males who attend. The aim of this international cross sectional survey was to gather information about Men's Sheds, the people who attend Men's Sheds, the activities at Men's Sheds, and the social and health dimensions of Men's Sheds. Results demonstrate that Men's Sheds are contributing a dual health and social role for a range of male subgroups. In particular, Men's Sheds have an outward social focus, supporting the social and mental health needs of men; health promotion and health literacy are key features of Men's Sheds. Men's Sheds have an important role to play in addressing the gendered health disparity that males face. They serve as an exemplar to health promotion professionals of a community development context where the aims of male health policy can be actualized as one part of a wider suite of global initiatives to reduce the gendered health disparity. PMID- 23648336 TI - Experiences of being a control group: lessons from a UK-based randomized controlled trial of group singing as a health promotion initiative for older people. AB - Existing randomized controlled trials within the health field suggest that the concept of randomization is not always well understood and that feelings of disappointment may occur when participants are not placed in their preferred arm. This may affect a study's rigour and ethical integrity if not addressed. We aimed to test whether these issues apply to a healthy volunteer sample within a health promotion trial of singing for older people. Written comments from control group participants at two points during the trial were analysed, together with individual semi-structured interviews with a small sample (n = 11) of this group. We found that motivation to participate in the trial was largely due to the appeal of singing and disappointment resulted from allocation to the control group. Understanding of randomization was generally good and feelings of disappointment lessened over time and with a post-research opportunity to sing. Findings suggest that measures should be put in place to minimize the potential negative impacts of randomized controlled trials in health promotion research. PMID- 23648339 TI - [Clinical characteristic and management of HER-2 positive node negative small tumor breast cancer (pT1abN0)]. PMID- 23648337 TI - AXL and MET crosstalk to promote gonadotropin releasing hormone (GnRH) neuronal cell migration and survival. AB - The membrane tyrosine kinase receptors, AXL and MET, are implicated in GnRH neuron migration and/or survival. We hypothesized that the receptors with their ligands, GAS6 and HGF, respectively may cross-talk in GnRH neuronal function. In NLT GnRH neuronal cells, MET co-immunoprecipitated with AXL, although HGF or GAS6 did not transphosphorylate AXL or MET, respectively. Co-expression of a kinase dead AXL blocked HGF activation of MET and indirectly AKT and p38MAPK. Silencing of AXL decreased HGF's ability to phosphorylate MET and activate AXL's downstream effectors, p38MAPK and AKT. HGF/MET signaling modulated neuron migration dependent and independent of AXL co-expression and p38MAPK. Conversely, AXL's control of GnRH neuronal survival was dependent on HGF/MET signaling. Together, these data support that the importance of membrane tyrosine kinase receptor crosstalk to regulate neuronal cell-specific developmental functions. PMID- 23648338 TI - Elevation of miR-221 and -222 in the internal mammary arteries of diabetic subjects and normalization with metformin. AB - Diabetes is a major risk factor for cardiovascular disease and is associated with increased intimal thickening and accelerated vascular smooth muscle cell (VSMC) proliferation. We measured the expression of two microRNAs that promote intimal thickening, miR-221/222, and mRNA encoding a downstream target, p27(Kip1), in internal mammary artery (IMA) segments collected from 37 subjects undergoing coronary artery bypass grafting. The segments were stratified into three groups: non-diabetic subjects (ND), diabetic subjects not on metformin (DMMet-), and diabetic subjects on metformin (DMMet+). The DMMet- group exhibited a significant increase in miR-221/222 and decrease in p27(Kip1) mRNA compared to both the ND and DMMet+ groups. miR-221/222 levels inversely correlated with metformin dose. VSMCs isolated from the IMAs of the DMMet- group proliferate at a faster rate than those of the ND and DMMet+ groups. Further studies into the importance of miR-221/222 in the increased intimal thickening observed in diabetic subjects is warranted. PMID- 23648340 TI - [Effects of polysomy 17 on HER-2 gene and protein expression and its clinicopathologic significance in breast cancer]. AB - OBJECTIVE: To explore the effects of polysomy 17 on human epidermal growth factor receptor-2 (HER-2) testing and study its clinicopathologic significance. METHODS: We retrospectively analyzed the HER-2 status by fluorescence in situ hybridization (FISH) and HER-2 protein expression by immunohistochemistry (IHC) in a cohort of 619 patients with invasive breast cancer. The relationship between polysomy 17 and various clinicopathologic parameters was assessed. RESULTS: Polysomy 17 was observed in 31.8% of cases, but more frequently in the IHC(3+) (41.9%) than in the IHC(2+)(27.7%) and IHC(1+/0) (11.1%) subgroup (P = 0.001). There was no significant correlation between the frequency of polysomy 17 and HER 2 status in each IHC subgroup (P > 0.05). Among the cases without gene amplification by FISH, 9 of 15 IHC(3+) cases showed polysomy 17. As compared with the amplified group, un-amplified polysomy 17 patients were associated with such good prognostic indicators as greater hormone receptor positivity (P < 0.001) and lower Ki-67 index (P = 0.003) with a trend towards those with neither amplification or polysomy. CONCLUSION: The frequency of polysomy 17 is partially correlated with HER-2 protein expression but not HER-2 amplification. And polysomy 17 is a major factor in strong HER-2 protein overexpression in 3+ non amplified cases. Tumors displaying un-amplified polysomy 17 resemble more HER-2 negative than HER-2-positive counterparts. PMID- 23648341 TI - [Effects of high glucose on in vitro invasiveness of human breast cancer cell line MDA-MB-435]. AB - OBJECTIVE: To explore the effects and underlying mechanisms of high glucose on in vitro invasiveness of human breast cancer cell line MDA-MB-435. METHODS: The invasiveness of MDA-MB-435 was determined by Matrigel-coated transwell chambers. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were employed to analyze the cellular expression of matrix metalloproteinase-9/matrix metalloproteinase-2/E-cadherin (MMP-9/MMP-2/E-cadherin) gene/protein. RESULTS: The invasive breast cancer cell numbers of each group (Glu 5.5, 11 and 25 mmol/L) were 50 +/- 5, 65 +/- 6 and 77 +/- 3 respectively. Cellular invasion was dramatically enhanced in the Glu 11 and 25 mmol/L group compared with the 5.5 mmol/L group. The MMP-9/MMP-2 protein expression increased significantly in the Glu 11 and 25 mmol/L groups compared with 5.5 mmol/L group while high glucose (Glu 11 and 25 mmol/L group) down-regulated significantly the E-cadherin mRNA/protein expression. CONCLUSION: High glucose can promote the in vitro invasiveness of human breast cancer cells through the altered expression of MMP 9/MMP-2/E-cadherin. PMID- 23648342 TI - [Effects of vinorelbine plus cisplatin as second-line neoadjuvant chemotherapy regimen in the treatment of breast cancer]. AB - OBJECTIVE: To study the value of a combination of vinorelbine and cisplatin (NP) as second-line neoadjuvant chemotherapy regimen for primary breast cancer. METHODS: Primary breast cancer patients on neoadjuvant chemotherapy and non responsive to anthracyclines plus taxanes received the NP regimen. The clinical objective response was evaluated with dynamic contrast-enhanced magnetic resonance imaging (MRI) according to RECIST 1.1 before operation. The pathological response was evaluated by the Miller-Payne grading system. And the toxicities were observed and evaluated according to National Cancer Institute Common Terminology Criteria Version 3.0 (NCI-CTC v3.0). RESULTS: A total of 33 breast cancer patients were examined. The outcomes were complete remission (CR, n = 0, 0%), partial remission (PR, n = 16, 48.5%), stable disease (n = 17, 51.5%) and progressive disease (n = 0, 0%). The clinical responsive rate (CR + PR) rate was 48.5%. The pathological response rates were G1 (n = 6, 18.2%), G2 (n = 6, 18.2%), G3 (n = 10, 30.3%), G4 (n = 9, 27.2%) and G5 (n = 2, 6.1%). And the pathological response (G3+G4+G5) was found in 21 cases (63.6%). The most common toxicities included neutropenia and nausea/vomiting. No serious toxicities were observed. CONCLUSION: As a well-tolerated and effective regimen, NP regimen may be recommended as an option of second-line neoadjuvant chemotherapy regimen for primary breast cancer. PMID- 23648343 TI - [Clinical observation of sunitinib treatment for refractory advanced breast cancer ulcer]. AB - OBJECTIVE: To observe the preliminary efficacies and adverse events of sunitinib in the treatment of metastatic breast cancer ulcer. METHODS: From December 2008 to May 2010, patients with advanced breast cancer ulcer took a single sunitinib. The dosage was adjusted on the basis of adverse events. And clinical response was evaluated. RESULTS: Nine patients with advanced breast cancer ulcer finished the treatment. The objective response and the clinical benefit time to progression of sunitinib were 3 and 7 patients with metastatic breast cancer ulcer, and the median time to progression (TTP) was 2.0 months. The most common adverse events included fatigue, hand-foot syndrome, neutropenia, thrombocytopenia and hypertension. CONCLUSION: Single-agent sunitinib treatment of refractory advanced breast cancer ulcer has marked efficacies. However, neutropenia, thrombocytopenia and hypertension are the major dose-limited toxicities. PMID- 23648344 TI - [Abnormality and significance of interleukin-9 and CD4(+)interleukin-9(+) T-cells in peripheral blood of patients with systemic lupus erythematosus]. AB - OBJECTIVE: To examine the protein and mRNA levels of interleukin-9(IL-9) and the frequencies of CD4(+)IL-9(+)T-cells in peripheral blood of patients with systemic lupus erythematosus (SLE) and explore the roles of double positive T cells and IL 9 in the pathogenesis of SLE and the effects of glucocorticoid. METHODS: Twenty eight hospitalized SLE patients were recruited and 12 healthy volunteers selected as normal controls. The mRNA levels of IL-9 in peripheral blood were measured by real time-polymerase chain reaction (RT-PCR), plasma protein of IL-9 by enzyme linked immunosorbent assay (ELISA) and frequencies of CD4(+)IL-9(+)T-cells by flow cytometry. And the differences between two groups and the effects of glucocorticoid were analyzed. RESULTS: (1) The mRNA levels of IL-9 were significantly elevated in SLE patients as compared with normal controls (P < 0.01). The serum levels of IL-9 were significantly higher in active and inactive SLE patients than those in healthy individuals (68 +/- 11 vs 26 +/- 6 ng/L, P < 0.01; 56 +/- 14 vs 26 +/- 6 ng/L, P < 0.05). The percentages of CD4(+)IL-9(+)T cells increased in active SLE patients (1.96% +/- 0.31%) versus inactive SLE patients (0.89% +/- 0.13%, P < 0.01) and healthy controls (0.28% +/- 0.05%, P < 0.001). And it was higher in inactive SLE patients than that in controls (P < 0.05). (2) The serum levels of IL-9 and the frequencies of CD4(+)IL-9(+)T-cells were positively correlated with SLE disease activity index (SLEDAI). (3) The frequencies of CD4(+)IL-9(+)T-cells and the serum levels of IL-9 in 8 untreated active SLE patients decreased at weeks 1, 2 and 3 after the therapy of methylprednisolone (0.8 mg*kg(-1)*d(-1)) versus those at pre-treatment. CONCLUSION: The abnormalities of IL-9 and CD4(+)IL-9(+)T-cells may play an important role in the pathogenesis of SLE. And the frequencies of CD4(+)IL-9(+)T cells and the levels of IL-9 are evaluative parameters of SLE activity and severity. PMID- 23648345 TI - [A cross-sectional survey on current status of type 2 diabetes mellitus with overweight or obesity in Guangdong province]. AB - OBJECTIVE: To explore the glycemic control status and related risk factors of overweight or obesity patients with type 2 diabetes mellitus (T2DM) in Guangdong province. METHODS: The medical records of overweight or obesity patients with T2DM from 60 tertiary and secondary hospitals in Guangdong Province were collected by questionnaire and physical examination. And the clinical data were analyzed to explore the influencing factors of glycemic control. The HbA1c level was used to assess glycemic control. HbA1c < 7.0% indicated that glycemic control was up to standard. RESULTS: From August 2011 to March 2012, 5241 T2DM patients were recruited. The scope of current analysis was restricted to 4768 subjects with true data and deficiency no more than 5%. There were 2252 males and 2516 females. The age range was from 16 to 90 years, a median age 59.0 (50.0 - 69.0) years, onset age of diabetes 52.0 (44.0 - 60.0) years; a range of disease duration from 1 day to 42 years and a median of 5.0 (2.0 - 11.0) years. The median body mass index was 26.33(24.88 - 28.34) kg/m(2) and median waist circumference 93.0 (88.0 - 100.0) cm. Median HbA1c was 8.1% (6.9% - 10.1%) and only 26.2% patients reached the target level of HbA1c < 7.0%. Influencing factors of poor glycemic control were central obesity, high levels of resting heart rate, concurrent fatty liver and high intensity of treatment. And influencing factors of good glycemic control were regular exercises, smoking cessation, regular glycemic monitoring and good control of total cholesterol/triglyceride. CONCLUSION: A majority of Guangdong type 2 diabetics fail to achieve target values for glycemic control. There is an urgent need for comprehensive management for improving glycemic control. PMID- 23648346 TI - [Surgical treatment for hypertrophic obstructive cardiomyopathy: a report of 118 cases]. AB - OBJECTIVE: To assess the clinical outcomes of transaortic extended septal myectomy on early and midterm survival of patients with hypertrophic obstructive cardiomyopathy (HOCM). METHODS: From October 2009 to April 2012, 118 consecutive patients underwent extended Morrow's procedure for HOCM. There were 69 males and 49 females with an average age of (46 +/- 13) years. Their clinical data were analyzed retrospectively. Preoperative transthoracic, intraoperative transoesophageal and postoperative transthoracic echocardiography was performed to assess septal thickness, left ventricular outflow tract (LVOT) gradient, mitral valve function and systolic anterior motion (SAM) of anterior mitral valve leaflet, etc. Concomitant surgical procedures were performed if other cardiac diseases required surgical interventions. Follow-up study was carried out during subsequent clinic visits at outpatient department and through telephone interviews with patients and their relatives. RESULTS: The septal thickness was (25 +/- 7) mm. SAM was detected in all. The in-hospital mortality was 0.8% (1/118) since one patient died of multiple organs failure one week later. Postoperative echocardiography demonstrated marked reduction in LVOT gradient (92 +/- 22 vs 13 +/- 10 mm Hg (1 mm Hg = 0.133 kPa), P = 0.000), New York Heart Association (NYHA) class (2.9 +/- 0.6 vs 1.2 +/- 0.4, P = 0.000) and significant improvement in mitral regurgitation. Concomitant surgical procedures were performed in 45 cases (38.1%, all for preexisting conditions). Complications included complete atrioventricular block (n = 3), first degree atrioventricular block (n = 6), complete left bundle branch block (n = 51), intraventricular conduction delay or left anterior division block (n = 26), transient renal dysfunction (n = 2) and intra-aortic-balloon-pumping (n = 2). No other severe complication was observed. During a follow-up period of 1 - 27 (7 +/- 6) months, there was no readmission or death. All patients reported significant increase in physical ability and obvious decrease in limiting symptoms. At the latest follow up, the NYHA functional class maintained grade I-II in all. And mitral regurgitation remained absent or mild. CONCLUSION: Surgical procedure for HOCM patients is both safe and efficacious. It provides an excellent relief of LVOT obstruction. PMID- 23648347 TI - [Retrospective analysis on therapeutic effect of autologous hematopoietic stem cell transplantation in multiple myeloma patients]. AB - OBJECTIVE: To evaluate the efficacy and prognostic factors of autologous hematopoietic stem cell transplantation (ASCT) in multiple myeloma (MM) patients. METHODS: Retrospective analysis was performed in 27 MM patients undergoing ASCT at our hospital from May 2004 to August 2011. After comparing with 28 patients achieving very good partial response (VGPR) or better outcome and not undergoing ASCT, the impact on the extent of response, progression-free survival (PFS) and overall survival (OS) as well as related prognostic factors of MM patients were analyzed. RESULTS: All patients successfully underwent hematopoietic reconstruction without transplantation-related mortality. The complete remission (CR) rate of ASCT group increased from 25.9% (7/27) at pre-ASCT to 70.4% (19/27) at post-ASCT (P < 0.01). The estimated 5-year rate of progression-free survival was 56.2% (median not reached) in the ASCT group and 24.9% (median 29 months) in the non-ASCT group (P < 0.05). The 5-year probability of overall survival was 52.2% (median not reached) in the ASCT group and 33.1% (median 60 months) in the non-ASCT group (P > 0.05). Univariate analysis in ASCT group demonstrated that maintenance/consolidation therapy was associated with PFS (P = 0.010) and OS (P = 0.008).Patients on induction therapy containing bortezomib and early ASCT maintenance therapy all survived without disease progression until final follow up (P = 0.010). CONCLUSIONS: ASCT can further increase the CR rate, prolong PFS and probably OS. The incorporation of novel agents into induction, consolidation and maintenance phases has optimized the anti-myeloma activity of ASCT and may be important for improved long-term outcomes. PMID- 23648348 TI - [Autopsy clinicopathologic comparison in different age groups of patients with coronary atherosclerosis]. AB - OBJECTIVE: To explore the features of coronary atherosclerosis among the patients at different ages and examine their risk factors and pathological characteristics. METHODS: Retrospective analysis was performed for the clinicopathologic data of 87 patients with coronary atherosclerosis confirmed through autopsy from February 1986 to December 2011 at our hospital. They were divided into 3 groups according to age (20 - < 40 years, n = 12; 40 - < 60 years, n = 24; >= 60 years, n = 51). Comparative analysis was performed for the degree of coronary artery stenosis and cardiac pathological changes, vulnerable plaque occurrence and morphological features of acute coronary syndrome among different patient groups. RESULTS: There were 56 males and 31 females with a mean age of 66.8 years (range: 23 - 80). Great statistical differences existed in the degree of coronary artery stenosis between different genders (P < 0.05) while there was no significant difference among the above age groups (P > 0.05). In the above age groups of patients with acute coronary syndrome, the incidence of big lipid core was 23.5%, 38.5% and 53.8% (chi(2) = 6.282, P = 0.043), that of thin fibrous cap 29.4%, 41.0% and 58.8% (chi(2) = 6.589, P = 0.037), that of inflammatory cell in 2 filtration 58.8%, 69.2% and 85.0% (chi(2) = 7.435, P = 0.024) and that of calcification formation 35.3%, 56.4% and 71.3% respectively (chi(2) = 8.599, P = 0.014). And the incidence of vulnerable plaque occurrence was 76.5%, 84.6% and 88.8% (chi(2) = 1.850, P = 0.397) in the above age groups. CONCLUSIONS: The features and risk factors of coronary atherosclerosis are different according to different ages and genders. Thus we should pay more attention to the early diagnosis and reasonable treatments of young patients and those with both mild coronary stenosis and vulnerable plaque. PMID- 23648349 TI - [Impact on tyrosinase expression and export from endoplasmic reticulum by inhibition of 26S proteasome]. AB - OBJECTIVE: To determine the impact on tyrosinase expression and export from endoplasmic reticulum by inhibition of 26S proteasome. METHODS: Western blot was used to detect 26S proteasome from 8 vitiligo patients and 4 healthy controls. Melanocytes were incubated with proteasome inhibitor (lactacystin) and further detected as follows: cell survival by MTT assay, proteasome activity with fluorescence, ultrastructure observation with electron microscope, co localization of tyrosinase and calreticulin (endoplasmic reticulum marker) by confocal laser scanning microscopy and 26S proteasome and tyrosinase with Western blot. RESULTS: The 26S proteasome expression level from lesions of vitiligo (1.05 +/- 0.40) was significantly lower than the donor sites (1.82 +/- 0.88) and the healthy controls (1.88 +/- 0.16) (P < 0.05). But no significant difference existed between the latter two groups (P > 0.05). Compared to the untreated group, a 12-h incubation of 10 umol/L lactacystin showed inhibitory effects on melanocytes (0.999 +/- 0.110 vs 1.372 +/- 0.127, P < 0.05) and significantly decreased proteasome activity (0.234 +/- 0.019 vs 1, P < 0.01). Expansion rate of endoplasmic reticulum in the lactacystin group (1.91 +/- 0.17) was significantly higher than that of the untreated cells (1.17 +/- 0.11) (P < 0.05). More tyrosinase co-localized with calreticulin in endoplasmic reticulum in lactacystin treated cells was observed than that of the untreated group. Compared with the untreated group, significantly decreased levels of tyrosinase (146 +/- 10 vs 269 +/- 8, P < 0.01) and tyrosinase activity (0.159 +/- 0.017 vs 0.221 +/- 0.019, P < 0.01) were shown in the lactacystin group (P < 0.05). CONCLUSIONS: Significantly decrease of 26S proteasome is found in lesions of vitiligo patients. Inhibition of 26S proteasome may lead to expansion of endoplasmic reticulum of melanocytes, impact export of tyrosinase from melanocyte endoplasmic reticulum and expression of tyrosinase. PMID- 23648350 TI - [A comparative study of trans-umbilicus laparoendoscopic one-trocar surgery and trans-umbilicus and abdominal wall two-trocar surgery in the treatment of pediatric hydrocele]. AB - OBJECTIVE: To explore the feasibility and clinical efficacies of umbilical one trocar laparoendoscopic surgery versus trans-umbilicus and abdominal wall two trocar laparoendoscopic surgery in the treatment of pediatric hydrocele. METHODS: Retrospective comparative analysis was conducted for 78 cases of hydrocele undergoing laparoscopic surgery at our hospital from January 2012 to May 2012. They were divided into two groups of umbilical one-trocar laparoscopic surgery (one-trocar, n = 32) and trans-umbilicus and abdominal wall two-trocar laparoscopic surgery (two-trocar, n = 46). And their profiles of operative duration, post-operative hospital stay and treatment cost were compared. RESULTS: All procedures were successful. No case converted into open surgery. Visual field of both methods was similar, but two-trocar group had a flexible visual angle. During a follow-up period of 3 - 6 months, there was no occurrence of postoperative complications. The average operative duration was (20 +/- 10) min at one side and (31 +/- 11) min at both sides in one-trocar group versus (20 +/- 8) min and (29 +/- 9) min in two-trocar group. There were no statistical significance (all P > 0.05). Cost in one-trocar group was (5199 +/- 599) yuan RMB and (5117 +/- 684)yuan RMB in two-trocar group (P > 0.05). CONCLUSIONS: Trans umbilicus laparoendoscopic one-trocar surgery is both feasible and safe in the treatment of pediatric hydrocele. Compared with two-trocar laparoscopic surgery, both approaches are similar in terms of operative duration, post-operative hospital stay and treatment cost. Since there is a single hidden navel scar, the former is labor-saving, may be handled by one operator and offers better cosmetic outcomes. PMID- 23648351 TI - [Alpha-linolenic acid improves insulin sensitivity in obese patients]. AB - OBJECTIVE: To explore the effects of alpha-linolenic acid on insulin sensitivity in obese patients. METHODS: From October 2011 to April 2012, 16 patients received an oral dose of alpha-linolenic acid for 8 weeks.Oral glucose tolerance test (OGTT) and insulin releasing test were performed before and after treatment. Homeostasis model assessment insulin resistance (HOMA-IR) index and area under curve of insulin (AUCI) were calculated to evaluate the insulin sensitivity. The levels of serum triglyceride, free fatty acids (FFA), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured after an overnight fast. RESULTS: Obese patients had significantly elevated serum insulin, triglyceride, FFA, IL-6 and TNF-alpha versus the subjects in normal control group (all P < 0.05). Obese patients were also more insulin-resistant than normal subjects based on a higher HOMA-IR (P < 0.05). Decreased serum insulin, triglyceride, FFA, IL-6 and TNF-alpha were observed after treatment. With the administration of alpha linolenic acid, HOMA-IR and AUCI significantly decreased in obese patients (HOMA IR: 1.8 +/- 0.2 vs 1.2 +/- 0.3, P < 0.05; AUCI: 1151 +/- 505 vs 768 +/- 347, P < 0.05). CONCLUSION: alpha-linolenic acid increases peripheral insulin sensitivity in obese patients and it may aid the prevention and treatment of type 2 diabetes mellitus and atherosclerotic vascular diseases. PMID- 23648352 TI - [Clinical analysis of hypoparathyroidism with altered serum muscle enzymes: report of 41 cases]. AB - OBJECTIVE: To examine the clinical features of hypoparathyroidism (HP) with altered serum muscle enzymes and explore the correlations with age, gender, disease duration, serum total calcium, serum total phosphorus and parathyroid hormone (PTH). METHODS: From January 2005 to October 2011, a total of 41 HP patients at our hospital were retrospectively analyzed. RESULTS: There were 16 patients with elevated serum muscle enzymes and 25 with normal serum muscle enzymes. The former group included 11 patients of idiopathic hypoparathyroidism (IHP) and 5 of pseudohypoparathyroidism (PHP); serum calcium was (1.53 +/- 0.25) mmol/L and serum phosphorus (2.1 +/- 0.6) mmol/L; medians of creatine kinase (CK), lactic dehydrogenase (LDH), aspartate amino transfer enzymes (AST) were 309 (126 - 10 046), 279 (131 - 741) and 27 (17 - 467) U/L in HP patients respectively. And the latter group included 20 IHP patients and 5 PHP ones; serum calcium was (1.64 +/- 0.29) mmol/L and serum phosphorus (2.2 +/- 0.6) mmol/L. The levels of serum muscle enzyme were compared before and after treatment in the former group. And they significantly declined with the rising serum level of calcium after treatment. The serum levels of CK (r = -0.82), LDH (r = -0.55) and AST (r = -0.56) in HP patients with elevated serum muscle enzymes had a negative correlation with the serum level of calcium (all P < 0.05). And there was no correlation with age, gender, disease duration or serum total phosphorus (P > 0.05). CONCLUSION: Elevated serum muscle enzymes in HP patients have a negative correlation with serum level of calcium and there is no correlation with age, gender, disease duration, serum total phosphorus or parathyroid hormone. And elevated serum muscle enzymes are gradually restored with the normalized serum level of calcium. PMID- 23648353 TI - [Effect of tumor necrosis factor-alpha on expression of interleukin-17 receptor C in pulmonary microvascular endothelial cells in rats]. AB - OBJECTIVE: To explore the effects of tumor necrosis factor-alpha (TNF-alpha) or methylprednisolone on the expression of interleukin-17 receptor C (IL-17RC) in rat pulmonary microvascular endothelial cells (RPMVEC). METHODS: Culture RPMVEC were randomly divided into dose-dependent and time-dependent groups. In dose dependent group, cells were cultured with TNF-alpha (0, 0.1, 1, 10 ug/L TNF alpha) for 3 h. In time-dependent group, cells were cultured with TNF-alpha (10 ug/L) for 0, 1, 3, 6, 12 h. In the drug intervention group, cells were cultured with TNF-alpha (10 ug/L) or methylprednisolone (200 ug/L) +TNF-alpha (10 ug/L) for 3 h respectively. The expression of IL-17RC in isolated and cultured RPMVEC was identified by reverse transcription-polymerase chain reaction (RT-PCR), Western blot and immunocytochemistry. The changes of IL-17RC mRNA were detected by RT-PCR after the stimulation of RPMVEC by TNF-alpha or methylprednisolone. RESULTS: RT-PCR and Western blot revealed that IL-17RC mRNA and protein were present in RPMVEC. The product of IL-17RC immunocytochemical reaction was predominantly located in cytoplasm and cytomembrane. In RPMVEC TNF-alpha significantly up-regulated IL-17RC mRNA in a dose-dependent manner (0 ug/L TNF alpha group: 0.241 +/- 0.010, 0.1 ug/L TNF-alpha group: 0.372 +/- 0.017, 1 ug/L TNF-alpha group: 0.452 +/- 0.017, 10 ug/L TNF-alpha group: 0.643 +/- 0.042, F = 33.774, P < 0.05). In time-dependent group, the expression of IL-17RC mRNA rose at 1 h (0.417 +/- 0.038), peaked at 3 h (0.674 +/- 0.018), then decreased gradually at 6 h (0.378 +/- 0.035), but stayed higher at 12 h (0.318 +/- 0.032). When compared with 0 h group (0.197 +/- 0.008), there were significant differences (F = 37.903, P < 0.05). Methylprednisolone caused a marked attenuation of TNF-alpha-induced IL-17RC expression (0.333 +/- 0.031 vs 0.660 +/- 0.026, F = 89.637, P < 0.05). CONCLUSIONS: IL-17RC is predominantly present in cytomembrane and cytoplasm of RPMVEC. TNF-alpha up-regulates the expression of IL 17RC mRNA. Methylprednisolone inhibits the elevated expression of IL-17RC mRNA induced by TNF-alpha so as to relieve the inflammatory response of PMVEC. PMID- 23648354 TI - [Inhibitory effects of luteolin on human gastric carcinoma xenografts in nude mice and its mechanism]. AB - OBJECTIVE: To explore the in vivo anticancer effects of luteolin with BGC-823 gastric carcinoma xenografts in nude mice and elucidate its mechanism. METHODS: After modeling of gastric carcinoma xenografts in nude mice, 40 BALB/c (nu/nu) nude mice were randomly divided into 5 groups (n = 8 each). And an intraperitoneal injection of luteolin was administered at 10 mg/kg (low-dose), 20 mg/kg (middle-dose) and 40 mg/kg (high-dose) groups. And 5-fluorouracil (30 mg/kg) and control groups were also established. The growth curves of xenografts in nude mice were drawn and weight inhibition rates measured. The morphological features were detected by hematoxylin and eosin staining. And the protein expression levels of vascular endothelial growth factor A (VEGF-A) and matrix metalloproteinase 9 (MMP-9) were measured by immunohistochemistry. RESULTS: In vivo tumor formation test showed that tumor volume in nude mice treated with luteolin was smaller than that of control group. Tumor weights of high-dose luteolin group were lighter than those of the control ((0.29 +/- 0.01) vs (0.38 +/- 0.03) g). And the difference was statistically significant (P < 0.01). The rate of tumor inhibition in high-dose luteolin group was up to 24.87%. Lymphocytic invasion of tumor tissue was observed under light microscope in the treatment groups. Results of immunohistochemistry showed the positive cell integral of VEGF in middle and high-dose luteolin groups were 1.25 +/- 0.17 and 1.00 +/- 0.07 respectively. Both were significantly lower than that of control group (1.50 +/- 0.15, both P < 0.05). The positive cell integral of MMP-9 in high dose luteolin group was markedly lower than that of control group (3.75 +/- 1.43 vs 9.00 +/- 1.08, P < 0.01). CONCLUSIONS: Luteolin can effectively inhibit the in vivo growth of gastric tumor. The mechanism may be correlated with the stimulation of immune response and the down-regulated expressions of VEGF-A and MMP-9. PMID- 23648356 TI - Pharmacological strategies for targeting BAT thermogenesis. AB - Biopsies following positron emission tomography coupled to computer tomography (PET-CT) imaging have confirmed the presence of thermogenically active brown adipose tissue (BAT) in adult humans, leading to suggestions that it could be stimulated to treat obesity and its associated morbidities. The mechanisms regulating thermogenesis in BAT are better understood than ever before, and many new hypotheses for increasing the amount of brown fat or its activity are currently being explored. The challenge now is to identify safe ways to manipulate specific aspects of the physiological regulation of thermogenesis, in a manner that will be bioenergetically effective. This review outlines the nature of these regulatory mechanisms both in terms of their cellular specificity and probable effectiveness given the physiological paradigms in which thermogenesis is activated. Similarly, their potential for being targeted by new or existing drugs is discussed, drawing on the known mechanisms of action of various pharmacological agents and some probable limitations that should be considered. PMID- 23648358 TI - Proceedings of the International Society for Haemaphereis (ISFH) meeting, The Hague, April,2012. PMID- 23648355 TI - Evidence relevant to untargeted and transgenerational effects in the offspring of irradiated parents. AB - In this article we review health effects in offspring of human populations exposed as a result of radiotherapy and some groups exposed to chemotherapy. We also assess risks in offspring of other radiation-exposed groups, in particular those of the Japanese atomic bomb survivors and occupationally and environmentally exposed groups. Experimental findings are also briefly surveyed. Animal and cellular studies tend to suggest that the irradiation of males, at least at high doses (mostly 1Gy and above), can lead to observable effects (including both genetic and epigenetic) in the somatic cells of their offspring over several generations that are not attributable to the inheritance of a simple mutation through the parental germline. However, studies of disease in the offspring of irradiated humans have not identified any effects on health. The available evidence therefore suggests that human health has not been significantly affected by transgenerational effects of radiation. It is possible that transgenerational effects are restricted to relatively short times post exposure and in humans conception at short times after exposure is likely to be rare. Further research that may help resolve the apparent discrepancies between cellular/animal studies and studies of human health are outlined. PMID- 23648357 TI - Air pollutants, genes and early childhood acute bronchitis. AB - BACKGROUND: Studies have reported gene-by-environment interaction for chronic respiratory conditions but none on acute illnesses in children. We investigated, longitudinally, whether genotype modifies the relationship of environmental exposures (second-hand tobacco smoke, polycyclic aromatic hydrocarbons, particulate matter <2.5MUm (PM2.5)) with acute bronchitis in children below two years. METHODS: A random sample of 1133 children, born between 1994 and 1998, in two districts of the Czech Republic, was followed-up from birth, of which 793 were genotyped. Pediatric records were abstracted for respiratory illnesses. Second-hand tobacco smoke exposure from household members was obtained through questionnaires and verified using urine cotinine. Air monitoring provided estimates of ambient polycyclic aromatic hydrocarbons and PM2.5. Additionally, we collected information on a range of potential confounders including breastfeeding history, indoor fuel use, other children in household, maternal characteristics, ambient temperature etc. DNA was extracted from tissues taken from the middle of the placenta, opposite the umbilical cord. We examined six single nucleotide polymorphisms (GSTM1, GSTP1, GSTT1, CYP1A1 MspI, EPHX1 exon 3 and 4) and one (EPHX1) diplotype. To investigate effect measure modification we constructed logistic regression models using generalized estimating equations (for repeated observations) stratified by genotypes. RESULTS: The EPHX1 low activity diplotype consistently imparts greater susceptibility to bronchitis from second-hand tobacco smoke, polyclic aromatic hydrocarbons (PAH) and PM2.5. Each of these three classes of exposure also showed elevated risk for bronchitis in the presence of either one or two histidines at exon 3 and exon 4 of EPHX1. Additional effect modifiers include CYP1A1 and GSTT1. CONCLUSION: Several xenobiotic metabolizing genes may modify the impact of second-hand tobacco smoke and ambient air pollutants, polycyclic aromatic hydrocarbons and PM2.5, on acute bronchitis in preschool children. PMID- 23648359 TI - Glutamate-AMPAR interaction in a model of synaptic transmission. AB - Over the last several years we have investigated the excitatory synaptic response by means of a mathematical model based on a detailed description of the synapse geometry, the Brownian motion of Glutamate molecules and their binding to postsynaptic receptors. Recently, the basic model has been modified for the numbers, the size and the 3D structure of receptors according to new data from the literature. Some results of simulations performed with the updated model are shown here. They were aimed to study the synaptic response in relation to the binding probability, to the probable height of the receptors in the synaptic cleft, and to the space-time distribution of Glutamate/Receptor collisions. A first series of simulations permitted to determine a possible range of values for the binding probability of Glutamate to receptors. Other simulations, investigating the changes induced on the synaptic response by the variations of the height of AMPA receptors in synaptic cleft, allowed to identify the height producing the higher amplitude peak of the mEPSCs. Finally, two new statistical descriptors for analyzing the synaptic response were presented. The first is based on the study of the space distribution of the number of Glutamate/Receptor collisions. Simulations investigating the effects of an increasing eccentricity of the releasing vesicle allowed assessing this method. The second one considers the inter-collision times between Glutamate molecules and binding sites. The results of some of the last simulations demonstrated its capacity to highlight the subtleties and the randomness underlying the activation of the receptors. This article is part of a Special Issue entitled Neural Coding 2012. PMID- 23648360 TI - Prenatal immune challenge in rats increases susceptibility to seizure-induced brain injury in adulthood. AB - Maternal infection during pregnancy is associated with an increased risk of neurodevelopmental injury. Our aim was to investigate whether prenatal immune challenge could alter susceptibility to seizure-induced brain injury in adulthood. Pregnant Wistar rats were injected intraperitoneally with lipopolysaccharide (LPS) or normal saline (NS) at days 15 and 16 of gestation. At postnatal day 45, seizure susceptibility was assessed in response to lithium pilocarpine (LiPC) in adult offspring. Four groups were studied, including normal control (NS-NS), prenatal inflammation (LPS-NS), adult seizure (NS-LiPC), and "two-hit" (LPS-LiPC) groups. Our results demonstrated that adult rat offspring of LPS-exposed dams showed significantly greater susceptibility to LiPC-induced seizures, as well as enhanced hippocampal neuronal injury after seizures. Furthermore, animals in the "two-hit" group performed significantly worse than those from the NS-LiPC group in the open field test and Morris water maze. Our findings suggest that prenatal immune activation can cause a long-lasting increase in seizure susceptibility and predispose the brain to the damaging effect of seizures later in life. PMID- 23648361 TI - Edaravone protects against glutamate-induced PERK/EIF2alpha/ATF4 integrated stress response and activation of caspase-12. AB - As a potent novel free radical scavenger, edaravone has been reported to have neuroprotective effects in both animals and humans, although the underlying mechanisms remain unclear. In our study, we generated a culture of almost pure neurons, which were either left untreated or prophylactically treated with edaravone, then exposed to 50 MUM glutamate for 10 min. Flow Cytometry analysis was performed to quantify the percentage of apoptotic cells. Ultrastructural changes in the endoplasmic reticulum were observed by electron microscopy. Immunofluorescence and western blotting for activation of selected related molecules, including PERK (pancreatic ER stress kinase, PERK), eIF2alpha (eukaryotic initiation factor 2 alpha, eIF2alpha), activating ATF4 (transcription factor 4, ATF4), and caspase-12 were examined. In Glutamate-treated group, the sequential activation of PERK, eIF2alpha, ATF4 and caspase-12 could be observed at 2h, and peaked at 24h. However, treatment with edaravone was able to prevent these changes. In addition, the morphology of the endoplasmic reticulum was better preserved and the percentage of apoptotic cells was lower in cells treated with edaravone. In summary, our results indicate that ISR (PERK/eIF2/ATF4 integrated stress response, ISR) plays an important role in glutamate-induced nerve cells death, and that edaravone could protect neurons against glutamate induced endoplasmic reticulum stress. PMID- 23648362 TI - Surgical treatment of impending and pathological fractures of tibia. AB - Advances in adjuvant and neoadjuvant therapies have improved the prognosis of cancer patients leading to an increasing incidence of bone metastases and consequent long bone fractures. In the present study the authors consider the indications and the different surgical options of treatment of tibial pathological lesions. 13 patients (14 lesions, 6 pathological fractures), treated according to histotype and lesion localisation, were retrospectively evaluated. Using generic outcome instruments such as the Eastern Cooperative Oncology Group (ECOG) and Quality of life questionnaire of European Organization for Research and Treatment of Cancer (QLQ-C30) pain, mobility and use of analgesics were evaluated before and after surgery. In all patients, mechanical stabilisation of the osteolytic lesion was achieved. There were no pathological fractures, and no implant mechanical failure. All patients reported pain relief, with a relevant reduction in the amount of analgesics used. Surgical treatment of tibial metastases has to be decided taking into consideration the histotype, localisation of the metastases and life expectancy. The treatment has to be all encompassing in a solitary lesion in patients with a good prognosis but less invasive in plurimetastatic patients with poor prognosis. Acquisition of good mechanical stability is crucial for a successful outcome. PMID- 23648363 TI - Unravelling the debate over orthopaedic trauma transfers: The sender's perspective. AB - INTRODUCTION: The increasing frequency of orthopaedic trauma patient transfers is an issue at the centre of the current orthopaedic "call crisis" that has the potential to inundate resources at tertiary care centres. Appropriateness of transfer has been investigated only from the perspective of receiving surgeons. This study investigates the suitability and reasons for orthopaedic trauma patient transfer from the viewpoint of transferring surgeons. METHODS: A questionnaire was e-mailed to a random sampling of 500 active members of the American Academy of Orthopaedic Surgeons and the Orthopaedic Trauma Association. Surgeons were split into three groups: senders of trauma patients (senders); orthopaedic traumatologists who receive transfers (traumatologist receivers); and other trauma transfer receivers that are not traumatologists (non-traumatologist receivers). The perceived complexity and appropriateness for transfer of eight virtual case scenarios were determined, along with the specific reasons mitigating transfer. RESULTS: 51 Senders, 90 traumatologist receivers, and 98 non traumatologist receivers completed 239 surveys. There was agreement between groups for case complexity and appropriateness for transfer in five of eight case scenarios (p<0.05). Fracture complexity was cited as the primary reason for transfer by 28% of senders. However, just as common was a lack of resources at the sending hospital; OR equipment (18%), critical care services (18%), and inability to handle the immediacy of the case (7%) were also cited. Likelihood of uninsured status was the least common reason for transfer (1%). CONCLUSIONS: In most cases, both senders and receivers of orthopaedic trauma have similar viewpoints regarding fracture complexity and appropriateness of transfer. Sending surgeons cite case complexity and a lack of hospital resources as the primary reasons for patient transfer. Mandating increased call for orthopaedic surgeons at non-trauma centres without a concomitant increase in hospital resources is unlikely to substantially reduce unnecessary patient transfers to higher level facilities. PMID- 23648364 TI - The remarkable conformational plasticity of alpha-synuclein: blessing or curse? AB - The aggregation of the protein alpha-synuclein (alpha-SYN) is believed to be a critical event in Parkinson's disease (PD). alpha-SYN is characterized by a remarkable conformational plasticity, adopting different conformations depending on the environment. In vitro, alpha-SYN lacks a well-defined structure. Therefore, it was classified as an 'intrinsically disordered protein'. A debate has recently begun over how alpha-SYN behaves in the cell: is it an intrinsically disordered protein or a stable tetramer with a low propensity for aggregation? In this review, we discuss the aggregation of alpha-SYN and describe factors that influence this process and their potential relevance in PD pathogenesis. We address the ways in which aggregated alpha-SYN mediates toxicity and might lead to PD, and propose possible therapeutic strategies. PMID- 23648365 TI - Novel adaptations to zinc-silicate glass polyalkenoate cements: the unexpected influences of germanium based glasses on handling characteristics and mechanical properties. AB - Aluminum-free glass polyalkenoate cements (GPC) have been hindered for use as injectable bone cements by their inability to balance handling characteristics with mechanical integrity. Currently, zinc-based, aluminum-free GPCs demonstrate compression strengths in excess of 60MPa, but set in c. 1-2 min. Previous efforts to extend the setting reaction have remained clinically insufficient and are typically accompanied by a significant drop in strength. This work synthesized novel glasses based on a zinc silicate composition with the inclusion of GeO2, ZrO2, and Na2O, and evaluated the setting reaction and mechanical properties of the resultant GPCs. Germanium based GPCs were found to have working times between 5 and 10 min, setting times between 14 and 36 min, and compression strengths in excess of 30 MPa for the first 30 days. The results of this investigation have shown that the inclusion of GeO2, ZrO2, and Na2O into the glass network have produced, for the first time, an aluminum-free GPC that is clinically viable as injectable bone cements with regards to handling characteristics and mechanical properties. PMID- 23648366 TI - Heterogeneous PVA hydrogels with micro-cells of both positive and negative Poisson's ratios. AB - Many models describing the deformation of general foam or auxetic materials are based on the assumption of homogeneity and order within the materials. However, non-uniform heterogeneity is often an inherent nature in many porous materials and composites, but difficult to measure. In this work, inspired by the structures of auxetic materials, the porous PVA hydrogels with internal inby concave pores (IICP) or interconnected pores (ICP) were designed and processed. The deformation of the PVA hydrogels under compression was tested and their Poisson's ratio was characterized. The results indicated that the size, shape and distribution of the pores in the hydrogel matrix had strong influence on the local Poisson's ratio, which varying from positive to negative at micro-scale. The size-dependency of their local Poisson's ratio reflected and quantified the uniformity and heterogeneity of the micro-porous structures in the PVA hydrogels. PMID- 23648367 TI - Critical review of: Efficacy of immunoglobulin plus prednisone for prevention of coronary artery prednisolone for prevention of coronary abnormalities in severe Kawasaki disease (RAISE study): a randomized, open-label, blinded-endpoints trial. PMID- 23648368 TI - [Usefulness of plasma lopinavir levels during pregnancy]. PMID- 23648369 TI - [Anaerobic bacteria 150 years after their discovery by Pasteur]. AB - In 2011 we celebrated the 150th anniversary of the discovery of anaerobic bacteria by Louis Pasteur. The interest of the biomedical community on such bacteria is still maintained, and is particularly focused on Clostridium difficile. In the past few years important advances in taxonomy have been made due to the genetic, technological and computing developments. Thus, a significant number of new species related to human infections have been characterised, and some already known have been reclassified. At pathogenic level some specimens of anaerobic microflora, that had not been isolated from human infections, have been now isolated in some clinical conditions. There was emergence (or re-emergence) of some species and clinical conditions. Certain anaerobic bacteria have been associated with established infectious syndromes. The virulence of certain strains has increased, and some hypotheses on their participation in certain diseases have been given. In terms of diagnosis, the routine use of MALDI-TOF has led to a shortening of time and a cost reduction in the identification, with an improvement directly related to the improvement of data bases. The application of real-time PCR has been another major progress, and the sequencing of 16srRNA gene and others is currently a reality for several laboratories. Anaerobes have increased their resistance to antimicrobial agents, and the emergence of resistance to carbapenems and metronidazole, and multi-resistance is a current reality. In this situation, linezolid could be an effective alternative for Bacteroides. Fidaxomicin is the only anti-anaerobic agent introduced in the recent years, specifically for the diarrhoea caused by C.difficile. Moreover, some mathematical models have also been proposed in relation with this species. PMID- 23648370 TI - Effects of oxytocin on behavioral and ERP measures of recognition memory for own race and other-race faces in women and men. AB - Oxytocin has been shown to affect human social information processing including recognition memory for faces. Here we investigated the neural processes underlying the effect of oxytocin on memorizing own-race and other-race faces in men and women. In a placebo-controlled, double-blind, between-subject study, participants received either oxytocin or placebo before studying own-race and other-race faces. We recorded event-related potentials (ERPs) during both the study and recognition phase to investigate neural correlates of oxytocin's effect on memory encoding, memory retrieval, and perception. Oxytocin increased the accuracy of familiarity judgments in the recognition test. Neural correlates for this effect were found in ERPs related to memory encoding and retrieval but not perception. In contrast to its facilitating effects on familiarity, oxytocin impaired recollection judgments, but in men only. Oxytocin did not differentially affect own-race and other-race faces. This study shows that oxytocin influences memory, but not perceptual processes, in a face recognition task and is the first to reveal sex differences in the effect of oxytocin on face memory. Contrary to recent findings in oxytocin and moral decision making, oxytocin did not preferentially improve memory for own-race faces. PMID- 23648371 TI - Improved dose-volume histogram estimates for radiopharmaceutical therapy by optimizing quantitative SPECT reconstruction parameters. AB - In radiopharmaceutical therapy, an understanding of the dose distribution in normal and target tissues is important for optimizing treatment. Three dimensional (3D) dosimetry takes into account patient anatomy and the nonuniform uptake of radiopharmaceuticals in tissues. Dose-volume histograms (DVHs) provide a useful summary representation of the 3D dose distribution and have been widely used for external beam treatment planning. Reliable 3D dosimetry requires an accurate 3D radioactivity distribution as the input. However, activity distribution estimates from SPECT are corrupted by noise and partial volume effects (PVEs). In this work, we systematically investigated OS-EM based quantitative SPECT (QSPECT) image reconstruction in terms of its effect on DVHs estimates. A modified 3D NURBS-based Cardiac-Torso (NCAT) phantom that incorporated a non-uniform kidney model and clinically realistic organ activities and biokinetics was used. Projections were generated using a Monte Carlo (MC) simulation; noise effects were studied using 50 noise realizations with clinical count levels. Activity images were reconstructed using QSPECT with compensation for attenuation, scatter and collimator-detector response (CDR). Dose rate distributions were estimated by convolution of the activity image with a voxel S kernel. Cumulative DVHs were calculated from the phantom and QSPECT images and compared both qualitatively and quantitatively. We found that noise, PVEs, and ringing artifacts due to CDR compensation all degraded histogram estimates. Low pass filtering and early termination of the iterative process were needed to reduce the effects of noise and ringing artifacts on DVHs, but resulted in increased degradations due to PVEs. Large objects with few features, such as the liver, had more accurate histogram estimates and required fewer iterations and more smoothing for optimal results. Smaller objects with fine details, such as the kidneys, required more iterations and less smoothing at early time points post-radiopharmaceutical administration but more smoothing and fewer iterations at later time points when the total organ activity was lower. The results of this study demonstrate the importance of using optimal reconstruction and regularization parameters. Optimal results were obtained with different parameters at each time point, but using a single set of parameters for all time points produced near-optimal dose-volume histograms. PMID- 23648372 TI - Cannabis induces a clinical response in patients with Crohn's disease: a prospective placebo-controlled study. AB - BACKGROUND & AIMS: The marijuana plant Cannabis sativa has been reported to produce beneficial effects for patients with inflammatory bowel diseases, but this has not been investigated in controlled trials. We performed a prospective trial to determine whether cannabis can induce remission in patients with Crohn's disease. METHODS: We studied 21 patients (mean age, 40 +/- 14 y; 13 men) with Crohn's Disease Activity Index (CDAI) scores greater than 200 who did not respond to therapy with steroids, immunomodulators, or anti-tumor necrosis factor-alpha agents. Patients were assigned randomly to groups given cannabis, twice daily, in the form of cigarettes containing 115 mg of Delta9-tetrahydrocannabinol (THC) or placebo containing cannabis flowers from which the THC had been extracted. Disease activity and laboratory tests were assessed during 8 weeks of treatment and 2 weeks thereafter. RESULTS: Complete remission (CDAI score, <150) was achieved by 5 of 11 subjects in the cannabis group (45%) and 1 of 10 in the placebo group (10%; P = .43). A clinical response (decrease in CDAI score of >100) was observed in 10 of 11 subjects in the cannabis group (90%; from 330 +/- 105 to 152 +/- 109) and 4 of 10 in the placebo group (40%; from 373 +/- 94 to 306 +/- 143; P = .028). Three patients in the cannabis group were weaned from steroid dependency. Subjects receiving cannabis reported improved appetite and sleep, with no significant side effects. CONCLUSIONS: Although the primary end point of the study (induction of remission) was not achieved, a short course (8 weeks) of THC-rich cannabis produced significant clinical, steroid-free benefits to 10 of 11 patients with active Crohn's disease, compared with placebo, without side effects. Further studies, with larger patient groups and a nonsmoking mode of intake, are warranted. ClinicalTrials.gov, NCT01040910. PMID- 23648374 TI - How can we determine the molecular clock of malaria parasites? AB - The association of contemporary hosts and their parasites might reflect either cospeciation or more recent shifts among existing hosts. Cospeciation implies that lineages of hosts and parasites diverge in parallel at the same time, but testing this prediction requires time-calibrated phylogenies, which are particularly difficult to obtain in organisms that leave few fossils. It has successively become clear that host shifts have been frequent in the evolutionary history of malaria parasites, but dating these host shifts cannot be done without calibrated phylogenies. Hence, it remains unresolved how long contemporary hosts and vectors have been coevolving with their malaria parasites. This review addresses conflicting rate estimates of molecular evolution and suggests research directions to aid dating diversification events in malaria parasites. PMID- 23648373 TI - Specific serotonin reuptake inhibitors prevent interferon-alpha-induced depression in patients with hepatitis C: a meta-analysis. AB - BACKGROUND & AIMS: Interferon-alpha (IFN-alpha)-induced depression is a major complication to treatment of chronic hepatitis C virus (HCV) infection. Specific serotonin reuptake inhibitors (SSRIs) can be used to treat depression, but it is not clear whether they can prevent depression in patients receiving IFN therapy for chronic HCV infection. METHODS: We performed a meta-analysis by searching the Cochrane Library, PubMed, and EMBASE databases through 2013 for published results from randomized, placebo-controlled trials evaluating the utility of SSRIs in preventing IFN-induced depression in HCV patients. We analyzed data from 7 studies with a total of 662 patients. The incidence of IFN-induced major depression and depression severity were defined as primary outcomes. Sustained virologic response, completion of antiviral therapy, and tolerability were considered secondary outcomes. RESULTS: A meta-analysis of IFN-induced major depression revealed that prophylactic SSRIs reduced the risk of depression, compared with placebo (relative risk [RR], 0.56; 95% confidence interval [CI], 0.37-0.84; P = .005). Proportions of patients achieving a sustained virologic response (RR, 1.02; 95% CI, 0.79-1.32; P = .87) and completing antiviral therapy (RR, 0.98; 95% CI, 0.66-1.44; P = .91) were similar between patients given SSRIs and controls. Prophylactic SSRIs were tolerated in patients with HCV during treatment. CONCLUSIONS: On the basis of a meta-analysis of 7 randomized controlled trials, prophylactic administration of SSRIs to patients with HCV significantly lowered the incidence of IFN-induced major depression, compared with placebo, and the SSRIs were well tolerated. PMID- 23648375 TI - Epidemic of equine coronavirus at Obihiro Racecourse, Hokkaido, Japan in 2012. AB - Equine coronavirus (ECoV) outbreaks have occurred three times at Obihiro Racecourse in Hokkaido, Japan. The third ECoV outbreak occurred between late February and early April 2012. The main clinical signs of affected horses were anorexia, pyrexia and leucopenia; gastrointestinal disease was observed in about 10% of affected horses. Two ECoV strains were isolated from diarrheal samples. All paired sera (9/9) collected from febrile horses showed seroconversion by neutralization test. Sequence and phylogenetic analysis of the ECoV isolated showed that putative amino acid sequences in S and N genes were highly conserved among ECoV strains. In contrast, sequences of the region coding 4.7 kDa non structural protein (p 4.7) differed among the strains. Because of the diversity of the p4.7 region, this region should be useful for epidemiological investigation of ECoV. PMID- 23648376 TI - Static magnetic field induced hypovitaminosis D in rat. AB - In the following study, we mainly investigate the effects of static magnetic field (SMF) (128 mT, 1 hr/day during 5 consecutive days) on 25-hydroxyvitamin D3 and calcium homeostasis. Wistar male rats, weighing 50-70 g, were randomly divided into four experimental groups: control, SMF-exposed rat, co-exposed rats (the last day and after exposure rats received a single dose of vitamin D per os) and supplemented with vitamin D group (without exposure to SMF). Exposure to SMF induced a decrease of plasmatic 25-hydroxyvitamin D3 level (P < 0.001). While, calcium and phosphorus levels were not affected (P > 0.05). The same treatment failed also to alter body, relative liver and kidney weights. Interestingly, oral supplementation with vitamin D corrected hypovitaminosis D induced by SMF. Likewise, the same treatment failed to alter calcium homeostasis. More studies are needed to evaluate how SMF induces hypovitaminosis D. PMID- 23648377 TI - Neurons and circuits for odor processing in the piriform cortex. AB - Increased understanding of the early stages of olfaction has lead to a renewed interest in the higher brain regions responsible for forming unified 'odor images' from the chemical components detected by the nose. The piriform cortex, which is one of the first cortical destinations of olfactory information in mammals, is a primitive paleocortex that is critical for the synthetic perception of odors. Here we review recent work that examines the cellular neurophysiology of the piriform cortex. Exciting new findings have revealed how the neurons and circuits of the piriform cortex process odor information, demonstrating that, despite its superficial simplicity, the piriform cortex is a remarkably subtle and intricate neural circuit. PMID- 23648378 TI - Use of health, education, and social services by individuals with fetal alcohol spectrum disorder. AB - BACKGROUND: Fetal Alcohol Spectrum Disorder (FASD) is the leading cause of intellectual disability in western society, presenting a significant burden on health, education and social services. Quantifying the burden of FASD is important for service planning and policy and program development. OBJECTIVE: To describe the health, education and social service use of individuals with FASD to provide an indication of the burden of service use of the disorder. METHODS: Using a matched-cohort design health, education and social service data were linked with clinical records on individuals 6+ years diagnosed with FASD between 1999/2000-2009/10 (N=717). Matching was 2:1 with a general population (gPop) and asthma group by age, sex and area-level income. Adjusted rates and relative risks were calculated using Generalized Linear Models. RESULTS: Hospitalizations were higher in the FASD compared to gPop (adjusted relative risk=3.44 (95% confidence interval=2.29, 5.17)) and asthma (2.87 (1.94, 4.25)) groups, whereas for physician visits and overall prescriptions, the FASD group differed from only the gPop group (1.58 (1.34, 1.84); 1.44 (1.22, 1.72), respectively). Antibiotics, pain killers and anti-psychotics were similar across groups whereas antidepressants and psychostimulants were higher in the FASD group (antidepressants: FASD vs. gPop 8.76 (2.82, 27.21); FASD vs. asthma 2.10 (1.15, 3.83); psychostimulants: FASD vs. gPop 5.78 (2.89, 11.57); FASD vs. asthma 2.47 (1.37, 4.47)). Attention-deficit?hyperactivity disorder was higher in the FASD than the gPop and asthma groups (6.41 (3.29, 12.49); 3.12 (1.97, 4.93), respectively). Education and social service use was higher for the FASD than either of the other groups for all measures (FASD vs. gPop and FASD vs. asthma, respectively for: grade repetition 3.06 (1.58, 5.94); 3.48 (1.79, 6.78); receipt of any special education funding 9.22 (6.23, 13.64); 6.10 (4.14, 8.99); family receipt of income assistance 1.74 (1.33, 2.27); 1.89 (1.45, 2.47); child in care 13.19 (5.84, 29.78);10.70 (4.80, 23.88); and receipt of child welfare services 5.70 (4.21, 7.71); 4.94 (3.67, 6.66)). CONCLUSION: The health, education and social service utilization burden of individuals with FASD is substantial, greater than that of individuals in the general population and with chronic illness (i.e., asthma). The findings highlight the need for multisystem supports for those with FASD, and comprehensive prevention programs. PMID- 23648379 TI - Value of melanocytic-associated immunohistochemical markers in the diagnosis of malignant melanoma: a review and update. AB - Since the identification of S100 protein as an immunohistochemical marker that could be useful in the diagnosis of melanoma in the early 1980s, a large number of other melanocytic-associated markers that could potentially be used to assist in the differential diagnosis of these tumors have also been investigated. A great variation exists, however, among these markers, not only in their expression in some subtypes of melanoma, particularly desmoplastic melanoma, but also in their specificity because some of them can also be expressed in nonmelanocytic neoplasms, including various types of soft tissue tumors and carcinomas. This article reviews the information that is currently available on the practical value of some of the markers that have more often been recommended for assisting in the diagnosis of melanomas, including those that have only recently become available. PMID- 23648380 TI - Low papillary structure in lepidic growth component of lung adenocarcinoma: a unique histologic hallmark of aggressive behavior. AB - Small-sized lung adenocarcinomas often contain a lepidic growth component in part. The term lepidic growth has recently been used to represent a growth pattern of neoplastic cells along preexisting alveolar structures. We reviewed 91 small-sized (<=3 cm) invasive lung adenocarcinomas with a lepidic component to study the histopathologic and clinicopathologic characteristics. In the lepidic component of invasive adenocarcinoma, we have identified a morphologically unique structure characterized by proliferation of low papillae, consisting of neoplastic cells piling up toward the alveolar space, and we defined this architecture as "low papillary structure." There were 18 cases with the low papillary structure in the lepidic components, whereas 73 cases did not have the structure. In the lepidic component, the cases with the low papillary structure had higher Ki-67 labeling index (15.7%) and more frequent p53 overexpression (50.0%) than did those without the structure (9.4% and 16.4%, respectively). Based on clinicopathologic findings, the presence of low papillary structure was significantly associated with lymphatic invasion (P = .023) and lymph node metastasis (P = .001). Furthermore, the patients with the low papillary structure in the lepidic components demonstrated significantly shorter disease-free and overall survival than did those without the structure (P = .001 and P = .010, respectively). We conclude that the low papillary structure is a significant histologic feature in a lepidic component and is associated with aggressive cancer behavior in lung adenocarcinoma. PMID- 23648381 TI - Focusing on the structure and the function of Pin1: new insights into the opposite effects of fever on cancers and Alzheimer's disease. AB - A new molecular mechanism is proposed to explain the opposite effects of fever on cancers and Alzheimer's disease (AD). The proposal is based on the experimental discovery that the fever stress interferes the structure and the activity of Pin1, which plays uniquely opposite roles in the pathogenesis of cancers and AD. Pin1 is the only known cis-trans isomerase that specifically isomerizes the pSer/pThr-Pro motifs in proteins, facilitating kinds of signaling pathways. The up-regulation of Pin1 can amplify multiple oncogenic signaling pathways, resulting in cancers, while the down-regulation of Pin1 can cause many pathological characteristics of AD. Recently, we found that Pin1 is sensitive to heat treatment, and heating can gradually damage both of the structure and the function of Pin1. So, we hypothesize that the fever stress, which is usually induced by febrile diseases or hyperthermia treatment, may lead to the damaged structure of Pin1 and the decreased activity of it in vivo, resulting in the decreased risk of cancers and the increased risk of AD. Numerous epidemiological and experimental researches on cancers and AD support the hypothesis. The hypothesis not only provides new insights into the opposite effects of fever on cancers and AD, but also gives new clues for understanding the interacting effects of the environmental and the genetic factors in the complicated pathogenesis of cancers and AD. PMID- 23648382 TI - Endovascular treatment for acute ischemic stroke: in search of evidence. PMID- 23648383 TI - Behavioural variant frontotemporal dementia: clinical and therapeutic approaches. AB - INTRODUCTION: Behavioural variant frontotemporal dementia (bvFTD) is the most frequent presentation in the clinical spectrum of frontotemporal dementia (FTD) and it is characterised by progressive changes in personality and conduct. Major breakthroughs in molecular biology and genetics made during the last two decades have lent us a better understanding of this syndrome, which may be the first manifestation in many different neurodegenerative diseases. DEVELOPMENT: We reviewed the main epidemiological, clinical, diagnostic and therapeutic aspects of bvFTD. Most cases manifest sporadically and the average age of onset is 58 years. Current criteria for bvFTD propose three levels of diagnostic certainty: possible, probable, and definite. Clinical diagnosis is based on a detailed medical history provided by family members and caregivers, in conjunction with neuropsychological testing. Treatments which have been used in bvFDT to date are all symptomatic and their effectiveness is debatable. New drugs designed for specific molecular targets that are implicated in frontotemporal lobar degeneration are being developed. CONCLUSIONS: BvFDT is a frequent cause of dementia. It is a non-specific syndrome associated with heterogeneous histopathological and biomolecular findings. The definition of clinical subtypes complemented by biomarker identification may help predict the underlying pathology. This knowledge, along with the development of drugs designed for molecular targets, will offer new treatment possibilities. PMID- 23648384 TI - Biomarkers: a new approach to behavioural variant frontotemporal dementia. AB - INTRODUCTION: Lobar frontotemporal degeneration (FTLD) encompasses a group of molecular disease defined by the deposition of an abnormal protein in the central nervous system. Behavioural variant frontotemporal dementia (bvFTD) is the most frequent clinical presentation of FTLD. The past two decades of research have contributed to a better understanding of this entity, which may be the first manifestation in many different neurodegenerative disorders. DEVELOPMENT: We reviewed correlations between clinical, pathological, and genetic findings and the main disease biomarkers of FTLD, with particular interest in bvFTD. Anatomical pathology findings in FTLD are heterogeneous and the syndrome is not associated with any one specific histopathological type. Promising available biomarkers include structural and functional neuroimaging techniques and biochemical and genetic biomarkers. Disease-modifying drugs designed for specific molecular targets that are implicated in FTLD pathogenesis are being developed. CONCLUSIONS: BvFTD is a frequent cause of dementia. Of all the clinical variants of FTLD, behavioural variant is the one in which establishing a correlation between clinical and pathological signs is the most problematic. A biomarker evaluation may help predict the underlying pathology; this approach, in conjunction with the development of disease-modifying drugs, offers new therapeutic possibilities. PMID- 23648385 TI - Adolescents' awareness of cancer risk factors and associations with health related behaviours. AB - Increasing adolescents' awareness of the contribution of modifiable lifestyle factors to cancer risk may influence life-long patterns of healthy behaviour. However, little is known about adolescents' awareness of cancer risk factors and the effectiveness of awareness-raising interventions. This study assessed adolescents' cancer awareness and the effectiveness of an existing cancer specific school-based intervention delivered by Teenage Cancer Trust. The Cancer Awareness Measure was completed by 478 adolescents (male: 250, 52.3%) aged 11-17 years (mean: 13.8, standard deviation: 1.24) in four UK schools; 422 adolescents provided paired data 2 weeks before and 2 weeks after the intervention delivered in 3 schools, and twice 4 weeks apart in the fourth (control) school. Adolescents recognized on average 4.4 (of 11) cancer risk factors. With the exception of smoking, adolescents' awareness of cancer risk factors was low. Awareness significantly increased after the intervention (4.6-5.7, P < 0.001). There was no significant change in the control school. Intervention effect was greater among females. This educational intervention is an effective way to raise adolescents' awareness of cancer risk factors. However, further cross-sectional and experimental studies are required to definitively assess adolescents' awareness of cancer risk factors and the effectiveness of this educational intervention. PMID- 23648386 TI - Potent toxins in Arctic environments--presence of saxitoxins and an unusual microcystin variant in Arctic freshwater ecosystems. AB - Cyanobacteria are the predominant phototrophs in freshwater ecosystems of the polar regions where they commonly form extensive benthic mats. Despite their major biological role in these ecosystems, little attention has been paid to their physiology and biochemistry. An important feature of cyanobacteria from the temperate and tropical regions is the production of a large variety of toxic secondary metabolites. In Antarctica, and more recently in the Arctic, the cyanobacterial toxins microcystin and nodularin (Antarctic only) have been detected in freshwater microbial mats. To date other cyanobacterial toxins have not been reported from these locations. Five Arctic cyanobacterial communities were screened for saxitoxin, another common cyanobacterial toxin, and microcystins using immunological, spectroscopic and molecular methods. Saxitoxin was detected for the first time in cyanobacteria from the Arctic. In addition, an unusual microcystin variant was identified using liquid chromatography-mass spectrometry. Gene expression analyses confirmed the analytical findings, whereby parts of the sxt and mcy operon involved in saxitoxin and microcystin synthesis, were detected and sequenced in one and five of the Arctic cyanobacterial samples, respectively. The detection of these compounds in the cryosphere improves the understanding of the biogeography and distribution of toxic cyanobacteria globally. The sequences of sxt and mcy genes provided from this habitat for the first time may help to clarify the evolutionary origin of toxin production in cyanobacteria. PMID- 23648387 TI - Spontaneous firing rate changes in cat primary auditory cortex following long term exposure to non-traumatic noise: tinnitus without hearing loss? AB - Changes of neural activity in animal models have been correlated with tinnitus in humans. For instance, increased spontaneous firing rates (SFR), increased spontaneous neural synchrony, and cortical tonotopic map reorganization may underlie this phantom auditory percept. The aim of this study is to quantify the changes in SFR activity in the cat primary auditory cortex, after long-term exposure to different types of non-traumatic acoustic environments. For that purpose, four different groups of adult cats were exposed to moderate-level (~70dB SPL), behaviorally irrelevant sounds for several weeks to months, and their SFRs were compared with those in control cats. The sounds consisted of random multi-frequency tone pip ensembles with various bandwidths (2-4kHz, 4 20kHz, and a pair of third-octave bands centered at 4 and 16kHz), as well as a "factory noise". Auditory brainstem response (ABR) thresholds, ABR wave 3 amplitudes at ~55 and 75dB SPL, and distortion product otoacoustic emission (DPOAE) amplitudes were unaffected by the exposure. However, we found that the SFR decreased within the exposure frequency range and increased outside the exposure range. This increased SFR for units with characteristic frequencies outside the exposure frequency range, which was slow to reverse after the exposure offset, suggests a mechanism for tinnitus in the absence of hearing loss. PMID- 23648388 TI - Association of P2X7 receptor gene polymorphisms with sporadic Parkinson's disease in a Han Chinese population. AB - Previous studies have indicated that genetic polymorphisms in the P2X7 receptors may influence the occurrence and development of sporadic Parkinson's diseases (PD). In our study, two DNA polymorphisms at P2X7 receptor gene: 1513A>C (rs3751143) and 1729T>A (rs1653624) were examined by PCR-RFLP analysis in 285 sporadic patients and 285 healthy controls in Han Chinese population. For 1513A>C polymorphism, there were significant differences in genotype distribution in PD group and late-onset PD (LOPD) group relative to the control groups respectively (P=0.015 and P=0.032, respectively), as well as between male PD and the controls subgroup (P=0.031). However, there were no significant differences in the genotype and allele frequencies of 1729T>A polymorphism between groups. Our study revealed that the P2X7 receptors 1513A>C polymorphism is a risk factor for sporadic PD, LOPD and male PD in Han Chinese population, while 1729T>A polymorphism is not significantly associated with Parkinson's disease. PMID- 23648389 TI - A novel di terpene para-hydroquinone compound derived from cryptoquinone protects neuronal cells against oxidative stress and activates the Nrf2/ARE pathway. AB - Green plant-origin electrophilic compounds are a newly recognized class of neuroprotective compounds that provide neuroprotection through activation of the Nrf2/ARE pathway. Electrophilic hydroquinones are of particular interest due to their ability to become electrophilic quinones upon auto-oxidation. Although green plants frequently produce a variety of electrophilic compounds, the detailed mechanisms of action of these compounds remain unknown. Here, we focused on the neuroprotective effects of 11,14-dihydroxy-8,11,13-abietariene (DA1), derived from a para-hydroquinone-type pro-electrophilic compound from the cryptoquinone. DA1 activated the Nrf2/ARE pathway, induced phase 2 enzymes, and increased glutathione, thus protecting neuronal cells from oxidative stress. DA1 had a very broad safety zone (199.41 fold) at least in our system. Thus, DA1 is a novel neuroprotective pro-electrophilic diterpene from green plant. PMID- 23648391 TI - Musculoskeletal pain among critical-care nurses by availability and use of patient lifting equipment: an analysis of cross-sectional survey data. AB - BACKGROUND: Patient handling is a major risk factor for musculoskeletal injuries among nurses. Lifting equipment is a main component of safe patient handling programs that aim to prevent musculoskeletal injury. However, the actual levels of lift availability and usage are far from optimal. OBJECTIVE: To examine the effect of patient lifting equipment on musculoskeletal pain by level of lift availability and lift use among critical-care nurses. DESIGN AND PARTICIPANTS: A cross-sectional postal survey of a random sample of 361 critical-care nurses in the United States. METHODS: The survey collected data on low-back, neck, and shoulder pain, lift availability, lift use, physical and psychosocial job factors, and sociodemographics. Musculoskeletal pain was assessed by three types of measures: any pain, work-related pain, and major pain. Multivariable logistic regressions were used to examine the associations between musculoskeletal pain and lift variables, controlling for demographic and job factors. RESULTS: Less than half (46%) of respondents reported that their employer provided lifts. Of 168 nurses who had lifts in their workplace, the level of lift availability was high for 59.5%, medium for 25.0%, and low for 13.7%; the level of lift use was high for 32.1%, medium for 31.5%, and low for 31.5%. Significant associations were found between lift availability and work-related low-back and shoulder pain. Compared to nurses without lifts, nurses reporting high-level lift availability were half as likely to have work-related low-back pain (OR=0.50, 95% CI 0.26 0.96) and nurses reporting medium-level lift availability were 3.6 times less likely to have work-related shoulder pain (OR=0.28, 95% CI 0.09-0.91). With respect to lift use, work-related shoulder pain was three times less common among nurses reporting medium-level use (OR=0.33, 95% CI 0.12-0.93); any neck pain was three times more common among nurses reporting low-level use (OR=3.13, 95% CI 1.19-8.28). CONCLUSIONS: Greater availability and use of lifts were associated with less musculoskeletal pain among critical-care nurses. These findings suggest that for lift interventions to be effective, lifts must be readily available when needed and barriers against lift use must be removed. PMID- 23648390 TI - Dual immunofluorescence study of citrullinated proteins in Alzheimer diseased frontal cortex. AB - Deimination is a post-translational modification of proteins in which selected arginine amino acids are enzymatically converted to citrullines. Using dual-color immunofluorescence, the present study is the first to examine the frontal cortex of patients with Alzheimer's disease (AD) versus age-matched controls with an established monoclonal antibody (F95) against peptidyl-citrulline moieties. In AD specimens, a number of new findings were discovered, including evidence for deiminated proteins in extracellular plaques, the walls of large blood vessels, the nuclei of selective neurons immunoreactive for phosphorylated tau and numerous reactive astrocytes concentrated around extracellular plaques, ventricular surfaces and at the interface between the gray and white matter of the cortex. Although the identities of these citrullinated proteins remain largely unknown, the present study adds to the growing number of locations in which deiminated proteins may be found in the brains of patients with AD. PMID- 23648392 TI - Need-based intervention is an effective strategy for improving the nutritional status of older people living in a nursing home: a randomized controlled trial. AB - BACKGROUND: Nutrition is a key element in geriatric health. Protein-energy malnutrition is common in institutionalized persons. OBJECTIVE: This study examined the effectiveness of a need-based "routine screening and timely intervention" strategy in improving the nutritional status of persons living in nursing homes. DESIGN: A 24-week randomized, double-blind, controlled trial. SETTING: A privately managed geriatric nursing home in Taiwan. PARTICIPANTS: Ninety-two >=65-year old persons who were <=25kg/m(2), >1 month residence, able to self-feed or receive oral feeding, without acute infection and non-bed-ridden. METHODS: Prospective participants were stratified by gender and then randomly assigned to either the control group (n=45) or the intervention group (n=47). Each subject in the intervention group was given a 50g/day soy-protein-based nutritional supplement if he/she was rated as undernourished according to the Mini Nutritional Assessment (MNA, score <=24) and BMI <=24kg/m(2). The supplement contained 9.5g protein, 250kcal energy and all essential micro-nutrients. The supplementation would be suspended once either one of the "at risk" condition was corrected. Nutritional rating with the MNA took place at baseline and every 4 weeks during the trial. Biochemical indicators were measured at baseline, mid point (week-12) and end-point (week-24). Results were analyzed with the two sample t-test, and the generalized estimating equations (GEE) controlled for demographic and health-related variables. RESULTS: Of the 92 subjects, 82 completed the trial; 7 withdrew and 3 died during the trial. Results showed that the need-based intervention was an effective and appropriate strategy for improving the nutritional status of persons at risk of undernourishment. The intervention significantly improved body weight, BMI, mid-arm circumference, calf circumference, and serum albumin and cholesterol concentrations at all intervals (all p<0.05). However, the intervention did not significantly improve hematocrit, hemoglobin or lymphocyte count status. CONCLUSIONS: Results suggest that the need based nutritional intervention can be a practical and useful strategy for improving the nutritional status of persons living in nursing homes and save on healthcare cost. The potential application of this strategy deserves the attention of health planners. PMID- 23648394 TI - The steps to health employee weight management randomized control trial: rationale, design and baseline characteristics. AB - BACKGROUND: The workplace can be an important setting for addressing obesity. An increasing number of employers offer weight management programs. PURPOSE: Present the design, rationale and baseline characteristics of the Steps to Health study (STH), a randomized trial to evaluate the effectiveness of two preexisting employee weight management programs offered at Duke University and Medical Center. METHODS: 550 obese (BMI >=30) employee volunteers were randomized 1:1 to two programs. Baseline data, collected between January 2011 and July 2012, included height/weight, accelerometry, workplace injuries, health care utilization, and questionnaires querying socio-cognitive factors, perceptions of health climate, physical activity, and dietary intake. In secondary analyses participants in the two programs will also be compared to a non-randomized observational control group of obese employees. RESULTS: At baseline, the mean age was 45 years, 83% were female, 41% white, and 53% black. Mean BMI was 37.2. Participants consumed a mean of 2.37 servings of fruits and vegetables per day (in the past week), participated in 11.5 min of moderate-to-vigorous physical activity, and spent 620 min being sedentary. CONCLUSION: STH addresses the need for evaluation of worksite interventions to promote healthy weight. In addition to having direct positive effects on workers' health, worksite programs have the potential to increase productivity and reduce health care costs. PMID- 23648393 TI - Arsenic exposure induces the Warburg effect in cultured human cells. AB - Understanding how arsenic exacts its diverse, global disease burden is hampered by a limited understanding of the particular biological pathways that are disrupted by arsenic and underlie pathogenesis. A reductionist view would predict that a small number of basic pathways are generally perturbed by arsenic, and manifest as diverse diseases. Following an initial observation that arsenite exposed cells in culture acidify their media more rapidly than control cells, the report here shows that low level exposure to arsenite (75ppb) is sufficient to induce aerobic glycolysis (the Warburg effect) as a generalized phenomenon in cultured human primary cells and cell lines. Expanded studies in one such cell line, the non-malignant pulmonary epithelial line, BEAS-2B, established that the arsenite-induced Warburg effect was associated with increased accumulation of intracellular and extracellular lactate, an increased rate of extracellular acidification, and inhibition by the non-metabolized glucose analog, 2-deoxy-D glucose. Associated with the induction of aerobic glycolysis was a pathway-wide induction of glycolysis gene expression, as well as protein accumulation of an established glycolysis master-regulator, hypoxia-inducible factor 1A. Arsenite induced alteration of energy production in human cells represents the type of fundamental perturbation that could extend to many tissue targets and diseases. PMID- 23648396 TI - An industry statistician's perspective on PHC drug development. AB - In the past decade, the cost of drug development has increased significantly. The estimates vary widely but frequently quoted numbers are staggering-it takes 10-15 years and billions of dollars to bring a drug to patients. To a large extent this is due to many long, expensive and ultimately unsuccessful drug trials. While one approach to combat the low yield on investment could be to continue searching for new blockbusters, an alternative method would lead us to focus on testing new targeted treatments that have a strong underlying scientific rationale and are more likely to provide enhanced clinical benefit in population subsets defined by molecular diagnostics. Development of these new treatments, however, cannot follow the usual established path; new strategies and approaches are required for the co-development of novel therapeutics and the diagnostic. In this paper we will review, from the point of view of industry, the approaches to, and challenges of drug development strategies incorporating predictive biomarkers into clinical programs. We will outline the basic concepts behind co-development with predictive biomarkers and summarize the current regulatory paradigm. We will present guiding principles of personalized health care (PHC) development and review the statistical, strategic, regulatory and operational challenges that statisticians regularly encounter on development programs with a PHC component. Some practical recommendations for team statisticians involved in PHC drug development are included. The majority of the examples and recommendations are drawn from oncology but broader concepts apply across all therapeutic areas. PMID- 23648397 TI - Simultaneous reconstruction of emission activity and attenuation coefficient distribution from TOF data, acquired with external transmission source. AB - The simultaneous PET data reconstruction of emission activity and attenuation coefficient distribution is presented, where the attenuation image is constrained by exploiting an external transmission source. Data are acquired in time-of flight (TOF) mode, allowing in principle for separation of emission and transmission data. Nevertheless, here all data are reconstructed at once, eliminating the need to trace the position of the transmission source in sinogram space. Contamination of emission data by the transmission source and vice versa is naturally modeled. Attenuated emission activity data also provide additional information about object attenuation coefficient values. The algorithm alternates between attenuation and emission activity image updates. We also proposed a method of estimation of spatial scatter distribution from the transmission source by incorporating knowledge about the expected range of attenuation map values. The reconstruction of experimental data from the Siemens mCT scanner suggests that simultaneous reconstruction improves attenuation map image quality, as compared to when data are separated. In the presented example, the attenuation map image noise was reduced and non-uniformity artifacts that occurred due to scatter estimation were suppressed. On the other hand, the use of transmission data stabilizes attenuation coefficient distribution reconstruction from TOF emission data alone. The example of improving emission images by refining a CT based patient attenuation map is presented, revealing potential benefits of simultaneous CT and PET data reconstruction. PMID- 23648398 TI - The incidence of acute urinary retention secondary to BPH is increasing among California men. AB - BACKGROUND: Current epidemiological patterns of adverse events of clinical BPH remain unclear. We investigated trends in acute urinary retention (AUR) associated with BPH in a large, population-based cohort. METHODS: We utilized the California Office of Statewide Health Planning and Development Database to examine 3 724 016 emergency room (ER) visits in California among men aged ? 50 years from 2007 to 2010. Outcomes included AUR for which BPH was the primary diagnosis, AUR for which BPH was a secondary diagnosis and urethral catheterization for AUR. We generated adjusted odds ratios (ORadj) using multivariate logistic regression to determine longitudinal trends. RESULTS: A total of 17 023 men presented with a diagnosis of BPH-associated AUR, the unadjusted incidence of which increased from 4.00 per 1000 ER visits in 2007 to 5.23 per 1000 ER visits in 2010 (P<0.001). In adjusted analyses, primary AUR (ORadj=1.25; 95% confidence interval (CI), 1.19-1.32; P<0.001) and secondary AUR (ORadj=1.80; 95% CI, 1.62-2.00; P<0.001) increased 25% and 80%, respectively. Urethral catheterization for primary (ORadj=1.30; 95% CI, 1.22-1.39; P<0.001) and secondary (ORadj=1.82; 95% CI, 1.57-2.11; P<0.001) AUR increased 30% and 82%, respectively. Asian race (P<0.001), Hispanic race (P<0.001) and commercial insurance (P<0.001) were associated with significantly increased risks of AUR and urethral catheterization. CONCLUSIONS: Between 2007 and 2010, the observed incidence of BPH-associated AUR increased substantially in a large and ethnically diverse male population of the United States. PMID- 23648395 TI - DASH for asthma: a pilot study of the DASH diet in not-well-controlled adult asthma. AB - This pilot study aims to provide effect size confidence intervals, clinical trial and intervention feasibility data, and procedural materials for a full-scale randomized controlled trial that will determine the efficacy of Dietary Approaches to Stop Hypertension (DASH) as adjunct therapy to standard care for adults with uncontrolled asthma. The DASH diet encompasses foods (e.g., fresh fruit, vegetables, and nuts) and antioxidant nutrients (e.g., vitamins A, C, E, and zinc) with potential benefits for persons with asthma, but it is unknown whether the whole diet is beneficial. Participants (n = 90) will be randomized to receive usual care alone or combined with a DASH intervention consisting of 8 group and 3 individual sessions during the first 3 months, followed by at least monthly phone consultations for another 3 months. Follow-up assessments will occur at 3 and 6 months. The primary outcome measure is the 7-item Juniper Asthma Control Questionnaire, a validated composite measure of daytime and nocturnal symptoms, activity limitations, rescue medication use, and percentage predicted forced expiratory volume in 1 second. We will explore changes in inflammatory markers important to asthma pathophysiology (e.g., fractional exhaled nitric oxide) and their potential to mediate the intervention effect on disease control. We will also conduct pre-specified subgroup analyses by genotype (e.g., polymorphisms on the glutathione S transferase gene) and phenotype (e.g., atopy, obesity). By evaluating a dietary pattern approach to improving asthma control, this study could advance the evidence base for refining clinical guidelines and public health recommendations regarding the role of dietary modifications in asthma management. PMID- 23648399 TI - Human studies using isotope labeled fatty acids: answered and unanswered questions. AB - Human studies using deuterium-labeled fatty acids have answered many questions related to the metabolism and health effects of dietary fats. These studies also raised a number of unanswered questions and unresolved issues. For example, studies with cis and trans positional isomers dispelled concerns and allegations that the isomers in partially hydrogenated fats were poorly absorbed, accumulate in undesirable phospholipid acyl positions, mimic stearic acid and competed with oleic acid. Trans 18:1 isomers were metabolically intermediate between 16:0 and 18:0, so the unanswered question is why are the metabolic properties of trans fatty acids not consistent with their physiological effects? Results from 2H-18:0 studies address questions regarding stearic acid absorption and desaturation. Contrary to accepted dogma, stearic acid was well absorbed and less than 10% was desaturation to oleic acid. The still unanswered question is what is the metabolic basis for why 18:0 is less hypercholesterolemic than other saturated fatty acids? The question of whether humans convert 18:3n-3 to EPA and DHA was investigated by feeding male subjects a mixture of 2H-18:3n-3 and 2H-18:2n-6. The unequivocal answer was that 18:3n-3 is converted to EPA and DHA and the conversions for 18:3n-3 to 20:5n-3 and 18:2n-6 to 20:4n-6 were about equal. A major issue that remains unresolved is the wide variability between studies for the estimated conversion of 18:3n-3 to 20:5n-3 and 22:6n-3. The commercial availability of liquid oils hardened by interesterified with 18:0 has raised the question of whether fatty acids in the sn-2 and sn-1,3 TAG positions are metabolically equivalent. To answer this question, subjects were fed triglycerides containing 2H-16:0 and 2H-18:2n-6 at specific sn-1(3) and sn-2 acyl positions. The result was that dietary fatty acids at the sn-1(3) and sn-2 triacylglycerol positions are essentially metabolically equivalent. PMID- 23648400 TI - Quantitative correlation between counterion (X) affinity to cationic micelles and X-induced micellar growth for X = 2,4-; 2,5-; 2,6- and 3,4-dichlorobenzoate ions. AB - A semi empirical kinetic (SEK) method has been used to determine the ratio of cetyltrimethylammonium bromide (CTABr) micellar binding constants of counterion X and Br- (a reference counterion), i.e. K(X)/K(Br) (=R(X)(Br)). The values of K(X) and K(Br) have been derived from the kinetic parameters obtained in the presence spherical/non-spherical and spherical micelles, respectively. This rather new method gives the respective mean values of R(X)(Br) as 45+/-2, 25+/-3, 4.7+/-0.6 and 119+/-10 for X=2,4-, 2,5-, 2,6- and 3,4-Cl2C6H3CO2- (Cl2Bz'Na). Literature lacks the report on the values of R(X)(Br) for all X except for X=2,6 Cl2C6H3CO2- (2,6-Cl2Bz'-) for which the reported value is 5.0. Rheological properties, such as shear thinning behavior, reveal indirectly the presence of wormlike micelles (WM) in the CTABr micellar solutions containing MX for all X except X=2,6-Cl2Bz'-. The micelles remain spherical within [2,6-Cl2Bz'-] range 0.01-0.34 M at 0.015 M CTABr. The maxima of the plots of zero shear viscosity, eta0, (obtained from the initial plateau region of flow curves, i.e. eta vs. gamma curve) vs. [MX] (MX=2,4-, 2,5- and 3,4-Cl2Bz'Na) at 0.015 M CTABr also support indirectly the presence of linear, entangled and branched WM. PMID- 23648401 TI - Monolayer compression induces fluidization in binary system of partially fluorinated alcohol (F4H11OH) with DPPC. AB - A two-component Langmuir monolayer consisting of (perfluorobutyl)undecanol (F4H11OH) and dipalmitoylphosphatidylcholine (DPPC), a major component of pulmonary surfactants in mammals, has been investigated at the air-water interface. The binary monolayer has been systematically examined from both thermodynamic and morphological perspectives. The excess Gibbs free energy of mixing has been calculated from surface pressure (pi)-molecular area (A) isotherms, and the results indicate that the miscibility of the two-component system shows a maximum in thermodynamical stability when the mole fraction (X(F4H11OH)) is 0.3. Results from a two-dimensional phase diagram (pi vs. X(F4H11OH)) are consistent with these findings and depict the degree of miscibility resulting from the variation in the transition and collapse pressures relative to the concentration of X(F4H11OH). The miscibility is also supported by in situ Brewster angle microscopy and fluorescence microscopy, as well as ex situ atomic force microscopy for the system after transfer onto a mica substrate. Aside from temperature, a known driving force for the fluidization of DPPC monolayers is a change in surface composition caused by the addition of additive molecules. In the present study, however, the fluidization is driven by increasing surface pressures even at constant X(F4H11OH). Such a fluidization is a fascinating property when looked at in context of its potential implications for pulmonary replacement therapy, and hence, this study provides a fundamental insight into designing fluorinated materials for biomedical use. PMID- 23648402 TI - Effect of dietary polyphenols from hop (Humulus lupulus L.) pomace on adipose tissue mass, fasting blood glucose, hemoglobin A1c, and plasma monocyte chemotactic protein-1 levels in OLETF rats. AB - Hop (Humulus lupulus L.) pomace contains procyanidin-rich polyphenols, which are large oligomeric compounds of catechin. We studied the effect of high dose (1%) of dietary hop pomace polyphenols (HPs) in Otsuka Long-EvansTokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. By 70 days, the rats fed HPs tended to have a lower body weight and reduced mesenteric white adipose tissue weight than the rats fed a control diet. Triglyceride levels in both plasma and liver tended to be lower in the HPs-fed group than in the control group. Dietary HPs substantially suppressed the activities of hepatic fatty acid synthetase, glucose-6-phosphate dehydrogenase, and malic enzyme, through the suppression of SREBP1c mRNA expression in OLETF rats. Moreover, in the HPs-fed group, monocyte chemotactic protein-1 (MCP-1) expression and fasting blood glucose levels at 40 days, and hemoglobin A1c (HbA1c) levels at 70 days were significantly lower than those in the control group. Thus, dietary HPs may exert an ameliorative function on hepatic fatty acid metabolism, glucose metabolism, and inflammatory response accompanying the increase of the adipose tissue mass in OLETF rats. PMID- 23648403 TI - Biotransformation of (+)-fenchone by Salmonella typhimurium OY1002/2A6 expressing human CYP2A6 and NADPH-P450 reductase. AB - In this study, biotransformation of (+)-fenchone (compound 1) by Salmonella typhimurium OY1002/2A6 expressing human CYP2A6 and NADPH-P450 reductase yielded two oxidized metabolites, namely, (+)-(1S,6R)-6-endo-hydroxyfenchone (compound 2) and (+)-(1S,6S)-6-exo-hydroxyfenchone (compound 3). The conversion rate of compound 1 to compound 2 and 3 was 2.4% and 5.2%, respectively. This is the first study that succeeded in metabolizing compound 1 to obtain large amounts of metabolite 2 and 3 by using S. typhimurium OY1002/2A6 expressing human CYP2A6 and NADPH-P450 reductase. PMID- 23648404 TI - Transesterification of triglycerides by dried biomass of Aspergillus sp. AB - Fungus isolate, Aspergillus sp. (RBD01), which was isolated from biocontaminated clarified butter was evaluated for its potential to transesterify used edible and non-edible oils for generation of alkyl esters, when used as biocatalyst as dry biomass. The work aimed at determining the potential of dry biomass of Aspergillus sp. (RBD01) to transesterify used cottonseed oil and non-edible oils viz., jatropha and karanj under various culture conditions. A conversion of oil (cotton seed) to ethyl ester to the extent of 84% was obtained at reaction temperature of 35 degrees C, with 20% biomass and step-wise addition of ethanol at 1:5 molar ratio (oil to ethanol), within total reaction time of 36 h. Under similar conditions, transesterification of Jatropha and Karanj oils resulted in only 75 and 78.2% ethyl ester. Further, with reference to the effect of frying on transesterification, increase in frying time decreased the extent of transesterification from 84% to 30%. PMID- 23648405 TI - Jacaric acid is rapidly metabolized to conjugated linoleic acid in rats. AB - We have shown previously that jacaric acid (JA; 8c,10t,12c-18:3), which has a conjugated triene system, has a strong anti-tumor effect. However, the characteristics of absorption and metabolism of JA have yet to be determined in vivo, and the details of absorption and metabolism of JA in the small intestine are particularly unclear. This information is required for effective use of JA in humans. Therefore, in this study we examined absorption and metabolism of JA using cannulation of the thoracic duct in rats. Emulsions of two test oils, jacaranda seed oil and tung oil, which contain JA and alpha-eleostearic acid (alpha-ESA; 9c,11t,13t-18:3), respectively, were administered to rats and lymph from the thoracic duct was collected over 24 h. We examined the rate of absorption of JA and possible conversion to a conjugated linoleic acid (CLA)containing a conjugated diene system. The positional isomerism of the CLA produced by JA metabolism was determined using gas chromatography-electron impact/mass spectrometry. The rate of absorption and percentage conversion of JA were compared with those of alpha-ESA. We found that JA is rapidly absorbed and converted to a CLA in rats and that the percentage conversion of JA was lower than that of alpha-ESA. This is the first report on the absorption and metabolism of JA and this information may be important for application of JA as a functional food. PMID- 23648406 TI - Novel compound, (2Z,6E)-1-hydroxy-3,7-dimethyl-2,6-octadien-8-oic acid produced from biotransformation of nerol by Spodoptera litura larvae. AB - Biotransformation of nerol by larvae of the common cutworm (Spodoptera litura) was investigated. The resulting major metabolites were (2Z,6E)-1-hydroxy-3,7 dimethyl-2,6-octadien-8-oic acid and 8-hydroxynerol, and the minor metabolites were 9-hydroxynerol and (2Z,6E)-1-hydroxy-3,7-dimethyl-2,6-octadien-8-al. (2Z,6E) 1-Hydroxy-3,7-dimethyl-2,6-octadien-8-oic acid is a novel compound. The results indicate that biotransformation of nerol by S. litura larvae involved 2 pathways; the main pathway involved oxidation at the methyl group of the geminal dimethyl at C-8 position followed by carboxylation, and the minor pathway involved oxidation at the methyl group of the geminal dimethyl at C-9 position. PMID- 23648407 TI - Characterization of mannosylerythritol lipids containing hexadecatetraenoic acid produced from cuttlefish oil by Pseudozyma churashimaensis OK96. AB - Biosurfactants are surface-active compounds produced by microorganisms. Mannosylerythritol lipids (MEL) are promising biosurfactants produced by Ustilaginomycetes, and their physicochemical and biochemical properties differ depending on the chemical structure of their hydrophilic and/or hydrophobic moieties. To further develop MEL derivatives and expand their potential applications, we focused our attention on the use of cuttlefish oil, which contains polyunsaturated fatty acids (e.g., docosahexaenoic acid, C22:6, and eicosapentaenoic acid, C20:5, as the sole carbon source. Among the microorganisms capable of producing MEL, only nine strains were able to produce them from cuttlefish oil. On gas chromatography-mass spectrometry (GC/MS) analysis, we observed that Pseudozyma churashimaensis OK96 was particularly suitable for the production of MEL-A, a MEL containing hexadecatetraenoic acid (C16:4) (23.6% of the total unsaturated fatty acids and 7.7% of the total fatty acids). The observed critical micelle concentration (CMC) and surface tension at CMC of the new MEL-A were 5.7*10-6 M and 29.5 mN/m, respectively, while those of MEL-A produced from soybean oil were 2.7*10-6 M and 27.7 mN/m, respectively. With polarized optical and confocal laser scanning microscopies, the self-assembling properties of MEL-A were found to be different from those of conventional MEL. Furthermore, based on the DPPH radical-scavenging assay, the anti-oxidative activity of MEL-A was found to be 2.1-fold higher than that of MEL-A produced from soybean oil. Thus, the newly identified MEL-A is attractive as a new functional material with excellent surface-active and antioxidative properties. PMID- 23648408 TI - Analysis of the essential oil from Gaillardia pulchella Foug. and its antioxidant activity. AB - The essential oil from Gaillardia pulchella Foug. flowers was obtained by hydrodistillation and its chemical composition was analyzed by gas chromatography mass spectrometry (GC-MS). Twenty-eight compounds representing 92.63% of the essential oil were identified, of which the most prominent were n-Hexadecanoic acid (26.90%), Phytol (7.58%) and Cyclopropaneoctanoic acid, 2-[[2-[(2 ethylcyclopropyl) methyl] cyclopropyl] methyl]-, methyl ester (6.73%). Meanwhile, antioxidant activity of the essential oil was tested. The essential oil showed certain antioxidant activity in 1,1-diphenyl-2-picrylhydrazyl (DPPH) with an EC50 of 70.95 MUg/ml. This is the first report on the essential oil of this particular species. Its bioactivities warrant further studies. PMID- 23648409 TI - First case on successful management of manganism with renal transplantation. PMID- 23648410 TI - Antiviral immune response after live yellow fever vaccination of a kidney transplant recipient treated with IVIG. PMID- 23648411 TI - Synthesis of the novel (+/-)-2-methoxy-6-icosynoic acid--a fatty acid that induces death of neuroblastoma cells. AB - The first total synthesis for the novel fatty acid (+/-)-2-methoxy-6-icosynoic acid was accomplished in seven steps and in a 14% overall yield starting from 2 (4-bromobutoxy)-tetrahydro-2H-pyran. The title compound displayed an EC50=23+/-1 MUM against the human SH-SY5Y neuroblastoma cell line and an EC50=26+/-1 MUM against the human adenocarcinoma cervix cell line (HeLa) after 48 h of exposure. The corresponding non-methoxylated analog 6-icosynoic acid did not display cytotoxicity (EC50>500 MUM) toward the studied cell lines as well as the 2 methoxyicosanoic acid (EC50>300 MUM). The critical micelle concentration (CMC=20 30 MUM) for the (+/-)-2-methoxy-6-icosynoic acid was also determined. It was found that alpha-methoxylation decreases the CMC of a fatty acid. PMID- 23648412 TI - Muscular senescence in cetaceans: adaptation towards a slow muscle fibre phenotype. AB - Sarcopenia, or senile muscle atrophy, is the slow and progressive loss of muscle mass with advancing age that constitutes the most prevalent form of muscle atrophy. The effects of ageing on skeletal muscle have been extensively studied in humans and laboratory animals (mice), while the few reports on wild animals are based on short-lived mammals. The present study describes the age-related changes in cetacean muscles regarding the three factors that determine muscle mass: fibre size, fibre number, and fibre type. We show that the skeletal muscle fibres in cetaceans change with advancing age, evolving towards a slower muscle phenotype. We suggest that this physiological evolution constitutes an adaptation that allows these marine mammals to perform prolonged, deep dives. PMID- 23648413 TI - Transferrin receptor-1 iron-acquisition pathway - synthesis, kinetics, thermodynamics and rapid cellular internalization of a holotransferrin-maghemite nanoparticle construct. AB - BACKGROUND: Targeting nanoobjects via the iron-acquisition pathway is always reported slower than the transferrin/receptor endocytosis. Is there a remedy? METHODS: Maghemite superparamagnetic and theragnostic nanoparticles (diameter 8.6nm) were synthesized, coated with 3-aminopropyltriethoxysilane (NP) and coupled to four holotransferrin (TFe2) by amide bonds (TFe2-NP). The constructs were characterized by X-ray diffraction, transmission electron microscopy, FTIR, X-ray Electron Spectroscopy, Inductively Coupled Plasma with Atomic Emission Spectrometry. The in-vitro protein/protein interaction of TFe2-NP with transferrin receptor-1 (R1) and endocytosis in HeLa cells were investigated spectrophotometrically, by fast T-jump kinetics and confocal microscopy. RESULTS: In-vitro, R1 interacts with TFe2-NP with an overall dissociation constant KD=11nM. This interaction occurs in two steps: in the first, the C-lobe of the TFe2-NP interacts with R1 in 50MUs: second-order rate constant, k1=6*10(10)M( 1)s(-1); first-order rate constant, k-1=9*10(4)s(-1); dissociation constant, K1d=1.5MUM. In the second step, the protein/protein adduct undergoes a slow (10,000s) change in conformation to reach equilibrium. This mechanism is identical to that occurring with the free TFe2. In HeLa cells, TFe2-NP is internalized in the cytosol in less than 15min. CONCLUSION: This is the first time that a nanoparticle-transferrin construct is shown to interact with R1 and is internalized in time scales similar to those of the free holotransferrin. GENERAL SIGNIFICANCE: TFe2-NP behaves as free TFe2 and constitutes a model for rapidly targeting theragnostic devices via the main iron-acquisition pathway. PMID- 23648416 TI - Association of periodontitis with carotid artery intima-media thickness and arterial stiffness in community-dwelling people in Japan: the Nagasaki Islands study. AB - OBJECTIVE: Recent studies have suggested an association between periodontitis and atherosclerosis; however, the relationship between periodontal status and arterial alterations should be clarified. The purpose of this study was to examine associations between periodontal status and carotid intima-media thickness (cIMT) and arterial stiffness using the cardio-ankle vascular index (CAVI) in community dwellers. METHODS: A community-based cross-sectional study of 1053 subjects >=40 years with 10 teeth or more was conducted in Goto, Japan from 2008 to 2010. RESULTS: In a multiple linear regression analysis adjusted for age, sex, number of present teeth, and other confounders, each 1-mm increase in mean periodontal pocket depth corresponded to a 0.02-mm increase in maximal cIMT (beta = 0.018; P = 0.049) and also to a 0.1 increase in mean CAVI (beta = 0.133; P = 0.040). In addition, each 1-mm increase in the mean periodontal attachment loss corresponded to a 0.01-mm increase in maximal cIMT (beta = 0.013; P = 0.040). A multiple logistic regression analysis revealed that each 1-mm increase in mean periodontal pocket depth was associated with an increased risk of a maximal cIMT >1 mm (adjusted odds ratio [OR], 1.430; 95% confidence interval [CI], 1.067 1.918; P = 0.017) and mean CAVI of >=8 (OR, 1.323; 95% CI, 1.003-1.743; P = 0.047). Furthermore, each 1-mm increase in mean periodontal attachment loss was associated with an increased risk of a maximal cIMT >1 mm (OR, 1.251; 95% CI, 1.032-1.516; P = 0.022). CONCLUSION: A linear, dose-dependent relationship was found between periodontal pocket depth, cIMT, and arterial stiffness. PMID- 23648414 TI - Methionine oxidation and reduction in proteins. AB - BACKGROUND: Cysteine and methionine are the two sulfur containing amino acids in proteins. While the roles of protein-bound cysteinyl residues as endogenous antioxidants are well appreciated, those of methionine remain largely unexplored. SCOPE: We summarize the key roles of methionine residues in proteins. MAJOR CONCLUSION: Recent studies establish that cysteine and methionine have remarkably similar functions. GENERAL SIGNIFICANCE: Both cysteine and methionine serve as important cellular antioxidants, stabilize the structure of proteins, and can act as regulatory switches through reversible oxidation and reduction. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. PMID- 23648417 TI - Beneficial effect of dehydroepiandrosterone on pulmonary hypertension in a rodent model of pulmonary hypertension in infants. AB - BACKGROUND: Pulmonary hypertension (PH) is a disease that affects the adult or infant population. Dehydroepiandrosterone (DHEA), a steroid hormone, has been previously shown to prevent and to reverse PH in an adult rat model. We thus investigated its effect in a rat-pup model of chronic hypoxic PH. METHODS: Animals were maintained for 3 wk in a hypobaric chamber to induce PH, with or without concomitant treatment with DHEA (30 mg/kg every alternate day). RESULTS: DHEA significantly reduced mean pulmonary artery pressure (measured by right cardiac catheterization), pulmonary artery remodeling (evaluated by histology), and right-ventricular hypertrophy (measured by echography and by the Fulton index). At the level of the pulmonary artery smooth muscle cell (PASMC), DHEA increased activity and expression of the large-conductance Ca2+-activated potassium channel (BKCa) (assessed by means of the patch clamp technique). DHEA also inhibited both serotonin- and KCl-induced contraction and smooth muscle cell proliferation. CONCLUSION: Collectively, these results indicate that DHEA prevents PH in infant rats and may therefore be clinically relevant for the management of PH in human infants. PMID- 23648418 TI - Immunolocalization of the calcium-sensing receptor in developing human kidney. AB - BACKGROUND: The calcium-sensing receptor (CSR) is a G-protein receptor that plays a critical role in calcium regulation. In the kidney, the CSR regulates calcium reabsorption in the thick ascending limb, where stimulation of the CSR inhibits calcium reabsorption in response to increased calcium in the peritubular fluid. In the collecting duct, apical CSR activation may play a role in osmoregulation, increasing water excretion in response to increased luminal calcium. METHODS: We studied the ontogeny of the CSR in developing human kidney using immunohistochemical methods. RESULTS: The CSR is first expressed in the S-shaped body in the region destined to form the ascending limb and distal tubule. Other regions of the S-shaped body, as well as ureteric buds, do not express the CSR. The CSR is observed in thick ascending limb as early as 20 wk of development. The CSR is not observed in proximal tubule or collecting duct between 20 and 40 wk of human development. CONCLUSION: During early human renal development, CSR expression is limited to the thick ascending limb and distal tubule, where this receptor may play a role in calcium homeostasis between 20 and 40 wk of human development. PMID- 23648419 TI - The ecotoxicological evaluation of Cylindrospermopsis raciborskii from Lake Balaton (Hungary) employing a battery of bioassays and chemical screening. AB - Ecotoxicity of four Cylindrospermopsis raciborskii strains (ACT 9502, ACT 9503, ACT 9504, ACT 9505) isolated from Lake Balaton (Hungary) was evaluated in four aquatic bioassays including the Thamnocephalus platyurus acute lethality test; Daphnia magna acute immobilization assay; D. magna feeding inhibition assay and Danio rerio embryo developmental toxicity assay, assisted by chemical screening for known toxins by HPLC-MS. For reference, we analyzed in parallel the toxin content and toxic effects of two previously characterized toxin-producing strains: the Australian cylindrospermopsin producer AQS C. raciborskii and the anatoxins producer Oscillatoria sp. PCC 6506. Bioassays were used to evaluate the overall toxicity of the hydrophilic bioactive metabolites pool synthesized by the selected cyanobacteria. Chemical screening has proven that the ACT C. raciborskii extracts investigated did not contained cylindrospermopsins and anatoxins. The relative toxicity of the ACT C. raciborskii aqueous extracts observed in each bioassay was comparable to the effects recorded for the anatoxins producer PCC 6506 strain while toxicity values (EC50/LC50) calculated for the AQS extract were in general one order of magnitude lower. Concerning sublethal effects of ACT C. raciborskii extracts to the D. rerio embryogenesis, the general morphological abnormality observed was a significant retardation of development. Overall, our results suggest that C. raciborskii populating Lake Balaton produce metabolites with significant bioactive potencies. Therefore, continued investigation of these unknown compounds is required. PMID- 23648420 TI - Biochemical and immunological characteristics of Peruvian Loxosceles laeta spider venom: neutralization of its toxic effects by anti-loxoscelic antivenoms. AB - This manuscript describes the general biochemical properties and immunological characteristics of Peruvian spider Loxosceles laeta venom (PLlv), which is responsible for the largest number of accidents involving venomous animals in Peru. In this work, we observed that the venom of this spider is more lethal to mice when compared with L. laeta venom from Brazil (BLlv). The LD50 of PLlv was 1.213 mg/kg when the venom was intradermally injected. The venom displayed sphingomyelinase activity and produced dermonecrotic, hemorrhagic and edema effects in rabbits. 2-D SDS-PAGE separation of the soluble venoms resulted in a protein profile ranging from 20 to 205 kDa. Anti-PLlv and anti-BLlv sera produced in rabbits and assayed by ELISA showed that rabbit antibodies cross-reacted with PLlv and BLlv and also with other Brazilian Loxosceles venoms. Western blotting analysis showed that bands corresponding to 25-35 kDa are the proteins best recognized in every Loxosceles spp venoms analyzed. The immunized rabbits displayed protective effect after challenge with PLlv and BLlv. In vitro assays with horse anti-loxoscelic antivenoms produced in Brazil and Peru demonstrated that these commercial antivenoms were efficient to inhibit the sphingomyelinase activity of PLlv and BLlv. PMID- 23648421 TI - Toxic effects of pure anatoxin-a on biomarkers of rainbow trout, Oncorhynchus mykiss. AB - Anatoxin-a is a neurotoxin produced by various bloom-forming cyanobacteria. Although it shows widespread occurrence and is highly toxic to rodents, its mechanisms of action and biotransformation, and effects in fish species are still poorly understood. The main aim of this study was, thus, to investigate sub lethal effects of anatoxin-a on selected biochemical markers in rainbow trout fry in order to get information about the mechanisms of toxicity and biotransformation of this toxin in fish. Trout fry were administered sub-lethal doses of anatoxin-a (0.08-0.31 MUg g-1) intraperitoneally. Livers and muscle tissue were collected 72 h later for quantification of key enzyme activities as biochemical markers. Enzymes assessed in muscle tissues were related to cholinergic transmission (acetylcholinesterase [AChE]), energy metabolism (lactate dehydrogenase [LDH] and NADP+-dependent isocitrate dehydrogenase [IDH]). Enzymes assessed in the liver were involved in biotransformation (ethoxyresorufin O-deethylase [EROD] and glutathione S-transferases [GST]). The results indicated a significant increasing trend for AChE activity with the dose of anatoxin-a, possibly representing an attempt to cope with overstimulation of muscle activity by the toxin, which competes with acetylcholine for nicotinic receptors binding. Anatoxin-a was also found to significantly induce the activities of liver EROD and GST, indicating the involvement of phase I and II biotransformation in its detoxification. Likewise, lactate dehydrogenase activity recorded in fry muscle increased significantly with the dose of anatoxin-a, suggesting an induction of the anaerobic pathway of energy production to deal with toxic stress induced by the exposure. Altogether, the results suggest that under continued exposure in the wild fish may experience motor difficulties, possibly becoming vulnerable to predators, and be at increased metabolic demand to cope with energetic requirements imposed by anatoxin-a biotransformation mechanisms. PMID- 23648422 TI - The effect of temperature on the effects of the phospholipase A2 neurotoxins beta bungarotoxin and taipoxin at the neuromuscular junction. AB - Snake venom neurotoxins with phospholipase A2 affect the neuromuscular junction with three distinct phases. There is a transient decrease in twitch height, followed by a facilitatory phase and finally a progressive blockade. It has been suggested that the initial phase is a direct consequence of the binding of the toxins to nerve terminals. This study was designed to determine whether the initial phase is present under conditions that would reduce the enzyme activity of the toxins. At 27 degrees C, beta-bungarotoxin and taipoxin exhibited all three phases, i.e. 5-6 min after exposure to the preparation, twitch height was significantly reduced (P < 0.5) to 50 +/- 4% and 64 +/- 9% of control respectively. This was followed by facilitation and subsequent blockade. However, at 20 degrees C, neither toxin exhibited the first phase while the second phase, although reduced, clearly occurred and the blocking activity of these toxins always appeared. The data clearly demonstrate that the initial fall is temperature dependent as reducing the temperature from 27 degrees C to 20 degrees C blocks the first phase. As the second phase still occurs the toxins must have bound to their target. Therefore, the first phase cannot simply be a toxin binding step. PMID- 23648423 TI - New alpha-adrenergic property for synthetic MTbeta and CM-3 three-finger fold toxins from black mamba. AB - Despite their isolation more than fifteen years ago from the venom of the African mamba Dendroaspis polylepis, very few data are known on the functional activity of MTbeta and CM-3 toxins. MTbeta was initially classified as a muscarinic toxin interacting non-selectively and with low affinity with the five muscarinic receptor subtypes while no biological function was determined for CM-3. Recent results highlight the multifunctional activity of three-finger fold toxins for muscarinic and adrenergic receptors and reveal some discrepancies in the pharmacological profiles of their venom-purified and synthetic forms. Here, we report the pharmacological characterization of chemically-synthesized MTbeta and CM-3 toxins on nine subtypes of muscarinic and adrenergic receptors and demonstrate their high potency for alpha-adrenoceptors and in particular a sub nanomolar affinity for the alpha1A-subtype. Strikingly, no or very weak affinity were found for muscarinic receptors, highlighting that pharmacological characterizations of venom-purified peptides may be risky due to possible contaminations. The biological profile of these two homologous toxins looks like that one previously reported for the Dendroaspis angusticeps rho-Da1a toxin. Nevertheless, MTbeta and CM-3 interact more potently than rho-Da1a with alpha1B- and alpha1D-AR subtypes. A computational analysis of the stability of the MTbeta structure suggests that mutation S38I, could be involved in this gain in function. PMID- 23648424 TI - AhV_aPA-induced vasoconstriction involves the IP3Rs-mediated Ca2+ releasing. AB - AhV_aPA, the acidic PLA2 purified from Agkistrodon halys pallas venom, was previously reported to possess a strong enzymatic activity and can remarkably induce a further contractile response on the 60 mM K+-induced contraction with an EC50 in 369 nM on mouse thoracic aorta rings. In the present study, we found that the p-bromo-phenacyl-bromide (pBPB), which can completely inhibit the enzymatic activity of AhV_aPA, did not significantly reduce the contractile response on vessel rings induced by AhV_aPA, indicating that the vasoconstrictor effects of AhV_aPA are independent of the enzymatic activity. The inhibitor experiments showed that the contractile response induced by AhV_aPA is mainly attributed to the Ca2+ releasing from Ca2+ store, especially sarcoplasmic reticulum (SR). Detailed studies showed that the Ca2+ release from SR is related to the activation of inositol trisphosphate receptors (IP3Rs) rather than ryanodine receptors (RyRs). Furthermore, the vasoconstrictor effect could be strongly reduced by pre-incubation with heparin, indicating that the basic amino acid residues on the surface of AhV_aPA may be involved in the interaction between AhV_aPA and the molecular receptors. These findings offer new insights into the functions of snake PLA2 and provide a novel pathogenesis of A. halys pallas venom. PMID- 23648425 TI - SNP typing reveals similarity in Mycobacterium tuberculosis genetic diversity between Portugal and Northeast Brazil. AB - Human tuberculosis is an infectious disease caused by bacteria from the Mycobacterium tuberculosis complex (MTBC). Although spoligotyping and MIRU-VNTR are standard methodologies in MTBC genetic epidemiology, recent studies suggest that Single Nucleotide Polymorphisms (SNP) are advantageous in phylogenetics and strain group/lineages identification. In this work we use a set of 79 SNPs to characterize 1987 MTBC isolates from Portugal and 141 from Northeast Brazil. All Brazilian samples were further characterized using spolygotyping. Phylogenetic analysis against a reference set revealed that about 95% of the isolates in both populations are singly attributed to bacterial lineage 4. Within this lineage, the most frequent strain groups in both Portugal and Brazil are LAM, followed by Haarlem and X. Contrary to these groups, strain group T showed a very different prevalence between Portugal (10%) and Brazil (1.5%). Spoligotype identification shows about 10% of mis-matches compared to the use of SNPs and a little more than 1% of strains unidentifiability. The mis-matches are observed in the most represented groups of our sample set (i.e., LAM and Haarlem) in almost the same proportion. Besides being more accurate in identifying strain groups/lineages, SNP-typing can also provide phylogenetic relationships between strain groups/lineages and, thus, indicate cases showing phylogenetic incongruence. Overall, the use of SNP-typing revealed striking similarities between MTBC populations from Portugal and Brazil. PMID- 23648427 TI - Molecular epidemiology of American/Asian genotype DENV-2 in Peru. AB - During the past decade, countries in South America have reported dengue hemorrhagic fever (DHF) associated with American/Asian genotype of dengue virus serotype 2 (DENV-2). DENV-2 strains have been associated with large outbreaks of dengue fever and DHF in numerous regions of Peru since the mid-1990s, but studies to address the origins, distribution, and genetic diversity of DENV-2 strains have been limited. To address this knowledge gap, we sequenced the envelope gene region of DENV-2 isolates from Peru, Ecuador, Paraguay, and Bolivia. Sequences were aligned and compared to a global sample of DENV-2 viruses. Phylogenetic analysis confirmed the circulation of two DENV-2 genotypes in Peru: American (prior to 2001) and American/Asian (2000 to present). American/Asian genotype variants can be classified into two lineages, and these were introduced into Peru from the north (Ecuador, Colombia, and/or Venezuela) and the east (Brazil and Bolivia). American/Asian lineage II replaced lineage I after 2009. We estimate the time to the most recent common ancestor for American/Asian DENV-2 genotype in the Americas was in 1980, and 1984 and 1989 for lineages I and II, respectively. In light of evidence for increased virulence of lineage II of American/Asian DENV 2, our results support the need for continuous monitoring for the emergence of new DENV genotypes that may be associated with severe disease. PMID- 23648428 TI - All risk factors and confounders should be discussed in order to precisely describe the ankle-brachial index and albuminuria. PMID- 23648429 TI - Arterial wall elasticity measured using the phased tracking method and atherosclerotic risk factors in patients with type 2 diabetes. AB - AIM: The aim of this study was to investigate the relationship between atherosclerotic manifestations and brachial and radial arterial wall elasticity (AWE) measured using the phased tracking method in patients with type 2 diabetes mellitus (T2DM). METHODS: This study included T2DM patients (n= 220, mean age 59 years) without a history of stroke or coronary artery disease. The brachial AWE, radial AWE, carotid mean intima-media thickness (IMT), max-IMT and flow-mediated vasodilation (FMD) were measured. The patients were classified according to the number of atherosclerotic risk factors, including obesity, dyslipidemia and hypertension. Group 1 included T2DM patients only, group 2 included patients with two risk factors, group 3 included patients with three risk factors and group 4 included patients with four risk factors. The patients were also divided into two groups according to microangiopathic complications, including retinopathy and nephropathy. The between-group differences were analyzed. RESULTS: The brachial AWE (548, 697, 755 and 771 kPa for groups 1, 2, 3 and 4, respectively) and radial AWE (532, 637, 717 and 782 kPa for groups 1, 2, 3 and 4, respectively) significantly increased in association with an increasing number of risk factors. The brachial AWE and radial AWE were significantly higher in the patients with microangiopathic complications than in those without microangiopathic complications (brachial AWE 797 and 694 kPa and radial AWE 780 and 660 kPa, respectively). Receiver operating characteristic curve analyses revealed that, for brachial AWE and radial AWE, the area under the curve was equal to the max IMT and higher than the mean-IMT and FMD. CONCLUSIONS: Upper limb AWE measurement can reflect the degree of atherosclerosis risk overload and may be useful for evaluating vascular complications in T2DM patients. PMID- 23648426 TI - Evolution of community- and healthcare-associated methicillin-resistant Staphylococcus aureus. AB - Staphylococcus aureus is a prominent cause of human infections globally. The high prevalence of infections is compounded by antibiotic resistance--a significant problem for treatment. Methicillin-resistant S. aureus (MRSA) is endemic in hospitals and healthcare facilities worldwide, and is an increasingly common cause of community-associated bacterial infections in industrialized countries. Although much focus is placed on the role of S. aureus as a human pathogen, it is in fact a human commensal organism that has had a relatively long coexistence with the human host. Many S. aureus infections can be explained by host susceptibility or other predisposing risk factors. On the other hand, the emergence/re-emergence of successful S. aureus clones (referred to as epidemic waves) suggests a rapid bacterial adaption and evolution, which includes the emergence of antibiotic resistance and increased virulence and/or transmissibility. It is within this context that we review our understanding of selected S. aureus epidemic waves, and highlight the use of genome sequencing as a means to better understand the evolution of each lineage. PMID- 23648431 TI - Optical scattering with hyperspectral imaging to classify longissimus dorsi muscle based on beef tenderness using multivariate modeling. AB - The objective of this study was to develop a non-destructive method for classifying cooked-beef tenderness using hyperspectral imaging of optical scattering on fresh beef muscle tissue. A hyperspectral imaging system (lambda=922-1739 nm) was used to collect hyperspectral scattering images of the longissimus dorsi muscle (n=472). A modified Lorentzian function was used to fit optical scattering profiles at each wavelength. After removing highly correlated parameters extracted from the Lorentzian function, principal component analysis was performed. Four principal component scores were used in a linear discriminant model to classify beef tenderness. In a validation data set (n=118 samples), the model was able to successfully classify tough and tender samples with 83.3% and 75.0% accuracies, respectively. Presence of fat flecks did not have a significant effect on beef tenderness classification accuracy. The results demonstrate that hyperspectral imaging of optical scattering is a viable technology for beef tenderness classification. PMID- 23648432 TI - The effect of salt and fibre direction on water dynamics, distribution and mobility in pork muscle: a low field NMR study. AB - The effect of salt concentration and fibre orientation on water within the meat matrix was investigated by low-field nuclear magnetic resonance (LF-NMR), water binding capacity (WBC), diffusion studies and histological analysis. Pork M. longissimus thoracis et lumborum samples were cured with 5.7, 15.3 or 26.3% w/w NaCl at a parallel or perpendicular fibre direction. NMR transverse (T2) relaxation identified three water components (T2b, T21 and T22) which all exhibited characteristics correlated to WBC. Results indicated that T2b increases with increasing NaCl concentration. Increasing intra-myofibrillar water and decreasing extra-myofibrillar water resulted in the highest WBC. Water diffused more quickly into the extra-myofibrillar space in samples cured at a parallel fibre direction. This water remained loosely bound in samples cured with the saturated solution (26.3% w/w NaCl) leading to decreased WBC. This study provides further information on water binding within the meat matrix by applying the results of LF-NMR to traditional water-binding theories. PMID- 23648433 TI - Two cardiac troponin assays not affected by hemolysis--a patient safety issue. PMID- 23648430 TI - APP/PS1 mice overexpressing SREBP-2 exhibit combined Abeta accumulation and tau pathology underlying Alzheimer's disease. AB - Current evidence indicates that excess brain cholesterol regulates amyloid-beta (Abeta) deposition, which in turn can regulate cholesterol homeostasis. Moreover, Abeta neurotoxicity is potentiated, in part, by mitochondrial glutathione (mGSH) depletion. To better understand the relationship between alterations in cholesterol homeostasis and Alzheimer's disease (AD), we generated a triple transgenic mice featuring sterol regulatory element-binding protein-2 (SREBP-2) overexpression in combination with APPswe/PS1DeltaE9 mutations (APP/PS1) to examine key biochemical and functional characteristics of AD. Unlike APP/PS1 mice, APP/PS1/SREBP-2 mice exhibited early mitochondrial cholesterol loading and mGSH depletion. Moreover, beta-secretase activation and Abeta accumulation, correlating with oxidative damage and neuroinflammation, were accelerated in APP/PS1/SREBP-2 mice compared with APP/PS1 mice. Triple transgenic mice displayed increased synaptotoxicity reflected by loss of synaptophysin and neuronal death, resulting in early object-recognition memory impairment associated with deficits in spatial memory. Interestingly, tau pathology was present in APP/PS1/SREBP-2 mice, manifested by increased tau hyperphosphorylation and cleavage, activation of tau kinases and neurofibrillary tangle (NFT) formation without expression of mutated tau. Importantly, in vivo treatment with the cell permeable GSH ethyl ester, which restored mGSH levels in APP/PS1/SREBP-2 mice, partially prevented the activation of tau kinases, reduced abnormal tau aggregation and Abeta deposition, resulting in attenuated synaptic degeneration. Taken together, these results show that cholesterol-mediated mGSH depletion is a key event in AD progression, accelerating the onset of key neuropathological hallmarks of the disease. Thus, therapeutic approaches to recover mGSH may represent a relevant strategy in the treatment of AD. PMID- 23648434 TI - Lenalidomide for second-line treatment of advanced hepatocellular cancer: a Brown University oncology group phase II study. AB - PURPOSE: To assess the activity and toxicity of lenalidomide for patients with advanced hepatocellular cancer (HCC) previously treated with sorafenib. MATERIALS AND METHODS: Patients with advanced HCC who progressed on or were intolerant to sorafenib were eligible. Patients received lenalidomide 25 mg orally for 1 to 21 days in a 28-day cycle until disease progression or unacceptable toxicities. RESULTS: Forty patients were enrolled and were classified according to the Child Pugh score: 19 were Child-Pugh A, 16 patients were Child-Pugh B, and 5 were Child Pugh C. Seventeen patients had extrahepatic disease. Grade 4 neutropenia occurred in 1 of 40 patients (2.5%). Grade 3 fatigue (n=3) and rash (n=4) were the most common nonhematologic toxicities attributable to lenalidomide. Six of 40 patients (15%) had a partial response. Two patients (5%) have not progressed at 36 and 32 months. The median progression-free survival was 3.6 months and the median overall survival was 7.6 months. CONCLUSIONS: Lenalidomide can be administered to patients with advanced HCC and hepatic dysfunction. Promising, and in a small percentage of patients, durable activity has been demonstrated. Investigations are needed to explore the mechanism of action of lenalidomide in HCC. PMID- 23648435 TI - Decision making and factors influencing long-term satisfaction with prophylactic mastectomy in women with breast cancer. AB - PURPOSE: Studies demonstrate an increasing rate of contralateral prophylactic mastectomy (CPM). The purpose of this study is to evaluate decision making and factors influencing women's long-term satisfaction with CPM. Descriptive analysis is used to analyze the results of our designed questionnaire approved by our Institutional Review Board. METHODS: We searched our institutional cancer registry for patients diagnosed with breast cancer between 2000 and 2010. The studied time frame is of significance as this study is the first to measure response rate in questions examining patient satisfaction for >1 year after undergoing CPM. The questionnaire was mailed to all consented participants to examine factors contributing to the choice of CPM and postoperative satisfaction. RESULTS: Of the 206 women included in the study, 147 were aged up to 50 years. Majority of women who underwent CPM in this cohort was with a bachelor's degree or higher, married or partnered women, and women earning >$60,000/y. Almost all women were "happy with overall surgery" and would recommend CPM to other patients. Psychological factors, such as fear of recurrence, were more commonly associated with the decision for CPM in patients with invasive carcinoma. Opinions of partners, relatives, friends, and physicians further contributed to the decision to undergo surgery. The availability of reconstruction was also an influential factor in the overall decision. CONCLUSIONS: The majority of our study participants experienced long-term satisfaction with the surgical procedure of CPM. From our analysis, we can confidently say that fear of cancer recurrence and the opinions of others, among other factors, were influencing contributors toward the decision of undergoing CPM. PMID- 23648436 TI - Utilization of surgery, chemotherapy, radiation therapy, and hospice at the end of life for patients diagnosed with metastatic melanoma. AB - OBJECTIVES: To examine the patterns of utilization of radiation therapy, chemotherapy, surgery, and hospice at the end-of-life care for patients diagnosed with metastatic melanoma. METHODS: We identified 816 Medicare beneficiaries toward who were 65 years of age or older, with pathologically confirmed metastatic malignant melanoma between January 1, 2000, and December 31, 2007. We evaluated trends and associations between sociodemographic and health service characteristics and the use of hospice care, chemotherapy, surgery, and radiation therapy. RESULTS: We found increasing use of surgery for patients with metastatic melanoma from 13% in 2000 to 30% in 2007 (P=0.03 for trend), and no significant fluctuation in the use of chemotherapy (P=0.43) or radiation therapy (P=0.46). Older patients were less likely to receive radiation therapy or chemotherapy. The use of hospice care increased from 61% in 2000 to 79% in 2007 (P=0.07 for trend). Enrollment in short-term (1 to 3 d) hospice care use increased, whereas long-term hospice care (>=4 d) remained stable. Patients living in the SEER (Surveillance, Epidemiology and End Results) northeast and south regions were less likely to undergo surgery. Patients enrolled in long-term hospice care used significantly less chemotherapy, surgery, and radiation therapy. CONCLUSIONS: Surgery and hospice care use increased over the years of this study, whereas the use of chemotherapy and radiation therapy remained consistent for patients diagnosed with metastatic melanoma. PMID- 23648438 TI - Role of radiation therapy as immune activator in the era of modern immunotherapy for metastatic malignant melanoma. AB - Metastatic melanoma is difficult to treat, and often portends a grim prognosis. For patients with cerebral metastases, the prognosis is even more dire. Systemic immunotherapy and targeted agents are emerging as the mainstay of treatment for metastatic melanoma. Although immunotherapy has been shown to prolong relapse free survival and long-term control of micrometastatic disease, the response rate is suboptimal, prompting the need to optimize and improve therapy. Accumulating evidence suggests that in addition to effective locoregional control, radiation therapy (RT) may induce immune activation and expansion of T lymphocytes recognizing melanocyte-specific antigens including activated cytotoxic T lymphocytes that can potentially kill melanoma cells. In some cases, RT contributes to the clearance of metastatic disease in distant, nonirradiated regions, a bystander phenomenon called the abscopal effect. Here, we evaluate the potential promise of ablative radiation treatment in the era of modern immunotherapy by presenting a patient with metastatic melanoma who remained disease free for over 3 years after an initial diagnosis of advanced metastatic melanoma with brain, subcutaneous tissue, mesenteric, pelvic, and retroperitoneal involvement. The patient failed initial stereotactic radiosurgery, but responded to whole-brain RT in combination with interleukin-2 immunotherapy. Thus, combination RT with immunotherapy may be synergistic by promoting the release and processing of melanoma antigens that can be presented by dendritic cells. This in turn may augment the response to therapies that center on expansion and/or activation of antitumor T cells. PMID- 23648439 TI - Impact of radiographic findings on for prognosis skin cancer with perineural invasion. AB - OBJECTIVES: Update our experience using radiotherapy (RT) for head-and-neck squamous or basal cell carcinoma with clinical perineural invasion (PNI) and correlate radiographic findings with outcomes. MATERIALS AND METHODS: We treated 65 patients with cT4N0 head-and-neck skin cancers with clinical PNI from 1965 to 2009 (N0 disease, 59; N1 disease, 6). Treatment included RT alone (N=18), RT with concurrent chemotherapy (N=14), surgery and postoperative RT (N=26), or postoperative RT with concurrent chemotherapy (N=5), and preoperative RT and surgery (N=2). Patients were stratified by imaging-negative disease (N=11), minimal or moderate peripheral disease (N=18), and macroscopic and/or central disease (N=36). Median RT dose was 72.6 Gy (50.4 to 79.2 Gy). Median follow-up overall and for living patients was 5.4 and 11.6 years, respectively. RESULTS: Five-year outcomes for imaging-negative disease versus minimal/moderate peripheral disease versus macroscopic/central disease were: local control, 81% versus 60% versus 47% (P=0.23); local-regional control, 80% versus 54% versus 47% (P=0.22); neck control, 100% versus 89% versus 93% (P=0.45); and distant metastasis-free survival, 89% versus 100% versus 93% (P=0.57), respectively. Five year survival rates for imaging-negative disease versus minimal/moderate peripheral disease versus macroscopic/central disease were: overall survival, 82% versus 50% versus 52% (P=0.26), and cause-specific survival, 100% versus 58% versus 65% (P=0.08). Twenty-two (34%) patients had 1 or more severe (grade >=3) late complications. CONCLUSIONS: There is a nonsignificant trend towards improved local control for imaging-negative patients and patients with minimal/moderate peripheral disease compared with macroscopic/central disease. Although survival appears better for imaging-negative patients, extent of imaging-positive PNI did not impact overall or cause-specific survival. PMID- 23648437 TI - Outcomes After Multidisciplinary Treatment of Inflammatory Breast Cancer in the Era of Neoadjuvant HER2-directed Therapy. AB - OBJECTIVES: We previously reported survival trends among patients with inflammatory breast cancer (IBC) over a 30-year period before 2005. Here we evaluated survival outcomes for women with IBC diagnosed before or after October 2006, in the era of HER2-directed therapy and after opening a dedicated multidisciplinary IBC clinic. METHODS: We retrospectively identified and reviewed 260 patients with newly diagnosed IBC without distant metastasis, 168 treated before October 2006 and 92 treated afterward. Most patients received anthracycline and taxane-based neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation. Survival outcomes were compared between the 2 groups. RESULTS: Median follow-up time was 29 months for the entire cohort (39 and 24 mo for patients treated before and after October 2006). Patients treated more recently were more likely to have received neoadjuvant HER2-directed therapy for HER2-positive tumors (100% vs. 54%, P=0.001). No differences were found in receipt of hormone therapy. Three-year overall survival rates were 63% for those treated before and 82% for those treated after October 2006 (log-rank P=0.02). Univariate Cox analysis demonstrated better overall survival among patients treated after October 2006 than among those treated beforehand (hazard ratio [HR] 0.5; 95% confidence interval [CI], 0.34-0.94); a trend toward improved survival was noted in the multivariate analysis (HR=0.47; 95% CI, 0.19-1.16; P=0.10). Significant factors in the multivariate model included HER2-directed therapy (HR=0.38; 95% CI, 0.17-0.84; P=0.02) and estrogen receptor positivity (HR=0.32; 95% CI, 0.14-0.74; P=0.01). CONCLUSIONS: Survival improved in the context of the IBC clinic and prompt initiation of neoadjuvant HER2-directed therapeutics. PMID- 23648441 TI - Association of short duration from initial symptoms to specialist consultation with poor survival in soft-tissue sarcomas. AB - INTRODUCTION: The association of symptom duration with survival remains controversial in soft-tissue sarcoma (STS). MATERIALS AND METHODS: We determined whether the length from initial symptoms to specialist consultation affects prognosis in STSs. We retrospectively reviewed 152 primary STS patients (with 142 non-small round cell sarcomas) who consulted our specialist hospital. The factors that affected the length of the period from the initial symptoms to specialist consultation and the length of the delay at the clinic before specialist hospital referral were investigated. The relation between the length of the period from symptom onset and overall survival was also analyzed. RESULTS: Unplanned excision and superficial tumor were significantly associated with increasing duration from the initial symptoms to specialist hospital referral. Multivariate analysis revealed that tumors over 5 cm (P=0.002 and 0.005) and symptoms within 6 months (P=0.017 and 0.016) were independent poor prognostic factors of overall survival among the pretreatment factors when analyzing all and non-small round cell STSs. CONCLUSIONS: This is a first report to show the independent prognostic role of symptom duration in STSs on multivariate analysis. Considering the impact of symptom duration on survival in these heterogenous tumors, careful follow-up and consideration of treatment are necessary for patients with short symptom duration. PMID- 23648440 TI - The Association Between Chemoradiation-related Lymphopenia and Clinical Outcomes in Patients With Locally Advanced Pancreatic Adenocarcinoma. AB - OBJECTIVES: Lymphopenia is a common consequence of chemoradiation therapy yet is seldom addressed clinically. This study was conducted to determine if patients with locally advanced pancreatic cancer (LAPC) treated with definitive chemoradiation develop significant lymphopenia and if this affects clinical outcomes. METHODS: A retrospective analysis of patients with LAPC treated with chemoradiation at a single institution from 1997 to 2011 was performed. Total lymphocyte counts (TLCs) were recorded at baseline and then monthly during and after chemoradiation. The correlation between treatment-induced lymphopenia, established prognostic factors, and overall survival was analyzed using univariate Cox regression analysis. Important factors identified by univariate analysis were selected as covariates to construct a multivariate proportional hazards model for survival. RESULTS: A total of 101 patients met eligibility criteria. TLCs were normal in 86% before chemoradiation. The mean reduction in TLC per patient was 50.6% (SD, 40.6%) 2 months after starting chemoradiation (P<0.00001), and 46% had TLC<500 cells/mm. Patients with TLC<500 cells/mm 2 months after starting chemoradiation had inferior median survival (8.7 vs. 13.3 mo, P=0.03) and PFS (4.9 vs. 9.0 mo, P=0.15). Multivariate analysis revealed TLC<500 cells/mm to be an independent predictor of inferior survival (HR=2.879, P=0.001) along with baseline serum albumin (HR=3.584, P=0.0002), BUN (HR=1.060, P=0.02), platelet count (HR=1.004, P=0.005), and radiation planning target volume (HR=1.003, P=0.0006). CONCLUSIONS: Severe treatment-related lymphopenia occurs frequently after chemoradiation for LAPC and is an independent predictor of inferior survival. PMID- 23648442 TI - Evaluation of factors influencing the groundwater chemistry in a small tropical island of Malaysia. AB - Groundwater chemistry of small tropical islands is influenced by many factors, such as recharge, weathering and seawater intrusion, among others, which interact with each other in a very complex way. In this work, multivariate statistical analysis was used to evaluate the factors controlling the groundwater chemistry of Kapas Island (Malaysia). Principal component analysis (PCA) was applied to 17 hydrochemical parameters from 108 groundwater samples obtained from 18 sampling sites. PCA extracted four PCs, namely seawater intrusion, redox reaction, anthropogenic pollution and weather factors, which collectively were responsible for more than 87% of the total variance of the island's hydrochemistry. The cluster analysis indicated that three factors (weather, redox reaction and seawater intrusion) controlled the hydrochemistry of the area, and the variables were allocated to three groups based on similarity. A Piper diagram classified the island's water types into Ca-HCO3 water type, Na-HCO3 water type, Na-SO4-Cl water type and Na-Cl water type, indicating recharge, mixed, weathering and leached from sewage and seawater intrusion, respectively. This work will provide policy makers and land managers with knowledge of the precise water quality problems affecting the island and can also serve as a guide for hydrochemistry assessments of other islands that share similar characteristics with the island in question. PMID- 23648443 TI - Pure and social disparities in distribution of dentists: a cross-sectional province-based study in Iran. AB - During past decades, the number of dentists has continuously increased in Iran. Beside the quantity, the distribution of dentists affects the oral health status of population. The current study aimed to assess the pure and social disparities in distribution of dentists across the provinces in Iran in 2009. Data on provinces' characteristics, including population and social situation, were obtained from multiple sources. The disparity measures (including Gini coefficient, index of dissimilarity, Gaswirth index of disparity and relative index of inequality (RII)) and pairwise correlations were used to evaluate the pure and social disparities in the number of dentists in Iran. On average, there were 28 dentists per 100,000 population in the country. There were substantial pure disparities in the distribution of dentists across the provinces in Iran. The unadjusted and adjusted RII values were 3.82 and 2.13, respectively; indicating area social disparity in favor of people in better-off provinces. There were strong positive correlations between density of dentists and better social rank. It is suggested that the results of this study should be considered in conducting plans for redistribution of dentists in the country. In addition, further analyses are needed to explain these disparities. PMID- 23648444 TI - The role of the MTHFR 677C>T polymorphism in methotrexate-induced liver toxicity: a meta-analysis in patients with cancer. AB - Methotrexate (MTX), one of the important pillars in the treatment of different forms of cancer, is associated with the development of hepatotoxicity. The 677C>T variant (rs1801133) in the methylenetetrahydrofolate reductase (MTHFR) gene might affect the development of hepatotoxicity. Results in literature are, however, contradictive. The aim of this study was to evaluate the role of the MTHFR 677C>T polymorphism in MTX-induced hepatotoxicity by analyzing a Dutch cohort of pediatric patients treated with high doses of MTX and subsequently performing a meta-analysis. Ninety-eight patients receiving 542 courses of high-dose MTX were genotyped for the MTHFR 677C>T variant. Hepatotoxicity was evaluated retrospectively according to common terminology criteria for adverse events National Cancer Institute criteria. The influence of MTHFR 677C>T on hepatotoxicity was examined using a generalized estimating equation (GEE) analysis. A fixed-effect meta-analysis based on this and previous studies investigating the association between the MTHFR 677C>T polymorphism and uniformly coded hepatotoxicity was performed. The GEE analysis showed an increased risk of developing hepatotoxicity for T versus C allele (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.0-3.2, P=0.04). This finding was not supported by the meta-analysis including seven studies and 1044 patients; the OR for the 677T versus C allele was 1.1 (95% CI 0.84-1.5, P=0.25). Heterogeneity between studies was observed, possibly related to differences in MTX dose and leucovorin rescue. In conclusion, in patients with cancer, the MTHFR 677T allele has only a minor role in the development of MTX-induced hepatotoxicity. Observed heterogeneity between studies warrants further study into (tailored) leucovorin rescue. PMID- 23648445 TI - EDCs, estrogenicity and genotoxicity reduction in a mixed (domestic + textile) secondary effluent by means of ozonation: a full-scale experience. AB - WWTP (wastewater treatment plant) effluents are considered to be a major source for the release in the aquatic environment of EDCs (Endocrine-Disrupting Compounds), a group of anthropogenic substances able to alter the normal function of the endocrine system. The application of conventional processes (e.g. activated sludge with biological nitrogen removal) does not provide complete elimination of all these micropollutants and, consequently, an advanced treatment should be implemented. This experimental work was conducted on the tertiary ozonation stage of a 140,000 p.e. activated sludge WWTP, treating a mixed domestic and textile wastewater: an integrated monitoring, including both chemical (nonylphenol, together with the parent compounds mono- and di ethoxylated, and bisphenol A were chosen as model EDCs) and biological (estrogenic and genotoxic activities) analyses, was carried out. Removal efficiencies of measured EDCs varied from 20% to 70%, depending on flow conditions (ozone dosage being 0.5 gO3/gTOC). Biological tests, furthermore, displayed that the oxidation stage did not significantly reduce (only by 20%) the estrogenicity of the effluent and revealed the presence and/or formation of genotoxic compounds. These results highlight the importance of the application of an integrated (biological+chemical) analytical procedure for a global evaluation of treatment suitability; poor performances recorded in this study have been attributed to the presence of a significant industrial component in the influent wastewater. PMID- 23648446 TI - Characterization and identification of a chlorine-resistant bacterium, Sphingomonas TS001, from a model drinking water distribution system. AB - This study describes the identification and characterization of a new chlorine resistant bacterium, Sphingomonas TS001, isolated from a model drinking water distribution system. The isolate was identified by 16s rRNA gene analysis and morphological and physiological characteristics. Phylogenetic analysis indicates that TS001 belongs to the genus Sphingomonas. The model distribution system HPC results showed that, when the chlorine residual was greater than 0.7 mg L(-1), 100% of detected heterotrophic bacteria (HPC) was TS001. The bench-scale inactivation efficiency testing showed that this strain was very resistant to chlorine, and 4 mg L(-1) of chlorine with 240 min retention time provided only approximately 5% viability reduction of TS001. In contrast, a 3-log inactivation (99.9%) was obtained for UV fluencies of 40 mJ cm(-2). A high chlorine-resistant and UV sensitive bacterium, Sphingomonas TS001, was documented for the first time. PMID- 23648447 TI - Hazard assessment of United Arab Emirates (UAE) incense smoke. AB - Incense burning inside the home, a common practice in Arabian Gulf countries, has been recognized as a potentially modifiable source of indoor air pollution. To better understand potential adverse effects of incense burning in exposed individuals, we conducted a hazard assessment of incense smoke exposure. The goals of this study were first to characterize the particles and gases emitted from Arabian incense over time when burned, and secondly to examine in vitro human lung cells responses to incense smoke. Two types of incense (from the United Arab Emirates) were burned in a specially designed indoor environmental chamber (22 m(3)) to simulate the smoke concentration in a typical living room and the chamber air was analyzed. Both particulate (PM) concentrations and sizes were measured, as were gases carbon monoxide (CO), sulfur dioxide (SO2), oxides of nitrogen (NOx), formaldehyde (HCHO), and carbonyls. During the burn, peak concentrations were recorded for PM (1.42 mg/m(3)), CO (122 pm), NOx (0.3 ppm), and HCHO (85 ppb) along with pentanal (71.9 MUg/m(3)), glyoxal (84.8 MUg/m(3)), and several other carbonyls. Particle sizes ranged from 20 to 300 nm with count median diameters ranging from 65 to 92 nm depending on time post burn-out. PM, CO, and NOx time-weighted averages exceeded current government regulation values and emissions seen previously from environmental tobacco smoke. Charcoal emissions were the main contributor to both the high CO and NOx concentrations. A significant cell inflammatory response was observed in response to smoke components formed from incense burning. Our hazard evaluation suggests that incense burning contributes to indoor air pollution and could be harmful to human health. PMID- 23648448 TI - Detection of pharmaceuticals and personal care products (PPCPs) in near-shore habitats of southern Lake Michigan. AB - Pharmaceuticals and personal care products (PPCPs) have been documented throughout the United States freshwaters but research has focused largely on lotic systems. Because PPCPs are designed to have a physiological effect, it is likely that they may also influence aquatic organisms. Thus, PPCPs may negatively impact aquatic ecosystems. The objectives of this research were to quantify PPCP abundance in near-shore habitats of southern Lake Michigan and identify factors related to PPCP abundance. Stratified sampling was conducted seasonally at four southern Lake Michigan sites. All sites and depths had measurable PPCP concentrations, with mean individual compound concentrations of acetaminophen (5.36 ng/L), caffeine (31.0 ng/L), carbamazepine (2.23 ng/L), cotinine (4.03 ng/L), gemfibrozil (7.03 ng/L), ibuprofen (7.88 ng/L), lincomycin (4.28 ng/L), naproxen (6.32 ng/L), paraxanthine (1,7-dimethylxanthine; 46.2 ng/L), sulfadimethoxine (0.94 ng/L), sulfamerazine (0.92 ng/L), sulfamethazine (0.92 ng/L), sulfamethoxazole (26.0 ng/L), sulfathiazole (0.92 ng/L), triclocarban (5.72 ng/L), trimethoprim (5.15 ng/L), and tylosin (3.75 ng/L). Concentrations of PPCPs varied significantly among sampling times and locations (river mouth vs offshore), with statistical interactions between the main effects of site and time as well as time and location. Concentrations of PPCPs did not differ with site or depth. Temperature, total carbon, total dissolved solids, dissolved oxygen, and ammonium concentrations were related to total pharmaceutical concentrations. These data indicate that PPCPs are ubiquitous and persistent in southern Lake Michigan, potentially posing harmful effects to aquatic organisms. PMID- 23648449 TI - Leaf litter decomposition of native and introduced tree species of contrasting quality in headwater streams: how does the regional setting matter? AB - Terrestrial plant litter is important in sustaining stream food webs in forested headwaters. Leaf litter quality often decreases when native species are replaced by introduced species, and a lower quality of leaf litter inputs may alter litter decomposition at sites afforested with non-native species. However, since detritivore composition and resource use plasticity may depend on the prevalent litter inputs, the extent of the alteration in decomposition can vary between streams. We tested 2 hypotheses using 2 native and 3 introduced species of tree differing in quality in 4 Iberian regions with contrasting vegetational traits: 1) decomposition rates of all plant species would be higher in regions where streams normally receive litter inputs of lower rather than higher quality; 2) a higher resource-use plasticity of detritivores in regions vegetated with plants of lower litter quality will cause a greater evenness in decomposition rates among plant species compared to regions where streams normally receive higher quality plant litter inputs. Results showed a highly consistent interspecific ranking of decomposition rates across regions driven by litter quality, and a significant regional effect. Hypothesis 1 was supported: decomposition rates of the five litter types were generally higher in streams from regions vegetated with species producing leaf litter of low quality, possibly due to the profusion of caddisfly shredders in their communities. Hypothesis 2 was not supported: the relative differences in decomposition rates among leaf litter species remained essentially unaltered across regions. Our results suggest that, even in regions where detritivores can be comparatively efficient using resources of low quality, caution is needed particularly when afforestation programs introduce plant species of lower litter quality than the native species. PMID- 23648450 TI - Galectin-9 in tumor biology: a jack of multiple trades. AB - Galectin family members have been shown to exert multiple roles in the context of tumor biology. Several recent findings support a similar multi-faceted role for galectin-9. Galectin-9 expression is frequently altered in cancer as compared to normal tissues. In addition, an increasing amount of evidence suggests that galectin-9 is involved in several aspects of tumor progression, including tumor cell adhesion and survival, immune escape and angiogenesis. Also, galectin-9 shows potential as a prognostic marker and a therapeutic target for several malignancies. In this review we summarize both the established and the emerging roles of galectin-9 in tumor biology and discuss the potential application of galectin-9 in anti-cancer therapy. PMID- 23648451 TI - Discrete event simulation model of sudden cardiac death predicts high impact of preventive interventions. AB - Sudden Cardiac Death (SCD) is responsible for at least 180,000 deaths a year and incurs an average cost of $286 billion annually in the United States alone. Herein, we present a novel discrete event simulation model of SCD, which quantifies the chains of events associated with the formation, growth, and rupture of atheroma plaques, and the subsequent formation of clots, thrombosis and on-set of arrhythmias within a population. The predictions generated by the model are in good agreement both with results obtained from pathological examinations on the frequencies of three major types of atheroma, and with epidemiological data on the prevalence and risk of SCD. These model predictions allow for identification of interventions and importantly for the optimal time of intervention leading to high potential impact on SCD risk reduction (up to 8-fold reduction in the number of SCDs in the population) as well as the increase in life expectancy. PMID- 23648452 TI - Half-dose enoxaparin vs. full-dose enoxaparin for postoperative bridging therapy in patients after cardiac surgery: which dose regimen should be preferred? AB - BACKGROUND: Patients who require oral anticoagulation (OAC) after cardiac surgery due to an increased risk for thromboembolic events should receive bridging therapy with heparin until the INR is in a therapeutic range. For this purpose, unfractionated heparin (UFH) or low molecular weight heparin (LMWH) can be used. Recently published studies have demonstrated the safety and efficiency of therapeutic dose LMWH as bridging anticoagulant in cardiac surgery. The present study compares a full-therapeutic dose regimen with a half-therapeutic dose regimen of LMWH looking for safety and efficiency. PATIENTS AND METHODS: This study represents a retrospective, single-center cohort study. In a period of 19 months all patients in whom a postoperative bridging therapy after cardiac surgery was necessary (atrial fibrillation, mechanical heart valve replacement, tricuspid valve repair, intracardiac patch implantation, excision of intracardiac tumors) were selected. In the first part of the study, patients received full dose (FD = 1 mg/kg bodyweight twice daily) LMWH (Enoxaparin). Analogously, patients in the second part of the study were treated with half-dose (HD = 0.5 mg/kg bodyweight twice daily) LMWH. In case of renal insufficiency (GFR <30 ml/min) the dose was adjusted to one daily application. The duration of follow-up was the patients' entire stay in hospital. Main outcome parameters were bleeding, thromboembolic events, and death. The first dose of LMWH was given on the morning of the first postoperative day, considered that the bleeding risk was acceptable. OAC (Phenprocoumon) was started on the evening of the first postoperative day. RESULTS: Altogether 402 out of 3133 patients met the inclusion criteria (201 patients in each group). Despite a reduced renal function in the HD-group (p = 0.002) both groups were well matched. Mortality was significantly higher in the HD-group than in the FD-group (5.5% vs. 0.5%, p = 0.003) but not related to the anticoagulation regimen. We observed more bleeding events in the FD-group (11 vs. 5, p = 0.126) but vice versa more thromboembolic events in the HD-group (9 vs. 5, p = 0.277). In the HD-group postoperative dialysis was required more often (29 vs. 12, p = 0.011) and there was a higher incidence of patients who were psychic disorientated (42 vs. 26, p = 0.033). The hospital stay was longer in the FD group (FD: 15.1 +/- 9.3 days, HD 12.5 +/- 8.1 days, p = 0.003). CONCLUSION: This study shows that a bridging therapy with LMWH is feasible and safe no matter which dose-regimen is used. The differences observed seem not to be related to the anticoagulation. The decision of using a full-dose or half-dose LMWH bridging regimen should be determined by the individual risk of the patient and the general bleeding risk of the procedure. PMID- 23648453 TI - Evaluation of microvascularization in focal salivary gland lesions by contrast enhanced ultrasonography (CEUS) and Color Doppler sonography. AB - OBJECTIVE: To evaluate the dynamic microvascularization of focal salivary gland lesions by contrast-enhanced ultrasound (CEUS) and Color Doppler sonography. MATERIALS AND METHODS: One hundred and sixty-eight patients with 183 major salivary gland lesions (mean age, 56 years; age range, 12-83 years) underwent gray-scale ultrasonography (US), Color Doppler (CD) and CEUS. The CD and CEUS patterns were classified into three types (scores 0-3). Combined score grades were calculated based on the CD and CEUS pattern scores. The time-intensity curve (TIC) parameters of CEUS were then analyzed. Sensitivity, specificity, negative predictive value and positive predictive value of combined score grades were also calculated. RESULTS: Among all the lesions, there were 161 in parotid gland, 22 in submandibular gland and 157 lesions were benign and 26 were malignant. For score grades (combined CEUS patterns with CD types), scores 1-2 were graded as benign; scores 3-4 were graded as indetermination-suspicious benign or malignant and scores 5-6 were graded as malignant.score 5-6 and score 1-2 indicated 24 (92.3%) and 135 (85.9%) malignant and benign lesions confirmed pathologically, respectively. The sensitivity and negative predicted value of combined score grades for malignant lesions were 92.3% and 98.5%, respectively. In addition, TIC analysis indicates that PI and AUC in malignant lesions were higher than those in benign lesions (p = 0.04 and 0.02, respectively). CONCLUSION: The combined score grade could be a useful method to assess the macro-and micro-vascularization and to differentiated diagnose benign and malignant lesions in major salivary glands. PMID- 23648454 TI - Making progress in implementing quality in Canadian medical laboratories. PMID- 23648455 TI - Role of a quality management system in improving patient safety - laboratory aspects. AB - OBJECTIVES: The aim of this study is to describe how implementation of a quality management system (QMS) based on ISO 15189 enhances patient safety. DESIGN AND METHODS: A literature review showed that several European hospitals implemented a QMS based on ISO 9001 and assessed the impact on patient safety. An Internet search showed that problems affecting patient safety have occurred in a number of laboratories across Canada. The requirements of a QMS based on ISO 15189 are outlined, and the impact of the implementation of each requirement on patient safety is summarized. The Quality Management Program - Laboratory Services in Ontario is briefly described, and the experience of Ontario laboratories with Ontario Laboratory Accreditation, based on ISO 15189, is outlined. RESULTS: Several hospitals that implemented ISO 9001 reported either a positive impact or no impact on patient safety. Patient safety problems in Canadian laboratories are described. Implementation of each requirement of the QMS can be seen to have a positive effect on patient safety. Average laboratory conformance on Ontario Laboratory Accreditation is very high, and laboratories must address and resolve any nonconformities. Other standards, practices, and quality requirements may also contribute to patient safety. CONCLUSION: Implementation of a QMS based on ISO 15189 provides a solid foundation for quality in the laboratory and enhances patient safety. It helps to prevent patient safety issues; when such issues do occur, effective processes are in place for investigation and resolution. Patient safety problems in Canadian laboratories might have been prevented had effective QMSs been in place. Ontario Laboratory Accreditation has had a positive impact on quality in Ontario laboratories. PMID- 23648456 TI - Sporadic superficial diffuse neurofibromas with repeated local recurrence over many years and a tendency toward malignant change: a report of 3 cases. AB - Sporadic superficial (cutaneous/subcutaneous) neurofibromas are normally small tumors that do not recur after excision or undergo malignant change. In contrast to this, I have encountered 3 cases in which a solitary sporadic superficial diffuse neurofibroma was large, recurred locally on multiple occasions extending over 30 years, and exhibited malignant change at least once. The first patient was a 44-year-old black woman who had a superficial diffuse neurofibroma with a focus of epithelioid malignant peripheral nerve sheath tumor (MPNST) excised from her left upper arm. The tumor recurred locally 14 times over a period of 381/2 years; most specimens demonstrated only neurofibroma, but the 11th and 14th recurrences also had areas of epithelioid MPNST (extensive in the latter recurrence). There was no follow-up information after the last recurrence was excised except that the patient died of an unknown cause 3 years later. The second patient was a 39-year-old white woman who had a superficial neurofibroma excised from her scalp. A local recurrence was excised 30 years later and demonstrated a small focus of spindle cell MPNST in addition to neurofibroma. There were 6 further recurrences over the ensuing 14 years, of which the last 3 had components of spindle cell MPNST that extended into the skull bone and skeletal muscle. For these, radiotherapy was performed in addition to excision, and the patient had no evidence of tumor when last seen 1 year after the last recurrence was excised (she died 2 mo later of an unknown and presumably incidental cause). The third patient was a 28-year-old black woman who had a mass excised from her back that she was told was benign. A local recurrence was excised from the same area about 10 years later, again with a benign diagnosis (no details were available about these 2 specimens). Another recurrence was excised 36 years after the original excision; this demonstrated an extensive superficial diffuse neurofibroma with at least 2 small foci of spindle cell MPNST. A further recurrence was excised slightly >1 year later and showed superficial diffuse neurofibroma with some cellular areas but no definite MPNST. The patient was lost to follow-up after this. In addition to their diffuse infiltrative nature, a distinctive finding in the neurofibromas in all 3 cases was the presence of a focal to patchy lymphocytic chronic inflammatory infiltrate. Despite the difference in the character of the MPNST components (epithelioid in the first case, spindle cell in the other 2), the cases had sufficient histologic and clinical similarities to suggest that they represent a distinctive type of superficial neurofibroma. PMID- 23648457 TI - A comparison of CMV detection in gastrointestinal mucosal biopsies using immunohistochemistry and PCR performed on formalin-fixed, paraffin-embedded tissue. AB - Cytomegalovirus (CMV) can precipitate and exacerbate gastrointestinal (GI) mucosal injury. The gold standard for CMV detection in formalin-fixed, paraffin embedded (FFPE) tissue is immunohistochemistry (IHC). Although CMV polymerase chain reaction (PCR) on fresh tissue may be a valuable adjunct to IHC, its utility is unknown for FFPE tissues. We therefore evaluated quantitative, real time CMV PCR in a total of 102 FFPE GI biopsy specimens from 74 patients with a history of hematopoietic stem cell or solid organ transplant, inflammatory bowel disease, human immunodeficiency virus infection, or unspecified colitis. CMV DNA was detected by PCR in 90.9% (30/33) of IHC-positive, 14.5% (8/55) of IHC negative, and 20.0% (1/5) of IHC-equivocal FFPE tissues. Quantitation of CMV DNA copies normalized to beta-globin demonstrated a wide range of values (median 0.276; range, 0.0004 to 144.50). Importantly, 93.3% (14/15) of patients with IHC positive, active colitis showed no evidence of CMV in matched concurrent, histologically normal biopsies tested by PCR. These results suggest that CMV PCR on FFPE GI biopsies complements IHC and has the potential to identify additional patients who may benefit from anti-CMV therapy. PMID- 23648458 TI - Pedunculated serrated polyp with histologic features of sessile serrated adenoma: a clinicopathologic and molecular study. AB - In this study, we describe a previously undescribed pedunculated serrated polyp of the colon showing typical features of sessile serrated adenoma/polyp (SSA/P). All polyps were pedunculated, located in the proximal colon, small in size, and occurred in elderly patients. Histologically, the polyps showed typical features of SSA/P in the basal crypts with irregular, asymmetric expression of Ki-67. All polyps showed the BRAF-V600E mutation. The cells in the polyps did not show obvious cytologic dysplasia, prominent serration, or diffuse cytoplasmic eosinophilia with any occurrence of the so-called "ectopic crypt formation." We consider pedunculated serrated polyp showing features of SSA/P as a previously undescribed form of serrated adenoma/polyp in the spectrum of serrated neoplasia, which might represent a pedunculated variant of SSA/P or a precursor lesion of proximally located traditional serrated adenomas in the earliest stage. PMID- 23648459 TI - Rectal neuroendocrine and L-cell tumors: diagnostic dilemma and therapeutic strategy. AB - Rectal neuroendocrine tumors (NETs) are currently divided into L-cell and non-L cell types. In the World Health Organization 2010 classification, L-cell tumors are defined as borderline, whereas non-L-cell tumors are considered to represent malignancies. To establish differential diagnostic criteria and therapeutic strategy, we investigated the pathologic features of rectal NETs associated with lymph node metastasis and the clinicopathologic significance of the L-cell phenotype. We analyzed 284 patients with rectal NETs. Factors, including T stage, mitosis, histologic pattern, lymphatic invasion, tumor border, and lymph node metastasis, were retrospectively evaluated. We also evaluated tumor immunoreactivity for L-cell markers, including glucagon-like peptide 1, pancreatic peptide, and peptide YY, in 240 cases. L-cell immunoreactivity was detected in 189 of 240 NETs (79%). Of the factors evaluated, only age and the frequency of lymphatic invasion were significantly different between patients with L-cell and non-L-cell tumors. Of the 284 patients, 18 (6.3%) had lymph node metastases. Lymphatic invasion and T stage were independent risk factors for lymph node metastasis. Subgroup analysis based on tumor size showed lymph node metastasis in 0%, 4%, 24%, and 100% of patients with NETs with a size of <5, 5 to 9, 10 to 14, and >= 15 mm, respectively. Depth of tumor invasion, lymphatic invasion, and mitosis were correlated with tumor size (P<0.0001). In conclusion, L-cell phenotype alone does not guarantee favorable biological characteristics. The clinical management of rectal NETs should depend on tumor size. Careful pathologic examination of lymphatic invasion is necessary. PMID- 23648460 TI - High-level microsatellite instability in appendiceal carcinomas. AB - High-level microsatellite instability (MSI-high) is found in approximately 15% of all colorectal adenocarcinomas (CRCs) and in at least 20% of right-sided cancers. It is most commonly due to somatic hypermethylation of the MLH1 gene promoter region, with familial cases (Lynch syndrome) representing only 2% to 3% of CRCs overall. In contrast to CRC, MSI-high in appendiceal adenocarcinomas is rare. Only 4 MSI-high appendiceal carcinomas and 1 MSI-high appendiceal serrated adenoma have been previously reported, and the prevalence of MSI in the appendix is unknown. We identified 108 appendiceal carcinomas from MD Anderson Cancer Center in which MSI status had been assessed by immunohistochemistry for the DNA mismatch-repair proteins MLH1, MSH2, MSH6, and PMS2 (n=83), polymerase chain reaction (n=7), or both (n=18). Three cases (2.8%) were MSI-high, and 1 was MSI low. The 3 MSI-high cases included: (1) a poorly differentiated nonmucinous adenocarcinoma with loss of MLH1/PMS2 expression, lack of MLH1 promoter methylation, and lack of BRAF gene mutation, but no detected germline mutation in MLH1 from a 39-year-old man; (2) an undifferentiated carcinoma with loss of MSH2/MSH6, but no detected germline mutation in MSH2 or TACSTD1, from a 59-year old woman; and (3) a moderately differentiated mucinous adenocarcinoma arising in a villous adenoma with loss of MSH2/MSH6 expression, in a 38-year-old man with a strong family history of CRC who declined germline testing. When the overall group of appendiceal carcinomas was classified according to histologic features and precursor lesions, the frequencies of MSI-high were: 3 of 108 (2.8%) invasive carcinomas, 3 of 96 (3.1%) invasive carcinomas that did not arise from a background of goblet cell carcinoid tumors, and 0 of 12 (0%) signet ring and mucinous carcinomas arising in goblet cell carcinoid tumors. These findings, in conjunction with the previously reported MSI-high appendiceal carcinomas, highlight the low prevalence of MSI in the appendix as compared with the right colon and suggest that MLH1 promoter methylation is not a mechanism for MSI in this location. PMID- 23648461 TI - Chromosomal rearrangements of 6p25.3 define a new subtype of lymphomatoid papulosis. AB - Lymphomatoid papulosis (LyP) is an indolent cutaneous lymphoproliferative disorder with clinical and pathologic features overlapping those of both reactive conditions and aggressive lymphomas. Recurrent genetic abnormalities in LyP have not been previously identified. Here, we describe the clinical, immunophenotypic, and genetic characteristics of cutaneous lymphoproliferative lesions showing distinctive and previously undescribed histologic features in 11 patients. All patients were older adults (67 to 88 y) with predominantly localized lesions and clinical presentations suggesting benign inflammatory dermatoses or low-grade epithelial tumors. Histologically, lesions showed a biphasic growth pattern, with small cerebriform lymphocytes in the epidermis and larger transformed lymphocytes in the dermis. All had a T-cell immunophenotype. The pathologic features raised the possibility of an aggressive T-cell lymphoma such as transformed mycosis fungoides. However, no patient developed disseminated skin disease or extracutaneous spread. Untreated lesions regressed spontaneously. All cases harbored chromosomal rearrangements of the DUSP22-IRF4 locus on 6p25.3. The overall findings suggest that these cases represent a newly recognized LyP subtype characterized by 6p25.3 rearrangements. The benign clinical course in all 11 patients despite pathologic features mimicking an aggressive lymphoma emphasizes the importance of clinicopathologic correlation, incorporating molecular genetic analysis when possible, during the evaluation of cutaneous lymphoproliferative disorders. PMID- 23648462 TI - Fallopian tube intraluminal tumor spread from noninvasive precursor lesions: a novel metastatic route in early pelvic carcinogenesis. AB - Pelvic serous carcinoma is usually advanced stage at diagnosis, indicating that abdominal spread occurs early in carcinogenesis. Recent discovery of a precursor sequence in the fallopian tube, culminating in serous tubal intraepithelial carcinoma (STIC), provides an opportunity to study early disease events. This study aims to explore novel metastatic routes in STICs. A BRCA1 mutation carrier (patient A) who presented with a STIC and tubal intraluminal shedding of tumor cells upon prophylactic bilateral salpingo-oophorectomy (PBSO) instigated scrutiny of an additional 23 women who underwent a PBSO and 40 patients with pelvic serous carcinoma involving the tubes. Complete serial sectioning of tubes and ovaries of patient A did not reveal invasive carcinoma, but subsequent staging surgery showed disseminated abdominal disease. STIC, intraluminal tumor cells, and abdominal metastases displayed an identical immunohistochemical profile (p53/WT1/PAX8/PAX2) and TP53 mutation. In 16 serous carcinoma patients (40%) tubal intraluminal tumor cells were found, compared with none in the PBSO group. This is the first description of a STIC, which plausibly metastasized without the presence of invasion through intraluminal shedding of malignant surface epithelial cells in the tube and subsequently spread throughout the peritoneal cavity. These findings warrant a reconsideration of the malignant potential of STICs and indicate that intraluminal shedding could be a risk factor for early intraperitoneal metastasis. Although rare in the absence of invasive cancer, we show that intraluminal shedding of tumor cells in the fallopian tubes from serous carcinoma cases are common and a likely route of abdominal spread. PMID- 23648463 TI - Clear cell papillary renal cell carcinoma-like tumors in patients with von Hippel Lindau disease are unrelated to sporadic clear cell papillary renal cell carcinoma. AB - Clear cell papillary renal cell carcinoma (CCPRCC) shares morphologic overlap with clear cell renal cell carcinoma, although it lacks chromosome 3p and VHL gene abnormalities. Rare cases have been reported in von Hippel-Lindau (VHL) patients (germline mutation of the VHL gene), the significance of which is uncertain. We analyzed morphologic, immunohistochemical, and molecular features in 14 CCPRCC-like tumors and 13 clear cell renal cell carcinomas from 12 patients with VHL disease. Gross appearance of CCPRCC-like tumors ranged from yellow orange to tan, red-brown, or extensively cystic. Histologic features included: small papillary tufts (79%), branched tubules (71%), branched papillae (64%), flattened peripheral cysts (64%), and apically aligned nuclei (43%). Almost all CCPRCC-like tumors (82%) lacked the characteristic immunoprofile of sporadic CCPRCC (CK7, CAIX, CD10, AMACR), often showing diffuse CD10 labeling (64%), negative or focal CK7 reactivity (55%), or both (18%). Three tumors (27%) showed strong AMACR staining. Chromosome 3p deletion was often present (82%), similar to that observed in clear cell renal cell carcinomas (80%); no CCPRCC-like tumor had chromosome 7 or 17 abnormalities. In summary, tumors that histologically resemble CCPRCC sometimes occur in patients with VHL disease but usually lack the characteristic immunohistochemical and molecular profile, suggesting that they do not share the same pathogenesis. PMID- 23648464 TI - A multicenter study directly comparing the diagnostic accuracy of gene expression profiling and immunohistochemistry for primary site identification in metastatic tumors. AB - Metastatic tumors with an uncertain primary site can be a difficult clinical problem. In tens of thousands of patients every year, no confident diagnosis is ever issued, making standard-of-care treatment impossible. Gene expression profiling (GEP) tests currently available to analyze these difficult-to-diagnose tumors have never been directly compared with the diagnostic standard of care, immunochemistry (IHC). This prospectively conducted, blinded, multicenter study compares the diagnostic accuracy of GEP with IHC in identifying the primary site of 157 formalin-fixed paraffin-embedded specimens from metastatic tumors with known primaries, representing the 15 tissues on the GEP test panel. Four pathologists rendered diagnoses by selecting from 84 stains in 2 rounds. GEP was performed using the Pathwork Tissue of Origin Test. Overall, GEP accurately identified 89% of specimens, compared with 83% accuracy using IHC (P=0.013). In the subset of 33 poorly differentiated and undifferentiated carcinomas, GEP accuracy exceeded that of IHC (91% to 71%, P=0.023). In specimens for which pathologists rendered their final diagnosis with a single round of stains, both IHC and GEP exceeded 90% accuracy. However, when the diagnosis required a second round, IHC significantly underperformed GEP (67% to 83%, P<0.001). GEP has been validated as accurate in diagnosing the primary site in metastatic tumors. The Pathwork Tissue of Origin Test used in this study was significantly more accurate than IHC when used to identify the primary site, with the most pronounced superiority observed in specimens that required a second round of stains and in poorly differentiated and undifferentiated metastatic carcinomas. PMID- 23648465 TI - Pancreatic intraglandular metastasis predicts poorer outcome in postoperative patients with pancreatic ductal carcinoma. AB - Intraorgan metastasis of a primary cancer within the organ of origin, such as intrahepatic metastasis of hepatocellular carcinoma, is one of the key features for clinicopathologic staging of the cancer. Pancreatic intraglandular metastasis (P-IM) of pancreatic ductal carcinoma (PDC) is encountered occasionally but has not yet been evaluated. The aim of this study was to investigate the clinicopathologic characteristics and prognostic value of P-IM in patients with PDC. The histopathologic features of 393 consecutive patients with PDC who had undergone pancreatic resection at the National Cancer Center Hospital, Tokyo, between 2003 and 2010 were reviewed. For the purposes of the study, P-IM was defined as an independent tumor showing histopathologic features similar to those of the primary one. Twenty-six cases of P-IM were identified in 21 (5.3%) of the reviewed patients. The incidence of P-IM at each stage of the TNM classification was 0% (0/7) at stage IA, 17% (1/6) at stage IB, 5% (5/92) at stage IIA, 4% (11/252) at stage IIB, 0% (0/1) at stage III, and 11% (4/35) at stage IV. Univariate survival analysis showed that both overall survival and disease-free survival for patients with P-IM were significantly shorter than for those without P-IM (P<0.001 and P=0.019, respectively). Multivariate survival analysis showed that P-IM was significantly correlated with shorter overall survival (P=0.002; hazard ratio=2.239; 95% confidence interval: 1.328-3.773). Our findings suggest that the presence of P-IM in patients with PDC is an independent prognosticator and may represent aggressive tumor behavior. PMID- 23648466 TI - From powder to technical body: the undervalued science of catalyst scale up. AB - Progress in catalysis has been, is, and will always be motivated by societal needs (e.g. environment, energy, chemicals, fuels), with the ultimate aim of improving process efficiency on a technical scale. Technical catalysts are often complex multicomponent millimetre-sized bodies consisting of active phases, supports, and numerous additives in shaped forms suitable for their commercial application. They can differ strongly in composition, structure, porosity, and performance from research catalysts, i.e. laboratory-developed materials constituted by a single bulk or supported active phase in powder form, which are the predominant focus of academic investigations. The industrial manufacture of heterogeneous catalysts, encompassing the upscaled preparation, formulation, and structuring, is encircled by secrecy and is decisive for the overall process viability. Yet despite the tremendous relevance, understanding the added complexity of these multicomponent systems and the consequences for the respective structure-property-function relationships has been largely neglected. Accordingly, our review examines the intricacies of the scale up of heterogeneous catalysts. While emphasising the lack of fundamental knowledge we point out the multiple functions that additives could provide by enhancing the mass and heat transfer properties, acting as co-catalysts, or imparting improved chemical, mechanical, or thermal stability. Recent exemplary studies developing rational approaches to prepare, characterise, and evaluate technical catalysts are analysed in detail and new directions for research in this field are put forward. PMID- 23648467 TI - Involved-field radiation therapy for locoregionally recurrent ovarian cancer. AB - OBJECTIVE: To evaluate the effectiveness of definitive involved-field radiation therapy (IFRT) for selected patients with locoregionally-recurrent ovarian cancer. METHODS: We retrospectively reviewed records of 102 epithelial ovarian cancer patients treated with definitive IFRT (>=45Gy). IFRT was directed to localized nodal (49%) and extranodal (51%) recurrences. RESULTS: The median time from diagnosis to IFRT was 36 months (range, 1-311), and the median follow-up after IFRT was 37 months (range, 1-123). Patients received a median of three chemotherapy courses before IFRT (range, 0-9). Five-year overall (OS) and progression-free survival (PFS) rates after IFRT were 40% and 24% respectively; the 5-year in-field disease control rate was 71%. Thirty-five patients (35%) had no evidence of disease at a median of 38 months after IFRT (range, 7-122), including 25 continuously without disease for a median of 61 months (range, 17 122) and 10 with salvage treatment following disease recurrence, disease-free for a median of 39 months after salvage treatment (range, 7-92). Eight clear cell carcinoma patients had higher 5-year OS (88% versus 37%; p=0.05) and PFS (75% versus 20%; p=0.01) rates than other patients. Patients sensitive to initial platinum chemotherapy had a higher 5-year OS rate than platinum-resistant patients (43% versus 27%, p=0.03). Patients who required chemotherapy for recurrence after IFRT often benefitted from longer chemotherapy-free intervals after than before IFRT. CONCLUSIONS: Definitive IFRT can yield excellent local control, protracted disease-free intervals, and even cures in carefully selected patients. RT should be considered a tool in the curative management of locoregionally-recurrent ovarian cancer. PMID- 23648468 TI - Total laparoscopic radical trachelectomy in the treatment of early squamous cell cervical cancer: a retrospective study with 8-year follow-up. AB - OBJECTIVE: The objective of this study was to evaluate the surgical, oncologic, and obstetrical outcomes of total laparoscopic radical trachelectomy (LRT) in patients with early-stage squamous cell cervical cancer who want to preserve their fertility. METHODS: Twenty-five patients with early-stage cervical cancer were treated by total LRT from January 2005 to December 2012. Data regarding operational time, blood loss, intraoperative-and post-operative complications, recurrence, and subsequent pregnancies were recorded. Other published reports on LRT were also reviewed. RESULTS: The median age of the patients was 29 years (range 22-34 years). The median surgical time was 232 min (range, 180-340 min). The median blood loss was 120 ml (range, 50-200 ml), and the median length of hospitalization was 3.3 days (range, 2-4 days). The median time to return to daily activities was 2 days (range, 1-3 days). No intra-operative complications occurred; three patients had post-operative complications. The median follow-up time was 66 months (range, 1-82 months), and no recurrences were observed. Twelve patients attempted to conceive during the follow-up, and nine succeeded. CONCLUSIONS: In this retrospective analysis, total LRT was an effective and safe procedure for patients with early-stage cervical carcinoma who wished to preserve fertility. A larger prospective study with long-term pregnancy and survival analyses is warranted. PMID- 23648469 TI - Evaluation of exposures to healthcare personnel from cisplatin during a mock demonstration of intra-operative intraperitoneal chemotherapy administration. AB - Ovarian cancer is the leading cause of death from gynecologic malignancies in the United States. In 2006, the National Cancer Institute released an announcement supporting the use of intraperitoneal (IP) chemotherapy in advanced ovarian cancer. It remains unanswered how many cycles of IP chemotherapy are required to maintain a survival advantage. There may be a benefit with as few as three IP cycles and possibly as few as one IP chemotherapy cycle. OBJECTIVE: In preparation for a clinical trial in which chemotherapy would be administered intra-operatively, the question of exposure to healthcare personnel arose, therefore, the purpose of this study was to perform an evaluation of healthcare personnel exposure to cisplatin during a mock demonstration of intraperitoneal chemotherapy administration. MATERIALS AND METHODS: The National Institute of Occupational Safety and Health (NIOSH), the Women's Cancer Center of Nevada, and the staff of the University Medical Center, Las Vegas, participated in this mock demonstration. Employees wore personal protective equipment recommended by NIOSH. Wipe, area, and breathing zone air samples were taken from the pharmacy and operating room, and during sterilization of equipment. RESULTS: All samples were negative for cisplatin, except for one surface wipe from the floor of the operating room (OR) after the mock procedure. Upon sanitization of the OR, no cisplatin was detected on the floor. CONCLUSION: This was the first study evaluating the exposure of healthcare personnel to the administration of cisplatin intra-operatively. NIOSH endorsed this practice so long as the employees adhere to using the recommended personal protective equipment. PMID- 23648470 TI - The Patient Protection and Affordable Care Act: impact on the care of gynecologic oncology patients in the absence of Medicaid expansion in central Virginia. AB - OBJECTIVE: Many gynecologic oncology (GO) patients in Virginia are low income and their care is supplemented by Disproportionate Share Hospital (DSH) funds. Our objective is to estimate how many new GO patients may lose access to care if the state forgoes Medicaid expansion. METHODS: New patients referred to the GO service between July 1, 2010 and July 1, 2012 were identified. Data were collected regarding age, race, referral diagnosis, payor, and state pay scale. Pay scale 1 (PS1) is equal to the federal poverty level (FPL). Assumptions included the following: (1) pay scale is a surrogate for income, (2) PS1 patients will be ineligible for discounted insurance through the exchanges, and (3) decreasing DSH funds will result in a reduction of the free-care pool. RESULTS: There were 1623 referrals to the GO service and the majority (83%) was Caucasian. The payor distribution was 44% commercial insurance, 5.6% Medicaid, 31% Medicare, and 10.4% uninsured. Among the 361 women who were PS1, 32% were uninsured. Thirty percent of PS1 patients were minorities and 47.4% had a malignancy. Of note, 52% of new patients with cervical cancer were PS1. CONCLUSION: Seven percent of new GO patients are PS1 and uninsured. This population contains a disproportionate number of minorities and women with cancer. These women will have difficulty affording care as DSH funding decreases, particularly in states with lean Medicaid that opt out of Medicaid expansion. The burden of lack of access to care will be shouldered by an unfortunate few. PMID- 23648471 TI - Risk of second primary cancer among women with breast cancer: a population-based study in Granada (Spain). AB - OBJECTIVE: The higher risk of developing new cancers in breast cancer survivors is a public health concern. Our aim was to examine risk of second primary cancers among women diagnosed with breast cancer. METHODS: We studied two cohorts of female cancer patients identified in a population-based cancer registry in Granada (Spain): women first diagnosed with a primary breast cancer (n=5897) and those with a primary cancer in another site (n=22,814), followed during 1985-2007 for second cancers and breast cancer occurrence, respectively. We used Standardized Incidence Ratios (SIRs) to estimate second cancer risk by age (<50y, >=50y), time since diagnosis (<=5y, >5y) and calendar periods (<=1995, >1996). SIR for breast cancer was calculated in the second cohort. RESULTS: The risk of developing second cancers (n=314) was 39% higher (95% CI=1.23-1.54) among breast cancer patients, and particularly high among women under 50 (SIR=1.96, 95% CI=1.48-2.44). Excess risk for endometrial cancer (SIR=3.04, 95% CI=2.14-3.94) was statistically significant and remained so in women over 50. Younger women were at higher risk of second ovarian cancer (SIR=4.90, 95% CI=1.27-8.53). Increased SIRs were observed during the first five years after breast cancer diagnosis, whereas SIRs decreased thereafter. Breast cancer incidence (n=171) was not higher among women previously diagnosed with other cancer types (SIR=0.86, 95% CI=0.74-1.00). CONCLUSION: Women diagnosed with breast cancer have a higher incidence of second primary cancers, particularly of endometrial cancer in women over 50 at diagnosis, and ovarian cancer in younger women. These findings may be explained by treatment-related effects or shared risk factors. PMID- 23648472 TI - Occupational exposure to formaldehyde and genetic damage in the peripheral blood lymphocytes of plywood workers. AB - OBJECTIVES: We sought to clarify the association of occupational formaldehyde exposure with DNA strand breaks, chromosome damage and DNA-protein crosslinks (DPCs) in the peripheral blood (PB) lymphocytes of plywood workers. METHODS: We determined Olive tail moment (OTM) values, micronucleus (MN) frequencies and DPC rates of the PB lymphocytes in 178 workers divided into control and lower and higher exposure groups according to their current formaldehyde exposure levels and examined the association of each end point with formaldehyde exposure levels and with the number of work years. We also examined each end point in an additional 62 workers before and after an 8-hour formaldehyde exposure for validating the association. RESULTS: OTM values increased significantly in the two exposure groups compared with those in the control group (p<0.05 for both) and were associated with increasing formaldehyde exposure levels (ptrend=0.002), while MN frequencies increased with increasing numbers of work years (ptrend<0.001). The dynamic study showed that OTM values and DPC rates increased after an 8-hour formaldehyde exposure compared with those before the exposure (p<0.001, p=0.019, respectively), that, in a dose-dependent manner, OTM values were associated with formaldehyde exposure levels during work hours (p=0.005) and that MN frequencies before and after the 8-hour work exposure were associated with numbers of work years (p=0.029, p<0.001, respectively). CONCLUSIONS: We found a dose-response relationship between the current formaldehyde exposure levels and DNA strand breaks and between duration of exposure and chromosome damage in the PB lymphocytes of plywood workers. PMID- 23648473 TI - Occupational asthma in female factory worker resulting from exposure to savinase in dishwashing tablets-a case study. AB - OBJECTIVES: Savinase is one of the endopeptidases widely used in washing detergents. Its ability to cause respiratory allergy has been known. Up to now, most cases of occupational asthma (OA) to savinase have been described among workers involved in the manufacture of laundry detergents. We present a case study of 51-year-old female worker of a dishwashing tablets factory, who had been packaging ready-made tablets into foil wrappers for 4 years and developed respiratory symptoms, such as cough, dyspnoea and wheezing. METHODS: A number of clinical procedures were performed, including the clinical examination, routine laboratory tests, evaluation of total and allergen-specific serum IgE (asIgE) to enzymes, skin prick tests for common allergens, rest spirometry, inhalation methacholine challenge test and a single-blind, placebo-controlled specific inhalation challenge test (SICT) with dishwashing tablets. RESULTS: Clinical findings and results of routine laboratory tests were within normal limits. Baseline nonspecific bronchial hyperreactivity was revealed. In patient's serum blood we found significantly elevated asIgE to savinase. Decline of FEV1 and PEF in late phase of asthmatic reaction was observed during the specific challenge test. The patient reported chest tightness between 5-12 hours after exposure to dishwashing tablet ingredients. Cytological assessment of an induced sputum revealed increase in the percentage of eosinophils 24 hours after specific challenge in comparison to values noted before the SICT. CONCLUSIONS: Positive clinical response to the challenge confirmed in objective method tests validated the diagnosis of OA. PMID- 23648474 TI - Case-control study of semicircular lipoatrophy, a new occupational disease in office workers. AB - OBJECTIVES: Semicircular lipoatrophy (SL) is an emerging occupational pathology. Its etiology is poorly understood. We intend to establish the probable risk factors and estimate the relative risk. METHODS: A case-control study was performed. Our company had 55 diagnosed cases. As controls, we used the 3 closest healthy coworkers to each case. We calculated the chi square, odds ratio and logistic regression for different exposures, during the 3 years from September 2007 to August 2010. RESULTS: There was 100% participation for the cases and 70.9% for the controls (ratio 1 : 2.1 case-control). The only risk variables found were female gender (p<0.02) and exposure to leaning on the edge of a table (p<0.01). In addition, a breakdown by sex objectifies a much stronger association with leaning on the edge of a table in women (p<0.01) than men (p 0.67). CONCLUSIONS: Female gender and leaning on the edge of a table (repeated microtrauma), especially in women, are risk factors for development of SL. Other variables seem to be confounding factors associated with female gender. There were no SL cases showing statistically significant relations with history of cancer or autoimmune diseases. There was also no significance with regard to wearing jeans. There is therefore a new risk for office staff in addition to the more traditional disorders (musculoskeletal, ocular, and psychosocial). Further studies are necessary to evaluate what we consider an underdiagnosed condition, since there is a large percentage of people that are potentially exposed and we found very little information in the literature on the matter. PMID- 23648475 TI - Lung inflammation induces IL-1beta expression in hypoglossal neurons in rat brainstem. AB - Perinatal inflammation is associated with respiratory morbidity. Immune modulation of brainstem respiratory control centers may provide a link for this pathobiology. We exposed 11-day old rats to intratracheal lipopolysaccharide (LPS, 0.5 MUg/g) to test the hypothesis that intrapulmonary inflammation increases expression of the proinflammatory cytokine IL-1beta within respiratory related brainstem regions. Intratracheal LPS resulted in a 32% increase in IL 1beta protein expression in the medulla oblongata. In situ hybridization showed increased intensity of IL-1beta mRNA but no change in neuronal numbers. Co localization experiments showed that hypoglossal neurons express IL-1beta mRNA and immunostaining showed a 43% increase in IL-1beta protein-expressing cells after LPS exposure. LPS treatment also significantly increased microglial cell numbers though they did not express IL-1beta mRNA. LPS-induced brainstem expression of neuronal IL-1beta mRNA and protein may have implications for our understanding of the vulnerability of neonatal respiratory control in response to a peripheral proinflammatory stimulus. PMID- 23648476 TI - Prevalence of left heart contrast in healthy, young, asymptomatic humans at rest breathing room air. AB - Our purpose was to report the prevalence of healthy, young, asymptomatic humans who demonstrate left heart contrast at rest, breathing room air. We evaluated 176 subjects (18-41 years old) using transthoracic saline contrast echocardiography. Left heart contrast appearing <=3 cardiac cycles, consistent with a patent foramen ovale (PFO), was detected in 67 (38%) subjects. Left heart contrast appearing >3 cardiac cycles, consistent with the transpulmonary passage of contrast, was detected in 49 (28%) subjects. Of these 49 subjects, 31 were re evaluated after breathing 100% O2 for 10-15min and 6 (19%) continued to demonstrate the transpulmonary passage of contrast. Additionally, 18 of these 49 subjects were re-evaluated in the upright position and 1 (5%) continued to demonstrate the transpulmonary passage of contrast. These data suggest that ~30% of healthy, young, asymptomatic subjects demonstrate the transpulmonary passage of contrast at rest which is reduced by breathing 100% O2 and assuming an upright body position. PMID- 23648477 TI - Identification and validation of a new set of five genes for prediction of risk in early breast cancer. AB - Molecular tests predicting the outcome of breast cancer patients based on gene expression levels can be used to assist in making treatment decisions after consideration of conventional markers. In this study we identified a subset of 20 mRNA differentially regulated in breast cancer analyzing several publicly available array gene expression data using R/Bioconductor package. Using RTqPCR we evaluate 261 consecutive invasive breast cancer cases not selected for age, adjuvant treatment, nodal and estrogen receptor status from paraffin embedded sections. The biological samples dataset was split into a training (137 cases) and a validation set (124 cases). The gene signature was developed on the training set and a multivariate stepwise Cox analysis selected five genes independently associated with DFS: FGF18 (HR = 1.13, p = 0.05), BCL2 (HR = 0.57, p = 0.001), PRC1 (HR = 1.51, p = 0.001), MMP9 (HR = 1.11, p = 0.08), SERF1a (HR = 0.83, p = 0.007). These five genes were combined into a linear score (signature) weighted according to the coefficients of the Cox model, as: 0.125FGF18 - 0.560BCL2 + 0.409PRC1 + 0.104MMP9 - 0.188SERF1A (HR = 2.7, 95% CI = 1.9-4.0, p < 0.001). The signature was then evaluated on the validation set assessing the discrimination ability by a Kaplan Meier analysis, using the same cut offs classifying patients at low, intermediate or high risk of disease relapse as defined on the training set (p < 0.001). Our signature, after a further clinical validation, could be proposed as prognostic signature for disease free survival in breast cancer patients where the indication for adjuvant chemotherapy added to endocrine treatment is uncertain. PMID- 23648478 TI - A Chimeric UDP-glucose pyrophosphorylase produced by protein engineering exhibits sensitivity to allosteric regulators. AB - In bacteria, glycogen or oligosaccharide accumulation involves glucose-1 phosphate partitioning into either ADP-glucose (ADP-Glc) or UDP-Glc. Their respective synthesis is catalyzed by allosterically regulated ADP-Glc pyrophosphorylase (EC 2.7.7.27, ADP-Glc PPase) or unregulated UDP-Glc PPase (EC 2.7.7.9). In this work, we characterized the UDP-Glc PPase from Streptococcus mutans. In addition, we constructed a chimeric protein by cutting the C-terminal domain of the ADP-Glc PPase from Escherichia coli and pasting it to the entire S. mutans UDP-Glc PPase. Both proteins were fully active as UDP-Glc PPases and their kinetic parameters were measured. The chimeric enzyme had a slightly higher affinity for substrates than the native S. mutans UDP-Glc PPase, but the maximal activity was four times lower. Interestingly, the chimeric protein was sensitive to regulation by pyruvate, 3-phosphoglyceric acid and fructose-1,6-bis-phosphate, which are known to be effectors of ADP-Glc PPases from different sources. The three compounds activated the chimeric enzyme up to three-fold, and increased the affinity for substrates. This chimeric protein is the first reported UDP-Glc PPase with allosteric regulatory properties. In addition, this is a pioneer work dealing with a chimeric enzyme constructed as a hybrid of two pyrophosphorylases with different specificity toward nucleoside-diphospho-glucose and our results turn to be relevant for a deeper understanding of the evolution of allosterism in this family of enzymes. PMID- 23648479 TI - Molecular interaction of a new antibacterial polymer with a supported lipid bilayer measured by an in situ label-free optical technique. AB - The interaction of the antibacterial polymer-branched poly(ethylene imine) substituted with quaternary ammonium groups, PEO and alkyl chains, PEI25QI5J5A815 with a solid supported lipid bilayer was investigated using surface sensitive optical waveguide spectroscopy. The analysis of the optogeometrical parameters was extended developing a new composite layer model in which the structural and optical anisotropy of the molecular layers was taken into consideration. Following in situ the change of optical birefringence we were able to determine the composition of the lipid/polymer surface layer as well as the displacement of lipid bilayer by the antibacterial polymer without using additional labeling. Comparative assessment of the data of layer thickness and optical anisotropy helps to reveal the molecular mechanism of antibacterial effect of the polymer investigated. PMID- 23648480 TI - The protein level of PGC-1alpha, a key metabolic regulator, is controlled by NADH NQO1. AB - PGC-1alpha is a key transcription coactivator regulating energy metabolism in a tissue-specific manner. PGC-1alpha expression is tightly regulated, it is a highly labile protein, and it interacts with various proteins--the known attributes of intrinsically disordered proteins (IDPs). In this study, we characterize PGC-1alpha as an IDP and demonstrate that it is susceptible to 20S proteasomal degradation by default. We further demonstrate that PGC-1alpha degradation is inhibited by NQO1, a 20S gatekeeper protein. NQO1 binds and protects PGC-1alpha from degradation in an NADH-dependent manner. Using different cellular physiological settings, we also demonstrate that NQO1-mediated PGC 1alpha protection plays an important role in controlling both basal and physiologically induced PGC-1alpha protein level and activity. Our findings link NQO1, a cellular redox sensor, to the metabolite-sensing network that tunes PGC 1alpha expression and activity in regulating energy metabolism. PMID- 23648481 TI - MEN1 is a melanoma tumor suppressor that preserves genomic integrity by stimulating transcription of genes that promote homologous recombination-directed DNA repair. AB - Multiple endocrine neoplasia type 1 is a familial cancer syndrome resulting from loss-of-function mutations in the MEN1 gene. We previously identified the tumor suppressor MEN1 as a gene required for oncogene-induced senescence in melanocytes, raising the possibility that MEN1 is a melanoma tumor suppressor. Here we show that MEN1 expression is lost in a high percentage of human melanomas and melanoma cell lines. We find that melanocytes depleted of MEN1 are deficient in homologous recombination (HR)-directed DNA repair, which is accompanied by increased nonhomologous end-joining activity. Following DNA damage, MEN1 levels increase as a result of phosphorylation by the DNA damage kinase ATM/ATR. Most importantly, we show that MEN1 functions by directly stimulating the transcription of several genes, including BRCA1, RAD51, and RAD51AP1, that encode proteins involved in HR. MEN1 and its coactivator, the mixed-lineage leukemia histone methyltransferase, are recruited to the BRCA1, RAD51, and RAD51AP1 promoters by estrogen receptor 1, resulting in increased histone H3-lysine 4 trimethylation and transcription. Collectively, our results indicate that MEN1 is a melanoma tumor suppressor that functions by stimulating the transcription of genes involved in HR-directed DNA repair. PMID- 23648482 TI - LKB1 controls human bronchial epithelial morphogenesis through p114RhoGEF dependent RhoA activation. AB - LKB1 is a Ser/Thr kinase that plays an important role in controlling both energy metabolism and cell polarity in metazoan organisms. LKB1 is also a tumor suppressor, and homozygous, inactivating mutations are found in a wide range of human cancers. In lung cancer, inactivating mutations are found in 10 to 50% of cases, but the consequences of functional loss in this context are poorly understood. We report here that LKB1 is required for the maturation of apical junctions in the human bronchial epithelial cell line 16HBE14o- (16HBE). This activity is dependent on an interaction with the Rho guanine nucleotide exchange factor p114RhoGEF but is independent of LKB1 kinase activity. Together, LKB1 and p114RhoGEF control RhoA activity in these cells to promote apical junction assembly. PMID- 23648483 TI - Novel insights into the role of Neurospora crassa NDUFAF2, an evolutionarily conserved mitochondrial complex I assembly factor. AB - Complex I deficiency is commonly associated with mitochondrial oxidative phosphorylation diseases. Mutations in nuclear genes encoding structural subunits or assembly factors of complex I have been increasingly identified as the cause of the diseases. One such factor, NDUFAF2, is a paralog of the NDUFA12 structural subunit of the enzyme, but the mechanism by which it exerts its function remains unknown. Herein, we demonstrate that the Neurospora crassa NDUFAF2 homologue, the 13.4 L protein, is a late assembly factor that associates with complex I assembly intermediates containing the membrane arm and the connecting part but lacking the N module of the enzyme. Furthermore, we provide evidence that dissociation of the assembly factor is dependent on the incorporation of the putative regulatory module composed of the subunits of 13.4 (NDUFA12), 18.4 (NDUFS6), and 21 (NDUFS4) kDa. Our results demonstrate that the 13.4 L protein is a complex I assembly factor functionally conserved from fungi to mammals. PMID- 23648485 TI - A novel domino strategy for forming poly-substituted quaternary imidazoles through a Cs2CO3-promoted aryl migration process. AB - A new domino strategy for the synthesis of highly functionalized quaternary imidazole derivatives via [3 + 2] heterocyclization, involving aryl migration and ring-opening of oxirane, has been developed. This domino reaction enables the successful assembly of three new sigma bonds including two C-N bonds in a simple operation. Features of this strategy include the mild conditions, convenient operation, and short reaction periods (15-20 min). PMID- 23648486 TI - The Fusarium Graminearum virulence factor FGL targets an FKBP12 immunophilin of wheat. AB - Wheat scab, caused by the fungal pathogen Fusarium graminearum is a devastating disease worldwide. Despite an extensive and coordinated effort to investigate this pathosystem, little progress has been made to understand the molecular basis of host-pathogen interactions, for example how the pathogen causes disease in plant. Recently, a secreted lipase (FGL1) has been identified from the fungus and shown to be an important virulence factor; however, the intrinsic function of FGL1 in plant is unknown. Here, we report the identification of the molecular components that may possibly be involved in the FGL virulence pathway using yeast two hybrid system. FGL gene was amplified from a local virulent strain (F15) and shown to be 99.5% identical to the original published FGL at the amino acid level. We showed that transient expression of this FGL gene by Agroinfiltration in tobacco leaves causes cell death further implicating the role of FGL in virulence. To identify FGL initial physical target in plant, we screened two wheat cDNA libraries using the FGL protein as the bait. From both libraries, a small FKBP-type immunophilin protein, designated wFKBP12, was found to physically interact with FGL. The direct interaction of FGL with wFKBP12 was confirmed in living onion epidermal cells by biomolecular fluorescence complementation (BiFC) assay. To investigate further, we then used wFKBP12 protein as bait and identified an elicitor-responsive protein that contains a potential Ca(2+) binding domain. Semi-quantitative PCR showed that this elicitor-responsive gene is down-regulated during the F. graminearum infection suggesting that this protein may be an important component in FGL virulence pathway. This work serves as an initial step to reveal how fungal lipases act as a general virulence factor. PMID- 23648484 TI - NF-E2 p45 is important for establishing normal function of platelets. AB - NF-E2 is a heterodimeric transcription factor consisting of p45 and small Maf subunits. Since p45(-/-) mice display severe thrombocytopenia, p45 is recognized as a critical regulator of platelet production from megakaryocytes. To identify direct p45 target genes in megakaryocytes, we used chromatin immunoprecipitation (ChIP) sequencing to analyze the genome-wide chromatin occupancy of p45 in primary megakaryocytes. p45 target gene candidates obtained from the analysis are implicated in the production and function of platelets. Two of these genes, Selp and Myl9, were verified as direct p45 targets through multiple approaches. Since P-selectin, encoded by Selp, plays a critical role in platelet function during thrombogenesis, we tested whether p45 determines the intrinsic reactivity and potency of platelets generated from megakaryocytes. Mice expressing a hypomorphic p45 mutant instead of wild-type p45 in megakaryocytes (p45(-/-):DeltaNTD-Tg mice) displayed platelet hypofunction accompanied by mild thrombocytopenia. Furthermore, lung metastasis of melanoma cells, which requires platelet activation, was repressed in p45(-/-):DeltaNTD-Tg mice compared to control mice, validating the impaired function of platelets produced from p45(-/-):DeltaNTD-Tg megakaryocytes. By activating genes in megakaryocytes that mediate platelet production and function, p45 determines the quantity and quality of platelets. PMID- 23648488 TI - [The pathway of uncertainty]. PMID- 23648487 TI - Identification of multiple binding sites for the THAP domain of the Galileo transposase in the long terminal inverted-repeats. AB - Galileo is a DNA transposon responsible for the generation of several chromosomal inversions in Drosophila. In contrast to other members of the P-element superfamily, it has unusually long terminal inverted-repeats (TIRs) that resemble those of Foldback elements. To investigate the function of the long TIRs we derived consensus and ancestral sequences for the Galileo transposase in three species of Drosophilids. Following gene synthesis, we expressed and purified their constituent THAP domains and tested their binding activity towards the respective Galileo TIRs. DNase I footprinting located the most proximal DNA binding site about 70 bp from the transposon end. Using this sequence we identified further binding sites in the tandem repeats that are found within the long TIRs. This suggests that the synaptic complex between Galileo ends may be a complicated structure containing higher-order multimers of the transposase. We also attempted to reconstitute Galileo transposition in Drosophila embryos but no events were detected. Thus, although the limited numbers of Galileo copies in each genome were sufficient to provide functional consensus sequences for the THAP domains, they do not specify a fully active transposase. Since the THAP recognition sequence is short, and will occur many times in a large genome, it seems likely that the multiple binding sites within the long, internally repetitive, TIRs of Galileo and other Foldback-like elements may provide the transposase with its binding specificity. PMID- 23648489 TI - [Experiences and changes in parents of children with infant cerebral palsy: a qualitative study]. AB - BACKGROUND: The diagnosis of infant cerebral palsy (ICP) is a traumatic event that can provoke multiple effects and changes in the family. The aim of the study is to discover the difficulties that parents face in the process of parenting, especially in the initial period following diagnosis. METHODS: A qualitative study was carried out through semi-structured interviews. Sixteen mothers and fathers whose children were diagnosed with cerebral palsy participated in the study. Data analysis was performed with Atlas.ti 6.2 software following a strategy of open coding. RESULTS: The reception of the diagnosis is perceived as an unexpected event that makes parents change expectations and hopes related to their children. The mode of relation with the child with ICP is different from that with other children as parents are more focused on the possibility of improvement and the future evolution of their child. Changes in different aspects of the lives of these parents are shown, such as demands on time, their economic and labour situation, as well as the relationship of the couple. CONCLUSIONS: In providing care for children with cerebral palsy it is necessary to take the problems of the parents into account, especially in the initial period after diagnosis. The process of parenting a child with cerebral palsy entails many changes in the family so a global perspective is needed to organize interventions. PMID- 23648491 TI - [Development and validation of a scale on sense of suffering: the "Humanizar" Scale]. AB - BACKGROUND: There are studies on the causes and sense of suffering, but not a measuring instrument for clinical and research use that eliminates the subjectivity of the evaluator. The aim of this article is to analyse the meaning that people give to suffering and its underlying factors by developing a measuring scale. METHODS: Descriptive and correlational study for scale validation. Following a review of the literature, a list of items was developed that were subjected to a validity analysis: content through judges, criterion through external variable contrast, and construct using exploratory factor analysis. Reliability using Cronbach alpha coefficient. RESULTS: The questionnaire was answered by 253 people, 83% (207) women and 17% (42) men, average age 41.37 years. The 24 item scale offered a Cronbach alpha of 0.871. Seven dimensions were obtained that explained 62.42% of total variance. Five factors were named Transcendence (26.367% of the variance), Punishment (9.929%), Catalyst of change (6.498%), Masochism (5.691%) and Inherent to life (5.254%). Except the last one, all the subscales obtained an alpha superior to 0.67. No gender differences were found, although they were found depending on the existence or absence of religious beliefs. CONCLUSIONS: The "Humanizar" Scale is a valid and reliable scale with a coherent structure of five factors. It collects the meaning that a person gives to suffering, leaving open the possibility of exploration depending on populations and on whether or not there are religious beliefs. PMID- 23648490 TI - [Elaboration and validation of an informative document on adenoamigdalectomy for patients]. AB - BACKGROUND: Access to up-to-date and understandable health information is a growing citizen demand, as well as an ethical duty and a legal regulation. Written information reinforces information transmitted orally during the consultation and improves recall capacity. Adenoamigdalectomy is an intervention that affects a high number of patients, the majority from the child population that has a high emotional sensitivity, and it is experienced by parents with considerable anxiety. An informative guide on adenoamigdalectomy was elaborated and validated. The aim of this article is to describe the process of elaborating the document, emphasizing its validation and results. MATERIAL AND METHODS: The document was validated in three phases: A) Clinical content validated by professionals with a checklist and a consensus meeting; B) Analysis of grammatical legibility according to the Flesch index; C) Validation of lexical legibility with citizens by means of a validation guide and interviews. RESULTS: The validation by professionals and citizens was highly positive. The professionals stressed the accuracy of the content and corrected some imprecisions. They made suggestions concerning format, writing style and length. The citizens stressed understandable language, resolution of doubts, respectful tone and their satisfaction with the initiative. They also differed on aspects such as their opinion of the document's length. CONCLUSIONS: The validation of informative documents by both professionals and patients is a process of great interest. Lack of agreement in their analyses makes it clear why it is important to include both sectors. The document was improved by their contributions. PMID- 23648492 TI - [New geolocation system in Navarre to reduce urgent response times in mountainous and dispersed areas]. AB - Identification of all urgent home alerts in mountainous and dispersed areas through the 112 system is normally done using the name of the farmhouse or dwelling, which makes it impossible to localize them with normal GPS means. The aim of this article is to obtain a valid geolocation system in out-of-hospital emergencies that is adapted to the nomenclature and geography of the area, and that can be implanted in all mobile health devices. This will provide exact precision without any loss of time in journeys, so as to avoid an increase in morbidity and mortality due to delays in attention given by professionals, whether or not they know the area. It should be possible to extrapolate this system to other points in the geography of Navarre and Spain. A geolocation tool was created adapted to the orography and specific nomenclature of the chosen pilot area (the Baztan valley) and it was made compatible with the two possible modes of current navigational software, with and without mobile data coverage (on line and off line). This system was integrated into non-corporative health mobile phones using KML archives and applied to the 913 geolocated farmhouses, with its real utility verified in the urgent home alerts registered between the months of May and September 2012. It was possible to reach the farmhouse (routing) requiring urgent attention without getting lost on the road or forest route, irrespective of access characteristics, because the localization of the destination had been registered beforehand in these files (this is the great difference with current GPS systems). PMID- 23648493 TI - [Herpes zoster incidence in diabetic patients]. AB - BACKGROUND: To assess the risk of herpes zoster in people with diabetes mellitus in comparison with the general population. METHODS: Using computerized clinical reports form primary health care in Navarre, Spain, we analyzed the incidence of herpes zoster in people aged over 30 years in 2006 by diagnosis of diabetes, and adjusting for age and sex. RESULTS: Among 26,793 diabetes patients 409 cases of herpes zoster were diagnosed (15 per 1000). Nineteen point three percent of cases occurred in diabetes patients. Diabetes presented an adjusted relative risk of 2.1 (95% CI 1.9-2.4), and increased to 3.7 (95% CI 2.0-6.8) in the 30-44 year age group. Of the total number of cases of herpes zoster in the population, 7.2% were attributable to diabetes. CONCLUSION: Diabetes increases the risk of, and has a relevant role in, the incidence of herpes zoster. PMID- 23648494 TI - [Recomendations of vaccination in patients with inflammatory bowel disease (IBD)]. AB - The concept of inflammatory bowel disease (IBD) covers three entities: ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis (IC). These diseases have in common a chronic and relapsing course, alternating periods marked by inflammatory activity with other quiescent periods, in which the patient is asymptomatic. For many years treatment of the disease, especially in acute phases, was based on the use of corticoids. However, in recent decades we have witnessed significant advances from the therapeutic point of view. It is estimated that during the course of the disease's evolution 80% of patients will need corticoids, 40% immunomodulators (IMM), and as many as 20% will require a biological medicine to control their disease. While all of this is accompanied by an improvement in quality of life, less hospital admissions or surgical interventions, their use also involves an increase in the risk of suffering infections, either due to germs normally found in the community or opportunistic infections. Moreover, infections are a cause of morbidity and mortality associated with IBD and some of them can be prevented with vaccinations, hence the importance that vaccination programs are acquiring in this groups of patients. We present a review of the relevant literature and propose a vaccination protocol for patients diagnosed with IBD. PMID- 23648495 TI - [The role of occupational context factors in medication administration errors]. AB - BACKGROUND: The incidence of medication administration errors (MAE) is high and costly for patients and health institutions. Human factors and factors relating to the work context intervene in their occurrence. The aim of this article is to identify the role of factors in the work setting related to occurrence of MAEs in the hospital field. METHODS: A narrative review of the literature. Eight articles were included following a review of MEDLINE, CINAHL and COCHRANE LIBRARY databases for the 2002-2012 period. RESULTS: Distractions and interruptions, work overload, design of units and characteristics of the material stood out amongst the work context factors intervening in the occurrence of medication administration errors. CONCLUSIONS: The creation of organizational artefacts to reduce interruptions; patient involvement in medication administration; the introduction of new technologies and improving the labelling of medications can help reduce the incidence of medication administration errors. To advance in identifying and managing factors that are precursors of medication administration errors, we recommend the carrying out of studies or reviews of prospective cohorts. PMID- 23648496 TI - [Osteonecrosis of the jaw associated with bisphosphonate therapy in primary osteoporosis. Review of the literature]. AB - BACKGROUND: The aim of this review was to study risk factors involved in osteonecrosis of the jaw after oral surgery in patients treated with bisphosphonates due to primary osteoporosis. METHODS: In order to find relevant related publications, we conducted a systematic search in specialized (Cochrane Database of Systematic Reviews, Trip Database) and general (Medline, Embase, Isi Web of Knowledge) bibliographical databases. The search strategy included the terms osteonecrosis, adults and oral surgery. It was limited to papers focused on human adults undergoing dentoalveolar surgery while being treated with bisphosphonates due to primary osteoporosis, which had been published in the English or Spanish languages between January 2006 and January 2012. Systematic reviews, meta-analyses, practice guidelines, randomized clinical trials and case report series were included. RESULTS: Fourteen papers (case report series) including 43 cases of osteonecrosis of the jaw were selected. Jaw and extraction were the most frequent localization and dental procedure related to the lesions. Mean age of patients was 71.94 years, with lesions being more frequent among women. Alendronate was the bisphosphonate used in the majority of cases, with a mean duration of treatment before osteonecrosis of the jaw appeared of 48.25 months. CONCLUSIONS: Well-designed, prospective and retrospective studies are needed to evaluate the real weight of each of those factors considered to entail a potential risk of osteonecrosis of the jaw. PMID- 23648498 TI - [Congenital transmission of Chagas disease in non-endemic countries. The use of PCR for diagnosis: advantages over conventional techniques]. PMID- 23648497 TI - [Emergent drugs (II): the Pharming phenomenon]. AB - The use of medicines, with or without medical prescription, for recreational ends by the young population has received little attention from doctors. In the USA, one in five adolescents has used medicines for recreational purposes, and consultations in Emergency Departments for medicine abuse have exceeded those for illegal drugs. Although few data are available in Spain, such consumption is situated between 3.1 and 8.6% according to surveys. The medicines most used are dextromethorphan and methylphenidate. The former, on sale without prescription, presents a varied symptomatology, dosage and dependent metabolic action, ranging from euphoria to hallucinations. Methylphenidate, taken orally, nasally or intravenously, is used as a stimulant in substitution for cocaine and is one of the medicines most diverted onto the illicit market at the world level. In principle, other substances like modafinil and propofol present a limited incidence of non-medical use, but they have a probable abuse potential that should be borne in mind, above all in the health context. Finally, opiates like fentanyl, oxycodone and buprenorphine, with new pharmaceutical presentations, have recently become generalized in the therapeutic arsenal of many medical specialities; they are giving rise to phenomena of abuse, dependence and diversion towards the illicit market. Demands for detoxification treatment, their mixture with illegal substances, and cases of death should alert us to the abuse of these medicines. PMID- 23648499 TI - [Dynamic ultrasound assistance for distal femoral vein cannulation]. PMID- 23648500 TI - [Closed depressed fracture of the posterior fossa in an elderly patient]. PMID- 23648501 TI - [Monogenic obesity genes]. PMID- 23648502 TI - [Colonoscopic diagnosis of acute appendicitis with atypical presentation]. PMID- 23648503 TI - [Insular territories and advanced life support units]. PMID- 23648504 TI - [Epistaxis as a side effect of treatment of bladder hyperactivity with oxybutynin]. PMID- 23648505 TI - [Monoclonal gammopathy and visceral leishmaniasis]. PMID- 23648506 TI - [DIEP flap reconstruction after palliative curettage mastectomy in locally advanced breast cancer]. AB - BACKGROUND: Curettage mastectomy is indicated as a palliative treatment in locally advanced breast cancer. We present our experience with the use of a DIEP flap reconstruction following extensive mastectomy. METHODS: We report the case of a patient with very advanced local breast cancer that was subsidiary to aggressive palliative surgery after chemotherapy. RESULTS: It was considered that the closure that could be performed with the latissimus dorsi muscle was unsuitable, therefore a DIEP flap was performed. The patient was discharged uneventfully. CONCLUSION: The DIEP reconstruction offers great cutaneous extension. It can be a resource in highly selected cases of locally advanced breast cancer in which surgery becomes the main treatment. PMID- 23648507 TI - Gastric lipoma and pyloric obstruction in a 51-year-old woman. AB - Gastric lipoma is considered a rare condition that may constitute a challenging diagnosis. A 51-year-old woman presented dysphagia and abdominal pain, and an upper digestive endoscopic study disclosed a gastric tumor located in the submucosa of the pyloric antrum. Conclusive diagnosis was established after repeated endoscopic biopsies, and the patient was subjected to an atypical gastrectomy, which evolved into a pyloric stenosis. This complication was appropriately corrected and the patient remains symptomless, under outpatient surveillance. PMID- 23648508 TI - [Malignant priapism: conservative management of a case]. AB - Priapism is an urological emergency which requires investigation, especially to differentiate between ischemic and non-ischemic priapism. Initial management is carried out through aspiration and gasometry of blood from the corpus cavernosum. We report the case of a 69-year-old patient with urothelium carcinoma of the bladder T2 G3 and metastasis in urethra/corpus cavernosum who requested an emergency consultation because of edema and a penile erection lasting several days. Due to the poor prognosis and the imaging test, a conservative management was carried out. PMID- 23648509 TI - Infiltrating gastric adenocarcinoma with disseminated osteoblastic metastases. AB - We report the case of a man with a diagnosis of invasive gastric adenocarcinoma associated with scattered osteoblastic metastases. This 65-year-old patient was admitted with nausea, vomiting and abdominal pain, in addition to loss of weight (13 Kg in 3 months). Upper digestive endoscopy revealed extensive infiltrating changes in the body of the stomach, and histopathologic data confirmed the diagnosis of a Borrmann IV gastric adenocarcinoma. Complementary exams were indicative of a gastric cancer with bone metastases, characterized by disseminated osteoblastic images of the scintigraphy of the skeleton. Palliative chemotherapy was the treatment of first choice. High serum levels of CA 19-9, CEA and alkaline phosphatase can constitute useful indicative tools of this challenging condition. Images from a scintigraphy study of the skeleton can characterize the type and extension of bone metastases. The aim of this case study is to report a case of a very uncommon condition, considering that disseminated osteoblastic metastases rarely develop in this kind of tumor. PMID- 23648510 TI - [Septic arthritis of the hip by Haemophilus Influenzae type F in childhood: a case report]. AB - Septic arthritis of the hip is an acute infection, predominantly of bacterial etiology. Although Staphylococcus aureus is the primary pathogen in any age group, other potentially pathogenic microorganisms exist. We describe the case of an 18-month patient with septic arthritis of the hip with a rare causal agent (Haemophilus influenzae type F) and a good outcome. This case highlights the importance of considering other less common etiologic agents for septic arthritis in children, performing arthrocentesis with synovial fluid culture before starting antibiotic treatment, whenever this is possible. In addition, as in this case, it should be noted that a positive synovial fluid culture for Haemophilus influenzae forces typification of the bacteria in order to rule out or confirm a vaccine failure. PMID- 23648511 TI - The LIM-Homeodomain transcription factor Islet-1 is required for the development of sympathetic neurons and adrenal chromaffin cells. AB - Islet-1 is a LIM-Homeodomain transcription factor with important functions for the development of distinct neuronal and non-neuronal cell populations. We show here that Islet-1 acts genetically downstream of Phox2B in cells of the sympathoadrenal cell lineage and that the development of sympathetic neurons and chromaffin cells is impaired in mouse embryos with a conditional deletion of Islet-1 controlled by the wnt1 promotor. Islet-1 is not essential for the initial differentiation of sympathoadrenal cells, as indicated by the correct expression of pan-neuronal and catecholaminergic subtype specific genes in primary sympathetic ganglia of Islet-1 deficient mouse embryos. However, our data indicate that the subsequent survival of sympathetic neuron precursors and their differentiation towards TrkA expressing neurons depends on Islet-1 function. In contrast to spinal sensory neurons, sympathetic neurons of Islet-1 deficient mice did not display ectopic expression of genes normally present in the CNS. In Islet 1 deficient mouse embryos the numbers of chromaffin cells were only mildly reduced, in contrast to that of sympathetic neurons, but the initiation of the adrenaline synthesizing enzyme PNMT was abrogated and the expression level of chromogranin A was diminished. Microarray analysis revealed that developing chromaffin cells of Islet-1 deficient mice displayed normal expression levels of TH, DBH and the transcription factors Phox2B, Mash-1, Hand2, Gata3 and Insm1, but the expression levels of the transcription factors Gata2 and Hand1, and AP-2beta were significantly reduced. Together our data indicate that Islet-1 is not essentially required for the initial differentiation of sympathoadrenal cells, but has an important function for the correct subsequent development of sympathetic neurons and chromaffin cells. PMID- 23648513 TI - Neuroglobin protein is upregulated in Alzheimer's disease. AB - Neuroglobin is a neuronal protein with protective effects in animal models of stroke and Alzheimer's disease, but the relevance of these effects to Alzheimer's disease in humans is unknown. We measured neuroglobin levels by western blot and immunostained hippocampal sections for neuroglobin, cell-type protein markers, and amyloid-beta, in brain tissue obtained at autopsy from patients with Alzheimer's disease. Neuroglobin levels were increased in early and moderately advanced Alzheimer's disease compared to controls, but declined to control levels in severe disease. In patients with Alzheimer's disease, neuroglobin was detected within neurons, as well as at extracellular sites associated with amyloid-beta deposits. We conclude that, as in transgenic mouse models, neuroglobin may influence the course of clinical Alzheimer's disease. PMID- 23648512 TI - The widely used Wnt1-Cre transgene causes developmental phenotypes by ectopic activation of Wnt signaling. AB - The Wnt1-Cre transgenic mouse line is extensively used in the study of the development of the neural crest and its derivatives and the midbrain. The Wnt1 gene has important developmental roles in formation of the midbrain-hindbrain boundary, regulation of midbrain size, and neurogenesis of ventral midbrain dopaminergic (mDA) neurons. Here, we report that Wnt1-Cre transgenic mice exhibit phenotypes in multiple aspects of midbrain development. Significant expansion of the midbrain and increased proliferation in the developing inferior colliculus is associated with ectopic expression of Wnt1. Marked elevation of Wnt1 expression in the ventral midbrain is correlated with disruption of the differentiation program of ventral mDA neurons. We find that these phenotypes can be attributed to ectopic expression of Wnt1 from the Wnt1-Cre transgene leading to the ectopic activation of canonical Wnt/beta-catenin signaling. Since these caveats could complicate the utility of Wnt1-Cre in some developmental circumstances, we report a new Wnt1-Cre2 transgenic mouse line that can serve the same purposes as the original without the associated phenotypic complications. These studies reveal an important caveat to a widely-used reagent, provide an improved version of this reagent, and indicate that the original Wnt1-Cre transgenic mouse line may be useful as a gain of function model for interrogating Wnt signaling mechanisms in multiple aspects of midbrain development. PMID- 23648514 TI - An intervention to enhance Alzheimer's disease clinical research participation among older African Americans. AB - BACKGROUND: Alzheimer's disease (AD) rates are higher among African Americans than in other racial or ethnic groups. However, Black elders participate in research at lower rates than Whites. OBJECTIVE: The present study aimed to: (1) implement an informational protocol for African Americans elders and their loved ones about the benefits of clinical research and brain donation program participation in AD, and (2) quantitatively assess changes in knowledge, attitudes, and trust. METHODS: Participants included 52 African American participants from the Boston University Alzheimer's Disease Center research registry (74 +/- 8 years, 83% female) and 11 loved ones. Registry participants completed a pre- and post-group survey assessing brain donation knowledge, factors influencing brain donation, attitudes about medical research, and trust in medical researchers. RESULTS: There were no significant changes in mean scores between the pre- and post-group surveys. However, post-group outcomes revealed that 69% of participants shared details from the protocol with loved ones, 27% expressed an interest in joining Center-sponsored studies, and 10% indicated an interest in changing their brain donation status. CONCLUSION: The informational protocol implemented in this study is an effective method to encourage family discussions about brain donation and increase interest in other AD research studies. Longitudinal follow-up is necessary to assess the long-term implications of these groups on participation in a brain donation program. PMID- 23648515 TI - Uridine prodrug improves memory in Tg2576 and TAPP mice and reduces pathological factors associated with Alzheimer's disease in related models. AB - Uridine prodrug PN401 has been shown to have neuroprotective effects in models of Parkinson's disease and Huntington's disease. These age-related neurodegenerative diseases including Alzheimer's disease (AD) are associated with mitochondrial dysfunction, oxidative stress, and inflammation. Attenuation of these pathological factors in AD, in addition to amyloid fibrils and neurofibrillary tangles, is critical to prevent cognitive impairment. The effects of PN401 treatment were tested in the Tg2576 and Tg2576 X P301L (TAPP) mouse models of AD. Treatment with PN401 reduced impairments in the Tg2576 mice in contextual fear conditioning and novel object recognition. In the TAPP mice, PN401 reduced the impairments in novel object recognition and social transmission of food preference. PN401 also improved motor behavior and reduced anxiety-like behavior in the TAPP mice. TAPP mouse hippocampal tau phosphorylation and lipid peroxidation were reduced by PN401 treatment. Increased tau phosphorylation was significantly correlated with worsening novel object recognition memory. PN401 did not affect amyloid plaque area in the AD mice. In other AD-related animal studies, PN401 treatment reduced blood-brain barrier damage due to intracortical LPS, elevation of serum TNFalpha due to systemic LPS, and hippocampal CA1 neuronal loss in the gerbil stroke model. Uridine dose-dependently protected cells from chemical hypoxia and ceramide, and decreased formation of reactive oxygen species and mitochondrial DNA damage due to hydrogen peroxide. These protective effects were achieved by raising uridine levels to at least 25-50 MUM and serum uridine levels in this range in humans were obtained with oral PN401. PMID- 23648517 TI - Hg2+-promoted photoactivation of triazolyl rhodamine. AB - Hg(2+) was able to induce the ring-opening of glycosyl triazolyl rhodamines after 26 h incubation at room temperature in MeCN-DMSO (99 : 1). This reaction can be dramatically accelerated by irradiation at 313 nm, by reducing the response time to 2 min. Selectivity towards Hg(2+) has also been demonstrated, except for Cu(2+), other metal ions showed almost no influence on this photochromic process. Detailed mechanistic investigations indicated that a small amount of DMSO played an important role during the photochromic transformation, probably by stabilising the excited open form of the triazolyl rhodamine-Hg(2+) complex. PMID- 23648516 TI - Amyloid-beta positron emission tomography imaging probes: a critical review. AB - The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the imaging of amyloid-beta deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-beta plaques are currently at various stages of FDA approval. However, a number of factors appear to preclude these probes from clinical utilization. As the available "amyloid specific" positron emission tomography imaging probes have failed to demonstrate diagnostic value and have shown limited utility for monitoring therapeutic interventions in humans, a debate on their significance has emerged. The aim of this review is to identify and discuss critically the scientific issues contributing to the extensive inconsistencies reported in the literature on their purported in vivo amyloid specificity and potential utilization in patients. PMID- 23648518 TI - Different propofol-remifentanil or sevoflurane-remifentanil bispectral index levels for electrocorticographic spike identification during epilepsy surgery. AB - BACKGROUND: Medical therapy, the cornerstone of managing epilepsy, still fails a substantial portion of patients. Little information is available regarding the potential impact of different bispectral index (BIS) levels on electrocorticographic spike identification for surgical epileptic foci resection. METHODS: Twenty-two intractable epilepsy subjects were randomly allocated to the propofol-remifentanil or sevoflurane-remifentanil groups, and were further randomized to four BIS85 (BIS 71-85), BIS70 (BIS 56-70), BIS55 (BIS 41-55), and BIS40 (BIS <=40) sequence order. RESULTS: Two-way ANOVA revealed no differences between groups in spike frequency (P = 0.720), spike amplitude (P = 0.647), or number of spiking leads (P = 0.653). In the propofol and sevoflurane groups, decreasing BIS levels increased mean +/- SD spike/min frequency (P < 0.001 and P < 0.001) at BIS85 (10 +/- 12 and 10 +/- 8), BIS70 (19 +/- 17 and 17 +/- 15), BIS55 (22 +/- 17 and 18 +/- 8), and BIS40 (25 +/- 15 and 23 +/- 17). Furthermore, in the propofol and sevoflurane groups, decreasing BIS levels increased spike microvolt amplitude (P = 0.006 and P = 0.009) at BIS85 (1,100 +/- 400 and 750 +/- 400), BIS70 (1,200 +/- 460 and 850 +/- 490), BIS55 (1,300 +/- 560 and 940 +/- 700), and BIS40 (1,400 +/- 570 and 1,300 +/- 700). Whereas, in the propofol and sevoflurane groups, there was no difference in the location or number of spiking leads (P = 0.057 and P = 0.109) at the four BIS levels. Compared with BIS85, spike frequency in the propofol and sevoflurane groups increased 100 and 170% at BIS70, 116 and 180% at BIS55, and 132 and 230% at BIS40. Compared with BIS85, spike amplitude increased 108 and 113% at BIS70, 121 and 125% at BIS55, and 128 and 170% at BIS40. CONCLUSION: Decreasing BIS levels in the propofol and sevoflurane groups enhanced epileptogenic spike frequency and amplitude with the same location and number of spiking leads. PMID- 23648519 TI - Application of the continual reassessment method to dose-finding studies in regional anesthesia: an estimate of the ED95 dose for 0.5% bupivacaine for ultrasound-guided supraclavicular block. AB - BACKGROUND: Previously reported estimates of the ED95 doses for local anesthetics used in brachial plexus blocks vary. The authors used the continual reassessment method, already established in oncology trials, to determine the ED95 dose for 0.5% bupivacaine for the ultrasound-guided supraclavicular block. METHODS: A double-blind, prospective trial was scheduled for 40 patients of American Society of Anesthesiologists class I-III presenting for upper limb surgery and supraclavicular block. The study dose to be administered was arbitrarily divided into six dose levels (12, 15, 18, 21, 24, and 27 ml) with a priori probabilities of success of 0.5, 0.75, 0.90, 0.95, 0.98, and 0.99 respectively. A continual reassessment method statistical program created a dose-response curve, which would shift direction depending on the success or failure of the block. Our starting dose was 21 ml and the next allocated dose was reestimated by the program to be the dose level with the updated posterior response probability closest to 0.95. RESULTS: After recruitment of eight patients, our initial dose levels and associated probabilities were deemed too low to determine the ED95. Updated a prioris were calculated from the statistical program, and the study recommenced with a new starting dose of 30 ml. On completion, the ED95 dose was estimated to be 27 ml (95% CI, 24-28 ml). CONCLUSIONS: The continual reassessment method trial design provided a credible estimate for the ED95 dose for 0.5% bupivacaine for our technique of supraclavicular block and may be of value as a statistically robust method for dose-finding studies in anesthesiology. PMID- 23648520 TI - Bayesian statistical inference in anesthesiology. PMID- 23648521 TI - A rare case of dual emission in a neutral heteroleptic iridium(III) complex. AB - Herein we describe the synthesis and characterization of a neutral heteroleptic iridium complex bearing an unusual 2-pyridyl-6-methylthiazine dioxide ligand (pythdo). X-ray crystallographic analysis reveals that in the complex, the pythdo ligand is twisted and puckered, resulting in very low photoluminescent quantum efficiency. The emission profile is structured. Excited state lifetime measurements along with oxygen quenching studies point to a rare case of dual emission from different excited states whereby the high energy bands possess significant ligand-centered ((3)LC) character while the lower energy bands are predominantly characterized as a mixture of charge transfer ((3)CT) states. A detailed computational analysis corroborates the unusual photophysical behavior. PMID- 23648522 TI - Nutritional quality of major meals consumed away from home in Brazil and its association with the overall diet quality. AB - OBJECTIVE: The objective of the study is to evaluate the nutritional quality of meals consumed away from home and its association with overall diet quality. METHOD: Data was obtained from 834 participants of a Health Survey in Sao Paulo, Brazil. Food intake was measured by a 24-hour dietary recall applied telephonically using the Automated Multiple-Pass Method. Overall dietary quality was assessed by the Brazilian Healthy Eating Index Revised (B-HEIR) and the Meal Quality Index (MQI) was used to evaluate dietary quality of the main meals. The association between the B-HEIR and the MQI was assessed by linear regression analysis. RESULTS: The consumption of at least one of the three main meals away from home was reported for 32% of respondents (70 adolescents, 156 adults and 40 elderly). The average MQI score of lunch consumed away from home was lower than lunch consumed at home, with higher amounts of total and saturated fats. The average score of B-HEIR was 58 points and was associated with the MQI score, energy, meal consumption location and gender. CONCLUSION: Lunch consumed away from home presented the worst quality, being higher in total and saturated fat. However, the meals consumed at home also need improvement. PMID- 23648523 TI - Social inequalities in clustering of oral health related behaviors in a national sample of British adults. AB - OBJECTIVES: 1. To assess clustering of oral health related behaviors among a sample of British adults. 2. To determine the variation in clustering of oral health related behaviors by socioeconomic position. METHOD: We used secondary analysis of the Adult Dental Health Survey 2009 data. Health behaviors referred to smoking, tooth brushing frequency, dental visits and sugar consumption. Clustering was assessed by pairwise correlations, counts of clustering of health compromising behaviors and comparison of observed/expected ratios. Logistic regression was used to assess variation in clustering of oral health related behaviors by socioeconomic position crudely and adjusted for age, gender and self rated oral health. RESULTS: There were weak correlations between four health behaviors. Very low prevalence of clustering was reported. Higher observed to expected ratio was observed for clustering patterns with lower prevalence. Multivariate logistic regression showed clear, strong and significant educational gradients in associations between different clustering patterns of health compromising behaviors and educational attainment. These educational gradients remained significant after adjusting for age, gender and self-reported oral health. CONCLUSION: Very clear and strong educational gradients were observed throughout patterns of clustering of oral health compromising behaviors, suggesting chances of having detrimental behavioral clustering are lower in more educated groups in population. PMID- 23648524 TI - BCG shortage in Europe. PMID- 23648525 TI - Smoking trajectories from midlife to old age and the development of non-life threatening health problems: a 34-year prospective cohort study. AB - OBJECTIVE: To examine how trajectories of smoking observed over a 34-year period, were associated with the progression of mobility impairment, musculoskeletal pain, and symptoms of psychological distress from midlife to old age. METHOD: The Swedish Level of Living Survey (LNU) and the Swedish Panel Study of the Oldest Old (SWEOLD) were merged to create a nationally representative longitudinal sample of Swedish adults (aged 30-50 at baseline; n=1060), with four observation periods, from 1968 through 2002. Five discrete smoking trajectory groups were treated as predictors of variation in health trajectories using multilevel regression. RESULTS: At baseline, there were no differences in mobility impairment between smoking trajectory groups. Over time all smokers, particularly persistent and former heavy smokers, exhibited faster increases in mobility problems compared with persistent non-smokers. Additionally, all smoking groups reported more pain symptoms than the non-smokers, at baseline and over time, but most of these differences did not reach statistical significance. Persistent heavy smokers reported elevated levels of psychological distress at baseline and over time. CONCLUSION: Smokers, and even some former smokers, who survive into old age appear to be at increased risk for non-life-threatening conditions that can diminish quality of life and increase demands for services. PMID- 23648526 TI - Determinants of H1N1 vaccination uptake in England. AB - OBJECTIVE: This study aims to investigate which individual characteristics influenced the uptake of the 2009 H1N1 vaccination in England. The vaccination was provided for free to a specified target group who also received invitation letters, but the coverage rate was still far from universal among them. METHODS: Data from the 2010 edition of the Health Survey for England are used (size of the estimation sample: 7211). In order to partial out the effect of unobservable time costs, attitudes or access to vaccinations, immunisations against the seasonal and pandemic influenza are jointly estimated. RESULTS: Health risks, health behaviours and preferences, and exposure to various information help explain the immunisation decision. Receiving the seasonal flu vaccine increases the probability of H1N1 vaccination uptake by 20 percentage points. CONCLUSIONS: The widespread refusal of the vaccination can be worrying for the control of potential future pandemics. Providing clear, well targeted information, ensuring that high risk groups are contacted, and raising the level of health consciousness can increase the coverage rate with vaccinations. PMID- 23648527 TI - [Recent advances in understanding the role of innate immunity in the pathogenesis of inflammatory bowel disease]. PMID- 23648528 TI - [Innate immunity in the pathogenesis of inflammatory bowel disease]. PMID- 23648529 TI - [Innate immunity in chronic viral hepatitis]. PMID- 23648530 TI - [Innate immunity and autoimmune liver diseases]. PMID- 23648531 TI - [Innate immunity in autoimmune pancreatitis]. PMID- 23648532 TI - [Revision of the training curriculum of Japan Society of Gastroenterology]. PMID- 23648533 TI - [Revision of the training curriculum of Japan Society of Gastroenterology: gastroenterologist's role and professionalism]. PMID- 23648534 TI - [Revision of the training curriculum of Japan Society of Gastroenterology: upper gastrointestinal tract]. PMID- 23648535 TI - [Revision of the training curriculum of Japan Society of Gastroenterology: lower gastrointestinal tract]. PMID- 23648536 TI - [Revision of the training curriculum of Japan Society of Gastroenterology: liver]. PMID- 23648537 TI - [Revision of the training curriculum of Japan Society of Gastroenterology: biliary tract and pancreas]. PMID- 23648538 TI - [Gadolinium as an alternative radiocontrast agent in patients with allergy to iodine-based contrast provide for useful diagnostic imagings and safely treatment of biliary tract diseases]. AB - Diagnosis and treatment of biliary tract disease requires an intraductal radiocontrast agent. Although iodine-based contrast medium is commonly used, some patients show severe allergy to iodinated contrast agent. We have retrospectively reviewed the usefulness and safety of gadolinium as an alternative radiocontrast agent in 3 patients with allergy to iodine-based contrast medium in the diagnosis and treatment of biliary tract diseases. In case 1, percutaneous transhepatic biliary drainage and cholangiography were performed successfully and it was possible to visualize an intrahepatic bile duct stone. Percutaneous transhepatic cholangioscopic lithotomy was performed and the intrahepatic bile duct stone was removed. In case 2, endoscopic biliary lithotripsy was performed. In case 3, percutaneous transhepatic cholangiography and cholangioscopy provided a diagnosis of moderately differentiated carcinoma. He underwent pancreatoduodenectomy. Postoperative cholangiograms were also obtained successfully. Gadolinium contrast agent is an alternative to iodine-based cholangiography for the patients with allergy to iodine. PMID- 23648539 TI - [A case of alpha-fetoprotein-producing fetal gut-like small intestinal cancer]. AB - A 72-year-old Japanese woman was admitted because of vomiting and abdominal pain. An enhanced computed tomography scan showed a small intestinal obstruction due to ileal wall thickening and multiple liver metastases. Her serum alpha-fetoprotein (AFP) level was high at 1671.9ng/ml. An ileocecal resection was performed. The histological diagnosis was AFP-producing small intestinal cancer resembling the primitive gut epithelium of a fetus. The present case suggested that even intestinal cancer could produce AFP. PMID- 23648540 TI - [Disseminated varicella-zoster virus infection complicated with severe abdominal pain and colonic pseudo-obstruction]. AB - A 48-year-old man was admitted to our hospital complaining of acute severe abdominal pain and constipation. He had received bone marrow transplantation for acute myelogenous leukemia 5 months previously and immunosuppressant treatment for chronic graft-versus-host disease. Abdominal X-ray and CT scan films revealed his large intestine widely dilated and filled with air, and colonic pseudo obstruction was diagnosed. It was difficult to ascertain the cause of the symptoms until 6 days after onset of the abdominal pain when disseminated zoster eruption appeared over his whole body. It was disseminated varicella-zoster and complicated with colonic pseudo-obstruction. He was treated with acyclovir. It is important to suspect disseminated varicella-zoster and treat early immunocompromised patients complaining of severe acute abdominal pain and colonic pseudo-obstruction. PMID- 23648541 TI - [A case of intragastric wall abscess formation during bevacizumab combined chemotherapy]. AB - A 38-year-old man was given a diagnosis of as sigmoid colon cancer and underwent sigmoid colectomy. Post-operative pathological staging was stage IIIb. He then underwent adjuvant chemotherapy. One year and 4 months after the surgery, CT scans revealed multiple liver and lung metastases. He was given mFOLFOX6+bevacizumab, which was changed later to FOLFIRI+bevacizumab. After these chemotherapies, he was admitted to the hospital due to sudden abdominal pain and high grade fever. Obstructive jaundice was initially diagnosed, but detailed study of initial CT revealed intragastric wall abscess. After the drainage of the abscess, his conditions improved. We speculated that the abscess formation was caused by mucosal damage due to bevacizumab. PMID- 23648542 TI - [A surgically resected case of AFP and PIVKA-II producing gastric cancer with hepatic metastasis]. AB - A 78-year-old man was admitted for workup for a liver tumor. Both serum AFP and PIVKA-II levels were high (2260ng/ml and 806mAU/ml, respectively). Contrast enhanced CT scan and MRI using Gd-EOB-DTPA demonstrated a liver tumor in segment 6 resembling the imaging patterns of hepatocellular carcinoma (HCC), while the upper gastrointestinal endoscopy revealed a type 2 gastric cancer in the gastric antrum. Although the liver metastasis of the gastric cancer was undeniable, we performed partial resection of segment 6 of the liver and distal gastrectomy under a preoperative diagnosis of double cancer. Histopathologically, gastric tumor consisted of two components, such as well differentiated adenocarcinoma and hepatoid adenocarcinoma. The histology of the liver tumor was similar to that of the hepatoid component in the stomach lesion. Immunohistochemical staining revealed both the gastric and the liver tumors to be positive for AFP and PIVKA II, yielding a definite diagnosis of AFP and PIVKA-II producing gastric cancer with liver metastasis. Because many cases of this disease have liver metastases at presentation with confusing images with HCC, the diagnosis of liver tumors should be carefully differentiated in the gastric cancer patients with liver tumors, high serum AFP and PIVKA-II levels. PMID- 23648543 TI - [A case of gallbladder metastasis from a malignant perivascular epithelioid cell tumor of the bladder]. AB - The perivascular epithelioid cell family of tumors (PEComas) includes common lesions such as angiomyolipomas, lymphangioleiomyomas, and clear cell "sugar" tumors of the lung. Less frequently, PEComas arise in various other locations throughout the body, including the soft tissue, bone, and the visceral organs. We report the case of a 64-year-old man who underwent total cystectomy because of a primary malignant PEComa of the bladder in August 2010. The patient was treated with the mammalian target of rapamycin inhibitor for lung and bone metastasis from April 2011 and showed stable disease. Computed tomography showed a growing mass in the neck of the gallbladder 5 months later, which was suspected to be gallbladder cancer. Cholecystectomy and lymphadenectomy was performed in February 2012, and histopathological examination indicated gallbladder metastasis from the primary malignant PEComa of the bladder. This is, to our knowledge, the first report of malignant PEComa metastasis to the gallbladder. PMID- 23648544 TI - [A case of advanced gastric cancer with liver abscesses]. AB - A man visited to our hospital because of high grade fever. Computed tomography revealed multilocular space occupying lesion which were suspected liver abscess. Upper gastrointestinal endoscopy showed an advanced gastric cancer with an ulcer on antrum. Antibiotics decreased the level of CRP, concurrently with the reduction of liver space occupying lesion. While he underwent distal gastrectomy, pathological examination demonstrated the existence of bacterial foci and microabscesses on the surface of the gastric cancer. We speculate in this case that liver abscesses were formed by the infection of resident bacteria through portal vein. PMID- 23648545 TI - [A case of type 2 autoimmune pancreatitis associated with Crohn disease]. AB - A 45-year-old woman visited our hospital due to upper left quadrant pain and melena. Colonoscopy revealed longitudinal ulcers in the transverse colon. The endoscopic findings and pathological examination of a biopsy specimen led to diagnosis of Crohn disease, and mesalazine was administered. Although the colorectal lesions showed improvement with mesalazine, a blood test revealed elevation of biliary enzymes. Endoscopic retrograde cholangiopancreatography showed diffuse narrowing of the main pancreatic duct and smooth stricture of the distal bile duct. Steroid therapy improved the pancreatic lesion, which was diagnosed as type 2 autoimmune pancreatitis. PMID- 23648547 TI - Oral administration of the CCR5 inhibitor, maraviroc, blocks HIV ex vivo infection of Langerhans cells within the epithelium. PMID- 23648546 TI - Smad4 loss in mouse keratinocytes leads to increased susceptibility to UV carcinogenesis with reduced Ercc1-mediated DNA repair. AB - Smad4 loss occurs frequently in human skin squamous cell carcinoma (SCC), but it is unknown whether this loss increases UV-induced carcinogenesis, a major etiological factor in skin cancer. In the present study, mice with keratinocyte specific Smad4 deletion (K14.Smad4(-/-)) and wild-type (WT) littermates were chronically UV-irradiated. Compared with WT, K14.Smad4(-/-) mice exhibited increased DNA damage and increased susceptibility to UV-induced skin cancer. Among genes involved in repairing UV-induced DNA damage, Excision repair cross complementation group 1 (Ercc1) messenger RNA was significantly reduced in UV treated K14.Smad4(-/-) skin compared with WT skin. Further analysis revealed that Smad4 loss confers reduced Snail binding to the Ercc1 regulatory elements, resulting in reduced Ercc1 transcription. Consistently, transient transfection of Snai1 into Smad4(-/-) keratinocytes led to increased repair of UV-induced DNA lesions. Transfection of Ercc1 into Smad4(-/-) keratinocytes restored repair of UV-induced DNA damage. Further, immunostaining revealed that the presence of Smad4 protein is associated with the presence of Snail and Ercc1 proteins in human skin SCC and precancerous actinic keratoses. Collectively, Smad4 loss associated Snail reduction compromises Ercc1-mediated DNA repair, contributing to increased UV-induced skin carcinogenesis. Thus, we identified a role for Snail in UV-induced DNA repair. PMID- 23648548 TI - Identification of CD3+CD4-CD8- T cells as potential regulatory cells in an experimental murine model of graft-versus-host skin disease (GVHD). AB - We have developed K14-mOVA transgenic (Tg) mice that express membrane-associated ovalbumin (mOVA) under the control of a K14 promoter, as well as double Tg mice, by crossing them with OT-I mice that have a TCR recognizing the OVA peptide. When injected with CD8(+) OT-I cells, K14-mOVA Tg mice develop graft-versus-host disease (GVHD), whereas double Tg mice are protected. This suggests that, in double Tg mice, regulatory mechanisms may prevent infused OT-I cells from inducing GVHD. We demonstrated that, after adoptive transfer, TCRalphabeta(+)CD3(+)CD4(-)CD8(-)NK1.1(-) double-negative (DN) T cells are increased in the peripheral lymphoid organs and skin of double Tg mice and exhibit a Valpha2(+)Vbeta5(+)TCR that has the same TCR specificity as OT-I cells. These DN T cells isolated from tolerant double Tg mice proliferated in response to OVA peptide and produced IFN-gamma in the presence of IL-2. These cells could also suppress the proliferation of OT-I cells and were able to specifically kill activated OT-I cells through Fas/Fas ligand interaction. These findings suggest that DN T cells that accumulate in double Tg mice have regulatory functions and may have a role in the maintenance of peripheral tolerance in vivo. PMID- 23648549 TI - Mutations in IL36RN in patients with generalized pustular psoriasis. PMID- 23648550 TI - Effects of hearing aid amplification on voice F0 variability in speakers with prelingual hearing loss. AB - To investigate the audio-vocal feedback responses of (F0) to hearing amplification in severe-to-profound prelingual hearing loss (SPHL) using power spectral analysis of F0 contour of sustained vowels. Sustained phonations of vowel/a/of seventeen participants with SPHL were acquired with and without hearing-aid amplifications. The vocal intensity was visually fed back to the participants to help controlling the vocal intensity at 65-75 dBA and 85-95 dBA. The F0 contour of the phonations was extracted and submitted to spectral analysis to measure the extent of F0 fluctuations at different frequency ranges. The results showed that both high vocal intensity and hearing-aid amplification significantly improved voice F0 control by reducing the low-frequency fluctuations (low-frequency power, LFP, 0.2-3 Hz) in F0 spectrum. However, the enhanced feedback from higher vocal intensity and/or hearing amplification was not adequate to reduce the LFP to the level of a normal hearing person. Moreover, we found significant and negative correlations between LFP and supra-threshold feedback intensity (phonation intensity - hearing threshold level) for the frequencies of 500-2000 Hz. Increased vocal intensity, as well as hearing-aid amplification, improved voice F0 control by reducing the LFP of F0 spectrum, and the subtle changes in voices could be well explored using spectral analysis of F0. PMID- 23648551 TI - Structural characteristics and anticancer activity of fucoidan from the brown alga Sargassum mcclurei. AB - Three different fucoidan fractions were isolated and purified from the brown alga, Sargassum mcclurei. The SmF1 and SmF2 fucoidans are sulfated heteropolysaccharides that contain fucose, galactose, mannose, xylose and glucose. The SmF3 fucoidan is highly sulfated (35%) galactofucan, and the main chain of the polysaccharide contains a ->3)-alpha-L-Fucp(2,4SO3-)-(1->3)-alpha-L Fucp(2,4SO3-)-(1-> motif with 1,4-linked 3-sulfated alpha-L-Fucp inserts and 6 linked galactose on reducing end. Possible branching points include the 1,2,6- or 1,3,6-linked galactose and/or 1,3,4-linked fucose residues that could be glycosylated with terminal beta-D-Galp residues or chains of alternating sulfated 1,3-linked alpha-L-Fucp and 1,4-linked beta-D-Galp residues, which have been identified in galactofucans for the first time. Both alpha-L-Fucp and beta-D-Galp residues are sulfated at C-2 and/or C-4 (and some C-6 of beta-D-Galp) and potentially the C-3 of terminal beta-D-Galp, 1,4-linked beta-D-Galp and 1,4 linked alpha-L-Fucp residues. All fucoidans fractions were less cytotoxic and displayed colony formation inhibition in colon cancer DLD-1 cells. Therefore, these fucoidan fractions are potential antitumor agents. PMID- 23648552 TI - Balibalosides, an original family of glucosylated sesterterpenes produced by the Mediterranean sponge Oscarella balibaloi. AB - The chemical investigation of the recently described Mediterranean Homoscleromorpha sponge Oscarella balibaloi revealed an original family of five closely related glucosylated sesterterpenes 1-4, named balibalosides. Their structure elucidation was mainly inferred from NMR and HRMS data analyses. Balibalosides differ by the pattern of acetyl substitutions on the three sugar residues linked to the same aglycone sesterterpenoid core. From a biosynthetic perspective, these compounds may represent intermediates in the pathways leading to more complex sesterterpenes frequently found in Dictyoceratida, a sponge Order belonging to Demospongiae, a clade which is phylogenetically distinct from the Homoscleromorpha. While steroid and triterpenoid saponins were already well known from marine sponges, balibalosides are the first examples of glycosilated sesterterpenes. PMID- 23648553 TI - Recognition and binding of apocytochrome c to P. aeruginosa CcmI, a component of cytochrome c maturation machinery. AB - The biogenesis of c-type cytochromes (Cytc) is a process that in Gram-negative bacteria demands the coordinated action of different periplasmic proteins (CcmA I), whose specific roles are still being investigated. Activities of Ccm proteins span from the chaperoning of heme b in the periplasm to the specific reduction of oxidized apocytochrome (apoCyt) cysteine residues and to chaperoning and recognition of the unfolded apoCyt before covalent attachment of the heme to the cysteine thiols can occur. We present here the functional characterization of the periplasmic domain of CcmI from the pathogen Pseudomonas aeruginosa (Pa-CcmI*). Pa-CcmI* is composed of a TPR domain and a peculiar C-terminal domain. Pa-CcmI* fulfills both the ability to recognize and bind to P. aeruginosa apo-cytochrome c551 (Pa-apoCyt) and a chaperoning activity towards unfolded proteins, as it prevents citrate synthase aggregation in a concentration-dependent manner. Equilibrium and kinetic experiments with Pa-CcmI*, or its isolated domains, with peptides mimicking portions of Pa-apoCyt sequence allow us to quantify the molecular details of the interaction between Pa-apoCyt and Pa-CcmI*. Binding experiments show that the interaction occurs at the level of the TPR domain and that the recognition is mediated mainly by the C-terminal sequence of Pa-apoCyt. The affinity of Pa-CcmI* to full-length Pa-apoCyt or to its C-terminal sequence is in the range expected for a component of a multi-protein complex, whose task is to receive the apoCyt and to deliver it to other components of the apoCyt:heme b ligation protein machinery. PMID- 23648556 TI - Bisoprolol, ramipril and simvastatin determination in dried blood spot samples using LC-HRMS for assessing medication adherence. AB - The use of dried blood spot (DBS) collection cards was investigated for the quantification of three therapeutic drugs used in cardiovascular therapy for assessing medication adherence. A liquid chromatography-high resolution mass spectrometry (LC-HRMS) method was developed and validated for the determination of bisoprolol, ramipril and simvastatin. Whole blood spiked with target analytes was used to produce 30 MUl blood spots on specimen collection cards. An 8mm disc was cut from the dried blood spot and extracted using methanol: water (70:30, v/v) containing the internal standard, atenolol. Extracts were vortexed, sonicated and then centrifuged. Gradient chromatographic elution was achieved using a Zorbax Eclipse C18 HD 100 mm * 2.1 mm, 1.8 MUm pore size column and a mobile phase flow rate of 0.6 ml/min and the column oven temperature at 40 degrees C with a run time of 3 min. MS detection was carried out in electrospray positive ion mode for the three target drugs and for the IS. Drug recoveries from spiked blood spots were >= 92% for bisoprolol and ramipril and ~43% for simvastatin and the drugs were stable in DBS for at least 12 weeks. Validation of the LC-HRMS method showed good linearity and the accuracy (relative error) and precision (coefficient of variation) values were within the pre-defined limits of <= 15% at all concentrations. Matrix effects and the effects of different volumes of blood applied to the collection card were investigated. The LC-HRMS method successfully identified control volunteers who were known to be either adherent or non-adherent. There were no false positives from volunteers taking other cardiovascular drugs or from volunteers receiving no medication. PMID- 23648557 TI - Screening of target compounds from Fructus Piperis using high alpha1A adrenoreceptor expression cell membrane chromatography online coupled with high performance liquid chromatography tandem mass spectrometry. AB - Benign prostatic hyperplasia (BPH) is a common disease in elderly men. The main treatment for BPH is alpha-adrenergic antagonists and 5alpha-reductase inhibitors. In this study, a two-dimensional (2D) alpha1A cell membrane chromatography (CMC) online liquid chromatography/mass spectrometry system was built. Fructus Piperis, a traditional Chinese medicine and food homolog, was assayed with this 2D system. Piperine was identified as the active compound acting on alpha1A receptors. A competitive binding assay and molecular docking assay were performed to investigate the binding sites and the affinity of piperine for the alpha1A receptor. The results of the competitive binding assay (dissociation equilibrium constant of tamsulosin was 1.43 * 10(-6)M and piperine was 2.13 * 10(-6)M) and molecular docking assay (total score for tamsulosin binding with the alpha1A receptor was 6.9719, and for piperine it was 4.4891) corresponded with the retention time of tamsulosin and piperine on the alpha1A/CMC column. PMID- 23648558 TI - Simultaneous determination of three Curcuminoids in Curcuma wenyujin Y.H.chen et C.Ling. by liquid chromatography-tandem mass spectrometry combined with pressurized liquid extraction. AB - A sensitive and efficient method based on pressurized liquid extraction (PLE) followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed for simultaneous identification and quantification of three Curcuminoids in Curcuma wenyujin Y.H.chen et C.Ling., a well known traditional Chinese medicinal herb. PLE was performed using methanol as the extractant, and with the temperature set at 100 degrees C and the pressure at 1500 psi. Shorter extraction time and less solvent consumption were obtained compared to other extraction methods. LC was performed by using a Waters XBridge C18 column (150 mm * 2.1 mm i.d., 3.5 MUm) and a mobile phase of acetonitrile containing 0.1% acetic acid. The operating parameters were thoroughly optimized. The recoveries ranged from 92.4% to 104.1% and relative standard deviations were lower than 3.6%. The method was applied to the determination of Curcumin, Demethoxycurcumin and Bisdemethoxycurcumin contained in Curcuma wenyujin Y.H.chen et C.Ling. samples, which provided a new analytical approach for analysis and quality assessment of traditional Chinese medicines. PMID- 23648559 TI - Syntax does not necessarily precede semantics in sentence processing: ERP evidence from Chinese. AB - Two event-related potential experiments were conducted to examine whether the processing of syntactic category or syntactic subcategorization frame always needs to temporally precede semantic processing during the reading of Chinese sentences of object-subject-verb construction. The sentences contained (a) no anomalies, (b) semantic only anomalies, (c) syntactic category plus semantic anomalies, or (d) transitivity plus semantic anomalies. In both experiments, all three types of anomalies elicited a broad negativity between 300 and 500 ms. This negativity included an N400 effect, given its distribution. Moreover, syntactic category plus semantic anomalies elicited a P600 response, whereas the other two types of anomalies did not. The finding of N400 effects suggests that semantic integration can be attempted even when the processing of syntactic category or syntactic subcategorization frame is unsuccessful. Thus, syntactic processing is not a necessary prerequisite for the initiation of semantic integration in Chinese. PMID- 23648560 TI - Nicotine is a pain reliever in trauma- and chemotherapy-induced neuropathy models. AB - Chemotherapy-induced neuropathies are widespread disorders evoked by characteristic damage of the nervous system. Sensory alterations, as paresthesia and dysesthesia, and severe pain are disabling side effects that altered quality of life, leading to therapy discontinuation. These kind of neuropathies are extremely difficult to treat and actual therapies are generally palliative. A great deal of interest has evolved around the relevance of nicotinic receptors as target for chronic pain therapy. Selective receptor subtype modulators have been described as active in pain relief. On the other hand, the profile of nicotine as such, or delivered by tobacco smoke, is a matter of debate since the analgesic properties may be impaired by receptor desensitization and tolerance. Nicotine acute effect on nociceptive threshold was evaluated in the Chronic Constriction Injury model in comparison with neuropathies induced by chemotherapeutic agents. Fourteen days after nerve injury, intraperitoneally administered nicotine (0.5 1.5 mg/kg) reduced hypersensitivity to noxious and non-noxious stimuli. Painful neuropathic state was alternatively established by the intravenously injection of the antiviral agent dideoxycytidine (25 mg/kg). Nicotine significantly reduced antiviral-dependent alterations of the nociceptive threshold. Moreover, nicotine decreased neuropathic pain induced by repeated intraperitoneal administration of the anticancer agent oxaliplatin (2.4 mg/kg), lowering the hypersensitivity to mechanical and thermal stimuli. In conclusion, intraperitoneal nicotine administration controls neuropathic pain evoked by traumatic or toxic nervous system alterations. These results support the nAChR modulation as a possible therapeutic approach to the complex, undertreated chemotherapy-induced neuropathies. PMID- 23648561 TI - Pleiotropic antioxidant potential of rosuvastatin in preventing cardiovascular disorders. AB - Rosuvastatin is a promising synthetic hydrophillic statin which provides potential benefits in reducing cardiovascular risk factors. Rosuvastatin has potent ability to diminish low density lipoprotein, very low density lipoprotein, triglycerides and enhance high density lipoprotein level to manage high cholesterol level and associated cardiovascular diseases. Intriguingly, numerous studies demonstrated that rosuvastatin can reverse the cardiac disorders such as hypertension, atherosclerosis, ischemic heart disease, congestive heart failure and cardiomyopathy by reducing reactive oxygen species mediated oxidative stress. Rosuvastatin maintain the balance between oxidant generation and oxidant scavenging by reducing NADPH (nicotinamide adenine dinucleotide phosphate) dependent production of reactive oxygen species, suppressing endothelial nitric oxide synthase (eNOS) uncoupling, inducing and upregulating antioxidant defense mechanism. This review, summaries pleiotropic antioxidant evidences of rosuvastatin in favor of cardioprotection. PMID- 23648562 TI - An endovascular canine stroke model: middle cerebral artery occlusion with autologous clots followed by ipsilateral internal carotid artery blockade. AB - Stroke is one of the leading causes of death worldwide and the main reason for long-term disability. An appropriate animal model of stroke is urgently required for understanding the exact pathophysiological mechanism of stroke and testing any new therapeutic regimen. Our work aimed to establish a canine stroke model occluding the middle cerebral artery (MCA) and blocking the ipsilateral internal carotid artery (ICA), and to assess the infarct lesions by magnetic resonance imaging. The stroke model was generated by injecting two autologous clots into each MCA, followed by 2-h ipsilateral ICA blockade (ilICAB) using a catheter in 15 healthy adult beagles. Outcome measurements included 24-h and 7-day postocclusion T2-weighted imaging (T2WI)-based infarct volume calculation. In addition, pial collateral score, canine neurobehavioral score and histopathologic results were documented. Out of 15 dogs, 12 with successful MCA occlusion (MCAO) and ilICAB survived 7 days without complications or casualties and MCA were reperfused at 7 days after occlusion. High signal intensity in the basal ganglia and cerebral cortex on T2WI was initially observed in each dog at 6 h after the procedure. The mean percentage hemispherical infarct volume corrected for edema in all dogs on T2WI at 24 h after occlusion was 12.99+/-1.57%, and the degree of variability was 12.08%. The infarct volumes at 24 h after occlusion correlated with pial collateral scores and canine neurobehavioral scores well. This canine stroke model with combined MCAO and ilICAB reported here were proven to be highly feasible and reproducible. PMID- 23648563 TI - The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response. AB - Connective tissue growth factor (CTGF/CCN2) is a matricellular protein susceptible to proteolytic degradation. CCN2 levels have been suggested as a potential risk biomarker in several chronic diseases. In body fluids, CCN2 full length and its degradation fragments can be found; however, their in vivo effects are far from being elucidated. CCN2 was described as a profibrotic mediator, but this concept is changing to a proinflammatory cytokine. In vitro, CCN2 full length and its C-terminal module IV (CCN2(IV)) exert proinflammatory properties. Emerging evidence suggest that Th17 cells, and its effector cytokine IL-17A, participate in chronic inflammatory diseases. Our aim was to explore whether CCN2(IV) could regulate the Th17 response. In vitro, stimulation of human naive CD4+ T lymphocytes with CCN2(IV) resulted in differentiation to Th17 phenotype. The in vivo effects of CCN2(IV) were studied in C57BL/6 mice. Intraperitoneal administration of recombinant CCN2(IV) did not change serum IL-17A levels, but caused an activation of the Th17 response in the kidney, characterized by interstitial infiltration of Th17 (IL17A+/CD4+) cells and upregulation of proinflammatory mediators. In CCN2(IV)-injected mice, elevated renal levels of Th17-related factors (IL-17A, IL-6, STAT3 and RORgammat) were found, whereas Th1/Th2 cytokines or Treg-related factors (TGF-beta and Foxp-3) were not modified. Treatment with an anti-IL-17A neutralizing antibody diminished CCN2(IV) induced renal inflammation. Our findings unveil that the C-terminal module of CCN2 induces the Th17 differentiation of human Th17 cells and causes a renal Th17 inflammatory response. Furthermore, these data bear out that IL-17A targeting is a promising tool for chronic inflammatory diseases, including renal pathologies. PMID- 23648566 TI - Ultrasound monitoring of RBC aggregation as a real-time marker of the inflammatory response in a cardiopulmonary bypass swine model. AB - OBJECTIVES: In many pathological conditions, including high-risk surgery, the severity of the inflammatory response is related to the patient outcome. However, determining the patient inflammatory state presents difficulties, as markers are obtained intermittently through blood testing with long delay. RBC aggregation is a surrogate marker of inflammation that can be quantified with the ultrasound Structure Factor Size and Attenuation Estimator. The latter is proposed as a real time inflammation monitoring technique for patient care. DESIGN: Ten swine underwent a 90-minute cardiopulmonary bypass, and surveillance was maintained during 120 minutes in the postbypass period. To promote the inflammatory reaction, lipopolysaccharide was administrated two times prior to surgery in six of those swine (lipopolysaccharide group). During the whole procedure, the Structure Factor Size and Attenuation Estimator cellular imaging method displayed a RBC aggregation index (W) computed from images acquired within the pump circuit and the femoral vein. Interleukin-6, interleukin-10, C-reactive protein, haptoglobin, immunoglobulin G, and fibrinogen concentrations were measured at specific periods. MAIN RESULTS: Compared with controls, the lipopolysaccharide group exhibited higher W within the pump circuit (p < 0.05). In the femoral vein, W was gradually amplified in the lipopolysaccharide group during cardiopulmonary bypass and the postbypass period (p < 0.05), whereas interleukin levels were higher in the lipopolysaccharide group but only at the end of cardiopulmonary bypass and beginning of postbypass (p < 0.05). CONCLUSIONS: Continuous RBC aggregation monitoring can characterize the evolving inflammatory response during and after cardiopulmonary bypass. The Structure Factor Size and Attenuation Estimator is proposed as a real-time noninvasive monitoring technique to anticipate inflammation-related complications during high-risk surgery or critical care situations. Because RBC aggregation promotes vascular resistance and thrombosis, W could also provide early information on vascular disorders in those clinical situations. PMID- 23648567 TI - Niacin suppresses the mitogen-activated protein kinase pathway and attenuates brain injury after cardiac arrest in rats. AB - OBJECTIVES: To determine whether niacin attenuates brain injury and improves neurological outcome after cardiac arrest in rats and if its therapeutic benefits are associated with suppression of the mitogen-activated protein kinase pathway. DESIGN: Prospective laboratory study. SETTING: University laboratory. SUBJECTS: Male Sprague-Dawley rats (n=77). INTERVENTIONS: After 6 minutes of no flow time induced by ventricular fibrillation, cardiopulmonary resuscitation was provided and return of spontaneous circulation was achieved. Animals were then administered vehicle, single low dose (360 mg/kg; at 1 hr postreturn of spontaneous circulation), single high dose (1080 mg/kg; at 1 hr), or repeated low dose of niacin (360 mg/kg/d for 3 d; at 1, 24, and 48 hr) through an orogastric tube. MEASUREMENTS AND MAIN RESULTS: Neurologic deficit scales were scored at 24 hours, 72 hours, and 7 days postreturn of spontaneous circulation. Single high dose of niacin improved neurologic deficit scales at 48 hours and 7 days, and repeated low dose of niacin improved neurologic deficit scales at 7 days. Then, a separate set of animals were killed at 72 hours postreturn of spontaneous circulation, and brain tissues were harvested. Single high dose and repeated low dose of niacin attenuated cellular apoptosis and neuronal damage in hippocampal cornu ammonis 1 and decreased axonal injury and microglial activation in corpus callosum. They increased nicotinamide adenine dinucleotide, reduced nicotinamide adenine dinucleotide phosphate and reduced glutathione levels, and decreased malondialdehyde level in brain tissues. Furthermore, they suppressed the phosphorylations of p38 and c-Jun N-terminal kinase/stress-activated protein kinase and the cleavage of caspase 3. However, they failed to enhance extracellular signal-regulated kinases 1/2 phosphorylation. CONCLUSIONS: Single high dose and repeated low dose of niacin attenuated brain injury and improved neurological outcome after cardiac arrest in rats. Their therapeutic benefits were associated with suppressions of the phosphorylations of p38 and c-Jun N terminal kinase/stress-activated protein kinase and the cleavage of caspase 3. PMID- 23648568 TI - Epidemiology of obstetric-related ICU admissions in Maryland: 1999-2008*. AB - OBJECTIVE: To define the prevalence, indications, and temporal trends in obstetric-related ICU admissions. DESIGN: Descriptive analysis of utilization patterns. SETTING: All hospitals within the state of Maryland. PATIENTS: All antepartum, delivery, and postpartum patients who were hospitalized between 1999 and 2008. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 2,927 ICU admissions from 765,598 admissions for antepartum, delivery, or postpartum conditions using appropriate International Classification of Diseases, 9th Revision, Clinical Modification codes. The overall rate of ICU utilization was 419.1 per 100,000 deliveries, with rates of 162.5, 202.6, and 54.0 per 100,000 deliveries for the antepartum, delivery, and postpartum periods, respectively. The leading diagnoses associated with ICU admission were pregnancy-related hypertensive disease (present in 29.9% of admissions), hemorrhage (18.8%), cardiomyopathy or other cardiac disease (18.3%), genitourinary infection (11.5%), complications from ectopic pregnancies and abortions (10.3%), nongenitourinary infection (10.1%), sepsis (7.1%), cerebrovascular disease (5.8%), and pulmonary embolism (3.7%). We assessed for changes in the most common diagnoses in the ICU population over time and found rising rates of sepsis (10.1 per 100,000 deliveries to 16.6 per 100,000 deliveries, p = 0.003) and trauma (9.2 per 100,000 deliveries to 13.6 per 100,000 deliveries, p = 0.026) with decreasing rates of anesthetic complications (11.3 per 100,000 to 4.7 per 100,000, p = 0.006). The overall frequency of obstetric-related ICU admission and the rates for other indications remained relatively stable. CONCLUSIONS: Between 1999 and 2008, 419.1 per 100,000 deliveries in Maryland were complicated by ICU admission. Hospitals providing obstetric services should plan for appropriate critical care management and/or transfer of women with severe morbidities during pregnancy. PMID- 23648569 TI - Hijacking of Rho GTPases during bacterial infection. AB - Highly pathogenic bacteria, including Yersinia, Salmonella, E. coli and Clostridia, produce an amazing array of virulence factors that target Rho proteins. These pathogens exploit and/or impair many aspects of Rho protein activities by activating or inhibiting these key molecular switches. Here, we describe examples illustrating how modulation of Rho protein activity is the underlying molecular mechanism used by pathogens to disrupt host epithelial/endothelial barriers, paralyze immune cell migration and phagocytic functions, invade epithelial cells, replicate, and form reservoirs or disseminate in epithelia. Remarkably, emerging evidence points to the capacity of target cells to not only perceive the imbalance of Rho activity induced by virulence factors but also to respond by stimulating the production of anti-microbial responses that alert the host to the pathogenic threat. Furthermore, toxins that activate Rho proteins have been extremely useful in revealing the exquisite cellular regulations of these GTPases, notably by the ubiquitin and proteasome system. Finally, a number of studies indicate that toxins targeting Rho proteins have great potential in the development of new therapeutic tools. PMID- 23648570 TI - Insulin suppresses distal-less homeobox 5 expression through the up-regulation of microRNA-124 in 3T3-L1 cells. AB - Distal-less homeobox 5 (Dlx5) is a pro-osteogenic but anti-adipogenic transcription factor that regulates lineage commitment in mesenchymal stem cells. Although the expression of Dlx5 is known to be decreased by adipogenic stimuli, the mechanism of Dlx5 down-regulation has not yet been clarified. MicroRNAs (miRNAs) are small regulatory RNAs that post-transcriptionally regulate many biological functions, including cell differentiation. In this study, we examined whether miRNAs are involved in down-regulation of Dlx5 following adipogenic stimuli. We screened candidate miRNAs that have a direct target site in the Dlx5 3'UTR using computational prediction programs, selected seven miRNA candidates with the highest binding score and observed their expression levels in 3T3-L1 murine pre-adipocytes. Among the miRNAs examined, only miR-124 was significantly up-regulated by 24-h incubation in adipogenic medium. Among the four components of adipogenic stimuli (1-methy-3-isobutyl xanthine, insulin, indomethacin and dexamethasone), insulin exhibited the highest stimulatory effect on miR-124 expression. Insulin significantly increased the expression of miR-124 precursors including pri-miR-124-1, pri-miR124-2 and pri-miR-124-3. LY294002, an inhibitor of phosphatidylinositol-3-kinase, prevented the regulatory effect of insulin on the expression levels of miR-124 and Dlx5. Over-expression of a miR-124 mimic decreased the expression of Dlx5 while increasing adipogenic differentiation in 3T3-L1 cells. Blocking miR-124 with anti-miR-124, a hairpin inhibitor of miR-124, increased the expression level of Dlx5 and suppressed adipogenic differentiation. When reporter assays were performed with a reporter construct containing the Dlx5 3'UTR sequence downstream of a luciferase gene, miR-124 mimic suppressed, but anti-miR-124 enhanced, luciferase activity in an miR-124 binding site-dependent manner. These results suggest that insulin-induced miR-124 plays a pivotal role in post-transcriptional regulation of Dlx5 during adipogenic differentiation and that miR-124 exerts pro-adipogenic effects by targeting Dlx5, at least in part. PMID- 23648572 TI - A pH-sensitive charge-conversion system for doxorubicin delivery. AB - A novel pH-sensitive charge-conversion shielding system was designed by the electrostatic binding of polyethylenimine (PEI)-poly(l-lysine)-poly(l-glutamic acid) (PELG), PEI, and cis-aconityl-doxorubicin (CAD). Doxorubicin (DOX) was modified by cis-aconityl linkage to form acid-sensitive CAD, which was then adsorbed by the positively charged PEI. The PEI/CAD complexes were subsequently shielded with the pH-responsive charge-conversion PELG. In normal tissues, the PELG/PEI/CAD complexes were negatively charged; in acidic tumor tissues, the shielding PELG was positively charged and detached from the PELG/PEI/CAD complexes. The resulting positively charged PEI/CAD complexes thus became exposed and were endocytosed. CAD was then cleaved in the acidic intracellular environment of endosomes and lysosomes, and converted back into DOX. The charge reversal of the PELG/PEI/CAD complexes was verified by zeta potential analysis at different pH values. Moreover, DOX release increased with decreasing pH. Cell uptake and confocal laser scanning microscopy analyses showed that, at pH 6.8, PELG/PEI/CAD had the highest endocytosis rate and more DOX entered cell nuclei. More importantly, the system showed remarkable cytotoxicity against cancer cells. These results revealed that the combination of pH-sensitive charge-conversion shielding with pH-sensitive drug release is a potential drug delivery system for tumor treatment. PMID- 23648571 TI - Stiffness and adhesivity control aortic valve interstitial cell behavior within hyaluronic acid based hydrogels. AB - Bioactive and biodegradable hydrogels that mimic the extracellular matrix and regulate valve interstitial cells (VIC) behavior are of great interest as three dimensional (3-D) model systems for understanding mechanisms of valvular heart disease pathogenesis in vitro and the basis for regenerative templates for tissue engineering. However, the role of stiffness and adhesivity of hydrogels in VIC behavior remains poorly understood. This study reports the synthesis of methacrylated hyaluronic acid (Me-HA) and oxidized and methacrylated hyaluronic acid, and the subsequent development of hybrid hydrogels based on modified HA and methacrylated gelatin (Me-Gel) for VIC encapsulation. The mechanical stiffness and swelling ratio of the hydrogels were tunable with the molecular weight of the HA and the concentration/composition of the precursor solution. The encapsulated VIC in pure HA hydrogels with lower mechanical stiffness showed a more spreading morphology compared to their stiffer counterparts and dramatically up-regulated alpha smooth muscle actin expression, indicating more activated myofibroblast properties. The addition of Me-Gel in Me-HA facilitated cell spreading, proliferation and VIC migration from encapsulated spheroids and better maintained the VIC fibroblastic phenotype. The VIC phenotype transition during migration from encapsulated spheroids in both Me-HA and Me-HA/Me-Gel hydrogel matrixes was also observed. These findings are important for the rational design of hydrogels for controlling the VIC morphology, and for regulating the VIC phenotype and function. The Me-HA/Me-Gel hybrid hydrogels accommodated with VIC are promising as valve tissue engineering scaffolds and 3-D models for understanding valvular pathobiology. PMID- 23648573 TI - A tunable synthetic hydrogel system for culture of retinal ganglion cells and amacrine cells. AB - The central nervous system consists of complex groups of individual cells that receive electrical, chemical and physical signals from their local environment. Standard in vitro cell culture methods rely on two-dimensional (2-D) substrates that poorly simulate in vivo neural architecture. Neural cells grown in three dimensional (3-D) culture systems may provide an opportunity to study more accurate representations of the in vivo environment than 2-D cultures. Furthermore, each specific type of neuron depends on discrete compositions and physical properties of their local environment. Previously, we developed a library of hydrogels composed of poly(ethylene glycol) and poly(l-lysine) which exhibit a wide range of mechanical properties. Here, we identified specific scaffolds from this library that readily support the survival, migration and neurite outgrowth of purified retinal ganglion cells and amacrine cells. These data address important biological questions about the interaction of neurons with the physical and chemical properties of their local environment and provide further insight for engineering neural tissue for cell-replacement therapies following injury. PMID- 23648574 TI - Polyvinylpyrrolidone microneedles enable delivery of intact proteins for diagnostic and therapeutic applications. AB - We present a method of fabricating microneedles from polyvinylpyrrolidone (PVP) that enables delivery of intact proteins (or peptides) to the dermal layers of the skin. PVP is known to self-assemble into branched hollow fibers in aqueous and alcoholic solutions; we utilized this property to develop dissolvable patches of microneedles. Proteins were dissolved in concentrated PVP solution in both alcohol and water, poured into polydimethylsiloxane templates shaped as microneedles and, upon evaporation of solvent, formed into concentric, fibrous, layered structures. This approach of making PVP microneedles overcomes problems in dosage, uniform delivery and stability of protein formulation as compared to protein-coated metallic microneedles or photopolymerized PVP microneedles. Here we characterize the PVP microneedles and measure the delivery of proteins into skin. We show that our method of fabrication preserves the protein conformation. These microneedles can serve as a broadly useful platform for delivering protein antigens and therapeutic proteins to the skin, for example for allergen skin testing or immunotherapy. PMID- 23648576 TI - Does the topical use of epinephrine for sinus floor augmentation affect systemic hemodynamics? AB - PURPOSE: Although epinephrine is one of the most commonly used vasoconstrictor in association with local anesthesia in dentistry, systemic effects of topical admission of epinephrine for sinus augmentation have not been investigated yet. The purpose of this study was to reveal the safety of epinephrine as a topical vasoconstrictor in sinus augmentation procedures. PATIENTS AND METHODS: Forty three healthy patients who require sinus floor augmentation for dental implant placement were included in this study. Patients were divided into 2 groups according to the application of either epinephrine-soaked cottonoid or saline soaked cottonoid for sinus floor augmentation, and heart rate, systolic, and diastolic pressures were evaluated and compared before, during, and after the procedure. RESULTS: Although there were changes in heart rate, systolic, and diastolic blood pressures, no statistical significance was observed for neither heart rate nor systolic and diastolic blood pressures (P > 0.05). CONCLUSIONS: This study showed that the topical use of 1/100,000 epinephrine ensures efficacy by helping the clinician to elevate the sinus membrane and keeps the changes in systemic hemodynamics within safe limitations. PMID- 23648577 TI - Effect of rhBMP-2 upon maxillary sinus augmentation: a comprehensive review. AB - PURPOSE: The purpose of this review was to summarize the recent in vitro and in vivo research findings in areas where rhBMP-2 was used as a grafting material for sinus augmentation. MATERIALS AND METHODS: An electronic literature search for relevant articles published in English was conducted in the PubMed database from February 1996 to August 2012. Randomized clinical trials or prospective human clinical and animal trials were included with the primary objective to compare and evaluate the effectiveness of rhBMP-2 for sinus augmentation. RESULTS: A total of 3 human studies and 4 animal trials qualified the selection criteria that were included in this review. In humans, the selected studies indicated that rhBMP-2 induces new bone formation with comparable bone quality or amount of newly formed bone to that induced by autogenous bone graft. Furthermore, no differences have been reported between new bone induced by rhBMP-2 and native bone. Animal model studies also demonstrated regular bone formation induced by rhBMP-2, followed by normal maturation of new bone. CONCLUSION: All these studies demonstrate the osteoinductive and osteogenic capacity of rhBMP-2 and support it as an alternative for autogenous bone in sinus floor augmentation. PMID- 23648578 TI - Correlation between insertion torque and survival rates in immediately loaded implants in the maxilla: a retrospective study. AB - OBJECTIVE: To evaluate the correlation between insertion torque and the survival rate of immediately loaded implants placed in the maxilla. METHODS: 390 NobelReplace (Nobel Biocare USA, Yorba Linda, CA) Select Tapered implants were placed in the maxillae of 145 patients over a 15-month period. The insertion torque was measured using a digital torque wrench. RESULTS: Of the 390 implants, only 9 (2.3%) failed. The 381 successful implants were placed with an average insertion torque of 72.1 N.cm. Insertion torque values of failed implants varied between 45.8 and 134 N.cm, with an average of 69.2 N.cm. Of the 9 failed implants, 8 were abutments in multiple-unit implant-supported prostheses, and 1 was a single-unit implant. CONCLUSIONS: Although insertion torque undoubtedly plays an important role in the primary stability and successful osseointegration of implants, there seems to be no correlation between insertion torque and implant failure above 35 N.cm threshold of insertion torque. Immediate loading of implants in the maxilla is a successful and predictable treatment option with failure rates approaching those of traditional 2-stage surgery. PMID- 23648575 TI - JUN regulates early transcriptional responses to axonal injury in retinal ganglion cells. AB - The AP1 family transcription factor JUN is an important molecule in the neuronal response to injury. In retinal ganglion cells (RGCs), JUN is upregulated soon after axonal injury and disrupting JUN activity delays RGC death. JUN is known to participate in the control of many different injury response pathways in neurons, including pathways controlling cell death and axonal regeneration. The role of JUN in regulating genes involved in cell death, ER stress, and regeneration was tested to determine the overall importance of JUN in regulating RGC response to axonal injury. Genes from each of these pathways were transcriptionally controlled following axonal injury and Jun deficiency altered the expression of many of these genes. The differentially expressed genes included, Atf3, Ddit3, Ecel1, Gadd45alpha, Gal, Hrk, Pten, Socs3, and Sprr1a. Two of these genes, Hrk and Atf3, were tested for importance in RGC death using null alleles of each gene. Disruption of the prodeath Bcl2 family member Hrk did not affect the rate or amount of RGC death after axonal trauma. Deficiency in the ATF/CREB family transcription factor Atf3 did lessen the amount of RGC death after injury, though it did not provide long term protection to RGCs. Since JUN's dimerization partner determines its transcriptional targets, the expression of several candidate AP1 family members were examined. Multiple AP1 family members were induced by axonal injury and had a different expression profile in Jun deficient retinas compared to wildtype retinas (Fosl1, Fosl2 and Jund). Overall, JUN appears to play a multifaceted role in regulating RGC response to axonal injury. PMID- 23648580 TI - Photochemistry and photophysics of the amino and imino tautomers of 1 methylcytosine: tautomerisation as a side product of the radiationless decay. AB - The photochemistry and photophysics of the amino-oxo (AO) and imino-oxo (IO) tautomers of 1-methylcytosine are investigated with ab initio calculations, using the CASPT2//CASSCF approach. Our aim is to rationalize recent experimental results which show that the AO tautomer has an excited state lifetime of about 1 ps, similar to cytosine (J.-W. Ho, H.-C. Yen, W.-K. Chou, C.-N. Weng, L.-H. Cheng, H.-Q. Shi, S.-H. Lai and P.-Y. Cheng, J. Phys. Chem. A, 2011, 115, 8406 8418), and that irradiation with wavelengths shorter than 308 nm induces the AO >IO tautomerization (I. Reva, M. J. Nowak, L. Lapinski and R. Fausto, J. Phys. Chem. B, 2012, 116, 5703-5710). For the canonical AO tautomer we find two analogous decay mechanisms to those described previously for cytosine, involving a conical intersection of ethylenic type and one where the amino group is bent out of plane. Decay through these intersections provides an unreactive return path to the AO ground state species. More importantly, we have identified new decay paths that lead from the two intersections to the trans-IO tautomer, without a barrier. These paths provide the possibility of forming the IO tautomer, presumably in small yields, as a side product of the radiationless decay. Thus, we have established for the first time computationally the mechanism of the UV-induced tautomerization, which is compatible with the well-established decay mechanism for cytosine. For the IO tautomer, we also find a mechanism for the excited state interconversion of the cis and trans forms and for efficient radiationless decay through a conical intersection where the imino group is perpendicular to the ring and bent out of the plane. These results are likely to be valid also for cytosine. PMID- 23648579 TI - Tetraspanin-13 modulates voltage-gated CaV2.2 Ca2+ channels. AB - Integration of voltage-gated Ca(2+) channels in a network of protein-interactions is a crucial requirement for proper regulation of channel activity. In this study, we took advantage of the specific properties of the yeast split-ubiquitin system to search for and characterize so far unknown interaction partners of CaV2 Ca(2+) channels. We identified tetraspanin-13 (TSPAN-13) as an interaction partner of the alpha1 subunit of N-type CaV2.2, but not of P/Q-type CaV2.1 or L- and T-type Ca(2+) channels. Interaction could be located between domain IV of CaV2.2 and transmembrane segments S1 and S2 of TSPAN-13. Electrophysiological analysis revealed that TSPAN-13 specifically modulates the efficiency of coupling between voltage sensor activation and pore opening of the channel and accelerates the voltage-dependent activation and inactivation of the Ba(2+) current through CaV2.2. These data indicate that TSPAN-13 might regulate CaV2.2 Ca(2+) channel activity in defined synaptic membrane compartments and thereby influences transmitter release. PMID- 23648584 TI - When aging-onset diabetes is coming across with Alzheimer disease: comparable pathogenesis and therapy. AB - Diabetes mellitus is a metabolic disorder that is characterized by high blood glucose because of the insulin-resistance and insulin-deficiency in Type 2, while the insulin deficiency due to destruction of islet cells in the pancreas in Type 1. The development of Type 2 diabetes is caused by a combination of lifestyle and genetic factors. Aging patients with diabetes are at increased risk of developing cognitive and memory dysfunctions, which is one of the significant symptoms of Alzheimer disease (AD). Also, over 2/3 of AD patients were clinically indentified with impairment of glucose. Cognitive dysfunction would be associated with poor self-care ability in diabetes patients. This review will briefly summarize the current knowledge of the pathogenesis of these two diseases and highlight similarities in their pathophysiologies. Furthermore, we will shortly discuss recent progress in the insulin-targeted strategy, aiming to explore the inner linkage between these two diseases in aging populations. PMID- 23648585 TI - Effects of dihydrotestosterone on synaptic plasticity of hippocampus in male SAMP8 mice. AB - The senescence-accelerated-prone mouse 8 (SAMP8) has been proposed as a suitable, naturally derived animal model for investigating the fundamental mechanisms of Alzheimer's disease (AD). In addition, the serum testosterone levels decrease quickly in the natural growth process of this model. This study investigated the effect of androgen deficiency on the synaptic plasticity of hippocampus in male SAMP8 mice after castration and dihydrotestosterone (DHT) administration. We observed the dendritic spines and synapses using Golgi staining and transmission electron microscope. Androgen deficiency after castration significantly reduced the number of apical dendritic thorns, and the abnormal ultrastructure of excitatory synapses was more obvious. Androgen replacement therapy reversed this change. To explore the protective mechanisms and neurological basis of DHT, we researched the changes of expression of GluN1 subunit-containing N-methyl-D aspartate receptors (NMDARs) and synaptophysin (SYN), which are closely related to synaptic plasticity. Comparisons were made among results observed with immunohistochemistry techniques, Western blots analysis and RT-PCR analysis. The GluN1 and SYN regulation at the protein and mRNA levels probably be related to the DHT-induced morphological synaptic plasticity. This study will be helpful for understanding the function of androgen, and it provides a valuable theoretical basis about the protective and therapeutic targets of androgen in AD. PMID- 23648586 TI - Metabolic changes in the auditory cortex in presbycusis demonstrated by MR spectroscopy. AB - In humans, aging is accompanied by the deterioration of the hearing function- presbycusis. The major etiology for presbycusis is the loss of hair cells in the inner ear; less well known are changes in the central auditory system. Therefore, we used 1H magnetic resonance spectroscopy at 3T tomograph to examine metabolite levels in the auditory cortex of three groups of subjects: young healthy subjects less than 30 years old and subjects older than 65 years either with mild presbycusis corresponding to their age or with expressed presbycusis. Hearing function in all subjects was examined by pure tone audiometry (125-16,000 Hz). Significant differences were found in the concentrations of glutamate and N acetylaspartate, with lower levels in aged subjects. Lactate was particularly increased in subjects with expressed presbycusis. Significant differences were not found in other metabolites, including GABA, between young and elderly subjects. The results demonstrate that the age-related changes of the inner ear are accompanied by a decrease in the excitatory neurotransmitter glutamate as well as a lactate increase in the auditory cortex that is more expressed in elderly subjects with large hearing threshold shifts. PMID- 23648587 TI - Light-dark condition regulates sirtuin mRNA levels in the retina. AB - Sirtuins (Sirt1-7) are nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylases/ADP-ribosyltransferases that modulate many metabolic responses affecting aging. Sirtuins expressed in tissues and organs involved in systemic metabolism have been extensively studied. However, the characteristics of sirtuins in the retina, where local energy expenditure changes dynamically in response to light stimuli, are largely unknown. Here we analyzed sirtuin mRNA levels by real-time PCR, and found that all seven sirtuins are highly expressed in the retina compared with other tissues, such as liver. We then analyzed the sirtuin mRNA profiles in the retina over time, under a 12-h light/12-h dark cycle (LD condition) and in constant darkness (DD condition). All seven sirtuins showed significant daily variation under the LD condition, with all except Sirt6 being increased in the dark phase. The expression patterns were different under the DD condition, suggesting that sirtuin mRNA levels except Sirt6 are affected by light dark condition. These findings were not obtained in the brain and liver. In addition, the mRNA expression patterns of Nicotinamide phosphoribosyltransferase (Nampt), peroxisome proliferator-activated receptor gamma coactivator (PGC1alpha), and transcription factor A, mitochondrial (Tfam) in the retina, were similar to those of the sirtuins except Sirt6. Our observations provide new insights into the metabolic mechanisms of the retina and the sirtuins' regulatory systems. PMID- 23648591 TI - A molecular precursor approach to monodisperse scintillating CeF3 nanocrystals. AB - A series of anhydrous cerium(III) trifluoroacetate complexes with neutral O-donor ligands, namely Ce2(OAc)(TFA)5(DMF)3 (1), Ce(TFA)3(L)x [x = 2, L = THF (2), DMF (3), DMSO (4); x = 1, L = diglyme (5)] and Ce2(TFA)6(DMSO)x(DMF)y [x = 6, y = 0 (6); x = 4, y = 2 (7)] (where OAc = acetate, TFA = trifluoroacetate, THF = tetrahydrofuran, DMF = dimethylformamide, DMSO = dimethylsulphoxide, and diglyme = MeO(C2H4O)2Me] were synthesized and completely characterized by elemental analysis, FT-IR spectroscopy and TG-DTA-MS studies. A partially hydrated complex [Ce(TFA)3(diglyme)(H2O)] (8) was obtained by slow evaporation of the THF solution of anhydrous 5 in the air. The single crystal X-ray diffraction analysis of 1, 3, 4, and 6-8 showed the versatile bonding mode of the TFA ligand (terminal, chelating and bridging). These complexes, on decomposition in 1-octadecene in inert atmosphere, gave CeF3 nanoparticles of 8-11 nm size. The complex 5 proved to be the best precursor in the series because of the ability of the diglyme ligand to act as capping reagent during decomposition to render the CeF3 particles monodisperse in organic solvents. The obtained CeF3 nanoparticles were characterized by FT-IR, EDX analysis and TEM studies and their luminescence and scintillation responses under UV and X-ray excitation were studied and compared with that of CeF3 single crystal. PMID- 23648593 TI - Understanding acid lability of cysteine protecting groups. AB - Cys-disulfide bonds contribute to the stabilization of peptide and protein structures. The synthesis of these molecules requires a proper protection of Cys residues, which is crucial to prevent side-reactions and also to achieve the correct Cys connectivity. Here we undertook a mechanistic study of a set of well known acid-labile Cys protecting groups, as well other new promising groups, in order to better understand the nature of their acid-lability. The stability of the carbocation generated during the acid treatment was found to have a direct impact on the removal of the protective groups from the corresponding protected Cys-containing peptides. Hence a combination of steric and conjugative effects determines the stability of the carbocations generated. Here we propose diphenylmethyl (Dpm) as a promising protecting group on the basis of its intermediate relative carbocation stability. All the optimized geometries and energies presented in this study were determined using a B3LYP/6-31G(d,p) calculation. The results discussed herein may be of broader applicability for the development of new protecting groups. PMID- 23648594 TI - Retention of halogenated solutes on stationary phases containing heavy atoms. AB - To examine the effects of weak intermolecular interactions on solid-phase extraction (SPE) and chromatographic separation, we synthesized some novel stationary phases with a heavy atom effect layer by immobilizing halogenated aromatic rings and hydroxyl groups onto the surface of a hydrophilic base polymer. Using SPE cartridges packed with the functionalized materials, we found that the heavy atom stationary phases could selectively retain halophenols in organic solvents, such as 1-propanol which blocks the hydrogen bonding, or acetonitrile which blocks the pi-pi interaction. The extraction efficiency of the materials toward the halophenols depended on the dipole moments of phenoxy groups present as functional groups. On the other hand, the extraction efficiency of solutes toward the functional group depended on their molar refractions, i.e., induced dipole moments. The retention of the solutes to the stationary phase ultimately depended on not only strong intermolecular interactions, but also the effects of weak interactions such as the dispersion force. PMID- 23648595 TI - A-type proanthocyanidins from the stems of Ephedra sinica (Ephedraceae) and their antimicrobial activities. AB - Phytochemical investigation of the n-BuOH-soluble fraction of the EtOH extract of the herbaceous stems of Ephedra sinica, which is known as Ephedrae Herba in Traditional Chinese Medicine, led to the isolation and identification of 12 A type proanthocyanidins, containing five dimers, two trimers and five tetramers [i.e., (+)-epigallocatechin-(2alpha->O->7,4alpha->8)-(-)-catechin, named ephedrannin D1, a dimer; epigallocatechin-(2alpha->O->7,4alpha->8) epigallocatechin-(4alpha->8)-catechin (ephedrannin Tr1), a trimer; and epigallocatechin-(2alpha->O->7,4alpha->8)-epigallocatechin-(4alpha->8) epigallocatechin-(2alpha->O->7,4alpha->8)-gallocatechin, named ephedrannin Te1, a tetramer). Tetramers composed of gallocatechin are reported for the first time in Ephedraceae. Catechin, epicatechin, gallocatechin, epigallocatechin and four known dimers were also isolated. The structures were elucidated by extensive spectroscopic analysis. The absolute configurations of the 4alpha linkages, which were confirmed by NOESY and CD experiments, are the outstanding characteristic of most of these isolated A-type proanthocyanidins. The antimicrobial activities of these compounds were tested by measuring the minimum inhibitory concentrations (MIC) against bacteria (both Gram positive and Gram negative) and fungi, and were found to be in the range of 0.00515-1.38 mM. Compounds 6, 8, 10 and 11 exhibited moderate antimicrobial activities against Canidia albicans. PMID- 23648597 TI - Balance and vestibular function. PMID- 23648596 TI - pH effect upon HbGp oligomeric stability: characterization of the dissociated species by AUC and DLS studies. AB - Glossoscolex paulistus (HbGp) extracellular hemoglobin is a giant oligomeric protein. It is constituted by 144 heme containing subunits and non-heme structures (linkers), with a total molecular mass of 3.6MDa. AUC and DLS studies were developed for three HbGp forms, oxy-, met- and cyanomet-, at several pH values, in order to characterize the species in solution upon oligomeric dissociation. Isolated SEC fractions, trimer and dodecamer, are less stable as compared to the whole oxy-HbGp. The monomer d displays a large thermal stability up to 59 degrees C. Hydrodynamic properties of the isolated subunits are very similar to those described for them in the whole protein, in the presence of urea or at pH 10.0. The degree of HbGp oligomeric dissociation, in alkaline pH, depends significantly on the iron oxidation state. Also on the ligand coordinated to the heme iron. Thus, at pH 8.0, the oxy-HbGp is partially dissociated, while the met-form is fully dissociated. The cyanomet-HbGp remains undissociated. Our present results show that the effect of pH on the HbGp oligomeric stability is similar to that associated to the urea-induced unfolding. Simultaneous use of AUC and DLS allowed the characterization of the species in the SEC fractions of isolated HbGp subunits. PMID- 23648598 TI - Anatomy of the vestibular system: a review. AB - INTRODUCTION: A sense of proper sensory processing of head motion and the coordination of visual and postural movements to maintain equilibrium is critical to everyday function. The vestibular system is an intricate organization that involves multiple levels of sensory processing to achieve this goal. PURPOSE: This chapter provides an overview of the anatomical structures and pathways of the vestibular system. SUMMARY: The five major vestibular structures are located in the inner ear and include: the utricle, the saccule, and the lateral, superior, and posterior semicircular canals. Hair cells on the neuroepithelium of the peripheral vestibular organs carry sensory impulses to primary processing centers in the brainstem and the cerebellum. These areas send input via ascending and descending projections to coordinate vital reflexes, such as the vestibuloocular reflex and the vestibulospinal reflex, which allow for the proper orientation of the eyes and body in response to head motion. Specific connections regarding higher level cortical vestibular structures are poorly understood. CONCLUSION: Vestibular centers in the brainstem, cerebellum, and cerebral cortex function to integrate sensory information from the peripheral vestibular organs, visual system, and proprioceptive system to allow for proper balance and orientation of the body in its environment. PMID- 23648599 TI - The assessment of balance and dizziness in the TBI patient. AB - OBJECTIVES: All degrees of traumatic brain injury (TBI) are associated with balance dysfunction and/or dizziness. The clinician assessing and managing patients with TBI should become familiar with vestibular and non-vestibular causes of dizziness and imbalance, and be able to perform screening tests to determine when referral to a vestibular specialist is warranted. This chapter outlines the clinical pathways to be followed in history-taking, physical examination, and assessment. INTRODUCTION: Dizziness, vertigo, balance dysfunction and gait ataxia can have their origin in the vestibular system, elsewhere, or be multifactorial. The complex anatomy and physiology of the balance canals, otolithic organs, and vestibular nerves peripherally, and the vestibular nuclei centrally, as well as the neural connections between vestibular, oculomotor, and proprioceptive systems will be covered in clinically pertinent detail. METHODS: A majority of diagnosis of dizziness/vertigo can be made after a proper history has been obtained. This can be challenging in all dizzy patients, and more so in the TBI patient in whom memory and recall may be impaired. The reader will learn how to use tools such as dizziness questionnaires as well as targeted history taking to elicit the information. Similarly, the addition of a programmatic, targeted physical examination of the dizzy patient will allow the clinician to fine-tune the diagnosis between peripheral and central causes. RESULTS: Once history and examination have narrowed the diagnostic possibilities, appropriate testing--in the vestibular laboratory and radiologic testing--is indicated. The reader will learn when these tests should be considered, and what the findings will show. Treatment can then be targeted for maximal outcome. CONCLUSION: Managing TBI is challenging; the addition of dizziness or balance complaints in these individuals makes it even more so. This paper seeks to provide a useful roadmap clinical pathway for assessment of these patients with appropriate and timely referral for treatment. PMID- 23648600 TI - Inner ear disorders. AB - OBJECTIVES: To present a framework for the diagnosis and treatment of inner ear disorders, with an emphasis on problems common to neuro-rehabilitation. INTRODUCTION: Disorders of the inner ear can cause hearing loss, tinnitus, vertigo and imbalance. Hearing loss can be conductive, sensorineural, or mixed; conductive hearing loss arises from the ear canal or middle ear, while sensorineural hearing loss arises from the inner ear or auditory nerve. Vertigo is a hallucination of motion, and is the cardinal symptom of vestibular system disease. It should be differentiated from other causes of dizziness: gait imbalance, disequilibrium, lightheadedness (pre-syncope). Vertigo can be caused by problems in the inner ear or central nervous system. METHODS: The diagnosis of inner ear disorders begins with a targeted physical examination. The initial work up of hearing loss is made by audiometry, and vertigo by electronystagmography (ENG). Supplemental tests and MRI are obtained when clinically indicated. RESULTS: The clinical pattern and duration of vertigo are the most important clinical features in the diagnosis. Common inner ear causes of vertigo include: vestibular neuritis (sudden, unilateral vestibular loss), Meniere's disease (episodic vertigo), benign paroxysmal positional vertigo (BPPV), and bilateral vestibular loss. Common central nervous system causes of vertigo include: post concussion syndrome, cervical vertigo, vestibular migraine, cerebrovascular disease, and acoustic neuroma. CONCLUSION: A basic knowledge of vestibular physiology, coupled with a understanding of common vestibular syndromes, will lead to correct diagnosis and treatment in most cases. PMID- 23648601 TI - Special tools for the assessment of balance and dizziness in individuals with mild traumatic brain injury. AB - INTRODUCTION: Although a majority of patients following minor traumatic brain injury recover to their pre-morbid functional level, persistent activity and participation limitations can occur in the refractory patient. These long-term consequences of brain injury may only become apparent months to years after the injury. In order to quantify these long-term sequella, laboratory, clinical and functional outcome measures may not only identify needed areas of treatment, but may also assist in determining the impact of the treatment on the individuals function. PURPOSE: The aim of this manuscript is to review the clinical utility of vestibular laboratory testing and the bedside vestibular examination in patients following mild traumatic brain injury. In addition, the validity and inter-observer reliability of functional outcome measures commonly used in individuals with mTBI will also be reviewed. SUMMARY: Because of the diffuse pathology seen with mTBI, multiple tests are needed to determine the resultant impairment and their impact on the patient's activity level and participation level. Laboratory test and bedside tests of vestibular impairment are reviewed. Functional outcome measures including the Dynamic Gait Index, the Functional Gait Assessment, the Balance Error Scoring System, and Dual Task Performance are reviewed for their appropriateness in quantifying the effect of mTBI at activity level and participation level of the individual. CONCLUSION: TBI rehabilitation services are increasingly exemplified by the needs of patients, rather than by the underlying pathology or diagnosis. Basing treatment decisions and treatment timing on laboratory, clinical, and functional testing can optimize the rehabilitation outcome. PMID- 23648602 TI - Neurocognitive measures in the assessment of vestibular disturbance in patients with brain injury. AB - INTRODUCTION: Problems with balance and dizziness are one of the most common complaints of individuals who have experienced a brain injury and are reported in up to 90% of cases. Despite the ubiquity of vestibular disturbance in this population, there remains a dearth of research on the interaction between physiological and cognitive systems responsible for maintaining balance. PURPOSE: The purpose of this article is to review studies on the interaction of physiological and cognitive processes required to maintain balance that may aide assessment and recovery of balance disturbance in patients with brain injury. SUMMARY: This article provides a review of research on the role of higher order cognitive processes in maintaining balance and rational for further inclusion of neurocognitive measures in the assessment of vestibular disturbance. CONCLUSION: Greater inclusion of neurocognitive measures in assessment of vestibular disturbance provides a method of assessment containing increased ecological validity compared to traditional assessments, better prepares patients for discharge, and may reduce the incidence of future injury. PMID- 23648603 TI - Vision rehabilitation for visual-vestibular dysfunction: the role of the neuro optometrist. AB - INTRODUCTION: This article discusses, in a clinically relevant format, the importance of including a neuro-optometrist as a member of the management team for patients with balance disorders. PURPOSE: To review the importance of vision and visual processing for maintaining a sense of balance and equilibrium and the role of the neuro-optometrist in the overall rehabilitation of patients with balance disorders SUMMARY: Dizziness, balance problems and the sensation that the space world is moving (vertigo) are one of the most commonly reported problems in general medical practice. Persons with a central nervous system injury or other idiopathic causes of visual processing problems or who have functional vision problems that are not adequately managed, often experience extreme difficulty with balance and movement, as well as with their perception of space. Consequently, the patient often experiences difficulty functioning in an environment with excessive visual stimulation such as a grocery store or shopping mall. Symptoms of disequilibrium, vestibular and balance problems are commonly a result of VOR disturbance secondary to an inner ear problem and an unstable binocularity. CONCLUSION: The combination of neuro-optomertic rehabilitative therapy and balance therapy will result in a is an effective treatment for reducing or resolving these symptoms. PMID- 23648604 TI - Physiology and pathology of saccades and gaze holding. AB - INTRODUCTION: Foveation is the fundamental requirement for clear vision. Saccades rapidly shift the gaze to the interesting target while gaze holding ensures foveation of the desired object. PURPOSE: We will review the pertinent physiology of saccades and gaze holding and their pathophysiology leading to saccadic oscillations, slow saccades, saccadic dysmetria, and nystagmus. SUMMARY: Motor commands for saccades are generated at multiple levels of the neuraxis. The frontal and parietal eye field send saccadic commands to the superior colliculus. Latter then projects to the brain-stem saccadic burst generator. The brain-stem burst generators guarantee optimum signal to ensure rapid saccadic velocity, while the neural integrator, by mathematically integrating the saccadic pulse, facilitates stable gaze holding. Reciprocal innervations that ensure rapid saccadic velocity are prone to inherent instability leading to saccadic oscillations. In contrast, suboptimal function of the burst generators causes slow saccades. Impaired error correction, either at the cerebellum or the inferior olive, leads to impaired saccade adaptation and ultimately saccadic dysmetria and oculopalatal tremor. Impairment in the function of neural integrator causes nystagmus. CONCLUSION: Neurophysiology of saccades, gaze holding, and their deficits are well recognized. These principles can be implemented to define novel therapeutic and rehabilitation approaches. PMID- 23648605 TI - Evaluation and treatment of vestibular dysfunction in children. AB - INTRODUCTION: The effect of vestibular dysfunction since birth is more debilitating than that attained later in life, and unlike adults, children with vestibular dysfunction since or shortly after birth do not recover function without intervention. PURPOSE: The purpose of this report is to provide an overview of the etiology of vestibular dysfunction in children as well as the related impairments, and to describe testing methods and evidence based interventions to ameliorate the vestibular related impairments in children. SUMMARY: In recent years, investigations have revealed that vestibular dysfunction is more common in children than previously thought, with consequent impairments in motor development, balance and reading abilities. The dysfunction may be due to central or peripheral lesions, each with distinct presentation of symptoms and test results. Common etiologies and clinical presentation of vestibular dysfunction in children are reviewed; appropriate screening and diagnostic techniques and efficacious medical and rehabilitation interventions are presented. CONCLUSION: Despite advances in clinical and diagnostic testing of vestibular function in children and infants, testing of vestibular function is not typically done. Comprehensive testing of signs and symptoms is critical for diagnosis and implementation of appropriate interventions. PMID- 23648606 TI - Vestibular rehabilitation following mild traumatic brain injury. AB - INTRODUCTION: Vertigo, dizziness, and imbalance are a symptom complex that is commonly found following concussion. Early metabolic changes following concussion may lead to worsening of the injury and symptoms in individuals not properly managed from the outset. When symptoms do not recover spontaneously, skilled vestibular rehabilitation can be an effective modality in an attempt to normalize the individual's vestibular responses. PURPOSE: The purpose of this review is to appraise the current and accepted methods available to the skilled clinician in quantifying and treating vestibular dysfunction following concussion. Incidence and prognostic indicators will be reviewed along with common barriers to recovery. SUMMARY: Vestibular Rehabilitation following concussion utilizes similar tools and techniques employed when treating those solely with peripheral pathology. The clinician must not only have a solid understanding of when and why certain exercises are required, but also be willing to accept that less exercise may be indicated in this population. As injury to the system following mild traumatic brain injury can include both peripheral and central structures, the duration of therapy and the time to recovery may be prolonged. Co-morbidities including cognitive and behavioral issues, visual-perceptual dysfunction, metabolic dysfunction, and autonomic dysfunction may hamper the effectiveness of the traditional Vestibular Rehabilitation approach. As successful treatment does not occur in a vacuum, working closely with other disciplines well versed in treating these co-morbid issues will help the individual to obtain optimal recovery. CONCLUSION: Vestibular Rehabilitation is an effective modality for managing dizziness, vertigo, and imbalance following concussion. Careful consideration of the acuity of the injury, along with effective management of co morbid conditions will optimize the result. PMID- 23648607 TI - Pharmacology of balance and dizziness. AB - INTRODUCTION: Dizziness and vertigo encompass a spectrum of balance-related symptoms caused by a variety of etiologies. Balance is affected by many systems: proprioceptive pathways, and visual, cerebellar, vestibulocochlear, and vascular/vasovagal systems. Treatment includes antihistamines, antiemetics, benzodiazepines, anti-inflammatory, anti-Meniere's, anti-migraine, antidepressants, anticonvulsants, and aminopyridines. Many medications may cause these balance-related symptoms. Onset characteristics differ and may be reversible or irreversible. Ototoxic drugs may affect the cochlea, the vestibular system, or both. Medications, whether at "therapeutic" or toxic doses, have a spectrum of side effects, depending on the medication and individual. PURPOSE: The section on drugs that treat dizziness and balance deficiencies was divided to elaborate on medications by classes and etiology specific treatment. Drugs with potential to cause balance-related symptoms were chosen to elaborate on specific medical issues encountered in rehabilitation. Background on advantages of certain drugs and methods to minimize adverse effects are reviewed. SUMMARY: Effective treatment depends on generating an accurate diagnosis, using the appropriate drug, appropriate dosage, and for an appropriate duration. For every medication, there is a spectrum of side effects at "therapeutic" and toxic doses, depending on the medication and individual. CONCLUSION: Practitioners must ensure correct diagnoses and cater their treatments to the patients' clinical scenario and medical units' capacities. PMID- 23648608 TI - Vestibular and balance treatment of the concussed athlete. AB - OBJECTIVES: The purpose of this chapter is to provide an update on the clinical management of vestibular and balance dysfunction in a concussed athlete with a focus on diagnosis, initial work-up, and initial and continuing management. Although much is still unknown about the etiology of vestibular and balance dysfunction in a concussed athlete, we briefly review current theories about neural pathophysiology to help link proposed treatment methodologies. INTRODUCTION: The treatment and management of vestibular and balance dysfunction in concussed athletes requires a multidisciplinary approach and is based on continuous reassessment of the presenting symptoms. The clinical challenge toward managing persistent symptoms of the post-concussive athlete is discerning whether a set of symptoms match diagnostic testing and whether further neurological work up is necessary. Because there are no discrete time boundaries to make such judgment calls, we offer a guide to help with the difficult clinical decisions necessary to treat the post-concussive athlete. METHODS: Literature search was performed using the following keywords: Vestibular and balance dysfunction, concussion, concussed athlete and treatment, vestibular rehabilitation therapy. Original research studies, literature reviews, and clinical guidelines were reviewed between 1997 and 2012, with the majority of articles dating beyond 2004. Although we acknowledge that post-concussive states lie within a continuum, we decided to divide treatment and management into three stages: time after initial impact, recovery, and prolonged recovery. RESULTS: In post-concussive athletes, impairments in balance may exist as a result of transmitted force to peripheral and central neural substrates that integrate sensory information and coordinate motor function. Corroborative information, clinical examination, neuropsychological testing, and continual reassessment are means to determine severity of dysfunction and track clinical course and resolution of symptoms. Persistence of symptoms beyond initial impact may require medication trials or adjustments that are tailored to the patient's medical history and/or neurocognitive rehabilitative techniques such as vestibular rehabilitation therapy to prevent progression of neurologic sequelae. Prolonged recovery of more than six months may require neurological consultation. CONCLUSION: Concussion management and treatment of vestibular and balance impairments in athletes should be assessed in a stepwise manner, from initial impact to resolution of symptoms. If symptoms are prolonged, impaired neuronal mechanisms or irreversible cerebral damage may underlie persistent symptoms and cognitive deficits seen in neurocognitive testing. Management protocols are currently focused on individualized assessment of neurocognitive assessment and comprehensive symptomatic evaluation (Reddy et al., 2008). It is widely accepted that neurocognitive and resolution of concussion-induced symptoms must be resolved prior to returning to sport or play and therefore, the athlete should be reassessed and treated until symptoms resolved. PMID- 23648609 TI - Evaluation of a computer-based neuropsychological training in children with attention-deficit hyperactivity disorder (ADHD). AB - BACKGROUND: We report the effects of a computer-based neuropsychological training in children with Attention-Deficit Hyperactivity Disorder (ADHD). We hypothesized that a specific training focusing on attentional dysfunction would result in an improvement of inattention, observable in test performance, behavior and performance during experimental school lessons and in parent and teacher ratings of the related core symptom. METHOD: We chose a within-subject-control-design with a 4 week baseline period and subsequent 12 to 15 weekly training-sessions. 30 children (6 to 13 years old) with a diagnosis of ADHD (ICD 10: F 90.0) and no other comorbidities participated in the study. RESULTS: The training revealed significant improvement in training parameters of the neuropsychological training and in the symptoms of inattention and deportment as rated during experimental school lessons. However, generalization of training effects as measured by parent and teacher ratings was not detected. CONCLUSIONS: We conclude that neuropsychological training could be helpful as one adjunct module in the complex treatment of ADHD but to prove clinical value, similar training programs must focus more strongly on individually existing neuropsychological deficits. Training programs should be more intensive and should eventually be combined with home based training access. PMID- 23648610 TI - Effectiveness of foot wedge and carrying weighted bag on loading the paretic lower limb in children with hemiparetic cerebral palsy. AB - AIMS: To investigate the effect of foot wedge and carrying weighted bag on loading the paretic lower limb in children with hemiparetic CP. DESIGN: Cross sectional study. PARTICIPANTS: A convenient sample of 18 ambulant children with spastic hemiparetic CP was evaluated. Fifteen matched normal children acted as a control group. METHODS: Using two calibrated scales, measurements of weight supported on each lower limb were obtained under four different standing conditions. RESULTS: During quiet standing, the percentage of weight supported on the paretic limb was 35.59% with symmetry index equals 0.57. Standing with the non-paretic foot is placed on a lateral foot wedge, was the best condition that increased the percentage of weight supported on the paretic limb to 47.18% and improved the symmetry index to 0.90. Non-significant improvement of symmetry index 0.61 was recorded when carrying a weighted bag with the paretic hand, but carrying with the non-paretic hand unnecessarily loads the non-paretic limb and further decreases the symmetry index to 0.49. CONCLUSIONS: Using a lateral foot wedge beneath the non-paretic foot and carrying a weighted bag with the paretic hand improve the loading function of the paretic limb and relief the non-paretic limb from overloading. PMID- 23648611 TI - Association between BDNF-196 G>A and BDNF-270 C>T polymorphisms, BDNF concentration, and rTMS-supported long-term rehabilitation outcome after ischemic stroke. AB - BACKGROUND: The efficacy of rehabilitation in ischemic stroke patients likely varies because of brain plasticity. One of the main neurotrophins in the central nervous system is brain-derived neurotrophic factor (BDNF). OBJECTIVES: This study aimed to determine allelic and genotypic distribution of BDNF-196 G>A and 270 C>T polymorphisms, and to assess the impact of repetitive transcranial magnetic stimulation (rTMS) on serum BDNF concentrations measured before rehabilitation, after the first 6 h of rehabilitation, and after 3 weeks of rehabilitation. METHODS: Twenty-six patients with hand paresis and 20 with aphasia were randomly assigned to treatment with rTMS or sham stimulation (placebo group). RESULTS: In men with aphasia, after the first 6 h of rTMS supported rehabilitation, BDNF concentration was lower among rTMS-treated patients than placebo-treated patients. A similar difference was observed in women with aphasia after 3 weeks of rTMS-supported rehabilitation. No significant differences in serum BDNF concentration were observed in patients with different BDNF-196 G>A or -270 C>T genotypes. During the observation period, BDNF concentration did not differ significantly between patients who improved and those who did not. DISCUSSION: One possible explanation for the observed difference between rTMS-stimulated and sham-stimulated patients is the suppression of BDNF production by rTMS in the healthy brain hemisphere. PMID- 23648612 TI - Motor outcome prediction using diffusion tensor tractography of the corticospinal tract in large middle cerebral artery territory infarct. AB - BACKGROUND: Middle cerebral artery (MCA) territory infarct is the most common type of cerebral vascular territory infarct. Accurate prediction of motor outcome is important for stroke rehabilitation. OBJECTIVES: We conducted an investigation of prognostic factors of motor outcome in patients with a large MCAterritory infarction, using diffusion tensor tractography (DTT) of the corticospinal tract (CST). METHODS: A total of 37 consecutive hemiparetic patients with a large MCA territory infarct were recruited for this study; DTT was performed within 5-30 days after onset. Patients were classified into three groups according to DTT findings: in group A - CST integrity was preserved around infarct regions, in group B - CSTs were discontinuous, and, in group C - the upper ends of CSTs did not reach infarcted regions. Fractional anisotropy (FA) ratio of the affected CST (versus the unaffected ipsilateral CST) was calculated, and evaluation of motor function was performed using the Motricity Index (MI), modified Brunnstrom classification (MBC) score, and the functional ambulation category (FAC) score at onset and at six months after onset. RESULTS: Significantly greater changes in motor function (MI, MBC, and FAC) were observed between onset and six months post onset in group A, compared with groups B and C (p < 0.05). However, no significant difference was observed between groups B and C (p > 0.05). FA ratios showed positive correlation with six-month MIs, and scores for MBC and FAC (p < 0.05). CONCLUSIONS: Results of this study demonstrate the usefulness of early DTT findings of CSTs for prediction of motor outcome in patients with a large MCA territory infarct. PMID- 23648613 TI - Segmental muscle vibration improves reaching movement in patients with chronic stroke. A randomized controlled trial. AB - BACKGROUND: Segmental muscle vibration (SMV) has been used to improve gait and to reduce spasticity in stroke patients. No data exist about the possibility to improve upper limb motor function by using SMV. METHODS: Forty-four patients with hemiparesis following chronic stroke were randomized to an experimental (n = 24) and a control group (n = 20). Patients in the experimental group received two weeks of general physical therapy and SMV over the biceps brachii and flexor carpi ulnaris muscles of the paretic side, while those in the control group received two weeks of general physical therapy. Kinematic analysis of reaching movement was performed at baseline and two weeks after treatment ended. RESULTS: Normalized jerk, indicating the smoothness of movement, significantly improved in the experimental group, with significant difference emerging between groups at the post-treatment evaluation. Patients in the experimental group also displayed a significant improvement for mean linear velocity, mean angular velocity at shoulder, distance to target at the end of movement and movement duration. No differences emerged between baseline and post-treatment evaluations in the control group. CONCLUSIONS: when added to general physical therapy, SMV is effective in improving, in a short-term period, upper limb motor performances of reaching movement in chronic stroke patients. PMID- 23648614 TI - Change in the contractile behavior of muscle fibers in subjects with primary muscle dysfunction. AB - The mechanical and metabolic characteristics of skeletal muscle fibers can interfere with muscle contractile performance in healthy subjects. Few studies have investigated the degree of association between muscle function and muscle fiber morphology in patients with myopathy. A biopsy was obtained from the left biceps brachii muscle of 12 subjects with myopathic disorders. The relative cross sectional area of type 2 fibers and their subtypes was determined by the ATPase technique. Relative torque (RT) was calculated by dividing isokinetic elbow flexion peak torque (PT) values (90 and 180 degrees s-1) by isometric PT values. Correlations were analyzed using Spearman's coefficient (r). The relative cross sectional area of type 2b fibers was positively correlated with RT90 (r = 0.71, P = 0.009) and RT180 (r = 0.73, P = 0.007). The relative cross-sectional area of type 2a fibers showed a moderate and negative correlation with RT180 (r = -0.62, P = 0.03) and a low correlation with RT90 (r = -0.57, P = 0.05). In contrast to healthy subjects, patients with myopathy presented changes in the contractile behavior of type 2a fibers and compensatory adaptations in type 2b fibers. The results suggest that RT in combination with morphometric parameters provides data regarding muscle function in patients with myopathic disorders and can contribute to the establishment of therapeutic exercises. PMID- 23648615 TI - Effect of specialized task training of each hemisphere on interlimb transfer in individuals with hemiparesis. AB - BACKGROUND: Therapeutic concept of interlimb transfer provides very important information relevant to patients with stroke because it can be applied to help these patients recover movement skills disrupted following unilateral damage to the brain. OBJECTIVES: The purpose of this study was to determine the transfer effects for both specialized training in each hemisphere and reversed training of a specialized task. METHODS: Twenty patients (ten women and ten men) with stroke and hemiparesis participated. All participants were in Brunnstrom recovery stage five or higher for arm and hand function and had Mini-Mental State Examination scores >=25. We used a training task involving a modified static cone, modified box and block, and modified pegboard tasks. The specified-training group performed the reaching movements (based on grip, reach, and release movements) in a modified training setting in which left-handed participants began from a single starting location and proceeded to one of three target locations (1S3T condition), and the right-handed participants started form one of three starting locations and proceeded to a single target location (3S1T condition). The unspecified training group performed these movements starting under reverse-start and target conditions. RESULTS: As a result of the left-to-right limb transfer in the specified-training group differed significantly in duration from that in the pre-training group. Also, the biceps brachii and triceps (lateral head) muscles were significantly more active after performing the specified training than before. On the other hand, the activity of the upper trapezius muscle did not significantly differ after specified training compared with before training. CONCLUSION: Consequently, a symmetric transfer advantage was observed that depended on the characteristic resources of each hemisphere. The transfer of specified training from one arm to the other had a more positive influence on functional recovery than did unspecified training for patients with stroke and hemiparesis. PMID- 23648616 TI - Optimization of mirror therapy to excite ipsilateral primary motor cortex. AB - BACKGROUND: Mirror illusion therapy (mirror therapy) is based on the experimental substrate of a visual illusion of active hand movement to excite ipsilateral primary motor cortex (iM1). PURPOSE: We tested whether iM1 excitability could be modulated by enabling or disabling vision of the active hand during mirror therapy. METHOD: Motor cortical activations of healthy right-handed participants were identified by magnetoencephalography. Participants performed voluntary index finger extension of their dominant and non-dominant hands, separately, while viewing mirror reflection images of their active hand superimposed upon their hidden inactive hand. This was performed either with vision of the active hand (uncovered viewing condition) or without vision of the active hand (covered viewing condition). RESULTS: In the covered viewing condition, the iM1could be excited in all participants (n = 10) and this excitation did not differ whether the active hand was the dominant or non-dominant hand. However, in the uncovered viewing condition, dominant and non-dominant hands were able to excite iM1 only in some participants (n = 4 and n = 7, respectively). Moreover, the participants' responses to the illusion validation questionnaire revealed that the covered viewing condition could cause clearer visual illusion for the active hand than the uncovered viewing condition. CONCLUSION: Disabling vision of the active hand during mirror therapy was more effective to excite iM1 responses by creating more immersive visual illusion of the active hand. PMID- 23648617 TI - Effects of robot-guided passive stretching and active movement training of ankle and mobility impairments in stroke. AB - OBJECTIVES: To investigate the effects of controlled passive stretching and active movement training using a portable rehabilitation robot on stroke survivors with ankle and mobility impairment. METHODS: Twenty-four patients at least 3 months post stroke were assigned to receive 6 week training using the portable robot in a research laboratory (robot group) or an instructed exercise program at home (control group). All patients underwent clinical and biomechanical evaluations in the laboratory at pre-evaluation, post-evaluation, and 6-week follow-up. RESULTS: Subjects in the robot group improved significantly more than that in the control group in reduction in spasticity measured by modified Ashworth scale, mobility by Stroke Rehabilitation Assessment of Movement (STREAM), the balance by Berg balance score, dorsiflexion passive range of motion, dorsiflexion strength, and load bearing on the affected limb during gait after 6-week training. Both groups improved in the STREAM, dorsiflexion active range of motion and dorsiflexor strength after the training, which were retained in the follow-up evaluation. CONCLUSION: Robot-assisted passive stretching and active movement training is effective in improving motor function and mobility post stroke. PMID- 23648618 TI - Botulinum toxin in gait dysfunction due to ankle clonus: a case series. AB - OBJECTIVES: Our purpose is to assess the effectiveness of Botulinum toxin (Btx) on gait dysfunction due to ankle clonus in neurological patients. METHODS: We use a retrospective case note review of 11 patients attending the Regional Acquired Brain Injury Unit (RABIU), Musgrave Park Hospital, Belfast, Northern Ireland. All patients had received Btx for the treatment of ankle clonus. Demographic data including diagnosis and time since neurological insult was collected. Information regarding walking speed and assistance required to walk before and after Btx treatment was analysed. RESULTS: In 10 of 11 patients, walking speed was significantly improved at 4-6 weeks post Btx injections (P = 0.006) and at 14-16 weeks post Btx injections (P = 0.005). Eight patients reduced their level of dependency on assistance. Subjective improvements in levels of pain, gait pattern and 'toe clawing' were also reported. CONCLUSIONS: Our findings suggest that Botulinum toxin has a role in treating ankle clonus in neurological patients, where it interferes in gait. Walking speed and level of dependence on others improved in this group. PMID- 23648619 TI - Acoustic characteristics of vowel sounds in patients with Parkinson disease. AB - The purpose of this study was to define the acoustic voice and speech characteristics of patients with Parkinson disease (PD). Seven female patients with PD and seven female healthy controls participated in this study. Each subject was instructed to vocalize extended corner vowels (/a/, /e/, /i/, /u/) three times for at least 5 seconds at a comfortable voice loudness and tone. The voice was analyzed using the Praat program. As a result, female patients with PD showed a significant increase in jitter and noise-to-harmonics ratio (NHR). In addition, F1 and F2 among the PD patients demonstrated asymmetric centralization of unrounded vowels (/a/, /e/, /i/) in high/low/front/back positions of the tongue, consequently leading to a significant decrease in vowel space area, compared to healthy controls. This study showed the acoustic characteristics of vowel sounds not only by laryngeal variables such as abnormal jitter and NHR, but also by articulatory variables such as asymmetric centralization and reduced vowel space area in female patients with PD. Therefore, it is important to use these objective and sensitive variables to evaluate the status or severity of hypokinetic dysarthria in patients with PD. PMID- 23648620 TI - Effects of whole-body vibration training on physical function in patients with multiple sclerosis. AB - OBJECTIVE: The aim of this randomized controlled trial was to test the hypothesis that a three-week whole body vibration (WBV) training in addition to a standard rehabilitation program improves walking ability in patients with Multiple Sclerosis (MS). PATIENTS AND METHOD: Sixty patients with definite MS were randomly allocated to the intervention or control group. Training sessions were performed three times per week for three weeks. Patients adopted a moderate squat position on a vibration platform. The training sessions comprised series of 3 * 60-sec exercise sets with increasing amplitude between sessions from 1 to 2 mm. During the exercise series, the vibration platform was turned on for the intervention group and switched off for the control group. A mixed factor ANOVA was used to compare sit to stand test, timed up and go test, 10-meter walk test, and 6-min walk test data between patient groups and between baseline and follow up. RESULTS: All outcome measures improved from baseline to follow-up (P < 0.001). The 6-minute walk test showed significantly greater improvements from baseline to follow-up for the intervention than for the control group (P < 0.001). CONCLUSION: Determinants of walking ability in patients with MS that are specific to walking endurance tasks are most affected by vibration training designed to improve strength endurance. PMID- 23648621 TI - Proximal weakness due to injury of the corticoreticular pathway in a patient with traumatic brain injury. AB - BACKGROUND: The corticoreticular pathway (CRP) innervates the proximal muscles of extremities and axial muscles; therefore, it is involved in postural control and gait. We report on a patient who exhibited proximal weakness due to a CRP injury, which was evaluated using diffusion tensor tractography (DTT). METHODS: A 62-year old male patient who had been injured in a traffic accident underwent conservative management for a contusional hemorrhage in the right frontotemporal lobes, and a subdural and epidural hematoma in the right temporoparietal lobes. The patient exhibited right proximal weakness (shoulder: 3+, hip: 3+) at two weeks after onset. Findings on brain MRI revealed encephalomalactic lesions in both frontal lobes. RESULTS: Findings on DTT of the left CRP showed discontinuation at the midbrain level; in contrast, the integrities of the corticospinal tract in both hemispheres were maintained from the cerebral cortex to the medulla along the known pathway of the corticospinal tract. CONCLUSION: The proximal weakness of the right shoulder and hip observed in this patient appeared to be attributed to injury of the left CRP. PMID- 23648622 TI - Increase in functional abilities following a residential educational and neurorehabilitation programme in young adults with acquired brain injury. AB - OBJECTIVES: To characterize and determine the pre-injury and injury-related variables that are linked to the extent of functional recovery following rehabilitation at a mixed therapy and educational residential programme and whether these variables differ for traumatic brain injury (TBI) and non traumatic brain injury (nonTBI). METHODS: 106 young adults (age 16-36 years) with moderate to-severe TBI who had attended and been discharged from the centre since 2002 were included. Clients received 5 hours of education and/or therapy each day. Functional level was assessed using the FIM + FAM. Regression analysis was used to determine possible predictors of functional independence at discharge. MAIN OUTCOMES AND RESULTS: Clients with TBI and nonTBI made clinically and statistically significant improvements in their functional abilities during their neurorehabilitation. For the combined TBI and nonTBI group, FIM + FAM scores at discharge were predicted by FIM + FAM at admission and length of stay. These two predictors explained 80% of the variance in the FIM + FAM score at discharge. CONCLUSION: Both clients with TBI and nonTBI benefited from a mixed inpatient neurorehabilitation programme. This benefit was predicted by their functional abilities at admission and the length of stay. These findings are of importance as it becomes increasingly necessary to demonstrate who will benefit from residential intensive neurorehabilitation as opposed to community therapy. PMID- 23648623 TI - Just how bad is it? Comparison of the mental health of Mexican traumatic brain injury caregivers to age-matched healthy controls. AB - OBJECTIVE: To compare the mental health of family caregivers of individuals with Traumatic brain injury (TBI) to an age-matched healthy control from Guadalajara, Mexico. SETTING: Hospital Civil Fray Antonio Alcade, a public medical facility in Guadalajara, Mexico. PARTICIPANTS: Ninety family caregivers of individuals with TBI and 89 healthy controls (n = 179) did not differ with respect to age, sex, marital status, education, or household income. MAIN OUTCOME MEASURES: Outcome measures assessed satisfaction with life (Satisfaction with Life Scale), depression (Patient Health Questionnaire-9), social support (Interpersonal Support Evaluation List), self-esteem (Rosenberg Self-Esteem Scale), and anxiety (State-Trait Anxiety Inventory). RESULTS: A multivariate analysis of variance found that in comparison to controls, TBI caregivers reported substantially lower mental health scores across all indices, as well as lower social support in two out of three comparisons. The effect sizes of the social support differences were small; two out of five mental health differences reached medium-sized effects; and the other three reached large-sized effects. CONCLUSIONS: Because TBI caregivers' mental health influences the quality of informal care they can provide, mental health interventions for family caregivers are an extremely important part of TBI rehabilitation in Latin America, especially considering familism as a core value in Latino culture. PMID- 23648625 TI - A less conservative method to adjust for familywise error rate in neuropsychological research: the Holm's sequential Bonferroni procedure. AB - BACKGROUND: The traditional Bonferroni method is a commonly used post hoc hypothesis test to adjust for familywise error rate inflation; however, a less well-known derivative of this test, the Holm's sequential procedure, provides an alternative method for familywise error rate correction. This less conservative approach is particularly relevant to studies investigating neuropsychological functioning because of the extent to which neuropsychological datasets tend to include interrelated outcome measures, reducing the relevance of the universal null hypothesis assumption, on which the traditional Bonferroni method relies. METHODS: Mathematical illustrations demonstrating how to compute the two adjustments are provided. The two methods are compared using a simple hypothetical dataset. RESULTS: By using the divisors (n - j + 1) in lieu of n, Holm's sequential procedure is guaranteed to never reject fewer hypotheses than the traditional Bonferroni adjustment. CONCLUSIONS: The Holm's sequential procedure corrects for Type I error as effectively as the traditional Bonferroni method while retaining more statistical power. Although the Holm's sequential procedure is more complicated to compute than the traditional Bonferroni method, the Holm's sequential procedure may be a more appropriate method for adjusting familywise error rate inflation in many types of neuropsychological research. PMID- 23648624 TI - Changes in simple visual matching task performance and physiological signals in intellectually and developmentally disabled people due to administration of highly concentrated oxygen. AB - BACKGROUND: This study attempted to identify the effect of administration of highly concentrated oxygen on simple visual matching task performance, blood oxygen saturation [SpO2 (%)], and heart rate [HR (bpm)] of intellectually and developmentally disabled people. METHODS: Nineteen intellectually and developmentally disabled people (mean age 30.6 +/- 5.7 years) participated in an experiment consisting of a simple visual matching task performed under 21% and 92% oxygen. SpO2 and HR were measured under both oxygen conditions. RESULTS: When 92% oxygen was supplied, the response time decreased, SpO2 increased, and HR decreased compared to the vales obtained using 21% oxygen. The response time decreased for subjects with a high SpO2 and HR during the simple visual matching task phase. CONCLUSION: This result supports the hypothesis that administration of highly concentrated oxygen can positively affect the cognitive performance of intellectually and developmentally disabled people. PMID- 23648626 TI - To cool or not to cool: evolution of the treatment of burns in the 18th century. AB - The 18th century represents a transitional period in evolution of surgery and burn treatment, a time just before major advances such as asepsis, burn excision and skin grafting, were to revolutionise surgical practice. The medical minds of this era first began to question the centuries of dogma and speculation that were at the heart of medicine. The evolution of the treatment of burns in this crucial time is reviewed from the perspective of two of the exceptional medical minds of that era John Hunter and James Earle. Many of their observations are still valid today and their influence would prove inspirational in ushering in modern era of burn management. PMID- 23648627 TI - In vitro regulatory models for systems biology. AB - The reductionist approach has revolutionized biology in the past 50 years. Yet its limits are being felt as the complexity of cellular interactions is gradually revealed by high-throughput technology. In order to make sense of the deluge of "omic data", a hypothesis-driven view is needed to understand how biomolecular interactions shape cellular networks. We review recent efforts aimed at building in vitro biochemical networks that reproduce the flow of genetic regulation. We highlight how those efforts have culminated in the rational construction of biochemical oscillators and bistable memories in test tubes. We also recapitulate the lessons learned about in vivo biochemical circuits such as the importance of delays and competition, the links between topology and kinetics, as well as the intriguing resemblance between cellular reaction networks and ecosystems. PMID- 23648628 TI - Cell-free platforms for flexible expression and screening of enzymes. AB - As was witnessed from PCR technology, in vitro applications of biosynthetic machinery can expand the horizon of biotechnology. Cell-free protein synthesis has emerged as a powerful technology that can potentially transform the concept of bioprocess. With the ability to harness the synthetic power of biology without many of the constraints of cell-based systems, cell-free protein synthesis enables instant creation of protein molecules from diverse sources of genetic information. Enzyme discovery and engineering is the field of particular interest among the possible applications of cell-free protein synthesis since many of the intrinsic limitations associated with traditional cell-based expression screening of enzymes can be effectively addressed. Cell-free synthesis not only offers excellent throughput in the generation of enzymes, it allows facile integration of expression and analysis of enzymes, greatly accelerating the process of enzyme discovery. This review article is thus intended to survey recent progress in cell free protein synthesis technology focused on its applications in enzyme expression and screening. PMID- 23648631 TI - Identification of the N-Methyl-D-aspartate receptor (NMDAR)-related epitope, NR2B, in the normal human ovary: implication for the pathogenesis of anti-NMDAR encephalitis. AB - N-methyl-D-aspartate receptors (NMDARs) are one type of ionotropic glutamate receptors (GluRs) and are heterotetrametric cation channels composed of NMDAR1 (NR1), NMDAR2 (NR2A, 2B, 2C or 2D) and NMDAR3 (NR3A or NR3B) subunits. The main subunits are NR1 and NR2 and their combinations are classified into several diverse forms including NR1/NR1/NR2A/NR2A, NR1/NR1/NR2B/NR2B and NR1/NR1/NR2A/NR2B. NMDARs are physiologically related to synapse development and synaptic plasticity in the central nervous system. Anti-NMDAR encephalitis is a form of autoimmune limbic encephalitis mainly affecting young women, with various manifestations including initial psychiatric symptoms, subsequent unresponsiveness, intractable generalized seizure, dysautonomia and orofacial dyskinesia. This disorder is often accompanied by ovarian teratoma that is originated from oocytes. Anti-neural antibody for the NR1/NR2 heteromer of NMDAR has been identified as a disease-specific hallmark. It has been emphasized that neural components in ovarian teratoma act as a trigger to produce anti-NMDAR antibodies, although about half of the patients with anti-NMDAR encephalitis are not associated with ovarian teratoma. To identify NMDAR-related epitopes located outside of the brain, we performed immunohistochemical examinations of normal human ovary and testis using specific antibodies against NR1, NR2A and NR2B, respectively, and found expression of the NR2B epitope in the cytoplasm of oocytes. In contrast, the testis showed no immunohistochemical reactivity. Therefore, oocytes contain NMDAR-related epitopes including NR2B. The NMDAR related epitopes in normal oocytes may cause an antigen-antibody reaction in certain pathological conditions. The presence of NR2B immunoreactivity in oocytes may account for the fact that anti-NMDAR encephalitis predominantly affects young females. PMID- 23648632 TI - A dynamic multi-organ-chip for long-term cultivation and substance testing proven by 3D human liver and skin tissue co-culture. AB - Current in vitro and animal tests for drug development are failing to emulate the systemic organ complexity of the human body and, therefore, to accurately predict drug toxicity. In this study, we present a multi-organ-chip capable of maintaining 3D tissues derived from cell lines, primary cells and biopsies of various human organs. We designed a multi-organ-chip with co-cultures of human artificial liver microtissues and skin biopsies, each a (1)/100,000 of the biomass of their original human organ counterparts, and have successfully proven its long-term performance. The system supports two different culture modes: i) tissue exposed to the fluid flow, or ii) tissue shielded from the underlying fluid flow by standard Transwell(r) cultures. Crosstalk between the two tissues was observed in 14-day co-cultures exposed to fluid flow. Applying the same culture mode, liver microtissues showed sensitivity at different molecular levels to the toxic substance troglitazone during a 6-day exposure. Finally, an astonishingly stable long-term performance of the Transwell(r)-based co-cultures could be observed over a 28-day period. This mode facilitates exposure of skin at the air-liquid interface. Thus, we provide here a potential new tool for systemic substance testing. PMID- 23648629 TI - The trade-off between wiring cost and network topology in white matter structural networks in health and migraine. AB - The human brain organization of cortical networks has optimized trade-off architecture for the economical minimization of connection distance and maximizing valuable topological properties; however, whether this network configuration is disrupted in chronic migraine remains unknown. Here, employing the diffusion tensor imaging and graph theory approaches to construct white matter networks in 26 patients with migraine (PM) and 26 gender-matched healthy controls (HC), we investigated relationships between structural connectivity, cortical network architecture and anatomical distance in the two groups separately. Compared with the HC group, the patients showed longer global distance connection in PM, with proportionally less short-distance and more medium-distance; correspondingly, the patients showed abnormal global topology in their structural networks, mainly presented as a higher clustering coefficient. Moreover, the abnormal association between these two network features was also found. Intriguingly, the network measure that combined the nodal anatomical distance and network topology could distinguish PM from HC with high accuracy of 90.4%. We also demonstrated a high reproducibility of our findings across different parcellation schemes. Our results demonstrated that long-term migraine may result in a abnormal optimization of a trade-off between wiring cost and network topology in white matter structural networks and highlights the potential for combining spatial and topological aspects as a network marker, which may provide valuable insights into the understanding of brain network reorganization that could be attributed to the underlying pathophysiology resulting from migraine. PMID- 23648633 TI - A new HPLC-based assay for the measurement of fructosamine-3-kinase (FN3K) and FN3K-related protein activity in human erythrocytes. AB - BACKGROUND: An impact on glycation, and possibly on diabetic complications, is attributed to fructosamine-3-kinase (FN3K) and its related protein (FN3K-RP) because they degrade Amadori compounds in vivo. Little is known about individual differences in FN3K-RP activity, which might contribute to an individual risk for diabetic complications. METHODS: An HPLC-based activity assay for FN3K-RP in erythrocytes with the substrate N-alpha-hippuryl-N-epsilon-psicosyllysine was developed. The activities of FN3K and FN3K-RP were also analysed in erythrocytes of 103 consecutive participants of a health-care survey amongst a high-risk group for diabetes. The potential associations of these activities with the subjects' health background (anthropometric data, glucose tolerance and HbA1c, blood lipids, history of metabolic diseases in the subjects and their families, and medication) were examined. RESULTS: The interindividual variability of FN3K-RP is less pronounced than that of FN3K [60-135 vs. 2.8-12.5 mU/g haemoglobin (Hb)]. No correlations with age, sex, body weight, blood cholesterol, or plasma glucose in an oral glucose tolerance test were observed. Subjects with kidney disease had higher activity of mainly FN3K-RP [111+/-15 vs. 98+/-18 mU/g Hb, mean+/-standard deviations (SDs), n=16 vs. 87, p=0.009], whereas subjects whose parents or siblings had a stroke showed lower FN3K activity (6.2+/-1.6 vs. 7.1+/-1.8 mU/g Hb, mean+/-SD, n=24 vs. 66, p=0.040). CONCLUSIONS: There is a likely impact of FN3K and FN3K-RP on the glycation cascade in vivo with potential positive and negative effects. The new screening method enables further studies to elucidate the function and importance of FN3K-RP. PMID- 23648634 TI - Prognostic utility of biochemical markers of cardiovascular risk: impact of biological variability. AB - BACKGROUND: Although a variety of biochemical markers are used to help predict the risk of cardiovascular disease, the prognostic utility of any marker used as a risk assessment tool is dependent on the long- and short-term biological variability that the marker shows in different individuals. METHODS: We measured total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol; triglycerides; high-sensitivity C-reactive protein (hsCRP); total fibrinogen; and gamma' fibrinogen in blood samples collected from 15 apparently healthy individuals over the course of 1 year. Repeated measures variation estimates were used to calculate short- and long-term intraclass correlation coefficients (ICC), within- and between-subject coefficients of variation (CVI and CVG, respectively), validity coefficients, and indices of individuality for each marker. RESULTS: HDL cholesterol demonstrated the lowest variability profile, with an ICC of 0.84 and CVI of 11.1 (95% CI: 8.3, 17.0). hsCRP showed the highest levels of short- and long-term within-subject variability [CVI (95% CI): 54.8 (32.8, 196.3) and 77.1 (53.3, 141.3), respectively]. Stated differently, it would require five separate measurements of hsCRP, performed on samples collected over multiple days, to provide the risk assessment information provided by a single measurement of HDL cholesterol. gamma' Fibrinogen demonstrated an ICC of 0.79 and CVI of 14.3 (95% CI: 10.6, 21.9). CONCLUSIONS: hsCRP showed very high biological variability, such that a single measurement of hsCRP lacks sufficient clinical utility to justify routine measurement. The variability profile of gamma' fibrinogen was not markedly different than HDL cholesterol, necessitating only a limited number of measurements to establish an individual's risk of cardiovascular disease. PMID- 23648636 TI - The syndrome of the "obsessive-compulsory scientist": a new mental disorder? AB - Obsessive-compulsive disorder (OCD) is the fourth most common mental disorder. Such a high prevalence inherently means that several unsuspected individuals might be affected, plausibly including several scientists who might more or less unconsciously express obsessive-compulsory (OC) activities in their routine activity. PMID- 23648635 TI - Establishment of reference values for novel urinary biomarkers for renal damage in the healthy population: are age and gender an issue? AB - BACKGROUND: Recently, a lot of research has focused on the discovery of novel renal biomarkers. Among others, the urinary kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) have been proven to be promising biomarkers in a wide variety of renal pathologies. However, little is known about the normal concentrations in urine of healthy subjects. Therefore, the goal of our study is to establish reference values for urinary KIM-1, NGAL, N acetyl-beta-D-glucosamidase (NAG), and cystatin C in a healthy population, taking into account possible effects of age and gender. METHODS: We collected urine samples from 338 healthy, nonsmoking subjects between 0 and 95 years old. Subjects with elevated alpha1-microglobulin values were excluded. Next to the urinary concentrations of KIM-1, NGAL, NAG, and cystatin C, we measured urinary creatinine and specific gravity to correct for urinary dilution. The possible effect of age and gender on the four urinary biomarkers was investigated, and the reference values were established. RESULTS: For the absolute urinary concentrations of the biomarkers, age had a significant effect on all the biomarkers, except for cystatin C, whereas gender significantly affected all four of them, except for NAG. The normalization of biomarkers for creatinine and specific gravity had an effect on the correlation between the biomarkers on one hand and age and gender on the other. CONCLUSIONS: In conclusion, age and gender had different effects on KIM-1, NGAL, NAG, and cystatin C. Based on this knowledge, age- and gender-specific reference values for KIM-1, NGAL, NAG, and cystatin C were established. PMID- 23648637 TI - ABO blood group: old dogma, new perspectives. AB - Human blood group antigens are glycoproteins and glycolipids expressed on the surface of red blood cells and a variety of human tissues, including the epithelium, sensory neurons, platelets and the vascular endothelium. Accumulating evidence indicate that ABO blood type is implicated in the development of a number of human diseases, including cardiovascular and neoplastic disorders. In this review, beside its physiologic role in immunohematology and transfusion medicine, we summarize the current knowledge on the association between the ABO blood group and the risk of developing thrombotic events and cancers. PMID- 23648639 TI - Managing risk and marginalizing identities: on captivity and citizenship. Introduction. PMID- 23648638 TI - Suppression of coronary atherosclerosis by helix B surface Peptide, a nonerythropoietic, tissue-protective compound derived from erythropoietin. AB - Erythropoietin (EPO), a type I cytokine originally identified for its critical role in hematopoiesis, has been shown to have nonhematopoietic, tissue-protective effects, including suppression of atherosclerosis. However, prothrombotic effects of EPO hinder its potential clinical use in nonanemic patients. In the present study, we investigated the antiatherosclerotic effects of helix B surface peptide (HBSP), a nonerythropoietic, tissue-protective compound derived from EPO, by using human umbilical vein endothelial cells (HUVECs) and human monocytic THP-1 cells in vitro and Watanabe heritable hyperlipidemic spontaneous myocardial infarction (WHHLMI) rabbits in vivo. In HUVECs, HBSP inhibited apoptosis (~70%) induced by C-reactive protein (CRP), a direct mediator of atherosclerosis. By using a small interfering RNA approach, Akt was shown to be a key molecule in HBSP-mediated prevention of apoptosis. HBSP also attenuated CRP-induced production of tumor necrosis factor (TNF)-alpha and matrix metalloproteinase-9 in THP-1 cells. In the WHHLMI rabbit, HBSP significantly suppressed progression of coronary atherosclerotic lesions as assessed by mean cross-sectional stenosis (HBSP 21.3 +/- 2.2% versus control peptide 38.0 +/- 2.7%) and inhibited coronary artery endothelial cell apoptosis with increased activation of Akt. Furthermore, TNF-alpha expression and the number of M1 macrophages and M1/M2 macrophage ratio in coronary atherosclerotic lesions were markedly reduced in HBSP-treated animals. In conclusion, these data demonstrate that HBSP suppresses coronary atherosclerosis, in part by inhibiting endothelial cell apoptosis through activation of Akt and in association with decreased TNF-alpha production and modified macrophage polarization in coronary atherosclerotic lesions. Because HBSP does not have the prothrombotic effects of EPO, our study may provide a novel therapeutic strategy that prevents progression of coronary artery disease. PMID- 23648640 TI - Effects of disulfiram on QTc interval in non-opioid-dependent and methadone treated cocaine-dependent patients. AB - OBJECTIVES: Methadone and cocaine are each known to prolong the QTc interval, a risk factor for developing potentially fatal cardiac arrhythmias. Disulfiram, often administered in the context of methadone maintenance to facilitate alcohol abstinence, has been shown to have some efficacy for cocaine dependence. Disulfiram has differential effects on cocaine and methadone metabolism, but its impact on methadone- or cocaine-induced changes in QTc interval is unclear. Thus, the effects of disulfiram on QTc interval in a subset of cocaine-dependent patients participating in a 14-week, randomized, double-blind, placebo-controlled clinical trial of disulfiram were prospectively determined. METHODS: Opioid dependent participants were inducted onto methadone (weeks 1-2; MT) and both MT and non-opioid-dependent (UT) participants were randomized to receive disulfiram (weeks 3-14) at one of the following doses: 0, 250, 375, or 500 mg/d. Electrocardio-grams were obtained before study entry and during weeks 2 and 4. RESULTS: Complete QTc-interval data in 23 MT and 18 UT participants were analyzed. QTc interval tended to be higher in MT participants relative to UT participants, regardless of disulfiram dose and time point, but disulfiram did not differentially alter QTc interval. QTc interval was, however, significantly greater in participants with recent cocaine use than in those with no recent use. CONCLUSIONS: These results suggest that cocaine use and possibly MT status, but not disulfiram, are risk factors for QTc prolongation. PMID- 23648642 TI - Residential addiction treatment for injection drug users requiring intravenous antibiotics: a cost-reduction strategy. AB - OBJECTIVES: Injection drug users (IDUs) are prone to developing infections and complications requiring prolonged intravenous (IV) antibiotic treatment. Our institution's unique multidisciplinary approach provides special consideration and successful management of IDUs in a residential addiction treatment facility with nurse-administered IV antibiotics. Our hypothesis is that hospital costs can be reduced by providing both IV antibiotics and addiction treatment in a community residential treatment setting outside the hospital. METHODS: A retrospective chart review was performed for inpatients requiring prolonged antibiotic treatment who were admitted to the university teaching hospital between January 2006 and December 2011 and were treated at the residential addiction treatment facility. Data were gathered to characterize this population of patients and estimate cost savings. RESULTS: A total of 205 patients were sent to the residential addiction treatment facility from 2006 to 2011. The majority were African American, men, and in their early forties. Heroin was the most popular injected substance, but most patients were polysubstance users, including alcohol and tobacco. The most common infections were osteomyelitis and septic arthritis. There was a 73% completion rate of antibiotic treatment in this program. The relapse rate for return to illicit drug use was at least 32%. This program has resulted in a significant cost savings of $2.43 million in a 6-year period. CONCLUSIONS: The program saved $2.43 million over 6 years for the health care system by reducing hospital length of stay with safe and appropriate discharge planning for IDUs with infections requiring long-term IV antibiotics. PMID- 23648643 TI - Immunity to bacterial infection in the chicken. AB - Bacterial infections remain important to the poultry industry both in terms of animal and public health, the latter due to the importance of poultry as a source of foodborne bacterial zoonoses such as Salmonella and Campylobacter. As such, much focus of research to the immune response to bacterial infection has been to Salmonella. In this review we will focus on how research on avian salmonellosis has developed our understanding of immunity to bacteria in the chicken from understanding the role of TLRs in recognition of bacterial pathogens, through the role of heterophils, macrophages and gammadelta lymphocytes in innate immunity and activation of adaptive responses to the role of cellular and humoral immunity in immune clearance and protection. What is known of the immune response to other bacterial infections and in particular infections that have emerged recently as major problems in poultry production including Campylobacter jejuni, Avian Pathogenic Escherichia coli, Ornithobacterium rhinotracheale and Clostridium perfringens are discussed. PMID- 23648644 TI - Intracellular infections in Drosophila melanogaster: host defense and mechanisms of pathogenesis. AB - The fruit-fly Drosophila melanogaster has emerged as a powerful model to study innate immunity against intracellular pathogens. To combat infection, the fly relies on multiple lines of defense, many of which are shared with mammals and arthropod vectors of human diseases. In addition to conserved immune pathways, the ease of performing sophisticated genetic screens has allowed the identification of novel host immune factors and novel pathogen virulence factors. Recently, some groups have exploited this to simultaneously analyze the host and pathogen genetics of intracellular infection. This review aims to unravel the Drosophila immune response against intracellular pathogens, highlighting recent discoveries. PMID- 23648645 TI - Antigen targeting to APC: from mice to veterinary species. AB - Antigen delivery to receptors expressed on antigen presenting cells (APC) has shown to improve immunogenicity of vaccines in mice. An enhancement of cytotoxic T lymphocyte (CTL), helper T cell or humoral responses was obtained depending on the type of APC and the surface molecule targeted. Although this strategy is being also evaluated in livestock animals with promising results, some discrepancies have been found between species and pathogens. The genetic diversity of livestock animals, the different pattern of expression of some receptors among species, the use of different markers to characterize APC in large animals and sometimes the lack of reagents make difficult to compare results obtained in different species. In this review, we summarize the data available regarding antigen targeting to APC receptors in cattle, sheep and pig and discuss the results found in these animals in the context of what has been obtained in mice. PMID- 23648646 TI - Chicken immunoregulatory Ig-like receptor families: an overview and expression details on ggTREM-A1. AB - Paired immunoregulatory receptors facilitate the coordination of the immune response at the cellular level. In recent years, our group characterized chicken homologues to mammalian immunoregulatory Ig-like receptor families. The first part of this review focuses on the current progress on chicken immunoregulatory Ig-like receptor families. One of these receptors is gallus gallus TREM-A1, which was described as the only member of the chicken TREM family with activating potential. The second part of this review presents a study initiated to further characterize ggTREM-A1 expression. For this purpose we established real-time RT PCR and generated a specific mab to analyze the expression profile of ggTREM-A1 on mRNA and protein level, respectively. GgTREM-A1 mRNA was predominantly expressed in macrophages, but was also detected in brain, bone marrow, bursa, thymus, spleen and PBMC. Analyzing ggTREM-A1 surface expression by mab staining validated the expression on macrophages. Additionally, we showed high expression on blood monocytes, heterophils and NK cells and on monocytes isolated from bone marrow. Moreover, we detected ggTREM-A1 protein also on thrombocytes, B and T cell subsets, but antigen expression seemed to be lower and more variable in these cells. Immunohistochemistry of chicken brain tissue, combining ggTREM-A1 mab and various markers specific for various brain cell subsets showed expression of ggTREM-A1 on microglial cells, but also on neurons, astrocytes and oligodendrocytes. In conclusion, ggTREM-A1 is expressed on a variety of cells, relevant for the immune system, possibly combining physiological function of different mammalian TREM. PMID- 23648648 TI - Microencapsulation of tannic acid for oral administration to inhibit carbohydrate digestion in the gastrointestinal tract. AB - The prevalence of diabetes mellitus and obesity is rapidly rising worldwide. Recently, there is increasing evidence that phytochemicals such as polyphenols in our diet could directly inhibit the activities of key digestive enzymes, representing a novel method of controlling and preventing diabetes mellitus and obesity. More research is required to determine how to effectively utilize phytochemicals within the gastrointestinal (GI) tract to obtain maximum inhibition of digestive enzymes. This study investigated the inhibition efficiency of tannic acid (TA) on alpha-amylase as compared with other potential inhibitors using an in vitro method. The inhibition mode and kinetics were studied. The results showed that tannic acid (TA) is more effective in inhibiting alpha-amylase than a commercial starch blocker (Phase 2 Starch Blocker), and some selected flavonoids and polyphenols including quercetin, rutin, and polyphenon from green tea. It is also found that inhibition of alpha-amylase by TA in the GI tract is difficult if administered orally due to the non-specific and reversible noncompetitive interaction between tannic acid and alpha-amylase or other proteins. Accordingly, a pH-sensitive delivery system using calcium-alginate microspheres encapsulating tannic acid was successfully developed for oral administration to inhibit carbohydrate digestion in the GI tract. The encapsulated TA in calcium-alginate microspheres could be protected from the proteins in the stomach, and sustain release and inhibit alpha-amylase activity in the small intestine. PMID- 23648641 TI - Human immunodeficiency virus infection heightens concurrent risk of functional dependence in persons with long-term methamphetamine use. AB - OBJECTIVES: Disability among long-term methamphetamine (MA) users is multifactorial. This study examined the additive adverse impact of human immunodeficiency virus (HIV) infection, a common comorbidity in MA users, on functional dependence. METHODS: A large cohort of participants (N = 798) stratified by lifetime MA-dependence diagnoses (ie, MA+ or MA-) and HIV serostatus (ie, HIV+ or HIV-) underwent comprehensive baseline neuromedical, neuropsychiatric, and functional research evaluations, including assessment of neurocognitive symptoms in daily life, instrumental and basic activities of daily living, and employment status. RESULTS: Independent, additive effects of MA and HIV were observed across all measures of functional dependence, independent of other demographic, psychiatric, and substance-use factors. The prevalence of global functional dependence increased in the expected stepwise fashion across the cohort, with the lowest rates in the MA-/HIV- group (29%) and the highest rates in the MA+/HIV+ sample (69%). The impact of HIV on MA-associated functional dependence was moderated by nadir CD4 count, such that polysubstance use was associated with greater disability among those HIV-infected persons with higher but not lower nadir CD4 count. Within the MA+/HIV+ cohort, functional dependence was reliably associated with neurocognitive impairment, lower cognitive reserve, polysubstance use, and major depressive disorder. CONCLUSIONS: HIV infection confers an increased concurrent risk of MA-associated disability, particularly among HIV-infected persons without histories of immune compromise. Directed referrals, earlier HIV treatment, and compensatory strategies aimed at counteracting the effects of low cognitive reserve, neurocognitive impairment, and psychiatric comorbidities on functional dependence in MA+/HIV+ individuals may be warranted. PMID- 23648650 TI - Wireless laser range finder system for vertical displacement monitoring of mega trusses during construction. AB - As buildings become increasingly complex, construction monitoring using various sensors is urgently needed for both more systematic and accurate safety management and high-quality productivity in construction. In this study, a monitoring system that is composed of a laser displacement sensor (LDS) and a wireless sensor node was proposed and applied to an irregular building under construction. The subject building consists of large cross-sectional members, such as mega-columns, mega-trusses, and edge truss, which secured the large spaces. The mega-trusses and edge truss that support this large space are of the cantilever type. The vertical displacement occurring at the free end of these members was directly measured using an LDS. To validate the accuracy and reliability of the deflection data measured from the LDS, a total station was also employed as a sensor for comparison with the LDS. In addition, the numerical simulation result was compared with the deflection obtained from the LDS and total station. Based on these investigations, the proposed wireless displacement monitoring system was able to improve the construction quality by monitoring the real-time behavior of the structure, and the applicability of the proposed system to buildings under construction for the evaluation of structural safety was confirmed. PMID- 23648649 TI - Microbial biosensors: engineered microorganisms as the sensing machinery. AB - Whole-cell biosensors are a good alternative to enzyme-based biosensors since they offer the benefits of low cost and improved stability. In recent years, live cells have been employed as biosensors for a wide range of targets. In this review, we will focus on the use of microorganisms that are genetically modified with the desirable outputs in order to improve the biosensor performance. Different methodologies based on genetic/protein engineering and synthetic biology to construct microorganisms with the required signal outputs, sensitivity, and selectivity will be discussed. PMID- 23648654 TI - [Diagnosis and therapy of failed back syndrome]. PMID- 23648652 TI - Adherence associated with oral medications in the treatment of spasticity. AB - OBJECTIVE: To examine adherence to baclofen, tizanidine, and dantrolene (U.S. Food and Drug Administration-approved oral spasticity medications), and identified determinants of adherence. DESIGN: A retrospective administrative claims data analysis that used medical and pharmacy claims data and enrollment information from a large, national U.S. health plan. SUBJECTS AND METHODS: The subjects were commercial health plan members who initiated treatment on baclofen, tizanidine, or dantrolene from January 1, 2004, through September 30, 2009, and who had stroke, spinal cord injury, traumatic brain injury, cerebral palsy, or multiple sclerosis. Descriptive and logistic regression statistical analyses were performed. MAIN OUTCOME MEASUREMENTS: Outcomes were adherence, measured as continuous medication possession ratio (MPR) and as a binary indicator (MPR >=0.80, adherent; MPR <0.80, nonadherent), change in oral spasticity medication, and use of nonoral spasticity therapy. RESULTS: The study population included 2840 subjects. Adherence overall was poor: the range of mean unadjusted MPR values was 0.10-0.50, which indicated that, at best, the subjects were adherent to their index spasticity medications for 50% of their treatment periods. Unadjusted overall MPRs for baclofen and tizanidine were 20.4% and 9.1%, respectively. Fewer than 5% of subjects changed oral spasticity medications. The results of logistic regression to identify determinants of adherence showed that subjects treated with tizanidine versus baclofen had 37.4% lower odds of adherence and that subjects with traumatic brain injury versus stroke had 77.5% lower odds of adherence. The odds of adherence increased with age and with preindex contracture or decubitus ulcer. CONCLUSIONS: Adherence to oral spasticity medication was poor irrespective of index spasticity medication or condition. Results from this study indicated that physicians cannot assume that patients are adherent to prescribed oral spasticity medications. A more complete understanding of the reasons behind nonadherence is required. PMID- 23648655 TI - [The efficiency of cilostazol for cerebral vasospasm following subarachnoid hemorrhage]. AB - Delayed ischemic deficit following subarachnoid hemorrhage(SAH)is a major source of morbidity and mortality after rupture of an intracranial aneurysm. Once symptomatic cerebral vasospasm has occured, available treatments do not provide good outcomes for all patients. Symptomatic vasospasm results in serious sequelae for 10-15% of patients and the etiology and pathogenesis remain unclear. Cilostazol is a specific inhibitor of cAMP(cyclic adenosine monophosphate)phosphodiesterase, and is used for treating ischemic symptoms of peripheral vascular disease. Cilostazol has various actions, such as inhibiting vascular smooth muscle proliferation, and increasing nitric oxide(NO)levels derived from endothelial cells. The present study included 81 patients with SAH caused by ruptured cerebral aneurysms treated in two hospitals between June, 2008 and September, 2009. All patients were treated with clipping surgery, and were classified into two groups: 25 patients who received cilostazol from postoperative day 1 to 14 or 28; and 56 control patients. Clinical symptoms due to cerebral vasospasm and frequency of severe spasm were compared between each of the groups. The frequencies of severe spasm appearing on angiography(age>65)and symptomatic cerebral vasospasm were lower in the cilostazol group than in controls. These findings suggest that cilostazol may prevent symptomatic cerebral vasospasm after subarachnoid hemorrhage. PMID- 23648657 TI - [A case of infected subdural hematoma accompanied by cerebral infarction]. AB - Infected subdural hematoma(ISH)is a rare disease caused by hematogenous infection of a preexisting subdural hematoma. We report a rare case of ISH accompanied by cerebral infarction. A 76-year-old man who had suffered a closed head injury 3 months before presented fever, headache and left hemiparesis during the medical treatment of acute cholangitis and obstructive jaundice with pancreatic cancer at the department of surgical gastroenterology. At the consultation, computed tomography(CT)scan indicated right chronic subdural hematoma. We performed a burr hole opening surgery on the same day. Abscess and hematoma was aspirated from the subdural space, and methicillin-resistant Staphylococcus aureus(MRSA)was detected in this specimen. Thus the diagnosis of the infected subdural hematoma was confirmed. However, despite the antibiotics therapy, follow-up CT showed a low-density area close to the residual abscess, which suggested cerebral infarction. Cerebral angiography showed a vasospasm at the cortical segment of the right middle cerebral artery near the residual abscess. Eventually we carried out a small craniotomy to evacuate the abscess. Our case showed that prompt surgical treatment is required in case of ISH and the whole hematoma and abscess should be removed as soon as possible with an image diagnosis and an additional surgical operation. PMID- 23648656 TI - [Harvest of the superficial temporal artery using the Lone Star Retractor System TM: technical note]. AB - Extracranial-intracranial(EC-IC)bypass is an important method of treating ischemic stroke and intracranial disease requiring sacrifice of the parent artery. The most commonly used donor artery for EC-IC bypass surgery is the superficial temporal artery(STA). But there are few reports of details of harvest methods of the STA. We describe our harvest methods of the STA using the Lone Star Retractor SystemTM. After draping, the Lone Star Retractor SystemTM is placed on the head. Skin incision is on the parietal branch of the STA. Under the surgical microscope, the dermis is cut by a scalpel from the distal side of the STA. The incised wound was tensioned by the blunt hooks(elastic stay)of the Lone Star Retractor SystemTM. Connective tissue around the STA was dissected and cut by a high voltage bipolar coagulator from the distal to the proximal side of the STA. The advantage of using of The Lone Star Retractor SystemTM for the STA harvest is that, using a surgical microscope, it is easy to set the elastic stay on the wound. PMID- 23648658 TI - [Internal coil trapping for a doughnut-shaped giant intracranial aneurysm: a case report]. AB - We present the case of a 65-year-old woman with a doughnut-shaped giant intracranial aneurysm that was treated using endovascular internal coil trapping. She presented with a history of headache. Magnetic resonance imaging and cerebral angiography showed a doughnut-shaped giant intracranial aneurysm in the intracavernous portion of the internal cerebral artery. A microcatheter was placed distal to the internal cerebral artery, along the wall of the aneurysm. The aneurysm was then occluded by internal coil trapping without bypass surgery, because the outcome of the balloon occlusion test was acceptable. The aneurysm was completely obliterated without causing permanent neurological deficits. PMID- 23648659 TI - [A primary epileptogenic tuber revealed after corpus callosotomy in a patient with tuberous sclerosis complex and multiple tubers]. AB - Identification of primary epileptogenic tuber is often challenging in patients with bilateral multiple tubers in tuberous sclerosis complex. We report a 3 year old girl with tuberous sclerosis complex presenting with intractable epilepsy and multiple tubers, who was successfully treated by corpus callosotomy and subsequent resective surgery. She initially presented with West syndrome which was intractable to ACTH therapy and multiple antiepileptic medications. Her EEG was characterized by generalized and multifocal spikes, and by non-focal changes at seizure onset. Ictal single photon emission computed tomography(SPECT)showed no focal hyperperfusion. Total corpus callosotomy was performed to alleviate her drop attacks. Post-operatively, interictal spikes were completely lateralized to the right hemisphere. Since her seizures were still kept uncontrolled with medications, second pre-surgical evaluation was planned and ictal SPECT disclosed focal hyperperfusion at a tuber in the right frontal lobe. After complete resection of the right frontal tuber, she was completely seizure free on antiepileptic medications for 1 year with no additional neurological deficits. Generalized or multifocal electroencephalographic(EEG)spikes are occasionally lateralized to one hemisphere after corpus callosotomy, which may help identifying the primary epileptogenic focus. Repeat pre-surgical evaluation is important after corpus callosotomy in patients with generalized or multifocal epileptiforms in EEG. PMID- 23648660 TI - [A case of a paraspinal arteriovenous fistula presenting with retroperitoneal hemorrhage treated by staged transarterial and transvenous embolization]. AB - We report a rare case of a paraspinal arteriovenous fistula(AVF)treated by combined transarterial and transvenous embolization(TAE/TVE). A 72-year-old woman was admitted after a traffic accident. Abdominal enhanced CT disclosed pre existing large varices at the L3-L4 level in the right retroperitoneum with multiple feeding arteries and veins draining into the extradural venous plexus in the spinal canal. The lesion was diagnosed as a paraspinal AVF. Four days later, the patient went into a state of shock. Emergency abdominal CT showed retroperitoneal hemorrhage due to rupture of the varix. TAE of the feeders from the right L1-L4 arteries was performed, and rebleeding from the varix was prevented. Three months later, follow-up CTA showed regrowth of the AVF, and TVE was performed. Two microcatheters were navigated transvenously into the varix, and detachable coils were delivered into the small compartment just downstream to the shunts, leading to complete obliteration. We conclude that transarterial flow reduction followed by occlusion of the venous side of the shunts is effective to achieve cure of a complex and high-flow paraspinal AVF. PMID- 23648661 TI - [Treatment and pre-surgical planning for fusiform vertebral aneurysm]. PMID- 23648662 TI - [(9)Embolization of cerebral and spinal AVM]. PMID- 23648663 TI - In vivo activity of ursolic and oleanolic acids during the acute phase of Trypanosoma cruzi infection. AB - Reduction in the parasitemic levels of the Y strain of Trypanosoma cruzi in mice treated with oral or intraperitoneal ursolic (UA) and oleanolic (OA) acids was evaluated during the acute phase of Chagas' disease. Oral administration of UA and OA (50mg/kg/day) provided the most significant reduction in the parasitemic peak, while intraperitoneal administration of UA and OA did not significantly affect the biological activity of the Y strain of T. cruzi. Interleukin levels in mice treated by the intraperitoneal route were compared to untreated chagasic mice. Reduced gamma-IFN levels and enhanced IL-10 concentrations potentially explain the exacerbated parasitemia. Our data suggests an immunosuppressive effect for UA and OA, which could interfere with host control of parasitemia. Optimal results were achieved with oral administration. This observation may be explained by the low intestinal absorption of UA and OA, could cause a reduced immune response and promote parasite control. Taken together, these data demonstrate that triterpenes could be interesting compounds to develop therapeutically for the treatment of Chagas' disease. PMID- 23648664 TI - Ability of TEP1 in intestinal flora to modulate natural resistance of Anopheles dirus. AB - Blocking transmission of malaria is a reliable way to control and eliminate infection. However, in-depth knowledge of the interaction between Plasmodium and mosquito is needed. Studies suggest that innate immunity is the main mechanism inhibiting development of malaria parasites in the mosquito. Recent studies have found that use of antibiotics that inhibit the mosquito gut flora can reduce the immune response of Anopheles gambiae, thereby contributing to the development of malaria parasites. In our study, we used the non susceptible model of Anopheles dirus-Plasmodium yoelii to explore the effect of Anopheles intestinal flora on the natural resistance of A. dirus to P. yoelii. We found that in mosquitoes infected with Plasmodium, the intestinal flora can regulate expression of thioester-containing protein (TEP1) via an RNAi gene-silencing approach. Our results suggest that in the absence of TEP1, the natural microbiota cannot suppress the development of P. yoelii in A. dirus. This suggests that AdTEP1 plays an important role in the resistance of A. dirus to P. yoelii. The intestinal flora may modulate the development of P. yoelii in A. dirus by regulating TEP1 expression. PMID- 23648665 TI - Neospora caninum: infection induces high lysosomal activity. AB - Neospora caninum is a protozoan that causes abortion in cattle and neuromuscular lesions in dogs, making it an important target of veterinary medicine. Lysosomes are cellular organelles responsible for important biological functions as cellular defense mechanisms. The aim of this work was to evaluate the lysosomal stability of rat gliocytes infected in vitro with N. caninum. Rat glial cultures were infected at a ratio of 1:1 (cell/parasite). The enzymatic activity of acid phosphatase (orthophosphoric-monoester phosphohydrolase, EC 3.1.3.2) was assayed in the medium of control and infected cell cultures. The activity observed at 24h of incubation was 0.4+/-0.08mU/mg/min for control cells and 1.3+/-0.5mU/mg/min for infected cells. After 72h, control and infected cells exhibited activities of 1.3+/-0.5 and 4.1+/-0.9mU/mg/min, respectively. These results suggested that lysosomal compartment plays an important role in the mechanisms of cellular infection by N. caninum. PMID- 23648666 TI - Culture medium type affects endocytosis of multi-walled carbon nanotubes in BEAS 2B cells and subsequent biological response. AB - We examined the cytotoxicity of multi-walled carbon nanotubes (MWCNTs) and the resulting cytokine secretion in BEAS-2B cells or normal human bronchial epithelial cells (HBEpCs) in two types of culture media (Ham's F12 containing 10% FBS [Ham's F12] and serum-free growth medium [SFGM]). Cellular uptake of MWCNT was observed by fluorescent microscopy and analyzed using flow cytometry. Moreover, we evaluated whether MWCNT uptake was suppressed by 2 types of endocytosis inhibitors. We found that BEAS-2B cells cultured in Ham's F12 and HBEpCs cultured in SFGM showed similar biological responses, but BEAS-2B cells cultured in SFGM did not internalize MWCNTs, and the 50% inhibitory concentration value, i.e., the cytotoxicity, was increased by more than 10-fold. MWCNT uptake was suppressed by a clathrin-mediated endocytosis inhibitor and a caveolae mediated endocytosis inhibitor in BEAS-2B cells cultured in Ham's F12 and HBEpCs cultured in SFGM. In conclusion, we suggest that BEAS-2B cells cultured in a medium containing serum should be used for the safety evaluation of nanomaterials as a model of normal human bronchial epithelial cells. However, the culture medium composition may affect the proteins that are expressed on the cytoplasmic membrane, which may influence the biological response to MWCNTs. PMID- 23648668 TI - SETBP1 mutation analysis in 944 patients with MDS and AML. PMID- 23648669 TI - Acute erythroid leukemia (AEL) can be separated into distinct prognostic subsets based on cytogenetic and molecular genetic characteristics. PMID- 23648667 TI - Long-term outcome with lenalidomide and dexamethasone therapy for newly diagnosed multiple myeloma. AB - The combination of lenalidomide and dexamethasone (Len-Dex) is a commonly used initial therapy for newly diagnosed multiple myeloma (MM). Although the initial response rates and toxicity are well known, long-term outcome is not well described. We studied 286 consecutive patients with newly diagnosed MM initially treated with Len-Dex. The median (range) age at diagnosis was 63 (28-92) years, 166 (58%) patients <= 65 years and 175 (61%) male. The median estimated duration on Len-Dex was 5.3 months with overall response (>= partial response) of 72%, including 26% with very good partial response or better. The median overall survival (OS) from the diagnosis was not reached (NR) and the estimated 5-year survival was 71%. The median time to first disease progression, irrespective of transplant status, was 30.2 months. Overall, 143 (50%) patients underwent stem cell transplant. The median OS was NR for patients <= 70 years and 5.8 years for the older patients (P=0.01). The 5-year OS estimate for patients in International Staging System stage 1, 2 and 3 were 82, 65, and 44% respectively. There were 21 new second malignancies after MM diagnosis (6.6%). The median survival exceeding 7 years reflects the efficacy of novel agents. The risk of second malignancies doesn't appear to be excessive in this population. PMID- 23648670 TI - Early intervention with allogeneic hematopoietic cell transplantation during chemotherapy-induced aplasia in patients with high-risk acute myeloid leukemia. PMID- 23648671 TI - SOX11 overexpression is a specific marker for mantle cell lymphoma and correlates with t(11;14) translocation, CCND1 expression and an adverse prognosis. PMID- 23648672 TI - Effects of Stimulants and SSRIs on Brain Function in Children: Emerging Clues from fMRI Studies. PMID- 23648673 TI - Diffusion tensor imaging predicts the outcome of constraint-induced movement therapy in chronic infarction patients with hemiplegia: A pilot study. AB - PURPOSE: To test whether diffusion tensor imaging could evaluate potential motor capability of patients with chronic cerebral infarction. METHODS: We used constraint-induced movement therapy (CIMT) as a rehabilitation, which reveals potential motor capability. We also investigated the relationship between the outcome of CIMT and the ratio between fractional anisotropy values (rFA) in affected and unaffected sites of the corticospinal tract before CIMT. Imaging was performed in cerebral infarction patients (n = 14) and the rFA of the posterior limb of internal capsule (PLIC) was measured before CIMT. Patients were evaluated before and after CIMT using the Fugl-Meyer (F-M) assessment, Wolf Motor Function Test, Action Research Arm Test, and Motor Activity Log and association between PLIC- rFA and these scores was determined. RESULTS: All patients showed an improvement in mobility following the 10-day CIMT session. Strong positive correlation was found only between F-M after CIMT and PLIC-rFA (r = 0.8098, p = 0.0004). A strong linear relationship was observed after CIMT. CONCLUSION: These data support PLIC-rFA as a new marker of the CIMT-induced improvement in motor function (F-M). PMID- 23648675 TI - Evaluation of the inhibitory effects of antihypertensive drugs on human carboxylesterase in vitro. AB - Human carboxylesterase (CES) 1A and CES2, two major forms of human CES, dominate the pharmacokinetics of most prodrugs such as imidapril and irinotecan (CPT-11). Antihypertensive drugs are often prescribed for clinical therapy concurrently with others. Moreover, two or more antihypertensive drugs are ubiquitously combined. The influences of antihypertensive drugs on the activity of CES remain undefined. In the present study, the inhibitory effects of 17 antihypertensive drugs on the CES1A1 and CES2 activities were evaluated. Imidapril and CPT-11 were used as substrates and cultured with liver microsomes in vitro. The imidapril hydrolase activities by recombinant CES1A1 and human liver microsomes (HLM) were intensely inhibited by telmisartan and nitrendipine (K(i) = 0.49 +/- 0.09 and 1.12 +/- 0.39 uM for CES1A1, 1.69 +/- 0.17 uM and 1.24 +/- 0.27 uM for HLM, respectively). However, other drugs did not exert strong inhibition. The enzyme hydrolase activity of recombinant CES2 was substantially inhibited by diltiazem and verapamil (K(i) = 0.25 +/- 0.02 and 3.84 +/- 0.99 uM, respectively). Hence, diltiazem, verapamil, nitrendipine and telmisartan may attenuate the drug efficacy of catalyzed prodrugs by changing the activities of CES1A1 and CES2. PMID- 23648674 TI - Motor neuron target selectivity and survival after prolonged axotomy. AB - PURPOSE: After a cut peripheral nerve is repaired, motor neurons usually regenerate across the lesion site, however they often enter an inappropriate Schwann cell tube and may be directed to an inappropriate target organ such as skin, resulting in continued loss of function. In fact, only about 10% of adults who receive a peripheral nerve repair display full functional recovery. The reasons for this are many and complex, however one aspect is whether the motor neuron has undergone a prolonged period of axotomy prior to nerve repair. Previous studies have suggested a deleterious effect of prolonged axotomy. METHODS: We examined the influence of prolonged axotomy on target selectivity using a cross-reinnervation model of rat obturator motor neurons regrowing into the distal femoral nerve, with its normal bifurcating pathways to muscle and skin. RESULTS: Surprisingly, we found that a prolonged period of axotomy resulted in an increase in motor neuron regeneration accuracy. In addition, we found that regeneration accuracy could be increased even further by a simple surgical manipulation of the distal terminal nerve pathway to skin. CONCLUSIONS: These results suggest that under certain conditions prolonged axotomy may not be detrimental to the final accuracy of motor neuron regeneration and highlight that a simple manipulation of terminal nerve pathways may be one approach to increase such regeneration accuracy. PMID- 23648676 TI - Cytochrome P450 metabolic activities in the small intestine of cynomolgus macaques bred in Cambodia, China, and Indonesia. AB - Cynomolgus macaques, used in drug metabolism studies due to their evolutionary closeness to humans, are mainly bred in Asian countries, including Cambodia, China, and Indonesia. Cytochromes P450 (P450s) are important drug-metabolizing enzymes, present in the liver and small intestine, major drug metabolizing organs. Previously, our investigation did not find statistically significant differences in hepatic P450 metabolic activities measured in cynomolgus macaques bred in Cambodia (MacfaCAM) and China (MacfaCHN). In the present study, P450 metabolic activity was investigated in the small intestine of MacfaCAM and MacfaCHN, and cynomolgus macaques bred in Indonesia (MacfaIDN) using P450 substrates, including 7-ethoxyresorufin, coumarin, bupropion, paclitaxel, diclofenac, S-mephenytoin, bufuralol, chlorzoxazone, and testosterone. The results indicated that P450 metabolic activity of the small intestine was not statistically significantly different (<2.0-fold) in MacfaCAM, MacfaCHN, and MacfaIDN. In addition, statistically significant sex differences were not observed (<2.0-fold) in any P450 metabolic activity in MacfaCAM as supported by mRNA expression results. These results suggest that P450 metabolic activity of the small intestine does not significantly differ statistically among MacfaCAM, MacfaCHN, and MacfaIDN. PMID- 23648677 TI - UDP-glucuronosyltransferase 2B15 (UGT2B15) is the major enzyme responsible for sipoglitazar glucuronidation in humans: retrospective identification of the UGT isoform by in vitro analysis and the effect of UGT2B15*2 mutation. AB - Recently, genotyping in clinical studies has revealed that UGT2B15 genetic polymorphism has an influence on the clinical pharmacokinetics of sipoglitazar. In this study, the UGT responsible for sipoglitazar was retrospectively identified by in vitro analysis. A study using UGT-expressing supersomes revealed that sipoglitazar glucuronidation was more extensively catalyzed by UGT1A1, 1A3, 1A6, 2B4, and 2B15 than by other UGTs. Enzyme kinetic studies for sipoglitazar glucuronidation and recent findings related to mRNA expression analysis of UGTs narrowed the involved isoforms down to UGT1A1 and UGT2B15 among these five human UGTs. In a correlation study between sipoglitazar glucuronidation and UGT isoform specific activities, the glucuronidation of S-oxazepam, a specific substrate for UGT2B15, strongly correlated with that of sipoglitazar, as compared with that of beta-estradiol, a representative UGT1A1 substrate. The analysis of the species difference strengthens the possibility of UGT2B15 rather than that of UGT1A1. These in vitro findings indicate that UGT2B15 is principally responsible for sipoglitazar glucuronidation. Moreover, the UGT2B15*2 mutation significantly increased the Km value of sipoglitazar in the kinetic analysis using recombinant His-tag UGT2B15*1- or *2-membrane fractions. These results show that sipoglitazar is a good example to elucidate the relationship between phenotype and genotype for UGT2B15 from in vitro analysis. PMID- 23648678 TI - Frequency of the functionally relevant aryl hydrocarbon receptor repressor (AhRR) Pro185Ala SNP in Papua New Guinea. AB - The diverse cultural and social habits of the Papua New Guinea (PNG) population include betel quid chewing and more recently smoking. The formation of DNA adducts from betel quid is mediated by the cytochrome P450 (CYP) enzymes, including CYP1A2. The tobacco smoke compounds can induce CYP1A2. The transcription factor AhR (aryl hydrocarbon receptor) is involved in the regulation of CYP1A2 expression. AhR activity is itself regulated by other transcription factors, including the aryl hydrocarbon receptor repressor (AhRR). The AhRR Pro185Ala (rs2292596; 565C>G) minor allele was recently associated with a lower AhR repressor activity, leading to a higher CYP1A2 inducibility. We investigated AhRR Pro185Ala SNP in the East Sepik populations in PNG and found a high frequency of 53.4% of the minor allele, significantly different from other Asian populations. We can hypothesize that a high frequency of the AhRR SNP can be a risk factor in the incidence of oral cancer and other neoplasias in PNG due to higher inducibility of CYP1A2. The potential role of AhRR pharmacogenetics in the risk of developing cancers associated with betel quid chewing and smoking should be addressed and clarified in future epidemiological studies in PNG. PMID- 23648679 TI - Osteonectin expression in surrounding stroma of craniopharyngiomas: association with recurrence rate and brain infiltration. AB - Craniopharyngioma is an epithelial tumor of the sellar region with a high survival rate but a high rate of recurrence, especially in children. Hypothalamic involvement, tumor recurrence, and multiple treatments result in clinical deterioration and impaired quality of life. Using immunohistochemistry, we investigated the expression pattern of osteonectin, a marker of tumor invasion and aggressive behavior, in 43 cases of craniopharyngioma. We observed a positive correlation of osteonectin expression in connective-type stromal tissue surrounding the epithelial tumor cells of craniopharyngioma with the extent of central nervous system infiltration and recurrence rate (P < .001). Given the previous success of chemotherapeutic agents that target the tumor microenvironment, our findings on osteonectin expression in stroma of craniopharyngiomas might, hopefully, be a guide to find newer prognostic markers capable of estimating the risk of progression or recurrence. They may also aid in the development of therapeutics that target tumor microenvironment to improve patient outcome. PMID- 23648680 TI - Intranasal administration of oxytocin: behavioral and clinical effects, a review. AB - The intranasal (IN-) administration of substances is attracting attention from scientists as well as pharmaceutical companies. The effects are surprisingly fast and specific. The present review explores our current knowledge about the routes of access to the cranial cavity. 'Direct-access-pathways' from the nasal cavity have been described but many additional experiments are needed to answer a variety of open questions regarding anatomy and physiology. Among the IN-applied substances oxytocin (OT) has an extensive history. Originally applied in women for its physiological effects related to lactation and parturition, over the last decade most studies focused on their behavioral 'prosocial' effects: from social relations and 'trust' to treatment of 'autism'. Only very recently in a microdialysis study in rats and mice, the 'direct-nose-brain-pathways' of IN-OT have been investigated directly, implying that we are strongly dependent on results obtained from other IN-applied substances. Especially the possibility that IN-OT activates the 'intrinsic' OT-system in the hypothalamus as well needs further clarification. We conclude that IN-OT administration may be a promising approach to influence human communication but that the existing lack of information about the neural and physiological mechanisms involved is a serious problem for the proper understanding and interpretation of the observed effects. PMID- 23648681 TI - New insights into pollution and the cardiovascular system: 2010 to 2012. PMID- 23648682 TI - Hampton's hump and Palla's sign in pulmonary embolism. PMID- 23648683 TI - Spontaneous rupture of a papillary muscle. PMID- 23648684 TI - Letter by Giannini et al regarding article, "cerebral embolization during transcatheter aortic valve implantation: a transcranial Doppler study". PMID- 23648685 TI - Letter by Erdoes et al regarding article, "cerebral embolization during transcatheter aortic valve implantation: a transcranial Doppler study". PMID- 23648686 TI - Perovskite LaTiO3-Ag0.2 nanomaterials for nonenzymatic glucose sensor with high performance. AB - In this paper, a nonenzymatic glucose biosensor based on perovskite LaTiO3 Ag0.2(LTA) modified electrode was presented. The morphology and the composition of the perovskite LaTiO3-Ag0.2 nanomaterials were characterized by using scanning electron microscopy (SEM) and X-ray diffraction (XRD) respectively. The LaTiO3 Ag0.2(LTA) composite was investigated by electrochemical characterization using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Under optimal conditions, CV and chronoamperometry (I-t) study revealed that, compared with the bare glassy carbon electrode (GCE), the modified electrode showed a remarkable increase in the efficiency of the electrocatalytic oxidation of glucose, starting at around +0.70 V (vs. Ag/AgCl). The prepared sensor exhibited a high sensitivity of 784.14 uAmM-1 cm-2, a low detection limit of 2.1*10-7 M and a wide linear range from 2.5 uM to 4 mM (R=0.9997). More importantly, the LTA modified electrode was also relatively insensitive to commonly interfering species such as ascorbic acid (AA), uric acid (UA), dopamine (DA) in high potential. Moreover, the nonenzymatic sensor was applied to the determination of glucose in human serum samples and the results were in good agreement with clinical data. Electrodes modified with perovskite nanomaterials are highly promising for nonenzymatic electrochemical detection of glucose because of their high sensitivity, fast response, excellent stability and good reproducibility. PMID- 23648687 TI - Stainless steel modified with an aminosilane layer and gold nanoparticles as a novel disposable substrate for impedimetric immunosensors. AB - In this work, stainless steel (SS) was used as a substrate to fabricate an inexpensive and disposable impedimetric immunosensor. SS surface was modified with a stable thin layer of 3-aminopropyltriethoxysilane (APTES), and followed by electrodeposition of gold nanoparticles (GNPs). The morphology and size of the electrodeposited GNPs were studied using scanning electron microscopy (SEM) and atomic force microscopy (AFM). The interfacial properties of the SS electrode after each modification step were characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) in a solution containing [Fe(CN)6]3 /4- as a redox probe. The results indicated that APTES layer was successfully formed on the electrode surface and GNPs enhanced the conductivity and sensitivity of the electrode. The applicability of the proposed assembled electrode in electrochemical immunosensors was followed by immobilizing doxorubicin-specific monoclonal antibodies onto the GNP-modified electrode to determine doxorubicin concentration using the EIS technique. The relative charge transfer resistance was found to increase linearly with doxorubicin concentration in two ranges from 2.5 to 30.0 and 30.0 to 100.0 pg mL-1. The detection limit of the immunosensor was 1.7 pg mL-1 (3s(b)/m) doxorubicin. The satisfactory results were obtained from determination of doxorubicin concentrations in spiked human serum samples. The recoveries were in the range of 88.0-122.2%. These results indicate that modified SS electrodes are promising sensing elements to construct economical electrochemical immunosensors for routine quantitative analyses. PMID- 23648688 TI - Mechanism and enhancement of the surface stress caused by a small-molecule antigen and antibody binding. AB - Generation of microcantilever bending from biochemical interactions can have wide applications, ranging from high-throughput molecular detection to bioactuation. However, the origin of the biochemically induced surface stress causing the bending is a subject of much scientific debate and interest. Unlike a compressive surface stress caused by biomacromolecule antigen and antibody binding, here we show that a small molecule antigen and antibody binding on the surface gives rise to a tensile stress. We propose that the tensile stress is induced by antibody conformational change which manifests itself as Fab arm motion that exposes the C1q binding site of the antibody due to antigen binding. A microcantilever immunosensor was developed for the detection of Chlorimuron-ethyl (CE). We found that antibodies with oriented immobilization induce a greater resultant surface stress than those with random immobilization. The length of linker between the surface and the antibody plays an important role on the stress transmission. The shorter the length, the greater the surface stress. These mechanism and principles will underpin the design of devices and coatings to significantly lower the small molecule detection limit and may also have an impact on our understanding of antigen and antibody binding. PMID- 23648690 TI - In-silico identification of cardiovascular disease-related SNPs affecting predicted microRNA target sites. AB - INTRODUCTION: MicroRNAs (miRNAs) are small RNAs that play an important role in the regulation of gene expression. miRNA dysregulation has been associated with phenotypic changes, including cardiovascular diseases (CVDs). OBJECTIVES: The aim of the study was to obtain a list of single nucleotide polymorphisms (SNPs) related to CVDs, with computationally predicted effect on miRNA binding sites, which would verify the hypothesis that miRNA dysregulation can lead to the development of CVDs. MATERIALS AND METHODS: SNPs, CVDs, and miRNAs were the 3 factors subjected to analysis. Based on the publicly available databases, we created a set of SNPs associated with the phenotype of interest and of SNPs located in known miRNA binding sites. We then merged the records assigned by the same SNP, which allowed us to indicate miRNA target sites, whose variants may be associated with CVDs. The results were supplemented with the additional data such as miRNA and mRNA coexpression, differences in the expression between various tissues, and Expression Quantitative Trait Locus analysis. Only in-silico methods, on the basis of publically available information tools and databases, were used. RESULTS: We obtained a list of 47 entries, constituting unique miRNA SNP allele-phenotype linkages. CONCLUSIONS: Computational approach supports the hypothesis of the linkage between alterations in miRNA function and numerous CVDs. Given the high frequency of SNP incidence, this pathomechanism may be common in the population. Although the obtained results need to be further experimentally validated, limiting the number of interactions to the most probable ones will facilitate the identification of clinically significant associations. PMID- 23648691 TI - Epistemological problems in Cognitive Archaeology: an anti-relativistic proposal towards methodological uniformity. AB - Cognitive archaeology (CA) has an inherent and major problem. The coupling between extinct minds, brains and behaviors cannot be investigated in a laboratory. Without direct testability, there is a risk that theories in CA will remain merely subjective opinions in which "anything goes". To counter this risk, opponents of relativism originally argued that CA should adopt a method of validation based on "indirectly" testing inferences from the archaeological record. In this paper, we will offer a two-part analysis. In the first part, we will discuss problems with the original anti-relativistic agenda. While we agree with the necessity of developing a rational methodology for this discipline, in our view previous analyses have significant weak points that need to be strengthened. In particular, we will propose that "indirect testability" should be superseded by a methodology based upon deductive mappings from networks of theories, followed by a plausibility-selection stage. This methodology will be implemented by adopting an extension of Barnard's (2010b) proposals for mapping hierarchical systems. In the second part, we will compare our methods with those currently adopted in the CA debate. From this analysis, it will emerge that some proposals in CA are inconsistent with our methodology and are incommensurable with those that are consistent with it. Furthermore, we will show that theories in CA can advance contradictory conclusions precisely because they have been developed using different methods. We conclude that a universal methodology, like that proposed here, is needed for CA to become more objective. It is also crucial for creating conditions for coherent and productive debate among different schools of thought in the field of cognitive evolution. PMID- 23648692 TI - Primates' constructional abilities. AB - In this paper we propose a model of early constructional abilities of human and nonhuman Primates and show how the model applies to the data available in the relative literature, that we review. We also compare our model with primatological models of object combination and tool use. We finally consider what the archaeological record on structures allows us to hypothesize about the evolution of constructional abilities in the Homo species. PMID- 23648694 TI - Disfiguring facial hemangioma compromising labial functionality: a case report. AB - Hemangiomas are proliferative lesions characterized by increased endothelial cell turnover. Lip hemangiomas can distort lip anatomy and are at increased risk of ulceration and/or bleeding, which lead to impaired function and disfigurement. Surgery can provide active treatment but it can be problematic because vermilion tissue is unique and not found elsewhere on the body. Since there is no similar tissue that can easily be used for reconstructing missing vermilion, its preservation is essential for a satisfactory cosmetic result. We present the case of a 74 year old woman suffering from a large hemangioma of the mid-face and particulary with an angiomatous ulcerated lesion at the level of the lower lip. We describe clinical management and surgical treatment of this pathology. PMID- 23648695 TI - Cell-based immunotherapy against gliomas: from bench to bedside. AB - Glioblastoma (GBM) comprises 51% of all gliomas and is the most malignant form of brain tumors with a median survival of 18-21 months. Standard-of-care treatment includes maximal surgical resection of the tumor mass in combination with radiation and chemotherapy. However, as the poor survival rate indicates, these treatments have not been effective in preventing disease progression. Cellular immunotherapy is currently being explored as therapeutic approach to treat malignant brain tumors. In this review, we discuss advances in active, passive, and vaccine-based immunotherapeutic strategies for gliomas both at the bench and in the clinic. PMID- 23648696 TI - Generation of a hypomorphic model of propionic acidemia amenable to gene therapy testing. AB - Propionic acidemia (PA) is a recessive genetic disease that results in an inability to metabolize certain amino acids and odd-chain fatty acids. Current treatment involves restricting consumption of these substrates or liver transplantation. Deletion of the Pcca gene in mice mimics the most severe forms of the human disease. Pcca(-) mice die within 36 hours of birth, making it difficult to test intravenous systemic therapies in them. We generated an adult hypomorphic model of PA in Pcca(-) mice using a transgene bearing an A138T mutant of the human PCCA protein. Pcca(-/-)(A138T) mice have 2% of wild-type PCC activity, survive to adulthood, and have elevations in propionyl-carnitine, methylcitrate, glycine, alanine, lysine, ammonia, and markers associated with cardiomyopathy similar to those in patients with PA. This adult model allowed gene therapy testing by intravenous injection with adenovirus serotype 5 (Ad5) and adeno-associated virus 2/8 (AAV8) vectors. Ad5-mediated more rapid increases in PCCA protein and propionyl-CoA carboxylase (PCC) activity in the liver than AAV8 and both vectors reduced propionylcarnitine and methylcitrate levels. Phenotypic correction was transient with first generation Ad whereas AAV8 mediated long-lasting effects. These data suggest that this PA model may be a useful platform for optimizing systemic intravenous therapies for PA. PMID- 23648697 TI - No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. AB - BACKGROUND & AIMS: Patients with non-celiac gluten sensitivity (NCGS) do not have celiac disease but their symptoms improve when they are placed on gluten-free diets. We investigated the specific effects of gluten after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates (fermentable, oligo-, di , monosaccharides, and polyols [FODMAPs]) in subjects believed to have NCGS. METHODS: We performed a double-blind cross-over trial of 37 subjects (aged 24-61 y, 6 men) with NCGS and irritable bowel syndrome (based on Rome III criteria), but not celiac disease. Participants were randomly assigned to groups given a 2 week diet of reduced FODMAPs, and were then placed on high-gluten (16 g gluten/d), low-gluten (2 g gluten/d and 14 g whey protein/d), or control (16 g whey protein/d) diets for 1 week, followed by a washout period of at least 2 weeks. We assessed serum and fecal markers of intestinal inflammation/injury and immune activation, and indices of fatigue. Twenty-two participants then crossed over to groups given gluten (16 g/d), whey (16 g/d), or control (no additional protein) diets for 3 days. Symptoms were evaluated by visual analogue scales. RESULTS: In all participants, gastrointestinal symptoms consistently and significantly improved during reduced FODMAP intake, but significantly worsened to a similar degree when their diets included gluten or whey protein. Gluten specific effects were observed in only 8% of participants. There were no diet specific changes in any biomarker. During the 3-day rechallenge, participants' symptoms increased by similar levels among groups. Gluten-specific gastrointestinal effects were not reproduced. An order effect was observed. CONCLUSIONS: In a placebo-controlled, cross-over rechallenge study, we found no evidence of specific or dose-dependent effects of gluten in patients with NCGS placed diets low in FODMAPs. PMID- 23648698 TI - Long-term control of arterial hypertension and regression of left ventricular hypertrophy with treatment of primary aldosteronism. AB - Primary aldosteronism (PA), a common cause of high blood pressure (BP), induces left ventricular (LV) hypertrophy and an excess rate of cardiovascular events. Whether its treatment provides long-term cure of hypertension and regression of cardiovascular damage remains uncertain. To the aim of assessing the effect of treatment of PA on BP and LV changes, we prospectively recruited 323 patients in a long-term follow-up study entailing serial echocardiography evaluations. Of them, 180 had PA and were assigned to either adrenalectomy (n=110) or medical therapy (n=70) on the basis of the adrenal vein sampling. The remaining 143 were consecutive optimally treated primary hypertensive patients. At baseline, the PA patients had more inappropriate LV mass than PH patients (27.1% versus 16.2%; P=0.020), despite similar BP values. At a median follow-up of 36 months (range, 6 225), BP was lowered (P<0.0001 versus baseline) to similar values in adrenalectomized (135+/-15/83+/-9 mm Hg), medically treated PA (133+/-11/83+/-7 mm Hg), and PH (139+/-15/86+/-9 mm Hg) patients. To this end, the adrenalectomized patients required significantly less drugs than the other groups. In PA patients, the LV mass index and the rate of LV hypertrophy fell through LV inward remodeling to the level of optimally treated PH patients, indicating that the LV work markedly decreased. Findings were similar when long term (>=5 and >=10 years) data were examined. Thus, an early diagnosis and a specific treatment of PA warrant normalization of BP and reversal of detrimental LV changes at long term. PMID- 23648699 TI - Determinants of progression of aortic stiffness in hemodialysis patients: a prospective longitudinal study. AB - Aortic stiffness is associated with increased cardiovascular mortality in patients with chronic kidney disease. However, the rate of progression of arterial stiffness and the role of cardiovascular risk factors in the progression of arterial stiffness has never been established in a longitudinal study. In a prospective, longitudinal, observational study, carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were assessed in 109 hemodialysis patients at baseline and after a mean follow-up of 1.2 years. We examined the impact of age, atherosclerotic cardiovascular disease, diabetes mellitus, dialysis vintage, and pentosidine (a well-characterized, advanced glycation end products) on the rate of progression of aortic stiffness. The annual rate of changes in carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were 0.84 m/s per year (95% confidence interval, 0.50-1.12 m/s per year) and -0.66 m/s per year (95% confidence interval, -0.85 to -0.47 m/s per year), respectively. Older subjects, and patients with diabetes mellitus or atherosclerotic cardiovascular disease had higher aortic stiffness at baseline, however, the rate of progression of aortic stiffness was only determined by plasma pentosidine levels (P=0.001). The degree of baseline aortic stiffness was a significant determinant of the regression of brachial stiffness (P<0.001) suggesting that the regression of brachial stiffness occurs in response to central aortic stiffness. These findings suggest that traditional cardiovascular risk factors may play some role in the progression of aortic stiffness before development of advanced chronic kidney disease, and that the enhanced rate of progression of aortic stiffness in chronic kidney disease patients on dialysis are probably determined by more specific chronic kidney disease-related risk factors such as advanced-glycation end products. PMID- 23648701 TI - Role of the carotid body in obesity-related sympathoactivation. PMID- 23648700 TI - Mechanism of inhibition of tubuloglomerular feedback by CO and cGMP. AB - Tubuloglomerular feedback (TGF) is a mechanism that senses NaCl in the macula densa (MD) and causes constriction of the afferent arteriole. CO, either endogenous or exogenous, inhibits TGF at least in part via cGMP. We hypothesize that CO in the MD, acting via both cGMP-dependent and -independent mechanisms, attenuates TGF by acting downstream from depolarization and calcium entry into the MD cells. In vitro, microdissected rabbit afferent arterioles and their MD were simultaneously perfused and TGF was measured as the decrease in afferent arteriole diameter. MD depolarization was induced with ionophores, while adding the CO-releasing molecule-3 to the MD perfusate at nontoxic concentrations. CO releasing molecule-3 blunted depolarization-induced TGF at 50 MUmol/L, from 3.6+/ 0.4 to 2.5+/-0.4 um (P<0.01), and abolished it at 100 MUmol/L, to 0.1+/-0.1 MUm (P<0.001; n=6). When cGMP generation was blocked by guanylyl cyclase inhibitor LY83583 added to the MD, CO-releasing molecule-3 no longer affected depolarization-induced TGF at 50 MUmol/L (2.9+/-0.4 versus 3.0+/-0.4 um) but partially inhibited TGF at 100 MUmol/L (to 1.3+/-0.2 MUm; P<0.05; n=9). Experiments using eicosatetraynoic acid and indomethacin suggest arachidonic acid metabolites do not mediate the cGMP-independent effect of CO. We then added the calcium ionophore A23187 to the MD, which caused TGF (4.1+/-0.6 MUmol/L); A23187 induced TGF was inhibited by CO-releasing molecule-3 at 50 MUmol/L (1.9+/-0.6 MUmol/L; P<0.01) and 100 MUmol/L (0.2+/-0.5 MUmol/L; P<0.001; n=6). We conclude that CO inhibits TGF acting downstream from depolarization and calcium entry, acting via cGMP at low concentrations, but additional mechanisms of action may be involved at higher concentrations. PMID- 23648702 TI - Blood pressure response to patterns of weather fluctuations and effect on mortality. AB - Very few studies have looked at longitudinal intraindividual blood pressure responses to weather conditions. There are no data to suggest that specific response to changes in weather will have an impact on survival. We analyzed >169 000 clinic visits of 16 010 Glasgow Blood Pressure Clinic patients with hypertension. Each clinic visit was mapped to the mean West of Scotland monthly weather (temperature, sunshine, rainfall) data. Percentage change in blood pressure was calculated between pairs of consecutive clinic visits, where the weather alternated between 2 extreme quartiles (Q(1)-Q(4) or Q(4)-Q(1)) or remained in the same quartile (Q(n)-Q(n)) of each weather parameter. Subjects were also categorized into 2 groups depending on whether their blood pressure response in Q(1)-Q(4) or Q(4)-Q(1) were concordant or discordant to Q(n)-Q(n). Generalized estimating equations and Cox proportional hazards model were used to model the effect on longitudinal blood pressure and mortality, respectively. Q(n) Q(n) showed a mean 2% drop in blood pressure consistently, whereas Q(4)-Q(1) showed a mean 2.1% and 1.6% rise in systolic and diastolic blood pressure, respectively. However, Q(1)-Q(4) did not show significant changes in blood pressure. Temperature-sensitive subjects had significantly higher mortality (1.35 [95% confidence interval, 1.06-1.71]; P=0.01) and higher follow-up systolic blood pressure (1.85 [95% confidence interval, 0.24-3.46]; P=0.02) compared with temperature-nonsensitive subjects. Blood pressure response to temperature may be one of the underlying mechanisms that determine long-term blood pressure variability. Knowing a patient's blood pressure response to weather can help reduce unnecessary antihypertensive treatment modification, which may in turn increase blood pressure variability and, thus, risk. PMID- 23648703 TI - Interaction between chromosome 2 and 3 regulates pulse pressure in the stroke prone spontaneously hypertensive rat. AB - In an F2 cross between stroke-prone spontaneously hypertensive (SHRSP) and Wistar Kyoto (WKY) rats, we previously identified blood pressure quantitative trait loci (QTL) on rat chromosome (RNO) 2 and a pulse pressure QTL on RNO3. The aims of this study were to confirm the QTL on RNO3 and to investigate interaction between RNO2 and RNO3 loci through the generation and phenotypic assessment of single RNO3 congenic (SP.WKY(Gla)3a) and bicongenic (SP.WKY(Gla)2a/3a) strains. Hemodynamic profiling, vascular function, and renal histology were examined in these newly generated strains along with the previously reported RNO2 congenic strain (SP.WKY(Gla)2a). Our results demonstrate significant equivalent reduction in systolic, diastolic, and pulse pressure phenotypes in SP.WKY(Gla)3a and SP.WKY(Gla)2a rats, whereas greater reductions were observed with the SP.WKY(Gla)2a/3a bicongenic strain achieving blood pressure levels similar to normotensive WKY rats. Epistasis was observed between pulse pressure QTL on RNO2 and 3 at baseline and during 1% salt challenge. Vascular function and renal pathology studies indicate that QTL on RNO3 are responsible for salt-induced kidney pathology, whereas QTL on RNO2 seem to have greater impact on vascular function. RNO3 congenic and bicongenic strains have confirmed the importance of SHRSP alleles in the RNO3 congenic interval on pulse pressure variability and end organ damage. These strains will allow interrogation of complex gene-gene and gene-environment interactions contributing to salt-sensitive hypertension and renal pathology in the SHRSP rat. PMID- 23648704 TI - Allele-specific expression of angiotensinogen in human subcutaneous adipose tissue. AB - The angiotensinogen gene is genetically linked with hypertension, but the mechanistic basis for association of sequence variants in the promoter and coding region of the gene remains unclear. An E-box at position -20 has been hypothesized to control the level of angiotensinogen expression, but its mechanistic importance for angiotensinogen expression in human tissues is uncertain. We developed an allele-specific polymerase chain reaction-based assay to distinguish between angiotensinogen mRNA derived from variants at the -20 position (rs5050) in the angiotensinogen promoter in adipose tissues obtained during surgery. The assay takes advantage of linkage disequilibrium between the rs5050 (located in the promoter) and rs4762 (located in the coding region) single nucleotide polymorphisms. This strategy allowed us to assess the level of allele specific expression in A-20C heterozygous subjects comparing the relative proportion of each allele with the total, thus eliminating the problem of variability in the level of total angiotensinogen mRNA among subjects. We show that angiotensinogen mRNA derived from the -20C allele is expressed significantly higher than that derived from the -20A allele in subcutaneous adipose tissue, and increased expression correlates with enriched chromatin binding of upstream stimulatory factor-2 to the -20C E-box compared with -20A. This may be depot selective because we were unable to detect these differences in omental adipose. This provides the first data directly comparing expression of angiotensinogen mRNA and differential transcription factor binding derived from 2 variant alleles in human tissue where the ratio of expression of one allele to another can be accurately determined. PMID- 23648705 TI - p53 mediates autophagy and cell death by a mechanism contingent on Bnip3. AB - Myocardial ischemia and angiotensin II activate the tumor suppressor p53 protein, which promotes cell death. Previously, we showed that the Bcl-2 death gene Bnip3 is highly induced during ischemia, where it triggers mitochondrial perturbations resulting in autophagy and cell death. However, whether p53 regulates Bnip3 and autophagy is unknown. Herein, we provide new compelling evidence for a novel signaling axis that commonly links p53 and Bnip3 for autophagy and cell death. p53 overexpression increased endogenous Bnip3 mRNA and protein levels resulting in mitochondrial defects leading to loss of mitochondrial DeltaPsi(m). This was accompanied by an increase in autophagic flux and cell death. Notably, genetic loss of function studies, such as Atg7 knock-down or pharmacological inhibition of autophagy with 3-methyl adenine, suppressed cell death induced by p53- indicating that p53 induces maladaptive autophagy. Our previous work demonstrated that Bnip3 induces mitochondrial defects and autophagic cell death. Conversely, loss of function of Bnip3 in cardiac myocytes or Bnip3(-/-) mouse embryonic fibroblasts prevented mitochondrial targeting of p53, autophagy, and cell death. To our knowledge, these data provide the first evidence for the dual regulation of autophagy and cell death of cardiac myocytes by p53 that is mutually dependent on and obligatorily linked to Bnip3 gene activation. Hence, our findings may explain more fundamentally, how, autophagy and cell death are dually regulated during cardiac stress conditions where p53 is activated. PMID- 23648706 TI - Functional role of TRPV4-KCa2.3 signaling in vascular endothelial cells in normal and streptozotocin-induced diabetic rats. AB - The small conductance and intermediate conductance Ca(2+)-activated K(+) channels are known to be involved in the endothelium-dependent hyperpolarization. Ca(2+) entry into endothelial cells stimulates these channels, causing membrane hyperpolarization in endothelial cells and underlying smooth muscle cells. In the present study, with the use of coimmunoprecipitation and double immunolabeling methods, we demonstrated a physical interaction of transient receptor potential vanilloid 4 (TRPV4) with K(Ca)2.3 in rat mesenteric artery endothelial cells. Acetylcholine and 4alpha-PDD mainly acted through TRPV4-K(Ca)2.3 pathway to induce smooth muscle hyperpolarization and vascular relaxation. K(Ca)3.1 was also involved in the process but at a much lesser degree than that of K(Ca)2.3. Stimulating TRPV4-K(Ca)2.3 signaling pathway also increased local blood flow in mesenteric beds and reduced systemic blood pressure in anesthetized rats. In streptozotocin-induced diabetic rats, the expression levels of TRPV4 and K(Ca)2.3 were reduced, which could be an underlying reason for the dysfunction of endothelium-dependent hyperpolarization in these animals. These results demonstrated an important physiological and pathological role of TRPV4-K(Ca)2.3 signaling pathway in vascular endothelial cells. PMID- 23648707 TI - Reduction of porcine parvovirus infectivity in the presence of protecting osmolytes. AB - Osmolytes are natural compounds found in the cells of many organisms that stabilize intracellular proteins against environmental stresses. Protecting osmolytes can promote protein folding, whereas denaturing osmolytes have the opposite effect. A variety of osmolytes were tested for their antiviral activity against porcine parvovirus (PPV). PPV is a non-enveloped, icosahedral, single strand DNA virus. We have discovered two protecting osmolytes, trimethylamine N oxide (TMAO) and glycine that reduce the infectivity of PPV by four logs (99.99%). We hypothesize that both osmolytes stabilize viral capsid proteins and prevent them from assembling into viable virus particles. The advantage of the antiviral compounds found is that they can be applied post-infection, which increases their potential to serve as a therapeutic drug. PMID- 23648708 TI - Effect of chloroquine on feline infectious peritonitis virus infection in vitro and in vivo. AB - Feline infectious peritonitis (FIP) is a feline coronavirus-induced fatal disease in domestic and wild cats. Several studies have investigated potential treatments for FIP. However, there have been no reports on agents that have exhibited a therapeutic effect. Recently, chloroquine has been reported to antiviral effect. We investigated whether chloroquine can be used to treat FIP in vitro and in vivo. It was demonstrated that chloroquine has inhibitory effect against the replication of FIPV and anti-inflammatory effect in vitro. In vivo study using cats with experimentally induced FIP, the clinical score of chloroquine-treatment groups were better than in chloroquine-untreated group. However, alanine aminotransferase levels increased in the chloroquine-treated groups. It will be necessary to further investigate the possibility of FIP treatment with a combination of chloroquine and other agents. PMID- 23648709 TI - Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a. AB - The future interferon-free treatment of hepatitis C virus (HCV) infection could include NS3 protease inhibitors (PIs) for potent pan-genotypic effect. We studied the prevalence of pre-existing PI resistance associated amino acid variants (RAVs) in 126 treatment-naive patient samples of HCV genotypes 1a, 2b and 3a, the most common genotypes in Sweden. The NS3 genes were each amplified by nested PCR method with degenerated primers to enable a broad genotype analysis. Population sequencing method was used, and the sequences were aligned with the NS3 sequence from HCV genotype 1a H77 strain. Interpretation of fold-change resistance to NS3 candidate drugs were done from already published phenotypic resistance data. The prevalence of known PI RAVs at baseline in genotype 1a was 28% (15/53), either single (V36L or Q80K/R) or combinations (T54A/S and V55A/I) of mutation(s). In genotype 2b, specific mutations like V36L, Q80G and S122R of viral NS3 protease gene were found in 100% (11/11). These may be the natural polymorphisms unique to genotype 2b. Similarly, specific mutations like V36L and D168Q were found uniquely in all 3a samples (30/30). The natural PI RAVs found in genotype 1a, although with relatively weak resistance, could still render up to 10-fold resistance to the approved (boceprevir and telaprevir) and the 2nd generation PIs (faldaprevir and simeprevir). Moreover, the natural polymorphisms in genotype 2b (i.e. S122R) and 3a (i.e. D168Q), with inherent PI drug resistance of up to 20 and 700 fold respectively, would explain why current PIs are primarily directed against genotype 1. PMID- 23648711 TI - Increased risk of gastrointestinal malignancy in patients with diabetes mellitus and correlations with anti-diabetes drugs: a nationwide population-based study in Taiwan. AB - OBJECTIVE: Although the major cause of morbidity and mortality in patients with diabetes mellitus (DM) is cardiovascular disease, DM is also associated with certain site-specific cancers. However, whether DM is associated with an increased risk of cancer of the digestive tract remains undetermined. A nationwide, population-based database in Taiwan was analyzed to explore the relationship between DM and cancer of the digestive organs. METHODS: From 2000 to 2007, a study cohort consisting of 39,515 patients with newly diagnosed diabetes without a previous diagnosis of gastrointestinal (GI) cancer was identified from the National Health Insurance Research Database in Taiwan. A control cohort of 79,030 age- and sex-matched non-diabetic subjects was selected to compare the occurrence of GI malignancies between the two groups. The association between the incidence of GI cancers and the use of glucose-lowering therapies was also investigated. RESULTS: During the 7-year follow-up period, GI cancers developed in 929 diabetic patients (2.35%) and 1,126 subjects (1.42%) in the comparison cohort. DM was associated with a 2.75-fold (95% confidence interval (CI), 2.51 3.02) higher risk of developing GI malignancy. Among GI cancers, the incidences of stomach (adjusted hazard ratio (HR), 1.49; 95% CI, 1.16-1.92), liver (adjusted HR, 2.65; 95% CI, 2.29-3.07), colon (adjusted HR, 1.58; 95% CI, 1.28-1.94) and pancreatic cancers (adjusted HR, 4.35; 95% CI, 2.93-6.47) were significantly increased in the patients with DM. An analysis of the effects of various glucose lowering therapies in the diabetic patients revealed the use of alpha-glucosidase inhibitors to be associated with a lower risk of hepatic cancer (adjusted HR, 0.62; 95% CI, 0.4-0.94). Thiazolidinedione (TZD) treatment was associated with lower stomach (adjusted HR, 0.11; 95% CI, 0.02-0.82) and hepatic cancer risks (adjusted HR, 0.46; 95% CI, 0.29-0.73), while sulfonylurea use was associated with a lower colon cancer risk (adjusted HR, 0.74; 95% CI, 0.51-1.09) and a higher pancreatic cancer risk (adjusted HR, 2.36; 95% CI, 1.21-4.61). CONCLUSION: Patients with DM have an increased risk of GI malignancy that may be affected by the use of different categories of glucose-lowering therapies. PMID- 23648710 TI - Profiling of the kinome of cytomegalovirus-infected cells reveals the functional importance of host kinases Aurora A, ABL and AMPK. AB - Human cytomegalovirus infection can lead to life-threatening clinical manifestations particularly in the immunocompromised host. Current therapy options face severe limitations leading to a continued search for alternative drug candidates. Viral replication is dependent on a balanced interaction between viral and cellular proteins. Especially protein kinases are important regulators of virus-host interaction indicated by remarkable kinome alterations induced upon HCMV infection. Here we report a novel approach of kinome profiling with an outcome that suggests an important role of specific cellular protein kinases, such as AMPK, ABL2 and Aurora A. Inhibition of AMPK and ABL kinases showed a significant reduction, whereas inhibition of Aurora A kinase led to a slight activation of HCMV replication, as measured in a GFP reporter-based replication assay. Furthermore, analysis of the mode of antiviral action suggested a substantial benefit for the efficiency of viral replication at the immediate early (AMPK) or early-late (ABL) phases of HCMV gene expression. In contrast, inhibition of Aurora A kinase promoted an enhancement of viral early-late gene expression, suggesting a putative role of Aurora A signaling in host defense. Thus, the combined data provide new information on host cell kinases involved in viral replication and uncovered potential targets for future antiviral strategies. PMID- 23648712 TI - Reduced-dose cyclosporine with mycophenolate mofetil and prednisone significantly improves the long-term glomerular filtration rate and graft survival. AB - OBJECTIVE: It remains debated whether reduced doses of chronic calcineurin inhibitors benefit graft survival. METHODS: This retrospective study analyzed 60 first cadaveric renal transplant recipients who received cyclosporine (CSA), mycophenolate mofetil (MMF) and prednisone (CMP group) and 71 recipients who received reduced-dose CSA with prednisone and MMF (RCMP group). All recipients were followed for at least 96 months. The Modification of Diet in Renal Disease (MDRD) glomerular filtration rate (GFR) calculated at different time points, graft survival, the incidence of chronic allograft nephropathy (CAN) and the acute rejection rate within six months were analyzed and compared between the two groups. RESULTS: The incidence of acute rejection within six months post transplant was 15.5% (11/71) in the RCMP group and 13.3% (8/60) in the CMP group. This difference was not significant (p=0.727). The MDRD-calculated GFR in the CMP group reached a peak at 24 months post-transplant (66.6 +/- 20.2 mL/min/1.73 m(2)) then decreased gradually. In contrast, in the RCMP group, the GFR reached a peak at 36 months post-transplant (76.9 +/- 19.6 mL/min/1.73 m(2)). The GFR from month 36 to month 96 was significantly higher in the RCMP group than in the CMP group. The Kaplan-Meier calculated death-censored graft survival in the RCMP group was significantly higher than that observed in the CMP group, with an estimated cumulative proportion surviving at 96 months of 95.5% in the RCMP group and 83.5% in the CMP group. The incidence of CAN within 96 months was 5.6% (4/71) in the RCMP group vs. 16.7% (10/60) in the CMP group (p=0.042). CONCLUSION: An RCMP regimen can significantly improve the long-term GFR level and benefit graft survival. PMID- 23648713 TI - Epstein-Barr viral load in cerebrospinal fluid as a diagnostic marker of central nervous system involvement of AIDS-related lymphoma. AB - OBJECTIVE: AIDS-related lymphoma (ARL) often involves the central nervous system (CNS). Although the diagnostic value of Epstein-Barr virus (EBV)-DNA in cerebrospinal fluid (CSF) in detecting HIV-positive primary CNS lymphoma (PCNSL) has been established, its usefulness for identifying CNS involvement of systemic ARL remains elusive. In this study, we evaluated the utility of the EBV-DNA load in CSF in identifying CNS involvement in patients with systemic ARL. METHODS: We retrospectively reviewed the clinical and pathological data of consecutive ARL patients managed at our clinic between January 1998 and June 2012. Sixty-two patients with ARL, including eight PCNSL patients and 52 systemic ARL patients, and 63 controls underwent CSF EBV-DNA load evaluations before receiving chemotherapy. ARL-related CNS involvement was defined as any lesion diagnosed histologically or radiologically as a lymphoma in the brain, meninges, spine, cranial nerves or oculus. RESULTS: A cut off value of 200 copies/mL predicted the presence of CNS lesions with a sensitivity of 70% and a specificity of 85% in both the PCNSL and systemic ARL patients, while a sensitivity of 75% and a specificity of 93% were obtained for systemic ARL. A cut off value of 2,000 (3.30 log) copies/mL provided the best specificity (100%), with a sensitivity of 50%. CONCLUSION: Our results support the clinical utility of evaluating the quantitative EBV-DNA load in the CSF for the diagnosis of CNS involvement of systemic ARL as well as PCNSL. PMID- 23648714 TI - The response to second-line induction with bortezomib and dexamethasone is predictive of long-term outcomes prior to high-dose chemotherapy with autologous stem cell transplantation for multiple myeloma. AB - OBJECTIVE: We retrospectively investigated the efficacy and predictive factors for the treatment outcomes of bortezomib plus dexamethasone (BD) as second-line induction therapy prior to high-dose chemotherapy supported by autologous stem cell transplantation (HDT/ASCT) in multiple myeloma (MM) patients. METHODS: Sixty six transplant eligible MM patients treated by the Kyoto Clinical Hematology Study Group between 2006 and 2011 were investigated. Conventional induction chemotherapy, including vincristine, doxorubicin and dexamethasone (VAD) and high dose dexamethasone (HDD), was used as first-line induction therapy in all patients, seven (10.6%) of whom attained a very good partial response (VGPR). Of the 59 patients who did not attain VGPR with VAD or HDD, 33 were given BD as second-line induction therapy prior to HDT/ASCT. RESULTS: Patients not treated with BD induction showed an overall response rate (ORR, i.e., better than partial response) of 85.3% after induction therapy, while the ORR of patients treated with BD induction improved from 42.4% after conventional induction therapy to 84.8% after BD. The overall survival (OS) and progression-free survival (PFS) of patients not treated with BD induction were not significantly influenced by the response to induction therapy. Among the patients treated with BD, failure in attaining VGPR prior to ASCT was associated with a significantly shorter PFS and it also tended to show a shorter OS, while the disease stage and achievement of a complete response after HDT/ASCT had no impact on OS or PFS. CONCLUSION: The achievement of at least VGPR with second-line BD induction therapy is a prerequisite for attaining longer OS and PFS after HDT/ASCT. PMID- 23648715 TI - Efficacy of intravenous cyclophosphamide therapy for neuromyelitis optica spectrum disorder. AB - OBJECTIVE: Neuromyelitis optica (NMO) is an inflammatory disease that affects the optic nerve and spinal cord. Optic neuritis and longitudinally extensive myelitis associated with systemic autoimmune disease have been recently defined as NMO spectrum disorder (NMOSD). In this study, we report the efficacy of intravenous cyclophosphamide (IVCY) therapy for NMOSD. METHODS: Four patients diagnosed with NMOSD were enrolled in this study. The expanded disability status scale (EDSS) score was used to evaluate the degree of severity. All of the patients received intravenous methylprednisolone (IVMP; 1 g/day for three days), and two patients also received plasmapheresis (PP). All of the patients were administered IVCY treatment. RESULTS: Anti-AQP4 antibodies were present in the sera of all patients. All patients exhibited longitudinally extensive transverse myelitis (LETM). Only one patient who fulfilled the criteria for a diagnosis of NMO exhibited optic neuritis. Two patients developed relapse under treatment with low dose prednisolone (PSL) before the administration of IVCY. The patients in this study exhibited a median improvement in the EDSS score following IVCY treatment from 8.0 to 5.75. Adverse effects were observed in only one patient. CONCLUSION: This study, despite its retrospective design, demonstrated the therapeutic efficacy of IVCY for NMOSD in both the acute and chronic phases of the disease and determined the IVCY dosage for Japanese women with NMOSD. Additionally, this study provided evidence that for NMOSD patients with severe disabilities, IVCY added to IVMP and PP may be a useful therapeutic modality. PMID- 23648716 TI - Acute aortic thrombosis during cisplatin based chemotherapy for gastric cancer. AB - The development of aortic thrombosis without the presence of atheroscrelosis, dissection, or aneurysms is rare. A cancer-related hypercoagulable state is a well-known risk factor for venous thrombosis, however, atrial thrombosis has rarely been reported in cancer patients. Cisplatin-based chemotherapy is known to cause various side-effects. Detecting aortic thrombosis is important because it is a fatal condition. We herein present the first reported case of endo-aortic thrombosis occurring during cisplatin-based chemotherapy for gastric cancer. PMID- 23648717 TI - Giant coronary artery aneurysms associated with Kawasaki disease detected on whole-heart magnetic resonance coronary angiographic screening. AB - Kawasaki disease (KD) is one of the most important causes of coronary artery aneurysms in children and young adults. However, the natural course of the disease and the patient prognosis remain obscure. A 72-year-old asymptomatic man with undiagnosed KD underwent whole-heart magnetic resonance coronary angiography during a health checkup. The imaging disclosed giant aneurysms in the proximal portion of the right coronary artery and the left anterior descending artery. The patient was successfully treated with coronary artery bypass grafting. The present case suggests that there may be a substantial number of patients who have attained middle to old age with undiagnosed KD. PMID- 23648718 TI - Reversible cardiomyopathy associated with autoimmune polyendocrine syndrome type II. AB - Recovery of the ventricular function in a patient with cardiomyopathy is very rare. Autoimmune polyendocrine syndrome is also very rare. We herein report a case of reversed cardiomyopathy associated with autoimmune polyendocrine syndrome type II (Schmidt's syndrome) composed of Addison's disease, vitiligo and Hashimoto's thyroiditis. The ventricular function and size were reversed following the administration of suitable hormone replacement therapy for polyendocrine syndrome. PMID- 23648719 TI - Serial Tc-99m MAG3 renography evaluating the recovery of acute kidney injury associated with minimal change nephrotic syndrome. AB - Acute kidney injury (AKI) is a well-recognized complication of minimal change nephrotic syndrome (MCNS). Previous reports support the concept that AKI associated with MCNS is reversible; however, information regarding the hemodynamic basis of AKI in MCNS is insufficient. We herein describe a case of AKI in a man with MCNS. In this case, monitoring the longitudinal changes in renal perfusion using serial Tc-99m-MAG3 renal scanning was beneficial for evaluating the pathophysiological background associated with the development of AKI. The potential impact of serial renal scanning in MCNS patients with AKI will also be discussed. PMID- 23648720 TI - Use of corticosteroids in the treatment of cholesterol crystal embolism after cardiac catheterization: a report of four Japanese cases. AB - Cholesterol crystal embolism (CCE) is a serious complication associated with invasive vascular procedures. The prognosis of the renal involvement type of CCE is very poor, and there is currently no established treatment, other than supportive therapy. We herein report four cases of CCE with severe atherosclerosis wherein the renal function progressively deteriorated after cardiac catheterization. In three of the four patients, low-dose corticosteroids (0.3 mg/kg/day) improved the renal function, whereas the fourth patient died from CCE of the digestive system. This report reviews the literature on CCE and discusses possible therapeutic options. PMID- 23648721 TI - Multifocal conduction block in a patient with sarcoid neuropathy: successful treatment with intravenous immunoglobulin. AB - A 54-year-old-woman with sarcoidosis presented with progressive symmetric, predominantly distal weakness and sensory dysfunction with areflexia in all four limbs. Nerve conduction studies showed multifocal conduction blocks in several nerves. Oral steroids were ineffective; however, intravenous immunoglobulin (IVIG) therapy rapidly and repeatedly improved the patient's neurologic symptoms with a resolution of the conduction blocks. Multifocal conduction blocks are not frequently reported in patients with sarcoid neuropathy, but they may respond to early treatment with IVIG. PMID- 23648722 TI - Varicella-zoster virus pneumonia in an immunocompetent patient. PMID- 23648723 TI - Carotid artery dissection associated with an elongated styloid process. PMID- 23648724 TI - Lip biopsy in Mikulicz's disease phenotype IgG4-related disease. PMID- 23648725 TI - Graft infection imaging with FDG and FDG-labeled leukocytes. PMID- 23648726 TI - Valproic acid and MELAS: a word of warning. PMID- 23648727 TI - The interplay between genome organization and nuclear architecture of primate evolutionary neo-centromeres. AB - An Evolutionary Neo-Centromere (ENC) is a centromere that emerged in an ectopic region of a chromosome during evolution. It is thought that the old centromere must be inactivated because dicentric chromosomes are not viable. The aim of the present study was to investigate whether 3D arrangement in the interphase nucleus of the novel and old centromeric domains was affected by the repositioning event. The data we present here strongly indicate that the ENC phenomenon does not affect the 3D location of either novel or old centromeres. Very likely, other features, such as gene density, rather than the newly acquired or lost functions, define positioning in the nucleus. PMID- 23648730 TI - The European Union's chemical legislation needs revision. PMID- 23648731 TI - Substance identification of nanomaterials not key to ensuring their safe use. PMID- 23648732 TI - A tiered approach. PMID- 23648733 TI - Nanoparticle dispersity in toxicology. PMID- 23648735 TI - Nanoscale devices: untangling nanowire assembly. PMID- 23648736 TI - Magnetic resonance imaging: silicon for the future. PMID- 23648737 TI - Magnetic sensors: nanoparticles detect infection. PMID- 23648738 TI - Cold atoms: trapped by nanostructures. PMID- 23648739 TI - Magnetic nanostructures: vortex states a la carte. PMID- 23648741 TI - Topical laser application enhances enamel fluoride uptake and tribological properties. AB - Topical fluoride treatment prevents dental caries. However, the resulting calcium fluoride-like deposits are soft and have poor wear resistance; therefore, frequent treatment is required. Lasers quickly heat surfaces and can be made portable and suitable for oral remedies. We examined the morphology, nanohardness, elastic modulus, nanowear, and fluoride uptake of fluoride-treated enamel followed by CO2 laser irradiation for 5 and 10 sec, respectively. We found that laser treatments significantly increased the mechanical properties of the calcium-fluoride-like deposits. The wear resistance of the calcium-fluoride-like deposits improved about 34% after laser irradiation for 5 sec and about 40% following irradiation for 10 sec. We also found that laser treatments increased fluoride uptake by at least 23%. Overall, laser treatment significantly improved fluoride incorporation into dental tissue and the wear resistance of the protective calcium-fluoride layer. PMID- 23648742 TI - Effect of allergen sensitization on external root resorption. AB - In orthodontic tooth movement (OTM), we should be concerned about external root resorption (ERR) as an undesirable iatrogenic problem, but its mechanisms are not fully understood. Since our previous epidemiologic studies found that patients with allergic diseases showed higher rates of ERR during orthodontic treatment, we explored the possible effect of allergic sensitization on ERR. In ovalbumin (OVA)-sensitized Brown-Norway rats, the amounts of ERR and OTM were greater than those in animals subjected to orthodontic force alone. The expression levels of RANKL and pro-inflammatory cytokines were increased in the periodontal tissues of sensitized rats with OTM, compared with control rats. Furthermore, leukotriene B4 (LTB4), a potent lipid mediator of allergic inflammation, and enzymes of the 5 lipoxygenase pathway, the biosynthetic pathway of leukotrienes, were also up regulated. We found that low doses of aspirin suppressed ERR in allergen sensitized rats, as well as the expressions of RANKL, pro-inflammatory cytokines, and LTB4. The present findings indicate that allergen sensitization has adverse effects on ERR under OTM, and that aspirin is a potential therapeutic agent for combating ERR. PMID- 23648743 TI - Monitoring for potential residual disease activity by serum insulin-like growth factor 1 and soluble Klotho in patients with acromegaly after pituitary surgery: is there an impact of the genomic deletion of exon 3 in the growth hormone receptor (d3-GHR) gene on "safe" GH cut-off values? AB - BACKGROUND: Acromegaly is an illness usually defined by excessively high growth hormone (GH) and insulin like growth factor 1 (IGF-1) levels, the latter mainly reflecting GH action on the liver. IGF-1, also known as somatomedin C, mediates several actions of GH. The diagnosis and management of acromegaly is relatively straight forward, but long-term follow-up of patients can be difficult, as elevated IGF-1 levels can occur in the presence of apparently normalised GH levels and late recurrence of acromegaly may arise despite previous suppression on oral glucose tolerance testing. Data suggest this applies especially to patients in whom the GH receptor lacks exon 3. In such patients, GH may not always be a useful marker of disease, and traditional GH cut-offs may be misleading. Recent data suggest that soluble Klotho (sKlotho), besides and in addition to IGF-1, may help monitor the activity of GH-producing adenomas (presumably reflecting GH action on the kidneys) and may be a useful supplementary tool. METHODS: GHR genotyping was performed in 112 patients with acromegaly. IGF-1 and sKlotho levels were measured in the sera of patients before and after transsphenoidal surgery, with emphasis on patients judged inconclusively cured by surgery or with small residual tumour masses shortly after surgery. Patients were assessed for recurrence of acromegaly with GH levels (random or nadir during an oGTT). RESULTS: Of the 48 patients who underwent surgery between 2000 and 2009 and who had well-documented longer term follow-up at our institution, 29 had no biochemical evidence of residual disease activity after transsphenoidal surgery (marked reduction in IGF-1 and sKlotho levels, GH suppressible to <1 ng/ml) and were classified as in remission. 2 of these patients developed recurrent symptoms of acromegaly during follow-up with increasing levels of IGF-1 and sKlotho, and both patients were carriers of the d3 GHR genotype. CONCLUSIONS: Acromegalic patients with the d3-GHR polymorphism might be - for a given low postsurgical GH level - at higher risk for recurrence and may require a lower GH nadir during oGTT to be classified as in remission. Soluble Klotho could be useful in the follow-up of acromegalic patients. The question arises whether sKlotho not only reflects the activity of GH-secreting pituitary adenomas but whether Klotho (ectodomain clipping?) could also mediate selected actions of GH. PMID- 23648744 TI - [The best reviwers of April 2013]. PMID- 23648746 TI - Editorial Comment of: Current role of surgery for high risk prostate cancer. PMID- 23648745 TI - Current role of surgery for high risk prostate cancer. AB - In this review, the role of surgery in patients with adverse tumor characteristics and a high risk of tumor progression are discussed. In the current PSA era the proportion of patients presenting with high risk prostate cancer (PCa) is estimated to be between 15% and 25% with a 10-year cancer specific survival in the range of 80-90% for those receiving active local treatment. The treatment of high risk prostate cancer is a contemporary challenge. Surgery in this group is gaining popularity since 10-year cancer specific survival data of over 90% has been described. Radical prostatectomy should be combined with extended lymphadenectomy. Adjuvant or salvage therapies may be needed in more than half of patients , guided by pathologic findings and postoperative PSA. Unfortunately there are no randomized controlled trials comparing radical prostatectomy to radiotherapy and no single treatment can be universally recommended. This group of high risk prostate cancer patients should be considered a multi-disciplinary challenge; however, for the properly selected patient, radical prostatectomy either as initial or as the only therapy can be considered an excellent treatment. PMID- 23648747 TI - Cost-Benefit of incorporating the detection of circulating prostate cells in a screening programme for prostate cancer. AB - OBJECTIVES: Prostate cancer is the second most common cancer in men after skin cancer, screening is used to detect early stage cancer using serum prostate specific antigen(PSA). A level of PSA > 4.0ng/m as a cut-off point or abnormal digital rectal examination (DRE) are used to indicate a prostate biopsy. Nevertheless, non-malignant pathologies can increase serum PSA level so that 70% of biopsies are negative for cancer, and thus potentially unnecessary, causing anxiety, costly clinical tests and prolonged follow-up. Thus the search for new biomarkers is important. Circulating primary prostate cells (CPCs) may be such a marker. We analyze a cohort of patients using CPCs to detect prostate cancer in men with a serum PSA >4.0ng/ml or abnormal DRE in terms of cost-benefit. METHODS: A cohort of 263 patients with a PSA >4.0 ng/ml and a test to detect CPCs who underwent prostate biopsy were analyzed. The results of both tests were compared with biopsy results; sensibility, specificity, and predictive values were calculated. Costs of each test, process, drug costs and complications were determined as well as indirect costs. RESULTS: Of the 263 patients, 77 (28.6%) had prostate cancer detected, for the test using CPCs there was a sensibility of 85.7%, specificity of 90.3% and negative predictive value of 93.9%. Thus men CPC negative may not need a prostate biopsy. Potential savings for the 263 patients were between ?32,068 in a public health service and ?69,253 for inpatient private health insurance patients. Follow up cost were higher in false-positive CPC patients but, as there were fewer false positive patients, total costs were lower. CONCLUSIONS: The use of primary CPC detection as a complementary test in men with a serum PSA >4.0ng/ml to indicate prostate biopsy is a specific, cost effective test, eliminating approximately 70% of prostate biopsies. This results in a significant health care saving both in direct and indirect costs, in the costs of complications. Implementation costs were minimal as equipment and reagents are part of the routine clinical laboratory. The method deserves further investigation to confirm the results. PMID- 23648748 TI - Impact of overactive bladder treatment on the quality of life of patients over 60 with associated pathologies. AB - OBJECTIVES: To study the impact of treatments prescribed in usual practice to control Overactive Bladder (OAB) on health-related quality of life (HRQoL) of patients with associated pathologies. METHODS: 1.434 patients over 60 years with newly diagnosed OAB and at least one associated pathology (urinary or genital skin infections, sleep disorders, depression, hypertension) were recruited in 300 urological/gynecological practices in Spain. During the first visit, socio demographic and basic clinical information were registered and the therapeutic strategy for OAB was prescribed following usual clinical practice The patients filled out the HRQoL SF-12 questionnaire. On the second visit (4-6 months later) the HRQoL was re-evaluated. HRQoL was compared between sexes (Mann-Whitney) and between visits (Wilcoxon for related samples). Multiple regression models were performed in order to study the variables independently associated with HRQoL. RESULTS: Valid data is given for 1,274 patients for visit 1 and 1,153 for visit 2. 71.51% of the sample were female. Mean age was 68.17 (6.19). A significant improvement in the HRQoL was found on the second visit. Factors independently associated with lower score in both summary index of SF-12: first visit, female gender and Charlson Index. Additional factors associated with reduction of the physical component score: age, all associated pathologies and treatment using vaginal pessaries. Additional factors associated with the mental component score: treatment for depression, sleep disorders, use of vesical reeducation and the modification of treatment using diuretics. CONCLUSIONS. The treatments prescribed in usual clinical practice to alleviate OAB are effective in notably improving the HRQoL of patients in general, both physically and mentally. PMID- 23648749 TI - Urethral mini-sling for the treatment of neurogenic sphincteric incompetence in pediatric and young adult patients. AB - OBJECTIVES: A first experience was carried out in three research centers using a new urethral sling for the treatment of male and female pediatric and young adult population with urinary incontinence caused by neurogenic sphincteric incompetence. METHODS: This was a prospective pilot study of patients with neurogenic sphincteric incompetence needing clean intermittent catheterization. All patients were treated by the implantation of Nephis(r) mini-sling (Promedon, Argentina) over the proximal urethra. Twenty-eight patients were included, 19 females and 9 males. Mean age was 13.4 (SD 7.8 years). The median follow-up was 16.5 (12-24) months. Urodynamic studies were carried out pre and postoperatively to assess the nature of the incontinence and to quantify the outcomes after implantation. A voiding diary was also used to evaluate the Daytime Dryness Intervals between catheterization. RESULTS: Leak Point Pressure increased from a preoperative mean value of 24.3 cmH2O (SD 6.5) to 51.0 cmH2O (SD14.3) (p<0.0005). The initial mean for Daytime Dryness Interval was 60.4min (SD 9.1) and postoperatively rose to 195.6 (SD 59.4) (p<0.0005). Only one major complication was registered: a sling had to be removed due to erosion in a patient who underwent a concomitant bladder neck reconstruction due to an ectopic ureter repair. CONCLUSIONS: The mini-sling was easy to implant and urodynamic results suggest it is effective in the treatment of neurogenic sphincteric incompetence. This statement is also supported by voiding diary records. PMID- 23648750 TI - Lytic lesions in a patient with past history of renal cancer. AB - OBJECTIVE: To study lytic lesions in a patient with past history of renal cancer. METHODS: A 62 year-old man was admitted to hospital for investigation of the cause of polyostotic bone pain. RESULTS: Brown tumors due to hyperparathyroidism turned out to be the cause of bone pain. CONCLUSIONS: Differential diagnosis is important in daily practice in order to provide a correct treatment for each condition. PMID- 23648751 TI - Paratesticular rhabdomyosarcoma: a case report. AB - OBJECTIVE: To report a case of paratesticular rhadomyosarcoma and to perform a bibliographic review. METHODS: We report the case of a 16-year-old male referred to our Department because of a left paratesticular hard tumor with progressive growth. Ultrasound examination showed a paratesticular heterogeneous mass with Internal flow on Doppler. RESULTS: The patient underwent left inguinal orchiectomy, with pathological diagnosis of rhabdomyosarcoma. He refused adjuvant chemotherapy. After being disease-free for 13 months, he presented with left colic pain. Ultrasound and CT examinations showed a left paraaortic retroperitoneal mass causing grade III ureterohydronephrosis, and lung metastases. Despite rescue chemotherapy treatment, there was no response and the abdominal mass progressed. A surgical approach was not possible since patient showed a rapid clinical worsening leading to his death a few weeks later. CONCLUSIONS: Paratesticular sarcomas are very uncommon tumors with poor prognosis. PMID- 23648752 TI - Laparoscopic partial nephrectomy with selective polar clamping using the simon clamp: initial experience. AB - OBJECTIVE: To report our initial experience in 3 cases of laparoscopic partial nephrectomy with selective parenchymal clamping using a novel laparoscopic clamp. METHODS: A total of 3 laparoscopic partial nephrectomies were performed using the Simon clamp (Aesculap). Mean patient age was 67 years (range 60 to 74 years), two patients were males. All patients had an ASA score of 2. Mean tumor size was 2.2 cm (range 2 to 2.4 cm) and all tumors were of the lower pole. Two tumors were on the right kidney and one on the left kidney. RESULTS: Mean operative time was 100 minutes (range 70 to 120 min). Mean operative bleeding was 16 ml (range 0 to 50 ml). Mean warm ischemia time of the renal pole was 33 minutes (range 30 to 40 min). All patients were discharged on postoperative day 2. There was no intra or postoperative complications. Surgical margins were negative in all cases. CONCLUSION: The Simon clamp allows for tumor resection without bleeding and for renal defect repair without collateral renal injury. We hope that in the future the development of other instruments will allow for selective clamping in any tumor location. PMID- 23648753 TI - Adrenal cavernous hemangioma: is presurgical diagnosis with imaging test possible. AB - OBJECTIVE: To describe a case of adrenal cavernous hemangioma in a 67 year old man who presented left lumbar pain. METHODS: Abdominal ultrasound, contrast enhanced ultrasound of the lesion, abdominal-pelvic CT scan, and then left adrenalectomy and pathology were performed RESULTS: Imaging studies showed a large solid-cystic mass with 12 * 11 cm diameters in the left adrenal gland, well defined, with calcifications, which showed peripheral arterial globular contrast enhancement on CT and ultrasound. The lesion displaced neighboring structures without other findings in the abdominopelvic study. The pathology report after adrenalectomy was: cavernous hemangioma with calcifications, ossifications and necrosis. CONCLUSIONS: Cavernous hemangioma is a rare cause of adrenal mass. The globular peripheral contrast uptake and gradual filling of the lesion on dynamic imaging studies (Ultrasound or CT) and phlebolith type calcifications suggest the diagnosis of typical angioma. However, the presence of thrombosis, necrosis and calcifications in large lesions confer an unusual dynamic behavior and force pathology for definitive diagnosis. PMID- 23648754 TI - Intrarenal pseudoaneurysm after percutaneous nephrolithotomy. Renal angiography and selective embolization. AB - OBJECTIVE: We present a case of intrarrenal pseudoaneuysm after percutaneous nephrolithotomy. The treatment was selective embolization of the pseudoaneurysm. We discuss the role of computerized angiotomography and angiography in these cases. We present a review of the related literature. METHODS: A computerized angiotomography (angio CT) was performed because of suspicion of a delayed vascular lesion after percutaneous nephrolithectomy. Faced with the findings of the angio CT an selective renal artery arteriography and selective embolization was performed. RESULTS: The angiotomography shows an enhanced nodular contrast in the lower third of the left kidney with a scarred area at this level suggestive of hemorrhage due to vascular lesion.Through puncture of the right common femoral artery, arteriography was performed on the left renal artery with, objectifying an amputated artery related to the bleeding situation in the calyx. After localization of the point of hemorrhage, the vessel was embolized with a 3 mm metallic microspiral GCD, 6 cm in length After embolization, the evolution of the patient was satisfactory. CONCLUSIONS: Intrarenal pseudoaneurysm is the most frequent cause of late bleeding after percutaneous nephrolithotomy. The most common symptom is hematuria that can be severe and require active treatment in order to inhibit the hemorrhage. In these cases, computerized angiotomography and angiography take on a very important diagnostic role, the latter offering the possibility to treat the hemorrhage through selective embolization of the pseudoaneurysm. PMID- 23648755 TI - Cutaneous metastasis from renal clear cell carcinoma. PMID- 23648756 TI - Urethral foreign body. PMID- 23648757 TI - Kinetic characterization of Brocadia spp.-dominated anammox cultures. AB - In this study, kinetic analyses were conducted for two Brocadia-dominated enrichment cultures, granular and flocculent, retrieved from lab-scale anaerobic ammonium oxidation (anammox) reactors. Substrate KS ranged from 0.35 to 0.69 mMN and VSmax ranged from 0.67 to 0.88 mmol Ng(-1)VSSh(-1). The model respected the experimentally measured stoichiometry of N-compounds, serving as an independent validation. Growth kinetics of the flocculent sludge was also studied, which indicates a MUmax of 0.0984 d(-1) and a YX/S of 0.105 mol C-biomass mol( 1)NH4(+). The flocculent enrichment culture was used to determine the stoichiometric equation. The kinetic parameters of the Brocadia spp. cultures measured here can be used for optimizing applications of the anammox process. PMID- 23648758 TI - Harvesting microalgae grown on wastewater. AB - The costs and life cycle impacts of microalgae harvesting for biofuel production were investigated. Algae were grown in semi-continuous culture in pilot-scale photobioreactors under natural light with anaerobic digester centrate as the feed source. Algae suspensions were collected and the optimal coagulant dosages for metal salts (alum, ferric chloride), cationic polymer (Zetag 8819), anionic polymer (E-38) and natural coagulants (Moringa Oleifera and Opuntia ficus-indica cactus) were determined using jar tests. The relative dewaterability of the algae cake was estimated by centrifugation. Alum, ferric chloride and cationic polymer could all achieve >91% algae recovery at optimal dosages. Life cycle assessment (LCA) and cost analysis results revealed that cationic polymer had the lowest cost but the highest environmental impacts, while ferric chloride had the highest cost and lowest environmental impacts. Based on the LCA results, belt presses are the recommended algae dewatering technology prior to oil extraction. PMID- 23648759 TI - Glymes as benign co-solvents for CaO-catalyzed transesterification of soybean oil to biodiesel. AB - The base (such as CaO)-catalyzed heterogeneous preparation of biodiesel encounters a number of obstacles including the need for CaO pretreatment and the reactions being incomplete (typically 90-95% yields). In this study, a number of glymes were investigated as benign solvents for the CaO-catalyzed transesterification of soybean oil into biodiesel with a high substrate loading (typically soybean oil >50% v/v). The triglyceride-dissolving capability of glymes led to a much faster reaction rate (>98% conversions in 4h) than in methanol alone (typically 24h) and minimized the saponification reaction when catalyzed by anhydrous CaO or commercial lime without pre-activation. The use of glyme (e.g. P2) as co-solvent also activates commercial lime to become an effective catalyst without calcination pretreatment. The SEM images suggest a dissolution-agglomeration process of CaO surface in the presence of P2, which could remove the CaCO3 and Ca(OH)2 layer coated on the surface of lime. PMID- 23648760 TI - A novel lignin degradation bacterial consortium for efficient pulping. AB - A lignin degradation bacterial consortium named LDC was screened from the sludge of a reeds pond by a restricted subculture. It could break down 60.9% lignin in reeds at 30 degrees C under conditions of static culture within 15 days. In order to analyze the diversity of LDC, plate isolation, 16S rDNA clone library and ARDRA (Amplified Ribosomal DNA Restriction Analysis) were performed. Six bacterial strains were isolated from LDC and eighteen DNA phylotypes were identified from 230 bacterial analyzed clones. They were classified into Clostridiales(9.1%), Geovibrio thiophilus (5.1%), Desulfomicrobium (10.9%), Pseudomonas sp. (25.2%), Azoarcus sp. (5.1%), Thauera (5.1%), Paenibacillus sp. (5.1%), Cohnella sp. (2.2%), Acinetobacter sp. (3.1%), Microbacterium (7.8%), and uncultured bacterium (21.3%). In addition, physical characteristics of paper hand sheets between biological pretreatment and chemical pretreatment were compared. The results showed that LDC had the capability of lignin degradation and was efficient for pulping, which would provide a new choice for biopulping. PMID- 23648761 TI - Conversion of organic solid waste to hydrogen and methane by two-stage fermentation system with reuse of methane fermenter effluent as diluting water in hydrogen fermentation. AB - In this study, a two-stage system converting organic solid waste (food waste+sewage sludge) to H2 and CH4 was operated. In the first stage of dark fermentative hydrogen production (DFHP), a recently proposed method that does not require external inoculum, was applied. In the second stage, anaerobic sequencing batch reactor (ASBR) and an up-flow anaerobic sludge blanket reactor (UASBr) were followed to treat H2 fermenter effluent. (H2+CH4-ASBR) system showed better performance in terms of total biogas conversion (78.6%), while higher biogas production rate (2.03 L H2/Lsystem/d, 1.96 L CH4/Lsystem/d) was achieved in (H2+CH4-UASBr) system. To reduce the alkali addition requirement in DFHP process, CH4 fermenter effluent was tested as a diluting water. Both the ASBR and UASBr effluent was effective to keep the pH above 6 without CH4 production. In case of using ASBR effluent, H2 production dropped by 15%, but alkali addition requirement was reduced by 50%. PMID- 23648762 TI - Pt/Al2O3-catalytic deoxygenation for upgrading of Leucaena leucocephala-pyrolysis oil. AB - The aim of this study was to improve the quality of bio-oil produced from the pyrolysis of Leucaena leucocephala trunks via catalytic deoxygenation using Pt/Al2O3 (Pt content=1.32% (w/w)). The minimum molar ratio of oxygen/carbon (O/C) at 0.14 was achieved when the amount of catalyst was 10% (w/w, bio-oil) and was applied under 4 bar of initial nitrogen pressure at 340 degrees C for 1h. The reaction mechanism of the catalytic deoxygenation, in terms of reforming, water gas shift and dehydration reactions, was proposed. To consider the effect of different biomass types on the efficiency of catalytic deoxygenation, the bio oils obtained from the pyrolysis of sawdust, rice straw and green microalgae were likewise evaluated for direct comparison. PMID- 23648763 TI - A simple approach for the efficient production of hydrogen from Taihu Lake Microcystis spp. blooms. AB - The death and subsequent decomposition of algal blooms is capable of depleting dissolved O2 to anaerobic levels, and this can de-inactivate hydrogenases. Inspired by this fact, a simple method for efficient H2 production from algal bloom biomass was developed. Direct transfer of Taihu Lake Microcystis spp. blooms into dark conditions resulted in H2 evolution, and yield was much greater than compared to Microcystis spp. cultured in the laboratory and reported previously in the literature. Further, efficient H2 production was inhibited significantly by light, which was most likely due to reduced O2 content and the stimulation of hydrogenase activity. Therefore, a simple approach for efficient H2 production from Taihu Lake Microcystis spp. blooms is presented. Furthermore, a post-treatment strategy for dealing with large quantities of refloated algal blooms is proposed. PMID- 23648764 TI - Optimization of CO2 bio-mitigation by Chlorella vulgaris. AB - Biofixation of CO2 by microalgae has been recognized as an attractive approach to CO2 mitigation. The main objective of this work was to maximize the rate of CO2 fixation ( [Formula: see text] ) by the green microalga Chlorella vulgaris P12 cultivated photoautotrophically in bubble column photobioreactors under different CO2 concentrations (ranging from 2% to 10%) and aeration rates (ranging from 0.1 to 0.7 vvm). Results showed that the maximum [Formula: see text] (2.22 gL(-1)d( 1)) was obtained by using 6.5% CO2 and 0.5 vvm after 7 days of cultivation at 30 degrees C. Although final biomass concentration and maximum biomass productivity of microalgae were affected by the different cultivation conditions, no significant differences were obtained in the biochemical composition of microalgal cells for the evaluated levels of aeration and CO2. The present study demonstrated that optimization of microalgal cultivation conditions can be considered a useful strategy for maximizing CO2 bio-mitigation by C. vulgaris. PMID- 23648765 TI - A noncanonical NF-kappaB pathway through the p50 subunit regulates Bcl-2 overexpression during an oxidative-conditioning hormesis response. AB - Cells can respond to damage and stress by activating various repair and survival pathways. One of these responses can be induced by preconditioning the cells with sublethal stress to provoke a prosurvival response that will prevent damage and death, and which is known as hormesis. Bcl-2, an antiapoptotic protein recognized by its antioxidant and prosurvival functions, has been documented to play an important role during oxidative-conditioning hormesis. Using an oxidative hormetic model, which was previously established in the L929 cell line by subjecting the cells to a mild oxidative stress of 50 MUM H2O2 for 9 h, we identified two different transductional mechanisms that participate in the regulation of Bcl-2 expression during the hormetic response. These mechanisms converge in activating the nuclear transcription factor NF-kappaB. Interestingly, the noncanonical p50 subunit of the NF-kappaB family is apparently the subunit that participates during the oxidative-hormetic response. PMID- 23648767 TI - Non healing legs ulcers infected with Stenotrophomonas maltophilia. AB - Stenotrophomonas maltophilia (S.M.) is a Gram-negative bacillus, naturally resistant to cephalosporins and carbapenems, which can colonize different sites and may be responsible for serious infections for which treatment is a real challenge. This was rarely reported as cutaneous pathogenic organism causing cellulitis-like lesions, paronychia, mucocutaneous ulcers and ecthyma gangrenosum in immunocompromised individuals. We report a case of non-healing legs ulcer infected with Stenotrophomonas maltophilia. PMID- 23648768 TI - Mapping memory function in the medial temporal lobe with the immediate-early gene Arc. AB - For the past two decades an increasing number of studies have underlined the crucial role of the immediate - early gene Arc in plasticity processes thought to sustain memory function. Because of the high spatial and temporal resolution of this technique, the detection of Arc products appears to have become a new standard for the mapping of cognitive processes. To date, most Arc studies have focused on identifying the contribution of the hippocampal subfields CA1 and CA3 to spatial processes. In contrast, few have investigated their role in non spatial memory, or the role of other medial temporal lobe (MTL) areas in spatial and non-spatial memory. This short review describes recent studies focusing on these issues. After a brief overview of Arc's functions, we report a set of studies that put to the test some well-accepted theories in recognition memory. First, we describe data indicating that the parahippocampal areas may not be strictly segregated into spatial and non-spatial streams, as originally described. Second, we report findings revealing a functional segregation along the dorsoventral axis in CA1, but not in CA3. Finally, we bring evidence for a segregation of CA3 along the proximodistal axis and discuss the involvement of a proximal CA3-distal CA1 network during non-spatial memory. In summary, 'Arc imaging' appears to be a powerful tool to identify neural substrates of cognitive processes, not only in the hippocampus but also in the remaining of the MTL. Moreover, because of its fundamental role in synaptic processes, it offers a rare and exciting opportunity to further bridge plasticity processes and memory function. PMID- 23648769 TI - The effect of job strain on psychological morbidity and quality of life in military hospital nurses in Taiwan: a follow-up study. AB - This study investigated changes in job strain in female nurses serving in a military hospital system being restructured and the effect of these changes on psychological morbidity and quality of life (QOL). Questionnaire surveys were sent twice to 618 nurses working in three military hospitals in southern Taiwan at the beginning and at follow up a half year later. A Job Content Questionnaire was used to divide subjects into high and low strain groups. The General Health Questionnaire and the WHO QOL Questionnaire were used to assess psychological morbidity and QOL. Four hundred eighteen nurses completed the study. Initially, the high strain group had a greater prevalence of psychological morbidity and lower QOL than the low strain group. At follow up, high strain group did not have a greater prevalence of psychological morbidity, though significant differences in QOL remained. Job control and social support directly affected the QOL (B=0.42, p<0.001; B=0.41, p=0.038, respectively) and the psychological demand affected directly on psychological morbidity (B=0.12, p<0.001). Job control and psychological demand are different aspects in job strain to impact the psychological morbidity and QOL in nurses working in military hospitals in Taiwan. PMID- 23648770 TI - Hazardous workplace review program in Taiwan. AB - In Taiwan, relevant mid-term plans and projects of mitigating occupational hazards have been launched in recent years in the hopes of lowering the incidence of occupational hazards. In light of the lack of objective methodologies for researches on issues pertaining occupational safety and health, this research aims to explore the priorities of safety and health issues through focal groups, expert questionnaires and interviews on relevant issues such as hazard installations identified in R181 Prevention of Major Industrial Accidents Recommendation, 1993 proposed during the 18th World Congress on Safety and Health at work in Seoul 2008. Results revealed that distribute reports of major domestic/foreign occupational disasters to relevant sectors for the prevention of major accidents is needed, both from the importance and feasibility analysis. It is the only topic that scored over 4 points in average for expert and focal group consensus. Furthermore, the experts and focal groups came to consensus in the ranking of priority for 4 items, namely: 1) Installations containing/using large quantities of hazardous materials should be prioritized for inspection, 2) Incorporation of hazard installation review/inspection into OSH management system accreditation, 3) Impose operation shutdown as a means of penalty) and 4) Prioritize the promotion of preliminary PHA. PMID- 23648771 TI - A cross-sectional study on association of work environment, coping style, and other risk factors with depression among caregivers in group homes in Japan. AB - A cross-sectional study was conducted to explore the potential association between work environment and/or stress coping ability, and depressive status among caregivers working for "group homes (GHs)" in Japan. In January 2010, 438 out of 700 caregivers working at GHs in Sapporo City returned completed questionnaires to us. The questionnaires consisted of the Center of Epidemiological Scales-Depression, items about worker's attributions, Ozeki's coping scale, and so on. An analysis using a logistic regression model was used to find the associations adjusting for gender and age. Subjects who were 45 yr or older, had a spouse, had job training, a standard workload and scored high in emotion-oriented coping were significantly associated with a decreased risk of depression. Subjects who were less proud of their job, less willing to continue care for the frail elderly and had fewer acceptances by their supervisors or colleagues for consultation were significantly associated with an increased risk of depression. This study supports our hypothesis that there can be possible variables among individual factors, work environment and/or coping style for stress which may modulate a risk on the depressive status of caregivers. PMID- 23648772 TI - A prospective study of psychosocial work characteristics and long sick leave of Japanese male employees in multiple workplaces. AB - The aim of this study was to identify psychosocial work characteristics associated with long sick leave in a large population of male Japanese employees in multiple workplaces. We examined various psychosocial work characteristics (job overload, job control, supervisor support, coworker support, support by family and friends, role ambiguity, role conflict, intragroup conflict and intergroup conflict) of employees in six factories at the base line. We then conducted a follow-up survey on the recorded long sick leaves of >= 30 continuous days taken by the employees due to any medical condition. We found 574 cases of long sick leave out of 15,531 subjects during an average 5.07-yr follow-up. The results showed that high supervisor support was significantly associated with a decrease in the hazard ratio (HR) of long sick leave after adjustment for several confounding factors (95%CI; 0.69-0.97). High role ambiguity also tended to increase HR, but without reaching significance (95%CI; 0.99-1.41). The results suggest that supervisor support in the workplace may be important to reduce long sick leave in Japanese male employees. PMID- 23648773 TI - Hyperpolarization of amino acid precursors to neurotransmitters with parahydrogen induced polarization. AB - Several important neurotransmitter precursors were hyperpolarized via homogeneous hydrogenation with parahydrogen. Polarization enhancement was achieved for (1)H and (13)C spins by several orders of magnitude compared to thermal spectra. Such large signal enhancements of these molecules could facilitate neurotransmitter studies. PMID- 23648774 TI - Mesotocin and maternal care of chicks in native Thai hens (Gallus domesticus). AB - Oxytocin (OT) is known to induce and regulate maternal behaviors in mammals via the supraoptic nucleus and paraventricular nucleus (PVN), whereas the function of mesotocin (MT; the avian homolog of OT) is poorly understood in birds. To elucidate the association of MT and the regulation of maternal behaviors in birds, we studied changes in the number of MT-immunoreactive (ir) neurons in native Thai chickens using immunohistochemistry. We observed that MT-ir neurons and fibers appeared in discrete regions located close to the third ventricle from the level of the preoptic area through the anterior hypothalamus with an abundance observed in the nucleus supraopticus, pars ventralis (SOv), nucleus preopticus medialis (POM), and PVN. The number of MT-ir neurons was low in the SOv, POM, and PVN of non-laying hens, but it increased gradually when the hens entered the laying stage, and peaked in incubating and rearing hens. We compared the number of MT-ir neurons in the SOv, POM, and PVN of native Thai hens rearing chicks (R) with that of non-rearing chicks (NR). The number of MT-ir neurons was high in the R hens, but low in the NR hens in these nuclei. For the first time, these results indicate that the association between the MT neurons and the presence of chicks might, in part, play a role in the neuroendocrine reorganization to establish and maintain maternal behaviors in native Thai chickens. MTergic activity is likely related to the contribution of rearing behavior in this equatorial precocial species. PMID- 23648775 TI - Endocrinology of sociality: comparisons between sociable and solitary individuals within the same population of African striped mice. AB - The social organization of species ranges from solitary-living to complex social groups. While the evolutionary reasons of group-living are well studied, the physiological mechanisms underlying alternative social systems are poorly understood. By studying group-living and solitary individuals of the same species, we can determine hormonal correlates of sociality without the problem of confounding phylogenetic factors. The African striped mouse (Rhabdomys pumilio) is a socially flexible species, which can be solitary or alternatively form complex family groups, depending on population density and the extent of reproductive competition. We predicted group-living striped mice to show signs of reproductive suppression and social stress, resulting in higher corticosterone but lower testosterone levels when compared to solitary-living individuals. To determine whether differences in social organization correlated with hormonal differences, we collected blood samples from free-living striped mice during four breeding seasons when we experimentally induced solitary-living in philopatric individuals by locally reducing population density. Striped mice that were group living did not change their corticosterone or estosterone levels during the study, indicating that there was no temporal effect during the breeding season. Striped mice of both sexes had significantly lower corticosterone levels after switching from group- to solitary-living. Solitary males - but not solitary females - had higher testosterone levels than group-living conspecifics. Our results suggest that group-living results in physiological stress and can induce reproductive suppression, at least in philopatric males. The switch to solitary living may thus be a tactic to avoid reproductive competition within groups, and is associated with decreased stress hormone levels and onset of independent reproduction. PMID- 23648776 TI - Sensitization of sexual behavior in ovariectomized rats by chronic estradiol treatment. AB - The ovariectomized (OVX) rat treated with estradiol benzoate (EB) is used to elucidate neuroendocrine mechanisms of sexual behavior. Chronic behavioral and pharmacological manipulations can be confounded by rising baselines, since females are behaviorally more sensitive to repeated EB injections. The literature lacks a systematic examination of chronic effects of EB administered alone to the sexually experienced OVX rat. Long-Evans rats were repeatedly treated (8 tests) with s.c. injections of 2, 5, or 10 MUg EB at different time intervals (4 or 8 days). Female sexual behaviors as well as receipt of mounts, intromissions and ejaculations from the male were observed in the unilevel 4-hole pacing chamber. The effects of adrenalectomy (ADX) and strain (Long-Evans vs. Wistar) were also assessed. Long-Evans OVX rats treated with 5 MUg EB every 8 days showed persistently low levels of sexual behavior. Sensitization was most robust following 10 MUg EB at 4-day intervals. Very few sexual behaviors were ever induced by 2 MUg EB. ADX did not affect the development of behavioral sensitization by 10MUg EB. Therefore, to achieve a low steady state of sexual behaviors in sexually experienced Long-Evans OVX rats 5MUg of EB administered every 8days is optimal, whereas a persistently high level of sexual behaviors is induced with 10 MUg EB administered every 4 days. OVX Wistar rats are behaviorally more sensitive to EB. Behavioral sensitization to EB may serve as a mechanism to optimize reproductive success. PMID- 23648777 TI - Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study. AB - BACKGROUND: The purpose of this study was to assess the incidence of neurological complications in patients with infective endocarditis, the risk factors for their development, their influence on the clinical outcome, and the impact of cardiac surgery. METHODS AND RESULTS: This was a retrospective analysis of prospectively collected data on a multicenter cohort of 1345 consecutive episodes of left-sided infective endocarditis from 8 centers in Spain. Cox regression models were developed to analyze variables predictive of neurological complications and associated mortality. Three hundred forty patients (25%) experienced such complications: 192 patients (14%) had ischemic events, 86 (6%) had encephalopathy/meningitis, 60 (4%) had hemorrhages, and 2 (1%) had brain abscesses. Independent risk factors associated with all neurological complications were vegetation size >=3 cm (hazard ratio [HR] 1.91), Staphylococcus aureus as a cause (HR 2.47), mitral valve involvement (HR 1.29), and anticoagulant therapy (HR 1.31). This last variable was particularly related to a greater incidence of hemorrhagic events (HR 2.71). Overall mortality was 30%, and neurological complications had a negative impact on outcome (45% of deaths versus 24% in patients without these complications; P<0.01), although only moderate to severe ischemic stroke (HR 1.63) and brain hemorrhage (HR 1.73) were significantly associated with a poorer prognosis. Antimicrobial treatment reduced (by 33% to 75%) the risk of neurological complications. In patients with hemorrhage, mortality was higher when surgery was performed within 4 weeks of the hemorrhagic event (75% versus 40% in later surgery). CONCLUSIONS: Moderate to severe ischemic stroke and brain hemorrhage were found to have a significant negative impact on the outcome of infective endocarditis. Early appropriate antimicrobial treatment is critical, and transitory discontinuation of anticoagulant therapy should be considered. PMID- 23648778 TI - Cardiovascular health: the importance of measuring patient-reported health status: a scientific statement from the American Heart Association. PMID- 23648780 TI - Smart solutions from the plant kingdom. PMID- 23648782 TI - Amphiphilic glycopolymer nanoparticles as vehicles for nasal delivery of peptides and proteins. AB - Nasal drug delivery system has been a very promising route for delivery of proteins and peptides for the reason that it can avoid degradation in gastrointestinal tract and metabolism by liver enzymes. However, the bioavailability of proteins and peptides is still low due to the rapid clearance of mucociliary. Here, to prolong the residence time of drugs and improve their absorption, we prepared amphiphilic glycopolymer poly(2-lactobionamidoethyl methacrylate-random-3-acrylamidophenylboronic acid) (p(LAMA-r-AAPBA), and the glycopolymer could assemble into the nanoparticles with narrow size distribution. Insulin, as a model drug, was efficiently encapsulated within the nanoparticles, and loading capacity was up to 12%. In vitro study revealed that the insulin release could be controlled by modifying the composition of glycopolymers. Cell viability showed that p(LAMA-r-AAPBA) nanoparticles had good cytocompatibility. Moreover, the mechanism of nanoparticle internalization into Calu-3 cells was a combination mechanism of clathrin-mediated endocytosis and lipid raft/caveolae mediated endocytosis. Importantly, there was a significant decrease in the blood glucose levels after the nasal administration of p(LAMA-r-AAPBA) nanoparticles to diabetic rats. Therefore, p(LAMA-r-AAPBA) glycopolymers have a potential application as a nasal delivery systems for proteins and peptides. PMID- 23648781 TI - Dopaminergic modulation of affective and social deficits induced by prenatal glucocorticoid exposure. AB - Prenatal stress or exposure to elevated levels of glucocorticoids (GCs) can impair specific neurobehavioral circuits leading to alterations in emotional processes later in life. In turn, emotional deficits may interfere with the quality and degree of social interaction. Here, by using a comprehensive behavioral approach in combination with the measurement of ultrasonic vocalizations, we show that in utero GC (iuGC)-exposed animals present increased immobility in the forced swimming test, pronounced anhedonic behavior (both anticipatory and consummatory), and an impairment in social interaction at different life stages. Importantly, we also found that social behavioral expression is highly dependent on the affective status of the partner. A profound reduction in mesolimbic dopaminergic transmission was found in iuGC animals, suggesting a key role for dopamine (DA) in the etiology of the observed behavioral deficits. Confirming this idea, we present evidence that a simple pharmacological approach-acute L-3,4-dihydroxyphenylacetic acid (L-DOPA) oral administration, is able to normalize DA levels in iuGC animals, with a concomitant amelioration of several dimensions of the emotional and social behaviors. Interestingly, L-DOPA effects in control individuals were not so straightforward; suggesting that both hypo- and hyperdopaminergia are detrimental in the context of such complex behaviors. PMID- 23648783 TI - The role of hepatic transport and metabolism in the interactions between pravastatin or repaglinide and two rOatp inhibitors in rats. AB - A change in the function or expression of hepatic drug transporters may have significant effect on the efficacy or safety of orally administered drugs. Although a number of clinical drug-drug interactions associated with hepatic transport proteins have been reported, in practice it is not always straightforward to discriminate other pathways (e.g. drug metabolism) from being involved in these interactions. The present study was designed to assess the interactions between organic anion transporting polypeptide (Oatp) substrates (pravastatin or repaglinide) and inhibitors (spironolactone or diphenhydramine) in vivo in rats. The mechanisms behind the interactions were then investigated using in vitro tools (isolated hepatocytes and rat liver microsomes). The results showed a significant increase in the systemic exposures of pravastatin (2.5-fold increase in AUC) and repaglinide (1.8-fold increase in AUC) after co administration of spironolactone to rats. Diphenhydramine increased the AUC of repaglinide by 1.4-fold. The in vivo interactions observed in rats between Oatp substrates and inhibitors may a priori be classified as transport-mediated drug drug interactions. However, mechanistic studies performed in vitro using both isolated rat hepatocytes and rat liver microsomes showed that the interaction between pravastatin and spironolactone may be solely linked to the inhibition of pravastatin uptake in liver. On the contrary, the inhibition of cytochrome P450 seemed to be the reason for the interactions observed between repaglinide and spironolactone. Although the function and structure of transport proteins may vary between rats and humans, the approach used in the present study can be applied to humans and help to understand the role of drug transport and drug metabolism in a given drug-drug interaction. This is important to predict and mitigate the risk of drug-drug interactions for a candidate drug in pre-clinical development, it is also important for the optimal design of drug-drug interactions studies in the clinic. PMID- 23648784 TI - Surgery. Translating trials to clinical practice in cardiac surgery. PMID- 23648785 TI - Interventional cardiology. PCI without surgical backup--evidence-based, but wise? PMID- 23648786 TI - Prevention. Low adoption of healthy lifestyles. PMID- 23648787 TI - Imaging: myocardial thinning is not always transmural scarring. PMID- 23648788 TI - Double-blind comparative trial with 2 antiregurgitation formulae. AB - BACKGROUND AND AIM: Many mothers consult physicians because of frequent infant regurgitation. Guidelines recommend reassurance and dietary treatment as first approaches. The aim of the present study was to test and compare the efficacy of 2 antiregurgitation formulae (ARF). METHODS: A prospective, double-blind, randomized cross-over trial was performed for a 1-month period in 115 formula-fed infants (ages 2 weeks-5 months) comparing 2 ARF (ARF-1: nonhydrolyzed protein, locust bean gum; ARF-2: specific whey hydrolysate, locust bean gum, specially treated starch). The primary endpoint was the incidence of regurgitation. RESULTS: At inclusion, mean age was 9.1 weeks; anthropometric parameters did not differ between the groups. According to the intention-to-treat analysis, the mean number of episodes of regurgitation decreased from 8.25 to 2.32 with ARF-1 and to 1.89 with ARF-2 (statistically significant difference between both ARF, P = 0.0091). The mean score of regurgitated volume decreased significantly more with ARF-2 than with ARF-1 (P = 0.0265). There was no significant difference in stool frequency and consistency between both groups. CONCLUSIONS: The efficacy of both ARF was demonstrated by the decreased number and volume of regurgitations. ARF-2 was statistically more effective than ARF-1. Comparative trials enable the selection of the best therapeutic option. PMID- 23648789 TI - Health-related quality of life in children with intestinal failure. AB - OBJECTIVES: Survival of infants with intestinal failure (IF) has increased in the past decade; however, data on their health-related quality of life (HRQOL) are lacking. We hypothesized that HRQOL would be lower among children with IF compared with that of healthy children. METHODS: We performed a cross-sectional study of the HRQOL of children enrolled in the outpatient intestinal rehabilitation program at Seattle Children's Hospital using the PedsQL 4.0 Generic Core Scales parent proxy-report and the Family Impact Module questionnaires. Parents were asked 2 open-ended questions pertaining to the suitability and completeness of the PedsQL to assess their and their child's HRQOL. RESULTS: Parents of 23 children with IF completed the questionnaires. Compared with norms for healthy children, parents reported significantly lower total PedsQL scores for children ages 1 to 2 years (mean difference -13.16, 95% confidence interval [CI] -21.86 to -4.46; P = 0.003) and 2 to 6 years (mean difference -15.57, 95% CI -22.66 to -8.48; P < 0.001). Scores were also lower for children younger than 1 year (mean difference -6.43, 95% CI -13.93 to 1.07), although this test was not statistically significant. No measured demographic or clinical characteristics were associated with HRQOL. The majority of parents (65%) said the PedsQL failed to address important effects of IF on children and their families. CONCLUSIONS: Children with IF and their parents have a decreased HRQOL compared with healthy children as measured by the PedsQL survey. A disease specific module or separate HRQOL questionnaire is needed for a more comprehensive assessment of HRQOL in children with IF. PMID- 23648791 TI - Diabetes mellitus in microvillus inclusion disease. PMID- 23648790 TI - Self-management in pediatric inflammatory bowel disease: A clinical report of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. AB - This clinical report aims to review key self-management and adherence issues in pediatric inflammatory bowel disease (IBD) and to provide recommendations for health care providers regarding evidence-based assessment and treatment approaches to promote optimal self-management. Self-management difficulties in the form of nonadherence to treatment regimens are common in pediatric IBD and are influenced by various disease-related, individual, family, and health professional relationship factors. To promote adaptive self-management, health care providers are encouraged to adopt a long-term preventive orientation, which includes routine screening of barriers to self-management and nonadherence in the context of routine clinic appointments. The use of a multimethod approach to assessment that incorporates objective measures (eg, pill counts or bioassays) may be particularly advantageous. Individualized treatment approaches that incorporate evidence-based practices, such as providing written treatment plans and offering opportunities to practice and receive feedback on skills, may help to ameliorate minor self-management concerns; however, more severe or chronic self-management problems may require a referral for behavioral health intervention. Additional research to broaden our understanding of self-management in domains beyond medication adherence and to evaluate the effect of clinic-based interventions is imperative. PMID- 23648792 TI - Colon preparation for children: the quest for the ideal protocol. PMID- 23648793 TI - Origins of power-law degree distribution in the heterogeneity of human activity in social networks. AB - The probability distribution of number of ties of an individual in a social network follows a scale-free power-law. However, how this distribution arises has not been conclusively demonstrated in direct analyses of people's actions in social networks. Here, we perform a causal inference analysis and find an underlying cause for this phenomenon. Our analysis indicates that heavy-tailed degree distribution is causally determined by similarly skewed distribution of human activity. Specifically, the degree of an individual is entirely random - following a "maximum entropy attachment" model - except for its mean value which depends deterministically on the volume of the users' activity. This relation cannot be explained by interactive models, like preferential attachment, since the observed actions are not likely to be caused by interactions with other people. PMID- 23648794 TI - Temperature sensitivity of cellulase adsorption on lignin and its impact on enzymatic hydrolysis of lignocellulosic biomass. AB - Unproductive enzyme adsorption is an important factor in addition to steric hindrance of lignin that limits the enzymatic hydrolysis of lignocellulosic biomass. While both are important factors, enzymatic hydrolysis of pretreated biomass is most likely conducted in the presence of certain amount of lignin residues that may not necessarily present accessibility hindrance, but can competitively absorb the enzyme. This paper presents a study with purified lignin samples to elucidate the role of unproductive enzyme adsorption. It appeared that lignin adsorbed cellulase quickly at 4 degrees C with adsorption equilibrium reached within 1h, similar to that observed for crystalline cellulose. Increasing temperature to 50 degrees C (typical hydrolytic reaction condition) facilitated the rate of cellulase adsorption on cellulose with a peak of adsorption reached at 0.25 h; however, adsorption on lignin was surprisingly slower and took over 12h to reach equilibrium, which was accompanied with a 10-fold increase in adsorption capacity. Despite the high adsorption capacity of lignin (which is comparable to that of cellulose) at 50 degrees C, the presence of added lignin imposed only minimal impact on the enzyme apparent activity, most likely due to the slow adsorption kinetics of lignin. PMID- 23648795 TI - Drug-DNA interactions and their study by UV-Visible, fluorescence spectroscopies and cyclic voltametry. AB - The present paper review the drug-DNA interactions, their types and applications of experimental techniques used to study interactions between DNA and small ligand molecules that are potentially of pharmaceutical interest. DNA has been known to be the cellular target for many cytotoxic anticancer agents for several decades. Understanding how drug molecules interact with DNA has become an active research area at the interface between chemistry, molecular biology and medicine. In this review article, we attempt to bring together topics that cover the breadth of this large area of research. The interaction of drugs with DNA is a significant feature in pharmacology and plays a vital role in the determination of the mechanisms of drug action and designing of more efficient and specifically targeted drugs with lesser side effects. Several instrumental techniques are used to study such interactions. In the present review, we will discuss UV-Visible spectroscopy, fluorescence spectroscopy and cyclic voltammetry. The applications of spectroscopic techniques are reviewed and we have discussed the type of information (qualitative or quantitative) that can be obtained from the use of each technique. Not only have novel techniques been applied to study drug-DNA interactions but such interactions may also be the basis for the development of new assays. The interaction between DNA and drugs can cause chemical and conformational modifications and, thus, variation of the electrochemical properties of nucleobases. PMID- 23648796 TI - Protoapigenone derivatives: albumin binding properties and effects on HepG2 cells. AB - Protoapigenone (Pa) is a flavone aglycone with a p-quinol structure in its B ring. It was first discovered in Thelypteris torresiana, a native fern in Taiwan. Recent studies highlighted that protoapigenone and some of its derivatives show very potent anticancer activity against several types of tumors, using both in vitro and in vivo models. Despite the growing body of evidence on the selective anticancer potential of protoapigenone and its derivatives, no data are available on their pharmacokinetical properties. In our present research, albumin binding properties of Pa and seven different 1'-O-alkyl protoapigenone derivatives were analyzed as well as their biochemical effects on HepG2 tumor cell line in comparison with the flavone apigenin. Our results are in good accordance with the data of previous investigations of 1'-O-alkylated derivatives of protoapigenone (with the exception of isopropyl and allyl derivatives) showing similar or higher antitumor effects than Pa. Furthermore structural changes in Pa cause a very remarkable influence on plasma albumin binding affinity of the derivatives. Our investigation proves that parallel with changes of lipophilic character and extent of plasma protein binding properties of Pa derivatives a consequent alteration occurs in their pharmacokinetic behavior without losing the pharmacodynamic effect. Based on our study a better understanding of the structural and biochemical behavior of different chemically modified flavonoid derivatives could be achieved making further design of in vivo experiments feasible. PMID- 23648797 TI - ctDNA binding affinity and in vitro antitumor activity of three Keggin type polyoxotungestates. AB - The ctDNA-binding properties and in vitro antitumor activity of three water soluble Keggin type polyoxometalates (POMs): K6H[CoW11O39CpZr].nH2O, K6H[CoW11O39CpTi.nH2O and K7H2[CoW11O39CpFe].nH2O (abbreviated as CoWCpZr, CoWCpTi and CoWCpFe, respectively) were investigated using UV-Vis absorption spectroscopy, fluorescence spectrophotometry, cyclic voltammetry and MTT assay. The results of UV-Vis, fluorescence and cyclic voltammetry rule out intercalating binding mode and propose the groove or outside stacking binding of these POMs with ctDNA. The values of 1.30*10(4) M(-1), 1.15*10(4) M(-1) and 3.10*10(3) M(-1) were obtained for binding constant of CoWCpZr, CoWCpTi and CoWCpFe to ctDNA, respectively. The redox potential of POMs shift to more negative values in the presence of ctDNA which can be related to domination of electrostatic interaction in this system. The antitumor activity tests of these polyoxometalates (POMs) were carried out on two types of human cancer cells, MCF-7 and HEK-293 by MTT method. The results show the higher antitumor activity of CoWCpFe respect to two other that is related to its highest penetrating effectiveness for MCF-7 cells. Therefore, the antitumor activity of these POMs depends not only on their affinity to ctDNA but also strongly on their penetration ability to the cell membrane. PMID- 23648799 TI - Structure-function relationship of the foam-like pomelo peel (Citrus maxima)-an inspiration for the development of biomimetic damping materials with high energy dissipation. AB - The mechanical properties of artificial foams are mainly determined by the choice of bulk materials and relative density. In natural foams, in contrast, variation to optimize properties is achieved by structural optimization rather than by conscious substitution of bulk materials. Pomelos (Citrus maxima) have a thick foam-like peel which is capable of dissipating considerable amounts of kinetic energy and thus this fruit represents an ideal role model for the development of biomimetic impact damping structures. This paper focuses on the analysis of the biomechanics of the pomelo peel and on its structure-function relationship. It deals with the determination of the onset strain of densification of this foam like tissue and on how this property is influenced by the arrangement of vascular bundles. It was found here that the vascular bundles branch in a very regular manner-every 16.5% of the radial peel thickness-and that the surrounding peel tissue (pericarp) attains its exceptional thickness mainly by the expansion of existing interconnected cells causing an increasing volume of the intercellular space, rather than by cell division. These findings lead to the discussion of the pomelo peel as an inspiration for fibre-reinforced cast metallic foams with the capacity for excellent energy dissipation. PMID- 23648800 TI - Advanced glycation end-products and cathepsin cysteine protease in type 2 diabetic patients. AB - INTRODUCTION: In type 2 diabetes, chronic hyperglycemia induces multi-faceted disturbances and contributes to late diabetic complications. Nonenzymatic glycation, leading to formation of advanced glycation end-products (AGEs), is one of the most important consequences of hyperglycemia. Alterations in the function of some proteolytic enzymes are also observed in diabetes. OBJECTIVES: The aim of the study was to assess the changes in and correlations between the plasma levels of AGEs and the activity of a proteolytic enzyme - cysteine cathepsin B - in plasma and neutrophils derived from patients with type 2 diabetes. PATIENTS AND METHODS: In 102 patients with type 2 diabetes and 55 healthy adults, the plasma levels of total AGEs, low-molecular-weight AGEs (LWM-AGEs), and high-molecular weight AGEs (HWM-AGEs) as well as cathepsin B activity in plasma and neutrophils were measured by fluorescence methods. Diabetic complications in patients were also evaluated. RESULTS: Diabetic patients had significantly higher levels and activities of all the parameters compared with the control group. Moreover, in these patients, HMW-AGEs correlated negatively with plasma cathepsin B and LMW AGEs with neutrophil cathepsin B. In the quartiles of the increasing levels of HMW-AGEs and LMW-AGEs, a successive decrease of cathepsin B in plasma and neutrophils, respectively, was observed. In patients with different late diabetic complications only the plasma level of LMW-AGEs was significantly different. CONCLUSIONS: Our study showed a significant increase of all forms of AGEs and corresponding changes in the activity of cathepsin B, both in plasma and neutrophils. A significant correlation between AGEs and cathepsin B as well as the ambiguous character of their alterations in patients with late diabetic complications indicate that they exert a complex effect on the course of diabetes. PMID- 23648801 TI - RANEY(r) Ni catalyzed transfer hydrogenation of levulinate esters to gamma valerolactone at room temperature. AB - A catalytic transfer hydrogenation process was developed for the production of gamma-valerolactone (GVL) from ethyl levulinate (EL) and a H-donor at room temperature. Ethyl levulinate was almost quantitatively converted to gamma valerolactone. Further, a two step process for producing GVL from biomass derived platform molecules was also reported. PMID- 23648802 TI - False memories and memory confidence in borderline patients. AB - BACKGROUND AND OBJECTIVES: Mixed results have been obtained regarding memory in patients with borderline personality disorder (BPD). Prior reports and anecdotal evidence suggests that patients with BPD are prone to false memories but this assumption has to been put to firm empirical test, yet. METHODS: Memory accuracy and confidence was assessed in 20 BPD patients and 22 healthy controls using a visual variant of the false memory (Deese-Roediger-McDermott) paradigm which involved a negative and a positive-valenced picture. RESULTS: Groups did not differ regarding veridical item recognition. Importantly, patients did not display more false memories than controls. At trend level, borderline patients rated more items as new with high confidence compared to healthy controls. CONCLUSIONS: The results tentatively suggest that borderline patients show uncompromised visual memory functions and display no increased susceptibility for distorted memories. PMID- 23648803 TI - Biological and statistical approaches for modeling exposure to specific trihalomethanes and bladder cancer risk. AB - Lifetime exposure to trihalomethanes (THM) has been associated with increased risk of bladder cancer. We explored methods of analyzing bladder cancer risk associated with 4 THM (chloroform, bromodichloromethane, dibromochloromethane, and bromoform) as surrogates for disinfection by-product (DBP) mixtures in a case control study in Spain (1998-2001). Lifetime average concentrations of THM in the households of 686 incident bladder cancer cases and 750 matched hospital-based controls were calculated. Several exposure metrics were modeled through conditional logistic regression, including the following analyses: total THM (MUg/L), cytotoxicity-weighted sum of total THM (pmol/L), 4 THM in separate models, 4 THM in 1 model, chloroform and the sum of brominated THM in 1 model, and a principal-components analysis. THM composition, concentrations, and correlations varied between areas. The model for total THM was stable and showed increasing dose-response trends. Models for separate THM provided unstable estimates and inconsistent dose-response relationships. Risk estimation for specific THM is hampered by the varying composition of the mixture, correlation between species, and imprecision of historical estimates. Total THM (MUg/L) provided a proxy measure of DBPs that yielded the strongest dose-response relationship with bladder cancer risk. A variety of metrics and statistical approaches should be used to evaluate this association in other settings. PMID- 23648804 TI - Regional and neighborhood disparities in the odds of type 2 diabetes: results from 5 population-based studies in Germany (DIAB-CORE consortium). AB - The objective of this study was to investigate the association between residential environment and type 2 diabetes. We pooled cross-sectional data from 5 population-based German studies (1997-2006): the Cardiovascular Disease, Living and Ageing in Halle Study, the Dortmund Health Study, the Heinz Nixdorf Recall Study, the Cooperative Health Research in the Region of Augsburg Study, and the Study of Health in Pomerania. The outcome of interest was the presence of self reported type 2 diabetes. We conducted mixed logistic regression models in a hierarchical data set with 8,879 individuals aged 45-74 years on level 1; 226 neighborhoods on level 2; and 5 study regions on level 3. The analyses were adjusted for age, sex, social class, and employment status. The odds ratio for type 2 diabetes was highest in eastern Germany (odds ratio = 1.98, 95% confidence interval: 1.81, 2.14) and northeastern Germany (odds ratio = 1.58, 95% confidence interval: 1.40, 1.77) and lowest in southern Germany (reference) after adjustment for individual variables. Neighborhood unemployment rates explained a large proportion of regional differences. Individuals residing in neighborhoods with high unemployment rates had elevated odds of type 2 diabetes (odds ratio = 1.62, 95% confidence interval: 1.25, 2.09). The diverging levels of unemployment in neighborhoods and regions are an independent source of disparities in type 2 diabetes. PMID- 23648805 TI - Evaluating the impact of database heterogeneity on observational study results. AB - Clinical studies that use observational databases to evaluate the effects of medical products have become commonplace. Such studies begin by selecting a particular database, a decision that published papers invariably report but do not discuss. Studies of the same issue in different databases, however, can and do generate different results, sometimes with strikingly different clinical implications. In this paper, we systematically study heterogeneity among databases, holding other study methods constant, by exploring relative risk estimates for 53 drug-outcome pairs and 2 widely used study designs (cohort studies and self-controlled case series) across 10 observational databases. When holding the study design constant, our analysis shows that estimated relative risks range from a statistically significant decreased risk to a statistically significant increased risk in 11 of 53 (21%) of drug-outcome pairs that use a cohort design and 19 of 53 (36%) of drug-outcome pairs that use a self-controlled case series design. This exceeds the proportion of pairs that were consistent across databases in both direction and statistical significance, which was 9 of 53 (17%) for cohort studies and 5 of 53 (9%) for self-controlled case series. Our findings show that clinical studies that use observational databases can be sensitive to the choice of database. More attention is needed to consider how the choice of data source may be affecting results. PMID- 23648806 TI - Free-style perforator flaps in the reconstruction of the lower limb. AB - INTRODUCTION: The evolving concept of free-style flaps with one or more perforators able to lend support, has been shown to have noteworthy advantages in the context of reconstructive surgery, especially in relation to the distal portion of the lower limb. Among the advantages, an analogy of the covering tissues with pre-existing ones in the compromised area, reduced morbidity of the donor site, less time spent in theatre and a greater flexibility from the surgeons' point of view. MATERIAL AND METHODS: Between 2009 and 2012, 18 patients were treated with local free-style flaps for lesions involving the leg and the foot. The median age of the patients, (11 men and 7 women) was 63.2 years. Subsequently, the patients were followed up for 6 months-1 year. RESULTS: In the period following surgery all the free style flaps have survived completely; further surgery has not been warranted. Healing of the donor sites took place by primary intention in 17 cases; in one case, a V-Y advancement flap adapted as a cover for a loss of substance of the calcaneus, it occurred by secondary intention. DISCUSSION AND CONCLUSIONS: Lower limb reconstruction, in virtue of the fact that adjacent tissues for reconstruction are scarce and vascularization is an issue, has always constituted a problem which has not been easy to solve for the surgeon. The application of the free-style concept to loco-regional flaps has yielded satisfactory results in our experience, from both a functional as well as an aesthetic point of view. PMID- 23648807 TI - LOX-1 in the maintenance of cytoskeleton and proliferation in senescent cardiac fibroblasts. AB - Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) is one of the most important receptors for binding and uptake of ox-LDL in endothelial cells, vascular smooth muscle cells and cardiomyocytes. In this study in cultured mice heart fibroblasts, we describe a decrease in LOX-1 expression as these cells go through successive passages. Further, fibroblast aging is associated with significant changes in morphology and proliferation ability. The same phenomena were observed in primary cardiac fibroblasts isolated from the aged mice (130 week). We also noted that the senescent fibroblasts have increased susceptibility to apoptosis and have a disorganized cytoskeleton. To ascertain the contribution of LOX-1 in the decline in proliferative ability and morphological changes in the aged cells, senescent fibroblasts were transfected with h-LOX-1. Transfection with h-LOX-1 resulted in cytoskeleton reorganization and partial restoration of the expression of related proteins, CDC42 and p70 S6 kinase. Upregulation of LOX 1 also significantly enhanced their proliferation potential and restored the expression of related genes Mdm2 and phos-Akt, and modestly reduced the expression of aging markers 4-HNE and beta-catenin. These findings suggest that LOX-1 contributes, at least in part, to the process of fibroblast senescence and may be viewed as a new aging maker. PMID- 23648810 TI - Novel combination of collagen dynamics analysis and transcriptional profiling reveals fibrosis-relevant genes and pathways. AB - Collagen deposition is a key process during idiopathic pulmonary fibrosis; however, little is known about the dynamics of collagen formation during disease development. Tissue samples of early stages of human disease are not readily available and it is difficult to identify changes in collagen content, since standard collagen analyses do not distinguish between 'old' and 'new' collagen. Therefore, the current study aimed to (i) investigate the dynamics of new collagen formation in mice using bleomycin-induced lung fibrosis in which newly synthesized collagen was labeled with deuterated water and (ii) use this information to identify genes and processes correlated to new collagen formation. Lung fibrosis was induced in female C57Bl/6 mice by bleomycin instillation. Animals were sacrificed at 1 to 5 weeks after fibrosis induction. Collagen synthesized during the week before sacrifice was labeled with deuterium by providing mice with deuterated drinking water. After sacrifice, we collected lung tissue for microarray analysis, determination of new collagen formation, and histology. Furthermore, we measured in vitro the expression of selected genes after transforming growth factor (TGF) beta1-induced myofibroblast differentiation. Deuterated water labeling showed a strong increase in new collagen formation already during the first week after fibrosis induction and a complete return to baseline at five weeks. Correlation of new collagen formation data with gene expression data allowed us to create a gene expression signature of fibrosis within the lung and revealed fibrosis-specific processes, among which proliferation. This was confirmed by measuring cell proliferation and collagen synthesis simultaneously using deuterated water incorporation in a separate experiment. Furthermore, new collagen formation strongly correlated with gene expression of e.g. elastin, Wnt-1 inducible signaling pathway protein 1, tenascin C, lysyl oxidase, and type V collagen. Gene expression of these genes was upregulated in vitro in fibroblasts stimulated with TGFbeta1. Together, these data demonstrate, using a novel combination of technologies, that the core process of fibrosis, i.e. the formation of new collagen, correlates not only with a wide range of genes involved in general extracellular matrix production and modification but also with cell proliferation. The observation that the large majority of the genes which correlated with new collagen formation also were upregulated during TGFbeta1-induced myofibroblast differentiation provides further evidence for their involvement in fibrosis. PMID- 23648812 TI - Association between respiratory tract infections and incidence of falls in nursing home residents. AB - INTRODUCTION: Falls are complex incidents caused by a combination of intrinsic impairments and disabilities with or without accompanying environmental hazards. OBJECTIVES: The aim of the study was to assess the relationship between respiratory tract infections (RTIs) and the incidence of falls, and to further link the history of falls to functional status in nursing homes residents. PATIENTS AND METHODS: The study involved 255 residents at 3 nursing homes aged 65 years and older. Falls and RTIs were registered during 1 year, and, afterwards, a comprehensive geriatric assessment was performed in each subject. RESULTS: Falls occurred in 104 subjects, and 17 falls resulted in a fracture. The waist-to-hip ratio (WHR) was lower among subjects with fractures compared with those without fractures. Subjects with a fracture in history had a significantly worse functional status in terms both of basic and instrumental daily activities. Nursing home residents with a history of falls more often suffered from infections than those without such history (1.53 +/-1.31 vs. 1.03 +/-1.17, respectively, P <0.001). Similarly, subjects with a history of fractures more often suffered from infections than those without such history (1.82 +/-1.07 vs. 1.19 +/-1.26; P = 0.012). After adjustment for other covariates in a multivariate model, RTIs remained an independent predictor of falls and fractures. CONCLUSIONS: The risk of falls and fractures in nursing home residents is associated with the occurrence of RTIs. A low WHR is a risk factor for falls with fractures. Older subjects with a history of fracture are characterized by a worse functional status. Preventing infections may probably reduce the number of falls and fractures in older nursing homes residents. PMID- 23648813 TI - Oral lesions in the course of myelofibrosis successfully treated using combination therapy with thalidomide, betamethasone, and cytarabine. PMID- 23648811 TI - Small non-coding RNAs encoded within the herpes simplex virus type 1 latency associated transcript (LAT) cooperate with the retinoic acid inducible gene I (RIG-I) to induce beta-interferon promoter activity and promote cell survival. AB - The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is abundantly expressed in latently infected trigeminal ganglionic sensory neurons. Expression of the first 1.5 kb of LAT coding sequences restores wild type reactivation to a LAT null HSV-1 mutant. The anti-apoptosis functions of the first 1.5 kb of LAT coding sequences are important for wild type levels of reactivation from latency. Two small non-coding RNAs (sncRNAs) contained within the first 1.5 kb of LAT coding sequences are expressed in trigeminal ganglia of latently infected mice, they cooperate to inhibit apoptosis, and reduce the efficiency of productive infection. In this study, we demonstrated that LAT sncRNA1 cooperates with the RNA sensor, retinoic acid inducible gene I (RIG-I), to stimulate IFN-beta promoter activity and NF-kappaB dependent transcription in human or mouse cells. LAT sncRNA2 stimulated RIG-I induction of NF-kappaB dependent transcription in mouse neuroblastoma cells (Neuro-2A) but not human 293 cells. Since it is well established that NF-kappaB interferes with apoptosis, we tested whether the sncRNAs cooperated with RIG-I to inhibit apoptosis. In Neuro 2A cells, both sncRNAs cooperated with RIG-I to inhibit cold-shock induced apoptosis. Double stranded RNA (PolyI:C) stimulates RIG-I dependent signaling; but enhanced cold-shock induced apoptosis. PolyI:C, but not LAT sncRNAs, interfered with protein synthesis when cotransfected with RIG-I, which correlated with increased levels of cold-shock induced apoptosis. LAT sncRNA1 appeared to interact with RIG-I in transiently transfected cells suggesting this interaction stimulates RIG-I. PMID- 23648814 TI - Massive soft tissue calcifications in severe hyperparathyroidism secondary to end stage renal disease. PMID- 23648815 TI - Untypical coexistence of autosomal dominant polycystic kidney disease and adrenal incidentaloma. PMID- 23648816 TI - Comment on "disease activity in patients with long-lasting rheumatoid arthritis is associated with changes in peripheral blood lymphocyte subpopulations". PMID- 23648817 TI - Comment on "disease activity in patients with long-lasting rheumatoid arthritis is associated with changes in peripheral blood lymphocyte subpopulations": authors' reply. PMID- 23648819 TI - MicroRNA-155 regulates T cell proliferation through targeting GSK3beta in cardiac allograft rejection in a murine transplantation model. AB - Here we investigated the activity and regulation of miR-155 during cardiac allograft rejection (AR), and to examine the feasibility of using miR-155 as a biomarker of graft status. Expression of miR-155 in graft-infiltrating lymphocytes (GIL), T cells isolated from spleen (TFS), and lymphocytes separated from blood (LFB) was significantly increased during cardiac AR while GSK3beta was downregulated in GIL and TFS. Inhibition of miR-155 impaired lymphocyte proliferation and enhanced the expression of GSK3beta. Moreover, pharmacological inactivation of GSK3beta resulted in rescue of the proliferative capability of T cells pretreated with a miR-155 inhibitor. Luciferase reporter assay confirmed that miR-155 interacted with the 3'-untranslated region (UTR) of GSK3beta directly. In particular, the miR-155 in LFB can distinguish recipients with AR from syngeneic controls from POD 3 and later. The present study provides a better understanding of the pathophysiological process underlying cardiac AR progression. PMID- 23648818 TI - Bifidobacterium infantis suppression of Peyer's patch MIP-1alpha and MIP-1beta secretion during Salmonella infection correlates with increased local CD4+CD25+ T cell numbers. AB - The outcome following infection depends on the generation of an immune response that results in control of the pathogenic microorganism, while limiting inflammatory collateral damage to the host. Bifidobacterium infantis 35624 was shown to be protective against Salmonella associated host injury via a Treg dependent mechanism. In this study, we further examined the mechanisms by which B. infantis-induced Tregs protect against Salmonella-associated inflammation. B. infantis 35624 feeding to Salmonella-infected mice significantly reduced Peyer's patch MIP-1alpha and MIP-1beta secretion. Chemokine secretion was significantly inversely correlated with Peyer's patch CD4+CD25+ cell numbers. In vitro, CD25+ T cells, but not CD25- T cells, specifically inhibited TNF-alpha and IFN-gamma secretion. However, both CD25+ and CD25- T cells suppressed MIP-1alpha and MIP 1beta secretion to the same extent. This study suggests that although B. infantis 35624-induced Tregs correlate with inhibition of chemokine secretion within the mucosa of pathogen infected animals, indirect cellular mechanisms may play a role. PMID- 23648820 TI - Semaphorin 4A is dynamically regulated during thymocyte development in mice. AB - Semaphorins are important regulators of peripheral T and B-cell mediated immune responses in mice and humans. Modulatory roles of semaphorins in T cell development are also being characterized. We carefully analyzed the gene expression and protein levels of semaphorins 4A, 4D, and 7A at various developmental stages of T cell maturation in the thymus of C57BL/6 mice. Sema7a was expressed at very low levels, while Sema4d was abundant at all developmental stages of mouse thymocytes. We found the most interesting pattern of gene regulation and protein localization for semaphorin 4A. Both semaphorin 4A mRNA and protein were clearly detected on the earliest progenitors and were downregulated through thymic development. SEMA4A protein also showed a distinct cortico-medullary pattern of localization. Our findings contribute to an understanding of the complex roles played by semaphorins in the network of spatially and temporally regulated cues underpinning T cell development in the thymus. PMID- 23648821 TI - Osmotic actuation modelling for innovative biorobotic solutions inspired by the plant kingdom. AB - Osmotic-driven plant movements are widely recognized as impressive examples of energy efficiency and low power consumption. These aspects motivate the interest in developing an original biomimetic concept of new actuators based on the osmotic principle exploited by plants. This study takes a preliminary step in this direction, by modelling the dynamic behaviour of two exemplificative yet relevant implementations of an osmotic actuator concept. In more detail, the considered implementations differ from each other in the way actuation energy storage is achieved (through a piston displacement in the former case, through membrane bulging in the latter). The dynamic problem is analytically solved for both cases; scaling laws for the actuation figures of merit (namely characteristic time, maximum force, maximum power, power density, cumulated work and energy density) as a function of model parameters are obtained for the bulging implementation. Starting from such performance indicators, a preliminary dimensioning of the envisaged osmotic actuator is exemplified, based on design targets/constraints (such as characteristic time and/or maximum force). Moreover, model assumptions and limitations are discussed towards effective prototypical development and experimental testing. Nonetheless, this study takes the first step towards the design of new actuators based on the natural osmotic principle, which holds potential for disruptive innovation in many fields, including biorobotics and ICT solutions. PMID- 23648823 TI - Sarcoma: primary retroperitoneal sarcoma-predicting survival. PMID- 23648824 TI - Gastrointestinal cancer: turning up trumps for new CRC subtypes. PMID- 23648827 TI - Urological cancer: walking the tightrope of survival and quality of life with ADT. PMID- 23648829 TI - Reshaping molecules through cocrystallization. Comparison of the structures of Hg{Co(CO)4}2 and Hg{Co(CO)4}2.C60.toluene. AB - Cocrystallization of Hg{Co(CO)4}2 with C60 produces Hg{Co(CO)4}2.C60.toluene in which the geometry of the Hg{Co(CO)4}2 molecule is rearranged to fit between the remarkably well ordered fullerenes. PMID- 23648828 TI - Taxane benefit in breast cancer--a role for grade and chromosomal stability. AB - Chromosomal instability, which is a characteristic of many human cancers, contributes to intratumour heterogeneity and has been functionally implicated in resistance to taxane therapy in tumour models. However, defining the status of tumour chromosomal instability in a given tumour to test this hypothesis remains challenging. Measurements of numerical and structural chromosomal heterogeneity demonstrate that histological grade correlates with chromosomal instability in oestrogen receptor (ER)-positive breast cancer. Using data on adjuvant taxane therapy in women with breast cancer, we propose that patients with low-grade ER positive tumours, which are thought to be chromosomally stable, might derive unexpected benefit from taxane therapy. We discuss the implications of the relationships between tumour grade, chromosomal instability and intratumour heterogeneity, the development of high-throughput methods to define tumour chromosomal instability and the potential use of chromosomal instability to tailor therapy. PMID- 23648830 TI - Abamectin resistance in Drosophila is related to increased expression of P glycoprotein via the dEGFR and dAkt pathways. AB - Many insects have evolved resistance to abamectin but the mechanisms involved in this resistance have not been well characterized. P-glycoprotein (P-gp), an ATP dependent drug-efflux pump transmembrane protein, may be involved in abamectin resistance. We investigated the role of P-gp in abamectin (ABM) resistance in Drosophila using an ABM-resistant strain developed in the laboratory. A toxicity assay, Western blotting analysis and a vanadate-sensitive ATPase activity assay all demonstrated the existence of a direct relationship between P-gp expression and ABM resistance in these flies. Our observations indicate that P-gp levels in flies' heads were higher than in their thorax and abdomen, and that both P-gp levels and LC(50) values were higher in resistant than in susceptible and P-gp deficient strains. In addition, P-gp levels in the blood-brain barrier (BBB) of resistant flies were higher than in susceptible and P-gp-deficient flies, which is further evidence that a high level of P-gp in the BBB is related to ABM resistance. Furthermore, we found greater expression of Drosophila EGFR (dEGFR) in the resistant strain than in the susceptible strain, and that the level of Drosophila Akt (dAkt) was much higher in resistant than in susceptible flies, whereas that in P-gp-deficient flies was very low. Compared to susceptible flies, P-gp levels in the resistant strain were markedly suppressed by the dEGFR and dAkt inhibitors lapatinib and wortmannin. These results suggest that the increased P-gp in resistant flies was regulated by the dEGFR and dAkt pathways and that increased expression of P-gp is an important component of ABM resistance in insects. PMID- 23648832 TI - Oral delivery of anticancer drugs: challenges and opportunities. AB - The present report focuses on the various aspects of oral delivery of anticancer drugs. The significance of oral delivery in cancer therapeutics has been highlighted which principally includes improvement in quality of life of patients and reduced health care costs. Subsequently, the challenges incurred in the oral delivery of anticancer agents have been especially emphasized. Sincere efforts have been made to compile the various physicochemical properties of anticancer drugs from either literature or predicted in silico via GastroPlusTM. The later section of the paper reviews various emerging trends to tackle the challenges associated with oral delivery of anticancer drugs. These invariably include efflux transporter based-, functional excipient- and nanocarrier based approaches. The role of drug nanocrystals and various others such as polymer based- and lipid based-nanocarriers in the bioavailability enhancement along with their clinical outcomes has also been discussed exhaustively. Furthermore, an insight on the various absorption mechanisms of these nanocarriers across the gastrointestinal tract has also been highlighted. PMID- 23648831 TI - Dating human cultural capacity using phylogenetic principles. AB - Humans have genetically based unique abilities making complex culture possible; an assemblage of traits which we term "cultural capacity". The age of this capacity has for long been subject to controversy. We apply phylogenetic principles to date this capacity, integrating evidence from archaeology, genetics, paleoanthropology, and linguistics. We show that cultural capacity is older than the first split in the modern human lineage, and at least 170,000 years old, based on data on hyoid bone morphology, FOXP2 alleles, agreement between genetic and language trees, fire use, burials, and the early appearance of tools comparable to those of modern hunter-gatherers. We cannot exclude that Neanderthals had cultural capacity some 500,000 years ago. A capacity for complex culture, therefore, must have existed before complex culture itself. It may even originated long before. This seeming paradox is resolved by theoretical models suggesting that cultural evolution is exceedingly slow in its initial stages. PMID- 23648834 TI - New PLGA-P188-PLGA matrix enhances TGF-beta3 release from pharmacologically active microcarriers and promotes chondrogenesis of mesenchymal stem cells. AB - The use of injectable scaffolding materials for in vivo tissue regeneration has raised great interest in various clinical applications because it allows cell implantation through minimally invasive surgical procedures. In case of cartilage repair, a tissue engineered construct should provide a support for the cell and allow sustained in situ delivery of bioactive factors capable of inducing cell differentiation into chondrocytes. Pharmacologically active microcarriers (PAMs), made of biodegradable poly(d,l-lactide-co-glycolide acid) (PLGA), are a unique system, which combines these properties in an adaptable and simple microdevice. However, a limitation of such scaffold is low and incomplete protein release that occurs using the hydrophobic PLGA based microspheres. To circumvent this problem, we developed a novel formulation of polymeric PAMs containing a P188 poloxamer, which protects the protein from denaturation and may positively affect chondrogenesis. This poloxamer was added as a free additive for protein complexation and as a component of the scaffold covalently linked to PLGA. This procedure allows getting a more hydrophilic scaffold but also retaining the protective polymer inside the microcarriers during their degradation. The novel PLGA-P188-PLGA PAMs presenting a fibronectin-covered surface allowed enhanced MSC survival and proliferation. When engineered with TGFbeta3, they allowed the sustained release of 70% of the incorporated TGF-beta3 over time. Importantly, they exerted superior chondrogenic differentiation potential compared to previous FN-PAM-PLGA-TGF-beta3, as shown by an increased expression of specific cartilage markers such as cartilage type II, aggrecan and COMP. Therefore, this microdevice represents an efficient easy-to-handle and injectable tool for cartilage repair. PMID- 23648835 TI - In vivo distribution and ex vivo permeation of cyclosporine A prodrug aqueous formulations for ocular application. AB - Cyclosporine A is a poorly water-soluble, immunosuppressive drug used to treat a variety of ocular diseases. Its limited solubility makes challenging the development of a cyclosporine A-based eye drop for ocular topical application. Based on the prodrug strategy, the practically insoluble cyclosporine A was converted into a freely soluble prodrug. Such a water-soluble prodrug made it possible to develop water-based concentrated eye drops. The prodrug formulations were tested for their ex vivo permeation and in vivo distribution at three concentrations (equivalent to 0.05%, 0.50% and 2.00% w/v cyclosporine A). The ex vivo permeation experiments were performed on corneal and conjunctival epithelia. The in vivo distribution evaluated the total cyclosporine A present in the ocular structures as well as in serum, spleen and cervical lymphatic ganglions. Each prodrug formulation was compared to conventionally used cyclosporine A eye drops at an equivalent concentration. The experimental results showed that the tested eye drops behaved differently. The prodrug formulation was characterized by the following: i) preferential conjunctival penetration, ii) an interesting capacity to create large tissue deposits and iii) a lower risk of systemic complications and immunosuppression. The prodrug aqueous eye drop was demonstrated to be a patient-friendly option for the treatment of ocular diseases requiring high ocular levels of cyclosporine A, pushing the boundaries of the current therapeutic arsenal. PMID- 23648836 TI - Oligomeric states along the folding pathways of beta2-microglobulin: kinetics, thermodynamics, and structure. AB - The transition of proteins from their soluble functional state to amyloid fibrils and aggregates is associated with the onset of several human diseases. Protein aggregation often requires some structural reshaping and the subsequent formation of intermolecular contacts. Therefore, the study of the conformation of excited protein states and their ability to form oligomers is of primary importance for understanding the molecular basis of amyloid fibril formation. Here, we investigated the oligomerization processes that occur along the folding of the amyloidogenic human protein beta2-microglobulin. The combination of real-time two dimensional NMR data with real-time small-angle X-ray scattering measurements allowed us to derive thermodynamic and kinetic information on protein oligomerization of different conformational states populated along the folding pathways. In particular, we could demonstrate that a long-lived folding intermediate (I-state) has a higher propensity to oligomerize compared to the native state. Our data agree well with a simple five-state kinetic model that involves only monomeric and dimeric species. The dimers have an elongated shape with the dimerization interface located at the apical side of beta2-microglobulin close to Pro32, the residue that has a trans conformation in the I-state and a cis conformation in the native (N) state. Our experimental data suggest that partial unfolding in the apical half of the protein close to Pro32 leads to an excited state conformation with enhanced propensity for oligomerization. This excited state becomes more populated in the transient I-state due to the destabilization of the native conformation by the trans-Pro32 configuration. PMID- 23648833 TI - Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA. AB - We developed, synthesized, and tested a multifunctional nanostructured lipid nanocarrier-based system (NLCS) for efficient delivery of an anticancer drug and siRNA directly into the lungs by inhalation. The system contains: (1) nanostructured lipid carriers (NLC); (2) anticancer drug (doxorubicin or paclitaxel); (3) siRNA targeted to MRP1 mRNA as a suppressor of pump drug resistance; (4) siRNA targeted to BCL2 mRNA as a suppressor of nonpump cellular resistance and (5) a modified synthetic analog of luteinizing hormone-releasing hormone (LHRH) as a targeting moiety specific to the receptors that are overexpressed in the plasma membrane of lung cancer cells. The NLCS was tested in vitro using human lung cancer cells and in vivo utilizing mouse orthotopic model of human lung cancer. After inhalation, the proposed NLCS effectively delivered its payload into lung cancer cells leaving healthy lung tissues intact and also significantly decreasing the exposure of healthy organs when compared with intravenous injection. The NLCS showed enhanced antitumor activity when compared with intravenous treatment. The data obtained demonstrated high efficiency of proposed NLCS for tumor-targeted local delivery by inhalation of anticancer drugs and mixture of siRNAs specifically to lung cancer cells and, as a result, efficient suppression of tumor growth and prevention of adverse side effects on healthy organs. PMID- 23648837 TI - pH-triggered conformational switching of the diphtheria toxin T-domain: the roles of N-terminal histidines. AB - pH-induced conformational switching is essential for functioning of diphtheria toxin, which undergoes a membrane insertion/translocation transition triggered by endosomal acidification as a key step of cellular entry. In order to establish the sequence of molecular rearrangements and side-chain protonation accompanying the formation of the membrane-competent state of the toxin's translocation (T) domain, we have developed and applied an integrated approach that combines multiple techniques of computational chemistry [e.g., long-microsecond-range, all atom molecular dynamics (MD) simulations; continuum electrostatics calculations; and thermodynamic integration (TI)] with several experimental techniques of fluorescence spectroscopy. TI calculations indicate that protonation of H257 causes the greatest destabilization of the native structure (6.9 kcal/mol), which is consistent with our early mutagenesis results. Extensive equilibrium MD simulations with a combined length of over 8 MUs demonstrate that histidine protonation, while not accompanied by the loss of structural compactness of the T domain, nevertheless results in substantial molecular rearrangements characterized by the partial loss of secondary structure due to unfolding of helices TH1 and TH2 and the loss of close contact between the C- and N-terminal segments. The structural changes accompanying the formation of the membrane competent state ensure an easier exposure of the internal hydrophobic hairpin formed by helices TH8 and TH9, in preparation for its subsequent transmembrane insertion. PMID- 23648840 TI - Crystal structure of tannase from Lactobacillus plantarum. AB - Tannins are water-soluble polyphenolic compounds in plants. Hydrolyzable tannins are derivatives of gallic acid (3,4,5-trihydroxybenzoic acid) or its meta depsidic forms that are esterified to polyol, catechin, or triterpenoid units. Tannases are a family of esterases that catalyze the hydrolysis of the galloyl ester bond in hydrolyzable tannins to release gallic acid. The enzymes have found wide applications in food, feed, beverage, pharmaceutical, and chemical industries since their discovery more than a century ago, although little is known about them at the molecular level, including the details of the catalytic and substrate binding sites. Here, we report the first three-dimensional structure of a tannase from Lactobacillus plantarum. The enzyme displays an alpha/beta structure, featured by a large cap domain inserted into the classical serine hydrolase fold. A catalytic triad was identified in the structure, which is composed of Ser163, His451, and Asp419. During the binding of gallic acid, the carboxyl group of the molecule forges hydrogen-bonding interactions with the catalytic triad of the enzyme while the three hydroxyl groups make contacts with Asp421, Lys343, and Glu357 to form another hydrogen-bonding network. Mutagenesis studies demonstrated that these residues are indispensable for the activity of the enzyme. Structural studies of the enzyme in complex with a number of substrates indicated that the interactions at the galloyl binding site are the determinant force for the binding of substrates. The single galloyl binding site is responsible for the esterase and depsidase activities of the enzyme. PMID- 23648838 TI - Colocalization of fast and slow timescale dynamics in the allosteric signaling protein CheY. AB - It is now widely recognized that dynamics are important to consider for understanding allosteric protein function. However, dynamics occur over a wide range of timescales, and how these different motions relate to one another is not well understood. Here, we report an NMR relaxation study of dynamics over multiple timescales at both backbone and side-chain sites upon an allosteric response to phosphorylation. The response regulator, Escherichia coli CheY, allosterically responds to phosphorylation with a change in dynamics on both the microsecond-to-millisecond (MUs-ms) timescale and the picosecond-to-nanosecond (ps-ns) timescale. We observe an apparent decrease and redistribution of MUs-ms dynamics upon phosphorylation (and accompanying Mg(2+) saturation) of CheY. Additionally, methyl groups with the largest changes in ps-ns dynamics localize to the regions of conformational change measured by MUs-ms dynamics. The limited spread of changes in ps-ns dynamics suggests a distinct relationship between motions on the MUs-ms and ps-ns timescales in CheY. The allosteric mechanism utilized by CheY highlights the diversity of roles dynamics play in protein function. PMID- 23648839 TI - Three-dimensional structure of CAP-gly domain of mammalian dynactin determined by magic angle spinning NMR spectroscopy: conformational plasticity and interactions with end-binding protein EB1. AB - Microtubules and their associated proteins play important roles in vesicle and organelle transport, cell motility and cell division. Perturbation of these processes by mutation typically gives rise to severe pathological conditions. In our efforts to obtain atomic information on microtubule-associated protein/microtubule interactions with the goal to understand mechanisms that might potentially assist in the development of treatments for these diseases, we have determined the three-dimensional structure of CAP-Gly (cytoskeleton associated protein, glycine-rich) domain of mammalian dynactin by magic angle spinning NMR spectroscopy. We observe two conformations in the beta2 strand encompassing residues T43-V44-A45, residues that are adjacent to the disease associated mutation, G59S. Upon binding of CAP-Gly to microtubule plus-end tracking protein EB1, the CAP-Gly shifts to a single conformer. We find extensive chemical shift perturbations in several stretches of residues of CAP-Gly upon binding to EB1, from which we define accurately the CAP-Gly/EB1 binding interface. We also observe that the loop regions may exhibit unique flexibility, especially in the GKNDG motif, which participates in the microtubule binding. This study in conjunction with our previous reports suggests that conformational plasticity is an intrinsic property of CAP-Gly likely due to its unusually high loop content and may be required for its biological functions. PMID- 23648841 TI - A dual-color genetically engineered mouse model for multispectral imaging of the pancreatic microenvironment. AB - OBJECTIVES: To develop a mouse model for multispectral fluorescence imaging of the pancreas and pancreatic microenvironment. METHODS: Cre/loxP technology was used to develop this model. We crossed mT/mG indicator mice, engineered to constitutively express a conditional tdTomato transgene that converts to green fluorescent protein (GFP) expression after exposure to Cre recombinase, with Pdx1 Cre transgenic mice. To characterize this model for studies of pancreas biology, we performed bright light and fluorescence imaging of body cavities and intact organs and confocal microscopy of pancreata from offspring of Pdx1-Cre and mT/mG crosses. RESULTS: Pdx1-Cre-mT/mG mice demonstrated bright GFP expression within the pancreas and duodenum and intense tdTomato expression in all other organs. Green fluorescent protein expression was mosaic in Pdx1-Cre-mT/mG pancreata, with most showing extensive conversion from tdTomato to GFP expression within the epithelial-derived elements of the pancreatic parenchyma. Because both GFP and tdTomato are membrane targeted, individual cell borders were clearly outlined in confocal images of mT/mG pancreata. CONCLUSIONS: This mouse model enables multispectral fluorescence imaging of individual cells and cell processes at the microscopic level of the pancreatic microenvironment; it should prove valuable for a variety of fluorescence imaging studies, ranging from pancreatic development to pancreatic cancer biology. PMID- 23648842 TI - Early measures of hemoconcentration and inflammation are predictive of prolonged hospitalization from post- endoscopic retrograde cholangiopancreatography pancreatitis. AB - OBJECTIVES: Hemoconcentration markers are predictors of severe acute pancreatitis but have not been specifically evaluated in post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). METHODS: Case-control study of patients undergoing ERCP for suspected sphincter of Oddi dysfunction. We identified patients with PEP (PEP positive) and controls (PEP negative) in a 1:2 ratio. blood urea nitrogen (BUN) and hematocrit (Hct) were measured before procedure, upon admission, and 24 hours later. Preprocedure levels of BUN and Hct were analyzed to control for confounders. Among the PEP-positive patients, BUN level, Hct level, and systemic inflammatory response syndrome are compared between severe and mild/moderate cases. RESULTS: There were 149 PEP-positive patients, including 18 patients (12.1%) with severe PEP and 301 PEP-negative controls. After adjusting, higher preprocedure BUN level (odds ratio [OR], 1.05 [1.01, 1.10]; P < 0.02) and pancreatic sphincterotomy (OR, 1.60 [1.01, 2.55]; P < 0.05) were associated with PEP, whereas older age (OR, 0.98 [0.96, 0.99]; P < 0.02) and a greater body mass index (OR, 0.97 [0.94, 0.99]; P < 0.03) with a lower rate.Difference in BUN level of 0.0 or greater (failure to decline) had a sensitivity of 71% and a specificity of 79% for differentiating severe from mild/moderate PEP. Patients with severe PEP were more likely to have systemic inflammatory response syndrome upon admission (44.4% [21.5, 67.4]) and after 24 hours (61.1% [38.6, 83.6] versus mild/moderate (9.2% [4.2, 14.1], 10.6% [5.4,16.0]; P < 0.0001 for each). CONCLUSIONS: Preprocedure BUN level is associated with the development of PEP. The preprocedure BUN level and failure of the BUN level to decline during the first 24 hours are associated with prolonged hospitalization. PMID- 23648843 TI - Toward a better understanding of pancreatic ductal adenocarcinoma: glimmers of hope? AB - Pancreatic ductal adenocarcinoma (PDAC) imposes a heavy burden of disease, especially in the most developed countries, and the mortality rate has not declined over the past decades. Therefore, there is an urgent need for a better understanding of the molecular mechanisms of PDAC, which may help to improve early detection, prognosis, and treatment efficiency.This review focuses on PDAC epidemiology and on recent advances in our understanding of the molecular mechanisms of PDAC carcinogenesis. We discuss the cancer stem cell hypothesis, which provides a rationale for the pervasive resistance of PDAC to chemoradiotherapy and explains the disease recurrence after the currently used genotoxic treatment.Identification of an inherited predisposition to PDAC due to genetic factors should allow high-risk groups to benefit from early detection programs. The presence in biofluids of stable tumor-specific microRNAs (miRs) makes them the most promising biomarkers potentially capable of detecting tumors long before their clinical manifestation. The cancer stem cell hypothesis made it realistic to anticipate a clinical impact of miR-based therapy (miR mimics and antagomirs) to overcome the otherwise insurmountable barrier of frequent resistance of PDAC to chemoradiotherapy.The investigation of miRs in PDAC may provide exciting novel strategies for both diagnosis and treatment. PMID- 23648844 TI - Twenty-one proteins up-regulated in human H-ras oncogene transgenic rat pancreas cancers are up-regulated in human pancreas cancer. AB - OBJECTIVES: We have established rat models of pancreatic ductal adenocarcinoma (PDAC) in which expression of a human H-ras(G12V) or K-ras(G12V) oncogene regulated by the Cre/lox system drives pancreatic carcinogenesis. Pancreatic ductal adenocarcinoma which develops in H-ras(G12V) and K-ras(G12V) transgenic rats is cytogenetically and histopathologically similar to human PDAC. The present study was designed to determine the feasibility of using the commercially available H-ras(G12V) transgenic rat to find diagnostic protein biomarkers for human pancreatic cancer. METHODS: For an animal model to be useful for searching for protein biomarkers for a disease, it is essential that proteins that are up regulated in the model are also up-regulated in humans. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to compare H-ras(G12V) transgenic rat PDAC with surrounding normal pancreas tissue. RESULTS: We identified 30 up-regulated proteins in the H-ras(G12V) transgenic rat PDAC lesions; importantly, 21 human homologs of these 30 rat proteins are up-regulated in human pancreatic cancer patients. CONCLUSIONS: These results indicate that numerous proteins that are up-regulated in H-ras(G12V) transgenic rat PDAC are also up-regulated in human pancreatic cancer; therefore, this rat model can be used to search for diagnostic biomarkers for this disease. PMID- 23648846 TI - Bizzarre parosteal osteochondromatous proliferation: case report. AB - Nora's tumor, also known as bizzarre parosteal osteochondromatous proliferation (POPB), is an exophytic outgrowth arising from the cortical surface of the bone that consists of a mixture of bone, cartilage and fibrous tissue. It is a benign lesion with atipical microscopic features and a tendency to recur. It must be distinguishable from parosteal osteogenic sarcoma, parosteal chondrosarcoma, osteochondroma, florid reactive periostitis, turret exostosis, subungueal exostosis, myositis ossificans. The treatment is surgical, but a high rate of local relapse is described. The diagnosis is histological. We report a case of a patient with POPB involving the foot, underwent surgical excision and with no evidence of recurrence at one year. PMID- 23648847 TI - Pichia pastoris: a recombinant microfactory for antibodies and human membrane proteins. AB - During the last few decades, it has become evident that the compatibility of the yeast biochemical environment with the ability to process and translate the RNA transcript, along with its capacity to modify a translated protein, are relevant requirements for selecting this host cell for protein expression in several pharmaceutical and clinical applications. In particular, Pichia pastoris is used as an industrial host for recombinant protein and metabolite production, showing a powerful capacity to meet required biomolecular target production levels in high-throughput assays for functional genomics and drug screening. In addition, there is a great advantage to using P. pastoris for protein secretion, even at high molecular weights, since the recovery and purification steps are simplified owing to relatively low levels of endogenous proteins in the extracellular medium. Clearly, no single microexpression system can provide all of the desired properties for human protein production. Moreover, chemical and physical bioprocess parameters, including culture medium formulation, temperature, pH, agitation, aeration rates, induction, and feeding strategies, can highly influence product yield and quality. In order to benefit from the currently available wide range of biosynthesis strategies using P. pastoris, this mini review focuses on the developments and technological fermentation achievements, providing both a comparative and an overall integration analysis. The main aim is to highlight the relevance and versatility of the P. pastoris biosystem to the design of more cost-effective microfactories to meet the increasing demands for recombinant membrane proteins and clinical antibodies for several therapeutic applications. PMID- 23648848 TI - Biogeographical distribution and diversity of bacterial communities in surface sediments of the South China Sea. AB - This paper aims at an investigation of the features of bacterial communities in surface sediments of the South China Sea (SCS). In particular, biogeographical distribution patterns and the phylogenetic diversity of bacteria found in sediments collected from a coral reef platform, a continental slope, and a deep sea basin were determined. Bacterial diversity was measured by an observation of 16S rRNA genes, and 18 phylogenetic groups were identified in the bacterial clone library. Planctomycetes, Deltaproteobacteria, candidate division OP11, and Alphaproteobacteria made up the majority of the bacteria in the samples, with their mean bacterial clones being 16%, 15%, 12%, and 9%, respectively. By comparison, the bacterial communities found in the SCS surface sediments were significantly different from other previously observed deep-sea bacterial communities. This research also emphasizes the fact that geographical factors have an impact on the biogeographical distribution patterns of bacterial communities. For instance, canonical correspondence analyses illustrated that the percentage of sand weight and water depth are important factors affecting the bacterial community composition. Therefore, this study highlights the importance of adequately determining the relationship between geographical factors and the distribution of bacteria in the world's seas and oceans. PMID- 23648849 TI - Monitoring the ecology of Bacillus during Daqu incubation, a fermentation starter, using culture-dependent and culture-independent methods. AB - Daqu, a traditional fermentation starter, has been used to produce attractively flavored foods such as vinegar and Chinese liquor for thousands of years. Although Bacillus spp. are one of the dominant microorganisms in Daqu, more precise information is needed to reveal why and how Bacillus became dominant in Daqu, and next, to assess the impact of Bacillus sp. on Daqu and its derived products. We combined culture-dependent and culture-independent methods to study the ecology of Bacillus during Daqu incubation. Throughout the incubation, 67 presumptive Bacillus spp. isolates were obtained, 52 of which were confirmed by 16S rDNA sequencing. The identified organisms belonged to 8 Bacillus species: B. licheniformis, B. subtilis, B. amyloliquefaciens, B. cereus, B. circulans, B. megaterium, B. pumilus, and B. anthracis. A primer set specific for Bacillus and related genera was used in a selective PCR study, followed by a nested DGGE PCR targeting the V9 region of the 16S rDNA. Species identified from the PCR-DGGE fingerprints were related to B. licheniformis, B. subtilis, B. amyloliquefaciens, B. pumilus, B. benzoevorans, and B. foraminis. The predominant species was found to be B. licheniformis. Certain B. licheniformis strains exhibited potent antimicrobial activities. The greatest species diversity occurred at the Liangmei stage of Daqu incubation. To date, we lack sufficient knowledge of Bacillus distribution in Daqu. Elucidating the ecology of Bacillus during Daqu incubation would enable the impact of Bacillus on Daqu to be accessed, and the quality and stabilization of Daqu-derived products to be optimized. PMID- 23648850 TI - Characterization of gibberellin biosynthetic gene cluster from Fusarium proliferatum. AB - Gibberellins (GAs) are a group of phytohormones that control many developmental processes in higher plants. We report the cloning and expression pattern of gibberellin biosynthesis genes from a new GA-producing fungus, Fusarium proliferatum (strain KGL0401). These genes sequences are deposited in the National Center for Biotechnology Information (NCBI) under accession numbers EF119831, EF119832, DQ313173, DQ313174, DQ313175, DQ313176, and DQ313177. The expression level of these genes was maximal at a 0.5 M : 0.17 M carbon : nitrogen ratio, and minimal at a 0.25 M : 0.47 M carbon : nitrogen ratio. PMID- 23648851 TI - Development of a new duplex real-time polymerase chain reaction assay for detection of dicer in G. gallus. AB - Recently, there has been a growing body of evidence showing that cellular microRNAs (miRNAs) are involved in virus-host interactions. Numerous studies have focused on analyses of the expression profiles of cellular miRNAs, but the expression patterns of Dicer, which is responsible for the generation of miRNAs, have only rarely been explored in Gallus gallus. We developed a duplex realtime reverse transcriptase polymerase chain reaction (RTPCR) assay for the relative quantification of the mRNAs of Dicer and beta-actin in G. gallus. To apply this method, the expression of Dicer in avian cells after infection with avian leukosis virus subgroup J (ALV-J) was detected using our established duplex real time RT-PCR. The duplex realtime RT-PCR assay is sufficiently sensitive, specific, accurate, reproducible, and cost-effective for the detection of Dicer in G. gallus. Furthermore, this study, for the first time, demonstrated that ALV J can induce differential expression of Dicer mRNA in the ALV-J-infected cells. PMID- 23648852 TI - 1-Deoxynojirimycin isolated from a Bacillus subtilis stimulates adiponectin and GLUT4 expressions in 3T3-L1 adipocytes. AB - We have demonstrated that 1-deoxynojirimycin (DNJ) isolated from Bacillus subtilis MORI could enhance the levels of adiponectin and its receptors in differentiated 3T3-L1 adipocytes, which has been shown to be effective in lowering blood glucose levels and enhancing insulin sensitivity. DNJ was not toxic to differentiated 3T3-L1 adipocytes for up to a concentration of 5 microM. In terms of expression levels of adiponectin and its receptors (AdipoR1 and AdipoR2), DNJ in concentrations as low as 0.5 microM elevated both mRNA and protein levels of adiponectin and transcript levels of AdipoR1 and AdipoR2. In addition, DNJ increased phosphorylation of 5' adenosine monophosphateactivated protein kinase (AMPK) in a statistically significant manner. Finally, treatment with DNJ resulted in increased mRNA expression of glucose transporter 4 (GLUT4), which encodes for a glucose transporter, along with a significant increase in glucose uptake into the adipocytes based on results of a 2-deoxy-D-[3H] glucose uptake assay. Our findings indicate that DNJ may greatly facilitate glucose uptake into adipose tissues by increasing the action of adiponectin via its up regulated expression as well as its receptor genes. In addition, the glucose lowering effects of DNJ may be achieved by an increased abundance of GLUT4 protein in the plasma membrane, as a consequence of the increased transcript levels of the GLUT4 gene and the activation of AMPK. PMID- 23648853 TI - Microbiological features and bioactivity of a fermented manure product (preparation 500) used in biodynamic agriculture. AB - The fermented manure derivative known as Preparation 500 is traditionally used as a field spray in biodynamic agriculture for maintaining and increasing soil fertility. This work aimed at characterizing the product from a microbiological standpoint and at assaying its bioactive properties. The approach involved molecular taxonomical characterization of the culturable microbial community; ARISA fingerprints of the total bacteria and fungal communities; chemical elemental macronutrient analysis via a combustion analyzer; activity assays for six key enzymes; bioassays for bacterial quorum sensing and chitolipooligosaccharide production; and plant hormonelike activity. The material was found to harbor a bacterial community of 2.38 * 10(8) CFU/g dw dominated by Grampositives with minor instances of Actinobacteria and Gammaproteobacteria. ARISA showed a coherence of bacterial assemblages in different preparation lots of the same year in spite of geographic origin. Enzymatic activities showed elevated values of beta-glucosidase, alkaline phosphatase, chitinase, and esterase. The preparation had no quorum sensing-detectable signal, and no rhizobial nod gene-inducing properties, but displayed a strong auxin-like effect on plants. Enzymatic analyses indicated a bioactive potential in the fertility and nutrient cycling contexts. The IAA activity and microbial degradation products qualify for a possible activity as soil biostimulants. Quantitative details and possible modes of action are discussed. PMID- 23648854 TI - p-Terphenyls from fungus Paxillus curtisii chelate irons: a proposed role of p terphenyls in fungus. AB - Diverse p-terphenyl compounds, named curtisians, have been isolated from the fungus Paxillus curtisii, and degradation of wood by this fungus is thought to be progressed by iron chelation of p-terphenyl curtisians. In this study, the iron chelation ability of p-terphenyls has been proved by chrome azurol S (CAS) assay, reducing power, and UV-visible spectroscopic analyses. The catechol moiety of p terphenyl is an essential factor for the potent iron chelation ability, and thus deacylated curtisian with a tetrahydroxyl moiety in the central ring of p terphenyl is more effective than acylated curtisians. PMID- 23648855 TI - Nutritional studies on production of antibacterial activity by the zebra mussel antagonist, Pseudomonas fluorescens CL0145A. AB - Pseudomonas fluorescens strain CL0145A was discovered at the New York State Museum Field Research Laboratory as an effective agent against the environmentally destructive zebra mussel, which has contaminated US waters. Dried cells of the microbe are being commercialized as an environmentally friendly solution to the problem. We found that antibiotic activity against the Gram positive bacterium Bacillus subtilis is produced and excreted by this strain. We have carried out studies to optimize production of the antibiotic. Studies were begun in a complex corn meal medium. Activity was found in both cells and culture supernates and was maximal after one day of fermentation. Static fermentation conditions were found to be superior to shaken culture. Production of extracellular antibiotic in complex medium was found to be dependent on the content of sucrose and enzymehydrolyzed casein. Indeed, production was greater in sucrose plus enzyme-hydrolyzed casein than in the complex medium. Of a large number of carbon sources studied as improvements over sucrose, the best was glycerol. An examination of nitrogen sources showed that production was improved by replacement of enzymehydrolyzed casein with soy hydrolysates. Production in the simple glycerol-Hy-Soy medium was not improved by addition of an inorganic salt mixture or by complex nitrogen sources, with the exception of malt extract. In an attempt to keep the medium more defined, we studied the effect of amino acids and vitamins as replacements for malt extract. Of 21 amino acids and 7 vitamins, we found tryptophan, glutamine, biotin, and riboflavin to be stimulatory. The final medium contained glycerol, Hy- Soy, tryptophan, glutamine, biotin, and riboflavin. PMID- 23648856 TI - Isolation and biochemical characterization of Bacillus pumilus lipases from the Antarctic. AB - Lipase-producing bacterial strains were isolated from Antarctic soil samples using the tricaprylin agar plate method. Seven strains with relatively strong lipase activities were selected. All of them turned out to be Bacillus pumilus strains by the 16S rRNA gene sequence analysis. Their corresponding lipase genes were cloned, sequenced, and compared. Finally, three different Bacillus pumilus lipases (BPL1, BPL2, and BPL3) were chosen. Their amino acid sequence identities were in the range of 92-98% with the previous Bacillus pumilus lipases. Their optimum temperatures and pHs were measured to be 40 degrees C and pH 9. Lipase BPL1 and lipase BPL2 were stable up to 30 degrees C, whereas lipase BPL3 was stable up to 20 degrees C. Lipase BPL2 was stable within a pH range of 6-10, whereas lipase BPL1 and lipase BPL3 were stable within a pH range of 5-11, showing strong alkaline tolerance. All these lipases exhibited high hydrolytic activity toward pnitrophenyl caprylate (C8). In addition, lipase BPL1 showed high hydrolytic activity toward tributyrin, whereas lipase BPL2 and lipase BPL3 hydrolyzed tricaprylin and castor oil preferentially. These results demonstrated that the three Antarctic Bacillus lipases were alkaliphilic and had a substrate preference toward short- and mediumchain triglycerides. These Antarctic Bacillus lipases might be used in detergent and food industries. PMID- 23648857 TI - Effect of gene amplifications in porphyrin pathway on heme biosynthesis in a recombinant Escherichia coli. AB - A recombinant E. coli co-expressing ALA synthase (hemA), NADP-dependent malic enzyme (maeB), and dicarboxylic acid transporter (dctA) was reported to synthesize porphyrin derivatives including iron-containing heme. To enhance the synthesis of bacterial heme, five genes of the porphyrin biosynthetic pathway [pantothenate kinase (coaA), ALA dehydratase (hemB), 1-hydroxymethylbilane synthase (hemC), uroporphyrinogen III synthase (hemD), and uroporphyrinogen III decarboxylase (hemE)] were amplified in the recombinant E. coli co-expressing hemA-maeB-dctA. Pantothenate kinase expression enabled the recombinant E. coli to accumulate intracellular CoA. Intracellular ALA was the most enhanced by uroporphyrinogen III synthase expression, porphobilinogen by ALA dehydratase expression, and uroporphyrin and coproporphyrin by 1- hydroxymethylbilane synthase expression. The strain coexpressing coaA, hemA, maeB, and dctA produced heme of 0.49 micromol/g-DCW, which was twice as much from the strain without coaA expression. Further strain improvement for the porphyrin derivatives is discussed based on the results. PMID- 23648858 TI - Genetic transformation of the yeast Dekkera/Brettanomyces bruxellensis with non homologous DNA. AB - Yeast Dekkera/Brettanomyces bruxellensis is probably the most common contaminant in wineries and ethanol production processes. The considerable economic losses caused by this yeast, but also its ability to produce and tolerate high ethanol concentrations, make it an attractive subject for research with potential for industrial applications. Unfortunately, efforts to understand the biology of D. bruxellensis and facilitate its broader use in industry are hampered by the lack of adequate procedures for delivery of exogenous DNA into this organism. Here we describe the development of transformation protocols (spheroplast transformation, LiAc/PEG method, and electroporation) and report the first genetic transformation of yeast D. bruxellensis. A linear heterologous DNA fragment carrying the kanMX4 sequence was used for transformation, which allowed transformants to be selected on plates containing geneticin. We found the spheroplast transformation method using 1M sorbitol as osmotic stabilizer to be inappropriate because sorbitol strikingly decreases the plating efficiency of both D. bruxellensis spheroplast and intact cells. However, we managed to modify the LiAc/ PEG transformation method and electroporation to accommodate D. bruxellensis transformation, achieving efficiencies of 0.6-16 and 10-20 transformants/microg DNA, respectively. The stability of the transformants ranged from 93.6% to 100%. All putative transformants were analyzed by Southern blot using the kanMX4 sequence as a hybridization probe, which confirmed that the transforming DNA fragment had integrated into the genome. The results of the molecular analysis were consistent with the expected illegitimate integration of a heterologous transforming fragment. PMID- 23648859 TI - Exopolysaccharide produced by Pediococcus acidilactici M76 isolated from the Korean traditional rice wine, makgeolli. AB - This work is aimed to increase knowledge of the functional exopolysaccharide (EPS) from lactic acid bacteria (LAB) in makgeolli, a Korean fermented rice wine. Among LAB strains isolated from makgeolli, strain M76 was selected as a functional strain producing a bioactive EPS, based on its antioxidative activity on the DPPH radical. The 16S rRNA gene sequencing analysis showed a high sequence similarity (99.0%) with P. acidilactici, but had different biochemical properties with the already known P. acidilactici type strains in the aspect of carbohydrates utilization. The obtained P. acidilactici M76 produced a soluble EPS above 2 g/l. One-step chromatography using gel filtration after ethanol precipitation from the supernatant of P. acidilactici M76 was enough to obtain purified EPS with a single peak, showing a molecular mass of approximately 67 kDa. Componential and structural analyses of EPS by TLC, HPLC, and FT-IR indicated that the EPS is a glucan, consisting of glucose units. The purified EPS had antioxidant activity on the DPPH radical of 45.8% at a concentration of 1 mg/ml. The purified EPS also showed proliferative effect on the pancreatic RIN m5F cell line and remarkable protection activity on alloxan-induced cytotoxicity. This potent antioxidant and antidiabetic EPS by LAB in makgeolli may contribute to understanding the functionality of makgeolli. PMID- 23648860 TI - Effect of culture conditions and signal peptide on production of human recombinant N-acetylgalactosamine-6-sulfate sulfatase in Escherichia coli BL21. AB - The production and characterization of an active recombinant N acetylgalactosamine-6-sulfate sulfatase (GALNS) in Escherichia coli BL21(DE3) has been previously reported. In this study, the effect of the signal peptide (SP), inducer concentration, process scale, and operational mode (batch and semi continuous) on GALNS production were evaluated. When native SP was presented, higher enzyme activity levels were observed in both soluble and inclusion bodies fractions, and its removal had a significant impact on enzyme activation. At shake scale, the optimal IPTG concentrations were 0.5 and 1.5 mM for the strains with and without SP, respectively, whereas at bench scale, the highest enzyme activities were observed with 1.5 mM IPTG for both strains. Noteworthy, enzyme activity in the culture media was only detected when SP was presented and the culture was carried out under semi-continuous mode. We showed for the first time that the mechanism that in prokaryotes recognizes the SP to mediate sulfatase activation can also recognize a eukaryotic SP, favoring the activation of the enzyme, and could also favor the secretion of the recombinant protein. These results offer significant information for scaling-up the production of human sulfatases in E. coli. PMID- 23648861 TI - Effect of mild-thiol reducing agents and alpha2,3-sialyltransferase expression on secretion and sialylation of recombinant EPO in CHO cells. AB - We have previously reported that N-acetylcysteine (NAC) not only delayed apoptosis but also enhanced the production of recombinant erythropoietin (EPO) in Chinese hamster ovary (CHO) cell culture. To investigate the production enhancement mechanism, the effects of similar thiolreducing agents were studied. Intriguingly, all mild reducing agents examined including mercaptoethanesulfonic acid (MESNA), thiolactic acid (TLA), and thioglycolate (TG) were shown to block apoptosis and increase EPO production. A pulse-chase study of EPO secretion revealed that all four thiol-reducing agents increased the EPO secretion rate; among them TLA showed the highest rate. In terms of product quality, the sialic acid content of the glycoprotein is one of the most important factors. It was reported that a number of glycoproteins produced by CHO cells often have incomplete sialylation, particularly under high-producing conditions. Human alpha2,3-sialyltransferase (alpha2,3-ST) was introduced into EPO-producing CHO cells in order to compensate for the reduced sialylation during supplementation with NAC. When alpha2,3-ST was expressed in the presence of NAC, reduced sialylation was restored and an even more sialylated EPO was produced. Thus, our study is significant in that it offers increased EPO production while still allowing the prevention of decreased sialylation of EPO. PMID- 23648862 TI - Biomineralization of calcium carbonate polymorphs by the bacterial strains isolated from calcareous sites. AB - Microbially induced calcium carbonate precipitation (MICCP) is a naturally occurring biological process that has various applications in remediation and restoration of a range of building materials. In the present investigation, five ureolytic bacterial isolates capable of inducing calcium carbonate precipitation were isolated from calcareous soils on the basis of production of urease, carbonic anhydrase, extrapolymeric substances, and biofilm. Bacterial isolates were identified as Bacillus megaterium, B. cereus, B. thuringiensis, B. subtilis, and Lysinibacillus fusiformis based on 16S rRNA analysis. The calcium carbonate polymorphs produced by various bacterial isolates were analyzed by scanning electron microscopy, confocal laser scanning microscopy, X ray diffraction, and Fourier transmission infra red spectroscopy. A strainspecific precipitation of calcium carbonate forms was observed from different bacterial isolates. Based on the type of polymorph precipitated, the technology of MICCP can be applied for remediation of various building materials. PMID- 23648863 TI - Biodegradation capacity utilization as a new index for evaluating biodegradation rate of methane. AB - Density of catalytic organisms can determine the biodegradation capacity and specific biodegradation rate (SBR). A new index, biodegradation capacity utilization (BCU, %), was developed for estimating the extent of actual biodegradation of a gas compound over the full capacity. Three methanotrophic cultures were serially diluted (1-1/25), and methane SBR and BCU were measured. Consistently, biomass reduction increased the SBR and decreased the BCU. Linearity (p < 0.05, r > 0.97) between the BCU and cell density indicated the reflection of biodegradation capacity by BCU. Therefore, BCU is indicative of whether the density of catalytic organisms is pertinent for SBR evaluation of low soluble gaseous compounds. PMID- 23648864 TI - Selective inhibition of ammonia oxidation and nitrite oxidation linked to N2O emission with activated sludge and enriched nitrifiers. AB - Nitrification in wastewater treatment emits a significant amount of nitrous oxide (N2O), which is one of the major greenhouse gases. However, the actual mechanism or metabolic pathway is still largely unknown. Selective nitrification inhibitors were used to determine the nitrification steps responsible for N2O emission with activated sludge and enriched nitrifiers. Allylthiourea (86 microM) completely inhibited ammonia oxidation and N2O emission both in activated sludge and enriched nitrifiers. Sodium azide (24 microM) selectively inhibited nitrite oxidation and it led to more N2O emission than the control experiment both in activated sludge and enriched nitrifiers. The inhibition tests showed that N2O emission was mainly related to the activity of ammonia oxidizers in aerobic condition, and the inhibition of ammonia monooxygenase completely blocked N2O emission. On the other hand, N2O emission increased significantly as the nitrogen flux from nitrite to nitrate was blocked by the selective inhibition of nitrite oxidation. PMID- 23648865 TI - Immunomodulatory and anti-allergic effects of orally administered Lactobacillus species in ovalbumin-sensitized mice. AB - We investigated the effects of orally administered probiotic bacteria (Lactobacillus species) as allergic immune modulators in ovalbumin (OVA) sensitized mice. BALB/c mice were intraperitoneally injected with OVA twice at a 2-week interval for allergy sensitization. The mice were then orally administered Lactobacillus casei YIT9029 (L1), L. casei HY7201 (L2), L. brevis HY7401 (L3), or L. plantarum HY20301 (L4) every 2 days for 3 weeks. Total IgE levels significantly decreased in sera of L3-administered mice but increased in the other groups. OVA-specific IgE levels decreased slightly in sera of mice administered L1, L3, and L4 but increased significantly in L2-administered mice. In passive cutaneous anaphylaxis (PCA) using sera from administered mice, only the L3-administered group showed reaction inhibition. High expression of TLR-2 with interferon (IFN)-gamma stimulation on peripheral blood mononuclear cells occurred in L3- or L4-administered mice. Th1 cytokines, including IFN-gamma and interleukin (IL)- 12, increased in splenocytes of L3-administered mice; however, IL-4 decreased in L1- and L4-administered groups; IL-5 decreased in all experimental groups. IL-6 decreased in the L3-administered group; and IL-10 decreased in L1-, L2-, and L3-administered groups. L3 induced antiallergic effects by increasing Th1 cytokines, decreasing Th2 cytokines, and inhibiting the PCA reaction, whereas L2 administration increased allergic effects. PMID- 23648866 TI - Repression of type-1 fimbriae in Shiga toxin-producing Escherichia coli O91:H21 isolated from asymptomatic human carriers in Korea. AB - Seventy-four Shiga toxin-producing Escherichia coli (STEC) isolates belonging to the serotype O91:H21 were isolated from 1,643 asymptomatic human carriers in a STEC outbreak at Gwangju in Korea. Although the isolates did not cause any symptoms, all of them produced Shiga toxins 1 (Stx1) and 2 (Stx2). In order to determine why these strains cause no symptoms, we explored the differences in virulence potential between the asymptomatic STEC O91:H21 isolates and symptomatic STEC O91:H21 strains (ATCC 51435 and ATCC 51434). The asymptomatic STEC O91:H21 isolates showed strongly reduced cytopathic effects compared with the symptomatic strains when intact bacterial cells were used as an inoculant. Moreover, we found a reduced adherence phenotype when testing asymptomatic strains on HeLa cells. Real-time quantitative PCR results suggest that transcriptional repression of the genes encoding type-1 fimbriae occurs in the asymptomatic isolates but not in the symptomatic strains. PMID- 23648867 TI - Biomimetics on seed dispersal: survey and insights for space exploration. AB - Seeds provide the vital genetic link and dispersal agent between successive generations of plants. Without seed dispersal as a means of reproduction, many plants would quickly die out. Because plants lack any sort of mobility and remain in the same spot for their entire lives, they rely on seed dispersal to transport their offspring throughout the environment. This can be accomplished either collectively or individually; in any case as seeds ultimately abdicate their movement, they are at the mercy of environmental factors. Thus, seed dispersal strategies are characterized by robustness, adaptability, intelligence (both behavioral and morphological), and mass and energy efficiency (including the ability to utilize environmental sources of energy available): all qualities that advanced engineering systems aim at in general, and in particular those that need to enable complex endeavors such as space exploration. Plants evolved and adapted their strategy according to their environment, and taken together, they enclose many desirable characteristics that a space mission needs to have. Understanding in detail how plants control the development of seeds, fabricate structural components for their dispersal, build molecular machineries to keep seeds dormant up to the right moment and monitor the environment to release them at the right time could provide several solutions impacting current space mission design practices. It can lead to miniaturization, higher integration and packing efficiency, energy efficiency and higher autonomy and robustness. Consequently, there would appear to be good reasons for considering biomimetic solutions from plant kingdom when designing space missions, especially to other celestial bodies, where solid and liquid surfaces, atmosphere, etc constitute and are obviously parallel with the terrestrial environment where plants evolved. In this paper, we review the current state of biomimetics on seed dispersal to improve space mission design. PMID- 23648868 TI - Gold nanoparticle cluster-plasmon-enhanced fluorescent silica core-shell nanoparticles for X-ray computed tomography-fluorescence dual-mode imaging of tumors. AB - Owing to the surface plasmon resonance-enhanced electromagnetic field, clustered gold nanoparticles-fluorescent silica core-shell nanoparticles became excited within the therapeutic window and fluoresced strongly in this window. The nanoparticles enabled tumor detection using fluorescence imaging and X-ray computed tomography. PMID- 23648869 TI - Intracellular delivery of artificial transcription factors fused to the protein transduction domain of HIV-1 Tat. AB - Protein transduction domains (PTDs), such as the TAT peptide derived from HIV Tat protein, may transduce macromolecules into cells. In the present study, the TAT peptide-fused artificial transcription factors (ATFs) were generated by fusion of the N-terminal TAT peptide with SV40 promoter-targeted three-fingered C2H2 zinc finger proteins and the KRAB transcriptional repression domain. The fusion proteins were then expressed in an E .coli system and purified by Ni-NTA affinity chromatography. The purified fusion proteins were tested on mammalian cell lines CHO DG44 and L929. TAT-ATF-S, which contains the zinc fingers that bind to the SV40 promoter with high specificity, exhibited the desired transcriptional repression activity to the reported genes, indicating the successful cellular delivery and desired conformation of TAT-ATF-S. Our study has provided a new strategy for intracellular ATF delivery. PMID- 23648871 TI - Diabetes: Betatrophin--inducing beta-cell expansion to treat diabetes mellitus? PMID- 23648872 TI - Obesity: Bile acids and bariatric surgery. PMID- 23648873 TI - Just a lot of hot air? Volatile anesthetics in children with status asthmaticus. PMID- 23648874 TI - Critical pertussis: can we restrain it?. PMID- 23648875 TI - Bicaval approach to venovenous extracorporeal membrane oxygenation in children: just do it... carefully. PMID- 23648876 TI - B-type natriuretic peptides are a marker for congenital heart disease in neonates: cheap, feasible, and accurate; why not use them for screening?. PMID- 23648877 TI - When less is more: big problem, small change, better outcomes. PMID- 23648878 TI - Premedication for tracheal intubation: any good reason for treating newborn infants differently?. PMID- 23648879 TI - Enigma of low-serum zinc, selenium, and prolactin with lymphopenia. PMID- 23648881 TI - Is the Wada test necessary prior to epilepsy surgery? AB - The Wada test was initially used to identify the hemisphere of language dominance prior to epilepsy surgery, but was subsequently applied to identify patients at risk of amnesia after temporal resection. The Wada test was later found useful in lateralizing the epileptogenic zone, predicting postoperative memory function, and predicting postoperative seizure control. The Wada test became more widely used, and in many centers became a standard component of the presurgical evaluation of epilepsy. Yet, several problems and disadvantages have surrounded the Wada test, including absence of standardized technique, overestimation of postoperative deficits, and risks and discomforts related to the invasive nature of the procedure. The Wada test may be omitted in patients who have excellent localization of the epileptogenic zone and who do not appear at risk for postoperative memory or language compromise. In addition, there is a promising alternative in functional magnetic resonance imaging (fMRI), which has already demonstrated excellent agreement with the Wada test for language dominance. Progress is being made in memory fMRI as well. The Wada test identifies the capacity of one hemisphere to sustain memory, and language functions while the other hemisphere is inactivated, while fMRI identifies regions activated by language or memory tasks. Some of these activated regions may not be essential for the activating tasks. Before fMRI can fully replace the Wada test it has to specifically identify those activated regions that are essential for memory or language function, and also measure the memory reserves of the hemisphere contralateral to surgery. PMID- 23648880 TI - Bivalirudin in pediatric patients maintained on extracorporeal life support. AB - OBJECTIVE: Anticoagulation with heparin is standard of care for patients maintained on extracorporeal life support. Very limited evidence exists for the use of alternative anticoagulants during extracorporeal life support. Patients with heparin-induced thrombocytopenia, heparin resistance, and evidence of significant thrombosis while on heparin may be candidates for alternative anticoagulation. The objective of this analysis is to present evidence for the use of bivalirudin during extracorporeal life support in pediatric patients. DESIGN: Case series. SETTING: University of California, Davis Medical Center. PATIENTS: Twelve critically ill, pediatric patients receiving bivalirudin for anticoagulation during extracorporeal life support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twelve patients meeting entry criteria received bivalirudin during the study period. The median patient age was 8 days (range, 1 d to 6 yr). Eight patients were neonates. Eight patients were male. Nine patients were supported with venoarterial extracorporeal life support. Median duration of extracorporeal life support was 226 hours (range, 111-913) and median time on bivalirudin was 92 hours (range, 60-230). Bivalirudin bolus doses were administered to select patients without bleeding complications. The maintenance dose that corresponded with initial target activated partial thromboplastin time ranged from 0.045 to 0.48 mg/kg/hr with a median rate of 0.16 mg/kg/hr. The median dose for days 1, 3, and 5 was 0.135, 0.175, and 0.267 mg/kg/hr, respectively. The correlation (r2) between dose adjustment and activated partial thromboplastin time response was 0.264. CONCLUSIONS: This is the largest case series describing the use of a direct thrombin inhibitor in pediatric extracorporeal life support patients. The maintenance dose range reflected considerable inter-patient variability. There was an observed increase in dose requirements with time. Bivalirudin, with close monitoring, is a potential option for pediatric patients on extracorporeal life support who have developed heparin induced thrombocytopenia, heparin resistance, or significant thrombosis while on heparin. PMID- 23648882 TI - Study of the anatomical variations of the musculocutaneous nerve. AB - OBJECTIVE: To study the anatomical variations of the musculocutaneous nerve. METHODS: Fifty-four arms from embalmed adult cadavers were utilized for this investigation. They were carefully dissected and examined for any anatomical variations of the musculocutaneous nerve. This study was performed at the Department of Anatomy, King Abdul-Aziz University, Jeddah, Kingdom of Saudi Arabia between 2001 and 2003. RESULTS: Four anomalies of the musculocutaneous nerve were found in this study. One case showed that the musculocutaneous nerve pierced the coracobrachialis muscle and passed inside the muscle for some distance. The nerve pierced the coracobrachialis muscle again, and it ran downward and medially and joined the median nerve at the middle of the arm. The brachial artery was sandwiched between the musculocutaneous and the median nerves. Three cases demonstrated that the musculocutaneous nerve did not pierce the coracobrachialis muscle and passed downward and medial to it. The nerve joined the median nerve at the junction of the upper third with the lower two thirds of the arm. The musculocutaneous nerve was completely absent in one case. In another case, the musculocutaneous nerve originated from the upper part of the median nerve. CONCLUSION: The knowledge of the anatomical variations of the musculocutaneous nerve may have clinical and surgical implications. PMID- 23648883 TI - The significance of the neurovascular structures passing through the spinoglenoid notch. AB - OBJECTIVE: To define the detailed anatomy of the neurovascular bundle at the spinoglenoid notch and to report the dimensions of these structures in cadavers. METHODS: In the present study, the external diameters of suprascapular artery, vein and nerve were measured at the spinoglenoid notch region in 18 formalin fixed cadavers (36 shoulders) by using a caliper. The study was carried out in the dissection laboratory of Anatomy Departments of Hacettepe University, Ankara University, Ankara and Mersin University, Mersin, Turkey, between 2002 and 2003. RESULTS: The average external diameter for the suprascapular vein was 2.6 mm, artery was 2.2 mm and nerve was 2.2 mm. The spinoglenoid notch was roofed by the spinoglenoid ligament and appeared as a fibroosseous foramen in all cadavers. We found that the vascular structures (suprascapular artery and vein) occupied 68.5% and the suprascapular nerve occupied 31.5% of this foramen. CONCLUSION: Although the diameters of the vascular structures at the spinoglenoid notch measured by magnetic resonance imaging have been reported, to our knowledge, external diameters of these structures at the spinoglenoid notch have not been described in cadavers. We believe that detailed anatomy of suprascapular neurovascular bundle at the spinoglenoid notch should be appreciated for better understanding of risk factors possibly causing the suprascapular nerve entrapment syndrome, specially for those who are involved in violent overhead sports activities such as volleyball and baseball. PMID- 23648884 TI - Prediction of outcome of subarachnoid hemorrhage. A proposed scoring system. AB - OBJECTIVE: The aim of this study was to identify factors that affect the outcome of patients with aneurysmal subarachnoid hemorrhage treated at King Khalid University Hospital (KKUH), Riyadh, Kingdom of Saudi Arabia. METHODS: The medical records of 30 consecutive patients with verified ruptured cerebral aneurysm treated at KKUH between 1993 and 1996 were reviewed looking for factors that affect the outcome of surgery. Statistically significant factors were selected to design a scoring system for prediction of the outcome. This scoring system was then used to predict the outcome of the next 40 patients between 1997 and 2000. RESULTS: The preoperative Hunt and Hess grade, amount of subarachnoid hemorrhage in computerized tomography scan, aneurysm size and progressive hydrocephalus were the most significant factors that affect the outcome. There was significant association between the score value and the outcome, patients with low scores had negligible morbidity and mortality. CONCLUSION: The scoring system is simple, easily applicable and can be used to predict the outcome of patients with aneurysmal subarachnoid hemorrhage with a high degree of accuracy. PMID- 23648885 TI - Profile of stroke in Gizan, Kingdom of Saudi Arabia. AB - OBJECTIVE: The epidemiological characteristics of stroke at different geographical locations in the Kingdom of Saudi Arabia (KSA) have not been fully investigated. Reports from some areas indicate that stroke is one of the major causes of morbidity and mortality in the population. The present study was carried out to determine the clinical profile of stroke, its subtypes and associated risk factors in Gizan Province, KSA. METHODS: Data on consecutive patients with stroke admitted to King Fahd Central Hospital, Gizan, KSA over a 2 year period from January 1997 to December 1998, were retrospectively analyzed. Diagnosis was confirmed by computerized tomography of the brain. Etiologic and risk factors were identified by relevant clinical, laboratory and imaging investigations. RESULTS: Two hundred and forty-one patients (146 males and 95 females; mean age 64.5) were hospitalized during the study period. The subtypes of stroke comprised cerebral infarction (65.6%); intracerebral hemorrhage (30.7%) and sub-arachnoid hemorrhage (3.7%). Coma and convulsions were more frequent among patients with hemorrhagic strokes compared to the subgroup with cerebral infarction. Major risk factors included hypertension (45.6%), heart diseases with or without atrial fibrillation (31.1%) and diabetes mellitus (22.8%). In 19 (7.9%) patients, no risk factor was found. In-hospital mortality occurred in 20.3% (49 of 241 patients), with no significant difference in the rates in the different subtypes. CONCLUSION: The crude incidence (estimated as 15.9 per 100, 000) in Gizan, KSA, a largely rural area is lower than the reported rates in urban areas of KSA. However, intracerebral hemorrhage had a higher relative frequency, suggesting a geographic variation in the subtypes at different areas. The establishment of rehabilitation centers in the province will reduce the heavy burden on health services and relatives. The incidence and prevalence of stroke must be reduced by appropriate strategy with the objectives of preventing or modifying risk factors such as hypertension, diabetes mellitus and smoking. A national stroke registry should be strengthened to provide further information on the epidemiology of stroke in KSA. PMID- 23648886 TI - Topiramate for the treatment of intractable childhood epilepsy. AB - OBJECTIVE: Topiramate (TPM) is a new antiepileptic drug, which has a wide spectrum of activities suggesting a potentially valuable therapeutic profile. Our objective is to report our experience in treating children with intractable epilepsy. METHODS: Prospective, open label, add on trial of TPM in treating consecutive children with intractable epilepsy (defined as recurrent seizures after at least 3 antiepileptic medication trials) seen between May 1, 1999 and April 28, 2002 at King Faisal Specialist Hospital and Research Centre and King Abdulaziz University Hospital in Jeddah, Kingdom of Saudi Arabia. Follow up by 2 pediatric neurologists was performed. Therapeutic response was recorded as complete (no seizures), good (>50% seizure reduction), fair (<50% seizure reduction), or none. RESULTS: Sixty-two children (36 males and 26 females) aged between 2 months and 16 years (mean 6 years) were treated with TPM and followed for up to 3 years (mean 15 months). Most children (55%) had daily seizures and were tried on multiple antiepileptic drugs (mean 4.6). Nineteen (31%) children had Lennox-Gastaut syndrome. After the introduction of TPM, 21 (34%) became completely seizure free and 24 (39%) had >50% seizure reduction. Children with daily seizures were reduced from 55% before TPM to 13% on TPM (p=0.0007). Side effects were reported in 21 (34%) children in the form of decreased appetite, weight loss, and sedation. The majority was transient; however, TPM had to be withdrawn in 7 (11%) children because of progressive weight loss or seizure worsening. Follow up renal ultrasound was performed on 34 (55%) children and was always normal. CONCLUSION: Topiramate is a very effective antiepileptic drug with a broad spectrum of antiepileptic activities. Most side effects were transient, however, careful monitoring of body weight is recommended. PMID- 23648887 TI - Children's falls from heights in Ahwaz, Iran. AB - OBJECTIVE: To describe the epidemiology of children's falls in Ahwaz, Iran and to suggest its possible causes and preventive measures. METHODS: A one-year study was carried out in Ahwaz, Iran in 1999. All children aged 0-15 years who were taken to the accident and emergency (A&E) departments of all urban hospitals because of a vertical fall from heights were investigated. All parents of children were interviewed by using a questionnaire that included demographic and fall characteristic information. RESULTS: During the year of study, 2403 fall injuries were admitted to A&E departments, comprising 10.1% of all children's injuries. There were 64.5% boys and 35.5% girls. Patients ranged in age from 5 months to 15 years (mean 5.9 years), and were distributed equally between Fars and Arabs. The most frequent falls originated from windows and roofs (32.6%), from stairs (24.6%), and from playground equipment (9.3%). Many fall injuries took place at or near the home (77.5%), and involved the head (71.7%). CONCLUSION: A combination of targeted information and safety regulations could be an essential effort for reducing the incidence of children's falls from heights. This requires educating the parents to the hazards of falls and to mandate safer housing. PMID- 23648888 TI - Magnetic resonance imaging determination of the ventriculus terminalis. AB - We report a case of ventriculus terminalis, presenting with specific neurological symptoms including low back pain and bilateral sciatica. Magnetic resonance images showed a cystic lesion with regular margins localized in the lumbar enlargement of the spinal cord. The lesion was an oval shape with no internal septa. Its dimensions were 9.6 mm craniocaudally, 3.5 mm mediolaterally and 3.5 mm anteroposteriorly. Intralesional fluid had the same signal as cerebrospinal fluid in all magnetic resonance sequences. Pericystic spinal cord intensity was normal, and the cyst did not cause additional enlargement of the distal cord. During spinal cord evaluations, ventriculus terminalis should be kept in mind as a normal anatomic developmental phenomenon that can be seen on magnetic resonance images. PMID- 23648889 TI - Delayed treatment of cervical fracture. Dislocation in a 4-year-old. PMID- 23648890 TI - Sandhoff disease in an extreme preterm baby with bilateral syndactyly. PMID- 23648891 TI - Impact of prognostic factors on outcome in patients with severe head trauma. PMID- 23648892 TI - A boy with sporadic seizures. PMID- 23648894 TI - Glucuronides from metabolites to medicines: a survey of the in vivo generation, chemical synthesis and properties of glucuronides. AB - Covering: 1998 to 2011. Previous review: Nat. Prod. Rep., 1998, 15, 173-186. The fourteen years that have passed since the previous review on this topic have seen a significant increase of interest in many aspects of glucuronide chemistry and biology. Glucuronides are the most important class of phase 2 xenobiotic metabolites and typically act in a detoxifying role. While this is generally true for O-alkyl and O-aryl glucuronides, a number of glucuronides are known to be pharmacologically active per se. Additionally the use of glucuronide prodrugs, notably to ameliorate the cytotoxicity of anticancer agents, has markedly increased. Whereas the previous review covered only the synthesis of O glucuronides, we now include N-, S- and C-glucuronides also and discuss both synthetic and biological aspects. Synthetic methods for all classes of glucuronides are reviewed and updated, together with advances in the enzymatic synthesis of glucuronides and methods for their detection. Finally we discuss the biological reactivity of glucuronides where known, including the important morphine-6-glucuronide. A lively debate has continued for several years on whether O-acyl glucuronide metabolites of carboxylic acids are toxic, affecting both the safety assessment of well-used drugs and new drug development programmes. We summarise the current understanding, together with other known examples of interaction between glucuronides and macromolecules. PMID- 23648895 TI - Relationship between food preferences and PROP taster status of college students. AB - How food tastes plays a key role in our food choices and eating behavior, with important implications for health and nutrition. The negative relationship of genetically predisposed sensitivity to 6-n-propylthiouracil (PROP) and food preferences for bitter, creamy, and spicy foods, and alcohol is often reported in both scholarly and popular literature. Our review of research indicates the empirical results are far from conclusive. We conducted a questionnaire-based study to examine enjoyment ratings for 12 foods and beverages often reported to be disliked by PROP supertasters. We measured PROP ratings on the modified gLMS scale and administered a questionnaire to assess food preferences of a sample of 139 college undergraduates. Analysis of variance showed no significant group differences between supertasters, medium tasters, and nontasters in ratings of how much they liked brussels sprouts, raw broccoli, cabbage, spinach, black coffee, dark chocolate, crushed red pepper, jalapenos, chili peppers, red wine, beer, creamy salad dressing, or mayonnaise. Preferences for only two foods out of twelve, dark chocolate and chili peppers, had a significant correlation with PROP sensitivity in the predicted negative direction. While statistically significant, these correlations were low and of little practical significance. The role of culture in shaping attitudes toward food is proposed as a more powerful influence than the genetic factors that relate to PROP sensitivity. PMID- 23648893 TI - Antigen-based vs. systemic immunomodulation in type 1 diabetes: the pros and cons. AB - In type 1 diabetic patients insulin-producing pancreatic beta-cells are destroyed by an orchestrated immune process involving self-reactive auto-antigen-specific CD4+ and CD8+ T cells. Efforts to reverse or prevent this destructive immunological cascade have led to promising results in animal models, however, the transition to the clinic has yet been unsuccessful. In addition, current clinical studies lack reliable biomarkers to circumscribe end-point parameters and define therapeutic success. Here, we give a current overview of both antigen specific and non-specific systemic immunomodulatory approaches with a focus on the therapies verified or under evaluation in a clinical setting. While both approaches have their advantages and disadvantages, rationally designed combination therapies may yield the highest therapeutic efficacy. In order for future strategies to be effective, new well-defined biomarkers need to be developed and the extrapolation process of dose, timing and frequency from in vivo models to patients needs to be carefully reconsidered. PMID- 23648896 TI - Small human islets comprised of more beta-cells with higher insulin content than large islets. AB - For the past 30 years, data have suggested that unique islet populations exist, based on morphology and glucose sensitivity. Yet little has been done to determine the mechanism of these functional differences. The purpose of this study was to determine whether human islets were comprised functionally unique populations, and to elucidate a possible mechanism. Islets or pancreatic sections from 29 human donors were analyzed. Islets were isolated and measured for insulin secretion, cell composition and organization, insulin and glucagon granule density and insulin content. Insulin secretion was significantly greater in small compared with large islets. In sectioned human pancreata, beta-cells comprised a higher proportion of the total endocrine cells in small islets (63%) than large islets (39%). A higher percentage of beta-cells in small islets contacted blood vessels (44%) compared with large islets (31%). Total insulin content of isolated human islets was significantly greater in the small (1323 +/- 512 MUIU/IE) compared with large islets (126 +/- 48 MUIU/IE). There was less immunostaining for insulin in the large islets from human pancreatic sections, especially in the core of the islet, compared with small islets. The results suggest that differences in insulin secretion between large and small islets may be due to a higher percentage of beta-cells in small islets with more beta-cells in contact with blood vessels and a higher concentration of insulin/beta-cell in small islets. PMID- 23648897 TI - The American College of Chest Physicians Lung Cancer Guidelines (3rd edition): is the pulmonologist moving from special teams to quarterback? PMID- 23648898 TI - Antibiotic stewardship in hospital-acquired pneumonia. PMID- 23648899 TI - When should specific occupational challenge tests be performed? PMID- 23648900 TI - A new application for CPAP in preventing atrial fibrillation. PMID- 23648902 TI - Point: Should phrenic nerve stimulation be the treatment of choice for spinal cord injury? Yes. PMID- 23648903 TI - Counterpoint: Should phrenic nerve stimulation be the treatment of choice for spinal cord injury? No. PMID- 23648904 TI - Rebuttal from Dr Wolfe. PMID- 23648905 TI - Rebuttal from Dr Gay. PMID- 23648906 TI - The changing face of outpatient bronchoscopy in 2013. AB - In 2013, the outpatient hospital payment from Medicare for a transbronchial needle aspiration more than doubled. At the same time, the recently updated American College of Chest Physicians guidelines for the diagnosis and management of lung cancer now recommend needle techniques, such as transbronchial needle aspiration, over surgical staging. The convergence of these two events will accelerate the existing forces of technology and economics that have been influencing both the practices of outpatient bronchoscopy and mediastinoscopy and the management of patients with lung cancer over the past 20 years. PMID- 23648907 TI - Small airway obstruction in COPD: new insights based on micro-CT imaging and MRI imaging. AB - The increase in total cross-sectional area in the distal airways of the human lung enhances the mixing of each tidal breath with end-expiratory gas volume by slowing bulk flow and increasing gas diffusion. However, this transition also favors the deposition of airborne particulates in this region because they diffuse 600 times slower than gases. Furthermore, the persistent deposition of toxic airborne particulates stimulates a chronic inflammatory immune cell infiltration and tissue repair and remodeling process that increases the resistance in airways <2 mm in diameter four to 40-fold in COPD. This increase was originally attributed to lumen narrowing because it increases resistance in proportion to the change in lumen radius raised to the fourth power. In contrast, removal of one-half the number of tubes arranged in parallel is required to double their resistance, and approximately 90% need to be removed to explain the increase in resistance measured in COPD. However, recent reexamination of this problem based on micro-CT imaging indicates that terminal bronchioles are both narrowed and reduced to 10% of the control values in the centrilobular and 25% in the panlobular emphysematous phenotype of very severe (GOLD [Global Initiative for Chronic Obstructive Lung Disease] grade IV) COPD. These new data indicate that both narrowing and reduction in numbers of terminal bronchioles contribute to the rapid decline in FEV1 that leads to severe airway obstruction in COPD. Moreover, the observation that terminal bronchiolar loss precedes the onset of emphysematous destruction suggests this destruction begins in the very early stages of COPD. PMID- 23648908 TI - Preventing acute exacerbations and hospital admissions in COPD. AB - COPD is a leading cause of morbidity and mortality worldwide and is now the third leading cause of death in the United States. Acute exacerbations of COPD (AECOPDs) are common events that often lead to hospitalization, and their frequency worsens with disease progression. AECOPDs are associated with worsened quality of life, increased health-care costs, and increased mortality. Accordingly, there is great interest in preventing AECOPDs to improve outcomes. Both pharmacologic and nonpharmacologic interventions alter the frequency of AECOPDs and COPD-related hospitalizations. To examine the best available evidence, we restricted this review to include studies that used randomized controlled designs lasting at least 6 months. Pharmacologic interventions discussed include inhaled corticosteroids, long-acting beta-agonists, long-acting antimuscarinic agents, macrolide antibiotics, and phosphodiesterase-4 inhibitors. The nonpharmacologic interventions discussed include lung volume reduction surgery, pulmonary rehabilitation, and disease management programs. PMID- 23648909 TI - Lungs in a warming world: climate change and respiratory health. AB - Climate change is a health threat no less consequential than cigarette smoking. Increased concentrations of greenhouse gases, and especially CO2, in the earth's atmosphere have already warmed the planet substantially, causing more severe and prolonged heat waves, temperature variability, air pollution, forest fires, droughts, and floods, all of which put respiratory health at risk. These changes in climate and air quality substantially increase respiratory morbidity and mortality for patients with common chronic lung diseases such as asthma and COPD and other serious lung diseases. Physicians have a vital role in addressing climate change, just as they did with tobacco, by communicating how climate change is a serious, but remediable, hazard to their patients. PMID- 23648910 TI - Chronic pulmonary emboli and radiologic mimics on CT pulmonary angiography: a diagnostic challenge. AB - Chronic pulmonary thromboembolism (CPE) is a challenging diagnosis for clinicians. It is an often-forgotten diagnosis and can be difficult to detect and easily misdiagnosed. The radiologic features on CT pulmonary angiography are subtle and can be further compounded by pathologic mimics and unusual findings observed with disease progression. Diagnosis is important because CPE can lead to progressive pulmonary hypertension, morbidity, and mortality. Moreover, chronic thromboembolic pulmonary hypertension is the only category of pulmonary hypertension with an effective curative treatment in the form of pulmonary endarterectomy. Therefore, CPE must be considered and recognized early. The features of chronic pulmonary emboli on CT scans can be categorized into vascular or parenchymal findings. Endoluminal signs include totally or partially occlusive thrombi and webs and bands. Parenchymal features such as mosaic attenuation and pulmonary infarction are also noted, in addition to features of pulmonary artery hypertension. Additional findings have been noted, including cavitation of infarcts, microbial colonization of cavities, and bronchopleural fistulae. As CPE can be diagnosed at different stages of its disease pathway, such findings may not necessarily arouse suspicion toward a causative diagnosis of chronic embolism. To aid diagnosis for clinicians, this article describes the characteristic vascular and parenchymal CT scan features of chronic emboli, as well as important ancillary findings. We also provide an illustrative case series focusing on CT pulmonary angiography specifically as an imaging modality to highlight the progressive nature of CPE and its sequelae, as well as important radiologic mimics to consider in the differential diagnosis. PMID- 23648911 TI - Contracting for directorships. AB - Hospitals are required to have a medical director of respiratory care as a condition of their participation in the Federal Medicare and Medicaid programs. This gives physicians opportunities to improve the quality of care for the patients in their community, to diversify income streams, and to assist hospitals to meet regulatory requirements for quality. The contracts for these positions are usually provided by the hospital, so it is imperative that physicians know how to protect their interests, what is expected of them, if they are being paid fairly, and that the contract is compliant with all regulatory issues. The directorship relationship with the hospital that provides designated health services and the "stand in the shoes" definition of direct compensation also gives physicians and physician practices guidance to determine if their group and individual physicians are compliant with Stark and antikickback regulations. This article guides physicians through the process of reviewing a contract for medical directorship or service line management services. Information on compensation in the directorship market can be found in at least two standard surveys. Duties and compensation vary among entities and frequently include incentive-based compensation for improving quality measures and operations. Directorships are evolving to service line management as more of the hospital's reimbursement is linked to clinical quality and patient satisfaction. This article does not offer legal advice, nor is it meant to be all inclusive. Physicians should consult a health-care attorney for any questions before signing any contract. PMID- 23648912 TI - An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor. AB - We report a case of Cryptococcus neoformans pneumonia in a patient taking ruxolitinib, a janus kinase 1,2 inhibitor approved for the treatment of myelofibrosis. We hypothesize that ruxolitinib contributed to this infection through its effects on cell-mediated immunity. Clinicians should be aware of the potential for intracellular or opportunistic infections associated with this novel drug class. PMID- 23648913 TI - Hemodynamic monitoring. AB - Hemodynamic assessment is a key component of the evaluation of the critically ill patients and has both diagnostic and prognostic utility. This review outlines a general approach to assessment of hemodynamics and perfusion, and then discusses various hemodynamic parameters: heart rate, BP, intravascular (central venous and pulmonary artery) pressures, cardiac output, and myocardial performance, within the context not only of how they are best measured but also how they should be used in a clinical context. Hemodynamics are best assessed using a combination of not only different hemodynamic parameters but also those with the inclusion of clinical indices of perfusion. The benefits of these techniques, as with all medical testing and interventions, must be weighed against any potential risks. Although what to measure and how to measure it is important, what is most important is how to use the information. Evaluating the response to therapeutic interventions is frequently the most useful way to employ hemodynamic monitoring techniques. For the practitioner, learning how to select from a robust set of hemodynamic tools and how to tailor their use to individual clinical settings will allow for optimal patient care. PMID- 23648915 TI - A 30-year-old woman with recurrent lower respiratory tract infections. PMID- 23648914 TI - Genetic and immunologic aspects of sleep and sleep disorders. AB - The study of genetics is providing new and exciting insights into the pathogenesis, diagnosis, and treatment of disease. Both normal sleep and several types of sleep disturbances have been found to have significant genetic influences, as have traits of normal sleep, such as those evident in EEG patterns and the circadian sleep-wake cycle. The circadian sleep-wake cycle is based on a complex feedback loop of genetic transcription over a 24-h cycle. Restless legs syndrome (RLS) and periodic limb movements in sleep (PLMS) have familial aggregation, and several genes have a strong association with them. Recent genome wide association studies have identified single nucleotide polymorphisms linked to RLS/PLMS, although none has a definite functional correlation. Narcolepsy/cataplexy are associated with HLA DQB1*0602 and a T-cell receptor alpha locus, although functional correlations have not been evident. Obstructive sleep apnea is a complex disorder involving multiple traits, such as anatomy of the oropharynx, ventilatory control, and traits associated with obesity. Although there is clear evidence of familial aggregation in the obstructive sleep apnea syndrome, no specific gene or locus has been identified for it. Angiotensin converting enzyme has been proposed as a risk variant, but evidence is weak. Fatal familial insomnia and advanced sleep phase syndrome are sleep disorders with a definite genetic basis. PMID- 23648916 TI - A 35-year-old woman with unusual behavior and prolonged respiratory failure. PMID- 23648921 TI - Influence of obstructive sleep apnea on cognitive impairment in patients with COPD. PMID- 23648922 TI - Response. PMID- 23648923 TI - Antithrombotic and thrombolytic therapy for valvular disease: can this guideline apply to Chinese? PMID- 23648924 TI - The predictive value of interferon-gamma release assays and tuberculin skin test: what about those not vaccinated with Bacillus Calmette-Guerin? PMID- 23648925 TI - Response. PMID- 23648926 TI - Response. PMID- 23648927 TI - Endobronchial ultrasound and extended roles: know thy limitations. PMID- 23648928 TI - Relationship between pulmonary emphysema and renal function in smokers. PMID- 23648929 TI - Response. PMID- 23648930 TI - Response. PMID- 23648931 TI - Survival in untreated stage I lung cancer. PMID- 23648932 TI - Not all wheezing is from COPD. PMID- 23648934 TI - Pancreatic cancer: Radioactive Listeria delivers killer hit to metastatic pancreatic cancer. PMID- 23648935 TI - State-of-the-art medical prevention of postoperative recurrence of Crohn's disease. AB - Postoperative recurrence of Crohn's disease is a frequent and often severe sequela of the disease. Until a few years ago it was deemed inescapable, as all the conventional medications used to treat the disease have been proven of little benefit in preventing recurrence after surgical treatment. In the past few years, anti-TNF agents given immediately after surgery have shown a remarkable efficacy in the prevention of disease recurrence. Large, randomized, controlled trials are currently underway to confirm these findings. Anti-TNF treatment of endoscopic lesions that occur after surgery seems to be less effective than using TNF antagonists to prevent recurrence. However, although the data are limited, this treatment strategy seems to be still superior to all the other prevention strategies that are not based on anti-TNF agents. Limited data are available on long-term outcomes of patients treated with anti-TNF agents after surgery. They suggest that these medications are safe and effective after many years of treatment. In addition, these agents might prevent recurrence even at doses lower than those used in patients with Crohn's disease who have not had surgery. PMID- 23648940 TI - Gut microbiota: Intestinal bacteria influence brain activity in healthy humans. PMID- 23648939 TI - Advances in motility testing--current and novel approaches. AB - Disorders of gastrointestinal motility are frequently seen in clinical practice. Apart from motility disorders, factors leading to lowered visceroperception thresholds are recognized as commonly involved in the pathogenesis of functional gastrointestinal disorders. The wide array of gastrointestinal motility and viscerosensitivity tests available is in contrast with the relatively limited number of tests used universally in clinical practice. The main reason for this discrepancy is that the outcome of a test only becomes truly important when it carries clinical consequences. The main goal of this Review is to assess the place of the presently available gastrointestinal motility and sensitivity tests in the clinical armamentarium of the gastroenterologist. PMID- 23648942 TI - A novel tracking tool for the analysis of plant-root tip movements. AB - The growth process of roots consists of many activities, such as exploring the soil volume, mining minerals, avoiding obstacles and taking up water to fulfil the plant's primary functions, that are performed differently, depending on environmental conditions. Root movements are strictly related to a root decision strategy, which helps plants to survive under stressful conditions by optimizing energy consumption. In this work, we present a novel image-analysis tool to study the kinematics of the root tip (apex), named analyser for root tip tracks (ARTT). The software implementation combines a segmentation algorithm with additional software imaging filters in order to realize a 2D tip detection. The resulting paths, or tracks, arise from the sampled tip positions through the acquired images during the growth. ARTT allows work with no markers and deals autonomously with new emerging root tips, as well as handling a massive number of data relying on minimum user interaction. Consequently, ARTT can be used for a wide range of applications and for the study of kinematics in different plant species. In particular, the study of the root growth and behaviour could lead to the definition of novel principles for the penetration and/or control paradigms for soil exploration and monitoring tasks. The software capabilities were demonstrated by experimental trials performed with Zea mays and Oryza sativa. PMID- 23648941 TI - Ras signal triggers beta-amyloid precursor protein (APP) expression. AB - It has recently been discovered that the Drosophila beta-amyloid protein precursor like (Appl) gene, the ortholog of the human beta-Amyloid Precursor Protein (APP) gene, is transcriptionally activated by receptor tyrosine kinase activity that involves Ras/MAPK signaling in vivo. This regulation is specifically controlled in photoreceptor neurons of the Drosophila retina. This suggests that some cases of Alzheimer disease, those which have been associated with high expression of the APP gene, may involve Ras signal transduction. PMID- 23648945 TI - Cleavable trifunctional biotin reagents for protein labelling, capture and release. AB - Trifunctional biotin reagents incorporating cleavable linkers are evaluated for their usage in protein enrichment. A linker based on the Dde protecting group leads to efficient release of protein targets under mild conditions. It additionally contains a masked trypsin cleavage site, which eliminates the majority of the tag during tryptic digestion. PMID- 23648943 TI - GEF-H1: orchestrating the interplay between cytoskeleton and vesicle trafficking. AB - Vesicle trafficking is crucial for delivery of membrane compartments as well as signaling molecules to specific sites on the plasma membrane for regulation of diverse processes such as cell division, migration, polarity establishment and secretion. Rho GTPases are well-studied signaling molecules that regulate actin cytoskeleton in response to variety of extracellular stimuli. Increasing amounts of evidence suggest that Rho proteins play a critical role in vesicle trafficking in both the exocytic and endocytic pathways; however, the molecular mechanism underlying the process remains largely unclear. We recently defined a mechanism of action for RhoA in membrane trafficking pathways through regulation of the octameric complex exocyst in a manuscript published in Developmental Cell. We have shown that microtubule-associated RhoA-activating factor GEF-H1 is involved in endocytic and excocytic vesicle trafficking. GEF-H1 activates RhoA in response to RalA GTPase, which in turn regulates the localization and the assembly of exocyst components and exocytosis. Our work defines a mechanism for RhoA activation in response to RalA signaling and during vesicle trafficking. These results provide a framework for understanding how RhoA/GEF-H1 regulates the coordination of actin and microtubule cytoskeleton modulation and vesicle trafficking during migration and cell division. PMID- 23648947 TI - An acute change in lung allocation score and survival after lung transplantation: a cohort study. AB - BACKGROUND: Lung transplantation is an effective treatment for patients with advanced lung disease. In the United States, lungs are allocated on the basis of the lung allocation score (LAS), a composite measure of transplantation urgency and utility. Clinical deteriorations result in increases to the LAS; however, whether the trajectory of the LAS has prognostic significance is uncertain. OBJECTIVE: To determine whether an acute increase in the LAS before lung transplantation is associated with reduced posttransplant survival. DESIGN: Retrospective cohort study of adult lung transplant recipients listed for at least 30 days between 4 May 2005 (LAS implementation) and 31 December 2010 in the United Network for Organ Sharing registry. An acute increase in the LAS was defined as an LAS change (LASDelta) greater than 5 units between the 30 days before and the time of transplantation. Multivariable Cox proportional hazard models were used to examine the relationship between an LASDelta >5 and posttransplant graft survival. SETTING: All U.S. lung transplantation centers. PATIENTS: 5749 lung transplant recipients. MEASUREMENTS: Survival time after lung transplantation. RESULTS: 702 (12.2%) patients experienced an LASDelta >5. These patients had significantly worse posttransplant survival (hazard ratio, 1.31 [95% CI, 1.11 to 1.54]; P = 0.001]) after adjustment for the LAS at transplantation (LAS-T) and other clinical covariates. The effect of an LASDelta >5 was independent of the LAS-T, underlying diagnosis, center volume, or donor characteristics. LIMITATION: Analysis was based on center-reported data. CONCLUSION: An acute increase in LAS before transplantation is associated with posttransplant survival after adjustment for LAS-T. Further emphasis on serial assessment of the LAS could improve the ability to offer accurate prediction of survival after transplantation. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 23648948 TI - Action to stop smoking in suspected tuberculosis (ASSIST) in Pakistan: a cluster randomized, controlled trial. AB - BACKGROUND: Tobacco use is responsible for a large proportion of the total disease burden from tuberculosis. Pakistan is one of the 10 high-burden countries for both tuberculosis and tobacco use. OBJECTIVE: To assess the effectiveness of a behavioral support intervention and bupropion in achieving 6-month continuous abstinence in adult smokers with suspected pulmonary tuberculosis. DESIGN: Cluster randomized, controlled trial. (Current Controlled Trials: ISRCTN08829879) SETTING: Health centers in the Jhang and Sargodha districts in Pakistan. PATIENTS: 1955 adult smokers with suspected tuberculosis. INTERVENTION: Health centers were randomly assigned to provide 2 brief behavioral support sessions (BSS), BSS plus 7 weeks of bupropion therapy (BSS+), or usual care. MEASUREMENTS: The primary end point was continuous abstinence at 6 months after the quit date and was determined by carbon monoxide levels in patients. Secondary end points were point abstinence at 1 and 6 months. RESULTS: Both treatments led to statistically significant relative risks (RRs) for abstinence compared with usual care (RR for BSS+, 8.2 [95% CI, 3.7 to 18.2]; RR for BSS, 7.4 [CI, 3.4 to 16.4]). Equivalence between the treatments could not be established. In the BSS+ group, 275 of 606 patients (45.4% [CI, 41.4% to 49.4%]) achieved continuous abstinence compared with 254 of 620 (41.0% [CI, 37.1% to 45.0%]) in the BSS group and 52 of 615 (8.5% [CI, 6.4% to 10.9%]) in the usual care group. There was substantial heterogeneity of program effects across clusters. LIMITATIONS: Imbalances in the urban and rural proportions and smoking habits among treatment groups, and inability to confirm adherence to bupropion treatment and validate longer-term abstinence or the effect of smoking cessation on tuberculosis outcomes. CONCLUSION: Behavioral support alone or in combination with bupropion is effective in promoting cessation in smokers with suspected tuberculosis. PRIMARY FUNDING SOURCE: International Development Research Centre. PMID- 23648950 TI - Risk stratification of lung transplant candidates: implications for organ allocation. PMID- 23648949 TI - Management strategies for asymptomatic carotid stenosis: a systematic review and meta-analysis. AB - BACKGROUND: Adults with asymptomatic carotid artery stenosis are at increased risk for ipsilateral carotid territory ischemic stroke. PURPOSE: To examine comparative evidence on management strategies for asymptomatic carotid stenosis and the incidence of ipsilateral stroke with medical therapy alone. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, U.S. Food and Drug Administration documents, and review of references through 31 December 2012. STUDY SELECTION: Randomized, controlled trials (RCTs) and prospective or retrospective nonrandomized, comparative studies of medical therapy alone, carotid endarterectomy (CEA) plus medical therapy, or carotid artery stenting (CAS) plus medical therapy for adults with asymptomatic carotid stenosis, as well as single-group prospective cohort studies of medical therapy, were reviewed. DATA EXTRACTION: Two investigators extracted information on study and population characteristics, results, and risk of bias. DATA SYNTHESIS: Forty-seven studies in 56 publications were eligible. The RCTs comparing CAS and CEA were clinically heterogeneous; 1 RCT reported more but not statistically significant ipsilateral stroke events (including any periprocedural stroke) in CAS compared with CEA, whereas another RCT, in a population at high surgical risk for CEA, did not. Three RCTs showed that CEA reduced the risk for ipsilateral stroke (including any periprocedural stroke) compared with medical therapy alone, but these results may no longer be applicable to contemporary clinical practice. No RCT compared CAS versus medical therapy alone. The summary incidence of ipsilateral stroke across 26 cohorts receiving medical therapy alone was 1.68% per year. LIMITATIONS: Studies defined asymptomatic status heterogeneously. Participants in RCTs did not receive best-available medical therapy. CONCLUSION: Future RCTs of asymptomatic carotid artery stenosis should explore whether revascularization interventions provide benefit to patients treated by best-available medical therapy. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 23648951 TI - The big problem. PMID- 23648952 TI - Hepatitis C virus testing of persons born during 1945-1965. PMID- 23648946 TI - Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE: To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN: Randomized, double blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING: Academic and private hospitals. PARTICIPANTS: Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION: Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS: Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS: The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION: The study was terminated early. CONCLUSION: Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE: Gilead Sciences. PMID- 23648953 TI - Hepatitis C virus testing of persons born during 1945-1965. PMID- 23648954 TI - Hepatitis C virus testing of persons born during 1945-1965. In response. PMID- 23648955 TI - Probiotics for the prevention of Clostridium difficile-associated diarrhea. PMID- 23648956 TI - Probiotics for the prevention of Clostridium difficile-associated diarrhea. PMID- 23648957 TI - Probiotics for the prevention of Clostridium difficile-associated diarrhea. In response. PMID- 23648958 TI - Melanotan and the posterior reversible encephalopathy syndrome. PMID- 23648959 TI - In the clinic. Pulmonary hypertension. PMID- 23648960 TI - Tracing the emergence of categorical speech perception in the human auditory system. AB - Speech perception requires the effortless mapping from smooth, seemingly continuous changes in sound features into discrete perceptual units, a conversion exemplified in the phenomenon of categorical perception. Explaining how/when the human brain performs this acoustic-phonetic transformation remains an elusive problem in current models and theories of speech perception. In previous attempts to decipher the neural basis of speech perception, it is often unclear whether the alleged brain correlates reflect an underlying percept or merely changes in neural activity that covary with parameters of the stimulus. Here, we recorded neuroelectric activity generated at both cortical and subcortical levels of the auditory pathway elicited by a speech vowel continuum whose percept varied categorically from /u/ to /a/. This integrative approach allows us to characterize how various auditory structures code, transform, and ultimately render the perception of speech material as well as dissociate brain responses reflecting changes in stimulus acoustics from those that index true internalized percepts. We find that activity from the brainstem mirrors properties of the speech waveform with remarkable fidelity, reflecting progressive changes in speech acoustics but not the discrete phonetic classes reported behaviorally. In comparison, patterns of late cortical evoked activity contain information reflecting distinct perceptual categories and predict the abstract phonetic speech boundaries heard by listeners. Our findings demonstrate a critical transformation in neural speech representations between brainstem and early auditory cortex analogous to an acoustic-phonetic mapping necessary to generate categorical speech percepts. Analytic modeling demonstrates that a simple nonlinearity accounts for the transformation between early (subcortical) brain activity and subsequent cortical/behavioral responses to speech (>150-200 ms) thereby describing a plausible mechanism by which the brain achieves its acoustic to-phonetic mapping. Results provide evidence that the neurophysiological underpinnings of categorical speech are present cortically by ~175 ms after sound enters the ear. PMID- 23648961 TI - Functional MRI and neural responses in a rat model of Alzheimer's disease. AB - Based on the hypothesis that brain plaques and tangles can affect cortical function in Alzheimer's disease (AD), we investigated functional responses in an AD rat model (called the Samaritan Alzheimer's rat achieved by ventricular infusion of amyloid peptide) and age-matched healthy control. High-field functional magnetic resonance imaging (fMRI) and extracellular neural activity measurements were applied to characterize sensory-evoked responses. Electrical stimulation of the forepaw led to BOLD and neural responses in the contralateral somatosensory cortex and thalamus. In AD brain we noted much smaller BOLD activation patterns in the somatosensory cortex (i.e., about 50% less activated voxels compared to normal brain). While magnitudes of BOLD and neural responses in the cerebral cortex were markedly attenuated in AD rats compared to normal rats (by about 50%), the dynamic coupling between the BOLD and neural responses in the cerebral cortex, as assessed by transfer function analysis, remained unaltered between the groups. However thalamic BOLD and neural responses were unaltered in AD brain compared to controls. Thus cortical responses in the AD model were indeed diminished compared to controls, but the thalamic responses in the AD and control rats were quite similar. Therefore these results suggest that Alzheimer's disease may affect cortical function more than subcortical function, which may have implications for interpreting altered human brain functional responses in fMRI studies of Alzheimer's disease. PMID- 23648962 TI - Diffusion tensor magnetic resonance histology reveals microstructural changes in the developing rat brain. AB - The postnatal period is a remarkably dynamic phase of brain growth and development characterized by large-scale macrostructural changes, as well as dramatic microstructural changes, including myelination and cortical layering. This crucial period of neurodevelopment is uniquely susceptible to a wide variety of insults that may lead to neurologic disease. MRI is an important tool for studying both normal and abnormal neurodevelopmental changes, and quantitative imaging strategies like diffusion tensor imaging (DTI) allow visualization of many of the complex microstructural changes that occur during postnatal life. Diffusion tensor magnetic resonance histology (DT-MRH) provides particularly unique insight into cytoarchitectural changes in the developing brain. In this study, we used DT-MRH to track microstructural changes in the rat brain throughout normal postnatal neurodevelopment. We provide examples of diffusion tensor parameter changes in both white matter and gray matter structures, and correlate these changes with changes in cytoarchitecture. Finally, we provide a comprehensive database of image sets as a foundation for future studies using DT MRH to characterize abnormal neurodevelopment in rodent models of neurodevelopmental disease. PMID- 23648963 TI - In vivo architectonics: a cortico-centric perspective. AB - Recent advances in noninvasive structural imaging have opened up new approaches to cortical parcellation, many of which are described in this special issue on In Vivo Brodmann Mapping. In this introductory article, we focus on the emergence of cortical myelin maps as a valuable way to assess cortical organization in humans and nonhuman primates. We demonstrate how myelin maps are useful in three general domains: (i) as a way to identify cortical areas and functionally specialized regions in individuals and group averages; (ii) as a substrate for improved intersubject registration; and (iii) as a basis for interspecies comparisons. We also discuss how myelin-based cortical parcellation is complementary in important ways to connectivity-based parcellation using functional MRI or diffusion imaging and tractography. These observations and perspectives provide a useful background and context for other articles in this special issue. PMID- 23648964 TI - The neural correlates of the face attractiveness aftereffect: a functional near infrared spectroscopy (fNIRS) study. AB - Extensive behavioral evidence shows that our internal representation of faces, or face prototype, can be dynamically updated by immediate experience. This is illustrated by the robust attractiveness aftereffect phenomenon whereby originally unattractive faces become attractive after we are exposed to a set of unattractive faces. Although behavioral evidence suggests this effect to have a strong neural basis, limited neuroimaging evidence exists. Here we used functional near-infrared spectroscopy methodology (fNIRS) to bridge this gap. During the pre-adaptation trials, participants judged the attractiveness of three sets of faces: normal/undistorted faces, compressed faces (the internal features and distances between them were compressed), and expanded faces (the internal features and distances between them were stretched). Then, participants were shown extremely compressed faces for 5 min as adaptation stimuli, after which participants judged the same three sets of faces in post-adaptation trials. Behaviorally, after the adaptation trials, participants rated the compressed faces more attractive whereas they judged the other two sets of faces as less attractive, replicating the robust adaptation effect. fNIRS results showed that short-term exposure to compressed faces led to significant decreases in neural activity to all face types, but in a more extended network of cortical regions in the frontal and occipital cortexes for undistorted faces. Taken together, these findings suggest that the face attractiveness aftereffect mainly reflects changes in the neural representation of the face prototype in response to recent exposures to new face exemplars. PMID- 23648965 TI - The impact of distractor congruency on stimulus processing in retinotopic visual cortex. AB - The brain is frequently confronted with sensory information that elicits conflicting response choices. While much research has addressed the top down control mechanisms associated with detection and resolution of response competition, the effects of response competition on sensory processing in the primary visual cortex remain unclear. To address this question we modified a typical 'flanker task' (Eriksen and Eriksen, 1974) so that the effects of response competition on human early retinotopic visual cortex could be assessed. Healthy human participants were scanned using fMRI while making a speeded choice response that classified a target object image into one of two categories (e.g. fruits, animals). An irrelevant distractor image that was either congruent (same image as target), incongruent (image from opposite category as target), or neutral (image from task-irrelevant category, e.g. household items) was also present on each trial, but in a different quadrant of the visual field relative to the target. Retinotopic V1 areas responding to the target stimuli showed increased response to targets in the presence of response-incongruent (compared to response-neutral) distractors. A negative correlation with behavioral response competition effects indicated that an increased primary visual cortical response to targets in the incongruent (vs. neutral) trials is associated with a reduced response competition effect on behavior. These results suggest a novel conflict resolution mechanism in the primary visual cortex. PMID- 23648966 TI - Actuators based on liquid crystalline elastomer materials. AB - Liquid crystalline elastomers (LCEs) exhibit a number of remarkable physical effects, including the unique, high-stroke reversible mechanical actuation when triggered by external stimuli. This article reviews some recent exciting developments in the field of LCE materials with an emphasis on their utilization in actuator applications. Such applications include artificial muscles, industrial manufacturing, health and microelectromechanical systems (MEMS). With suitable synthetic and preparation pathways and well-controlled actuation stimuli, such as heat, light, electric and magnetic fields, excellent physical properties of LCE materials can be realized. By comparing the actuating properties of different systems, general relationships between the structure and the properties of LCEs are discussed. How these materials can be turned into usable devices using interdisciplinary techniques is also described. PMID- 23648967 TI - Growth, structural and optical characterization of a new nonlinear optical crystal--hippuric acid doped potassium di hydrogen phosphate. AB - Potassium di hydrogen phosphate (KDP) is an efficient nonlinear optical crystal employed in frequency conversion applications. 1mol% hippuric acid doped potassium di hydrogen phosphate (HAKDP) crystals with the dimensions 35*8*4 mm(3) were grown using the slow evaporation technique. The grown HAKDP crystal is iso structural with pure KDP, but a variation in the crystallographic parameters was observed. The UV-VIS-NIR study suggests that the crystal is highly transparent in the region 340-1200 nm. The functional groups present in the grown crystal were observed in the FTIR analysis. The powder SHG test performed on the grown crystal revealed the NLO efficiency of the crystal has increased due to doping when compared with pure KDP crystal. PMID- 23648968 TI - Synthesis, characterization and density functional theory investigations of the electronic, photophysical and charge transfer properties of donor-bridge-acceptor triaminopyrazolo[1,5-a]pyrimidine dyes. AB - We have synthesized multifunctional dyes 3-(4-methyl-phenylazo)-6-(4-nitro phenylazo)-2,5,7-triaminopyrazolo[1,5-a]pyrimidine (4a) and 3-(4-methyl phenylazo)-6-(4-acetyl-phenylazo)-2,5,7-triaminopyrazolo[1,5-a]pyrimidine (4b), then characterized by IR, (1)H NMR and (13)C NMR techniques. The ground state geometries have been computed by using density functional theory at B3LYP/6 31G(*) level of theory. The absorption spectra have been calculated by using time dependent density functional theory with and without solvent. The highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) are delocalized and localized on throughout the backbone, respectively. Solvent also play important role towards elevating the dipole moment. Significant red shift in absorption wavelengths have been observed in methanol compared to without solvent. We discussed the electron injection, electronic coupling constant and light harvesting efficiency. PMID- 23648969 TI - Infection: resistance is futile. PMID- 23648970 TI - Infection: the interferon paradox. PMID- 23648971 TI - Type 2 immunity: regenerating muscles the type 2 way. PMID- 23648972 TI - White matter deficits in first episode schizophrenia: an activation likelihood estimation meta-analysis. AB - BACKGROUND: Diffusion tensor imaging (DTI) has been widely used in psychiatric research and has provided evidence of white matter abnormalities in first episode schizophrenia (FES). The goal of the present meta-analysis was to identify white matter deficits by DTI in FES. METHODS: A systematic search was conducted to collect DTI studies with voxel-wised analysis of the fractional anisotropy (FA) in FES. The coordinates of regions with FA changes were meta-analyzed using the activation likelihood estimation (ALE) method which weighs each study on the basis of its sample size. RESULTS: A total of 8 primary studies were selected, including 271 FES patients and 297 healthy controls. Among these studies, 52 regions showed reductions in the FA in FES while 2 regions had increased FA. Consistent FA reductions in the white matter of the right deep frontal and left deep temporal lobes were identified in all FES patients relative to healthy controls. Fiber tracking showed that the main tracts involved were the cingulum bundle, the left inferior longitudinal fasciculus, the left inferior fronto occipital fasciculus and the interhemispheric fibers running through the corpus callosum. CONCLUSIONS: The current findings provide evidence confirming the lack of connection in the fronto-limbic circuitry at the early stages of the schizophrenia. Because the coordinates reported in the primary literature were highly variable, future investigations with large samples would be required to support the identified white matter changes in FES. PMID- 23648973 TI - Macrocycle-embedded beta-lactams as novel inhibitors of the Penicillin Binding Protein PBP2a from MRSA. AB - Assuming that bicyclic beta-lactams endowed with high conformational adaptability should more easily form acyl-enzyme complexes with PBP2a than the traditional antibiotics, we have prepared a series of bis-2-oxo-azetidinyl macrocycles as potential inhibitors. The compounds are formally "head-head" (HH) cyclodimers of 1-(omega-alkenoyl)-3-(S)-(omega'-alkenoylamino)-2-azetidinones, with various lengths of the alkene chains, obtained by two successive metathesis reactions using the Grubbs catalyst. All compounds behave as acylating inhibitors of PBP2a and one beta-lactam (5c), embedded into the largest ring (32 atoms), features an activity close to that of Ceftobiprole. Conformational analyses, theoretical reactivity models and docking experiments in PBP2a cavity allow to propose a novel pharmacophore, i.e. the 3-(S)-acylamino-1-acyl-2-azetidinone ring, with the syn-conformation of the imide function, associated to a flexible macrocycle favoring the opening of the active site. PMID- 23648976 TI - The voice of Arab Unity. PMID- 23648974 TI - Synthesis and evaluation of antimicrobial activity of hydrazones derived from 3 oxido-1H-imidazole-4-carbohydrazides. AB - In this work we reported the synthesis and evaluation of in vitro antimicrobial activities of hydrazones 6 obtained from 3-oxido-1H-imidazole-4-carbohydrazides 4. All new compounds were characterized by spectroscopic methods. Hydrazones 6 were tested for their in vitro antimicrobial activity against four Gram-positive and four Gram-negative strains of bacteria as well as one fungal species. Three of the tested compounds appeared to be promising agents against reference strains of Escherichia coli, Staphylococcus aureus and Staphylococcus epidermidis. They were also tested against twelve clinical isolates of S. aureus and their cytotoxic effect on murine fibroblasts and HeLa human tumor cell line was determined. PMID- 23648977 TI - Current surgical treatment of Parkinson's disease. AB - There has been a renaissance in the surgical management of Parkinson's disease. This has been due to long-term effects of levodopa and a better understanding of the basal ganglia and its circuitry. Ablative surgery and neurostimulation are the only realistic surgical options at present. Although surgical treatments, such as ablation and stimulation are effective, they are not useful for stopping the progression or restoring the system. Neural transplantation helps restore the system by using a number of techniques. Targets mostly used are in the thalamus, globus pallidus and subthalamic nucleus. A number of factors must be considered including patient's age, disability and his wishes. Globus pallidus stimulation might be preferable for patients who suffer from dyskinesia as a major source of disability. Pallidotomy might be appropriate in cases where frequent stimulator adjustments are impractical. Subthalamic nucleus stimulation is more suitable for patients with significant off periods and in younger patients in whom it may be desirable to maintain intact circuitry. Fetal neural transplantation, stem cell transplantation, xenotransplantation, adrenal medullary transplantation and transplantation of genetically engineered cells are at various stages of development and research. Ethical issues surrounding these process are likely to arouse strong emotions and have to be carefully considered. PMID- 23648975 TI - 2-Arylpaullones are selective antitrypanosomal agents. AB - Antileishmanial paullone-chalcone hybrid molecules display antiparasitic activity against Trypanosoma brucei rhodesiense blood stream forms, albeit with low selectivity against human THP-1 cells. In order to develop less toxic analogues, paullones with acrylamide or aryl substituents in 2-position were synthesized, of which the latter exhibited potent antiparasitic activity with excellent selectivity profiles. The most potent compound identified in this study was 9 tert-butyl-2-(4-morpholinophenyl)paullone (3i) which inhibited the parasites at submicromolar concentrations (GI50 = 510 nM) with a selectivity index of 157. PMID- 23648978 TI - Anti-spasticity medications. AB - Spasticity is common in patients with a variety of central nervous system disorders. It can lead to significant disability or cause complications that may result in severe morbidity. In such patients, treatment of spasticity is warranted. Several oral and parenteral medications are available for use in the treatment of spasticity. This article reviews the pharmacological properties and therapeutic effectiveness of these medications to provide a practical objective guide for physicians who may be involved in the management of spasticity. PMID- 23648979 TI - Response to beta interferon 1b among Saudi patients with multiple sclerosis. AB - OBJECTIVE: To determine the efficacy and tolerability of subcutaneous beta interferon 1b (B1F1b) among Saudi patients with remitting-relapsing multiple sclerosis (R-R MS). METHODS: An open label study held at the Neurology Division of the Armed Forces Hospital, Riyadh from March 1997 until December 2001. Thirty two consecutive patients below the age of 50 years with clinically definite R-R MS according to Poser's Criteria and expanded disability status scale below 5.5 were enrolled in treatment with subcutaneous B1F1b 8 million IU 3 times a week. The primary outcome measures used were: reduction in annual relapses, proportion of relapse-free patients, and the mean time to the first relapse after treatment was started. The secondary outcome measures used were the time to progression in disability, tolerability and safety of the beta interferon. RESULTS: Only 28 patients were analyzed to assess the outcome measures, the other 4 patients dropped out and were followed-up. Twenty were women and 8 were men (female:male ratio of 2.5:1). There was a significant reduction in relapse-rate in all patients, 32.5% were relapse-free, while 37.5% showed reduction in the number of relapses. None of our patients showed progression of disability (P<0.0249). Mild adverse reactions were seen in 38.5%, influenza-like illness occurred in 53.6%, and injection-site reaction in 35.7%. CONCLUSION: Subcutaneous B1F1b is effective in patients with R-R MS, especially in reducing relapse rate, probable disability, and it is well tolerated. However, longer follow-up is necessary to evaluate the role of B1F1b in preventing disability. PMID- 23648980 TI - Spinal brace in tuberculosis of spine. AB - OBJECTIVE: To present our experience in the management of 22 patients with thoracolumbar spine tuberculosis (TB) using a chemotherapy regimen and locally custom-made spinal brace. METHODS: Twenty-two patients with thoracolumbar spine TB had been treated conservatively by chemotherapy and locally custom-made spinal brace and followed for 36-48 months from June 1996 to June 2000 in the Department of Orthopedics and Trauma, Algamhoria Teaching Hospital, Aden, Republic of Yemen. In 14 cases, 2 vertebrae were involved, whereas in 8 cases involvement was only of one vertebra. All had persistent back pain: 2 had neurological deficit, Frankel grade A and B (9%), and 12 (54%) had gibbus deformity. RESULTS: At the end of the observation period, all patients had no pain (based on the adjective rating scale). Fourteen thoracic and 3 psoas abscesses resolved by 18 months. Four cases (18%) had deterioration of the angle of kyphosis. Five cases (22.5%) had progressive vertebral loss. Twelve cases (84%) had bony fusion at 36 months. CONCLUSION: Chemotherapy regimen and locally custom-made spinal brace is not costly, needs neither admission nor surgical intervention that demands skills and experience and can be recommended for uncomplicated thoracolumbar spinal TB. PMID- 23648981 TI - Cauterization of inferior nasal turbinate for idiopathic headache. AB - OBJECTIVE: Idiopathic headache is a stressful complaint, whose treatment is not well established. Our study is an attempt to examine the relationship between idiopathic headache and inferior turbinate cauterization as a surgical treatment, and to explain the central physiological effect of cauterization. METHODS: Thirty four patients, 15 females and 19 males complaining of idiopathic headache were treated by inferior turbinate cauterization. Cauterization of the inferior-medial aspect of the turbinate was carried out once under local anesthesia for few seconds. This study was performed between November 1993 and December 1996, a joint project of the Zarka Government Hospital, Zarka and Faculty of Medicine, University of Jordan, Amman, Jordan. RESULTS: More than 82% of the patients showed significant improvement in the sense of decreased headache. CONCLUSION: Cautery of the nasal turbinate could be a novel method for treatment of idiopathic headache. PMID- 23648982 TI - Cerebral palsy in Saudi children. AB - OBJECTIVE: To describe the clinical profile, and identify its risk factors, of cerebral palsy (CP) as seen in a cohort of consecutive Saudi children aged between one and 3 years of age prospectively over a one-year period. METHODS: Saudi children aged 1-3 years with CP (diagnosis based on specified criteria) were selected from children presenting to the Neurology service at the King Fahd Hospital of the University, Al-Khobar, Kingdom of Saudi Arabia with delayed milestones, seizures, mental retardation and difficulty with walking and evaluated at 3-monthly intervals for one year from January to December 2000. Information on gestation duration, labor and delivery, birth weight and the medical history of the mothers was obtained. Cranial computerized tomography and electroencephalography were carried out in addition to baseline investigations (toxoplasmosis, other, rubella, cytomegalovirus, and herpes simplex virus serology, serum lactate, pyruvate, amino acid screen, thyroid function tests, and chromosome analysis). Somatosensory, molecular genetics and muscle biopsy for histopathologic and histochemical studies were not performed in any of the patients. RESULTS: One hundred and eighty-seven children with CP were seen during the study period: 109 males (mean age 20.3 +/- 8.69 months); 78 females (mean age 20.6 +/- 8.55 months). Seventy-three had microcephaly (<5th percentile) with a mean head circumference of 44.5 +/- 3.69 cms for males and 43.0 +/- 4.16 for females. The main symptoms were inability to walk independently (54%), delayed speech (52%) and seizures (45%). The main neurologic features were motor weakness (85%), spasticity (60%), language dysfunction (42%), mental retardation (31%) and head lag (30%). A history of previous CP in the family was obtained in 8 patients (4%) but none of them had other features of hereditary spastic paraplegia. Electroencephalography abnormalities, present in 113 (73%) were more frequent in those without seizures than with seizures. Cranial computerized tomography abnormalities were mainly cerebral atrophy (60%) and hydrocephalus (53.7%). Twenty-five percent were from twin pregnancies; 56 (34%) were of low birth weight, 20% were pre-term deliveries, birth asphyxia was present in 165 and breech presentation was encountered in 8%. CONCLUSION: The main risk factors identified were twin pregnancy, pre-term delivery, prolonged labor, low birth weight and a history of previous CP in the family. Our findings suggest that improved maternal and childcare particularly in the ante and perinatal periods may reduce the incidence of CP in this environment. PMID- 23648983 TI - Seroprevalence of herpes simplex and varicella zoster virus among diabetic and non-diabetic patients with acute peripheral facial palsy. AB - OBJECTIVE: The aim was to study the prevalence of herpes simplex virus (HSV) and varicella zoster virus (VZV) seropositive patients among diabetic patients with acute peripheral facial paralysis (APFP) as compared to non-diabetics with APFP and a healthy control group. METHODS: Participants consisted of 40 diabetic patients and 40 non-diabetic patients with APFP from Hai Al-Jamea Hospital, Jeddah, Kingdom of Saudi Arabia studied over a period from July 2000 to December 2001. In addition, 20 age and sex matched healthy volunteers were included as a control group. Paired sera were obtained from all participants within the first 4 days of the illness (acute phase) and 2-3 weeks later (convalescent phase). Paired sera were also obtained from the control group within an equivalent period. Detection of immunoglobulin (Ig) M and IgG class antibodies to HSV and VZV in these sera was carried out using enzyme-linked immunosorbent assays kits. The demonstration of IgM antibodies, 2-fold elevations of IgG antibodies or both was considered positive evidence for virus infection. RESULTS: The present study has shown that there was no statistically significant difference in the prevalence of HSV-seropositive patients in the diabetic and non-diabetic patients with Bell's palsy; however, it was significantly higher in both groups than in the healthy control group. There were no statistically significant differences in the prevalence of VZV-seropositive patients among the 3 groups. CONCLUSION: The significantly high prevalence of HSV-seropositive patients among the diabetic as well as the non-diabetic patients with Bell's palsy suggests an equally important role of HSV infection in the pathogenesis of Bell's palsy in the diabetic as in the non-diabetic patients. PMID- 23648984 TI - Pharmacotherapies of addiction. AB - OBJECTIVE: Millions of drug addicts worldwide require proper treatment together with good quality care. This article aims to critically review the psychopharmacology of drug addictions. METHODS: MEDLINE was systematically searched for studies describing drug treatment of addictions. Numerous studies were obtained and grouped according to the drug used to treat addictions. RESULTS: Although there are many effective antiaddictive drugs in the therapeutic armamentarium of drug addictions, a great number of patients tend to develop poor drug compliance, multiple relapses, and continue to suffer from chronic addictions coupled with negative biopsychosocial consequences. CONCLUSION: Aside from enhancing the public awareness of the devastating effects of drug addictions through regular and effective mass media campaigns, scientific efforts should be continued in order to develop new antiaddictive drugs with better clinical profiles for the treatment of patients with addictions. PMID- 23648985 TI - Survey of inpatients child and adolescent psychiatric referrals in a teaching hospital in Saudi Arabia. AB - OBJECTIVE: To answer the question of which specialties utilize the service of child and adolescent liaison psychiatry and what are the problems that are likely to bring a child or an adolescent to the attention of psychiatry. METHODS: The case records of all inpatient children and adolescents younger than 18 years, who were referred to the psychiatric team at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia over a period of 6 years between July 1992 and July 1998, were retrospectively reviewed in regard to sociodemographic data, referring specialties and reason for referral. RESULTS: Seven percent of referred patients were younger than 18 years. Most were Saudi nationals. Females outnumbered males. Most of the referrals were by the neurologists, endocrinologists and gastroenterologists. The most common reasons for referral were behavioral disturbances and absence of physical findings that could explain the complaint. CONCLUSION: Low utilization of child and adolescent liaison psychiatry, reflecting the ability of pediatricians and physicians to recognize psychiatrically disturbed children and adolescents compared to adults, may explain the small number of referrals. PMID- 23648986 TI - Polyradiculopathy. A rare complication of neurobrucellosis. AB - Neurobrucellosis is chronic brucellosis affecting the nervous system. It may mimic many neurological diseases but it rarely presents as polyradiculopathy. Brucellar radiculopathy was diagnosed in 6 patients who presented with weakness of the lower extremities. Five patients had lumbar puncture, 4 had magnetic resonance imaging of lumbar spine and 4 had nerve conduction studies. Five patients had areflexia and weakness; one had areflexia with proprioceptive ataxia. All patients had positive Brucella serology; cerebrospinal fluid showed lymphocytic pleocytosis, elevated protein, normal-low glucose; brucella serology was positive in all specimens. Nerve conduction studies showed absent F-wave in 2 patients and polyradiculopathy with secondary motor axonopathy in 2 patients; motor conduction velocity was normal in all. Magnetic resonance imaging with gadolinium injection showed enhancement of lumbar nerve root in 3 patients, and no enhancement in one. All patients improved after treatment with antibiotics and lumbar root enhancement disappeared. Symptoms of myelopathy were unmasked after radiculopathy had resolved in one patient. In endemic areas, brucella infection should be considered in the differential diagnosis of radiculopathy. Radiculopathy is probably due to inflammation of the meninges and the intrathecal portion of the roots. The pathogenesis of myelopathy may involve demyelination as spasticity persists or worsens after radiculopathy improves. PMID- 23648987 TI - Petro-cavernous chondroma. CT and MRI features. AB - The authors report an unusual location of a benign chondroma of the petro sphenoidal synchondrosis extending into the cavernous sinus. Computerized tomography and magnetic resonance image features were characteristic of chondroid tumor. However, pathologic verification is mandatory in order to distinguish chondroma from chondroblastoma or chondroid chordoma. PMID- 23648988 TI - Pacinian neuroma. AB - Neural tumors composed of Pacinian corpuscles are rare and have only occasionally been reported in the literature. All such lesions, which have been reported to date, have been benign. One such lesion described here presented as a painful lesion on the right hand in a 17-year-old Omani female. There was history of trap door injury 7 years back involving the wrist, thumb and index finger. The patient gradually developed multiple bosselated nodules near the first web space with gradually increasing pain. This case is being reported for the first time in the Sultanate of Oman. We herein report this case due to its rarity. PMID- 23648989 TI - Goldenhar syndrome and hereditary tyrosinemia type 1. AB - We report a case of Goldenhar syndrome and hereditary tyrosinemia type 1 (HTT1), to our knowledge an association not previously described. This case further increases the diversity of observations and clinical descriptions of patients with this complex syndrome. We discuss pathogenetic aspects, and demonstrate further evidence of the effectiveness of 2-(2-nitro-4-trifluoromethyl benzoyl) 1,3-cyclohexanedione in the treatment of HTT1. PMID- 23648990 TI - Traumatic fat embolism syndrome. AB - Traumatic fat embolism syndrome occurs most often following fractures of long bones sustained in road traffic accidents and is a common cause of medical consultation from the orthopedic surgery department. The sub-clinical presentation is subtle and expresses itself by the presence of hypoxemia, while the full clinical syndrome compromises respiratory insufficiency, an altered consciousness and a characteristic petechial rash. Recognition is simple once the patient is viewed in the context of his or her clinical setting. Diagnosis is aided further by the presence of hematological and biochemical abnormalities including anemia, thrombocytopenia, an elevated erythrocyte sedimentation rate and fat macroglobulinemia. Imaging by chest radiograph, computed tomography or magnetic resonance of the brain is used to confirm the extent of the respective organ involvement and to exclude alternative pathologies. The release of free fatty acids into the circulation and their subsequent effects is the key pathological event. Treatment is based on supportive care and high-dose corticosteroid therapy. We report a patient with traumatic fat embolism syndrome who developed the syndrome's classical symptoms and signs following fracture of the long bones of his left lower leg. Admission to an intensive care unit, mechanical ventilatory support with positive end-expiratory pressure and corticosteroid therapy lead to his improvement and allowed eventual open reduction and internal fixation and discharge of our patient. Modern therapy offers a relatively good prognosis for patients with traumatic fat embolism syndrome; the optimal dose and timing of corticosteroid therapy in prophylaxis and treatment however, remain the subject of intense debate. PMID- 23648991 TI - Amoplasia congenita: A rare form of arthrogryposis. PMID- 23648992 TI - Radiology quiz. PMID- 23648993 TI - Radiation safety in nuclear cardiology-current knowledge and practice: results from the 2011 American Society of Nuclear Cardiology member survey. PMID- 23648994 TI - On-off control of burst high frequency electrical stimulation to suppress 4-AP induced seizures. AB - OBJECTIVE: The goal of this study was to investigate, using model simulations and animal experiments, the efficiency and the side effects of burst high frequency stimulation combined with on-off control in seizure suppression. APPROACH: A modified mathematical hippocampal seizure model was created to provide evidence of the eligibility of this approach. In the experimental setup, two recording electrodes were inserted into bilateral septal CA1 of the hippocampus, and a stimulation electrode was placed on the ventral hippocampal commissure of a rat. After seizures had been induced by 4-aminopyridine treatment, on-off control stimulation was used to suppress the seizures at 20 s intervals. The stimulation time, cumulative charge and post-stimulation suppression were used to assess the effects of burst duration. MAIN RESULTS: The results showed that burst stimulation could suppress the seizures during the control period and burst stimulation of a shorter duration could keep the seizure suppressed with less effort. By decreasing the burst duration, the cumulative stimulation time became shorter, the delivered cumulative charge became lower, and the cumulative time of post-stimulation suppression became longer. SIGNIFICANCE: The on-off control stimulation not only prolonged the duration of suppression but also avoided the side effects of the conversion of seizure patterns. In particular, decreasing the specified burst duration increased the efficiency of the burst stimulation. PMID- 23648995 TI - Diagnosis of schistosomiasis japonica with interfacial co-assembly-based multi channel electrochemical immunosensor arrays. AB - Schistosomiasis control remains to be an important and challenging task in the world. However, lack of quick, simple, sensitive and specific sero-diagnostic test is still a hurdle in the control practice. The commonly employed enzyme linked immuno-sorbent assay (ELISA) relies on the native soluble egg antigen (SEA) that is limited in supply. Here we developed an electrochemical immunosensor array (ECISA) assay with an interfacial co-assembly strategy. A recombinant Schistosoma japonicum (Sj) calcium-binding protein (SjE16) was used as a principal antigen, while the SEA as a minor, co-assembling agent, with a ratio of 8:1 (SjE16: SEA, Sj16EA), which was co-immobilized on a disposable 16 channel screen-printed carbon electrode array. A portable electrochemical detector was employed to detect antibodies in serum samples. The sensitivity of ECISA reached 100% with minimal cross-reactions. Therefore, we have demonstrated that this rapid, sensitive and specific ECISA technique has the potential to perform large-scale on-site screening of Sj infection. PMID- 23648996 TI - Genetic decay of balancer chromosomes in Drosophila melanogaster. AB - Theoretical considerations predict that balancer chromosomes in Drosophila melanogaster should accumulate numerous deleterious mutations with time. We counted the number of recessive lethal mutations on two balancer chromosomes from the In(2LR)SM1/In(2LR)Pm strain maintained in our lab, after making the balancers heterozygous with deficiencies from second-chromosome Kyoto Deficiency kit strains. We detected 10 recessive lethal mutations in the balancer In(2LR)Pm, which is consistent with the mutation rate estimated previously. However, we detected only three mutations, a significantly smaller number, in the balancer In(2LR)SM1, although this may be an artifact. In conclusion, we observed genetic decay over an estimable timescale by using balancers with historical records. Thus, balancers of any strain may have accumulated many unidentified recessive lethal mutations. PMID- 23648997 TI - Copper-catalyzed asymmetric 1,4-conjugate addition of Grignard reagents to linear alpha,beta,gamma,delta-unsaturated ketones. AB - A highly regioselective and enantioselective copper-catalyzed 1,4-conjugate addition of Grignard reagents to linear alpha,beta,gamma,delta-unsaturated ketones was developed. The 1,4-addition products were obtained regioselectively in high yields with up to 98% ee. PMID- 23648998 TI - Vitrectomy combined with periocular/intravitreal injection of steroids for rhegmatogenous retinal detachment associated with choroidal detachment. AB - PURPOSE: To study the anatomical outcome of rhegmatogenous retinal detachment combined with choroidal detachment after pars plana vitrectomy with periocular/intravitreal injection of steroids. METHODS: Seventy-seven eyes that have rhegmatogenous retinal detachment combined with choroidal detachment were treated by pars plana vitrectomy with oral prednisolone (Group A) or periocular/intravitreal injection of steroids (Group B) and then divided into 5 subgroups according to different intraocular tamponade agents; Group A1: oral steroids and silicone oil, Group A2: oral steroids and C(3)F(8), Group B1: periocular/intravitreal steroid injections and silicone oil, Group B2: periocular steroid injection and silicone oil, and Group B3: periocular steroid injection and C(3)F(8). Anatomical reattachment of the retina was measured at 12 months after surgery. RESULTS: There was no significant difference in retinal reattachment rate between eyes in Group A and eyes in Group B (77.4% vs. 73.9%, P = 0.726). The retinal reattachment rates were 83.3% in Group A1, 69.2% in Group A2, 82.4% in Group B1, 73.3% in Group B2, and 64.3% in Group B3. There was no statistical difference in the retinal reattachment rates between any of the groups. CONCLUSION: For the treatment of rhegmatogenous retinal detachment combined with choroidal detachment, pars plana vitrectomy with periocular/intravitreal corticosteroids was comparable in reattachment rate to pars plana vitrectomy with systemic steroids, suggesting an acceptable alternative for patients with this condition who cannot tolerate systemic steroids. PMID- 23648999 TI - Outer retina analysis by optical coherence tomography in cone-rod dystrophy patients. AB - PURPOSE: To analyze the outer retinal layers using spectral domain optical coherence tomography (SD-OCT) in patients with cone-rod dystrophy. METHODS: The diagnosis of cone-rod dystrophy was determined by primary cone involvement or concomitant loss of both cones and rods. Electroretinography showed implicit time shift at 30-Hz flicker response and prevalent decrease of photopic over scotopic responses. Using SD-OCT, the outer retina was retrospectively evaluated in 24 eyes of 12 patients with cone-rod dystrophy. From the innermost to the outermost, the four studied hyperreflective outer retinal bands were labeled Band 1, the external limiting membrane; Band 2, the ellipsoid zone; Band 3, the interdigitation zone between the cone outer segments and the apical processes of the retinal pigment epithelium; and Band 4, the retinal pigment epithelium complex. RESULTS: The mean age of study patients was 30 years, and the median visual acuity was 20/30. A ring maculopathy appearance involving the fovea area was observed in all study eyes. There was an absence of interdigitation zone in the entire length of SD-OCT scan, including the foveal area, in all 24 study eyes. Outside the foveal area, the external limiting membrane and ellipsoid zone were intact in all study eyes. The intensity of the ellipsoid zone was decreased in the entire length of SD-OCT scan in all study eyes. Within the foveal area, there was loss of the external limiting membrane and ellipsoid zone in 20 (83%) and 22 eyes (92%), respectively. The retinal pigment epithelium complex was identified in all study eyes. None of the study eyes revealed cystoid macular edema. CONCLUSION: SD-OCT scans demonstrated complete absence of the interdigitation zone in patients with cone-rod dystrophy. Consistent with the known histology of animal models of cone dystrophy, this finding may represent abnormal outer retinal morphology, including an absence of the outer segments themselves or a defective or absent interdigitation between the apical processes of the retinal pigment epithelium with the cone outer segments. PMID- 23649000 TI - The anesthetized guinea pig: an effective early cardiovascular derisking and lead optimization model. AB - INTRODUCTION: In recent years, the anesthetized guinea pig has been used increasingly to evaluate the cardiovascular effects of drug-candidate molecules during lead optimization prior to conducting longer, more resource intensive safety pharmacology and toxicology studies. The aim of these studies was to evaluate the correlations between pharmacologically-induced ECG changes in the anesthetized cardiovascular guinea pig (CVGP) with ECG changes in conscious non rodent telemetry models, human clinical studies and effects on key cardiac ion channels. METHODS: We compared the effects of 38 agents on ion channel inhibition to their ECG effects in the CVGP. 26 of these agents were also evaluated in non rodent telemetry and compared to the results in the CVGP. RESULTS: The CVGP was highly sensitive for detecting QTc, PR and QRS interval prolongation mediated by inhibition of hERG, hCav1.2 and hNav1.5, respectively. There were robust correlations between ion channel inhibitory potencies and the free plasma concentrations (Cu) producing prolongation of the QTc, PR or QRS interval. Further evaluation showed that ECG changes in the CVGP were predictive of their effects on the QTc, PR and QRS intervals in non-rodent telemetry models with 92%, 92% and 100% accuracy, respectively. The CVGP proved to be 100% specific and 88%, 75% and 100% sensitive for QTc, PR and QRS interval prolongation, respectively. Similarly, the Cu that prolonged the QTc, PR and QRS in CVGP and humans correlated well. DISCUSSION: The CVGP is a sensitive model for assessing QTc, PR and QRS prolongation elicited by effects on hERG, hCav1.2 and hNav1.5, respectively. ECG changes in the CVGP are predictive of changes in non-rodent telemetry models and in humans (QTc). ECG parameters can be reliably evaluated with the CVGP model which increases the efficiency of CV derisking. Importantly, the design and implementation of this model is consistent with the "3Rs" for animal research. PMID- 23649001 TI - TIE-2 and VEGFR kinase activities drive immunosuppressive function of TIE-2 expressing monocytes in human breast tumors. AB - PURPOSE: Tumor-associated TIE-2-expressing monocytes (TEM) are highly proangiogenic cells critical for tumor vascularization. We previously showed that, in human breast cancer, TIE-2 and VEGFR pathways control proangiogenic activity of TEMs. Here, we examine the contribution of these pathways to immunosuppressive activity of TEMs. EXPERIMENTAL DESIGN: We investigated the changes in immunosuppressive activity of TEMs and gene expression in response to specific kinase inhibitors of TIE-2 and VEGFR. The ability of tumor TEMs to suppress tumor-specific T-cell response mediated by tumor dendritic cells (DC) was measured in vitro. Characterization of TEM and DC phenotype in addition to their interaction with T cells was done using confocal microscopic images analysis of breast carcinomas. RESULTS: TEMs from breast tumors are able to suppress tumor-specific immune responses. Importantly, proangiogenic and suppressive functions of TEMs are similarly driven by TIE-2 and VEGFR kinase activity. Furthermore, we show that tumor TEMs can function as antigen-presenting cells and elicit a weak proliferation of T cells. Blocking TIE-2 and VEGFR kinase activity induced TEMs to change their phenotype into cells with features of myeloid dendritic cells. We show that immunosuppressive activity of TEMs is associated with high CD86 surface expression and extensive engagement of T regulatory cells in breast tumors. TIE-2 and VEGFR kinase activity was also necessary to maintain high CD86 surface expression levels and to convert T cells into regulatory cells. CONCLUSIONS: These results suggest that TEMs are plastic cells that can be reverted from suppressive, proangiogenic cells into cells that are able to mediate an antitumoral immune response. PMID- 23649002 TI - A NOTCH3 transcriptional module induces cell motility in neuroblastoma. AB - PURPOSE: Neuroblastoma is a childhood tumor of the peripheral sympathetic nervous system with an often lethal outcome due to metastatic disease. Migration and epithelial-mesenchymal transitions have been implicated in metastasis but they are hardly investigated in neuroblastoma. EXPERIMENTAL DESIGN: Cell migration of 16 neuroblastoma cell lines was quantified in Transwell migration assays. Gene expression profiling was used to derive a migration signature, which was applied to classify samples in a neuroblastoma tumor series. Differential expression of transcription factors was analyzed in the subsets. NOTCH3 was prioritized, and inducible transgene expression studies in cell lines were used to establish whether it functions as a master switch for motility. RESULTS: We identified a 36 gene expression signature that predicts cell migration. This signature was used to analyse expression profiles of 88 neuroblastoma tumors and identified a group with distant metastases and a poor prognosis. This group also expressed a known mesenchymal gene signature established in glioblastoma. Neuroblastomas recognized by the motility and mesenchymal signatures strongly expressed genes of the NOTCH pathway. Inducible expression of a NOTCH intracellular (NOTCH3-IC) transgene conferred a highly motile phenotype to neuroblastoma cells. NOTCH3-IC strongly induced expression of motility- and mesenchymal marker genes. Many of these genes were significantly coexpressed with NOTCH3 in neuroblastoma, as well as colon, kidney, ovary, and breast tumor series. CONCLUSION: The NOTCH3 transcription factor is a master regulator of motility in neuroblastoma. A subset of neuroblastoma with high expression of NOTCH3 and its downstream-regulated genes has mesenchymal characteristics, increased incidence of metastases, and a poor prognosis. PMID- 23649003 TI - Platinum-based chemotherapy for variant castrate-resistant prostate cancer. AB - PURPOSE: Clinical features characteristic of small-cell prostate carcinoma (SCPC), "anaplastic," often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined "anaplastic" clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels relative to tumor burden, or short response to androgen deprivation therapy. EXPERIMENTAL DESIGN: A 120-patient phase II trial of first-line carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity. RESULTS: Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after four cycles of CD and EP, respectively. Median overall survival (OS) was 16 months [95% confidence interval (CI), 13.6-19.0 months]. Of the seven "anaplastic" criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy. CONCLUSION: Our findings support the hypothesis that patients with "anaplastic" prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with castration resistant prostate cancer and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population. PMID- 23649005 TI - High-contrast subcutaneous vein detection and localization using multispectral imaging. AB - Multispectral imaging has shown promise in subcutaneous vein detection and localization in human subjects. While many limitations of single-wavelength methods are addressed in multispectral vein detection methods, their performance is still limited by artifacts arising from background skin reflectance and optimality of postprocessing algorithms. We propose a background removal technique that enhances the contrast and performance of multispectral vein detection. We use images acquired at visible wavelengths as reference for removing skin reflectance background from subcutaneous structures in near infrared images. Results are validated by experiments on human subjects. PMID- 23649006 TI - Initial validity and reliability of the Banff Patella Instability Instrument. AB - BACKGROUND: Patellofemoral instability is a well-recognized problem, but there are currently no published patient-reported quality of life outcome measures that are disease specific for the treatment of this population. PURPOSE: To establish the content validity, initial construct validity, and initial reliability of the Banff Patella Instability Instrument (BPII). STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: The content of the BPII was validated using a modified 3-stage Ebel procedure and analysis of floor and ceiling effects. As a measure of internal consistency, the Cronbach alpha was utilized to assess how reliably the 32 items of the questionnaire measured a similar construct. Test-retest reliability of the BPII was calculated using an intraclass correlation coefficient (ICC). Construct validity was evaluated on 150 questionnaires completed by patients with a confirmed diagnosis of patellofemoral instability. A one-way between-group analysis of variance was employed to determine if the BPII was able to differentiate between patients presenting at the initial orthopaedic consultation relative to patients presenting at 6 months and 12 months postoperatively. RESULTS: Content validity was clearly established as each item in the BPII achieved a minimum of 83.3% agreement (range, 83.3% 100%) for relevance among the expert panelists. The average agreement was 96.9%; 24 items achieved 100% agreement. There was no evidence of floor or ceiling effects. Reliability (internal consistency) of the BPII was established at the initial orthopaedic consultation (alpha = .91), 6 months postoperatively (alpha = .97), and 12 months postoperatively (alpha = .97). Test-retest analysis resulted in an ICC of 0.98 between tests. Construct validity was established as there was a statistically significant difference in BPII scores at the initial orthopaedic consultation and 6-month and 12-month postoperative appointments (F2,146 = 75.62; P < .001). CONCLUSION: The BPII demonstrates content validity, strong initial reliability, and a statistically significant level of construct validity in patients with patellofemoral instability. This population includes patients with recurrent patellofemoral instability as well as surgically stabilized patients. PMID- 23649004 TI - Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model. AB - PURPOSE: Neuroblastoma is one of the commonest extracranial tumors of childhood. The majority of patients present with metastatic disease for which outcome remains poor. Immunotherapy is an attractive therapeutic approach for this disease, and a number of neuroblastoma tumor antigens have been identified. Here, we examine the therapeutic potential of combining immunomodulatory monoclonal antibodies (mAb) with peptide vaccination in murine neuroblastoma models. EXPERIMENTAL DESIGN: Neuroblastoma-bearing mice were treated with mAb targeting 4 1BB, CD40, and CTLA-4 alone, or in combination with a peptide derived from the tumor antigen survivin (GWEDPPNDI). Survivin-specific immune response and therapeutic efficacy were assessed. RESULTS: In the Neuro2a model, treatment of established tumor with anti-4-1BB, anti-CD40, or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40% to 60% of mice. This is dependent on natural killer (NK) and CD8(+) T cells and is associated with tumor CD8(+) lymphocyte infiltrate. Successful therapy is achieved only if mAb is given to mice once tumors are established, suggesting dependence on sufficient tumor to provide antigen. In the more aggressive AgN2a and NXS2 models, single-agent mAb therapy provides ineffective therapy. However, if mAb (anti-CTLA-4) is given in conjunction with survivin peptide vaccination, then 60% long-term survival is achieved. This is associated with the generation of survivin-specific T-cell immunity, which again is only shown in the presence of tumor antigen. CONCLUSIONS: These data suggest that the combination of antigen and costimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal residual disease setting. PMID- 23649007 TI - Evaluation of epiphyses in the skeletally immature knee using magnetic resonance imaging: a pilot study to analyze parameters for anterior cruciate ligament reconstruction. AB - BACKGROUND: Questions have been raised concerning the height of the tibial epiphysis as an important factor related to the safety of intra-articular anterior cruciate ligament (ACL) reconstruction in skeletally immature knees. However, normal values for this parameter have yet to be established on cross sectional magnetic resonance imaging (MRI). PURPOSE: To determine normal values for the height of the tibial epiphysis and width of the lateral femoral condylar epiphysis in children and adolescents by use of MRI. STUDY DESIGN: Cross sectional study; Level of evidence, 3. METHODS: An electronic search was conducted for pediatric knee MRI examinations at the authors' institution from August 2007 to July 2011. The height of the tibial epiphysis was determined on the sagittal T1-weighted image best containing the ACL footplate. Lateral femoral condylar width was recorded on coronal proton-density-weighted images. The intraclass correlation coefficient (ICC) was calculated to determine interobserver agreement. Knees were stratified by age into 2 groups based on potential risk of iatrogenic growth plate injury: Group 1 consisted of boys younger than 13 years (range, 7-12 years) and girls younger than 12 years (range, 10-11 years); group 2 consisted of boys between the ages of 13 and 16 years and girls between the ages of 12 and 14 years. Each cohort was further stratified by sex. RESULTS: Group 1 consisted of 17 boys (mean age, 10.4 years) and 5 girls (mean age, 10.8 years), and group 2 contained 23 boys (mean age, 14.4 years) and 14 girls (mean age, 13.7 years). There was a total of 59 knees. No difference was found for average tibial epiphyseal height between group 1 (15.26 +/- 1.25 mm) and group 2 (15.01 +/- 2.14 mm). However, there was a statistically significant difference related to sex in each cohort: boys versus girls in group 1 (15.63 +/- 1.15 mm vs 14.00 +/- 0.62 mm, respectively; P = .007) and boys versus girls in group 2 (16.00 +/- 1.88 mm vs 13.40 +/- 1.47 mm, respectively; P = .0001). The average femoral condylar width for both cohorts was greater than 28 mm where femoral tunnel location would be expected. The ICC was strong (>0.7) at tibial and femoral locations where tunnel placement would be expected. CONCLUSION: The average height of the tibial epiphysis in both children and adolescents is 15 mm. Girls had shorter tibial epiphyses than boys, but further studies are necessary to determine whether this difference is clinically relevant. Lateral femoral condylar width in children and adolescents can be expected to be greater than 28 mm. PMID- 23649008 TI - Degenerative joint disease of the acromioclavicular joint: a review. AB - Osteoarthritis of the acromioclavicular (AC) joint is a common condition causing anterior or superior shoulder pain, especially with overhead and cross-body activities. This most commonly occurs in middle-aged individuals because of degeneration to the fibrocartilaginous disk that cushions the articulations. Diagnosis relies on history, physical examination, imaging, and diagnostic local anesthetic injection. Diagnosis can be challenging given the lack of specificity with positive physical examination findings and the variable nature of AC joint pain. Of note, symptomatic AC osteoarthritis must be differentiated from instability and subtle instability, which may have similar symptoms. Although plain radiographs can reveal degeneration, diagnosis cannot be based on this alone because similar radiographic findings can be seen in asymptomatic individuals. Nonoperative therapy can provide symptomatic relief, whereas patients with persistent symptoms can be considered for resection arthroplasty by open or arthroscopic technique. Both techniques have proven to provide predictable pain relief; however, each has its own unique set of potential complications that may be minimized with an improved understanding of the anatomical and biomechanical characteristics of the joint along with meticulous surgical technique. PMID- 23649010 TI - The mechanical interaction between three geometric types of nylon core suture and a running epitenon suture in repair of porcine flexor tendons. AB - The effect of core suture geometry on the mechanical interaction with the epitenon suture in terms of gap prevention, failure strength and mode of failure was investigated in a flexor tendon repair model. A total of 48 porcine flexor tendons were repaired using three techniques with distinct core suture geometry: single Kessler; double Kessler; and cruciate repair. Cyclic linear testing was carried out with and without a simple running epitenon suture. At failure load the epitenon suture reduced gapping by 87% in the double Kessler, 42% in the single Kessler and 15% in cruciate repairs. It increased the strengths of the repairs by 58%, 33% and 24%, respectively. Kessler repairs failed mainly by suture rupture, with and without epitenon suture, but cruciate repairs failed mainly by suture pull-out. The epitenon suture did not have a significant mechanical effect on the three repairs. Rather, its effect varied with the core suture geometry. The greatest effect occurred with double Kessler repairs. PMID- 23649009 TI - Electrically conductive magnetic nanowires using an electrochemical DNA templating route. AB - The fabrication of electrically conducting magnetic nanowires has been achieved using electrochemical DNA-templating of iron. In this approach, binding of the Fe(2+) cations to the DNA "template" molecules has been utilised to promote growth along the molecular axis. Formation of Fe within the product material was verified by XRD and XPS studies, which confirmed an iron/oxide "core-shell" structure. The effectiveness of the DNA duplex to direct the metal growth in one dimension was highlighted by AFM which reveals the product material to comprise high aspect ratio nanostructured architectures. These "nanowires" were observed to have morphologies consisting of densely packed linear arrangements of metal particles along the template, with wire diameters up to 26 nm. The structures were confirmed to be electrically conductive, as expected for such Fe-based materials, and to display superparamagnetic behaviour, consistent with the small size and particulate nature of the nanowires. PMID- 23649011 TI - Secondary displacement of distal radius fractures treated by bridging external fixation. AB - Loss of reduction remains an important problem after treatment of distal radius fractures, whatever the type of bone fixation. We assessed retrospectively the rate of secondary displacement after external fixation of distal radius fractures in order to identify possible risk factors for instability. We reviewed the pre operative and serial post-operative radiographs of a retrospective series of 35 distal radius fractures treated by bridging external fixation. When classified according to the Societe Francaise d'Orthopedie et Traumatologie (SOFCOT) criteria, the rate of secondary displacement was 48.5%. At final follow up, the reduction was anatomical in 12% and acceptable in 83%. There was malunion in 5%. The loss of reduction concerned primarily the distal radius palmar tilt and was moderate. No correlation was found with age, gender, type of fracture, degree of initial displacement, associated ulnar fracture, or seniority of the treating surgeon. PMID- 23649012 TI - Combined joint fusion for index and middle carpometacarpal instability in elite boxers. AB - Isolated instability of the index and middle finger carpometacarpal joints is uncommon. An unpublished injury pattern in a consecutive series of 13 elite boxers is described, with mid-term radiological and functional results of two novel surgical treatments. All the boxers (from Australia and the UK) were unable to compete owing to pain and weakness. Four boxers were managed initially by open reduction and temporary K-wire fixation. Nine boxers underwent primary carpometacarpal arthrodesis. All were able to return to their previous level of competition. One boxer who had undergone a soft tissue reconstruction competed at international level but required an arthrodesis because of recurrent symptoms. In elite boxers, simple reduction and wiring may be appropriate for an acute injury causing index or middle finger carpometacarpal joint instability, however, arthrodesis is the treatment of choice when instability and degenerative changes are present. PMID- 23649014 TI - Outcome measures and their measurement properties for trapeziometacarpal osteoarthritis: a systematic literature review. AB - The objective was to identify all outcome measures used in studies on trapeziometacarpal osteoarthritis (TMC OA) and evaluate their measurement properties. In a two-step systematic literature review, we first identified studies including TMC OA patients and extracted all outcome measures. They were categorized according to the Outcome Measures in Rheumatology (OMERACT) core set for OA including five dimensions: pain, physical function, global assessment, imaging, and quality of life (QoL). Secondly, we retrieved articles on the measurement properties of the identified outcome measures for TMC OA patients. First, 316 articles including 101 different outcome measures were identified, addressing the OMERACT pain and function domains most frequently but under representing QoL. Second, 12 articles investigating measurement properties of 12 outcome measures were identified. The methodological quality of these studies was poor to fair, implying that based on the literature no recommendations to use any of the outcome measures can yet be made. PMID- 23649013 TI - A unique case of temporary epiphysiodesis in an adolescent patient with ulnocarpal impaction syndrome. PMID- 23649015 TI - Extensor tendon dislocation of the hand: six cases in a family. PMID- 23649016 TI - Surgical findings in the treatment of Dupuytren's disease after initial treatment with clostridial collagenase (Xiaflex). AB - We investigated the difficulty of surgical fasciectomy after previous treatment with clostridial collagenase injection. The 35 clinicians who had participated in the initial trials of this injection were contacted via email. Twenty-eight responded, nine of whom reported on 15 patients. Most (seven of nine) felt there was no significant distortion of anatomy and rated the level of technical difficulty as equivalent to a primary Dupuytren's fasciectomy at the observed degree of contracture (nine of 15 cases). One respondent (four of 15 cases) reported significantly more difficulty and grossly distorted anatomy. One surgical complication, a wound dehiscence, was reported. PMID- 23649017 TI - Diabetes: Pre-eclampsia: association with increased risk of diabetes. PMID- 23649018 TI - Acute kidney injury: Perioperative sodium bicarbonate infusion for prevention of acute kidney injury--no benefit and possible harm. PMID- 23649019 TI - Transplantation: Alloantibodies in simultaneous liver-kidney transplantation. PMID- 23649021 TI - Effects of copper on germination and reserve mobilization in Vicia sativa L. seeds. AB - The effects of different copper concentrations on percentage germination, increase in fresh weight and radicle growth of Vicia sativa L. seeds were studied. Physiological studies showed that the germination rate was not affected up to a concentration of 5 * 10-3 M, but already at 10-3 M the copper stopped root elongation. Structural and ultrastructural observations of embryo and cotyledon reserve mobilization showed that inhibition of radicle growth at 10-3 M Cu concentration cannot be ascribed to nutrient shortage but probably to an effect of copper on radicle cell division and elongation. In seeds treated with 5 * 10-3 M CuBr2, the copper completely inhibited cotyledon protein mobilization, so that embryo protein mobilization supported normal growth of the radicle up to 30 h after imbibition. The particular protein content of adjacent cotyledon cells is also discussed. PMID- 23649022 TI - Sample size determination. Influencing factors and calculation strategies for survey research. AB - The paper reviews both the influencing factors and calculation strategies of sample size determination for survey research. It indicate the factors that affect the sample size determination procedure and explains how. It also provides calculation methods (including formulas) that can be applied directly and easily to estimate the sample size needed in most popular situations. PMID- 23649023 TI - Management of status epilepticus. AB - Status epilepticus (SE) is defined as a condition characterized by an epileptic seizure that is so frequently repeated or so prolonged as to create a fixed and lasting condition. Any type of epileptic seizure can develop into SE. Status epilepticus can be classified as generalized convulsive, non-convulsive and simple partial. Generalized convulsive SE includes tonic clonic seizures with either a partial or a generalized onset. Generalized tonic clonic status is defined when consecutive seizures occur without recovery of consciousness between them. Generalized tonic clonic SE is a medical emergency associated with a high morbidity and mortality if untreated. The most common etiology of SE is non compliance to antiepileptic drugs. Other causes include alcohol withdrawal, cerebrovascular lesions, drug intoxication, central nervous system infections, neoplasms and acute metabolic derangements. The metabolic-biochemical complication of SE includes respiratory and metabolic acidosis, anoxia, hyperazotemia, hyperkalemia, hypoglycemia, hyponatremia and autonomic and endocrine dysfunctions. Prognosis of SE depends on the duration and etiology of SE. Vigorous treatment of SE is recommended. Effective medical treatment of SE includes Benzodiazepines, Phenytoin, Barbiturates and several other new antiepileptic drugs. In this presentation, we discuss the updated management of SE and propose a protocol for management of convulsive SE. PMID- 23649020 TI - Three feasible strategies to minimize kidney injury in 'incipient AKI'. AB - Acute kidney injury (AKI) is common and increasing in hospitalized patients. The earlier recognition of renal injury, at a stage described as 'incipient AKI', may allow renoprotective strategies to be initiated at a time when more kidney tissue is salvageable. 'Incipient AKI' represents renal injury as manifested by new onset proteinuria, cellular activity on urine microscopy, or elevated novel biomarkers of kidney injury in the absence of clinical data that meet current diagnostic criteria for AKI. We propose three strategies to preserve kidney function and minimize further kidney injury in patients with 'incipient AKI'. These include--when appropriate for the prevailing cause of 'incipient AKI'--use of low-chloride-containing intravenous solutions, continued use of renin angiotensin system antagonists, and use of diuretics to achieve adequate control of intravascular volume. The combined approach of the early diagnosis of AKI and early employment of feasible therapeutic strategies may slow the growth of clinical AKI, AKI requiring renal replacement therapy and chronic kidney disease, and might reduce AKI-associated mortality. PMID- 23649024 TI - Pre-postnatal morphogenesis of rat hippocampal pyramidal cells. AB - OBJECTIVE: To follow-up the morphological changes of the neuroblasts as they develop to pyramidal cell in the hippocampal cerebral cortex beginning from 15 days prenatal and ending 14 days postnatal. Particular metric and numerical estimations of the dendrites developed from these cells were carried out. METHODS: Fifty pregnant rats classified into 5 groups were used to obtain 15 and 18 day embryos; birth, 7 day and 14 day pups. Brains of these animals were processed for histological examination using iron hematoxylin and golgi mixed methods of staining from paraffin sections. Multiplicity and length of the dendrites were assessed. The practical work was carried out in the Anatomy Department of the School of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia during the year 2002. RESULTS: At 15 days prenatal, a few pyramidal cells appeared which greatly increased at 18 days prenatal with the development of their beaded apical dendrites. At birth, the dendrite stem became shorter but had more branches and beads. Postnatal one and 2 weeks consecutively witnessed the arise of axons and basal dendrites. CONCLUSION: These results showed the very early postnatal full morphological development of the hippocampus cortex pyramidal cells. The progressive increase in length of the apical dendrites during the period from 18 days prenatal when they first appeared to 14 days postnatal was highly significant (P< 0.00). PMID- 23649025 TI - Effect of nifedipine on alprazolam - induced anxiolysis and brain GABA level changes in albino rats. AB - OBJECTIVE: The present study investigates the effects of alprazolam (ALP) and nifedipine alone or in combination on behavior and on g-aminobutyric acid (GABA) levels, in discrete brain regions of albino rats. METHODS: The anxiolytic effect was studied using a plus maze model and brain levels of GABA were measured using high performance liquid chromatography. Four acute treatment groups of rats were used. In the first they were treated with 1% Tween 80 (1ml/kg), in the second with nifedipine (10mg/kg), in the third with ALP (2mg/kg) and in the fourth with ALP in addition to nifedipine in the respective doses. The work was carried out at the Faculty of Pharmacy of Al-Fateh University, Tripoli, Libya in the first half of 2002. RESULTS: The results indicate that the anxiolytic effect of ALP was not modified by nifedipine. Nifedipine by itself significantly decreased the motor activity (decrease in total lines crossed), this effect was apparently antagonized by ALP. Alprazolam administration produced an increase of GABA levels in cerebellum and striatum and a decrease in the brain stem. Nifedipine per-se had no effect on GABA levels in the brain stem but it partially antagonized ALP induced inhibitory effect on GABA in this region. Alprazolam significantly increased GABA levels in the striatum, while nifedipine alone had no effect on neurotransmitter levels and did not modify the ALP effect in this brain region. Alprazolam or nifedipine had no significant effect on GABA levels in midbrain, cerebral cortex and whole brain. There were no significant changes in GABA levels in midbrain and whole brain with drug combination. However, the combination decreased GABA levels significantly in the cerebral cortex. CONCLUSION: It may be concluded that, the anxiolytic effect of ALP possibly occurs through changes in brain GABA levels (an increase in cerebellum and striatum with a decrease in brain stem). The effect was not modified by nifedipine which per se had no affect on GABA levels in any brain area. The significant decrease in GABA levels in cerebral cortex by ALP-nifedipine combination may be due to the mutual closure of calcium channel (mentioned in literature) resulting in inhibition of the EAA ergic input to GABA-ergic neuron. PMID- 23649026 TI - Newly diagnosed seizures in adults. AB - OBJECTIVE: To study the clinical, electroencephalographic (EEG) and computed tomography (CT) profile in a hospital population of over 18-years adult patients with newly diagnosed recurrent seizures. METHODS: The clinical profiles obtained from history including detailed description of the seizures, examination, EEG and CT findings were recorded prospectively for all over-18 patients who were referred to the electrodiagnostic service at King Fahd Hospital of the University, Al-Khobar, Eastern Province, Kingdom of Saudi Arabia from January 1, 1996 to December 31, 1997. The data was entered into a standard database file and analyzed using a personal computer. RESULTS: Seventy-three patients (43 males, 30 females, mean age 32.3 years) with newly diagnosed recurrent seizures were studied. A positive family history of seizures was found in 12.3%. The main seizure types were partial in 27 (37%), partial with secondary generalization in 22 (30.1%) and generalized in 24 (32.9%). The types of epileptic syndromes included localization-related 34 (46.6%), generalized 24 (32.9%) and undetermined 15 (20.5%). The EEG was abnormal in 45 (61.6%) with epileptiform activity, focal in 22 (48.9%), generalized in 11 (24.4%) and non-epileptiform activity in 12 (26.7%). The cranial CT findings were normal in 44 patients (60.3%) and abnormal in 29 (39.7%) patients, with focal lesions in 19 (65.5%) and generalized cerebral atrophy in 10 (34.5%). CONCLUSION: Our results showed that partial and partial with secondary generalization seizures are the most frequent seizure type and the most common epileptic syndrome was the localization-related type in this age group. These results are comparable to previous population- and hospital-based western reports. PMID- 23649027 TI - Clinical pattern of seizures in hospitalized children. AB - OBJECTIVE: Seizures continue to be a major problem in the pediatric age group. The cause and clinical presentation of these seizures are vast and variable. This is a prospective study, conducted with the aim of assessing the magnitude and presentation of this problem in the region of Al-Madina Al-Munawara, Kingdom of Saudi Arabia. METHODS: All the cases of seizures admitted to Madina Maternity & Children's Hospital, Al-Madina Al-Munawara, Kingdom of Saudi Arabia from April 2000 to July 2000 were included in the study. The age groups studied were from 8 days old to 14 years. RESULTS: Out of 1593 patients admitted to the Pediatric Department, 138 (8.7%) were admitted with seizures. Fifty-one (37%) cases were of established epilepsy, 42 (30.4%) of febrile convulsions and 27 (19.6%) of hypocalcemic convulsions. The rest of the total includes first attack of non febrile seizure, neonatal seizures, encephalitis and drug toxicity. CONCLUSION: We observed and concluded that seizures due to epilepsy remain the most common cause, with febrile convulsion and hypocalcemic convulsion a second and third major causes. As observed, we also recommend further studies into the association of hypocalcemic seizures with underlying active rickets in the pediatric age group. PMID- 23649028 TI - Topiramate for the treatment of infants with early myoclonic encephalopathy. AB - OBJECTIVE: Early myoclonic encephalopathy (EME) is a rare epileptic syndrome characterized by neonatal onset of severe recurrent seizures of multiple types often resistant to antiepileptic drugs (AEDs). Topiramate (TPM) is a new AED, which has a wide spectrum of antiepileptic activities suggesting a potentially valuable therapeutic profile. There is limited clinical data available on TPM use in infants and our aim is to report our experience with TPM for the treatment of infants with intractable seizures secondary to EME. METHODS: Prospective, open label, add on trial of TPM in treating a series of infants with EME at King Faisal Specialist Hospital and Research Centre and King Abdul-Aziz University Hospital, Jeddah, Kingdom of Saudi Arabia between June 1999 and March 2002. Topiramate was started at 12.5 mg/day and was increased by doubling the dose every week until the minimum effective dose was reached (seizure free outcome) or up to a maximum of 10 mg/kg/day. RESULTS: Four consecutive infants (2 males and 2 females) were included. In addition to daily seizures, they all had global hypotonia, developmental delay, and progressive microcephaly. The syndrome was cryptogenic in 3, and one had nonketotic hyperglycinemia. Initial electroencephalograms showed generalized epileptic burst suppression pattern. Infants were tried on multiple AEDs (6-11, mean 7.5) with no success. Topiramate was added at age 5-12 months (mean 9) reaching a maximum dose of 5.5-10 mg/kg/day (mean 7.6). The infants were then followed for up to 19 months (mean 13.5). After introducing TPM, one infant became completely seizure free and 3 had significant (>50%) seizure reduction. Electroencephalograms in 3 infants showed marked improvement. One infant had weight loss that resulted in discontinuing the drug after 6 months. Follow-up renal ultrasound findings were normal in all infants. CONCLUSION: Topiramate is effective and safe in treating infants with intractable epilepsy secondary to EME. PMID- 23649029 TI - Hypoxic ischemic encephalopathy. Incidence and risk factors in North Western Saudi Arabia. AB - OBJECTIVE: To find the incidence, early outcome and the associated risk factors of hypoxic ischemic encephalopathy(HIE) in Madina Al-Munawara, Kingdom of Saudi Arabia (KSA) and compare it with other centers. Also, to find out whether any of these risk factors are preventable. METHODS: We conducted a case controlled study of HIE in Madina Maternity and Children's Hospital, Madina Al-Munawara, KSA over a one-year-period, from June 1995 to May 1996. All the inborn term babies without major congenital malformations that developed HIE were included in the study. A term baby born next to the index case was taken as a control for each case. Data was collected for possible risk factors. The incidence of risk factors in the 2 groups was analyzed and compared statistically. RESULTS: A total of 70 cases of HIE were recorded in the study period giving an incidence of 5.5 cases per 1000 term births. This incidence is lower compared to many developing countries and comparable to other centers. Among the maternal factors, being a primigravida, with no antenatal care, presence of pregnancy induced hypertension, and complications of pregnancy were significantly higher in the study population. Similarly, the frequency of prolonged 2nd stage of labor, antepartum hemorrhage, delivery by emergency cesarean section (CS) or the use of instruments was significantly higher in the study group. Babies suffering from intrauterine growth retardation and male sex were also at significantly higher risk. The average hospital stay of the cases was 12 days. Twelve cases of severe HIE died before discharge from the hospital giving an overall mortality rate of 17.1%. CONCLUSION: The incidence of HIE and birth asphyxia reported in different studies varies widely. The incidence in our hospital is much lower than reported in many studies from developing countries. The important associated risk factors includes being a primigravida mother, lack of antenatal care, pregnancy induced hypertension, prolonged 2nd stage of labor, delivery by use of instruments or emergency CS and intrauterine growth retardation. Improvement in antenatal care and intra-partum monitoring can decrease the incidence of HIE. The threshold for intervention in cases with fetal distress needs to be lower. PMID- 23649030 TI - Non paraneoplastic opsoclonus - myoclonus syndrome. AB - We analyzed the features of opsoclonus syndrome as a manifestation of post viral encephalopathy in 3 patients (one child and 2 adults). This is the first report of opsoclonus-myoclonus syndrome in the Arabian Peninsula. Symptoms appeared a few days after a viral-like illness in all patients. We excluded the possibility of paraneoplastic syndrome as investigations were carried out and follow-up did not reveal malignancy. One patient received a relatively long duration steroid treatment, another one received steroids in pulsed therapy, the third did not receive any specific treatment. The outcome was very good with improvement except in one who had severe sequelae. PMID- 23649031 TI - Cyclosporine therapy. Does it provoke neurological complications in Behcet's disease. AB - Cyclosporine was suggested recently by Japanese workers to provoke central nervous systems symptoms in Behcet's disease. We report 2 cases supporting this notion. Our aim is to draw the attention of physicians to such phenomenon as cyclosporine being frequently advocated in the treatment of uveitis due to Behcet's disease. PMID- 23649032 TI - Fluconazole for the treatment of Cryptococcus neoformans meningitis in an immunocompetent host. AB - We present a case of a 23-year-old immunocompetent male who presented with chronic meningitis and was diagnosed as cryptococcal meningitis by positive cryptococcal antigen titer. The cerebrospinal fluid culture was positive for Cryptococcus neoformans. He was treated initially with amphotericin B but was later changed to fluconazole due to toxicity. This case highlights the use of fluconazole to successfully treat chronic meningitis in an immunocompetent host. PMID- 23649033 TI - Stalking behavior in an organic lesion. PMID- 23649035 TI - Radiology quiz. PMID- 23649034 TI - Traumatic fat embolism syndrome. PMID- 23649036 TI - Validation of finite element model of transcranial electrical stimulation using scalp potentials: implications for clinical dose. AB - OBJECTIVE: During transcranial electrical stimulation, current passage across the scalp generates voltage across the scalp surface. The goal was to characterize these scalp voltages for the purpose of validating subject-specific finite element method (FEM) models of current flow. APPROACH: Using a recording electrode array, we mapped skin voltages resulting from low-intensity transcranial electrical stimulation. These voltage recordings were used to compare the predictions obtained from the high-resolution model based on the subject undergoing transcranial stimulation. MAIN RESULTS: Each of the four stimulation electrode configurations tested resulted in a distinct distribution of scalp voltages; these spatial maps were linear with applied current amplitude (0.1 to 1 mA) over low frequencies (1 to 10 Hz). The FEM model accurately predicted the distinct voltage distributions and correlated the induced scalp voltages with current flow through cortex. SIGNIFICANCE: Our results provide the first direct model validation for these subject-specific modeling approaches. In addition, the monitoring of scalp voltages may be used to verify electrode placement to increase transcranial electrical stimulation safety and reproducibility. PMID- 23649037 TI - Bioinspired angle-independent photonic crystal colorimetric sensing. AB - An angle-independent photonic crystal (PhC) colorimetric sensor was developed by using a stimuli-response hydrogel to replicate the template arrays of isotropic photonic crystal beads (PCBs) for the detection of Hg(2+). PMID- 23649038 TI - Biological properties of melanoma and endothelial cells after plasmid AMEP gene electrotransfer depend on integrin quantity on cells. AB - The data on the biological responsiveness of melanoma and endothelial cells that are targeted by Antiangiogenic MEtargidin Peptide (AMEP) are limited; therefore, the antiproliferative, antimetastatic and antiangiogenic effects of AMEP were investigated in murine melanoma and human endothelial cells after plasmid AMEP gene electrotransfer into the cells in vitro. Plasmid AMEP, a plasmid coding for the disintegrin domain of metargidin targeting specific integrins, had cytotoxic and antiproliferative effects on murine melanoma and human endothelial cells. Among the metastatic properties of cells, migration, invasion and adhesion were investigated. Plasmid AMEP strongly affected the migration of murine melanoma and human endothelial cell lines and also affected the invasion of highly metastatic murine melanoma B16F10 and human endothelial cell lines. There was no effect on cell adhesion on Matrigel(TM) or fibronectin in all cell lines. The antiangiogenic effect was shown with tube formation assay, where human microvascular endothelial cell line (HMEC-1) proved to be more sensitive to plasmid AMEP gene electrotransfer than the human umbilical vein endothelial cell line (HUVEC). The study indicates that antiproliferative and antimetastatic biological responses to gene electrotransfer of plasmid AMEP in murine melanoma cells were dependent on the integrin quantity on melanoma cells and not on the expression level of AMEP. The strong antiangiogenic effect expressed in human endothelial cell lines was only partly dependent on the quantity of integrins and seemed to be plasmid AMEP dose dependent. PMID- 23649039 TI - Phospholipid composition and electric charge in healthy and cancerous parts of human kidneys. AB - Phospholipids are ubiquitous in nature and are essential for the lipid bilayer of cell membranes. Their structural and functional properties are pivotal for the survival of the cell. In this study the phospholipids of healthy and cancerous human renal tissues from the same patients are compared with special reference to the electric charge of the membrane. A simple and highly effective normal-phase method is described for analyzing phospholipids content. This work is focused on changes of phospholipids content (PtdIns, phosphatidylinositol; PtdSer, phosphatidylserine; PtdEtn, phosphatidylethanoloamine; PtdCho, phosphatidylcholine) in cell membranes of renal cancer of pT1 stage, G2 grade, without metastasis. Surface charge density of healthy and cancerous human renal tissues was measured by electrophoresis. The measurements were carried out at various pH of solution. Depending on the surface charge density as a function of pH, acidic (C(TA)) and basic (C(TB)) functional group concentrations and their average association constants with hydrogen (K(AH)) or hydroxyl (K(BOH)) ions were evaluated. The process of cancer transformation was accompanied by an increase in total amount of phospholipids as well as an increase in C(TA) and K(BOH), whereas K(AH) and C(TB) were decreased compared with unchanged tumor cells. PMID- 23649040 TI - Attending rounds in the current era: what is and is not happening. AB - IMPORTANCE: General medicine rounds by attending physicians provide the foundation for patient care and education in teaching hospitals. However, the detailed activities of these rounds in the current era are not well characterized. OBJECTIVE: To describe the characteristics of attending rounds for internal medicine inpatients in a large teaching hospital system. DESIGN: A cross sectional observational study of attending rounds in internal medicine. Rounds were observed directly by research assistants. SETTING: Four teaching hospitals associated with a large public medical school. PARTICIPANTS: Fifty-six attending physicians and 279 trainees treating 807 general medicine inpatients. MAIN OUTCOMES AND MEASURES: Duration and location of rounds, composition of teams, and frequency of 19 potential activities during rounds. RESULTS: We observed 90 days of rounds. A typical rounding day consisted of 1 attending with 3 trainees visiting a median of 9 (range, 2-18 [SD, 2.9]) patients for a median of 2.0 hours (range, 25-241 [SD, 2.7] minutes). On rounds, teams most frequently discussed the patient care plan (96.7% of patients), reviewed diagnostic studies (90.7%), communicated with patients (73.4%), and discussed the medication list (68.8%). Teams infrequently discussed invasive lines or tubes (9.3%) or nursing notes (6.2%) and rarely communicated with nurses (12.0%) or taught physical examination skills (14.6%), evidence-based medicine topics (7.2%), or learner-identified topics (3.2%). Many commonly performed activities occurred infrequently at the bedside. CONCLUSIONS AND RELEVANCE: Most activities on attending rounds do not take place at the bedside. The teams discuss patient care plans and test results most of the time but fail to include many items that may be of significant value, including specific aspects of patient care, interprofessional communication, and learner-centered education. Future studies are needed to further assess the implications of these observations. PMID- 23649041 TI - Interleukin-1beta induces a reversible cardiomyopathy in the mouse. AB - BACKGROUND: Inflammatory mediators play a key role in the development and progression of heart failure. Interleukin-1beta (IL-1beta) is a prototypical inflammatory cytokine that suppresses myocyte contractility following acute administration. METHODS: Healthy mice were randomly assigned to daily intraperitoneal injections of recombinant murine IL-1beta (3 MUg/kg in 0.2 ml) or matching volumes of NaCl 0.9 % solution (vehicle) for 15 days. Echocardiography was performed at baseline and 4 h (acute), followed by repeat measurements immediately prior to IL-1beta or saline injections on days 5, 10, and 15 (chronic). Final echocardiography was performed on day 20 (5 days after last treatment). A subgroup of animals underwent isoproterenol challenge to evaluate contractile reserve at baseline, 4 h (acute), 15 days (chronic) and 20 days (recovery). RESULTS: IL-1beta reduced left ventricular fractional shortening (LVFS) at 4 h versus vehicle (-24 vs. 0 %, respectively, P < 0.05). This reduction was maintained throughout chronic dosing at day 15. IL-1beta-treated mice also showed impaired contractile reserve with a right shift of the dose response curve to isoproterenol (P < 0.05) at 4 h and 15 days. By day 20, 5 days after stopping IL-1beta, LVFS and contractile reserve had returned to baseline. CONCLUSIONS: IL-1beta induces a reversible contractile dysfunction associated with impaired response to beta-receptor stimulation. PMID- 23649043 TI - Shigella antigen-specific B memory cells are associated with decreased disease severity in subjects challenged with wild-type Shigella flexneri 2a. AB - The role of Shigella-specific B memory (BM) in protection has not been evaluated in human challenge studies. We utilized cryopreserved pre- and post-challenge peripheral blood mononuclear cells and sera from wild-type Shigella flexneri 2a (wt-2457T) challenges. Challenged volunteers were either naive or subjects who had previously ingested wt-2457T or been immunized with hybrid Escherichia coli Shigella live oral candidate vaccine (EcSf2a-2). BM and antibody titers were measured against lipopolysaccharide (LPS) and recombinant invasion plasmid antigen B (IpaB); results were correlated with disease severity following challenge. Pre-challenge IgA IpaB-BM and post-challenge IgA LPS-BM in the previously exposed subjects negatively correlated with disease severity upon challenge. Similar results were observed with pre-challenge IgG anti-LPS and anti IpaB titers in vaccinated volunteers. Inverse correlations between magnitude of pre-challenge IgG antibodies to LPS and IpaB, as well as IgA IpaB-BM and post challenge IgA LPS-BM with disease severity suggest a role for antigen-specific BM in protection. PMID- 23649042 TI - Subantimicrobial-dose doxycycline treatment increases serum cholesterol efflux capacity from macrophages. AB - OBJECTIVE: Subantimicrobial-dose doxycycline (SDD) treatment has been reported to reduce the severity of chronic inflammation and to increase serum high-density lipoprotein cholesterol. In a double-blind, placebo-controlled clinical trial, we determined whether SDD affects the ability of serum to facilitate cholesterol removal from macrophages. METHODS: Forty-five postmenopausal osteopenic women with periodontitis were randomly assigned to take placebo (n = 26) or doxycycline hyclate (20 mg, n = 19) tablets twice daily for 2 years. Serum samples were collected at baseline, 1-, and 2-year appointments. The cholesterol efflux capacity of serum from cultured human macrophages (THP-1) was measured. RESULTS: SDD subjects demonstrated a significant increase in serum-mediated cholesterol efflux from macrophages at both time points compared to baseline (p < 0.04 for each). Mean cholesterol efflux levels over the first year of follow-up were 3.0 percentage points (unit change) higher among SDD subjects compared to placebo subjects (p = 0.010), while there was no significant difference in 2-year changes. There were no significant differences in the changes of apolipoprotein A I, apolipoprotein A-II, or serum amyloid A levels between the groups. CONCLUSIONS: Our results suggest that SDD treatment may reduce the risk of cardiovascular disease in this patient group by increasing the cholesterol efflux capacity of serum. PMID- 23649044 TI - Characterization of direct radiation-induced immune function and molecular signaling changes in an antigen presenting cell line. AB - Radiation therapy is a widely used cancer treatment and pre-transplantation conditioning regimen that has the potential to influence anti-tumor and post transplantation immune responses. Although conventionally fractionated radiation doses can suppress immune responses by depleting lymphocytes, single high doses of local tumor radiation can enhance immune responses. Using phospho-flow cytometry analysis of a human monocytic cell line, we identified novel radiation induced changes in the phosphorylation state of NFkappaB family members known in other cell types to maintain and regulate immune function. These phosphorylation changes were p53 independent, but were strongly dependent upon ATM activation due to DNA damage. We found that radiation promotes the activation and APC functional maturation through phosphorylation of NFkappaB Essential Modulator (NEMO). Our results and the analytic methods are especially well suited to the study of functional changes in APC when radiation is used for immune modulation in clinical protocols. PMID- 23649045 TI - The role of miR-155 in regulatory T cells and rheumatoid arthritis. AB - Recently, various micro(mi)RNAs have been found deregulated in the setting of rheumatoid arthritis (RA), but their role in the pathogenesis of this disease remains a matter of debate. In the meanwhile, increasing evidence indicates a defective function of regulatory T cells (Tregs) in RA. This review discusses relevant studies addressing the function of Tregs and Cytotoxic T-Lymphocyte Antigen 4 in RA, provides recent data on the role of miRNAs for Tregs homeostasis, and focuses on the role of miR-155 in Tregs. In a final perspective section we discuss the potential impact of therapeutic miR-155 modulation in RA. PMID- 23649047 TI - Influence of filler charge on gloss of composite materials before and after in vitro toothbrushing. AB - OBJECTIVES: This study evaluated the gloss behaviour of experimental resin composites loaded with different filler percentages, immediately after polishing and after toothbrushing simulation. METHODS: Sixteen disc-shaped specimens were fabricated for each different-charged composite (40%, 50%, 60%, 70% and 75%) and polished with SiC abrasive papers. Gloss measurements were made prior to simulated toothbrushing. The specimens were subjected to the simulation for 5, 15, 30 and 60 min using an electrical toothbrush with a standardized pressure while being immersed in a toothpaste/artificial saliva slurry. RESULTS: Baseline composite gloss values ranged from 69.7 (40%) to 81.3 (75%) GU (gloss units) and from 18.1 (40%) to 32.3 (75%) GU after 1h of brushing. Highest gloss values were obtained by 75%-charged resin, while the lowest values were obtained by the 40% charged one. CONCLUSIONS: All tested materials showed a gloss decrease. However, the higher filler load a composite resin has, the higher gloss it can achieve. CLINICAL SIGNIFICANCE: Gloss of resin composite materials is an important factor in determining aesthetic success of anterior restorations, and this property may vary according to the filler charge of the restorative material. Higher filler load of a composite resin results in higher gloss values. PMID- 23649046 TI - UpSET-ting the balance: modulating open chromatin features in metazoan genomes. AB - Appropriate gene expression relies on the sophisticated interplay between genetic and epigenetic factors. Histone acetylation and an open chromatin configuration are key features of transcribed regions and are mainly present around active promoters. Our recent identification of the SET-domain containing protein UpSET established a new functional link between the modulation of open chromatin features and active recruitment of well-known co-repressors in metazoans. Structurally, the SET domain of UpSET resembles H3K4 and H3K36 methyltransferases; however, it is does not confer histone methyltransferase activity. Rather than methylating histones to regulate gene expression like other SET domain-containing proteins, UpSET fine-tunes transcription by modulating the chromatin structure around active promoters resulting in suppression of expression of off-target genes or nearby repetitive elements. Chromatin modulation by UpSET occurs in part through its interaction with histone deacetylases. Here, we discuss the different scenarios in which UpSET could play key roles in modulating gene expression. PMID- 23649048 TI - 25th ISDR Conference. PMID- 23649049 TI - Effect of two different dentin desensitizers on shear bond strength of two different bonding agents to dentin: an in vitro study. AB - OBJECTIVE: The objective of the study was to compare the effect of two different desensitizers on shear bond strength of two different fifth-generation single bottle adhesive agents on dentin surface. MATERIALS AND METHODS: Sixty human premolars were taken and divided into six groups of 10 samples each. The first two groups were the control groups and were not pretreated with any desensitizer; the remaining four groups were the experimental groups and were pretreated with either DenshieldTM or Sensodent-KTM desensitizer. The specimens in each group were subjected to acid etching, application of adhesive (Single Bond or Prime and Bond NT), and application of hybrid composite resin (Z-100) according to the standard protocol. The specimens were subjected to shear bond strength testing, using a Lloyds universal testing machine (EZ20), followed by stereomicroscopic evaluation of the fracture mode at the debonded interface. RESULTS: Statistically significant difference existed between the two bonding agents in the control groups (group 1 and 2), with Prime and Bond NT showing higher bond strength than Single Bond. No statistically significant difference existed between either control or pretreated with any desensitizer when either of the adhesive systems was used. Prime and Bond NT showed statistically higher bond strength value when teeth were pretreated with Sensodent-KTM (groups 5 and 6). No statistically significant difference in bond strength values were observed between the bonding agents when pretreated with DenshieldTM desensitizer. PMID- 23649050 TI - Comparison of the roles of serratiopeptidase and dexamethasone in the control of inflammation and trismus following impacted third molar surgery. AB - INTRODUCTION: Surgical extraction of lower 3 rd molar is the most frequent intervention in oral surgery. This procedure is often associated with significant post operative swelling that may have both biological and social implications. Various studies have been done using different anti inflammatory drugs to study their impact on inflammation. MATERIAL AND METHODS: This study was conducted on 110 patients who had undergone surgical removal of mandibular third molar. The subjects were divided into two groups by double blind method. In addition to post operative swelling and pain , trismus was evaluated using two different groups of drugs. RESULTS: One group was administered 1 mg of dexamethazone every 8 hours for 3 days post operatively. The other group was administered 10 mg of serratiopaptidase every 8 hours for 3 days post operatively. Swelling, pain and trismus were assessed on the 1 st , 3 rd , 5 th and 7 th post operative days. The results of the studies were statistically analysed. CONCLUSION: The results showed dexamethazone was more effective in reduction of swelling and pain in comparison with serratiopaptidase. Both dexamethazone and serratiopaptidase had the same effect on trismus. PMID- 23649052 TI - Determination of the relative parallelism of occlusal plane to three ala-tragal lines in various skeletal malocclusions: a cephalometric study. AB - BACKGROUND: Establishment of a proper occlusal plane is needed for developing an occlusion that is compatible with the biomechanics of a stomatognathic system. There has been a great deal of controversy regarding the anatomic reference point/s taken for identifying the Camper's plane (Ala-Tragus) to which the occlusal plane is oriented parallel in regular complete denture Prosthodontic practice. There has been no study in literature to correlate the occlusal plane to the Camper's plane in various skeletal malocclusions using landmarks on a lateral Cephalogram. AIM: The aim of the study is to determine the relative parallelism of the occlusal plane to ala-tragal lines in various malocclusions. METHODOLOGY: A total of sixty subjects belonging to Class I, Class II and class III malocclusions were selected for the study. Markings with radiopaque marker of 1 mm diameter were adhered against the superior, middle and inferior border of the tragus and against the lower borer of ala of the nose. Lateral cephalograms were obtained for all of the patients. Tracing was performed for all of these radiographs. STATISTICAL ANALYSIS USED: Analysis of Variance (ANOVA) test and Post-Hoc test of Bonferroni were used to compare the angles formed at the superior, middle and inferior borders with the occlusal plane. RESULTS: The result from the present study showed that in Class I and Class III malocclusion, the line drawn from the lower border of ala of the nose to the inferior position of the tragus (Camper' plane C) was relatively parallel to occlusal plane; and, in Class II malocclusion, the line drawn from the lower border of ala of nose to middle border of tragus (Camper's plane B) was relatively parallel to occlusal plane. PMID- 23649051 TI - Effect of periodontal therapy on circulating levels of endotoxin in women with periodontitis: a pilot clinical trial. AB - CONTEXT: Periodontitis is a potential risk factor for adverse pregnancy outcomes due to the presence of a subgingival load of pathogenic bacteria. Instrumentation of periodontal pockets during treatment may result in bacteremia and/or endotoxemia. AIMS: The aim of this pilot clinical trial was to determine the immediate post-scaling and root planing (SRP) level of circulating endotoxin in females presenting with chronic periodontitis. SETTINGS AND DESIGN: A before-and after pilot clinical trial among rural women of low socioeconomic status attending the outpatient department (OPD) for periodontitis. MATERIALS AND METHODS: Twenty-four women aged 25-35 years, with at least five teeth having probing depth (PD) >= 5 mm, were selected for the study. The clinical trial was divided into three phases: phase 0 (screening), phase I (just before scaling), and phase II (15 min after scaling). Phase 0, one day prior to SRP, was used to assess the eligibility of the patients and record the periodontal status. Endotoxin levels were assessed by a semiquantitative gel-clot assay, the limulus amoebocyte lysate (Lonza(r)), at phase I and phase II. STATISTICAL ANALYSIS USED: The Chi-square test was used for statistical analysis. RESULTS: There was significant increase of endotoxins levels (P<.05) immediately after scaling (15 min). CONCLUSIONS: SRP can lead to endotoxemia, possibly by release of endotoxins by bacteria of periodontal origin, into the systemic circulation. PMID- 23649053 TI - An ultrasonographic evaluation of masseter muscle thickness in different dentofacial patterns. AB - OBJECTIVES: The aim of this study is to compare the masseter muscle thickness in different vertical dentofacial patterns and identify the possible sexual dimorphism and also to correlate masseter muscle thickness with craniofacial morphology using cephalometric parameters. MATERIALS AND METHODS: The masseter muscle thickness was measured using ultrasonography in 60 subjects (30 females and 30 males). Standardized lateral and posteroanterior cephalograms were taken to determine the facial morphology. The subjects were divided into three vertical pattern groups (I, II, and III) according to their Jarabak ratio: hypodivergent ( n = 20), normodivergent (n = 20), and hyperdivergent (n = 20). The sample was further subdivided into males and female subgroups. RESULTS: Masseter muscle thickness relaxed (MMTR) in hypodivergent group was 13.94 +/- 1.51. Mean value of MMTR in normodivergent group was 12.53 +/- 1.21 and the MMTR in hyperdivergent group was 11.13 +/- 1.18. The mean value of masseter muscle thickness contracted (MMTC) in hypodivergent group was 15.46 +/- 1.33. Mean value of MMTC in normodivergent group was 13.81 +/- 1.38 and the mean value of MMTC in hyperdivergent group was 12.27 +/- 1.26. MMTC showed a significant, negative correlation with mandibular plane angle and gonial angle. Posterior facial height, symphysis width, intermolar width of maxillary first molars, maxillary width, and facial width (bizygomatic width) showed significant ( P < 0.05 or P < 0.01) positive correlation. CONCLUSION: The masseter muscle thickness varied among the three vertical dentofacial patterns and sexual dimorphism also existed except in the hyperdivergent group. Masseter muscle thickness was found to be negatively correlated to vertical facial pattern and positively associated with transverse craniofacial morphology. PMID- 23649054 TI - Effect of a glass ionomer cement and a fluoride varnish on cross-sectional microhardness values of artificial occlusal caries: in vitro study. AB - CONTEXT: Active white spot lesions (WSLs) are a great concern to clinicians. AIMS: This in vitro experiment analyzed cross-sectional microhardness (CSMH) values of occlusal artificially induced active WSLs (control groups D/A, D/B and D/C) along with experimental groups where these lesions were: Exposed to an artificial high risk cariogenic challenge (HRCC) using pH cycling; treated with a glass ionomer cement (GIC) and then exposed to artificial HRCC; or a fluoride varnish (FV) and afterwards submitted to the same artificial HRCC. MATERIALS AND METHODS: Sixty unerupted human third molars were sectioned buccolingually on the occlusal surface and demineralized for 42 days. One half of each tooth was allocated to control groups (D/A, D/B, and D/C) and the other were used as test groups: A (pH cycling); B (GIC + pH cycling); and C (FV + pH cycling). CSMH test was performed for sound, demineralized, and treated specimens. STATISTICAL ANALYSIS USED: Different depths for CSMH values did not have a normal distribution (Kolmogrov-Smirnov test) and for that matter Wilcoxon and T Test were applied (significance level of 5%). RESULTS: Mean depth of the lesion was 120 MUm. A number of samples both in the test groups (n = 37) as in control groups (n = 47) had a lower Knoo p value (softening) or surface erosion. Comparisons between control and test groups only showed statistical difference at a depth 140 MUm (P = 0.010) in control group D/A and for test group B at 20 MUm (P = 0.004) and at 40 MUm (P = 0.007). CONCLUSIONS: This in vitro study demonstrated that the use of GIC over an artificial active WSLs and exposed to an artificially HRCC setting tend to express some effect in increased surface KHN values. PMID- 23649056 TI - Vitapan 3D-master shade guide showed no fluorescence emission. AB - OBJECTIVES: To determine the fluorescence property of Vitapan 3D-Master shade guide tabs with a spectrophotometer. MATERIALS AND METHODS: Fluorescence property of 29 shade tabs, in both of original and ground-to-flat forms, was determined by a reflection spectrophotometer. Color difference (DeltaE*ab-FL) by the inclusion and exclusion of the UV component of a standard daylight simulator (CIE standard illuminant D65) was calculated to determine the fluorescence color change. Fluorescence peak was expressed as the difference in spectral reflectance values by the UV component. RESULTS AND CONCLUSION: DeltaE*ab-FL values were in the range of 0.2 to 2.7 (mean: 1.2 +/- 0.6) for the original and 0.5 to 1.6 (mean: 0.9 +/- 0.1) for the ground-to-flat tabs, which was significantly different based on paired t-test (p<0.05); however, fluorescence peak was not detected in all the shade tabs. Therefore, fluorescence property of Vitapan 3D-Master shade guide should be modified to have similar fluorescence property of natural teeth and corresponding restorative materials. PMID- 23649055 TI - Association between oral health-related quality of life and atraumatic restorative treatment in school children: an exploratory study. AB - BACKGROUND: The present study's objectives were to compare the perceptions of oral health-related quality of life (OHRQoL) among school children presents dental caries with that of caries-free school children, and to evaluate the subjective impact of atraumatic restorative treatment (ART) on the OHRQoL of school children. DESIGN: Exploratory study. SETTING: Public school in Piracicaba, Brazil. MATERIALS AND METHODS: The sample was composed of 30 children in the age group of 8-10 years. The children were divided into two groups: one with caries and other without caries. The information related to OHRQoL was obtained through the administration of the Child Perceptions Questionnaires (CPQ 8-10 ). To evaluate the impact of ART on the school children's OHRQoL, the CPQ 8-10 was re administered 4 weeks after the initial treatment. For statistical analysis we used the nonparametric Wilcoxon test for two dependent variables (test and re test groups) and the nonparametric Mann-Whitney test for independent variables (test and control groups). RESULTS: It was observed that children with dental caries reported larger impact of oral health conditions on the quality of life when compared with the caries-free group, especially in the emotional and social well-being domains ( P <=.05). After the school children who presented with dental caries received ART, there was improvement in the median scores of CPQ 8 10 in all of the domains, but particularly in the functional limitation domain ( P <=.05). CONCLUSION: Dental caries exerts a strong influence on the OHRQoL of children. ART was shown to be a simple and painless caries management approach that could improve the OHRQoL of school children. PMID- 23649057 TI - Influence of adhesion promoters and curing-light sources on the shear bond strength of orthodontic brackets. AB - CONTEXT: The effect of different curing units on bond strength of orthodontic brackets is still unclear when utilizing nanofilled composites in comparison with traditional Transbond-XT. AIM: To evaluate the influence of two adhesive promoters and two curing-light units on the shear bond strength (SBS) of orthodontic brackets. SETTINGS AND DESIGN: The factors under study were adhesive promoters (nanofilled composite - Filtek-Z350 flowable restorative and conventional orthodontic adhesive - Transbond XT) and curing-light units (halogen lamp - Ultralux and LED device - Radii-Call). MATERIAL AND METHODS: Forty lower bovine incisors were utilized. The teeth were distributed in four groups (n = 10) according to the combination between adhesive promoters and curing-light units. Scotchbond Multipurpose-Plus and Transbond-XT primer were used to bond Filtek Z350 Flowable Restorative and Transbond-XT, respectively. After storage in distilled water for 24 h, the brackets were subjected to SBS test at a speed of 0.5 mm/min until bracket debonding. The Adhesive Remnant Index (ARI) was assigned at fractured specimens. STATISTICAL ANALYSIS USED: Analysis of variance and Tukey test were utilized. The Kruskal-Wallis test was used to compare ARI scores between the groups (p<0.05). RESULTS: There was statistically significant difference between the adhesive promoters tested. Transbond-XT showed higher SBS means than Filtek-Z350. There was no statistically significant difference between both curing-light units tested in this study, neither between ARI scores. CONCLUSIONS: The conventional orthodontic adhesive presented higher bond strength than the nanofilled composite, although both materials interacted similarly to the teeth. The curing-light devices tested did not influence on bond strength of orthodontic brackets. PMID- 23649058 TI - The microbiology of the peri-implant sulcus following successful implantation of oral prosthetic treatments. AB - BACKGROUND: Oral implants are widely used in partially and fully edentulous patients; however, the integration of an implant can be endangered by factors such as intraoral bacteria or inflammatory reactions. The purpose of this study was to evaluate the microbial flora present in the sulcus around dental implants and to assess the relationship between gingival health and microbial flora present. MATERIALS AND METHODS: Twenty patients who had received oral implants with no complications were followed for a period of 9 months. Assessment of probing depth, the presence of bleeding on probing and microbial sampling from the peri-implant sulcus were performed at three different time points- 4 weeks after surgery, 1 month and 6 months after loading. The samples were taken by paper points and transferred to the microbiology lab in thioglyocolate cultures. In order to do a colony count and isolate the aerobic capnophilic and anerobic bacteria the samples were cultured and incubated on laboratory media. The colonies were also identified using various diagnostic tests. Alterations in the presence of various bacterial species over time and gum health were tested using analysis of variance (ANOVA) with Tukey's test post hoc. RESULTS: The average pocket depth for each patient ranged from 1.37 +/- 0.39 mm to 2.55 +/- 0.72 mm. The bacteria isolated from the cultured samples included aerobic, facultative anerobic, obligate anerobic and capnophilic bacteria. CONCLUSION: The anerobic conditions created in the peri-implant sulcus might with time enhance the number of anerobic bacteria present following dental implant loading. PMID- 23649059 TI - Salivary flow and dental caries in Brazilian youth with type 1 diabetes mellitus. AB - BACKGROUND: Although type 1 diabetes mellitus (T1DM) has a significant impact on oral health, its association with dental caries is yet not clear. AIM: The aim of this study was to evaluate the salivary flow rate and caries in Brazilian youth with type 1 diabetes mellitus. SETTING AND DESIGN: A Cross-sectional study was performed in a tertiary university hospital. MATERIALS AND METHODS: Fifty-one age matched subjects suffering from type 1 diabetes mellitus were selected for the study and evaluated for the following: salivary flow rate, number of decayed, missing and filled tooth in permanent dentition (DMF-T) and decayed, extracted, filled tooth index in the deciduous dentition (def-t); visible plaque index (VPI) and gingival bleeding index (GBI). STATISTICS AND ANALYSIS: The t test was utilized when the variables showed normal distribution. The Mann-Whitney test was utilized for comparing non-normal variables. Kolmorgorov-Smirnov test was used to assess the normality assumption. The differences were considered significant when P < 0.05. RESULTS: The age and gender distribution of patients and controls was 11.3 +/- 3.4 years (56% males) and 11.9 +/- 3.4 years (37% males). The mean glycated hemoglobin value in the diabetics was 9.7 +/- 1.9%. Salivary flow rate was lower in the diabetic patients as compared to controls (P = 0.02). No differences were found in the DMF-T/def-t indices of diabetic and non-diabetic patients (P = 0.43/0.14). VPI was similar in both the groups (P = 0.15). GBI was higher in the diabetics (8.1 vs. 5.18; P = 0.11). There were no differences in the dental caries experience and dental plaque in the two groups. CONCLUSION: The lower salivary flow rate in diabetics could have been related to their higher GBI. The higher GBI in the diabetics is a matter of concern in the diabetics and is a sign for higher chances of developing periodontal problems. PMID- 23649060 TI - Flowable resin and marginal gap on tooth third medial cavity involving enamel and radicular cementum: a SEM evaluation of two restoration techniques. AB - PURPOSE: The aim of this study is to investigate the presence and the extent of a possible marginal gap after the interposition of a flowable composite between the composite restoration and the dental structures (enamel and cementum). This technique is also used to eliminate the infiltration in a zone of the cavity preparation that is frequently at a risk of secondary decay. MATERIALS AND METHODS: Fifteen human premolars extracted for orthodontic reasons were used for the study. A cavity with mesial and distal margin in enamel and cementum was realized in every tooth. The cavities were then restored with an adhesive system (ScotchBond 3MO) and composite (Filtek Supreme 3MO); and, a fine layer of flowable composite was applied in the distal margin of each cavity. Scanning electron microscopy (SEM) in secondary electron imaging (S.E.I.) modality was used for the study and identifying the marginal gaps in the composite restorations. Data was investigated on the mesial and distal margin of each cavity at the restoration-enamel interface, and at the restoration-cementum interface. The interfaces were divided in four groups: Group A (enamel/composite); Group B (enamel/flow/composite); Group C (cementum/composite); and, Group D (cementum/flow/composite). RESULTS: By the comparison of the gap's average width found in each group, it is evidenced that the average width of the gap increases when the interface moves from the coronal to the radicular end (Group A 0,1 +/- 0,4 MUm Vs Group C 12,3 +/- 11,6 MUm; Group B 0,2 +/- 0,8 MUm Vs Group D 2,8 +/- 6,6 MUm). Correlating the measurements of the marginal gap's average width among the Group A and Group B, no significant variations were obtained; and instead, on comparing Group C with Group D, the gap's average width decreases. CONCLUSION: The interposition of a low elastic modulus composite between the adhesive layer and the composite resin allows an improvement of the cementum-restoration interface by the means of a lower shrinkage stress during polymerization. PMID- 23649061 TI - The use of stereophotogrammetry in oral surgery: measurement of area changes after secondary epithelization and grafting vestibuloplasties. AB - OBJECTIVE: Stereophotogrammetry (SPT) is a method in which three-dimensional coordinates are calculated from multiple two-dimensional projections. The purpose of this study was to compare the surface area changes between the secondary healing and grafting vestibuloplasty techniques in the mandible by using a stereophotogrammetric technique (SPT). PATIENTS AND METHODS: Thirteen patients were included in this study: six patients were managed by using full-thickness skin or palatal mucosa grafts (two full-thickness palatal mucosal grafts and four full-thickness skin grafts); the remaining seven patients, who did not accept a second surgery for graft harvesting, underwent secondary epithelization vestibuloplasties. Postoperative changes of surgical areas were measured by using SPT. STATISTICAL ANALYSES: The Wilcoxon (intragroup comparisons) and Mann-Whitney U (intergroup comparisons) tests were used for analysis of data. RESULTS: In the grafting vestibuloplasty group, the surface area gain was statistically significant (P < 0.05). In the secondary epithelization vestibuloplasty group, there was no significant difference (P > 0.05), with even decrease of surface area being noted in some cases. CONCLUSION: SPT is a valid method for measurement of intraoral soft tissue changes. PMID- 23649062 TI - Mandibular bone changes induced by head and neck radiotherapy. AB - CONTEXT: The mandible is inevitably affected by radiation during radiotherapy of head and neck cancers. Surveys have shown that most of the emphasis has been on osteoradionecrosis (ORN), while the other bony changes occurring in this area have been largely ignored. AIMS: In this study we examine the radiologic changes in the mandible of irradiated patients using panoramic radiography and compare it with the mandible in non-irradiated cases. MATERIALS AND METHODS: Mandibular bone changes of 48 patients who had received therapeutic radiation for head and neck cancer were assessed. We measured the width of the cortex and the width of the mandibular canal on panoramic radiographs and assessed the changes by comparison with the mandibular bones of non-irradiated subjects. Clinical evaluations were performed for assessing maximum jaw opening, masticatory muscle tenderness, and presence of mucosal ulcers and/or exposed bone in the oral cavity. STATISTICAL ANALYSIS: Paired t-test, Chi-square test, and Mann-Whitney test were used for statistical analysis. P < 0.05 was taken to indicate statistical significance. RESULTS: There was no evidence of mucosal ulceration or exposed bone in irradiated patients. There was significant relationship between the number of years after radiotherapy and the degree of limitation of mouth opening (P = 0.000). Receipt of concurrent chemotherapy did not seem to have any additive effect on the width of mandibular canal or the thickness of the mandibular cortex. CONCLUSION: Reduction in the width of the mandibular cortex and dimensions of the inferior alveolar canal could be considered as one of the effects of head and neck radiotherapy. PMID- 23649064 TI - Influence of the instrumentation technique and apical preparation diameter on calcium hydroxide filling in simulated curved canals. AB - OBJECTIVE: This study evaluated the influence of the instrumentation technique and apical preparation size on the filling capacity of a calcium hydroxide (CH) based paste. MATERIALS AND METHODS: Fifty simulated curved canals were prepared in acrylic blocks (five groups; n = 10 each). In three groups, the canals were preflared with Gates-Glidden drills and the apical stop was prepared with #25, 30 or 35 Flexofile files. In the other two groups, the canals were prepared with ProTaper rotary instruments and the apical stop was prepared with F1 and F2. A CH paste was injected into the canals using a special syringe. The four sides of the blocks were scanned with the root curvature to the mesial, buccal, distal and palatal faces. The amount (%) of filling in the total canal area and in the apical 5 mm was obtained [analysis of variance (ANOVA); Tukey's test; alpha = 0.05]. Qualitative analysis of apical filling was done (absence vs. presence of filling deficiencies) (chi-square test; alpha = 0.05). RESULTS: There was no significant difference in canal filling among the groups at any block side. Presence of voids was associated with the simulated mesial and distal faces. CONCLUSIONS: An effective canal filling with the CH paste was not achieved in all cases. Canal filling failure occurred mostly in the apical third. Filling deficiencies can be better visualized in canals with mesial and distal root curvatures. PMID- 23649063 TI - Comparative evaluation of two commercially available desensitizing agents for the treatment of dentinal hypersensitivity. AB - AIMS: A randomized clinical trail was designed to compare the efficacy of two commercially available desensitizing agents (fluoride varnish containing 6% sodium fluoride and 6% calcium fluoride and a gel containing 6% potassium nitrate and 0.11% fluoride ions) in the treatment of dentinal hypersensitivity. SETTINGS AND DESIGN: Randomized clinical trial. MATERIALS AND METHODS: Twenty-one patients were selected. Subjects were evaluated using three different stimuli, i.e., tactile test, air blast test and cold water test. They were then randomly divided into two groups. Patients in group I were treated with fluoride varnish and group II patients were treated with gel containing 6% potassium nitrate and 0.11% fluoride ions. The patients were examined at baseline, immediately after application of the agent, at 1 week, 1 month and 3 months interval. STATISTICAL ANALYSIS: Statistical analysis was done using unpaired "t" test, paired "t" test and Chi-square test with Yate's correction. RESULTS: The results were analyzed; it was seen that patients treated in group I showed significantly better results compared to group II patients at 1 month and 3 months interval. Teeth which required repeat dose and those which did not require repeat dose were comparable in number. CONCLUSIONS: Both the agents showed significant reduction in sensitivity at all time intervals compared to baseline. A comparatively significant reduction in sensitivity score was seen in patients treated with fluoride varnish and it appeared to be more effective in providing long-term relief against all the three test stimuli. Teeth with initial high sensitivity score required repeat doses, which was comparable for both the groups. PMID- 23649065 TI - Influence of ceramic surface treatment on shear bond strength of ceramic brackets. AB - OBJECTIVE: To compare four different surface treatment methods and determine which produces adequate bond strength between ceramic brackets and facets of porcelain (feldspathic), and evaluate the Adhesive Remnant Index (ARI) scores. MATERIALS AND METHODS: Ten facets of porcelain specimens with glazed surfaces were used for each group. The specimens were randomly assigned to one of the following treatment conditions of the porcelain surface: (1) no surface treatment (control group), (2) fine diamond bur + orthophosphoric acid gel 37%, (3) hydrofluoric acid (HFL) 10%, and (4) HFL 10% + silane. Ceramic brackets were bonded with the adhesive cement Transbond XT. The shear bond strength values were measured on a universal testing machine at a crosshead speed of 0.5 mm/min. RESULTS: There was a significant difference (P<0.05) between the control group and all other groups. There was no significant difference (P<0.05) between treated porcelain surface with diamond bur + orthophosphoric acid gel 37% (4.8 MPa) and HFL 10% (6.1 MPa), but the group treated with HFL 10% had clinically acceptable bond strength values. The group treated with HFL 10% + silane (17.5 MPa) resulted in a statistically significant higher tensile bond strength (P<0.05). In group 4, 20% of the porcelain facets displayed damage. CONCLUSION: Etching of the surface with HFL increased the bond strength values. Silane application was recommended to bond a ceramic bracket to the porcelain surface in order to achieve bond strengths that are clinically acceptable. PMID- 23649066 TI - Relationship of third molar movement during orthodontic treatment and root angulation. AB - BACKGROUND: Curved roots of teeth might cause difficulty in root canal treatment and removal. Beside genetic factors, root morphology of the third molars is affected by environmental factors such as mesial migration. However no studies examine the relation between the amount of third molars' movement and their root angles. The purpose of this study was to evaluate the relation between the amount of third molar movement during orthodontic treatment and the angulation of third molar roots. MATERIALS AND METHODS: The records of 39 patients who had apical closure after orthodontic treatment were evaluated. Root curvature was measured on panoramics using the angle between an occlusal reference line and central line of the most apical ninth of the root. The amount of tooth movement of third molars was measured on the pre- and post- treatment lateral cephalometric radiographs by measuring tooth distance from a perpendicular line. Pearson correlation analysis was preformed to obtain relation of the amount of third molar's movement and its root angulation. RESULTS: In maxillary arch the correlation between tooth movement and root angulation was positive and not significant relation but in mandibular arch this relation was negative and not significant. ( P > 0.05) CONCLUSION: The relation between the amount of third molar movement and its root angulation was not statistically significant. Therefore movement of third molars during orthodontic treatment should not be assumed as an etiologic factor of root angulations. PMID- 23649068 TI - An in vitro comparison of microleakage of two self-etched adhesive and the one bottle adhesive used in pit and fissure sealant with or without saliva contamination. AB - AIMS AND OBJECTIVES: To minimize the deleterious effects of contaminated enamel on bonding, some authors have advocated the use of adhesive systems under the sealant. The aim of this study was to compare the microleakage of two self-etch and the one-bottle adhesive used in pit and fissure sealant with or without saliva contamination. MATERIALS AND METHODS: Sixty extracted premolar teeth were assigned to the six groups. Group 1: Acid +saliva +single bond +sealant, Group 2: Acid +single bond +sealant, Group 3: Saliva +S (3) bond +sealant, Group 4: S (3) bond +sealant, Group 5: Saliva +protect bond +sealant, Group 6: Protect bond +sealant. The teeth were thermocycled and immersed in 2% basic fuchsine dye for 24 h, then sectioned and examined with a stereomicroscope under *40 magnification. The results were evaluated with Kruskal-Wallis and Dunn tests. RESULTS: Group 2 has the lower microleakage scores than Groups 4 and 6. Also, Group 6 has the lower microleakage scores than Group 4, and generally an increase in microleakage was observed in each group related to contamination. CONCLUSION: The best technique of sealant therapy in saliva contaminated and non- contaminated condition is the use of acid-etching and bonding agent. PMID- 23649067 TI - Radiographic study of patients with ectodermal dysplasia and partial. AB - AIM: To investigate the association between gender and type of cleft with hypodontia and to verify if the presence of the cleft interferes with hypodontia of one or more type of teeth in patients with ectodermal dysplasia attending the Hospital for Rehabilitation of Craniofacial Anomalies (HRCA), University of Sao Paulo (USP). MATERIALS AND METHODS: Panoramic radiographs of 54 patients of both genders (29 males, 25 females), from the files of the oral radiology sector of HRCA/USP, presenting with ectodermal dysplasia and cleft lip and/or palate were evaluated by radiographic observation of hypodontia of one or more types of teeth. STATISTICAL ANALYSIS: We performed descriptive statistics and statistical analysis by Fisher test. RESULTS: Hypodontia was observed in 50% of females and 50.88% of males; 50% for cleft palate and 50.59% for complete cleft lip and palate. Only 22.22% of patients with cleft palate and 6.67% with complete cleft lip and palate presented with hypodontia of one type of teeth, whereas 77.78% of cases with cleft palate and 93.33% with complete cleft lip and palate displayed hypodontia of more than one type of teeth. CONCLUSION: Based on the present methodology, there were no statistically significant differences in hypodontia of one or more types of teeth between genders or types of cleft. PMID- 23649069 TI - Role of dental pulp in identification of the deceased individual by establishing ABO blood grouping and Rhesus factor. AB - OBJECTIVES: The study was conducted to emphasize the sensitivity and specificity of dental pulp in identifying the ABO Blood group, Rhesus factor and also to emphasize the role of dental pulp in forensic odontology to identify the deceased individual. MATERIALS AND METHODS: The study was conducted on 60 patients. The samples obtained from finger-prick method from those 60 patients were considered as control and the samples obtained from the pulp were considered as case. The blood grouping, Rhesus typing for capillary blood drawn by finger prick was done by slide-agglutination method and the blood grouping, Rhesus typing for extracted dental pulp was done by absorption-elution method. RESULTS: Fifty seven teeth out of sixty showed positive results. Blood group elicited from capillary blood done by slide-agglutination method matched with that of the pulpal blood group elicited by absorption-elution method. Three showed negative results. CONCLUSION: As the teeth are the hardest, most stable biological material, resist adverse environmental conditions and the pulpal tissue inside the teeth is well protected, the blood group antigen from pulp remains stable for long. Thus, the high potential value of dental pulp tissue is highlighted in this study. PMID- 23649070 TI - An in vivo study to determine the range of posterior teeth disclusion on working side in canine-guided occlusion. AB - BACKGROUND AND OBJECTIVES: This study was done with the objectives to determine the range of functional zone between the intercuspal positions and edge to edge position, the range of incomplete and complete disclusion of posterior teeth in canine-guided occlusion, and to have a gender comparison and comparison between right and left sides of the obtained values. MATERIALS AND METHODS: Thirty-five subjects showing canine-guided occlusion and Angle's class I canine and molar relation were chosen for the study. Maxillary midline and a corresponding line on the mandible were marked in maximum intercuspation with marker pen in the patient's mouth. Lines from 1 to 5 mm were marked on maxillary central incisor with marker pen. A dental floss was looped around the distal surface of mandibular last molar and the subject was asked to make left lateral movement (working side) at 1-mm intervals. The point at which floss was freed posteriorly was considered as initial disclusion and the point at which edges of maxillary and mandibular canines contacted was considered as complete disclusion. RESULTS: Most of the male and female subjects in the study showed progressive disclusion on right side and delayed disclusion on left side. The range of complete disclusion was 3-4 mm in males and 2-3 mm in females irrespective of the side. The range of functional zone was 1-4 mm irrespective of side or gender. INTERPRETATION AND CONCLUSION: There is a need to redefine canine guidance in terms of immediate disclusion, delayed disclusion, and progressive disclusion. PMID- 23649071 TI - Imaging modalities in head-and-neck cancer patients. AB - Accurate staging and timely assessment is critical in head-and-neck cancer patients for formulating the appropriate treatment strategy. Therefore, optimizing pretreatment imaging for diagnosis is of great importance. Computerized tomography (CT), introduced in the early 70s, followed by magnetic resonance imaging (MRI) and positron emission tomography (PET), refinements in ultrasonography (USG), advances in nuclear medicine, and applications such as sentinel node lymphoscintigraphy have greatly added to diagnostic accuracy. Post treatment CT or MRI is of value when a recurrent tumor is suspected. It can confirm the presence of such a lesion and determine its extent. This is important information for determining the possibility of salvage therapy. PMID- 23649072 TI - Replantation of an avulsed tooth with an extended extra oral period. AB - In this study, we have reported a case of the replantation of a maxillary incisor with an extended extraoral period following a traumatic avulsion. After storage in normal saline, the root surface of the avulsed tooth was conditioned with citric acid and treated with a triple antibiotic solution. The tooth socket was filled with Emdogain before replantation. A 12 month, 18 month and a 5 year follow-up clinical examination revealed the patient to be asymptomatic, and the tooth was functional. The recall radiograph showed no evidence of renewed periradicular breakdown and apical root resorption. PMID- 23649073 TI - Rubber dam as a barrier membrane in the treatment of periodontal osseous defect. AB - BACKGROUND: Barrier membrane helps in periodontal regeneration by preventing the migration of epithelial cells and cells from the gingival connective tissue onto the root surface. Different types of membranes have been used to regenerate periodontal tissues. There are very few documented reports where rubber dam has been used as a barrier membrane for regeneration of periodontal defects. CASE DESCRIPTION: A female patient aged 20 years with localized aggressive periodontal disease participated in this clinical report. Infrabony defect in the lower anterior region was selected for surgical treatment. Rubber dam was trimmed to cover the defect. Orthodontic treatment was done for the realignment of malpositioned teeth 1 year after the surgery and patient was followed up for a period of 3 years after surgery. RESULTS: Rubber barrier membrane did not result in any untoward side effects. Patient did not show any sign of inflammation or recurrence of probing depth at 3-year follow-up period. CLINICAL IMPLICATIONS: Rubber dam as barrier membrane yields good results. PMID- 23649074 TI - Hand-Schuller-Christian disease. AB - Langerhan cell histiocytosis, formerly known as histiocytosis X, traditionally denotes a group of diseases that stem from proliferative reticuloendothelial disturbances.The etiology and pathogenesis of the disease remain debatable. In this paper we report a case of Langerhan cell histiocytosis in a 3 1/2 -year-old child who reported to the department of oral pathology with gingival enlargements. The radiological features and histopathological features are also discussed. PMID- 23649075 TI - Dentigerous cyst with an impacted third molar obliterating complete maxillary sinus. AB - Dentigerous cyst is the most commonly occurring odontogenic cyst after radicular cyst and accounts for 15% of all true cysts in the jaws. The cyst is more common in mandible than in maxilla. The dentigerous cyst is commonly associated with impacted mandibular third molars. In maxilla, the incidence is rare. Dentigerous cyst in maxillary sinus in association with an impacted third molar is an uncommon entity. We present a case of dentigerous cyst associated with an impacted third molar, completely obliterating the maxillary sinus in a 28-year old female. PMID- 23649076 TI - Utility of the visual analog scale in dentistry. PMID- 23649077 TI - Oral anticoagulant therapy. PMID- 23649078 TI - The influence of metal substrates and porcelains on the shade of metal-ceramic complex: a spectrophotometric study. AB - BACKGROUND: The final esthetic outcome of a metal-ceramic restoration is influenced by several factors including the type of the underlying metal as well as the brand of the ceramic. SETTINGS AND DESIGN: An in vitro study. AIMS: The purpose of the in vitro study was to investigate the influence of four types of metal-ceramic alloys and two porcelain systems on the color co-ordinates of the metal-ceramic complex. It also aimed at establishing a color index which correlated the color of the metal-ceramic combination to the yellow-blue axis. MATERIALS AND METHODS: Twenty-four disc-shaped metal specimens of 12 mm * 1 mm were cast from base metal alloys, nickel-chromium (Ni-Cr) (Wiron 99), cobalt chromium (Co-Cr) (Wirobond C), a palladium (Pd)-rich noble metal alloy (Spartan Plus), and a high noble gold (Au) alloy (Pontostar). These discs were covered with two commercially available feldspathic porcelains (Vita Omega and Shofu Vintage) of A3 shade to a total thickness of 1.2 mm. Each group had six specimens, of which three were coated with Vita Omega and the remaining with Shofu Vintage. Opaque and dentin layers were applied to a standardized thickness of 0.2 mm +/- 0.05 mm and 1 mm +/- 0.05 mm, respectively onto the metal surface after air abrasion with 50 MUm alumina particles. The reflectance spectra were measured with a spectrophotometer and data were recorded in L*, a* and b* coordinates in the CIE Lab Color Order System. STATISTICAL ANALYSIS: Analysis of variance (ANOVA) and path analysis were the statistical tools employed to analyze the data. A critical difference (CD) value was calculated for each color co ordinate to make comparisons between each metal-ceramic combination. A color index for each metal-ceramic complex was also calculated from the color co ordinates obtained. RESULTS: ANOVA revealed that significant differences existed between the metal-porcelain combination at 0.01 ( P < 0.01) level. The L* value was significantly higher for Au and Co-Cr alloys with Vita Omega porcelain. The a* value was highest for Ni-Cr alloy when combined with Shofu Vintage ceramic. The b* value of Au alloy with Vita Omega porcelain was significantly higher than any other metal-ceramic combination. The color co-ordinates of Pd alloy with both porcelain systems did not show any significant differences. Gold alloy with Vita Omega showed the highest color index value. CONCLUSION: The variations in metal ceramic alloy and porcelain can influence the shade of a metal-ceramic restoration. Color index value was the highest for gold alloy. PMID- 23649079 TI - Phenotypic and growth characterization of human mesenchymal stem cells cultured from permanent and deciduous teeth. AB - CONTEXT: A step-by-step approach to harvesting stem cells from the pulp of permanent and deciduous teeth, the problems faced during culture, and the differences in the growth properties and morphology of cells obtained from both the sources has been discussed as a precursor to the use of these cells in therapy. AIMS: To isolate, culture, and study the morphology and growth characteristics of mesenchymal stem cells from the dental pulp of permanent teeth (dental pulp stem cells; DPSC) and exfoliated deciduous teeth (stem cells from human exfoliated deciduous; SHED). SETTINGS AND DESIGN: Cell culture study carried out at the Department of Oral and Maxillofacial Pathology, Ragas Dental College and Hospital, Chennai. MATERIALS AND METHODS: Fifteen permanent teeth and thirteen deciduous teeth from ten subjects were used. The growth characteristics and phenotype of cultured DPSCs and SHED were studied from the fourth passage on 24-well plates. STATISTICAL ANALYSIS USED: Data analysis was done using SPSS (r) version 10.05. Linear regression analysis was performed to derive the slope from growth curves and Mann-Whitney U test was performed to compare the fibroblastoid: epithelioid cell ratio between permanent and deciduous tooth pulp groups. RESULTS: Protocol for the culture of DPSC and SHED was standardized. DPSC and SHED populations were morphologically distinct. The cells from permanent tooth pulp showed a higher proportion of spindle-shaped fibroblastoid cells, whereas deciduous pulp culture showed a higher proportion of epithelioid cells. The seeding efficiency of DPSC - 88.9% (14 th permanent tooth pulp) and 91.7% (15 th permanent tooth pulp) was higher as compared to SHED - 84.25% (10 th deciduous tooth pulp). CONCLUSIONS: Permanent and deciduous teeth are both viable sources of stem cells. The permanent teeth were easier to culture because of a lower chance of contamination with oral microflora. The growth characteristics of the cells obtained from both these sources were similar. However, there was a difference in the ratio of fibroblastoid cells to epithelioid cells between the cultures obtained from the permanent and deciduous teeth. PMID- 23649081 TI - Comparative evaluation of the antimicrobial efficacy of four chewing sticks commonly used in South India: an in vitro study. AB - BACKGROUND AND AIM: The use of chewing sticks has been well documented since ancient times in India. Chewing sticks are a good alternative to the toothbrush for maintaining oral hygiene. The present study was designed and conducted to compare and evaluate the antimicrobial effects of the aqueous extracts of neem, miswak, mango, and banyan chewing sticks against two bacterial species considered the most important in the initiation and progression of dental caries, namely Streptococcus mutans and Lactobacillus acidophilus, respectively. MATERIALS AND METHODS: Twigs of the above mentioned chewing sticks were sun dried and powdered, and sterile aqueous solutions of 10%, 25% and 50% concentrations were prepared. Culture plates for S mutans and L acidophilus were prepared and the growth was transferred to nutrient agar and Mueller-Hinton agar; antimicrobial activity of the extracts was tested after 72 h, using the disc diffusion method. Normal saline was used as control. RESULTS: The antimicrobial activity of neem, miswak, and mango extracts increased as their concentrations increased. Both banyan extract and saline showed no antimicrobial activity against the organisms tested. CONCLUSION AND RECOMMENDATIONS: Based on the zones of inhibition, aqueous extracts of neem showed the most antimicrobial activity against S mutans, while miswak extracts showed superior antimicrobial activity against L acidophilus. We recommend further phytochemical and pharmacological studies to discover newer nonsynthetic tooth pastes and mouthwashes. PMID- 23649080 TI - Sublingual piroxicam in the management of postoperative pain after surgical removal of impacted mandibular third molar. AB - INTRODUCTION: Surgical removal of impacted mandibular third molar is one of the most commonly performed procedures in oral and maxillofacial surgical practice. The role of preoperative and postoperative medications for management of postoperative complications has been extensively evaluated. AIM: To assess the therapeutic effect of a single dose of 40 mg sublingual piroxicam (study group) vs 150 mg oral diclofenac (50 mg thrice a day) (control group) in patients undergoing surgical removal of impacted mandibular third molar. MATERIALS AND METHODS: A total of 100 patients with asymptomatic impacted mandibular third molars were randomized into two groups. One group received two 20-mg tablets of piroxicam once daily on the first and second postoperative days, followed by one 20-mg tablet on the third post-operative day. The other group received one tablet of diclofenac 50 mg orally thrice daily on the first, second, and third post operative days. Repeated extraoral examinations were done for continuous assessment of swelling, trismus, and reduction in pain. Overall impression of the treating physician and the patient regarding efficacy of study drugs were recorded at the end of the study. RESULTS: In the piroxicam group there was >50% reduction in pain on all three days postoperatively. The incidence of swelling and trismus was found to be higher in the control group as compared to the study group. Adverse events, such as gastrointestinal (GI) disturbances, were significantly higher in the diclofenac group (11%) as compared to the piroxicam group (0%). CONCLUSION: Two sublingual piroxicam 20 mg tablets once daily has better efficacy and tolerability profile than diclofenac 50 mg one tablet thrice daily in the management of pain after surgical removal of impacted mandibular third molar. PMID- 23649082 TI - Three-dimensional finite element analysis of immediate loading mini over denture implants with and without acrylonitrile O-ring. AB - AIM OF THE STUDY: The aim of the study was to check the stress absorbed by the bone around mini over-denture dental implant with and without acrylonitrile O ring under two different loading conditions. The initial stress absorbed by the implant plays a significant role in the success of the immediate loading implants. MATERIALS AND METHODS: A three-dimensional finite element analysis using Pro-E mechanical finite element software was used to check the stress absorbed by the bone with and without acrylonitrile O-ring. The implant and the mandible where modeled from the data obtained from C.T. scan and optical projector using reverse engineering process. Two different loading conditions of 80 N and 220 N were determined and the analysis was done. RESULTS: The result showed at lower loads (80 N), there was not much difference in the stress absorbed by the cancellous bone with or without acrylonitrile O-ring, but at higher loads (220), there was difference in the stress absorbed by the cancellous bone with (0.03508 Mpa) and without acrylonitrile O-ring (3.874 Mpa) which showed that significant stress was absorbed by the acrylonitrile O-ring. CONCLUSION: This study proves that higher loads during parafunctional movement were absorbed by the acrylonitrile O-ring increasing the success of the implants. PMID- 23649083 TI - Microbiology of the white coat in a dental operatory. AB - BACKGROUND: It remains important to have a thorough knowledge of the micro-flora harboring the white coats of doctors to minimize cross-contamination and improve patient safety by reducing the risk of nosocomial infections. This study presents the microbiological analysis of the white coats in clinical departments of a dental college and hospital. MATERIALS AND METHODS: The swabs for the study were taken from the white coats of undergraduate students posted in various clinical departments, interns, and the post-graduate students. The microbial contamination was studied by observing and recording the colony morphology on the culture plates, Gram's staining with light microscopic screening of the slides, and the biochemical characterization of the isolates using standard microbiology protocols. RESULTS: Microbiological analysis of swabs taken from the white coats in the dental operatory showed that 100% coats had bacterial contamination. Out of 30 swabs collected, 46 cultures were obtained. 50% cultures showed Gram positive cocci, making it the major microbial group contaminating the white coats in the dental operatory. CONCLUSION: The presented study highlights the fact that the white coats are a potential source of cross infection. The results of this study mandate a strict audit process and protocols to be set in place for preventing cross-contamination from the white coats in a dental operatory. PMID- 23649084 TI - Utilization of oral health care services among adults attending community outreach programs. AB - INTRODUCTION: Good oral health is a mirror of overall health and well-being. Oral health is determined by diet, oral hygiene practices, and the pattern of dental visits. Poor oral health has significant social and economic consequences. Outreach programs conducted by dental schools offer an opportunity for early diagnosis and treatment, dental health education, and institution of preventive measures. OBJECTIVE: To assess the utilization of oral healthcare services among adults attending outreach programs. MATERIALS AND METHODS: This study included 246 adults aged 18-55 years attending community outreach programs in and around Bangalore. Using a questionnaire we collected data on dental visits, perceived oral health status, reasons for seeking care, and barriers in seeking care. Statistical significance was assessed using the Chi-square test. RESULTS: In this sample, 28% had visited the dentist in the last 12 months. Males visited dentist more frequently than females. The main reason for a dental visit was for tooth extraction (11%), followed by restorative and endodontic treatment 6%. The main barriers to utilization of dental services were high cost (22%), inability to take time off from child care duties (19.5%), and fear of the dentist or dental tools (8.5%). CONCLUSION: The utilization of dental services in this population was poor. The majority of the dental visits were for treatment of acute symptoms rather than for preventive care. High cost was the main barrier to the utilization of dental services. Policies and programs should focus on these factors to decrease the burden of oral diseases and to improve quality of life among the socioeconomically disadvantaged. PMID- 23649085 TI - Stromal response in different histological grades of oral squamous cell carcinoma: a histochemical study. AB - OBJECTIVES: The aim of the study is to evaluate the connective tissue changes in different grades of Oral Squamous Cell Carcinoma (OSCC's) and the influence of these changes in predicting the biological behavior of these tumors. MATERIALS AND METHODS: A total of 39 cases of OSCC's and 6 sections of controls were examined using seven connective tissue special histochemical stains. RESULTS: Staining intensity of collagen, reticulin, acid mucins, fibrin, glycoproteins, sulfated mucins, elastic fibers around the tumor islands and within the connective tissue was observed. CONCLUSIONS: Tumor cells which grow progressively in the host stroma have the capacity to pre-empt and subvert the response of host, which is essential for their growth and spread. CLINICAL RELEVANCE: The reactive changes in the tumor stroma may alter the biological aggressiveness of oral cancer, and by incorporating this concept into a prognostic system, we may help to reflect the biologic diversity of oral cancer and predict its clinical outcomes. PMID- 23649086 TI - Metastatic follicular thyroid carcinoma to the mandible. AB - Metastatic tumors are of great significance since few cases may represent the only symptom of an undiscovered underlying malignancy. Metastatic tumors rarely metastasize to the oral region despite the fact that many common primary neoplasms frequently metastasize to bone. The true incidence of metastatic tumors in the bones of the jaw is unknown, as jaws are not always included in radiographic skeletal surveys for metastasis. Sometimes oral metastasis may be the first evidence of metastasis from its primary site. A case of metastatic follicular thyroid carcinoma to the mandible is presented here, along with the discussion of clinical and histological features. The present case not only emphasizes the importance of considering metastasis in the differential diagnosis of a radiolucent lesion in the mandible, but also emphasizes in the improvement of the overall survival rate and treatment results by an early detection of metastatic disease. PMID- 23649087 TI - Radiotherapy complications and their possible management in the head and neck region. AB - Oral complications from radiation to the head and neck or chemotherapy for any malignancy can compromise patients' health and quality of life and affect their ability to complete planned cancer treatment. For some patients the complications can be so debilitating that they may tolerate only lower doses of therapy, postpone scheduled treatments, or discontinue treatment entirely. Oral complications can also lead to serious systemic infections. Medically necessary oral care before, during, and after cancer treatment can prevent or reduce the incidence and severity of oral complications, enhancing both patient survival and quality of life. In the present article we present an overview of oral complications, and their possible management, after radiation therapy in the head and-neck region. PMID- 23649090 TI - Redox balance via lactate dehydrogenase is important for multiple stress resistance and virulence in Enterococcus faecalis. AB - Enterococcus faecalis is a highly stress resistant opportunistic pathogen. The intrinsic ruggedness of this bacterium is supposed to be the basis of its capacity to colonize the hostile environments of hospitals and to cause several kinds of infections. We show in this work that general resistance to very different environmental stresses depends on the ability of E. faecalis to maintain redox balance via lactate dehydrogenase (LDH). Furthermore, LDH deficient mutants are less successful than the wild type at colonizing host organs in a murine model of systemic infection. Taken together, our results, as well as those previously published for Staphylococcus aureus (A. R. Richardson, S. J. Libby, and F. C. Fang, Science 319:1672-1676, 2008), identify LDH as an attractive drug target. These drugs may have additional applications, as in the fight against glycopeptide antibiotic-resistant bacteria and even cancer. PMID- 23649089 TI - Hypoxia-inducible factor 1-regulated lysyl oxidase is involved in Staphylococcus aureus abscess formation. AB - Hypoxia-inducible factor 1 (HIF-1) is the key transcription factor involved in the adaptation of mammals to hypoxia and plays a crucial role in cancer angiogenesis. Recent evidence suggests a leading role for HIF-1 in various inflammatory and infectious diseases. Here we describe the role of HIF-1 in Staphylococcus aureus infections by investigating the HIF-1-dependent host cell response. For this purpose, transcriptional profiling of HIF-1alpha-deficient HepG2 and control cells, both infected with Staphylococcus aureus, was performed. Four hours after infection, the expression of 190 genes, 24 of which were regulated via HIF-1, was influenced. LOX (encoding lysyl oxidase) was one of the upregulated genes with a potential impact on the course of S. aureus infection. LOX is an amine oxidase required for biosynthetic cross-linking of extracellular matrix components. LOX was upregulated in vitro in different cell cultures infected with S. aureus and also in vivo, in kidney abscesses of mice intravenously infected with S. aureus and in clinical skin samples from patients with S. aureus infections. Inhibition of LOX by beta-aminopropionitrile (BAPN) did not affect the bacterial load in kidneys or blood but significantly influenced abscess morphology and collagenization. Our data provide evidence for a crucial role of HIF-1-regulated LOX in abscess formation. PMID- 23649091 TI - Human leukocyte antigens and cellular immune responses to anthrax vaccine adsorbed. AB - Interindividual variations in vaccine-induced immune responses are in part due to host genetic polymorphisms in the human leukocyte antigen (HLA) and other gene families. This study examined associations between HLA genotypes, haplotypes, and homozygosity and protective antigen (PA)-specific cellular immune responses in healthy subjects following immunization with Anthrax Vaccine Adsorbed (AVA). While limited associations were observed between individual HLA alleles or haplotypes and variable lymphocyte proliferative (LP) responses to AVA, analyses of homozygosity supported the hypothesis of a "heterozygote advantage." Individuals who were homozygous for any HLA locus demonstrated significantly lower PA-specific LP than subjects who were heterozygous at all eight loci (median stimulation indices [SI], 1.84 versus 2.95, P = 0.009). Similarly, we found that class I (HLA-A) and class II (HLA-DQA1 and HLA-DQB1) homozygosity was significantly associated with an overall decrease in LP compared with heterozygosity at those three loci. Specifically, individuals who were homozygous at these loci had significantly lower PA-specific LP than subjects heterozygous for HLA-A (median SI, 1.48 versus 2.13, P = 0.005), HLA-DQA1 (median SI, 1.75 versus 2.11, P = 0.007), and HLA-DQB1 (median SI, 1.48 versus 2.13, P = 0.002) loci, respectively. Finally, homozygosity at an increasing number (>= 4) of HLA loci was significantly correlated with a reduction in LP response (P < 0.001) in a dose-dependent manner. Additional studies are needed to reproduce these findings and determine whether HLA-heterozygous individuals generate stronger cellular immune response to other virulence factors (Bacillus anthracis LF and EF) than HLA-homozygous subjects. PMID- 23649093 TI - Bovine respiratory syncytial virus and Histophilus somni interaction at the alveolar barrier. AB - Our previous studies showed that Histophilus somni and bovine respiratory syncytial virus (BRSV) act synergistically in vivo to cause more severe bovine respiratory disease than either agent alone causes. Since H. somni surface and secreted immunoglobulin binding protein A (IbpA) causes retraction of bovine alveolar type 2 (BAT2) cells and invasion between BAT2 cells in vitro, we investigated mechanisms of BRSV-plus-H. somni infection at the alveolar barrier. BRSV treatment of BAT2 cells prior to treatment with IbpA-rich H. somni concentrated culture supernatant (CCS) resulted in increased BAT2 cell rounding and retraction compared to those with either treatment alone. This mimicked the increased alveolar cell thickening in calves experimentally infected with BRSV followed by H. somni compared to that in calves infected with BRSV or H. somni alone. BRSV-plus-H. somni CCS treatment of BAT2 cells also enhanced paracellular migration. The effect of matrix metalloproteinases (MMPs) was investigated as well because microarray analysis revealed that treatment with BRSV plus H. somni synergistically upregulated BAT2 cell expression of mmp1 and mmp3 compared to that in cells treated with either agent alone. Enzyme-linked immunosorbent assay (ELISA) confirmed that MMP1 and MMP3 protein levels were similarly upregulated. In collagen I and collagen IV (targets for MMP1 and MMP3, respectively) substrate zymography, digestion was increased with supernatants from dually treated BAT2 cells compared with those from singly treated cells. Enhanced breakdown of collagen IV in the basal lamina and of fibrillar collagen I in the adjacent interstitium in the dual infection may facilitate dissemination of H. somni infection. PMID- 23649092 TI - Novel synthetic (poly)glycerolphosphate-based antistaphylococcal conjugate vaccine. AB - Staphylococcal infections are a major source of global morbidity and mortality. Currently there exists no antistaphylococcal vaccine in clinical use. Previous animal studies suggested a possible role for purified lipoteichoic acid as a vaccine target for eliciting protective IgG to several Gram-positive pathogens. Since the highly conserved (poly)glycerolphosphate backbone of lipoteichoic acid is a major antigenic target of the humoral immune system during staphylococcal infections, we developed a synthetic method for producing glycerol phosphoramidites to create a covalent 10-mer of (poly)glycerolphosphate for potential use in a conjugate vaccine. We initially demonstrated that intact Staphylococcus aureus elicits murine CD4(+) T cell-dependent (poly)glycerolphosphate-specific IgM and IgG responses in vivo. Naive mice immunized with a covalent conjugate of (poly)glycerolphosphate and tetanus toxoid in alum plus CpG-oligodeoxynucleotides produced high secondary titers of serum (poly)glycerolphosphate-specific IgG. Sera from immunized mice enhanced opsonophagocytic killing of live Staphylococcus aureus in vitro. Mice actively immunized with the (poly)glycerolphosphate conjugate vaccine showed rapid clearance of staphylococcal bacteremia in vivo relative to mice similarly immunized with an irrelevant conjugate vaccine. In contrast to purified, natural lipoteichoic acid, the (poly)glycerolphosphate conjugate vaccine itself exhibited no detectable inflammatory activity. These data suggest that a synthetic (poly)glycerolphosphate-based conjugate vaccine will contribute to active protection against extracellular Gram-positive pathogens expressing this highly conserved backbone structure in their membrane-associated lipoteichoic acid. PMID- 23649094 TI - H-NS plays a role in expression of Acinetobacter baumannii virulence features. AB - Acinetobacter baumannii has become a major problem in the clinical setting with the prevalence of infections caused by multidrug-resistant strains on the increase. Nevertheless, only a limited number of molecular mechanisms involved in the success of A. baumannii as a human pathogen have been described. In this study, we examined the virulence features of a hypermotile derivative of A. baumannii strain ATCC 17978, which was found to display enhanced adherence to human pneumocytes and elevated levels of lethality toward Caenorhabditis elegans nematodes. Analysis of cellular lipids revealed modifications to the fatty acid composition, providing a possible explanation for the observed changes in hydrophobicity and subsequent alteration in adherence and motility. Comparison of the genome sequences of the hypermotile variant and parental strain revealed that an insertion sequence had disrupted an hns-like gene in the variant. This gene encodes a homologue of the histone-like nucleoid structuring (H-NS) protein, a known global transcriptional repressor. Transcriptome analysis identified the global effects of this mutation on gene expression, with major changes seen in the autotransporter Ata, a type VI secretion system, and a type I pilus cluster. Interestingly, isolation and analysis of a second independent hypermotile ATCC 17978 variant revealed a mutation to a residue within the DNA binding region of H NS. Taken together, these mutants indicate that the phenotypic and transcriptomic differences seen are due to loss of regulatory control effected by H-NS. PMID- 23649095 TI - Selenium status alters the immune response and expulsion of adult Heligmosomoides bakeri worms in mice. AB - Heligmosomoides bakeri is a nematode with parasitic development exclusively in the small intestine of infected mice that induces a potent STAT6-dependent Th2 immune response. We previously demonstrated that host protective expulsion of adult H. bakeri worms from a challenge infection was delayed in selenium (Se) deficient mice. In order to explore mechanisms associated with the delayed expulsion, 3-week-old female BALB/c mice were placed on a torula yeast-based diet with or without 0.2 ppm Se, and after 5 weeks, they were inoculated with H. bakeri infective third-stage larvae (L3s). Two weeks after inoculation, the mice were treated with an anthelmintic and then rested, reinoculated with L3s, and evaluated at various times after reinoculation. Analysis of gene expression in parasite-induced cysts and surrounding tissue isolated from the intestine of infected mice showed that the local-tissue Th2 response was decreased in Se deficient mice compared to that in Se-adequate mice. In addition, adult worms recovered from Se-deficient mice had higher ATP levels than worms from Se adequate mice, indicating greater metabolic activity in the face of a suboptimal Se-dependent local immune response. Notably, the process of worm expulsion was restored within 2 to 4 days after feeding a Se-adequate diet to Se-deficient mice. Expulsion was associated with an increased local expression of Th2 associated genes in the small intestine, intestinal glutathione peroxidase activity, secreted Relm-beta protein, anti-H. bakeri IgG1 production, and reduced worm fecundity and ATP-dependent metabolic activity. PMID- 23649096 TI - The Dot/Icm effector SdhA is necessary for virulence of Legionella pneumophila in Galleria mellonella and A/J mice. AB - Legionella pneumophila is an intracellular bacterium that resides within amoebae and macrophages in a specialized compartment termed the Legionella-containing vacuole (LCV). As well as providing an intracellular niche for replication, the LCV helps to prevent the release of bacterial components into the cytoplasm. Recognition of these components as danger signals by the host activates immune responses leading to clearance of the bacterium. Here, we examined the role of two important virulence factors of L. pneumophila, the potent danger signal flagellin and the translocated Dot/Icm type IVB secretion system effector SdhA, which is crucial to maintain LCV integrity, in the Galleria mellonella infection model. We demonstrate that flagellin expression does not contribute to virulence, replication, or induction of clearance mechanisms. Conversely, SdhA expression is important for virulence. We found that in the absence of SdhA, the LCV in hemocytes showed signs of instability and leakage. Furthermore, in contrast to wild-type L. pneumophila, a DeltasdhA mutant caused a transient depletion of hemocytes and reduced mortality. Analysis of the DeltasdhA mutant in the A/J mouse model also showed a significant replication defect. Together, our data underline the crucial importance of SdhA in infection across different model organisms. PMID- 23649097 TI - Biofilm formation avoids complement immunity and phagocytosis of Streptococcus pneumoniae. AB - Streptococcus pneumoniae is a frequent member of the microbiota of the human nasopharynx. Colonization of the nasopharyngeal tract is a first and necessary step in the infectious process and often involves the formation of sessile microbial communities by this human pathogen. The ability to grow and persist as biofilms is an advantage for many microorganisms, because biofilm-grown bacteria show reduced susceptibility to antimicrobial agents and hinder recognition by the immune system. The extent of host protection against biofilm-related pneumococcal disease has not been determined yet. Using pneumococcal strains growing as planktonic cultures or as biofilms, we have investigated the recognition of S. pneumoniae by the complement system and its interactions with human neutrophils. Deposition of C3b, the key complement component, was impaired on S. pneumoniae biofilms. In addition, binding of C-reactive protein and the complement component C1q to the pneumococcal surface was reduced in biofilm bacteria, demonstrating that pneumococcal biofilms avoid the activation of the classical complement pathway. In addition, recruitment of factor H, the downregulator of the alternative pathway, was enhanced by S. pneumoniae growing as biofilms. Our results also show that biofilm formation diverts the alternative complement pathway activation by a PspC-mediated mechanism. Furthermore, phagocytosis of pneumococcal biofilms was also impaired. The present study confirms that biofilm formation in S. pneumoniae is an efficient means of evading both the classical and the PspC-dependent alternative complement pathways the host immune system. PMID- 23649099 TI - Plasma volume expansion by 0.9% NaCl during sepsis/systemic inflammatory response syndrome, after hemorrhage, and during a normal state. AB - OBJECTIVE: The objective of this study was to determine the degree of plasma volume expansion by 0.9% NaCl in relation to the infused volume, in sepsis/systemic inflammatory response syndrome (SIRS), after a standardized hemorrhage, and in a normal condition. DESIGN: Prospective, randomized animal study. SETTING: The study was performed at a university hospital laboratory. SUBJECTS: Thirty anesthetized adult male rats were included in the study. INTERVENTIONS: The study was performed in three groups: a sepsis/SIRS group (the S group), in which sepsis/SIRS was induced by cecal ligation and incision; a hemorrhage group (the H group), in which the rats were left without intervention for 4 h and bled 8 mL/kg thereafter; and a group that was left without intervention (the N group). Then, 4 h after baseline, all three groups were given an infusion of 0.9% NaCl (32 mL/kg) for 15 min. Baseline was defined as the time point when the surgical preparation was finished. MEASUREMENTS AND MAIN RESULTS: Plasma volumes were measured using I-albumin dilution technique at baseline, after 4 h, and 20 min after the end of infusion. The plasma volume-expanding effect 20 min after end of infusion was 0.6% +/- 2.9% in the S group, 20% +/- 6.4% in the H group, and 12% +/- 11% in the N group, compared with just before start of infusion. CONCLUSIONS: The present study in rats showed that the plasma volume-expanding effect after an infusion of 0.9% NaCl was smaller in a septic/SIRS state than after hemorrhage and in a normal state. This indicates that the plasma volume-expanding effect of a crystalloid is dependent on pathophysiologic changes in sepsis/SIRS. PMID- 23649098 TI - Characteristics and outcomes of patients with vasoplegic versus tissue dysoxic septic shock. AB - BACKGROUND: The current consensus definition of septic shock requires hypotension after adequate fluid challenge or vasopressor requirement. Some patients with septic shock present with hypotension and hyperlactatemia greater than 2 mmol/L (tissue dysoxic shock), whereas others have hypotension alone with normal lactate (vasoplegic shock). OBJECTIVE: The objective of this study was to determine differences in outcomes of patients with tissue dysoxic versus vasoplegic septic shock. METHODS: This was a secondary analysis of a large, multicenter randomized controlled trial. Inclusion criteria were suspected infection, two or more systemic inflammatory response criteria, and systolic blood pressure less than 90 mmHg after a fluid bolus. Patients were categorized by presence of vasoplegic or tissue dysoxic shock. Demographics and Sequential Organ Failure Assessment scores were evaluated between the groups. The primary outcome was in-hospital mortality. RESULTS: A total of 247 patients were included, 90 patients with vasoplegic shock and 157 with tissue dysoxic shock. There were no significant differences in age, race, or sex between the vasoplegic and tissue dysoxic shock groups. The group with vasoplegic shock had a lower initial Sequential Organ Failure Assessment score than did the group with tissue dysoxic shock (5.5 vs. 7.0 points; P = 0.0002). The primary outcome of in-hospital mortality occurred in 8 (9%) of 90 patients with vasoplegic shock compared with 41 (26%) of 157 in the group with tissue dysoxic shock (proportion difference, 17%; 95% confidence interval, 7% 26%; P < 0.0001; log-rank test P = 0.02). After adjusting for confounders, tissue dysoxic shock remained an independent predictor of in-hospital mortality. CONCLUSIONS: In this analysis of patients with septic shock, we found a significant difference in in-hospital mortality between patients with vasoplegic versus tissue dysoxic septic shock. These findings suggest a need to consider these differences when designing future studies of septic shock therapies. PMID- 23649100 TI - Impact of high ratios of plasma-to-red cell concentrate on the incidence of acute respiratory distress syndrome in UK transfused combat casualties. AB - Trauma transfusion strategies, which incorporate balanced red-cell concentrate (RCC)-to-fresh frozen plasma (FFP) ratios, may be associated with improved survival in massively transfused patients. However, the use of this approach in nonmassively transfused patients has led to concern regarding an increase in acute respiratory distress syndrome (ARDS). The aim of this study was to assess the incidence of ARDS in transfused UK military casualties. All UK military casualties receiving an RCC transfusion within a 16-month period were identified from the UK Trauma Registry, and chest radiographs retrieved. If bilateral infiltrates were present, case notes were retrieved to calculate the PaO2/FIO2 ratio in accordance with the American-European Consensus Conference criteria. Patients were divided into massively transfused (>= 10 U/24 h) and nonmassively transfused (<10 U/24 h) receiving a high ratio (>= 0.75) or low (<0.75) RCC:FFP ratio. The primary outcome was the development of ARDS within 7 days of transfusion. Primary blast lung injury was excluded. Of 145 patients identified, 144 had records available for analysis with a median injury severity score of 21. The majority were injured by explosion (76%), and the remainder by gunshot (24%). There were 60 nonmassively transfused patients with 18 in the low and 42 in the high RCC:FFP ratio groups. Of the remaining 80 massively transfused patients, 11 were in the low and 73 were in the high-ratio groups. There was no difference in the incidence of ARDS between low- and high-ratio groups in either nonmassively transfused (22.2% vs. 9.5%; P = 0.232) or massively transfused (18.2% vs. 23.3%; P = 1.000) casualties. There was no statistically significant increase in the incidence of ARDS in UK casualties treated with high, compared with low, ratios of plasma to RCC. PMID- 23649101 TI - Neural repair and rehabilitation: Fibroblast-derived OPCs--hope for remyelination therapy? PMID- 23649103 TI - Double-faced gamma-Fe2O3||SiO2 nanohybrids: flame synthesis, in situ selective modification and highly interfacial activity. AB - Double-faced gamma-Fe2O3||SiO2 nanohybrids (NHs) and their in situ selective modification on silica faces with the 3-methacryloxypropyltrimethoxysilane molecules have been successfully prepared by a simple, rapid and scalable flame aerosol route. The double-faced NHs perfectly integrate magnetic hematite hemispheres and non-magnetic silica parts into an almost intact nanoparticle as a result of phase segregation during the preparation process. The unique feature allows us to easily manipulate these particles into one-dimensional chain-like nanostructures. On the other hand, in situ selectively modified double-faced gamma-Fe2O3||SiO2 NHs possess excellent interfacial activities, which can assemble into many interesting architectures, such as interfacial film, magnetic responsive capsules, novel magnetic liquid marbles and so forth. The modified NHs prefer to assemble at the interface of water-oil or oil-water systems. It is believed that the highly interfacial active NHs are not only beneficial for the development of interface reaction in a miniature reactor, but also very promising functional materials for other smart applications. PMID- 23649104 TI - The effectiveness of a near-infrared vascular imaging device to support intravenous cannulation in children with dark skin color: a cluster randomized clinical trial. AB - BACKGROUND: Poor vein visibility can make IV cannulation challenging in children with dark skin color. In the operating room, we studied the effectiveness of a near-infrared vascular imaging device (VascuLuminator) to facilitate IV cannulation in children with dark skin color. METHODS: In the operating room of a general hospital in Curacao, all consecutive children (0-15 years of age) requiring IV cannulation were included in a pragmatic cluster randomized clinical trial. The VascuLuminator was made available to anesthesiologists at the operating complex in randomized clusters of 1 week. RESULTS: Success at first attempt was 63% (27/43, 95% confidence interval [CI], 47%-77%) in the VascuLuminator group vs 51% (23 of 45 patients, 95% CI, 36%-66%) in the control group (P = 0.27). Median time to successful cannulation was 53 seconds (interquartile range: 34-154) in the VascuLuminator group and 68 seconds (interquartile range: 40-159) in the control group (P = 0.54), and hazard ratio was 1.12 (95% CI, 0.73-1.71). CONCLUSION: The VascuLuminator has limited value in improving success at first attempt of facilitating IV cannulation in children with dark skin color. PMID- 23649105 TI - Pressure-induced structural phase transition and equation of state of LiTaO3. AB - Using in situ high-pressure x-ray diffraction and ab initio techniques, a high pressure structure of LiTaO3 has been determined to be an orthorhombic phase with the space group Pnma. At ambient temperature, the transition pressure from the R3c phase (the ordinary phase at ambient pressure and temperature) to the Pnma phase is about 33.0 GPa and the phase transition is reversible. This phase transition can be reproduced qualitatively by ab initio calculations, but with a lower transition pressure of 19.9 GPa. The equation of state of LiTaO3 is also reported. PMID- 23649102 TI - The history and future of telestroke. AB - This Review focuses on the application of telemedicine to the care of patients with acute stroke (telestroke), from the prehospital setting through hospitalization. Telestroke has grown remarkably in the past decade and has entered mainstream care for patients with acute stroke. Telestroke enables such patients to be remotely evaluated, thereby allowing optimal treatment and management even in clinically underserved areas and removing geographical disparities in access to expert care. Telestroke systems enable thrombolytic treatment to be administered in community and rural hospitals, and facilitate the appropriate transfer of patients with complex conditions (who require critical care services and neurosurgical or intra-arterial interventions) to a comprehensive stroke centre. Decision-analytic models show that telestroke is cost-effective from both a societal and a hospital perspective. Limitations to the use of telestroke in the USA include the need for state licensing and credentialling of physicians, and the technical requirements of a minimum network bandwidth (which is still lacking in some regions). However, the opportunity exists for telestroke to become the backbone of an electronic stroke unit and to be used to identify and enrol patients in clinical trials of acute stroke treatment. The use of telestroke in the prehospital setting has been hampered by limited telecommunication availability, but these problems might be mitigated by fourth-generation cellular data networks. PMID- 23649107 TI - Efficient isonitrile hydration through encapsulation within a hexameric self assembled capsule and selective inhibition by a photo-controllable competitive guest. AB - Catalytic hydration of neutral isonitriles to yield the corresponding N formylamides was achieved by reversible encapsulation in a self-assembled hexameric resorcin[4]arene capsule. Encapsulation of a photochromic dithienylethene bis-cation provides different levels of competitive inhibition depending on the geometry assumed by the cationic inhibitor. PMID- 23649106 TI - Isolation and characterization of epithelial and myogenic cells by "fishing" for the morphologically distinct cell types in rat primary periodontal ligament cultures. AB - The periodontal ligament (PDL) contains various cell populations and plays a central role in the maintenance, repair, and regeneration of the periodontium, i.e., tooth-supporting structures. Because primary cells isolated from PDL tissue are heterogeneous, the establishment of an effective isolation method for cells of interest is desired. In the present study, two morphologically distinct cell types were identified in confluent primary cultures derived from rat PDL. To isolate these cell populations, a small piece of filter paper soaked with trypsin EDTA was placed directly onto the target cell population, enabling the cells to detach from the culture dish. The filter papers were then transferred into fresh culture dishes to establish outgrowth cultures; these two steps constitute the "cell fishing" method. The "fished" cell types were propagated and subcultured for further analyses. In morphological evaluation, immunocytochemical analyses, and reverse transcription-polymerase chain reaction, the isolated cells exhibited a polygonal appearance or a mono- or multinucleated appearance, with a high cytoplasm-to-nucleus ratio, leading to their being characterized as epithelial or myogenic cell populations, respectively. Surprisingly, a notable proportion of the multinuclear cells in the primary and subsequent isolated cultures demonstrated dramatic, spontaneous contractions, a feature typical of skeletal muscle cells. Finally, the isolated cell populations maintained a normal karyotype with a diploid chromosomal number. These results demonstrated that physiological epithelial and skeletal muscle cells can be obtained from primary PDL cultures without artificial induction using growth factors or chemicals, and can be propagated as individual lineage-committed cell populations; the populations consisted of differentiated and progenitor cells that maintained chromosomal stability. This simple, classical culture procedure provides new insights into the biological properties of PDL cells, which are potentially important for the differentiation of tissue or somatic stem cells and for the development of future cell-based therapies for dental and muscular diseases. PMID- 23649108 TI - Semiology of temporal lobe epilepsies. AB - Temporal lobe epilepsies (TLE) represent the majority of the partial symptomatic/cryptogenic epilepsies. Excellent results of epilepsy surgery in well selected patients have encouraged a search for localizing and lateralizing signs that could assist in the identification of the best surgical candidates. Seizure types in TLE include simple partial, complex partial and secondarily generalized seizures. Temporal lobe seizures most often arise in the amygdalo-hippocampal region. More than 90% of patients with mesial TLE report an aura, most commonly an epigastric sensation that often has a rising character. Other autonomic symptoms, psychic symptoms, and certain sensory phenomena (such as olfactory) also occur. The complex partial seizures of mesial TLE often involve motor arrest, oroalimentary automatisms or non-specific extremity automatisms at onset. Ictal manifestations that have lateralizing value include dystonic posturing (contralateral), early head turning (usually ipsilateral), and adversive head turning in transition to generalization (contralateral). Well-formed ictal language favors right temporal localization. Ictal vomiting, spitting, and drinking tend to be right sided. The duration of TLE complex partial seizures is generally greater than one minute and postictal confusion usually occurs. When postictal aphasia is noted a left-sided lateralization is favored. A lateral temporal onset is less common in TLE, and is most often suggested by an auditory aura. Somatosensory and visual auras are highly unlikely with TLE, and suggest neocortical extratemporal localization. A cephalic aura is non-specific, but is more common in frontal lobe epilepsy. PMID- 23649109 TI - Pervasive developmental disorders. Etiological, diagnostic and treatment conundrum. AB - Pervasive developmental disorders are severe childhood psychiatric disorders that afflict millions of children worldwide. Despite availability of tremendous data on these disorders, there is a paucity of information among clinicians including mental health professionals. Pervasive developmental disorders, caused by multiple neurobiological and environmental etiologies, are characterized mainly by impaired social interactions, impaired communication and language, and abnormal repetitive interests and behaviors. A clear understanding of the underlying pathophysiological mechanisms of pervasive developmental disorders requires routine developmental surveillance, extensive clinical diagnostic workup and laboratory investigations. The children with pervasive developmental disorders need a multimodal treatment approach. In Arabian Gulf countries, research is warranted to explore different aspects of these disorders. PMID- 23649110 TI - Comparative evaluation of multiple choice question formats. Introducing a knowledge score. AB - OBJECTIVE: Over the last 6 years different multiple choice question (MCQ) formats have been used in postgraduate examinations for trainees in psychiatry. In phase 1 - K-type True/False (T/F) items with negative marking; in phase 2 combined T/F and type-A one-best answer (OBA) questions without negative marking; in phase 3 exclusively OBA without negative marking. The study compares the gross scores (GS) obtained with different MCQ formats, and introduces knowledge score (KS). METHODS: The study was conducted in the Saudi Council for Health Specialties, Riyadh, Kingdom of Saudi Arabia from 1996 to 2002. The mean percentile scores obtained by all postgraduate trainees sitting any Part I or Part II Saudi Board Examination in Psychiatry were subjected to a comparative analysis. RESULTS: A total of 110 candidates sat 18 examinations returning 143 papers containing a total of 32,375 MCQ options. Phase 1 generated lowest overall mean GS (47.8%), phase 3 occupied an intermediate position (53.1%) and phase 2 produced the highest score (68.3%). The KS, to the contrary, generated strikingly similar results for all the 3 phases (47.8, 50.5 and 49.5%) indicating that the marked differences in the GS were probably related to benefits obtained from guessing in the absence of negative marking. In this respect, the OBA produced considerably higher KS scores than the T/F, presumably due to its facilitating extra benefits from cueing, partial knowledge and judgement. CONCLUSION: Different MCQ formats generate dissimilar quantitative results. The OBA format seems superior to the T/F format in crediting judgement and application of knowledge. In non-negatively marked MCQ tests, the suggested KS provides results comparable to those of negatively marked tests. Pass marks in MCQ tests should be calibrated according to the used format. PMID- 23649111 TI - Use of methylprednisolone in acute spinal injury. AB - OBJECTIVE: To obtain an appraisal for the use of methylprednisolone (MP) in the early management of acute spinal cord injury (SCI) in our health system and the attitude to its use. METHODS: A printed questionnaire on MP in acute SCI was distributed to all major spinal and neurosurgical centers in Riyadh, Kingdom of Saudi Arabia between October and November 2001. RESULTS: A total of 31 replies were collected for statistical analysis. There were 23 replies from doctors (74%) who see 5 or more cases of acute SCI per year. Sixteen doctors (53%) use MP in acute SCI (National Acute Spinal Cord Injury Studies [NASCIS] protocol) regularly, 11 (37%) use it occasionally and 3 (10%) never use it. The use of MP in acute SCI was suggested as a standard of care by 16%, recommended only by 48% and considered optional by 35%. In addition, a review of the literature on the results of the NASCIS I, II and III was conducted. CONCLUSION: Our results confirm the diversities in clinical practice regarding the use of MP in acute SCI. They also raise the issue of the need for specialized centers in spinal trauma with a unified protocol for treatment throughout the Kingdom. PMID- 23649112 TI - Magnetic resonance imaging of normal lumbar intervertebral foraminal height. AB - OBJECTIVE: To study the pattern and changes of lumbar intervertebral foraminal heights in an asymptomatic Jordanian sample relative to age, sex, level, and correlate values with midpoint vertebral and disc heights. METHODS: One hundred and fifty-three patients (87 male and 66 female) were selected during the study period. The study was carried out at the Jordan University Hospital, Amman, Jordan from June 1999 to June 2000. Parasagittal magnetic resonance images were used to measure intervertebral foraminal heights at all lumbar levels. Values were statistically analyzed and the significance of differences in the means of foraminal heights at different levels in every age group and among age groups was determined. Foraminal height indices and correlation coefficients with midpoint vertebral and disc heights were calculated. RESULTS: The study revealed that the mean foraminal height measured is 20.9 mm +/-1.7 with a range of 17.1-24 mm. Foraminal heights increased significantly in a craniocaudal pattern reaching a maximum at lumber (L)2/3 in females and at L3/4 in males followed by continuous significant decrease reaching their minimum at L5/sacral (S) 1. In relation to age, foraminal heights decreased significantly in females reaching their minimum in the 7th decade. In males, foraminal heights at L3/4 until L5/S1 increased significantly reaching their maximum in the 5th decade followed by significant decrease reaching their minimum in the 7th decade. Foraminal height indices remained relatively constant. A fair degree of correlation of foraminal heights with intervertebral disc heights and vertebral body heights was evident. CONCLUSION: Foraminal heights show different level- and age-dependent characteristic pattern of change between asymptomatic males and females. Changes of foraminal heights seem to directly reflect changes of vertebral body heights. These changes are considered normal age-dependent changes, and are discussed under consideration of adaptation to physical activity and changing hormonal levels. PMID- 23649113 TI - Clinical profile of myasthenia gravis in the Sultanate of Oman. AB - OBJECTIVE: Clinical study and follow up of myasthenia gravis patients in Oman. METHODS: Follow up of 50 consecutive myasthenia gravis patients referred to the Sultan Qaboos University Hospital, Oman for a median period of 3 years from 1997 to 2000. We based the diagnosis on the clinical picture, repetitive nerve stimulation tests and edrophonium test. We performed a computerized tomography scan of the chest and anti-acetylcholine receptor antibodies. We reviewed the results of immuno modulatory treatment including thymectomy and compared these with other studies RESULTS: Of 50 patients, 6 had purely ocular myasthenia. Of the 44 with generalized myasthenia, 28 had bulbar involvement and 12 required ventilatory support. Eight out of 29 thymectomized patients had drug free remission after 2 years. There was worsening of myasthenic symptoms in only one out of 8 pregnancies and deliveries. CONCLUSION: Bulbar and ventilatory involvement are more common in our series as compared with western data. Pregnancy and delivery were well tolerated. PMID- 23649114 TI - Electromyographic changes in thyrotoxicosis. AB - OBJECTIVE: To document electromyographic (EMG) changes in thyrotoxic patients, and to categorize the type of myopathic process in thyrotoxicosis. METHODS: This case control study was designed to show the EMG changes in thyrotoxic patients and to compare these findings with that of normal aged matched controls to show the significance of these changes in thyrotoxic patients. Student's test was applied on the results and P value was extracted. Subjects in this study were chosen according to certain criteria depending mainly on their blood level of thyroid hormone (triiodothyronine and thyroxine) and thyrotropin. All of them are thyrotoxic patients, with age range between 15-45 years. There were 25 patients, 15 female and 10 male. Another 25 subjects of the same age and sex were chosen as normal controls. Patients with features of myopathy or neuropathy from diseases other than thyrotoxicosis were excluded carefully from studied patients and the normal controls. RESULTS: The EMG findings in thyrotoxic patients were as follows: No spontaneous activities in the proximal muscles (deltoid and in rectus femoris muscles). The amplitude of the motor unit action potentials ranged between 200-800 microv with a mean of 488.8+/-159.3 microv in the deltoid muscle, while the amplitude of the action potential in rectus femoris muscle in thyrotoxic patients ranged between 350-900 microv. In abductor pollicis brevis muscle the action potential amplitude in thyrotoxic patients ranged between 500 2150 microv, there was significant difference between thyrotoxic patients and normal controls. The duration of the motor unit potential in thyrotoxic patients ranged between 7-11.5 msec with a mean of 8.51+/-1.24 msec in the deltoid muscle, slightly higher figures in rectus femoris muscle, indicating significant difference in the duration of action potential between patients and normal controls. The other parameters of the EMG study indicate a myopathic process involving proximal muscles in 76% of thyrotoxic patients and a neuropathic process involving distal muscles in 28% of thyrotoxic patients. CONCLUSION: Thyrotoxicosis involves proximal muscles more than distal muscles. The myopathic process in thyrotoxicosis can be observed clearly in the EMG study of the proximal muscles. The EMG findings in thyrotoxic myopathy includes short duration polyphasic potentials with early recruitment full interference pattern. The distal muscles in thyrotoxic patients may show EMG findings of a rather neuropathic process. PMID- 23649115 TI - Autonomic dysfunction in multiple sclerosis. AB - OBJECTIVE: Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system. Autonomic dysfunction in MS patients may cause significant morbidity. The aim of this controlled cross sectional study was to investigate the prevalence, pattern and severity of autonomic dysfunction in Iraqi MS patients and to correlate them with patient's age, disease course, duration and severity. METHODS: Fifty-five patients with clinically definite MS according to Poser's criteria attending Baghdad MS clinic at Baghdad Teaching Hospital were studied between July 2000 and August 2001. Each patient was assessed according to a detailed protocol paper. Expanded disability status scale was used to assess the severity of the disease. The severity of autonomic symptoms was classified according to autonomic nervous system disability scale (ANSDS). Five standardized autonomic cardiovascular (Ewing) tests were performed for every patient which included: heart rate responses to deep breathing, Valsalva maneuver and standing, and blood pressure responses to standing and sustained hand grip. Forty matched healthy subjects were studied as a control group who were assessed with the same protocol paper, ANSDS and Ewing tests. RESULTS: Autonomic symptoms were significantly more prevalent in MS patients than in the controls. Cardiovascular, urinary and gastrointestinal symptoms were highly prevalent. The severity of the different autonomic symptoms as assessed by ANSDS, were higher in the patients than the controls. All 5 Ewing tests in the patients showed highly significant abnormal results as compared to those of the control. Definite parasympathetic derangement was found in 45.5% of the patients while combined sympathetic and parasympathetic derangements were found in 34.5% of the patients. There were significant correlations between the finding of definite autonomic dysfunctions and the age of the patients at the time of assessment and the duration of the disease. CONCLUSION: Autonomic dysfunctions as assessed by a formal interview, ANSDS and by Ewing tests were common in Iraqi MS patients. Careful attention to autonomic disturbances should be considered in the routine evaluation of MS patients which might help in improving their quality of life. PMID- 23649116 TI - Mental health training in primary care. Impact on physicians knowledge. AB - OBJECTIVE: The objective of this study was to measure changes in the Primary Health Care (PHC) physicians' knowledge towards mental illnesses after a short term training course. METHODS: The interventive study consisted of a sample of 31 PHC physicians randomly selected from different PHC centers in Eastern Saudi Arabia. The physicians were exposed to a 4-day intensive training course in mental illnesses in June 1999. They were assessed using multiple choice questions testing before (pre-test) and after (post-test) to assess their knowledge regarding mental illnesses. RESULTS: The analysis of the accumulated data indicated that there was a significant improvement in the PHC physicians' knowledge of mental illnesses after the course (p<0.0001). The effect of recall bias was excluded in the post-test evaluation. In addition, multiple regression analysis indicated that the undergraduate psychiatric training courses had a positive contribution in both pre- and post-tests. CONCLUSION: The authors surmised that a mental training course could improve the knowledge base of PHC physicians. Furthermore, by giving substantial weight to the undergraduate and internship psychiatric training might improve the delivery of mental health services at the PHC level. PMID- 23649117 TI - Hemophilus influenzae serotype-b meningitis in an adult immunocompetent patient. AB - We present a case of meningitis caused by Hemophilus influenzae type-b in an immunocompetent 41-year-old Saudi lady. The patient was successfully treated with Ceftriaxone for 10 days. A review of Hemophilus influenzae meningitis in adults and the impact of conjugated vaccine on the epidemiology of the disease are given. PMID- 23649118 TI - Neonatal cerebral infarction presented with limb ischemia. AB - Cerebral infarction of newborn infants is a rare condition. It remains the least predictable etiology of neonatal seizures, and the appreciation of its occurrence among physicians needs to be re-addressed. The most common presenting feature is seizure. We report 2 full term newborn infants who developed middle cerebral infarction. These infants presented primarily with ischemic limbs for several hours before the evolution of seizures. PMID- 23649119 TI - Huge occipital myxomatous plexiform neurofibroma in the absence of neurofibromatosis. AB - A case of huge occipital myxomatous plexiform neurofibroma is presented. The lesion slowly enlarged since childhood and was associated with suboccipital bone hypoplasia. At operation the lesion was clearly originating from the occipital nerve and was totally excised. The case represents a rare occurrence of occipital myxomatous plexiform neurofibroma and suboccipital bone hypoplasia in the absence of evidence of neurofibromatosis. PMID- 23649120 TI - Gilles de la Tourette syndrome treated effectively with clozapine. AB - A report of Gilles de la Tourette syndrome in a 16-year-old male and a 20-year old female from the Kingdom of Saudi Arabia, illustrating difficulties in diagnosis, comorbidity and management. A successful trial of clozapine therapy after failure of conventional treatments is reported over a period of more than 2 years and discussed. PMID- 23649122 TI - Atrial septal aneurysm and stroke. PMID- 23649121 TI - Unusual presentation of echinococcal cysts. AB - We report a case of echinococcal disease affecting the brain and the kidney. The case is unusual because of multiplicity of the intracerebral lesion and sparing of the liver and lungs. The intracerebral lesion was presented with epileptic convulsions. This was successfully treated surgically. Subsequently renal echinococcal cysts were identified. These were treated by partial nephrectomy due to the location of the cysts. The patient is disease free at 8 years. PMID- 23649123 TI - Cognitive effects of deep brain stimulation for essential tremor: evaluation at 1 and 6 years. AB - Only a few studies have explored cognitive changes with deep brain stimulation (DBS) in patients with essential tremor (ET). Furthermore, the cognitive effects after years of electrical stimulation are unknown. Assessing the impact of stereotactic electrode implantation and the actual electrical stimulation on cognition in patients with ET in the short and long term is of interest, because DBS is increasingly applied and can offer deeper insight into human brain functions. We examined nine ET patients before surgery (PRE-SURGERY), and 1 and 6 years thereafter with DBS switched on (DBS-ON) and off (DBS-OFF). Standardized neuropsychological tests and reaction time tests were applied. There were no differences in tasks of verbal fluency, memory, and executive and intellectual functions comparing PRE-SURGERY, DBS-ON, and DBS-OFF at 1 and 6 years post surgery. Imaging data revealed that the dorsolateral prefrontal cortex and mamillo-thalamic tracts crucial for cognitive functioning were spared by electrode implantation. Additionally, with electrodes targeting the thalamus and adjacent subthalamic area, the actual electrical stimulation did not affect neuropsychological functioning. However, lesions caused by electrode implantation led to an increase in simple reaction time, while the actual electrical stimulation restored impaired reaction time. This is the second largest study of neuropsychological functioning in patients with ET treated with DBS, and the first covering a neuropsychological long-term follow-up over 6 years. Neither stereotactic surgery nor electrical stimulation affected higher cognitive processes. This study proposes that cerebello-thalamo-cortical pathways in humans are involved in tasks of simple reaction time. PMID- 23649124 TI - Inhibition of protein synthesis or mTOR in the basolateral amygdala blocks retrieval-induced memory strengthening. AB - Fear memory retrieval can lead to either reconsolidation (accompanied or not by strengthening of the memory trace) or extinction. Here, we show that non reinforced retrieval of inhibitory avoidance (IA) conditioning can induce memory strengthening assessed in a subsequent retention test trial. Infusion of the protein synthesis inhibitor cycloheximide or the mTOR inhibitor rapamycin into the rat basolateral complex of the amygdala (BLA) after a reactivation (retrieval) session impaired retrieval-induced strengthening. Intra-BLA infusion of the mRNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) after retrieval had no effect. These findings provide the first evidence suggesting that non-reinforced IA retrieval can lead to memory strengthening through a mechanism dependent on protein synthesis and mTOR activity in the BLA. PMID- 23649125 TI - Percutaneous treatment of bladder stones in children: 10 years experience, is blind access safe? AB - PURPOSE: Bladder stones are more commonly found in children from developing countries. Open cystolithotomy or transurethral cystolithalopaxy are the traditional treatments but a percutaneous approach has been advocated. We present our experience with percutaneous cystolithotomy in children with bladder stones without any ultrasonic or fluoroscopic guidance. MATERIALS AND METHOD: From April 2001 to October 2011, a total of 147 children (135 boys and 12 girls) with a mean (range) age of 4.07 (1-12.5) years underwent percutaneous cystolithotripsy (PCCL). The mean (range) stone diameter was 2.74 (0.8-5) cm. 138 children (94 %) had a solitary stone while nine (6 %) had more than one stone. The main component of the stones was calcium oxalate in 70 patients (48.6 %). RESULTS: All children were stone-free after one PCCL; no recurrent stones developed. The mean (range) PCCL procedure time was 29.6 (12 to 48) min and intraoperative blood loss was scant. Perioperative complications were few. The mean (range) hospital stay was 1.2 (1-3) days. CONCLUSIONS: Blind access PCCL (without any ultrasonic or fluoroscopic guidance) is a facile and safe approach for removing stones in the pediatric bladder stones. Advantages include the lack of ionizing radiation, no need for opacification by iodine contrast media and low relative cost. We recommend this minimally invasive technique for management of large bladder stones (larger than 1 cm) in children. To our knowledge, this is the largest single-center series reported on percutaneous cystolithotripsy of endemic bladder stones in children. PMID- 23649126 TI - Attending rounds: where do we go from here?: comment on "Attending rounds in the current era". PMID- 23649127 TI - Reducing sequence artifacts in amplicon-based massively parallel sequencing of formalin-fixed paraffin-embedded DNA by enzymatic depletion of uracil-containing templates. AB - BACKGROUND: Formalin-fixed, paraffin-embedded (FFPE) tissues are routinely used for detecting mutational biomarkers in patients with cancer. A previous intractable challenge with FFPE DNA in genetic testing has been the high number of artifactual single-nucleotide changes (SNCs), particularly for the detection of low-level mutations. Pretreatment of FFPE DNA with uracil-DNA glycosylase (UDG) can markedly reduce these C:G>T:A SNCs with a small panel of amplicons. This procedure has implications for massively parallel sequencing approaches to mutation detection from DNA. We investigated whether sequence artifacts were problematic in amplicon-based massively parallel sequencing and what effect UDG pretreatment had on reducing these artifacts. METHODS: We amplified selected amplicons from lung cancer FFPE DNAs using the TruSeq Cancer Panel. SNCs occurring at a frequency <10% were considered most likely to represent sequence artifacts and were enumerated for both UDG-treated and -untreated DNAs. RESULTS: Massively parallel sequencing of FFPE DNA samples showed multiple SNCs, predominantly C:G>T:A changes, with a significant proportion occurring above the background sequencing error (defined as 1%). UDG pretreatment markedly reduced C:G>T:A SNCs without affecting the detection of true somatic mutations. However, C:G>T:A changes within CpG dinucleotides were often resistant to the UDG treatment as a consequence of 5-methyl cytosine being deaminated to thymine rather than uracil. CONCLUSIONS: UDG pretreatment greatly facilitates the accurate discrimination of mutations in FFPE samples by use of amplicon-based approaches. This is particularly important when working with samples with low tumor purity or for the assessment of mutational heterogeneity in tumors. PMID- 23649128 TI - The importance of commutability of reference materials used as calibrators: the example of ceruloplasmin. AB - BACKGROUND: Different methods for ceruloplasmin tend to give different results in external quality assessment schemes. During the production of the certified reference material ERM-DA470k/IFCC discrepant measurement results were also found for ceruloplasmin measured with different methods, and consequently the protein could not be certified in the material. METHODS: We performed a commutability study with 30 serum samples and the reference materials ERM-DA470, ERM DA470k/IFCC, and ERM-DA472/IFCC, using 6 different methods. Data were analyzed according to the CLSI Guideline C53-A to assess whether the reference materials had the same behavior as the serum samples with respect to measurement results obtained with combinations of the methods used. RESULTS: Measurement results from different methods showed a good linear correlation for the serum samples. ERM DA470 showed marked noncommutability for certain combinations of methods. ERM DA470k/IFCC and ERM-DA472/IFCC were commutable for more combinations of methods. The lack of commutability of ERM-DA470 for certain combinations of methods correlates with results from the UK National External Quality Assessment Service showing discrepancies between results from these methods. For serum stored in the presence of sodium azide the results from different methods are essentially equivalent. CONCLUSIONS: Ceruloplasmin in ERM-DA470 is a fully documented example of a situation in which, due to lack of commutability, the use of a common material for calibration did not lead to harmonization . PMID- 23649129 TI - Improving MEG performance with additional tangential sensors. AB - Recently, the signal space separation (SSS) method, based on the multipole expansion of the magnetic field, has become increasingly important in magnetoencephalography (MEG). Theoretical arguments and simulations suggest that increasing the asymmetry of the MEG sensor array from the traditional, rather symmetric geometry can significantly improve the performance of the method. To test this concept, we first simulated addition of tangentially oriented standard sensor elements to the existing 306-channel Elekta Neuromag sensor array, and evaluated and optimized the performance of the new sensor configuration. Based on the simulation results, we then constructed a prototype device with 18 additional tangential triple-sensor elements and a total of 360 channels. The experimental results from the prototype are largely in agreement with the simulations. In application of the spatial SSS method, the 360-channel device shows an approximately 100% increase in software shielding capability, while residual reconstruction noise of evoked responses is decreased by 20%. Further, the new device eliminates the need for regularization while applying the SSS method. In conclusion, we have demonstrated in practice the benefit of reducing the symmetry of the MEG array, without the need for a complete redesign. PMID- 23649130 TI - Temperature measurement methods during direct heat arterial tissue fusion. AB - Fusion of biological tissues through direct and indirect heating is a growing area of medical research, yet there are still major gaps in understanding this procedure. Several companies have developed devices which fuse blood vessels, but little is known about the tissue's response to the stimuli. The need for accurate measurements of tissue behavior during tissue fusion is essential for the continued development and improvement of energy delivery devices. An experimental study was performed to measure the temperatures experienced during tissue fusion and the resulting burst pressure of the fused arteries. An array of thermocouples was placed in the lumen of a porcine splenic artery segment and sealed using a ConMed Altrus thermal fusion device. The temperatures within the tissue, in the device, and at the tissue-device interface were recorded. These measurements were then analyzed to calculate the temperature profile in the lumen of the artery. The temperature in the artery at the site of tissue fusion was measured to range from 142 to 163 degrees C using the ConMed Altrus. The corresponding burst pressure for arteries fused at this temperature was measured as 416 +/- 79 mmHg. This study represents the first known experimental measurement of temperature at the site of vessel sealing found in the literature. PMID- 23649131 TI - Debulking from within: a robotic steerable cannula for intracerebral hemorrhage evacuation. AB - New approaches to intracerebral hemorrhage management are motivated by its high incidence and 40% mortality rate. Surgery is sometimes attempted to decompress the brain, although patient outcomes are similar regardless of whether surgery occurs. We hypothesize that surgical decompression is not more effective because current open surgical techniques disrupt healthy brain tissue to access the clot formed by the hemorrhage, offsetting the benefits of surgery. To address this, we propose a less invasive needle-based approach in which the clot is debulked from within using a superelastic, precurved aspiration cannula that is deployed from a needle. The tip of this aspiration cannula is controlled by coordinated insertion and retraction of the cannula and needle, as well as axial rotation of the cannula. We describe the design of a sterilizable and biocompatible robot that can control the three degrees of freedom of the needle and cannula. Image guidance is achieved by adapting an approach originally developed for brain biopsy. We provide an optimization method for the selection of the precurvatures of one or more sequentially used aspiration cannulas to maximize hemorrhage evacuation, based on preoperative medical image data. In vitro experiments demonstrate the feasibility of evacuating 83-92% of hemorrhage volume, depending on the number of tubes and deployment method used. PMID- 23649132 TI - Electrodes for long-term esophageal electrocardiography. AB - The emerging application of long-term and high-quality ECG recording requires alternative electrodes to improve the signal quality and recording capability of surface skin electrodes. The esophageal ECG has the potential to overcome these limitations but necessitates novel recorder and lead designs. The electrode material is of particular interest, since the material has to ensure conflicting requirements like excellent biopotential recording properties and inertness. To this end, novel electrode materials like PEDOT and silver-PDMS as well as established electrode materials such as stainless steel, platinum, gold, iridium oxide, titanium nitride, and glassy carbon were investigated by long-term electrochemical impedance spectroscopy and model-based signal analysis using the derived in vitro interfacial properties in conjunction with a dedicated ECG amplifier. The results of this novel approach show that titanium nitride and iridium oxide featuring microstructured surfaces did not degrade when exposed to artificial acidic saliva. These materials provide low electrode potential drifts and insignificant signal distortion superior to surface skin electrodes making them compatible with accepted standards for ambulatory ECG. They are superior to the noble and polarizable metals such as platinum, silver, and gold that induced more signal distortions and are superior to esophageal stainless steel electrodes that corrode in artificial saliva. The study provides rigorous criteria for the selection of electrode materials for prolonged ECG recording by combining long term in vitro electrode material properties with ECG signal quality assessment. PMID- 23649134 TI - Hypertension: the prevention paradox. PMID- 23649135 TI - Gender-violence and health care: How health system can step in. AB - Gender-violence also known as domestic violence, domestic abuse, spousal abuse or intimate partner violence, can be broadly defined as a pattern of abusive behaviors by one or both partners in an intimate relationship such as marriage, dating, family, friends or cohabitation. It can manifest as physical aggression, sexual abuse, emotional abuse, intimidation, stalking and economic and food deprivation. In most countries gender violence is a crime; though scope of the domestic or gender violence act and severity of punishment varies considerably between the countries. PMID- 23649136 TI - An assessment of hepatitis B vaccine introduction in India: Lessons for roll out and scale up of new vaccines in immunization programs. AB - BACKGROUND: Hepatitis B vaccine was introduced in the Universal Immunization Program (UIP) of 10 states of India in the year 2007-08. This assessment was planned and conducted to ascertain the reasons for low reported coverage of Hepatitis B (Hep B) vaccine in comparison of similarly timed diphtheria, pertussis, and tetanus (DPT) vaccine; to identify operational and programmatic challenges in new vaccine introductions, and to derive lessons for scale up of Hep B vaccination (or for introduction of any new vaccine) in UIP of India. MATERIALS AND METHODS: Purposive sampling with both quantitative and qualitative data collection. Two districts each were purposively selected from 5 of the 10 states, which introduced Hep B vaccine, in the year 2007-08, in India. A protocol was devised and data was collected through desk review, in-depth interviews and on-site observation at state, districts and facility levels. The assessment was completed in December 2009. RESULTS: Coverage with three doses of Hep B vaccine was lower than similarly timed three doses of DPT vaccine. Poor stock management ("stock outs or nil stocks" at various levels), incomplete recording and reporting, perceived costly vaccine & related fear of wastage of vaccine in 10 dose vial, and incomplete knowledge amongst health functionaries about vaccination schedule were the main reasons cited for reported lower coverage. Hep B vaccine birth dose was introduced in only 3 of 5 states evaluated. The additional reasons for low Hep B birth dose coverage were lack of knowledge amongst Health Workers about birth dose administration, no mechanism for recording birth dose, and insufficient trainings, official communications, and coordination at various levels. CONCLUSIONS: There had been a few challenges in the introduction of Hepatitis B vaccination in India, however, this provide opportunity to learn for future scale up. For successful introduction and expansion of any new vaccine in national or state immunization program; clear and timely central level instructions and oversight and improved stock management is required. At state and district levels; quality trainings, effective supervision and monitoring, improving data recording and reporting are key factor for success. The additional focus on Hep B birth dose administration may help in improving coverage. PMID- 23649137 TI - Courses in reproductive and child health in India: an overview. AB - Defining the human resource needs for providing quality maternal, newborn, and child health services across such a large and diverse population country like India is truly challenging. The effective response to significant challenges and increased requirements of evidence-based effectiveness of the public health projects on maternal and child health is putting pressure on existing program managers to acquire new advanced academic training and information. The data regarding the existing courses on reproductive and child health and related fields in the country were obtained by a predefined search made on the Internet through the Google search engine in December 2011. The collected data were the name and location of the institution offering the respective course, theme, course duration, course structure, eligibility criteria, and mode of learning. In India, around 15 institutes are offering certificate/postgraduate diploma courses on maternal and child health either as a regular program or through distance education program. The admission procedure for each institute is independent of others. The courses vary in terms of duration, eligibility criteria, and fee structure. Conceptualizing an educational initiative in response to national demands for increased workforce capacity to eliminate key medical and nonmedical educational barriers and financial and nonfinancial barriers to advanced academic preparation would enhance the quality of services available in the region. PMID- 23649138 TI - Factors associated with low birth weight among newborns in an urban slum community in Bhopal. AB - A community based cohort study on birth weight of newborns was conducted among pregnant women of an urban slum in Bhupal, India. The study was carried out to assess the magnitude of low birth weight (LBW) and factors contributing it in an urban slum community. Socio-demographic and maternal characteristics were examined applying statistical techniques to find out the variables associated with the LBW. An additional schedule was used to collect information from mothers about their socio-demographic background, dietary intake and the rest during the pregnancy. Weight of newborns of mothers registered in the study and delivering at the district hospital was recorded. Mean birth weight of newborns of 290 registered mothers was 2.57 +/- 0.36 g. One hundred and five newborns (36.2%) had a birth weight lesser than 2500 g. Among different variables studied, statistically significant association was found in case of occupation, daily calorie intake and duration of day-time rest taken by pregnant women. PMID- 23649139 TI - Prevalence of diabetes mellitus, impaired fasting glucose, impaired glucose tolerance, and its correlates among police personnel in Bankura District of West Bengal. AB - A cross-sectional study was conducted among police personnel (N = 1817) in Bankura District, West Bengal, India to estimate the prevalence of diabetes mellitus (DM), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and its correlates during July-November, 2011. Participants were enquired about their age, gender, physical activity, and predominant occupational activity. Diagnosis of DM, IFG, and IGT was based on a history, fasting, and 2-h post-load blood glucose estimation as per World Health Organization (WHO) criteria. Body mass index, waist circumference (WC), and blood pressure (BP) were estimated. Out of 1817 subjects, DM was found in 15%, 1.1% had IFG and 5.7% had IGT. Age >50 years, family history of diabetes, hypertension, and abdominal obesity were found to be significantly associated with DM and IGT, whereas IFG was significantly associated with the family history of diabetes and hypertension. High prevalence of diabetes and pre-diabetic condition warrants early effective intervention to keep the police force healthy and agile. PMID- 23649140 TI - Anti-inflammatory effect of vitamin D on gingivitis: a dose response randomised controlled trial. AB - In a randomized controlled trial, a daily Oral Vitamin D supplementation was given in dose of 2000 IU for Group A, 1000 IU for Group B , 500 IU for Group C and placebo for Group D over 3 months period to assess the anti-inflammatory effect of vitamin D on gingivitis at various doses. The changes in gingival scores were measured at the period of 1 st , 2 nd and 3 rd month. Gingivitis score changed in direct proportion to the dose of vitamin D supplementation. Group A mean gingival scores were 2.4 (baseline); 1.7 (1 st month), 0.8 (2 nd month) and 0.3 (3 rd month). The group B the mean baseline gingival score from 2.3 reduced to 2.0 (month), 1.1 (two months) and 0.5 (third month). Group C had baseline gingival scores of 2.2 and 1.9 (1 st month), 1.4 (2 nd month) and 0.8 (last visit). Comparing baseline gingivitis scores with later visit score by Wilcoxon paired test, the anti-inflammatory effect was significantly seen in group A after one month itself, group B at two months and group C at 3 rd month after oral vitamin D supplementation. However, Group D did not show any significant anti-inflammatory effect. PMID- 23649141 TI - A study on socio-demographic characteristics of alcoholics attending the de addiction center at Burdwan medical college and hospital in West Bengal. AB - Prevalence of alcohol use in India is reported to be 21.4% and there is increasing alcohol intake among the young people. The present study was undertaken to study the socio-demographic characteristics of patients having alcohol-related disorders attending the de-addiction center at Burdwan Medical College in West Bengal and to find out some factors responsible for that. A clinic-based descriptive cross-sectional study was conducted among 187 patients with the help of pre-tested pre-designed schedule after obtaining informed consent. Data analysis was carried out with the help of Epi info software version 6. Majority of the patients were male, in productive age group and married. Age of initiation and amount of alcohol intake were significantly associated with positive family history of alcoholism. Children having family history of alcoholism should be counseled to prevent development of alcoholism. PMID- 23649142 TI - Characteristics of childhood tuberculosis patients registered under RNTCP in Varanasi, Uttar Pradesh. AB - Childhood tuberculosis (TB) reflects on-going transmission. Data on childhood TB from TB registers under Revised National Tuberculosis Control Program of 2008 and 2009 in Varanasi district was analyzed. Proportion of childhood TB was 8.3% of total registered cases 12,242. It was lower than estimated 10-20% in endemic areas. In rural Tuberculosis Units childhood case detection was poor. Case detection in <=5 years was very less. The childhood cases were detected mainly in adolescent age group. Thus, childhood TB is remaining a under diagnosed/under reported disease in India. It needs attention to increase the detection of childhood TB cases to control TB in general population. PMID- 23649143 TI - Suicide an emerging public health problem: evidence from rural Haryana, India. AB - Analysis of annual mortality data for year 2002-2009 of twenty eight villages in Ballabgarh block of rural Haryana was carried out to calculate suicide rates per 100,000 population. In addition, informal discussions were carried out amongst health providers to understand their perceptions regarding suicides. In a period of 8 years, out of total 4552 deaths, 163 (3.5%) deaths were attributed to suicides giving a suicide rate of 24.4/100,000 population (95% CI 24.1- 24.7). Mean years of productive life lost for males and females were estimated to be 44.4 (SD 1.1) years and 39.9 (SD 1.4) years respectively. Poisoning (41.1%) was the most common mode of suicide followed by hanging (36.8%) and burns (14.7%). Health workers also perceived suicide as major problem in the community and marital conflict was identified as major cause for suicides. There is need to address the complex issue of suicide by public- health approach at the community level. PMID- 23649144 TI - Assessment of village water and sanitation committee in a district of Tamil Nadu, India. AB - A descriptive study was conducted among 75 members of five Village Water and Sanitation Committees (VWSCs) and 15 local residents in Tamil Nadu, India to assess committee's formation and decision making process. There were 64% females and rest were males, all aged between 20 years and 45 years. A total of 50.7% of them passed 12 th standard and 29.3% belonged to self-help groups. Although, all of them were aware about presence of guidelines, none of them knew its contents. About 20% opined that meetings were not being conducted regularly. All members said that they had problems in attending meeting regularly, take decisions if at least 10 (67%) members are present and fund was not adequate for 1 year period. One-third of local residents did not know the committee formation process and none of them aware about guidelines. Formation and decision making process of VWSC should be improved to tackle the sanitation problem. PMID- 23649145 TI - Optimizing the routes and locations for primary healthcare clinics using network analysis: a geographic information systems application. PMID- 23649146 TI - Acceptance of vaccination against the 2009 pandemic influenza a among health-care workers in Pune, Maharashtra. PMID- 23649147 TI - Role of public health dentist towards domestic violence. PMID- 23649151 TI - But I don't have any complications. PMID- 23649150 TI - Right-ventricular global longitudinal strain may predict neo-aortic arch obstruction after Norwood/Sano procedure in children with hypoplastic left heart syndrome. AB - Neo-aortic arch obstruction (NAAO) is a common complication following the Norwood/Sano procedure (NP) for hypoplastic left heart syndrome (HLHS) and is associated with increased morbidity and mortality. However, there is currently no objective method for predicting which patients will develop NAAO. This study was designed to test the hypothesis that hemodynamic changes from development of NAAO after NP in patients with HLHS will lead to changes in myocardial dynamics that could be detected before clinical symptoms develop with strain analysis using velocity vector imaging. Patients with HLHS who had at least one cardiac catheterization after NP were identified retrospectively. Strain analysis was performed on all echocardiograms preceding the first catheterization and any subsequent catheterization performed for intervention on NAAO. Twelve patients developed NAAO and 30 patients never developed NAAO. Right ventricular strain was worse in the group that developed NAAO (-6.2 vs. -8.6 %, p = 0.040) at a median of 59 days prior to diagnosis of NAAO. Those patients that developed NAAO following NP were significantly younger at the time of first catheterization than those that did not develop NAAO (92 +/- 50 vs. 140 +/- 36 days, p = 0.001). This study demonstrates that right ventricular GLS is abnormal in HLHS patients following NP and worsening right ventricular strain may be predictive of the future development of NAAO. PMID- 23649152 TI - Managing the patient with failed cartilage restoration. AB - In comparison to the amount of published information on the surgical management of cartilage defects in general, there has been a relative lack of emphasis regarding the management of patients who present with failed attempts at index cartilage repair. The objectives of this review are to: (1) identify patient and procedure-specific factors that are associated with failed cartilage surgery; (2) identify strategies that have the potential to decrease failure rates after articular cartilage restoration; and (3) develop an algorithmic approach to managing patients who present with prior failed cartilage procedures. PMID- 23649148 TI - Positive and negative influence of the matrix architecture on antitumor immune surveillance. AB - The migration of T cells and access to tumor antigens is of utmost importance for the induction of protective anti-tumor immunity. Once having entered a malignant site, T cells encounter a complex environment composed of non-tumor cells along with the extracellular matrix (ECM). It is now well accepted that a deregulated ECM favors tumor progression and metastasis. Recent progress in imaging technologies has also highlighted the impact of the matrix architecture found in solid tumor on immune cells and especially T cells. In this review, we argue that the ability of T cells to mount an antitumor response is dependent on the matrix structure, more precisely on the balance between pro-migratory reticular fiber networks and unfavorable migration zones composed of dense and aligned ECM structures. Thus, the matrix architecture, that has long been considered to merely provide the structural framework of connective tissues, can play a key role in facilitating or suppressing the antitumor immune surveillance. A new challenge in cancer therapy will be to develop approaches aimed at altering the architecture of the tumor stroma, rendering it more permissive to antitumor T cells. PMID- 23649153 TI - Thromboembolic complications in arthroscopic surgery. AB - Venous thromboembolism (VTE) is a relatively rare complication of arthroscopic surgery but has the potential to cause significant morbidity and even mortality. VTE has been reported after shoulder and knee arthroscopy prompting controversial guidelines to be proposed. More limited studies are available regarding hip and ankle arthroscopy and 1 case of deep venous thrombosis in the contralateral leg status after hip arthroscopy exists. No reports have been published regarding VTE after elbow or wrist arthroscopy to these authors' knowledge. In this article, a systematic review of the literature was conducted to analyze the incidence, treatment, and prevention of thromboembolic complications in arthroscopy. PMID- 23649154 TI - Management of infections after arthroscopy. AB - Management and evaluations of infections after arthroscopy of the knee and shoulder can be difficult and fraught with complications, both medical and legal. This article reviews the literature regarding arthroscopic infections from a historical perspective and discusses the treatment of knee and shoulder infections as well as the complications associated with delayed treatment. It is critical to make the diagnosis as soon as possible subsequent to the initial procedure to avoid postoperative sequelae consisting of stiffness and a decrease in function. PMID- 23649155 TI - Complications of elbow and wrist arthroscopy. AB - Arthroscopy is a valuable tool in the diagnosis and treatment of various elbow and wrist disorders. Because of the close proximity of vital neurovascular structures, arthroscopy of these joints must be undertaken with a thorough understanding of the anatomy and with experience with the surgical procedures. Although there are reports of complications from procedures in both joints, there is a lack of agreement as to the rate and types of complications. We reviewed the literature to help the reader develop a comprehensive understanding of the risks and plentiful complications associated with arthroscopic procedures of the elbow and wrist and to describe strategies to prevent adverse outcomes. PMID- 23649156 TI - Complications of arthroscopic shoulder surgery. AB - Shoulder arthroscopic procedures have become common in today's orthopedic practice. The safety of shoulder arthroscopy though well established, is not without complications both minor and significant. The true incidence of complications is difficult to identify in the current literature. However, as with all procedures, complications associated with shoulder arthroscopy do occur. General complications (ie, infection), those specific to shoulder arthroscopy (ie, positioning) and those associated with specific procedures (ie, failure) all have been recognized. The purpose of this article is to review the current literature regarding complications in shoulder arthroscopy, provide insight into the risk factors and types of complications and to provide guidelines on the prevention and management of complications if and when they occur. PMID- 23649157 TI - Complications in hip arthroscopy. AB - Over the past several years, hip arthroscopy has become an effective treatment option for a variety of intra-articular and extra-articular pathologies. With the rapid growth in the technical capabilities of hip arthroscopy, there has been much interest in the indications, limitations, and complications associated with the procedure. The procedure remains technically demanding and carries with it a steep surgical learning curve that may lead to heterogeneity in individual surgeon complication rates. Furthermore, with expanding indications and treatment of pathology in the peripheral compartment, peritrochanteric, and subgluteal space, it is vital to remain cognizant of all potential pitfalls that may occur throughout the entire procedure. This article reviews the complications associated with hip arthroscopy, from preoperative planning through postoperative care. PMID- 23649158 TI - Recognizing and managing complications in ACL reconstruction. AB - The number of anterior cruciate ligament reconstruction is increasing. Avoiding complications in anterior cruciate ligament reconstruction requires attention to surgical details. Errors during graft harvest, tunnel drilling, graft placement, graft fixation, or the presence of unrecognized pathology can lead to poor outcome. Postoperatively attention must be paid to range of motion, progress with physical therapy, and functional return to activity. Prompt recognition of complications is essential to minimize adverse patient outcomes. PMID- 23649159 TI - Complications of osteotomies about the knee. AB - High tibial osteotomy and distal femoral osteotomy are 2 popular techniques for the treatment of monocompartmental osteoarthritis of the knee joint in young patients. Injury to the popliteal neurovascular bundle is still considered to be the most severe complication during an osteotomy procedure even if the rate of occurrence is very low. Loss of correction and hardware failures are more frequent, but not as devastating. Patella baja and modification of tibial slope are associated with high tibial osteotomy. In contrast, complications most commonly associated with distal femoral osteotomy include nonunion and failure of the internal fixation. In general with evolution of techniques and fixation devices, complication rates seem to be reduced. A summary and literature review of complications associated with knee osteotomies will be discussed in this paper. PMID- 23649149 TI - The pathogenesis of cardiac fibrosis. AB - Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-beta and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease. PMID- 23649160 TI - Avoiding complications in patellofemoral surgery. AB - The diagnosis and treatment of patellofemoral disorders can challenge even the experienced orthopedic surgeon. Differential diagnosis is broad and multiple anatomic abnormalities must be taken into account in order to manage care. The majority of patients with patellofemoral disorders can be treated successfully nonoperatively. When nonoperative management fails, and in the carefully selected patient, a variety of surgical options exist based on the anatomic pathology involved, but each brings its own potential for complication. We discuss several of the surgical treatment options that are available to the orthopedic surgeon for the treatment of patellofemoral disorders, including lateral retinacular release, medial soft-tissue reconstructive procedures, and bony procedures (including trochleoplasty and tibial tubercle osteotomy. We describe potential complications of each procedure and what the orthopedic surgeon can do to avoid them. PMID- 23649161 TI - Anticipating problems unique to revision ACL surgery. AB - Anterior cruciate ligament (ACL) injuries are common in the athletic population. In fact, ACL reconstruction has become one of the most common orthopedic procedures. With the increasing number of primary ACL reconstructions being performed combined with the continued expectations of high-level athletes, revision ACL reconstruction is likely to become more frequent. Revision ACL reconstruction poses several diagnostic and technical challenges compared to primary reconstructions. The purpose of this article is to highlight problems that are unique to revision ACL reconstruction such as tunnel malposition, tunnel widening, preexisting hardware, and injuries to concomitant structures in the knee. Recognizing and avoiding these pitfalls are crucial to obtaining a successful result after revision ACL reconstruction. PMID- 23649162 TI - Complications in ankle and foot arthroscopy. AB - Arthroscopy has many potential complications, whether it is done in the ankle, shoulder, knee, or other joints. Foot and ankle arthroscopy has progressed significantly since its beginning by Burman in 1931. Over the past 2 decades, arthroscopy equipment and instrumentation has improved and newer techniques have been developed. A heightened interest in foot and ankle arthroscopy has grown as diagnostic and imaging capabilities have improved. As the number of arthroscopic procedures of the foot and ankle has increased, so has the opportunity for significant complications. PMID- 23649163 TI - Magnetic field dependence of non-local lateral spin-valve signals beyond the Hanle effect. AB - We present a theoretical model of spin transport in metallic lateral valves that takes into account spin scattering on magnetic impurities. We show that the model agrees with recent experimental findings of increasing non-local spin signals by in-plane magnetic field, which is parallel to the injected spins. The increase arises due to reduction of conduction electron spin flips on magnetic impurities present at the metal-ferromagnet interfaces as they freeze out under application of the magnetic field. PMID- 23649164 TI - Solution-dispersible Au nanocube dimers with greatly enhanced two-photon luminescence and SERS. AB - We report the synthesis of 43-nm diameter Au nanocube dimers by using Ag(+) ions as competitive ligands to freeze L-cysteine-induced assembly process of the nanocubes to a desirable stage. Ascribed to the resonant interparticle coupling with an newly arising plasmon band at 710 nm and local field enhancement, the two photon luminescence intensity of the Au nanocube dimers in solution was over 20 times stronger than that of the monomers in the wavelength range 555-620 nm. Furthermore, by coupling Raman tags onto the nanocube surface, a solution-based surface-enhanced Raman scattering (SERS) of the nanocube dimers had an enhancement factor of over 10 times compared to the isolated nanocubes. To sum up, with high stability in solution and attractive optical properties, the Au nanocube dimers have potential applications in in vivo bio-imaging and solution based SERS. PMID- 23649166 TI - Monitoring foreign gene incorporation into the plastome of Chlamydomonas reinhardtii by multiplex qPCR. AB - The genetic material of the Chlamydomonas reinhardtii chloroplast can be easily manipulated and creation of transgenic plastomes is of interest for both photosynthetic research and for biofuel and biomass production. Because multiple copies of the chloroplast genome are present, it is important to understand whether, following the introduction of a foreign gene, the resulting transgenic plastome is homoplasmic or heteroplasmic. By quantitative PCR together with a simple DNA extraction procedure and a series of DNA oligonucleotides the following protocol will determine the extent of foreign gene incorporation into a host chloroplast plastome. This approach is used to follow the degree of heteroplasmy following biolistic transformation of several transgenic strains. The approach used is quick, simple to set up, and gives an accurate quantitation of foreign genes within of the chloroplast plastome. Possible future uses of the technique are discussed. PMID- 23649165 TI - Microfluidic platforms for mechanobiology. AB - Mechanotransduction has been a topic of considerable interest since early studies demonstrated a link between mechanical force and biological response. Until recently, studies of fundamental phenomena were based either on in vivo experiments with limited control or direct access, or on large-scale in vitro studies lacking many of the potentially important physiological factors. With the advent of microfluidics, many of the previous limitations of in vitro testing were eliminated or reduced through greater control or combined functionalities. At the same time, imaging capabilities were tremendously enhanced. In this review, we discuss how microfluidics has transformed the study of mechanotransduction. This is done in the context of the various cell types that exhibit force-induced responses and the new biological insights that have been elucidated. We also discuss new microfluidic studies that could produce even more realistic models of in vivo conditions by combining multiple stimuli or creating a more realistic microenvironment. PMID- 23649169 TI - Structural health and the politics of African American masculinity. AB - This commentary describes ways in which notions of African American men's "health" attained by individual choice-embedded in the notion that African American men should visit doctors or engage in fewer risky behaviors-are at times in tension with larger cultural, economic, and political notions of "health." It argues that efforts to improve the health of Black men must take structural factors into account, and failure to do so circumvents even well-intentioned efforts to improve health outcomes. Using historical examples, the article shows how attempts to identify and intervene into what are now called social determinants of health are strengthened by addressing on-the-ground diagnostic disparities and also the structural violence and racism embedded within definitions of illness and health. And, that, as such, we need to monitor structural barriers to health that exist in institutions ostensibly set up to incarcerate or contain Black men and in institutions ostensibly set up to help them. PMID- 23649167 TI - Kinetics and functional diversity among the five members of the NADP-malic enzyme family from Zea mays, a C4 species. AB - NADP-malic enzyme (NADP-ME) is involved in different metabolic pathways in several organisms due to the relevant physiological functions of the substrates and products of its reaction. In plants, it is one of the most important proteins that were recruited to fulfil key roles in C4 photosynthesis. Recent advances in genomics allowed the characterization of the complete set of NADP-ME genes from some C3 species, as Arabidopsis thaliana and Oryza sativa; however, the characterization of the complete NADP-ME family from a C4 species has not been performed yet. In this study, while taking advantage of the complete Zea mays genome sequence recently released, the characterization of the whole NADP-ME family is presented. The maize NADP-ME family is composed of five genes, two encoding plastidic NADP-MEs (ZmC4- and ZmnonC4-NADP-ME), and three cytosolic enzymes (Zmcyt1-, Zmcyt2-, and Zmcyt3-NADP-ME). The results presented clearly show that each maize NADP-ME displays particular organ distribution, response to stress stimuli, and differential biochemical properties. Phylogenetic footprinting studies performed with the NADP-MEs from several grasses, indicate that four members of the maize NADP-ME family share conserved transcription factor binding motifs with their orthologs, indicating conserved physiological functions for these genes in monocots. Based on the results obtained in this study, and considering the biochemical plasticity shown by the NADP-ME, it is discussed the relevance of the presence of a multigene family, in which each member encodes an isoform with particular biochemical properties, in the evolution of the C4 NADP-ME, improved to fulfil the requirements for an efficient C4 mechanism. PMID- 23649168 TI - CCR4 mediates CCL17 (TARC)-induced migration of human colon cancer cells via RhoA/Rho-kinase signaling. AB - BACKGROUND: Accumulating data suggest a role of chemokines in tumor cell metastasis. CCR4 has been implicated in hematologic malignancies and recently also in solid tumors. Herein, we hypothesized that CCR4 might be expressed and support migration of colon cancer cells. METHODS: We used quantitative RT-PCR and flow cytometry to determine mRNA and surface expression of CCR4 on colon cancer cell lines (HT-29) and (AZ-97). Total RhoA and active RhoA protein levels in CCL17-stimulated colon cancer cells were quantified using ELISA and G-LISA assays. Migration assays were performed to evaluate colon cancer cells chemotaxis. In vitro tumor growth was assessed using proliferation assay. RESULTS: Our results show clear-cut mRNA levels and surface expression of CCR4 on a colon cancer cell line (HT-29) and on tumor cells (AZ-97). CCR4 ligand CCL17 (TARC) was a potent stimulator of colon cancer cell migration. This CCL17-induced colon cancer cell migration was inhibited by pre-incubation of the colon cancer cells with an antibody directed against CCR4 or an antagonist against CCR4. CCL17 induced signaling in colon cancer cells revealed that CCL17 increased mRNA formation of RhoA-C in colon cancer cells. Our results also found that CCL17 increased total RhoA and active RhoA protein levels in colon cancer cells. The Rho-kinase inhibitor Y-27632 abolished CCL17-induced colon cancer cell chemotaxis. In addition, inhibition of isoprenylation by GGTI-2133 markedly reduced colon cancer cell migration triggered by CCL17. CONCLUSIONS: Our novel data indicate for the first time that the CCL17-CCR4 axis might be involved in the spread of colon cancer cells. PMID- 23649170 TI - Using research to inform policy. PMID- 23649172 TI - Selective and sensitive turn-on fluorescent sensing of arsenite based on cysteine fused tetraphenylethene with AIE characteristics in aqueous media. AB - Herein, a cysteine-functionalized derivative of TPE is presented as the first fluorescent organic dye for selective, label-free, sub-ppb level detection of As(3+) in aqueous media by taking the advantage of the aggregation induced emission feature. Besides, the first discrimination between the most toxic As(3+) and less toxic As(5+) was obtained. PMID- 23649171 TI - Health behaviors and all-cause mortality in African American men. AB - Because of the excess burden of preventable chronic diseases and premature death among African American men, identifying health behaviors to enhance longevity is needed. We used data from the Third National Health and Nutrition Examination Survey 1988-1994 (NHANES III) and the NHANES III Linked Mortality Public-use File to determine the association between health behaviors and all-cause mortality and if these behaviors varied by age in 2029 African American men. Health behaviors included smoking, drinking, physical inactivity, obesity, and a healthy eating index score. Age was categorized as 25-44 years (n = 1,045), 45-64 years (n = 544), and 65 years and older (n = 440). Cox regression analyses were used to estimate the relationship between health behaviors and mortality within each age group. All models were adjusted for marital status, education, poverty-to-income ratio, insurance status, and number of health conditions. Being a current smoker was associated with an increased risk of mortality in the 25- to 44-year age group, whereas being physically inactive was associated with an increased risk of mortality in the 45- to 64-year age-group. For the 65 years and older age-group, being overweight or obese was associated with decreased mortality risk. Efforts to improve longevity should focus on developing age-tailored health promoting strategies and interventions aimed at smoking cessation and increasing physical activity in young and middle-aged African American men. PMID- 23649173 TI - Fattening fasting: hungry grocery shoppers buy more calories, not more food. PMID- 23649174 TI - A variant of blueberry necrotic ring blotch virus associated with red lesions in blueberry. AB - The complete genome of a variant of the multi-segmented (+) RNA virus blueberry necrotic ring blotch virus (BNRBV), which has not been assigned to a genus, was obtained from foliar red lesions on southern highbush blueberries grown in Alachua Co., Florida. The genome organization of this variant, BNRBV-RL, is the same as that of BNRBV: four genomic segments and seven ORFs (one ORF on each of RNA 1, RNA 2, and RNA 4 and as many as four ORFs on RNA 3). BLAST analysis revealed nucleic acid sequence identities of 89 %, 90 %, 90 % and 86 % to BNRBV RNA 1, RNA 2, RNA 3 and RNA 4, respectively. Phylogenetic analysis of the amino acid sequence of the putative RdRp domain indicated that BNRBV-RL was closely related to BNRBV and less related to citrus leprosis virus type C and three other mite-transmitted viruses. The nucleotide and amino acid sequence differences between BNRBV-RL and BNRBV combined with differences in symptom expression in blueberry would suggest that BNRBV-RL is a strain of BNRBV. PMID- 23649175 TI - Complete nucleotide sequence of a strain of cherry mottle leaf virus associated with peach wart disease in peach. AB - The complete nucleotide sequence and genome organization of a peach virus isolate from a naturally infected peach tree showing typical peach wart-like symptoms on the fruit surface was determined and compared to sequences of members of the family Betaflexiviridae. The genome consists of 7,987 nucleotides, excluding the poly-A tail, and has four open reading frames (ORFs). Analysis of the whole genome and putative proteins encoded by each ORF revealed greatest sequence similarity to a cherry isolate of cherry mottle leaf virus (CMLV). The two isolates have similar genome organizations and share 88 and 93 % homology in their corresponding products of the replicase and coat protein genes, respectively. CMLV has been reported from several Prunus spp. and may be associated with peach wart-like disease symptoms on peach fruit. PMID- 23649176 TI - Comparative analysis of the genomes of Clostera anastomosis (L.) granulovirus and Clostera anachoreta granulovirus. AB - Clostera anastomosis (L.) granulovirus (CaLGV) and Clostera anachoreta granulovirus (ClanGV) are both capable of infecting each other's native host insects. Despite this, we have little information on their genetic relationship. The complete nucleotide sequence of CaLGV was determined and compared with that of the genome of ClanGV. The circular, double-stranded DNA CaLGV genome (GenBank accession no. KC179784) had a G+C content of 46.7 % and was 101,818 bp in size (331 bp larger than the ClanGV genome). Overall, the CaLGV nucleotide sequence was found to be 90 % identical to that of ClanGV. It contained a total of 123 ORFs, 119 of which had ClanGV homologues, with an identical transcription direction and ORF organization. Seventy-five of the 119 ORFs showed 90 % or greater identity to their ClanGV homologues. CaLGV contained only a single identifiable homologous region (hrs)/repeat region (similar to ClanGV hr4). The mean frequency of nucleotide substitutions in the CaLGV/ClanGV coding regions was 8.33 %. CaLGV contained four unique ORFs (CaL23, CaL39, CaL48 and CaL92). Eight ORFs found in both CaLGV and ClanGV have no homologues in other baculoviruses. Intergenic regions of CaLGV and ClanGV occupied 6.6 % and 7 % of their respective genomes. CaLGV appears closer phylogenetically to ClanGV than to any other baculoviruses. PMID- 23649177 TI - Characterization and complete genome sequence of a virulent bacteriophage B4 infecting food-borne pathogenic Bacillus cereus. AB - Bacillus cereus causes food poisoning, resulting in vomiting and diarrhea, due to production of enterotoxins. As a means of controlling this food-borne pathogen, the virulent bacteriophage B4 was isolated and characterized. Bacterial challenge assays showed that phage B4 effectively inhibited growth of members of the B. cereus group as well as B. subtilis, and growth inhibition persisted for over 20 h. One-step growth analysis also revealed the host lysis activity of phage B4, with relatively short eclipse/latent times (10/15 min) and a large burst size (>200 PFU). The complete genome of phage B4, containing a 162-kb DNA with 277 ORFs, was analyzed. The endolysin encoded by the phage B4 genome accounts for the cell lysis activity of this phage. These results suggest that phage B4 has potential as a biological agent to control B. cereus propagation. PMID- 23649178 TI - On cheating. PMID- 23649179 TI - 3D-2D registration of cerebral angiograms: a method and evaluation on clinical images. AB - Endovascular image-guided interventions (EIGI) involve navigation of a catheter through the vasculature followed by application of treatment at the site of anomaly using live 2D projection images for guidance. 3D images acquired prior to EIGI are used to quantify the vascular anomaly and plan the intervention. If fused with the information of live 2D images they can also facilitate navigation and treatment. For this purpose 3D-2D image registration is required. Although several 3D-2D registration methods for EIGI achieve registration accuracy below 1 mm, their clinical application is still limited by insufficient robustness or reliability. In this paper, we propose a 3D-2D registration method based on matching a 3D vasculature model to intensity gradients of live 2D images. To objectively validate 3D-2D registration methods, we acquired a clinical image database of 10 patients undergoing cerebral EIGI and established "gold standard" registrations by aligning fiducial markers in 3D and 2D images. The proposed method had mean registration accuracy below 0.65 mm, which was comparable to tested state-of-the-art methods, and execution time below 1 s. With the highest rate of successful registrations and the highest capture range the proposed method was the most robust and thus a good candidate for application in EIGI. PMID- 23649180 TI - Graph-based IVUS segmentation with efficient computer-aided refinement. AB - A new graph-based approach for segmentation of luminal and external elastic lamina (EEL) surface of coronary vessels in gated 20 MHz intravascular ultrasound (IVUS) image sequences (volumes) is presented. The approach consists of a fully automated segmentation stage ("new automated" or NA) and a user-guided computer aided refinement ("new refinement" or NR) stage. Both approaches are based on the LOGISMOS approach for simultaneous dual-surface graph-based segmentation. This combination allows the user to efficiently combine general information about IVUS image appearance and case-specific IVUS morphology and therefore deal with frequently occurring issues like calcified plaque-causing signal shadowing-and imaging artifacts. The automated segmentation stage starts with pre-segmenting the lumen to automatically define the lumen centerline, which is used to transform the segmentation task into a LOGISMOS-family graph optimization problem. Following the automated segmentation, the user can inspect the result and correct local or regional segmentation inaccuracies by (iteratively) providing approximate clues regarding the location of the desired surface locations. This expert information is utilized to modify the previously calculated cost functions, locally re-optimizing the underlying modified graph without a need to start the new optimization from scratch. Validation of our method was performed on 41 gated 20 MHz IVUS data sets for which an expert defined independent standard was available. Resulting from the automated stage of the approach (NA), the mean and standard deviation of the root mean square area errors for the luminal and external elastic lamina surfaces were 1.12 +/-0.67 mm (2) and 2.35 +/-1.61 mm (2) , respectively. Following the refinement stage (NR), the root mean square area errors significantly decreased to 0.82 +/-0.44 mm (2) and 1.17 +/-0.65 mm (2) for the same surfaces, respectively ( for both surfaces). The approach is delivering a previously unachievable speed of obtaining clinically relevant segmentations compared to the current approaches of automated segmentation followed by manual editing. PMID- 23649181 TI - Magnetostimulation limits in magnetic particle imaging. AB - For magnetic particle imaging (MPI), specific absorption rate (SAR) and more critically magnetostimulation (i.e., dB/dt) safety limits will determine the optimal scan parameters, such as the drive field strength and frequency. These parameters will impact the scanning speed, field-of-view (FOV) and signal-to noise ratio in MPI. Understanding the potential safety hazards of the drive field is critical for scaling MPI for human use. In this work, we demonstrate that magnetostimulation is the primary magnetic safety consideration in MPI, and we describe the first human-subject magnetostimulation threshold experiments for MPI using homogeneous coils. Our experiments, performed on the arm and leg, indicate that magnetostimulation thresholds monotonically decrease with increasing frequency. Additionally, we show for the first time that a strong inverse correlation exists between the threshold and the body part size. The chronaxie time, on the other hand, did not vary with body part size. We conclude with an estimation of the magnetostimulation thresholds for a full-body MPI scanner: a mean asymptotic threshold of 14.3 mT-pp (peak-to-peak) with a mean chronaxie time of 289 MUs, which correspond to a magnetostimulation threshold of about 15 mT-pp for frequencies between 25 and 50 kHz. These findings will have a great impact on the optimization of MPI parameters, especially in determining the number of partial FOVs required to cover a region of interest. PMID- 23649182 TI - Identification and characterization of ten new water gaps in seeds and fruits with physical dormancy and classification of water-gap complexes. AB - BACKGROUND AND AIMS: Physical dormancy (PY) occurs in seeds or fruits of 18 angiosperm families and is caused by a water-impermeable palisade cell layer(s) in seed or fruit coats. Prior to germination, the seed or fruit coat of species with PY must become permeable in order to imbibe water. Breaking of PY involves formation of a small opening(s) (water gap) in a morpho-anatomically specialized area in seeds or fruits known as the water-gap complex. Twelve different water gap regions in seven families have previously been characterized. However, the water-gap regions had not been characterized in Cucurbitaceae; clade Cladrastis of Fabaceae; subfamilies Bombacoideae, Brownlowioideae and Bythnerioideae of Malvaceae; Nelumbonaceae; subfamily Sapindoideae of Sapindaceae; Rhamnaceae; or Surianaceae. The primary aims of this study were to identify and describe the water gaps of these taxa and to classify all the known water-gap regions based on their morpho-anatomical features. METHODS: Physical dormancy in 15 species was broken by exposing seeds or fruits to wet or dry heat under laboratory conditions. Water-gap regions of fruits and seeds were identified and characterized by use of microtome sectioning, light microscopy, scanning electron microscopy, dye tracking and blocking experiments. KEY RESULTS: Ten new water-gap regions were identified in seven different families, and two previously hypothesized regions were confirmed. Water-gap complexes consist of (1) an opening that forms after PY is broken; (2) a specialized structure that occludes the gap; and (3) associated specialized tissues. In some species, more than one opening is involved in the initial imbibition of water. CONCLUSIONS: Based on morpho-anatomical features, three basic water-gap complexes (Types-I, -II and III) were identified in species with PY in 16 families. Depending on the number of openings involved in initial imbibition, the water-gap complexes were sub divided into simple and compound. The proposed classification system enables understanding of the relationships between the water-gap complexes of taxonomically unrelated species with PY. PMID- 23649183 TI - Immune activation in irritable bowel syndrome: can neuroimmune interactions explain symptoms? AB - Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal (GI) tract characterized by pain or discomfort from the lower abdominal region, which is associated with altered bowel habit. Despite its prevalence, there is currently a lack of effective treatment options for patients. IBS has long been considered as a neurological condition resulting from alterations in the brain gut axis, but immunological alterations are increasingly reported in IBS patients, consistent with the hypothesis that there is a chronic, but low-grade, immune activation. Mediators released by immune cells act to either dampen or amplify the activity of GI nerves. Release of a number of these mediators correlates with symptoms of IBS, highlighting the importance of interactions between the immune and the nervous systems. Investigation of the role of microbiota in these interactions is in its early stages, but may provide many answers regarding the mechanisms underlying activation of the immune system in IBS. Identifying what the key changes in the GI immune system are in IBS and how these changes modulate viscerosensory nervous function is essential for the development of novel therapies for the underlying disorder. PMID- 23649184 TI - Tracking the molecular features of nonpolypoid colorectal neoplasms: a systematic review and meta-analysis. AB - OBJECTIVES: Nonpolypoid colorectal neoplasms (NP-CRNs) are proposed as a major contributor to the occurrence of interval cancers, but their underlying biology remains controversial. We conducted a systematic review and meta-analysis to clarify the major biological events in NP-CRNs. METHODS: We systematically searched for studies examining molecular characteristics of NP-CRNs. We performed random effect meta-analyses. We measured the heterogeneity among studies using I(2) and possible publication bias using funnel plots. RESULTS: Fifty-three studies on KRAS, APC, or BRAF mutations, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), or DNA promoter hypermethylation were included. We observed less KRAS mutations (summary odds ratio (OR) 0.30, confidence interval (CI)=0.19-0.46, I(2)=77.4%, CI=70.1-82.9) and APC mutations (summary OR 0.42, CI=0.24-0.72, I(2)=22.6%, CI=0.0-66.7) in NP-CRNs vs. protruded CRNs, whereas BRAF mutations were more frequent (summary OR 2.20, CI=1.01-4.81, I(2)=0%, CI=0-70.8), albeit all with large heterogeneity. Less KRAS mutations were especially found in NP-CRNs subtypes: depressed CRNs (summary OR 0.12, CI=0.05-0.29, I(2)=0%, CI=0-67.6), non-granular lateral spreading tumors (LSTs NG) (summary OR 0.61, CI=0.37-1.0, I(2)=0%, CI=0-74.6), and early nonpolypoid carcinomas (summary OR 0.11, CI=0.06-0.19, I(2)=0%, CI=0-58.3). MSI frequency was similar in NP-CRNs and protruded CRNs (summary OR 0.99, CI=0.21-4.71, I(2)=70.3%, CI=38.4-85.7). Data for promoter hypermethylation and CIMP were inconsistent, precluding meaningful conclusions. CONCLUSIONS: This meta-analysis provides indications that NP-CRNs are molecularly different from protruded CRNs. In particular, some subtypes of NP-CRNs, the depressed and LST-NG, are featured by less KRAS mutations than polypoid CRNs. Prospective, multicenter studies are needed to clarify the molecular pathways underlying nonpolypoid colorectal carcinogenesis and potential implications for surveillance intervals. PMID- 23649185 TI - Opportunistic infections with anti-tumor necrosis factor-alpha therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials. AB - OBJECTIVES: Several anti-tumor necrosis factor-alpha (TNFalpha) antibodies have demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC). These drugs carry the theoretical risk of opportunistic infection, but no systematic review and meta-analysis has examined this issue specifically. METHODS: MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through to November 2012). Randomized controlled trials (RCTs) recruiting adults with active or quiescent CD or UC comparing anti-TNFalpha therapy with placebo were eligible. Dichotomous data were pooled to obtain a relative risk (RR) of opportunistic infection, with a 95% confidence interval (CI). The number needed to harm (NNH) was estimated from the reciprocal of the risk difference from the meta-analysis. RESULTS: The search strategy identified 20,563 citations, 21 of which were eligible, reporting 22 separate RCTs with between 2 and 56 weeks of follow-up. In total, there were 39 (0.9%) opportunistic infections among 4,135 patients allocated to anti-TNFalpha therapy, compared with 9 (0.3%) among 2,919 assigned to placebo. Among patients receiving active therapy these included eight cases of Mycobacterium tuberculosis, eight cases of herpes simplex infection, six cases of oral or esophageal candidiasis, six cases of herpes zoster infection, two cases of varicella-zoster virus infection, two cases of cytomegalovirus or Epstein-Barr virus infection, and one case of Nocardia infection. The RR of developing an opportunistic infection was significantly higher with anti-TNFalpha therapy (2.05; 95% CI 1.10-3.85, NNH=500; 95% CI 200-1,567). The RR of tuberculosis infection was 2.52 (95% CI 0.62-10.21). CONCLUSIONS: Anti-TNF therapy doubles the risk of opportunistic infections in inflammatory bowel disease patients. This underlines the importance of adherence to guidelines for their prevention and management. PMID- 23649186 TI - B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. AB - OBJECTIVES: Rituximab, an anti-CD20 monoclonal antibody that selectively depletes B cells, has shown promise in autoantibody-associated, immune-mediated disorders. As ursodeoxycholic acid (UDCA) is not successful in all patients with primary biliary cirrhosis (PBC), additional treatment options are necessary. The objective of this study was to assess the safety and efficacy of rituximab in patients with PBC refractory to UDCA. METHODS: Fourteen PBC patients refractory to UDCA received two rituximab infusions (1,000 mg) 2 weeks apart. The primary efficacy outcome was normalization and/or 25% improvement in serum alkaline phosphatase (ALP) concentration at 6 months. RESULTS: The median age was 53 years, and 92% were female and antimitochondrial antibody (AMA) positive. The median UDCA dosage was 15.3 mg/kg/day (interquartile range 14.5-17.8). Although rituximab was well tolerated, one patient withdrew due to an asthma exacerbation during the first infusion. Effective B-cell depletion was observed in the remaining 13 patients, including three that developed human anti-chimeric antibodies. ALP normalization and/or >= 25% improvement was observed in three patients (23%) at 6, 12, and 18 months. Significant reductions in median ALP (from 259 U/l at baseline to 213 U/l at 6 months; median decrease 16%), and serum IgM and AMA levels were observed at 6 months. Although fatigue was stable, pruritus improved in 60% of patients at 12 months (vs. 8% with worsening pruritus). CONCLUSIONS: Selective B-cell depletion with rituximab was safe and associated with a significant decrease in autoantibody production, but had limited biochemical efficacy in PBC patients with an incomplete response to UDCA. PMID- 23649187 TI - Epidemiology and public health research productivity in Africa. PMID- 23649188 TI - Authors' response to: Epidemiology and public health research productivity in Africa. PMID- 23649189 TI - A randomized, phase II, three-arm study of two schedules of ixabepilone or paclitaxel plus bevacizumab as first-line therapy for metastatic breast cancer. AB - The aim of this phase II trial was to estimate the objective response rate (ORR) of two different schedules of ixabepilone [weekly or every 3 weeks (Q3W)] combined with bevacizumab, relative to a reference arm of weekly paclitaxel and bevacizumab. Patients with human epidermal growth factor receptor 2-normal, chemotherapy-naive metastatic breast cancer (MBC) were randomized 3:3:2 to ixabepilone 16 mg/m(2) weekly plus bevacizumab 10 mg/kg Q2W (Arm A: n = 46); ixabepilone 40 mg/m(2) Q3W (reduced to 32 mg/m(2) after four cycles of treatment) plus bevacizumab 15 mg/kg Q3W (Arm B: n = 45); or paclitaxel 90 mg/m(2) weekly plus bevacizumab 10 mg/kg intravenous infusion Q2W (Arm C: n = 32). Of 123 randomized patients, 122 were treated. All were followed for >=19 months; 5 % of patients remained on study treatment at the time of this analysis. Grade 3 or 4 neutropenia was more common in Arm B (60 %) than Arms A (16 %) or C (22 %); other adverse events were similar. The investigator-assessed ORR was 48, 71, and 63 % for Arms A, B, and C, respectively. Median progression-free survival (randomized patients) was 9.6 months in Arm A, 11.9 months in Arm B, and 13.5 months in Arm C. In conclusion, ixabepilone Q3W plus bevacizumab has clinical activity as first line therapy for MBC relative to paclitaxel plus bevacizumab, but with significantly greater risk of grade 3 or 4 neutropenia. In addition, these data suggest that weekly dosing of ixabepilone may be less active than Q3W dosing, but with less neutropenia. PMID- 23649190 TI - Beta blockers and angiotensin-converting enzyme inhibitors' purported benefit on breast cancer survival may be explained by aspirin use. AB - Preclinical and epidemiologic evidence supports a possible role for beta adrenergic blocking drugs (beta-blockers), and angiotensin-converting enzyme inhibitors (ACEIs) in promoting survival after breast cancer. However, these drugs are often used concurrently with aspirin, and there is a growing body of evidence indicating a survival benefit for aspirin. Therefore, we analyzed the use of beta-blockers and ACEIs after a breast cancer diagnosis and their association with breast cancer mortality, both individually, combined with each other, and in combination with aspirin use in the Nurses' Health Study, using updated measures of medication use and Cox proportional hazards models. There were 4,661 women with stages I-III breast cancer included; 292 breast cancer deaths occurred during median follow-up time of 10.5 years. Modeled individually, the multivariable relative risk and 95 % confidence intervals (RR, 95 % CI) for breast cancer death were (0.76, 0.54-1.05) for beta blockers, (0.89, 0.60-1.32) for ACEIs, and (0.46, 0.35-0.60) for aspirin. Modeled simultaneously, the multivariable (RR, 95 % CI) for breast cancer death were (0.83, 0.60-1.16) for beta blockers, (1.00, 0.68-1.46) for ACEIs, and (0.46, 0.35-0.61) for aspirin. We did not see a significant association with beta blockers and survival, but there was a suggestion. Our study was limited in that we could not assess type of beta blocker and the number of events among users was still quite low. We found no evidence of a protective effect for ACEIs. The strong protective association with aspirin use confounds the associations with these other drugs and underscores the importance of considering aspirin use in analyses of breast cancer survival. PMID- 23649192 TI - Two new labdane diterpenes from fresh leaves of Leonurus japonicus and their degradation during drying. AB - Degradation of the components of Leonurus Herb was examined during drying. Compounds 1 and 2 were detected on TLC at lower temperature, but not at higher temperature. Their chemical structures were determined by spectral methods. They immediately decomposed even at 40 degrees C in chloroform solution. They are believed to be transformed through a retro-aldol reaction. Compounds 1 and 2 have not been previously reported. PMID- 23649193 TI - Azoles and bis-azoles: synthesis and biological evaluation as antimicrobial and anti-cancer agents. AB - Novel hydrazonoyl halides 3, 5 and bis-hydrazonoyl halides 7, 9 were synthesized. The synthetic utility of bis-hydrazonoyl halide 7 was explored to prepare novel bis-azole 13 with antipyrine moiety. On the other hand, [1,3,4]thiadiazol-2(3H) ylidene 17 and thiazol-2(3H)-ylidene 21 derivatives, with antipyrine moiety, were prepared from the reaction of 3-mercapto-3-(phenylamino)acrylamide derivative 10 with N-phenyl benzenecarbohydrazonoyl chloride (14) and 3-(2-bromoacetyl)-2H chromen-2-one (18), respectively. The structures of the isolated products were confirmed by spectral data (IR, (1)H-NMR, (13)C-NMR, MS) and elemental analyses. The anti-cancer activitiy of the synthesized products against the colon carcinoma (HCT) cell line was determined and the results revealed promising activity of compound 3. In addition, the antimicrobial activity of some selected products was evaluated. The results proclaimed that compounds 9, 17, and 21 have high antibacterial activity against Gram-positive bacteria (SA, BS) and Gram-negative bacteria (PA, EC). PMID- 23649194 TI - Synthesis and antimicrobial activity of azole derivatives. AB - A new class of mono and bis heterocycles, sulfonylmethaneamido linked oxazoles, thiazoles, imidazoles, pyrrolyl oxazoles, pyrrolyl thiazoles and pyrrolyl imidazoles were prepared adopting simple and versatile synthetic methodologies. The compound chloro substituted imidazolyl styrylsulfonylacetamide is the most potent antimicrobial agent particularly against Pseudomonas aeruginosa and Penicillium chrysogenum. PMID- 23649195 TI - Synthesis, docking studies, pharmacological activity and toxicity of a novel pyrazole derivative (LQFM 021)--possible effects on phosphodiesterase. AB - This study describes the synthetic route and molecular computational docking of LQFM 021, as well as examines its biological effects and toxicity. The docking studies revealed strong interaction of LQFM 021 to phosphodiesterase-3 (PDE-3). In isolated arteries, the presence of endothelium potentiates the relaxation for LQFM 021 and the inhibition cyclic nucleotides reduced the relaxation. Pre contraction with KCl (45 mM), the treatment with tetraethylammonium (TEA) (5 mM) and inhibition of reticular Ca(2+)-ATPase showed an inhibitory effect on relaxation. Moreover, the compound reduced the contraction evoked by the Ca(2+) influx. Acute toxicity tests revealed that the compound was practically nontoxic. In conclusion, this study showed that a new synthetic derivative of pyrazole is a possible PDE-3 inhibitor and has vasorelaxant activity and low toxicity. PMID- 23649196 TI - Synthesis of diosgenin-ibuprofen derivatives and their activities against insulin dependent diabetes mellitus. AB - The synthesis and anti-diabetes activities of diosgenin-ibuprofen derivatives were investigated. Ibuprofen (IBU) was chemically coupled with diosgenin either directly or through amino acid esters linkers. The effects of these compounds on lipopolysaccharide (LPS)-induced nitric oxide (NO) generation were assessed. The results showed spirost-5-en-3beta-yl (2-(4-isobutyl-phenyl)-propionate) (4) was of better activity to suppress the production of NO in the supernatant of LPS stimulated RAW264.7 cells. In vivo investigation on nonobese diabetic (NOD) mice indicated that compound 4 decreased the incidence of insulin-dependent diabetes mellitus (IDDM; type 1 diabetes) of NOD mice which suggested a potential activity of compound 4 against type 1 diabetes. PMID- 23649197 TI - A study of the various factors that affect the properties of molecularly imprinted polymers. AB - We evaluated the adsorbability and selectivity of (S)-valine anilide imprinted molecularly imprinted polymer (MIP) using a batch procedure that is both independent and precise. This study revealed important information about the relationship between the performance of MIPs and experimental factors such as the components of MIP synthesis and a reaction solvent. Herein, we also describe the problems associated with the preparation of a "non-imprinted polymer," which is often used to evaluate the effect of a template molecule, and we propose a new type of reference polymer, "blank polymer." PMID- 23649198 TI - Isolation of six isoprenylated biflavonoids from the leaves of Garcinia subelliptica. AB - The acetone-soluble parts of Garcinia subelliptica leaves were analyzed and six new biflavonoids were isolated, i.e., garciniaflavones A-F (1-6), as well as the five known biflavonoids amentoflavone (7), podocarpusflavone A (8), (+) morelloflavone (9), (+)-morelloflavone-7"-O-beta-glucopyranoside (10), and (+) 4'''-O-methylmorelloflavone (11) and the three triterpenoids oleanan-3-one, beta amyrin, and cycloartenol. The structures of the isolates were established based on spectroscopic analyses, including a detailed NMR spectroscopic investigation. The new biflavonoids are rare mono-isoprenylated derivatives that have a flavone (3'-8")-flavone core (1-4: amentoflavone type) and a flavanone-(3-8")-flavone core (5, 6: morelloflavone type). The absolute configurations of the morelloflavone-type biflavonoids (5, 6) were confirmed by circular dichroism to be 2R,3S. The biflavonoids with an isoprenyloxy group (1) and a 2-hydroxy-3 methyl-3-butenyl group (2), and the morelloflavone-type biflavonoids with a C(5) unit are the first examples in nature. We found that 7, one of the major biflavonoids, strongly inhibited hypoxia-inducible factor-1 in human embryonic kidney 293 cells under hypoxic conditions. PMID- 23649199 TI - Efficient synthesis of dichlorodenafil, an unapproved sildenafil analogue appearing in non-prescription supplements. AB - We have developed an efficient synthesis of dichlorodenafil (4), an unapproved sildenafil analogue isolated from dietary supplements. Our sequence employs POCl(3)-mediated chlorination of readily available chloroacetyl compound 7 followed by selective hydrolysis of the chloro-heterocycle function. Our synthesis confirms the structure of the illegal additive, and will provide regulatory agencies with ready access to authentic standard samples of dichlorodenafil (4) to aid in their mission to protect the public from unapproved and potentially harmful erectile dysfunction (ED) drug analogues that are added to herbal and dietary supplements without providing users with appropriate toxicological or pharmacological information. PMID- 23649200 TI - Two new diterpenoids from cell cultures of Salvia miltiorrhiza. AB - A new spiroketallactone, epi-danshenspiroketallactone A (1) and a new C18 norditerpenoid, normiltioane (2) along with 21 known compounds, were isolated from cell cultures of Salvia miltiorrhiza. Their structures were elucidated on the basis of extensive spectroscopic analyses. In the in vitro assays, the compounds 9-11, 21-23 exhibited the significant antitumor activity with the IC(50) ranges of 1.0-8.3 uM. PMID- 23649201 TI - Structures of ryobunins A-C from the leaves of Clethra barbinervis. AB - From a MeOH extract of the leaves of Clethra barbinervis Sieb. et Zucc., ryobunins A-C, three new triterpene glucosides, i.e. one ursane, one seco-ursane and one oleanane-type glucoside, along with four known compounds were isolated. Their structures were elucidated based on chemical and spectral evidence. PMID- 23649202 TI - Deprotection of the methoxymethyl group on 3-spiro-2-oxindole under basic conditions. AB - Deprotection of a methoxymethyl (MOM) group on an oxindole nitrogen under basic conditions is demonstrated. The mechanisms of both the deprotection and the formation of N-methyloxindole were revealed by using deuterated NaOMe-MeOH in mechanistic studies. PMID- 23649203 TI - Five new nortriterpenoid glycosides from the bulbs of Scilla scilloides. AB - Five new norlanostane-type triterpenoid glycosides were isolated from the bulbs of Scilla scilloides DRUCE (Liliaceae). Their chemical structures were determined on the basis of spectroscopic data as well as chemical evidence. PMID- 23649204 TI - Inappropriate and cloned clinical histories on radiology request forms for sick children. AB - BACKGROUND: An appropriate clinical history improves the perception and interpretation of radiographic examinations in children and adults. However, clinical history provided on radiology request has not been studied for its appropriateness and frequency of cloned clinical history. OBJECTIVE: The purpose of this study was to determine the frequency of inappropriate histories and cloned histories at a tertiary-care children's hospital. MATERIALS AND METHODS: We analyzed radiology request forms of 388 outpatient and inpatient radiographic examinations obtained on 3 days during the same month at a tertiary-care children's hospital. Appropriateness of the clinical history was judged by its relevance to the examination ordered and appropriate associated billable ICD-9 code. Cloning was defined as identical clinical histories appearing on the radiology request on three consecutive days. Cloned histories were further subdivided as being appropriate or inappropriate. RESULTS: A total of 18% (70/388) of the requests for clinical history were either inappropriate, cloned or both. Neonatal intensive care unit (NICU) referrals constituted the majority (82%, 9/11) of combined inappropriate history and cloning. NICU referrals accounted for 52% (28/54) of all inappropriate clinical histories, a significantly higher percentage than other inpatient locations (P = 0.006). The cardiovascular intensive care unit (CVICU) was the second most common patient location for inappropriate clinical histories (11%, 6/54). About one-third of the radiographic requests from the NICU had inappropriate histories (35%, 28/79). Among the outpatient referrals, 50% (4/8) of the inappropriate histories were from the emergency department. The most common cloned histories included "hypoplastic left heart syndrome" (15%, 4/27), "endotracheal tube placement" (11%, 3/27) and "evaluate lung fields and bowel" (11%, 3/27). The most commonly cloned clinical history was seen on referrals from the NICU at 63% (17/27), a significantly higher percentage than other inpatient locations (P = 0.006). The CVICU unit accounted for the second most common patient location for cloned clinical histories (26%, 7/27). The cloned clinical history on the referral request for radiography was unjustified in 48% (13/27) of the cases. NICU referrals had 85% (11/13) of the unjustified cloned histories. CONCLUSION: Inpatient units, particularly the NICU, were most likely to have inappropriate histories and cloning. Cloning was clinically justified in about half of the cases of cloning. The patterns of inappropriate histories and cloning suggest possible corrective measures. PMID- 23649205 TI - Temporal and occipital lobe features in children with hypochondroplasia/FGFR3 gene mutation. AB - BACKGROUND: Thanatophoric dysplasia (TD) and hypochondroplasia are both caused by FGFR3 (fibroblast growth factor receptor 3) gene mutations. Temporal lobe dysplasia has been well described in thanatophoric dysplasia; however, only a couple of anecdotal cases of temporal lobe dysplasia in hypochondroplasia have been described. OBJECTIVE: To define temporal lobe abnormalities in patients with hypochondroplasia, given that they share the same genetic mutation. MATERIALS AND METHODS: We identified brain imaging studies of nine children with hypochondroplasia. The temporal lobes were assessed on CT and MRI for size and configuration of the temporal horn and aberrant sulcation of the inferior surface of the temporal lobe. RESULTS: All children had a triangular-shape temporal horn and deep transverse fissures of the inferior temporal lobe surface. Neuroimaging in our cohort revealed enlarged temporal lobes and oversulcation of the mesial temporal and occipital lobes, with abnormal inferomedial orientation of these redundant gyri. Hippocampal dysplasia was also universal. CONCLUSION: We confirmed frequent inferomesial temporal and occipital lobe abnormalities in our cohort of children with hypochondroplasia. Murine models with mutant fgfr3 display increased neuroprogenitor proliferation, cortical thickness and surface area in the temporo-occipital cortex. This is thought to result in excessive convolution and likely explains the imaging findings in this patient cohort. (Note that fgfr3 is the same genetic mutation in mice as FGFR3 is in humans.). PMID- 23649206 TI - Fetal MRI on a multi-element digital coil platform. AB - Fetal MRI has an increasing list of indications and is most commonly employed when anomalies detected by prenatal ultrasonography require further characterization. This may occur when sonography is technically challenging or where specific MRI findings will determine pre- and postnatal management, including critical in utero and/or peripartum interventions. In these circumstances, there are high expectations for MRI to sort out complex diagnostic dilemmas through exquisite anatomical imaging that fetal surgeons and obstetricians can comprehend and relay to their patients. These expectations, in light of evolving clinical innovations, continue to drive advances in fetal imaging. Increasing signal-to-noise ratio (SNR) is fundamental to improving MR image quality, and proper coil selection is a key component of this pursuit. Since the introduction of parallel imaging techniques, the numbers of elements in phased-array coils have been continuously increased to achieve high SNR and shorter scan times. With the invention of a digital coil platform, it is now possible to connect combinations of multiple coil elements to enhance SNR beyond the capabilities of the adult eight-channel torso-coil routinely used in fetal imaging. This paper describes the application of multi-element radiofrequency coils on a digital broadband imaging platform with unique coil combinations to perform dedicated fetal MRI. PMID- 23649208 TI - Wishful thinking will not do it! Practitioners and decision-makers need tools to implement evidence-informed public health. PMID- 23649207 TI - Is procedural sedation with propofol acceptable for complex imaging? A comparison of short vs. prolonged sedations in children. AB - BACKGROUND: Concerns exist in the community of non-anesthesiologist sedation providers regarding the appropriateness of prolonged sedations using propofol for outpatient procedures. OBJECTIVE: To investigate interventions required, completion rate and resource use in prolonged vs. short sedations using propofol in outpatients. MATERIALS AND METHODS: We reviewed retrospectively 213 children sedated with propofol by a non-anesthesiologist sedation service. Cohorts were composed a priori of children sedated for >=1 h and <1 h. Comparisons were made regarding need for interventions, sedation duration, sedation completion to discharge time, and procedural completion rate. RESULTS: Most sedations were for MRI (87.5% short vs. 94.5% prolonged) with no statistically significant difference in overall need for interventions (75.2% prolonged vs. 65.4% short) nor completion to discharge times (30.7 +/- 11.5 min [prolonged] vs. 30.3 +/- 11.7 min [short]) between both groups. One child failed to complete the intended scan. No one required endotracheal intubation or unplanned admission. CONCLUSION: Prolonged outpatient sedations with propofol conducted by appropriately trained non-anesthesiology sedation providers appears effective for imaging procedures with no increase in interventions or increased resource burden compared to short sedations. This information can assist all stakeholders in determining scope of practice and guidelines for moderately longer pediatric sedations with propofol. PMID- 23649209 TI - Neutron study of the magnetism in NiCl2.4SC(NH2)2. AB - We study the strongly anisotropic quasi-one-dimensional S = 1 quantum magnet NiCl2.4SC(NH2)2 using elastic and inelastic neutron scattering. We demonstrate that a magnetic field splits the excited doublet state and drives the lower doublet state to zero energy at a critical field Hc1. For Hc1 < H < Hc2, where Hc2 indicates the transition to a fully magnetized state, three-dimensional magnetic order is established with the AF moment perpendicular to the magnetic field. We mapped the temperature/magnetic field phase diagram, and we find that the total ordered magnetic moment reaches m(tot) = 2.1 MUB at the field MU(0)H = 6 T and is thus close to the saturation value of the fully ordered moment. We study the magnetic spin dynamics in the fully magnetized state for H > Hc2, and we demonstrate the presence of an AF interaction between Ni(2+) on the two interpenetrating sublattices. In the antiferromagnetically ordered phase, the spin-waves that develop from the lower-energy doublet are split into two modes. This is most likely the result of the presence of the AF interaction between the interpenetrating lattices. PMID- 23649210 TI - Paediatric rheumatology: uPA-uPAR at the heart of cardiac neonatal lupus. PMID- 23649211 TI - Clinical guidelines: can wise choices solve the health-care crisis? PMID- 23649212 TI - Paediatric rheumatology: new risk loci for JIA identified. PMID- 23649213 TI - Topochemical transformation route to atomically thick Co3O4 nanosheets realizing enhanced lithium storage performance. AB - We first demonstrate the rational design and fabrication of novel atomically thick Co3O4 nanosheets (ATCNs) with a specific facet exposed by topochemical transformation from layered intermediate precursors to optimize energy storage. The eminently enhanced lithium storage performance can be attributed not only to the synergistic advantages of inorganic graphene analogues but also the increase of Co(2+) atoms and charge redistribution for ATCNs, which were first revealed by means of synchrotron radiation X-ray absorption near-edge spectroscopy. This work opens the window for the preparation of non-layered atomically thick nanosheets, which will significantly enrich the species of inorganic graphene analogues and optimize energy storage by reasonable materials design and fabrication. PMID- 23649214 TI - Reduction of airway complications with fluid management protocol in patients undergoing cervical decompression and fusion across the cervicothoracic junction. AB - STUDY DESIGN: Retrospective comparative cohort analysis. OBJECTIVE: To evaluate the effect of an intraoperative and intensive care unit protocol on incidence of airway complications for patients undergoing combined anterior-posterior cervical decompression and fusion crossing the cervicothoracic junction (CTAPF). SUMMARY OF BACKGROUND DATA: Airway compromise remains an important potential complication for patients undergoing CTAPF. Volume of intravenous fluid replacement perioperatively has been correlated with risk of airway complications in this patient population. METHODS: A retrospective cohort study was performed comparing airway complications (postoperative airway edema requiring reintubation and/or prolonged need for intubation) in patients undergoing CTAPF prior to and after introduction of a standardized protocol. The protocol required limitation of crystalloid fluid resuscitation intraoperatively, with maintenance of blood pressure using vasopressors. Comparisons between the 2 cohorts included operative time, intraoperative blood loss, volume of IV fluid replacement, and incidence of airway complications and dysphagia. RESULTS: Among patients operated prior to establishment of the protocol, 45% (9/20) experienced airway edema requiring extended intubation or reintubation. This rate was reduced to zero among 8 patients operated after the adoption of the protocol (P = 0.029). Intraoperative IV fluid volumes were reduced from 6190 mL to 4802 mL after institution of the protocol (P = 0.016). EBL and total surgical time did not differ between the 2 cohorts (1024 mL vs. 869 mL, P = 0.443; and 6.76 hr vs. 7.18 hr, P = 0.460). Incidence of dysphagia was not significantly different between the 2 cohorts. CONCLUSION: Establishment of a fluid and airway management protocol for patients undergoing CTAPF reduced the incidence of prolonged intubation or reintubation. Given the potentially life-threatening impact of loss of airway patency, intraoperative restriction of IV fluid while maintaining adequate blood pressure may be helpful in increasing the safety of surgical intervention in this complex patient population. LEVEL OF EVIDENCE: 4. PMID- 23649215 TI - Assessment of pain behavior in a rat model of intervertebral disc injury using the CatWalk gait analysis system. AB - STUDY DESIGN: Pain behavior and immunohistological analysis in intervertebral disc (IVD) injury model. OBJECTIVE: To investigate pain behavior in a rat model of IVD injury using the CatWalk system. SUMMARY OF BACKGROUND DATA: There are few reports examining low back pain behavior in animal models. The CatWalk is a computer-assisted gait analysis system that provides an automated way to assess gait function and pain-related alterations of this behavior. METHODS: In the IVD injury group, L5-L6 IVDs were injured with a 24-gauge needle. Simultaneously, the neurotracer Fluoro-Gold (FG; Fluorochrome, Denver, CO) was injected into the L5 L6 IVDs. In the sham group, FG was injected into the L5-L6 IVDs only. Animals in the control group received no operation. One, 2, 3, and 4 weeks after surgery, the gait of rats in the 3 groups was investigated using the CatWalk system. One, 2, and 4 weeks after surgery, in IVD injury and sham groups, dorsal root ganglions from the L1 to L6 levels were resected. Dorsal root ganglions were immunostained for calcitonin gene-related peptide. RESULTS: In the IVD injury group, the mean stands of hind paws and the mean duty cycle of front paws at some time points were significantly higher than those in the sham group. Furthermore, the mean stride length of the front and hind paws and the mean swing speed of the front and hind paws at some time points were significantly shorter than those in the sham group. The proportion of calcitonin gene-related peptide-immunoreactive, FG-labeled neurons among all FG-labeled dorsal root ganglion neurons in the IVD injury group was significantly higher than the corresponding proportion in the sham group. CONCLUSION: These results suggest that IVD injury produced significant changes in rat gait, including longer stance phases and shorter strides. In the future, we may be able to apply the CatWalk system to the evaluation of behavior associated with pain in models of low back pain. LEVEL OF EVIDENCE: N/A. PMID- 23649216 TI - Prospective randomized trial of chemonucleolysis compared with surgery for soft disc herniation with 1-year, intermediate, and long-term outcome: part II: the radiological outcome. AB - STUDY DESIGN: A prospective consecutive series of 100 patients computer randomized into 2 groups to have treatment by either chemonucleolysis or surgery. OBJECTIVE: To compare the radiological findings preoperatively with the clinical outcome between the groups at 1 year, 10 to 13, and 24 to 27 years of follow-up. SUMMARY OF BACKGROUND DATA: Chemonucleolysis was introduced in 1964 and became widely used. Its efficacy was proven by several randomized studies when compared with a placebo and surgery. However, it ceased to be manufactured in 2001. METHODS: One hundred consecutive patients were enrolled for the study and randomized according to age, sex, and disc level. Preoperatively, their anteroposterior, lateral lumbar spine, and lateral lumbosacral angle radiographs were obtained, and a myelogram was performed. At 10 to 13 years, 32 of the original patients (18 chemonucleolysis and 14 surgery) and at 24 to 27 years, 45 patients (24 chemonucleolysis and 21 surgery) were assessed by lateral lumbosacral angle radiographs. RESULTS: Using the myelographical findings, small, medium, and large herniations were digested by chymopapain with more of the failures being the larger ones. There was an equal degree of degenerative change as measured by disc height loss in the young and older age groups and the degree of degenerative change did not relate to outcome. The size of the defect did not relate to the degree of disc height loss. There was a slight loss of disc height over time in both groups. There was no difference in the loss of disc height between the treatments at any of the follow-up time points. CONCLUSION: Chemonucleolysis is as effective as surgery when assessed according to intention to-treat analysis. The loss of disc height over time is the same in both groups. The authors think that restoration of its availability would be beneficial to patients. LEVEL OF EVIDENCE: 1. PMID- 23649217 TI - An evaluation of web sites recommended by UK NHS consultants to patients with adolescent idiopathic scoliosis at the first point of diagnosis. AB - STUDY DESIGN: An Internet-based evaluation of Web sites using a validated assessment tool. OBJECTIVE: To evaluate the quality of information on scoliosis Web sites recommended by UK NHS consultants. SUMMARY OF BACKGROUND DATA: One of the most common sources of inquiry on the Web is for the purposes of health related information. The number of Web sites in the field of scoliosis has increased, yet the quality of information is reported to continue to be of poor quality. The 2 previous studies in this area identified Web sites for evaluation through the use of a single search term, "scoliosis," on the 5 most popular search engines. METHODS: Seven Web sites were identified for inclusion in this study from the results of a survey of UK NHS consultants. These were independently evaluated by 3 reviewers using a validated information assessment tool, the DISCERN instrument. DISCERN scores were analyzed for correlation between reviewers. Web sites were also analyzed for the presence or absence of the quality assurance certification, Health On the Net code. RESULTS: Significant correlations between the DISCERN scores were found for reviewers 1 and 2 (tau = 0.878, P = 0.006) and reviewers 2 and 3 (tau = 0.732, P = 0.029). The highest mean cumulative score for all items achieved by any of the Web sites evaluated was 49 (maximum = 80, minimum = 15). Only one Web site was found to display the Health On the Net code. CONCLUSION: Healthcare professionals should be aware of the content of Web sites that they recommend to patients. Web sites should be designed so the content suits patient needs. Web sites should be maintained such that content is up to date, evidence based, impartial, and written in plain language. LEVEL OF EVIDENCE: N/A. PMID- 23649218 TI - Goal achievement model for low back pain. PMID- 23649220 TI - Texture enhanced histogram equalization using TV- L1 image decomposition. AB - Histogram transformation defines a class of image processing operations that are widely applied in the implementation of data normalization algorithms. In this paper, we present a new variational approach for image enhancement that is constructed to alleviate the intensity saturation effects that are introduced by standard contrast enhancement (CE) methods based on histogram equalization. In this paper, we initially apply total variation (TV) minimization with a L(1) fidelity term to decompose the input image with respect to cartoon and texture components. Contrary to previous papers that rely solely on the information encompassed in the distribution of the intensity information, in this paper, the texture information is also employed to emphasize the contribution of the local textural features in the CE process. This is achieved by implementing a nonlinear histogram warping CE strategy that is able to maximize the information content in the transformed image. Our experimental study addresses the CE of a wide variety of image data and comparative evaluations are provided to illustrate that our method produces better results than conventional CE strategies. PMID- 23649219 TI - Morbidity and mortality associated with the utilization of restraints : a review of literature. AB - Use of physical restraints remains a highly controversial topic. Even with proven efficacy in restraint usage across multiple settings, for years, investigators have debated whether or not the risks outweigh the benefits. There is a growing concern regarding restraints-related negative consequences. Although over the past two decades, with new regulations, education and training, there has been a reduction in the prevalence of restraint episodes, morbidity and mortality are still disconcerting. Given this subject remains an issue today, a more up-to-date review of available literature is warranted. This article reviews the current literature surrounding the utilization of restraints that has been published over last 10 years with particular emphasis on restraints-related adverse outcomes. The vast amount of literature during the past decade demonstrates an increased awareness in potential dangers, as well as highlights new areas of research in restraint utilization. Despite the proliferation of studies, there continues to remain a lack of evidence from prospective studies that would elucidate the dangers from theory to practice. PMID- 23649221 TI - A novel joint data-hiding and compression scheme based on SMVQ and image inpainting. AB - In this paper, we propose a novel joint data-hiding and compression scheme for digital images using side match vector quantization (SMVQ) and image inpainting. The two functions of data hiding and image compression can be integrated into one single module seamlessly. On the sender side, except for the blocks in the leftmost and topmost of the image, each of the other residual blocks in raster scanning order can be embedded with secret data and compressed simultaneously by SMVQ or image inpainting adaptively according to the current embedding bit. Vector quantization is also utilized for some complex blocks to control the visual distortion and error diffusion caused by the progressive compression. After segmenting the image compressed codes into a series of sections by the indicator bits, the receiver can achieve the extraction of secret bits and image decompression successfully according to the index values in the segmented sections. Experimental results demonstrate the effectiveness of the proposed scheme. PMID- 23649222 TI - Effects of multimedia vocabulary instruction on adolescents with learning disabilities. AB - The purpose of this experimental study is to investigate the effects of using content acquisition podcasts (CAPs), an example of instructional technology, to provide vocabulary instruction to adolescents with and without learning disabilities (LD). A total of 279 urban high school students, including 30 with LD in an area related to reading, were randomly assigned to one of four experimental conditions with instruction occurring at individual computer terminals over a 3-week period. Each of the four conditions contained different configurations of multimedia-based instruction and evidence-based vocabulary instruction. Dependent measures of vocabulary knowledge indicated that students with LD who received vocabulary instruction using CAPs through an explicit instructional methodology and the keyword mnemonic strategy significantly outperformed other students with LD who were taught using the same content, but with multimedia instruction that did not adhere to a specific theoretical design framework. Results for general education students mirrored those for students with LD. Students also completed a satisfaction measure following instruction with multimedia and expressed overall agreement that CAPs are useful for learning vocabulary terms. PMID- 23649223 TI - Swiss contributions to war surgery during the Great War. AB - BACKGROUND: The role of neutral Switzerland during World War I is somewhat mysterious and its diplomatic history has never been fully disclosed. One of the activities might have determined its role: based on its relationship to the International Committee of the Red Cross, wounded multinational prisoners-of-war were interned in Swiss hospitals and Swiss physicians worked in a medical capacity in military hospitals on both sides of the front. QUESTIONS/PURPOSES: The main question is whether the activities of the Swiss authorities reflected a charitable diplomatic role while retaining the country's traditional neutral stance. Supplementary practical questions included: How did Switzerland carry out the exchange of severely wounded prisoners of war? How did Swiss physicians function in the war zones? What were the medical objectives and the ultimate results of wartime surgery in Switzerland? METHODS: This study is based on archival material from the Swiss Federal Archive in Bern (BAR) and original publications of Swiss and German physicians in professional journals. The search was performed manually in the BAR evaluating the file "Landesverteidigung (national defense)" from 1848 to 2009. Original publications and journals were searched manually in the central libraries of Munich, Heidelberg, Zurich, and Bern. RESULTS: The evaluation of Swiss diplomatic activities confirmed that Switzerland's charitable mission was aimed to enforce its neutral position and that Swiss authorities were able to efficiently manage the resulting problems. The engagement of Swiss surgeons in war surgery contributed to their experience and knowledge and yielded the development of many innovative medical devices and operating procedures, numerous of which are still known today. CONCLUSION: While maintaining its neutral position, Switzerland was able to deal with the practical problems while gaining innovative medical knowledge still valid today. PMID- 23649225 TI - Bundled payments in total joint arthroplasty: targeting opportunities for quality improvement and cost reduction. AB - BACKGROUND: Understanding the type and magnitude of services that patients receive postdischarge and the financial impact of readmissions is crucial to assessing the feasibility of accepting bundled payments. QUESTIONS/PURPOSES: The purposes of this study were to (1) determine the cost and service components of a 30-day total joint arthroplasty (TJA) episode of care; (2) analyze the portion of the total payment that is used for postdischarge services, including home care; and (3) to evaluate the frequency of readmissions and their impact on total episode-of-care payments. METHODS: All payments to Medicare providers (hospitals, postacute care facilities, physicians, and other healthcare providers) for services beginning with the index procedure and extending 30-days postdischarge were analyzed for 250 Medicare beneficiaries undergoing primary or revision TJA from a single institution over a 12 months. Payments and services were aggregated by procedure type and categorized as index procedure, postacute care, and related hospital readmissions. RESULTS: Mean episode-of-care payments ranged from USD 25,568 for primary TJA in patients with no comorbidities to USD 50,648 for revision TJA in patients with major comorbidities or complications, with wide variability within and across procedures. Postdischarge payments accounted for 36% of total payments. A total of 49% of patients were transferred to postacute care facilities, accounting for 70% of postdischarge payments. The overall 30-day unplanned readmission rate was 10%, accounting for 11% of postdischarge payments. CONCLUSIONS: Episode-of-care payments for TJAs vary widely depending on the type of procedure, patient comorbidities and complications, discharge disposition, and readmission rates. Postdischarge care accounted for more than one-third of total episode payments and varied substantially across patients and procedures. PMID- 23649224 TI - Veterans with diabetes receive arthroplasty more frequently and at a younger age. AB - BACKGROUND: A future increase in total joint arthroplasties in patients with diabetes seems likely considering the prevalence of osteoarthritis and diabetes mellitus are increasing. However, the rates of arthroplasty in the population of patients with diabetes are unclear. QUESTIONS/PURPOSES: We sought to determine whether lower extremity arthroplasties in a veteran population with diabetes is different from a similar population without diabetes. The following specific questions were asked: (1) Is the rate of TKA in veterans with diabetes higher than in those without diabetes? (2) Is the rate of THA in veterans with diabetes higher than in those without diabetes? (3) Are arthroplasty revision rates greater in veterans with diabetes than in veterans without diabetes? METHODS: The US Department of Veterans Affairs Health administrative data from fiscal year 2000 was used to identify persons with primary or secondary TKA or THA. The rate of surgeries among a diabetic population was compared with that among a nondiabetic population. RESULTS: The diabetic cohort received total joint arthroplasties at a higher rate than the nondiabetic cohort at all ages younger than 66 years, with a range of odd ratios from 1.3 to 3.4. In answer to our specific questions, (1) the rate of TKA (95% CI, 2.1-3.7), (2) the rate of THA (95% CI, 1.0-2.6), and (3) the rates of arthroplasty revision (95% CI, 0.9-5.8 TKA and 0.7-6.8 THA) were higher in veterans with diabetes. Furthermore, those with diabetes in the youngest age group studied received total joint arthroplasties and revision surgeries at approximately double the rates of those without diabetes. CONCLUSIONS: If these findings hold true for the population as a whole, they imply that clinicians in the United States may see a sharp increase in younger diabetic candidates for joint arthroplasty. PMID- 23649226 TI - Radiation minimization strategies for medical imaging : comment on "radiation safety in nuclear cardiology-current knowledge and practice". PMID- 23649228 TI - Experimental observation of C60 LUMO splitting in the C60(2-) dianions due to the Jahn-Teller effect. Comparison with the C60(-) radical anions. AB - New fullerene salts (TMP(+))2.(C60(2-)).(C6H4Cl2)2 (1), {DB-18-crown 6.[Na(+)].(C6H5CN)2}2.(C60(2-)).C6H5CN.C6H4Cl2 (2), {cryptand[2,2,2].(Na(+))}2.(C60(2-)) (3) and (PPN(+))2.(C60(2-)).(C6H4Cl2)2 (4) were obtained as single crystals. Their crystal structures were solved and their optical and magnetic properties were analyzed. The spectra of the salts in the IR and UV-visible-NIR ranges indicate the formation of C60(2-) dianions in 1-4. These salts show similar behavior in EPR measurements, explained by the diamagnetic ground state of the C60(2-) dianions and the thermal population of the excited triplet state, which is separated by an energy gap of 487-540 cm(-1). The magnetic susceptibility of 4 also increased above 130 K due to the population of the excited triplet state. The observed splitting of the C60 LUMO is attributed to the Jahn-Teller (JT) effect. We analyzed the splitting by an extended Huckel method using the single-crystal structural data for the compounds containing neutral, mono- and dianions of C60. The splitting of the initially triply degenerated C60 LUMO produces three molecular orbitals. The gap between the lowest and highest orbitals is very small in neutral C60 (128-140 cm(-1)), it increases in C60(-) (500-710 cm(-1)) and increases further in C60(2-) (1080-1670 cm(-1)). It was found that the splitting of the C60 LUMO is realized in different ways for the mono- and dianions. The ground and first excited state are separated in C60(-) by a small gap of 55-180 cm(-1) only. This gap is noticeably larger in the C60(2-) dianions and falls into the 760-1390 cm(-1) range. PMID- 23649227 TI - Cytokinin-induced cell death is associated with elevated expression of alternative oxidase in tobacco BY-2 cells. AB - N(6)-benzyladenine (BA) and N(6)-benzyladenosine ([9R]BA) induce massive production of reactive oxygen species (ROS) that is eventually followed by a loss of cell viability in tobacco BY-2 cells (Mlejnek et al. Plant Cell Environ 26:1723-1735, 2003, Plant Sci 168:389-395, 2005). Results presented in this work suggest that the main sources of ROS are likely mitochondria and that the maintenance of the mitochondrial transmembrane potential is crucial for ROS production in cytokinin-treaded BY-2 cells. Therefore, the possible involvement of alternative oxidase (AOX) in cell death process induced by BA and [9R]BA was studied. About three- to fourfold increase in mRNA levels of AOX1 was observed a few hours after the BA and [9R]BA addition into the growth medium. The elevated expression of AOX1 mRNA could be prevented by adding adenine and adenosine which simultaneously reduced the cytotoxic effects of BA and [9R]BA, respectively. N(6) benzyladenine 7-beta-D-glucoside ([7G]BA) which is a common non-toxic metabolite of BA and [9R]BA did not affect the AOX1 mRNA expression. Although AOX1 seemed to be involved in protection of BY-2 cells against the abiotic stress induced by BA and [9R]BA, the results do not support the idea that it protects cells from death exclusively by scavenging of reactive oxygen species. Indeed, N-propyl gallate, an inhibitor of AOX, decreased cell survival despite it concomitantly decreased the ROS production. This finding is in contrast to the effect of salicylhydroxamic acid, another well-known inhibitor of AOX, which also increased the number of dying cells while it increased the ROS production. PMID- 23649229 TI - Analysis of the tolerance of pathogenic enterococci and Staphylococcus aureus to cell wall active antibiotics. AB - OBJECTIVES: Tolerance refers to the phenomenon that bacteria do not significantly die when exposed to bactericidal antibiotics. Enterococci are known for their high tolerance to these drugs, but the molecular reasons why they resist killing are not understood. In a previous study we showed that the superoxide dismutase (SOD) is implicated in this tolerance. This conclusion was based on the results obtained with one particular strain of Enterococcus faecalis and therefore the objective of the present communication was to analyse whether dependence of tolerance on active SOD is a general phenomenon for enterococci and another Gram positive pathogen, Staphylococcus aureus. METHODS: Mutants deficient in SOD activity were constructed in pathogenic enterococci. The wild-type sodA gene was cloned into an expression vector and transformed into SOD-deficient strains for complementation with varying levels of SOD activity. Previously constructed SOD deficient strains of S. aureus were also included in this study. Tolerance to vancomycin and penicillin was then tested. RESULTS: We demonstrated that the dependence on SOD of tolerance to vancomycin and penicillin is a common trait of antibiotic-susceptible pathogenic enterococci. By varying the levels of expression we could also show that tolerance to vancomycin is directly correlated to SOD activity. Interestingly, deletion of the sodA gene in a non-tolerant Enterococcus faecium strain did not further sensitize the mutant to bactericidal antibiotics. Finally, we showed that the SOD enzymes of S. aureus are also implicated in tolerance to vancomycin. CONCLUSION: High tolerance of enterococci to cell wall active antibiotics can be reversed by SOD deficiency. PMID- 23649231 TI - Iron metabolism and risk of cancer in the Swedish AMORIS study. AB - OBJECTIVES: Pre-clinical studies have shown that iron can be carcinogenic, but few population-based studies investigated the association between markers of the iron metabolism and risk of cancer while taking into account inflammation. We assessed the link between serum iron (SI), total-iron binding capacity (TIBC), and risk of cancer by levels of C-reactive protein (CRP) in a large population based study (n = 220,642). METHODS: From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (>20 years old) with baseline measurements of serum SI, TIBC, and CRP. Multivariate Cox proportional hazards regression was carried out for standardized and quartile values of SI and TIBC. Similar analyses were performed for specific cancers (pancreatic, colon, liver, respiratory, kidney, prostate, stomach, and breast cancer). To avoid reverse causation, we excluded those with follow-up <3 years. RESULTS: We found a positive association between standardized TIBC and overall cancer [HR 1.03 (95% CI 1.01-1.05)]. No statistically significant association was found between SI and cancer risk except for postmenopausal breast cancer [HR for standardized SI 1.09 (95% CI 1.02-1.15)]. The association between TIBC and specific cancer was only statistically significant for colon cancer [i.e., HR for standardized TIBC: 1.17 (95% CI 1.08-1.28)]. A borderline interaction between SI and levels of CRP was observed only in stomach cancer. CONCLUSIONS: As opposed to pre-clinical findings for serum iron and cancer, this population-based epidemiological study showed an inverse relation between iron metabolism and cancer risk. Minimal role of inflammatory markers observed warrants further study focusing on developments of specific cancers. PMID- 23649232 TI - Impact of hormone replacement therapy use on mammographic screening outcomes. AB - PURPOSE: This study aims to measure the impact of HRT use at the time of screening on rates of screen-detected invasive breast cancer (IBC) and ductal carcinoma in situ (DCIS), interval cancers and investigative procedures, within a well-established population-based mammography screening program. METHODS: Using South Australian BreastScreen data from 1998 to 2009 pertaining to 819,722 screening episodes, Poisson regression models were undertaken to estimate the incidence risk ratios (IRR) for various screening outcomes at both the first and subsequent screening rounds, among women who had been using HRT in the 6 months prior to screening compared with those who had not. RESULTS: Current HRT use was associated with increased risk of recall for assessment, biopsy procedures, and breast cancer diagnosis among BreastScreen participants. Risk of screen-detected breast cancer was increased at subsequent screening rounds (IRR = 1.30, 95% confidence interval 1.18-1.34), but not at women's first screening round (1.05, 0.88-1.25). This increased risk applied to IBC (1.35, 1.27-1.45), but not to DCIS (1.04, 0.89-1.23). Interval cancer risk was elevated among HRT users following both the first screen (1.77, 1.33-2.37) and subsequent screening episodes (1.92, 1.72-2.15). CONCLUSIONS: Increased risks of recall, biopsy rates, screen detected, and interval cancers among HRT users have important implications for population-based breast cancer screening programs. Our findings support the concept that HRT use may increase the growth of preexisting cancers. Lack of effect on DCIS could imply different etiology or time frames for DCIS and IBC development or increased transition from preinvasive to invasive disease due to HRT use. PMID- 23649233 TI - Optimization of enzymatic treatment for compound K production from white ginseng extract by response surface methodology. AB - Ginsenoside 20-O-beta-D glucopyranosyl-20(S)-protopanaxadiol (compound K), a minor ginsenoside, is not found in white raw ginseng, but has better bioavailability than the major ginsenosides in ginseng. Employing commercial enzyme packages for industrial applications, the optimum conditions for enzymatic transformation for the highest content of compound K was explored to enhance the health benefits of ginseng extract. Cytolase PCL 5 was selected from commercial enzyme packages nominated for high beta-glucosidase activity. By response surface methodology, the optimal conditions were identified as 78 h of treatment at pH 4.3 at 55.4 degrees C for 2.068 mg/mL of compound K, showing good agreement with the experimental value. PMID- 23649234 TI - Atrogin-1/MAFbx, a muscle-specific ubiquitin ligase, is highly expressed in the smooth muscle of the chicken gizzard. AB - This study was conducted to investigate the expression of atrogin-1/MAFbx, a muscle-specific ubiquitin ligase, in the smooth muscle of the chicken gizzard. Atrogin-1/MAFbx mRNA expression was detected in the skeletal muscle, heart (cardiac muscle), gizzard (smooth muscle), brain, and liver of chicks, with highest expression in the smooth muscle of the gizzard. The expression of atrogin 1/MAFbx mRNA in the smooth muscle of the gizzard was increased by fasting (24 h), and this increase was reduced by refeeding (2 h). These results indicate that atrogin-1/MAFbx mRNA is highly expressed in the smooth muscle of the chicken gizzard, and that the expression of it is regulated by nutritional conditions. PMID- 23649235 TI - Increased growth of a hydrogenotrophic methanogen in co-culture with a cellulolytic bacterium under cathodic electrochemical regulation. AB - Bioelectrochemical (-0.8 V, -0.3 V, and +0.6 V vs. Ag/AgCl) and non bioelectrochemical co-cultures of a hydrogenotrophic methanogen and a cellulolytic bacterium were conducted. Unlike non-bioelectrochemical co-cultures, a cathodic reaction (-0.8 V) increased the growth of the hydrogenotrophic methanogen and the cellulolytic bacterium, by 6.0- and 2.2-fold respectively, and increased cellulose degradation. In contrast, anodic reactions (-0.3 V, +0.6 V) influenced them negatively. PMID- 23649236 TI - Structure-activity relationship for (+)-taxifolin isolated from silymarin as an inhibitor of amyloid beta aggregation. AB - Silymarin, the seed extract of Silybium marianum, has preventive effects against Alzheimer's disease-like pathogenesis in vivo. We isolated (+)-taxifolin (4) from silymarin as an inhibitor of aggregation of the 42-residue amyloid beta-protein. Structure-activity relationship studies revealed the 3',4'-dihydroxyl groups to be critical to the anti-aggregative ability, whereas the 7-hydroxyl group and the stereochemistry at positions 2 and 3 were not important. PMID- 23649237 TI - Plausible novel ribose metabolism catalyzed by enzymes of the methionine salvage pathway in Bacillus subtilis. AB - The methionine salvage pathway (MSP) recycles reduced sulfur from 5 methylthioribose. Here we propose a novel ribose metabolic pathway performed by MSP enzymes of Bacilli. MtnK, an initial catalyst of MSP, had significant ribose kinase activity, with Vmax and Km values of 2.9 umol min(-1) mg of protein(-1) and 4.8 mM. Downstream enzymes catalyzed the isomerization of ribose-1-phosphate and subsequent dehydration, enolization, dephosphorylation, and dioxygenation. PMID- 23649238 TI - Changes in B-group vitamin status in adenine-induced chronic renal failure rats. AB - The purpose of this study was to determine the effects of chronic renal failure (CRF) on B-group vitamin status using model rats in which adenine-induced CRF. We measured B-groups vitamins in the urine, blood, liver, and kidney. These results showed that renal failure affected the distribution, metabolism, and renal clearance of water-soluble vitamins, and that the effects were different with each vitamin. PMID- 23649239 TI - Neither endogenous abscisic acid nor endogenous jasmonate is involved in salicylic acid-, yeast elicitor-, or chitosan-induced stomatal closure in Arabidopsis thaliana. AB - Salicylic acid (SA), yeast elicitor (YEL), and chitosan (CHT) induced stomatal closure in Arabidopsis wild-type and aba2-2 plants, induced stomatal closure in fluridon-treated wild-type plants, and induced stomatal closure in aos mutants. These results suggest that neither endogenous abscisic acid nor endogenous jasmonic acid is involved in SA-, YEL-, or CHT-induced stomatal closure. PMID- 23649240 TI - Improvement of ethanol production from D-lactic acid by constitutive expression of lactate transporter Jen1p in Saccharomyces cerevisiae. AB - To improve ethanol production from D-lactate, Jen1p, a monocarboxylate-proton symporter, was constitutively expressed in Saccharomyces cerevisiae NAM34-4C. The mutant produced 2.4 g/L of ethanol, approximately 2.4 times higher than that of the wild-type strain. A monocarboxylate/proton symporter gene (JEN1) null mutant was also constructed. It produced 0.19 g/L of ethanol, 5 times lower than that of the wild-type strain. PMID- 23649241 TI - Inhibition by dietary D-psicose of body fat accumulation in adult rats fed a high sucrose diet. AB - We investigated the anti-obesity effects of dietary D-psicose on adult rats fed a high-sucrose diet. Wistar rats (16 weeks old) that had previously been fed a high sucrose diet (HSD) were fed HSD or a high-starch diet (HTD) with or without 5% D psicose for 8 weeks. The food efficiency, carcass fat percentage, abdominal fat accumulation, and body weight gain were all significantly suppressed by dietary D psicose. PMID- 23649242 TI - Teratogenic factors affect transcription factor expression. AB - Chemical compounds are produced every day, many with adverse effects on human health, and hence it is vital to predict the risks to humans simply, rapidly, and accurately. Teratogens have a serious impact on fetal development. This has been studied mainly by phenotypic analysis of experimental animals. However, since phenotypes can vary within different species, we established a new evaluation system based on our recent finding that teratogens influence Hox gene expression in mice. Similarly to the Hox gene expression changes, the expression patterns of several transcription factors involved in development, including the Dlx, Irx, Sall, and T-box families, were altered after 6 h of exposure to retinoic acid (RA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The expression changes in Dlx4, Dlx6, Irx5, Sall2, Sall3, Sall4, Tbx10, and Tbx22 were linked to teratogen induced phenotypes, and our results indicate that expression changes in developmental transcription factors can help to predict teratogenic risk. PMID- 23649243 TI - Dual-fluorescent RNA probes with an extremely large stokes shift. AB - Fluorescent probes are powerful and indispensable tools for imaging RNA in vivo and in vitro. To simultaneously visualize multiple RNA targets in a cell, it is necessary to develop probes which emit fluorescence with different colors by excitation at a single wavelength. We synthesized OMUpy1 and OMUpy2 in this study with a cyanine dye respectively conjugated at their 5' ends. A fluorescent analysis revealed these probes to have yellow or pink fluorescence derived from the cyanine dyes with an extremely large Stokes shift. Three color-coded fluorescent images were also obtained in the presence of target RNAs. PMID- 23649244 TI - Algicidal sesquiterpene hydroquinones from the brown alga Dictyopteris undulata. AB - Bioassay-guided fractionation of a methanol extract of the brown alga, Dictyopteris undulata, led to the isolation of a novel sesquiterpene hydroquinone named zonarenone, together with seven known sesquiterpene hydroquinones, zonarol, isozonarol, yahazunol, zonaroic acid, chromazonarol, isochromazonarol, and 2 (3,7,11-trimethyl-2,6,10-dodecatrienyl)hydroquinone. The structure of zonarenone was elucidated on the basis of spectroscopic information. The isolated compounds, excepting zonaroic acid, showed moderate to high cell lysis activity against the red tide microalgal species, Heterosigma akashiwo and Heterocapsa circularisquama, at a concentration of 1 ug/mL. PMID- 23649245 TI - Molecular diversity of tuliposide A-converting enzyme in the tulip. AB - Tuliposide A-converting enzyme (TCEA) catalyzes the conversion of 6-tuliposide A to its lactonized aglycon, tulipalin A, in the tulip (Tulipa gesneriana). The TgTCEA gene, isolated previously from petals, was transcribed in all tulip tissues but not in the bulbs despite the presence of TCEA activity, which allowed prediction of the presence of a TgTCEA isozyme gene preferentially expressed in the bulbs. Here, the TgTCEA-b gene, the TgTCEA homolog, was identified in bulbs. TgTCEA-b polypeptides showed approximately 77% identity to the petal TgTCEA. Functional characterization of the recombinant enzyme verified that TgTCEA-b encoded the TCEA. Moreover, the TgTCEA-b was found to be localized to plastids, as found for the petal TgTCEA. Transcript analysis revealed that TgTCEA-b was functionally transcribed in the bulb scales, unlike the TgTCEA gene, whose transcripts were absent there. In contrast, TgTCEA-b transcripts were in the minority in other tissues where TgTCEA transcripts were dominant, indicating a tissue preference for the transcription of those isozyme genes. PMID- 23649246 TI - Comparative study on the photostability of arbutin and deoxy arbutin: sensitivity to ultraviolet radiation and enhanced photostability by the water-soluble sunscreen, benzophenone-4. AB - Arbutin and deoxy arbutin may release hydroquinone under some conditions. We therefore investigated the photostability of arbutin and deoxy arbutin in an aqueous solution. The results revealed arbutin and deoxy arbutin to be photolabile in an aqueous solution. Deoxy arbutin was less stable than arbutin when exposed to UV radiation. The hydroquinone concentration was also increased during the radiation period in both solutions. Benzophenone-4 could clearly improve the photostability of arbutin during the period of UV radiation, but only slightly enhance the photostability of deoxy arbutin. PMID- 23649247 TI - Pentose oxidation by acetic acid bacteria led to a finding of membrane-bound purine nucleosidase. AB - D-Ribose and 2-deoxy-D-ribose were oxidized to 4-keto-D-ribonate and 2-deoxy-4 keto-D-ribonate respectively by oxidative fermentation, and the chemical structures of the oxidation products were confirmed to be as expected. Both pentoses are important sugar components of nucleic acids. When examined, purine nucleosidase activity predominated in the membrane fraction of acetic acid bacteria. This is perhaps the first finding of membrane-bound purine nucleosidase. PMID- 23649248 TI - Assessment of key amino-acid residues of CD36 in specific binding interaction with an oxidized low-density lipoprotein. AB - CD36 binds oxidized low-density lipoprotein (oxLDL). A synthetic peptide comprising amino-acid residues 149-168 of mouse CD36 was recently found to bind fluorescence-labeled oxLDL particles. Based on our oxLDL-binding analysis of various synthetic CD36 peptides, we suggest that not only hydrophilic residues (e.g., Lys164 and Lys166) but also hydrophobic ones (e.g., Phe153, Leu158, and Leu161) are critical to binding. PMID- 23649249 TI - Biochanin A protects against acute carbon tetrachloride-induced hepatotoxicity in rats. AB - Biochanin A (BCA) is an isoflavone found in red clover possessing multiple pharmacological activities including antimicrobial, antioxidant, and anticancer ones. The present study aimed to assess its hepatoprotective potential at different doses in a carbon tetrachloride (CCl4)-induced hepatotoxicity model in rats. The effects on hepatic injury were explored by measuring serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Furthermore, the serum levels of glucose, urea, creatinine, total bilirubin, total proteins, triglycerides, and total cholesterol were determined. The metabolic capacity of the liver was assessed by measuring changes in cytochrome P450 2E1 activity. The underlying mechanisms were substantiated by measuring oxidative stress markers as catalase, superoxide dismutase, glutathione peroxidase, glutathione transferase, glutathione reductase, reduced glutathione, total antioxidant capacity, and lipid peroxidation, as well as inflammation markers such as nitric oxide, inducible nitric oxide synthase, cyclooxygenase2, tumor necrosis factor-alpha, and leukocyte-common antigen. The results were confirmed by histopathological examination, and the median lethal dose was determined to confirm the safety of the drug. BCA successively protected against CCl4-induced damage, normalizing many parameters to that of the control group. The study indicates that BCA possesses multimechanistic hepatoprotective activity that can be attributed to its antioxidant, anti-inflammatory, and immunomodulatory actions. PMID- 23649250 TI - Genome-wide screening to study breeding methods to improve the nitrogen accumulation ability of yeast without gene recombinant techniques. AB - To remove nitrogen efficiently from high-concentration organic wastewater, we studied breeding methods using Saccharomyces cerevisiae as a model yeast with improved nitrogen accumulation ability. By DNA microarray analysis under various nitrogen concentrations with two nitrogen sources (peptone and L-asparagine), we obtained 295 commonly overexpressed (over 2-fold) genes and 283 commonly underexpressed (under one-half) genes under nitrogen-starvation conditions. We speculated that overexpression or underexpression recombination of some of these genes might enhance nitrogen uptake. Because a complete collection of nonessential gene deletion strains had been created, we investigated the nitrogen accumulation profiles of underexpressed gene deletion strains. From 256 nonessential gene deletion strains, three (URE2, SNO1, and AVT3) were selected. Strain SUD2 (ure2Delta::kanMX4) improved by 1.2-fold total nitrogen per cell (TN/OD660) as compared to the parent strain, S288c. Positive selection of methylamine-resistant mutants to obtain URE2 mutants was useful for improving nitrogen accumulation ability without recombinant techniques. PMID- 23649251 TI - High-throughput screening of inhibitors targeting Agr/Fsr quorum sensing in Staphylococcus aureus and Enterococcus faecalis. AB - Staphylococcus aureus and Enterococcus faecalis employ cyclic peptide-mediated quorum sensing (QS) systems, termed agr and fsr respectively, to regulate the expression of a series of virulence genes. To identify quorum sensing inhibitors (QSIs) that target agr/fsr systems, an efficient screening system was established. In addition to the gelatinase-induction assay to examine E. faecalis fsr QS, the use of an S. aureus agr reporter strain that carries luciferase and green fluorescence protein genes under the agr P3 promoter facilitated the development of a high-throughput screen (HTS) for QSIs. As a result of screening of 906 actinomycetes culture extracts, four showed QSI activity against the agr and fsr systems without growth inhibitory activity. The extracts were purified on a small scale, and three HPLC peaks were obtained with obvious QSI activity. In sum, the established HTS system is a promising strategy for the discovery of anti pathogenic agents targeting cyclic peptide-mediated QS in Gram-positive pathogens. PMID- 23649252 TI - Magnesium chloride concentration-dependent formation of tofu-like precipitates with different physicochemical properties. AB - A wet precipitate is generated in the process of making tofu by adding a coagulant to the basic soymilk ingredient. We investigated the magnesium chloride concentration-dependent change in the precipitate weight. The wet precipitate weight dramatically increased following a short plateau phase at a low concentration of magnesium chloride. It is interesting that this weight slightly decreased following a long plateau phase at a high concentration. These low and high concentrations respectively induced precipitates with a smooth surface and rough surface. The precipitate with a smooth surface had a higher water content than that with a rough surface. These precipitates also had obviously different solubility in various chemical reagents. The different properties indicate that these precipitates were formed by different intermolecular interactions. These results can be utilized to more clearly understand the mechanisms involved in tofu formation. PMID- 23649253 TI - Analysis of magnetotactic behavior by swimming assay. AB - Prokaryotic organelles called magnetosomes allow magnetotactic bacteria to navigate along geomagnetic field lines. In this study, we modified a swimming assay commonly used to assess bacterial motility to develop a new method of assessing magnetotactic motility. By this method, the swimming assay was performed in an artificial magnetic field. Magnetotactic bacteria formed a wedge shaped swimming halo that elongated parallel to the magnetic field. Magnetotactic motility was qualitatively assessed by comparing halo shapes. We termed this method the magnetic swimming assay. On the magnetic swimming assay, the mamK deletion strain formed a shorter halo than the wild type, indicating that the assay sensitively detects differences in magnetotactic motility. Moreover, we isolated two spontaneous magnetotactic motility mutants using magnetic swimming plates. Our findings indicate that the magnetic swimming assay is a useful method for the sensitive analysis of magnetotaxis phenotypes and mutant screening. PMID- 23649254 TI - Determination by LC-MS of juvenile hormone titers in hemolymph of the silkworm, Bombyx mori. AB - Juvenile hormone (JH) I, II and III in the hemolymph of the silkworm, Bombyx mori were quantified by liquid chromatography-mass spectrometry (LC-MS). JHs were treated with methanol and trifluoroacetic acid to convert into JH methoxyhydrines (JH-MHs). The key to the analytical condition for JH-MHs was the addition of 5 uM sodium acetate to the eluting solution. Each JH-MH was observed as the sodium adduct ion with good sensitivity. This improved method enabled the titration of JH I, II and III in hemolymph of the silkworm to be monitored from the 3rd instar through to the early pupal stage. A peak of JH I was observed immediately after ecdysis in the 3rd and 4th instar stages. The JH I titer sharply decreased on day 1 and reached the lowest level before ecdysis, but there was no peak at the beginning of the 5th stadium, and no apparent increase was observed until pupation. PMID- 23649255 TI - Contribution of structural reversibility to the heat stability of the tropomyosin shrimp allergen. AB - Tropomyosins are common heat-stable crustacean allergens. However, their heat stability and their effects on antigenicity have not been clarified. We purified tropomyosin in this study from raw kuruma prawns (Marsupenaeus japonicus) without heat processing. SDS-PAGE of the purified protein showed a band at approximately 35 kDa that cross-reacted with IgE from the serum of a shrimp-allergic patient, identifying it as Pen j 1. The circular dichroism spectrum of native Pen j 1 revealed the common alpha-helical structure of tropomyosins which easily collapsed upon heating to 80 degrees C. However, there were no insoluble aggregates after heating, and the protein regained its native CD spectral pattern after cooling to 25 degrees C. There was no significant difference in total IgG production between mice sensitized with native and heated Pen j 1. These results suggest that heat-denatured Pen j 1 refolded upon cooling and maintained its antigenicity following the heat treatment. PMID- 23649256 TI - Nitric oxide induces vascular endothelial growth factor expression in the rat placenta in vivo and in vitro. AB - We investigated the role of nitric oxide (NO) in vascular endothelial growth factor (VEGF) expression in the rat placenta. A nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine-methyl ester (L-NAME), was constantly infused into pregnant rats 6-24 h before sacrifice on gestational day (GD) 15.5. NO production declined to about 15% of the control level as monitored by NO trapping and electron paramagnetic resonance spectroscopy. VEGF mRNA expression was temporally decreased by L-NAME, but recovered to normal levels after 24 h of treatment, whereas hypoxia inducible factor (HIF)-1alpha and induced NOS (iNOS) expression increased. VEGF expression decreased significantly in placental explants after 6 h of co-treatment with L-NAME and lipopolysaccharide, an iNOS inducer. Our data indicate that NO induce VEGF expression in vivo and in vitro in the rat placenta, suggesting that peaked NO production was maintained by a reciprocal relationship between NO and VEGF via HIF-1alpha. PMID- 23649257 TI - Glucosinolate degradation products, isothiocyanates, nitriles, and thiocyanates, induce stomatal closure accompanied by peroxidase-mediated reactive oxygen species production in Arabidopsis thaliana. AB - Isothiocyanates, nitriles, and thiocyanates are degradation products of glucosinolates in crucifer plants. In this study, we investigated the stomatal response to allyl isothiocyanate (AITC), 3-butenenitrile (3BN), and ethyl thiocyanate (ESCN) in Arabidopsis. AITC, 3BN, and ESCN induced stomatal closure in the wild type and the atrbohD atrbohF mutant. Stomatal closure was inhibited by catalase and salicylhydroxamic acid (SHAM). The degradation products induced extracellular reactive oxygen species (ROS) production in the rosette leaves, and intracellular ROS accumulation, NO production, and cytosolic free calcium concentration ([Ca(2+)]cyt) oscillations in guard cells, which were inhibited by SHAM. These results suggest that glucosinolate degradation products induce stomatal closure accompanied by extracellular ROS production mediated by SHAM sensitive peroxidases, intracellular ROS accumulation, and [Ca(2+)]cyt oscillation in Arabidopsis. PMID- 23649258 TI - Distribution of major xanthones in the pericarp, aril, and yellow gum of mangosteen (Garcinia mangostana linn.) fruit and their contribution to antioxidative activity. AB - Xanthone compounds in mangosteen (Garcinia mangostana Linn.) fruit have been reported to have biological activities including antioxidative and anti inflammatory effects, and the major xanthone compounds in mangosteen are alpha mangostin and gamma-mangostin. The objectives of this research were to quantify and qualify the major xanthones in each part of the mangosteen fruit with and without yellow gum from the point of view of effective utilization of agricultural product. Quantitative evaluation revealed that yellow gum had extremely high amounts of alpha-mangostin and gamma-mangostin (382.2 and 144.9 mg/g on a wet basis, respectively) followed by pericarp and aril. In mangosteen fruit with yellow gum inside, xanthones seemed to have shifted from the pericarp and to have concentrated in a gum on the surface of aril, and there was almost no difference between the amounts of alpha-mangostin and gamma-mangostin in whole fruits with and without yellow gum. Pericarp and yellow gum showed much higher radical-scavenging activity and ferric reducing antioxidant potential than the aril. PMID- 23649259 TI - Identification of rice beta-glucosidase with high hydrolytic activity towards salicylic acid beta-D-glucoside. AB - beta-Glucosidases (EC 3.2.1.21) split beta-glucosidic linkages at the non reducing end of glucosides and oligosaccharides to release beta-D-glucose. One of the important functions of plant beta-glucosidase is deglucosylation of inactive glucosides of phytohormones to regulate levels of active hormones. Tuberonic acid is a jasmonate-related compound that shows tuber-inducing activity in the potato. We have identified two enzymes, OsTAGG1 and OsTAGG2, that have hydrolytic activity towards tuberonic acid beta-D-glucoside in rice (Oryza sativa L.). The expression of OsTAGG2 is upregulated by wounding and by methyl jasmonate, suggesting that this isozyme is involved in responses to biotic stresses and wounding, but the physiological substrate of OsTAGG2 remains ambiguous. In this study, we produced recombinant OsTAGG2 in Pichia pastoris (rOsTAGG2P), and investigated its substrate specificity in detail. From 1 L of culture medium, 2.1 mg of purified recombinant enzyme was obtained by ammonium sulfate precipitation and Ni-chelating column chromatography. The specific activity of rOsTAGG2P (182 U/mg) was close to that of the native enzyme (171 U/mg), unlike recombinant OsTAGG2 produced in Escherichia coli, which had approximately 3-fold lower specific activity than the native enzyme. The optimum pH and temperature for rOsTAGG2P were pH 3.4 and 60 degrees C. After pH and heat treatments, the enzyme retained its original activity in a pH range of 3.4-9.8 and below 55 degrees C. Native OsTAGG2 and rOsTAGG2P showed 4.5-4.7-fold higher activities towards salicylic acid beta-D-glucoside, an inactive storage-form of salicylic acid, than towards tuberonic acid beta-D-glucoside (TAG), although OsTAGG2 was originally isolated from rice based on TAG-hydrolytic activity. PMID- 23649260 TI - A preparation of cow's late colostrum fraction containing alphas1-casein promoted the proliferation of cultured rat intestinal IEC-6 epithelial cells. AB - Colostrum is a complex mixture of bioactives that promotes neonate growth. Recently, we have found by in vivo study that skimmed, sterilized, and concentrated bovine late colostrum (SCBLC), obtained from a Holstein herd on days 6-7 after parturition, had an ability to maintain intestinal integrity. In the present study we investigated effects of SCBLC on rat intestinal IEC-6 cell proliferation in vitro. A fraction containing alphas1-casein was found to have a robust stimulation effect as compared to other protein fractions from SCBLC and even the alphas1-casein fraction from milk from other Holstein herds. Furthermore, the SCBLC alphas1-casein molecule demonstrated not only slightly slower mobility on both SDS- and native-PAGE than other bovine milk alphas1 caseins, but also a peculiar conformation reminiscent of moltenglobule in the circular dichroism spectrum. These findings may be of relevant to the competence of SCBLC to preserve intestinal integrity. PMID- 23649261 TI - Identification of alkylbenzene sulfonate surfactants leaching from an acrylonitrile butadiene rubber as novel inhibitors of calcineurin activity. AB - Calcineurin (CN) is a Ca(2+)/calmodulin (CaM) dependent serine/threonine protein phosphatase and plays important role in several cellular functions in both higher and lower eukaryotes. Here we report inhibition of CN by linear alkylbenzene sulfonate. The clue to the finding was obtained while identifying the inhibitory material leaching from acrylonitrile butadiene rubber used for packing. Using standard dodecylbenzene sulfonate (C12-LAS), we obtained strong inhibition of CN with a half maximal inhibitory concentration of 9.3 uM, whereas analogs such as p octylbenzene sulfonate and SDS hardly or only slightly affected CN activity. Three alkaline phosphatases, derived from shrimp, bacteria, and calf-intestine, which exhibit similar enzymatic activities to CN, were not inhibited by C12-LAS at concentrations of up to 100 uM. Furthermore, C12-LAS did not inhibit Ca(2+)/CaM-dependent myosin light chain kinase activity when tested at concentrations of up to 36 uM. The results indicate that C12-LAS is a potent selective inhibitor of CN activity. PMID- 23649262 TI - Studies targeting alpha-glucosidase inhibition, antiangiogenic effects, and lipid modification regulation: background, evaluation, and challenges in the development of food ingredients for therapeutic purposes. AB - Since the discovery of alpha-glucosidase inhibitors and their inhibitory effects on the digestion of carbohydrates, promising results have been obtained as to the antidiabetic effects of this family of compounds. Antiangiogenic compounds have been identified that suppress tumor growth via a unique mechanism, confirming that such compounds can act as clinically applicable anticancer agents. Lipid peroxidation and lipid glycation have been suggested to play roles in food deterioration and in the pathophysiology of human diseases such as atherogenesis and diabetes, and antioxidative and antiglycative compounds can potentially be used in the prevention of food deterioration as well as to treat disease. On this basis, this review describes studies of alpha-glucosidase inhibition by mulberry 1-deoxynojirimycin, antiangiogenic effects of rice bran tocotrienol, and membrane lipid peroxidation/glycation and its inhibitors. These studies are ongoing in our work, with an emphasis on analytical techniques. PMID- 23649263 TI - Utilization of lactic acid bacterial genes in Synechocystis sp. PCC 6803 in the production of lactic acid. AB - Metabolic pathway engineering of cyanobacteria for the production of industrially important chemicals from atmospheric CO2 has generated interest recently. Here, we engineered Synechocystis sp. PCC 6803 to produce lactic acid using a lactate dehydrogenase (ldh) gene from various lactic acid-producing bacteria, Lactococcus lactis (ldhB and ldhX), Lactobacillus plantarum (ldhL and ldh), and Lactobacillus rhamnosus (ldhL). The lactic acid was secreted outside the cell using a transporter (lldp) gene from L. plantarum. Expression of each ldh in Synechocystis sp. PCC6803 was ascertained by reverse-transcriptase polymerase chain reaction. Five transformants led to the production of L-lactic acid. Co expression of lldp with ldhB from L. plantarum or ldhL from L. rhamnosus led to the secretion of lactic acid into the medium at concentration of 0.17 +/- 0.02 or 0.14 +/- 0.02 mM after 18 d of cultivation. PMID- 23649264 TI - Potential involvement of N-terminal acetylation in the quantitative regulation of the epsilon subunit of chloroplast ATP synthase under drought stress. AB - In plants, modulation of photosynthetic energy conversion in varying environments is often accompanied by adjustment of the abundance of photosynthetic components. In wild watermelon (Citrullus lanatus L.), proteome analysis revealed that the epsilon subunit of chloroplast ATP synthase occurs as two distinct isoforms with largely-different isoelectric points, although encoded by a single gene. Mass spectrometry (MS) analysis of the epsilon isoforms indicated that the structural difference between the epsilon isoforms lies in the presence or absence of an acetyl group at the N-terminus. The protein level of the non-acetylated epsilon isoform preferentially decreased in drought, whereas the abundance of the acetylated epsilon isoform was unchanged. Moreover, metalloprotease activity that decomposed the epsilon subunit was detected in a leaf extract from drought stressed plants. Furthermore, in vitro assay suggested that the non-acetylated epsilon subunit was more susceptible to degradation by metalloaminopeptidase. We propose a model in which quantitative regulation of the epsilon subunit involves N-terminal acetylation and stress-induced proteases. PMID- 23649265 TI - Establishment of an in vitro model of the human placental barrier by placenta slice culture and ussing chamber. AB - Our purpose was to establish an in vitro model of the human placental barrier based on placenta slice culture and Ussing chamber. The villous morphology, beta human chorionic gonadotropin (beta-hCG), mRNA and efflux function of P glycoprotein (P-gp), and the permeability of the fluorescent marker were confirmed. The results showed that syncytiotrophoblast cells with abundant endoplasmic reticulum and mitochondria were covered with a dense microvillus in the placenta slice. The beta-hCG secretion levels in the Ussing chamber were 274.13 +/- 13.52 mIU/mL at 5 h, significantly higher than that in the incubator 95.2 +/- 13.14 mIU/mL, and beta-hCG continued to secrete for 48 h. P-gp mRNA was expressed in the placenta slice. The Rho123 apparent permeability coefficient (Papp) value from maternal side to the fetal side was 26.34 +/- 1.87 nm/s, but it was significantly increased, to 289.55 +/- 6.02 nm/s after adding verapamil. The Rho123 efflux value was >2. The fluorescein Papp value was (3.42 +/- 0.24) * 10( 3) nm/s. In contrast, the fluorescein isothiocyanate-dextran (FD70) Papp value was (3.93 +/- 0.08) * 10(-5) nm/s. This indicates that the placenta slice in the Ussing chamber had the activity of a placenta, and can act as a valuable in vitro model of placental barrier. PMID- 23649266 TI - Identification of major facilitator transporters involved in cellulase production during lactose culture of Trichoderma reesei PC-3-7. AB - Although lactose is a preferred cellulase inducer in the industrial production of cellulase by Trichoderma reesei, the mechanism of induction is not fully understood. Because sugar transporters might be involved at an early step of induction by oligosaccharides, we sought permeases associated with cellulase induction by lactose. Two such MFS sugar transporters in the T. reesei hyper cellulolytic PC-3-7 strain, an industrial cellulase producer developed in Japan, were identified in a screening for lactose permeases. Disruption of the genes encoding these two transporters resulted in decreased lactose uptake and delayed growth in lactose culture. Further, the deletion strains produced less cellulase when cultivated on lactose. No substantial differences were observed in cellulase production when PC-3-7 was cultivated in cellulose-based medium. The present work provides evidence that these transporters are critical for cellulase production in lactose culture. PMID- 23649267 TI - Intracellular retention and subsequent release of bovine milk lactoferrin taken up by human enterocyte-like cell lines, Caco-2, C2BBe1 and HT-29. AB - Lactoferrin (LF) is an iron-binding glycoprotein contained in milk and other exocrine fluids, and is believed to have multiple biological functions. We investigated the intracellular dynamics of LF taken up by three lines of human enterocytes and the subsequent release of internalized LF by using two-site ELISA and confocal microscopy. LF taken up by Caco-2 cells was kept partially intact within the cells and subsequently released to the medium as degraded fragments of 30-50 kDa. The retention and subsequent release of LF by Caco-2 cells were much more abundant than those of ovalbumin, ovomucoid and lysozyme. Such results characteristic of LF were also similarly observed in C2BBe1 and HT29 cells more markedly. LF was detected as punctate signals and partially colocalized with the lactoferrin receptor, intelectin-1, in the respective cytoplasm and nuclei of Caco-2 and C2BBe1 cells. In contrast, LF within the HT-29 cells was detected as much smaller punctate signals scattered in the cytoplasm. PMID- 23649268 TI - Screening and characterization of novel bacteriocins from lactic acid bacteria. AB - Bacteriocins produced by lactic acid bacteria (LAB) are expected to be safe antimicrobial agents. While the best studied LAB bacteriocin, nisin A, is widely utilized as a food preservative, various novel ones are required to control undesirable bacteria more effectively. To discover novel bacteriocins at the early step of the screening process, we developed a rapid screening system that evaluates bacteriocins produced by newly isolated LAB based on their antibacterial spectra and molecular masses. By means of this system, various novel bacteriocins were identified, including a nisin variant, nisin Q, a two peptide bacteriocin, lactococcin Q, a leaderless bacteriocin, lacticin Q, and a circular bacteriocin, lactocyclicin Q. Moreover, some LAB isolates were found to produce multiple bacteriocins. They were characterized as to their structures, mechanisms of action, and biosynthetic mechanisms. Novel LAB bacteriocins and their biosynthetic mechanisms are expected for applications such as food preservation and peptide engineering. PMID- 23649269 TI - Mammalian ESCRT-III-related protein IST1 has a distinctive met-pro repeat sequence that is essential for interaction with ALG-2 in the presence of Ca2+. AB - ALG-2 is an EF-hand-type Ca(2+)-binding protein that interacts with a variety of intracellular proteins that possess Pro-rich regions (PRRs) in mammalian cells. IST1 is an endosomal sorting complex required for transport (ESCRT)-III-related charged multivesicular body protein (CHMP)-like protein, but unlike other ESCRT III proteins, mammalian IST1 has a PRR and a distinctive sequence of Met-Pro repeats. We found that ALG-2 binds to IST1 by Far-Western analysis using biotinylated ALG-2 as probe, and that the Met-Pro repeat sequence is essential for interaction. The results of pulldown assays using Strep-tagged ALG-2 and lysates of cells expressing GFP-fused IST1 proteins indicated that the binding of ALG-2 to IST1 is Ca(2+)-dependent, and that it is enhanced by co-expression with CHMP1 proteins. Moreover, pulldown assays using various mutants of GST-ALG-2 revealed that the ability of IST1 to bind to mutants is different from those of known ALG-2-interacting proteins, suggesting that IST1 binds to ALG-2 by a different mode of recognition. PMID- 23649270 TI - Effects of fats and oils on the bioaccessibility of carotenoids and vitamin E in vegetables. AB - The low bioavailability of lipophilic micronutrients is mainly caused by their limited solubilization to an aqueous micelle, which hinders their ability to be taken up by the intestines. Bioaccessibility is the ratio of the solubilized portion to the whole amount ingested. We evaluated in this study the effects of individual fats and oils and their constituents on the bioaccessibility of carotenoids and vitamin E in vegetables by simulated digestion. Various fats and oils and long-chain triacylglycerols enhanced the bioaccessibility of beta carotene present in spinach, but not of lutein and alpha-tocopherol, which are less hydrophobic than beta-carotene. Free fatty acid, monoacylglycerol, and diacylglycerol also enhanced the bioaccessibility of beta-carotene present in spinach. In addition to the long-chain triacylglycerols, their hydrolyzates formed during digestion would facilitate the dispersion and solubilization of beta-carotene into mixed micelles. Dietary fats and oils would therefore enhance the bioaccessibility of hydrophobic carotenes present in vegetables. PMID- 23649271 TI - L-Glutamate secretion by the N-terminal domain of the Corynebacterium glutamicum NCgl1221 mechanosensitive channel. AB - The Corynebacterium glutamicum NCgl1221 mechanosensitive channel mediates L glutamate secretion by sensing changes in membrane tension caused by treatments such as biotin limitation and penicillin. The NCgl1221 protein has an N-terminal domain (1-286 a.a.) homologous to the Escherichia coli MscS and a long C-terminal domain (287-533 a.a.) of unknown function. In order to investigate the role of the C-terminal domain in L-glutamate secretion, we constructed a series of C terminally truncated mutants of NCgl1221. We found that the N-terminal domain, homologous to E. coli MscS, retained the ability to cause L-glutamate secretion in response to the treatment. Electrophysiological analysis confirmed that the N terminal domain mediated L-glutamate secretion. 3D homology modeling has suggested that the N-terminal domain of NCgl1221 has an extra loop structure (221 232 a.a.) that is not found in most other MscS proteins. The mutant NCgl1221, deleted for this loop structure, lost the ability to secrete L-glutamate. In addition, we found that mutant NCgl1221 lacking the C-terminal extracytoplasmic domain (420-533 a.a.) produced L-glutamate without any inducing treatment. These results suggest that the N-terminal domain is necessary and sufficient for the excretion of L-glutamate in response to inducing treatment, and that the C terminal extracytoplasmic domain has a negative regulatory role in L-glutamate production. PMID- 23649272 TI - The periodontopathogenic bacterium Eikenella corrodens produces an autoinducer-2 inactivating enzyme. AB - Eikenella corrodens produces autoinducer-2 (AI-2) in the mid log phase, and AI-2 activity decreases dramatically during the stationary phase. We investigated the mechanism underlying this decrease in AI-2 activity. To analyze the mechanism, we extracted and purified AI-2 from the supernatant of mid-log-phase culture. Simultaneously, the stationary-phase culture supernatant was fractionated by ammonium sulfate precipitation. On incubating purified AI-2 and 4-hydroxy-5 methyl-3(2H)-furanone (MHF) with each fraction, the 30% fraction decreased both AI-2 and MHF activities. The data suggest that AI-2 and MHF were rendered inactive in the same manner. Heat and/or trypsin treatment of the 30% fraction did not completely arrest AI-2 inactivation, suggesting that partially heat stable proteins are involved in AI-2 inactivation. We observed that an enzyme converted MHF to another form. This suggests that E. corrodens produces an AI-2 inactivating enzyme, and that AI-2 can be degraded or modified by it. PMID- 23649273 TI - Fission yeast leucine-rich repeat protein Lrp1 is essential for cell morphogenesis as a component of the morphogenesis Orb6 network (MOR). AB - In eukaryotes, cell morphogenesis is regulated coordinately with the cell cycle. In fission yeast, the morphogenesis network MOR (morphogenesis Orb6 network) consists of 5 conserved proteins, Pmo25, Nak1, Mor2, Orb6, and Mob2, and is essential for cell polarity control and cell separation following cytokinesis. Here we show that the conserved leucine-rich repeat protein Lrp1 is required for cell morphogenesis as a newly recognized component of MOR. Lrp1 has 4 leucine rich repeats in its N-terminus and is a homolog of the budding yeast Sog2, which is a component of the RAM network (regulation of Ace2 activity and cellular morphogenesis). Lrp1 was essential for both cell growth and cell morphogenesis as were the other MOR components. Lrp1 was localized to the SPBs (spindle pole bodies, the yeast equivalent of the animal centrosome) throughout the cell cycle and to the medial ring during cytokinesis. Lrp1 interacted with Nak1 and was important for Orb6 kinase activity. Thus Lrp1 proved to function upstream of Orb6 in cell morphogenesis. PMID- 23649274 TI - A point mutation in ftmD blocks the fumitremorgin biosynthetic pathway in Aspergillus fumigatus strain Af293. AB - Fumitremorgins (FTMs), tremorgenic mycotoxins produced by the human pathogen Aspergillus fumigatus, are prenylated indole alkaloids that have been extensively studied in view of their diverse chemical structures and biological activities. Their biosynthetic gene (ftm) cluster was identified on the basis of the genome sequence of A. fumigatus. However, it has been reported that the ftm cluster in genome reference strain Af293 is inactive, which makes complete understanding of the FTM pathway difficult. Hence, we used an FTM-producing strain of A. fumigatus, BM939, to dissect the FTM pathway. Here, we delineate the genetic determinant for the observed defect in the FTM pathway in A. fumigatus Af293. Metabolite profiling and sequence comparison of the two strains revealed a point mutation in ftmD as a possible cause of altered metabolite production in strain Af293. FTM production in Af293 was restored when a DNA fragment containing ftmD from BM939 was introduced. Biochemical analysis indicated that FtmD is a methyltransferase that catalyzes the conversion of 6-hydroxytryprostatin B into tryprostatin A. The mutated FtmD retained enzymatic activity but did not function under physiological conditions, resulting in blockage of the FTM pathway in A. fumigatus Af293. PMID- 23649275 TI - Salak plum peel extract as a safe and efficient antioxidant appraisal for cosmetics. AB - The antioxidant activities of Salak plum (Salacca edulis) peel extracts were assessed by 1, 1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azino-bis(3 ethylbenzothaiazoline)-6-sulfonic acid (ABTS), and ferric reducing ability of plasma (FRAP) assays. The ethyl acetate (EtOAc) fraction was the most potent (DPPHIC50=2.932 +/- 0.030 ug/mL, ABTSIC50=7.933 +/- 0.049 ug/mL, FRAPEC=7,844.44 +/- 40.734). Chlorogenic acid was detected as the marker (1.400 +/- 0.102 g/kg). The EtOAc fraction was non-cytotoxic in vero and normal human fibroblast (NHF) cells. It exhibited cellular oxidative prevention and damage treatment at 5-40 ug/mL in NHF cells. Salak plum peel loaded liposome consisting of lecithin and hydrophobically modified hydroxyethylcellulose (HMHEC) was developed and found stable with adequate entrapment efficacy. Thus Salak plum peel was highlighted as a potential ecological antioxidant for health promotion aspects, and for cosmetics. PMID- 23649276 TI - Different expression profiles of bioactive peptides in Pelophylax nigromaculatus from distinct regions. AB - Amphibian skin is an abundant repository of bioactive peptides, important components of the defensive system. The variability of the bioactive peptide repertoires of individual species remains unclear. In this study, dark-spotted frogs were collected from Kunming in Yunnan Province, China and Guiyang in Guizhou Province, China to determine whether the bioactive peptides in amphibian skin differ between the two regions. Eight antimicrobial peptides and an antioxidant peptide were identified by screening of cDNA library. Among the identified peptides, three antimicrobial peptides (pelophylaxin-2GY, temporin 1GY, and temporin-1KM) and an antioxidant peptide (antioxidin-PN) are reported here for the first time. Nigrocin-1, nigrocin-2, and pelophylaxin-2 were expressed by frogs in both regions. Pelophylaxin-2GY and temporin-1GY were found only in the frogs from Guiyang, whereas antioxidin-PN, esculetin-1, esculetin-2, and temporin-1KM were found only in those from Kunming. This difference was confirmed by allele-specific RT-PCR. The bioactive peptides expressed clearly varied between these populations of the same species. PMID- 23649277 TI - Lateral cephalometric standards of Germans with normal occlusion from 6 to 17 years of age. AB - The aim of this study was to analyze sagittal and vertical dentofacial dimensions in subjects with normal occlusions during the juvenile and adolescents age periods to establish age- and gender-specific lateral cephalometric standard values for Germans during their active growth period. The study group consisted of a sample of 32 untreated subjects with normal occlusions. Lateral cephalograms were analyzed at 11 consecutive stages, from 6-13 and from 15-17 years of age. A customized cephalometric analysis was used to measure 53 variables. Statistical comparisons of gender-specific differences were performed by means of Mann Whitney U tests.Anterior and posterior cranial base lengths, midfacial length as well as mandibular length were recorded to be significantly larger in male subjects at the age of 6 years. For most of the linear measurements, significantly larger craniofacial distances were recorded in males from the age of 15 years onward. There were no statistically significant gender differences with regard to most angular measurements at subsequent age groups. Soft tissue analysis revealed flatter profiles in females than in males from the age of 10-11 years onward, while age-dependent changes in the soft tissue profile were similar in both genders.In untreated subjects with normal occlusion craniofacial development of the hard and soft tissues can be considered age- and gender dependent. Therefore age- and gender-specific differences of linear craniofacial distances should be taken into account for diagnosis and treatment planning in children and adolescents. The present results can be used as reference values for children and adolescents of German origin. PMID- 23649278 TI - Accuracy of torque-limiting devices for mini-implant removal: an in vitro study. AB - INTRODUCTION: Mini-implants, due to their potential for osseointegration, are exposed to torque levels that may cause them to fracture during removal. Thus, it is advisable to control the torque levels applied during mini-implant removal. MATERIALS AND METHODS: A torque sensor with strain gauges was used to analyze torque-limiting devices for their accuracy in reverse (counterclockwise) operation. Eight devices were tested in this manner, including a group of hand operated drivers (n=3), a group of battery-operated drivers (n=4), and a mains operated surgical unit (n=1). Each device was analyzed eight times at each of the various torque levels. Shapiro-Wilk, Kruskal-Wallis H-, and Mann-Whitney U-tests were used to analyze the results. RESULTS: Most of the various devices revealed significant differences upon comparison. The accuracy of torque control offered by the three hand drivers was clinically acceptable. As two of the four battery operated drivers did not feature torque limitation in reverse mode, they did not prevent high torque levels from occurring. Likewise, some of the maximum torque levels observed in conjunction with the other two battery-operated drivers and the mains-operated surgical unit exceeded considerably the clinically recommended range of 10-25 Ncm. CONCLUSION: Although miniscrews can be removed successfully with hand-operated drivers while limiting torque, we advise against the use of battery-operated drivers or mains-operated surgical units not offering torque limitation in reverse mode. PMID- 23649279 TI - Are there differences on tooth movement between different sectional canine retractors? AB - The aim of this study was to compare the effects of two retraction springs, demonstrating differences in reactivation and constancy of force, on tooth movement during canine distalization. Upper and lower canines of 16 patients (9 females, 7 males; mean age 14.6+/-1.7 years) with Angle Class I or II malocclusion were included in the study. Left upper and lower canines were distalized using Poul Gjessing (PG) retractors, whereas right canines of the same patients were distalized using Hybrid retractors. Angular and linear measurements were performed on lateral cephalometric radiographs and dental models taken prior to and at the end of canine distalization. Paired Samples t-test, Repeated Measures of Analysis of Variance and Greenhouse-Geisser tests were used for statistical analysis. The mean rates of canine distalization in PG retractors were 1.03 and 0.88 mm/months and 1.13 and 0.93 mm/months for Hybrid retractors for upper and lower canines, respectively. No significant differences were detected in the rate of canine distalization, sagittal and vertical movement of canines, and first molars between retractors or arches. Despite the differences in reactivation and constancy of the forces between PG and Hybrid retractors, both revealed similar canine distalization, distal tipping, rotation, and anchorage loss of molars. As a clinical point of view, Hybrid retractors could provide more benefits due to fewer activation requirements. PMID- 23649280 TI - Questionnaire study of electronic wear-time tracking as experienced by patients and parents during treatment with removable orthodontic appliances. AB - OBJECTIVE: To survey how patients and parents rate microelectronic wear-time tracking (TheraMon((r))) during treatment with removable orthodontic appliances. PATIENTS AND METHODS: A total of 125 patients with a mean age of 11.99 years whose treatment involved removable appliances with a built-in microsensor for wear-time documentation were enrolled in a questionnaire study addressing electronic wear-time tracking. Respondents included the patients and their parents. RESULTS: A total of 86% of the patients reported that the orthodontic appliance's comfort was unaffected by the installed sensor. A majority of respondents had a favorable impression of wear-time tracking. Printed wear-time documents from the clinician's computer were considered a "nice certificate of compliance" by 46% of patients, and 38% of them stated that they intended to improve their compliance when faced with a poor record. Indeed, 48% of parents believe that wear-time tracking can improve the therapeutic success, while 32% believe that it can reduce the duration of treatment. Around 10% of respondents felt that the sensors were unnecessary and not recommendable. CONCLUSION: These favorable ratings by patients and their parents may help future patients and users to decide for or against microelectronic wear-time tracking. Randomized studies are needed to demonstrate whether the sheer presence of a wear-time sensor stimulates compliance on its own. PMID- 23649283 TI - Randomized trial of partial vs. stepwise caries removal: 3-year follow-up. PMID- 23649284 TI - Effectiveness of autofluorescence to identify suspicious oral lesions-a prospective, blinded clinical trial. PMID- 23649281 TI - Pubertal status of children and adolescents during orthodontic treatment. AB - OBJECTIVE: Most orthodontic therapy in Germany takes place during puberty. However, since boys and girls experience puberty very differently, we can expect differences in their pubertal status when undergoing orthodontic therapy. In this study we addressed the stages of pubertal development in male and female children and adolescents undergoing orthodontic treatment. SUBJECTS AND METHODS: A total of 1011 individuals were randomly selected from a population-based representative sample of school students aged 10-18 years in the German city of Halle/Saale. This cohort was evaluated for the prevalence of orthodontic treatment and--using a modified German version of the Pubertal Development Scale--for pubertal status. An orthodontic subgroup of these boys and girls was analyzed for age distribution and pubertal stage (chi(2) test). RESULTS: The orthodontic subgroup included 296 boys and girls (accounting for 29.3% of the total sample), 50% of whom (n=148) had already attained advanced stages of pubertal development. Broken down by gender, we observed advanced stages in 60% of the girls versus 38% of the boys (p<0.001). However, this gender-specific difference was not reflected in the orthodontic subgroup's age distribution (p>0.05). Irrespective of gender, most subjects undergoing orthodontic treatment were 12 or 13 years old. CONCLUSION: Boys and girls in Germany undergo orthodontic treatment at the same age. Given the delayed onset of puberty in boys, most are still pre-pubertal, whereas most girls have reached an advanced stage of puberty by the time they undergo treatment--a discrepancy that could have therapeutic implications. PMID- 23649285 TI - Development of a multichannel vestibular prosthesis prototype by modification of a commercially available cochlear implant. AB - No adequate treatment exists for individuals who remain disabled by bilateral loss of vestibular (inner ear inertial) sensation despite rehabilitation. We have restored vestibular reflexes using lab-built multichannel vestibular prostheses (MVPs) in animals, but translation to clinical practice may be best accomplished by modification of a commercially available cochlear implant (CI). In this interim report, we describe preliminary efforts toward that goal. We developed software and circuitry to sense head rotation and drive a CI's implanted stimulator (IS) to deliver up to 1 K pulses/s via nine electrodes implanted near vestibular nerve branches. Studies in two rhesus monkeys using the modified CI revealed in vivo performance similar to our existing dedicated MVPs. A key focus of our study was the head-worn unit (HWU), which magnetically couples across the scalp to the IS. The HWU must remain securely fixed to the skull to faithfully sense head motion and maintain continuous stimulation. We measured normal and shear force thresholds at which HWU-IS decoupling occurred as a function of scalp thickness and calculated pressure exerted on the scalp. The HWU remained attached for human scalp thicknesses from 3-7.8 mm for forces experienced during routine daily activities, while pressure on the scalp remained below capillary perfusion pressure. PMID- 23649286 TI - Design and validation of a morphing myoelectric hand posture controller based on principal component analysis of human grasping. AB - An ideal myoelectric prosthetic hand should have the ability to continuously morph between any posture like an anatomical hand. This paper describes the design and validation of a morphing myoelectric hand controller based on principal component analysis of human grasping. The controller commands continuously morphing hand postures including functional grasps using between two and four surface electromyography (EMG) electrodes pairs. Four unique maps were developed to transform the EMG control signals in the principal component domain. A preliminary validation experiment was performed by 10 nonamputee subjects to determine the map with highest performance. The subjects used the myoelectric controller to morph a virtual hand between functional grasps in a series of randomized trials. The number of joints controlled accurately was evaluated to characterize the performance of each map. Additional metrics were studied including completion rate, time to completion, and path efficiency. The highest performing map controlled over 13 out of 15 joints accurately. PMID- 23649288 TI - Prostate cancer: active surveillance in African American men. PMID- 23649291 TI - Kidney cancer: Multiphasic CT to distinguish small renal mass subtype. PMID- 23649292 TI - Kidney cancer: AXIS trial data confirm axitinib as second-line option for mRCC. PMID- 23649294 TI - Comparative study about some physical properties, in vitro digestibility and immunoreactivity of soybean protein isolate for infant formula. AB - The objective of this study was to determine molecular weight subunit distributions of soy protein isolate (SPI) by SDS-PAGE and gel size exclusion chromatography, and further to investigate the differences of thixotropy, viscosity, in vitro digestibility and immunoreactivity of SPI for infant formula produced in Chinese domestic companies and world famous SPI manufacturers such as Dupont and Fuji. The molecular subunit distributions were analyzed by SDS-PAGE and gel size exclusion chromatography, indicating that Solae and Fuji were hydrolyzed by proteolytic enzymes. The thixotropy of Fuji and Solae significantly reduced around by 95 %, compared with those of Mantianxue and Dupont Zhengzhou. The allergen contents of Fuji and Solae strikingly decreased by 60 and 84 % respectively, in contrast to that of Mantianxue. The in vitro protein digestibility of Solae at the end of pepsin and trypsin digestion markedly increased by 11.7 and 11.3 %, respectively, in comparison to those of Mantianxue. Suitable enzymatic hydrolyzed SPIs showed lower thixotropy, viscosity, immunoreactivity and higher in vitro protein digestibility than those from the other SPIs. The lower thixotropy indicates low difficulty or shear stress in swallowing for infants. The lower immunoreactivity will improve the safety of SPI for cow milk allergic babies. PMID- 23649296 TI - Two new drugs for homozygous familial hypercholesterolemia: managing benefits and risks in a rare disorder. PMID- 23649298 TI - Adhesion: role of bulk viscoelasticity and surface roughness. AB - We study the adhesion between smooth polydimethylsiloxane (PDMS) rubber balls and smooth and rough poly(methyl methacrylate) (PMMA) surfaces, and between smooth silicon nitride balls and smooth PDMS surfaces. From the measured viscoelastic modulus of the PDMS rubber we calculate the viscoelastic contribution to the crack-opening propagation energy gammaeff(v,T) for a wide range of crack tip velocities v and for several temperatures T. The Johnson-Kendall-Roberts (JKR) contact mechanics theory is used to analyze the ball pull-off force data, and gammaeff(v,T) is obtained for smooth and rough surfaces. We conclude that gammaeff(v,T) has contributions of similar magnitude from both the bulk viscoelastic energy dissipation close to the crack tip, and from the bond breaking process at the crack tip. The pull-off force on the rough surfaces is strongly reduced compared to that of the flat surface, which we attribute mainly to the decrease in the area of contact on the rough surfaces. PMID- 23649297 TI - Illumina sequencing of 16S rRNA tag revealed spatial variations of bacterial communities in a mangrove wetland. AB - The microbial community plays an essential role in the high productivity in mangrove wetlands. A proper understanding of the spatial variations of microbial communities will provide clues about the underline mechanisms that structure microbial groups and the isolation of bacterial strains of interest. In the present study, the diversity and composition of the bacterial community in sediments collected from four locations, namely mudflat, edge, bulk, and rhizosphere, within the Mai Po Ramsar Wetland in Hong Kong, SAR, China were compared using the barcoded Illumina paired-end sequencing technique. Rarefaction results showed that the bulk sediment inside the mature mangrove forest had the highest bacterial alpha-diversity, while the mudflat sediment without vegetation had the lowest. The comparison of beta-diversity using principal component analysis and principal coordinate analysis with UniFrac metrics both showed that the spatial effects on bacterial communities were significant. All sediment samples could be clustered into two major groups, inner (bulk and rhizosphere sediments collected inside the mangrove forest) and outer mangrove sediments (the sediments collected at the mudflat and the edge of the mangrove forest). With the linear discriminate analysis scores larger than 3, four phyla, namely Actinobacteria, Acidobacteria, Nitrospirae, and Verrucomicrobia, were enriched in the nutrient-rich inner mangrove sediments, while abundances of Proteobacteria and Deferribacterias were higher in outer mangrove sediments. The rhizosphere effect of mangrove plants was also significant, which had a lower alpha diversity, a higher amount of Nitrospirae, and a lower abundance of Proteobacteria than the bulk sediment nearby. PMID- 23649300 TI - [Why rheumatoid arthritis needs cardiologists]. AB - Rheumatoid arthritis (RA) is associated with a shortened life expectancy. Most premature deaths are caused by cardiovascular (CV) events; therefore it is of importance to consider the increased CV risk when treating RA patients. Traditional CV risk factors cannot fully explain the increased risk but the common understanding is that inflammation significantly contributes to the excess risk observed. Without the use of correction factors commonly used risk calculators underestimate the true CV risk in RA patients. Methotrexate and TNF inhibitors appear to be beneficial with regard to the CV risk. To date there are only few recommendations for interventions in the CV system of RA patients which go beyond those formulated for the general population. The present manuscript summarizes the published evidence concerning the increased CV risk in RA patients. PMID- 23649303 TI - A comparison of intra-operative margin management techniques in breast-conserving surgery: a standardised approach reduces the likelihood of residual disease without increasing operative time. AB - INTRODUCTION: Breast-conserving surgery (BCS) is established as a standard treatment option for women with early-stage invasive breast cancers. Margin status predicts local disease recurrence. Up to 59 % of patients may undergo re excision of their tumour cavity to establish clear margins. Intra-operative margin assessment may decrease re-excision rates. It is unclear if this procedure increases operative time. We compared intra-operative macroscopic assessment of margins, routine cavity shave margins and no formal intra-operative margin assessment to assess their impact on re-excision rates, residual disease burden and operative time. METHODS: Over a 42 month period, 188 patients from our retrospective breast cancer database were reviewed in our study. Of these, 68 had macroscopic margin assessment, 70 had cavity shave margins and 50 had no formal intra-operative assessment. Statistical analysis was performed as appropriate. RESULTS: Formal intra-operative margin assessment had a re-excision rate of 25 %, compared with 34 % for those without formal assessment. Formal assessment had a significantly reduced likelihood of having residual disease following the primary procedure (p = 0.02). Close margins (<2 mm) also predicted the presence of residual disease (p = 0.01). There was no difference in operative duration between the groups. CONCLUSION: Directed intra-operative margin assessment reduces residual disease burden in BCS without increasing operative duration. PMID- 23649304 TI - C -> N and N -> C solution phase peptide synthesis using the N-acyl 4 nitrobenzenesulfonamide as protection of the carboxylic function. AB - In this paper we describe a solution phase peptide synthesis strategy using the 4 nitrobenzenesulfonamido/N-methyl-4-nitrobenzenesulfonamido group as a protecting/activating system of the carboxyl function. The 4 nitrobenzenesulfonamido group is stable during peptide chain elongation (Fmoc chemistry). The N-aminoacyl or N-dipeptidyl-4-nitrobenzensulfonamides, when activated by methylation, can be easily coupled with another amino acid or reconverted into the free-carboxyl function amino acids or peptides. This activatable protecting group allows both the C -> N and the N -> C direction solution phase peptide synthesis. We also verified that the absolute configuration at the chiral centers does not change during the coupling reactions. PMID- 23649305 TI - Studies on the microbial synthesis and characterization of polyhydroxyalkanoates containing 4-hydroxyvalerate using gamma-valerolactone. AB - In this study, the ability of Cupriavidus sp. USMAA2-4 to synthesize polyhydroxyalkanoates (PHA) containing 4-hydroxyvalerate monomer (4HV) was studied through one-stage cultivation using gamma-valerolactone as the carbon precursor. The presence of 4HV monomer unit in the polymer was detected through gas chromatography analysis, proving the capability of this wild strain bacterium to produce poly(3-hydrxybutyrate-co-3-hydroxyvalerate-co-4-hydroxyvalerate) [P(3HB-co-3HV-co-4HV)] terpolymer. Existence of a 4HV monomer unit in the PHA produced was further confirmed through (13)C and (1)H NMR analysis. P(3HB-co-88 % 3HV-co-1 % 4HV) terpolymer with the highest PHA content of 63 wt% was obtained through combination of 0.14 wt% C of gamma-valerolactone with 0.42 wt% C of oleic acid. Various compositions of P(3HB-co-3HV-co-4HV) terpolymer with 3HV and 4HV compositions ranging from 11 to 94 mol% and from 1 to 4 mol%, respectively, were acquired by manipulating gamma-valerolactone and oleic acid concentrations. The molecular weight and the thermal and mechanical properties of four different compositions of terpolymers-P(3HB-co-91 % 3HV-co-1 % 4HV), P(3HB-co-55 % 3HV-co-2 % 4HV), P(3HB-co-27 % 3HV-co-2 % 4HV), and P(3HB-co-9 % 3HV-co-1 % 4HV)-were characterized. Among these terpolymers, P(3HB-co-27 % 3HV-co-2 % 4HV) terpolymer with a molecular weight of 5.7 (10(5) Da) exhibited the highest elongation to break (264 %). The monomer unit compositional distributions of these terpolymers were investigated through acetone-water fractionation analysis. The results suggested that these produced terpolymers had broad 3HV compositional distribution and narrow 4HV compositional distribution. PMID- 23649306 TI - Olive flounder (Paralichthys olivaceus) cystatin C: cloning, mRNA expression, and enzymatic characterization of olive flounder cystatin C. AB - Cystatins are endogenous inhibitors of mammalian lysosomal cysteine proteinases, such as cathepsins B, L, H, and S. Cystatin C belongs to the type 2 cystatin family. In this study, the 751-bp cystatin C cDNA (PoCystatin C) of olive flounder (Paralichthys olivaceus) was cloned by screening from the olive flounder cDNA library. The mRNA expression of the PoCystatin C gene was examined in various tissues from normal and lipopolysaccharide (LPS)-stimulated olive flounder by RT-PCR and was compared with inflammatory cytokines IL-1beta, IL-6, and IL-8. PoCystatin C transcripts ubiquitously existed in all normal and LPS stimulated tissues that were tested. The recombinant PoCystatin C protein was expressed in Escherichia coli BL21(DE3) in pColdTM TF DNA expression vector as a 70-kDa fusion protein. The protease inhibitory activities of recombinant PoCystatin C toward papain cysteine protease, piscine cathepsins (L, S, K, F, and X), and bovine cathepsin B were measured with the synthetic fluorogenic peptide substrates. PoCystatin C tightly inhibited papain cysteine protease, whereas cathepsins L, S, K, F, X, and B were inhibited with lower affinities. Our results indicate that the P. olivaceus cystatin C is a homolog of mammalian cystatin C due to its sequence, structure, tissue expression, and biochemical activity. PMID- 23649307 TI - Survival of Listeria monocytogenes cells and the effect of extended frozen storage (-20 degrees C) on the expression of its virulence gene. AB - Listeria monocytogenes is the main bacteria incriminated in contaminating cold storage food and ready-to-eat products. Survival of four L. monocytogenes food isolates was examined during freezing and cold storage. Slices of artisanal cheese were inoculated with Listeria strains and incubated at -20 degrees C. Their survival rate was recorded during the storage period. Then, transcript levels of four virulence genes (hlyA, iap, fri, and flaA) were evaluated using a semiquantitative reverse transcriptase PCR. Our results revealed that after 6 months of frozen storage, the number of L. monocytogenes cells had declined by 2.04 +/- 0.1 log10 colony-forming units (CFU) g(-1), 2.52 +/- 0.1 log10 CFU g( 1), and 2.58 +/- 0.1 log10 CFU g(-1) for the strains S2, S3, and S4, respectively. Our data revealed that all the studied genes (hlyA, iap, fri, and flaA) were expressed after 6 months of incubation in artisanal cheese at -20 degrees C, and the transcript level has been affected by the factor freezing, whether for the reference strain ATCC 19115 or for other isolates. The iap gene expression was decreased for the four strains after 6 months of storage, and hlyA expression rate was consistently slightly lower. Transcript levels of fri and flaA genes were consistently higher in L. monocytogenes cells before cold exposure than in stressed cells and were significantly affected by the freezing process. PMID- 23649308 TI - Antimicrobial and antibiofilm activity of designed and synthesized antimicrobial peptide, KABT-AMP. AB - Lysine-rich peptide, designated as KABT-AMP, was designed and synthesized to supersede the irrational use of chemical antibiotics as standard therapy. KABT AMP is a 22-amino acid helical cationic peptide (+10) and amphipathic in nature. The antimicrobial kinetics of the peptide was ascertained in the representative strains of gram-positive, gram-negative, and fungal strains, viz., Staphylococcus aureus MTCC 2940, Escherichia coli MTCC 2939, and Candida albicans MTCC 227, respectively. KABT-AMP was synthesized by solid-phase synthesis and purified using reverse-phase high-performance liquid chromatography which resulted in >95 % purity, and matrix-assisted laser desorption/ionization time of flight revealed the mass of the peptide to be 2.8 kDa. KABT-AMP showed significant broad-spectrum antimicrobial activity against the bacterial and fungal strains analyzed in the present study with survivability of 30.8, 30.6, and 31.7 % in E. coli, S. aureus, and C. albicans, respectively, at 6 h. KABT-AMP also demonstrated antibiofilm activity against the tested biofilm forming clinical isolate, Candida tropicalis. The putative membranolytic activity of the peptide was substantiated by electron microscopic analysis. Results reveal that KABT-AMP will exhibit noteworthy antimicrobial activity against multidrug-resistant bacteria and fungus at micromolar concentrations with minimal cytotoxicity and thus could be conceived for biomedical application. PMID- 23649309 TI - Atomic insight into copper nanostructures nucleation on bending graphene. AB - Some findings in heterogeneous nucleation that the structural features of a growing crystal are usually inherited from the heterogeneous nucleus, although attracting more and more attention, are not yet well understood. Here we report numerical simulations of copper nucleation on bending graphene (BG) to explore the microscopic details of how the curved surface influences the freezing structure of the liquid metal. The simulation result clearly shows that copper atoms become layered at the solid-liquid interface in a "C"-shaped pattern resembling the BG. This kind of shape control decays with increasing distance from the wall and the outmost layers transform into twin crystal composed of two fcc wedges. It is found that the final structures have striking correlations with the curvature radius, central angle and arc length of the BG. Our study would provide an opportunity for comprehensive and satisfactory understanding of the heterogeneous nucleation on curved surfaces. PMID- 23649310 TI - Meta-analysis of contemporary short- and long-term mortality rates in patients diagnosed with critical leg ischaemia. AB - BACKGROUND: Critical leg ischaemia (CLI) has been associated with high mortality rates. There is a lack of contemporary data on both short- and long-term mortality rates in patients diagnosed with CLI. METHODS: This was a systematic literature search for studies prospectively reporting mortality in patients diagnosed with CLI. Meta-analysis and meta-regression models were developed to determine overall mortality rates and specific patient-related factors that were associated with death. RESULTS: A total of 50 studies were included in the analysis The estimated probability of all-cause mortality in patients with CLI was 3.7 per cent at 30 days, 17.5 per cent at 1 year, 35.1 per cent at 3 years and 46.2 per cent at 5 years. Men had a statistically significant survival benefit at 30 days and 3 years. The presence of ischaemic heart disease, tissue loss and older age resulted in a higher probability of death at 3 years. CONCLUSION: Early mortality rates in patients diagnosed with CLI have improved slightly compared with previous historical data, but long-term mortality rates are still high. PMID- 23649311 TI - Characterization of CACNA2D3 as a putative tumor suppressor gene in the development and progression of nasopharyngeal carcinoma. AB - Apart from beta-catenin accumulation, loss of 3p21 is one of the most frequent genetic alterations in numerous malignancies including nasopharyngeal carcinoma (NPC). Herein, we characterized a novel candidate tumor suppressor gene (TSG) CACNA2D3, a voltage-dependent subunit alpha 2 delta 3 of a calcium channel complex. Downregulation of CACNA2D3 was frequently detected in primary NPCs and NPC cell lines compared with their nontumorigenic counterparts. Attenuated CACNA2D3 expression may be associated with loss of heterozygosity (LOH) at intragenic single-nucleotide polymorphism sites (rs589281, rs1449325 and rs6797113) and/or epigenetic silencing by methylation and histone deacetylation. Given the extensive effects of calcium in cancer, we then investigated the tumor suppressive role and underlying mechanism of CACNA2D3 in the development and progression of NPC. CACNA2D3 was stably transfected into NPC cell lines (C666 and SUNE1) at levels comparative with the normal nasopharynx, alongside siRNA mediated silencing in an immortalized nasopharyngeal epithelial cell line (NP69) to conduct in vivo and in vitro functional assays. Our findings show that CACNA2D3-mediated increase in intracellular calcium (Ca2+) can induce mitochondrial-mediated apoptosis and activation of NLK (through the Wnt/Ca2+ pathway) to antagonize Wnt signaling-mediated anchorage-dependent and independent cell proliferation (via CCND1 and CMYC), invasion (via MMP7) and epithelial-to mesynchemal transition (via SNAIL). As the expression pattern of calcium channels and their degree of functionality can change with the progression of cancer, CACNA2D3 may indeed be a promising biomarker for NPC. Our study also warrants further exploration in the potential therapeutic use of existing epigenetic targeting drugs (e.g., 5-azacytidine, SAHA) to reconstitute CACNA2D3-associated tumor suppression in NPC. PMID- 23649313 TI - Brown adipose tissue transplantation improves whole-body energy metabolism. PMID- 23649312 TI - Does dietary salt induce autoimmunity? AB - Two recent publications suggest that dietary salt may polarize TH17 cells and therefore increase the risk of developing autoimmune disease. Where low salt diets can readily be tested for their therapeutic effects in autoimmune disease, more work is needed to connect dietary salts with the development of immunopathology. PMID- 23649314 TI - Mouse models uncap novel roles of SSBs. AB - Three recently published reports, including one in Cell Research, generated Ssb1 knockout mice and demonstrated critical roles of this protein in regulating skeletogenesis, telomere homeostasis and tumor suppression. PMID- 23649315 TI - Developmental pruning of early-stage myelin segments during CNS myelination in vivo. PMID- 23649316 TI - Jugular venous congestion in acute pulmonary embolism. PMID- 23649317 TI - Serial evaluation of hepatic function profile after Fontan operation. AB - Moderate persistent elevation of the gamma-glutamyltransferase (gammaGT) level is a frequent finding during long-term follow-up of patients with total cavopulmonary connection (TCPC) for palliation of functionally univentricular hearts. Serial intraindividual data revealed a significant increase in the gammaGT level within a minimum 4-year interval in more than 80 % of cases. The level of gammaGT elevation showed a significant correlation to hemodynamic parameters such as systemic ventricular end diastolic pressure and mean pulmonary artery pressure, but did not strongly correlate with duration of follow-up or other liver function parameters, which were less frequent and less impressively deranged. None of the patients had signs of synthetic dysfunction. With increasing postoperative follow-up, abnormalities of sonographic hepatic texture including increased echogenicity, inhomogeneity, or liver surface nodularity were found. All 17 patients with liver surface nodularity had a follow-up period of over 10 years. Structural abnormalities did not correlate with biochemical or hemodynamic parameters. Doppler evaluation revealed inspiratory dependence of hepatic vein flow in more than 90 % as a relevant finding after TCPC; a decrease in portal vein flow velocity was observed in many patients. Since long-term survivors after Fontan procedure are at an increased risk of cardiac hepatopathy and cirrhosis, detailed routine investigation and monitoring of hepatic morphology are needed. PMID- 23649318 TI - Case series of a rare complication of CABG. Fistula between the internal mammary artery and pulmonary vasculature. AB - BACKGROUND: There are few reports in the literature on the development of a fistulous connection between the left internal mammary artery (LIMA) and the pulmonary vasculature (PV) after coronary artery bypass grafting (CABG). This type of fistula may cause angina after CABG. Various mechanisms in the pathophysiology of this rare condition have been proposed. METHODS: We evaluated 537 consecutive patients with CABG surgery who underwent coronary angiography at our institution between January 2011 and March 2012. The post-CABG angiograms were evaluated for LIMA-PV fistula formation. Presence of a LIMA-PV fistula was defined as opacification of the PV or parenchyma after injection of radiopaque contrast medium into the LIMA. RESULTS: We found that 5 of 537 patients (0.93 %) had a LIMA-PV fistula on post-CABG coronary angiograms. The mean age of patients with a LIMA-PV fistula was 61.4 years (range, 51-72 years) and all patients were male. Coronary angiography was performed in the setting of myocardial infarction for 2 patients with a LIMA-PV fistula, and stable angina pectoris was the indication for coronary angiography in the remaining 3 patients. The mean diagnosis time of LIMA-PV fistula after CABG was 3.4 years (range, 1-9 years). None of the patients had a history of redo-CABG, perioperative mediastinitis, or pneumonia. CONCLUSION: LIMA-PV fistulas may occur more frequently than reported on post-CABG angiogram findings. Angina in post-CABG patients may be associated with a LIMA-PV fistula, and selective cannulation of the LIMA with careful evaluation of the angiographic images may provide proper diagnosis and treatment of this entity. PMID- 23649319 TI - Fingerprints of periprocedural coronary microembolization on multimodality intravascular imaging. PMID- 23649320 TI - Left atrial deformation and nonischemic dilated cardiomyopathy. A 2D speckle tracking imaging study. AB - BACKGROUND: Left ventricular filling pressure (LVFP) is raised by the compromised contraction and impaired ventricular compliance in dilated hearts with systolic dysfunction. Timely recognition and staging of this condition are important for planning of the treatment strategy and making the prognosis. Two-dimensional speckle- tracking echocardiography (2D-STE) has recently enabled the quantification of left atrial (LA) myocardial deformation dynamics. In this study, echocardiographic indicators of increased LVFP and NT-pro-BNP were compared with LA strain measured by 2D-STE. METHODS: A total of 49 nonischemic dilated cardiomyopathy (DCMP) patients were included in the study. All patients underwent standard 2D echocardiography. In the 2D-STE analysis of the LA, global longitudinal LA strain during ventricular systole (GLAs-res) and strain during late diastole (GLAs-pump) were obtained. NT-pro-BNP levels were measured. The patients were divided into two groups--normal (group 1) and increased (group 2) LVFP--according to E/A ratio, E velocity, and E/E' ratio. RESULTS: LAVi-max, LAVi min, and NT-pro-BNP were higher in group 2, whereas LAtotalEF, LAactiveEF, GLAs res, and GLAs-pump were lower. In univariate analysis, a good negative correlation was seen between GLAs-res vs. NT-pro-BNP, GLAs-res vs. LAVi-max, and GLAs-res vs. E/E' ratio; a good negative correlation was present between GLAs pump vs. NT-pro-BNP, GLAs-pump vs. LAVi-max, and GLAs-pump vs. E/E' ratio. LAVi max, LAactiveEF, NT-pro-BNP, GLas-res, and GLAs-pump were studied by logistic regression analysis. GLAs-res (p = 0.009, OR = 0.593, 95 % CI 0.4-0.877), NT-pro BNP (p = 0.028, OR = 1.027, 95 % CI 1.003-1.052), and LAactiveEF (p = 0.022, OR = 0.001, 95 % CI 0.001-0.024) were found to be independent predictors of increased LVFP. CONCLUSION: 2D-STE-based LA function is impaired in patients with nonischemic DCMP. LA reservoir and pump function parameters together with NT-pro BNP levels might be useful in estimating LVFP in this patient group. PMID- 23649321 TI - Renal impairment and coronary collaterals in patients with acute coronary syndrome. AB - OBJECTIVE: We aimed to elucidate the relationship between mild-to-moderate renal impairment and the development of coronary collateral vessels (CCV) in patients with acute coronary syndrome (ACS). METHODS: We enrolled 461 patients with ACS who underwent coronary angiography for the first time. The development of CCV was assessed with the Rentrop score. Kidney function was classified according to the estimated glomerular filtration rate (eGFR). The Gensini score was used to show the extent of atherosclerosis. RESULTS: The mean eGFR value was 89.9 +/- 24.3 U/l for patients with no development of collaterals and 82.7 +/- 20.5 for patients who had CCV. The mean age was 59 +/- 11 years and 349 patients (75.7 %) were male. Rentrop classifications 1-2-3 (presence of CCV) were determined in 222 (48.1 %) patients. The presence of CCV was significantly associated with low levels of eGFR (p = 0.001), increased serum creatinine levels (p = 0.034), high levels of serum albumin (0.036), and the Gensini score (p < 0.001). Multivariate analysis showed that the Gensini score was an independent predictor of the presence of CCV (OR = 1.090, 95 % CI: 1.032-1.151, p = 0.002). CONCLUSION: We suggest that the association between mild-to-moderate renal impairment and the presence of CCV may be explained by increased myocardial ischemia and severe CAD. PMID- 23649322 TI - Serum biomarkers and the prognosis of AMI patients. AB - BACKGROUND: It has been proven that serum lactate dehydrogenase (LDH) and total bilirubin (TB) increase during acute myocardial infarction (AMI). However, how they influence the prognosis of AMI patients is still not completely known. METHODS: A total of 239 patients diagnosed with AMI and admitted to the Fourth Clinical Hospital of Harbin Medical University, between 2007 and 2008, were enrolled in this study. All the patients had not undergone primary percutaneous coronary intervention (PCI) because the time window (24 h) was missed. They all underwent PCI 1 week after the onset of symptoms. Serum high-sensitivity C reactive protein (hs-CRP), TB, LDH, and other biomarkers were determined between 24 and 48 h of symptom onset. All of the patients were followed up for an average of 3.2+/-0.4 years for occurrence of major adverse cardiac events (MACE). RESULTS: Patients with MACE had significantly higher levels of hs-CRP, LDH, cystatin C, uric acid, a higher ratio of LDH and TB (LDH/TB), and a lower level of TB: 8.48+/-3.84 vs. 2.13+/-1.32 MUmol/l, p<0.01; 1,355.8+/-654.3 vs. 1,151.7+/ 415.4 U/l, p<0.01; 1.69+/-0.76 vs. 1.00+/-0.46 mg/l, p<0.01; 419.6+/-109.2 vs. 343.2+/-108.2 MUmol/l, p<0.01 and 141.1+/-46.2 vs. 61.2+/-26.5, p<0.01; 18.3+/ 6.7 vs. 14.8+/-6.6 mg/l, p<0.01, respectively. In the multivariate COX analysis, LDH, cystatin C, and LDH/TB were significantly associated with the prognosis of these patients. CONCLUSIONS: Patients under higher oxidative stress tend to have more MACE. LDH, cystatin C, and LDH/TB are strongly related to the prognosis of AMI patients undergoing elective PCI. PMID- 23649323 TI - Coverage with evidence development for Medicare beneficiaries: challenges and next steps. PMID- 23649325 TI - Vaginal films for drug delivery. AB - Vaginal dosage forms have been studied in relation to many drugs as the vagina presents several advantages as a site for drug delivery, such as large surface area, rich blood supply, avoidance of the first-pass effect, relatively high permeability to several drugs, and self-insertion. Traditional vaginal dosage forms have been associated with disadvantages such as low residence time and discomfort and have been surpassed by newly designed drug delivery systems, particularly those based on bioadhesive polymers. Vaginal films are solid dosage forms that rapidly dissolve in contact with vaginal fluids and are unlikely to be associated with leakage and messiness. They have been studied for some female genital problems, aiming either contraceptive, antimicrobial, or microbicide effects. Precise and complex processes of manufacturing and characterization are required to achieve successful film formulation. Although scarce, the available user's acceptability studies show promising results. Vaginal films gather a lack of opportunities for both therapeutic and prophylactic actions, and therefore should be considered when designing and developing new vaginal drug delivery systems. PMID- 23649326 TI - Challenges of drug delivery systems that contribute to cancer chemotherapy. Foreword. PMID- 23649327 TI - Alteration of tumor microenvironment for improved delivery and intratumor distribution of nanocarriers. AB - Nanocarrier-based cancer chemotherapeutics are thought to increase therapeutic efficiency and reduce the side effects of associated chemotherapeutic agents by altering the agents' pharmacokinetics and tissue distribution following intravenous administration. In spite of these favorable properties, nanocarrier based cancer chemotherapeutics are not always effective because of their heterogeneous intratumoral localization. Homogeneous distribution of nanocarriers in a tumor would improve the efficacy of nanocarrier-based cancer chemotherapeutics. In this article, we describe and discuss some trials that attempt to manipulate the barriers in the tumor microenvironment that hinder extravasation through the tumor vasculature and penetration of nanocarriers in solid tumors. Alterations of the tumor microenvironment that relate directly to the intratumoral distribution of nanocarriers may be potential strategies to improve the delivery of nanocarrier-based cancer chemotherapeutics. PMID- 23649324 TI - Skill acquisition and utilization during evidence-based psychosocial treatments for childhood disruptive behavior problems: a review and meta-analysis. AB - We review 85 empirical articles published since 2000 that measured the acquisition and/or utilization of parent management skills and/or child cognitive behavioral skills in the context of an evidence-based treatment (EBT) for childhood behavior problems. Results showed that: (1) there are no standardized measures of skill acquisition or skill utilization that are used across treatments, (2) little is known about predictors, correlates, or outcomes associated with skill acquisition and utilization, and (3) few studies systematically examined techniques to enhance the acquisition and utilization of specific skills. Meta-analytic results from a subset of 68 articles (59 studies) showed an overall treatment-control ES = .31, p < .01 for skill acquisition and ES = .20, p = ns for skill utilization. We recommend that future research focus on the following three areas: (1) development of standardized measures of skill acquisition and utilization from a "common elements" perspective that can used across EBTs; (2) assessment of the predictors, correlates, and outcomes associated with skill acquisition and utilization; and (3) development of innovative interventions to enhance the acquisition and utilization of cognitive behavioral and parent management skills. PMID- 23649328 TI - Nanoparticle-based passive drug targeting to tumors: considerations and implications for optimization. AB - There are many potential barriers to the effective delivery of small-molecule drugs to solid tumors. Most small-molecule chemotherapeutic drugs have a large volume of distribution upon intravenous administration, which is often associated with a narrow therapeutic index due to their high level of toxicity in healthy tissues. Nanoparticle-based therapeutics for tumor targeting have emerged as one of the promising approaches to overcome the lack of tissue specificity of conventional chemotherapeutic drugs. Various different concepts have been envisioned for nanoparticle-mediated drug targeting. Among them, the passive drug targeting strategy has been the most widely investigated, and numerous preclinical studies have provided insights into the validity of the strategy. This review article briefly introduces our recent findings related to the passive drug targeting strategy including its application in anti-angiogenic therapy, along with considerations to be taken into account and implications for the rational design of a passive drug targeting strategy. PMID- 23649329 TI - Development of liposomal anticancer drugs. AB - Liposomes are drug delivery systems that can alter the pharmacokinetic properties of compounds. The adverse effects of anticancer agents are a limiting factor for cancer chemotherapy, therefore, liposomal formulations have the potential to improve the therapeutic efficacy of anticancer agents by enhancing their accumulation in tumors and reducing non-selective distribution to normal tissues, which is known as the enhanced permeability and retention effect. To develop a liposomal anticancer agent as a drug product, its formulation must be designed to ensure its quality until it is administered to patients and to exert maximum potency in clinical use rather than in animal experiments. The chemical stability and physicochemical stability of the ingredients are key factors in the design of liposomal formulations. Drug release rates are critical factors in the therapeutic efficacy of liposomal drug products because the encapsulated drug has no pharmacological activity, and only released drug can exert antitumor/toxic activities. Liposomes should maintain the drug in a stable state in the circulation and then promptly release it after accumulation in the target tissue in order to achieve a sufficient drug concentration. To understand the profile of the formulation and to guarantee the quality of drug product, a reliable analytical method that can determine the released and encapsulated drugs in biological fluids is required. Simple online solid phase extractions of the released and encapsulated drugs using a column-switching HPLC system meet the requirements and this system enables accurate in vitro release testing and in vivo pharmacokinetic evaluation. This review introduces the process of liposomal drug product development from various viewpoints. PMID- 23649330 TI - Recent advances in claudin-targeting technology. AB - Most malignant tumors are derived from epithelium, and pathologic microorganisms often invade the body through the mucosal epithelium. Thus epithelial tissues are potent targets for drug delivery. The tight junction (TJ) is the intercellular seal in epithelial cell sheets. Claudins (CLs) are a family of tetratransmembrane proteins with a molecular mass of approximately 23 kDa. CLs are key structural and sealing components of TJs. CLs are often overexpressed in malignant tumors. CL-4 is highly expressed in the epithelial cells covering mucosal immune tissues. Therefore CLs may be potent targets for drug delivery, cancer therapy, and mucosal vaccination. Herein, we overview a series of our studies using the C terminal fragment of Clostridium perfringens enterotoxin to target and bind CLs; we also discuss the efficacy of CL-targeted drug delivery. PMID- 23649332 TI - Application of hospital preparations for cancer treatment, and an approach toward their commercialization. AB - In Japan, pharmacists who are in consultation with doctors independently prepare medications in an attempt to meet the needs of patients in the hospital. In particular, the need for hospital preparations to treat cancer is high and diverse. However, unlike gov]ernment-approved medications, independently and individually prepared hospital preparations raise concerns about their effectiveness, safety, economic efficiency, quality control, etc. One way to address these concerns is to commercialize these preparations and to understand the difference between necessity and demand from various points of view. We have conducted nation-wide utilization surveys and evaluated the literature on hospital preparations. On the basis of the findings of this survey, we have concluded that pharmaceutical companies and the government need to implement the commercialization of hospital preparations in clinical practice. In this report, we discuss the significance of commercialization of hospital preparations, concerns regarding pharmaceutical preparations, and our recent efforts on cancer treatment. We hope to continuously contribute to society and to medical care by improving individualized care and by commercializing medications needed in clinical practice. PMID- 23649331 TI - Clinical application of drug delivery systems in cancer chemotherapy: review of the efficacy and side effects of approved drugs. AB - In recent years, drug delivery systems (DDS) have been developed, along with anticancer agents for those systems based on the concept of achieving a better clinical response and tolerability. Several clinical trials have shown that these drugs have better clinical effects in the treatment of many cancers, leading to their expanded indications. Liposomal doxorubicin is one DDS agent used to treat AIDS-related Kaposi's sarcoma and ovarian cancer in Japan. In addition to those two indications, the Food and Drug Administration (FDA) approved this drug for the treatment of multiple myeloma in 2007. Another DDS agent approved in Japan is nanoparticle albumin-bound paclitaxel, which has been used in the treatment of breast cancer. Most recently, this drug has been approved for the treatment of non-small cell lung cancer in the U.S.A. Although these DDS agents appear to be less toxic than conventional drugs, DDS-specific side effects such as various skin reactions, hypersensitivity reaction, and peripheral neuropathy sometimes occur. Therefore, medical staff must understand DDS anticancer agents fully, including characteristic side effects, to achieve the desired clinical outcomes. PMID- 23649333 TI - Macrophage migration inhibitory factor is a possible candidate for the induction of microalbuminuria in diabetic db/db mice. AB - Preventing the onset of microalbuminuria in diabetic nephropathy is a problem that needs urgent rectification. The use of a mouse model for diabetes is vital in this regard. For example, db/db mice exhibit defects in the leptin receptor Ob Rb sub-type, while the ob/ob strain exhibits defects in the leptin ligand. These mouse strains demonstrate type 2 diabetes, either with or without microalbuminuria, respectively. The purpose of the present study was to use DNA microarray technology to screen for the gene responsible for the onset of diabetic microalbuminuria. Using Affymetrix Mouse Gene ST 1.0 arrays, microarray analysis was performed using total RNA from the kidneys of ob control, ob/ob, db/m, and db/db mice. Microarray and quantitative reverse transcription polymerase chain reaction (RT-PCR) indicated that transcription of the macrophage migration inhibitory factor (MIF) gene was significantly enhanced in the kidneys of db/db mice. Western blotting showed that levels of MIF protein was enhanced in the kidneys of both diabetic db/db and ob/ob mice. On the other hand, elevation of urinary MIF excretion detected by enzyme-linked immunosorbent assay (ELISA) was only in db/db mice and preceded the onset of microalbuminuria. Immunofluorescence studies revealed that MIF was expressed in mouse kidney glomeruli. While MIF expression was enhanced in the diabetic kidneys of both mouse strains, the elevated secretion from db/db mouse kidneys may be responsible for initiating the onset of microalbuminuria in diabetic nephropathy. PMID- 23649334 TI - Baicalein 6-O-beta-D-glucopyranuronoside is a main metabolite in the plasma after oral administration of baicalin, a flavone glucuronide of scutellariae radix, to rats. AB - Baicalin (BG) and its aglycone, baicalein (B) are strong antioxidants that exert various pharmacological actions and show unique metabolic fates in the rat. The aim of the present study was to identify major metabolite(s) besides BG in rat plasma after oral administration of BG or B. The main metabolite was detected by HPLC equipped with an electrochemical detector at a potential of +500 mV and identified as baicalein 6-O-beta-D-glucopyranuronoside (B6G) by HPLC/MS/MS. When BG at a dose of 20 mg/kg was administered orally to Wistar rats, the level of B6G in plasma was higher than that of BG. Cmax and the area under the concentration curve from 0 to 24 h (AUC0-24 h) values of the plasma B6G were 1.66 +/- 0.34 uM and 19.8 3.9 +/- uM . h, respectively, whereas those of BG were 0.853 +/- 0.065 uM and 10.0 +/- 3.1 uM . h, respectively. When B was administered, similar results were also obtained. B6G-producing activities from B were found in microsomes of both rat jejunum and liver, in spite of the low activity. Rat everted jejunal sacs formed B6G after application of B, but only in a small amount that was excreted into the mucosal side, and not the serosal side, indicating little contribution to the appearance of B6G in plasma. On the other hand, when B was injected into the rat portal vein, B6G was detected at a higher level than BG in the systemic circulation, demonstrating the hepatic contribution to the appearance of plasma B6G. PMID- 23649335 TI - Inhibitory effects of Saururi chinensis extracts on melanin biosynthesis in B16F10 melanoma cells. AB - Saururus chinensis has been used in folk medicine in Korea for the treatment of edema, jaundice, gonorrhea, and several inflammatory diseases. Saururi chinensis extracts (SCE) have demonstrated anti-inflammatory and anti-oxidant activities, as well as anti-asthmatic, antihypertensive, anti-angiogenic, and therapeutic activities for atopic dermatitis. However, the inhibitory activity of SCE on the melanogenesis signaling pathway is not completely understood. This study examined the effects of SCE on the melanogenesis signaling pathway activated by alpha melanocyte-stimulating hormone (alpha-MSH). We found that SCE inhibited melanin production in a dose-dependent manner without causing cytotoxicity in B16F10 cells. Interestingly, SCE decreased alpha-MSH-induced tyrosinase activity in B16F10 cells but did not inhibit tyrosinase activity under cell-free conditions. The results of this study indicate that SCE may reduce pigmentation by way of an indirect, nonenzymatic mechanism. We also found that SCE decreased alpha-MSH induced microphthalmia-associated transcription factor (MITF) and tyrosinase expression and induced the activation of extracellular signal-regulated kinase (ERK). These results suggest that the depigmenting effect of SCE may result from downregulation of MITF and tyrosinase expression due to increased ERK activity. Thus, our results provide evidence that SCE might be useful as a potential skin whitening agent. PMID- 23649337 TI - Effects of ginsenoside Rg3 on alpha9alpha10 nicotinic acetylcholine receptor mediated ion currents. AB - Ginsenosides is a low molecular weight substance found in ginseng as one of the active ingredients. Ginsenosides, like other herbal medicines, has a wide range of neuropharmacological actions including neuroprotective effects. The alpha9alpha10 nicotinic acetylcholine receptor is one of numerous nicotinic acetylcholine receptors that exists as a heteropentameric form in auditory hair cells of the cochlea. In this study, we report the effects of ginsenosides on rat alpha9alpha10 nicotinic acetylcholine receptor-mediated ion currents using the two-electrode voltage clamp technique. Treatment with acetylcholine evoked inward currents (IACh) in oocytes heterologously expressing the alpha9alpha10 nicotinic acetylcholine receptor. Ginsenosides blocked IACh in order of potency of Rg3> Rb2> CK>Re = Rg2> Rf>Rc> Rb1> Rg1 with reversible manners, and the blocking effect of Rg3 on IACh was same after pre-application than co-application of Rg3. The half maximal inhibitory concentration (IC50) of Rg3 was 39.6 +/- 4.9 um. Rg3 induced IACh inhibition was not affected by acetylcholine concentration and was independent of membrane holding potential. Although the inhibitory effect of Rg3 on IACh was abolished in oocytes expressing alpha9 subunit alone, indicating that the presence of alpha10 subunit might be required for Rg3-induced regulations of alpha9alpha10 nicotinic acetylcholine receptor channel activity. These results indicate that alpha10 subunit of alpha9alpha10 nicotinic acetylcholine receptor might play an important role in Rg3-induced regulation of the alpha9alpha10 nicotinic acetylcholine receptor. PMID- 23649336 TI - Cytoprotective effect of alpha-lipoic acid on paraquat-exposed human bronchial epithelial cells via activation of nuclear factor erythroid related factor-2 pathway. AB - Alpha-lipoic acid (LA), a metabolic antioxidant, is a natural compound and its biological function has been well studied in various human diseases. The present study was designed to investigate the cytoprotective effect and the molecular mechanisms of LA in paraquat (PQ)-induced oxidative stress injury using BEAS-2B human bronchial epithelial cells. LA co-treatment prevented PQ-induced BEAS-2B cell death. LA also prevented PQ-induced increases in total reactive oxygen species (ROS), lactate dehydrogenase (LDH) and malondialdehyde (MDA). LA also increased the expression of detoxifying phase II enzyme encoding genes and antioxidant genes including HO-1, NQO1, CAT, GPX3 and GPX4, resulting in the attenuation of the decreases of antioxidants during PQ-induced oxidative stress. Nuclear factor erythroid related factor 2 (Nrf2) was induced by LA. Additionally, translocation of Nrf2 from the cytoplasm to the nucleus was promoted by LA treatment. While LA was responsible for the upregulation of Nrf2, it also activated and up-regulated the downstream proteins heme oxygenase-1 (HO-1) and reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) quinone oxidoreductase 1 (NQO1). The data collectively suggest that the beneficial effect of LA involving the activation of cytoprotective antioxidant genes make LA a potential candidate in the prevention of PQ-induced oxidative stress-related bronchial cell death, pending clinically relevant studies. PMID- 23649338 TI - Effectiveness and safety of antiemetic aprepitant in Japanese patients receiving high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation. AB - For patients receiving high-dose chemotherapy, a 5-hydroxytryptamine 3 receptor antagonist combined with dexamethasone is a standard antiemetic therapy. Despite this prophylactic anti-emetic treatment, many patients still suffer from uncontrollable emesis. In this study, we retrospectively evaluated the antiemetic effectiveness and safety of aprepitant (a neurokinin-1 receptor antagonist) in addition to 5-HT3 antagonist in Japanese patients with hematologic malignancy receiving high-dose chemotherapy prior to autologous peripheral blood stem cell transplantation (auto-PBSCT). Twenty-six patients received aprepitant and granisetron (the aprepitant group), whereas, 22 patients received granisetron alone (the control group). All patients received 3 mg of granisetron intravenously 30 min before chemotherapy administration. Patients in the aprepitant group additionally received 125 mg of aprepitant 60-90 min before administration of the first moderately to highly emetogenic chemotherapy. On the next day or thereafter, 80 mg of aprepitant was administered in the morning until the last administration of moderately to highly emetogenic anticancer drugs. The percentage of patients who achieved complete response (CR), defined as no emesis with only grade 1-2 nausea, in the aprepitant group was significantly higher than that in the control group (42% vs. 5%, p=0.003). Logistic regression analysis showed that non-prophylactic use of aprepitant was significantly associated with non-CR. The frequencies of adverse drug events (ADEs) were not significantly different between two groups. In conclusion, the results of this study suggest that the addition of aprepitant to granisetron can improve the antiemetic effect without increasing ADEs in patients receiving high-dose chemotherapy prior to auto-PBSCT. PMID- 23649339 TI - Effects of oakmoss and its components on biofilm formation of Legionella pneumophila. AB - Oakmoss and its components are known as antibacterial agents, specifically against Legionella pneumophila. In the present study, we investigated the effects of oakmoss and its components (phenol, didepside and isochromen derivatives) on L. pneumophila biofilm formation, with particular reference to the bactericidal activity (minimum bactericidal concentration; MBC) of these components against the bacterial cells in the biofilm. Of the 20 compounds tested, two didepside derivatives and four phenol derivatives reduced biofilm formation by more than 50% of that observed for the control at their respective minimum inhibitory concentrations (1/2*MIC). The inhibitory activities of these compounds were either equivalent to or greater than that of the clarithromycin reference. Isochromen derivatives had no effect on biofilm formation. Analysis of bactericidal activity of didepside and isochromen derivatives revealed that three of four didepside derivatives and one of four isochromen derivatives exhibited high bactericidal activity (MBC: 32.0-74.7 ug/mL) against the L. pneumophila in the biofilm after 24 h or 48 h of co-incubation; the antibacterial activities of these compounds were almost equivalent to clarithromycin and chlorhexidine gluconate (MBC: 42.7-64.0 ug/mL) that were used as references. Thus, based on their anti-biofilm forming and bactericidal activities, didepside derivatives are considered to be good candidates for disinfectants against L. pneumophila. PMID- 23649340 TI - Suppression of inflammatory reactions by terpinen-4-ol, a main constituent of tea tree oil, in a murine model of oral candidiasis and its suppressive activity to cytokine production of macrophages in vitro. AB - The onset of oral candidiasis is accompanied by inflammatory symptoms such as pain in the tongue, edema or tissue damage and lowers the quality of life (QOL) of the patient. In a murine oral candidiasis model, the effects were studied of terpinen-4-ol (T-4-ol), one of the main constituents of tea tree oil, Melaleuca alternifolia, on inflammatory reactions. When immunosuppressed mice were orally infected with Candida albicans, their tongues showed inflammatory symptoms within 24 h after the infection, which was monitored by an increase of myeloperoxidase activity and macrophage inflammatory protein-2 in their tongue homogenates. Oral treatment with 50 uL of 40 mg/mL terpinen-4-ol 3h after the Candida infection clearly suppressed the increase of these inflammatory parameters. In vitro analysis of the effects of terpinen-4-ol on cytokine secretion of macrophages indicated that 800 ug/mL of this substance significantly inhibited the cytokine production of the macrophages cultured in the presence of heat-killed C. albicans cells. Based on these findings, the role of the anti-inflammatory action of T-4 ol in its therapeutic activity against oral candidiasis was discussed. PMID- 23649341 TI - The protective effects of piceatannol from passion fruit (Passiflora edulis) seeds in UVB-irradiated keratinocytes. AB - The use of naturally occurring botanicals with substantial antioxidant activity to prevent photoageing is receiving increasing attention. We have previously identified piceatannol and scirpusin B, which is a dimer of piceatannol, as strong antioxidants that are present in passion fruit (Passiflora edulis) seeds. In the present study, the effects of passion fruit seed extract, piceatannol, and scirpusin B on human keratinocytes were investigated. The passion fruit seed extract and piceatannol upregulated the glutathione (GSH) levels in keratinocytes in a dose-dependent manner, indicating that piceatannol is an active component of the passion fruit seed extract in keratinocytes. The pretreatment with piceatannol also suppressed the UVB-induced generation of reactive oxygen species (ROS) in the keratinocytes. In addition, the transfer of the medium from the UVB irradiated keratinocytes to non-irradiated fibroblasts enhanced matrix metalloproteinase (MMP)-1 activity, and this MMP-1 induction was reduced when the keratinocytes were pretreated with piceatannol. These results suggest that piceatannol attenuates the UVB-induced activity of MMP-1 along with a reduction of ROS generation in keratinocytes. Thus, piceatannol and passion fruit seed extract containing high amounts of piceatannol are potential anti-photoageing cosmetic ingredients. PMID- 23649342 TI - Enhanced plasmid DNA transfer into tumor cells by nanoparticle composed of cholesteryl triamine and diamine. AB - Previously, we prepared cationic nanoparticles (NP and NP-N) composed of cholesteryl diamine (OH-Chol, (3S)-N-(2-(2-hydroxyethylamino)ethyl)cholesteryl-3 carboxamide) and cholesteryl triamine (OH-N-Chol, (3S)-N-(2-(2-(2 hydroxyethylamino)ethylamino)ethyl)cholesteryl-3-carboxamide), respectively, with Tween 80 for small interfering RNA (siRNA) delivery into tumor cells. In this study, we prepared NP-0.25 N composed of OH-Chol and OH-N-Chol at a molar ratio of 3/1 with Tween 80, and evaluated the transfection efficiency of plasmid DNA (pDNA) into tumor cells. NP-N exhibited lower transfection activity than NP; however, NP-0.25 N showed higher transfection activity than both NP and NP-N in various tumor cells. NP-0.25 N increased the amount of internalized pDNA by increased cellular association, and improved the escape from endosomes after clathrin-mediated endocytosis. The results of the experiments suggested that cholesteryl triamine may have potential as a helper lipid to increase the transfection for pDNA delivery by cationic cholesterol-based nanoparticles. PMID- 23649343 TI - Therapeutic effects of autologous lymphocytes activated with trastuzumab for xenograft mouse models of human breast cancer. AB - Trastuzumab (TTZ) is molecular targeted drug used for metastatic breast cancer patients overexpressing human epidermal growth factor receptor 2 (HER2). Therapeutic effects of lymphocytes activated with TTZ (TTZ-LAK) using xenograft mouse models of human breast cancer (MDA-MB-453) cells were examined in vivo. Remarkable reduction of tumor volume in a xenograft mouse models intravenously treated with TTZ-LAK cells after the subcutaneously inoculated of MDA-MB-453 cells was verified in vivo. The migration of TTZ-LAK cells in tumor of mouse models subcutaneously inoculated MDA-MB-453 cells was observed on the basis of histological analysis using immunostaining with CD-3. Induction of apoptosis in tumor of xenograft mice treated with TTZ-LAK cells was observed in micrographs using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method. It was noteworthy that the therapeutic effects of TTZ-LAK cells along with apoptosis were obtained for xenograft mouse models of human breast tumor in vivo. PMID- 23649344 TI - Identification of acyl-CoA thioesterase in mouse mesenteric lymph nodes. AB - Acyl-CoA thioesterases (ACOTs) are a group of enzymes that catalyze the hydrolysis of fatty acyl-CoAs to free fatty acids and CoA, with the potential to regulate the intracellular levels of these molecules. In this study, we show that a cytosolic isoform, ACOT7, is expressed at a significant level in the mesenteric lymph nodes (MLNs) of mice. While crude preparations of the mesenteric visceral fat contained significant levels of palmitoyl-CoA thioesterase activity, enzyme activity was concentrated 6.9-fold in MLNs compared with the residual adipose portion after excision of MLNs. When MLN homogenates were centrifuged, 82% of the enzyme activity was recovered in the cytosolic fraction, concomitant with almost exclusive recovery of ACOT7. Immunoprecipitation using anti-ACOT7 antibody estimated that 87% of enzyme activity in the homogenates was accounted for by ACOT7. On MLN sections, the germinal centers of secondary lymphoid follicles were immunostained with the antibody. In MLNs of mice fasted for 16 h, ACOT7 levels were induced 1.8-fold, which reflected a 1.5-fold increase in enzyme activity. These findings suggest that ACOT7 may be involved in dietary intake-associated responses in fatty acid metabolism in MLNs. PMID- 23649345 TI - 16S ribosomal RNA gene-based phylogenetic analysis of abundant bacteria in river, canal and potable water in Bangkok, Thailand. AB - In Southeast Asian countries, industrialization and urbanization is occurring rapidly, and water pollution in rivers and canals poses serious problems in some areas, especially in cities. Excess inflow of domestic, agricultural, and industrial wastewater to freshwater environments disturbs the aquatic microbial ecosystem, which can further pollute water by inhibiting biodegradation of pollutants. Therefore, monitoring of microbes in freshwater environment is important to identify changes in indigenous microbial populations and to estimate the influence of wastewater inflows on them. Polymerase chain reaction (PCR) denaturing gradient gel electrophoresis (DGGE) analysis is suitable for monitoring changes in microbial communities caused by human activities, but this method can be difficult in eutrophic freshwater samples that contain PCR inhibitors. In this study, we optimized DNA extraction procedures and PCR conditions for DGGE analysis of bacterial populations in freshwater samples (canal, river, and tap water) collected in Bangkok, Thailand. A simple freeze thaw procedure was effective for extracting DNA from bacterial cells in the samples, and LA Taq with added bovine serum albumin provided the best PCR amplification. The PCR-DGGE approach revealed that the most common bacteria in freshwater samples belonged to Gammaproteobacteria, while a Gram-positive bacterium was present at Bangkok Noi Canal. Temporally and spatially continuous analyses of bacterial populations in Bangkok canals and rivers by PCR-DGGE approach should be useful to recognize disturbances of microbial ecosystems caused by excess inflows of wastewater. PMID- 23649346 TI - Response to the letter by Shailendra Kapoor: AMACR is an emerging diagnostic and prognostic tool in systemic malignancies. PMID- 23649347 TI - FGF23 concentrations measured using "intact" assays similar but not interchangeable. PMID- 23649348 TI - Degradation of polyvinyl alcohol under mechanothermal stretching. AB - Mechanical and thermal properties of polyvinyl alcohol (PVA) are characterized and analyzed using in situ X-ray photoelectron spectroscopy (XPS) and quantum chemistry calculations. It is found that the carbon peaks-commonly used as the reference for spectroscopic analysis-shift under mechanical and thermal stretching. Results also indicate that, at different temperatures and among the various functional groups present in PVA, the carbon in the C-O group is the most stable. Computational calculations showed that Hartree-Fock/10-31G (d) reproduces the binding energy of core carbon electrons with an accuracy of 95%, which is enough to characterize bonds, allowing the results of the spectroscopic analysis to be corroborated. PMID- 23649349 TI - Study on the role of SBA-15 in the oxidative dehydrogenation of n-butane over vanadia catalyst using density functional theory. AB - The first step in the mechanism of n-butane oxidative dehydrogenation (ODH) on a V4O10 cluster and V4O10 supported SBA-15 is examined using DFT method. The activation and adsorption energies, oxidation state of V atoms are calculated. Over V4O10 the obtained results indicate that the activation of C-H bond of methylene group can occur at both the terminal and the bridging oxygen atoms with similar barrier (21.5-22.5 kcal mol(-1)). The role of SBA-15 (with and without modification by Al) in n-butane adsorption step has been studied in detail. SBA 15 itself has mild effect on the reaction process, but the substitution of silicon atoms by aluminum atoms results in an active supporter for V2O5 in ODH reaction. In that, the ratio of Si/Al will decide the direction of initial interaction steps between n-butane and catalyst surface and it will result in the selectivity of the reaction products. PMID- 23649350 TI - Structures and stabilities of ScBn (n = 1-12) clusters: an ab initio investigation. AB - The geometries, stabilities, and electronic properties of ScBn (n = 1-12) clusters have been systematically investigated by using density functional theory B3LYP method and coupled-cluster theory CCSD(T) method. It is found that the ground state isomers of ScBn have planar or quasi-planar structure when n <= 6, which can be viewed as a B atom of the corresponding Bn+1 cluster is substituted by a Sc atom. From n >= 7, the ground state isomers favor nest-like structure, in which the Sc atom sits on a nest-like Bn cluster. The calculated second-order differences of energies manifest that the magic numbers of stability are n = 3, 7, 8, 9 and 11 for the ScB n clusters. Further analysis indicates that the ScB7 cluster with C 6v symmetry represents the outstanding stable ScBn cluster, as confirmed by its electronic structure and molecular orbitals. PMID- 23649351 TI - Metagenomic mining of feruloyl esterases from termite enteric flora. AB - A metagenome expression library was created from Trinervitermes trinervoides termite hindgut symbionts and subsequently screened for feruloyl esterase (FAE) activities, resulting in seven recombinant fosmids conferring feruloyl esterase phenotypes. The amino acid sequence lengths of the seven FAE encoding open reading frames (ORFs) ranged from 260 to 274 aa and encoded polypeptides of between 28.9 and 31.4 kDa. The highest sequence identity scores for the seven ORFs against the GenBank database were between 45 and 59 % to a number of carboxyl ester hydrolyses. The seven FAE primary structures contained sequence motifs that correspond well with a classical pentapeptide (G-x-S-x-G) serine hydrolyse signature motif which harbours the catalytic serine residue in other FAE families. Six of the seven fae genes were successfully expressed heterologously in Escherichia coli, and the purified enzymes exhibited temperature optima range of 40-70 degrees C and the pH optima of between 6.5 and 8.0. The k(cat)/K(M) ratios for the six characterised FAEs showed the following order of substrate preference: methyl sinapate > methyl ferulate > ethyl ferulate. All six FAEs showed poor conversion rates against methyl p-coumarate and methyl caffeate, both of which lacked the methoxy (O-CH3) group substituent on the aromatic ring of the ester substrates, emphasising the requirement for at least one methoxy group on the aromatic ring of the hydroxycinnamic acid ester substrate for optimal FAE activity. PMID- 23649352 TI - Rubisco mutants of Chlamydomonas reinhardtii enhance photosynthetic hydrogen production. AB - Molecular hydrogen (H2) is an ideal fuel characterized by high enthalpy change and lack of greenhouse effects. This biofuel can be released by microalgae via reduction of protons to molecular hydrogen catalyzed by hydrogenases. The main competitor for the reducing power required by the hydrogenases is the Calvin cycle, and rubisco plays a key role therein. Engineered Chlamydomonas with reduced rubisco levels, activity and stability was used as the basis of this research effort aimed at increasing hydrogen production. Biochemical monitoring in such metabolically engineered mutant cells proceeded in Tris/acetate/phosphate culture medium with S-depletion or repletion, both under hypoxia. Photosynthetic activity, maximum photochemical efficiency, chlorophyll and protein levels were all measured. In addition, expression of rubisco, hydrogenase, D1 and Lhcb were investigated, and H2 was quantified. At the beginning of the experiments, rubisco increased followed by intense degradation. Lhcb proteins exhibited monomeric isoforms during the first 24 to 48 h, and D1 displayed sensitivity under S depletion. Rubisco mutants exhibited a significant decrease in O2 evolution compared with the control. Although the S-depleted medium was much more suitable than its complete counterpart for H2 production, hydrogen release was observed also in sealed S-repleted cultures of rubisco mutated cells under low-moderate light conditions. In particular, the rubisco mutant Y67A accounted for 10-15-fold higher hydrogen production than the wild type under the same conditions and also displayed divergent metabolic parameters. These results indicate that rubisco is a promising target for improving hydrogen production rates in engineered microalgae. PMID- 23649355 TI - Assessment of eye and body dose for interventional radiologists, cardiologists, and other interventional staff. AB - A dose limit for the eye of 20 mSv, as proposed by the ICRP, could be exceeded by interventional clinicians. Data on eye dose levels for interventional radiologists and cardiologists provided by medical physicists from hospitals around the UK have been collated. The results indicate that most hospitals would require one or more interventional clinicians to be classified and several would have exceeded a 20 mSv limit. Dose data in the literature have been reviewed to derive factors that might be used to predict eye dose levels based on dose per procedure or kerma-area product workload. These could be used in prior risk assessments to establish monitoring practice. An alternative approach to personnel dose monitoring in radiology applications using a collar dosimeter worn outside the lead apron as the first dosimeter is proposed. The collar dosimeter would provide an assessment of eye dose in terms of Hp(3) and body dose in terms of Hp(10), which could be divided by ten to provide an assessment of effective dose. If Hp(3) exceeded 1 mSv per month, regular monitoring with a head dosimeter would be recommended, and if Hp(10) exceeded 2 mSv per month, then an under-apron dosimeter should also be worn. PMID- 23649354 TI - The physiological significance of a coronary stenosis differentially affects contractility and mitochondrial function in viable chronically dysfunctional myocardium. AB - The reversibility of viable dysfunctional myocardium after revascularization is variable and the reasons for this are unknown. Using 2D-DIGE, we tested the hypothesis that this could reflect the extent of molecular remodeling of myocardial tissue in the absence of infarction. Swine with a progressive left anterior descending (LAD) stenosis were studied 2 months (n = 18) or 3 months (n = 22) post-instrumentation. Coronary flow reserve (vasodilated/rest) was severely reduced at 2 months (LAD 2.6 +/- 0.4 versus 5.1 +/- 0.4 in normal, p < 0.05) and became critically impaired after 3 months (LAD 1.1 +/- 0.2, p < 0.05 vs. 2 months). Despite progression in stenosis severity, reductions in wall thickening at 2 months (LAD 37 +/- 4% vs. remote 86 +/- 9%, p < 0.05) were unchanged at 3 months (LAD 32 +/- 3%, p = ns). Contractile dysfunction was primarily related to reductions (LAD/normal) in contractile proteins which were not affected by stenosis severity (e.g., troponin T, 2 months 0.82 +/- 0.03 vs. 0.74 +/- 0.03 at 3 months, p-ns). In contrast, mitochondrial function and proteins were normal at 2 months but declined with progression to a critical stenosis (state 3 respiration at 3 months 145 +/- 13 vs. 216 +/- 5 ng-atoms O2 mg(-1) min(-1) at 2 months, p < 0.05). In a similar fashion, increases in stress (e.g., alphaB crystalline 2.13 +/- 0.2 vs. 1.17 +/- 0.13 at 2 months, p < 0.05) and cytoskeletal proteins (e.g., desmin 1.63 +/- 0.12 vs. 1.24 +/- 0.10 at 2 months, p < 0.05) only developed with more advanced remodeling from a critical stenosis. We conclude that similar degrees of chronic contractile dysfunction can have diverse intrinsic molecular adaptations to ischemia. This spectrum of adaptations may underlie variability in the time course and extent of reversibility in viable chronically dysfunctional myocardium after revascularization. PMID- 23649356 TI - On-chip microlasers for biomolecular detection via highly localized deposition of a multifunctional phospholipid ink. AB - We report on a novel approach to realize on-chip microlasers, by applying highly localized and material-saving surface functionalization of passive photonic whispering gallery mode microresonators. We apply dip-pen nanolithography on a true three-dimensional structure. We coat solely the light-guiding circumference of pre-fabricated poly(methyl methacrylate) resonators with a multifunctional molecular ink. The functionalization is performed in one single fabrication step and simultaneously provides optical gain as well as molecular binding selectivity. This allows for a direct and flexible realization of on-chip microlasers, which can be utilized as biosensors in optofluidic lab-on-a-chip applications. In a proof-of-concept we show how this highly localized molecule deposition suffices for low-threshold lasing in air and water, and demonstrate the capability of the ink-lasers as biosensors in a biotin-streptavidin binding experiment. PMID- 23649358 TI - Raising standards. PMID- 23649357 TI - Ultrasound for carpal tunnel syndrome screening in manual laborers. AB - INTRODUCTION: Manual laborers are at increased risk for carpal tunnel syndrome (CTS), and a combination of history, physical examination, and nerve conduction studies is often used to screen for CTS in this population. Neuromuscular ultrasound may be a better screening tool, because it is painless. In this study we compare the accuracy of nerve conduction studies and ultrasound for CTS screening. METHODS: Five hundred thirteen manual laborers were screened prospectively for CTS using nerve conduction studies and neuromuscular ultrasound, and the accuracy of the 2 techniques was compared using the Katz hand diagram as the diagnostic standard. RESULTS: The ROC curves for the 2 techniques were not significantly different (P = 0.542), indicating that the approaches had similar diagnostic accuracy. CONCLUSIONS: Neuromuscular ultrasound is a painless technique that has diagnostic accuracy similar to nerve conduction studies and can be used to screen large populations at risk for CTS. PMID- 23649359 TI - The design principle of paddle motifs in voltage sensors. PMID- 23649360 TI - Direct BAKtivation. PMID- 23649353 TI - Characterization of the methanogen community in a household anaerobic digester fed with swine manure in China. AB - Household anaerobic digesters have been installed across rural China for biogas production, but information on methanogen community structure in these small biogas units is sparsely available. By creating clone libraries for 16S rRNA and methyl coenzyme M reductase alpha subunit (mcrA) genes, we investigated the methanogenic consortia in a household biogas digester treating swine manure. Operational taxonomic units (OTUs) were defined by comparative sequence analysis, seven OTUs were identified in the 16S rRNA gene library, and ten OTUs were identified in the mcrA gene library. Both libraries were dominated by clones highly related to the type strain Methanocorpusculum labreanum Z, 64.0 % for 16S rRNA gene clones and 64.3 % for mcrA gene clones. Additionally, gas chromatography assays showed that formic acid was 84.54 % of the total volatile fatty acids and methane was 57.20 % of the biogas composition. Our results may help further isolation and characterization of methanogenic starter strains for industrial biogas production. PMID- 23649361 TI - Unraveling the structural basis of GPCR activation and inactivation. PMID- 23649362 TI - From pseudo-ceRNAs to circ-ceRNAs: a tale of cross-talk and competition. PMID- 23649367 TI - In-depth safety-focused analysis of solvents used in electrolytes for large scale lithium ion batteries. AB - To better rule out the complex fire risk related to large format lithium ion cells, a detailed and systematic evaluation, both at component and cell levels, could be an invaluable milestone. Therefore, combustion analysis was conducted for major single organic solvents and their mixtures used in lithium ion battery technology, both in oxygen rich and lean environments using a Tewarson calorimeter. Well controlled test conditions have enabled the determination of key parameters governing the fire induced hazards such as flash point, ease of ignition, heat release rate, effective heat of combustion, specific mass loss rate, as well as the assessment of fire induced toxicity. Moreover, a rule of thumb for the screening of new solvents including the safety perspective such as the Boie correlation and N-factor were introduced for predicting the heat of combustion and combustion kinetics, respectively, prior to conducting any experimental work. Fire induced toxicity of single solvents and their mixtures was also briefly examined by performing toxic gas measurements. PMID- 23649363 TI - A role for eIF4AII in microRNA-mediated mRNA silencing. PMID- 23649368 TI - The effect of enriched milk with selenium and vitamin E on growth rate, hematology, some blood biochemical factors, and immunoglobulins of newborn goat kids. AB - Thirty male and female (n = 15 for each one) Markhoz newborn goat kids (aged 7 +/ 3 days) were distributed in a randomized block design in a 2 * 2 + 1 factorial arrangement: two levels of sodium selenite as a source of selenium (0.2 or 0.3 ppm Se), two levels of alpha-tocopherol acetate as a source of vitamin E (150 or 200 IU Vit E), and one control treatment with six repetitions per treatment (each replicate included three male and three female kids). Animals were fed daily by Se-Vit E-enriched milk (Se-Vit E treatments) or non-enriched milk (control treatment). Growth rate, hematology, and serum biological parameters were measured. The levels of serum albumin (P < 0.01), serum globulin (P < 0.05), total serum protein levels (P < 0.01), erythrocyte counts (RBC) (P < 0.001), hemoglobin (P < 0.001), hematocrit (P < 0.001), leukocyte counts (WBC) (P < 0.001), IgA (P < 0.05), IgG (P < 0.01), and IgM (P < 0.01) significantly differed among treatments, while no significant differences were observed for calcium, lymphocyte, neutrophil average daily gain and body weight among treatments. Kids feeding by enriched milk with 0.3 ppm Se and 200 IU Vit E had significantly higher serum total protein, globulin, RBC, IgA, IgG, and IgM compared to control and those fed by enriched milk to 0.2 ppm Se and 200 IU Vit E had significantly higher WBC counts. PMID- 23649369 TI - Selenium: a protective factor for Kaschin-Beck disease in Qing-Tibet Plateau. AB - There is a close relationship between selenium deficiency and Kaschin-Beck disease (KBD). Although the etiology of KBD is not known and selenium deficiency is not its actual cause, it is an important environmental risk factor. In particular, in the Qing-Tibet Plateau, a selenium-deficient region, the prevalence of KBD is serious and still increasing and continues to damage public health. By providing selenium to the population in appropriate amounts, and especially to children, KBD can be effectively controlled and prevented. PMID- 23649370 TI - Bis(alpha-furancarboxylato)oxovanadium(IV) exerts durable antidiabetic effects and suppresses matrix metalloproteinase-2 activity in spontaneous type 2 diabetic KKAy mice. AB - Vanadium compounds maintain euglycemic effects in diabetic rats long after drug withdrawal and bis(alpha-furancarboxylato)oxovanadium(IV) (BFOV) possesses potent antidiabetic effects in diabetic rats. Here, we investigated the treatment and posttreatment effects of BFOV in diabetic Kuo Kondo [1, 2] with Ay gene (KKAy) mice, and whether these effects were associated with changes in matrix metalloproteinases (MMPs). KKAy mice received normal saline or BFOV initially at 70 MUmol/kg/day for 1 month, which was tapered to 17 MUmol/kg/day in the next 2 months and discontinued thereafter. Compared to diabetic controls, fasting plasma glucose (FPG) was reduced by 46 and 19 % in KKAy mice after 70 MUmol/kg BFOV for 1 month and 3 months after BFOV withdrawal, respectively. OGTT and ITT showed improved glucose tolerance and a better response of FPG to insulin with a significant decrease in HOMA-IR and a marked rise in the insulin sensitivity index after 70 MUmol/kg BFOV for 1 month and 4 months after BFOV withdrawal (P <0.05 in all vs. diabetic controls). BFOV treatment resulted in a moderate but significant reduction in body weight and systolic blood pressure (SBP) at 1 month of treatment and 4 months following BFOV withdrawal (P <0.05 in all vs. diabetic controls). Gelatin zymography showed that serum MMP2 activity was significantly reduced and immunoblotting assays further showed that MMP2 expression was markedly downregulated in the liver after 1 month of treatment with 70 MUmol/kg and 4 months after BFOV withdrawal (P <0.05 in all vs. diabetic controls). These results suggested that BFOV possessed potent treatment and posttreatment effects in KKAy mice with improved metabolic profile and reduced body weight and SBP. Furthermore, these effects were associated with decreased MMP2 expression and activity in diabetic KKAy mice. PMID- 23649371 TI - Liquid chromatography-tandem mass spectrometric assay for aliskiren, a novel renin inhibitor in micro-volumes of human plasma: a pharmacokinetic application in healthy South Indian male subjects. AB - This paper describes a simple, rapid and sensitive liquid chromatography/tandem mass spectrometry assay for the determination of aliskiren in human plasma using nevirapine as an internal standard. Analyte and the internal standard were extracted from 100 MUL of human plasma via liquid-liquid extraction using tert butyl methyl ether. The chromatographic separation was achieved on a C18 column using a mixture of acetonitrile and 0.1% formic acid (90:10, v/v) as the mobile phase at a flow rate of 0.9 mL/min. The calibration curve obtained was linear (r(2) >= 0.99) over the concentration range of 0.10-1013 ng/mL. Method validation was performed as per US Food and Drug Administration guidelines and the results met the acceptance criteria. A run time of 2.2 min for each sample made it possible to analyze a greater number of samples in a short time, thus increasing the productivity. The proposed method was found to be applicable to clinical studies. PMID- 23649372 TI - Proline catalyzed sequential alpha-aminooxylation or -amination/reductive cyclization of o-nitrohydrocinnamaldehydes: a high yield synthesis of chiral 3 substituted tetrahydroquinolines. AB - A new sequential organocatalytic method for the synthesis of chiral 3-substituted (X = OH, NH2) tetrahydroquinoline derivatives (THQs) [ee up to 99%, yield up to 87%] based on alpha-aminooxylation or -amination followed by reductive cyclization of o-nitrohydrocinnamaldehydes has been described. This methodology has been efficiently demonstrated in the synthesis of two important bioactive molecules namely (-)-sumanirole (96% ee) and 1-[(S)-3-(dimethylamino)-3,4-dihydro 6,7-dimethoxy-quinolin-1(2H)-yl]propanone (92% ee). PMID- 23649374 TI - Effect of amiloride on experimental acid-induced heartburn in non-erosive reflux disease. AB - BACKGROUND: Acid-sensing ion channels (ASICs) are esophageal nociceptors that are candidates to mediate heartburn in non-erosive reflux disease (NERD). Amiloride, a diuretic, is known to inhibit ASICs. For this reason, we sought a role for ASICs in mediating heartburn by determining whether amiloride could block heartburn in NERD induced by esophageal acid perfusion. METHODS: In a randomized double-blind crossover study, we perfused the esophagus with amiloride or (saline) placebo prior to eliciting acid-induced heartburn in patients with a history of proton pump inhibitor-responsive NERD. Those with NERD and positive modified Bernstein test were randomized to perfusion with amiloride, 1 mmol/l, or placebo for 5 min, followed by repeat acid-perfusion. Heartburn severity and time to onset was measured and the process repeated following crossover to the alternative agent. RESULTS: 14 subjects completed the study. Amiloride did not reduce the frequency (100 vs. 100 %) or severity of acid-induced heartburn (Mean 2.50 +/- SEM 0.33 vs. 2.64 +/- 0.45), respectively. There was a trend towards longer time to onset of heartburn for amiloride versus placebo (Mean 2.93 +/- SEM 0.3 vs. 2.36 +/- 0.29 min, respectively), though these differences did not reach statistical significance (p > 0.05). CONCLUSIONS: Amiloride had no significant effect on acid-induced heartburn frequency or severity in NERD, although there was a trend towards prolonged time to onset of symptoms. PMID- 23649373 TI - Synthesis and pharmacological evaluation of some novel thebaine derivatives: N (tetrazol-1H-5-yl)-6,14-endoethenotetrahydrothebaine incorporating the 1,3,4 oxadiazole or the 1,3,4-thiadiazole moiety. AB - In this study, we synthesized some novel N-(tetrazol-1H-5-yl)-6,14 endoethenotetrahydrothebaine 7alpha-substituted 1,3,4-oxadiazole and 1,3,4 thiadiazole derivatives as potential analgesic agents. The structures of the compounds were established on the basis of their IR, 1H NMR, 13C NMR, 2D NMR, and high-resolution mass spectral data. The analgesic activity was evaluated by a rat hot plate test model and a rat tail-flick model. Compound 12 showed analgesic activity higher than that of morphine. In addition to a histopathological and biochemical evaluation, the LD50 dose for the most active compound 12 was determined. PMID- 23649376 TI - Trying to prevent the clogged drain: optimizing the yield and function of portal vein-infused islets. PMID- 23649375 TI - Reactive increase in gastric mucus secretion is an adaptive defense mechanism against low-dose aspirin-induced gastropathy. AB - BACKGROUND: Gastric mucus is considered to play an essential role in gastric mucosal defense mechanisms, especially when irritants are present in the stomach. AIM: To investigate the relationship between low-dose aspirin-induced gastropathy and gastric secretory function, especially gastric mucus secretion, in healthy volunteers. METHODS: Thirty male, asymptomatic, Helicobacter pylori pylori negative healthy volunteers were asked to take 100 mg of enteric-coated aspirin (Bayaspirin) once a day for 10 days. Endoscopic examination was performed before and 3 and 10 days after drug administration. The extent of endoscopically assessed gastric mucosal injury was semi-quantitatively evaluated according to the modified Lanza score. The pentagastrin-stimulated gastric juice was collected for 10 min during the endoscopic examination and subjected to analysis for gastric acid (mEq/10 min) or mucus (mg hexose/10 min) output. RESULTS: Overall, the 10-day aspirin treatment significantly increased gastric mucus secretion from 0.8 (interquartile range 1.7) to 1.6 (1.6) mg hexose/10 min (P < 0.05), with a concomitant and significant decrease in the gastric acid/mucus ratio from 4.3 (5.2) to 2.9 (4.7) (P < 0.01). Subsequent analysis of two subgroups of volunteers categorized according to their endoscopic status ("severe gastropathy" vs. "modest gastropathy") revealed that changes in gastric secretory parameters occurred exclusively in those subjects without severe gastric injury; there was no alteration in these parameters in subjects with severe gastric injury. CONCLUSIONS: The results of this study suggest that the reactive increase in gastric mucus secretion is an adaptive defense mechanism against low-dose aspirin induced gastropathy. In some individuals, such a response may be insufficient to prevent the development of severe mucosal injury and even ulcers and their complications. PMID- 23649377 TI - Small intestinal bacterial overgrowth and orocecal transit time in patients of inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) consists of Ulcerative colitis (UC) and Crohn's disease (CD). These two conditions share many common features diarrhea, bloody stools, weight loss, abdominal pain, fever and fatigue. Small intestinal bacterial overgrowth (SIBO) is frequent in patients with CD but it has not been studied in UC Indian patients. AIM: The study was planned to measure orocecal transit time (OCTT) and SIBO in UC and CD patients. METHODS: One hundred thirty-seven patients of IBD (95 UC and 42 CD) and 115 healthy controls were enrolled. OCTT and SIBO were measured by lactulose and glucose hydrogen breath test respectively. Concentration of hydrogen and methane were measured by SC microlyser from Quintron, USA. RESULTS: Mean+/-standard deviation (SD) of OCTT in patients of IBD was significantly higher as compared to controls. Furthermore, OCTT was significantly higher in CD patients as compared to UC patients. It was also observed that occurrence of SIBO was significantly higher in IBD patients as compared to controls. The occurrence of SIBO in CD (45.2%) was significantly higher as compared to patients in UC (17.8%) group. Percentage of methane positive IBD patients (2.9%) was significantly lower as compared to methane positive controls (24.4%). CONCLUSION: OCTT was significantly delayed in IBD patients as compared to controls and in CD patients as compared to UC patients. OCTT was significantly higher in SIBO positive IBD patients as compared to SIBO negative patients. Thus, we can suggest that delayed OCTT would have been the cause of increased SIBO in these patients. PMID- 23649380 TI - Preserving personal autonomy in a genomic testing era. PMID- 23649381 TI - Response to Lindor et al. PMID- 23649382 TI - Avicenna's view on medical genetics. PMID- 23649385 TI - Hairy roots as a vaccine production and delivery system. AB - Prevention of infectious diseases by vaccination is often limited because of the lack of safe, effective, and accessible vaccines. Traditional vaccines are expensive and require special conditions for storage, distribution, and administration. Plants have potential for large-scale production of a variety of inexpensive and highly effective recombinant proteins for biomedical and pharmaceutical applications, including subunit vaccines. There are several approaches for the production of vaccine antigens in plants, including transient expression systems based on Agrobacterium delivery of binary vectors or plant viral vectors, stable transgenic plants, and plant cell or tissue cultures. Axenic plant cultures maintained under defined physical and chemical conditions appear to be an attractive production platform when target proteins need to be synthesized in a fully controlled environment. Hairy root cultures meet the criteria for such a system. Hairy root cultures, generated from edible plants and producing target antigens, provide a potential approach for the development of vaccines for oral delivery. With this approach, there are no protein extraction and purification costs and the active biomolecule is protected by the plant cell wall during passage through the upper gastrointestinal tract. This allows for gradual release of antigen at mucosal surfaces in the gut. Lyophilized hairy root cultures expressing vaccine antigens can be stored at ambient temperature for extended periods of time, which should facilitate storage and distribution, ultimately allowing for large populations to be vaccinated. PMID- 23649386 TI - Supporting high-value Part D Medicare choices for low-income beneficiaries: comment on "Cognition and take-up of subsidized drug benefits by Medicare beneficiaries". PMID- 23649387 TI - [Development of experimental techniques and evaluation to support evidence-based medicine (EBM)]. PMID- 23649384 TI - Molecular targeted therapies in non-GIST soft tissue sarcomas: what the radiologist needs to know. AB - Non-gastrointestinal stromal soft tissue sarcomas are uncommon neoplasms that have a dismal prognosis due to a high incidence of metastases and a poor response to conventional chemotherapy. The identification of characteristic genetic alterations in several of these tumors has opened the window for molecular targeted therapies in patients who have failed conventional chemotherapy. Imaging plays a critical role in assessing the response to these novel therapeutic agents. Just like the response of gastrointestinal stromal tumors to imatinib, the response of non-gastrointestinal stromal soft tissue sarcomas to molecular targeted drugs is better evaluated on imaging by alternate tumor response criteria such as the Choi criteria. In addition, these drugs are associated with distinct class-specific drug toxicities that can come to attention for the first time on imaging. The purpose of this article is to provide a primer for the radiologist on the various molecular targeted therapies in advanced/metastatic non-gastrointestinal stromal soft tissue sarcomas with emphasis on the role of imaging in assessing treatment response and complications. PMID- 23649388 TI - [Antitumor effects of a plant extract mixture]. AB - Cancer is the most common cause of death in Japan. Fundamental and clinical studies on cancer were conducted from the viewpoint of Western medicine so far. However, a sustained complete remission has not been achieved yet. In order to alleviate the side effects of anticancer drugs, some traditional herbal medicines (Kampo medicines) have been prescribed to cancer patients. We have been studying on antitumor substances in medicinal herbs and found an antitumor medicinal herb named Rhus verniciflua (lacquer, Urushi in Japanese). To investigate the antitumor effect in vitro, a plant extract mixture was prepared from six medicinal herbs containing lacquer. The plant extract mixture containing lacquer (Rv-PEM) inhibited the proliferation of several mouse and human tumor cell lines. Rv-PEM had more potent inhibitory effect on the proliferation of human leukemia cell lines (MOLT-3, KG-1) than on other tumor cell lines. The IC50 values of Rv PEM on MOLT-3 and KG-1 cells were 0.208 and 0.293 mg/mL, respectively. After treating Rv-PEM to the tumor cells, DNA fragmentation and Caspase-3 and -9 activity increased in the treated cells. The mechanisms of the inhibitory proliferation activity of Rv-PEM would involve apoptosis of human leukemia cells (MOLT-3, KG-1, K-562) by the mitochondrial pathway. PMID- 23649389 TI - [Elucidation of mechanisms underlying docosahexaenoic acid-induced antinociception]. AB - Docosahexaenoic acid (DHA), a predominant of n-3 polyunsaturated fatty acids (n-3 PUFA), has numerous beneficial physiological effects, including neuroprotection and cardiovascular protection. Recently, a possible involvement of n-3 PUFA in pain control has gathered considerable attention because numerous studies have reported a regulatory role of n-3 PUFAs. However, the mechanisms underlying how DHA exerts antinociceptive effect remain unknown. Here, we performed elucidation of mechanisms underlying DHA-induced antinociception. DHA administration dose dependently exerted an antinociceptive effect. This effect was abolished by pretreated with the beta-funaltrexamine (beta-FNA), a MU-opioid receptor antagonist, and the nartrindole (NTI), a delta-opioid receptor antagonist, but not by the nor-binaltorphimine (nor-BNI), a kappa-opioid receptor antagonist. In the radioligand binding assay, DHA itself did not have the affinity for MU-, delta- and kappa- opioid receptor. Furthermore, the pretreatment of anti beta endorphin antiserum inhibited DHA-induced antinociception. The plasma levels of beta-endorphin increased 30 min after DHA administration. The beta-endorphin immunoreactivity in the brain increased at 30 min after DHA treatment. Expression of GPR40 protein was widely observed in the brain as well as the spinal cord. The intracerebroventricular but not intrathecal injection of DHA and GW9508, a GPR40/GPR120 agonist, significantly reduced formalin-induced pain behavior. The beta-endorphin immunoreactivity in the brain increased at 10 and 20 min after intracerebroventricular injection of DHA and GW9508. These findings suggest that DHA-induced antinociception via beta-endorphin release may be mediated through GPR40 signaling in the supraspinal area. PMID- 23649390 TI - [Imaging monitoring method of CaMKII activity by immunohistochemical analysis in schizophrenic model rats]. AB - Schizophrenia is characterized by various behavioral abnormalities including cognitive dysfunction. Neonatal ventral hippocampus (NVH)-lesioned rats had been known as neurodevelopmental animal model similar to schizophrenia. Previous observations indicate that postpubertal NVH-lesioned rats exhibit impairments in prepulse inhibition (PPI), spontaneous locomotion, social interaction behavior and working memory. Here, we document the neurochemical basis of those defects in NVH-lesioned rats. Since Ca2+/calmodulin-dependent protein kinase II (CaMKII), which is NMDA receptor downstream kinase, is essential for memory and learning acquisition, we developed a protocol to monitor the spatial changes in CaMKII autophosphorylation using immunohistochemical imaging of whole brain slices with anti-autophosphorylated CaMKII antibody in order to address mechanisms underlying impaired cognitive function in NVH-lesioned rats. Immunohistochemical analyses using anti-autophosphorylated CaMKII antibody revealed that CaMKII autophosphorylation was significantly reduced in the medial prefrontal cortex (mPFC) of NVH-lesioned rats compared with control animals. This immunohistochemical technique is useful to investigate temporal and special changes in CaMKII activity in rodent brain and to evaluate drugs to improve the cognitive impairment. PMID- 23649392 TI - [Structural basis for beta-galactosidase associated with lysosomal disease]. AB - G(M1)-gangliosidosis and Morquio B are rare lysosomal storage diseases associated with a neurodegenerative disorder or dwarfism and skeletal abnormalities, respectively. These diseases are caused by deficiencies in the lysosomal enzyme human beta-D-galactosidase (h-beta-GAL), which lead to accumulations of the h beta-GAL substrates, G(M1) ganglioside and keratan sulfate due to mutations in the h-beta-GAL gene. H-beta-GAL is an exoglycosidase that catalyzes the hydrolysis of terminal beta-linked galactose residues. Here, we present the crystal structures of h-beta-GAL in complex with its catalytic product galactose or with its inhibitor 1-deoxygalactonojirimycin. H-beta-GAL showed a novel homodimer structure; each monomer was comprised of a catalytic TIM barrel domain followed by beta-domain 1 and beta-domain 2. The long loop region connecting the TIM barrel domain with beta-domain 1 was responsible for the dimerization. To gain structural insight into the molecular defects of h-beta-GAL in the above diseases, the disease-causing mutations were mapped onto the three-dimensional structure. Finally, the possible causes of the diseases are discussed. PMID- 23649393 TI - [Structural study of polyglutamine tract-binding protein 1]. AB - Polyglutamine tract-binding protein 1 (PQBP1) is a nuclear protein that regulates transcription and pre-mRNA splicing. In addition, the mutations in the PQBP1 gene are known to cause hereditary mental retardation. This review summarizes current knowledge about the solution structure of PQBP1. PQBP1 is an intrinsically disordered protein: its polar-rich domain and C-terminal domain are disordered under physiological conditions. PQBP1 binds to its target molecule U5-15kD via a continuous 23-residue segment of the C-terminal domain. The function of PQBP1 in the pre-mRNA splicing is also discussed. PMID- 23649394 TI - [Structural biology for developing antimalarial compounds]. AB - The human malaria parasite Plasmodium falciparum is responsible for the death of more than a million people each year. The emergence of strains of this malaria parasite resistant to conventional drug therapy has stimulated the search for antimalarial compounds with novel modes of action. Here the structure-function relationship studies for two Plasmodium proteins are presented. One example is the structural studies for S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum (PfSAHH) and the other example is those for 1-deoxy-D-xylulose reductoisomerase from Plasmodium falciparum (PfDXR). In the former study, the clue for design of species specific PfSAHH inhibitors was obtained by the structural comparison of the active site of PfSAHH with that of human SAHH (HsSAHH). Our study revealed that the inhibitor selectivity depends on the difference of only one amino acid residue in the active site; Cys59 in PfSAHH vs. Thr60 in HsSAHH. In the latter study, the inhibition of PfDXR enzyme by fosmidomycin has proved to be efficient in the treatment of uncomplicated malaria in recent clinical trials conducted in Gabon and Thailand. Our crystal structure analyses of PfDXR/inhibitor complexes revealed the molecular basis of fosmidomycin's action in P. falciparum. We expect that the structure-function relationship studies on Plasmodium proteins are useful for developing the more effective antimalarial compounds. PMID- 23649395 TI - [Strategies for the structural determination of G protein-coupled receptors: from an example of histamine H1 receptor]. AB - G protein-coupled receptors (GPCRs) are major therapeutic drug targets and represent more than 30% of the market share of all prescription drugs. The high resolution three-dimensional structures of the target receptors provide good initial models for structure-based approaches to drug screening and drug design, which are considered to accelerate drug discovery. However, significant bottlenecks at the expression, purification and crystallization stages of structure determination of GPCRs have existed. Here, we review recent techniques for the determination of GPCR structures. In particular, we focus on the protein engineering techniques that have been used to overcome bottlenecks in expression/purification and crystallization, including our development of a platform using budding yeast for the rapid construction and evaluation of GPCR variants for structural studies. We also present our success in determining the crystal structure of the histamine H1 receptor (H1R) in complex with doxepin, an inverse agonist antihistamine. The H1R structure revealed the low selectivity of doxepin to aminergic receptors and provides key information that should aid the development of highly selective antihistamines. PMID- 23649396 TI - [Entry mechanism of morbillivirus family]. AB - The genus Morbillivirus includes measles virus, canine distemper virus and rinderpest virus. These are highly contagious and exhibit high mortality. These viruses have the attachment glycoprotein, hemagglutinin (H), at the virus surface, which bind to signaling lymphocyte activation molecule (SLAM) and Nectin 4 as receptors for the entry. However, the molecular mechanism for this entry has been limitedly understood. Here we summarize the current topics, (1) newly identified receptor, Nectin 4, (2) crystal structures of H-receptor complexes and (3) detail biochemical studies of the H-F communication for the entry. These provide insight on the mechanism of morbillivirus entry event and furthermore drug developments. PMID- 23649397 TI - [Metabolism and biological function of cardiolipin]. AB - Cardiolipin (CL) is a phospholipid, which is exclusively located in mitochondria, and has a unique structure that consists of 2 phosphate residues and 4 kinds of fatty acyl chains. Cardiolipin plays an important role in regulating various kinds of mitochondrial proteins such as electron transport complexes, carrier proteins and phosphate kinases, and is also essential for the organization of particular mitochondrial structures such as cristae and contact sites. Mitochondrial phospholipase D hydrolyzes CL to produce phosphatidic acid, which is required for mitochondrial fusion. Oxidative stress-induced peroxidation of CL occurs because CL is rich in polyunsaturated fatty acids, especially linoleic acid. Accumulation of CL hydroperoxide (CLOOH) triggers the initiation of apoptosis. Formation of CLOOH causes the release of proapoptotic factors such as cytochrome c from the inner mitochondrial membrane and triggers opening of the permeability transition pore. Levels of CL decrease in the heart following ischemia or disease. Apoptosis is enhanced in temperature-dependent mutant cells whose amounts of CL reduce to half when compared to that of wild type cells. Low levels of CL cause the accumulation of CLOOH and enhance sensitivity to apoptosis. Accumulation of CLOOH in mitochondria causes instability of the membrane, because swelling of mitochondria is induced by the presence of CLOOH in the membrane and is significantly enhanced in CLOOH-loaded mitochondria by the addition of inducer of swelling. PMID- 23649398 TI - [Synthetic medicinal chemistry of the biomolecular components mimics]. AB - We are studying the medicinal synthetic chemistry of biomolecular component mimics such as carbohydrates, nucleosides, amino acids, and peptides. In this review, the synthesis and biological activities of iminosugars as carbohydrate mimics are discussed. Glycosidases and glycosyltransferases are involved in a wide range of anabolic and catabolic process, including digestion, the lysosomal catabolism of glycoconjugates, glycoprotein biosynthesis. Hence, modifying or blocking these processes in vivo using inhibitors is a topic of great interest from the therapeutic point of view. Iminosugars are sugars in which the endocyclic oxygen is replaced by a basic nitrogen atom. They are regarded as transition state mimics in certain types of enzyme reactions. This makes the field of iminosugars as carbohydrate mimics an exciting area of research. We synthesized all of the stereoisomers of polyhydroxypiperidines such as fagomine, 1-deoxynojirimycine, and isofagomine. In addition, their both enantiomers, as substrates for a variety of glycosidases were evaluated. Secondly, the asymmetric synthesis of alpha-1-C-alkyl-arabinoiminofuranoses was achieved by asymmetric allylic alkylation, RCM, and Negishi cross coupling as key reactions. Surprisingly, the L-forms showed a quite potent inhibitory activity toward rat intestinal maltase, while the activities of the D-forms were much weaker. Some of the prepared L-forms showed potent inhibitory activities towards intestinal maltase, with IC50 values comparable to those of commercial drugs such as acarbose, voglibose, and miglitol, which are used in the treatment of type 2 diabetes. Among them, the inhibitory activity towards intestinal sucrase of alpha 1-C-L-butylarabinoiminofuranose was quite strong towards intestinal sucrase compared to the above commercial drugs. PMID- 23649399 TI - [Factors contributing to increases in serum creatinine following treatment with a sulfamethoxazole-trimethoprim combination product: retrospective analysis of Japanese patients with normal renal function]. AB - Japanese patients with normal renal function were retrospectively analyzed to characterize increases in serum creatinine (SCr) observed following the use of a sulfamethoxazole-trimethoprim (SMX-TMP) combination product and identify factors affecting these increases. In the patients studied (n=49), an individual comparison was conducted for the three factors of age group [<=74 years (n=21) vs. >=75 years (n=28)], sex [male (n=24) vs. female (n=25)], and total dose throughout the treatment period [<=7 g (n=24) vs. >=8 g (n=25)] to determine the extent of SCr increase following SMX-TMP combination product use. SCr increased significantly following SMX-TMP combination product use in patients <=74 years of age and >=75 years of age, in both males and females, and in patients with a total dose of >=8 g (8 to 96 g) (p<0.05). Multivariate logistic regression analysis was used to determine the independence of these factors. Total dose was identified as an independent factor and had an odds ratio of 6.571 [95% confidence interval=1.735-24.882, p=0.006]. Post-treatment percent increases in SCr were compared using pre-treatment levels as the baseline. The group with a total dose of >=8 g (mean 29.8 g) had a significant SCr increase of 18.4% (p=0.002), while the increase in the <=7 g (mean 5.3 g) group was only 4.5%. The data showed that SCr increased by about 20% when the total dose taken over the treatment period was around 30 g (about 2.4 g as TMP) and indicated that total dose contributes more than age and sex to the post-treatment increase in SCr. PMID- 23649400 TI - Single-bone intramedullary fixation of unstable both-bone diaphyseal forearm fractures in children leads to increased re-displacement: a multicentre randomised controlled trial. AB - INTRODUCTION: Both-bone diaphyseal forearm fractures in children can be stabilised without cast by a flexible intramedullary nail in both the radius and the ulna. Adequate results with single-bone fixation combined with a complementary cast are also reported. However, because those results are based on a selection of children, this trial investigates whether single-bone intramedullary fixation, compared with both-bone intramedullary fixation, results in similar pronation and supination in children with an unstable diaphyseal both bone forearm fracture. MATERIALS AND METHODS: In four Dutch hospitals, 24 consecutive children aged <16 years with a displaced unstable both-bone diaphyseal forearm fracture were randomly allocated to single-bone or both-bone intramedullary fixation. Primary outcome was limitation of pronation and supination 9 months after initial trauma. Secondary outcomes were limitation of flexion/extension of wrist/elbow, complication rate, operation time, cosmetics of the fractured arm, complaints in daily life, and assessment of radiographs. RESULTS: Between January 2006 and August 2010, 11 children were randomised to single-bone fixation and 13 to both-bone fixation. In the both-bone fixation group, two fractures were stabilized by only one nail. In both groups, median limitation of pronation/supination at 9-month follow-up was 5 degrees -10 degrees . In both groups operation time was similar but in the single-bone fixation group cast immobilisation was longer (median of 37 vs. 28 days). In four children, re displacement of the fracture occurred in those fractures without an intramedullary nail. CONCLUSIONS: These results caution against the use of single bone fixation in all both-bone forearm fractures. This method may lead to increased re-displacement and reduced clinical results. PMID- 23649401 TI - Schwannoma in neurofibromatosis type 1: a pitfall for detecting malignancy by metabolic imaging. AB - Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome characterized by the development of multiple peripheral nerve sheath tumors, the majority of which are benign neurofibromas. However, malignant peripheral nerve sheath tumors (MPNSTs) occur with a 10 % lifetime risk in patients with NF1, often developing within a neurofibroma. When clinical suspicion for an MPNST arises, imaging with FDG PET and MRI is performed to characterize a peripheral tumor for potential malignancy. In this report, we describe a patient with NF-1 who had two peripheral tumors with similar features by PET, both suspicious for MPNST, but differing features by MRI, one of which was subsequently determined to be an MPNST and the second to be a schwannoma. PMID- 23649402 TI - DynaMesh(r) in the repair of laparoscopic ventral hernia: a prospective trial. AB - PURPOSE: To investigate mesh-related complications in patients undergoing laparoscopic ventral hernia repair using DynaMesh(r). METHODS: In the period 1 January 2005 through 31 December 2010, 181 consecutive patients undergoing laparoscopic ventral hernia repair in our day surgery unit using DynaMesh(r) were entered prospectively in the National Danish Hernia Database. Data concerning abdominal reoperations after hernia repair were later collected on all 181 patients from the National Danish Health Registry. Postoperative telephone interviews were conducted estimating postoperative pain and patient satisfaction. RESULTS: Six % (11 patients) were reoperated because of mesh-related complications. Three had small bowel obstruction and one had a colonic fistula with mesh infection, all causing bowel resection and mesh removal. Mesh-related cutaneous fistula was seen in one patient. Six patients had a symptomatic recurrence requiring reoperation. Abdominal wall hematomas were seen in two cases, while two other patients had symptomatic large seromas, of which one was drained surgically. After a median follow-up of 34 months (range 12-63) in 140 patients, 66 % were pain free (0 on the Numeric Rating Scale (NRS)). Of 26 patients with moderate to severe pain (NRS > 3) at follow-up, only 4 regretted the operation. Sixteen patients thought they had a recurrence, of these only 3 regretted the operation. CONCLUSION: The use of DynaMesh(r) in laparoscopic ventral hernia repair was associated with a 6 % risk of mesh-related reoperation in a high volume setting. Despite chronic pain in 19 %, after 34 months follow-up patient satisfaction was high. PMID- 23649405 TI - Simultaneous measurement of liquid absorbance and refractive index using a compact optofluidic probe. AB - We present a novel optical technique for simultaneously measuring the absorbance and the refractive index of a thin film using an infrared optofluidic probe. Experiments were carried on two different liquids and the results agree with the bibliographical data. The ultimate goal is to achieve a multi-functional micro optical device for analytical applications. PMID- 23649403 TI - A systematic review of randomised control trials assessing mesh fixation in open inguinal hernia repair. AB - PURPOSE: The technique for fixation of mesh has been attributed to adverse patient and surgical outcomes. Although this has been the subject of vigorous debate in laparoscopic hernia repair, the several methods of fixation in open, anterior inguinal hernia repair have seldom been reviewed. The aim of this systematic review was to determine whether there is any difference in patient based (recurrence, post-operative pain, SSI, quality of life) or surgical outcomes (operative time, length of operative stay) with different fixation methods in open anterior inguinal hernioplasty. METHODS: A literature search was performed in PubMed, EMBASE and the Cochrane Library databases. Randomised clinical trials assessing more than one method of mesh fixation (or fixation versus no fixation) of mesh in adults (>18 years) in open, anterior inguinal hernia repair, with a minimum of 6-month follow-up and including at least one of the primary outcome measures (recurrence, chronic pain, surgical site infection) were included in the review. Secondary outcomes analysed included post-operative pain (within the first week), quality of life, operative time and length of hospital stay. RESULTS: Twelve randomised clinical trials, which included 1,992 primary inguinal hernia repairs, were eligible for inclusion. Four studies compared n-butyl-2 cyanoacrylate (NB2C) glues to sutures, two compared self fixing meshes to sutures, four compared fibrin sealant to sutures, one compared tacks to sutures, and one compared absorbable sutures to non-absorbable sutures. The majority of the trials were rated as low or very low-quality studies. There was no significant difference in recurrence or surgical site infection rates between fixation methods. There was significant heterogeneity in the measurement of chronic pain. Three trials reported significantly lower rates of chronic pain with fibrin sealant or glue fixation compared to sutures. A further three studies reported lower pain rates within the first week with non-suture fixation techniques compared to suture fixation. A significant reduction in operative time, ranging form 6 to 17.9 min with non-suture fixation, was reported in five of the studies. Although infrequently measured, there were no significant differences in length of hospital stay or quality of life between fixation methods. CONCLUSIONS: There is insufficient evidence to promote fibrin sealant, self-fixing meshes or NB2C glues ahead of suture fixation. However, these products have been shown to be at least substantially equivalent, and moderate quality RCTs have suggested that both fibrin sealant and NB2C glues may have a beneficial effect on reducing immediate post-operative pain and chronic pain in at-risk populations, such as younger active patients. It will ultimately be up to surgeons and health-care policy makers to decide whether based on the limited evidence these products represent a worthwhile cost for their patients. PMID- 23649404 TI - Improving tension decrease in components separation technique. AB - PURPOSE: The purpose of this study is to evaluate the tension at the aponeurotic edges after the undermining of the anterior rectus sheath associated with the classic components separation in cadavers. METHODS: Twenty fresh adult cadavers were placed supine and an incision in the anterior rectus sheath was done, thus exposing the posterior sheath. The two levels to be studied were marked 3 cm above and 2 cm below the umbilicus. An analogical dynamometer was used to measure the traction values, consecutively during four stages as follows: initial stage, no aponeurotic undermining; Stage 1, separation of the anterior rectus sheaths; Stage 2, after Stage 1 the external oblique aponeurosis were incised along the semilunaris and the external oblique muscles were undermined; Stage 3, after Stage 2 rectus muscles were completely separated from their posterior sheaths. Statistical analysis was done by Friedman's analysis of variance (p < 0.05). RESULTS: There was a progressive and significant decrease in tension along the stages (Friedman's analysis of variance, p < 0.001). Traction indexes were higher in the initial stage and became gradually lower along the other stages. CONCLUSION: The undermining of the anterior rectus sheaths helps to decrease tension during the components separation technique. LEVEL OF EVIDENCE: Level V, experimental study. PMID- 23649406 TI - Innervation pattern of the suprascapular nerve within supraspinatus: a three dimensional computer modeling study. AB - The relationship between the innervation pattern of the suprascapular nerve (SSN) and the muscle architecture of supraspinatus has not been thoroughly investigated. The supraspinatus is composed of two architecturally distinct regions: anterior and posterior. Each of these regions is further subdivided into three parts: superficial, middle and deep. The purpose of this study was to investigate the course of the SSN throughout the volume of supraspinatus and to relate the intramuscular branches to the distinct regions and parts of the supraspinatus. The SSN was dissected in thirty formalin embalmed cadaveric specimens and digitized throughout the muscle volume in six of those specimens. The digitized data were modeled using Autodesk((r)) Maya((r)) 2011. The three dimensional (3D) models were used to relate the intramuscular innervation pattern to the muscle and tendon architecture defined by Kim et al. (2007, Clin Anat 20:648-655). The SSN bifurcated into two main trunks: medial and lateral. All parts of the anterior region were predominantly innervated by the medial trunk and its proximal and medial branches, whereas all parts of the posterior region predominantly by the lateral trunk and its posterolateral and/or posteromedial branches. The posterior region also received innervation from the proximal branch of the medial trunk in half of the specimens. These findings provide evidence that the anterior and posterior regions are distinct with respect to their innervation. The 3D map of the innervation pattern will aid in planning future clinical studies investigating muscle activation patterns and provide insight into possible injury of the nerve with supraspinatus pathology and surgical techniques. PMID- 23649407 TI - Synthesis of the decalin core of codinaeopsin via an intramolecular Diels-Alder reaction. AB - We describe the synthesis of the decalin core of codinaeopsin (1), a tryptophan polyketide hybrid natural product with promising antimalarial activity (IC50 4.7 MUM, against Plasmodium falciparum), via an intramolecular Diels-Alder (IMDA) reaction. A convergent synthesis was developed to prepare the precursors for the IMDA reaction in 10 steps. The exo cycloadducts were derived from thermal, IMDA reactions of the substrates containing a Weinreb amide or ester conjugated dienophile, and the endo adducts were from Lewis acid promoted reactions of the substrates with a formyl group. Both exo and endo products of the IMDA were exclusively isolated and characterized by NMR spectroscopy. One endo cycloadduct was further confirmed with X-ray crystallography. Theoretical calculations reveal the influence of the substituents of the decalin core on the IMDA process. PMID- 23649408 TI - Simultaneous measurement of J(HH) and two different (n)J(CH) coupling constants from a single multiply edited 2D cross-peak. AB - Three different J-editing methods (IPAP, E.COSY and J-resolved) are implemented in a single NMR experiment to provide spin-state-edited 2D cross-peaks from which a simultaneous measurement of different homonuclear and heteronuclear coupling constants can be performed. A new J-selHSQMBC-IPAP experiment is proposed for the independent measurement of two different (n)J(CH) coupling constants along the F2 and F1 dimensions of the same 2D cross-peak. In addition, the E.COSY pattern provides additional information about the magnitude and relative sign between J(HH) and (n)J(CH) coupling constants. PMID- 23649410 TI - Graphene oxide induced formation of Pt-CeO2 hybrid nanoflowers with tunable CeO2 thickness for catalytic hydrolysis of ammonia borane. AB - Pt-CeO2: Flowerlike Pt-CeO2 hybrids on reduced graphene oxide (RGO) can be prepared by treating Pt cubes with Ce(NO3)3 in the presence of graphene oxide. The density of the CeO2 coating around the Pt cubes depends on the amount of Ce(NO3)3 used. The as-obtained samples exhibit high stability and activity for the catalytic hydrolysis of ammonia borane (AB). PMID- 23649411 TI - Optimization of an Adsorption-Elution Method with a Negatively Charged Membrane to Recover Norovirus from Lettuce. AB - Viral pathogens, such as norovirus (NoV), are frequently associated with foodborne gastroenteritis worldwide, and the detection of NoV in food requires appropriate methods and the use of process controls. In this study, an adsorption elution concentration method using negatively charged membranes was optimized to recover NoV from lettuce, using murine norovirus 1 (MNV-1) as a human NoV (HuNoV) surrogate. Initially, three elution buffers were evaluated by direct elution using a Stomacher(r) apparatus with a filter bag and different concentrations of MNV-1 genomic copies. The eluates were filtered in a Stericup(r) and concentrated by a Centriprep Concentrator(r), and the viral RNA was quantified by real-time PCR that was preceded by reverse transcription. The MNV-1 recovery efficiency varied based on the buffers used, ranging from 5.2 to 9.8 % for PBS pH 7.2, 0.2 18 % for glycine NaCl pH 9.5 and 10.8-33.3 % for glycine Tris-HCl pH 9.5. Further analysis of the glycine Tris-HCl pH 9.5 buffer revealed that gentle-shaking, direct elution could replace the use of a Stomacher(r), with recovery rates reaching 66 and 32 % for MNV-1 and HuNoV, respectively, all of which suggested that this procedure is a quick and efficient method for recovering NoV from lettuce. PMID- 23649412 TI - Diamond nanoparticles as a new platform for the sequestration of waste carbon. AB - The use of carbon nanostructures to capture and store waste carbon, such as methane and carbon dioxide, is intrinsically attractive, particularly if the same molecules can be subsequently used as synthetic precursors. However, to facilitate adsorption of these highly stable species high pressures are required, and fragile carbon-based nanostructures may not survive. By combining electronic structure simulations and ab initio thermodynamics, we have investigated the thermochemical conditions required to adsorb CH, CH2, CO and CO2 on diamond nanoparticles, which can withstand higher temperatures and pressures than alternative carbon-based nanostructures. We find that, while CO2 must be over saturated to facilitate stable adsorption (with high efficiency), the strength of the resultant C-O bonds means that desorption will not occur spontaneously when atmospheric pressure is resumed. PMID- 23649414 TI - Drug patents: the high price of watchdog litigation. PMID- 23649413 TI - Prevalence estimates of chronic kidney disease in Canada: results of a nationally representative survey. AB - BACKGROUND: Chronic kidney disease is an important risk factor for death and cardiovascular-related morbidity, but estimates to date of its prevalence in Canada have generally been extrapolated from the prevalence of end-stage renal disease. We used direct measures of kidney function collected from a nationally representative survey population to estimate the prevalence of chronic kidney disease among Canadian adults. METHODS: We examined data for 3689 adult participants of cycle 1 of the Canadian Health Measures Survey (2007-2009) for the presence of chronic kidney disease. We also calculated the age-standardized prevalence of cardiovascular risk factors by chronic kidney disease group. We cross-tabulated the estimated glomerular filtration rate (eGFR) with albuminuria status. RESULTS: The prevalence of chronic kidney disease during the period 2007 2009 was 12.5%, representing about 3 million Canadian adults. The estimated prevalence of stage 3-5 disease was 3.1% (0.73 million adults) and albuminuria 10.3% (2.4 million adults). The prevalence of diabetes, hypertension and hypertriglyceridemia were all significantly higher among adults with chronic kidney disease than among those without it. The prevalence of albuminuria was high, even among those whose eGFR was 90 mL/min per 1.73 m(2) or greater (10.1%) and those without diabetes or hypertension (9.3%). Awareness of kidney dysfunction among adults with stage 3-5 chronic kidney disease was low (12.0%). INTERPRETATION: The prevalence of kidney dysfunction was substantial in the survey population, including individuals without hypertension or diabetes, conditions most likely to prompt screening for kidney dysfunction. These findings highlight the potential for missed opportunities for early intervention and secondary prevention of chronic kidney disease. PMID- 23649415 TI - Atypical femoral fractures associated with long-term bisphosphonate use. PMID- 23649409 TI - Volatile substance misuse: an updated review of toxicity and treatment. AB - Educational campaigns and legislative actions may have led to an overall decrease in the prevalence of volatile substance misuse (VSM) in many countries; however, it is still a common practice throughout the world. Studies currently suggest that girls are misusing volatile substances more than before and at a prevalence rate equal to or exceeding that of boys in several countries. Products that may be misused are ubiquitous and relatively easy to acquire. The most commonly misused substances in recent studies are fuels such as butane or petrol and compressed gas dusters and deodorants that may contain fluorocarbons and/or butane. Detection of VSM is challenging, therefore physicians must maintain a high level of suspicion based on history and clinical presentation. Clues to misuse are often subtle and may include the patient's proximity to a volatile substance or paraphernalia when found intoxicated, dermal burns, blisters, pigments, or rashes, and chemical odors. The primary targets of toxicity are the brain and the heart. The leading cause of death from VSM is from ventricular dysrhythmias. Treatment of toxicity begins with support of airway, breathing, and circulation. Exogenous catecholamines should be avoided if possible due to the theoretical "sensitized" and irritable myocardium. In the case of ventricular dysrhythmias, direct current defibrillation and/or beta-adrenergic receptor antagonism should be used. New evidence demonstrates the addictive potential of VSM yet effective therapy remains uncertain. Further research is needed in developing methods for preventing, detecting, and treating the harmful effects of VSM. PMID- 23649417 TI - Breast cancer in men. PMID- 23649418 TI - Fibromyalgia: evolving concepts over the past 2 decades. PMID- 23649419 TI - UBC takes over Therapeutics Initiative after provincial cuts. PMID- 23649420 TI - Mixed reviews on removing fallopian tubes to prevent ovarian cancer. PMID- 23649421 TI - Birth control "debacle" prompts calls for swifter public notices. PMID- 23649422 TI - Measles outbreaks threaten those averse to vaccine. PMID- 23649426 TI - Review of the quantitative analysis of cholesteryl ester transfer protein inhibitors. AB - Clinical investigations of choleteryl ester transfer protein (CETP) inhibitors are still underway owing to its promise of reducing risk factors in patients with cardiovascular disease. Although several CETP inhibitors have reached late phase clinical testing, there is a paucity of publications that describe the determination of various CETP inhibitors in human and/or animal matrices. An attempt is made in this review to collate bioanalytical information on three CETP inhibitors (anacetrapib, dalcetrapib and torcetrapib) and its metabolites, where data were available and reported. As elaborated in the review, owing to numerous structural issues coupled with chromatography/detection challenges indigenous to the class, a wide array of analytical tools, detection systems, interesting process manipulations and separation nuances have been utilized for the quantitative analysis of CETP inhibitors and applicable metabolites. PMID- 23649425 TI - Reduced renal clearance of cefotaxime in asians with a low-frequency polymorphism of OAT3 (SLC22A8). AB - Organic anion transporter 3 (OAT3, SLC22A8), a transporter expressed on the basolateral membrane of the proximal tubule, plays a critical role in the renal excretion of organic anions including many therapeutic drugs. The goal of this study was to evaluate the in vivo effects of the OAT3-Ile305Phe variant (rs11568482), present at 3.5% allele frequency in Asians, on drug disposition with a focus on cefotaxime, a cephalosporin antibiotic. In HEK293-Flp-In cells, the OAT3-Ile305Phe variant had a lower maximum cefotaxime transport activity, Vmax , [159 +/- 3 nmol*(mg protein)(-1) /min (mean +/- SD)] compared with the reference OAT3 [305 +/- 28 nmol*(mg protein)(-1) /min, (mean +/- SD), p < 0.01], whereas the Michaelis-Menten constant values (Km ) did not differ. In healthy volunteers, we found volunteers that were heterozygous for the Ile305Phe variant and had a significantly lower cefotaxime renal clearance (CLR ; mean +/- SD: 84.8 +/- 32.1 mL/min, n = 5) compared with volunteers that were homozygous for the reference allele (158 +/- 44.1 mL/min, n = 10; p = 0.006). Furthermore, the net secretory component of cefotaxime renal clearance (CLsec ) was reduced in volunteers heterozygous for the variant allele [33.3 +/- 31.8 mL/min (mean +/- SD)] compared with volunteers homozygous for the OAT3 reference allele [97.0 +/- 42.2 mL/min (mean +/- SD), p = 0.01]. In summary, our study suggests that a low frequency reduced-function polymorphism of OAT3 associates with reduced cefotaxime CLR and CL(sec) . PMID- 23649427 TI - Interlaboratory evaluation of rodent pulmonary responses to engineered nanomaterials: the NIEHS Nano GO Consortium. AB - BACKGROUND: Engineered nanomaterials (ENMs) have potential benefits, but they also present safety concerns for human health. Interlaboratory studies in rodents using standardized protocols are needed to assess ENM toxicity. METHODS: Four laboratories evaluated lung responses in C57BL/6 mice to ENMs delivered by oropharyngeal aspiration (OPA), and three labs evaluated Sprague-Dawley (SD) or Fisher 344 (F344) rats following intratracheal instillation (IT). ENMs tested included three forms of titanium dioxide (TiO2) [anatase/rutile spheres (TiO2 P25), anatase spheres (TiO2-A), and anatase nanobelts (TiO2-NBs)] and three forms of multiwalled carbon nanotubes (MWCNTs) [original (O), purified (P), and carboxylic acid "functionalized" (F)]. One day after treatment, bronchoalveolar lavage fluid was collected to determine differential cell counts, lactate dehydrogenase (LDH), and protein. Lungs were fixed for histopathology. Responses were also examined at 7 days (TiO2 forms) and 21 days (MWCNTs) after treatment. RESULTS: TiO2-A, TiO2-P25, and TiO2-NB caused significant neutrophilia in mice at 1 day in three of four labs. TiO2-NB caused neutrophilia in rats at 1 day in two of three labs, and TiO2-P25 and TiO2-A had no significant effect in any of the labs. Inflammation induced by TiO2 in mice and rats resolved by day 7. All MWCNT types caused neutrophilia at 1 day in three of four mouse labs and in all rat labs. Three of four labs observed similar histopathology to O-MWCNTs and TiO2-NBs in mice. CONCLUSIONS: ENMs produced similar patterns of neutrophilia and pathology in rats and mice. Although interlaboratory variability was found in the degree of neutrophilia caused by the three types of TiO2 nanoparticles, similar findings of relative potency for the three types of MWCNTs were found across all laboratories, thus providing greater confidence in these interlaboratory comparisons. PMID- 23649428 TI - MicroRNA profiling in locally advanced esophageal cancer indicates a high potential of miR-192 in prediction of multimodality therapy response. AB - To identify possible predictive markers, our study aimed to characterize microRNA (miRNA) profiles of responder and nonresponder in the multimodality therapy of locally advanced esophageal cancer. Initially, a microarray-based approach was performed including eight patients with esophageal cancer. Patients received neoadjuvant chemoradiation followed by surgical resection. Major histopathological response was defined if resected specimens contained less than 10% vital tumor cells (major/minor response: 4/4 patients). Intratumoral RNA was isolated from both, pretherapeutic tissue biopsies in addition to corresponding surgical specimens. The profile of 768 miRNAs was analyzed in 16 specimens (preneoadjuvant and postneoadjuvant therapy). Selected miRNAs were than analyzed on pretherapeutic and post-therapeutic biopsies of 80 patients with esophageal cancer, who underwent multimodality therapy (major/minor response: 30/50 patients). Comprehensive miRNA profiling identified miRNAs in pretherapeutic biopsies that were significantly different between major/minor responders. Based on the microarray results, miR-192, miR-194 and miR-622 were selected and the dysregulated miRNAs were studied on an extended series of esophageal cancer patients. The expression of miR-192, miR-194 and miR-622 was significantly reduced after neoadjuvant therapy confirming the array profiling data. Importantly, the pretherapeutic intratumoral expression of miR-192 and miR-194 was significantly associated with the histopathologic response of esophageal squamous cell carcinoma to multimodal therapeutic treatment. Therefore, in patients with locally advanced esophageal cancer undergoing neoadjuvant chemoradiation followed by esophagectomy, miR-192 and miR-194 in pretherapeutic biopsies are considered as indicators of major histopathologic regression. PMID- 23649431 TI - Introduction to the Third Edition: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. PMID- 23649432 TI - Methodology for development of guidelines for lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence based clinical practice guidelines. AB - BACKGROUND: The objective was to develop high-quality and comprehensive evidence based guidelines on the diagnosis and management of lung cancer. METHODS: A carefully crafted panel of lung cancer experts, methodologists, and other specialists was assembled and reviewed for relevant conflicts of interest. The American College of Chest Physicians guideline methodology was used. Population, intervention, comparator, outcome (PICO)-based key questions and defined criteria for eligible studies were developed to inform the search strategies, subsequent evidence summaries, and recommendations. Research studies, systematic reviews, and meta-analyses, where they existed, were assessed for quality and summarized to inform the recommendations. RESULTS: Each recommendation was developed with supporting evidence and the consensus of the writing committees. Controversial recommendations were identified for further consultation by the entire panel, with anonymous voting to achieve consensus. CONCLUSIONS: The final recommendations can be trusted by health-care providers, patients, and other stakeholders since they are based on the current evidence in these areas and were developed with trustworthy processes for guideline development. PMID- 23649434 TI - Executive Summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. PMID- 23649436 TI - Establishing the diagnosis of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: Lung cancer is usually suspected in individuals who have an abnormal chest radiograph or have symptoms caused by either local or systemic effects of the tumor. The method of diagnosis of lung cancer depends on the type of lung cancer (small cell lung cancer or non-small cell lung cancer [NSCLC]), the size and location of the primary tumor, the presence of metastasis, and the overall clinical status of the patient. The objective of this study was to determine the test performance characteristics of various modalities for the diagnosis of suspected lung cancer. METHODS: To update previous recommendations on techniques available for the initial diagnosis of lung cancer, a systematic search of the MEDLINE, Healthstar, and Cochrane Library databases covering material to July 2011 and print bibliographies was performed to identify studies comparing the results of sputum cytology, conventional bronchoscopy, flexible bronchoscopy (FB), electromagnetic navigation (EMN) bronchoscopy, radial endobronchial ultrasound (R-EBUS)-guided lung biopsy, transthoracic needle aspiration (TTNA) or biopsy, pleural fluid cytology, and pleural biopsy with histologic reference standard diagnoses among at least 50 patients with suspected lung cancer. Recommendations were developed by the writing committee, graded by a standardized method (see the article "Methodology for Development of Guidelines for Lung Cancer" in this guideline), and reviewed by all members of the Lung Cancer Guideline Panel prior to approval by the Thoracic Oncology NetWork, the Guidelines Oversight Committee, and the Board of Regents of the American College of Chest Physicians. RESULTS: Sputum cytology is an acceptable method of establishing the diagnosis of lung cancer, with a pooled sensitivity rate of 66% and a specificity rate of 99%. However, the sensitivity of sputum cytology varies according to the location of the lung cancer. For central, endobronchial lesions, the overall sensitivity of FB for diagnosing lung cancer is 88%. The diagnostic yield of bronchoscopy decreases for peripheral lesions. Peripheral lesions < 2 or > 2 cm in diameter showed a sensitivity of 34% and 63%, respectively. R-EBUS and EMN are emerging technologies for the diagnosis of peripheral lung cancer, with diagnostic yields of 73% and 71%, respectively. The pooled sensitivity of TTNA for the diagnosis of lung cancer was 90%. A trend toward lower sensitivity was noted for lesions < 2 cm in diameter. TTNA is associated with a higher rate of pneumothorax compared with bronchoscopic procedures. In a patient with a malignant pleural effusion, pleural fluid cytology is reported to have a mean sensitivity of about 72%. A definitive diagnosis of metastatic disease to the pleural space can be estalished with a pleural biopsy. The diagnostic yield for closed pleural biopsy ranges from 38% to 47% and from 75% to 88% for image-guided closed biopsy. Thoracoscopic biopsy of the pleura carries the highest diagnostic yield, 95% to 97%. The accuracy in differentiating between small cell and non small cell cytology for the various diagnostic modalities was 98%, with individual studies ranging from 94% to 100%. The average false-positive and false negative rates were 9% and 2%, respectively. Although the distinction between small cell and NSCLC by cytology appears to be accurate, NSCLCs are clinically, pathologically, and molecularly heterogeneous tumors. In the past decade, clinical trials have shown us that NSCLCs respond to different therapeutic agents based on histologic phenotypes and molecular characteristics. The physician performing diagnostic procedures on a patient suspected of having lung cancer must ensure that adequate tissue is acquired to perform accurate histologic and molecular characterization of NSCLCs. CONCLUSIONS: The sensitivity of bronchoscopy is high for endobronchial disease and poor for peripheral lesions < 2 cm in diameter. The sensitivity of TTNA is excellent for malignant disease, but TTNA has a higher rate of pneumothorax than do bronchoscopic modalities. R-EBUS and EMN bronchoscopy show potential for increasing the diagnostic yield of FB for peripheral lung cancers. Thoracoscopic biopsy of the pleura has the highest diagnostic yield for diagnosis of metastatic pleural effusion in a patient with lung cancer. Adequate tissue acquisition for histologic and molecular characterization of NSCLCs is paramount. PMID- 23649437 TI - Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: This section of the guidelines is intended to provide an evidence based approach to the preoperative physiologic assessment of a patient being considered for surgical resection of lung cancer. METHODS: The current guidelines and medical literature applicable to this issue were identified by computerized search and were evaluated using standardized methods. Recommendations were framed using the approach described by the Guidelines Oversight Committee. RESULTS: The preoperative physiologic assessment should begin with a cardiovascular evaluation and spirometry to measure the FEV1 and the diffusing capacity for carbon monoxide (Dlco). Predicted postoperative (PPO) lung functions should be calculated. If the % PPO FEV1 and % PPO Dlco values are both > 60%, the patient is considered at low risk of anatomic lung resection, and no further tests are indicated. If either the % PPO FEV1 or % PPO Dlco are within 60% and 30% predicted, a low technology exercise test should be performed as a screening test. If performance on the low technology exercise test is satisfactory (stair climbing altitude > 22 m or shuttle walk distance > 400 m), patients are regarded as at low risk of anatomic resection. A cardiopulmonary exercise test is indicated when the PPO FEV1 or PPO Dlco (or both) are < 30% or when the performance of the stair-climbing test or the shuttle walk test is not satisfactory. A peak oxygen consumption (VO2 peak) < 10 mL/kg/min or 35% predicted indicates a high risk of mortality and long-term disability for major anatomic resection. Conversely, a VO2 peak > 20 mL/kg/min or 75% predicted indicates a low risk. CONCLUSIONS: A careful preoperative physiologic assessment is useful for identifying those patients at increased risk with standard lung cancer resection and for enabling an informed decision by the patient about the appropriate therapeutic approach to treating his or her lung cancer. This preoperative risk assessment must be placed in the context that surgery for early-stage lung cancer is the most effective currently available treatment of this disease. PMID- 23649435 TI - Clinical and organizational factors in the initial evaluation of patients with lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: This guideline is intended to provide an evidence-based approach to the initial evaluation of patients with known or suspected lung cancer. It also includes an assessment of the impact of timeliness of care and multidisciplinary teams on outcome. METHODS: The applicable current medical literature was identified by a computerized search and evaluated using standardized methods. Recommendations were framed using the approach described by the Guidelines Oversight Committee of the American College of Chest Physicians. Data sources included MEDLINE and the Cochrane Database of Systematic Reviews. RESULTS: Initial evaluation should include a thorough history and physical examination; CT imaging; pulmonary function tests; and hemoglobin, electrolyte, liver function, and calcium levels. Additional testing for distant metastases and paraneoplastic syndromes should be determined on the basis of these results. Paraneoplastic syndromes may have an adverse impact on cancer treatment, so they should be controlled rapidly with the goal of proceeding with definitive cancer treatment in a timely manner. Although the relationship between timeliness of care and survival is difficult to quantify, efforts to deliver timely care are reasonable and should be balanced with the need to attend to other dimensions of health-care quality (eg, safety, effectiveness, efficiency, equality, consistency with patient values and preferences). Quality care will require multiple disciplines. Although it is difficult to assess the impact, we suggest that a multidisciplinary team approach to care be used, particularly for patients requiring multimodality therapy. CONCLUSIONS: The initial evaluation of patients with lung cancer should include a thorough history and physical examination, pulmonary function tests, CT imaging, basic laboratory tests, and selective testing for distant metastases and paraneoplastic syndromes. PMID- 23649438 TI - The stage classification of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - The current Lung Cancer Stage Classification system is the seventh edition, which took effect in January 2010. This article reviews the definitions for the TNM descriptors and the stage grouping in this system. PMID- 23649440 TI - Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: Correctly staging lung cancer is important because the treatment options and prognosis differ significantly by stage. Several noninvasive imaging studies and invasive tests are available. Understanding the accuracy, advantages, and disadvantages of the available methods for staging non-small cell lung cancer is critical to decision-making. METHODS: Test accuracies for the available staging studies were updated from the second iteration of the American College of Chest Physicians Lung Cancer Guidelines. Systematic searches of the MEDLINE database were performed up to June 2012 with the inclusion of selected meta analyses, practice guidelines, and reviews. Study designs and results are summarized in evidence tables. RESULTS: The sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis were approximately 55% and 81%, respectively, confirming that CT scanning has limited ability either to rule in or exclude mediastinal metastasis. For PET scanning, estimates of sensitivity and specificity for identifying mediastinal metastasis were approximately 77% and 86%, respectively. These findings demonstrate that PET scanning is more accurate than CT scanning, but tissue biopsy is still required to confirm PET scan findings. The needle techniques endobronchial ultrasound needle aspiration, endoscopic ultrasound-needle aspiration, and combined endobronchial ultrasound/endoscopic ultrasound-needle aspiration have sensitivities of approximately 89%, 89%, and 91%, respectively. In direct comparison with surgical staging, needle techniques have emerged as the best first diagnostic tools to obtain tissue. Based on randomized controlled trials, PET or PET-CT scanning is recommended for staging and to detect unsuspected metastatic disease and avoid noncurative resections. CONCLUSIONS: Since the last iteration of the staging guidelines, PET scanning has assumed a more prominent role both in its use prior to surgery and when evaluating for metastatic disease. Minimally invasive needle techniques to stage the mediastinum have become increasingly accepted and are the tests of first choice to confirm mediastinal disease in accessible lymph node stations. If negative, these needle techniques should be followed by surgical biopsy. All abnormal scans should be confirmed by tissue biopsy (by whatever method is available) to ensure accurate staging. Evidence suggests that more complete staging improves patient outcomes. PMID- 23649441 TI - Diagnostic surgical pathology in lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: This article provides evidence-based background and recommendations for the development of American College of Chest Physicians guidelines for the diagnosis and management of lung cancer. Specific population, intervention, comparison, and outcome questions were addressed to arrive at consensus recommendations. METHODS: A systematic search of the medical and scientific literature using MEDLINE and PubMed was performed for the years 1990 to 2011 and limited to literature on humans and articles written in English. Our approach to examining the evidence and formulating recommendations is described in the "Methodology for Lung Cancer Evidence Review and Guideline Development: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (2nd Edition)" and updated in "Methodology for Development of Guidelines for Lung Cancer: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines." RESULTS: Pathologic examination results of lung cancers should be recorded in a synoptic form to include important prognostic features of histologic type, tumor size and location, involvement of visceral pleura, extension to regional and distant lymph nodes, and metastatic spread to visceral organs and bone to increase completeness of recording. It is important for the surgical pathologist to make distinctions between malignant mesothelioma and pleural adenocarcinomas, small cell and non small cell carcinomas, adenocarcinomas and squamous cell carcinomas, and primary and metastatic carcinomas of the lung. In challenging cases of pathologic differential diagnosis, additional studies may enable the separation of distinct tumor types. CONCLUSIONS: Pathologic assessment of lung cancers is a crucial component for the diagnosis, management, and prognosis of lung cancer, making the pathologist a critical member of the clinical and management team. Selective diagnostic techniques, including limited designed immunohistochemical panels, and decision analysis will increase diagnostic accuracy. PMID- 23649442 TI - Diagnosis and treatment of bronchial intraepithelial neoplasia and early lung cancer of the central airways: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: Bronchial intraepithelial lesions may be precursors of central airway lung carcinomas. Identification and early treatment of these preinvasive lesions might prevent progression to invasive carcinoma. METHODS: We systematically reviewed the literature to develop evidence-based recommendations regarding the diagnosis and treatment of intraepithelial lesions. RESULTS: The risk and timeline for progression of bronchial intraepithelial lesions to carcinoma in situ (CIS) or invasive carcinoma are not well understood. Multiple studies show that autofluorescence bronchoscopy (AFB) is more sensitive that white light bronchoscopy (WLB) to identify these lesions. In patients with severe dysplasia or CIS in sputum cytology who have chest imaging studies showing no localizing abnormality, we suggest use of WLB; AFB may be used as an adjunct when available. Patients with known severe dysplasia or CIS of central airways should be followed with WLB or AFB, when available. WLB or AFB is also suggested for patients with early lung cancer who will undergo resection for delineation of tumor margins and assessment of synchronous lesions. However, AFB is not recommended prior to endobronchial therapy for CIS or early central lung cancer. Several endobronchial techniques are recommended for the treatment of patients with superficial limited mucosal lung cancer who are not candidates for resection. CONCLUSION: Additional information is needed about the natural history and rate of progression of preinvasive central airway lesions. Patients with severe dysplasia or CIS may be treated endobronchially; however, it remains unclear if these therapies are associated with improved patient outcomes. PMID- 23649443 TI - Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: The treatment of stage I and II non-small cell lung cancer (NSCLC) in patients with good or low surgical risk is primarily surgical resection. However, this area is undergoing many changes. With a greater prevalence of CT imaging, many lung cancers are being found that are small or constitute primarily ground glass opacities. Treatment such as sublobar resection and nonsurgical approaches such as stereotactic body radiotherapy (SBRT) are being explored. With the advent of minimally invasive resections, the criteria to classify a patient as too ill to undergo an anatomic lung resection are being redefined. METHODS: The writing panel selected topics for review based on clinical relevance to treatment of early-stage lung cancer and the amount and quality of data available for analysis and relative controversy on best approaches in stage I and II NSCLC: general surgical care vs specialist care; sublobar vs lobar surgical approaches to stage I lung cancer; video-assisted thoracic surgery vs open resection; mediastinal lymph node sampling vs lymphadenectomy at the time of surgical resection; the use of radiation therapy, with a focus on SBRT, for primary treatment of early-stage NSCLC in high-risk or medically inoperable patients as well as adjuvant radiation therapy in the sublobar and lobar resection settings; adjuvant chemotherapy for early-stage NSCLC; and the impact of ethnicity, geography, and socioeconomic status on lung cancer survival. Recommendations by the writing committee were based on an evidence-based review of the literature and in accordance with the approach described by the Guidelines Oversight Committee of the American College of Chest Physicians. RESULTS: Surgical resection remains the primary and preferred approach to the treatment of stage I and II NSCLC. Lobectomy or greater resection remains the preferred approach to T1b and larger tumors. The use of sublobar resection for T1a tumors and the application of adjuvant radiation therapy in this group are being actively studied in large clinical trials. Every patient should have systematic mediastinal lymph node sampling at the time of curative intent surgical resection, and mediastinal lymphadenectomy can be performed without increased morbidity. Perioperative morbidity and mortality are reduced and long-term survival is improved when surgical resection is performed by a board-certified thoracic surgeon. The use of adjuvant chemotherapy for stage II NSCLC is recommended and has shown benefit. The use of adjuvant radiation or chemotherapy for stage I NSCLC is of unproven benefit. Primary radiation therapy remains the primary curative intent approach for patients who refuse surgical resection or are determined by a multidisciplinary team to be inoperable. There is growing evidence that SBRT provides greater local control than standard radiation therapy for high-risk and medically inoperable patients with NSCLC. The role of ablative therapies in the treatment of high-risk patients with stage I NSCLC is evolving. Radiofrequency ablation, the most studied of the ablative modalities, has been used effectively in medically inoperable patients with small (< 3 cm) peripheral NSCLC that are clinical stage I. PMID- 23649445 TI - Treatment of stage III non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - OBJECTIVES: Stage III non-small cell lung cancer (NSCLC) describes a heterogeneous population with disease presentation ranging from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky nodal disease. This review updates the published clinical trials since the last American College of Chest Physicians guidelines to make treatment recommendations for this controversial subset of patients. METHODS: Systematic searches were conducted through MEDLINE, Embase, and the Cochrane Database for Systematic Review up to December 2011, focusing primarily on randomized trials, selected meta-analyses, practice guidelines, and reviews. RESULTS: For individuals with stage IIIA or IIIB disease, good performance scores, and minimal weight loss, treatment with combined chemoradiotherapy results in better survival than radiotherapy alone. Consolidation chemotherapy or targeted therapy following definitive chemoradiation for stage IIIA is not supported. Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation. Most of the arguments made regarding patient selection for neoadjuvant therapy and surgical resection provide evidence for better prognosis but not for a beneficial impact of this treatment strategy; however, weak comparative data suggest a possible role if only lobectomy is needed in a center with a low perioperative mortality rate. The evidence supports routine platinum based adjuvant chemotherapy following complete resection of stage IIIA lung cancer encountered unexpectedly at surgery. Postoperative radiotherapy improves local control without improving survival. CONCLUSIONS: Multimodality therapy is preferable in most subsets of patients with stage III lung cancer. Variability in the patients included in randomized trials limits the ability to combine results across studies and thus limits the strength of recommendations in many scenarios. Future trials are needed to investigate the roles of individualized chemotherapy, surgery in particular cohorts or settings, prophylactic cranial radiation, and adaptive radiation. PMID- 23649439 TI - Epidemiology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: Ever since a lung cancer epidemic emerged in the mid-1900 s, the epidemiology of lung cancer has been intensively investigated to characterize its causes and patterns of occurrence. This report summarizes the key findings of this research. METHODS: A detailed literature search provided the basis for a narrative review, identifying and summarizing key reports on population patterns and factors that affect lung cancer risk. RESULTS: Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products and exposure to secondhand tobacco smoke, occupational lung carcinogens, radiation, and indoor and outdoor air pollution. Cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death. Smoking prevalence in developing nations has increased, starting new lung cancer epidemics in these nations. A positive family history and acquired lung disease are examples of host factors that are clinically useful risk indicators. Risk prediction models based on lung cancer risk factors have been developed, but further refinement is needed to provide clinically useful risk stratification. Promising biomarkers of lung cancer risk and early detection have been identified, but none are ready for broad clinical application. CONCLUSIONS: Almost all lung cancer deaths are caused by cigarette smoking, underscoring the need for ongoing efforts at tobacco control throughout the world. Further research is needed into the reasons underlying lung cancer disparities, the causes of lung cancer in never smokers, the potential role of HIV in lung carcinogenesis, and the development of biomarkers. PMID- 23649444 TI - Molecular biology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - Based on recent bench and clinical research, the treatment of lung cancer has been refined, with treatments allocated according to histology and specific molecular features. For example, targeting mutations such as epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors has been particularly successful as a treatment modality, demonstrating response rates in selected patients with adenocarcinoma tumors harboring EGFR mutations that are significantly higher than those for conventional chemotherapy. However, the development of new targeted therapies is, in part, highly dependent on an improved understanding of the molecular underpinnings of tumor initiation and progression, knowledge of the role of molecular aberrations in disease progression, and the development of highly reproducible platforms for high throughput biomarker discovery and testing. In this article, we review clinically relevant research directed toward understanding the biology of lung cancer. The clinical purposes of this research are (1) to identify susceptibility variants and field molecular alterations that will promote the early detection of tumors and (2) to identify tumor molecular alterations that serve as therapeutic targets, prognostic biomarkers, or predictors of tumor response. We focus on research developments in the understanding of lung cancer somatic DNA mutations, chromosomal aberrations, epigenetics, and the tumor microenvironment, and how they can advance diagnostics and therapeutics. PMID- 23649447 TI - Special treatment issues in non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: This guideline updates the second edition and addresses patients with particular forms of non-small cell lung cancer that require special considerations, including Pancoast tumors, T4 N0,1 M0 tumors, additional nodules in the same lobe (T3), ipsilateral different lobe (T4) or contralateral lung (M1a), synchronous and metachronous second primary lung cancers, solitary brain and adrenal metastases, and chest wall involvement. METHODS: The nature of these special clinical cases is such that in most cases, meta-analyses or large prospective studies of patients are not available. To ensure that these guidelines were supported by the most current data available, publications appropriate to the topics covered in this article were obtained by performing a literature search of the MEDLINE computerized database. Where possible, we also reference other consensus opinion statements. Recommendations were developed by the writing committee, graded by a standardized method, and reviewed by all members of the Lung Cancer Guidelines panel prior to approval by the Thoracic Oncology NetWork, Guidelines Oversight Committee, and the Board of Regents of the American College of Chest Physicians. RESULTS: In patients with a Pancoast tumor, a multimodality approach appears to be optimal, involving chemoradiotherapy and surgical resection, provided that appropriate staging has been carried out. Carefully selected patients with central T4 tumors that do not have mediastinal node involvement are uncommon, but surgical resection appears to be beneficial as part of their treatment rather than definitive chemoradiotherapy alone. Patients with lung cancer and an additional malignant nodule are difficult to categorize, and the current stage classification rules are ambiguous. Such patients should be evaluated by an experienced multidisciplinary team to determine whether the additional lesion represents a second primary lung cancer or an additional tumor nodule corresponding to the dominant cancer. Highly selected patients with a solitary focus of metastatic disease in the brain or adrenal gland appear to benefit from resection or stereotactic radiosurgery. This is particularly true in patients with a long disease-free interval. Finally, in patients with chest wall involvement, provided that the tumor can be completely resected and N2 nodal disease is absent, primary surgical resection should be considered. CONCLUSIONS: Carefully selected patients with more uncommon presentations of lung cancer may benefit from an aggressive surgical approach. PMID- 23649446 TI - Treatment of stage IV non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: Stage IV non-small cell lung cancer (NSCLC) is a treatable, but not curable, clinical entity in patients given the diagnosis at a time when their performance status (PS) remains good. METHODS: A systematic literature review was performed to update the previous edition of the American College of Chest Physicians Lung Cancer Guidelines. RESULTS: The use of pemetrexed should be restricted to patients with nonsquamous histology. Similarly, bevacizumab in combination with chemotherapy (and as continuation maintenance) should be restricted to patients with nonsquamous histology and an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1; however, the data now suggest it is safe to use in those patients with treated and controlled brain metastases. Data at this time are insufficient regarding the safety of bevacizumab in patients receiving therapeutic anticoagulation who have an ECOG PS of 2. The role of cetuximab added to chemotherapy remains uncertain and its routine use cannot be recommended. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as first-line therapy are the recommended treatment of those patients identified as having an EGFR mutation. The use of maintenance therapy with either pemetrexed or erlotinib should be considered after four cycles of first-line therapy in those patients without evidence of disease progression. The use of second- and third-line therapy in stage IV NSCLC is recommended in those patients retaining a good PS; however, the benefit of therapy beyond the third-line setting has not been demonstrated. In the elderly and in patients with a poor PS, the use of two-drug, platinum-based regimens is preferred. Palliative care should be initiated early in the course of therapy for stage IV NSCLC. CONCLUSIONS: Significant advances continue to be made, and the treatment of stage IV NSCLC has become nuanced and specific for particular histologic subtypes and clinical patient characteristics and according to the presence of specific genetic mutations. PMID- 23649448 TI - Treatment of small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: Small cell lung cancer (SCLC) is a lethal disease for which there have been only small advances in diagnosis and treatment in the past decade. Our goal was to revise the evidence-based guidelines on staging and best available treatment options. METHODS: A comprehensive literature search covering 2004 to 2011 was conducted in MEDLINE, Embase, and five Cochrane databases using SCLC terms. This was cross-checked with the authors' own literature searches and knowledge of the literature. Results were limited to research in humans and articles written in English. RESULTS: The staging classification should include both the old Veterans Administration staging classification of limited stage (LS) and extensive stage (ES), as well as the new seventh edition American Joint Committee on Cancer/International Union Against Cancer staging by TNM. The use of PET scanning is likely to improve the accuracy of staging. Surgery is indicated for carefully selected stage I SCLC. LS disease should be treated with concurrent chemoradiotherapy in patients with good performance status. Thoracic radiotherapy should be administered early in the course of treatment, preferably beginning with cycle 1 or 2 of chemotherapy. Chemotherapy should consist of four cycles of a platinum agent and etoposide. ES disease should be treated primarily with chemotherapy consisting of a platinum agent plus etoposide or irinotecan. Prophylactic cranial irradiation prolongs survival in those individuals with both LS and ES disease who achieve a complete or partial response to initial therapy. To date, no molecularly targeted therapy agent has demonstrated proven efficacy against SCLC. CONCLUSION: Evidence-based guidelines are provided for the staging and treatment of SCLC. LS-SCLC is treated with curative intent with 20% to 25% 5 year survival. ES-SCLC is initially responsive to standard treatment, but almost always relapses, with virtually no patients surviving for 5 years. Targeted therapies have no proven efficacy against SCLC. PMID- 23649450 TI - Complementary therapies and integrative medicine in lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence based clinical practice guidelines. AB - BACKGROUND: Physicians are often asked about complementary therapies by patients with cancer, and data show that the interest in and use of these therapies among patients with cancer is common. Therefore, it is important to assess the current evidence base on the benefits and risks of complementary therapies (modalities not historically used in modern Western medicine). METHODS: A systematic literature review was carried out and recommendations were made according to the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines development methodology. RESULTS: A large number of randomized controlled trials, systematic reviews, and meta-analyses, as well as a number of prospective cohort studies, met the predetermined inclusion criteria. These trials addressed many different issues pertaining to patients with lung cancer, such as symptoms of anxiety, mood disturbance, pain, quality of life, and treatment-related side effects. The available data cover a variety of interventions, including acupuncture, nutrition, mind-body therapies, exercise, and massage. The body of evidence supports a series of recommendations. An evidenced-based approach to modern cancer care should integrate complementary therapies with standard cancer therapies such as surgery, radiation, chemotherapy, and best supportive care measures. CONCLUSIONS: Several complementary therapy modalities can be helpful in improving the overall care of patients with lung cancer. PMID- 23649451 TI - Follow-up and surveillance of the patient with lung cancer after curative-intent therapy: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: These guidelines are an update of the evidence-based recommendations for follow-up and surveillance of patients after curative-intent therapy for lung cancer. Particular updates pertain to whether imaging studies, health-related quality-of-life (HRQOL) measures, tumor markers, and bronchoscopy improve outcomes after curative-intent therapy. METHODS: Meta-analysis of Observational Studies in Epidemiology guidelines were followed for this systematic review, including published studies on posttreatment outcomes in patients who received curative-intent therapy since the previous American College of Chest Physicians subject review. Four population, intervention, comparison, and outcome questions were formulated to guide the review. The MEDLINE and CINAHL databases were searched from June 1, 2005, to July 8, 2011, to ensure overlap with the search strategies used previously. RESULTS: A total of 3,412 citations from MEDLINE and 431 from CINAHL were identified. Only 303 were relevant. Seventy-six of the 303 articles were deemed eligible on the basis of predefined inclusion criteria after full-text review, but only 34 provided data pertaining directly to the subject of the questions formulated to guide this review. In patients undergoing curative intent surgical resection of non-small cell lung cancer, chest CT imaging performed at designated time intervals after resection is suggested for detecting recurrence. It is recommended that treating physicians who are able to incorporate the patient's clinical findings into decision-making processes be included in follow-up and surveillance strategies. The use of validated HRQOL instruments at baseline and during follow-up is recommended. Biomarker testing during surveillance outside clinical trials is not suggested. Surveillance bronchoscopy is suggested for patients with early central airway squamous cell carcinoma treated by curative-intent photodynamic therapy and for patients with intraluminal bronchial carcinoid tumor who have undergone curative-intent bronchoscopic treatment with Nd:YAG laser or electrocautery. CONCLUSIONS: There is a paucity of well-designed prospective studies specifically targeting follow up and surveillance modalities aimed at improving survival or QOL after curative intent therapy. Additional research is warranted to clarify which curative-intent treatment modalities affect HRQOL the most and to identify patients who are at the most risk for recurrence or impaired QOL after treatment. Further evidence is needed to determine how the frequency and duration of surveillance programs that include imaging studies, QOL measurements, tumor markers, or bronchoscopy affect patient morbidity, survival, HRQOL, and health-care costs. PMID- 23649452 TI - Symptom management in patients with lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: Many patients with lung cancer will develop symptoms related to their disease process or the treatment they are receiving. These symptoms can be as debilitating as the disease progression itself. To many physicians these problems can be the most difficult to manage. METHODS: A detailed review of the literature using strict methodologic review of article quality was used in the development of this article. MEDLINE literature reviews, in addition to Cochrane reviews and other databases, were used for this review. The resulting article lists were then reviewed by experts in each area for quality and finally interpreted for content. RESULTS: We have developed recommendations for the management of many of the symptom complexes that patients with lung cancer may experience: pain, dyspnea, airway obstruction, cough, bone metastasis, brain metastasis, spinal cord metastasis, superior vena cava syndrome, hemoptysis, tracheoesophageal fistula, pleural effusions, venous thromboembolic disease, depression, fatigue, anorexia, and insomnia. Some areas, such as dyspnea, are covered in considerable detail in previously created high-quality evidence-based guidelines and are identified as excellent sources of reference. The goal of this guideline is to provide the reader recommendations based on evidence supported by scientific study. CONCLUSIONS: Improved understanding and recognition of cancer-related symptoms can improve management strategies, patient compliance, and quality of life for all patients with lung cancer. PMID- 23649453 TI - Palliative and end-of-life care in lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: In the United States, lung cancer is a major health problem that is associated with significant patient distress and often limited survival, with some exceptions. The purpose of this article is to address the role of palliative and end-of-life care in the management of patients with lung cancer and to address the need for good communication skills to provide support to patients and families. METHODS: This article is based on an extensive review of the medical literature up to April 2012, with some articles as recent as August 2012. The authors used the PubMed and Cochrane databases, as well as EBESCO Host search, for articles addressing palliative care, supportive care, lung neoplasm, and quality of life in cancer or neoplasm, with no limitation on dates. The research was limited to human studies and the English language. RESULTS: There was no "definitive" work in this area, most of it being concurrence based rather than evidence based. Several randomized controlled trials were identified, which are reviewed in the text. The article focuses on the assessment and treatment of suffering in patients with lung cancer, as well as the importance of communication in the care of these patients over the course of the disease. The aim of medical care for patients with terminal lung cancer is to decrease symptom burden, enhance the quality of remaining life, and increase survival benefit. A second objective is to emphasize the importance of good communication skills when addressing the needs of the patient and his or her family, starting at the time of diagnosis, which in itself is a life-changing event. Too often we do it poorly, but by using patient-centered communication skills, the outcome can be more satisfactory. Finally, the article addresses the importance of advance care planning for patients with lung cancer, from the time of diagnosis until the last phase of the illness, and it is designed to enhance the physician's role in facilitating this planning process. CONCLUSIONS: This article provides guidance on how to reduce patient distress and avoid nonbeneficial treatment in patients with lung cancer. The goal is to decrease symptom burden, enhance quality of life, and increase survival benefit. Good communication and advance care planning are vital to the process. PMID- 23649449 TI - Chemoprevention of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: Lung cancer is the most common cause of cancer death in men and women in the United States. Cigarette smoking is the main risk factor. Former smokers are at a substantially increased risk of developing lung cancer compared with lifetime never smokers. Chemoprevention refers to the use of specific agents to reverse, suppress, or prevent the process of carcinogenesis. This article reviews the major agents that have been studied for chemoprevention. METHODS: Articles of primary, secondary, and tertiary prevention trials were reviewed and summarized to obtain recommendations. RESULTS: None of the phase 3 trials with the agents beta-carotene, retinol, 13-cis-retinoic acid, alpha-tocopherol, N-acetylcysteine, acetylsalicylic acid, or selenium has demonstrated beneficial and reproducible results. To facilitate the evaluation of promising agents and to lessen the need for a large sample size, extensive time commitment, and expense, surrogate end point biomarker trials are being conducted to assist in identifying the most promising agents for later-stage chemoprevention trials. With the understanding of important cellular signaling pathways and the expansion of potentially important targets, agents (many of which target inflammation and the arachidonic acid pathway) are being developed and tested which may prevent or reverse lung carcinogenesis. CONCLUSIONS: By integrating biologic knowledge, additional early phase trials can be performed in a reasonable time frame. The future of lung cancer chemoprevention should entail the evaluation of single agents or combinations that target various pathways while working toward identification and validation of intermediate end points. PMID- 23649454 TI - Treatment of tobacco use in lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: Continued tobacco use in the setting of lung cancer management is frequently confounding and always of critical importance. We summarized the published literature concerning the management of tobacco dependence in patients with lung cancer and offer recommendations for integrating dependence treatment into ongoing oncologic care. METHODOLOGY: MEDLINE, Embase, CINAHL, PsychINFO, and the Cochrane Collaborative databases were searched for English language randomized clinical trials, cohort studies, case-control studies, secular trend analyses, and case series relevant to the a priori identified clinical questions. Evidence grading, integration, and genesis of recommendations followed the methods described in "Methodology for Development of Guidelines for Lung Cancer" in the American College of Chest Physicians Lung Cancer Guidelines, 3rd ed. RESULTS: We describe the approach to tobacco dependence in patients with lung cancer at various phases in the evolution of cancer care. For example, among patients undergoing lung cancer screening procedures, we recommend against relying on the screening itself, including procedures accompanied solely by self help materials, as an effective strategy for achieving abstinence. Among patients with lung cancer undergoing surgery, intensive perioperative cessation pharmacotherapy is recommended as a method for improving abstinence rates. Cessation pharmacotherapy is also recommended for patients undergoing chemotherapy, with specific recommendations to use bupropion when treating patients with lung cancer with depressive symptoms, as a means of improving abstinence rates, depressive symptoms, and quality of life. CONCLUSIONS: Optimal treatment of lung cancer includes attention to continued tobacco use, with abstinence contributing to improved patient-related outcomes at various phases of lung cancer management. Effective therapeutic interventions are available and are feasibly integrated into oncologic care. A number of important clinical questions remain poorly addressed by the existing evidence. PMID- 23649455 TI - Screening for lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - BACKGROUND: Lung cancer is by far the major cause of cancer deaths largely because in the majority of patients it is at an advanced stage at the time it is discovered, when curative treatment is no longer feasible. This article examines the data regarding the ability of screening to decrease the number of lung cancer deaths. METHODS: A systematic review was conducted of controlled studies that address the effectiveness of methods of screening for lung cancer. RESULTS: Several large randomized controlled trials (RCTs), including a recent one, have demonstrated that screening for lung cancer using a chest radiograph does not reduce the number of deaths from lung cancer. One large RCT involving low-dose CT (LDCT) screening demonstrated a significant reduction in lung cancer deaths, with few harms to individuals at elevated risk when done in the context of a structured program of selection, screening, evaluation, and management of the relatively high number of benign abnormalities. Whether other RCTs involving LDCT screening are consistent is unclear because data are limited or not yet mature. CONCLUSIONS: Screening is a complex interplay of selection (a population with sufficient risk and few serious comorbidities), the value of the screening test, the interval between screening tests, the availability of effective treatment, the risk of complications or harms as a result of screening, and the degree with which the screened individuals comply with screening and treatment recommendations. Screening with LDCT of appropriate individuals in the context of a structured process is associated with a significant reduction in the number of lung cancer deaths in the screened population. Given the complex interplay of factors inherent in screening, many questions remain on how to effectively implement screening on a broader scale. PMID- 23649457 TI - Snack (healthily) before shopping: comment on "Fattening fasting". PMID- 23649458 TI - The effect of immune therapy on surgical site infection following Crohn's Disease resection. AB - BACKGROUND: Patients with Crohn's disease are increasingly receiving antitumour necrosis factor alpha (anti-TNF-alpha) therapy. Whether anti-TNF-alpha therapy increases the risk of postoperative infectious complications in Crohn's disease is a matter of debate. METHODS: This was a retrospective study of three referral centres. The charts of patients who underwent ileocaecal or ileocolonic resection for Crohn's disease between 2000 and 2011 were reviewed. The impact of baseline characteristics and Crohn's disease-related medications on the risk of postoperative intra-abdominal infectious complications was investigated by univariable and multivariable analysis. RESULTS: A total of 217 patients were included in the study. Median age at the time of surgery was 36.8 (range 15-78) years. A postoperative intra-abdominal infection occurred in 24 (11.1 per cent) of 217 patients. No deaths were reported. On univariable analysis, age less than 25 years (P = 0.023), steroid use (P = 0.017), anti-TNF-alpha therapy (P = 0.043) and anti-TNF-alpha treatment in combination with steroids (P = 0.004) were associated with an increased risk of postoperative intra-abdominal infectious complications. On multivariable analysis, only anti-TNF-alpha therapy in combination with steroids significantly increased this risk (odds ratio 8.03, 95 per cent confidence interval 1.93 to 33.43; P = 0.035). CONCLUSION: Combined use of steroids and anti-TNF-alpha therapy was associated with an increased risk of postoperative intra-abdominal infectious complications. PMID- 23649459 TI - Synthesis, in vitro antimicrobial and antioxidant activities of some new 4,5 dihydro-1H-1,2,4-triazol-5-one derivatives. AB - A series of compounds derived from 4,5-dihydro-1H-1,2,4-triazol-5-one were synthesized and characterized by spectral data. The 12 new compounds were analyzed for their potential in vitro antioxidant activities by three different methods. Compound 4f showed the best activity for the iron binding. In addition, the compounds 4 were titrated potentiometrically with tetrabutylammonium hydroxide in non-aqueous solvents. The RP-HPLC capacity factors (k') of the series were also determined on a C18 column, with methanol/water as the mobile phase. The correlation between log k' with the percentage of methanol in the mobile phase was used for the determination of the log kw values for these compounds. The antimicrobial activities of these compounds were also screened against bacteria and yeast. PMID- 23649456 TI - Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. AB - OBJECTIVES: The objective of this article is to update previous evidence-based recommendations for evaluation and management of individuals with solid pulmonary nodules and to generate new recommendations for those with nonsolid nodules. METHODS: We updated prior literature reviews, synthesized evidence, and formulated recommendations by using the methods described in the "Methodology for Development of Guidelines for Lung Cancer" in the American College of Chest Physicians Lung Cancer Guidelines, 3rd ed. RESULTS: We formulated recommendations for evaluating solid pulmonary nodules that measure > 8 mm in diameter, solid nodules that measure <= 8 mm in diameter, and subsolid nodules. The recommendations stress the value of assessing the probability of malignancy, the utility of imaging tests, the need to weigh the benefits and harms of different management strategies (nonsurgical biopsy, surgical resection, and surveillance with chest CT imaging), and the importance of eliciting patient preferences. CONCLUSIONS: Individuals with pulmonary nodules should be evaluated and managed by estimating the probability of malignancy, performing imaging tests to better characterize the lesions, evaluating the risks associated with various management alternatives, and eliciting their preferences for management. PMID- 23649460 TI - Endurance training enhances skeletal muscle interleukin-15 in human male subjects. AB - Regular endurance exercise promotes metabolic and oxidative changes in skeletal muscle. Overexpression of interleukin-15 (IL-15) in mice exerts similar metabolic changes in muscle as seen with endurance exercise. Muscular IL-15 production has been shown to increase in mice after weeks of regular endurance running. With the present study we aimed to determine if muscular IL-15 production would increase in human male subjects following 12 weeks of endurance training. In two different studies we obtained plasma and muscle biopsies from young healthy subjects performing: (1) 12 weeks of ergometer cycling exercise five times per week with plasma and biopsies before and after the intervention, and (2) 3 h of ergometer cycling exercise with plasma and biopsies before and after the exercise bout and well into recovery. We measured changes in plasma IL-15, muscle IL-15 mRNA and IL 15 protein. Twelve weeks of regular endurance training induced a 40% increase in basal skeletal muscle IL-15 protein content (p < 0.01), but with no changes in either muscle IL-15 mRNA or plasma IL-15 levels. However, an acute bout of 3-h exercise did not show significant changes in muscle IL-15 or plasma IL-15 levels. The induction of muscle IL-15 protein in humans following a regular training period supports previous findings in mice and emphasizes the hypothesis of IL-15 taking part in skeletal muscle adaptation during training. PMID- 23649461 TI - Relative antioxidant activities of quercetin and its structurally related substances and their effects on NF-kappaB/CRE/AP-1 signaling in murine macrophages. AB - Reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by the oxidative burst in activated macrophages and neutrophils cause oxidative stressimplicated diseases. Quercetin is flavonoid that occurs naturally in plants and is widely used as a nutritional supplement due to its antioxidant and anti inflammatory properties. In this study, we investigated antioxidant activities and mechanisms of action in zymosan-induced macrophages of quercetin and quercetin-related flavonoids such as quercitrin, isoquercitrin, quercetin 3-O beta-(2"-galloyl)-rhamnopyranoside (QGR) and quercetin 3-O-beta-(2"-galloyl) glucopyranoside (QGG) as well as gallic acid, a building moiety of QGR and QGG. QGR and QGG exhibited stronger antioxidant activities compared with quercetin, whereas quercitrin, isoquercitrin and gallic acid exhibited weak-tono antioxidant activities, assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, superoxide production, superoxide scavenging, nitric oxide (NO) production, peroxynitrite (ONOO(-)) scavenging and myeloperoxidase (MPO) activity. Regarding mechanisms, the quercetincontaining flavonoids QGR and QGG differentially targeted compared with quercetin in the NF-kappaB signaling pathway that inhibited the DNA binding activity of the NF-kappaB complex without affecting the degradation and phosphorylation of IkappaBalpha and NF-kappaB phosphorylation. In addition, QGR and QGG inhibited CRE and activator protein (AP-1) transcriptional activity and JNK phosphorylation by inhibiting the cAMP/protein kinase A (PKA) and protein kinase C (PKC) signaling in a different manner than quercetin. Our results showed that although QGR and QGG exhibited stronger antioxidant activities than querce-tin in macrophages, their mechanisms of action in terms of the NF-kappaB, PKA and PKC signaling pathways were different. PMID- 23649462 TI - Functional and molecular imaging of localized and recurrent prostate cancer. AB - Prostate cancer is the most common malignancy among American men. Imaging of localized and recurrent prostate cancer is challenging since conventional imaging techniques are limited. New imaging techniques such as multiparametric MRI and PET with targeted tracers have been investigated extensively in the last decade. As a result, the role of novel imaging techniques for the detection of localized and recurrent prostate cancer has recently expanded. In this review, novel functional and molecular imaging techniques used in the management of localized and recurrent prostate cancer are discussed. PMID- 23649463 TI - An international confirmatory study of the prognostic value of early PET/CT in diffuse large B-cell lymphoma: comparison between Deauville criteria and DeltaSUVmax. AB - PURPOSE: The role of interim PET/CT in guiding therapeutic strategies in diffuse large B-cell lymphoma (DLBCL) is debated, mainly because interpretation rules vary among centres. This study aimed to explore the reproducibility and confirm the prognostic value of early PET/CT using the Deauville criteria and DeltaSUVmax. METHODS: This international confirmatory study retrospectively evaluated 114 patients with newly diagnosed DLBCL treated with a rituximab containing regimen. All patients underwent 18F-FDG PET/CT at baseline (PET0) and after two cycles (PET2), with no therapy change based on the latter. Scans were interpreted by three observers using the Deauville five-point scale and DeltaSUVmax between PET0 and PET2 was calculated. Interpretations were evaluated for interobserver agreement and for progression-free survival (PFS) prediction. RESULTS: Median follow-up was 39 months. Early PET/CT was predictive of outcome when interpreted with the Deauville criteria and DeltaSUVmax. Using the five point scale, the overall kappa value was 0.66 with the reference background set in the liver (score >=4) and interobserver agreement was even better using a 66% DeltaSUVmax cut-off (kappa = 0.83). Moreover, the prognostic value of interim PET was slightly inferior when using a Deauville score >=4 than when using a 66% DeltaSUVmax cut-off: for the Deauville score the 3-year PFS estimate was 59% (45 73%) in PET2-positive patients vs. 81% (71-91%) in PET2-negative patients (P = 0.003); for the 66% DeltaSUVmax cut-off the 3-year PFS estimate was 44% (23-65%) in PET2-positive patients vs. 79% (70-88%) in PET2-negative patients (P = 0.0002). CONCLUSION: Although the Deauville criteria are valid for assessing the prognostic value of early PET/CT in DLBCL, computation of the DeltaSUVmax leads to better performance and interobserver reproducibility, and should be preferred when a baseline scan is available. PMID- 23649464 TI - Impact of conization type on the resected cone volume: results of a retrospective multi-center study. AB - PURPOSE: The extent of conization seems to influence the risk of preterm birth. The aim of this study was to compare the cone volume after surgical resection with large loop excision of the transformation zone (LLETZ) and cold knife conization (CKC). METHODS: The present retrospective multi-center study comprises 804 consecutive women, who underwent LLETZ (n = 412) or CKC (n = 392) between 2004 and 2009. Univariate and multivariable analyses were performed to compare cone volumes removed by LLETZ and CKC and identify independent risk factors for large cone volume. RESULTS: The median resected cone volume after LLETZ was significantly smaller [1.6 cm(3) (0.8-2.9)] than after CKC [2.1 cm(3) (1.4-3.5)] (<0.0001). Complete resection rates were comparable in both groups. Conization method, cone depth, and institution type were independent risk factors for removal of a large cone volume. CONCLUSION: CKC removes larger cone volumes than LLETZ without the advantage of higher complete resection rates. PMID- 23649465 TI - The importance of renal Doppler ultrasonographic evaluation in acute ureteral obstruction in pregnant women. PMID- 23649467 TI - Leukemia surfaceome analysis reveals new disease-associated features. AB - A better description of the leukemia cell surface proteome (surfaceome) is a prerequisite for the development of diagnostic and therapeutic tools. Insights into the complexity of the surfaceome have been limited by the lack of suitable methodologies. We combined a leukemia xenograft model with the discovery-driven chemoproteomic Cell Surface Capture technology to explore the B-cell precursor acute lymphoblastic leukemia (BCP-ALL) surfaceome; 713 cell surface proteins, including 181 CD proteins, were detected through combined analysis of 19 BCP-ALL cases. Diagnostic immunophenotypes were recapitulated in each case, and subtype specific markers were detected. To identify new leukemia-associated markers, we filtered the surfaceome data set against gene expression information from sorted, normal hematopoietic cells. Nine candidate markers (CD18, CD63, CD31, CD97, CD102, CD157, CD217, CD305, and CD317) were validated by flow cytometry in patient samples at diagnosis and during chemotherapy. CD97, CD157, CD63, and CD305 accounted for the most informative differences between normal and malignant cells. The ALL surfaceome constitutes a valuable resource to assist the functional exploration of surface markers in normal and malignant lymphopoiesis. This unbiased approach will also contribute to the development of strategies that rely on complex information for multidimensional flow cytometry data analysis to improve its diagnostic applications. PMID- 23649466 TI - Recent progress toward epigenetic therapies: the example of mixed lineage leukemia. AB - The importance of epigenetic gene regulatory mechanisms in normal and cancer development is increasingly evident. Genome-wide analyses have revealed the mutation, deletion, and dysregulated expression of chromatin-modifying enzymes in a number of cancers, including hematologic malignancies. Genome-wide studies of DNA methylation and histone modifications are beginning to reveal the landscape of cancer-specific chromatin patterns. In parallel, recent genetic loss-of function studies in murine models are demonstrating functional involvement of chromatin-modifying enzymes in malignant cell proliferation and self-renewal. Paradoxically, the same chromatin modifiers can, depending on cancer type, be either hyperactive or inactivated. Increasingly, cross talk between epigenetic pathways is being identified. Leukemias carrying MLL rearrangements are quintessential cancers driven by dysregulated epigenetic mechanisms in which fusion proteins containing N-terminal sequences of MLL require few or perhaps no additional mutations to cause human leukemia. Here, we review how recent progress in the field of epigenetics opens potential mechanism-based therapeutic avenues. PMID- 23649468 TI - The lupus anticoagulant: results from 2257 patients attending a high-risk pregnancy clinic. AB - Routine investigation for recurrent pregnancy loss includes measurement of antiphospholipid antibodies under the perception that the lupus anticoagulant (LAC) is prevalent in this population. Our tertiary clinic sees ~250 new patients with recurrent pregnancy loss annually, in addition to those with systemic lupus erythematosus and/or antiphospholipid syndrome. We measure LAC using a 4-assay panel that expands on the 2 assays recommended by the International Society on Thrombosis and Haemostatis (ISTH) guidelines. Of 2257 patients tested for LAC during a 6-year period, 62 (2.7%) repeatedly tested positive. Only 5 patients (0.2%) had both a history of early recurrent miscarriage and LAC positivity. Patients with LAC had a significantly more frequent history of thrombosis (35.5% vs 2.4%). LAC was absent in an overwhelming majority of women with exclusively early recurrent pregnancy loss but was associated with sporadic stillbirth. Among our panel of assays, none was predominant, and an increasing number of positive assays was associated with an increased history of morbidity. Therefore, our results do not support the ISTH contention that 2 assays are sufficient to identify and describe patients with LAC. We found that a confirmed, repeated LAC was very infrequent even in a high-risk setting. PMID- 23649469 TI - EBV-positive diffuse large B-cell lymphoma of the elderly. AB - Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly, initially described in 2003, is a provisional entity in the 2008 World Health Organization classification system and is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in patients >50 years of age and in whom there is no known immunodeficiency or history of lymphoma. These tumors are more common in Asia but also occur in North America and Europe at a low frequency. These neoplasms exhibit a morphologic continuum, from polymorphous to monomorphous, but morphologic features do not correlate with prognosis as all patients have a clinically aggressive course. Most EBV-positive DLBCL of the elderly patients have an activated B-cell immunophenotype and are characterized by prominent nuclear factor-kappaB activation. Cytogenetic complexity is usually low. In this review, we comprehensively delineate the data emerging from analyses of EBV latency program, microRNA-mediated EBV viral oncogenesis, functional genomics of EBV and its biology, and differential diagnosis challenge for EBV positive DLBCL of the elderly. It is hoped that the improved understanding of these tumors will lead to the development of novel therapeutic approaches, enhance the effectiveness of clinical trials, and improve prognosis. PMID- 23649470 TI - Characterization of a novel NKG2D and NKp46 double-mutant mouse reveals subtle variations in the NK cell repertoire. AB - The immunoreceptors NKG2D and NKp46 are known for their capacity to activate natural killer (NK) cell cytotoxicity and secretory responses in the contexts of tumors and infections, yet their roles in NK cell education remain unclear. Here, we provide the first characterization of mice deficient for both NKG2D and NKp46 receptors to address the relevance of their concomitant absence during NK cell development and function. Our findings reveal that NK cells develop normally in double-mutant (DKO) mice. Mice lacking NKG2D but not NKp46 showed subtle differences in the percentages of NK cells expressing inhibitory Ly49 receptors and the adhesion molecule DNAM-1. A slightly increased percentage of terminally differentiated NK cells and functional response to in vitro stimuli was observed in some experiments. These alterations were modest and did not affect NK cell function in vivo in response to mouse cytomegalovirus infection. NKp46 deficiency alone, or in combination with NKG2D deficiency, had no effect on frequency or function of NK cells. PMID- 23649471 TI - Trends in overweight among women differ by occupational class: results from 33 low- and middle-income countries in the period 1992-2009. AB - OBJECTIVE: There has been an increase in overweight among women in low- and middle-income countries but whether these trends differ for women in different occupations is unknown. We examined trends by occupational class among women from 33 low- and middle-income countries in four regions. DESIGN: Cross-national study with repeated cross-sectional demographic health surveys. SUBJECTS: Height and weight were assessed at least twice between 1992 and 2009 in 248,925 women aged 25-49 years. Interviews were conducted to assess occupational class, age, place of residence, educational level, household wealth index, parity, age at first birth and breastfeeding. We used logistic and linear regression analyses to assess the annual percent change in overweight (body mass index >25 kg m(-2)) by occupational class. RESULTS: The prevalence of overweight ranged from 2.2% in Nepal in 1992-1997 to 75% in Egypt in 2004-2009. In all the four regions, women working in agriculture had consistently lower prevalence of overweight, while women from professional, technical, managerial as well as clerical occupational classes had higher prevalence. Although the prevalence of overweight increased in all the occupational classes in most regions, women working in agriculture and production experienced the largest increase in overweight over the study period, while women in higher occupational classes experienced smaller increases. To illustrate, overweight increased annually by 0.5% in Latin America and the Caribbean and by 0.7% in Sub-Saharan Africa among women from professional, technical and managerial classes, as compared with 2.8% and 3.7%, respectively, among women in agriculture. CONCLUSION: The prevalence of overweight has increased in most low- and middle-income countries, but women working in agriculture and production have experienced larger increases than women in higher occupational classes. PMID- 23649472 TI - The melanocortin system and insulin resistance in humans: insights from a patient with complete POMC deficiency and type 1 diabetes mellitus. AB - The central melanocortin system is essential for the regulation of long-term energy homeostasis in humans. Rodent experiments suggest that this system also affects glucose metabolism, in particular by modulating peripheral insulin sensitivity independently of its effect on adiposity. Rare patients with complete genetic defects in the central melanocortin system can provide insight into the role of this system in glucose homeostasis in humans. We here describe the eighth individual with complete proopiomelanocortin (POMC) deficiency and the first with coincidental concomitant type 1 diabetes, which provides a unique opportunity to determine the role of melanocortins in glucose homeostasis in human. Direct sequencing of the POMC gene in this severely obese patient with isolated adrenocorticotropic hormone deficiency identified a homozygous 5' untranslated region mutation -11C>A, which we find to abolish normal POMC protein synthesis, as assessed in vitro. The patient's insulin requirements were as expected for his age and pubertal development. This unique patient suggests that in humans the central melanocortin system does not seem to affect peripheral insulin sensitivity, independently of its effect on adiposity. PMID- 23649473 TI - Plankton diversity and water quality assessment of three freshwater lakes of Mandi (Himachal Pradesh, India) with special reference to planktonic indicators. AB - The present study deals with the limnobiotic status of three selected lakes of Himachal Pradesh using physicochemical and biological parameters (especially phytoplankton and zooplankton) over a period of 2 years. One hundred forty-eight species belonging to nine groups of phytoplankton and 79 species belonging to five groups of zooplankton were identified from the lakes. Trophic level and the pollution status of the lakes were assessed upon the basis of Shannon diversity index (H'), species richness index (S), and physicochemical parameters. Plankton population size was correlated with biotic and abiotic parameters (pH, alkalinity, temperature, dissolved oxygen, transparency, phosphate, chloride, and nitrate). The present investigation revealed that the distribution of plankton species depended upon the physicochemical parameters of the environment. Based on water quality standards given by the Central Pollution Control Board, the water quality was between "A-B" at Prashar wetland, "C-D" at Kuntbhyog Lake, and "D-E" at Rewalsar Lake. The results from the present study indicated that the potential of planktons as bioindicators of trophic status is very high. PMID- 23649474 TI - Characterizing spatiotemporal non-stationarity in vegetation dynamics in China using MODIS EVI dataset. AB - This paper evaluated the spatiotemporal non-stationarity in the vegetation dynamic based on 1-km resolution 16-day composite Moderate Resolution Imaging Spectroradiometer (MODIS) Enhanced Vegetation Index (EVI) datasets in China during 2001-2011 through a wavelet transform method. First, it revealed from selected pixels that agricultural crops, natural forests, and meadows were characterized by their distinct intra-annual temporal variation patterns in different climate regions. The amplitude of intra-annual variability generally increased with latitude. Second, parameters calculated using a per-pixel strategy indicated that the natural forests had the strongest variation pattern from seasonal to semiannual scales, and the multiple-cropping croplands typically showed almost equal variances distributed at monthly, seasonal, and semiannual scales. Third, spatiotemporal non-stationarity induced from cloud cover was also evaluated. It revealed that the EVI temporal profiles were significantly distorted with regular summer cloud cover in tropical and subtropical regions. Nevertheless, no significant differences were observed from those statistical parameters related to the interannual and interannual components between the de clouded and the original MODIS EVI datasets across the whole country. Finally, 12 vegetation zones were proposed based on spatiotemporal variability, as indicated by the magnitude of interannual and intra-annual dynamic components, normalized wavelet variances of detailed components from monthly to semiannual scale, and proportion of cloud cover in summer. This paper provides insightful solutions for addressing spatiotemporal non-stationarity by evaluating the magnitude and frequency of vegetation variability using monthly, seasonal, semiannual to interannual scales across the whole study area. PMID- 23649475 TI - Retraction note to: Detection of bacterial endotoxin in drinking tap and bottled water in Kuwait. PMID- 23649476 TI - 2-Nitroso-1-naphthol as a selective reagent for preconcentration of cobalt by vortex assisted combined with solidification of organic droplet and its determination by flame atomic absorption spectrometry. AB - Highly rapid and selective vortex-assisted liquid-liquid microextraction based on solidification of organic drop has been used for determination of cobalt ion. 2 Nitroso-1-naphthol (2N1N) was used as a selective complexing agent to form stable cobalt-2N1N complex which can be extracted with 1-undecanol at a short time by the assistance of vortex agitator system followed by its determination using flame atomic absorption spectrometry. In vortex assisted, vigorous vortex stream as well as the vibrant effect of vortex system cause very fine droplets of extraction solvent to be produced and extraction occurred at a short time. Some parameters influencing the extraction process such as pH of samples, concentration of 2-nitroso-1-naphthol, extraction solvent volume, extraction time, ionic strength and surfactant addition, as well as interferences were evaluated in detail and optimum conditions were selected. At the optimum conditions, the calibration curve was linear in the range of 15 to 400 MUg L(-1) of cobalt ions. The relative standard deviation based on ten replicate analysis of sample solution containing 50 MUg L(-1) of cobalt was 3.4%. The detection limit (calculated as the concentration equivalent to three times of the standard deviation of the blank divided by the slope of the calibration curve after preconcentration) was 5.4 MUg L(-1). The accuracy of the proposed method was successfully evaluated by the analysis of certified reference materials. This selective and highly rapid method was used for determination of cobalt ions in different water samples. PMID- 23649477 TI - Dissipation and residue behavior of mepiquat on wheat and potato field application. AB - A modified LC-MS method for the analysis of mepiquat residue in wheat, potato, and soil was developed and validated. A hydrophilic interaction liquid chromatographic column has been successfully used to retain and separate the mepiquat. Mepiquat residue dynamics and final residues in supervised field trials at Good Agricultural Practice (GAP) conditions in wheat, potato, and soil were studied. The limits of quantification for mepiquat in all samples were all 0.007 mg kg(-1), which were lower than their maximum residue limits. At fortification levels of 0.04, 0.2, and 2 mg kg(-1) in all samples, recoveries ranged from 77.5 to 116.4% with relative standard deviations of 0.4-7.9% (n = 5). The dissipation half-lives (T 1/2) of mepiquat in soil (wheat), wheat plants, soil (potato), and potato plants were 4.5-6.3, 3.0-5.6, 2.2-4.6, and 2.4-3.2 days, respectively. The final residues of mepiquat were below 0.153 mg kg(-1) in soil (wheat), 0.052 1.900 mg kg(-1) in wheat, below 0.072 mg kg(-1) in soil (potato), and below 1.173 mg kg(-1) in potato at harvest time. Moreover, pesticide risk assessment for all the detected residues was conducted. A maximum 0.0012% of acceptable daily intake (150 mg kg(-1)) for national estimated daily intake indicated low dietary risk of these products. PMID- 23649478 TI - Topography of the greater palatine artery and the palatal vault for various types of periodontal plastic surgery. AB - The purpose of the present study is to provide useful data that could be applied to various types of periodontal plastic surgery by detailing the topography of the greater palatine artery (GPA), looking in particular at its depth from the palatal masticatory mucosa (PMM) and conducting a morphometric analysis of the palatal vault. Forty-three hemisectioned hard palates from embalmed Korean adult cadavers were used in this study. The morphometry of the palatal vault was analyzed, and then the specimens were decalcified and sectioned. Six parameters were measured using an image-analysis system after performing a standard calibration. In one specimen, the PMM was separated from the hard palate and subjected to a partial Sihler's staining technique, allowing the branching pattern of the GPA to be observed in a new method. The distances between the GPA and the gingival margin, and between the GPA and the cementoenamel junction were greatest at the maxillary second premolar. The shortest vertical distance between the GPA and the PMM decreased gradually as it proceeded anteriorly. The GPA was located deeper in the high-vault group than in the low-vault group. The premolar region should be recommended as the optimal donor site for tissue grafting, and in particular the second premolar region. The maximum size and thickness of tissue that can be harvested from the region were 9.3 mm and 4.0 mm, respectively. PMID- 23649479 TI - Multiple vascular variations at the vicinity of the left kidney. AB - Although isolated variations of the renal artery, renal vein and testicular artery are commonly described in the literature, the concurrent presence of variations in all three of these vessels has seldom been reported. Here, we report concurrent vascular variations in the vicinity of the left kidney. The left renal vein was found to have a retropelvic tributary, and a communicating vein connecting the inferior vena cava and retropelvic tributary was also noted. In addition, the left renal artery separated into anterior and posterior divisions just before reaching the hilum. The anterior division further divided into two segmental branches which had a peculiar 'ram horn' shape. The posterior division of the renal artery entered the substance of the kidney without forming any further branches. The left testicular artery arose from the aorta above the level of the renal artery and then passed in front of left renal vessels following a tortuous course. The anatomical knowledge of this unusual vascular pattern may be useful during renal vascular reconstruction, treatment of renal artery stenosis, endoscopic surgeries and clinical evaluation of renovascular hypertension. PMID- 23649480 TI - Swedish mutant APP suppresses osteoblast differentiation and causes osteoporotic deficit, which are ameliorated by N-acetyl-L-cysteine. AB - Reduced bone mineral density and hip fracture are frequently observed in patients with Alzheimer's disease (AD). However, mechanisms underlying their association remain poorly understood. Amyloid precursor protein (APP) is a transmembrane protein that is ubiquitously expressed in bone marrow stromal cells (BMSCs), osteoblasts (OBs), macrophages (BMMs), and osteoclasts (OCs). Mutations in the APP gene identified in early-onset AD patients are believed to cause AD. But little is known about APP's role in bone remodeling. Here, we present evidence for Swedish mutant APP (APPswe) in suppression of OB differentiation and function in culture and in mouse. APP expression in BMSCs increases during aging. Ubiquitous expression of APPswe in young adult Tg2576 transgenic mice (under the control of a prion promoter) recaptured skeletal "aging-like" deficits, including decreased OB genesis and bone formation, increased adipogenesis and bone marrow fat, and enhanced OC genesis and bone resorption. Remarkably, selective expression of APPswe in mature OB-lineage cells in TgAPPswe-Ocn mice (under the control of osteocalcin [Ocn] promoter-driven Cre) also decreased OB genesis and increased OC formation, resulting in a trabecular bone loss. These results thus suggest a cell-autonomous role for APPswe in suppressing OB formation and function, but a nonautonomous effect on OC genesis. Notably, increased adipogenesis and elevated bone marrow fat were detected in young adult Tg2576 mice, but not in TgAPPswe-Ocn mice, implying that APPswe in BMSCs and/or multicell types in bone marrow promotes bone marrow adipogenesis. Intriguingly, the skeletal aging-like deficits in young adult Tg2576 mice were prevented by treatment with N-acetyl-L-cysteine (NAC), an antioxidant, suggesting that reactive oxygen species (ROS) may underlie APPswe-induced osteoporotic deficits. Taken together, these results demonstrate a role for APPswe in suppressing OB differentiation and bone formation, implicate APPswe as a detrimental factor for AD-associated osteoporotic deficit, and reveal a potential clinical value of NAC in the treatment of osteoporotic deficits. (c) 2013 American Society for Bone and Mineral Research. PMID- 23649482 TI - Treatment of rheumatoid arthritis with methotrexate in Congolese patients. AB - Methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA) but data concerning the effectiveness of treatment with this compound are lacking in the Congolese population. In the present study, the evolution of RA in Congolese patients on MTX treatment is reported from before disease-modifying antirheumatic drug (DMARD) initiation till 20 months later. All consecutive DMARD naive RA patients (ACR 1987 criteria) attending the rheumatology unit of the University Hospital of Kinshasa from January 2008 to September 2010 were included. All were treated with MTX (started at 7.5 mg/week) and bridging steroids (started at 30mg/day). Treatment adaptations of MTX and concomitant drugs are reported as well as evolution of disease activity (DAS28-ESR), functionality (Health Assessment Questionnaire), radiological damage, and safety over 20 months. Of 98 patients recruited, more than one third were lost at follow up. A follow-up visit at 20 months was available for 51 patients. These 48 women and 3 men had a mean age of 51.2 +/- 13 years and a mean delay from symptom onset till their first visit of 3.2 years. At 20 months, the average MTX dose was 9.7 mg weekly. A second DMARD was added in three patients. The average dose of prednisone at 20 months was 7.5 mg daily. A significant improvement of DAS28 and functional disability was observed and 35.3 % of patients entered remission (DAS28 <2.6). A progression of X-ray damage was observed in one third of patients. Two patients had to stop MTX because of severe side effects and two patients developed diabetes. Methotrexate and bridging steroids therapy is effective also in sub-Saharan Africa but the average weekly MTX dose remains low. Implementation of a regular follow-up is a major issue. PMID- 23649483 TI - Systemic lupus erythematosus and HIV infection: a whimsical relationship. Reports of two cases and review of the literature. AB - Systemic lupus erythematosus (SLE) is rarely reported in association with HIV infection. We describe two unpredictable cases and provide a review of the literature. Retrospective analysis of the medical records of two HIV-infected patients diagnosed with SLE and admitted at Luigi Sacco Hospital (Milano, Italy). Search of the literature from 1981 to 2012 and review of the cases reported. Case 1: a 32-year-old HIV-infected African woman who developed a SLE flare after re introduction of antiretroviral therapy (ART). The flare was characterized by bullous skin eruption and membranous glomerulonephritis. Case 2: a 44-year-old Caucasian woman, admitted to our hospital because of lacunar stroke: HIV infection and SLE were simultaneously diagnosed. LITERATURE: 55 cases of SLE in the setting of HIV infection were reported. Forty-five patients met the requirements of the American College of Rheumatology for the diagnosis of SLE. The diagnosis of SLE preceded HIV infection in six patients. On the contrary, in 29 patients, HIV infection was reported before SLE. Median CD4+ count at SLE diagnosis was 361 cells/MUl. A SLE manifestation following ART immune recovery was documented in 18.2% of the cases. On the contrary, the progression of HIV infection paralleled with SLE remission in 22.5% of the patients. The study shows that an autoimmune disease such as SLE can occur despite the loss of immunocompetence caused by HIV infection. Moreover, SLE and HIV infection influence each other possibly through immunologic mechanisms determining awkward manifestations. PMID- 23649485 TI - Quantification of conjugated metabolites of drugs in biological matrices after the hydrolysis with beta-glucuronidase and sufatase: a review of bio-analytical methods. AB - Glucuronidation and sulfation represent two major pathways in phase II drug metabolism in humans and other mammalian species. The great majority of drugs, for example, polyphenols, flavonoids and anthraquinones, could be transformed into sulfated and glucuronidated conjugates simultaneously and extensively in vivo. The pharmacological activities of drug conjugations are normally decreased compared with those of their free forms. However, some drug conjugates may either bear biological activities themselves or serve as excellent sources of biologically active compounds. As the bioactivities of drugs are thought to be relevant to the kinetics of their conjugates, it is essential to study the pharmacokinetic behaviors of the conjugates in more detail. Unfortunately, the free forms of drugs cannot be detected directly in most cases if their glucuronides and sulfates are the predominant forms in biological samples. Nevertheless, an initial enzymatic hydrolysis step using beta-glucuronidase and/or sulfatase is usually performed to convert the glucuronidated and/or sulfated conjugates to their free forms prior to the extraction, purification and other subsequent analysis steps in the literature. This review provides fundamental information on drug metabolism pathways, the bio-analytical strategies for the quantification of various drug conjugates, and the applications of the analytical methods to pharmacokinetic studies. PMID- 23649486 TI - Prediction of drug-polymer miscibility through the use of solubility parameter based Flory-Huggins interaction parameter and the experimental validation: PEG as model polymer. AB - Important consideration for developing physically stable solid dispersion is miscibility of drug in carrier matrix. It is possible to predict thermodynamics of binary system through free energy calculations based on Flory-Huggins interaction parameter (chi(dp)). In present study, PEG 6000 as model polymer and dataset comprising commonly used drugs/excipients was selected. The three dimensional solubility parameter based on group contribution method was utilized for systemic calculation of chi(dp) of the polymer with each compound in data set. On the basis of the values of chi(dp), it was possible to categorize all the compounds into three distinct categories, Types I and II: compounds predicted to be miscible and immiscible respectively with the polymer in all proportions and Type III: compounds expected to exhibit composition dependent miscibility behavior. The Bagley plot showed that majority of points for Type I fall in a region, which can approximately be delimited by a circle. Experimental verification through thermal analysis revealed that though it was possible to predict correctly miscibility behavior of Type II class compounds, distinction between Types I and III was less evident. Hence, solubility parameter based chi(dp) may be used as an initial tool for fast screening of immiscible combination of polymer and drug. PMID- 23649481 TI - The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. AB - introduction: Glucocorticoid (GC) therapy in Duchenne muscular dystrophy (DMD) has altered disease progression, necessitating contemporary natural history studies. METHODS: The Cooperative Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 DMD males, ages 2-28 years. A comprehensive battery of measures was obtained. RESULTS: A novel composite functional "milestone" scale scale showed clinically meaningful mobility and upper limb abilities were significantly preserved in GC-treated adolescents/young adults. Manual muscle test (MMT)-based calculations of global strength showed that those patients <10 years of age treated with steroids declined by 0.4 +/- 0.39 MMT unit/year, compared with -0.4 +/- 0.39 MMT unit/year in historical steroid-naive subjects. Pulmonary function tests (PFTs) were relatively preserved in steroid-treated adolescents. The linearity and magnitude of decline in measures were affected by maturational changes and functional status. CONCLUSIONS: In DMD, long-term use of GCs showed reduced strength loss and preserved functional capabilities and PFTs compared with previous natural history studies performed prior to the widespread use of GC therapy. PMID- 23649487 TI - Improving cancer research. Leaders cite collaboration and increased areas of study as ways to fight the disease. PMID- 23649484 TI - Overview of vasculitis and vasculopathy in rheumatoid arthritis--something to think about. AB - The vasculature plays a crucial role in inflammation and atherosclerosis associated with the pathogenesis of rheumatoid arthritis. Vasculitis in rheumatoid arthritis is associated with longstanding disease, has an important impact on a patient's quality of life and influences patient life expectancy. Seropositivity, specific human leukocyte antigen variations, antibodies to cyclic citrullinated peptides, and cigarette smoking are among the genetic and environmental predictors of rheumatoid vasculitis. Atherosclerosis is an early and common finding in rheumatoid arthritis and it correlates with disease duration, activity, and severity. Apart from conventional risk factors such as cigarette smoking, physical inactivity, obesity, arterial hypertension, dyslipidemia and diabetes mellitus, rheumatoid arthritis-related risk factors including disease duration, severity and activity, rheumatoid factor and antibodies to cyclic citrullinated peptides status, functional impairment, C reactive protein, radiographic changes, presence of the shared epitope, and treatment modalities are all implicated in the development of accelerated atherosclerosis. Atherosclerosis is also considered an inflammatory disease; thus, it may share common pathogenic mechanisms with rheumatic diseases such as rheumatoid arthritis. Advances in treatment of rheumatoid arthritis with disease modifying biologic and nonbiologic agents will probably continue to reduce the incidence of vasculitis. Since the goal of treatment for rheumatoid arthritis is to decrease inflammatory burden, successful treatment may theoretically reduce the risk of accelerated atherosclerosis. PMID- 23649488 TI - Childbirth delay may reduce risk of an aggressive breast cancer. PMID- 23649489 TI - Imaging-guided biopsy detects prostate cancer. PMID- 23649491 TI - Matriptase-2 gene (TMPRSS6) variants associate with breast cancer survival, and reduced expression is related to triple-negative breast cancer. AB - Matriptase-2 (TMPRSS6) has been identified as a breast cancer risk factor. Here, we examined relationships between TMPRSS6 genetic variations and breast cancer risk and survival, and determined the gene and protein expressions in breast tumors and assessed their clinical importance. Thirteen TMPRSS6 polymorphisms were genotyped in 462 invasive breast cancer cases and 458 controls. Gene expression was analyzed from 83 tumors and protein expression from 370 tumors. We then assessed the statistical significance of associations among genotypes, clinicopathological characteristics and survival. The TMPRSS6 variant rs2543519 was associated with breast cancer risk (p = 0.032). Multivariate analysis showed that four variants had effects on survival-rs2543519 (p = 0.017), rs2235324 (p = 0.038), rs14213212 (p = 0.044) and rs733655 (p = 0.021)-which were used to create a group variable that was associated with poorer prognosis correlating with more alleles related to reduced survival (p = 0.006; risk ratio, 2.375; 95% confidence interval, 1.287-4.382). Low gene expression was related to triple-negative breast cancer (p = 0.0001), and lower protein expression was detected in undifferentiated (p = 0.019), large (p = 0.014) and ductal or lobular tumors (p = 0.036). These results confirm the association of TMRRSS6 variants with breast cancer risk and survival. Matriptase-2 levels decrease with tumor progression, and lower gene expression is seen in poor-prognosis-related triple-negative breast cancers. Our study is the first to show that matriptase-2 gene variants are related to breast cancer prognosis, supporting matriptase-2 involvement in tumor development. PMID- 23649490 TI - Quantitative phosphoproteomics analysis reveals broad regulatory role of heparan sulfate on endothelial signaling. AB - Heparan sulfate (HS) is a linear, abundant, highly sulfated polysaccharide that expresses in the vasculature. Recent genetic studies documented that HS critically modulates various endothelial cell functions. However, elucidation of the underlying molecular mechanism has been challenging because of the presence of a large number of HS-binding ligands found in the examined experimental conditions. In this report, we used quantitative phosphoproteomics to examine the global HS-dependent signaling by comparing wild type and HS-deficient endothelial cells that were cultured in a serum-containing medium. A total of 7222 phosphopeptides, corresponding to 1179 proteins, were identified. Functional correlation analysis identified 25 HS-dependent functional networks, and the top five are related to cell morphology, cellular assembly and organization, cellular function and maintenance, cell-to-cell communication, inflammatory response and disorder, cell growth and proliferation, cell movement, and cellular survival and death. This is consistent with cell function studies showing that HS deficiency altered endothelial cell growth and mobility. Mining for the underlying molecular mechanisms further revealed that HS modulates signaling pathways critically related to cell adhesion, migration, and coagulation, including ILK, integrin, actin cytoskeleton organization, tight junction and thrombin signaling. Intriguingly, this analysis unexpectedly determined that the top HS-dependent signaling is the IGF-1 signaling pathway, which has not been known to be modulated by HS. In-depth analysis of growth factor signaling identified 22 HS dependent growth factor/cytokine/growth hormone signaling pathways, including those both previously known, such as HGF and VEGF, and those unknown, such as IGF 1, erythropoietin, angiopoietin/Tie, IL-17A and growth hormones. Twelve of the identified 22 growth factor/cytokine/growth hormone signaling pathways, including IGF-1 and angiopoietin/Tie signaling, were alternatively confirmed in phospho receptor tyrosine kinase array analysis. In summary, our SILAC-based quantitative phosphoproteomic analysis confirmed previous findings and also uncovered novel HS dependent functional networks and signaling, revealing a much broader regulatory role of HS on endothelial signaling. PMID- 23649492 TI - [Peripartum cardiomyopathy: diagnostic and therapeutic challenge]. PMID- 23649493 TI - Burden of disease from toxic waste sites in India, Indonesia, and the Philippines in 2010. AB - BACKGROUND: Prior calculations of the burden of disease from toxic exposures have not included estimates of the burden from toxic waste sites due to the absence of exposure data. OBJECTIVE: We developed a disability-adjusted life year (DALY) based estimate of the disease burden attributable to toxic waste sites. We focused on three low- and middle-income countries (LMICs): India, Indonesia, and the Philippines. METHODS: Sites were identified through the Blacksmith Institute's Toxic Sites Identification Program, a global effort to identify waste sites in LMICs. At least one of eight toxic chemicals was sampled in environmental media at each site, and the population at risk estimated. By combining estimates of disease incidence from these exposures with population data, we calculated the DALYs attributable to exposures at each site. RESULTS: We estimated that in 2010, 8,629,750 persons were at risk of exposure to industrial pollutants at 373 toxic waste sites in the three countries, and that these exposures resulted in 828,722 DALYs, with a range of 814,934-1,557,121 DALYs, depending on the weighting factor used. This disease burden is comparable to estimated burdens for outdoor air pollution (1,448,612 DALYs) and malaria (725,000 DALYs) in these countries. Lead and hexavalent chromium collectively accounted for 99.2% of the total DALYs for the chemicals evaluated. CONCLUSIONS: Toxic waste sites are responsible for a significant burden of disease in LMICs. Although some factors, such as unidentified and unscreened sites, may cause our estimate to be an underestimate of the actual burden of disease, other factors, such as extrapolation of environmental sampling to the entire exposed population, may result in an overestimate of the burden of disease attributable to these sites. Toxic waste sites are a major, and heretofore underrecognized, global health problem. PMID- 23649494 TI - Cost consideration in the clinical guidance documents of physician specialty societies in the United States. AB - IMPORTANCE: Despite increasing concerns regarding the cost of health care, the consideration of costs in the development of clinical guidance documents by physician specialty societies has received little analysis. OBJECTIVE: To evaluate the approach to consideration of cost in publicly available clinical guidance documents and methodological statements produced between 2008 and 2012 by the 30 largest US physician specialty societies. DESIGN: Qualitative document review. MAIN OUTCOMES AND MEASURES: Whether costs are considered in clinical guidance development, mechanism of cost consideration, and the way that cost issues were used in support of specific clinical practice recommendations. RESULTS: Methodological statements for clinical guidance documents indicated that 17 of 30 physician societies (57%) explicitly integrated costs, 4 (13%) implicitly considered costs, 3 (10%) intentionally excluded costs, and 6 (20%) made no mention. Of the 17 societies that explicitly integrated costs, 9 (53%) consistently used a formal system in which the strength of recommendation was influenced in part by costs, whereas 8 (47%) were inconsistent in their approach or failed to mention the exact mechanism for considering costs. Among the 138 specific recommendations in these guidance documents that included cost as part of the rationale, the most common form of recommendation (50 [36%]) encouraged the use of a specific medical service because of equal effectiveness and lower cost. CONCLUSIONS AND RELEVANCE: Slightly more than half of the largest US physician societies explicitly consider costs in developing their clinical guidance documents; among these, approximately half use an explicit mechanism for integrating costs into the strength of recommendations. Many societies remain vague in their approach. Physician specialty societies should demonstrate greater transparency and rigor in their approach to cost consideration in documents meant to influence care decisions. PMID- 23649495 TI - Hybrid nanoscale organic molecular crystals assembly as a photon-controlled actuator. PMID- 23649496 TI - How to prevent cut-out and cut-through in biaxial proximal femoral nails: is there anything beyond lag screw positioning and tip-apex distance? AB - PURPOSE: Hip perforation is a major complication in proximal femoral nailing. For biaxial nails, knowledge of their biomechanics is limited. Besides re-evaluation of accepted risk factors like the tip-apex distance (TAD), we analysed the influence of anti-rotational pin length. METHODS: We compared 22 hip perforation cases to 50 randomly chosen controls. TAD, lag-screw position, angle between lag screw and femoral neck axis, lag-screw gliding capacity, displacement and anti rotational pin length were investigated. RESULTS: Hip perforation was associated with a higher angle of deviation between lag-screw and femoral neck axis (p = 0.001), a lower telescoping capacity of the lag screw (p = 0.02), and higher TAD (p = 0.048). If the anti-rotational pin exceeded a line connecting the tip of the nail and the lag screw (NS line), hip perforation incidence was increased (p = 0.009). Inadequate pin length resulted in an odds ratio of 10.8 for hip perforation (p = 0.001). CONCLUSIONS: In biaxial nails anti-rotational element positioning is underestimated, however, crucial. PMID- 23649497 TI - RF surface receive array coils: the art of an LC circuit. AB - The radiofrequency (RF) receive array coil is a complicated device with many inductors and capacitors and serves as one of the most critical magnetic resonance imaging (MRI) electronic devices. It directly determines the achievable level of signal-to-noise ratio (SNR). Simply put, however, the RF coil is nothing but an LC circuit. The receive array coil was first proposed more than 20 years ago, evolving from a simple arrangement with a few electronic channels to a complicated system of 128 channels, enabling highly sophisticated parallel imaging, at different field strengths. This article summarizes the basic concepts pertaining to RF receive coil arrays and their associated SNR and reviews the theories behind the major components of such arrays. This includes discussions of the intrinsic SNR of a receive coil, the matching circuits, low-noise preamplifiers, coupling/decoupling amongst coils, the coupling between receive and transmit coils, decoupling via preamplifiers, and baluns. An 8-channel receive array coil on a cylindrical former serves as a useful example for demonstrating various points in the review. PMID- 23649499 TI - Cosmetic rhinoseptoplasty in acute nasal bone fracture. AB - OBJECTIVE: Traditionally, rhinoseptoplasty for nasal bone fracture is only considered after an unsatisfactory outcome from initial closed reduction. However, better surgical outcomes may be achieved if rhinoseptoplasty is performed at the same time as the nasal bone fracture reduction. This study investigated the surgical outcomes of patients who underwent rhinoseptoplasty concomitantly with nasal bone fracture reduction according to their computed tomography image-based nasal bone fracture classifications. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary care medical center. SUBJECTS AND METHODS: Fifty-six patients who underwent rhinoseptoplasty concomitantly with nasal bone fracture reduction were enrolled in this study. Nasal bone fractures were classified into 6 types by computed tomography scans. Two independent facial plastic surgeons evaluated the outcomes 6 months postoperatively using a visual analog scale. The nasal tip projection and rotation were measured using the pre- and postoperative profile views. RESULTS: The satisfaction scores of type I, IIo, and IIIo fractures without septal fracture were significantly higher than those of type II, III, and IV fractures with septal fractures. Among the patients, 82.1% underwent lower vault surgery. The nasal tip projection and rotation were increased after surgery in patients without septal fractures, whereas the tip rotation was elevated but the projection was unchanged postoperatively in patients with septal fractures. CONCLUSION: Rhinoseptoplasty for acute nasal bone fractures can be performed at the same time as nasal bone fracture reduction. However, nasal bone fracture with septal fracture should be managed carefully. PMID- 23649498 TI - Is Montgomery tracheal Safe-T-Tube clinical failure induced by biofilm? AB - OBJECTIVES: Montgomery Safe-T-Tube deterioration and early biofilm colonization may explain the discomfort claimed by many patients and clinical failures. The aim of the study was to analyze the deterioration of Montgomery Safe-T-Tube morphological and mechanical properties in vivo in 16 patients by using microbiological methods, optical and electron microscopy, and engineering tests. STUDY DESIGN: Prospective controlled study at a single medical center. SETTING: University hospital. SUBJECTS AND METHODS: The study, conducted from April 2007 to February 2012 at the "Sapienza" University of Rome, was designed to collect 2 Montgomery Safe-T-Tubes from each patient. The first was removed 3 to 15 days after insertion (group A) and the second at least 90 days after (group B). Specimens underwent microbiologic assays, electron microscopic analysis, immunocytologic analysis, and mechanical tests. RESULTS: Microorganisms were not isolated in 2 group A cases (12%), whereas they were in all group B cases. Biofilm was identified in 11 of 16 (69%) group A samples and in 16 of 16 (100%) group B samples (P = .0149) using scanning electron microscopy. Immunohistochemistry showed monocyte-granulocyte line cells producing interleukin 1beta on the external surfaces of Montgomery Safe-T-Tubes. The tensile test showed that the wear related to the longer period of use makes Montgomery Safe-T Tubes more rigid than newer ones. CONCLUSION: Early biofilm colonization takes place in Montgomery Safe-T-Tubes in most cases. The mechanical decay could be justified in part by the destructive biofilm activity and by the release of inflammatory effectors and enzymes. PMID- 23649500 TI - Buccinator myomucosal flap for reconstruction of glossectomy defects. AB - OBJECTIVE: The use of the myomucosal flap from the buccinator muscle is a valuable reconstruction method for intraoral defects. We report the clinical advantages and pitfalls of using the buccinator myomucosal flap for tongue reconstruction after intraoral resection of tongue cancer. STUDY DESIGN: Prospective study. SETTING: University hospital. SUBJECTS AND METHODS: We used buccal artery-based buccinator myomucosal flaps for tongue reconstruction in 11 partial or total edentulous patients who underwent resection of tongue cancer. The size and site of the tongue defect ranged from one-third to one-half of the tongue in the lateral border. We analyzed the clinical features and oncologic and functional outcomes to define adequate indications. RESULTS: All flaps were successfully harvested and transposed, and the donor sites were primarily closed. The pedicles were safely divided 2 to 3 weeks postoperatively. In 8 of 11 patients, concurrent upper neck dissection was performed without compromising blood supply to the flap. The range of tongue motion and the volume of the reconstructed tongue were satisfactory, and the patients experienced no difficulties in swallowing or speech. CONCLUSION: Particularly in edentulous patients, the buccal myomucosal flap can be a good option for reconstructing partial tongue defects after cancer surgery. PMID- 23649502 TI - Contribution of QSART to the diagnosis of small fiber neuropathy. AB - INTRODUCTION: We evaluated incorporation of the quantitative sudomotor axon reflex test (QSART) into the diagnostic criteria for small fiber neuropathy (SFN) as an addition to quantitative sensory testing (QST) and intraepidermal nerve fiber density (IENFD) testing. METHODS: One hundred one patients with clinically suspected SFN underwent QSART, QST, and skin biopsy. The diagnostic yield of existing SFN criteria in these patients was compared with criteria incorporating QSART. The new combined diagnostic criteria were evaluated. RESULTS: SFN was diagnosed in 38 of the 101 patients (38%) using current criteria. Addition of QSART existing SFN criteria resulted in an increased diagnostic yield to 67 patients (66%). Applying new SFN criteria requiring abnormality in at least 2 assessments among QSART, QST, and IENFD resulted in a diagnosis of SFN in 57 patients (56%). CONCLUSION: Assessment of both somatic and peripheral autonomic small nerve fibers enhances diagnostic criteria for SFN. PMID- 23649503 TI - Role of maternal childhood trauma on parenting among depressed mothers of psychiatrically ill children. AB - BACKGROUND: Independently, maternal depression and maternal history of childhood abuse confer risk for impaired parenting. These associations may be compounded when depressed mothers with histories of childhood abuse are faced with the challenge of parenting offspring who themselves struggle with mental health problems. This study examined the relationships among maternal history of childhood abuse, maternal depression, and parenting style in the context of parenting a psychiatrically ill child, with an emphasis on examining maternal emotional abuse and neglect. We hypothesized that maternal childhood emotional abuse would be associated with maladaptive parenting strategies (lower levels of maternal acceptance and higher levels of psychological control), independent of maternal depression severity and other psychosocial risk factors. METHOD: Ninety five mother-child dyads (children ages 7-18) were recruited from child mental health centers where children were receiving treatment for at least one internalizing disorder. Participating mothers met DSM-IV criteria for major depressive disorder. Mothers reported on their own childhood abuse histories and children reported on their mothers' parenting. RESULTS: Regression analyses demonstrated that maternal childhood emotional abuse was associated with child reports of lower maternal acceptance and greater psychological control, controlling for maternal depression severity, and other psychosocial risk factors. CONCLUSIONS: When treating psychiatrically ill children, it is important for a child's clinician to consider mothers' childhood abuse histories in addition to their history of depression. These mothers appear to have additional barriers to effective parenting. PMID- 23649505 TI - A concise synthesis of L-pyrrolysine. AB - Organocatalysis: A concise synthesis of L-pyrrolysine has been accomplished in six steps from simple starting materials. The facile synthetic strategy relies on an organocatalytic Michael addition, an efficient amide coupling, and a challenging method for the imine-bond construction. PMID- 23649504 TI - Novel gene expression model for outcome prediction in paediatric medulloblastoma. AB - Medulloblastoma is the most frequent type of embryonal tumour in the paediatric population. The disease progression in patients with this tumour may be connected with the presence of stem/tumour-initiating cells, but the precise source and characteristics of such cells is still a subject of debate. Thus, we tried to analyse biomarkers for which a connection with the presence of stem/tumour initiating cells was suggested. We evaluated the transcriptional level of the ATOH1, FUT4, NGFR, OTX1, OTX2, PROM1 and SOX1 genes in 48 samples of medulloblastoma and analysed their usefulness in the prediction of disease outcome. The analyses showed a strong correlation of PROM1, ATOH1 and OTX1 gene expression levels with the outcome (p <= 0.2). On the basis of the multivariate Cox regression analysis, we propose a three-gene model predicting risk of the disease, calculated as follows: RS(risk score) =( 0:81 x PROM1) + (0:18 x OTX1) + (0:02 x ATOH1). Survival analysis revealed a better outcome among standard-risk patients, with a 5-year survival rate of 65 %, compared to the 40 % rate observed among high-risk patients. The most promising advantage of such molecular analysis consists in the identification of molecular markers influencing clinical behaviour, which may in turn be useful in therapy optimization. PMID- 23649506 TI - ATF4 promotes bone angiogenesis by increasing VEGF expression and release in the bone environment. AB - Activating transcription factor 4 (ATF4) is a critical transcription factor for bone remodeling; however, its role in bone angiogenesis has not been established. Here we show that ablation of the Atf4 gene expression in mice severely impaired skeletal vasculature and reduced microvascular density of the bone associated with dramatically decreased expression of hypoxia-inducible factor 1alpha (HIF 1alpha) and vascular endothelial growth factor (VEGF) in osteoblasts located on bone surfaces. Results from in vivo studies revealed that hypoxia/reoxygenation induction of HIF-1alpha and VEGF expression leading to bone angiogenesis, a key adaptive response to hypoxic conditions, was severely compromised in mice lacking the Atf4 gene. Loss of ATF4 completely prevented endothelial sprouting from embryonic metatarsals, which was restored by addition of recombinant human VEGF protein. In vitro studies revealed that ATF4 promotion of HIF-1alpha and VEGF expression in osteoblasts was highly dependent upon the presence of hypoxia. ATF4 interacted with HIF-1alpha in hypoxic osteoblasts, and loss of ATF4 increased HIF 1alpha ubiquitination and reduced its protein stability without affecting HIF 1alpha mRNA stability and protein translation. Loss of ATF4 increased the binding of HIF-1alpha to prolyl hydroxylases, the enzymes that hydroxylate HIF-1a protein and promote its proteasomal degradation via the pVHL pathway. Furthermore, parathyroid hormone-related protein (PTHrP) and receptor activator of NF-kappaB ligand (RANKL), both well-known activators of osteoclasts, increased release of VEGF from the bone matrix and promoted angiogenesis through the protein kinase C- and ATF4-dependent activation of osteoclast differentiation and bone resorption. Thus, ATF4 is a new key regulator of the HIF/VEGF axis in osteoblasts in response to hypoxia and of VEGF release from bone matrix, two critical steps for bone angiogenesis. PMID- 23649508 TI - Treatment of obstructive sleep apnea hypopnea syndrome caused by glossoptosis with tongue-base suspension. AB - The objective of the study was to evaluate a surgical method to treat patients with obstructive sleep apnea hypopnea syndrome (OSAHS) caused by suspected glossoptosis. Seventy-eight patients with OSAHS caused by suspected glossoptosis were non-randomly divided into two groups. The 45 patients in the first group received uvulopalatopharyngoplasty (UPPP) and tongue-base suspension (Repose). The 33 patients in the second group received UPPP alone. Follow-up was conducted over 6 months, and polysomnography was used to determine the effects of treatment. Follow-up results revealed that the apnea-hypopnea index (AHI) and ESS scores of the patients from both groups were substantially decreased compared to the corresponding values before surgery. The lowest oxygen saturation (LaSo2) of both groups was improved, compared to the level before surgery. The degree of improvement in patients treated with UPPP + Repose was significantly greater than that seen in patients treated with UPPP alone. In the UPPP + Repose group, 17 patients were cured, 23 showed marked improvement, and 5 did not improve. In the UPPP alone group, 1 patient was cured, 16 showed marked improvement, and 16 did not improve. The marked improvement rates of the two groups were 88.9 and 51.5 %, respectively, a significant difference. Patients who show glossopharyngeal obstruction during sleep, and have normal glossopharyngeal airway morphology when awake, should be suspected to have glossoptosis. Repose surgery is an effective operation for the patients with OSAHS suspected glossoptosis. PMID- 23649509 TI - Efficacy of OK-432 sclerotherapy in treatment of lymphatic malformations: long term follow-up results. AB - Lymphatic malformations (LMs) are rare congenital tumors of the lymphatic system often affecting the head and neck area. Because of cosmetic and functional symptoms most patients need to be treated. Traditionally surgical treatment has been considered to be the first-line treatment for LM. However, it is challenging because of the need for complete excision. The risk of poor cosmetic result and damage to surrounding structures is high. Since Ogita presented OK-432 as a treatment for LM in 1987, it has been widely used as the primary treatment. Many papers have been published on this topic but with relatively short follow-up times. We present a material of 36 LMs treated with OK-432 during the period of 1999-2009 and with an average follow-up time of 6 years. Immediate post-treatment results were compared with the late follow-up findings. Primary and late response to therapy was evaluated with an MRI scan by measuring the change in lesion size. At the follow-up visit, all patients were clinically examined and they answered a symptom questionnaire. Later 26/36 patients were also available for a quality of life questionnaire. Primarily 67% demonstrated a complete or marked response. At the follow-up 64% showed a complete or marked response, in 11% the final response was better than the initially observed and only 2 patients had relapsed. The initial response predicted the long-term outcome accurately and the effect of OK 432 sclerotherapy seems to be long lasting. According to the MRI evaluation 80% and subjectively 94% of the patients benefitted from the treatment. Quality of life questionnaire showed high post-treatment satisfaction. We found OK-432 sclerotherapy to be a safe and effective treatment with a long lasting effect in the management of macrocystic LMs. PMID- 23649511 TI - Anatomical relationship and positions of the lumbar and sacral segments of the spinal cord according to the vertebral bodies and the spinal roots. AB - Segments of the spinal cord generally do not correspond to the respective vertebral level and there are many anatomical variations in terms of the segment and the level of vertebra. The aim of this study is to investigate the variations and levels of lumbar and sacral spinal cord segments with reference to the axilla of the T11, T12, and L1 spinal nerve roots and adjacent vertebrae. Morphometric measurements were made on 16 formalin fixed adult cadaveric spinal cords. We observed termination of the spinal cord between the axilla of the L1 and L2 spinal nerve roots in 15 specimens (93.8%). In all cadavers the emergence of the T11, T12, and the L1 spinal nerve roots was at the level of the lower one-third of the same vertebral body. In 15 specimens (93.8%), the beginning of the lumbar spinal cord segment was found to be above the T11 spinal nerve root axilla and corresponded to the upper one-third of the T11 vertebral body. The beginning of the sacral spinal cord segment occurred above the L1 spinal nerve root axilla and corresponded to the upper one-third of the L1 vertebral body. The results of this study showed that when the conus medullaris is located at the L1-L2 level, the beginning of the lumbar spinal cord segment always corresponds to the body of T11 vertebra. This study provides detailed information about the correspondence of the spinal cord segments with reference to the axilla of the spinal nerve roots. PMID- 23649510 TI - Inner ear damage following electric current and lightning injury: a literature review. AB - Audiovestibular sequelae of electrical injury, due to lightning or electric current, are probably much more common than indicated in literature. The aim of the study was to review the impact of electrical injury on the cochleovestibular system. Studies were identified through Medline, Embase, CINAHL and eMedicine databases. Medical Subject Headings used were 'electrical injury', 'lightning', 'deafness' and 'vertigo'. All prospective and retrospective studies, case series and case reports of patients with cochlear or vestibular damage due to lightning or electrical current injury were included. Studies limited to external and middle ear injuries were excluded. Thirty-five articles met the inclusion criteria. Fifteen reported audiovestibular damage following electric current injury (domestic or industrial); a further 15 reported lightning injuries and five concerned pathophysiology and management. There were no histological studies of electrical current injury to the human audiovestibular system. The commonest acoustic insult after lightning injury is conductive hearing loss secondary to tympanic membrane rupture and the most frequent vestibular symptom is transient vertigo. Electrical current injuries predominantly cause pure sensorineural hearing loss and may significantly increase a patient's lifetime risk of vertigo. Theories for cochleovestibular damage in electrical injury include disruption of inner ear anatomy, electrical conductance, hypoxia, vascular effects and stress response hypothesis. The pathophysiology of cochleovestibular damage following electrical injury is unresolved. The mechanism of injury following lightning strike is likely to be quite different from that following domestic or industrial electrical injury. The formulation of an audiovestibular management protocol for patients who have suffered electrical injuries and systematic reporting of all such events is recommended. PMID- 23649512 TI - Biometry of the fetal corpus callosum by three-dimensional ultrasound. AB - OBJECTIVES: To construct reference ranges of quantitative characteristics of the fetal corpus callosum. METHODS: Women referred to a tertiary center for sonographic examination were recruited to undergo a detailed fetal scan from 17 to 41 weeks of gestation. Three-dimensional (3D) sonographic volumes of normal fetal brains were acquired and analyzed offline. We obtained three different measurements of the corpus callosal length, as well as the height (/thickness) of its segments, namely the rostrum, genu, body and splenium. RESULTS: Initially we recruited 604 pregnant women, of whom 138 were excluded because of various disorders/abnormalities, multiple pregnancy or gestational age < 18 weeks. Thus, included in the analysis were 466 sonographic volumes of normal fetal brains from singleton pregnancies, acquired by transabdominal ( n = 170) or transvaginal (n = 296) ultrasound. The corpus callosum was visualized as a hypoechoic structure. Reference ranges were established for the following parameters: curved corpus callosal length, inner-inner corpus callosal length, outer-outer corpus callosal length, rostrum height, genu height, body height and splenium height. We observed non-linear growth and an approximately four-fold increase in all corpus callosal lengths, a three-fold increase in rostrum height, a four-fold increase in genu height, a two-fold increase in body height and a three-fold increase in splenium height between 18 and 41 weeks. The growth patterns of rostrum and body height appeared to be similar: there was rapid development until 24 and 22 weeks of gestation, respectively, and growth slowed beyond this period. The growth patterns of genu and splenium were also similar, being characterized by progressive growth throughout gestation. CONCLUSIONS: Using 3D ultrasound, we have constructed reference charts for measurements of the corpus callosum. Knowledge of the normal growth pattern may be useful for evaluation of abnormal development of the corpus callosum, and so help in the accurate diagnosis of pathologies such as hypogenesis and dysgenesis. PMID- 23649507 TI - A perspective of comparative salivary and breast pathology. Part I: microstructural aspects, adaptations and cellular events. AB - This is the first part of a review comparing the pathology of salivary and mammary glands. Here, less obvious similarities and differences in functional histology and their influences on pathology are examined with emphasis on myoepithelial cells, stromal components, analogues of mucosa-associated lymphoid tissue, steroid receptors, and intraparenchymal cells of monocytic lineage. Particular cell phenotypes (oncocytic, apocrine, neuroendocrine and clear) are critically evaluated and responses to atrophy, infarction and fine-needle aspiration biopsy procedures are highlighted together with aspects of metaplasia, regeneration, ageing and microcalcification. Areas of controversy or uncertainty which may benefit from further investigations are also discussed. PMID- 23649513 TI - Host modulation in rheumatoid arthritis patients with TNF blockers significantly decreases biochemical parameters in periodontitis. AB - The aim of this study was to evaluate the effects of host modulation therapy on periodontal and biochemical parameters. Sixteen rheumatoid arthritis patients newly scheduled for anti-tumour necrosis factor (TNF) therapy were screened for 30 days. Periodontal parameters (clinical attachment level, probing pocket depth, bleeding on probing, plaque index and gingival index) as well as salivary and gingival crevicular fluid (GCF), interleukin (IL)-1beta, IL-8 and monocyte chemoattractant protein-1 (MCP-1) levels of the patients were evaluated at baseline and on the 30th day of therapy. GCF volume, IL-1beta and IL-8 levels (p = 0.007, p = 0.017 and p = 0.009, respectively) of the periodontitis patients significantly decreased. Although there was a decrease in all these parameters in healthy patients, it was below statistical significance. Salivary IL-8 and MCP-1 levels significantly decreased in periodontitis patients (p = 0.028 and p = 0.013, respectively), but IL-1beta levels remained unchanged. These results suggest that TNF blockers may significantly modify host response in terms of biochemical parameters of the periodontium and may mask significant associations such as those reported between periodontitis and rheumatoid arthritis. PMID- 23649514 TI - Biliary ascariasis causing gallbladder stump cholecystitis. PMID- 23649515 TI - Esophageal duplication cyst. PMID- 23649516 TI - Direct interaction between cholera toxin and dendritic cells is required for oral adjuvant activity. AB - Cholera toxin (CT) binds to GM1-ganglioside receptors present on all nucleated cells. Despite this, it is a very potent mucosal adjuvant that has a dramatic impact on immune cells, as well as nerve and epithelial cells, causing diarrhea. This fact has hampered our understanding of whether the adjuvanticity of CT is direct or indirect, as cells that bind CT may or may not be involved in its adjuvant function. The mucosal barrier is maintained by tight junctions between epithelial cells but dendritic cells (DCs) can protrude luminal dendrites. Here we investigated which cells are involved in the immune augmenting effect of CT. We explored oral immunizations with ovalbumin (OVA) and CT in bone marrow chimeric mice deficient in GM1-ganglioside in defined cellular subsets. We found that chimeric mice lacking GM1 in nonhematopoietic cells, including epithelial cells, mounted an unaltered intestinal IgA response. In contrast, chimeric mice lacking GM1-expressing hematopoietic cells in general, or specifically GM1 expressing conventional DCs (cDCs), largely failed to elicit anti-OVA adaptive immune responses. Therefore, the adjuvanticity of CT does not require epithelial activation, but is directly dependent on the binding of CT to gut cDCs via GM1 ganglioside. These results could have important implications for the generation of novel oral adjuvants. PMID- 23649517 TI - Synthesis and biological evaluation of novel bromophenol derivatives as carbonic anhydrase inhibitors. AB - Here, we provide an alternative synthesis of the natural bromophenol 3,4-dibromo 5-(2,3-dibromo-4,5-dihydroxybenzyl)-6-(ethoxymethyl)benzene-1,2-diol (3) and the first synthesis of (4,5-dihydroxy-2-methylphenyl)(3,4-dihydroxyphenyl)methanone (18) and its brominated derivatives 19-21. The compounds were characterized and tested against the two most studied members of the pH regulatory enzyme family, carbonic anhydrase (CA). The inhibitory potencies of the novel compounds and two natural bromophenols 2, 3 were analyzed at the human isoforms hCA I and hCA II as targets and the KI values were calculated. The KI values of the novel compounds were measured in the range of 13.7-32.7 mM for the hCA I isozyme and 0.65-1.26 mM for the hCA II isozyme. The structurally related compound 14 was also tested in order to understand the structure-activity relationship, and the clinically used sulfonamide acetazolamide (AZA)was tested for comparison reasons. All of the compounds exhibited competitive inhibition with 4-nitrophenylacetate as substrate. The compounds showed strong inhibitory activity against hCA I, being more effective as compared to the clinically used AZA (KI: 36.2 mM), but rather less activity against hCA II. PMID- 23649518 TI - Transforming growth factor-beta-induced cross talk between p53 and a microRNA in the pathogenesis of diabetic nephropathy. AB - Elevated p53 expression is associated with several kidney diseases including diabetic nephropathy (DN). However, the mechanisms are unclear. We report that expression levels of transforming growth factor-beta1 (TGF-beta), p53, and microRNA-192 (miR-192) are increased in the renal cortex of diabetic mice, and this is associated with enhanced glomerular expansion and fibrosis relative to nondiabetic mice. Targeting miR-192 with locked nucleic acid-modified inhibitors in vivo decreases expression of p53 in the renal cortex of control and streptozotocin-injected diabetic mice. Furthermore, mice with genetic deletion of miR-192 in vivo display attenuated renal cortical TGF-beta and p53 expression when made diabetic, and have reduced renal fibrosis, hypertrophy, proteinuria, and albuminuria relative to diabetic wild-type mice. In vitro promoter regulation studies show that TGF-beta induces reciprocal activation of miR-192 and p53, via the miR-192 target Zeb2, leading to augmentation of downstream events related to DN. Inverse correlation between miR-192 and Zeb2 was observed in glomeruli of human subjects with early DN, consistent with the mechanism seen in mice. Our results demonstrate for the first time a TGF-beta-induced feedback amplification circuit between p53 and miR-192 related to the pathogenesis of DN, and that miR 192-knockout mice are protected from key features of DN. PMID- 23649522 TI - Perception of individuality in bat vocal communication: discrimination between, or recognition of, interaction partners? AB - Different cognitive processes underlying voice identity perception in humans may have precursors in mammals. A perception of vocal signatures may govern individualised interactions in bats, which comprise species living in complex social structures and are nocturnal, fast-moving mammals. This paper investigates to what extent bats recognise, and discriminate between, individual voices and discusses acoustic features relevant for accomplishing these tasks. In spontaneous presentation and habituation-dishabituation experiments, we investigated how Megaderma lyra perceives and evaluates stimuli consisting of contact call series with individual-specific signatures from either social partners or unknown individuals. Spontaneous presentations of contact call stimuli from social partners or unknown individuals elicited strong, but comparable reactions. In the habituation-dishabituation experiments, bats dishabituated significantly to any new stimulus. However, reactions were less pronounced to a novel stimulus from the bat used for habituation than to stimuli from other bats, irrespective of familiarity, which provides evidence for identity discrimination. A model separately assessing the dissimilarity of stimuli in syllable frequencies, syllable durations and inter-call intervals relative to learned memory templates accounted for the behaviour of the bats. With respect to identity recognition, the spontaneous presentation experiments were not conclusive. However, the habituation-dishabituation experiments suggested that the bats recognised voices of social partners as the reaction to a re-habituation stimulus differed after a dishabituation stimulus from a social partner and an unknown bat. PMID- 23649520 TI - Exaggerated glucagon-like peptide 1 response is important for improved beta-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes. AB - beta-Cell function improves in patients with type 2 diabetes in response to an oral glucose stimulus after Roux-en-Y gastric bypass (RYGB) surgery. This has been linked to the exaggerated secretion of glucagon-like peptide 1 (GLP-1), but causality has not been established. The aim of this study was to investigate the role of GLP-1 in improving beta-cell function and glucose tolerance and regulating glucagon release after RYGB using exendin(9-39) (Ex-9), a GLP-1 receptor (GLP-1R)-specific antagonist. Nine patients with type 2 diabetes were examined before and 1 week and 3 months after surgery. Each visit consisted of two experimental days, allowing a meal test with randomized infusion of saline or Ex-9. After RYGB, glucose tolerance improved, beta-cell glucose sensitivity (beta GS) doubled, the GLP-1 response greatly increased, and glucagon secretion was augmented. GLP-1R blockade did not affect beta-cell function or meal-induced glucagon release before the operation but did impair glucose tolerance. After RYGB, beta-GS decreased to preoperative levels, glucagon secretion increased, and glucose tolerance was impaired by Ex-9 infusion. Thus, the exaggerated effect of GLP-1 after RYGB is of major importance for the improvement in beta-cell function, control of glucagon release, and glucose tolerance in patients with type 2 diabetes. PMID- 23649519 TI - Tetrahydrobiopterin has a glucose-lowering effect by suppressing hepatic gluconeogenesis in an endothelial nitric oxide synthase-dependent manner in diabetic mice. AB - Endothelial nitric oxide synthase (eNOS) dysfunction induces insulin resistance and glucose intolerance. Tetrahydrobiopterin (BH4) is an essential cofactor of eNOS that regulates eNOS activity. In the diabetic state, BH4 is oxidized to 7,8 dihydrobiopterin, which leads to eNOS dysfunction owing to eNOS uncoupling. The current study investigates the effects of BH4 on glucose metabolism and insulin sensitivity in diabetic mice. Single administration of BH4 lowered fasting blood glucose levels in wild-type mice with streptozotocin (STZ)-induced diabetes and alleviated eNOS dysfunction by increasing eNOS dimerization in the liver of these mice. Liver has a critical role in glucose-lowering effects of BH4 through suppression of hepatic gluconeogenesis. BH4 activated AMP kinase (AMPK), and the suppressing effect of BH4 on gluconeogenesis was AMPK-dependent. In addition, the glucose-lowering effect and activation of AMPK by BH4 did not appear in mice with STZ-induced diabetes lacking eNOS. Consecutive administration of BH4 in ob/ob mice ameliorated glucose intolerance and insulin resistance. Taken together, BH4 suppresses hepatic gluconeogenesis in an eNOS-dependent manner, and BH4 has a glucose-lowering effect as well as an insulin-sensitizing effect in diabetic mice. BH4 has potential in the treatment of type 2 diabetes. PMID- 23649523 TI - Incorporation of soybean by-product okara and inulin in a probiotic soy yoghurt: texture profile and sensory acceptance. AB - BACKGROUND: This study evaluated the effect of inulin and okara flour on textural and sensory properties of probiotic soy yoghurt (SY) throughout 28 days of storage at 4 degrees C. Employing a 2(2) design, four formulations of SY produced from soymilk and fermented with an ABT-4 culture (Lactobacillus acidophilus La-5, Bifidobacterium animalis Bb-12 and Streptococcus thermophilus) were studied: SY-C (control); SY-I (with inulin); SY-O (with okara); SY-IO (with inulin + okara). RESULTS: The addition of okara and the refrigerated storage led to significant differences in the instrumental texture parameters of SY (P < 0.05). Inulin and okara did not affect SY sensory acceptability (P > 0.05), but there was a tendency for higher scores in the presence of inulin. On the other hand, the storage period, particularly at 21 days, was unfavourable regarding the acceptance of the different SY. CONCLUSION: The results showed that the addition of okara flour and the storage were significant factors to increase firmness of the soy yoghurts. SY acceptability was not affected by the incorporation of inulin or okara. These results suggest that okara, discarded as industrial waste, may be used in probiotic soy yoghurt, helping to increase the nutritional and functional properties without altering its acceptability. PMID- 23649524 TI - Physician specialty society clinical guidelines and bending the cost curve: comment on "Cost consideration in the clinical guidance documents of physician specialty societies in the United States". PMID- 23649526 TI - [Local flaps for the closure of facial defects]. AB - Local flaps for the closure of facial defects after trauma, tumor resection or due to malformations have been well known since ancient times and allow good to satisfying functional and aesthetic results. Based on the characteristics of skin and soft tissue nearly all clinical situations can be resolved by stretching, rotating and transposing flaps depending on the localization. A good surgical technique is essential for the success. The basic principles are briefly described and suggestions for the application of flaps to different localizations are given. For analgesia local anesthesia is sufficient. As could be demonstrated multitudinously the method is ideal for closure of small to large defects in the face; therefore, microvascular surgery can be extremely restricted in treating defects of the face. PMID- 23649525 TI - [Cochlear implants in children and adolescents]. AB - Cochlear implants (CI) have become standard in the treatment of prelingual, postlingual and perilingual deafness and hearing loss in children. Bilateral implants are considered standard for bilaterally affected children. The benefits for speech and language development, as well as speech intelligibility brought by CI-enabled hearing are greatest if these are received as soon after diagnosis as possible. Continued improvements in preoperative diagnostics, electrode design, speech coding strategies and surgical techniques, have broadened the CI applications spectrum. Nowadays--with the exception of cochlear- and cochlear nerve aplasia--almost all malformations are manageable with CIs. New indications concern partial and unilateral deafness. Treatment with CIs requires exceptional team work. In addition to ongoing medical care of the children, the involvement of parents and relatives in the cooperation between surgeons, audiologists, teachers and specialist centers is important for successful rehabilitation. PMID- 23649527 TI - Extended lymphadenectomy in gastric cancer is debatable. AB - Much debate still exists regarding the appropriate extent of lymphadenectomy for gastric adenocarcinoma. In high incidence countries in Eastern Asia, more extensive (e.g. D2) lymphadenectomies are standard, and these surgeries are generally done by experienced surgeons with low morbidity (<20 %) and mortality (<1 %). In United States and Western Europe, where the incidence of gastric adenocarcinoma is much lower, the majority of patients are treated at non referral centers with less extensive (e.g. D1 or D0) lymphadenectomy. This symposium article first reviews early studies that led to recommendations for less extensive lymphadenectomy. Two large prospective, randomized trials performed in the United Kingdom and the Netherlands in the 1990s failed to demonstrate a survival benefit of D2 over D1 lymphadenectomy, but these trials have been criticized for inadequate surgical training and high surgical morbidity (43-46 %) and high mortality rates (10-13 %) in the D2 group. We then discuss more contemporary studies that support more extensive lymphadenectomy with a minimum of 16 lymph nodes for adequate staging. The 15-year follow-up of the Netherlands trial now demonstrates an improved disease-specific survival and locoregional recurrence in the D2 group. A prospective, randomized trial from Taiwan found a survival benefit of more extensive lymphadenectomies, and another randomized trial from Japan found adding dissection of para-aortic nodes to a D2 lymphadenectomy did not improve survival. Western surgeons have increasingly accepted the importance of performing more than a D1 node dissection, and Eastern surgeons are accepting that more than a D2 node dissection does not improve survival and increases morbidity. Thus both Eastern and Western approaches are favoring D2 lymphadenectomy as a standard, and on this topic we appear to be harmonizing. PMID- 23649528 TI - Undergraduate surgery clerkship and the choice of surgery as a career: perspective from a developing country. AB - BACKGROUND: There are concerns regarding a possible decline in the proportion of students choosing surgery as a career in some countries in sub-Saharan Africa. Published works indicate that most students choose their ultimate career during undergraduate training. The present study was undertaken to assess the medical student's perception of the surgery clerkship and determine its influence in the choice of surgery as a career. METHODS: The study involved a cross-sectional survey of 2009 and 2010 graduating medical classes of the University of Nigeria based on self-administered questionnaires. The clerkship evaluation was assessed on a 3-point Likert scale (1 = poor; 3 = excellent). RESULTS: The response rate was 70.3 % (275/391); 179 (65.1 %) of the students were males and 96 (34.9 %), females. Sixty-one (22.2 %) rated the overall quality of their surgery clerkship as excellent (mean rating = 2). Compared with the other three major clerkships, surgery has the lowest rating for overall quality (mean rating: surgery = 2; others = 2.2). Aspects of the clerkship experience that contributed to the overall lower rating of surgery include quality of opportunity to participate in direct patient care; clarity of posting goals and objectives; experience in learning history taking skills, basic physical examination skills, and interpretation of laboratory data; accessibility of faculty; and students' perception that they were treated in a respectful manner. The major suggestions to improve clerkship quality were these: (1) more involvement in direct patient care (n = 154; 56 %), and (2) improvement in student-faculty interaction (n = 9 1; 33.1 %). Overall, 96 (34.9 %) students selected surgery as a specialty, and 39.3 % (108/275) selected the other three major specialties. Surgery was selected by 17/48 (35.4 %), 59/166 (35.5 %), and 20/61 (32.8 %) students who rated the surgery clerkship as "poor," "just right," and "excellent," respectively (p = 0.876). Factors indicated as major influences in the choice of surgical specialty included personal satisfaction 41.7 % (40/96), clerkship experience 36.4 % (35/96), and diligence of faculty 13.5 % (13/96). CONCLUSIONS: Periodic assessment of the satisfaction of medical students regarding their surgical clerkship experience is important. In our setting, we have identified aspects of the surgical clerkship that could be improved to enhance the quality of the experience, ensure the attractiveness of the field to the most qualified candidates, and boost interest in surgery as a career. PMID- 23649529 TI - Induction chemotherapy or chemoradiotherapy followed by radical esophagectomy for T4 esophageal cancer: results of a prospective cohort study. AB - BACKGROUND: We hypothesized that the survival rate of patients undergoing R0 esophagectomy after induction chemotherapy or chemoradiotherapy for unresectable T4 esophageal cancer (URT4) would be similar to that of patients undergoing esophagectomy for immediately resectable esophageal cancer with no unfavorable prognostic factors (RNU). METHODS: Between April 2002 and June 2012, 87 of 283 patients with esophageal cancer who presented at the University Hospital of the Ryukyus were enrolled in this prospective cohort study. Tumors were classified as RNU and URT4 in 44 and 43 of the 87 patients, respectively. Outcomes of treatment for URT4 patients were compared with those of RNU patients. RESULTS: The R0 resection rate (61 %) and in-hospital mortality rate (20 %) of URT4 patients were significantly poorer than those of RNU patients (98 and 2.3 %, respectively), although the morbidity rate was similar in the two groups (63 and 52 %, respectively). The 5-year survival rate (35 %) of URT4 patients was significantly poorer than that of RNU patients (67 %) in the intention-to-treat analysis. However, no significant difference was noted between the two survival curves for cases of R0 resection (5-year survival rate, 60 % vs. 69 %). Multivariate analysis revealed R status as the only significant independent prognostic factor for URT4 patients (P < 0.001; hazard ratio = 8.279). CONCLUSIONS: Satisfactory survival rates can be achieved if R0 resection is performed after induction treatment in patients with T4 esophageal cancer, although secondary radical esophagectomy is associated with a higher risk of in-hospital mortality. PMID- 23649530 TI - Evaluation of office ultrasound usage among Australian and New Zealand breast surgeons. AB - BACKGROUND: Surgeon performed ultrasound (US) is being increasingly embraced by breast surgeons worldwide as an integral part of patient assessment. The extent of its application within Australia and New Zealand is not well documented. The present study aimed to evaluate its current usage patterns and to determine suitable future training models. METHODS: An online survey was sent to members of Breast Surgeons of Australia and New Zealand (BreastSurgANZ) between July and September 2010, with emphases on practice demographics, access to US equipment, usage, biopsy patterns, and training. RESULTS: Of the 126 surveys sent, 59 were returned. The majority of respondents were metropolitan based (64 %), worked in both public and private sectors (71 %), and practiced endocrine or general surgery (85 %), as well as breast surgery. A preponderance of surgeons had access to equipment (63 %), performed at least 1 US monthly (63 %), but did not perform regular guided biopsies. Rural practice did not affect access or usage patterns. Most respondents underwent structured US training (73 %), which was associated with greater US and biopsy usage, biopsy complexity, intraoperative applications, and cross discipline applications (p < 0.03). Most surgeons favored a structured training program for future trainees (83 %). CONCLUSIONS: The majority of breast surgeons from Australia and New Zealand have adopted office US to varying degrees. Geographic variation did not lead to access inequity and variation in scanning patterns. Formal US training may result in a wider scope of clinical applications by increasing operator confidence and is the preferred model within a specialist breast surgical curriculum. PMID- 23649531 TI - Prescribing of sick leave by surgeons: a survey based on hypothetical patient cases. AB - BACKGROUND: Physicians regard the tasks of sick-listing and work ability assessments problematic and among the most challenging duties in their practice. Few studies have analyzed sick leave prescribing practices, and the practices have been shown to vary among physicians. The aim of this study was to examine the prescribing of sick leave by surgeons and factors that affect these prescribing practices. METHODS: A questionnaire study with 19 hypothetical patient cases was conducted among 338 Finnish surgeons. The effects of both physician-related and local structural background variables on sick leave prescribing were studied using univariate and multiple linear regression models. The economic consequences of the variation in sick leave prescribing were estimated. RESULTS: The overall number of days of sick leave prescribed for the entire group of 19 patient cases averaged 281.4 days (range = 134-490 days). With the same diagnosis, surgeons prescribed more days of sick leave for patients who do physical work than for those who work in an office. Older surgeons with more working experience and those working in smaller municipalities or in smaller hospitals prescribed longer sick leave than others. Clinical specialists tended to prescribe longer sick leave than those still in specialty training. CONCLUSION: Structured education for surgeons on prescribing sick leave, together with defined guidelines, could produce more uniform practices and improve equality among patients. PMID- 23649532 TI - Thyroid surgery in a district hospital: a vertical program embedded in a rural hospital. PMID- 23649534 TI - Isoprenoid biosynthesis: ferraoxetane or allyl anion mechanism for IspH catalysis? PMID- 23649535 TI - In vivo detection of lipid-rich plaque by using a 40-MHz intravascular ultrasound: a comparison with optical coherence tomography findings. AB - iMAPTM has recently been introduced as a new tissue characterization method using the 40-MHz intravascular ultrasound (IVUS). However, few data have been published on the comparative findings of other imaging modalities in vivo. We examined 108 matched lesions from 70 patients (35 with stable angina and 35 with acute coronary syndrome) that underwent percutaneous coronary intervention (PCI) using pre-PCI OCT and IVUS. Identification of OCT-derived lipid-rich plaques and thin cap fibroatheroma (TCFA) was performed using iMAPTM. OCT-derived lipid-rich plaques and TCFAs were detected in 56 (51.8 %) and 20 (18.6 %) lesions, respectively. The iMAPTM analysis identified significantly greater percentage of necrotic area (%NA) in the lesions with lipid-rich plaques than in those without [46.5 (29.4-56.9) vs. 24.6 (10.3-41.6) %, p < 0.01]. In the receiver operating characteristic (ROC) analysis, the optimal %NA cut-off value for identifying lipid-rich plaques was 33 % (AUC: 0.75; sensitivity: 73.2 %; specificity: 67.3 %). A greater plaque burden and a larger necrotic area were detected using iMAPTM in the OCT-derived TCFAs than in the non-TCFAs [81.5 (77.3-86.8) vs. 72.7 (60.6 81.0) %, p < 0.01; 7.6 (4.3-9.6) mm(2) vs. 2.7 (1.0-6.0) mm(2), p < 0.01]. For the iMAPTM-derived TCFAs, combinations of variables such as necrotic area, % plaque burden, and absolute plaque area showed a relatively low positive predictive value and high negative predictive value (plaque burden >75 % and confluent luminal necrotic area >4.0 mm(2); sensitivity: 75.0 %; specificity: 71.6 %; PPV: 37.5 %; NPV: 92.6 %; and diagnostic accuracy: 72.2 %). The results showed that iMAPTM tissue characterization may help to detect lipid-rich plaque and rule out TCFAs in vivo. PMID- 23649536 TI - Estrogen receptor alpha: molecular mechanisms and emerging insights. AB - Estrogen receptor alpha (ERalpha) is a cellular receptor for the female sex hormone estrogen and other natural and synthetic ligands and play critical roles in normal development and physiology and in the etiology and treatment of endocrine-related diseases. ERalpha is a member of the nuclear receptor superfamily of transcription factors and regulates target gene expression in a ligand-dependent manner. It has also been shown to interact with G-protein coupled receptors and associated signaling molecules in the cytoplasm. Transcriptionally, ERalpha either binds DNA directly through conserved estrogen response element sequence motifs or indirectly by tethering to other interacting transcription factors and nucleate transcriptional regulatory complexes which include an array of co-regulator proteins. Genome-scale studies of ERalpha transcriptional activity and localization have revealed mechanistic complexity and insights including novel interactions with several transcription factors, including FOXA1, AP-2g, GATA3, and RUNX1, which function as pioneering, collaborative, or tethering factors. The major challenge and exciting prospect moving forward is the comprehensive definition and integration of ERalpha complexes and mechanisms and their tissue-specific roles in normal physiology and in human diseases. PMID- 23649537 TI - PSA screening and deaths from prostate cancer after diagnosis--a population based analysis. AB - BACKGROUND: The United States Preventative Health Task Force recently recommended prostate specific antigen (PSA) screening be abandoned, believing the results of prior studies failed to show benefits that outweighed risks. Prior analyses did not include a complete 10 year follow-up in their analyses. METHODS: SEER rate sessions were used to obtain for U.S. White and Black men age-adjusted incidence rates for prostate cancer, in total and by loco-regional and distant (D2) spread for 1983-2009, as well as for prostate cancer diagnoses with associated prostate cancer deaths within 10 years of diagnosis (incidence based mortality rates) for 1983-1999. The SEER-Stat Program was used to tabulate rate estimates and calculate standard errors. The Joinpoint Regression Program was used to provide estimates and 95% confidence intervals (CI) of annual percent changes (APC) and times at which APC changed (joinpoints), as well as to test for parallelism to see if APC's differed between groups of rates. RESULTS: All analyses showed a 1991-1993 joinpoint, consistent with an impact of PSA screening. Between 1991 and 1999, incidence based mortality rates showed a decline for Whites of 10.9% (CI 9.2%-12.7%) and for Blacks of 11.6% (CI 9.7%-13.4%); incidence based mortality and D2 spread rate curves were similar (P > 0.05, test for parallelism). CONCLUSION: Incidence based mortality declined by about 10% per year between 1991 and 1999 in a fashion similar to that of D2 spread, but not loco-regional spread or overall, incidence. PMID- 23649538 TI - Interlaboratory evaluation of in vitro cytotoxicity and inflammatory responses to engineered nanomaterials: the NIEHS Nano GO Consortium. AB - BACKGROUND: Differences in interlaboratory research protocols contribute to the conflicting data in the literature regarding engineered nanomaterial (ENM) bioactivity. OBJECTIVES: Grantees of a National Institute of Health Sciences (NIEHS)-funded consortium program performed two phases of in vitro testing with selected ENMs in an effort to identify and minimize sources of variability. METHODS: Consortium program participants (CPPs) conducted ENM bioactivity evaluations on zinc oxide (ZnO), three forms of titanium dioxide (TiO2), and three forms of multiwalled carbon nanotubes (MWCNTs). In addition, CPPs performed bioassays using three mammalian cell lines (BEAS-2B, RLE-6TN, and THP-1) selected in order to cover two different species (rat and human), two different lung epithelial cells (alveolar type II and bronchial epithelial cells), and two different cell types (epithelial cells and macrophages). CPPs also measured cytotoxicity in all cell types while measuring inflammasome activation [interleukin-1beta (IL-1beta) release] using only THP-1 cells. RESULTS: The overall in vitro toxicity profiles of ENM were as follows: ZnO was cytotoxic to all cell types at >= 50 MUg/mL, but did not induce IL-1beta. TiO2 was not cytotoxic except for the nanobelt form, which was cytotoxic and induced significant IL-1beta production in THP-1 cells. MWCNTs did not produce cytotoxicity, but stimulated lower levels of IL-1beta production in THP-1 cells, with the original MWCNT producing the most IL-1beta. CONCLUSIONS: The results provide justification for the inclusion of mechanism-linked bioactivity assays along with traditional cytotoxicity assays for in vitro screening. In addition, the results suggest that conducting studies with multiple relevant cell types to avoid false-negative outcomes is critical for accurate evaluation of ENM bioactivity. PMID- 23649540 TI - Prospective study of substance-induced and independent major depressive disorder among individuals with substance use disorders in a nationally representative sample. AB - BACKGROUND: Depression and substance use disorders (SUDs) commonly co-occur, which presents diagnostic challenges in classifying independent major depressive disorder (MDD) versus substance-induced depressive disorder (SIDD). It remains unclear if distinct characteristics and/or patterns in temporal course distinguish MDD-SUD and SIDD to guide these decisions. Further, evidence suggests that a significant portion of individuals with SIDD are later reclassified as having independent MDD. Continued research to improve our understanding of differences between these two and changes in reclassification over time is necessary for diagnostic clarification and to guide clinical decisions when treating depression in the context of SUDs. METHODS: The current study compared individuals with MDD-SUD versus SIDD at baseline and examined reclassification of DSM-IV Axis I diagnoses over a 3-year follow up in a large, nationally representative epidemiological sample (n = 2,121). RESULTS: Findings demonstrated that SIDD was extremely rare at both time points. At baseline, individuals with SIDD were more likely to be non-White, have less education, less likely to have insurance, less likely to have dysthymia or alcohol abuse, and more likely to have drug dependence compared to those with independent MDD. Of individuals with SIDD at Wave 1 who had a depressive episode between Waves 1 and 2, the overwhelming majority (>95%) had an independent MDD, not SIDD, episode. There were no significant group differences in the incidence of other mood disorders or SUDs at Wave 2. CONCLUSIONS: Findings have important etiological and treatment implications for the classification and treatment of depression in the context of SUDs. PMID- 23649539 TI - Transcription start site evolution in Drosophila. AB - Transcription start site (TSS) evolution remains largely undescribed in Drosophila, likely due to limited annotations in non-melanogaster species. In this study, we introduce a concise new method that selectively sequences from the 5'-end of mRNA and used it to identify TSS in four Drosophila species, including Drosophila melanogaster, D. simulans, D. sechellia, and D. pseudoobscura. For verification, we compared our results in D. melanogaster with known annotations, published 5'-rapid amplification of cDNA ends data, and with RNAseq from the same mRNA pool. Then, we paired 2,849 D. melanogaster TSS with its closest equivalent TSS in each species (likely to be its true ortholog) using the available multiple sequence alignments. Most of the D. melanogaster TSSs were successfully paired with an ortholog in each species (83%, 86%, and 55% for D. simulans, D. sechellia, and D. pseudoobscura, respectively). On the basis of the number and distribution of reads mapped at each TSS, we also estimated promoter-specific expression (PSE) and TSS peak shape, respectively. Among paired TSS orthologs, the location and promoter activity were largely conserved. TSS location appears important as PSE, and TSS peak shape was more frequently divergent among TSS that had moved. Unpaired TSS were surprisingly common in D. pseudoobscura. An increased mutation rate upstream of TSS might explain this pattern. We found an enrichment of ribosomal protein genes among diverged TSS, suggesting that TSS evolution is not uniform across the genome. PMID- 23649541 TI - Towards compression-sensitive magnetic resonance elastography of the liver: sensitivity of harmonic volumetric strain to portal hypertension. AB - PURPOSE: To assess induced oscillating volumetric strain as a biomarker for intrahepatic blood pressure abnormalities. MATERIALS AND METHODS: Harmonic vibrations of 25 and 50 Hz frequency were induced in the liver and measured by fast 3D vector field magnetic resonance elastography (MRE), followed by processing of the decomposed curl (shear) and divergence (compression) fields. After an initial study on an excised sheep liver, a group of 13 patients with hepatic hypertension were examined before and after implantation of a transjugular intrahepatic portosystemic shunt (TIPS). RESULTS: In the sheep liver specimen, volumetric strain decreased with excess portal pressure, whereas shear strain was not sensitive to portal pressure. In the patient cohort, volumetric strain was significantly higher after TIPS placement (P = 1.38.10(-5) ), while neither shear strain nor the shear modulus were affected. Normalized changes in volumetric strain were significantly correlated with the hepatic venous pressure gradient (R(2) = 0.7258, P = 6.95.10(-5) ) and portal venous pressure (R(2) = 0.5028, P = 0.0016). CONCLUSION: These results indicate for the first time the sensitivity of volumetric strain to symptomatically high values of tissue pressure and motivate further developments in compression-sensitive MRE and poroelastography towards image-based and noninvasive markers of tissue pressure. PMID- 23649543 TI - Dibenzopentalenes from B(C6F5)3-induced cyclization reactions of 1,2 bis(phenylethynyl)benzenes. AB - 'Lene' and mean: The strong Lewis acid B(C6F5)3 efficiently converts some bis(arylethynyl)benzenes into dibenzopentalenes through a series of Lewis acid induced cyclization reactions at room temperature. Thus the reaction has the potential to be useful in the synthesis of substituted dibenzopentalene derivatives which are difficult to make by conventional means. PMID- 23649544 TI - Accumulation of arsenic, lead, copper, and zinc, and synthesis of phytochelatins by indigenous plants of a mining impacted area. AB - Several native plants, able to grow in an unconfined mining impacted area that is now in close vicinity with urban areas, were evaluated for their ability to accumulate heavy metals. The main soil contaminants were As, Pb, Cu, and Zn. Sampling of the rhizospheric metal polluted soil showed that Euphorbia prostrata Aiton, Parthenium incanum Kunth, and Zinnia acerosa (DC.) A. Gray were able to grow in the presence of high amounts of mixtures of these elements. The plants accumulated the metals in the above ground parts and increased the synthesis of thiol molecules. E. prostrata showed the highest capacity for accumulation of the mixture of elements (588 MUg g DW(-1)). Analysis of the thiol-molecules profile showed that these plants synthesized high amounts of long-chain phytochelatins, accompanied by low amounts of monothiol molecules, which may be related to their higher resistance to As and heavy metals. The three plants showed translocation factors from roots to leaves >1 for As, Pb, Cu, and Zn. Thus, by periodically removing aerial parts, these plants could be useful for the phytoremediation of semi-arid and arid mining impacted areas, in which metal hyper-accumulator plants are not able to grow. PMID- 23649542 TI - A common landscape for membrane-active peptides. AB - Three families of membrane-active peptides are commonly found in nature and are classified according to their initial apparent activity. Antimicrobial peptides are ancient components of the innate immune system and typically act by disruption of microbial membranes leading to cell death. Amyloid peptides contribute to the pathology of diverse diseases from Alzheimer's to type II diabetes. Preamyloid states of these peptides can act as toxins by binding to and permeabilizing cellular membranes. Cell-penetrating peptides are natural or engineered short sequences that can spontaneously translocate across a membrane. Despite these differences in classification, many similarities in sequence, structure, and activity suggest that peptides from all three classes act through a small, common set of physical principles. Namely, these peptides alter the Brownian properties of phospholipid bilayers, enhancing the sampling of intrinsic fluctuations that include membrane defects. A complete energy landscape for such systems can be described by the innate membrane properties, differential partition, and the associated kinetics of peptides dividing between surface and defect regions of the bilayer. The goal of this review is to argue that the activities of these membrane-active families of peptides simply represent different facets of what is a shared energy landscape. PMID- 23649545 TI - Photocatalytic degradation of N-heterocyclic aromatics-effects of number and position of nitrogen atoms in the ring. AB - This study demonstrates the influences of position, number of nitrogen (N) atoms and -C-N- or -N=N- linkage present in the six membered heterocyclic compounds such as pyridine, pyrazine, and pyridazine on their photocatalytic degradation by Au, Ag, and Fe(+2) deposited TiO(2) photocatalyst. The photodegradation rate of these heterocyclic compounds follow the order pyridine > pyrazine > pyridazine due to the different extent of hydroxylation and difference in position and number of N atoms in the aromatic moiety. The Au photodeposition significantly improved the TiO(2) photoactivity as compared to Ag and Fe(+2) loading. The presence of two N atoms in pyrazine and pyridazine as compared to one N atom in pyridine hamper the nucleophilc attack of OH radicals in comparison to easy hydroxylation of pyridine ring. There is 1 N atom, 4C-C, 1C-N and 1C=N bond in pyridine, 2 N atoms in the 1 and 4 positions, 2C-C, 2C-N bonds and 2C=N bonds in pyrazine, and pyridazine ring contains 2 N atoms in the 1 and 2 positions, 3C-C, 1N-N bond and 2C=N bonds. The bond strength/energy decreases gradually as: C=N- (615 KJ/mol) > -N=N- (418 KJ/mol) > -C-C- (347 KJ/mol) > -C-N- (305 KJ/mol) > -N N- (163 KJ/mol). As pyridine has 1C-N, 1C=N, and no N-N bond, it photodegrades easily as compared to 1 N-N and 2C=N bonds of pyridazine of lowest photodecomposition rate. The improved photoactivity of Au-TiO(2) is explained on the basis of its favorable redox potential, work function, and electron-capturing capacity, etc. PMID- 23649546 TI - Perfluorinated compounds and organochlorine pesticides in soils around Huaihe River: a heavily contaminated watershed in Central China. AB - Perfluorinated compounds (PFCs) and organochlorine pesticides (OCPs) were analyzed in surface soils along the Huaihe River. Sixteen target PFCs and nine OCPs were quantified in soils from a region of intensive industrial and agricultural development. Concentrations of PFCs and OCPs ranged from less than the limit of detection (LOD) to 1.22 ng/g and 3.63 to 227 ng/g, respectively. Contamination by OCPs was more serious than that of PFCs, which was consistent with the fact that OCPs were widely used in agriculture of the district while there was no known production or application of PFCs in the study area. The predominant PFCs in soils were PFOA and PFOS with concentrations that ranged from 35 years, there was no difference in FDG ovarian uptake before and after chemotherapy. There was a negative relationship between the time elapsed from end of chemotherapy to the incidence of uptake in the ovary (p < 0.001). Bilateral ovarian uptake was significantly more prevalent in women < 35 years after chemotherapy (p < 0.01), with a significant negative dependence to time from the end of chemotherapy (p < 0.05). There was no statistically significant difference in FDG uptake in the uterus before and after chemotherapy in both age groups, as well as in SUVmax measurements in the ovaries and uterus. Chemotherapy may affect physiological FDG uptake in reproductive organs of women of reproductive age. PMID- 23649549 TI - Angiopoietin-2 expression is correlated with angiogenesis and overall survival in oral squamous cell carcinoma. AB - This study sought to determine the expression of angiopoietin-2 (Ang-2) and vascular endothelial cell growth factor (VEGF) in oral squamous cell carcinoma (OSCC) and assess their correlations with tumor progression, angiogenesis, vessel maturation, and clinical survival. Tumor tissue from 102 OSCC patients, adjacent noncancerous oral tissue from 79 OSCC patients, and normal oral mucosa from 35 control patients were examined for Ang-2 and VEGF expression using conventional immunohistochemistry. Microvessel density (MVD) and vessel maturation index (VMI) were assessed by double-label immunohistochemistry staining using anti-CD34 and anti-alpha-smooth muscle actin, respectively. Although the proportion of OSCC samples positive for Ang-2 or VEGF expression was significantly higher than that observed in the adjacent noncancerous tissue and normal oral mucosa (P < 0.001), neither Ang-2 nor VEGF expression was associated with the clinicopathological parameters analyzed in OSCC patients. However, MVD and VMI were significantly associated with the expression of Ang-2 (P = 0.001 and P = 0.014, respectively); VEGF expression was associated MVD (P = 0.004). The MVD of OSCC tissues expressing both Ang-2 and VEGF was significantly higher than observed in the double-negative samples (P < 0.05). Multivariate regression and Kaplan-Meier analyses revealed that Ang-2 was negatively associated with the overall survival of OSCC patients. Expression of Ang-2 was associated with angiogenesis and vessel maturation in OSCC. Further studies will evaluate the prognostic value of determining Ang-2 expression in OSCC. PMID- 23649551 TI - X-linked Charcot-Marie-Tooth disease predominates in a cohort of multiethnic Malaysian patients. AB - INTRODUCTION: Data regarding Charcot-Marie-Tooth disease is lacking in Southeast Asian populations. We investigated the frequency of the common genetic mutations in a multiethnic Malaysian cohort. METHODS: Patients with features of Charcot Marie-Tooth disease or hereditary liability to pressure palsies were investigated for PMP22 duplication, deletion, and point mutations and GJB1, MPZ, and MFN2 point mutations. RESULTS: Over a period of 3 years, we identified 25 index patients. A genetic diagnosis was reached in 60%. The most common were point mutations in GJB1, accounting for X-linked Charcot-Marie-Tooth disease (24% of the total patient population), followed by PMP22 duplication causing Charcot Marie-Tooth disease type 1A (20%). We also discovered 2 novel GJB1 mutations, c.521C>T (Proline174Leucine) and c.220G>A (Valine74Methionine). CONCLUSIONS: X linked Charcot-Marie-Tooth disease was found to predominate in our patient cohort. We also found a better phenotype/genotype correlation when applying a more recently recommended genetic approach to Charcot-Marie-Tooth disease. PMID- 23649552 TI - Lack of effect of bioactive-rich extracts of pomegranate, persimmon, nettle, dill, kale and Sideritis and isolated bioactives on platelet function. AB - BACKGROUND: The health benefits of fruit and vegetable-rich diets may be partly due to modulation of platelet activity by bioactive phytochemicals. The aim of this study was to investigate the effects of bioactive-rich plant extracts and isolated bioactive metabolites on platelet function. Blood samples (n =15 subjects) were treated with extracts of bioactive-rich plants consumed as traditional foods in the Black Sea region, or with human metabolites of the bioactives quercetin and sulforaphane. Platelet function was assessed using the PFA-100. RESULTS: None of the extracts containing various flavonoids, glucosinolates and other bioactives, or isolated bioactive metabolites of quercetin or sulforaphane, caused significant changes in PFA-100 closure time (CT). In contrast, the positive controls (aspirin and Abciximab) consistently caused significant increases in CT for the platelet agonists epinephrine and ADP, respectively. CONCLUSION: These data do not support the notion that these plant bioactives can improve human platelet function. PMID- 23649553 TI - Some unusual types of formation of the ansa cervicalis in humans and proposal of a new morphological classification. AB - Ansa cervicalis (ansa hypoglossi) is a peripheral nerve structure-the primary choice for laryngeal reinnervation. Because the ansa formation is quite variable in humans, it is an object of a number of proposed classifications. Two interesting cases of formation of the ansa cervicalis were found during routine anatomical dissections. In the first case the unusual ansa had three basic roots a superior one from the hypoglossal nerve, an aberrant middle root from the vagus nerve and an inferior root, coming from the cervical ventral branches. In the second case an ansa was described having roots from the vagus nerve and cervical ventral branches. Based on the reported variations and extensive review of the pertinent literature, a new morphological classification of the ansa cervicalis formation in human is proposed here. PMID- 23649554 TI - PTH(1-84) replacement therapy in hypoparathyroidism: a randomized controlled trial on pharmacokinetic and dynamic effects after 6 months of treatment. AB - Untreated, hypoparathyroidism (hypoPT) is a state of hypocalcemia with inappropriately low plasma parathyroid hormone (PTH) levels and hyperphosphatemia. PTH administration normalizes plasma calcium and phosphate levels and reduces the doses of calcium and active vitamin D analogues needed. To develop an evidence-based clinical algorithm to monitor hypoPT patients treated with recombinant human PTH (rhPTH[1-84]) injected subcutaneously in the thigh, we performed a 24-hour monitoring study of pharmacokinetic and pharmacodynamic effects in a group of 38 patients who had completed a 6-month randomized study on effects of treatment with a fixed rhPTH(1-84) dose of 100 ug/d or similar placebo as an add-on to conventional treatment. PTH levels rose immediately, reaching a median peak level of 26.5 (interquartile range [IQR], 20.1-42.5) pmol/L 15 minutes following injection. Thereafter, levels gradually decreased until reaching predosing levels after 16 hours, with a plasma half-life of 2.2 (1.7 2.5) hours. rhPTH(1-84) changed the diurnal rhythms of ionized calcium levels and 1,25-dihydroxyvitamin D (1,25[OH]2 D) levels, with rising levels following injection. Ionized calcium peaked after 7.0 (5.0-10.0) hours. Asymptomatic hypercalcemia was present in 71% of the rhPTH(1-84)-treated patients. Compared with placebo, 24-hour urinary calcium, phosphate, and magnesium did not change, although the diurnal variation in renal excretion rates changed significantly in response to treatment. In conclusion, as a safety precaution, we recommend occasionally measuring calcium levels at approximately 7 hours after administration in order to reveal episodes of hypercalcemia. A 100-ug daily dose of rhPTH(1-84) appears to be too high in some patients, suggesting a need for a device allowing for individual dose adjustments. PMID- 23649555 TI - The new guidelines for paternity analysis in Germany-how many STR loci are necessary when investigating duo cases? AB - The requirements in the new German guidelines for paternity analysis have not only changed according to the so-called Gendiagnostikgesetz, the new German law regulating human genetic as well as paternity analyses, but also regarding the minimal number of short tandem repeats (STRs) which should be investigated (15 STRs) and the minimal required average exclusion chance (99.999 %). Even in paternity analyses involving only two people (e.g., father and child or mother and child), this exclusion chance is mandatory. A retrospective analysis of 330 father-child cases from our routine investigations showed in 142 cases (43 %) an individual exclusion chance below 99.999 % when using 15 STRs as required, in our routine work provided by the Powerplex(r) 16 kit which is reported to have an average exclusion chance of 99.988 %. Therefore, these same 330 father-child pairs were additionally analysed using the Powerplex(r) 21 kit and 120 of these duos were additionally analysed using the Powerplex(r) ESX17 kit enabling the analysis of 20 or 16 loci respectively. Now, an individual exclusion chance of more than 99.999 % could be achieved in 95.5 % (Powerplex(r) 21; calculation without the results of D6S1043), 98.8 % (Powerplex(r) 21; calculation with the results of D6S1043, using allele frequencies established in this study for a German and a West African population) and 98.3 % (Powerplex(r) ESX17). These data clearly demonstrate that in duo cases, more than the required 15 STR loci have to be investigated to obtain sufficient results. PMID- 23649556 TI - The metastatic microenvironment: lung-derived factors control the viability of neuroblastoma lung metastasis. AB - Recent data suggest that the mechanisms determining whether a tumor cell reaching a secondary organ will enter a dormant state, progress toward metastasis, or go through apoptosis are regulated by the microenvironment of the distant organ. In neuroblastoma, 60-70% of children with high-risk disease will ultimately experience relapse due to the presence of micrometastases. The main goal of this study is to evaluate the role of the lung microenvironment in determining the fate of neuroblastoma lung metastases and micrometastases. Utilizing an orthotopic mouse model for human neuroblastoma metastasis, we were able to generate two neuroblastoma cell populations-lung micrometastatic (MicroNB) cells and lung macrometastatic (MacroNB) cells. These two types of cells share the same genetic background, invade the same distant organ, but differ in their ability to create metastasis in the lungs. We hypothesize that factors present in the lung microenvironment inhibit the propagation of MicroNB cells preventing them from forming overt lung metastasis. This study indeed shows that lung-derived factors significantly reduce the viability of MicroNB cells by up regulating the expression of pro-apoptotic genes, inducing cell cycle arrest and decreasing ERK and FAK phosphorylation. Lung-derived factors affected various additional progression-linked cellular characteristics of neuroblastoma cells, such as the expression of stem-cell markers, morphology, and migratory capacity. An insight into the microenvironmental effects governing neuroblastoma recurrence and progression would be of pivotal importance as they could have a therapeutic potential for the treatment of neuroblastoma residual disease. PMID- 23649557 TI - Leukemia and risk of recurrent Escherichia coli bacteremia: genotyping implicates E. coli translocation from the colon to the bloodstream. AB - In patients with leukemia, the portal(s) and reasons for the persistence of an Escherichia coli recurrent bacteremia remain unclear. Adult Hematology Clinic (AHC) databases at the State Clinical Hospital in Gdansk were reviewed to evaluate the frequency of E. coli bacteremia between 2002 and 2005. Blood and bowel E. coli strains were obtained and the genetic relatedness of the strains was analyzed. The rate of E. coli bacteremia per 1,000 admissions at the AHC was higher (85.0) than in the other clinics of the hospital (2.9), p < 0.001. A higher mortality was observed in patients with a history of E. coli versus non-E. coli bacteremia [30/95 (31 %) vs. 53/430 (12 %), p < 0.001]; 72.8 % of patients with leukemia had an unknown source of bacteremia. In 2005, 6 out of 25 (24 %) patients with leukemia had >=2 episodes of E. coli-positive blood cultures. These gastrointestinal E. coli isolates were replaced within 3-8 weeks with a new E. coli H genotype. A recurrent episode of bacteremia was usually caused by an infection with a transient E. coli H genotype identical to that found in the subject's bowel. Consistent with the definition of bowel/blood translocation, the bowel appeared to be a portal for E. coli in these subjects and, hence, a clear source for their recurring bacteremia. PMID- 23649558 TI - Color polymorphism in a land snail Cepaea nemoralis (Pulmonata: Helicidae) as viewed by potential avian predators. AB - Avian predation is one of the most probable factors maintaining polymorphism of shell coloration in Cepaea nemoralis. This assumption is justified by the fact that birds frequently forage on snails and their prey choice varies with morph coloration. However, in all preceding studies, the conspicuousness of morphs was determined only by using human vision which is significantly different from birds' visual perception. In this study, we assessed how birds perceive colors of four Cepaea nemoralis morphs using physiological models of avian color vision. We calculated combined chromatic and achromatic contrast between shells and three habitat background types as a measure of shell conspicuousness. The degree of background color matching in Cepaea nemoralis depended on both shell morph and habitat type. On average, banded morphs were more conspicuous than unbanded morphs. Morphs were the most cryptic against dry vegetation and the most conspicuous on bare ground. We also found a significant interaction between habitat type and color morph. The relative conspicuousness of shell morphs depended on habitat and was the most variable against green vegetation. Our study provides the first insight into how potential avian predators view Cepaea nemoralis morphs. The results are discussed in light of multiple hypotheses explaining selective predation on Cepaea nemoralis morphs. PMID- 23649559 TI - Rational design of an apoptosis-inducing photoreactive DNA intercalator. PMID- 23649560 TI - Ophthalmic surgical training following modernising medical careers: regional variation in experience across the UK. AB - OBJECTIVES: To evaluate surgical experience among current doctors appointed into ophthalmology training posts since the introduction of the Modernising Medical Careers programme. Additionally, to identify regional variations in surgical experience and training programme delivery. DESIGN: A cross-sectional survey. SETTING: The UK's four largest deaneries (Schools of Ophthalmology). PARTICIPANTS: Trainee ophthalmologists, all having completed three or more years of training, who were appointed to the new ophthalmic specialty training programme. PRIMARY AND SECONDARY OUTCOME MEASURES: The mean annual surgical rate for each deanery in phacoemulsification cataract extractions and experience in other common elective and emergency surgical operations. Second, to calculate the mean timetabled clinical activity. RESULTS: The responses of 40 doctors were analysed, with a response rate of 83%. Overall, the phacoemulsification rate was 73.52+/-29.24 operations/year. This was significantly higher in the South Thames Deanery (99.69+/-26.16, p=0.0005) and significantly lower in the North Western Deanery (48.08+/-19.72, p=0.0008). The annual mean complex cataract rate was 5.21+/-4.38. Only 40% were confident in dealing with the most common complication of cataract surgery (vitreous loss). The mean trabeculectomy (surgery for glaucoma) rate was 0.47+/-1.16 and for squint surgery it was 3.54+/-2.82 operations/year. Regarding the common ocular trauma surgery, 42.5% had not sutured a corneal laceration and 60% a globe rupture. 50% thought the training programme would adequately prepare them surgically. The timetabled clinical activity was highest in the South Thames Deanery (48.17 h/week) and lowest in the North Western Deanery (40.82 h/week) due to variations in the European Working Time Directive implementation and on-call commitments. CONCLUSIONS: Significant regional variations in surgical training experience exist between UK deaneries, particularly with respect to cataract surgery, and they appear to be correlated to timetabled activity. Experience and confidence levels in managing complex cataract surgery and complications were low and experience with previously commonly performed elective and emergency operations was minimal. Although doctors from all the regions surveyed were very likely to achieve the minimum cataract extractions required for specialist training completion, we have identified shortcomings of the current training programme that need attention. PMID- 23649562 TI - How positive emotions build physical health: perceived positive social connections account for the upward spiral between positive emotions and vagal tone. AB - The mechanisms underlying the association between positive emotions and physical health remain a mystery. We hypothesize that an upward-spiral dynamic continually reinforces the tie between positive emotions and physical health and that this spiral is mediated by people's perceptions of their positive social connections. We tested this overarching hypothesis in a longitudinal field experiment in which participants were randomly assigned to an intervention group that self-generated positive emotions via loving-kindness meditation or to a waiting-list control group. Participants in the intervention group increased in positive emotions relative to those in the control group, an effect moderated by baseline vagal tone, a proxy index of physical health. Increased positive emotions, in turn, produced increases in vagal tone, an effect mediated by increased perceptions of social connections. This experimental evidence identifies one mechanism perceptions of social connections-through which positive emotions build physical health, indexed as vagal tone. Results suggest that positive emotions, positive social connections, and physical health influence one another in a self sustaining upward-spiral dynamic. PMID- 23649563 TI - A noisy-channel account of crosslinguistic word-order variation. AB - The distribution of word orders across languages is highly nonuniform, with subject-verb-object (SVO) and subject-object-verb (SOV) orders being prevalent. Recent work suggests that the SOV order may be the default in human language. Why, then, is SVO order so common? We hypothesize that SOV/SVO variation can be explained by language users' sensitivity to the possibility of noise corrupting the linguistic signal. In particular, the noisy-channel hypothesis predicts a shift from the default SOV order to SVO order for semantically reversible events, for which potential ambiguity arises in SOV order because two plausible agents appear on the same side of the verb. We found support for this prediction in three languages (English, Japanese, and Korean) by using a gesture-production task, which reflects word-order preferences largely independent of native language. Other patterns of crosslinguistic variation (e.g., the prevalence of case marking in SOV languages and its relative absence in SVO languages) also straightforwardly follow from the noisy-channel hypothesis. PMID- 23649565 TI - Great expectations: lessons learned from a volunteer project in India. PMID- 23649564 TI - Heat and radiofrequency plasma glow discharge pretreatment of a titanium alloy promote bone formation and osseointegration. AB - Orthopedic and dental implants manifest increased failure rates when inserted into low density bone. We determined whether chemical pretreatments of a titanium alloy implant material stimulated new bone formation to increase osseointegration in vivo in trabecular bone using a rat model. Titanium alloy rods were untreated or pretreated with heat (600 degrees C) or radiofrequency plasma glow discharge (RFGD). The rods were then coated with the extracellular matrix protein fibronectin (1 nM) or left uncoated and surgically implanted into the rat femoral medullary cavity. Animals were euthanized 3 or 6 weeks later, and femurs were removed for analysis. The number of trabeculae in contact with the implant surface, surface contact between trabeculae and the implant, and the length and area of bone attached to the implant were measured by histomorphometry. Implant shear strength was measured by a pull-out test. Both pretreatments and fibronectin enhanced the number of trabeculae bonding with the implant and trabeculae-to-implant surface contact, with greater effects of fibronectin observed with pretreated compared to untreated implants. RFGD pretreatment modestly increased implant shear strength, which was highly correlated (r(2) = 0.87-0.99) with measures of trabecular bonding for untreated and RFGD-pretreated implants. In contrast, heat pretreatment increased shear strength 3-5-fold for both uncoated and fibronectin-coated implants at 3 and 6 weeks, suggesting a more rapid increase in implant-femur bonding compared to the other groups. In summary, our findings suggest that the heat and RFGD pretreatments can promote the osseointegration of a titanium alloy implant material. PMID- 23649566 TI - Vitamin D deficiency and nonspecific musculoskeletal pain. PMID- 23649567 TI - Magnification: you can't effectively practice minimally invasive biomimetic dentistry without it. PMID- 23649568 TI - Prosthetic conversion for an interim All-on-4 appliance. PMID- 23649569 TI - A case of justifiable criticism, or not? PMID- 23649570 TI - Successful management of oral ranula: a rare case in an infant. AB - An oral ranula is a retention cyst that arises from the sublingual gland as a result of ductal obstruction and fluid retention. This report describes the successful management of a rare case of oral ranula in an infant. A 4-month-old male infant was referred for emergency treatment due to a 2-month history of a swelling in the right sublingual region. The examination revealed a lesion of approximately 3.5 cm in diameter, which was jeopardizing the infant's breastfeeding. The lesion's dimensions suggested a ranula. Surgical specimens were sent for histopathological analysis to confirm the diagnosis. Although there are many different ways to treat an oral ranula, the marsupialization method was followed in this case due to the serious consequences of the infant's restricted access to nourishment. The treatment proved to be successful and after 18 months of follow-up, there was no sign of recurrence. PMID- 23649571 TI - Mechanical properties of nanofilled and microhybrid composites cured by different light polymerization modes. AB - This study compared nanofilled and microhybrid composites polymerized by different light polymerization modes, and the effects these modes had on the mechanical properties of the composites. The following mechanical properties were measured: Vickers microhardness numbers, diametral tensile strength, flexural strength, and flexural modulus. The filler content (Wt%) present in the resins was investigated. Data were treated statistically by ANOVA and Tukey's test (P <= 0.05) and the interaction of the inorganic content with the mechanical properties was analyzed by Pearson's correlation (P <= 0.05). The nanofilled material showed a higher percentage of inorganic filler and better mechanical properties when compared to the microhybrid composite. The correlation of Wt% with the tested properties was positive for all but the flexural strength test. Different light polymerization modes were shown not to have a significant influence on the mechanical properties of the composites in this study. PMID- 23649572 TI - Extensive central ossifying fibroma of the maxilla: a case report. AB - Central ossifying fibroma (COF) is a benign osteogenic neoplasm, with fibrous tissue and calcifications similar to bone, which has the clinical presentation of an asymptomatic bulging. It is more common in the mandibular premolar and molar region, in the third and fourth decades of life, and in women more frequently than men. Surgical removal is the treatment of choice and additional reconstruction is essential due to the functional and esthetic problems faced by the patient. This article describes the surgical treatment and subsequent reconstruction in a 22-year-old man with COF and an expansile lesion of the anterior maxilla. Enucleation of the lesion was performed and porous high-density polyethylene biomaterial was used for reconstruction. PMID- 23649573 TI - Effect of thermocycling and water storage on bond longevity of two self-etch adhesives. AB - Despite recent improvements in adhesive systems and their bond strength to enamel and dentin, the resin-tooth interface appears to be the weakest part of tooth colored restorations; in addition, there are concerns regarding bond durability of self-etch adhesives (SEAs). This in vitro study investigated the bond durability of 2 such adhesives following thermocycling and water storage. Forty eight intact human third molars were sectioned mesiodistally and mounted in acrylic resin so that buccal and lingual surfaces were positioned horizontally. All enamel and dentin surfaces were ground flat and polished on silicon carbide papers. Samples were separated into 2 groups (n = 24). A 1-step SEA was applied to one group, while a 2-step SEA was applied to the other, according to manufacturers' instructions. Half of the specimens in each group underwent shear bond strength (SBS) testing after 24 hours of incubation, while the other half were tested after 3000 thermal cycles and 6 months of water incubation. SBS data were analyzed using 2-way ANOVA, 1-way ANOVA, and a post hoc Tukey test at a significance level of 0.05. Under the limitations of the present study, the 2 step SEA demonstrated higher baselines and aged bond strength to dental tissues compared to the 1-step SEA; in addition, the enamel bond strength of the 2-step SEA improved after aging. PMID- 23649574 TI - Clinical and SEM characterization of prolonged retention of a primary tooth with pulpectomy. AB - Root canal filling with zinc oxide-eugenol (ZOE) paste following primary tooth pulpectomy is a common practice in pediatric dentistry. This material offers high clinical and radiographic success rates. In some cases, however, it is not resorbed along with the root of the primary tooth. The aim of this study was to describe a case of prolonged retention of a primary maxillary incisor that was subjected to pulpectomy and filled with ZOE paste in order to characterize the aspects of root resorption using scanning electron microscopy. PMID- 23649575 TI - The occlusal guard: a simplified technique for fabrication and equilibration. AB - Hard occlusal guards have been used effectively to treat myofacial pain originating from parafunctional activities. Also, they can protect the natural dentition when it opposes porcelain restorations, help to evaluate changes in occlusal vertical dimension during full mouth rehabilitation, minimize further tooth loss in patients with abfraction lesions, and redirect occlusal loads more favorably onto dental implant-supported prostheses. A simplified technique is described to fabricate a properly designed wax model of an occlusal guard that can be processed in acrylic in the same manner used to construct a complete denture. PMID- 23649576 TI - In vivo dental plaque pH after consumption of dairy products. AB - This in vivo study assessed plaque pH in subjects following the consumption of different dairy products. After receiving parental consent to participate, subjects (12-15 years old) were asked to refrain from brushing their teeth for 48 hours prior to the study. At baseline, plaque pH was determined at 4 different sites. Each of the subjects was then assigned randomly to 1 of 4 subgroups and each subgroup was given either cheese, milk, yogurt, or paraffin (control). After baseline, all subjects were allowed to chew and/or swish their respective product for 3 minutes and pH was assessed subsequently at different time intervals. Statistical analysis was performed using unpaired t-test and 1-way ANOVA. The results showed a statistically significant change in mean plaque pH after consuming different dairy products, as the plaque pH after 30 minutes was higher in the cheese group than that of the milk and yogurt groups, both of which showed a pH toward baseline after 30 minutes. These results suggest that cheese has the highest anticariogenic property among the dairy products studied, and that milk and yogurt can be considered as noncariogenic. PMID- 23649577 TI - Using a fiber-reinforced composite fixed partial denture to restore a missing posterior tooth: a case report. AB - With the advent of new adhesive technologies, fiber-reinforced composite fixed partial dentures (FRC-FPDs) have become an inexpensive, esthetic and useful restorative option for patients missing a single tooth. This article describes a case involving an inlay-retained FRC-FPD with a prefabricated fiber-reinforced pontic substructure. In addition, a 6-year follow-up is presented. The FRC-FPD fully restored the single missing molar with simple and conservative intracoronal preparations in the proximal teeth and was deemed clinically acceptable after the evaluation period. The clinical procedures to build a FRC-FPD with a prefabricated fiber-reinforced pontic substructure typically are finished by the clinician in 1 or 2 visits without laboratory assistance, making it a viable alternative for patients who cannot afford implant-based treatment or a conventional metal-ceramic FPD. PMID- 23649578 TI - Comparative evaluation of diode laser, stannous fluoride gel, and potassium nitrate gel in the treatment of dentinal hypersensitivity. AB - The aim of the present study was to compare the efficacy of diode laser (DL) with stannous fluoride and potassium nitrate gels in the treatment of dentinal hypersensitivity (DH). Fifty-four subjects, ages 25-45, having 2 adjacent teeth sensitive to air blast stimulation were included. The subjects were divided randomly into 3 groups (n= 18): Group A, subjects treated with DL; Group B, subjects treated with 0.4% stannous fluoride gel; and Group C, subjects treated with 5% potassium nitrate gel. Each group was evaluated at baseline; at weekly intervals for 2 consecutive weeks; and at 1, 3, and 6 months. All 3 groups showed decreases in the DH scores between baseline and 6 months This was more pronounced in Group A at all time intervals. When the 3 groups were compared between baseline and Week 1, there was a statistically significant decrease across all 3 groups between (P = 0.0020). The greatest difference in the DH scores between baseline and Week 1 was in Group A, compared to Groups B and C. The 940 nm DL was not only efficacious, but also brought about improved immediate relief as compared to stannous fluoride and potassium nitrate gels in the reduction of DH. PMID- 23649579 TI - Management of dentinogenesis imperfecta: a review of two case reports. AB - Dentinogenesis imperfecta (DI) is an inherited disorder that affects dentin and often manifests as tooth discoloration; in addition, the dentition is also extremely susceptible to wear. Treatment of DI focuses primarily on protecting affected dentin, reducing sensitivity, and improving esthetics. Routine restorative materials, such as amalgams and composites, may be used. In more severe cases, the treatment of choice is full coverage crowns, while bonding of veneers may be used to improve the esthetics of the anterior teeth. This study presents two cases of Type II DI in the same family and the management of each case. Restorative management included amalgams, composite veneers, crowns, bridges, and overdentures. PMID- 23649580 TI - Blue lesion of alveolar ridge. Gingival cyst. PMID- 23649581 TI - Giant calculus: review and report of a case. AB - Dental calculus is a common oral finding. The term giant calculus is used to describe unusually large deposits of dental calculus. Several extreme cases have been reported in the dental literature. The specific etiology of these cases remains uncertain. This paper reviews previously reported cases, and presents another extreme example of giant calculus. PMID- 23649582 TI - Use of a visible light-cured periodontal dressing material as a temporary restoration for inlay/onlay preparations. AB - There are numerous materials that are used as temporaries for inlay and onlay preparations while the permanent restoration is being made. This article looks at 2 types of temporary materials that were placed into inlay or onlay preparations by student dentists: a methylmethacrylate acrylic material (DuraLay Inlay Pattern Resin) and a visible light-cured (VLC) periodontal surgical dressing (Barricaid). The resilience and effectiveness of both products are compared and evaluated for use as temporary restorations in inlay or onlay preparations. The study found that use of the VLC periodontal dressing material offers a novel technique for a quick and efficient method to provide a temporary restoration for various inlay and onlay preparations. PMID- 23649583 TI - Strategy for apexification of wide-open apex associated with extensive periapical lesion in a weakened root. AB - This case report describes successful apexification for a challenging case involving a 30-year-old man, who suffered from dental trauma involving tooth No. 7 (which had occurred several years earlier) and recently experienced acute periapical abscess in this region. Radiographic analysis revealed incomplete root formation, a wide-open apex, thin root canal walls, and an extensive periapical lesion. Chemomechanical debridement was performed gently using K-files and irrigation with a 1% sodium hypochlorite solution. The root canal was filled with a calcium hydroxide paste, which was replaced periodically. At 18 months post treatment, an apical barrier tissue and significant reduction of periapical radiolucency were observed; at that time, the entire root canal was filled with gray mineral trioxide aggregate (MTA). At a follow-up 16 months later, the tooth had normal function and periapical repair was complete. PMID- 23649584 TI - Hydrogen peroxide penetration into the pulp chamber and dental permeability after bleaching. AB - This study sought to quantify the concentration of hydrogen peroxide (HP) in the pulp chamber and evaluate changes on dental permeability after bleaching with 3 HP concentrations (10%, 35%, and 50%). This study was divided into 2 experiments and the bleaching treatments consisted of 3 applications of HP for 30 minutes during a single session. The first experiment tested HP penetration into the pulp chamber of 4 experimental groups (n = 10) of bovine crowns, which were divided by HP concentration: an unbleached control group (0% HP), 10% HP, 35% HP, and 50% HP. Acetate buffer solution was placed into the pulp chamber and after each application of HP. This solution was collected to determine spectrophotometrically the concentration of HP that reached the pulp chamber. The second experiment evaluated dental permeability. Bovine crowns were divided into 3 groups (n = 10). The crowns were connected to a permeability device and the initial permeability was measured at 10 psi. Three different concentrations of HP gels (10%, 35% and 50%) were applied to the buccal enamel surfaces and the dental permeability was measured after the first, second, and third applications of HP. The data were analyzed by 2-way ANOVA and Tukey test (P <= 0.05). All concentrations of HP reached the pulp chamber, although no significant differences were noted between the 3 concentrations tested (P > 0.05). However, the increase of dental permeability in the group that received 50% HP was significantly higher than the 10% HP group (P < 0.05). The results indicate that the HP bleaching treatments increased dental permeability. PMID- 23649585 TI - Managing dislodged locator from a titanium alloy implant bar in an implant supported bar overdenture: a clinical report. AB - An implant-supported prosthesis is a successful treatment option for edentulous patients. This article reports on a case that has not been documented in the literature involving complications in a maxillary implant-supported bar overdenture, followed by the management of the complications. PMID- 23649586 TI - Autogenous bonding of lower incisors: case report and 17-year follow-up. AB - Among injuries that affect permanent teeth, the most prevalent is an uncomplicated crown fracture. Currently, autogenous bonding of the fragments is still the procedure of choice to restore fractured anterior teeth if the fragments are recovered by the patient and taken to a dental office within a reasonable time in an appropriate storage medium. There is no study or case report in the literature regarding autogenous bonding of lower incisors. This study presents a case with a 17-year follow-up for a 9-year-old patient who underwent uncomplicated crown fractures of the permanent mandibular central incisors and was treated by autogenous bonding of the tooth fragments. After 17 years, clinical and radiographic dental elements present vitality, and the restorations remain without major cosmetic changes. This case shows that autogenous bonding can be considered as a treatment option in the management of fractured lower incisors. PMID- 23649587 TI - Postoperative recovery after mandibular third molar surgery: a criteria for selection of type of surgical site closure. AB - This study sought to evaluate postoperative recovery after mandibular third molar surgery, with and without the use of sutures. This study utilized 50 healthy subjects (19 females and 31 males, 18-40 years of age) with bilateral impacted third molars. Two impacted teeth were removed from each patient (60 min maximum operating time). For each patient, the surgical site on one side of the mouth was closed for primary healing by using nonresorbable sutures, while the surgical site on the other side of the mouth was left open for secondary healing. Postoperative recovery was assessed by determining pain (using a visual analog scale) and swelling (by measuring anatomical landmarks pre- and postoperatively on Days 2, 5, and 7) Any incidence of socket infection and hemorrhage were considered to be complications. Both statistical analysis and clinical observation showed that the surgical sites with nonresorbable sutures showed greater swelling and a higher intensity of pain than the surgical sites without sutures; however, there were no statistical or clinical differences in pain and swelling postsurgery at Day 7. The results suggest secondary closure (that is, without sutures) after third molar surgery will produce less postoperative discomfort than primary closure (with nonresorbable sutures). PMID- 23649588 TI - Maintenance of stem cell self-renewal in head and neck cancers requires actions of GSK3beta influenced by CD44 and RHAMM. AB - Cells sorted from head and neck cancers on the basis of their high expression of CD44 have high potency for tumor initiation. These cells are also involved in epithelial to mesenchymal transition (EMT) and we have previously reported that cancer stem cells (CSCs) exist as two biologically distinct phenotypes. Both phenotypes are CD44(high) but one is also ESA(high) and maintains epithelial characteristics, the other is ESA(low) , has mesenchymal characteristics and is migratory. Examining CD44-regulated signal pathways in these cells we show that CD44, and also RHAMM, act to inhibit phosphorylation of glycogen synthase kinase 3beta (GSK3beta). We show that inhibitory phosphorylation reduces the formation of both "tumor spheres" and "holoclone" colonies, functional indicators of stemness. GSK3beta inhibition also reduces the expression of stem cell markers such as Oct4, Sox2, and Nanog and upregulates expression of the differentiation markers Calgranulin B and Involucrin in the CD44(high) /ESA(high) cell fraction. Transition of CSCs out of EMT and back to the epithelial CSC phenotype is induced by GSK3beta knockdown. These results indicate that GSK3beta plays a central role in determining and maintaining the phenotypes and behavior of CSCs in vitro and are likely to be involved in controlling the growth and spread of tumors in vivo. PMID- 23649589 TI - Systematic optimization model and algorithm for binding sequence selection in computational enzyme design. AB - A systematic optimization model for binding sequence selection in computational enzyme design was developed based on the transition state theory of enzyme catalysis and graph-theoretical modeling. The saddle point on the free energy surface of the reaction system was represented by catalytic geometrical constraints, and the binding energy between the active site and transition state was minimized to reduce the activation energy barrier. The resulting hyperscale combinatorial optimization problem was tackled using a novel heuristic global optimization algorithm, which was inspired and tested by the protein core sequence selection problem. The sequence recapitulation tests on native active sites for two enzyme catalyzed hydrolytic reactions were applied to evaluate the predictive power of the design methodology. The results of the calculation show that most of the native binding sites can be successfully identified if the catalytic geometrical constraints and the structural motifs of the substrate are taken into account. Reliably predicting active site sequences may have significant implications for the creation of novel enzymes that are capable of catalyzing targeted chemical reactions. PMID- 23649590 TI - Assessment of exocrine pancreatic function by secretin-stimulated magnetic resonance cholangiopancreaticography and diffusion-weighted imaging in healthy controls. AB - PURPOSE: To characterize and quantify exocrine pancreatic function by secretin stimulated magnetic resonance cholangiopancreaticography (s-MRCP) and diffusion weighted imaging (DWI) in healthy subjects and compare these findings to morphological features, ie, pancreatic volume and secretin-stimulated peak bicarbonate concentration measured in pancreatic juice. MATERIALS AND METHODS: Pancreatic magnetic resonance imaging (MRI) (1.5 T) was performed in 20 healthy volunteers among which 10 underwent gastroscopy with duodenal intubation. MRI included T2-weighted imaging and DWI acquired before and 1, 5, 9, and 13 minutes after secretin administration. Secreted pancreatic juice volumes were calculated based on the sequential T2-weighted images and pancreatic volumes and apparent diffusion coefficient (ADC) values were estimated. RESULTS: The mean pancreatic secretion rate declined from 9.5 mL/min at 1-5 minutes (postsecretin) to 2.9 mL/min at 9-13 minutes. Pancreatic head ADC values significantly increased from baseline (1.29 * 10(-3) mm(2) /s) to 1 minute postsecretin (1.48 * 10(-3) mm(2) /s) (P = 0.003). Secreted pancreatic juice volume at 1 minute after secretin correlated positively with peak bicarbonate concentration (n = 10, P = 0.05). CONCLUSION: Secretin-stimulated MRCP and DWI can characterize and quantify exocrine pancreatic function in healthy subjects. These imaging methods may prove relevant for patients with exocrine pancreatic dysfunction. PMID- 23649591 TI - Antioxidant properties and UV absorbance pattern of mycosporine-like amino acids analogs synthesized in an environmentally friendly manner. AB - In current study, we report efficient and clean procedure for preparing mycosporine-like amino acids (MMAs) analogs and evaluate their ultraviolet absorbance properties and antioxidant activities. The ultraviolet radiation absorbance patterns of the compounds were recorded and then used to define their molar absorptivities. The antioxidant activities were assessed using 1,1-diphenyl 2-picrylhydrazyl (DPPH) radical scavenging and superoxide radical scavenging assays. Eight of nine compounds showed good activity against superoxide radicals, as only one of the analogs exhibited a measurable IC50 in the DPPH assay. PMID- 23649592 TI - Enantioselective total synthesis of (-)-blennolide A. AB - Blennolide A can be synthesized through an enantioselective domino Wacker/carbonylation/methoxylation reaction of 7a with 96 % ee and an enantioselective Wacker oxidation of 7b with 89 % ee. Further transformations led to the alpha,beta-unsaturated ester (E)-17, which was subjected to a highly selective Michael addition, introducing a methyl group to give 18a. After a threefold oxidation and an intramolecular acylation, the tetrahydroxanthenone 4 was obtained, which could be transformed into (-)-blennolide A (ent-1) in a few steps. PMID- 23649593 TI - Estrogen promotes the growth of decidual stromal cells in human early pregnancy. AB - Interleukin-24 (IL-24) is a novel tumor suppressor gene, which has suppressor activity in a broad spectrum of human cancer cells. The present study aimed to elucidate the biological function of IL-24 and its receptors (IL-20R1, IL-20R2 and IL-22R1) in decidual stromal cells (DSCs) at human maternal-fetal interface. The DSCs behaviors in vitro were verified by viability (MTT, 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and apoptosis assay, respectively. Additionally, the effects of pregnancy-associated hormones on IL-24 and the effect of IL-24 on the correspondent functional molecules were investigated by ELISA, in-cell western and flow cytometry, respectively. Here we found that DSCs expressed IL-24 and its receptors, and IL-24 obviously suppressed the viability and stimulated the apoptosis in DSCs. On the contrary, both anti-IL 24 and IL-22R1 neutralizing antibodies markedly promoted growth and reduced the apoptosis. Estrogen but not progesterone could significantly decrease IL-24 but not its receptors, and these effects could be abolished by the antagonist of estrogen receptor beta (ERbeta). IL-24 significantly restricted the stimulatory effect of estrogen on the viability, anti-apoptosis, anti-apoptosis gene Bcl-2 and proliferation relative gene Ki-67 in DSCs. Our study has demonstrated that IL 24/IL-20R2/IL-22R1 axis is involved in the regulation of estrogen/ERbeta signaling on the growth of DSCs through up-regulating the expression of Bcl-2 and Ki67, which suggests that estrogen plays an important role in DSC growth of the early pregnancy through down-regulating IL-24. PMID- 23649595 TI - Biarylphosphonite gold(I) complexes as superior catalysts for oxidative cyclization of propynyl arenes into indan-2-ones. PMID- 23649594 TI - Bioactive-rich Sideritis scardica tea (mountain tea) is as potent as Camellia sinensis tea at inducing cellular antioxidant defences and preventing oxidative stress. AB - BACKGROUND: In several countries, tea (hot-water infusions of dried Camellia sinensis (CS) leaves) is a major source of antioxidant flavonoids, and its consumption has been associated with several favourable outcomes. Other plants used for the preparation of herbal teas are sources of phenolic antioxidant compounds; among them Sideritis scardica (SS) is used for the preparation of a popular drink throughout Eastern and Central Europe. We have compared the effects of an SS extract to a CS extract in HepG2 cells to set the scientific basis for the exploitation of other herbal teas in counteraction of oxidative stress. RESULTS: Although SS extract had a lower phenolic concentration and total antioxidant capacity than CS extract, their cellular antioxidant effects were similar. The different phenolic pattern of the extracts suggests that the protective activity is not limited to catechins. CONCLUSION: Although further research is needed, our data represent a first contribution for the evaluation of the potential effect of SS in increasing antioxidant defences. (c) 2013 Society of Chemical Industry. PMID- 23649598 TI - Characterization of zwitterionic phosphatidylcholine-based bilayer vesicles as efficient self-assembled virus-like gene carriers. AB - Entrapment of plasmid DNA (pDNA) in an aqueous compartment separated from the bulk external aqueous medium by a phospholipid bilayer resembles a structure similar to a primitive living cell, and interestingly, this phenomenon occurs completely self-assembled. Being inspired by such a structure as well as using the dehydration-rehydration technique, we were able to encapsulate pDNA without using multivalent cations and with high efficiency (98 %) into noncationic lipid bilayer vesicles. These liposomes which were composed of dimyristoyl-sn-glycero-3 phosphocholine unlike cationic liposomes, were nontoxic. The obtained liposome structure was able protect DNA against nuclease and was completely stable, in a way that even after 6 months, it still kept the pDNA in its structure, and there was a small change in its size (100-150 nm) determined by dynamic light scattering. The purpose of this research is to polarize the researchers' interest toward utilization of neutral liposomes originating from the cell membrane as the most efficient carrier for gene delivery. We indicated that in using such carriers, which are the most similar synthetic structures to viruses, their inability in electrostatic interaction with DNA would not be an obstacle for entrapping nucleic acids. PMID- 23649599 TI - Interaction of erythromycin ethylsuccinate and acetaminophen with protein fraction of extracellular polymeric substances (EPS) from various bacterial aggregates. AB - Extracellular polymeric substances (EPS) are, along with microbial cells, the main components of the biological sludges used in wastewater treatment and natural biofilms. EPS play a major role in removing pollutants from water by means of sorption. The ability of soluble EPS (S-EPS) and bound EPS (B-EPS) derived from various bacterial aggregates (flocs, granules, biofilms) to bind at pH 7.0 +/- 0.1 to two pharmaceutical substances, acetaminophen (ACE) and erythromycin ethylsuccinate (ERY), has been investigated using the fluorescence quenching method. Two intense fluorescence peaks, A (Ex/Em range, 200-250/275-380 nm) and B (Ex/Em range, 260-320/275-360 nm), corresponding respectively to the aromatic protein region and soluble microbial by-product-like region, were identified in a three-dimensional excitation-emission matrix of EPS samples. The fluorescence peak, which corresponds to humic-like substances, was also identified though at low intensity. The ability of EPS to bind ACE was found to exceed that for ERY. The aromatic protein fraction of EPS displays a slightly higher affinity for drugs than that shown by the soluble microbial by-product like fraction. The S-EPS and B-EPS present the same affinity for ACE and ERY. The effective quenching constants (log K) derived from the Stern-Volmer Equation equaled at peak A (with S-EPS): 3.7 +/- 0.2 to 4.0 +/- 0.1 for ACE and 2.1 +/- 0.3 to 2.7 +/- 0.1 for ERY. With B-EPS, these values were 3.9 +/- 0.1 to 4.0 +/- 0.1 for ACE and 2.0 +/- 0.2 to 2.6 +/- 0.1 for ERY. Our results suggest that the weaker EPS affinity for ERY than for ACE serves to partially explain why only about 50-80 % of ERY is removed from wastewater at the treatment plant. Moreover, this work demonstrates that EPS from natural river biofilms are able to bind drugs, which in turn may limit the mobility of drugs in natural waters. PMID- 23649600 TI - Prolonged environmental exposure of arsenic through drinking water on the risk of hypertension and type 2 diabetes. AB - Prolonged exposure to inorganic arsenic has been a severe environmental public health issue worldwide in the recent decades. Increasing evidence has suggested a possible role of prolonged arsenic exposure through drinking water in the development of arsenic-induced chronic noncancer diseases, among which hypertension and type 2 diabetes (T2D) are the focus of concern. Although exposure to high levels of arsenic has been reported to be associated with excess risk of hypertension or T2D in a dose-dependent manner, the association has yet to be established, especially low-level exposure. This cross-sectional study was designed to evaluate the potential association between prolonged environmental arsenic exposure through drinking water and the prevalence of hypertension and T2D in Inner Mongolia, China, with emphasis on the assessment of low-level exposure. In this study (a total of 669 men and women), we found that the blood pressure levels were significantly correlated with cumulative arsenic exposure and that the systolic blood pressure of the subjects with arsenic exposure>50 MUg/L was significantly higher than those of the subjects with <10 and 10-50 MUg/L exposure. Significant prevalence of hypertension was found in the subjects of the >50 MUg/L group both before and after adjustment for confounders. In addition, a significant negative relationship was found between urinary arsenic percentage of dimethylated arsenic (DMA%) and the prevalence of hypertension in the >50 MUg/L group. However, low-level arsenic exposure (10-50 MUg/L) was not statistically associated with hypertension. No significant difference of blood glucose was found among the groups with different arsenic exposure levels. No statistical association was found between arsenic exposure and T2D. Our findings suggested that prolonged arsenic exposure might play a role in the development of hypertension; however, only high-level arsenic was associated with the risk of hypertension. Our findings also indicated that lower DMA% might be related with the increased susceptibility of arsenic-induced hypertension. PMID- 23649601 TI - Effect of biochars on adsorption of Cu(II), Pb(II) and Cd(II) by three variable charge soils from southern China. AB - The purpose of this study is to compare the relative contribution of different mechanisms to the enhanced adsorption of Cu(II), Pb(II) and Cd(II) by variable charge soils due to incorporation of biochars derived from crop straws. The biochars were prepared from the straws of canola and peanut using an oxygen limited pyrolysis method at 350 degrees C. The effect of biochars on adsorption and desorption of Cu(II), Pb(II) and Cd(II) by and from three variable charge soils from southern China was investigated with batch experiments. Based on the desorption of pre-adsorbed heavy metals, the electrostatic and non-electrostatic adsorptions were separated. EDTA was used to replace the heavy metals complexed with biochars and to evaluate the complexing ability of the biochars with the metals. The incorporation of biochars increased the adsorption of Cu(II), Pb(II) and Cd(II) by the soil; peanut straw char induced a greater increase in the adsorption of the three metals. The increased percentage of Cd(II) adsorption induced by biochars was much greater than that for the adsorption of Cu(II) and Pb(II). Cu(II) adsorption on three variable charge soils was enhanced by the two biochars mainly through a non-electrostatic mechanism, while both electrostatic and non-electrostatic mechanisms contributed to the enhanced adsorption of Pb(II) and Cd(II) due to the biochars. Peanut straw char had a greater specific adsorption capacity than canola straw char and thus induced more non electrostatic adsorption of Cu(II), Pb(II) and Cd(II) by the soils than did the canola straw char. The complexing ability of the biochars with Cu(II) and Pb(II) was much stronger than that with Cd(II) and thus induced more specific adsorption of Cu(II) and Pb(II) by the soils than that of Cd(II). Biochars increased heavy metal adsorption by the variable charge soils through electrostatic and non electrostatic mechanisms, and the relative contribution of the two mechanisms varied with metals and biochars. PMID- 23649602 TI - Effects of bisphenol A on ammonium assimilation in soybean roots. AB - Bisphenol A (BPA), which is ubiquitous in the environment, is an example of an endocrine-disrupting compound (EDC). Ammonium assimilation has an important function in plant growth and development. However, insufficient information on the potential effect of BPA on ammonium assimilation in plants is available. In this study, the effects of BPA on ammonium assimilation in roots of soybean seedlings were investigated. During the stress period, 1.5 mg L(-1) of BPA improved glutamine synthetase (GS)/glutamate synthase (GOGAT) cycle and glutamate dehydrogenase (GDH) pathway in ammonium assimilation. The amino acid and the soluble protein contents increased in the soybeans. At 17.2 and 50.0 mg L(-1) of BPA, the GS/GOGAT cycle was inhibited and the GDH pathway was promoted. The amino acid content increased and the soluble protein content decreased. During the recovery period, the GS/GOGAT cycle and the GDH pathway recovered at 1.5 and 17.2 mg L(-1) of BPA but not at 50.0 mg L(-1) of BPA. The amino acid content continuously increased and the soluble protein content decreased compared with those in the control treatment. In summary, BPA treatment could affect the contents of soluble protein and amino acid in the soybean roots by regulating ammonium assimilation. PMID- 23649603 TI - Utilization of nSiO2, fly ash, and nSiO 2/fly ash composite for the remediation of triphenyltin (TPT) from contaminated seawater. AB - The removal of triphenyltin chloride from contaminated simulated seawater with adsorption method was discussed. The adsorbents used are fly ash, nSiO2, and nSiO2/fly ash composite. The results showed that the adsorption of the adsorbents increases with increase in the adsorbent dose, contact time, pH, stirring speed, initial TPT concentration, and decreased with increase in temperature. The adsorption fitted well with the Freundlich isotherm, showing that the adsorbent and TPT combined with function groups and the adsorption kinetics followed the pseudo-second-order kinetic model. The thermodynamic parameters were also evaluated. Optimal conditions for the adsorption of TPT from simulated seawater were applied to TPT removal from natural seawater. A higher removal efficiency of TPT (>99%) was obtained for the nSiO2/fly ash composite but not for fly ash and nSiO2. PMID- 23649604 TI - Cognition and take-up of subsidized drug benefits by Medicare beneficiaries. AB - IMPORTANCE: Take-up of the Medicare Part D low-income subsidy (LIS) by eligible beneficiaries has been low despite the attractive drug coverage it offers at no cost to beneficiaries and outreach efforts by the Social Security Administration. OBJECTIVE: To examine the role of beneficiaries' cognitive abilities in explaining this puzzle. DESIGN AND SETTING: Analysis of survey data from the nationally representative Health and Retirement Study. PARTICIPANTS: Elderly Medicare beneficiaries who were likely eligible for the LIS, excluding Medicaid and Supplemental Security Income recipients who automatically receive the subsidy without applying. MAIN OUTCOMES AND MEASURES: Using survey assessments of overall cognition and numeracy from 2006 to 2010, we examined how cognitive abilities were associated with self-reported Part D enrollment, awareness of the LIS, and application for the LIS. We also compared out-of-pocket drug spending and premium costs between LIS-eligible beneficiaries who did and did not report receipt of the LIS. Analyses were adjusted for sociodemographic characteristics, household income and assets, health status, and presence of chronic conditions. RESULTS: Compared with LIS-eligible beneficiaries in the top quartile of overall cognition, those in the bottom quartile were significantly less likely to report Part D enrollment (adjusted rate, 63.5% vs 52.0%; P = .002), LIS awareness (58.3% vs 33.3%; P = .001), and LIS application (25.5% vs 12.7%; P < .001). Lower numeracy was also associated with lower rates of Part D enrollment (P = .03) and LIS application (P = .002). Reported receipt of the LIS was associated with significantly lower annual out-of-pocket drug spending (adjusted mean difference, -$256; P = .02) and premium costs (-$273; P = .02). CONCLUSIONS AND RELEVANCE: Among Medicare beneficiaries likely eligible for the Part D LIS, poorer cognition and numeracy were associated with lower reported take-up. Current educational and outreach efforts encouraging LIS applications may not be sufficient for beneficiaries with limited abilities to process and respond to information. Additional policies may be needed to extend the financial protection conferred by the LIS to all eligible seniors. PMID- 23649606 TI - Modelling the benefits of early diagnosis of pancreatic cancer using a biomarker signature. AB - Pancreatic cancer (PC) has a poor prognosis, with a 5-year survival of 3-4%. This is mainly due to late diagnosis because of diffuse symptoms, where 80-85% of the patients are inoperable. Consequently, early diagnosis would be of significant benefit, resulting in a potential 5-year survival of 30-40%. However, new technologies must be carefully evaluated concerning effectiveness and healthcare costs. We have developed a framework for modelling cost and health effects from early detection of PC, which for the first time allowed us to analyse its cost effectiveness. A probabilistic cohort model for estimating costs and quality adjusted life-years (QALY) arising from screening for PC, compared to a "wait-and see"-approach, was designed. The test accuracy, Swedish survival and costs by tumour stage, expected life gain from early detection and pretest probabilities in risk groups, were retrieved from previous investigations. In a cohort of newly diagnosed diabetic patient (incidence 0.71%) the incremental cost per QALY gained (ICER) was ?13,500, which is considered cost-effective in Europe. Results were mainly sensitive to the incidence with the ICER ranging from ?315 to ?204,000 (familial PC 35% and general population 0.046%, respectively). This is the first study focusing on clinical implementation of advanced testing and what is required for novel technologies in cancer care to be cost-effective. The model clearly demonstrated the potential of multiplexed proteomic-testing of PC and also identified the requirements for test accuracy. Consequently, it can serve as a model for assessing the possibilities to introduce advanced test platforms also for other cancer indications. PMID- 23649605 TI - In vivo tibial compression decreases osteolysis and tumor formation in a human metastatic breast cancer model. AB - Bone metastasis, the leading cause of breast cancer-related deaths, is characterized by bone degradation due to increased osteoclastic activity. In contrast, mechanical stimulation in healthy individuals upregulates osteoblastic activity, leading to new bone formation. However, the effect of mechanical loading on the development and progression of metastatic breast cancer in bone remains unclear. Here, we developed a new in vivo model to investigate the role of skeletal mechanical stimuli on the development and osteolytic capability of secondary breast tumors. Specifically, we applied compressive loading to the tibia following intratibial injection of metastatic breast cancer cells (MDA MB231) into the proximal compartment of female immunocompromised (SCID) mice. In the absence of loading, tibiae developed histologically-detectable tumors with associated osteolysis and excessive degradation of the proximal bone tissue. In contrast, mechanical loading dramatically reduced osteolysis and tumor formation and increased tibial cancellous mass due to trabecular thickening. These loading effects were similar to the baseline response we observed in non-injected SCID mice. In vitro mechanical loading of MDA-MB231 in a pathologically relevant 3D culture model suggested that the observed effects were not due to loading-induced tumor cell death, but rather mediated via decreased expression of genes interfering with bone homeostasis. Collectively, our results suggest that mechanical loading inhibits the growth and osteolytic capability of secondary breast tumors after their homing to the bone, which may inform future treatment of breast cancer patients with advanced disease. PMID- 23649607 TI - A differential pattern of gene expression in skeletal muscle of tumor-bearing rats reveals dysregulation of excitation-contraction coupling together with additional muscle alterations. AB - INTRODUCTION: Cachexia is a wasting condition that manifests in several types of cancer. The main characteristic of this condition is a profound loss of muscle mass. METHODS: By using a microarray system, expression of several hundred genes was screened in skeletal muscle of rats bearing a cachexia-inducing tumor, the AH 130 Yoshida ascites hepatoma. This model induced a strong decrease in muscle mass in the tumor-bearing animals, as compared with their healthy counterparts. RESULTS: The results show important differences in gene expression in EDL skeletal muscle between tumor-bearing animals with cachexia and control animals. CONCLUSIONS: The differences observed pertain to genes related to intracellular calcium homeostasis and genes involved in the control of mitochondrial oxidative phosphorylation and protein turnover, both at the level of protein synthesis and proteolysis. Assessment of these differences may be a useful tool for the design of novel therapeutic strategies to fight this devastating syndrome. PMID- 23649608 TI - Recombination of lophyl radicals in pyrrolidinium-based ionic liquids. AB - The recombination of photolytically generated lophyl radicals has been investigated by UV/Vis spectroscopy in 1-alkyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imides (NTf2) in comparison with 1-butyl-3 methylimidazolium NTf2 , dimethyl sulfoxide, and triacetin. The 1-alkyl-1 methylpyrrolidinium-based ionic liquids contain an alkyl substituent varying between butyl and decyl groups. Optically pure ionic liquids are used in these studies. Temperature-dependent investigation of lophyl radical recombination shows an increase in the radical recombination rate with increasing temperature in each solvent, which is caused by decreasing viscosity with increasing temperature. Furthermore, the viscosity of the 1-alkyl-1-methylpyrrolidinium NTf2 increases nearly linearly within the row of these ionic liquids. In contrast, the recombination of the photolytically generated lophyl radicals is significantly faster in the ionic liquids than in the traditional organic solvents under investigation. Moreover, the recombination rate increases with the length of the alkyl chain bound at the cation of the ionic liquid at a given temperature. This may be caused by an increase in the extent of lophyl radical recombination within the solvent cage. Solvent cage effects dominate in the case of lophyl radical recombination in ionic liquids bearing a long alkyl chain or if the temperature is near the melting temperature of the ionic liquid. The positive value of the activation entropy supports this hypothesis. The results obtained are important for discussion of bimolecular radical reactions in ionic liquids. PMID- 23649609 TI - FAB-D: German version of the Frontal Assessment Battery. AB - Executive dysfunction (ED) is a frequent consequence of neurological disorders, such as stroke, trauma or dementia, but also appears in normal aging. We developed a German version of the Frontal Assessment Battery (FAB-D), a short test which has previously been developed (Dubois et al., Neurology 55:1621-1626, 2000) to detect ED during bedside screening. A sample of 401 cognitively intact subjects aged 50-95 was tested with the FAB-D and several neuropsychological tests tapping executive functions, memory and calculation abilities. Aim of the study was to receive normative data for different age and educational groups, and to learn which tests predict performance on the FAB-D. We found clear effects of age and education; furthermore, FAB-D performance was predicted by other tests of executive functioning, but also by calculation and memory abilities. The present study reports data of healthy individuals and may be useful for comparing patients' performance with a normative sample. PMID- 23649610 TI - Trunk bradykinesia and foveation delays during whole-body turns in spasmodic torticollis. AB - We have investigated how the abnormal head posture and motility in spasmodic torticollis interferes with ecological movements such as combined eye-to-foot whole-body reorientations to visual targets. Eight mildly affected patients and 10 controls voluntarily rotated eyes and body in response to illuminated targets of eccentricities up to +/- 180 degrees . The experimental protocol allowed separate evaluation of the effects of target location, visibility and predictability on movement parameters. Patients' latencies of eye, head, trunk and foot motion were prolonged but showed a normal modification pattern when target location was predictable. Peak head-on-trunk displacement and velocity were reduced both ipsi- and contralaterally with respect to the direction of torticollis. Surprisingly, peak trunk velocity was also reduced, even more than in previously studied patients with Parkinson's disease. As a consequence, patients made short, hypometric gaze saccades and only exceptionally foveated initially nonvisible targets with a single large gaze shift (4 % of predictable trials as opposed to 30 % in controls). Foveation of distant targets was massively delayed by more than half a second on average. Spontaneous dystonic head movements did not interfere with the execution of voluntary gaze shifts. The results show that neck dystonia does not arise from gaze (head-eye) motor centres but the eye-to-foot turning synergy is seriously compromised. For the first time we identify significant 'secondary' complications of torticollis such as trunk bradykinesia and foveation delays, likely to cause additional disability in patients. Eye movements per se are intact and compensate for the reduced head/trunk performance in an adaptive manner. PMID- 23649611 TI - Effects of Er:YAG and Er,Cr:YSGG laser irradiation on the adhesion to eroded dentin. AB - Limited information is available regarding the adhesion to eroded dentin. This study aims to evaluate the effect of different surface treatments on eroded dentin morphology and on microtensile bond strength (MUTBS) of adhesive systems to this substrate. Ninety-six extracted third molars were randomly divided into eight groups (n = 12) according to the type of surface treatment and the adhesive system: G1 = Control + Clearfil SE Bond [SE], G2 = Diamond bur [DB] + SE, G3 = Er:YAG laser (60 mJ, 2 Hz, 0.12 W, 19.3 J/ cm(2)) + SE, G4 = Er,Cr:YSGG laser (50 mJ, 30 Hz, 1.5 W, 4.5 J/ cm(2)) + SE, G5 = Control + Single Bond [SB], G6 = DB + SB, G7 = Er:YAG + SB, G8 = Er,Cr:YSGG + SB. The erosive cycling was performed by immersion in 0.05 M citric acid (pH 2.3, 10 min, 6x/day) and in supersaturated solution (pH 7.0, 1 h, between acid attacks), during 5 days. Blocks of composite were bonded to the samples according to the manufacturers' instructions. After 24 h-storage in distilled/deionized water (37 degrees C), stick-shaped samples were obtained and submitted to MUTBS test. Each surface treatment was analyzed under scanning electron microscopy (n = 4) and the bond strength values (megapascal) were analyzed by two-way ANOVA and Tukey tests (alpha = 0.05). All surface treatments lead to changes on eroded dentin. G4 showed the highest bond strength mean (28.3 +/- 9.2 MPa), which was statistically significant higher than all the other groups (p < 0.05). The surface treatment with Er,Cr:YSGG laser irradiation (4.5 J/cm(2)/50 mJ/30 Hz/140 MUs) prior to bonding with a self-etching adhesive system significantly increases adhesion to eroded dentin, as compared to conventional treatment. PMID- 23649612 TI - Cellular uptake of 9-hydroxypheophorbide-alpha and its photoactivation to induce ER stress-related apoptosis in human cervical cancer cells. AB - The 9-hydroxypheophorbide-alpha (9-HPbD) is a chlorophyll derivative and was found to be very effective for photodynamic therapy of tumor cells. The current study investigates uptake, retention, and intracellular localization of 9-HPbD by HeLa, human cervical cancer cells via fluorescence spectrophotometry and confocal laser scanning microscopy, and its photodynamic effect against human cervical carcinoma cell. HeLa cells exposed to 9-HPbD exhibited a linear uptake of photosensitizer during the first 12 h, and after removal of 9-HPbD, cell fluorescence was observed to decrease gradually over the next 12 h. Cells treated with 9-HPbD and stained with a panel of organelle-specific fluorescence probes (MitoTracker, LysoTracker, and ER-Tracker) revealed an intracellular fluorescence distribution restricted to cytoplasmic compartments with no detectable fluorescence in the nucleus. The 9-HPbD showed cytotoxicity effect against HeLa cells in 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Endoplasmic reticulum (ER) disruption and cellular calcium dynamics also showed a photoactivation followed by cell death. The apoptotic effect of 9-HPbD was confirmed by caspase 3 activity study and immunofluorescence study of caspase 12. Morphological observation through the transmission electron microscopy and scanning electron microscopy also confirmed that 9-HPbD can induce apoptosis in HeLa cells. Therefore, it can be concluded that maximum uptake and clearance time of 9-HPbD was 12 h with endoplasmic reticulum as the major organelle site in cellular uptake, and 9-HPbD can induce apoptosis in HeLa cells through ER stress related pathways via activation of caspase 12. PMID- 23649613 TI - The effect of Er,Cr:YSGG laser irradiation on titanium discs with microtextured surface morphology. AB - Both mechanical and chemical methods can be used to clean and decontaminate implant surfaces. Incomplete debridement of infected tissue and failure to clear endotoxins can result in graft failure and a return of the defect. Recently, lasers have gained popularity for sterilizing and cleaning implant surfaces. We determined the effects of laser treatment on the surface characteristics of titanium discs with a Laser-Lok surface. The discs were irradiated with an erbium, chromium: yttrium, scandium, gallium, garnet (Er,Cr:YSGG) laser under various conditions (R1-9). Scanning electron microscopy was used to evaluate the surface. Considerable surface alterations such as melting and flattening were seen at R6 (2 W, 20 Hz, 4 mm, 45 s) and R8 (3 W, 25 Hz, 2 mm, 45 s). In addition, cracking was seen at R8. The laser parameters should be optimized to conserve surface characteristics during the irradiation of implant surfaces. PMID- 23649614 TI - The efficacy of the use of IR laser phototherapy associated to biphasic ceramic graft and guided bone regeneration on surgical fractures treated with miniplates: a histological and histomorphometric study on rabbits. AB - The aim of the present study was to assess, by light microscopy and histomorphometry, the repair of surgical fractures fixed with internal rigid fixation (IRF) treated or not with IR laser (lambda780 nm, 50 mW, 4 * 4 J/cm(2) = 16 J/cm(2), phi = 0.5 cm(2), CW) associated or not to the use of hydroxyapatite and guided bone regeneration. Surgical tibial fractures were created under general anesthesia on 15 rabbits that were divided into 5 groups, maintained on individual cages, at day/night cycle, fed with solid laboratory pelted diet, and had water ad libidum. The fractures in groups II, III, IV, and V were fixed with miniplates. Animals in groups III and V were grafted with hydroxyapatite and GBR technique used. Animals in groups IV and V were irradiated at every other day during two weeks (4 * 4 J/cm(2), 16 J/cm(2) = 112 J/cm(2)). Observation time was that of 30 days. After animal death, specimens were taken, routinely processed to wax, cut and stained with HA and Sirius red, and used for histological assessment. The results of both analyses showed a better bone repair on all irradiated subjects especially when the biomaterial and GBR were used. In conclusion, the results of the present investigation are important clinically as they are suggestive that the association of hydroxyapatite, and laser light resulted in a positive and significant repair of complete tibial fractures treated with miniplates. PMID- 23649615 TI - Lasers and lights for the treatment of striae distensae. AB - Striae distensae (SD) or "stretch marks" are a common and well-recognized dermatologic entity affecting patients of all ages, genders, and ethnicities. The treatment of SD has long been plagued by disappointing outcomes and remains a frustrating entity for both physicians and patients. While striae may become less conspicuous over time, they rarely resolve without intervention. Inspired by the success of lasers for the treatment of scars and rhytides, these devices have been applied to the treatment of SD in the hopes of achieving similar efficacy. PMID- 23649616 TI - Long-term follow-up on affinity maturation and memory B-cell generation in patients with common variable immunodeficiency. AB - PURPOSE: Common variable immunodeficiency (CVID) comprises a heterogeneous group of primary immunodeficiency disorders. Immunophenotyping of memory B cells at the time of diagnosis is increasingly used for the classification of patients into subgroups with different clinical prognoses. The EUROclass classification is a widely used method. Levels of somatic hypermutation (SHM) have proven useful as a prognostic marker for recurrent respiratory tract infections. As time of presentation and diagnosis is highly variable in CVID patients, and diagnostic delay is a common problem, it is important to know whether classification parameters are stable over time. The purpose of the study was to address this question in a cohort of 33 CVID patients followed from 3 to 19 years after diagnosis (average follow-up 8.8 years). METHODS: Levels of class-switched memory B cells were analyzed using flow cytometric immunophenotyping, and patients were classified according to the EUROclass criteria. Affinity maturation of B cells was measured using Igkappa-REHMA, which assesses somatic hypermutation in kappa light chain transcripts. Clinical manifestations in terms of splenomegaly, autoimmune disease and granulomatous disease were also determined. RESULTS: Switched memory B cells and levels of SHM were not consistently stable markers in a long-term follow-up setting. At a given time during follow-up, 60% of the patients were assigned to the EUROclass group SmB- (less than 2% switched memory B cells), but only 23% were consistently assigned to this group. Associations between clinical manifestations and levels of switched memory B cells or SHM were not observed in our study. CONCLUSION: Based on our findings, we suggest that immunologic characteristics in CVID patients should be evaluated several times after diagnosis using internationally standardized methods. PMID- 23649617 TI - A novel use of structural equation models to examine factors associated with prediabetes among adults aged 50 years and older: National Health and Nutrition Examination Survey 2001-2006. AB - OBJECTIVE: To use structural modeling to test a hypothesized model of causal pathways related with prediabetes among older adults in the U.S. RESEARCH DESIGN AND METHODS: Cross-sectional study of 2,230 older adults (>= 50 years) without diabetes included in the morning fasting sample of the 2001-2006 National Health and Nutrition Examination Surveys. Demographic data included age, income, marital status, race/ethnicity, and education. Behavioral data included physical activity (metabolic equivalent hours per week for vigorous or moderate muscle strengthening, walking/biking, and house/yard work), and poor diet (refined grains, red meat, added sugars, solid fats, and high-fat dairy). Structural equation modeling was performed to examine the interrelationships among these variables with family history of diabetes, high blood pressure, BMI, large waist (waist circumference: women, >= 35 inches; men, >= 40 inches), triglycerides >= 200 mg/dL, and total and HDL (>= 60 mg/dL) cholesterol. RESULTS: After dropping BMI and total cholesterol, our best-fit model included three single factors: socioeconomic position (SEP), physical activity, and poor diet. Large waist had the strongest direct effect on prediabetes (0.279), followed by male sex (0.270), SEP (-0.157), high blood pressure (0.122), family history of diabetes (0.070), and age (0.033). Physical activity had direct effects on HDL (0.137), triglycerides (-0.136), high blood pressure (-0.132), and large waist (-0.067); poor diet had direct effects on large waist (0.146) and triglycerides (0.148). CONCLUSIONS: Our results confirmed that, while including factors known to be associated with high risk of developing prediabetes, large waist circumference had the strongest direct effect. The direct effect of SEP on prediabetes suggests mediation by some unmeasured factor(s). PMID- 23649618 TI - Computational studies and experimental results--an example of excellent teamwork in studying carbocyclization. AB - In silico veritas? Maybe not the whole truth, but very helpful suggestions and guidelines for the experimental work can be deduced from computational studies on Rh-catalyzed [3+2+1] cycloaddition reactions for the construction of cis-fused bicyclohexenones from alkylidenecyclopropanes and carbon monoxide. PMID- 23649619 TI - Interferon-inducible transmembrane protein 3 (IFITM3) restricts reovirus cell entry. AB - Reoviruses are double-stranded RNA viruses that infect the mammalian respiratory and gastrointestinal tract. Reovirus infection elicits production of type I interferons (IFNs), which trigger antiviral pathways through the induction of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified, the functions of many of these genes are unknown. The interferon inducible transmembrane (IFITM) proteins are one class of ISGs that restrict the cell entry of some enveloped viruses, including influenza A virus. One family member, IFITM3, localizes to late endosomes, where reoviruses undergo proteolytic disassembly; therefore, we sought to determine whether IFITM3 also restricts reovirus entry. IFITM3-expressing cell lines were less susceptible to infection by reovirus, as they exhibited significantly lower percentages of infected cells in comparison to control cells. Reovirus replication was also significantly reduced in IFITM3-expressing cells. Additionally, cells expressing an shRNA targeting IFITM3 exhibited a smaller decrease in infection after IFN treatment than the control cells, indicating that endogenous IFITM3 restricts reovirus infection. However, IFITM3 did not restrict entry of reovirus infectious subvirion particles (ISVPs), which do not require endosomal proteolysis, indicating that restriction occurs in the endocytic pathway. Proteolysis of outer capsid protein MU1 was delayed in IFITM3-expressing cells in comparison to control cells, suggesting that IFITM3 modulates the function of late endosomal compartments either by reducing the activity of endosomal proteases or delaying the proteolytic processing of virions. These data provide the first evidence that IFITM3 restricts infection by a nonenveloped virus and suggest that IFITM3 targets an increasing number of viruses through a shared requirement for endosomes during cell entry. PMID- 23649620 TI - Androgens up-regulate transcription of the Notch inhibitor Numb in C2C12 myoblasts via Wnt/beta-catenin signaling to T cell factor elements in the Numb promoter. AB - Androgen signaling via the androgen receptor is a key pathway that contributes to development, cell fate decisions, and differentiation, including that of myogenic progenitors. Androgens and synthetic steroids have well established anabolic actions on skeletal muscle. Wnt and Notch signaling pathways are also essential to myogenic cell fate decisions during development and tissue repair. However, the interactions among these pathways are largely unknown. Androgenic regulation of Wnt signaling has been reported. Nandrolone, an anabolic steroid, has been shown to inhibit Notch signaling and up-regulate Numb, a Notch inhibitor. To elucidate the mechanisms of interaction between nandrolone and Wnt/Notch signaling, we investigated the effects of nandrolone on Numb expression and Wnt signaling and determined the roles of Wnt signaling in nandrolone-induced Numb expression in C2C12 myoblasts. Nandrolone increased Numb mRNA and protein levels and T cell factor (Tcf) transcriptional activity via inhibition of glycogen synthase kinase 3beta. Up-regulation of Numb expression by nandrolone was blocked by the Wnt inhibitors, sFRP1 and DKK1, whereas Wnt3a increased Numb mRNA and protein expression. In addition, we observed that the proximal promoter of the Numb gene had functional Tcf binding elements to which beta-catenin was recruited in a manner enhanced by both nandrolone and Wnt3a. Moreover, site-directed mutagenesis indicated that the Tcf binding sites in the Numb promoter are required for the nandrolone-induced Numb transcriptional activation in this cell line. These results reveal a novel molecular mechanism underlying up-regulation of Numb transcription with a critical role for increased canonical Wnt signaling. In addition, the data identify Numb as a novel target gene of the Wnt signaling pathway by which Wnts would be able to inhibit Notch signaling. PMID- 23649621 TI - Exposure to factor VIII protein in the presence of phosphatidylserine induces hypo-responsiveness toward factor VIII challenge in hemophilia A mice. AB - Administration of recombinant factor VIII (FVIII), an important co-factor in blood clotting cascade, elicits unwanted anti-FVIII antibodies in hemophilia A (HA) patients. Previously, FVIII associated with phosphatidylserine (PS) showed significant reduction in the anti-FVIII antibody response in HA mice. The reduction in the immune response to FVIII-PS could be due either to a failure of the immune system to recognize the antigen (i.e. immunological ignorance) or to an active induction of an antigen-specific nonresponsiveness (i.e. immunological tolerance). If it were a result of tolerance, one would predict that pre-exposure to FVIII-PS would render the mice hypo-responsive to a subsequent FVIII challenge. Here, we have demonstrated that naive HA mice that were pretreated with FVIII-PS showed a significantly reduced FVIII immune response to further challenge with native FVIII and that this decreased responsiveness could be adoptively transferred to other mice. An increase in number of FoxP3-expressing CD4(+) regulatory T-cells (Treg) was observed for the FVIII-PS-immunized group as compared with animals that received FVIII alone, suggesting the involvement of Treg in PS-mediated hypo-responsiveness. The PS-mediated reduction in antibody response was reversed by the co-administration of function-blocking anti-TGF-beta antibody with FVIII-PS. The decreased response to FVIII induced by FVIII-PS was determined to be antigen-specific because the immune response to another non cross-reactive antigen (ovalbumin) was not altered. These results are consistent with the notion that FVIII-PS is tolerogenic and suggest that immunization with this tolerogenic form of the protein could be a useful treatment option to minimize immunogenicity of FVIII and other protein-based therapeutics. PMID- 23649622 TI - Mechanism of endogenous regulation of the type I interferon response by suppressor of IkappaB kinase epsilon (SIKE), a novel substrate of TANK-binding kinase 1 (TBK1). AB - TANK-binding kinase 1 (TBK1) serves as a key convergence point in multiple innate immune signaling pathways. In response to receptor-mediated pathogen detection, TBK1 phosphorylation promotes production of pro-inflammatory cytokines and type I interferons. Increasingly, TBK1 dysregulation has been linked to autoimmune disorders and cancers, heightening the need to understand the regulatory controls of TBK1 activity. Here, we describe the mechanism by which suppressor of IKKepsilon (SIKE) inhibits TBK1-mediated phosphorylation of interferon regulatory factor 3 (IRF3), which is essential to type I interferon production. Kinetic analyses showed that SIKE not only inhibits IRF3 phosphorylation but is also a high affinity TBK1 substrate. With respect to IRF3 phosphorylation, SIKE functioned as a mixed-type inhibitor (K(i, app) = 350 nM) rather than, given its status as a TBK1 substrate, as a competitive inhibitor. TBK1 phosphorylation of IRF3 and SIKE displayed negative cooperativity. Both substrates shared a similar Km value at low substrate concentrations (~50 nM) but deviated >8-fold at higher substrate concentrations (IRF3 = 3.5 MUM; SIKE = 0.4 MUM). TBK1-SIKE interactions were modulated by SIKE phosphorylation, clustered in the C-terminal portion of SIKE (Ser-133, -185, -187, -188, -190, and -198). These sites exhibited striking homology to the phosphorylation motif of IRF3. Mutagenic probing revealed that phosphorylation of Ser-185 controlled TBK1-SIKE interactions. Taken together, our studies demonstrate for the first time that SIKE functions as a TBK1 substrate and inhibits TBK1-mediated IRF3 phosphorylation by forming a high affinity TBK1 SIKE complex. These findings provide key insights into the endogenous control of a critical catalytic hub that is achieved not by direct repression of activity but by redirection of catalysis through substrate affinity. PMID- 23649623 TI - HMGB1 protein does not mediate the inflammatory response in spontaneous spinal cord regeneration: a hint for CNS regeneration. AB - Uncontrolled, excessive inflammation contributes to the secondary tissue damage of traumatic spinal cord, and HMGB1 is highlighted for initiation of a vicious self-propagating inflammatory circle by release from necrotic cells or immune cells. Several regenerative-competent vertebrates have evolved to circumvent the second damages during the spontaneous spinal cord regeneration with an unknown HMGB1 regulatory mechanism. By genomic surveys, we have revealed that two paralogs of HMGB1 are broadly retained from fish in the phylogeny. However, their spatial-temporal expression and effects, as shown in lowest amniote gecko, were tightly controlled in order that limited inflammation was produced in spontaneous regeneration. Two paralogs from gecko HMGB1 (gHMGB1) yielded distinct injury and infectious responses, with gHMGB1b significantly up-regulated in the injured cord. The intracellular gHMGB1b induced less release of inflammatory cytokines than gHMGB1a in macrophages, and the effects could be shifted by exchanging one amino acid in the inflammatory domain. Both intracellular proteins were able to mediate neuronal programmed apoptosis, which has been indicated to produce negligible inflammatory responses. In vivo studies demonstrated that the extracellular proteins could not trigger a cascade of the inflammatory cytokines in the injured spinal cord. Signal transduction analysis found that gHMGB1 proteins could not bind with cell surface receptors TLR2 and TLR4 to activate inflammatory signaling pathway. However, they were able to interact with the receptor for advanced glycation end products to potentiate oligodendrocyte migration by activation of both NFkappaB and Rac1/Cdc42 signaling. Our results reveal that HMGB1 does not mediate the inflammatory response in spontaneous spinal cord regeneration, but it promotes CNS regeneration. PMID- 23649624 TI - Characterization and favorable in vivo properties of heterodimeric soluble IL 15.IL-15Ralpha cytokine compared to IL-15 monomer. AB - Interleukin-15 (IL-15), a 114-amino acid cytokine related to IL-2, regulates immune homeostasis and the fate of many lymphocyte subsets. We reported that, in the blood of mice and humans, IL-15 is present as a heterodimer associated with soluble IL-15 receptor alpha (sIL-15Ralpha). Here, we show efficient production of this noncovalently linked but stable heterodimer in clonal human HEK293 cells and release of the processed IL-15.sIL-15Ralpha heterodimer in the medium. Purification of the IL-15 and sIL-15Ralpha polypeptides allowed identification of the proteolytic cleavage site of IL-15Ralpha and characterization of multiple glycosylation sites. Administration of the IL-15.sIL-15Ralpha heterodimer reconstituted from purified subunits resulted in sustained plasma IL-15 levels and in robust expansion of NK and T cells in mice, demonstrating pharmacokinetics and in vivo bioactivity superior to single chain IL-15. These identified properties of heterodimeric IL-15 provide a strong rationale for the evaluation of this molecule for clinical applications. PMID- 23649625 TI - Identification of a secondary promoter within the human B cell receptor component gene hCD79b. AB - The human B cell-specific protein, CD79b (also known as Igbeta and B29) constitutes an essential signal transduction component of the B cell receptor. Although its function is central to the triggering of B cell terminal differentiation in response to antigen stimulation, the transcriptional determinants that control CD79b gene expression remain poorly defined. In the present study, we explored these determinants using a series of hCD79b transgenic mouse models. Remarkably, we observed that the previously described hCD79b promoter along with its associated enhancer elements and first exon could be deleted without appreciable loss of hCD79b transcriptional activity or tissue specificity. In this deletion setting, a secondary promoter located within exon 2 maintained full levels and specificity of hCD79b transcription. Of note, this secondary promoter was also active, albeit at lower levels, in the wild-type hCD79b locus. The activity of the secondary promoter was dependent on the action(s) of a conserved sequence element mapping to a chromatin DNase I hypersensitive site located within intron 1. mRNA generated from this secondary promoter is predicted to encode an Igbeta protein lacking a signal sequence and thus unable to serve normal B cell receptor function. Although the physiologic role of the hCD79b secondary promoter and its encoded protein remain unclear, the current data suggest that it has the capacity to play a role in normal as well as pathologic states in B cell proliferation and function. PMID- 23649626 TI - Isolation and characterization of the small subunit of the uptake hydrogenase from the cyanobacterium Nostoc punctiforme. AB - In nitrogen-fixing cyanobacteria, hydrogen evolution is associated with hydrogenases and nitrogenase, making these enzymes interesting targets for genetic engineering aimed at increased hydrogen production. Nostoc punctiforme ATCC 29133 is a filamentous cyanobacterium that expresses the uptake hydrogenase HupSL in heterocysts under nitrogen-fixing conditions. Little is known about the structural and biophysical properties of HupSL. The small subunit, HupS, has been postulated to contain three iron-sulfur clusters, but the details regarding their nature have been unclear due to unusual cluster binding motifs in the amino acid sequence. We now report the cloning and heterologous expression of Nostoc punctiforme HupS as a fusion protein, f-HupS. We have characterized the anaerobically purified protein by UV-visible and EPR spectroscopies. Our results show that f-HupS contains three iron-sulfur clusters. UV-visible absorption of f HupS has bands ~340 and 420 nm, typical for iron-sulfur clusters. The EPR spectrum of the oxidized f-HupS shows a narrow g = 2.023 resonance, characteristic of a low-spin (S = ½) [3Fe-4S] cluster. The reduced f-HupS presents complex EPR spectra with overlapping resonances centered on g = 1.94, g = 1.91, and g = 1.88, typical of low-spin (S = ½) [4Fe-4S] clusters. Analysis of the spectroscopic data allowed us to distinguish between two species attributable to two distinct [4Fe-4S] clusters, in addition to the [3Fe-4S] cluster. This indicates that f-HupS binds [4Fe-4S] clusters despite the presence of unusual coordinating amino acids. Furthermore, our expression and purification of what seems to be an intact HupS protein allows future studies on the significance of ligand nature on redox properties of the iron-sulfur clusters of HupS. PMID- 23649628 TI - Enzymatic detoxication, conformational selection, and the role of molten globule active sites. AB - The role of conformational ensembles in enzymatic reactions remains unclear. Discussion concerning "induced fit" versus "conformational selection" has, however, ignored detoxication enzymes, which exhibit catalytic promiscuity. These enzymes dominate drug metabolism and determine drug-drug interactions. The detoxication enzyme glutathione transferase A1-1 (GSTA1-1), exploits a molten globule-like active site to achieve remarkable catalytic promiscuity wherein the substrate-free conformational ensemble is broad with barrierless transitions between states. A quantitative index of catalytic promiscuity is used to compare engineered variants of GSTA1-1 and the catalytic promiscuity correlates strongly with characteristics of the thermodynamic partition function, for the substrate free enzymes. Access to chemically disparate transition states is encoded by the substrate-free conformational ensemble. Pre-steady state catalytic data confirm an extension of the conformational selection model, wherein different substrates select different starting conformations. The kinetic liability of the conformational breadth is minimized by a smooth landscape. We propose that "local" molten globule behavior optimizes detoxication enzymes. PMID- 23649629 TI - Hepatitis B viral RNA directly mediates down-regulation of the tumor suppressor microRNA miR-15a/miR-16-1 in hepatocytes. AB - Hepatitis B virus (HBV) is a key risk factor for the development of hepatocellular carcinoma (HCC). Recent work suggests a functional link between HCC and microRNA expression, but the mechanism underlying the functional interaction between microRNA and HBV infection has remained largely elusive. Here we present evidence that the microRNA machinery serves as a defense system against HBV infection, which, in turn, reprograms the expression of specific microRNAs. We demonstrate a critical role of miR-15a/miR-16-1 in this functional interplay between microRNA and HBV infection, but in contrast to various indirect mechanisms mediated by viral proteins, we unexpectedly found that the HBx transcript directly triggers the down-regulation of miR-15a/miR-16-1 via the microRNA targeting sequences in the viral RNA. Because miR-15a and miR-16-1 are well known tumor suppressor microRNAs in multiple human cancers, our findings raise the intriguing possibility that viral RNA-mediated down-regulation of specific tumor suppressor microRNAs may contribute to HCC development in HBV infected cells. PMID- 23649627 TI - Adenylyl cyclase anchoring by a kinase anchor protein AKAP5 (AKAP79/150) is important for postsynaptic beta-adrenergic signaling. AB - Recent evidence indicates that the A kinase anchor protein AKAP5 (AKAP79/150) interacts not only with PKA but also with various adenylyl cyclase (AC) isoforms. However, the physiological relevance of AC-AKAP5 binding is largely unexplored. We now show that postsynaptic targeting of AC by AKAP5 is important for phosphorylation of the AMPA-type glutamate receptor subunit GluA1 on Ser-845 by PKA and for synaptic plasticity. Phosphorylation of GluA1 on Ser-845 is strongly reduced (by 70%) under basal conditions in AKAP5 KO mice but not at all in D36 mice, in which the PKA binding site of AKAP5 (i.e. the C-terminal 36 residues) has been deleted without affecting AC association with GluA1. The increase in Ser 845 phosphorylation upon beta-adrenergic stimulation is much more severely impaired in AKAP5 KO than in D36 mice. In parallel, long term potentiation induced by a 5-Hz/180-s tetanus, which mimics the endogenous theta-rhythm and depends on beta-adrenergic stimulation, is only modestly affected in acute forebrain slices from D36 mice but completely abrogated in AKAP5 KO mice. Accordingly, anchoring of not only PKA but also AC by AKAP5 is important for regulation of postsynaptic functions and specifically AMPA receptor activity. PMID- 23649630 TI - Transcription factors SOX4 and SOX11 function redundantly to regulate the development of mouse retinal ganglion cells. AB - SOX family proteins belong to the high-mobility-group (HMG) domain-containing transcription factors, and function as key players to regulate embryonic development and cell fate determination. The highly related group C Sox genes Sox4 and Sox11 are widely expressed in the development of mouse retina and share a similar expression pattern with each other in this process. Here, to investigate the roles of Sox4 and Sox11 in the retinal development, Sox4, Sox11, and Sox4/Sox11 conditional knock-out (CKO) mice with deletion of Sox4, Sox11, and Sox4/Sox11 in retinas were generated. Our studies demonstrated that targeted disruption of Sox4 or Sox11 in retinas caused a moderate reduction of generation of RGCs. However, a complete loss of RGCs was observed in Sox4/Sox11-null retinas, suggesting the two genes play similar roles in the development of RGCs. Our further analysis confirms that Sox4 and Sox11 function redundantly to regulate the generation of RGCs at early embryonic stages as well as the survival of RGCs at late embryonic stages. In addition, we demonstrated that loss of Math5 impairs the expression of Sox4 and Sox11 in the ganglion cell layer while deletion of Brn3b has no effect on the expression of Sox4 and Sox11. Taken together, these findings elucidate SoxC genes as essential contributors to maintain the survival of RGCs, and imply their intermediate position between Math5 and Brn3b in the genetic hierarchy of RGC development. PMID- 23649631 TI - c-MYC-regulated miR-23a/24-2/27a cluster promotes mammary carcinoma cell invasion and hepatic metastasis by targeting Sprouty2. AB - Emerging evidence indicates that the miR-23a/24-2/27a cluster may possess a causal role in mammary tumorigenesis and function as a novel class of oncogenes. However, the regulatory mechanism of the miR-23a/24-2/27a cluster in mammary carcinoma cell invasion and migration is still largely unknown. We observed that the expression levels of miR-23a, miR-24-2 and miR-27a were significantly higher in breast cancer with lymph node metastasis, compared with that from patients without lymph node metastasis or normal tissue. Forced expression of the miR 23a/24-2/27a cluster promoted mammary carcinoma cell migration, invasion, and hepatic metastasis, through targeting Sprouty2 (SPRY2) and consequent activation of p44/42 MAPK. Epidermal growth factor induced the expression of the transcription factor c-MYC, which promoted the expression of mature miR-23a, miR 24-2, and miR-27a and subsequently decreased expression of SPRY2 and activated p44/42 MAPK to promote mammary carcinoma cell migration and invasion. We therefore suggest a novel link between epidermal growth factor and the miR-23a/24 2/27a cluster via the regulation of c-MYC, providing the potential for the miR 23a/24-2/27a cluster to be used as biomarker in the diagnosis and/or treatment of breast cancer. PMID- 23649632 TI - Smad2 is essential for maintenance of the human and mouse primed pluripotent stem cell state. AB - Human embryonic stem cells and mouse epiblast stem cells represent a primed pluripotent stem cell state that requires TGF-beta/activin signaling. TGF-beta and/or activin are commonly thought to regulate transcription through both Smad2 and Smad3. However, the different contributions of these two Smads to primed pluripotency and the downstream events that they may regulate remain poorly understood. We addressed the individual roles of Smad2 and Smad3 in the maintenance of primed pluripotency. We found that Smad2, but not Smad3, is required to maintain the undifferentiated pluripotent state. We defined a Smad2 regulatory circuit in human embryonic stem cells and mouse epiblast stem cells, in which Smad2 acts through binding to regulatory promoter sequences to activate Nanog expression while in parallel repressing autocrine bone morphogenetic protein signaling. Increased autocrine bone morphogenetic protein signaling caused by Smad2 down-regulation leads to cell differentiation toward the trophectoderm, mesoderm, and germ cell lineages. Additionally, induction of Cdx2 expression, as a result of decreased Smad2 expression, leads to repression of Oct4 expression, which, together with the decreased Nanog expression, accelerates the loss of pluripotency. These findings reveal that Smad2 is a unique integrator of transcription and signaling events and is essential for the maintenance of the mouse and human primed pluripotent stem cell state. PMID- 23649633 TI - Selective binding of antimicrobial porphyrins to the heme-receptor IsdH-NEAT3 of Staphylococcus aureus. AB - The Isd (iron-regulated surface determinant) system of the human pathogen Staphylococcus aureus is responsible for the acquisition of heme from the host organism. We recently reported that the extracellular heme receptor IsdH-NEAT3 captures and transfers noniron antimicrobial porphyrins containing metals in oxidation state (III). However, it is unclear if geometric factors such as the size of the metal (ionic radius) affect binding and transfer of metalloporphyrins. We carried out an ample structural, functional, and thermodynamic analysis of the binding properties of antimicrobial indium(III) porphyrin, which bears a much larger metal ion than the iron(III) of the natural ligand heme. The results demonstrate that the NEAT3 receptor recognizes the In(III)-containing PPIX in a manner very similar to that of heme. Site-directed mutagenesis identifies Tyr642 as the central element in the recognition mechanism as suggested from the crystal structures. Importantly, the NEAT3 receptor possesses the remarkable ability to capture dimers of metalloporphyrin. Molecular dynamics simulations reveal that IsdH-NEAT3 does not require conformational changes, or large rearrangements of the residues within its binding site, to accommodate the much larger (heme)2 ligand. We discuss the implications of these findings for the design of potent inhibitors against this family of key receptors of S. aureus. PMID- 23649635 TI - Function of ezrin-radixin-moesin proteins in migration of subventricular zone derived neuroblasts following traumatic brain injury. AB - Throughout life, newly generated neuroblasts from the subventricular zone migrate toward the olfactory bulb through the rostral migratory stream. Upon brain injury, these migrating neuroblasts change their route and begin to migrate toward injured regions, which is one of the regenerative responses after brain damage. This injury-induced migration is triggered by stromal cell-derived factor 1 (SDF1) released from microglia near the damaged site; however, it is still unclear how these cells transduce SDF1 signals and change their direction. In this study, we found that SDF1 promotes the phosphorylation of ezrin-radixin moesin (ERM) proteins, which are key molecules in organizing cell membrane and linking signals from the extracellular environment to the intracellular actin cytoskeleton. Blockade of ERM activation by overexpressing dominant-negative ERM (DN-ERM) efficiently perturbed the migration of neuroblasts. Considering that DN ERM-expressing neuroblasts failed to maintain proper migratory cell morphology, it appears that ERM-dependent regulation of cell shape is required for the efficient migration of neuroblasts. These results suggest that ERM activation is an important step in the directional migration of neuroblasts in response to SDF1 CXCR4 signaling following brain injury. PMID- 23649634 TI - HOX antisense lincRNA HOXA-AS2 is an apoptosis repressor in all trans retinoic acid treated NB4 promyelocytic leukemia cells. AB - HOXA cluster antisense RNA 2 (HOXA-AS2) is a long non-coding RNA located between the HOXA3 and HOXA4 genes in the HOXA cluster. Its transcript is expressed in NB4 promyelocytic leukemia cells and human peripheral blood neutrophils, and expression is increased in NB4 cells treated with all trans retinoic acid (ATRA). Knockdown of HOXA-AS2 expression by transduced shRNA decreases the number of viable cells and increases the proportion of apoptotic cells, measured by annexin V binding and by activity and cleavage of caspases-3, -8, and -9. The increase in death of HOXA-AS2 knockdown cells was accompanied by an elevated TNF-related apoptosis-inducing ligand (TRAIL) levels, but ATRA-induced NB4 cells treated with TRAIL did show an increase in HOXA-AS2 expression. These results demonstrate that ATRA induction of HOXA-AS2 suppresses ATRA-induced apoptosis, possibly through a TRAIL-mediated pathway. HOXA-AS2-mediated negative regulation thus contributes to the fine-tuning of apoptosis during ATRA-induced myeloid differentiation in NB4 cells. PMID- 23649636 TI - [Intravenous immunoglobulin treatment in idiopathic inflammatory myopathy]. AB - Idiopathic inflammatory myopathies are chronic, systemic autoimmune diseases, characterized by symmetric and progressive weakness of proximal muscles in the upper and lower extremities. Treatment of the disease presents a complex challenge and it needs practical knowledge. In this review the authors summarize current treatment options, and discuss intravenous immunoglobulin treatment in therapy-unresponsive cases. Relevant data from the international literature is collected, too. Benefits and side effects of this treatment are also disclosed. PMID- 23649637 TI - [The role of vitamin D deficiency in the pathogenesis of falls and fractures]. AB - The diverse effects of vitamin D in human body became known during the last years. Vitamin D deficiency causes many problems in medical care. Important roles of vitamin D are the regulation of calcium metabolism and the effect on bone metabolism. The authors review literature data on vitamin D deficiency recognized as an important risk factor in the pathogenesis of falls and fractures and they call attention of Hungarian physicians to the importance of vitamin D substitution. Supplementation of vitamin D deficiency is particularly important in the elderly age-group. PMID- 23649638 TI - [Combined l-thyroxine and l-triiodothyronine replacement therapy in congenital hypothyroidism]. AB - INTRODUCTION: L-thyroxine replacement therapy is the treatment of choice for hypothyroidism. Recently, several studies suggested to complete it with l triiodothyronine in acquired hypothyroidism. AIM: To study the role of combined l thyroxine and l-triiodothyronine therapy in special cases with congenital hypothyroidism. METHOD: Data of 16 patients (age: 11.9 +/- 6.3 years; mean +/- SD) are presented who had high serum free thyroxine values or even above the upper limit of reference range (21.16 +/- 2.5 pmol/l) together with nonsuppressed TSH levels (15.7 +/- 5.7 mIU/l), and therefore received l-triiodothyronine in completion (0.18 +/- 0.09 MUg/kg) once a day. RESULTS: The combined replacement therapy resulted in a rapid improvement of the hormone parameters (TSH: 4.2 +/- 3.15 mIU/l; free thyroxine: 16.55 +/- 2.4 and free triiodothyronine: 7.4 +/- 1.8 pmol/l). The efficiency of this combined therapy proved to be more evident (TSH: 4.33 +/- 3.2 mIU/l; free thyroxine: 16.85 +/- 3.1 and free triiodothyronine: 6.4 +/- 0.85 pmol/l) in 10 patients treated for a longer period of time (duration of treatment: 2.9 +/- 2.0 years). The dose of thyroxine substitution decreased from 2.6 +/- 0.9 to 2.18 +/- 0.6 MUg/kg/day), the ratio of these hormones was between 5:1 and 19:1 and the quotient of free fractions was normalized (3.8 +/- 0.4->2.6 +/- 0.3) during the replacement therapy. CONCLUSIONS: According to the observation of the authors a serious disturbance of feed-back mechanism may develop in some (>5%) children with congenital hypothyroidism (increased TSH release despite elevated free thyroxine level) after normal function of the feed back system for years. Hormone parameters of these patients improve, then become normal on combined therapy supporting the rationale for this treatment method. PMID- 23649639 TI - [Laparoscopic skills training -- novel methods]. AB - INTRODUCTION: Simulation for skill training has a long history in surgery. Initially, surgeons practiced on animals or human cadavers, which is costly and raises ethical questions. Emerging hygienic requirements lead to the development of "artificial" phantoms, on which suturing, anastomoses and other elements of the procedure could be practiced on. Similarly, in minimal invasive surgery surgeons need extensive practice to learn the correct techniques, and to acquire sufficient skills. Laparoscopy requires specific training devices, ranging from animal models to virtual reality simulators. AIM: This work focused on physical simulators, development of affordable phantoms and adjoin tasks for a personal laparoscopic training box. Authors described five new tasks that were added to the classical curriculum. METHODS: The tasks included leading the line, ligation, preparation-ligation, leading a string and camera handling. Data was were derived from a trial with 30 participants. They were categorized into 3 groups: laymen, general practitioner residents (non-surgeons) and surgery residents. Subjective assessment of the new tasks was performed using a 20-points questionnaire (NASA Task Load Index). Participants were asked about the usefulness, mental, physical, temporal demand, performance, effort and frustration. Accomplishment time was also recorded for each task (as well as the number or errors, where applicable). In addition, 10 consecutive task execution sessions were recorded, and in some cases, users' performance was tracked over a follow-up period of several days. RESULTS: Participants considered the tasks suitable and relevant for education, and also approved them for self-education purposes. The three groups showed statistically significant differences in performance, based on their average completion time. CONCLUSION: The follow-up studies showed continuous progress in the completion of individual tasks. PMID- 23649640 TI - [Antihypertensive drug trials also reveal renoprotective effects]. AB - The author analyzes the applicability of the renin-angiotensin system blocking drugs in patients with chronic kidney disease emphasizing their renoprotective (blood pressure and albuminuria lowering) and cardiovascular risk decreasing effects. As opposed to a previously-published statement, the author believes that their application is fundamental, particularly in combination with calcium antagonist drugs. Relying on many references the author suggests that combined treatment with different renin-angiotensin system blocking drugs cannot be entirely ruled out, although it is not yet recommended. PMID- 23649642 TI - Palladium-catalyzed allylic substitution at four-membered-ring systems: formation of eta1-allyl complexes and electrocyclic ring opening. PMID- 23649643 TI - Ebselen reduces the toxicity of mechlorethamine in A-431 cells via inhibition of apoptosis. AB - A series of test compounds were evaluated for an ability to reduce the toxicity of the nitrogen mustard mechlorethamine (HN2) in vitro. The test compounds included resveratrol, pterostilbene, vitamin C, ebselen, ebselen diselenide, and ebselen-sulfur. Among them, ebselen demonstrated the highest degree of protection against HN2 toxicity. To this end, pretreatment of the cells with ebselen offered protection against the toxicant whereas no protection was observed when cells were first incubated with HN2 and then treated with ebselen. Significant increases in caspase 3 and caspase 9 activities were observed in response to HN2, and ebselen was found to reduce these effects. Taken together, the data presented here indicate that ebselen is an effective countermeasure to nitrogen mustard in vitro, which is worthy of future investigation in vivo. PMID- 23649645 TI - Versatile reactivity of a lithium tris(aryl)plumbate(II) towards organolanthanoid compounds: stable lead-lanthanoid-metal bonds or redox processes. AB - Redox chemistry: Redox-active europium complexes based on a new tris(2 pyridyl)plumbate ligand are described. Reactions of [LiPb(2-py(R))3(thf)] (py(R) = C5H3-6-OtBu) with tri- or divalent lanthanoid metals resulted in the first stable Pb-Ln-bonded complexes or unprecedented redox reactions, involving, for example, the pentametallic complex depicted. PMID- 23649644 TI - Nutraceutical nanoemulsions: influence of carrier oil composition (digestible versus indigestible oil) on beta-carotene bioavailability. AB - BACKGROUND: Carotenoids, such as beta-carotene, are widely used in foods and beverages as natural colorants and nutraceuticals. We investigated the influence of carrier oil composition (ratio of digestible to indigestible oil) on the physical stability, microstructure and bioaccessibility of beta-carotene nanoemulsions using a simulated gastrointestinal tract model. RESULTS: beta Carotene nanoemulsions (d < 150 nm) were formed by high-pressure homogenization using sucrose monoester and lysolecithin as emulsifiers, and mixtures of corn oil (digestible) and lemon oil (indigestible) as the lipid phase. All of the nanoemulsions underwent extensive droplet aggregation under mouth, stomach and small intestine conditions. The extent of free fatty acid production in the small intestine increased as the amount of digestible oil in the droplets increased. The bioaccessibility of beta-carotene also increased with increasing digestible oil content, ranging from ~5% for the pure lemon oil system to ~76% for the pure corn oil system. This effect was attributed to the ability of mixed micelles formed from triglyceride digestion products (free fatty acids and monoglycerides) to solubilize beta-carotene. CONCLUSIONS: This study provides important information for developing effective delivery systems for lipophilic bioactive components in food and beverage applications. PMID- 23649646 TI - Late-life alcohol consumption and cognitive function in elderly men. AB - Moderate alcohol consumption (one to two drinks per day) has been associated with better cognitive function and lower risk of developing dementia in the elderly. In light of alcohol's well-known neurotoxic properties, more evidence from well controlled population-based studies is required. The objective of this study was to examine whether self-reported alcohol intake at age 70 is linked to cognitive function (assessed by trail making tests (TMTs) A and B, which are measures of attention, mental speed, and flexibility) in a population-based cohort consisting of 652 cognitively healthy elderly men. Linear regression models were used to assess both cross-sectional (i.e., age 70) and prospective (i.e., age 77) associations between alcohol intake and cognitive function. The analyses were adjusted for education, body mass index, energy intake, self-reported physical activity, smoking, a history of hypertension or diabetes, apolipoprotein E epsilon4 status, and cholesterol levels at the age of 70. Baseline data were obtained from 1990 to 1996. Self-reported alcohol intake (mean 6.9 +/- 7.1 g/day) was associated with better performance on TMT-B at ages 70 and 77 (beta = -0.87, p < 0.001). In contrast, alcohol intake was not predictive of the difference in performance on these tests between ages 70 and 77. Despite cross-sectional associations with performance in a test of executive functioning, moderate intake of alcohol was not linked to differences in cognitive performance between ages 70 and 77 in the present study. Thus, our findings do not support the view that daily moderate alcohol consumption is a recommendable strategy to slow cognitive aging in elderly populations. PMID- 23649647 TI - High macro-collinearity between lima bean (Phaseolus lunatus L.) and the common bean (P. vulgaris L.) as revealed by comparative cytogenetic mapping. AB - Common bean (P. vulgaris) and lima bean (P. lunatus) are the most important crop species from the genus Phaseolus. Both species have the same chromosome number (2n = 22) and previous cytogenetic mapping of BAC clones suggested conserved synteny. Nevertheless, karyotype differences were observed, suggesting structural rearrangements. In this study, comparative cytogenetic maps for chromosomes 3, 4 and 7 were built and the collinearity between the common bean and lima bean chromosomes was investigated. Thirty-two markers (30 BACs and 2 bacteriophages) from P. vulgaris were hybridized in situ on mitotic chromosomes from P. lunatus. Nine BACs revealed a repetitive DNA pattern with pericentromeric distribution and 23 markers showed unique signals. Nine of these markers were mapped on chromosome 3, eight on chromosome 4 and six on chromosome 7. The order and position of all analyzed BACs were similar between the two species, indicating a high level of macro-collinearity. Thus, although few inversions have probably altered centromere position in other chromosomes, the main karyotypic differences were associated with the repetitive DNA fraction. PMID- 23649648 TI - Mapping QTL for grain yield and other agronomic traits in post-rainy sorghum [Sorghum bicolor (L.) Moench]. AB - Sorghum, a cereal of economic importance ensures food and fodder security for millions of rural families in the semi-arid tropics. The objective of the present study was to identify and validate quantitative trait loci (QTL) for grain yield and other agronomic traits using replicated phenotypic data sets from three post rainy dry sorghum crop seasons involving a mapping population with 245 F9 recombinant inbred lines derived from a cross of M35-1 * B35. A genetic linkage map was constructed with 237 markers consisting of 174 genomic, 60 genic and 3 morphological markers. The QTL analysis for 11 traits following composite interval mapping identified 91 QTL with 5-12 QTL for each trait. QTL detected in the population individually explained phenotypic variation between 2.5 and 30.3 % for a given trait and six major genomic regions with QTL effect on multiple traits were identified. Stable QTL across seasons were identified. Of the 60 genic markers mapped, 21 were found at QTL peak or tightly linked with QTL. A gene-based marker XnhsbSFCILP67 (Sb03g028240) on SBI-03, encoding indole-3-acetic acid-amido synthetase GH3.5, was found to be involved in QTL for seven traits. The QTL-linked markers identified for 11 agronomic traits may assist in fine mapping, map-based gene isolation and also for improving post-rainy sorghum through marker-assisted breeding. PMID- 23649649 TI - Identification and mapping in spring wheat of genetic factors controlling stem rust resistance and the study of their epistatic interactions across multiple environments. AB - Stem rust (Puccinia graminis f. sp. tritici) is responsible for major production losses in hexaploid wheat (Triticum aestivum L.) around the world. The spread of stem rust race Ug99 and variants is a threat to worldwide wheat production and efforts are ongoing to identify and incorporate resistance. The objectives of this research were to identify quantitative trait loci (QTL) and to study their epistatic interactions for stem rust resistance in a population derived from the Canadian wheat cultivars AC Cadillac and Carberry. A doubled haploid (DH) population was developed and genotyped with DArT((r)) and SSR markers. The parents and DH lines were phenotyped for stem rust severity and infection response to Ug99 and variant races in 2009, 2010 and 2011 in field rust nurseries near Njoro, Kenya, and to North American races in 2011 and 2012 near Swift Current, SK, Canada. Seedling infection type to race TTKSK was assessed in a bio containment facility in 2009 and 2012 near Morden, MB. Eight QTL for stem rust resistance and three QTL for pseudo-black chaff on nine wheat chromosomes were identified. The phenotypic variance (PV) explained by the stem rust resistance QTL ranged from 2.4 to 48.8 %. AC Cadillac contributed stem rust resistance QTL on chromosomes 2B, 3B, 5B, 6D, 7B and 7D. Carberry contributed resistance QTL on 4B and 5A. Epistatic interactions were observed between loci on 4B and 5B, 4B and 7B, 6D and 3B, 6D and 5B, and 6D and 7B. The stem rust resistance locus on 6D interacted synergistically with 5B to improve the disease resistance through both crossover and non-crossover interactions depending on the environment. Results from this study will assist in planning breeding for stem rust resistance by maximizing QTL main effects and epistatic interactions. PMID- 23649650 TI - Earliness per se QTLs and their interaction with the photoperiod insensitive allele Ppd-D1a in the Cutler * AC Barrie spring wheat population. AB - Earliness per se regulates flowering time independent of environmental signals and helps to fine tune the time of flowering and maturity. In this study, we aimed to map earliness per se quantitative trait loci (QTLs) affecting days to flowering and maturity in a population developed by crossing two spring wheat cultivars, Cutler and AC Barrie. The population of 177 recombinant inbred lines (RILs) was genotyped for a total of 488 SSR and DArT polymorphic markers on all 21 chromosomes. Three QTLs of earliness per se affecting days to flowering and maturity were mapped on chromosomes 1B (QEps.dms-1B1 and QEps.dms-1B2) and 5B (QEps.dms-5B1), in individual environments and when all the environments were combined. A QTL affecting flowering time (QFlt.dms-4A1) was identified on chromosome 4A. Two grain yield QTLs were mapped on chromosome 5B, while one QTL was mapped on chromosome 1D. The population segregated for the photoperiod insensitive gene, Ppd-D1a, and it induced earlier flowering by 0.69 days and maturity by 1.28 days. The photoperiod insensitive allele Ppd-D1a interacted in an additive fashion with QTLs for flowering and maturity times. The earliness per se QTL QFlt.dms-5B.1 inducing earlier flowering could help to elongate grain filling duration for higher grain yield. Hence, chromosome 5B possesses promising genomic regions that may be introgressed for higher grain yield with earlier maturity through marker-assisted selection in bread wheat. PMID- 23649651 TI - Association mapping of maturity and plant height using SNP markers with the sorghum mini core collection. AB - Plant height and maturity are two critical traits in sorghum breeding. To develop molecular tools and to identify genes underlying the traits for molecular breeding, we developed 14,739 SNP markers used to genotype the complete sorghum [Sorghum bicolor (L.) Moench] mini core collection. The collection was evaluated in four rainy and three post-rainy season environments for plant height and maturity. Association analysis identified six marker loci linked to height and ten to maturity in at least two environments with at least two SNPs in each locus. Of these, 14 were in close proximity to previously mapped height/maturity QTL in sorghum. Candidate genes for maturity or plant height close to the marker loci include a sugar transporter (SbSUC9), an auxin response factor (SbARF3), an FLC and FT regulator (SbMED12), and a photoperiod response gene (SbPPR1) for maturity and peroxidase 53, and an auxin transporter (SbLAX4) for plant height. Linkage disequilibrium analysis showed that SbPPR1 and SbARF3 were in regions with reduced sequence variation among early-maturing accessions, suggestive of past purifying selection. We also found a linkage disequilibrium block that existed only among the accessions with short plant height in rainy season environments. The block contains a gene homologous to the Arabidopsis flowering time gene, LUMINIDEPENDENS (LD). Functional LD promotes early maturity while mutation delays maturity, affecting plant height. Previous studies also found reduced sequence variations within this gene. These newly-mapped SNP markers will facilitate further efforts to identify plant height or maturity genes in sorghum. PMID- 23649652 TI - Effects of manganese superoxide dismutase (MnSOD) expression on regulation of esophageal cancer cell growth and apoptosis in vitro and in nude mice. AB - Manganese superoxide dismutase (MnSOD) catalyzes superoxide radical (O2 (-)) into hydrogen peroxide (H2O2), which is further catalyzed by the combined action of glutathione peroxidase (GPx) and catalase (CAT) into water and oxygen. MnSOD plays a role in cell protection from superoxide damage. This study aimed to investigate the effects of MnSOD on regulation of esophageal squamous cell carcinoma cell growth, apoptosis, and cell cycle distribution in vitro and tumor formation and growth in nude mouse xenografts. The data showed that differential levels of MnSOD expression had different effects on tumor cell proliferation, apoptosis, plating efficiency (PE), and cell cycle distribution in vitro and tumor formation and growth in nude mice. In particular, high levels of MnSOD expression promoted TE-1 cell growth and PE rate in vitro and in nude mice, whereas moderate MnSOD expression suppressed tumor cell growth and PE rate but induced more cell apoptosis. Thus, these data demonstrated the dual effects of MnSOD protein in esophageal squamous cell carcinoma and further study will confirm these current data. PMID- 23649653 TI - Association between MTHFR Ala222Val (rs1801133) polymorphism and bladder cancer susceptibility: a systematic review and meta-analysis. AB - Folate metabolism is thought to play an important role in carcinogenesis through its involvement in both DNA methylation and nucleotide synthesis. The association between the MTHFR Ala222Val polymorphism and bladder cancer has been widely reported, however, in general the data from published studies with individually low statistical power were controversial and underpowered. Hence, we performed a meta-analysis to investigate the association between bladder cancer and MTHFR Ala222Val in different inheritance models. Fourteen studies including a total of 3,570 bladder cancer cases and 3,926 controls for MTHFR rs1801133 polymorphism were included in the meta-analysis. Data were extracted from these studies and odds ratios with corresponding 95 % confidence intervals (95 % CI) were computed to estimate the strength of the association. Overall, the MTHFR Ala222Val polymorphism was not associated with the development of bladder cancer in all genetic models (Ala/Ala vs. Val/Val--OR = 0.961, 95 % CI = 0.763-1.209; Ala/Ala vs. Ala/Val--OR = 0.918, 95 % CI = 0.795-1.060--Ala/Val vs. Val/Val--OR = 1.022, 95 % CI = 0.852-1.227; dominant model--OR = 0.998, 95 % CI = 0.869-1.145; recessive model--OR = 0.921, 95 % CI = 0.794-1.069; Ala allele vs. Val allele--OR = 0.957, 95 % CI = 0.857-1.067). In the stratified analyses, no significant associations were found among different descent populations and sources of controls. Our meta-analysis suggests that the MTHFR Ala222Val polymorphism not contributes to the development of bladder cancer. PMID- 23649654 TI - CYP2A6 deletion polymorphism is associated with decreased susceptibility of lung cancer in Asian smokers: a meta-analysis. AB - Cytochrome P450 2A6 (CYP2A6) is an enzyme involved in the metabolism of some tobacco carcinogens, which is an important risk factor of lung cancer. Among CYP2A6 allelic variants, CYP2A6*4 presents a whole gene deletion that accounts for the majority of poor metabolizer. In this study, a meta-analysis was performed to assess the association between CYP2A6*4 and risk of lung cancer. Literature searches were conducted to identify peer-reviewed manuscripts published up to December 20, 2012. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were calculated in a fixed-effects model and a random effects model when appropriate. Eight eligible studies with 3,203 lung cancer cases and 2,839 controls were included in this study. Overall, no significant association was observed in CYP2A6*4 with the risk of lung cancer under any genetic model for all samples after correction. However, subgroup analysis showed that significant associations were observed in Asian with pooled OR (95 %CI) of 0.761 (0.672-0.861) for allele comparison, 0.769 (0.668-0.886) for dominant model, and 0.522 (0.359-0.760) for recessive model. Furthermore, after stratifying Asian samples according to smoking status, significant associations were only observed in smokers with pooled OR (95 %CI) of 0.713 (0.607-0.838) for allele comparison, 0.720 (0.596-0.869) for dominant model, and 0.444 (0.275 0.715) for recessive model. This meta-analysis suggests that the CYP2A6*4 polymorphism was associated with susceptibility of lung cancer for smokers in Asian. The whole gene deletion of CYP2A6 might decrease the risk of tobacco related lung cancer in Asian. PMID- 23649655 TI - CCL19/CCR7 upregulates heparanase via specificity protein-1 (Sp1) to promote invasion of cell in lung cancer. AB - CCL19/chemokine receptor 7 (CCR7) has been found to be associated with tumor growth, angiogenesis, invasion, and lymph node metastasis. Our previous study demonstrated that CCR7 overexpressed in non-small cell lung cancer (NSCLC) and had close relationship with tumor invasion and lymph node metastasis. However, the molecular mechanism of CCR7 promoting invasion of human NSCLC cells is still unclear. In this study, we demonstrated that human lung adenocarcinoma A549 cells treated with recombinant human CCL19 could obviously upregulate the expression of Sp1 and heparanase at both the mRNA and protein levels. After blockage of CCR7, Sp1 and heparanase expressions were inhibited. Following inhibition of Sp1, heparanase expression was downregulated. The analysis showed the promoter region of heparanase gene containing a number of potential sp1 binding sites (5'-GGGGC 3'). Chromatin immunoprecipitation analysis demonstrated that Sp1 could bind to the heparanase promoter. Cell invasion assays showed that the invasion ability of A549 cells was increased with CCL19 incubation compared to the control cells. These results suggested that CCL19/CCR7 may upregulate the expression of heparanase via Sp1 and contribute to the invasion of A549 cells. PMID- 23649656 TI - Provision of spiritual support to patients with advanced cancer by religious communities and associations with medical care at the end of life. AB - IMPORTANCE: Previous studies report associations between medical utilization at the end-of-life (EoL) and religious coping and spiritual support from the medical team. However, the influence of clergy and religious communities on EoL outcomes is unclear. OBJECTIVE: To determine whether spiritual support from religious communities influences terminally ill patients' medical care and quality of life (QoL) near death. DESIGN, SETTING, AND PARTICIPANTS: A US-based, multisite cohort study of 343 patients with advanced cancer enrolled from September 2002 through August 2008 and followed up (median duration, 116 days) until death. Baseline interviews assessed support of patients' spiritual needs by religious communities. End-of-life medical care in the final week included the following: hospice, aggressive EoL measures (care in an intensive care unit [ICU], resuscitation, or ventilation), and ICU death. MAIN OUTCOMES AND MEASURES: End-of life QoL was assessed by caregiver ratings of patient QoL in the last week of life. Multivariable regression analyses were performed on EoL care outcomes in relation to religious community spiritual support, controlling for confounding variables, and were repeated among high religious coping and racial/ethnic minority patients. RESULTS: Patients reporting high spiritual support from religious communities (43%) were less likely to receive hospice (adjusted odds ratio [AOR], 0.37; 95% CI, 0.20-0.70 [P = .002]), more likely to receive aggressive EoL measures (AOR, 2.62; 95% CI, 1.14-6.06 [P = .02]), and more likely to die in an ICU (AOR, 5.22; 95% CI, 1.71-15.60 [P = .004]). Risks of receiving aggressive EoL interventions and ICU deaths were greater among high religious coping (AOR, 11.02; 95% CI, 2.83-42.89 [P < .001]; and AOR, 22.02; 95% CI, 3.24 149.58 [P = .002]; respectively) and racial/ethnic minority patients (AOR, 8.03; 95% CI, 2.04-31.55 [P = .003]; and AOR, 11.21; 95% CI, 2.29-54.88 [P = .003]; respectively). Among patients well-supported by religious communities, receiving spiritual support from the medical team was associated with higher rates of hospice use (AOR, 2.37; 95% CI, 1.03-5.44 [P = .04]), fewer aggressive interventions (AOR, 0.23; 95% CI, 0.06-0.79 [P = .02]) and fewer ICU deaths (AOR, 0.19; 95% CI, 0.05-0.80 [P = .02]); and EoL discussions were associated with fewer aggressive interventions (AOR, 0.12; 95% CI, 0.02-0.63 [P = .01]). CONCLUSIONS AND RELEVANCE: Terminally ill patients who are well supported by religious communities access hospice care less and aggressive medical interventions more near death. Spiritual care and EoL discussions by the medical team may reduce aggressive treatment, highlighting spiritual care as a key component of EoL medical care guidelines. PMID- 23649657 TI - A metaphor analysis of recovering substance abusers' sensemaking of medication assisted treatment. AB - In this study, we examined metaphors invoked by people recovering from opioid dependence as they described the challenges and successes of using medication assisted treatment. Metaphors provide linguistic tools for expressing issues that are confusing, complex, hidden, and difficult to state analytically or literally. Using data from eight focus groups with 68 participants representing four ethnic minority groups, we conducted a grounded analysis to show how recovering substance users communicatively constructed addiction and recovery. The primary medication, methadone, was framed as "liquid handcuffs" that allowed those in recovery to quit "hustling," get "straight," and find "money in their pockets." Nonetheless, methadone also served as a "crutch," leaving them still feeling like "users" with "habits" who "came up dirty" to friends and family. In this analysis, we tease out implications of these metaphors, and how they shed light on sensemaking, agency, and related racial- and class-based structural challenges in substance abuse recovery. PMID- 23649658 TI - Ocular tremor in Parkinson's disease is due to eye, not head oscillation. PMID- 23649661 TI - Rapidly reversible manipulation of molecular activity with dual chemical dimerizers. PMID- 23649659 TI - Role of BDNF in central motor structures and motor diseases. AB - Brain-derived neurotrophic factor (BDNF), belonging to the neurotrophic family of growth factors, has a widespread distribution in the central and peripheral nervous systems. In central motor structures including the motor cortex, cerebellum, basal ganglia, and spinal cord, BDNF exerts both neurotrophic and direct electrophysiological effects via a high-affinity tyrosine receptor kinase B receptor and a common low-affinity p75 neurotrophin receptor. The underlying signaling pathways mainly involve mitogen-activated protein kinase cascades, phosphatidylinositol 3-kinase pathway, and phospholipase C-gamma pathway. The loss of BDNF usually leads to neurodegeneration in these motor centers and eventually results in several severe motor diseases, such as amyotrophic lateral sclerosis, spinocerebellar ataxias, Parkinson's disease, Huntington's disease, as well as vestibular syndrome. In this review, we summarize the recent understanding of functions of BDNF in motor structures and suggest that BDNF may be a potent candidate for the treatment of these neurodegenerative motor diseases. PMID- 23649662 TI - A molecularly defined iron-catalyst for the selective hydrogenation of alpha,beta unsaturated aldehydes. AB - A selective iron-based catalyst system for the hydrogenation of alpha,beta unsaturated aldehydes to allylic alcohols is presented. Applying the defined iron tetraphos complex [FeF(L)][BF4] (L = P(PhPPh2)3) in the presence of trifluoroacetic acid a broad range of aldehydes are reduced in high yields using low catalyst loadings (0.05-1 mol %). Excellent chemoselectivity for the reduction of aldehydes in the presence of other reducible moieties, for example, ketones, olefins, esters, etc. is achieved. Based on the in situ detected hydride species [FeH(H2)(L)](+) a catalytic cycle is proposed that is supported by computational calculations. PMID- 23649664 TI - Predicting how individuals approach enrichment: regulatory focus in cotton-top tamarins (Sanguinus oedipus). AB - Evidence is mounting that personality is associated with health and well-being in humans and other animals. In a step towards increasing our understanding of this link, we applied regulatory focus theory, a motivational perspective from social psychology, to the behavior of zoo-housed cotton top tamarins. We tested whether regulatory focus "personality," that is stable differences in whether an individual is motivated by gains versus safety, would 1) produce individual differences in behavior and 2) predict how individuals interact with enrichment. First, we characterized individuals with respect to several key behaviors: eating in the open, hiding, and time spent near the front of the exhibit. The monkeys were consistent in their behavioral tendencies across the 6-month study, allowing regulatory focus classification. One monkey showed evidence of being a promotion individual, that is, more motivated by gains than safety. One monkey showed evidence of being a prevention-individual, that is, more motivated by safety than gains. The other monkeys were stable in their behavior and showed evidence of being intermediate-individuals, that is, they favored neither gains nor safety. Using these characterizations, we predicted distinct patterns of individual object interactions with enrichment. For example, we predicted that a promotion individual (favoring gains over safety) would approach potential gains faster than a prevention-individual (favoring safety over gains). Counter-intuitively, however, we also predicted that a promotion-individual would approach non-gains slower than a prevention-individual concerned with safety. We found support for our predictions, which suggests that regulatory focus theory could be a useful tool for understanding how and why individuals interact with environmental enrichment. PMID- 23649665 TI - Labour exploitation and health: a case series of men and women seeking post trafficking services. AB - Research on the health of trafficked men and on the health problems associated with trafficking for labor exploitation are extremely limited. This study analysed data from a case series of anonymised case records of a consecutive sample of 35 men and women who had been trafficked for labor exploitation in the UK and who were receiving support from a non-governmental service between June 2009 and July 2010. Over three-quarters of our sample was male (77 %) and two thirds aged between 18 and 35 years (mean 32.9 years, SD 10.2). Forty percent reported experiencing physical violence while they were trafficked. Eighty-one percent (25/31) reported one or more physical health symptoms. Fifty-seven percent (17/30) reported one or more post-traumatic stress symptoms. A substantial proportion of men and women who are trafficked for labor exploitation may experience violence and abuse, and have physical and mental health symptoms. People who have been trafficked for forced labor need access to medical assessment and treatment. PMID- 23649666 TI - Validity of temporal measures as proxies for measuring acculturation in Asian Indian survey respondents. AB - There are few validated acculturation measures for Asian Indians in the U.S. We used the 2004 California Asian Indian Tobacco Survey to examine the relationship between temporal measures and eleven self-reported measures of acculturation. These items were combined to form an acculturation scale. We performed psychometric analysis of scale properties. Greater duration of residence in the U.S., greater percentage of lifetime in the U.S., and younger age at immigration were associated with more acculturated responses to the items for Asian Indians. Item-scale correlations for the 11-item acculturation scale ranged from 0.28-0.55 and internal consistency reliability was 0.73. Some support was found for a two factor solution; one factor corresponding to cultural activities (alpha = 0.70) and the other to social behaviors (alpha = 0.59). Temporal measures only partially capture the full dimensions of acculturation. Our scale captured several domains and possibly two dimensions of acculturation. PMID- 23649668 TI - The corneal transplant score: a simple corneal graft candidate calculator. AB - BACKGROUND: Shortage of corneas for transplantation has created long waiting lists in most countries. Transplant calculators are available for many organs. The purpose of this study is to describe a simple automatic scoring system for keratoplasty recipient candidates, based on several parameters that we consider most relevant for tissue allocation, and to compare the system's accuracy in predicting decisions made by a cornea specialist. METHODS: Twenty pairs of candidate data were randomly created on an electronic spreadsheet. A single priority score was computed from the data of each candidate. A cornea surgeon and the automated system then decided independently which candidate in each pair should have surgery if only a single cornea was available. RESULTS: The scoring system can calculate values between 0 (lowest priority) and 18 (highest priority) for each candidate. Average score value in our randomly created cohort was 6.35 +/- 2.38 (mean +/- SD), range 1.28 to 10.76. Average score difference between the candidates in each pair was 3.12 +/- 2.10, range 0.08 to 8.45. The manual scoring process, although theoretical, was mentally and emotionally demanding for the surgeon. Agreement was achieved between the human decision and the calculated value in 19 of 20 pairs. Disagreement was reached in the pair with the lowest score difference (0.08). CONCLUSIONS: With worldwide donor cornea shortage, waiting for transplantation can be long. Manual sorting of priority for transplantation in a long waiting list is difficult, time-consuming and prone to error. The suggested system may help achieve a justified distribution of available tissue. PMID- 23649667 TI - Hes1 desynchronizes differentiation of pluripotent cells by modulating STAT3 activity. AB - Robust development of the early embryo may benefit from mechanisms that ensure that not all pluripotent cells differentiate at exactly the same time: such mechanisms would build flexibility into the process of lineage allocation. This idea is supported by the observation that pluripotent stem cells differentiate at different rates in vitro. We use a clonal commitment assay to confirm that pluripotent cells commit to differentiate asynchronously even under uniform differentiation conditions. Stochastic variability in expression of the Notch target gene Hes1 has previously been reported to influence neural versus mesodermal differentiation through modulation of Notch activity. Here we report that Hes1 also has an earlier role to delay exit from the pluripotent state into all lineages. The early function of Hes1 to delay differentiation can be explained by an ability of Hes1 to amplify STAT3 responsiveness in a cell autonomous manner. Variability in Hes1 expression therefore helps to explain why STAT3 responsiveness varies between individual ES cells, and this in turn helps to explain why pluripotent cells commit to differentiate asynchronously. PMID- 23649670 TI - Nanostructured 3D electrode architectures for high-rate Li-ion batteries. AB - By initially depositing a sub-10 nm-thick SnO2 film, the microstructural evolution that is often considered problematic can be utilized to form Sn nanoparticles on the surface of a 3D current collector for enhanced cycling stability. The work described here highlights a novel approach for the uniform deposition of Sn nanoparticles, which can be used to design electrodes with high capacities and high-rate capabilities. PMID- 23649669 TI - Dietary flavonoid, lignan and antioxidant capacity and risk of hepatocellular carcinoma in the European prospective investigation into cancer and nutrition study. AB - Limited epidemiological evidence suggests a protective role for plant foods rich in flavonoids and antioxidants in hepatocellular cancer (HCC) etiology. Our aim was to prospectively investigate the association between dietary intake of flavonoids, lignans and nonenzymatic antioxidant capacity (NEAC) and HCC risk. Data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 477,206 subjects (29.8% male) recruited from ten Western European countries, was analyzed. Flavonoid, lignan and NEAC intakes were calculated using a compilation of existing food composition databases linked to dietary information from validated dietary questionnaires. Dietary NEAC was based on ferric reducing antioxidant capacity (FRAP) and total radical-trapping antioxidant parameter (TRAP). Hepatitis B/C status was measured in a nested case control subset. During a mean follow-up of 11-years, 191 incident HCC cases (66.5% men) were identified. Using Cox regression, multivariable adjusted models showed a borderline nonsignificant association of HCC with total flavonoid intake (highest versus lowest tertile, HR = 0.65, 95% CI: 0.40-1.04; p(trend) = 0.065), but not with lignans. Among flavonoid subclasses, flavanols were inversely associated with HCC risk (HR = 0.62, 95% CI: 0.39-0.99; p(trend) = 0.06). Dietary NEAC was inversely associated with HCC (FRAP: HR 0.50, 95% CI: 0.31-0.81; p(trend) = 0.001; TRAP: HR 0.49, 95% CI: 0.31-0.79; p(trend) = 0.002), but statistical significance was lost after exclusion of the first 2 years of follow up. This study suggests that higher intake of dietary flavanols and antioxidants may be associated with a reduced HCC risk. PMID- 23649671 TI - Intravesical therapy in recurrent cystitis: a multi-center experience. AB - Approximately 20-30% of women suffer from recurrent cystitis. Recently, the problem of bacterial internalization, especially by Escherichia coli, has been significantly emerging as the main cause of recurrent episodes. It is believed that such a process is favored by damage to the urothelial mucous membrane. Concerning this, intravesical therapy with hyaluronic acid alone or in association with chondroitin sulfate was shown to improve urothelium thickness and reduction of bacterial load in the urine. The aim of our study was to assess whether intravesical therapy with hyaluronic acid (HA) and chondroitin sulfate (CS) is more effective than antibiotic therapy in reducing episodes and symptoms of recurrent urinary tract infections. We compared the number of recurring episodes in three groups of patients affected by recurrent urinary tract infections assigned to three different therapeutic regimens: the first group was treated only with HA and CS, the second group with HA and CS associated with fosfomycin, and the third group was treated only with fosfomycin (F). We assessed the number of recurrent episodes for each patient that occurred during a 6- to 12 month follow-up. The results showed 72.7% of patients in the HA-CS group, 75% in the fosfomycin + HA-CS group, and only 30.4% in the fosfomycin group were event free at follow-up. The results were analyzed using the Fisher's exact test. In conclusion, intravesical therapy with hyaluronic acid and chondroitin sulfate is an effective therapeutic approach to treat and prevent episodes of recurrent cystitis. PMID- 23649672 TI - Colorimetric and fluorometric detection of neomycin based on conjugated polydiacetylene supramolecules. AB - Utilizing the colorimetric and fluorogenic changes, a system based on polydiacetylenes (PDAs) is developed for the detection of neomycin. The PDA supramolecules polymerized from the mixed liposome composed of N-(3 hydroxyphenyl)pentacosa-10,12-diynamide (PCDA-AP) and pentacosa-10,12-diynoic acid (PCDA) at an optimized ratio of 1:9 display a unique colorimetric change (blue to red) and fluorescent enhancement in the presence of neomycin. The detection limit for neomycin is estimated to be 2.55 * 10(-7) M by the fluorogenic method. The optical changes induced by neomycin can be attributed to the disruption of the hydrogen bonding between phenol and carboxylic acid from PCDA-AP and PCDA. PMID- 23649673 TI - The effects of health status and health shocks on hours worked. AB - We investigate the impact of health on working hours. This is in recognition of the fact that leaving the labour market because of persistently low levels of health status, or because of new health shocks, is only one of the possible responses open to employees. We use the first six waves of the Household, Income and Labour Dynamics in Australia (HILDA) Survey to estimate the joint effect of health status and health shocks on working hours. To account for zero working hours, we use a dynamic random effects Tobit model of working hours. We follow Heckman (1981) and approximate the unknown initial conditions with a static equation that utilises information from the first wave of the data. Predicted individual health status is used to ameliorate the possible effects of measurement error and endogeneity. We conclude that overall, lower health status results in fewer working hours and that when they occur, health shocks lead to further reductions in working hours. Estimation results show that the model performs well in separating the time-persistent effect of health status and the potentially more transient health shocks on working hours. PMID- 23649675 TI - The electrophilic alpha-amination of alpha-alkyl-beta-ketoesters with in situ generated nitrosoformates. PMID- 23649676 TI - Recognizing and preventing medication administration errors. AB - Proper medication administration in the long-term care facility is vitally important, as many medications have specific administration parameters that are essential to their optimal efficacy. Pharmacists servicing long-term care facilities play an integral role in observing medication administration in the facility and educating facility staff on proper administration techniques. By being vigilant to potential problems, pharmacists can help ensure that facility residents receive their medications appropriately. PMID- 23649674 TI - Anti-tumor effects of various furocoumarins isolated from the roots, seeds and fruits of Angelica and Cnidium species under ultraviolet A irradiation. AB - We examined the effects on cell proliferation of 10 methoxyfurocoumarins and 7 dihydrofurocumarins isolated from Umbelliferae medicinal plants, and their mechanisms of action against B16F10 melanoma cells or in melanin-possessing hairless mice implanted with B16F10 melanoma cells, under UVA irradiation. Furocoumarins having a methoxy group, such as bergapten (1), xanthotoxin (2), phellopterin (4), byakangelicin (6), neobyakangelicin (8), isobergapten (9) and sphondin (10), showed anti-proliferative activity and caused G2/M arrest at concentrations of 0.05-15.0 MUM. The 7 dihydrofurocoumarins had no effect. UVA plus 1, 2, 4, 6 and sec-O-acetylbyakagelicin (7), having one methoxy group at the C-5 position and a linear-type conformation, reduced tumor growth and final tumor weight in B16F10-bearing mice at 0.5 or 1.0 mg/kg (intraperitoneal injection). UVA plus 1 and 2 increased Chk1 phosphorylation and decreased cdc2 (Thr 161) phosphorylation in the melanoma cells. The anti-tumor actions of UVA plus furocoumarins having a methoxy group might be due to the arrest of the cell cycle at G2/M through an increase in phospho-Chk1 and reduction in phospho-cdc2. PMID- 23649677 TI - Pharmacist-managed oral anticoagulation therapy in the community setting. AB - Pharmacists are at the forefront when caring for patients requiring anticoagulation resulting from chronic conditions, complex medications therapy, or at risk for drug interactions. As a consequence, there is a greater need for pharmacist-managed anticoagulation clinics in the community setting. This article will review special considerations for oral anticoagulant therapy in the elderly, collaborative therapy management, establishment of policies and procedures, documentation of patient visits, patient counseling, and barriers to successful anticoagulation management. It will also discuss evidence-based guidelines for the use of oral anticoagulants and compare the agents currently approved by the Food and Drug Administration. Finally, barriers to anticoagulation management will be examined, including issues with adherence and communication with patients and health care providers. PMID- 23649678 TI - Evaluation of type 2 diabetes mellitus medication management and control in older adults. AB - OBJECTIVES: The primary aims of this study were to characterize glycemic control and pharmacologic management in older patients and to compare glycemic control and pharmacological management in patients 65 to 79 years of age ("young-old") with those 80 to 89 years of age ("old-old"). We hypothesized that patients 80 to 89 years of age would be prescribed fewer medications and would have higher A1c values compared with younger patients. DESIGN: Retrospective medical record review. SETTING: This study was conducted in outpatient clinics within a university hospital setting. PATIENTS, PARTICIPANTS: This study included 400 adults 65 to 89 years of age with a diagnosis of type 2 diabetes mellitus and at least one A1c measurement over 12 months. MAIN OUTCOME MEASURES: A1c measurements and diabetes mellitus medications were assessed in these patients. RESULTS: The overall mean A1c was similar in the young-old compared with the old-old (7.1 +/- 1.1% vs. 7.0 +/- 1.1%; P = NS). There was no difference between groups for any of the A1c ranges studied. Fewer diabetes medications were prescribed in the old-old compared with the young-old (P = 0.003). In the young-old compared with the old old, metformin (51.0% vs. 33.0%; P < 0.01), glucagon-like peptide-1 agonists (6.7% vs. 0%; P < 0.01), insulin glargine/detemir (24.7% vs. 13.0%; P < 0.05), and short-acting insulin (15.0% vs. 7.0%; P < 0.05) were more frequently prescribed. CONCLUSION: Our results indicate that glycemic control was similar between the young-old and old-old. However, the old-old required fewer diabetic medications for this same level of glycemic control. PMID- 23649679 TI - Resistant hypertension in the elderly: optimizing outcomes while avoiding adverse effects. AB - Resistant hypertension (HTN) is defined as blood pressure (BP) that remains above goal, despite the concurrent use of three antihypertensive agents of different classes. This case describes an 89-year-old patient with an extensive history of resistant HTN and a complicated medication regimen who was referred to a pharmacy services clinic for medication review and assistance in management of antihypertensive medications. After the initial visit, the patient presented to the clinic with complaints of dizziness and fatigue and was found to be hypotensive. This case study discusses the important role of the pharmacist as part of a health care team in improving medication adherence and managing a patient's BP. PMID- 23649680 TI - Use of electronic personal health records to identify patients at risk for aspirin-induced gastrointestinal bleeding. AB - OBJECTIVE(S): The aim of this paper is to describe the utility of electronic personal health records (ePHRs) to identify patients with potential risk factors for aspirin-induced upper gastrointestinal bleeding (UGIB). SETTING: ER-Card, LLC. a for-profit ePHR company located in Rhode Island from October 2008 to May 2010. PRACTICE DESCRIPTION: Clinical pharmacists reviewed the records of 615 patients enrolled in an ePHR service. Records included patient self-report of all known medical conditions, current prescription medications, and self-care therapies utilized. PRACTICE INNOVATION: Pharmacists reviewed ePHR profiles for actual or potential medication-related problems. Patients taking low-dose aspirin (81 mg-325 mg daily) were screened for known additional risk factors for aspirin induced UGIB. Patients identified were notified to contact their provider for information and/or providers were contacted directly by pharmacists with therapy recommendations. MAIN OUTCOME MEASURE(S): Number of patients at increased risk for aspirin-induced UGIB as a result of concomitant medications. RESULTS: Ninety seven patients (16% of total records screened) with an average age of 72.1 years had risk factors for aspirin induced UGIB. In addition to daily aspirin therapy patients reported regular use of nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors (38%), other antiplatelet agents (22%), anticoagulants (24%), corticosteroids (4%), or a combination of these medications (12%). None of the patients included in this analysis reported use of prescribed or overthe-counter gastroprotective therapy (such as proton-pump inhibitors or histamine-2 receptor antagonists). CONCLUSION: Pharmacist screening of patient self-reported health information as part of an ePHR service can result in the detection of a significant number of patients at increased risk for aspirin induced UGIB. PMID- 23649681 TI - Self-testing and self-management of warfarin anticoagulation therapy in geriatric patients. AB - Although anticoagulation therapy with warfarin is necessary for many patients, the burden of frequent clinic visits for monitoring of therapy can pose a potential problem for some older adults. As self-monitoring of warfarin therapy has grown in popularity, a recent meta-analysis has reviewed data relating to self-testing and self-management of anticoagulation therapy. This same study also analyzed outcomes in the elderly, finding a potential benefit for self-monitoring in this population. This potential benefit, combined with the difficulties many elderly patients have attending clinic visits because of a lack of mobility or unavailability of transportation, makes self-monitoring of warfarin a viable option for carefully selected elderly patients. Pharmacists can play a vital role in educating patients about self-monitoring of oral anticoagulation therapy as well as identifying those elderly patients who are good candidates for its use. PMID- 23649682 TI - Medical apps worth having. AB - Medical applications (apps) for smart phones have grown in popularity, with minimal oversight by regulatory agencies. A few Web-based resources exist that evaluate apps using peer review or certification standards. Eight clinical apps are presented along with brief explanations of each. Many users believe apps improve patient care and clinical decision-making, but until additional research is conducted, these assertions remain untested assumptions. PMID- 23649684 TI - Effects of uvulopalatopharyngoplasty with or without radiofrequency tongue base reduction on voice in patients with obstructive sleep apnea. AB - OBJECTIVES/HYPOTHESIS: To investigate voice change as a complication after uvulopalatopharyngoplasty (UPPP) with or without radiofrequency tongue base reduction (RTBR) in patients with obstructive sleep apnea. STUDY DESIGN: Before and after study. METHODS: Twenty-two patients with suspected velopharyngeal collapse only underwent uvulopalatopharyngoplasty (UPPP group). Twenty-five patients with velopharyngeal and retrolingual collapse underwent concurrent UPPP with RTBR (RTBR group). All patients were evaluated before surgery and at 8 weeks after surgery. Acoustic measures included mean fundamental frequency (mF0), maximal phonation time (MPT), jitter, shimmer, noise-to-harmonic ratio (NHR), hypernasality test, and the first three formant frequencies (F1, F2, F3) for sustained vowels. Voice handicap index (VHI) was used to determine subjective voice change. RESULTS: Postoperative values for mF0, MPT, jitter, shimmer, NHR, hypernasality test, and F1 did not significantly change in either group following surgery. There were the significant decreases at the F2 of /u/ and the F3 of /o/ in the UPPP group, and at the F2 of /o/ and the F3 of /a/, /i/, and /o/ in the RTBR group. Postoperative VHI score was increased only in the RTBR group. CONCLUSIONS: UPPP and UPPP with RTBR have an impact on formant frequencies of vowels. Despite a relatively small number of patients, it is apparent that UPPP with RTBR influences VHI. Patients, especially professional voice users, should be advised of this before considering the surgery. PMID- 23649683 TI - Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model. AB - BACKGROUND: Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas may affect the cytotoxic drug distribution by normalizing the blood-brain barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib. METHODS: Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation, TMZ (50 mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for 6 h following TMZ administration. Cediranib (6 mg/kg) was then given orally, and 12 h later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment. RESULTS: After dosing of oral TMZ only, ECF-TMZ mean C(max) and area under the concentration curve(AUC(0-infinity)) within the tumor were 0.59 MUg/mL and 1.82 MUg h/mL, respectively. Post-cediranib, ECF-TMZ mean C(max) and AUC(0-infinity) were 0.83 MUg/mL and 3.72 +/- 0.61 MUg h/mL within the tumor, respectively. This represented a 1.4-fold (p = 0.3) and 2.0-fold (p = 0.06) increase in the ECF-TMZ C(max) and AUC(0-infinity), respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB "normalization" profile following cediranib treatment. CONCLUSIONS: In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to the treatment of TMZ alone with radiographic evidence of a normalized BBB. PMID- 23649685 TI - Deposition and characterization of luminescent Eu(tta)3phen-doped parylene-based thin-film materials. AB - Herein, novel host-guest films produced by coarse vacuum cosublimation of the parylene C dimer and Eu(tta)3phen are prepared and studied. Eu(tta)3phen sublimation at different temperatures allows films with different concentrations of the Eu complex to be obtained. The films are characterized by Rutherford backscattering spectrometry (RBS), FTIR spectroscopy, X-ray diffraction (XRD), atomic force microscopy (AFM), and UV/Vis absorption and emission spectroscopy. RBS, FTIR, and XRD reveal the incorporation of Eu(tta)3phen into the parylene matrix. AFM evidences the very flat film surface, which is particularly advantageous for optical applications. UV/Vis absorption and emission analyses confirm that the optical properties of Eu(tta)3phen are preserved in the deposited films. Fluorescence measurements evidence the occurrence of an energy transfer process between parylene and Eu(tta)3phen, and this results in an increase in the light emitted by the Eu complex that is as much as five times higher than that emitted by Eu(tta)3phen alone. PMID- 23649686 TI - Urinary nerve growth factor: a biomarker of detrusor overactivity? A systematic review. AB - Nerve growth factor (NGF) is a signalling protein that interacts with specific receptors in autocrine, paracrine and endocrine modes. It is produced by bladder smooth muscle and urothelium. Patients with overactive bladder and detrusor overactivity (DO) have been found to have increased urinary NGF levels in several small studies. The objective of the review was to assess the accuracy of NGF as a biomarker in the diagnosis of DO by a systematic review of the literature. A systematic search of MEDLINE, Embase, CINAHL, MEDION and LILACS databases was conducted (inception till December 2012). Selection criteria included studies where NGF (as a biomarker for DO) and urodynamics were performed in humans with symptoms of overactive bladder. Two reviewers independently selected articles and extracted data on study characteristics, quality and results. All the eight included studies were of case-control design. A meta-analysis was not performed as there were variations in the quality, methods of performing the NGF assay, different NGF cut-offs used and the format of reporting findings. Two studies used a cut-off of 0.05 for NGF levels. Six studies observed a trend towards higher NGF levels in patients with DO. There was a trend towards higher NGF in patients with DO. However, the data are imprecise and hence cannot be recommended for use in current clinical practice. PMID- 23649687 TI - Histology of the vaginal wall in women with pelvic organ prolapse: a literature review. AB - INTRODUCTION AND HYPOTHESIS: The pathophysiology of pelvic organ prolapse (POP) is incompletely understood. The purpose of this study is to describe the current knowledge about histology of the vaginal wall and its possible involvement in the pathogenesis of pelvic organ prolapse. METHODS: Eligible studies were selected through a MEDLINE search covering January 1986 to December 2012. The research was limited to English-language publications. RESULTS: Investigations of changes in the vaginal tissue that occur in women with genital prolapse are currently still limited and produced contrary results. The heterogeneity of the patients and the control groups in terms of age, parity and hormonal status, of the localization of biopsies and the histological methods as well as the lack of validation of the quantification procedures do not allow clear and definitive conclusions to be drawn. CONCLUSIONS: This review shows that current knowledge of the histological changes observed in women with POP are inconclusive and relatively limited. More studies are needed in this specific field to better understand the mechanisms that lead to POP. PMID- 23649688 TI - 1H, 13C and 15N resonance assignments for the fibrillin-1 EGF2-EGF3-hybrid1 cbEGF1 four-domain fragment. AB - Fibrillins are large extracellular glycoproteins that form the principal component of microfibrils. These perform a vital structural function in the extracellular matrix of many tissues. Fibrillins have also been implicated in mediating a number of protein-protein interactions, some of which may be significant in regulating growth factors such as transforming growth factor beta. Here we present the backbone and side-chain (1)H, (13)C and (15)N assignments for a 19 kDa protein fragment derived from the N-terminus of human fibrillin-1, encompassing four domains in total. These domains include the second and third epidermal growth factor-like (EGF) domains, the first hybrid domain (hyb1), and the first calcium-binding EGF domain of fibrillin-1. This region of fibrillin-1 is of particular interest as the hyb1 domain has been suggested to play a role in microfibril assembly, as well as several other protein-protein interactions. PMID- 23649689 TI - Subcutaneous immunoglobulin treatment of inclusion-body myositis stabilizes dysphagia. PMID- 23649690 TI - Advancing research on spiritual influences at the end of life: comment on "Provision of spiritual support to patients with advanced cancer by religious communities and associations with medical care at the end of life". PMID- 23649692 TI - Reciprocal regulation of cyclooxygenase 2 and heme oxygenase 1 upon arsenic trioxide exposure in normal human lung fibroblast. AB - Detoxification enzyme heme oxygenase 1 (HO-1) and proinflammation enzyme cyclooxygenase 2 (Cox-2) are key response proteins that function to promote the survival of cells exposed to arsenic trioxide (ATO). However, whether there is a cross-regulation between them in ATO-treated cells remains poorly investigated. In this study, concomitant upregulation of Cox-2 and HO-1 induced by ATO was observed in normal human lung fibroblasts. Cox-2 inhibitor NS398 suppressed the upregulation of HO-1, whereas HO-1 inhibitor protoporphyrin IX zinc (II) stimulated the expression of Cox-2. Both proteins were regulated by p38, and the feedback regulation of HO-1 on Cox-2 was mediated through p38. Our results confirmed the reciprocal regulations between Cox-2 and HO-1 in ATO-treated normal cells and shed light on the understanding of protecting cells from injury caused by ATO while simultaneously decreasing the inflammation responses, which may be related to the carcinogenicity of ATO. PMID- 23649691 TI - Intrabodies as neuroprotective therapeutics. AB - The process of misfolding of proteins that can trigger a pathogenic cascade leading to neurodegenerative diseases largely originates intracellularly. It is possible to harness the specificity and affinity of antibodies to counteract either protein misfolding itself, or the aberrant interactions and excess stressors immediately downstream of the primary insult. This review covers the emerging field of engineering intracellular antibody fragments, intrabodies and nanobodies, in neurodegeneration. Huntington's disease has provided the clearest proof of concept for this approach. The model systems and readouts for this disorder power the studies, and the potential to intervene therapeutically at early stages in known carriers with projected ages of onset increases the chances of meaningful clinical trials. Both single-chain Fv and single-domain nanobodies have been identified against specific targets; data have allowed feedback for rational design of bifunctional constructs, as well as target validation. Intrabodies that can modulate the primary accumulating protein in Parkinson's disease, alpha-synuclein, are also reviewed, covering a range of domains and conformers. Recombinant antibody technology has become a major player in the therapeutic pipeline for cancer, infectious diseases, and autoimmunity. There is also tremendous potential for applying this powerful biotechnology to neurological diseases. PMID- 23649694 TI - Congenital cardiac forum: hypoplastic left heart syndrome. PMID- 23649693 TI - A multimodal imaging analysis of subcortical gray matter in fragile X premutation carriers. AB - Approximately 40% of males with the fragile X premutation develop fragile X associated tremor/ataxia syndrome after age 50. Although the thalamus and basal ganglia play a crucial role in movement disorders, their involvement in fragile X premutation carriers has not been systematically investigated. The current study characterized structural abnormalities associated with fragile X premutation carriers (with and without fragile X-associated tremor/ataxia syndrome) in the thalamus, caudate nucleus, putamen, and globus pallidus using T1-weighted and diffusion tensor imaging. Male premutation carriers with fragile X-associated tremor/ataxia syndrome showed significant volume atrophy and diffusion-weighted signal loss in all 4 structures compared with the control group. They also exhibited volume atrophy and diffusion-weighted signal loss in the thalamus and striatum compared with the premutation carriers without fragile X-associated tremor/ataxia syndrome. Importantly, many of the measurements exhibited robust correlations with symptom severity, with volume and diffusion-weighted imaging measurements displaying negative correlations and fractional anisotropy measurements displaying positive correlations. The current study demonstrated involvement of all 4 subcortical gray matter structures in fragile X-associated tremor/ataxia syndrome, with significant volume atrophy, and possible iron deposition indicated by the diffusion-weighted signal loss. The significant correlation between the subcortical measurements and symptom severity suggests the benefits of tracking structural changes in subcortical gray matter in future longitudinal studies for early detection and disease monitoring. (c) 2013 Movement Disorder Society. PMID- 23649696 TI - Wellness as welfare. PMID- 23649699 TI - A whole-mount immunofluorescence protocol for three-dimensional imaging of the embryonic mammary primordium. AB - Whole-mount immunofluorescent staining facilitates the profiling of protein expression patterns within diverse and complex tissues. Thanks to the application of antibodies on whole mounted instead of sectioned specimens, this technique has many advantages with respect to the preservation of biological and pathological features of specimens when compared to conventional immunohistological methods. Here, we describe a protocol and optimal conditions of whole-mount immunofluorescence for studying the formation of mammary primordia. We also show an example three-dimensional reconstruction of a mammary primordium based on z stacked images of a whole-mount stained specimen using confocal microscopy and image analysis software. PMID- 23649698 TI - Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, or CADASIL, one of the most common inherited small vessel diseases of the brain, is characterized by a progressive loss of vascular smooth muscle cells and extracellular matrix accumulation. The disease is caused by highly stereotyped mutations within the extracellular domain of the NOTCH3 receptor (Notch3(ECD)) that result in an odd number of cysteine residues. While CADASIL-associated NOTCH3 mutations differentially affect NOTCH3 receptor function and activity, they all are associated with early accumulation of Notch3(ECD)-containing aggregates in small vessels. We still lack mechanistic explanation to link NOTCH3 mutations with small vessel pathology. Herein, we hypothesized that excess Notch3(ECD) could recruit and sequester functionally important proteins within small vessels of the brain. We performed biochemical, nano-liquid chromatography-tandem mass spectrometry and immunohistochemical analyses, using cerebral and arterial tissue derived from patients with CADASIL and mouse models of CADASIL that exhibit vascular lesions in the end- and early stage of the disease, respectively. Biochemical fractionation of brain and artery samples demonstrated that mutant Notch3(ECD) accumulates in disulphide cross linked detergent-insoluble aggregates in mice and patients with CADASIL. Further proteomic and immunohistochemical analyses identified two functionally important extracellular matrix proteins, tissue inhibitor of metalloproteinases 3 (TIMP3) and vitronectin (VTN) that are sequestered into Notch3(ECD)-containing aggregates. Using cultured cells, we show that increased levels or aggregation of Notch3 enhances the formation of Notch3(ECD)-TIMP3 complex, promoting TIMP3 recruitment and accumulation. In turn, TIMP3 promotes complex formation including NOTCH3 and VTN. In vivo, brain vessels from mice and patients with CADASIL exhibit elevated levels of both insoluble cross-linked and soluble TIMP3 species. Moreover, reverse zymography assays show a significant elevation of TIMP3 activity in the brain vessels from mice and patients with CADASIL. Collectively, our findings lend support to a Notch3(ECD) cascade hypothesis in CADASIL disease pathology, which posits that aggregation/accumulation of Notch3(ECD) in the brain vessels is a central event, promoting the abnormal recruitment of functionally important extracellular matrix proteins that may ultimately cause multifactorial toxicity. Specifically, our results suggest a dysregulation of TIMP3 activity, which could contribute to mutant Notch3(ECD) toxicity by impairing extracellular matrix homeostasis in small vessels. PMID- 23649697 TI - Dissecting the uncinate fasciculus: disorders, controversies and a hypothesis. AB - The uncinate fasciculus is a bidirectional, long-range white matter tract that connects lateral orbitofrontal cortex and Brodmann area 10 with the anterior temporal lobes. Although abnormalities in the uncinate fasciculus have been associated with several psychiatric disorders and previous studies suggest it plays a putative role in episodic memory, language and social emotional processing, its exact function is not well understood. In this review we summarize what is currently known about the anatomy of the uncinate, we review its role in psychiatric and neurological illnesses, and we evaluate evidence related to its putative functions. We propose that an overarching role of the uncinate fasciculus is to allow temporal lobe-based mnemonic associations (e.g. an individual's name + face + voice) to modify behaviour through interactions with the lateral orbitofrontal cortex, which provides valence-based biasing of decisions. The bidirectionality of the uncinate fasciculus information flow allows orbital frontal cortex-based reward and punishment history to rapidly modulate temporal lobe-based mnemonic representations. According to this view, disruption of the uncinate may cause problems in the expression of memory to guide decisions and in the acquisition of certain types of learning and memory. Moreover, uncinate perturbation should cause problems that extend beyond memory to include social-emotional problems owing to people and objects being stripped of personal value and emotional history and lacking in higher-level motivational value. PMID- 23649700 TI - Neuregulin 3 and erbb signalling networks in embryonic mammary gland development. AB - We review the role of Neuregulin 3 (Nrg3) and Erbb receptor signalling in embryonic mammary gland development. Neuregulins are growth factors that bind and activate its cognate Erbb receptor tyrosine kinases, which form a signalling network with established roles in breast development and breast cancer. Studies have shown that Nrg3 expression profoundly impacts early stages of embryonic mammary development. Network analysis shows how Nrg/Erbb signals could integrate with other major regulators of embryonic mammary development to elicit the morphogenetic processes and cell fate decisions that occur as the mammary lineage is established. PMID- 23649701 TI - Social and emotional processing as a behavioural endophenotype in eating disorders: a pilot investigation in twins. AB - OBJECTIVES: Emotional processing difficulties are potential risk markers for eating disorders that are also present after recovery. The aim of this study was to examine these traits in twins with eating disorders. METHODS: The Reading the Mind in the Eyes test, Emotional Stroop task and the Difficulties in Emotion Regulation Scale were administered to 112 twins with and without eating disorders (DSM IV-TR eating disorder criteria). Generalised estimating equations compared twins with eating disorders against unaffected co-twins and control twins, and within-pair correlations were calculated for clinical monozygotic (n = 50) and dizygotic twins (n = 20). RESULTS: Emotion recognition difficulties, attentional biases to social threat and difficulties in emotion regulation were greater in twins with eating disorders, and some were present in their unaffected twin siblings. Evidence for a possible genetic basis was highest for emotion recognition and attentional biases to social stimuli. CONCLUSION: Emotion recognition difficulties and sensitivity to social threat appear to be endophenotypes associated with eating disorders. However, the limited statistical power means that these findings are tentative and require further replication. PMID- 23649702 TI - Aspirin hydrolysis in human and experimental animal plasma and the effect of metal cations on hydrolase activities. AB - The hydrolyzing properties of plasma esterases for aspirin were investigated in human plasma and plasma from experimental animals. The observed rates of aspirin hydrolysis were in the following order: rabbit > human > monkey > rat > mouse > dog > minipig. In human, monkey, and dog plasma, aspirin was hydrolyzed by their major hydrolases, paraoxonase (PON), butyrylcholinesterase (BChE), and albumin. In rabbit, mouse, and rat plasma, carboxylesterase (CES) was determined to be the enzyme responsible for aspirin hydrolysis, and in mouse and rat plasma, especially the latter, hydrolase activity was increased by the addition of ethopropazine, a specific inhibitor of BChE. Interestingly, divalent cations affected the plasma activity by enhancing or inhibiting the hydrolase activity of plasma BChE. The addition of 2 mM calcium increased the hydrolysis of aspirin in human, monkey, and dog plasma by 2.7-, 1.9-, and 2.3-fold, respectively. Magnesium showed a similar but lesser effect. Increasing concentrations of calcium and magnesium resulted in a two-phase stimulatory effect on aspirin hydrolysis in human plasma. In contrast, the addition of zinc had an inhibitory effect on plasma BChE activity. It is postulated that calcium and magnesium bind to BChE and thereby change the conformation of the enzyme to a more appropriate position for aspirin hydrolysis. PMID- 23649703 TI - Dynamic modeling of cytochrome P450 inhibition in vitro: impact of inhibitor depletion on IC50 shift. AB - The impact of inhibitor depletion on the determination of shifted IC50 (IC50 determined after 30 minutes of preincubation with inhibitor) is examined. In addition, IC50-shift data are analyzed using a mechanistic model that incorporates the processes of inhibitor depletion, as well as reversible and time dependent inhibition. Anomalies such as a smaller-than-expected shift in IC50 and even increases in IC50 with preincubation were explained by the depletion of inhibitor during the preincubation. The IC50-shift assay remains a viable approach to characterizing a wide range of reversible and time-dependent inhibitors. However, as with more traditional time-dependent inactivation methods, it is recommended that IC50-shift experimental data be interpreted with some knowledge of the magnitude of inhibitor depletion. For the most realistic classification of time-dependent inhibitors using IC50-shift methods, shifted IC50 should be calculated using observed inhibitor concentrations at the end of the incubation rather than nominal inhibitor concentrations. Finally, a mechanistic model that includes key processes, such as competitive inhibition, enzyme inactivation, and inhibitor depletion, can be used to describe accurately the observed IC50 and shifted IC50 curves. For compounds showing an IC50 fold shift >1.5 based on the observed inhibitor concentrations, reanalyzing the IC50 shift data using the mechanistic model appeared to allow for reasonable estimation of Ki, KI, and kinact directly from the IC50 shift experiments. PMID- 23649704 TI - Combinatorial metabolism notably affects human systemic exposure to ginsenosides from orally administered extract of Panax notoginseng roots (Sanqi). AB - Ginsenosides are medicinal ingredients of the cardiovascular herb Panax notoginseng roots (Sanqi). Here, we implemented a human study (ChiCTR-ONC 09000603; www.chictr.org) to characterize pharmacokinetics and metabolism of ginsenosides from an orally ingested Sanqi-extract (a 1:10 water extract of Sanqi) and the human plasma and urine samples were analyzed by liquid chromatography-mass spectrometry. Plasma and urinary compounds derived from ginsenosides included: 1) intestinally absorbed ginsenosides Ra3, Rb1, Rd, F2, Rg1, and notoginsenoside R1; and 2) the deglycosylated products compound-K, 20(S) protopanaxadiol, 20(S)-protopanaxatriol, and their oxidized metabolites. The systemic exposure levels of the first group compounds increased as the Sanqi extract dose increased, but those of the second group compounds were dose independent. The oxidized metabolites of 20(S)-protopanaxadiol and 20(S) protopanaxatriol represented the major circulating forms of ginsenosides in the bloodstream, despite their large interindividual differences in exposure level. The metabolites were formed via combinatorial metabolism that consisted of a rate limiting step of ginsenoside deglycosylation by the colonic microflora and a subsequent step of sapogenin oxidation by the enterohepatic cytochrome P450 enzymes. Significant accumulation of plasma ginsenosides and metabolites occurred in the human subjects receiving 3-week subchronic treatment with the Sanqi extract. Plasma 20(S)-protopanaxadiol and 20(S)-protopanaxatriol could be used as pharmacokinetic markers to reflect the subjects' microbial activities, as well as the timely-changes and interindividual differences in plasma levels of their respective oxidized metabolites. The information gained from the current study is relevant to pharmacology and therapeutics of Sanqi. PMID- 23649706 TI - Progress in VZV vaccination? Some concerns. AB - Since 1995, many countries have been aiming to replace the natural immunity against varicella by a vaccine-induced immunity to protect against varicella and herpes zoster. While the frequency of varicella in childhood has been significantly reduced, in future, herpes zoster morbidity might increase in the elderly due to the weaker immunity post-vaccination and the absence of immunity boosting silent reinfections. In countries, where less than 90 % of children are covered by universal vaccination, varicella zoster virus (VZV) infection is not completely eradicated, but might move from childhood to the age of young adults who suffer from more serious complications. A special VZV vaccine against herpes zoster in adults aged >60 years has proven to be effective in many cases, but not all vaccinees. This might lead to problems regarding the acceptance of vaccination and delay rapid antiviral therapy to prevent the post-zosteric neuralgia. An efficacious-inactivated VZV vaccine to protect immunocompromised patients is still missing. VZV vaccines and vaccination strategies have to be optimised to avoid that the quality of life and cost savings from varicella reduction in childhood are offset by more VZV diseases in adults. PMID- 23649705 TI - Genomic differences in the background of different severity in juvenile-onset respiratory papillomatoses associated with human papillomavirus type 11. AB - This study aimed to compare complete genome sequences of human papillomavirus (HPV) type 11 from two solitary papillomas (considered minimally aggressive), two moderately (six and nine episodes) and two highly aggressive (30 and 33 episodes) juvenile-onset respiratory papillomatoses. Genomic regions were sequenced using the Sanger method; sequences were compared to available GenBank genomes. Activity of the long control region (LCR) was assessed in HEp-2 cell line using luciferase assays and compared to that of the reference (GenBank Accession Number M14119). Site-directed mutagenesis was performed to confirm the association of polymorphisms with differences in LCR activity. Eleven alterations resulted in amino acid changes in different open reading frames. A72E in E1 and Q86K in E2 proteins were exclusively present in a moderately aggressive disease, L1 alterations A476V and S486F were unique to a severe papillomatosis. HPV11s in both solitary papillomas had identical LCRs containing a T7546C polymorphism, which strongly attenuated LCR activity, as confirmed by site-directed mutagenesis. This strong attenuator polymorphism was also present in the other four genomes showing significantly higher activities, but in these other alterations with demonstrable but statistically not significant attenuating (A7413C, 7509 T deletion) or enhancing (C7479T, T7904A) effect on transactivating potential (as demonstrated by site-directed mutagenesis) were also detected. LCR activities corresponded well to severity, excepting the highly aggressive papillomatosis with the L1 alterations. Presence of intratypic variants cannot explain differences in severity of respiratory papillomatoses associated with HPV11; virulence seems to be determined by the interaction of multiple genetic differences. PMID- 23649707 TI - W-Co discrete complex exhibiting photo- and thermo-induced magnetisation. AB - Molecular (photo)switch: A W-Co photomagnetic discrete complex can be prepared through the self-assembly of preformed building blocks. [Co(bik)3][{W(CN)8}3{Co(bik)2}3]?2 H2O?13 CH3CN (see figure) exhibits a thermally induced electron-transfer-coupled spin transition between the two states: Co(HS)(II)-W(V)<->Co(LS)(III)-W(IV). It also shows photomagnetic effects at low temperature. PMID- 23649708 TI - Design of degradable click delivery systems. AB - Click chemistry has had a significant impact in the field of materials science over the last 10 years, as it has enabled the design of new hybrid building blocks, leading to multifunctional and responsive materials. One key application for such materials is in the biomedical field, such as gene or drug delivery. However, to meet the functional requirements of such applications, tailored degradability of these materials under biological conditions is critical. There has been an increasing interest in combining click chemistry techniques with a range of degradable or responsive building blocks as well as investigating new or milder chemistries to design click delivery systems that are capable of physiologically relevant degradation. This Feature Article will cover some of the different approaches to synthesize degradable click delivery systems and their investigation for therapeutic release. PMID- 23649709 TI - Metronomic chemotherapy following the maximum tolerated dose is an effective anti tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells. AB - In this article, the effectiveness of a multi-targeted chemo-switch (C-S) schedule that combines metronomic chemotherapy (MET) after treatment with the maximum tolerated dose (MTD) is reported. This schedule was tested with gemcitabine in two distinct human pancreatic adenocarcinoma orthotopic models and with cyclophosphamide in an orthotopic ovarian cancer model. In both models, the C-S schedule had the most favourable effect, achieving at least 80% tumour growth inhibition without increased toxicity. Moreover, in the pancreatic cancer model, although peritoneal metastases were observed in control and MTD groups, no dissemination was observed in the MET and C-S groups. C-S treatment caused a decrease in angiogenesis, and its effect on tumour growth was similar to that produced by the MTD followed by anti-angiogenic DC101 treatment. C-S treatment combined an increase in thrombospondin-1 expression with a decrease in the number of CD133+ cancer cells and triple-positive CD133+/CD44+/CD24+ cancer stem cells (CSCs). These findings confirm that the C-S schedule is a challenging clinical strategy with demonstrable inhibitory effects on tumour dissemination, angiogenesis and CSCs. PMID- 23649710 TI - Electron and ion transport in Li2O2. AB - Bulk Li2O2 is shown to exhibit ionic conductivity via lithium vacancies and electronic conductivity via electron holes (localized as superoxide ions). This is the first systematic study on the charge carrier chemistry of peroxides with high relevance for the performance kinetics of Li-oxygen batteries. PMID- 23649711 TI - Fingolimod modulates peripheral effector and regulatory T cells in MS patients. AB - Multiple sclerosis (MS) is a complex neurological disease where, in genetically predisposed individuals, the unbalanced interplay between pathogenic and regulatory T cells will result in the progression of the autoimmune assault to neural antigens. Fingolimod (FTY720), an oral sphingosine 1-phosphate modulator recently approved for the treatment of MS, inhibits the egress of T cells from lymph nodes acting specifically on naive and memory T cells and sparing effector T cells. Here we characterized IL-17 and IFNgamma producing effector CD4 and CD8 positive T cells as well as CD4 positive CD25(high)CD127(low) regulatory T cells in MS patients before and 1 month after treatment was started. We observed that fingolimod did not significantly affect the percentage of CCR6 and CD161 positive T cells in both CD4 and CD8 compartments. In contrast, it significantly reduced the levels of both CD4+ CCR6+ CD161+ and CD8+ CCR6+ CD161+ producing IFNgamma alone or in combination with IL-17. The percentage of IL-17 secreting cells in both subsets was affected by the treatment to a lesser extent. Finally, we observed that CD4+ CD25(high)CD127(low) regulatory T cells were decreased in MS patients compared to healthy controls and fingolimod significantly increased their frequencies. All together these findings demonstrate that fingolimod functionally modulates the ability of potentially pathogenic effector cells to produce relevant pro-inflammatory cytokines and increases the number of circulating regulatory T cells possibly contributing in restoring a balance between these populations. PMID- 23649712 TI - An energetic limit on spatial release from masking. AB - This study tested the hypothesis that energetic masking limits the benefits obtained from spatial separation in multiple-talker listening situations, particularly for listeners with sensorineural hearing loss. A speech target was presented simultaneously with two or four speech maskers. The target was always presented diotically, and the maskers were either presented diotically or dichotically. In dichotic configurations, the maskers were symmetrically placed by introducing interaural time differences (ITDs) or infinitely large interaural level differences (ILDs; monaural presentation). Target-to-masker ratios for 50 % correct were estimated. Thresholds in all separated conditions were poorer in listeners with hearing loss than listeners with normal hearing. Moreover, for a given listener, thresholds were similar for conditions with the same number of talkers per ear (e.g., ILD with four talkers equivalent to ITD with two talkers) and hence the same energetic masking. The results are consistent with the idea that increased energetic masking, rather than a specific spatial deficit, may limit performance for hearing-impaired listeners in spatialized speech mixtures. PMID- 23649714 TI - Experimental and first-principles characterization of functionalized magnetic nanoparticles. AB - Magnetic iron oxide nanoparticles synthesized by coprecipitation and thermal decomposition yield largely monodisperse size distributions. The diameters of the coprecipitated particles measured by X-ray diffraction and transmission electron microscopy are between approximately 9 and 15 nm, whereas the diameters of thermally decomposed particles are in the range of 8 to 10 nm. Coprecipitated particles are indexed as magnetite-rich and thermally decomposed particles as maghemite-rich; however, both methods produce a mixture of magnetite and maghemite. Fourier transform IR spectra reveal that the nanoparticles are coated with at least two layers of oleic acid (OA) surfactant. The inner layer is postulated to be chemically adsorbed on the nanoparticle surface whereas the rest of the OA is physically adsorbed, as indicated by carboxyl O-H stretching modes above 3400 cm(-1). Differential thermal analysis (DTA) results indicate a double stepped weight loss process, the lower-temperature step of which is assigned to condensation due to physically adsorbed or low-energy bonded OA moieties. Density functional calculations of Fe-O clusters, the inverse spinel cell, and isolated OA, as well as OA in bidentate linkage with ferrous and ferric atoms, suggest that the higher-temperature DTA stage could be further broken down into two regions: one in which condensation is due ferrous/ferrous- and/or ferrous/ferric OA and the other due to condensation from ferrous/ferric- and ferric/ferric-OA complexes. The latter appear to form bonds with the OA carbonyl group of energy up to fivefold that of the bond formed by the ferrous/ferrous pairs. Molecular orbital populations indicate that such increased stability of the ferric/ferric pair is due to the contribution of the low-lying Fe(3+) t(2g) states into four bonding orbitals between -0.623 and -0.410 a.u. PMID- 23649716 TI - Lipomatous congenital melanocytic nevus presenting as a neck mass in a young adult. AB - Congenital melanocytic nevus (CMN) is a melanocytic proliferation that has its onset at birth or shortly thereafter and shows characteristic histopathologic features including symmetric proliferation of benign melanocytes, extension of nevus cells into the deep reticular dermis and subcutis, maturation of melanocytes with descent, tracking of melanocytes around and within adnexal structures, vessels, or nerves and splaying of collagen bundles by nevus cells arranged in single rows or cords. We report the case of a 34 year old previously healthy woman who presented with a progressively enlarging soft tissue mass in the right neck and back adjacent to a medium sized CMN. Magnetic resonance imaging showed multiple lipomatous masses within the soft tissues of the posterior superficial neck. Subsequent excision of the soft tissue mass showed a well circumscribed lipomatous lesion with diffuse infiltration by benign appearing melanocytes within the fat lobules. Excision of the mass was not accompanied by overlying skin and, thus, posed a diagnostic challenge. Sudden increase in the size of a CMN is worrisome for the development of a melanoma, however, this lesion lacked significant cytologic atypia and mitotic figures, and had a low proliferative index by Ki-67 immunohistochemistry. This case serves to illustrate the initial diagnostic dilemma as well as the plasticity of the neural crest cells. PMID- 23649713 TI - Modulation of neutrophil NETosis: interplay between infectious agents and underlying host physiology. AB - The ability of neutrophils and other leucocyte members of the innate immune system to expel their DNA into the extracellular environment in a controlled manner in order to trap and kill pathogenic microorganisms lead to a paradigm shift in our understanding of host microbe interactions. Surprisingly, the neutrophil extracellular trap (NET) cast by neutrophils is very wide and extends to the entrapment of viruses as well as multicellular eukaryotic parasites. Not unexpectedly, it has emerged that pathogenic microorganisms can employ a wide array of strategies to avoid ensnarement, including expression of DNAse enzymes that destroy the lattice backbone of NETs. Alternatively, they may use molecular mimicry to avoid detection or trigger events leading to the expression of immune modulatory cytokines such as IL-10, which dampen the NETotic response of neutrophils. In addition, the host microenvironment may contribute to the innate immune response by the production of lectin-like molecules that bind to bacteria and promote their entrapment on NETs. An example of this is the production of surfactant protein D by the lung epithelium. In addition, pregnancy provides a different challenge, as the mother needs to mount an effective response against pathogens, without harming her unborn child. An examination of these decoy and host response mechanisms may open the path for new therapies to treat pathologies mediated by overt NETosis. PMID- 23649717 TI - Explaining sex difference in cancer risk: might it be related to excess iron? PMID- 23649718 TI - Muscle-related differences in mechanomyography-force relationships are model dependent. AB - INTRODUCTION: In this study we examined the mechanomyographic amplitude (MMG(RMS))-force relationships with log-transform and polynomial regression models for the vastus lateralis (VL), rectus femoris (RF), and first dorsal interosseous (FDI) muscles. METHODS: Twelve healthy (age 23 +/- 3 years) men performed isometric ramp contractions of the leg extensors and index finger from 10% to 80% of their maximal voluntary contraction (MVC) with MMG sensors positioned on the VL, RF, and FDI. Log-transform and polynomial regression models were fitted to the relationships. RESULTS: There were differences for the a terms (intercepts) and b terms (slopes) from the log-transform model between the FDI, VL, and RF; however, there were no consistent differences identified with the polynomial regression models. CONCLUSIONS: The log-transform model quantified differences in the patterns of responses between the FDI and the leg extensors, but polynomial regression could not distinguish such differences. PMID- 23649719 TI - Organocatalysis by neutral multidentate halogen-bond donors. PMID- 23649721 TI - Diagnosis of Pompe disease: muscle biopsy vs blood-based assays. AB - The diagnosis of Pompe disease (acid maltase deficiency, glycogen storage disease type II) in children and adults can be challenging because of the heterogeneous clinical presentation and considerable overlap of signs and symptoms found in other neuromuscular diseases. This review evaluates some of the methods used in the diagnosis and differential diagnosis of late-onset Pompe disease. Muscle biopsy is commonly used as an early diagnostic tool in the evaluation of muscle disease. However, experience has shown that relying solely on visualizing a periodic acid-Schiff-positive vacuolar myopathy to identify late-onset Pompe disease often leads to false-negative results and subsequent delays in identification and treatment of the disorder. Serum creatine kinase level can be normal or only mildly elevated in late-onset Pompe disease and is not very helpful alone to suggest the diagnosis, but in combination with proximal and axial weakness it may raise the suspicion for Pompe disease. A simple blood-based assay to measure the level of alpha-glucosidase activity is the optimal initial test for confirming or excluding Pompe disease. A timely and accurate diagnosis of late-onset Pompe disease likely will improve patient outcomes as care standards including enzyme replacement therapy can be applied and complications can be anticipated. Increased awareness of the clinical phenotype of Pompe disease is therefore warranted to expedite diagnostic screening for this condition with blood-based enzymatic assays. PMID- 23649720 TI - Phenomenology and classification of dystonia: a consensus update. AB - This report describes the consensus outcome of an international panel consisting of investigators with years of experience in this field that reviewed the definition and classification of dystonia. Agreement was obtained based on a consensus development methodology during 3 in-person meetings and manuscript review by mail. Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia is classified along 2 axes: clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features); and etiology, which includes nervous system pathology and inheritance. The clinical characteristics fall into several specific dystonia syndromes that help to guide diagnosis and treatment. We provide here a new general definition of dystonia and propose a new classification. We encourage clinicians and researchers to use these innovative definition and classification and test them in the clinical setting on a variety of patients with dystonia. (c) 2013 Movement Disorder Society. PMID- 23649722 TI - Utilization of computed tomography image-guided navigation in orbit fracture repair. PMID- 23649723 TI - Genetic diversity and conservation in a small endangered horse population. AB - The Old Kladruber horses arose in the 17th century as a breed used for ceremonial purposes. Currently, grey and black coat colour varieties exist as two sub populations with different recent breeding history. As the population underwent historical bottlenecks and intensive inbreeding, loss of genetic variation is considered as the major threat. Therefore, genetic diversity in neutral and non neutral molecular markers was examined in the current nucleus population. Fifty microsatellites, 13 single nucleotide polymorphisms (SNPs) in immunity-related genes, three mutations in coat colour genes and one major histocompatibility (MHC DRA) gene were studied for assessing genetic diversity after 15 years of conservation. The results were compared to values obtained in a similar study 13 years ago. The extent of genetic diversity of the current population was comparable to other breeds, despite its small size and isolation. The comparison between 1997 and 2010 did not show differences in the extent of genetic diversity and no loss of allele richness and/or heterozygosity was observed. Genetic differences identified between the black and grey sub-populations observed 13 years ago persisted. Deviations from the Hardy-Weinberg equilibrium found in 19 microsatellite loci and in five SNP loci are probably due to selective breeding. No differences between neutral and immunity-related markers were found. No changes in the frequencies of markers associated with two diseases, melanoma and insect bite hypersensitivity, were observed, due probably to the short interval of time between comparisons. It, thus, seems that, despite its small size, previous bottlenecks and inbreeding, the molecular variation of Old Kladruber horses is comparable to other horse breeds and that the current breeding policy does not compromise genetic variation of this endangered population. PMID- 23649724 TI - Proportional hazards model with varying coefficients for length-biased data. AB - Length-biased data arise in many important applications including epidemiological cohort studies, cancer prevention trials and studies of labor economics. Such data are also often subject to right censoring due to loss of follow-up or the end of study. In this paper, we consider a proportional hazards model with varying coefficients for right-censored and length-biased data, which is used to study the interact effect nonlinearly of covariates with an exposure variable. A local estimating equation method is proposed for the unknown coefficients and the intercept function in the model. The asymptotic properties of the proposed estimators are established by using the martingale theory and kernel smoothing techniques. Our simulation studies demonstrate that the proposed estimators have an excellent finite-sample performance. The Channing House data is analyzed to demonstrate the applications of the proposed method. PMID- 23649725 TI - ENaC contribution to epithelial wound healing is independent of the healing mode and of any increased expression in the channel. AB - Previous work from our laboratory and others has shown that, in some epithelia, the epithelial sodium channel (ENaC) increases its expression during wound healing. In these cases, inhibition of the channel determines a decrease in the healing rate, a result suggesting a role for ENaC in the overall healing process. To understand further this role of ENaC in epithelia, we explored the participation of ENaC in wound healing in four cultured epithelial cell lines selected on the basis of their different embryonic origins, function and modality of healing, i.e., by lamellipodial cell crawling or by actin cable formation. Three of the cell lines (bovine corneal endothelial cells, rabbit corneal epithelial cells and Madin-Darby canine kidney cells) exhibited an increase in ENaC expression and consequent membrane potential depolarization and an increase in cytosolic sodium and calcium, whereas one line (bovine aortal endothelial cells, BAEC) did not exhibit any of these changes. In all of the cell lines, however, ENaC inhibition determined a similar decrease in the rate of wound healing. In BAEC monolayers, the increase in ENaC activity produced plasma membrane depolarization, increased cytosolic sodium and calcium, and augmented the velocity of healing. These novel findings contribute to the idea that ENaC plays a critical role in wound healing in various epithelia, independently of the modality of healing and of any increase in the expression of the channel. PMID- 23649726 TI - Nucleobase-caged peptide nucleic acids: PNA/PNA duplex destabilization and light triggered PNA/PNA recognition. AB - The 2-(o-nitrophenyl)-propyl (NPP) group is used as caging group to mask the nucleobases adenine and cytosine in N-(2-aminoethyl)glycine peptide nucleic acids (aeg-PNA). The adeninyl and cytosinyl nucleo amino acid building blocks Fmoc a(NPP) -aeg-OH and Fmoc-c(NPP) -aeg-OH were synthesized and incorporated into PNA sequences by Fmoc solid phase synthesis relying on high stability of the NPP nucleobase protecting group toward Fmoc-cleavage, coupling, capping, and resin cleavage conditions. Removal of the nucleobase caging group was achieved by UV LED irradiation at 365 nm. The nucleobase caging groups provided sterical crowding effecting the Watson-Crick base pairing, and thereby, the PNA double strand stabilities. Duplex formation can completely be suppressed for complementary PNA containing caging groups in both strands. PNA/PNA recognition can be completely restored by UV light-triggered release of the photolabile protecting group. PMID- 23649727 TI - The future of diabetes education: expanded opportunities and roles for diabetes educators. AB - PURPOSE: The purpose of the article is to explore challenges and opportunities associated with the state of practice for diabetes education and diabetes educators. METHODS: Observations, assumptions, predictions, and recommendations based on a literature review and the 2011 workforce study and workforce summit held by the American Association of Diabetes Educators (AADE) are presented. RESULTS: Demand for diabetes educators is projected to increase. The employer base will broaden beyond traditional outpatient venues and extend into industry, retail pharmacy clinics, and community-based organizations. Increasing roles in management, quality assurance, and technology interface design are possible for diabetes educators. Challenges limiting diabetes education such as poor understanding of what diabetes educators do and underutilization of diabetes education continue to need redress. CONCLUSIONS: Increasing utilization of diabetes education and insight about health care trends can allow diabetes educators to thrive in the workplace of the future. Diabetes educators are urged to promote the evidence concerning the benefits of diabetes education, to work to increase physician referrals, and to acquire needed competencies for the workplace of the future. PMID- 23649728 TI - Tetrameric cyclic double helicates as a scaffold for a molecular Solomon link. PMID- 23649729 TI - Designing user interfaces to enhance human interpretation of medical content based image retrieval: application to PET-CT images. AB - PURPOSE: Content-based image retrieval (CBIR) in medicine has been demonstrated to improve evidence-based diagnosis, education, and teaching. However, the low clinical adoption of CBIR is partially because the focus of most studies has been the development of feature extraction and similarity measurement algorithms with limited work on facilitating better understanding of the similarity between complex volumetric and multi-modality medical images. In this paper, we present a method for defining user interfaces (UIs) that enable effective human user interpretation of retrieved images. METHODS: We derived a set of visualisation and interaction requirements based on the characteristics of modern volumetric medical images. We implemented a UI that visualised multiple views of a single image, displayed abstractions of image data, and provided access to supplementary non-image data. We also defined interactions for refining the search and visually indicating the similarities between images. We applied the UI for the retrieval of multi-modality positron emission tomography and computed tomography (PET-CT) images. We conducted a user survey to evaluate the capabilities of our UI. RESULTS: Our proposed method obtained a high rating ( >= 4 out of 5) in the majority of survey questions. In particular, the survey responses indicated the UI presented all the information necessary to understand the retrieved images, and did so in an intuitive manner. CONCLUSION: Our proposed UI design improved the ability of users to interpret and understand the similarity between retrieved PET-CT images. The implementation of CBIR UIs designed to assist human interpretation could facilitate wider adoption of medical CBIR systems. PMID- 23649731 TI - Two-dimensional silica sieve plates mimicking the diatom valve. AB - Sieve and take: A biomimetic strategy was designed to fabricate two-dimensional silica sieve plates (SSP) by use of catanionic surfactants as composite template and L-tartrate with hydroxyl and carboxyl groups as regulator. Tartrate was found to combine two capabilities in the formation of SSP structures: the connection of adjacent silica structures through H bonding and the separation of adjacent structures through electrostatic repulsion. PMID- 23649730 TI - Projection-based visual guidance for robot-aided RF needle insertion. AB - PURPOSE: The use of projector-based augmented reality (AR) in surgery may enable surgeons to directly view anatomical models and surgical data from the patient's surface (skin). It has the advantages of a consistent viewing focus on the patient, an extended field of view and augmented interaction. This paper presents an AR guidance mechanism with a projector-camera system to provide the surgeon with direct visual feedback for supervision of robotic needle insertion in radiofrequency (RF) ablation treatment. METHODS: The registration of target organ models to specific positions on the patient body is performed using a surface matching algorithm and point-based registration. An algorithm based on the extended Kalman filter and spatial transformation is used to intraoperatively compute the virtual needle's depth in the patient's body for AR display. RESULTS: Experiments of this AR system on a mannequin were conducted to evaluate AR visualization and accuracy of virtual RF needle insertion. The average accuracy of 1.86 mm for virtual needle insertion met the clinical requirement of 2 mm or better. The feasibility of augmented interaction with a surgical robot using the proposed open AR interface with active visual feedback was demonstrated. CONCLUSIONS: The experimental results demonstrate that this guidance system is effective in assisting a surgeon to perform a robot-assisted radiofrequency ablation procedure. The novelty of the work lies in establishing a navigational procedure for percutaneous surgical augmented intervention integrating a projection-based AR guidance and robotic implementation for surgical needle insertion. PMID- 23649732 TI - Discrepancy in bone mineral densities at different skeletal sites in hip osteoarthritis patients. AB - OBJECTIVE: Increased femoral neck bone mineral density (BMD) in a hip with osteoarthritis (OA) has been previously reported, however, it is possible that increased BMD at sites other than the hip joint is influenced by the disease process of OA. Therefore, we measured BMD at locations different from the hip joint and determined whether higher BMD was also observed at these different skeletal sites in hip OA patients. METHODS: We measured BMD in 68 women (average age 61.0 years) scheduled to undergo total hip arthroplasty for end-stage OA and 100 healthy women (average age 60.9 years) as age-matched controls. BMD at the lumbar spine, radius, and calcaneus was measured by dual-energy X-ray absorptiometry (DXA). Moreover, we measured speed of sound (SOS), broadband ultrasound attenuation (BUA), and stiffness index of the calcaneus by quantitative ultrasonography (QUS). RESULTS: BMD obtained by DXA at the lumbar spine and radius was significantly higher in hip OA patients than in controls. However, at the calcaneus, no significant differences were observed between the groups in BMD obtained by DXA. SOS, BUA, and stiffness index obtained by QUS were significantly lower in the OA group than in controls. CONCLUSION: Higher BMDs of the spine and radius suggest that the incidence of osteoporosis is inversely associated with the incidence of OA. However, it remains unclear whether lack of difference in BMD and lower SOS, BUA, and stiffness index of the calcaneus in the OA group was secondary to the effect walking disturbance resulting from hip pain. Our data suggest that hip OA patients have higher BMD than healthy women, and that inactivity or immobilization caused by hip OA may reduce BMD in the lower limb. PMID- 23649733 TI - Long-term treatment with Sitagliptin, a dipeptidyl peptidase-4 inhibitor, reduces colon carcinogenesis and reactive oxygen species in 1,2-dimethylhydrazine-induced rats. AB - Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) increase colon cancer risk. Antidiabetic drugs stabilizing incretin hormones, such as inhibitors of dipeptidyl peptidase-4 activity (DPP4i), may affect colon carcinogenesis; however, the data remain controversial. Therefore, the authors studied whether long-term administration of the DPP4i Sitagliptin (SITA) affects 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis. Male F344 rats fed a high fat (HF) diet promoting colon carcinogenesis and IR, were induced with DMH (100 mg/kg * 2 times). One week later, the animals were allocated to two groups: one continuing with HF diet (controls; n = 8) and one receiving SITA (n = 8) mixed in the diet (260 ppm). Body weight, food consumption and glycemia were not affected by SITA. Fifteen weeks after DMH, the number of the precancerous lesions mucin depleted foci (MDF) was significantly lower in rats treated with SITA [MDF/colon: 9.5 +/- 0.9 and 6.4 +/- 0.9 in controls (n = 8) and SITA groups (n = 8), respectively; means +/- SE, p < 0.05]. Reactive oxygen species in the blood were also significantly lower in the SITA group [6.75 +/- 0.69 and 5.63 +/- 0.75 (H2 O2 in mM) in controls (n = 5) and SITA (n = 6), respectively; means +/- SE, p < 0.05]. Rats treated with SITA had a lower DPP4 activity in the intestine but not in the plasma. Intestine growth morphometric parameters and colon proliferation, as proliferating cell nuclear antigen expression, were not affected by SITA. In conclusion, the results suggest a protective effect of DPP4i against colon carcinogenesis that could be exploited in chemoprevention trials. PMID- 23649734 TI - Room temperature synthesis of heptazine-based microporous polymer networks as photocatalysts for hydrogen evolution. AB - Two emerging material classes are combined in this work, namely polymeric carbon nitrides and microporous polymer networks. The former, polymeric carbon nitrides, are composed of amine-bridged heptazine moieties and showed interesting performance as a metal-free photocatalyst. These materials have, however, to be prepared at high temperatures, making control of their chemical structure difficult. The latter, microporous polymer networks have received increasing interest due to their high surface area, giving rise to interesting applications in gas storage or catalysis. Here, the central building block of carbon nitrides, a functionalized heptazine as monomer, and tecton are used to create microporous polymer networks. The resulting heptazine-based microporous polymers show high porosity, while their chemical structure resembles the ones of carbon nitrides. The polymers show activity for the photocatalytic production of hydrogen from water, even under visible light illumination. PMID- 23649735 TI - Continuous glucose monitoring: 40 years, what we've learned and what's next. AB - After 40 years of research and development, today continuous glucose monitoring (CGM) is demonstrating the benefit it provides for millions with diabetes. To provide in vivo accuracy, new permselective membranes and mediated systems have been developed to prevent enzyme saturation and to minimize interference signals. Early in vivo implanted sensor research clearly showed that the foreign body response was a more difficult issue to overcome. Understanding the biological interface and circumventing the inflammatory response continue to drive development of a CGM sensor with accuracy and reliability performance suitable in a closed-loop artificial pancreas. Along with biocompatible polymer development, other complimentary algorithm and data analysis techniques have improved the performance of commercial systems significantly. For example, the mean average relative difference of Dexcom's CGM system improved from 26 to 14% and its use life was extended from 3 to 7 d. Significant gains in usability, including size, flexibility, insertion, calibration, and data interface, have been incorporated into new generations of commercial CGM systems. Besides Medtronic, Dexcom, and Abbott, other major players are also investing in CGM. Becton Dickinson is conducting clinical trials with an optical galactose glucose binding system. Development of fully implanted sensor systems fulfills the desire for a discreet, reliable CGM system. Research continues to find innovative ways to help make living with diabetes easier and more normal, and new segments are being pursued (intensive care unit, surgery, behavior modification) in which CGM is being utilized. PMID- 23649736 TI - ASFinder: a tool for genome-wide identification of alternatively splicing transcripts from EST-derived sequences. AB - Expressed Sequence Tags (ESTs) are a rich resource for identifying Alternatively Splicing (AS) genes. The ASFinder webserver is designed to identify AS isoforms from EST-derived sequences. Two approaches are implemented in ASFinder. If no genomic sequences are provided, the server performs a local BLASTN to identify AS isoforms from ESTs having both ends aligned but an internal segment unaligned. Otherwise, ASFinder uses SIM4 to map ESTs to the genome, then the overlapping ESTs that are mapped to the same genomic locus and have internal variable exon/intron boundaries are identified as AS isoforms. The tool is available at http://proteomics.ysu.edu/tools/ASFinder.html. PMID- 23649737 TI - Analysis of non-synonymous single-nucleotide polymorphisms and population variability of PLD2 gene associated with hypertension. AB - We have determined the non-synonymous Single-Nucleotide Polymorphisms (nsSNPs) of PLD2 gene and its variations in different populations to understand its role in hypertension. Out of 350 SNPs, six are found to be non-synonymous, of which two showed significant damaging effect and SNP variability with large differences among the Minor Allele Frequency (MAF) observed in various populations. The amino acid change found for rs2286672 is from arginine to cysteine, i.e., from largest amino acid containing guanidino group to a small amino acid containing sulfhydryl group, and for rs3764897, it is from glycine to serine, i.e., from a hydrophobic amino acid to a hydrophilic amino acid. Hence, owing to the complete change in side chains and polarity of the amino acid residues brought about by these SNPs, the structure of the protein might be altered and hence the function might be affected, leading to dysregulation of blood pressure. PMID- 23649738 TI - Predicting pathologic complete response to neoadjuvant chemotherapy in breast cancer using sparse logistic regression. AB - We utilised Sparse Logistic Regression (SLR) to build two sparse and interpretable predictors. The first one (SLR-65) was based on a signature consisting of the top 65 probe sets (59 genes) differentially expressed between Pathologic Complete Response (PCR) and Residual Disease (RD) cases, and the second one (SLR-Notch) was based on the genes involved in the Notch singling related pathways (113 genes). The two predictors produced better predictions than the predictor in a previous study. The SLR-65 selected 16 informative genes and the SLR-Notch selected 12 informative genes. PMID- 23649739 TI - A discrete search algorithm for finding the structure of protein backbones and side chains. AB - Some information about protein structure can be obtained by using Nuclear Magnetic Resonance (NMR) techniques, but they provide only a sparse set of distances between atoms in a protein. The Molecular Distance Geometry Problem (MDGP) consists in determining the three-dimensional structure of a molecule using a set of known distances between some atoms. Recently, a Branch and Prune (BP) algorithm was proposed to calculate the backbone of a protein, based on a discrete formulation for the MDGP. We present an extension of the BP algorithm that can calculate not only the protein backbone, but the whole three-dimensional structure of proteins. PMID- 23649740 TI - An ensemble learning approach for prediction of phosphorylation sites. AB - Protein phosphorylation plays a fundamental role in most of the cellular regulatory pathways. Experimental identification of phosphorylation sites is labour-intensive and often limited by the availability and optimisation of enzymatic reaction. An ensemble learning approach that combines different encodings using a meta-learner was developed which was catalyzed by four protein kinase families and three residues. A predictor is constructed to predict the true and false phosphorylation sites based on Support Vector Machines (SVM), and knowledge based encoding method is used for amino sequences. Different encoding methods catch different aspects of amino sequences feature. The stacking SVM approach was applied to combine these aspects and improved both sensitivity and specificity. PMID- 23649741 TI - Using multivariate methods to infer knowledge from genomic data. AB - Since the introduction of genome sequencing techniques several methods for genomic data preprocessing and analysis have been published and applied to answer different biological questions. Rarely, multivariate methods have been used to extract knowledge about protein roles. Two of the most informative types of data are gene expression data (microarrays) and phylogenetic profiles indicating presence of genes in other organisms and therefore providing information about their co-evolution. Here we show that these two types of data, analyzed by means of principal component analysis and non parametric discriminant analysis, provide useful information about protein function and their participation in virulence processes. PMID- 23649742 TI - Cytochrome Oxidase I (COI) sequence conservation and variation patterns in the yellowfin and longtail tunas. AB - Tunas are commercially important fishery worldwide. There are at least 13 species of tuna belonging to three genera, out of which genus Thunnus has maximum eight species. On the basis of their availability, they can be characterised as oceanic such as Thunnus albacares (yellowfin tuna) or coastal such as Thunnus tonggol (longtail tuna). Although these two are different species, morphological differentiation can only be seen in mature individuals, hence misidentification may result in erroneous data set, which ultimately affect conservation strategies. The mitochondrial DNA cytochrome oxidase c subunit 1 (COI) gene is one of the most popular markers for population genetic and phylogeographic studies across the animal kingdom. The present study aims to study the sequence conservation and variation in mitochondrial Cytochrome Oxidase I (COI) between these two species of tuna. COI sequence analysis of yellowfin and longtail revealed the close relationship between them in Thunnus genera. The present study is the first direct comparison of mitochondrial COI sequences of these two tuna species. PMID- 23649743 TI - Comparison of gene expression profiles between pansensitive and multidrug resistant strains of Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis has developed resistance to anti-tuberculosis first line drugs. Multidrug-resistant strains complicate the control of tuberculosis and have converted it into a worldwide public health problem. Mutational studies of target genes have tried to envisage the resistance in clinical isolates; however, detection of these mutations in some cases is not sufficient to identify drug resistance, suggesting that other mechanisms are involved. Therefore, the identification of new markers of susceptibility or resistance to first-line drugs could contribute (1) to specifically diagnose the type of M. tuberculosis strain and prescribe an appropriate therapy, and (2) to elucidate the mechanisms of resistance in multidrug-resistant strains. In order to identify specific genes related to resistance in M. tuberculosis, we compared the gene expression profiles between the pansensitive H37Rv strain and a clinical CIBIN:UMF:15:99 multidrug-resistant isolate using microarray analysis. Quantitative real-time PCR confirmed that in the clinical multidrug-resistant isolate, the esxG, esxH, rpsA, esxI, and rpmI genes were upregulated, while the lipF, groES, and narG genes were downregulated. The modified genes could be involved in the mechanisms of resistance to first-line drugs in M. tuberculosis and could contribute to increased efficiency in molecular diagnosis approaches of infections with drug resistant strains. PMID- 23649744 TI - Witchcraft beliefs and witch hunts: an interdisciplinary explanation. AB - This paper proposes an interdisciplinary explanation of the cross-cultural similarities and evolutionary patterns of witchcraft beliefs. It argues that human social dilemmas have led to the evolution of a fear system that is sensitive to signs of deceit and envy. This was adapted in the evolutionary environment of small foraging bands but became overstimulated by the consequences of the Agricultural Revolution, leading to witch paranoia. State formation, civilization, and economic development abated the fear of witches and replaced it in part with more collectivist forms of social paranoia. However, demographic economic crises could rekindle fear of witches-resulting, for example, in the witch craze of early modern Europe. The Industrial Revolution broke the Malthusian shackles, but modern economic growth requires agricultural development as a starting point. In sub-Saharan Africa, witch paranoia has resurged because the conditions for agricultural development are lacking, leading to fighting for opportunities and an erosion of intergenerational reciprocity. PMID- 23649745 TI - "Shrink-to-fit" superhydrophobicity: thermally-induced microscale wrinkling of thin hydrophobic multilayers fabricated on flexible shrink-wrap substrates. AB - An approach to the design of flexible superhydrophobic surfaces based on thermally induced wrinkling of thin, hydrophobic polymer multilayers on heat shrinkable polymer films is reported. This approach exploits shrinking processes common to "heat-shrink" plastics, and can thus be used to create "shrink-to-fit" superhydrophobic coatings on complex surfaces, manipulate the dimensions and densities of patterned features, and promote heat-activated repair of full thickness defects. PMID- 23649746 TI - Quantitative analysis of organic vocal fold pathologies in females by high-speed endoscopy. AB - OBJECTIVES/HYPOTHESIS: Quantitative analysis of endoscopic high-speed video recordings of vocal fold vibrations has been growing in importance in recent years. The videos have mainly been analyzed using subjective evaluation, but this is examiner dependent, and the results show inadequate interobserver agreement. The aims of this study were therefore to identify appropriate objective parameters for analyzing high-speed recordings to differentiate healthy voice production from organic disorders. STUDY DESIGN: METHODS: A total of 152 females were examined, divided into 77 healthy and 75 with four different pathological conditions: laryngeal epithelial thickening, Reinke edema, vocal fold polyps, and vocal fold cysts. Vocal fold vibrations were recorded with a high-speed camera (4,000 Hz, 256 * 256 pixels) during sustained phonation. Parameters computed from the glottal area waveform (GAW) and from phonovibrogram (PVG) were analyzed. Multiparametric linear discriminant analysis was performed to classify pathological conditions versus the healthy group. RESULTS: Twenty of 44 parameters were identified that are capable of distinguishing between the individual types of pathology. PVG parameters showed better performance than GAW parameters. Parameters representing vibrational periodicity via standard deviation showed better performance than absolute parameters. In addition, linear discriminant analysis achieved reliable differentiation between healthy and pathological vocal fold vibrations: 72% for the five-class problem (all groups separately) and 88% for the two-class problem (healthy vs. all pathologies taken as one class). CONCLUSIONS: The study succeeded in defining objective parameters for analyzing endoscopic high-speed videos and suggesting first parameters for differentiation between healthy dynamics and dynamics of organic pathologies. PMID- 23649747 TI - Accessory limb induction on flank region and its muscle regulation in axolotl. AB - BACKGROUND: Urodele amphibians have high regeneration capability that has been studied for a long time. Recently, a new experimental system called the accessory limb model was developed and becomes alternative choice for amphibian limb regeneration study. Although the accessory limb model has many advantages, an improvement was needed for some specific analysis, such as studying muscle origin. For that purpose, an accessory limb induction on nonlimb regions was attempted. RESULTS: Accessory limb induction on a nonlimb region (flank) was possible by nerve deviation and limb skin grafting. Retinoic acid injections improved the induction rate. The induced limb possessed the same tissue context as a normal limb. Muscle cells were also abundantly observed. It is speculated that the muscle cells are derived from flank muscle tissues, because limb muscle cells are a migratory cell population and the accessory limb was induced apart from the original limb. We also found that migration of the muscle cells was regulated by Hgf/cMet signaling as in other vertebrates. CONCLUSIONS: Accessory limb induction was possible even in the nonlimb flank region. The flank-induced limb would be useful for further analysis of limb regeneration, especially for migratory cell populations such as muscle cells. PMID- 23649749 TI - Canomad: report of a case with a 40-year history and autopsy. Is this a sensory ganglionopathy with neuromuscular junction blockade? AB - INTRODUCTION: An 80-year-old man had a 40-year history of chronic sensory ataxic neuropathy and 11 years of relapsing/remitting episodes of rapid deterioration with perioral paresthesiae and weakness of bulbar, respiratory, and limb muscles. METHODS: An immunoglobulin M (IgM) paraprotein was detected 12 years before death, and Waldenstrom macroglobulinemia was diagnosed on bone marrow biopsy 3 years before death. Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and anti-disialyl antibodies (CANOMAD) was diagnosed. RESULTS: Comprehensive autopsy showed severe dorsal column atrophy and dorsal root ganglionopathy. A different pathology was identified in cranial and peripheral nerves, dorsal roots, and cauda equina, comprising infiltration of clonal B-lymphocytes within the endoneurium, perineurium, and leptomeninges. CONCLUSIONS: The autopsy provides evidence of the pathogenesis of the relapsing remitting component of CANOMAD, and we postulate that this may relate to the presence of clonal IgM anti-disiayl gangliosides secreting B-lymphocytes within nerves. PMID- 23649748 TI - Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. AB - IMPORTANCE: Narcolepsy, a disorder associated with HLA-DQB1*06:02 and caused by hypocretin (orexin) deficiency, is diagnosed using the Multiple Sleep Latency Test (MSLT) following nocturnal polysomnography (NPSG). In many patients, a short rapid eye movement sleep latency (REML) during the NPSG is also observed but not used diagnostically. OBJECTIVE: To determine diagnostic accuracy and clinical utility of nocturnal REML measures in narcolepsy/hypocretin deficiency. DESIGN, SETTING, AND PARTICIPANTS: Observational study using receiver operating characteristic curves for NPSG REML and MSLT findings (sleep studies performed between May 1976 and September 2011 at university medical centers in the United States, China, Korea, and Europe) to determine optimal diagnostic cutoffs for narcolepsy/hypocretin deficiency compared with different samples: controls, patients with other sleep disorders, patients with other hypersomnias, and patients with narcolepsy with normal hypocretin levels. Increasingly stringent comparisons were made. In a first comparison, 516 age- and sex-matched patients with narcolepsy/hypocretin deficiency were selected from 1749 patients and compared with 516 controls. In a second comparison, 749 successive patients undergoing sleep evaluation for any sleep disorders (low pretest probability for narcolepsy) were compared within groups by final diagnosis of narcolepsy/hypocretin deficiency. In the third comparison, 254 patients with a high pretest probability of having narcolepsy were compared within group by their final diagnosis. Finally, 118 patients with narcolepsy/hypocretin deficiency were compared with 118 age- and sex-matched patients with a diagnosis of narcolepsy but with normal hypocretin levels. MAIN OUTCOME AND MEASURES: Sensitivity and specificity of NPSG REML and MSLT as diagnostic tests for narcolepsy/hypocretin deficiency. This diagnosis was defined as narcolepsy associated with cataplexy plus HLA-DQB1*06:02 positivity (no cerebrospinal fluid hypocretin-1 results available) or narcolepsy with documented low (<= 110 pg/mL) cerebrospinal fluid hypocretin-1 level. RESULTS: Short REML (<=15 minutes) during NPSG was highly specific (99.2% [95% CI, 98.5%-100.0%] of 516 and 99.6% [95% CI, 99.1%-100.0%] of 735) but not sensitive (50.6% [95% CI, 46.3%-54.9%] of 516 and 35.7% [95% CI, 10.6%-60.8%] of 14) for patients with narcolepsy/hypocretin deficiency vs population-based controls or all patients with sleep disorders undergoing a nocturnal sleep study (area under the curve, 0.799 [95% CI, 0.771-0.826] and 0.704 [95% CI, 0.524-0.907], respectively). In patients with central hypersomnia and thus a high pretest probability for narcolepsy, short REML remained highly specific (95.4% [95% CI, 90.4%-98.3%] of 132) and similarly sensitive (57.4% [95% CI, 48.1%-66.3%] of 122) for narcolepsy/hypocretin deficiency (area under the curve, 0.765 [95% CI, 0.707-0.831]). Positive predictive value in this high pretest probability sample was 92.1% (95% CI, 83.6%-97.0%). CONCLUSIONS AND RELEVANCE: Among patients being evaluated for possible narcolepsy, short REML (<=15 minutes) at NPSG had high specificity and positive predictive value and may be considered diagnostic without the use of an MSLT; absence of short REML, however, requires a subsequent MSLT. PMID- 23649750 TI - A behavioral view on chimpanzee personality: exploration tendency, persistence, boldness, and tool-orientation measured with group experiments. AB - Human and nonhuman animals show personality: temporal and contextual consistency in behavior patterns that vary among individuals. In contrast to most other species, personality of chimpanzees, Pan troglodytes, has mainly been studied with non-behavioral methods. We examined boldness, exploration tendency, persistence and tool-orientation in 29 captive chimpanzees using repeated experiments conducted in an ecologically valid social setting. High temporal repeatability and contextual consistency in all these traits indicated they reflected personality. In addition, Principal Component Analysis revealed two independent syndromes, labeled exploration-persistence and boldness. We found no sex or rank differences in the trait scores, but the scores declined with age. Nonetheless, there was considerable inter-individual variation within age classes, suggesting that behavior was not merely determined by age but also by dispositional effects. In conclusion, our study complements earlier rating studies and adds new traits to the chimpanzee personality, thereby supporting the existence of multiple personality traits among chimpanzees. We stress the importance of ecologically valid behavioral research to assess multiple personality traits and their association, as it allows inclusion of ape studies in the comparison of personality structures across species studied behaviorally, and furthers our attempts to unravel the causes and consequences of animal personality. PMID- 23649751 TI - Subsidies to predators, apparent competition and the phylogenetic structure of prey communities. AB - Ecosystems are fragmented by natural and anthropogenic processes that affect organism movement and ecosystem dynamics. When a fragmentation restricts predator but not prey movement, then the prey produced on one side of an ecosystem edge can subsidize predators on the other side. When prey flux is high, predator density on the receiving side increases above that possible by in situ prey productivity, and when low, the formerly subsidized predators can impose strong top-down control of in situ prey--in situ prey experience apparent competition from the subsidy. If predators feed on some evolutionary clades of in situ prey over others, then subsidy-derived apparent competition will induce phylogenetic structure in prey composition. Dams fragment the serial nature of river ecosystems by prohibiting movement of organisms and restricting flowing water. In the river tailwater just below a large central Mexican dam, fish density was high and fish gorged on reservoir-derived zooplankton. When the dam was closed, water flow and the zooplankton subsidy ceased, densely packed pools of fish formed, fish switched to feed on in situ prey, and the tailwater macroinvertebrate community was phylogenetic structured. We derived expectations of structure from trait-based community assembly models based on macroinvertebrate body size, tolerance to anthropogenic disturbance, and fish-diet selectivity. The diet selectivity model best fit the observed tailwater phylogenetic structure. Thus, apparent competition from subsidies phylogenetically structures prey communities, and serial variation in phylogenetic community structure can be indicative of fragmentation in formerly continuous ecosystems. PMID- 23649752 TI - Combustion influences on natural abundance nitrogen isotope ratio in soil and plants following a wildfire in a sub-alpine ecosystem. AB - This before-and-after-impact study uses the natural abundance N isotope ratio (delta(15)N) to investigate the effects of a wildfire on sub-alpine ecosystem properties and processes. We measured the (15)N signatures of soil, charred organic material, ash and foliage in three sub-alpine plant communities (grassland, heathland and woodland) in south-eastern Australia. Surface bulk soil was temporarily enriched in (15)N immediately after wildfire compared to charred organic material and ash in all plant communities. We associated the enrichment of bulk soil with fractionation of N during combustion and volatilization of N, a process that also explains the sequential enrichment of (15)N of unburnt leaves > ash > charred organic material in relation to duration and intensity of heating. The rapid decline in (15)N of bulk soil to pre-fire values indicates that depleted ash, containing considerable amounts of total N, was readily incorporated into the soil. Foliar delta(15)N also increased with values peaking 1 year post-fire. Foliar enrichment was foremost coupled with the release of enriched NH4(+) into the soil owing to isotopic discrimination during volatilization of soluble N and combustion of organic material. The mode of post fire regeneration influenced foliar (15)N enrichment in two species indicating use of different sources of N following fire. The use of natural abundance of (15)N in soil, ash and foliage as a means of tracing transformation of N during wildfire has established the importance of combustion products as an important, albeit temporary source of inorganic N for plants regenerating after wildfire. PMID- 23649753 TI - Corticosterone secretion patterns prior to spring and autumn migration differ in free-living barn swallows (Hirundo rustica L.). AB - Recent studies of long-distance migratory birds show that behavioural and physiological changes associated with predictable or unpredictable challenges during the annual cycle are distinctively regulated by hormones. Corticosterone is the primary energy regulating hormone in birds. Corticosterone levels are elevated during stresses but they are also modulated seasonally according to environmental conditions and life-history demands. We measured the baseline and stress-induced levels of corticosterone in the barn swallow (Hirundo rustica L.) just before spring and autumn migrations in South Africa and Finland, respectively. Barn swallows completing their pre-breeding moult had low body condition (residual body mass) and high baseline corticosterone levels in the wintering grounds. In contrast, baseline corticosterone levels in Finland were low and not related to residual mass. These data contradict the first prediction of the migration modulation hypothesis (MMH) by showing no association with baseline corticosterone levels and pre-migratory fuelling. Yet, the adrenocortical response to the capture and handling stress was notably blunted in South Africa compared to a strong response in Finland. Further, individuals that had started fuelling in Finland showed a reduced response to the handling stress. Taken together, elevated baseline corticosterone levels and high residual mass may blunt the adrenocortical response in long-distance migrants and aerial feeders such as the barn swallow. This observation lends support to the second prediction of the MMH. PMID- 23649754 TI - Ecophysiology and genetic structure of polar versus temperate populations of the lichen Cetraria aculeata. AB - We studied polar and temperate samples of the lichen Cetraria aculeata to investigate whether genetical differences between photobionts are correlated with physiological properties of the lichen holobiont. Net photosynthesis and dark respiration (DR) at different temperatures (from 0 to 30 degrees C) and photon flux densities (from 0 to 1,200 MUmol m(-2) s(-1)) were studied for four populations of Cetraria aculeata. Samples were collected from maritime Antarctica, Svalbard, Germany and Spain, representing different climatic situations. Sequencing of the photobiont showed that the investigated samples fall in the polar and temperate clade described in Fernandez-Mendoza et al. (Mol Ecol 20:1208-1232, 2011). Lichens with photobionts from these clades differ in their temperature optimum for photosynthesis, maximal net photosynthesis, maximal DR and chlorophyll content. Maximal net photosynthesis was much lower in Antarctica and Svalbard than in Germany and Spain. The difference was smaller when rates were expressed by chlorophyll content. The same is true for the temperature optima of polar (11 degrees C) and temperate (15 and 17 degrees C) lichens. Our results indicate that lichen mycobionts may adapt or acclimate to local environmental conditions either by selecting algae from regional pools or by regulating algal cell numbers (chlorophyll content) within the thallus. PMID- 23649755 TI - Xylem cavitation vulnerability influences tree species' habitat preferences in miombo woodlands. AB - Although precipitation plays a central role in structuring Africa's miombo woodlands, remarkably little is known about plant-water relations in this seasonally dry tropical forest. Therefore, in this study, we investigated xylem vulnerability to cavitation for nine principal tree species of miombo woodlands, which differ in habitat preference and leaf phenology. We measured cavitation vulnerability (Psi(50)), stem-area specific hydraulic conductivity (K S), leaf specific conductivity (K L), seasonal variation in predawn water potential (Psi(PD)) and xylem anatomical properties [mean vessel diameter, mean hydraulic diameter, mean hydraulic diameter accounting for 95 % flow, and maximum vessel length (V L)]. Results show that tree species with a narrow habitat range (mesic specialists) were more vulnerable to cavitation than species with a wide habitat range (generalists). Psi(50) for mesic specialists ranged between -1.5 and -2.2 MPa and that for generalists between -2.5 and -3.6 MPa. While mesic specialists exhibited the lowest seasonal variation in Psi(PD), generalists displayed significant seasonal variations in Psi(PD) suggesting that the two miombo habitat groups differ in their rooting depth. We observed a strong trade-off between K S and Psi(50) suggesting that tree hydraulic architecture is one of the decisive factors setting ecological boundaries for principal miombo species. While vessel diameters correlated weakly (P > 0.05) with Psi(50), V L was positively and significantly correlated with Psi(50). Psi(PD) was significantly correlated with Psi(50) further reinforcing the conclusion that tree hydraulic architecture plays a significant role in species' habitat preference in miombo woodlands. PMID- 23649756 TI - Predation resistance does not trade off with competitive ability in early colonizing mosquitoes. AB - The tradeoff between colonization and competitive ability has been proposed as a mechanism for ecological succession, and this tradeoff has been demonstrated in multiple successional communities. The tradeoff between competitive ability and predation resistance is also a widely-described phenomenon; however, this tradeoff is not usually postulated as a cause of ecological succession. Early successional species that arrive before predator colonization could be either (1) less vulnerable to predation than their successors, by virtue of being poor competitors (direct competition-predation tradeoff); or (2) equally or more vulnerable to predation, because they normally colonize ahead of predators in succession and therefore are not evolutionarily adapted to avoid predators that they rarely encounter (no competition-predation tradeoff). To test these alternative hypotheses, we established water-filled containers in an oak-hickory forest. We allowed half of the containers to be naturally colonized by early successional Culex mosquitoes, mid-successional Aedes mosquitoes, and the mosquito predator Toxorhynchites rutilus. In the other half of the containers, we prevented Aedes colonization via systematic removal of Aedes eggs, but allowed Culex and T. rutilus to colonize. The numbers of mature Culex larvae and pupae, and later the total number of Culex, were significantly greater in containers where Aedes had been removed, which suggests that Culex are competitively suppressed by Aedes. Toxorhynchites rutilus abundance and colonization rate were unaffected by the removal of Aedes, and densities of both Culex and Aedes decreased significantly with T. rutilus abundance in both treatments. In laboratory bioassays showed that Culex were significantly more vulnerable to predation by T. rutilus than were Aedes. These data are consistent with the hypothesis that Culex and Aedes demonstrate a direct colonization-competition tradeoff, and are inconsistent with the hypothesis of a direct competition predation tradeoff. PMID- 23649757 TI - Disentangling herbivore impacts on Populus tremuloides: a comparison of native ungulates and cattle in Canada's Aspen Parkland. AB - Ungulates impact woody species' growth and abundance but little is understood about the comparative impacts of different ungulate species on forest expansion in savanna environments. Replacement of native herbivore guilds with livestock [i.e., beef cattle (Bos taurus)] has been hypothesized as a factor facilitating trembling aspen (Populus tremuloides Michx.) encroachment into grasslands of the Northern Great Plains. We used a controlled herbivory study in the Parklands of western Canada to compare the impact of native ungulates and cattle on aspen saplings. Native ungulate treatments included a mixed species guild and sequences of herbivory by different ungulates [bison (Bison bison subsp. bison), elk (Cervus elaphus) then deer (Odocoileus hemionus); or deer, elk, then bison]. Herbivory treatments were replicated in three pastures, within which sets of 40 marked aspen saplings (<1.8 m) were tracked along permanent transects at 2-week intervals, and compared to a non-grazed aspen stand. Stems were assessed for mortality and incremental damage (herbivory, leader breakage, stem abrasion and trampling). Final mortality was greater with exposure to any type of herbivore, but remained similar between ungulate treatments. However, among all treatments, the growth of aspen was highest with exposure only to cattle. Herbivory of aspen was attributed primarily to elk within the native ungulate treatments, with other forms of physical damage, and ultimately sapling mortality, associated with exposure to bison. Overall, these results indicate that native ungulates, specifically elk and bison, have more negative impacts on aspen saplings and provide evidence that native and domestic ungulates can have different functional effects on woody plant dynamics in savanna ecosystems. PMID- 23649758 TI - Molecular and biochemical characterization of a novel intronic single point mutation in a Tunisian family with glycogen storage disease type III. AB - Genetic deficiency of the glycogen debranching enzyme causes glycogen storage disease type III, an autosomal recessive inherited disorder. The gene encoding this enzyme is designated as AGL gene. The disease is characterized by fasting hypoglycemia, hepatomegaly, growth retardation, progressive myopathy and cardiomyopathy. In the present study, we present clinical features and molecular characterization of two consanguineous Tunisian siblings suffering from Glycogen storage disease type III. The full coding exons of the AGL gene and their corresponding exon-intron boundaries were amplified for the patients and their parents. Gene sequencing identified a novel single point mutation at the conserved polypyrimidine tract of intron 21 in a homozygous state (IVS21-8A>G). This variant cosegregated with the disease and was absent in 102 control chromosomes. In silico analysis using online resources showed a decreased score of the acceptor splice site of intron 21. RT-PCR analysis of the AGL splicing pattern revealed a 7 bp sequence insertion between exon 21 and exon 22 due to the creation of a new 3' splice site. The predicted mutant enzyme was truncated by the loss of 637 carboxyl-terminal amino acids as a result of premature termination. This novel mutation is the first mutation identified in the region of Bizerte and the tenth AGL mutation identified in Tunisia. Screening for this mutation can improve the genetic counseling and prenatal diagnosis of GSD III. PMID- 23649759 TI - Celastrol exerts synergistic effects with PHA-665752 and inhibits tumor growth of c-Met-deficient hepatocellular carcinoma in vivo. AB - PHA665752 (PHA), a selective small molecule c-Met Inhibitor, potently inhibited HGF-stimulated and constitutive c-Met phosphorylation, as well as HGF and c-Met driven phenotypes of a variety of tumor cells including hepatocellular carcinoma cells. However, these effects were impaired in c-Met-deficient cancer cells. In the present study, we investigated the potential anti-human c-Met-deficient hepatocellular carcinoma effects of Celastrol, a novel triterpene, and its combination with PHA. Human hepatocellular carcinoma cells BEL-7402 (c-Met positive) and Huh7 (c-Met-deficient) were treated with different dose of PHA with or without equal dose of Celastrol, and cell growth, cell cycle and apoptosis were evaluated, respectively, by MTT assay, flow cytometry and Caspase3/7 activity. Nude mice bearing Huh7 xenografts were used to assess the in vivo anti tumor activity. Our results showed that Celastrol at high concentration (>1.0 MUM) induced G2/M arrest and apoptosis with the activation of Caspase3/7 in Huh7 cells whereas at low concentration (<1.0 MUM) had no obvious effects. Low concentration Celastrol presented significant combined effects with PHA on Huh7 cells and Huh7 xenografts in terms of growth inhibition, migration inhibition and apoptosis induction. These results suggest that Celastrol and its combination with PHA present the therapeutic potential on c-Met-deficient hepatocellular carcinoma, and deserve further preclinical and clinical studies. PMID- 23649760 TI - The Cdx-2 polymorphism in the VDR gene is associated with increased risk of cancer: a meta-analysis. AB - The Cdx-2 polymorphism in VDR gene has been extensively investigated for association with cancer risk, however, results of different studies have been inconsistent. The objective of this study is to assess the relationship of the Cdx-2 polymorphism in VDR and cancer risk by meta-analysis. All eligible case control studies were searched in Pubmed, Embase, CNKI and Wanfang databases. Odds ratios (OR) with the 95 % confidence intervals (CI) were used to assess the association. A total of 12,906 cases and 13,700 controls in 18 case-control studies were included. The results indicated that the AA homozygote carriers had a 16 % increased risk of cancer, when compared with the homozygote GG and heterozygote AG (OR = 1.16, 95 % CI 1.05-1.29 for AA vs. GG+AG). In the subgroup analysis by ethnicity, significant elevated risks were associated with AA homozygote carriers in Caucasians (OR = 1.16, 95 % CI 1.01-1.33, and P = 0.04) and African Americans (OR = 1.31, 95 % CI 1.07-1.61, and P = 0.01). In the subgroup analysis by cancer types, the polymorphism was associated with increased risk of breast cancer (OR = 1.23, 95 % CI 1.04-1.46, and P = 0.02). This meta analysis suggested that the Cdx-2 polymorphism of VDR gene would be a risk factor for cancer. To further evaluate gene-to-gene and gene-to-environmental interactions between polymorphisms of VDR gene and cancer risk, more studies with large groups of patients are required. PMID- 23649761 TI - DNA methylation: the future of crime scene investigation? AB - Proper detection and subsequent analysis of biological evidence is crucial for crime scene reconstruction. The number of different criminal acts is increasing rapidly. Therefore, forensic geneticists are constantly on the battlefield, trying hard to find solutions how to solve them. One of the essential defensive lines in the fight against the invasion of crime is relying on DNA methylation. In this review, the role of DNA methylation in body fluid identification and other DNA methylation applications are discussed. Among other applications of DNA methylation, age determination of the donor of biological evidence, analysis of the parent-of-origin specific DNA methylation markers at imprinted loci for parentage testing and personal identification, differentiation between monozygotic twins due to their different DNA methylation patterns, artificial DNA detection and analyses of DNA methylation patterns in the promoter regions of circadian clock genes are the most important ones. Nevertheless, there are still a lot of open chapters in DNA methylation research that need to be closed before its final implementation in routine forensic casework. PMID- 23649762 TI - RNA-binding protein Rbm47 binds to Nanog in mouse embryonic stem cells. AB - Embryonic stem cells (ES cells) are pluripotent cells capable for self-renewal and to differentiate to all cell types. Finding the molecular mechanisms responsible for these unique characteristics of ES cells is important. RNA binding proteins play important roles in post-transcriptional gene regulation by binding to specific mRNA targets. In this study, we investigated the targets of RNA-binding protein Rbm47 in mouse ES cells. Overexpression of HA epitope-tagged Rbm47 in mouse ES cells followed by RNA-binding protein immunoprecipitation, and then RT-PCR analysis of co-immunoprecipitated RNA showed that Rbm47 binds to Nanog transcript in mouse ES cells and doesn't bind to Sox2 and Oct4 transcripts in these cells. This finding can give rise to reveal molecular mechanisms underlying pluripotency and stemness of ES cells and will be necessary for efficient application of these cells in regenerative medicine and tissue engineering. PMID- 23649763 TI - Bone morphogenetic proteins (BMPs) expression in the femoral heads of patients with avascular necrosis. AB - Avascular necrosis (AVN) is a disorder of the bone repair process which usually results in femoral head (FH) destruction. Bone morphogenetic proteins (BMPs) are the key proteins regulating bone remodelling and healing. BMPs gene expression levels were analyzed in the normal and necrotic sites of osteonecrotic FHs. Quantitative RT-PCR for BMP-2, -4, -6, -7 genes was performed in bone tissue samples from 47 osteonecrotic FHs. Protein levels of BMP-2, -4, -6 were estimated by Western Blot. Statistical analysis was performed using the Wilcoxon signed rank test. BMP-2 and BMP-6 mRNA levels were higher in the normal than the necrotic site (normal/necrotic: 16.8/6.8 and 1.75/1.64, respectively). On the contrary, BMP-4 mRNA levels were higher in the necrotic (0.75) than the normal (0.62), while BMP-7 mRNA levels were extremely low. At the protein level, BMP-2 continued to have a higher expression in the normal region (normal/necrotic: 0.67/0.64). BMP-4 and -6 were detected at higher levels in the necrotic site (normal/necrotic: 0.51/0.61 for BMP-4, 0.51/0.56 for BMP-6), while BMP-7 was not detectable. Different BMP levels between the normal and necrotic site, as well as discrepancies between the gene and protein expression pattern suggest a different regulation mechanism for BMPs between the two regions of FHs. The understanding of the expression pattern and the correlation of BMPs could lead to a more successful use in the prevention and treatment of AVN. PMID- 23649764 TI - A1E inhibits proliferation and induces apoptosis in NCI-H460 lung cancer cells via extrinsic and intrinsic pathways. AB - It has been reported that extracts from Asian traditional/medical herbs possess therapeutic agents against cancers, metabolic diseases, inflammatory diseases, and other intractable diseases. In this study, we assessed the molecular mechanisms involved in the anticancer effects of A1E, the extract of Korean medicinal herbs. We examined the role of the cytotoxic and apoptotic pathways in the cancer chemopreventive activity in non-small-cell lung cancer (NSCLC) cell lines NCI-H460 and NCI-H1299. A1E inhibited the proliferation of NCI-H460 more efficiently than NCI-H1299 (p53(-/-)) cells. The apoptosis was detected by nuclear morphological changes, annexin V-FITC/PI staining, cell cycle analysis, western blot, RT-PCR, and measurement of mitochondrial membrane potential. A1E induced cellular morphological changes and nuclear condensation at 24 h in a dose dependent manner. A1E also perturbed cell cycle progression at the sub-G1 stage and altered cell cycle regulatory factors in NCI-H460 cells. Furthermore, A1E inhibited the PI3K/Akt and NF-kappaB survival pathways, and it activated apoptotic intrinsic and extrinsic pathways. A1E increased the expression levels of members of the extrinsic death receptor complex FasL and FADD. In addition, A1E treatment induced cleavage of caspase-8, caspase-9, caspase-3, and poly ADP ribose polymerase (PARP), whereas the expression levels of Bcl-2 and Bcl-xl were downregulated. A1E induced mitochondrial membrane potential collapse and cytochrome C release. Our results suggest that A1E induces apoptosis via activation of both extrinsic and intrinsic pathways and inhibition of PI3K/Akt survival signaling pathways in NCI-H460 cells. In conclusion, these data demonstrate the potential of A1E as a novel chemotherapeutic agent in NSCLC. PMID- 23649765 TI - MicroRNA profiling in lymphocytes and serum of tyrosinemia type-I patients. AB - Tyrosinemia type-I results from lack of fumarylacetoacetate hydrolase (FAH), which is a liver enzyme and also shown to be present in lymphocytes, fibroblasts, and cultured amniotic fluid cells. In young infants, symptoms of untreated Tyrosinemia type-I are restricted to severe liver involvement. Later in the first year; however, it is known to be present with liver and renal tubular dysfunction associated with growth failure and rickets. MicroRNAs are small regulatory RNAs that function post-transcriptionally. They target commonly 3'-UTR of the mRNAs and inhibit protein expression by either blocking the synthesis or causing degradation of the mRNAs. MiRNA deregulation was observed in a variety of pathologic conditions but their roles in metabolic diseases were remained unsolved. We studied 6 patients with classical phenotypes of Tyrosinemia type-I. To identify possible miRNAs targeting FAH transcripts, microarray profiling of 961 miRNAs for lymphocytes and serum is performed. Computational algorithms are used for prediction of putative mRNA-miRNA interactions. A number of deregulated miRNAs, targeting the non-conserved sites on FAH transcripts were found. Besides, there are some miRNAs that are similarly altered both in lymphocytes and serum, possibly contributing to the disease phenotype. Since miRNAs may have an active role in the enzymatic pathway of tyrosine catabolism, characterizing miRNA profile in fibroblasts of tyrosinemia patients is also important because miRNAs would have distinctive role in disease pathogenesis and they are promising for future therapeutic studies. PMID- 23649766 TI - Novel SNPs in the bovine ADIPOQ and PPARGC1A genes are associated with carcass traits in Hanwoo (Korean cattle). AB - Adiponectin (ADIPOQ) modulates several biological processes including energy homeostasis, glucose and lipid metabolism. The bovine ADIPOQ gene was located near the QTL affecting marbling, ribeye muscle area and fat thickness on BTA1. The gene encoding peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PPARGC1A) was located within the QTL region of the traits on BTA6. Moreover, its protein product has various biological functions such as cellular energy homeostasis, including adaptive thermogenesis, adipogenesis and gluconeogenesis. Therefore, the ADIPOQ and PPARGC1A genes are a positional and functional candidate gene for carcass traits in beef cattle. The objectives of this study were to identify polymorphisms in the bovine ADIPOQ and PPARGC1A genes, to evaluate their associations with carcass traits in Hanwoo (Korean cattle) population. We identified nine SNPs in the ADIPOQ gene. Two SNPs (DQ156119: g.1436T > C and DQ156119: g.1454A > G) in the promoter region were recognized as new SNPs identified in Hanwoo. Association analysis indicated that the g.1454A > G SNP genotype was significantly associated with effects on LMA (P = 0.004) and BF (P = 0.021). The ADIPOQ haplotype was also found to have significant effect on the LMA. In the PPARGC1A gene, we identified 11 SNPs in the two unexplored regions (intron 3 and 5). Among them, seven SNPs were located in intron 3 and four SNPs were located in intron 5. Of these 11 putative novel SNPs, two SNPs (AY839822: g.292C > T and AY839823: g.1064C > T) with minor allele frequency (MAF) > 0.20 were examined for associations with carcass traits. The association analysis revealed that both SNPs in PPARGC1A gene were significantly associated with LMA (P < 0.05). These findings suggest that the SNPs of bovine ADIPOQ and PPARGC1A genes may be a useful molecular marker for selection of carcass traits in Hanwoo. PMID- 23649767 TI - Arabidopsis CBL-interacting protein kinase (CIPK6) is involved in plant response to salt/osmotic stress and ABA. AB - The CBL-CIPK signaling pathway represents a central and critical signaling system involved in plant response to abiotic stress and hormone signaling. In this study, we focused on AtCIPK6 gene, which have been shown to be required for development and salt tolerance in Arabidopsis, but the transcriptional regulatory mechanism of AtCIPK6 gene and whether it plays a role in ABA signaling is still unknown. Here, we showed that in addition to its expression induced by salt and drought stress, the transcripts of AtCIPK6 gene were largely accumulated in abscisic acid treated seedling, compared to basal level expression. Moreover, promoter sequence analysis revealed that there are some elements involved in stress and hormone response detected in the promoter region of AtCIPK6. AtCIPK6p:GUS transgenic assays unraveled that AtCIPK6 promoter is salt/osmotic stress- and ABA-inducible. Overexpression of AtCIPK6 gene in Arabidopsis increased plant tolerance to salt stress, but sensitivity to ABA. Our results contribute to the understanding of transcriptional regulatory mechanism of AtCIPK6 gene and may also provide a good stress-inducible promoter candidate for transgenic engineering. PMID- 23649768 TI - Influence of GSTO2 (N142D) genetic polymorphism on acute renal rejection. AB - Acute renal allograft rejection remains an important problem following kidney transplantation. Several immunological and non-immunological factors intervene in renal graft rejection. Glutathione S-transferase super family is one of the important enzymes for biotransformation of both exogenous and endogenous xenobiotic compounds such as immunosuppressive drugs. The new class of this family is omega that includes two subunits GSTO1 and GSTO2. In this study 282 samples were collected from renal recipients of Namazi hospital in Shiraz-Iran during 2007-2010 years. Also 300 healthy samples as control group were collected from Shiraz population, included in our study. The primary outcome of this study was defined as biopsy-proven acute rejection during 1 year of renal transplantation. We applied polymerase chain reaction-restriction fragment length polymorphism method for determination of GSTO2 N142D polymorphism. Our result showed no significant association between GSTO2 polymorphism and acute rejection. Also this genetic variant has no significant effect with the risk of end stage renal disease. Cadaveric donor type for acute rejection significantly differed between acute rejection and non acute rejection patients (P=0.004). The combination effect of donor type and GSTO2 polymorphism indicates DD genotype with cadaver donor type increase risk of acute rejection (OR=3.82, 95% CI 1.80 12.37, P=0.02). PMID- 23649769 TI - Hepatocellular carcinoma and liver cirrhosis TP53 mutation analysis reflects a moderate dietary exposure to aflatoxins in Espirito Santo State, Brazil. AB - The close relationship between aflatoxins and 249ser TP53 gene mutation (AGG to AGT, Arg to Ser) in hepatocellular carcinoma (HCC) makes this mutation an indirect indicator of dietary contamination with this toxin. We have examined the prevalence of codon 249 TP53 mutation in 41 HCC and 74 liver cirrhosis (without HCC) cases diagnosed at the HUCAM University Hospital in Vitoria, Espirito Santo State, Brazil. DNA was extracted from paraffin sections and from plasma. The mutation was detected by DNA amplification, followed by restriction endonuclease digestion and confirmed by direct sequencing. DNA restriction showed 249ser mutation in 16 HCC and 13 liver cirrhosis, but sequencing confirmed mutations in only 6 HCC and 1 liver cirrhosis. In addition, sequencing revealed 4 patients with mutations at codon 250 (250ser and 250leu) in HCC cases. The prevalence of TP53 mutation was 10/41 (24.3%) in HCC and 1/74 (1.4%) in liver cirrhosis. No relationship between the presence of mutations and the etiology of HCC was observed. TP53 exon 7 mutations, which are related to aflatoxins exposure, were found at 14.6% (249ser), 7.3% (250leu) and 2.4% (250ser) in 41 cases of HCC and 1.4% in 74 liver cirrhosis (without HCC) cases, suggesting a moderate dietary exposure to aflatoxins in the Espirito Santo State, Brazil. PMID- 23649770 TI - Associations between FCGR2A rs1801274, FCGR3A rs396991, FCGR3B NA1/NA2 polymorphisms and periodontitis: a meta-analysis. AB - The aim of this study was to determine whether the Fcgamma receptors (FCGRs) polymorphisms confer susceptibility to periodontitis in ethnically different populations. We did a literature search using PubMed and Embase, and conducted a meta-analysis on the associations between the FCGR2A H131R (rs1801274), FCGR3A F158V (rs396991), and FCGR3B NA1/NA2 polymorphisms and periodontitis using allele contrast, the recessive model, the dominant model, and the homozygote contrast. A total of 17 separate comparisons with 1,421 patients with periodontitis and 1,454 controls, involving six Caucasian, six East Asian, two African and one South Asian population were considered in the meta-analysis. Meta-analysis of the FCGR2A H131R polymorphism showed no association between periodontitis and the FCGR2A R allele (OR=0.987, 95% CI=0.881-1.107, p=0.827). Stratification by ethnicity revealed an association between the RR+RH genotype with periodontitis in Caucasian population (OR=0.624, 95% CI=0.479-0.813, p=4.7*10(-5)), but not in East Asian, and African populations. Meta-analysis of the FCGR3A F158V polymorphism revealed an association between the FCGR3A V allele and periodontitis is in Caucasians (OR=1.457, 95% CI=1.014-2.092, p=0.042), but not in East Asians and Africans. In addition, analysis using the dominant model and homozygote contrast showed the same pattern for the FCGR3A V allele. Meta analysis of the FCGR3B NA1/NA2 polymorphism using the recessive model revealed a significant association between the NA2/NA2 genotype and periodontitis in aggressive periodontitis (OR=2.853, 95% CI=1.673-4.863, 1.1*10(-5)). This meta analysis demonstrates that the FCGR2A, and FCGR3A polymorphisms may confer susceptibility to periodontitis in Caucasians, and that the FCGR3B polymorphism may be associated with susceptibility to aggressive periodontitis. PMID- 23649771 TI - Genetic variation of the CYP17 and susceptibility to endometrial cancer: a meta analysis. AB - Excessive estrogenic influence is known to be associated with initiation/promotion of endometrial cancer (EC). Common variants among genes coding for enzymes in sex steroid biosynthetic pathways may influence the risk of EC. Cytochrome P450c17alpha (CYP17), a gene that codes for a key enzyme (cytochrome P450c17alpha) in a rate-limiting step of estrogen biosynthesis has attracted considerable attention as a candidate gene for EC. The relationship between CYP17 and EC has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 13 studies involving a total of 3,258 cases and 4,614 controls for -34T>C (rs743572) polymorphism of the CYP17 gene to evaluate the effect of CYP17 on genetic susceptibility for EC. An overall random effects odds ratio of 0.71 (95% confidence interval 0.58-0.88, P=0.001) was found under recessive genetic model. Stratified analysis based on ethnicity, sample size and Hardy-Weinberg equilibrium status was conducted to explore potential heterogeneity. This meta-analysis demonstrated that the C allele of -34T>C in CYP17 is a protective factor associated with decreased EC susceptibility, but these associations vary in different ethnic populations. PMID- 23649772 TI - The role of IL15 gene variants in visceral leishmaniasis among Iranian patients. AB - The role of IL-15 in the protection against Leishmania (L) parasites has been clarified in previous studies, in which IL-15 similar to IFN-gamma induces IL-12 production and stimulates the leishmaniacidal activity of the macrophages infected with L. infantum. Furthermore, the increased level of IL-15 in acute visceral leishmaniasis patients (VL) can suppress Th2 cytokines such as IL-4. Since different single nucleotide polymorphisms (SNPs) in the IL15 gene have been described, this study aimed to investigate the association of the SNPs at the positions 267, 367, 13,687 and 14,035 with VL. The IL15 gene variants were compared between two groups consisting of 117 VL patients and 146 healthy individuals using polymerase chain reaction-restriction fragment length polymorphism. The results showed that the frequencies of the alleles 267C (83.9 vs. 73.5%, P=0.0035), 13687A (22.4 vs. 12.8%, P=0.032), genotype 267CC (68.5 vs. 55.6%, P=0.031), haplotypes CGCA (16 vs. 8.3%, P=0.02) and TACA (11.2 vs. 4.8%, P=0.02) were significantly higher in the controls than those in the patients, while the genotypes 267TT (8.5 vs. 0.7%, P=0.0016), 13687CC (78.6 vs. 65.5%, P=0.015), the haplotypes TGCT (10 vs. 2.5%, P=0.00002) and TGCA (5.7 vs. 0.35%, P=0.000001) were significantly more frequent in the patients. In conclusion, it may be speculated that these gene variants with probable effects on the IL-15 production can serve as the factors influencing VL among Iranian population. However, to clarify the association of these variants with the level of IL-15, further studies are recommended. PMID- 23649773 TI - Differences of DNA methylation profiles between monozygotic twins' blood samples. AB - Monozygotic twins (MZs) share an identical genomic sequence, which makes it impossible to discriminate one another with conventional genetic markers like STRs. On the other hand, phenotypic discordance between MZs implies the existence of different epigenetic characteristics. DNA methylation, an essential epigenetic modification, however, might be a potential biomarker to solve the forensic puzzle. In this study, we examined 22 pairs of MZs with a methylation BeadChip including 27,578 CpG sites. The results suggested that MZs exhibited remarkable differences of genome-wide 5-methylcytosine. According to a set of criteria of selection, 92 CpG sites with significant differences of methylation status within MZs were identified from the global epigenome. In conclusion, this pilot study suggested that CpG methylation profile could be a useful biomarker in individual identification of MZs. PMID- 23649774 TI - Mortality risk in former smokers with breast cancer: pack-years vs. smoking status. AB - It is unclear why successful quitting at time of breast cancer diagnosis should remove risk from a significant lifetime of smoking. Studies concluding this may be biased by how smoking is measured in many epidemiological cohorts. In the late 1990s, a randomized trial of diet and breast cancer outcomes enrolled early-stage female breast cancer survivors diagnosed within the previous 4 years. Smoking history and key covariate measures were available at study entry for 2,953 participants. Participants were followed for an average of 7.3 years (96% response rate). There were 10.1% deaths (83% from breast cancer). At enrollment, 55.2% were never smokers, 41.2% former smokers and 4.6% current smokers. Using current smoking status in a Cox regression, there was no increased risk for former smokers for either all-cause mortality [hazard ratio (HR) = 1.11; 95% confidence interval (CI) = 0.87-1.41; p-value = 0.42) or breast cancer mortality. However, when we categorized on extensive lifetime exposure, former smokers with 20+ pack-years of smoking (25.8%) had a significantly higher risk of both all cause (HR = 1.77; 95% CI = 1.17-2.48; p-value = 0.0007) and breast cancer specific mortality (HR = 1.62; 95% CI = 1.11-2.37; p-value = 0.01). Lifetime smoking exposure, not current status, should be used to assess mortality risk among former smokers. PMID- 23649775 TI - Spatial variation in landscape-level CO2 and CH4 fluxes from arctic coastal tundra: influence from vegetation, wetness, and the thaw lake cycle. AB - Regional quantification of arctic CO2 and CH4 fluxes remains difficult due to high landscape heterogeneity coupled with a sparse measurement network. Most of the arctic coastal tundra near Barrow, Alaska is part of the thaw lake cycle, which includes current thaw lakes and a 5500-year chronosequence of vegetated thaw lake basins. However, spatial variability in carbon fluxes from these features remains grossly understudied. Here, we present an analysis of whole ecosystem CO2 and CH4 fluxes from 20 thaw lake cycle features during the 2011 growing season. We found that the thaw lake cycle was largely responsible for spatial variation in CO2 flux, mostly due to its control on gross primary productivity (GPP). Current lakes were significant CO2 sources that varied little. Vegetated basins showed declining GPP and CO2 sink with age (R(2) = 67% and 57%, respectively). CH4 fluxes measured from a subset of 12 vegetated basins showed no relationship with age or CO2 flux components. Instead, higher CH4 fluxes were related to greater landscape wetness (R(2) = 57%) and thaw depth (additional R(2) = 28%). Spatial variation in CO2 and CH4 fluxes had good satellite remote sensing indicators, and we estimated the region to be a small CO2 sink of -4.9 +/- 2.4 (SE) g C m(-2) between 11 June and 25 August, which was countered by a CH4 source of 2.1 +/- 0.2 (SE) g C m(-2) . Results from our scaling exercise showed that developing or validating regional estimates based on single tower sites can result in significant bias, on average by a factor 4 for CO2 flux and 30% for CH4 flux. Although our results are specific to the Arctic Coastal Plain of Alaska, the degree of landscape-scale variability, large-scale controls on carbon exchange, and implications for regional estimation seen here likely have wide relevance to other arctic landscapes. PMID- 23649776 TI - Oxidation of water under visible-light irradiation over modified BaTaO2N photocatalysts promoted by tungsten species. PMID- 23649777 TI - Comparison of pain-resilient working individuals to population-based case controls with/without momentary low back pain. AB - BACKGROUND: Few studies have examined the 20% of individuals who never experience an episode of low back pain (LBP). To date, no investigation has been undertaken that examines a group who claim to have never experienced LBP in their lifetime in comparison to two population-based case-control groups with and without momentary LBP. This study investigates whether LBP-resilient workers between 50 and 65 years had better general health, demonstrated more positive health behaviour and were better able to achieve routine activities compared with both case-control groups. METHODS: Forty-two LBP-resilient participants completed the same pain assessment questionnaire as a population-based LBP sample from a nationwide, large-scale cross-sectional survey in Switzerland. The LBP-resilient participants were pairwise compared to the propensity score-matched case controls by exploring differences in demographic and work characteristics, and by calculating odds ratios (ORs) and effect sizes. A discriminant analysis explored group differences, while the multiple logistic regression analysis specified single indicators which accounted for group differences. RESULTS: LBP-resilient participants were healthier than the case controls with momentary LBP and achieved routine activities more easily. Compared to controls without momentary LBP, LBP-resilient participants had a higher vitality, a lower workload, a healthier attitude towards health and behaved more healthily by drinking less alcohol. CONCLUSIONS: By demonstrating a difference between LBP-resilient participants and controls without momentary LBP, the question that arises is what additional knowledge can be attained. Three underlying traits seem to be relevant about LBP-resilient participants: personality, favourable work conditions and subjective attitudes/attributions towards health. These rationales have to be considered with respect to LBP prevention. PMID- 23649779 TI - Peptide-column interactions and their influence on back exchange rates in hydrogen/deuterium exchange-MS. AB - Hydrogen/deuterium exchange (HDX) methods generate useful information on protein structure and dynamics, ideally at the individual residue level. Most MS-based HDX methods involve a rapid proteolytic digestion followed by LC/MS analysis, with exchange kinetics monitored at the peptide level. Localizing specific sites of HDX is usually restricted to a resolution the size of the host peptide because gas-phase processes can scramble deuterium throughout the peptide. Subtractive methods may improve resolution, where deuterium levels of overlapping and nested peptides are used in a subtractive manner to localize exchange to smaller segments. In this study, we explore the underlying assumption of the subtractive method, namely, that the measured back exchange kinetics of a given residue is independent of its host peptide. Using a series of deuterated peptides, we show that secondary structure can be partially retained under quenched conditions, and that interactions between peptides and reversed-phase LC columns may both accelerate and decelerate residue HDX, depending upon peptide sequence and length. Secondary structure is induced through column interactions in peptides with a solution-phase propensity for structure, which has the effect of slowing HDX rates relative to predicted random coil values. Conversely, column interactions can orient random-coil peptide conformers to accelerate HDX, the degree to which correlates with peptide charge in solution, and which can be reversed by using stronger ion pairing reagents. The dependency of these effects on sequence and length suggest that subtractive methods for improving structural resolution in HDX-MS will not offer a straightforward solution for increasing exchange site resolution. PMID- 23649778 TI - Evaluation of selected binding domains for the analysis of ubiquitinated proteomes. AB - Ubiquitination is an abundant post-translational modification that consists of covalent attachment of ubiquitin to lysine residues or the N-terminus of proteins. Mono- and polyubiquitination have been shown to be involved in many critical eukaryotic cellular functions and are often disrupted by intracellular bacterial pathogens. Affinity enrichment of ubiquitinated proteins enables global analysis of this key modification. In this context, the use of ubiquitin-binding domains is a promising but relatively unexplored alternative to more broadly used immunoaffinity or tagged affinity enrichment methods. In this study, we evaluated the application of eight ubiquitin-binding domains that have differing affinities for ubiquitination states. Small-scale proteomics analysis identified ~200 ubiquitinated protein candidates per ubiquitin-binding domain pull-down experiment. Results from subsequent Western blot analyses that employed anti ubiquitin or monoclonal antibodies against polyubiquitination at lysine 48 and 63 suggest that ubiquitin-binding domains from Dsk2 and ubiquilin-1 have the broadest specificity in that they captured most types of ubiquitination, whereas the binding domain from NBR1 was more selective to polyubiquitination. These data demonstrate that with optimized purification conditions, ubiquitin-binding domains can be an alternative tool for proteomic applications. This approach is especially promising for the analysis of tissues or cells resistant to transfection, of which the overexpression of tagged ubiquitin is a major hurdle. PMID- 23649780 TI - Biomechanical properties of the plantar flexor muscle-tendon complex 6 months post-rupture of the Achilles tendon. AB - We compared the effects of a non-weight bearing protocol (NWB) and a weight bearing (WB) protocol on energy stored, stiffness, and shock absorption in the plantar flexor muscle-tendon unit of patients managed non-operatively following an Achilles tendon rupture. Thirty-eight subjects were randomized to a WB cast fitted with a Bohler iron or a traditional non-weight-bearing cast. At a 6-month follow-up, a biomechanical assessment utilizing an isokinetic dynamometer allowed measurement of peak passive torque, energy stored, shock absorption, and stiffness. The WB group had greater peak passive torque (~ 20%). Irrespective of group, peak passive torque in unaffected legs was greater (~ 26%) than affected legs. Across the groups, energy stored in the NWB group was 74% of the WB group. The energy stored in affected legs was 80% of that in unaffected legs. Shock absorption was not significantly different across legs or groups. Irrespective of group, affected legs had significantly less stiffness (20-40%). While the augmentation of plaster with a Bohler iron to allow increased weight bearing had positive effects, deficits in affected compared to unaffected legs irrespective of group were notable, and should be addressed prior to participation in vigorous physical activities. PMID- 23649781 TI - Two isostructural explosive cocrystals with significantly different thermodynamic stabilities. PMID- 23649782 TI - Discussing uncertainty and risk in primary care: recommendations of a multi disciplinary panel regarding communication around prostate cancer screening. AB - BACKGROUND: Shared decision making improves value-concordant decision-making around prostate cancer screening (PrCS). Yet, PrCS discussions remain complex, challenging and often emotional for physicians and average-risk men. OBJECTIVE: In July 2011, the Centers for Disease Control and Prevention convened a multidisciplinary expert panel to identify priorities for funding agencies and development groups to promote evidence-based, value-concordant decisions between men at average risk for prostate cancer and their physicians. DESIGN: Two-day multidisciplinary expert panel in Atlanta, Georgia, with structured discussions and formal consensus processes. PARTICIPANTS: Sixteen panelists represented diverse specialties (primary care, medical oncology, urology), disciplines (sociology, communication, medical education, clinical epidemiology) and market sectors (patient advocacy groups, Federal funding agencies, guideline-development organizations). MAIN MEASURES: Panelists used guiding interactional and evaluation models to identify and rate strategies that might improve PrCS discussions and decisions for physicians, patients and health systems/society. Efficacy was defined as the likelihood of each strategy to impact outcomes. Effort was defined as the relative amount of effort to develop, implement and sustain the strategy. Each strategy was rated (1-7 scale; 7 = maximum) using group process software (ThinkTank(TM)). For each group, intervention strategies were grouped as financial/regulatory, educational, communication or attitudinal levers. For each strategy, barriers were identified. KEY RESULTS: Highly ranked strategies to improve value-concordant shared decision-making (SDM) included: changing outpatient clinic visit reimbursement to reward SDM; development of evidence-based, technology-assisted, point-of-service tools for physicians and patients; reframing confusing prostate cancer screening messages; providing pre visit decision support interventions; utilizing electronic health records to promote benchmarking/best practices; providing additional training for physicians around value-concordant decision-making; and using re-accreditation to promote training. CONCLUSIONS: Conference outcomes present an expert consensus of strategies likely to improve value-concordant prostate cancer screening decisions. In addition, the methodology used to obtain agreement provides a model of successful collaboration around this and future controversial cancer screening issues, which may be of interest to funding agencies, educators and policy makers. PMID- 23649783 TI - Implementing smoking cessation guidelines for hospitalized veterans: effects on nurse attitudes and performance. AB - BACKGROUND: A minority of hospitalized smokers actually receives assistance in quitting during hospitalization or cessation counseling following discharge. This study aims to determine the impact of a guideline-based intervention on 1) nurses' delivery of the 5A's (Ask-Advise-Assess-Assist-Arrange follow-up) in hospitalized smokers, and 2) nurses' attitudes toward the intervention. METHODS: We conducted a pre-post guideline implementation trial involving 205 hospitalized smokers on the inpatient medicine units at one US Department of Veterans Affairs (VA) medical center. The intervention included: 1) academic detailing of nurses on delivery of brief cessation counseling, 2) modification of the admission form to facilitate 5A's documentation, and 3) referral of motivated inpatients to receive proactive telephone counseling. Based on subject interviews, we calculated a nursing 5A's composite score for each patient (ranging from 0 to 9). We used linear regression with generalized estimating equations to compare the 5A's composite score (and logistic regression to compare individual A's) across periods. We compared 29 nurses' ratings of their self-efficacy and decisional balance ("pros" and "cons") with regard to cessation counseling before and after guideline implementation. Following implementation, we also interviewed a purposeful sample of nurses to assess their attitudes toward the intervention. RESULTS: Of 193 smokers who completed the pre-discharge interview, the mean nursing 5A's composite score was higher after guideline implementation (3.9 vs. 3.1, adjusted difference 1.0, 95 % CI 0.5-1.6). More patients were advised to quit (62 vs. 48 %, adjusted OR = 2.1, 95 % CI = 1.2-3.5) and were assisted in quitting (70 vs. 45 %, adjusted OR = 2.9, 95 % CI = 1.6-5.3) by a nurse during the post-implementation period. Nurses' attitudes toward cessation counseling improved following guideline implementation (35.3 vs. 32.7 on "pros" subscale, p = 0.01), without significant change on the "cons" subscale. CONCLUSIONS: A multifaceted intervention including academic detailing and adaptation of the nursing admission template is an effective strategy for improving nurses' delivery of brief cessation counseling in medical inpatients. PMID- 23649785 TI - Statin use and osteoarthritis. PMID- 23649784 TI - Primary care clinicians' recognition and management of depression: a model of depression care in real-world primary care practice. AB - BACKGROUND: Depression is prevalent in primary care (PC) practices and poses a considerable public health burden in the United States. Despite nearly four decades of efforts to improve depression care quality in PC practices, a gap remains between desired treatment outcomes and the reality of how depression care is delivered. OBJECTIVE: This article presents a real-world PC practice model of depression care, elucidating the processes and their influencing conditions. DESIGN: Grounded theory methodology was used for the data collection and analysis to develop a depression care model. Data were collected from 70 individual interviews (60 to 70 min each), three focus group interviews (n = 24, 2 h each), two surveys per clinician, and investigators' field notes on practice environments. Interviews were audiotaped and transcribed for analysis. Surveys and field notes complemented interview data. PARTICIPANTS: Seventy primary care clinicians from 52 PC offices in the Midwest: 28 general internists, 28 family physicians, and 14 nurse practitioners. KEY RESULTS: A depression care model was developed that illustrates how real-world conditions infuse complexity into each step of the depression care process. Depression care in PC settings is mediated through clinicians' interactions with patients, practice, and the local community. A clinician's interactional familiarity ("familiarity capital") was a powerful facilitator for depression care. For the recognition of depression, three previously reported processes and three conditions were confirmed. For the management of depression, 13 processes and 11 conditions were identified. Empowering the patient was a parallel process to the management of depression. CONCLUSIONS: The clinician's ability to develop and utilize interactional relationships and resources needed to recognize and treat a person with depression is key to depression care in primary care settings. The interactional context of depression care makes empowering the patient central to depression care delivery. PMID- 23649786 TI - Getting back to basics. PMID- 23649788 TI - Screening for rare sequence variants in the THAP1 gene in a primary dystonia cohort. PMID- 23649787 TI - Community-partnered cluster-randomized comparative effectiveness trial of community engagement and planning or resources for services to address depression disparities. AB - BACKGROUND: Depression contributes to disability and there are ethnic/racial disparities in access and outcomes of care. Quality improvement (QI) programs for depression in primary care improve outcomes relative to usual care, but health, social and other community-based service sectors also support clients in under resourced communities. Little is known about effects on client outcomes of strategies to implement depression QI across diverse sectors. OBJECTIVE: To compare the effectiveness of Community Engagement and Planning (CEP) and Resources for Services (RS) to implement depression QI on clients' mental health related quality of life (HRQL) and services use. DESIGN: Matched programs from health, social and other service sectors were randomized to community engagement and planning (promoting inter-agency collaboration) or resources for services (individual program technical assistance plus outreach) to implement depression QI toolkits in Hollywood-Metro and South Los Angeles. PARTICIPANTS: From 93 randomized programs, 4,440 clients were screened and of 1,322 depressed by the 8 item Patient Health Questionnaire (PHQ-8) and providing contact information, 1,246 enrolled and 1,018 in 90 programs completed baseline or 6-month follow-up. MEASURES: Self-reported mental HRQL and probable depression (primary), physical activity, employment, homelessness risk factors (secondary) and services use. RESULTS: CEP was more effective than RS at improving mental HRQL, increasing physical activity and reducing homelessness risk factors, rate of behavioral health hospitalization and medication visits among specialty care users (i.e. psychiatrists, mental health providers) while increasing depression visits among users of primary care/public health for depression and users of faith-based and park programs (each p < 0.05). Employment, use of antidepressants, and total contacts were not significantly affected (each p > 0.05). CONCLUSION: Community engagement to build a collaborative approach to implementing depression QI across diverse programs was more effective than resources for services for individual programs in improving mental HRQL, physical activity and homelessness risk factors, and shifted utilization away from hospitalizations and specialty medication visits toward primary care and other sectors, offering an expanded health-home model to address multiple disparities for depressed safety-net clients. PMID- 23649789 TI - Enzyme-controlled sensing-actuating nanomachine based on Janus Au-mesoporous silica nanoparticles. AB - Novel Janus nanoparticles with Au and mesoporous silica faces on opposite sides were prepared using a Pickering emulsion template with paraffin wax as the oil phase. These anisotropic colloids were employed as integrated sensing-actuating nanomachines for enzyme-controlled stimuli-responsive cargo delivery. As a proof of concept, we demonstrated the successful use of the Janus colloids for controlled delivery of tris(2,2'-bipyridyl) ruthenium(II) chloride from the mesoporous silica face, which was grafted with pH-sensitive gatelike scaffoldings. The release was mediated by the on-demand catalytic decomposition of urea by urease, which was covalently immobilized on the Au face. PMID- 23649791 TI - Molecular-targeted agents combination therapy for cancer: developments and potentials. AB - Although chemotherapy has advanced into the era of targeted drugs, the antitumor efficacies of current therapies are limited, most likely because of the high degree of cancer clonal heterogeneity, intratumor genetic heterogeneity and cell signal complexity. As shutdown of a single target does not necessarily eradicate the cancer, the use of combinations of molecular-targeted agents (MATs) has been proposed, and some pioneering research has been conducted to examine the efficacy of this strategy. In this article, the clinical and preclinical studies that are underway in an attempt to improve the anticancer efficacy of chemotherapies through combination strategies are summarized. Studies of combining cytotoxic agents with MATs, coinhibiting two or more targets in a single pathway or coinhibiting parallel or compensatory pathways as well as specific combinations will be introduced, and the antitumor potentials of each combination strategy will be evaluated. PMID- 23649790 TI - Which bundles of features in a Web-based personally controlled health management system are associated with consumer help-seeking behaviors for physical and emotional well-being? AB - BACKGROUND: Personally controlled health management systems (PCHMS), which include a personal health record (PHR), health management tools, and consumer resources, represent the next stage in consumer eHealth systems. It is still unclear, however, what features contribute to an engaging and efficacious PCHMS. OBJECTIVE: To identify features in a Web-based PCHMS that are associated with consumer utilization of primary care and counselling services, and help-seeking rates for physical and emotional well-being concerns. METHODS: A one-group pre/posttest online prospective study was conducted on a university campus to measure use of a PCHMS for physical and emotional well-being needs during a university academic semester (July to November 2011). The PCHMS integrated an untethered personal health record (PHR) with well-being journeys, social forums, polls, diaries, and online messaging links with a health service provider, where journeys provide information for consumer participants to engage with clinicians and health services in an actionable way. 1985 students and staff aged 18 and above with access to the Internet were recruited online. Logistic regression, the Pearson product-moment correlation coefficient, and chi-square analyses were used to associate participants' help-seeking behaviors and health service utilization with PCHMS usage among the 709 participants eligible for analysis. RESULTS: A dose-response association was detected between the number of times a user logged into the PCHMS and the number of visits to a health care professional (P=.01), to the university counselling service (P=.03), and help-seeking rates (formal or informal) for emotional well-being matters (P=.03). No significant association was detected between participant pre-study characteristics or well-being ratings at different PCHMS login frequencies. Health service utilization was strongly correlated with use of a bundle of features including: online appointment booking (primary care: OR 1.74, 95% CI 1.01-3.00; counselling: OR 6.04, 95% CI 2.30 15.85), personal health record (health care professional: OR 2.82, 95% CI 1.63 4.89), the poll (health care professional: OR 1.47, 95% CI 1.02-2.12), and diary (counselling: OR 4.92, 95% CI 1.40-17.35). Help-seeking for physical well-being matters was only correlated with use of the personal health record (OR 1.73, 95% CI 1.18-2.53). Help-seeking for emotional well-being concerns (including visits to the university counselling service) was correlated with a bundle comprising the poll (formal or informal help-seeking: OR 1.03, 95% CI 1.00-1.05), diary (counselling: OR 4.92, 95% CI 1.40-17.35), and online appointment booking (counselling: OR 6.04, 95% CI 2.30-15.85). CONCLUSIONS: Frequent usage of a PCHMS was significantly associated with increased consumer health service utilization and help-seeking rates for emotional health matters in a university sample. Different bundles of PCHMS features were associated with physical and emotional well-being matters. PCHMS appears to be a promising mechanism to engage consumers in help-seeking or health service utilization for physical and emotional well being matters. PMID- 23649792 TI - Mechanical loss in multiferroic materials at high frequencies: friction and the evolution of ferroelastic microstructures. AB - Energy absorption in multiferroic materials stems typically from strain relaxation which can be strong even when no extrinsic defects exist in the material. Computer simulations of a simple two-dimensional model on a generic, proper ferroelastic material identify the dissipative mechanisms associated with the dynamical motion as: a) advance and retraction of needle-shaped twin domains and, b) movement of kinks inside twin boundaries. Both movements involve friction losses. PMID- 23649793 TI - Invasive fibroblasts: fundamental difference between sporadic inclusion body myositis and polymyositis. AB - INTRODUCTION: Sporadic inclusion body myositis (sIBM) is a progressive disease that leads to extensive muscle weakness. The aim of this study was to determine whether the number and distribution of fibroblasts differ in sIBM when compared with polymyositis. METHODS: Immunofluorescence double labeling was performed on 35 biopsies with antibodies directed against perlecan and CD90, procollagen I, CD34, and CD105. In addition, nonserial ultrathin sections were studied from 3 biopsies of each condition. RESULTS: Fibroblasts expressing CD90 and CD34 accumulated in the endomysial compartment in polymyositis and sIBM. In addition, cells expressing CD90 were found beneath the basal lamina in both conditions. At the ultrastructural level in polymyositis, fibroblasts invaded the myofiber, with focal destruction of the basement membrane. In sIBM, by contrast, invasive fibroblasts were ensheathed by the intact myofiber basement membrane. CONCLUSIONS: The impact of intruding fibroblasts on satellite cells remains to be established. PMID- 23649794 TI - Polythioethers by thiol-ene click polyaddition of alpha,omega-alkylene thiols. AB - The straightforward synthesis of a series of poly(thioether)s by photoinduced thiol-ene click polyaddition of alpha,omega-alkylene thiols is reported. It is found that linear and telechelic poly(thioether)s can be directly obtained from alpha,omega-alkylene thiols with, for example, alkyl chain length of m = 1,2,3, and 9. The reaction proceeds without additives such as (radical) initiators or metal compounds and can simply be carried out by UV-irradiation of the bulk monomer or monomer solution. Ex situ kinetic studies reveal that the reaction proceeds by a typical a step-growth polyaddition mechanism. As the homologue series of poly(thioether)s are now synthetically accessible, new direct pathways to tailored poly(alkyl sulphoxide)s and poly(alkyl sulfone)s are now possible. PMID- 23649795 TI - Net primary productivity and rain-use efficiency as affected by warming, altered precipitation, and clipping in a mixed-grass prairie. AB - Grassland productivity in response to climate change and land use is a global concern. In order to explore the effects of climate change and land use on net primary productivity (NPP), NPP partitioning [fBNPP , defined as the fraction of belowground NPP (BNPP) to NPP], and rain-use efficiency (RUE) of NPP, we conducted a field experiment with warming (+3 degrees C), altered precipitation (double and half), and annual clipping in a mixed-grass prairie in Oklahoma, USA since July, 2009. Across the years, warming significantly increased BNPP, fBNPP , and RUEBNPP by an average of 11.6%, 2.8%, and 6.6%, respectively. This indicates that BNPP was more sensitive to warming than aboveground NPP (ANPP) since warming did not change ANPP and RUEANPP much. Double precipitation stimulated ANPP, BNPP, and NPP but suppressed RUEANPP , RUEBNPP , and RUENPP while half precipitation decreased ANPP, BNPP, and NPP but increased RUEANPP , RUEBNPP , and RUENPP . Clipping interacted with altered precipitation in impacting RUEANPP , RUEBNPP , and RUENPP , suggesting land use could confound the effects of precipitation changes on ecosystem processes. Soil moisture was found to be a main factor in regulating variation in ANPP, BNPP, and NPP while soil temperature was the dominant factor influencing fBNPP . These findings suggest that BNPP is critical point to future research. Additionally, results from single-factor manipulative experiments should be treated with caution due to the non-additive interactive effects of warming with altered precipitation and land use (clipping). PMID- 23649796 TI - The expert advantage in dynamic pattern recall persists across both attended and unattended display elements. AB - We examined how differences in attention influence how expert and novice basketball players encode into memory the specific structural information contained within patterns of play from their sport. Our participants were primed during a typical recall task to focus attention on either attacking or defending player formations before being asked to recall the attended or unattended portion of the pattern. Adherence to the instructional set was confirmed through an analysis of gaze distributions. Recall performance was superior for the experts relative to the novices across both the attended and unattended attacking and defensive pattern structures. Expert recall of attacker positions was unchanged with and without attention, whereas recall accuracy for the positions of defenders diminished without attention, as did the novices' recall of both attack and defense formations. The findings suggest that experienced performers are better than novices at encoding the elements from a complex and dynamic pattern in the absence of focused attention, with this advantage being especially evident in relation to the recall of attacking structure. Some revision of long-term memory theories of expertise will be necessary to accommodate these findings. PMID- 23649797 TI - Fast ion transport and phase separation in a mechanically driven flow of electrolytes through tortuous sub-nanometer nanochannels. AB - Both nanostructured materials and nanotubes hold tremendous promises for separation and purification applications, such as water desalination. By using molecular dynamics, herein, we compare the transport of aqueous electrolyte solutions through a Y-zeolite, which features interconnected, tortuous sub nanometer nanopores, and a model silica nanotube, which has the same composition but is straight and has much lower surface complexity. In the Y-zeolite, ion transport is faster than the transport of water molecules, thus leading to a phenomenon of phase separation in which a gradient of salt concentration is generated along the flow direction. However, similar transport characteristics and phase separation are not found in the model silica nanotube. Detailed analysis suggests that, in nanochannels with complicated geometries, such as those of the Y-zeolite, the structural and flow characteristics of confined nanofluids are highly coupled, thus influencing the transport of ions and solvents and causing the phenomenon of phase separation. PMID- 23649798 TI - Tissue-specific venous expression of the EPH family receptor EphB1 in the skin vasculature. AB - BACKGROUND: The major arteries and veins are formed early during development. The molecular tools to identify arterial and venous endothelial cells improve our understanding of arterial-venous differentiation and branching morphogenesis. Compared with arterial differentiation, relatively little is known about what controls venous development, due to lack of definitive molecular markers for venous endothelial cells. RESULTS: Here we report that the antibody against EphB1, an EphB class receptor, makes it possible to establish a reliable whole mount immunohistochemical analysis of venous identity with greater resolution than previously possible in embryonic and adult skin vasculature models. EphB1 expression is restricted to the entire venous vasculature throughout embryonic development to adulthood, whereas the previously established venous marker EphB4 is also detectable in lymphatic vasculature. This venous-restricted expression of EphB1 is established after the vascular remodeling of the primary capillary plexus has occurred. Compared with its venous-specific expression in the skin, however, EphB1 is not restricted to the venous vasculature in yolk sac, trunk and lung. CONCLUSIONS: These studies introduce EphB1 as a new venous-restricted marker in a tissue-specific and time-dependent manner. PMID- 23649799 TI - Effectiveness of an 8-week exercise programme on pain and specificity of neck muscle activity in patients with chronic neck pain: a randomized controlled study. AB - BACKGROUND: Although exercise can be effective for relief of neck pain, little is known about the effect of exercise on the neural control of neck muscles. METHODS: A randomized controlled trial was conducted on 46 women with chronic neck pain to investigate the immediate effectiveness of an 8-week exercise programme on pain and directional specificity of neck muscle activity. At baseline, the patients completed questionnaires including the neck disability index (NDI) and performed a circular contraction of their head in the horizontal plane at 15 N force, with continuous change in force direction in the range 0-360 degrees . Electromyography (EMG) was recorded from the sternocleidomastoid (SCM) and splenius capitis (SCap) muscles. Tuning curves of the EMG amplitude were computed, which depicts muscle activity over a range of force directions. The mean point of the tuning curves defined a directional vector, which determined the specificity of muscle activity. Patients were randomly assigned either to a training or control group. RESULTS: A significant between-group difference in the change in NDI was observed. A reduction in NDI was observed following training (pre: 18.2 +/- 7.4; post: 14.1 +/- 6.5; p < 0.01) but not for the control group (pre: 17.5 +/- 6.3; post: 16.6 +/- 7.4). The training group showed higher specificity of muscle activity post-intervention (pre: 18.6 +/- 9.8%, post: 24.7 +/- 14.3%; p < 0.05), whereas no change occurred for the control group (pre: 19.4 +/- 11.9%, post: 18.2 +/- 10.1%). CONCLUSION: An exercise programme that aims to enhance motor control of the cervical spine improves the specificity of neck muscle activity and reduces pain and disability in patients with neck pain. PMID- 23649801 TI - Successful treatment of nonunion with teriparatide after failed ankle arthrodesis for Charcot arthropathy. AB - We describe a case of successful treatment to nonunion after multiple arthrodesis operations for Charcot arthropathy with teriparatide. We describe the case of a 25-year-old woman with severe Type I diabetes mellitus that resulted in nonunion after multiple arthrodesis operations for Charcot arthropathy. The woman sustained a femoral shaft fracture for which she underwent surgery with intramedullary nail fixation. Immediately after surgery, an empiric course of teriparatide was initiated. Femoral shaft fracture healing was observed after 2 weeks, and the woman was able to walk 12 weeks after the surgery, at which point plain film and computed tomography images revealed complete union of the ankle. PMID- 23649802 TI - Diagnostic measures for sarcopenia and bone mineral density. AB - SUMMARY: Currently used diagnostic measures for sarcopenia utilize different measures of muscle mass, muscle strength, and physical performance. These diagnostic measures associate differently to bone mineral density (BMD), as an example of muscle-related clinical outcome. These differences should be taken into account when studying sarcopenia. INTRODUCTION: Diagnostic measures for sarcopenia utilize different measures of muscle mass, muscle strength, and physical performance. To understand differences between these measures, we determined the association with respect to whole body BMD, as an example of muscle-related clinical outcome. METHODS: In the European cross-sectional study MYOAGE, 178 young (18-30 years) and 274 healthy old participants (69-81 years) were recruited. Body composition and BMD were evaluated using dual-energy X-ray densitometry. Diagnostic measures for sarcopenia were composed of lean mass as percentage of body mass, appendicular lean mass (ALM) as percentage of body mass, ALM divided by height squared (ALM/height(2)), knee extension torque, grip strength, walking speed, and Timed Up and Go test (TUG). Linear regression models were stratified for sex and age and adjusted for age and country, and body composition in separate models. RESULTS: Lean mass and ALM/height(2) were positively associated with BMD (P < 0.001). Significance remained in all sex and age subgroups after further adjustment for fat mass, except in old women. Lean mass percentage and ALM percentage were inversely associated with BMD in old women (P < 0.001). These inverse associations disappeared after adjustment for body mass. Knee extension torque and handgrip strength were positively associated with BMD in all subgroups (P < 0.01), except in old women. Walking speed and TUG were not related to BMD. CONCLUSIONS: The associations between diagnostic measures of sarcopenia and BMD as an example of muscle-related outcome vary widely. Differences between diagnostic measures should be taken into account when studying sarcopenia. PMID- 23649803 TI - Elastin fibers display a versatile microfibril network in articular cartilage depending on the mechanical microenvironments. AB - Elastin fibers are major extracellular matrix macromolecules that are critical in maintaining the elasticity and resilience of tissues such as blood vessels, lungs and skins. However, the role of elastin in articular cartilage is poorly defined. The present study investigated the organization of elastin fiber in articular cartilage, its relationship to collagen fibers and the architecture of elastin fibers from different mechanical environments by using a kangaroo model. Five morphologies of elastin fibers were identified: Straight fiber, straight fiber with branches, branching fibers directly associated with chondrocyte, wave fiber and fine elastin. The architecture of the elastin network varied significantly with cartilage depth. In the most superficial layer of tibial plateau articular cartilage, dense elastin fibers formed a distinctive cobweb-like meshwork which was parallel to the cartilage surface. In the superficial zone, elastin fibers were well organized in a preferred orientation which was parallel to collagen fibers. In the deep zone, no detectable elastin fiber was found. Moreover, differences in the organization of elastin fibers were also observed between articular cartilage from the tibial plateau, femoral condyle, and distal humerus. This study unravels the detailed microarchitecture of elastin fibers which display a well-organized three-dimensional versatile network in articular cartilage. Our findings imply that elastin fibers may play a crucial role in maintaining the integrity, elasticity, and the mechanical properties of articular cartilage, and that the local mechanical environment affects the architectural development of elastin fibers. PMID- 23649804 TI - Defective nuclear import of Tpr in Progeria reflects the Ran sensitivity of large cargo transport. AB - The RanGTPase acts as a master regulator of nucleocytoplasmic transport by controlling assembly and disassembly of nuclear transport complexes. RanGTP is required in the nucleus to release nuclear localization signal (NLS)-containing cargo from import receptors, and, under steady-state conditions, Ran is highly concentrated in the nucleus. We previously showed the nuclear/cytoplasmic Ran distribution is disrupted in Hutchinson-Gilford Progeria syndrome (HGPS) fibroblasts that express the Progerin form of lamin A, causing a major defect in nuclear import of the protein, translocated promoter region (Tpr). In this paper, we show that Tpr import was mediated by the most abundant import receptor, KPNA2, which binds the bipartite NLS in Tpr with nanomolar affinity. Analyses including NLS swapping revealed Progerin did not cause global inhibition of nuclear import. Rather, Progerin inhibited Tpr import because transport of large protein cargoes was sensitive to changes in the Ran nuclear/cytoplasmic distribution that occurred in HGPS. We propose that defective import of large protein complexes with important roles in nuclear function may contribute to disease-associated phenotypes in Progeria. PMID- 23649805 TI - The asymmetric segregation of damaged proteins is stem cell-type dependent. AB - Asymmetric segregation of damaged proteins (DPs) during mitosis has been linked in yeast and bacteria to the protection of one cell from aging. Recent evidence suggests that stem cells may use a similar mechanism; however, to date there is no in vivo evidence demonstrating this effect in healthy adult stem cells. We report that stem cells in larval (neuroblast) and adult (female germline and intestinal stem cell) Drosophila melanogaster asymmetrically segregate DPs, such as proteins with the difficult-to-degrade and age-associated 2,4-hydroxynonenal (HNE) modification. Surprisingly, of the cells analyzed only the intestinal stem cell protects itself by segregating HNE to differentiating progeny, whereas the neuroblast and germline stem cells retain HNE during division. This led us to suggest that chronological life span, and not cell type, determines the amount of DPs a cell receives during division. Furthermore, we reveal a role for both niche dependent and -independent mechanisms of asymmetric DP division. PMID- 23649806 TI - Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint. AB - The DNA damage response (DDR) pathway and its core component tumor suppressor p53 block cell cycle progression after genotoxic stress and represent an intrinsic barrier preventing cancer development. The serine/threonine phosphatase PPM1D/Wip1 inactivates p53 and promotes termination of the DDR pathway. Wip1 has been suggested to act as an oncogene in a subset of tumors that retain wild-type p53. In this paper, we have identified novel gain-of-function mutations in exon 6 of PPM1D that result in expression of C-terminally truncated Wip1. Remarkably, mutations in PPM1D are present not only in the tumors but also in other tissues of breast and colorectal cancer patients, indicating that they arise early in development or affect the germline. We show that mutations in PPM1D affect the DDR pathway and propose that they could predispose to cancer. PMID- 23649807 TI - The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A. AB - Coordination of cell cycle events in space and time is crucial to achieve a successful cell division. Here, we demonstrate that UBXN-2, a substrate adaptor of the AAA ATPase Cdc48/p97, is required to coordinate centrosome maturation timing with mitosis. In UBXN-2-depleted Caenorhabditis elegans embryos, centrosomes recruited more AIR-1 (Aurora A), matured precociously, and alignment of the mitotic spindle with the axis of polarity was impaired. UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 and the spindle alignment defect was partially rescued by co-depleting AIR-1, indicating that UBXN-2 controls these processes via AIR-1. Similarly, depletion in human cells of the UBXN-2 orthologues p37/p47 resulted in an accumulation of Aurora A at centrosomes and a delay in centrosome separation. The latter defect was also rescued by inhibiting Aurora A. We therefore postulate that the role of this adaptor in cell cycle regulation is conserved. PMID- 23649808 TI - p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. AB - Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL 6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo. In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM. Moreover, altered HMGB1 expression induced a p53-dependent senescent growth arrest. Senescent fibroblasts secreted oxidized HMGB1, which stimulated cytokine secretion through TLR-4 signaling. HMGB1 depletion, HMGB1 blocking antibody, or TLR-4 inhibition attenuated senescence-associated IL-6 secretion, and exogenous HMGB1 stimulated NF-kappaB activity and restored IL-6 secretion to HMGB1-depleted cells. Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence associated inflammation. PMID- 23649809 TI - Atypicalities in cortical structure, handedness, and functional lateralization for language in autism spectrum disorders. AB - Language is typically a highly lateralized function, with atypically reduced or reversed lateralization linked to language impairments. Given the diagnostic and prognostic role of impaired language for autism spectrum disorders (ASDs), this paper reviews the growing body of literature that examines patterns of lateralization in individuals with ASDs. Including research from structural and functional imaging paradigms, and behavioral evidence from investigations of handedness, the review confirms that atypical lateralization is common in people with ASDs. The evidence indicates reduced structural asymmetry in fronto-temporal language regions, attenuated functional activation in response to language and pre-linguistic stimuli, and more ambiguous (mixed) hand preferences, in individuals with ASDs. Critically, the evidence emphasizes an intimate relationship between atypical lateralization and language impairment, with more atypical asymmetries linked to more substantive language impairment. Such evidence highlights opportunities for the identification of structural and functional biomarkers of ASDs, affording the potential for earlier diagnosis and intervention implementation. PMID- 23649810 TI - [Massive ovarian edema in a 13-year-old girl]. AB - Massive ovarian edema is a rare tumor-like condition found in young women resulting from accumulation of fluid mostly due to partial or intermittent torsion of the ovary or secondary, to a preexisting ovarian lesion. We report a case of a 13-year-old girl presenting with an ovarian mass measuring 16 cm. CA-12 5 levels were slightly elevated. Concerns regarding underlying malignancy led to salpingo-oophorectomy. Pathological evaluation revealed a massive ovarian edema and multiple thromboses of ovarian veins. Differentiating massive ovarian edema from malignant ovarian tumor is crucial to prevent patients from undergoing unnecessary surgery. PMID- 23649811 TI - Use of preoperative CHA2 DS2 -VASc score to predict the risk of atrial fibrillation after cardiothoracic surgery: a nested case-control study from the Atrial Fibrillation Suppression Trials (AFIST) I, II, and III. AB - STUDY OBJECTIVE: To evaluate whether the preoperative CHA2 DS2 -VASc score predicts the risk of atrial fibrillation (AF) after cardiothoracic surgery (CTS). DESIGN: Retrospective, nested case-control study. PATIENTS: A total of 560 patients undergoing coronary artery bypass grafting and/or valvular surgery from the Atrial Fibrillation Suppression Trials I, II, and III. MEASUREMENTS AND MAIN RESULTS: All variables showing a univariate association (p<=0.20) with AF occurrence were entered into a backward stepwise multivariate logistic regression analysis to control for potential confounders and to calculate adjusted odds ratios (AORs) with 95% confidence intervals (CIs). The population was age 67.8 +/ 8.6 (mean +/- SD) years and 77.1% male, with CHA2 DS2 -VASc scores of 0-1 (low) in 34 patients (6.1%), 2-3 (medium) in 261 patients (46.6%), and more than 3 (high) in 265 patients (47.3%). Post-CTS AF occurred in 177 patients (31.6%), with 27%, 23%, and 41% in the low-, medium-, and high-CHA2 DS2 -VASc score groups, respectively. The high-score group had a 2.3-fold increased odds of developing AF versus the medium-score group (p<0.0001). The differences between the high- and medium-score groups when each group was compared with the low-score group were not statistically significant. On the multivariate logistic regression analysis, CHA2 DS2 -VASc score was associated with development of AF (AOR 1.20, 95% CI 1.06-1.36). CONCLUSION: Increasing CHA2 DS2 -VASc score was an independent predictor for the development of post-CTS AF, with patients in the high-score group having the highest overall incidence. PMID- 23649812 TI - Targeting potassium channels Kv1.3 and KC a 3.1: routes to selective immunomodulators in autoimmune disorder treatment? AB - The Kv1.3 and KC a 3.1 potassium channels are promising targets for the treatment of autoimmune disorders. Many Kv1.3 and KC a 3.1 blockers have a more favorable adverse event profiles than existing immunosuppressants, suggesting the selectivity of Kv1.3 and KC a 3.1 blockade. The Kv1.3 and KC a 3.1 blockers exert differential effects in different autoimmune diseases. The Kv1.3 inhibitors or gene deletion have been shown to have benefits in multiple sclerosis, type 1 diabetes, rheumatoid arthritis, psoriasis, and rapidly progressive glomerulonephritis. The KC a 3.1 blockers have demonstrated efficacy in human primary biliary cirrhosis and showed protective effects in animal models of severe colitis, allergic encephalomyelitis, inflammatory bowel disease, and multiple sclerosis. The KC a 3.1 blockers are not considered candidates for treatment of multiple sclerosis. The selective immunosuppressive effects of the Kv1.3 and KC a 3.1 blockers are due to the differences in their distribution on autoimmune-related immune cells and tissues and beta1 integrin (very late activating antigen)-Kv1.3 channel cross-talk. PMID- 23649813 TI - Clinical pharmacy services in heart failure: an opinion paper from the Heart Failure Society of America and American College of Clinical Pharmacy Cardiology Practice and Research Network. AB - Heart failure (HF) care takes place in multiple settings, with a variety of providers, and generally involves patients who have multiple comorbidities. This situation is a "perfect storm" of factors that predispose patients to medication errors. The goals of this paper are to outline potential roles for clinical pharmacists in a multidisciplinary HF team, to document outcomes associated with interventions by clinical pharmacists, to recommend minimum training for clinical pharmacists engaged in HF care, and to suggest financial strategies to support clinical pharmacy services within a multidisciplinary team. As patients transition from inpatient to outpatient settings and between multiple caregivers, pharmacists can positively affect medication reconciliation and education, assure consistency in management that results in improvements in patient satisfaction and medication adherence, and reduce medication errors. For mechanical circulatory support and heart transplant teams, the Centers for Medicare and Medicaid Services considers the participation of a transplant pharmacology expert (e.g., clinical pharmacist) to be a requirement for accreditation, given the highly specialized and complex drug regimens used. Although reports of outcomes from pharmacist interventions have been mixed owing to differences in study design, benefits such as increased use of evidence-based therapies, decreases in HF hospitalizations and emergency department visits, and decreases in all-cause readmissions have been demonstrated. Clinical pharmacists participating in HF or heart transplant teams should have completed specialized postdoctoral training in the form of residencies and/or fellowships in cardiovascular and/or transplant pharmacotherapy, and board certification is recommended. Financial mechanisms to support pharmacist participation in the HF teams are variable. Positive outcomes associated with clinical pharmacist activities support the value of making this resource available to HF teams. PMID- 23649815 TI - Induction of albumin expression in HepG2 cells using immobilized simplified recombinant fibronectin protein. AB - Optimization of the extracellular environment is very important for hepatocyte function in vitro. We expressed new chimeric proteins of the collagen-binding domain (CBD) with cell attachment site (CAS) of fibronectin to enhance hepatocyte function, and the CBD-CAS proteins were immobilized on collagen-coated plates. We hypothesized that the high density of CAS would increase activity of the integrin dependent intracellular signaling pathway, thus inducing hepatocyte function. Expression of albumin in the human hepatocyte cell line HepG2 was assessed on CBD CAS-immobilized dishes. The results indicated that the CBD-CAS-immobilized plates induced albumin expression. Immobilized CBD-CAS induced activation of focal adhesion kinase and integrin-ligand clustering on the cell membrane. These results suggest that immobilized CBD-CAS improves the function of HepG2 cells. This system could therefore be applied to drug metabolism assay in the development of new drugs. PMID- 23649816 TI - Postdeglutitive residue in idiopathic unilateral vocal fold paralysis: a quantitative videofluoroscopic study. AB - OBJECTIVES/HYPOTHESIS: To quantitate postdeglutitive residue and determine its association with paralysis duration (<=6 vs. >=6 months) in patients with idiopathic unilateral vocal fold paralysis (UVFP). STUDY DESIGN: Primary institutional retrospective review. METHODS: Twenty patients (mean age, 72 years) with idiopathic UVFP and 13 patients (mean age, 66 years) with isolated recurrent laryngeal nerve paralysis (RLNP) who underwent videofluoroscopic swallow studies (VFSSs) were included. Vallecular and pyriform sinus (PS) residues in the anteroposterior view were analyzed quantitatively. In both regions, the symmetry of the affected versus nonaffected sides between patients with idiopathic UVFP and RLNP were compared. Residual differences between short- versus long-term paralysis duration in idiopathic UVFP patients alone were also evaluated. RESULTS: The affected PS of the idiopathic group demonstrated significantly increased residue (P = .007) as compared with the nonaffected PS, but with no significant difference with respect to the vallecula (P = .183). There was no significant difference in the RLNP group. When compared with RLNP patients, the idiopathic group showed significantly increased residue on the affected PS (P = .002), but differences in the vallecular residue were nonsignificant. Pharyngeal residue and the duration of paralysis in idiopathic UVFP patients were not significantly different. CONCLUSIONS: Idiopathic UVFP patients were more likely to demonstrate increased residue and asymmetry toward the involved region as compared with RLNP patients, suggesting that nerve involvement in idiopathic UVFP may not be exclusive to the RLN. PMID- 23649817 TI - Evidence for treatment of muscular vein thrombosis in orthopaedic patients. AB - BACKGROUND: Does below-knee symptomatic muscular (gastrocnemius or soleus) vein thrombosis (MVT) warrant investigation and treatment in post-operative orthopaedic patients? We performed a literature search and evaluated the evidence looking for guidance regarding this question. MATERIALS AND METHODS: We performed a literature search with the use of PubMed, Medline and Google Scholar from 1950 to September 2011. Search terms included "muscular vein thrombosis" (MVT) and "isolated gastrocnemius or soleus vein thrombosis" (IGSVT). We reviewed the eight level II studies relevant to our search, only one of which was in a specific orthopaedic population. RESULTS: Studies looking at the rates of progression of isolated MVT have shown conflicting results. There is also a lack of consensus between studies that compare progression amongst groups with or without anticoagulant treatment. The majority of the studies do not distinguish between medical, surgical or orthopaedic patients. CONCLUSIONS: We cannot confidently recommend commencement of anticoagulation treatment upon identification of MVT in post-operative orthopaedic patients. We can only suggest that, once MVT is diagnosed, the patient should undergo serial ultrasound scan (USS) duplex scans, and if propagation is identified, then treatment may be deemed beneficial. LEVEL OF EVIDENCE: III (review of non-randomized controlled cohort/follow-up studies). PMID- 23649818 TI - Surgical treatment of chronic acromioclavicular dislocation with biologic graft vs synthetic ligament: a prospective randomized comparative study. AB - BACKGROUND: Acromioclavicular (AC) dislocation involves complete loss of articular contact; it is defined as chronic when it follows conservative management or unsuccessful surgical treatment. MATERIALS AND METHODS: The study compared the clinical and radiographic outcomes of AC joint stabilization performed in 40 patients with chronic dislocation using a biological allograft (group A) or a synthetic ligament (group B). Demographic data included: M/F: 25/15; mean age: 35 +/- 3.2 years; previous surgery in 11 patients, including Weaver-Dunn (3), coracoacromial ligament repair (4), stabilization with K-wires (4). Dislocation was type III in 14 (35 %) and type IV in 26 (65 %) patients. Clinical assessment was with the Constant-Murley score (pre- and postoperative) and with the modified UCLA score. Enrollment started in January 2004 and was completed in March 2008. Patients were evaluated at 1 and 4 years. Postoperative X-rays were examined to assess joint stability in the coronal and axial planes, coracoclavicular ossification, and signs of AC joint osteoarthritis and distal clavicular osteolysis. RESULTS: The "biological" group achieved significantly better clinical scores than the "synthetic" group at both 1 and 4 years. Poor subjective satisfaction and lower clinical scores were found in the 3 patients (1 from group A and 2 from group B) who experienced complete postoperative dislocation. No significant correlations were found with other radiographic parameters. CONCLUSIONS: The biological graft afforded better clinical and radiographic outcomes than the synthetic ligament in patients with chronic AC joint instability. Fixation to the clavicle constitutes the main weakness of both approaches and needs improving. PMID- 23649819 TI - Calculation of pediatric femoral fracture rotation from direct roentgenograms. AB - BACKGROUND: Radiologic determination of pediatric femoral fracture rotation has been debated. Measuring the antetorsion angle of the fractured femur by computed tomography and comparing it with the opposite side has been the method of choice for this purpose. However, no simple method for direct measurement of femoral fracture rotation exists in the literature. In this study, our aim was to test a mathematical method of measuring the axial plane malrotation from direct roentgenograms. MATERIALS AND METHODS: A pediatric femoral shaft fracture model was produced. The bone was secured to a wooden frame that allowed the distal part of the fracture to rotate around an axis. Radiographs were taken at known intervals of rotation ranging from the neutral position to 60 degrees external rotation and to 60 degrees internal rotation in 5 degrees increments of rotation. Five independent, blinded observers measured the radiographs and calculated the fracture rotation according to a standard formula. Calculated rotation values were compared with known rotation values. RESULTS: Calculated rotation values were close to actual rotation values throughout the arc of rotation. The mean absolute error of five observers for all measurements of external and internal rotation was 3.97 degrees (+/-0.83). The correlation coefficient between calculated and actual rotation values was 0.9927. The interobserver intraclass correlation coefficient for calculated rotation was 0.997. CONCLUSIONS: Absolute error and correlation coefficient values indicate that this method is accurate and reliable in determining the fracture rotation. PMID- 23649820 TI - Inhibition of IkappaB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse. AB - Nuclear factor kappaB (NF-kappaB) plays a pivotal role in sepsis. Activation of NF-kappaB is initiated by the signal-induced ubiquitylation and subsequent degradation of inhibitors of kappa B (IkappaBs) primarily via activation of the IkappaB kinase (IKK). This study was designed to investigate the effects of IKK inhibition on sepsis-associated multiple organ dysfunction and/or injury (MOD) and to elucidate underlying signaling mechanisms in two different in vivo models: male C57BL/6 mice were subjected to either bacterial cell wall components [lipopolysaccharide and peptidoglycan (LPS/PepG)] or underwent cecal ligation and puncture (CLP) to induce sepsis-associated MOD. At 1 hour after LPS/PepG or CLP, mice were treated with the IKK inhibitor IKK 16 (1 mg/kg body weight). At 24 hours, parameters of organ dysfunction and/or injury were assessed in both models. Mice developed a significant impairment in systolic contractility (echocardiography), and significant increases in serum creatinine, serum alanine aminotransferase and lung myeloperoxidase activity, thus indicating cardiac dysfunction, renal dysfunction, hepatocellular injury and lung inflammation, respectively. Treatment with IKK 16 attenuated the impairment in systolic contractility, renal dysfunction, hepatocellular injury and lung inflammation in LPS/PepG-induced MOD and in polymicrobial sepsis. Compared with mice that were injected with LPS/PepG or underwent CLP, immunoblot analyses of heart and liver tissues from mice that were injected with LPS/PepG or underwent CLP and were also treated with IKK 16 revealed: (1) significant attenuation of the increased phosphorylation of IkappaBalpha; (2) significant attenuation of the increased nuclear translocation of the NF-kappaB subunit p65; (3) significant attenuation of the increase in inducible nitric oxide synthase (iNOS) expression; and (4) a significant increase in the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). Here, we report for the first time that delayed IKK inhibition reduces MOD in experimental sepsis. We suggest that this protective effect is (at least in part) attributable to inhibition of inflammation through NF-kappaB, the subsequent decrease in iNOS expression and the activation of the Akt-eNOS survival pathway. PMID- 23649821 TI - Muscarinic cholinergic receptor (M2) plays a crucial role in the development of myopia in mice. AB - Myopia is a huge public health problem worldwide, reaching the highest incidence in Asia. Identification of susceptible genes is crucial for understanding the biological basis of myopia. In this paper, we have identified and characterized a functional myopia-associated gene using a specific mouse-knockout model. Mice lacking the muscarinic cholinergic receptor gene (M2; also known as Chrm2) were less susceptible to lens-induced myopia compared with wild-type mice, which showed significantly increased axial length and vitreous chamber depth when undergoing experimental induction of myopia. The key findings of this present study are that the sclera of M2 mutant mice has higher expression of collagen type I and lower expression of collagen type V than do wild-type mice and mice that are mutant for other muscarinic subtypes, and, therefore, M2 mutant mice were resistant to the development of experimental myopia. Pharmacological blockade of M2 muscarinic receptor proteins retarded myopia progression in the mouse. These results suggest for the first time a role of M2 in growth-related changes in extracellular matrix genes during myopia development in a mammalian model. M2 receptor antagonists might thus provide a targeted therapeutic approach to the management of this refractive error. PMID- 23649822 TI - Conditional deletion of neurogenin-3 using Nkx2.1iCre results in a mouse model for the central control of feeding, activity and obesity. AB - The ventral hypothalamus acts to integrate visceral and systemic information to control energy balance. The basic helix-loop-helix transcription factor neurogenin-3 (Ngn3) is required for pancreatic beta-cell development and has been implicated in neuronal development in the hypothalamus. Here, we demonstrate that early embryonic hypothalamic inactivation of Ngn3 (also known as Neurog3) in mice results in rapid post-weaning obesity that is associated with hyperphagia and reduced energy expenditure. This obesity is caused by loss of expression of Pomc in Pomc- and Cart-expressing (Pomc/Cart) neurons in the arcuate nucleus, indicating an incomplete specification of anorexigenic first order neurons. Furthermore, following the onset of obesity, both the arcuate and ventromedial hypothalamic nuclei become insensitive to peripheral leptin treatment. This conditional mouse mutant therefore represents a novel model system for obesity that is associated with hyperphagia and underactivity, and sheds new light upon the roles of Ngn3 in the specification of hypothalamic neurons controlling energy balance. PMID- 23649825 TI - Chameleon luminophore for sensing temperatures: control of metal-to-metal and energy back transfer in lanthanide coordination polymers. PMID- 23649823 TI - Evidence for transgenerational metabolic programming in Drosophila. AB - Worldwide epidemiologic studies have repeatedly demonstrated an association between prenatal nutritional environment, birth weight and susceptibility to adult diseases including obesity, cardiovascular disease and type 2 diabetes. Despite advances in mammalian model systems, the molecular mechanisms underlying this phenomenon are unclear, but might involve programming mechanisms such as epigenetics. Here we describe a new system for evaluating metabolic programming mechanisms using a simple, genetically tractable Drosophila model. We examined the effect of maternal caloric excess on offspring and found that a high-sugar maternal diet alters body composition of larval offspring for at least two generations, augments an obese-like phenotype under suboptimal (high-calorie) feeding conditions in adult offspring, and modifies expression of metabolic genes. Our data indicate that nutritional programming mechanisms could be highly conserved and support the use of Drosophila as a model for evaluating the underlying genetic and epigenetic contributions to this phenomenon. PMID- 23649824 TI - Reduced prevalence of cognitive impairment in families with exceptional longevity. AB - IMPORTANCE: Family studies of centenarians and long-lived persons have found substantial familial aggregation of survival to extreme ages; however, the extent to which such familial longevity is characterized by cognitively intact survival is not established. OBJECTIVE: To determine whether families with exceptional longevity are protected against cognitive impairment consistent with Alzheimer disease. DESIGN: Cross-sectional analysis. SETTING: Multisite study in New York, Massachusetts, Pennsylvania, and Denmark. PARTICIPANTS: A total of 1870 individuals (1510 family members and 360 spouse controls) recruited through the Long Life Family Study. MAIN OUTCOME AND MEASURE: Prevalence of cognitive impairment based on a diagnostic algorithm validated using the National Alzheimer's Coordinating Center data set. RESULTS: The cognitive algorithm classified 546 individuals (38.5%) as having cognitive impairment consistent with Alzheimer disease. Long Life Family Study probands had a slightly but not statistically significant reduced risk of cognitive impairment compared with spouse controls (121 of 232 for probands vs 45 of 103 for spouse controls; odds ratio = 0.7; 95% CI, 0.4-1.4), whereas Long Life Family Study sons and daughters had a clearly reduced risk of cognitive impairment (11 of 213 for sons and daughters vs 28 of 216 for spouse controls; odds ratio = 0.4; 95% CI, 0.2-0.9). Restriction to nieces and nephews in the offspring generation attenuated this effect (37 of 328 for nieces and nephews vs 28 of 216 for spouse controls; odds ratio = 0.8; 95% CI, 0.4-1.4). CONCLUSIONS AND RELEVANCE: Rates of cognitive impairment characteristic of Alzheimer disease were relatively high. In the proband generation, rates were comparable across family members and spouse controls, whereas sons and daughters of probands had significantly lower rates than spouse controls. Results suggest a delayed onset of cognitive impairment in families with exceptional longevity, but assessment of age-specific incidence rates is required to confirm this hypothesis. PMID- 23649826 TI - Risk factors for false positive and for false negative test results in screening with fecal occult blood testing. AB - Differences in the risk of a false negative or a false positive fecal immunochemical test (FIT) across subgroups may affect optimal screening strategies. We evaluate whether subgroups are at increased risk of a false positive or a false negative FIT result, whether such variability in risk is related to differences in FIT sensitivity and specificity or to differences in prior CRC risk. Randomly selected, asymptomatic individuals were invited to undergo colonoscopy. Participants were asked to undergo one sample FIT and to complete a risk questionnaire. We identified patient characteristics associated with a false negative and false positive FIT results using logistic regression. We focused on statistically significant differences as well as on variables influencing the false positive or negative risk for which the odds ratio exceeded 1.25. Of the 1,426 screening participants, 1,112 (78%) completed FIT and the questionnaire; 101 (9.1%) had advanced neoplasia. 102 Individuals were FIT positive, 65 (64%) had a false negative FIT result and 66 (65%) a false positive FIT result. Participants at higher age and smokers had a significantly higher risk of a false negative FIT result. Males were at increased risk of a false positive result, so were smokers and regular NSAID users. FIT sensitivity was lower in females. Specificity was lower for males, smokers and regular NSAID users. FIT sensitivity was lower in women. FIT specificity was lower in males, smokers and regular NSAID users. Our results can be used for further evidence based individualization of screening strategies. PMID- 23649827 TI - Partial effectiveness of acetazolamide in a mild form of GLUT1 deficiency: a pediatric observation. PMID- 23649828 TI - Ultrasonic pretreatment and acid hydrolysis of sugarcane bagasse for succinic acid production using Actinobacillus succinogenes. AB - Immense interest has been devoted to the production of bulk chemicals from lignocellulose biomass. Diluted sulfuric acid treatment is currently one of the main pretreatment methods. However, the low total sugar concentration obtained via such pretreatment limits industrial fermentation systems that use lignocellulosic hydrolysate. Sugarcane bagasse hemicellulose hydrolysate is used as the carbon and nitrogen sources to achieve a green and economical production of succinic acid in this study. Sugarcane bagasse was ultrasonically pretreated for 40 min, with 43.9 g/L total sugar obtained after dilute acid hydrolysis. The total sugar concentration increased by 29.5 %. In a 3-L fermentor, using 30 g/L non-detoxified total sugar as the carbon source, succinic acid production increased to 23.7 g/L with a succinic acid yield of 79.0 % and a productivity of 0.99 g/L/h, and 60 % yeast extract in the medium could be reduced. Compared with the detoxified sugar preparation method, succinic acid production and yield were improved by 20.9 and 20.2 %, respectively. PMID- 23649829 TI - At-line near-infrared spectroscopy for monitoring concentrations in temperature triggered glutamate fermentation. AB - Rapid development in the glutamate fermentation industry has dictated the need for effective fermentation monitoring by rapid and precise methods that provide real-time information for quality control of the end-product. In recent years, near-infrared (NIR) spectroscopy and multivariate calibration have been developed as fast, inexpensive, non-destructive and environmentally safe techniques for industrial applications. The purpose of this study was to develop models for monitoring glutamate, glucose, lactate and alanine concentrations in the temperature-triggered process of glutamate fermentation. NIR measurements of eight batches of samples were analyzed by partial least-squares regression with several spectral pre-processing methods. The coefficient of determination (R (2)), model root-mean square error of calibration (RMSEC), root-mean square error of prediction (RMSEP) and residual predictive deviation (RPD) of the test calibration for the glutamate concentration were 0.997, 3.11 g/L, 2.56 g/L and 19.81, respectively. For the glucose concentration, R (2), RMSEC, RMSEP and RPD were 0.989, 1.37 g/L, 1.29 g/L and 9.72, respectively. For the lactate concentration, R (2), RMSEC, RMSEP and RPD were 0.975, 0.078 g/L, 0.062 g/L and 6.29, respectively. For the alanine concentration, R (2), RMSEC, RMSEP and RPD were 0.964, 0.213 g/L, 0.243 g/L and 5.29, respectively. New batch fermentation as an external validation was used to check the models, and the results suggested that the predictive capacity of the models for the glutamate fermentation process was good. PMID- 23649830 TI - Three-dimensional architectures incorporating stereoregular donor-acceptor stacks. AB - We report the synthesis of two [2]catenane-containing struts that are composed of a tetracationic cyclophane (TC(4+)) encircling a 1,5-dioxynaphthalene (DNP)-based crown ether, which bears two terphenylene arms. The TC(4+) rings comprise either 1) two bipyridinium (BIPY(2+)) units or 2) a BIPY(2+) and a diazapyrenium (DAP(2+)) unit. These degenerate and nondegenerate catenanes were reacted in the presence of Cu(NO3)2?2.5 H2O to yield Cu-paddlewheel-based MOF-1050 and MOF-1051. The solid-state structures of these MOFs reveal that the metal clusters serve to join the heptaphenylene struts into grid-like 2D networks. These 2D sheets are then held together by infinite donor-acceptor stacks involving the [2]catenanes to produce interpenetrated 3D architectures. As a consequence of the planar chirality associated with both the DNP and hydroquinone (HQ) units present in the crown ether, each catenane can exist as four stereoisomers. In the case of the nondegenerate (bistable) catenane, the situation is further complicated by the presence of translational isomers. Upon crystallization, however, only two of the four possible stereoisomers--namely, the enantiomeric RR and SS forms--are observed in the crystals. An additional element of co-conformational selectivity is present in MOF-1051 as a consequence of the substitution of one of the BIPY(2+) units by a DAP(2+) unit: only the translational isomer in which the DAP(2+) unit is encircled by the crown ether is observed. The overall topologies of MOF-1050 and MOF-1051, and the selective formation of stereoisomers and translational isomers during the kinetically driven crystallization, provide evidence that weak noncovalent bonding interactions play a significant role in the assembly of these extended (super)structures. PMID- 23649831 TI - Biology, genes, and resilience: toward a multidisciplinary approach. AB - Variability in response to stressful environmental exposures is at the core of resilience research. In order to understand why some individuals show resilient functioning in the face of adversity, one needs to understand the mechanisms through which risky environments lead to pathology in some and not others, and the ways in which risk and protective factors affect these processes. Understanding the interplay between genetic and biological processes and different environments is necessary in order to elucidate the causal pathways through which individuals show resilience or vulnerability in the face of adversity. PMID- 23649832 TI - Coping with violence: a comprehensive framework and implications for understanding resilience. AB - Interpersonal violence is present at all levels of influence in the social ecology and can have comprehensive and devastating effects on child and adolescent development through multiple simultaneous channels of exposure. Children's experiences with violence have been linked with a range of behavioral and mental health difficulties including posttraumatic stress disorder and aggressive behavior. In this article, we offer a conceptual framework delineating the ways in which children and adolescents might encounter violence, and a theoretical integration describing how violence might impact mental and behavioral health outcomes through short- and long-term processes. We propose that coping reactions are fundamental to the enduring effects of violence exposure on their psychosocial development and functioning. Finally, we discuss the manner in which coping efforts can support resilience among children exposed to violence and suggest new directions for research and preventive intervention aimed at optimizing outcomes for children at risk of exposure. PMID- 23649833 TI - The mTERF protein MOC1 terminates mitochondrial DNA transcription in the unicellular green alga Chlamydomonas reinhardtii. AB - The molecular function of mTERFs (mitochondrial transcription termination factors) has so far only been described for metazoan members of the protein family and in animals they control mitochondrial replication, transcription and translation. Cells of photosynthetic eukaryotes harbour chloroplasts and mitochondria, which are in an intense cross-talk that is vital for photosynthesis. Chlamydomonas reinhardtii is a unicellular green alga widely used as a model organism for photosynthesis research and green biotechnology. Among the six nuclear C. reinhardtii mTERF genes is mTERF-like gene of Chlamydomonas (MOC1), whose inactivation alters mitorespiration and interestingly also light acclimation processes in the chloroplast that favour the enhanced production of biohydrogen. We show here from in vitro studies that MOC1 binds specifically to a sequence within the mitochondrial rRNA-coding module S3, and that a knockout of MOC1 in the mutant stm6 increases read-through transcription at this site, indicating that MOC1 acts as a transcription terminator in vivo. Whereas the level of certain antisense RNA species is higher in stm6, the amount of unprocessed mitochondrial sense transcripts is strongly reduced, demonstrating that a loss of MOC1 causes perturbed mitochondrial DNA (mtDNA) expression. Overall, we provide evidence for the existence of mitochondrial antisense RNAs in C. reinhardtii and show that mTERF-mediated transcription termination is an evolutionary-conserved mechanism occurring in phototrophic protists and metazoans. PMID- 23649835 TI - Tertiary structure of bacterial selenocysteine tRNA. AB - Selenocysteine (Sec) is translationally incorporated into proteins in response to the UGA codon. The tRNA specific to Sec (tRNA(Sec)) is first ligated with serine by seryl-tRNA synthetase (SerRS). In the present study, we determined the 3.1 A crystal structure of the tRNA(Sec) from the bacterium Aquifex aeolicus, in complex with the heterologous SerRS from the archaeon Methanopyrus kandleri. The bacterial tRNA(Sec) assumes the L-shaped structure, from which the long extra arm protrudes. Although the D-arm conformation and the extra-arm orientation are similar to those of eukaryal/archaeal tRNA(Sec)s, A. aeolicus tRNA(Sec) has unique base triples, G14:C21:U8 and C15:G20a:G48, which occupy the positions corresponding to the U8:A14 and R15:Y48 tertiary base pairs of canonical tRNAs. Methanopyrus kandleri SerRS exhibited serine ligation activity toward A. aeolicus tRNA(Sec) in vitro. The SerRS N-terminal domain interacts with the extra-arm stem and the outer corner of tRNA(Sec). Similar interactions exist in the reported tRNA(Ser) and SerRS complex structure from the bacterium Thermus thermophilus. Although the catalytic C-terminal domain of M. kandleri SerRS lacks interactions with A. aeolicus tRNA(Sec) in the present complex structure, the conformational flexibility of SerRS is likely to allow the CCA terminal region of tRNA(Sec) to enter the SerRS catalytic site. PMID- 23649834 TI - Identification of the nature of reading frame transitions observed in prokaryotic genomes. AB - Our goal was to identify evolutionary conserved frame transitions in protein coding regions and to uncover an underlying functional role of these structural aberrations. We used the ab initio frameshift prediction program, GeneTack, to detect reading frame transitions in 206 991 genes (fs-genes) from 1106 complete prokaryotic genomes. We grouped 102 731 fs-genes into 19 430 clusters based on sequence similarity between protein products (fs-proteins) as well as conservation of predicted position of the frameshift and its direction. We identified 4010 pseudogene clusters and 146 clusters of fs-genes apparently using recoding (local deviation from using standard genetic code) due to possessing specific sequence motifs near frameshift positions. Particularly interesting was finding of a novel type of organization of the dnaX gene, where recoding is required for synthesis of the longer subunit, tau. We selected 20 clusters of predicted recoding candidates and designed a series of genetic constructs with a reporter gene or affinity tag whose expression would require a frameshift event. Expression of the constructs in Escherichia coli demonstrated enrichment of the set of candidates with sequences that trigger genuine programmed ribosomal frameshifting; we have experimentally confirmed four new families of programmed frameshifts. PMID- 23649836 TI - Estrogen and insulin-like growth factor 1 synergistically promote the development of lung adenocarcinoma in mice. AB - Estrogen receptor (ER) and insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Based on their previous findings, the authors sought to investigate whether estrogen and IGF-1 act synergistically to promote lung adenocarcinoma (LADE) development in mice. LADE was induced with urethane in ovariectomized Kunming mice. Tumor-bearing mice were divided into seven groups: 17beta-estradiol (E2), E2+fulvestrant (Ful; estrogen inhibitor), IGF-1, IGF-1+AG1024 (IGF-1 inhibitor), E2+IGF-1, E2+IGF-1+Ful+AG1024 and control groups. After 14 weeks, the mice were sacrificed, and then the tumor growth was determined. The expression of ERalpha/ERbeta, IGF-1, IGF-1R and Ki67 was examined using tissue-microarray-immunohistochemistry, and IGF-1, p-ERbeta, p IGF-1R, p-MAPK and p-AKT levels were determined based on Western blot analysis. Fluorescence-quantitative polymerase chain reaction was used to detect the mRNA expression of ERbeta, ERbeta2 and IGF-1R. Tumors were found in 93.88% (46/49) of urethane-treated mice, and pathologically proven LADE was noted in 75.51% (37/49). In the E2+IGF-1 group, tumor growth was significantly higher than in the E2 group (p < 0.05), the IGF-1 group (p < 0.05) and control group (p < 0.05). Similarly, the expression of ERbeta, p-ERbeta, ERbeta2, IGF-1, IGF-1R, p-IGF-1R, p-MAPK, p-AKT and Ki67 at the protein and/or mRNA levels was markedly higher in the ligand group than in the ligand + inhibitor groups (all p < 0.05). This study demonstrated for the first time that estrogen and IGF-1 act to synergistically promote the development of LADE in mice, and this may be related to the activation of the MAPK and AKT signaling pathways in which ERbeta1, ERbeta2 and IGF-1R play important roles. PMID- 23649837 TI - Surface functionalized hydrophobic porous particles toward water treatment application. AB - A microfluidic-based approach for the fabrication of organic contaminants absorbing core-shell particles is demonstrated. The hydrophobic porous core absorbs oil while the hydrophilic surface enables the particles to be well dispersed in aqueous solutions. These particles can uptake oil from aqueous solution saturated with oil or via direct contact with oil blobs as depicted in the figure. PMID- 23649838 TI - Interactive effects in transfer-appropriate processing for event-based prospective memory: the roles of effort, ongoing task, and PM cue properties. AB - Past studies (e.g., Marsh, Hicks, & Cook Journal of Experimental Psychology: Learning, Memory, and Cognition 31:68-75, 2005; Meiser & Schult European Journal of Cognitive Psychology 20:290-311, 2008) have shown that transfer-appropriate processing (TAP) effects in event-based prospective memory (PM) depend on the effort directed toward the ongoing task. In the present study, we addressed mixed findings from these studies and examined monitoring in TAP and transfer inappropriate processing (TIP) conditions. In two experiments, a semantic or orthographic ongoing task was paired with a PM cue that either was matched in processing (TAP) or did not match in processing (TIP). Within each condition, effort was varied across trials. The results indicated that PM accuracy was higher in TAP than in TIP conditions, regardless of effort condition, supporting the findings reported by Meiser and Schult. Ex-Gaussian functions were fit to the mean reaction times (cf. Brewer Journal of Psychology 219:117-124, 2011) in order to examine monitoring across conditions. The analysis of distributional skew (tau parameter) showed sensitivity to ongoing task instructions and properties of the PM cues. These results support Meiser and Schult's suggestion that TIP conditions require more attentional processing, and they also afford novel discussion on the interactive effects of ongoing task condition, PM cue properties, and manipulations of effort. PMID- 23649839 TI - Simple electrodiagnostic method for Morton neuroma. AB - INTRODUCTION: We describe a simple and quickly applied electrodiagnostic method for confirming the diagnosis of interdigital neuropathy caused by Morton neuroma (MN). METHODS: Interdigital nerves II-III and III-IV were stimulated with surface electrodes simultaneously touching the lateral side of 1 toe and the medial side of the other. Recording was also made with surface electrodes. The results of 20 normal controls and 14 patients with MN were evaluated. RESULTS: The amplitude and peak latency values elicited in the patients as well as the interside differences revealed an acceptable abnormality rate between 57.1% and 71.4%. CONCLUSIONS: Although the most popular and effective method of MN diagnosis is clinical evaluation supported by imaging, electrophysiological studies can, in selected patients, provide valuable information. PMID- 23649840 TI - Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. AB - Gene expression analysis has been established as a tool for the characterization of genotoxic mechanisms of chemical mutagens. It has been suggested that expression analysis is capable of distinguishing compounds that cause DNA damage from those that interfere with mitotic spindle function. Formaldehyde (FA) is known to be a DNA-reactive substance which mainly induces chromosomal damage in cultured mammalian cells. However, there has been concern that FA might also induce leukemia-specific aneuploidies, although recent cytogenetic studies excluded a relevant aneugenic potential of FA. We now investigated whether gene expression profiling can be used as a molecular tool to further characterize FA's genotoxic mode of action and to differentiate between clastogenic and aneugenic activity. TK6 cells were exposed to FA for 4 and 24 h, and changes in gene expression were analyzed using a whole-genome human microarray. Results were compared to the expression profiles of two DNA-damaging clastogens (methyl methanesulfonate and ethyl methanesulfonate) and two aneugens (colcemid and vincristine). The genotoxic activity of FA, MMS and EMS under these conditions was confirmed by comet assay experiments. The gene expression profiles indicated that clastogens and aneugens induce discriminable gene expression patterns. Exposure of TK6 cells to FA led to a discrete gene expression pattern, and all toxicogenomics analyses revealed a closer relationship of FA with clastogens than with aneugens. PMID- 23649842 TI - Organic anion transporter 5 (Oat5) renal expression and urinary excretion in rats treated with cisplatin: a potential biomarker of cisplatin-induced nephrotoxicity. AB - Cisplatin is one of the most potent chemotherapeutic antitumor drugs used in the treatment of a wide range of solid tumors. Its primary dose-limiting side effect is nephrotoxicity. The organic anion transporter 5 (Oat5) is exclusively localized in the kidney. Oat5 urinary excretion was recently proposed as a potential early biomarker of acute kidney injury (AKI). The aim of this study was to evaluate Oat5 renal expression and its urinary excretion in rats exposed to different doses of cisplatin, in comparison with traditional markers of renal injury, like renal histology, creatinine and urea plasma levels, creatinine clearance, protein and glucose urinary levels and urinary alkaline phosphatase (AP) activity. Male Wistar rats were treated with a single injection of cisplatin at different doses of 1, 2, 5 and 10 mg/kg b.w., i.p. (Cis1, Cis2, Cis5 and Cis10, n = 4, respectively) and experiments were carried out 48 h after cisplatin administration. The renal expression of Oat5 was evaluated by immunohistochemistry and Western blotting. Oat5 abundance, AP activity, creatinine, glucose and proteins were assayed in urine. Creatinine clearance and creatinine and urea plasma levels were also evaluated. In this experimental model, plasma urea and creatinine levels, creatinine clearance, AP urinary activity and protein and glucose urinary levels were significantly modified only at the highest cisplatin dose of 10 mg/kg b.w., i.p., as compared to control rats. In contrast, Oat5 urinary abundance was increased in a dose-related manner after the administration of cisplatin. Oat5 urinary abundance was elevated at a dose as low as 1 mg/kg b.w., i.p., implying renal perturbation, when no modifications of traditional markers of renal injury are yet observed. Oat5 renal expression was decreased in a dose-related manner, both in homogenates and apical membranes from cisplatin-treated kidneys. The increase in urinary Oat5 excretion might explain the decrease in the amount of Oat5 molecules in the renal tubule cells. Hence, the preclinical animal results showed in this work propose that Oat5 urinary excretion might potentially serve as a non-invasive early biomarker of cisplatin-induced AKI. PMID- 23649841 TI - Relative oral bioavailability of glycidol from glycidyl fatty acid esters in rats. AB - In order to quantify the relative bioavailability of glycidol from glycidyl fatty acid esters in vivo, glycidyl palmitoyl ester and glycidol were orally applied to rats in equimolar doses. The time courses of the amounts of glycidol binding to hemoglobin as well as the excretion of 2,3-dihydroxypropyl mercapturic acids were determined. The results indicate that glycidol is released from the glycidyl ester by hydrolysis and rapidly distributed in the organism. In relation to glycidol, there was only a small timely delay in the binding to hemoglobin for the glycidol moiety released from the ester which may be certainly attributed to enzymatic hydrolysis. In both cases, however, an analogous plateau was observed representing similar amounts of hemoglobin binding. With regard to the urinary excretion of mercapturic acids, also similar amounts of dihydroxypropyl mercapturic acids could be detected. In an ADME test using a virtual double tag (3H, 14C) of glycidyl palmitoyl ester, a diverging isotope distribution was detected. The kinetics of the 14C-activity reflected the kinetics of free glycidol released after hydrolysis of the palmitoyl ester. In view of this experimental data obtained in rats, it is at present justified for the purpose of risk assessment to assume complete hydrolysis of the glycidyl ester in the gastrointestinal tract. Therefore, assessment of human exposure to glycidyl fatty acid ester should be regarded as an exposure to the same molar quantity of glycidol. PMID- 23649843 TI - The emerging mycotoxin, enniatin B1, down-modulates the gastrointestinal toxicity of T-2 toxin in vitro on intestinal epithelial cells and ex vivo on intestinal explants. AB - Enniatins, the most prevalent emerging mycotoxins, represent an emerging food safety issue, because of their common co-occurrence with other fusariotoxins such as trichothecenes co-produced by Fusarium spp on field grains and because of their extensive prevalence in grains. In this study, the intestinal toxicity of enniatin B1 (ENN) alone and mixed with the most toxic trichothecene T-2 toxin (T2) was characterized by using two biological models from pig, the most sensitive species: the intestinal cell line IPEC1 (in vitro exposure) and jejunal explants (ex vivo exposure). Dose-dependent decreases in cell proliferation in IPEC1 and in the histopathological scores of explants were observed for ENN at MUM-levels and for T2 at nM-levels, with IC50 values for ENN of 15.8 and 29.7 MUM, and for T2 of 9.3 and 15.1 nM in vitro and ex vivo, respectively. Interaction analysis by probabilistic and by determinist approaches showed a less than additive effect both in vitro and ex vivo, at IC50 values, with increasing antagonism with decreasing concentrations of toxins. The results obtained by the determinist median-effect dose analysis and by the nonlinear regression analysis were concordant. All the median-effect doses estimated for IPEC cells were included in the IC50 confidence intervals of the nonlinear regression fitting. Given the occurrence of enniatins, potential synergy following the co-occurrence of enniatins and the major fusariotoxins, especially trichothecene B deoxynivalenol should be investigated. PMID- 23649845 TI - Clinical features of chronic pain with neuropathic characteristics: a symptom based assessment using the pain DETECT questionnaire. AB - BACKGROUND: In general, chronic pain is categorized into two mechanism-based groups: nociceptive and neuropathic pain. This dichotomous approach is questioned and a dimensional perspective is suggested. The present study investigated neuropathic characteristics in different syndromes of chronic pain. We also examined the association of neuropathic characteristics with various pain related and psychological variables. METHODS: From April 2010 to January 2012, 400 patients suffering from a chronic pain condition enrolled for multidisciplinary pain treatment were considered for inclusion in the study. Criteria for inclusion were age over 18 years and having chronic pain according to ICD-10 (F45.41) criteria. The pain DETECT questionnaire was used to assess neuropathic characteristics of pain. RESULTS: Thirty-seven percent of patients with different pain diagnoses demonstrated distinct neuropathic characteristics. The diagnostic groups for neuropathic pain, musculoskeletal pain and post traumatic or surgical pain showed the most neuropathic features. The level of depression, pain chronicity and intensity, disability and length of hospital stay were significantly higher in patients suffering from neuropathic symptoms. A high level of depression and pain chronicity as well as high intensity of pain explained most of the variance in the neuropathic scores. Disability and length of hospital stay significantly predicted neuropathic characteristics only when examined separately, but not if included in a common regression model. CONCLUSIONS: Any type of chronic pain may have more or less neuropathic characteristics. The pain-related parameters of high intensity and chronicity as well as negative affectivity and functional disability strongly correlate with neuropathic characteristics of pain. PMID- 23649846 TI - Probing the gamma-turn in a short proline dipeptide chain. AB - The small peptide derived from proline, N-acetyl-prolinamide (Ac-Pro-NH2), has been investigated using a combination of Fourier transform microwave spectroscopy with laser ablation. Spectral signatures belonging to only one conformer have been detected in the supersonic expansion. Rotational constants and nuclear quadrupole coupling constants of the two (14)N nuclei have been used in the characterization of a gamma-turn structure in the gas phase, which is stabilized by a CO...HN intramolecular hydrogen bond closing a seven-membered ring. A methyl group internal rotation barrier of 354 cm(-1) has been determined from the analysis of the A-E splittings. PMID- 23649844 TI - Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression. AB - Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients' fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels. PMID- 23649847 TI - Effects of ocean warming and acidification on survival, growth and skeletal development in the early benthic juvenile sea urchin (Heliocidaris erythrogramma). AB - Co-occurring ocean warming, acidification and reduced carbonate mineral saturation have significant impacts on marine biota, especially calcifying organisms. The effects of these stressors on development and calcification in newly metamorphosed juveniles (ca. 0.5 mm test diameter) of the intertidal sea urchin Heliocidaris erythrogramma, an ecologically important species in temperate Australia, were investigated in context with present and projected future conditions. Habitat temperature and pH/pCO2 were documented to place experiments in a biologically and ecologically relevant context. These parameters fluctuated diurnally up to 10 degrees C and 0.45 pH units. The juveniles were exposed to three temperature (21, 23 and 25 degrees C) and four pH (8.1, 7.8, 7.6 and 7.4) treatments in all combinations, representing ambient sea surface conditions (21 degrees C, pH 8.1; pCO2 397; OmegaCa 4.7; OmegaAr 3.1), near-future projected change (+2-4 degrees C, -0.3-0.5 pH units; pCO2 400-1820; OmegaCa 5.0-1.6; OmegaAr 3.3-1.1), and extreme conditions experienced at low tide (+4 degrees C, 0.3-0.7 pH units; pCO2 2850-2967; OmegaCa 1.1-1.0; OmegaAr 0.7-0.6). The lowest pH treatment (pH 7.4) was used to assess tolerance levels. Juvenile survival and test growth were resilient to current and near-future warming and acidification. Spine development, however, was negatively affected by near-future increased temperature (+2-4 degrees C) and extreme acidification (pH 7.4), with a complex interaction between stressors. Near-future warming was the more significant stressor. Spine tips were dissolved in the pH 7.4 treatments. Adaptation to fluctuating temperature-pH conditions in the intertidal may convey resilience to juvenile H. erythrogramma to changing ocean conditions, however, ocean warming and acidification may shift baseline intertidal temperature and pH/pCO2 to levels that exceed tolerance limits. PMID- 23649850 TI - Punctal plugs versus artificial tears for treating primary Sjogren's syndrome with keratoconjunctivitis SICCA: a comparative observation of their effects on visual function. AB - To compare the effects of treatment with punctal plugs versus artificial tears on visual function for primary Sjogren's syndrome with dry eye. Forty-two eyes of 42 patients with primary Sjogren's syndrome were enrolled and were allocated randomly into artificial tears (AT) group and punctal plugs (PP) group. Ocular Surface Disease Index (OSDI) was used, and fluorescent staining for tear film break-up time (BUT), the Schirmer test I (STI) and contrast sensitivity was performed before treatment and was repeated 3 months after treatment. A follow-up of 3 months was achieved in 40 eyes of 40 patients, including 19 eyes in artificial tears group and 21 eyes in punctal plugs group. Statistically significant improvements were observed in the OSDI scores (AT: 52.6 +/- 5.7, 15.9 +/- 4.2; PP: 55.8 +/- 4.9, 15.1 +/- 4.2), corneal fluorescein staining scores (AT: 2.60 +/- 1.76, 0.30 +/- 0.57; PP: 1.91 +/- 1.60, 0.09 +/- 0.29), STI (AT: 3.85 +/- 2.03, 8.95 +/- 2.72; PP: 3.36 +/- 1.62, 11.41 +/- 2.65), and BUT (AT: 2.60 +/- 1.39, 6.00 +/- 1.81; PP: 2.27 +/- 1.12, 7.82 +/- 1.84) after treatment compared to those of pre-treatment. The values of STI (AT: 5.10 +/- 1.80; PP: 8.05 +/- 1.53) and BUT (AT: 3.40 +/- 1.31; PP: 5.68 +/- 1.13) in punctal plugs group were significantly more improved than those in the artificial tears group. The medium- and high-level frequencies contrast sensitivities were greatly improved in simulated daylight, night, and glare disability conditions after treatment with artificial tears and punctal plugs. However, the changes in contrast sensitivity did not significantly differ between groups. Both artificial tears and punctal plugs relieved dry eye symptoms, repaired corneal lesions, enhanced tear film stability, and improved contrast sensitivity. Punctal plugs could improve tear film stability and elongate the BUT better than artificial tears. PMID- 23649849 TI - Development and evaluation of a self-report tool to predict low pharmacy refill adherence in elderly patients with uncontrolled hypertension. AB - OBJECTIVE: To develop and evaluate a short self-report tool to predict low pharmacy refill adherence in older patients with uncontrolled hypertension. DESIGN: Cross-sectional analysis of survey and administrative data from the Cohort Study of Medication Adherence Among Older Adults (CoSMO). PARTICIPANTS: A total of 394 adults with uncontrolled blood pressure; mean +/- SD age was 76.6 +/ 5.6 years, 33.0% were black, 66.0% were women, and 23.4% had a low medication possession ratio (MPR). MEASUREMENTS AND MAIN RESULTS: We considered 164 self reported candidate items for development of a prediction rule for low (less than 0.8) versus high (0.8 or more) MPR from pharmacy refill data. Risk prediction models were evaluated by using best subsets analyses, and the final model was chosen based on clinical relevance and model parsimony. Bootstrap simulations assessed internal validity. The performance of the final four-item model was compared to the eight-item Morisky Medication Adherence Scale (MMAS-8) and the nine-item Hill-Bone Compliance Scale. The four-item self-report tool for predicting pharmacy refill adherence showed moderate discrimination (C statistic 0.704, 95% confidence interval [CI], 0.683-0.714) and good model fit (Hosmer Lemeshow chi2 = 1.238, p=0.743). Sensitivity and specificity were 67.4% and 67.8%, respectively. The concordance (C) statistics for MMAS-8 and the Hill-Bone Compliance Scale were lower at 0.665 (95% CI 0.632-0.683) and 0.660 (95% CI 0.622 0.674), respectively. CONCLUSION: A four-item self-report tool moderately discriminated low from high pharmacy refill adherers, and its test performance was comparable with existing eight- and nine-item adherence scales. Parsimonious self-report tools predicting low pharmacy refill in patients with uncontrolled blood pressure could facilitate hypertension management in the elderly. PMID- 23649848 TI - Effects of smoking on D2/D3 striatal receptor availability in alcoholics and social drinkers. AB - Studies have reported lower striatal D2/D3 receptor availability in both alcoholics and cigarette smokers relative to healthy controls. These substances are commonly co-abused, yet the relationship between comorbid alcohol/tobacco abuse and striatal D2/D3 receptor availability has not been examined. We sought to determine the degree to which dual abuse of alcohol and tobacco is associated with lower D2/D3 receptor availability. Eighty-one subjects (34 nontreatment seeking alcoholic smokers [NTS-S], 21 social-drinking smokers [SD-S], and 26 social-drinking non-smokers [SD-NS]) received baseline [(11)C]raclopride scans. D2/D3 binding potential (BPND = Bavail/KD) was estimated for ten anatomically defined striatal regions of interest (ROIs). Significant group effects were detected in bilateral pre-commissural dorsal putamen, bilateral pre-commissural dorsal caudate; and bilateral post-commissural dorsal putamen. Post-hoc testing revealed that, regardless of drinking status, smokers had lower D2/D3 receptor availability than non-smoking controls. Chronic tobacco smokers have lower striatal D2/D3 receptor availability than non-smokers, independent of alcohol use. Additional studies are needed to identify the mechanisms by which chronic tobacco smoking is associated with striatal dopamine receptor availability. PMID- 23649851 TI - Oral delivery of low molecular weight heparin by polyaminomethacrylate coacervates. AB - PURPOSE: Oral bioavailability of low molecular weight heparin (LMWH) can be achieved by several advanced drug delivery approaches. Here, a new preparation method for coacervates (CAs) using non-toxic polyethylene glycol derivates was developed. METHODS: LMWH were coacervated with polyaminomethacrylates (Eudragit(r) RL or RS) using polyethylene glycol (PEG) derivatives as non-toxic solvents. CAs were analyzed for their physicochemical properties and pharmacokinetic parameters were determined for different formulations in rabbits. RESULTS: CAs from both polymer types using various PEGs were of irregular shape and had particle sizes of around 40 MUm, encapsulation efficiencies of >90%, and complete LMWH in vitro release was obtained within 2 h. In vivo, oral Absorption at doses of 300 IU/kg was rather low (F < 2.5%) while dose increase resulted in a maximum at 600 IU/kg (FRL: 6.0 +/- 1.2%; FRS: 5.8 +/- 2.5%) and 1,200 IU/kg did not result in higher bioavailability (FRL: 4.6 +/- 0.4%; FRS: 4.1 +/- 0.8%). CAs were applicable to various LMWH types where the oral availability decreased in the order fondaparinux>enoxaparin>nadroparin>certoparin depending mainly on the molecular weight. CONCLUSIONS: CAs prepared by an organic solvent-free method allowed the oral delivery of LMWHs. The therapeutic efficiency and the simple and solvent-free manufacturing process underlines the high potential of this new preparation method. PMID- 23649853 TI - An atom-economical approach to functionalized single-walled carbon nanotubes: reaction with disulfides. PMID- 23649852 TI - Preclinical models used for immunogenicity prediction of therapeutic proteins. AB - All therapeutic proteins are potentially immunogenic. Antibodies formed against these drugs can decrease efficacy, leading to drastically increased therapeutic costs and in rare cases to serious and sometimes life threatening side-effects. Many efforts are therefore undertaken to develop therapeutic proteins with minimal immunogenicity. For this, immunogenicity prediction of candidate drugs during early drug development is essential. Several in silico, in vitro and in vivo models are used to predict immunogenicity of drug leads, to modify potentially immunogenic properties and to continue development of drug candidates with expected low immunogenicity. Despite the extensive use of these predictive models, their actual predictive value varies. Important reasons for this uncertainty are the limited/insufficient knowledge on the immune mechanisms underlying immunogenicity of therapeutic proteins, the fact that different predictive models explore different components of the immune system and the lack of an integrated clinical validation. In this review, we discuss the predictive models in use, summarize aspects of immunogenicity that these models predict and explore the merits and the limitations of each of the models. PMID- 23649856 TI - Fabrication of Ag nanoparticles embedded in TiO2 nanotubes: using electrospun nanofibers for controlling plasmonic effects. AB - Composites of electrospun poly(ethylene oxide) (PEO) fibers and silver nanoparticles (Ag NPs) were used as a soft template for coating with TiO2 by atomic layer deposition (ALD). Whereas the as-deposited TiO2 layers on PEO fibers and Ag NPs were completely amorphous, the TiO2 layers were transformed into polycrystalline TiO2 nanotubes (NTs) with embedded Ag NPs after calcination. Their plasmonic effect can be controlled by varying the thickness of the dielectric Al2 O3 spacer between Ag NPs and dye molecules by means of the ALD process. Electronic and spectroscopic analyses demonstrated enhanced photocurrent generation and solar-cell performance due to the intense electromagnetic field of the dye resulting from the surface plasmon effect of the Ag NPs. PMID- 23649857 TI - Fatal B-cell lymphoma following chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. AB - IMPORTANCE: Recent reports on chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) suggest that patients who have a relapse respond very well and that disease progression can be avoided if timely corticosteroid therapy is started. We report on a well-documented patient who presented with clinical, radiological, and pathological characteristics of CLIPPERS and who had an unfavorable outcome. OBSERVATIONS: We present the clinical, imaging, laboratory, brain biopsy, and autopsy findings of a 57-year-old male patient with CLIPPERS who repeatedly responded well to high dose corticosteroids. During follow-up, however, treatment failed, and he had a biopsy-confirmed diagnosis of lymphomatoid granulomatosis that evolved into fatal B-cell lymphoma of the central nervous system. CONCLUSIONS AND RELEVANCE: The clinical and imaging features of CLIPPERS include an abundance of differential diagnoses, and the follow-up periods of the described cases classified as CLIPPERS have been limited. Therefore, the question remains whether CLIPPERS is an actual new disease entity or represents a syndrome that includes different overlapping diseases and their prestages. Our case report shows that a typical presentation of CLIPPERS does not uniformly imply a favorable outcome, even when timely treatment regimens have been given. PMID- 23649858 TI - Evaluation of active transition, a website-delivered physical activity intervention for university students: pilot study. AB - BACKGROUND: While physical activity in individuals tends to decline steadily with age, there are certain periods where this decline occurs more rapidly, such as during early adulthood. Interventions aimed at attenuating the declines in physical activity during this transition period appear warranted. OBJECTIVE: The purpose of the study was to test the feasibility and efficacy of a theoretically informed, website-delivered physical activity intervention aimed at students entering university. METHODS: Using a quasi-experimental design, 65 participants (44 females; mean age 18.51, SD 0.91) were assigned to either an intervention (receiving website access plus weekly prompts) or comparison condition (receiving unprompted website access only), completing questionnaires at baseline and follow up 8 weeks later. The intervention website, "Active Transition", was specifically designed to target students' physical activity cognitions and self-regulatory skills. RESULTS: Intervention usage was low, with only 47% (18/38) of participants assigned to the intervention condition logging into the website 2 or more times. Among the broader student sample, there were significant declines in students' physical activity behaviors (F1,63=18.10, P<.001), attitudes (F1,62=55.19, P<.001), and perceived behavioral control (F1,62 =17.56, P<.001). In comparisons between intervention users (29/65, individuals logging in 2 or more times) and non-users (36/65, individuals logging in once or not at all), there was a significant interaction effect for intervention usage and time on perceived behavioral control (F1,62=5.13, P=.03). CONCLUSIONS: Poor intervention usage suggests that future efforts need to incorporate innovative strategies to increase intervention uptake and better engage the student population. The findings, however, suggest that a website-delivered intervention aimed at this critical life stage may have positive impact on students' physical activity cognitions. Future studies with more rigorous sampling designs are required. PMID- 23649859 TI - Mania during antidepressant withdrawal in late-onset depression. PMID- 23649860 TI - The other face of the coin: the caregiver burden in frontotemporal lobar degeneration. PMID- 23649861 TI - Exploring sleep-related outcomes in patients with mild to moderate Alzheimer's disease initiating acetylcholinesterase inhibitor therapy: the Morpheus survey. PMID- 23649862 TI - Development of myenteric cholinergic neurons in ChAT-Cre;R26R-YFP mice. AB - Cholinergic neurons are the major excitatory neurons of the enteric nervous system (ENS), and include intrinsic sensory neurons, interneurons, and excitatory motor neurons. Cholinergic neurons have been detected in the embryonic ENS; however, the development of these neurons has been difficult to study as they are difficult to detect prior to birth using conventional immunohistochemistry. In this study we used ChAT-Cre;R26R-YFP mice to examine the development of cholinergic neurons in the gut of embryonic and postnatal mice. Cholinergic (YFP+) neurons were first detected at embryonic day (E)11.5, and the proportion of cholinergic neurons gradually increased during pre- and postnatal development. At birth, myenteric cholinergic neurons comprised less than half of their adult proportions in the small intestine (25% of myenteric neurons were YFP+ at P0 compared to 62% in adults). The earliest cholinergic neurons appear to mainly project anally. Projections into the presumptive circular muscle were first observed at E14.5. A subpopulation of cholinergic neurons coexpress calbindin through embryonic and postnatal development, but only a small proportion coexpressed neuronal nitric oxide synthase. Our study shows that cholinergic neurons in the ENS develop over a protracted period of time. PMID- 23649863 TI - The academic impact of the Triological Society theses--Mosher and Fowler awards: citations, impact factor, and h-index. AB - OBJECTIVES/HYPOTHESIS: The Triological Society requires thesis submission for full membership. Accepted theses (AT) may be recognized with designations of: Mosher Awards (MA), Fowler Awards (FA), Honorable Mention for Basic Science (HMBS), and Honorable Mention for Clinical Science (HMCS). We sought to determine and compare the scholarly impact of Triological Society theses, their authors, and whether differences exist between AT and those that receive special recognition. STUDY DESIGN: Retrospective analysis of awards and theses compiled by The Triological Society home office from 1998 to 2011. METHODS: Thomson Reuters' Integrated Search Interface (ISI) Web of Knowledge and Google Scholar and were used to determine citations and the author's h-index. Trend and statistical analysis was performed. RESULTS: Of the 307 Triological Society theses examined, 275 were published and had record of citation. H-indices and number of citations were found to be nonparametric; thus, median and quartile (1(st) -3(rd) quartiles) values were found to be the following: AT 11 (4-26), MA 18 (9-25), FA 6 (1-28), HMBS 11 (4-26), and HMCS 16 (1-28) for number of citations per published thesis. H-indices of authors with accepted theses were AT 15 (10-19), MA 16 (15-23), FA 18 (10-23), HMBS 16 (11-19), and HMCS 15 (11-21). When comparing all groupings of theses and award winners with bibliometric indices, no statistical significance was found (P >0.5). CONCLUSIONS: The Triological Society cultivates a competitive pool of applicants as membership is highly regarded. Negligible difference in citations and author h-index were observed between AT, MA, and FA theses indicated that the level of excellence is uniform, and thesis submission remains influential and prestigious. PMID- 23649865 TI - Dissolution kinetics of nanocrystals. AB - A simple series of test-tube experiments is all it takes to quantify a largely neglected nano-effect responsible for a dramatic increase-by orders of magnitude in the surface-area-normalized rate of dissolution of nanocrystals. Though the observed variation in this specific rate as a function of size is unprecedented, the effect may be rationalized in terms of the classic atomistic theory of crystal growth and dissolution. PMID- 23649866 TI - Recurrent infection in the left thumb. AB - INTRODUCTION: Infections of the hand may be associated with lymphangitis and lymphadenitis. In most cases, bacterial infections are responsible but these may be also due to viral infections. MATERIAL AND METHODS: We describe a clinical case of a recurrent infection in the left thumb of a health male. Bacterial and viral cultures were performed. RESULTS: Herpes simplex virus (HSV) type 2 was isolated on viral culture and on direct fluorescent antibody testing; so, the final diagnosis was herpetic whitlow. CONCLUSIONS: Herpetic whitlow should be considered in cases of recurrent finger infections. PMID- 23649864 TI - Cardiac PDEs and crosstalk between cAMP and cGMP signalling pathways in the regulation of contractility. AB - Elucidation of cAMP and cGMP signalling in the heart remains a hot topic, and new regulatory mechanisms continue to appear. Studying the influence of phosphodiesterases on 5-HT4 receptor signalling in porcine atrium, a paper from this issue of the journal expands findings of a crosstalk between cardiac cGMP and cAMP signalling recently discovered in failing rat ventricle to a different species and cardiac region. The overall data suggest that cGMP, produced following stimulation of the NPR-B receptor for C-type natriuretic peptide (CNP), inhibits cAMP degradation by phosphodiesterase 3 and thereby enhances cAMP mediated signalling from beta-adrenoceptors and 5-HT4 receptors to inotropic effects. In porcine atrium, this effect can be seen both as an increase in inotropic effect and as a reduced fade of the inotropic effect with time. Thus, accumulating evidence brings together several active fields of research, including cardiac phosphodiesterases, compartmentation of cyclic nucleotide signalling and the field of natriuretic peptides. If present in human hearts, this effect of CNP may have clinical implications. PMID- 23649867 TI - Molecular diagnosis of endometrial cancer from uterine aspirates. AB - Rapid and reliable diagnosis of endometrial cancer (EC) in uterine aspirates is highly desirable. Current sensitivity and failure rate of histological diagnosis limit the success of this method and subsequent hysteroscopy is often necessary. Using quantitative reverse transcriptase-polymerase chain reaction on RNA from uterine aspirates samples, we measured the expression level of 20 previously identified genes involved in EC pathology, created five algorithms based on combinations of five genes and evaluated their ability to diagnose EC. The algorithms were tested in a prospective, double-blind, multicenter study. We enlisted 514 patients who presented with abnormal uterine bleeding. EC was diagnosed in 60 of the 514 patients (12%). Molecular analysis was performed on the remnants of aspirates and results were compared to the final histological diagnoses obtained through biopsies acquired by aspiration or guided by hysteroscopy, or from the specimens resected by hysterectomy. Algorithm 5 was the best performing molecular diagnostic classifier in the case-control and validation study. The molecular test had a sensitivity of 81%, specificity of 96%, positive predictive value (PPV) of 75% and negative predictive value (NPV) of 97%. A combination of the molecular and histological diagnosis had a sensitivity of 91%, specificity of 97%, PPV of 79% and NPV of 99% and the cases that could be diagnosed on uterine aspirate rose from 76 to 93% when combined with the molecular test. Incorporation of the molecular diagnosis increases the reliability of a negative diagnosis, reduces the need for hysteroscopies and helps to identify additional cases. PMID- 23649868 TI - Polo-like kinase 1 is essential for the first mitotic division in the mouse embryo. AB - Polo-like kinase 1 (PLK1), a member of the serine/threonine protein kinases family, is involved in multiple steps of mitotic progression. It regulates centrosome maturation, mitotic spindle formation, and cytokinesis. While studied extensively in somatic cells, little is known about PLK1 activities in the mammalian preimplantation embryo. We examined the role of PLK1 in the one-cell mouse embryo. Western blotting showed that the PLK1 protein content increased significantly during the S-phase of the one-cell stage and declined during the first mitotic division. Activation of PLK1 preceded nuclear envelope breakdown (NEBD) in both pronuclei at the entry to first embryo mitosis. Immunofluorescence revealed the presence of phosphorylated, active PLK1 (pThr(210) -PLK1) in both male and female pronuclei, and in the microtubule-organizing centers (MTOCs) shortly before NEBD. During the first mitotic metaphase, pThr(210) -PLK1 accumulated at the spindle poles and was also associated with condensed chromosomes. Inhibition of PLK1 activity with a specific PLK1 inhibitor, BI 2536, at the one-cell stage induced the formation of a bipolar spindle that displayed disordered microtubular arrangements and dislocated, condensed chromosomes. Although such embryos entered mitosis, they did not complete mitosis and arrested at metaphase. Time-lapse recording revealed progressive misalignment of condensed chromosomes during first mitotic metaphase. These data indicate that PLK1 activity is not essential for entry into first mitosis, but is required for the events leading up to metaphase-anaphase transition in the one-cell mouse embryo. PMID- 23649869 TI - Tumor lysis syndrome soon after treatment with hydroxyurea followed by nilotinib in two patients with chronic-phase chronic myelogenous leukemia. AB - Nilotinib, a second-generation tyrosine kinase inhibitor with 20- to 30-fold greater potency than imatinib, was developed to overcome imatinib intolerance or resistance. Recently, nilotinib has been approved as a first-line treatment for chronic myelogenous leukemia in the US and Japan. Tumor lysis syndrome (TLS) is an extremely rare adverse event that can occur during treatment with nilotinib, with only a few reported cases to date. Herein, we report two patients who developed TLS soon after the start of treatment with nilotinib. While in the first case, which co-presented with underlying mild-to-moderate renal insufficiency due to polycystic kidney disease, the TLS resolved on discontinuation of the drug, the second patient, who had an exceedingly high white blood cell count, presented with disseminated intravascular coagulation and severe liver injury triggered by TLS that developed after the start of nilotinib treatment, and died of multiple organ failure. Therefore, caution is necessary when this drug is used in the first-line setting in patients with renal insufficiency or a high tumor burden. PMID- 23649870 TI - Notes on "roux en y gastric bypass increases ethanol intake in the rat" by Davis et al. PMID- 23649871 TI - Response to Hajnal et al. PMID- 23649872 TI - Ultralow contact resistance at an epitaxial metal/oxide heterojunction through interstitial site doping. AB - Heteroepitaxial growth of Cr metal on Nb-doped SrTiO3(001) is accompanied by Cr diffusion to interstitial sites within the first few atomic planes, an anchoring of the Cr film to the substrate, charge transfer from Cr to Ti, and metallization of the near-surface region, as depicted in the figure. The contact resistance of the resulting interface is exceedingly low. PMID- 23649874 TI - Calcium-binding protein expression in peritoneal endometriosis-associated nerve fibres. AB - BACKGROUND: Recent studies demonstrated the potential involvement of nerve fibres in the chronic inflammatory process of endometriosis. We aimed to characterize nerve fibres in the proximal and distal areas of the peritoneal endometriotic lesions in order to understand the chronic inflammatory process in endometriosis. METHODS: Peritoneal endometriotic lesions (proximal area) (n = 17), the matching unaffected peritoneum (distal area) and healthy peritoneum of patients without endometriosis (n = 15) were analysed with the neuronal markers PGP 9.5, calbindin, calretinin and parvalbumin. Peritoneal fluids of women with and without endometriosis were used for Western blot analysis and for the neuronal growth assay. The protein expression of neuronal PC-12 cells incubated with peritoneal fluids was analysed. RESULTS: The overall nerve fibre density was significantly reduced in the distal area of the lesion when compared with the proximal area or with healthy peritoneum. The density of calbindin-, calretinin- and parvalbumin-positive nerve fibres was significantly increased in the endometriosis group. Calretinin expression was elevated in the peritoneal fluid of women with symptomatic endometriosis when compared with women with asymptomatic endometriosis. Furthermore, PC-12 cells incubated with peritoneal fluid of women with endometriosis showed a higher proliferation rate and a stronger neurite outgrowth than the control group. PC-12 cells incubated in peritoneal fluids of women with endometriosis expressed less calretinin but more calbindin than the control group. CONCLUSIONS: Calcium-binding proteins seem to be increased in endometriosis-associated nerve fibres and might play an important role in the chronic inflammatory condition and the pain pathogenesis of endometriosis. PMID- 23649873 TI - Tanycyte-like cells form a blood-cerebrospinal fluid barrier in the circumventricular organs of the mouse brain. AB - Tanycytes are highly specialized ependymal cells that form a blood-cerebrospinal fluid (CSF) barrier at the level of the median eminence (ME), a circumventricular organ (CVO) located in the tuberal region of the hypothalamus. This ependymal layer harbors well-organized tight junctions, a hallmark of central nervous system barriers that is lacking in the fenestrated portal vessels of the ME. The displacement of barrier properties from the vascular to the ventricular side allows the diffusion of blood-borne molecules into the parenchyma of the ME while tanycyte tight junctions control their diffusion into the CSF, thus maintaining brain homeostasis. In the present work, we combined immunohistochemical and permeability studies to investigate the presence of tanycyte barriers along the ventricular walls of other brain CVOs. Our data indicate that, unlike cuboidal ependymal cells, ependymal cells bordering the CVOs possess long processes that project into the parenchyma of the CVOs to reach the fenestrated capillary network. Remarkably, these tanycyte-like cells display well-organized tight junctions around their cell bodies. Consistent with these observations, permeability studies show that this ependymal layer acts as a diffusion barrier. Together, our results suggest that tanycytes are a characteristic feature of all CVOs and yield potential new insights into their involvement in regulating the exchange between the blood, the brain, and the CSF within these "brain windows." PMID- 23649875 TI - Comparative characteristics of endothelial-like cells derived from human adipose mesenchymal stem cells and umbilical cord blood-derived endothelial cells. AB - Adult peripheral blood contains a limited number of endothelial progenitor cells that can be isolated for treatment of ischemic diseases. The adipose tissue became an interesting source of stem cells for regenerative medicine. This study aimed to investigate the phenotype of cells obtained by culturing adipose-derived mesenchymal stem cells (ad-MSCs) in the presence of endothelial growth supplements compared to endothelial cells obtained from umbilical cord blood (UCB). Passage 3 ad-MSCs and mononuclear layer from UCB were cultured in presence of endothelial growth media for 3 weeks followed by their characterization by flow cytometry and polymerase chain reaction. After culture in endothelial inductive media, ad-MSCs expressed endothelial genes and some endothelial marker proteins as CD31 and CD34, respectively. Adipose tissue could be a reliable source for easy obtaining, expanding and differentiating MSCs into endothelial like cells for autologous cell-based therapy. PMID- 23649876 TI - Accurate control of multishelled Co3O4 hollow microspheres as high-performance anode materials in lithium-ion batteries. PMID- 23649877 TI - Identification of microRNAs in Caragana intermedia by high-throughput sequencing and expression analysis of 12 microRNAs and their targets under salt stress. AB - KEY MESSAGE: 142 miRNAs were identified and 38 miRNA targets were predicted, 4 of which were validated, in C. intermedia . The expression of 12 miRNAs in salt stressed leaves was assessed by qRT-PCR. MicroRNAs (miRNAs) are endogenous small RNAs that play important roles in various biological and metabolic processes in plants. Caragana intermedia is an important ecological and economic tree species prominent in the desert environment of west and northwest China. To date, no investigation into C. intermedia miRNAs has been reported. In this study, high throughput sequencing of small RNAs and analysis of transcriptome data were performed to identify both conserved and novel miRNAs, and also their target mRNA genes in C. intermedia. Based on sequence similarity and hairpin structure prediction, 132 putative conserved miRNAs (12 of which were confirmed to form hairpin precursors) belonging to 31 known miRNA families were identified. Ten novel miRNAs (including the miRNA* sequences of three novel miRNAs) were also discovered. Furthermore, 36 potential target genes of 17 known miRNA families and 2 potential target genes of 1 novel miRNA were predicted; 4 of these were validated by 5' RACE. The expression of 12 miRNAs was validated in different tissues, and these and five target mRNAs were assessed by qRT-PCR after salt treatment. The expression levels of seven miRNAs (cin-miR157a, cin-miR159a, cin miR165a, cin-miR167b, cin-miR172b, cin-miR390a and cin-miR396a) were upregulated, while cin-miR398a expression was downregulated after salt treatment. The targets of cin-miR157a, cin-miR165a, cin-miR172b and cin-miR396a were downregulated and showed an approximately negative correlation with their corresponding miRNAs under salt treatment. These results would help further understanding of miRNA regulation in response to abiotic stress in C. intermedia. PMID- 23649878 TI - Comparative transcriptome analysis of pepper (Capsicum annuum) revealed common regulons in multiple stress conditions and hormone treatments. AB - KEY MESSAGE: Global transcriptome analysis revealed common regulons for biotic/abiotic stresses, and some of these regulons encoding signaling components in both stresses were newly identified in this study. In this study, we aimed to identify plant responses to multiple stress conditions and discover the common regulons activated under a variety of stress conditions. Global transcriptome analysis revealed that salicylic acid (SA) may affect the activation of abiotic stress-responsive genes in pepper. Our data indicate that methyl jasmonate (MeJA) and ethylene (ET)-responsive genes were primarily activated by biotic stress, while abscisic acid (ABA)-responsive genes were activated under both types of stresses. We also identified differentially expressed gene (DEG) responses to specific stress conditions. Biotic stress induces more DEGs than those induced by abiotic and hormone applications. The clustering analysis using DEGs indicates that there are common regulons for biotic or abiotic stress conditions. Although SA and MeJA have an antagonistic effect on gene expression levels, SA and MeJA show a largely common regulation as compared to the regulation at the DEG expression level induced by other hormones. We also monitored the expression profiles of DEG encoding signaling components. Twenty-two percent of these were commonly expressed in both stress conditions. The importance of this study is that several genes commonly regulated by both stress conditions may have future applications for creating broadly stress-tolerant pepper plants. This study revealed that there are complex regulons in pepper plant to both biotic and abiotic stress conditions. PMID- 23649879 TI - How much does it cost to care for survivors of colorectal cancer? Caregiver's time, travel and out-of-pocket costs. AB - PURPOSE: Cancer treatment is increasingly delivered in an outpatient setting. This may entail a considerable economic burden for family members and friends who support patients/survivors. We estimated financial and time costs associated with informal care for colorectal cancer. METHODS: Two hundred twenty-eight carers of colorectal cancer survivors diagnosed on October 2007-September 2009 were sent a questionnaire. Informal care costs included hospital- and domestic-based foregone caregiver time, travel expenses and out-of-pocket (OOP) costs during two phases: diagnosis and treatment and ongoing care (previous 30 days). Multiple regression was used to determine cost predictors. RESULTS: One hundred fifty-four completed questionnaires were received (response rate = 68%). In the diagnosis and treatment phase, weekly informal care costs per person were: hospital-based costs, incurred by 99% of carers, mean = ?393 (interquartile range (IQR), ?131 ?541); domestic-based time costs, incurred by 85%, mean = ?609 (IQR, ?170-?976); and domestic-based OOP costs, incurred by 68%, mean = ?69 (IQR, ?0-?110). Ongoing costs included domestic-based time costs incurred by 66% (mean = ?66; IQR, ?0 ?594) and domestic-based OOP costs incurred by 52% (mean = ?52; IQR, ?0-?64). The approximate average first year informal care cost was ?29,842, of which 85 % was time costs, 13% OOP costs and 2% travel costs. Significant cost predictors included carer age, disease stage, and survivor age. CONCLUSION: Informal caregiving associated with colorectal cancer entails considerable time and OOP costs. This burden is largely unrecognised by policymakers, service providers and society in general. These types of studies may facilitate health decision-makers in better assessing the consequences of changes in cancer care organisation and delivery. PMID- 23649880 TI - Institutional review board barriers and solutions encountered in the Collaboration Among Pharmacists and Physicians to Improve Outcomes Now Study: a national multicenter practice-based implementation trial. AB - STUDY OBJECTIVE: To categorize institutional review board (IRB) challenges and solutions encountered in a multicenter practice-based research network (PBRN) study and to assess the impact of IRB requirements on the willingness of individual principal investigators (PIs) to participate in future PBRN studies. DESIGN: Descriptive analysis of IRB challenges and solutions encountered in the Collaboration Among Pharmacists and Physicians to Improve Outcomes Now (CAPTION) trial, a multicenter prospective cluster-randomized study conducted by the National Interdisciplinary Primary Care PBRN, and a correlational analysis from a survey of individual site PIs. MEASUREMENTS AND MAIN RESULTS: IRB barriers encountered and solutions were categorized for study sites. A survey of study site PIs was conducted with a correlational analysis assessing the impact of various IRB requirements and the willingness of individual PIs to participate in future PBRN studies; of 31 study sites participating in the CAPTION study, 28 study-site PIs were surveyed. IRBs posed a number of challenges including bias regarding the source of the application, issues regarding study design, study instruments, access to patient records, study procedures, Spanish-only speaking subjects, role of clinic physicians, interdepartmental concerns, and updates at continuing review. Responses from the PI survey (21 of 28 PIs surveyed [75% response rate]) indicated that the willingness of an individual to serve as a PI in the future was inversely related to the perceived difficulty of obtaining initial (rS = -0.599, p=0.004) and continuing (rS = -0.464, p=0.034) IRB approval. CONCLUSION: Significant time and resources were required to address various challenges associated with IRB approval, which had a negative impact on an individual PI's willingness to participate in future PBRN projects. A revision of current rules and regulations regarding the protection of human subjects for practice-based studies, improvement in IRB processes, and support from coordinating centers may decrease the burden associated with IRB approval and increase participation in practice-based research. PMID- 23649881 TI - Potential adverse events of endosseous dental implants penetrating the maxillary sinus: long-term clinical evaluation. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to evaluate the nature and incidence of long-term maxillary sinus adverse events related to endosseous implant placement with protrusion into the maxillary sinus. STUDY DESIGN: Retrospective cohort study. METHODS: All patients who underwent placement of endosseous dental implants with clinical evidence of implant penetration into the maxillary sinus with membrane perforation were included in this study. Only patients with a minimum follow-up of 5 years after implant placement were included in this study. Maxillary sinus assessment was both clinical and radiological. RESULTS: Eighty-three implants with sinus membrane perforation in 70 patients met the study's inclusion criteria. Mean age was 65.96 years +/- 14.23. Twelve patients had more than one implant penetrating the maxillary sinus, and seven of them had bilateral sinus perforation. Estimated implant penetration was <= 3 mm in all cases. The average clinical and radiological follow-up was 9.98 years +/- 3.74 (range 60-243 months). At the follow-up appointments, there were no clinical or radiological signs of sinusitis in any patient. CONCLUSION: This long-term study, spreading over a period of up to 20 years, indicates that no sinus complication was observed following implant penetration into the maxillary sinus. Furthermore, absence of occurrence of such complications is related to the maintenance of successful osseointegration. A contrario, and in the presence of an acute or chronic maxillary sinusitis, the differential diagnosis must always consider other potential odontogenic and nonodontogenic etiologies. PMID- 23649882 TI - Determination of dopamine D2 receptor occupancy by lurasidone using positron emission tomography in healthy male subjects. AB - RATIONALE: A positron emission tomography (PET) study of dopamine D2 receptor occupancy was conducted to support a rational dose selection for clinical efficacy studies with lurasidone, an atypical antipsychotic that was approved for the treatment of schizophrenia by the FDA in late 2010. OBJECTIVES: To determine the dopamine D2 receptor occupancy of lurasidone in the ventral striatum, putamen and caudate nucleus, and to characterize the relationship between lurasidone serum concentration and D2 receptor occupancy. METHODS: A single oral dose of lurasidone (10, 20, 40, 60, or 80 mg) was administered sequentially to healthy male subjects (n = 4 in each cohort). Two PET scans were performed. For each scan, 20 mCi of [11C]raclopride was administered intravenously as a bolus injection, followed immediately by 90 min of PET scan acquisitions. RESULTS: The D2 receptor occupancy levels were 41-43% for 10 mg, 51-55% for 20 mg, 63-67% for 40 mg, 77-84% for 60 mg, and 73-79% for 80 mg of lurasidone. The relationship between D2 receptor occupancy and the mean serum lurasidone concentration during the PET scan (C PET) was similar for the putamen, caudate nucleus, and ventral striatum regions. Mean D2 receptor occupancy levels correlated well with average peak serum concentration of lurasidone. CONCLUSIONS: In healthy volunteers, single doses of lurasidone 40-80 mg resulted in D2 receptor occupancy levels of >60%, a level of receptor occupancy previously associated with clinical response for atypical antipsychotics. PMID- 23649883 TI - Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics. AB - RATIONALE: Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine. OBJECTIVE: The major aims were to investigate the pharmacokinetics and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model. METHODS: Mephedrone was administered to male Sprague-Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min. RESULTS: Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (alpha = 10.23 h(-1), beta = 1.86 h(-1)). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10% and the percentage of mephedrone protein binding was 21.59 +/- 3.67%. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85 +/- 0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic-pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect. CONCLUSIONS: We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude, and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity. PMID- 23649884 TI - NMDA receptor antagonists distort visual grouping in rats performing a modified two-choice visual discrimination task. AB - RATIONALE: Visual perception is impaired during pathological psychosis, which can be mimicked by NMDA receptor antagonists. However, the underlying mechanisms are poorly understood, partly due to limits of current rodent models for visual integration. OBJECTIVES: The objectives of the study are (1) to develop a rodent task that can differentiate between effects on perception and nonspecific effects on task performance and (2) to test whether NMDA receptor antagonists affect visual perception in rats. METHODS: We used an adaptation of Glass patterns to assess visual grouping in rats using a two-choice visual discrimination task in an infrared touch screen conditioning chamber. After rats learned to discriminate between a radial and a concentric bipole pattern, the ability to discriminate between these patterns was tested at various levels of distortion and a psychometric function was fit to obtain the maximum task performance and signal level needed for half-maximum performance. RESULTS: NMDA receptor antagonists ketamine and phencyclidine at low doses increased the signal quality needed to discriminate between the visual patterns, without affecting the ability to discriminate between undistorted images. At higher doses, the ability to perform the task even with undistorted images was impaired, which was associated with stereotypic behaviour and increased impulsivity. CONCLUSIONS: The Glass pattern based visual grouping task is able to differentiate the effect of psychotomimetic NMDA receptor antagonists on visual perception from the effects on motor and memory functions. The half-maximum performance signal level allows quantification of cognitive psychosis in rodents, which can be translated to human psychometric functions and can be used in the development of more effective treatments. PMID- 23649886 TI - A survey of educational uses of molecular visualization freeware. AB - As biochemists, one of our most captivating teaching tools is the use of molecular visualization. It is a compelling medium that can be used to communicate structural information much more effectively with interactive animations than with static figures. We have conducted a survey to begin a systematic evaluation of the current classroom usage of molecular visualization. Participants (n = 116) were asked to complete 11 multiple choice and 3 open ended questions. To provide more depth to these results, interviews were conducted with 12 of the participants. Many common themes arose in the survey and the interviews: a shared passion for the use of molecular visualization in teaching, broad diversity in software preference, the lack of uniform standards for assessment, a desire for more quality resources, and the challenge of enabling students to incorporate visualization in their learning. The majority of respondents had used molecular visualization for more than 5 years and mentioned 32 different visualization tools used, with Jmol and PyMOL clearly standing out as the most frequently used programs at the present time. The most common uses of molecular visualization in teaching were lecture and lab illustrations, followed by exam questions, in-class or in-laboratory exercises, and student projects, which frequently included presentations. While a minority of instructors used a grading rubric/scoring matrix for assessment of student learning with molecular visualization, many expressed a desire for common use assessment tools. PMID- 23649887 TI - Stroke rehabilitation: issues for physiotherapy and physiotherapy research to improve life after stroke. PMID- 23649888 TI - A rational approach towards a new ferrocenyl pyrrolidine for stereoselective enamine catalysis. AB - Ironing out the details: Proline and pyrrolidine derivatives (Hayashi- Jorgensen catalysts) are considered "work horses" in organocatalysis. This report describes a new effective ferrocenyl pyrrolidine catalyst that is able to perform well in benchmark organocatalytic reactions (see figure). The ferrocene moiety controls the conformational space and a simple alkyl group effectively covers a face of the derived enamine. This new framework can find applications in organocatalysis, and in general, in new ligand design. PMID- 23649889 TI - Mild therapeutic hypothermia after out-of-hospital cardiac arrest complicating ST elevation myocardial infarction: long-term results in clinical practice. AB - BACKGROUND: Recently, mild therapeutic hypothermia (MTH) has been integrated into the European resuscitation guidelines to improve outcomes after out-of-hospital cardiac arrest (OHCA). Data on long-term results are limited, especially in patients with acute ST-elevation myocardial infarction (STEMI). HYPOTHESIS: Invasive MTH influences long-term prognosis after OHCA due to STEMI. METHODS: We analyzed 48 patients who underwent emergency coronary angiography for STEMI after witnessed OHCA. In 24 consecutive patients, MTH was performed via intravascular cooling (CoolGard System, 34 degrees C maintained for 24 hours) after initialization by rapid infusion of cold saline. Clinical, procedural, and mortality data were compared to 24 historical controls. Neurological recovery was assessed using the Cerebral Performance Category score (CPC) at 30-day and 1-year follow-up. RESULTS: Median time delay until arrival of emergency medical service was 6 minutes (MTH group) vs 6.5 minutes (controls) (P = 0.16). Initial rhythm was ventricular fibrillation in 75% vs 66.7% (P = 0.75). There were no differences regarding baseline characteristics, angiographic findings, and success of cardiac catheterization procedures. MTH was not associated with a higher frequency of bleeding complications or of pneumonia. Thirty-day mortality was 33.3% in both groups. One-year mortality was 37.5% (MTH group) vs 50% (controls) (P = 0.56). At 1 year, favorable neurological outcome (CPC <=2) was significantly more frequent in the MTH group (58.3% vs 20.8%, P = 0.017). Multivariate analysis identified MTH as independent predictor of favorable neurological outcome (P < 0.02, odds ratio: 12.73). CONCLUSIONS: MTH via intravascular cooling improves neurological long-term prognosis after OHCA due to STEMI and is safe in clinical practice. PMID- 23649885 TI - Pharmacological traits of delta opioid receptors: pitfalls or opportunities? AB - RATIONALE: Delta opioid receptors (DORs) have been considered as a potential target to relieve pain as well as treat depression and anxiety disorders and are known to modulate other physiological responses, including ethanol and food consumption. A small number of DOR-selective drugs are in clinical trials, but no DOR-selective drugs have been approved by the Federal Drug Administration and some candidates have failed in phase II clinical trials, highlighting current difficulties producing effective delta opioid-based therapies. Recent studies have provided new insights into the pharmacology of the DOR, which is often complex and at times paradoxical. OBJECTIVE: This review will discuss the existing literature focusing on four aspects: (1) Two DOR subtypes have been postulated based on differences in pharmacological effects of existing DOR selective ligands. (2) DORs are expressed ubiquitously throughout the body and central nervous system and are, thus, positioned to play a role in a multitude of diseases. (3) DOR expression is often dynamic, with many reports of increased expression during exposure to chronic stimuli, such as stress, inflammation, neuropathy, morphine, or changes in endogenous opioid tone. (4) A large structural variety in DOR ligands implies potential different mechanisms of activating the receptor. CONCLUSION: The reviewed features of DOR pharmacology illustrate the potential benefit of designing tailored or biased DOR ligands. PMID- 23649890 TI - Implications of a data-driven approach to treatment with growth hormone in children with growth hormone deficiency and Turner syndrome. AB - BACKGROUND: Response to growth hormone (GH) therapy may vary between individual patients. Therefore the use of GH in children should be closely monitored to avoid over, under, or ineffective treatment regimens. The treatment response can be evaluated using growth prediction models. In an effort to improve the accuracy of these prediction models, Ranke et al. (J Clin Endocrinol Metab 95(3):1229-37) proposed a novel 'data-driven' approach based on a quantitative analysis of a large cohort of patients from the Pfizer International Growth Database (KIGS) treated with Genotropin (human growth hormone). This model allows physicians to predict and evaluate the level of growth response and responsiveness for their patients so they can adapt treatment accordingly. By comparing the actually observed and the predicted growth response the ability of an individual to respond to GH (responsiveness) can be estimated and further treatment can be adapted accordingly OBJECTIVE: To determine the potential population level reduction in the amount of GH used and impact on height outcome of using this data-driven approach to guide treatment decisions, compared to conventional, 'experience-based' GH treatment in prepubertal patients with growth hormone deficiency (GHD) or Turner syndrome (TS). METHODS: A model was developed to study the height outcome and the total amount of GH used in the presence or absence of data-driven treatment decisions. The proportion of patients for whom height outcome could be improved or GH use could be reduced (i.e. for low compliance, high or low responder) was estimated using the KIGS cohort. The analysis assumed that this segmentation allows physicians to tailor dosage to the individual patient's needs or even to discontinue therapy when it is not effective. The analysis used a 4-year time horizon, with Germany as an example country, but results are extendable to other countries. Only the total amount of GH used was included, and effects were defined as the height outcome after 4 years. RESULTS: The analysis estimated that an evidence-driven approach may reduce the total amount of GH utilized by 7.0 % over 4 years for the treatment of short stature in prepubertal patients with GHD and TS in Germany. Despite the reduction in drug use the average growth outcomes remained unaffected with the new treatment approach. Univariate and probabilistic sensitivity analyses showed that the results are robust. CONCLUSIONS: Our analysis showed that using a data-driven approach to guide treatment decisions for children with GHD or TS is estimated to result in efficiencies in the amount of GH used, without reducing the average growth in the population. PMID- 23649891 TI - Compliance with pharmacotherapy and direct healthcare costs in patients with Parkinson's disease: a retrospective claims database analysis. AB - BACKGROUND: Parkinson's disease (PD) is a progressive neurological disorder for which, at present, there is no cure. Current therapy is largely based on the use of dopamine agonists and dopamine replacement therapy, designed to control the signs and symptoms of the disease. The majority of current treatments are administered in tablet form and can involve multiple daily doses, which may contribute to sub-optimal compliance. Previous studies with small groups of patients suggest that non-compliance with treatment can result in poor response to therapy and may ultimately increase direct and indirect healthcare costs. OBJECTIVE: To determine the extent of non-compliance within the general PD population in the USA as well as the patient characteristics and healthcare costs associated with compliance and non-compliance. METHODS: A retrospective analysis from a managed care perspective was conducted using data from the USA PharMetrics patient-centric claims database. PharMetrics claims data were complete from 31 December 2005 to 31 December 2009. Patients were included if they had at least two diagnoses for PD between 31 December 2005 and 31 December 2008, were older than 18 years of age, were continuously enrolled for at least 12 months after the date of the most recent PD diagnosis, and had no missing or invalid data. The follow-up period was the most recent 12-month block of continuous enrollment that occurred between 2006 and 2009. Patients were required to have at least one PD related prescription within the follow-up period. The medication possession ratio (MPR) was used to categorise patients as compliant or non-compliant. Direct all cause annual healthcare costs for patients with PD were estimated for each patient, and regression analyses were conducted to determine predictors for non compliance. RESULTS: A total of 15,846 patients were included, of whom 46 % were considered to be non-compliant with their prescribed medication (MPR <0.8). Predictors of non-compliance included prescription of a medication administered in multiple daily doses (p < 0.0001), a period of <2 years since the initial PD diagnosis (p = 0.0002), a diagnosis of gastrointestinal disorder (p < 0.0001), and a diagnosis of depression (p < 0.0001). Non-compliance was also found to be related to age, with a lower odds of non-compliance in patients aged 41-80 years than in patients aged >=81 years (p < 0.05). Although total drug mean costs were higher for compliant patients than non-compliant patients (driven mainly by the cost of PD-related medications), the mean costs associated with emergency room and inpatient visits were higher for patients non-compliant with their prescribed medication. Overall, the total all-cause annual healthcare mean cost was lower for compliant ($77,499) than for non-compliant patients ($84,949; p < 0.0001). CONCLUSION: Non-compliance is prevalent within the general USA PD population and is associated with a recent PD diagnosis, certain comorbidities, and multiple daily treatment dosing. Non-compliance may increase the burden on the healthcare system because of greater resource usage compared with the compliant population. Treatments that require fewer daily doses may have the potential to improve compliance, which in turn could reduce the economic burden associated with PD. PMID- 23649892 TI - A pilot discrete choice experiment to explore preferences for EQ-5D-5L health states. AB - BACKGROUND: The EQ-5D-5L has recently been developed to improve the sensitivity of the widely used three-level version. Valuation studies are required before the use of this new instrument can be adopted. The use of discrete choice experiments (DCEs) in this area is a promising area of research. PURPOSE: To test the plausibility and acceptability of estimating an Australian algorithm for the newly developed five-level version of the EQ-5D using a DCE. METHODS: A choice experiment was designed, consisting of 200 choice sets blocked such that each respondent answered 10 choice sets. Each choice set presented two health state duration combinations, and an immediate death option. The experiment was implemented in an online Australian-representative sample. A random-effects probit model was estimated. To explore the feasibility of the approach, an indicative algorithm was developed. The algorithm is transformed to a 0 to 1 scale suitable for use to estimate quality-adjusted life-year weights for use in economic evaluation. RESULTS: A total of 973 respondents undertook the choice experiment. Respondents were slightly younger and better educated than the general Australian population. Of the 973 respondents, 932 (95.8 %) completed all ten choice sets, and a further 12 completed some of the choice sets. In choice sets in which one health state-duration combination dominated another, the dominant option was selected on 89.5 % of occasions. The mean and median completion times were 17.9 and 9.4 min, respectively, exhibiting a highly skewed distribution. The estimation results are broadly consistent with the monotonic nature of the EQ-5D-5L. Utility is increasing in life expectancy (i.e., respondents tend to prefer health profiles with longer life expectancy), and mainly decreases in higher levels in each dimension of the instrument. A high proportion of respondents found the task clear and relatively easy to complete. CONCLUSIONS: DCEs are a feasible approach to the estimation of utility weights for more complex multi-attribute utility instruments such as the EQ-5D-5L. PMID- 23649894 TI - Exploring health professionals' experiences of medication errors in Saudi Arabia. AB - BACKGROUND: There is a paucity of literature originating from the Middle East on medication errors. OBJECTIVE: To explore the experiences of healthcare professionals around medication errors and medication error reporting. Setting Saudi Arabia. METHOD: Questionnaire survey of those attending medication error continuing education sessions. MAIN OUTCOME MEASURES: Experiences of medication errors in terms of number, type and severity in the preceding 12 months; barriers to reporting errors to health authorities; potential strategies to improve error reporting. RESULTS: Sixty-one (61/106, 57.5 %) questionnaires were completed. Thirty-five respondents (57.3 %) reported observing 51 errors during the preceding 12 months. Thirty-five errors (68.6 %) were described: wrong medication prescribed, dispensed or administered (11, 31.4 %); wrong dose prescribed (9, 25.7 %); inappropriate prescribing (issues of drug selection, monitoring) (9, 25.7 %); inappropriate route of administration (2), prescription duplication (2) and equipment failure (2). Patient outcomes resulting from these errors were described by the respondents as 'caused patient harm' in 14 instances. Three key barriers to reporting were: lack of awareness of the reporting policy; workload and time constraints associated with reporting; and unavailability of the reporting form. CONCLUSION: Findings indicate a potential need to review medication error reporting systems in Saudi Arabia to heighten health professional awareness and improve the reporting culture. PMID- 23649893 TI - Cost minimization of HLA-B*1502 screening before prescribing carbamazepine in Thailand. AB - BACKGROUND: Carbamazepine (CBZ) is broadly used for the treatment of epilepsy, neuropathic pain and other neurological diseases, owing to its effectiveness and low price. CBZ can induce Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). There are several studies that found an association between HLA B*1502 and CBZ-induced SJS/TEN, especially in people of Thai origin. In Thailand the prevalence of HLA-B*1502 was found to be in the range 8.1-14 %. OBJECTIVE: This study aimed to determine if screening for HLA-B*1502 in Thai patients who were to receive CBZ is cost effective. Setting Srinagarind Hospital, Khon Kaen University, Thailand. METHOD: A comparison between treatment cost of CBZ induced SJS/TEN and the HLAB*1502 screening costs in the Thai population. MAIN OUTCOME MEASURE: Comparison of the costs of treatment of CBZ induced SJS/TEN and costs of HLA-B*1502 screening test. Results When persons having the HLA-B*1502 allele receive CBZ, the chance of developing SJS/TEN is as high as 88.1 %, while persons without the HLA-B*1502 allele do not develop SJS/TEN. Therefore, a model was calculated to compare the cost of treatment between HLA-B*1502 testing before giving CBZ and if the patients were not tested for HLAB*1502. It was found that screening 100 patients before giving CBZ would save an amount of 98,549.94 baht per 100 cases of CBZ-prescribed patients. CONCLUSION: The screening for HLA B*1502 allele before giving carbamazepine is cost effective. The results of the present study may also apply to other populations if the HLA-B*1502 frequency is high enough. PMID- 23649895 TI - Molecular characterization of carbamoyl-phosphate synthetase (CPS1) deficiency using human recombinant CPS1 as a key tool. AB - The urea cycle disease carbamoyl-phosphate synthetase deficiency (CPS1D) has been associated with many mutations in the CPS1 gene [Haberle et al., 2011. Hum Mutat 32:579-589]. The disease-causing potential of most of these mutations is unclear. To test the mutations effects, we have developed a system for recombinant expression, mutagenesis, and purification of human carbamoyl-phosphate synthetase 1 (CPS1), a very large, complex, and fastidious enzyme. The kinetic and molecular properties of recombinant CPS1 are essentially the same as for natural human CPS1. Glycerol partially replaces the essential activator N-acetyl-l-glutamate (NAG), opening possibilities for treating CPS1D due to NAG site defects. The value of our expression system for elucidating the effects of mutations is demonstrated with eight clinical CPS1 mutations. Five of these mutations decreased enzyme stability, two mutations drastically hampered catalysis, and one vastly impaired NAG activation. In contrast, the polymorphisms p.Thr344Ala and p.Gly1376Ser had no detectable effects. Site-limited proteolysis proved the correctness of the working model for the human CPS1 domain architecture generally used for rationalizing the mutations effects. NAG and its analogue and orphan drug N-carbamoyl-l-glutamate, protected human CPS1 against proteolytic and thermal inactivation in the presence of MgATP, raising hopes of treating CPS1D by chemical chaperoning with N-carbamoyl-l-glutamate. PMID- 23649896 TI - Genetic analysis of inherited leukodystrophies: genotype-phenotype correlations in the CSF1R gene. AB - IMPORTANCE: The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. Recently, Rademakers and colleagues identified mutations in the CSF1R gene as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), offering the possibility for an in-life diagnosis. The detection of mutations in this gene in cases diagnosed with different clinical entities further demonstrated the difficulties in the clinical diagnosis of HDLS. OBJECTIVE: To better understand the genetic role of mutations in this gene, we sequenced a large cohort of adult-onset leukodystrophy cases. DESIGN: Whole-exome sequencing and follow up-screening by Sanger sequencing. SETTING: Collaborative study between the Institute of Neurology, University College London and the Inserm, Paris, France. PARTICIPANTS: A total of 114 probands, mostly European patients, with a diagnosis of adult-onset leukodystrophy or atypical cases that could fit within a picture of leukodystrophy. These included 3 extended families within the spectrum of leukodystrophy phenotype. INTERVENTIONS: Whole-exome sequencing in a family and Sanger sequencing of CSF1R. MAIN OUTCOMES AND MEASURES: Mutations in CSF1R. RESULTS: We identified 12 probands with mutations in CSF1R. The clinical diagnoses given to these patients included dementia with spastic paraplegia, corticobasal degeneration syndrome, and stroke disorders. Our study shows that CSF1R mutations are responsible for a significant proportion of clinically and pathologically proven HDLS. CONCLUSIONS AND RELEVANCE: These results give an indication of the frequency of CSF1R mutations in a European leukodystrophy series and expand the phenotypic spectrum of disorders that should be screened for this gene. PMID- 23649897 TI - Genome-wide organization and expression profiling of the NAC transcription factor family in potato (Solanum tuberosum L.). AB - NAC [no apical meristem (NAM), Arabidopsis thaliana transcription activation factor [ATAF1/2] and cup-shaped cotyledon (CUC2)] proteins belong to one of the largest plant-specific transcription factor (TF) families and play important roles in plant development processes, response to biotic and abiotic cues and hormone signalling. Our genome-wide analysis identified 110 StNAC genes in potato encoding for 136 proteins, including 14 membrane-bound TFs. The physical map positions of StNAC genes on 12 potato chromosomes were non-random, and 40 genes were found to be distributed in 16 clusters. The StNAC proteins were phylogenetically clustered into 12 subgroups. Phylogenetic analysis of StNACs along with their Arabidopsis and rice counterparts divided these proteins into 18 subgroups. Our comparative analysis has also identified 36 putative TNAC proteins, which appear to be restricted to Solanaceae family. In silico expression analysis, using Illumina RNA-seq transcriptome data, revealed tissue specific, biotic, abiotic stress and hormone-responsive expression profile of StNAC genes. Several StNAC genes, including StNAC072 and StNAC101that are orthologs of known stress-responsive Arabidopsis RESPONSIVE TO DEHYDRATION 26 (RD26) were identified as highly abiotic stress responsive. Quantitative real time polymerase chain reaction analysis largely corroborated the expression profile of StNAC genes as revealed by the RNA-seq data. Taken together, this analysis indicates towards putative functions of several StNAC TFs, which will provide blue-print for their functional characterization and utilization in potato improvement. PMID- 23649899 TI - Failure to account for selection-bias. PMID- 23649900 TI - Glycosyl-modified diporphyrins for in vitro and in vivo fluorescence imaging. AB - The application of probes for optical imaging is becoming popular as they have high safety and good biocompatibility. We prepared two kinds of glycosyl-modified diporphyrins, and their potentials as fluorescent probes were tested for the first time. After preparation of the glycosyl-modified porphyrin monomers, Ag promoted coupling of the monomers was used to obtain glucose-modified porphyrin dimer (GPD) and lactose-modified porphyrin dimer (LPD). The strong interaction between the two porphyrin rings achieves red-shifted emission, and thus circumvents autofluorescence and light-scattering in biological samples. Although the glycosylation improves solubility, it also yielded selective attachment to cell membranes, and to chorions of early developmental-stage zebrafish. Patch clamp experiments revealed the biocompatibility and low toxicity of GPD and LPD. Moreover, an in vivo imaging experiment provided direct evidence that zebrafish chorion contains sugar-binding proteins. The modification and derivatization make porphyrins potential bioimaging probes for specific optical imaging. PMID- 23649898 TI - Repression of global protein synthesis by Eif1a-like genes that are expressed specifically in the two-cell embryos and the transient Zscan4-positive state of embryonic stem cells. AB - Mouse embryonic stem (ES) cells are prototypical stem cells that remain undifferentiated in culture for long periods, yet maintain the ability to differentiate into essentially all cell types. Previously, we have reported that ES cells oscillate between two distinct states, which can be distinguished by the transient expression of Zscan4 genes originally identified for its specific expression in mouse two-cell stage embryos. Here, we report that the nascent protein synthesis is globally repressed in the Zscan4-positive state of ES cells, which is mediated by the transient expression of newly identified eukaryotic translation initiation factor 1A (Eif1a)-like genes. Eif1a-like genes, clustered on Chromosome 12, show the high sequence similarity to the Eifa1 and consist of 10 genes (Eif1al1-Eif1al10) and 9 pseudogenes (Eif1al-ps1-Eif1al-ps9). The analysis of the expressed sequence tag database showed that Eif1a-like genes are expressed mostly in the two-cell stage mouse embryos. Microarray analyses and quantitative real-time polymerase chain reaction analyses show that Eif1a-like genes are expressed specifically in the Zscan4-positive state of ES cells. These results indicate a novel mechanism to repress protein synthesis by Eif1a-like genes and a unique mode of protein synthesis regulation in ES cells, which undergo a transient and reversible repression of global protein synthesis in the Zscan4-positive state. PMID- 23649901 TI - Comparison of hyperpolarized (3)He and (129)Xe MRI for the measurement of absolute ventilated lung volume in rats. AB - PURPOSE: MRI using hyperpolarized noble gases, (3)He and (129)Xe, provides noninvasive assessments of lung structure and function. Previous work demonstrated that absolute ventilated lung volumes (aVLV) measured in rats using hyperpolarized (3)He agree well with micro-CT. METHODS: In this work, aVLV measurements were performed in rats using hyperpolarized (129)Xe MRI and compared with hyperpolarized (3)He measurements of aVLV under matched ventilation conditions. Whole-lung compliance was also determined. Partial volume, apparent diffusion coefficient, and effective transverse relaxation time corrections were applied during postprocessing to reduce bias between methods. RESULTS: Mean apparent diffusion coefficient of the trachea was 0.83 +/- 0.09 cm(2)/s and 0.067 +/- 0.011 cm(2)/s for (3)He and (129)Xe, respectively. Mean apparent diffusion coefficient of parenchyma was 0.21 +/- 0.07 cm(2)/s and 0.027 +/- 0.008 cm(2)/s for (3)He and (129)Xe, respectively. Mean transverse relaxation time values were 1.57 +/- 0.25 ms and 2.80 +/- 0.25 ms for (3)He and (129)Xe, respectively, in a model trachea and 3.18 +/- 1.00 ms and 4.88 +/- 0.60 ms for (3)He and (129)Xe, respectively, for lung parenchyma. Mean aVLV values were 7.07 +/- 0.67 mL and 6.99 +/- 1.00 mL at 14 cmH2O and 4.88 +/- 0.71 mL and 5.36 +/- 0.76 mL at 10 cmH2O obtained with (3)He and (129)Xe, respectively, demonstrating good agreement between (129)Xe and (3)He. CONCLUSIONS: (129)Xe offers an important alternative to (3)He for hyperpolarized gas MRI of aVLV in rats. PMID- 23649902 TI - Patient and carer views on participating in clinical trials for prodromal Alzheimer's disease and mild cognitive impairment. AB - OBJECTIVE: There is great interest in conducting clinical trials of disease modifying therapies in the prodromal (early, pre-dementia), asymptomatic stages of Alzheimer's disease. Diagnostic biomarker tests offer a means of identifying prodromal patients, but it is unclear how potential participants feel about their use. Deciding whether to take part in a clinical trial is a complex process in which eligible participants must balance risks and discomforts against uncertain benefits. We sought to explore the views of potential participants through qualitative research methods. METHODS: Focus groups with people with early memory problems, current and former family carers explored attitudes towards participating in clinical trials in the prodromal stages of the disease, using an example of anti-amyloid antibody-therapy (immunotherapy), which are currently in development. RESULTS: Despite the complexities involved, almost all participants had a clear idea about whether they, personally, would like to take part. Many were highly motivated to obtain an unambiguous diagnosis, regardless of their desire to participate in a clinical trial. Participants expressed minimal concern regarding the risk of adverse events associated with immunotherapy, whereas certain tests and trial procedures provoked greater anxiety. People with memory problems were found to assess the study demands in relation to their own priorities and circumstances. CONCLUSIONS: The priorities of patients might be different to clinicians and those who design and regulate clinical trials. Patient views can be used to inform the ethical debate around the disclosure of biomarker status, the design of clinical trials and the content of trial information. PMID- 23649904 TI - Universal electric-field-driven resistive transition in narrow-gap Mott insulators. AB - A striking universality in the electric-field-driven resistive switching is shown in three prototypical narrow-gap Mott systems. This model, based on key theoretical features of the Mott phenomenon, reproduces the general behavior of this resistive switching and demonstrates that it can be associated with a dynamically directed avalanche. This model predicts non-trivial accumulation and relaxation times that are verified experimentally. PMID- 23649903 TI - Association of height and pubertal timing with lipoprotein subclass profile: exploring the role of genetic and environmental effects. AB - OBJECTIVES: Little is known about the relationship between growth and lipoprotein profile. We aimed to analyze common genetic and environmental factors in the association of height from late childhood to adulthood and pubertal timing with serum lipid and lipoprotein subclass profile. METHODS: A longitudinal cohort of Finnish twin pairs (FinnTwin12) was analyzed using self-reported height at 11-12, 14, 17 years and measured stature at adult age (21-24 years). Data were available for 719 individual twins including 298 complete pairs. Serum lipids and lipoprotein subclasses were measured by proton nuclear magnetic resonance spectroscopy. Multivariate variance component models for twin data were fitted. Cholesky decomposition was used to partition the phenotypic covariation among traits into additive genetic and unique environmental correlations. RESULTS: In men, the strongest associations for both adult height and puberty were observed with total cholesterol, low-density lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, and low-density lipoprotein particle subclasses (max. r = -0.19). In women, the magnitude of the correlations was weaker (max. r = 0.13). Few associations were detected between height during adolescence and adult lipid profile. Early onset of puberty was related to an adverse lipid profile, but delayed pubertal development in girls was associated with an unfavorable profile, as well. All associations were mediated mainly by additive genetic factors, but unique environmental effects cannot be disregarded. CONCLUSIONS: Early puberty and shorter adult height relate to higher concentrations of atherogenic lipids and lipoprotein particles in early adulthood. Common genetic effects behind these phenotypes substantially contribute to the observed associations. PMID- 23649905 TI - Incremental health care utilization and costs for acute otitis media in children. AB - OBJECTIVES/HYPOTHESIS: Determine the incremental health care costs associated with the diagnosis and treatment of acute otitis media (AOM) in children. STUDY DESIGN: Cross-sectional analysis of a national health-care cost database. METHODS: Pediatric patients (age < 18 years) were examined from the 2009 Medical Expenditure Panel Survey. From the linked medical conditions file, cases with a diagnosis of AOM were extracted, along with comorbid conditions. Ambulatory visit rates, prescription refills, and ambulatory health care costs were then compared between children with and without a diagnosis of AOM, adjusting for age, sex, region, race, ethnicity, insurance coverage, and Charlson comorbidity Index. RESULTS: A total of 8.7 +/- 0.4 million children were diagnosed with AOM (10.7 +/ 0.4% annually, mean age 5.3 years, 51.3% male) among 81.5 +/- 2.3 million children sampled (mean age 8.9 years, 51.3% male). Children with AOM manifested an additional +2.0 office visits, +0.2 emergency department visits, and +1.6 prescription fills (all P <0.001) per year versus those without AOM, adjusting for demographics and medical comorbidities. Similarly, AOM was associated with an incremental increase in outpatient health care costs of $314 per child annually (P <0.001) and an increase of $17 in patient medication costs (P <0.001), but was not associated with an increase in total prescription expenses ($13, P = 0.766). CONCLUSIONS: The diagnosis of AOM confers a significant incremental health-care utilization burden on both patients and the health care system. With its high prevalence across the United States, pediatric AOM accounts for approximately $2.88 billion in added health care expense annually and is a significant health care utilization concern. PMID- 23649906 TI - Acidic saline-induced pain as a model for experimental masseter myalgia in healthy subjects. AB - BACKGROUND: Repeated injection of acidic saline into skeletal muscles of the leg in rodents induces a prolonged bilateral mechanical hyperalgesia that persists for up to 30 days and may be useful to model widespread muscle pain conditions. In this study, repeated injection of acidic (pH 3.3) saline solution into the masseter muscle of healthy human subjects was undertaken to determine if these injections are painful and whether they would induce a prolonged period of muscle sensitization to artificial and/or natural mechanical stimulation of the masseter and temporalis muscles. METHODS: Eighteen subjects (10 male, 8 female) participated in the study. Subjects received two injections of 0.5 mL acidic or regular isotonic saline 2 days apart, in a randomized, double blind, crossover design. RESULTS: There was no significant difference in pain intensity ratings when acidic saline injections were compared with regular saline injections. Pain area drawings were, however, significantly larger in response to the first injection of acidic saline than to the second injection of acidic saline or to either the first or second injection of regular saline. Repeated injection of acidic saline did not significantly alter pressure pain thresholds from the masseter or temporalis muscles on either the injected side or the opposite side over the 10-day post injection monitoring period. There was also no effect of injections on chewing. CONCLUSION: These findings indicate that, unlike in some rodent models, repeated injection of low pH solutions into jaw muscles of humans fails to induce a period of prolonged muscle hyperalgesia. PMID- 23649907 TI - Consciousness in dolphins? A review of recent evidence. AB - For millennia, dolphins have intrigued humans. Scientific study has confirmed that bottlenose dolphins are large-brained, highly social mammals with an extended developmental period, flexible cognitive capacities, and powerful acoustic abilities including a sophisticated echolocation system. These findings have led some to ask if dolphins experience aspects of consciousness. Recent investigations targeting self-recognition/self-awareness and metacognition, constructs tied to consciousness on some accounts, have analyzed the dolphin's ability to recognize itself in a mirror or on a video as well as to monitor its own knowledge in a perceptual categorization task. The current article reviews this work with dolphins and grapples with some of the challenges in designing, conducting, and interpreting these studies as well as with general issues related to studying consciousness in animals. The existing evidence does not provide a convincing case for consciousness in dolphins. For productive scientific work on consciousness in dolphins (and other animals including humans), we need clearer characterizations of consciousness, better methods for studying it, and appropriate paradigms for interpreting outcomes. A current focus on metamemory in animals offers promise for future discovery in this area. PMID- 23649908 TI - Communication in bottlenose dolphins: 50 years of signature whistle research. AB - Bottlenose dolphins (Tursiops truncatus) produce individually distinctive signature whistles that broadcast the identity of the caller. Unlike voice cues that affect all calls of an animal, signature whistles are distinct whistle types carrying identity information in their frequency modulation pattern. Signature whistle development is influenced by vocal production learning. Animals use a whistle from their environment as a model, but modify it, and thus invent a novel signal. Dolphins also copy signature whistles of others, effectively addressing the whistle owner. This copying occurs at low rates and the resulting copies are recognizable as such by parameter variations in the copy. Captive dolphins can learn to associate novel whistles with objects and use these whistles to report on the presence or absence of the object. If applied to signature whistles, this ability would make the signature whistle a rare example of a learned referential signal in animals. Here, we review the history of signature whistle research, covering definitions, acoustic features, information content, contextual use, developmental aspects, and species comparisons with mammals and birds. We show how these signals stand out amongst recognition calls in animals and how they contribute to our understanding of complexity in animal communication. PMID- 23649911 TI - The role of radiation in retroperitoneal sarcomas. AB - OPINION STATEMENT: Retroperitoneal sarcomas form a group of rare malignancies that require expertise in every aspect of management. Patients benefit from referral to cancer centers that can provide comprehensive, multidisciplinary, oncologic management. The role of radiation in retroperitoneal sarcoma management is, appropriately, the subject of considerable controversy due to the absence of high-level evidence proving its efficacy. Nonetheless, the preponderance of available data suggests that radiation therapy likely improves local control and, in some settings, may favorably impact resectability and survival. These outcome observations coupled with the lower doses (45-54 Gy) and normal tissue displacement characteristic of preoperative radiation therapy leads us to favor preoperative radiotherapy followed by oncologic resection for most retroperitoneal sarcomas. This strategy appears to provide the highest chance of safe and successful delivery of multimodal therapy, which can otherwise be hindered by postoperative complications as a result of technically challenging surgery and normal tissue radiation dose tolerances. Dose-escalation and selective integrative boosts to "at-risk" margins are attractive strategies that merit, and arguably require, further clinical evaluation. We believe that postoperative radiotherapy should be reserved for very high-risk cases and should be treated to a dose of >=60 Gy respecting normal tissue dose tolerances. An additional approach that we consider in the postoperative setting is close surveillance with consideration of preoperative radiotherapy at recurrence before repeat surgical resection. Highly conformal radiotherapy techniques, such as IMRT with image guidance, should be employed to minimize dose to normal tissues and thereby allow delivery of efficacious radiation doses. If feasible, referral to a treatment facility with proton beam therapy should be discussed with the patient, especially if normal tissue dose constraints cannot be met using IMRT/IGRT. Participation in prospective studies should be highly encouraged. PMID- 23649912 TI - Gene replacement and elimination using lambdaRed- and FLP-based tool to re-direct carbon flux in acetogen biocatalyst during continuous CO2/H2 blend fermentation. AB - A time- and cost-efficient two-step gene elimination procedure was used for acetogen Clostridium sp. MT1834 capable of fermenting CO2/H2 blend to 245 mM acetate (p < 0.005). The first step rendered the targeted gene replacement without affecting the total genome size. We replaced the acetate pta-ack cluster with synthetic bi-functional acetaldehyde-alcohol dehydrogenase (al-adh). Replacement of pta-ack with al-adh rendered initiation of 243 mM ethanol accumulation at the expense of acetate production during CO2/H2 blend continuous fermentation (p < 0.005). At the second step, al-adh was eliminated to reduce the genome size. Resulting recombinants accumulated 25 mM mevalonate in fermentation broth (p < 0.005). Cell duplication time for recombinants with reduced genome size decreased by 9.5 % compared to Clostridium sp. MT1834 strain under the same fermentation conditions suggesting better cell energy pool management in the absence of the ack-pta gene cluster in the engineered biocatalyst. If the first gene elimination step was used alone for spo0A gene replacement with two copies of synthetic formate dehydrogenase in recombinants with a shortened genome, mevalonate production was replaced with 76.5 mM formate production in a single step continuous CO2/H2 blend fermentation (p < 0.005) with cell duplication time almost nearing that of the wild strain. PMID- 23649913 TI - Teaching arrangements of carbohydrate metabolism in biochemistry curriculum in Peking University Health Science Center. AB - Biochemistry occupies a unique place in the medical school curricula, but the teaching of biochemistry presents certain challenges. One of these challenges is facilitating students' interest in and mastery of metabolism. The many pathways and modes of regulation can be overwhelming for students to learn and difficult for professors to teach in an engaging manner. The first chapter of the metabolism section in current Chinese biochemistry textbooks covers carbohydrate metabolism. Medical students usually complain about the difficulty of this subject. Here we discuss how to facilitate learning by rearranging the subjects in this introductory chapter of biochemical metabolism and to lay a solid foundation for future study. The strategy involves reorganizing the order in which subjects are taught from simple to complex and from short to long metabolic pathways. Most students taking the curriculum consider that the strategy engages their learning interests in biochemistry and enhances their learning outcomes. PMID- 23649915 TI - Prosocial motivation, stress and burnout among direct support workers. AB - AIM: This study explores whether the desire to engage in work that is beneficial to others moderates the effects of stress on burnout. METHOD: Based on a survey of 1570 direct support professionals in Ontario, this study conducted linear regression analyses and tested for the interaction effects of prosocial motivation on occupational stress and burnout. RESULTS: Prosocial motivation significantly moderated the association of emotional exhaustion (EE) and role boundary stress with depersonalization (DP). Prosocial motivation also moderated the effects of role ambiguity stress with a direct support worker's sense of personal accomplishment. In contrast, prosocial motivation magnified feelings of EE when interacted with a sense of personal accomplishment. CONCLUSIONS: Prosocial motivation plays an important role in explaining the relatively low levels of DP in the sector. The study advances our understanding of the key components of burnout among direct support workers. PMID- 23649914 TI - Abacavir pharmacogenetics--from initial reports to standard of care. AB - Abacavir is a nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus infection as part of a multidrug, highly active antiretroviral therapy regimen. Despite its efficacy, approximately 5% of individuals who receive abacavir develop an immune-mediated hypersensitivity reaction (HSR) that warrants immediate discontinuation of abacavir and switching to an alternative antiretroviral regimen. Abacavir HSR is associated with individuals who carry the *57:01 variant in the human leukocyte antigen B (HLA-B) gene. There is a large volume of evidence to show that those who carry HLA-B*57:01 are at significantly increased risk of developing HSR and should not receive abacavir. Pharmacogenetic screening to ensure individuals who carry HLA-B*57:01 do not receive abacavir can reduce the incidence of HSR and is now considered the standard of care before prescribing abacavir. Genetic testing to prevent abacavir HSR is currently one of the best examples of integrating pharmacogenetic testing into clinical practice. PMID- 23649916 TI - Endothelial cell adhesion molecule CD146: implications for its role in the pathogenesis of COPD. AB - CD146 is an adhesion molecule localized at endothelial cell junctions and facilitates cell-cell interactions. The circulating soluble form (sCD146) lacks both the intracellular and the transmembrane domains. In this study we show that CD146 expression was significantly decreased in the lung tissue of smokers with chronic obstructive pulmonary disease (COPD) and also in rats exposed to second hand smoke (SHS). Concurrently, levels of sCD146 were increased in both the plasma and bronchoalveolar lavage fluid (BALF) of COPD patients as well as in BALF from rats exposed to SHS. Decreased or abolished CD146 protein expression in rat pulmonary micro- and macrovascular endothelial cells was found after treatment with cigarette smoke extract (CSE), proinflammatory cytokine interleukin 18 (IL-18) or after silencing CD146 expression with siRNA. The decrease in CD146 protein was accompanied by increased endothelial monolayer permeability and enhanced macrophage infiltration in vitro. In CD146 knockout (KO) mice, distinct perivascular oedema was seen and increased numbers of inflammatory cells, along with increased protein levels in BALF. Increased sCD146 was found in BALF and plasma from patients with COPD. The circulating plasma levels of sCD146 correlated positively with the presence of anti-endothelial cell antibodies (AECAs). sCD146 in combination with AECAs may be useful markers for early detection of COPD. Our study indicates that loss of CD146 function damages pulmonary endothelial integrity. This damage may represent part of the pathophysiological processes that are involved in the basic aetiology of COPD/emphysema. PMID- 23649918 TI - Current prevention practice for venous thromboembolism in Japanese intensive care units. AB - Venous thromboembolism (VTE) is a well-recognized life-threatening complication in the intensive care unit (ICU). However, no data have been reported regarding the prevalence and methods of prevention of VTE in Japanese ICUs. This study aimed to document the current practice of VTE prevention across a broad sample of medical-surgical ICU patients in Japan. In November 2010, we performed a point prevalence survey of Japanese ICUs in training facilities for intensive care specialists. We recorded data from five consecutive ICU patients in each facility at any time on the day of the survey. A total of 470 patients were registered in this study. VTE prophylaxis was received by 85.3 % of participants. Of these, 69.8 % received mechanical prophylaxis and 12.5 % received pharmacological methods, with 17.7 % receiving both methods. Analyzing a comparison of the presence or absence of a hospital prevention protocol, the protocol group had higher rates of receiving prophylaxis (88.8 % vs. 80.0 %, P < 0.01) than the no protocol group. In conclusion, VTE prophylaxis by mechanical methods was the main method in a high number of medical-surgical ICU patients in Japan. The ICUs with a hospital VTE prevention protocol in place performed significantly higher rates of prophylaxis than those without a protocol. PMID- 23649917 TI - Is microvascular decompression surgery a high risk for postoperative nausea and vomiting in patients undergoing craniotomy? AB - PURPOSE: Patients undergoing microvascular decompression surgery often experience postoperative nausea and vomiting (PONV). However, there is little information about the incidence of PONV after microvascular decompression. We hypothesized that microvascular decompression is an especially high-risk procedure for PONV in patients undergoing neurosurgery, and investigated risk factors related to PONV after neurosurgery. METHODS: All patients who underwent craniotomy in our institution during a period of 2 years were investigated retrospectively. Medical charts were reviewed to identify PONV during the 24-h postoperative period and related risk factors. Multivariate logistic regression analysis was conducted to elucidate the impact of microvascular decompression on PONV after craniotomy. RESULTS: Among 556 craniotomy cases, 350 patients met the inclusion criteria. Multivariate logistic regression analysis showed that microvascular decompression was an independent risk factor for PONV after craniotomy (odds ratio 5.38, 3.02 9.60), in addition to female gender, non-smoker status, amount of intraoperative fentanyl administered, and cerebrovascular surgery. CONCLUSION: In this retrospective study, microvascular decompression surgery was an especially high risk factor for PONV in patients undergoing craniotomy. It may be necessary to adopt a combination of prophylactic methods to reduce the incidence of PONV after microvascular decompression. PMID- 23649919 TI - Efficacy of endotracheal lidocaine administration with continuous infusion of remifentanil for attenuating tube-induced coughing during emergence from total intravenous anesthesia. AB - PURPOSE: Although attenuation of tube-induced coughing is necessary in specific types of surgery, the best method for such attenuation is still unclear. We studied the combined intervention of endotracheal lidocaine and intravenous remifentanil compared to intravenous remifentanil alone with respect to coughing during emergence from anesthesia. METHODS: We examined 60 ASA 1-2 patients (age, 20-69 years) undergoing tympanoplasty under general anesthesia. Anesthesia was induced with propofol, remifentanil, and rocuronium. The trachea was intubated using a laryngotracheal instillation of topical anaesthetic (LITA) tracheal tube. Anesthesia was maintained with propofol and remifentanil (0.1-0.3 MUg/kg/min). Propofol was discontinued and remifentanil (0.1 MUg/kg/min) was continued at the end of the operation. Patients were randomly allocated to the lidocaine (n = 30) and control groups (n = 30). We administered 3 ml 4 % lidocaine via the LITA tube to patients in lidocaine group at the end of the operation. The trachea was extubated when the patient regained consciousness and followed orders. Coughing was evaluated using a 4-point scale by an observer who examined the video records at extubation. RESULTS: Fewer patients in lidocaine group (8 of 30) than in control group (18 of 30, p < 0.01) coughed. Fewer patients in lidocaine group (2 of 30) than in control group (12 of 30, p < 0.01) had moderate or severe cough (scale 2 or 3). CONCLUSIONS: This study is consistent with the finding that endotracheal lidocaine administration and continuous infusion of remifentanil before extubation is useful to prevent coughing on emergence from anesthesia. PMID- 23649920 TI - Application of PEEP using the i-gel during volume-controlled ventilation in anesthetized, paralyzed patients. AB - PURPOSE: This prospective, randomized trial was designed to assess whether the i gel supraglottic airway device is suitable for volume-controlled ventilation while applying positive end-expiratory pressure (PEEP) of 5 cmH(2)O under general anesthesia. It was believed that this device might improve arterial oxygenation. METHODS: Forty adult patients (aged 20-60 years) scheduled for elective orthopedic surgery were enrolled in this study. Twenty patients were ventilated without external PEEP [zero positive end-expiratory pressure (ZEEP) group], and the other 20 were ventilated with PEEP 5 cmH(2)O (PEEP group) after placing an i gel device. Volume-controlled ventilation at a tidal volume (TV) of 8 ml/kg of ideal body weight, leak volume, and arterial blood gas analysis were investigated. RESULTS: The incidences of a significant leak were similar in the ZEEP and PEEP groups (3/20 and 1/20, respectively; P = 0.605), as were leak volumes. No significant PaO(2) difference was observed between the two groups at 1 h after satisfactory i-gel insertion (215 +/- 38 vs. 222 +/- 54; P = 0.502). CONCLUSIONS: The use of an i-gel during PEEP application at 5 cmH(2)O did not increase the incidence of a significant air leak, and a PEEP of 5 cmH(2)O failed to improve arterial oxygenation during controlled ventilation in healthy adult patients. PMID- 23649921 TI - Water-induced pyroelectricity from nonpolar crystals of amino acids. PMID- 23649922 TI - Tricycles by a new Ugi variation and Pictet-Spengler reaction in one pot. AB - Subsequent mild cyclization of aromatic substrates by Pictet-Spengler condensation stereoselectively gave new tricyclic compounds. Examples are described in decent yields over two steps in one pot, and a crystal structure is also presented to support the proposed structures. PMID- 23649923 TI - Accuracy validation of incident photon fluence on DQE for various measurement conditions and X-ray units. AB - Detective quantum efficiency (DQE) is widely used as a comprehensive metric for X ray image evaluation in digital X-ray units. The incident photon fluence per air kerma (SNR2(in)) is necessary for calculating the DQE. The International Electrotechnical Commission (IEC) reports the SNR2(in) under conditions of standard radiation quality, but this SNR2(in) might not be accurate as calculated from the X-ray spectra emitted by an actual X-ray tube. In this study, we evaluated the error range of the SNR2(in) presented by the IEC62220-1 report. We measured the X-ray spectra emitted by an X-ray tube under conditions of standard radiation quality of RQA5. The spectral photon fluence at each energy bin was multiplied by the photon energy and the mass energy absorption coefficient of air; then the air kerma spectrum was derived. The air kerma spectrum was integrated over the whole photon energy range to yield the total air kerma. The total photon number was then divided by the total air kerma. This value is the SNR2(in). These calculations were performed for various measurement parameters and X-ray units. The percent difference between the calculated value and the standard value of RQA5 was up to 2.9%. The error range was not negligibly small. Therefore, it is better to use the new SNR2(in) of 30694 (1/(mm(2) MUGy)) than the current [Formula: see text] of 30174 (1/(mm(2) MUGy)). PMID- 23649924 TI - Simultaneous assay for ten bacteria and toxins in spiked clinical samples using a microflow cytometer. AB - Bacterial infection and intoxication can present with common symptoms. The ability to identify a bacteria or toxin rapidly in clinical samples is critical for administering the appropriate treatment. The microflow cytometer has previously demonstrated the ability to test for six bacteria and toxins simultaneously in buffer. In this study, the number of bacteria and toxins analyzed was increased to ten, positive and negative controls were incorporated in all assays, and most importantly, multiplexed immunoassays were demonstrated in clinical matrices. The multiplexed assays using the microflow cytometer demonstrated detection limits similar to or better than other reported antibody based methods for pathogen detection (ELISA, lateral flow, array biosensors). In most cases, detection from complex clinical matrices (serum and nasal wash) achieved limits of detection equivalent to those for spiked buffer samples. Clinical samples spiked with bacteria and/or toxins were also analyzed successfully in blind trials. PMID- 23649925 TI - Optimization of malaria detection based on third harmonic generation imaging of hemozoin. AB - The pigment hemozoin is a natural by-product of the metabolism of hemoglobin by the parasites which cause malaria. Previously, hemozoin was demonstrated to have a very high nonlinear optical response enabling third harmonic generation (THG) imaging. In this study, we present a complete characterization of the nonlinear THG response of natural hemozoin in malaria-infected red blood cells, as well as in pure isostructural synthesized hematin anhydride, in order to determine optimal imaging parameters for detection. Our study demonstrates the wavelength range for optimal pulsed femtosecond laser excitation of THG from hemozoin crystals. In addition, we show the hemozoin crystal detection as a function of crystal size, incident laser power, and the emission response of the hemozoin crystals to different incident laser polarization states. Our systematic measurements of the nonlinear optical response from hemozoin establish detection limits, which are essential for the optimal design of malaria detection technologies that exploit the THG response of hemozoin. PMID- 23649926 TI - Preparation of homogeneous samples of double-labelled protein suitable for single molecule FRET measurements. AB - Preparation of pure and homogenous site specifically single- and double-labelled biopolymers suitable for spectroscopic determination of structural characteristics is a major current challenge in biopolymers chemistry. In particular, proper analysis of single-molecule Forster resonance energy transfer measurements is based on the spectral characteristics of the probes. Heterogeneity of any of the probes may introduce errors in the analysis, and hence, care must be taken to avoid preparation of inhomogeneous labelled biopolymer samples. When we prepared samples of Escherichia coli adenylate kinase (AK) mutants labelled with either Atto 488 or Atto 647N, the products were spectrally inhomogeneous and the composition of the mixture changed gradually over time. We show here that the inhomogeneity was not a result of variation in the dye interaction with neighbouring side chains. Rather, the slow drift of the spectral characteristics of the probes was a characteristic of an irreversible chemical transformation probably due to the hydrolysis of the succinimide ring of the attached dye into its succinamic acid form. Overnight incubation of the labelled protein in mild basic solution accelerated the interconversion, yielding homogeneous labelled samples. Using this procedure, we obtained stable homogenous AK mutant labelled at residues 142 and 188. PMID- 23649927 TI - Interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK) and the estrogen receptor activities in regulating rat pituitary tumor cell (GH3) growth in vitro. AB - Estrogen receptor alpha has a role in regulating rat somatolactotroph tumor cell growth (GH3 cells). AMP-activated protein kinase (AMPK) is a metabolic checkpoint which is able to negatively regulate intracellular signaling downstream of growth factors receptors in conditions increasing cellular AMP levels. We have recently reported on the role of AMPK activation in affecting viability and proliferation of GH3 cells. In the present study, we investigated the interplay between ER- and AMPK-pathways. Results can be regarded as relevant to the development of novel multi-targeted pharmacological therapies against pituitary tumors. We confirmed that estradiol (E2) and the ER antagonist fulvestrant exert stimulatory and inhibitory effects, respectively on GH3 cell growth in a competitive manner. The upstream kinase LKB1 is known to phosphorylate and activate AMPK. Here we showed that neither E2 nor fulvestrant caused a downregulation of LKB1 expression and phospho-AMPK levels in GH3 cells. Actually, fulvestrant strongly reduced the phosphorylation of ACC, which is a direct target of AMPK and a known index of AMPK activity. 2-deoxyglucose, a compound reducing glucose utilization, caused an increase in AMPK activity vs baseline and was able to hinder the stimulatory effect of E2 on cell viability, confirming that the exposure of GH3 cells to estrogens does not prevent them from being responsive to the inhibitory activity of compounds activating AMPK. Finally, the AMPK activator AICAR (AMP analog) did not cause further decrease in cell viability in the course of co-treatments with fulvestrant versus fulvestrant alone, in agreement with impaired phospho-AMPK activity in the presence of the anti-estrogen. PMID- 23649929 TI - A sensitive method for the determination of levamisole in serum by electrochemiluminescence. AB - A novel method was developed for the determination of levamisole by electrochemiluminescence. The method was based on electrochemiluminescence signal enhancement produced by Ru(bpy)(3)(2+), which reacted with the tertiary amine group of levamisole on a platinum electrode in 12 mmol/L borate buffer (pH 9). A linear relationship between the luminous intensity and concentration of levamisole in the range 0-1 * 10(-7) mol/L was obtained and the detection limit was 1.76 * 10(-11) mol/L. The method is sensitive, selective, simple and convenient. The method has been successfully applied to the analysis of levamisole in serum. PMID- 23649930 TI - Is head and neck melanoma different from trunk and extremity melanomas with respect to sentinel lymph node status and clinical outcome? AB - BACKGROUND: Previous studies showed conflicting and inconsistent results regarding the effect of anatomic location of the melanoma on sentinel lymph node (SLN) positivity and/or survival. This study was conducted to evaluate and compare the effect of the anatomic locations of primary melanoma on long-term clinical outcomes. METHODS: All consecutive cutaneous melanoma patients (n=2,079) who underwent selective SLN dissection (SLND) from 1993 to 2009 in a single academic tertiary-care medical center were included. SLN positive rate, disease free survival (DFS), and overall survival (OS) were determined. Kaplan-Meier survival, univariate, and multivariate analyses were performed to determine predictive factors for SLN status, DFS, and OS. RESULTS: Head and neck melanoma (HNM) had the lowest SLN-positive rate at 10.8% (16.8% for extremity and 19.3% for trunk; P=0.002) but had the worst 5-year DFS (P<0.0001) and 5-year OS (P<0.0001) compared with other sites. Tumor thickness (P<0.001), ulceration (P<0.001), HNM location (P=0.001), mitotic rate (P<0.001), and decreasing age (P<0.001) were independent predictive factors for SLN-positivity. HNM with T3 or T4 thickness had significantly lower SLN positive rate compared with other locations (P<=0.05). Also, on multivariate analysis, HNM location versus other anatomic sites was independently predictive of decreased DFS and OS (P<0.001). By Kaplan-Meier analysis, HNM was associated significantly with the worst DFS and OS. CONCLUSIONS: Primary melanoma anatomic location is an independent predictor of SLN status and survival. Although HNM has a decreased SLN-positivity rate, it shows a significantly increased risk of recurrence and death as compared with other sites. PMID- 23649928 TI - Functional analysis of a de novo ACTB mutation in a patient with atypical Baraitser-Winter syndrome. AB - Exome sequence analysis can be instrumental in identifying the genetic etiology behind atypical disease. We report a patient presenting with microcephaly, dysmorphic features, and intellectual disability with a tentative diagnosis of Dubowitz syndrome. Exome analysis was performed on the patient and both parents. A de novo missense variant was identified in ACTB, c.349G>A, p.E117K. Recent work in Baraitser-Winter syndrome has identified ACTB and ACTG1 mutations in a cohort of individuals, and we rediagnosed the patient with atypical Baraitser-Winter syndrome. We performed functional characterization of the variant actin and show that it alters cell adhesion and polymer formation supporting its role in disease. We present the clinical findings in the patient, comparison of this patient to other patients with ACTB/ACTG1 mutations, and results from actin functional studies that demonstrate novel functional attributes of this mutant protein. PMID- 23649931 TI - Gd-EOB-DTPA-enhanced MRI is better than MDCT in decision making of curative treatment for hepatocellular carcinoma. AB - BACKGROUND: We assessed the change in the therapeutic decision among curative treatments after adding Gd-EOB-DTPA-enhanced MRI to triple-phase MDCT for patients with early-stage HCC. METHODS: This study retrospectively investigated two groups: 33 pathologically confirmed HCC patients after liver transplantation in group 1; 34 HCC patients without pathology in group 2. In group 1, we simulated the therapeutic decision-making process by pretransplant MDCT and Gd EOB-DTPA-enhanced MRI. In group 2, including the 34 early-stage HCC patients consecutively enrolled, we investigated the change of therapeutic decision after adding Gd-EOB-DTPA-enhanced MRI to MDCT. RESULTS: In the simulation from group 1, after adding Gd-EOB-DTPA-enhanced MRI, 33.3% (11/33 patients) of treatment decisions were changed from the decision based on MDCT alone. Among 22 patients considered eligible for resection and 33 patients for radiofrequency ablation, the therapeutic decision was changed for 10 patients in the surgical group and 4 patients for the RFA group (45.5 and 12.1%). In group 2, the rate of change in the therapeutic decision after adding Gd-EOB-DTPA-enhanced MRI to MDCT was 41.2% (14/34 patients). In group 1 with explants pathology, the median diameter of HCCs not detected by MDCT but detected by Gd-EOB-DTPA-enhanced MRI was 1.15 cm (0.3 3.0 cm). The median diameter of HCCs seen only in the explanted liver was 1.0 cm (0.3-1.7 cm), and 60.7% of them were well-differentiated HCCs. CONCLUSIONS: This study suggests that performing Gd-EOB-DTPA-enhanced MRI before deciding on curative treatment for early-stage HCC may improve the accuracy of treatment decision for early-stage HCC. PMID- 23649932 TI - Surgery for the intact primary and stage IV breast cancer...lacking "robust evidence". PMID- 23649933 TI - The late-phase inflammatory response after drug-eluting stent implantation. AB - Recent advances in drug-eluting stent (DES) technology have succeeded in preventing restenosis. In addition to inhibiting smooth muscle cell proliferation, DES greatly inhibits the local inflammatory response in the acute phase after implantation, leading to prevention of restenosis. However, a unique issue in DES implantation is an impairment of reendothelialization, which may result in abnormal wound healing. Consequently, a late-phase inflammatory relapse could appear in the long term after DES implantation. In this study, we measured serum levels of inflammatory markers, including interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, matrix metalloproteinase-9, and myeloperoxidase, as well as high-sensitivity C-reactive protein at follow-up coronary angiography (mean 9 months) in 54 patients who received DES stenting who did not experience restenosis, and compared them with 51 patients receiving bare-metal stents (BMS) without restenosis. The level of IL 6 was over the measurement threshold (>=2.22 pg/ml) in 12 patients (21 %) in the DES group, but in only 2 patients (4 %) in the BMS group (P = 0.003). IL-8 was significantly higher in the DES group than in the BMS group (4.51 +/- 2.40 vs 3.84 +/- 1.34 pg/ml, P = 0.015). The levels of other biomarkers were similar between the two groups. DES showed an increase in inflammatory cytokines in the late phase after implantation in comparison with patients who received BMS, suggesting late-stage inflammation. Therefore, the wound-healing response after DES implantation might be different from that after BMS. PMID- 23649935 TI - Physicochemical and functional comparability between the proposed biosimilar rituximab GP2013 and originator rituximab. AB - BACKGROUND: Regulatory approval for a biosimilar product is provided on the basis of its comparability to an originator product. A thorough physicochemical and functional comparability exercise is a key element in demonstrating biosimilarity. Here we report the characterization of a proposed biosimilar rituximab (GP2013) and originator rituximab. OBJECTIVE: To compare GP2013 with originator rituximab using an extensive array of routine analytical and extended characterization methods. METHODS: Primary and higher order protein structures were analyzed using a variety of methods that included high-performance liquid chromatography electrospray ionization mass spectrometry (HPLC-ESI-MS), peptide mapping with UV and MS detection, circular dichroism (CD), Fourier transform infrared (FTIR) spectroscopy, hydrogen deuterium exchange (HDX) MS, 1D (1)H nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography and differential scanning calorimetry (DSC). Charge and amino acid modifications were assessed using cation exchange chromatography (CEX) and peptide mapping using reversed-phase (RP) HPLC. Boronate affinity chromatography was used to determine the relative amount of glycation. Glycans were identified and quantified after 2 aminobenzamide (2-AB) labeling and separation using normal phase HPLC with fluorescence and MS detection, respectively. Glycan site occupancy was determined using reducing capillary electrophoresis with sodium dodecyl sulfate (CE-SDS). Size heterogeneity was determined using reducing and non-reducing CE-SDS, size exclusion chromatography (SEC) and asymmetric flow field flow fractionation (AF4). Biological characterization included a series of bioassays (in vitro target binding, antibody-dependent cell-mediated cytotoxicity [ADCC], complement dependent cytotoxicity [CDC] and apoptosis) and surface plasmon resonance (SPR) Fc receptor binding assays. RESULTS: Intact mass analysis of GP2013 and the heavy and light chains using RP HPLC-ESI-MS revealed the expected molecular mass of rituximab. The amino acid sequence was shown to be identical between GP2013 and the originator rituximab. Further sequence confirmation using RP-HPLC-UV/MS peptide mapping showed non-distinguishable chromatograms for Lys-C digested GP2013 and originator rituximab. The higher order structure of GP2013 was shown to be indistinguishable from originator rituximab using a large panel of redundant and orthogonal methods. GP2013 and originator rituximab were comparable with regard to charge variants, specific amino acid modifications and the glycan pattern. GP2013 was also shown to have similar purity, aggregate and particle levels when compared with the originator. Functionally, and by using a comprehensive set of bioassays and binding assays covering a broad range of rituximab's functional activities, GP2013 could not be distinguished from originator rituximab. CONCLUSION: GP2013 was shown to be physicochemically highly similar to originator rituximab at the level of primary and higher order structure, post-translational modifications and size variants. An extensive functional characterization package indicated that GP2013 has the same biological properties as originator rituximab. PMID- 23649936 TI - Canakinumab: a guide to its use in acute gouty arthritis flares. AB - Canakinumab (Ilaris(r)), an anti-interleukin-1beta monoclonal antibody, is a novel approach to treat acute gouty arthritis flares in a targeted population of patients in whom treatment options are limited. Relative to on-demand treatment with intramuscular triamcinolone acetonide 40 mg, on-demand treatment with subcutaneous canakinumab 150 mg significantly relieved the pain and inflammation of a new gout flare, and reduced the risk of new flares in patients with acute gouty arthritis flares in whom standard treatment with non-steroidal anti inflammatories and/or colchicine was inappropriate. Canakinumab has an acceptable tolerability profile in this difficult-to-treat population. The increased risk of infections and neutropenia associated with canakinumab treatment can be minimized by following the recommended precautions. PMID- 23649934 TI - Presynaptic pH and vesicle fusion in Drosophila larvae neurones. AB - Both intracellular pH (pHi) and synaptic cleft pH change during neuronal activity yet little is known about how these pH shifts might affect synaptic transmission by influencing vesicle fusion. To address this we imaged pH- and Ca(2+) sensitive fluorescent indicators (HPTS, Oregon green) in boutons at neuromuscular junctions. Electrical stimulation of motor nerves evoked presynaptic Ca(2+) i rises and pHi falls (~0.1 pH units) followed by recovery of both Ca(2+) i and pHi. The plasma-membrane calcium ATPase (PMCA) inhibitor, 5(6)-carboxyeosin diacetate, slowed both the calcium recovery and the acidification. To investigate a possible calcium-independent role for the pHi shifts in modulating vesicle fusion we recorded post-synaptic miniature end-plate potential (mEPP) and current (mEPC) frequency in Ca(2+) -free solution. Acidification by propionate superfusion, NH(4)(+) withdrawal, or the inhibition of acid extrusion on the Na(+)/H(+) exchanger (NHE) induced a rise in miniature frequency. Furthermore, the inhibition of acid extrusion enhanced the rise induced by propionate addition and NH(4)(+) removal. In the presence of NH(4)(+), 10 out of 23 cells showed, after a delay, one or more rises in miniature frequency. These findings suggest that Ca(2+) -dependent pHi shifts, caused by the PMCA and regulated by NHE, may stimulate vesicle release. Furthermore, in the presence of membrane permeant buffers, exocytosed acid or its equivalents may enhance release through positive feedback. This hitherto neglected pH signalling, and the potential feedback role of vesicular acid, could explain some important neuronal excitability changes associated with altered pH and its buffering. PMID- 23649938 TI - Ataxia-telangiectasia-mutated protein expression with microsatellite instability in gastric cancer as prognostic marker. AB - The prognostic significance of ataxia-telangiectasia-mutated (ATM) expression in gastric cancer remains unclear. The functional loss of ATM gene exhibits a biologic correlation with microsatellite instability (MSI). In this study, we investigated the significance of ATM expression with MSI by evaluating gastric cancer patients who had underwent curative resection. ATM expression was classified into low ATM expression (-, +/-, +) and high ATM expression (++, +++) using immunohistochemistry analysis. MSI status was classified as MSI-negative (MSS, MSI-low) and MSI-positive (MSI-high). Of 321 patients, 205 (63.9%) exhibited low ATM expression and 116 (36.1%) exhibited high ATM expression. Low ATM expression was more frequently identified in patients of older age, more advanced stage and with MSI-positive tumor (p = 0.025, p = 0.001 and p = 0.014, respectively). The probability of 5-year disease-free survival (DFS) and overall survival (OS) was lower in low ATM expression group compared with the high ATM expression group (DFS: 62.5%, 76.4%, p = 0.017, OS: 65.9%, 78.5%, p = 0.027, respectively). According to MSI status, a subgroup of MSI-negative and low ATM expression cases exhibited the worst prognosis for DFS and OS; this subgroup also exhibited poorer DFS according to multivariable analysis (hazard radio = 1.8, 95% confidence interval, 1.2-2.8, p = 0.010), although prognostic value of ATM expression alone did not remain in the multivariable analysis. Taken together, these findings indicate that ATM expression with MSI status is an independent factor for gastric cancer prognosis in gastric cancer patients who received curative surgery. PMID- 23649939 TI - The sensitivity of backscattering coefficients to elastic scattering cross sections and electron stopping powers. AB - The sensitivity of Monte Carlo estimates of backscattering coefficients eta to the accuracy of their input data is examined by studying the percentage change in eta due to changes of 10% and 20% in the differential elastic scattering cross section dsigma/dOmega and corresponding changes in the stopping power S(E) in the primary energy range 200-10,000 eV. To a good approximation equivalent elastic and inelastic scattering changes produce equal and opposite shifts in eta, a result consistent with predictions of transport theory. For medium to high atomic numbers an x% error in the specification of either S(E) or dsigma/dOmega produces a percentage change in eta significantly less than x%, while at low atomic number Deltaeta/eta increases approximately linearly with ln E so that Monte Carlo predictions are then more sensitive to parameter precision at high energy. PMID- 23649940 TI - Bacterium induces cryptic meroterpenoid pathway in the pathogenic fungus Aspergillus fumigatus. AB - Stimulating encounter: The intimate, physical interaction between the soil derived bacterium Streptomyces rapamycinicus and the human pathogenic fungus Aspergillus fumigatus led to the activation of an otherwise silent polyketide synthase (PKS) gene cluster coding for an unusual prenylated polyphenol (fumicycline A). The meroterpenoid pathway is regulated by a pathway-specific activator gene as well as by epigenetic factors. PMID- 23649937 TI - Cationic host defence peptides: potential as antiviral therapeutics. AB - There is a pressing need to develop new antiviral treatments; of the 60 drugs currently available, half are aimed at HIV-1 and the remainder target only a further six viruses. This demand has led to the emergence of possible peptide therapies, with 15 currently in clinical trials. Advancements in understanding the antiviral potential of naturally occurring host defence peptides highlights the potential of a whole new class of molecules to be considered as antiviral therapeutics. Cationic host defence peptides, such as defensins and cathelicidins, are important components of innate immunity with antimicrobial and immunomodulatory capabilities. In recent years they have also been shown to be natural, broad-spectrum antivirals against both enveloped and non-enveloped viruses, including HIV-1, influenza virus, respiratory syncytial virus and herpes simplex virus. Here we review the antiviral properties of several families of these host peptides and their potential to inform the design of novel therapeutics. PMID- 23649941 TI - The TRIPSE: a process-oriented exam for large undergraduate classes. AB - The TRIPSE (tri-partite problem solving exercise), a process-oriented exam that mimics the scientific process, was used previously in small classes (15-25). Provided limited data, students frame explanations and design experimental tests that they later revise with additional information. Our 6-year experience using it with larger numbers (155-204) in a freshman biology course, suggests that it could provide a means of assessing individual student performance. Students rated the learning value of this experience to be significantly higher than a standard MCQ on a 10-point scale (TRIPSEs 8.2, CI 8.1/8.4 vs. MCQs 4.9, CI 4.8/5.1, n = 712). Additionally, we tested one cohort (n = 146) with a group TRIPSE (groups of 6), and found that this variant also provided a valuable learning experience (8.0, CI 7.7/8.3). PMID- 23649943 TI - Perioperative process errors and delays in otolaryngology at a Veterans Hospital: prospective study. AB - OBJECTIVES/HYPOTHESIS: To understand the leading causes for process errors and delays in the otolaryngology operating room and recognize the impact of process errors and delays on patient safety, operating room resources and hospital costs. STUDY DESIGN: Prospective, observational study. METHODS: A 4-week study was conducted during 1 calendar month in 2012, evaluating 23 elective otolaryngology cases. A standardized data collection tool was developed and refined based on prestudy pilot observations. Two trained observers recorded relevant times and actions from patient check-in time in the preoperative holding area to the "wheels out" time. RESULTS: The mean case observation time was 220.0 +/- 167.8 minutes, with mean duration of operation length being 107.0 +/- 146.2 minutes. The perioperative period was divided into six stages: patient holding, room preparation, preintubation, postintubation, intraoperative, and postextubation. One hundred process errors were recorded (average of 4.3 per case), 34% of which were due to communication failures. Forty delays were observed, resulting in 336 minutes of standstill delay. Again, communication failures represented the most common etiology, with 17 communication failures resulting in 146 minutes of standstill delay. The preintubation stage was most affected by delay, with 1 in 6 minutes comprising standstill delay. CONCLUSION: Process errors and significant delays were common in cases performed at our institution; communication errors were the most common etiology. There is opportunity for preoperative team discussion and the use of technology to minimize communication-related process errors and standstill delays. Further work is currently being undertaken to study this critical issue across specialties. PMID- 23649942 TI - ESPIRiT--an eigenvalue approach to autocalibrating parallel MRI: where SENSE meets GRAPPA. AB - PURPOSE: Parallel imaging allows the reconstruction of images from undersampled multicoil data. The two main approaches are: SENSE, which explicitly uses coil sensitivities, and GRAPPA, which makes use of learned correlations in k-space. The purpose of this work is to clarify their relationship and to develop and evaluate an improved algorithm. THEORY AND METHODS: A theoretical analysis shows: (1) The correlations in k-space are encoded in the null space of a calibration matrix. (2) Both approaches restrict the solution to a subspace spanned by the sensitivities. (3) The sensitivities appear as the main eigenvector of a reconstruction operator computed from the null space. The basic assumptions and the quality of the sensitivity maps are evaluated in experimental examples. The appearance of additional eigenvectors motivates an extended SENSE reconstruction with multiple maps, which is compared to existing methods. RESULTS: The existence of a null space and the high quality of the extracted sensitivities are confirmed. The extended reconstruction combines all advantages of SENSE with robustness to certain errors similar to GRAPPA. CONCLUSION: In this article the gap between both approaches is finally bridged. A new autocalibration technique combines the benefits of both. PMID- 23649944 TI - Large zeolite H-ZSM-5 crystals as models for the methanol-to-hydrocarbons process: bridging the gap between single-particle examination and bulk catalyst analysis. AB - The catalytic, deactivation, and regeneration characteristics of large coffin shaped H-ZSM-5 crystals were investigated during the methanol-to-hydrocarbons (MTH) reaction at 350 and 500 degrees C. Online gas-phase effluent analysis and examination of retained material thereof were used to explore the bulk properties of large coffin-shaped zeolite H-ZSM-5 crystals in a fixed-bed reactor to introduce them as model catalysts for the MTH reaction. These findings were related to observations made at the individual particle level by using polarization-dependent UV-visible microspectroscopy and mass spectrometric techniques after reaction in an in situ microspectroscopy reaction cell. Excellent agreement between the spectroscopic measurements and the analysis of hydrocarbon deposits by means of retained hydrocarbon analysis and time-of-flight secondary-ion mass spectrometry of spent catalyst materials was observed. The obtained data reveal a shift towards more condensed coke deposits on the outer zeolite surface at higher reaction temperatures. Zeolites in the fixed-bed reactor setup underwent more coke deposition than those reacted in the in situ microspectroscopy reaction cell. Regeneration studies of the large zeolite crystals were performed by oxidation in O2 /inert gas mixtures at 550 degrees C. UV-visible microspectroscopic measurements using the oligomerization of styrene derivatives as probe reaction indicated that the fraction of strong acid sites decreased during regeneration. This change was accompanied by a slight decrease in the initial conversion obtained after regeneration. H-ZSM-5 deactivated more rapidly at higher reaction temperature. PMID- 23649946 TI - Soluble mediators of diabetic macular edema: the diagnostic role of aqueous VEGF and cytokine levels in diabetic macular edema. AB - Diabetic macular edema (DME) is a significant cause of vision loss and represents an important clinical and public health problem. It is characterized by breakdown of the blood retinal barrier with fluid accumulation in the sub-retinal and intra retinal spaces. Although several hypotheses exist for the causes of diabetic macular edema, specific molecular mechanisms remain unclear. Current thinking includes the role of vascular endothelial growth factor (VEGF) and inflammatory cytokines in vascular permeability. We review studies showing a relationship between elevated aqueous VEGF, monocyte chemoattractant protein -1, interleukin 6, or interleukin 8 in association with DME and as predictors of DME. The presence of mediators in both the angiogenesis and inflammatory pathways data suggest a multifactorial model for the development of DME. Further studies targeting individual cytokine activity will be important to our understanding of the pathogenesis and treatment. PMID- 23649945 TI - Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. AB - Diabetic kidney disease causes significant morbidity and mortality among people with type 1 diabetes (T1D). Intensive glucose and blood pressure control have thus far failed to adequately curb this problem and therefore a major need for novel treatment approaches exists. Multiple observations link serum uric acid levels to kidney disease development and progression in diabetes and strongly argue that uric acid lowering should be tested as one such novel intervention. A pilot of such a trial, using allopurinol, is currently being conducted by the Preventing Early Renal Function Loss (PERL) Consortium. Although the PERL trial targets T1D individuals at highest risk of kidney function decline, the use of allopurinol as a renoprotective agent may also be relevant to a larger segment of the population with diabetes. As allopurinol is inexpensive and safe, it could be cost-effective even for relatively low-risk patients, pending the completion of appropriate trials at earlier stages. PMID- 23649947 TI - Antioxidants and diabetic retinopathy. AB - The biochemical perturbations in diabetes mellitus (DM) create the conditions for the production of free radicals, the consequence of which is increased oxidative stress. Evidence has accrued over the past 2 decades that suggests that oxidative stress is an important pathogenetic factor in the development of diabetic retinopathy (DR). Experimental data show that the use of strategies that ameliorate oxidative stress can prevent and retard the development of DR in the animal model. Clinical observations also suggest that reducing oxidative stress may help to reverse pathological manifestations of DR. The present article constitutes an examination of the role of antioxidants in the management of DR and the current state of clinically relevant knowledge. PMID- 23649948 TI - Progesterone and estrogen responsiveness to father-toddler interaction. AB - OBJECTIVES: We assessed the responsiveness of salivary progesterone (P4) and estradiol (E2) to father-child interaction, including testing for differences in short-term hormonal change based on paternal characteristics. We also predicted that P4 exposure during the study period would relate positively to post interaction paternal mood. METHODS: We conducted an in-home intervention study in which fathers (n = 44) played with their toddlers. Subjects provided saliva samples before interacting with their children, with additional collections 40 and 70 min later. RESULTS: E2 did not significantly change over the study period (P > 0.4). P4 declined significantly from baseline to 40 min (P < 0.05) and 70 min (P < 0.001). Men reporting that the interaction made them feel very happy/relaxed had greater P4 exposure from baseline through 70 min (area under the curve) compared with men reporting less positive post-interaction mood (P < 0.05). This relationship persisted after controlling for cortisol. Men's % decrease in P4 (baseline to 40 min) was significantly greater if they had an infant (P < 0.05), while fathers' % decline in E2 (baseline to 70 min) was larger if they had more children (P < 0.05). CONCLUSIONS: These results require replication but could indicate that grouping fathers with different levels of experience obscures meaningful variation in hormonal responses to child interaction. Our findings appear consistent with the effects of P4 as a mood enhancer and suggest future research should explore the possible role of P4 as hormonal mechanism that could reinforce or facilitate paternal investment. PMID- 23649949 TI - Long-term antinociception by electroacupuncture is mediated via peripheral opioid receptors in free-moving rats with inflammatory hyperalgesia. AB - BACKGROUND: Electroacupuncture (EA) has been widely accepted and applied as an important acupuncture-related technique for acupuncture analgesia (AA) research. The involvement of opioid peptides and receptors in acute AA has been shown via pre-EA application of opioid receptor/peptide antagonists. In this study, we intended to reproducibly institute acupoint position and needling excluding influences from anaesthesia or restrainers on rats with complete Freund's adjuvant (CFA) hind paw inflammatory pain, as well as to explore opioid dependency and anti-inflammatory effects in sustained acupuncture analgesia. METHODS: Accurate position and needling approach on acupoint GB30 was modelled by computer-based three-dimensional (3D) images and followed by an optimal EA treatment protocol (100 Hz, 2-3 mA, 20 min) at 0 and 24 h post-CFA in conscious free-moving rats. Opioid receptor antagonists, naloxone (NLX) and naltrindole (NTI) were applied intraplantarly post-EA at late phase (96 h) of CFA. Nociceptive thresholds were assessed by paw pressure threshold (Randall-Sellito) or paw withdrawal latency (Hargreaves), and anti-inflammatory effects were evaluated by measurement of plantar temperature and paw volume. RESULTS: EA elicited significant sustained mechanical and thermal antinociception up to 144 h. Mechanical antinociception of EA was suppressed by peripheral intraplantar application of NLX and NTI. EA also reduced paw temperature and volume during the same time frame indicating anti-inflammatory effects. CONCLUSIONS: By employing a reproducible EA treatment model on GB30 in free-moving rats, we demonstrated the involvement of peripheral opioid receptors mediated EA-induced long-term antinociception. Future studies should examine the specific neuroimmunological connection of EA-induced sustained antinociception in inflammation. PMID- 23649950 TI - Area-wide management of Aedes albopictus. Part 2: gauging the efficacy of traditional integrated pest control measures against urban container mosquitoes. AB - BACKGROUND: Aedes (Stegomyia) albopictus (Skuse) is an important disease vector and biting nuisance. During the 2009 active season, six ~1000-parcel sites were studied, three in urban and three in suburban areas of New Jersey, United States, to examine the efficacy of standard integrated urban mosquito control strategies applied area wide. Active source reduction, larviciding, adulticiding and public education (source reduction through education) were implemented in one site in each county, an education-only approach was developed in a second site and a third site was used as an untreated experimental control. Populations were surveyed weekly with BG-Sentinel traps and ovitraps. RESULTS: A substantial reduction in Ae. albopictus populations was achieved in urban sites, but only modest reductions in suburban sites. Education alone achieved significant reductions in urban adult Ae. albopictus. Egg catches echoed adult catches only in suburban sites. CONCLUSIONS: There are significant socioeconomic and climatic differences between urban and suburban sites that impact upon Ae. albopictus populations and the efficacy of the control methods tested. An integrated pest management approach can affect abundances, but labor-intensive, costly source reduction was not enough to maintain Ae. albopictus counts below a nuisance threshold. Nighttime adult population suppression using truck-mounted adulticides can be effective. Area-wide cost-effective strategies are necessary. PMID- 23649952 TI - Error estimation in environmental DNA targets quantification due to PCR efficiencies differences between real samples and standards. PMID- 23649953 TI - Total synthesis of starfish saponin goniopectenoside B. AB - Star quality: Goniopectenoside B, a minor asterosaponin from starfish Goniopecten demonstrans with antifouling activity, has been synthesized in a convergent 21 steps and in 4.3 % overall yield starting from adrenosterone. This represents the first synthesis of a complex asterosaponin, which are ubiquitous and characteristic in starfish as defense chemicals (see figure). PMID- 23649954 TI - Diabetes mellitus and corticotherapy as risk factors for alendronate-related osteonecrosis of the jaws: a study in Wistar rats. AB - BACKGROUND: The purpose of this study was to investigate the influence of diabetes and corticotherapy on the development of osteonecrosis of the jaws associated with sodium alendronate. METHODS: Rats were allocated into 4 groups of 11 animals each, representing different treatments: (1) alendronate; (2) alendronate and corticotherapy; (3) alendronate and diabetes; and (4) control. Tooth extractions were performed in all animals, and histological analysis was performed by hematoxylin and eosin staining and immunohistochemistry using anti bone morphogenetic protein (BMP)-4 and anti-matrix metalloproteinase (MMP)-13 antibodies. RESULTS: On hematoxylin and eosin analysis, proportions of inflammatory infiltrate, microbial colonies, and osteonecrosis were significantly greater in the diabetes group. BMP-4 expression in connective tissue was higher in the corticosteroid group than the alendronate group. There were no significant differences between the other groups. MMP-13 expression did not differ between the groups analyzed. CONCLUSION: Diabetes but not corticotherapy is associated with jaw osteonecrosis in rats undergoing alendronate therapy and subjected to tooth extractions. PMID- 23649956 TI - Association of clinical parameters of operatively treated thoracolumbar fractures with quality of life parameters. AB - PURPOSE: The intention of the current work was to assess the association between clinical parameters and seven different quality of life (QoL) instruments after surgical treatment of thoracolumbar spinal fractures after an average follow-up of 4.2 years. METHODS: The following human-related quality of life and PRO measures of 66 patients were correlated to clinical parameters such as fingertip to-floor distance (FFD), Schober measurement, pressure and percussion pain in the lumbopelvine area (PPP), and paravertebral muscle tension: reALOS, SF-36, VAS, VAS spine score, BDI, the GBB-24, and the IES-R. RESULTS: Overall, there was a significant association between the clinical parameters of the thoracolumbar spine such as PPP, paravertebral muscle tension, FFD and Schober's sign on one side, and the seven tested instruments on the other side. CONCLUSIONS: PPP and FFD as well as a small Schober measurement are clinical parameters which significantly influence QoL after surgical treatment of thoracolumbar fractures. PMID- 23649957 TI - Tubular surgery with the assistance of endoscopic surgery via midline approach for lumbar spinal canal stenosis: a technical note. AB - PURPOSE: We devised a tubular surgery with the assistance of endoscopic surgery via midline approach to the spinal canal to preserve the bilateral facet joints and the paravertebral muscles when treating lumbar spinal canal stenosis. We report details of this operative procedure. METHODS: A 2-cm incision is made in the skin in the midline of the intervertebral level to be decompressed. The spinous process on the cranial side is partially excised, and incisions along the ligament fiber are made in the midline of the supraspinous and interspinous ligaments to expose the ligamentum flavum. After the lamina and the inferior parts of the bilateral facet joints are adequately excised, the microendoscopic discectomy system is inserted. With this procedure, no muscular tissue is seen in the surgical site. The portal approach is small, but if full advantage is taken of the spinal microendoscope's merits, the bilateral facet joints are preserved and wide decompression of deep parts is possible. The microendoscope is positioned above the spinal canal to provide a good symmetrical field of view to enable easy anatomical orientation. RESULTS: Bilateral intervertebral joints were satisfactorily preserved in ten patients who received this surgery. All became ambulatory on the day after surgery and the clinical results remained favorable 3 years after the operation. CONCLUSION: Tubular surgery with the assistance of endoscopic surgery via a midline approach is a minimally invasive surgical procedure with favorable results that enables preservation of paravertebral muscles and bilateral facet joints. PMID- 23649958 TI - Effect of transdermal isopropyl alcohol on the international normalized ratio in five warfarin-treated patients. AB - Warfarin, an anticoagulant with a narrow therapeutic window, is largely metabolized by cytochrome P450 2C9. Isopropyl alcohol has been shown to inhibit the activity of this enzyme. Use of topical isopropyl alcohol as a rubefacient may place patients at risk for systemic exposure. Isopropyl alcohol's effect on the international normalized ratio (INR) has not been well characterized. We describe five patients who experienced INR elevations after topical application of isopropyl alcohol. Each patient's INR was therapeutic for at least seven visits prior to becoming supratherapeutic. All patients confirmed drug adherence and denied medication or dietary changes. Seventy percent isopropyl alcohol was used in all cases over a large body surface area of intact skin multiple times daily for several days. All patients experienced a 10% or greater increase in their INR compared to previous levels. On discontinuation of isopropyl alcohol, each patient's INR returned to and remained in therapeutic range for the next 2 months. Prediction of isopropyl alcohol's effect of the INR is confound by several factors, notably the BSA covered, concentration of alcohol in the product, contact time with the skin, and skin integrity. It is important that clinicians inquire about the use of isopropyl alcohol and educate patients about its potential risk in those receiving warfarin therapy. PMID- 23649959 TI - Propagation of error in ocular pharmacokinetic parameters estimate of azithromycin in rabbits. AB - The ocular pharmacokinetic (PK) of azithromycin in rabbit eye tissues was evaluated following single-dose and multiple-dose administrations of azithromycin. Because of destructive sampling, only the average ocular tissue concentration-time curve could be captured and used to estimate the PK parameters failing to obtain their standard deviations. In the present study, formulas were explained in details to estimate the major PK parameter errors in destructive sampling. The PK parameters were obtained by analyzing average ocular tissue concentration-time curve and their standard deviations were calculated using the formula proposed in this paper. A case study was included to elucidate the potential application of the formulas. F-test for equality of variances and independent-samples t-test were carried out between test formulation and reference formulation in PK parameters. Thus, a new and simple method was proposed to compare PK behavior for these studies using destructive sampling, which can be potentially applied into other cases in the future. PMID- 23649960 TI - Sequential imaging demonstrating os odontoideum formation after a fracture through the apical odontoid epiphysis: case report and review of the literature. AB - INTRODUCTION: The mechanism of formation of an os odontoideum is controversial and likely multifactorial. One theory states that the apex of the odontoid separates from the body because of a fracture. The intact alar and apical ligaments pull the fractured segment superiorly. The independent vascular supply of the apex allows the fractured bone to remain viable and remodel into the smooth, corticated bone characteristic of an os odontoideum. However, there are no publications with direct radiographic evidence supporting the theory. CASE REPORT: In this paper, the authors present a 7-year-old child with a fracture through the apical odontoid epiphysis, extending into the body of the dens. Serial imaging studies demonstrate progressive separation of the apex from the body of the odontoid. The fractured segment begins to remodel and assume the classic form of an os. CONCLUSION: The authors consider this case to be radiographic evidence supporting an acquired/traumatic origin of os odontoideum. Further, the mechanism of fracture through a cartilaginous epiphysis may explain the formation of an os after "normal" x-ray images or following seemingly minor trauma. PMID- 23649962 TI - Recent advances in the study of enzyme promiscuity in the tautomerase superfamily. AB - Catalytic promiscuity and evolution: Many enzymes exhibit catalytic promiscuity- the ability to catalyze reactions other than their biologically relevant one. These reactions can serve as starting points for both natural and laboratory evolution of new enzymatic functions. Recent advances in the study of enzyme promiscuity in the tautomerase superfamily are discussed. PMID- 23649963 TI - Simultaneous hyper- and hypomethylation at imprinted loci in a subset of patients with GNAS epimutations underlies a complex and different mechanism of multilocus methylation defect in pseudohypoparathyroidism type 1b. AB - Most patients with pseudohypoparathyroidism type 1b (PHP-1b) display a loss of imprinting (LOI) encompassing the GNAS locus resulting in PTH resistance. In other imprinting disorders, such as Russell-Silver or Beckwith-Wiedemann syndrome, we and others have shown that the LOI is not restricted to one imprinted locus but may affect other imprinted loci for some patients. Therefore, we hypothesized that patients with PHP-1b might present multilocus imprinting defects. We investigated, in 63 patients with PHP-1b, the methylation pattern of eight imprinted loci: GNAS, ZAC1, PEG1/MEST, ICR1, and ICR2 on chromosome 11p15, SNRPN, DLK1/GTL2 IG-DMR, and L3MBTL1. We found multilocus imprinting defects in four PHP-1b patients carrying broad LOI at the GNAS locus (1) simultaneous hypermethylation at L3MBTL1 differentially methylated region 3 (DMR3), and hypomethylation at PEG1/MEST DMR (n = 1), (2) hypermethylation at the L3MBTL1 (DMR3) (n = 1) and at the DLK1/GTL2 IG-DMR (n = 1), and (3) hypomethylation at the L3MBTL1 DMR3 (n = 1). We suggest that mechanisms underlying multilocus imprinting defects in PHP-1b differ from those of other imprinting disorders having only multilocus loss of methylation. Furthermore, our results favor the hypothesis of "epidominance", that is, the phenotype is controlled by the most severely affected imprinted locus. PMID- 23649961 TI - Use of new oral anticoagulants in antiphospholipid syndrome. AB - The current mainstay of treatment of thrombotic APS is long-term anticoagulation with oral vitamin K antagonists (VKA) such as warfarin. However, the use of warfarin is problematic, particularly in patients with antiphospholipid syndrome (APS). The new oral anticoagulants (NOAC) include dabigatran etexilate (Pradaxa(r)), a direct thrombin inhibitor, and rivaroxaban (Xarelto(r)), Apixaban (Eliquis) and Edoxaban (Lixiana(r)), which are direct anti-Xa inhibitors. Unlike warfarin, these agents do not interact with dietary constituents and alcohol, have few reported drug interactions, and monitoring of their anticoagulant intensity is not routinely required due to their predictable anticoagulant effects. In this chapter, we discuss clinical and laboratory aspects of NOAC. These agents have been approved for several therapeutic indications based on phase III prospective randomised controlled clinical trials using warfarin at a target INR of 2.5 (i.e. range 2.0-3.0) as the comparator. However these trials may not be directly applicable to patients with antiphospholipid syndrome (APS) where prospective clinical studies of NOAC are the way forward. PMID- 23649965 TI - Organocatalytic enantioselective direct vinylogous Michael addition of gamma substituted butenolides to 3-aroyl acrylates and 1,2-diaroylethylenes. AB - Adding value: The direct vinylogous Michael addition of gamma-substituted butenolides with a series of 3-aroyl acrylates and 1,2-diaroylethylenes has been demonstrated. This organocatalytic method delivers highly enantio- and diastereomerically pure gamma,gamma-disubstituted butenolides with adjacent quaternary and tertiary stereocenters (see scheme). PMID- 23649964 TI - Brivaracetam disposition in mild to severe hepatic impairment. AB - Brivaracetam is a high-affinity synaptic vesicle protein 2A (SV2A) ligand in clinical development for epilepsy. This open-label, single-dose study evaluated brivaracetam disposition in participants with different degrees of hepatic impairment versus matched healthy controls. Twenty-six participants (38-72 years; 19 males and 7 females) with hepatic impairment classified by Child-Pugh score (mild, n = 6; moderate, n = 7; severe, n = 7) or normal hepatic function (n = 6) received a single oral dose of 100 mg brivaracetam. The pharmacokinetics of brivaracetam and its three main metabolites (acid, hydroxy, hydroxyacid) were determined and correlated with impairment severity. Dynamic liver function tests correlated with hepatic impairment severity. The plasma half-life of brivaracetam was 9.8, 14.2, 16.4, and 17.4 hours and the area under the plasma concentration time curve was 29.7, 44.6, 46.7, and 47.1 ug h/mL in healthy controls and participants with mild, moderate, and severe liver impairment, respectively. Production of the acid metabolite was increased and the hydroxylated metabolites were decreased in participants with hepatic impairment versus healthy controls. Exposure to brivaracetam increased by 50-60% in patients with hepatic impairment, irrespective of severity. The relative importance of biotransformation pathways was altered; cytochrome P450 (CYP)-dependent hydroxylation decreased; CYP independent acid metabolite formation increased concomitantly. PMID- 23649966 TI - PathOpt--a global transition state search approach: outline of algorithm. AB - We propose a new algorithm to determine reaction paths and test its capability for Ar12 and Ar13 clusters. Its main ingredient is a search for the local minima on a (n-1) dimensional hyperplane (n = dimension of the complete system in Cartesian coordinates) lying perpendicular to the straight line connection between initial and final states. These minima are part of possible reaction paths and are, hence, used as starting points for an uphill search to the next transition state. First, path fragments are obtained from subsequent relaxations starting from these transition states. They can be combined with information from the straight line connection procedure to obtain complete paths. Our test computations for Ar12 and Ar13 clusters prove that PathOpt delivers several reaction paths in one round. PMID- 23649967 TI - Differing effects of prosaccades and antisaccades on postural stability. AB - The goal of the study was to examine the effect of different types of eye movements on postural stability. Ten healthy young adults (25 +/- 3 years) participated in the study. Postural control was measured by the TechnoConcept(c) platform and recorded in Standard Romberg and Tandem Romberg conditions while participants performed five oculomotor tasks: two fixation tasks (central fixation cross, without and with distractors), two prosaccade tasks toward peripheral targets displayed 4 degrees to the left or to the right of the fixation cross (reactive saccades induced by a gap 0 ms paradigm and voluntary saccades induced by an overlap 600 ms paradigm) and one antisaccade task (voluntary saccade made in the opposite direction of the visual target). The surface, the length, and the mean speed of the center of pressure were analyzed. We found that saccadic eye movements improved postural stability with respect to the fixation tasks. Furthermore, antisaccades were found to decrease postural stability compared to prosaccades (reactive as well as voluntary saccades). This result is in line with the U-shaped nonlinear model described by Lacour et al. (Neurophysiol Clin 38:411-421, 2008), showing that a secondary task performed during a postural task could increase (prosaccade task) or decrease (antisacade task) postural stability depending on its complexity. We suggest that the different degree of attentional resources needed for performing prosaccade or antisaccade tasks are, most likely, responsible for the different effect on postural control. PMID- 23649968 TI - Predictive mechanisms in the control of contour following. AB - In haptic exploration, when running a fingertip along a surface, the control system may attempt to anticipate upcoming changes in curvature in order to maintain a consistent level of contact force. Such predictive mechanisms are well known in the visual system, but have yet to be studied in the somatosensory system. Thus, the present experiment was designed to reveal human capabilities for different types of haptic prediction. A robot arm with a large 3D workspace was attached to the index fingertip and was programmed to produce virtual surfaces with curvatures that varied within and across trials. With eyes closed, subjects moved the fingertip around elliptical hoops with flattened regions or Limacon shapes, where the curvature varied continuously. Subjects anticipated the corner of the flattened region rather poorly, but for the Limacon shapes, they varied finger speed with upcoming curvature according to the two-thirds power law. Furthermore, although the Limacon shapes were randomly presented in various 3D orientations, modulation of contact force also indicated good anticipation of upcoming changes in curvature. The results demonstrate that it is difficult to haptically anticipate the spatial location of an abrupt change in curvature, but smooth changes in curvature may be facilitated by anticipatory predictions. PMID- 23649969 TI - Aging of sensorimotor processes: a systematic study in Fitts' task. AB - Though age-related decrease in information-processing capacities is hypothesized to be a prominent cause of behavioral slowing, it has been scarcely systematically studied in goal-directed motor tasks. The present study investigated how the decrease in information processing affects the sensorimotor processes underlying the control of a discrete Fitts' task. The index of difficulty (ID) of the task was manipulated using changes in either target distance (D) or target width (W). In each manipulation, movement (MTs), acceleration (ATs) and deceleration times (DTs) of young and older participants were compared across eight ID levels. They were analyzed with efficiency functions, state traces and Brinley plots. Our results showed that older participants were always slower. However, in both age groups, MTs were longer in D manipulation, which resulted from a slowing of both ATs and DTs, while W manipulation affected mainly DTs. In D manipulation, equivalent age-related slowing ratios were observed for AT and DT (1.3). In W manipulation, ATs of older participants were additively slower than those of young participants. Conversely, DTs presented a multiplicative slowing ratio of 1.3. These findings showed that ID manipulations differentially loaded information processing in the nervous system and that age-related slowing of multisensory control processes was independent of the manipulated dimension. Nevertheless, ID manipulations revealed different age-related adaptations to task constraints, suggesting that D and W manipulations are complementary means to assess age-related slowing of the processes involved in target-directed rapid-aiming tasks, with D scaling being more specific to capture the slowing of force-impulse control. PMID- 23649970 TI - Meningococcal groups C and Y and haemophilus B tetanus toxoid conjugate vaccine (HibMenCY-TT; MenHibrix((r))): a review. AB - The meningococcal groups C and Y and Haemophilus b (Hib) tetanus toxoid conjugate vaccine (HibMenCY-TT) contains Neisseria meningitidis serogroup C and Y capsular polysaccharide antigens, and Hib capsular polysaccharide [polyribosyl-ribitol phosphate (PRP)]. The HibMenCY-TT vaccine is available in the USA for use as active immunization to prevent invasive disease caused by N. meningitidis serogroups C (MenC) and Y (MenY), and Hib in children 6 weeks-18 months of age. HibMenCY-TT is the first meningococcal vaccine available for use in the USA that can be administered to infants as young as 6 weeks of age. In a randomized, controlled, phase III clinical trial, the HibMenCY-TT vaccine, administered to infants at 2, 4, 6 and 12-15 months of age, was immunogenic against MenC and MenY, and met the prespecified criteria for immunogenicity. Anti-PRP antibodies, which have been shown to correlate with protection against Hib invasive disease, were also induced in the infants who received the HibMenCY-TT vaccine, with induced levels of this antibody noninferior to those occurring in the control group of infants who received a Hib tetanus toxoid conjugate vaccine at 2, 4, and 6 months and a single dose of Hib conjugated to N. meningitidis outer membrane protein at 12-15 months. In several randomized, controlled clinical trials, HibMenCY-TT was coadministered with vaccines that are routinely administered to infants and toddlers in the USA. These vaccines included: diphtheria and tetanus toxoids and acellular pertussis adsorbed, hepatitis B (recombinant) and inactivated poliovirus vaccine combined; 7-valent Streptococcus pneumoniae polysaccharide conjugate vaccine; measles, mumps and rubella vaccine; and varicella vaccine. Coadministration of these vaccines did not interfere with the immunogenicity of the HibMenCY-TT vaccine. Similarly, immune responses to the coadministered vaccines were not affected by the HibMenCY-TT vaccine. The tolerability profile of the HibMenCY-TT vaccine in infants and toddlers in the phase III trial was considered to be clinically acceptable and comparable to that of the Hib conjugate vaccines received by the control group. PMID- 23649971 TI - Combination molecularly targeted drug therapy in metastatic melanoma: progress to date. AB - Previously characterized by a median overall survival of between 6 and 12 months, metastatic melanoma now has a number of novel and effective treatment options. The ability to target the mitogen-activated protein kinase (MAPK) pathway with BRAF (v-raf murine sarcoma viral oncogene homolog B1) or MEK (mitogen-activated protein kinase kinase) inhibitors can result in rapid clinical benefit, but is too often associated with limited durability of response. Resistance inevitably develops either via reactivation of the MAPK pathway or via bypass signalling pathways, such as the PI3K (phosphoinositide 3-kinase) pathway. Combination strategies are thus appealing with an aim to overcome potential resistance mechanisms. Already, the combination of the BRAF inhibitor, dabrafenib, along with the MEK inhibitor, trametinib, has shown promising results clinically and with an improved toxicity profile. Other combination strategies with agents that target the PI3K pathway, angiogenesis, and the immune system are in development or already underway, although potential overlapping toxicities require close monitoring. The currently available molecularly targeted agents that target the MAPK pathway and development of combination therapies for treatment of metastatic melanoma are discussed in further detail. PMID- 23649972 TI - Different pH-dependencies of the two synaptic adhesion molecules N-cadherin and cadherin-11 and the possible functional implication for long-term potentiation. AB - Ca(2+) -dependent adhesion molecules, cadherins, localised at synaptic sites are critically involved in long-term potentiation (LTP). N-cadherin is thought to promote LTP whereas cadherin-11 seems to counteract LTP. Since high synaptic activity is accompanied by local transient changes of the pH in the synaptic cleft, we studied whether the binding activity of cadherins is dependent on the pH and whether this might play a role during LTP. By atomic force microscopy (AFM) and laser tweezer experiments, we could show on the single molecule level as well as in a cell-based system that a decrease of the pH from 7.4 to 7.0 will result in a significant weakening of N-cadherin binding activity but in an increase of cadherin-11 binding. These differences in the pH dependencies of both molecules could be one explanation for their opposing roles during LTP. High frequency stimulation will lead to a local acidosis in the synaptic cleft resulting in weakening of N-cadherin-mediated adhesion facilitating synaptic remodeling and LTP induction, whereas cadherin-11 bonds will be strengthened counteracting synaptic remodeling and LTP generation. PMID- 23649973 TI - Connecting discrete stereoclusters by using DFT and NMR spectroscopy: the case of nivariol. AB - The structural determination of small organic molecules is mainly undertaken by using NMR techniques, although it is increasingly supplemented by using computational methods. NMR parameters, such as chemical shifts and coupling constants, are extremely sensitive indicators of local molecular conformation and are a source of structural evidence. However, their interpretation is fairly challenging in many circumstances, such as the case of the new polyether squalene derivative nivariol, the structure of which was elucidated by means of NMR spectroscopy and DFT calculations. The potential flexibility of this molecule and the high number of quaternary carbon atoms that it contains make its configurational assignment very difficult. Moreover, the relative configuration of four separated stereoclusters was established and subsequently connected by using NOE and J-based analysis, as well as by a comparison of its experimental (13)C NMR chemical shifts with the corresponding population-weighted values, as calculated by using DFT methods. Limitations of these used approaches became apparent but were overcome by combining the two methods. PMID- 23649974 TI - The receptor tyrosine kinase Axl in cancer: biological functions and therapeutic implications. AB - The receptor tyrosine kinase Axl has been implicated in the malignancy of different types of cancer. Emerging evidence of Axl upregulation in numerous cancers, as well as reports demonstrating that its inhibition blocks tumor formation in animal models, highlight the importance of Axl as a new potential therapeutic target. Furthermore, recent data demonstrate that Axl plays a pivotal role in resistance to chemotherapeutic regimens. In this review we discuss the functions of Axl and its regulation and role in cancer development, resistance to therapy, and its importance as a potential drug target, focusing on acute myeloid leukemia, breast, prostate and non-small cell lung cancers. PMID- 23649975 TI - Local field of view imaging for alias-free undersampling with nonlinear spatial encoding magnetic fields. AB - PURPOSE: Nonlinear spatial encoding magnetic fields result in an inhomogeneous image resolution. Within this study, this characteristic property of nonlinear encoding is investigated with regard to its potential to accelerate MRI acquisitions. THEORY: A dependency between k-space coverage and local resolvability of the image causes k-space samples to have a spatially localized contribution to the reconstruction of the spin density. On the basis of this observation, a concept for alias-free data undersampling is developed, which is referred to as the local field of view concept. METHODS: On the basis of this concept, a fast sampling trajectory is developed. It is evaluated with simulations and experiments (both using a phantom and in vivo) for MRI with, as an example, pure quadrupolar encoding fields. To demonstrate that the concept is only applicable to (spatially) nonlinear encoding, a comparison with linear encoding is provided. RESULTS: Application of the local field of view concept results in a localized adaptation of the image resolution by undersampling higher frequency k-space samples without introducing aliasing. CONCLUSIONS: A new effect of nonlinear spatial encoding magnetic fields was found, which allows more efficient data sampling and at the same time counterbalancing the natural variation in image resolution. PMID- 23649976 TI - Switchable nanoporous sheets by the aqueous self-assembly of aromatic macrobicycles. PMID- 23649977 TI - Ambient-light-mediated copper-catalyzed C-C and C-N bond formation. AB - Bringing to light: The rediscovery of visible light as an abundant energy source for organic reactions has most recently brought copper-catalyzed coupling reactions to the center of attention. This Highlight summarizes the most significant advancements in the field of C-C and C-N coupling reactions in which covalent copper-substrate complexes are photo-activated. PMID- 23649979 TI - High sensitivity micro-elastometry: applications in blood coagulopathy. AB - Highly sensitive methods for the assessment of clot structure can aid in our understanding of coagulation disorders and their risk factors. Rapid and simple clot diagnostic systems are also needed for directing treatment in a broad spectrum of cardiovascular diseases. Here we demonstrate a method for micro elastometry, named resonant acoustic spectroscopy with optical vibrometry (RASOV), which measures the clot elastic modulus (CEM) from the intrinsic resonant frequency of a clot inside a microwell. We observed a high correlation between the CEM of human blood measured by RASOV and a commercial thromboelastograph (TEG), (R = 0.966). Unlike TEG, RASOV requires only 150 MUL of sample and offers improved repeatability. Since CEM is known to primarily depend upon fibrin content and network structure, we investigated the CEM of purified clots formed with varying amounts of fibrinogen and thrombin. We found that RASOV was sensitive to changes of fibrinogen content (0.5-6 mg/mL), as well as to the amount of fibrinogen converted to fibrin during clot formation. We then simulated plasma hypercoagulability via hyperfibrinogenemia by spiking whole blood to 150 and 200% of normal fibrinogen levels, and subsequently found that RASOV could detect hyperfibrinogenemia-induced changes in CEM and distinguish these conditions from normal blood. PMID- 23649980 TI - Comparison of three hydroxyapatite/beta-tricalcium phosphate/collagen ceramic scaffolds: an in vivo study. AB - Calcium-phosphate ceramics, which have a composition similar to bone mineral, represent a potentially interesting synthetic bone graft substitute. In the present study, three porous hydroxyapatite (HA)/beta-tricalcium phosphate (beta TCP)/collagen ceramic scaffolds were developed, characterized, and tested for their bone repairing capacity and osteoinductive potential in a New Zealand Rabbit model. The ratio of the ceramic components HA/-TCP/collagen varied from 40/30/30 to 50/20/30 and 60/20/20 (in wt %), respectively. None of the ceramic scaffolds succeeded in completely bridging the 6 mm calvarian defect with new bone after 60 days implantation. 60/20/20 ceramic scaffolds showed significantly more bone formation in the pores and in the periphery of the graft than the other two materials. Histomorphometric analysis revealed that the 40/30/30 scaffold produced best bone-to-implant contact (67.23 +/- 0.34% with higher quality, closer contact) in comparison with 50/20/30 (54.87 +/- 0.32%), and 60/20/20 (48.53 +/- 0.31%). Both physicochemical and structural properties of the ceramic composites affected their in vivo behavior, either dependently or independently, emphasizing the importance of assessing bone repair parameters individually. The scaffolds may offer clinical applications in reconstructive surgery for treating bone pathologies. PMID- 23649981 TI - Efficient hydrogen liberation from formic acid catalyzed by a well-defined iron pincer complex under mild conditions. AB - Hydrogen liberation: An attractive approach to reversible hydrogen storage applications is based on the decomposition of formic acid. The efficient and selective hydrogen liberation from formic acid is catalyzed by an iron pincer complex in the presence of trialkylamine. Turnover frequencies up to 836 h-1 and turnover numbers up to 100,000 were achieved at 40 degrees C. A mechanism including well-defined intermediates is suggested on the basis of experimental and computational data. PMID- 23649982 TI - Thrombospondin-4 contributes to spinal cord injury-induced changes in nociception. AB - BACKGROUND: Our previous data have indicated that nerve injury-induced up regulation of thrombospondin-4 (TSP4) proteins in dorsal spinal cord plays a causal role in neuropathic pain state development in a spinal nerve ligation model. To investigate whether TSP4 proteins also contribute to the development of centrally mediated changes in nociception after spinal cord injury (SCI), we investigated whether SCI induced TSP4 dysregulation, and if so, whether this change correlated with changes in nociception in a T9 spinal cord contusion injury model. METHODS: Behavioural sensitivity to mechanical, thermal stimuli and locomotor function recovery were tested blindly in SCI or sham rats post-injury. Intrathecal antisense or mismatch control oligodeoxynucleotides were used to treat SCI rats with nociceptive hyperreflexia, and Western blots were used to measure TSP4 protein levels in dorsal spinal cord samples. RESULTS: SCI induced below-level hindpaw hypersensitivity to stimuli. TSP4 protein levels are up regulated in dorsal spinal cord of SCI rats with nociceptive hyperreflexia, but not in SCI rats without nociceptive hyperreflexia. There was no significant difference in motor function recovery post-injury between SCI rats with or without nociceptive hyperreflexia. Intrathecal treatment with TSP4 antisense, but not mismatch control, oligodeoxynucleotides led to reversal of injury-induced TSP4 up-regulation and nociceptive hyperreflexia in SCI rats. CONCLUSIONS: SCI leads to TSP4 up-regulation in lumbar spinal cord that may play a critical role in mediating centrally mediated behavioural hypersensitivity. Blocking this pathway may be helpful in management of SCI-induced changes in nociception. PMID- 23649984 TI - Highly selective hydroxylation of benzene to phenol by wild-type cytochrome P450BM3 assisted by decoy molecules. PMID- 23649983 TI - Ambient vapor samples activate the Nrf2-ARE pathway in human bronchial epithelial BEAS-2B cells. AB - Ambient air pollutants have been reported to induce oxidative stress based inflammatory responses in humans and experimental animals. However, most of these reports describe the actions of the particulate phase of ambient and exhaust samples. We describe here results of studies investigating the actions of the vapor phase of ambient air samples collected in the midtown area of Los Angeles on human bronchial epithelial BEAS-2B cells using DNA microarray analysis. Among 26 genes whose expression increased fourfold or more, four genes were associated with detoxifying genes regulated by the transcription factor Nrf2. Consistent with these results, the vapor samples activate the Nrf2-ARE pathway, resulting in up-regulation of heme oxygenase-1 (HO-1), glutamate cysteine ligase modifier subunit, and cystine transporter (xCT) mRNA and proteins. No appreciable increases in pro-inflammatory genes were observed. These results suggest that ambient vapor samples activate the Nrf2-ARE pathway but not an inflammatory response. Also, treatment of the vapor samples with glutathione resulted in reduction in the Nrf2 activation and HO-1 induction, suggesting that electrophiles in vapor samples contribute to this Nrf2-dependent antioxidant or adaptive response. PMID- 23649985 TI - Clinical response and tumor control based on long-term follow-up and patient reported outcomes in patients with chemodectomas of the skull base and head and neck region treated with highly conformal radiation therapy. AB - BACKGROUND: The purpose of this study was to evaluate long-term outcome after radiation therapy (RT) for skull base or head-and-neck chemodectomas. METHODS: We treated 39 patients with chemodectomas with RT. Patients were treated with either single dose stereotactic radiosurgery, fractionated stereotactic radiotherapy, or intensity modulated radiotherapy (IMRT), depending on the size and anatomy of the lesion. At primary diagnosis, 16 patients were treated with surgical resection (41%), 4 with interventional embolization (10%), and 19 with primary RT (49%). Single doses of 18 Gy/80% isodose were applied. For fractionated treatments delivered as primary RT, a median total dose of 57.6 Gy was delivered. Five patients were treated with re-irradiation, of which 4 were treated with fractionated regimens; total dose was 28.8 Gy, 30 Gy, 40 Gy, and 56 Gy in 1.8 to 2 Gy single fractions. RESULTS: Clinical symptoms improved in 18 patients (46%), remained unchanged in 10 patients (26%), and worsening of sequelae was observed in only 1 patient, which was associated with tumor progression. Actuarial local control was 97% at 10 years. Overall survival was 89% at 5 years and 87% at 10 years. Deaths were not disease-related except in 3 patients with tumor progression. No secondary malignancies were observed. CONCLUSION: RT has been established as a treatment alternative for patients with glomus tumors. Long-term local control is very high, with good clinical response to treatment. PMID- 23649986 TI - Thioamides: versatile bonds to induce directional and cooperative hydrogen bonding in supramolecular polymers. AB - The amide bond is a versatile functional group and its directional hydrogen bonding capabilities are widely applied in, for example, supramolecular chemistry. The potential of the thioamide bond, in contrast, is virtually unexplored as a structuring moiety in hydrogen-bonding-based self-assembling systems. We report herein the synthesis and characterisation of a new self assembling motif comprising thioamides to induce directional hydrogen bonding. N,N',N''-Trialkylbenzene-1,3,5-tris(carbothioamide)s (thioBTAs) with either achiral or chiral side-chains have been readily obtained by treating their amide based precursors with P2S5. The thioBTAs showed thermotropic liquid crystalline behaviour and a columnar mesophase was assigned. IR spectroscopy revealed that strong, three-fold, intermolecular hydrogen-bonding interactions stabilise the columnar structures. In apolar alkane solutions, thioBTAs self-assemble into one dimensional, helical supramolecular polymers stabilised by three-fold hydrogen bonding. Concentration- and temperature-dependent self-assembly studies performed by using a combination of UV and CD spectroscopy demonstrated a cooperative supramolecular polymerisation mechanism and a strong amplification of supramolecular chirality. The high dipole moment of the thioamide bond in combination with the anisotropic shape of the resulting cylindrical aggregate gives rise to sufficiently strong depolarised light scattering to enable depolarised dynamic light scattering (DDLS) experiments in dilute alkane solution. The rotational and translational diffusion coefficients, D(trans) and D(rot), were obtained from the DDLS measurements, and the average length, L, and diameter, d, of the thioBTA aggregates were derived (L = 490 nm and d = 3.6 nm). These measured values are in good agreement with the value L(w) = 755 nm obtained from fitting the temperature-dependent CD data by using a recently developed equilibrium model. This experimental verification validates our common practice for determining the length of BTA-based supramolecular polymers from model fits to experimental CD data. The ability of thioamides to induce cooperative supramolecular polymerisation makes them effective and broadly applicable in supramolecular chemistry. PMID- 23649987 TI - Reconstruction of intracranial vertebral artery with radial artery and occipital artery grafts for fusiform intracranial vertebral aneurysm not amenable to endovascular treatment: technical note. AB - BACKGROUND: Symptomatic fusiform intracranial vertebral artery aneurysms pose a formidable treatment challenge when not amenable to endovascular treatment. In this paper, we illustrate the microsurgical management of such an aneurysm. METHODS: To prevent neurological deterioration, anatomical reconstruction preserving all vessels including posterior inferior cerebellar artery and perforators is essential. In this case illustration, the occipital artery was used as a donor to a perforator originating from the aneurysmal segment. This bypass was performed in an end-to-side fashion. Subsequently, the aneurysmal component of the vertebral artery was resected and an end-to-side (V4 to V3) bypass was performed using a radial artery graft. RESULTS: The patient achieved complete resection of the aneurysm preserving normal anatomy of the posterior circulation without any ischemic complications. CONCLUSIONS: Complex cerebral artery bypass techniques are essential in the armamentarium of cerebrovascular for the treatment of complex lesions not amenable to endovascular therapy. PMID- 23649988 TI - Intraperitoneal treatment with S100B enhances hippocampal neurogenesis in juvenile mice and after experimental brain injury. AB - BACKGROUND: Neurogenesis is documented in adult mammals including humans, is promoted by neurotrophic factors, and constitutes an innate repair mechanism following brain injury. The glial neurotrophic protein S100B is released following various types of brain injuries, enhances hippocampal neurogenesis and improves cognitive function following brain injury in rats when applied intrathecally. The present study was designed to elucidate whether the beneficial effect of S100B on injury-induced neurogenesis can be confirmed in mice when applied intraperitoneally (i.p.), and whether this effect is dose-dependent. METHODS: Male juvenile mice were subjected to a unilateral parietal cryolesion or sham injury, and treated with S100B at 20nM, 200nM or vehicle i.p. once daily. Hippocampal progenitor cell proliferation was quantified following labelling with bromo-deoxyuridine (BrdU, 50 mg/KG i.p.) in the germinative area of the dentate gyrus, the subgranular zone (SGZ), on day 4 as well as on cell survival and migration to the granular cell layer (GCL) on day 28. Progenitor cell differentiation was assessed following colabelling with the glial marker GFAP and the neuronal marker NeuN. RESULTS: S100B enhanced significantly the early progenitor cell proliferation in the SGZ as well as cell survival and migration to the GCL, and promoted neuronal differentiation. While these effects were predominately dose-dependent, 200nM S100B failed to enhance the proliferation in the SGZ on day 4 post-injury. CONCLUSION: We conclude that S100B participates in hippocampal neurogenesis after injury at lower nanomolar concentrations. Therefore S100B may serve as a potential adjunct treatment to promote neuroregeneration following brain damage. PMID- 23649989 TI - Intraoperative fluorescence for resection of hemangioblastomas. AB - BACKGROUND: Resection of hemangioblastomas can be challenging due to their high vascularity and intimate association with neighboring cerebrovascular structures. The authors present their intraoperative findings using fluorescein angiography and fluorescence for removal of hemangioblastomas in an attempt to improve the safety and extent of resection. METHODS: From April through August 2012, four patients were diagnosed with hemangioblastomas, 3 in the cerebellum and 1 in the medulla oblongata. Low-dose (4 mg/kg) sodium fluorescein was injected intravenously immediately before microdissection. The area of interest was inspected through a microscope-integrated fluorescent module. RESULTS: In three superficially located tumors, the vascular pattern of feeding and draining vessels could be easily identified with fluorescein angiography. The resection of the tumors was guided using real-time fluorescence mode. For each patient, histopathologic examination of the lesion confirmed the diagnosis of hemangioblastoma. All samples of fluorescent tissue resected were confirmed to contain tumor. No patient experienced any complication. CONCLUSION: Low-dose sodium fluorescein used in conjunction with a microscope-integrated fluorescence module is a potentially useful tool for localization, vascular characterization, and resection of hemangioblastomas. PMID- 23649990 TI - Ceftaroline-induced eosinophilic pneumonia. AB - We present a case of eosinophilic pneumonia due to ceftaroline used for the treatment of methicillin-resistant Staphylococcus aureus bacteremia associated with a postoperative spinal infection. Our patient developed shortness of breath and hypoxemia on the fifth week of ceftaroline therapy. Chest imaging disclosed diffuse bilateral infiltrates. Laboratory abnormalities included peripheral eosinophilia and eosinophilic predominant bronchoalveolar lavage fluid. The combination of ceftaroline discontinuation plus initiation of steroid treatment resulted in complete resolution of signs, symptoms, and radiologic abnormalities. We speculate about possible mechanisms underlying this adverse event and diagnostic criteria for drug-induced eosinophilic pneumonia. PMID- 23649991 TI - Dissecting the structure and mechanism of a complex duplication-triplication rearrangement in the DMD gene. AB - Pathogenic complex genomic rearrangements are being increasingly characterized at the nucleotide level, providing unprecedented opportunities to evaluate the complexities of mutational mechanisms. Here, we report the molecular characterization of a complex duplication-triplication rearrangement involving exons 45-60 of the DMD gene. Inverted repeats facilitated this complex rearrangement, which shares common genomic organization with the recently described duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) events; specifically, a 690-kb region comprising DMD exons from 45 to 60 was duplicated in tandem, and another 46-kb segment containing exon 51 was inserted inversely in between them. Taking into consideration (1) the presence of a predicted PRDM9 binding site in the near vicinity of the junction involving two inverted L1 elements and (2) the inherent properties of X-Y chromosome recombination during male meiosis, we proposed an alternative two-step model for the generation of this X-linked DMD DUP-TRP/INV-DUP event. PMID- 23649993 TI - Acid active receptor-specific peptide ligand for in vivo tumor-targeted delivery. AB - Targeting therapy of tumors in their early stages is crucial to increase the survival rate of cancer patients. Currently most drug-delivery systems target the neoplasia through the tumor-associated receptors overexpressed on the cancer cell membrane. However, the expression of these receptors on normal cells and tissues is inevitable, which leads to unwanted accumulation and side effects. Characteristics of the tumor microenvironment, such as acidosis, are pervasive in almost all solid tumors and can be easily accessed. It is shown that the different extracellular pH value can be used to activate/inactivate the receptor mediated endocytosis on tumor/normal cells. This idea is implemented by conjugating a shielding molecule at the terminus of a receptor-specific ligand via a pH-sensitive hydrazone bond. The acid-activated detachment of the shielding molecule and enhanced tumor/background accumulation ratio are demonstrated. These results suggest that acid active receptor-specific peptide ligand-modified tumor targeting delivery systems have potential use in the treatment of tumors. PMID- 23649992 TI - Bioactivity-guided genome mining reveals the lomaiviticin biosynthetic gene cluster in Salinispora tropica. AB - The use of genome sequences has become routine in guiding the discovery and identification of microbial natural products and their biosynthetic pathways. In silico prediction of molecular features, such as metabolic building blocks, physico-chemical properties or biological functions, from orphan gene clusters has opened up the characterization of many new chemo- and genotypes in genome mining approaches. Here, we guided our genome mining of two predicted enediyne pathways in Salinispora tropica CNB-440 by a DNA interference bioassay to isolate DNA-targeting enediyne polyketides. An organic extract of S. tropica showed DNA interference activity that surprisingly was not abolished in genetic mutants of the targeted enediyne pathways, ST_pks1 and spo. Instead we showed that the product of the orphan type II polyketide synthase pathway, ST_pks2, is solely responsible for the DNA-interfering activity of the parent strain. Subsequent comparative metabolic profiling revealed the lomaiviticins, glycosylated diazofluorene polyketides, as the ST_pks2 products. This study marks the first report of the 59 open reading frame lomaiviticin gene cluster (lom) and supports the biochemical logic of their dimeric construction through a pathway related to the kinamycin monomer. PMID- 23649994 TI - New direct compression excipient from tigernut starch: physicochemical and functional properties. AB - Tigernut starch has been isolated and modified by forced retrogradation of the acidic gel by freezing and thawing processes. Relevant physicochemical and functional properties of the new excipient (tigernut starch modified by acid gelation and accelerated (forced) retrogradation (ST(AM))) were evaluated as a direct compression excipient in relation to the native tigernut starch (ST(NA)), intermediate product (tigernut starch modified by acid gelation (ST(A))), and microcrystalline cellulose (MCC). The particle morphology, swelling capacity, moisture sorption, differential scanning calorimeter (DSC) thermographs and X-ray powder diffraction (XRD) patterns, flow, dilution capacity, and tablet disintegration efficiency were evaluated. The particles of ST(NA) were either round or oval in shape, ST(A) were smooth with thick round edges and hollowed center while ST(AM) were long, smooth, and irregularly shaped typically resembling MCC. The DSC thermographs of ST(NA) and MCC showed two endothermic transitions as compared with ST(A) and ST(AM) which showed an endothermic and an exothermic. The moisture uptake, swelling, flow, and dilution capacity of ST(AM) were higher than those of MCC, ST(A), and ST(NA). The XRD pattern and moisture sorption profile of ST(AM) showed similarities and differences with ST(NA), ST(A), and MCC that relate the modification. Acetylsalicylic acid (ASA) tablets containing ST(AM) disintegrated at 3+/-0.5 min as compared with the tablets containing ST(NA), ST(A), and MCC which disintegrated at 8.5+/-0.5, 10+/-0.5, and 58+/-0.8 min, respectively. The study shows the physicochemical properties of tigernut starch modified by forced retrogradation as well as its potential as an efficient direct compression excipient with enhanced flow and disintegration abilities for tablets production. PMID- 23649995 TI - Formulation and in vivo evaluation of orally disintegrating tablets of clozapine/hydroxypropyl-beta-cyclodextrin inclusion complexes. AB - The aim of this study was to improve the solubility and oral bioavailability of clozapine (CLZ), a poorly water-soluble drug subjected to substantial first-pass metabolism, employing cyclodextrin complexation technique. The inclusion complexes were prepared by an evaporation method. Phase solubility studies, differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy were used to evaluate the complexation of CLZ with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and the formation of true inclusion complexes. Characterization and dissolution studies were carried out to evaluate the orally disintegrating tablets (ODTs) containing CLZ/HP-beta-CD complexes prepared by direct compression. Finally, the bioavailability studies of the prepared ODTs were performed by oral administration to rabbits. The ODTs showed a higher in vitro dissolution rate and bioavailability compared with the commercial tablets. It is evident from the results herein that the developed ODTs provide a promising drug delivery system in drug development, owing to their excellent performance of a rapid onset of action, improved bioavailability, and good patient compliance. PMID- 23649996 TI - A novel multi-unit tablet for treating circadian rhythm diseases. AB - This study aimed to develop and evaluate a novel multi-unit tablet that combined a pellet with a sustained-release coating and a tablet with a pulsatile coating for the treatment of circadian rhythm diseases. The model drug, isosorbide-5 mononitrate, was sprayed on microcrystalline cellulose (MCC)-based pellets and coated with Eudragit((r)) NE30D, which served as a sustained-release layer. The coated pellets were compressed with cushion agents (a mixture of MCC PH-200/ MCC KG-802/PC-10 at a ratio of 40:40:20) at a ratio of 4:6 using a single-punch tablet machine. An isolation layer of OpadryII, swellable layer of HPMC E5, and rupturable layer of Surelease((r)) were applied using a conventional pan-coating process. Central-composite design-response surface methodology was used to investigate the influence of these coatings on the square of the difference between release times over a 4 h time period. Drug release studies were carried out on formulated pellets and tablets to investigate the release behaviors, and scanning electron microscopy (SEM) was used to monitor the pellets and tablets and their cross-sectional morphology. The experimental results indicated that this system had a pulsatile dissolution profile that included a lag period of 4 h and a sustained-release time of 4 h. Compared to currently marketed preparations, this tablet may provide better treatment options for circadian rhythm diseases. PMID- 23649997 TI - Efficacy of concomitant and adjuvant temozolomide in glioblastoma treatment. A multicentre randomized study. AB - BACKGROUND AND PURPOSE: The common treatment in patients with newly diagnosed glioblastoma multiforme is the ultimately radical surgical removal of the tumour combined with radiotherapy. This study compared safety and efficacy of radiotherapy alone with radiotherapy combined with temozolomide (TMZ) given before, during, and after radiotherapy. MATERIAL AND METHODS: The patients operated on for glioblastoma multiforme during the first 21 postoperative days were randomly assigned to the group treated with radiotherapy alone (involved field radiotherapy in 2 Gy fractions daily five times a week up to the total of 60 Gy over 6 weeks of treatment) or to the group treated with radiotherapy and TMZ, initially in the dose of 200 mg/m2 during 5 postoperative days and after 23 days followed by 75 mg/m2 of body surface area daily, 7 days a week (from the first to the last day of radiotherapy). On completion of radiotherapy, five complementary courses of TMZ were introduced (150-200 mg/m2 for 5 days, repeated every 28 days). The primary outcome measure was overall survival. RESULTS: Fifty eight patients from 3 centres were included in the study. The mean age of patients was 55 years and all the patients underwent a surgical procedure of glioblastoma removal. The mean overall survival in the group treated with TMZ was 16.0 months, whereas in the group with radiotherapy alone the overall survival reached 12.5 months. 24-month survival reached 23% in patients treated with TMZ and 6.7% in those who received radiotherapy only. Haematological complications of third or fourth degree were present in 10% of patients treated with radiotherapy and TMZ. CONCLUSIONS: The introduction of TMZ before, during and after radiotherapy for newly diagnosed glioblastoma multiforme gives clinically and statistically significant improvement of survival with unremarkably increased toxicity of the treatment. PMID- 23649998 TI - Corticomotor excitability in drug-naive patients with Parkinson disease. AB - BACKGROUND AND PURPOSE: This study aimed to assess the indices of corticomotor excitability (CE) in drug-naive Parkinson disease (PD) patients and to investigate its relationship with asymmetry and severity of clinical symptoms. MATERIAL AND METHODS: Eleven (4 men) drug-naive PD patients (mean age: 53.1 +/- 9.8 years) and 13 (7 men) healthy controls (mean age: 51.7 +/- 4.2 years) were included. All PD patients were rated on the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) with measurement of the side-specific score separately for arms and legs. Resting motor threshold (RMT), central silent period (CSP), amplitude of motor evoked potential (MEP) and central motor conduction time (CMCT) evoked by a single pulse of the transcranial magnetic stimulation were recorded in all subjects from the left and right abductor digiti minimi (ADM) and extensor digitorum brevis (EDB). RESULTS: Parkinson disease patients showed higher MEP (1.8 +/- 0.9 vs. 1.1 +/- 0.8 mV, p < 0.05) and shorter CMCT (6.1 +/- 0.9 vs. 7.4 +/- 1.0 ms, p < 0.05) recorded from the ADM on the more affected side. CSP recorded from the more affected ADM was under the normal range in five and from the less affected ADM in four PD patients. For CSP recorded from the EDB, respective values are four for the more affected side and three for the less affected side. The rigidity from the more affected arm and leg correlated negatively with the respective CSP recorded from the ADM (r = -0.74, p < 0.01) and EDB (r = -0.68, p < 0.04). CONCLUSIONS: In the early stage of untreated PD the CE parameters are altered only on the more affected side. The shortening of CSP reflects the severity of rigidity on the more affected side. PMID- 23649999 TI - Reoperations of patients with low-grade gliomas in eloquent or near eloquent brain areas. AB - BACKGROUND AND PURPOSE: Reoperations of patients with recurrent low-grade gliomas (LGG) are not always recommended due to a higher risk of neurological deficits when compared to initial surgery. The purpose of the present study was to evaluate surgical outcomes of patients operated on for recurrent LGG. MATERIAL AND METHODS: Sixteen patients who had surgery for recurrent LGG out of 68 LGG patients who underwent surgery at the Department of Neurosurgery in Sosnowiec, Poland between 2005 and 2011 were enrolled in the study. RESULTS: A large tumour volume prior to the initial surgery was the most significant parameter influencing LGG progression (96.6 cm3 vs. 47.9 cm3, p = 0.01). Increased incidence of epileptic seizures and decreased mental ability according to Karnofsky score were the most common symptoms associated with tumour recurrence. In the group of patients with malignant transformation, the relative cerebral blood volume (rCBV) was considerably increased (1.21 vs. 2.41, p < 0.01). No statistically significant difference was found in terms of the extent of resection between initial surgery and reoperation. Similarly, no significant difference was found in the number of patients with a permanent neurological deficit after initial surgery and reoperation. CONCLUSIONS: Reoperations of the patients with recurrent LGG are not burdened with a higher risk of neurological sequelae when compared to initial surgery. The extent of resection during the surgery for LGG recurrence is comparable to initial surgery. The increase of rCBV seems to be a significant biomarker that indicates malignant transformation. PMID- 23650000 TI - Concentration of 25(OH)D3 and calcium and phosphorus metabolism in patients suffering from relapsing-remitting multiple sclerosis. A pilot study. AB - BACKGROUND AND PURPOSE: The aim of this study was to evaluate the concentration of 25(OH)D3 and the indices of calcium and phosphorus metabolism at different times of relapsing-remitting multiple sclerosis (MS). The relationships between the concentrations of 25(OH)D3 and the indices of calcium-phosphate metabolism were determined, depending on the duration of disease and vitamin and unsaturated fatty acids supplementation. MATERIAL AND METHODS: Thirty patients (15 at the early stage and 15 at the advanced stage of MS) were enrolled. Each patient underwent neurological examination; neurological motor disability was defined according to the Expanded Disability Status Scale (EDSS). The results were compared to the values obtained in the control group (15 individuals) selected according to the age of subjects, their residence, ethnicity and gender. RESULTS: Significantly lower serum concentrations of 25(OH)D3 in MS patients compared to the control group were found. MS patients at the advanced stage of the disease (duration of 5-6 years) had lower 25(OH)D3 concentrations than patients at the early stage of MS. Among patients in an advanced stage of MS, significantly lower levels of 25(OH)D3 were found in women compared to men with a similar level of physical disability. CONCLUSIONS: Lower serum concentrations of 25(OH)D3 in MS patients compared to the control group were found. The lowest concentrations of 25(OH)D3 were found in female patients aged 20-40 and in patients with a longer disease duration without substantial impairment of calcium-phosphate metabolism. PMID- 23650001 TI - Two mutations in one dystrophin gene. AB - BACKGROUND AND PURPOSE: Duchenne/Becker muscular dystrophies (DMD/BMD) lead to progressive irreversible muscle deterioration caused by recessive mutations in the dystrophin encoding gene (Xp21.1). Approximately 60% of mutations are deletions, 10% are duplications and the remaining 30% are point mutations. The aim of the study is to present the rare occurrence of two pathogenic mutations (deletions or duplications) in one allele of the dystrophin gene. MATERIAL AND METHODS: DNA of patients from 1364 DMD/ BMD families was tested. Two techniques - PCR-multiplex and multiplex ligation-dependent probe amplification - were used to search for mutations in the dystrophin gene. RESULTS: Deletion was detected in 648 families and duplication was found in 74 families (analysis in progress). In two families, presence of two mutations in one gene was documented - in the first family two deletions were found (exons 45-49 and 60-61), and in the second family two duplications were detected (exons 2-7 and 50-59). One of the deletions disrupted the reading frame, and the other deletion retained the reading frame. Both duplications also retained the reading frame of the gene but in both families the disease took a severe course (DMD). In the family with two duplications prenatal diagnosis was also carried out, and carriership of both mutations was discovered in the female fetus. CONCLUSIONS: In the analyzed group of DMD/BMD families, the frequency of combined occurrence of two mutations in one gene was 2 per 722 (0.3%). The phenomenon of detected non-contiguous deletions and duplications is presented together with 31 similar cases published so far. PMID- 23650002 TI - The effects of fetal allogeneic umbilical cord tissue transplant following experimental spinal cord injury on urinary bladder morphology. AB - BACKGROUND AND PURPOSE: In continuation of our previous experimental study on spinal cord injury (SCI) using fetal stem cells, we investigated here the effects of fetal allogeneic umbilical cord tissue transplant on the urinary bladder morphology in a rat SCI model. MATERIAL AND METHODS: Five pregnant albino Wistar rats at 12 days of gestation were used to obtain the umbilical cord cell graft. In Group 1 (n = 5), Th8-Th9 laminectomy was performed. Group 2 (n = 5) received spinal cord injury. In Group 3 (n = 5), the cultured fetal umbilical cord cells coated with alginate gel were placed into the lesion cavity. In Group 4 (n = 5), only alginate sponges without umbilical cord cells were placed into the injury cavity. The bladders of animals were analyzed pathologically at 21 days after surgery. RESULTS: The thickness of the epithelium and the lamina propria did not differ among studied groups (p > 0.05). The lamina muscularis thickness was significantly higher in Group 2 and Group 4 than the others (p < 0.05). The bladder weight was similar among Groups 1, 2, and 3 (p > 0.05). Fibrosis was significantly increased in Group 2 (p < 0.05); it was greater in Group 2 than in Group 3 (p < 0.05) but did not differ between Groups 1 and 3 (p > 0.05). CONCLUSIONS: This study suggests that allogeneic umbilical cord tissue transplantation after SCI may prevent bladder wall hypertrophy and fibrosis in the rat SCI model. PMID- 23650003 TI - Evaluation of efficacy, safety and tolerability of fingolimod in patients with the relapsing form of multiple sclerosis - 12-month observation. A preliminary report. AB - BACKGROUND AND PURPOSE: Oral fingolimod 0.5 mg daily was approved in the European Union in 2011 for the treatment of relapsing multiple sclerosis in the aggressive form and as a second line treatment in patients with high disease activity despite interferon beta therapy. The aim of this study was the evaluation of efficacy, safety and tolerance of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) during a 12-month observation period. MATERIAL AND METHODS: The investigated group consisted of 11 patients aged between 23 and 63 years. All patients underwent immunomodulatory treatment (disease modifying drugs - DMD) or immunomodulatory treatment in combination with mitoxantrone (Mx) without a positive effect for 3-5 years. Patients received oral fingolimod 0.5 mg daily during 12 months. Disability was evaluated with Kurtzke Expanded Disability Status Scale (EDSS) scale. Safety and tolerability of fingolimod were evaluated by adverse events monitoring, laboratory tests, and ophthalmological and skin assessment. RESULTS: Before the initiation of fingolimod treatment all the patients progressed in disability and in MRI changes including five cases with gadolinium-enhancing lesions. During fingolimod treatment there was no new relapse in any patient and no patient stopped the treatment because of any adverse event. During the 12-month treatment, EDSS improvement was observed in seven patients, three patients were stable, and one patient progressed by 0.5 point in the EDSS. CONCLUSIONS: In our study patients fingolimod was effective, safe and well tolerated independently of disease activity and previous treatment. PMID- 23650004 TI - The beta-fibrinogen -455G/A gene polymorphism and the risk of ischaemic stroke in a Polish population. AB - BACKGROUND AND PURPOSE: Ischaemic stroke is considered to be multifactorial and interactions between environmental and genetic factors play an important role. Although vascular risk factors are well known, the genetic ones are still undiscovered. In the present study, we assessed the significance of the beta fibrinogen -455G/A gene polymorphism and the risk of ischaemic stroke in a Polish population. MATERIAL AND METHODS: 426 ischaemic stroke patients classified according to stroke aetiologies (small vessel disease, large vessel disease or cardioembolic stroke) and 234 controls were included in the study. The association of the beta-fibrinogen genotypes with ischaemic stroke was tested using logistic regression analysis under dominant, recessive or additive models of inheritance. RESULTS: The allele and genotype distributions of the beta fibrinogen -455G/A gene polymorphism did not differ significantly between patients and controls (patients: G - 75%, GG - 56.6%, GA - 36.8%, AA - 6.6%; controls: G - 73.7%, GG - 57.3%, GA - 32.9%, AA - 9.8%; p > 0.05, chi2). In addition, logistic regression analysis adjusted for the known risk factors, i.e. hypertension, ischaemic heart disease, myocardial infarction, hypercholesterolaemia, diabetes mellitus and smoking, did not show a role of the studied polymorphism in ischaemic stroke. CONCLUSIONS: The beta-fibrinogen 455G/A gene polymorphism is not a risk factor for ischaemic stroke in a Polish population. PMID- 23650005 TI - Lack of association of CR1, PICALM and CLU gene polymorphisms with Alzheimer disease in a Polish population. AB - BACKGROUND AND PURPOSE: Recent genome-wide association studies have indicated 3 new susceptibility loci for Alzheimer disease (AD): complement receptor 1 (CR1), clusterin (CLU), and the phosphatidylinositol-binding clathrin assembly protein (PICALM). We investigated the influence of the rs6656401 single nucleotide polymorphisms (SNP) of the CR1 gene, the rs3851179 SNP of the PICALM gene, and the rs11136000 SNP of the CLU gene on risk of AD in a Polish population. MATERIAL AND METHODS: In 253 Caucasian AD patients and 240 controls, analyses identifying the rs6656401, rs3851179 and rs11136000 SNPs and APOE common polymorphisms were performed. RESULTS: No significant differences were observed in the distribution of the rs6656401 of CR1, rs3851179 of PICALM and rs11136000 of CLU SNPs between AD patients and controls. The APOE epsilon4 common polymorphism was strongly re lated to the risk of AD. CONCLUSION: Our results suggest that investigated SNPs are not associated with AD in a Polish population. PMID- 23650006 TI - [Wilson disease - factors affecting clinical presentation]. AB - Wilson disease (WD) is a genetic disorder with copper metabolism disturbances leading to copper accumulation in many organs with their secondary damage. It is caused by mutation in the ATP7B gene on chromosome 13, which encodes ATP-ase 7B involved in copper transport. The age of neurologic symptom onset in WD is 20-30 years, but there is a wide spectrum of disease including: age at onset, clinical signs and treatment efficacy. More than 500 mutations of ATP7B have been described so far, but the WD genotype does not explain the disease variability. Several other factors are suspected to influence WD presentation, including polymorphisms in the genes encoding: apolipoprotein E, prion-related protein, methyltenetetrahydrofolate reductase, Murr1, antioxidant-1, X-linked inhibitor of apoptosis as well as iron metabolism disturbances, gender impact, inflammatory reactions and oxidative stress. The explanation of their significance can change the therapy of WD. The aim of our study was to review and assess the clinical significance of the factors affecting WD presentation. PMID- 23650007 TI - [Peripheral nervous system involvement in the course of herpes virus infections]. AB - The herpes viruses are associated with both central and pe-ripheral nervous system complications. Patients with symptoms suggestive of herpes viruses infections coexisting with peri-phe-ral nervous system manifestations, especially Guillain-Barre syndrome, mononeuropathy, plexopathy and radiculopathy, should be screened for the herpes viruses infections in the differential diagnosis. The purpose of this review is to discuss the etiology, pathogenesis and treatment of the neuropathies in the course of herpes viruses infections. PMID- 23650008 TI - A case of a solitary form of Castleman disease: ten-year follow-up. AB - Castleman disease (CD) is a rare atypical lymphoproliferative process of obscure pathogenesis. An intracranial localization of the condition is extremely rare. We present a case of a 29-year-old man, who harbored an intracranial plasma cell variant of CD in the form of a tumor mimicking meningioma and was followed up to 10 years after surgical excision of the lesion. The histopathological examination showed massive infiltration of mononuclear cells, composed mainly of lymphocytes and matured plasmocytes, as well as many small thin-walled vessels surrounded with plasma cells and lymphocytes. This picture was consistent with a plasma cell type of CD. Ten-year follow-up supports a notion that total surgical excision of the solitary intracranial infiltration is curative in plasma cell type of CD. PMID- 23650009 TI - Cluster headache - a symptom of different problems or a primary form? A case report. AB - Headache with severe, strictly one-sided unilateral attacks of pain in orbital, supraorbital, temporal localisation lasting 15-180 minutes occurring from once every two days to 8 times daily, typically with one or more autonomic symptoms, is recognized as cluster headache (CH). Headache with normal neurological examination and abnormal neuroimaging studies, mimicking cluster headache, is reported by several authors. We present an elderly woman with a cluster-like headache probably associated with other comorbidities. We differentiate between primary, but 'atypical' CH and symptomatic cluster headache due to frontal sinusitis, pontine venous angioma or vascular compression of the trigeminal nerve root. This headache is not so rare in the general population and its secondary causes must be ruled out before the diagnosis of a primary headache as cluster headache is made. PMID- 23650010 TI - Tuberculosis of the spine masquerading as a spine lymphoma. A case report and discussion of diagnostic and therapeutic traps. PMID- 23650011 TI - [Tadeusz Markiewicz - the researcher's profile and his role in the studies on neuromyelitis optica]. PMID- 23650012 TI - Response to comments by Kalager et al. and Zahl et al. PMID- 23650013 TI - When is protein binding important? AB - The present paper is an ode to a classic citation by Benet and Hoener (2002. Clin Pharm Ther 71(3):115-121). The now classic paper had a huge impact on drug development and the way the issue of protein binding is perceived and interpreted. Although the authors very clearly pointed out the limitations and underlying assumptions for their delineations, these are too often overlooked and the classic paper's message is misinterpreted by broadening to cases that were not intended. Some members of the scientific community concluded from the paper that protein binding is not important. This was clearly not intended by the authors, as they finished their paper with a paragraph entitled: "When is protein binding important?" Misinterpretation of the underlying assumptions in the classic work can result in major pitfalls in drug development. Therefore, we revisit the topic of protein binding with the intention of clarifying when clinically relevant changes should be considered during drug development. PMID- 23650014 TI - Localization of scopolamine induced electrocortical brain activity changes, in healthy humans at rest. AB - To prevent the participants of parabolic flights from nausea they are optionally treated with subcutaneously injected antiemetic scopolamine. The range of side effects of this substance include reductions of the alpha-2 frequency band. Previous studies, however, have given no information as to which generator centers are responsible for this effect. The objective of this study therefore, is to identify the cortex area that may be responsible for this effect. Six participants were subcutaneously administered 0.7 mg of scopolamine. EEG was recorded for 10 minutes before to 20 minutes after injection. Data preprocessing followed including filtering and artifact minimization. A statistical analysis was performed with sLORETA/eLORETA software for each subject over a time window from 3 minutes before to 17-20 minutes after scopolamine injection. Results show, that in the BA7, the precuneus, on both hemispheres suffered a alpha-2 activity decrease in absolute power. The identified brain cortex center is an important hub with high connectivity and centrality values within the neural network. It contributes to the control of movement and to space orientation. Therefore, an activity alteration in this area can possibly explain the antiemetic effect of scopolamine and open a window to understand the origin of motion sickness. PMID- 23650015 TI - A brief history of G-protein coupled receptors (Nobel Lecture). PMID- 23650016 TI - Oligothiophene-bridged bis(arylene ethynylene) small molecules for solution processible organic solar cells with high open-circuit voltage. AB - A new series of conjugated oligothiophene-bridged bis(arylene ethynylene) small molecules have been designed, synthesized, and characterized by photophysical, electrochemical and computational methods. These compounds were found to have optimal LUMO levels that ensure effective charge transfer from these compounds to [6,6]-phenyl-C71-butyric acid methyl ester (PC70BM). They were utilized as good electron-donor materials that can be blended with electron-acceptor PC70BM in the fabrication of solution-processed molecular bulk heterojunction (BHJ) solar cells. All of these BHJ devices showed very high open-circuit voltage (V(oc)) of 0.90-0.97 V, and the best power conversion efficiency achieved was 3.68%. The high V(oc) is consistent with the deeper low-lying HOMO level and is relatively insensitive to the donor : acceptor blend ratio. The spin-coated thin films of these small molecules showed p-channel field-effect charge transport with the hole mobilities of up to 2.04*10(-4) cm(2) V(-1) s(-1). These compounds illuminate the potential of solution-processible small-molecular aryl acetylide compounds for efficient power generation in photovoltaic implementation. PMID- 23650018 TI - In vitro biological and mechanical evaluation of various scaffold materials for myocardial tissue engineering. AB - A cardiac patch is a construct devised in regenerative medicine to replace necrotic heart tissue after myocardial infarctions. The cardiac patch consists of a scaffold seeded with stem cells. To identify the best scaffold for cardiac patch construction we compared polyurethane, Collagen Cell Carriers, ePTFE, and ePTFE SSP1-RGD regarding their receptiveness to seeding with mesenchymal stem cells isolated from umbilical cord tissue. Seeding was tested at an array of cell seeding densities. The bioartificial patches were cultured for up to 35 days and evaluated by scanning electron microscopy, microscopy of histological stains, fluorescence microscopy, and mitochondrial assays. Polyurethane was the only biomaterial which resulted in an organized multilayer (seeding density: 0.750 * 10(6) cells/cm(2)). Cultured over 35 days at this seeding density the mitochondrial activity of the cells on polyurethane patches continually increased. There was no decrease in the E Modulus of polyurethane once seeded with cells. Seeding of CCC could only be realized at a low seeding density and both ePTFE and ePTFE SSP1-RGD were found to be unreceptive to seeding. Of the tested scaffolds polyurethane thus crystallized as the most appropriate for seeding with mesenchymal stem cells in the framework of myocardial tissue engineering. PMID- 23650017 TI - A comparison of D2 receptor specific binding in obese and normal-weight individuals using PET with (N-[(11)C]methyl)benperidol. AB - Previous PET imaging studies have demonstrated mixed findings regarding dopamine D2/D3 receptor availability in obese relative to nonobese humans. Nonspecific D2/D3 radioligands do not allow for separate estimation of D2 receptor (D2R) and D3 receptor (D3R) subtypes of the D2 receptor family, which may play different roles in behavior and are distributed differently throughout the brain. These radioligands are also displaceable by endogenous dopamine, confounding interpretation of differences in receptor availability with differing levels of dopamine release. The present study used PET imaging with the D2R-selective radioligand (N-[(11)C] methyl)benperidol ([(11)C]NMB), which is nondisplaceable by endogenous dopamine, to estimate D2R specific binding (BPND) and its relationship to body mass index (BMI) and age in 15 normal-weight (mean BMI = 22.6 kg/m(2)) and 15 obese (mean BMI = 40.3 kg/m(2)) men and women. Subjects with illnesses or taking medications that interfere with dopamine signaling were excluded. Striatal D2R BPND was calculated using the Logan graphical method with cerebellum as a reference region. D2R BPND estimates were higher in putamen and caudate relative to nucleus accumbens, but did not differ between normal-weight and obese groups. BMI values did not correlate with D2R BPND . Age was negatively correlated with putamen D2R BPND in both groups. These results suggest that altered D2R specific binding is not involved in the pathogenesis of obesity per se and underscore the need for additional studies evaluating the relationship between D3R, dopamine reuptake, or endogenous dopamine release and human obesity. PMID- 23650019 TI - Unmet needs in the prediction and detection of metastases in prostate cancer. AB - The therapeutic landscape for the treatment of advanced prostate cancer is rapidly evolving, especially for those patients with metastatic castration resistant prostate cancer (CPRC). Despite advances in therapy options, the diagnostic landscape has remained relatively static, with few guidelines or reviews addressing the optimal timing or methodology for the radiographic detection of metastatic disease. Given recent reports indicating a substantial proportion of patients with CRPC thought to be nonmetastatic (M0) are in fact metastatic (M1), there is now a clear opportunity and need for improvement in detection practices. Herein, we discuss the current status of predicting the presence of metastatic disease, with a particular emphasis on the detection of the M0 to M1 transition. In addition, we review current data on newer imaging technologies that are changing the way metastases are detected. Whether earlier detection of metastatic disease will ultimately improve patient outcomes is unknown, but given that the therapeutic options for those with metastatic and nonmetastatic CPRC vary, there are considerable implications of how and when metastases are detected. PMID- 23650020 TI - Oncology comparative effectiveness research: a multistakeholder perspective on principles for conduct and reporting. AB - Comparative effectiveness research (CER) can assist patients, clinicians, purchasers, and policy makers in making more informed decisions that will improve cancer care and outcomes. Despite its promise, the factors that distinguish CER from other types of evidence remain mysterious to many oncologists. One concern is whether CER studies will improve decision making in oncology or only add to the massive amount of research information that decision makers must sift through as part of their professional responsibilities. In this report, we highlight several issues that distinguish CER from the most common way evidence is generated for cancer therapy-phase I-III clinical trials. To identify the issues that are most relevant to busy decision makers, we assembled a panel of active professionals with a wide range of roles in cancer care delivery. This panel identified five themes that they considered most important for CER in oncology, as well as fundamental threats to the validity of individual CER studies-threats they termed the "kiss of death" for their applicability to practice. In discussing these concepts, we also touched upon the notion of whether cancer is special among health issues with regard to how evidence is generated and used. PMID- 23650021 TI - Factors influencing the effectiveness of scalp cooling in the prevention of chemotherapy-induced alopecia. AB - The success of scalp cooling in preventing or reducing chemotherapy-induced alopecia (CIA) is highly variable between patients and chemotherapy regimens. The outcome of hair preservation is often unpredictable and depends on various factors. Methods. We performed a structured search of literature published from 1970 to February 2012 for articles that reported on factors influencing the effectiveness of scalp cooling to prevent CIA in patients with cancer. Results. The literature search identified 192 reports, of which 32 studies were considered relevant. Randomized studies on scalp cooling are scarce and there is little information on the determinants of the result. The effectiveness of scalp cooling for hair preservation depends on dose and type of chemotherapy, with less favorable results at higher doses. Temperature seems to be an important determinant. Various studies suggest that a subcutaneous scalp temperature less than 22 degrees C is required for hair preservation. Conclusions. The effectiveness of scalp cooling for hair preservation varies by chemotherapy type and dose, and probably by the degree and duration of cooling. PMID- 23650022 TI - Intervertebral disc internal deformation measured by displacements under applied loading with MRI at 3T. AB - PURPOSE: Noninvasive assessment of tissue mechanical behavior could enable insights into tissue function in healthy and diseased conditions and permit the development of effective tissue repair treatments. Measurement of displacements under applied loading with MRI (dualMRI) has the potential for such biomechanical characterization on a clinical MRI system. METHODS: dualMRI was translated from high-field research systems to a 3T clinical system. Precision was calculated using repeated tests of a silicone phantom. dualMRI was demonstrated by visualizing displacements and strains in an intervertebral disc and compared to T2 measured during cyclic loading. RESULTS: The displacement and strain precisions were 24 um and 0.3% strain, respectively, under the imaging parameters used in this study. Displacements and strains were measured within the intervertebral disc, but no correlations were found with the T2 values. CONCLUSION: The translation of dualMRI to a 3T system unveils the potential for in vivo studies in a myriad of tissue and organ systems. Because of the importance of mechanical behavior to the function of a variety of tissues, it's expected that dualMRI implemented on a clinical system will be a powerful tool in assessing the interlinked roles of structure, mechanics, and function in both healthy and diseased tissues. PMID- 23650023 TI - The impact of positive circumferential margin on survival following oesophagectomy using the new 7th TNM classification. AB - OBJECTIVES: Previous studies looking at the influence of positive circumferential margin (CRM) on survival after oesophagectomy are conflicting. This may be due to the fact that older versions of the TNM classification were used, which do not predict survival as accurately as the new 7th edition. We examine whether CRM involvement has an impact on survival when the 7th TNM classification is used. METHODS: Over a 10-year period, 199 patients who had undergone potentially curative resection for oesophageal cancer with postoperative histopathological T3 were identified. A total of 151 (75.9%) were found to have CRM involvement (<1 mm), and these were compared with patients in whom the CRM was free of tumour. Cancers were staged according to the International Union against Cancer TNM 7th edition. First, univariate and then multivariate Cox regression analysis were performed to assess the factors influencing survival. Potentially significant predictors (P < 0.1) from the univariate analysis were inserted in the forward stepwise Cox regression model and was allowed to remain in the final model if a P value of <0.05 was achieved. A sub-group analysis was also performed for different N-stages (N0-N3). RESULTS: After all analyses were performed, CRM involvement was found to have no effect on survival following oesophagectomy [hazard ratio 1.28 (95% CI: 0.82-2.01) (P = 0.28)]. This was seen for all N stages. Stage of disease, age at operation, % predicted forced expiratory volume in 1 second and shortness of breath [(according to New York Heart Association classification)] were all significant predictors of survival. CONCLUSIONS: With this study, it became clear that CRM involvement does not affect long-term survival of patients after oesophagectomy. Patients with CRM involvement should not necessarily be considered to have had an incomplete resection. PMID- 23650024 TI - Surgery following primary right ventricular outflow tract stenting for Fallot's tetralogy and variants: rehabilitation of small pulmonary arteries. AB - OBJECTIVES: Primary surgical repair of Tetralogy of Fallot (ToF) in small infants with small pulmonary arteries (PAs) or complex anatomies can be hazardous. We assessed the effect of right ventricular outflow tract (RVOT) stenting on subsequent surgical intervention with attention to growth of the PAs. METHODS: Primary RVOT stenting was performed in 32 symptomatic patients with ToF physiology. Twenty patients had surgical intervention, with 15 undergoing complete repair to date. Median age at stenting was 61 (range 8-406) days, and median weight, 3.9 (range 1.8-12.2) kg. RESULTS: Stenting improved saturations from 72 +/- 8 to 92 +/- 2% (P < 0.001). Four patients required early surgical palliation for persistent desaturation (within 4 weeks). Twenty patients went on to have surgical intervention at a median time of 220 days after stenting. There was no operative mortality after complete repair. Removing the stent lengthened the procedure time and 86% required transannular patch (TAP; bypass time 109 +/- 42 min, cross clamp 68 +/- 29 min). Median intensive therapy unit stay was 2 days. There was 1 late death at 3 months due to chronic lung disease. The median left PA Z-score increased from a preinterventional value of -1.27 (-0.19 to 2.87) to a presurgical value of +0.11 (-4.12 to +1.97). The median right PA Z score increased from -2.02 (-1.77 to -4.68) to -0.65 (-0.29 to -2.04) over the preinterventional and presurgical time intervals. Growth was greatest in the right PA. CONCLUSIONS: Primary RVOT stenting facilitates staged palliation for ToF in small infants and complex anatomies. Improved PA blood flow generated by the stent leads to growth of the branch PAs and may improve the substrate for subsequent surgical repair. Surgery is safe; however, the majority will require a TAP. PMID- 23650025 TI - The next generation of fenestrated endografts: results of a clinical trial to support an expanded indication for aortic arch aneurysm treatment. AB - OBJECTIVES: Short- and mid-term data regarding the use of precurved, fenestrated endografts have shown that these devices are both safe and effective in carefully selected patients. The first generation of the product was limited to patients with proximal landing zones (LZs) of >20 mm. The next generation of these endografts has been refined to enable the treatment of patients with shorter proximal seal zones (<20 mm), using smaller fenestrations and a greater diversity of skeletons. We reviewed the clinical studies involving the next-generation product and analysed the morphological characteristics of aortic arch aneurysms that were successfully treated. METHODS: Next-generation endografts were used to treat 393 patients with aortic arch aneurysms at 35 medical institutions during 2010 and 2011. There were 371 (94%) patients with sealing zones <20 mm and 244 (62%) with sealing zones <15 mm. The proximal sealing length was 2-35 (14.2 +/- 5.1) mm. RESULTS: Technical success was achieved in 390 (99.2%) patients. Of the treated patient population, 6 patients died, 7 experienced strokes and 17 were subsequently identified to have Type I endoleaks. In cases with proximal LZs <15 mm, the aneurysm was more likely to develop an endoleak. The proximal sealing zones (11 +/- 12 vs 9 +/- 13 mm) were not significantly associated with the development of endoleaks, but the proximal aortic diameters were (34.0 +/- 13.3 vs 36.6 +/- 6.3 mm; P < 0.01), in the univariate analysis. In the discriminant analysis, the maximum length of the aneurysm was the only factor that was predictive of Type I endoleaks (73 +/- 55 vs 97 +/- 59 mm; P < 0.001). CONCLUSIONS: The next generation of precurved, fenestrated endografts shows promise as devices for aortic arch aneurysms with a <15-mm proximal sealing zone. These devices have a significant advantage in cases where the LZ has a short neck. However, more refinement is necessary to prevent Type I endoleaks, so that these devices can be used with aortic vessels with large proximal diameters and large aneurysms. PMID- 23650026 TI - How could right ventricular outflow tract stenting be made into one of the many small steps on the long road to solid evidence of rehabilitation of pulmonary arteries? PMID- 23650027 TI - BRAF V600E mutation detection by immunohistochemistry in colorectal carcinoma. AB - The serine/threonine-protein kinase B-raf (BRAF) is an oncogene mutated in various neoplasms, including 5-15% of colorectal carcinomas. The T1799A point mutation, responsible for a large majority of these alterations, results in an amino acid substitution (V600E) causing the constitutive activation of a protein kinase cascade. BRAF V600E in MLH1 deficient tumors implicates somatic tumor-only methylation of the MLH1 promoter region instead of a germline MLH1 mutation. BRAF V600E also predicts poor prognosis in microsatellite stable colorectal cancers and may be a marker of resistance to anti-EGFR therapy in metastatic disease. Currently, only molecular methods are available for assessing BRAF mutational status. An immunohistochemical approach is evaluated here. Colon cancers from 2008 to 2012 tested by pyrosequencing for BRAF V600E mutation were selected. A total of 31 tumors with (n = 14) and without (n = 17) the BRAF V600E mutation were analyzed by immunohistochemistry using a commercially available antibody specific to the V600E-mutated protein. All 14 colorectal carcinomas with the BRAF V600E mutation demonstrated cytoplasmic positivity in tumor cells with the anti BRAF antibody. In a minority of cases, staining intensity for the mutated tumor samples was weak (n = 2) or heterogeneous (n = 4); however, the majority of cases showed diffuse, strong cytoplasmic positivity (8 of 14 cases). None of the 17 BRAF wild-type colorectal cancers showed immunoreactivity to the antibody. The overall sensitivity and specificity of the immunohistochemical BRAF V600E assay was 100%. Detection of the BRAF V600E mutation in colorectal cancer by immunohistochemistry is a viable alternative to molecular methods. PMID- 23650028 TI - An innovative, interdisciplinary, and multi-technique study of gilding and painting techniques in the decoration of the main altarpiece of Miranda do Douro Cathedral (XVII-XVIII(th) centuries, Portugal). AB - The research results presented in this paper are part of a larger study on the materials and techniques used in polychrome altarpieces of gilded woodcarving decoration ("talha dourada") in Portugal. The paper focuses on a narrative Portuguese Altarpiece from Miranda do Douro, considered one of the masterpieces of "talha dourada" among all the retables of the Iberian Peninsula in XVII(th) and XVIII(th) centuries. Although on the Portuguese territory, the altarpiece was made by artists from the Royal Spanish school of Valladolid, under a mannerist style. Thus the study opens a window on the artists' circulation between Spain and Portugal and influences of the Spanish schools in Baroque epoch on the Portuguese "talha". During its history this altarpiece underwent several transformations and extensive conservation treatments in 1989. On this occasion more than 50 samples were collected and analyzed using an interdisciplinary multi technique methodology. 27 of these samples are chosen for this study in order to investigate the chromatic palette, the materials and techniques used in the polychromy of the retable. A novel protocol of investigation using different conventional and unconventional analytical techniques (OM + fluorescent staining tests on cross-sections, Raman microscopy, XRD, XRF, X-ray micro-CT, SEM-EDX, MALDI-TOF-MS and LC-MS/MS) was established within an innovative research project (http://sites.fct.unl.pt/gilt-teller/) and applied on these samples. This protocol is necessary to confirm the results obtained in the 1989 campaign and to have further insight into the gilding and polychrome decoration materials and techniques and the additional information reported in the historical documents. The material and technical history of this important altarpiece will be thus re documented from a scientific perspective, meant to confirm and bring new information on the decorative technique used in the creation of this complex Portuguese monument. PMID- 23650029 TI - Self-assembled monolayers of phosphonic acids with enhanced surface energy for high-performance solution-processed N-channel organic thin-film transistors. PMID- 23650030 TI - Expanding sports drug testing assays: mass spectrometric characterization of the selective androgen receptor modulator drug candidates RAD140 and ACP-105. AB - RATIONALE: Anabolic agents have been top-ranked for many years among statistics of adverse analytical findings compiled by the World Anti-Doping Agency (WADA). Besides archetypical anabolic-androgenic steroids (AAS), alternative substances with similar effects concerning bone and muscle anabolism have been therapeutically pursued. A prominent emerging class of drugs is the chemically heterogeneous group of selective androgen receptor modulators (SARMs), some of which have been detected in doping control samples between 2009 and 2012 despite missing clinical approval. METHODS: In order to support the momentum of expanding the preventive and proactive measures among anti-doping laboratories, the analytical characterization of substances with misuse potential is of great importance. In the present study, the SARM drug candidates RAD140 (comprising a 5 phenyloxadiazole nucleus) and ACP-105 (bearing an N-substituted tropanol pharmacophore) were studied regarding their mass spectrometric behavior under ESI MS(/MS) and EI-MS(/MS) conditions. Reference material was synthesized according to established protocols and dissociation pathways of RAD140 and ACP-105 were elucidated with liquid chromatography/electrospray ionization quadrupole/time-of flight or iontrap/orbitrap and gas chromatography/electron ionization quadrupole/time-of-flight high resolution/high accuracy mass spectrometry. RESULTS: Fragmentation pathways to diagnostic product ions of RAD140 (e.g. m/z 223 and 205 using ESI-MS/MS and m/z 421 and 349 using EI-MS/MS) and ACP-105 (such as m/z 233 and 193 or 231 and 217 for ESI-MS/MS and EI-MS/MS measurements, respectively) were proposed as substantiated by determined elemental compositions and MS(n) experiments as well as comparison to spectra of a structural analog. Notably, for the formation of the characteristic fragment ion at m/z 421 of RAD140, the comparably seldom intramolecular migration of a trimethylsilyl residue triggered by electron ionization was suggested as corroborated by all of the above-mentioned analytical means. CONCLUSIONS: The obtained data will support future sports drug testing methods and facilitate and accelerate the implementation of this analyte and related compounds or metabolites in both GC/MS(/MS)- and LC/MS(/MS)-based routine doping control procedures. PMID- 23650031 TI - Metabolite identification of a new tyrosine kinase inhibitor, HM781-36B, and a pharmacokinetic study by liquid chromatography/tandem mass spectrometry. AB - RATIONALE: HM781-36B (1-[4-[4-(3,4-dichloro-2-fluorophenylamino)-7 methoxyquinazolin-6-yloxy]-piperidin-1-yl]prop-2-en-1-one hydrochloride) is a new anticancer drug to treat advanced solid tumors in clinical trial. In order to understand the behavior of HM781-36B in vitro and in vivo we validated an analytical method for HM781-36B and its major metabolites in plasma. METHODS: In vivo and in vitro metabolism of HM781-36B was studied in dog plasma, urine and feces as well as using human and dog liver microsomes with extraction by ethyl acetate or methyl tert-butyl ether, respectively, and successfully separated by high-performance liquid chromatography diode-array detection mass spectrometry (HPLC-DAD/MS). Ten metabolites were identified by LC/ESI-ion trap mass spectrometry (MS, MS(2) , MS(3) and MRM) and LC/Q-TOF-MS/MS for exact mass measurement. For accurate characterization of the major metabolites, authentic standards (M1, M2, M4, and M10) were synthesized. RESULTS: Ten metabolites of HM781-36B in an in vitro mixture were separated and identified by LC/ESI-MS(n) . The MS/MS spectral patterns of the parent drug and metabolites exhibited two characteristic ions (A- and B-type ions) attributed to the cleavage of the ether bond between the piperidine ring and the quinazoline ring, providing important information on the site of chemical conversion during the metabolism. Six hydroxylated derivatives including dehalogenation and demethylation, two N-oxide forms, a demethylated form and de-acryloylpiperideine metabolites were observed. CONCLUSIONS: The LC/ESI-ion trap MS(n) technique was effective in obtaining structural information and yielded diagnostic ions for the identification of diverse metabolites. The multiple metabolic pathways of HM781-36B were suggested in in vitro and in vivo samples and the dihydroxylation (M1) and demethylation (M2) appeared to be the major metabolites. PMID- 23650032 TI - Laser desorption ionisation quadrupole ion trap time-of-flight mass spectrometry of titanium-carbon thin films. AB - RATIONALE: Titanium-carbon (Ti-C) ceramic thin films (abbreviated as n-TiC/a-C:H) are very important for industrial applications. However, their chemical structure is still not completely resolved. The aim of this study was to determine the chemical composition of such n-TiC/a-C:H layers prepared by balanced magnetron sputtering under various experimental conditions. METHODS: Mass spectrometric analysis of Ti-C thin films was carried out via laser desorption ionisation (LDI) using a quadrupole ion trap and reflectron time-of-flight analyser. The stoichiometry of clusters formed via laser ablation was determined, and the relative abundances of species for which the isotopic patterns overlaps were estimated using a least-squares program. RESULTS: Ti-C films were found to be composites of (i) pure and hydrogenated TiC, (ii) titanium oxycarbides, and (iii) titanium oxides of various degrees of hydrogenation (all embedded in an amorphous and/or diamond-like carbon matrix). Hydrogenated titanium oxycarbide was the main component of the surface layer, whereas deeper layers were composed primarily of TiC and titanium oxides (also embedded in the carbon matrix). CONCLUSIONS: Mass spectrometry proved useful for elucidating the chemical structure of the hard ceramic-like Ti-C layers produced by magnetron sputtering. The Ti-C layers were found to be complex composites of various chemical entities. Knowledge of the resolved structure could accelerate further development of these kinds of materials. PMID- 23650033 TI - Analysis of mexicanolide- and phragmalin-type limonoids from Heynea trijuga using high-performance liquid chromatography/electrospray tandem mass spectrometry. AB - RATIONALE: Limonoids, a class of tetranortriterpenoids, exhibit various biological effects, including acting as potent antifeedants and insect growth regulators against various pests. The analysis of phragmalin- and mexicanolide type limonoids by collision-induced dissociation tandem mass spectrometry (CID MS/MS) has not been reported. METHODS: A high-performance liquid chromatography/electrospray ionization (HPLC/ESI)-MS/MS method was developed to investigate the fragmentation patterns of [M+NH4 ](+) ions for nine reference phragmalin- and mexicanolide-type limonoids. The method was also used in the identification of limonoid compounds in botanic extracts of Heynea trijuga. RESULTS: The losses of side chains and the furan part were the major fragmentation patterns. However, there was variation in the relative abundances of product ions resulting from the same fragmentation pathways. A total of 89 phragmalin- and mexicanolide-type limonoids in botanic extracts of Heynea trijuga were detected and 50 of these compounds were identified or tentatively characterized based on elemental constituents, fragmentation pathways, and the profile of the major product ions of reference compounds. In addition, the isomers could be tentatively distinguished. CONCLUSIONS: An HPLC/ESI-MS/MS method was developed and could be used to simultaneously identify and screen phragmalin- and mexicanolide-type limonoids in botanic extracts of Heynea trijuga. PMID- 23650034 TI - A miniature condensed-phase membrane introduction mass spectrometry (CP-MIMS) probe for direct and on-line measurements of pharmaceuticals and contaminants in small, complex samples. AB - RATIONALE: High-throughput, automated analytical measurements are desirable in many analytical scenarios, as are rapid sample pre-screening techniques to identify 'positive' samples for subsequent measurements using more time-consuming conventional methodologies (e.g., liquid chromatography/mass spectrometry (LC/MS)). A miniature condensed-phase membrane introduction mass spectrometry (CP MIMS) probe for the direct and continuous, on-line measurement of pharmaceuticals and environmental contaminants in small, complex samples is presented. METHODS: A miniature polydimethylsiloxane hollow fibre membrane (PDMS-HFM) probe is coupled with an electrospray ionization (ESI) triple quadrupole mass spectrometer. Analytes are transported from the probe to the ESI source by a methanol acceptor phase. The probe can be autosampler mounted and directly inserted in small samples (>=400 MUL) allowing continuous and simultaneous pptr-ppb level detection of target analytes (chlorophenols, triclosan, gemfibrozil, nonylphenol) in complex samples (artificial urine, beer, natural water, waste water, plant tissue). RESULTS: The probe has been characterized and optimized for acceptor phase flow rate, sample mixing and probe washing. Signal response times, detection limits and calibration data are given for selected ion monitoring (SIM) and tandem mass spectrometry (MS/MS) measurements of target analytes at trace levels. Comparisons with flow cell type CP-MIMS systems are given. Analyte depletion effects are evaluated for small samples (>=400 MUL). On-line measurements in small volumes of complex samples, temporally resolved reaction monitoring and in situ/in vivo demonstrations are presented. CONCLUSIONS: The miniature CP-MIMS probe developed was successfully used for the direct, on-line detection of target analytes in small volumes (40 mL to 400 MUL) of complex samples at pptr to low ppb levels. The probe can be readily automated as well as deployed for in situ/in vivo monitoring, including reaction monitoring, small sample measurements and direct insertion in living plant tissue. PMID- 23650035 TI - Analysis of furo[3,2-c]tetrahydroquinoline and pyrano[3,2-c]tetrahydroquinoline derivatives as antitumor agents and their metabolites by liquid chromatography/electrospray ionization tandem mass spectrometry. AB - RATIONALE: Tetrahydroquinoline derivatives possess a broad range of biological activities. Since few studies have been reported concerning metabolites of furo[3,2-c]tetrahydroquinoline- and pyrano[3,2-c]tetrahydroquinoline-derived antitumor agents, the proposed fragmentation mechanisms and their metabolites were investigated in this study. METHODS: The fragmentation pathways of eight furo[3,2-c]tetrahydroquinoline derivatives and six pyrano[3,2 c]tetrahydroquinoline derivatives were analyzed using electrospray ionization tandem mass spectrometry. Hydrogen/deuterium (H/D) exchange reactions were employed to identify the proposed structures of the product ions. In addition, compounds were incubated with human liver microsomes (HLM) at 37 degrees C for 8 h and the related metabolites were analyzed by liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). RESULTS: Two protonation modes were summarized and protonation occurring on the oxygen atom of furan or pyran ring could trigger the cleavage of the C-O bond, followed by the elimination of a molecule of water and the substituent at the C2 site, respectively. On the other hand, a proton added to the nitrogen atom may lead to the loss of dihydrofuran or dihydropyran from the protonated molecules. Apart from the general proposed fragmentation pathways above, the variations on the C2 site could result in some specific fragmentation patterns. Further incubating compound B1 with HLM in vitro produced two major metabolites, and the structures were proposed by tandem mass experiments together with the fragmentation mechanisms of these compounds. CONCLUSIONS: These observations play an important role in monitoring and characterization of the presence and metabolites of furo[3,2-c]tetrahydroquinoline and pyrano[3,2-c]tetrahydroquinoline derivatives in complex mixtures, and can provide some applications in further pharmaceutical and therapeutic research. PMID- 23650036 TI - Surface-activated chemical ionization-electrospray ionization mass spectrometry combined with two-dimensional serial chromatography is a powerful tool for drug stability studies. AB - RATIONALE: Drug stability is an important quality-control issue for pharmaceutical and clinical practices. Among the analytical techniques that address this issue, liquid chromatography/mass spectrometry (LC/MS) can be very useful, especially when assessing the quality of liquid formulations, because it is intrinsically sensitive, selective, and a rapid analytical technique. However, LC/MS suffers from technical drawbacks, e.g., matrix effects, and the production of in-source degradation products, which can limit its usefulness. METHODS: To overcome the aforementioned drawbacks associated with LC/MS, we introduce an innovative approach (2D-LC/SACI-ESI-MS/MS) that incorporates two-dimensional liquid chromatography (2D-LC) in conjunction with an MS system consisting of a surface-activated chemical ionization-electrospray ionization chamber (SACI-ESI), an ion trap MS analyzer, and tandem mass spectrometry. RESULTS: To validate our 2D-LC/SACI-ESI-MS/MS system stability studies were performed on the computerized tomography contrast agents, iohexol, iodixanol, iopamidol, iomeprol, iopromide, and iobitridol, either alone or in binary combination. The matrix effects, in source analyte degradation, and analytical performance were compared with those obtained using a one-dimensional LC/MS configuration. The accuracy coefficient of variance (CV) = 1-4%, and degradation (loss of water and other chemical moieties) was greatly reduced, attesting to the usefulness of this system for drug stability measurements. CONCLUSIONS: Our new approach improves the performance (sensitivity, accuracy, and signal stability) of LC/MS instrumentation for drug stability measurements by reducing signal suppression effects and in-source chemical reactions. PMID- 23650037 TI - Investigation of Galaxolide degradation products generated under oxidative and irradiation processes by liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry and comprehensive two-dimensional gas chromatography/time-of flight mass spectrometry. AB - RATIONALE: Polycyclic musks have become a concern due to their bioaccumulation potential and ecotoxicological effects. The HHCB transformation product (TP) (1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl-cyclopenta[gamma]-2-benzopyran; HHCB-lactone) is the most stable intermediate generated and it is frequently detected in river waters. The aim of this work was the identification of relevant TPs generated from UV irradiation and ozone treatments. METHODS: Identification of HHCB TPs was carried out by liquid chromatography/hybrid quadrupole time-of flight mass spectrometry (LC/ESI-QTOF-MS) and two-dimensional gas chromatography/electron impact time-of-flight mass spectrometry (GC*GC-EI-TOF MS). With LC/ESI-QTOF-MS, TPs were characterized by means of mass accuracy in both full-scan and MS/MS modes through information-dependent acquisition (IDA) and direct injection on-column. With stir bar sorptive extraction (SBSE)-GC*GC-EI TOF-MS, identification was based on the enhanced separation capacity and screening of unknowns through the acquisition of full-range mass spectra. RESULTS: The effectiveness of these complementary techniques allowed a detailed evaluation of the main TPs. Eighteen TPs were elucidated based on mass accuracy, in both full-scan and MS/MS modes using LC/ESI-QTOF-MS with mass errors below 5 ppm and 10 ppm (mostly), respectively. Most of the TPs had not been analytically identified in previous studies. Separation of the enantiomeric species (R) and (S) of HHCB-lactone, and the identification of other relevant TPs, was performed using SBSE-GC*GC-EI-TOF-MS. CONCLUSIONS: LC/ESI-QTOF-MS and GC*GC-EI-TOF-MS analysis provides the best alternative for TP identification of chemicals of concern, which have a wide range of polarities and isobaric compounds. A prediction of PBT (persistence, bioaccumulation and toxicity) using the PBT Profiler program suggested a classification of 'very persistent' and 'very toxic' for most of the TPs identified. PMID- 23650038 TI - Applicability of non-linear versus linear fractional abundance calibration plots for the quantitative determination of triacylglycerol regioisomers by tandem mass spectrometry. AB - RATIONALE: Regioisomeric analysis of triacylglycerols is important in understanding lipid biochemistry and the involvement of lipids in disease and nutrition. The use of calibration plots employing fractional abundances provides a simple and rapid method for such analyses. These plots are believed to be linear, but evidence exists for non-linearity. The behavior of such plots needs to be understood to allow for proper interpretation of regioisomeric data. METHODS: Solutions of five regioisomer pairs were prepared from pure standards and used to construct calibration plots using triple-stage tandem mass spectrometry (MS(3) ) with electrospray ionization (ESIMS(3) ) and cationization by lithium ions. The data were taken by direct infusion with an AB SCIEX QTRAP 2000 QqLIT mass spectrometer. RESULTS: Non-linear calibration plots were observed for the four isomer pairs containing the polyunsaturated eicosapentaenoic (20:5) and docosahexaenoic (22:6) acids paired with palmitic acid (16:0) or myristic acid (14:0), while the pair including palmitic and stearic (18:0) acids provided a linear plot. A non-linear model was developed for these plots and then verified experimentally. CONCLUSIONS: The fractional abundance calibration plots used in regioisomeric analysis of triacylglycerols are intrinsically non-linear, but may appear linear if the scatter in data points obscures the curvature, if the curvature is slight, or if the response factors for the two isomers in the regioisomer pair are similar. Therefore, linearity should not be assumed for these types of measurements until confirmed experimentally. PMID- 23650039 TI - Dehydrodimerization of pterostilbene during electrospray ionization mass spectrometry. AB - RATIONALE: Pterostilbene is a member of the hydroxystilbene family of compounds commonly found in plants such as blueberry and grapes. During the analysis of this compound by electrospray ionization mass spectrometry (ESI-MS), an ion was observed that corresponds to the dehydrodimer of pterostilbene in mass-to-charge ratio. Since such unexpected dimerization may lead to decreased monomer signal during quantitative analysis, it was of interest to identify the origin and structure of the observed pterostilbene dimer and examine the experimental conditions that influence its formation. METHODS: Liquid Chromatography/Mass Spectrometry (LC/MS), Nuclear Magnetic Resonance (NMR), and High-Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) were used to examine the origin of the dimerization products. The structure of the formed pterostilbene dimer was examined by performing MS(n) analysis on the dimer ion. Effects of solvent composition, analyte concentration, radical scavenger, and other experimental conditions on the dimerization were also studied. RESULTS: LC/MS and NMR analyses clearly showed that the starting solution did not contain the pterostilbene dimer. Solvent type and radical scavenger concentration were found to have pronounced effects on the dimer formation. Particularly, presence of acetonitrile or ammonium acetate had favorable effects on the extent of dimerization during ESI-MS analysis whereas hydroquinone and butylated hydroquinone had negative effects. Dimer formation decreased at high flow rates and when fused-silica capillary was used as the spray needle. CONCLUSIONS: The data indicate that this dimerization occurs as a result of solution-phase electrochemical reactions taking place during the electrospray process. A possible structure for this dimer was proposed based on the MS(n) analysis and was similar to that of the enzymatically derived pterostilbene dehydrodimer already reported in the literature. PMID- 23650040 TI - Interpreting raw biological mass spectra using isotopic mass-to-charge ratio and envelope fingerprinting. AB - RATIONALE: Soft ionization, high-resolution mass spectrometry is widely used to characterize large biological molecules, such as proteins. Deconvolution ('deisotoping') of isotopic envelopes (iEs) in biological mass spectra into monoisotopic or average masses is challenging due to low signals and heavily overlapped iEs, resulting in many wrong interpretations. METHODS: Isotopic envelopes (iEs) are directly used without deisotoping to identify biological molecules. An algorithm, isotopic mass-to-charge ratio (m/z) and envelope fingerprinting (iMEF), was implemented in the ProteinGoggle search engine for top down intact protein database searching. iMEF combines isotopic m/z fingerprinting (iMF) and isotopic envelop fingerprinting (iEF), where 'Isotopic mass-to-charge ratio' means the m/z value of the most abundant isotopic peak within the iE of a precursor or product ion. iMF is used to 'fish' precursor or product ion candidates from the database, which is pre-built and contains all iE information (precursor and product ions) of all proteoforms of the studied system. iEF identifies matching precursor or product ions. A protein is finally identified with user-specified total number of matching product ions and post-translational modification scores. RESULTS: The working principles of iMEF and ProteinGoggle, and the definition of a set of related parameters and scoring metrics, are illustrated with high-resolution tandem mass spectrometric analysis of a mixture of ubiquitin and the HUMAN histone H4 proteoforms. Ubiquitin was confidently identified from its CID, ETD, and HCD spectra with 57, 91, and 66 matching product ions, respectively; 125 proteoforms were confidently found from the H4 dataset. The locations of PTMs in 54 and 6 isoforms were partially and fully identified. CONCLUSIONS: Database search with iMEF bypasses 'deisotoping' avoiding associated errors, and also provides full quality control of matching precursor and product ions and finally protein IDs. Overlapped iEs of different product ions could also be confidently unwrapped in situ. Improvement and addition of more functionalities and utilities of ProteinGoggle are underway. PMID- 23650041 TI - Use of graphene as a matrix to minimize reduction in the process of matrix assisted laser desorption/ionization. PMID- 23650042 TI - Size distributions of ambient shock-generated particles: implications for inlet ionization. PMID- 23650043 TI - On the structural, mechanical, and biodegradation properties of HA/beta-TCP robocast scaffolds. AB - Hydroxyapatite/beta-tricalcium phosphate (HA/beta-TCP) composite scaffolds have shown great potential for bone-tissue engineering applications. In this work, ceramic scaffold with different HA/beta-TCP compositions (pure HA, 60HA/40beta TCP, and 20HA/80beta-TCP) were fabricated by a robotic-assisted deposition (robocasting) technique using water-based hydrogel inks. A systematic study was conducted to investigate the porosity, mechanical property, and degradation of the scaffolds. Our results indicate that, at a similar volume porosity, the mechanical strength of the sintered scaffolds increased with the decreasing rod diameter. The compressive strength of the fabricated scaffolds (porosity ~ 25-80 vol %) varied between ~3 and ~50 MPa, a value equal or higher than that of human cancellous bone (2-12 MPa). Although there was a slight increase of Ca and P ions in water after 5 month, no noticeable degradation of the scaffolds in SBF or water was observed. Our findings from this work indicate that composite calcium phosphate scaffolds with customer-designed chemistry and architecture may be fabricated by a robotic-assisted deposition method. PMID- 23650044 TI - A tandem chemoenzymatic methylation by S-adenosyl-L-methionine. AB - Keep 'em methylated: The in situ preparation of the cofactor AdoMet was achieved by allowing the biosynthetic enzyme SalL to operate in the reverse direction by presentation of 5'-chloro-5'-deoxyadenosine at low salt concentrations. This reaction was readily coupled with DNA and small molecule methyltransferases to afford a regioselective method for chemo-enzymatic methylation and isotope incorporation. PMID- 23650045 TI - Erythrocyte nitric oxide synthase as a surrogate marker for mercury-induced vascular damage: the modulatory effects of naringin. AB - In this study, endothelial nitric oxide synthase activity and nitric oxide (NO) production by human erythrocytes in the presence and absence of mercuric chloride (HgCl2 ), L-arginine (L-ARG), N omega- nitro-L-arginine methyl ester (L-NAME), and naringin (NAR) were investigated. In addition, the levels of reduced glutathione (GSH) and related enzymes were estimated in erythrocytes hemolysate. The protein carbonyl content (PCC) and thiobarbituric acid-reactive substances (TBARS) levels were also determined. The results of this study revealed that the treatment of erythrocytes with either HgCl2 or L-NAME induced a significant decrease in NOS activity and nitrite levels compared with control cells. Furthermore, mercury exposure significantly increased the levels of PCC and TBARS but reduced the GSH level. The activities of glucose-6-phosphate dehydrogenase, glutathione reductase, glutathione peroxidase, and glutathione-S-transferase (GST) were inhibited. The exposure of erythrocytes to HgCl2 in combination with L ARG, NAR, or both ameliorated the investigated parameters compared with erythrocytes incubated with HgCl2 alone. These results indicate that mercury exposure decreased both erythrocyte NOS activity and nitrite production, and that these parameters might be indicative of mercury exposure. The data also suggest that concomitant treatment with NAR can restore NO bioavailability through either its metal-chelating properties or its antioxidant activity. PMID- 23650046 TI - The dissection room experience: A factor in the choice of organ and whole body donation--a Nigerian survey. AB - The psychosocial impact of human dissection on the lives of medical and health science students has been noted. To assess the impact of the dissection room experience on one's willingness to become a whole body and organ donor, the attitudes of 1,350 students and professionals from the medical, health, and non health related disciplines to body and organ donation were studied. The participants were broken into categories according to degree of exposure to human dissection. Participants who were never exposed to the dissection experience showed more willingness to donate their bodies than those who were exposed. With the exception of the physiotherapy department, the students and professionals from the health science departments who were exposed to the dissection room but never engaged in dissection showed the most unwillingness to donate their bodies (P < 0.001). An unwillingness to donate oneself was noted as one of the negative impacts associated with exposure to the dissection room. Willingness to donate an organ correlated positively with the level of exposure to the dissection room (P < 0.001). Most of the reasons for unwillingness were traceable to negative perceptions of the dissection room as a result of poor and disrespectful management of the human cadavers. PMID- 23650047 TI - Intertwined nanocarbon and manganese oxide hybrid foam for high-energy supercapacitors. AB - Rapid charging and discharging supercapacitors are promising alternative energy storage systems for applications such as portable electronics and electric vehicles. Integration of pseudocapacitive metal oxides with single-structured materials has received a lot of attention recently due to their superior electrochemical performance. In order to realize high energy-density supercapacitors, a simple and scalable method is developed to fabricate a graphene/MWNT/MnO2 nanowire (GMM) hybrid nanostructured foam, via a two-step process. The 3D few-layer graphene/MWNT (GM) architecture is grown on foamed metal foils (nickel foam) via ambient pressure chemical vapor deposition. Hydrothermally synthesized alpha-MnO2 nanowires are conformally coated onto the GM foam by a simple bath deposition. The as-prepared hierarchical GMM foam yields a monographical graphene foam conformally covered with an intertwined, densely packed CNT/MnO2 nanowire nanocomposite network. Symmetrical electrochemical capacitors (ECs) based on GMM foam electrodes show an extended operational voltage window of 1.6 V in aqueous electrolyte. A superior energy density of 391.7 Wh kg(-1) is obtained for the supercapacitor based on the GMM foam, which is much higher than ECs based on GM foam only (39.72 Wh kg(-1) ). A high specific capacitance (1108.79 F g(-1) ) and power density (799.84 kW kg(-1) ) are also achieved. Moreover, the great capacitance retention (97.94%) after 13 000 charge discharge cycles and high current handability demonstrate the high stability of the electrodes of the supercapacitor. These excellent performances enable the innovative 3D hierarchical GMM foam to serve as EC electrodes, resulting in energy-storage devices with high stability and power density in neutral aqueous electrolyte. PMID- 23650048 TI - Estimation of causal mediation effects for a dichotomous outcome in multiple mediator models using the mediation formula. AB - Mediators are intermediate variables in the causal pathway between an exposure and an outcome. Mediation analysis investigates the extent to which exposure effects occur through these variables, thus revealing causal mechanisms. In this paper, we consider the estimation of the mediation effect when the outcome is binary and multiple mediators of different types exist. We give a precise definition of the total mediation effect as well as decomposed mediation effects through individual or sets of mediators using the potential outcomes framework. We formulate a model of joint distribution (probit-normal) using continuous latent variables for any binary mediators to account for correlations among multiple mediators. A mediation formula approach is proposed to estimate the total mediation effect and decomposed mediation effects based on this parametric model. Estimation of mediation effects through individual or subsets of mediators requires an assumption involving the joint distribution of multiple counterfactuals. We conduct a simulation study that demonstrates low bias of mediation effect estimators for two-mediator models with various combinations of mediator types. The results also show that the power to detect a nonzero total mediation effect increases as the correlation coefficient between two mediators increases, whereas power for individual mediation effects reaches a maximum when the mediators are uncorrelated. We illustrate our approach by applying it to a retrospective cohort study of dental caries in adolescents with low and high socioeconomic status. Sensitivity analysis is performed to assess the robustness of conclusions regarding mediation effects when the assumption of no unmeasured mediator-outcome confounders is violated. PMID- 23650050 TI - Overdiagnosis of breast cancer in Norway: what have the authors adjusted for? PMID- 23650049 TI - Protective effects of carbenoxolone are associated with attenuation of oxidative stress in ischemic brain injury. AB - Accumulating evidence has suggested that the gap junction plays an important role in the determination of cerebral ischemia, but the underlying mechanisms remain to be elucidated. In this study, we assessed the effect of a gap-junction blocker, carbenoxolone (CBX), on ischemia/reperfusion-induced brain injury and the possible mechanisms. By using the transient cerebral ischemia model induced by occlusion of the middle cerebral artery for 30 min followed by reperfusion for 24 h, we found that pre-administration of CBX (25 mg/kg, intracerebroventricular injection, 30 min before cerebral ischemic surgery) diminished the infarction size in rats. And this was associated with a decrease of reactive oxygen species generation and inhibition of the activation of astrocytes and microglia. In PC12 cells, H2O2 treatment induced more coupling and apoptosis, while CBX partly inhibited the opening of gap junctions and improved the cell viability. These results suggest that cerebral ischemia enhances the opening of gap junctions. Blocking the gap junction with CBX may attenuate the brain injury after cerebral ischemia/reperfusion by partially contributing to amelioration of the oxidative stress and apoptosis. PMID- 23650051 TI - Role of Nrf2 in cancer photodynamic therapy: regulation of human ABC transporter ABCG2. AB - Photodynamic therapy (PDT) is a recently developed anticancer treatment that utilizes the generation of singlet oxygen and other reactive oxygen species in cancer tissue. In response to oxidative stress, NF-E2-related transcription factor (Nrf2) encoded by the NFE2L2 gene plays a key role in transcriptional upregulation of many target genes, including those for metabolizing enzymes and transporters essential for cellular defense. Recent studies have provided evidence that Nrf2 regulates the transcription of the human ABC transporter ABCG2 gene, which is critically involved in the cellular accumulation of porphyrins in PDT. Nrf2 interacts with the antioxidant responsive element (ARE) located in the promoter region of human ABCG2 gene. Nrf2-specific siRNA treatments suppressed the induction of ABCG2 expression after the photoactivation of porphyrins in vitro. One SNP (-617C>A; rs6721961) in the ARE-like loci of the human Nrf2 gene is considered to affect the positive feedback loop of transcriptional activation of the Nrf2 gene as well as its target genes including ABCG2. Since patients have demonstrated individual differences in their response to PDT, Nrf2-mediated transcriptional activation of the ABCG2 gene in cancer may affect patients' responses to PDT as well as chemotherapy. PMID- 23650052 TI - Detection rates of the Fetal Anomaly Screening Programme (FASP) 11 key conditions in one unit: is the recommended annual audit of any value? PMID- 23650053 TI - Exchanges on obesity and smoking. PMID- 23650054 TI - "Enhanced, edgier": a euphemism for "shame and embarrassment"? PMID- 23650055 TI - If shaming reduced obesity, there would be no fat people. PMID- 23650056 TI - Obesity stigma: a failed and ethically dubious strategy. PMID- 23650057 TI - Good and bad ideas in obesity prevention. PMID- 23650058 TI - National obesity rates: a legitimate health policy endpoint? PMID- 23650059 TI - Obesity and blame: elusive goals for personal responsibility. PMID- 23650061 TI - PEPFAR's antiprostitution "loyalty oath": Politicizing Public Health. PMID- 23650062 TI - A "fair use" exception for public health uses of medical information? PMID- 23650064 TI - The predictable irrationality of righteous minds, and the work of ethicists. PMID- 23650063 TI - Found your DNA on the web: reconciling privacy and progress. PMID- 23650065 TI - Preventing sin: the ethics of vaccines against smoking. PMID- 23650066 TI - Shots for tots? PMID- 23650067 TI - "Ever vigilant" in "Ethically Impossible": structural injustice and responsibility in PHS research in Guatemala. PMID- 23650069 TI - Ethical challenges in refugee health: a global public health concern. PMID- 23650071 TI - Catalytic disproportionation of the superoxide intermediate from electrochemical O2 reduction in nonaqueous electrolytes. AB - Tris(pentafluorophenyl)borane (TPFPB) was found to be an efficient catalyst for rapid superoxide (O2(-)) disproportionation. The kinetics for the catalytic disproportionation reaction is much faster than the reaction between O2(-) and propylene carbonate. Therefore, the negative impact of the reaction between the electrolyte and O2(-) produced by the O2 reduction is minimized. The cathodic current for O2 reduction can be doubled in the presence of TPFPB. The high reduction current resulted from the pseudo two-electron O2-reduction reaction due to the replenishment of O2 at the electrode surface. This discovery could lead to a new avenue for the development of high-capacity, high-rate, rechargeable Li-air batteries. PMID- 23650072 TI - Evaluation of the effects of a metabotropic glutamate receptor 5-antagonist on electrically induced pain and central sensitization in healthy human volunteers. AB - BACKGROUND: This study aimed to investigate the effect of a single dose of the mGluR5-antagonist AZD9272 on electrically induced pain, central sensitization and axon reflex flare. METHODS: This was a randomized, double-blind, placebo controlled crossover study. Twenty-five healthy male volunteers received a single oral dose of AZD9272 or placebo on two occasions separated by 10-20 days. Electrical stimulation with a constant current for 100 min delivered through intracutaneous electrodes inserted on the forearm was used to induce a stable level of pain (6 of 10 on a 0-10 numerical rating scale; NRS). Pain intensity was assessed every 10 min during stimulation. The area of punctate hyperalgesia, area of dynamic mechanical allodynia, and area and intensity of flare reaction were measured every 20 min during stimulation. The stimulation procedure, current intensity and measurements were identical at both treatment visits. The AUC0-100 min (area under curve, 100 min stimulation) was calculated for each variable. The AUC0-100 min for pain NRS and hyperalgesia area were defined as primary variables. Linear mixed effects models were used for the statistical analysis. RESULTS: Twenty-one subjects completed the study per protocol. No significant differences were found between AZD9272 and placebo regarding any of the AUC0-100 min variables for pain NRS, hyperalgesia area, allodynia area, flare area or flare intensity. The plasma levels of AZD9272 were maximal during the pain measurements and corresponded to >50% brain mGluR5 receptor occupancy. CONCLUSION: Single doses of the centrally acting mGluR5-antagonist AZD9272 did not reduce C-fibre evoked pain, central sensitization or flare reaction. PMID- 23650074 TI - Variable selection in monotone single-index models via the adaptive LASSO. AB - We consider the problem of variable selection for monotone single-index models. A single-index model assumes that the expectation of the outcome is an unknown function of a linear combination of covariates. Assuming monotonicity of the unknown function is often reasonable and allows for more straightforward inference. We present an adaptive LASSO penalized least squares approach to estimating the index parameter and the unknown function in these models for continuous outcome. Monotone function estimates are achieved using the pooled adjacent violators algorithm, followed by kernel regression. In the iterative estimation process, a linear approximation to the unknown function is used, therefore reducing the situation to that of linear regression and allowing for the use of standard LASSO algorithms, such as coordinate descent. Results of a simulation study indicate that the proposed methods perform well under a variety of circumstances and that an assumption of monotonicity, when appropriate, noticeably improves performance. The proposed methods are applied to data from a randomized clinical trial for the treatment of a critical illness in the intensive care unit. PMID- 23650075 TI - Investigation on infrared laser desorption of solid matrix using scanning electron microscope and fast photography. AB - Infrared light from a pulsed optical parametric oscillator laser system was used to irradiate succinic acid (SA), a usual solid matrix used in matrix-assisted laser desorption ionization, under vacuum. Ablated SA particles were trapped using a silica plate mounted 3.0 mm above and parallel to the sample surface. The morphology and particle size of ablated particles at different laser fluences were investigated using a scanning electron microscope (SEM). The dynamics of plume propagation for SA desorption process was studied with fast photography at atmospheric pressure. Plume expanding at 1.12 J/cm(2) laser fluence was recorded using a high-speed CMOS camera and corresponding propagation distance was measured. The solid matrix desorption was driven by phase explosion according to plume model fitting, which was consistent with the results of SEM. PMID- 23650073 TI - Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes. AB - Inflammation is a common component of acute injuries of the central nervous system (CNS) such as ischemia, and degenerative disorders such as Alzheimer's disease. Glial cells play important roles in local CNS inflammation, and an understanding of the roles for microRNAs in glial reactivity in injury and disease settings may therefore lead to the development of novel therapeutic interventions. Here, we show that the miR-181 family is developmentally regulated and present in high amounts in astrocytes compared to neurons. Overexpression of miR-181c in cultured astrocytes results in increased cell death when exposed to lipopolysaccharide (LPS). We show that miR-181 expression is altered by exposure to LPS, a model of inflammation, in both wild-type and transgenic mice lacking both receptors for the inflammatory cytokine TNF-alpha. Knockdown of miR-181 enhanced LPS-induced production of pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1beta, IL-8) and HMGB1, while overexpression of miR-181 resulted in a significant increase in the expression of the anti-inflammatory cytokine IL-10. To assess the effects of miR-181 on the astrocyte transcriptome, we performed gene array and pathway analysis on astrocytes with reduced levels of miR-181b/c. To examine the pool of potential miR-181 targets, we employed a biotin pull-down of miR-181c and gene array analysis. We validated the mRNAs encoding MeCP2 and X linked inhibitor of apoptosis as targets of miR-181. These findings suggest that miR-181 plays important roles in the molecular responses of astrocytes in inflammatory settings. Further understanding of the role of miR-181 in inflammatory events and CNS injury could lead to novel approaches for the treatment of CNS disorders with an inflammatory component. PMID- 23650076 TI - Constitutive formulations for the mechanical investigation of colonic tissues. AB - A constitutive framework is provided for the characterization of the mechanical behavior of colonic tissues, as a fundamental tool for the development of numerical models of the colonic structures. The constitutive analysis is performed by a multidisciplinary approach that requires the cooperation between experimental and computational competences. The preliminary investigation pertains to the review of the tissues histology. The complex structural configuration of the tissues and the specific distributions of fibrous elements entail the nonlinear mechanical behavior and the anisotropic response. The identification of the mechanical properties requires to perform mechanical tests according to different loading situations, as different loading directions. Because of the typical functionality of colon structures, the tissues mechanics is investigated by tensile tests, which are performed on taenia coli and haustra specimens from fresh pig colons. Accounting for the histological investigation and the results from the mechanical tests, a specific hyperelastic framework is provided within the theory of fiber-reinforced composite materials. Preliminary analytical formulations are defined to identify the constitutive parameters by the inverse analysis of the experimental tests. Finite element models of the specimens are developed accounting for the actual configuration of the colon structures to verify the quality of the results. The good agreement between experimental and numerical model results suggests the reliability of the constitutive formulations and parameters. Finally, the developed constitutive analysis makes it possible to identify the mechanical behavior and properties of the different colonic tissues. PMID- 23650077 TI - Rational design of anode materials based on Group IVA elements (Si, Ge, and Sn) for lithium-ion batteries. AB - Lithium-ion batteries (LIBs) represent the state-of-the-art technology in rechargeable energy-storage devices and they currently occupy the prime position in the marketplace for powering an increasingly diverse range of applications. However, the fast development of these applications has led to increasing demands being placed on advanced LIBs in terms of higher energy/power densities and longer life cycles. For LIBs to meet these requirements, researchers have focused on active electrode materials, owing to their crucial roles in the electrochemical performance of batteries. For anode materials, compounds based on Group IVA (Si, Ge, and Sn) elements represent one of the directions in the development of high-capacity anodes. Although these compounds have many significant advantages when used as anode materials for LIBs, there are still some critical problems to be solved before they can meet the high requirements for practical applications. In this Focus Review, we summarize a series of rational designs for Group IVA-based anode materials, in terms of their chemical compositions and structures, that could address these problems, that is, huge volume variations during cycling, unstable surfaces/interfaces, and invalidation of transport pathways for electrons upon cycling. These designs should at least include one of the following structural benefits: 1) Contain a sufficient number of voids to accommodate the volume variations during cycling; 2) adopt a "plum pudding"-like structure to limit the volume variations during cycling; 3) facilitate an efficient and permanent transport pathway for electrons and lithium ions; or 4) show stable surfaces/interfaces to stabilize the in situ formed SEI layers. PMID- 23650078 TI - Combined saturation/inversion recovery sequences for improved evaluation of scar and diffuse fibrosis in patients with arrhythmia or heart rate variability. AB - PURPOSE: To develop arrhythmia-insensitive inversion recovery sequences for improved visualization of myocardial scar and quantification of diffuse fibrosis. METHODS: A novel preparation pre-pulse, called saturation pulse prepared heart rate-independent inversion recovery, is introduced, which consists of a combination of saturation and inversion pulses to remove the magnetization history in each heartbeat in late gadolinium enhancement (LGE) imaging and eliminate the need for rest periods in T1 mapping. The proposed LGE and T1 mapping sequences were evaluated against conventional LGE and modified Look Locker inversion sequences using numerical simulations, phantom and imaging in healthy subjects and patients with suspected or known cardiovascular disease. RESULTS: Simulations and phantom experiments show that the saturation pulse prepared heart-rate-independent inversion recovery pre-pulse in LGE reduces ghosting artifacts and results in perfect nulling of the healthy myocardium in the presence of arrhythmia. In T1 mapping, saturation pulse prepared heart-rate independent inversion recovery results in (a) reduced scan time (17 vs. 9 heartbeats), (b) insensitivity to heart rate for long T1, and (c) increased signal homogeneity for short T1. LGE images in a patient in atrial fibrillation during the scan show improved myocardial nulling. In vivo T1 maps demonstrate increased signal homogeneity in blood pools and myocardium. CONCLUSION: The proposed sequences are insensitive to heart rate variability, yield improved LGE images in the presence of arrhythmias, as well as T1 mapping with shorter scan times. PMID- 23650080 TI - Serological cross-reactivity between human polyomaviruses. AB - Until 2006, BKPyV and JCPyV were the only known human polyomaviruses. A third polyomavirus, simian virus 40 whose natural host is the macaque was accidently introduced into man because of contaminated poliovirus vaccines, although there is epidemiological evidence that SV40 may be transmitted between man independently from contaminated vaccines. Since 2007, 10 new human polyomaviruses have been identified: KIPyV, WUPyV, Merkel cell polyomavirus, trichodysplasia spinulosa-associated polyomavirus, and human polyomaviruses 6, 7, 9, 10, STL, and 12. Moreover, the DNA of the monkey lymphotropic polyomavirus has been amplified from human peripheral blood. Seroepidemiological studies frequently based on the presence of antibodies against the major capsid protein VP1 or virus-like particles indicate that most human adults have been exposed to many, if not all, human polyomaviruses. However, because of the high amino acid sequence identity between VP1 of some human polyomaviruses, cross-reactivity of antibodies is occasionally observed. In addition, human sera possess reactivity against VP1 of polyomaviruses from other species, suggesting serological cross-reaction with known or closely related, yet unidentified human polyomaviruses and/or the possibility of zoonotic transmission. Thus, current serological results should be interpreted with caution, and controls excluding cross-reactivity with other polyomaviruses are required. PMID- 23650079 TI - Tubal ligation, hysterectomy and epithelial ovarian cancer in the New England Case-Control Study. AB - Previous studies have observed that tubal ligation and hysterectomy are associated with a decreased risk of ovarian cancer; however, little is known about whether these associations vary by surgical characteristics, individual characteristics or tumor histology. We used logistic regression to examine tubal ligation, simple hysterectomy and hysterectomy with unilateral oophorectomy in relation to risk of epithelial ovarian cancer in the New England Case-Control Study. Our primary analysis included 2,265 cases and 2,333 controls. Overall, tubal ligation was associated with a lower risk of epithelial ovarian cancer [odds ratio (OR) = 0.82, 95% confidence interval (CI): 0.68-0.97], especially for endometrioid tumors (OR = 0.45, 95% CI: 0.29-0.69). The inverse association between tubal ligation and ovarian cancer risk was stronger for women who had undergone the procedure at the time of last delivery (OR = 0.60, 95% CI: 0.42 0.84) rather than at a later time (OR = 0.93, 95% CI: 0.75-1.15). Overall, simple hysterectomy was not associated with ovarian cancer risk (OR: 1.09, 95% CI: 0.83 1.42), although it was associated with a nonsignificant decreased risk of ovarian cancer among women who underwent the procedure at age 45 or older (RR: 0.64, 95% CI: 0.40-1.02) or within the last 10 years (OR = 0.65, 95% CI: 0.38-1.13). Overall, women who had a hysterectomy with a unilateral oophorectomy had significantly lower risk of ovarian cancer (OR = 0.65, 95% CI: 0.45-0.94). In summary, tubal ligation and hysterectomy with unilateral oophorectomy were inversely associated with ovarian cancer risk in a large population-based case control study. Additional research is necessary to understand the potential biologic mechanisms by which these procedures may reduce ovarian cancer risk. PMID- 23650081 TI - Medical students' understanding of the concept of a soul. AB - The concept of a soul has been discussed throughout religious, philosophical, and scientific circles, yet no definitive description exists. Recent interviews with medical students during the production of a documentary film identified that many believed in the concept of a soul. This study explores students' understanding of the concept of a soul. The 2011 cohort of second-year medical students at the University of Otago in Dunedin, New Zealand were invited to participate in an online survey with a free text response asking students to describe their understanding of the soul. The descriptions of the soul included the soul as a "spirit" or "life force" and some described the soul as giving a person their "values" and "personality." Students discussed the location of a soul with most stating that the soul was not attached to the body, but others mentioned the heart or the brain as the seat of the soul. A common theme related to the mortality of the soul emerged, with most believing that the soul left the body at death. Some students' concept of a soul was related to their religious beliefs, while others who did not believe in the concept of a soul described it as a "myth" used to bring comfort at the time of death. Medical students have varied opinions on the concept and importance of the soul. It is important to recognize the diversity of views when exploring the process of death and spirituality with medical students. PMID- 23650082 TI - High density unaggregated Au nanoparticles on ZnO nanorod arrays function as efficient and recyclable photocatalysts for environmental purification. AB - Photodegradation of organic pollutants in aqueous solution is a promising method for environmental purification. Photocatalysts capable of promoting this reaction are often composed of noble metal nanoparticles deposited on a semiconductor. Unfortunately, the separation of these semiconductor-metal nanopowders from the treated water is very difficult and energy consumptive, so their usefulness in practical applications is limited. Here, a precisely controlled synthesis of a large-scale and highly efficient photocatalyst composed of monolayered Au nanoparticles (AuNPs) chemically bound to vertically aligned ZnO nanorod arrays (ZNA) through a bifunctional surface molecular linker is demonstrated. Thioctic acid with sufficient steric stabilization is used as a molecular linker. High density unaggregated AuNPs bonding on entire surfaces of ZNA are successfully prepared on a conductive film/substrate, allowing easy recovery and reuse of the photocatalysts. Surprisingly, the ZNA-AuNPs heterostructures exhibit a photodegradation rate 8.1 times higher than that recorded for the bare ZNA under UV irradiation. High density AuNPs, dispersed perfectly on the ZNA surfaces, significantly improve the separation of the photogenerated electron-hole pairs, enlarge the reaction space, and consequently enhance the photocatalytic property for degradation of chemical pollutants. Photoelectron, photoluminescence and photoconductive measurements confirm the discussion on the charge carrier separation and photocatalytic experimental data. The demonstrated higher photodegradation rates demonstrated indicate that the ZNA-AuNPs heterostructures are candidates for the next-generation photocatalysts, replacing the conventional slurry photocatalysts. PMID- 23650084 TI - Better primary stability with porous titanium particles than with bone particles in cemented impaction grafting: an in vitro study in synthetic acetabula. AB - AIMS: Impaction bone grafting creates new bone stock after hip joint replacement. Utilizing a synthetic bone substitute instead of bone might increase primary stability and is not associated with graft shortage and pathogen transmission. This study compares the initial stability of a graft layer of porous titanium particles (TiP), cancellous bone particles, and a 1:2 bone-titanium mix in synthetic cemented acetabular reconstructions. Displacement was measured by radiostereometric analysis after cyclic loading (1 Hz, maximum stress 2.5 MPa). Shear stress resistance was quantified by a lever out test of the cup. Cement penetration was quantified from cross-sections. FINDINGS: Titanium reconstructions showed less residual displacement (0.13 +/- 0.13 mm) than pure bone particle reconstructions (0.57 +/- 0.18 mm) (p < 0.01). Titanium reconstructions were also more resistant to shear stress (p < 0.001). The bone titanium mix showed intermediate results. Cement penetrated deeper into the bone particle graft layers (4.8 +/- 0.7) than into the titanium graft layers (3.8 +/- 0.5 mm) (p < 0.02). CONCLUSIONS: Cemented acetabular revision reconstructions with porous TiP show better initial stability despite less cement penetration than bone particle reconstructions. Realistic preclinical in vivo testing should explore the hypothesis that porous TiP offer a safe alternative to the current gold standard of bone grafts. PMID- 23650083 TI - Magnetic resonance imaging-based three-dimensional bone shape of the knee predicts onset of knee osteoarthritis: data from the osteoarthritis initiative. AB - OBJECTIVE: To examine whether magnetic resonance imaging (MRI)-based 3 dimensional (3-D) bone shape predicts the onset of radiographic knee osteoarthritis (OA). METHODS: We conducted a case-control study using data from the Osteoarthritis Initiative by identifying knees that developed incident tibiofemoral radiographic knee OA (case knees) during followup, and matching them each to 2 random control knees. Using knee MRIs, we performed active appearance modeling of the femur, tibia, and patella and linear discriminant analysis to identify vectors that best classified knees with OA versus those without OA. Vectors were scaled such that -1 and +1 represented the mean non-OA and mean OA shapes, respectively. We examined the relation of 3-D bone shape to incident OA (new-onset Kellgren and Lawrence [K/L] grade >=2) occurring 12 months later using conditional logistic regression. RESULTS: A total of 178 case knees (incident OA) were matched to 353 control knees. The whole joint (i.e., tibia, femur, and patella) 3-D bone shape vector had the strongest magnitude of effect, with knees in the highest tertile having a 3.0 times higher likelihood of developing incident radiographic knee OA 12 months later compared with those in the lowest tertile (95% confidence interval [95% CI] 1.8-5.0, P < 0.0001). The associations were even stronger among knees that had completely normal radiographs before incidence (K/L grade of 0) (odds ratio 12.5 [95% CI 4.0-39.3]). Bone shape at baseline, often several years before incidence, predicted later OA. CONCLUSION: MRI-based 3-D bone shape predicted the later onset of radiographic OA. Further study is warranted to determine whether such methods can detect treatment effects in trials and provide insight into the pathophysiology of OA development. PMID- 23650086 TI - New deposition technique for metal films containing inorganic fullerene-like (IF) nanoparticles. AB - This study describes a new method for fabrication of thin composite films using physical vapor deposition (PVD). Titanium (Ti) and hybrid films of titanium containing tungsten disulphide nanoparticles with inorganic fullerene-like structure (Ti/IF-WS2) were fabricated with a modified PVD machine. The evaporation process includes the pulsed deposition of IF-WS2 by a sprayer head. This process results in IF-WS2 nanoparticles embedded in a Ti matrix. The layers were characterized by various techniques, which confirm the composition and structure of the hybrid film. The Ti/IF-WS2 shows better wear resistance and a lower friction coefficient when compared to the Ti layer or Ti substrate. The Ti/IF films show very good antireflective properties in the visible and near-IR region. Such films may find numerous applications, for example, in the aerospace and medical technology. PMID- 23650087 TI - Discovery of a sexual cycle in Aspergillus lentulus, a close relative of A. fumigatus. AB - Aspergillus lentulus was described in 2005 as a new species within the A. fumigatus sensu lato complex. It is an opportunistic human pathogen causing invasive aspergillosis with high mortality rates, and it has been isolated from clinical and environmental sources. The species is morphologically nearly identical to A. fumigatus sensu stricto, and this similarity has resulted in their frequent misidentification. Comparative studies show that A. lentulus has some distinguishing growth features and decreased in vitro susceptibility to several antifungal agents, including amphotericin B and caspofungin. Similar to the once-presumed-asexual A. fumigatus, it has only been known to reproduce mitotically. However, we now show that A. lentulus has a heterothallic sexual breeding system. A PCR-based mating-type diagnostic detected isolates of either the MAT1-1 or MAT1-2 genotype, and examination of 26 worldwide clinical and environmental isolates revealed similar ratios of the two mating types (38% versus 62%, respectively). MAT1-1 and MAT1-2 idiomorph regions were analyzed, revealing the presence of characteristic alpha and high-mobility-group (HMG) domain genes, together with other more unusual features such as a MAT1-2-4 gene. We then demonstrated that A. lentulus possesses a functional sexual cycle with mature cleistothecia, containing heat-resistant ascospores, being produced after 3 weeks of incubation. Recombination was confirmed using molecular markers. However, isolates of A. lentulus failed to cross with highly fertile strains of A. fumigatus, demonstrating reproductive isolation between these sibling species. The discovery of the A. lentulus sexual stage has significant implications for the management of drug resistance and control of invasive aspergillosis associated with this emerging fungal pathogen. PMID- 23650089 TI - Total synthesis of (-)-rhizopodin. PMID- 23650088 TI - Trypanosoma brucei Tb927.2.6100 is an essential protein associated with kinetoplast DNA. AB - The mitochondrial DNA of trypanosomatid protozoa consists of a complex, intercatenated network of tens of maxicircles and thousands of minicircles. This structure, called kinetoplast DNA (kDNA), requires numerous proteins and multiprotein complexes for replication, segregation, and transcription. In this study, we used a proteomic approach to identify proteins that are associated with the kDNA network. We identified a novel protein encoded by Tb927.2.6100 that was present in a fraction enriched for kDNA and colocalized the protein with kDNA by fluorescence microscopy. RNA interference (RNAi) knockdown of its expression resulted in a growth defect and changes in the proportion of kinetoplasts and nuclei in the cell population. RNAi also resulted in shrinkage and loss of the kinetoplasts, loss of maxicircle and minicircle components of kDNA at similar rates, and (perhaps secondarily) loss of edited and pre-edited mRNA. These results indicate that the Tb927.2.6100 protein is essential for the maintenance of kDNA. PMID- 23650090 TI - Low-temperature oxidation of ethylene over platinum nanoparticles supported on mesoporous silica. PMID- 23650091 TI - Reversible reactivity by optic nerve astrocytes. AB - Reactive astrocytes are typically studied in models that cause irreversible mechanical damage to axons, neuronal cell bodies, and glia. Here, we evaluated the response of astrocytes in the optic nerve head to a subtle injury induced by a brief, mild elevation of the intraocular pressure. Astrocytes demonstrated reactive remodeling that peaked at three days, showing hypertrophy, process retraction, and simplification of their shape. This was not accompanied by any significant changes in the gene expression profile. At no time was there discernible damage to the optic axons, as evidenced by electron microscopy and normal anterograde and retrograde transport. Remarkably, the morphological remodeling was reversible. These findings underscore the plastic nature of reactivity. They show that reactivity can resolve fully if the insult is removed, and suggest that reactivity per se is not necessarily deleterious to axons. This reaction may represent very early events in the sequence that eventually leads to glial scarring. PMID- 23650093 TI - Perspectives and potential applications of mitochondria-targeted antioxidants in cardiometabolic diseases and type 2 diabetes. AB - There is abundant evidence to suggest that mitochondrial dysfunction is a main cause of insulin resistance and related cardiometabolic comorbidities. On the other hand, insulin resistance is one of the main characteristics of type 2 diabetes, obesity, and metabolic syndrome. Lipid and glucose metabolism require mitochondria to generate energy, and when O2 consumption is low due to inefficient nutrient oxidation, there is an increase in reactive oxygen species, which can impair different types of molecules, including DNA, lipids, proteins, and carbohydrates, thereby inducing proinflammatory processes. Factors which contribute to mitochondrial dysfunction, such as mitochondrial biogenesis and genetics, can also lead to insulin resistance in different insulin-target tissues, and its association with mitochondrial dysfunction can culminate in the development of cardiovascular diseases. In this context, therapies that improve mitochondrial function may also improve insulin resistance. This review explains mechanisms of mitochondrial function related to the pathological effects of insulin resistance in different tissues. The pathogenesis of cardiometabolic diseases will be explained from a mitochondrial perspective and the potential beneficial effects of mitochondria-targeted antioxidants as a therapy for modulating mitochondrial function in cardiometabolic diseases, especially diabetes, will also be considered. PMID- 23650092 TI - Transcutaneous electrical nerve stimulation and conditioned pain modulation influence the perception of pain in humans. AB - BACKGROUND: Research in animal models suggests that transcutaneous electrical nerve stimulation (TENS) and conditioned pain modulation (CPM) produce analgesia via two different supraspinal pathways. No known studies have examined whether TENS and CPM applied simultaneously in human subjects will enhance the analgesic effect of either treatment alone. The purpose of the current study was to investigate whether the simultaneous application of TENS and CPM will enhance the analgesic effect of that produced by either treatment alone. METHODS: Sixty healthy adults were randomly allocated into two groups: (1) CPM plus active TENS; (2) CPM plus placebo TENS. Pain threshold for heat (HPT) and pressure (PPT) were recorded from subject's left forearm at baseline, during CPM, during active or placebo TENS, and during CPM plus active or placebo TENS. CPM was induced by placing the subjects' contralateral arm in a hot water bath (46.5 degrees C) for 2 min. TENS (100 MUs, 100 Hz) was applied to the forearm for 20 min at a strong but comfortable intensity. RESULTS: Active TENS alone increased PPT (but not HPT) more than placebo TENS alone (p = 0.011). Combining CPM and active TENS did not significantly increase PPT (p = 0.232) or HPT (p = 0.423) beyond CPM plus placebo TENS. There was a significant positive association between PPT during CPM and during active TENS (r(2) = 0.46; p = 0.003). CONCLUSIONS: TENS application increases PPT; however, combining CPM and TENS does not increase the CPM's hypoalgesic response. CPM effect on PPT is associated with the effects of TENS on PPT. PMID- 23650094 TI - Concise enantioselective synthesis of cephalosporolide B, (4R)-4-OMe cephalosporolide C, and (4S)-4-OMe-cephalosporolide C. AB - Ring around the rosie: The effective enantioselective synthesis of the antimalarial nonenolide title compounds was achieved in a convergent strategy. Oxy-Michael addition reaction was used to introduce the chiral methoxy group at C 4, and ring-closing metathesis (RCM) reaction (53 % yield) facilitated the key construction of the 10-membered ring. PMID- 23650095 TI - Organic-inorganic hybrid supermicroporous iron(III) phosphonate nanoparticles as an efficient catalyst for the synthesis of biofuels. AB - Here we report a novel family of crystalline, supermicroporous iron(III) phosphonate nanomaterials (HFeP-1-3, HFeP-1-2, and HFeP-1-4) with different Fe(III)-to-organophosphonate ligand mole ratios. The materials were synthesized by using a hydrothermal reaction between benzene-1,3,5-triphosphonic acid and iron(III) chloride under acidic conditions (pH ~ 4.0). Powder X-ray diffraction, N2 sorption, transmission and scanning electron microscopy (TEM and SEM) image analysis, thermogravimetric and differential thermal analysis (TGA-DTA), and FTIR spectroscopic tools were used to characterize the materials. The triclinic crystal phase [P1(2) space group] of the hybrid iron phosphonate was established by a Rietveld refinement of the PXRD analysis of HFeP-1-3 by using the MAUD program. The unit cell parameters are a = 8.749(1), b = 8.578(1), c = 17.725(3) A; alpha = 104.47(3), beta = 97.64(1), gamma = 113.56(3) degrees ; and V = 1013.41 A(3). With these crystal parameters, we proposed an 24-membered-ring open framework structure for HFeP-1. Compound HFeP-1-3, with an starting Fe/ligand molar ratio of 3.0, shows the highest Brunauer-Emmett-Telller (BET) surface area of 556 m(2) g(-1) and uniform supermicropores of approximately 1.1 nm. The acidic surface of the porous iron(III) phosphonate nanoparticles was used in a highly efficient and recyclable catalytic transesterification reaction for the synthesis of biofuels under mild reaction conditions. PMID- 23650096 TI - Systematic investigation of parameters affecting the performance of an agitated filter-dryer. AB - A systematic experimental investigation of contact drying operation was carried out in an agitated Charles Thompson filter-dryer. In this study, the effect of process parameters (wall temperature, impeller speed, fill level) on the drying performance in the filter-dryer is quantified as a function of bed temperature and solvent concentration. In addition, the impact of drying conditions on the particle size distribution was also examined. It was found that in the range of parameters investigated, drying rate increased with wall temperature and reduced bed depth. The effect of impeller speed was variable where favorable drying conditions were strongly dependent on the particle properties. Moreover, decrease in the particle size was evident with an increase in impeller speed and decrease in the bed depth due to increased collision frequency and reduction in the fill volume both leading to particle attrition respectively. Besides, the average wall to solid heat transfer coefficient is also estimated for variable operating conditions. PMID- 23650097 TI - Virtually justifiable homicide: the effects of prosocial contexts on the link between violent video games, aggression, and prosocial and hostile cognition. AB - Previous work has shown that playing violent video games can stimulate aggression toward others. The current research has identified a potential exception. Participants who played a violent game in which the violence had an explicitly prosocial motive (i.e., protecting a friend and furthering his nonviolent goals) were found to show lower short-term aggression (Study 1) and show higher levels of prosocial cognition (Study 2) than individuals who played a violent game in which the violence was motivated by more morally ambiguous motives. Thus, violent video games that are framed in an explicitly prosocial context may evoke more prosocial sentiments and thereby mitigate some of the short-term effects on aggression observed in previous research. While these findings are promising regarding the potential aggression-reducing effects of prosocial context, caution is still warranted as a small effect size difference (d = .2-.3), although nonsignificant, was still observed between those who played the explicitly prosocial violent game and those who played a nonviolent game; indicating that aggressive behavior was not completely eliminated by the inclusion of a prosocial context for the violence. PMID- 23650098 TI - A dose-finding approach based on shrunken predictive probability for combinations of two agents in phase I trials. AB - We develop a novel dose-finding method for two-agent combination phase I trials on the basis of the shrunken predictive probability of toxicity. In this method, a shrinkage logistic regression model that allows distinct shrinkage multipliers for the coefficients of the main effects of two agents and their interaction on the probability of toxicity constructs the toxicity outcome. We also propose dose escalation/de-escalation decision rules on the basis of the shrunken predictive probability of toxicity. Simulation studies under various patterns of monotonic dose-response relationships for combinations of two agents demonstrated that the proposed method performed no worse than the existing two dose-finding methods we selected. PMID- 23650099 TI - A morphological analysis of the transition between the embryonic primitive intestine and yolk sac in bovine embryos and fetuses. AB - The yolk sac (YS) is the main source of embryonic nutrition during the period when the placenta has not yet formed. It is also responsible for hematopoiesis because the blood cells develop from it as part of the primitive embryonic circulation. The objective of this study was to characterize the transitional area between the YS and primitive gut using the techniques of light microscopy, transmission electron microscopy, and immunohistochemistry to detect populations of pluripotent cells by labeling with Oct4 antibody. In all investigated embryos, serial sections were made to permit the identification of this small, restricted area. We identified the YS connection with the primitive intestine and found that it is composed of many blood islands, which correspond to the vessels covered by vitelline and mesenchymal cells. We identified large numbers of hemangioblasts inside the vessels. The mesenchymal layer was thin and composed of elongated cells, and the vitelline endodermal membrane was composed of large, mono- or binucleated cells. The epithelium of the primitive intestine comprised stratified columnar cells and undifferentiated mesenchymal cells. The transitional area between the YS and the primitive intestine was very thin and composed of cells with irregular shapes, which formed a delicate lumen containing hemangioblasts. In the mesenchyme of the transitional area, there were a considerable number of small vessels containing hemangioblasts. Using Oct4 as a primary antibody, we identified positive cells in the metanephros, primordial gonad, and hepatic parenchyma as well as in YS cells, suggesting that these regions contain populations of pluripotent cells. PMID- 23650100 TI - Study of a novel three-dimensional scaffold to repair bone defect in rabbit. AB - Both decalcified bone matrix (DBM) and fibrin gel possess good biocompatibility, so they are used as scaffolds to culture bone marrow mesenchymal stem cells (BMSCs). The feasibility and efficacy of using compound material being made of decalcified bone matrix and fibrin gel as a three-dimensional scaffold for bone growth were investigated. BMSCs were isolated from the femur of rabbit, then seeded in prepared scaffolds after incubation for 28 days in vitro. In vivo: 30 New Zealand White Rabbits received bone defect in left radius and divided three treatment groups randomly: (1) BMSCs/decalcified bone matrix/fibrin glue as experimental group; (2) decalcified bone matrix/fibrin glue without cells as control group; (3) nothing was implanted into the bone defects as blank group. The observation period of specimens was 12 weeks, and were analyzed bone formation in terms of serum proteomics (2D-PAGE and MALDI-TOF-TOF-MS), hematoxylin-eosin (HE) staining, ALP staining, and Osteopontin immunofluorescence detection. The experimental group present in three peculiar kinds of proteins, whose Geninfo identifier (GI) number were 136466, 126722803, and 126723746, respectively, correspond to TTR protein, ALB protein, RBP4 protein, and the histological inspections were superior to the other group. The content of osteopontin in experimental group was significantly higher than control group (p < 0.05). The overall results indicated that a combined material being made of BMSCs/decalcified bone matrix/fibrin glue can result in successful bone formation and decalcified bone matrix/fibrin glue admixtures can be used as a scaffold for bone tissue engineering. PMID- 23650101 TI - Multiple genetic variant association testing by collapsing and kernel methods with pedigree or population structured data. AB - Searching for rare genetic variants associated with complex diseases can be facilitated by enriching for diseased carriers of rare variants by sampling cases from pedigrees enriched for disease, possibly with related or unrelated controls. This strategy, however, complicates analyses because of shared genetic ancestry, as well as linkage disequilibrium among genetic markers. To overcome these problems, we developed broad classes of "burden" statistics and kernel statistics, extending commonly used methods for unrelated case-control data to allow for known pedigree relationships, for autosomes and the X chromosome. Furthermore, by replacing pedigree-based genetic correlation matrices with estimates of genetic relationships based on large-scale genomic data, our methods can be used to account for population-structured data. By simulations, we show that the type I error rates of our developed methods are near the asymptotic nominal levels, allowing rapid computation of P-values. Our simulations also show that a linear weighted kernel statistic is generally more powerful than a weighted "burden" statistic. Because the proposed statistics are rapid to compute, they can be readily used for large-scale screening of the association of genomic sequence data with disease status. PMID- 23650102 TI - A population-based prospective study of energy-providing nutrients in relation to all-cause cancer mortality and cancers of digestive organs mortality. AB - The effect of dietary composition on mortality in low-income countries is largely unknown. We evaluated whether percentages of dietary energy derived from protein, fat and carbohydrates were associated with all-cause and cancer mortalities in a Bangladeshi population. Data from a prospective population-based cohort study of 17,244 men and women were used. Percentages of dietary energy derived from protein, fat and carbohydrates, assessed using a validated food-frequency questionnaire at baseline, were analyzed in relation to mortality over an average of 9 years (155,126 person-years) of follow-up. Cox proportional hazards regression models were used to estimate hazard ratios for all cause, all cancer and cancers of the digestive organs mortalities. Percentage of dietary energy from protein appeared to be significantly associated with cancer mortality. Fully adjusted hazard ratios for cancer mortality in increasing tertiles of percentage of dietary energy from protein were 1.0 (reference), 1.21 (0.73, 2.00) and 1.84 (1.08, 3.15) (p for trend = 0.023). These associations were much stronger for deaths from cancers of the digestive organs with fully adjusted hazard ratios in increasing tertiles of percentage of dietary energy from protein being 1.0 (reference), 2.25 (0.91, 5.59) and 4.85 (1.88, 12.51) (p for trend = 0.001). No significant associations in relation to cancer-related mortality were observed for percentage of dietary energy from fat. Novel findings from this prospective study show protein is an important risk factor or proxy to an important risk factor for cancer mortality especially from digestive organ cancers in Bangladesh. PMID- 23650103 TI - T1rho mapping of pediatric epiphyseal and articular cartilage in the knee. AB - PURPOSE: To evaluate the feasibility of measuring T1rho values in epiphyseal cartilage in children, we have conducted a novel study of spin locking techniques. Adult articular cartilage has been widely studied with spin locking techniques by magnetic resonance imaging. However, no results are available for in vivo T1rho imaging of developing cartilage. MATERIALS AND METHODS: Ten volunteers of age 6 +/- 3 years were recruited to have T1rho mapping performed on the knee at the conclusion of their clinical study. T1rho maps were generated using a spin-lock cluster followed by a fast spin-echo imaging sequence. Regions of interest (ROIs) were placed in non-load-bearing (NLB), load-bearing (LB), and articular cartilage. RESULTS: Student's t-tests were performed to compare means among the ROIs. Mean T1rho for epiphyseal and articular cartilage was 49.8 +/- 9 and 76.6 +/- 7 ms, respectively. LB and NLB T1rho vales were 47.1 +/- 9.5 and 52.5 +/- 9 ms, respectively. Significant differences were found in T1rho values between epiphyseal and articular cartilage layers (P = 0.0001). No difference in T1rho was observed between NLB and LB layers. A modest trend was also noted for epiphyseal and articular cartilage regions with age. CONCLUSION: It is feasible to quantify differences in epiphyseal and articular cartilage layers with SL techniques. T1rho holds promise as a noninvasive method of studying normal and abnormal developmental states of cartilage in children. PMID- 23650104 TI - An enriched multimedia eBook application to facilitate learning of anatomy. AB - This pilot study compared the use of an enriched multimedia eBook with traditional methods for teaching the gross anatomy of the heart and great vessels. Seventy-one first-year students from an Australian medical school participated in the study. Students' abilities were examined by pretest, intervention, and post-test measurements. Perceptions and attitudes toward eBook technology were examined by survey questions. Results indicated a strongly positive user experience coupled with increased marks; however, there were no statistically significant results for the eBook method of delivery alone outperforming the traditional anatomy practical session. Results did show a statistically significant difference in the final marks achieved based on the sequencing of the learning modalities. With initial interaction with the multimedia content followed by active experimentation in the anatomy lab, students' performance was improved in the final test. Obtained data support the role of eBook technology in modern anatomy curriculum being a useful adjunct to traditional methods. Further study is needed to investigate the importance of sequencing of teaching interventions. PMID- 23650105 TI - Multiwall carbon nanotubes mediate macrophage activation and promote pulmonary fibrosis through TGF-beta/Smad signaling pathway. AB - Multiwall carbon nanotubes (MWCNTs) have been widely used in many disciplines due to their unique physical and chemical properties, but have also raised great concerns about their possible negative health impacts, especially through occupational exposure. Although recent studies have demonstrated that MWCNTs induce granuloma formation and/or fibrotic responses in the lungs of rats or mice, their cellular and molecular mechanisms remain largely unaddressed. Here, it is reported that the TGF-beta/Smad signaling pathway can be activated by MWCNTs and play a critical role in MWCNT-induced pulmonary fibrosis. Firstly, in vivo data show that spontaneously hypertensive (SH) rats administered long MWCNTs (20-50 MUm) but not short MWCNTs (0.5-2 MUm) exhibit increased fibroblast proliferation, collagen deposition and granuloma formation in lung tissue. Secondly, the in vivo experiments also indicate that only long MWCNTs can significantly activate macrophages and increase the production of transforming growth factor (TGF)-beta1, which induces the phosphorylation of Smad2 and then the expression of collagen I/III and extracellular matrix (ECM) protease inhibitors in lung tissues. Finally, the present in vitro studies further demonstrate that the TGF-beta/Smad signaling pathway is indeed necessary for the expression of collagen III in fibroblast cells. Together, these data demonstrate that MWCNTs stimulate pulmonary fibrotic responses such as fibroblast proliferation and collagen deposition in a TGF-beta/Smad-dependent manner. These observations also suggest that tube length acts as an important factor in MWCNT induced macrophage activation and subsequent TGF-beta1 secretion. These in vivo and in vitro studies further highlight the potential adverse health effects that may occur following MWCNT exposure and provide a better understanding of the cellular and molecular mechanisms by which MWCNTs induce pulmonary fibrotic reactions. PMID- 23650106 TI - Protein resistance of surfaces modified with oligo(ethylene glycol) aryl diazonium derivatives. AB - Anti-fouling surfaces are of great importance for reducing background interference in biosensor signals. Oligo(ethylene glycol) (OEG) moieties are commonly used to confer protein resistance on gold, silicon and carbon surfaces. Herein, we report the modification of surfaces using electrochemical deposition of OEG aryl diazonium salts. Using electrochemical and contact angle measurements, the ligand packing density is found to be loose, which supports the findings of the fluorescent protein labelling that aryl diazonium OEGs confer resistance to nonspecific adsorption of proteins albeit lower than alkane thiol terminated OEGs. In addition to protein resistance, aryl diazonium attachment chemistry results in stable modification. In common with OEG species on gold electrodes, OEGs with distal hydroxyl moieties do confer superior protein resistance to those with a distal methoxy group. This is especially the case for longer derivatives where superior coiling of the OEG chains is possible. PMID- 23650107 TI - Francis (Frank) Hugh Ruddle (1929-2013). PMID- 23650108 TI - How to image the fetal corpus callosum. PMID- 23650109 TI - Molecular definition of the pro-tumorigenic phenotype of glioma-activated microglia. AB - Microglia are myeloid cells residing in the central nervous system that participate in inflammatory responses and could promote injury and repair. Gliomas attract microglia and polarize them into tumor-supporting cells that participate in matrix remodeling, invasion, angiogenesis, and suppression of adaptive immunity. Although signaling pathways and critical regulators underlying classical inflammation are well established, signal transduction and transcriptional circuits underlying the alternative activation of microglia are poorly known. Using primary rat microglial cultures exposed to glioma conditioned medium or lipopolysaccharide (LPS), we demonstrate that microglia adapt different fates and polarize into pro-inflammatory or alternatively activated cells. Glioma derived factors increased cell motility, phagocytosis, and sustained proliferation of microglial cells that was mediated by enhanced focal adhesion kinase and PI-3K/Akt signaling. The signals from glioma cells induced ERK and p38 MAPK but not JNK signaling and failed to activate pro-inflammatory Stat1 and NFkappaB signaling in microglial cells. Transcriptome analysis of microglial cultures at 6 h after exposure to glioma-conditioned medium or LPS revealed different patterns of gene expression. Glioma-induced activation was associated with induction of genes coding for ID (inhibitor of DNA binding) 1/3 and c-Myc, markers of the alternative phenotype Arg1, MT1-MMP, CXCL14, and numerous cytokines/chemokines implicated in immune cell trafficking. Many classical inflammation-related genes and signaling pathways failed to be induced. Our study indicates for the first time molecular pathways that direct microglia toward the pro-invasive, immunosuppressive phenotype. PMID- 23650110 TI - Silver-catalyzed isocyanide-alkyne cycloaddition: a general and practical method to oligosubstituted pyrroles. PMID- 23650111 TI - Chain-shattering polymeric therapeutics with on-demand drug-release capability. PMID- 23650112 TI - Thiol-yne click reactions on alkynyl-dopamine-modified reduced graphene oxide. AB - The large-scale preparation of graphene is of great importance due to its potential applications in various fields. We report herein a simple method for the simultaneous exfoliation and reduction of graphene oxide (GO) to reduced GO (rGO) by using alkynyl-terminated dopamine as the reducing agent. The reaction was performed under mild conditions to yield rGO functionalized with the dopamine derivative. The chemical reactivity of the alkynyl function was demonstrated by post-functionalization with two thiolated precursors, namely 6 (ferrocenyl)hexanethiol and 1H,1H,2H,2H-perfluorodecanethiol. X-ray photoelectron spectroscopy, UV/Vis spectrophotometry, Raman spectroscopy, conductivity measurements, and cyclic voltammetry were used to characterize the resulting surfaces. PMID- 23650113 TI - Risk of second primary malignancy in patients with AL amyloidosis treated with lenalidomide. PMID- 23650114 TI - Psychodynamic therapy from the perspective of self-organization. a concept of change and a methodological approach for empirical examination. AB - Observations from therapeutic practice and a series of empirical findings, for example, those on discontinuous change in psychotherapeutic processes, suggest modelling the therapeutic process as a self-organizing system with stable and critical instable phases and abrupt transitions. Here, a concept of psychotherapeutic change is presented that applies self-organization theory to psychodynamic principles. The authors explain the observations and considerations that form the basis of the concept and present some connections with existing findings and concepts. On the basis of this model, they generated two hypotheses regarding the co-occurrence of instability and discontinuous change and the degree of synchrony between the therapist and patient. A study design to test these hypotheses was developed and applied to a single case (psychodynamic therapy). After each session, patient and therapist rated their interaction. A measure of instability was calculated across the resulting time series. Sequences of destabilization were observed. On the basis of points of extreme instability, the process was divided into phases. Local instability maxima were accompanied by significant discontinuous change. Destabilization was highly synchronous in therapist and patient ratings. The authors discussed the concept and the methodological procedure. The approach enables the operationalization of crises and to empirically assess the significance of critical phases and developments within the therapeutic relationship. KEY PRACTITIONER MESSAGE: We present a concept of change that applies self-organization theory to psychodynamic therapy. We empirically tested the hypotheses formulated in the concept based on an extract of 125 long-term psychodynamic therapy sessions. We continuously monitored the therapeutic interaction and calculated a measure of the instability of the assessments. We identified several sequences of stable and unstable episodes. Episodes of high instability were accompanied by discontinuous change. On the basis of these episodes of high instability, we divided the process into four phases. Mean values of variables differed across these phases. Destabilization proved to be highly synchronous in therapist and patient ratings. The approach allows to empirically assess critical phases and developments within the therapeutic relationship. PMID- 23650115 TI - Genetic variants in C-type lectin genes are associated with colorectal cancer susceptibility and clinical outcome. AB - Inflammatory responses play a vital role at different stages of colorectal carcinogenesis. C-type lectins mediate inflammatory/immune responses and participate in immune escape of pathogens and tumors. Our study aimed to evaluate the correlation between polymorphisms in three C-type lectin genes, CD209, MBL2 and REG4, and colorectal cancer (CRC) risk and clinical outcome. We genotyped 15 potentially functional single nucleotide polymorphisms (SNPs) and assessed their associations with CRC risk in a case-control study of 1353 CRC cases and 767 healthy controls from the Czech Republic. We also analyzed these SNPs in relation to overall and event-free survival in 414 patients. Two CD209 SNPs were associated with CRC risk after adjustment for multiple comparison. Minor allele carriers of the promoter SNP rs2287886 had an increased risk of CRC (OR 1.30, 95% CI 1.08-1.56), while minor allele carriers of the 3'UTR SNP, rs7248637, had a decreased risk (OR 0.74, 95% CI 0.60-0.91). Multivariate survival analyses, including age, gender, TNM stage and grade, showed that patients without distant metastasis at the time of diagnosis and carrying the rs2994809 T allele had a decreased overall and event-free survival (HR 2.11, 95% CI 1.20-3.72 and HR 2.00, 95% CI 1.18-3.39, respectively). We show that SNPs in CD209 may affect CRC risk, while a SNP in REG4 may be a useful marker for CRC progression. PMID- 23650116 TI - A pharmacokinetic standard for babies and adults. AB - The pharmacokinetic behavior of medicines used in humans follows largely predictable patterns across the human age range from premature babies to elderly adults. Most of the differences associated with age are in fact due to differences in size. Additional considerations are required to describe the processes of maturation of clearance processes and postnatal changes in body composition. Application of standard approaches to reporting pharmacokinetic parameters is essential for comparative human pharmacokinetic studies from babies to adults. A standardized comparison of pharmacokinetic parameters obtained in children and adults is shown for 46 drugs. Appropriate size scaling shows that children (over 2 years old) are similar to adults. Maturation changes are generally completed within the first 2 years of postnatal life; consequently babies may be considered as immature children, whereas children are just small adults. PMID- 23650118 TI - Large-area plasmonic substrate of silver-coated iron oxide nanorod arrays for plasmon-enhanced spectroscopy. AB - One-dimensional iron oxide materials fabricated on conducting glass substrates and their unique properties make these nanostructures promising candidates for a wide range of applications. Herein, vertically oriented alpha-Fe2O3 nanorod arrays synthesized under hydrothermal conditions over a large area are described, as an active platform for surface-enhanced resonance Raman scattering (SERRS) and surface-enhanced fluorescence (SEF). From scanning electron microscopy images the formation of a homogeneous distribution of vertically oriented rods in a large area is confirmed. For activating the localized surface plasmon resonances, which are responsible for SERRS and SEF, a 6 nm layer of Ag is deposited onto the alpha Fe2O3 nanorod arrays by physical vapor deposition to form Ag islands. PMID- 23650117 TI - Sustained delivery of bioactive TGF-beta1 from self-assembling peptide hydrogels induces chondrogenesis of encapsulated bone marrow stromal cells. AB - Tissue engineering strategies for cartilage defect repair require technology for local targeted delivery of chondrogenic and anti-inflammatory factors. The objective of this study was to determine the release kinetics of transforming growth factor beta1 (TGF-beta1) from self-assembling peptide hydrogels, a candidate scaffold for cell transplant therapies, and stimulate chondrogenesis of encapsulated young equine bone marrow stromal cells (BMSCs). Although both peptide and agarose hydrogels retained TGF-beta1, fivefold higher retention was found in peptide. Excess unlabeled TGF-beta1 minimally displaced retained radiolabeled TGF-beta1, demonstrating biologically relevant loading capacity for peptide hydrogels. The initial release from acellular peptide hydrogels was nearly threefold lower than agarose hydrogels, at 18% of loaded TGF-beta1 through 3 days as compared to 48% for agarose. At day 21, cumulative release of TGF-beta1 was 32-44% from acellular peptide hydrogels, but was 62% from peptide hydrogels with encapsulated BMSCs, likely due to cell-mediated TGF-beta1 degradation and release of small labeled species. TGF-beta1 loaded peptide hydrogels stimulated chondrogenesis of young equine BMSCs, a relevant preclinical model for treating injuries in young human cohorts. Self-assembling peptide hydrogels can be used to deliver chondrogenic factors to encapsulated cells making them a promising technology for in vivo, cell-based regenerative medicine. PMID- 23650119 TI - Protective effects of lipoic acid and mesna on cyclophosphamide-induced haemorrhagic cystitis in mice. AB - The protective roles of lipoic acid (LA)/vitamin C (VC) and mesna on preventing cyclophosphamide (CYP)-induced haemorrhagic cystitis (HC) were investigated. Swiss mice were divided into five groups randomly. HC was induced by a single dose of CYP injection (150-mg kg(-1) bodyweight). Group I was injected with saline (four times in total) throughout as control group. Group II received CYP and three equal doses of saline. Group III received CYP and three doses of mesna, whereas Group IV (or Group V) received CYP, mesna + two doses of VC (or LA). All injections were performed intraperitoneally. After 24 h of cystitis induction, the bladders were collected for all the experiments. Histological characterization showed that CYP injection resulted in severe HC. Reactive oxygen species (ROS) and thiobarbituric acid reactive substances' levels were increased in CYP group. The activities of antioxidant enzymes, e.g. superoxide dismutase, catalase, glutathione S-transferase and glutathione peroxidase, were inhibited significantly in CYP groups, respectively. In addition, activation of c-jun N terminal kinases (JNK) and p38 mitogen-activated protein kinase (MAPK) may be involved in the mechanism of CYP-induced HC but not extracellular signal regulated kinases (ERK). Significant suppression of p38 phosphorylation on Group V suggests that LA and mesna may have synergistic beneficial effect. In Groups III-V, all the parameters of HC and oxidative stress were inhibited significantly. Taking together, we found that these results illustrated that ROS play an important role on CYP-induced HC and the administration of LA/VC with mesna may have therapeutic potential against CYP-induced bladder HC. PMID- 23650121 TI - Controlled fabrication of intermolecular junctions of single-walled carbon nanotube/graphene nanoribbon. AB - Intramolecular junctions can be formed in single-walled carbon nanotubes (SWNTs) by introducing a pentagon and/or heptagon into the hexagonal carbon lattice. The realization of these carbon-based molecular electronics is still quite challenging. Here, it is reported that nickel or cobalt catalyzed etching can be applied to partially unzip an SWNT into an intermolecular junction of SWNT/graphene nanoribbon, directly confirmed by atomic force microscopy and Raman spectroscopy. PMID- 23650120 TI - The structural basis of G-protein-coupled receptor signaling (Nobel Lecture). PMID- 23650122 TI - Morphometric evaluation of proximal femur in patients with unilateral total hip prosthesis. AB - It is important to know the morphometric characteristics of the proximal femur. This is necessary to reduce the risk of complications related to surgical procedures performed in the area due to vascular, metabolic, or traumatic causes. It is of importance for achieving the alignment of the prosthesis to be implanted as well. The aim of this study was to evaluate the morphometric characteristics of the proximal femur and to establish a database for making and performing total hip prosthesis. Anteroposterior (AP) pelvic radiographs of 162 cases, with a mean age of 65.6 years, who had undergone unilateral total hip arthroplasty were used in this study. Femoral head diameter (FHD), femoral neck width (FNW), femoral neck length (FNL), femoral neck axis length (FNAL), intertrochanteric line length (ILL), and neck-shaft angle (NSA) were measured on radiographs obtained digitally using setrapacs media. FHD was found to be 48.1 +/- 3.7 mm, FNW 35.4 +/- 4.2 mm, FNL 30.8 +/- 6.1 mm, FNAL 98.6 +/- 9.4 mm, ILL 81.1 +/- 7.9 mm, and NSA 130.4 +/- 5.1 degrees on average. The comparison of the mean values for females and males revealed a statistically significant difference between the FHD, FNW, FNL, FNAL, and ILL (P = 0.000). There was no statistically significant difference in NSA between males and females (P = 0.356). A weak correlation was found between age and parameter values using correlation analysis (r < 0.24, P > 0.05). In morphometric assessment of the proximal femur, taking into consideration regional and sexual differences is of importance for prosthesis design and surgical success. PMID- 23650123 TI - Cytochrome P450 genes induced by bispyribac-sodium treatment in a multiple herbicide-resistant biotype of Echinochloa phyllopogon. AB - BACKGROUND: Incremental herbicide metabolism by cytochrome P450 monooxygenases (P450s) has been proposed as the basis for resistance to bispyribac-sodium (bispyribac) in a multiple-herbicide-resistant biotype of Echinochloa phyllopogon. Upon exposure to bispyribac, strong induction of bispyribac metabolising P450 activity has been reported in the resistant line, indicating that P450s induced by bispyribac are involved in the bispyribac resistance. RESULTS: A polymerase chain reaction (PCR)-based cloning strategy was used to isolate 39 putative P450 genes from the bispyribac-resistant line of E. phyllopogon. Expression analysis by real-time PCR revealed that seven of the isolated genes were upregulated in response to bispyribac treatment of seedlings at the three-leaf stage. The transcript levels and protein sequences of the seven genes were compared between the bispyribac-resistant line and a susceptible line. CYP71AK2 and CYP72A254 were transcribed prominently in the bispyribac-resistant line. Amino acid polymorphisms were found in three genes, including CYP72A254. CONCLUSION: Upregulated expression of these genes is consistent with the inducible herbicide-metabolising P450 activity under bispyribac stress that was reported in a previous study. This is the first study to compare P450 genes in arable weed species in order to elucidate the mechanism for P450-mediated herbicide resistance. PMID- 23650124 TI - A novel approach to identify responder subgroups and predictors of response to low- and high-dose capsaicin patches in postherpetic neuralgia. AB - BACKGROUND: Treatment of chronic pain conditions is commonly assessed at specific endpoints at preset times during or after treatment by analysis of the total study population. An alternative approach is the identification of specific patient subgroups characterized by differential response patterns in their analgesic response and to determine the presence of significant predictors of effect. METHODS: Data from four double-blind, randomized controlled trials on the efficacy of topical capsaicin 8% (Qutenza) versus an active control (capsaicin 0.04%) in patients with postherpetic neuropathic pain were combined. Longitudinal pharmacodynamic, mixture and covariate analyses were performed on the pooled dataset. RESULTS: Data from 1248 patients treated with Qutenza (n = 722) or topical low-dose capsaicin 0.04% (n = 526) were successfully analysed. Five distinct response subgroups were detected with different treatment efficacies, including a group of non-responders, a group showing partial analgesic effect and a group showing full analgesic effect. Active control and Qutenza had similar response profiles, but the proportional distribution of patients among the five response groups was in favour of Qutenza, with 40% less non-responders and 25% more patients showing a full analgesic response. For Qutenza, important predictors of efficacy were efficacy of lidocaine pretreatment and greater pretreatment pain score variability. CONCLUSIONS: The analyses indicate the existence of different response groups to treatment with Qutenza and an active control patch that may possibly be related to different pain mechanisms among these groups, despite a presumed common underlying disease process, and that require different treatment approaches among subgroups. PMID- 23650126 TI - A novel effect of polychlorinated biphenyls: impairment of the tight junctions in the mouse epididymis. AB - Polychlorinated biphenyls (PCBs) exhibit a broad range of adverse biological effects, including reproductive toxicity. However, the mechanisms by which PCBs disrupt the epididymis remain obscure. We analyzed the gene expression profile in mice epididymis exposed to PCBs (Aroclor 1254) at doses comparable to human exposure using a cDNA microarray. Differentially expressed genes were involved in a variety of function categories and biological pathways, including GTP binding, nucleosome assembly, and ribosome and protein disulfide isomerase. The differentially expressed genes related to GTP binding were highly enriched. The abundance of GTP binding proteins related to tight junctions being reduced and the phosphorylation level of their downstream effectors were impaired after exposure to PCBs. The results of tracer studies demonstrated that the permeability of blood-epididymis barrier was increased by PCB exposure. In addition, PCB exposure also disrupted the expression of the tight junction proteins, zonula occludens-1 and occludin. We demonstrated for the first time that exposure to PCBs at doses relevant for the general population was able to affect the blood-epididymis barrier in mice through altering GTP binding and tight junction proteins. Our results provided a novel insight into the molecular mechanisms linking PCB exposure to sperm maturation. PMID- 23650127 TI - CD36 mediates endothelial dysfunction downstream of circulating factors induced by O3 exposure. AB - Inhaled pollutants induce the release of vasoactive factors into the systemic circulation, but little information is available regarding the nature of these factors or their receptors. The pattern recognition receptor CD36 interacts with many damage-related circulating molecules, leading to activation of endothelial cells and promoting vascular inflammation; therefore, we hypothesized that CD36 plays a pivotal role in mediating cross talk between inhaled ozone (O3)-induced circulating factors and systemic vascular dysfunction. O3 exposure (1 ppm * 4h) induced lung inflammation in wild-type (WT) mice, which was absent in the CD36 deficient (CD36(-/-)) mice. Acetylcholine (ACh)-evoked vasorelaxation was impaired in isolated aortas from O3-exposed WT mice but not in vessels from CD36( /-) mice. To delineate whether vascular impairments were caused by lung inflammation or CD36-mediated generation of circulating factors, naive aortas were treated with diluted serum from control or O3-exposed WT mice, which recapitulated the impairments of vasorelaxation observed after inhalation exposures. Aortas from CD36(-/-) mice were insensitive to the effects of O3 induced circulating factors, with robust vasorelaxation responses in the presence of serum from O3-exposed WT mice. Lung inflammation was not a requirement for production of circulating vasoactive factors, as serum from O3-exposed CD36(-/-) mice could inhibit vasorelaxation in naive WT aortas. These results suggest that O3 inhalation induces the release of circulating bioactive factors capable of impairing vasorelaxation to ACh via a CD36-dependent signaling mechanism. Although lung inflammatory and systemic vascular effects were both dependent on CD36, the presence of circulating factors appears to be independent of CD36 and inflammatory responses. PMID- 23650129 TI - Hybrid photoacoustic and ultrasound section imaging with optical ultrasound detection. AB - A setup is proposed that provides perfectly co-registered photoacoustic (PA) and ultrasound (US) section images. Photoacoustic and ultrasound backscatter signals are generated by laser pulses coming from the same laser system, the latter by absorption of some of the laser energy on an optically absorbing target near the imaged object. By measuring both signals with the same optical detector, which is focused into the selected section by use of a cylindrical acoustic mirror, the information for both images is acquired simultaneously. Co-registered PA and US images are obtained after applying the inverse Radon transform to the data, which are gathered while rotating the object relative to the detector. Phantom experiments demonstrate a resolution of 1.1 mm between the sections of both imaging modalities and a in-plane resolution of about 60 um and 120 um for the US and PA modes, respectively. The complementary contrast mechanisms of the two modalities are shown by images of a zebrafish. PMID- 23650128 TI - Arsenic-stimulated lipolysis and adipose remodeling is mediated by G-protein coupled receptors. AB - Arsenic in drinking water promotes a number of diseases that may stem from dysfunctional adipose lipid and glucose metabolism. Arsenic inhibits adipocyte differentiation and promotes insulin resistance; however, little is known of the impacts of and mechanisms for arsenic effects on adipose lipid storage and lipolysis. Based on our earlier studies of arsenic-signaling mechanisms for vascular remodeling and inhibition of adipogenesis, we investigated the hypothesis that arsenic acts through specific adipocyte G-protein-coupled receptors (GPCRs) to promote lipolysis and decrease lipid storage. We first demonstrated that 5-week exposure of mice to 100 MUg/l of arsenic in drinking water stimulated epididymal adipocyte hypertrophy, reduced the adipose tissue expression of perilipin (PLIN1, a lipid droplet coat protein), and increased perivascular ectopic fat deposition in skeletal muscle. Incubating adipocytes, differentiated from adipose-derived human mesenchymal stem cell, with arsenic stimulated lipolysis and decreased both Nile Red positive lipid droplets and PLIN1 expression. Arsenic-stimulated lipolysis was not associated with increased cAMP levels. However, preincubation of adipocytes with the Gi inhibitor, Pertussis toxin, attenuated As(III)-stimulated lipolysis and lipid droplet loss. Antagonizing Gi-coupled endothelin-1 type A and B receptors (EDNRA/EDNRB) also attenuated arsenic effects, but antagonizing other adipose Gi-coupled receptors that regulate fat metabolism was ineffective. The endothelin receptors have different roles in arsenic responses because only EDNRA inhibition prevented arsenic-stimulated lipolysis, but antagonists to either receptor protected lipid droplets and PLIN1 expression. These data support a role for specific GPCRs in arsenic signaling for aberrant lipid storage and metabolism that may contribute to the pathogenesis of metabolic disease caused by environmental arsenic exposures. PMID- 23650130 TI - Preferences of heart failure patients in daily clinical practice: quality of life or longevity? AB - AIMS: Knowledge of patient preferences is vital for delivering optimal healthcare. This study uses utility measurement to assess the preferences of heart failure (HF) patients regarding quality of life or longevity. The utility approach represents the perspective of a patient; facilitates the combination of mortality, morbidity, and treatment regimen into a single score; and makes it possible to compare the effects of different interventions in healthcare. METHODS AND RESULTS: Patient preferences of 100 patients with HF were assessed in interviews using the time trade-off (TTO) approach. Health-related quality of life (HR-QoL) was assessed with the EQ-5D and the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Patients' own estimation of life expectancy was assessed with a visual analogue scale (VAS). Of the 100 patients (mean age 70 +/- 9 years; 71% male), 61% attach more weight to quality of life over longevity; while 9% and 14% were willing to trade 6 and 12 months, respectively, for perfect health and attach more weight to quality of life. Patients willing to trade time had a significantly higher level of NT-proBNP and reported significantly more dyspnoea during exertion. Predictors of willingness to trade time were higher NT proBNP and lower EQ VAS. CONCLUSION: The majority of HF patients attach more weight to quality of life over longevity. There was no difference between both groups with respect to life expectancy described by the patients. These insights enable open and personalized discussions of patients' preferences in treatment and care decisions, and could guide the future development of more patient centred care. PMID- 23650131 TI - Galectin-3 in heart failure with preserved ejection fraction. AB - In the last decades it has been appreciated that many patients with heart failure (HF) suffer from HF with preserved ejection fraction (HFpEF). The diagnosis and treatment of HFpEF is difficult, as we lack specific markers of the disease and no specific treatments have been identified. Galectin-3 has a strong relationship to several aspects of the pathophysiology of HF, especially myocardial fibrosis, the transition from compensated to decompensated HF, and co-morbidities such as renal disease and diabetes. Many of these traits are very commonly observed in patients with HFpEF, and this suggests that galectin-3 may be particularly important and useful in the study of HFpEF. This review summarizes our knowledge of the role of galectin-3 in fibrosis, specifically in experimental models of HF and HFpEF. Galectin-3 may be a marker and also a causal factor, and experimental studies suggested that galectin-3 may be a target for therapy in HFpEF. The detrimental effects of aldosterone may, in part, be conferred via galectin-3, and there are data to suggest that aldosterone blockers are of more benefit in patients with high levels of galectin-3. Furthermore, the relationship of galectin-3 to clinical correlates of developing HFpEF in human subjects is discussed, and the association between increased levels of galectin-3 and new onset HF and mortality in the general population is highlighted. Additionally, the usefulness of galectin-3 in patients with established HFpEF is described. We conclude that galectin-3 may be useful for early detection, phenotyping, risk stratification, and therapeutic targeting of individuals with early or established HFpEF in which fibrosis is a major contributor to the disease. Finally, we propose areas of further research that should validate the role of galectin-3 in HFpEF. PMID- 23650132 TI - The burden of heart failure in Africa. PMID- 23650133 TI - Azulenophenanthrenes from 2,2'-di(arylethynyl)biphenyls through C-C bond cleavage of a benzene ring. PMID- 23650135 TI - Graphitic carbon-nanoparticle-based single-label nanobeacons. AB - Shining a nanobeacon: Single-label nanobeacon sensors were constructed by using graphitic carbon nanoparticles (CNPs) and their oxides as energy acceptors (see figure; FRET=fluorescence resonance energy transfer). Excellent sensing performances were achieved with simplified operation and lowered cost. PMID- 23650134 TI - Pathway-based approaches for sequencing-based genome-wide association studies. AB - For analyzing complex trait association with sequencing data, most current studies test aggregated effects of variants in a gene or genomic region. Although gene-based tests have insufficient power even for moderately sized samples, pathway-based analyses combine information across multiple genes in biological pathways and may offer additional insight. However, most existing pathway association methods are originally designed for genome-wide association studies, and are not comprehensively evaluated for sequencing data. Moreover, region-based rare variant association methods, although potentially applicable to pathway based analysis by extending their region definition to gene sets, have never been rigorously tested. In the context of exome-based studies, we use simulated and real datasets to evaluate pathway-based association tests. Our simulation strategy adopts a genome-wide genetic model that distributes total genetic effects hierarchically into pathways, genes, and individual variants, allowing the evaluation of pathway-based methods with realistic quantifiable assumptions on the underlying genetic architectures. The results show that, although no single pathway-based association method offers superior performance in all simulated scenarios, a modification of Gene Set Enrichment Analysis approach using statistics from single-marker tests without gene-level collapsing (weighted Kolmogrov-Smirnov [WKS]-Variant method) is consistently powerful. Interestingly, directly applying rare variant association tests (e.g., sequence kernel association test) to pathway analysis offers a similar power, but its results are sensitive to assumptions of genetic architecture. We applied pathway association analysis to an exome-sequencing data of the chronic obstructive pulmonary disease, and found that the WKS-Variant method confirms associated genes previously published. PMID- 23650136 TI - Protective effects of hydroxytyrosol on liver ischemia/reperfusion injury in mice. AB - SCOPE: Hydroxytyrosol (HT), a main phenolic compound in olive oil, has been proved to be a potent antioxidant and has beneficial effects on health. However, the effect of HT on oxidative liver damage, as seen in ischemia/reperfusion (I/R) injury, is unknown. Here, we examined whether HT could protect liver against I/R injury. METHODS AND RESULTS: By using a mouse model, we found that HT administration protects against hepatic I/R injury, as indicated by the decreased levels of serum aminotransferase and less parenchymal necrosis and apoptosis. Serum levels of tumor necrosis factor-alpha, interleukin-6, macrophage inflammatory protein 2, as well as reactive oxygen species (ROS) content in liver tissues, were all decreased by HT, the latter correlated with the reduction of hepatic malondialdehyde (an index of oxidative stress) content and increased activities and expressions of liver antioxidant enzymes superoxide dismutase and catalase. The protective effect was also seen in isolated hepatocytes anoxia/reoxygenation assay. CONCLUSION: HT exerts protective effects against hepatic I/R injury in mice, which might be associated with its anti-oxidative, anti-inflammatory, and anti-apoptotic properties. HT may be an effective hepatoprotective agent and a promising candidate for the treatment of liver I/R injury. PMID- 23650137 TI - Diffusion tensor imaging of normal-appearing white matter in unilateral cerebral arterial occlusive disease. AB - PURPOSE: To use MR with diffusion tensor imaging (DTI) and conventional and high b value to assess diffusion changes in normal-appearing white matter (NAWM) in patients with unilateral, severe stenosis, or occlusion of the middle cerebral artery (MCA). MATERIALS AND METHODS: In total, 28 patients with NAWM and unilateral, severe stenosis, or occlusion of the MCA underwent DTI with b values 1000 and 2200 s/mm(2) at 3.0T MR. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), radial diffusivity (eigenvalues lambda1 , lambda2 ), and axial diffusivity (eigenvalue lambda3 ) were measured for the ipsilateral and contralateral corona radiata. RESULTS: Mean FA was significantly lower for the ipsilateral than contralateral corona radiata with high b value, 2200 s/mm(2) , and ipsilateral corona radiata with conventional low b value, 1000 s/mm(2) (all P < 0.01). Mean ADC, lambda1 , lambda2 , and lambda3 were significantly higher for the ipsilateral than contralateral corona radiata with high b value (all P < 0.05) but not for ipsilateral than contralateral corona radiata with low b value (P > 0.05). CONCLUSION: DTI with a high b value detects diffusion changes in NAWM in patients with unilateral, severe stenosis, or occlusion of the MCA not seen with conventional b value or conventional MRI contrasts. PMID- 23650138 TI - Viscosity mixing rules for binary systems containing one ionic liquid. AB - In this work the applicability of four of the most commonly used viscosity mixing rules to [ionic liquid (IL)+molecular solvent (MS)] systems is assessed. More than one hundred (IL+MS) binary mixtures were selected from the literature to test the viscosity mixing rules proposed by 1) Hind (Hi), 2) Grunberg and Nissan (G-N), 3) Herric (He) and 4) Katti and Chaudhri (K-C). The analyses were performed by estimating the average (absolute or relative) deviations, AADs and ARDs, between the available experimental data and the predicted ideal mixture viscosity values obtained by means of each rule. The interaction terms corresponding to the adjustable parameters inherent to each rule were also calculated and their trends discussed. PMID- 23650139 TI - Quantitative atlas of blood-brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset. AB - The purpose of this study was to determine the protein amounts of blood-brain barrier (BBB) permeability-related transporters, receptors, and tight junction proteins in Sprague Dawley and Wistar rats and common marmoset, and also to investigate inter-species and inter-strain differences across rodents and primates. Quantification of target proteins in isolated brain capillaries was conducted by liquid chromatography-tandem mass spectrometry-based quantitative targeted absolute proteomics, with in silico peptide selection. Most target proteins showed inter-rodent, inter-primate species, and inter-rat strain differences of less than 2-fold. Comparison of rat and human BBB showed that P glycoprotein, multidrug resistance-associated protein 4, monocarboxylate transporter 1, l-type amino acid transporter, and organic anion transporter 3 exhibited differences of more than two-fold in protein abundance, whereas the amounts of breast cancer resistance protein, glucose transporter 1, and insulin receptor were similar in rat and human. In contrast, the differences between marmoset and human BBB were less than 2-fold for almost all measured proteins. Thus, the molecular basis of BBB functions may be similar in marmoset and human, whereas that of rats shows significant differences. The marmoset may be a good model to access in vivo human BBB permeability characteristics, as an alternative to rat and macaque monkey. PMID- 23650140 TI - Incompleteness as a link between obsessive-compulsive personality traits and specific symptom dimensions of obsessive-compulsive disorder. AB - This paper examines the contribution of incompleteness/'not just right experiences' (NJREs) to an understanding of the relationship between obsessive compulsive disorder (OCD) and obsessive-compulsive personality traits (OCPTs). It investigates the association of specific OCD symptom dimensions with OCPTs, conceptualized as continuous phenomena that are also observable below the diagnostic threshold. As empirical findings and clinical observation suggest that incompleteness feelings/NJREs may play a significant affective and motivational role for certain OCD subtypes, but also for patients with accentuated OCPTs, we hypothesized that OCPTs are selectively linked with incompleteness-associated OCD symptom dimensions (ordering, checking, hoarding and counting). Moreover, we assumed that this selective relationship cannot be demonstrated any more after statistical control of incompleteness, whereas it is preserved after statistical control of anxiety, depression, pathological worry and harm avoidance. Results from a study with a large clinical sample (n = 185) partially support these hypotheses and suggest that NJREs may be an important connecting link between specific OCD symptom dimensions, in particular ordering and checking, and accentuated OCPTs. KEY PRACTITIONER MESSAGE: Obsessive-compulsive personality traits (OCPTs) are positively related to obsessive-compulsive disorder symptom dimensions (ordering, checking, hoarding and counting) hypothesized or found to be associated with incompleteness/'not just right experiences' (NJREs), but not to washing and obsessions. This positive relationship, which is strongest for ordering and checking, is eliminated when NJREs are statistically controlled. Ordering, checking and accentuated OCPTs may share NJREs as a common affective motivational underpinning.Dysfunctional behaviour patterns of people with accentuated OCPTs or obsessive-compulsive personality disorder (OCPD) may be viewed as efforts to avoid or reduce subjectively intolerable NJREs. On the basis of such a conceptualization of OCPD as an emotional disorder, a novel treatment approach for OCPD focusing on habituation to NJREs could be developed. PMID- 23650141 TI - How does SHIP1/2 balance PtdIns(3,4)P2 and does it signal independently of its phosphatase activity? AB - The number of cellular events identified as being directly or indirectly modulated by phosphoinositides dramatically increased in the recent years. Part of the complexity results from the fact that the seven phosphoinositides play second messenger functions in many different areas of growth factors and insulin signaling, cytoskeletal organization, membrane dynamics, trafficking, or nuclear signaling. PtdIns(3,4)P2 is commonly reported as a product of the SH2 domain containing inositol 5-phosphatases 1/2 (SHIP1 and SHIP2) that dephosphorylate PtdIns(3,4,5)P3 at the 5-position. Here we discuss recent interest in PtdIns(3,4)P2 signaling highlighting its involvement in key cellular mechanisms such as cell adhesion, migration, and cytoskeletal regulation. We question and discuss the involvement of SHIP2 either as a PI 5-phosphatase or as a scaffold protein in insulin signaling, cytoskeletal dynamics, and endocytosis of growth factor receptors. PMID- 23650142 TI - Ultrastructure investigation of the secondary insemination system of the gamasid mite Hattena cometis domrow (Acari: Anactinotrichida: Ameroseiidae). AB - Many gamasid mites, mainly of the taxon Dermanyssina, possess a secondarily evolved insemination system that is generally described as occurring in two types, the laelapid and the phytoseiid-type, which are structurally considerably different. Considering that Dermanyssina represent the most recent and most diverse group of gamasid mites, it was expected that a greater diversity of insemination system than reflected by the two types could be present and could give an idea of its evolution within the taxon. Here, the authors present a description of the fine-structure of the female secondary insemination system in the dermanyssine mite Hattena cometis. The system consists of a pair of sperm induction pores (solenostomes) and short sperm access ducts (tubules) which end in a syncytium. The syncytial strands of both sides meet medially under the ovary s.str., where they form a spherical syncytial spermatheca. Mature sperm cells of a modified ribbon type were seen in the syncytial parts of the system. The insemination system of Hattena cometis is regarded as a modification of the laelapid type. However, it is much simpler than that of Varroa destructor, the only other gamasid mite with the laelapid type studied ultrastructurally until now, and shows also some structural differences (e.g., no presence of an unpaired sperm duct). Hence, the present study suggests that some intermediate types might be revealed in future ultrastructure studies representing steps in the evolution of the insemination system in the Dermanyssina. PMID- 23650143 TI - Jose Maria Vargas (1786-1854): Reformer of anatomical studies in Venezuela. AB - Jose Maria Vargas (1786-1854): Venezuelan medical doctor, surgeon, optician, anatomist, chemist, botanist, professor, geologist, mineralogist, and mathematician. Second President of Venezuela (1835-1836), First republican dean, he reformed medicine studies in 1827 establishing human anatomical dissection in the Universidad Central de Venezuela where he taught human anatomy between 1827 and 1853 along with surgery and chemistry. In 1838, he wrote Curso de Lecciones y demostraciones Anatomicas, the first book on the subject printed in Venezuela for the teaching of human anatomy. PMID- 23650144 TI - Polarization of porous hydroxyapatite scaffolds: influence on osteoblast cell proliferation and extracellular matrix production. AB - Improvements to clinically used biomaterials such as hydroxyapatite (HA) are of potential benefit to the patient. One modification, the addition of surface charges, has been shown to have an important role influencing cell response. In this study, porous HA scaffolds with both positive and negative surface charges were manufactured. The samples were sintered in air to produce porous HA ceramic scaffolds in the form of cylinders 12 mm in height * 7 mm in diameter. These were polarized with a dc voltage of 3 kV/cm. MC3T3E1 cells were placed on either negative or positive ends of the charged (or unpoled control) HA scaffolds. At 7 days, picogreen analysis was performed to analyze the cell number at the negative (4 mm), central (4 mm), and positive (4 mm) portions of the 12 mm cylindrical scaffold. At 4 weeks, micro-CT analysis was performed to quantify the regional volume of mineralized matrix deposition on the 3D scaffold. At 7 days, there were significantly more cells present at the negative end of the scaffold when seeded from the negative end in comparison to the other samples tested. Micro-CT data at 4 weeks correlated with this finding, demonstrating an increase in mineralized matrix at the negatively charged end of the scaffold seeded from the negative end in comparison to the positively charged and unpoled control scaffolds. The results indicate that the charge on HA influences cell activity and that this phenomenon can be translated to a clinically relevant porous scaffold structure. PMID- 23650145 TI - Total syntheses of (+/-)-fawcettimine, (+/-)-fawcettidine, (+/-)-lycoflexine, and (+/-)-lycoposerramine-Q. AB - The total syntheses of four fawcettimine-related Lycopodium alkaloids, (+/-) fawcettimine, (+/-)-fawcettidine, (+/-)-lycoposerramine-Q, and (+/-)-lycoflexine, were completed in a highly stereoselective manner. The Pauson-Khand reaction of 4 methylidene-6-siloxyoct-1-en-7-yne followed by regio- and stereoselective hydrogenation led to the short-step preparation of the bicyclo[4.3.0]nonenone intermediate bearing a methyl group with the required stereochemistry. The subsequent chemical manipulation of the bicyclic compound afforded the 6-5-9 membered tricyclic dioxo compound, which was then transformed into the four targeted alkaloids in an alternative and more efficient fashion. PMID- 23650147 TI - Resveratrol 3-O-D-glucuronide and resveratrol 4'-O-D-glucuronide inhibit colon cancer cell growth: evidence for a role of A3 adenosine receptors, cyclin D1 depletion, and G1 cell cycle arrest. AB - SCOPE: Resveratrol is a plant-derived polyphenol with chemotherapeutic properties in animal cancer models and many biochemical effects in vitro. Its bioavailability is low and raises the possibility that the metabolites of resveratrol have biological effects. Here we investigate the actions of resveratrol 3-O-D-glucuronide, resveratrol 4-O-D-glucuronide, and resveratrol 3-O Dsulfate on the growth of colon cancer cells in vitro. METHODS AND RESULTS: The growth of Caco-2, HCT-116, and CCL-228 cells was measured using the neutral red and MTT assays. Resveratrol and each metabolite inhibited cell growth with IC50 values of 9.8-31 MUM. Resveratrol caused S phase arrest in all three cell lines. Resveratrol 3-O-D-glucuronide and resveratrol 4-O-D-glucuronide caused G1 arrest in CCL-228 and Caco-2 cells. Resveratrol 3-O-D-sulfate had no effect on cell cycle. Growth inhibition was reversed by an inhibitor of AMP-activated protein kinase (compound C) or an adenosine A3 receptor antagonist (MRS1191). The A3 receptor agonist 2Cl-IB-MECA inhibited growth and A3 receptors were detected in all cell lines. The resveratrol glucuronides also reduced cyclin D1 levels but at higher concentrations than in growth experiments and generally did not increase phosphorylated AMP-activated protein kinase. CONCLUSION: Resveratrol glucuronides inhibit cell growth by G1 arrest and cyclin D1 depletion, and our results strongly suggest a role for A3 adenosine receptors in this inhibition. PMID- 23650148 TI - A tetrapositive metal ion in the gas phase: thorium(IV) coordinated by neutral tridentate ligands. PMID- 23650149 TI - Optical induction of muscle contraction at the tissue scale through intrinsic cellular amplifiers. AB - The smooth muscle cell is the principal component responsible for involuntary control of visceral organs, including vascular tonicity, secretion, and sphincter regulation. It is known that the neurotransmitters released from nerve endings increase the intracellular Ca(2+) level in smooth muscle cells followed by muscle contraction. We herein report that femtosecond laser pulses focused on the diffraction-limited volume can induce intracellular Ca(2+) increases in the irradiated smooth muscle cell without neurotransmitters, and locally increased intracellular Ca(2+) levels are amplified by calcium-induced calcium-releasing mechanisms through the ryanodine receptor, a Ca(2+) channel of the endoplasmic reticulum. The laser-induced Ca(2+) increases propagate to adjacent cells through gap junctions. Thus, ultrashort-pulsed lasers can induce smooth muscle contraction by controlling Ca(2+), even with optical stimulation of the diffraction-limited volume. This optical method, which leads to reversible and reproducible muscle contraction, can be used in research into muscle dynamics, neuromuscular disease treatment, and nanorobot control. PMID- 23650150 TI - Genetic toxicity of dillapiol and spinosad larvicides in somatic cells of Drosophila melanogaster. AB - BACKGROUND: Higher rates of diseases transmitted from insects to humans led to the increased use of organophosphate insecticides, proven to be harmful to human health and the environment. New, more effective chemical formulations with minimum genetic toxicity effects have become the object of intense research. These formulations include larvicides derived from plant extracts such as dillapiol, a phenylpropanoid extracted from Piper aduncum, and from microorganisms such as spinosad, formed by spinosyns A and D derived from the Saccharopolyspora spinosa fermentation process. This study investigated the genotoxicity of dillapiol and spinosad, characterising and quantifying mutation events and chromosomal and/or mitotic recombination using the somatic mutation and recombination test (SMART) in wings of Drosophila melanogaster. RESULTS: Standard cross larvae (72 days old) were treated with different dillapiol and spinosad concentrations. Both compounds presented positive genetic toxicity, mainly as mitotic recombination events. Distilled water and doxorubicin were used as negative and positive controls respectively. CONCLUSION: Spinosad was 14 times more genotoxic than dillapiol, and the effect was found to be purely recombinogenic. However, more studies on the potential risks of insecticides such as spinosad and dillapiol are necessary, based on other experimental models and methodologies, to ensure safe use. PMID- 23650151 TI - Status of iodine deficiency among children in national capital territory Of Delhi -a cross-sectional study. AB - Iodine deficiency disorder is a public health problem in NCT of Delhi. The present study was conducted in NCT of Delhi to assess the current iodine nutrition status among school age children (6-11 years). Thirty clusters (schools) were selected by utilizing the population proportionate to size (PPS) cluster sampling methodology. A total of 1393 school age children were included. Urine samples were collected and tested for urinary iodine excretion (UIE). The Median UIE was found to be 200 ug/L. The salt samples collected from study subjects revealed that 87% of salt samples had stipulated level of iodine of 15 ppm and more. In order to eliminate IDD, there is a need to sustain the supply of iodized salt and monitor its iodine content regularly. PMID- 23650146 TI - A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. AB - Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P <= 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case control studies. In the combined data from these two stages, additional genome wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 * 10( 13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 * 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations. PMID- 23650152 TI - Design and evaluation of a monolithic drug-in-adhesive patch for testosterone based on styrene-isoprene-styrene block copolymer. AB - The purpose of the present study was to design and evaluate a monolithic drug-in adhesive patch with a novel pressure-sensitive adhesive (PSA) matrix based on styrene-isoprene-styrene (SIS) block copolymer. Testosterone was selected as the model drug. The orthogonal array design for ternary mixtures was employed to optimize the amounts of SIS, C-5 hydrocarbon resin, and liquid paraffin. The drug release percentage, water vapor permeability, adhesive properties were chosen as response variables. The patch formulation was optimized by investigating the effects of the drug loading capacity, the type, and amount of permeation enhancer on the adhesive properties and skin permeation. The compositions of the optimal matrix were: 120 g of SIS copolymer, 120 g of C-5 hydrocarbon resin, 60 g of liquid paraffin. An optimized formulation with maximum skin permeation and acceptable adhesive properties was developed incorporating 2% testosterone and 6% isopropyl myristate. No significant differences for in vitro release, skin permeation, and in vivo absorption were observed between the optimal formulation and Testopatch(r). The stability evaluation showed that the patches were stable at 25 degrees C/60% relative humidity for 6 months. The result indicated that SIS copolymer was a suitable and compatible polymer for the development of PSA. PMID- 23650154 TI - Orthorhombic In2O3: a metastable polymorph of indium sesquioxide. PMID- 23650153 TI - The relation between antisocial and borderline personality symptoms and early maladaptive schemas in a treatment seeking sample of male substance users. AB - Individuals with substance use disorders are more likely to have antisocial and borderline personality disorder than non-substance abusers. Recently, research has examined the relations between early maladaptive schemas and personality disorders, as early maladaptive schemas are believed to underlie personality disorders. However, there is a dearth of research on the relations between early maladaptive schemas and personality disorders among individuals seeking treatment for substance abuse. The current study examined the relations among early maladaptive schemas and antisocial and borderline personality within in a sample of men seeking substance abuse treatment (n = 98). Results demonstrated that early maladaptive schema domains were associated with antisocial and borderline personality symptoms. Implications of these findings for substance use treatment and research are discussed. KEY PRACTITIONER MESSAGE: Antisocial (ASPD) and Borderline (BPD) personality disorder symptoms are prevalence among individuals seeking substance abuse treatment. Early maladaptive schemas are believed to underlie the development of ASPD and BPD symptoms, and are also prevalence among individuals seeking substance use treatment. Findings from the current study suggest that specific early maladaptive schema domains predict ASPD and BPD symptoms in a substance abuse treatment seeking sample of adult males. The treatment of ASPD and BPD among men seeking substance use treatment may want to focus on early maladaptive schemas. PMID- 23650155 TI - Watching single nanoparticles grow in real time through supercontinuum spectroscopy. AB - A fast dark-field scattering technique capturing full broadband spectra with millisecond time-resolution enables us to monitor the growth or assembly of single nano-objects in situ and in real time. Applying this technique to study the growth of single gold nanorods, together with scanning electron microscopy and finite-difference time-domain simulations, reveals precise quantitative information about gold nanorod growth kinetics. PMID- 23650156 TI - How does pheomelanin synthesis contribute to melanomagenesis?: Two distinct mechanisms could explain the carcinogenicity of pheomelanin synthesis. AB - Recently, we reported that melanoma risk in redheads is linked not only to pale skin, but also to the synthesis of the pigment - called pheomelanin - that gives red hair its color. We demonstrated that pheomelanin synthesis is associated with increased oxidative stress in the skin, yet we have not uncovered the chemical pathway between the molecule pheomelanin and the DNA damage that drives melanoma formation. Here, we hypothesize two possible pathways. On one hand, pheomelanin might generate reactive oxygen species (ROS) that directly or indirectly cause oxidative DNA damage. On the other hand, pheomelanin synthesis might consume cellular antioxidant stores and make the cell nucleus more vulnerable to other endogenous ROS. Uncovering the mechanistic pathway between pheomelanin and oxidative DNA damage will be an important step in developing strategies to lower melanoma risk in redheads. PMID- 23650157 TI - The public's knowledge and beliefs about obsessive compulsive disorder. AB - BACKGROUND: Obsessive compulsive disorder (OCD) is a disabling condition associated with significant personal and societal burdens. Despite the availability of efficacious treatments, in most cases, the disorder remains unrecognized and untreated. Lack of knowledge (i.e. poor mental health literacy, MHL) regarding OCD may be an impediment to seeking treatment. Therefore, the current study assessed public knowledge and beliefs about OCD and examined factors influencing MHL. METHODS: Five hundred seventy-seven US adults participated in a telephone survey. After hearing a vignette describing someone with OCD, participants' MHL for OCD was assessed across three domains as follows: recognition of OCD, knowledge and beliefs about available help, and concerns about being negatively evaluated for reporting symptoms. RESULTS: The majority of participants (90.9%) reported that the symptoms were a cause for concern and that the person in the vignette should seek professional help (89.5%). However, only one-third of respondents correctly labeled the disorder as OCD. More respondents were optimistic about the likely success of psychotherapy than medication, but primary care physicians were the most frequently reported source of professional help. Finally, less education, lower income, and being in an older cohort were associated with poorer recognition of OCD. CONCLUSIONS: When presented with brief vignettes describing a person with OCD, most community members can recognize the benefits of seeking professional help. However, recognition of the disorder and knowledge of treatment options can be improved. PMID- 23650158 TI - Selection and recombinant phenotyping of a novel CMX001 and cidofovir resistance mutation in human cytomegalovirus. AB - CMX001 is an orally available lipid acyclic nucleotide phosphonate that delivers high intracellular levels of cidofovir (CDV)-diphosphate and exhibits enhanced in vitro antiviral activity against a wide range of double-stranded DNA viruses, including cytomegalovirus (CMV). Mutations in the DNA polymerase of CMV that impart resistance to CDV also render the virus resistant to CMX001. Here, we report a novel resistance mutation that arose under the selective pressure of CMX001. The wild-type CMV strain AD169 was propagated in human foreskin fibroblasts under increasing concentrations of CMX001 over 10 months, and the resulting strain (named CMX001(R)) was less susceptible to CDV and CMX001 in a plaque reduction assay. Genotypic analysis of virus strain CMX001(R) via conventional sequencing of the genes encoding the CMV DNA polymerase (UL54) and UL97 kinase (UL97) demonstrated one mutation that changed the wild-type aspartate to glutamate at position 542 in UL54. A recombinant virus with this novel D542E mutation was generated via bacterial artificial chromosome-mediated marker transfer experiments. Subsequent phenotypic resistance analysis of the D542E mutant demonstrated reductions in susceptibility of greater than 10-fold to CMX001 and CDV, but no resistance to foscarnet (FOS) or ganciclovir (GCV). Analysis of replicative fitness showed that both strain CMX001(R) and the D542E mutant viruses demonstrated a smaller plaque phenotype and slower replication kinetics than their respective parent viruses. These data describe the first resistance mutation generated under the selective pressure of CMX001 and suggest that CMX001 may have a unique resistance profile associated with reduced viral replication and maintenance of sensitivity to FOS and GCV. PMID- 23650159 TI - Transition metal-alpha-amino acid complexes with antibiotic activity against Mycobacterium spp. AB - Synthetic iridium-, rhodium-, and ruthenium-amino acid complexes with hydrophobic l-amino acids have antibiotic activity against Mycobacterium spp., including Mycobacterium bovis BCG and the rapidly growing species Mycobacterium abscessus and Mycobacterium chelonae. Concentrations of transition metal-amino acid complexes demonstrating hemolysis or cytotoxicity were 10- to 25-fold higher than were the MICs. PMID- 23650160 TI - Pharmacodynamics modeling to optimize dosage regimens of sulbactam. AB - The aim of this study was to reveal population pharmacokinetics and assess the efficacies of various dosage regimens of sulbactam in terms of the probability of target attainment with this agent over a range of MICs. Monte Carlo simulations were performed to determine the probability of attaining specific pharmacodynamic targets. The results indicated that a regimen consisting of a 4-h infusion of 3 g of sulbactam every 8 h would be an alternative treatment option for less susceptible pathogens. PMID- 23650161 TI - Determination of voriconazole serum concentration by bioassay, a valid method for therapeutic drug monitoring for clinical laboratories. AB - We describe here a simple, fast, and reliable bioassay method for therapeutic drug monitoring of voriconazole. Fifty-eight clinical and external quality control samples were evaluated with this microbiological assay, and results were compared with those obtained with a previously validated chromatographic method. A good correlation between both assays was observed. This particular microbiological method was demonstrated to be simple and offers enough precision and accuracy to perform voriconazole therapeutic drug monitoring in laboratories without specialized equipment. PMID- 23650162 TI - Human simulated studies of aztreonam and aztreonam-avibactam to evaluate activity against challenging gram-negative organisms, including metallo-beta-lactamase producers. AB - Secondary to the stability of aztreonam against metallo-beta-lactamases, coupled with avibatam's neutralizing activity against often coproduced extended-spectrum beta-lactamases (ESBLs) or AmpC enzymes, the combination of aztreonam and avibactam has been proposed as a principal candidate for the treatment of infections with metallo-beta-lactamase-producing Gram-negative organisms. Using the neutropenic-mouse thigh infection model, we evaluated the efficacy of human simulated doses of aztreonam-avibactam and aztreonam against 14 Enterobacteriaceae and 13 Pseudomonas aeruginosa isolates, of which 25 produced metallo-beta-lactamases. Additionally, six P. aeruginosa isolates were also evaluated in immunocompetent animals. A humanized aztreonam dose of 2 g every 6 h (1-h infusion) was evaluated alone and in combination with avibactam at 375 or 600 mg every 6 h (1-h infusion), targeting the percentage of the dosing interval in which free-drug concentrations remained above the MIC (fT>MIC). Efficacy was evaluated as the change in bacterial density after 24 h compared with the bacterial density at the initiation of dosing. Aztreonam monotherapy resulted in reductions of two of the Enterobacteriaceae bacterial isolates (aztreonam MIC, <= 32 MUg/ml; fT>MIC, >= 38%) and minimal activity against the remaining isolates (aztreonam MIC, >= 128 MUg/ml; fT>MIC, 0%). Alternatively, aztreonam-avibactam therapy resulted in the reduction of all 14 Enterobacteriaceae isolates (aztreonam-avibactam MICs, <=16 MUg/ml; fT>MIC, >= 65%) and no difference between the 375- and 600-mg doses of avibactam was noted. Similar pharmacodynamically predictable activity against P. aeruginosa was noted in studies with neutropenic and immunocompetent mice, with activity occurring when the MICs were <= 16 MUg/ml and variable efficacy noted when the MICs were >= 32 MUg/ml. Again, no difference in efficacy between the 375- and 600-mg doses of avibactam was observed. Aztreonam-avibactam represents an attractive treatment option for infections with metallo-beta-lactamase-producing Gram-negative pathogens that coproduce ESBLs or AmpC. PMID- 23650164 TI - Intrapulmonary pharmacokinetics of GSK2251052 in healthy volunteers. AB - The plasma and intrapulmonary pharmacokinetics (PK) of intravenous (i.v.) GSK2251052, a novel boron-containing antimicrobial, were evaluated in healthy adult subjects. Thirty subjects underwent bronchoscopy and timed bronchoalveolar lavage (BAL) either following a single dose (cohort 1) or after 5 twice-daily doses (cohort 2) of 1,500 mg GSK2251052 i.v. Serial PK and safety assessments were obtained throughout the study. Bronchoscopy was performed on a single occasion in each subject at 2, 6, or 12 h after start of infusion. Noncompartmental analysis was performed to calculate PK parameters. Thirty subjects completed the study. The mean clearance (CL), volume of distribution at steady state (Vss), and half-life (t1/2) values were 22 liters/h, 231 liters, and 10.7 h, respectively. Approximately 30% of the dose was excreted unchanged in urine. The GSK2251052 concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) were approximately 50% and 500 to 600%, respectively, compared to the concentration in plasma. the GSK2251052 exposures in ELF and AM were comparable following single- and repeat-dose administration. The most frequently reported drug-related adverse event (AE) was mild to moderate infusion site reactions (7 subjects) that occurred primarily in the repeat-dose cohort. No serious drug-related AEs or clinically significant trends in laboratory values, vital signs, or electrocardiograms were observed. GSK2251052 given as a 1,500-mg infusion was generally tolerated following single- or repeat-dose administration. GSK2251052 distributes into both the ELF and AM of healthy volunteers, which supports further study in patients with pneumonia. PMID- 23650163 TI - Efficacy of liposomal amphotericin B and posaconazole in intratracheal models of murine mucormycosis. AB - Mucormycosis is a life-threatening fungal infection almost uniformly affecting diabetics in ketoacidosis or other forms of acidosis and/or immunocompromised patients. Inhalation of Mucorales spores provides the most common natural route of entry into the host. In this study, we developed an intratracheal instillation model of pulmonary mucormycosis that hematogenously disseminates into other organs using diabetic ketoacidotic (DKA) or cyclophosphamide-cortisone acetate treated mice. Various degrees of lethality were achieved for the DKA or cyclophosphamide-cortisone acetate-treated mice when infected with different clinical isolates of Mucorales. In both DKA and cyclophosphamide-cortisone acetate models, liposomal amphotericin B (LAmB) or posaconazole (POS) treatments were effective in improving survival, reducing lungs and brain fungal burdens, and histologically resolving the infection compared with placebo. These models can be used to study mechanisms of infection, develop immunotherapeutic strategies, and evaluate drug efficacies against life-threatening Mucorales infections. PMID- 23650165 TI - Can intermittent dosing optimize prolonged linezolid treatment of difficult multidrug-resistant tuberculosis? AB - We evaluated treatment with linezolid, dosed at 800 mg once daily for 1 to 4 months as guided by sputum culture status and tolerance and then at 1,200 mg thrice weekly until >= 1 year after culture conversion, in addition to individually optimized regimens among 10 consecutive patients with extensively drug-resistant tuberculosis or fluoroquinolone-resistant multidrug-resistant tuberculosis. All achieved stable cure, with anemia corrected and neuropathy stabilized, ameliorated, or avoided after switching to intermittent dosing. Serum linezolid profiles appeared better optimized. PMID- 23650166 TI - pH Dependence of microbe sterilization by cationic antimicrobial peptides. AB - We recently described a family of cationic antimicrobial peptides (CAMPs) selected from a combinatorial library that exhibited potent, broad-spectrum activity at neutral pH and low ionic strength. To further delimit the utility and activity profiles of these peptides, we investigated the effects of solution conditions, such as pH and ionic strength, on the efficacy of the peptide antimicrobials against a panel of microorganisms. Peptide minimum sterilizing concentrations (MSCs) varied linearly with pH for each subtype within our family of CAMPs for all organisms tested. The peptides were much less effective against Gram-negative bacteria at high pH, consistent with a decrease in net positive charge on the peptides. A similar trend was observed for the fungus Candida albicans. Surprisingly, the opposite pH trend was observed with the Gram-positive Staphylococcus aureus. In addition, an additive ionic strength effect was observed with increasing buffer strengths at identical pH values. The extreme difference in the observed pH behavior between Gram-negative and Gram-positive organisms is attributed to the presence of native charged molecules in the much thicker peptidoglycan layer of the Gram-positive organism. The novel species specific effects of pH observed here have important implications for applications using CAMPs and for the design of novel CAMPs. PMID- 23650167 TI - Hydrophobic gentamicin-loaded nanoparticles are effective against Brucella melitensis infection in mice. AB - The clinical management of human brucellosis is still challenging and demands in vitro active antibiotics capable of targeting the pathogen-harboring intracellular compartments. A sustained release of the antibiotic at the site of infection would make it possible to reduce the number of required doses and thus the treatment-associated toxicity. In this study, a hydrophobically modified gentamicin, gentamicin-AOT [AOT is bis(2-ethylhexyl) sulfosuccinate sodium salt], was either microstructured or encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles. The efficacy of the formulations developed was studied both in vitro and in vivo. Gentamicin formulations reduced Brucella infection in experimentally infected THP-1 monocytes (>2-log10 unit reduction) when using clinically relevant concentrations (18 mg/liter). Moreover, in vivo studies demonstrated that gentamicin-AOT-loaded nanoparticles efficiently targeted the drug both to the liver and the spleen and maintained an antibiotic therapeutic concentration for up to 4 days in both organs. This resulted in an improved efficacy of the antibiotic in experimentally infected mice. Thus, while 14 doses of free gentamicin did not alter the course of the infection, only 4 doses of gentamicin-AOT-loaded nanoparticles reduced the splenic infection by 3.23 logs and eliminated it from 50% of the infected mice with no evidence of adverse toxic effects. These results strongly suggest that PLGA nanoparticles containing chemically modified hydrophobic gentamicin may be a promising alternative for the treatment of human brucellosis. PMID- 23650168 TI - Phosphatidylinositol 4-kinase III beta is essential for replication of human rhinovirus and its inhibition causes a lethal phenotype in vivo. AB - Human rhinovirus (HRV) is the predominant cause of the common cold, but more importantly, infection may have serious repercussions in asthmatics and chronic obstructive pulmonary disorder (COPD) patients. A cell-based antiviral screen against HRV was performed with a subset of our proprietary compound collection, and an aminothiazole series with pan-HRV species and enteroviral activity was identified. The series was found to act at the level of replication in the HRV infectious cycle. In vitro selection and sequencing of aminothiazole series resistant HRV variants revealed a single-nucleotide mutation leading to the amino acid change I42V in the essential HRV 3A protein. This same mutation has been previously implicated in resistance to enviroxime, a former clinical-stage antipicornavirus agent. Enviroxime-like compounds have recently been shown to target the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIbeta). A good correlation between PI4KIIIbeta activity and HRV antiviral potency was found when analyzing the data over 80 compounds of the aminothiazole series, covering a 750-fold potency range. The mechanism of action through PI4KIIIbeta inhibition was further demonstrated by small interfering RNA (siRNA) knockdown of PI4KB, which reduced HRV replication and also increased the potency of the PI4KIIIbeta inhibitors. Inhibitors from two different structural classes with promising pharmacokinetic profiles and with very good selectivity for PI4KIIIbeta were used to dissociate compound-related toxicity from target-related toxicity. Mortality was seen in all dosing groups of mice treated with either compound, therefore suggesting that short-term inhibition of PI4KIIIbeta is deleterious. PMID- 23650169 TI - Fetal safety of macrolides. AB - Macrolide antibiotics are largely used in pregnancy for different bacterial infections. Their fetal safety has been studied by several groups, yielding opposing results. In particular, there have been studies claiming an association between macrolides and cardiovascular malformations. Exposure in early infancy has been associated with pyloric stenosis and intussusception. This has led to an avoidance in prescribing macrolides to pregnant women in several Scandinavian countries. The Objectives of the present study was to investigate the fetal safety of this class of drug by linking a large administrative database of drug dispensing and pregnancy outcome in Southern Israel. A computerized database of medications dispensed from 1999 to 2009 to all women registered in the Clalit health maintenance organization in southern Israel was linked with two computerized databases containing maternal and infant hospitalization records. Also, medical pregnancy termination data were analyzed. The following confounders were controlled for: maternal age, ethnicity, maternal pregestational diabetes, parity, and the year the mother gave birth or went through medical pregnancy termination. First- and third-trimester exposures to macrolide antibiotics as a group and to individual drugs were analyzed. During the study period there were 105,492 pregnancies among Clalit women that met the inclusion criteria. Of these, 104,380 ended in live births or dead fetuses and 1,112 in abortion due to medical reasons. In the first trimester of pregnancy, 1,033 women were exposed to macrolides. There was no association between macrolides and either major malformations [odds ratio (OR), 1.08; 95% confidence interval (CI), 0.84 to 1.38)] or specific malformations, after accounting for maternal age, parity, ethnicity, prepregnancy diabetes, and year of exposure. During the third trimester of pregnancy, 959 women were exposed to macrolides. There was no association between such exposure and perinatal mortality, low birth weight, low Apgar score, or preterm delivery. Similarly, no associations were demonstrated with pyloric stenosis or intussusception. Use of macrolides in the first trimester of pregnancy is not associated with an increased risk of major malformations. Exposure in the third trimester is not likely to increase neonatal risks for pyloric stenosis or intussusception in a clinically meaningful manner. PMID- 23650170 TI - Low rate of macrolide resistance in Mycoplasma pneumoniae strains in Germany between 2009 and 2012. PMID- 23650171 TI - SatR is a repressor of fluoroquinolone efflux pump SatAB. AB - Streptococcus suis is an emerging zoonotic agent responsible for high-mortality outbreaks among the human population in China. In this species, the ABC transporter SatAB mediates fluoroquinolone resistance when overexpressed. Here, we describe and characterize satR, an open reading frame (ORF) encoding a MarR superfamily regulator that acts as a repressor of satAB. satR is cotranscribed with satAB, and its interruption entails the overexpression of the pump, leading to a clinically relevant increase in resistance to fluoroquinolones. PMID- 23650172 TI - Randomized trial of the virologic response during up to two years of entecavir adefovir combination therapy in multiple-drug-refractory chronic hepatitis B virus patients. AB - A 1-year trial with entecavir plus adefovir resulted in a rate of virological response (VR) higher than that seen with lamivudine plus adefovir in multiple drug-refractory chronic hepatitis B (CHB) patients. This extension study enrolled 89 of 90 patients who completed a 52-week randomized trial comparing treatment with entecavir plus adefovir (EA) to treatment with lamivudine plus adefovir (LA). At the baseline of the original study, all patients had lamivudine resistant hepatitis B virus (HBV) and serum HBV DNA > 2,000 IU/ml despite prior lamivudine plus adefovir therapy. Of the 89 enrolled patients, 45 initially randomized to receive entecavir plus adefovir and the other 44 randomized to receive lamivudine plus adefovir received entecavir plus adefovir for an additional 52 weeks (EA-EA and LA-EA, respectively). The proportions of patients with a VR (serum HBV DNA < 60 IU/ml) gradually increased in both groups and were comparable at week 104 (42.2% in the EA-EA group and 34.1% in the LA-EA group; P = 0.51). The mean reductions in serum HBV DNA from baseline in the two groups were similar (-2.8 log10 IU/ml and -2.8 log10 IU/ml, respectively; P = 0.87). At week 104, the number of patients who retained the preexisting HBV mutants resistant to adefovir or entecavir had decreased from 8 to 2 in the EA-EA group and from 15 to 6 in the LA-EA group (P = 0.27). Both study groups had favorable safety profiles. In conclusion, up to 104 weeks of entecavir plus adefovir treatment was associated with a progressive VR, a decrease of levels of preexisting drug-resistant mutants, and no selection for additional resistance mutants of HBV in multiple-drug-refractory CHB patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01023217.). PMID- 23650173 TI - Cytomegalovirus UL97 kinase catalytic domain mutations that confer multidrug resistance. AB - Human cytomegalovirus UL97 kinase mutations that commonly confer ganciclovir resistance cluster in different parts of the gene than those conferring resistance to maribavir, an experimental UL97 kinase inhibitor. The drug resistance, growth, and autophosphorylation phenotypes of several unusual UL97 mutations in the kinase catalytic domain were characterized. Mutations V466G and P521L, described in clinical specimens from ganciclovir-treated subjects, conferred a UL97 kinase knockout phenotype with no autophosphorylation, a severe growth defect, and high-level ganciclovir, cyclopropavir, and maribavir resistance, similar to mutations at the catalytic lysine residue K355. Mutations F342S and V356G, observed after propagation under cyclopropavir in vitro, showed much less growth attenuation and moderate- to high-level resistance to all three drugs while maintaining UL97 autophosphorylation competence and normal cytopathic effect in cell culture, a novel phenotype. F342S is located in the ATP-binding P loop and is homologous to a c-Abl kinase mutation conferring resistance to imatinib. UL97 mutants with relatively preserved growth fitness and multidrug resistance are of greater concern in antiviral therapy than the severely growth impaired UL97 knockout mutants. Current diagnostic genotyping assays are unlikely to detect F342S and V356G, and the frequency of their appearance in clinical specimens remains undefined. PMID- 23650174 TI - Relationship of in vitro synergy and treatment outcome with daptomycin plus rifampin in patients with invasive methicillin-resistant Staphylococcus aureus infections. AB - We report the findings of a study examining the relationship between in vitro daptomycin-rifampin synergy and the therapeutic outcome of 12 patients with complex deep methicillin-resistant Staphylococcus aureus (MRSA) infections treated for prolonged periods with this combination. Checkerboard synergy was found in nine cases and was 100% predictive of therapeutic success; absence of synergy was found in three cases, two of which were therapeutic failures (P = 0.045). No relationship was observed between synergy and outcome by time-kill assessment. Checkerboard synergy may predict clinical response to daptomycin plus rifampin for complex invasive MRSA infections requiring prolonged treatment. PMID- 23650175 TI - The comprehensive antibiotic resistance database. AB - The field of antibiotic drug discovery and the monitoring of new antibiotic resistance elements have yet to fully exploit the power of the genome revolution. Despite the fact that the first genomes sequenced of free living organisms were those of bacteria, there have been few specialized bioinformatic tools developed to mine the growing amount of genomic data associated with pathogens. In particular, there are few tools to study the genetics and genomics of antibiotic resistance and how it impacts bacterial populations, ecology, and the clinic. We have initiated development of such tools in the form of the Comprehensive Antibiotic Research Database (CARD; http://arpcard.mcmaster.ca). The CARD integrates disparate molecular and sequence data, provides a unique organizing principle in the form of the Antibiotic Resistance Ontology (ARO), and can quickly identify putative antibiotic resistance genes in new unannotated genome sequences. This unique platform provides an informatic tool that bridges antibiotic resistance concerns in health care, agriculture, and the environment. PMID- 23650176 TI - Impact of the chirality and curvature of carbon nanostructures on their interaction with aromatics and amino acids. AB - Understanding noncovalent interactions on the surfaces of carbon nanostructures (CNSs) is of fundamental importance and also has implications in nano- and biotechnology. The interactions of aromatic compounds such as benzene, naphthalene, and aromatic amino acids with CNSs of varying diameter, chirality, and curvature were systematically explored by using density functional theory. Planar graphene exhibits stronger binding affinity than curved carbon nanotubes (CNTs), whereas zigzag CNTs appear to show stronger binding affinity than armchair CNTs. For hydrocarbons, there exist two competing modes, namely, pi-pi stacking interactions and CH...pi interactions, which bring the aromatic motifs into parallel and perpendicular dispositions with respect to the CNSs, respectively. Our results reveal that pi-pi stacking interactions override CH...pi interactions in such cases. However, in the case of aromatic amino acids, pi-pi interactions can exist simultaneously along with a range of other interactions, including CH...pi. The polarizability and HOMO energy of the CNSs were found to be the key factors that determine the binding energies. The HOMO LUMO energy gaps of the CNSs were found to be undisturbed by the noncovalent functionalization of the aromatic molecules. PMID- 23650177 TI - Birth seasonality in Prader-Willi syndrome resulting from chromosome 15 microdeletion. PMID- 23650178 TI - Treatment of acute gouty arthritis in complex hospitalized patients with anakinra. AB - OBJECTIVE: To report our experience with the efficacy and safety of anakinra for acute gouty arthritis in medically complex hospitalized patients. METHODS: We reviewed the hospital charts of 26 patients treated with anakinra for crystal induced arthritis since 2007. Demographics, comorbid conditions, reason for anakinra use, response to treatment, and any adverse outcomes were recorded. RESULTS: Twenty-six patients received 40 courses of anakinra therapy. In 67% of patients, pain improved significantly within 24 hours, and complete resolution of signs and symptoms of gout occurred by day 5 in 72.5% of patients. Seven patients received multiple courses with no decrement in response with repeated treatments. Anakinra was well tolerated and no adverse outcomes were attributed to the medication. Only 1 patient appeared to be refractory to this form of interleukin 1 inhibition. CONCLUSION: Anakinra is an effective and safe alternative treatment for acute gouty arthritis in medically complex hospitalized patients who fail or cannot undergo more conventional therapy. PMID- 23650179 TI - omega-Hydroxylation of phylloquinone by CYP4F2 is not increased by alpha tocopherol. AB - SCOPE: The objective of this study was to investigate the initial catabolic step of vitamin E and K metabolism, the omega-hydroxylation by human cytochrome P450 4F2 (CYP4F2). METHODS AND RESULTS: Tocopherol (T) metabolism was compared using rat liver slices incubated with deuterated (d6)-RRR-alpha-T (d6-alpha-T), racemic 2S-alpha-T (2S, 4'RS, 8'RS alpha-T, 2S-alpha-T), or d2-gamma-T (d2-gamma-T). Following comparable uptake of each T by liver slices, twice as much 13'-OH-T was produced from 2S-alpha-T or d2-gamma-T (39 +/- 15 or 42 +/- 5 pmol/g liver, respectively) as from d6-alpha-T (17 +/- 2, p < 0.01). Kinetic studies were conducted using insect microsomes expressing human CYP4F2 incubated with d4 phylloquinone (d4-PK), d6-RRR-alpha-T, d3-SRR-alpha-T, or d2-gamma-T. CYP4F2 demonstrated similar apparent maximal velocities (Vmax) when either of the alpha Ts were used as substrates, which were less than the apparent d4-PK Vmax (p < 0.0002), while the CYP4F2 catalytic efficiency toward d4-PK (15.8 Vmax/Km) was five times greater than for alpha-Ts. Vitamin K had no effect on vitamin E catabolism, while vitamin E slightly decreased the d4-PK Vmax. CONCLUSION: CYP4F2 discriminates between Ts and PK in vitro, but alpha-T does not apparently increase PK omega-hydroxylation by this mechanism. PMID- 23650180 TI - Multimodal magnetic core-shell nanoparticles for effective stem-cell differentiation and imaging. PMID- 23650181 TI - Large-scale production of nanographene sheets with a controlled mesoporous architecture as high-performance electrochemical electrode materials. AB - Graphene is considered as a rising-star material because of its unique properties and it is a promising material for applications in many fields. In recent years, experiments on graphene fabricated by using versatile methods have shed light on the crucial problem of aggregation and restacking, which is induced by strong pi pi stacking and van der Waals forces, but preparation methods for real-world applications are still a great challenge. Here we report a facile, rapid, and environmentally friendly process, the burn-quench method, that allows large-scale and controlled synthesis of ordered mesoporous nanographene with 1-5 layers, which has a high surface area and electric conductivity. Electrodes composed of nanographene with a mesoporous architecture used both in electrochemical capacitors and lithium-ion batteries have a high specific capacitance, rate capability, energy density, and cyclic stability. Our results represent an important step toward large-scale graphene synthesis based on this new burn quench method for applications in high-performance electrochemical energy storage devices. PMID- 23650182 TI - Investigation of the carboxylate position during the acylation reaction catalyzed by biaryl DMAP derivatives with an internal carboxylate. PMID- 23650183 TI - De novo intragenic deletion of the autism susceptibility candidate 2 (AUTS2) gene in a patient with developmental delay: a case report and literature review. PMID- 23650184 TI - A longitudinal study of respiratory infections in British National Hunt racehorses. PMID- 23650185 TI - Chick genomics. PMID- 23650186 TI - A systematic review of school-based suicide prevention programs. AB - OBJECTIVE: Suicide is one of the leading causes of death among youth today. Schools are a cost-effective way to reach youth, yet there is no conclusive evidence regarding the most effective prevention strategy. We conducted a systematic review of the empirical literature on school-based suicide prevention programs. METHOD: Studies were identified through MEDLINE and Scopus searches, using keywords such as "suicide, education, prevention and program evaluation." Additional studies were identified with a manual search of relevant reference lists. Individual studies were rated for level of evidence, and the programs were given a grade of recommendation. Five reviewers rated all studies independently and disagreements were resolved through discussion. RESULTS: Sixteen programs were identified. Few programs have been evaluated for their effectiveness in reducing suicide attempts. Most studies evaluated the programs' abilities to improve students' and school staffs' knowledge and attitudes toward suicide. Signs of Suicide and the Good Behavior Game were the only programs found to reduce suicide attempts. Several other programs were found to reduce suicidal ideation, improve general life skills, and change gatekeeper behaviors. CONCLUSIONS: There are few evidence-based, school-based suicide prevention programs, a combination of which may be effective. It would be useful to evaluate the effectiveness of general mental health promotion programs on the outcome of suicide. The grades assigned in this review are reflective of the available literature, demonstrating a lack of randomized controlled trials. Further evaluation of programs examining suicidal behavior outcomes in randomized controlled trials is warranted. PMID- 23650187 TI - Coherent anti-Stokes emission from gold nanorods and its potential for imaging applications. AB - We used coherent anti-Stokes scattering (CAS) to characterize individual gold nanorods (GNRs) and GNR aggregates. By creating samples with different densities of GNRs on silicon wafer substrates, we were able to determine surface coverage by scanning electron microscopy (SEM) and then correlate the coverage to the CAS intensities of the samples. The observed CAS signal intensity was quadratically dependent on the number of particles. We also examined the CAS signal as a function of the excitation polarization and found that the strongest signals in regularly oriented GNRs were observed when the beam polarization was aligned with the longitudinal axis of the GNRs. Irregularly oriented GNRs exhibited a different scattering pattern to that observed for regularly oriented GNRs. The polarization-dependent scattering from oriented GNRs showed cos(6)(theta) behavior. By imaging nanoscale-sized GNR patterns using CAS and evaluating the results with SEM, we show that CAS can be used for efficient, label-free imaging of nanoscale metallic particles. PMID- 23650188 TI - Apolipoprotein A5 deficiency aggravates high-fat diet-induced obesity due to impaired central regulation of food intake. AB - Mutations in apolipoprotein A5 (APOA5) have been associated with hypertriglyceridemia in humans and mice. This has been attributed to a stimulating role for APOA5 in lipoprotein lipase-mediated triglyceride hydrolysis and hepatic clearance of lipoprotein remnant particles. However, because of the low APOA5 plasma abundance, we investigated an additional signaling role for APOA5 in high-fat diet (HFD)-induced obesity. Wild-type (WT) and Apoa5(-/-) mice fed a chow diet showed no difference in body weight or 24-h food intake (Apoa5(-/ ), 4.5+/-0.6 g; WT, 4.2+/-0.5 g), while Apoa5(-/-) mice fed an HFD ate more in 24 h (Apoa5(-/-), 2.8+/-0.4 g; WT, 2.5+/-0.3 g, P<0.05) and became more obese than WT mice. Also, intravenous injection of APOA5-loaded VLDL-like particles lowered food intake (VLDL control, 0.26+/-0.04 g; VLDL+APOA5, 0.11+/-0.07 g, P<0.01). In addition, the HFD-induced hyperphagia of Apoa5(-/-) mice was prevented by adenovirus-mediated hepatic overexpression of APOA5. Finally, intracerebroventricular injection of APOA5 reduced food intake compared to injection of the same mouse with artificial cerebral spinal fluid (0.40+/-0.11 g; APOA5, 0.23+/-0.08 g, P<0.01). These data indicate that the increased HFD-induced obesity of Apoa5(-/-) mice as compared to WT mice is at least partly explained by hyperphagia and that APOA5 plays a role in the central regulation of food intake. PMID- 23650189 TI - Human glutathione S-transferase A (GSTA) family genes are regulated by steroidogenic factor 1 (SF-1) and are involved in steroidogenesis. AB - Steroidogenic factor 1 (SF-1) is a master regulator for steroidogenesis. In this study, we identified novel SF-1 target genes using a genome-wide promoter tiling array and a DNA microarray. SF-1 was found to regulate human glutathione S transferase A (GSTA) family genes (hGSTA1-hGSTA4), a superfamily of detoxification enzymes clustered on chromosome 6p12. All hGSTA genes were up regulated by transduction of SF-1 into human mesenchymal stem cells, while knockdown of endogenous SF-1 in H295R cells down-regulated all hGSTA genes. Chromatin immunoprecipitation assays, however, revealed that SF-1 bound directly to the promoters of hGSTA3 and weakly of hGSTA4. Chromosome conformation capture assays revealed that the coordinated expression of the genes was based on changes in higher-order chromatin structure triggered by SF-1, which enables the formation of long-range interactions, at least between hGSTA1 and hGSTA3 gene promoters. In steroidogenesis, dehydrogenation of the 3-hydroxy group and subsequent Delta(5)-Delta(4) isomerization are thought to be enzymatic properties of 3beta-hydroxysteroid dehydrogenase (3beta-HSD). Here, we demonstrated that, in steroidogenic cells, the hGSTA1 and hGSTA3 gene products catalyze Delta(5) Delta(4) isomerization in a coordinated fashion with 3beta-HSD II to produce progesterone or Delta(4)-androstenedione from their Delta(5)-precursors. Thus, hGSTA1 and hGSTA3 gene products are new members of steroidogenesis working as Delta(5)-Delta(4) isomerases. PMID- 23650191 TI - Assessing neuropsychological impairment using Reitan and Wolfson's screening battery. AB - The aim was to verify the applicability of Reitan and Wolfson's proposed neuropsychological screening battery for adults (2006, 2008) in the Czech population. The sample consisted of 70 participants aged 19-65 years, all of whom were examined using a screening method as well as the full Halstead-Reitan neuropsychological battery (HRNB). The correlation, logistic regression, ROC curve analysis, sensitivity and specificity, and positive and negative predictive values were all calculated. The Pearson correlation between the screening scale of neuropsychological deficit and the General Neuropsychological Deficit Scale (GNDS) from HRNB was 0.78 (p < .001). When optimal cut-off scores of 8 were utilized (in accordance with Horwitz, Lynch, McCaffrey, & Fisher in Screening for neuropsychological impairment using Reitan and Wolfsons preliminary neuropsychological test battery. Archives of Clinical Neuropsychology, 23, 393 398, 2008, but different from Reitan, & Wolfson in The use of serial testing in evaluating the need for comprehensive neuropsychological testing of adults. Applied Neuropsychology, 15, 21-32, 2008), 78.6% of individuals were correctly classified having neuropsychological impairment or no impairment according to the GNDS. Our results confirm that this neuropsychological screening battery has good psychometric properties in the Czech population. PMID- 23650190 TI - Asn441 plays a key role in folding and function of the Na+/I- symporter (NIS). AB - The Na(+)/I(-) symporter (NIS) is a plasma membrane glycoprotein that mediates active I(-) transport in the thyroid, the first step in the biosynthesis of the iodine-containing thyroid hormones T3 and T4. Several NIS mutants have been identified as a cause of congenital I(-) transport defect (ITD), and their investigation has yielded valuable mechanistic information on NIS. Here we report a thorough characterization of the ITD-causing NIS mutation in which the sixth intracellular loop residues 439-443 are missing. This mutant protein was intracellularly retained, incompletely glycosylated, and intrinsically inactive. Engineering 5 Ala at positions 439-443 partially recovered cell surface targeting and activity (~15%). Strikingly, NIS with the sequence 439-AANAA-443, in which Asn was restored at position 441, was targeted to the plasma membrane and exhibited ~95% the transport activity of WT NIS. Based on our NIS homology model, we propose that the side chain of N441, a residue conserved throughout most of the SLC5 family, interacts with the main chain amino group of G444, capping the alpha-helix of transmembrane segment XII and thus stabilizing the structure of the molecule. Our data provide insight into a critical interhelical interaction required for NIS folding and activity. PMID- 23650192 TI - Direct asymmetric vinylogous aldol reaction of allyl ketones with isatins: divergent synthesis of 3-hydroxy-2-oxindole derivatives. PMID- 23650193 TI - Determination of rimantadine in human urine by HPLC using a monolithic stationary phase and on-line post-column derivatization. AB - In the present study, we propose the first HPLC method coupled to postcolumn derivatization for the determination of rimantadine in human urine samples. The analyte and amantadine (internal standard) were isocratically separated using an RP monolithic stationary phase (100 * 4.6 mm id) with a mobile phase consisting of CH3OH/phosphate buffer (25 mmol/L, pH 3.0) at a volume ratio of 50:50. Postcolumn derivatization involved on-line reaction with o-phthalaldehyde (20 mmol/L) and N-acetyl-cysteine (5 mmol/L) at alkaline medium (100 mmol/L borate pH 11.0). Spectrofluorimetric detection at lambda(ex)/lambda(em) = 340/455 nm enabled the selective and sensitive determination of rimantadine in urine samples at a range of 50-500 ng/mL with an LOD of 5 ng/mL. Human urine samples were analyzed successfully after SPE using hydrophilic-lipophilic balanced RP cartridges (30 mg/mL, Oasis HLB). Recoveries ranged between 89.7 and 102.7%. PMID- 23650194 TI - CO2 sorbents with scaffold-like Ca-Al layered double hydroxides as precursors for CO2 capture at high temperatures. AB - A highly stable high-temperature CO2 sorbent consisting of scaffold-like Ca-rich oxides (Ca-Al-O) with rapid absorption kinetics and a high capacity is described. The Ca-rich oxides were prepared by annealing Ca-Al-NO3 layered double hydroxide (LDH) precursors through a sol-gel process with Al(O(i)P)3 and Ca(NO3)2 with Ca(2+)/Al(3+) ratios of 1:1, 2:1, 4:1, and 7:1. XRD indicated that only LDH powders were formed for Ca(2+)/Al(3+) ratios of 2:1. However, both LDH and Ca(OH)2 phases were produced at higher ratios. Both TEM and SEM observations indicated that the Ca-Al-NO3 LDHs displayed a scaffold-like porous structure morphology rather than platelet-like particles. Upon annealing at 600 degrees C, a highly stable porous network structure of the CaO-based Ca-Al-O mixed oxide (CAMO), composed of CaO and Ca12Al14O33, was still present. The CAMO exhibited high specific surface areas (up to 191 m(2)g(-1)) and a pore size distribution of 3-6 nm, which allowed rapid diffusion of CO2 into the interior of the material, inducing fast carbonation/calcination and enhancing the sintering-resistant nature over multiple carbonation/calcination cycles for CO2 absorption at 700 degrees C. Thermogravimetric analysis results indicated that a CO2 capture capacity of approximately 49 wt% could be obtained with rapid absorption from the porous 7:1 CAMO sorbents by carbonation at 700 degrees C for 5 min. Also, 94-98% of the initial CO2 capture capability was retained after 50 cycles of multiple carbonation/calcination tests. Therefore, the CAMO framework is a good isolator for preventing the aggregation of CaO particles, and it is suitable for long-term cyclic operation in high-temperature environments. PMID- 23650195 TI - Endovascular treatment of ruptured internal carotid artery pseudoaneurysms after irradiation for nasopharyngeal carcinoma patients. AB - OBJECTIVES. To evaluate the efficacy and complications of endovascular treatment for ruptured internal carotid artery pseudoaneurysms following irradiation of nasopharyngeal carcinoma. DESIGN. Retrospective case series. SETTING. Tertiary neurosurgical referral unit of a Hong Kong public hospital. PATIENTS. Patients with ruptured radiation-induced internal carotid artery pseudoaneurysms that were treated endovascularly from October 1999 to October 2011 at Queen Elizabeth Hospital were reviewed. Hospital records, imaging, and angiographic data were studied. RESULTS. During the study period, 15 such nasopharyngeal carcinoma patients were treated by endovascular means at Queen Elizabeth Hospital. Ten presented with epistaxis, three with otorrhagia (bleeding from the ear), and two with both. Therapeutic occlusion of the affected internal carotid artery was performed in four patients, and stenting of the artery (with or without coil obliteration of the pseudoaneurysm) was performed in 11. Immediate haemostasis was achieved in all cases. One (7%) of the 15 patients endured symptomatic recurrence of the pseudoaneurysm, and in another an asymptomatic residual pseudoaneurysm was noted in the follow-up angiogram. Three patients suffered clinically significant procedure-related complications, including cerebral infarction (n=2) and brain abscess (n=1). In the angiograms obtained after a mean post-treatment interval of 13 (range, 0.7-60) months, the stent patency rate was 67%. All three patients with occluded stents were asymptomatic. CONCLUSIONS. Ruptured internal carotid artery pseudoaneurysms following radiotherapy is a rare but life-threatening condition. Endovascular treatment by occlusion or reconstruction of the internal carotid artery with stents provides immediate haemostasis and obliteration of the pseudoaneurysms, with a low recurrence rate. Long-term follow-up is necessary to look out for delayed post-treatment complications. PMID- 23650196 TI - Balloon tamponade for postpartum haemorrhage: case series and literature review. AB - OBJECTIVES: To audit the use of intrauterine balloon tamponade for the management of massive postpartum haemorrhage and compare outcomes with those documented in the literature. DESIGN: Retrospective case series. SETTING: Obstetric Unit of a regional hospital in Hong Kong. PATIENTS: All cases with severe postpartum haemorrhage from January 2011 to June 2012 in which Bakri intrauterine balloon catheters were used for management. MAIN OUTCOME MEASURE: Successful management with prevention of hysterectomy. RESULTS: A total of 19 cases were identified. The postpartum haemorrhage was successfully treated without the need for additional procedures in 15 patients. Hysterectomy was avoided in a further two cases by recourse to radiologically guided uterine artery embolisation. In two patients, balloon tamponade failed in that hysterectomy was carried out. Thus, the overall success rate of intrauterine balloon tamponade alone was 79%, which was comparable to reported rates in the literature. CONCLUSION: Bakri balloon tamponade is an effective means of managing massive postpartum haemorrhage, and should be adopted in protocols to manage such patients. PMID- 23650197 TI - Subinguinal microsurgical varicocelectomy for male factor subfertility: ten-year experience. AB - OBJECTIVE: To investigate the impact of subinguinal microsurgical varicocelectomy on semen parameters and pregnancy outcomes in couples with male factor subfertility. DESIGN: Case series. SETTING: Male Infertility Clinic in an academic institution in Hong Kong. PATIENTS: The clinical records of 42 consecutive subfertile male patients who had subinguinal microsurgical varicocelectomy (from January 2000 to December 2009) were retrospectively reviewed. All the patients had a known history of subfertility and abnormalities in one or more semen parameters. Female subfertility factors were not addressed. Only grade 2 or higher clinically palpable varicoceles were operated on. MAIN OUTCOME MEASURES: Preoperative and postoperative semen analyses based on the World Health Organization criteria; the outcome measures included changes in semen parameters and whether a pregnancy ensued. RESULTS: The mean age of patients and their spouses were 38 and 33 years, respectively. The mean duration of infertility was 4 years; 37 patients had primary infertility and five had secondary infertility. The mean (+/- standard deviation) sperm concentration improved from 12 +/- 19 million/mL to 23 +/- 29 million/mL following varicocelectomy (P<0.001), the mean sperm motility improved from 26% +/- 16% to 32% +/- 18% (P<0.001), and the mean normal morphology increased from 5% +/- 7% to 6% +/- 6% (P<0.001). Postoperatively, 23 (55%) of the patients achieved pregnancy, 11 (26%) being spontaneous, 1 (2%) by intrauterine insemination, and 11 (26%) by in-vitro fertilisation. Among 20 patients with severe preoperative oligospermia (<5 million/mL), statistically significant improvements occurred in postoperative mean sperm concentration, motility and morphology (all P<0.001), and five (25%) of them achieved a spontaneous pregnancy. There was one intra operative injury to the testicular artery with immediate repair and no testicular atrophy. Five (12%) of the patients had recurrences. No preoperative factors appeared predictive of a pregnancy ensuing. CONCLUSIONS: In couples with male infertility due to varicoceles, subinguinal microsurgical varicocelectomy was shown to improve sperm concentrations, motility and morphology, and the likelihood of a pregnancy. Spontaneous pregnancy was achieved in 25% of the couples in which the man had severe oligospermia. PMID- 23650198 TI - Application of endotoxin and cytokine adsorption haemofilter in septic acute kidney injury due to Gram-negative bacterial infection. AB - OBJECTIVE: Endotoxins and cytokines play an important role in the pathogenesis of multi-organ failure and mortality in patients suffering from severe Gram-negative bacterial infection. The aim of this study was to determine whether in patients with such infections, use of a haemofilter with enhanced endotoxin haemoadsorption and cytokine removal properties helps to overcome organ dysfunction. DESIGN: Prospective case series study with historical controls. SETTING: A regional hospital in Hong Kong. PATIENTS: From October 2011 to June 2012, patients with sepsis-induced acute kidney injury due to Gram-negative bacteria were recruited. Continuous venovenous haemofiltration using oXiris haemofilter was performed. The patients' APACHE (Acute Physiology And Chronic Health Evaluation) II and inclusion criteria matched those of a series of selected historical controls who had been treated with continuous venovenous haemofiltration using polysulfone-based haemofilter from 2009 to 2011. The percentage reduction in the Sequential Organ Failure Assessment score by 24 and 48 hours, the percentage reduction of noradrenaline equivalent usage by 48 hours, as well as intensive care unit and hospital mortality in the two groups were compared. RESULTS: Pre-treatment biochemical parameters and vasopressor use in the six patients undergoing the intervention and the 24 historical controls were similar. The mean circuit life of oXiris was about 61 hours. The Sequential Organ Failure Assessment score was significantly reduced by 37% at 48 hours post initiation of oXiris-continuous venovenous haemofiltration versus an increment of 3% in the historical controls. No significant side-effect was detected. Mortality was similar in the two groups. CONCLUSION: The haemofilter membrane with enhanced endotoxin adsorption and cytokine removal capacity was a safe alternative to traditional polysulfone-based continuous venovenous haemofiltration and expedited improvement in organ dysfunction. PMID- 23650199 TI - Aspirin desensitisation for Chinese patients with coronary artery disease. AB - OBJECTIVE. To assess the efficacy and safety of aspirin desensitisation in Chinese patients with coronary artery disease. DESIGN. Case series. SETTING. A regional hospital in Hong Kong. PATIENTS. Chinese patients with coronary artery disease and a history of a hypersensitivity reaction to aspirin or non-steroidal anti-inflammatory drug, who underwent aspirin desensitisation between February 2008 and July 2012. RESULTS. There were 24 Chinese patients with coronary artery disease who were admitted to our unit for aspirin desensitisation during this period. The majority (79%) were clinical admissions for desensitisation; eight (33%) of them developed a hypersensitivity reaction during desensitisation. Half of the latter had only limited cutaneous reactions and were able to complete the desensitisation protocol and developed aspirin tolerance. Overall, 20 (83%) of the patients were successfully desensitised at the initial attempt. No serious adverse reactions occurred in the cohort. Twelve of the patients had significant coronary artery disease revealed by coronary angiography and received a percutaneous coronary intervention, nine of whom received drug-eluting stents while three received bare metal stents due to financial constraints. All 11 successfully desensitised patients received aspirin and clopidogrel as double antiplatelet therapy after percutaneous coronary intervention. The remaining patient had a bare metal stent implant due to failed aspirin desensitisation. CONCLUSION. Given the potentially different genetic basis of aspirin hypersensitivity in different ethnicities, recourse to desensitisation in the Chinese population has not previously been addressed. This study demonstrated that aspirin desensitisation using a rapid protocol can be performed effectively and safely in Chinese patients. Our results were comparable to those in other reported studies involving other ethnicities. Successful aspirin desensitisation permits patients to pursue long-term double antiplatelet therapy that includes aspirin after percutaneous coronary intervention, and thus allows the use of drug eluting stents as a feasible option. PMID- 23650200 TI - Prevalence of abnormal Papanicolaou smears in female sex workers in Hong Kong. AB - OBJECTIVE. To investigate the prevalence of pre-cancerous uterine cervix lesions as detected in Papanicolaou (Pap) smears from female sex workers in Hong Kong. DESIGN. Retrospective analysis of laboratory records. SETTING. Private anatomical pathology laboratory, Hong Kong. PATIENTS. Female sex workers undergoing Pap smear examinations at two non-governmental organisations between 2006 and 2012. MAIN OUTCOME MEASURES. Detection of pre-cancerous uterine cervical conditions and their management. RESULTS. A total of 2697 satisfactory Pap smears from female sex workers were performed during the study period from 2006 to 2012. In these subjects, the point prevalence of low-grade squamous intraepithelial lesion and atypical squamous cells of unknown significance was 10.12% (compared with 3.92% for the general population during the same period), whereas that of high-grade squamous intraepithelial lesions and atypical squamous cells of unknown significance with or without high-grade intraepithelial lesions was 2.22% (compared with 0.54% in the general population). For both categories of lesions, the higher prevalence among female sex workers than in the general population was statistically significant. Most patients who had abnormal Pap smears received proper referrals and follow-up management according to recommended guidelines. CONCLUSIONS. Female sex workers in Hong Kong as a group had a significantly higher prevalence of abnormal Pap smears than the general population. Non governmental organisations providing free-of-charge screening services to these women helped early detection and proper follow-up for those who had abnormal Pap smears, whilst also increasing their awareness of women's health issues. PMID- 23650201 TI - Proliferation of embryonic cardiomyocytes in zebrafish requires the sodium channel scn5Lab. AB - In mice, homozygous deletion of the cardiac sodium channel Scn5a results in defects in cardiac morphology and embryonic death before robust sodium current can be detected. In zebrafish, morpholino knockdown of cardiac sodium channel orthologs scn5Laa and scn5Lab perturbs specification of precardiac mesoderm and inhibits growth of the embryonic heart. It is not known which developmental processes are perturbed by sodium channel knockdown and whether reduced cell number is from impaired migration of cardiac progenitors into the heart, impaired myocyte proliferation, or both. We found that embryos deficient in scn5Lab displayed defects in primary cardiogenesis specific to loss of nkx2.5, but not nkx2.7. We generated kaede reporter fish and demonstrated that embryos treated with anti-scn5Lab morpholino showed normal secondary differentiation of cardiomyocytes at the arterial pole between 30 and 48 h post-fertilization. However, while proliferating myocytes were readily detected at 48 hpf in wild type embryos, there were no BrdU-positive cardiomyocytes in embryos subjected to anti-scn5Lab treatment. Proliferating myocytes were present in embryos injected with anti-tnnt2 morpholino to phenocopy the silent heart mutation, and absent in embryos injected with anti-tnnt2 and anti-scn5Lab morpholinos, indicating cardiac contraction is not required for the loss of proliferation. These data demonstrate that the role of scn5Lab in later heart growth does not involve contribution of the secondary heart field, but rather proliferation of cardiomyocytes, and appears unrelated to the role of the channel in cardiac electrogenesis. PMID- 23650202 TI - Elements of morphology: standard terminology for the external genitalia. AB - An international group of clinicians working in the field of dysmorphology has initiated the standardization of terms used to describe human morphology. The goals are to standardize these terms and reach consensus regarding their definitions. In this way, we will increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients. Discussions with other workers in dysmorphology and related fields, such as developmental biology and molecular genetics, will become more precise. Here we introduce the anatomy of the male and female genitalia, and define and illustrate the terms that describe the major characteristics of these body regions. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. PMID- 23650203 TI - Free fatty acid effects on myokine production in combination with exercise mimetics. AB - SCOPE: We aimed to study the effects of free fatty acids (FFAs) alone and combined with the exercise mimetics adrenaline and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) in the production of IL6, IL15 and Irisin in muscle cells, using a time-sequential model. METHODS AND RESULTS: Differentiated C2C12 myotubes were treated with FFA, adrenaline or AICAR alone for 0, 1, 3, 8, 12 and 24 h and with double or triple combinations for 0, 3 and 24 h. Levels of mRNA in cells and protein in the medium were measured. Adrenaline, AICAR and FFA showed no significant effects on Irisin expression, while the presence in the culture of adrenaline and/or AICAR decreased IL15 mRNA expression. On contrary, the three signals showed a deep, rapid impact on the IL6 induction, especially when both AICAR and FFA were present. CONCLUSION: The different response in IL6 versus IL15 regulation may be explained by their different energy-activating versus muscle cell-hypertrophy suggested roles, considering that adrenaline and AMPK are involved in the activation of energy-generating pathways. Moreover, the results suggest FFAs are components that may regulate IL6 production and may have a role in muscle-adipose tissue crosstalk. PMID- 23650204 TI - Superhydrophobic activated carbon-coated sponges for separation and absorption. AB - Highly porous activated carbon with a large surface area and pore volume was synthesized by KOH activation using commercially available activated carbon as a precursor. By modification with polydimethylsiloxane (PDMS), highly porous activated carbon showed superhydrophobicity with a water contact angle of 163.6 degrees . The changes in wettability of PDMS- treated highly porous activated carbon were attributed to the deposition of a low-surface-energy silicon coating onto activated carbon (confirmed by X-ray photoelectron spectroscopy), which had microporous characteristics (confirmed by XRD, SEM, and TEM analyses). Using an easy dip-coating method, superhydrophobic activated carbon-coated sponges were also fabricated; those exhibited excellent absorption selectivity for the removal of a wide range of organics and oils from water, and also recyclability, thus showing great potential as efficient absorbents for the large-scale removal of organic contaminants or oil spills from water. PMID- 23650206 TI - New drug approval times and safety warnings in the United States and Canada, 1992 2011. AB - BACKGROUND: New drug approvals in the US and Canada were reviewed in short-term studies in the 1990s. A database of drugs approved in both countries between 1992 and 2011 exists allowing for a longer time horizon to assess trends. OBJECTIVE: To compare review times of drugs approved in the US and Canada over the 20-year period and their duration on the respective markets until any serious safety risk arose. METHODS: Data on submission and approval dates and review type were obtained from the regulatory agencies. RESULTS: 454 drugs were approved in both countries in the 20-year period for which the US median approval time was shorter than the Canadian median by >6 months (382 versus 574 days). Nevertheless, in 2007-11, the median approval times were closer in the two countries (302 and 356 days, respectively). 3% of the drugs were discontinued for safety reasons in both countries. The 10-year survival rate without a serious safety warning was significantly lower in Canada (58.4%) than in the US (69.3%). Being approved in 2002-11 with a shorter review time had the greatest impact on a drug receiving a serious safety warning. CONCLUSIONS: Overall, new drug approval times in the two countries in the last five years were closer, although some important differences remain so that Canadians still wait longer for some new drugs to be approved. The survival rate of a drug without a serious warning decreased substantially in the last decade in both countries, especially in drugs approved with shorter review times. PMID- 23650205 TI - Functional defect of peripheral neutrophils in mice with induced deletion of CXCR2. AB - Type 2 CXC chemokine receptor CXCR2 plays roles in development, tumorigenesis, and inflammation. CXCR2 also promotes demyelination and decreases remyelination by actions toward hematopoietic cells and nonhematopoietic cells. Germline CXCR2 deficient (Cxcr2(-/-) ) mice reported in 1994 revealed the complexity of CXCR2 function and its differential expression in varied cell-types. Here, we describe Cxcr2(fl/fl) mice for which the targeting construct was generated by recombineering based on homologous recombination in E. coli. Without recombination Cxcr2(fl/fl) mice have CXCR2 expression on neutrophils in peripheral blood, bone marrow and spleen. Cxcr2(fl/fl) mice were crossed to Mx Cre mice in which Cre recombinase is induced by Type I interferons, elicited by injection with polyinosinic-polycytidylic acid (poly(I:C)). CXCR2-deficient neutrophils were observed in poly(I:C) treated Cxcr2(fl/fl) ::Mx-Cre(+) (Cxcr2 CKO) mice, but not in poly(I:C) treated Cxcr2(f//+) ::Mx-Cre(+) mice. CXCR2 deletion was mainly observed peripherally but not in the CNS. Cxcr2-CKO mice showed impaired neutrophil migration in sterile peritonitis. Cxcr2-CKO mice reported here will provide a genetic reagent to dissect roles of CXCR2 in the neutrophil granulocyte lineage. Furthermore Cxcr2(fl/fl) mice will provide useful genetic models to evaluate CXCR2 function in varied cell populations. PMID- 23650207 TI - Principal components methods for narrow-sense heritability in the analysis of multidimensional longitudinal cognitive phenotypes. AB - BACKGROUND: Genetic association studies of longitudinal cognitive phenotypes are an alternate approach to discovering genetic risk factors for Alzheimer's disease (AD). However, the standard linear mixed model approach is limited in the face of multidimensional longitudinal data and multiple genotypes. In this setting, the principal components of heritability (PCH) approach may increase efficiency by deriving a linear combination of phenotypes to maximize the heritability attributable to a particular genetic locus. The current study investigated the performance of two PCH methods, the Principal Components of Heritability Association Test (PCHAT) and C2BAT, in detecting association of the known AD susceptibility allele APOE-epsilon4 with cognitive function at baseline and decline in cognition over time. METHODS: PCHAT, C2BAT, and standard linear mixed models were used to test for association between APOE-epsilon4 allele and performance on 19 neuropsychological tests using subjects without dementia at baseline from the Religious Orders Study (ROS) (n = 693) and Memory and Aging Project (MAP) (n = 778). Analyses were conducted across the three methods for three nested phenotype definitions (all 19 measures, executive function and episodic memory measures, and episodic memory only), and for baseline data only versus longitudinal change. RESULTS: In all cases, APOE-epsilon4 was significantly associated with baseline level of and change over time in cognitive function, and PCHAT and C2BAT yielded evidence of association comparable to or stronger than conventional methods. CONCLUSION: PCHAT, C2BAT, and other PCH methods may have utility for genetic association studies of multidimensional cognitive and other phenotypes by maximizing genetic information while limiting multiple comparisons. PMID- 23650210 TI - Catalytic characteristics of AgCu bimetallic nanoparticles in the oxygen reduction reaction. AB - Intensive research on oxygen reduction reaction (ORR) catalysts has been undertaken to find a Pt substitute or reduce the amount of Pt. Ag nanoparticles are potential Pt substitutes; however, the weak oxygen adsorption energy of Ag prompted investigation of other catalysts. Herein, we prepared AgCu bimetallic nanoparticle (NP) systems to improve the catalytic performance and compared the catalytic performance of Ag, Cu, AgCu (core-shell), and AgCu (alloy) NP systems as new catalyst by investigating the adsorption energy of oxygen and the activation energy of oxygen dissociation, which is known to be the rate determining step of ORR. By analyzing HOMO-level isosurfaces of metal NPs and oxygen, we found that the adsorption sites and the oxygen adsorption energies varied with different configurations of NPs. We then plotted the oxygen adsorption energies against the energy barrier of oxygen dissociation to determine the catalytic performance. AgCu (alloy) and Cu NPs exhibited strong adsorption energies and low activation-energy barriers. However, the overly strong oxygen adsorption energy of Cu NPs hindered the ORR. PMID- 23650208 TI - LC/MS characterization of rotenone induced cardiolipin oxidation in human lymphocytes: implications for mitochondrial dysfunction associated with Parkinson's disease. AB - SCOPE: Rotenone is a toxicant believed to contribute to the development of Parkinson's disease. METHODS AND RESULTS: Using human peripheral blood lymphocytes we demonstrated that exposure to rotenone resulted in disruption of electron transport accompanied by the production of reactive oxygen species, development of apoptosis and elevation of peroxidase activity of mitochondria. Employing LC/MS-based lipidomics/oxidative lipidomics we characterized molecular species of cardiolipin (CL) and its oxidation/hydrolysis products formed early in apoptosis and associated with the rotenone-induced mitochondrial dysfunction. CONCLUSION: The major oxidized CL species - tetra-linoleoyl-CL - underwent oxidation to yield epoxy-C18:2 and dihydroxy-C18:2 derivatives predominantly localized in sn-1 and sn-2 positions, respectively. In addition, accumulation of mono-lyso-CL species and oxygenated free C18:2 were detected in rotenone-treated lymphocytes. These oxidation/hydrolysis products may be useful for the development of new biomarkers of mitochondrial dysfunction. PMID- 23650209 TI - Identifying cis-regulatory changes involved in the evolution of aerobic fermentation in yeasts. AB - Gene regulation change has long been recognized as an important mechanism for phenotypic evolution. We used the evolution of yeast aerobic fermentation as a model to explore how gene regulation has evolved and how this process has contributed to phenotypic evolution and adaptation. Most eukaryotes fully oxidize glucose to CO2 and H2O in mitochondria to maximize energy yield, whereas some yeasts, such as Saccharomyces cerevisiae and its relatives, predominantly ferment glucose into ethanol even in the presence of oxygen, a phenomenon known as aerobic fermentation. We examined the genome-wide gene expression levels among 12 different yeasts and found that a group of genes involved in the mitochondrial respiration process showed the largest reduction in gene expression level during the evolution of aerobic fermentation. Our analysis revealed that the downregulation of these genes was significantly associated with massive loss of binding motifs of Cbf1p in the fermentative yeasts. Our experimental assays confirmed the binding of Cbf1p to the predicted motif and the activator role of Cbf1p. In summary, our study laid a foundation to unravel the long-time mystery about the genetic basis of evolution of aerobic fermentation, providing new insights into understanding the role of cis-regulatory changes in phenotypic evolution. PMID- 23650211 TI - The retention behaviour of amino acids in hydrophilic interaction liquid chromatography on zwitterionic stationary phases. AB - The retention behaviour of amino acids was studied in hydrophilic LC on zwitterionic stationary phases. Evaluation of the influences of acetonitrile/water content, ammonium acetate (NH4Ac) concentration and mobile phase pH values was performed. Fourteen amino acids were tested and they were all retained to varying extents, with poorer retention in high water content eluents. The linear relationship between the logarithm of retention factor and log(water content) indicated that adsorption dominated or at least was partly involved in the separation mechanism. Electrostatic and hydrophilic interactions also contributed to the retention of these amino acids under different separation conditions with various mobile phase pH values and NH4Ac concentrations. Thus, the overall retention mechanism could be explained as a combination of adsorption, electrostatic and hydrophilic interactions. The magnitude and contribution of each mechanism is dependent on the nature of the analyte and the separation conditions applied. PMID- 23650212 TI - Autism spectrum disorders: the quest for genetic syndromes. AB - Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disabilities with various etiologies, but with a heritability estimate of more than 90%. Although the strong correlation between autism and genetic factors has been long established, the exact genetic background of ASD remains unclear. A number of genetic syndromes manifest ASD at higher than expected frequencies compared to the general population. These syndromes account for more than 10% of all ASD cases and include tuberous sclerosis, fragile X, Down, neurofibromatosis, Angelman, Prader-Willi, Williams, Duchenne, etc. Clinicians are increasingly required to recognize genetic disorders in individuals with ASD, in terms of providing proper care and prognosis to the patient, as well as genetic counseling to the family. Vice versa, it is equally essential to identify ASD in patients with genetic syndromes, in order to ensure correct management and appropriate educational placement. During investigation of genetic syndromes, a number of issues emerge: impact of intellectual disability in ASD diagnoses, identification of autistic subphenotypes and differences from idiopathic autism, validity of assessment tools designed for idiopathic autism, possible mechanisms for the association with ASD, etc. Findings from the study of genetic syndromes are incorporated into the ongoing research on autism etiology and pathogenesis; different syndromes converge upon common biological backgrounds (such as disrupted molecular pathways and brain circuitries), which probably account for their comorbidity with autism. This review paper critically examines the prevalence and characteristics of the main genetic syndromes, as well as the possible mechanisms for their association with ASD. PMID- 23650213 TI - Pseudocapacitive hausmannite nanoparticles with (101) facets: synthesis, characterization, and charge-transfer mechanism. AB - Hausmannite Mn3 O4 octahedral nanoparticles of 18.3 +/- 7.0 nm with (101) facets have been prepared by an oxygen-mediated growth. The electrochemical properties of the Mn3 O4 particles as pseudocapacitive cathode materials were characterized both in half-cells and in button-cells. The Mn3 O4 nanoparticles exhibited a high mass-specific capacitance of 261 F g(-1), which was calculated from cyclic voltammetry analyses, and a capacitive retention of 78% after 10,000 galvanostatic charge-discharge cycles. The charge-transfer mechanisms of the Mn3 O4 nanoparticles were further studied by using synchrotron-based in situ X-ray absorption near edge spectroscopy and XRD. Both measurements showed concurrently that throughout the potential window of 0-1.2 V (vs. Ag/AgCl), a stable spinel structure of Mn3 O4 remained, and a reversible electrochemical conversion between tetrahedral [Mn(II) O4 ] and octahedral [Mn(III) O6 ] units accounted for the redox activity. Density functional theory calculations further corroborated this mechanism by confirming the enhanced redox stability afforded by the abundant and exposed (101) facets of Mn3 O4 octahedra. PMID- 23650214 TI - Absorption and metabolic fate of bioactive dietary benzoxazinoids in humans. AB - SCOPE: Benzoxazinoids, which are natural compounds recently identified in mature whole grain cereals and bakery products, have been suggested to have a range of pharmacological properties and health-protecting effects. There are no published reports concerned with the absorption and metabolism of bioactive benzoxazinoids in humans. METHODS AND RESULTS: The absorption, metabolism, and excretion of ten different dietary benzoxazinoids were examined by LC-MS/MS by analyzing plasma and urine from 20 healthy human volunteers after daily intake of 143 MUmol of total benzoxazinoids from rye bread and rye buns. The results showed that 2-beta D-glucopyranosyloxy-1,4-benzoxazin-3-one (HBOA-Glc) and its oxidized analog, 2 beta-D-glucopyranosyloxy-4-hydroxy-1,4-benzoxazin-3-one (DIBOA-Glc), were the major circulating benzoxazinoids. After consuming a benzoxazinoid diet for 1 week, morning urine contained eight benzoxazinoids with abundant HBOA-Glc (219 nmol * MUmol-1 of creatinine). The sulfate and glucuronide conjugates of 2 hydroxy-1,4-benzoxazin-3-one (HBOA) and 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA) were detected in plasma and urine, indicating substantial phase II metabolism. Direct absorption of lactam glycosides, the reduction of hydroxamic acid glycosides, glucuronidation, and sulfation were the main mechanisms of the absorption and metabolism of benzoxazinoids. CONCLUSION: These results indicate that following ingestion in healthy humans, a range of unmetabolized bioactive dietary benzoxazinoids and their sulfate and glucuronide conjugates appear in circulation and urine. PMID- 23650215 TI - Small-platelet thrombocytopenia in a family with autosomal recessive inheritance pattern. AB - We describe the clinical and laboratory features of a family of Arab ancestry and consanguinity. Five affected individuals were diagnosed in two sibships. All affected members have small platelets, severe to moderate thrombocytopenia of neonatal onset, increased bleeding tendency and bleeding complications such as: life-threatening massive hemoperitoneum due to corpus luteum rupture during ovulation and severe mucosal bleeding. The familial involvement and early onset of the disease support the presence of a congenital genetic disorder with an autosomal recessive inheritance pattern. This does not fit the clinical spectrum of any of the currently known thrombocytopenia disorders. PMID- 23650216 TI - Evaluation of matrix effects in different multipesticide residue analysis methods using liquid chromatography-tandem mass spectrometry, including an automated two dimensional cleanup approach. AB - Pesticide residue analysis is an important part of food quality control. Three of the most widely used methods are the DFG S19 (extraction with acetone), the ChemElut method (extraction with methanol), and QuEChERS (quick, easy, cheap, effective, rugged, safe; acetonitrile-based). Despite many developments in the field of sample preparation, matrix effects are still one of the most disturbing problems in routine analysis. In this study, we compare the matrix effects in LC MS analysis after using these three methods in pesticide analysis. Using postcolumn infusion, we were able to visualize all suppressions over the whole chromatogram in matrix-effect profiles. Recently, we also presented a system for the determination of up to 300 pesticides from various kinds of fruit and vegetables. For the measurement, we injected an aliquot of a raw acetonitrile extract. The subsequent cleanup was carried out fully automated by a multidimensional LC. Matrix compounds and analytes are separated in the first dimension on a hydrophilic interaction LC column. In this study, we also compared this new approach with the classical methods. The matrix-effect profiles showed less suppression with the hydrophilic interaction LC-based cleanup. A final evaluation of the partitioning steps of all methods confirmed the benefits of the chromatographic cleanup approach. PMID- 23650217 TI - Cardioprotective effects of cocoa: clinical evidence from randomized clinical intervention trials in humans. AB - Cocoa is an important source of polyphenols, which comprise 12-18% of its total dry weight. The major phenolic compounds in cocoa and cocoa products are mainly flavonoids such as epicatechin, catechin, and proanthocyanidins. These products contain higher amounts of flavonoids than other polyphenol-rich foods. However, the bioavailability of these compounds depends on other food constituents and their interactions with the food matrix. Many epidemiological and clinical intervention trials have concluded that the ingestion of flavonoids reduces the risk factors of developing cardiovascular disease. This review summarizes the new findings regarding the effects of cocoa and chocolate consumption on cardiovascular risk factors. The mechanisms involved in the cardioprotective effects of cocoa flavonoids include reduction of oxidative stress, inhibition of low-density lipoproteins oxidation and platelet aggregation, vasodilatation of blood vessels, inhibition of the adherence of monocytes to vascular endothelium, promotion of fibrinolysis, and immunomodulatory and anti-inflammatory activity. Scientific evidence supports a cause and effect relationship between consumption of cocoa flavonoids and the maintenance of normal endothelium-dependent vasodilation, which contributes to normal blood flow. However, larger randomized trials are required to definitively establish the impact of cocoa and cocoa products consumption on hard cardiovascular outcomes. PMID- 23650218 TI - Association of aggression with a novel microRNA binding site polymorphism in the wolframin gene. AB - Rare mutations in the WFS1 gene lead to Wolfram syndrome, a severe multisystem disorder with progressive neurodegeneration and diabetes mellitus causing life threatening complications and premature death. Only a few association studies using small clinical samples tested the possible effects of common WFS1 gene variants on mood disorders and suicide, the non-clinical spectrum has not been studied yet. Self-report data on Aggression, Impulsiveness, Anxiety, and Depression were collected from a large (N = 801) non-psychiatric sample. Single nucleotide polymorphisms (SNPs) were selected to provide an adequate coverage of the entire WFS1 gene, as well as to include putative microRNA binding site polymorphisms. Molecular analysis of the assumed microRNA binding site variant was performed by an in vitro reporter-gene assay of the cloned 3' untranslated region with coexpression of miR-668. Among the 17 WFS1 SNPs, only the rs1046322, a putative microRNA (miR-668) binding site polymorphism showed significant association with psychological dimensions after correction for multiple testing: those with the homozygous form of the minor allele reported higher aggression on the Buss-Perry Aggression Questionnaire (P = 0.0005). Functional effect of the same SNP was also demonstrated in a luciferase reporter system: the minor A allele showed lower repression compared to the major G allele, if co-expressed with miR-668. To our knowledge, this is the first report describing a microRNA binding site polymorphism of the WFS1 gene and its association with human aggression based on a large, non-clinical sample. PMID- 23650219 TI - Treatment with topotecan plus cyclophosphamide in children with first relapse of neuroblastoma. AB - BACKGROUND: Reports of responses and toxicities of salvage therapies for relapsed neuroblastoma are rare and often confounded by effects of additional treatments. Our objective was to describe the outcomes and toxicities for a topotecan and cyclophosphamide (TOPO/CTX) regimen for first relapse or progression of high-risk neuroblastoma. METHODS: We retrospectively reviewed charts of relapsed or refractory neuroblastoma patients treated between 1999 and 2009 with our standard of-care outpatient TOPO/CTX (0.75 and 250 mg/m(2) /day * 5 days q3-4 weeks). RESULTS: Twenty-seven patients received 343 cycles of TOPO/CTX (median 10 cycles per patient, range 1-32). Most patients (N = 25) had undergone autologous stem cell transplantation. Seventeen (63%) patients had an objective response (CR + PR + MR). The 3-year progression-free survival (PFS) after relapse was 11 +/- 6% and 3-year overall survival (OS) after relapse was 33 +/- 9%. The median PFS was 1.2 years and the median OS was 2.3 years. Five patients are alive with follow-up of 3.1-5.5 years. Shorter time from diagnosis to relapse (6-18 months) was associated with shorter OS. The majority of patients experienced chemotherapy delays, transfusions, and febrile neutropenia, including eight bacterial infections. The mean number of hospitalized days was less than one per cycle. CONCLUSIONS: TOPO/CTX was well tolerated and resulted in response rates and PFS similar to those reported for patients treated on COG 9462. Our study provides additional toxicity, historical endpoints, and time-to-progression data against which new agents and combination therapies using TOPO/CTX as a backbone can be measured. PMID- 23650220 TI - Effect of the structural characteristics of binary Pt-Ru and ternary Pt-Ru-M fuel cell catalysts on the activity of ethanol electrooxidation in acid medium. AB - In view of their possible use as anode materials in acid direct ethanol fuel cells, the electrocatalytic activity of Pt-Ru and Pt-Ru-M catalysts for ethanol oxidation has been investigated. This minireview examines the effects of the structural characteristics of Pt-Ru, such as the degree of alloying and Ru oxidation state, on the electrocatalytic activity for ethanol oxidation. PMID- 23650221 TI - Reply: Sensorineural hearing loss in OPA1-linked disorders. PMID- 23650222 TI - Reply: Blood-cerebrospinal fluid barrier dysfunction in patients with neurological symptoms during the 2011 Northern German Escherichia coli serotype O104:H4 outbreak. PMID- 23650223 TI - Reply: Levodopa increases functional connectivity in the cerebellum and brainstem in Parkinson's disease. PMID- 23650224 TI - Reply: Microcystic macular degeneration from optic neuropathy: not inflammatory, not trans-synaptic degeneration. PMID- 23650226 TI - Reply: Morality: incomplete without the cerebellum? PMID- 23650229 TI - Substantial genetic link between IQ and working memory: implications for molecular genetic studies on schizophrenia. the European twin study of schizophrenia (EUTwinsS). AB - While evidence is accumulating to support specific neurocognitive deficits as putative endophenotypes for schizophrenia, the heritability of these deficits in healthy subjects and whether they share common genetic influences, is not well established. In the present study, 529 healthy adult twins from two centers within the European Twin Study Network on Schizophrenia (EUTwinsS) were assessed on two domains that are consistently found to be particularly compromised in schizophrenia. Specifically, Intellectual Quotient Score (IQ) and the Letter Number Sequencing Test (LNS), a measure of working memory, were measured in all twins. Latent variable components were explored through structural equation modeling, and common genetic underpinnings were examined using bivariate analyses. Results showed that the phenotypic correlation between IQ and working memory was almost entirely attributed to shared genetic variance (95.5%). We discuss the potential use of a combined measure of IQ and working memory to improve the power of molecular studies in detecting the genetic mechanisms underlying schizophrenia. PMID- 23650231 TI - Incidence of multiple sclerosis in multiple racial and ethnic groups. AB - OBJECTIVE: To determine whether the incidence of multiple sclerosis (MS) varies by race/ethnicity in a multiethnic, population-based cohort. METHODS: We conducted a retrospective cohort study of more than 9 million person-years of observation from the multiethnic, community-dwelling members of Kaiser Permanente Southern California health plan from January 1, 2008 to December 31, 2010. Incidence of MS and risk ratios comparing incidence rates between racial/ethnic groups were calculated using Poisson regression. RESULTS: We identified 496 patients newly diagnosed with MS who met McDonald criteria. The average age at diagnosis was 41.6 years (range 8.6-78.3 years) and 70.2% were women. The female preponderance was more pronounced among black (79.3%) than white, Hispanic, and Asian individuals with MS (67.8%, 68.1%, and 69.2%, respectively; p = 0.03). The incidence of MS was higher in blacks (10.2, 95% confidence interval [CI] 8.4 12.4; p < 0.0001) and lower in Hispanics (2.9, 95% CI 2.4-3.5; p < 0.0001) and Asians (1.4, 95% CI 0.7-2.4; p < 0.0001) than whites (6.9, 95% CI 6.1-7.8). Black women had a higher risk of MS (risk ratio 1.59, 95% CI 1.27-1.99; p = 0.0005) whereas black men had a similar risk of MS (risk ratio 1.04, 95% CI = 0.67-1.57) compared with whites. CONCLUSIONS: Our findings do not support the widely accepted assertion that blacks have a lower risk of MS than whites. A possible explanation for our findings is that people with darker skin tones have lower vitamin D levels and thereby an increased risk of MS, but this would not explain why Hispanics and Asians have a lower risk of MS than whites or why the higher risk of MS among blacks was found only among women. PMID- 23650232 TI - APRONES: neurology research and education in the Democratic Republic of the Congo. PMID- 23650230 TI - Xanthohumol ameliorates atherosclerotic plaque formation, hypercholesterolemia, and hepatic steatosis in ApoE-deficient mice. AB - SCOPE: Xanthohumol (XN), a prenylated antioxidative and anti-inflammatory chalcone from hops, exhibits positive effects on lipid and glucose metabolism. Based on its favorable biological properties, we investigated whether XN attenuates atherosclerosis in western-type diet-fed apolipoprotein-E-deficient (ApoE-/-) mice. METHODS AND RESULTS: XN supplementation markedly reduced plasma cholesterol concentrations, decreased atherosclerotic lesion area, and attenuated plasma concentrations of the proinflammatory cytokine monocyte chemoattractant protein 1. Decreased hepatic triglyceride and cholesterol content, activation of AMP-activated protein kinase, phosphorylation and inactivation of acetyl-CoA carboxylase, and reduced expression levels of mature sterol regulatory element binding protein (SREBP)-2 and SREBP-1c mRNA indicate reduced lipogenesis in the liver of XN-fed ApoE-/- mice. Concomitant induction of hepatic mRNA expression of carnitine palmitoyltransferase-1a in ApoE-/- mice-administered XN suggests increased fatty acid beta-oxidation. Fecal cholesterol concentrations were also markedly increased in XN-fed ApoE-/- mice compared with mice fed western-type diet alone. CONCLUSION: The atheroprotective effects of XN might be attributed to combined beneficial effects on plasma cholesterol and monocyte chemoattractant protein 1 concentrations and hepatic lipid metabolism via activation of AMP activated protein kinase. PMID- 23650233 TI - Skin rash in meningitis and meningoencephalitis. PMID- 23650234 TI - Neon neurons. PMID- 23650235 TI - Brain MRI evolution of metronidazole intoxication. PMID- 23650239 TI - Mystery case: central neurocytoma: characterization by MRI and MRS. PMID- 23650240 TI - Teaching NeuroImages: mind the gap! Postfixational blindness due to traumatic rupture of the optic chiasm. PMID- 23650241 TI - Teaching NeuroImages: hemorrhagic cavernoma with secondary development of hypertrophic olivary degeneration. AB - Hypertrophic olivary degeneration (HOD) is secondary degeneration of the inferior olivary nucleus (ION) due to a primary lesion in the dento-rubro-olivary pathway. This pathway is known as the Guillain and Mollert triangle, containing the dentate nucleus and the contralateral red and inferior olivary nuclei (figure e-1 on the Neurology(r) Web site at www.neurology.org). The commonest presenting symptom is palatal myoclonus occurring 8-12 months after the primary insult. MRI of the ION initially has normal results (figure 1). Three phases of HOD exist on MRI: hyperintense signal change without hypertrophy, hyperintense signal change with hypertrophy (figure 2), and regression of hypertrophy with persistent hyperintense signal.(1.) PMID- 23650242 TI - Formation and in vitro biocompatibility of biomimetic hydroxyapatite coatings on chemically treated carbon substrates. AB - Carbon derived materials such as pyrolytic carbon or carbon-carbon composites (CCCs) exhibit excellent mechanical properties making them promising candidates for bone replacement. However, these materials are considered bioinert and not to induce bone formation in vivo. In this study, a two-step chemical surface treatment including etching with HCl/HNO3 solution and subsequent soaking in CaCl2 solution was applied to carbon substrates in order to activate the materials surface towards bioactive behavior. The bioactivity was proven by soaking the samples in simulated body fluid (SBF) and formation of carbonated hydroxyapatite layer (HCA), which indicates the ability of the material to bond to bone in vivo. The materials surface is shown to be functionalized through the chemical etching creating COO(-)Ca(2+) complexes on the surface as confirmed by FTIR and XPS analyses. These ionic complexes provide nucleation sites for HAp precipitation. After similar immersion time in SBF under the condition of local supersaturation the thickness and homogeneity of the HAp layer were found to depend on the chemical pretreatment with HCl/HNO3. Homogenous HAp layers with a thickness ranging from ~ 6 to ~ 17 MUm were achieved. The proposed bioactivating treatment of carbon stimulates HAp formation in vivo and can be considered an easy biomimetic approach for coating carbon derived materials with bone-like hydroxyapatite. In vitro cell assay with osteosarcoma cells (MG-63) showed increased cell viability (+70%) on HAp coated carbon substrates as compared to uncoated reference while both materials induced ALP expression in MG-63 cells confirming the osteoblastic phenotype. PMID- 23650243 TI - Estradiol production by the Bidder's organ of the toad Rhinella arenarum (Amphibia, Anura). Seasonal variations in plasma estradiol. AB - In bufonids, the Bidder's organ (BO), located in the anterior pole of the testis, is sometimes referred to as a rudimentary ovary because of the presence of previtellogenic follicles. In males of Rhinella arenarum it has been demonstrated that some follicles are vitellogenic and also express several steroidogenic enzymes in follicular cells. The purpose of this study is to describe seasonal variations in plasma estradiol (E(2)) and in aromatase activity of the BO, and to determine the capacity of the BO to synthesize E(2) from cholesterol in males of R. arenarum. E(2) was determined by radioimmunoassay and aromatase activity was measured by transformation of radioactive substrates into products. Results indicate that plasma E(2) reached the highest concentration in April and the lowest one in animals captured in June, showing a progressive increase to the end of the year. Plasma E(2) and total activity of aromatase in the BO were significantly lower during the pre-reproductive season than during the reproductive and post-reproductive seasons. It was also demonstrated that the BO is able to produce E(2) from endogenous substrates throughout the year. No correlation was found between plasma E(2) and total BO weight, while there was a significant correlation between plasma E(2) and total activity of aromatase, and between plasma E(2) and E(2) produced in vitro. Taken together, these results demonstrate seasonal variations in plasma E(2), in bidderian total activity of aromatase and, that the BO of adult males of R. arenarum is able to produce E(2) from endogenous substrates. PMID- 23650244 TI - The genomic psychiatry cohort: partners in discovery. AB - The Genomic Psychiatry Cohort (GPC) is a longitudinal resource designed to provide the necessary population-based sample for large-scale genomic studies, studies focusing on Research Domain Criteria (RDoC) and/or other alternate phenotype constructs, clinical and interventional studies, nested case-control studies, long-term disease course studies, and genomic variant-to-phenotype studies. We provide and will continue to encourage access to the GPC as an international resource. DNA and other biological samples and diagnostic data are available through the National Institute of Mental Health (NIMH) Repository. After appropriate review and approval by an advisory board, investigators are able to collaborate in, propose, and co-lead studies involving cohort participants. PMID- 23650245 TI - Self-assembled peptide-polyoxometalate hybrid nanospheres: two in one enhances targeted inhibition of amyloid beta-peptide aggregation associated with Alzheimer's disease. AB - Amyloid fibril formation is a critical step in Alzheimer's disease (AD) pathogenesis. Inhibition of Abeta aggregation has shown promising against AD and has been used in clinic trials. Here, a novel strategy is reported for the self assembly of polyoxometalate-peptide (POM@P) hybrid particles as bifunctional Abeta inhibitors. The two-in-one bifunctional POM@P nanoparticles show an enhanced inhibition effect on amyloid aggregation in mice cerebrospinal fluid. Incorporating a clinically used Abeta fibril-staining dye, congo red (CR), into the hybrid colloidal spheres, the nanoparticles can also act as an effective fluorescent probe to monitor the inhibition process of POM@P via CR fluorescence change in real time. It is believed that such flexible organic-inorganic hybrid systems may prompt the design of new multifunctional materials for AD treatment. PMID- 23650246 TI - Longitudinal relationship of low leisure satisfaction but not depressive symptoms with systemic low-grade inflammation in dementia caregivers. AB - OBJECTIVES: This study aimed to further elucidate the biobehavioral mechanisms linking dementia caregiving with an increased cardiovascular disease risk. We hypothesized that both elevated depressive symptoms and a behavioral correlate of depression, low leisure satisfaction, are associated with systemic inflammation. METHOD: We studied 121 elderly Alzheimer's disease caregivers who underwent 4 annual assessments for depressive symptoms, leisure satisfaction, and circulating levels of inflammatory markers. We used mixed-regression analyses controlling for sociodemographic and health-relevant covariates to examine longitudinal relationships between constructs of interest. RESULTS: There were inverse relationships between total leisure satisfaction and tumor necrosis factor-alpha (TNF-alpha; p = .047), interleukin-8 (IL-8; p < .001), and interferon-gamma (IFG; p = .020) but not with IL-6 (p = .21) and C-reactive protein (p = .65). Lower enjoyment from leisure activities was related to higher levels of TNF-alpha (p = .045), IL-8 (p < .001), and IFG (p = .002), whereas lower frequency of leisure activities was related only to higher IL-8 levels (p = .023). Depressive symptoms were not associated with any inflammatory marker (all p values > .17). Depressive symptoms did not mediate the relationship between leisure satisfaction and inflammation. DISCUSSION: Lower satisfaction with leisure activities is related to higher low-grade systemic inflammation. This knowledge may provide a promising way of improving cardiovascular health in dementia caregivers through behavioral activation treatments targeting low leisure satisfaction. PMID- 23650247 TI - What do we (need to) know about the melatonin in crustaceans? AB - Melatonin (N-acetyl-5-methoxy-tryptamine) was first discovered from the bovine pineal gland extract in 1958. Since then, its synthesis, metabolism, physiological, and patho-physiological functions are well studied in vertebrates; there is an increasing recognition of melatonin in invertebrates and especially in crustaceans. The presence of melatonin in crustaceans is now well documented and some functional aspects in the framework of crustacean biology have been demonstrated. This review aims at giving a comprehensive overview of the various physiological events regulated by this pleiotropic hormone. Topics include: glucose homeostasis, regulation of reproduction, molting, limb regeneration, and antioxidant properties. Finally, perspectives on current and possible research are offered. PMID- 23650249 TI - Real-time activity bioassay of single osteoclasts using a silicon nanocrystal impregnated artificial matrix. AB - The lack of an in vitro real-time osteoclast (OC) activity assay has hampered mechanistic studies of bone resorption. Such an assay is developed, employing a hydroxyapatite matrix impregnated with alkyl-capped silicon nanocrystals, which is capable of monitoring the time-course of resorption by single osteoclasts. Resorption of the matrix by OC releases the nanocrystals, which are internalized by the cell and detected as an increase in OC luminescence. This particular choice of nanocrystals is motivated by their bright pH-independent luminescence, proportional to concentration, and by their rapid uptake without cytotoxicity. In this in vitro assay, OCs are inhibited by calcitonin (CT) and methyl-beta cyclodextrin (MCD), and stimulated by receptor activator of nuclear factor kappa B ligand (RANKL) in the expected manner. The kinetics of the assay exhibit a lag phase representing cell attachment and commencement of resorption processes, followed by a growth of cell luminescence intensity, and the whole time-course is satisfactorily described by the logistic equation. PMID- 23650250 TI - Blood-based gene-expression predictors of PTSD risk and resilience among deployed marines: a pilot study. AB - Susceptibility to PTSD is determined by both genes and environment. Similarly, gene-expression levels in peripheral blood are influenced by both genes and environment, and expression levels of many genes show good correspondence between peripheral blood and brain. Therefore, our objectives were to test the following hypotheses: (1) pre-trauma expression levels of a gene subset (particularly immune-system genes) in peripheral blood would differ between trauma-exposed Marines who later developed PTSD and those who did not; (2) a predictive biomarker panel of the eventual emergence of PTSD among high-risk individuals could be developed based on gene expression in readily assessable peripheral blood cells; and (3) a predictive panel based on expression of individual exons would surpass the accuracy of a model based on expression of full-length gene transcripts. Gene-expression levels were assayed in peripheral blood samples from 50 U.S. Marines (25 eventual PTSD cases and 25 non-PTSD comparison subjects) prior to their deployment overseas to war-zones in Iraq or Afghanistan. The panel of biomarkers dysregulated in peripheral blood cells of eventual PTSD cases prior to deployment was significantly enriched for immune genes, achieved 70% prediction accuracy in an independent sample based on the expression of 23 full length transcripts, and attained 80% accuracy in an independent sample based on the expression of one exon from each of five genes. If the observed profiles of pre-deployment mRNA-expression in eventual PTSD cases can be further refined and replicated, they could suggest avenues for early intervention and prevention among individuals at high risk for trauma exposure. PMID- 23650251 TI - Modulated crosslinking of macroporous polymeric cryogel affects in vitro cell adhesion and growth. AB - Cell to matrix interactions affect in vitro cell adherence and proliferation and further decide the fate of tissue development for biomedical applications. This study demonstrates the role of crosslinking in altering the surface properties of 3D porous cryogel matrices. Glutaraldehyde and 1-ethyl-3(3-dimethylaminopropyl) carbodiimide crosslinkers are used separately for the crosslinking of alginate and gelatin (i.e., AG(G) and AG(EN)), respectively. The difference in crosslinking affects the physiochemical properties of these matrices leading to variable cell behavior as demonstrated using four different cell types, which show homogeneous cell growth in AG(G) and spheroid cell growth in AG(EN). The present study shows successful use of controlled crosslinking in directing the cell growth for tissue engineering. PMID- 23650253 TI - Heart-fatty acid-binding and tau proteins relate to brain injury severity and long-term outcome in subarachnoid haemorrhage patients. AB - BACKGROUND: Vasospasm and other secondary neurological insults may follow subarachnoid haemorrhage (SAH). Biomarkers have the potential to stratify patient risk and perhaps serve as an early warning sign of delayed ischaemic injury. METHODS: Serial cerebrospinal fluid (CSF) samples were collected from 38 consecutive patients with aneurysmal SAH admitted to the neurosurgical intensive care unit. We measured heart-fatty acid-binding protein (H-FABP) and tau protein (tau) levels in the CSF to evaluate their association with brain damage, and their potential as predictors of the long-term outcome. H-FABP and tau were analysed in relation to acute clinical status, assessed by the World Federation of Neurological Surgeons (WFNS) scale, radiological findings, clinical vasospasm, and 6-month outcome. RESULTS: H-FABP and tau increased after SAH. H-FABP and tau were higher in patients in poor clinical status on admission (WFNS 4-5) compared with milder patients (WFNS 1-3). Elevated H-FABP and tau levels were also observed in patients with early cerebral ischaemia, defined as a CT scan hypodense lesion visible within the first 3 days after SAH. After the acute phase, H-FABP, and tau showed a delayed increase with the occurrence of clinical vasospasm. Finally, patients with the unfavourable outcome (death, vegetative state, or severe disability) had higher peak levels of both proteins compared with patients with good recovery or moderate disability. CONCLUSIONS: H-FABP and tau show promise as biomarkers of brain injury after SAH. They may help to identify the occurrence of vasospasm and predict the long-term outcome. PMID- 23650254 TI - Haemodialysis before emergency surgery in a patient treated with dabigatran. AB - Novel oral anticoagulants (NOAs) which directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban and apixaban) have recently been developed. We report the first case of perioperative management of a patient treated with dabigatran requiring haemodialysis before emergency surgery. A 62-yr-old woman visited the emergency department for a left bi-malleolar ankle fracture; she had a past medical history of severe ischaemic cardiomyopathy, alcoholic cirrhosis Child B, and moderate chronic renal insufficiency. The patient was treated with dabigatran for a left ventricular aneurysm with thrombus. Cutaneous manifestation of a voluminous haematoma required emergency surgery. Blood tests revealed dabigatran anticoagulant activity of 123 ng ml(-1) (therapeutic values: 85-200 ng ml(-1)), activated partial thromboplastin time of 63 s, and a prothrombin ratio of 68%, indicating that dabigatran disturbed coagulation. We decided to perform emergency haemodialysis before surgery. After 2 h, the anticoagulant activity of dabigatran was 11 ng ml(-1), allowing surgery. Surgery proceeded without any problems and the postoperative period was unremarkable. This case highlights the difficulties for the anaesthesiologist regarding emergency perioperative management of patients treated with NOAs and confirms the efficacy of haemodialysis in cases of dabigatran treatment. NOAs should be prescribed with caution, especially for patients with renal or hepatic disease, at least as long as no antagonist is available. In cases of deferred operative urgency in haemodynamically stable patients treated with dabigatran, haemodialysis should be considered to reverse dabigatran's anticoagulant effects. PMID- 23650256 TI - N-Glycosylation of Gel1 or Gel2 is vital for cell wall beta-glucan synthesis in Aspergillus fumigatus. AB - Fungal cell wall is a dynamic structure that communicates with and protects the cell from outside stress. In Aspergillus fumigatus, the cell wall beta-glucans are mainly elongated by beta-1,3-glucanosyltransferases Gels, which consist of seven family members (Gel1-7) utilizing beta-1,3-glucan chains as substrates. Previously, we have shown that the mutant deficient of N-glycan processing displays a reduction in the cell wall beta-glucans, suggesting that N glycosylation is required for the proper function of beta-1,3 glucanosyltransferase. To verify this hypothesis, in this study, the gene encoding beta-1,3-glucanosyltransferase Gel1 or Gel2 was deleted in the Deltacwh41 mutant to construct a double-mutant Deltagel1Deltacwh41 or Deltagel2Deltacwh41. The growth phenotypes of both double mutants were similar to the single-mutant Deltacwh41, suggesting that Gel1 and Gel2 are proteins that are mainly affected by deficient N-glycan processing in Deltacwh41. Furthermore, the mutant Deltagel1(Gel1-NM) or Deltagel2(Gel2-NM), in which all potential N glycosylation sites on Gel1 or Gel2 were removed by site-directed mutagenesis, showed phenotypes similar to the single-mutant Deltagel1 or Deltagel2. Biochemical analysis revealed that N-glycosylation was essential for the function of Gel1 or Gel2 and thus required for beta-glucan synthesis in A. fumigatus. PMID- 23650255 TI - Arachidonic acid closes innexin/pannexin channels and thereby inhibits microglia cell movement to a nerve injury. AB - Pannexons are membrane channels formed by pannexins and are permeable to ATP. They have been implicated in various physiological and pathophysiological processes. Innexins, the invertebrate homologues of the pannexins, form innexons. Nerve injury induces calcium waves in glial cells, releasing ATP through glial pannexon/innexon channels. The ATP then activates microglia. More slowly, injury releases arachidonic acid (ArA). The present experiments show that ArA itself reduced the macroscopic membrane currents of innexin- and of pannexin-injected oocytes; ArA also blocked K(+) -induced release of ATP. In leeches, whose large glial cells have been favorable for studying control of microglia migration, ArA blocked glial dye-release and, evidently, ATP-release. A physiological consequence in the leech was block of microglial migration to nerve injuries. Exogenous ATP (100 uM) reversed the effect, for ATP causes activation and movement of microglia after nerve injury, but nitric oxide directs microglia to the lesion. It was not excluded that metabolites of ArA may also inhibit the channels. But for all these effects, ArA and its non-metabolizable analog eicosatetraynoic acid (ETYA) were indistinguishable. Therefore, ArA itself is an endogenous regulator of pannexons and innexons. ArA thus blocks release of ATP from glia after nerve injury and thereby, at least in leeches, stops microglia at lesions. PMID- 23650257 TI - Standard fluorescent imaging of live cells is highly genotoxic. AB - Fluorescence microscopy is commonly used for imaging live mammalian cells. Here, we describe studies aimed at revealing the potential genotoxic effects of standard fluorescence microscopy. To assess DNA damage, a high throughput platform for single cell gel electrophoresis is used (e.g., the CometChip). Light emitted by three standard filters was studied: (a) violet light [340-380 nm], used to excite DAPI and other blue fluorophores, (b) blue light [460-500 nm] commonly used to image green fluorescent protein (GFP) and Calcein AM, and (c) green light [528-553 nm], useful for imaging red fluorophores. Results show that exposure of samples to light during imaging is indeed genotoxic even when the selected wavelengths are outside the range known to induce significant damage levels. Shorter excitation wavelengths and longer irradiation times lead to higher levels of DNA damage. We have also measured DNA damage in cells expressing enhanced GFP or stained with Calcein AM, a widely used green fluorophore. Data show that Calcein AM leads to a synergistic increase in the levels of DNA damage and that even cells that are not being directly imaged sustain significant DNA damage from exposure to indirect light. The nature of light-induced DNA damage during imaging was assessed using the Fpg glycosylase, an enzyme that enables quantification of oxidative DNA damage. Oxidative damage was evident in cells exposed to violet light. Furthermore, the Fpg glycosylase revealed the presence of oxidative DNA damage in blue-light exposed cells for which DNA damage was not detected using standard analysis conditions. Taken together, the results of these studies call attention to the potential confounding effects of DNA damage induced by standard imaging conditions, and identify wavelength, exposure time, and fluorophore as parameters that can be modulated to reduce light-induced DNA damage. PMID- 23650258 TI - Enhanced intercalation dynamics and stability of engineered micro/nano-structured electrode materials: vanadium oxide mesocrystals. AB - An additive and template free process is developed for the facile synthesis of VO2 (B) mesocrystals via the solvothermal reaction of oxalic acid and vanadium pentoxide. The six-armed star architectures are composed of stacked nanosheets homoepitaxially oriented along the [100] crystallographic register with respect to one another, as confirmed by means of selected area electron diffraction and electron microscopy. It is proposed that the mesocrystal formation mechanism proceeds through classical as well as non-classical crystallization processes, and is possibly facilitated or promoted by the presence of a reducing/chelating agent. The synthesized VO2 (B) mesocrystals are tested as a cathodic electrode material for lithium-ion batteries, and show good capacity at discharge rates ranging from 150-1500 mA g(-1) and a cyclic stability of 195 mA h g(-1) over fifty cycles. The superb electrochemical performance of the VO2 (B) mesocrystals is attributed to the porous and oriented superstructure that ensures large surface area for redox reaction and short diffusion distances. The mesocrystalline structure ensures that all the surfaces are in intimate contact with the electrolyte, and that lithium-ion intercalation occurs uniformly throughout the entire electrode. The exposed (100) facets also lead to fast lithium intercalation, and the homoepitaxial stacking of nanosheets offers a strong inner-sheet binding force that leads to better accommodation of the strain induced during cycling, thus circumventing the capacity fading issues typically associated with VO2 (B) electrodes. PMID- 23650260 TI - Large-scale production of diesel-like biofuels - process design as an inherent part of microorganism development. AB - Industrial biotechnology is playing an important role in the transition to a bio based economy. Currently, however, industrial implementation is still modest, despite the advances made in microorganism development. Given that the fuels and commodity chemicals sectors are characterized by tight economic margins, we propose to address overall process design and efficiency at the start of bioprocess development. While current microorganism development is targeted at product formation and product yield, addressing process design at the start of bioprocess development means that microorganism selection can also be extended to other critical targets for process technology and process scale implementation, such as enhancing cell separation or increasing cell robustness at operating conditions that favor the overall process. In this paper we follow this approach for the microbial production of diesel-like biofuels. We review current microbial routes with both oleaginous and engineered microorganisms. For the routes leading to extracellular production, we identify the process conditions for large scale operation. The process conditions identified are finally translated to microorganism development targets. We show that microorganism development should be directed at anaerobic production, increasing robustness at extreme process conditions and tailoring cell surface properties. All the same time, novel process configurations integrating fermentation and product recovery, cell reuse and low-cost technologies for product separation are mandatory. This review provides a state-of-the-art summary of the latest challenges in large-scale production of diesel-like biofuels. PMID- 23650259 TI - A role for synaptic zinc in ProSAP/Shank PSD scaffold malformation in autism spectrum disorders. AB - The establishment and maintenance of synaptic contacts as well as synaptic plasticity are crucial factors for normal brain function. The functional properties of a synapse are largely dependent on the molecular setup of synaptic proteins. Multidomain proteins of the ProSAP/Shank family act as major organizing scaffolding elements of the postsynaptic density (PSD). Interestingly, ProSAP/Shank proteins at glutamatergic synapses have been linked to a variety of Autism Spectrum Disorders (ASDs) including Phelan McDermid Syndrome, and deregulation of ProSAP/Shank has been reported in Alzheimer's disease. Although the precise molecular mechanism of the dysfunction of these proteins remains unclear, an emerging model is that mutations or deletions impair neuronal circuitry by disrupting the formation, plasticity and maturation of glutamatergic synapses. Several PSD proteins associated with ASDs are part of a complex centered around ProSAP/Shank proteins and many ProSAP/Shank interaction partners play a role in signaling within dendritic spines. Interfering with any one of the members of this signaling complex might change the output and drive the system towards synaptic dysfunction. Based on recent data, it is possible that the concerted action of ProSAP/Shank and Zn(2+) is essential for the structural integrity of the PSD. This interplay might regulate postsynaptic receptor composition, but also transsynaptic signaling. It might be possible that environmental factors like nutritional Zn(2+) status or metal ion homeostasis in general intersect with this distinct pathway centered around ProSAP/Shank proteins and the deregulation of any of these two factors may lead to ASDs. PMID- 23650261 TI - Assessing main death pathways in T lymphocytes from HIV infected individuals. AB - Increased lymphocyte death is a hallmark of human immunodeficiency virus (HIV) infection. Although virological factors have been linked to this phenomenon, increased cell death rates are still observed in treated individuals in which viral replication is halted. To understand the nature of this remaining altered cell death, we have developed a simple and fast assay to assess major cell death pathways in lymphocytes isolated from HIV-infected individuals. The combination of three factors: (i) antibody staining to identify CD3(+) CD4(+) and CD3(+) CD8(+) cells, (ii) assessment of mitochondrial and plasma membrane function using DiOC6(3) or JC-1 probes and vital dyes, and (iii) caspase inhibition, allowed for the quantification of caspase-independent and -dependent cell death in CD4 and CD8 T cells. The latter mechanism was divided in intrinsic and extrinsic apoptotic pathways according to the sensitivity of the dissipation of mitochondrial membrane potential to Z-VAD-fmk or Q-VD-oPH treatment. Our data show similar results for both caspase inhibitors in treated infected individuals, whereas Q-VD-oPH showed a more potent inhibition in viremic individuals, yielding lower levels of intrinsic apoptosis. Comparison of DiOC6(3) and JC-1 probes yielded similar results in CD4 T cells, allowing for a clear definition of death mechanism in these cells. However, in CD8 T-cells, JC-1 showed heterogeneous staining and detected significantly lower levels of cell death with a higher contribution of intrinsic apoptosis. In conclusion, we provide a simple method to assess CD4 T-cell death mechanisms in HIV-infected individuals. The reasons and consequences of mitochondrial heterogeneity in CD8 T-cells require further evaluation. PMID- 23650263 TI - Graphene/polyaniline/poly(4-styrenesulfonate) hybrid film with uniform surface resistance and its flexible dipole tag antenna application. AB - A graphene/polyaniline/poly(4-styrenesulfonate) (G/PANI/PSS)-based conducting paste is successfully fabricated by introducing a PANI/PSS nanofiller into a multilayer graphene matrix by mechanical blending. As a compatibilizer, the PSS binder increases the dispersibility, interfacial interactions, and mechanical interlocking between the multilayer graphene matrix and PANI, thereby allowing surface resistance with narrow distribution. High concentrations of this PSS binder, obtained using ex situ polymerization, further improve the adhesion of the hybrid film to a flexible substrate. The minimum surface resistance of the screen-printed G/PANI/PSS hybrid film is approximately 10 Omega sq(-1) for a 70 MUm uniform thickness. When bent to angles of -30 degrees , the flexible hybrid film exhibits an approximately 6% decrease in surface resistance. The surface resistance after 500 bending cycles increases by only 10 Omega sq(-1) , which is 14 times that of smaller, graphene-based thin films. The micropatterned, screen printed G/PANI/PSS hybrid film is evaluated as a practical dipole tag antenna. High-resolution patterns are formed in the hybrid film by the inherently high surface tension and the properties of grains within the domain-based structure. The G/PANI/PSS-based dipole tag antenna has a bandwidth of 28.7 MHz, a high transmitted power efficiency of 98.5%, and a recognition distance of 0.42 m at a mean frequency of 910 MHz. These characteristics indicate that the G/PANI/PSS based dipole tag antenna could be used as a signal-receiving apparatus, much like a radio-frequency identification tag, for detecting nearby objects. PMID- 23650262 TI - Autophagy opposes p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-associated hereditary breast cancer. AB - Hereditary breast cancers stem from germline mutations in susceptibility genes such as BRCA1, BRCA2, and PALB2, whose products function in the DNA damage response and redox regulation. Autophagy is an intracellular waste disposal and stress mitigation mechanism important for alleviating oxidative stress and DNA damage response activation; it can either suppress or promote cancer, but its role in breast cancer is unknown. Here, we show that similar to Brca1 and Brca2, ablation of Palb2 in the mouse mammary gland resulted in tumor development with long latency, and the tumors harbored mutations in Trp53. Interestingly, impaired autophagy, due to monoallelic loss of the essential autophagy gene Becn1, reduced Palb2-associated mammary tumorigenesis in a Trp53-wild-type but not conditionally null background. These results indicate that, in the face of DNA damage and oxidative stress elicited by PALB2 loss, p53 is a barrier to cancer development, whereas autophagy facilitates cell survival and tumorigenesis. PMID- 23650264 TI - A three-dimensional atlas of human tongue muscles. AB - The human tongue is one of the most important yet least understood structures of the body. One reason for the relative lack of research on the human tongue is its complex anatomy. This is a real barrier to investigators as there are few anatomical resources in the literature that show this complex anatomy clearly. As a result, the diagnosis and treatment of tongue disorders lags behind that for other structures of the head and neck. This report intended to fill this gap by displaying the tongue's anatomy in multiple ways. The primary material used in this study was serial axial images of the male and female human tongue from the Visible Human (VH) Project of the National Library of Medicine. In addition, thick serial coronal sections of three human tongues were rendered translucent. The VH axial images were computer reconstructed into serial coronal sections and each tongue muscle was outlined. These outlines were used to construct a three dimensional (3D) computer model of the tongue that allows each muscle to be seen in its in vivo anatomical position. The thick coronal sections supplement the 3D model by showing details of the complex interweaving of tongue muscles throughout the tongue. The graphics are perhaps the clearest guide to date to aid clinical or basic science investigators in identifying each tongue muscle in any part of the human tongue. PMID- 23650265 TI - Functional monolithic platforms: chromatographic tools for antibody purification. AB - Polymer monoliths are an efficient platform for antibody purification. The use of monoclonal antibodies (mAbs) and engineered antibody structures as therapeutics has increased exponentially over the past few decades. Several approaches use polymer monoliths to purify large quantities of antibody with defined clinical and performance requirements. Functional monolithic supports have attracted a great deal of attention as they offer practical advantages for antibody purification, such as more rapid analysis, smaller sample volume requirements and the opportunity for a greater target molecule enrichment. This review focuses on the development of synthetic and natural polymer-based monoliths for antibody purification. The materials and methods employed in monolith production are discussed, highlighting the properties of each system. We also review the structural characterization techniques available using monolithic systems and their performance under different chromatographic approaches to antibody capture and release. Finally, a summary of monolithic platforms developed for antibody separation is presented, as well as expected trends in research to solve current and future challenges in this field. This review comprises a comprehensive analysis of proposed solutions highlighting the remarkable potential of monolithic platforms. PMID- 23650266 TI - Development of microbial resistant thermosensitive Ag nanocomposite (gelatin) hydrogels via green process. AB - In this investigation, an ecofriendly method for the synthesis of silver nanoparticles (AgNPs) using biodegradable gelatin as a stabilizing agent is reported. Here, we prepared thermosensitive silver nanocomposite hydrogels composed of gelatin and N-isopropylacrylamide. In this green process AgNPs were formed from Ag(+) ions and reduced with leaf [Azadirachta indica (neem leaf)] extracts, resulting in a hydrogel network. The Ag(0) nanoparticles affect the hydrogel strength and improved the biological activity (inactivation effect of bacteria) of the biodegradable hydrogels. The resulted hydrogel structure, morphology, thermal, swelling behavior, degradation, and antibacterial properties were systematically investigated. The biodegradable thermosensitive silver nanocomposite hydrogels developed were tested for antibacterial activities. The results indicate that these biodegradable silver nanocomposite hydrogels are suitable potential candidates for antibacterial applications. PMID- 23650267 TI - Liposomal encapsulation of a near-infrared fluorophore enhances fluorescence quenching and reliable whole body optical imaging upon activation in vivo. AB - In the past decade, there has been significant progress in the development of water soluble near-infrared fluorochromes for use in a wide range of imaging applications. Fluorochromes with high photo and thermal stability, sensitivity, adequate pharmacological properties and absorption/emission maxima within the near infrared window (650-900 nm) are highly desired for in vivo imaging, since biological tissues show very low absorption and auto-fluorescence at this spectrum window. Taking these properties into consideration, a myriad of promising near infrared fluorescent probes has been developed recently. However, a hallmark of most of these probes is a rapid clearance in vivo, which hampers their application. It is hypothesized that encapsulation of the near infrared fluorescent dye DY-676-COOH, which undergoes fluorescence quenching at high concentrations, in the aqueous interior of liposomes will result in protection and fluorescence quenching, which upon degradation by phagocytes in vivo will lead to fluorescence activation and enable imaging of inflammation. Liposomes prepared with high concentrations of DY-676-COOH reveal strong fluorescence quenching. It is demonstrated that the non-targeted PEGylated fluorescence activatable liposomes are taken up predominantly by phagocytosis and degraded in lysosomes. Furthermore, in zymosan-induced edema models in mice, the liposomes are taken up by monocytes and macrophages which migrate to the sites of inflammation. Opposed to free DY-676-COOH, prolonged stability and retention of liposomal-DY-676-COOH is reflected in a significant increase in fluorescence intensity of edema. Thus, protected delivery and fluorescence quenching make the DY-676-COOH-loaded liposomes a highly promising contrast agent for in vivo optical imaging of inflammatory diseases. PMID- 23650268 TI - Calibration procedures for the quantitative determination of membrane potential in human cells using anionic dyes. AB - Quantitative determinations of the cell membrane potential of lymphocytes (Wilson et al., J Cell Physiol 1985;125:72-81) and thymocytes (Krasznai et al., J Photochem Photobiol B 1995;28:93-99) using the anionic dye DiBAC4 (3) proved that dye depletion in the extracellular medium as a result of cellular uptake can be negligible over a wide range of cell densities. In contrast, most flow cytometric studies have not verified this condition but rather assumed it from the start. Consequently, the initially prepared extracellular dye concentration has usually been used for the calculation of the Nernst potential of the dye. In this study, however, external dye depletion could be observed in both large IGR-1 and small LCL-HO cells under experimental conditions, which have often been applied routinely in spectrofluorimetry and flow cytometry. The maximum cell density at which dye depletion could be virtually avoided was dependent on cell size and membrane potential and definitely needed to be taken into account to ensure reliable results. In addition, accepted calibration procedures based on the partition of sodium and potassium (Goldman-Hodgkin-Katz equation) or potassium alone (Nernst equation) were performed by flow cytometry on cell suspensions with an appropriately low cell density. The observed extensive lack of concordance between the correspondingly calculated membrane potential and the equilibrium potential of DiBAC4 (3) revealed that these methods require the additional measurement of cation parameters (membrane permeability and/or intracellular concentration). In contrast, due to the linear relation between fluorescence and low DiBAC4 (3) concentrations, the Nernst potential of the dye for totally depolarized cells can be reliably used for calibration with an essentially lower effort and expense. PMID- 23650269 TI - Cranial muscle development in the model organism ambystoma mexicanum: implications for tetrapod and vertebrate comparative and evolutionary morphology and notes on ontogeny and phylogeny. AB - There is still confusion about the homology of several cranial muscles in salamanders with those of other vertebrates. This is true, in part, because of the fact that many muscles present in early ontogeny of amphibians disappear during development and specifically during metamorphosis. Resolving this confusion is important for the understanding of the comparative and evolutionary morphology of vertebrates and tetrapods because amphibians are the phylogenetically most plesiomorphic tetrapods, concerning for example their myology, and include two often used model organisms, Xenopus laevis (anuran) and Ambystoma mexicanum (urodele). Here we provide the first detailed report of the cranial muscle development in axolotl from early ontogenetic stages to the adult stage. We describe different and complementary types of general muscle morphogenetic gradients in the head: from anterior to posterior, from lateral to medial, and from origin to insertion. Furthermore, even during the development of neotenic salamanders such as axolotls, various larval muscles become indistinct, contradicting the commonly accepted view that during ontogeny the tendency is mostly toward the differentiation of muscles. We provide an updated comparison between these muscles and the muscles of other vertebrates, a discussion of the homologies and evolution, and show that the order in which the muscles appear during axolotl ontogeny is in general similar to their appearance in phylogeny (e.g. differentiation of adductor mandibulae muscles from one anlage to four muscles), with only a few remarkable exceptions, as for example the dilatator laryngis that appears evolutionary later but in the development before the intermandibularis. PMID- 23650270 TI - Plasma surface modification of fibroporous polycarbonate urethane membrane by polydimethyl siloxane: structural characterization, mechanical properties, and in vitro cytocompatibility evaluation. AB - This article reports the surface modification of electrospun polycarbonate urethane membrane with polydimethyl siloxane (PDMS) using plasma-induced grafting technique for biomedical applications. The nonwoven membranes were characterized for their structure, performance, and compatibility with cells. The surface modification was confirmed by means of attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and energy dispersive X-ray analysis (EDXA). ATR-FTIR and EDXA analyses displayed characteristic absorption peaks of PDMS for the membrane. The structure and morphology of the developed membranes were studied using scanning electron microscope and microcomputed tomography (uCT). Scanning electron microscopy and uCT revealed the fibrous morphology and percentage porosity of the membranes before and after plasma modification. Static mechanical tests showed that the tensile strength was greater than 8 MPa. Physical characterization of the membranes after immersion in hydrolytic and oxidative media supports their biostability. Cytotoxicity of the membrane was evaluated using L929 fibroblast cells, and the results indicated that the membrane is cytocompatible. Accordingly, these results highlight the potential of this fibrous membrane for biomedical applications. PMID- 23650271 TI - Biotechnology essay competition: biotechnology and sustainable food practices. AB - Biotechnology Journal announces our second biotechnology essay competition with the theme "biotechnology and sustainable food practices", open to all undergraduate students. PMID- 23650272 TI - Magneto-controllable capture and release of cancer cells by using a micropillar device decorated with graphite oxide-coated magnetic nanoparticles. AB - Aiming to highly efficient capture and analysis of circulating tumor cells, a micropillar device decorated with graphite oxide-coated magnetic nanoparticles is developed for magneto-controllable capture and release of cancer cells. Graphite oxide-coated, Fe3 O4 magnetic nanoparticles (MNPs) are synthesized by solution mixing and functionalized with a specific antibody, following by the immobilization of such modified MNPs on our designed micropillar device. For the proof-of-concept study, a HCT116 colorectal cancer cell line is employed to exam the capture efficiency. Under magnetic field manipulation, the high density packing of antibody-modified MNPs on the micropillars increases the local concentration of antibody, as well as the topographic interactions between cancer cells and micropillar surfaces. The flow rate and the micropillar geometry are optimized by studying their effects on capture efficiency. Then, a different number of HCT116 cells spiked in two kinds of cell suspension are investigated, yielding capture efficiency >70% in culture medium and >40% in blood sample, respectively. Moreover, the captured HCT116 cells are able to be released from the micropillars with a saturated efficiency of 92.9% upon the removal of applied magnetic field and it is found that 78% of the released cancer cells are viable, making them suitable for subsequent biological analysis. PMID- 23650273 TI - Human NK cell receptors/markers: a tool to analyze NK cell development, subsets and function. AB - Natural killer (NK) cells are important components of the innate immunity and play a key role in host defense by virtue of their ability to release cytokines and to mediate cytolytic activity against tumor cells and virus-infected cells. NK cells were first described more than 30 years ago on the basis of their peculiar functional capabilities. Subsequently, thanks to the production of a variety of monoclonal antibodies, it became possible to identify surface receptors and markers expressed by NK cells as well as to characterize their functional properties. Here, we provide a brief historical overview about the discovery of human NK cell receptors and we delineate the main phenotypic features of differentiating and mature NK cells in healthy donors as well as their alterations in certain pathologic conditions. PMID- 23650274 TI - The place of surface anatomy in the medical literature and undergraduate anatomy textbooks. AB - The aims of this review were to examine the place of surface anatomy in the medical literature, particularly the methods and approaches used in teaching surface and living anatomy and assess commonly used anatomy textbooks in regard to their surface anatomy contents. PubMed and MEDLINE databases were searched using the following keywords "surface anatomy," "living anatomy," "teaching surface anatomy," "bony landmarks," "peer examination" and "dermatomes". The percentage of pages covering surface anatomy in each textbook was calculated as well as the number of images covering surface anatomy. Clarity, quality and adequacy of surface anatomy contents was also examined. The search identified 22 research papers addressing methods used in teaching surface anatomy, 31 papers that can help in the improvement of surface anatomy curriculum, and 12 anatomy textbooks. These teaching methods included: body painting, peer volunteer surface anatomy, use of a living anatomy model, real time ultrasound, virtual (visible) human dissector (VHD), full body digital x-ray of cadavers (Lodox((r)) Statscan((r)) images) combined with palpating landmarks on peers and the cadaver, as well as the use of collaborative, contextual and self-directed learning. Nineteen of these studies were published in the period from 2006 to 2013. The 31 papers covered evidence-based and clinically-applied surface anatomy. The percentage of surface anatomy in textbooks' contents ranged from 0 to 6.2 with an average of 3.4%. The number of medical illustrations on surface anatomy varied from 0 to 135. In conclusion, although there has been a progressive increase in publications addressing methods used in teaching surface anatomy over the last six to seven years, most anatomy textbooks do not provide students with adequate information about surface anatomy. Only three textbooks provided a solid explanation and foundation of understanding surface anatomy. PMID- 23650275 TI - Discovery of piperidine-linked pyridine analogues as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. AB - In our continued efforts to discover more active and less toxic HIV-1 non nucleoside reverse transcriptase inhibitors, we recently designed a novel series of piperidine-linked pyridine analogues on the basis of diarylpyrimidine derivatives, among which two drugs-etravirine and rilpivirine-are approved for use by the US FDA. The title compounds were evaluated for activity against wild type and resistant mutant strains of HIV-1 as well as HIV-2 in MT-4 cells. The highly potent compound BD-c1 (EC50 =10 nM, CC50 >=146 MUM, SI>=14 126) displays lower cytotoxicity and higher selectivity than etravirine (EC50 =2.2 nM, CC50 =28 MUM, SI=12 884) against wild-type HIV-1. Compound BD-e2 (EC50 =5.1 nM) shows greater antiviral efficacy against wild-type HIV-1 than do the four reference drugs nevirapine, delavirdine, efavirenz, and zidovudine. Many compounds were also found to be active against the frequently observed drug-resistant double mutant (K103N+Y181C) HIV-1 strain. Herein we report the design, synthesis, anti HIV evaluation, preliminary structure-activity relationships, and molecular simulations of novel piperidine-linked pyridine analogues. PMID- 23650276 TI - Ammonium and guanidinium dendron-carbon nanotubes by amidation and click chemistry and their use for siRNA delivery. AB - A series of multi-walled carbon nanotube (MWCNT) conjugates is described, functionalized with different dendrons bearing positive charges at their termini (i.e. ammonium or guanidinium groups). The dendrimeric units are anchored to the nanotube scaffolds using two orthogonal synthetic approaches, amidation and click reactions. The final nanohybrids are characterized by complementary analytical techniques, while their ability to interact with siRNA is investigated by means of agarose gel electrophoresis. The demonstration of the cell uptake capacity, the low cytotoxicity, and the ability of these cationic conjugates to silence cytotoxic genes suggests them to be promising carriers for genetic material. PMID- 23650277 TI - Influence of micro and submicro poly(lactic-glycolic acid) fibers on sensory neural cell locomotion and neurite growth. AB - For successful peripheral nerve regeneration, a complex interplay of growth factors, topographical guidance structure by cells and extracellular matrix proteins, are needed. Aligned fibrous biomaterials with a wide variety in fiber diameter have been used successfully to support neuronal guidance. To better understand the importance of size of the topographical features, we investigated the directionality of neuronal migration of sensory ND7/23 cells on aligned electrospun poly(lactic-glycolic acid) PLGA fibers in the range of micrometer and submicrometer diameters by time-lapse microscopy. Cell trajectories of single ND7/23 cells were found to significantly follow topographies of PLGA fibers with micrometer dimensions in contrast to PLGA fibers within the submicrometer range, where cell body movement was observed to be independent of fibrous structures. Moreover, neurite alignment of ND7/23 cells on various topographies was assessed. PLGA fibers with micrometer dimensions significantly aligned 83.3% of all neurites after 1 day of differentiation compared to similar submicrometer structures, which orientated 25.8% of all neurites. Interestingly, after 7 days of differentiation ND7/23 cells on submicrometer PLGA fibers increased their alignment of neurites to 52.5%. Together, aligned PLGA fibers with micrometer dimensions showed a superior influence on directionality of neuronal migration and neurite outgrowth of sensory ND7/23 cells, indicating that electrospun micro PLGA fibers might represent a potential material to induce directionality of neuronal growth in engineering applications for sensory nerve regeneration. PMID- 23650278 TI - In vivo response to an implanted shape memory polyurethane foam in a porcine aneurysm model. AB - Cerebral aneurysms treated by traditional endovascular methods using platinum coils have a tendency to be unstable, either due to chronic inflammation, compaction of coils, or growth of the aneurysm. We propose to use alternate filling methods for the treatment of intracranial aneurysms using polyurethane based shape memory polymer (SMP) foams. SMP polyurethane foams were surgically implanted in a porcine aneurysm model to determine biocompatibility, localized thrombogenicity, and their ability to serve as a stable filler material within an aneurysm. The degree of healing was evaluated via gross observation, histopathology, and low vacuum scanning electron microscopy imaging after 0, 30, and 90 days. Clotting was initiated within the SMP foam at time 0 (<1 h exposure to blood before euthanization), partial healing was observed at 30 days, and almost complete healing had occurred at 90 days in vivo, with minimal inflammatory response. PMID- 23650279 TI - The implementation of clay modeling and rat dissection into the human anatomy and physiology curriculum of a large urban community college. AB - After a considerable amount of research and experimentation, cat dissection was replaced with rat dissection and clay modeling in the human anatomy and physiology laboratory curricula at La Guardia Community College (LAGCC), a large urban community college of the City University of New York (CUNY). This article describes the challenges faculty overcame and the techniques used to solve them. Methods involved were: developing a laboratory manual in conjunction with the publisher, holding training sessions for faculty and staff, the development of instructional outlines for students and lesson plans for faculty, the installation of storage facilities to hold mannequins instead of cat specimens, and designing mannequin clean-up techniques that could be used by more than one thousand students each semester. The effectiveness of these curricular changes was assessed by examining student muscle practical examination grades and the responses of faculty and students to questionnaires. The results demonstrated that the majority of faculty felt prepared to teach using clay modeling and believed the activity was effective in presenting lesson content. Students undertaking clay modeling had significantly higher muscle practical examination grades than students undertaking cat dissection, and the majority of students believed that clay modeling was an effective technique to learn human skeletal, respiratory, and cardiovascular anatomy, which included the names and locations of blood vessels. Furthermore, the majority of students felt that rat dissection helped them learn nervous, digestive, urinary, and reproductive system anatomy. Faculty experience at LAGCC may serve as a resource to other academic institutions developing new curricula for large, on-going courses. PMID- 23650280 TI - Chain folding controlled by an isomeric repeat unit: helix formation versus random aggregation in acetylene-bridged carbazole-bipyridine co-oligomers. AB - An unprecedented, positional effect of the isomeric repeat unit on chain folding in donor-acceptor-linked oligomers, which contain alternating bipyridine and carbazole moieties that are connected through an acetylinic linkage, is reported. 4,4'-Linked oligomer 1 adopts an intrachain helical conformation (CD-active) in CHCl3/MeCN (20:80 v/v), whereas oligomer 2, which contains an isomeric 6,6' linkage, forms interchain randomly coiled aggregates (CD-inactive). The substitution position plays a significant role in controlling the variations in electronic effects and dipole moments around the bipyridyl moiety, which are responsible for this observed phenomenon. Two model compounds of oligomers 1 and 2 (3 and 4, respectively) were prepared and their properties were compared. A systematic investigation of the photophysical and CD properties of these structures, as well as theoretical studies, support our conclusions. PMID- 23650281 TI - Colloidal synthesis of ternary AgFeS2 nanocrystals and their transformation to Ag2S-Fe7S8 heterodimers. AB - Ternary-/hetero-nanocrystals: a facile one-pot colloidal route for controlled synthesis of ternary AgFeS2 nanocrystals, which have a band gap of 1.21 eV, is presented for the first time. Such ternary AgFeS2 nanocrystals can transform to Ag2 S-Fe7 S8 heterodimers by internal thermal reaction at elevated temperature, providing a new route to synthesize semiconductor hetero-nanostructures. PMID- 23650282 TI - Loss of ARF sensitizes transgenic BRAFV600E mice to UV-induced melanoma via suppression of XPC. AB - Both genetic mutations and UV irradiation (UVR) can predispose individuals to melanoma. Although BRAF(V600E) is the most prevalent oncogene in melanoma, the BRAF(V600E) mutant is not sufficient to induce tumors in vivo. Mutation at the CDKN2A locus is another melanoma-predisposing event that can disrupt the function of both p16(INK4a) and ARF. Numerous studies have focused on the role of p16(INK4a) in melanoma, but the involvement of ARF, a well-known p53 activator, is still controversial. Using a transgenic BRAF(V600E) mouse model previously generated in our laboratory, we report that loss of ARF is able to enhance spontaneous melanoma formation and cause profound sensitivity to neonatal UVB exposure. Mechanistically, BRAF(V600E) and ARF deletion synergize to inhibit nucleotide excision repair by epigenetically repressing XPC and inhibiting the E2F4/DP1 complex. We suggest that the deletion of ARF promotes melanomagenesis not by abrogating p53 activation but by acting in concert with BRAF(V600E) to increase the load of DNA damage caused by UVR. PMID- 23650283 TI - GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors. AB - Most breast cancers at diagnosis are estrogen receptor-positive (ER(+)) and depend on estrogen for growth and survival. Blocking estrogen biosynthesis by aromatase inhibitors has therefore become a first-line endocrine therapy for postmenopausal women with ER(+) breast cancers. Despite providing substantial improvements in patient outcome, aromatase inhibitor resistance remains a major clinical challenge. The receptor tyrosine kinase, RET, and its coreceptor, GFRalpha1, are upregulated in a subset of ER(+) breast cancers, and the RET ligand, glial-derived neurotrophic factor (GDNF) is upregulated by inflammatory cytokines. Here, we report the findings of a multidisciplinary strategy to address the impact of GDNF-RET signaling in the response to aromatase inhibitor treatment. In breast cancer cells in two-dimensional and three-dimensional culture, GDNF-mediated RET signaling is enhanced in a model of aromatase inhibitor resistance. Furthermore, GDNF-RET signaling promoted the survival of aromatase inhibitor-resistant cells and elicited resistance in aromatase inhibitor-sensitive cells. Both these effects were selectively reverted by the RET kinase inhibitor, NVP-BBT594. Gene expression profiling in ER(+) cancers defined a proliferation-independent GDNF response signature that prognosed poor patient outcome and, more importantly, predicted poor response to aromatase inhibitor treatment with the development of resistance. We validated these findings by showing increased RET protein expression levels in an independent cohort of aromatase inhibitor-resistant patient specimens. Together, our results establish GDNF-RET signaling as a rational therapeutic target to combat or delay the onset of aromatase inhibitor resistance in breast cancer. PMID- 23650285 TI - Pore size-dependent immunogenic activity of mesoporous silica-based adjuvants in cancer immunotherapy. AB - Commonly used aluminum hydroxide (Alum) adjuvant provokes a strong type 2 helper T cell (Th2) response for mediating antibody production but is rather ineffective for disease prevention that requires type 1 helper T cell (Th1) response for mediating cellular immunity in human vaccination. Here, for the purpose of inducing Th1 antitumor immunity, a mesoporous silica (MS)-based adjuvant is prepared. Three kinds of MS particles with nearly identical particle size and surface area but different pore sizes of 4, 7 and 10 nm were prepared. No serious in vitro cytotoxicity was observed for the MS particles at 5, 20, 50, and 100 MUg/mL. Pathogen-associated molecular patterns (PAMPs) were immobilized with apatite (Ap) on MS to prepare the MS-based and PAMP-loaded adjuvants (MS-Ap-PAMP adjuvants). Macrophage-like cells cultured in the presence of MS-Ap-PAMP adjuvant with a MS pore size of 10 nm showed the maximum in vitro immunogenic activity. Injection of the MS-Ap-PAMP adjuvant with a MS pore size of 10 nm in combination with liquid nitrogen-treated tumor tissue (derived from Lewis lung carcinoma cells) to C57BL/6 mice markedly inhibited the development of rechallenged tumor in vivo, while no such antitumor immunity was induced in injection of Alum mixed with PAMP in combination with liquid nitrogen-treated tumor tissue. The MS-Ap PAMP adjuvant contributed to the elicitation of a potent systemic Th1 antitumor immunity in vivo. PMID- 23650284 TI - The steroid receptor coactivator-3 is required for the development of castration resistant prostate cancer. AB - The transcriptional coactivator SRC-3 plays a key role in enhancing prostate cancer cell proliferation. Although SRC-3 is highly expressed in advanced prostate cancer, its role in castration-resistant prostate cancer (CRPC) driven by PTEN mutation is unknown. We documented elevated SRC-3 in human CRPC and in PTEN-negative human prostate cancer. Patients with high SRC-3 and undetectable PTEN exhibited decreased recurrence-free survival. To explore the causal relationship in these observations, we generated mice in which both Pten and SRC 3 were inactivated in prostate epithelial cells (Pten3CKO mice), comparing them with mice in which only Pten was inactivated in these cells (PtenCKO mice). SRC-3 deletion impaired cellular proliferation and reduced tumor size. Notably, while castration of PtenCKO control mice increased the aggressiveness of prostate tumors relative to noncastrated counterparts, deletion of SRC-3 in Pten3CKO mice reversed all these changes. In support of this finding, castrated Pten3CKO mice also exhibited decreased levels of phospho-Akt, S6 kinase (RPS6KB1), and phosphorylated S6 protein (RPS6), all of which mediate cell growth and proliferation. Moreover, these tumors appeared to be more differentiated as evidenced by higher levels of Fkbp5, an AR-responsive gene that inhibits Akt signaling. Lastly, these tumors also displayed lower levels of certain androgen repressed genes such as cyclin E2 and MMP10. Together, our results show that SRC 3 drives CRPC formation and offer preclinical proof of concept for a transcriptional coactivator as a therapeutic target to abrogate CRPC progression. PMID- 23650286 TI - Comparison of cell-loading methods in hydrogel systems. AB - Bone regenerative medicine, based on the combined use of cells and scaffolds, represents a promising strategy in bone regeneration. Hydrogels have attracted huge interests for application as a scaffold for minimally invasive surgery. Collagen and oligo(poly(ethylene glycol)fumarate) (OPF) hydrogels are the representatives of two main categories of hydrogels, that is, natural- and synthetic-based hydrogels. With these the optimal cell-loading (i.e., cell distribution inside the hydrogels) method was assessed. The cell behavior of both bone marrow- and adipose tissue-derived mesenchymal stem cells (BM- and AT-MSCs) in three loading methods, which are dispersed (i.e., homogeneous cell encapsulation, D), sandwich (i.e., cells located in between two hydrogel layers, S), and spheroid (i.e., cell pellets encapsulation, Sp) loading in two hydrogel systems (i.e., collagen and OPF), was compared. The results suggested that the cell behavior was influenced by the hydrogel type, meaning cells cultured in collagen hydrogels had higher proliferation and osteogenic differentiation capacity than in OPF hydrogels. In addition, AT-MSCs exhibited higher proliferation and osteogenic properties compared to BM-MSCs. However, no difference was observed for mineralization among the three loading methods, which did not approve the hypothesis that S and Sp loading would increase osteogenic capacity compared to D loading. In conclusion, D and Sp loading represents two promising cell loading methods for injectable bone substitute materials that allow application of minimally invasive surgery for cell-based regenerative treatment. PMID- 23650287 TI - Systems biology of the functional and dysfunctional endothelium. AB - This review provides an overview of the effect of blood flow on endothelial cell (EC) signalling pathways, applying microarray technologies to cultured cells, and in vivo studies of normal and atherosclerotic animals. It is found that in cultured ECs, 5-10% of genes are up- or down-regulated in response to fluid flow, whereas only 3-6% of genes are regulated by varying levels of fluid flow. Of all genes, 90% are regulated by the steady part of fluid flow and 10% by pulsatile components. The associated gene profiles show high variability from experiment to experiment depending on experimental conditions, and importantly, the bioinformatical methods used to analyse the data. Despite this high variability, the current data sets can be summarized with the concept of endothelial priming. In this concept, fluid flows confer protection by an up-regulation of anti atherogenic, anti-thrombotic, and anti-inflammatory gene signatures. Consequently, predilection sites of atherosclerosis, which are associated with low-shear stress, confer low protection for atherosclerosis and are, therefore, more sensitive to high cholesterol levels. Recent studies in intact non atherosclerotic animals confirmed these in vitro studies, and suggest that a spatial component might be present. Despite the large variability, a few signalling pathways were consistently present in the majority of studies. These were the MAPK, the nuclear factor-kappaB, and the endothelial nitric oxide synthase-NO pathways. PMID- 23650288 TI - The phosphodiesterase-5 inhibitor vardenafil reduces oxidative stress while reversing pulmonary arterial hypertension. AB - AIMS: Oxidative stress is implicated in the pathology of pulmonary arterial hypertension (PAH). Previously, we demonstrated that vardenafil, a phosphodiesterase-5 inhibitor, has potential as therapy for PAH, although the mechanism remained uncharacterized. Here, we aimed to determine baseline levels of oxidative stress in PAH and investigate whether vardenafil affects oxidative stress levels while improving PAH. METHODS AND RESULTS: Sprague-Dawley rats with monocrotaline-induced PAH were administered oral vardenafil 1 mg kg-1 day-1 for 21 days (n = 12). Treatment-naive patients (n = 15) with PAH were treated with vardenafil 5 mg twice daily for 3 months. Haemodynamic data and plasma levels of nitrate/nitrite and products of oxidative damage were determined in rats and patients. Histopathology, immunohistochemistry, and assessments of oxidative/anti oxidative enzyme expression were performed in rat lung tissue. Compared with baseline (patients) or untreated controls (rats), vardenafil significantly reduced pulmonary vascular resistance and increased cardiac output (CO). In rats, vardenafil suppressed proliferation and enhanced apoptosis of pulmonary artery smooth muscle cells, attenuating small pulmonary artery remodelling, and right ventricular hypertrophy. Vardenafil significantly reduced levels of oxidative stress biomarkers, such as 8-iso-prostaglandin-F2alpha and 3-nitrotyrosine, and significantly increased nitric oxide (NO) levels in rats and patients. Furthermore, vardenafil significantly increased endothelial NO synthase expression and superoxide dismutase activity, and down-regulated nicotinamide adenine dinucleotide phosphate oxidase expression in rat lung tissue. CONCLUSION: Vardenafil reduces oxidative stress in rats and humans while improving PAH, warranting investigation of oxidative stress pathways as targets for PAH therapy. PMID- 23650289 TI - Functional bimodality in the brain networks of preterm and term human newborns. AB - The spontaneous brain activity exhibits long-range spatial correlations detected using functional magnetic resonance imaging (fMRI) signals in newborns when (1) long neuronal pathways are still developing, and (2) the electrical brain activity consists of developmentally unique, intermittent events believed to guide activity-dependent brain wiring. We studied this spontaneous electrical brain activity using multichannel electroencephalography (EEG) of premature and fullterm babies during sleep to assess the development of spatial integration during last months of gestation. Correlations of frequency-specific amplitudes were found to follow a robust bimodality: During low amplitudes (low mode), brain activity exhibited very weak spatial correlations. In contrast, the developmentally essential high-amplitude events (high mode) showed strong spatial correlations. There were no clear spatial patterns in the early preterm, but clear frontal and parieto-occipital modules at term age. A significant fronto occipital gradient was also seen in the development of the graph measure clustering coefficient. Strikingly, no bimodality was found in the fMRI recordings of the fullterm babies, suggesting that early EEG activity and fMRI signal reflect different mechanisms of spatial coordination. The results are compatible with the idea that early developing human brain exhibits intermittent long-range spatial connections that likely provide the endogenous guidance for early activity-dependent development of brain networks. PMID- 23650290 TI - Evolutionary characteristics of A/Hangzhou/1/2013 and source of avian influenza virus H7N9 subtype in China. PMID- 23650291 TI - What can we learn and what do we need to know amidst the iatrogenic outbreak of Exserohilum rostratum meningitis? AB - The tragedy of the ongoing epidemic of meningitis caused by Exserohilum rostratum brings into focus the epidemiology, risk factors, pathogenesis, diagnosis, and treatment of a multitude of opportunistic mold infections of the central nervous system. Herein we provide our perspective regarding the translational research objectives of this infection that are needed to make an impact on this important healthcare crisis. PMID- 23650292 TI - A quality-improvement collaborative project to reduce pressure ulcers in PICUs. AB - BACKGROUND AND OBJECTIVE: Pediatric patients are at risk for developing pressure ulcers (PUs) and associated pain, infection risk, and prolonged hospitalization. Stage III and IV ulcers are serious, reportable events. The objective of this study was to develop and implement a quality-improvement (QI) intervention to reduce PUs by 50% in our ICUs. METHODS: We established a QI collaborative leadership team, measured PU rates during an initial period of rapid-cycle tests of change, developed a QI bundle, and evaluated the PU rates after the QI implementation. The prospective study encompassed 1425 patients over 54 351 patient-days in the PICU and NICU. RESULTS: The PU rate in the PICU was 14.3/1000 patient-days during the QI development and 3.7/1000 patient-days after QI implementation (P < .05), achieving the aim of 50% reduction. The PICU rates of stages I, II, and III conventional and device-related PUs decreased after the QI intervention. The PU rate in the NICU did not change significantly over time but remained at a mean of 0.9/1000 patient-days. In the postimplementation period, 3 points were outside the control limits, primarily due to an increase in PUs associated with pulse oximeters and cannulas. CONCLUSIONS: The collaborative QI model was effective at reducing PUs in the PICU. Pediatric patients, particularly neonates, are at risk for device-related ulcers. Heightened awareness, early detection, and identification of strategies to mitigate device-related injury are necessary to further reduce PU rates. PMID- 23650293 TI - Malpractice risk among US pediatricians. AB - OBJECTIVE: To characterize malpractice risk among US pediatricians. METHODS: We analyzed malpractice claims of all pediatricians and other physicians covered by a nationwide liability insurer from 1991 to 2005 (n = 1630 pediatricians; 40 916 total physicians). We characterized annual malpractice risk among pediatricians compared with other physicians. We characterized claims according to patient age, injury type, months required to resolve the claim, and whether an indemnity payment was made. We estimated how patient age and injury type were associated with whether a claim resulted in payment to a patient (and if so, payment size) and the time required to resolve the claim. RESULTS: The annual percentage of pediatricians facing a malpractice claim was 3.1% (7.4% among other physicians, P < .001). Among 404 claims, 83 (20.5%) resulted in an indemnity payment and 15 (3.7%) resulted in a payment exceeding $1 million. Annual rates of indemnity were lower among pediatricians (0.5%) than other physicians (1.6%, P < .001), whereas rates of payments exceeding $1 million were similar (0.13% among pediatricians and 0.11% among other physicians, P = .57). The mean indemnity payment was $562 180 (SD $667 962). Cases with permanent injury (n = 172) had larger mean payments ($703 373) compared with fatalities ($559 102; n = 131) or temporary or psychological injuries ($127 663; n = 101), P < .05. The mean time to resolution was 23.4 months (SD 21.8 months). CONCLUSIONS: Indemnity payments among pediatricians are infrequent but large, particularly in cases with permanent patient injury rather than death or temporary injury. The time required to resolve claims may be considered to be long. PMID- 23650294 TI - RCT of timolol maleate gel for superficial infantile hemangiomas in 5- to 24-week olds. AB - OBJECTIVE: Timolol maleate 0.5% gel is a safe and effective medication for treating superficial infantile hemangiomas (IHs) in infants with a median age of 9 weeks. METHODS: Forty-one infants who had superficial IHs without ulceration and not near mucosal surfaces were recruited and randomly assigned to placebo and treatment (timolol maleate 0.5% gel) groups. Efficacy was assessed by performing blinded volume measurements at weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, and 24 and blinded investigator photograph scoring at weeks 0, 12, and 24. Safety was assessed by measuring heart rate and systolic and diastolic blood pressure at weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, and 24. RESULTS: Fifteen of the 19 infants receiving treatment and 17 of the 22 infants receiving placebo completed the study. Significant color change on the blinded photographic scores was noted at week 24 of the study (P = .003). There was a significantly higher proportion of treated IHs that reduced in size by >5% at weeks 20 and 24 (P < .02). The predicted proportion of IH volume change was also significantly less for treated IHs from week 16 onward when compared with placebo (P < .05). There was no significant variation in blood pressure and heart rate between the groups. CONCLUSIONS: Topical timolol maleate 0.5% gel with a maximum dose of 0.5 mg per day is a safe and effective option for small superficial IHs that have not ulcerated and are not on mucosal surfaces. PMID- 23650295 TI - Inconsolable infant crying and maternal postpartum depressive symptoms. AB - OBJECTIVE: To quantify the extent to which maternal report of inconsolable infant crying, rather than colic (defined by Wessel's criteria of daily duration of fussing and crying >3 hours), is associated with maternal postpartum depressive symptoms. METHODS: Participants were 587 mothers who were recruited shortly before or after delivery and followed longitudinally. At 5 to 6 weeks postpartum, mothers recorded the duration and mode (fussing, crying, or inconsolable crying) of their infant's distress by using the Baby's Day Diary. The Edinburgh Postnatal Depression Scale (EPDS) was administered at enrollment and at 8 weeks postpartum. Using regression models that included baseline EPDS scores and multiple confounders, we examined associations of colic and inconsolable crying with later maternal EPDS scores at 8 weeks postpartum. RESULTS: Sixty mothers (10%) met the EPDS threshold for "possible depression" (score >=9) at 8 weeks postpartum. For mothers reporting >20 minutes of inconsolable crying per day, the adjusted odds ratio for an EPDS score >=9 was 4.0 (95% confidence interval: 2.0-8.1), whereas the adjusted odds ratio for possible depression in mothers whose infants had colic was 2.0 (95% confidence interval: 1.1-3.7). These associations persisted after adjusting for baseline depression symptoms. CONCLUSIONS: Maternal report of inconsolable infant crying may have a stronger association with postpartum depressive symptoms than infant colic. Asking a mother about her ability to soothe her infant may be more relevant for potential intervention than questions about crying and fussing duration alone. PMID- 23650296 TI - Pediatric hydrocarbon-related injuries in the United States: 2000-2009. AB - OBJECTIVE: To generate national estimates of hydrocarbon-related exposures occurring in children <=5 years of age who were treated in US emergency departments or called a regional poison control center. METHODS: This retrospective review compared hydrocarbon-related injuries that occurred from January 1, 2000, through December 31, 2009, that were reported to the National Poison Data System and the National Electronic Injury Surveillance System for children <=5 years of age. RESULTS: From 2000 through 2009, the National Poison Data System reported 65 756 actual calls to regional poison centers, and the National Electronic Injury Surveillance System reported an estimated 40 158 emergency department visits for hydrocarbon-related injuries. Individuals involved were predominantly male and 1 to 2 years of age. Ingestion was the most common mechanism of injury, and most injuries did not result in hospitalization. The rate of emergency department visits and calls to poison centers decreased significantly (P < .0001) over the 10-year study period. Exposures to hydrocarbons demonstrated seasonal variation, with more occurrences in the summer months. CONCLUSIONS: The comparison of the two data sets illustrates a similar trend in hydrocarbon-related injuries in children. Although cases have declined, most likely due to existing prevention efforts, hydrocarbons are still a large source of preventable exposure and injury in children. PMID- 23650297 TI - Effectiveness of decision support for families, clinicians, or both on HPV vaccine receipt. AB - OBJECTIVE: To improve human papillomavirus (HPV) vaccination rates, we studied the effectiveness of targeting automated decision support to families, clinicians, or both. METHODS: Twenty-two primary care practices were cluster randomized to receive a 3-part clinician-focused intervention (education, electronic health record-based alerts, and audit and feedback) or none. Overall, 22, 486 girls aged 11 to 17 years due for HPV vaccine dose 1, 2, or 3 were randomly assigned within each practice to receive family-focused decision support with educational telephone calls. Randomization established 4 groups: family focused, clinician-focused, combined, and no intervention. We measured decision support effectiveness by final vaccination rates and time to vaccine receipt, standardized for covariates and limited to those having received the previous dose for HPV #2 and 3. The 1-year study began in May 2010. RESULTS: Final vaccination rates for HPV #1, 2, and 3 were 16%, 65%, and 63% among controls. The combined intervention increased vaccination rates by 9, 8, and 13 percentage points, respectively. The control group achieved 15% vaccination for HPV #1 and 50% vaccination for HPV #2 and 3 after 318, 178, and 215 days. The combined intervention significantly accelerated vaccination by 151, 68, and 93 days. The clinician-focused intervention was more effective than the family-focused intervention for HPV #1, but less effective for HPV #2 and 3. CONCLUSIONS: A clinician-focused intervention was most effective for initiating the HPV vaccination series, whereas a family-focused intervention promoted completion. Decision support directed at both clinicians and families most effectively promotes HPV vaccine series receipt. PMID- 23650299 TI - A tale of two hospitals: the evolution of phototherapy treatment for neonatal jaundice. PMID- 23650298 TI - Allergen-specific immunotherapy for pediatric asthma and rhinoconjunctivitis: a systematic review. AB - BACKGROUND AND OBJECTIVE: Subcutaneous immunotherapy (SCIT) is approved in the United States for the treatment of pediatric asthma and rhinitis; sublingual immunotherapy (SLIT) does not have regulatory approval but is used in clinical practice. The objective of this study was to systematically review the evidence regarding the efficacy and safety of SCIT and SLIT for the treatment of pediatric asthma and allergic rhinoconjunctivitis. METHODS: Two independent reviewers selected articles for inclusion, extracted data, and graded the strength of evidence for each clinical outcome. All studies were randomized controlled trials of children with allergic asthma or rhinoconjunctivitis treated with SCIT or an aqueous formulation of SLIT. Data sources were Medline, Embase, LILACS, CENTRAL, and the Cochrane Central Register of Controlled Trials through May 2012. RESULTS: In 13 trials, 920 children received SCIT or usual care; in 18 studies, 1583 children received SLIT or usual care. Three studies compared SCIT with SLIT head to-head in 135 children. The strength of evidence is moderate that SCIT improves asthma and rhinitis symptoms and low that SCIT improves conjunctivitis symptoms and asthma medication scores. Strength of evidence is high that SLIT improves asthma symptoms and moderate that SLIT improves rhinitis and conjunctivitis symptoms and decreases medication usage. The evidence is low to support SCIT over SLIT for improving asthma or rhinitis symptoms or medication usage. Local reactions were frequent with SCIT and SLIT. There was 1 report of anaphylaxis with SCIT. CONCLUSIONS: Evidence supports the efficacy of both SCIT and SLIT for the treatment of asthma and rhinitis in children. PMID- 23650300 TI - Providing care for immigrant, migrant, and border children. AB - This policy statement, which recognizes the large changes in immigrant status since publication of the 2005 statement "Providing Care for Immigrant, Homeless, and Migrant Children," focuses on strategies to support the health of immigrant children, infants, adolescents, and young adults. Homeless children will be addressed in a forthcoming separate statement ("Providing Care for Children and Adolescents Facing Homelessness and Housing Insecurity"). While recognizing the diversity across and within immigrant, migrant, and border populations, this statement provides a basic framework for serving and advocating for all immigrant children, with a particular focus on low-income and vulnerable populations. Recommendations include actions needed within and outside the health care system, including expansion of access to high-quality medical homes with culturally and linguistically effective care as well as education and literacy programs. The statement recognizes the unique and special role that pediatricians can play in the lives of immigrant children and families. Recommendations for policies that support immigrant child health are included. PMID- 23650301 TI - Use of antihypotensive therapies in extremely preterm infants. AB - OBJECTIVE: To investigate the relationships among blood pressure (BP) values, antihypotensive therapies, and in-hospital outcomes to identify a BP threshold below which antihypotensive therapies may be beneficial. METHODS: Prospective observational study of infants 23(0/7) to 26(6/7) weeks' gestational age. Hourly BP values and antihypotensive therapy use in the first 24 hours were recorded. Low BP was investigated by using 15 definitions. Outcomes were examined by using regression analysis controlling for gestational age, the number of low BP values, and illness severity. RESULTS: Of 367 infants enrolled, 203 (55%) received at least 1 antihypotensive therapy. Treated infants were more likely to have low BP by any definition (P < .001), but for the 15 definitions of low BP investigated, therapy was not prescribed to 3% to 49% of infants with low BP and, paradoxically, was administered to 28% to 41% of infants without low BP. Treated infants were more likely than untreated infants to develop severe retinopathy of prematurity (15% vs 8%, P = .03) or severe intraventricular hemorrhage (22% vs 11%, P < .01) and less likely to survive (67% vs 78%, P = .02). However, with regression analysis, there were no significant differences between groups in survival or in-hospital morbidity rates. CONCLUSIONS: Factors other than BP contributed to the decision to use antihypotensive therapies. Infant outcomes were not improved with antihypotensive therapy for any of the 15 definitions of low BP investigated. PMID- 23650302 TI - Disparities in disability after traumatic brain injury among Hispanic children and adolescents. AB - OBJECTIVE: To compare the extent of disability in multiple areas of functioning after mild, moderate, and severe traumatic brain injury (TBI) between Hispanic and non-Hispanic white (NHW) children. METHODS: This was a prospective cohort study of children aged <18 years treated for a TBI between March 1, 2007, and September 30, 2008. Hispanic (n = 74) and NHW (n = 457) children were included in the study. Outcome measures were disability in health-related quality of life, adaptive skills, and participation in activities 3, 12, 24, and 36 months after injury compared with preinjury functioning. We compared change in outcome scores between Hispanic and NHW children at each follow-up time. All analyses were adjusted for age, gender, severity and intent of injury, insurance, family function at baseline, parental education, and income. RESULTS: The health-related quality of life for all children was lower at all follow-up times compared with baseline. Although NHW children showed some improvement during the first 3 years after injury, Hispanic children remained significantly impaired. Significant differences were also observed in the domains of communication and self-care abilities after TBI. Differences between groups in scores for participation in activities were also present but were only significant 3 months after injury. CONCLUSIONS: Hispanic children with TBI report larger and long-term reductions in their quality of life, participation in activities, communication, and self-care abilities compared with NHW children. The reasons for these differences need to be better understood and interventions implemented to improve the outcomes of these children. PMID- 23650303 TI - Nemaline myopathy with dilated cardiomyopathy in childhood. AB - We present a case of a 9-year-old boy with nemaline myopathy and dilated cardiomyopathy. The combination of nemaline myopathy and cardiomyopathy is rare, and this is the first reported case of dilated cardiomyopathy associated with childhood-onset nemaline myopathy. A novel mutation, p.W358C, in ACTA1 was detected in this patient. An unusual feature of this case was that the patient's cardiac failure developed during early childhood with no delay of gross motor milestones. The use of a beta-blocker did not improve his clinical course, and the patient died 6 months after diagnosis of dilated cardiomyopathy. Congenital nonprogressive nemaline myopathy is not necessarily a benign disorder: deterioration can occur early in the course of dilated cardiomyopathy with neuromuscular disease, and careful clinical evaluation is therefore necessary. PMID- 23650304 TI - Pacifier cleaning practices and risk of allergy development. AB - OBJECTIVE: Immune stimulation through exposure to commensal microbes may protect against allergy development. Oral microbes may be transferred from parents to infants via pacifiers. We investigated whether pacifier cleaning practices affected the risk of allergy development. METHODS: A birth-cohort of 184 infants was examined for clinical allergy and sensitization to airborne and food allergens at 18 and 36 months of age and, in addition, promptly on occurrence of symptoms. Pacifier use and pacifier cleaning practices were recorded during interviews with the parents when the children were 6 months old. The oral microbiota of the infants was characterized by analysis of saliva samples collected at 4 months of age. RESULTS: Children whose parents "cleaned" their pacifier by sucking it (n = 65) were less likely to have asthma (odds ratio [OR] 0.12; 95% confidence interval [CI] 0.01-0.99), eczema (OR 0.37; 95% CI 0.15 0.91), and sensitization (OR 0.37; 95% CI 0.10-1.27) at 18 months of age than children whose parents did not use this cleaning technique (n = 58). Protection against eczema remained at age 36 months (hazard ratio 0.51; P = .04). Vaginal delivery and parental pacifier sucking yielded independent and additive protective effects against eczema development. The salivary microbiota differed between children whose parents cleaned their pacifier by sucking it and children whose parents did not use this practice. CONCLUSIONS: Parental sucking of their infant's pacifier may reduce the risk of allergy development, possibly via immune stimulation by microbes transferred to the infant via the parent's saliva. PMID- 23650305 TI - Analysis of pediatric clinical drug trials for neuropsychiatric conditions. AB - BACKGROUND AND OBJECTIVE: Neuropsychiatric conditions represent a large and increasing disease burden in children. A number of drugs are available for the treatment of these conditions, but most drugs have not been adequately tested in children, and off-label drug use remains widespread. We sought to define and quantify recent and ongoing clinical research on the use of neuropsychiatric drugs in children. METHODS: Drug trials registered in ClinicalTrials.gov between 2006 and 2011 and studying neuropsychiatric conditions were selected and classified based on the drug's Food and Drug Administration (FDA) approval status in children. We measured the proportion of trials seeking to expand the use of a drug to pediatric patients and the proportion of available drugs studied in children. RESULTS: Only 10% of neuropsychiatric trials focused on children. Of 303 drugs studied in both pediatric and adult populations, 90% lacked FDA approval in children and 97% were not approved in children for the indication studied. However, only 19% of all neuropsychiatric drugs were under study in pediatric populations, with as few as 8% of either antidepressant or antipsychotic drugs. Overall, 76% of pediatric drug trials examined a drug previously unapproved in children and 26% explored the use of a drug for a new indication. CONCLUSIONS: Despite the rising prevalence of neuropsychiatric disease and the paucity of FDA-approved pediatric drugs, only a small proportion of trials focus on pediatric populations and these trials cover only a fraction of available drugs. This deficiency is most pronounced for depression and schizophrenia. PMID- 23650306 TI - Safety and utilization of influenza immunization in children with inflammatory bowel disease. AB - OBJECTIVE: Influenza immunization is recommended for children with IBD, however safety concerns may limit uptake. This study assessed whether immunization was associated with adverse events in IBD patients using a population-based database of children with IBD. METHODS: All children <19 years diagnosed with IBD in Ontario, Canada between 1999-2009 were identified using health administrative data, and matched to non-IBD controls. Self-controlled case series (SCCS) analyses determined health services event rates (outpatient visits, hospitalizations and emergency visits) in any 2-week risk period to 180 days post immunization compared to a no-risk control period. Relative incidence (RI) was calculated for overall and IBD-related events and rates were compared between IBD cases and controls using relative incidence ratios (RIR). RESULTS: A total of 4916 IBD patients were matched to 21 686 controls. IBD patients were more likely to have received immunization than controls (25.3% vs 13.2%, P < .001). No increased event rates existed in IBD cases during risk periods (pooled RI 0.95, 95% CI 0.84-1.07), including hospitalizations and emergency visits. There was a slightly higher event rate in IBD cases versus controls for days 3-14 (RIR 1.60, 95% CI 1.05-2.44, P = .03). IBD-related visit rates were lower in risk periods compared to control period (pooled RI 0.81, 95% CI 0.68-0.96). CONCLUSIONS: There was no increase in health services use in the post-vaccine risk period in IBD patients, and there was evidence for a protective effect of influenza immunization against IBD-related health services use. Influenza immunization is safe in children with IBD and should be encouraged to improve poor coverage rates. PMID- 23650307 TI - Honey pacifier use among an indigent pediatric population. AB - BACKGROUND: Use of honey pacifiers by infants presenting to a pediatric clinic at a county hospital in Houston, Texas, was observed by several of our staff members. Although we could not find any published studies linking the use of honey pacifiers to infant botulism, we also could not find any studies assessing the prevalence of honey pacifier use in general. METHODS: We conducted a cross sectional, descriptive study using a novel survey that had 19 items. The survey was administered to the parents of children up to age 12 months presenting to a county hospital pediatric clinic for well-child care in Houston, Texas, from February 2010 to April 2011. RESULTS: There were 397 respondents. Approximately 11% of the respondents reported using honey pacifiers with their infant children. Reasons for use included tradition, infant preference, and perceived health benefits (eg, helps with constipation or colic). Approximately 20% of the honey pacifier users and 23% of the entire group reported knowledge of honey potentially causing an illness in children <12 months of age. Nearly 40% of all respondents also reported using herbal or folk remedies. CONCLUSIONS: Honey pacifier use was relatively common among this population, seen in ~1 out of 10 respondents. A majority of the mothers surveyed (~80%) were unaware of the potential dangers of giving honey to infants under age 12 months. Herbal medicine use was also common. PMID- 23650313 TI - Are 'unsustainable trends' finally coming to a stop? PMID- 23650309 TI - Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure. AB - BACKGROUND: Slowed Na+ current (INa) decay and enhanced late INa (INa-L) prolong the action potential duration (APD) and contribute to early afterdepolarizations. Cardiac resynchronization therapy (CRT) shortens APD compared with dyssynchronous heart failure (DHF); however, the role of altered Na+ channel gating in CRT remains unexplored. METHODS AND RESULTS: Adult dogs underwent left-bundle branch ablation and right atrial pacing (200 beats/min) for 6 weeks (DHF) or 3 weeks followed by 3 weeks of biventricular pacing at the same rate (CRT). INa and INa-L were measured in left ventricular myocytes from nonfailing, DHF, and CRT dogs. DHF shifted voltage-dependence of INa availability by -3 mV compared with nonfailing, enhanced intermediate inactivation, and slowed recovery from inactivation. CRT reversed the DHF-induced voltage shift of availability, partially reversed enhanced intermediate inactivation but did not affect DHF induced slowed recovery. DHF markedly increased INa-L compared with nonfailing. CRT dramatically reduced DHF-induced enhanced INa-L, abbreviated the APD, and suppressed early afterdepolarizations. CRT was associated with a global reduction in phosphorylated Ca2+/Calmodulin protein kinase II, which has distinct effects on inactivation of cardiac Na+ channels. In a canine AP model, alterations of INa L are sufficient to reproduce the effects on APD observed in DHF and CRT myocytes. CONCLUSIONS: CRT improves DHF-induced alterations of Na+ channel function, especially suppression of INa-L, thus, abbreviating the APD and reducing the frequency of early afterdepolarizations. Changes in the levels of phosphorylated Ca2+/Calmodulin protein kinase II suggest a molecular pathway for regulation of INa by biventricular pacing of the failing heart. PMID- 23650310 TI - Classification of acute decompensated heart failure: an automated algorithm compared with a physician reviewer panel: the Atherosclerosis Risk in Communities study. AB - BACKGROUND: An algorithm to classify heart failure (HF) end points inclusive of contemporary measures of biomarkers and echocardiography was recently proposed by an international expert panel. Our objective was to assess agreement of HF classification by this contemporaneous algorithm with that by a standardized physician reviewer panel, when applied to data abstracted from community-based hospital records. METHODS AND RESULTS: During 2005-2007, all hospitalizations were identified from 4 US communities under surveillance as part of the Atherosclerosis Risk in Communities (ARIC) study. Potential HF hospitalizations were sampled by International Classification of Diseases discharge codes and demographics from men and women aged >= 55 years. The HF classification algorithm was automated and applied to 2729 (n=13854 weighted hospitalizations) hospitalizations in which either brain natriuretic peptide measures or ejection fraction were documented (mean age, 75 years). There were 1403 (54%; n=7534 weighted) events classified as acute decompensated HF by the automated algorithm, and 1748 (68%; n=9276 weighted) such events by the ARIC reviewer panel. The chance-corrected agreement between acute decompensated HF by physician reviewer panel and the automated algorithm was moderate (kappa=0.39). Sensitivity and specificity of the automated algorithm with ARIC reviewer panel as the referent standard were 0.68 (95% confidence interval, 0.67-0.69) and 0.75 (95% confidence interval, 0.74-0.76), respectively. CONCLUSIONS: Although the automated classification improved efficiency and decreased costs, its accuracy in classifying HF hospitalizations was modest compared with a standardized physician reviewer panel. PMID- 23650314 TI - After CLASS: the long-term care commission's search for a solution. PMID- 23650315 TI - The slowdown in health care spending in 2009-11 reflected factors other than the weak economy and thus may persist. AB - During and immediately after the recent recession, national health expenditures grew exceptionally slowly. During 2009-11 per capita national health spending grew about 3 percent annually, compared to an average of 5.9 percent annually during the previous ten years. Policy experts disagree about whether the slower health spending growth was temporary or represented a long-term shift. This study examined two factors that might account for the slowdown: job loss and benefit changes that shifted more costs to insured people. Based on an examination of data covering more than ten million enrollees with health care coverage from large firms in 2007-11, we found that these enrollees' out-of-pocket costs increased as the benefit design of their employer-provided coverage became less generous in this period. We conclude that such benefit design changes accounted for about one-fifth of the observed decrease in the rate of growth. However, we also observed a slowdown in spending growth even when we held benefit generosity constant, which suggests that other factors, such as a reduction in the rate of introduction of new technology, were also at work. Our findings suggest cautious optimism that the slowdown in the growth of health spending may persist--a change that, if borne out, could have a major impact on US health spending projections and fiscal challenges facing the country. PMID- 23650316 TI - If slow rate of health care spending growth persists, projections may be off by $770 billion. AB - Despite earlier forecasts to the contrary, US health care spending growth has slowed in the past four years, continuing a trend that began in the early 2000s. In this article we attempt to identify why US health care spending growth has slowed, and we explore the spending implications if the trend continues for the next decade. We find that the 2007-09 recession, a one-time event, accounted for 37 percent of the slowdown between 2003 and 2012. A decline in private insurance coverage and cuts to some Medicare payment rates accounted for another 8 percent of the slowdown, leaving 55 percent of the spending slowdown unexplained. We conclude that a host of fundamental changes--including less rapid development of imaging technology and new pharmaceuticals, increased patient cost sharing, and greater provider efficiency--were responsible for the majority of the slowdown in spending growth. If these trends continue during 2013-22, public-sector health care spending will be as much as $770 billion less than predicted. Such lower levels of spending would have an enormous impact on the US economy and on government and household finances. PMID- 23650317 TI - Treated disease prevalence and spending per treated case drove most of the growth in health care spending in 1987-2009. AB - Analysis of data from the National Medical Expenditure Survey and the Medical Expenditure Panel Surveys from 1987-2009 reinforces previous observations that increased prevalence of treated disease has become the main driver of increased spending on health care in the United States. Higher treated disease prevalence and higher spending per treated case were associated with 50.8 percent and 39.0 percent, respectively, of the spending increase seen in the population ages eighteen and older, while their joint effect accounts for the remaining 10.2 percent. The proportion of increased spending attributable to increased treated prevalence alone is particularly high in the Medicare population: 77.7 percent, compared to 33.5 percent among the privately insured. Moreover, the current findings reveal a substantial contribution to the increase in total spending (10.4 percent) from a doubling of the share of the population considered to be obese and from increases in treatment intensity, a component of spending per treated case (11.9 percent), in 1987-2009. Constraining the cost of health care will require policy options focused on reducing the incidence of disease, as well as improved understanding of the extent to which more aggressive treatments for chronic conditions do, or do not, result in lower morbidity and mortality. PMID- 23650318 TI - Additional reductions in Medicare spending growth will likely require shifting costs to beneficiaries. AB - Policy makers have considerable interest in reducing Medicare spending growth. Clarity in the debate on reducing Medicare spending growth requires recognition of three important distinctions: the difference between public and total spending on health, the difference between the level of health spending and rate of health spending growth, and the difference between growth per beneficiary and growth in the number of beneficiaries in Medicare. The primary policy issue facing the US health care system is the rate of spending growth in public programs, and solving that problem will probably require reforms to the entire health care sector. The Affordable Care Act created a projected trajectory for Medicare spending per beneficiary that is lower than historical growth rates. Although opportunities for one-time savings exist, any long-term savings from Medicare, beyond those already forecast, will probably require a shift in spending from taxpayers to beneficiaries via higher beneficiary premium contributions (overall or via means testing), changes in eligibility, or greater cost sharing at the point of service. PMID- 23650319 TI - Large increases in spending on postacute care in Medicare point to the potential for cost savings in these settings. AB - Identifying policies that will cut or constrain US health care spending and spending growth dominates reform efforts, yet little is known about whether the drivers of spending levels and of spending growth are the same. Policies that produce a one-time reduction in the level of spending, for example by making hospitals more efficient, may do little to reduce subsequent annual spending growth. To identify factors causing health care spending to grow the fastest, we focused on three conditions in the Medicare population: heart attacks, congestive heart failure, and hip fractures. We found that spending on postacute care-long term hospital care, rehabilitation care, and skilled nursing facility care--was the fastest growing major spending category and accounted for a large portion of spending growth in 1994-2009. During that period average spending for postacute care doubled for patients with hip fractures, more than doubled for those with congestive heart failure, and more than tripled for those with heart attacks. We conclude that policies aimed at controlling acute care spending, such as bundled payments for short-term hospital spending and physician services, are likely to be more effective if they include postacute care, as is currently being tested under Medicare's Bundled Payment for Care Improvement Initiative. PMID- 23650320 TI - Supplemental coverage associated with more rapid spending growth for Medicare beneficiaries. AB - Lowering both Medicare spending and the rate of Medicare spending growth is important for the nation's fiscal health. Policy makers in search of ways to achieve these reductions have looked at the role that supplemental coverage for Medicare beneficiaries plays in Medicare spending. Supplemental coverage makes health care more affordable for beneficiaries but also makes beneficiaries insensitive to the cost of their care, thereby increasing the demand for care. Ours is the first empirical study to investigate whether supplemental Medicare coverage is associated with higher rates of spending growth over time. We found that supplemental insurance coverage was associated with significantly higher rates of overall spending growth. Specifically, employer-sponsored and self purchased supplemental coverage were associated with annual total spending growth rates of 7.17 percent and 7.18 percent, respectively, compared to 6.08 percent annual growth for beneficiaries without supplemental coverage. Results for Medicare program spending were more equivocal, however. Our results are consistent with the belief that current trends away from generous employer sponsored supplemental coverage and efforts to restrict the generosity of supplemental coverage may slow spending growth. PMID- 23650321 TI - Public financing of the Medicare program will make its uniform structure increasingly costly to sustain. AB - The US Medicare program consumes an ever-rising share of the federal budget. Although this public spending can produce health and social benefits, raising taxes to finance it comes at the cost of slower economic growth. In this article we describe a model incorporating the benefits of public programs and the cost of tax financing. The model implies that the "one-size-fits-all" Medicare program, with everyone covered by the same insurance policy, will be increasingly difficult to sustain. We show that a Medicare program with guaranteed basic benefits and the option to purchase additional coverage could lead to more unequal health spending but slower growth in taxation, greater overall well being, and more rapid growth of gross domestic product. Our framework highlights the key trade-offs between Medicare spending and economic prosperity. PMID- 23650322 TI - Three large-scale changes to the Medicare program could curb its costs but also reduce enrollment. AB - With Medicare spending projected to increase to 24 percent of all federal spending and to equal 6 percent of the gross domestic product by 2037, policy makers are again considering ways to curb the program's spending growth. We used a microsimulation approach to estimate three scenarios: imposing a means-tested premium for Part A hospital insurance, introducing a premium support credit to purchase health insurance, and increasing the eligibility age to sixty-seven. We found that the scenarios would lead to reductions in cumulative Medicare spending in 2012-36 of 2.4-24.0 percent. However, the scenarios also would increase out-of pocket spending for enrollees and, in some cases, cause millions of seniors not to enroll in the program and to be left without coverage. To achieve substantial cost savings without causing substantial lack of coverage among seniors, policy makers should consider benefit changes in combination with other options, such as some of those now being contemplated by the Obama administration and Congress. PMID- 23650323 TI - Medicare essential: an option to promote better care and curb spending growth. AB - Medicare's core benefit design reflects private insurance as of 1965, with separate coverage for hospital and physician services (and now prescription drugs) and no protection against catastrophic costs. Modernizing Medicare's benefit design to offer comprehensive benefits, financial protection, and incentives to choose high-value care could improve coverage and lower beneficiary costs. We describe a new option we call Medicare Essential, which would combine Medicare's hospital, physician, and prescription drug coverage into an integrated benefit with an annual limit on out-of-pocket expenses for covered benefits. Cost sharing would be reduced for enrollees who seek care from high-quality low-cost providers. Out-of-pocket savings from lower premiums and health care costs for a Medicare Essential enrollee could be $173 per month, compared to what an enrollee would pay with traditional Medicare, prescription drug and private supplemental coverage. Financed by a budget-neutral premium, we estimate that this new plan choice could reduce total health spending relative to current projections by $180 billion and reduce employer retiree spending by $90 billion during 2014-23. Given its potential, such an alternative should be a part of the debate over the future of Medicare. PMID- 23650324 TI - Health policy leader's focus is on best care. PMID- 23650325 TI - Standardized Clinical Assessment And Management Plans (SCAMPs) provide a better alternative to clinical practice guidelines. AB - Variability in medical practice in the United States leads to higher costs without achieving better patient outcomes. Clinical practice guidelines, which are intended to reduce variation and improve care, have several drawbacks that limit the extent of buy-in by clinicians. In contrast, standardized clinical assessment and management plans (SCAMPs) offer a clinician-designed approach to promoting care standardization that accommodates patients' individual differences, respects providers' clinical acumen, and keeps pace with the rapid growth of medical knowledge. Since early 2009 more than 12,000 patients have been enrolled in forty-nine SCAMPs in nine states and Washington, D.C. In one example, a SCAMP was credited with increasing clinicians' rate of compliance with a recommended specialist referral for children from 19.6 percent to 75 percent. In another example, SCAMPs were associated with an 11-51 percent decrease in total medical expenses for six conditions when compared with a historical cohort. Innovative tools such as SCAMPs should be carefully examined by policy makers searching for methods to promote the delivery of high-quality, cost-effective care. PMID- 23650326 TI - Case studies of orthopedic surgery in California: the virtues of care coordination versus specialization. AB - Two overarching frameworks compete to address the organizational ills of the health care system. One framework diagnoses lack of coordination and prescribes integration and global payment. The other diagnoses loss of focus and prescribes specialization and episode payment. This article, based on research and interviews, assesses how the two frameworks manifest themselves at two high volume orthopedic hospitals in Irvine, California. The Kaiser Permanente Irvine Medical Center is part of a large and diversified health system. The Hoag Orthopedic Institute is a single-specialty facility jointly owned by the physicians and the hospital. Market outcomes, such as the merger of the Hoag specialty hospital into a larger diversified health system, suggest that Kaiser's focus on coordination of patient care from preadmission to postdischarge is a key factor in its success. But Hoag's specialization also leads to improved efficiencies. The integrated approach appears to be prevailing. At the same time, large diversified organizations might obtain further efficiencies by pursuing service-line strategies as described in this article--for instance, by providing incentives for efficiency and quality for each specialty and type of care. PMID- 23650327 TI - Achieving health care cost containment through provider payment reform that engages patients and providers. AB - The best opportunity to pursue cost containment in the next five to ten years is through reforming provider payment to gradually diminish the role of fee-for service reimbursement. Public and private payers have launched many promising payment reform pilots aimed at blending fee-for-service with payment approaches based on broader units of care, such as an episode or patients' total needs over a period of time, a crucial first step. But meaningful cost containment from payment reform will not be achieved until Medicare and Medicaid establish stronger incentives for providers to contract in this way, with discouragement of nonparticipation increasing over time. In addition, the models need to evolve to engage beneficiaries, perhaps through incentives for patients to enroll in an accountable care organization and to seek care within that organization's network of providers. PMID- 23650328 TI - Contrary to cost-shift theory, lower Medicare hospital payment rates for inpatient care lead to lower private payment rates. AB - Many policy makers believe that when Medicare constrains its payment rates for hospital inpatient care, private insurers end up paying higher rates as a result. I tested this "cost-shifting" theory using a unique new data set that combines MarketScan private claims data with Medicare hospital cost reports. Contrary to the theory, I found that hospital markets with relatively slow growth in Medicare inpatient hospital payment rates also had relatively slow growth in private hospital payment rates during 1995-2009. Using regression analyses, I found that a 10 percent reduction in Medicare payment rates led to an estimated reduction in private payment rates of 3 percent or 8 percent, depending on the statistical model used. These payment rate spillovers may reflect an effort by hospitals to rein in their operating costs in the face of lower Medicare payment rates. Alternatively, hospitals facing cuts in Medicare payment rates may also cut the payment rates they seek from private payers to attract more privately insured patients. My findings indicate that repealing cuts in Medicare payment rates would not slow the growth in spending on hospital care by private insurers and would in fact be likely to accelerate the growth in private insurers' costs and premiums. PMID- 23650329 TI - Policy makers will need a way to update bundled payments that reflects highly skewed spending growth of various care episodes. AB - Bundled payment entails paying a single price for all services delivered as part of an episode of care for a specific condition. It is seen as a promising way to slow the growth of health care spending while maintaining or improving the quality of care. To implement bundled payment, policy makers must set base payment rates for episodes of care and update the rates over time to reflect changes in the costs of delivering care and the components of care. Adopting the fee-for-service paradigm of adjusting payments with uniform update rates would be fair and accurate if costs increased at a uniform rate across episodes. But our analysis of 2003 and 2007 US commercial claims data showed spending growth to be highly skewed across episodes: 10 percent of episodes accounted for 82.5 percent of spending growth, and within-episode spending growth ranged from a decline of 75 percent to an increase of 323 percent. Given that spending growth was much faster for some episodes than for others, a situation known as skewness, policy makers should not update episode payments using uniform update rates. Rather, they should explore ways to address variations in spending growth, such as updating episode payments one by one, at least at the outset. PMID- 23650330 TI - Federal spending on behavioral health accelerated during recession as individuals lost employer insurance. AB - The 2007-09 recession had a dramatic effect on behavioral health spending, with the effect most prominent for private, state, and local payers. During the recession behavioral health spending increased at a 4.6 percent average annual rate, down from 6.1 percent in 2004-07. Average annual growth in private behavioral health spending during the recession slowed to 2.7 percent from 7.2 percent in 2004-07. State and local behavioral health spending showed negative average annual growth, -1.2 percent, during the recession, compared with 3.7 percent increases in 2004-07. In contrast, federal behavioral health spending growth accelerated to 11.1 percent during the recession, up from 7.2 percent in 2004-07. These behavioral health spending trends were driven largely by increased federal spending in Medicaid, declining private insurance enrollment, and severe state budget constraints. An increased federal Medicaid match reduced the state share of Medicaid spending, which prevented more drastic cuts in state-funded behavioral health programs during the recession. Federal Medicaid served as a critical safety net for people with behavioral health treatment needs during the recession. PMID- 23650331 TI - To cover their child, one couple navigates a health insurance maze in Pennsylvania. PMID- 23650332 TI - A report on eight early-stage state and regional projects testing value-based payment. AB - To help contain health care spending and improve the quality of care, practitioners and policy makers are trying to move away from fee-for-service toward value-based payment, which links providers' reimbursement to the value, rather than the volume, of services delivered. With funding from the Robert Wood Johnson Foundation, eight grantees across the country are designing and implementing value-based payment reform projects. For example, in Salem, Oregon, the Physicians Choice Foundation is testing "Program Oriented Payments," which include incentives for providers who follow a condition-specific program of care designed to meet goals set jointly by patient and provider. In this article we describe the funding rationale and the specific objectives, strategies, progress, and early stages of implementation of the eight projects. We also share some early lessons and identify prerequisites for success, such as ensuring that providers have broad and timely access to data so they can meet patients' needs in cost-effective ways. PMID- 23650333 TI - 'Desa SIAGA', the 'Alert Village': the evolution of an iconic brand in Indonesian public health strategies. AB - In 1999, the Ministry of Women's Empowerment in Indonesia worked with advertisers in Jakarta and international technical advisors to develop the concept of 'Suami SIAGA', the 'Alert Husband', confronting Indonesian males with their responsibilities to be aware of their wives' needs and ensure early access if needed to trained obstetrics care. The model was rapidly expanded to apply to the 'Desa SIAGA', the 'Alert Village', with communities assuming the responsibility for awareness of the risks of pregnancy and childbirth, and supporting registered pregnant mothers with funding and transportation for emergency obstetric assistance, and identified blood donors. Based on the participant observation, interviews and documentary analysis, this article uses a systems perspective to trace the evolution of that iconic 'brand' as new national and international actors further developed the concept and its application in provincial and national programmes. In 2010, it underwent a further transformation to become 'Desa Siaga Aktif', a national programme with responsibilities expanded to include the provision of basic health services at village level, and the surveillance of communicable disease, monitoring of lifestyle activities and disaster preparedness, in addition to the management of obstetric emergencies. By tracking the use of this single 'brand', the study provides insights into the complex adaptive system of policy and programme development with its rich interactions between multiple international, national, provincial and sectoral stakeholders, the unpredictable responses to feedback from these actors and their activities and the resultant emergence of new policy elements, new programmes and new levels of operation within the system. PMID- 23650334 TI - Poor retention does not have to be the rule: retention of volunteer community health workers in Uganda. AB - Globally, health worker shortages continue to plague developing countries. Community health workers are increasingly being promoted to extend primary health care to underserved populations. Since 2004, Healthy Child Uganda (HCU) has trained volunteer community health workers in child health promotion in rural southwest Uganda. This study analyses the retention and motivation of volunteer community health workers trained by HCU. It presents retention rates over a 5 year period and provides insight into volunteer motivation. The findings are based on a 2010 retrospective review of the community health worker registry and the results of a survey on selection and motivation. The survey was comprised of qualitative and quantitative questions and verbally administered to a convenience sample of project participants. Between February 2004 and July 2009, HCU trained 404 community health workers (69% female) in 175 villages. Volunteers had an average age of 36.7 years, 4.9 children and some primary school education. Ninety six per cent of volunteer community health workers were retained after 1 year (389/404), 91% after 2 years (386/404) and 86% after 5 years (101/117). Of the 54 'dropouts', main reasons cited for discontinuation included 'too busy' (12), moved (11), business/employment (8), death (6) and separation/divorce (6). Of 58 questionnaire respondents, most (87%) reported having been selected at an inclusive community meeting. Pair-wise ranking was used to assess the importance of seven 'motivational factors' among respondents. Those highest ranked were 'improved child health', 'education/training' and 'being asked for advice/assistance by peers', while the modest 'transport allowance' ranked lowest. Our findings suggest that in our rural, African setting, volunteer community health workers can be retained over the medium term. Community health worker programmes should invest in community involvement in selection, quality training, supportive supervision and incentives, which may promote improved retention. PMID- 23650335 TI - Approach to the patient with hypogonadotropic hypogonadism. AB - Hypogonadotropic hypogonadism (HH) or secondary hypogonadism is defined as a clinical syndrome that results from gonadal failure due to abnormal pituitary gonadotropin levels. HH may result from either absent or inadequate hypothalamic GnRH secretion or failure of pituitary gonadotropin secretion. Several congenital and acquired causes, including functional and organic forms, have been associated with this condition. One important aspect of the HH diagnosis is that it may reflect the presence of a tumor of the hypothalamic pituitary region or even a systemic disease. On the other hand, functional forms of HH, characterized by a transient defect in GnRH secretion, are relatively common in women, in response to significant weight loss, exercise, or stress leading to hypothalamic amenorrhea. HH is typically characterized by low circulating sexual steroids associated with low or inappropriately normal gonadotropin levels. The precise and early diagnosis of HH can prevent negative physical and psychological sequelae, preserve normal peak bone mass, and restore the fertility in affected patients. PMID- 23650336 TI - Approach to testing growth hormone (GH) secretion in obese subjects. AB - Identification of adults with GH deficiency (GHD) is challenging because clinical features of adult GHD are not distinctive and because clinical suspicion must be confirmed by biochemical tests. Adults are selected for testing for adult GHD if they have a high pretest probability of GHD, ie, if they have hypothalamic pituitary disease, if they have received cranial irradiation or central nervous system tumor treatment, or if they survived traumatic brain injury or subarachnoid hemorrhage. Testing should only be carried out if a decision has already been made that if deficiency is found it will be treated. There are many pharmacological GH stimulation tests for the diagnosis of GHD; however, none fulfill the requirements for an ideal test having high discriminatory power; being reproducible, safe, convenient, and economical; and not being dependent on confounding factors such as age, gender, nutritional status, and in particular obesity. In obesity, GH secretion is reduced, GH clearance is enhanced, and stimulated GH secretion is reduced, causing a false-positive result. This functional hyposomatotropism in obesity is fully reversed by weight loss. In conclusion, GH stimulation tests should be avoided in obese subjects with very low pretest probability. PMID- 23650337 TI - Clinical genetic testing for Kallmann syndrome. PMID- 23650338 TI - When is a U-curve actually a J-curve? Is it really too much of a good thing? PMID- 23650339 TI - From Japan with love: another tessera in the hypophysitis mosaic. PMID- 23650344 TI - Fact sheet. Anorexia. PMID- 23650345 TI - Mycobacterial toxin MazF-mt6 inhibits translation through cleavage of 23S rRNA at the ribosomal A site. AB - The Mycobacterium tuberculosis genome contains an unusually high number of toxin antitoxin modules, some of which have been suggested to play a role in the establishment and maintenance of latent tuberculosis. Nine of these toxin antitoxin loci belong to the mazEF family, encoding the intracellular toxin MazF and its antitoxin inhibitor MazE. Nearly every MazF ortholog recognizes a unique three- or five-base RNA sequence and cleaves mRNA. As a result, these toxins selectively target a subset of the transcriptome for degradation and are known as "mRNA interferases." Here we demonstrate that a MazF family member from M. tuberculosis, MazF-mt6, has an additional role--inhibiting translation through targeted cleavage of 23S rRNA in the evolutionarily conserved helix/loop 70. We first determined that MazF-mt6 cleaves mRNA at (5')UU?CCU(3') sequences. We then discovered that MazF-mt6 also cleaves M. tuberculosis 23S rRNA at a single UUCCU in the ribosomal A site that contacts tRNA and ribosome recycling factor. To gain further mechanistic insight, we demonstrated that MazF-mt6-mediated cleavage of rRNA can inhibit protein synthesis in the absence of mRNA cleavage. Finally, consistent with the position of 23S rRNA cleavage, MazF-mt6 destabilized 50S-30S ribosomal subunit association. Collectively, these results show that MazF toxins do not universally act as mRNA interferases, because MazF-mt6 inhibits protein synthesis by cleaving 23S rRNA in the ribosome active center. PMID- 23650346 TI - Sulfur isotopes in coal constrain the evolution of the Phanerozoic sulfur cycle. AB - Sulfate is the second most abundant anion (behind chloride) in modern seawater, and its cycling is intimately coupled to the cycling of organic matter and oxygen at the Earth's surface. For example, the reduction of sulfide by microbes oxidizes vast amounts of organic carbon and the subsequent reaction of sulfide with iron produces pyrite whose burial in sediments is an important oxygen source to the atmosphere. The concentrations of seawater sulfate and the operation of sulfur cycle have experienced dynamic changes through Earth's history, and our understanding of this history is based mainly on interpretations of the isotope record of seawater sulfates and sedimentary pyrites. The isotope record, however, does not give a complete picture of the ancient sulfur cycle. This is because, in standard isotope mass balance models, there are more variables than constraints. Typically, in interpretations of the isotope record and in the absence of better information, one assumes that the isotopic composition of the input sulfate to the oceans has remained constant through time. It is argued here that this assumption has a constraint over the last 390 Ma from the isotopic composition of sulfur in coal. Indeed, these compositions do not deviate substantially from the modern surface-water input to the oceans. When applied to mass balance models, these results support previous interpretations of sulfur cycle operation and counter recent suggestions that sulfate has been a minor player in sulfur cycling through the Phanerozoic Eon. PMID- 23650348 TI - True scale-invariant random spatial networks. AB - Some aspects of real-world road networks seem to have an approximate scale invariance property, motivating study of mathematical models of random networks whose distributions are exactly invariant under Euclidean scaling. This requires working in the continuum plane, so making a precise definition is not trivial. We introduce an axiomatization of a class of processes we call scale-invariant random spatial networks, whose primitives are routes between each pair of points in the plane. One concrete model, based on minimum-time routes in a binary hierarchy of roads with different speed limits, has been shown to satisfy the axioms, and two other constructions (based on Poisson line processes and on dynamic proximity graphs) are expected also to do so. We initiate study of structure theory and summary statistics for general processes in the class. Many questions arise in this setting via analogies with diverse existing topics, from geodesics in first-passage percolation to transit node-based route-finding algorithms. PMID- 23650347 TI - Retargeting of the Bacillus thuringiensis toxin Cyt2Aa against hemipteran insect pests. AB - Although transgenic crops expressing Bacillus thuringiensis (Bt) toxins have been used successfully for management of lepidopteran and coleopteran pest species, the sap-sucking insects (Hemiptera) are not particularly susceptible to Bt toxins. To overcome this limitation, we demonstrate that addition of a short peptide sequence selected for binding to the gut of the targeted pest species serves to increase toxicity against said pest. Insertion of a 12-aa pea aphid gut binding peptide by adding to or replacing amino acids in one of three loops of the Bt cytolytic toxin, Cyt2Aa, resulted in enhanced binding and toxicity against both the pea aphid, Acyrthosiphon pisum, and the green peach aphid, Myzus persicae. This strategy may allow for transgenic plant-mediated suppression of other hemipteran pests, which include some of the most important pests of global agriculture. PMID- 23650349 TI - Phosphorylation-dependent conformational changes and domain rearrangements in Staphylococcus aureus VraR activation. AB - Staphylococcus aureus VraR, a vancomycin-resistance-associated response regulator, activates a cell-wall-stress stimulon in response to antibiotics that inhibit cell wall formation. X-ray crystal structures of VraR in both unphosphorylated and beryllofluoride-activated states have been determined, revealing a mechanism of phosphorylation-induced dimerization that features a deep hydrophobic pocket at the center of the receiver domain interface. Unphosphorylated VraR exists in a closed conformation that inhibits dimer formation. Phosphorylation at the active site promotes conformational changes that are propagated throughout the receiver domain, promoting the opening of a hydrophobic pocket that is essential for homodimer formation and enhanced DNA binding activity. This prominent feature in the VraR dimer can potentially be exploited for the development of novel therapeutics to counteract antibiotic resistance in this important pathogen. PMID- 23650350 TI - Modeling nuclear volume isotope effects in crystals. AB - Mass-independent isotope fractionations driven by differences in volumes and shapes of nuclei (the field shift effect) are known in several elements and are likely to be found in more. All-electron relativistic electronic structure calculations can predict this effect but at present are computationally intensive and limited to modeling small gas phase molecules and clusters. Density functional theory, using the projector augmented wave method (DFT-PAW), has advantages in greater speed and compatibility with a three-dimensional periodic boundary condition while preserving information about the effects of chemistry on electron densities within nuclei. These electron density variations determine the volume component of the field shift effect. In this study, DFT-PAW calculations are calibrated against all-electron, relativistic Dirac-Hartree-Fock, and coupled cluster with single, double (triple) excitation methods for estimating nuclear volume isotope effects. DFT-PAW calculations accurately reproduce changes in electron densities within nuclei in typical molecules, when PAW datasets constructed with finite nuclei are used. Nuclear volume contributions to vapor crystal isotope fractionation are calculated for elemental cadmium and mercury, showing good agreement with experiments. The nuclear-volume component of mercury and cadmium isotope fractionations between atomic vapor and montroydite (HgO), cinnabar (HgS), calomel (Hg2Cl2), monteponite (CdO), and the CdS polymorphs hawleyite and greenockite are calculated, indicating preferential incorporation of neutron-rich isotopes in more oxidized, ionically bonded phases. Finally, field shift energies are related to Mossbauer isomer shifts, and equilibrium mass independent fractionations for several tin-bearing crystals are calculated from (119)Sn spectra. Isomer shift data should simplify calculations of mass independent isotope fractionations in other elements with Mossbauer isotopes, such as platinum and uranium. PMID- 23650351 TI - Evolution of the plankton paleome in the Black Sea from the Deglacial to Anthropocene. AB - The complex interplay of climate shifts over Eurasia and global sea level changes modulates freshwater and saltwater inputs to the Black Sea. The dynamics of the hydrologic changes from the Late Glacial into the Holocene remain a matter of debate, and information on how these changes affected the ecology of the Black Sea is sparse. Here we used Roche 454 next-generation pyrosequencing of sedimentary 18S rRNA genes to reconstruct the plankton community structure in the Black Sea over the last ca. 11,400 y. We found that 150 of 2,710 species showed a statistically significant response to four environmental stages. Freshwater chlorophytes were the best indicator species for lacustrine conditions (>9.0 ka B.P.), although the copresence of previously unidentified marine taxa indicated that the Black Sea might have been influenced to some extent by the Marmara Sea since at least 9.6 ka calendar (cal) B.P. Dinoflagellates, cercozoa, eustigmatophytes, and haptophytes responded most dramatically to the gradual increase in salinity after the latest marine reconnection and during the warm and moist mid-Holocene climatic optimum. According to paired analysis of deuterium/hydrogen (D/H) isotope ratios in fossil alkenones, salinity increased rapidly with the onset of the dry Subboreal after ~5.2 ka B.P., leading to an increase in marine fungi and the first occurrence of marine copepods. A gradual succession of dinoflagellates, diatoms, and chrysophytes occurred during the refreshening after ~2.5 ka cal B.P. with the onset of the cool and wet Subatlantic climate and recent anthropogenic perturbations. PMID- 23650352 TI - Control of slippage with tunable bubble mattresses. AB - Tailoring the hydrodynamic boundary condition is essential for both applied and fundamental aspects of drag reduction. Hydrodynamic friction on superhydrophobic substrates providing gas-liquid interfaces can potentially be optimized by controlling the interface geometry. Therefore, establishing stable and optimal interfaces is crucial but rather challenging. Here we present unique superhydrophobic microfluidic devices that allow the presence of stable and controllable microbubbles at the boundary of microchannels. We experimentally and numerically examine the effect of microbubble geometry on the slippage at high resolution. The effective slip length is obtained for a wide range of protrusion angles, theta, of the microbubbles into the flow, using a microparticle image velocimetry technique. Our numerical results reveal a maximum effective slip length, corresponding to a 23% drag reduction at an optimal theta ~ 10 degrees . In agreement with the simulation results, our measurements correspond to up to 21% drag reduction when theta is in the range of -2 degrees to 12 degrees . The experimental and numerical results reveal a decrease in slip length with increasing protrusion angles when >/~ 10 degrees . Such microfluidic devices with tunable slippage are essential for the amplified interfacial transport of fluids and particles. PMID- 23650353 TI - Frequent adaptation and the McDonald-Kreitman test. AB - Population genomic studies have shown that genetic draft and background selection can profoundly affect the genome-wide patterns of molecular variation. We performed forward simulations under realistic gene-structure and selection scenarios to investigate whether such linkage effects impinge on the ability of the McDonald-Kreitman (MK) test to infer the rate of positive selection (alpha) from polymorphism and divergence data. We find that in the presence of slightly deleterious mutations, MK estimates of alpha severely underestimate the true rate of adaptation even if all polymorphisms with population frequencies under 50% are excluded. Furthermore, already under intermediate rates of adaptation, genetic draft substantially distorts the site frequency spectra at neutral and functional sites from the expectations under mutation-selection-drift balance. MK-type approaches that first infer demography from synonymous sites and then use the inferred demography to correct the estimation of alpha obtain almost the correct alpha in our simulations. However, these approaches typically infer a severe past population expansion although there was no such expansion in the simulations, casting doubt on the accuracy of methods that infer demography from synonymous polymorphism data. We propose a simple asymptotic extension of the MK test that yields accurate estimates of alpha in our simulations and should provide a fruitful direction for future studies. PMID- 23650354 TI - Dynamic vaccine blocks relapse to compulsive intake of heroin. AB - Heroin addiction, a chronic relapsing disorder characterized by excessive drug taking and seeking, requires constant psychotherapeutic and pharmacotherapeutic interventions to minimize the potential for further abuse. Vaccine strategies against many drugs of abuse are being developed that generate antibodies that bind drug in the bloodstream, preventing entry into the brain and nullifying psychoactivity. However, this strategy is complicated by heroin's rapid metabolism to 6-acetylmorphine and morphine. We recently developed a "dynamic" vaccine that creates antibodies against heroin and its psychoactive metabolites by presenting multihaptenic structures to the immune system that match heroin's metabolism. The current study presents evidence of effective and continuous sequestration of brain-permeable constituents of heroin in the bloodstream following vaccination. The result is efficient blockade of heroin activity in treated rats, preventing various features of drugs of abuse: heroin reward, drug induced reinstatement of drug seeking, and reescalation of compulsive heroin self administration following abstinence in dependent rats. The dynamic vaccine shows the capability to significantly devalue the reinforcing and motivating properties of heroin, even in subjects with a history of dependence. In addition, targeting a less brain-permeable downstream metabolite, morphine, is insufficient to prevent heroin-induced activity in these models, suggesting that heroin and 6 acetylmorphine are critical players in heroin's psychoactivity. Because the heroin vaccine does not target opioid receptors or common opioid pharmacotherapeutics, it can be used in conjunction with available treatment options. Thus, our vaccine represents a promising adjunct therapy for heroin addiction, providing continuous heroin antagonism, requiring minimal medical monitoring and patient compliance. PMID- 23650355 TI - Salts drive controllable multilayered upright assembly of amyloid-like peptides at mica/water interface. AB - Surface-assisted self-assembly of amyloid-like peptides has received considerable interest in both amyloidosis research and nanotechnology in recent years. Despite extensive studies, some controlling factors, such as salts, are still not well understood, even though it is known that some salts can promote peptide self assemblies through the so-called "salting-out" effect. However, they are usually noncontrollable, disordered, amorphous aggregates. Here, we show via a combined experimental and theoretical approach that a conserved consensus peptide NH2 VGGAVVAGV-CONH2 (GAV-9) (from representative amyloidogenic proteins) can self assemble into highly ordered, multilayered nanofilaments, with surprising all upright conformations, under high-salt concentrations. Our atomic force microscopy images also demonstrate that the vertical stacking of multiple layers is highly controllable by tuning the ionic strength, such as from 0 mM (monolayer) to 100 mM (mainly double layer), and to 250 mM MgCl2 (double, triple, quadruple, and quintuple layers). Our atomistic molecular dynamics simulations then reveal that these individual layers have very different internal nanostructures, with parallel beta-sheets in the first monolayer but antiparallel beta-sheets in the subsequent upper layers due to their different microenvironment. Further studies show that the growth of multilayered, all upright nanostructures is a common phenomenon for GAV-9 at the mica/water interface, under a variety of salt types and a wide range of salt concentrations. PMID- 23650356 TI - Gene regulatory network for neurogenesis in a sea star embryo connects broad neural specification and localized patterning. AB - A great challenge in development biology is to understand how interacting networks of regulatory genes can direct the often highly complex patterning of cells in a 3D embryo. Here, we detail the gene regulatory network that describes the distribution of ciliary band-associated neurons in the bipinnaria larva of the sea star. This larva, typically for the ancestral deuterostome dipleurula larval type that it represents, forms two loops of ciliary bands that extend across much of the anterior-posterior and dorsal-ventral ectoderm. We show that the sea star first likely uses maternally inherited factors and the Wnt and Delta pathways to distinguish neurogenic ectoderm from endomesoderm. The broad neurogenic potential of the ectoderm persists throughout much of gastrulation. Nodal, bone morphogenetic protein 2/4 (Bmp2/4), and Six3-dependent pathways then sculpt a complex ciliary band territory that is defined by the expression of the forkhead transcription factor, foxg. Foxg is needed to define two molecularly distinct ectodermal domains, and for the formation of differentiated neurons along the edge of these two territories. Thus, significantly, Bmp2/4 signaling in sea stars does not distinguish differentiated neurons from nonneuronal ectoderm as it does in many other animals, but instead contributes to the patterning of an ectodermal territory, which then, in turn, provides cues to permit the final steps of neuronal differentiation. The modularity between specification and patterning likely reflects the evolutionary history of this gene regulatory network, in which an ancient module for specification of a broad neurogenic potential ectoderm was subsequently overlaid with a module for patterning. PMID- 23650357 TI - Combined effect of a peptide-morpholino oligonucleotide conjugate and a cell penetrating peptide as an antibiotic. AB - A cell-penetrating peptide (CPP)-morpholino oligonucleotide (MO) conjugate (PMO) that has an antibiotic effect in culture had some contaminating CPPs in earlier preparations. The mixed conjugate had gene-specific and gene-nonspecific effects. An improved purification procedure separates the PMO from the free CPP and MO. The gene-specific effects are a result of the PMO, and the nonspecific effects are a result of the unlinked, unreacted CPP. The PMO and the CPP can be mixed together, as has been shown previously in earlier experiments, and have a combined effect as an antibiotic. Kinetic analysis of these effects confirm this observation. The effect of the CPP is bacteriostatic. The effect of the PMO appears to be bacteriocidal. An assay for mutations that would alter the ability of these agents to affect bacterial viability is negative. PMID- 23650358 TI - Heterochromatin protein Sir3 induces contacts between the amino terminus of histone H4 and nucleosomal DNA. AB - The regulated binding of effector proteins to the nucleosome plays a central role in the activation and silencing of eukaryotic genes. How this binding changes the properties of chromatin to mediate gene activation or silencing is not fully understood. Here we provide evidence that association of the budding yeast silent information regulator 3 (Sir3) silencing protein with the nucleosome induces a conformational change in the amino terminus of histone H4 that promotes interactions between the conserved H4 arginines 17 and 19 (R17 and R19) and nucleosomal DNA. Substitutions of H4R17 and R19 with alanine abolish silencing in vivo, but have little or no effect on binding of Sir3 to nucleosomes or histone H4 peptides in vitro. Furthermore, in both the previously reported crystal structure of the Sir3-bromo adjacent homology (BAH) domain bound to the Xenopus laevis nucleosome core particle and the crystal structure of the Sir3-BAH domain bound to the yeast nucleosome core particle described here, H4R17 and R19 make contacts with nucleosomal DNA rather than with Sir3. These results suggest that Sir3 binding generates a more stable nucleosome by clamping H4R17 and R19 to nucleosomal DNA, and raise the possibility that such induced changes in histone DNA contacts play major roles in the regulation of chromatin structure. PMID- 23650360 TI - The phase transition of matrix recovery from Gaussian measurements matches the minimax MSE of matrix denoising. AB - Let X(0) be an unknown M by N matrix. In matrix recovery, one takes n < MN linear measurements y(1),...,y(n) of X(0), where y(i) = Tr(A(T)iX(0)) and each A(i) is an M by N matrix. A popular approach for matrix recovery is nuclear norm minimization (NNM): solving the convex optimization problem min ||X||*subject to y(i) =Tr(A(T)(i)X) for all 1 <= i <= n, where || . ||* denotes the nuclear norm, namely, the sum of singular values. Empirical work reveals a phase transition curve, stated in terms of the undersampling fraction delta(n,M,N) = n/(MN), rank fraction rho=rank(X0)/min {M,N}, and aspect ratio beta=M/N. Specifically when the measurement matrices Ai have independent standard Gaussian random entries, a curve delta*(rho) = delta*(rho;beta) exists such that, if delta > delta*(rho), NNM typically succeeds for large M,N, whereas if delta < delta*(rho), it typically fails. An apparently quite different problem is matrix denoising in Gaussian noise, in which an unknown M by N matrix X(0) is to be estimated based on direct noisy measurements Y =X(0) + Z, where the matrix Z has independent and identically distributed Gaussian entries. A popular matrix denoising scheme solves the unconstrained optimization problem min|| Y-X||(2)(F)/2+lambda||X||*. When optimally tuned, this scheme achieves the asymptotic minimax mean-squared error M(rho;beta) = lim(M,N -> infinity)inf(lambda)sup(rank(X) <= rho . M)MSE(X,X(lambda)), where M/N -> . We report extensive experiments showing that the phase transition delta*(rho) in the first problem, matrix recovery from Gaussian measurements, coincides with the minimax risk curve M(rho)=M(rho;beta) in the second problem, matrix denoising in Gaussian noise: delta*(rho)=M(rho), for any rank fraction 0 < rho < 1 (at each common aspect ratio beta). Our experiments considered matrices belonging to two constraint classes: real M by N matrices, of various ranks and aspect ratios, and real symmetric positive semidefinite N by N matrices, of various ranks. PMID- 23650359 TI - WRKY8 transcription factor functions in the TMV-cg defense response by mediating both abscisic acid and ethylene signaling in Arabidopsis. AB - WRKY transcription factors are key players in the plant immune response, but less is known about their involvement in antiviral defense than about their roles in defense against bacterial or fungi pathogens. Here, we report that Arabidopsis thaliana WRKY DNA-binding protein 8 (WRKY8) has a role in mediating the long distance movement of crucifer-infecting tobacco mosaic virus (TMV-cg). The expression of WRKY8 was inhibited by TMV-cg infection, and mutation of WRKY8 accelerated the accumulation of TMV-cg in systemically infected leaves. Quantitative RT-PCR analysis showed that the expression of ABA insensitive 4 (ABI4) was reduced and the expression of 1-aminocyclopropane-1-carboxylic acid synthase 6 (ACS6) and ethylene response factor 104 (ERF104) was enhanced in the systemically infected leaves of wrky8. Immunoprecipitation assays demonstrated that WRKY8 could bind selectively to putative W-boxes of the ABI4, ACS6, and ERF104 promoters. Furthermore, TMV-cg infection enhanced WRKY8 binding to the ABI4 promoter but reduced the binding of WRKY8 to the ACS6 and ERF104 promoters, indicating that regulation of ABI4, ACS6, and ERF104 by WRKY8 is at least partially dependent on TMV-cg. Exogenous applications of abscisic acid (ABA) reduced the systemic accumulation of TMV-cg. Mutations in ABA deficient 1, ABA deficient 2, ABA deficient 3, or abi4 accelerated systemic TMV-cg accumulation. In contrast, exogenous application of aminocyclopropane-1-carboxylic acid enhanced the systemic accumulation of TMV-cg, but mutations in acs6, erf104, or an octuple acs mutant inhibited systemic TMV-cg accumulation. Our results demonstrate that WRKY8 is involved in the defense response against TMV-cg through the direct regulation of the expression of ABI4, ACS6, and ERF104 and may mediate the crosstalk between ABA and ethylene signaling during the TMV-cg-Arabidopsis interaction. PMID- 23650361 TI - Activated microglia enhance neurogenesis via trypsinogen secretion. AB - White matter neurons in multiple sclerosis brains are destroyed during demyelination and then replaced in some chronic multiple sclerosis lesions that exhibit a morphologically distinct population of activated microglia [Chang A, et al. (2008) Brain 131(Pt 9):2366-2375]. Here we investigated whether activated microglia secrete factors that promote the generation of neurons from white matter cells. Adult rat brain microglia (resting or activated with lipopolysaccharide) were isolated by flow cytometry and cocultured with neonatal rat optic nerve cells in separate but media-connected chambers. Optic nerve cells cocultured with activated microglia showed a significant increase in the number of cells of neuronal phenotype, identified by neuron-specific class III beta tubulin (TUJ-1) labeling, compared with cultures with resting microglia. To investigate the possible source of the TUJ-1-positive cells, A2B5-positive oligodendrocyte progenitor cells and A2B5-negative cells were isolated and cocultured with resting and activated microglia. Significantly more TUJ-1 positive cells were generated from A2B5-negative cells (~70%) than from A2B5 positive cells (~30%). Mass spectrometry analysis of microglia culture media identified protease serine 2 (PRSS2) as a factor secreted by activated, but not resting, microglia. When added to optic nerve cultures, PRSS2 significantly increased neurogenesis, whereas the serine protease inhibitor, secretory leukocyte protease inhibitor, decreased activated microglia-induced neurogenesis. Collectively our data provide evidence that activated microglia increase neurogenesis through secretion of PRSS2. PMID- 23650362 TI - Heat shock protein (Hsp) 70 is an activator of the Hsp104 motor. AB - Heat shock protein (Hsp) 104 is a ring-forming, protein-remodeling machine that harnesses the energy of ATP binding and hydrolysis to drive protein disaggregation. Although Hsp104 is an active ATPase, the recovery of functional protein requires the species-specific cooperation of the Hsp70 system. However, like Hsp104, Hsp70 is an active ATPase, which recognizes aggregated and aggregation-prone proteins, making it difficult to differentiate the mechanistic roles of Hsp104 and Hsp70 during protein disaggregation. Mapping the Hsp70 binding sites in yeast Hsp104 using peptide array technology and photo-cross linking revealed a striking conservation of the primary Hsp70-binding motifs on the Hsp104 middle-domain across species, despite lack of sequence identity. Remarkably, inserting a Strep-Tactin binding motif at the spatially conserved Hsp70-binding site elicits the Hsp104 protein disaggregating activity that now depends on Strep-Tactin but no longer requires Hsp70/40. Consistent with a Strep Tactin-dependent activation step, we found that full-length Hsp70 on its own could activate the Hsp104 hexamer by promoting intersubunit coordination, suggesting that Hsp70 is an activator of the Hsp104 motor. PMID- 23650363 TI - Skeletal muscle PGC-1alpha controls whole-body lactate homeostasis through estrogen-related receptor alpha-dependent activation of LDH B and repression of LDH A. AB - The peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC 1alpha) controls metabolic adaptations. We now show that PGC-1alpha in skeletal muscle drives the expression of lactate dehydrogenase (LDH) B in an estrogen related receptor-alpha-dependent manner. Concomitantly, PGC-1alpha reduces the expression of LDH A and one of its regulators, the transcription factor myelocytomatosis oncogene. PGC-1alpha thereby coordinately alters the composition of the LDH complex and prevents the increase in blood lactate during exercise. Our results show how PGC-1alpha actively coordinates lactate homeostasis and provide a unique molecular explanation for PGC-1alpha-mediated muscle adaptations to training that ultimately enhance exercise performance and improve metabolic health. PMID- 23650364 TI - Fluorescence thermometry enhanced by the quantum coherence of single spins in diamond. AB - We demonstrate fluorescence thermometry techniques with sensitivities approaching 10 mK . Hz(-1/2) based on the spin-dependent photoluminescence of nitrogen vacancy (NV) centers in diamond. These techniques use dynamical decoupling protocols to convert thermally induced shifts in the NV center's spin resonance frequencies into large changes in its fluorescence. By mitigating interactions with nearby nuclear spins and facilitating selective thermal measurements, these protocols enhance the spin coherence times accessible for thermometry by 45-fold, corresponding to a 7-fold improvement in the NV center's temperature sensitivity. Moreover, we demonstrate these techniques can be applied over a broad temperature range and in both finite and near-zero magnetic field environments. This versatility suggests that the quantum coherence of single spins could be practically leveraged for sensitive thermometry in a wide variety of biological and microscale systems. PMID- 23650365 TI - Complex history of the amphibian-killing chytrid fungus revealed with genome resequencing data. AB - Understanding the evolutionary history of microbial pathogens is critical for mitigating the impacts of emerging infectious diseases on economically and ecologically important host species. We used a genome resequencing approach to resolve the evolutionary history of an important microbial pathogen, the chytrid Batrachochytrium dendrobatidis (Bd), which has been implicated in amphibian declines worldwide. We sequenced the genomes of 29 isolates of Bd from around the world, with an emphasis on North, Central, and South America because of the devastating effect that Bd has had on amphibian populations in the New World. We found a substantial amount of evolutionary complexity in Bd with deep phylogenetic diversity that predates observed global amphibian declines. By investigating the entire genome, we found that even the most recently evolved Bd clade (termed the global panzootic lineage) contained more genetic variation than previously reported. We also found dramatic differences among isolates and among genomic regions in chromosomal copy number and patterns of heterozygosity, suggesting complex and heterogeneous genome dynamics. Finally, we report evidence for selection acting on the Bd genome, supporting the hypothesis that protease genes are important in evolutionary transitions in this group. Bd is considered an emerging pathogen because of its recent effects on amphibians, but our data indicate that it has a complex evolutionary history that predates recent disease outbreaks. Therefore, it is important to consider the contemporary effects of Bd in a broader evolutionary context and identify specific mechanisms that may have led to shifts in virulence in this system. PMID- 23650366 TI - Optimal fold symmetry of LH2 rings on a photosynthetic membrane. AB - An intriguing observation of photosynthetic light-harvesting systems is the N fold symmetry of light-harvesting complex 2 (LH2) of purple bacteria. We calculate the optimal rotational configuration of N-fold rings on a hexagonal lattice and establish two related mechanisms for the promotion of maximum excitation energy transfer (EET). (i) For certain fold numbers, there exist optimal basis cells with rotational symmetry, extendable to the entire lattice for the global optimization of the EET network. (ii) The type of basis cell can reduce or remove the frustration of EET rates across the photosynthetic network. We find that the existence of a basis cell and its type are directly related to the number of matching points S between the fold symmetry and the hexagonal lattice. The two complementary mechanisms provide selection criteria for the fold number and identify groups of consecutive numbers. Remarkably, one such group consists of the naturally occurring 8-, 9-, and 10-fold rings. By considering the inter-ring distance and EET rate, we demonstrate that this group can achieve minimal rotational sensitivity in addition to an optimal packing density, achieving robust and efficient EET. This corroborates our findings i and ii and, through their direct relation to S, suggests the design principle of matching the internal symmetry with the lattice order. PMID- 23650367 TI - Direct observation of intermediates formed during steady-state electrocatalytic O2 reduction by iron porphyrins. AB - Heme/porphyrin-based electrocatalysts (both synthetic and natural) have been known to catalyze electrochemical O2, H(+), and CO2 reduction for more than five decades. So far, no direct spectroscopic investigations of intermediates formed on the electrodes during these processes have been reported; and this has limited detailed understanding of the mechanism of these catalysts, which is key to their development. Rotating disk electrochemistry coupled to resonance Raman spectroscopy is reported for iron porphyrin electrocatalysts that reduce O2 in buffered aqueous solutions. Unlike conventional single-turnover intermediate trapping experiments, these experiments probe the system while it is under steady state. A combination of oxidation and spin-state marker bands and metal ligand vibrations (identified using isotopically enriched substrates) allow in situ identification of O2-derived intermediates formed on the electrode surface. This approach, combining dynamic electrochemistry with resonance Raman spectroscopy, may be routinely used to investigate a plethora of metalloporphyrin complexes and heme enzymes used as electrocatalysts for small-molecule activation. PMID- 23650369 TI - Study of the fluoro- and chlorodimethylbutyl cations. AB - A comparative study of the 2,3-dimethyl-3-fluoro-2-butyl cation and its chloro analog was carried out by the ab initio/GIAO-CCSD(T) (gauge invariant atomic orbital-coupled cluster with single, double, and perturbative triple excitation) method. The structures and (13)C NMR chemical shifts of the cations were calculated at the GIAO-CCSD(T)/tzp/dz//MP2/cc-pVTZ level. Bridged fluoronium ion 1, carbenium ion 2, and fluorocarbenium ion 3 were found to be minima on the potential energy surface. Bridged fluoronium ion 1, although a minimum on the potential energy surface, is 12.8 kcal/mol less stable than the open chain fluorobutyl cation 3. In contrast to the fluorinated ion, bridged chloronium ion 5 was found to be the lowest energy minimum being 10.6 kcal/mol more stable than ion 6 and 7.4 kcal/mol more stable than ion 7. PMID- 23650368 TI - X-ray structure of an AdoMet radical activase reveals an anaerobic solution for formylglycine posttranslational modification. AB - Arylsulfatases require a maturating enzyme to perform a co- or posttranslational modification to form a catalytically essential formylglycine (FGly) residue. In organisms that live aerobically, molecular oxygen is used enzymatically to oxidize cysteine to FGly. Under anaerobic conditions, S-adenosylmethionine (AdoMet) radical chemistry is used. Here we present the structures of an anaerobic sulfatase maturating enzyme (anSME), both with and without peptidyl substrates, at 1.6-1.8 A resolution. We find that anSMEs differ from their aerobic counterparts in using backbone-based hydrogen-bonding patterns to interact with their peptidyl-substrates, leading to decreased sequence specificity. These anSME structures from Clostridium perfringens are also the first of an AdoMet radical enzyme that performs dehydrogenase chemistry. Together with accompanying mutagenesis data, a mechanistic proposal is put forth for how AdoMet radical chemistry is coopted to perform a dehydrogenation reaction. In the oxidation of cysteine or serine to FGly by anSME, we identify D277 and an auxiliary [4Fe-4S] cluster as the likely acceptor of the final proton and electron, respectively. D277 and both auxiliary clusters are housed in a cysteine rich C-terminal domain, termed SPASM domain, that contains homology to ~1,400 other unique AdoMet radical enzymes proposed to use [4Fe-4S] clusters to ligate peptidyl-substrates for subsequent modification. In contrast to this proposal, we find that neither auxiliary cluster in anSME bind substrate, and both are fully ligated by cysteine residues. Instead, our structural data suggest that the placement of these auxiliary clusters creates a conduit for electrons to travel from the buried substrate to the protein surface. PMID- 23650370 TI - Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration. AB - The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left "naked" (free from the nuclear lamina). Thus, farnesylation of lamin B1--but not lamin B2--is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration. PMID- 23650372 TI - Weather and anomalous heat flow occurring near absolute zero. PMID- 23650371 TI - CaBP1, a neuronal Ca2+ sensor protein, inhibits inositol trisphosphate receptors by clamping intersubunit interactions. AB - Calcium-binding protein 1 (CaBP1) is a neuron-specific member of the calmodulin superfamily that regulates several Ca(2+) channels, including inositol 1,4,5 trisphosphate receptors (InsP3Rs). CaBP1 alone does not affect InsP3R activity, but it inhibits InsP3-evoked Ca(2+) release by slowing the rate of InsP3R opening. The inhibition is enhanced by Ca(2+) binding to both the InsP3R and CaBP1. CaBP1 binds via its C lobe to the cytosolic N-terminal region (NT; residues 1-604) of InsP3R1. NMR paramagnetic relaxation enhancement analysis demonstrates that a cluster of hydrophobic residues (V101, L104, and V162) within the C lobe of CaBP1 that are exposed after Ca(2+) binding interact with a complementary cluster of hydrophobic residues (L302, I364, and L393) in the beta domain of the InsP3-binding core. These residues are essential for CaBP1 binding to the NT and for inhibition of InsP3R activity by CaBP1. Docking analyses and paramagnetic relaxation enhancement structural restraints suggest that CaBP1 forms an extended tetrameric turret attached by the tetrameric NT to the cytosolic vestibule of the InsP3R pore. InsP3 activates InsP3Rs by initiating conformational changes that lead to disruption of an intersubunit interaction between a "hot-spot" loop in the suppressor domain (residues 1-223) and the InsP3 binding core beta-domain. Targeted cross-linking of residues that contribute to this interface show that InsP3 attenuates cross-linking, whereas CaBP1 promotes it. We conclude that CaBP1 inhibits InsP3R activity by restricting the intersubunit movements that initiate gating. PMID- 23650373 TI - Profile of Vivian W.-W. Yam. Interview by Farooq Ahmed. PMID- 23650374 TI - Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor. AB - Receptor-mediated transcytosis across the blood-brain barrier (BBB) may be a useful way to transport therapeutics into the brain. Here we report that transferrin (Tf)-containing gold nanoparticles can reach the brain parenchyma from systemic administration in mice through a receptor-mediated transcytosis pathway. This transport is aided by tuning the nanoparticle avidity to Tf receptor (TfR), which is correlated with nanoparticle size and total amount of Tf decorating the nanoparticle surface. Nanoparticles of both 45 nm and 80 nm diameter reach the brain parenchyma, and their accumulation there (visualized by silver enhancement light microscopy in combination with transmission electron microscopy imaging) is observed to be dependent on Tf content (avidity); nanoparticles with large amounts of Tf remain strongly attached to brain endothelial cells, whereas those with less Tf are capable of both interacting with TfR on the luminal side of the BBB and detaching from TfR on the brain side of the BBB. The requirement of proper avidity for nanoparticles to reach the brain parenchyma is consistent with recent behavior observed with transcytosing antibodies that bind to TfR. PMID- 23650375 TI - Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation. AB - Procaspase-3 (P3) and procaspase-7 (P7) are activated through proteolytic maturation to form caspase-3 (C3) and caspase-7 (C7), respectively, which serve overlapping but nonredundant roles as the executioners of apoptosis in humans. However, it is unclear if differences in P3 and P7 maturation mechanisms underlie their unique biological functions, as the structure of P3 remains unknown. Here, we report structures of P3 in a catalytically inactive conformation, structures of P3 and P7 bound to covalent peptide inhibitors that reveal the active conformation of the zymogens, and the structure of a partially matured C7:P7 heterodimer. Along with a biochemical analysis, we show that P3 is catalytically inactive and matures through a symmetric all-or-nothing process. In contrast, P7 contains latent catalytic activity and matures through an asymmetric and tiered mechanism, suggesting a lower threshold for activation. Finally, we use our structures to design a selection strategy for conformation specific antibody fragments that stimulate procaspase activity, showing that executioner procaspase conformational equilibrium can be rationally modulated. Our studies provide a structural framework that may help to explain the unique roles of these important proapoptotic enzymes, and suggest general strategies for the discovery of proenzyme activators. PMID- 23650376 TI - Presynaptic maturation in auditory hair cells requires a critical period of sensory-independent spiking activity. AB - The development of neural circuits relies on spontaneous electrical activity that occurs during immature stages of development. In the developing mammalian auditory system, spontaneous calcium action potentials are generated by inner hair cells (IHCs), which form the primary sensory synapse. It remains unknown whether this electrical activity is required for the functional maturation of the auditory system. We found that sensory-independent electrical activity controls synaptic maturation in IHCs. We used a mouse model in which the potassium channel SK2 is normally overexpressed, but can be modulated in vivo using doxycycline. SK2 overexpression affected the frequency and duration of spontaneous action potentials, which prevented the development of the Ca(2+)-sensitivity of vesicle fusion at IHC ribbon synapses, without affecting their morphology or general cell development. By manipulating the in vivo expression of SK2 channels, we identified the "critical period" during which spiking activity influences IHC synaptic maturation. Here we provide direct evidence that IHC development depends upon a specific temporal pattern of calcium spikes before sound-driven neuronal activity. PMID- 23650377 TI - Mechanism for nitrogen isotope fractionation during ammonium assimilation by Escherichia coli K12. AB - Organisms that use ammonium as the sole nitrogen source discriminate between [(15)N] and [(14)N] ammonium. This selectivity leaves an isotopic signature in their biomass that depends on the external concentration of ammonium. To dissect how differences in discrimination arise molecularly, we examined a wild-type (WT) strain of Escherichia coli K12 and mutant strains with lesions affecting ammonium assimilatory proteins. We used isotope ratio mass spectrometry (MS) to assess the nitrogen isotopic composition of cell material when the strains were grown in batch culture at either high or low external concentrations of NH3 (achieved by controlling total NH4Cl and pH of the medium). At high NH3 (>= 0.89 uM), discrimination against the heavy isotope by the WT strain (-19.20/00) can be accounted for by the equilibrium isotope effect for dissociation of NH4(+) to NH3 + H(+). NH3 equilibrates across the cytoplasmic membrane, and glutamine synthetase does not manifest an isotope effect in vivo. At low NH3 (<= 0.18 uM), discrimination reflects an isotope effect for the NH4(+) channel AmtB ( 14.10/00). By making E. coli dependent on the low-affinity ammonium-assimilatory pathway, we determined that biosynthetic glutamate dehydrogenase has an inverse isotope effect in vivo (+8.80/00). Likewise, by making unmediated diffusion of NH3 across the cytoplasmic membrane rate-limiting for cell growth in a mutant strain lacking AmtB, we could deduce an in vivo isotope effect for transport of NH3 across the membrane (-10.90/00). The paper presents the raw data from which our conclusions were drawn and discusses the assumptions underlying them. PMID- 23650378 TI - Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS-NO-nitrite signaling. AB - Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by severe intestinal necrosis and for which breast milk represents the most effective protective strategy. Previous studies have revealed a critical role for the lipopolysaccharide receptor toll-like receptor 4 (TLR4) in NEC development through its induction of mucosal injury, yet the reasons for which intestinal ischemia in NEC occurs in the first place remain unknown. We hypothesize that TLR4 signaling within the endothelium plays an essential role in NEC development by regulating perfusion to the small intestine via the vasodilatory molecule endothelial nitric oxide synthase (eNOS). Using a unique mouse system in which we selectively deleted TLR4 from the endothelium, we now show that endothelial TLR4 activation is required for NEC development and that endothelial TLR4 activation impairs intestinal perfusion without effects on other organs and reduces eNOS expression via activation of myeloid differentiation primary response gene 88. NEC severity was significantly increased in eNOS(-/-) mice and decreased upon administration of the phosphodiesterase inhibitor sildenafil, which augments eNOS function. Strikingly, compared with formula, human and mouse breast milk were enriched in sodium nitrate--a precursor for enteral generation of nitrite and nitric oxide--and repletion of formula with sodium nitrate/nitrite restored intestinal perfusion, reversed the deleterious effects of endothelial TLR4 signaling, and reduced NEC severity. These data identify that endothelial TLR4 critically regulates intestinal perfusion leading to NEC and reveal that the protective properties of breast milk involve enhanced intestinal microcirculatory integrity via augmentation of nitrate-nitrite-NO signaling. PMID- 23650379 TI - Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. AB - Aberrant protein aggregation and mitochondrial dysfunction have each been linked to aging and a number of age-onset neurodegenerative disorders, including Parkinson disease. Loss-of-function mutations in parkin, an E3 ubiquitin ligase that functions to promote the ubiquitin-proteasome system of protein degradation and also in mitochondrial quality control, have been implicated in heritable forms of Parkinson disease. The question of whether parkin can modulate aging or positively impact longevity, however, has not been addressed. Here, we show that ubiquitous or neuron-specific up-regulation of Parkin, in adult Drosophila melanogaster, increases both mean and maximum lifespan without reducing reproductive output, physical activity, or food intake. Long-lived Parkin overexpressing flies display an increase in K48-linked polyubiquitin and reduced levels of protein aggregation during aging. Recent evidence suggests that Parkin interacts with the mitochondrial fission/fusion machinery to mediate the turnover of dysfunctional mitochondria. However, the relationships between parkin gene activity, mitochondrial dynamics, and aging have not been explored. We show that the mitochondrial fusion-promoting factor Drosophila Mitofusin, a Parkin substrate, increases in abundance during aging. Parkin overexpression results in reduced Drosophila Mitofusin levels in aging flies, with concomitant changes in mitochondrial morphology and an increase in mitochondrial activity. Together, these findings reveal roles for Parkin in modulating organismal aging and provide insight into the molecular mechanisms linking aging to neurodegeneration. PMID- 23650380 TI - Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels. AB - Voltage-gated KCNQ1 (Kv7.1) potassium channels are expressed abundantly in heart but they are also found in multiple other tissues. Differential coassembly with single transmembrane KCNE beta subunits in different cell types gives rise to a variety of biophysical properties, hence endowing distinct physiological roles for KCNQ1-KCNEx complexes. Mutations in either KCNQ1 or KCNE1 genes result in diseases in brain, heart, and the respiratory system. In addition to complexities arising from existence of five KCNE subunits, KCNE1 to KCNE5, recent studies in heterologous systems suggest unorthodox stoichiometric dynamics in subunit assembly is dependent on KCNE expression levels. The resultant KCNQ1-KCNE channel complexes may have a range of zero to two or even up to four KCNE subunits coassembling per KCNQ1 tetramer. These findings underscore the need to assess the selectivity of small-molecule KCNQ1 modulators on these different assemblies. Here we report a unique small-molecule gating modulator, ML277, that potentiates both homomultimeric KCNQ1 channels and unsaturated heteromultimeric (KCNQ1)4(KCNE1)n (n < 4) channels. Progressive increase of KCNE1 or KCNE3 expression reduces efficacy of ML277 and eventually abolishes ML277-mediated augmentation. In cardiomyocytes, the slowly activating delayed rectifier potassium current, or IKs, is believed to be a heteromultimeric combination of KCNQ1 and KCNE1, but it is not entirely clear whether IKs is mediated by KCNE saturated KCNQ1 channels or by channels with intermediate stoichiometries. We found ML277 effectively augments IKs current of cultured human cardiomyocytes and shortens action potential duration. These data indicate that unsaturated heteromultimeric (KCNQ1)4(KCNE1)n channels are present as components of IKs and are pharmacologically distinct from KCNE-saturated KCNQ1-KCNE1 channels. PMID- 23650381 TI - Visualizing cellular interactions with a generalized proximity reporter. AB - Interactions among neighboring cells underpin many physiological processes ranging from early development to immune responses. When these interactions do not function properly, numerous pathologies, including infection and cancer, can result. Molecular imaging technologies, especially optical imaging, are uniquely suited to illuminate complex cellular interactions within the context of living tissues in the body. However, no tools yet exist that allow the detection of microscopic events, such as two cells coming into close proximity, on a global, whole-animal scale. We report here a broadly applicable, longitudinal strategy for probing interactions among cells in living subjects. This approach relies on the generation of bioluminescent light when two distinct cell populations come into close proximity, with the intensity of the optical signal correlating with relative cellular location. We demonstrate the ability of this reporter strategy to gauge cell-cell proximity in culture models in vitro and then evaluate this approach for imaging tumor-immune cell interactions using a murine breast cancer model. In these studies, our imaging strategy enabled the facile visualization of features that are otherwise difficult to observe with conventional imaging techniques, including detection of micrometastatic lesions and potential sites of tumor immunosurveillance. This proximity reporter will facilitate probing of numerous types of cell-cell interactions and will stimulate the development of similar techniques to detect rare events and pathological processes in live animals. PMID- 23650382 TI - Specialized bat tongue is a hemodynamic nectar mop. AB - Nectarivorous birds and bats have evolved highly specialized tongues to gather nectar from flowers. Here, we show that a nectar-feeding bat, Glossophaga soricina, uses dynamic erectile papillae to collect nectar. In G. soricina, the tip of the tongue is covered with long filamentous papillae and resembles a brush or mop. During nectar feeding, blood vessels within the tongue tip become engorged with blood and the papillae become erect. Tumescence and papilla erection persist throughout tongue retraction, and nectar, trapped between the rows of erect papillae, is carried into the mouth. The tongue tip does not increase in overall volume as it elongates, suggesting that muscle contraction against the tongue's fixed volume (i.e., a muscular hydrostat) is primarily responsible for tip elongation, whereas papilla erection is a hydraulic process driven by blood flow. The hydraulic system is embedded within the muscular hydrostat, and, thus, intrinsic muscle contraction may simultaneously increase the length of the tongue and displace blood into the tip. The tongue of G. soricina, together with the tongues of nectar-feeding bees and hummingbirds, which also have dynamic surfaces, could serve as valuable models for developing miniature surgical robots that are both protrusible and have highly dynamic surface configurations. PMID- 23650383 TI - Calcium-dependent protein kinase/NADPH oxidase activation circuit is required for rapid defense signal propagation. AB - In animals and plants, pathogen recognition triggers the local activation of intracellular signaling that is prerequisite for mounting systemic defenses in the whole organism. We identified that Arabidopsis thaliana isoform CPK5 of the plant calcium-dependent protein kinase family becomes rapidly biochemically activated in response to pathogen-associated molecular pattern (PAMP) stimulation. CPK5 signaling resulted in enhanced salicylic acid-mediated resistance to the bacterial pathogen Pst DC3000, differential plant defense gene expression, and synthesis of reactive oxygen species (ROS). Using selected reaction monitoring MS, we identified the plant NADPH oxidase, respiratory burst oxidase homolog D (RBOHD), as an in vivo phosphorylation target of CPK5. Remarkably, CPK5-dependent in vivo phosphorylation of RBOHD occurs on both PAMP- and ROS stimulation. Furthermore, rapid CPK5-dependent biochemical and transcriptional activation of defense reactions at distal sites is compromised in cpk5 and rbohd mutants. Our data not only identify CPK5 as a key regulator of innate immune responses in plants but also support a model of ROS-mediated cell to-cell communication, where a self-propagating mutual activation circuit consisting of the protein kinase, CPK5, and the NADPH oxidase RBOHD facilitates rapid signal propagation as a prerequisite for defense response activation at distal sites within the plant. PMID- 23650384 TI - Expression of recombinant human complement C1q allows identification of the C1r/C1s-binding sites. AB - Complement C1q is a hexameric molecule assembled from 18 polypeptide chains of three different types encoded by three genes. This versatile recognition protein senses a wide variety of immune and nonimmune ligands, including pathogens and altered self components, and triggers the classical complement pathway through activation of its associated proteases C1r and C1s. We report a method for expression of recombinant full-length human C1q involving stable transfection of HEK 293-F mammalian cells and fusion of an affinity tag to the C-terminal end of the C chain. The resulting recombinant (r) C1q molecule is similar to serum C1q as judged from biochemical and structural analyses and exhibits the characteristic shape of a bunch of flowers. Analysis of its interaction properties by surface plasmon resonance shows that rC1q retains the ability of serum C1q to associate with the C1s-C1r-C1r-C1s tetramer, to recognize physiological C1q ligands such as IgG and pentraxin 3, and to trigger C1r and C1s activation. Functional analysis of rC1q variants carrying mutations of LysA59, LysB61, and/or LysC58, in the collagen-like stems, demonstrates that LysB61 and LysC58 each play a key role in the interaction with C1s-C1r-C1r-C1s, with LysA59 being involved to a lesser degree. We propose that LysB61 and LysC58 both form salt bridges with outer acidic Ca(2+) ligands of the C1r and C1s CUB (complement C1r/C1s, Uegf, bone morphogenetic protein) domains. The expression method reported here opens the way for deciphering the molecular basis of the unusual binding versatility of C1q by mapping the residues involved in the sensing of its targets and the binding of its receptors. PMID- 23650386 TI - Persistence and origin of the lunar core dynamo. AB - The lifetime of the ancient lunar core dynamo has implications for its power source and the mechanism of field generation. Here, we report analyses of two 3.56-Gy-old mare basalts demonstrating that they were magnetized in a stable and surprisingly intense dynamo magnetic field of at least ~13 MUT. These data extend the known lifetime of the lunar dynamo by ~160 My and indicate that the field was likely continuously active until well after the final large basin-forming impact. This likely excludes impact-driven changes in rotation rate as the source of the dynamo at this time in lunar history. Rather, our results require a persistent power source like precession of the lunar mantle or a compositional convection dynamo. PMID- 23650385 TI - Structural basis of the relaxed state of a Ca2+-regulated myosin filament and its evolutionary implications. AB - Myosin filaments of muscle are regulated either by phosphorylation of their regulatory light chains or Ca(2+) binding to the essential light chains, contributing to on-off switching or modulation of contraction. Phosphorylation regulated filaments in the relaxed state are characterized by an asymmetric interaction between the two myosin heads, inhibiting their actin binding or ATPase activity. Here, we have tested whether a similar interaction switches off activity in myosin filaments regulated by Ca(2+) binding. Cryo-electron microscopy and single-particle image reconstruction of Ca(2+)-regulated (scallop) filaments reveals a helical array of myosin head-pair motifs above the filament surface. Docking of atomic models of scallop myosin head domains into the motifs reveals that the heads interact in a similar way to those in phosphorylation regulated filaments. The results imply that the two major evolutionary branches of myosin regulation--involving phosphorylation or Ca(2+) binding--share a common structural mechanism for switching off thick-filament activity in relaxed muscle. We suggest that the Ca(2+)-binding mechanism evolved from the more ancient phosphorylation-based system to enable rapid response of myosin-regulated muscles to activation. Although the motifs are similar in both systems, the scallop structure is more tilted and higher above the filament backbone, leading to different intermolecular interactions. The reconstruction reveals how the myosin tail emerges from the motif, connecting the heads to the filament backbone, and shows that the backbone is built from supramolecular assemblies of myosin tails. The reconstruction provides a native structural context for understanding past biochemical and biophysical studies of this model Ca(2+)-regulated myosin. PMID- 23650387 TI - Kif7 is required for the patterning and differentiation of the diaphragm in a model of syndromic congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH) is a common birth defect that results in a high degree of neonatal morbidity and mortality, but its pathological mechanisms are largely unknown. Therefore, we performed a forward genetic screen in mice to identify unique genes, models, and mechanisms of abnormal diaphragm development. We identified a mutant allele of kinesin family member 7 (Kif7), the disorganized diaphragm (dd). Embryos homozygous for the dd allele possess communicating diaphragmatic hernias, central tendon patterning defects, and increased cell proliferation with diaphragmatic tissue hyperplasia. Because the patterning of the central tendon is undescribed, we analyzed the expression of genes regulating tendonogenesis in dd/dd mutant embryos, and we determined that retinoic acid (RA) signaling was misregulautted. To further investigate the role of Kif7 and RA signaling in the development of the embryonic diaphragm, we established primary mesenchymal cultures of WT embryonic day 13.5 diaphragmatic cells. We determined that RA signaling is necessary for the expression of tendon markers as well as the expression of other CDH-associated genes. Knockdown of Kif7, and retinoic acid receptors alpha (Rara), beta (Rarb), and gamma (Rarg) indicated that RA signaling is dependent on these genes to promote tendonogenesis within the embryonic diaphragm. Taken together, our results provide evidence for a model in which inhibition of RA receptor signaling promotes CDH pathogenesis through a complex gene network. PMID- 23650388 TI - Interventions for avian influenza A (H5N1) risk management in live bird market networks. AB - Highly pathogenic avian influenza virus subtype H5N1 is endemic in Asia, with live bird trade as a major disease transmission pathway. A cross-sectional survey was undertaken in northern Vietnam to investigate the structure of the live bird market (LBM) contact network and the implications for virus spread. Based on the movements of traders between LBMs, weighted and directed networks were constructed and used for social network analysis and individual-based modeling. Most LBMs were connected to one another, suggesting that the LBM network may support large-scale disease spread. Because of cross-border trade, it also may promote transboundary virus circulation. However, opportunities for disease control do exist. The implementation of thorough, daily disinfection of the market environment as well as of traders' vehicles and equipment in only a small number of hubs can disconnect the network dramatically, preventing disease spread. These targeted interventions would be an effective alternative to the current policy of a complete ban of LBMs in some areas. Some LBMs that have been banned still are very active, and they likely have a substantial impact on disease dynamics, exhibiting the highest levels of susceptibility and infectiousness. The number of trader visits to markets, information that can be collected quickly and easily, may be used to identify LBMs suitable for implementing interventions. This would not require prior knowledge of the force of infection, for which laboratory-confirmed surveillance would be necessary. These findings are of particular relevance for policy development in resource scarce settings. PMID- 23650389 TI - Cross-talk between MET and EGFR in non-small cell lung cancer involves miR-27a and Sprouty2. AB - In the past decade, we have observed exciting advances in lung cancer therapy, including the development of targeted therapies. However, additional strategies for early detection and tumor-based therapy are still essential in improving patient outcomes. EGF receptor (EGFR) and MET (the receptor tyrosine kinase for hepatocyte growth factors) are cell-surface tyrosine kinase receptors that have been implicated in diverse cellular processes and as regulators of several microRNAs (miRNAs), thus contributing to tumor progression. Here, we demonstrate a biological link between EGFR, MET, and the miRNA cluster 23a ~ 27a ~ 24-2. We show that miR-27a regulates MET, EGFR, and Sprouty2 in lung cancer. In addition, we identify both direct and indirect mechanisms by which miR-27a can regulate both MET and EGFR. Thus, we propose a mechanism for MET and EGFR axis regulation that may lead to the development of therapeutics in lung cancer. PMID- 23650390 TI - Ultraconserved words point to deep language ancestry across Eurasia. AB - The search for ever deeper relationships among the World's languages is bedeviled by the fact that most words evolve too rapidly to preserve evidence of their ancestry beyond 5,000 to 9,000 y. On the other hand, quantitative modeling indicates that some "ultraconserved" words exist that might be used to find evidence for deep linguistic relationships beyond that time barrier. Here we use a statistical model, which takes into account the frequency with which words are used in common everyday speech, to predict the existence of a set of such highly conserved words among seven language families of Eurasia postulated to form a linguistic superfamily that evolved from a common ancestor around 15,000 y ago. We derive a dated phylogenetic tree of this proposed superfamily with a time depth of ~14,450 y, implying that some frequently used words have been retained in related forms since the end of the last ice age. Words used more than once per 1,000 in everyday speech were 7- to 10-times more likely to show deep ancestry on this tree. Our results suggest a remarkable fidelity in the transmission of some words and give theoretical justification to the search for features of language that might be preserved across wide spans of time and geography. PMID- 23650391 TI - Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. AB - Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3 mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature. PMID- 23650392 TI - Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. AB - Deep vein thrombosis and pulmonary embolism are major health problems associated with high mortality. Recently, DNA-based neutrophil extracellular traps (NETs) resulting from the release of decondensed chromatin, were found to be part of the thrombus scaffold and to promote coagulation. However, the significance of nuclear decondensation and NET generation in thrombosis is largely unknown. To address this, we adopted a stenosis model of deep vein thrombosis and analyzed venous thrombi in peptidylarginine deiminase 4 (PAD4)-deficient mice that cannot citrullinate histones, a process required for chromatin decondensation and NET formation. Intriguingly, less than 10% of PAD4(-/-) mice produced a thrombus 48 h after inferior vena cava stenosis whereas 90% of wild-type mice did. Neutrophils were abundantly present in thrombi formed in both groups, whereas extracellular citrullinated histones were seen only in thrombi from wild-type mice. Bone marrow chimera experiments indicated that PAD4 in hematopoietic cells was the source of the prothrombotic effect in deep vein thrombosis. Thrombosis could be rescued by infusion of wild-type neutrophils, suggesting that neutrophil PAD4 was important and sufficient. Endothelial activation and platelet aggregation were normal in PAD4(-/-) mice, as was hemostatic potential determined by bleeding time and platelet plug formation after venous injury. Our results show that PAD4-mediated chromatin decondensation in the neutrophil is crucial for pathological venous thrombosis and present neutrophil activation and PAD4 as potential drug targets for deep vein thrombosis. PMID- 23650393 TI - Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man. AB - Mutations in gene RASA1 have been historically associated with capillary malformation-arteriovenous malformation, but sporadic reports of lymphatic involvement have yet to be investigated in detail. To investigate the impact of RASA1 mutations in the lymphatic system, we performed investigational near infrared fluorescence lymphatic imaging and confirmatory radiographic lymphangiography in a Parkes-Weber syndrome (PKWS) patient with suspected RASA1 mutations and correlated the lymphatic abnormalities against that imaged in an inducible Rasa1 knockout mouse. Whole-exome sequencing (WES) analysis and validation by Sanger sequencing of DNA from the patient and unaffected biological parents enabled us to identify an early-frameshift deletion in RASA1 that was shared with the father, who possessed a capillary stain but otherwise no overt disease phenotype. Abnormal lymphatic vasculature was imaged in both affected and unaffected legs of the PKWS subject that transported injected indocyanine green dye to the inguinal lymph node and drained atypically into the abdomen and into dermal lymphocele-like vesicles on the groin. Dermal lymphatic hyperplasia and dilated vessels were observed in Rasa1-deficient mice, with subsequent development of chylous ascites. WES analyses did not identify potential gene modifiers that could explain the variability of penetrance between father and son. Nonetheless, we conclude that the RASA1 mutation is responsible for the aberrant lymphatic architecture and functional abnormalities, as visualized in the PKWS subject and in the animal model. Our unique method to combine investigatory near-infrared fluorescence lymphatic imaging and WES for accurate phenoptyping and unbiased genotyping allows the study of molecular mechanisms of lymphatic involvement of hemovascular disorders. PMID- 23650394 TI - Structural plasticity of the cellular prion protein and implications in health and disease. AB - Two lines of transgenic mice expressing mouse/elk and mouse/horse prion protein (PrP) hybrids, which both form a well-structured beta2-alpha2 loop in the NMR structures at 20 degrees C termed rigid-loop cellular prion proteins (RL PrP(C)), presented with accumulation of the aggregated scrapie form of PrP in brain tissue, and the mouse/elk hybrid has also been shown to develop a spontaneous transmissible spongiform encephalopathy. Independently, there is in vitro evidence for correlations between the amino acid sequence in the beta2 alpha2 loop and the propensity for conformational transitions to disease-related forms of PrP. To further contribute to the structural basis for these observations, this paper presents a detailed characterization of RL-PrP(C) conformations in solution. A dynamic local conformational polymorphism involving the beta2-alpha2 loop was found to be evolutionarily preserved among all mammalian species, including those species for which the WT PrP forms an RL PrP(C). The interconversion between two ensembles of PrP(C) conformers that contain, respectively, a 310-helix turn or a type I beta-turn structure of the beta2-alpha2 loop, exposes two different surface epitopes, which are analyzed for their possible roles in the still evasive function of PrP(C) in healthy organisms and/or at the onset of a transmissible spongiform encephalopathy. PMID- 23650395 TI - Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels. AB - Pharmacological augmentation of neuronal KCNQ muscarinic (M) currents by drugs such as retigabine (RTG) represents a first-in-class therapeutic to treat certain hyperexcitatory diseases by dampening neuronal firing. Whereas all five potassium channel subtypes (KCNQ1-KCNQ5) are found in the nervous system, KCNQ2 and KCNQ3 are the primary players that mediate M currents. We investigated the plasticity of subtype selectivity by two M current effective drugs, retigabine and zinc pyrithione (ZnPy). Retigabine is more effective on KCNQ3 than KCNQ2, whereas ZnPy is more effective on KCNQ2 with no detectable effect on KCNQ3. In neurons, activation of muscarinic receptor signaling desensitizes effects by retigabine but not ZnPy. Importantly, reduction of phosphatidylinositol 4,5-bisphosphate (PIP2) causes KCNQ3 to become sensitive to ZnPy but lose sensitivity to retigabine. The dynamic shift of pharmacological selectivity caused by PIP2 may be induced orthogonally by voltage-sensitive phosphatase, or conversely, abolished by mutating a PIP2 site within the S4-S5 linker of KCNQ3. Therefore, whereas drug-channel binding is a prerequisite, the drug selectivity on M current is dynamic and may be regulated by receptor signaling pathways via PIP2. PMID- 23650396 TI - Biopolymer-reinforced synthetic granular nanocomposites for affordable point-of use water purification. AB - Creation of affordable materials for constant release of silver ions in water is one of the most promising ways to provide microbially safe drinking water for all. Combining the capacity of diverse nanocomposites to scavenge toxic species such as arsenic, lead, and other contaminants along with the above capability can result in affordable, all-inclusive drinking water purifiers that can function without electricity. The critical problem in achieving this is the synthesis of stable materials that can release silver ions continuously in the presence of complex species usually present in drinking water that deposit and cause scaling on nanomaterial surfaces. Here we show that such constant release materials can be synthesized in a simple and effective fashion in water itself without the use of electrical power. The nanocomposite exhibits river sand-like properties, such as higher shear strength in loose and wet forms. These materials have been used to develop an affordable water purifier to deliver clean drinking water at US $2.5/y per family. The ability to prepare nanostructured compositions at near ambient temperature has wide relevance for adsorption-based water purification. PMID- 23650397 TI - Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis. AB - Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms mediating these effects are poorly understood. Here we identify the glucocorticoid receptor (GR) target gene, serum- and glucocorticoid inducible kinase 1 (SGK1), as one such mechanism. Using a human hippocampal progenitor cell line, we found that a small molecule inhibitor for SGK1, GSK650394, counteracted the cortisol-induced reduction in neurogenesis. Moreover, gene expression and pathway analysis showed that inhibition of the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation. Experiments combining the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, demonstrated that SGK1 was involved in the cortisol-induced reduction in progenitor proliferation both downstream of GR, by regulating relevant target genes, and upstream of GR, by increasing GR function. Corroborating the relevance of these findings in clinical and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Our findings identify SGK1 as a mediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression. PMID- 23650398 TI - Impaired learning resulting from respiratory syncytial virus infection. AB - Respiratory syncytial virus (RSV) is the major cause of respiratory illness in infants worldwide. Neurologic alterations, such as seizures and ataxia, have been associated with RSV infection. We demonstrate the presence of RSV proteins and RNA in zones of the brain--such as the hippocampus, ventromedial hypothalamic nucleus, and brainstem--of infected mice. One month after disease resolution, rodents showed behavioral and cognitive impairment in marble burying (MB) and Morris water maze (MWM) tests. Our data indicate that the learning impairment caused by RSV is a result of a deficient induction of long-term potentiation in the hippocampus of infected animals. In addition, immunization with recombinant bacillus Calmette-Guerin (BCG) expressing RSV nucleoprotein prevented behavioral disorders, corroborating the specific effect of RSV infection over the central nervous system. Our findings provide evidence that RSV can spread from the airways to the central nervous system and cause functional alterations to the brain, both of which can be prevented by proper immunization against RSV. PMID- 23650399 TI - Motile invaded neutrophils in the small intestine of Toxoplasma gondii-infected mice reveal a potential mechanism for parasite spread. AB - Toxoplasma gondii infection occurs through the oral route, but we lack important information about how the parasite interacts with the host immune system in the intestine. We used two-photon laser-scanning microscopy in conjunction with a mouse model of oral T. gondii infection to address this issue. T. gondii established discrete foci of infection in the small intestine, eliciting the recruitment and transepithelial migration of neutrophils and inflammatory monocytes. Neutrophils accounted for a high proportion of actively invaded cells, and we provide evidence for a role for transmigrating neutrophils and other immune cells in the spread of T. gondii infection through the lumen of the intestine. Our data identify neutrophils as motile reservoirs of T. gondii infection and suggest a surprising retrograde pathway for parasite spread in the intestine. PMID- 23650400 TI - The posttranslational modification cascade to the thiopeptide berninamycin generates linear forms and altered macrocyclic scaffolds. AB - Berninamycin is a member of the pyridine-containing thiopeptide class of antibiotics that undergoes massive posttranslational modifications from ribosomally generated preproteins. Berninamycin has a 2-oxazolyl-3-thiazolyl pyridine core embedded in a 35-atom macrocycle rather than typical trithiazolylpyridine cores embedded in 26-atom and 29-atom peptide macrocycles. We describe the cloning of an 11-gene berninamycin cluster from Streptomyces bernensis UC 5144, its heterologous expression in Streptomyces lividans TK24 and Streptomyces venezuelae ATCC 10712, and detection of variant and incompletely processed scaffolds. Posttranslational maturation in S. lividans of both the wild type berninamycin prepeptide (BerA) and also a T3A mutant generates macrocyclic compounds as well as linear variants, which have failed to form the pyridine and the macrocycle. Expression of the gene cluster in S. venezuelae generates a variant of the 35-atom skeleton of berninamycin, containing a methyloxazoline in the place of a methyloxazole within the macrocyclic framework. PMID- 23650401 TI - Climate change frames debate over the extinction of megafauna in Sahul (Pleistocene Australia-New Guinea). AB - Around 88 large vertebrate taxa disappeared from Sahul sometime during the Pleistocene, with the majority of losses (54 taxa) clearly taking place within the last 400,000 years. The largest was the 2.8-ton browsing Diprotodon optatum, whereas the ~100- to 130-kg marsupial lion, Thylacoleo carnifex, the world's most specialized mammalian carnivore, and Varanus priscus, the largest lizard known, were formidable predators. Explanations for these extinctions have centered on climatic change or human activities. Here, we review the evidence and arguments for both. Human involvement in the disappearance of some species remains possible but unproven. Mounting evidence points to the loss of most species before the peopling of Sahul (circa 50-45 ka) and a significant role for climate change in the disappearance of the continent's megafauna. PMID- 23650402 TI - History, novelty, and emergence of an infectious amphibian disease. PMID- 23650403 TI - Growth differentiation factor 9:bone morphogenetic protein 15 (GDF9:BMP15) synergism and protein heterodimerization. PMID- 23650404 TI - Fibrinous pericardial effusion in a three-dimensional echocardiography. PMID- 23650405 TI - Visual loss in early-stage chronic lymphocytic leukemia. PMID- 23650406 TI - Severe liver and skin toxicity after radiation and vemurafenib in metastatic melanoma. PMID- 23650407 TI - Phosphatase and tensin homolog deficiency and resistance to trastuzumab and chemotherapy. PMID- 23650409 TI - Time to tumor growth: a model end point and new metric system for oncology clinical trials. PMID- 23650408 TI - Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. AB - PURPOSE: Effective and less aggressive therapies are required for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for or have undergone autologous stem-cell transplantation (ASCT). The present phase II study assessed the efficacy and safety of bendamustine plus rituximab (BR) in this population. PATIENTS AND METHODS: Patients with relapsed or refractory DLBCL treated with one to three prior chemotherapy regimens received rituximab 375 mg/m(2) intravenous (IV) infusion on day 1 and bendamustine 120 mg/m(2) by IV infusion on days 2 and 3 of each 21-day cycle for up to six cycles. The primary end point was overall response rate (ORR), and the secondary end points were complete response (CR) rate, progression-free survival (PFS), and safety. RESULTS: Sixty-three patients were enrolled, and 59 received BR. The median age was 67 years (range, 36 to 75 years), and 62.7% of patients were 65 years of age or older. Fifty-seven patients (96.6%) were previously treated with rituximab-containing chemotherapy. The ORR was 62.7% (95% CI, 49.1% to 75.0%), with a CR rate of 37.3% (95% CI, 25.0% to 50.9%). The ORRs were comparable between patients >= 65 years of age and less than 65 years (62.2% and 63.6%, respectively). The median PFS was 6.7 months (95% CI, 3.6 to 13.7 months). The most frequently observed grade 3 or 4 adverse events were hematologic: lymphopenia (78.0%), neutropenia (76.3%), leukopenia (72.9%), CD4 lymphopenia (66.1%), and thrombocytopenia (22.0%). CONCLUSION: BR is a promising salvage regimen for patients with relapsed or refractory DLBCL after rituximab-containing chemotherapy, warranting further investigation. PMID- 23650410 TI - Management of an unusual case of intravascular large B-cell lymphoma of the penis, prostate, and bones with CNS relapse. PMID- 23650411 TI - Evaluation of tumor-size response metrics to predict overall survival in Western and Chinese patients with first-line metastatic colorectal cancer. AB - PURPOSE: To assess new metrics of tumor-size response to predict overall survival (OS) in colorectal cancer (CRC) in Western and Chinese patients. PATIENTS AND METHODS: Various metrics of tumor-size response were estimated using longitudinal tumor size models and data from two phase III studies that compared bevacizumab plus chemotherapy versus chemotherapy as first-line therapy in Western (n = 923) and Chinese (n = 203) patients with CRC. Baseline prognostic factors and tumor size metrics estimates were assessed in multivariate models to predict OS. Predictive performances of the models were assessed by simulating multiple replicas of the phase III studies. RESULTS: Time to tumor growth (TTG) was the best metric to predict OS. TTG fully captured bevacizumab effect. Chinese ethnicity had no impact on OS or on the TTG-OS relationships. The model correctly predicted OS distributions in each arm as well as bevacizumab hazard ratio (model prediction, 0.75 v 0.68 observed in Western patients; 95% prediction interval, 0.62 to 0.91). CONCLUSION: TTG captured therapeutic benefit with bevacizumab in first-line CRC patients. Chinese ethnicity had no impact. Longitudinal tumor size data coupled with model-based approaches may offer a powerful alternative in the design and analysis of early clinical studies. PMID- 23650413 TI - Epiphora and canalicular stenosis associated with adjuvant docetaxel in early breast cancer: is excessive tearing clinically important? PMID- 23650412 TI - Impact of PTEN protein expression on benefit from adjuvant trastuzumab in early stage human epidermal growth factor receptor 2-positive breast cancer in the North Central Cancer Treatment Group N9831 trial. AB - PURPOSE: It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) -positive trial-North Central Cancer Treatment Group (NCCTG) N9831. PATIENTS AND METHODS: The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with >= 1+ staining. Median follow-up was 6.0 years. RESULTS: Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN positive tumors. PTEN positivity was associated with hormone receptor negativity (chi(2) P < .001) and nodal positivity (chi(2) P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). CONCLUSION: In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status. PMID- 23650414 TI - Molecular cytogenetics and multiplex reverse-transcriptase polymerase chain reaction for risk stratification in acute myeloid leukemia. PMID- 23650415 TI - MicroRNA dysregulation in acute myeloid leukemia. PMID- 23650416 TI - Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. AB - PURPOSE: Entinostat is an oral isoform selective histone deacetylase inhibitor that targets resistance to hormonal therapies in estrogen receptor-positive (ER+) breast cancer. This randomized, placebo-controlled, phase II study evaluated entinostat combined with the aromatase inhibitor exemestane versus exemestane alone. PATIENTS AND METHODS: Postmenopausal women with ER+ advanced breast cancer progressing on a nonsteroidal aromatase inhibitor were randomly assigned to exemestane 25 mg daily plus entinostat 5 mg once per week (EE) or exemestane plus placebo (EP). The primary end point was progression-free survival (PFS). Blood was collected in a subset of patients for evaluation of protein lysine acetylation as a biomarker of entinostat activity. RESULTS: One hundred thirty patients were randomly assigned (EE group, n = 64; EP group, n = 66). Based on intent-to-treat analysis, treatment with EE improved median PFS to 4.3 months versus 2.3 months with EP (hazard ratio [HR], 0.73; 95% CI, 0.50 to 1.07; one sided P = .055; two-sided P = .11 [predefined significance level of .10, one sided]). Median overall survival was an exploratory end point and improved to 28.1 months with EE versus 19.8 months with EP (HR, 0.59; 95% CI, 0.36 to 0.97; P = .036). Fatigue and neutropenia were the most frequent grade 3/4 toxicities. Treatment discontinuation because of adverse events was higher in the EE group versus the EP group (11% v 2%). Protein lysine hyperacetylation in the EE biomarker subset was associated with prolonged PFS. CONCLUSION: Entinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ER+ advanced breast cancer in this signal-finding phase II study. Acetylation changes may provide an opportunity to maximize clinical benefit with entinostat. Plans for a confirmatory study are underway. PMID- 23650418 TI - Appropriateness and right price: an inseparable binomial to improve care and reduce cost. PMID- 23650417 TI - Use of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and risk of breast cancer recurrence: a Danish nationwide prospective cohort study. AB - PURPOSE: To estimate associations between use of beta-blockers, angiotensin converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs) and breast cancer recurrence in a large Danish cohort. PATIENTS AND METHODS: We enrolled 18,733 women diagnosed with nonmetastatic breast cancer between 1996 and 2003. Patient, treatment, and 10-year recurrence data were ascertained from the Danish Breast Cancer Cooperative Group registry. Prescription and medical histories were ascertained by linkage to the National Prescription Registry and Registry of Patients, respectively. beta-Blocker exposure was defined in aggregate and according to solubility, receptor selectivity, and individual drugs. ACE inhibitor and ARB exposures were defined in aggregate. Recurrence associations were estimated with multivariable Cox regression models in which time-varying drug exposures were lagged by 1 year. RESULTS: Compared with never users, users of any beta-blocker had a lower recurrence hazard in unadjusted models (unadjusted hazard ratio [HR] = 0.91; 95% CI, 0.81 to 1.0) and a slightly higher recurrence hazard in adjusted models (adjusted HR = 1.3; 95% CI, 1.1 to 1.5). Associations were similar for exposures defined by receptor selectivity and solubility. Although most individual beta-blockers showed no association with recurrence, metoprolol and sotalol were associated with increased recurrence rates (adjusted metoprolol HR = 1.5, 95% CI, 1.2 to 1.8; adjusted sotalol HR = 2.0, 95% CI, 0.99 to 4.0). ACE inhibitors were associated with a slightly increased recurrence hazard, whereas ARBs were not associated with recurrence (adjusted ACE inhibitor HR = 1.2, 95% CI, 0.97 to 1.4; adjusted ARBs HR = 1.1, 95% CI, 0.85 to 1.3). CONCLUSION: Our data do not support the hypothesis that beta-blockers attenuate breast cancer recurrence risk. PMID- 23650419 TI - miR-155 in acute myeloid leukemia: not merely a prognostic marker? PMID- 23650420 TI - Questionable validity of cardiac risk score on the basis of the NSABP B-31 model. PMID- 23650421 TI - Prevalence of excessive tearing in women with early breast cancer receiving adjuvant docetaxel-based chemotherapy. AB - PURPOSE: To define the incidence and impact of tearing in patients receiving adjuvant docetaxel-based chemotherapy and assess for lacrimal duct obstruction (LDO) as a causative factor. PATIENTS AND METHODS: Consecutive patients with early breast cancer recommended for docetaxel-based chemotherapy with no prior ocular symptoms were included. Before and after completion of chemotherapy, patients underwent lacrimal drainage evaluation by computed tomographic dacrocystography (CT-DCG) and ophthalmic assessment. Eye symptoms were assessed at baseline, during, and after completion of chemotherapy. RESULTS: Over a 22 month period, 100 patients were recruited. Asymptomatic LDO was present at baseline in 17% and 18% of patients, as assessed by ophthalmic review and CT-DCG, respectively. Overall, 86% of patients developed tearing, with no significant difference between those who did and did not have LDO (94% v 84%; P = .45). Blepharitis occurred in 37% and minor corneal epitheliopathy in 22% of patients, with neither condition predicting for the development of tearing. Impairment of visual activities was greatest after cycle one (70% of patients) but had decreased to < 5% by 4 months after treatment. CONCLUSION: Tearing occurs in the majority of patients receiving adjuvant docetaxel-based chemotherapy regimens and occurred similarly in patients with and without LDO. There was poor concordance between CT-DCG and ophthalmic examination in the detection of LDO. Tearing and other eye symptoms impaired visual activities, but in nearly all patients, both symptoms and functional impairment were mild and had resolved by 4 months after chemotherapy. Our study demonstrates docetaxel-related tearing is not caused by LDO, and as such, evaluation or stenting of the duct is not considered necessary. PMID- 23650422 TI - Genetic mediators of neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia. AB - PURPOSE: Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for neurocognitive problems, with significant interindividual variability in outcome. This study examined genetic polymorphisms associated with variability in neurocognitive outcome. PATIENTS AND METHODS: Neurocognitive outcomes were evaluated at the end of therapy in 243 survivors treated on an institutional protocol featuring risk-adapted chemotherapy without prophylactic cranial irradiation. Polymorphisms in genes related to pharmacokinetics or pharmacodynamics of antileukemic agents, drug metabolism, oxidative stress, and attention problems in noncancer populations were examined as predictors of outcome, using multiple general linear models and controlling for age at diagnosis, sex, race, and treatment intensity. RESULTS: Compared with national norms, the cohort demonstrated significantly higher rates of problems on direct assessment of sustained attention (P = .01) and on parent ratings of attention problems (P = .02). Children with the A2756G polymorphism in methionine synthase (MS) were more likely to demonstrate deficits in attentiveness (P = .03) and response speed (P = .02), whereas those with various polymorphisms in glutathione S-transferase demonstrated increased performance variability (P = .01) and reduced attentiveness (P = .003). Polymorphisms in monoamine oxidase (T1460CA) were associated with increased attention variability (P = .03). Parent-reported attention problems were more common in children with the Cys112Arg polymorphism in apoliopoprotein E4 (P = .01). CONCLUSION: These results are consistent with our previous report of association between attention problems and MS in an independent cohort of long-term survivors of childhood ALL treated with chemotherapy only. The results also raise the possibility of an impact from genetic predispositions related to oxidative stress and CNS integrity. PMID- 23650423 TI - Ovarian cancer incidence trends in relation to changing patterns of menopausal hormone therapy use in the United States. AB - PURPOSE: After a report from the Women's Health Initiative (WHI) in 2002, a precipitous decline in menopausal hormonal therapy (MHT) use in the United States was linked to a decline in breast cancer incidence rates. Given that MHT use is also associated with increased ovarian cancer risk, we tested whether ovarian cancer incidence rates changed after 2002. METHODS: Using the North American Association of Central Cancer Registries database (1995 to 2008; N = 171,142 incident ovarian cancers), we applied standard analytic approaches and age-period cohort (APC) models to estimate ovarian cancer incidence rate changes before (1995 to 2002) and after (2003 to 2008) the WHI report. RESULTS: Among women age >= 50 years, age-standardized ovarian cancer incidence declined by 0.8% per year (95% CI, -1.8% to -0.5% per year) before the WHI announcement; after the WHI report, the rate declined by 2.4% per year (95% CI, -2.5% to -2.2% per year). APC models confirmed an accelerated decline in ovarian cancer incidence after the WHI report, adjusted for age and birth cohort effects. This sudden change was notable among women most likely to have used MHT (ie, women age 50 to 69 years, white women, and residents of regions with highest MHT prescription frequency). The largest changes were found for the endometrioid histologic subtype. CONCLUSION: After a marked reduction in MHT use around 2002, ovarian cancer incidence rates demonstrated an accelerated decline, with the largest changes for endometrioid carcinomas. This strong temporal association, although not proving a causal role of hormones in ovarian carcinogenesis, suggests that future analytic research supporting cancer control efforts should clarify the role of hormonal exposures on the development and behavior of subtypes of ovarian cancer. PMID- 23650425 TI - Trajectories of psychological distress in adolescent and young adult patients with cancer: a 1-year longitudinal study. AB - PURPOSE: To examine prevalence and changes in symptoms of psychological distress over 1 year after initial cancer diagnosis in adolescent and young adult (AYA) patients with cancer. Sociodemographic and clinical predictors of changes in distress were examined. PATIENTS AND METHODS: In this multisite, longitudinal, prospective study of an ethnically diverse sample, 215 patients age 14 to 39 years were assessed for psychological distress within the first 4 months of diagnosis and again 6 and 12 months later. Linear mixed models with random intercept and slope estimated changes in distress, as measured by the Brief Symptom Inventory-18 (BSI-18). RESULTS: Within the first 4 months of diagnosis, 60 respondents (28%) had BSI-18 scores suggesting caseness for distress. On average, distress symptoms exceeded population norms at the time of diagnosis, dipped at the 6-month follow-up, but increased to a level exceeding population norms at the 12-month follow-up. A statistically significant decline in distress over 1 year was observed; however, the gradient of change was not clinically significant. Multivariate analyses revealed that the reduction in distress over time was primarily a function of being off treatment and involved in school or work. Notably, cancer type or severity was not associated with distress. CONCLUSION: Findings emphasize the importance of early psychosocial intervention for distress in AYAs as well as the need to manage treatment-related symptoms and facilitate AYAs' involvement in work or school to the extent possible. Continued research is needed to understand how distress relates to quality of life, functional outcomes, treatment, and symptom burden throughout the continuum of care. PMID- 23650424 TI - Clinical role of microRNAs in cytogenetically normal acute myeloid leukemia: miR 155 upregulation independently identifies high-risk patients. AB - PURPOSE: To evaluate the impact of miR-155 on the outcome of adults with cytogenetically normal (CN) acute myeloid leukemia (AML) in the context of other clinical and molecular prognosticators and to gain insight into the leukemogenic role of this microRNA. PATIENTS AND METHODS: We evaluated 363 patients with primary CN-AML. miR-155 levels were measured in pretreatment marrow and blood by NanoString nCounter assays that quantified the expression of the encoding gene MIR155HG. All molecular prognosticators were assessed centrally. miR-155 associated gene and microRNA expression profiles were derived using microarrays. RESULTS: Considering all patients, high miR-155 expression was associated with a lower complete remission (CR) rate (P < .001) and shorter disease-free survival (P = .001) and overall survival (OS; P < .001) after adjusting for age. In multivariable analyses, high miR-155 expression remained an independent predictor for a lower CR rate (P = .007) and shorter OS (P < .001). High miR-155 expressers had approximately 50% reduction in the odds of achieving CR and 60% increase in the risk of death compared with low miR-155 expressers. Although high miR-155 expression was not associated with a distinct microRNA expression profile, it was associated with a gene expression profile enriched for genes involved in cellular mechanisms deregulated in AML (eg, apoptosis, nuclear factor-kappaB activation, and inflammation), thereby supporting a pivotal and unique role of this microRNA in myeloid leukemogenesis. CONCLUSION: miR-155 expression levels are associated with clinical outcome independently of other strong clinical and molecular predictors. The availability of emerging compounds with antagonistic activity to microRNAs in the clinic provides the opportunity for future therapeutic targeting of miR-155 in AML. PMID- 23650426 TI - Integrating molecular biology into clinical practice. PMID- 23650427 TI - Health-related quality of life of adolescent and young adult patients with cancer in the United States: the Adolescent and Young Adult Health Outcomes and Patient Experience study. AB - PURPOSE: Adolescents and young adults (AYAs) diagnosed with cancer face numerous physical, psychosocial, and practical challenges. This article describes the health-related quality of life (HRQOL) and associated demographic and health related characteristics of this developmentally diverse population. PATIENTS AND METHODS: Data are from the Adolescent and Young Adult Health Outcomes and Patient Experience (AYA HOPE) study, a population-based cohort of 523 AYA patients with cancer, ages 15 to 39 years at diagnosis from 2007 to 2009. Comparisons are made by age group and with general and healthy populations. Multiple linear regression models evaluated effects of demographic, disease, health care, and symptom variables on multiple domains of HRQOL using the Pediatric Quality of Life Inventory (PedsQL) and the Short-Form Health Survey 12 (SF-12). RESULTS: Overall, respondents reported significantly worse HRQOL across both physical and mental health scales than did general and healthy populations. The greatest deficits were in limitations to physical and emotional roles, physical and social functioning, and fatigue. Teenaged patients (ages 15 to 17 years) reported worse physical and work/school functioning than patients 18 to 25 years old. Regression models showed that HRQOL was worse for those in treatment, with current/recent symptoms, or lacking health insurance at any time since diagnosis. In addition, sarcoma patients, Hispanic patients, and those with high school or lower education reported worse physical health. Unmarried patients reported worse mental health. CONCLUSION: Results suggest that AYAs with cancer have major decrements in several physical and mental HRQOL domains. Vulnerable subgroups included Hispanic patients, those with less education, and those without health insurance. AYAs also experienced higher levels of fatigue that were influenced by current symptoms and treatment. Future research should explore ways to address poor functioning in this understudied group. PMID- 23650428 TI - Cancer drugs in the United States: Justum Pretium--the just price. PMID- 23650429 TI - Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. AB - PURPOSE: Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. PATIENTS AND METHODS: Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8(+)-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. RESULTS: Thirty-four patients received unselected young TILs with a median of 8.0% CD4(+) lymphocytes, and 35 patients received CD8(+)-enriched TILs with a median of 0.3% CD4(+) lymphocytes. One month after TIL infusion, patients who received CD8(+)-enriched TILs had significantly fewer CD4(+) peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8(+)-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8(+)-enriched TILs responded. CONCLUSION: A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8(+) enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs. PMID- 23650430 TI - Efficacy of high-flow oxygen by nasal cannula with active humidification in a patient with acute respiratory failure of neuromuscular origin. AB - The treatment of choice for patients with respiratory failure of neuromuscular origin, especially in patients with hypercapnic respiratory acidosis, is noninvasive ventilation (NIV). Endotracheal intubation and invasive ventilation are indicated for patients with severe respiratory compromise or failure of NIV. In recent years, high-flow oxygen therapy and active humidification devices have been introduced, and emerging evidence suggests that high-flow oxygen may be effective in various clinical settings, such as acute respiratory failure, after cardiac surgery, during sedation and analgesia, in acute heart failure, in hypoxemic respiratory distress, in do-not-intubate patients, in patients with chronic cough and copious secretions, pulmonary fibrosis, or cancer, in critical areas and the emergency department. We report on a patient with amyotrophic lateral sclerosis who arrived at the emergency department with acute hypercapnic respiratory failure. She did not tolerate NIV and refused intubation, but was treated successfully with heated, humidified oxygen via high-flow nasal cannula. Arterial blood analysis after an hour on high-flow nasal cannula showed improved pH, P(aCO2), and awareness. The respiratory acidosis was corrected, and she was discharged after 5 days of hospitalization. Her response to high-flow nasal cannula was similar to that expected with NIV. We discuss the mechanisms of action of heated, humidified high-flow oxygen therapy. PMID- 23650431 TI - The adjunctive effect of nebulized furosemide in COPD exacerbation: a randomized controlled clinical trial. AB - OBJECTIVE: To examine the effect of nebulized furosemide as an adjunct to the conventional treatment of patients with COPD exacerbation in an emergency department. METHODS: In this randomized double-blinded clinical trial, patients with COPD exacerbation were randomized to receive 40 mg nebulized furosemide or placebo as an adjunct to the conventional treatments. We recorded changes in dyspnea severity (measured with a visual analog scale), FEV1, arterial blood gas measurements, blood pressure, heart rate, and breathing frequency at baseline and 1 hour after treatment. RESULTS: We randomized 100 patients, whose mean age was 73.1 +/- 8.7 y. The measured variables all improved significantly in both groups. FEV1, dyspnea, pH, mean blood pressure, and heart rate improved significantly more in the furosemide group. CONCLUSIONS: Nebulized furosemide benefits patients with COPD exacerbation. PMID- 23650432 TI - Effect of heliox on end-tidal CO2 measurement in healthy adults. AB - BACKGROUND: Therapeutic gases and other modalities delivered by inhalation may affect the accuracy of capnographic measurements in 2 ways. First is the specificity of the measurement of CO2 within the device, and second is the dilution effect of supplemental gases in the ambient air during CO2 sampling by the device. Our goal was to determine if variables such as inhaled gas composition, gas flows delivered via non-rebreather mask, and mouth open or closed affect measurements of end-tidal CO2 pressure (PETCO2) measured with the Capnostream 20 capnograph. METHODS: We measured PETCO2 and breathing frequency by capnography in 20 adult normal subjects, with coaching to maintain respiratory frequency between 10 and 20 breaths/min. SpO2 was monitored to detect hypoxemia. A 6 min wash-out period occurred between each 6 min level of testing. RESULTS: A mixed models analysis revealed that the mean +/- SD PETCO2 for all subjects and flows while breathing heliox (37 +/- 5 mm Hg) was not different (P = .50) from the value while breathing room air (36 +/- 5 mm Hg). Repeated measurements with given subjects over 6 min periods of breathing spontaneously 0 L/min, with 10 L/min, and with 15 L/min of either air or heliox showed no difference in PETCO2 related to flow: P = .97 for 0 L/min vs 10 L/min, P = .87 for 0 L/min vs. 15 L/min. CONCLUSIONS: In normal subjects, PETCO2 measurements with the Capnostream 20 were not affected by heliox or gas flow at 10 or 15 L/min through a non rebreathing mask. PMID- 23650433 TI - Influence of the admission pattern on the outcome of patients admitted to a respiratory intensive care unit: does a step-down admission differ from a step-up one? AB - BACKGROUND: The outcomes of patients admitted to a respiratory ICU (RICU) have been evaluated in the past, but no study has considered the influence of location prior to RICU admission. METHODS: We analyzed prospectively collected data from 326 consecutive patients admitted to a 7-bed RICU. The primary end points were survival and severity of morbidity-related complications, evaluated according to the patient's location prior to RICU admission. Three admission pathways were considered: step-down for patients transferred from the ICUs of our hospital; step-up for patients coming from our respiratory wards or other medical wards; and directly for patients coming from the emergency department. The secondary end point was the potential influence of several risk factors for morbidity and mortality. RESULTS: Of the 326 subjects, 92 (28%) died. Overall, subjects admitted in a step-up process had a significantly higher mortality (P < .001) than subjects in the other groups. The mortality rate was 64% for subjects admitted from respiratory ward, 43% for those from medical wards, and 18% for subjects from both ICU and emergency department (respiratory ward vs medical ward P = .04, respiratory ward vs emergency department P < .001, respiratory ward vs ICU P < .001, medical ward vs emergency department P < .001, and medical ward vs ICU P < .001). Subjects admitted from a respiratory ward had a lower albumin level, and Simplified Acute Physiology Score II was significantly higher in subjects following a step-up admission. About 30% of the subjects admitted from a respiratory ward received noninvasive ventilation as a "ceiling treatment." The highest odds ratios related to survival were subject location prior to RICU admission and female sex. Lack of use of noninvasive ventilation, younger age, female sex, higher albumin level, lower Simplified Acute Physiology Score II, higher Barthel score, and absence of chronic heart failure were also statistically associated with a lower risk of death. CONCLUSIONS: The pathway of admission to a RICU is a determinant of outcome. Patients following a step-up pattern are more likely to die. Other major determinants of survival are age, nutritional status and female sex. PMID- 23650434 TI - High resource utilization does not affect mortality in acute respiratory failure patients managed with tracheostomy. AB - BACKGROUND: Tracheostomy practice in patients with acute respiratory failure (ARF) varies greatly among institutions. This variability has the potential to be reflected in the resources expended providing care. In various healthcare environments, increased resource expenditure has been associated with a favorable effect on outcome. OBJECTIVE: To examine the association between institutional resource expenditure and mortality in ARF patients managed with tracheostomy. METHODS: We developed analytic models employing the University Health Systems Consortium (Oakbrook, Illinois) database. Administrative coding data were used to identify patients with the principal diagnosis of ARF, procedures, complications, post-discharge destination, and survival. Mean resource intensity of participating academic medical centers was determined using risk-adjusted estimates of costs. Mortality risk was determined using a multivariable approach that incorporated patient-level demographic and clinical variables and institution-level resource intensity. RESULTS: We analyzed data from 44,124 ARF subjects, 4,776 (10.8%) of whom underwent tracheostomy. Compared to low-resource intensity settings, treatment in high-resource-intensity academic medical centers was associated with increased risk of mortality (odds ratio 1.11, 95% CI 1.05 1.76), including those managed with tracheostomy (odds ratio high-resource intensity academic medical center with tracheostomy 1.10, 95% CI 1.04-1.17). We examined the relationship between complication development and outcome. While neither the profile nor number of complications accumulated differed comparing treatment environments (P > .05 for both), mortality for tracheostomy patients experiencing complications was greater in high-resource-intensity (95/313, 30.3%) versus low-resource-intensity (552/2,587, 21.3%) academic medical centers (P < .001). CONCLUSIONS: We were unable to demonstrate a positive relationship between resource expenditure and outcome in ARF patients managed with tracheostomy. PMID- 23650435 TI - A lesson from a rare cause of pulmonary embolism. PMID- 23650436 TI - Thoracic ultrasound-assisted selection for pleural biopsy with Abrams needle. AB - BACKGROUND: Closed pleural biopsy (CPB) in patients with malignant pleural effusion is less sensitive than cytology. Ultrasound-assisted CPB allows biopsies to be performed in the lower thoracic parietal pleura, where secondary spread from pleural metastases is initially more likely to be found. We analyzed whether choosing the point of entry for CPB with thoracic ultrasound assistance influences the diagnostic yield in malignant pleural effusion. METHODS: This prospective study included patients who underwent CPB performed by an experienced pulmonologist in 2008-2010 (group A) and thoracic ultrasound was used to select the biopsy site. The results were compared with a historical series of CPB performed by the same pulmonologist without the assistance of thoracic ultrasound (group B). An Abrams needle was used in all cases. We analyzed the obtaining of pleural tissue and the diagnostic yield. RESULTS: We included 114 CPBs from group A (23% tuberculous pleural effusion, 27% malignant pleural effusion) and 67 CPBs from group B (24% tuberculous pleural effusion, 30% malignant pleural effusion) (P = .70). Pleural tissue was obtained in 96.5% of the group A CPBs and 89.6% of the group B CPBs (P = .05). The diagnostic yields of CPB for tuberculous pleural effusion and malignant pleural effusion in group A were 89.5% and 77.4%, respectively, and 91.7% and 60%, respectively, in group B (P = .80 for tuberculous pleural effusion, and P = .18 for malignant pleural effusion). CONCLUSIONS: Selecting the point of entry for CPB using thoracic ultrasound increases the likelihood of obtaining pleural tissue and the diagnostic yield, but without statistical significance. We recommend ultrasound-assisted CPB to investigate pleural effusion, since the diagnostic yield of a pleural biopsy with an Abrams needle increased by > 17% in subjects with malignant pleural effusion. PMID- 23650437 TI - Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins. AB - Endoplasmic reticulum (ER) stress in intestinal secretory cells has been linked with colitis in mice and inflammatory bowel disease (IBD). Endogenous intestinal glucocorticoids are important for homeostasis and glucocorticoid drugs are efficacious in IBD. In Winnie mice with intestinal ER stress caused by misfolding of the Muc2 mucin, the glucocorticoid dexamethasone (DEX) suppressed ER stress and activation of the unfolded protein response (UPR), substantially restoring goblet cell Muc2 production. In mice lacking inflammation, a glucocorticoid receptor antagonist increased ER stress, and DEX suppressed ER stress induced by the N-glycosylation inhibitor, tunicamycin (Tm). In cultured human intestinal secretory cells, in a glucocorticoid receptor-dependent manner, DEX suppressed ER stress and UPR activation induced by blocking N-glycosylation, reducing ER Ca(2+) or depleting glucose. DEX up-regulated genes encoding chaperones and elements of ER-associated degradation (ERAD), including EDEM1. Silencing EDEM1 partially inhibited DEX's suppression of misfolding-induced ER stress, showing that DEX enhances ERAD. DEX inhibited Tm-induced MUC2 precursor accumulation, promoted production of mature mucin, and restored ER exit and secretion of Winnie mutant recombinant Muc2 domains, consistent with enhanced protein folding. In IBD, glucocorticoids are likely to ameliorate ER stress by promoting correct folding of secreted proteins and enhancing removal of misfolded proteins from the ER. PMID- 23650438 TI - TNF receptor associated factor 3 plays a key role in development and function of invariant natural killer T cells. AB - TCR signaling is a prerequisite for early stage development of invariant natural killer T (iNKT) cells, whereas IL-15 signaling is required for expansion and maturation at later stages. In this study, we show that TNF receptor associated factor 3 (TRAF3) plays a critical role in the transition between these two distinct signaling pathways and developmental stages. TRAF3-deficient iNKT cells in CD4(Cre)TRAF3(flox/flox) (T-TRAF3(-/-)) mice exhibit defective up-regulation of T-bet and CD122, two critical molecules for IL-15 signaling, and as a consequence, IL-15-mediated iNKT cell proliferation and survival are impaired. Consistently, development of iNKT cells in T-TRAF3(-/-) mice shows a major defect at developmental stages 2 and 3, but not stages 0 and 1. We further demonstrated that defective T-bet up-regulation occurring during the stage 1 to stage 2 transition results from reduced TCR signaling in TRAF3(-/-) iNKT cells. In addition, mature TRAF3(-/-) iNKT cells displayed defective cytokine responses upon TCR stimulation. Collectively, our results reveal that by modulating the relative strength of TCR signaling, TRAF3 is an important regulator of iNKT cell development and functions. PMID- 23650439 TI - IL-2-dependent adaptive control of NK cell homeostasis. AB - Activation and expansion of T and B lymphocytes and myeloid cells are controlled by Foxp3(+) regulatory T cells (T reg cells), and their deficiency results in a fatal lympho- and myeloproliferative syndrome. A role for T reg cells in the homeostasis of innate lymphocyte lineages remained unknown. Here, we report that T reg cells restrained the expansion of immature CD127(+) NK cells, which had the unique ability to up-regulate the IL2Ralpha (CD25) in response to the proinflammatory cytokine IL-12. In addition, we observed the preferential accumulation of CD127(+) NK cells in mice bearing progressing tumors or suffering from chronic viral infection. CD127(+) NK cells expanded in an IL-2-dependent manner upon T reg cell depletion and were able to give rise to mature NK cells, indicating that the latter can develop through a CD25(+) intermediate stage. Thus, T reg cells restrain the IL-2-dependent CD4(+) T cell help for CD127(+) immature NK cells. These findings highlight the adaptive control of innate lymphocyte homeostasis. PMID- 23650440 TI - Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2. AB - Regulatory T (T reg) cells control progression to autoimmune diabetes in the BDC2.5/NOD mouse model by reining in natural killer (NK) cells that infiltrate the pancreatic islets, inhibiting both their proliferation and production of diabetogenic interferon-gamma. In this study, we have explored the molecular mechanisms underlying this NK-T reg cell axis, following leads from a kinetic exploration of gene expression changes early after punctual perturbation of T reg cells in BDC2.5/NOD mice. Results from gene signature analyses, quantification of STAT5 phosphorylation levels, cytokine neutralization experiments, cytokine supplementation studies, and evaluations of intracellular cytokine levels collectively argue for a scenario in which T reg cells regulate NK cell functions by controlling the bioavailability of limiting amounts of IL-2 in the islets, generated mainly by infiltrating CD4(+) T cells. This scenario represents a previously unappreciated intertwining of the innate and adaptive immune systems: CD4(+) T cells priming NK cells to provoke a destructive T effector cell response. Our findings highlight the need to consider potential effects on NK cells when designing therapeutic strategies based on manipulation of IL-2 levels or targets. PMID- 23650441 TI - IL-2-dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells. AB - The emergence of the adaptive immune system took a toll in the form of pathologies mediated by self-reactive cells. Regulatory T cells (T reg cells) exert a critical brake on responses of T and B lymphocytes to self- and foreign antigens. Here, we asked whether T reg cells are required to restrain NK cells, the third lymphocyte lineage, whose features combine innate and adaptive immune cell properties. Although depletion of T reg cells led to systemic fatal autoimmunity, NK cell tolerance and reactivity to strong activating self- and non self-ligands remained largely intact. In contrast, missing-self responses were increased in the absence of T reg cells as the result of heightened IL-2 availability. We found that IL-2 rapidly boosted the capacity of NK cells to productively engage target cells and enabled NK cell responses to weak stimulation. Our results suggest that IL-2-dependent adaptive-innate lymphocyte cross talk tunes NK cell reactivity and that T reg cells restrain NK cell cytotoxicity by limiting the availability of IL-2. PMID- 23650442 TI - Measurement Error Case Series Models with Application to Infection-Cardiovascular Risk in OlderPatients on Dialysis. AB - Infection and cardiovascular disease are leading causes of hospitalization and death in older patients on dialysis. Our recent work found an increase in the relative incidence of cardiovascular outcomes during the ~ 30 days after infection-related hospitalizations using the case series model, which adjusts for measured and unmeasured baseline confounders. However, a major challenge in modeling/assessing the infection-cardiovascular risk hypothesis is that the exact time of infection, or more generally "exposure," onsets cannot be ascertained based on hospitalization data. Only imprecise markers of the timing of infection onsets are available. Although there is a large literature on measurement error in the predictors in regression modeling, to date there is no work on measurement error on the timing of a time-varying exposure to our knowledge. Thus, we propose a new method, the measurement error case series (MECS) models, to account for measurement error in time-varying exposure onsets. We characterized the general nature of bias resulting from estimation that ignores measurement error and proposed a bias-corrected estimation for the MECS models. We examined in detail the accuracy of the proposed method to estimate the relative incidence. Hospitalization data from United States Renal Data System, which captures nearly all (> 99%) patients with end-stage renal disease in the U.S. over time, is used to illustrate the proposed method. The results suggest that the estimate of the cardiovascular incidence following the 30 days after infections, a period where acute effects of infection on vascular endothelium may be most pronounced, is substantially attenuated in the presence of infection onset measurement error. PMID- 23650443 TI - From P0 to P6 medicine, a model of highly participatory, narrative, interactive, and "augmented" medicine: some considerations on Salvatore Iaconesi's clinical story. AB - Salvatore Iaconesi was recently diagnosed with a brain tumor. He decided to share his clinical records not only with doctors but with everybody who wishes to find him a cure. "Because cure is not unique," he emphasizes "there are cures for the body and cures for the soul, and everyone, from a painter to a musician, can find me a cure. Please, feel free to take my clinical history for example and let it become a game, a video, a music, a picture, whatever you like." The emblematic hallmark of the changing times, Salvatore Iaconesi's case is an example of how many profound revolutions and steps medicine has undertaken during the past few centuries. Stemming from a form of remote medical paternalism and arriving at the concept of a therapeutic alliance, medicine nowadays faces challenges and opportunities at a level before unforeseeable and unimaginable. The new concept of P6 medicine (personalized, predictive, preventive, participatory, psychocognitive, and public) is discussed, together with its profound implications. PMID- 23650444 TI - Onset, longevity, and patient satisfaction with incobotulinumtoxinA for the treatment of glabellar frown lines: a single-arm, prospective clinical study. AB - BACKGROUND: IncobotulinumtoxinA (Bocouture((r))) is free from complexing proteins and effective for treating glabellar frown lines. PURPOSE: To determine the efficacy, onset, and duration of action of incobotulinumtoxinA for the treatment of glabellar frown lines. PATIENTS AND METHODS: In this single-arm, prospective, proof-of-concept study, 23 patients were treated with 25 U incobotulinumtoxinA, equally split between five injection sites in the glabella. Severity of glabellar frown lines was rated by an independent rater from standardized photographs using the validated Merz 5-point scale at several visits over 5 months following treatment. To assess patient satisfaction, patients completed a questionnaire before and 2 weeks after treatment. RESULTS: The percentage of responders at maximum frown 2-4 days after treatment was 95.2% and 85.0% when responders were defined as patients with >= 1-point and >= 2-point improvement on the 5-point scale compared with baseline, respectively. At this time point, 84% of the maximum effect had occurred. The responder rate at maximum frown, according to both definitions, was 100% for at least the next two visits (days 8 +/- 1 and 14 +/- 2). At all visits, the change from baseline in the mean glabellar frown-line score at maximum frown was statistically significant, with on average an almost 1 point improvement from baseline 5 months after treatment. CONCLUSION: IncobotulinumtoxinA is an effective and well-tolerated treatment for glabellar frown lines, with a rapid onset of action and a long duration of effect lasting for more than 5 months. PMID- 23650445 TI - Long-term survival for COPD patients receiving noninvasive ventilation for acute respiratory failure. AB - Implementation of noninvasive ventilation (NIV) as an add-on treatment has been routinely used in a non-intensive care setting since 2004 for patients with chronic obstructive pulmonary disease (COPD) and acute hypercapnic respiratory failure at a university hospital in Denmark. Although randomized controlled trials show lowered mortality rates in highly selected patients with acute exacerbation and respiratory failure, there are only few reports on long-term survival after receiving NIV. We present long-term all-cause mortality data from patients receiving NIV for the first time. METHOD: Data from medical records were retrospectively retrieved from all patients receiving NIV for the first time after being admitted acutely to an acute medical ward and further transfer to a respiratory ward with respiratory failure and a diagnosis of COPD in the period January 1, 2005 to December 31, 2007; patients were followed until January 2012. Demographic data collected included age, sex, diagnoses at discharge, and, when present, FEV1; a "not-to-intubate" order was also registered when listed. RESULTS: In total, 253 patients (143 female, 110 male) received NIV for the first time. The median age was 72 years (range 46-91 years). The 30-day mortality rate was 29.3%. The 5-year survival rate was 23.7%. Women showed a trend towards better survival than men (25.7% vs 19.2%, P = 0.25), and the trend was even more pronounced for patients with COPD. CONCLUSION: The mortality rate of patients receiving NIV is high, as expected in a real-life setting, but with a 5-year survival rate of 23.7% with a trend towards more female than male long-term survivors. PMID- 23650446 TI - Double-blind, comparative study of milnacipran and paroxetine in Japanese patients with major depression. AB - BACKGROUND AND METHODS: A double-blind, parallel-group, controlled study was performed to investigate if milnacipran was noninferior to paroxetine in terms of improvement in symptoms of depression in Japanese patients with major depressive disorders in a fixed-dose design. The efficacy and safety of milnacipran 200 mg/day were also assessed in comparison with those at the standard dose of 100 mg/day. RESULTS: Changes in 17-item Hamilton depression rating scale (HAM-D) total score (mean +/- standard deviation) for group M1 (milnacipran 100 mg/day), group M2 (milnacipran 200 mg/day), and group PX (paroxetine 30 or 40 mg/day) were -12.9 +/- 5.8, -12.8 +/- 6.1, and -13.1 +/- 6.2, respectively, and the estimated differences in total score for group PX (Dunnett's 95% simultaneous confidence interval) were 0.1 (-1.1 to 1.3) for group M1 and 0.3 (-0.9 to 1.5) for group M2. The noninferiority of groups M1 and M2 to group PX was thus confirmed, because the upper confidence limit of differences between groups M1 and PX and between groups M2 and PX was less than 2.0. The estimated mean difference of change in HAM-D total score (95% confidence interval) between groups M2 and M1 was 0.2 ( 0.9 to 1.2), indicating a comparable change in total score for both groups. The incidence of treatment-related adverse events was 71.7% for group M1, 68.8% for group M2, and 69.3% for group PX, indicating no significant difference between the three groups. CONCLUSION: These results demonstrate that milnacipran 100 mg/day and 200 mg/day is not inferior to paroxetine in terms of efficacy and safety. PMID- 23650447 TI - Mitochondrial dysfunction, oxidative stress, and major depressive disorder. AB - There is controversy about depression being a physical illness, in part because a reproducible, sensitive, and specific biologic marker is not available. However, there is evidence that mitochondrial dysfunction and oxidative stress may be associated with abnormal brain function and mood disorders, such as depression. This paper reviews selected human and animal studies providing evidence that intracellular mitochondrial metabolic dysfunction in specific brain regions is associated with major depressive disorder. This supports the hypothesis that chronic mitochondrial dysfunction in specific tissues may be associated with depression. Evaluation of mitochondrial dysfunction in specific tissues may broaden the perspective of depression beyond theories about neurotransmitters or receptor sites, and may explain the persistent signs and symptoms of depression. PMID- 23650448 TI - Retrospective analysis of factors associated with quetiapine dosage in the acute and subsequent six-month maintenance treatment of bipolar disorders. AB - BACKGROUND: Although quetiapine has often been used as monotherapy or adjunctive therapy in bipolar disorder, there is very limited clinical evidence regarding prescribing practices for quetiapine as maintenance treatment for bipolar disorder. METHODS: We reviewed the inpatient and outpatient records of 175 Chinese patients who received treatment with quetiapine for bipolar disorder both during and following hospitalization. We compared patients treated with high-dose (>300 mg/day) and low-dose (<=300 mg/day) quetiapine during the acute treatment phase and in the subsequent 6 months of maintenance treatment, with assessments at months 1, 3, and 6. Multifactor logistic regression analysis was performed to identify factors associated with quetiapine dosage. RESULTS: The proportion of patients receiving combination therapy of quetiapine and a mood stabilizer as acute and maintenance treatment was 99.4% and 84.6%, respectively. The mean dose of quetiapine when used for acute treatment in the 175 patients was 395.7 mg/day. The following factors were found to be independently associated with use of high dose quetiapine: male gender (odds ratio [OR] 2.712, 95% confidence interval [CI] 1.372-5.362, P < 0.01), a manic or mixed episode (OR 2.786, 95% CI 1.362-5.699, P < 0.01), and psychotic features (OR 2.658, 95% CI 1.318-5.361, P < 0.01). In the subsequent 6 months, the mean dose of quetiapine prescribed steadily decreased to 375.0 mg/day, 330.6 mg/day, and 293.7 mg/day at months 1, 3, and 6. The main factors associated with high-dose quetiapine in maintenance treatment were male gender (month 1, OR 2.761; month 3, OR 2.583; month 6, OR 2.686; P < 0.01) and a manic or mixed episode (month 1, OR 2.626; month 3, OR 2.334; P < 0.01). CONCLUSION: Higher doses of quetiapine (>300 mg/day) are more likely to be prescribed to patients who are male, those who are experiencing a manic or mixed episode, and those who have psychotic features during acute treatment of bipolar disorder. For patients who remain clinically stable during the subsequent months, the quetiapine dose should be adjusted according to patient gender and the most recent type of episode experienced. PMID- 23650449 TI - Tips for charting the course of a successful health research career. AB - Young health researchers all over the world often encounter difficulties in the early stages of their careers. Formal acquisition of research skills in academic settings does not always offer sufficient guidance to overcome these challenges. Based on the collective experiences of some young researchers and research mentors, we describe some tips for a successful health career and offer some useful resources. These tips include: institutional affiliation, early manuscript writing, early manuscript reviewing, finding a mentor, collaboration and networking, identifying sources of funding, establishing research interests, investing in research methods training, developing interpersonal and personal skills, providing mentorship, and balancing work with everyday life. The rationale behind these tips and how to achieve them is provided. PMID- 23650450 TI - Managing diabetic patients with moderate or severe renal impairment using DPP-4 inhibitors: focus on vildagliptin. AB - BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel classified oral anti-diabetic drugs for the treatment of type 2 diabetes mellitus (T2DM) that provide important reduction in glycated hemoglobin, with a low risk for hypoglycemia and no weight gain. In T2DM patients with reduced renal function, adequate glycemic control is essential to delay the progress of kidney dysfunction, but they are at a greater risk of experiencing hypoglycemic events, especially with longer-acting sulfonylureas and meglitinides. OBJECTIVE: To evaluate vildagliptin as an option to achieve glycemic control in T2DM patients with moderate or severe chronic kidney disease (CKD). METHODS: A comprehensive search in the literature was performed using the term "vildagliptin." Original articles and reviews exploring our topic were carefully selected. RESULTS: Vildagliptin provides effective glycemic control in patients with T2DM and CKD. Dose reductions are required for vildagliptin and other DPP-4 inhibitors, except linagliptin, in T2DM patients with moderate-to-severe CKD. Dose of vildagliptin had to be reduced by half (to 50 mg/day) both for moderate (estimated glomerular filtration rate [eGFR] >=30 to <=50 mL/min) and severe CKD (eGFR < 30 mL/min). Available results support a favorable efficacy, safety, and tolerability profile for vildagliptin in T2DM with moderate or severe renal failure. Preliminary data may suggest additional benefits beyond improvement of glycemic control. CONCLUSION: Vildagliptin can be safely used in T2DM patients with varying degrees of renal impairment. Dose adjustments for renal impairment are required. Potential long-term renal benefit of vildagliptin needs to be further explored. PMID- 23650451 TI - Perceived mental stress in women associated with psychosomatic symptoms, but not mortality: observations from the Population Study of Women in Gothenburg, Sweden. AB - PURPOSE: To investigate possible association between mental stress and psychosomatic symptoms, socioeconomic status, lifestyle, as well as incident mortality in a middle-aged female population followed over 37 years. METHODS: A prospective observational study initiated in 1968-1969, including 1462 women aged 60, 54, 50, 46, and 38 years, with follow-ups in 1974-1975, 1980-1981, and 2000 2001, was performed. Measures included self-reported mental stress as well as psychosomatic symptoms and smoking, physical activity, total cholesterol, S triglycerides, body mass index, waist-hip ratio, blood pressure, socioeconomic status and mortality. RESULTS: Smoking, not being single, and not working outside home were strongly associated with reported mental stress at baseline. Women who reported high mental stress in 1968-1969 were more likely to report presence of abdominal symptoms (odds ratio [OR] = 1.85, 95% confidence interval [CI]: 1.39 2.46), headache/migraine (OR = 2.04, 95% CI: 1.53-2.72), frequent infections (OR = 1.75, 95% CI: 1.14-2.70), and musculoskeletal symptoms (OR = 1.70, 95% CI: 1.30 2.23) than women who did not report mental stress. Women without these symptoms at baseline 1968-1969, but with perceived mental stress were more likely to subsequently report incident abdominal symptoms (OR = 2.15, 95% CI: 1.39-3.34), headache/migraine (OR = 2.27, 95% CI: 1.48-3.48) and frequent infections (OR = 2.21, 95% CI: 1.12-4.36) in 1974-1975 than women without mental stress in 1968 1969. There was no association between perceived mental stress at baseline and mortality over 37 years of follow-up. CONCLUSION: Women reporting mental stress had a higher frequency of psychosomatic symptoms than women who did not report these symptoms. Not working outside home and smoking rather than low socioeconomic status per se was associated with higher stress levels. Perception of high mental stress was not associated with increased mortality. PMID- 23650452 TI - Advances in antiplatelet technologies to improve cardiovascular disease morbidity and mortality: a review of ticagrelor. AB - Antiplatelet therapy is widely used with proven benefit for the prevention of further ischemic cardiac complications in patients with acute coronary syndrome. Treatment guidelines for acute coronary syndrome and percutaneous coronary intervention now recommend the use of oral antiplatelet agents including ticagrelor, prasugrel, or clopidogrel in combination with aspirin to comprise dual antiplatelet therapy for the prevention of recurrent ischemic events. The limitations of conventional antiplatelet therapy with clopidogrel or prasugrel include the potential for low response to clopidogrel identified through platelet reactivity or genetic testing, increased risk of bleeding with prasugrel, or slower return to normal platelet activity in patients who received either prasugrel or clopidogrel prior to emergent or planned surgical procedures. This review will discuss the pharmacokinetic and pharmacodynamic properties of ticagrelor in comparison to conventional P2Y12 receptor inhibitors and its utility in patients identified as low responders to clopidogrel. Completed clinical studies and substudies comparing ticagrelor to clopidogrel and ongoing clinical trials evaluating ticagrelor in acute coronary syndrome patients will also be reviewed. PMID- 23650453 TI - Review of Azithromycin Ophthalmic 1% Solution (AzaSite((r))) for the Treatment of Ocular Infections. AB - AzaSite((r)) (azithromomycin 1.0%) ophthalmic solution was approved in 2007 by the US Food and Drug Administration (FDA) as the first commercially available formulation of ophthalmic azithromycin for the treatment of bacterial conjunctivitis. AzaSite((r)) utilizes a vehicle delivery system called DuraSite((r)), which stabilizes and sustains the release of azithromycin to the ocular surface, leading to a longer drug residence time, less frequent dosing, and an increase in patient compliance. AzaSite((r)) is a broad spectrum antibiotic, effective against Gram-positive, Gram-negative, and atypical bacteria. AzaSite((r)) has been studied for the treatment of ocular conditions beyond its clinical indication. A number of clinical studies have evaluated its efficacy and safety in the management of ocular conditions such as bacterial conjunctivitis and blepharitis on both the pediatric and adult populations. This article aims to evaluate the peer-reviewed published literature on the use of azithromycin 1.0% ophthalmic for current and possible future ophthalmic uses. PMID- 23650454 TI - Safety and Efficacy of Ranibizumab in Macular Edema following Retinal Vein Occlusion. AB - Macular edema is the leading cause of visual impairment in patients with retinal vein occlusion. Limited improvements may be obtained with laser photocoagulation or intravitreal triamcinolone. However, according to the data provided by randomized clinical trials, intravitreal injections of ranibizumab (Lucentis; Genentech, South San Francisco, CA) constitute a new effective and safe option for the management of these vision-threatening diseases. The aim of the present review is to summarize the clinical evidence of ranibizumab for macular edema due to retinal vein occlusions. PMID- 23650455 TI - Acute Herpetic Keratitis: What is the Role for Ganciclovir Ophthalmic Gel? AB - Herpes simplex keratitis (HSK) is a major cause of corneal blindness in the world. Following the primary infection, the virus enters into a latent phase. Recurrent infectious or immune keratitis cause structural damage to the cornea, scarring, and may lead to blindness. Several commercially available topical and oral antiviral drugs for HSK are currently available. However, toxicity and low patient compliance hamper their use in HSK. Further, oral antiviral drugs alone are not always effective in HSK. Thus, there had been a need for safe and effective topical antiviral agents against HSK. Systemic ganciclovir has been in use for the treatment of cytomegalovirus infections. Recently, topical ganciclovir has become available for use in patients with HSK. Ganciclovir 0.15% ophthalmic gel has been shown to be both safe and effective against viruses of the herpes family. Topical ganciclovir ophthalmic gel is well tolerated and does not cause significant toxic effects on the ocular surface. Several multicenter studies have revealed the potential role of ganciclovir ophthalmic gel in the treatment and prophylaxis of epithelial HSK. In this paper, we have reviewed the pharmacology, efficacy, side effects, and the role of ganciclovir ophthalmic gel 0.15% in the treatment of acute herpetic keratitis. PMID- 23650456 TI - Oculo-Visual Findings among Industrial Mine Workers at Goldfields Ghana Limited, Tarkwa. AB - OBJECTIVE: The focus of this study was to evaluate the visual status of mine workers who were directly involved in mining and/or are exposed to the mining environment. METHODS: A hospital based cross-sectional study was conducted. Four hundred and six (406) workers were conveniently sampled for the study. Information on their socio-demographic data was also collected. In addition, all participants underwent ophthalmic examination. RESULTS: The mean age of the workers was 41.1 years. Visual impairment was found in 114 (28.1%) of the study population of which refractive error (56.8%) was the major cause. Presbyopia was also observed in 45.5% of the workers with only 30.3% of them wearing near correction. The prevalence of eye diseases were pterygium/pingueculae (25.8%), conjunctivitis (26.8%), suspected glaucoma (15.3%), and cataract (7.4%). CONCLUSIONS: Visual impairment and eye diseases were found among the miners. PMID- 23650458 TI - Gatifloxacin ophthalmic solution for treatment of bacterial conjunctivitis: safety, efficacy and patient perspective. AB - Gatifloxacin is a fourth generation fluroquinolone antibiotic that has been prescribed for systemic use. However, the drug which was developed by Kyorin (Japan) was linked to toxic reactions and death and was banned in the United States and Canada for use as an oral dosage form. It continues to be used as a topical application for ophthalmic conditions as the systemic toxicity seen when taking the drug orally has not been observed with ophthalmic use. The available data indicate that ocular use of gatifloxacin is safe, and effective against a broad spectrum of bacteria, including intracellular bacteria and anaerobes. PMID- 23650459 TI - Paracentesis as surgical intervention in traumatic hyphaema: opinions and practices of nigerian ophthalmologists. AB - INTRODUCTION: Various aspects of management of traumatic hyphaema are enmeshed in controversy. Surgery is done to prevent complications: optic atrophy and corneal blood staining occurring if a high risk exists of either or both occurring. Circumstances considered high risk do not enjoy universal consensus. OBJECTIVES: To determine what Nigerian ophthalmologists consider absolute indications for surgical intervention by means of anterior chamber paracentesis and hyphaema washout in closed globe traumatic hyphaema, evaluate these absolute indications, and attempt to evolve a guideline for surgical intervention based on areas of consensus and disagreement. METHOD: A semi-structured, pre-tested questionnaire with responses analyzed with SPSS 11 software. RESULT: Near universal agreement on indication exist on early corneal blood staining and sickle cell haemoglobinopathy. Differing views concern blackball, volume and duration of hyphaema and secondary hypertension-associated hyphaema. However, it appears surgery is embarked on earlier than other practitioners elsewhere may consider necessary. CONCLUSION: Risk level for non-surgical management against risk and benefit of surgery should be evaluated for each individual before surgery. PMID- 23650460 TI - Systemic reduction of interleukin-4 or interleukin-10 fails to reduce the frequency or severity of experimental cytomegalovirus retinitis in mice with retrovirus-induced immunosuppression. AB - Interleukin-4 (IL-4) and interleukin-10 (IL-10) are key cytokines whose increased production during systemic HIV infection has been associated with decreased cellular immunity during AIDS. We examined whether HIV-induced stimulation of IL 4 or IL-10 production leads to increased susceptibility to AIDS-related human cytomegalovirus retinitis. It was confirmed that there were increased amounts of IL-4 and IL-10 mRNA levels in mice with MAIDS of 10 weeks duration when most susceptible to MCMV retinitis. Surprisingly, however, MCMV-infected eyes of IL-4 /- and IL-10 -/- mice with MAIDS of 8 weeks duration exhibited retinitis and infectious virus equivalent to that observed in MCMV-infected eyes of wild-type mice with MAIDS. We conclude that neither IL-4 nor IL-10 alone play a role in increased susceptibility to MAIDS-related MCMV retinitis, but may work collectively with other retrovirus-induced immunosuppressive factors to allow for retinal disease. PMID- 23650461 TI - Peters' anomaly. AB - While conducting medical aid in Mozambique, a 41 year old African male presented to our eye clinic complaining of visual impairment. The male was found to have Peters' anomaly type 2, a rare congenital ocular malformation leading to sensory amblyopia and glaucoma. PMID- 23650457 TI - Clinical options for the reduction of elevated intraocular pressure. AB - Elevated IOP in clinical practice is usually seen in glaucoma or ocular hypertension. Glaucoma affects 60 million people worldwide and 8.4 million are bilaterally blind from this chronic disease.1 Options for reducing IOP rely on pharmacological agents, laser treatments and surgery which may be penetrating or non-penetrating. The last twenty years has seen significant changes in all of these strategies. This review aims to cover these clinical options and introduce some of the new technologies currently in development for the clinical lowering of IOP. PMID- 23650462 TI - Beta-amyloidolysis and glutathione in Alzheimer's disease. AB - In this review, we hypothesized the importance of the interaction between the brain glutathione (GSH) system, the proteolytic tissue plasminogen activator (t PA)/plasminogen/ plasmin system, regulated by plasminogen activator inhibitor (PAI-1), and neuroserpin in the pathogenesis of Alzheimer's disease. The histopathological characteristic hallmark that gives personality to the diagnosis of Alzheimer's disease is the accumulation of neurofibroid tangles located intracellularly in the brain, such as the protein tau and extracellular senile plaques made primarily of amyloidal substance. These formations of complex etiology are intimately related to GSH, brain protective antioxidants, and the proteolytic system, in which t-PA plays a key role. There is scientific evidence that suggests a relationship between aging, a number of neurodegenerative disorders, and the excessive production of reactive oxygen species and accompanying decreased brain proteolysis. The plasminogen system in the brain is an essential proteolytic mechanism that effectively degrades amyloid peptides ("beta-amyloidolysis") through action of the plasmin, and this physiologic process may be considered to be a means of prevention of neurodegenerative disorders. In parallel to the decrease in GSH levels seen in aging, there is also a decrease in plasmin brain activity and a progressive decrease of t-PA activity, caused by a decrease in the expression of the t-PA together with an increase of the PAI-1 levels, which rise to an increment in the production of amyloid peptides and a lesser clearance of them. Better knowledge of the GSH mechanism and cerebral proteolysis will allow us to hypothesize about therapeutic practices. PMID- 23650463 TI - Current and emerging therapies for the treatment of multiple sclerosis: focus on cladribine. AB - Multiple Sclerosis (MS) is a chronic inflammatory, immune-mediated, demyelinating disorder of the central nervous system with a heterogeneous clinical presentation and pathology in which activated lymphocytes play an important role in mediating tissue damage. Until recently, all first line therapies for MS were injectable. Several oral medications have been studied for preventative treatment of MS. Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog that has been used for the treatment of several hematologic neoplasms, with a unique lymphcytotoxic mechanism of action. Cladribine has been investigated as treatment of MS for more than 15 years. A recent placebo-controlled, double-blind study of cladribine, CLARITY, showed decreased relapse rates, risk of disability progression and MRI measures of disease activity at 96 weeks. Cladribine's strengths included high efficacy and convenient, biannual oral dosing. However, concerns about safety prevented the FDA from approving cladribine in 2011. Thus, use of cladribine for treatment of relapsing and remitting multiple sclerosis will remain off-label. PMID- 23650464 TI - Mood disorders, circadian rhythms, melatonin and melatonin agonists. AB - Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC). Melatonin (N-acetyl-5 hydroxytryptamine) is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD) and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light) or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse. PMID- 23650465 TI - Triggers for autism: genetic and environmental factors. AB - This report reviews the research on the factors that cause autism. In several studies, these factors have been verified by reproducing them in autistic animal models. Clinical research has demonstrated that genetic and environmental factors play a major role in the development of autism. However, most cases are idiopathic, and no single factor can explain the trends in the pathology and prevalence of autism. At the time of this writing, autism is viewed more as a multi-factorial disorder. However, the existence of an unknown factor that may be common in all autistic cases cannot be ruled out. It is hoped that future biological studies of autism will help construct a new theory that can interpret the pathology of autism in a coherent manner. To achieve this, large-scale epidemiological research is essential. PMID- 23650466 TI - Preventive agents for migraine: focus on the antiepileptic drugs. AB - Migraine is among the 10 most disabling disorders worldwide. It is characterized by episodes of moderate or severe headaches with various degree of disability, resulting in a considerable health burden upon the sufferers and their family. The objective of this article is to review the use of prophylaxis with antiepileptic drugs. Particular focus is given to their mechanism of action, metabolism, pharmacokinetics, safety profile, efficacy and to provide a summary of the most relevant clinical studies and patient preference. PMID- 23650467 TI - The safety and tolerability of newer antiepileptic drugs in children and adolescents. AB - Childhood epilepsy continues to be intractable in more than 25% of patients diagnosed with epilepsy. The introduction of new anti-epileptic drugs (AEDs) provides more options for treatment of children with epilepsy. We review the safety and tolerability of seven new AEDs (levetiracetam, lamotrigine, oxcarbazepine, rufinamide, topiramate, vigabatrin and zonisamide) focusing on their side effect profiles and safety in children and adolescents. Many considerations that are specific for children such as the impact of AEDs on the developing brain are not addressed during the development of new AEDs. They are usually approved as adjunctive therapies based upon clinical trials involving adult patients with partial epilepsy. However, 2 of the AEDs reviewed here (rufinamide and vigabatrin) have FDA approval in the U.S. for specific Pediatric epilepsy syndromes, which are discussed below. The Pediatrician or Neurologists decision on the use of a new AED is an evolutionary process largely dependent on the patient characteristics, personal/peer experiences and literature about efficacy and safety profiles of these medications. Evidence based guidelines are limited due to a lack of randomized controlled trials involving pediatric patients for many of these new AEDs. PMID- 23650468 TI - Sentra PM (a Medical Food) and Trazodone in the Management of Sleep Disorders. AB - Sleep disorders are a common and poorly treated disease state. This double blind, four arm placebo-controlled, randomized trial compared (1) low dose trazodone, (2) Sentra PM, a neurotransmitter based medical food, (3) the joint administration of trazodone and the medical food Sentra PM and (4) placebo. There were 111 subjects studied in 12 independent sites. Subjects underwent baseline screening, informed consent and an initial sleep questionnaire. After 14 days subjects underwent a second evaluation by questionnaire. At baseline and Day 14 the subjects underwent 24 hour ECG recordings that were analyzed in the frequency domain of heart rate variability. The specific high frequency parasympathetic autonomic nervous system activity was analyzed. The primary endpoints were sleep latency and parasympathetic autonomic nervous system improvement in sleeping hours. The results showed improvement in sleep latency for the Sentra PM and combination of Sentra PM and trazodone (-41 and -56 minutes P < 0.001). There was an improvement in quality of sleep for the amino acid formulation Sentra PM and the combination (3.86 and 6.48 Likert units on a 10 point scale P < 0.001). There was an activation of circadian activity percent at night in the medical food and combination groups while there was no change in parasympathetic activity in either the placebo or trazodone group. These data indicate that Sentra PM can improve the quality of sleep, the response to trazodone as a sleep medication and parasympathetic autonomic nervous system activity. PMID- 23650469 TI - Vitamin k antagonist warfarin for palliative treatment of metachromatic leukodystrophy, a compassionate study of four subjects. AB - MLD is characterized by accumulation of sulfatides in the brain. Vitamin K regulates two enzymes in sphingolipid biosynthesis and warfarin is known to lower brain sulfatides in rats and mice. We hypothesized that warfarin may mitigate the MLD phenotype by reducing the formation of sulfatides. This compassionate study recruited four advanced patients with clinical, biochemical and genetic confirmation of MLD. The patients were treated with warfarin according to the approved protocol for a total of 45 days. The battery of tests included proton MR spectroscopy (H-MRS) of brain and urinary sulfatide levels recorded at defined intervals. The patients tolerated the medication and there were no bleeding complications. The urinary sulfatide levels did not decline during the study period. The H-MRS showed decreased N-acetyl aspartate and elevated myoinositol levels in the basal ganglia which remained unchanged after treatment. Our study did not demonstrate any beneficial effects of warfarin in four advanced cases of MLD. The drug intervention however, was safe and deserves further evaluation through a larger study of longer duration. The metabolite abnormalities reported on H-MRS may be useful in longitudinal follow up of patients with MLD during drug trials. PMID- 23650470 TI - New and Emerging Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis: What is New and What is to Come. AB - The therapeutic landscape for multiple sclerosis (MS) is rapidly changing. Currently, there are eight FDA approved disease modifying therapies for MS including: IFN-beta-1a (Avonex, Rebif), IFN-beta-1b (Betaseron, Extavia), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri), and fingolimod (Gilenya). This review will highlight the experience to date and key clinical trials of the newest FDA approved agents, natalizumab and fingolimod. It will also review available efficacy and safety data on several promising therapies under active investigation including four monoclonal antibody therapies: alemtuzumab, daclizumab, ocrelizumab and ofatumumab and three oral agents: BG12, laquinimod, and teriflunomide. To conclude, we will discuss where each of these new therapies may best fit into treatment algorithms. PMID- 23650471 TI - Pharmacotherapeutic and Non-Pharmacological Options for Refractory and Difficult to-Treat Seizures. AB - It is currently estimated that about 20%-30% of adults and 10%-40% of children diagnosed with epilepsy suffer from uncontrolled or poorly controlled seizures, despite optimal medical management. In addition to its huge economic costs, treatment-refractory epilepsy has a widespread impact on patients' health-related quality of life. The present paper focuses on the concepts of refractory and difficult-to-treat seizures and their pharmacological management. Evidence on efficacy and tolerability of rational pharmacotherapy with antiepileptic drug combinations and of non-pharmacological treatment options such as epilepsy surgery, neurostimulation, metabolic treatment and herbal remedies is reviewed. The importance of early identification of the underlying etiology of the specific epilepsy syndrome is emphasized, to inform early prognosis and therapeutic strategies. PMID- 23650472 TI - Clinical utility of glatiramer acetate in the management of relapse frequency in multiple sclerosis. AB - Glatiramer acetate (GA) represents one of the most common disease-modifying therapies for multiple sclerosis. GA is currently approved for patients at high risk of developing clinically definite multiple sclerosis (CDMS) after having experienced a well-defined first clinical episode (clinically isolated syndrome or CIS) and for patients with relapsing-remitting multiple sclerosis (RRMS). GA's efficacy and effectiveness to reduce relapse frequency have been proved in placebo-controlled and observational studies. Comparative trials have also confirmed the lack of significant differences over other choices of treatment in the management of relapse frequency, and long-term studies have supported its effect at extended periods of time. Additionally, RRMS patients with suboptimal response to interferon beta may benefit from reduced relapse rate after switching to GA, and those with clinically isolated syndrome may benefit from delayed conversion to CDMS. All these results, together with its proven long-term safety and positive effect on patients' daily living, support the favorable risk-benefit of GA for multiple sclerosis treatment. PMID- 23650473 TI - Review of the treatment of restless legs syndrome: focus on gabapentin enacarbil. AB - The FDA approved gabapentin enacarbil in 2011 as the first non-dopaminergic agent for the treatment of restless legs syndrome (RLS) symptoms. Although gabapentin enacarbil is a pro-drug of gabapentin, its pharmacokinetics differ. Absorption of gabapentin enacarbil is more predictable, and inter-patient variability in bioavailability is lower than that of gabapentin. Studies have demonstrated superiority of gabapentin enacarbil compared to placebo. Comparisons to currently available RLS treatments are lacking, but clinical trials demonstrate comparable improvement in RLS symptoms to the dopamine agonists ropinirole and pramipexole, which are usually considered first-line therapy for daily RLS symptoms. Gabapentin enacarbil was well tolerated in clinical trials. The role of the drug in RLS treatment remains undefined, although it will likely be used as an alternative for refractory RLS when other treatments have failed. Additionally, gabapentin enacarbil may be recommended for patients with daily RLS symptoms that are less intense or are associated with pain as an alternative to dopamine agonists. PMID- 23650475 TI - Prefabricated patient-matched cranial implants for reconstruction of large skull defects. AB - Cranial defects can be caused by injury, infection, or tumor invasion. Large defects should be reconstructed to protect the brain and normalize the cerebral hemodynamics. The conventional method is to cover the defect with bone cement. Custom-made implants designed for the individual patient are now available. We report our experience with one such product in patients with large cranial defects (>7.6 cm in diameter). A CT scan with 2 mm slices and a three-dimensional reconstruction were obtained from the patient. This information was dispatched to the company and used as a template to form the implant. The cranial implant was received within four weeks. From 2005 to 2010, custom-made cranial implants were used in 13 patients with large cranial defects. In 10 of the 13 patients, secondary deep infection was the cause of the cranial defect. All the implants fitted well or very well to the defect. No infections were seen after implantation; however, one patient was reoperated on for an epidural hematoma. A custom-made cranial implant is considerably more expensive than an implant made of bone cement, but ensures that the defect is optimally covered. The use of custom-made implants is straightforward and timesaving, and they provide an excellent medical and cosmetic result. PMID- 23650474 TI - Pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: clinical strategies. AB - Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder of childhood that can result in significant functional impairment, and if not adequately treated can lead to impaired quality of life. Pharmacotherapy is considered the first-line treatment for ADHD in children and adolescents. We review both recent literature and seminal studies regarding the pharmacological treatment of ADHD in children and adolescents. There is ample evidence for the efficacy and safety of both stimulants and non-stimulants in the treatment of ADHD. We review important aspects of evaluation and assessment and discuss first line pharmacological treatments and as well as when to consider using alternative pharmacological agents. Treatment approaches to manage frequently seen comorbid disorders with ADHD are also covered. PMID- 23650476 TI - The role of estrogen, progesterone and aromatase in human non-small-cell lung cancer. AB - Lung cancer is the leading cause of cancer-related deaths in both men and women worldwide. Despite advances in treatment, patients have few effective therapeutic options and survival rates remain low. Emerging evidence suggests that the hormones estrogen and progesterone play a key role in the progression of non small-cell lung cancer (NSCLC). The aromatase enzyme, which is responsible for a key step in estrogen biosynthesis, elicits higher levels of estrogen in lung tumors as well as in metastases compared with nonmalignant tissues. Thus, aromatase may prove to be a key predictive biomarker for treatment of NSCLC. Epidemiologic and preclinical data show estrogens play a critical role in lung tumor development and progression. Two estrogen receptors, alpha and beta, are expressed in normal and in cancerous lung epithelium, and estrogen promotes gene transcription that stimulates cell proliferation and inhibits cell death. Furthermore, expression of both forms of estrogen receptor, progesterone receptor and aromatase in NSCLC specimens has been correlated with worse clinical outcomes. Combination therapies that include estrogen receptor downregulators and aromatase inhibitors are currently being assessed in Phase I-II clinical trials among patients with advanced NSCLC. Results will help guide future lung cancer management decisions, with a goal of achieving more effective and less toxic treatments for patients. PMID- 23650477 TI - Multifunctional upconversion-magnetic hybrid nanostructured materials: synthesis and bioapplications. AB - The combination of nanotechnology and biology has developed into an emerging research area: nano-biotechnology. Upconversion nanoparticles (UCNPs) have attracted a great deal of attention in bioapplications due to their high chemical stability, low toxicity, and high signal-to-noise ratio. Magnetic nanoparticles (MNPs) are also well-established nanomaterials that offer controlled size, ability to be manipulated externally, and enhancement of contrast in magnetic resonance imaging (MRI). As a result, these nanoparticles could have many applications in biology and medicine, including protein purification, drug delivery, and medical imaging. Because of the potential benefits of multimodal functionality in biomedical applications, researchers would like to design and fabricate multifunctional upconversion-magnetic hybrid nanostructured materials. The hybrid nanostructures, which combine UCNPs with MNPs, exhibit upconversion fluorescence alongside superparamagnetism property. Such structures could provide a platform for enhanced bioimaging and controlled drug delivery. We expect that the combination of unique structural characteristics and integrated functions of multifunctional upconversion-magnetic nanoparticles will attract increasing research interest and could lead to new opportunities in nano-bioapplications. PMID- 23650478 TI - Optimization of optical excitation of upconversion nanoparticles for rapid microscopy and deeper tissue imaging with higher quantum yield. AB - Relatively low quantum yield (QY), time-consuming scanning and strong absorption of light in tissue are some of the issues present in the development of upconversion nanoparticles (UCNPs) for biomedical applications. In this paper we systematically optimize several aspects of optical excitation of UCNPs to improve their applicability in bioimaging and biotherapy. A novel multi-photon evanescent wave (EW) excitation modality is proposed for UCNP-based microscopy. The scanning free, ultrahigh contrast and high spatiotemporal resolution method could simultaneously track a few particles in a large area with a speed of 3+up to 350 frames per second. The HeLa cancer cell membrane imaging was successfully performed using NaYF4: 20% Yb3+/2Er3+ targeting nanoparticles. Studies with different tissues were made to illustrate the impact of optical property parameters on the deep imaging ability of 920-nm band excitation. In the experiments a semiconductor laser with a 920 nm wavelength was used to excite UCNPs in tissue phantom at five depths. Our experimental and computational results have shown that in UCNP-based diffusion optical imaging with 920-nm laser excitation could lead to larger imaging depth range compared to traditional 974 nm excitation in a wide dynamic range of tissue species. As the QY is power density dependent, a pulsed laser is proposed to improve the QY of UCNPs. This proposal is promising in drastically increasing the imaging depth and efficiency of photodynamic therapy. PMID- 23650479 TI - Upconversion nanoparticles for photodynamic therapy and other cancer therapeutics. AB - Photodynamic therapy (PDT) is a non-invasive treatment modality for a variety of diseases including cancer. PDT based on upconversion nanoparticles (UCNPs) has received much attention in recent years. Under near-infrared (NIR) light excitation, UCNPs are able to emit high-energy visible light, which can activate surrounding photosensitizer (PS) molecules to produce singlet oxygen and kill cancer cells. Owing to the high tissue penetration ability of NIR light, NIR excited UCNPs can be used to activate PS molecules in much deeper tissues compared to traditional PDT induced by visible or ultraviolet (UV) light. In addition to the application of UCNPs as an energy donor in PDT, via similar mechanisms, they could also be used for the NIR light-triggered drug release or activation of 'caged' imaging or therapeutic molecules. In this review, we will summarize the latest progresses regarding the applications of UCNPs for photodynamic therapy, NIR triggered drug and gene delivery, as well as several other UCNP-based cancer therapeutic approaches. The future prospects and challenges in this emerging field will be also discussed. PMID- 23650480 TI - Sensing using rare-earth-doped upconversion nanoparticles. AB - Optical sensing plays an important role in theranostics due to its capability to detect hint biochemical entities or molecular targets as well as to precisely monitor specific fundamental psychological processes. Rare-earth (RE) doped upconversion nanoparticles (UCNPs) are promising for these endeavors due to their unique frequency converting capability; they emit efficient and sharp visible or ultraviolet (UV) luminescence via use of ladder-like energy levels of RE ions when excited at near infrared (NIR) light that are silent to tissues. These features allow not only a high penetration depth in biological tissues but also a high detection sensitivity. Indeed, the energy transfer between UCNPs and biomolecular or chemical indicators provide opportunities for high-sensitive bio- and chemical-sensing. A temperature-sensitive change of the intensity ratio between two close UC bands promises them for use in temperature mapping of a single living cell. In this work, we review recent investigations on using UCNPs for the detection of biomolecules (avidin, ATP, etc.), ions (cyanide, mecury, etc.), small gas molecules (oxygen, carbon dioxide, ammonia, etc.), as well as for in vitro temperature sensing. We also briefly summarize chemical methods in synthesizing UCNPs of high efficiency that are important for the detection limit. PMID- 23650481 TI - Upconversion nanophosphors Naluf4:Yb,Tm for lymphatic imaging in vivo by real time upconversion luminescence imaging under ambient light and high-resolution X ray CT. AB - Lanthanide upconversion nanophosphor (UCNP) has attracted increasing attention for potential applications in bioimaging due to its excellence in deep and high contrast imaging. To date, most upconversion imaging applications were demonstrated in dark surroundings without ambient light for higher signal-to noise ratio, which hindered the application of optical imaging guided surgery. Herein, the new established NaLuF4-based UCNP (NaLuF4:Yb,Tm, ~17 nm) with bright upconversion emission around 800 nm as imaging signal was used to realize imaging under ambient light to provide more convenient for clinician. Moreover, due to the existance of heavy element lutetium (Lu) in the host lattice, the NaLuF4:Yb,Tm nanoparticles can also be used as an X-ray CT imaging agent to enhance the imaging depth and in vivo imaging resolution. PMID- 23650482 TI - Theranostic upconversion nanoparticles (II). AB - This theme issue provides a comprehensive collection of original research articles as well as reviews on the creation of diverse types of theranostic upconversion nanoparticles, their fundamental interactions in biology, as well as their biophotonic applications in noninvasive diagnostics and therapy. PMID- 23650483 TI - Developing a tool to assess the quality of socio-demographic data in community health centres. AB - OBJECTIVE: The objectives of this study are to 1) create a quality assessment tool for socio-demographic data aligned with the needs of Community Health Centres (CHCs) and based on the data quality framework of the Canadian Institute for Health Information (CIHI), and 2) test the feasibility of the tool in CHCs. METHODS: The tool was developed based on both theoretical and practical knowledge. A review of the literature was performed to identify data quality frameworks and dimensions that could be employed. In addition, informal discussions with Community Health Centres staff members holding various positions were conducted and a team of subject matter experts was established. This approach supported the alignment between the tool (i.e., the indicators developed, the rating scale, and weighting system) and the setting for which it has been designed. The tool was pilot tested in five CHCs across Ontario. RESULTS: The decision to focus on socio-demographic data was based on findings from the discussions with staff members. The team established nine principles for the development of the tool, including the use of computer software, whenever possible, to query the data and ensure consistency of the measurement. Data quality scores ranged from 45 to 74 on a scale of 0 (lowest quality) to 100 (highest data quality), with one CHC that was not able to run all of the queries. The feedback from staff was positive and supports the feasibility of the tool as an application of the CIHI data quality framework in a local setting. CONCLUSION: Pilot test results demonstrate the feasibility of the tool and an applicability of the CIHI framework as a basis for developing tools for data quality assessment in health care organizations. PMID- 23650484 TI - Predictors of success for electronic health record implementation in small physician practices. AB - BACKGROUND: The federal government is promoting adoption of electronic health records (EHRs) through financial incentives for EHR use and implementation support provided by regional extension centers. Small practices have been slow to adopt EHRs. OBJECTIVES: Our objective was to measure time to EHR implementation and identify factors associated with successful implementation in small practices receiving financial incentives and implementation support. This study is unique in exploiting quantitative implementation time data collected prospectively as part of routine project management. METHODS: This mixed-methods study includes interviews of key informants and a cohort study of 544 practices that had worked with the Primary Care Information Project (PCIP), a publicly funded organization that since 2007 has subsidized EHRs and provided implementation support similar to that supplied by the new regional extension centers. Data from a project management database were used for a cohort study to assess time to implementation and predictors of implementation success. RESULTS: Four hundred and thirty practices (79%) implemented EHRs within the analysis period, with a median project time of 24.7 weeks (95% CI: 23.3 - 26.4). Factors associated with implementation success were: fewer providers, practice sites, and patients; fewer Medicaid and uninsured patients; having previous experience with scheduling software; enrolling in 2010 rather than earlier; and selecting an integrated EHR plus practice management product rather than two products. Interviews identified positive attitude toward EHRs, resources, and centralized leadership as additional practice-level predictors of success. CONCLUSIONS: A local initiative similar to current federal programs successfully implemented EHRs in primary care practices by offsetting software costs and providing implementation assistance. Nevertheless, implementation success was affected by practice size and other characteristics, suggesting that the federal programs can reduce barriers to EHR implementation but may not eliminate them. PMID- 23650485 TI - An e-health decision support system for improving compliance of health workers to the maternity care protocols in South Africa. AB - BACKGROUND: There are problems of quality in maternity services at primary health care level in South Africa. Many of these problems can be traced to non-adherence to the maternity care guidelines and lack of tools to support clinic staff and managers in their roles. OBJECTIVE: The aim of this research was to investigate the utility of e-health (computerized) decision support systems at addressing the problem of compliance of health workers to the maternity care guidelines at primary health care in South Africa. At present there are no documented studies on e-health clinical decision support systems for primary health care in South Africa, though clinical decision support systems for primary health care are listed as part of the e-health strategy of the National Department of Health. METHODS: An e-health decision support system named the Bacis (Basic Antenatal Care Information System) Program was developed, then implemented and evaluated at a primary health care clinic. The duration of the study was two years: this includes development, implementation and evaluation. RESULTS AND CONCLUSION: There was an overall improvement in compliance from 85.1 % to 89.3%. This result was not statistically significant. However when results were stratified into specific categories, the Bacis Program showed statistically significant improvement in compliance over the checklist system in three out of nine important categories. These are compliance at booking, patients younger than 18 years and patients booking after week 20. Further, insights and experience were also gained on development and implementation of clinical information systems at resource strained environments such as primary health care in South Africa. These results, insights and experience are invaluable for the implementation of the proposed e-health strategy in South Africa. PMID- 23650486 TI - A smartphone-based medication self-management system with realtime medication monitoring. AB - BACKGROUND: Most patients cannot remember their entire medication regimen and occasionally forget to take their medication. OBJECTIVES: The objective of the study was to design, develop, and demonstrate the feasibility of a new type of medication self-management system using smartphones with real-time medication monitoring. METHODS: We designed and developed a smartphone-based medication self management system (SMSS) based on interviews of 116 patients. The system offered patients two main functions by means of smartphones: (1) storage and provision of an accurate, portable medication history and medication-taking records of patients; and (2) provision of a reminder to take medication only when the patient has forgotten to take his/her medication. These functions were realized by two data input methods: (a) reading of prescription data represented in two dimensional barcodes using the smartphone camera and getting the photographic images of the pills; and (b) real-time medication monitoring by novel user friendly wireless pillboxes. RESULTS: Interviews suggested that a pocket-sized pillbox was demanded to support patient's medication-taking outside the home and pillboxes for home use should be adaptable to the different means of pillbox storage. In accordance with the result, we designed and developed SMSS. Ten patients participated in the feasibility study. In 17 out of 47 cases (36.2%), patients took their medication upon being presented with reminders by the system. Correct medication-taking occurrence was improved using this system. CONCLUSIONS: The SMSS is acceptable to patients and has the advantage of supporting ubiquitous medication self-management using a smartphone. We believe that the proposed system is feasible and provides an innovative solution to encourage medication self-management. PMID- 23650487 TI - Medical student appraisal: searching on smartphones. AB - BACKGROUND: The rapidly growing industry for mobile medical applications provides numerous smartphone resources designed for healthcare professionals. However, not all applications are equally useful in addressing the questions of early medical trainees. METHODS: Three popular, free, mobile healthcare applications were evaluated along with a Google(TM) web search on both Apple(TM) and Android(TM) devices. Six medical students at a large academic hospital evaluated each application for a one-week period while on various clinical rotations. RESULTS: Google(TM) was the most frequently used search method and presented multimedia resources but was inefficient for obtaining clinical management information. Epocrates(TM) Pill ID feature was praised for its clinical utility. Medscape(TM) had the highest satisfaction of search and excelled through interactive educational features. Micromedex(TM) offered both FDA and off-label dosing for drugs. DISCUSSION: Google(TM) was the preferred search method for questions related to basic disease processes and multimedia resources, but was inadequate for clinical management. Caution should also be exercised when using Google(TM) in front of patients. Medscape(TM) was the most appealing application due to a broad scope of content and educational features relevant to medical trainees. Students should also be cognizant of how mobile technology may be perceived by their evaluators to avoid false impressions. PMID- 23650488 TI - Comparison of manual versus automated data collection method for an evidence based nursing practice study. AB - OBJECTIVE: The objective of this study was to investigate and improve the use of automated data collection procedures for nursing research and quality assurance. METHODS: A descriptive, correlational study analyzed 44 orthopedic surgical patients who were part of an evidence-based practice (EBP) project examining post operative oxygen therapy at a Midwestern hospital. The automation work attempted to replicate a manually-collected data set from the EBP project. RESULTS: Automation was successful in replicating data collection for study data elements that were available in the clinical data repository. The automation procedures identified 32 "false negative" patients who met the inclusion criteria described in the EBP project but were not selected during the manual data collection. Automating data collection for certain data elements, such as oxygen saturation, proved challenging because of workflow and practice variations and the reliance on disparate sources for data abstraction. Automation also revealed instances of human error including computational and transcription errors as well as incomplete selection of eligible patients. CONCLUSION: Automated data collection for analysis of nursing-specific phenomenon is potentially superior to manual data collection methods. Creation of automated reports and analysis may require initial up-front investment with collaboration between clinicians, researchers and information technology specialists who can manage the ambiguities and challenges of research and quality assurance work in healthcare. PMID- 23650489 TI - Novel computerized health risk appraisal may improve longitudinal health and wellness in primary care: a pilot study. AB - OBJECTIVES: Health Risk Appraisals (HRAs) have been implemented in a variety of settings, however few studies have examined the impact of computerized HRAs systematically in primary care. The study aimed at the development and pilot testing of a novel, comprehensive HRA tool in primary care practices. METHODS: We designed, implemented and pilot tested a novel, web-based HRA tool in four pair matched intervention and control primary care practices (N = 200). Outcomes were measured before and 12 months after the intervention using the HRA, patient surveys, and qualitative feedback. Intervention patients received detailed feedback from the HRA and they were encouraged to discuss the HRA report at their next wellness visit in order to develop a personalized wellness plan. RESULTS: Estimated life expectancy and its derivatives, including Real Age and Wellness Score were significantly impacted by the HRA implementation (P<0.001). The overall rate of 10 preventive maneuvers improved by 4.2% in the intervention group vs. control (P = 0.001). The HRA improved the patient-centeredness of care, measured by the CAHPS PCC-10 survey (P = 0.05). HRA use was strongly associated with better self-rated overall health (OR = 4.94; 95% CI, 3.85-6.36) and improved up-to-dateness for preventive services (OR = 1.22; 95% CI, 1.12-1.32). A generalized linear model suggested that increase in Wellness Score was associated with improvements in patient-centeredness of care, up-to-dateness for preventive services and being in the intervention group (all P<0.03). Patients were satisfied with their HRA-experience, found the HRA report relevant and motivating and thought that it increased their health awareness. Clinicians emphasized that the HRA tool helped them and their patients converge on high-impact, evidence based preventive measures. CONCLUSIONS: Despite study limitations, results suggest that a comprehensive, web-based, and goal-directed HRA tool can improve the receipt of preventive services, patient-centeredness of care, behavioral health outcomes, and various wellness indicators in primary care settings. PMID- 23650490 TI - The contribution of the vaccine adverse event text mining system to the classification of possible Guillain-Barre syndrome reports. AB - BACKGROUND: We previously demonstrated that a general purpose text mining system, the Vaccine adverse event Text Mining (VaeTM) system, could be used to automatically classify reports of an-aphylaxis for post-marketing safety surveillance of vaccines. OBJECTIVE: To evaluate the ability of VaeTM to classify reports to the Vaccine Adverse Event Reporting System (VAERS) of possible Guillain-Barre Syndrome (GBS). METHODS: We used VaeTM to extract the key diagnostic features from the text of reports in VAERS. Then, we applied the Brighton Collaboration (BC) case definition for GBS, and an information retrieval strategy (i.e. the vector space model) to quantify the specific information that is included in the key features extracted by VaeTM and compared it with the encoded information that is already stored in VAERS as Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms (PTs). We also evaluated the contribution of the primary (diagnosis and cause of death) and secondary (second level diagnosis and symptoms) diagnostic VaeTM-based features to the total VaeTM based information. RESULTS: MedDRA captured more information and better supported the classification of reports for GBS than VaeTM (AUC: 0.904 vs. 0.777); the lower performance of VaeTM is likely due to the lack of extraction by VaeTM of specific laboratory results that are included in the BC criteria for GBS. On the other hand, the VaeTM-based classification exhibited greater specificity than the MedDRA-based approach (94.96% vs. 87.65%). Most of the VaeTM-based information was contained in the secondary diagnostic features. CONCLUSION: For GBS, clinical signs and symptoms alone are not sufficient to match MedDRA coding for purposes of case classification, but are preferred if specificity is the priority. PMID- 23650491 TI - Validation of an association rule mining-based method to infer associations between medications and problems. AB - BACKGROUND: In a prior study, we developed methods for automatically identifying associations between medications and problems using association rule mining on a large clinical data warehouse and validated these methods at a single site which used a self-developed electronic health record. OBJECTIVE: To demonstrate the generalizability of these methods by validating them at an external site. METHODS: We received data on medications and problems for 263,597 patients from the University of Texas Health Science Center at Houston Faculty Practice, an ambulatory practice that uses the Allscripts Enterprise commercial electronic health record product. We then conducted association rule mining to identify associated pairs of medications and problems and characterized these associations with five measures of interestingness: support, confidence, chi-square, interest and conviction and compared the top-ranked pairs to a gold standard. RESULTS: 25,088 medication-problem pairs were identified that exceeded our confidence and support thresholds. An analysis of the top 500 pairs according to each measure of interestingness showed a high degree of accuracy for highly-ranked pairs. CONCLUSION: The same technique was successfully employed at the University of Texas and accuracy was comparable to our previous results. Top associations included many medications that are highly specific for a particular problem as well as a large number of common, accurate medication-problem pairs that reflect practice patterns. PMID- 23650492 TI - Design of a medication reconciliation application: facilitating clinician-focused decision making with data from multiple sources. AB - BACKGROUND: Medication reconciliation is an essential, but resource-intensive process without a "gold standard" to measure medication adherence. Medication reconciliation applications that focus on facilitating clinicians' decision making are needed. Since no single available source of medication information is adequate, combining data sources may improve usefulness and outcomes. OBJECTIVES: We aimed to design a medication reconciliation application that could incorporate multiple data sources and convey information about patients' adherence to prescribed medications. We discuss design decisions integral to developing medication reconciliation applications for the electronic health record. The discussion is relevant for health IT developers, clinical providers, administrators, policy makers, and patients. Three hypotheses drove our design of this application: 1) Medication information comes from a variety of sources, each having benefits and limitations; 2) improvements in patient safety can result from reducing the cognitive burden and time required to identify medication changes; 3) a well-designed user interface can facilitate clinicians' understanding and clinical decision making. METHODS: Relying on evidence about interface design and medication reconciliation, an application for the electronic health record at an academic medical center in the U.S. was designed. Multiple decisions that considered the availability, value, and display of the medication data are explored: Information from different sources; interval changes in medications; the sorting of information; and the user interface. RESULTS: THE PROTOTYPE MEDICATION RECONCILIATION APPLICATION DESIGN REFLECTS THE VISUAL ORGANIZATION, CATEGORIZATION, MODALITY OF INTERACTIONS, AND PRESENTATION OF MEDICATION INFORMATION FROM THREE DATA SOURCES: patient, electronic health record, and pharmacy. CONCLUSIONS: A new medication reconciliation user interface displays information from multiple sources, indicates discrepancies among sources, displays information about adherence, and sorts the medication list in a useful display for clinical decision making. Gathering, verifying, and updating medication data are resource-intensive processes. The outcomes of integrating, interpreting, and presenting medication information from multiple sources remain to be studied. PMID- 23650493 TI - Monitoring adherence to evidence-based practices: a method to utilize HL7 messages from hospital information systems. AB - BACKGROUND: Clinical pathways are evidence-based recommendations for treating a diagnosis. Although implementations of clinical pathways have reduced medical errors, lowered costs, and improved patient outcomes, monitoring whether a patient is following the intended pathway is problematic. Implementing a variance reporting program is impeded by the lack of a reliable source of electronic data and automatic retrieval methods. OBJECTIVES: Our objective is to develop an automated method of measuring and reporting patient variance from a clinical pathway. METHODS: We identify a viable and ubiquitous data source for establishing the realized patient's path- Health Level Seven (HL7) formatted message exchanges between Hospital Information Systems. This is in contrast to current practices in most hospitals where data for clinical pathway variance reporting is obtained from multiple data sources, often retrospectively. This paper develops a method to use message exchanges to automatically establish and compare a patient's path against a clinical pathway. Our method not only considers pathway activities as is common practice, but also extracts patient outcomes from HL7 messages and reports this in addition to the variance. RESULTS: Using data from our partner hospital, we illustrate our clinical pathway variance analysis tool using major joint replacement patients. We validate our method by comparing audit results for a random sample of HL7 constructed pathways with data extracted from patient charts. We report several variances such as omitted laboratory tests or additional activities such as blood transfusions. Our method successfully identifies variances and reports them in a quantified way to support decisions related to quality control. CONCLUSIONS: OUR APPROACH DIFFERS FROM PREVIOUS STUDIES IN THAT A QUANTITATIVE MEASURE IS ESTABLISHED OVER THREE DIMENSIONS: (1) omissions from the pathway, (2) additions to the pathway, and (3) patient outcomes. By examining variances providers can evaluate clinical decisions, and support quality feedback and training mechanisms. PMID- 23650494 TI - Provider use of and attitudes towards an active clinical alert: a case study in decision support. AB - BACKGROUND: In a previous study, we reported on a successful clinical decision support (CDS) intervention designed to improve electronic problem list accuracy, but did not study variability of provider response to the intervention or provider attitudes towards it. The alert system accurately predicted missing problem list items based on health data captured in a patient's electronic medical record. OBJECTIVE: To assess provider attitudes towards a rule-based CDS alert system as well as heterogeneity of acceptance rates across providers. METHODS: We conducted a by-provider analysis of alert logs from the previous study. In addition, we assessed provider opinions of the intervention via an email survey of providers who received the alerts (n = 140). RESULTS: Although the alert acceptance rate was 38.1%, individual provider acceptance rates varied widely, with an interquartile range (IQR) of 14.8%-54.4%, and many outliers accepting none or nearly all of the alerts they received. No demographic variables, including degree, gender, age, assigned clinic, medical school or graduation year predicted acceptance rates. Providers' self-reported acceptance rate and perceived alert frequency were only moderately correlated with actual acceptance rates and alert frequency. CONCLUSIONS: Acceptance of this CDS intervention among providers was highly variable but this heterogeneity is not explained by measured demographic factors, suggesting that alert acceptance is a complex and individual phenomenon. Furthermore, providers' self-reports of their use of the CDS alerting system correlated only modestly with logged usage. PMID- 23650495 TI - Prediction and validation of gene-disease associations using methods inspired by social network analyses. AB - Correctly identifying associations of genes with diseases has long been a goal in biology. With the emergence of large-scale gene-phenotype association datasets in biology, we can leverage statistical and machine learning methods to help us achieve this goal. In this paper, we present two methods for predicting gene disease associations based on functional gene associations and gene-phenotype associations in model organisms. The first method, the Katz measure, is motivated from its success in social network link prediction, and is very closely related to some of the recent methods proposed for gene-disease association inference. The second method, called Catapult (Combining dATa Across species using Positive Unlabeled Learning Techniques), is a supervised machine learning method that uses a biased support vector machine where the features are derived from walks in a heterogeneous gene-trait network. We study the performance of the proposed methods and related state-of-the-art methods using two different evaluation strategies, on two distinct data sets, namely OMIM phenotypes and drug-target interactions. Finally, by measuring the performance of the methods using two different evaluation strategies, we show that even though both methods perform very well, the Katz measure is better at identifying associations between traits and poorly studied genes, whereas Catapult is better suited to correctly identifying gene-trait associations overall [corrected]. PMID- 23650496 TI - Pharmacokinetics and efficacy of PEGylated liposomal doxorubicin in an intracranial model of breast cancer. AB - INTRODUCTION: Breast cancer brain metastases (BCBM) are a challenging consequence of advanced BC. Nanoparticle agents, including liposomes, have shown enhanced delivery to solid tumors and brain. We compared pharmacokinetics (PK) and efficacy of PEGylated liposomal doxorubicin (PLD) with non-liposomal doxorubicin (NonL-doxo) in an intracranial model of BC. METHODS: Athymic mice were inoculated intracerebrally with MDA-MB-231-BR-luciferase-expressing cells. Tumor-bearing mice were administered PLD or NonL-doxo at 6 mg/kg IV * 1 and were euthanized prior to and 0.083, 1, 3, 6, 24, 72 and 96 h post-treatment. Samples were processed to measure sum total doxorubicin via HPLC. PLD and NonL-doxo were administered IV weekly as single agents (6 mg/kg) or in combination (4.5 mg/kg) with the PARP inhibitor, ABT-888, PO 25 mg/kg/day. Efficacy was assessed by survival and bioluminescence. RESULTS: Treatment with PLD resulted in approximately 1,500-fold higher plasma and 20-fold higher intracranial tumor sum total doxorubicin AUC compared with NonL-doxo. PLD was detected at 96 h; NonL doxo was undetectable after 24 h in plasma and tumor. Median survival of PLD treated animals was 32 days (d, [CI] 31-38), which was significantly longer than controls (26d [CI 25-28]; p = 0.0012) or NonL-doxo treatment (23.5d [CI 18-28], p = 0.0002). Combination treatment with PLD/ABT-888 yielded improved survival compared to NonL-doxo/ABT-888 (35d [CI 31-38] versus 29.5d [CI 25-34]; p = 0.006). CONCLUSIONS: PLD provides both PK and efficacy advantage over NonL-doxo in the treatment of an in vivo model of BCBM. The results provide preclinical rationale to translate findings into early phase trials of PLD, with or without ABT-888, for patients with BCBM. PMID- 23650497 TI - Detection and characterization of tick-borne encephalitis virus in Baltic countries and eastern Poland. AB - Ticks were collected from the vegetation in the Baltic countries Estonia, Latvia, Lithuania and eastern Poland and analyzed for the presence of tick-borne encephalitis virus (TBEV) by amplification of the partial E and NS3 genes. In Estonia we found statistically significant differences in the TBEV prevalence between I. persulcatus and I. ricinus ticks (4.23% and 0.42%, respectively). In Latvia, the difference in TBEV prevalence between the two species was not statistically significant (1.02% for I. persulcatus and 1.51% for I. ricinus, respectively). In Lithuania and Poland TBEV was detected in 0.24% and 0.11% of I. ricinus ticks, respectively. Genetic characterization of the partial E and NS3 sequences demonstrated that the TBEV strains belonged to the European subtype in all countries, as well as to the Siberian subtype in Estonia. We also found that in areas where ranges of two tick species overlap, the TBEV subtypes may be detected not only in their natural vector, but also in sympatric tick species. PMID- 23650498 TI - Do parentese prosody and fathers' involvement in interacting facilitate social interaction in infants who later develop autism? AB - BACKGROUND: Whether development of autism impacts the interactive process between an infant and his/her parents remains an unexplored issue. METHODOLOGY AND PRINCIPAL FINDINGS: Using computational analysis taking into account synchronic behaviors and emotional prosody (parentese), we assessed the course of infants' responses to parents' type of speech in home movies from typically developing (TD) infants and infants who will subsequently develop autism aged less than 18 months. Our findings indicate: that parentese was significantly associated with infant responses to parental vocalizations involving orientation towards other people and with infant receptive behaviours; that parents of infants developing autism displayed more intense solicitations that were rich in parentese; that fathers of infants developing autism spoke to their infants more than fathers of TD infants; and that fathers' vocalizations were significantly associated with intersubjective responses and active behaviours in infants who subsequently developed autism. CONCLUSION: The parents of infants who will later develop autism change their interactive pattern of behaviour by both increasing parentese and father's involvement in interacting with infants; both are significantly associated with infant's social responses. We stress the possible therapeutic implications of these findings and its implication for Dean Falk's theory regarding pre-linguistic evolution in early hominins. PMID- 23650499 TI - Targeting mitochondrial STAT3 with the novel phospho-valproic acid (MDC-1112) inhibits pancreatic cancer growth in mice. AB - New agents are needed to treat pancreatic cancer, one of the most lethal human malignancies. We synthesized phospho-valproic acid, a novel valproic acid derivative, (P-V; MDC-1112) and evaluated its efficacy in the control of pancreatic cancer. P-V inhibited the growth of human pancreatic cancer xenografts in mice by 60%-97%, and 100% when combined with cimetidine. The dominant molecular target of P-V was STAT3. P-V inhibited the phosphorylation of JAK2 and Src, and the Hsp90-STAT3 association, suppressing the activating phosphorylation of STAT3, which in turn reduced the expression of STAT3-dependent proteins Bcl xL, Mcl-1 and survivin. P-V also reduced STAT3 levels in the mitochondria by preventing its translocation from the cytosol, and enhanced the mitochondrial levels of reactive oxygen species, which triggered apoptosis. Inhibition of mitochondrial STAT3 by P-V was required for its anticancer effect; mitochondrial STAT3 overexpression rescued animals from the tumor growth inhibition by P-V. Our results indicate that P-V is a promising candidate drug against pancreatic cancer and establish mitochondrial STAT3 as its key molecular target. PMID- 23650500 TI - Genotype to phenotype mapping and the fitness landscape of the E. coli lac promoter. AB - Genotype-to-phenotype maps and the related fitness landscapes that include epistatic interactions are difficult to measure because of their high dimensional structure. Here we construct such a map using the recently collected corpora of high-throughput sequence data from the 75 base pairs long mutagenized E. coli lac promoter region, where each sequence is associated with its phenotype, the induced transcriptional activity measured by a fluorescent reporter. We find that the additive (non-epistatic) contributions of individual mutations account for about two-thirds of the explainable phenotype variance, while pairwise epistasis explains about 7% of the variance for the full mutagenized sequence and about 15% for the subsequence associated with protein binding sites. Surprisingly, there is no evidence for third order epistatic contributions, and our inferred fitness landscape is essentially single peaked, with a small amount of antagonistic epistasis. There is a significant selective pressure on the wild type, which we deduce to be multi-objective optimal for gene expression in environments with different nutrient sources. We identify transcription factor (CRP) and RNA polymerase binding sites in the promotor region and their interactions without difficult optimization steps. In particular, we observe evidence for previously unexplored genetic regulatory mechanisms, possibly kinetic in nature. We conclude with a cautionary note that inferred properties of fitness landscapes may be severely influenced by biases in the sequence data. PMID- 23650502 TI - A cross-sectional survey of the association between bilateral topical prostaglandin analogue use and ocular adnexal features. AB - We studied the relation between prostaglandin analogue use and ocular adnexal features. We used a prospective, cross-sectional study involving 157 current, 15 past, and 171 never users of prostaglandin analogues. Patients 50 years of age or older and without conditions affecting ocular adnexal anatomy underwent glaucoma medication use history, external digital photography and systematic external adnexal exam. Two masked readers assessed the digital photos for upper lid dermatochalasis and lower lid steatoblepharon using a validated grading scheme. Another masked clinical examiner also assessed upper lid ptosis, levator muscle function, and inferior scleral show. We performed ordinal logistic regression analysis accounting for multiple covariates to assess the relation between prostaglandin analogue use and adnexal features. Multivariable analyses indicated there was a 230-fold increased risk of incremental involution of dermatochalasis (odds ratio (OR) = 2.30; 95% confidence interval (CI) 1.43-3.69; p = 5.44E-04) and a 249-fold increased risk of incremental loss of lower lid steatoblepharon (OR = 2.49; 95% CI, 1.54-4.03; p= 1.98E-04) associated with current prostaglandin analogue use (bimatoprost 0.03%, travoprost 0.005%, or latanoprost 0.004%) versus prostaglandin analogue never or past users. Upper lid ptosis (OR = 4.04; 95% CI, 2.43-6.72; p = 7.37E-08), levator dysfunction (OR = 7.51; 95% CI, 3.39-16.65; p = 6.74E-07) and lower lid retraction (OR = 2.60; 95% CI, 1.58-4.28; p = 1.72E-04) were highly associated with current prostaglandin analogue use versus prostaglandin analogue never or past users. The associations between prostaglandin analogue use and deepening of the upper lid sulci and between prostaglandin analogue use and loss of inferior periorbital fat are confirmed in this multivariable analysis. The associations between prostaglandin analogue use and levator muscle dysfunction and between prostaglandin analogue use and upper lid ptosis represent significant side effects that could impact visual function in glaucoma patients. PMID- 23650501 TI - A randomized controlled trial of cognitive training using a visual speed of processing intervention in middle aged and older adults. AB - BACKGROUND: Age-related cognitive decline is common and may lead to substantial difficulties and disabilities in everyday life. We hypothesized that 10 hours of visual speed of processing training would prevent age-related declines and potentially improve cognitive processing speed. METHODS: Within two age bands (50 64 and >= 65) 681 patients were randomized to (a) three computerized visual speed of processing training arms (10 hours on-site, 14 hours on-site, or 10 hours at home) or (b) an on-site attention control group using computerized crossword puzzles for 10 hours. The primary outcome was the Useful Field of View (UFOV) test, and the secondary outcomes were the Trail Making (Trails) A and B Tests, Symbol Digit Modalities Test (SDMT), Stroop Color and Word Tests, Controlled Oral Word Association Test (COWAT), and the Digit Vigilance Test (DVT), which were assessed at baseline and at one year. 620 participants (91%) completed the study and were included in the analyses. Linear mixed models were used with Blom rank transformations within age bands. RESULTS: All intervention groups had (p<0.05) small to medium standardized effect size improvements on UFOV (Cohen's d = -0.322 to -0.579, depending on intervention arm), Trails A (d = -0.204 to -0.265), Trails B (d = -0.225 to -0.320), SDMT (d = 0.263 to 0.351), and Stroop Word (d = 0.240 to 0.271). Converted to years of protection against age-related cognitive declines, these effects reflect 3.0 to 4.1 years on UFOV, 2.2 to 3.5 years on Trails A, 1.5 to 2.0 years on Trails B, 5.4 to 6.6 years on SDMT, and 2.3 to 2.7 years on Stroop Word. CONCLUSION: Visual speed of processing training delivered on-site or at-home to middle-aged or older adults using standard home computers resulted in stabilization or improvement in several cognitive function tests. Widespread implementation of this intervention is feasible. TRIAL REGISTRATION: ClinicalTrials.gov NCT-01165463. PMID- 23650503 TI - Neuromuscular adjustments of the quadriceps muscle after repeated cycling sprints. AB - PURPOSE: This study investigated the supraspinal processes of fatigue of the quadriceps muscle in response to repeated cycling sprints. METHODS: Twelve active individuals performed 10 * 6-s "all-out" sprints on a cycle ergometer (recovery = 30 s), followed 6 min later by 5 * 6-s sprints (recovery = 30 s). Transcranial magnetic and electrical femoral nerve stimulations during brief (5-s) and sustained (30-s) isometric contractions of the knee extensors were performed before and 3 min post-exercise. RESULTS: Maximal strength of the knee extensors decreased during brief and sustained contractions (~11% and 9%, respectively; P<0.001). Peripheral and cortical voluntary activation, motor evoked potential amplitude and silent period duration responses measured during briefs contractions were unaltered (P>0.05). While cortical voluntary activation declined (P<0.01) during the sustained maximal contraction in both test sessions, larger reductions occurred (P<0.05) after exercise. Lastly, resting twitch amplitude in response to both femoral nerve and cortical stimulations was largely (> 40%) reduced (P<0.001) following exercise. CONCLUSION: The capacity of the motor cortex to optimally drive the knee extensors following a repeated-sprint test was shown in sustained, but not brief, maximal isometric contractions. Additionally, peripheral factors were largely involved in the exercise-induced impairment in neuromuscular function, while corticospinal excitability was well preserved. PMID- 23650504 TI - Reactivity of dogs' brain oscillations to visual stimuli measured with non invasive electroencephalography. AB - Studying cognition of domestic dogs has gone through a renaissance within the last decades. However, although the behavioral studies of dogs are beginning to be common in the field of animal cognition, the neural events underlying cognition remain unknown. Here, we employed a non-invasive electroencephalography, with adhesive electrodes attached to the top of the skin, to measure brain activity of from 8 domestic dogs (Canis familiaris) while they stayed still to observe photos of dog and human faces. Spontaneous oscillatory activity of the dogs, peaking in the sensors over the parieto-occipital cortex, was suppressed statistically significantly during visual task compared with resting activity at the frequency of 15-30 Hz. Moreover, a stimulus-induced low frequency (~2-6 Hz) suppression locked to the stimulus onset was evident at the frontal sensors, possibly reflecting a motor rhythm guiding the exploratory eye movements. The results suggest task-related reactivity of the macroscopic oscillatory activity in the dog brain. To our knowledge, the study is the first to reveal non-invasively measured reactivity of brain electrophysiological oscillations in healthy dogs, and it has been based purely on positive operant conditional training, without the need for movement restriction or medication. PMID- 23650505 TI - A randomized, observer-blinded immunogenicity trial of Cervarix((r)) and Gardasil((r)) Human Papillomavirus vaccines in 12-15 year old girls. AB - BACKGROUND: The current generation of Human Papillomavirus (HPV) vaccines, Cervarix(r) and Gardasil(r), exhibit a high degree of efficacy in clinical trials against the two high-risk (HR) genotypes represented in the vaccines (HPV16 and HPV18). High levels of neutralizing antibodies are elicited against the vaccine types, consistent with preclinical data showing that neutralizing antibodies can mediate type-specific protection in the absence of other immune effectors. The vaccines also confer protection against some closely related non-vaccine HR HPV types, although the vaccines appear to differ in their degree of cross protection. The mechanism of vaccine-induced cross-protection is unknown. This study sought to compare the breadth and magnitudes of neutralizing antibodies against non-vaccine types elicited by both vaccines and establish whether such antibodies could be detected in the genital secretions of vaccinated individuals. METHODS AND FINDINGS: Serum and genital samples were collected from 12-15 year old girls following vaccination with either Cervarix(r) (n = 96) or Gardasil(r) (n = 102) HPV vaccine. Serum-neutralizing antibody responses against non-vaccine HPV types were broader and of higher magnitude in the Cervarix(r), compared to the Gardasil(r), vaccinated individuals. Levels of neutralizing and binding antibodies in genital secretions were closely associated with those found in the serum (r = 0.869), with Cervarix(r) having a median 2.5 (inter-quartile range, 1.7-3.5) fold higher geometric mean HPV-specific IgG ratio in serum and genital samples than Gardasil(r) (p = 0.0047). There was a strong positive association between cross-neutralizing antibody seropositivity and available HPV vaccine trial efficacy data against non-vaccine types. CONCLUSIONS: These data demonstrate for the first time that cross-neutralizing antibodies can be detected at the genital site of infection and support the possibility that cross neutralizing antibodies play a role in the cross-protection against HPV infection and disease that has been reported for the current HPV vaccines. TRIAL REGISTRATION: ClinicalTrials.gov NCT00956553. PMID- 23650506 TI - Independent and combined effects of physical activity and sedentary behavior on blood pressure in adolescents: gender differences in two cross-sectional studies. AB - OBJECTIVES: To examine the independent and combined association of physical activity (PA) and sedentary behavior (SB) on both systolic (SBP) and diastolic blood pressure (DBP) in adolescents from two observational studies. METHODS: Participants from two cross-sectional studies, one conducted in Europe (n = 3,308; HELENA study) and the other in Brazil (n = 991; BRACAH study), were selected by complex sampling. Systolic and diastolic blood pressure (outcomes), PA and SB, both independently and combined, and potential confounders were analyzed. Associations were examined by multilevel linear regression. RESULTS: Performing the recommended amount of PA (>= 60 min/d) attenuated the effect of SB on DBP in BRACAH study girls and in boys from both studies. In contrast, PA did not attenuate the effects of SB on the SBP of girls in the HELENA study. The combination of less than recommended levels of PA with 2-4 h/d of sedentary behavior was found to be associated with increased SBP in boys from both studies. CONCLUSIONS: Meeting current PA recommendations could mediate the association between SB and DBP in both sexes. In boys, the joint effect of low levels of PA and excessive sedentary activity increases SBP levels. Longitudinal studies are required to confirm these findings. PMID- 23650507 TI - Novel insulin sensitizer modulates nutrient sensing pathways and maintains beta cell phenotype in human islets. AB - Major bottlenecks in the expansion of human beta-cell mass are limited proliferation, loss of beta-cell phenotype, and increased apoptosis. In our previous studies, activation of Wnt and mTOR signaling significantly enhanced human beta-cell proliferation. However, isolated human islets displayed insulin signaling pathway resistance, due in part to chronic activation of mTOR/S6K1 signaling that results in negative feedback of the insulin signaling pathway and a loss of Akt phosphorylation and insulin content. We evaluated the effects of a new generation insulin sensitizer, MSDC-0160, on restoring insulin/IGF-1 sensitivity and insulin content in human beta-cells. This novel TZD has low affinity for binding and activation of PPARgamma and has insulin-sensitizing effects in mouse models of diabetes and ability to lower glucose in Phase 2 clinical trials. MSDC-0160 treatment of human islets increased AMPK activity and reduced mTOR activity. This was associated with the restoration of IGF-1-induced phosphorylation of Akt, GSK-3, and increased protein expression of Pdx1. Furthermore, MSDC-0160 in combination with IGF-1 and 8 mM glucose increased beta cell specific gene expression of insulin, pdx1, nkx6.1, and nkx2.2, and maintained insulin content without altering glucose-stimulated insulin secretion. Human islets were unable to simultaneously promote DNA synthesis and maintain the beta-cell phenotype. Lithium-induced GSK-3 inhibition that promotes DNA synthesis blocked the ability of MSDC-0160 to maintain the beta-cell phenotype. Conversely, MSDC-0160 prevented an increase in DNA synthesis by blocking beta-catenin nuclear translocation. Due to the counteracting pathways involved in these processes, we employed a sequential ex vivo strategy to first induce human islet DNA synthesis, followed by MSDC-0160 to promote the beta-cell phenotype and insulin content. This new generation PPARgamma sparing insulin sensitizer may provide an initial tool for relieving inherent human islet insulin signaling pathway resistance that is necessary to preserve the beta-cell phenotype during beta-cell expansion for the treatment of diabetes. PMID- 23650508 TI - Analysis of high-altitude de-acclimatization syndrome after exposure to high altitudes: a cluster-randomized controlled trial. AB - The syndrome of high-altitude de-acclimatization commonly takes place after long term exposure to high altitudes upon return to low altitudes. The syndrome severely affects the returnee's quality of life. However, little attention has been paid to careful characterization of the syndrome and their underlying mechanisms. Male subjects from Chongqing (n = 67, 180 m) and Kunming (n = 70, 1800 m) visited a high-altitude area (3650 m) about 6 months and then returned to low-altitude. After they came back, all subjects were evaluated for high-altitude de-acclimatization syndrome on the 3(rd), 50(th), and 100(th). Symptom scores, routine blood and blood gas tests, and myocardial zymograms assay were used for observation their syndrome. The results showed that the incidence and severity of symptoms had decreased markedly on the 50(th) and 100(th) days, compared with the 3(rd) day. The symptom scores and incidence of different symptoms were lower among subjects returning to Kunming than among those returning to Chongqing. On the 3(rd) day, RBC, Hb, Hct, CK, CK-MB, and LDH values were significantly lower than values recorded at high altitudes, but they were higher than baseline values. On the 50(th) day, these values were not different from baseline values, but LDH levels did not return to baseline until the 100(th) day. These data show that, subjects who suffered high-altitude de-acclimatization syndrome, the recovery fully processes takes a long time (>= 100(th) days). The appearance of the syndrome is found to be related to the changes in RBC, Hb, Hct, CK, CK-MB, and LDH levels, which should be caused by reoxygenation after hypoxia. PMID- 23650509 TI - Construction of ontology augmented networks for protein complex prediction. AB - Protein complexes are of great importance in understanding the principles of cellular organization and function. The increase in available protein-protein interaction data, gene ontology and other resources make it possible to develop computational methods for protein complex prediction. Most existing methods focus mainly on the topological structure of protein-protein interaction networks, and largely ignore the gene ontology annotation information. In this article, we constructed ontology augmented networks with protein-protein interaction data and gene ontology, which effectively unified the topological structure of protein protein interaction networks and the similarity of gene ontology annotations into unified distance measures. After constructing ontology augmented networks, a novel method (clustering based on ontology augmented networks) was proposed to predict protein complexes, which was capable of taking into account the topological structure of the protein-protein interaction network, as well as the similarity of gene ontology annotations. Our method was applied to two different yeast protein-protein interaction datasets and predicted many well-known complexes. The experimental results showed that (i) ontology augmented networks and the unified distance measure can effectively combine the structure closeness and gene ontology annotation similarity; (ii) our method is valuable in predicting protein complexes and has higher F1 and accuracy compared to other competing methods. PMID- 23650510 TI - Home range utilisation and long-range movement of estuarine crocodiles during the breeding and nesting season. AB - The estuarine crocodile (Crocodylus porosus) is the apex-predator in waterways and coastlines throughout south-east Asia and Australasia. C. porosus pose a potential risk to humans, and management strategies are implemented to control their movement and distribution. Here we used GPS-based telemetry to accurately record geographical location of adult C. porosus during the breeding and nesting season. The purpose of the study was to assess how C. porosus movement and distribution may be influenced by localised social conditions. During breeding, the females (2.92 +/- 0.013 metres total length (TL), mean +/- S.E., n = 4) occupied an area<1 km length of river, but to nest they travelled up to 54 km away from the breeding area. All tagged male C. porosus sustained high rates of movement (6.49 +/- 0.9 km d(-1); n = 8) during the breeding and nesting period. The orientation of the daily movements differed between individuals revealing two discontinuous behavioural strategies. Five tagged male C. porosus (4.17 +/- 0.14 m TL) exhibited a 'site-fidelic' strategy and moved within well-defined zones around the female home range areas. In contrast, three males (3.81 +/- 0.08 m TL) exhibited 'nomadic' behaviour where they travelled continually throughout hundreds of kilometres of waterway. We argue that the 'site-fidelic' males patrolled territories around the female home ranges to maximise reproductive success, whilst the 'nomadic' males were subordinate animals that were forced to range over a far greater area in search of unguarded females. We conclude that C. porosus are highly mobile animals existing within a complex social system, and mate/con-specific interactions are likely to have a profound effect upon population density and distribution, and an individual's travel potential. We recommend that impacts on socio-spatial behaviour are considered prior to the implementation of management interventions. PMID- 23650511 TI - Impact of continuous positive airway pressure treatment on left ventricular ejection fraction in patients with obstructive sleep apnea: a meta-analysis of randomized controlled trials. AB - BACKGROUND: It has been known for a long time that obstructive sleep apnea (OSA) is associated with a decreased left ventricular ejection fraction (LVEF). Continuous positive airway pressure (CPAP) is the gold standard treatment for OSA; however, it is unknown whether or not CPAP treatment will improve the LVEF. The aim of the current study was to assess whether or not CPAP treatment improves the LVEF. A meta-analysis was conducted to determine the effect of CPAP treatment on the LVEF among patients with OSA. METHODS: A literature search of PubMed, the Web of Science, and Cochrane Collaboration's database were utilized to identify eligible reports for this trial. Ten randomized controlled trails were examined and the meta-analysis was performed using STATA 11. RESULTS: A significant improvement in the LVEF was observed after CPAP treatment (weighted mean difference(WMD) = 3.59, 95% CI = 1.74-5.44; P<0.001). Subgroup analysis revealed that patients with OSA and heart failure had a significant improvement in the LVEF after CPAP treatment (WMD = 5.18, 95% CI = 3.27-7.08; P<0.001); however, the LVEF of patients with OSA only increased 1.11% and there was no statistical significance (WMD = 1.11, 95% CI = -1.13-3.35; P = 0.331). Furthermore, based on univariate meta-regression analysis, only the baseline AHI had a statistically significant correlation with the LVEF. CONCLUSIONS: Our meta-analysis supports the notion that CPAP may improve the LVEF among patients with OSA. PMID- 23650512 TI - Measuring EGFR separations on cells with ~10 nm resolution via fluorophore localization imaging with photobleaching. AB - Detecting receptor dimerisation and other forms of clustering on the cell surface depends on methods capable of determining protein-protein separations with high resolution in the ~10-50 nm range. However, this distance range poses a significant challenge because it is too large for fluorescence resonance energy transfer and contains distances too small for all other techniques capable of high-resolution in cells. Here we have adapted the technique of fluorophore localisation imaging with photobleaching to measure inter-receptor separations in the cellular environment. Using the epidermal growth factor receptor, a key cancer target molecule, we demonstrate ~10 nm resolution while continuously covering the range of ~10-80 nm. By labelling the receptor on cells expressing low receptor numbers with a fluorescent antagonist we have found inter-receptor separations all the way up from 8 nm to 59 nm. Our data are consistent with epidermal growth factor receptors being able to form homo-polymers of at least 10 receptors in the absence of activating ligands. PMID- 23650513 TI - Macro-invertebrate decline in surface water polluted with imidacloprid. AB - Imidacloprid is one of the most widely used insecticides in the world. Its concentration in surface water exceeds the water quality norms in many parts of the Netherlands. Several studies have demonstrated harmful effects of this neonicotinoid to a wide range of non-target species. Therefore we expected that surface water pollution with imidacloprid would negatively impact aquatic ecosystems. Availability of extensive monitoring data on the abundance of aquatic macro-invertebrate species, and on imidacloprid concentrations in surface water in the Netherlands enabled us to test this hypothesis. Our regression analysis showed a significant negative relationship (P<0.001) between macro-invertebrate abundance and imidacloprid concentration for all species pooled. A significant negative relationship was also found for the orders Amphipoda, Basommatophora, Diptera, Ephemeroptera and Isopoda, and for several species separately. The order Odonata had a negative relationship very close to the significance threshold of 0.05 (P = 0.051). However, in accordance with previous research, a positive relationship was found for the order Actinedida. We used the monitoring field data to test whether the existing three water quality norms for imidacloprid in the Netherlands are protective in real conditions. Our data show that macrofauna abundance drops sharply between 13 and 67 ng l(-1). For aquatic ecosystem protection, two of the norms are not protective at all while the strictest norm of 13 ng l(-1) (MTR) seems somewhat protective. In addition to the existing experimental evidence on the negative effects of imidacloprid on invertebrate life, our study, based on data from large-scale field monitoring during multiple years, shows that serious concern about the far-reaching consequences of the abundant use of imidacloprid for aquatic ecosystems is justified. PMID- 23650514 TI - Conservation implications of changes in endemic Hawaiian Drosophilidae diversity across land use gradients. AB - Endemic Hawaiian Drosophilidae, a radiation of nearly 1000 species including 13 federally listed as endangered, occur mostly in intact native forest, 500-1500 m above sea level. But their persistence in disturbed forest and agricultural areas has not been documented. Thus, control efforts for agricultural pests may impact endemic species if previously undocumented refugia in agricultural areas may play a role in their conservation. To quantify whether invasive plants and agriculture habitats may harbor endemic Drosophilidae, we established standardized trapping arrays, with traps typically designed to control invasive fruit flies (Tephritidae), with 81 sites across native, disturbed and agricultural land use gradients on the islands of Hawai'i and Maui. We collected and identified, to species level, over 22,000 specimens. We found 121 of the possible 292 species expected to occur in the sampled areas, and the majority (91%) of the captured specimens belonged to 24 common species. Species diversity and numbers were greatest in the native forest, but 55% of the species occurred in the invasive strawberry guava belt and plantation forest, adjacent to and almost 500 m from native forest, and 22 species were collected in orchards and nonnative forest as far as 10 km from native habitats. Their persistence outside of native forest suggests that more careful management of disturbed forest and a reassessment of its conservation value are in order. Conservation efforts and assessments of native forest integrity should include the subset of species restricted to intact native forest, since these species are highly localized and particularly sensitive. Additionally, future efforts to control invasive pest fruit flies should consider the nontarget impacts of maintaining traps in and near native forest. This survey project demonstrates the utility of thorough biotic surveys and taxonomic expertise in developing both sensitive species lists and baseline diversity indices for future conservation and monitoring efforts. PMID- 23650515 TI - Enzyme inhibitor studies reveal complex control of methyl-D-erythritol 4 phosphate (MEP) pathway enzyme expression in Catharanthus roseus. AB - In Catharanthus roseus, the monoterpene moiety exerts a strong flux control for monoterpene indole alkaloid (MIA) formation. Monoterpene synthesis depends on the methyl-D-erythritol 4-phosphate (MEP) pathway. Here, we have explored the regulation of this pathway in response to developmental and environmental cues and in response to specific enzyme inhibitors. For the MEP pathway entry enzyme 1 deoxy-D-xylulose 5-phosphate synthase (DXS), a new (type I) DXS isoform, CrDXS1, has been cloned, which, in contrast to previous reports on type II CrDXS, was not transcriptionally activated by the transcription factor ORCA3. Regulation of the MEP pathway in response to metabolic perturbations has been explored using the enzyme inhibitors clomazone (precursor of 5-ketochlomazone, inhibitor of DXS) and fosmidomycin (inhibitor of deoxyxylulose 5-phosphate reductoisomerase (DXR)), respectively. Young leaves of non-flowering plants were exposed to both inhibitors, adopting a non-invasive in vivo technique. Transcripts and proteins of DXS (3 isoforms), DXR, and hydroxymethylbutenyl diphosphate synthase (HDS) were monitored, and protein stability was followed in isolated chloroplasts. Transcripts for DXS1 were repressed by both inhibitors, whereas transcripts for DXS2A&B, DXR and HDS increased after clomazone treatment but were barely affected by fosmidomycin treatment. DXS protein accumulated in response to both inhibitors, whereas DXR and HDS proteins were less affected. Fosmidomycin-induced accumulation of DXS protein indicated substantial posttranscriptional regulation. Furthermore, fosmidomycin effectively protected DXR against degradation in planta and in isolated chloroplasts. Thus our results suggest that DXR protein stability may be affected by substrate binding. In summary, the present results provide novel insight into the regulation of DXS expression in C. roseus in response to MEP-pathway perturbation. PMID- 23650516 TI - Human RECQ1 interacts with Ku70/80 and modulates DNA end-joining of double-strand breaks. AB - Genomic instability is a known precursor to cancer and aging. The RecQ helicases are a highly conserved family of DNA-unwinding enzymes that play key roles in maintaining genome stability in all living organisms. Human RecQ homologs include RECQ1, BLM, WRN, RECQ4, and RECQ5beta, three of which have been linked to diseases with elevated risk of cancer and growth defects (Bloom Syndrome and Rothmund-Thomson Syndrome) or premature aging (Werner Syndrome). RECQ1, the first RecQ helicase discovered and the most abundant in human cells, is the least well understood of the five human RecQ homologs. We have previously described that knockout of RECQ1 in mice or knockdown of its expression in human cells results in elevated frequency of spontaneous sister chromatid exchanges, chromosomal instability, increased load of DNA damage and heightened sensitivity to ionizing radiation. We have now obtained evidence implicating RECQ1 in the nonhomologous end-joining pathway of DNA double-strand break repair. We show that RECQ1 interacts directly with the Ku70/80 subunit of the DNA-PK complex, and depletion of RECQ1 results in reduced end-joining in cell free extracts. In vitro, RECQ1 binds and unwinds the Ku70/80-bound partial duplex DNA substrate efficiently. Linear DNA is co-bound by RECQ1 and Ku70/80, and DNA binding by Ku70/80 is modulated by RECQ1. Collectively, these results provide the first evidence for an interaction of RECQ1 with Ku70/80 and a role of the human RecQ helicase in double strand break repair through nonhomologous end-joining. PMID- 23650517 TI - ARID1A alterations are associated with FGFR3-wild type, poor-prognosis, urothelial bladder tumors. AB - Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological, genetic, and epigenetic levels. Exome sequencing has identified ARID1A as a novel tumor suppressor gene coding for a chromatin remodeling protein that is mutated in UBC. Here, we assess ARID1A alterations in two series of patients with UBC. In the first tumor series, we analyze exons 2-20 in 52 primary UBC and find that all mutant tumors belong to the aggressive UBC phenotype (high grade non-muscle invasive and muscle invasive tumors) (P = 0.05). In a second series (n = 84), we assess ARID1A expression using immunohistochemistry, a surrogate for mutation analysis, and find that loss of expression increases with higher stage/grade, it is inversely associated with FGFR3 overexpression (P = 0.03) but it is not correlated with p53 overexpression (P = 0.30). We also analyzed the expression of cytokeratins in the same set of tumor and find, using unsupervised clustering, that tumors with ARID1A loss of expression are generally KRT5/6-low. In this patient series, loss of ARID1A expression is also associated with worse prognosis, likely reflecting the higher prevalence of losses found in tumors of higher stage and grade. The independent findings in these two sets of patients strongly support the notion that ARID1A inactivation is a key player in bladder carcinogenesis occurring predominantly in FGFR3 wild type tumors. PMID- 23650518 TI - The complexity of standing postural control in older adults: a modified detrended fluctuation analysis based upon the empirical mode decomposition algorithm. AB - Human aging into senescence diminishes the capacity of the postural control system to adapt to the stressors of everyday life. Diminished adaptive capacity may be reflected by a loss of the fractal-like, multiscale complexity within the dynamics of standing postural sway (i.e., center-of-pressure, COP). We therefore studied the relationship between COP complexity and adaptive capacity in 22 older and 22 younger healthy adults. COP magnitude dynamics were assessed from raw data during quiet standing with eyes open and closed, and complexity was quantified with a new technique termed empirical mode decomposition embedded detrended fluctuation analysis (EMD-DFA). Adaptive capacity of the postural control system was assessed with the sharpened Romberg test. As compared to traditional DFA, EMD DFA more accurately identified trends in COP data with intrinsic scales and produced short and long-term scaling exponents (i.e., alpha(Short), alpha(Long)) with greater reliability. The fractal-like properties of COP fluctuations were time-scale dependent and highly complex (i.e., alpha(Short) values were close to one) over relatively short time scales. As compared to younger adults, older adults demonstrated lower short-term COP complexity (i.e., greater alpha(Short) values) in both visual conditions (p>0.001). Closing the eyes decreased short term COP complexity, yet this decrease was greater in older compared to younger adults (p<0.001). In older adults, those with higher short-term COP complexity exhibited better adaptive capacity as quantified by Romberg test performance (r(2) = 0.38, p<0.001). These results indicate that an age-related loss of COP complexity of magnitude series may reflect a clinically important reduction in postural control system functionality as a new biomarker. PMID- 23650519 TI - Misleading advertising for antidepressants in Sweden: a failure of pharmaceutical industry self-regulation. AB - BACKGROUND: The alleged efficacy of pharmaceutical industry self-regulation has been used to repudiate increased government oversight over promotional activity. European politicians and industry have cited Sweden as an excellent example of self-regulation based on an ethical code. This paper considers antidepressant advertising in Sweden to uncover the strengths and weaknesses of self-regulation. METHODOLOGY: We analyzed all antidepressant advertisements in the Swedish Medical Journal, 1994-2003. The regulation of these advertisements was analyzed using case reports from self-regulatory bodies. The authors independently reviewed this material to investigate: (1) extent of violative advertising; (2) pattern of code breaches; (3) rate at which the system reacted to violative advertising; (4) prevalence of and oversight over claims regarding antidepressant efficacy and disease causality, and (5) costs for manufactures associated with violative advertising. PRINCIPAL FINDINGS: Self-regulatory bodies identified numerous code breaches. Nonetheless, they failed to protect doctors from unreliable information on antidepressants, since as many as 247 of 722 (34%) advertisements breached the industry code. Self-regulatory bodies repeatedly failed to challenge inflated claims of antidepressant efficacy, lending evidence of lax oversight. On average, 15 weeks elapsed between printing and censure of a wrongful claim, and in 25% of cases 47 weeks or more elapsed. Industry paid roughly ?108000 in fines for violative advertising, adding an estimated additional average cost of 11% to each purchased violative advertisement, or amounting to as little as 0.009% of total antidepressant sales of around ?1.2 billion. CONCLUSIONS: Lax oversight, combined with lags in the system and low fines for violations, may explain the Swedish system's failure to pressure companies into providing reliable antidepressants information. If these shortcomings prove to be consistent across self-regulatory settings, and if appropriate measures are not taken to amend shortcomings, many countries may want to reconsider the current balance between self-regulation, and legislative control with government oversight. PMID- 23650520 TI - CLUSTOM: a novel method for clustering 16S rRNA next generation sequences by overlap minimization. AB - The recent nucleic acid sequencing revolution driven by shotgun and high throughput technologies has led to a rapid increase in the number of sequences for microbial communities. The availability of 16S ribosomal RNA (rRNA) gene sequences from a multitude of natural environments now offers a unique opportunity to study microbial diversity and community structure. The large volume of sequencing data however makes it time consuming to assign individual sequences to phylotypes by searching them against public databases. Since ribosomal sequences have diverged across prokaryotic species, they can be grouped into clusters that represent operational taxonomic units. However, available clustering programs suffer from overlap of sequence spaces in adjacent clusters. In natural environments, gene sequences are homogenous within species but divergent between species. This evolutionary constraint results in an uneven distribution of genetic distances of genes in sequence space. To cluster 16S rRNA sequences more accurately, it is therefore essential to select core sequences that are located at the centers of the distributions represented by the genetic distance of sequences in taxonomic units. Based on this idea, we here describe a novel sequence clustering algorithm named CLUSTOM that minimizes the overlaps between adjacent clusters. The performance of this algorithm was evaluated in a comparative exercise with existing programs, using the reference sequences of the SILVA database as well as published pyrosequencing datasets. The test revealed that our algorithm achieves higher accuracy than ESPRIT-Tree and mothur, few of the best clustering algorithms. Results indicate that the concept of an uneven distribution of sequence distances can effectively and successfully cluster 16S rRNA gene sequences. The algorithm of CLUSTOM has been implemented both as a web and as a standalone command line application, which are available at http://clustom.kribb.re.kr. PMID- 23650521 TI - A subdomain interaction at the base of the lever allosterically tunes the mechanochemical mechanism of myosin 5a. AB - The motor domain of myosin is the core element performing mechanochemical energy transduction. This domain contains the actin and ATP binding sites and the base of the force-transducing lever. Coordinated subdomain movements within the motor are essential in linking the ATPase chemical cycle to translocation along actin filaments. A dynamic subdomain interface located at the base of the lever was previously shown to exert an allosteric influence on ATP hydrolysis in the non processive myosin 2 motor. By solution kinetic, spectroscopic and ensemble and single-molecule motility experiments, we determined the role of a class-specific adaptation of this interface in the mechanochemical mechanism of myosin 5a, a processive intracellular transporter. We found that the introduction of a myosin 2-specific repulsive interaction into myosin 5a via the I67K mutation perturbs the strong-binding interaction of myosin 5a with actin, influences the mechanism of ATP binding and facilitates ATP hydrolysis. At the same time, the mutation abolishes the actin-induced activation of ADP release and, in turn, slows down processive motility, especially when myosin experiences mechanical drag exerted by the action of multiple motor molecules bound to the same actin filament. The results highlight that subtle structural adaptations of the common structural scaffold of the myosin motor enable specific allosteric tuning of motor activity shaped by widely differing physiological demands. PMID- 23650522 TI - Mycobacterium tuberculosis infection is associated with the development of erythema nodosum and nodular vasculitis. AB - BACKGROUND: Mycobacterium tuberculosis (MTB) infection has been suggested to contribute to the pathogenesis of erythema nodosum (EN) and nodular vasculitis (NV), the classic forms of panniculitis. However, there is little evidence to demonstrate the presence of MTB in the skin lesions. This study is aimed at evaluating the association between MTB infection and the development of EN and NV in a Chinese population. METHODS: A total of 107 patients (36 EN, 27 NV, and 44 others) with vasculitis and 40 control cases with other skin diseases were recruited and their skin lesion samples were subjected to real time polymerase chain reaction (PCR) analysis of the IS6110 and mpt64 gene fragments of MTB. Their blood mononuclear cells were tested for MTB antigen-specific IFN-gamma responses by QuantiFERON(r)-TB Gold In-Tube (IT) assays. RESULTS: PCR analysis revealed that 7/23 (30.4%) and 7/18 (38.9%) of the EN and NV samples were positive for the IS6110 DNA, respectively, which were significantly higher than 3/34 (8.8%) of other vasculitis (OV) and 3/40 (7.5%) of the control samples (p<0.05). The nested Real-Time PCR assay indicated that 6/7 (86%) of the IS6110 positive EN samples, all of the IS6110-positive NV and control samples, but only 1/3 of the IS6110-positive OV samples, were positive for the mpt64 gene. Similarly, 19/32 (59.4%) of the EN patients, 20/26 (76.9%) of the NV patients, and 17/36 (47.2%) of the OV patients were positive for MTB antigen-specific IFN gamma responses, which were significantly higher than 6/40 (15%) of the controls (p<0.05). CONCLUSION: Our data strongly suggest that MTB infection and active TB are associated with the development of NV and EN in Chinese. PMID- 23650523 TI - Interspecific differences between D. pulex and D. magna in tolerance to cyanobacteria with protease inhibitors. AB - It is known that cyanobacteria negatively affect herbivores due to their production of toxins such as protease inhibitors. In the present study we investigated potential interspecific differences between two major herbivores, Daphnia magna and Daphnia pulex, in terms of their tolerance to cyanobacteria with protease inhibitors. Seven clones each of D. magna and of D. pulex were isolated from different habitats in Europe and North America. To test for interspecific differences in the daphnids' tolerance to cyanobacteria, their somatic and population growth rates were determined for each D. magna and D. pulex clone after exposure to varying concentrations of two Microcystis aeruginosa strains. The M. aeruginosa strains NIVA and PCC(-) contained either chymotrypsin or trypsin inhibitors, but no microcystins. Mean somatic and population growth rates on a diet with 20% NIVA were significantly more reduced in D. pulex than in D. magna. On a diet with 10% PCC(-), the population growth of D. pulex was significantly more reduced than that of D. magna. This indicates that D. magna is more tolerant to cyanobacteria with protease inhibitors than D. pulex. The reduction of growth rates was possibly caused by an interference of cyanobacterial inhibitors with proteases in the gut of Daphnia, as many other conceivable factors, which might have been able to explain the reduced growth, could be excluded as causal factors. Protease assays revealed that the sensitivities of chymotrypsins and trypsins to cyanobacterial protease inhibitors did not differ between D. magna and D. pulex. However, D. magna exhibited a 2.3 fold higher specific chymotrypsin activity than D. pulex, which explains the observed higher tolerance to cyanobacterial protease inhibitors of D. magna. The present study suggests that D. magna may control the development of cyanobacterial blooms more efficiently than D. pulex due to differences in their tolerance to cyanobacteria with protease inhibitors. PMID- 23650524 TI - Distant mesenchymal progenitors contribute to skin wound healing and produce collagen: evidence from a murine fetal microchimerism model. AB - The contribution of distant and/or bone marrow-derived endogenous mesenchymal stem cells (MSC) to skin wounds is controversial. Bone marrow transplantation experiments employed to address this have been largely confounded by radiation resistant host-derived MSC populations. Gestationally-acquired fetal MSC are known to engraft in maternal bone marrow in all pregnancies and persist for decades. These fetal cells home to damaged maternal tissues, mirroring endogenous stem cell behavior. We used fetal microchimerism as a tool to investigate the natural homing and engraftment of distant MSC to skin wounds. Post-partum wild type mothers that had delivered transgenic pups expressing luciferase under the collagen type I-promoter were wounded. In vivo bioluminescence imaging (BLI) was then used to track recruitment of fetal cells expressing this mesenchymal marker over 14 days of healing. Fetal cells were detected in 9/43 animals using BLI (Fisher exact p = 0.01 versus 1/43 controls). These collagen type I-expressing fetal cells were specifically recruited to maternal wounds in the initial phases of healing, peaking on day 1 (n = 43, p<0.01). This was confirmed by detection of Y-chromosome+ve fetal cells that displayed fibroblast-like morphology. Histological analyses of day 7 wounds revealed vimentin-expressing fetal cells in dermal tissue. Our results demonstrate the participation of distant mesenchymal cells in skin wounds. These data imply that endogenous MSC populations are likely recruited from bone marrow to wounds to participate in healing. PMID- 23650525 TI - No behavioral or ERP evidence for a developmental lag in visual working memory capacity or filtering in adolescents and adults with ADHD. AB - Attention-deficit/hyperactivity disorder (ADHD) patients have both working memory (WM) and attention problems. Good attention skills are important for WM performance; individuals have higher WM capacity when being able to prevent storage of irrelevant information through efficient filtering. Since it is unknown how filtering ability is associated with WM performance in ADHD, this was investigated in the present study. A visuospatial working memory (VSWM) change detection task with distracting stimuli was administered to adolescents (12-16 years old) and adults (20-46 years old) with and without ADHD matched on education/IQ. Besides performance, contralateral delay activity (CDA) was measured; a neural correlate of the number of targets and distracters encoded and maintained in WM during the retention interval. Performance data showed similar WM-load, WM-distracter interference and developmental effects in ADHD and control groups. Adolescents' performance on the WM task deteriorated more than that of adults in the presence of distracters and with higher WM-load, irrespective of Diagnosis. The CDA data suggested that initially all groups encoded/maintained distracting information, but only adults were able to bounce this information from memory later in the retention interval, leading to better WM performance. The only effect of Diagnosis was a smaller CDA in adolescents and adults with ADHD than in age/IQ-matched controls when maintaining a low 1-item load, which was possibly related to an inability to keep attention focused at cued stimuli with low task demands. Overall, the development of filtering efficiency and VSWM storage capacity in adolescents with ADHD was not different from that in typically developing peers. PMID- 23650526 TI - The great silk alternative: multiple co-evolution of web loss and sticky hairs in spiders. AB - Spiders are the most important terrestrial predators among arthropods. Their ecological success is reflected by a high biodiversity and the conquest of nearly every terrestrial habitat. Spiders are closely associated with silk, a material, often seen to be responsible for their great ecological success and gaining high attention in life sciences. However, it is often overlooked that more than half of all Recent spider species have abandoned web building or never developed such an adaptation. These species must have found other, more economic solutions for prey capture and retention, compensating the higher energy costs of increased locomotion activity. Here we show that hairy adhesive pads (scopulae) are closely associated with the convergent evolution of a vagrant life style, resulting in highly diversified lineages of at least, equal importance as the derived web building taxa. Previous studies often highlighted the idea that scopulae have the primary function of assisting locomotion, neglecting the fact that only the distal most pads (claw tufts) are suitable for those purposes. The former observations, that scopulae are used in prey capture, are largely overlooked. Our results suggest the scopulae evolved as a substitute for silk in controlling prey and that the claw tufts are, in most cases, a secondary development. Evolutionary trends towards specialized claw tufts and their composition from a low number of enlarged setae to a dense array of slender ones, as well as the secondary loss of those pads are discussed further. Hypotheses about the origin of the adhesive setae and their diversification throughout evolution are provided. PMID- 23650527 TI - Bi-parental care contributes to sexually dimorphic neural cell genesis in the adult mammalian brain. AB - Early life events can modulate brain development to produce persistent physiological and behavioural phenotypes that are transmissible across generations. However, whether neural precursor cells are altered by early life events, to produce persistent and transmissible behavioural changes, is unknown. Here, we show that bi-parental care, in early life, increases neural cell genesis in the adult rodent brain in a sexually dimorphic manner. Bi-parentally raised male mice display enhanced adult dentate gyrus neurogenesis, which improves hippocampal neurogenesis-dependent learning and memory. Female mice display enhanced adult white matter oligodendrocyte production, which increases proficiency in bilateral motor coordination and preference for social investigation. Surprisingly, single parent-raised male and female offspring, whose fathers and mothers received bi-parental care, respectively, display a similar enhancement in adult neural cell genesis and phenotypic behaviour. Therefore, neural plasticity and behavioural effects due to bi-parental care persist throughout life and are transmitted to the next generation. PMID- 23650528 TI - Changes in gene expression profiling of apoptotic genes in neuroblastoma cell lines upon retinoic acid treatment. AB - To determine the effect of retinoic acid (RA) in neuroblastoma we treated RA sensitive neuroblastoma cell lines with 9-cis RA or ATRA for 9 days, or for 5 days followed by absence of RA for another 4 days. Both isomers induced apoptosis and reduced cell density as a result of cell differentiation and/or apoptosis. Flow cytometry revealed that 9-cis RA induced apoptosis more effectively than ATRA. The expression profile of apoptosis and survival pathways was cell line specific and depended on the isomer used. PMID- 23650529 TI - Immediate ecological impacts of the 2011 Tohoku earthquake tsunami on intertidal flat communities. AB - Following the Great East Japan Earthquake in 2011, a large tsunami developed and struck the Pacific coast of eastern Japan. To assess the immediate impacts of the tsunami on coastal communities, changes in taxon composition and richness of macrobenthic animals before and after the tsunami were examined at nine intertidal flats in Sendai Bay and the Sanriku Ria coast. The results showed that 30-80% of taxa indigenously inhabiting intertidal flats disappeared after the tsunami. Among animal types, endobenthic and sessile epibenthic animals were more vulnerable to the tsunami than mobile epibenthic animals like shore crabs and snails. For all the intertidal flats examined, animals that were originally dwellers in lower tidal zones and not recorded before the tsunami were also found right after the tsunami, indicating that the tsunami not only took away many benthic taxa from the intertidal flats but also brought in some taxa from elsewhere. However, overall changes in taxon community composition were greater for intertidal flats that experienced larger inundation heights. These results showed that the ecological impacts of the tsunami were proportional to the physical impacts as gauged by wave height and that mobile epibenthic animals were less vulnerable to the tsunami. PMID- 23650530 TI - Impact of colonoscopy bowel preparation on intestinal microbiota. AB - The gut microbiota is important in maintaining human health, but numerous factors have the potential to alter its composition. Our aim was to examine the impact of a standard bowel preparation on the intestinal microbiota using two different techniques. Fifteen subjects undergoing colonoscopy consumed a bowel preparation comprised of 10 mg bisacodyl and 2 L polyethylene glycol. The microbiota of stool samples, collected one month before, one week before (pre-colonoscopy), and one week, one month, and three to six months after colonoscopy (post-colonoscopy) was evaluated. Two samples were taken three to six months apart from five healthy subjects who did not undergo colonoscopy. Universal primers targeting the V2-V3 region of the 16S rRNA gene were used to PCR amplify all samples for denaturing gradient gel electrophoresis (PCR-DGGE). Pre- and post-colonoscopy samples were compared using Dice's similarity coefficients. Three samples from ten subjects who underwent colonoscopy, and both samples from the five subjects who didn't, were used for high-throughput sequencing of the V1-V3 region of the 16S rRNA gene. Samples were curated and analysed in Mothur. Results of the DGGE analyses show that the fecal microbiota of a small number of subjects had short-term changes. High-throughput sequencing results indicated that the variation between the samples of subjects who underwent colonoscopy was no greater than the variation observed between samples from subjects who did not. We conclude that bowel preparation does not have a lasting effect on the composition of the intestinal microbiota for the majority of subjects. PMID- 23650531 TI - Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways. AB - The relaxation response (RR) is the counterpart of the stress response. Millennia old practices evoking the RR include meditation, yoga and repetitive prayer. Although RR elicitation is an effective therapeutic intervention that counteracts the adverse clinical effects of stress in disorders including hypertension, anxiety, insomnia and aging, the underlying molecular mechanisms that explain these clinical benefits remain undetermined. To assess rapid time-dependent (temporal) genomic changes during one session of RR practice among healthy practitioners with years of RR practice and also in novices before and after 8 weeks of RR training, we measured the transcriptome in peripheral blood prior to, immediately after, and 15 minutes after listening to an RR-eliciting or a health education CD. Both short-term and long-term practitioners evoked significant temporal gene expression changes with greater significance in the latter as compared to novices. RR practice enhanced expression of genes associated with energy metabolism, mitochondrial function, insulin secretion and telomere maintenance, and reduced expression of genes linked to inflammatory response and stress-related pathways. Interactive network analyses of RR-affected pathways identified mitochondrial ATP synthase and insulin (INS) as top upregulated critical molecules (focus hubs) and NF-kappaB pathway genes as top downregulated focus hubs. Our results for the first time indicate that RR elicitation, particularly after long-term practice, may evoke its downstream health benefits by improving mitochondrial energy production and utilization and thus promoting mitochondrial resiliency through upregulation of ATPase and insulin function. Mitochondrial resiliency might also be promoted by RR-induced downregulation of NF-kappaB-associated upstream and downstream targets that mitigates stress. PMID- 23650532 TI - p53 Represses transcription of RING finger LIM domain-binding protein RLIM through Sp1. AB - RLIM acts as a negative regulator of LIM-Homeodomain proteins either by recruiting Sin3A/Histone Deacetylase (HDAC) co-repressor complex or through degradation of CLIM coactivator, thus playing an important role in embryonic development. Recent studies by different research groups have shown that RLIM acts as an X-encoded, dose-dependent inducer of X chromosome inactivation in mouse embryonic stem cells. However, until now, very little is known about the expression regulation of RLIM gene, and we tried to study the transcriptional regulation of RLIM gene. In the present study, we identified RLIM as a novel target of p53 and demonstrated that p53 repressed both mRNA and protein levels of RLIM. Expression of wild type p53, but not p53 mutants, led to repression of the RLIM promoter activity. We further identified four putative Sp1 elements (S1 to S4) on the RLIM promoter that are essential for p53-mediated repression of RLIM. Although p53 does not directly bind to the RLIM promoter, it physically interacts with and prevents the binding of Sp1 to the RLIM promoter. Thus, RLIM is a novel target of p53, and p53 exerts its inhibitory effect on RLIM expression by interfering with Sp1-mediated transcriptional activation on RLIM. Our results provided data to enlarge the knowledge of transcriptional regulation of RLIM and suggested a new pathway by which physiological and pathological activators of p53 may affect development. PMID- 23650533 TI - LPLUNC1 inhibits nasopharyngeal carcinoma cell growth via down-regulation of the MAP kinase and cyclin D1/E2F pathways. AB - Long-palate, lung and nasal epithelium clone 1 (LPLUNC1) gene expression is relatively tissue specific. It is highly expressed in nontumor nasopharyngeal epithelial tissues, but its expression is reduced in nasopharyngeal carcinoma (NPC), indicating that LPLUNC1 may be associated with the tumorigenesis of NPC. To study the effects of LPLUNC1 on NPC tumorigenesis, a full-length LPLUNC1 expression plasmid was stably transfected into the NPC cell line, 5-8F. Our data indicated that LPLUNC1 inhibited NPC cell proliferation in vitro and tumor formation in vivo. LPLUNC1 also delayed cell cycle progression from G1 to S phase and inhibited the expression of cyclin D1, cyclin-dependent kinase 4 (CDK4) and phosphorylated Rb. To further investigate the molecular mechanisms underlying the suppressive effects of LPLUNC1 on NPC tumorigenesis, cDNA microarray was performed. These studies revealed that LPLUNC1 inhibited the expression of certain mitogen-activated protein (MAP) kinases (MAPK) kinases and cell cycle related molecules. Western blotting confirmed that the expression of MEK1, phosphorylated ERK1/2, phosphorylated JNK1/2, c-Myc and c-Jun were inhibited by LPLUNC1. Furthermore, the transcriptional activity of AP-1 was down-regulated by LPLUNC1, suggesting that the MAPK signaling pathway is regulated by LPLUNC1. Taken together, the present study indicates that LPLUNC1 delays NPC cell growth by inhibiting the MAPK and cyclin D1/E2F pathways and suggests that LPLUNC1 may represent a promising candidate tumor suppressor gene associated with NPC. PMID- 23650534 TI - Gene expression analysis of peripheral blood cells reveals Toll-like receptor pathway deregulation in colorectal cancer. AB - Colorectal cancer is the leading cause of cancer-related deaths worldwide. The disease is curable when detected at an early stage. However, the compliance rate with current screening recommendations remains poor. An accurate, minimally invasive blood test that has the potential for greater patient compliance would be a welcome addition to the current methods. Recent data have shown that gene expression profile of peripheral blood cells can reflect disease states and thus have diagnostic value. In this study, genome-wide gene expression profiling of peripheral blood cells from 20 healthy controls and 20 colorectal cancer patients were performed using PAXgeneTM technology and Affymetrix GeneChip(r) microarrays. We identified a list of 1,469 genes that were differentially expressed between the healthy controls and cancer patients. Gene annotation and functional enrichment analysis revealed that those genes are mainly related to immune functions. Particularly, a set of genes belonging to the Toll-Like Receptor pathways were up-regulated in the colorectal cancer patients. These findings provide a new understanding of blood gene expression profile in colorectal cancer. Our result may serve as the basis for further development of blood biomarkers for the diagnosis and treatment of colorectal cancer. PMID- 23650535 TI - Association of the protein-tyrosine phosphatase DEP-1 with its substrate FLT3 visualized by in situ proximity ligation assay. AB - Protein-tyrosine phosphatases (PTPs) are important regulators of signal transduction processes. Essential for the functional characterization of PTPs is the identification of their physiological substrates, and an important step towards this goal is the demonstration of a physical interaction. The association of PTPs with their cellular substrates is, however, often transient and difficult to detect with unmodified proteins at endogenous levels. Density-enhanced phosphatase-1 (DEP-1/PTPRJ) is a regulator of hematopoietic cell functions, and a candidate tumor suppressor. However, association of DEP-1 with any of its proposed substrates at endogenous levels has not yet been shown. We have previously obtained functional and biochemical evidence for a direct interaction of DEP-1 with the hematopoietic receptor-tyrosine kinase Fms-like tyrosine kinase 3 (FLT3). In the current study we have used the method of in situ proximity ligation assay (in situ PLA) to validate this interaction at endogenous levels, and to further characterize it. In situ PLA readily detected association of endogenous DEP-1 and FLT3 in the human acute monocytic leukemia cell line THP-1, which was enhanced by FLT3 ligand (FL) stimulation in a time-dependent manner. Association peaked between 10 and 20 min of stimulation and returned to basal levels at 30 min. This time course was similar to the time course of FLT3 autophosphorylation. FLT3 kinase inhibition and DEP-1 oxidation abrogated association. Consistent with a functional role of DEP-1-FLT3 interaction, stable knockdown of DEP-1 in THP-1 cells enhanced FL-induced ERK1/2 activation. These findings support that FLT3 is a bona fide substrate of DEP-1 and that interaction occurs mainly via an enzyme-substrate complex formation triggered by FLT3 ligand stimulation. PMID- 23650536 TI - Task-free functional MRI in cervical dystonia reveals multi-network changes that partially normalize with botulinum toxin. AB - Cervical dystonia is characterized by involuntary, abnormal movements and postures of the head and neck. Current views on its pathophysiology, such as faulty sensorimotor integration and impaired motor planning, are largely based on studies of focal hand dystonia. Using resting state fMRI, we explored whether cervical dystonia patients have altered functional brain connectivity compared to healthy controls, by investigating 10 resting state networks. Scans were repeated immediately before and some weeks after botulinum toxin injections to see whether connectivity abnormalities were restored. We here show that cervical dystonia patients have reduced connectivity in selected regions of the prefrontal cortex, premotor cortex and superior parietal lobule within a distributed network that comprises the premotor cortex, supplementary motor area, primary sensorimotor cortex, and secondary somatosensory cortex (sensorimotor network). With regard to a network originating from the occipital cortex (primary visual network), selected regions in the prefrontal and premotor cortex, superior parietal lobule, and middle temporal gyrus areas have reduced connectivity. In selected regions of the prefrontal, premotor, primary motor and early visual cortex increased connectivity was found within a network that comprises the prefrontal cortex including the anterior cingulate cortex and parietal cortex (executive control network). Botulinum toxin treatment resulted in a partial restoration of connectivity abnormalities in the sensorimotor and primary visual network. These findings demonstrate the involvement of multiple neural networks in cervical dystonia. The reduced connectivity within the sensorimotor and primary visual networks may provide the neural substrate to expect defective motor planning and disturbed spatial cognition. Increased connectivity within the executive control network suggests excessive attentional control and while this may be a primary trait, perhaps contributing to abnormal motor control, this may alternatively serve a compensatory function in order to reduce the consequences of the motor planning defect inflicted by the other network abnormalities. PMID- 23650537 TI - Automatic temporal expectancy: a high-density event-related potential study. AB - How we compute time is not fully understood. Questions include whether an automatic brain mechanism is engaged in temporally regular environmental structure in order to anticipate events, and whether this can be dissociated from task-related processes, including response preparation, selection and execution. To investigate these issues, a passive temporal oddball task requiring neither time-based motor response nor explicit decision was specifically designed and delivered to participants during high-density, event-related potentials recording. Participants were presented with pairs of audiovisual stimuli (S1 and S2) interspersed with an Inter-Stimulus Interval (ISI) that was manipulated according to an oddball probabilistic distribution. In the standard condition (70% of trials), the ISI lasted 1,500 ms, while in the two alternative, deviant conditions (15% each), it lasted 2,500 and 3,000 ms. The passive over-exposition to the standard ISI drove participants to automatically and progressively create an implicit temporal expectation of S2 onset, reflected by the time course of the Contingent Negative Variation response, which always peaked in correspondence to the point of S2 maximum expectation and afterwards inverted in polarity towards the baseline. Brain source analysis of S1- and ISI-related ERP activity revealed activation of sensorial cortical areas and the supplementary motor area (SMA), respectively. In particular, since the SMA time course synchronised with standard ISI, we suggest that this area is the major cortical generator of the temporal CNV reflecting an automatic, action-independent mechanism underlying temporal expectancy. PMID- 23650538 TI - Recording visual evoked potentials and auditory evoked P300 at 9.4T static magnetic field. AB - Simultaneous recording of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) has shown a number of advantages that make this multimodal technique superior to fMRI alone. The feasibility of recording EEG at ultra-high static magnetic field up to 9.4 T was recently demonstrated and promises to be implemented soon in fMRI studies at ultra high magnetic fields. Recording visual evoked potentials are expected to be amongst the most simple for simultaneous EEG/fMRI at ultra-high magnetic field due to the easy assessment of the visual cortex. Auditory evoked P300 measurements are of interest since it is believed that they represent the earliest stage of cognitive processing. In this study, we investigate the feasibility of recording visual evoked potentials and auditory evoked P300 in a 9.4 T static magnetic field. For this purpose, EEG data were recorded from 26 healthy volunteers inside a 9.4 T MR scanner using a 32 channel MR compatible EEG system. Visual stimulation and auditory oddball paradigm were presented in order to elicit evoked related potentials (ERP). Recordings made outside the scanner were performed using the same stimuli and EEG system for comparison purposes. We were able to retrieve visual P100 and auditory P300 evoked potentials at 9.4 T static magnetic field after correction of the ballistocardiogram artefact using independent component analysis. The latencies of the ERPs recorded at 9.4 T were not different from those recorded at 0 T. The amplitudes of ERPs were higher at 9.4 T when compared to recordings at 0 T. Nevertheless, it seems that the increased amplitudes of the ERPs are due to the effect of the ultra-high field on the EEG recording system rather than alteration in the intrinsic processes that generate the electrophysiological responses. PMID- 23650539 TI - GTXOP: a game theoretic approach for QoS provisioning using transmission opportunity tuning. AB - In unsupervised contention-based networks such as EDCA mode of IEEE 802.11(e)(s), upon winning the channel, each node gets a transmission opportunity (TXOP) in which the node can transmit multiple frames consequently without releasing the channel. Adjusting TXOP can lead to better bandwidth utilization and QoS provisioning. To improve WLAN throughput performance, EDCA packet bursting can be used in 802.11e, meaning that once a station has gained an EDCA-TXOP, it can be allowed to transmit more than one frame without re-contending for the channel. Following the access to the channel, the station can send multiple frames as long as the total access time does not exceed the TXOP Limit. This mechanism can reduce the network overhead and increase the channel utilization instead. However, packet bursting may cause unfairness in addition to increasing jitter, delay and loss. To the best of the authors' knowledge, although TXOP tuning has been investigated through different methods, it has not been considered within a game theory framework. In this study, based on the analytical models of EDCA, a game theoretic approach called GTXOP is proposed to determine TXOP dynamically (i.e. according to the dynamisms of WLAN networks and the number of nodes in the network). Using GTXOP, each node can choose its TXOP autonomously, such that in addition to QoS improvement, the overall network performance is also improved. PMID- 23650541 TI - Potential of best practice to reduce impacts from oil and gas projects in the Amazon. AB - The western Amazon continues to be an active and controversial zone of hydrocarbon exploration and production. We argue for the urgent need to implement best practices to reduce the negative environmental and social impacts associated with the sector. Here, we present a three-part study aimed at resolving the major obstacles impeding the advancement of best practice in the region. Our focus is on Loreto, Peru, one of the largest and most dynamic hydrocarbon zones in the Amazon. First, we develop a set of specific best practice guidelines to address the lack of clarity surrounding the issue. These guidelines incorporate both engineering-based criteria and key ecological and social factors. Second, we provide a detailed analysis of existing and planned hydrocarbon activities and infrastructure, overcoming the lack of information that typically hampers large scale impact analysis. Third, we evaluate the planned activities and infrastructure with respect to the best practice guidelines. We show that Loreto is an extremely active hydrocarbon front, highlighted by a number of recent oil and gas discoveries and a sustained government push for increased exploration. Our analyses reveal that the use of technical best practice could minimize future impacts by greatly reducing the amount of required infrastructure such as drilling platforms and access roads. We also document a critical need to consider more fully the ecological and social factors, as the vast majority of planned infrastructure overlaps sensitive areas such as protected areas, indigenous territories, and key ecosystems and watersheds. Lastly, our cost analysis indicates that following best practice does not impose substantially greater costs than conventional practice, and may in fact reduce overall costs. Barriers to the widespread implementation of best practice in the Amazon clearly exist, but our findings show that there can be great benefits to its implementation. PMID- 23650540 TI - Role of microRNA profile modifications in hepatitis C virus-related mixed cryoglobulinemia. AB - Hepatitis C virus infection is closely related to lymphoproliferative disorders (LPDs), including mixed cryoglobulinemia (MC) and some lymphomas. Modification of the expression of specific microRNAs (miRNAs) has been associated with different autoimmune diseases and/or LPDs. No data exist about the modifications in miRNA expression in HCV-associated LPDs. The aim of this study was to analyze the expression levels of a panel of miRNAs previously associated with autoimmune/LPDs in a large population of HCV patients with and without MC or non-Hodgkin's lymphoma (NHL), to identify potential markers of evolution of HCV infection. PBMC expression of miR-Let-7d, miR-16, miR-21, miR-26b, miR-146a and miR-155 was evaluated by real-time PCR in 167 HCV patients (75 with MC [MC-HCV], 11 with HCV associated NHL [NHL-HCV], 81 without LPD [HCV]) and in 35 healthy subjects (HS). A significant increase in miR-21 (p<0.001), miR-16 (p<0.01) and miR-155 (p<0.01) expression was detected in PBMCs from only NHL patients whereas a significant decrease in miR-26b was detected in both MC and NHL subjects (p<0.01) when compared to HS and HCV groups. A restoration of miR-26b levels was observed in the post-treatment PBMCs of 35 HCV-MC patients experiencing complete virological and clinical response following antiviral therapy. This study, for the first time, shows that specific microRNAs in PBMC from HCV patients who developed MC and/or NHL are modulated differently. The specific, reversible downregulation of miR-26b strongly suggests the key role it plays in the pathogenesis of HCV related LPDs and its usefulness as a biomarker of the evolution of HCV infection to these disorders. PMID- 23650542 TI - Origin of an assemblage massively dominated by carnivorans from the miocene of Spain. AB - Carnivoran-dominated fossil sites provide precious insights into the diversity and ecology of species rarely recovered in the fossil record. The lower level assemblage of Batallones-1 fossil site (Late Miocene; Madrid Basin, Spain) has yielded one of the most abundant and diversified carnivoran assemblage ever known from the Cenozoic record of mammals. A comprehensive taphonomic study is carried out here in order to constrain the concentration mode of this remarkable assemblage. Another distinctive feature of Batallones-1 is that the accumulation of carnivoran remains took place in the context of a geomorphological landform (cavity formation through a piping process) practically unknown in the generation of fossil sites. Two characteristics of the assemblage highly restrict the probable causes for the accumulation of the remains: (1) the overwhelming number of carnivorans individuals; and (2) the mortality profiles estimated for the four most abundant taxa do not correspond to the classic mortality types but rather were the consequence of the behavior of the taxa. This evidence together with other taphonomic data supports the hypothesis that carnivoran individuals actively entered the cavity searching for resources (food or water) and were unable to exit. The scarcity of herbivores implies that the shaft was well visible and avoided by these taxa. Fossil bones exhibit a very good preservation state as a consequence of their deposition in the restricted and protective environment of the chamber. Batallones-1 had another assemblage (upper level assemblage) that was dominated by herbivore remains and that potentially corresponded to the final stages of the cavity filling. PMID- 23650543 TI - Recombinant mammaglobin A adenovirus-infected dendritic cells induce mammaglobin A-specific CD8+ cytotoxic T lymphocytes against breast cancer cells in vitro. AB - Mammaglobin A (MGBA) is a novel breast cancer-associated antigen almost exclusively over-expressed in primary and metastatic human breast cancers, making it a potential therapeutic target for breast cancer. The development of dendritic cell (DC)-induced tumor antigen specific CD8(+) cytotoxic T lymphocytes (CTLs) may hold promise in cancer immunotherapy. In this study we constructed recombinant replication-defective adenoviral (Ad) vectors encoding MGBA and evaluated their ability to trigger anti-tumor immunity in vitro. DCs were isolated from the human peripheral blood monocyte cells (PBMCs) of two HLA-A33(+) healthy female volunteers, and infected with adenovirus carrying MGBA cDNA (Ad MGBA). After that, the Ad-MGBA-infected DCs were used to stimulate CD8(+) CTLs in vitro and the latter was used for co-culture with breast cancer cell lines. The data revealed that infection with Ad-MGBA improved DC maturation and up-regulated the expression of co-stimulatory molecules and the secretion of interleukin-12 (IL-12), but down-regulated interleukin-10 (IL-10) secretion from DCs. Ad-MGBA infected DC-stimulated CD8(+)CTLs displayed the highest cytotoxicity towards HLA A33(+)/MGBA(+) breast cancer MDA-MB-415 cells compared with other CD8(+)CTL populations, and compared with the cytotoxicity towards HLA-A33(-)/MGBA(+) breast cancer HBL-100 cells and HLA-A33(-)/MGBA(-) breast cancer MDA-MB 231 cells. In addition, Ad-MGBA-infected DC-stimulated CD8(+) CTLs showed a high level of IFNgamma secretion when stimulated with HLA-A33(+)/MGBA(+) breast cancer MDA-MB 415 cells, but not when stimulated with HLA-A33(-)/MGBA(+) HBL-100 and HLA-A33( )/MGBA(-)MDA-MB-231 cells. In addition, killing of CD8(+)CTLs against breast cancer was in a major histocompability complex (MHC)-limited pattern. Finally, the data also determined the importance of TNF-alpha in activating DCs and T cells. These data together suggest that MGBA recombinant adenovirus-infected DCs could induce specific anti-tumor immunity against MGBA(+) breast cancers, which could provide a novel strategy in the immunotherapy of breast cancer. PMID- 23650544 TI - Differential use of TLR2 and TLR9 in the regulation of immune responses during the infection with Trypanosoma cruzi. AB - Pathogens express ligands for several TLRs that may play a role in the induction or control of the inflammatory response during infection. Concerning Trypanosoma cruzi, the agent of Chagas disease, we have previously characterized glycosylphosphatidylinositol (GPI) anchored mucin-like glycoproteins (tGPI-mucin) and unmethylated CpG DNA sequences as TLR2 and TLR9 agonists, respectively. Here we sought to determine how these TLRs may modulate the inflammatory response in the following cell populations: F4/80(+)CD11b(+) (macrophages), F4/80(low)CD11b(+) (monocytes) and MHCII(+)CD11c(high) (dendritic cells). For this purpose, TLR2(-/-) and TLR9(-/-) mice were infected with Y strain of T. cruzi and different immunological parameters were evaluated. According to our previous data, a crucial role of TLR9 was evidenced in the establishment of Th1 response, whereas TLR2 appeared to act as immunoregulator in the early stage of infection. More precisely, we demonstrated here that TLR2 was mainly used by F4/80(+)CD11b(+) cells for the production of TNF-alpha. In the absence of TLR2, an increased production of IL-12/IL-23p40 and IFN-gamma was noted suggesting that TLR2 negatively controls the Th1 response. In contrast, TLR9 was committed to IL 12/IL-23p40 production by MHCII(+)CD11c(high) cells that constitute the main source of IL-12/IL-23p40 during infection. Importantly, a down-regulation of TLR9 response was observed in F4/80(+)CD11b(+) and F4/80(low)CD11b(+) populations that correlated with the decreased TLR9 expression level in these cells. Interestingly, these cells recovered their capacity to respond to TLR9 agonist when MHCII(+)CD11c(high) cells were impeded from producing IL-12/IL-23p40, thereby indicating possible cross-talk between these populations. The differential use of TLR2 and TLR9 by the immune cells during the acute phase of the infection explains why TLR9- but not TLR2-deficient mice are susceptible to T. cruzi infection. PMID- 23650545 TI - Membrane phospholipid fatty acid composition regulates cardiac SERCA activity in a hibernator, the Syrian hamster (Mesocricetus auratus). AB - Polyunsaturated fatty acids (PUFA) have strong effects on hibernation and daily torpor. Increased dietary uptake of PUFA of the n-6 class, particularly of Linoleic acid (LA, C18:2 n-6) lengthens torpor bout duration and enables animals to reach lower body temperatures (T(b)) and metabolic rates. As previously hypothesized, this well-known influence of PUFA may be mediated via effects of the membrane fatty acid composition on sarcoplasmic reticulum (SR) Ca(2+-)ATPase 2a (SERCA) in the heart of hibernators. We tested the hypotheses that high proportions of n-6 PUFA in general, or specifically high proportions of LA (C18:2 n-6) in SR phospholipids (PL) should be associated with increased cardiac SERCA activity, and should allow animals to reach lower minimum T(b) in torpor. We measured activity of SERCA from hearts of hibernating and non-hibernating Syrian hamsters (Mesocricetus auratus) in vitro at 35 degrees C. Further, we determined the PL fatty acid composition of the SR membrane of these hearts. We found that SERCA activity strongly increased as the proportion of LA in SR PL increased but was negatively affected by the content of Docosahexaenoic acid (DHA; C22:6 n-3). SR PL from hibernating hamsters were characterized by high proportions of LA and low proportions of DHA. As a result, SERCA activity was significantly higher during entrance into torpor and in torpor compared to inter-bout arousal. Also, animals with increased SERCA activity reached lower T(b) during torpor. Interestingly, a subgroup of hamsters which never entered torpor but remained euthermic throughout winter displayed a phenotype similar to animals in summer. This was characterized by lower proportions of LA and increased proportions of DHA in SR membranes, which is apparently incompatible with torpor. We conclude that the PUFA composition of SR membranes affects cardiac function via modulating SERCA activity, and hence determines the minimum T(b) tolerated by hibernators. PMID- 23650546 TI - Comparative study of four time series methods in forecasting typhoid fever incidence in China. AB - Accurate incidence forecasting of infectious disease is critical for early prevention and for better government strategic planning. In this paper, we present a comprehensive study of different forecasting methods based on the monthly incidence of typhoid fever. The seasonal autoregressive integrated moving average (SARIMA) model and three different models inspired by neural networks, namely, back propagation neural networks (BPNN), radial basis function neural networks (RBFNN), and Elman recurrent neural networks (ERNN) were compared. The differences as well as the advantages and disadvantages, among the SARIMA model and the neural networks were summarized and discussed. The data obtained for 2005 to 2009 and for 2010 from the Chinese Center for Disease Control and Prevention were used as modeling and forecasting samples, respectively. The performances were evaluated based on three metrics: mean absolute error (MAE), mean absolute percentage error (MAPE), and mean square error (MSE). The results showed that RBFNN obtained the smallest MAE, MAPE and MSE in both the modeling and forecasting processes. The performances of the four models ranked in descending order were: RBFNN, ERNN, BPNN and the SARIMA model. PMID- 23650547 TI - Evidence for cross-tolerance to nutrient deficiency in three disjunct populations of Arabidopsis lyrata ssp. lyrata in response to substrate calcium to magnesium ratio. AB - Species with widespread distributions that grow in varied habitats may consist of ecotypes adapted to a particular habitat, or may exhibit cross-tolerance that enables them to exploit a variety of habitats. Populations of Arabidopsis lyrata ssp. lyrata (L.) O'Kane & Al-Shehbaz grow in a wide variety of edaphic settings including serpentine soil, limestone sand, and alluvial flood plains. While all three of these environments share some stressors, a crucial difference among these environments is soil calcium to magnesium ratio, which ranges from 25:1 in the limestone sand to 0.2:1 in serpentine soil. The three populations found on these substrates were subjected to three different Ca to Mg ratios under controlled environmental conditions during germination and rosette growth. Response to Ca to Mg ratio was evaluated through germination success and radicle growth rate, rosette growth rate, and the content of Ca and Mg in the rosette. All three populations were particularly efficient in fueling growth under nutrient deficiency, with the highest nutrient efficiency ratio for Ca under Ca deficiency and for Mg under Mg deficiency. Although the serpentine population had significantly higher leaf Ca to Mg ratio than the limestone or flood plain populations under all three Ca to Mg ratios, this increase did not result in any advantage in growth or appearance of the serpentine plants, during early life stages before the onset of flowering, even in the high Mg substrate. The three populations showed no population by substrate interaction for any of the parameters measured indicating that these populations may have cross-tolerance to substrate Ca to Mg ratio. PMID- 23650548 TI - The zebrafish orthologue of the dyslexia candidate gene DYX1C1 is essential for cilia growth and function. AB - DYX1C1, a susceptibility gene for dyslexia, encodes a tetratricopeptide repeat domain containing protein that has been implicated in neuronal migration in rodent models. The developmental role of this gene remains unexplored. To understand the biological function(s) of zebrafish dyx1c1 during embryonic development, we cloned the zebrafish dyx1c1 and used morpholino-based knockdown strategy. Quantitative real-time PCR analysis revealed the presence of dyx1c1 transcripts in embryos, early larval stages and in a wide range of adult tissues. Using mRNA in situ hybridization, we show here that dyx1c1 is expressed in many ciliated tissues in zebrafish. Inhibition of dyx1c1 produced pleiotropic phenotypes characteristically associated with cilia defects such as body curvature, hydrocephalus, situs inversus and kidney cysts. We also demonstrate that in dyx1c1 morphants, cilia length is reduced in several organs including Kupffer's vesicle, pronephros, spinal canal and olfactory placode. Furthermore, electron microscopic analysis of cilia in dyx1c1 morphants revealed loss of both outer (ODA) and inner dynein arms (IDA) that have been shown to be required for cilia motility. Considering all these results, we propose an essential role for dyx1c1 in cilia growth and function. PMID- 23650549 TI - Itm2a is a Pax3 target gene, expressed at sites of skeletal muscle formation in vivo. AB - The paired-box homeodomain transcription factor Pax3 is a key regulator of the nervous system, neural crest and skeletal muscle development. Despite the important role of this transcription factor, very few direct target genes have been characterized. We show that Itm2a, which encodes a type 2 transmembrane protein, is a direct Pax3 target in vivo, by combining genetic approaches and in vivo chromatin immunoprecipitation assays. We have generated a conditional mutant allele for Itm2a, which is an imprinted gene, by flanking exons 2-4 with loxP sites and inserting an IRESnLacZ reporter in the 3' UTR of the gene. The LacZ reporter reproduces the expression profile of Itm2a, and allowed us to further characterize its expression at sites of myogenesis, in the dermomyotome and myotome of somites, and in limb buds, in the mouse embryo. We further show that Itm2a is not only expressed in adult muscle fibres but also in the satellite cells responsible for regeneration. Itm2a mutant mice are viable and fertile with no overt phenotype during skeletal muscle formation or regeneration. Potential compensatory mechanisms are discussed. PMID- 23650550 TI - In vivo "MRI phenotyping" reveals changes in extracellular matrix transport and vascularization that mediate VEGF-driven increase in breast cancer metastasis. AB - PURPOSE: To gain new insights into the relationship between angiogenic factors in breast cancer and their effect on extracellular matrix (ECM) remodeling and metastasis, we characterized and validated the "metastatic signature" of human breast cancer cell lines engineered to overexpress VEGF in terms of in vivo MRI derived angiogenesis and ECM transport parameters. METHODOLOGY: MRI was used to evaluate the effects of overexpressing VEGF-A (VEGF165) on tumor angiogenesis and ECM remodeling in vivo, for two differentially metastatic human breast cancer cell lines: MCF-7 and MDA-MB-231. PRINCIPAL FINDINGS: Overexpression of VEGF elevated vascular volume in both MCF-7-VEGF and MDA-MB-231-VEGF tumors relative to their wild-type counterparts, but vascular permeability was elevated only in MCF-7-VEGF tumors. A significant increase in the volume of extravascular fluid drained as well as the number of ECM drainage voxels was detected in MCF-7-VEGF tumors relative to MCF-7 tumors, but not in MDA-MB-231-VEGF versus MDA-MB-231 tumors. The angiogenic effects of VEGF overexpression in both MCF-7-VEGF and MDA MB-231-VEGF tumors were validated histologically. MCF-7-VEGF tumors exhibited enhanced invasion and a greater fraction of cancer positive lungs and lymph nodes relative to MCF-7 tumors. CONCLUSIONS AND SIGNIFICANCE: In vivo MRI and histological data demonstrate that VEGF overexpression results in the progression of noninvasive MCF-7 and invasive MDA-MB-321 tumors to a more angiogenic phenotype. However, VEGF overexpression significantly altered ECM integrity only in MCF-7 tumors, causing them to progress to an invasive and metastatic phenotype. This study for the first time demonstrates the concurrent effects of VEGF overexpression and ECM remodeling on metastasis in vivo. Collectively, these findings demonstrate that in vivo MRI can non-invasively monitor changes in the tumor microenvironment that can potentially predict a cancer's ability to metastasize. PMID- 23650551 TI - Sensitization of Staphylococcus aureus to methicillin and other antibiotics in vitro and in vivo in the presence of HAMLET. AB - HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a protein-lipid complex from human milk with both tumoricidal and bactericidal activities. HAMLET exerts a rather specific bactericidal activity against some respiratory pathogens, with highest activity against Streptococcus pneumoniae, but lacks activity against most other bacterial pathogens, including Staphylococci. Still, ion transport associated with death in S. pneumoniae is also detected to a lower degree in insensitive organisms. In this study we demonstrate that HAMLET acts as an antimicrobial adjuvant that can increase the activity of a broad spectrum of antibiotics (methicillin, vancomycin, gentamicin and erythromycin) against multi drug resistant Staphylococcus aureus, to a degree where they become sensitive to those same antibiotics, both in antimicrobial assays against planktonic and biofilm bacteria and in an in vivo model of nasopharyngeal colonization. We show that HAMLET exerts these effects specifically by dissipating the proton gradient and inducing a sodium-dependent calcium influx that partially depolarizes the plasma membrane, the same mechanism induced during pneumococcal death. These effects results in an increased cell associated binding and/or uptake of penicillin, gentamicin and vancomycin, especially in resistant stains. Finally, HAMLET inhibits the increased resistance of methicillin seen under antibiotic pressure and the bacteria do not become resistant to the adjuvant, which is a major advantageous feature of the molecule. These results highlight HAMLET as a novel antimicrobial adjuvant with the potential to increase the clinical usefulness of antibiotics against drug resistant strains of S. aureus. PMID- 23650552 TI - p53 and cell cycle dependent transcription of kinesin family member 23 (KIF23) is controlled via a CHR promoter element bound by DREAM and MMB complexes. AB - The microtubule-dependent molecular motor KIF23 (Kinesin family member 23) is one of two components of the centralspindlin complex assembled during late stages of mitosis. Formation of this complex is known as an essential step for cytokinesis. Here, we identified KIF23 as a new transcriptional target gene of the tumor suppressor protein p53. We showed that p53 reduces expression of KIF23 on the mRNA as well as the protein level in different cell types. Promoter reporter assays revealed that this repression results from downregulation of KIF23 promoter activity. CDK inhibitor p21(WAF1/CIP1) was shown to be necessary to mediate p53-dependent repression. Furthermore, we identified the highly conserved cell cycle genes homology region (CHR) in the KIF23 promoter to be strictly required for p53-dependent repression as well as for cell cycle-dependent expression of KIF23. Cell cycle- and p53-dependent regulation of KIF23 appeared to be controlled by differential binding of DREAM and MMB complexes to the CHR element. With this study, we describe a new mechanism for transcriptional regulation of KIF23. Considering the strongly supporting function of KIF23 in cytokinesis, its p53-dependent repression may contribute to the prevention of uncontrolled cell growth. PMID- 23650553 TI - A phylogenetic perspective on the individual species-area relationship in temperate and tropical tree communities. AB - Ecologists have historically used species-area relationships (SARs) as a tool to understand the spatial distribution of species. Recent work has extended SARs to focus on individual-level distributions to generate individual species area relationships (ISARs). The ISAR approach quantifies whether individuals of a species tend have more or less species richness surrounding them than expected by chance. By identifying richness 'accumulators' and 'repellers', respectively, the ISAR approach has been used to infer the relative importance of abiotic and biotic interactions and neutrality. A clear limitation of the SAR and ISAR approaches is that all species are treated as evolutionarily independent and that a large amount of work has now shown that local tree neighborhoods exhibit non random phylogenetic structure given the species richness. Here, we use nine tropical and temperate forest dynamics plots to ask: (i) do ISARs change predictably across latitude?; (ii) is the phylogenetic diversity in the neighborhood of species accumulators and repellers higher or lower than that expected given the observed species richness?; and (iii) do species accumulators, repellers distributed non-randomly on the community phylogenetic tree? The results indicate no clear trend in ISARs from the temperate zone to the tropics and that the phylogenetic diversity surrounding the individuals of species is generally only non-random on very local scales. Interestingly the distribution of species accumulators and repellers was non-random on the community phylogenies suggesting the presence of phylogenetic signal in the ISAR across latitude. PMID- 23650554 TI - Progressive white matter microstructure damage in male chronic heroin dependent individuals: a DTI and TBSS study. AB - BACKGROUND: To investigate the WM microstructure deficits in heroin dependent individuals (HDIs) with different length of heroin dependence, and to investigate whether these WM deficits can be related to the duration of heroin use and to decision-making deficits in HDIs. METHODOLOGY/PRINCIPAL FINDINGS: Thirty-six HDIs [including eighteen sHDIs (duration of heroin dependent is less than 10 years) and eighteen lHDIs (duration of dependent is between 10:20 years)] and sixteen healthy controls participated in this study. Whole brain voxel-wise analysis of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da) and radial diffusivity (Dr) were performed by tract-based spatial statistics (TBSS) to localize abnormal WM regions among groups. TBSS demonstrated that sHDIs had significantly lower FA than controls in right orbito-frontal WM, bilateral temporal WM and right parietal WM. The lHDIs had significantly lower FA throughout the brain compared with the controls and sHDIs. The lHDIs had significantly lower Da than controls in bilateral inferior frontaloccipital fasciculus, bilateral splenium of corpus callosum, left inferior longitudinal fasciculus, and had significantly higher Dr than controls in bilateral uncinatus fasciculus, bilateral inferior frontaloccipital fasciculus and bilateral cortical spinal fasciculus. Volume-of-interest (VOI) analyses detect the changes of diffusivity indices in the regions with FA abnormalities revealed by control vs sHDIs. In most VOIs, FA reductions were caused by the increase in Dr as well as the decrease in Da. Correlation analysis was used to assess the relationship between FA and behavioral measures in HDIs and controls available. Significantly positively correlations were found between the FA values in the right orbital frontal WM, right parietal WM and IGT performance. CONCLUSIONS: The extent and severity of WM integrity deficits in HDIs was associated with the length of heroin dependent. Furthermore, abnormal WM microstructure may correlate with decision-making impairments in HDIs. PMID- 23650555 TI - Methylated BSA mimics amyloid-related proteins and triggers inflammation. AB - The mechanistic study of inflammatory or autoimmune diseases requires the generation of mouse models that reproduce the alterations in immune responses observed in patients. Methylated bovine serum albumin (mBSA) has been widely used to induce antigen-specific inflammation in targeted organs or in combination with single stranded DNA (ssDNA) to generate anti-nucleic acids antibodies in vivo. However, the mechanism by which this modified protein triggers inflammation is poorly understood. By analyzing the biochemical properties of mBSA, we found that mBSA exhibits features of an intermediate of protein misfolding pathway. mBSA readily interact with a list of dyes that have binding specificity towards amyloid fibrils. Intriguingly, mBSA displayed cytotoxic activity and its binding to ssDNA further enhanced formation of beta-sheet rich amyloid fibrils. Moreover, mBSA is recognized by the serum amyloid P, a protein unanimously associated with amyloid plaques in vivo. In macrophages, we observed that mBSA disrupted the lysosomal compartment, signaled along the NLRP3 inflammasome pathway, and activated caspase 1, which led to the production of IL-1beta. In vivo, mBSA triggered rapid and prominent immune cell infiltration that is dependent on IL 1beta induction. Taken together, these data demonstrate that by mimicking amyloidogenic proteins mBSA exhibits strong innate immune functions and serves as a potent adjuvant. These findings advance our understanding on the underlying mechanism of how aberrant immune responses lead to autoimmune reactions. PMID- 23650556 TI - Prognostic value of dehydroepiandrosterone-sulfate and other parameters of adrenal function in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Acute stroke has a high morbidity and mortality. We evaluated the predictive value of adrenal function testing in acute ischemic stroke. METHODS: In a cohort of 231 acute ischemic stroke patients, we measured dehydroepiandrosterone (DHEA), DHEA-Sulfate (DHEAS), cortisol at baseline and 30 minutes after stimulation with 1 ug ACTH. Delta cortisol, the amount of rise in the 1 ug ACTH-test, was calculated. Primary endpoint was poor functional outcome defined as modified Rankin scale 3-6 after 1 year. Secondary endpoint was nonsurvival after 1 year. RESULTS: Logistic regression analysis showed that DHEAS (OR 1.21, 95% CI 1.01-1.49), but not DHEA (OR 1.01, 95% CI 0.99-1.04), was predictive for adverse functional outcome. Neither DHEA (OR 0.99, 95% CI 0.96 1.03) nor DHEAS (OR 1.10, 95% CI 0.82-1.44) were associated with mortality. Baseline and stimulated cortisol were predictive for mortality (OR 1.41, 95% CI 1.20-1.71; 1.35, 95% CI 1.15-1.60), but only basal cortisol for functional outcome (OR 1.20, 95% CI 1.04-1.38). Delta cortisol was not predictive for functional outcome (OR 0.86, 95% CI 0.71-1.05) or mortality (OR 0.92, 95% CI 0.72 1.17). The ratios cortisol/DHEA and cortisol/DHEAS discriminated between favorable outcome and nonsurvival (both p<0.0001) and between unfavorable outcome and nonsurvival (p = 0.0071 and 0.0029), but are not independent predictors for functional outcome or mortality in multivariate analysis (adjusted OR for functional outcome for both 1.0 (95% CI 0.99-1.0), adjusted OR for mortality for both 1.0 (95% CI 0.99-1.0 and 1.0-1.01, respectively)). CONCLUSION: DHEAS and the cortisol/DHEAS ratio predicts functional outcome 1 year after stroke whereas cortisol levels predict functional outcome and mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT00390962 (Retrospective analysis of this cohort). PMID- 23650558 TI - Social brains in context: lesions targeted to the song control system in female cowbirds affect their social network. AB - Social experiences can organize physiological, neural, and reproductive function, but there are few experimental preparations that allow one to study the effect individuals have in structuring their social environment. We examined the connections between mechanisms underlying individual behavior and social dynamics in flocks of brown-headed cowbirds (Molothrus ater). We conducted targeted inactivations of the neural song control system in female subjects. Playback tests revealed that the lesions affected females' song preferences: lesioned females were no longer selective for high quality conspecific song. Instead, they reacted to all cowbird songs vigorously. When lesioned females were introduced into mixed-sex captive flocks, they were less likely to form strong pair-bonds, and they no longer showed preferences for dominant males. This in turn created a cascade of effects through the groups. Social network analyses showed that the introduction of the lesioned females created instabilities in the social structure: males in the groups changed their dominance status and their courtship patterns, and even the competitive behavior of other female group-mates was affected. These results reveal that inactivation of the song control system in female cowbirds not only affects individual behavior, but also exerts widespread effects on the stability of the entire social system. PMID- 23650557 TI - Calnexin-assisted biogenesis of the neuronal glycine transporter 2 (GlyT2). AB - The neuronal transporter GlyT2 is a polytopic, 12-transmembrane domain, plasma membrane glycoprotein involved in the removal and recycling of synaptic glycine from inhibitory synapses. Mutations in the human GlyT2 gene (SLC6A5) that cause deficient glycine transport or defective GlyT2 trafficking are the second most common cause of hyperekplexia or startle disease. In this study we examined several aspects of GlyT2 biogenesis that involve the endoplasmic reticulum chaperone calnexin (CNX). CNX binds transiently to an intermediate under glycosylated transporter precursor and facilitates GlyT2 processing. In cells expressing GlyT2, transporter accumulation and transport activity were attenuated by siRNA-mediated CNX knockdown and enhanced by CNX overexpression. GlyT2 binding to CNX was mediated by glycan and polypeptide-based interactions as revealed by pharmacological approaches and the behavior of GlyT2 N-glycan-deficient mutants. Moreover, transporter folding appeared to be stabilized by N-glycans. Co expression of CNX and a fully non-glycosylated mutant rescues glycine transport but not mutant surface expression. Hence, CNX discriminates between different conformational states of GlyT2 displaying a lectin-independent chaperone activity. GlyT2 wild-type and mutant transporters were finally degraded in the lysosome. Our findings provide further insight into GlyT2 biogenesis, and a useful framework for the study of newly synthesized GlyT2 transporters bearing hyperekplexia mutations. PMID- 23650559 TI - A microscopy study of the structural features of post-LASIK human corneas. AB - PURPOSE: To study the structural features of human post-LASIK corneas. METHODS: A pair of post-mortem donor corneas, from a 55-year old patient who underwent uncomplicated LASIK surgery five years previously, were bisected and fixed in 4% paraformaldehyde. The right cornea and one half of the left cornea were processed for light microscopy and scanning electron microscopy. One half of the right cornea was also examined by transmission electron microscopy. RESULTS: The flap bed interface could be easily detected several years after LASIK and, although the flap appeared to be in close association with the stromal bed, there was a noticeable absence of reconnection between adjacent severed lamellae. Tissue gaps were evident at the flap margin, which once free of cellular components revealed the presence of a few bridging fibres. CONCLUSION: Examination of corneas five years after LASIK revealed evidence of primitive reparative scar development at the wound interface, but no reconnection of severed collagen lamellae. Such findings may explain the occurrence of flap dislocation following trauma in some patients months or years after surgery. PMID- 23650560 TI - Integrating landscape disturbance and indicator species in conservation studies. AB - Successful conservation plans are conditioned by our ability to detect anthropogenic change in space and time and various statistical analyses have been developed to handle this critical issue. The main objective of this paper is to illustrate a new approach for spatial analysis in conservation biology. Here, we propose a two-step protocol. First, we introduce a new disturbance metric which provides a continuous measure of disturbance for any focal communities on the basis of the surrounding landscape matrix. Second, we use this new gradient to estimate species and community disturbance thresholds by implementing a recently developed method called Threshold Indicator Taxa ANalysis (TITAN). TITAN detects changes in species distributions along environmental gradients using indicators species analysis and assesses synchrony among species change points as evidence for community thresholds. We demonstrate our method with soil arthropod assemblages along a disturbance gradient in Terceira Island (Azores, Portugal). We show that our new disturbance metric realistically reflects disturbance patterns, especially in buffer zones (ecotones) between land use categories. By estimating species disturbance thresholds with TITAN along the disturbance gradient in Terceira, we show that species significantly associated with low disturbance differ from those associated with high disturbance in their biogeographical origin (endemics, non-endemic natives and exotics) and taxonomy (order). Finally, we suggest that mapping the disturbance community thresholds may reveal areas of primary interest for conservation, since these may host indigenous species sensitive to high disturbance levels. This new framework may be useful when: (1) both local and regional processes are to be reflected on single disturbance measures; (2) these are better quantified in a continuous gradient; (3) mapping disturbance of large regions using fine scales is necessary; (4) indicator species for disturbance are searched for and; (5) community thresholds are useful to understand the global dynamics of habitats. PMID- 23650561 TI - Mitochondrial functional state impacts spontaneous neocortical activity and resting state FMRI. AB - Mitochondrial Ca(2+) uptake, central to neural metabolism and function, is diminished in aging whereas enhanced after acute/sub-acute traumatic brain injury. To develop relevant translational models for these neuropathologies, we determined the impact of perturbed mitochondrial Ca(2+) uptake capacities on intrinsic brain activity using clinically relevant markers. From a multi compartment estimate of probable baseline Ca(2+) ranges in the brain, we hypothesized that reduced or enhanced mitochondrial Ca(2+) uptake capacity would decrease or increase spontaneous neuronal activity respectively. As resting state fMRI-BOLD fluctuations and stimulus-evoked BOLD responses have similar physiological origins [1] and stimulus-evoked neuronal and hemodynamic responses are modulated by mitochondrial Ca(2+) uptake capacity [2], [3] respectively, we tested our hypothesis by measuring hemodynamic fluctuations and spontaneous neuronal activities during normal and altered mitochondrial functional states. Mitochondrial Ca(2+) uptake capacity was perturbed by pharmacologically inhibiting or enhancing the mitochondrial Ca(2+) uniporter (mCU) activity. Neuronal electrical activity and cerebral blood flow (CBF) fluctuations were measured simultaneously and integrated with fMRI-BOLD fluctuations at 11.7T. mCU inhibition reduced spontaneous neuronal activity and the resting state functional connectivity (RSFC), whereas mCU enhancement increased spontaneous neuronal activity but reduced RSFC. We conclude that increased or decreased mitochondrial Ca(2+) uptake capacities lead to diminished resting state modes of brain functional connectivity. PMID- 23650562 TI - Overexpression of retinal degeneration slow (RDS) protein adversely affects rods in the rd7 model of enhanced S-cone syndrome. AB - The nuclear receptor NR2E3 promotes expression of rod photoreceptor genes while repressing cone genes. Mice lacking NR2E3 (Nr2e3(rd7/rd7) referred to here as rd7) are a model for enhanced S-cone syndrome, a disease associated with increased sensitivity to blue light and night blindness. Rd7 retinas have reduced levels of the outer segment (OS) structural protein retinal degeneration slow (RDS). We test the hypothesis that increasing RDS levels would improve the Rd7 phenotype. Transgenic mice over-expressing normal mouse peripherin/RDS (NMP) in rods and cones were crossed onto the rd7 background. Disease phenotypes were assessed in NMP/rd7 eyes and compared to wild-type (WT) and rd7 eyes at postnatal day 30. NMP/rd7 retinas expressed total RDS (transgenic and endogenous) message at WT levels, and NMP protein was correctly localized to the OS. NMP/rd7 retinas have shorter OSs compared to rd7 and WT and significantly reduced number of rosettes. NMP/rd7 mice also exhibited significant deficits in scotopic ERG amplitudes compared to rd7 while photopic amplitudes remained unaffected. Protein levels of rhodopsin, RDS, and the RDS homologue ROM-1 were significantly reduced in the NMP/rd7 retinas compared to rd7. We show that correcting the levels of RDS gene expression does not improve the phenotype of the rd7 suggesting that RDS deficiency is not responsible for the defect in this model. We suggest that the specific rod defect in the NMP/rd7 is likely associated with ongoing problems in the rd7 that are related to the expression of cone genes in rod cells, a characteristic of the model. PMID- 23650563 TI - Predatory bacteria: a potential ally against multidrug-resistant Gram-negative pathogens. AB - Multidrug-resistant (MDR) Gram-negative bacteria have emerged as a serious threat to human and animal health. Bdellovibrio spp. and Micavibrio spp. are Gram negative bacteria that prey on other Gram-negative bacteria. In this study, the ability of Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus to prey on MDR Gram-negative clinical strains was examined. Although the potential use of predatory bacteria to attack MDR pathogens has been suggested, the data supporting these claims is lacking. By conducting predation experiments we have established that predatory bacteria have the capacity to attack clinical strains of a variety of beta-lactamase-producing, MDR Gram-negative bacteria. Our observations indicate that predatory bacteria maintained their ability to prey on MDR bacteria regardless of their antimicrobial resistance, hence, might be used as therapeutic agents where other antimicrobial drugs fail. PMID- 23650564 TI - Comparative effectiveness of intravenous immunoglobulin for children with Kawasaki disease: a nationwide cohort study. AB - INTRODUCTION: Different immunoglobulin manufacturing processes may influence its effectiveness for Kawasaki disease. However, nationwide studies with longitudinal follow-up are still lacking. The aim of this study was to evaluate the comparative effectiveness of immunoglobulin preparations from a nationwide perspective. MATERIALS AND METHODS: This is a nationwide retrospective cohort study with a new user design. Data came from the National Health Insurance Research Database of Taiwan. From 1997 to 2008, children under 2 years old who received immunoglobulin therapy for the first time under the main diagnosis of Kawasaki disease were enrolled. The manufacturing processes were divided into beta-propiolactonation, acidification and those containing IgA. The endpoints were immunoglobulin non-responsiveness, acute aneurysm, prolonged use of anti platelets or anti-coagulants, and recurrence. RESULTS: In total, 3830 children were enrolled. beta-propiolactonation had a relative risk of 1.45 (95% CI 1.08~1.94) of immunoglobulin non-responsiveness, however, the relative risks for acidification and containing IgA were non-significant. For acute aneurysms, acidification had a relative risk of 1.49 (95% CI 1.17~1.90), however the relative risks for beta-propiolactonation and containing IgA were non significant. For prolonged use of anti-platelets or anti-coagulants, beta propiolactonation had a relative risk of 1.44 (95% CI 1.18~1.76), and acidification protected against them both with a relative risk of 0.82 (95% CI 0.69~0.97), whereas the relative risk for containing IgA was non-significant. For recurrence, all three factors were non-significant. CONCLUSIONS: The effectiveness of immunoglobulin may differ among different manufacturing processes. beta-propiolactonation had a higher risk of treatment failure and prolonged use of anti-platelets or anti-coagulants. Acidification may increase the risk of acute coronary aneurysms. PMID- 23650565 TI - Transcription factors that convert adult cell identity are differentially polycomb repressed. AB - Transcription factors that can convert adult cells of one type to another are usually discovered empirically by testing factors with a known developmental role in the target cell. Here we show that standard genomic methods (RNA-seq and ChIP seq) can help identify these factors, as most are more strongly Polycomb repressed in the source cell and more highly expressed in the target cell. This criterion is an effective genome-wide screen that significantly enriches for factors that can transdifferentiate several mammalian cell types including neural stem cells, neurons, pancreatic islets, and hepatocytes. These results suggest that barriers between adult cell types, as depicted in Waddington's "epigenetic landscape", consist in part of differentially Polycomb-repressed transcription factors. This genomic model of cell identity helps rationalize a growing number of transdifferentiation protocols and may help facilitate the engineering of cell identity for regenerative medicine. PMID- 23650566 TI - Investigation of sequential growth factor delivery during cuprizone challenge in mice aimed to enhance oligodendrogliogenesis and myelin repair. AB - Repair in multiple sclerosis involves remyelination, a process in which axons are provided with a new myelin sheath by new oligodendrocytes. Bone morphogenic proteins (BMPs) are a family of growth factors that have been shown to influence the response of oligodendrocyte progenitor cells (OPCs) in vivo during demyelination and remyelination in the adult brain. We have previously shown that BMP4 infusion increases numbers of OPCs during cuprizone-induced demyelination, while infusion of Noggin, an endogenous antagonist of BMP4 increases numbers of mature oligodendrocytes and remyelinated axons following recovery. Additional studies have shown that insulin-like growth factor-1 (IGF-1) promotes the survival of OPCs during cuprizone-induced demyelination. Based on these data, we investigated whether myelin repair could be further enhanced by sequential infusion of these agents firstly, BMP4 to increase OPC numbers, followed by either Noggin or IGF-1 to increase the differentiation and survival of the newly generated OPCs. We identified that sequential delivery of BMP4 and IGF-1 during cuprizone challenge increased the number of mature oligodendrocytes and decreased astrocyte numbers following recovery compared with vehicle infused mice, but did not alter remyelination. However, sequential delivery of BMP4 and Noggin during cuprizone challenge did not alter numbers of oligodendrocytes or astrocytes in the corpus callosum compared with vehicle infused mice. Furthermore, electron microscopy analysis revealed no change in average myelin thickness in the corpus callosum between vehicle infused and BMP4-Noggin infused mice. Our results suggest that while single delivery of Noggin or IGF-1 increased the production of mature oligodendrocytes in vivo in the context of demyelination, only Noggin infusion promoted remyelination. Thus, sequential delivery of BMP4 and Noggin or IGF-1 does not further enhance myelin repair above what occurs with delivery of Noggin alone. PMID- 23650568 TI - Intracellular reorganization and ionic signaling of the Phycomyces stage I sporangiophore in response to gravity and touch. AB - Unicellular zygomycete fungus Phycomyces blakesleeanus exhibits a typical apical growth that depends on a complex interaction of different physiological processes. Sensitivity to the light, wind, barriers, touch and gravity of Phycomyces sporangiophore implicate the existence of the cross-talk between different signaling pathways in the same cell. Touch and gravity in Phycomyces sporangiophore seem to share some common elements of Ca(2+) and H(+) ion-based signal transduction systems. Apoplastic Ca(2+) and H(+) ionic fluxes are important for establishing cell polarity in tip growing sporangiophore both in vertical and tilted position. Upon gravistimulation sporangiophores display asymmetric ionic distribution and intracellular reorganization leading to change in the growth pattern. PMID- 23650567 TI - MDA5 plays a crucial role in enterovirus 71 RNA-mediated IRF3 activation. AB - Induction of type-I interferons (IFNs), IFN-alpha/beta, is crucial to innate immunity against RNA virus infection. Cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors, including RIG-I and melanoma differentiation-associated gene 5 (MDA5), are critical pathogen sensors for activation of type-I IFN expression in response to RNA virus infection. MDA5 is required for type-I IFN expression in mouse models in response to infection by picornaviruses, such as encephalomyocarditis virus (EMCV) and coxsackievirus B3. Enterovirus 71 (EV71) belongs to picornaviridae and contains positive-stranded RNA genome that is linked with VPg protein at the 5' end. Although a recent study showed that EV71 3C protease could suppress RIG-I-mediated IFN-beta response, the cytoplasmic RIG I-like receptor that is directly involved in the recognition of EV71 RNA remains unclear. Using EV71-derived RNA as an agonist, we demonstrate that MDA5 is involved in EV71 RNA-mediated IRF3 activation and IFN-beta transcription. Our data also show that overexpression of the MDA5 protein reverses the suppression of IRF3 activation caused by EV71 infection. These results indicate that MDA5 is an important factor for EV71 RNA-activated type-I IFN expression. Furthermore, we also show that EV71 infection enhances MDA5 degradation and that the degradation could be inhibited by a broad spectrum caspase inhibitor. PMID- 23650569 TI - Diadenosine polyphosphates (Ap3A and Ap4A) behave as alarmones triggering the synthesis of enzymes of the phenylpropanoid pathway in Arabidopsis thaliana. AB - It is known that cells under stress accumulate various dinucleoside polyphosphates, compounds suggested to function as alarmones. In plants, the phenylpropanoid pathways yield metabolites protecting these organisms against various types of stress. Observations reported in this communication link these two phenomena and provide an example of a metabolic "addressee" for an "alarm" signaled by diadenosine triphosphate (Ap3A) or diadenosine tetraphosphate (Ap4A). In response to added Ap3A or Ap4A, seedlings of Arabidopsis thaliana incubated in full nutrition medium increased both the expression of the genes for and the specific activity of phenylalanine ammonia-lyase and 4-coumarate:coenzyme A ligase, enzymes that control the beginning of the phenylpropanoid pathway. Neither adenine mononucleotides (AMP, ADP or ATP) nor adenosine evoked such effects. Reactions catalyzed in vitro by these enzymes were not affected by Ap3A or Ap4A. PMID- 23650570 TI - An in vivo system involving co-expression of cyanobacterial flavodoxin and ferredoxin-NADP(+) reductase confers increased tolerance to oxidative stress in plants. AB - Oxidative stress in plants causes ferredoxin down-regulation and NADP(+) shortage, over-reduction of the photosynthetic electron transport chain, electron leakage to oxygen and generation of reactive oxygen species (ROS). Expression of cyanobacterial flavodoxin in tobacco chloroplasts compensates for ferredoxin decline and restores electron delivery to productive routes, resulting in enhanced stress tolerance. We have designed an in vivo system to optimize flavodoxin reduction and NADP(+) regeneration under stress using a version of cyanobacterial ferredoxin-NADP(+) reductase without the thylakoid-binding domain. Co-expression of the two soluble flavoproteins in the chloroplast stroma resulted in lines displaying maximal tolerance to redox-cycling oxidants, lower damage and decreased ROS accumulation. The results underscore the importance of chloroplast redox homeostasis in plants exposed to adverse conditions, and provide a tool to improve crop tolerance toward environmental hardships. PMID- 23650571 TI - Green algae Chlamydomonas reinhardtii possess endogenous sialylated N-glycans. AB - Green algae have a great potential as biofactories for the production of proteins. Chlamydomonas reinhardtii, a representative of eukaryotic microalgae, has been extensively used as a model organism to study light-induced gene expression, chloroplast biogenesis, photosynthesis, light perception, cell-cell recognition, and cell cycle control. However, little is known about the glycosylation machinery and N-linked glycan structures of green algae. In this study, we performed mass spectrometry analysis of N-linked oligosaccharides released from total extracts of Chlamydomonas reinhardtii and demonstrated that C. reinhardtii algae possess glycoproteins with mammalian-like sialylated N linked oligosaccharides. These findings suggest that C. reinhardtii may be an attractive system for expression of target proteins. PMID- 23650572 TI - Expressing the Erwinia amylovora type III effector DspA/E in the yeast Saccharomyces cerevisiae strongly alters cellular trafficking. AB - Erwinia amylovora is responsible for fire blight, a necrotic disease of apples and pears. E. amylovora relies on a type III secretion system (T3SS) to induce disease on host plants. DspA/E belongs to the AvrE family of type III effector. Effectors of the AvrE family are injected via the T3SS in plant cell and are important to promote bacterial growth following infection and to suppress plant defense responses. Their mode of action in the plant cells is unknown. Here we study the physiological effects induced by dspA/E expression in the yeast Saccharomyces cerevisiae. Expression of dspA/E in the yeast inhibits cell growth. This growth inhibition is associated with perturbations of the actin cytoskeleton and endocytosis. PMID- 23650573 TI - IGF-1 receptor is down-regulated by sunitinib induces MDM2-dependent ubiquitination. AB - The insulin like growth factor receptor subtype 1(IGF-1R) plays an important role in cancers transformation and progression. The aim is to investigate the effects of sunitinib on IGF-1R cell signaling transduction, especially on receptor phosphorylation and ubiquitination. In HEK293 cells, IGF-1R signaling pathways are activated in response to IGF-1, which induces obvious phosphorylations of receptor tyrosine and Akt, ERK. However, the phosphorylations of receptor tyrosine, Akt and ERK were significant inhibited by sunitinib. We found that both IGF-1 and sunitinib obviously down regulated the IGF-1R expression. For analysis the ubiquitination, HEK293 cells were simulated with 100 ng/ml IGF-1 or 10 nM sunitinib for 10 min after serum starvation for 24 h. Both IGF-1 and sunitinib could obviously induce the IGF-1R ubiquitination at 10 min compared with control (only serum free, no stimulation), indicating IGF-1 and sunitinib down-regulate the IGF-1R by increasing the receptor degradation through ubiquitination dependent proteasome pathway. We also found that MDM2 combined to IGF-1R in response to sunitinib stimulation. To confirm it, HEK293 cells were transfected with human HA-MDM2 (+MDM2) or siRNA to MDM2 (-MDM2). Following 24 h serum starvation, cells were stimulated with 10 nM sunitinib for 10 min. In over expressed MDM2 cells, IGF-1R was more ubiquitinated than that in mock-transfected cells (control), and no ubiquitination in -MDM2 cells. These results mean that sunitinib mediates ubiquitination of IGF-1R dependent on MDM2. In summary, sunitinib could block signaling transduction and mediate degradation of IGF-1R. PMID- 23650574 TI - Utrophin ABD binds to F-actin in an open conformation. AB - Structural analyses of actin binding regions comprising tandem calponin homology domains alone and when bound to F-actin have revealed a number of different conformations with calponin homology domains in 'open' and 'closed' positions. In an attempt to resolve these issues we have examined the properties of the utrophin actin binding domain in open and closed conformations in order to verify the conformation when bound to F-actin. Locking the actin binding domain in a closed conformation using engineered cysteine residues in each calponin homology domain reduced the affinity for F-actin without affecting the stoichiometry furthermore differential scanning calorimetry experiments revealed a reduction in melting temperature on binding to actin. The data suggest the amino-terminal utrophin actin binding domain is in an open conformation in solution and when bound to F-actin. PMID- 23650575 TI - A new hybrid bacteriocin, Ent35-MccV, displays antimicrobial activity against pathogenic Gram-positive and Gram-negative bacteria. AB - Bacteriocins and microcins are ribosomally synthesized antimicrobial peptides that are usually active against phylogenetically related bacteria. Thus, bacteriocins are active against Gram-positive while microcins are active against Gram-negative bacteria. The narrow spectrum of action generally displayed by bacteriocins from lactic acid bacteria represents an important limitation for the application of these peptides as clinical drugs or as food biopreservatives. The present study describes the design and expression of a novel recombinant hybrid peptide combining enterocin CRL35 and microcin V named Ent35-MccV. The chimerical bacteriocin displayed antimicrobial activity against enterohemorrhagic Escherichia coli and Listeria monocytogenes clinical isolates, among other pathogenic bacteria. Therefore, Ent35-MccV may find important applications in food or pharmaceutical industries. PMID- 23650576 TI - Inhibitory effects of choline-O-sulfate on amyloid formation of human islet amyloid polypeptide. AB - Choline-O-sulfate (2-(trimethylammonio)ethyl sulfate, COS) is a naturally occurring osmolyte that is synthesized by plants, lichens, algae, fungi, and several bacterial species. We examined the inhibitory effects of COS on amyloid formation of the human islet amyloid polypeptide (hIAPP or amylin) using a thioflavin T (ThT) fluorescence assay, circular dichroism spectroscopy and transmission electron microscopy. The results showed that COS suppresses a conformational change of hIAPP from a random coil to a beta-sheet structure, resulting in the inhibition of amyloid formation. Comparisons with various structural analogs including carnitine, acetylcholine and non-detergent sulfobetaines (NDSBs) using the ThT fluorescence assay showed that COS is the most effective inhibitor of hIAPP amyloid formation, suggesting that the sulfate group, which is unique to COS, significantly contributes to the inhibition. PMID- 23650577 TI - The Wnt pathway destabilizes adherens junctions and promotes cell migration via beta-catenin and its target gene cyclin D1. AB - The Wnt pathway regulates cell proliferation, mobility and differentiation. Among the many Wnt target genes is CCND1 which codes for cyclin D1. Cyclin D1, in complex with cdk4 and cdk6, regulates G1/S phase transition during cell cycle. Independently of CDK, cyclin D1 also regulates the migration of macrophages. Here we analyzed the effects of cyclin D1 on the migration of cancer cell lines using the transwell migration and scratch assays. We also tested the effect of cyclin D1 and beta-catenin on E-cadherin-mediated cell-cell contacts. Our results show that the Wnt pathway promotes cellular migration via its target gene cyclin D1. Moreover we show that cyclin D1 influences the actin cytoskeleton and destabilizes adherens junctions. PMID- 23650578 TI - Adipocyte pyruvate dehydrogenase kinase 4 expression is associated with augmented PPARgamma upregulation in early-life programming of later obesity. AB - We studied adipocytes from 8-week-old control rat offspring (CON) or rat offspring subjected to maternal low (8%) protein (MLP) feeding during pregnancy/lactation, a procedure predisposing to obesity. Acute exposure to isoproterenol or adenosine enhanced PDK4 and PPARgamma mRNA gene expression in CON and MLP adipocytes. Enhanced adipocyte Pdk4 expression correlated with increased PPARgamma expression. Higher levels of PDK4 and PPARgamma were observed in MLP adipocytes. SCD1 is a PPARgamma target. Isoproterenol enhanced adipocyte PDK4 and SCD1 gene expression in parallel. This could reflect augmented PPARgamma expression together with enhanced lipolytic stimulation to supply endogenous PPARgamma ligands, allowing enhanced adipocyte PDK4 and SCD1 expression via PPARgamma activation. In contrast, the effect of adenosine to increase PDK4 expression is independent of stimulation of lipolysis and, as SCD1 expression was unaffected by adenosine, unlikely to reflect PPARgamma activation. Increased adipocyte expression of both PDK4 and SCD1 in the MLP model could participate as components of a "thrifty" phenotype, favouring the development of obesity. PMID- 23650579 TI - Low-resolution structure of Drosophila translin. AB - Crystals of native Drosophila melanogaster translin diffracted to 7 A resolution. Reductive methylation of the protein improved crystal quality. The native and methylated proteins showed similar profiles in size-exclusion chromatography analyses but the methylated protein displayed reduced DNA-binding activity. Crystals of the methylated protein diffracted to 4.2 A resolution at BM14 of the ESRF synchrotron. Crystals with 49% solvent content belonged to monoclinic space group P21 with eight protomers in the asymmetric unit. Only 2% of low-resolution structures with similar low percentage solvent content were found in the PDB. The crystal structure, solved by molecular replacement method, refined to R work (R free) of 0.24 (0.29) with excellent stereochemistry. The crystal structure clearly shows that drosophila protein exists as an octamer, and not as a decamer as expected from gel-filtration elution profiles. The similar octameric quaternary fold in translin orthologs and in translin-TRAX complexes suggests an up-down dimer as the basic structural subunit of translin-like proteins. The drosophila oligomer displays asymmetric assembly and increased radius of gyration that accounts for the observed differences between the elution profiles of human and drosophila proteins on gel-filtration columns. This study demonstrates clearly that low-resolution X-ray structure can be useful in understanding complex biological oligomers. PMID- 23650580 TI - The Hsp90 inhibitor 17-AAG represses calcium-induced cytokeratin 1 and 10 expression in HaCaT keratinocytes. AB - Hsp90 is essential for maintaining the activity of numerous signaling factors, and plays a key role in cellular signal transduction networks. 17-Allylamino-17 demethoxygeldanamycin (17-AAG) is an ansamycin antibiotic that binds to Hsp90 and inhibits its function. HaCaT human keratinocytes were used to investigate the cellular and molecular functions of Hsp90 in keratinocyte differentiation. Inhibition of Hsp90 by 17-AAG leads to downregulation of the differentiation markers cytokeratin 1 and cytokeratin 10 at the protein and mRNA levels. PMID- 23650581 TI - MAP kinases bind endothelial nitric oxide synthase. AB - Endothelial nitric oxide synthase (eNOS) contains a motif similar to recognition sequences in known MAPK binding partners. In optical biosensing experiments, eNOS bound p38 and ERK with ~100 nM affinity and complex kinetics. Binding is diffusion-limited (k on ~ .15 * 10(6) M(-1) s(-1)). Neuronal NOS also bound p38 but exhibited much slower and weaker binding. p38-eNOS binding was inhibited by calmodulin. Evidence for a ternary complex was found when eNOS bound p38 was exposed to CaM, increasing the apparent dissociation rate. These observations strongly suggest a direct role for MAPK in regulation of NOS with implications for signaling pathways including angiogenesis and control of vascular tone. PMID- 23650582 TI - Restoring virulence to mutants lacking subunits of multiprotein machines: functional complementation of a Brucella virB5 mutant. AB - Complementation for virulence of a non-polar virB5 mutant in Brucella suis 1330 was not possible using a pBBR-based plasmid but was with low copy vector pGL10. Presence of the pBBR-based replicon in wildtype B. suis had a dominant negative effect, leading to complete attenuation in J774 macrophages. This was due to pleiotropic effects on VirB protein expression due to multiple copies of the virB promoter region and over expression of VirB5. Functional complementation of mutants in individual components of multiprotein complexes such as bacterial secretion systems, are often problematic; this study highlights the importance of using a low copy vector. PMID- 23650583 TI - GeneSetDB: A comprehensive meta-database, statistical and visualisation framework for gene set analysis. AB - Most "omics" experiments require comprehensive interpretation of the biological meaning of gene lists. To address this requirement, a number of gene set analysis (GSA) tools have been developed. Although the biological value of GSA is strictly limited by the breadth of the gene sets used, very few methods exist for simultaneously analysing multiple publically available gene set databases. Therefore, we constructed GeneSetDB (http://genesetdb.auckland.ac.nz/haeremai.html), a comprehensive meta-database, which integrates 26 public databases containing diverse biological information with a particular focus on human disease and pharmacology. GeneSetDB enables users to search for gene sets containing a gene identifier or keyword, generate their own gene sets, or statistically test for enrichment of an uploaded gene list across all gene sets, and visualise gene set enrichment and overlap using a clustered heat map. PMID- 23650584 TI - The anti-atherosclerotic di-peptide, Trp-His, inhibits the phosphorylation of voltage-dependent L-type Ca(2+) channels in rat vascular smooth muscle cells. AB - Trp-His is the only vasoactive di-peptide known to regulate intracellular Ca(2+) ([Ca(2+)]i) and prevent the onset of atherosclerosis in mice. In this study, we showed that Trp-His reduced the [Ca(2+)]i elevation in phospholipase C-activated vascular smooth muscle cells (VSMCs), while a mixture of the corresponding constituent amino acids did not show significant reduction. Furthermore, Trp-His suppressed calmodulin-dependent kinase II (CaMK II) activity in angiotensin II stimulated VSMCs, resulting in the inhibition of phosphorylation of voltage dependent L-type Ca(2+) channels (VDCC). Therefore, Trp-His potentially regulates the VDCC phosphorylation cascade through Ca(2+)-CaM/CaMK II. PMID- 23650585 TI - Formation of MgF3 (-)-dependent complexes between an AAA(+) ATPase and sigma(54.). AB - The widely distributed bacterial sigma(54)-dependent transcription regulates pathogenicity and numerous adaptive responses in diverse bacteria. Formation of the sigma(54)-dependent open promoter complex is a multi-step process driven by AAA(+) ATPases. Non-hydrolysable nucleotide analogues are particularly suitable for studying such complexity by capturing various intermediate states along the energy coupling pathway. Here we report a novel ATP analogue, ADP-MgF3 (-), which traps an AAA(+) ATPase with its target sigma(54). The MgF3 (-)-dependent complex is highly homogeneous and functional assays suggest it may represent an early transcription intermediate state valuable for structural studies. PMID- 23650586 TI - Tyrosine phosphorylation plays a role in increasing maspin protein levels and its cytoplasmic accumulation. AB - Maspin is a tumor suppressor with many biological activities, multiple ligands and different subcellular localizations. Its underlying molecular mechanism remains elusive. We hypothesized that phosphorylation might regulate maspin localization and function. Using two-dimensional gel electrophoresis with different focusing power followed by Western blot we identified four different maspin forms with the same molecular weight (42 kDa), but different isoelectric points. Three of these forms were sensitive to acidic phosphatase treatment, suggesting that they are phosphorylated. Sodium peroxidovanadate treatment, a protein-tyrosine phosphatase inhibitor, resulted in a rapid increase in maspin protein levels and cytoplasmic accumulation. These data show that there are three different maspin tyrosine phosphoforms. Inhibition of tyrosine phosphatases increased maspin protein levels and leads to its cytoplasmic accumulation. PMID- 23650587 TI - Using decision tree learning to predict the responsiveness of hepatitis C patients to drug treatment. AB - The recommended treatment for patients with chronic hepatitis C, pegylated interferon alpha (PEG-IFN-alpha) plus rebavirin (RBV), does not provide a sustained virologic response in all patients, especially those with hepatitis C virus (HCV) genotype 1. It is therefore important to predict whether or not a new patient with HCV genotype 1 will be cured by the recommended treatment. We propose a prediction method for a new patient using a decision tree learning model based on SNPs evaluated in a genome-wide association study. By the decision tree learning for 142 Japanese patients with HCV genotype 1 (78 with null virologic response and 64 with virologic response), we can predict with high probability (93%) whether or not a new patient with HCV will be helped by the recommended treatment. PMID- 23650588 TI - Dihydroartemisinin induces autophagy and inhibits the growth of iron-loaded human myeloid leukemia K562 cells via ROS toxicity. AB - Dihydroartemisinin (DHA), an active metabolite of artemisinin derivatives, is the most remarkable anti-malarial drug and has little toxicity to humans. Recent studies have shown that DHA effectively inhibits the growth of cancer cells. In the present study, we intended to elucidate the mechanisms underlying the inhibition of growth of iron-loaded human myeloid leukemia K562 cells by DHA. Mitochondria are important regulators of both autophagy and apoptosis, and one of the triggers for mitochondrial dysfunction is the generation of reactive oxygen species (ROS). We found that the DHA-induced autophagy of leukemia K562 cells, whose intracellular organelles are primarily mitochondria, was ROS dependent. The autophagy of these cells was followed by LC3-II protein expression and caspase-3 activation. In addition, we demonstrated that inhibition of the proliferation of leukemia K562 cells by DHA is also dependent upon iron. This inhibition includes the down-regulation of TfR expression and the induction of K562 cell growth arrest in the G2/M phase. PMID- 23650589 TI - Effects of carbon monoxide (CO) delivery by a CO donor or hemoglobin on vascular hypoxia inducible factor 1alpha and mitochondrial respiration. AB - We examined carbon monoxide (CO) delivery by carbon monoxide-releasing molecule 2 (CORM-2) or hemoglobin (Hb) on cellular oxygen sensing and mitochondrial respiration in bovine aortic endothelial cells (BAECs). CORM-2 reduced hypoxia inducible factor-1alpha (HIF-1alpha) and endothelin-1 (ET-1) expression in normoxic and hypoxic cells, but while Hb alone significantly reduced HIF-1alpha stabilization in hypoxic cells, CO delivered by Hb (Hb-CO) had no effect on HIF 1alpha stabilization. CO dose-dependently increased basal oxygen consumption and reduced overall mitochondrial respiratory capacity. Hb-CO increased basal oxygen consumption but did not alter respiratory capacity. Together, CO reduced ET-1, and, at low doses, had no effect on endothelial mitochondria oxygen consumption. CO ligation to Hb may be developed further as non-vasoactive oxygen therapeutic without compromising mitochondrial function. PMID- 23650590 TI - Oxidative stress adaptation in aggressive prostate cancer may be counteracted by the reduction of glutathione reductase. AB - Oxidative stress has been associated with prostate cancer development and progression due to an increase of reactive oxygen species (ROS). However, the mechanisms whereby ROS and the antioxidant system participate in cancer progression remain unclear. In order to clarify the influence of oxidative stress in prostate cancer progression, we performed this study in two human prostate cancer cell lines, PC3 and HPV10 (from metastasis and from localized cancer, respectively) and RWPE1 cells derived from normal prostate epithelium. Cells were treated with hydrogen peroxide (H2O2) and PC3 cells were also treated with diethyl maleate (DEM). The effect on cell growth, viability, mitochondria membrane potential and oxidative stress was analysed. Oxidative stress was evaluated based on ROS production, oxidative lesion of lipids (MDA) and on determination of antioxidants, including enzyme activity of glutathione peroxidase (Gl-Px), glutathione reductase (Gl-Red) and on the quantification of glutathione (GSH), glutathione-s-transferase (GST) and total antioxidant status (TAS). PC3 shows higher ROS production but also the highest GSH levels and Gl-Red activity, possibly contributing to oxidative stress resistance. This is also associated with higher mitochondrial membrane potential, TAS and lower lipid peroxidation. On the other hand, we identified Gl-Red activity reduction as a new strategy in overcoming oxidative stress resistance, by inducing H2O2 cytotoxicity. Therefore these results suggest Gl-Red activity reduction as a new potential therapeutic approach, in prostate cancer. PMID- 23650591 TI - BRAF, GNAQ, and GNA11 mutations and copy number in pediatric low-grade glioma. AB - Fifty-two samples of pediatric low-grade glioma (48 primary, 4 recurrent) were analyzed for BRAF copy number variation (digital PCR analysis, CopyCaller) and point mutations of BRAF V600E, and exon 5 Q209 in GNAQ, and GNA11, using the MALDI-TOF mass spectrometer with validation by direct sequencing. An increased BRAF copy number was found in 18/47 primary samples tested; 15 of them (83.3%) were pilocytic astrocytomas. A BRAF mutation was found in 3/48 primary tumors, all with a normal BRAF copy number and no GNAQ mutation. One sample had a GNAQ209 mutation (Q209P626) with a normal BRAF gene; none of the tumors had a GNA11Q209 mutation. Recurrent or progressive tumors, analyzed in four patients, had the same molecular genotype as their primary. Increased BRAF copy number and activating BRAF mutations may be involved in the development of low-grade glioma via overactivation of the Ras/Raf pathway. This is the first report of a mutation in GNAQ209 in pediatric low-grade glioma. Understanding the molecular mechanisms underlying glioma initiation and growth may assist in the development of targeted therapies. PMID- 23650592 TI - Lipoma preferred partner is a mechanosensitive protein regulated by nitric oxide in the heart. AB - Adaptor proteins play an important role in signaling pathways by providing a platform on which many other proteins can interact. Malfunction or mislocalization of these proteins may play a role in the development of disease. Lipoma preferred partner (LPP) is a nucleocytoplasmic shuttling adaptor protein. Previous work shows that LPP plays a role in the function of smooth muscle cells and in atherosclerosis. In this study we wanted to determine whether LPP has a role in the myocardium. LPP expression increased by 56% in hearts from pressure overload aortic-banded rats (p < 0.05 n = 4), but not after myocardial infarction, suggesting hemodynamic load regulates its expression. In vitro, LPP expression was 87% higher in cardiac fibroblasts than myocytes (p < 0.05 n = 3). LPP expression was downregulated in the absence of the actin cytoskeleton but not when microtubules were disassembled. We mechanically stretched cardiac fibroblasts using the Flexcell 4000 for 48 h (1 Hz, 5% maximum strain), which decreased total LPP total expression and membrane localization in subcellular fractions (p < 0.05, n = 5). However, L-NAME, an inhibitor of nitric oxide synthase (NOS), significantly upregulated LPP expression. These findings suggest that LPP is regulated by a complex interplay between NO and mechanical cues and may play a role in heart failure induced by increased hemodynamic load. PMID- 23650593 TI - The manner in which DNA is packaged with TFAM has an impact on transcription activation and inhibition. AB - For successful mitochondrial transgene expression, an optimal packaging exogenous DNA is an important issue. We report herein on the effects of DNA packaged with mitochondrial transcription factor A (TFAM), which packages mitochondrial DNA (mtDNA), on the transcription process. Our initial findings indicated that the transcription of the TFAM/DNA complex was activated, when the complex was formed at an optimal ratio. We also found that TFAM has a significant advantage over protamine, a nuclear DNA packaging protein, from the viewpoint of transcription efficiency. This result indicates that TFAM can be useful packaging protein for exogenous DNA to achieve mitochondrial transgene expression. PMID- 23650594 TI - Arabidopsis F-box protein containing a Nictaba-related lectin domain interacts with N-acetyllactosamine structures. AB - The Arabidopsis thaliana genome contains a small group of bipartite F-box proteins, consisting of an N-terminal F-box domain and a C-terminal domain sharing sequence similarity with Nictaba, the jasmonate-induced glycan-binding protein (lectin) from tobacco. Based on the high sequence similarity between the C-terminal domain of these proteins and Nictaba, the hypothesis was put forward that the so-called F-box-Nictaba proteins possess carbohydrate-binding activity and accordingly can be considered functional homologs of the mammalian sugar binding F-box or Fbs proteins which are involved in proteasomal degradation of glycoproteins. To obtain experimental evidence for the carbohydrate-binding activity and specificity of the A. thaliana F-box-Nictaba proteins, both the complete F-box-Nictaba sequence of one selected Arabidopsis F-box protein (in casu At2g02360) as well as the Nictaba-like domain only were expressed in Pichia pastoris and analyzed by affinity chromatography, agglutination assays and glycan micro-array binding assays. These results demonstrated that the C-terminal Nictaba-like domain provides the F-box-protein with a carbohydrate-binding activity that is specifically directed against N- and O-glycans containing N acetyllactosamine (Galbeta1-3GlcNAc and Galbeta1-4GlcNAc) and poly-N acetyllactosamine ([Galbeta1-4GlcNAc]n) as well as Lewis A (Galbeta1-3(Fucalpha1 4)GlcNAc), Lewis X (Galbeta1-4(Fucalpha1-3)GlcNAc, Lewis Y (Fucalpha1-2Galbeta1 4(Fucalpha1-3)GlcNAc) and blood type B (Galalpha1-3(Fucalpha1-2)Galbeta1-3GlcNAc) motifs. Based on these findings one can reasonably conclude that at least the A. thaliana F-box-Nictaba protein encoded by At2g02360 can act as a carbohydrate binding protein. The results from the glycan array assays revealed differences in sugar-binding specificity between the F-box protein and Nictaba, indicating that the same carbohydrate-binding motif can accommodate unrelated oligosaccharides. PMID- 23650595 TI - The complex structures of isocitrate dehydrogenase from Clostridium thermocellum and Desulfotalea psychrophila suggest a new active site locking mechanism. AB - Isocitrate dehydrogenase (IDH) catalyzes the oxidative NAD(P)(+)-dependent decarboxylation of isocitrate into alpha-ketoglutarate and CO2 and is present in organisms spanning the biological range of temperature. We have solved two crystal structures of the thermophilic Clostridium thermocellum IDH (CtIDH), a native open apo CtIDH to 2.35 A and a quaternary complex of CtIDH with NADP(+), isocitrate and Mg(2+) to 2.5 A. To compare to these a quaternary complex structure of the psychrophilic Desulfotalea psychrophila IDH (DpIDH) was also resolved to 1.93 A. CtIDH and DpIDH showed similar global thermal stabilities with melting temperatures of 67.9 and 66.9 degrees C, respectively. CtIDH represents a typical thermophilic enzyme, with a large number of ionic interactions and hydrogen bonds per residue combined with stabilization of the N and C termini. CtIDH had a higher activity temperature optimum, and showed greater affinity for the substrates with an active site that was less thermolabile compared to DpIDH. The uncompensated negative surface charge and the enlarged methionine cluster in the hinge region both of which are important for cold activity in DpIDH, were absent in CtIDH. These structural comparisons revealed that prokaryotic IDHs in subfamily II have a unique locking mechanism involving Arg310, Asp251' and Arg255 (CtIDH). These interactions lock the large domain to the small domain and direct NADP(+) into the correct orientation, which together are important for NADP(+) selectivity. PMID- 23650596 TI - Exploring potassium-dependent GTP hydrolysis in TEES family GTPases. AB - GTPases are important regulatory proteins that hydrolyze GTP to GDP. A novel GTP hydrolysis mechanism is employed by MnmE, YqeH and FeoB, where a potassium ion plays a role analogous to the Arginine finger of the Ras-RasGAP system, to accelerate otherwise slow GTP hydrolysis rates. In these proteins, two conserved asparagines and a 'K-loop' present in switch-I, were suggested as attributes of GTPases employing a K(+)-mediated mechanism. Based on their conservation, a similar mechanism was suggested for TEES family GTPases. Recently, in Dynamin, Fzo1 and RbgA, which also conserve these attributes, a similar mechanism was shown to be operative. Here, we probe K(+)-activated GTP hydrolysis in TEES (TrmE Era-EngA-YihA-Septin) GTPases - Era, EngB and the two contiguous G-domains, GD1 and GD2 of YphC (EngA homologue) - and also in HflX, another GTPase that also conserves the same attributes. While GD1-YphC and Era exhibit a K(+)-mediated activation of GTP hydrolysis, surprisingly GD2-YphC, EngB and HflX do not. Therefore, the attributes identified thus far, do not necessarily predict a K(+) mechanism in GTPases and hence warrant extensive structural investigations. PMID- 23650597 TI - Repressed induction of interferon-related microRNAs miR-146a and miR-155 in peripheral blood mononuclear cells infected with HCV genotype 4. AB - MicroRNAs regulate the expression of many genes and subsequently control various cellular processes, such as the immune response to viral infections mediated by type I interferon (IFN). In this study, the expression pattern of two interferon related microRNAs, miR-146a and miR-155, was examined in healthy and HCV-genotype 4-infected peripheral blood mononuclear cells (PBMCs) using qRT-PCR. In contrast to other viral infections, the expression pattern was similar in both healthy and infected PBMCs. This could be attributed to attenuation of IFN pathway by HCV, which was assessed by investigating the expression of MxA, an interferon stimulated gene, that showed lower expression in HCV-infected PBMCs. To determine the site of interference of HCV in the IFN pathway, expression of both microRNAs was examined following stimulation of PBMCs with IFN-alpha2a, an activator of the JAK/STAT pathway as well as with imiquimod, a toll-like receptor-7 (TLR-7) agonist that promotes interferon release. IFN stimulation induced the expression of miR-146a and miR-155 in HCV-infected and healthy PBMCs. Stimulation with imiquimod led to a down-regulation of both microRNAs in infected PBMCs, while it increased their expression in healthy PBMCs, indicating that HCV might interfere with miR-146a and miR-155 expression at sites upstream of interferon release, specifically in the TLR-7 pathway. The pattern of expression of both miR-146a and miR-155 was very similar with a strong positive correlation, but showed no correlation to the patients' clinical or histopathological parameters or response to treatment. In conclusion, HCV infection might repress the induction of miR 146a and miR-155 by interfering with TLR-7 signaling. PMID- 23650598 TI - CD248 expression on mesenchymal stromal cells is required for post-natal and infection-dependent thymus remodelling and regeneration. AB - The role of mesenchymal stromal cells (MSCs) in regulating immune responses in the thymus is currently unclear. Here we report the existence and role of a MSC population in the thymus that expresses the pericyte and MSC marker CD248 (endosialin). We show using a CD248-deficient mouse model, that CD248 expression on these cells is required for full post-natal thymus development and regeneration post-Salmonella infection. In CD248(-/-) mice the thymus is hypocellular and regeneration is poorer, with significant loss of all thymocyte populations. This identifies the requirement of CD248 to maintain optimal thymic cellularity post-partum and infection. PMID- 23650599 TI - Extended C-terminus and length of the linker connecting the G-domains are species specific variations in the EngA family of GTPases. AB - EngA is an essential protein involved in ribosome biogenesis. It is an unique GTPase, possessing two consecutive G-domains. Using sequence and phylogenetic analysis, we found two intriguing variants among EngA homologues - one with a shorter linker joining the G-domains and another with a longer linker, which additionally possesses an extended C-terminus. Interestingly, while the former variant is mainly restricted to firmicutes, the latter is found in nonfirmicutes. Chimeric proteins with interchanged linkers and extensions were generated to gauge the importance of these elements. Ribosome interaction experiments employing the chimeric proteins suggest that a precise combination of the linker and C-terminal extension are important features regulating EngA ribosome interactions in a variant-specific manner. PMID- 23650600 TI - Transformation of the fungus Absidia glauca by complementation of a methionine auxotrophic strain affected in the homoserine-acetyltransferase gene. AB - Transformation of fungi by complementation of auxotrophs is generally much more reliable than usage of antibiotic resistance markers. In order to establish such a system for the model zygomycete Absidia glauca, a stable methionine auxotrophic mutant was isolated after X-ray mutagenesis of the minus mating type and characterized at the molecular level. The mutant is disrupted in the coding region of the Met2-1 gene, encoding homoserine O-acetyltransferase. The corresponding wild type gene was cloned, sequenced and inserted into appropriate vector plasmids. Transformants are prototrophs and show restored methionine independent growth, based on complementation by the autonomously replicating plasmids. PMID- 23650601 TI - Evolution of an inhibitory RNA aptamer against T7 RNA polymerase. AB - Aptamers are promising gene components that can be used for the construction of synthetic gene circuits. In this study, we isolated an RNA aptamer that specifically inhibits transcription of T7 RNA polymerase (RNAP). The 38 nucleotide aptamer, which was a shortened variant of an initial SELEX isolate, showed moderate inhibitory activity. By stepwise doped-SELEX, we isolated evolved variants with strong inhibitory activity. A 29-nucleotide variant of a doped SELEX isolate showed 50% inhibitory concentration at 11 nM under typical in vitro transcription conditions. Pull-down experiments revealed that the aptamer inhibited the association of T7 RNAP with T7 promoter DNA. PMID- 23650602 TI - The role of substrate specificity and metal binding in defining the activity and structure of an intracellular subtilisin. AB - The dimeric intracellular subtilisin proteases (ISPs) found throughout Gram positive bacteria are a structurally distinct class of the subtilase family. Unlike the vast majority of subtilisin-like proteases, the ISPs function exclusively within the cell, contributing the majority of observed cellular proteolytic activity. Given that they are active within the cell, little is known about substrate specificity and the role of stress signals such as divalent metal ions in modulating ISP function. We demonstrate that both play roles in defining the proteolytic activity of Bacillus clausii ISP and propose the molecular basis of their effects. Enzyme kinetics reveal that one particular synthetic tetrapeptide substrate, Phe-Ala-Ala-Phe-pNA, is hydrolysed with a catalytic efficiency ~100-fold higher than any other tested. Heat-denatured whole proteins were found to be better substrates for ISP than the native forms. Substrate binding simulations suggest that the S1, S2 and S4 sites form defined binding pockets. The deep S1 cavity and wide S4 site are fully occupied by the hydrophobic aromatic side-chains of Phe. Divalent metal ions, probably Ca(2+), are proposed to be important for ISP activity through structural changes. The presence of >0.01 mM EDTA inactivates ISP, with CD and SEC suggesting that the protein becomes less structured and potentially monomeric. Removal of Ca(2+) at sites close to the dimer interface and the S1 pocket are thought to be responsible for the effect. These studies provide a new insight into the potential physiological function of ISPs, by reconciling substrate specificity and divalent metal binding to associate ISP with the unfolded protein response under stress conditions. PMID- 23650603 TI - Metabolomic profiling reveals that Drosophila melanogaster larvae with the y mutation have altered lysine metabolism. AB - Yellow (y) encodes a protein which is closely similar to major royal jelly proteins produced by bees. However, the function of y remains largely unknown. Metabolomic profiling was carried out on third instar Oregon R (OR) and yellow (y) Drosophila melanogaster larvae. Phenylalanine, tyrosine and DOPA were all elevated in y as might be expected since the mutation blocks melanin biosynthesis. The most consistent effects were related to lysine metabolism, with the lysine metabolite saccharopine being much higher in y. In addition, lysine acetate was elevated, and the levels of methyl lysines were lower, in y than in OR. PMID- 23650604 TI - The monoclonal antibody HCM31 specifically recognises the Sd(a) tetrasaccharide in goblet cell mucin. AB - Rat small intestinal goblet cell mucins reacting with monoclonal antibody HCM31 increase significantly during regeneration from experimental mucosal damage and at the period of expulsion of parasitic nematode, Nippostrongylus brasiliensis (N.b). The reduction in reactivity of HCM31 with mucin upon neuraminidase treatment, suggested that HCM31 recognizes sialylated oligosaccharide on mucin. HCM31-reactive sialomucins are therefore considered to play an important role in the physiological and pathological changes in the gastrointestinal mucosa. To determine the epitope for HCM31, oligosaccharide-alditols reacted with HCM31 were obtained from the small intestinal mucins of N.b-infected rats and purified by ion-exchange chromatography followed by normal-phase HPLC. Two HCM31-reactive oligosaccharide-alditols were obtained. Analyses using tandem mass spectrometry and NMR spectroscopy showed that these oligosaccharides were core 4 mucin-type oligosaccharides having a common tetrasaccharide sequence, NeuAcalpha2 3(GalNAcbeta1-4)Galbeta1-4GlcNAcbeta- (Sd(a) blood group antigen). These structures were not found in the small intestinal mucin oligosaccharides from uninfected rats. This epitope specificity of HCM31 was also confirmed using previously established anti-GM2 and anti-Sd(a) antibodies. Taken together, these results strongly suggest that HCM31 specifically recognizes mucin-type oligosaccharides with the Sd(a) tetrasaccharide sequence. Immunohistochemical examination of human gastrointestinal tracts showed that HCM31 site-specifically stained the goblet cells in normal sigmoid colon and normal rectum, but the goblet cells stained with HCM31 were reduced in the corresponding cancer tissues. HCM31 seems to be useful for diagnosis of colonic cancer and for examining the function of secretory-type mucin with Sd(a) antigen. PMID- 23650605 TI - Identification of condition-specific reference genes from microarray data for locusts exposed to hypobaric hypoxia. AB - Real-time quantitative polymerase chain reaction (qPCR) is a routine and robust approach for measuring gene expression. The stability of reference genes in qPCR is crucial for the accurate quantification of gene expression. To provide reliable reference genes for studying the transcriptional responses of locust muscles to hypobaric hypoxia, we first examined the gene expression stability of the frequently used housekeeping genes 18S, GAPDH, and beta-actin. However, the expression of these three housekeeping genes was influenced by hypobaric hypoxia. Consequently, we identified five novel candidate reference genes from the locust microarray data. The gene expression stability of the five candidates, together with the three classical housekeeping genes, were evaluated using two distinct algorithms implemented in geNorm and NormFinder. GeNorm identified Ach (acetyl CoA hydrolase) and Pgp (phosphoglycolate phosphatase-like) as the most stable genes and NormFinder further distinguished Ach as the most stable one. The validity of Ach as a reference gene was confirmed through comparison with 18S. This study exemplifies the necessity of validating reference genes before their application and the feasibility of identifying condition-specific reference genes from large-scale gene expression data. PMID- 23650606 TI - Antimalarial drug chloroquine counteracts activation of indoleamine (2,3) dioxygenase activity in human PBMC. AB - Antimalarial chloroquine is also used for the treatment of immune-mediated diseases. The interference of chloroquine with interferon-gamma-induced tryptophan breakdown and neopterin production has been investigated in human peripheral blood mononuclear cells (PBMC) in vitro. Micromolar concentrations (2 50 MUM) of chloroquine dose-dependently suppressed mitogen-induced tryptophan breakdown in PBMC but not in the myelomonocytic THP-1-Blue cell line, after 48 h of treatment. In stimulated PBMC, neopterin production was super-induced by 10 MUM chloroquine, while it was significantly suppressed at a concentration of 50 MUM. These anti-inflammatory effects may relate to the therapeutic benefit of chloroquine in inflammatory conditions and may widen the spectrum of its clinical applications. PMID- 23650607 TI - Tespa1 is a novel inositol 1,4,5-trisphosphate receptor binding protein in T and B lymphocytes. AB - Tespa1 has been recently reported to be a critical molecule in T-cell development, however, the precise molecular mechanisms of Tespa1 remain elusive. Here, we demonstrate that Tespa1 shows amino-acid sequence homology to KRAS induced actin-interacting protein (KRAP), an inositol 1,4,5-trisphosphate receptor (IP3R) binding protein, and that Tespa1 physically associates with IP3R in T and B lymphocytes. Two-consecutive phenylalanine residues (Phe185/Phe186) in Tespa1, which are conserved between Tespa1 and KRAP, are indispensable for the association between Tespa1 and IP3R. These findings suggest that Tespa1 plays critical roles in the immune system through the regulation of the IP3R. PMID- 23650608 TI - Amino acid determinants conferring stable sialidase activity at low pH for H5N1 influenza A virus neuraminidase. AB - Avian influenza A viruses (IAVs) and human 1918, 1957, and 1968 pandemic IAVs all have neuraminidases (NAs) that are stable at low pH sialidase activity, yet most human epidemic IAVs do not. We examined the pH stability of H5N1 highly pathogenic avian IAV (HPAI) NAs and identified amino acids responsible for conferring stability at low pH. We found that, unlike other avian viruses, most H5N1 IAVs isolated since 2003 had NAs that were unstable at low pH, similar to human epidemic IAVs. These H5N1 viruses are thus already human virus-like and, therefore, have the frequent infections of humans. PMID- 23650609 TI - Diacylglycerol kinase-dependent formation of phosphatidic acid molecular species during interleukin-2 activation in CTLL-2 T-lymphocytes. AB - Although effective liquid chromatography (LC)/mass spectrometry (MS) methods enabling the separation of phospholipid molecular species have been developed, there are still problems with an intracellular signaling molecule, phosphatidic acid (PA). In this study, we optimized LC/MS conditions to improve the quantitative detection of PA molecular species from a cellular lipid mixture. Using the newly developed LC/MS method, we showed that stimulation of CTLL-2 murine T-lymphocytes by interleukin-2 (IL-2) induced a significant increase of 36:1-, 36:2-, 40:5- and 40:6-diacyl-PA. A diacylglycerol kinase (DGK) inhibitor, R59949, attenuated the increase of 36:1-, 40:5-, 40:6-diacyl-PA, suggesting that DGK IL-2-dependently and selectively generated these diacyl-PA species. PMID- 23650610 TI - PAK1 limits the expression of the pro-apoptotic protein Bad in pancreatic islet beta-cells. AB - Human type 2 diabetes is associated with beta-cell apoptosis, and human islets from diabetic donors are ~80% deficient in PAK1 protein. Toward addressing linkage of PAK1 to beta-cell survival, PAK1-siRNA targeted MIN6 pancreatic beta cells were found to exhibit increased caspase-3 cleavage, cytosolic cytochrome-C and the pro-apoptotic protein Bad. PAK1(+/-) heterozygous mouse islets recapitulated the upregulation of Bad protein expression, as did hyperglycemic treatment of human or mouse islets; Bad levels were exacerbated most in PAK1(+/-) islets subjected to hyperglycemic stress. These data implicate PAK1 in beta-cell survival via quenching of Bad protein expression, and suggest PAK1 as potential molecular target to preserve beta-cell mass. PMID- 23650611 TI - Raloxifene inhibits hepatitis C virus infection and replication. AB - Postmenopausal women with chronic hepatitis C exhibited a poor response to interferon (IFN) therapy compared to premenopausal women. Osteoporosis is the typical complication that occurs in postmenopausal women. Recently, it was reported that an osteoporotic reagent, vitamin D3, exhibited anti-hepatitis C virus (HCV) activity. Therefore, we investigated whether or not another osteoporotic reagent, raloxifene, would exhibit anti-HCV activity in cell culture systems. Here, we demonstrated that raloxifene inhibited HCV RNA replication in genotype 1b and infection in genotype 2a. Raloxifene enhanced the anti-HCV activity of IFN-alpha. These results suggest a link between the molecular biology of osteoporosis and the HCV life cycle. PMID- 23650612 TI - The cytoplasmic tail of heparin-binding EGF-like growth factor regulates bidirectional intracellular trafficking between the plasma membrane and ER. AB - Heparin-binding epidermal growth factor (EGF)- like growth factor (HB-EGF) is synthesized in the ER, transported along the exocytic pathway, and expressed on the plasma membrane as a type I transmembrane protein. Upon extracellular stimulation, HB-EGF, either proHB-EGF or the shed form HB-EGF-CTF, undergoes endocytosis and is then transported retrogradely to the ER. In this study, we showed the essential contribution of the short cytoplasmic tail of HB-EGF (HB-EGF cyto) to the bidirectional intracellular trafficking between the ER and plasma membrane and revealed several critical amino acids residues that are responsible for internalization from the plasma membrane and ER targeting. We suggest that these anterograde and retrograde sorting signals within HB-EGF-cyto are strictly regulated by protein modification and conformation. PMID- 23650613 TI - Developmental expression of IL-12Rbeta2 on murine naive neonatal T cells counters the upregulation of IL-13Ralpha1 on primary Th1 cells and balances immunity in the newborn. AB - Upon exposure to Ag on the day of birth, neonatal mice mount balanced primary Th1 and Th2 responses, with the former displaying upregulated IL-13Ralpha1 expression. This chain associates with IL-4Ralpha to form a heteroreceptor (IL 4Ralpha/IL-13Ralpha1) that marks the Th1 cells for death by IL-4 produced by Th2 cells during rechallenge with Ag, hence the Th2 bias of murine neonatal immunity. The upregulation of IL-13Ralpha1 on neonatal Th1 cells was due to the paucity of IL-12 in the neonatal environment. In this study, we show that by day 8 after birth, naive splenic T cells are no longer susceptible to IL-13Ralpha1 upregulation even when exposed to Ag within the neonatal environment. Furthermore, during the 8-d lapse, the naive splenic T cells spontaneously and progressively upregulate the IL-12Rbeta2 chain, perhaps due to colonization by commensals, which induce production of IL-12 by cells of the innate immune system such as dendritic cells. In fact, mature T cells from the thymus, a sterile environment not accessible to microbes, did not upregulate IL-12Rbeta2 and were unable to counter IL-13Ralpha1 upregulation. Finally, the 8-d naive T cells were able to differentiate into Th1 cells even independently of IL-12 but required the cytokine to counter upregulation of IL-13Ralpha1. Thus, in neonatal mice, IL-12, which accumulates in the environment progressively, uses IL-12Rbeta2 to counter IL-13Ralpha1 expression in addition to promoting Th1 differentiation. PMID- 23650614 TI - STAT4-dependent and -independent Th2 responses correlate with protective immunity against lung infection with Pneumocystis murina. AB - Although it is clear that the loss of CD4(+) T cells is a predisposing factor for the development of Pneumocystis pneumonia, specific Th mechanisms mediating protection are not well understood. Th1, Th2, and Th17 responses have each been implicated in protective responses during infection. As STAT4 may promote Th1 and Th17 development, yet antagonize Th2 development, we investigated its role in Pneumocystis murina host defense. STAT4 was required for Th1 and, unexpectedly, Th2 responses in the lungs of C57BL/6 (BL/6) and BALB/c mice 14 d postchallenge, but only BALB/c Stat4(-/-) mice demonstrated susceptibility to P. murina lung infection. BL/6 Stat4(-/-), but not BALB/c Stat4(-/-), mice maintained an enhanced alternatively activated (M2) macrophage signature in the lungs, which we have previously reported to be associated with enhanced P. murina clearance. In addition, anti-P. murina class-switched Abs were increased in BL/6 Stat4(-/-) mice, but not BALB/c Stat4(-/-) mice. Supporting our experimental observations, plasma from HIV-infected individuals colonized with Pneumocystis jirovecii contained significantly lower levels of the Th2 cytokines IL-4, IL-5, and IL-13 compared with HIV-infected individuals who were not colonized. Collectively, our data suggest that robust local and systemic Th2-mediated responses are critical for immunity to Pneumocystis. PMID- 23650615 TI - Inhaled carbon monoxide accelerates resolution of inflammation via unique proresolving mediator-heme oxygenase-1 circuits. AB - Resolution of acute inflammation is an active event accompanied by biosynthesis of specialized proresolving mediators (SPM). We employed a systems approach to determine the impact of CO in resolution active programs during self-limited inflammation in mice. Compared with ambient air, inhaled CO gas (250 ppm) significantly limited PMN infiltration (~44%, 6 h) into peritoneum and shortened resolution interval from 4 to 2 h. We profiled exudate lipid mediators (LM) via metabololipidomics, CO reduced leukotriene B4 (21 +/- 11 versus 59 +/- 24 pg/mouse, 6 h), and elevated SPM including resolvin (Rv) D1 (27 +/- 4 versus 16 +/- 5 pg/mouse) and maresin 1 (26 +/- 9 versus 15 +/- 3 pg/mouse). With human macrophages, SPM (10 pM-10 nM) elevated heme oxygenase (HO)-1 (~50%, 8 h). CO also enhanced HO-1 expression and accumulation of RvD1 and RvD5, an action reversed by blockage of a key SPM biosynthesis enzyme 15-lipoxygenase type 1. Compared with normoxia, CO increased ~30% phagocytosis of opsonized zymosan with human macrophage, which was further enhanced by SPM (~100%). This CO increased phagocytosis was blocked by 15-lipoxygenase inhibition, and SPM stimulated phagocytosis was diminished by HO-1 inhibition. In murine peritonitis, both pre- and posttreatment with CO inhalation significantly increased macrophages carrying ingested apoptotic PMN in exudates and enhanced PMN apoptosis. Taken together, these results indicate that CO accelerates resolution of acute inflammation, shortens resolution intervals, enhances macrophage efferocytosis, and temporally regulates local levels of lipid mediator/SPM. Moreover, they provide proresolving mechanisms for HO-1/CO, which is part of the SPM-initiated resolution circuit. PMID- 23650616 TI - miR-142-3p is involved in CD25+ CD4 T cell proliferation by targeting the expression of glycoprotein A repetitions predominant. AB - Because of the numerous targets of microRNAs (miRNAs), functional dissection of specific miRNA/mRNA interactions is important to understand the complex miRNA regulatory mechanisms. Glycoprotein A repetitions predominant (GARP) is specifically expressed on regulatory CD25(+) CD4 T cells upon their activation. GARP has a long 3' untranslated region containing five highly conserved regions suggesting miRNA regulation of its expression. Although GARP is physiologically expressed on a cell subset characterized by stringent control of proliferation, amplification of the GARP gene has been found in many tumors characterized by uncontrolled proliferation. In this study, we investigated in detail miRNA regulation of GARP expression, in particular by miR-142-3p, and dissected the functional outcome of miR-142-3p/GARP mRNA interaction. We demonstrate that miR 142-3p binds directly to the 3' untranslated region of GARP and represses GARP protein expression by Argonaute 2-associated degradation of GARP mRNA. Functionally, miR-142-3p-mediated regulation of GARP is involved in the expansion of CD25(+) CD4 T cells in response to stimulation. The data indicate that miR-142 3p regulates GARP expression on CD25(+) CD4 T cells and, as a result, their expansion in response to activation. Our data provide novel insight into the molecular mechanisms controlling regulatory T cell expansion. They may also have implications for understanding tumor cell biology. PMID- 23650617 TI - Group V secretory phospholipase A2 is involved in macrophage activation and is sufficient for macrophage effector functions in allergic pulmonary inflammation. AB - We reported that Pla2g5-null mice lacking group V secretory phospholipase A2 (gV sPLA2) showed reduced eosinophilic pulmonary inflammation and Th2 cytokine generation when challenged with an extract from house dust mite Dermatophagoides farinae, compared with wild-type (WT) controls. Adoptive transfer studies suggested that gV-sPLA2 in dendritic cells was necessary for sensitization of Pla2g5-null mice, but was not sufficient to induce the effector phase of pulmonary inflammation. In this study, we demonstrate that gV-sPLA2 is inducibly expressed in mouse and human macrophages (M) activated by IL-4 and is required for the acquisition of M effector functions that facilitate the effector phase of pulmonary inflammation. We demonstrate that gV-sPLA2 expression in M is sufficient for the development of pulmonary inflammation, even when inflammation is induced by intrapulmonary administration of IL-4. The concentrations of CCL22/CCL17 and effector T cell recruitment are severely impaired in Pla2g5-null mice. Intratracheal transfers of enriched CD68(+) cells isolated from the lungs of D. farinae-challenged WT donor mice induce eosinophilia, chemokine production, and recruitment of T cells into the lungs of Pla2g5-null recipients previously sensitized by WT D. farinae-loaded dendritic cells. Our studies identified a unique function of gV-sPLA2 in activation of M and in their capacity to recruit T cells to amplify the effector phase of pulmonary inflammation. PMID- 23650618 TI - Roles of adipocytes and fibroblasts in activation of the alternative pathway of complement in inflammatory arthritis in mice. AB - The complement system is involved in mediation of joint damage in rheumatoid arthritis, with evidence suggesting activation of both the classical and alternative pathway (AP). The AP is both necessary and sufficient to mediate collagen Ab-induced arthritis, an experimental animal model of immune complex induced joint disease. The AP in mice is dependent on MASP-1/3 cleavage of pro factor D (pro-FD) into mature factor D (FD). The objectives of the current study were to determine the cells synthesizing MASP-1/3 and pro-FD in synovial tissue. Collagen Ab-induced arthritis was studied in wild-type C57BL/6 mice, and the localization of mRNA and protein for FD and MASP-1/3 in synovial adipose tissue (SAT) and fibroblast-like synoviocytes (FLS) was determined using various techniques, including laser capture microdissection. SAT was the sole source of mRNA for pro-FD. Cultured differentiated 3T3 adipocytes, a surrogate for SAT, produced pro-FD but no mature FD. FLS were the main source of MASP-1/3 mRNA and protein. Using cartilage microparticles (CMPs) coated with anti-collagen mAb and serum from MASP-1/3(-/-) mice as a source of factor B, pro-FD in 3T3 supernatants was cleaved into mature FD by MASP-1/3 in FLS supernatants. The mature FD was eluted from the CMP, and was not present in the supernatants from the incubation with CMP, indicating that cleavage of pro-FD into mature FD by MASP-1 occurred on the CMP. These results demonstrate that pathogenic activation of the AP can occur in the joint through immune complexes adherent to cartilage and the local production of necessary AP proteins by adipocytes and FLS. PMID- 23650619 TI - Candida albicans escapes from mouse neutrophils. AB - Candida albicans, the most commonly isolated human fungal pathogen, is able to grow as budding yeasts or filamentous forms, such as hyphae. The ability to switch morphology has been attributed a crucial role for the pathogenesis of C. albicans. To mimic disseminated candidiasis in humans, the mouse is the most widely used model organism. Neutrophils are essential immune cells to prevent opportunistic mycoses. To explore potential differences between the rodent infection model and the human host, we compared the interactions of C. albicans with neutrophil granulocytes from mice and humans. We revealed that murine neutrophils exhibited a significantly lower ability to kill C. albicans than their human counterparts. Strikingly, C. albicans yeast cells formed germ tubes upon internalization by murine neutrophils, eventually rupturing the neutrophil membrane and thereby, killing the phagocyte. On the contrary, growth and subsequent escape of C. albicans are blocked inside human neutrophils. According to our findings, this blockage in human neutrophils might be a result of higher levels of MPO activity and the presence of alpha-defensins. We therefore outline differences in antifungal immune defense between humans and mouse strains, which facilitates a more accurate interpretation of in vivo results. PMID- 23650620 TI - Proteome profiling of human neutrophil granule subsets, secretory vesicles, and cell membrane: correlation with transcriptome profiling of neutrophil precursors. AB - Neutrophils are indispensable in the innate immune defense against invading microorganisms. Neutrophils contain SVs and several subsets of granules that are essential for their function. Proteins present in neutrophil SVs and granules are synthesized during terminal granulopoiesis in the bone marrow. The heterogeneity of granules, as determined by marker proteins characteristic of each granule subset, is thought to result from differences in the biosynthetic windows of major classes of granule proteins, a process referred to as targeting by timing. Qualitative proteomic analysis of neutrophil granules, SVs, and plasma membrane has been performed before. Here, we performed subcellular fractionation on freshly isolated human neutrophils by nitrogen cavitation and density centrifugation on a four-layer Percoll gradient. Granule subsets were pooled and subjected to SDS-PAGE, and gel pieces were in-gel-digested with trypsin. The resulting peptides were analyzed using LTQ Orbitrap XL tandem MS. A total of 1292 unique proteins were identified and grouped, according to the neutrophil fraction, in which they displayed maximal expression. In addition to various known neutrophil proteins, several uncharacterized proteins were found, as well as proteins not described previously in neutrophils. To study the correlation between mRNA expression in neutrophil precursors and the localization of their cognate proteins, the distribution of 126 identified proteins was compared with their mRNA expression profiles. The neutrophil subcellular proteome profiles presented here may be used as a database in combination with the mRNA array database to predict and test the presence and localization of proteins in neutrophil granules and membranes. PMID- 23650621 TI - Delayed wound healing due to increased interleukin-10 expression in mice with lymphatic dysfunction. AB - Skin wound healing is an interactive process involving soluble mediators, ECM, resident cells, and infiltrating cells. Little is known about wound healing in the presence of lymphedema. In this study, we investigated wound healing using kCYC+/- mice, which demonstrate severe lymphatic dysfunction. Wound healing was delayed significantly in kCYC+/- mice when compared with WT mice. In wounded skin of kCYC+/- mice, mast cell numbers were increased compared with WT mice, whereas macrophage numbers were decreased. Moreover, IL-10 expression by mast cells was increased, and expression of bFGF, mainly produced by macrophages, was decreased in wounded skin of kCYC+/- mice compared with WT mice. We next crossed kCYC+/- mice with IL-10-/- mice, which were reported to show accelerated wound closure. In kCYC+/- IL-10+/- mice, time course of wound healing, numbers of macrophages, and IL-10 mRNA expression levels in wounded skin were comparable with WT IL-10+/- mice. Similar results were obtained using a different lymphedema model, in which circumferential skin excision was performed on the tails of mice to remove the superficial lymphatics. In summary, these findings suggest that IL-10 plays an important role in delayed wound healing in the setting of lymphatic dysfunction. PMID- 23650622 TI - In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1. AB - Atheroprotection by high density lipoprotein (HDL) is considered to be mediated through reverse cholesterol transport (RCT) from peripheral tissues. We investigated in vivo cholesterol fluxes through the RCT pathway in patients with low plasma high density lipoprotein cholesterol (HDL-c) due to mutations in APOA1. Seven carriers of the L202P mutation in APOA1 (mean HDL-c: 20 +/- 19 mg/dl) and seven unaffected controls (mean HDL-c: 54 +/- 11 mg/dl, P < 0.0001) received a 20 h infusion of (13)C2-cholesterol ((13)C-C). Enrichment of plasma and erythrocyte free cholesterol and plasma cholesterol esters was measured. With a three-compartment SAAM-II model, tissue cholesterol efflux (TCE) was calculated. TCE was reduced by 19% in carriers (4.6 +/- 0.8 mg/kg/h versus 5.7 +/ 0.7 mg/kg/h in controls, P = 0.02). Fecal (13)C recovery and sterol excretion 7 days postinfusion did not differ significantly between carriers and controls: 21.3 +/- 20% versus 13.3 +/- 6.3% (P = 0.33), and 2,015 +/- 1,431 mg/day versus 1456 +/- 404 mg/day (P = 0.43), respectively. TCE is reduced in carriers of mutations in APOA1, suggesting that HDL contributes to efflux of tissue cholesterol in humans. The residual TCE and unaffected fecal sterol excretion in our severely affected carriers suggest, however, that non-HDL pathways contribute to RCT significantly. PMID- 23650623 TI - Percentage of patients with spondyloarthritis in patients referred because of chronic back pain and performance of classification criteria: experience from the Spondyloarthritis Caught Early (SPACE) cohort. AB - OBJECTIVES: The objectives of the study are to describe the Spondyloarthritis Caught Early (SPACE) cohort, present the performance of various SpA classification criteria and compare patients fulfilling the imaging arm with patients fulfilling the clinical arm of the Assessment of Spondyloarthritis international Society (ASAS) axSpA criteria on demographics, presence of SpA features and level of disease activity. METHODS: Patients with back pain (>=3 months but <=2 years, onset <45 years) visiting the rheumatology outpatient clinic of the Leiden University Medical Center were included in the SPACE cohort. Patients were classified according to the modified New York (mNY), ESSG, Amor and ASAS axSpA criteria. The sensitivity and specificity of criteria were tested against a rheumatologist's diagnosis. RESULTS: In total, 157 patients were included; 92 patients fulfilled any criteria, 11 fulfilled the mNY (sensitivity 16.9%, specificity 100%), 68 the ESSG (sensitivity 64.6%, specificity 71.7%), 48 the Amor (sensitivity 47.7%, specificity 81.5%) and 60 the ASAS axSpA criteria (sensitivity 84.6%, specificity 94.6%). Of those 60 patients, 30 fulfilled the imaging arm and 30 the clinical arm. Patients in the imaging arm are statistically significantly more often male, have a longer symptom duration and less often a positive family history for SpA than patients fulfilling the clinical arm. Patients in both arms are very similar regarding all other SpA features and level of disease activity. CONCLUSION: The inclusion criteria of the SPACE cohort yield the same high numbers of SpA patients compared with referral strategies like inflammatory back pain, HLA-B27+ or sacroiliitis, yet are easier to apply. The ASAS axSpA criteria outperformed the other criteria; 38.2% fulfilled the ASAS axSpA criteria. Patients fulfilling the clinical arm of the ASAS axSpA reflect a group of patients similar to those fulfilling the imaging arm. PMID- 23650624 TI - Navigating the genome's "dark matter". PMID- 23650626 TI - Awaiting a moment of truth for oncolytic viruses. PMID- 23650627 TI - Simultaneous evaluation of p53 and p21 expression level for early cancer diagnosis using SERS technique. AB - Simultaneous detection of tumor suppressor p53 and cyclin-dependent kinase inhibitor p21 has been achieved for the first time with a high sensitivity using surface enhanced Raman scattering (SERS) technique. In this immunoassay, gold@silver core-shell nanorods (Au@Ag NRs) with a high SERS activity and chemical stability were chosen to fabricate immuno-probes, which were conjugated with different antibodies to specifically target each analyte. Qualitative and quantitative analysis of p53 and p21 were achieved by characterizing SERS signals of two different Raman reporters (4MBA and DTNB), which were labeled on the corresponding optical probes. In addition, we investigated the detection of these biomarkers in the medium of blood serum. Our experimental results indicate the excellent specificity, high sensitivity (1 pg mL(-1)), as well as the great reproducibility of this immunoassay. More importantly, this assay presents a powerful ability to detect multiple analytes due to the great multiplexing capacity of SERS spectroscopy. Since the combined evaluation of p53 and p21 expression level acts as an indicator for early cancer prediction, our demonstrated immunoassay will potentially promote the application of SERS technique to practical clinical diagnoses. PMID- 23650629 TI - Context homogeneity facilitates both distractor inhibition and target enhancement. AB - Homogeneous contexts were shown to result in prioritized processing of embedded targets compared to heterogeneous contexts (Duncan & Humphreys, 1989). The present experiment used behavioral and ERP measures to examine whether context homogeneity affects both enhancing relevant information and inhibiting irrelevant in contexts of varying homogeneity. Targets and distractors were presented laterally or on the vertical midline which allowed disentangling target- and distractor-related activity in the lateralized ERP (Hickey, diLollo, & McDonald, 2009). In homogeneous contexts, targets elicited an NT component from 150 ms on and a PD component from 200 ms on, showing early attention deployment at target locations and active suppression of distractors. In heterogeneous contexts, an NT component was also found from 150 ms on and PD was found from 250 ms on, suggesting delayed suppression of the distractor. Before 250 ms, distractors in heterogeneous contexts elicited a contralateral negativity, indicating attentional capture of the distractor prior to active suppression. In sum the present results suggest that top-down control of attention is more pronounced in homogeneous than in heterogeneous contexts. PMID- 23650628 TI - 18F-AFETP, 18F-FET, and 18F-FDG imaging of mouse DBT gliomas. AB - The goal of this study was to evaluate the (18)F-labeled nonnatural amino acid (S)-2-amino-3-[1-(2-(18)F-fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid ((18)F-AFETP) as a PET imaging agent for brain tumors and to compare its effectiveness with the more-established tracers O-(2-(18)F-fluoroethyl)-l tyrosine ((18)F-FET) and (18)F-FDG in a murine model of glioblastoma. The tracer (18)F-AFETP is a structural analog of histidine and is a lead compound for imaging cationic amino acid transport, a relatively unexplored target for oncologic imaging. METHODS: (18)F-AFETP was prepared using the click reaction. BALB/c mice with intracranially implanted delayed brain tumor (DBT) gliomas (n = 4) underwent biodistribution and dynamic small-animal PET imaging for 60 min after intravenous injection of (18)F-AFETP. Tumor and brain uptake of (18)F-AFETP were compared with those of (18)F-FDG and (18)F-FET through small-animal PET analyses. RESULTS: (18)F-AFETP demonstrated focally increased uptake in tumors with good visualization. Peak tumor uptake occurred within 10 min of injection, with stable or gradual decrease over time. All 3 tracers demonstrated relatively high uptake in the DBTs throughout the study. At late time points (47.5-57.5 min after injection), the average standardized uptake value with (18)F-FDG (1.9 +/- 0.1) was significantly greater than with (18)F-FET (1.1 +/- 0.1) and (18)F-AFETP (0.7 +/- 0.2). The uptake also differed substantially in normal brain, with significant differences in the standardized uptake values at late times among (18)F-FDG (1.5 +/- 0.2), (18)F-FET (0.5 +/- 0.05), and (18)F-AFETP (0.1 +/- 0.04). The resulting average tumor-to-brain ratio at the late time points was significantly higher for (18)F-AFETP (7.5 +/- 0.1) than for (18)F-FDG (1.3 +/- 0.1) and (18)F-FET (2.0 +/- 0.3). CONCLUSION: (18)F-AFETP is a promising brain tumor imaging agent, providing rapid and persistent tumor visualization, with good tumor-to-normal-brain ratios in the DBT glioma model. High tumor-to-brain, tumor-to-muscle, and tumor-to-blood ratios were observed at 30 and 60 min after injection, with higher tumor-to-brain ratios than obtained with (18)F-FET or (18)F-FDG. These results support further development and evaluation of (18)F AFETP and its derivatives for tumor imaging. PMID- 23650630 TI - Feature specificity in attentional capture by size and color. AB - Top-down guidance of visual attention has classically been thought to operate in a feature-specific manner. However, recent studies have shown that top-down visual attention can also be guided by information about target-nontarget feature relations (e.g., larger, redder, brighter). Here we recommend a minimal set of cues for differentiating between relational and feature-specific attentional guidance and examine contrasting predictions for the guidance of attention by size and color stimuli in a spatial cueing paradigm. In Experiment 1 we demonstrate that in search for size, when both feature-specific and relational strategies are available, participants adopt a relational search strategy. Experiment 2 shows that when feature-specific information is the only reliable information to guide attention to the target, participants are able to adopt a feature-specific set for size information. Finally, in Experiment 3 we extend our paradigm to differentiate between feature-specific and relational strategies in search for color. Together, these experiments help to clarify the conditions under which different attentional guidance strategies will be employed, and demonstrate a useful minimum cue requirement for differentiating between these two forms of top-down guidance. Implications for current theories of attention are discussed. PMID- 23650631 TI - Alterations to the remote control of Shh gene expression cause congenital abnormalities. AB - Multi-species conserved non-coding elements occur in the vertebrate genome and are clustered in the vicinity of developmentally regulated genes. Many are known to act as cis-regulators of transcription and may reside at long distances from the genes they regulate. However, the relationship of conserved sequence to encoded regulatory information and indeed, the mechanism by which these contribute to long-range transcriptional regulation is not well understood. The ZRS, a highly conserved cis-regulator, is a paradigm for such long-range gene regulation. The ZRS acts over approximately 1 Mb to control spatio-temporal expression of Shh in the limb bud and mutations within it result in a number of limb abnormalities, including polydactyly, tibial hypoplasia and syndactyly. We describe the activity of this developmental regulator and discuss a number of mechanisms by which regulatory mutations in this enhancer function to cause congenital abnormalities. PMID- 23650632 TI - From remote enhancers to gene regulation: charting the genome's regulatory landscapes. AB - Vertebrate genes are characterized by the presence of cis-regulatory elements located at great distances from the genes they control. Alterations of these elements have been implicated in human diseases and evolution, yet little is known about how these elements interact with their surrounding sequences. A recent survey of the mouse genome with a regulatory sensor showed that the regulatory activities of these elements are not organized in a gene-centric manner, but instead are broadly distributed along chromosomes, forming large regulatory landscapes with distinct tissue-specific activities. A large genome wide collection of expression data from this regulatory sensor revealed some basic principles of this complex genome regulatory architecture, including a substantial interplay between enhancers and other types of activities to modulate gene expression. We discuss the implications of these findings for our understanding of non-coding transcription, and of the possible consequences of structural genomic variations in disease and evolution. PMID- 23650633 TI - Functional anatomy of distant-acting mammalian enhancers. AB - Transcriptional enhancers are a major class of functional element embedded in the vast non-coding portion of the human genome. Acting over large genomic distances, enhancers play critical roles in the tissue and cell type-specific regulation of genes, and there is mounting evidence that they contribute to the aetiology of many human diseases. Methods for genome-wide mapping of enhancer regions are now available, but the functional architecture contained within human enhancer elements remains unclear. Here, we review recent approaches aimed at understanding the functional anatomy of individual enhancer elements, using systematic qualitative and quantitative assessments of mammalian enhancer variants in cultured cells and in vivo. These studies provide direct insight into common architectural characteristics of enhancers including the presence of multiple transcription factor-binding sites and the mixture of both transcriptionally activating and repressing domains within the same enhancer. Despite such progress in understanding the functional composition of enhancers, the inherent complexities of enhancer anatomy continue to limit our ability to predict the impact of sequence changes on in vivo enhancer function. While providing an initial glimpse into the mutability of mammalian enhancers, these observations highlight the continued need for experimental enhancer assessment as genome sequencing becomes routine in the clinic. PMID- 23650634 TI - Human genetic variation within neural crest enhancers: molecular and phenotypic implications. AB - Developmental gene expression programmes are coordinated by the specialized distal cis-regulatory elements called enhancers, which integrate lineage- and signalling-dependent inputs to guide morphogenesis. In previous work, we characterized the genome-wide repertoire of active enhancers in human neural crest cells (hNCC), an embryonic cell population with critical roles in craniofacial development. We showed that in hNCC, co-occupancy of a master regulator TFAP2A with nuclear receptors NR2F1 and NR2F2 correlates with the presence of permissive enhancer chromatin states. Here, we take advantage of pre existing human genetic variation to further explore potential cooperation between TFAP2A and NR2F1/F2. We demonstrate that isolated single nucleotide polymorphisms affecting NR2F1/F2-binding sites within hNCC enhancers can alter TFAP2A occupancy and overall chromatin features at the same enhancer allele. We propose that a similar strategy can be used to elucidate other cooperative relationships between transcription factors involved in developmental transitions. Using the neural crest and its major contribution to human craniofacial phenotypes as a paradigm, we discuss how genetic variation might modulate the molecular properties and activity of enhancers, and ultimately impact human phenotypic diversity. PMID- 23650635 TI - High-resolution analysis of cis-acting regulatory networks at the alpha-globin locus. AB - We have combined the circular chromosome conformation capture protocol with high throughput, genome-wide sequence analysis to characterize the cis-acting regulatory network at a single locus. In contrast to methods which identify large interacting regions (10-1000 kb), the 4C approach provides a comprehensive, high resolution analysis of a specific locus with the aim of defining, in detail, the cis-regulatory elements controlling a single gene or gene cluster. Using the human alpha-globin locus as a model, we detected all known local and long-range interactions with this gene cluster. In addition, we identified two interactions with genes located 300 kb (NME4) and 625 kb (FAM173a) from the alpha-globin cluster. PMID- 23650636 TI - Expression quantitative trait loci: present and future. AB - The last few years have seen the development of large efforts for the analysis of genome function, especially in the context of genome variation. One of the most prominent directions has been the extensive set of studies on expression quantitative trait loci (eQTLs), namely, the discovery of genetic variants that explain variation in gene expression levels. Such studies have offered promise not just for the characterization of functional sequence variation but also for the understanding of basic processes of gene regulation and interpretation of genome-wide association studies. In this review, we discuss some of the key directions of eQTL research and its implications. PMID- 23650637 TI - Deconvoluting complex tissues for expression quantitative trait locus-based analyses. AB - Breast cancer genome-wide association studies have pinpointed dozens of variants associated with breast cancer pathogenesis. The majority of risk variants, however, are located outside of known protein-coding regions. Therefore, identifying which genes the risk variants are acting through presents an important challenge. Variants that are associated with mRNA transcript levels are referred to as expression quantitative trait loci (eQTLs). Many studies have demonstrated that eQTL-based strategies provide a direct way to connect a trait associated locus with its candidate target gene. Performing eQTL-based analyses in human samples is complicated because of the heterogeneous nature of human tissue. We addressed this issue by devising a method to computationally infer the fraction of cell types in normal human breast tissues. We then applied this method to 13 known breast cancer risk loci, which we hypothesized were eQTLs. For each risk locus, we took all known transcripts within a 2 Mb interval and performed an eQTL analysis in 100 reduction mammoplasty cases. A total of 18 significant associations were discovered (eight in the epithelial compartment and 10 in the stromal compartment). This study highlights the ability to perform large-scale eQTL studies in heterogeneous tissues. PMID- 23650638 TI - Effects of gene regulatory reprogramming on gene expression in human and mouse developing hearts. AB - Lineage-specific regulatory elements underlie adaptation of species and play a role in disease susceptibility. We compared functionally conserved and lineage specific enhancers by cross-mapping 5042 human and 6564 mouse heart enhancers. Of these, 79 per cent are lineage-specific, lacking a functional orthologue. Heart enhancers tend to cluster and, commonly, there are multiple heart enhancers in a heart locus providing a regulatory stability to the locus. We observed little cross-clustering, however, between lineage-specific and functionally conserved heart enhancers suggesting regulatory function acquisition and development in loci previously lacking heart activity. We also identified 862 human-specific heart enhancers: 417 featuring sequence conservation with mouse (class II) and 445 with neither sequence nor function conservation (class III). Ninety-eight per cent of class III enhancers were deleted from the mouse genome, and we estimated a similar-sized enhancer gain in the human lineage. Human-specific enhancers display no detectable decrease in the negative selection pressure and are strongly associated with genes partaking in the heart regulatory programmes. The loss of a heart enhancer could be compensated by activity of a redundant heart enhancer; however, we observed redundancy in only 15 per cent of class II and III enhancer loci indicating a large-scale reprogramming of the heart regulatory programme in mammals. PMID- 23650639 TI - Chromatin organization and global regulation of Hox gene clusters. AB - During development, a properly coordinated expression of Hox genes, within their different genomic clusters is critical for patterning the body plans of many animals with a bilateral symmetry. The fascinating correspondence between the topological organization of Hox clusters and their transcriptional activation in space and time has served as a paradigm for understanding the relationships between genome structure and function. Here, we review some recent observations, which revealed highly dynamic changes in the structure of chromatin at Hox clusters, in parallel with their activation during embryonic development. We discuss the relevance of these findings for our understanding of large-scale gene regulation. PMID- 23650640 TI - CTCF: the protein, the binding partners, the binding sites and their chromatin loops. AB - CTCF has it all. The transcription factor binds to tens of thousands of genomic sites, some tissue-specific, others ultra-conserved. It can act as a transcriptional activator, repressor and insulator, and it can pause transcription. CTCF binds at chromatin domain boundaries, at enhancers and gene promoters, and inside gene bodies. It can attract many other transcription factors to chromatin, including tissue-specific transcriptional activators, repressors, cohesin and RNA polymerase II, and it forms chromatin loops. Yet, or perhaps therefore, CTCF's exact function at a given genomic site is unpredictable. It appears to be determined by the associated transcription factors, by the location of the binding site relative to the transcriptional start site of a gene, and by the site's engagement in chromatin loops with other CTCF-binding sites, enhancers or gene promoters. Here, we will discuss genome wide features of CTCF binding events, as well as locus-specific functions of this remarkable transcription factor. PMID- 23650642 TI - Regulation from a distance: long-range control of gene expression in development and disease. PMID- 23650641 TI - Deciphering cis-regulatory control in inflammatory cells. AB - In innate immune system cells, such as macrophages and dendritic cells, deployment of inducible gene expression programmes in response to microbes and danger signals requires highly precise regulatory mechanisms. The inflammatory response has to be tailored based on both the triggering stimulus and its dose, and it has to be unfolded in a kinetically complex manner that suits the different phases of the inflammatory process. Genomic characterization of regulatory elements in this context indicated that transcriptional regulators involved in macrophage specification act as pioneer transcription factors (TFs) that generate regions of open chromatin that enable the recruitment of TFs activated in response to external inputs. Therefore, competence for responses to a specific stimulus is programmed at an early stage of differentiation by factors involved in lineage commitment and maintenance of cell identity, which are responsible for the organization of a cell-type-specific cis-regulatory repertoire. The basic functional and organizational principles that regulate inflammatory gene expression in professional cells of the innate immune system provide general paradigms on the interplay between differentiation and environmental responses. PMID- 23650643 TI - Measurements of natural radioactivity concentration in drinking water samples of Shiraz city and springs of the Fars province, Iran, and dose estimation. AB - The Fars province is located in the south-west region of Iran where different nuclear sites has been established, such as Bushehr Nuclear Power Plant. In this research, 92 water samples from the water supplies of Shiraz city and springs of the Fars province were investigated with regard to the concentrations of natural radioactive elements, total uranium, (226)Ra, gross alpha and gross beta. (226)Ra concentration was determined by the (222)Rn emanation method. To measure the total uranium concentration, a laser fluorimetry analyzer (UA-3) was used. The mean concentration of (226)Ra in Shiraz's water resources was 23.9 mBq l(-1), while 93 % of spring waters have a concentration <2 mBq l(-1). The results of uranium concentration measurements show the mean concentrations of 7.6 and 6 MUg l(-1) in the water of Shiraz and springs of Fars, respectively. The gross alpha and beta concentrations measured by the evaporation method were lower than the limit of detection of the measuring instruments used in this survey. The mean annual effective doses of infants, children and adults from (238)U and (226)Ra content of Shiraz's water and spring waters were estimated. According to the results of this study, the activity concentration in water samples were below the maximum permissible concentrations determined by the World Health Organization and the US Environmental Protection Agency. Finally, the correlation between (226)Ra and total U activity concentrations and geochemical properties of water samples, i.e. pH, total dissolve solids and SO4(-2), were estimated. PMID- 23650644 TI - Use of methylphenidate for the management of fatigue in Chinese patients with cancer. AB - REASON FOR THE STUDY: Studies on methylphenidate for cancer-related fatigue showed conflicting results. This prospective study aims to determine whether methylphenidate is useful for relieving fatigue in Chinese patients with cancer. Chinese Version of Brief Fatigue Inventory (BFI-C) was administered on days 1, 8, and 29. Methylphenidate dose on day 1 was 5 mg daily then adjusted after day 8 according to response and side effects tolerance. MAIN FINDINGS: Only 48% of the 25 recruited patients were on methylphenidate by day 29. Overall, no significant improvement in fatigue level was observed after methylphenidate, though benefits were shown in subgroups with age <= 65 and higher baseline BFI-C values. PRINCIPAL CONCLUSIONS: Methylphenidate may be useful for management of cancer related fatigue in selected Chinese patients. PMID- 23650645 TI - Acute insulin resistance assessed by the homeostatic model assessment in acute coronary syndromes without previously known diabetes. AB - We assessed the incidence and the prognostic role for early death of acute insulin resistance (by means of homeostatic model assessment [HOMA] index) in 1350 patients with acute coronary syndrome (ACS) consecutively admitted to our intensive cardiac care unit (ICCU). The incidence of HOMA positivity was 5% (68 of 1350), with the highest percentage of HOMA positivity among ST-segment elevation myocardial infarction (STEMI). Patients with HOMA positivity showed a higher body mass index (P = .003), lower values of admission and discharge left ventricular ejection fraction (LVEF; P < .001 and P = .003, respectively), and higher levels of peak troponin I (Tn I; P < .001). The HOMA index was an independent predictor of early death (odds ratio 1.724, 95% confidence interval 1.252-2.375, P = .001). In patients with ACS and without previously known diabetes, acute insulin resistance (HOMA index) is associated with a larger myocardial damage (ie, higher values of peak Tn I and lower LVEF) and a greater inflammatory activation (indicated by correlation with leukocyte count). The HOMA positivity was an independent predictor of in-ICCU mortality. PMID- 23650646 TI - The knowledge and awareness of hypertension among patients with hypertension in central Poland: a pilot registry. AB - We assessed the differences in the knowledge and level of awareness of hypertension among patients with hypertension from Central Poland; 248 (57.6% females) patients diagnosed with hypertension completed a questionnaire. Most (79%) of the patients were unaware of the optimal blood pressure (BP) range. The elderly patients did not know the symptoms of hypertension (23.7%), were not willing to make lifestyle changes (57%-65%), and had a poor awareness of hypertension therapy in the absence of symptoms (28.7%). Poor BP control occurred mainly in rural residents (10.7%) and in people with higher education (39.3%). Untreated patients with hypertension did not know the symptoms of hypertension (29.2%), rarely measured BP (37.5%), but were more likely to engage in regular physical activity (70.8%). Efforts should be made to improve knowledge of hypertension, especially among the rural population, the elderly patients, those with a low-education level, and in young males who had the highest BP. PMID- 23650647 TI - Arterial stiffness: more complex than predicted. PMID- 23650648 TI - Subcapital oblique osteotomy for correction of bunionette deformity: medium-term results. AB - BACKGROUND: Many procedures have been described for correction of bunionette deformity. For symptomatic type I deformity, the authors have routinely performed a subcapital oblique osteotomy of the fifth metatarsal. The purpose of this study was to report the medium-term results of this procedure. METHODS: This is a retrospective review of patients who underwent subcapital oblique osteotomy for correction of type I bunionette deformity. Patients were evaluated radiographically and clinically. Sixteen feet in 14 patients were available at final follow-up. RESULTS: At a mean 2.9-year follow-up, 88% of patients had good or excellent clinical result, 88% of patients had no limitation in activity, and mean pain score on a visual analog scale was 1.6 out of 10. Radiographically, a statistical difference was found when we compared the preoperative and 6-week follow-up fifth metatarsophalangeal angle; however, no statistical difference was found in the fourth to fifth intermetatarsal angle at any time or in comparison of the preoperative and final follow-up fifth metatarsophalangeal angles. CONCLUSION: We found the subcapital oblique osteotomy of the fifth metatarsal to provide reliable clinical results for correction of painful type I bunionette deformity. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 23650649 TI - Tibiotalocalcaneal arthrodesis with bulk femoral head allograft for salvage of large defects in the ankle. AB - BACKGROUND: Tibiotalocalcaneal arthrodesis in patients with large segmental bony defects presents a substantial challenge to successful reconstruction. These defects typically occur following failed total ankle replacement, avascular necrosis of the talus, trauma, osteomyelitis, Charcot, or failed reconstructive surgery. This study examined the outcomes of tibiotalocalcaneal (TTC) arthrodesis using bulk femoral head allograft to fill this defect. METHODS: Thirty-two patients underwent TTC arthrodesis with bulk femoral head allograft. Patients who demonstrated radiographic union were contacted for SF-12 clinical scoring and repeat radiographs. Patients with asymptomatic nonunions were also contacted for SF-12 scoring alone. Preoperative, intraoperative, and postoperative factors were analyzed to determine positive predictors for successful fusion. RESULTS: Sixteen patients healed their fusion (50% fusion rate). Diabetes mellitus was found to be the only predictive factor of outcome; all 9 patients with diabetes developed a nonunion. In this series, 19% of the patients went on to require a below-knee amputation. CONCLUSIONS: Although the radiographic fusion rate was low, when the 7 patients who had an asymptomatic nonunion were combined with the radiographic union group, the overall rate of functional limb salvage rose to 71%. TTC arthrodesis using femoral head allograft should be considered a salvage procedure that is technically difficult and carries a high risk for complications. Patients with diabetes mellitus are at an especially high risk for nonunion. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 23650650 TI - [Phoenix(r) Vitek(r) in bacterial identification]. PMID- 23650651 TI - Reply to Gatesy and Springer: the multispecies coalescent model can effectively handle recombination and gene tree heterogeneity. PMID- 23650652 TI - Hospitals under no duty to disclose negative information unless asked. Emergency medicine: one may 'come to' an ED while still in an ambulance. Morales v. Sociedad Espanola De Auxilio Mutuo Y Beneficencia, 524 F.3d 54 (1st Cir. 2008).. PMID- 23650653 TI - Hospitals under no duty to disclose negative information unless asked. Negligent credentialing: surgeon must demonstrate competence to perform surgery to obtain privileges. Columbia/JFK Medical Center, Ltd. v. Sangounchitte, 977 So. 2d 639 (Ct. App. Fl. 2008). PMID- 23650654 TI - Hospitals under no duty to disclose negative information unless asked. Medical malpractice: completed suicide must be proximately related to assessment. Providence Health Center v. Dowell, S.W. 3d, No. 05-0386, 05-788 (Tex. May 23, 2008). PMID- 23650655 TI - Hospitals under no duty to disclose negative information unless asked. Apparent agency: patient must be aware of the disclaimer of agency. Boren v. Weeks, 251 S.W.3d 426 (Tenn. 2008). PMID- 23650656 TI - Hospitals under no duty to disclose negative information unless asked. Informed consent: informed consent required for a circumcision. D.N.N. v. Berestka, No. A06-2266 (Ct. App. Minn. Feb. 5, 2008). PMID- 23650657 TI - Wellcome Trust appoints new director. PMID- 23650658 TI - US Supreme Court to rule on anti-prostitution pledge. PMID- 23650659 TI - Aid shortfall causes agencies to rethink approach in Gaza. PMID- 23650660 TI - Rijksmuseum restored. PMID- 23650661 TI - Reconsidering the Declaration of Helsinki. PMID- 23650662 TI - Retraction notice to "In situ-forming hydrogels for sustained ophthalmic drug delivery." [COREL 122/2, 119-134]. PMID- 23650663 TI - Are our patients ever ''cured'' or just in ''remission?''. PMID- 23650664 TI - Viewpoint: Is there a role for a diabetes specialist on the AMU? PMID- 23650665 TI - Maps and missing malaria--if in doubt request a blood film. AB - The severe sequelae of infection from the conventionally termed 'benign' forms of malaria are being increasingly recognised, and delayed diagnosis and treatment lead to worse outcomes. The clinical picture can be non-specific and malaria epidemiology is constantly changing, presenting challenges for the acute clinician. The most critical step in the diagnosis of patients presenting in the U.K. is the clinician's awareness of the disease and its key presenting features. We describe a case of Plasmodium vivax malaria in a young man who presented with fever and diarrhoea, who had never travelled to a recognised malaria-endemic area. PMID- 23650666 TI - An unexpected cause of sepsis in a patient with dental decay. Rare example of an infected right atrial calcified myxoma, with extensive calcified pulmonary emboli. PMID- 23650667 TI - [Ovarian cancer; will the new challenge in gynecologic oncology?]. PMID- 23650668 TI - Assessment of emotional distress in chronic kidney disease patients and kidney transplant recipients. AB - OBJECTIVE: To assess the presence of emotional distress in patients with chronic kidney disease (CKD), and the effect of kidney transplant on these symptoms. MATERIAL AND METHODS: This was a two-part study. Part one was cross-sectional, observational, and descriptive, where 75 patients with CKD were evaluated for emotional distress with the Hospital Anxiety and Depression Scale (HAD) and the Symptom Checklist 90 (SCL-90). In part two, we longitudinally followed 19% of the study cohort to examine symptomatological changes after their kidney transplantation. RESULTS: The results of the HAD indicated that 30.7% of the study cohort with End-Stage Renal Disease (ESRD) showed anxious symptoms, and 25.3% showed depressive symptoms. The change in the HAD total score before and after kidney transplant was not significant. However, a significant decrease in total score on the SCL-90 was observed before and after transplantation. CONCLUSION: Improvement on emotional distress was found after kidney transplantation. PMID- 23650669 TI - The relationship between potential drug-drug interactions and mortality rate of elderly hospitalized patients. AB - BACKGROUND: The increase in drug-drug interactions (potential DDIs) is a consequence that older adults experience by high availability of prescription medications for an increasing variety of diseases. This increase in potential DDIs could be associated with mortality rate during hospitalization. OBJECTIVE: To determine whether the association between the presence of Potential DDIs and mortality rate in hospitalized elderly and to describe the frequency of potential DDIs and characterize drugs. MATERIAL AND METHODS: A retrospective research was performed by reviewing the medical records of patients 60 years and older who were admitted to a second-level care hospital. The Potential DDIs were identified through the Micromedex program. Comorbidity was classified according to the Charlson Index (CCI). Other variables such as gender, age, number and type of drug, type of interaction, and duration of hospital stay were evaluated. RESULTS: 505 patients were included, among whom the 62.77% presented at least one type of DDI. We found that 15.25% of moderate interactions were due to the combined use of angiotensin converting enzyme inhibitors and loop diuretics. Among serious interactions, 14.92% occurred due to the combined use of fluroquinolones and hypoglycemic agents. The duration of stay and a high comorbidity score, the presence of three or more interactions and exposure time to the interaction, were independently associated with mortality rate. CONCLUSIONS: This work shows that the occurrence of potential DDIs in the hospital environment for the elderly population is frequent and may be implicated in the cause of death for these patients. PMID- 23650670 TI - [Physician-patient with AIDS-relationship, as a model of clinical relation within the framework of the social security institutions in Mexico]. AB - OBJECTIVE: To examine the nature and level of physician involvement during a clinical encounter with a patient with a chronic condition, such as AIDS, and to explore how it is understood and constructed by them. MATERIAL AND METHODS: Qualitative design with participant observation and semi-structured interviews, with physicians and patients, conducted in hospitals of Social Security Institutions in Mexico City Data were analyzed using the constant comparative method developed in the grounded theory tradition. The emergent themes studied were the dynamics of the encounters, levels of participation of the physician, and attitudes of both participants. RESULTS: Irrespective of whether patients were seen for the first time, or subsequently, in outpatient consultation or in hospital, the physician focused on the solution of the biological problem and on the performance of a work commitment with the Institution. CONCLUSION: This study highlights the need to strengthen the incorporation of the ethics into daily clinical practice in order to transform a physician-patient relationship which is merely bureaucratic, focused on the solution of a biological problem and on the fulfillment of an institutional commitment, into a relationship which is truly professional and at the service of the patient. PMID- 23650671 TI - [Concurrent validity and efficiency of the CBTD for the surveillance of mental health on children and adolescents at a primary health care center in Mexico]. AB - BACKGROUND: Child psychopathology can e understood as normal development gone awry. Attention to psychosocial and behavioural problems has long been recommended as a critical component of well-child care. Likewise, screening for emotional and behavioural problems has been recommended as a routine part of health supervision visits. Different screening instruments have been developed and are widely used. Most of them include a dimensional measurement for internalizing, externalizing, and attention problems, but there is also the need to develop screening algorithms for specific psychiatric syndromes. OBJECTIVE: To present the concurrent validity and efficiency indicators of the Brief Screening and Diagnostic Questionnaire, CBTD, in a primary care health center (PCHC) at Mexico City, as a tool for the surveillance of mental health on children and adolescents. MATERIALS AND METHOD: A sample of 667 consecutive patients (4-16 years old) whose parents responded the CBTD. All patients who obtained a score of five or more symptoms were clinically interviewed using the MINI-KID, together with one of every ten subjects with a lower score. RESULTS: Efficiency showed a sensitivity of 68%, specificity of 82%, positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 57%. When two or more CBTD syndromes are present the PPV is almost 100%. Concurrent validity showed a fair agreement for most of the CBTD syndromes as compared to DSM-IV diagnoses. Syndromes suggesting brain abnormalities, not included in scales of other widely used screening instruments, showed a PPV of 92% and NPV of 96.4%. CONCLUSIONS: The screening results from the CBTD can be used either categorically or dimensionally facilitating the surveillance of mental health on children and adolescents as different syndromatic profiles can be identified and followed for evaluation, along with complementary familial and psychosocial information. PMID- 23650672 TI - Intercellular adhesion molecules and mortality for sepsis in infants younger than 1 year of life. AB - BACKGROUND: Adhesion molecules in sepsis syndrome are correlated with the severity of illness and may be considered as predictors of survival outcome in adults. However, only few studies have been performed in infants and none using international criteria for sepsis. OBJECTIVE: To determine whether adhesion molecules during the first 7 days of the disease could predict sepsis outcome and its severity. MATERIAL AND METHODS: We performed a prospective study in 88 infants with sepsis and 30 controls. Soluble intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin levels were determined at days 1, 3 and 7 of follow-up in those patients with sepsis and only one determination in the control group. The main outcome measure was mortality during 10 days of monitoring. RESULTS: Positive hemoculture was reported in 64(72.7%). ICAM-1, VCAM-1, and E-selectin levels were higher in the group of sepsis than in the control group. However, no association was found between ICAM 1, VCAM-1 or E-selectin levels with sepsis severity. Mortality linked to sepsis was observed in 9 patients (10.2%). In the logistic regression analysis, those variables positively associated with mortality were the increase in ICAM-1 levels > 250 ng/mL between day 1 to 3, number of amines and the baseline severity of sepsis. However, we did not identify in those patients who died a specific pattern in adhesion molecules levels during follow up. CONCLUSIONS: ICAM-1 levels, number of amines and severity of sepsis levels predict mortality during 10 days of monitoring in infants younger than 1 year of age with sepsis. PMID- 23650673 TI - [Evaluation of a physical exercise and nutritional guidance program given to workers at a health institute]. AB - OBJECTIVE: To report on the results of the first stage of the Pause for Your Health program, designed to promote physical exercise during the work journey day in addition to an eating plan to contribute to the employees' general well-being. MATERIAL AND METHODS: The participants were 36 employees of a national institute on health working at a research area. The indicators assessed before and after the program were: sedentary lifestyle, cardiovascular adaptation to exercise test, anthropometric measures, serico-lipoglycemic profile, blood pressure, perception of lifestyle and general well-being and finally opinion about program. RESULTS: Data showed significant changes in five anthropometric indicators, the most significant was waist circumference. As to clinical assessment, the most prominent change was observed in glucose level. The results also showed that people who were overweight at the start of the program at the end of it lost weight, which was statistically significant. CONCLUSIONS: Participants showed attitude of great involvement regarding physical activity and increased awareness of the best way to eat. One of the immediate benefits of using this program was that it allowed identifying risk factors among the employees and increased motivation to participate and to take specific measures regarding their health care. PMID- 23650674 TI - Genetic structure of three Native Mexican communities based on mtDNA haplogroups, and ABO and Rh blood group systems. AB - OBJECTIVE: The goals of this population genetics study were to describe mtDNA haplogroups and ABO and Rh blood group systems of 3 Native Mexican populations, to determine their genetic variability, and to compare their haplogroups with those of 13 Native Mexican populations previously reported. MATERIAL AND METHODS: The three communities under analysis were a Tepehua-speaking community from Huehuetla (Hidalgo state), an Otomi-speaking community from San Antonio el Grande (Hidalgo state), and a Zapotec-speaking community from Juchitan (Oaxaca state). Every subject studied in each community had four grandparents who were born in the same community and spoke the same language. The four Amerindian mtDNA haplogroups (A, B, C and D) were studied by restriction analysis and gel electrophoresis. RESULTS: Regarding the blood groups, the O group was the most frequent in the three populations (97.2, 94.7, and 86.2%, respectively), as well as the Rh+ group (100, 100, 84%). The three populations analyzed were in Hardy Weinberg equilibrium. In respect to the mtDNA haplogroups, A, B, C and D, their percentage was 33.3, 36.1, 13.9 and 5.6 % in Huehuetla; 39.5, 13.2, 39.5 and 2.6 % in San Antonio el Grande, and 55.3, 21.0, 7.9 and 5.2 % in Juchitan. Between 5 and 11% of the haplogroups were of non-Amerindian origin, probably due to admixture with Caucasian and African populations, as has been reported in the past. No statistically-significant differences were found among the three populations studied or between them and 13 previously reported Native Mexican populations. PMID- 23650675 TI - [Association between neuropathy and peripheral vascular insufficiency in patients with diabetes mellitus type 2]. AB - INTRODUCTION: Diabetes mellitus (DM) can present complications of neuropathy and peripheral arterial disease with high risk for developing foot ulcers and consequent amputations. OBJECTIVE: To identify the association between peripheral vascular disease, and neuropathy in type 2 Diabetes mellitus patients from the Hospital General de Zona No. 1 IMSS in Colima, Mexico. MATERIAL AND METHODS: Cross-sectional study of 80 patients with diabetes mellitus evaluated by means of the Edinburgh Claudication Questionnaire, Michigan Neuropathy Screening Instrument, ankle-arm index, Motor Nerve Conduction Velocity and H-reflex. RESULTS: 51 women and 29 men were studied. Mean age was 53.9 +/- 9.6 years, mean diabetes mellitus progression was 8 +/- 6.6 years and mean glucose level was 283 +/- 110 mg/mL. Neuropathy presented in 65 patients (81.2%). Ankle/arm index revealed 19% of patients presented with moderate peripheral vascular insufficiency. Motor Nerve Conduction Velocity was abnormal in 40% of patients and H-reflex was absent in 70%. DISCUSSION: Grade 2 motor-sensitive polyneuropathy was found in 70-80% of patients and moderate peripheral vascular insufficiency in 19%. It can thus be inferred that the complication of diabetic neuropathy appears before that of peripheral vessel damage. PMID- 23650676 TI - [Perioperative antibiotic prophylaxis in cancer surgery]. AB - The effectiveness of perioperative antibiotic prophylaxis in reducing surgical site infections has been demonstrated. Its utility is recognized for clean contaminated procedures and some clean surgeries. Prophylactic antibiotics are used as intended to cover the most common germs in the surgical site; first and second generation cephalosporins are the most used. For optimal prophylaxis, an antibiotic with a targeted spectrum should be administered at sufficiently high concentrations in serum, tissue, and the surgical wound during the time that the incision is open and risk of bacterial contamination. The infusion of the first dose of antimicrobial should begin within 60 min before surgical incision and should be discontinued within 24 h after the end of surgery The prolonged use of antibiotic prophylaxis leads to emergence of bacterial resistance and high costs. The principles of antimicrobial prophylaxis in cancer surgery are the same as those described for general surgery; it is recommended to follow and comply with the standard criteria. In mastectomies and clean head and neck surgery there are specific recommendations that differ from non-cancer surgery. In the case of very extensive surgeries, such as pelvic surgery or bone surgery with reconstruction, extension of antibiotics for 48-72 h should be considered. PMID- 23650677 TI - [Minimally invasive reoperation for failed antireflux surgery]. PMID- 23650678 TI - [Therapy of lysosomal storage diseases: update and perspectives]. AB - Lysosomal storage diseases (LSD) are caused by monogenic mutations in genes coding for multiple aberrant proteins involved in the catabolism of complex lipids, glycosaminoglycans, oligosaccharides, or nucleic acids. The pathophysiology of the LSD is due to abnormal accumulation of non-hydrolyzed substrate in the lysosomes, affecting the architecture and function of cells, tissues and organs. Due to their genic and allelic heterogeneity the LSD present a wide clinical spectrum in severity of symptoms, evolution and age of onset. The therapeutic strategy has two goals: 1) Palliative management of symptoms (splenectomy, surgery to improve or restore joints or bones, drugs for CNS symptoms, etc.), and 2) The correction of activity of the mutant protein, the former has two approaches: A) Replacing deficient protein (bone marrow transplantation, hematopoietic stem cells or umbilical cord blood cells; replacement with recombinant enzyme and gene therapy) and B) Activate or enhanced the functionality of the mutant enzyme with therapeutic small molecules. Neither of the known treatments is able to address all aspects of these multisystemic disorders, nor cure the patients. Currently, the combination of corrective therapy (CT) with paliative therapy (PT) is the most promising strategy to solve most of the multisystem manifestations. The multidisciplinary medical care is fundamental for diagnosis, treatment and control of disease. Nanotechnology opens a promising new era in the treatment of LSD. Finally, the LSD that has CT must be included in newborn screening programs in order to implement timely treatment and prevent irreversible damage. PMID- 23650679 TI - [Disputes and history of fetal heart monitoring]. AB - The concept of fetal heart monitoring to determine the fetal wellbeing state has been employed for almost 300 years, but in the last 50 years it has observed drastic changes due to the incorporation of the electronic devices that has started controversy since the moment of its description and point of start. The purpose of this article is to mention the key points and controversial moments in the history of the cardiotocography PMID- 23650681 TI - Reporting patients who should not be driving. PMID- 23650682 TI - Protecting Michigan auto no-fault insurance. PMID- 23650680 TI - [Third National Ovarian Consensus. 2011. Grupo de Investigacion en Cancer de Ovario y Tumores Ginecologicos de Mexico "GICOM"]. AB - INTRODUCTION: Ovarian cancer (OC) is the third most common gynecologic malignancy worldwide. Most of cases it is of epithelial origin. At the present time there is not a standardized screening method, which makes difficult the early diagnosis. The 5-year survival is 90% for early stages, however most cases present at advanced stages, which have a 5-year survival of only 5-20%. GICOM collaborative group, under the auspice of different institutions, have made the following consensus in order to make recommendations for the diagnosis and management regarding to this neoplasia. MATERIAL AND METHODS: The following recommendations were made by independent professionals in the field of Gynecologic Oncology, questions and statements were based on a comprehensive and systematic review of literature. It took place in the context of a meeting of two days in which a debate was held. These statements are the conclusions reached by agreement of the participant members. RESULTS: No screening method is recommended at the time for the detection of early lesions of ovarian cancer in general population. Staging is surgical, according to FIGO. In regards to the pre-surgery evaluation of the patient, it is recommended to perform chest radiography and CT scan of abdomen and pelvis with IV contrast. According to the histopathology of the tumor, in order to consider it as borderline, the minimum percentage of proliferative component must be 10% of tumor's surface. The recommended standardized treatment includes primary surgery for diagnosis, staging and cytoreduction, followed by adjuvant chemotherapy Surgery must be performed by an Oncologist Gynecologist or an Oncologist Surgeon because inadequate surgery performed by another specialist has been reported in 75% of cases. In regards to surgery it is recommended to perform total omentectomy since subclinic metastasis have been documented in 10 30% of all cases, and systematic limphadenectomy, necessary to be able to obtain an adequate surgical staging. Fertility-sparing surgery will be performed in certain cases, the procedure should include a detailed inspection of the contralateral ovary and also negative for malignancy omentum and ovary biopsy. Until now, laparoscopy for diagnostic-staging surgery is not well known as a recommended method. The recommended chemotherapy is based on platin and taxanes for 6 cycles, except in Stage IA, IB and grade 1, which have a good prognosis. In advanced stages, primary cytoreduction is recommended as initial treatment. Minimal invasion surgery is not a recommended procedure for the treatment of advanced ovarian cancer. Radiotherapy can be used to palliate symptoms. Follow up of the patients every 2-4 months for 2 years, every 3-6 months for 3 years and anually after the 5th year is recommended. Evaluation of quality of life of the patient must be done periodically. CONCLUSIONS: In the present, there is not a standardized screening method. Diagnosis in early stages means a better survival. Standardized treatment includes primary surgery with the objective to perform an optimal cytoreduction followed by chemotherapy Treatment must be individualized according to each patient. Radiotherapy can be indicated to palliate symptoms. PMID- 23650683 TI - Driving force: How Doctor Spanaki scored a win for her patients, her physician colleagues & all Michigan motorists. PMID- 23650684 TI - Employers: avoid penalties under Affordable Care Act. PMID- 23650685 TI - Haveman 2.0: Rebooting community health, expanding partnerships & showing value. Interview by Stacy Sellek. AB - After Gov. Rick Snyder's first Director of the Michigan Department of Community Health, Olga Dazzo, returned to the private sector in 2012, he tapped Grand Rapids native Jim Haveman to return to his former post and drive his aggressive health and wellness agenda forward - something the Governor refers to as a critical piece for reinventing Michigan. Haveman sat down with MSMS's Stacy Sellek to explain what he learned from his previous tenure at MDCH, how his experiences since then have shaped his approach to the job, and the importance of forging partnerships to move health care forward. PMID- 23650686 TI - Be wary of being a "Dr. House": relying too much on intuition is risky. PMID- 23650687 TI - The solution to increasing revenue? Work less. PMID- 23650688 TI - Spring cleaning at tax time. PMID- 23650689 TI - 2013 immunization schedule for adults includes key changes. PMID- 23650690 TI - In Lansing and Washington, the doors are open to physicians. PMID- 23650691 TI - Recent mass murders in the United States are guns and mental illness. PMID- 23650692 TI - Interview with Kyle L. Grazier, PhD, professor and chair, Department of Health Management and Policy, University of Michigan, Ann Arbor. Interview by Stephen J O'Connor. PMID- 23650693 TI - Increasing diversity in governance and management. PMID- 23650694 TI - Physician compensation in a world of health system consolidation and integration. PMID- 23650695 TI - Are real teams healthy teams? AB - This study examines the impact of real-team--as opposed to a team in name only- characteristics (i.e., team boundaries, stability of membership, and task interdependence) on team processes (i.e., team learning and emotional support) and team effectiveness in the long-term care sector. We employed a longitudinal survey in which the real-team characteristics and team processes were rated by team members, and team effectiveness was rated one year later by team members and managers. Our results show that team learning and emotional support are predictors of team effectiveness as rated by team members and managers. They also show that there is no such thing as a real team in the long-term care sector because each real-team characteristic has a different impact on team processes and effectiveness. Whereas one set of real-team characteristics (i.e., stability of membership) is beneficial for healthy team processes and team effectiveness, another set (i.e., team boundaries) has only an indirect effect on team effectiveness via team processes or is even detrimental (i.e., task interdependence). We conclude that more intensive teamwork in the long-term care sector will lead to better outcomes if this teamwork involves increased stability of membership and clarified team boundaries but not if it involves added task interdependency among team members. PMID- 23650696 TI - Discrete event simulation for healthcare organizations: a tool for decision making. AB - Healthcare organizations face challenges in efficiently accommodating increased patient demand with limited resources and capacity. The modern reimbursement environment prioritizes the maximization of operational efficiency and the reduction of unnecessary costs (i.e., waste) while maintaining or improving quality. As healthcare organizations adapt, significant pressures are placed on leaders to make difficult operational and budgetary decisions. In lieu of hard data, decision makers often base these decisions on subjective information. Discrete event simulation (DES), a computerized method of imitating the operation of a real-world system (e.g., healthcare delivery facility) over time, can provide decision makers with an evidence-based tool to develop and objectively vet operational solutions prior to implementation. DES in healthcare commonly focuses on (1) improving patient flow, (2) managing bed capacity, (3) scheduling staff, (4) managing patient admission and scheduling procedures, and (5) using ancillary resources (e.g., labs, pharmacies). This article describes applicable scenarios, outlines DES concepts, and describes the steps required for development. An original DES model developed to examine crowding and patient flow for staffing decision making at an urban academic emergency department serves as a practical example. PMID- 23650697 TI - Hospital ownership and community benefit: looking beyond uncompensated care. AB - Not-for-profit (NFP) hospitals have come under increased public scrutiny for management practices that are inconsistent with their charitable focus. Of particular concern is the amount of community benefit provided by NFP hospitals compared to for-profit (FP) hospitals given the substantial tax benefits afforded to NFP hospitals. This study examines hospital ownership and community benefit provision beyond the traditional uncompensated care comparison by using broader measures of community benefit that capture charitable services, community assessment and partnership, and community-oriented health services. The study sample includes 3,317 nongovernment, general, acute care, community hospitals that were in operation in 2006. Data for this study came from the 2006 American Hospital Association Hospital Survey and the 2006 Area Resource File. We used multivariate regression analyses to examine the relationship between hospital ownership and five indicators of community benefit, controlling for hospital characteristics, market demand, hospital competition, and state regulations for community benefit. We found that NFP hospitals report more community benefit activities than do FP hospitals that extend beyond uncompensated care. Our findings underscore the importance of defining and including activities beyond uncompensated care when evaluating community benefit provided by NFP hospitals. PMID- 23650698 TI - How satisfied are hospital systems with their ownership of retail clinics? AB - Retail clinics--while innovative--can no longer be considered a new model of healthcare delivery, as an increasing number of hospitals and health systems now own them. The purpose of this article is to explore the extent to which hospital systems are satisfied with their ownership of retail clinics. In terms of operational challenges, respondents to our survey, administered to representatives from 19 health systems, were relatively satisfied with clinic staffing and their relationship with the retailers regarding lease terms, store locations, and shopper demographics. They expressed mostly neutral levels of satisfaction with regulations and laws related to retail clinics and low satisfaction with insurance reimbursement and clinics' seasonal patterns. The two areas that received the lowest respondent satisfaction ratings were patient volume and response to marketing initiatives. When asked to share their perceptions of their organization's satisfaction with various strategic aspects of retail clinic ownership, respondents revealed that the clinics were achieving several important strategic goals, such as improved access, increased referrals, defense against competitors, and increased brand exposure. They indicated overall dissatisfaction with profitability and cost-reduction outcomes. We conclude that serious operational challenges and strategic threats must be overcome if retail clinics are to be a successful service line for hospitals and health systems. PMID- 23650699 TI - [Application experience of endoscopic treating sinus bone fibrous dysplasia under navigation guidance]. AB - OBJECTIVE: Research for surgical methods and experience of sinus fibrous dysplasia treatment by auxiliary nasal endoscopy image navigation. METHOD: Retrospective analysis of the records of 4 patients from March 2006 to December 2011 who were diagnosed as fibrous dysplasia of nasal sinuses, 2 male and 2 female, aged from 19 yrs to 55 yrs and average age was 38 yrs; 3 of them were destroyed of sinus floor, the other who had the bone fiber of sphenoidal sinus. By using 16 multi slice spiral CT and 3D reconstruction, the 4 cases were all treated by drill grinding abnormal fibrous tissue in the nasal sinus cavities with auxiliary nasal endoscopy image navigation, to achieve contour in the bone fiber cavities. RESULT: Lesions of 4 cases were accurately found and grinded under auxiliary nasal endoscopy image navigation. For 3 patients, headache, nasal congestion, facial discomfort and other symptoms have gradually disappeared after operation. However, one patient with sinus floor destroyed suffered facial swelling and pain 3 month after operation, with ineffective conservation treatment outcomes. After CT re-scan, it showed that there were a large number of bone residue in maxillary sinus during the re-operation. The reason was that the surgical cavity was not rinsed off which leaded to maxillary sinus congestion. With the methods of expansion of the maxillary sinus, flushing the cavity, and postoperative nasal and maxillary sinus rinse, symptoms disappeared 1 month later without recurrence. CONCLUSION: Patients with fibrous dysplasia of nasal sinuses are treated thoroughly, securely, and effectually, by drill grinding abnormal fibrous tissue in the nasal sinus cavities with auxiliary nasal endoscopy image navigation, to achieve contour in the bone fiber cavities. PMID- 23650700 TI - [Missed diagnosis and treatment discussion of Kartagener syndrome]. AB - OBJECTIVE: To investigate the clinical feature and diagnostic criteria of Kartagener syndrome, and related treatment of sinusitis and nasal polyps. METHOD: The clinical data of 5 patients which were diagnosed as complete Kartagener syndrome in The forth hospital of Hebei medical university were analyzed retrospectively. The first symptom of these patients was sinusitis. All of them accepted cardiac apical auscultation, X ray of orthophoria chest film and chest CT plain scan examination before diagnosis. All of them were treated intervention therapy in outpatient department,and 1 case accepted endoscopic sinus surgery in the hospital. The analysis of the data was to investigate the diagnosis in outpatient department and the perioperative therapy effect. RESULT: All of the 5 patients' clinical feature were total mirror situs inversus viscerum, Dexcrocardia and brochiectasis associated with infection, "signet ring sign", "tram line sign", "honeycomb sign" at different degree on chest CT, bilateral maxillary and ethmoidal sinus inflammation on sinus CT. All the 5 patients appeared bilateral secretor otitis media associated with conductive deafness at different degree. 4 cases accepted anti-inflammation,mucus diluted and medicine treatment to improve cilia activity. 1 case accepted medicine and endoscopic sinus operation for obvious nasal symptoms. After following up for years,all symptoms of the 5 patients relieved, so did recurrent bronchiectasis infection. 1 case with operation had obviously relieved symptom and no postoperative complication. CONCLUSION: Although complete Kartagener syndrome is infrequent disease, heart auscultation diagnosis and image examination are effective method to reduce missed diagnosis. Symptomatic treatment and suitable endoscopic sinus surgery method can reduce sinus symptom and the infection possibility of bronchiectasis effectively,which is beneficial for KS outcome. PMID- 23650701 TI - [Analysis on therapeutic efficacy of different approaches for treating fungal maxillary sinusitis]. AB - OBJECTIVE: To compare the response of simple endoscopic surgery and endoscopic surgery plus small windows through canine fossa surgery for fungal maxillary sinusitis. METHOD: Twenty-five patients were applied the endoscopic surgery plus small windows through Canine fossa surgery as the treatment group, and the other 25 were applied the simple endoscopic surgery as control. RESULT: During a follow up for 1-2 years, the effect of fungal maxillary sinusitis under endoscopic by dual approach is superior to simple endoscopic. There were obvious differences between the two groups(chi2 = 4.268, P < 0.05). CONCLUSION: Endoscopic surgery plus small windows through canine fossa surgery for fungal maxillary sinusitis can fully expose maxillary sinus cavity,destroy the abnormal tissues completely, change the low oxygen environment, ensure the normal physiological function of maxillary sinus mucosa, and really achieve radical minimally invasive purpose. PMID- 23650702 TI - [Report of 6 orbital apex syndrome caused by sinus diseases]. AB - OBJECTIVE: To investigate the diagnostic and therapeutic methods of orbital apex syndrome caused by sinus diseases and to achieve earlier diagnosis and timely treatment. METHOD: Clinical data of 6 cases in our department from January 2008 to March 2012 were retrospectively analyzed. RESULT: All cases had surgical treatment. All cases were preoperatively diagnosed by CT, MRI or intranasal endoscopy. The postoperative pathology showed 2 cases with fungal sphenoiditis, 2 cases with ethmoid mucocele and 2 cases with sphenoid mucocele. CONCLUSION: Orbital apex syndrome caused by sinus diseases is very rare. The possible causes of misdiagnosis are low incidence of the disease, nonspecific eye symptoms, and unawareness of the doctor, especially ophthalmologist. CT, MRI or intranasal endoscopy can greatly improve the diagnosis of the disease. Endoscopic sinus surgery is a safe and effective method for orbital apex syndrome caused by sinus diseases,which is the primary therapy for the disease. PMID- 23650703 TI - [Computed tomography analysis of anatomic structure related to endoscopic axilla approach for surgery of frontal sinus]. AB - OBJECTIVE: To observe the CT imaging features of anatomic structure related to endoscopic axilla approach for surgery of the frontal recess and frontal sinus. METHOD: Thirty patients without a history of frontal sinus disease were undergone 16 line high speed spiral computed tomography. The computed tomographic images were analyzed to measure the related structures. RESULT: The vertical distance from the front attachment point of the middle turbinate to the skull base was 13.88 +/- 2.59 mm. The horizontal distance from the top point of the axilla of the middle turbinate to the anterior wall of the frontal sinus outflow tract was 5.77 +/- 12.32 mm, to the anterior wall of the nasal cavity was 13.67 +/- 12.54 mm, to the lamina papyracea or lacrimal sac was 5.89 +/- 1.69 mm. CONCLUSION: Sixteen line high speed spiral computed tomography is helpful to endoscopic axilla approach for surgery of the frontal recess and frontal sinus. PMID- 23650704 TI - [Complications and treatment for button battery in the nose]. AB - OBJECTIVE: To investigate the injury of button battery to nose and discuss its management. METHOD: Thirteen cases with button battery in nose were reviewed. After the removal of button battery, nasal cavity irrigations were carried out carefully by nasal endoscopy in all cases. Gelfoam full of erythromycin eye ointment was used to cover the injured mucous membrane. RESULT: Among all the cases, 10 got full recovery without any complication. There are 2 cases of synechia nasal and 1 case of septum perforation. CONCLUSION: Removal as soon as possible, careful cleaning and systemic drug are necessary. Nose bleed, septum perforation, adhesion and rhinostenosis should be noticed. PMID- 23650705 TI - [The correlation of serum specific IgE detection and skin prick test in allergic rhinitis]. AB - OBJECTIVE: To investigate the correlation between serum specific immunoglobin E(sIgE) and skin prick test(SPT) and their differences of the positive rate. METHOD: One hundred and nine patients with allergic rhinitis were detected the serum slgE. The patients had positive symptoms and signs, positive SPT results with at least one allergen. RESULT: Specific IgE and SPT results of Dp,Df and Artemisia showed a positive correlation (r = 0.520, 0.4413, 0.764, P < 0.01). sIgE positive rates were 55.0%, 54.1% and 17.4% for Dp, Df and Artemisia respectively, whereas SPT positive rates were 68.8%,79.8% and 27.5% respectively. The difference between the positive rates of the sIgE and SPT was significant (chi2 = 27.93,18. 20,60. 60, are P< 0.01). CONCLUSION: There was a good correlation between specific IgE and SPT. SPT is more sensitive than sIgE, but SPT can not substitute for slgE,vice versa. PMID- 23650706 TI - [Analysis of total and specific IgE in serum of carvota mitis pollen-induced allergic rhinitis patients]. AB - OBJECTIVE: Exploring the relationship between total and specific IgE in serum and allergen skin test of carvota mitis pollen-induced allergic rhinitis patients. METHOD: Four hundred and-twenty-nine carvota mitis pollen-induced allergic rhinitis patients and 243 healthy control subjects were recruited. The experimental group carried out skin tests. and pollen-specific IgE were also examined by BSA-ELISA method. Total IgE in serum of all of the subjects were determined by ELISA. RESULT: The positive rate of the total IgE level of the patients were much higher than those of the controls (66.2% vs. 15.6%, P < 0.01). No statistically significance was found between the positivity of skin test and serum specific IgE of the experimental group (chi2 = 0.758 8, P > 0.05). The difference between serum-specific IgE and total IgE was statistically significant (chi2 = 50.639, P<0.01). There was no statistical significance of specific IgE and the total IgE in serum between long term residents in Haikou and Hainan Tourisms (P > 0.05). CONCLUSION: Allergen skin test and carvota mitis pollen specific IgE are two effective methods for the diagnosis of carvota mitis pollen induced allergic rhinitis. The detection of total IgE in serum of carvota mitis pollen-induced allergic rhinitis provides a reference value for diagnosis. The relationship between concentration of IgE in serum of the carvota mitis pollen induced allergic rhinitis and allergen contact duration is waiting for further study. PMID- 23650707 TI - [The role of sinomenine in treatment of allergic rhinitis mice model and its mechanism]. AB - OBJECTIVE: To explore the role of sinomenine in treatment of allergic rhinitis mice model and its possible mechanism. METHOD: We used ovalbumin (OVA) to make allergic rhinitis model of BALB/c mice. Saline was used in the control group. When we challenged the mice with OVA intranasally, the mice in sinomenine treatment group were feed by the food containing sinomenine. Mice were then killed 24 h after the last OVA challenge. The noses of mice from each group were removed en bloc and fixed, then each section was stained with hematoxylin and eosin. ELISA assay was used to measure the concentration of anti-OVA IgE, IL-4 and IFN-gamma. The proteins expressive level of T-bet and GATA3 were examined. RESULT: Nasal mucosa of the mice in sinomenine treatment group were not hyperplasia and without obvious infiltration of eosinophils. The concentration of anti-OVA IgE, IL-4 and IFN-gamma in the serum and T-bet and GATA3 expression levels of sinomenine treatment group were lower than those of allergic rhinitis group. CONCLUSION: The sinomenine can be used to treat allergic rhinitis mice, and the mechanism may rely on the improvements of the Th1/Th2 imbalance. PMID- 23650708 TI - [Clinical study about 18 cases with endoscopic surgery for nasal inverted papilloma]. AB - OBJECTIVE: To evaluate the method and value of the nose endoscopic surgery on thoroughly cutting the nose inverted papilloma. METHOD: Eighteen patients with nasal inverted papilloma were treated by the nasal endoscopic surgery were analyzed retrospectively. Among all patients, the nasal inverted papilloma excision by endoscopy was in 14 cases, the nasal endoscopy uniting Caldwell-Luc surgery was in 4 cases. RESULT: The average duration of follow-up was 2.6 years. No complications were found in 18 cases. Relapse was found in 3 cases during the follow-up period, showing 16.7% relapse rate. CONCLUSION: The nasal endoscopic surgery to cut the nasal inverted papilloma is a very safe and effective method,and the curative effect of the nose endoscopic uniting Caldwell-Luc surgery is very useful to these cases which the papilloma had destroyed generally into the maxillary sinus. PMID- 23650709 TI - [Endoscopic intranasal structure reconstruction surgery in treating rhinogenic headache]. AB - OBJECTIVE: To study the efficacy of endoscopic intranasal structure reconstruction surgery for rhinogenic headache. METHOD: One hundred and seventy cases of rhinologic headache were examined by nasal endoscopy and CT scan. The various abnormal anatomy were found in the patients. The nasal abnormality were corrected by nasal endoscopic surgery. RESULT: Followed up survey 6-12 months postoperatively, 156 cases were cured, the cure rate of 183 cases was 85.2%,18 cases were obviously recovered (9.8%). 9 cases did not recover. The clinical cure rate was 95.0%. CONCLUSION: Rhinogenic headache was caused by anatomic abnormality or disease. Endoscopic sinus surgery can accurately and completely clear the ill tissue, reconstruct the nasal structure, which have good therapeutic effect and important clinical value. PMID- 23650710 TI - [Investigation of swallowing function in the elderly]. AB - OBJECTIVE: To evaluate the swallowing function and the incidence of swallowing dysfunction in the elderly, and study the effect of age on swallowing function. METHOD: A total of 1040 (age > or = 55 years) elderly-to-be and elderly who undertaken the health examination in health examination center of our hospital from March 16, 2012 to April 9, 2012 were included in this study. The incidence of swallowing dysfunction in the elderly and the effect of age on swallowing function were evaluated. The subjects with stroke, esophageal cancer, parkinson's disease, deglutition syncope, esophageal spasm, thyrohyoid cyst and so on were defined as basic disease group, the other as normal group. The incidence of swallowing dysfunction was compared between the two groups. RESULT: The incidences of swallowing dysfunction in basic disease group and normal group were 74.4% (29/39) and 5.5% (55/1001), and there was a significant difference between the two groups (P < 0.001). The swallowing dysfunction rates of elderly-to-be and elderly in normal group were 2.9% (9/311) and 6.7/% (46/690) and the difference between the two groups was significant (P < 0.05). With the growth of age, the swallowing dysfunction rate in different age group increased, and the number of rapid swallow in 30 s decreased gradually (P < 0. 001). CONCLUSION: Stroke, esophageal cancer, Parkinson's disease and so on are the main causes of swallowing dysfunction in elderly. The swallowing dysfunction rate is 6.7% in the normal elderly. With the growth of age, the incidence of swallowing dysfunction is increased and the swallowing speed is decreased. PMID- 23650711 TI - [Dacryocystorhinostomy and trumpet-shaped tube placement under nasal endoscopy for the treatment of chronic dacryocystitis]. PMID- 23650712 TI - [Subperiosteal abscess of the orbit after sinus surgery: a case report]. PMID- 23650713 TI - [With aspirator monopolar electrocoagulation treatment of nasal bleeding a report of 120 cases]. PMID- 23650714 TI - [Pediatric tracheotomy: clinical analysis of 33 cases]. PMID- 23650715 TI - [Trauma induced left maxillary sinus dislocation of eyeball--a case report]. AB - Patient male, 27 year old. Left facial and head trauma for 6 hours, due to motor vehicle accident. Patient state of mind was clear at arrival to hospital. Body temperature: 36C; Pulse: 80 Time/Minute; Breath: 20 Time/Minute; Blood pressure: 120/80 mm Hg. An irregular, horizontal laceration at arch of left eyebrow, approximately 8-10 cm. A laceration on left wing of nose skin, approximately 1 cm. A laceration also under lower eyelid skin of right eye, approximately 2 cm. Left blepharedema and enophthalmos. Orbital and nasal sinuses CT indications:contusion and laceration of the left frontal lobe of brain; fracture of the left orbital frontal, ethmoid, sphenoid bone, left nasal, maxillary sinus and zygoma with soft tissue contusion and laceration; the left eyeball and optic nerve sunk into the maxillary sinus (See figure 1). DIAGNOSIS: (1) Multiple orbital fractures; (2) Left maxillary sinus dislocation of eyeball; (3) The left frontal lobe contusion and laceration of brain. PMID- 23650716 TI - [One case report of carotid body tumor resected with hemorrhage and artery repair]. AB - Carotid body tumors (CBT) were rare. One case with a mass in the right neck side suspected as CBT after preoperative examination was reported with hemorrhage, and artery repair in the resection of the mass, which was finally diagnosed as CBT by pathological examination. Its resection methods, postoperative complications and artery repair methods were discussed. PMID- 23650717 TI - [A case of rhinolith and actinomycosis]. AB - The patient presented with right nasal obstruction, purulent secretion in nasal meatus and dull headache for 3 years. A dark brown mass, irregular in shape, surface roughness and purulent secretion adherent, was seen in the nose, touched as coal tar stone. CT examination showed high density in the right nasal meatus. Postoperative pathological examination proved to be rhinolith and actinomycosis. PMID- 23650718 TI - [H1-antihistamines]. AB - While histamine plays an important role in the pathogenesis of allergic diseases, such as allergic rhinitis, H1-antihistamines, which have been using in the treatment of allergic diseases for more than 70 years, are considered as the cornerstone of the medication of allergic diseases. In this review, we discuss the history of histamine studies and anti-histamine discovery, the histamine receptors, as well as the mechanisms and the safety of H1-antihistamines. PMID- 23650719 TI - [Probiotics and allergic rhinitis]. AB - The prevalence of allergic diseases has increased in recent years, and primary prevention of allergic disease is considered to be an elusive goal. This paper summarizes the recent publications on probiotics in allergic rhinitis. It focuses on clinical and laboratory observations of treatment or prevention of allergic rhinitis. Probiotics administration represents different outcome, its effects depend on a variety of factors, such as dosing regimen, delivery method and the types of bacterium. Since the data from different research centers are conflicting, the further studies are required. PMID- 23650720 TI - [Angiotensin converting enzyme and Alzheimer's disease]. AB - Alzheimer's disease (AD) is an incurable degenerative disease of the central nervous system, leading to dementia. The basis of AD is neurodegenerative process that leads to death of neurons in the cerebral cortex. This neurodegenerative process is associated with the formation of neurofibrillary tangles in the brain and the deposition of senile plaques, the main component of which is a beta amyloid peptide (Abeta). Risk factors for AD are age, as well as hypertension, atherosclerosis, diabetes and hypercholesterolemia in the pathogenesis of which involved angiotensin converting enzyme (ACE)--key enzyme of the renin-angiotensin (RAS) and kallikrein-kinin (KKS) systems. Recently it was discovered that ACE, along with other metallopeptidases, participates in the metabolism of Abeta, cleaving the bonds at the N-terminal and C-terminal region of the molecule Abeta. The role of the ACE in the degradation processes of Abeta takes an interest. It is associated with the fact that the using of ACE inhibitors is the main therapeutic approach used in the treatment of various forms of hypertension and other cardiovascular diseases. However, until now not been resolved, can be used antihypertensive drugs that inhibit RAS for the treatment or prevention of AD. Currently, there are numerous studies on finding the relationship between RAS and AD. PMID- 23650721 TI - [The potential role for sphingolipids in neuropathogenesis of Alzheimer's disease]. AB - The review discusses the functional role of sphingolipids in the pathogenesis of Alzheimer's disease. Certain evidence exist that the imbalance of sphingolipids such as sphingomyelin, ceramide, sphingosine, sphingosine-1-phosphate and galactosylceramide in the brain of animals and humans, in the cerebrospinal fluid and blood plasma of patients with Alzheimer's disease play a crucial role in neuronal function by regulating growth, differentiation and cell death in CNS. Activation of sphingomyelinase, which leads to the accumulation of the proapoptotic agent, ceramide, can be considered as a new mechanism for AD and may be a prerequisite for the treatment of this disease by using drugs that inhibit sphingomyelinase activity. The role of sphingolipids as biomarkers for the diagnosis of the early stage of Alzheimer's disease and monitoring the effectiveness of treatment with new drugs is discussed. PMID- 23650722 TI - [Interstitial collagenase, gelatinases A and B and their endogenous inhibitors in squamous cell cervical carcinomas]. AB - Interstitial collagenase and gelatinases are matrix metalloproteinases (MMP), which play the key role in tumor invasion and metastasis. The aim of this study was to elucidate the peculiarities of expression of interstitial collagenase (MMP 1), gelatinases A and B (MMP-2 and MMP-9) and their endogenous tissue inhibitors TIMP-1 and TIMP-2 as invasive factors of squamous cell carcinomas (SCC) of human cervical cancer. The study was carried out using 24 specimens of SCC and 11 specimens of adjacent to tumor morphologically normal tissue. All carcinoma specimens expressed E7 HPV-16 gene. It was shown that the increase of MMP-1 and MMP-9 expression and low of TIMP-1 and TIMP-2 expression makes the main contribution to the destructive (invasive) potential of SCC. The change of MMP-2 expression is not so significant and it is less influenced to the destructive potential. Moreover, substantial expression of MMP-1, MMP-2 and MMP-9 was registered in the specimens of morphologically normal adjoining to tumor tissue. This expression was found to make an additional contribution to the destructive potential of cervical tumor. PMID- 23650723 TI - [Delta-sleep inducing peptide entrapment and release from polymer hydrogels based on modified polyvinyl alcohol in vitro]. AB - The aim of the study was to entrap delta-sleep inducing peptide (DSIP) in cross linked poly(vinyl alcohol)-based hydrogels of different structures and to evaluate peptide release kinetics from these hydrogels using an in vitro model. Isotropic and macroporous hydrogels on the basis of poly(vinyl alcohol) acrylic derivative (Acr-PVA) as well as macroporous hydogels containing epoxy groups which were synthesized by copolymerization of this monomer with glycidyl methacrylate. The isotropic hydrogels were fabricated at positive temperatures while the macroporous hydrogels (cryogels) were prepared at the temperatures below zero. The peptide was entrapped into macroporous modified PVA hydrogels by addition of a peptide solution on previously fabricated matrices, while into PVA GMA hydrogels containing epoxy groups peptide immobilization was carried out by incubation of hydrogel matrices in the peptide solution. In the case of isotropic hydrogels the peptide was added into the polymer mixture at a hydrogel formation reaction. The peptide release kinetics was studied by incubation of hydrogels in PBS (pH 7.4), in physiological solution (0.9% NaCl) and in water. DSIP concentration in supernatants was determined by phase-reverse HPLC. DSIP release from the macroporous PVA hydrogel after 30 min incubation was 74, 70 and 64% in water, PBS and 0.9% NaCl, relatively, and it was completed in 3 hs. From the isotropic hydrogel the release neither peptide nor products of its degradation was not observed even after 48 hs of incubation. For freshly prepared hydrogel the release kinetics was as follows: 27 and 78% in 30 and 33 hs, relatively. In the case of the lyophilized hydrogel samples the peptide release was 63% in 30 min incubation while drying patterns at room temperature for 3 days resulted in significant peptide loss because its structure damage. PMID- 23650724 TI - [Influence of ethanol-metabolising systems on intensity of lipid peroxidation processes in gastrointestinal tract of rats]. AB - The effects of some ethanol-metabolising systems (aldehyde dehydrogenase, catalase, cytochrome P450 2E1) on activation of lipid peroxidation (LPO) processes in gastrointestinal tract of rats have been studied using inhibitors of these systems. The intensity of LPO processes was evaluated by thiobarbituric acid-reactive products and chemiluminiscence intensity. It was found, that the acetadehyde metabolism play the main role in the indiction of lipid peroxidation in the gastrointestinal tract of rats. PMID- 23650725 TI - [Oxidised dextrans influence on reactive oxygen species generation by murine peritoneal exudate phagocytic cells]. AB - The effects of oxidized dextrans of different molecular weight on reactive oxygen species production and transmembrane mitochondrial potential of macrophages and neutrophils have been studied in vivo and in vitro. Oxidised dextrans demonstrated moderate direct antioxidant ability but induced intracellular oxidative stress through the increase of oxygen radical generation. This effect of the investigated compounds amplifies the cytotoxic and bactericidal potential of phagocytes and can influence isoniazid metabolism, thus increasing its efficiency in therapy of infectious diseases. PMID- 23650726 TI - [The effect of berberine administration of evaluation of the functional state of rat liver after ligation of common bile duct]. AB - On the eighth day after ligation of the common bile duct in rats a significant increase in the serum content of total lipids, cholesterol bilirubin and ALT, alkaline phosphatase, and gamma-glutamyltransferase was observed. In the microsomal fraction there was a marked decrease in the content and activity of microsomal monooxygenases. Introperitoneal injection of berberine (10 mg/kg) for 6 days caused a partial normalization of permeability of hepatocytes plasma membranes and activity microsomal flavin-containing monooxygenases. It is suggested that berberine is a substrate and inducer of flavin-containing monooxygenases. Membrane-stabilizing effect of berberine is probably realized at the level of inhibition of prooxidant status of liver cells. PMID- 23650727 TI - [Influence of vibration-induced stress on functional-metabolic status of blood leukocytes]. AB - The chronic stress in albino rats caused by exposure to the whole-body vibration induced the significant changes in the functional-metabolic status of the blood cells. It involved the phagocytosis level and the lysosomal cationic proteins in the neutrophils, oxidative and hydrolytic processes in the neutrophils and lymphocytes. All the determined intracellular parameters revealed the differentiated response to stress as well as to the additive combined administration of the antioxidants (glycine and alpha-tocopherol acetate). PMID- 23650728 TI - [An example of oscillatory (cyclic) reaction for prostaglandin chemistry]. AB - It is shown an ability of prostaglandin A1 to the oscillatory reaction which has significance both the theoretical and practical if prostaglandins are used for therapy. PMID- 23650729 TI - [Comparative studies on the genotoxic activity of a new palladium (II) acidocomplex vs cisplatin in human blood lymphocytes in vitro]. AB - A comparative study on the genotoxic activity of cisplatin versus morfozol, the first representative of a new class of cation-anion complexes of palladium [AH]2[PdCl4] (where A-methylmorpholine) has been performed using human lymphocytes in vitro. The results of the DNA-DNA cross-linking activity investigations showed that both compounds studied exhibited biphasic dose-effect relationship: a linear decrease in the DNA percent in the comet tail and the region of the "plateau". However, in the "plateau" region, morfozol reduced the DNA percent in the comet tail up to 6 times while cisplatin caused a 2-fold decrease only. Morfozol, like cisplatin, inducing DNA-protein cross-linking and generating reactive oxygen species, was more effective than cisplatin. PMID- 23650730 TI - [Investigation of molecular machine that integrates microtubules depolymerization and chromosomes movement in mitosis]. AB - The main goal of a dividing cell is to distribute its genetic material equally between two daughter cells. Each of the two sister chromatids comprising each chromosome should go into one of the daughter cells. This is possible thanks to polar protein polymers called microtubules, which form a structure called "spindle" during mitosis. Microtubules are one of the basic elements of the cytoskeleton, but at the same time they are highly dynamic. Minus ends of the microtubules attach to the two poles of the spindle, while their plus ends are constantly growing or shrinking, and are also able to attach to the chromosomes and to move them. Chromosomes attach to the microtubule ends with a special protein super-complex called kinetochore. Each sister chromatid in a pair attaches to the microtubules emanating from a corresponding spindle pole. Kinetochores are attached to the dynamic plus ends of the microtubules, but tubulin subunits are still able to attach and detach to these attached ends. One of the most important questions in mitosis is understanding of the mechanism that allows such attachment to be stable (since unstable attachments lead to chromosome loss and aneuploidy) yet dynamic (arrest of the microtubule dynamics stops mitosis). More than 100 proteins comprising the kinetochore are known today, but there is no clear mechanical view on the molecular machine that forms kinetochore-microtubule attachment. The difficulties in understanding this mechanism are due to the variety of theoretical views on the principle of such machine, as well as limited number of biochemically isolated candidates to test these hypotheses experimentally. Therefore, investigation of the properties of putative couplers of microtubule depolymerization and chromosome movement is an important task. PMID- 23650731 TI - [The cyclic organization of sleep in early ontogenesis in different conditions of intrauterine fetus development]. AB - The modern data about sleep development in early ontogenesis of newborns infants are presented. EEG-polysomnographic studies in newborns with different perinatal pathology document patterns of postnatal brain maturation have diagnostic and prognostic value. PMID- 23650732 TI - [Claudins as tight junction proteins: the molecular element of paracellular transport]. AB - Epithelium is a key structure of tissue barriers ensuring a creation of electrochemical and osmotic gradients. There are transcellular and paracellular types of transepithelium transport of molecules and ions. Epithelial layer permeability for paracellular transport as well as restriction of lateral integrative protein diffusion in a plasma membrane is determined by apical intercellular complex including tight junctions. Integrative proteins of the claudin family are basic molecular components of tight junctions. Properties of single claudins and their complexes define the differences in a degree of epithelial permeability. The subfamily of claudins forming charge- and size selective pores provides selective paracellular diffusion. The subfamily of claudins increasing epithelial impermeability strengthens epithelial barrier features. PMID- 23650733 TI - [C-peptide physiological effects]. AB - In the recent years there were numerous evidences that C-peptide, which was previously considered as a product of insulin biosynthesis, is one of the key regulators of physiological processes. C-peptide via heterotrimeric G(i/o) protein-coupled receptors activates a wide range of intracellular effector proteins and transcription factors and, thus, controls the inflammatory and neurotrophic processes, pain sensitivity, cognitive function, macro- and microcirculation, glomerular filtration. These effects of C-peptide are mainly expressed in its absolute or relative deficiency occurred in type 1 diabetes mellitus and they are less pronounced when the level of C-peptide is close to normal. Replacement therapy with C-peptide prevents many complications of type 1 diabetes, such as atherosclerosis, diabetic peripheral neuropathy, and nephropathy. C-peptide interacts with the insulin hexamer complexes and induces their dissociation and, as a result, regulates the functional activity of the insulin signaling system. At the same time, C-peptide at the concentrations above physiological may demonstrate pro-inflammatory effects on the endothelial cells and cause atherosclerotic changes in the vessels, which should be considered in the study of pathogenic mechanisms of complications of type 2 diabetes mellitus, where the level of C peptide is increased, as well as in the development of approaches for C-peptide application in clinic. This review is devoted contemporary achievements and unsolved problems in the study of C-peptide, as an important regulator of physiological and biochemical processes. PMID- 23650734 TI - [Gender-dependent effects of histone deacetylase inhibitor sodium valproate on early olfactory learning in 129Sv mice]. AB - In the brain, histone acetylation underlies both learning and the maintenance of long-term sustained effects of early experience which is further epigenetically inherited. However, the role of acetylation in learning previously has only been studied in adult animals: high level of learning could be dependent on high levels of histone H3 acetylation in the brain. The role of acetylation in the mechanisms of early learning has not been studied. In the present work, we were interested whether histone deacetylase inhibitor sodium valproate which increases the level of histone H3 acetylation will affect early olfactory discrimination learning in 8-day-old pups of 129Sv mice that are characterized by low efficiency of learning with imitation of maternal grooming. Multiple valproate injections from 3rd to 6th postnatal day had a gender-dependent effect: learning was selectively improved in male but not in female pups. In the female pups, learning improvement was observed after multiple injections of saline. Possible epigenetic mechanisms underlying these sex differences are discussed. PMID- 23650735 TI - [Comparative analysis of metabotropic and ionotropic glutamate striatal receptors blockade influence on rats locomotor behaviour]. AB - The influence of NMDA and metabotropic neostriatal glutamate receptors blockade to avoidance conditioning (in shuttle box) and free locomotor behavior (in open field) in chronic experiments in rats were investigated. The glutamate receptor antagonists were injected bilateral into striatum separately and with the GABA-A receptor antagonist picrotoxin (2 microg), that produced in rats the impairment of avoidance conditioning and choreo-myoklonic hyperkinesis. The most effective in preventing of negative picrotoxin influence on behavior was 5-type metabotropic glutamate receptors antagonist MTEP (3 microg). Separately injected MTEP did not influence on avoidance conditioning and free locomotor behavior. Unlike that, 1-type metabotropic glutamate receptors antagonist EMQMCM (3 microg) impaired normal locomotor behavior and did not prevent the picrotoxin effects. The NMDA glutamate receptors MK 801 (disocilpin--1 and 5 microg) impaired the picrotoxin-induced hyperkinesis, but did not to prevent the negative effects on avoidance conditioning; separately injected MK 801 reduced free locomotor activity. Based on location of investigated receptor types in neostriatal neurons membranes, we proposed that the most effective influence on 5-type metabotropic glutamate receptors is associated with their involvement in "indirect" efferent pathway, suffered in hyperkinetic extrapyramidal motor dysfunction--Huntington's chorea in human. PMID- 23650736 TI - [Changes in pulmonary arteries dilatation reserve during chronic obstructive pulmonary disease model formation]. AB - Model of chronic obstructive pulmonary disease (COPD) was induced in rats by nitrogen dioxide inhalation for 60 days. The effect of reagents-vasodilators on the isolated pulmonary arteries with a diameter less than 0.5 mm was studied in 15, 30 and 60 days of COPD induction. All vasodilators (beta-adrenoreceptor agonist izopreterenol, nitric oxide donor nitrosorbid, acetylcholine, activator of C-fibers capsaicin, corticosteroid beclometasone) dose-dependently decreased vascular tone of pulmonary arteries isolated from intact rats. On extension nitrogen dioxide exposure pulmonary arteries responded to the impact of all vasodilators by smaller relaxation. Dose-dependence of dilatation reaction disappeared. In the process of COPD model formation functioning of almost all pulmonary arterial wall neurotransmitter systems were broken. This led to decrease in vasodilators influence on vascular tone and could facilitate the development of pulmonary hypertension which is typical of COPD. PMID- 23650737 TI - [Hemodynamics in soft tissues after upper third of the leg lengthening by Ilizarov osteosynthesis technique]. AB - An experimental study has been performed. The leg was lengthened in 12 adult mongrel dogs by transosseous distraction osteosynthesis in the zone of upper third of the leg bone shaft by 14-18% of the segment length using the rate of 1.0 mm for 4 times. The formation of mechanically strong shaft part occurred after 35 days after device fixation. Under created conditions the unidirectional cyclic changes of blood circulation and morphofunctional state occurred in soft tissue segment, that were more marked in the extensor muscle group. Implementation of preventive-and-treatment measures directed to improvement of vascular elastotonic properties allowed to decrease the degree of disordering hemodynamics of the lengthened limb. This will have a positive effect on the final clinical outcome. PMID- 23650738 TI - [Membrane cholesterol oxidation effects on synaptic vesicle cycle in frog (RANA ridibunda) motor nerve terminals]. AB - In experiments on frog (Rana ridibunda) neuromuscular junction the influence of cholesterol oxidation on the presynaptic vesicular cycle was investigated. Application of cholesterol oxidase (1 u. a.) during 1/2 hour led to the oxidation of - 0.007 mg cholesterol per 1 g tissue and reduced stability of lipid rafts in the nerve terminals. Using electrophysiological techniques it was shown that the cholesterol oxidation decreases the evoked neurotransmitter release. In experiments with fluorescent FM-dyes the depression of the synaptic vesicles exo endocytosis and the dispersion of synaptic vesicles clusters were revealed. Comparative analysis of electrophysiological and optical data, as well as experiments with water soluble quencher of FM-dye indicated the possibility of some neurotransmitter release by "kiss-and-run" pathway, when short-lived fusion pore is formed. It was concluded that cholesterol oxidation inhibit evoked exocytosis, and also synaptic vesicle delivery from reserve pool to cites of exocytosis probably by break of the clusterization. Perhaps the synaptic vesicles of recycling pool release the neurotransmitter using the kiss-and-run mechanism. PMID- 23650739 TI - [Cyclosporin A-sensitive mitochondrial pore as a target of cardioprotective action of hydrogen sulfide donor]. AB - In experiments on a model of ischemia-reperfusion in Langendorff isolated rat hearts and isolated mitochondria we studied the role of hydrogen sulfide donor - sodium hydrosulfide (NaHS, 7.4 mg/kg) in modulating the sensitivity ofmitochondrial permeability transition pore opening. It was shown that NaHS increased the reserves of rat myocardium and had cardioprotective effects from ischemia-reperfusion. In experiments on isolated mitochondria NaHS in concentrations of 10(-6), 10(-5) and 5 x 10(-5) mol/L inhibited Ca(2+)-induced swelling of mitochondria. Preincubation of isolated mitochondria with K+(ATphi) channels inhibitor 5-hydroxydecanoate (10(-4) mol/L) reduced the protective effect of NaHS (10(-5) mol/L). Thus, we consider that NaHS protective effect from reperfusion disturbances of heart function was realized via inhibition of Ca(2+) induced mitochondrial permeability transition pore opening. PMID- 23650740 TI - [Visual cortex and its participation in retinal function regulation]. AB - The study of visual cortex local changes caused by strychnine and potassium chloride revealed significant changes (relief or depression) not of evoked potentials in the cortex only, but of unidirectional changes of the total electroretinogram (ERG) amplitude and its components as well (early receptor and oscillator retinal potentials). Cortex excitability decrease or increase resulted in inhibition or facilitation of early receptor potential development respectively due to weakening or strengthening of the inhibitory neurotransmitter GABA effect in photoreceptor synapses. Changes of ERG components and retinal oscillator potential corresponded to the changes of visual evoked potentials that reflected upon cortex inhibition or facilitation. This fact apparently indicates the changes of inhibitory neurotransmitter glutamate activity. PMID- 23650741 TI - [Lacrimal gland changes in sarcoidosis according to the results of spatial digital ultrasonography]. AB - Clinical changes of lacrimal gland (LG) in sarcoidosis are studied. 33 patients (66 orbits) with verified systemic sarcoidosis were examined using digital ultrasound. Different varieties of LG structural changes in sarcoidosis are studied. Different types of LG structural changes were determined in patients with sarcoidosis defined as pseudoedematous and combined forms. Analysis of the results let us reveal characteristic local acoustic changes. Obtained results may be useful for diagnosis of LG changes in patients with sarcoidosis. PMID- 23650742 TI - [Acoustic density of sclera as a prognostic factor of peripheral vitreochorioretinal degenerations in myopia: results of 10-years follow-up]. AB - Prognostic value of acoustic density of sclera (ADS) is studied in development of peripheral vitreochorioretinal degenerations (PVCRD) in myopia. Children aged 8 10 years old with noncomplicated high and moderate myopia were divided into two groups after ADS measurement: 1 with ADS < or = 39dB - unfavorable prognosis, 2 with ADS >39dB - favorable prognosis. Follow-up during 10 years with examinations twice a year confirmed prognosis accuracy: in the 1st group PVCRD developed 2.5 times as often as in the 2nd group (64.6 and 25.6% respectively). PMID- 23650743 TI - [The study of opportunity of aqueous humor filtration increase after nondestructive laser exposure of sclera in the site of pars plana projection (experimental study)]. AB - Increase of scleral water permeability due to formation of porous structure after exposure of pulsed periodic radiation of erbium-glass optical fiber laser with wave length 1,56 pm was demonstrated in experimental study of cadaver human eyes in vitro and eyes of experimental animals (rabbits) in vivo. Simultaneous complex laser exposure of pars plana and ciliary processes results in summation of morphological changes that provide decrease of aqueous humor secretion, uveal drainage and extension of suprachoroid space. A base for new noninvasive technology of nondestructive laser exposure in glaucoma treatment is established. PMID- 23650744 TI - [Analysis of factors causing peripheral visual field defects after vitreomacular surgery]. AB - As a result of the study analysis of potential causes of visual field defects (VFD) after vitreomacular surgery is performed. 110 cases are enrolled in the study: 81 patient with macular hole and 29 patients with epiretinal fibrosis. Correspondence of VFD to position of irrigation port including unusual inferior nasal position was revealed as well as VFD absence in epiretinal fibrosis operated without air pump. VFD did not appear after lowering of air pump pressure by 15-20 mmHg. The cause of VFD after vitreomacular surgery is a mechanical damage of internal retinal surface by directed air/gas jet after total fluid exchange with too high pressure in an air pump. This complication is an easily preventable iatrogenic effect and may serve as one of quality criterion for this treatment procedure. PMID- 23650745 TI - [Stereoscopic vision evaluation in patients after binocular implantation of different intraocular lens models]. AB - Stereoscopic vision in patients after binocular implantation of different intraocular lens (IOL) models was evaluated. 24 patients (48 eyes) after cataract surgery were enrolled in the study. Follow-up was 12 months. 1st group included 9 patients (18 eyes) after cataract surgery and implantation of Russian trifocal refractive-diffractive IOL MIOL-Record 3. 2nd group included 6 patients (12 eyes) after cataract surgery and implantation of Russian bifocal refractive-diffractive IOL MIOL-Accord 3. 3rd group included 9 patients (12 eyes) after cataract surgery and implantation of Russian monofocal IOL MIOL-2. Stereoscopic vision was evaluated using "Stereopsis" software with 25 cm distance 1 week, 1, 3, 6, 12 months after surgery. Clinical study did not reveal any statistically significant difference between groups (trifocal, bifocal and monofocal IOLs) in terms of stereopsis (p > 0.05). Stereopsis parameters were stable during the whole follow up period. Clinical study evaluating stereoscopic vision in patients after binocular implantation of different IOLs shows that patients with binocular implantation of bifocal and trifocal IOLs have good and stable stereoscopic vision parameters after surgery at least equal to patients with monofocal IOLs. PMID- 23650746 TI - [Complications after cataract extraction with intraocular lens implantation in infants aged 1-12 months]. AB - Postoperative complications after cataract extraction with intraocular lens (IOL) implantation in infants aged 1-12 months were studied. 97 children (138 eyes) were examined and cataract was extracted with IOL implantation. The most severe complications were observed in children with persistent hyperplastic primary vitreous syndrome, that requires development of methods and indications for surgery. Results of cataract surgery in infants depend on operator's experience in pediatric cavity surgery. PMID- 23650747 TI - [Differential diagnosis of early central choroidal melanoma and late stage age related macula degeneration]. AB - Clinical signs characteristic for early central choroidal melanoma (42 patients) and late stage age-related macula degeneration according to AREDS (47 patients) were determined in 89 patients. These signs allow to differentiate between tumor and degenerative process thus providing appropriate treatment. PMID- 23650748 TI - [Vitrectomy effect on ocular hydrodynamics in proliferative diabetic retinopathy and nonvascular pathology]. AB - The goal of the study was to determine vitrectomy effect on ocular hydrodynamics. Patients were divided into 2 groups: patients with diabetes mellitus (DM) were enrolled in the 1st group, indications for vitrectomy were vitreous hemorrhage or diabetic macula edema. The 2nd group included patients without DM, indications for vitrectomy were macula hole, epiretinal fibrosis. Electronic tonography was used to measure the main ocular hydrodynamic parameters before and 2-12 months after the surgery. Though intraocular pressure (IOP) increased after vitrectomy in all patients, the true IOP was normal in the majority of them (60%) and did not require medical correction. In the rest of cases IOP increase required medical treatment: in 23% during 1 month, in 11% during 6-12 months. In subsequent follow-up during 2 years no glaucoma signs were revealed. PMID- 23650749 TI - [Mechanical corneal injury diagnosis using infrared spectroscopy]. AB - Method for express diagnosis of mechanical corneal injury using infrared spectroscopic analysis of tear fluid is proposed. Differential diagnosis of open and closed corneal injuries in absence of clinical data is presented. Clinical material is provided by patients with open globe injuries--25 patients (25 eyes) and 25 patients (25 eyes) with closed globe injuries. 20 healthy adults (40 eyes) were included into the control group. Proposed method allows to develop treatment strategy, determine extent of surgical interventions in corneal trauma and predict the course of posttraumatic process and complications as well. PMID- 23650750 TI - [Corneal ulcer caused by Serratia marcescens: case report]. AB - A case of corneal ulcer caused by Serratia marcescens is reported in a patient with history of corneal microtrauma. Biological features (pathogenicity factors, antibiotic resistance) of isolated culture were characterized. Keratitis cases caused by this agent were analyzed. PMID- 23650751 TI - [Morphology and medical correction of reparative regeneration processes in corneal injury]. AB - Analysis of current literature on morphology of wound processes in the cornea during up-to-date techniques effecting keratogenesis is performed. PMID- 23650752 TI - [Keratoconus. Diagnostic and monitoring methods]. AB - Up-to-date methods for diagnosis and monitoring of keratoconus are reviewed. Main advantages and drawbacks in early keratoconus diagnosis are analyzed for such methods as videokeratography, ultrasound corneal pachymetry, aberrometry, scanning projection corneal topography, confocal microscopy. PMID- 23650753 TI - [Ocular signs in anterior and posterior cervical sympathetic syndrome]. AB - Features of anatomy and morphological changes of cervical spine resulting in sympathetic innervation defects, blood supply deficiency and ocular symptoms are reviewed. Results of experimental and clinical studies showing correlation of sympathetic cervical ganglions irritation and ocular pathologic conditions are presented. Ocular involvement in neurologic changes in anterior and posterior cervical sympathetic syndrome are reviewed. PMID- 23650754 TI - [Ocular changes in systemic atherosclerosis]. AB - Up-to-date aspects of ocular changes in systemic atherosclerosis are reviewed. At the present time despite of wide use of current methods of ocular blood circulation and retina examination there are no papers that allow to estimate dynamics of impairment of visual functions from different viewpoints (clinical, functional, blood flow, morphological etc.) in initial isolated ocular atherosclerosis. Etiology, pathogenesis and ideas about potential effect of systemic atherosclerosis on the eye are discussed. Features of blood flow in optic nerve head compared to retinal vessels are described. According to the last data correlation between the degree of reduction of a-wave of scotopic electroretinogram and deterioration of haemodynamic parameters exists. PMID- 23650755 TI - [A 40 year old palatal neurofibroma. A case report]. AB - Neurofibroma is a benign peripheral nerve sheath tumour, which arises from Schwann cells and perineural fibroblasts. It is one of the most frequent tumours of neural origin and its presence is one of the clinical criteria for the diagnosis of type 1 neurofibromatosis (NF-I) also known as von Recklinghausen's disease (VRD). Oral localization is rarer showing an incidence ranging from 4 to 7% in most series of different authors. The most frequent involvement site in oral neurofibromatosis is the tongue, followed by the oral mucosa and floor of the mouth; palate and maxillary-mandibular bones are a rare localization of the disease. The aim of this article is to report a case of NF-I with a huge, quite old palatal involvement and its treatment. PMID- 23650756 TI - [Complex prosthetic rehabilitation of a patient with temporomandibular dysfunction. Case report]. AB - There are varying opinions regarding the contribution of occlusal interferences to the development and progression of temporomandibular dysfunction (TMD). Several studies have demonstrated that the use of occlusal adjustment might prevent the development of TMD and the exacerbation of its symptoms. Since the aetiology of TMD is multiple, the prosthodontic treatment cannot always be sufficient, but tends to be effective in some cases. The present article describes a case of a complex prosthetic rehabilitation of a patient with TMD that originates from her previous prosthesis, resulting in reduced vertical dimension. Treatment included the registration of vertical and horizontal dimensions of occlusion by gothic arch (arrow-point) tracing. Degrees of the mandibular movement were recorded by digital axiograph (ARCUSdigma-KaVo) and transferred to a semi-adjustable articulator (KaVo Protar 5B). Appropriate vertical and horizontal occlusal dimensions and individual mandibular movements were then transferred to the final prosthesis. PMID- 23650757 TI - [Minimally invasive method for the restoration of localized anterior tooth wear. A case report]. AB - Wear localized on front teeth is quite common; the restoration of the lost tissue is generally difficult due to the lack of vertical space between the upper and lower teeth. The traditional prosthetic method would include further tooth preparation for complete crowns and for increasing the occlusal vertical dimension. By applying the Dahl concept the necessary vertical space can be created with the preservation of the tooth tissue in a relatively short period of time. Definitive restoration can be made for the replacement of lost enamel and dentine with a direct or indirect method. Due to the Dahl concept the preparation of the teeth and its potentially harmful consequences can be avoided, the treatment is non- or minimally invasive. In the presented case the lost palatal and incisal tooth tissue was replaced with palatal E.max Press ceramic laminate. After cementing the laminate the patient was advised to wear a night guard, because of bruxism, to counteract the extreme load on the laminates. PMID- 23650758 TI - [Complete attendance of a caries risk patient]. AB - An adult caries high risk patient reported to the clinic with acute complaint. After an adequate pain control patient was motivated to participate in the required periodontal, oral surgical, conservative dental and prosthodontic treatment. Based on her DMF-index scores, periodontal and plaque indexes, and high rates for Streptococcus mutans (CRT-test), and also her inappropriate diet deriving from her financial and social standing, the 38-year-old female patient was considered as a caries high risk patient. After oral hygienic instruction, motivation, supra and subgingival scaling, and extraction fillings and root canal treatments (including revisions as well) were carried out. Finally complete functional and esthetic rehabilitation have been fulfilled by fixed restorations. Caries is a widespread disease in Hungary, affecting 98,8% of the adult population. According to recent statistics despite an improving tendency, the application of many patients with the need of an entire dental rehabilitation is expected. Besides the importance of prevention and regular controls the treatment planning and the execution of a complete dental treatment remain a rather complex task even without the presence of any systemic diseases. The patients' co operation may be obtained after a comprehensive medical history and by means of different methods (bacterial tests, plaque indexes etc.) which demonstrate the results, to assure a sufficient and longterm outcome. PMID- 23650759 TI - [Prevalence of hypodontia at the department of pedodontics and orthodontics of Semmelweis University]. AB - Examination of hypodontia as one of the most frequent developmental disorder receives high importance in the national as well as in the international literature. As the disorder can affect the dental and mental development of the children therefore early diagnosis and treatment are necessary. The authors analyzed the OP radiograms of patients aged 6 to 18 who were registered between 2006 and 2011 at the Department of Pedodontics and Orthodontics of Semmelweis University, excluding children suffering from general diseases or other syndromes. The aim of the examination was to determine the occurrence of missing teeth germ cases in the registered database of the Department, diagnose the prevalence of aplasia and compare the results with the national and international literature. Out of the 900 patients (372 boys and 528 girls) included in the examination missing germs were diagnosed in 94 cases (10,44%). In most cases the germ of the lower second premolars was missing (34,64%), then came the upper lateral incisors (27,38%) and the aplasia of the upper second premolars (21,23%). There was no relevant difference between the two sides. The number of affected girls was higher by 25% than the number of boys. Most of the results are close to the result in international literature. PMID- 23650760 TI - [Change in condylar and mandibular morphology in juvenile idiopathic arthritis: cone beam volumetric imaging]. AB - The aim of this study is to show the importance of Cone Beam Computerized Tomography to volumetrically quantify TMJ damage in patients with JIA, measuring condylar and mandibular real volumes. 34 children with temporomandibular involvement by Juvenile Idiopathic Arthritis were observed by Cone Beam Computerized Tomography. 4 were excluded because of several imaging noises. The mandible was isolated from others craniofacial structures; the whole mandibular volume and its components' volumes (condyle, ramus, hemibody, hemisymphysis on right side and on left side) has been calculated by a 3D volume rendering technique. The results show a highly significant statistical difference between affected side volumetric values versus normal side volumetric values above all on condyle region (P < 0.01), while they don't show any statistical differences between right side versus left side. The Cone Beam Computerized Tomography represents a huge improvement in understanding of the condyle and mandibular morphological changes, even in the early stages of the Juvenile Idiopathic Arthritis. The JIA can lead in children to temporomandibular joint damage with facial development and growth alterations. PMID- 23650761 TI - ["Osteobiol" and other bone graft materials used in Hungary]. AB - In the first part of a series of publications in connection with different bone graft materials we review the literature by hungarian authors in the topic. In the last 10 years (2001-2011) 12 articles were published in the Fogorvosi Szemle and 11 articles in other Hungarian journals. 34 articles were published by Hungarian authors in foreign journals. These articles present results with autologous bone, bovine xenografts and synthetic bone graft materials. The literature concludes that beta-tricalcium phosphate and all previously mentioned materials present satisfactory results in bone augmentation procedures. Based on histological and histomorphometrical analysis in the case of large bony defects (large cysts, sinus elevation) the use of beta-tricalcium phosphate ensures better long term results in terms of "rebuilding" of the bone. We present a bone graft material new in Hungary: "Osteobiol", which differs from other bone graft materials in the sense it is a mixture of porcine bone and collagen. The authors summerize the material science of different bone graft materials including "Osteobiol". PMID- 23650762 TI - [Guidelines on the pharmacotherapy of the dental patient during pregnancy]. AB - Physiological differences occuring in pregnancy modify certain steps of dental treatments. Since in our everyday practice we meet expectant patients, we have to be aware of what kind of changes does this transitional state require from the dentist, how to do a good timing in the course of dental treatment, which are those medicaments that can be used safely and those which should be avoided. The summerized data in the article are to contribute the safe choice of the possibly necessary antibiotics during the treatments. Besides, dental care should not be delayed due to our doubts about local anestetics, because it may carry serious consequences later. Relying on the most up-to-date facts, moreover, we mention the guidelines of the use of analgesics during pregnancy in dentistry. The treatment of pregnant women does not differ to a high degree from those who are non-pregnant, yet some of its viewpoints need special attention and we have to take them into consideration in order to do the appropriate medical work. Basically, in our opinion, before every dental and dental surgical intervention it is essential to consult with the patient's gynaecologist and in agreement with him/her to determine the course of the medicinal treatment. PMID- 23650763 TI - Work safety among Polish health care workers in respect of exposure to bloodborne pathogens. AB - OBJECTIVES: Viral hepatitis is the second most often identified infectious illness acquired at work and it is mostly registered among health care personnel. This group of workers is at greater risk of exposure to blood and bloodborne pathogens, including hepatitis B and C viruses. The aims of this study were to evaluate the efficacy of methods promoting work safety in healthcare settings, to assess the frequency of exposures in the last 12 months prior to the study and to determine a rate of reporting them to appropriate authorities. METHODS: A total of 1138 Polish healthcare workers were interviewed during the study period (between 2009 and 2010). RESULTS: Sustaining accidental occupational percutaneous exposure during last 12 months was declared by 242 workers (21% of the whole group). Only in 146 cases these incidents were reported to authorities. Exposure incidents were associated with self-perception of high risk of exposure (OR = 3.69, p = 0.0027), employment in out-patient (vs. hospital-based) healthcare setting (OR = 1.71, p = 0.0089), conviction that the level of information about bloodborne infections conveyed at work was insufficient, lack of both exposure reporting system and knowledge about the ways of reporting. CONCLUSIONS: Despite the different established proposals of the post-exposure procedures, it turns out that particularly in small, not providing 24 hours service healthcare settings these procedures are not known or are not respected. More attention should be given to education, especially in regard to the risk of infection, advantages of post-exposure prophylaxis and reporting exposure incidents. PMID- 23650764 TI - Evaluation of activities aimed at preventing microbiological risks in dental practice. AB - BACKGROUND: Microbiological contamination of water in dental unit waterlines (DUWL) creates a risk of cross-infections, and is a source of biological risk factors in the work environment of a dentist. The aim of the study was to evaluate dentists' knowledge on DUWL microbiological contamination and the scope of activities/procedures they undertake to monitor it. MATERIALS AND METHOD: The questionnaire survey was conducted in 2010 among 107 Polish dentists using dental units in everyday clinical practice. RESULTS: It has been found that in their daily practice, dentists do not follow procedures leading to reduction or elimination of microbiological contamination of dental unit reservoir water. They are not aware of microbiological contamination of DUWL that supply working handpieces with water. They are unaware of the principles of dealing with dental water and water supply systems or the health risk posed by microbiological contamination of unit water for a dental team and patients. CONCLUSIONS: It is necessary to provide dentists with information on microbiological contamination of water in dental units, on the correct procedures of handling water and waterlines that supply working handpieces with water. PMID- 23650765 TI - [Age and duration of employment of health care workers with occupational viral hepatitis B and C]. AB - BACKGROUND: In this paper we present the study of the incidence of hepatitis B and C among health care workers in the Pomorskie voivodeship in the years 1999 2009. The aim of the study was to analyze the relationship between the certified occupational HCV and HBV infections and the age and duration of employment of infected health care workers. MATERIAL AND METHODS: To analyze the epidemiological situation of occupational hepatitis among health care workers in the Pomorskie voivodeship, the data 338 occupational disease certificates were obtained. RESULTS: Of the 338 certified cases of occupational viral hepatitis during this period 222 (65.7%) cases were diagnosed with hepatitis B, and 116 (34.3%) with hepatitis C. The total number of health care workers included 301 (89%) women, and 37 (11%) men. The majority of occupational hepatitis cases occurred in the following age groups 45-49, 40-44, 50-54 and 35-39 years. The mean age for the whole population was 46.20 years. The average duration of employment was 18.34 years, and it was lower for women than for men by 1.71 years (18.15 vs. 19.86). The cases of hepatitis mostly occurred during the periods of 15-19, 20-24 and 25-29 years of employment (50% of cases). CONCLUSIONS: These data suggest that the employees used to postpone the procedure of occupational disease certification. Short work experience confirms a higher risk of infection among employees of analytical laboratories and dental offices. The relationship between a higher risk of infection in workers and a shorter duration of employment (little work experience) was evidenced. PMID- 23650766 TI - [Nonlinear acoustic analysis in the evaluation of occupational voice disorders]. AB - BACKGROUND: Over recent years numerous papers have stressed that production of voice is subjected to the nonlinear processes, which cause aperiodic vibrations of vocal folds. These vibrations cannot always be characterized by means of conventional acoustic parameters, such as measurements of frequency and amplitude perturbations. Thus, special attention has recently been paid to nonlinear acoustic methods. The aim of this study was to assess the applicability of nonlinear cepstral analysis, including the evaluation of mel cepstral coefficients (MFCC), in diagnosing occupational voice disorders. MATERIAL AND METHODS: The study involved 275 voice samples of pathologic voice (sustained vowel "a" and four standardized sentences) registered in female teachers with the occupation-related benign vocal fold masses (BVFM), such as vocal nodules, polyps, and 200 voice samples of normal voices from the control group of females. The mean age of patients and controls was similar (45 vs. 43 years). Voice samples from both groups were analyzed, including MFCC evaluation. RESULTS: MFCC classification using the Sammon Mapping and Support Vector Machines yielded a considerable accuracy of the test. Voice pathologies were detected in 475 registered voice samples: for vowel "a" with 86% sensitivity and 90% specificity, and for the examined sentences the corresponding values varied between 87% and 100%, respectively. CONCLUSIONS: Nonlinear voice analysis with application of mel cepstral coefficients could be a useful and objective tool for confirming occupational-related lesions of the glottis. Further studies addressing this problem are being carried out. PMID- 23650767 TI - [Etiological factors for developing carpal tunnel syndrome in people who work with computers]. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is the most frequent mononeuropathy of upper extremities. From the early 1990's it has been suggested that intensive work with computers can result in CTS development, however, this relationship has not as yet been proved. The aim of the study was to evaluate occupational and non occupational risk factors for developing CTS in the population of computer-users. MATERIAL AND METHODS: The study group comprised 60 patients (58 women and 2 men; mean age: 53.8 +/- 6.35 years) working with computers and suspected of occupational CTS. A survey as well as both median and ulnar nerve conduction examination (NCS) were performed in all the subjects. RESULTS: The patients worked with use of computer for 6.43 +/- 1.71 h per day. The mean latency between the beginning of employment and the occurrence of first CTS symptoms was 12.09 +/ 5.94 years. All patients met the clinical and electrophysiological diagnostic criteria of CTS. In the majority of patients etiological factors for developing CTS were non-occupational: obesity, hypothyroidism, oophorectomy, past hysterectomy, hormonal replacement therapy or oral contraceptives, recent menopause, diabetes, tendovaginitis. In 7 computer-users etiological factors were not identified. CONCLUSION: The results of our study show that CTS is usually generated by different causes not related with using computers at work. PMID- 23650768 TI - [Respiratory symptoms among industrial workers exposed to water aerosol. A pilot study of process water and air microbial quality]. AB - BACKGROUND: The frequency of respiratory symptoms in workers exposed to water aerosol was evaluated along with the preliminary assessment of microbiological contamination of air and water used in glass processing plants. MATERIAL AND METHODS: A questionnaire survey was conducted in 131 workers from 9 glass processing plants. Questions focused on working conditions, respiratory symptoms and smoking habits. A pilot study of air and water microbiological contamination in one glass processing plant was performed. Water samples were tested for Legionella in accordance with EN ISO 11731-2:2008 and for total colony count according to PN-EN ISO 6222:2004. Air samples were tested for total numbers of molds and mildews. RESULTS: During the year preceding the survey acute respiratory symptoms occurred in 28.2% of participants, while chronic symptoms were reported by 29% of respondents. Increased risks of cough and acute symptoms suggestive of pneumonia were found among the respondents working at a distance up to 20 m from the source of water aerosol compared to other workers (OR = 2.7), with no difference in the frequency of other symptoms. A microbiological analysis of water samples from selected glass plant revealed the presence of L. pneumophila, exceeding 1000 cfu/100 ml. The number of bacteria and fungi detected in air samples (above 1000 cfu/m3) suggested that water aerosol at workplaces can be one of the sources of the air microbial contamination. CONCLUSIONS: The questionnaire survey revealed an increased risk of cough and acute symptoms suggestive of pneumonia in the group working at a shortest distance form the source of water aerosol. PMID- 23650769 TI - [Potential exposure to silver nanoparticles during spraying preparation for air conditioning cleaning]. AB - BACKGROUND: Unique properties of engineered nanomaterials (ENMs) and products made of them have contributed to a rapid progress in the production and application of ENMs in different branches of industry and in factories with different production scale. Bearing in mind that nano-objects (nanoplates, nanofibres, nanoparticles), emitted during ENM production and application, can cause many diseases, even those not yet recognized, extensive studies have been carried all over the world to assess the extent of exposure to nano-objects at workstations and related health effects in workers employed in ENM manufacture and application processes. MATERIAL AND METHODS: The study of potential exposure to silver nanoparticles contained in the preparation for air-conditioning cleaning (Nano Silver from Amtra Sp. z o.o.) involved the determination of concentrations and size distribution of particles, using different devices, allowing for tracing changes in a wide range of dimensions, from nano-size (10 nm) to micrometer-size (10 pm), of the particles which are usually inhaled by humans. RESULTS AND CONCLUSIONS: The results of the study shows that even during a short-term spraying of Nano Silver preparation (for 10 s) at the distance of 52 cm from the place of preparation spraying--particles of 10 nm-10 microm can be emitted into in the air. During a three-fold preparation spraying in similar conditions differences in concentration increase were observed, but in each case the particles remained in the air for a relatively long time. PMID- 23650770 TI - [Occupational exposure of welders to ultraviolet and "blue light" radiation emitted during TIG and MMA welding based on field measurements]. AB - BACKGROUND: The aim of the study was to present the results of welders' occupational exposure to "blue light" and UV radiation carried out at industrial workstations during TIG and MMA welding. MATERIALS AND METHODS: Measurements were performed at 13 workstations (TIG welding: 6; MMA welding: 7), at which different welding parameters and materials were used. The radiation level was measured using a wide-range radiometer and a set of detectors, whose spectral responses were adequately fit to particular hazard under study. The measurement points corresponded with the location of eye and hand. RESULTS: The highest values of eye irradiance were found for aluminum TIG welding. Effective irradiance of actinic UV was within the range E(s) = 7.79-37.6 W/m2; UVA total irradiance, E(UVA) = 18-53.1 W/m2 and effective blue-light irradiance E(B) = 35-67 W/m2. The maximum allowance time ranged from 1.7 to 75 s, which means that in some cases even unintentional very short eye exposure can exceed MPE. CONCLUSIONS: The influence of welded material and the type of electrode coating on the measured radiation level were evidenced. The exceeded value of MPE for photochemical hazard arising for the eyes and skin was found at all measured workstations. Welders should use appropriately the eye and face protective equipment and avoid direct staring at welding arc when starting an arc-welding operation. Besides, the lack of head and neck skin protection can induce acute and chronic harmful health effects. Therefore, an appropriate wear of personal protective equipment is essential for welders' health. PMID- 23650771 TI - [The influence of organic solvents on hearing and balance: a literature review]. AB - This manuscript presents an overview of current knowledge on the influence of organic solvents on the hearing and balance systems. The authors analyzed--the literature data concerning the results of all human and the most relevant animal studies, published untill 2012. Moreover, the guidelines for occupational medicine specialists were proposed on the basis of literature review and the authors' own scientific experience. The literature data and our studies revealed the increased risk of hearing loss in workers exposed to organic solvents only, and well documented potentiation of harmful effects of combinedexposure to organic solvents and noise. Hearing impairment is mainly observed in high frequencies, but lower frequencies can also be involved (0.5-4 kHz). The impairment induced by exposure to organic solvents is mild, up to several dBs. In the combined exposure to noise and solvents, the noise effect predominates. Organic solvents affect the central pathways of vestibular system although unilateral or bilateral vestibular hypofunction might also be a possible consequence of solvent exposure. Occupational exposure to organic solvents is a risk factor for hearing and balance impairments. Therefore, workers exposed to solvents should be covered by hearing loss prevention programs. Speech in noise test (HINT) and posturography seem to be the most suitable tests for hearing and balance prevention programme for organic solvent exposed workers. PMID- 23650772 TI - [Adverse cutaneous reactions induced by exposure to woods]. AB - Various adverse cutaneous reactions may occur as a result of exposure to wood dust or solid woods. These include allergic contact dermatitis, irritant contact dermatitis and, more rarely, contact urticaria, photoallergic and phototoxic reactions. Also cases of erythema multiforme-like reactions have been reported. Contact dermatitis, both allergic and irritant, is most frequently provoked by exotic woods, e.g. wood of the Dalbergia spp., Machaerium scleroxylon or Tectona grandis. Cutaneous reactions are usually associated with manual or machine woodworking, in occupational setting or as a hobby. As a result of exposure to wood dust, airborne contact dermatitis is often diagnosed. Cases of allergic contact dermatitis due to solid woods of finished articles as jewelry or musical instruments have also been reported. The aim of the paper is to present various adverse skin reactions related to exposure to woods, their causal factors and sources of exposure, based on the review of literature. PMID- 23650773 TI - [Influenza vaccinations of health care personnel]. AB - Influenza is one of the most common respiratory diseases affecting people of all age groups all over the world. Seasonal influenza leads to substantial morbidity and mortality on a global scale. Vaccines are undeniably one of the most important health advances of the past century, however, managing influenza in working populations remains a difficult issue. Vaccination of health care workers (HCW) is an efficient way to reduce the risk of occupational infection and to prevent nosocomial transmission to vulnerable patients. Despite this, achieving high immunization rates among those professionals is a challenge. Knowledge and attitudes of healthcare providers have significant impact on the frequency with which vaccines are offered and accepted, but many HCWs are poorly equipped to make informed recommendations about vaccine merits and risks. Principal reasons for vaccination are the willing not to be infected and avoiding transmission to patients and the family. The main reasons for refusing is lack of time, a feeling of invulnerability to vaccination, conviction of not being at risk, of being too young or in good health. Misconceptions about influenza vaccine efficacy, like adverse effects, and fear of contracting illness from the vaccine are significantly associated with noncompliance with vaccination. Therefore, strategies to increase awareness of the importance of recommending influenza immunization among health professionals are required. PMID- 23650774 TI - [XIX International Symposium on Ergonomics, Work Safety and Occupational Hygiene: "practical problems related with work protection in agriculture"]. PMID- 23650775 TI - Liver progenitor cells and therapeutic potential of stem cells in human chronic liver diseases. AB - Liver progenitor cells, thought to reside in the terminal bile ductules (canals of Hering) at the interface between portal tracts and liver lobule, proliferate during severe hepatic injury. They may contribute to hepatocyte regeneration, or even take over this role if the liver injury is severe and associated with an impairment of hepatocyte proliferation. They represent promising targets in an attempt to stimulate liver regeneration in chronic diseases. Recent studies on liver progenitor cell recruitment in response to injury in chronic viral hepatitis B, hepatitis C, alcoholic and non-alcoholic liver diseases are presented in this review, as well as clinical trials in which stem cells are administered as a therapeutic intervention to promote liver regeneration. Liver progenitor cell expansion is part of the disease process itself and may contribute to disease severity, mainly related to fibrosis. As the majority of these progenitor cells tend to acquire a biliary phenotype, their role in liver repair and improvement in liver function remains to be addressed. Present data on stem cell therapy are heterogeneous in terms of methods and endpoints; thus, results need to be carefully examined prior to drawing a conclusion on possible benefits. PMID- 23650776 TI - The roles of mesenchymal stem cells in gastric lesion and regeneration: applications in gastric diseases. AB - In recent years, many studies have focused on the roles of mesenchymal stem cells (MSCs) due to their contribution to tissue regeneration and tumorigenesis. However, the full profile of the roles of MSCs in gastric diseases has not been established. In this review, we aim to provide an overview on the roles of MSCs on cell lesion and regeneration in gastric diseases, including gastric ulcer, premalignant conditions and cancer. We will also discuss the mechanisms underlying the behaviors of MSCs in these diseases. PMID- 23650777 TI - Probiotics and IBD. AB - The pathophysiology of inflammatory bowel disease is still incompletely understood. While the development of the immune system and the establishment of the microflora take place during infancy young patients often have a more severe and extensive disease. The differences in composition and concentration of intestinal microbiota and aberrant immune responses towards the luminal bacteria prompted the concept of an 'ecological' approach to control the disease course. Probiotics, living, non pathogenic micro organisms with a beneficial effect on the host, and prebiotics, oligosaccharides promoting the growth of the beneficial microflora, have been studied to this effect. Results have so far been disappointing for Crohn's disease but encouraging for ulcerative colitis. An overview of studies using probiotics in adults or children and a perspective on specific pediatric issues is provided in this review. PMID- 23650778 TI - Risk factors associated with recurrent hemorrhage after the initial improvement of colonic diverticular bleeding. AB - We elucidated risk factors contributing to recurrent hemorrhage after initial improvement of colonic diverticular bleeding. 172 consecutive hospitalized patients diagnosed with colonic diverticular bleeding were analyzed. Recurrent hemorrhage after initial improvement of colonic diverticular bleeding is main outcome measure. We analyzed factors contributing to recurrent hemorrhage risk in univariate and multivariate analyses. The length of the observation period after improvement of colonic diverticular bleeding was 26.4 +/- 14.6 months (range, 1 79 months). The cumulative recurrent hemorrhage rate in all patients at 1 and 2 years was 34.8% and 41.8%, respectively. By univariate analysis, age > 70 years (P = 0.021), BMI > 25 kg/m2 (P = 0.013), the use of anticoagulant drugs (P = 0.034), the use of NSAIDs (P = 0.040), history of hypertension (P = 0.011), history of smoking (P = 0.030) and serum creatinine level > 1.5 mg/dL (P < 0.001) were found to be significant risk factors for recurrent colonic diverticular bleeding. By multivariate analysis, age > 70 years (Hazard ratio (HR), 1.905, 95% confidence interval (CI), 1.067-3.403, P = 0.029), history of hypertension (HR, 0.493, 95% CI, 0.245-0.993, P = 0.048) and serum creatinine level > 1.5 mg/dL (HR, 95% CI, 0.288-0.964, P = 0.044) were shown to be significant independent risk factors. Close observation after the initial improvement of colonic diverticular bleeding is needed, especially in elderly patients or patients with history of hypertension or renal deficiency. PMID- 23650779 TI - Evolution of colorectal cancer epidemiology in a setting of opportunistic screening. A 20 year national survey in Luxembourg. AB - Invasive colorectal cancer (CRC) is the second leading cause of cancer death in Luxembourg. There is no organized screening programme in Luxembourg. This study aims to obtain a precise epidemiological description of the evolution of invasive CRC and high grade intraepithelial neoplasia (HGIEN) from 1990 to 2009, extracted from the database of the Morphologic Tumor Registry. Tumor stages and observed survival rates were also recorded. They were compared to the change in use of colonoscopic procedures. During the 20-year period, 4810 invasive CRC cases and 1180 HGIEN were recorded. Incidence rose from 1990 to 2005 and declined thereafter, especially in women. A sharp rise in HGIEN was noted from 2004 onwards, paralleling the rates of colonoscopies. 76% of CRC cases were found in advanced stages pT3 and pT4. The pT stage distribution did not change over the observation period. Observed survival rates improved during the study period. CONCLUSION: Under opportunistic screening conditions, mainly through colonoscopy, the incidence of CRC was declinig in recent years, whereas HGIEN incidence is rising in Luxembourg. Tumor pT staging remained unchanged whereas survival rates improved. We conclude that opportunistic screening is of little benefit for CRC prevention. A national organized screening programme is warranted. PMID- 23650780 TI - Twice a day quadruple therapy for the first-line treatment of Helicobacter pylori in an area with a high prevalence of background antibiotic resistance. AB - BACKGROUND/AIMS: Bismuth-containing quadruple therapy given four times a day is effective in the first-line treatment of Helicobacter pylori. We aimed to investigate whether twice daily posology could eradicate H. pylori at a comparable rate in an area with a high prevalence of antibiotic resistance. MATERIALS AND METHODS: The study group consisted of 90 patients with treatment naive H. pylori. Patients were randomized to BOMT1 group (Bismuth citrate 2 x 600 mg, omeprazole 2 x 20 mg, metronidazole 2 x 500 mg, tetracycline 2 x 500 mg; for 14 days) and BOMT2 group (Bismuth citrate 2 x 600 mg, omeprazole 2 x 20 mg, metronidazole 3 x 500 mg, tetracycline 4 x 500 mg; for 14 days). H. pylori eradication was assessed by both C14-urea breath test and stool antigen test at least 8 weeks after treatment. RESULTS: Demographic characteristics and endoscopy findings of the groups were similar. Eighty-two patients completed the study (BOMT1= 38 and BOMT2 = 44) including H. pylori eradication assessment. The eradication rates determined by PP and ITT analyses were 86.8% and 733% for BOMT1 group, 90.1% and 88.9% for BOMT2 group, respectively. BOMT1 was found to be non inferior to BOMT2 treatment. Patients in BOMT2 group had a significantly higher rate of drug associated adverse events than BOMT1 (34.1% vs 9.3%; p = 0.008). CONCLUSIONS: Twice a day quadruple therapy is as effective as four times a day quadruple therapy in the first line treatment of H. pylori in a country with high resistance to metronidazole and clarithromycin and is more tolerable. PMID- 23650781 TI - Vitamin D levels in Egyptian HCV patients (genotype 4) treated with pegylated interferon. AB - BACKGROUND/AIM: Vitamin D has been shown to play an important immunomodulatory role. Deficiency of vitamin D has been recently associated to the lack of response to interferon therapy in Hepatitis C virus genotype 1 infected patients. This study aims to evaluate serum level of vitamin D and verify whether circulating vitamin D has any independent role in predicting the rates of HCV virologic response after the administration of pegylated interferon to Egyptian patients infected with genotype 4 HCV. METHODS: Fifty patients infected with HCV genotype 4 and not co-infected with neither Hepatitis B virus nor Human Immunodeffiency Virus were recruited for the study. They were treated with ribavirin-pegylated interferon alpha 2a. Viral titer was determined at baseline, at 12 weeks and at end of treatment (48 weeks). Vitamin D levels and a biochemical profile were obtained for the patients at baseline and at end of treatment. Vitamin D control group consisting of 20 healthy patients of similar age and weight to the study group were recruited to obtain vitamin D levels. RESULTS: Vitamin D levels in HCV infected patients were significantly lower than in healthy subjects. Responders to ribavirin plus pegylated interferon alpha 2a therapy had significantly higher vitamin D levels than non-responders. CONCLUSION: Vitamin D deficiency predicts an unfavorable response to interferon based treatment of HCV. PMID- 23650782 TI - MR enterography in children with Crohn disease: results from the Belgian pediatric Crohn registry (Belcro). AB - INTRODUCTION: Magnetic Resonance enterography (MRE) is an imaging modality avoiding ionizing radiation and the discomfort associated with enteroclysis. The results of MRE at diagnosis in the patients of the Belgian pediatric Crohn registry (Belcro) are compared to endoscopical and histological results. METHODS: Results of MRE, endoscopy and histology were obtained from the medical charts and assigned to one of the following segments: jejunum, ileum, ascending colon, transverse colon, descending colon or rectosigmoid. MRE images were reviewed in a blinded way by 4 radiologists with specific interest in pediatric MRE. RESULTS: From the Belcro registry, twenty-two patients underwent a MRE during their work up for Crohn disease. The results of endoscopy, histology and MRE were concordant (either all negative or positive) in the ileum in 16/18 patients and in the rectosigmoid, descending colon, transverse colon and ascending colon in resp 9, 8, 8 and 8/22 patients. In the non-concordant cases (MRE colon negative but endoscopy and/or histology positive), MRE could not reflect the subtle endoscopic or histologic lesions such as erosions that were described.In 4 cases where ileocaecal valve intubation was impossible ileal MRE findings were abnormal. MRE detected ileal stenosis, jejunal lesions and fistula in resp 4/22, 3/22 en 2/22 patients. The 100% and 75% interobserver agreement was resp 50-82% and 773-100% according to the different intestinal segments. CONCLUSIONS: MRE is a promising imaging modality avoiding radiation in Crohn disease. It should probably become the technique of first choice for the evaluation of extensive small bowel disease in children with Crohn disease. PMID- 23650783 TI - Towards a tailored therapy in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. As conventional treatments have shown only a modest impact on disease course, development of new therapeutic strategies based on the molecular biology of PDAC must be a high priority. The identification of relevant predictive and prognostic biomarkers which can be used to select patient subgroups that may benefit from conventional treatments and new targeted agents will be of considerable interest. We have demonstrated the ability of the metabolizing gemcitabine protein (the human Equilibrative nucleoside transporter 1 and the deoxycytidine kinase) in predicting the benefit of adjuvant gemcitabine-based therapy in resected PDAC patients. Beside these predictive biomarkers, we have evaluated different molecular factors that may impact on the likely course of this cancer. The chemokine receptor CXCR4 that has been shown to be implicated in PDAC tumorigenicity and aggressiveness could serve as a prognostic marker for survival after a curative-intent surgery and was associated with the pattern of tumour recurrence (distant versus local relapse). Our findings were validated in an independent cohort of patients. Overall our results suggested that (i) the benefit of an adjuvant gemcitabine-based therapy can be predicted based on the tumour expression of hENT1 and dCK, (ii) CXCR4 is an independent negative prognostic factor and an independent predictor of distant relapse suggesting that anti-CXCR4 targeting therapies can be a promising treatment in combination with cytotoxic chemotherapy in the adjuvant setting. These data open new perspectives for designing trials based on a molecular driven strategy. PMID- 23650784 TI - Acute cholecystitis caused by hemocholecyst: unusual clinical manifestation of gallbladder cancer. AB - Gallbladder cancer presenting as acute cholecystitis associated with a hemocholecyst is a rare entity. Up to date there are only 2 cases reported in literature. Acute cholecystitis may appear secondary to an obstruction of the cystic duct by the tumour itself or to an obstruction of the cystic duct by blood clots. CASE REPORT: A 74-years-old woman complained of right upper quadrant pain during the last 48 hours, associated to fever of 38 degrees C and vomits. Physical examination revealed a positive Murphy's sign. Laboratory data showed leukocytosis and mild increasement of liver enzymes. Ultrasonography revealed a mobile extense formation located antigravitatorily in fundus and body of the gallbladder. CT scan showed a mass adhered to the fundus and the body of the gallbladder without wall infiltration and contrast enhancement, suggestive of hemocholecyst. Laparoscopic cholecystectomy was performed, observing cholecystitis signs without any other relevant features. Pathology revealed a large amount of clotted blood inside the gallbladder, some of them obstructing the cystic duct; an irregularity was discovered in the gallbladder wall, whose microscopic analysis revealed a gallbladder adenocarcinoma, infiltrating up to the serosa (T3NxMx). The patient underwent a second operation with resection of the gallbladder bed and lymph node dissection of the hepatic hilium, without evidence of neoplastic infiltration. PMID- 23650785 TI - Colonic tuberculosis or Crohn's disease? An important differential diagnosis. AB - Abdominal tuberculosis can mimic any disease affecting the gastrointestinal tract such as infectious processes, tumors, periappendiceal abscess, and Crohn's disease. The differential diagnosis of Crohn's disease and intestinal tuberculosis is a dilemma to clinicians and pathologists as both are chronic granulomatous disorders with similar clinical features. Lower gastrointestinal bleeding is an infrequent presentation of both intestinal tuberculosis and Crohn's disease. Herein, we report a 56-year-old woman presenting with massive hematochezia due to isolated colon tuberculosis in whom the initial diagnostic work-up suggested Crohn's disease and review the current literature. Our report highlights the need for awareness of colonic tuberculosis in the differential diagnosis of massive hematochezia from Crohn's disease, especially before initiating treatment with immunosuppressive agents. PMID- 23650786 TI - Spontaneous liver bleeding in a patient with congenital arterioportal fistulisation. Presentation of a casus princeps and review of the literature. AB - We present the first case reported in the literature describing spontaneous liver haemorrhage due to diffuse arterioportal fistulae. A 48-year old Caucasian woman was admitted to the hospital complaining of acute epigastric pain eradiating to the right shoulder. Patient never had any penetrating or blunt abdominal trauma in the past nor any intervention on the liver. CT scan of the abdomen revealed a subcapsular haematoma originating from two bleeding sites in the right liver lobe. Arteriography of the common hepatic artery showed opacification of the portal branches, indicative of an arterioportal fistula. A hypertrophic feeding branch of the right hepatic artery was then embolized, resulting in disappearance of the fistula. After complete resolution of the haematoma, investigations to detect underlying liver lesions were repeatedly negative. Therefore we conclude that a diffuse congenital arterioportal fistula was the cause of spontaneous bleeding. This is to our knowledge the first case in whom a spontaneous liver bleeding secondary to diffuse arterioportal fistulisation is reported. A review of the literature regarding arterioportal fistulas and regarding the possible aetiology of spontaneous liver haematomas is provided. PMID- 23650787 TI - Inflammatory myofibroblastic tumor of the small bowel. PMID- 23650788 TI - Does endoscopic ultrasound-guided fine-needle aspiration of pancreatic cystic lesions provides adequate material for cytology and biochemical analysis? PMID- 23650789 TI - Pentoxifylline for slow to resolve hepatopulmonary syndrome post liver transplantation: helpful or unnecessary? PMID- 23650790 TI - Pineapple juice ingestion for gastric discomfort in diabetic gastroparesis. PMID- 23650791 TI - Ventricular tachyarrhythmia after adalimumab therapy in a patient with Crohn's disease. PMID- 23650792 TI - [Effect of electroacupuncture combined with cervical plexus block on stress responses in patients undergoing thyroid surgery]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) combined with cervical plexus block (CPB) on the stress response of patients undergoing thyroid surgery. METHODS: Forty thyroidectomy patients were randomly divided into sham EA plus CPB group (sham group) and EA+CPB group (20 cases in each group). For patients of the sham group, deep cervical plexus block (25% ropivacaine hydrochloride + 1% lidocaine hydrochloride) was performed first, followed by inserting acupuncture needles into bilateral Hegu (LI 4) and Neiguan (PC 6) separately without needle manipulation and then connecting the output wires of the EA therapeutic instrument to the handles of the acupuncture needles but without electric current output. For patients of the EA+CPB group, deep cervical plexus block was performed first followed by EA stimulation [10 Hz, (6 +/- 2) mA] of the bilateral LI 4 and PC 6 for 20 min. Systolic blood pressure (SBP), heart rate (HR) and breathing frequency were detected using a multipurpose monitor. Plasma adrenocorticotropic hormone (ACTH) and cortisol (Cor) contents were determined using chemiluminescence method, plasma epinephrine (E) level was detected by enzyme-linked immunosorbent assay, glucose (Glu) assayed by oxidase method, and plasma C-reactive protein (CRP) level detected using immumofluorescence technique. RESULTS: (1) During surgery, the patients' SBP and HR of both sham and EA groups were increased significantly compared with their basic values (P < 0.05), but the levels of the increased SBP and HR of the EA group were obviously lower than those of the sham group (P < 0.05). (2) The levels of plasma ACTH during surgery and at the immediate time after surgery, Cor level at the immediate time after surgery, plasma E and Glu contents during surgery, at the immediate time and on day 1 after surgery, and plasma CRP at the immediate time, and on day 1 and 3 after surgery in the sham group were upregulated considerably (P < 0.05), while the levels of plasma ACTH, Cor, E, Glu and CRP in the above-mentioned time-points of the EA group were all remarkably lower than those of the sham group (P < 0.05). CONCLUSION: EA combined with cervical plexus block significantly reduces peri-operative cardiovascular stress responses and inhibits abnormal increases of plasma stress hormones and inflammatory reaction in patients undergoing thyroid surgery. PMID- 23650793 TI - [Electroacupuncture intervention improved changes of skin barrier and color in type 2 diabetes rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) of auricular concha region (ACR), "Zusanli" (ST 36) and "Sanyinjiao"(SP 6) on abnormal skin barrier and color in streptozotocin (STZ)-induced type 2 diabetes mellitus (T 2 DM) rats so as to find a better therapeutic method. METHODS: Fifty male Sprague Dawley (SD) rats were randomized into control (n = 10), model (n = 13), EA-ST 36-SP 6 (n = 14) and EA-ACR (n = 13) groups. T 2 DM model was established by intraperitoneal injection of 1% STZ (50 mg/kg) and by feeding the animals with high-fat diet for 30 days. EA (15 Hz, 1 mA) was applied to bilateral "Zusanli" (ST 36), "Sanyinjiao" (SP 6) and ACR respectively for 30 min, once daily for 14 days. Multi Probe Adapter 9 skin measurement system (MPA 9) was used to measure the stratum corneum hydration (SCH), transepidermal water loss (TEWL), erythema index (El), melanin index (MI) and chromatic aberration values (L. a. b.) of the abdomenal and back (L1 - L6) skin, respectively. RESULTS: In comparison with the control group and pre-modeling, blood glucose contents of the model, EA-ST 36-SP 6 and EA-ACR groups were increased significantly (P < 0.01) after modeling. Compared with the model group, blood glucose levels of both EA-ST 36-SP 6 and EA ACR groups were down-regulated apparently (P < 0.01) after treatment. Thirty days after modeling, the SCH, TEWL, EI, MI, L. and a. levels of the back skin, and the SCH and L. levels of the abdominal skin were decreased significantly (P < 0.05), while the level of b. in the back skin, and those of TEWL, EL, a. and b. of the abdominal skin increased considerably in the model group (P < 0.05). After EA, the levels of SCH, TEWL MI, L. a. and b. in the EA-ST 36-SP 6 group, SCH, TEWL, L. and b. in the EA-ACR group of the back skin, and SCH, L. and b. of both EAST 36-SP 6 and EA-ACR groups, as well as EI and a. of the EA-ST 36-SP 6 group of the abdominal skin were reversed remarkably (P < 0.05). No significant differences were found between the EA-ST 36-SP 6 and model groups in the levels of El of the back skin, TEWL and MI of the abdominal skin, and between the EA-ACR and model groups in the levels of SCH, EI, MI and a. of the back skin, and TEWL, EI, MI and a. of the abdominal skin (P > 0.05). In spite of a mildly better therapeutic effect of EA-ST 36-SP 6 in regulating some of the abovementioned indexes, no significant differences were found between the two EA groups in all the indexes (P > 0.05). CONCLUSION: EA of both ST 36-SP 6 and ACR can effectively down regulate blood glucose level, suppress DM-induced decrease of SCH, TEWL, L. and a. of the back skin, and SCH of the abdominal skin, and down-regulate b. levels of the back and abdominal skin in T 2 DM rats, showing an improvement of the impaired skin barrier and color changes following EA intervention. PMID- 23650794 TI - [Effect of moxibustion of "dachangshu" (BL 25) area on pain reaction and TRPV 1 mRNA expression of bone marrow cells in visceral hyperalgesia rats]. AB - OBJECTIVE: To observe the effect of moxibustion of "Dachangshu" (BL 25) on pain reaction and expression of transient receptor potential vanilloid 1 (TRPV 1) of bone marrow cells in visceral hyperalgesia (VHA) rats so as to explore its mechanism underlying visceral pain-relief. METHODS: Twenty-eight male SD rats were divided into control group, control+moxibustion group, VHA model and VHA+moxibustion group (n = 7/group). The VHA model was made by giving colorectal distension (CRD, 60 mmHg) to the newborn rats for 1 min (repeated once again in 30 min) from postnatal day 8 on, once daily for a week. Moxibustion was applied to ipsilateral "Dachangshu"(BL 25) area for 40 min from the 8th week on after birth. Abdominal withdrawal reflex (AWR) and pain threshold during CRD were measured before and after moxibustion. The TRPV 1 mRNA expressio of bone marrow cells was detected by real time-POR. RESULTS: (1) The AWR score of the model group was significantly higher than that of the control group, but the pain threshold of the model group was significantly lower than that of the control group (P < 0.01), suggesting a VHA in model rats. (2) After moxibustion, the AWR scores were significantly lower in the VHA+moxibustion group than in the model group (P < 0.05, P < 0.01), and the pain threshold was remarkably higher in the former group than in the latter group (P < 0.01). Similar results were found in the control+moxibustion group compared to the control group: the decreased AWR scores (CRD 40 mmHg, 60 mmHg and 80 mmHg, P < 0.01) and the increased pain threshold (P < 0.05). (3) The TRPV 1 mRNA expression level of bone marrow cells was significantly lower in the VHA + moxibustion group than in the model group (P < 0.01). No significant difference was found between the control and moxibustion+control groups in TRPV 1 mRNA expression level (P > 0.05). CONCLUSION: Moxibustion of "Dachangshu" (BL 25) can reduce visceral hyperalgesia and down-regulate TRPV 1 mRNA expression of bone marrow cells in VHA rats, suggesting an involvement of TRPV 1 mRNA of bone marrow cells in CRD-induced visceral pain development. PMID- 23650795 TI - [PI 3 K/Akt signaling pathway contributed to the protective effect of acupuncture intervention on epileptic seizure-induced injury of hippocampal pyramidal cells in epilepsy rats]. AB - OBJECTIVE: To observe the protective effect of acupuncture stimulation on pyramidal cells in hippocampal CA 1 and CA 3 regions and to analyze the involvement of phosphatidy linositol-3-kinase (PI 3 K)/protein kinase B(PKB or Akt) signaling pathway in the acupuncture effect in epilepsy rats. METHODS: A total of 120 SD rats were randomly divided into normal control group, model group, LY 294002 (a specific antagonist for PI 3 K/Akt signaling) group, acupuncture+ LY 294002 group and acupuncture group (n = 24 in each group, 12 for H. E. staining, and 12 for electron microscope observation). Epilepsy model was established by intraperitoneal injection of pentylenetetrazol (PTZ, 5 microL). Manual acupuncture stimulation was applied to "Baihui" (GV 20) and "Dazhui" (GV 14) once daily for 5 days. Dimethyl Sulfoxide (DMSO, 5 microL, a control solvent) was given to rats of the normal, model and acupuncture groups, and LY294002 (5 microL, dissolved in DMSO) given to rats of the LY 294002 and acupuncture+ LY 294002 groups by lateral ventricular injection. Four hours and 24 h after modeling, the hippocampus tissues were sampled for observing pathological changes of CA 1 and CA 3 regions after H. E. staining under light microscope and for checkin ultrastructural changes of the pyramidal cells under transmission electron microscope. RESULTS: In comparison with the normal control group, the numbers of pyramidal cells of hippocampal CA 3 region in the model group were decreased significantly 4 h and 24 h after epileptic seizure (P < 0.01). While compared to the model group, the pyramidal cells of hippocampal CA 3 region in the acupuncture group were increased considerably in the number at both 4 h and 24 h after seizure (P < 0.01). No significant differences were found between the LY 294002 and model groups, and between the acupuncture+ LY 294002 and model groups in the numbers of pyramidal cells at 4 h and 24 h after seizure (P > 0.05). Findings of the light microscope and electron microscope showed that the injury severity of pyramidal cells of hippocampal CA 1 and CA 3 regions was moderate 4 h after epileptic seizure and even worse 24 h after seizure in the model group, LY 294002 group and acupuncture+ LY 294002 group, but relatively lighter in the acupuncture group. These results suggested an elimination of the acupuncture effect after blocking the PI 3 K/Akt signaling pathway by lateral ventricular injection of LY 294002 in epilepsy rats. CONCLUSION: Acupuncture intervention has a protective effect on pyramidal cells of hippocampal CA 1 and CA 3 regions in epilepsy rats, which is associated with the normal function of intracellular PI 3 K/Akt signaling pathway. PMID- 23650796 TI - [Effects of electroacupuncture at acupoints "changbingfang" on serum IL-4 content and colonic NF-kappaB p65 expression in rats with ulcerative colitis]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) of "Zhongwan"(CV 12), "Tianshu"(ST 20) and "Shangjuxu"(ST 37) (an acupoint prescription "Changbingfang" for treatment of intestinal disorders) on the expression of colonic nuclear factor kappaB p65 (NF-kappaB p65) protein expression and serum interleukin-4 (IL 4) content in rats, so as to explore its mechanism underlying improvement of ulcerative colitis (UC). METHODS: Thirty SD rats were randomly and equally divided into normal control, model and EA groups (10 rats/group). The UC model was made by enema with 8% acetic acid. EA stimulation (6 Hz/30 Hz) was delivered to "Zhongwan" (CV 12), "Tianshu" (ST 20) and "Shangjuxu" (ST 37) for 15 min separately, 0 h, 24 h and 48 h post-enema. The blood and colon tissues were taken for detection of serum IL-4 content with ELISA, and for assaying colonic NF kappaB p65 protein expression with immunohistochemistry and Western blot, respectively. RESULTS: Compared with the normal control group, colonic NF-kappaB p65 protein expression level shown by immunohistochemistry and Western blot and serum IL-4 content were significantly higher in the model group (P < 0.01, P < 0.05). After EA stimulation, colonic NF-kappaB p65 protein expression levels shown by both immunohistochemistry and Western blot were down-regulated significantly (P < 0.01, P < 0.05) and serum IL-4 content was up-regulated further in comparison with the model group (P < 0.01). CONCLUSION: EA of acupoint recipe "Changbingfang" can down-regulate the proinflammatory NF-kappaB p65 protein expression and up-regulate serum anti-inflammatory cytokine IL-4 level in rats, which may contribute to its effect in improving ulcerative colitis. PMID- 23650797 TI - [Effect of different intensities of electroacupuncture stimulation on expression of SOCS-3 and PPAR-gamma mRNA in adipose tissues of obesity rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on the expression of suppressor of cytokine signaling 3 (SOCS-3) and peroxisome proliferator-activated receptor (PPAR)-gamma genes in the epididymis adipose tissue of obesity rats so as to explore its mechanism underlying weight reduction. METHODS: SD rats were randomized into normal control, obesity model, EA-5 mA and EA-1 mA groups (10 rats/group). EA stimulation (6 Hz/20 Hz, 5 mA or 1 mA) was delivered to the bilateral "Zusanli" (ST 36) and "Sanyinjiao" (SP 6) for 15 min, once everyday for two weeks. The expression of SOCS-3 mRNA and PPAR-gamma mRNA in the epididymis adipose tissue was detected by reverse transcriptase polymerase chain reaction. RESULTS: Compared with the normal group, the body weight and expression of SOCS-3 and PPAR-gamma mRNA in the model group were up-regulated obviously (P < 0.01). Compared with the model group, the body weight and expression of SOCS-3 and PPAR gamma mRNA were significantly decreased in the EA group, with the effects of EA-5 mA being better than those of EA-1 mA. CONCLUSION: EA stimulation of ST 36-SP 6 can reduce body weight in rats with simple obesity, and the effect of higher intensity of EA is apparently better. Accordingly, EA intervention induces down regulation of SOCS-3 and PPAR-gamma mRNA expression in the epididymis adipose tissue. PMID- 23650798 TI - [Effect of electroacupuncture on expression of phosphorylated P 38 MAPK and IL 1beta in frontal lobe and hippocampus in rats with Alzheimer's disease]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) intervention on expression of phosphorylated mitogen activated protein kinase-P 38 (p-P 38 MAPK) protein and Interleukin 1beta (IL-1beta)mRNA in the frontal lobe and hippocampus in Alzheimer's disease (AD) rats so as to explore its mechanisms underlying improvement of AD in clinic. METHODS: Thirty-two SD rats were equally and randomly divided into normal control (normal), sham-operation (sham), model and EA groups. AD model was established by microinjection of Abeta(1-40) (10 microg/microL, 1 microL) into bilateral Meynert nucleus (AP: 1. 4 mm, L: 3 mm, H: 7 mm) and validated by water maze tests. Rats of the sham group were treated by microinjection of the same dose of normal saline into the bilateral Meynert Nucleus. EA (1 mA, 2 Hz) was applied to bilateral "Baihui" (GV 20), "Taixi" (KI 3) and "Zusanli" (ST 36) for 15 min, once daily for 12 sessions. Expression levels of p-P 38 MAPK protein and IL-1beta mRNA in the hippocampus and frontal lobe tissues were detected by Western blot and RT-PCR, respectively. RESULTS: In comparison with the normal group, the expression levels of p-P 38 MAPK protein and IL-1beta mRNA in the hippocampus and frontal lobe tissues were upregulated significantly in the model group (P < 0.01). After 12 sessions of EA intervention, the expression levels of both p-P 38 MAPK protein and IL-1beta mRNA were down-regulated significantly (P < 0.01, P < 0.05) in spite of being still higher than those of the normal group. No significant differences were found between the normal and sham groups in the expression levels of both p-P 38 MAPK protein and IL-1beta mRNA (P > 0.05). CONCLUSION: EA intervention can reduce the over expression of both p-P 38 MAPK protein and IL-1beta mRNA in the hippocampus and frontal cortex in AD rats, suggesting an improvement of AD after EA intervention by restraining the inflammatory reaction. PMID- 23650799 TI - [Influence of electroacupuncture stimulation of "tianshu" (ST 25), "quchi" (LI 11) and "shangjuxu" (ST 37) and their pairs on gastric motility in the rat]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of different acupoints or acupoint pairs on gastric motility so as to explore their modulation regularities under different conditions. METHODS: SD rats were randomly divided into normal control, starvation (food-deprivation for 24 h), atropine (antagonist for M-receptor), acetylcholine (Ach, agonist for M receptor), propranolol (antagonist for beta-receptor) and clenbuterol (agonist for beta 2-receptor) and paired-acupoint groups (30 rats/group). The intragastric pressure was measured via a pressure transducer connected to a balloon inserted in the stomach cavity. EA (2 Hz /15 Hz, 2 mA) was applied to the left "Tianshu" (ST 25),"Quchi" (LI 11) and "Shangjuxu" (ST 37) which were formed in pairs: ST 25 LI 11, ST 25-ST 37 and LI 11-ST 37 for 2 min following intravenous injection of atropine (0.1%, 0.8 mL/kg, 40 microL x min(-1) x kg(-1)), 0.1% acetylcholine (20 microL x min(-1) x kg(-1)), 0. 2% clenbuterol (80 microL x min(-1) x kg(-1)) and 0.4% propranolol (1 mL/kg,40 microL x min(-1) x kg(-1)) under food-deprivation conditions. RESULTS: After intravenous injection of atropine and clenbuterol, the intragastric pressure were decreased significantly (P < 0.05), while after administration of Ach and propranolol, the intragastric pressure increased markedly (P < 0.05). Under normal and starvation conditions, and after intravenous administration of M-receptor antagonist (atropine) and agonist (Ach), beta-receptor antagonist (propranolol) and agonist (clenbuterol), EA stimulation of ST 25 produced an apparently inhibitory effects on gastric motility (80.00%, 86.67%, 76.67%, 86.67%, 73.33% and 86.67%, respectively) and intragatric pressure (P < 0.05) with the tendency being starvation > normal, acetylcholine > atropine and clenbuterol > propranolol. Whereas EA stimulation of LI 11 and ST 37 mainly produced an excitatory effect on gastric motility (60.00%, 56.67%, 93.33%, 40.00%, 53.33% and 50.00%, respectively for LI 11; 66.67%, 60.00%, 80.00%, 53.33%, 46.67% and 73.33%, respectively for ST 37). Following EA stimulation of the paired-acupoint groups, ST 25-ST 37 induced a predominately inhibitory effect on gastric motility (50.00%) and intragastric pressure, while LI 11-ST 37 stimulation had a principally excitatory effect on gastric motility (53.33%), and ST 25-LI 11 showed no apparent effect (50.00%). CONCLUSION: EA stimulation of ST 25 area at the abdomen produces a predominant inhibitory effect on gastric motility, while EA of LI 11 and ST 37 on the upper and lower limbs induces an excitatory effect on gastric movement, when applied in pairs, EA of ST 25-ST 37 suppresses the gastric activity, and LI 11-ST 37 promotes the gastric activity, suggesting a specificity of the effect of different acupoint stimulation. PMID- 23650800 TI - [Influence of electroacupuncture intervention on free radical metabolism in athletes undergoing intensive endurance exercise]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) intervention on free radical metabolism in athletes during intensive endurance exercise, so as to reveal its mechanism underlying fatigue relief. METHODS: Thirty male college student volunteers were equally divided into control group, intensive endurance exercise group (exercise group for short) and EA group. Student volunteers in both exercise and EA groups were asked to conduct fixed quantitative load exercise (Harvard step test) for 30 min, once daily for 15 days. EA was applied to bilateral Xuehai (SP 10), Zusanli (ST36), Taichong (LR3), and Sanyinjiao (SP 6) for 30 min, once daily for 15 days. Serum malondialdehyde (MDA) contents and superoxide dismutase (SOD) activity levels on the day before exercise, one day after exercise and 15 days after EA intervention were detected by using thiomalonylurea colorimetric method and xanthine oxidase method, respectively. RESULTS: Compared with pre-exercise or the control group, serum MDA content and SOD activity after one day's intensive endurance exercise were increased significantly in both exercise and EA groups (P < 0.05, P < 0.01), and the ratios of SOD/MDA decreased considerably in the latter two groups (P < 0.01). At the time-point of post-EA intervention, serum MDA level was significantly higher in the exercise group than in the control group (P < 0.05), serum MDA content in the EA group was significantly lower than that in the exercise group (P < 0.05), and serum SOD activity in the EA group was significantly higher than that in the exercise group (P < 0.01). The ratio of SOD/ MDA was increased obviously in the EA group than in the exercise group (P < 0.01). CONCLUSION: EA can decrease serum MDA content and increase SOD activity and SOD/MDA in athletes experiencing intensive endurance exercise, which may contribute to its effect in relieving athletic fatigue. PMID- 23650801 TI - [Effects of weizhong (BL 40) area scraping on blood perfusion level of the skin microcirculation of qihaishu (BL 24) region at the ipsilateral back of the volunteer's body]. AB - OBJECTIVE: To observe the effect of Guasha (scraping) of Weizhong (BL 40) on the cutaneous blood perfusion of Qihaishu (BL 24) region of the Bladder Meridian on the back. METHODS: Ten healthy volunteer subjects were recuited in the present study. Weizhong (BL 40, at the politeal fossa) area was repeatedly scraped till regional flush using a cornu bubali scraping plate for 5 min after applying scraping oil to the regional skin. Then blood perfusion levels of the skin microcirculation around Weizhong (BL 40) and Qihaishu (BL 24) regions on the ipsilateral back were detected using a Laser Doppler flowmetry (PeriScan PIM II). RESULTS: Following scraping Weizhong (BL 40) region, the cutaneous blood perfusion levels in the stimulated region were increased significantly at the time-points of 0, 15, 60 and 90 min after scraping (P < 0.001, P < 0.01), while those of Qihaishu (BL 24) area at the lumbar part also showed a remarkable increase 15, 60 and 90 min after scraping compared with the basic value (P < 0.05). A positive correlation was found between BL 40 and BL 24 areas in the cutaneous blood perfusion levels after scraping BL 40 (P < 0.05). CONCLUSION: Scraping stimulation of Weizhong (BL 40) can improve the cutaneous microcirculation of the stimulated BL 40 and Qihaishu (BL 24) regions in healthy volunteers, suggesting a close connection between BL 40 and the back described in Chinese medicine. PMID- 23650802 TI - [Randomized controlled trails for "equilibrium-acupuncture" treatment of lumbar pain in patients with lumbar intervertebral disc prolapse]. AB - OBJECTIVE: To observe the effect of "equilibrium-acupuncture" intervention on lumbar pain in lumbar intervertebral disc prolapse patients. METHODS: A total of 287 patients with lumbar intervertebral disc prolapse syndrome were randomly assigned to equilibrium acupuncture group (n = 143) and routine acupuncture group (n = 144) using SAS (Statistical Analysis System) Software. Patients of the equilibrium acupuncture group were treated by acupuncture stimulation of bilateral "Yaotong" point (at the middle site of the forehead) and those of the routine acupuncture group treated by acupuncture stimulation of Ashi-points, Weizhong (BL 40), Jiaji (EX-B 2), Shenshu (BL 23), etc. The treatment was conducted once daily for 20 days, then, 3 months' follow-up was given. Pain scores including pain rating index (PRI) and visual analogue scale (VAS) were given to the patients before and after the treatment using Chinese version of Short-Form of McGill Pain Questionnaire. Present pain intensity (PPI) was evaluated after the treatment. RESULTS: Before the treatment, no significant differences were found between the equilibrium acupuncture group and the routine acupuncture group in PRI and VAS scores (P > 0.05). Following the treatment, the pain symptom was apparently improved in both groups, and the rates of pain improvement (including excellent, good and moderate improvement rates) of the equilibrium acupuncture group were significantly higher than those of the routine acupuncture group from the 1st to the 4th treatment sessions, in the 20th treatment session and the 2nd follow-up (P < 0.05); and the PRI and VAS scores of the equilibrium acupuncture group were significantly lower than those of the routine acupuncture group after the 18th and 20th sessions of treatment and the 3 months' follow-up (P < 0.05). The cases and percentages of patients without pain (PPI rating) were significantly more in the equilibrium acupuncture group than in the routine acupuncture group in the 18th and 20th treatment sessions and the 2nd follow-up (P < 0.05). The "equilibrium-acupuncture" is relatively superior to routine acupuncture in the instant effect and long-term effect. CONCLUSION: "Equilibrium-acupuncture" has a faster and stable long-term analgesic effect for lumbar intervertebral disc prolapse patients. PMID- 23650803 TI - [Effect of electroacupuncture intervention at different phases of post-operation on bladder function in patients undergoing cervical cancer operation]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) at different time points after cervical carcinoma surgery on urinary bladder function of uroschesis patients so as to determine the optimum time of acupuncture intervention. METHODS: Sixty cervical cancer post-operation patients with catheter due to uroschesis were randomly and equally divided into late treatment group (acupuncture intervention was given from the over 15th day on after surgery) and early treatment group (acupuncture was given from the 7th day to the 14th day after surgery). Bilateral Shangliao (BL 31), Ciliao (BL 32), Zhongliao (BL 33), Xialiao (BL 34), Zhibian (BL 54), Yinlingquan (SP 9) and Sanyinjiao (SP 6) were punctured with filiform needles combined with electrical stimulation of bilateral BL 31 and BL 34 for 30 min, once daily for 10 sessions. The residual urine volume was measured before treatment and after 5 and 10 sessions of treatment separately. RESULTS: After 5 and 10 sessions of treatment, the average residual urine volumes of both late treatment and early treatment groups were decreased significantly ( P< 0.05), and the residual urine volume level of the early treatment group was markedly lower than that of the late treatment group (P < 0.05). After 5 sessions of acupuncture treatment, of the two 30 cases in the late treatment and early treatment groups, 8 and 17 had an automatic micturition, 22 and 13 needed catheter retention, and following 10 sessions of treatment, 22 and 27 had an automatic micturition, and 8 and 3 still needed catheter retention, respectively. Regarding the functional recovery state of the urinary bladder, of the two 30 cases in the late treatment and early treatment groups, 6 and 14 were good, 24 and 16 poor respectively following 5 sessions of treatment; 15 and 22 were good, 15 and 8 were poor respectively following 10 sessions of treatment. The therapeutic effects of the early treatment group were apparently superior to those of the late treatment group. The number of the treatment sessions for recovering the bladder function was obviously fewer in the early treatment group than in the late treatment group (P < 0.05). CONCLUSION: Early acupuncture intervention is significantly better than late treatment for reducing residual urine volume and promoting bladder function recovery for uroschesis patients undergoing cervical cancer operation. PMID- 23650804 TI - [Comparison of pain thresholds of acupoints on the leg in healthy volunteers]. AB - OBJECTIVE: To detect the pain threshold of acupoints on the leg in healthy volunteers so as to analyze the sensory specificity of different acupoints. METHODS: A total of 66 healthy volunteers (34 male and 30 female) aged from 19 to 64 years were recruited in the present study. Pain thresholds of acupoints on the lower leg were detected by using an Electronic Von Frey Anesthesiometer after constructing an anthropometric diagram about the cutaneous division of the lower leg. RESULTS: 1) Among acupoints Shugu (BL 65), Jinggu (BL 64), Kunlun (BL 60), Chengshan (BL 57) of the Bladder Meridian from the heel to the popliteal fossa, and non-acupoint (1cun lateral to BL 60), no significant differences were found among these acupoint regions in the pain threshold (P > 0.05), while that of the non-acupoint was significantly higher in comparison with these acupoint regions (P < 0.05). 2) At the Zusanli (ST 36) level, no significant differences were found among the Yanglingquan (GB 34), Zusanli (ST 36) and Yinlingquan (SP 9) regions in the pain threshold (P > 0.05) and the pain threshold was obviously higher in the non-acupoint (1 cun lateral to ST36) than in the GB34, ST36 and SP 9 regions (P < 0.05). 3) At the Xiajuxu (ST39) level, no significant differences were found among the Xiajuxu (ST39), Waiqiu (GB 36), Yangjiao (GB35), Feiyang (BL58) and Lougu (SP7) regions in the pain threshold (P > 0.05), but the non acupoint (1 cun lateral to ST39) showed a higher threshold than those of the above-mentioned 5 acupoints (P < 0.05). 4) Among the 5 Xing-spring acupoints Dadu (SP2), Xingjian (LR2), Neiting (ST44) and Xiaxi (GB 43) distributing in the interdistal region, the pain threshold was lowest in the Neiting (ST 44) and highest in the Xiaxi (GB 43) regions (P < 0.05). 5) Among the acupoints Shuiquan (KI 5), Taixi (KI 3), Zhubin (KI 9) and Lougu (SP7) on the lower leg, the pain threshold was lowest in the Zhubin (KI 9) and highest in the Lougu (SP 7) regions (P < 0.05). CONCLUSION: In healthy subjects, the pain threshold is generally higher in the non-acupoint region and also shows a sparse lower sensory threshold in some acupoints as Neiting (ST 44), Zhubin (KI 9), etc. The specificity of acupoints needs being studied further. PMID- 23650805 TI - [Analysis on CHENG Dan-an's exploration of quantification acupuncture and moxibustion stimulation]. AB - As a physical therapy, there is a certain relationship between the stimulating quantity and the efficacy of acumoxibustion therapy. However, because of the thinking mode of traditional Chinese medicine in the ancient times, qualitative descriptions about acu-moxibustion stimulation in the classical literature are predominating. Mr. CHENG Dan-an, a famous master and educator of acupuncturology, conducted a series of exploration in both theory and clinical practice. In the present paper, the authors summarize Mr. Cheng's viewpoints about the quantification of acupuncture intervention from 1) the number of the selected acupoints in a session of treatment, 2) gauges and materials of the filiform acupuncture needles, 3) stimulating strength of the needling, including the duration of acupuncture needle retaining, depth of needling and intensity of the needling manipulation, 4) frequency of the acupuncture intervention (interval between every two sessions of treatment). Regarding the moxibustion therapy, the stimulating quantity including the duration of the ignited moxa and the number of moxa cones applied at the acupoint area should be varied according to the patients' physical constitutions, ages and the state of the illness or clinical conditions. Mr. Cheng also put forward his opinions about the quantification standards of moxibustion intervention. PMID- 23650806 TI - [Exterior-interior correlation of "heart" and body surface based on researches of classic literature and modern animal experiments]. AB - Exterior-interior relationship of meridians and zangfu organs is an important component of the theory of acupuncturology in Chinese medicine. According to the descriptions in classic works of Chinese medicine and findings of modern experimental researches, in the present paper, the authors analyzed the close association between the "Heart" and "Small Intestine", exterior-interior correlation between the Heart Meridian and Small Intestine Meridian, and between the "Heart" and body surface (acupoints), limbs, five sensory organs, etc. In addition, the authors also summarized the underlying mechanisms of the above mentioned exterior-interior relationship of the "Heart" and put forward some proposals for the future researches. PMID- 23650807 TI - [Progresses of studies on acupuncture analgesia for postoperative reaction]. AB - A large number of clinical trials and animal experiments have been carried out to focus on neurochemical mechanisms of acupuncture analgesia including postoperation pain relief, which may provide guidance for developing a novel clinical approach for postoperative analgesia. In the present paper, the authors review new progresses of researches on acupuncture analgesia for postoperative pain and side effects in the past few years from thyroidectomy, chest surgery, abdominal surgery, five sense organs (ear, nose, eye and throat) surgery, and others. Regarding the mechanism of acupuncture, central neurotransmitters (including the endop endorphin, 5-HT, gamma-aminobutyric acid, etc.), immune cytokines, cytokines from the spinal glia cells are complicated in the process of acupuncture analgesia. A lot of findings of researches demonstrated that acupuncture therapy is effective in reducing postoperative pain and adverse reactions as nausea, vomiting, etc. As a common technique widely used in the field of clinical medicine, the underlying mechanisms of acupuncture therapy for relieving post-surgery pain and side-effects should be studied profoundly in the future. PMID- 23650808 TI - [Recent circumstances of Japanese radiologists]. PMID- 23650809 TI - [A 10-year-old boy with exhibiting visual disturbance]. PMID- 23650810 TI - [Autoimmune encephalitis: up-to-date]. PMID- 23650811 TI - [Role of antibodies to glutamate receptors]. PMID- 23650812 TI - [Clinical characteristics of Rasmussen encephalitis with special reference to Japanese experience]. PMID- 23650813 TI - [The current debate on acute encephalitis with refractory, repetitive partial seizures (AERRPS)]. PMID- 23650814 TI - [Clinical features and treatment strategy in anti-nMDA receptor encephalitis]. PMID- 23650815 TI - [Congenital cerebral hypomyelination; from an establishment of disease entity to physiological/therapeutic perspectives]. PMID- 23650816 TI - [Congenital hypomyelinating leukodystrophies--from genomic dissection to molecular diagnosis and potential therapies]. PMID- 23650817 TI - [Clinical and molecular manifestations of congenital cerebral hypomyelination]. PMID- 23650818 TI - [MRI and MR spectroscopy in hypomyelinating disorders]. PMID- 23650819 TI - [Establishment of iPS cells from patients with CNS diseases]. PMID- 23650820 TI - [Recent issues concerning paid cares legally allowed to provide medical cares]. PMID- 23650821 TI - [Botulinum toxin in the treatment of cerebral palsy in childhood: the domesteic expert opinions and the role of pediatric neurologists in the management for severely handicapped children]. PMID- 23650822 TI - [Hypoglycemia due to a long-term treatment with an antibiotic with pivoxil moiety]. PMID- 23650823 TI - [Successful effect of tacrolimus in a 5-year-old boy presenting with repeated episodes of non-herpetic acute limbic encephalitis]. PMID- 23650824 TI - [Hypovolemic shock due to gastric variceal bleeding]. PMID- 23650825 TI - [An infrequent cause of extrahepatic cholestasis]. PMID- 23650826 TI - [Herman Boerhaave]. PMID- 23650827 TI - [Recurrent laryngitis in child: evaluation with multichannel intraluminal impedance]. AB - BACKGROUND: Gastro-esophageal reflux (GERD) is highly prevalent in children and there is a tendency to disappear or decrease its frequency in the first year. However, in certain circumstances this reflux can have adverse consequences and these cases are known as gastro-esophageal reflux disease (GERD). The clinical manifestations of GERD include typical and atypical or extra digestive symptoms. The association between GERD and chronic laryngeal symptoms may present clinically as recurrent croup, stridor, chronic or intermittent hoarseness, globus sensation, excessive chronic cough and posterior rhinorrhea. Multi-channel intraluminal impedance-pH 24 hours (IIM-pH 24h) is the diagnostic method of choice for the study of this association. OBJECTIVE: To describe the behavior and characteristics of GERD in patients with recurrent laryngitis. MATERIAL AND METHODS: This is a retrospective study involving pediatric patients with recurrent laryngitis (2 or more episodes in 6 months) referred for study of possible GERD. RESULTS: We evaluated 28 children. Only 7 of them had normal studies. CONCLUSION: There is a significant percentage of patients with normal 24 hour Ph monitoring that had not been diagnosed with GERD without IIM. There was not a characteristic pattern. PMID- 23650828 TI - [Value of immersion technique in the diagnosis of diseases of duodenal mucosa]. AB - INTRODUCTION: We used the immersion technique for the evaluation of duodenal mucosa for several years and we observed discordant results in relation to the literature. OBJECTIVE: To evaluate the immersion technique in the diagnosis of duodenal mucosa diseases. PATIENTS AND METHOD: We performed an upper endoscopy, immersion technique, chromoendoscopy and biopsies of the second portion of the duodenum to the patients who met the inclusion criteria. It was reported the presence of villi and the partial or total absence of them. RESULTS: The standard endoscopy showed absence of villi in 16 patients and normal mucosa in 384. The comparison between these results and those of the biopsies showed that biopsies were normal in 3 patients with presumed absence of villi and had a partial atrophy of villi in 1 patient with normal endoscopy. With the immersion technique and the chromoendoscopy we observed absence of villi in 13 patients and normal mucosa in 386. When we compared these results with those of the biopsies, we observed that 1 normal patient had a partial atrophy of villi. These results indicate that standard endoscopy has a sensitivity of 92%, a specificity of 99%, a positive predictive value of 81% and a negative predictive value of 99%. The immersion technique and chromoendoscopy have a sensitivity of 92%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 99%. CONCLUSION: In our experience the immersion technique does not improve the visualization of the villi compared with the standard endoscopy and the chromoendoscopy. PMID- 23650829 TI - [Viral load survey from geographical areas within Argentina with high hepatitis B virus prevalence]. AB - Several studies have demonstrated that viral load is a key factor to determine the development of HBV infection and to assess treatment options for the disease. There is a lack of studies analyzing viral load levels in chronic hepatitis B patients in Argentina and the epidemiologic information is limited. The aim of this study was to determine viral load levels and its distribution in patients diagnosed with chronic hepatitis B from geographical areas with high prevalence for HBV in Argentina. Fifty-one per cent of the study population had HBV DNA levels > or = 10(4) copies/ml and a median viral load of 11,910 copies/ml. The viral load was significantly higher in HBeAg seropositive patients compared with those seronegative for HBeAg (P < 0.05). Salta and Entre Rios provinces showed low viral loads, while Chaco, Misiones and Formosa provinces had a median viral load ranging between 10(4) and 10(5) copies/ ml. This is the first study providing detailed information on viral load in chronic hepatitis B patients from Argentina. Availability of viral load levels in chronic hepatitis B enables evaluation of implementation of actions to analyze follow-up and/or treatment options for preventing disease complications, improving health care and diminishing the potential burden on the health care system. PMID- 23650830 TI - [Surveillance of viral hepatitis in Argentina: analysis of information from sentinel units 2007-2010]. AB - In Argentina, the four strategies of epidemiological surveillance from the National System of Health Surveillance (SNVS) are Diseases of Mandatory Report (C2), Sentinel Units (SU), Laboratory Surveillance (SIVILA) and National Programs (National Plan of Blood, information from blood banks). They collect information about viral hepatitis (VH). The objective of this work was to analyze the information recorded by the SUs of VH for hepatitis B and C in the period between January 1th 2007 and December 31h 2010. In this period, out of the 1,769 cases recorded (entered by 21 of 24 SUs), 806 entries were hepatitis B, 848 hepatitis C and 115 belonged to other definitions. The relative proportions between hepatitis B and hepatitis C were heterogeneous between the SUs. The age distribution was homogeneous, being the predominant group in acute hepatitis B the 25- to 34-year old group. In hepatitis C, the age distribution was broader. The distribution by sex and risk factors was heterogeneous between the different SUs. In hepatitis C, genotype 1 was the predominant one. In conclusion, the information provided by the SUs contributes as an evidence of the public health problem posed by this pathology in our country. PMID- 23650831 TI - [Gastrointestinal histoplasmosis: an atypical presentation]. AB - Histoplasmosis is a systemic mycosis caused by Histoplasma capsulatum. It is an endemic disease in the American continent. It is spread hematogenously and any organ can be affected. It is more frequent in immunodeficient patients and the most common opportunist mycosis associated with HIV Exclusive gastrointestinal involvement is rare and invariably mortal without treatment. It is considered to be impossible to diagnose the disease based on the macroscopic aspect of lesions. We report a 43-year-old male in apparent good health status who was admitted with intermittent proctorrhagia of one year of evolution associated to burning proctalgia, without any further symptoms. A videocolonoscopy (VCC) with proctologic exam was conducted The patient was warned about the potential orificial origin of the bleeding and the importance of screening for colorectal neoplasia. The proctologic exam revealed internal congestive hemorrhoids. VCC showed during the routine exploration of the terminal ileon lesions both in that level and rectum, although of a different morphology. The colon had normal endoscopic appearance. Biopsies of both lesions identified Histoplasma. Later studies diagnosed HIV/AIDS and the patient was referred to the infectology department to complete diagnostic tests and begin treatment of both diseases. In conclusion, we present an atypical case of this mycosis because of its exclusive gastrointestinal allocation, in anasymptomatic patient, in apparent good health, with unknown HIV/AIDS, who was admitted because of a proctorrhagia of orificial origin. Endoscopic biopsies of lesions of different morphologies, located in the terminal ileon and rectum, allowed the diagnosis of this disease, that had no clinical expression. This casual endoscopic diagnosis enabled to change the life expectancy of the patient. We consider that the described endoscopic lesions in rectum are of a particular morphology and can rarely be found in other pathologies. The diffusion of these images could warn other endoscopists of these phenomena. PMID- 23650832 TI - [Laparoscopic treatment of sigmoid colon intussusception secondary to giant submucosal lipoma]. AB - Colonic lipomas have very low frequency, are usually asymptomatic and diagnosis is made incidentally. Seventy-five per cent of lipomas larger than 4 cm are symptomatic, causing abdominal pain, rectal bleeding, obstruction and exceptionally invagination. The resection of invaginated segment is mandatory in cases with invagination and can be performed by laparoscopy when colonic dilation is moderate. We present a 73-year-old man who entered the emergency department complaining of intermitent abdominal pain, rectal bleeding, absence of bowel movements and flatulence, during four days. A CT scan showed a generalized colonic dilation until left lower quadrant. A colo-colonic invagination secondary to an endoluminal lipoma was observed in sigmoid colon. A laparoscopic sigmoidectomy was performed with extracorporeal termino-terminal anastomosis. The postoperative period was uneventful and the patient was discharged from the hospital five days later. A sumbmucous colonic lipoma was diagnosed in the pathological study. PMID- 23650833 TI - [Perianal Kaposi's sarcoma. A case report and a review of the literature]. AB - Kaposi's sarcoma is the most common cancer in men who have sex with men with AIDS. The estimated prevalence in the United States is 25% in patients with positive serology for the human immunodeficiency virus (HIV). The commitment of the gastrointestinal tract is seen in 40% of patients with Kaposi's sarcoma related to AIDS but lesions can occur anywhere in the body and evolve rapidly. We present a 33-year-old patient who kept sex with men, with epidemiological history of hepatitis B and syphilis, who consulted the service of Coloproctology for perianal ulcer. He was studied according to the protocols of sexually transmitted diseases, was diagnosed HIV and an excision biopsy of the lesion was performed. The diagnosis of perianal Kaposi's sarcoma was reached. Kaposi's sarcoma-HIV was staged, no other lesions were found and the patient started antiretrovirals with poor response to therapy. He evolved with rapid progression of the disease and died with the presumptive diagnosis of Fournier's syndrome at three months after the excision biopsy. We conclude that perianal ulcers are a relatively common pathology in the office of Coloproctology and differential diagnosis are different according to the positivity for HIV or not and the patient's sexual practices. We consider that is important to publish and spread these cases. PMID- 23650834 TI - [Common variable immunodeficiency: digestive involvement of a systemic disease]. AB - Common variable immunodeficiency is characterized by a primary deficiency in antibody production that is clinically manifested by respiratory recurrent infections and gastrointestinal diseases (infectious, inflammatory and neoplastic). Above 50% of the patients have diarrhea and 10% develop idiopathic malabsorption and weight loss. We present the case of a 34-year-old woman submitted to our service for chronic diarrhea, abdominal pain and bloating and history of recurrent respiratory infections since childhood. The laboratory assessment showed severe hypoproteinemia and confirmed low IgG, IgA and IgM levels. Upper gastrointestinal endoscopy and videocapsule endoscopy showed a nodular duodenum with multiple polypoid-like formations all through the small bowel. Histology confirmed chronic duodenitis and Giardia lamblia infection. With the diagnosis of common variable immunodeficiency, monthly intravenous gammaglobulin infusion was initiated and metronidazole was indicated for Giardia lamblia infection achieving excellent clinical and laboratory response. PMID- 23650835 TI - [Inflammatory pseudotumor of the liver: a case of recurrence after resection]. AB - Inflammatory pseudo-tumor of the liver is a rare benign condition. Usually presented as a large liver mass, may cause obstruction or infiltration of the main vessels or biliary tree. The clinical presentation is mostly an inflammatory syndrome with acute abdominal pain. We present a 39-year-old female patient with abdominal pain, fever and jaundice. Images showed a 15-cm liver lesion in the left lobe of the liver. Malignancy could not be discarded and the patient underwent left hepatectomy. The histologic examination reported an inflammatory pseudo-tumor of the liver. The patient recurred after one year with the same symptoms and a 10-cm new lesion occupying segment I. Considered as a recurrence, medical treatment was decided tumor size decreased 50% after the first month and completely disappeared during the follow up. Two years later, the patient was readmitted with a new episode and a new 8-cm liver lesion in segment VII. She was treated again with anti-inflammatory medication and imaging control. Although inflammatory pseudo-tumor of the liver is a benign condition, it can have a recurrent behaviour. The differentiation with other malignant tumors sometimes is impossible by clinical and imaging presentation. PMID- 23650836 TI - [Hepatic pseudotumor in acute fascioliasis]. AB - We report a 61-year-old woman who was hospitalized because of abdominal pain in the right upper quadrant related to a liver tumor (ultrasound and tomographic findings). A collection of blood was obtained by a biopsy and there were no tumor cells. With the suspicion of acute fascioliasis (liver stage), due to severe eosinophilia and recent travel to endemic area of Fasciola hepatica, arc II and ELISA Fas 2 we carried out and were positive. Parasitological stool examinations were negative. During hospitalization a hepatic subcapsular hematoma presented as a complication and the patient developed fever because of cholangiolitic microabscesses in the left hepatic lobe. Percutaneous drainage was performed and positive cultures of secretions were obtained She received antibiotic coverage with vancomycin and imipenem. Treatment for Fasciola hepatica was initiated with nitaxozanida but it was discontinued due to oral intolerance. Later, she received a single dose of 250 mg triclabendazole with clinical and laboratory improvement. We presented this case because it is an unusual pseudotumoral presentation in acute hepatic fascioliasis. This parasitic disease is an emerging zoonosis in Peru. PMID- 23650837 TI - [Argentine consensus on hepatitis B]. PMID- 23650838 TI - [Analysis of mutations in father-son pairs within selected Y-STR loci]. AB - The objective of the study was to examine the mutation rates of Y-chromosomal STR from father-son pairs. The paternity in these cases was confirmed previously with the use of autosomal STR system performing standard analyses of genetic profiles of the mother, child and putative father (PI > = 100000). We examined 200 father son sample pairs from Northern Poland using the Y-STR 18-plex. We identified eleven mutations. Five mutations resulted in the gain of a repeat in the sons' chromosome and six resulted in a loss of a repeat. All the samples resulted in single repeat mutations from one sample, which contained a two repeat loss at DYS385. The overall average mutation rate estimate was 0.0031.There was no significant difference in the mutation rate between Y-STR loci of the 200 tested father-son pairs and the YHRD base. PMID- 23650839 TI - [Examples of application of X chromosomal markers in familial investigations and personal identification]. AB - Besides autosomal STR loci, markers of sex chromosomes, X and Y, are increasingly more commonly used in genetic analyses aiming at paternity testing or personal identification. The paper presents cases in which analysis of microsatellite loci of the X chromosome (X-STRs) was included in the routine examination and allowed for an unambiguous determination of the relationship between the tested individuals. The cases addressed paternity testing of female children, determination whether the examined women were paternal half-sisters, as well as personal identification of a deceased man. In none of the conducted expert opinions, the putative father's DNA sample was't available. Genotyping of X-STR markers was carried out with the use of commercial kits: Mentype Argus X-8 PCR Amplification Kit (Biotype) and Investigator Argus X-12 Kit (Qiagen). PMID- 23650840 TI - [Polymorphism in the SE33 locus in the Polish population]. PMID- 23650841 TI - [Identification of a novel Y-SNP in the USP9Y gene and its impact on genotyping alleles of the M46 locus]. AB - Y-chromosomal SNP markers are becoming increasingly more popular among forensic geneticists, but since they constitute variants specific to the ethnic origin, detailed population studies are required. Research into frequency of haplogroup N M46 in the Belarusian population detected a mutated allele in 22 males, including one with a very distinct Y-STR haplotype. Sequencing of the M46 locus of this individual revealed the presence of a novel Y-SNP nearby the M46 locus, which was responsible for the erroneous assignment of the Y chromosome to the haplogroup N M46. An impact of the identified polymorphism on discrimination of alleles of the M46 locus with various techniques was discussed, and solutions ensuring correctness of the genotyping results were proposed. PMID- 23650842 TI - [Suicide and depression in the postmortem evaluation of disturbed neuronal activity]. AB - The authors have reviewed the results of their postmortem neurohistological investigations related to the evaluation of impaired activity of brain structures relevant to pathophysiology of depression. Chronic changes in ribosomal DNA transcriptional activity have been indirectly suggested by the AgNOR staining method in neurons of the prefrontal limbic regions, the amygdala, the external globus pallidus, and the serotonergic dorsal raphe nucleus. The impact of processes leading to suicide has been clearly accentuated in contrast to the weak influence of unipolar-bipolar dichotomy. The present results support the view that suicide and depression constitute pathological phenomena with partially different neurobiology. They may be also relevant to forensic pathology. PMID- 23650843 TI - [Proposal of interpreting analytical results indicating borderline-legal alcohol concentration values in individuals after alcohol consumption or being alcohol intoxicated]. AB - Interpretation of analytical results indicating borderline-legal alcohol concentration values after the substance intake or intoxication requires consideration of many factors, such as: road safety, measurement uncertainty, determination of ethanol in breath, alcohol metabolism in the body, the possibility of residual alcohol in the mouth. Decree No 738 of the Chief of Police issued on 21 June 2011, introduces the obligation to verify the results ranging close to the borderline concentration of 0.1 mg/l by executing the third measurement, but the interpretation of these results is questionable. The paper proposes a new manner of taking measurements and their interpretation. Upon arriving at the scene the police should record the starting time of testing the driver and wait 15 minutes (the time required to eliminate residual alcohol). If, after that time, the first result falls within the borderline values legally described as the condition after alcohol consumption or alcohol intoxication, the second and third measurements should be taken immediately. Thus, three measurements taken quickly in a few minutes should not be affected by the alcohol metabolism in the body. If two of the three determined values are less than or equal to 0.09 mg/l, the driver should be pronounced sober. If two of the three results are within the range of 0.10-0.25 mg/l, the result indicates condition after alcohol intake. If two of the three results are equal to or more than 0.26 mg/l, the status of the driver may be described as alcohol intoxication. PMID- 23650844 TI - [Proposal of psychomotor skill assessment tests for drivers and a protocol for sampling and testing of saliva, blood and urine when there is reason to suspect involvement of substances with alcohol-like effect]. AB - The paper proposes tests to assess psychomotor impairment in drivers suspected of using substances acting similarly to alcohol. The authors also present a proposal for the protocol to be used in sampling and testing of saliva, blood and urine when psychoactive substance abuse has been suspected. A detailed procedure is based on the joined experience of German, U.S. and Polish police from Gdansk. The purpose of the appendix is to help police officers to perform and document tests confirming psychomotor impairment, as well as to provide the basis for saliva, urine and blood analysis. PMID- 23650845 TI - [Dextromethorphan (DXM): new methods of intoxications among teenagers--a case description]. AB - The study highlighted the problem of intoxication using substances and/or preparations, to which nowadays young people have unrestricted access. Based on the case developed in the Department of Forensic Medicine of the Medical University of Gdansk, our team members were able to gather information showing "ingenuity" of today's teenagers, which was reflected in the types of preparations used to induce a state of euphoria and intoxication. The study was based on the case of a 17-year-old woman, who took Acodin in combination with compressed air used to clean computer keyboards in order to induce psychoactive effects. The study used qualitative and quantitative methods: GC-FID and GC-MS. The results were compared with data from the literature. PMID- 23650846 TI - [An attempt at estimating the time of death based on limited data from death scene]. AB - The paper presents a case of murder, in which an important fact for the investigation was determination of the time of death. The problem was lack of relevant data from the death scene resulting from delayed and mismanaged external body examination, and particularly lack of body temperature measurement. Due to the gravity of the case, despite the lack of body temperature record, an attempt at estimating the time interval in which death occurred was undertaken. The time interval of 10 hours during which death most probably occurred was determined based on the stage of development of postmortem lividity, rigor mortis and also depositions of witnesses. If, however, body temperature at the death scene had been recorded, which should have been a routine action, the accuracy of the time of death estimation would most probably have been much higher. PMID- 23650847 TI - [A case of fatal lightning stroke at an unusual site--the city center]. AB - A case of a fatal lighting stroke involving a young man staying in a storm near the center of a big city is presented. The atypical character of this case lies in the fact that the lightning stroke usually occurs in open areas (mountains, fields, meadows), or involves people trying to find shelter from the storm under a tree or an isolated object in an open area. In the described case, a contributory factor to the lightning stroke was the fact that during the storm, the man was most probably standing on metal heating pipes, built in the 70's and 80's, long stretches of which were erected high above the ground. Metal used in the construction of the pipes most probably attracted lightning and generated the current which electrocuted the man standing on their surface. PMID- 23650848 TI - [The application of mitochondrial genomics to forensic investigations based on human mitochondrial DNA testing]. AB - In this study we present two forensic cases where mitochondrial DNA HVS I and HVS II haplotypes of evidentiary hairs match reference samples. Based on the information retrieved from mtDNA coding region of reference material, we selected single nucleotide polymorphisms (SNPs) located outside the HVS I and HVS II regions that could increase the informativeness of mtDNA analysis. The SNPs were typed via SNaPshot or dideoxy sequencing technology. In both cases the SNP results allowed for unambiguous exlusion of the evidence and for determining that reference samples originated from the same person. PMID- 23650849 TI - [What every physician should know about forensic DNA testing]. PMID- 23650850 TI - [The phenomenon of hyperostosis frontalis interna--state of the art knowledge]. AB - Hyperostosis frontalis interna (HFI) is an interesting but still a poor-known phenomenon, which may be found post-mortem. The authors have presented views on the aetiology, pathogenesis and symptomatology of HFI. The usefulness of this abnormality in the identification of sex and age has been pointed out. PMID- 23650851 TI - [System-forming functions of bound water in the mechanism of topochemical reactions of formation of ultrathin layers on water surface]. AB - The system-forming role of the surface layer of water in the process of formation of ultrathin layers from the epoxide oligomer and triethylenetetramine or phosphotungstic acid on the surface of the aqueous phase is shown. Previously, this process was studied experimentally. The surface layer of the aqueous phase plays the role of a matrix, on which an epoxide oligomer monolayer and triethylenetetramine or phosphotungstic acid molecules are immobilized by hydrogen-bonding with water molecules from above or from below this matrix, respectively. Thus, topochemical reactions between the epoxide oligomer and triethylenetetramine or between the epoxide oligomer molecules in the presence of phosphotungstic acid become possible, so that ultrathin network epoxide triethilenetetramine or epoxide layers are formed on the surface of water. PMID- 23650852 TI - [Computer modeling of parametric structures of water]. AB - The algorithm for the arrangement of hydrogen atoms in twist-hexacycle parametric structures of bound water is developed. The calculation of energetic properties is carried out using the TIP3P and Poltev-Malenkov potentials. Optimization of energy for these structures is fulfilled. PMID- 23650853 TI - [Ultrasonic cleavage of DNA in complexes with Ag(I), Cu(II), Hg(II)]. AB - We investigated a phenomenon of ultrasonic cleavage of DNA complexed with transition metal cations Ag(I), Cu(II) and Hg(II). We found the statistically significant dependence of relative intensity of cleavage on cation type and concentration. Each cation may cause two different types of distortion in the DNA double-helix depending on whether it binds to major or minor DNA groove. The intensity of ultrasonic cleavage decreases if cation binds to the major DNA groove; the intensity of cleavage increases if cation binds to the minor DNA groove and disturbs the hydrogen bonds of complementary base pairs or it intercalates between bases. Both types of DNA distortion can affect the intensity of N-S interconversion of deoxyribose. PMID- 23650854 TI - [Paramagnetic calcium melanins]. AB - Treatment of catechol, pyrogallol, DOPA, dopamine, norepinephrine, and natural polyhydroxy-1,4-naphthoquinone echinochrome by aqueous solution of potassium superoxide (KO2) in the presence of CaCl2 leads to the formation of water insoluble dark pigments with stable paramagnetic properties ("calcium melanins"). In control experiments in the same procedure without Ca2+, the pigments were not formed. EPR spectra of the calcium melanins had little difference from each other and from known melanins in shape, line width, and the g factor about 2,004. Addition of EDTA water solution to dried paramagnetic pigments leads to their fast dissolving and disappearing of EPR signal. Formation of similar polymers is also observed during autoxidation of o-diphenols in Ca(2+)-containing alkaline buffer solution, however, this process takes a few days instead of few seconds in the presence of KO2. Thus, calcium (and other divalent cation M2+) can consider as a key structural element in formation of M(2+)-catecholate paramagnetic Polymer. We assume the existence of two types of paramagnetic centers in melanin like polymer: M(2+)-stabilized o-semiquinone radical or bi-radical complex containing o-semiquinone and superoxide anion radicals, stabilized by M2+. PMID- 23650855 TI - [Singlet-triplet excitation fission in light-harvesting complexes of photosynthetic bacteria and in isolated carotenoids]. AB - Time-resolved electron paramagnetic resonance was used to study the properties of carotenoid triplet states populated in LH2 light-harvesting complexes of phototrophic bacteria Allochromatium minutissimum, Rhodopseudomonas palustris, and in carotenoid films free of bacteriochlorophyll. The study was performed on purified LH2 preparations not contaminated by reaction centers, and under selective pigment excitation. The obtained results enable a conclusion that the carotenoid triplet states, both in LH2 complexes and films, are populated in the process of homofission of singlet excitation into two triplets, which involves only carotenoid molecules. It is observed that the fission process in magnetic field leads to predominant population of the T0 spin sublevel of the triplet. One molecular spin sublevel of the triplet is demonstrated to possess an increased probability of intersystem crossing to the ground state, independent of the carotenoid configuration. Pigment composition of the LH2 protein heterodimers is discussed, and a conclusion of the possible PMID- 23650856 TI - [Highly reactive intermediates in photochemistry of chlorophyll]. AB - It is shown that chlorophyll (Chl) has photochemical activity in the reduction of O2 to H2O2. In the case of the monomeric forms of Chl, H2O2 formation occurs with the participation of 1O2, *OH and O2*-. Activity of Chl depends on its microenvironment, and pH of the system. Associated forms of Chl do not photosensitize 102 formation, but are active in transfer of electrons to oxygen, that leads to H2O2 generation. Also it is found that Chl associates are able to act as electron donors to reduce H2PO4- and subsequently form hydrogen atom. PMID- 23650857 TI - [Peculiarities of growth of the monocellular green algae culture after the influence of electromagnetic field in deuterated water-containing media]. AB - Exposing the inoculum of monocellular green algae Dunalialla tertiolecta and Tetraselmis viridis to 50 Hz electromagnetic field for several hours resulted in a reduced growth rate in both cultures. It was ascertained that heavy water inhibited growth of algae Dunaliella tertiolecta. The light water activated growth of the culture in the exponential phase only. PMID- 23650858 TI - [Electron transport and transmembrane proton transfer in photosynthetic systems of oxygenic type in silico]. AB - In this work, using a mathematical model of light-induced stages of photosynthesis, taking into account the key stages of pH-dependent regulation on the acceptor and donor sides of PS1, we analyzed electron and proton transport in chloroplasts of higher plants and cyanobacterial cells. A comparison of computer simulation results with experimental data showed that our model adequately described a complex non-monotonous kinetics of the light-induced redox transients of P700. Effects of atmospheric gases (CO2 and O2) on the kinetics of photooxidation of P700 and generation of the transmembrane pH difference were studied. We also analyzed how cyclic electron transport influenced the kinetics of electron transfer, the intrathylakoid pH, and ATP production. Within the framework of our model, we described the time-courses of electron flow through PS2 and distribution of electron fluxes on the acceptor side of PS1 in chloroplasts of higher plants and in cyanobacterial cells. It was demonstrated that contributions of cyclic electron transport and electron flow to O2 (the Mehler reaction) were significant during the initial phase of the induction period, but diminished upon the activation of the Calvin-Benson cycle. PMID- 23650860 TI - [Effect of potassium phenosan on structure of plasma membranes of mice liver cells in vitro]. AB - The effect of synthetic anti-oxidant potassium phenosan (PP, potassium salt of beta-(4-hydroxy-3,5-ditretbutil-phenyl)-propionic acid) on the structural state of the surface (8 angstroms) and deep (20-22 angstroms) lipid regions of plasma membranes of mice liver cells was studied by spin probes method in vitro in a wide range of concentrations (1(-5)-10(-21) M). Two stable free radicals, 5- and 16-redox-stearic acids (C5 and C16), were used as spin probes. The nonlinear polymodal dose-effect dependences were obtained for parameters that characterize the microviscosity of the lipid bilayer (tau(c)) in the site of localization of the probe C16, and the order parameter (S), which characterizes the stiffness of the surface layers of lipids in the site of localization of the probe C5. Statistically a reliable increase was observed for parameter tau(c) after addition of PP at concentrations 10(-5)-10(-7) M and 10(-18)-10(-19) M, and for parameter S after addition of PP at concentrations 10(-6)-10(-7) M and 10(-13) 10(-15) M. Peaks on both dose-effect curves were separated by the intervals of concentrations where PP had no effect on the studied physico-chemical characteristics of biomembranes. For PP concentrations which caused maximal changes in tau(c) and S, we investigated thermal dependence of these parameters and determined the thermally induced structural transitions. Comparing with control, ultra-low doses of PP (10(-13)-10(-15) M) and (10(-18)-10(-19) M) caused an appearance of additional thermally induced structural transition in the surface and deep regions of plasma membrane lipids. The possible role of the interaction of PP molecules with specific binding sites on plasma membranes and formation of nanoparticles of PP in very dilute aqueous solutions are discussed. PMID- 23650859 TI - [Interrelation between structural state, physicochemical properties and lipid composition in microbial cells]. AB - We performed complex investigations of antioxidant properties and the lipid composition of the five gram-negative bacteria depending on the cultivation season. Structural state, the lipid composition and physicochemical properties of lipids of the three gram-negative bacteria (Renobacter vacuolatum, Flectobacillus major WKM 869, Pseudomonas fluorescens) during their growth and mycelium of four species of the xylotrophic basidiomycetes (Panus tigrinus IBK-131, Fomes fomentarius M71, Laetiporus sulfureus M131, Piptoporus betulinus M60) during the lag phase were also studied. Changes in the composition of the lipid component in the studied bacteria led to considerable structural rearrangements in their membrane system during the growth of bacteria. It is shown that more hydrophilic regions of the lipid component are of paramount importance in maintaining the fluidity of the entire lipid bilayer in the basidiomycete mycelium. The scale and direction of the revealed interrelations between rotational correlation times of probes and the lipid composition depend both on localization of the probe in membrane and the composition and physicochemical properties of the microorganism lipids. PMID- 23650861 TI - [State of succinate dehydrogenase in the organism--"unbalanced" or hyperactive]. AB - Through the use of the original cytobiochemical method to study oxidation in mitochondria, preserving their native organization in network within cells in a blood smear, we revealed hyperactive state of succinate dehydrogenase, which is realized in the organism under physiological stress. It is consistent with the view of the non-equilibrium state of enzymes during activity. The mechanism of the succinate dehydrogenase hyperactivity moderation is based on the full functioning of alpha-ketoglutarate dehydrogenase, supported by oxidation of isocitric acid. PMID- 23650862 TI - [Interaction of surface-active base with fraction of membrane-bound Williams's protons]. AB - In the process of mitochondrial respiratory H(+)-pumps functioning, the fraction membrane-bound protons (R-protons), which have an excess of free energy is formed. According to R.J. Williams this fraction is included as energy source in the reaction of ATP synthesis. Previously, in our laboratory was found the formation of this fraction was found in the mitochondria and on the outer surface of mitoplast. On the mitoslast model we strictly shown that non-equilibrium R proton fraction is localized on the surface of the inner mitochondrial membrane. In this paper a surface-active compound--anion of 2,4,6-trichloro-3 pentadecylphenol (TCP-C15) is described, which selectively interacts with the R protons fraction in mitochondria. A detailed description of the specific interaction of the TCP-C15 with R-protons fraction in mitochondria is presented. Moreover, in this work it was found that phosphate transport system reacts with the R-protons fraction in mitochondria and plays the role of the endogenous volume regulation system of this fraction. The results of experiments are discussed in the terms of a local coupling model of the phosphorylation mechanism. PMID- 23650863 TI - [Physico-chemical features of dinitrosyl iron complexes with natural thiol containing ligands underlying biological activities of these complexes]. AB - Current notions and new experimental data of the authors on physico-chemical features of dinitrosyl iron complexes with natural thiol-containing ligands (glutathione or cysteine), underlying the ability of the complexes to act as NO molecule and nitrosonium ion donors, are considered. This ability determines various biological activities of dinitrosyl iron complexes--inducing long-lasting vasodilation and thereby long-lasting hypotension in human and animals, inhibiting pellet aggregation, increasing red blood cell elasticity, thereby stimulating microcirculation, and reducing necrotic zone in animals with myocardial infarction. Moreover, dinitrosyl iron complexes are capable of accelerating skin wound healing, improving the function of penile cavernous tissue, blocking apoptosis development in cell cultures. When decomposed dinitrosyl iron complexes can exert cytotoxic effect that can be used for curing infectious and carcinogenic pathologies. PMID- 23650864 TI - [Some properties of auditory neuron's model trained by firing caused by tones modulated by low-frequency noise]. AB - In many sensory systems the formation of burst firing can be observed along a way from the periphery to the central nuclei. We investigate the putative transformation of spontaneous activity in the auditory pathway using a neuron model trained by real firing recorded in the auditory nuclei of the frog. The model has 200 separate inputs (neuronal spines). It is supposed that every spine is a coincidence detector. Its output (synaptic potential) sharply increases at emergence of the precisely certain interpulse interval in an input pulse sequence. If the total synaptic potentials excess a threshold, the model generates output spike, which changes weight of all spines according to the simplified Hebb principle. The model was trained by real firing caused in the auditory nuclei of the frog by tones modulated by low-frequency noise in the frequency ranges of 0-15 Hz, 0-50 Hz or 0-150 Hz. After that training the synaptic weights of every spine essentially changed. Thus, along with some increase of weights of spines tuned to boundary frequencies of modulating noise, the most characteristic change was the emphasizing weights of spines tuned to short interpulse intervals. As a result the spontaneous activity passed through the trained model became much more bursting. Efficiency of a signal transmission in model was higher when input spontaneous activity of real cells contains bursts of spikes. Results of modeling are discussed in connection with modern physiological data demonstrating the functional advantage of bursting. PMID- 23650865 TI - [Molecular self-organization and multiple equilibrium systems]. AB - We have compared different types of natural self-organizing systems: crystal-like formation of multi molecular systems were conferred with self-organization in active media and dissipative structure formation. The comparison revealed a common feature of all such systems. They all have bi-(multi-)stable states. We propose a hypothesis that self-organization is impossible in systems that could not have bi-(multi-) stable states. PMID- 23650866 TI - [Chirality as a primary switch of hierarchical levels in molecular biological systems]. AB - A synergetic law, being of common physicochemical and biological sense, is formulated: any evolving system that possesses an excess of free energy and elements with chiral asymmetry, while being within one hierarchical level, is able to change the type of symmetry in the process of self-organization increasing its complexity but preserving the sign of a prevailing chirality (left - L or right - D twist). The same system tends to form spontaneously a sequence of hierarchical levels with alternating chirality signs of de novo formed structures and with an increase of the structures relative scales. In living systems, the hierarchy of conjugated levels of macromolecular structures that begins from the "lowest" asymmetric carbon serves as an anti-entropic factor as well as the structural basis of "selected mechanical degrees of freedom" in molecular machines. During transition of DNA to a higher level of structural and functional organization regular alterations of the chirality sign D-L-D-L and L-D L-D for DNA and protein structures, respectively, are observed. Sign-alternating chiral hierarchies of DNA and protein structure, in turn, form a complementary conjugated chiral pair that represents an achiral invariant, that "consummates" the molecular-biological block of living systems. The ability of a carbon atom to form choral compounds is an important factor that determined carbon basis of living systems on the Earth as well as their development though a series of chiral bifurcations. The hierarchy of macromolecular structures demarcated by the chirality sign predetermined the possibility of the "block" character of biological evolution. PMID- 23650867 TI - [L.A. Blumenfeld and study of photosynthesis by spectroscopy methods at Chair of Biophysics, Faculty of Physics, Moscow State University]. AB - Nowadays spectroscopy methods are widely employed to study photosynthesis. For instance, fluorescence methods are often in use to study virtually all steps of photosynthesis process. Theoretical models of phenomena under study are of importance for interpretation of experimental data. A decisive role of L.A. Blumenfeld, the former head of the Chair of Biophysics, Faculty of Physics, Moscow State University, in the study of photosynthesis process is shown in this work. PMID- 23650869 TI - Effect of screw insertion torque on mechanical properties of four locking systems. AB - OBJECTIVE: To evaluate the effect of screw insertion torque on the mechanical properties of four 3.5 mm locking systems: New Generation Devices (NGD), Securos (PAX), Synthes (SYN), and Veterinary Orthopedic Implants (VOI). STUDY DESIGN: In vitro mechanical study. METHODS: Screws were inserted at 1.5 Nm, 2.5 Nm, and 3.5 Nm torques, using dedicated drill guides and a calibrated torque screwdriver. Locking mechanisms were tested under shear loading conditions using a custom design probe. Tests were conducted under displacement control until failure. Load to failure and interface stiffness were compared between and within groups using a two-factor ANOVA (P < .05). Failure modes were described. RESULTS: The SYN group had significantly greater mechanical properties compared to all other groups at any given insertion torque. Insertion torque had a significant effect on the PAX group, increasing the load to failure by 126% when increasing the insertion torque from 1.5 Nm to 3.5 Nm. Insertion torque had no significant effect on the mechanical properties of the VOI group and limited effect on the NGD and SYN groups. Single failure mode, by screw head decoupling or screw shaft fracture, occurred in the SYN and VOI groups, respectively. In contrast, NGD and PAX systems failed through a combination of screw decoupling and/or bending. CONCLUSIONS: Regardless of insertion torque, the SYN locking mechanism showed the highest failure loads, interfacial stiffness as well as consistent failure mode. These findings highlight the dependability of this system. When using the PAX system an insertion torque of at least 2.5 Nm should be recommended. PMID- 23650868 TI - Preparation and evaluation at the delta opioid receptor of a series of linear leu enkephalin analogues obtained by systematic replacement of the amides. AB - Leu-enkephalin analogues, in which the amide bonds were sequentially and systematically replaced either by ester or N-methyl amide bonds, were prepared using classical organic chemistry as well as solid phase peptide synthesis (SPPS). The peptidomimetics were characterized using competition binding, ERK1/2 phosphorylation, receptor internalization, and contractility assays to evaluate their pharmacological profile over the delta opioid receptor (DOPr). The lipophilicity (LogD7.4) and plasma stability of the active analogues were also measured. Our results revealed that the last amide bond can be successfully replaced by either an ester or an N-methyl amide bond without significantly decreasing the biological activity of the corresponding analogues when compared to Leu-enkephalin. The peptidomimetics with an N-methyl amide function between residues Phe and Leu were found to be more lipophilic and more stable than Leu enkephalin. Findings from the present study further revealed that the hydrogen bond donor properties of the fourth amide of Leu-enkephalin are not important for its biological activity on DOPr. Our results show that the systematic replacement of amide bonds by isosteric functions represents an efficient way to design and synthesize novel peptide analogues with enhanced stability. Our findings further suggest that such a strategy can also be useful to study the biological roles of amide bonds. PMID- 23650870 TI - Pulmonary vein stenosis with Down syndrome: a rare and frequently fatal cause of pulmonary hypertension in infants and children. AB - Down syndrome (DS) patients are prone to pulmonary hypertension (PHTN) due to various cardiopulmonary causes. However, the association of DS with pulmonary vein stenosis (PVS) is not adequately described. We illustrate three cases from our center and an additional 13 cases from an extensive review of the literature of DS patients with PHTN and PVS. In DS patients PVS is rare, they were diagnosed at a young age (<7.2 months), had high mean pulmonary artery pressures (38 mm Hg), and had rapid progression of the stenosis with an increased mortality (91%) in patients with two or more vein involvement. In DS patients, PVS may be missed by echocardiography; thus, any DS patients with persistent PHTN should undergo cardiac catheterization to assess hemodynamics and to evaluate all four pulmonary veins. PMID- 23650871 TI - Nanofountain probe electroporation (NFP-E) of single cells. AB - The ability to precisely deliver molecules into single cells is of great interest to biotechnology researchers for advancing applications in therapeutics, diagnostics, and drug delivery toward the promise of personalized medicine. The use of bulk electroporation techniques for cell transfection has increased significantly in the past decade, but the technique is nonspecific and requires high voltage, resulting in variable efficiency and low cell viability. We have developed a new tool for electroporation using nanofountain probe (NFP) technology, which can deliver molecules into cells in a manner that is highly efficient and gentler to cells than bulk electroporation or microinjection. Here we demonstrate NFP electroporation (NFP-E) of single HeLa cells within a population by transfecting them with fluorescently labeled dextran and imaging the cells to evaluate the transfection efficiency and cell viability. Our theoretical analysis of the mechanism of NFP-E reveals that application of the voltage creates a localized electric field between the NFP cantilever tip and the region of the cell membrane in contact with the tip. Therefore, NFP-E can deliver molecules to a target cell with minimal effect of the electric potential on the cell. Our experiments on HeLa cells confirm that NFP-E offers single cell selectivity, high transfection efficiency (>95%), qualitative dosage control, and very high viability (92%) of transfected cells. PMID- 23650873 TI - Primary amines as directing groups in the Ru-catalyzed synthesis of isoquinolines, benzoisoquinolines, and thienopyridines. AB - Isoquinolines, benzoisoquinolines, thieno[3,2-c]pyridines and fused heteroaryl[2,3-c] pyridines, with a wide variety of substituents at different positions of the aromatic or heteroaromatic rings, have been synthesized by Ru catalyzed oxidative coupling of a broad range of benzylamines or heterocycles with internal alkynes. All benzylamines and heterocycles have unprotected primary amines as efficient directing groups. PMID- 23650872 TI - Ustilago maydis natural antisense transcript expression alters mRNA stability and pathogenesis. AB - Ustilago maydis infection of Zea mays leads to the production of thick-walled diploid teliospores that are the dispersal agent for this pathogen. Transcriptome analyses of this model biotrophic basidiomycete fungus identified natural antisense transcripts (NATs) complementary to 247 open reading frames. The U. maydis NAT cDNAs were fully sequenced and annotated. Strand-specific RT-PCR screens confirmed expression and identified NATs preferentially expressed in the teliospore. Targeted screens revealed four U. maydis NATs that are conserved in a related fungus. Expression of NATs in haploid cells, where they are not naturally occurring, resulted in increased steady-state levels of some complementary mRNAs. The expression of one NAT, as-um02151, in haploid cells resulted in a twofold increase in complementary mRNA levels, the formation of sense-antisense double stranded RNAs, and unchanged Um02151 protein levels. This led to a model for NAT function in the maintenance and expression of stored teliospore mRNAs. In testing this model by deletion of the regulatory region, it was determined that alteration in NAT expression resulted in decreased pathogenesis in both cob and seedling infections. This annotation and functional analysis supports multiple roles for U. maydis NATs in controlling gene expression and influencing pathogenesis. PMID- 23650874 TI - Role of immunotherapy in castration-resistant prostate cancer (CRPC). AB - Initial therapy for metastatic prostate cancer consists of androgenic suppression. However, this is only a palliative treatment with an effective duration that usually lasts 12-24 months. Historically, castration-resistant prostate cancer (CRPC) had been considered a chemoresistant tumour. In 2004, docetaxel received USA Food and Drug Administration approval as a first-line treatment for metastatic prostate cancer, after two independent phase III trials showed an increased survival benefit. Recently, five new drugs have shown increased survival in CRPC: sipuleucel-T (assymptomatic or minimally symptomatic), abiraterone acetate (before and after docetaxel), cabazitaxel (after docetaxel), MDV3100 (after docetaxel) and radium-223 (not suitable for docetaxel or after docetaxel). The identification of antigens in normal prostate tissue or prostate cancer that are recognised by immune effectors cells has resulted in several new studies based on immunotherapy. Prostate cancer disease provides a test system to determine the efficacy of vaccines for different reasons. This cancer is a tumour that grows relatively slowly. Recurrence is often diagnosed early (with many patients presenting only with biochemical progression), there is a biological marker that can predict prognosis and outcome (PSA doubling time), various specific antigens have been identified and characterised, and vaccines can be used with a good safety profile combined with anti-androgen therapy, chemotherapy, or radiotherapy. Here we provide a review of the main important immune treatments in CRPC. PMID- 23650875 TI - Anion-dependence of fast relaxation component in Na-, K-halide solutions at low concentrations measured by high-resolution microwave dielectric spectroscopy. AB - High-resolution microwave dielectric spectra of NaX, KX (X: F, Cl, Br, I) aqueous solutions of c = 0.05 and 0.1 M measured in the frequency range 0.2-26 GHz at 10 degrees C are analyzed. The dielectric relaxation (DR) spectrum of each solution, which deviates slightly from the bulk-water spectrum, is mathematically divided into the bulk-water spectrum and the spectrum of solute particles covered with a water layer using a mixture theory by assuming the existence of continuous bulk water phase. The solute spectra above 3 GHz are fitted with a linear series of pure water component (gamma dispersion with DR frequency fw), fast Debye component-1 with DR frequency f1 (>fw), and slow Debye component-2 with DR frequency f2 (30 degrees left, <30 degrees left, neutral, and <30 degrees right positions. When the head was in the >30 degrees left position, overlap was seen in 38 of 40 patients (95%). As the head was rotated from >30 degrees left to <30 degrees right, the CA-RIJV overlap (from 95% to 57.5%), and the cross-sectional area (from 14.2 mm to 8.7 mm) significantly decreased. In conclusion, when the head was turned to <30 degrees right, the CA-RIJV overlap significantly decreased, and the cross-sectional area also decreased. When clinicians determine the optimal head position before RIJV cannulation, it is important to consider the advantages and disadvantages of the different head positions from >30 degrees left to <30 degrees right. PMID- 23650893 TI - Social isolation in HIV-infected patients according to subjective patient assessment and DEXA-confirmed severity of lipodystrophy. AB - This study was designed to investigate the persistence of lipodystrophy (LD) related social distress and isolation in HIV-infected patients in the current era, according to confirmatory dual energy X-ray absorptiometry (DEXA) measurements. Cross-sectional interview data were collected from 168 HIV-positive adult patients taking more than 2 years of antiretroviral therapy (133 cases with LD diagnosed a mean of 7.2 years before; 35 without LD, controls). Mean time of HIV infection was 16.2 years (2.1-27.3), and the mean time of exposure to highly active antiretroviral therapy of 11.7 years (2.1-21.1). The presence and severity of LD, confirmed by DEXA measurements, correlated with social isolation through a validated scale, including avoidance of social relationships, sex, work, or sport activities. In comparison with control patients, social distress was observed for patients having moderate body changes. The significant correlation between LD and social isolation was irrespective of age, CD4+ count, HIV RNA level, AIDS diagnosis, time of HIV infection, anxiety, or depressive symptoms. These results confirm that patient assessment of LD is correlated with whole-body DEXA scan, and they highlight the role of LD as an independent cause of social isolation even after years of the diagnosis. PMID- 23650894 TI - Minimizing nurses' risks for needlestick injuries in the hospital setting. AB - Despite advances in safety mechanisms for sharps, nurses continue to be at high risk for needlestick injuries, with more than half of all nurses experiencing at least one needlestick injury during their careers. Needlestick injury risk appears to be the result of three incident factors: nurses' sense of urgency, variable shift work, and lower skill level related to years of experience, academic degree, and younger age. This article synthesizes the evidence related to these risk factors among nurses in the hospital setting. Evidence linking needlestick injury risk with both variable shift work and lower skill level is demonstrated. The evidence supporting a relationship between needlestick injury risk and nurses' sense of urgency is conflicting. It is the authors' goal to reduce needlestick injury risk for nurses; therefore, specific changes to hospital nursing practice are recommended based on the evidence identified. PMID- 23650895 TI - Factors associated with hospital staff nurses working on-call hours: a pilot study. AB - When nurses work on-call hours, they have limited ability to control the hours they work. Nurses may be required to work extra hours and, if they are unable to detach from work during break time, can experience fatigue and sleep disturbances. Previous studies have not examined factors associated with on-call work. In this pilot study, the authors examined state regulatory, organizational, and personal factors related to nurse on-call hours. Data were collected from registered nurses working in hospitals in two states; the final analytic sample consisted of 219 nurses. The authors found that four variables (teaching hospital employment, patient-to-nurse ratio, race/ethnicity of the nurse, and living with children) were significantly related to working on-call hours. Additional research is needed to understand nurse on-call hours and develop agency policies to promote nurses' health and well-being. PMID- 23650896 TI - Combined effect of cigarette smoking and occupational exposures on lung function: a cross-sectional study of rubber industry workers. AB - Workers in the rubber industry are exposed to pulmonary health hazards. The main purpose of this study was to assess the combined effect of cigarette smoking and occupational exposures on lung function. The exposed group consisted of tire manufacturing workers in production units and the non-exposed group included executives from the same factory. The researchers calculated the synergy index (SI) to determine the combined effect of exposures to cigarette smoke and pulmonary health hazards on lung function. A significant correlation was found between occupational exposures in the rubber industry and abnormal spirometric findings (p < .05). The synergistic effect of cigarette smoking and occupational exposures on lung function was significant (SI = 2.25; p < .05). This study demonstrated that occupational exposures and smoking may have a synergistic effect on the respiratory systems of tire manufacturing workers. The results suggest that tire manufacturing companies should consider establishing spirometric surveillance systems in their factories. Also, smoking cessation should be promoted, engineering controls applied, and respiratory protection provided to workers. PMID- 23650897 TI - Chemical composition and antioxidant activity of Algerian propolis. AB - Chemical composition of propolis samples from north Algeria was characterized by chromatographic and spectroscopic analyses. High-performance liquid chromatorgaphy with diode-array detection (HPLC-DAD) fingerprint of the methanol extracts allowed the definition of two main types of Algerian propolis (AP) directly related to their secondary metabolite composition. Investigation of two representative types of AP by preparative chromatographic procedure and mass spectrometric (MS) and NMR techniques led to the identification of their main constituents: caffeate esters and flavonoids from an AP type rich in phenolic compounds (PAP) and labdane and clerodane diterpenes, together with a polymethoxyflavonol, from an AP type containing mainly diterpenes (DAP). Subsequently, two specific HPLC-MS/MS methods for detection of PAP and DAP markers were developed to study the chemical composition of propolis samples of different north Algerian regions. Antioxidant activity of AP samples was evaluated by 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) assay, and a significant free-radical scavenging effect was observed for propolis of the PAP series rich in polyphenols. PMID- 23650898 TI - Person-centered care in Chinese residential care facilities: a preliminary measure. AB - OBJECTIVES: Person-centered care (PCC) is one of the most desirable approaches for elderly with dementia. However, it has not been initiated and systematically studied in China, on which lacking of reliable and valid measurement tools is one of the key barriers. This paper aims to validate person-centered care assessment tools (P-CAT) in a Chinese context. METHOD: The original 13-item was translated and back translated. And 11 items were added based on literature review and expert consultation. The resulting 24-item P-CAT-C was validated among a sample of formal caregivers (n = 330) in all 34 residential care facilities in urban Xi'an, a representative city in north-western China. Chinese versions of staff based measures of individualized care for institutionalized persons with dementia (IC) and caregiver psychological elder abuse behavior (CPEAB) scale were used to test the criterion validity. RESULTS: Confirmatory factor analysis (CFA) showed that a three-factor 15-item solution provided adequate fit indices to the data (chi(2) = 145.691, df = 81, p < 0.001, comparative fit index (CFI) = 0.926, Tucker-Lewis index (TLI) = 0.905, root mean square error of approximation (RMSEA) = 0.050). Four new items were identified and two original items were excluded. The three factors are named as (1) individualized care (6-item); (2) organizational support (6-item); and (3) environmental accessibility (3-item). The internal consistency coefficient (Cronbach's alpha = 0.684) is satisfactory. The interscale correlation among P-CAT-C, IC, and CPEAB showed good criterion validity. CONCLUSION: P-CAT-C is a culturally adapted version of the original P CAT, which showed satisfactory reliability and validity for evaluating PCC in Chinese residential care facilities. It also provides insight to other developing countries. PMID- 23650899 TI - Folate and asthma. AB - Findings from experimental studies and animal models led to the hypothesis that folic acid supplementation during pregnancy confers an increased risk of asthma. This review provides a critical examination of current experimental and epidemiologic evidence of a causal association between folate status and asthma. In industrialized nations, the prevalence of asthma was rising before widespread fortification of foodstuffs with folic acid or folate supplementation before or during pregnancy, thus suggesting that changes in folate status are an unlikely explanation for "the asthma epidemic." Consistent with this ecologic observation, evidence from human studies does not support moderate or strong effects of folate status on asthma. Given known protective effects against neural tube and cardiac defects, there is no reason to alter current recommendations for folic acid supplementation during conception or pregnancy based on findings for folate and asthma. Although we believe that there are inadequate data to exclude a weak effect of maternal folate status on asthma or asthma symptoms, such effects could be examined within the context of very large (and ongoing) birth cohort studies. At this time, there is no justification for funding new studies of folate and asthma. PMID- 23650900 TI - Accuracy and reliability of continuous glucose monitoring systems: a head-to-head comparison. AB - OBJECTIVE: This study assessed the accuracy and reliability of three continuous glucose monitoring (CGM) systems. RESEARCH DESIGN AND METHODS: We studied the Animas(r) (West Chester, PA) VibeTM with Dexcom(r) (San Diego, CA) G4TM version A sensor (G4A), the Abbott Diabetes Care (Alameda, CA) Freestyle(r) Navigator I (NAV), and the Medtronic (Northridge, CA) Paradigm(r) with EnliteTM sensor (ENL) in 20 patients with type 1 diabetes mellitus. All systems were investigated both in a clinical research center (CRC) and at home. In the CRC, patients received a meal with a delayed and increased insulin dose to induce a postprandial glucose peak and nadir. Hereafter, randomization determined which two of the three systems would be worn at home until the end of functioning, attempting use beyond manufacturer-specified lifetime. Patients performed at least five reference finger sticks per day. An analysis of variance was performed on all data points >=15 min apart. RESULTS: Overall average mean absolute relative difference (MARD) (SD) measured at the CRC was 16.5% (14.3%) for NAV and 16.4% (15.6%) for ENL, outperforming G4A at 20.5% (18.2%) (P<0.001). Overall MARD when assessed at home was 14.5% (16.7%) for NAV and 16.5 (18.8%) for G4A, outperforming ENL at 18.9% (23.6%) (P=0.006). Median time until end of functioning was similar: 10.0 (1.0) days for G4A, 8.0 (3.5) days for NAV, and 8.0 (1.5) days for ENL (P=0.119). CONCLUSIONS: In the CRC, G4A was less accurate than NAV and ENL sensors, which seemed comparable. However, at home, ENL was less accurate than NAV and G4A. Moreover, CGM systems often show sufficient accuracy to be used beyond manufacturer-specified lifetime. PMID- 23650901 TI - Patch pump versus conventional pump: postprandial glycemic excursions and the influence of wear time. AB - BACKGROUND AND AIMS: The aim of this study was to compare blood glucose and plasma insulin profiles after bolus insulin infusion by a patch pump (PP) versus a conventional pump (CP), directly after placement and after Day 3 of use. PATIENTS AND METHODS: Twenty patients with type 1 diabetes came in for two blocks of visits: one block of two visits while wearing the OmniPod(r) (Insulet Corp., Bedford, MA) insulin pump (PP) and one block of two visits while wearing the Medtronic Diabetes (Northridge, CA) Paradigm(r) pump (CP). Patients administered an identical mealtime insulin bolus of at least 6 IU. RESULTS: For PP, maximum glucose levels were 28.7% lower on Day 3 (P=0.020), when maximum insulin levels were 30.3% higher (P=0.002). For CP, maximum glucose levels were 26.5% lower on Day 3 (P=0.015), when maximum insulin levels were 46.4% higher (P=0.003). Glucose levels (mean [interquartile range]) were significantly lower on Day 3 for PP (168.2 [145.8] mg/dL vs. 139.4 [77.8] mg/dL; P=0.013), but not significantly so for CP (159.0 [66.1] mg/dL vs. 139.5 [57.9] mg/dL; P=0.084). Mean insulin levels were significantly higher on Day 3 for CP (195 [120] pmol/L vs. 230 [90] pmol/L; P=0.01), but not significantly so for PP (178 [106] pmol/L vs. 194 [120] pmol/L; P=0.099). There were no significant differences between the two catheter lengths. CONCLUSIONS: Postprandial glycemic excursions were lower on Day 3 of catheter wear time, but there were no differences between PPs and CPs. These findings support the proposal that catheter wear time plays an important role in insulin absorption. PMID- 23650902 TI - C-O bond cleavage of dimethyl ether by transition metal ions: a systematic study on catalytic properties of metals and performance of DFT functionals. AB - Studies were focused on late 3d and 4d transition metal ion (Fe, Co, Ni, Cu, Ru, Rh, Pd, and Ag) mediated activation of dimethyl ether, to investigate the intrinsic catalytic properties of metals on C-O bond cleavage. A set of density functional (DFT) methods (BLYP, B3LYP, M06, M06-L, B97-1, B97-D, TPSS, and PBE0) with aug-cc-pVTZ were utilized, and the results were calibrated with CCSD(T)/CBS. The utility of CCSD(T)/CBS calculations for these systems was validated by MRCI/aug-cc-pVTZ calculations. Calculations showed an interesting energetic trend as a function of metal; earlier transition metals tend to give smaller reaction barriers and more exergonic reactions than later metals. This applies to both 3d and 4d systems. For the performance of DFT functionals, PBE0 gave the lowest root mean squared deviations (RMSDs) in terms of both reaction energies and barriers for both 3d and 4d systems, compared to the other functionals. Our studies found that the percentage of Hartree-Fock (HF) exchange plays an important role in the accuracy of DFT methods for these systems, and 26% HF exchange for 3d systems and 34% HF exchange for 4d systems gave the lowest RMSDs. PMID- 23650903 TI - Effects of ceftriaxone-induced intestinal dysbacteriosis on dendritic cells of small intestine in mice. AB - Intestinal microflora plays a pivotal role in the development of the innate immune system and is essential in shaping adaptive immunity. Dysbacteriosis of intestinal microflora induces altered immune responses and results in disease susceptibility. Dendritic cells (DCs), the professional antigen-presenting cells, have gained increasing attention because they connect innate and adaptive immunity. They generate both immunity in response to stimulation by pathogenic bacteria and immune tolerance in the presence of commensal bacteria. However, few studies have examined the effects of intestinal dysbacteriosis on DCs. In this study, changes of DCs in the small intestine of mice under the condition of dysbacteriosis induced by ceftriaxone sodium were investigated. It was found that intragastric administration of ceftriaxone sodium caused severe dysteriosis in mice. Compared with controls, numbers of DCs in mice with dysbacteriosis increased significantly (P = 0.0001). However, the maturity and antigen presenting ability of DCs were greatly reduced. In addition, there was a significant difference in secretion of IL-10 and IL-12 between DCs from mice with dysbacteriosis and controls. To conclude, ceftriaxone-induced intestinal dysbacteriosis strongly affected the numbers and functions of DCs. The present data suggest that intestinal microflora plays an important role in inducing and maintaining the functions of DCs and thus is essential for the connection between innate and adaptive immune responses. PMID- 23650905 TI - Prevalence and factors predictive of long-acting reversible contraceptive use in a tertiary hospital in urban Ghana. AB - OBJECTIVE: To determine the prevalence, socio-demographic and reproductive factors associated with long-acting reversible contraceptive (LARC) use among clients resorting to reversible birth control methods in a tertiary hospital in Ghana. METHODS: Retrospective review of records of clients who opted for reversible family planning (FP) methods at Komfo Anokye Teaching Hospital, Kumasi, Ghana, from 1 July 2003 to 30 June 2008. We recorded data on their contraceptive history, and socio-demographic- and reproductive characteristics. Categorical variables were compared using the chi(2) test and factors associated with LARC uptake examined by binomial regression with a log-link function to estimate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: Of 5946 clients who opted for reversible contraception, 71% chose LARCs, and the remaining 29% chose shorter-acting contraceptives. LARCs were employed mainly by women with more living children (p trend < 0.001) who had previously used LARCs (adjusted RR: 1.49; 95% CI: 1.39-1.60). Over half of non-contraceptive users started with LARCs while 27% of women switched from shorter-acting contraceptives to LARCs. CONCLUSION: The prevalence of LARC uptake was much higher than the national average. Significant factors associated with current LARC use were the number of surviving children and previous LARC use. PMID- 23650904 TI - Glutaraldehyde cross-linked glutamate oxidase coated microelectrode arrays: selectivity and resting levels of glutamate in the CNS. AB - Glutaraldehyde is widely used as a cross-linking agent for enzyme immobilization onto microelectrodes. Recent studies and prior reports indicate changes in enzyme activity and selectivity with certain glutaraldehyde cross-linking procedures that may jeopardize the performance of microelectrode recordings and lead to falsely elevated responses in biological systems. In this study, the sensitivity of glutaraldehyde cross-linked glutamate oxidase-based microelectrode arrays to 22 amino acids was tested and compared to glutamate. As expected, responses to electroactive amino acids (Cys, Tyr, Trp) were detected at both nonenzyme-coated and enzyme-coated microelectrodes sites, while the remaining amino acids yielded no detectable responses. Electroactive amino acids were effectively blocked with a m-phenylene diamine (mPD) layer and, subsequently, no responses were detected. Preliminary results on the use of poly(ethylene glycol) diglycidyl ether (PEGDE) as a potentially more reliable cross-linking agent for the immobilization of glutamate oxidase onto ceramic-based microelectrode arrays are reported and show no significant advantages over glutaraldehyde as we observe comparable selectivities and responses. These results support that glutaraldehyde-cross linked glutamate oxidase retains sufficient enzyme specificity for accurate in vivo brain measures of tonic and phasic glutamate levels when immobilized using specific "wet" coating procedures. PMID- 23650906 TI - Management of patent ductus arteriosus in preterm infants: clinical judgment might be a fair option. AB - OBJECTIVE: The objective of this study was to find out the percentage of preterm infants that needed treatment for patent ductus arteriosus (PDA), when treatment decision was based on clinical signs and symptoms, besides echocardiographic findings. METHODS: Daily echocardiographic evaluation was conducted in 39 preterms <=29(6/7) weeks' gestation. Patients with ductus arteriosus were closely followed-up for clinical symptoms of PDA for treatment decision until ductus arteriosus was closed either spontaneously or by treatment. RESULTS: PDA was found in 25 (64%) infants. Mean gestational age and birth weight (BW) of the patients with PDA were 27.8 +/- 1.2 and 998 +/- 221 g, respectively. PDA closed spontaneously or had minimal ductal shunting before any signs and symptoms attributable to PDA were observed in 16 (41%) infants. Mean ductus size/BW ratio and mean left atrial/aortic root ratio were significantly higher in 9 (23%) symptomatic patients (2.06 +/- 0.75 versus 1.32 +/- 0.75 mm, p = 0.012 and 1.31 +/- 0.52 versus 1.19 +/- 0.2 mm, p = 0.043, respectively). PDA closure was observed after the first dose of ibuprofen in six of nine patients. CONCLUSION: Correlation of clinical signs with echocardiographic findings for the decision of PDA treatment can be appropriate to prevent unnecessary medical treatments. PMID- 23650907 TI - Assessing patient capacity to consent to treatment: an integrative review of instruments and tools. AB - AIMS AND OBJECTIVES: To provide a narrative synthesis of research findings on instruments or tools designed to aid assessment of patient capacity to consent to treatment. BACKGROUND: Capacity assessment is of significant priority within health care as a finding of incapacity is a vehicle for the removal of many of an individual's fundamental rights. Despite there being many instruments and tools available to aid health professionals in the assessment of patient capacity, there are no standardised guidelines from professional bodies that inform the assessment of mental capacity. DESIGN: Integrative review. METHOD: Primary studies of instruments or tools concerning assessment of patient capacity to consent to treatment, published in English in peer-reviewed journals between January 2005-December 2010, were included in the review. Review papers of capacity assessment instruments were included for years including and prior to 2006. RESULTS: Nineteen instruments were found which assess patient capacity to consent. Key themes were identified in terms of capacity domains assessed, psychometric properties, instrument implementation, patient populations studied and instrument versus clinician judgement. CONCLUSION: Despite a plethora of capacity assessment instruments and tools available, only a small number of instruments were found to have demonstrated both reliability and validity. Further research is required to improve the validity of existing capacity assessment instruments. RELEVANCE TO CLINICAL PRACTICE: Increased attention to patient rights and autonomy arguably places a considerable burden on healthcare professionals to facilitate capacity assessments across a continuum of health care. Despite a plethora of capacity assessment instruments and tools being available to healthcare professionals, a comprehensive assessment requires time and is often difficult in the acute care setting. A strictly formulaic approach to the assessment of capacity is unlikely to capture specific individual nuances; therefore, capacity assessment instruments should support, but not replace, experienced clinical judgement. PMID- 23650908 TI - Drug-induced hperpigemntation: a systematic review. AB - BACKGROUND: Acquired hyperpigmentation of the skin is sometimes interpreted as an adverse effect of drugs. Systematic studies are rare in the literature; predominantly case reports have been published. The present review provides evaluates the evidence for a causal relation. METHODS: The reports on a relationship between hyperpigmentation and drugs from 1970 until June 2012 found in MEDLINE and EMBASE were rated according to the SIGN grading system for clinical studies. In this system, the grade of evidence of each report is rated. The highest grade of evidence for each drug is cited. RESULTS: 306 publications were included. They were predominantly case reports; only a small number of case series was available. Only very few case-control-studies and randomized controlled trials (RCT) were found. For the majority of drugs, there was a low level of evidence for a causal relationship in drug-induced hyperpigmentation. A causal relationship is likely only for prostaglandins, minocycline, phenothiazine, nicotine, and antimalarial drugs. CONCLUSIONS: There is little evidence for drug-induced hyperpigmentation. A causal relationship appears liklely only for a limited number of drugs. PMID- 23650909 TI - Nephrotic syndrome and AA amyloidosis revealing adult-onset cryopyrin-associated periodic syndrome. AB - Cryopyrin-associated periodic syndrome (CAPS) is due to gain-of-function mutations in the cryopyrin gene, which determines an overactive inflammatory response. AA amyloidosis is a complication of this syndrome. A 53-year-old man was referred to us because of lower limb edema. Past history: at the age of 20, he complained of arthralgia/arthritis and bilateral hypoacusis. At the age of 35, he presented posterior uveitis, several episodes of conjunctivitis, and progressive loss of visual acuity. Laboratory tests disclosed nephrotic syndrome, and renal biopsy showed AA amyloidosis. He was given anakinra with improvement of arthritis. A genetic study revealed the p.D303N mutation in the cryopyrin gene, and he was diagnosed as having AA amyloidosis due to CAPS. Twenty-one months after starting anakinra, the arthritis has disappeared, although nephrotic-range proteinuria persisted. It is important to be aware of cryopyrin-associated periodic syndrome because it can cause irreversible complications, and there is effective therapy. PMID- 23650910 TI - Recombinant bovine growth hormone identification and the kinetic of elimination in rainbow trout treated by LC-MS/MS. AB - The efficiency of the administration of recombinant bovine growth hormone (rbGH) to enhance fish growth has been widely reported in the literature. Although its use is probable and has been described in several countries, rbGH is prohibited in the European Union (Council Decisions 1994/936/EC, 1999/879/EC). In this context, an analytical strategy was optimised in order to identify rbGH-treated fish. Currently, one of the most difficult challenges for the detection of rbGH in fish is probably the choice of the matrix and the corresponding available quantity for analysis. Therefore, based on a previous efficient protocol developed for mammalian species, a method was adapted for very limited serum volume (50 ul) and was successfully implemented to analyse serum collected from seven trout treated with rbGH. The detection of rbGH was possible from the very first day after administration and the hormone could easily be identified at least for 1 month with levels in the range 5-10 ug ml(-1). The limits of detection (LODs) estimated around 0.5 ug ml(-1) rbGH in fish serum are far below observed concentrations in incurred samples and therefore attest to the relevance of the developed protocol. PMID- 23650911 TI - Abnormal white matter correlates with neuropsychological impairment in children with localization-related epilepsy. AB - PURPOSE: The white matter (WM) is considered critical for linking cortical processing networks necessary for cognition. The aim of this study was to assess diffusion tensor imaging (DTI) measures of regional WM in children with nonlesional localization-related epilepsy in comparison to controls, and to determine the relation between lobar WM and neuropsychological performance. METHODS: Forty children with nonlesional localization-related epilepsy and 25 healthy controls with no neurological or psychiatric disorders and normal magnetic resonance imaging (MRI) were recruited. All patients and controls underwent neuropsychological testing that evaluated intelligence, language, memory, executive function, and motor function, as well as DTI to assess regional WM measures of fractional anisotropy (FA) and mean diffusivity (MD). The regional FA and MD were compared between patients and controls, and correlated with neuropsychological function. The relations between regional FA and MD with age at seizure onset and duration of epilepsy were assessed. KEY FINDINGS: Twenty-one patients had left-sided and 19 patients had right-sided epilepsy. There were no significant differences in seizure-related variables including age at seizure onset, duration of epilepsy, seizure frequency, and number of antiepileptic medications, as well as no significant differences in neuropsychological function and DTI measures of white matter in left-sided compared to right-sided epilepsy. Therefore, all the patients with epilepsy were treated as one group. Patients with epilepsy performed significantly worse on intelligence (p < 0.001), language (p < 0.001), and executive function (p = 0.001) evaluation than controls. Patients had significantly reduced FA in left frontal (p = 0.015), right frontal (p = 0.004), left temporal (p = 0.039), right temporal (p = 0.003), right parietal (p = 0.014), and right occipital (p = 0.025) WM relative to controls. There were no significant regional WM differences (all p > 0.05) in MD between patients and controls. There was a significant positive correlation between right temporal FA with language (r = 0.535, p < 0.001) and executive function (r = 0.617, p < 0.001), as well as between body of corpus callosum FA with intelligence (r = 0.536, p < 0.001) and language (r = 0.529, p < 0.001) in patients. Left parietal MD was significantly correlated with language (r = 0.545, p < 0.001) in patients. FA of right temporal WM was significantly associated with age at seizure onset (t = 4.97, p < 0.001). SIGNIFICANCE: There was widespread regional WM abnormality in children with nonlesional localization related epilepsy, which was associated with impaired neuropsychological function. The impairment in WM may reflect disruption in the connectivity for cortical processing networks, which is necessary for the development of cognition. PMID- 23650912 TI - Pre-existing IgG antibodies cross-reacting with the Fab region of infliximab predict efficacy and safety of infliximab therapy in inflammatory bowel disease. AB - BACKGROUND: Infliximab (IFX) is a chimeric murine/human anti-TNF antibody (Ab) used for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). Loss of response is common and associated with development of anti-IFX Abs during ongoing therapy. However, human anti-murine immunoglobulin Abs are common and may cross-react with the murine part of IFX. AIM: To investigate if Abs binding to IFX's Fab region (IFX-Fab) are present in IBD patients before exposure to IFX, and whether they predict efficacy and safety of IFX therapy. METHODS: Observational, retrospective cohort study of patients with CD (n = 29) and UC (n = 22). RESULTS: Pre-treatment levels of IFX-Fab reactive IgG Abs were significantly lower in CD patients in remission after 1 year of maintenance IFX (median 91 mU/L, n = 8) than in the rest of the patients (639 mU/L, n = 21; P < 0.01), and lower than in patients with secondary loss of response in particular (692 mU/L, n = 7; P < 0.01). A cut-off concentration of <439 mU IFX-Fab reactive IgG Ab per litre comprised all patients who later obtained long-term sustained remission on IFX (sensitivity 100%, specificity 67%). Similar trends were observed in UC. The pre-treatment levels of IFX-Fab reactive IgG Abs were markedly higher in patients developing infusion reactions to IFX (1037 mU/L, n = 7) than in the remaining patients (349 mU/L, n = 44; P = 0.036). CONCLUSIONS: IFX Fab reactive IgG antibodies present in serum from IBD patients before infliximab therapy associate with lack of long-term efficacy and safety. Assessments of such antibodies may help clinicians to choose between treatment with infliximab and more humanised agents. PMID- 23650913 TI - Merits of prophylactic sclerotherapy for esophageal varices concomitant unresectable hepatocellular carcinoma: prospective randomized study. AB - BACKGROUND: Several clinical studies of prophylactic therapy for esophageal varices have led to the conclusion that prophylactic therapy is of no value, and it is generally not accepted in the Western world. However, this is not the case in Japan. The present study evaluated the efficacy of prophylactic endoscopic injection sclerotherapy (EIS) in patients with unresectable hepatocellular carcinoma (HCC) and risky esophageal varices. PATIENTS AND METHODS: Twenty-seven patients with 'likely-to-bleed' esophageal varices concomitant with unresectable HCC were randomly allocated to two groups. Thirteen patients underwent prophylactic EIS (EIS group), whereas the remaining 14 patients were observed conservatively (control group). RESULTS: No bleeding from esophageal varices occurred in the EIS group during the entire period of this study, whereas in thecontrol group the cumulative bleeding rate was 44.8% in 6 months. Cumulative survival rates of patients in the EIS group and in the control group were 48.8% and 7.7% in 2 years, respectively. There was a statistically significant difference between the two groups in cumulative bleeding rate and survival rate (P < 0.01). CONCLUSION: This prospective study demonstrated that prophylactic EIS could prolong the survival of the patients with esophageal varices concomitant with unresectable HCC. Prophylactic EIS for patients with unresectable HCC may be, in part, justified according to the present study. PMID- 23650915 TI - Paralogous chemoreceptors mediate chemotaxis towards protein amino acids and the non-protein amino acid gamma-aminobutyrate (GABA). AB - The paralogous receptors PctA, PctB and PctC of Pseudomonas aeruginosa were reported to mediate chemotaxis to amino acids, intermediates of amino acid metabolism and chlorinated hydrocarbons. We show that the recombinant ligand binding regions (LBRs) of PctA, PctB and PctC bind 17, 5 and 2 l-amino acids respectively. In addition, PctC-LBR recognized GABA but not any other structurally related compound. l-Gln, one of the three amino acids that is not recognized by PctA-LBR, was the most tightly binding ligand to PctB suggesting that PctB has evolved to mediate chemotaxis primarily towards l-Gln. Bacteria were efficiently attracted to l-Gln and GABA, but mutation of pctB and pctC, respectively, abolished chemoattraction. The physiological relevance of taxis towards GABA is proposed to reside in an interaction with plants. LBRs were predicted to adopt double PDC (PhoQ/DcuS/CitA) like structures and site-directed mutagenesis studies showed that ligands bind to the membrane-distal module. Analytical ultracentrifugation studies have shown that PctA-LBR and PctB-LBR are monomeric in the absence and presence of ligands, which is in contrast to the enterobacterial receptors that require sensor domain dimers for ligand recognition. PMID- 23650914 TI - Impact of lymphovascular invasion on oncological outcomes in patients with upper tract urothelial carcinoma after radical nephroureterectomy. AB - OBJECTIVES: To assess the impact of lymphovascular invasion (LVI) on upper urinary tract urothelial carcinomas (UTUCs) in a multicentre study on cancer specific survival (CSS), recurrence-free survival and metastasis-free survival (MFS). To show the negative impact of LVI for patients with pN0/x disease and to stratify these patients into risk groups for metastatic relapse. PATIENTS AND METHODS: A multicentre retrospective study was performed on patients who underwent radical nephroureterectomy between 1995 and 2010. LVI status was evaluated as a prognostic factor for survival using univariate and multivariate Cox regression analysis. RESULTS: Overall, 551 patients were included and were divided into two groups: those without LVI (LVI-), n = 388 and those with LVI (LVI+), n = 163. LVI+ status was associated with high stage and grade UTUC and lymph node metastasis (P < 0.001). The 5-year CSS and MFS rates were significantly worse in the LVI+ group than in LVI- group (52.2 vs 84.5%, P < 0.001 and 43.8 vs 82.7%, P < 0.001, respectively). In multivariate analysis, LVI+ status was an independent prognostic factor for CSS and MFS (P = 0.04 and P < 0.001). These findings were confirmed for the pN0/x patient subgroup (n = 504, P < 0.001). In the pN0/x patient subgroup, we described a prognostic tool for MFS based on independent factors that permitted us to stratify patients into groups of high, intermediate or low risk of metastasis relapse. CONCLUSIONS: The presence of LVI was a strong predictor of a poor outcome for UTUC. When a lymphadenectomy has not been achieved, the report of LVI status is crucial to identfiy those patients at higher risk for metastatic relapse. PMID- 23650916 TI - Editorial. PMID- 23650917 TI - Undermining patient and public engagement and limiting its impact: the consequences of the Health and Social Care Act 2012 on collective patient and public involvement. AB - Patient and public involvement has been at the heart of UK health policy for more than two decades. This commitment to putting patients at the heart of the British National Health Service (NHS) has become a central principle helping to ensure equity, patient safety and effectiveness in the health system. The recent Health and Social Care Act 2012 is the most significant reform of the NHS since its foundation in 1948. More radically, this legislation undermines the principle of patient and public involvement, public accountability and returns the power for prioritisation of health services to an unaccountable medical elite. This legislation marks a sea-change in the approach to patient and public involvement in the UK and signals a shift in the commitment of the UK government to patient centred care. PMID- 23650918 TI - Monodisperse M(x)Fe(3-x)O4 (M = Fe, Cu, Co, Mn) nanoparticles and their electrocatalysis for oxygen reduction reaction. AB - Sub-10 nm nanoparticles (NPs) of M(II)-substituted magnetite MxFe3-xO4 (MxFe1 xO*Fe2O3) (M = Mn, Fe, Co, Cu) were synthesized and studied as electrocatalysts for oxygen reduction reaction (ORR) in 0.1 M KOH solution. Loaded on commercial carbon support, these MxFe3-xO4 NPs showed the M(II)-dependent ORR catalytic activities with MnxFe3-xO4 being the most active followed by CoxFe3-xO4, CuxFe3 xO4, and Fe3O4. The ORR activity of the MnxFe3-xO4 was further tuned by controlling x and MnFe2O4 NPs were found to be as efficient as the commercial Pt in catalyzing ORR. The MnFe2O4 NPs represent a new class of highly efficient non Pt catalyst for ORR in alkaline media. PMID- 23650919 TI - Antiphospholipid antibodies affect human endometrial angiogenesis: protective effect of a synthetic peptide (TIFI) mimicking the phospholipid binding site of beta(2) glycoprotein I. AB - PROBLEM: Aim of our study was to investigate whether TIFI, a syntetic peptide able to compete with anti-phospholipid antibodies (aPL) in the binding to endothelium, may restore aPL-inhibited endometrial angiogenesis. METHODS: The protective role of TIFI was evaluated on: i) aPL-inhibited of human endometrial endothelial cells (HEEC) angiogenesis in vitro; ii) aPL-inhibited vascular endothelial growth factor (VEGF) and metalloproteases (MMPs) expression; iii) aPL inhibited Nuclear Factor-kappaB (NF-kappaB) and Extracellular signal-Regulated Kinase (ERK) activation and (iv) angiogenesis in vivo. RESULTS: TIFI restores in a dose-dependent manner: i) aPL-mediated inhibition of HEEC angiogenesis in vitro and in vivo (P < 0.05), ii) VEGF (P < 0.001) and MMP-2 (P < 0.05) expression and iii) NF-kappaB DNA binding and ERK-1/2 activation (P < 0.05) inhibited by aPL. CONCLUSION: Our results show for the first time the protective effects of TIFI, as represented by its ability to interfere with aPL mediated anti-angiogenic activity. PMID- 23650920 TI - Probe mobility in native phosphocaseinate suspensions and in a concentrated rennet gel: effects of probe flexibility and size. AB - Pulsed field gradient nuclear magnetic resonance and proton nuclear magnetic resonance relaxometry were used to study the self-diffusion coefficients and molecular dynamics of linear (PEGs) and spherical probes (dendrimers) in native phosphocaseinate suspensions and in a concentrated rennet gel. It was shown that both the size and the shape of the diffusing molecules and the matrix topography affected the diffusion and relaxation rates. In suspensions, both translational and rotational diffusion decreased with increasing casein concentrations due to increased restriction in the freedom of motion. Rotational diffusion was, however, less hindered than translational diffusion. After coagulation, translational diffusion increased but rotational diffusion decreased. Analysis of the T2 relaxation times obtained for probes of different sizes distinguished the free short-chain relaxation formed from a few monomeric units from (i) the relaxation of protons attached to long polymer chains and (ii) the short-chain relaxation attached to a rigid dendrimer core. PMID- 23650921 TI - Flow-injection MS/MS for gas-phase chiral recognition and enantiomeric quantitation of a novel boron-containing antibiotic (GSK2251052A) by the mass spectrometric kinetic method. AB - The present work demonstrates, for the first time, the application of the mass spectrometric kinetic method for quantitative chiral purity determination by automatic flow-injection MS/MS. The particular compound analyzed is GSK2251052A, a novel boron-containing systemic antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections. Chiral recognition and quantitation of GSK2251052A was achieved based on the competitive dissociation kinetics of the Cu(II)-bound trimeric complex [Cu(II)(A)(ref*)2-H](+) (A = GSK2251052A or its R enantiomer, ref* = L-tryptophan) that gives rise to Cu(II)-bound dimeric complexes. The sensitive nature of the methodology and the linear relationship between the logarithm of the fragment ion abundance ratio and the optical purity, characteristic of the kinetic method, allow chiral purity determination of pharmaceutical compounds during enantioselective synthesis. By using flow injection MS/MS, enantiomeric quantitation of GSK2251052A by the kinetic method proved to be fast (2 min for analysis of each sample) and to have accuracy comparable to chiral LC-MS/MS and LC-UV methods as well as the method using chiral derivatization followed by LC-MS/MS analysis. This flow-injection MS/MS method represents an alternative approach to commonly used chromatographic techniques as a means of chiral purity determination and is particularly useful for rapid screening of chiral drugs during pharmaceutical development. PMID- 23650922 TI - Analysis of interleukin-1beta gene polymorphism and its association with generalized aggressive periodontitis disease. AB - Generalized aggressive periodontitis (GAP) is a subgroup of periodontal diseases among 20-35 years age group adults. Several studies have reported the association of interleukin-1beta gene polymorphism with periodontal diseases among different populations. The present study aimed at investigating the presence of IL-1beta polymorphism in GAP patients in Iran. Further, the presence of IL-1beta(+3954) gene polymorphism was evaluated in the GAP patients (n=26) and healthy individuals (n=26). All three genotypes (A1A1 [56%], A1A2 [28%], and A2A2 [16%]) were observed in healthy individuals, whereas only A1A1 (38.5%) and A2A2 (61.5%) were the genotypes observed in the patients. There was a significant positive association between distribution of IL-1beta genotypes and the risk of periodontitis disease (p=0.017). Further, there was a significant positive association between probing pocket depth and IL-1beta genotypes of patients (p=0.014). However, no meaningful correlation between genotype-clinical attachment loss and genotype bleeding on probing with the risk of GAP (p=0.418, p=0.819, respectively) was found. In conclusion, findings of the present study demonstrate a positive association between IL-1beta gene polymorphism and risk of periodontitis disease. PMID- 23650923 TI - How should we educate dental geriatricians? PMID- 23650924 TI - Clinical aspects of the use of dental adhesive materials in patients with chronic xerostomia. AB - Adhesives are commonly used by denture wearers to increase the retention and stability of the complete denture, to improve the chewing and masticatory abilities and to psychologically support the patient to make the complete denture more acceptable. Denture fixatives can be especially recommended for use and to aid retention for patients with dryness of the mouth, poor secretion of saliva and xerostomia (e.g. diabetes mellitus). Dental adhesives may be contaminated with bacteria, yeast and fungi during the manufacturing process, and they have been shown to initiate and promote microbial growth. Some products have been shown to release formaldehyde, which is cytotoxic to cell culture and fibroblasts and is a potent allergen. Patients with chronic xerostomia may use denture adhesives during the course of the treatment and disease. These patients are often immunocompromised, and microorganisms they are exposed to must be considered potential pathogens. PMID- 23650925 TI - The effect of local dry heat pack application on recovering the bruising associated with the subcutaneous injection of heparin. AB - AIMS AND OBJECTIVES: To determine the effect of the local dry heat pack application on recovering or alleviating the bruising associated with the subcutaneous injection of heparin. BACKGROUND: In studies conducted to prevent the bruising associated with the subcutaneous injection of heparin, it is observed that bruising cannot be prevented completely; however, there is a decrease in frequencies and sizes of bruising. There is no study aimed at accelerating the bruising recovery. DESIGN: Quasi-experimental. METHODS: Thirty three patients, who were treated for heparin and had bruising in the injection site, were included in the study. One of their upper arms with bruising was considered as the experimental arm, and the other upper arm with bruising was considered as the control arm. 'Local dry heat pack' application was performed on the bruising area in the experimental arm 72 hours after the heparin injection. As the bruising areas in the other upper arm were considered as the control arm, no application was performed. The sizes of bruising areas were drawn on the transparent film and determined as square centimetre. RESULTS: The size of bruising areas was 3.21 +/- 3.78 cm2 in the experimental arm and 5.22 +/- 4.45 cm2 in the control arm 120 hours after the injections. The difference between the bruising sizes of the experimental and control arms was statistically significant. CONCLUSIONS: It was observed that 'local dry heat pack' application had a positive effect on the recovery of bruising, associated with the subcutaneous injection of heparin. RELEVANCE TO CLINICAL PRACTICE: The acceleration of bruising recovery will enable decreasing patients' anxieties, improving their body image and increasing their adherence to therapy. PMID- 23650926 TI - Photodynamics of Schiff base salicylideneaniline: trajectory surface-hopping simulations. AB - We report a computational study on the photochemistry of the prototypical aromatic Schiff base salicylideneaniline in the gas phase using static electronic structure calculations (TDDFT, OM2/MRCI) and surface-hopping dynamics simulations (OM2/MRCI). Upon photoexcitation of the most stable cis-enol tautomer into the bright S1 state, we find an ultrafast excited-state proton transfer that is complete within tens of femtoseconds, without any C?N double bond isomerization. The internal conversion of the resulting S1 cis-keto species is initiated by an out-of-plane motion around the C-C single bond, which guides the molecule toward a conical intersection that provides an efficient deactivation channel to the ground state. We propose that the ease of this C-C single bond rotation regulates fluorescence quenching and photocoloration in condensed-phase environments. In line with previous work, we find the S1 cis-keto conformer to be responsible for fluorescence, especially in rigid surroundings. The S0 cis-keto species is a transient photoproduct, while the stable S0 trans-keto photoproduct is responsible for photochromism. The trajectory calculations yield roughly equal amounts of the S0 cis-enol and trans-keto photoproducts. Methodologically, full dimensional nonadiabatic dynamics simulations are found necessary to capture the preferences among competitive channels and to gain detailed mechanistic insight into Schiff base photochemistry. PMID- 23650927 TI - Development of a real-time RT-PCR assay for the simultaneous identification, quantitation and differentiation of avian metapneumovirus subtypes A and B. AB - In recent years, special attention has been paid to real-time polymerase chain reaction (PCR) for avian metapneumovirus (AMPV) diagnosis, due to its numerous advantages over classical PCR. A new multiplex quantitative real-time reverse transcription-PCR (qRT-PCR) with molecular beacon probe assay, designed to target the SH gene, was developed. The test was evaluated in terms of specificity, sensitivity and repeatability, and compared with conventional RT nested-PCR based on the G gene. All of the AMPV subtype A and B strains tested were amplified and specifically detected while no amplification occurred with other non-target bird respiratory pathogens. The detection limit of the assay was 10(-0.41) median infectious dose/ml and 10(1.15) median infectious dose/ml when the AMPV-B strain IT/Ty/B/Vr240/87 and the AMPV-A strain IT/Ty/A/259-01/03 were used, respectively, as templates. In all cases, the amplification efficiency was approximately 2 and the error values were <0.2. Standard curves, generated either using the serial dilution of an RNA suspension or RNA extracted from the serial dilution of titrated viral suspensions as templates, exhibited good linearity (R (2)>0.9375) between crossing point values and virus quantities, making the assay herein designed reliable for quantification. When the newly developed qRT-PCR was compared with a conventional RT nested-PCR, it showed greater sensitivity with RNA extracted from both positive controls and from experimentally infected birds. This assay can be effectively used for the detection, identification, differentiation and quantitation of AMPV subtype A or subtype B to assist in disease diagnosis and to carry out rapid surveillance with high levels of sensitivity and specificity. PMID- 23650928 TI - In vitro antibacterial activity and physicochemical properties of a crude methanol extract of the larvae of the blow fly Lucilia cuprina. AB - The emergence of multidrug-resistant bacterial strains has prompted the reintroduction of maggot therapy in the treatment of chronic, infected wounds. Many previous studies have demonstrated the potent antibacterial activity of larval excretions/secretions of the blowfly Lucilia sericata (Meigen) (Diptera:Calliphoridae) against bacteria. However, the antibacterial activity of its sibling species, Lucilia cuprina (Wiedemann) (Diptera:Calliphoridae) against a wide range of pathogenic bacteria has never been determined. The aim of this study was to develop a new procedure to produce whole body extract of larvae of L. cuprina via methanol extraction as well as to demonstrate the in vitro antibacterial activity of this extract against seven selected wound pathogens (Staphylococcus aureus, methicillin-resistant S. aureus, S. epidermidis, Streptococcus pyogenes, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli). The turbidimetric assay demonstrated that L. cuprina larval extract was significantly potent against all bacteria tested (P < 0.001). Additionally, colony-forming unit (CFU), agar well diffusion and minimum inhibitory concentration assays have confirmed the apparent potency of larval extract against P. aeruginosa. The reconstituted larval extract was highly robust and thermally stable. These observations substantiated the feasibility of the methanol extraction method in the production of larval extract. PMID- 23650929 TI - Submicrometer-sized Pickering emulsions stabilized by silica nanoparticles with adsorbed oleic acid. AB - Oil-water Pickering emulsions of about 200 nm were stabilized by nanosized hydrophilic silica after a simple surface treatment method. We have modified the aqueous silica nanoparticle dispersions by simple adsorption of oleic acid to their surfaces, improving the hydrophobicity of the particles while maintaining their charge and stability. The adsorption was monitored by small-angle X-ray scattering and electrophoretic measurements to estimate the interparticle interactions and surface charges. The effect of various parameters, such as nanoparticle concentration, amount of oleic acid, ionic strength, and pH, on the droplets' size and stability was investigated by dynamic light scattering. Furthermore, the ability of these modified silica nanoparticles to stabilize long chain alkanes, liquid paraffin, and liquid-crystalline phases was examined. PMID- 23650930 TI - Low levels of circulating alpha-1 antitrypsin are associated with spontaneous abortions. AB - OBJECTIVE: Alpha-1 antitrypsin (AAT), a circulating anti-inflammatory molecule, rises four- to sixfold during acute phase responses and during pregnancy. AAT deficiency is linked with various pregnancy complications. The aim of this study is to determine plasma concentrations and activity of AAT and serum cytokine levels in blood samples from women undergoing spontaneous abortions as compared with elective abortions. METHODS: A prospective case-control study consisted of patients with sporadic abortions (n = 15), recurrent spontaneous abortions (n = 14) and healthy pregnancies going through elective terminations (n = 11). Circulating AAT and cytokine levels were determined before dilatation and curettage. RESULTS: AAT levels were lower in both recurrent and sporadic spontaneous abortion groups compared with healthy pregnancies (1.421 +/- 0.08, 1.569 +/- 0.14 and 3.224 +/- 0.45 mg/ml, respectively, p < 0.001). Reduced AAT levels correlated with elevated proinflammatory cytokines. CONCLUSIONS: AAT levels in patients with either sporadic or recurrent spontaneous abortions were lower than normal pregnancies, and were associated with an inflammatory profile. Future studies should examine larger cohort groups, effects of earlier time points and the influence of antithrombotic therapy in such patients who are diagnosed with relatively low levels of circulating AAT, in an effort to improve pregnancy outcomes. PMID- 23650931 TI - Plasma kynurenic acid/tryptophan ratio: a sensitive and reliable biomarker for the assessment of renal function. AB - BACKGROUND: Decreased tryptophan (TRP) and increased kynurenine (KYN) and kynurenic acid (KYNA) in blood have been reported in patients and experimental animals with renal diseases. We investigated if these compounds could be used as new biomarkers for the assessment of renal function. METHODS: Eighty hospitalized hypertensive patients (20 with chronic kidney disease (CKD), and other 60 were considered as control) were enrolled for the investigation. Plasma TRP, KYN, and KYNA were determined by high-performance liquid chromatography. Change rate (CR) was employed to evaluate the sensitivity of the parameters of renal function. RESULTS: CR of plasma KYNA/TRP ratio (+103%) was much higher than the CRs of blood urea nitrogen (+44%), serum creatinine (+56%) and estimated glomerular filtration rate (-35%). Plasma KYNA/TRP ratio was in close relationship with blood urea nitrogen (r = 0.622), serum creatinine (r = 0.797), urine micro albumin/24-h (r = 0.518) and estimated glomerular filtration rate (r = -0.662), respectively, with all p-values <0.001. CONCLUSIONS: Plasma KYNA/TRP ratio was sensitive and reliable to indicate renal function and could be used as a new biomarker to assess the risk or presence of kidney disease. PMID- 23650932 TI - Glycine conjugation: importance in metabolism, the role of glycine N acyltransferase, and factors that influence interindividual variation. AB - INTRODUCTION: Glycine conjugation of mitochondrial acyl-CoAs, catalyzed by glycine N-acyltransferase (GLYAT, E.C. 2.3.1.13), is an important metabolic pathway responsible for maintaining adequate levels of free coenzyme A (CoASH). However, because of the small number of pharmaceutical drugs that are conjugated to glycine, the pathway has not yet been characterized in detail. Here, we review the causes and possible consequences of interindividual variation in the glycine conjugation pathway. AREAS COVERED: The authors review the importance of CoASH in metabolism, formation and toxicity of xenobiotic acyl-CoAs, and mechanisms for restoring levels of CoASH. They focus on GLYAT, glycine conjugation, how genetic variation in the GLYAT gene could influence glycine conjugation, and the emerging roles of glycine metabolism in cancer and musculoskeletal development. EXPERT OPINION: The substrate selectivity of GLYAT and its variants needs to be further characterized, as organic acids can be toxic if the corresponding acyl-CoA is not a substrate for glycine conjugation. GLYAT activity affects mitochondrial ATP production, glycine availability, CoASH availability, and the toxicity of various organic acids. Therefore, variation in the glycine conjugation pathway could influence liver cancer, musculoskeletal development, and mitochondrial energy metabolism. PMID- 23650933 TI - Estimation and comparison of cumulative incidences of biliary self-expandable metallic stent dysfunction accounting for competing risks. AB - BACKGROUND: Self-expandable metallic stent (SEMS) placement is widely carried out for distal malignant biliary obstruction, and survival analysis is used to evaluate the cumulative incidences of SEMS dysfunction (e.g. the Kaplan-Meier [KM] method and the log-rank test). However, these statistical methods might be inappropriate in the presence of 'competing risks' (here, death without SEMS dysfunction), which affects the probability of experiencing the event of interest (SEMS dysfunction); that is, SEMS dysfunction can no longer be observed after death. A competing risk analysis has rarely been done in studies on SEMS. PATIENTS AND METHODS: We introduced the concept of a competing risk analysis and illustrated its impact on the evaluation of SEMS outcomes using hypothetical and actual data. Our illustrative study included 476 consecutive patients who underwent SEMS placement for unresectable distal malignant biliary obstruction. RESULTS: A significant difference between cumulative incidences of SEMS dysfunction in male and female patients via theKM method (P = 0.044 by the log rank test) disappeared after applying a competing risk analysis (P = 0.115 by Gray's test). In contrast, although cumulative incidences of SEMS dysfunction via the KM method were similar with and without chemotherapy (P = 0.647 by the log rank test), cumulative incidence of SEMS dysfunction in the non-chemotherapy group was shown to be significantly lower (P = 0.031 by Gray's test) in a competing risk analysis. CONCLUSION: Death as a competing risk event needs to be appropriately considered in estimating a cumulative incidence of SEMS dysfunction, otherwise analytical results may be biased. PMID- 23650934 TI - Expression patterns of nociceptin in rats following experimental tooth movement. AB - OBJECTIVES: To determine the expression levels of nociceptin following experimental tooth movement. MATERIALS AND METHODS: A total of 72 male Sprague Dawley rats were divided into two groups: sham and experimental groups. For the experimental group, closed coil springs were used to mimic orthodontic force (80 g) between upper incisors and first molars, and the rats were killed at 0 hours, 4 hours, 12 hours, 1 day, 2 days, 5 days, 7 days, 10 days, and 14 days. All of these procedures were similar for the sham group, except for that no force was applied. The four rats killed at 0 hours without any intervention were used as the baseline control in each group. Trigeminal nucleus caudalis from both the ipsilateral and contralateral sides of force applications were obtained for immunostaining. RESULTS: Nociceptin was expressed in both the ipsilateral and contralateral sides of each group. Its expression levels started to increase on day 2, peaked on day 7, and returned to baseline on day 10 in the experimental group, while expression levels started to decrease on day 1 and returned to baseline on day 10 in the sham group. Moreover, the expression levels were similar between the ipsilateral and contralateral sides in each group. CONCLUSION: The expression levels of nociceptin were elevated following experimental tooth movement. The anesthetic agent used in this study (chloral hydrate) may have an antagonism with nociceptin. Due to bilateral innervation of anterior teeth and bilateral projection of nerve fibers, the expression levels of nociceptin were similar between ipsilateral and contralateral sides. PMID- 23650935 TI - Rapid simultaneous quantification of zearalenone and fumonisin B1 in corn and wheat by lateral flow dual immunoassay. AB - A lateral flow dual immunoassay (LFDIA) was developed for rapid quantitative detection of zearalenone (ZEN) and fumonisin B1 (FB1) in corn and wheat samples on a single test strip. Two test lines and the control line on the nitrocellulose membrane were coated with ZEN and FB1 conjugates and goat anti-mouse IgG, respectively. Colloidal gold nanoparticles were conjugated with monoclonal antibodies against ZEN or FB1. The intensity of the test lines was analyzed by a photometric strip reader to determine the concentrations of ZEN and FB1 based on the calibration curves of known concentrations versus intensity readings. Test parameters such as types of buffers, ratio of the two gold-labeled antibodies, and dilution of the sample extracts and the gold-labeled antibodies were optimized. The detection limit was 0.35 and 5.23 ng/mL for ZEN and FB1, respectively, and the corresponding detection ranges were 0.94-7.52 and 9.34 100.45 ng/mL, respectively. Spiked and natural samples were analyzed using both LFDIA and liquid chromatography-tandem mass spectrometry. The two methods had a good correlation (R(2) = 0.96). The dual quantitative LFDIA is sensitive, rapid, and easy-to-use for on-site testing of a large number of samples. PMID- 23650936 TI - Indirect scaling methods for testing quantitative emotion theories. AB - Two studies investigated the utility of indirect scaling methods, based on graded pair comparisons, for the testing of quantitative emotion theories. In Study 1, we measured the intensity of relief and disappointment caused by lottery outcomes, and in Study 2, the intensity of disgust evoked by pictures, using both direct intensity ratings and graded pair comparisons. The stimuli were systematically constructed to reflect variables expected to influence the intensity of the emotions according to theoretical models of relief/disappointment and disgust, respectively. Two probabilistic scaling methods were used to estimate scale values from the pair comparison judgements: Additive functional measurement (AFM) and maximum likelihood difference scaling (MLDS). The emotion models were fitted to the direct and indirect intensity measurements using nonlinear regression (Study 1) and analysis of variance (Study 2). Both studies found substantially improved fits of the emotion models for the indirectly determined emotion intensities, with their advantage being evident particularly at the level of individual participants. The results suggest that indirect scaling methods yield more precise measurements of emotion intensity than rating scales and thereby provide stronger tests of emotion theories in general and quantitative emotion theories in particular. PMID- 23650937 TI - The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). AB - Several different stimuli may induce chronic prostatic inflammation, which in turn would lead to tissue damage and continuous wound healing, thus contributing to prostatic enlargement. Patients with chronic inflammation and benign prostatic hyperplasia (BPH) have been shown to have larger prostate volumes, more severe lower urinary tract symptoms (LUTS) and a higher probability of acute urinary retention than their counterparts without inflammation. Chronic inflammation could be a predictor of poor response to BPH medical treatment. Thus, the ability to identify patients with chronic inflammation would be crucial to prevent BPH progression and develop target therapies. Although the histological examination of prostatic tissue remains the only available method to diagnose chronic inflammation, different parameters, such as prostatic calcifications, prostate volume, LUTS severity, storage and prostatitis-like symptoms, poor response to medical therapies and urinary biomarkers, have been shown to be correlated with chronic inflammation. The identification of patients with BPH and chronic inflammation might be crucial in order to develop target therapies to prevent BPH progression. In this context, clinical, imaging and laboratory parameters might be used alone or in combination to identify patients that harbour chronic prostatic inflammation. PMID- 23650939 TI - Blocking of stromal cell-derived factor-1 reduces neoangiogenesis in human endometriosis lesions in a mouse model. AB - PROBLEM: Endometriosis affects 5-10% of women and is characterized by the growth of endometrial tissue outside of the uterus. Establishing new blood supply is a fundamental requirement for endometriosis lesion growth. Endothelial progenitor cells (EPCs), recruited by stromal cell-derived factor-1 (SDF-1), contribute to neoangiogenesis in endometriotic lesions. We hypothesized that SDF-1 is central to the neoangiogenesis and survival of endometriotic lesions, and blocking of SDF 1 will reduce vascularization of lesions in a mouse model. METHOD OF STUDY: Using immunohistochemistry, we evaluated SDF-1 and CD34(+) EPCs in human endometriotic lesions and normal endometrium samples. EPCs were co-localized using CD34 and VEGFR2. Effects of SDF-1 blocking on endometriotic lesion survival were assessed in BALB/c-Rag2(-/-) /IL2rgamma(-/-) mice engrafted with human endometrium and treated with SDF-1-blocking antibody or an isotype control. Weekly blood samples from experimental mice were analyzed for cytokines and EPCs. RESULTS: SDF-1 and CD34(+) EPCs were abundant in human endometriotic lesions compared with eutopic endometrium. In our mouse model, SDF-1-blocking antibody reduced CD31(+) microvessels compared with isotype control. CONCLUSION: Blocking SDF-1 reduces neovascularization and survival of lesions in a mouse model of endometriosis. PMID- 23650938 TI - Circadian rhythms in acute intermittent porphyria--a pilot study. AB - BACKGROUND: Acute intermittent porphyria (AIP) is an inherited disorder of haem synthesis wherein a partial deficiency of porphobilinogen (PBG) deaminase (PBGD) with other factors may give rise to biochemical and clinical manifestations of disease. The biochemical hallmarks of active AIP are relative hepatic haem deficiency and uncontrolled up-regulation of hepatic 5-aminolevulinic acid (ALA) synthase-1 (ALAS1) with over-production of ALA and PBG. The treatment of choice is intravenous haem, which restores the deficient regulatory haem pool of the liver and represses ALAS1. Recently, haem has been shown to influence circadian rhythms by controlling their negative feedback loops. We evaluated whether subjects with AIP exhibited an altered circadian profile. MATERIALS AND METHODS: Over a 21-h period, we measured levels of serum cortisol, melatonin, ALA, PBG and mRNA levels (in peripheral blood mononuclear cells) of selected clock-controlled genes and genes involved in haem synthesis in 10 Caucasian (European-American) women who were either postmenopausal or had been receiving female hormone therapy, six of whom have AIP and four do not and are considered controls. RESULTS: Four AIP subjects with biochemical activity exhibited higher levels of PBG and lower levels and dampened oscillation of serum cortisol, and a trend for lower levels of serum melatonin, than controls or AIP subjects without biochemical activity. Levels of clock-controlled gene mRNAs showed significant increases over baseline in all subjects at 5 a.m. and 11 p.m., whereas mRNA levels of ALAS1, ALAS2 and PBGD were increased only at 11 p.m. in subjects with active AIP. CONCLUSIONS: This pilot study provides evidence for disturbances of circadian markers in women with active AIP that may trigger or sustain some common clinical features of AIP. PMID- 23650940 TI - Identifying risk factors for eggshell contamination by Bacillus cereus group bacteria in French laying farms. AB - 1. The growth of Bacillus cereus group bacteria often limits the shelf-life of pasteurised liquid egg products and is also a putative toxin producer. This study was performed to better understand the route of contamination by B. cereus in egg products by studying the factors affecting eggshell contamination on-farm. 2. Eggs were collected in warm and cold seasons in 50 conventional laying farms in Western France. Egg surfaces were analysed for the presence of B. cereus group bacteria, environmental measurements were recorded and production practices were identified through a questionnaire filled out by the farmers. 3. A total of 44% of the farms were contaminated by mesophilic and 10% by psychrotrophic B. cereus group bacteria. No significant effect of the season was observed, whatever the thermal type. Several procedures were associated with reduced eggshell contamination by mesophilic bacteria, including the limitation of dust formation from manure and feeding and efficient disinfection of the silo, houses and the sanitary wall between houses. 4. The research highlights the need to promote prevention strategies, from farm to fork, for the control of eggshell and putative subsequent egg product contamination by B. cereus group bacteria. PMID- 23650941 TI - Telehealth and telenursing perception and knowledge among university students of nursing in poland. AB - OBJECTIVE: Telehealth and telenursing are becoming the new reality in studying nursing. Little is known whether undergraduate nursing students receive adequate education on telenursing for patient care. The aim for this study was to evaluate the knowledge and attitude of nursing students toward telenursing. SUBJECTS AND METHODS: Students of nursing faculties from medical universities in Poland were invited to complete a survey about telehealth and telenursing. The survey was conducted utilizing a Web-based surveying platform ( www.mini-ankiety.pl ). RESULTS: We surveyed 308 undergraduate students of nursing faculty-291 females (94%) and 17 males (6%)-from medical universities in Poland. There were 116 students in their first year (course) (38%) and 96 students each in the second and third years (31%). Most of the students (220 [71%]) in the study group were in the age range from 20 to 23 years. The accurate definition of telemedicine was identified by 251 (82%) respondents. The definition of telenursing was recognized properly by 230 (75%) respondents. Of the students, 207 (67%) would anticipate telenursing service implementation into the national healthcare system, and 214 (69.49%) would appreciate the addition of telenursing classes to the curriculum. Students from a few universities showed significantly higher willingness to introduce telenursing classes into nursing curriculum and the intention to use telenursing services in their future nursing practice. The difference among universities could be influenced by regional e-health initiatives. This study has shown the rise of trust in technology along with the increase in the year of nursing study. CONCLUSIONS: The current generation of university students of nursing seems to be well educated in medical informatics and technology use. They are better prepared for and open to information society membership, including the practice of telehealth. The advancement in university education has an influence on positive attitudes toward telenursing and may become a milestone in the development of e-health in Poland. PMID- 23650943 TI - Retraction of "Folate malabsorption and its influence on DNA methylation during cancer development". PMID- 23650942 TI - Inclusiveness. PMID- 23650945 TI - The role of zinc in the interplay between pathogenic streptococci and their hosts. AB - Recent studies on pathogenic streptococci have revealed that zinc is a pivotal metal ion in their interaction with the host. In these streptococci, systems exist that ensure optimal use of zinc from the surrounding milieu, as well as export of zinc when concentrations exceed tolerance levels. Zinc uptake is of crucial importance for the virulence of streptococci, whereas elevated zinc levels induced in the host during infection are detrimental for these pathogens. The expression or activity of a number of putative surface proteins and virulence factors depends on zinc. Moreover, several metal sensor proteins that mediate the transcriptional response to zinc in streptococci have recently been characterized. A number of components of zinc- and other metal ion-acquisition systems are suitable as protective antigens and may be future targets for the development of new vaccines, thus providing opportunities for the development of novel therapies. This review will discuss the recent advancements in the important field of metal ion biology in relation to the virulence of pathogenic streptococci, with a central focus on zinc homeostasis in Streptococcus pneumoniae. PMID- 23650944 TI - Factors associated with numbers of remaining teeth among type 2 diabetes: a cross sectional study. AB - AIMS AND OBJECTIVES: To explore the factors associated with the numbers of remaining teeth among type 2 diabetes community residents. BACKGROUND: Promoting oral health is an important nursing role for patients with diabetes, especially in disadvantaged areas. However, limited research has been carried out on the relationship between numbers of remaining teeth, diabetes-related biomarkers and personal oral hygiene among diabetic rural residents. DESIGN: A cross-sectional, descriptive design with a simple random sample was used. METHODS: This study was part of a longitudinal cohort study of health promotion for preventing diabetic foot among rural community diabetic residents. It was carried out in 18 western coastal and inland districts of Chiayi County in central Taiwan. In total, 703 participants were enrolled in this study. RESULTS: The findings indicated that a high percentage of the participants (26%) had no remaining natural teeth. Nearly three quarters (74%) had fewer than 20 natural teeth. After controlling for the potential confounding factors, multivariate analysis demonstrated that the factors determining numbers of remaining teeth were age (p < 0.001), education (p < 0.001), using dental floss (p = 0.003), ankle brachial pressure index (p = 0.028), waist circumference (p = 0.024) and HbA1C (p = 0.033). CONCLUSIONS: Except for some unmodifiable factors, the factors most significantly associated with numbers of remaining teeth were less tooth-brushing with dental floss, abnormal ankle brachial pressure and poor glycemic control. RELEVANCE TO CLINICAL PRACTICE: This study highlights the importance of nursing intervention in oral hygiene for patients with type 2 diabetes. It is necessary to initiate oral health promotion activities when diabetes is first diagnosed, especially for older diabetic residents of rural or coastal areas who are poorly educated. PMID- 23650946 TI - Pituitary dysfunction after traumatic brain injury in children: is there a need for ongoing endocrine assessment? AB - BACKGROUND: Hypopituitarism has been widely described in adults after traumatic brain injury (TBI); however, the available data in paediatric populations are scarce. Here, we report the results of a prospective, long-term study in children, adolescents and young adults. STUDY GROUP: Thirty-seven children (age, 2 months to 19.9 years) of 51 eligible patients were followed for 1 year. Clinical and baseline endocrine variables were assessed in all 3 and 12 months after TBI; children >= 6 years underwent two stimulation tests (glucagon stimulation and megatest). RESULTS: In the group >=6 years, 11 of 23 patients (47.8%) had a subnormal GH peak 3 months after TBI that persisted in 8 of 23 patients (34%) after 1 year. The GH response showed no correlation with injury severity (GCS, Marshall classification). Growth velocity was normal in all patients, except for one. Body mass index (BMI) SDS increased significantly in the group with low GH response. A suboptimal cortisol was observed in 10 of 23 subjects, which normalized in all but three, 1 year thereafter. All patients but one showed a pubertal response to GnRH testing. No clinical or hormonal abnormalities were detectable in children <6 years. CONCLUSION: Our results recommend to prospectively follow children after TBI: firstly, because the impairment of pituitary function cannot be predicted, and secondly, to avoid the potential consequences of pituitary dysfunction. Prospective clinical trials are needed before recommending a systematic screening after TBI and/or GH therapy either in postpubertal children or in prepubertal children who grow normally. PMID- 23650947 TI - Multifunctional magnetic nanoparticles modified with polyethylenimine and folic acid for biomedical theranostics. AB - This paper describes the preparation of magnetic nanoparticles modified with polyethylenimine (PEI)-folic acid (PF) conjugate and their potential biomedical applications. Magnetic nanoparticles modified with (3-(2 aminoethylamino)propyltrimethoxysilane) (AEAPS) were first prepared using a ligand exchange method to provide biocompatibility and hydrophilicity, and further conjugated with PF to carry gene and enhance specific uptake into cancer cells. We demonstrated the feasibility of the multifunctional magnetic nanoparticles as contrast agents in magnetic resonance imaging (MRI) and as gene carriers for gene delivery. In vitro results revealed that the cytotoxicity of the multifunctional magnetic nanoparticles was lower compared to that of pristine magnetic nanoparticles. Furthermore, we demonstrated the specific uptake of the magnetic nanoparticles modified with PF to KB cells using WI-38 cells as comparison by confocal microscopy. The PF-modified magnetic nanoparticles can potentially be employed as theranostic nanoplatforms for targeted gene delivery to cancer cells and simultaneous magnetic resonance imaging. PMID- 23650948 TI - Pleiotropic effects of PPARgamma agonist on hemostatic activation in type 2 diabetes mellitus. AB - Thiazolidinediones (TZDs) represent a class of peroxisome proliferator-activated receptor (PPAR)gamma agonists widely used as insulin-sensitizers in the treatment of type 2 diabetes mellitus (T2DM). The beneficial effects of hypoglycemic drugs, including TZDs, on the hemostatic abnormalities associated to T2DM have been formerly related to improved metabolic control, rather than to direct effects. However, in recent years the pleiotropic effects of PPARgamma agonists on hemostatic function have become evident. In particular, the role of platelets as a pivotal player in diabetes complications by stimulating and sustaining inflammation has been lately acknowledged. Upon activation platelets synthesize and release many bioactive substances such as thromboxane A2 (TXA2) or pro inflammatory mediators including CD40 ligand (CD40L) that exert autocrine and paracrine activation processes in vascular inflammation leading to cardiovascular disease (CVD). Although PPARgamma is a nuclear hormone receptor, anucleate platelets also highly express this receptor and treatment with synthetic PPARgamma ligands dampens the release of soluble(s)CD40L and TXA2 in thrombin activated platelets. Moreover, PPARgamma through Sirtuin1 pathway has been implicated in modulating inflammatory and atherosclerotic processes in patients with T2DM. Therefore, in T2DM, where platelet activation contributes to the pathogenesis of CVD, TZDs may have an enhanced therapeutic role, despite some potentially serious adverse side effects. This review will discuss the pleiotropic effects of PPARgamma treatment on the hemostatic abnormalities associated with T2DM, with particular focus on platelet activation. PMID- 23650949 TI - Editorial: sulodexide, an old drug with recent renewed interest. PMID- 23650950 TI - Use of alpha-lipoic acid in prevention of contrast-induced nephropathy in diabetic patients. AB - In this prospective study, we aimed to determine the protective antioxidant role of alpha-lipoic acid (ALA) on development of contrast-induced nephropathy (CIN) in diabetic patients undergoing coronary angiography. Seventy-eight diabetic patients undergoing coronary angiography were included. Thirty-nine patients were randomized to control group and 39 patients to ALA group. Both groups were hydrated on the day of angiography, and the ALA group had also received three doses of "Thioctacid 600 mg HR, MEDA Manufacturing GmbH" in pill form. Serum creatinine clearance, cystatin C, and urinary neutrophil gelatinase-associated lipocalin (NGAL) were studied before and after angiography. We defined CIN as either >=25% or >=0.5 mg/dL increase in serum creatinine at 48th hour after angiography. Baseline clinical characteristics were similar in both groups. Mehran risk score and creatinine clearance were comparable in control and therapy groups (5.59 +/- 1.96 vs. 5.49 +/- 1.73, p = 0.54 and 89 +/- 21 vs. 96 +/- 24, p = 0.13, respectively). The volumes of contrast media (median values of 80 mL vs. 75 mL) and hydration with saline (2862 +/- 447 mL vs. 2637 +/- 592 mL) were also similar (p > 0.05). The incidence of CIN was the same (8%) in both the groups. Alterations in serum creatinine, cystatin C, and urinary NGAL levels before and after the procedure were comparable between the ALA and control groups (group p values were >0.05 in two-way repeated measures analysis of variance). We presented for the first time that ALA therapy added to hydration does not decrease the risk of CIN development in diabetic patients undergoing coronary angiography. PMID- 23650951 TI - Resolving the tension between CCS deployment and Chinese energy security. PMID- 23650952 TI - Influence of fetal acidemia on fetal heart rate analyzed by computerized cardiotocography in pregnancies with placental insufficiency. AB - OBJECTIVE: To determine the influence of fetal acidemia on fetal heart rate (FHR) parameters analyzed by computerized cardiotocography (cCTG) in pregnancies with placental insufficiency. METHODS: This was a cross-sectional study of 46 pregnancies with placental insufficiency between 26 and 34 weeks gestation by abnormal umbilical artery Doppler [pulsatility index (PI) > 95th percentile]. RESULTS: Twenty fetuses had acidemia at birth, pH < 7.20 (43.5%) and 26 had normal pH (56.5%). In the analysis of FHR parameters, fetal movements (FM) per hour was significantly lower in the group with acidemia (median = 2) when compared with the group with normal pH (median = 15, p = 0.019). The values of pH correlated positively with FM (rho = 0.35; p = 0.019, 95% CI: 0.061 to 0.577) and basal FHR (rho = 0.37, p = 0,011, 95% CI: 0.090 to 0.597) and negatively with the ductus venosus (DV) PI for veins (PIV) z-score (rho = -0.31, p = 0,036, 95% CI: 0.550 to -0.021). Logistic regression showed that the DV PIV z-score (p = 0.0232) and basal FHR (p = 0.0401) were independent variables associated with acidemia at birth. CONCLUSIONS: The present results suggest that cCTG parameters may be useful in the management of cases with early onset placental insufficiency in association with Doppler velocimetry assessment, and that basal FHR and DV-PIV are most clearly in association with acidemia at birth. PMID- 23650953 TI - Luminescent cell-penetrating pentadecanuclear lanthanide clusters. AB - A novel pentadecanuclear lanthanide hydroxy cluster [{Ln15(MU3 OH)20(PepCO2)10(DBM)10Cl}Cl4] (Ln = Eu (1), Tb (2)) featuring the first example with peptoids as supporting ligands was prepared and fully characterized. The solid-state structures of 1 and 2 were established via single-crystal X-ray crystallography. ESI-MS experiments revealed the retention of the cluster core in solution. Although OH groups are present, 1 showed intense red fluorescence with 11(1)% absolute quantum yield, whereas the emission intensity and the quantum yield of 2 were significantly weaker. In vitro investigations on 1 and 2 with HeLa tumor cells revealed an accumulation of the clusters in the endosomal lyosomal system, as confirmed by confocal microscopy in the TRLLM mode. The cytotoxicity of 1 and 2 toward the HeLa cells is moderate. PMID- 23650954 TI - Osteoporosis treatment: why ibandronic acid? AB - INTRODUCTION: In this article, we have summarized the specific evidence on ibandronic acid (or ibandronate) efficacy, tolerability, and feasibility acquired from trials and clinical use. AREAS COVERED: This critical review focuses on evidence from randomized controlled clinical trials, meta-analyses, surrogate markers, bridging trials, long-term extension studies, observational studies, clinical experiences in osteoporosis in addition to postmenopausal treatment adherence in clinical practice, and safety profile of ibandronic acid. EXPERT OPINION: Pivotal studies on ibandronic acid efficacy in terms of antifracture effects on nonvertebral fractures had some intrinsic limitations. However, a large body of indirect evidence suggests that ibandronate has significantly sustained vertebral and nonvertebral antifracture efficacies in women with postmenopausal osteoporosis, in comparison to those observed with other nitrogen containing bisphosphonates. Discrepancies in efficacy between the available bisphosphonate regimens appear to be a function of dose rather than to inherent differences in their respective therapeutic potential. Drugs or treatment regimens that minimize the risk of osteoporotic fractures and make the treatment of osteoporosis more convenient and suitable for patients are preferred: ibandronic acid marketed at oral doses of 150 mg once monthly and 3 mg quarterly as intravenous injection has these characteristics. The safety profile of ibandronic acid treatment appears to be good overall and in some cases better than that of other nitrogen-containing bisphosphonates. PMID- 23650955 TI - The interactive roles of parenting, emotion regulation and executive functioning in moral reasoning during middle childhood. AB - We examined mother-child co-operative behaviour, children's emotion regulation and executive function, as well as combinations of these factors, as predictors of moral reasoning in 89 10-year-old children. Dyadic co-operation was coded from videotaped observations of laboratory puzzle and speech tasks. Emotion regulation was derived from maternal report, and executive functioning was assessed with the Tower of London task. Moral reasoning was coded during mother-child conversations about morally ambiguous, peer-conflict situations. Two significant interactions indicated that children from more co-operative dyads who also had higher executive function skills had higher moral reasoning scores than other children, and children lower in both emotion regulation and executive function had lower moral reasoning scores than other children. The results contribute to the literature on the multiple and interactive levels of influence on moral reasoning in childhood. PMID- 23650956 TI - Senile systemic amyloidosis localized to the stomach. PMID- 23650957 TI - Ultrathin graphitic carbon nitride nanosheet: a highly efficient fluorosensor for rapid, ultrasensitive detection of Cu(2+). AB - A highly efficient fluorosensor based on ultrathin graphitic carbon nitride (g C3N4) nanosheets for Cu(2+) was developed. In the absence of metal ions, the nanosheets exhibit high fluorescence; the strong coordination of the Lewis basic sites on them to metal ions, however, causes fluorescence quenching via photoinduced electron transfer leading to the qualitative and semiquantitative detection of metal ions. This fluorosensor exhibits high selectivity toward Cu(2+). The whole detection process can be completed within 10 min with a detection limit as low as 0.5 nM. The use of test paper enables the naked-eye detection of Cu(2+) with a detection limit of 0.1 nmol. The practical use of this sensor for Cu(2+) determination in real water samples was also demonstrated. PMID- 23650958 TI - Red cell distribution width in migraine. AB - INTRODUCTION: Several studies support the role of inflammation in the pathogenesis of migraine. Red cell distribution width (RDW), a measure of heterogeneity in the size of circulating erythrocytes, is associated with adverse outcomes in patients with heart failure and stroke. This study was undertaken to assess the interrelationship between RDW and migraine. METHOD: Hundred migraine patients (52 with aura) and age- and sex-matched 100 control subjects were enrolled in the study. Migraine diagnosis was settled according to the International Classification of Headache Disorders-II diagnostic criteria, and each subject was evaluated in terms of headache characteristics including severity, frequency, duration of the migraine attack, and the duration of the disease. Routine hematological analysis was applied for both of the groups. RESULTS: RDW was found to be significantly higher in patients with migraine than controls (P < 0.001). RDW was independently associated with migraine in multivariate model (P < 0.001). A cutoff value of 13.2 for RDW with a sensitivity of 0.69 (0.59-0.78) and a specificity of 0.61 (0.51-0.71) was obtained in the ROC analyses (kappa = 0.300, P < 0.001). Clinical features, laboratory parameters, and headache characteristics did not significantly differ between the migraine patients with and without aura (P > 0.05). However, RDW was detected to positively correlate with attack duration in migraineurs (P < 0.05). CONCLUSION: Elevated RDW is associated with migraine requiring further efforts to clarify the actual underlying pathophysiology. PMID- 23650959 TI - Coating stability and surface characteristics of esthetic orthodontic coated archwires. AB - OBJECTIVE: To evaluate the coating thickness of four brands of as-received esthetic coated rectangular archwires and their surface characteristics and coating stability after 21 days of oral exposure compared to those of conventional stainless steel (SS) and nickel titanium (NiTi) ones. MATERIALS AND METHODS: The labial surface of the selected archwires was observed with a stereoscope and in a scanning electron microscope, and surface roughness was assessed with an atomic force microscope. The coating thickness of as-received wires and the percentage of coating lost on the labial surface of retrieved wires were measured using Image Pro Plus 4.5 software. RESULTS: All groups showed an average coating thickness of less than 0.002 inches. After oral exposure, archwires from two groups lost all coating on the labial surface. On average, 28.71% and 72.90% of the coating was lost in each of the other two groups, and the surface roughness of the remaining coating was higher than postclinical control wires. CONCLUSION: Coated archwires had a low esthetic value as they presented a nondurable coating. The remaining coating showed a severe deterioration and a greater surface roughness than postclinical control counterparts (conventional SS and NiTi wires). PMID- 23650960 TI - Additives promote Noyori-type reductions of a beta-keto-gamma-lactam: asymmetric syntheses of serotonin norepinephrine reuptake inhibitors. AB - Serotonin norepinephrine reuptake inhibitor (SNRI) pyrrolidinyl ether 2 was synthesized by employing a dynamic kinetic resolution (DKR) with enantio- and diastereoselective hydogenation on beta-keto-gamma-lactam 8 to afford beta hydroxy-gamma-lactam 9 with 96% ee and 94% de. Reduction of 9 and purification via the dibenzoyl-(L)-tartaric acid diastereomeric salt 16 enriched the ee and de to 100%. While screening hydrogenation reaction systems with ruthenium-BINAP catalysts to prepare 9, it was found that adding catalytic HCl and LiCl enabled higher yields. In addition, the rate and equilibrium of the DKR-hydrogenation of 8 to give 9 was studied by online NMR and chiral HPLC, which indicated that one of the enantiomers of 8 was reducing faster to 9 than the equilibration of the stereocenter of 8. PMID- 23650961 TI - Isolation, Identification, and Bioactivity of Monoterpenoids and Sesquiterpenoids from the Mycelia of Edible Mushroom Pleurotus cornucopiae. AB - Edible mushroom is a profilic source of bioactive metabolites for the development of drugs and nutraceuticals. In this work, four new monoterpenoids (1-4) and one new sesquiterpenoid (6) were isolated from the mycelia of edible mushroom Pleurotus cornucopiae fermented on rice. Their structures were established by nuclear magnetic resonance, mass spectrometry, and circular dichroism (CD) data analysis. Compound 1 possesses an unusual spiro[benzofuran-3,2'-oxiran] skeleton. The absolute configuration of the 6,7-diol moieties in compounds 1, 2, and 6 was assigned using the in situ dimolybdenum CD method. Compounds 1-5, 7, and 8 showed moderate inhibitory activity against nitric oxide production in lipopolysaccaride activated macrophages, with IC50 values in the range of 60-90 MUM. Compounds 6 and 7 also exhibited slight cytotoxicity against HeLa and HepG2 cells. PMID- 23650962 TI - Aspeverin, a new alkaloid from an algicolous strain of Aspergillus versicolor. AB - A novel carbamate- and cyano-containing alkaloid, aspeverin (1), was isolated from the culture of an algicolous Aspergillus versicolor strain (dl-29). The structure and absolute configuration were unambiguously identified by NMR, IR, ECD, and mass spectrometric methods as well as quantum chemical calculations. 1 exhibited potent bioactivities against some marine-derived organisms. PMID- 23650963 TI - The transillumination technique as a method for the assessment of spermatogenesis using medicinal plants: the effect of extracts of black maca (Lepidium meyenii) and camu camu (Myrciaria dubia) on stages of the spermatogenic cycle in male rats. AB - Transillumination technique for assessment of stages of spermatogenic cycle is a useful tool for toxicological studies. This study was designed to determine the effect of two medicinal plants on spermatogenesis in male rats using the transillumination technique. For this, the effect of the combination of a fruit with highest content of ascorbic acid (Myrciaria dubia, camu camu) and extract of black maca (Lepidium meyenii) on seminiferous tubule stages scored by transillumination on intact tubules in adult male rats was assessed. Animals were treated during seven days with vehicle, black maca, camu camu or a mixture of black maca + camu camu and assessed for daily sperm production (DSP), stages of spermatogenic cycle as well as antioxidant activity and levels of flavonoids and polyphenols. Black maca increased stages of spermiation (VII-VIII) and mitosis of germ cells (IX-XI), whereas camu camu increased stages of mitosis (IX-XI) and meiosis (XII). Mixture of maca + camu camu increased stages of spermiation, mitosis and meiosis. All treatments increased DSP (p<0.05) and epididymal sperm count (p<0.05). Total polyphenols, flavonoids levels and antioxidant activity were higher in camu camu (p<0.001) than in black maca. In conclusion, M. dubia (camu camu) has potential effects improving spermatogenesis and co-administered with maca increase stages of mitosis, meiosis and spermiation of the spermatogenic cycle as assessed by the transillumination technique. This technique is becoming increasingly a useful tool for assessment spermatogenesis. PMID- 23650964 TI - Apoptosis induction and histological changes in rat kidney following Cd-doped silica nanoparticle exposure: evidence of persisting effects. AB - Abstract Histological and immunocytochemical methods were used to examine rat's renal responses to intratracheal (i.t.) instillation of model cadmium-containing silica nanoparticles (Cd-SiNPs) and also exploring whether these potential modifications would be associated with toxicogenomic changes. Renal effects of Cd SiNPs (1 mg/rat), CdCl2 (400 ug/rat), SiNPs (600 ug/rat) or 0.1 ml saline (control), assessed 7 and 30 d post-i.t., included (i) induction of apoptosis, (ii) cell proliferation and (iii) the overall toxic response evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, proliferating cell nuclear antigen (PCNA) immunohistochemistry as well as Periodic acid Schiff and Hematoxylin & Eosin, respectively. Area-specific apoptosis was observed in all treatment groups, the cortex and inner medulla being the most affected regions: the apoptotic changes were apparent seven days post-exposure in both areas and were still observable in inner medulla at day 30. Apoptotic frequency increase was more pronounced in Cd-SiNP-treated animals compared to either CdCl2 or SiNPs groups. At day 7, the observed parallel increased number of PCNA immunopositive cells may be associated with an enhanced cell proliferation aimed at replacing the damaged cells. Histopathological findings demonstrated comparable morphological changes of the renal structure (at glomerular and tubular levels) occurring after all treatments at both time-points and more markedly 30 d after instillation. Both morphological and toxicogenomic evaluations confirmed long-lasting renal effects of Cd-SiNPs on apoptosis and regulatory processes. Bare SiNPs i.t. administration caused morphological and apoptotic changes but did not modify gene expression profile in kidney. These findings substantiate the notion that multiple assays and an integrated testing strategy should be recommended to characterize toxicological responses to nanoparticles in mammalian systems. PMID- 23650965 TI - Sum frequency generation spectroscopy of imidazolium-based ionic liquids with cyano-functionalized anions at the solid salt-liquid interface. AB - A surface-sensitive nonlinear vibrational spectroscopic technique, sum frequency generation (SFG), has been used to study cyano-containing ionic liquids in contact with two different solid salt surfaces. Specifically, the interfacial chemistry of BaF2(111) single-crystal and solid NaCl{100} surfaces in contact with ionic liquids such as [BMIM][SCN], [BMIM][DCA], [BMIM][TCM], and [EMIM][TCB] has been investigated. Spectral features in both C-H and C-N stretching regions were assigned, with a detailed discussion of the nature of surface interactions and ordering of the ionic liquid ions at the interface of the different crystals. Results showed that [BMIM](+) cations adhered closely via Coulombic interactions to the negatively charged NaCl{100} surface, while [SCN](-), [TCM](-), and [DCA]( ) anions revealed a strong electrostatic affinity to the positively charged BaF2(111) surface. Ions of the ionic liquid adsorbed to the solid salt surface to form a Helmholtz-like electric double layer. The linear [SCN](-) anion has a particularly strong affinity to the BaF2(111) surface, resulting in a first layer of anions directly in contact with BaF2(111) containing an effective negative surface excess charge. This promoted ordering of the cations in the second layer to counter the charge excess. At the BaF2(111)-[EMIM][TCB] interface, however, a strongly bound layer of anions populating the first layer resulted in a much larger counterion charge delivered near the crystal salt surface than required to effectively neutralize the initial surface charge from the crystal. As a result, strong resonances from the cation were observed at the BaF2(111) surface, suggesting a more complicated structure of the double layer at the interface than a simple Helmholtz-type model. PMID- 23650966 TI - The correlations of sexual activity, sleep problems, emotional distress, attachment styles with quality of life: comparison between gynaecological cancer survivors and noncancer women. AB - AIMS AND OBJECTIVES: To compare quality of life and its related factors, which include sexual activity, sleep problems, depression, anxiety and attachment styles in close relationships, between gynaecological cancer survivors and noncancer women. BACKGROUND: The majority of studies focus on examining the relationships between the late-treatment side effects and quality of life in gynaecological cancer survivors. As a result, there is insufficient information about what are the correlations between psychosocial factors and quality of life in gynaecological cancer survivors. DESIGN: Cross-sectional study. METHODS: The quality of life of the 85 gynaecological cancer patients who had completed active treatments for at least six months was compared with the 85 age-matched women without cancer history. Measures included SF-12 Health Surveys, Medical Outcomes Study Sleep Scale, Beck Depression Inventory-II, State-Trait Anxiety Inventory, Sexual Activity Questionnaire and Experiences in Close Relationships-Revised. RESULTS: There were no significant differences in the quality of life between gynaecological cancer survivors and noncancer women. However, higher attachment related anxiety in close relationship was the main factor associated with the lower physical quality of life in the gynaecological cancer survivor group. In contrast, older ages were correlated with lower physical quality of life in noncancer women. Anxiety level was the main factor associated with lower mental quality of life for both groups. CONCLUSIONS: Different from noncancer women, the psychosocial factor of insecure attachment in close relationships was the main factor associated with physical quality of life for gynaecological cancer survivors. Anxiety status was the common factor correlated with mental quality of life for cancer and noncancer women. RELEVANCE TO CLINICAL PRACTICE: Developing psychosocial interventions focusing on secure attachment in close relationships and anxiety management could improve physical and mental components of quality of life among gynaecological cancer survivors. PMID- 23650967 TI - Accuracy and preference of measuring resting energy expenditure using a handheld calorimeter in healthy adults. AB - BACKGROUND: Accurate estimates of energy expenditure are required in clinical nutrition in order to determine the requirements of individuals and to inform feeding regimes. Calorimetry can provide accurate measurements but is often impractical in clinical or community settings; prediction equations are widely used to estimate resting energy expenditure (REE) but have limited accuracy. A portable, self-calibrating, handheld calorimeter (HHC) may offer an alternative way of determining REE. The aim of the study was to evaluate whether estimates of REE derived using an HHC are closer to accurate measurements than values calculated using selected prediction equations. METHODS: REE was measured in 36 healthy adults aged 21-58 years using a flow-through indirect calorimeter (FIC) and HHC. Estimated REE was calculated using three predictive equations (Harris & Benedict; Schofield; Henry). Differences in REE between the 'gold standard' values derived using the FIC and those derived using the HHC and equations were examined using paired t-tests and Bland Altman plots. RESULTS: Mean REEHHC was significantly lower than mean REEFIC [4556 +/- 1042 kJ (1089 +/- 249 kcal) versus 6230 +/- 895 kJ (1489 +/- 214 kcal), P = 0.000] and also significantly lower than mean values calculated using all three equations. The mean difference between REEHHC and REEFIC [1674 +/- 908 kJ (400 +/- 217 kcal)] was significantly greater (P = 0.000) than the mean differences between the values calculated using the three prediction equations [272 +/- 490 kJ (65 +/- 117 kcal) (Harris-Benedict), 264 +/- 510 kJ (63 +/- 122 kcal) (Schofield), 84 +/- 502 kJ (20 +/- 120 kcal) (Henry)]. CONCLUSIONS: The HHC provides estimates of REE in healthy people that are less accurate than those calculated using the prediction equations and so does not provide a useful alternative. PMID- 23650968 TI - Faster absorption and higher systemic bioavailability of intranasal fentanyl spray compared to oral transmucosal fentanyl citrate in healthy subjects. AB - CONTEXT: Intranasal fentanyl spray (INFS) was developed for the treatment of breakthrough pain in cancer patients using an alternative route of administration. OBJECTIVE: The aim of this clinical study was to investigate the pharmacokinetic (PK) profile and bioavailability of INFS in healthy subjects compared to oral transmucosal fentanyl citrate (OTFC). MATERIALS AND METHODS: In a randomized, single-center, open-label, two-way crossover PK study, 24 subjects (12 male, 12 female, mean age 25.2 years) received INFS (single-dose delivery system 200 MUg/100 MUl) and OTFC (buccal lozenge, 200 ug). Naltrexone was given to prevent potential adverse reactions. Frequent plasma samples were taken up to 96 h and analyzed by LC-MS/MS with a lower limit of quantitation of 25 pg/ml. Primary PK parameter was the area under the fentanyl plasma concentration-time curve (AUC(0-inf)). RESULTS: Compared to OTFC, a much faster absorption rate was observed for INFS which was supported by the much earlier appearance of detectable fentanyl plasma levels and a shorter T(max). At 15 min post-dose, the mean plasma fentanyl levels reached 602 pg/ml for INFS and 29 pg/ml for OTFC. Significantly higher C(max) and AUC values were obtained with INFS compared to OTFC. Although administered for 15 min, consumption of OTFC was incomplete in many incidences (~70%) upon visual inspection. No safety concerns were identified for fentanyl administration in combination with oral naltrexone. DISCUSSION AND CONCLUSION: One dose of INFS gives significantly higher plasma fentanyl levels and significantly higher bioavailability than OTFC based on dose-normalized AUC. PMID- 23650969 TI - Adiponectin, visfatin and regional fat depots in normal weight obese premenopausal women. AB - BACKGROUND: Normal weight obesity (NWO) is defined as percentage body fat (%BF) above 30% or %BF in the upper tertile in normal weight subjects. Using these criteria, we assessed lipid profiles, glucose metabolism parameters, blood pressure and regional fat in 91 premenopausal women with NWO and 54 age-matched healthy controls. METHODS: We measured total cholesterol, high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides (TG), glucose, insulin, visfatin and adiponectin.%BF, abdominal fat (Android) and hip fat (Gynoid) were measured by dual-energy X-ray absorptiometry. Insulin resistance was evaluated by homoeostasis model assessment (HOMA-IR). RESULTS: Women with NWO had higher diastolic blood pressure (DBP) (P = 0.003), LDL (P = 0.048), TG (P = 0.004) Android (P = 0.008) and Gynoid (P = 0.007) levels, but lower HDL (P = 0.009) than healthy controls. The NWO women had one (P = 0.041), two (P = 0.007) or three (P = 0.002) metabolic syndrome components more frequently than the controls. Across %BF tertiles, the number of metabolic syndrome components significantly increased (R = 0.21; P = 0.02), as did Gynoid (R = 0.83; P < 0.001) and Android (R = 0.81; P < 0.001) levels. Android (but not Gynoid) level was linearly associated with DBP (R = 0.194; P = 0.019), HDL (R = -0.295; P = 0.0004) and TG (R = 0.183; P = 0.031). Visfatin and adiponectin levels were comparable in both groups. Visfatin was inversely correlated with cholesterol, LDL and HOMA-IR. Adiponectin was inversely correlated with the Android/Gynoid and Android/Total fat ratios. CONCLUSIONS: Compared with healthy controls, women with NWO had higher DBP, TG, LDL, and regional fat and lower HDL. These findings seem to be associated more with excess Android fat than excess %BF. PMID- 23650970 TI - Heart rate variability in pubertal girls with type 1 diabetes: its relationship with glycaemic control, insulin resistance and hyperandrogenism. AB - OBJECTIVE: To examine the association between glycaemic control, insulin resistance and hyperandrogenism on cardiac autonomic function in peripubertal girls with type 1 diabetes. DESIGN: Prospective, clinic-based study of 125 girls with diabetes and 46 age-matched nondiabetic girls. MEASUREMENTS: Heart rate variability (HRV) parameters derived from a 10-min ECG recording using LabChart Pro were as follows: standard deviation of mean NN intervals (SDNN), where NN = adjacent QRS complexes; root mean squared difference of successive NN intervals (RMSSD) - estimates of overall HRV; and low-/high-frequency (LF:HF) ratio - an estimate of the sympathovagal balance. Androgens and sex hormone binding globulin (SHBG) were measured in girls with diabetes, and free androgen index (FAI) calculated. HRV and anthropometry were measured in nondiabetic controls. RESULTS: Adolescents with diabetes (median age 15.1 years [13.3-16.0], diabetes duration 7.0 years [4.6-10.0] and median HbA1c 8.4% [7.5-9.3]) had higher HR and lower HRV compared with controls. Using multivariate models in the diabetes group, higher HR was associated with higher HbA1c, total daily dose insulin/kg body weight and systolic BP standard deviation scores (SDS), whilst reduced HRV was associated with higher HbA1c (SDNN, RMSSD and LF:HF ratio), lower SHBG (SDNN and RMSSD) and higher weight SDS (LF:HF ratio). Higher FAI was associated with higher HR and reduced HRV measures in the univariate analyses only. CONCLUSIONS: In adolescent girls with diabetes, reduced HRV parameters are associated with worse glycaemic control, lower SHBG and higher weight SDS. SHBG should be considered in the cardiac risk models for this population. PMID- 23650971 TI - Photodynamic therapy for skin rejuvenation: treatment options - results of a consensus conference of an expert group for aesthetic photodynamic therapy. AB - In addition to providing effective treatment for non-melanoma skin cancers or their precursors, photodynamic therapy (PDT) has also attracted considerable attention for its use on aesthetic dermatology. In a first consensus publication the mechanisms of action of its photorejuvenation effects and recent studies were presented; in this paper treatment protocols for the different anatomical regions exposed to chronic sun damage like face, neck, decollete and the back of the hands are given and suitable procedures for pre- and after-care are discussed. PMID- 23650972 TI - Traditional and commercial turkeys show similar susceptibility to foot pad dermatitis and behavioural evidence of pain. AB - 1. An experiment was conducted to compare the development and clinical significance of foot pad dermatitis (FPD) in 4 lines of turkey poults kept on wet or dry litter for 6 d. 2. Turkeys kept on wet litter were less active and expressed fewer unique sequences of behaviour than poults kept on dry litter, suggesting that high FPD scores are associated with pain during movement. 3. Heavier lines of turkeys had higher mean foot scores that developed earlier, than those in a traditional line, but the effect was relatively small and not statistically significant after 6 d, whereas there were large differences between individuals within line. 4. Body weight gains were greater, and feed intake was lower in the commercial lines kept on dry litter compared with wet litter. There were no differences in water intake between poults kept on wet or dry litter. PMID- 23650973 TI - Reduced plasma zinc levels, lipid peroxidation, and inflammation biomarkers levels in hemodialysis patients: implications to cardiovascular mortality. AB - Despite the fact that low plasma zinc (Zn) levels play important roles in the oxidative stress, the relationships between lipid peroxidation and inflammation biomarkers with low plasma Zn levels have not been investigated in chronic kidney disease (CKD) patients. The aim of this study was to evaluate the Zn plasma levels, electronegative LDL [LDL(-)] levels, and inflammation markers as predictors of cardiovascular (CV) mortality in hemodialysis (HD) patients. Forty five HD patients (28 men, 54.2 +/- 12.7 years, 62.2 +/- 51.4 months on dialysis and BMI 24.3 +/- 4.1 kg/m(2)) were studied and compared to 20 healthy individuals (9 men, 51.6 +/- 15.6 years, BMI 25.2 +/- 3.9 kg/m(2)) and followed for 24 months to investigate the risks for CV mortality. LDL(-) levels were measured by ELISA, plasma Zn levels by atomic absorption spectrophotometry, C-reactive protein (CRP) level by immunoturbidimetric method, and tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) levels by a multiplex assay kit. HD patients presented low plasma Zn levels (54.9 +/- 16.1 MUg/dL) and high-LDL(-) (0.18 +/- 0.12 U/L) and TNF-alpha (5.5 +/- 2.2 pg/mL) levels when compared to healthy subjects (78.8 +/- 9.4MU g/dL, 0.10 +/- 0.08U/L, 2.4 +/- 1.1 pg/mL, respectively, p < 0.05). Zn plasma levels were negatively correlated to TNF-alpha (r = -0.49; p = 0.0001) and LDL(-) (r = -0.33; p = 0.008). During the 2 years, 24.4% of the patients died, all due to CV disease. Analysis by the Cox model showed that high CRP, TNF-alpha, IL-6 levels, and long duration of HD were significant predictors of mortality. In conclusion, reduced Zn levels were associated with lipid peroxidation and inflammation, and we confirm here in a Brazilian cohort of HD patients that inflammation markers are strong predictors of CV death. PMID- 23650974 TI - Validated assessment scale for platysmal bands. AB - BACKGROUND: Marked platysmal bands in the neck are an unwelcome sign of aging. Botulinum neurotoxin type A has been used successfully to treat this indication, but there is a need for a validated tool for accurate assessment of dynamic platysmal bands to evaluate treatment efficacy objectively. OBJECTIVE: To develop a scale for objective assessment of dynamic platysmal bands and to validate its use in the clinical setting. METHODS: A new 5-point photonumeric assessment scale for platysmal bands was developed. Ten experts experienced in aesthetic dermatology used the scale to rate frontal and lateral neck photographs of 50 subjects in two separate validation cycles. Inter- and intrarater reliability of the scale was assessed. RESULTS: The scale comprises five ratings of platysmal band severity ranging from 0 (no relevant prominence of platysmal bands) to 4 (very severe prominence of platysmal bands). Interrater reliability was "almost perfect," with intraclass correlation coefficients of 0.81 for the first validation cycle and 0.82 for the second. Mean intrarater reliability was also high (0.89), with Pearson correlation coefficients ranging between 0.87 and 0.91. CONCLUSION: The new 5-point dynamic platysmal band photonumeric assessment scale is a valuable tool for use in the aesthetic clinical setting. PMID- 23650975 TI - A changing framework for urban water systems. AB - Urban water infrastructure and the institutions responsible for its management have gradually evolved over the past two centuries. Today, they are under increasing stress as water scarcity and a growing recognition of the importance of factors other than the cost of service provision are forcing a reexamination of long-held ideas. Research and development that supports new technological approaches and more effective management strategies are needed to ensure that the emerging framework for urban water systems will meet future societal needs. PMID- 23650976 TI - Field-flow fractionation and hydrodynamic chromatography on a microfluidic chip. AB - We present gravitational field-flow fractionation and hydrodynamic chromatography of colloids eluting through 18 MUm microchannels. Using video microscopy and mesoscopic simulations, we investigate the average retention ratio of colloids with both a large specific weight and neutral buoyancy. We consider the entire range of colloid sizes, including particles that barely fit in the microchannel and nanoscopic particles. Ideal theory predicts four operational modes, from hydrodynamic chromatography to Faxen-mode field-flow fractionation. We experimentally demonstrate, for the first time, the existence of the Faxen-mode field-flow fractionation and the transition from hydrodynamic chromatography to normal-mode field-flow fractionation. Furthermore, video microscopy and simulations show that the retention ratios are largely reduced above the steric inversion point, causing the variation of the retention ratio in the steric- and Faxen-mode regimes to be suppressed due to increased drag. We demonstrate that theory can accurately predict retention ratios if hydrodynamic interactions with the microchannel walls (wall drag) are added to the ideal theory. Rather than limiting the applicability, these effects allow the microfluidic channel size to be tuned to ensure high selectivity. Our findings indicate that particle velocimetry methods must account for the wall-induced lag when determining flow rates in highly confining systems. PMID- 23650977 TI - Butyrylcholinesterase (BChE) activity is associated with the risk of preeclampsia: influence on lipid and lipoprotein metabolism and oxidative stress. AB - OBJECTIVE: To determine the butyrylcholinesterase (BChE) activity and phenotypes in preeclampsia and its possible association with lipid and lipoprotein metabolism and oxidative stress in preeclamptic women. METHODS: In a case-control study, 101 pregnant women with normal pregnancy and 198 women with preeclampsia from Western Iran were studied. The serum BChE activity and phenotypes were measured using spectrophotometric method. The apolipoprotein E (APOE) genotypes were identified using PCR-RFLP. The serum malondialdehyde (MDA) level and total antioxidant capacity (TAC) were determined by HPLC and commercial kits, respectively. RESULTS: The BChE activity and the frequency of non-usual BChE phenotype in preeclamptic women were significantly lower and higher, respectively compared to controls. There was a higher BChE activity in the presence of APOE epsilon3epsilon4 compared to epsilon3epsilon3 genotype in preeclamptic women. In addition, there were significant positive correlations between BChE activity and the levels of low-density lipoprotein-cholesterol, high-density lipoprotein cholesterol, total cholesterol (TC) and TAC. However, there was a negative but significant correlation between BChE activity and MDA level. CONCLUSIONS: Our study for the first time indicated that BChE activity might be involved in the pathogenesis of preeclampsia through influence on lipid and lipoprotein metabolism and oxidative stress. PMID- 23650978 TI - Tocilizumab: a novel humanized anti-interleukin 6 (IL-6) receptor antibody for the treatment of patients with non-RA systemic, inflammatory rheumatic diseases. AB - Tocilizumab is a highly effective therapeutic agent for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. Furthermore, a large amount of case study data reveals that tocilizumab can be an effective therapy for not only rheumatoid arthritis but also for other mostly rare inflammatory rheumatic diseases. By blocking the interleukin-6 pathway tocilizumab can be a useful therapeutic alternative when conventional treatment fails. It is successful in treating diseases such as the adult-onset Still's disease, amyloidosis, giant cell arteritis, multiple myeloma, polymyalgia rheumatica, relapsing polychondritis, remitting seronegative symmetrical synovitis with pitting edema-syndrome, systemic lupus erythematosus, systemic sclerosis, and Takayasu arteritis. Studies underway are now recruiting patients to acquire further data on treating patients with non-rheumatic arthritis, inflammatory diseases. This review focuses on tocilizumab as a promising agent for treating rare and orphan diseases in rheumatology for which no satisfactory treatment is yet available. PMID- 23650979 TI - Emotions as signals of normative conduct. AB - Social interactions are heavily norm-based and these norms need to be learned. For this, the emotional reactions of other's in response to a norm transgression can serve as signals. We were able to show that when a group responds with anger to a norm transgressing behaviour, participants were better able to correctly infer the norm than when the group responded with sadness or emotional neutrality. We further tested a process-model showing that this inference is based on the participants' understanding of the groups' appraisals of the behaviour. That is, participants who were able to reverse engineer the underlying appraisal of norm-incompatibility from the emotion expressions inferred the norm more readily. Humans as a social species, require efficient means to quickly adapt to new situations and to perform flawlessly in social contexts. Emotion information is one of the instruments that can be used in this quest. PMID- 23650980 TI - Apples and oranges: a comparison of costing methods for obesity. AB - Obesity has escalated to epidemic proportions over the past 30 years resulting in increased disease burden and healthcare costs. The aim of this paper was to analyse different costing methods for obesity. Several databases have been searched to identify eligible literature estimating obesity cost. These were categorized into databases, patient-attributable fraction (PAF) and modelling studies. Studies from the United States were used to explore effects of study designs on cost outcomes. Our results show that cost outcomes are largely affected by underlying study designs, such as population size, age, cost categories (medical expenditure vs. total costs), length of the data collection and body mass index cut-offs. Three study types are likely to have an impact on reported costs, with modelling studies providing the most conservative estimates. Database studies can help to increase the overall awareness of the economic burden of obesity. PAF studies can make the obesity disease more tangible by drawing connections to diseases. Decision makers need to be aware of the different purposes and weaknesses of the studies when interpreting cost outcomes. Further research is needed to refine the existing methods and provide high quality data accounting for the complexity of the disease. PMID- 23650982 TI - Bone mineral density, vertebral fractures and body mass index in postmenopausal women with abdominal aortic calcification. AB - BACKGROUND: Evidence suggest that there are connections between osteoporosis and cardiovascular diseases. OBJECTIVES: The aim of the study was to analyze the relationship between radiological measurements of abdominal aorta calcifications (AAC) and bone mineral density (BMD) in postmenopausal women. METHODS: In this cross-sectional study were included 125 postmenopausal women 50-84 years of age. BMD of the spine and hip was measured by dual energy X-ray absorptiometry (DXA). AAC were assessed by lateral radiographs of lumbar spine (L1-L4), using the antero-posterior severity score (0-24). Vertebral fractures were evaluated from T4 to L4 using Genant's semiquantitative method. RESULTS: Forty-one (32.8%) patients had osteoporosis and 61 (48.8%) had AAC with a mean score of 3.1. Postmenopausal women with AAC were older and had significantly lower femoral neck and trochanteric BMD than subjects without AAC (all p < 0.01). There were no significant differences in the frequency of fractures between subjects with AAC and those without AAC (p > 0.05). In univariate analysis, age, height, weight, femoral and trochanter BMD were significantly associated with the severity of AAC score. In multiple regression analysis, femoral neck BMD, but not lumbar spine, trochanter BMD or age, was an independent predictor of AAC. CONCLUSIONS: Reduced femoral neck BMD is negatively associated with the presence of AAC in postmenopausal women. The association between BMD and AAC seems to be age independent, which suggests a common pathogenesis for bone loss and vascular calcifications. PMID- 23650983 TI - Heart failure in hospitalized patients with diabetic foot ulcers: clinical characteristics and their relationship with prognosis. AB - BACKGROUND: In the present study we: (i) evaluated the incidence of heart failure (HF) in patients with diabetic foot ulcer (DFU); and (ii) investigated the relationship between the clinical characteristics in these patients and prognosis. METHODS: The clinical characteristics of 330 consecutive Chinese patients (137 men, 193 women) hospitalized for DFU were collected and assessed to determine the effects of HF on DFU. All patients were followed for 3 months and rates of healing, the development of new ulcers, amputations, and mortality were calculated at the end of the follow-up period. RESULTS: Heart failure was present in 64.3% of patients with DFU, with the prevalence of HF increasing with Wagner grade from Wagner 1 through to Wagner 5 (42.4%, 59.1%, 64.7%, 73.3%, and 87.0%, respectively), higher than the 33.6% prevalence in diabetic patients without DFU (Wagner 0). The presence of HF conferred a greater increased relative risk of a worse prognosis. The 3-month healing rates of DFU in patients with and without HF were 60.3% and 75.7%, respectively. Recurrence (13.2% vs 7.5%) and amputations (28.6% vs 20.0%) were more frequent in patients with than without HF (P < 0.05). All-cause mortality was recorded for 14 of 126 patients with HF compared with three of 70 patients without HF (11.1% vs 4.3%, respectively; P < 0.05). CONCLUSIONS: The prevalence of HF is high in Chinese inpatients with DFU, with the presence of HF indicating a worse prognosis for these patients. PMID- 23650984 TI - Polyphenolic and hydroxycinnamate contents of whole coffee fruits from China, India, and Mexico. AB - Air-dried whole coffee fruits, beans, and husks from China, India, and Mexico were analyzed for their chlorogenic acids (CGA), caffeine, and polyphenolic content. Analysis was by HPLC and Orbitrap exact mass spectrometry. Total phenol, total flavonol, and antioxidant capacity were measured. The hydroxycinnamate profile consisted of caffeoylquinic acids, feruloyquinic acids, dicaffeoylquinic acids, and caffeoyl-feruloylquinic acids. A range of flavan-3-ols as well as flavonol conjugates were detected. The CGA content was similar for both Mexican and Indian coffee fruits but was much lower in the samples from China. Highest levels of flavan-3-ols were found in the Indian samples, whereas the Mexican samples contained the highest flavonols. Amounts of CGAs in the beans were similar to those in the whole fruits, but flavan-3-ols and flavonols were not detected. The husks contained the same range of polyphenols as those in the whole fruits. The highest levels of caffeine were found in the Robusta samples. PMID- 23650985 TI - Kinetic resolution of beta-substituted olefinic carboxylic acids by asymmetric bromolactonization. AB - A strategically novel kinetic resolution of beta-substituted olefinic carboxylic acids is developed by asymmetric bromolactonization using an organocatalyst, 4 tBuPh-tris 1b. The cyclization stage, which provides delta-lactone, is proposed to be operative for discrimination of each enantiomer of carboxylic acids. PMID- 23650986 TI - Respiratory rate records: the repeated rate? PMID- 23650987 TI - Formulation and evaluation of novel solid lipid microparticles as a sustained release system for the delivery of metformin hydrochloride. AB - The low encapsulation efficiency of conventional solid lipid microparticles (SLMs) especially for hydrophilic drugs has remained a challenge to drug formulation experts. This work seeks to address the issue of inefficient delivery of metformin hydrochloride (MTH), a potent hydrophilic oral antihyperglycemic agent, using novel SLMs based on solidified reverse micellar solutions (SRMS) prepared by melt-emulsification using a lipid derived from Capra hircus and Phospholipon(r) 90H. Characterization based on size, morphology, zeta potential, polydispersity index, encapsulation efficiency (EE%), loading capacity (LC) and time-resolved stability were carried out on the SLMs. The in vitro release of MTH from the SLMs was performed in phosphate buffer (pH 7.4) while the in vivo antidiabetic properties were investigated in alloxan-induced diabetic rats. Stable, spherical and smooth SLMs were obtained. Loading of MTH into the SLMs had no effect on the surface charge of the particles. The SLMs with 1.0%w/w PEG 4000 resulted in significantly (p < 0.05) higher EE% while those with 2.0%w/w gave the least. The LC values ranged from 20.3 to 29.1 and 14.6 to 24.1 for SLMs containing 500 mg and 250 mg of MTH, respectively. The in vitro release studies revealed significant release of MTH from the SLMs whereas the in vivo antidiabetic studies indicated that novel SLMs containing 500 mg of MTH gave significantly (p < 0.05) higher glucose reduction than glucophage(r). This research has shown that SLMs based on SRMS offer a new and better approach of delivering MTH, thus encouraging further development of this formulation. PMID- 23650988 TI - Do clinical and behavioural correlates of obese patients seeking bariatric surgery differ from those of individuals involved in conservative weight loss programme? AB - BACKGROUND: Clinical practice has suggested that, in severely obese patients seeking bariatric surgery, clinical conditions, behavioural characteristics and psychological status might all differ from those of their counterparts starting conventional conservative therapy. METHODS: Two groups of obese patients with closely similar body mass values were considered. The first group included individuals voluntarily and spontaneously seeking biliopancreatic diversion and the second group comprised patients at the beginning of a weight loss programme. After anthropometric and metabolic evaluation, the patients underwent an alimentary interview; eating behaviour and psychological status were assessed by Three Factor Eating Questionnaire and by Toronto Alexithymia Scale (TAS). RESULTS: Among bariatric candidates, a greater number of individuals with type 2 diabetes and dyslipidaemia and high tendency to disinhibition and susceptibility to hunger scores was observed, whereas the other aspects of eating pattern were essentially similar. In the two groups, no difference in TAS score and or number of patients with alexithymic traits was observed. Finally, a logistic regression model showed that only age and metabolic derangement predicted the bariatric option, whereas eating behaviour or psychological status did not influence individual therapeutic choice. CONCLUSIONS: Independently of the degree of obesity, bariatric surgery was requested by the more metabolically deranged patients, whereas, in the surgical candidates, the eating pattern and psychological conditions were very similar to those of obese persons at the beginning of a conservative weight loss programme. These results suggest a highly realistic and practical attitude in severely obese patients towards obesity and bariatric surgery. PMID- 23650989 TI - Synthesis, rotational dynamics, and photophysical characterization of a crystalline linearly conjugated phenyleneethynylene molecular dirotor. AB - We report the synthesis, crystal structure, solid-state dynamics, and photophysical properties of 6,13-bis((4-(3-(3-methoxyphenyl)-3,3-diphenylprop-1 yn-1-yl)phenyl)ethynyl)-5,7,12,14-tetrahydro-5,14:7,12-bis([1,2]benzeno)pentacene (1), a molecular dirotor with a 1,4-bis((4-ethynylphenyl)ethynyl)benzene (BEPEB) chromophore. The incorporation of a pentiptycene into the molecular dirotor provides a central stator and a fixed phenylene ring relative to which the two flanking ethynylphenylene rotators can explore various torsion angles; this allows the BEPEB fluorophore dynamics to persist in the solid state. X-ray diffraction studies have shown that molecular dirotor 1 is packed so that all the BEPEB fluorophores adopt a parallel alignment, this is ideal for the development of functional materials. Variable temperature, quadrupolar echo (2)H NMR studies have shown that phenylene rotator flipping has an activation energy of 9.0 kcal/mol and a room temperature flipping frequency of ~2.6 MHz. Lastly, with measurements in solution, glasses, and crystals, we obtained evidence that the fluorescence excitation and emission spectra of the phenyleneethynylene chromophores is dependent on the extent of conjugation between the phenylene rings, as determined by their relative dihedral angles. This work provides a promising starting point for the development of molecular dirotors with polar groups whose amphidynamic nature will allow for the rapid shifting of solid-state absorption, fluorescence, and birefringence, in response to external electric fields. PMID- 23650991 TI - Myofibroblastic differentiation of stromal cells in giant cell tumor of bone: an immunohistochemical and ultrastructural study. AB - The nature of the mononuclear stromal cells (MSCs) in giant cell tumor of bone (GCTB) has not been thoroughly investigated. The purpose of this study was to evaluate the degree and significance of myofibroblastic differentiation in 18 cases of GCTB by immunohistochemistry (IH) and/or electron microscopy (EM). All immunostained cases were found positive for smooth muscle actin (SMA) and/or muscle specific actin (MSA), most in 1-33% of the MSCs. Ultrastructurally, most MSCs were fibroblasts, and a significant number of cells displayed myofibroblastic differentiation. Myofibroblasts are an important component of MSCs in GCTB. The myofibroblastic population may be responsible in part for the production of matrix metalloproteinases (MMPs), which probably play a role in bone destruction, tumor aggression, and recurrence. PMID- 23650990 TI - Primary cilia metaplasia in renal transplant biopsies with acute tubular injury. AB - Primary cilia are hair-like organelles singly distributed along the apical surface of proximal and distal nephron tubules as mechanosensors. The goal of this study was to use electron microscopy to systemically evaluate cilia changes in acute tubular injury (ATI) from both transplant and native renal biopsies. Three groups of cases were included: control group 1-native biopsies without major changes in renal tubules; study group 2-native biopsies with prominent ATI; and study group 3-renal transplant biopsies with prominent ATI (delayed renal function group). Extensive search for ciliary structures along renal tubules was conducted in each case, focused on proximal tubular areas with injured (diminished) apical microvilli. Singly located cilia were found in 3/19 specimens in control group 1, 4/18 in group 2 (native ATI), and 6/24 in group 3 (transplant ATI). Importantly, there were clusters of cilia in proximal tubules with markedly diminished apical microvilli in 3/24 biopsies from 2 patients in group 3, but none from groups 1 and 2. The clusters of cilia ranged from 6 to 15 individual cilia along the apical surface with diminished apical microvilli. Under high magnifications, the cilia demonstrated 9 pairs of peripheral microtubules without a central pair of microtubules, consistent with primary cilia (9 + 0) rather than motile cilia (9 + 2). In summary, the authors found clusters of cilia in proximal tubules with remarkable apical microvillar injury in 3 renal transplant biopsies with ATI, implying a reactive, or repairing, process following tubular injury, thus they name this finding "cilia metaplasia". PMID- 23650992 TI - Comparison of the ultrastructural and immunophenotypic characteristics of human umbilical cord-derived mesenchymal stromal cells and in situ cells in Wharton's jelly. AB - The umbilical cord contains mucinous connective tissue, called Wharton's jelly. It consists of stromal cells, collagen fibers, and amorphous ground substances composed of proteoglycan. Recently, these stromal cells have been redefined as a new cell therapy source, named human umbilical cord-derived mesenchymal stromal cells (hUCMSCs). However, there are few studies on the ultrastructural features and immune-phenotypic characteristics of isolated hUCMSCs and comparisons with the cells found in original cord tissues. In this study, the authors describe and compare the phenotypic characteristics of hUCMSCs with cells in the umbilical cord in order to know the kinds of cells and ultrastructural changes. Isolated hUCMSCs showed similar ultrastructure with few structural differences from in situ stromal cells, and they are relatively homogenous and well-developed mesenchymal cells that demonstrate a myofibroblastic phenotype. PMID- 23650993 TI - Evaluation of the possible protective role of quercetin on letrozole-induced testicular injury in male albino rats. AB - BACKGROUND: The purpose of this study was to appraise the possible adverse effects of quercetin against the aromatase inhibitor letrozole-induced developmental toxicity potential in male Wistar rats. METHODS: Control male albino rats were received vehicles used for flavonoids and vehicle used for letrozole. The rats in the first experimental group received letrozole at 0.04 mg/kg body weight (bwt) for 3 months. The second experimental group was treated with the flavonoid quercetin by gavage at a dose of 50 mg/kg bwt for 10 consecutive days after letrozole administration. RESULTS: Major treatment-related effects of letrozole included a dose-dependent increase in hormone levels and lipid peroxidation following exposure to 0. 04 mg/kg letrozole; and severe abnormalities with severe cellular deformation and disorganization in both spermatogenic and interstitial cells. The seminiferous tubules of the testes of the animals given quercetin and letrozole exhibited a rather normal appearance and the measured hormone levels were restored to nearly the normal levels. CONCLUSION: Exposure doses of letrozole that are equal to the daily recommended human dose has toxic effects on the spermatogenic lineage in rats, while simultaneous treatment of quercetin and letrozole could prevent the deleterious effects on testicular tissue caused by letrozole administration. PMID- 23650994 TI - Curative effect of crude exopolysaccharides of some macrofungi on alcohol-induced liver damage. AB - Abstract The authors investigate the curative effects of crude exopolysaccharides (EPS) produced by four Basidomycetes strains on the symptoms of alcoholic liver injury. EPSs were administered to experimental groups at levels of 100 mg per kg body weight per day for 7 days using an oral zonde needle after the onset of the disease. Serum levels of alanine transaminase (ALT), lactate dehydrogenase (LDH), DNA fragmentation, caspase-3 activities, and mitochondrial outer membrane integrity were determined following sacrifice of the rats. Light and transmission electron microscope (TEM) studies were performed on liver sections for histopathological and cytological evaluations. EPS that was obtained from Coprinus comatus OBCC 1014 decreased serum ALT level and increased outer membrane integrity, and allowed for the regaining of histologically and cytologically normal hepatocyte and tissue views. As a result, based on the obtained data, it can be argued that among all studied mushroom strains crude exopolysaccharides from Coprinus comatus OBCC 1014 strain have therapeutic potential for alcoholic liver injury according to control groups. PMID- 23650995 TI - Mitochondrial changes in adenocarcinoma of the pancreas. AB - The aim of our study was to analyse the mitochondrial ultrastructure in primary ductal adenocarcinomas of the pancreas and to compare it with normal pancreatic cells. 52 samples of adenocarcinoma of the pancreas obtained by surgical resection or by endosonographic biopsy were examined. Compared to normal mitochondrial ultrastructure in non-tumorous cells, the mitochondria in cancer cells had a dense matrix and condensed configuration or with lucent-swelling matrix associated with disarrangement and distortion of cristae and partial or total cristolysis. Functionally, these structural alterations presume the presence of hypoxia-tolerant and hypoxia-sensitive cancer cells. PMID- 23650996 TI - Circulating levels of pegvisomant and endogenous growth hormone during prolonged pegvisomant therapy in patients with acromegaly. AB - OBJECTIVE: To investigate whether pegvisomant treatment in acromegaly induces gradual elevations in endogenous serum growth hormone (GH) levels and whether serum pegvisomant levels predict the therapeutic outcome. PATIENTS AND METHODS: Seventeen patients (6 women), mean age 46.3 years (range: 23.2-76.2), were studied. For each patient, four hospital visits were identified including 'active disease' (no treatment) and last follow-up. At each visit, 12 blood samples were drawn during 3 h including an oral glucose tolerance test (OGTT). Eight patients received a somatostatin analogue in addition to pegvisomant on the last visit. RESULTS: Median (range) pegvisomant doses (mg/day) were 10 (10-10), 15 (10-15) and 15 (10-15) at visits 2, 3 and 4, respectively, and the mean duration of pegvisomant treatment was 17.5 +/- 3.2 (SEM) months. Serum IGF-I changed significantly during the treatment period with the highest level at baseline and lowest levels at visits 3 and 4. GH levels increased in a dose-dependent manner during pegvisomant treatment and decreased at visit 4. Changes in IGF-I levels correlated negatively with changes in serum pegvisomant levels between visits. Serum pegvisomant at each visit correlated with baseline growth hormone levels, whereas no associations between serum pegvisomant and either dose, gender, age or body weight were found. CONCLUSIONS: (1) Serum GH levels increased initially, but remained stable during prolonged pegvisomant treatment in patients with acromegaly, (2) serum pegvisomant levels predicted the reduction in serum IGF-I during treatment and (3) the interindividual variation in serum pegvisomant levels seems not predicted by either age, gender or body composition. PMID- 23650997 TI - Effects of exogenous xylanase on performance, nutrient digestibility and caecal thermal profiles of broilers given wheat-based diets. AB - 1. Five dietary treatments were used in a 49 d broiler trial to assess the effect of xylanase on performance, nutrient digestibility and thermal profiles of the caeca and head. Treatments included an industry-standard control diet and four further diets where xylanase was introduced with or without a metabolisable energy density dilution either from day one or the introduction was delayed until d 28. 2. The addition of xylanase with no associated energy dilution from day one resulted in the most consistent beneficial effects on performance, with significant improvements in weight gain compared with the industry-standard to d 28 and at d 49. Addition of xylanase from d 28 (with no energy dilution) was the second most successful strategy and resulted in a significant improvement in feed conversion ratio (FCR) from d 29 to 49 and overall. 3. Addition of xylanase improved ileal digestible energy values at d 28 by around 0.35 MJ/kg and ileal nitrogen digestibility coefficients by around 3%. On d 49 xylanase improved ileal digestible energy values by around 0.9 MJ/kg and ileal nitrogen digestibility coefficients by around 4.6%. 4. Thermal imaging of the head and caeca of three birds per replicate on d 49 revealed a significant increase in caecal surface temperature following xylanase addition with no effect on head temperature profile. These increases were particularly large (around 1.4oC, or 3.9%) when xylanase was added from day one with no corresponding energy dilution in feed formulation. 5. It can be concluded that supplemental xylanase is effective in improving performance and nutrient digestibility in broilers given wheat-based diets. The correlation between the magnitude of this effect and the increased temperature in the caeca presents additional evidence that the hind-gut microflora may play an important, if yet unquantified, role in the outworking of these mechanisms. PMID- 23650998 TI - GS6, a member of the GRAS gene family, negatively regulates grain size in rice. AB - Grain size is an important yield-related trait in rice. Intensive artificial selection for grain size during domestication is evidenced by the larger grains of most of today's cultivars compared with their wild relatives. However, the molecular genetic control of rice grain size is still not well characterized. Here, we report the identification and cloning of Grain Size 6 (GS6), which plays an important role in reducing grain size in rice. A premature stop at the +348 position in the coding sequence (CDS) of GS6 increased grain width and weight significantly. Alignment of the CDS regions of GS6 in 90 rice materials revealed three GS6 alleles. Most japonica varieties (95%) harbor the Type I haplotype, and 62.9% of indica varieties harbor the Type II haplotype. Association analysis revealed that the Type I haplotype tends to increase the width and weight of grains more than either of the Type II or Type III haplotypes. Further investigation of genetic diversity and the evolutionary mechanisms of GS6 showed that the GS6 gene was strongly selected in japonica cultivars. In addition, a "ggc" repeat region identified in the region that encodes the GRAS domain of GS6 played an important historic role in the domestication of grain size in rice. Knowledge of the function of GS6 might aid efforts to elucidate the molecular mechanisms that control grain development and evolution in rice plants, and could facilitate the genetic improvement of rice yield. PMID- 23650999 TI - How do foragers decide when to leave a patch? A test of alternative models under natural and experimental conditions. AB - A forager's optimal patch-departure time can be predicted by the prescient marginal value theorem (pMVT), which assumes they have perfect knowledge of the environment, or by approaches such as Bayesian updating and learning rules, which avoid this assumption by allowing foragers to use recent experiences to inform their decisions. In understanding and predicting broader scale ecological patterns, individual-level mechanisms, such as patch-departure decisions, need to be fully elucidated. Unfortunately, there are few empirical studies that compare the performance of patch-departure models that assume perfect knowledge with those that do not, resulting in a limited understanding of how foragers decide when to leave a patch. We tested the patch-departure rules predicted by fixed rule, pMVT, Bayesian updating and learning models against one another, using patch residency times (PRTs) recorded from 54 chacma baboons (Papio ursinus) across two groups in natural (n = 6175 patch visits) and field experimental (n = 8569) conditions. We found greater support in the experiment for the model based on Bayesian updating rules, but greater support for the model based on the pMVT in natural foraging conditions. This suggests that foragers may place more importance on recent experiences in predictable environments, like our experiment, where these experiences provide more reliable information about future opportunities. Furthermore, the effect of a single recent foraging experience on PRTs was uniformly weak across both conditions. This suggests that foragers' perception of their environment may incorporate many previous experiences, thus approximating the perfect knowledge assumed by the pMVT. Foragers may, therefore, optimize their patch-departure decisions in line with the pMVT through the adoption of rules similar to those predicted by Bayesian updating. PMID- 23651001 TI - Phosphate separation and recovery from wastewater by novel electrodialysis. AB - Stimulated by the depletion of phosphate resources, phosphate recovery systems have been studied in recent years. The use of struvite reactors has proven to be an effective phosphate recovery process. However, the struvite reactor effluent still consists of an excessive amount of phosphate that cannot be recovered nor can be directly discharged. In this study, selectrodialysis (SED) was used to improve the efficiency of phosphate recovery from a struvite reactor: SED was implemented in such a way that phosphate from the effluent of an USAB (upflow anaerobic sludge blanket) reactor was transferred to the recycled effluent of a struvite reactor. Prior to the experiments, synthetic water with chloride and phosphate was used to characterize the efficiency of SED for phosphate separation. Results indicate that SED was successful in concentrating phosphate from the feed stream. The initial current efficiency reached 72%, with a satisfying (9 mmol L(-1)) phosphate concentration. In the experiments with the anaerobic effluent as the phosphate source for enrichment of the effluent of the struvite reactor, the phosphate flux was 16 mmol m(-2) h(-1). A cost evaluation shows that 1 kWh electricity can produce 60 g of phosphate by using a full scale stack, with a desalination rate of 95% on the feed wastewater. Finally, a struvite precipitation experiment shows that 93% of phosphate can be recovered. Thus, an integrated SED-struvite reactor process can be used to improve phosphate recovery from wastewater. PMID- 23651002 TI - Synthetic biology. PMID- 23651004 TI - The organism is the product. AB - A new industry model is emerging where microbes are first developed by specialist organism engineering firms and then deployed by customers in specific application areas. It is now realistic for companies without prior fermentation experience to purchase and deploy an engineered organism to expand their business. PMID- 23651005 TI - Engineering artificial small RNAs for conditional gene silencing in Escherichia coli. AB - It has become increasingly evident that noncoding small RNAs (sRNAs) play a significant and global role in bacterial gene regulation. A majority of the trans acting sRNAs in bacteria interact with the 5' untranslated region (UTR) and/or the translation initiation region of the targeted mRNAs via imperfect base pairing, resulting in reduced translation efficiency and/or mRNA stability. Additionally, bacterial sRNAs often contain distinct scaffolds that recruit RNA chaperones such as Hfq to facilitate gene regulation. In this study, we describe a strategy to engineer artificial sRNAs that can regulate desired endogenous genes in Escherichia coli. Using a fluorescent reporter gene that was translationally fused to a native 5' mRNA leader sequence, active artificial sRNAs were screened from libraries in which natural sRNA scaffolds were fused to a randomized antisense domain. Artificial sRNAs that posttranscriptionally repress two endogenous genes ompF and fliC were isolated and characterized. We anticipate that the artificial sRNAs will be useful for dynamic control and fine tuning of endogenous gene expression in bacteria for applications in synthetic biology. PMID- 23651006 TI - j5 DNA assembly design automation software. AB - Recent advances in Synthetic Biology have yielded standardized and automatable DNA assembly protocols that enable a broad range of biotechnological research and development. Unfortunately, the experimental design required for modern scar-less multipart DNA assembly methods is frequently laborious, time-consuming, and error prone. Here, we report the development and deployment of a web-based software tool, j5, which automates the design of scar-less multipart DNA assembly protocols including SLIC, Gibson, CPEC, and Golden Gate. The key innovations of the j5 design process include cost optimization, leveraging DNA synthesis when cost-effective to do so, the enforcement of design specification rules, hierarchical assembly strategies to mitigate likely assembly errors, and the instruction of manual or automated construction of scar-less combinatorial DNA libraries. Using a GFP expression testbed, we demonstrate that j5 designs can be executed with the SLIC, Gibson, or CPEC assembly methods, used to build combinatorial libraries with the Golden Gate assembly method, and applied to the preparation of linear gene deletion cassettes for E. coli. The DNA assembly design algorithms reported here are generally applicable to broad classes of DNA construction methodologies and could be implemented to supplement other DNA assembly design tools. Taken together, these innovations save researchers time and effort, reduce the frequency of user design errors and off-target assembly products, decrease research costs, and enable scar-less multipart and combinatorial DNA construction at scales unfeasible without computer-aided design. PMID- 23651007 TI - Cloning the Acholeplasma laidlawii PG-8A genome in Saccharomyces cerevisiae as a yeast centromeric plasmid. AB - Cloning of whole genomes of the genus Mycoplasma in yeast has been an essential step for the creation of the first synthetic cell. The genome of the synthetic cell is based on Mycoplasma mycoides, which deviates from the universal genetic code by encoding tryptophan rather than the UGA stop codon. The feature was thought to be important because bacterial genes might be toxic to the host yeast cell if driven by a cryptic promoter active in yeast. As we move to expand the range of bacterial genomes cloned in yeast, we extended this technology to bacteria that use the universal genetic code. Here we report cloning of the Acholeplasma laidlawii PG-8A genome, which uses the universal genetic code. We discovered that only one A. laidlawii gene, a surface anchored extracellular endonuclease, was toxic when cloned in yeast. This gene was inactivated in order to clone and stably maintain the A. laidlawii genome as a centromeric plasmid in the yeast cell. PMID- 23651008 TI - An E. coli cell-free expression toolbox: application to synthetic gene circuits and artificial cells. AB - Cell-free protein synthesis is becoming a powerful technique to construct and to study complex informational processes in vitro. Engineering synthetic gene circuits in a test tube, however, is seriously limited by the transcription repertoire of modern cell-free systems, composed of only a few bacteriophage regulatory elements. Here, we report the construction and the phenomenological characterization of synthetic gene circuits engineered with a cell-free expression toolbox that works with the seven E. coli sigma factors. The E. coli endogenous holoenzyme E(70) is used as the primary transcription machinery. Elementary circuit motifs, such as multiple stage cascades, AND gate and negative feedback loops are constructed with the six other sigma factors, two bacteriophage RNA polymerases, and a set of repressors. The circuit dynamics reveal the importance of the global mRNA turnover rate and of passive competition induced transcriptional regulation. Cell-free reactions can be carried out over long periods of time with a small-scale dialysis reactor or in phospholipid vesicles, an artificial cell system. This toolbox is a unique platform to study complex transcription/translation-based biochemical systems in vitro. PMID- 23651009 TI - The role of ion channelopathies in sudden cardiac death: implications for clinical practice. AB - Sudden cardiac death (SCD) following ventricular tachyarrhythmias constitutes an important clinical cause of mortality; 4% of cases may involve ion channel mediated cellular excitation in structurally normal hearts. Alterations in such processes could disturb action potential conduction, depolarization/ repolarization gradients, or Ca(2+) homeostasis with potential arrhythmogenic consequences. Although SCD may be the first presentation of arrhythmic syndromes, patients may present to the general physician with symptoms of palpitations or hemodynamic compromise, including dizziness, seizure, or syncope, particularly following exertion. In all inherited cardiac death syndromes, first-degree relatives should be referred to a cardiologist and should undergo testing appropriate for the condition. While management of patients at risk of SCD largely centers on risk stratification and, if necessary, insertion of an implantable cardioverter-defibrillator, there are a number of other, pharmacological, treatments being developed. Furthermore, as the genetic basis of these diseases becomes established, genetic testing will form an increasingly important part of diagnosis, and gene-specific therapy is an area under investigation. This article bridges the gap between molecular medicine and clinical practice by reviewing recent developments in the pathophysiological understanding of SCD, and their implications for the management of patients with these complex diseases. PMID- 23651010 TI - Pregnancy intention and postpartum depression: secondary data analysis from a prospective cohort. AB - OBJECTIVE: To assess the relationship between unintended pregnancy and postpartum depression. DESIGN: Secondary analysis of data from a prospective pregnancy cohort. SETTING: The study was performed at the University of North Carolina prenatal care clinics. POPULATION/SAMPLE: Pregnant women enrolled for prenatal care at the University of North Carolina Hospital Center. METHODS: Participants were questioned about pregnancy intention at 15-19 weeks of gestation, and classified as having an intended, mistimed or unwanted pregnancy. They were evaluated for postpartum depression at 3 and 12 months postpartum. Log binomial regression was used to assess the relationship between unintended pregnancy and depression, controlling for confounding by demographic factors and reproductive history. MAIN OUTCOME MEASURES: Depression at 3 and 12 months postpartum, defined as Edinburgh Postpartum Depression Scale score >13. RESULTS: Data were analysed for 688 women at 3 months and 550 women at 12 months. Depression was more likely in women with unintended pregnancies at both 3 months (risk ratio [RR] 2.1, 95% confidence interval [95% CI] 1.2-3.6) and 12 months (RR 3.6, 95% CI 1.8-7.1). Using multivariable analysis adjusting for confounding by age, poverty and education level, women with unintended pregnancies were twice as likely to have postpartum depression at 12 months (RR 2.0, 95% CI 0.96-4.0). CONCLUSION: While many elements may contribute to postpartum depression, unintended pregnancy could also be a contributing factor. Women with unintended pregnancy may have an increased risk of depression up to 1 year postpartum. PMID- 23651011 TI - Distribution patterns in generalized vitiligo. AB - BACKGROUND: Vitiligo is a common pigmentation disorder affecting approximately 1% of the world population. Nonetheless, its distribution pattern is not well investigated. OBJECTIVE: The aim of this study was to investigate whether the distribution pattern of vitiligo is dependent on the clinical characteristics. METHODS: A total of 700 generalized vitiligo patients were included in this retrospective observational cohort study. RESULTS: The most important predilection areas were the face (87%), followed by acral areas (76.3%) and extremities (59.7%). In women, joints (P = 0.002) (especially elbows), hips (P < 0.001), trunk (P < 0.001) and body folds (P < 0.001) (especially axillas) were more frequently affected compared to men. In contrast, in men more depigmentations in the beard area and genital area were observed (P < 0.001). Vitiligo at a young age is more prone to be localized at the lower extremities whereas the upper extremities are more susceptible at an older age. In the face, the periocular area is linked to a younger age, in contrast to the perioral area. Acral areas were more frequently affected in patients with autoimmune disorders (in particular thyroid disease) (P = 0.001). CONCLUSION: These results point to important differences in the distribution pattern according to the clinical characteristics. Although in some of these areas Koebner's phenomenon probably plays a role, other differences may represent a specific characteristic vulnerability related to the age, gender or typical association with autoimmune disease. PMID- 23651012 TI - Biomechanical performance of leather and modern football helmets. AB - With the increased national concern about concussions in football, recent research has focused on evaluating the impact performance of modern football helmets. Specifically, this technical note offers a biomechanical analysis of classic leather helmets compared with modern helmets. Furthermore, modern helmets were examined to illustrate the performance differences between the better- and worse-performing ones. A total of 1224 drop tests were performed from a range of drop heights and impact locations on 11 different helmet types (10 modern and 1 leather helmet model). The resulting head acceleration was used to assess the risk of concussion for each drop test. The results of this analysis demonstrate that modern helmets are significantly and substantially superior to leather helmets in all impact scenarios, and that notable differences exist among modern helmets. PMID- 23651013 TI - Leather football helmets. PMID- 23651014 TI - Probing Maxwell's demon with a nanoscale thermometer. AB - A precise definition for a quantum electron thermometer is given, as an electron reservoir coupled locally (e.g., by tunneling) to a sample, and brought into electrical and thermal equilibrium with it. A realistic model of a scanning thermal microscope with atomic resolution is then developed, including the effect of thermal coupling of the probe to the ambient environment. We show that the temperatures of individual atomic orbitals or bonds in a conjugated molecule with a temperature gradient across it exhibit quantum oscillations, whose origin can be traced to a realization of Maxwell's demon at the single-molecule level. These oscillations may be understood in terms of the rules of covalence describing bonding in pi-electron systems. Fourier's law of heat conduction is recovered as the resolution of the temperature probe is reduced, indicating that the macroscopic law emerges as a consequence of coarse graining. PMID- 23651015 TI - Implementation of a clinical research pharmacogenomics program at an academic medical center: role of the genetics healthcare professional. PMID- 23651016 TI - Malaria pharmacogenomics: return to the future. PMID- 23651018 TI - Pharmacogenomics: past, present & future. Interview by Theo Bond. PMID- 23651019 TI - Research highlights from the latest articles in pharmacogenomics of tacrolimus and organ transplantation. PMID- 23651020 TI - Institutional profile: University of Florida and Shands Hospital Personalized Medicine Program: clinical implementation of pharmacogenetics. PMID- 23651021 TI - GWAS replication study confirms the association of PDE3A-SLCO1C1 with anti-TNF therapy response in rheumatoid arthritis. AB - AIM: The present study was undertaken to replicate the association of candidate genes for anti-TNF response in rheumatoid arthritis. Candidate genes were selected from a recent genome-wide association study on anti-TNF response performed in a population from Denmark. MATERIALS & METHODS: Genomic DNA was obtained from 315 Spanish rheumatoid arthritis patients having received an anti TNF agent as their first biological therapy. SNPs from NR2FR2, MAP2K6, CBLN2 and PDE3A-SLCO1C1 candidate loci were genotyped. RESULTS: The PDE3A-SLCO1C1 locus rs3794271 SNP showed a highly significant association with anti-TNF treatment response (p = 1.74 * 10-5). Combining the statistical evidence from the Spanish and Danish rheumatoid arthritis cohorts, the associated rs3794271 SNP reached a genome-wide significance level of association (p = 3.3 * 10-10). CONCLUSION: The present findings establish the PDE3A-SLCO1C1 locus as a strong genetic marker of anti-TNF therapy response. PMID- 23651022 TI - Assessment of a pharmacogenomic marker panel in a polypharmacy population identified from electronic medical records. AB - BACKGROUND: The ADME Core Panel assays 184 variants across 34 pharmacogenes, many of which are difficult to accurately genotype with standard multiplexing methods. METHODS: We genotyped 326 frequently medicated individuals of European descent in Vanderbilt's biorepository linked to de-identified electronic medical records, BioVU, on the ADME Core Panel to assess quality and performance of the assay. We compared quality control metrics and determined the extent of direct and indirect marker overlap between the ADME Core Panel and the Illumina Omni1-Quad. RESULTS: We found the quality of the ADME Core Panel data to be high, with exceptions in select copy number variants and markers in certain genes (notably CYP2D6). Most of the common variants on the ADME panel are genotyped by the Omni1, but absent rare variants and copy number variants could not be accurately tagged by single markers. CONCLUSION: Our frequently medicated study population did not convincingly differ in allele frequency from reference populations, suggesting that heterogeneous clinical samples (with respect to medications) have similar allele frequency distributions in pharmacogenetics genes compared with reference populations. PMID- 23651023 TI - Impact of CYP2C9 polymorphisms on the vulnerability to pharmacokinetic drug-drug interactions during acenocoumarol treatment. AB - AIM: The objective of this study was to investigate the impact of CYP2C9 polymorphisms and drug-drug interactions on the risk of overanticoagulation in patients treated with acenocoumarol, a vitamin K antagonist. MATERIALS & METHODS: A prospective observational study was performed on patients starting acenocoumarol (n = 115). CYP2C9 genotypes were assessed. Data on International Normalized Ratio, comedications and doses of acenocoumarol were collected during the first 35 days of therapy. Overanticoagulation was defined as the occurrence of at least one International Normalized Ratio >=4. RESULTS: The presence of a CYP2C9 inhibitor or a CYP2C9 polymorphisms statistically increased the risk of overanticoagulation (hazard ratio [HR]: 2.8, p < 0.001 and HR: 1.7, p = 0.04, respectively). The presence of CYP2C9 polymorphisms almost tripled the risk of overanticoagulation (HR: 2.91, p = 0.01) in the presence of a clinically significant drug-drug interaction. CONCLUSION: These findings support the fact that CYP2C9 genotyping could be useful to identify patients requiring closer monitoring, especially when a drug-drug interaction is expected. PMID- 23651025 TI - Genes and beans: pharmacogenomics of renal transplant. AB - Advances in the management of patients after solid organ transplantation have led to dramatic decreases in rates of acute rejection, but long-term graft and patient survival have remained unchanged. Individualized therapy after transplant will ideally provide adequate immunosuppression while limiting the adverse effects of drug therapy that significantly impact graft survival. Therapeutic drug monitoring represents the best approximation of individualized drug therapy in transplant at this time; however, obtaining pharmacogenomic data in transplant patients has the potential to enhance our current practice. Polymorphisms of target genes that impact pharmacokinetics have been identified for most immunosuppressants, including tacrolimus, cyclosporine, mycophenolate, azathioprine and sirolimus. In the future, pre-emptive assessment of a patient's genetic profile may inform drug selection and provide information on specific doses that will improve efficacy and limit toxicity. PMID- 23651026 TI - CDA gene polymorphisms and enzyme activity: genotype-phenotype relationship in an Italian-Caucasian population. AB - AIM: To assess the distribution of CDA activity from whole blood of 142 healthy subjects, determining its main predictors among genetic (six CDA SNPs) and physiological factors (age and gender). Moreover, we performed a kinetic study of the two CDA protein variants (Q27 and K27) determined by the rs2072671 SNP. MATERIALS & METHODS: CDA activity was assessed by HPLC. Selected CDA SNPs were genotyped by PCR-based methods. Recombinant CDA protein variants (Q27 and K27) were expressed in an Escherichia coli strain SO5201 and kinetic assays were performed. RESULTS: The mean value of CDA activity was 0.051 +/- 0.024 mU/mg and followed a normal distribution in the study population. Carriers of the CDA*2B ( 451T/-92G/-31Del/79C/435C) haplotype displayed higher CDA activity compared with the others. CDA -451G>A, -92A>G and 79A>C (K27Q) SNPs displayed significant associations with CDA activity. The best predictive model of CDA activity included the variables gender and CDA 79A>C (K27Q). Cytidine is the preferential substrate for the variant Q27. CONCLUSION: We suggest the analysis of both CDA activity and CDA 79A>C (K27Q) SNP in future prospective trials with cytidine analogs, alone or in combination, in order to identify the best marker to secure the administration of these anticancer therapies. PMID- 23651027 TI - Evaluation of 5-fluorouracil pharmacokinetic models and therapeutic drug monitoring in cancer patients. AB - 5-fluorouracil (5-FU) remains the cornerstone of all currently applied regimens for the treatment of patients with cancers of the gastrointestinal tract, breast, and head and neck. Unfortunately, a large variation in the clearance of 5-FU has been observed between patients, suggesting that some patients might receive nonoptimal 5-FU doses. However, therapeutic drug monitoring of 5-FU has been shown to result in reduced intra- and inter-individual variability in 5-FU plasma levels and pharmacokinetically guided dose adjustments of 5-FU-containing therapy results in a significantly improved efficacy and tolerability. To date, compartmental Michaelis-Menten elimination-based modeling has proven to be a sensitive and accurate tool for analyzing the pharmacokinetics of 5-FU and to identify patients with a dihydropyrimidine dehydrogenase deficiency. These Michaelis-Menten models also allow the use of a limited sampling strategy and offer the opportunity to predict a priori the 5-FU plasma concentrations in patients receiving adapted doses of 5-FU. PMID- 23651024 TI - Association of genetic variation in pharmacodynamic factors with methadone dose required for effective treatment of opioid addiction. AB - AIM: The interindividual variability in the dose required for effective methadone maintenance treatment (MMT) for opioid addiction may be influenced in part by genetic variations in genes encoding pharmacodynamic factors of methadone. This study was conducted to identify some of these variants. MATERIALS & METHODS: This study focused on 11 genes encoding components of the opioidergic (OPRM1, POMC and ARRB2), the dopaminergic (ANKK1 and DRD2) and the glutamatergic pathways (GRIN1 and GRIN2A), as well as the neurotrophin system (NGFB, BDNF, NTRK1 and NTRK2). The study includes 227 Israeli patients undergoing stable MMT. RESULTS: Out of the 110 variants analyzed, 12 SNPs (in BDNF, NTRK2, OPRM1, DRD2 and ANKK1) were associated with methadone dose (nominal p < 0.05). Of these SNPs, ANKK1 rs7118900 and DRD2 rs2283265 are known to affect gene expression. Logistic regression of five representative SNPs discriminated between individuals requiring a methadone dose of >120 mg/day and <120 mg/day (p = 0.019), and showed moderate sensitivity and specificity (AUC of 0.63 in receiver operating characteristic analysis). CONCLUSION: This data should stimulate further research on the potential influence and clinical significance of these variants on MMT. PMID- 23651028 TI - OPRM1 rs1799971 polymorphism and opioid dependence: evidence from a meta analysis. AB - The OPRM1 gene encodes the u-opioid receptor, which is the primary site of action of most opioids. Several studies and three meta-analyses have examined a possible link between the exonic OPRM1 A118G (rs1799971) polymorphism and opioid dependence; however, results have been inconclusive. Therefore, a systematic review and meta-analysis have been carried out to examine whether this polymorphism is associated with opioid dependence. Thirteen studies (n = 9385), comprising 4601 opioid dependents and 4784 controls, which evaluated association of the OPRM1 rs1799971 polymorphism with susceptibility to opioids, were included in this study. Our meta-analysis showed significant association between this polymorphism and susceptibility to opioid dependence in overall studies under a codominant model, as well as susceptibility to opioid dependence or heroin dependence in Asians under an autosomal dominant model. The nonsynonymous OPRM1 rs1799971 might be a risk factor for addiction to opioids or heroin in an Asian population. PMID- 23651029 TI - SGLT2: a potential target for the pharmacogenetics of Type 2 diabetes? AB - The kidney has attracted the attention of diabetologists as an organ involved in the regulation of glucose homeostasis not only by gluconeogenesis, but also by renal glucose excretion. Sodium-glucose cotransporters (SGLTs), particularly SGLT2, are responsible for reabsorption of up to 99% of the filtered glucose. SGLT2 is coded by the SLC5A2 gene, which maps on chromosome 16. Pharmacological reduction of tubular glucose reabsorption results in improved glycemic control in Type 2 diabetic patients. Since the SGLTs reabsorb most of the filtered glucose (90%), it is not surprising that mutations in SLC5A2 cause familial renal glucosuria. A recent study pointed out a possible role of common genetic variation in SLC5A2 in the control of glucose homeostasis. SLC5A2 polymorphisms might therefore represent potential candidates for pharmacogenomic studies targeting the impact of these variants on the efficacy of antidiabetic treatment that is based on inhibition of SGLT2 activity. PMID- 23651030 TI - Pharmacogenetics in clinical practice: how far have we come and where are we going? AB - Recent years have seen great advances in our understanding of genetic contributors to drug response. Drug discovery and development around targeted genetic (somatic) mutations has led to a number of new drugs with genetic indications, particularly for the treatment of cancers. Our knowledge of genetic contributors to variable drug response for existing drugs has also expanded dramatically, such that the evidence now supports clinical use of genetic data to guide treatment in some situations, and across a variety of therapeutic areas. Clinical implementation of pharmacogenetics has seen substantial growth in recent years and groups are working to identify the barriers and best practices for pharmacogenetic-guided treatment. The advances and challenges in these areas are described and predictions about future use of genetics in drug therapy are discussed. PMID- 23651032 TI - Recent development on naphthoquinone derivatives and their therapeutic applications as anticancer agents. AB - INTRODUCTION: A large number of natural products including several synthetic drugs possess naphthoquinone chromophore. Various methods have been devised for their synthesis. Several naphthoquinone derivatives have been found to possess diverse biological properties especially anticancer activity which has stimulated keen interest and research in this field. AREAS COVERED: The present review provides recent therapeutic patent literature (2000 - 2012) describing the applications of naphthoquinones and their derivatives on anticancer activities. Information from articles published in international peer-reviewed journals has been included to comprise a more exhaustive review. EXPERT OPINION: With the advent of stem cell research and molecular mechanism associated with cure of cancer, the use of classical and novel naphthoquinone structures have been more frequently noted in recent (2000 - 2012) patented agents for treatment of cancer. PMID- 23651033 TI - Nanoparticle mediated brain targeted delivery of gallic acid: in vivo behavioral and biochemical studies for protection against scopolamine-induced amnesia. AB - CONTEXT: Gallic acid (GA) has well-documented antioxidant and CNS effects affecting glutathione, catalase and malonaldehyde levels in brain. OBJECTIVE: This study was designed to evaluate the anti-amnesic activity of pure GA in scopolamine (SC)-induced amnesic models and to enhance its effects using Tween 80(r)-coated nanoparticles. METHODS: GA-loaded chitosan nanoparticles (GANP) and corresponding Tween 80(r)-coated batch (cGANP) were formulated. Amnesia was induced by using SC (0.4 mg/kg, i.v.). GA, GANP, cGANP (dose equivalent to GA 10 mg/kg, i.p.) and positive control Piracetam (400 mg/kg, i.p.) were administered for successive 7 days to male Swiss albino mice. The in vivo pharmacodynamic study was performed using Morris water maze (MWM) and elevated plus maze (EPM) models; locomotor activity using photoactometer and brain acetyl cholinesterase (AChE) activity was also studied. KEY FINDINGS: GA-treated mice exhibited significant decrease in transfer latency in the EPM test; increase in time spent in target quadrant in MWM and reduced AChE activity. GA significantly reversed SC induced amnesic activity. There was no significant change in locomotor activity of the mice by GA and its nanoparticle formulations. These effects were significantly increased by the administration of cGANP compared with pure GA administration but no significant change was observed for GANP. CONCLUSION: GA possesses anti-amnesic activity by reversing the SC-induced amnesia which may be attributed to its anti-cholinesterase activity. Tween 80(r)-coated nanoparticle approach with improved brain targeting may serve as an effective approach to enhance its anti-amnesic effect. PMID- 23651034 TI - Prevalence of arrhythmia-associated gene mutations and risk of sudden cardiac death in the Finnish population. AB - BACKGROUND: Sudden cardiac death (SCD) remains a major cause of death in Western countries. It has a heritable component, but previous molecular studies have mainly focused on common genetic variants. We studied the prevalence, clinical phenotypes, and risk of SCD presented by ten rare mutations previously associated with arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, or catecholaminergic polymorphic ventricular tachycardia. METHODS: The occurrence of ten arrhythmia-associated mutations was determined in four large prospective population cohorts (FINRISK 1992, 1997, 2002, and Health 2000, n = 28,465) and two series of forensic autopsies (The Helsinki Sudden Death Study and The Tampere Autopsy Study, n = 825). Follow-up data were collected from national registries. RESULTS: The ten mutations showed a combined prevalence of 79 per 10,000 individuals in Finland, and six of them showed remarkable geographic clustering. Of a total of 715 SCD cases, seven (1.0%) carried one of the ten mutations assayed: three carried KCNH2 R176W, one KCNH2 L552S, two PKP2 Q59L, and one RYR2 R3570W. CONCLUSIONS: Arrhythmia-associated mutations are prevalent in the general Finnish population but do not seem to present a major risk factor for SCD, at least during a mean of 10-year follow-up of a random adult population sample. PMID- 23651035 TI - Cotton AnnGh3 encoding an annexin protein is preferentially expressed in fibers and promotes initiation and elongation of leaf trichomes in transgenic Arabidopsis. AB - The annexins are a multifamily of calcium-regulated phospholipid-binding proteins. To investigate the roles of annexins in fiber development, four genes encoding putative annexin proteins were isolated from cotton (Gossypium hirsutum) and designated AnnGh3, AnnGh4, AnnGh5, and AnnGh6. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) results indicated that AnnGh3, AnnGh4, and AnnGh5 were preferentially expressed in fibers, while the transcripts of AnnGh6 were predominantly accumulated in roots. During fiber development, the transcripts of AnnGh3/4/5 genes were mainly accumulated in rapidly elongating fibers. With fiber cells further developed, their expression activity was dramatically declined to a relatively low level. In situ hybridization results indicated that AnnGh3 and AnnGh5 were expressed in initiating fiber cells (0-2 DPA). Additionally, their expression in fibers was also regulated by phytohormones and [Ca(2+)]. Subcellular localization analysis discovered that AnnGh3 protein was localized in the cytoplasm. Overexpression of AnnGh3 in Arabidopsis resulted in a significant increase in trichome density and length on leaves of the transgenic plants, suggesting that AnnGh3 may be involved in fiber cell initiation and elongation of cotton. PMID- 23651036 TI - Preventive effects of Monascus on androgen-related diseases: androgenetic alopecia, benign prostatic hyperplasia, and prostate cancer. AB - Androgen-related diseases impair the well-being of many aging men. Unfortunately, the medications used to treat these diseases have many side effects. Therefore, there is a significant need for the development of novel drugs to treat androgen related diseases. In this study, we investigated the effects of Monascus cursory extraction (M-CE) on androgen-related diseases, including androgenetic alopecia (AGA), benign prostatic hyperplasia (BPH) and prostate cancer. We found that M-CE suppressed baldness in male B6CBAF1/j mice. Furthermore, M-CE decreased PSA levels, indicating a protective effect of M-CE on testosterone-induced hyperplasia. M-CE also significantly decreased tumor volume and tumor incidence in an N-methyl-N-nitrosourea (MNU)/testosterone-induced rat prostate cancer model and markedly decreased dihydrotestosterone (DHT) but not testosterone. Additionally, PCNA expression was decreased in the prostate of rats treated with M-CE. These results suggest that M-CE could be a new potential therapeutic candidate for the treatment of androgen-related diseases. PMID- 23651037 TI - Imidazole incorporated semicarbazone derivatives as a new class of anticonvulsants: design, synthesis and in-vivo screening. AB - A series of novel imidazole incorporated semicarbazones was synthesized using an appropriate synthetic route and characterized by spectral analysis (IR, 1H NMR, 13C NMR and Mass). The anticonvulsant activity of the synthesized compounds was determined using doses of 30, 100, and 300 mg kg-1 against maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) induced seizure and minimal neurotoxicity test. Six compounds exhibited protection in both models and 2-(1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene)-N-p-tolylsemicarbazone emerged as the most active compound of the series without any neurotoxicity and significant CNS depressant effect. Liver enzyme estimations (SGOT, SGPT, Alkaline phosphatase) of the compound also showed no significant change in the enzymes levels. Moreover, it caused 80% elevation of gamma-amino butyric acid (GABA) levels in the whole mice brain, thus indicating that it could be a promising candidate in designing of a potent anticonvulsant drug. PMID- 23651038 TI - Self-expanding plastic stent removed after radiochemotherapy for advanced esophageal cancer. AB - Endoscopic evaluation after chemoradiotherapy (CR) is impossible with an esophageal stent in place. The main study objective was to evaluate self expanding plastic stent (SEPS) removal post-CR. Secondary end-points were the improvement of dysphagia and patients' quality of life. From October 2008 to March 2011, 20 dysphagic patients who suffered from advanced esophageal cancer were enrolled in a multicenter, prospective study. SEPS was inserted prior to CR and then removed endoscopically. SEPS efficiency (dysphagia score) and tolerance, as well as the patients' quality of life (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire validated for the esophagus), were monitored. Continuous variables were compared using a paired t test analysis for matched data. A P-value of less than 0.05 was considered statistically significant. Twenty patients (15 men and 5 women), aged 61.5 years (+/-9.88) (range 43-82 years), with adenocarcinoma (n = 12) and squamous cell carcinoma (n = 8), were enrolled. SEPS were successfully inserted in all patients (100%). There was one perforation and three episodes of migration. All of these complications were medically treated. The mean dysphagia score at the time of stent placement was 2.79 (0.6). Mean dysphagia scores obtained on day 1 and day 30 post-SEPS placement were 0.7 (0.9) (P < 0.0001) and 0.45 (0.8) (P < 0.0001), respectively. Quality of Life Questionnaire validated for the esophagus score showed an improvement in dysphagia (P = 0.01) and quality of oral feeding (P = 0.003). All SEPS were removed endoscopically without complications. In two patients, the stent was left in place due to metastatic disease. SEPS are extractable after CR of esophageal cancer. Early stenting by SEPS prior to and during CR may reduce dysphagia and improve quality of oral alimentation. PMID- 23651039 TI - Chemical catalysis by the translocator protein (18 kDa). AB - Translocator proteins (18 kDa) (TSPOs) are conserved integral membrane proteins. In both eukaryotes and prokaryotes, TSPOs interact with porphyrins, precursors of heme, and photosynthetic pigments. Here we demonstrate that bacterial TSPOs catalyze rapid porphyrin degradation in a light- and oxygen-dependent manner. The reaction is inhibited by a synthetic TSPO ligand PK11195 and by mutations of conserved residues, which affect either porphyrin binding or catalytic activity. We hypothesize that TSPOs are ancient enzymes mediating porphyrin catabolism with the consumption of reactive oxygen species. PMID- 23651040 TI - Regioselective photocyclization to prepare multifunctional blocks for ladder conjugated materials. AB - Multifunctional building blocks 8 and 9 were efficiently synthesized by fusing a perylene-3,4,9,10-tetracarboxylic acid bisimide (PBI) core with o phenylenediamine, and they were condensed with a pyrenedione and a pyrenetetraone, respectively, to construct new ladder-type conjugated oligomers 12 and 13. In the key photocyclization step, an unusual regioselectivity at the position ortho to the nitro group was discovered in the coupling of the o nitroaniline functional units at the bay sites of PBI. Bulk-heterojunction solar cells based on 12 and 13 as the acceptors exhibited reasonable performance. PMID- 23651041 TI - Fatigue related to radiotherapy for breast and/or gynaecological cancer: a systematic review. AB - AIMS AND OBJECTIVES: To assess the profile, evaluation criteria and fatigue treatment. BACKGROUND: Fatigue, characterised by tiredness, weakness or lack of energy, involves physical, cognitive and emotional aspects. Its aetiology is not well defined and the prevalence ranges from 30-70% in women with breast cancer, reaching up to 80% when they are undergoing radiotherapy. This is one of the most frequent side effects of radiotherapy, and it may interfere with self-esteem, social activities and quality of life. DESIGN: Literature systematic review. METHODS: A search for studies published from 2000-2010 was carried out in Pubmed, Scielo and Bireme databases, using the descriptors fatigue and radiotherapy and their correlates in Portuguese. RESULTS: We selected 12 articles of 1085 found. The number of studies involving breast cancer was higher than those related to gynaecological cancer. Functional Assessment of Cancer Therapy-Fatigue was the most used scale specifically for the evaluation of fatigue. Pretreatment fatigue level may be an important risk factor to aggravate it during radiotherapy and decrease the quality of life. Five studies proposed interventions, all of them involving nonpharmacological therapies: cognitive-behavioural therapy associated with hypnosis, moderate-intensity physical exercises, stretching programmes, yoga and polarity therapy. The studies showed good results in relation to fatigue, physical and psychological aspects, and quality of life. CONCLUSION: Early detection of fatigue, using appropriate scales, is relevant to propose suitable treatments and achieve better clinical conditions, adherence and continuity of radiotherapy treatment, aiming to ensure more effective responses. RELEVANCE TO CLINICAL PRACTICE: Fatigue is a frequent symptom in patients undergoing radiotherapy. It may become a factor that limits or prevents the continuity of radiotherapy and therefore should be diagnosed in the initial appointments, so that it can be properly treated. PMID- 23651042 TI - Efficient C-H/C-N and C-H/C-CO-N conversion via decatungstate-photoinduced alkylation of diisopropyl azodicarboxylate. AB - Tetrabutylammonium decatungstate (TBADT) accelerated the addition of C-H bonds to the N?N double bond of diisopropyl azodicarboxylate (DIAD) under irradiation conditions. The photoinduced three-component coupling between cyclic alkanes, CO, and DIAD was also achieved to give the corresponding acyl hydrazides. PMID- 23651043 TI - Design and development of (99m)tc-'4+1'-labeled dextran-mannose derivatives as potential radiopharmaceuticals for sentinel lymph node detection. AB - The synthesis, labeling, and biological evaluation of a dextran derivative (DCM 30-iso) as potential radiopharmaceutical for sentinel lymph node imaging is presented. DCM-30-iso bears mannose as active moiety and isocyanide as ligand for technetium through the formation of a '4+1' Tc(III) mixed-ligand complex. A second derivative without mannose (DC-25-iso) was also prepared and evaluated as control. DCM-30-iso and DC-25-iso were synthesized from dextran in four steps (>50% overall yield) and characterized by spectroscopic methods. Labeling with (99m)Tc was achieved by reaction with 2,2',2''-nitrilotris(ethanethiol) and (99m)Tc-EDTA. Radiochemical purity was above 90% and was stable for at least 4 hours postlabeling at 37 degrees C. The identity of the (99m)Tc complex was established through comparative HPLC studies using the well-characterized analogous Re-DC-25-iso complex. Biodistribution and imaging experiments of (99m)Tc-DCM-30-iso showed high uptake in the popliteal lymph node, which could be blocked with preinjection of mannose, and very low uptake in other nodes and organs. The nonmannosylated (99m)Tc-DC-25-iso derivative showed negligible uptake in all lymph nodes. The novel dextran-mannose derivative DCM-30-iso can be successfully labeled with (99m)Tc to give a well-characterized '4+1' complex with favorable biological properties as sentinel lymph node imaging agent. PMID- 23651045 TI - Assembly of MreB filaments on liposome membranes: a synthetic biology approach. AB - The physical interaction between the cytoskeleton and the cell membrane is essential in defining the morphology of living organisms. In this study, we use a synthetic approach to polymerize bacterial MreB filaments inside phospholipid vesicles. When the proteins MreB and MreC are expressed inside the liposomes, the MreB cytoskeleton structure develops at the inner membrane. Furthermore, when purified MreB is used inside the liposomes, MreB filaments form a 4-10 MUm rigid bundle structure and deform the lipid vesicles in physical contact with the vesicle inner membrane. These results indicate that the fibrillation of MreB filaments can take place either in close proximity of deformable lipid membrane or in the presence of associated protein. Our finding might be relevant for the self-assembly of cytoskeleton filaments toward the construction of artificial cell systems. PMID- 23651046 TI - Monitoring alkane degradation by single BioBrick integration to an optimal cellular framework. AB - Synthetic biology enables rewiring and reconstruction of desirable biochemical routes using well-characterized BioBricks. One goal is to optimize these biological systems in terms of robustness, functionality, and simplicity. Thus, in addition to optimizing the molecular level of the metabolic network, choosing an optimal "chassis" can have a great significance in the constructed system. As an example, this study presents a simplified system for monitoring and studying long-chain n-alkane degradation in Acinetobacter baylyi ADP1 online, provided by a single BioBrick insertion, bacterial luciferase luxAB. The system exploits the natural alkane degradation machinery of ADP1 and a sensitive response of bacterial luciferase to a specific intermediate, providing important aspects to natural alkane degradation kinetics. The study suggests the monitoring system to be applicable in the field of environmental biotechnology and emphasizes the utility of ADP1 as a host in both model systems and applications. PMID- 23651047 TI - Editorial. PMID- 23651048 TI - Involvement and unusual substrate specificity of a prolyl oligopeptidase in class III lanthipeptide maturation. AB - Lanthipeptides represent an important group of ribosomally synthesized and post translationally modified peptides (RiPPs). Commonly, in the last steps of their maturation, a part of the peptide, termed the leader, is removed, providing the active compound. This contribution describes for the first time the identification of a protease involved in the removal of the leader peptide of a class III lanthipeptide. Four putative class III biosynthetic gene clusters were identified in bacterial genomes, each containing a gene encoding a prolyl oligopeptidase (POP). Further in vitro investigations of the gene cluster from Kribbella flavida , involving reconstitution of the biosynthesis of the new lanthipeptide flavipeptin, proved that a POP-type FlaP protease is responsible for leader removal. Interestingly, detailed in vitro studies of the substrate specificity revealed that FlaP is specific to the post-translationally modified peptide and can discriminate between N- and C-terminal rings. Therefore, it has been shown for the first time that factors other than size and amino acid sequence might be involved in substrate recognition by POPs. PMID- 23651049 TI - Experience over 12 years with home enteral nutrition in a healthcare area of Spain. AB - BACKGROUND: The wide spread use of long-term enteral nutrition and the substantive costs dictate a need to study the outcome, as well as the clinical and epidemiological characteristics, of these patients. The present study aimed to analyse the incidence and characteristics of a cohort of patients on home enteral nutrition (HEN) over 12 years. MATERIALS AND METHODS: A prospective observational study was performed between January 1999 and December 2010. All adult patients living in Valladolid West area who were discharged from the hospital on HEN were prospectively studied and followed up. RESULTS: The incidence of HEN ranged between 9.52 per 100, 000 inhabitants in 2001 to 30.0 per 100,000 inhabitants in 2009. HEN was administered orally in 472 patients (68.28%) (group 1), and through a nasogastric tube in 168 patients (24.30%), a percutaneous enteral gastrostomy tube in 47 patients (6.80%) and a jejunostomy in four patients (0.60%) (group 2; 219 patients). During the course of HEN, 31 patients had diarrhoea (4.5%), 17 patients had constipation and 12 patients had nausea. The mean (SD) duration of HEN was 159.9 (97) days. In multivariable analysis, an independent factor associated with death was age (hazard ratio = 1.03; 95% confidence interval - 1.01-1.05), adjusted by sex, route and diagnosis. CONCLUSIONS: HEN has a high incidence in our area and it is a valid and safe technique for nutrition support. PMID- 23651050 TI - Different crystallographic one-dimensional MnO2 nanomaterials and their superior performance in catalytic phenol degradation. AB - Three one-dimensional MnO2 nanoparticles with different crystallographic phases, alpha-, beta-, and gamma-MnO2, were synthesized, characterized, and tested in heterogeneous activation of Oxone for phenol degradation in aqueous solution. The alpha-, beta-, and gamma-MnO2 nanostructured materials presented in morphologies of nanowires, nanorods, and nanofibers, respectively. They showed varying activities in activation of Oxone to generate sulfate radicals for phenol degradation depending on surface area and crystalline structure. alpha-MnO2 nanowires exhibited the highest activity and could degrade phenol in 60 min at phenol concentrations ranging in 25-100 mg/L. It was found that phenol degradation on alpha-MnO2 followed first order kinetics with an activation energy of 21.9 kJ/mol. The operational parameters, such as MnO2 and Oxone loading, phenol concentration and temperature, were found to influence phenol degradation efficiency. It was also found that alpha-MnO2 exhibited high stability in recycled tests without losing activity, demonstrating itself to be a superior heterogeneous catalyst to the toxic Co3O4 and Co(2+). PMID- 23651051 TI - Monitoring brain function with aEEG in term asphyxiated infants before and during cooling. PMID- 23651052 TI - Treatment of severe autoimmune blistering skin diseases with combination of protein A immunoadsorption and rituximab: a protocol without initial high dose or pulse steroid medication. AB - BACKGROUND: Skin blistering diseases due to autoantibodies are typically treated with high dose systemic corticosteroids and other conventional immunosuppressants. However, in severe cases, this treatment may not be sufficient to achieve disease control or contraindicated because of comorbidity. METHODS: We describe 15 patients (pts.) with such diseases: 6 pts. with pemphigus vulgaris, 3 pts. with bullous pemphigoid, 3 pts. with mucous membrane pemphigoid (MMP), one being anti-laminin-332-MMP (AL332-MMP), 2 pts. with pemphigus foliaceus and 1 pt. with epidermolysis bullosa acquisita (EBA). Patients were treated with a combination of protein A immunoadsorption (PAIA, 3-21 treatments) and rituximab (3-6 treatments) in addition to low dose conventional immunosuppression. RESULTS: All patients showed rapid clinical improvement starting within the first 4 weeks and decline of circulating autoantibody levels. Complete/partial remission was 88%/12% in pemphigus and 71%/29% in subepidermal blistering diseases. Overall relapse rate was 13% with an average follow-up of 22 months. In the AL332-MMP pt. the PAIA/rituximab treatment was stopped because of an oesophagus cancer considered as the paraneoplastic cause of the skin disease. CONCLUSION: Combined treatment with PAIA and rituximab showed rapid and long lasting response, thereby allowing substantial reduction of dosage of concomitant immunosuppressive medication. We hereby confirm data from other investigators that PAIA/rituximab treatment is a promising therapeutical modality for pemphigus, pemphigoids and EBA, characterized by a favourable ratio of beneficial efficacy and minimized long-term adverse effects. PMID- 23651056 TI - A brief tool to assess capacity to consent for medical care among homeless individuals with problematic substance use: study protocol. AB - BACKGROUND: Public health care increasingly uses outreach models to engage individuals who are marginalized, many of whom misuse substances. Problematic substance use, together with marginalization from the health care system, among homeless adults makes it difficult to assess their capacity to consent to medical care. Tools have been developed to assess capacity to consent; however, these tools are lengthy and unsuitable for outreach settings. The primary objective of this study is to develop, validate, and pilot a brief but sensitive screening instrument which can be used to guide clinicians in assessing capacity to consent in outreach settings. The goal of this paper is to outline the protocol for the development of such a tool. METHODS/DESIGN: A brief assessment tool will be developed and compared to the MacArthur Competency Assessment Tool for Treatment (MacCAT-T). As list of 36 possible questions will be created by using qualitative data from clinician interviews, as well as concepts from the literature. This list will be rated by content experts according to the extent that it corresponds to the test objectives. The instrument will be validated with 300 homeless adult volunteers who self-report problematic substance use. Participants will be assessed for capacity using the MacCAT-T and the new instrument. A combination of Classical Test Theory and advanced psychometric methods will be used for the psychometric analysis. Corrected Item-Total correlation will be examined to identify items that discriminate poorly. Guided exploratory factor analysis will be conducted on the final selection of items to confirm the assumptions for a unidimensional polytomous Rasch model. If unidimensionality is confirmed, an unstandardized Cronbach Alpha will be calculated. If multi-dimensionality is detected, a multidimensional Rasch analysis will be conducted. Results from the new instrument will be compared to the total score from the MacCAT-T by using Pearson's correlation test. The new instrument will then be piloted in real-time by street outreach clinicians to determine the acceptability and usefulness of the new instrument. DISCUSSION: This research will build on the existing knowledge about assessing capacity to consent and will contribute new knowledge about assessing individuals whose judgment is impaired by substance use. PMID- 23651054 TI - Sleep duration, insomnia, and coronary heart disease among postmenopausal women in the Women's Health Initiative. AB - BACKGROUND: Long and short sleep duration are associated with increased risk for coronary heart disease (CHD) and cardiovascular disease (CVD); however, evidence is inconsistent. We sought to identify whether self-reported sleep duration and insomnia, based on a validated questionnaire, are associated with increased incident CHD and CVD among postmenopausal women. METHODS: Women's Health Initiative Observational Study Participants (N=86,329; 50-79 years) who reported on sleep at baseline were followed for incident CVD events. Associations of sleep duration and insomnia with incident CHD and CVD were evaluated using Cox proportional hazards models over 10.3 years. RESULTS: Women with high insomnia scores had elevated risk of CHD (38%) and CVD (27%) after adjustment for age and race, and in fully adjusted models (hazard ratio [HR]=1.19, 95% confidence interval [CI] 1.09-1.30; 1.11 95% CI 1.03-2.00). Shorter (<=5 hours) and longer (>=10 hours) sleep duration demonstrated significantly higher incident CHD (25%) and CVD (19%) in age- and race-adjusted models, but this was not significant in fully adjusted models. Formal tests for interaction indicated significant interactions between sleep duration and insomnia for risk of CHD (p<0.01) and CVD (p=0.02). Women with high insomnia scores and long sleep demonstrated the greatest risk of incident CHD compared to midrange sleep duration (HR=1.93, 95% CI 1.06-3.51) in fully adjusted models. CONCLUSIONS: Sleep duration and insomnia are associated with CHD and CVD risk, and may interact to cause almost double the risk of CHD and CVD. Additional research is needed to understand how sleep quality modifies the association between prolonged sleep and cardiovascular outcomes. PMID- 23651053 TI - Targeting TGF-beta signaling in cancer. AB - INTRODUCTION: The transforming growth factor-beta (TGF-beta) signaling pathway has a pivotal role in tumor suppression and yet, paradoxically, in tumor promotion. Functional context dependent insights into the TGF-beta pathway are crucial in developing TGF-beta-based therapeutics for cancer. AREAS COVERED: This review discusses the molecular mechanism of the TGF-beta pathway and describes the different ways of tumor suppression by TGF-beta. It is then explained how tumors can evade these effects and how TGF-beta contributes to further growing and spreading of some of the tumors. In the last part of the review, the data on targeting TGF-beta pathway for cancer treatment is assessed. This review focuses on anti-TGF-beta based treatment and other options targeting activated pathways in tumors where the TGF-beta tumor suppressor pathway is lost. Pre-clinical as well up to date results of the most recent clinical trials are given. EXPERT OPINION: Targeting the TGF-beta pathway can be a promising direction in cancer treatment. However, several challenges still exist, the most important are differentiating between the carcinogenic effects of TGF-beta and its other physiological roles, and delineating the tumor suppressive versus the tumor promoting roles of TGF-beta in each specific tumor. Future studies are needed in order to find safer and more effective TGF-beta-based drugs. PMID- 23651057 TI - Papular mycosis fungoides: report of two patients, literature review, and conceptual re-appraisal. AB - Recent reports of 10 patients have proposed a papular variant of mycosis fungoides (MF), characterized by the appearance of papules in the absence of patches and the presence of histopathologic features of classic patch/plaque stage MF. Given the overlapping clinical and pathologic features between this proposed entity and lymphomatoid papulosis (LyP)-type B, however, the optimal classification for such cases remains somewhat unclear. Herein, two patients are described who presented to the dermatology clinic with persistent erythematous papular eruptions on the trunk, upper and lower extremities and histopathology compatible with MF. Of note, these patients represent the oldest reported cases of papular MF, and one patient had documented peripheral blood involvement by atypical CD4+ cells. The clinicopathologic characteristics of this purported entity suggest that it may occupy the intersection between MF and CD30+ lymphoproliferative disorders. These two cases expand the clinicopathologic spectrum of papular MF to include older individuals, and further emphasize the importance of recognition of this morphology as a possible MF manifestation. Furthermore, consideration of our cases in conjunction with the previously documented 10 other patients in the literature, offers potential insight into the relationship between MF and CD30+ lymphoproliferative disorders. PMID- 23651058 TI - Increased prion protein processing and expression of metabotropic glutamate receptor 1 in a mouse model of Alzheimer's disease. AB - Prion protein (PrP(C) ), a glycosylphosphatidylinositol-anchored protein corrupted in prion diseases, has been shown recently to interact with group I metabotropic glutamate receptors (mGluRs). Moreover, both PrP(C) and mGluRs were proposed to function as putative receptors for beta-amyloid in Alzheimer's disease. PrP(C) can be processed in neurons via alpha or beta-cleavage to produce PrP(C) fragments that are neuroprotective or toxic, respectively. We found PrP(C) alpha-cleavage to be 2-3 times higher in the cortex of APPswe/PS1dE9 mice, a mouse model of Alzheimer's disease. A similar age-dependent increase was observed for PrP(C) beta-cleavage. Moreover, we observed considerable age-dependent increase in cortical expression of mGluR1, but not mGluR5. Exposure of cortical neuronal cultures to beta-amyloid oligomers upregulated mGluR1 and PrP(C) alpha cleavage, while activation of group I mGluRs increased PrP(C) shedding from the membrane, likely due to increased levels of a disintegrin and metalloprotease10, a key disintegrin for PrP(C) shedding. Interestingly, a similar increase in a disintegrin and metalloprotease10 was detected in the cortex of 9-month-old APPswe/PS1dE9 animals. Our experiments reveal novel and complex processing of PrP(C) in connection with mGluR overexpression that seems to be triggered by beta amyloid peptides. Prion protein (PrP(C) ) and metabotropic glutamate receptors (mGluR) are implicated in Alzheimer's disease (AD). We found age-dependent increase in PrP(C) processing, ADAM10 and mGluR1 levels in AD mouse model. These changes could be reproduced in cultured cortical neurons treated with Abeta peptide. Our findings suggest that increased levels of Abeta can trigger compensatory responses that may affect neuronal toxicity. PMID- 23651059 TI - Lewis acid-catalyzed cyclization of enaminones with propargylic alcohols: regioselective synthesis of multisubstituted 1,2-dihydropyridines. AB - A highly efficient BF3.Et2O-catalyzed cascade reaction of enaminones with propargylic alcohols under mild reaction conditions has been developed. This methodology offers regioselective access to multisubstituted 1,2-dihydropyridines in good to excellent yields. PMID- 23651060 TI - Encapsulation of plai oil/2-hydroxypropyl-beta-cyclodextrin inclusion complexes in polyvinylpyrrolidone (PVP) electrospun nanofibers for topical application. AB - The aim of this study was to prepare electrospun polyvinylpyrrolidone (PVP)/2 hydroxypropyl-beta-cyclodextrin (HPbetaCD) nanofiber mats and to incorporate plai oil (Zingiber Cassumunar Roxb.). The plai oil with 10, 20 and 30% wt to polymer were incorporated in the PVP/HPbetaCD solution and electrospun to obtain nanofibers. The morphology and structure of the PVP and PVP/HPbetaCD nanofiber mats with and without the plai oil were analyzed using scanning electron microscopy (SEM). The thermal behaviors of the nanofiber mats were characterized using differential scanning calorimeter (DSC). Terpinen-4-ol was used as a marker of the plai oil. The amount of plai oil remaining in the PVP/HPbetaCD nanofiber mats was determined using gas chromatography-mass spectoscopy (GC-MS). The SEM images revealed that all of the fibers were smooth. The average diameter of fibers was 212-450 nm, and decreased with the increasing of plai oil content. The release characteristics of plai oil from the fiber showed the fast release followed by a sustained release over the experimental time of 24 h. The release rate ranged was in the order of 10% > 20% ~ 30% plai oil within 24 h. Electrospun fibers with 20% plai oil loading provided the controlled release and also showed the highest plai oil content. Hence, this electrospun nanofiber has a potential for use as an alternative topical application. PMID- 23651061 TI - Peptide-targeted delivery of a pH sensor for quantitative measurements of intraglycosomal pH in live Trypanosoma brucei. AB - Studies of dynamic changes in organelles of protozoan parasite Trypanosoma brucei have been limited, in part because of the difficulty of targeting analytical probes to specific subcellular compartments. Here we demonstrate application of a ratiometric probe for pH quantification in T. brucei glycosomes. The probe consists of a peptide encoding the peroxisomal targeting sequence (F-PTS1, acetyl CKGGAKL) coupled to fluorescein, which responds to pH. When incubated with living parasites, the probe is internalized within vesicular structures that colocalize with a glycosomal marker. Inhibition of uptake of F-PTS1 at 4 degrees C and pulse-chase colocalization with fluorescent dextran suggested that the probe is initially taken up by non-receptor-mediated endocytosis but is subsequently transported separately from dextran and localized within glycosomes, prior to the final fusion of labeled glycosomes and lysosomes as part of glycosomal turnover. Intraorganellar measurements and pH calibration with F-PTS1 in T. brucei glycosomes indicate that the resting glycosomal pH under physiological conditions is 7.4 +/- 0.2. However, incubation in glucose-depleted buffer triggered mild acidification of the glycosome over a period of 20 min, with a final observed pH of 6.8 +/- 0.3. This glycosomal acidification was reversed by reintroduction of glucose. Coupling of ratiometric fluorescent sensors and reporters to PTS peptides offers an invaluable tool for monitoring in situ glycosomal response(s) to changing environmental conditions and could be applied to additional kinetoplastid parasites. PMID- 23651062 TI - RACK1 (receptor for activated C-kinase 1) interacts with FBW2 (F-box and WD repeat domain-containing 2) to up-regulate GCM1 (glial cell missing 1) stability and placental cell migration and invasion. AB - GCM1 (glial cell missing 1) is a short-lived transcription factor essential for placental development. The F-box protein, FBW2 (F-box and WD-repeat domain containing 2), which contains five WD (tryptophan-aspartate) repeats, recognizes GCM1 and mediates its ubiquitination via the SCFFBW2 E3 ligase complex. Although the interaction between GCM1 and FBW2 is facilitated by GCM1 phosphorylation, it is possible that this interaction might be regulated by additional cellular factors. In the present study, we perform tandem-affinity purification coupled with MS analysis identifying RACK1 (receptor for activated C-kinase 1) as an FBW2 interacting protein. RACK1 is a multifaceted scaffold protein containing seven WD repeats. We demonstrate that the WD repeats in both RACK1 and FBW2 are required for the interaction of RACK1 and FBW2. Furthermore, RACK1 competes with GCM1 for FBW2 and thereby prevents GCM1 ubiquitination, which is also supported by the observation that GCM1 is destabilized in RACK1-knockdown BeWo placental cells. Importantly, RACK1 knockdown leads to decreased expression of the GCM1 target gene HTRA4 (high-temperature requirement protein A4), which encodes a serine protease crucial for cell migration and invasion. As a result, migration and invasion activities are down-regulated in RACK1-knockdown BeWo cells. The present study reveals a novel function for RACK1 to regulate GCM1 activity and placental cell migration and invasion. PMID- 23651063 TI - Including nurses in care models for older people with mild to moderate depression: an integrative review. AB - AIMS AND OBJECTIVES: The aim of this integrative literature review was twofold: (1) to investigate different collaborative programmes for older people with depression living at home with diverse access to care and (2) to describe conceptualisation of the nurses' role and interventions within these care models. BACKGROUND: One in four older people who visits a General Practitioner suffers from depression. Depression is a concern for 15% of all older home-care service clients. Detecting and managing depression in older people is highlighted as a key role of nurses. A literature review has been conducted to investigate collaborative models of care, aimed at ensuring low-threshold access to care and exploring the scope of nurse practice within these models. METHODS: Literature review comprising 14 studies and reviews. RESULTS: Three different collaborative care programmes (Collaborative Care Model, Community Mental Health Team and Psychogeriatric Assessment and Treatment in City Housing programme) were identified. In all programmes, the essential aspects were complex and multifaceted interventions, provided by a variety of healthcare professionals, but the access to care differed. All studies described the role of nurses differently and with wide variations. CONCLUSIONS: Despite a broad scope of practice, nurses play a pivotal role within the different models of care. Nurses have to have the educational background and expertise in mental health issues to recognise depression and eventually be able to provide more comprehensive interventions to alleviate depression in older people. RELEVANCE TO PRACTICE: Collaboration is needed to meet the needs of older people with depression. New forms of work divisions are pivotal to achieve this objective. PMID- 23651064 TI - Diagnostic efficacy of myeloperoxidase to identify acute coronary syndrome in subjects with chest pain. AB - BACKGROUND: Early diagnosis of acute coronary syndrome (ACS) is frequently a challenging task. AIMS: To assess the role of novel biomarkers to identify ACS. METHODS: Concentrations of lipids, lipoproteins, oxidized LDL (oxLDL), high sensitivity C-reactive protein (hsCRP), paraoxonase-1 (PON1), secretory phospholipase A2 (sPLA2), and myeloperoxidase (MPO) were measured in 703 patients (mean age 65.5 +/- 11.2 years; 422 men, 281 women) without diabetes mellitus assigned to coronary angiogram. The subjects were divided into three groups: ACS (n = 242), stable angina pectoris (SAP) (n = 242), and normal coronary artery (NCA) (n = 219). RESULTS: HDL-cholesterol (HDL-C) (P < 0.001) and apolipoproteinA I concentrations (P < 0.0001) were lowest in subjects with ACS. LDL-C (P = 0.008) and non-HDL (P < 0.0001) were higher in the ACS group than in the SAP group. Leukocyte count (P < 0.0001), oxLDL (P < 0.05), hsCRP (P < 0.001), sPLA2 (P < 0.05), and MPO (P < 0.0001) were highest in the ACS group. In multivariate models, comprising all biomarkers, elevated level of MPO had the best discriminatory power to identify patients with ACS. Receiver-operating characteristic curve with and without MPO comparison differed significantly (P = 0.03 for both ACS versus NCA and ACS versus SAP). CONCLUSION: Our study shows that ACS associates with low HDL-C and biomarkers of oxidative stress and inflammation. The addition of MPO in biomarker panels might improve diagnostic accuracy for ACS. PMID- 23651065 TI - Fruit and vegetables on prescription: a brief intervention in primary care. AB - BACKGROUND: Increasing fruit and vegetable consumption is a goal for the U.K. Therefore, the effectiveness of a fruit and vegetable voucher scheme coupled with key 'five-a-day' consumption messages as a brief intervention in primary care consultations was assessed in the present study. METHODS: One thousand one hundred and eighty-eight vouchers as a prescription for fruits and vegetables were routinely distributed to patients attending a primary healthcare centre in a deprived area, and 124 volunteer patients routinely attending the centre were included. Telephone-based questionnaires were used to examine changes in consumption over the short and medium term. Other key aspects assessed in the evaluation related to fruit and vegetable purchasing behaviour, knowledge relating to what constitutes a portion size, the relationship between food and health, and barriers to consumption. RESULTS: Although 76.2% of participants used the prescription vouchers when purchasing fruits and vegetables, a significant change in the consumption or purchasing behaviour was not observed (P > 0.05). Participants' level of knowledge relating to the number of portions recommended and the portion size of different fruits and vegetables showed a moderate increase from baseline over the short and medium term. The primary barriers to fruit and vegetable consumption were reported as 'the quality of fresh fruits and vegetables' and 'the money available to spend on food'. CONCLUSIONS: The use of 'the fruit and vegetable on prescription' scheme was an effective method of engaging participants in improving awareness of key diet-related health messages. However, further intervention is required to produce a significant impact on the actual behaviour change. PMID- 23651066 TI - Formulation and evaluation of mucoadhesive buccal films impregnated with carvedilol nanosuspension: a potential approach for delivery of drugs having high first-pass metabolism. AB - CONTEXT: Mucoadhesive buccal films containing three layers (mucoadhesive layer, nanosuspension containing layer and backing membrane) were incorporated with carvedilol nanosuspension. OBJECTIVE: Formulation and evaluation of nanosuspension incorporated mucoadhesive buccal films of carvedilol for bioavailability enhancement by avoiding first-pass metabolism. METHODS: Carvedilol-loaded nanosuspension was prepared by a precipitation-ultrasonication method with varying concentrations of the polymer. The formulation was analyzed for size, size distribution, surface charge and morphology. Optimized nanosuspension was incorporated into drug gel layer which was sandwiched between a mucoadhesive layer and a backing layer to form tri-layered buccal films. They were evaluated for their physical, mechanical and bioadhesive parameters followed by in vitro and in vivo studies. RESULTS AND DISCUSSION: Nanosuspension showed a negative zeta potential (-17.21 mV) with a diameter of around 495 nm and a polydispersity index of 0.203. Nanosuspension incorporated drug gel layer (62.4% drug loading) was optimized to contain 3% HPMC and 50 mg Carbopol 934P. The mucoadhesive layer and the backing layer were optimized to contain 3% HPMC and 1% ethyl cellulose, respectively. In vitro drug release was 69% and 62.4% in 9 h across synthetic membrane and porcine buccal mucosa, respectively. In vivo studies conducted in rabbit model showed 916% increase in the relative bioavailability in comparison to marketed oral tablet formulation. The C(max) and T(max) of the prepared formulation increased due to increased surface area of drug and also by-passing hepatic metabolism. CONCLUSION: The drug delivery system has been designed as a novel platform for potential buccal delivery of drugs having high first-pass metabolism. PMID- 23651068 TI - Improving the scoring of protein-ligand binding affinity by including the effects of structural water and electronic polarization. AB - Docking programs that use scoring functions to estimate binding affinities of small molecules to biological targets are widely applied in drug design and drug screening with partial success. But accurate and efficient scoring functions for protein-ligand binding affinity still present a grand challenge to computational chemists. In this study, the polarized protein-specific charge model (PPC) is incorporated into the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method to rescore the binding poses of some protein-ligand complexes, for which docking programs, such as Autodock, could not predict their binding modes correctly. Different sampling techniques (single minimized conformation and multiple molecular dynamics (MD) snapshots) are used to test the performance of MM/PBSA combined with the PPC model. Our results show the availability and effectiveness of this approach in correctly ranking the binding poses. More importantly, the bridging water molecules are found to play an important role in correctly determining the protein-ligand binding modes. Explicitly including these bridging water molecules in MM/PBSA calculations improves the prediction accuracy significantly. Our study sheds light on the importance of both bridging water molecules and the electronic polarization in the development of more reliable scoring functions for predicting molecular docking and protein-ligand binding affinity. PMID- 23651067 TI - Combined zoledronic acid and meloxicam reduced bone loss and tumour growth in an orthotopic mouse model of bone-invasive oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is common in cats and humans and invades oral bone. We hypothesized that the cyclooxygenase (COX)-2 inhibitor, meloxicam, with the bisphosphonate, zoledronic acid (ZOL), would inhibit tumour growth, osteolysis and invasion in feline OSCC xenografts in mice. Human and feline OSCC cell lines expressed COX-1 and COX-2 and the SCCF2 cells had increased COX-2 mRNA expression with bone conditioned medium. Luciferase-expressing feline SCCF2Luc cells were injected beneath the perimaxillary gingiva and mice were treated with 0.1 mg kg(-1) ZOL twice weekly, 0.3 mg kg(-1) meloxicam daily, combined ZOL and meloxicam, or vehicle. ZOL inhibited osteoclastic bone resorption at the tumour bone interface. Meloxicam was more effective than ZOL at reducing xenograft growth but did not affect osteoclastic bone resorption. Although a synergistic effect of combined ZOL and meloxicam was not observed, combination therapy was well-tolerated and may be useful in the clinical management of bone-invasive feline OSCC. PMID- 23651069 TI - Decreased total antioxidants in patients with primary open angle glaucoma. AB - PURPOSE: To evaluate total antioxidant status (TAS) in the plasma of primary open angle glaucoma (POAG) patients and to compare it to that of the control group. Additionally, we aim to investigate the association of various POAG clinical indices with TAS level. MATERIALS AND METHODS: Plasma samples were obtained from 139 POAG patients and 148 glaucoma-free controls of matching age, sex, and ethnicity. TAS in all samples was determined by spectrophotometric and enzyme linked immunosorbent assay methods.We studied the possible association of the TAS level with various clinical indices relevant to POAG. RESULTS: The mean (+/-SD) total antioxidant (TAS) value was lower among patients: 0.47 (+/-0.32), than controls: 0.97 (+/-0.43) and this difference was statistically significant (p<0.0001). TAS concentration was not significantly associated neither with the level of intraocular pressure, nor with number of anti-glaucoma medications (p = 0.532 and 0.084 respectively). However, TAS level shows a trend towards reduction with increased severity of glaucoma presented in a reversed significant association with cup/disc ratio (p = 0.043). CONCLUSIONS: Our findings provide evidence that TAS decreases in the plasma of POAG patients and that it may play a role in POAG pathogenesis. Association of TAS level with increased cup-to-disc ratio highlights TAS potential role as a predictive-marker for POAG-severity. PMID- 23651071 TI - Engineering a photoactivated caspase-7 for rapid induction of apoptosis. AB - Apoptosis is a cell death program involved in the development of multicellular organisms, immunity, and pathologies ranging from cancer to HIV/AIDS. We present an engineered protein that causes rapid apoptosis of targeted cells in monolayer culture after stimulation with blue light. Cells transfected with the protein switch L57V, a tandem fusion of the light-sensing LOV2 domain and the apoptosis executing domain from caspase-7, rapidly undergo apoptosis within 60 min after light stimulation. Constant illumination of under 5 min or oscillating with 1 min exposure had no effect, suggesting that cells have natural tolerance to a short duration of caspase-7 activity. Furthermore, the overexpression of Bcl-2 prevented L57V-mediated apoptosis, suggesting that although caspase-7 activation is sufficient to start apoptosis, it requires mitochondrial contribution to fully commit. PMID- 23651072 TI - Feedback control of protein expression in mammalian cells by tunable synthetic translational inhibition. AB - Feedback regulation plays a crucial role in dynamic gene expression in nature, but synthetic translational feedback systems have yet to be demonstrated. Here we use an RNA/protein interaction-based synthetic translational switch to create a feedback system that tightly controls the expression of proteins of interest in mammalian cells. Feedback is mediated by modified ribosomal L7Ae proteins, which bind a set of RNA motifs with a range of affinities. We designed these motifs into L7Ae-encoding mRNA. Newly translated L7Ae binds its own mRNA, inhibiting further translation. This inhibition tightly feedback-regulates the concentration of L7Ae and any fusion partner of interest. A mathematical model predicts system behavior as a function of RNA/protein affinity. We further demonstrate that the L7Ae protein can simultaneously and tunably regulate the expression of multiple proteins of interest by binding RNA control motifs built into each mRNA, allowing control over the coordinated expression of protein networks. PMID- 23651073 TI - A comparison of two strategies for affinity maturation of a BH3 peptide toward pro-survival Bcl-2 proteins. AB - The Bcl-2 family of proteins regulates apoptosis at the level of mitochondrial permeabilization. Pro-death members of the family, including Bak and Bax, initiate apoptosis, whereas pro-survival members such as Bcl-x(L) and Mcl-1 antagonize the function of Bak and Bax via heterodimeric interactions. These heterodimeric interactions are primarily mediated by the binding of the helical amphipathic BH3 domain from a pro-death protein to a hydrophobic cleft on the surface of the pro-survival protein. Since high levels of pro-survival Bcl-2 proteins are present in many cancers, peptides corresponding to pro-death BH3 domains hold promise as therapeutics. Here we apply a high-throughput flow cytometry assay to engineer the Bak BH3 domain for improved affinity toward the pro-survival proteins Bcl-x(L) and Mcl-1. Two strategies, engineering the hydrophobic face of the Bak BH3 peptide and increasing its overall helicity, are successful in identifying Bak BH3 variants with improved affinity to Bcl-x(L) and Mcl-1. Hydrophobic face engineering of the Bak BH3 peptide led to variants with up to a 15-fold increase in affinity for Bcl-x(L) and increased specificity toward Bcl-x(L). Engineering of the helicity of Bak BH3 led to modest (3- to 4 fold) improvements in affinity with retention of promiscuous binding to all pro survival proteins. HeLa cell killing studies demonstrate that the affinity matured Bak BH3 variants retain their expected biological function. PMID- 23651074 TI - Venous thromboembolism in patients receiving perioperative chemotherapy for esophagogastric cancer. AB - The association between venous thromboembolism and chemotherapy for esophagogastric cancer is well known in patients treated with palliative intent. Whether this risk extends to the neoadjuvant and perioperative setting is unclear. A retrospective interrogation of databases of patients receiving perioperative chemotherapy for potentially curative intent at the Leicester (2006 2011) and Nottingham (2004-2011) esophagogastric cancer centers was performed. Thromboembolic events were diagnosed in 48 of 384 patients (12.5%), 21 (5.5%) at presentation, 12 (3%) during neoadjuvant chemotherapy, and 15 (3.9%) in the postoperative period. There were no deaths from thromboembolic disease. By site these comprised catheter-related axillary vein thrombosis in 7 patients, deep venous thrombosis in 12 patients, and pulmonary embolism in 29 patients. Twenty five of the 29 pulmonary emboli were incidental findings on staging computed tomography imaging. Combination chemotherapy with epirubicin, cisplatin, and capecitabine appeared to carry the greatest risk for the development of thromboembolism. Seven of the 12 patients (58%) who developed thromboembolism during neoadjuvant chemotherapy did not proceed to surgery because of deterioration in performance status. Preoperative thromboembolic disease resulted in a significant increase in the interval between chemotherapy and surgery, but did not influence either length of hospital stay or survival. Venous thromboembolism will develop in 12.5% of patients treated with potentially curative intent. This adverse event can occur at any time during the patient journey. In contrast to the commonly held view, this did not translate into a poorer prognosis. PMID- 23651075 TI - Prediction of human metabolism of the sedative-hypnotic zaleplon using chimeric mice transplanted with human hepatocytes. AB - 1. Human chimeric mice (h-PXB mice) having humanized liver, constructed by transplantation of human hepatocytes, were evaluated as an experimental model for predicting human drug metabolism. Metabolism of zaleplon in h-PXB mice was compared with that in rat chimeric mice (r-PXB mice) constructed by transplantation of rat hepatocytes. 2. Zaleplon is metabolized to 5-oxo-zaleplon by aldehyde oxidase and to desethyl-zaleplon by cytochrome P450 (CYP3A4) in rat and human liver preparations. 3. Liver S9 fraction of h-PXB mice metabolized zaleplon to 5-oxo-zaleplon and desethyl-zaleplon in similar amounts. However, liver S9 fractions of r-PXB and control (urokinase-type plasminogen activator transgenic severe combined immunodeficient) mice predominantly metabolized zaleplon to desethyl-zaleplon. 5-Oxo-zaleplon was detected as a minor metabolite. 4. Oxidase activity of h-PXB mouse liver cytosol toward zaleplon was about 10 fold higher than that of r-PXB or control mice. In contrast, activities for desethyl-zaleplon formation were similar in liver microsomes from these mice, as well as rat and human liver microsomes. 5. In vivo, the level of 5-oxo-zaleplon in plasma of h-PXB mice was about 7-fold higher than that in r-PXB or control mice, in agreement with the in vitro data. Thus, aldehyde oxidase in h-PXB mice functions as human aldehyde oxidase, both in vivo and in vitro. 6. In contrast, the plasma level of desethyl-zaleplon in r-PXB and control mice was higher than that in h-PXB mice. 7. These results suggest h-PXB mice with humanized liver could be a useful experimental model to predict aldehyde oxidase- and CYP3A4 mediated drug metabolism in humans. PMID- 23651076 TI - Physiological parameters after nonpharmacological analgesia in preterm infants: a randomized trial. AB - AIM: To compare the influence of three different nonpharmacological interventions on cortical activation, heart rate and peripheral oxygen saturation (SaO2 ) after heelstick in preterm infants. METHODS: Twenty five preterm infants between 24 0/7 and 32 0/7 weeks of gestational age were randomized to either oral sucrose (S), facilitated tucking (FT) or a combination of the two interventions (SFT) prior to five heelsticks each within the first 14 days of life. SaO2 , heart rate and oxygenation of the somatosensory cortex, measured by near infrared spectroscopy (NIRS), were analysed. RESULTS: Hundred and twenty five heelsticks were performed. The heart rate increased significantly after heelstick in all three intervention groups (p < 0.004 in all groups). The increase was higher in the FT group compared with the other groups (S: p = 0.007; SFT: p = 0.004). There was no difference among the two groups receiving sucrose (S and SFT; p = 0.87). SaO2 did not change significantly after heelstick in all intervention groups. Near infrared spectroscopy measurements did not show a significant change in the curve but patients in the FT group showed a trend towards higher average oxygenation of the contralateral somatosensory cortex. CONCLUSION: Oral sucrose seems to be more effective in reducing reaction to pain than FT. Application of both interventions did not show an additive effect. PMID- 23651077 TI - Manzamenone O, new trimeric fatty acid derivative from a marine sponge Plakortis sp. AB - A new structurally unique trimeric fatty acid derivative, manzamenone O (1), was isolated from a marine sponge Plakortis sp. Manzamenone O (1) has a novel skeleton consisting of C-C bonded octahydroindenone and dioxabicyclo[3.3.0]octane moieties and three long aliphatic chains. The structure of 1 was elucidated on the basis of spectroscopic data and conformational analysis. Manzamenone O (1) exhibited antimicrobial activity against Micrococcus luteus, Aspergillis niger, and Trichophyton mentagrophytes. PMID- 23651078 TI - Phosphorylation of Ser-180 of rat aquaporin-4 shows marginal affect on regulation of water permeability: molecular dynamics study. AB - Water permeation through rat aquaporin-4 (rAQP4), predominantly found in mammalian brain is regulated by phosphorylation of Ser-180. The present study has been carried out to understand the structural mechanism of regulation of water permeability across the channel. Molecular dynamics (MD) simulations have been carried out to investigate the structural changes caused due to phosphorylation of Ser-180 in the tetrameric assembly of rAQP4 along with predicted C-terminal region (255-323). The interactions involving opposite charges are observed between cytoplasmic loops and the C-terminal region during MD simulations. This results in movement of C-terminal region of rAQP4 towards the cytoplasmic mouth of water channel. Despite this movement, there was a gap between C-terminal region and cytoplasmic mouth of the channel through which water molecules were able to gain entry into the channel. The interactions between C-terminus and loop D of neighboring monomers in a tetrameric assembly appear to prevent the complete closure of cytoplasmic mouth of the water channel. Further, the rates of water permeation through phosphorylated and unphosphorylated rAQP4 have also been compared. The simulation studies showed a continuous movement of water in a single file across pore of unphosphorylated as well as phosphorylated rAQP4. PMID- 23651079 TI - Reproductive outcomes and risk of subsequent illness in women diagnosed with postpartum psychosis. AB - OBJECTIVES: Women who experience postpartum psychosis (PP) seek guidance on further pregnancies and risk of illness; however, empirical data are limited. This study describes reproductive and mental health outcomes in women diagnosed with PP and examines clinical risk factors as predictors of further illness. METHODS: A retrospective cohort design was used; 116 women who experienced episodes of mania or depression with psychotic features within six weeks of childbirth were recruited. All subjects underwent clinical diagnostic interviews and medical case notes were reviewed. RESULTS: Only 33% of women had an antecedent history, of which 34% had bipolar disorder and 55% unipolar depression. Only 58% of those with PP in their first pregnancy had a subsequent pregnancy, and 18% of marriages ended following the PP episode. Clinical presentation at the time of initial episode did not influence the timing of the onset of symptoms, treatment, or recovery. Although 86% of patients received treatment within 30 days of onset, 26% of women reported ongoing symptoms at a year after delivery. The recurrence rate of PP was 54.4%; a longer duration of the index episode (p < 0.05) and longer latency between the index PP and next pregnancy predicted a subsequent PP. The rate of subsequent non-puerperal episodes was 69%, and all these episodes were bipolar. CONCLUSIONS: Postpartum psychosis is difficult to predict in women with no antecedent history and is associated with a high rate of subsequent puerperal and non-puerperal illness. Risk of further illness needs to be conveyed in order to allow fully informed decisions to be made regarding future pregnancies. PMID- 23651080 TI - Fuzzy liquid analysis by an array of nonspecifically interacting reagents: the taste of fluorescence. AB - Complex or unknown liquid analysis requires extensive instrumentation and laboratory work; simple field devices usually have serious limitations in functionality, sensitivity, and applicability. This communication presents a novel, effective, and simple approach to fingerprinting liquids. The method is based on nonspecific interactions of the sample liquid, a long lifetime luminescent europium label, and various surface modulators in an array form that is readily converted to a field analysis MUTAS system. As compared to existing e nose or e-tongue techniques, the method is unique both in terms of sensitivity and usability, mainly due to the well-known unique properties of the europium label. This communication demonstrates the use of this new method in distinguishing different wines, waters, alcohols, and artificially modified berry juices. PMID- 23651081 TI - Novel glyoxalases from Arabidopsis thaliana. AB - We examined six Arabidopsis thaliana genes from the DJ-1/PfpI superfamily for similarity to the recently characterized bacterial and animal glyoxalases. Based on their sequence similarities, the six genes were classified into two sub-groups consisting of homologs of the human DJ-1 gene and the PH1704 gene of Pyrococcus horikoshii. Unlike the homologs from other species, all the A. thaliana genes have two tandem domains, which may have been created by gene duplication. The six AtDJ-1 proteins (a-f) were expressed in Escherichia coli for enzymatic assays with glyoxals. The DJ-1d protein, which belongs to the PH1704 sub-group, exhibits the highest activity against methylglyoxal and glyoxal, and K(m) values of 0.10 and 0.27 mm were measured for these two substrates, respectively, while the corresponding k(cat) values were 1700 and 2200 min(-1), respectively. The DJ-1a and DJ-1b glyoxalases exhibited higher specificity towards glyoxal. The other three proteins have either no or extremely low activity for glyoxals. For the DJ 1d enzyme, the residues, Cys120/313 and Glu19/212 at the active site and His121/314 and Glu94/287 at the oligomeric interface were mutated to alanines. As in other enzymes characterized to date, mutation of either the Cys or the Glu residues of the active site completely abolished enzyme activity, whereas mutation of the interface residues produced a variable decrease in activity. DJ 1d differs from its animal and bacterial homologs with respect to the configuration of its catalytic residues and the oligomeric property of the enzyme. When the wild-type DJ-1d enzyme was expressed in E. coli, the bacteria became resistant to glyoxals. PMID- 23651083 TI - Induction immunosuppression in liver transplantation: a review. AB - Antibody therapy for induction is seldom used in liver transplantation in the United States, but continues to be used in approximately 10% of patients. The most commonly used antibody at the current time is basiliximab (Simulect, Novartis) and is used in adults with renal dysfunction at the time of liver transplantation with the intention of delaying introduction of calcineurin inhibitors. In children, the same antibody is commonly used in order to reduce rates of acute rejection. Most patients, adult and pediatric, are treated with initially higher levels of tacrolimus rather than antibody induction. PMID- 23651082 TI - Development of land use regression models for particle composition in twenty study areas in Europe. AB - Land Use Regression (LUR) models have been used to describe and model spatial variability of annual mean concentrations of traffic related pollutants such as nitrogen dioxide (NO2), nitrogen oxides (NOx) and particulate matter (PM). No models have yet been published of elemental composition. As part of the ESCAPE project, we measured the elemental composition in both the PM10 and PM2.5 fraction sizes at 20 sites in each of 20 study areas across Europe. LUR models for eight a priori selected elements (copper (Cu), iron (Fe), potassium (K), nickel (Ni), sulfur (S), silicon (Si), vanadium (V), and zinc (Zn)) were developed. Good models were developed for Cu, Fe, and Zn in both fractions (PM10 and PM2.5) explaining on average between 67 and 79% of the concentration variance (R(2)) with a large variability between areas. Traffic variables were the dominant predictors, reflecting nontailpipe emissions. Models for V and S in the PM10 and PM2.5 fractions and Si, Ni, and K in the PM10 fraction performed moderately with R(2) ranging from 50 to 61%. Si, NI, and K models for PM2.5 performed poorest with R(2) under 50%. The LUR models are used to estimate exposures to elemental composition in the health studies involved in ESCAPE. PMID- 23651084 TI - Expression of phospho-Ca(2+) /calmodulin-dependent protein kinase II in the pre Botzinger complex of rats. AB - The pre-Botzinger complex (pre-BotC) in the ventrolateral medulla oblongata is a presumed kernel of respiratory rhythmogenesis. Ca(2+) -activated non-selective cationic current is an essential cellular mechanism for shaping inspiratory drive potentials. Ca(2+) /calmodulin-dependent protein kinase II (CaMKII), an ideal 'interpreter' of diverse Ca(2+) signals, is highly expressed in neurons in mediating various physiological processes. Yet, less is known about CaMKII activity in the pre-BotC. Using neurokinin-1 receptor as a marker of the pre BotC, we examined phospho (P)-CaMKII subcellular distribution, and found that P CaMKII was extensively expressed in the region. P-CaMKII-ir neurons were usually oval, fusiform, or pyramidal in shape. P-CaMKII immunoreactivity was distributed within somas and dendrites, and specifically in association with the post synaptic density. In dendrites, most synapses (93.1%) examined with P-CaMKII expression were of asymmetric type, occasionally with symmetric type (6.9%), whereas in somas, 38.1% were of symmetric type. P-CaMKII asymmetric synaptic identification implicates that CaMKII may sense and monitor Ca(2+) activity, and phosphorylate post-synaptic proteins to modulate excitatory synaptic transmission, which may contribute to respiratory modulation and plasticity. In somas, CaMKII acts on both symmetric and asymmetric synapses, mediating excitatory and inhibitory synaptic transmission. P-CaMKII was also localized to the perisynaptic and extrasynaptic regions in the pre-BotC. PMID- 23651086 TI - Traditional Australian Aboriginal medicinal plants: an untapped resource for novel therapeutic compounds? PMID- 23651085 TI - Structural changes in the hydrophobic hinge region adversely affect the activity and fidelity of the I260Q mutator DNA polymerase beta. AB - The I260Q variant of DNA polymerase beta is an efficient mutator polymerase with fairly indiscriminate misincorporation activities opposite all template bases. Previous modeling studies have suggested that I260Q harbors structural variations in its hinge region. Here, we present the crystal structures of wild type and I260Q rat polymerase beta in the presence and absence of substrates. Both the I260Q apoenzyme structure and the closed ternary complex with double-stranded DNA and ddTTP show ordered water molecules in the hydrophobic hinge near Gln260, whereas this is not the case in the wild type polymerase. Compared to wild type polymerase beta ternary complexes, there are subtle movements around residues 260, 272, 295, and 296 in the mutant. The rearrangements in this region, coupled with side chain movements in the immediate neighborhood of the dNTP-binding pocket, namely, residues 258 and 272, provide an explanation for the altered activity and fidelity profiles observed in the I260Q mutator polymerase. PMID- 23651087 TI - Heparin-functionalized nanocapsules: enabling targeted delivery of antimalarial drugs. PMID- 23651089 TI - Ask the experts: past, present and future of the rule of five. AB - Coined in 1997, by Christopher Lipinki et al., the rule of five (Ro5) comprises a set of parameters that determine drug-likeness for oral delivery. The parameters are as follows: no more than five hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms); no more than ten hydrogen bond acceptors (nitrogen or oxygen atoms); a molecular mass less than 500 Da; and an octanol water partition coefficient log P no greater than 5. Future Medicinal Chemistry invited a selection of leading researchers to express their views on Lipinski's Ro5, which has influenced drug design for over a decade. Their enlightening responses provide an insight into the current and future role of Ro5, and other rules of thumb, in the evolving world of medicinal chemistry. PMID- 23651090 TI - Analyzing compound and project progress through multi-objective-based compound quality assessment. AB - BACKGROUND: Compound-quality scoring methods designed to evaluate multiple drug properties concurrently are useful to analyze and prioritize output from drug design efforts. However, formalized multiparameter optimization approaches are not widely used in drug design. METHODS: We rank molecules synthesized in drug discovery projects using simple and aggregated desirability functions reflecting medicinal chemistry 'rules'. Our quality score deals transparently with missing data, a key requirement in drug-hunting projects where data availability is often limited. We further estimate confidence in the interpretation of such a compound quality measure. CONCLUSION: Scores and associated confidences provide systematic insight in the quality of emerging chemical equity. Tracking quality of synthetic output over time yields valuable insight into the progress of drug-design teams, with potential applications in risk and resource management of a drug portfolio. PMID- 23651091 TI - Targeting the vitamin biosynthesis pathways for the treatment of malaria. AB - The most severe form of malaria is Malaria tropica, caused by Plasmodium falciparum. There are more than 1 billion people that are exposed to malaria parasites leading to more than 500,000 deaths annually. Vaccines are not available and the increasing drug resistance of the parasite prioritizes the need for novel drug targets and chemotherapeutics, which should be ideally designed to target selectively the parasite. In this sense, parasite-specific pathways, such as the vitamin biosyntheses, represent perfect drug-target characteristics because they are absent in humans. In the past, the vitamin B9 (folate) metabolism has been exploited by antifolates to treat infections caused by malaria parasites. Recently, two further vitamin biosynthesis pathways - for the vitamins B6 (pyridoxine) and B1 (thiamine) - have been identified in Plasmodium and analyzed for their suitability to discover new drugs. In this review, the current status of the druggability of plasmodial vitamin biosynthesis pathways is summarized. PMID- 23651092 TI - Cholera: pathophysiology and emerging therapeutic targets. AB - Cholera is a diarrheal disease that remains an important global health problem with several hundreds of thousands of reported cases each year. This disease is caused by intestinal infection with Vibrio cholerae, which is a highly motile gram-negative bacterium with a single-sheathed flagellum. In the course of cholera pathogenesis, V. cholerae expresses a transcriptional activator ToxT, which subsequently transactivates expressions of two crucial virulence factors: toxin-coregulated pilus and cholera toxin (CT). These factors are responsible for intestinal colonization of V. cholerae and induction of fluid secretion, respectively. In intestinal epithelial cells, CT binds to GM1 ganglioside receptors on the apical membrane and undergoes retrograde vesicular trafficking to endoplasmic reticulum, where it exploits endoplasmic reticulum-associated protein degradation systems to release a catalytic A1 subunit of CT (CT A1) into cytoplasm. CT A1, in turn, catalyzes ADP ribosylation of alpha subunits of stimulatory G proteins, leading to a persistent activation of adenylate cyclase and an elevation of intracellular cAMP. Increased intracellular cAMP in human intestinal epithelial cells accounts for pathogenesis of profuse diarrhea and severe fluid loss in cholera. This review provides an overview of the pathophysiology of cholera diarrhea and discusses emerging drug targets for cholera, which include V. cholerae virulence factors, V. cholerae motility, CT binding to GM1 receptor, CT internalization and intoxication, as well as cAMP metabolism and transport proteins involved in cAMP-activated Cl(-) secretion. Future directions and perspectives of research on drug discovery and development for cholera are discussed. PMID- 23651093 TI - Amygdalin analogs for the treatment of psoriasis. AB - Psoriasis is one of the most prevalent immune-mediated illness worldwide. The disease can still only be managed rather than cured, so treatments are aimed at clearing skin lesions and preventing their recurrence. Several treatments are available depending on the extent of the psoriatic lesion. Among the topical treatments corticostereoids, vitamin D3 analogs and retinoids are commonly used. However, these treatments may have adverse effects in the long term. Conversely, systemic conventional treatments include immunosuppresors such as cyclosporin or methotrexate associated with high toxicity levels. Biologicals are alternative therapeutical agents introduced in the last 10 years. These include fusion proteins or monoclonal antibodies designed to inhibit the action of specific cytokines or to prevent T-lymphocyte activation. However, due to recent knowledge on the etiology of the disease, diverse new small molecules have appeared as promising alternatives for the treatment of psoriasis. Among them, inhibitors of JAK3, inhibitors of PDE 4 and amygdalin analogs. The latter are promising small molecules presently in preclinical studies which are the object of the present report. PMID- 23651094 TI - Honokiol analogs: a novel class of anticancer agents targeting cell signaling pathways and other bioactivities. AB - Honokiol (3,5-di-(2-propenyl)-1,1-biphenyl-2,2-diol) is a natural bioactive neolignan isolated from the genus Magnolia. In recent studies, honokiol has been observed to have anti-angiogenic, anticancer, anti-inflammatory, neuroprotective and GABA-modulating properties in vitro and in preclinical models. Honokiol and its analogs target multiple signaling pathways including NF-kappaB, STAT3, EGFR, mTOR and caspase-mediated common pathway, which regulate cancer initiation and progression. Honokiol and its targets of action may be helpful in the development of effective analogs and targeted cancer therapy. In this review, recent data describing the molecular targets of honokiol and its analogs with anticancer and some other bioactivities are discussed. PMID- 23651095 TI - New modalities in conformationally constrained peptides for potency, selectivity and cell permeation. AB - There has been a resurgence of interest in peptide pharmaceuticals as they have an advantage of potency, selectivity and less toxicity compared with small molecule therapeutics. The main draw back of peptides is lack of stability to biological media. Constraining a peptide has been one of the approaches to improving in vivo stability of the peptides. Several new modalities in constraining peptides have been developed over recent years and this review highlights some of the new developments. The newer cyclization strategies have rendered, in some cases, oral activity, cell permeability, improved potency at the target receptor, selectivity against receptor subtypes and improved stability to enzymes. As chemists further understand the rules governing cell permeability, oral absorption and enhancing stability of peptides, we can expect to see more peptides entering clinic for many unmet medical needs. PMID- 23651097 TI - On being a memory expert witness: Three cases. AB - I describe three legal cases in which I acted as a memory expert witness. The cases contain remarkable accounts of memories. Such memories are by no means unusual in legal cases, are often over retention intervals measured in decades, and contain details the specificity of which is highly unusual. For example, recalling from childhood verbatim conversations, clothes worn by self and others, the weather, actions that at the time could not have been understood, details that could not have been known, precise durations and calendar dates, and much more. I show how our scientific understanding of memory can help courts reach more informed decisions about such fantastical "memories" and how these memories constitute data that as researchers we should seek to understand. PMID- 23651098 TI - Dermal pleomorphic liposarcoma resembling pleomorphic fibroma: report of a case and review of the literature. AB - Pleomorphic liposarcoma (PLPS) is a rare, high-grade sarcoma defined by the presence of pleomorphic lipoblasts. Constituting 5% of all liposarcomas, PLPS usually arises in deep soft tissues of the extremities, with rare occurrences in the dermis and subcutis. We describe a unique case of an 85-year-old Caucasian gentleman with a 1 year history of a pedunculated, pink, non-tender papule on the dorsum of his left arm, measuring 1.0 cm in maximum dimension. Biopsy revealed a dermal collection of atypical epithelioid and spindle cells superimposed on a sclerotic background, resembling a pleomorphic fibroma on low power. On high power, a central focus of discrete adipocytic differentiation with pleomorphic lipoblasts was present. Tumor cells were positive for S-100 and negative for desmin, actin, CD68, keratin, MART-1 and CD34. Clinicopathologic findings were consistent with PLPS and the diagnosis was made. PLPS is rarely localized to the dermis and one with low power features resembling a pleomorphic fibroma has not been previously described in the literature. PMID- 23651099 TI - Caring for families of the terminally ill in Malaysia from palliative care nurses' perspectives. AB - AIMS AND OBJECTIVES: To describe the process that nurses experienced in engaging with families in Malaysian palliative care settings and the challenges they faced. BACKGROUND: In palliative care settings, nurses and the terminally ill person's family members interact very closely with each other. It is important for nurses to work with families to ensure that the care of the terminally ill person is optimised. RESEARCH DESIGN: A qualitative design using grounded theory methods was used to describe how nurses engaged with families and the challenges they faced. METHODS: Twenty-two nurses from home care and inpatient palliative care settings across Malaysia participated in this study. Data were collected through seven interviews and eight focus group discussions conducted between 2007 2009. RESULTS: The main problem identified by nurses was the different expectations to patient care with families. The participants used the core process of Engaging with families to resolve these differences and implemented strategies described as Preparing families for palliative care, Modifying care and Staying engaged to promote greater consistency and quality of care. When participants were able to resolve their different expectations with families, these resulted in positive outcomes, described as Harmony. However, negative outcomes of participants not being able to resolve their different expectations with families were Disharmony. CONCLUSIONS: This study highlights the importance of engaging and supporting families of the terminally ill as well as providing a guide that may be used by nurses and carers to better respond to families' needs and concerns. RELEVANCE TO CLINICAL PRACTICE: The study draws attention to the need for formal palliative care education, inclusive of family care, to enable nurses to provide the terminally ill person and their family effective and appropriate care. PMID- 23651100 TI - Pivotal role of P450-P450 interactions in CYP3A4 allostery: the case of alpha naphthoflavone. AB - We investigated the relationship between oligomerization of CYP3A4 (cytochrome P450 3A4) and its response to ANF (alpha-naphthoflavone), a prototypical heterotropic activator. The addition of ANF resulted in over a 2-fold increase in the rate of CYP3A4-dependent debenzylation of 7-BFC [7-benzyloxy-4 (trifluoromethyl)coumarin] in HLM (human liver microsomes), but failed to produce activation in BD Supersomes or Baculosomes containing recombinant CYP3A4 and NADPH-CPR (cytochrome P450 reductase). However, incorporation of purified CYP3A4 into Supersomes containing only recombinant CPR reproduced the behaviour observed with HLM. The activation in this system was dependent on the surface density of the enzyme. Although no activation was detectable at an L/P (lipid/P450) ratio >=750, it reached 225% at an L/P ratio of 140. To explore the relationship between this effect and CYP3A4 oligomerization, we probed P450-P450 interactions with a new technique that employs LRET (luminescence resonance energy transfer). The amplitude of LRET in mixed oligomers of the haem protein labelled with donor and acceptor fluorophores exhibited a sigmoidal dependence on the surface density of CYP3A4 in SupersomesTM. The addition of ANF eliminated this sigmoidal character and increased the degree of oligomerization at low enzyme concentrations. Therefore the mechanisms of CYP3A4 allostery with ANF involve effector-dependent modulation of P450-P450 interactions. PMID- 23651101 TI - Cellular and molecular mechanisms controlling the migration of neocortical interneurons. AB - The discovery, approximately 15 years ago, that cortical GABAergic interneurons originate outside the pallium has revolutionized our understanding of the development of the cerebral cortex. It is now clear that glutamatergic pyramidal cells and GABAergic interneurons follow largely distinct development programs, a notion that has challenged our views on how these neurons assemble to form precise neural circuits. In this review, I summarize our current knowledge of the mechanisms that control the migration of neocortical interneurons, a process that can be subdivided into three consecutive phases: migration to the cortex, intracortical dispersion, and layering. PMID- 23651102 TI - Formulation and evaluation of metformin hydrochloride-loaded niosomes as controlled release drug delivery system. AB - Lactic acidosis is a serious, metabolic complication that may occur due to metformin hydrochloride (MH) accumulation during the treatment of diabetes mellitus. The aim of this study is to enhance the bioavailability of MH by oral route. Span 40 and cholesterol were used for the preparation of MH-loaded niosomes by the reverse phase evaporation technique. Dicetyl phosphate (DCP) and 1,2-dioleoyl-3-trimethylammonium-propane chloride salt (DOTAP) were used to obtain negatively and positively charged vesicles, respectively. The mean particle size ranged from 223.5 to 384.6 nm and the MH-loaded niosomes' surface was negatively charged in the absence of charge inducing agents (-16.6 +/- 1.4 mV) and also with DCP (-26.9 +/- 1.0 mV), while it was positively charged (+8.7 +/- 1.2 mV) with DOTAP. High entrapment efficiency was observed in all the formulations. MH-loaded niosomes were found to effectively sustain the release of drug, particularly with positively charged niosomes. The bioavailability of MH loaded niosomes was assessed by measuring the serum values of glucose and metformin in the different studied Wistar rats groups. The pharmacokinetic data of MH-loaded niosomal preparation showed a significant prolongation and increased intensity of hypoglycemic effect more than that observed for free MH solution. Area above the blood glucose levels-time curve (AAC), maximum hypoglycemic response and time of maximum response (T(max)) were significantly higher (p < 0.001) when MH was administered in niosomal form compared to free drug solution. It could be concluded that MH-loaded niosome is promising extended-release preparation with better hypoglycemic efficiency. PMID- 23651103 TI - Metabolic syndrome predicts all-cause mortality in persons with human immunodeficiency virus. AB - We examined the association between metabolic syndrome (MS) and its individual defining criteria on all-cause mortality in human immunodeficiency virus (HIV) infected persons. We used data from 567 HIV-infected participants of the Nutrition for Healthy Living study with study visits between 9/1/2000 and 1/31/2004 and determined mortality through 12/31/2006. MS was defined using modified National Cholesterol Education Program guidelines. Cox proportional hazards for all-cause mortality were estimated for baseline MS status and for its individual defining criteria. There were 83 deaths with median follow-up of 63 months. Baseline characteristics associated with increased risk of mortality were: older age in years (univariate hazard ratio [HR] 1.04, p<0.01), current smoking (HR 1.99, p=0.02), current heroin use (HR 1.97, p=0.02), living in poverty (HR 2.0, p<0.01), higher mean HIV viral load (HR 1.81, p<0.01), and having a BMI <18 (HR 5.84, p<0.01). For MS and its criteria, only low HDL was associated with increased risk of mortality on univariate analysis (HR 1.84, p=0.01). However, metabolic syndrome (adjusted HR 2.31, p=0.02) and high triglycerides (adjusted HR 3.97, p<0.01) were significantly associated with mortality beyond 36 months follow-up. MS, low HDL, and high triglycerides are associated with an increased risk of mortality in HIV-infected individuals. PMID- 23651104 TI - Conformity of pediatric/adolescent HIV clinics to the patient-centered medical home care model. AB - The patient-centered medical home (PCMH) has been introduced as a model for providing high-quality, comprehensive, patient-centered care that is both accessible and coordinated, and may provide a framework for optimizing the care of youth living with HIV (YLH). We surveyed six pediatric/adolescent HIV clinics caring for 578 patients (median age 19 years, 51% male, and 82% black) in July 2011 to assess conformity to the PCMH. Clinics completed a 50-item survey covering the six domains of the PCMH: (1) comprehensive care, (2) patient centered care, (3) coordinated care, (4) accessible services, (5) quality and safety, and (6) health information technology. To determine conformity to the PCMH, a novel point-based scoring system was devised. Points were tabulated across clinics by domain to obtain an aggregate assessment of PCMH conformity. All six clinics responded. Overall, clinics attained a mean 75.8% [95% CI, 63.3 88.3%] on PCMH measures-scoring highest on patient-centered care (94.7%), coordinated care (83.3%), and quality and safety measures (76.7%), and lowest on health information technology (70.0%), accessible services (69.1%), and comprehensive care (61.1%). Clinics moderately conformed to the PCMH model. Areas for improvement include access to care, comprehensive care, and health information technology. Future studies are warranted to determine whether greater clinic PCMH conformity improves clinical outcomes and cost savings for YLH. PMID- 23651105 TI - Utility of an interactive voice response system to assess antiretroviral pharmacotherapy adherence among substance users living with HIV/AIDS in the rural South. AB - Promoting HIV medication adherence is basic to HIV/AIDS clinical care and reducing transmission risk and requires sound assessment of adherence and risk behaviors such as substance use that may interfere with adherence. The present study evaluated the utility of a telephone-based Interactive Voice Response self monitoring (IVR SM) system to assess prospectively daily HIV medication adherence and its correlates among rural substance users living with HIV/AIDS. Community dwelling patients (27 men, 17 women) recruited from a non-profit HIV medical clinic in rural Alabama reported daily medication adherence, substance use, and sexual practices for up to 10 weeks. Daily IVR reports of adherence were compared with short-term IVR-based recall reports over 4- and 7-day intervals. Daily IVR reports were positively correlated with both recall measures over matched intervals. However, 7-day recall yielded higher adherence claims compared to the more contemporaneous daily IVR and 4-day recall measures suggestive of a social desirability bias over the longer reporting period. Nearly one-third of participants (32%) reported adherence rates below the optimal rate of 95% (range=0-100%). Higher IVR-reported daily medication adherence was associated with lower baseline substance use, shorter duration of HIV/AIDS medical care, and higher IVR utilization. IVR SM appears to be a useful telehealth tool for monitoring medication adherence and identifying patients with suboptimal adherence between clinic visits and can help address geographic barriers to care among disadvantaged, rural adults living with HIV/AIDS. PMID- 23651106 TI - Trends in the spectrum of engagement in HIV care and subsequent clinical outcomes among men who have sex with men (MSM) at a Boston community health center. AB - Despite known benefits, only 19-28% of HIV-infected Americans are virologically suppressed (defined as <=200 copies/mL). Engagement in HIV care represents a continuum from patients unaware they are infected to virological suppression. The electronic medical record of all newly diagnosed HIV-infected MSM seen at Fenway Health between 2000 and 2010 were reviewed. Patients were "engaged" if they had one negative HIV test and/or one physical exam within 24 months prior to their HIV diagnosis (n=291). All others were considered "new" (n=463). MSM engaged in care prior to HIV diagnosis were more often identified in acute retroviral syndrome or on routine screening, more rapidly linked to care, and less often diagnosed with a concomitant STI than those who were not engaged in care. Nearly 19% of all patients were diagnosed with AIDS the same time they were diagnosed with HIV. Blacks and those with higher CD4 counts at diagnosis were less likely to be virologically suppressed at 1 year. Between 2000 and 2010, patients retained in care were more likely to initiate ART and be virologically suppressed within 1 year independent of initial HIV viral load and CD4 count. Engagement in care prior to seroconversion influences important HIV outcomes. Programs that care for at risk populations should institute routine opt-out HIV testing and test-and-treat programs to optimize HIV care and prevention. PMID- 23651107 TI - Linking and retaining HIV patients in care: the importance of provider attitudes and behaviors. AB - Retention in HIV treatment may reduce morbidity and mortality, as well as slow the epidemic. Myriad barriers to retention include stigma, homophobia, structural barriers, transportation, and insurance. The purpose of this study was to evaluate patient perceptions of provider attitudes among HIV-infected persons within a state-wide public hospital system in Louisiana. A convenience sample of patients attending HIV clinics throughout the state participated in an anonymous interview. Factors associated with negative perceptions of care were evaluated in conjunction with a validated stigma measure. Factors associated with having a delayed entry into or break in care were evaluated in conjunction with perceived stigma. Between 2/1/09 and 7/31/11, 479 participants were interviewed and had sufficient data available, of whom 53.4% were male, 79.3% were African American, and 29.4% reported a break or delayed entry into HIV care of >1 year. A break in care was associated with perceiving that the doctor or health professionals do not listen carefully most or all of the time (p<0.01), having an elevated stigma score (p<0.05), and indicating that providers dislike caring for HIV-infected people (p<0.01). Women were more likely to have an elevated stigma score than men (p<0.01), as were participants over 30 (p<0.01); those with a gay/bisexual orientation (p<0.05) were less likely to have an elevated stigma score. Those with a break in care were less likely to have Medicaid (p<0.05). Providers play a key role in the retention of HIV-infected persons in care and are critical to improving outcomes and slowing the epidemic. Development of novel approaches to reduce stigma are imperative in improving retention. PMID- 23651108 TI - Gender disparities in HIV risk behavior and access to health care in St. Petersburg, Russia. AB - Over 40,000 HIV-infected individuals live in St Petersburg, Russia. Population characteristics and barriers to care are largely undefined. 152 consecutive patients receiving HIV care at two sites completed a questionnaire in Spring 2011. Rates of chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection, alcohol use, and rates of antiretroviral uptake were similar by gender. Males reported a higher history of injection drug use (80.3% vs. 48.7%; p<0.01) and tuberculosis infection (18.8% vs. 1.6%; p<0.01). Females were more likely to have had a child (63.3% vs. 31.5%; p<0.01) and be currently raising that child within their residence (49.3% vs. 15.3%; p<0.01). Unprotected sex (60.5% vs. 17.8%; p<0.01) and a history of sexually transmitted infection (37.7% vs. 20.3%; p=0.03) were more common in females. Females utilized social services more frequently (34.2% vs. 11.9%; p<0.01). There is a heavy burden of concurrent infectious disease, substance use and abuse, mental health illness, and need for social service support in this population. Important differences exist between genders in service uptake and utilization. Further evaluation of these differences may help inform the allocation of limited resources in this high HIV prevalence region of Russia. PMID- 23651109 TI - Entropy from state probabilities: hydration entropy of cations. AB - Entropy is an important energetic quantity determining the progression of chemical processes. We propose a new approach to obtain hydration entropy directly from probability density functions in state space. We demonstrate the validity of our approach for a series of cations in aqueous solution. Extensive validation of simulation results was performed. Our approach does not make prior assumptions about the shape of the potential energy landscape and is capable of calculating accurate hydration entropy values. Sampling times in the low nanosecond range are sufficient for the investigated ionic systems. Although the presented strategy is at the moment limited to systems for which a scalar order parameter can be derived, this is not a principal limitation of the method. The strategy presented is applicable to any chemical system where sufficient sampling of conformational space is accessible, for example, by computer simulations. PMID- 23651110 TI - The effect of coffee consumption on the development of hepatocellular carcinoma in hepatitis B virus endemic area. AB - BACKGROUND & AIMS: Coffee consumption is inversely related to the risk of cirrhosis or hepatocellular carcinoma (HCC). However, the protective effect of coffee drinking against the risk of HCC was not established in HBV-prevalent region. To elucidate the relationship between lifetime coffee consumption and the risk of HCC development under the consideration of replication status of HBV. METHODS: A hospital-based case-control study was performed in 1364 subjects. A total of 258 HCC patients, 480 health-check examinees (control 1, HCE) and 626 patients with chronic liver disease other than HCC (control 2, CLD) were interviewed on smoking, alcohol and coffee drinking using a standardized questionnaire. HBV e-antigen (HBeAg) status and serum HBV DNA levels were measured in patients infected with HBV. RESULTS: After adjustment for age, gender, obesity, DM, presence of hepatitis virus (except for HCE) and lifetime alcohol drinking/smoking, a high lifetime coffee consumption (>=20 000 cups) was an independent protective factor against HCC, in each analyses using healthy and risky control groups respectively (HCE group, OR 0.56, 95% CI 0.33-0.95; CLD group, OR 0.55, 95% CI 0.36-0.85). However, the high coffee consumption did not affect the HCC risk in patients with HBV (OR 0.64, 95% CI 0.36-1.14) after adjustment for HBeAg status, serum HBV DNA level and antiviral therapy. CONCLUSIONS: A high lifetime coffee consumption was negatively associated with a HCC development. However, this difference of coffee exposure with the HCC group was reduced in chronic hepatitis B patients by the dominant role of viral replication. PMID- 23651112 TI - When it rains, it pores. PMID- 23651113 TI - Parts-based assembly of synthetic transmembrane proteins in mammalian cells. AB - Transmembrane proteins span cellular membranes such as the plasma membrane and endoplasmic reticulum (ER) membrane to mediate inter- and intracellular interactions. An N-terminal signal peptide and transmembrane helices facilitate recruitment to the ER and integration into the membrane, respectively. Using a parts-based assembly approach in this study, we confirm that the minimum requirement to create a transmembrane protein is indeed only a transmembrane helix (TM). When transfected in mammalian cells, our fusion proteins in the schematic form X-TM-Y were localized to vesicles, the golgi apparatus, the nuclear envelope, or the endoplasmic reticulum, consistent with ER targeting. Further studies to determine orientation showed that X was facing the cytoplasm, and Y the lumen. Lastly, in our fusion proteins with an N-terminal TM, the TM effectively reversed the orientation of X and Y. This knowledge can be applied to the parts-based engineering of synthetic transmembrane proteins with varied functions and biological applications. PMID- 23651114 TI - Proteins from an unevolved library of de novo designed sequences bind a range of small molecules. AB - The availability of large collections of de novo designed proteins presents new opportunities to harness novel macromolecules for synthetic biological functions. Many of these new functions will require binding to small molecules. Is the ability to bind small molecules a property that arises only in response to biological selection or computational design? Or alternatively, is small molecule binding a property of folded proteins that occurs readily amidst collections of unevolved sequences? These questions can be addressed by assessing the binding potential of de novo proteins that are designed to fold into stable structures, but are "naive" in the sense that they (i) share no significant sequence similarity with natural proteins and (ii) were neither selected nor designed to bind small molecules. We chose three naive proteins from a library of sequences designed to fold into 4-helix bundles and screened for binding to 10,000 compounds displayed on small molecule microarrays. Several binders were identified, and binding was characterized by a series of biophysical assays. Surprisingly, despite the similarity of the three de novo proteins to one another, they exhibit selective ligand binding. These findings demonstrate the potential of novel proteins for molecular recognition and have significant implications for a range of applications in synthetic biology. PMID- 23651115 TI - MAP(2.0)3D: a sequence/structure based server for protein engineering. AB - The Mutagenesis Assistant Program (MAP) is a web-based tool to provide statistical analyses of the mutational biases of directed evolution experiments on amino acid substitution patterns. MAP analysis assists protein engineers in the benchmarking of random mutagenesis methods that generate single nucleotide mutations in a codon. Herein, we describe a completely renewed and improved version of the MAP server, the MAP(2.0)3D server, which correlates the generated amino acid substitution patterns to the structural information of the target protein. This correlation aids in the selection of a more suitable random mutagenesis method with specific biases on amino acid substitution patterns. In particular, the new server represents MAP indicators on secondary and tertiary structure and correlates them to specific structural components such as hydrogen bonds, hydrophobic contacts, salt bridges, solvent accessibility, and crystallographic B-factors. Three model proteins (D-amino oxidase, phytase, and N acetylneuraminic acid aldolase) are used to illustrate the novel capability of the server. MAP(2.0)3D server is available publicly at http://map.jacobs university.de/map3d.html. PMID- 23651116 TI - Nitric oxide-releasing xerogels synthesized from N-diazeniumdiolate-modified silane precursors. AB - Nitric oxide (NO)-releasing xerogel materials were synthesized using N diazeniumdiolate-modified silane monomers that were subsequently co-condensed with an alkoxysilane. The NO-release characteristics were tuned by varying the aminosilane structure and concentration. The resulting materials exhibited maximum NO release totals and durations ranging from 0.45-3.2 MUmol cm(-2) and 20 90 h, respectively. The stability of the xerogel networks was optimized by varying the alkoxysilane backbone identity, water to silane ratio, base catalyst concentration, reaction time, and drying conditions. The response of glucose biosensors prepared using the NO-releasing xerogel (15 mol % N-diazeniumdiolate modified N-2-(aminoethyl)-aminopropyltrimethoxysilane) as an outer sensor membrane was linear (R(2) = 0.979) up to 24 mM glucose. The sensitivity (3.4 nA mM(-1)) of the device to glucose was maintained for 7 days in phosphate buffered saline. The facile sol-gel synthetic route, along with the NO release and glucose biosensor characteristics, demonstrates the versatility of this method for biosensor membrane applications. PMID- 23651117 TI - Preparation and properties of carboxymethyl kappa-carrageenan/alginate blend fibers. AB - Carboxymethyl kappa-carrageenan (CMkappaC)/alginate (AL) blend fibers were prepared by spinning their mixture solution through a viscose-type spinneret into a coagulating bath containing aqueous CaCl2 and ethanol. The structure and properties of blend fibers were studied with the aid of infrared spectroscopy, scanning electron microscopy, X-ray diffraction, and thermogravimetric analysis. The analyses indicated a good miscibility between AL and CMkappaC because of the strong interaction of the intermolecular hydrogen bonds. The mechanical properties and water-retention properties were also measured. The best values of tensile strength and breaking elongation were obtained when CMkappaC content was 30 wt.%. The water-retention properties and thermostability improved by blending method. Antibacterial fibers, obtained by the treatment of the fibers with an aqueous solution of silver nitrate, exhibited good antibacterial activity to Staphylococcus aureus. PMID- 23651118 TI - C-reactive protein and leucocyte counts drop faster using the HeartShield(r) device in patients with DSWI. AB - Right ventricular heart rupture is a devastating complication associated with negative pressure wound therapy (NPWT) in cardiac surgery. The use of a rigid barrier disc (HeartShieldTM) has been suggested to offer protection against this lethal complication by preventing the heart from being drawn up by the negative pressure and damaged by the sharp sternum bone edges. Seven patients treated with conventional NPWT and seven patients treated with NPWT with a protective barrier disc (HeartShield) were compared with regard to bacterial clearance and infection parameters including C-reactive protein levels and leucocyte counts. C-reactive protein levels and leucocyte counts dropped faster and bacterial clearance occurred earlier in the HeartShield(r) group compared with the conventional NPWT group. Negative biopsy cultures were shown after 3.1 +/- 0.4 NPWT dressing changes in the HeartShield group, and after 5.4 +/- 0.6 NPWT dressing changes in the conventional NPWT group (P < 0.001). All patients were followed up with clinical check-up after 3 months. None of the patients in the HeartShield group had any signs of reinfection such as deep sternal wound infection (DSWI) or sternal fistulas, whereas in the conventional NPWT group, two patients had signs of sternal fistulas that demanded hospitalisation. HeartShield hinders the right ventricle to come into contact with the sharp sternal edges during NPWT and thereby protects from heart damage. This study shows that using HeartShield is beneficial in treating patients with DSWI. Improved wound healing by HeartShield may be a result of the efficient drainage of wound effluents from the thoracic cavity. PMID- 23651120 TI - Tracking the formation of a polynuclear Co16 complex and its elimination and substitution reactions by mass spectroscopy and crystallography. AB - We present the syntheses and structures of the biggest chiral cobalt coordination cluster, [Co16(L)4(H3L)8(N3)6](NO3)2.16H2O.2CH3OH (1, where H4L = S,S-1,2-bis(1H benzimidazol-2-yl)-1,2-ethanediol). 1 consists of two Co4O4 cubes (Co4(L)2(H3L)2) alternating with Co2(EO-N3)2Co2 (Co4(L)2(H3L)2(N3)2), bridged by the benzimidazole and azide nitrogen atoms to form a twisted ring. The ligand adopts both cis and trans forms, and all the rings have the same chiralilty. ESI-MS of 1 from a methanol solution of crystals reveals the fragment [Co16(L)4(H3L)8(N3)6+2H](4+), suggesting the polynuclear core is stable in solution. ESI-MS measurements from the reaction solution found smaller fragments, [Co4(H3L)4-H](3+), [Co4(H3L)4-2H](2+), [Co4(H3L)4(N3)2](2+), and [Co2(H3L)2](2+), and ESI-MS from a methanol solution of the solid deposit found in addition the Co16 core. These results and the dependence on the synthesis time allow us to propose the process for the formation of 1, which opens up a new way for the direct observation of the ligand-controlled assembly of clusters. In addition, the isolation of [Co4(H3L)4](NO3)4.4H2O (2) consisting of separate Co4O4 cubes with the ligands being only cis in crystalline form supports the proposal. Interestingly, N3(-) is replaced by either CH3O(-) or OH(-), and this is the first time that high-resolution ESI-MS is successfully utilized to examine both the step-by-step elimination and substitution of inner bridging ligands in such a high nuclear complex. Increasing the voltage results in stepwise elimination of azide from the parent cluster. The preliminary magnetic susceptibility of 1 indicates ferromagnetic cubes antiferromagnetically coupled to the squares within the cluster, though in a field of 2.5 kOe, weak and slow relaxation is observed below 4 K. PMID- 23651119 TI - Mass flowering of the tropical tree Shorea beccariana was preceded by expression changes in flowering and drought-responsive genes. AB - Community-level mass flowering, known as general flowering, which occurs in South East Asia at supra-annual irregular intervals, is considered a particularly spectacular phenomenon in tropical ecology. Recent studies have proposed several proximate factors inducing general flowering, such as drought and falls in minimum temperature. However, limited empirical data on the developmental and physiological processes have been available to test the significance of such factors. To overcome this limitation and test the hypotheses that general flowering is triggered by the proposed factors, we conducted an 'ecological transcriptome' study of a mass flowering species, Shorea beccariana, comparing meteorological data with genome-wide expression patterns obtained using next generation sequencing. Among the 98 flowering-related genes identified, the homologs of a floral pathway integrator, SbFT, and a floral repressor, SbSVP, showed dramatic transcriptional changes before flowering, and their flowering functions were confirmed using transgenic Arabidopsis thaliana. Expression in drought-responsive and sucrose-induced genes also changed before flowering. All these expression changes occurred when the flowering-inducing level of drought was reached, as estimated using data from the preceding 10 years. These genome wide expression data support the hypothesis that drought is a trigger for general flowering. PMID- 23651121 TI - Comparison of gaseous oxidized Hg measured by KCl-coated denuders, and nylon and cation exchange membranes. AB - The chemical compounds that make up gaseous oxidized mercury (GOM) in the atmosphere, and the reactions responsible for their formation, are not well understood. The limitations and uncertainties associated with the current method applied to measure these compounds, the KCl-coated denuder, are not known due to lack of calibration and testing. This study systematically compared the uptake of specific GOM compounds by KCl-coated denuders with that collected using nylon and cation exchange membranes in the laboratory and field. In addition, a new method for identifying different GOM compounds using thermal desorption is presented. Different GOM compounds (HgCl2, HgBr2, and HgO) were found to have different affinities for the denuder surface and the denuder underestimated each of these compounds. Membranes measured 1.3 to 3.7 times higher GOM than denuders in laboratory and field experiments. Cation exchange membranes had the highest collection efficiency. Thermodesorption profiles for the release of GOM compounds from the nylon membrane were different for HgO versus HgBr2 and HgCl2. Application of the new field method for collection and identification of GOM compounds demonstrated these vary as a function of location and time of year. Understanding the chemistry of GOM across space and time has important implications for those developing policy regarding this environmental contaminant. PMID- 23651122 TI - A quantitative review of neurocognition in euthymic late-life bipolar disorder. AB - OBJECTIVES: A sizeable body of work has consistently documented that a number of euthymic mixed-age bipolar disorder subjects exhibit prominent impairments in a variety of cognitive domains. By contrast, knowledge about neuropsychological functioning in elderly patients is scant, despite being necessary for the adequate treatment of this population and the understanding of illness evolution. The aim of this study was to combine findings from the available literature in order to examine the pattern and extent of cognitive deficits in euthymic late life bipolar disorder subjects. METHODS: A literature search was conducted through the online databases PubMed, ScienceDirect, EBSCO, and Wiley-Blackwell, covering the period between January 1990 and April 2012. Effect sizes reflecting patient-control differences for 10 cognitive variables were extracted from selected investigations and combined by means of meta-analytical procedures. RESULTS: No significant patient-control differences were found for global cognitive status as assessed with the Mini-Mental State Examination and the Clock Drawing Test. Significant overall effect sizes (Hedges' g) of between 0.61 and 0.88 were noted for sustained attention, digit span (forwards and backwards), delayed recall, serial learning, cognitive flexibility, and verbal fluency (phonemic and categorical). CONCLUSIONS: The extent of cognitive dysfunction in euthymic late-life bipolar disorder subjects may be, on average, similar to that reported for remitted young adult patients. Larger effect sizes of impairment may be associated with late illness onset. Implications and future directions for research are proposed. PMID- 23651123 TI - Clinical features, anger management and anxiety: a possible correlation in migraine children. AB - BACKGROUND: Psychological factors can increase severity and intensity of headaches. While great attention has been placed on the presence of anxiety and/or depression as a correlate to a high frequency of migraine attacks, very few studies have analyzed the management of frustration in children with headache. Aim of this study was to analyze the possible correlation between pediatric migraine severity (frequency and intensity of attacks) and the psychological profile, with particular attention to the anger management style. METHODS: We studied 62 migraineurs (mean age 11.2 +/- 2.1 years; 29 M and 33 F). Patients were divided into four groups according to the attack frequency (low, intermediate, high frequency, and chronic migraine). Pain intensity was rated on a 3-levels graduate scale (mild, moderate and severe pain). Psychological profile was assessed by Picture Frustration Study test for anger management and SAFA-A scale for anxiety. RESULTS: We found a relationship between IA/OD index (tendency to inhibit anger expression) and both attack frequency (r = 0.328, p = 0.041) and intensity (r = 0.413, p = 0.010). When we analyzed the relationship between anxiety and the headache features, a negative and significant correlation emerged between separation anxiety (SAFA-A Se) and the frequency of attacks (r = -0.409, p = 0.006). In our patients, the tendency to express and emphasize the presence of the frustrating obstacle (EA/OD index) showed a positive correlation with anxiety level ("Total anxiety" scale: r = 0.345; p = 0.033). CONCLUSIONS: Our results suggest that children suffering from severe migraine tend to inhibit their angry feelings. On the contrary, children with low migraine attack frequency express their anger and suffer from separation anxiety. PMID- 23651125 TI - Acute physiological effects of whole body vibration (WBV) on central hemodynamics, muscle oxygenation and oxygen consumption in individuals with chronic spinal cord injury. AB - PURPOSE: (1) Investigate the acute effects of whole body vibration (WBV) on central hemodynamic responses, muscle oxygenation and oxygen consumption (VO2) in individuals with spinal cord injury (SCI) versus sex, age and activity-matched able-bodied (AB) individuals. (2) Assess the effects of three WBV frequencies on all outcome measures. METHODS: Eleven males with SCI and 10 AB individuals were recruited. Subjects completed three WBV exercise sessions at 30, 40 and 50 Hz. Heart rate (HR), mean arterial blood pressure (MAP), stroke volume (SV), cardiac output (CO), VO2 and relative changes in oxygenated (Delta[HbMbO2]), deoxygenated (Delta[HHbMb]) and total (Delta[HbMbtot]) heme groups were obtained when VO2 steady state was achieved for: pre-WBV sitting, pre-WBV standing, WBV and post WBV standing. RESULTS: Both groups demonstrated small but significant increases in VO2, Delta[HbMbO2] and Delta[HbMbtot]; but the increases were larger in the SCI group. A significant decrease Delta[HHbMb] was observed in the SCI group. No frequency effect was observed. CONCLUSION: The WBV responses do not appear sufficient to induce cardiovascular benefits in the SCI population. WBV may be helpful for individuals with SCI in improving lower limb peripheral blood flow and coping with orthostatic hypotension symptoms earlier in their rehabilitation programs. PMID- 23651124 TI - Choline transporter-like protein 4 (CTL4) links to non-neuronal acetylcholine synthesis. AB - Synthesis of acetylcholine (ACh) by non-neuronal cells is now well established and plays diverse physiologic roles. In neurons, the Na(+) -dependent, high affinity choline transporter (CHT1) is absolutely required for ACh synthesis. In contrast, some non-neuronal cells synthesize ACh in the absence of CHT1 indicating a fundamental difference in ACh synthesis compared to neurons. The aim of this study was to identify choline transporters, other than CHT1, that play a role in non-neuronal ACh synthesis. ACh synthesis was studied in lung and colon cancer cell lines focusing on the choline transporter-like proteins, a five gene family choline-transporter like protein (CTL)1-5. Supporting a role for CTLs in choline transport in lung cancer cells, choline transport was Na(+) -independent and CTL1-5 were expressed in all cells examined. CTL1, 2, and 5 were expressed at highest levels and knockdown of CTL1, 2, and 5 decreased choline transport in H82 lung cancer cells. Knockdowns of CTL1, 2, 3, and 5 had no effect on ACh synthesis in H82 cells. In contrast, knockdown of CTL4 significantly decreased ACh secretion by both lung and colon cancer cells. Conversely, increasing expression of CTL4 increased ACh secretion. These results indicate that CTL4 mediates ACh synthesis in non-neuronal cell lines and presents a mechanism to target non neuronal ACh synthesis without affecting neuronal ACh synthesis. PMID- 23651126 TI - Systematic review of ICF core set from 2001 to 2012. AB - PURPOSE: This study systemically reviewed the published literature on the ICF core set. METHOD: A computer search of the MEDLINE, PubMed and SCOPUS databases was conducted between 2001 and December 2012. Articles reporting on the development of a set or sets of ICF categories for specific disease or health conditions were selected for a systematic review. RESULTS: The analysis included 116 articles from 36 journals, with the majority of papers having been published in 2011 and 2012. In these studies, spinal cord injury was the most frequently reported disease. The majority of the experts involved in the consensus process were physicians and physical therapists. CONCLUSION: This systematic review of studies on ICF core sets provided background information on the current developmental status of ICF core sets. Our findings also highlight possible directions for future research. PMID- 23651127 TI - The perceptions of people with multiple sclerosis about the NHS provision of physiotherapy services. AB - PURPOSE: In 2008, the Royal College of Physicians (RCP) and MS Trust conducted a second audit of NHS services for people with MS (PwMS). Using the free text comments obtained from the RCP and MS Trust audit, this study aimed to perform content analysis on the views of PwMS about MS services, focussing on physiotherapy provision. METHOD: A total of 757 PwMS included a free text comment on MS services and an additional 41 commented separately about physiotherapy services. The data were analysed using content analysis, which identified three main themes, positive, negative and neutral and subsequent categories and sub categories. Intra- and inter-rater reliability were assessed and the data were manipulated to address the research aim. RESULTS: This study found that the majority of the free text comments on MS services were negative (55%). Physiotherapy provision was rated the most negative of NHS services (38%), with the primary complaints being lack of information about services and excessive waiting times for appointments. CONCLUSION: This study has revealed that NHS physiotherapy provision is not meeting the needs of PwMS. PMID- 23651128 TI - Facilitators and barriers for eating behaviour changes in obstructive sleep apnoea and obesity - a qualitative content analysis. AB - PURPOSE: Obesity is a major risk factor for obstructive sleep apnoea syndrome, a condition known causing lack of sleep continuity and daytime sleepiness. Weight loss interventions are recommended, however knowledge on what facilitate and impede eating behaviour change is lacking for this particular population. The aim of this study was to identify personal conceptions of prerequisites for eating behaviour change. METHOD: A qualitative study on 15 patients with obstructive sleep apnoea syndrome (OSAS; apnoea-hypopnoea index >15) and obesity (Mean body mass index 38.2). Semi-structured interviews were conducted and data were transcribed and analysed using qualitative content analysis with researcher triangulation for trustworthiness. RESULTS: Data were organised according to barriers and facilitators for changing eating behaviour. Identified barriers were desire and reward, cravings and emotional control, low self-confidence, insufficient support, taxing behaviours, cost, lack of knowledge about healthy eating strategies, perceived helplessness and low susceptibility. Identified facilitators were positive expectations, fear of negative consequences, experience of success, support and follow-up, accessibility, applied skills for healthy eating, personal involvement and challenged self-image. CONCLUSION: This study adds knowledge on important barriers and facilitators of eating behaviour change according to individuals with obesity and OSAS. Information used to inform a tailored behavioural medicine intervention targeting eating behaviours. IMPLICATIONS FOR REHABILITATION: Patients with obstructive sleep apnoea syndrome (OSAS) benefit from weight loss and eating behaviour changes are recommended. Patients' views on prerequisites for eating behaviour change are important to plan, conduct and tailor behaviour change interventions. These aspects have hitherto not been elaborated in patients with OSAS. Considerations on patient's self-image and perceived susceptibility along with providing strategies for controlling the desire and rewarding feeling associated with eating are emphasised. PMID- 23651129 TI - Is applying the same exercise-based inpatient program to normal and reduced left ventricular function patients the best strategy after coronary surgery? A focus on autonomic cardiac response. AB - PURPOSE: To assess whether the same exercise-based inpatient program applied to patients with normal and reduced left ventricular function (LVF) evokes a similar cardiac autonomic response after coronary artery bypass graft (CABG). METHOD: Forty-four patients post-CABG, subgrouped according to normal LVF [LVFN: n = 23; left ventricular ejection fraction (LVEF) >= 55%] and reduced LVF (LVFR: n = 21; LVEF 35-54%), were included. All initiated the exercise protocol on post operative day 1 (PO1), following a whole progressive program until discharge. Cardiac autonomic response was assessed by the indices of heart rate variability (HRV) at rest and during exercise (extremity range of motion and ambulation). RESULTS: During ambulation, lower values of HRV indices were found in the LVFR group compared with the LVFN group [standard deviation of all RR (STDRR; 6.1 +/- 2.7 versus 8.9 +/- 4.7 ms), baseline width of the RR histogram (TINN; 30.6 +/- 14.8 versus 45.8 +/- 24.9 ms), SD2 (14.8 +/- 8.0 versus 21.3 +/- 9.0 ms), Shannon entropy (3.6 +/- 0.5 versus 3.9 +/- 0.4) and correlation dimension (0.08 +/- 0.2 versus 0.2 +/- 0.2)]. Also, when comparing the ambulation to rest change, lower values were observed in the LVFR group for linear (STDRR, TINN, RR TRI, rMSSD) and non-linear (SD2 and correlation dimension) HRV indices (p < 0.05). On PO1, we observed only intra-group differences between rest and exercise (extremity range of motion), for mean intervals between heart beats and heart rate. CONCLUSION: For patients with LVFN, the same inpatient exercise protocol triggered a more attenuated autonomic response compared with patients with LVFR. These findings have implications as to how exercise should be prescribed according to LVF in the early stages following recovery from CABG. Implications for Rehabilitation Exercise-based inpatient program, performed by post-CABG patients who have normal left ventricular function, triggered a more attenuated cardiac autonomic response compared with patients with reduced left ventricular function. Volume of the inpatient exercises should be prescribed according to the left ventricular function in the early stages following recovery from CABG. PMID- 23651130 TI - The influence of inspiratory muscle training on diaphragmatic mobility, pulmonary function and maximum respiratory pressures in morbidly obese individuals: a pilot study. AB - PURPOSE: To investigate whether 12 week inspiratory muscle training (IMT) has any impact on pulmonary function, maximum respiratory pressures and diaphragmatic mobility (DM) in morbidly obese subjects. METHOD: Thirty-one morbidly obese individuals were assessed. Volunteers were randomised into two groups. The IMT group (n = 16) followed an IMT protocol for 12 weeks, with a training load of 30% of maximal inspiratory pressure (PImax). The control group (CG) (n = 15) followed the same protocol but without inspiratory load. RESULTS: A total of 14 subjects performed IMT for 12 weeks. Significant increases in PImax (-86.86 +/- -20.70 cmH2O versus -106.43 +/- -32.97 cmH2O, p < 0.05) and maximal voluntary ventilation (97.84 +/- 37.06 L/min versus 115.17 +/- 34.17 L/min, p < 0.05) were observed in the IMT group when compared to baseline. However, only FIV1 significantly differed between the IMT group and the CG after the 12 week protocol (3.35 +/- 0.96 L versus 2.22 +/- 1.07 L, respectively; p < 0.05). No significant differences were found in DM after the IMT protocol was performed. CONCLUSION: IMT improved PImax and altered the FIV1. These results suggest that the improvements in muscular respiratory efficiency were insufficient to mobilise the diaphragm and modify ventilation mechanics. Pre-operative IMT may be a valuable approach in obese patients for preventing post-operative pulmonary complications. http://clinicaltrials.org -- NCT01449643 -- The Influence of IMT on Diaphragmatic Mobility in Morbidly Obese. IMPLICATIONS FOR REHABILITATION: Morbid Obesity Morbid obesity is a disabling condition that has a serious negative impact on lung function, respiratory muscle function and quality of life. Inspiratory Muscle Training (IMT) is a technique which aims to improve pulmonary expansion and to prevent post surgery complications on morbid obese individuals. This study shows significantly increased on maximal inspiratory pressure, maximal voluntary ventilation and promoted changes on spirometric variables after IMT. PMID- 23651131 TI - Laser photodynamic treatment for in situ squamous cell carcinoma of the glans monitored by reflectance confocal microscopy. AB - While mutilating surgery can be avoided with non-surgical treatment of in situ squamous cell carcinoma (SCC) of the penis, such as photodynamic therapy (PDT), this procedure is not followed by histological evaluation to verify the total removal of the lesion, leading to possible recurrence. We present the first case of in situ penile SCC treated with laser PDT, where the efficacy of the treatment was monitored by reflectance confocal microscopy (RCM) using a handheld camera. In the future RCM may be regarded as a complementary technique to assess the efficacy of non-surgical treatment of mucous membrane cancers. PMID- 23651132 TI - Differentiated thyroid carcinomas and their B7H1 shield. PMID- 23651133 TI - Is there a role for ambulatory blood pressure monitoring in pregnancy? AB - 1. Ambulatory blood pressure monitoring (ABPM) has been used in pregnancy for just over 20 years now and is generally well tolerated. Normal values have been established for different gestations; these are slightly higher than conventional blood pressure (BP) in normal pregnancy, presumably reflecting greater activity during the 24 h of ABPM recordings. 2. Ambulatory blood pressure monitoring is a better predictor than conventional BP for the development of pre-eclampsia and fetal growth restriction, but it is not sensitive or specific enough to be recommended for these purposes in routine practice. 3. Studies of ABPM have shown that sleep hypertension is common in women with gestational hypertension or pre eclampsia, but detecting this in routine clinical practice does not aid usual decision making in the pregnancy, including timing of delivery. 4. Studies using ABPM have found that pregnant women who are working outside the home have higher BP than non-working women, but these data should not be interpreted to mean that not working during pregnancy will prevent gestational hypertension or pre eclampsia. 5. The best role for ABPM is to determine whether women with office hypertension in early pregnancy have true (usually essential) hypertension or white-coat hypertension. The latter can be managed without antihypertensives and pregnancy outcomes appear good, although possibly with a slightly increased incidence of pre-eclampsia. 6. Women who have had pre-eclampsia are at greater life-time risk for cardiovascular diseases; several years postpartum these women have slightly higher ABPM-measured BP than women who had normal pregnancies and a greater propensity to metabolic syndrome. PMID- 23651134 TI - Synthesis of 3-aza-bicyclo[3.1.0]hexan-2-one derivatives via gold-catalyzed oxidative cyclopropanation of N-allylynamides. AB - N-allylynamides with various functional groups and different substitution patterns can be converted into 3-aza-bicyclo[3.1.0]hexan-2-one derivatives in moderate to high yield using IMesAuCl/AgBF4 as the catalyst and pyridine N-oxide as the oxidant. A noncarbene mediated approach is proposed as the mechanism. PMID- 23651135 TI - Rostroventrolateral medulla neurons with commissural projections provide input to sympathetic premotor neurons: anatomical and functional evidence. AB - The activity of neurons in the rostral ventrolateral medulla (RVLM) is critical for the generation of vasomotor sympathetic tone. Multiple pre-sympathetic pathways converge on spinally projecting RVLM neurons, but the origin and circumstances in which such inputs are active are poorly understood. We have previously shown that input from the contralateral brainstem contributes to the baseline activity of this population: in the current study we investigate the distribution, phenotype and functional properties of RVLM neurons with commissural projections in the rat. We firstly used retrograde transport of fluorescent microspheres to identify neurons that project to the contralateral RVLM. Labelled neurons were prominent in a longitudinal column that extended over 1 mm caudal from the facial nucleus and contained hybridisation products indicating enkephalin (27%), GABA (15%) and adrenaline (3%) synthesis and included 6% of bulbospinal neurons identified by transport of cholera toxin B. Anterograde transport of fluorescent dextran-conjugate from the contralateral RVLM revealed extensive inputs throughout the RVLM that frequently terminated in close apposition with catecholaminergic and bulbospinal neurons. In urethane anaesthetised rats we verified that 28/37 neurons antidromically activated by electrical stimulation of the contralateral pressor region were spontaneously active, of which 13 had activity locked to central respiratory drive and 15 displayed ongoing tonic discharge. In six tonically active neurons sympathoexcitatory roles were indicated by spike-triggered averages of splanchnic sympathetic nerve activity. We conclude that neurons in the RVLM project to the contralateral brainstem, form synapses with sympathetic premotor neurons, and have functional properties consistent with sympthoexcitatory function. PMID- 23651136 TI - What neurochemistry tells us about the retina. PMID- 23651137 TI - Watchmakers' glaucoma. AB - We present the first reported case of an 'apparent' unilateral glaucoma in the eye used by a watchmaker with a monocular loupe. We hypothesise that it was caused by the pressure from the orbicularis oculi muscle contraction associated with holding it in position for long periods of time. We believe that users of this kind of optical instrument should avoid wearing it always in the same eye or using it for long periods of time and should be monitored closely by routine ophthalmic examinations. PMID- 23651138 TI - Professor Norhani Mohidin: pioneer, educator and champion of optometry in Malaysia. PMID- 23651140 TI - Sexual transgression and social disconnection: healing through community-based sociotherapy in Rwanda. AB - A distinguishing feature of the 1994 genocide against the Tutsi and the preceding 1990-1994 war in Rwanda was the social intimacy of the crimes committed. The legacy of this kind of violence includes distrust in social relations within communities and families, an increase of violence in everyday social interaction, transgressive sexual engagements, and a range of psychological problems. Many people feel nostalgia for their past social life, but are unable to change their current situation. In 2005, a community-based sociotherapy programme was introduced into this context of mental and social distress. The goal was to help people regain feelings of dignity and safety and to reduce distress. This paper is based on qualitative research, in particular, case studies. It explores how sociotherapy, as a specific form of peer group counselling, may facilitate the healing of suffering related to issues of sexuality, violence within the family and the breakdown of social connections on a community level. PMID- 23651141 TI - Assessment of the integrity of compounds stored in assay-ready plates using a kinase sentinel assay. AB - Sentinel assays are a convenient adjunct to LC-MS purity assessment to monitor the integrity of compounds in pharmaceutical screening collections over time. To assess the stability of compounds stored both at room temperature and at -20 degrees C in assay-ready plates that were either vacuum pack-sealed using a convenient industrial vacuum sealing method or individually sealed using conventional foil seals, a diverse collection of ~ 5,000 compounds was assayed using a robust biochemical kinase assay at intervals over a one year period. Assay results at each time point were compared to those of initial assay using a series of correlations of compound Percent of Control (POC) values as well as IC50 values of a subset of compounds in 200 nL or 500 nL plates. The fraction of hits in common between initial assays and assays at later time points ranged from 82% to 95% over one year and remained relatively constant over time with all storage temperatures or sealing methods tested. A majority of the hits that exhibited a consistent gradual trend to lower potency over one year storage were shifted to lower potency upon the rapid removal of DMSO solvent. Compound precipitation rather than compound decomposition is the likely reason for trends to lower potency for most such compounds over the storage period. Plates stored at room temperature featured a significantly higher fraction of hits that exhibited a trend to lower apparent potency than those stored at -20 degrees C suggesting that this lower temperature is preferable for longer-term storage. PMID- 23651142 TI - Transareola single-site endoscopic thyroidectomy: clinical study of 28 cases with thyroid nodules. AB - OBJECTIVES: To investigate the feasibility and safety of transareola single-site endoscopic thyroidectomy. SUBJECTS AND METHODS: Twenty-eight patients with thyroid nodules were involved in this study. An incision was cut on a single areola, and a laparoendoscope apparatus and an operating apparatus were implanted. The thyroid gland was exposed using the neck suture suspension technique, and the damaged thyroid gland was removed with an ultrasonic scalpel. The operation time, intraoperative bleeding volume, postoperative pain score, and cosmetic satisfaction score were calculated. RESULTS: Unilateral subtotal thyroidectomy was performed in 12 cases, unilateral partial thyroidectomy in 14 cases, and bilateral partial thyroidectomy in 2 cases. For the former 14 cases, the operation time was 145-205 minutes, with a mean duration of 170 minutes; the operation time ranged from 125 to 150 minutes, with a mean of 135 minutes, for the latter 14 cases. The intraoperative bleeding volume was 15-40 mL, with a mean of 25 mL. The total postoperative wound drainage was 80-135 mL, with a mean of 110 mL. The drainage tube was removed 3-4 days after surgery. The visual analog scale score was 1-5 at 24 hours postoperatively, with a mean score of 3.10. Postoperative pathological examination diagnosed thyroid adenoma in 11 cases and nodular goiter in 17 cases. CONCLUSIONS: Transareola single-site endoscopic thyroidectomy is feasible and safe and has the advantages of a covert incision, small subcutaneous separation area, and high cosmetic satisfaction. The operation time shortens with the increasing number of patients undergoing operations. PMID- 23651143 TI - Multiple organ retraction during urological laparoscopic surgery. AB - PURPOSE: During laparoscopic surgery, as in open surgery, exposure is critical. We describe our surgical technique that provides intra-abdominal multiple organ retraction in order to obtain a stable surgical field and adequate exposure. MATERIALS AND METHODS: The Flex ArmTM surgical holder (Mediflex Surgical Products, Islandia, NY) is an adjustable, spring-loaded articulating instrument holder. The device offers the flexibility of the attachment of multiple arms (up to three) on the same rod, which can rotate 360 degrees to aid in positioning. This device permits multiple laparoscopic instruments to be held simultaneously. We used this device for multiple organ retraction during urological laparoscopic surgery (retroperitoneoscopic radical prostatectomy, n=5; laparoscopic radical nephrectomy, n=3; laparoscopic partial nephrectomy, n=2; laparoscopic pyeloplasty, n=2). RESULTS: We achieved significant improvements in the efficiency of retraction of the liver, kidney, colon, and prostate during urological laparoscopic surgery. Our method maintains a constant surgical field through the proper retractor position and the proper amount of isometric force for optimal exposure. CONCLUSIONS: With this device, instrument migration due to muscle fatigue and organ injury as a result of excessive force are all substantially reduced. We believe that this technique may be helpful not only in urological laparoscopic surgery, but also in laparoscopic approaches in other departments. PMID- 23651144 TI - A novel single agent for nutritional supplementation following Roux-en-Y gastric bypass. AB - BACKGROUND: Duodenal bypass and intestinal malabsorption from Roux-en-Y gastric bypass (RYGB) can exacerbate known nutritional deficiencies of morbidly obese patients and worsen symptoms. Preventatively, most bariatric patients use postoperative nutritional supplementation. This study evaluated Nuvista((r)) (Nutricia North America, Rockville, MD) and its potential as an adequate single nutritional supplement. SUBJECTS AND METHODS: From October 2009 to June 2010, 25 patients enrolled in a prospective, consecutive pilot study. Each underwent laparoscopic RYGB. The study group consumed two packs of Nuvista daily. The control group received standard nutritional supplements. Both groups had the same postoperative diet. Laboratory and demographics were compared at baseline and 12 months. Statistical analysis included paired t test, and a value of P<.05 was significant. RESULTS: The study and control groups (16 and 9 patients, respectively) had statistically similar demographic profiles. Both groups had preoperative elevations of hemoglobin A1c (HbA1c) (6.2% and 6.2%, respectively), low-density lipoprotein (LDL) (108.2 mg/dL and 199.2 mg/dL, respectively), and high-density lipoprotein (HDL) (55.1 mg/dL and 48.0 mg/dL, respectively) and deficiencies in vitamin D with respective mean values of 20.6 ng/mL and 22.7 ng/mL (normal range, 30-100 ng/mL). Postoperatively, the study group had significant increases in phosphorus (P=.02), iron (P=.03), vitamin D (P=.05), zinc (P=.01), and HDL (P<=.01) and significant decreases in body mass index (BMI) (P<=.01), creatinine (P=.02), HbA1c (P=.01), triglycerides (P<=.01), and LDL (P<=.01). The control group had a significant increase in HDL (P=.01) and significant decreases in BMI (P<=.01), hemoglobin (P=.01), creatinine (P<=.01), albumin (P=.05), HbA1c (P=.05), zinc (P<=.01), triglycerides (P=.03), and LDL (P=.01). No change in mean parathyroid hormone value was seen. CONCLUSIONS: Nuvista can provide adequate supplementation to bariatric patients 12 months after RYGB. Lifelong biochemical follow-up is necessary to personalize the diet and nutritional supplementation to compensate for the pathophysiologic changes of the gastric bypass. PMID- 23651145 TI - Laparoscopic en bloc resection of ureter with a cuff of bladder during radical nephroureterectomy for lower ureteric tumors: a matched-paired analysis. AB - BACKGROUND: Surgical management of the lower end of the ureter during laparoscopic nephroureterectomy remains a matter of debate. The commonest method during laparoscopic nephroureterectomy-endoscopic incision-has been shown to have a higher recurrence rate compared with open surgical excision with a cuff of bladder. In addition, the literature still lacks comparative studies between different approaches to support and guide the current clinical practice. PATIENTS AND METHODS: Three consecutive series of patients undergoing laparoscopic radical nephrectomy for transitional cell carcinoma located in the lower one-third of the ureter with different methods (laparoscopic en bloc resection of ureter with a cuff of bladder, open surgical excision, and endoscopic incision) of dealing with the lower end were compared in their short-term surgical and oncological outcomes. The primary outcome was recurrence at 12 months of follow-up. The secondary outcomes were hospital stay, positive surgical margins, and duration of catheterization. RESULTS: Analysis of perioperative and postoperative outcomes revealed laparoscopic en bloc resection of the lower end of the ureter with a cuff of bladder is a safe and feasible approach with the advantages of the laparoscopic approach such as less hospital stay compared with the open approach. The analysis of oncological outcomes in this feasibility study showed a higher rate of recurrences in the endoscopic approach. CONCLUSIONS: Laparoscopic en bloc resection of the lower end of the ureter with a cuff of bladder during nephroureterectomy for tumors located in the lower one-third of ureters is safe and feasible in terms of perioperative outcomes and early oncological results. We acknowledge that the small sample size and the nonrandomized design are a limit of the study. Thus, prospective randomized controlled trials are recommended to prove the superiority of one approach over the others. PMID- 23651146 TI - The effectiveness of memory rehabilitation following neurological disabilities: a qualitative inquiry of patient perspectives. AB - The evidence for the effectiveness of memory rehabilitation following neurological conditions, mainly studied through quantitative methodologies, has been equivocal. This study aimed to examine feedback from participants who had been through a randomised controlled trial (RCT) comparing two types of memory rehabilitation with a self-help control. It was envisaged that this information would offer a detailed understanding of patient experience of going through a trial and the perceived effects of having attended group sessions. Through 31 in depth interviews, data collected were thematically analysed. The seven themes identified highlighted improvements in insight and awareness of memory problems and their neurological conditions, knowledge and skills about using memory aids; and as a consequence, improvements in cognitive functions, mood, and confidence, assertiveness and control over their condition. Participants also reported an altered perspective of life that helped them deal with their problems, and the therapeutic effects of attending group sessions. While these improvements were mainly reported in the intervention groups, even those in the control group reported some benefits. This study highlights that it is both feasible and advantageous to embed qualitative research within the traditional RCT methodology to arrive at a more nuanced understanding of patient experiences and intervention outcomes. PMID- 23651147 TI - A normative-speaker validation study of two indices developed to quantify tongue dorsum activity from midsagittal tongue shapes. AB - This study reported adult scores on two measures of tongue shape, based on midsagittal tongue shape data from ultrasound imaging. One of the measures quantified the extent of tongue dorsum excursion, and the other measure represented the place of maximal excursion. Data from six adult speakers of Scottish Standard English without speech disorders were analyzed. The stimuli included a range of consonants in consonant-vowel sequences, with the vowels /a/ and /i/. The measures reliably distinguished between articulations with and without tongue dorsum excursion, and produced robust results on lingual coarticulation of the consonants. The reported data can be used as a starting point for collecting more typical data and for analyzing disordered speech. The measurements do not require head-to-transducer stabilization. Possible applications of the measures include studying tongue dorsum overuse in people with cleft palate, and typical and disordered development of coarticulation. PMID- 23651148 TI - Calcitonin promotes mouse pre-implantation development: involvement of calcium mobilization and P38 mitogen-activated protein kinase activation. AB - The study was designed to examine the effects of calcitonin (CT) on the development of murine pre-implantation embryos and possible molecular mechanisms involved in the process. In the present study, the 2-cell embryos were treated with different concentration of CT in vitro for the indicated time and the results demonstrated that CT promoted the development of the pre-implantation embryos in a dosage-dependent manner by increasing the intracellular Ca(2+) level. Furthermore, the present study showed that CT significantly increased the expression of phospho-P38MAPK (Mitogen-Activated Protein Kinase) of the pre implantation embryos by Western blots and pre-treatment of specific P38MAPK inhibitor significantly reduced the promotion effects of CT on the embryonic development in vitro culture. Moreover, the results of intrauterine horn injection showed that the average number of embryos implanted in CT-antibody or specific P38 MAPK inhibitor-treated uterus was significantly lower than that of the corresponding control, respectively. And the observation of tissue specimen suggested that some embryos were degenerated in CT-antibody or specific P38 MAPK inhibitor-treated uterus, and adipose vacuoles were present in the decidual cells. In conclusion, CT promoted the development of pre-implantation embryos and the intracellular Ca(2+) -dependent P38MAPK signal molecule was involved in the process. PMID- 23651149 TI - Renal lymph nodes for tumor staging: appraisal of 871 nephrectomies with examination of hilar fat. AB - CONTEXT: Despite decades of research, the role of lymphadenectomy in the management of renal cell carcinoma (RCC) is still not clearly defined. Before the implementation of targeted therapies, lymph node metastases were considered to be a portent of markedly decreased survival, regardless of the tumor stage. However, the role of lymphadenectomy and the relative benefit of retroperitoneal lymph node dissection in the context of modern adjunctive therapies have not been conclusively addressed in the clinical literature. The current pathologic literature does not offer clear recommendations with regard to the minimum number of lymph nodes that should be examined in order to accurately stage the pN in renal cell carcinoma. Although gross examination of the hilar fat to assess the nodal status is performed routinely, it has not yet been determined whether this approach is adequate. OBJECTIVE: To evaluate the status of lymph nodes and their rate of identification in the pathologic examination of nephrectomy specimens in adult renal malignancies. DESIGN: We reviewed the operative and pathology reports of 871 patients with renal malignancies treated by nephrectomy. All tumors were classified according to the seventh edition of the Tumor-Nodes-Metastasis classification. Patients were divided into 3 groups: Nx, no lymph nodes recovered; N0, negative; and N1, with positive lymph nodes. Grossly visible lymph nodes were submitted separately; as per grossing protocol, hilar fatty tissue was submitted for microscopic examination. We evaluated the factors that affected the number of lymph nodes identified and the variables that allowed the prediction of nodal involvement. RESULTS: Lymph nodes were recovered in 333 of 871 patients (38%): hilar in 125 patients, nonhilar in 137 patients, and hilar and nonhilar in 71 patients. Patients with positive lymph nodes (n = 87) were younger, had larger primary tumors, and had lymph nodes of average size, as well as a higher pT stage, nuclear grade, and rate of metastases. Metastases were seen only in grossly identified lymph nodes (65% hilar, 16% nonhilar); all microscopic nodes were negative. Even with the microscopic examination of fat, hilar lymph nodes were recovered in only 22.5% of patients. A nonhilar route of node metastasis was suspected in 40 patients. CONCLUSIONS: Only grossly identifiable lymph nodes, both hilar and nonhilar, were positive for metastases. Although microscopic examination of the hilar fat increased the number of lymph nodes recovered, the identification rate of these nodes was low (22.5%), and such microscopic nodes were invariably negative. Hence, microscopic examination of the hilar fat may be unnecessary. PMID- 23651150 TI - Detection of BRAF p.V600E Mutations in Melanoma by Immunohistochemistry Has a Good Interobserver Reproducibility. AB - CONTEXT: Assessment of BRAF p.V600E mutational status has become necessary for treatment of patients with metastatic melanoma. Detection of p.V600E mutation by immunohistochemistry was recently reported in several tumor types. OBJECTIVE: To evaluate the interobserver reproducibility of BRAF p.V600E detection by immunohistochemistry in melanoma. DESIGN: Immunohistochemistry with VE1 antibody was performed on metastatic melanomas of 67 patients. Staining interpretation was performed on digital image virtual slides of tissue microarrays. The p.V600E status was determined by 7 pathologists from 3 European laboratories, blinded for other interpretations and for molecular biology results. RESULTS: Melanomas had p.V600E (n = 30), p.V600K (n = 4), p.K601E (n = 1), p.600-601delinsE (n = 1), or no p.V600 mutations (n = 31). Staining of p.V600E within mutated cells was cytoplasmic and diffuse, and for each case the staining on the 3 tissue microarray cores was similar. In 53 cases (79.1%) the 7 pathologists had perfect concordance. Agreement of interobserver reproducibility was almost perfect (kappa = 0.81 [0.77-0.85]). Only 2 false-positive responses (0.9%) were obtained. The specificities reported were 100% for 5 pathologists (two of whom previously trained for p.V600E interpretation), and 97% for 2 untrained pathologists. CONCLUSIONS: Detection of BRAF p.V600E mutation by immunohistochemistry in melanomas has an excellent interobserver reproducibility. Our results suggest that immunohistochemistry could be used as a first step for detection of BRAF p.V600E mutation, to identify patients with melanoma as candidates for BRAF inhibitors. PMID- 23651152 TI - Promoting collaborative interdisciplinary research at the Duke Center for Systems Biology. PMID- 23651153 TI - Tetracycline-regulated expression implemented through transcriptional activation combined with proximal and distal repression. AB - Tetracycline-regulated expression systems are widely used to control ectopic gene expression in mammalian cells. However, background or "leaky" expression in the "off" state can limit applications that require control of expression at low levels. In this work we have engineered a tetracycline-regulated expression system with an improved range of control and lower background expression. To lower background expression without diminishing the controllable expression range, we designed a feed-forward scheme that repressed both expression of the gene of interest and the transcriptional activator. By using a tetracycline responsive repressor that can modify chromatin and repress transcription over short and long distances, we were able to repress these two expression targets using a single tetracycline-responsive genetic element. This dual-targeting repressor/activation system demonstrated decreased background expression in its "off" state and a 25-fold range of expression in response to doxycycline. This study demonstrates that genetic circuits can be improved by leveraging trans acting factors with long-range capabilities. PMID- 23651154 TI - A synthetic post-transcriptional controller to explore the modular design of gene circuits. AB - The assembly from modular parts is an efficient approach for creating new devices in Synthetic Biology. In the "bottom-up" designing strategy, modular parts are characterized in advance, and then mathematical modeling is used to predict the outcome of the final device. A prerequisite for bottom-up design is that the biological parts behave in a modular way when assembled together. We designed a new synthetic device for post-transcriptional regulation of gene expression and tested if the outcome of the device could be described from the features of its components. Modular parts showed unpredictable behavior when assembled in different complex circuits. This prevented a modular description of the device that was possible only under specific conditions. Our findings shed doubts into the feasibility of a pure bottom-up approach in synthetic biology, highlighting the urgency for new strategies for the rational design of synthetic devices. PMID- 23651155 TI - A modified Cre-lox genetic switch to dynamically control metabolic flow in Saccharomyces cerevisiae. AB - The control of metabolic flow is a prerequisite for efficient chemical production in transgenic microorganisms. Exogenous genes required for the biosynthesis of target chemicals are expressed under strong promoters, while the endogenous genes of the original metabolic pathway are repressed by disruption or mutation. These genetic manipulations occasionally cause harmful effects to the host. In the lactate-producing yeast Saccharomyces cerevisiae, where endogenous pyruvate decarboxylase (PDC) is disrupted and exogenous lactate dehydrogenase (LDH) is introduced, PDC deletion is extremely detrimental to cell growth but is required for efficient production of lactate. A suitable means to dynamically control the metabolic flow from ethanol fermentation during the growth phase to lactate fermentation during the production phase is needed. Here, we demonstrated that this flow can be controlled by the exclusive expression of PDC and LDH with a Cre lox genetic switch. This switch was evaluated with a gene cassette that encoded two different fluorescence proteins and enabled changes in genotype and phenotype within 2 and 10 h, respectively. Transgenic yeast harboring this switch and the PDC-LDH cassette showed a specific growth rate (0.45 h (-1)) that was almost the same as that of wild-type (0.47 h (-1)). Upon induction of the genetic switch, the transgenic yeast produced lactate from up to 85.4% of the glucose substrate, while 91.7% of glucose went to ethanol before induction. We thus propose a "metabolic shift" concept that can serve as an alternative means to obtain gene products that are currently difficult to obtain by using conventional methodologies. PMID- 23651156 TI - Elucidation of small RNAs that activate transcription in bacteria. AB - Small non-coding RNA (sRNA) control of gene expression has been shown to play a prominent role in genetic regulation. While the majority of identified bacterial sRNAs exert their control at the translational level, a few examples of bacterial sRNAs that inhibit transcription have also been identified. Using an engineered combinatorial RNA library, we have elucidated bacterial sRNAs that activate transcription of a target gene in E. coli to varying degrees. Mutation of the strongest activator modified its activation potential. Our results suggest that transcriptional activation of our target gene results from recruitment of the bacterial RNA polymerase complex to the promoter region. These data, coupled with the malleability of RNA, provide a context to define synthetic control of genes in bacteria at the transcriptional level. PMID- 23651157 TI - An in vitro autogene. AB - Recent technological advances have allowed development of increasingly complex systems for in vitro evolution. Here, we describe an in vitro autogene composed of a self-amplifying T7 RNA polymerase system. Functional autogene templates in cell-free lysate produce T7 RNA polymerase, which amplifies the autogene genetic information through a positive feedback architecture. Compartmentalization of individual templates within a water-in-oil emulsion links genotype and phenotype, allowing evolution. PMID- 23651158 TI - Bronchial thermoplasty failure in severe persistent asthma: a case report. AB - INTRODUCTION: Bronchial thermoplasty (BT) is an emerging therapy for patients with severe persistent asthma who remain poorly controlled despite standard maximal medical therapy. Thermoplasty elicits asthma control over time by applying thermal radiofrequency energy to airways to ablate underlying smooth muscle. While this therapy is suggested to eliminate such smooth muscle permanently, no human studies have examined the possibility of treatment failure. CASE REPORT: We present a 62-year-old female with severe, refractory asthma symptoms who underwent BT without apparent complications. However, severe symptoms including multiple clinical exacerbations persisted despite BT treatment. Repeat endobronchial biopsy done six months after BT treatment demonstrated persistent smooth muscle hyperplasia in multiple airways that previously had been treated. The patient continued to have uncontrolled, refractory asthma despite multiple therapies. CONCLUSION: This case is the first to describe a failure of BT to reduce or eliminate airway smooth muscle in a patient with severe persistent asthma. It suggests the potential for treatment failure in the management of these patients after BT and highlights the need for further study of potential BT-refractory patients. PMID- 23651159 TI - Supramolecular control of the spin-dependent dynamics of long-lived charge separated states at the micellar interface as studied by magnetic field effect. AB - Spin selectivity in long-lived charge separation at the micellar interface is studied using the magnetic field effect (MFE). An amphiphilic viologen is complexed with a nonionic surfactant to form a supramolecular acceptor cage, of which the size is controlled by the acceptor concentration, as confirmed by dynamic light scattering measurement. Photoinduced electron transfer (ET) from a guest polyaromatic molecule to the viologen moiety is observed spin-dependently with time-resolved fluorescence (trFL) and transient absorption (TA). A negative MFE on the radical yield is successfully observed, which indicates generation of singlet-born long-lived radical pair that is realized by supramolecular control of the donor-acceptor (D-A) distances. The dominance of the singlet-precursor MFE is sensitive to the acceptor concentration, which presumably affects the D-A distance as well as the cage size. However, theoretical analysis of the MFE gives large recombination rates of ca. 10(8) s(-1), which indicate the contribution of spin-allowed recombination of the pseudocontact radical pair generated by still active in-cage diffusion. Dependence of the viologen concentration and alkyl chain length on the recombination and escape dynamics is discussed in terms of precursor spin states and the microenvironments in the cage. PMID- 23651160 TI - Complex structures between the N-type calcium channel (CaV2.2) and omega conotoxin GVIA predicted via molecular dynamics. AB - The N-type voltage-gated Ca(2+) channel CaV2.2 is one of the important targets for pain management. omega-Conotoxins isolated from venoms of cone snails, which specifically inhibit CaV2.2, are promising scaffolds for novel analgesics. The inhibitory action of omega-conotoxins on CaV2.2 has been examined experimentally, but the modes of binding of the toxins to this and other related subfamilies of Ca(2+) channels are not understood in detail. Here molecular dynamics simulations are used to construct models of omega-conotoxin GVIA in complex with a homology model of the pore domain of CaV2.2. Three different binding modes in which the side chain of Lys2, Arg17, or Lys24 from the toxin protrudes into the selectivity filter of CaV2.2 are considered. In all the modes, the toxin forms a salt bridge with an aspartate residue of subunit II just above the EEEE ring of the selectivity filter. Using the umbrella sampling technique and potential of mean force calculations, the half-maximal inhibitory concentration (IC50) values are calculated to be 1.5 and 0.7 nM for the modes in which Lys2 and Arg17 occlude the ion conduction pathway, respectively. Both IC50 values compare favorably with the values of 0.04-1.0 nM determined experimentally. The similar IC50 values calculated for the different binding modes demonstrate that GVIA can inhibit CaV2.2 with alternative binding modes. Such a multiple-binding mode mechanism may be common for omega-conotoxins. PMID- 23651161 TI - Persistent firing supported by an intrinsic cellular mechanism in hippocampal CA3 pyramidal cells. AB - Short-term information retention is crucial for information processing in the brain. It has long been suggested that the hippocampal CA3 region is able to support short-term information retention through persistent neural firing. Theoretical studies have shown that this persistent firing can be supported by abundant excitatory recurrent connections in CA3. However, it remains unclear whether individual cells can support persistent firing. In this study, using in vitro whole-cell patch-clamp recordings in a rat hippocampal slice preparation, we show that hippocampal CA3 pyramidal cells support persistent firing under perfusion of the cholinergic agonist carbachol (10 MUm). Furthermore, in contrast to earlier theoretical studies, this persistent firing is independent of ionotropic glutamatergic synaptic transmission and is supported by the calcium activated non-selective cationic current. Because cholinergic receptor activation is crucial for short-term memory tasks, persistent firing in individual cells may support short-term information retention in the hippocampal CA3 region. PMID- 23651162 TI - A case of nicorandil-induced unilateral corneal ulceration. AB - Nicorandil, a second-generation nitro derivative, has been reported to induce single or multiple ulcerations in many locations, including oral, anal, perianal, vulvovaginal, perivulval, penile, gastrointestinal, colic, peristomal and skin locations. Ocular locations are now highly suspected. Herein, we report the case of a 78-year-old woman who experienced corneal ulceration at second cataract surgery (right eye) while being treated with nicorandil for 3 years. Four years before, she had had an uneventful first cataract surgery (left eye). The ulcers healed within 6 weeks after simple withdrawal of nicorandil, an expected delay for this type of chemical ulcer. The substitution of nicorandil with classic nitric oxide donors has already been done without complication. Surgical intervention is unnecessary and inappropriate. Case reports of ocular side effects induced by nicorandil are rare and probably underestimated. PMID- 23651163 TI - Methotrexate: should we start using it in clinical practice? AB - Therapeutic approaches in inflammatory bowel disease have changed significantly in the past decade. Early aggressive immunosuppression has become the mainstay of therapy for patients at risk for complicated disease. Azathioprine is the most widely used immunosuppressant; however, a subgroup of patients is intolerant or refractory. Since the late 1990s, methotrexate (MTX) has become more widely used as an immunomodulator in patients with chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. Yet according to recent clinical data, methotrexate remained the second most commonly used immunosuppressive in inflammatory bowel diseases. Two landmark trials and subsequent studies provided evidence for the use of methotrexate in Crohn's disease, both for induction and maintenance of remission. The evidence is less solid in ulcerative colitis, for which results of further randomized controlled trials are pending (e.g. Meteor, Merit). A potential new indication of MTX could be combination therapy with biologicals. While this is state of the art therapy in rheumatoid arthritis, data in inflammatory bowel diseases are less clear. Some studies suggest that combination with immunosuppressants could prevent the development of anti-drug antibodies, while others suggested anti- TNF induced autoimmune disorders as a potential indication. In contrast, improved efficacy was not reported by one study (COMMIT). Limitations include frequent side effects, route of administration, pregnancy and concerns about long-term safety. This review summarizes current knowledge on the efficacy and side effects of methotrexate, and tries to reevaluate the drug in the current IBD armamentarium. PMID- 23651164 TI - Differential scanning calorimetry as a tool to investigate the transfer of anticancer drugs to biomembrane model. AB - Different anticancer drugs clinically approved by international regulatory organizations present poor water solubility and low stability after systemic injection. Their administration requires suitable carriers capable of maximizing therapeutic efficacy. Lipid and polymeric nanotherapeutics, particularly liposomes, are widely used to deliver chemotherapeutics in the clinic. The interaction between chemotherapeutics and biocompatible lipids and polymers can affect their efficacy and play a pivotal role in chemotherapy. Phospholipids are the main components of liposomes and their interactions with therapeutic agents are widely investigated in the pharmaceutical field using differential scanning calorimetry (DSC). In this work, DSC was exploited to investigate the interaction between hydrophobic chemotherapeutics, i.e. docetaxel, tamoxifen and lapatinib, with lipid vesicles. Lipid carriers are prepared using dimyristoylphosphatidylcholine (DMPC), a phosphatidylcholine derivative, showing the same physicochemical features of the main lipids in the biological membranes. DMPC was used as a biological membrane model to evaluate interaction, passage, diffusion, and adsorption of chemotherapeutics. These processes were evaluated through the variation of thermotropic parameters of the biological membrane model. DSC studies were carried out in heating and cooling mode. Results demonstrated a modification of calorimetric curves and this effect is strictly related to the molar fraction and physicochemical features of chemotherapeutics. Furthermore, the interaction between chemotherapeutics and biological membranes affects their internalization and distribution inside tumors and this process depends on gel-liquid crystal transition of phospholipids. DSC results provide suitable information about this effect and can be used as tool to predict further interaction between chemotherapeutics and biological membranes. PMID- 23651165 TI - PPAR-gamma in ulcerative colitis: a novel target for intervention. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor, originally described in adipose tissue, that controls the expression of a large number of regulatory genes in lipid metabolism and insulin sensitization. Well known by endocrinologists, thiazolidinediones (TZDs) are classical PPARgamma synthetic agonists which were currently used as insulin-sensitizing agents in the treatment of type 2 diabetes. While the clinical benefits of TZDs in treating metabolic disorders have been clearly demonstrated, new studies performed in animal models of colitis and in patients with ulcerative colitis have also revealed the key roles of PPARgamma activation in the regulation of inflammation and immune response, notably in the colon through epithelial cells. During inflammation, PPAR acts directly to negatively regulate gene expression of proinflammatory genes in a ligand-dependent manner by antagonizing the activities of other transcription factors such as members of the NF-kappaB and AP-1 families. A major mechanism that underlies the ability of PPARs to interfere with the activities of these transcription factors has been termed transrepression. PPARgamma acts by inhibiting signaldependent transcription factors that mediate inflammatory programs of gene activation. However, due to safety issues concerning particularly the greater risk of myocardial infarction, use of TZDs has been severely limited for the treatment of type 2 diabetes and/or inflammatory diseases, justifying the development of a new family of PPARgamma agonists with major transrepressive effects and without toxicity. By the demonstration that the anti-inflammatory effects of 5- aminosalicylic acid (5 ASA) in patients with ulcerative colitis were mediated by PPARgamma activation, several molecules having 5-ASA similarities have been developed and screened leading to the selection of a aminophenyl-alpha-methoxypropionic acids named GED 0507-34-Levo (GED). This compound activating PPARgamma has 100-to 150-fold higher anti-inflammatory activity than 5-ASA. This new PPAR modulator is giving promising results both in vitro and in vivo, without toxicity and is currently evaluated in a phase 2 clinical trial. The aim of this review is to present and discuss the evidence suggesting that PPARgamma targeting is of therapeutic interest in the treatment of UC. PMID- 23651166 TI - Clinical strategies for the blockade of IL-18 in inflammatory bowel diseases. AB - Interleukin 18 (IL-18) is an IL-1 super family cytokine that is involved in infection, inflammation and autoimmune diseases. Mounting evidence suggests that IL-18 exert a dual role in inflammation and homeostasis. IL-18 can act as a promoter of T cell immunities, such as type 1 and 17 helper T cell responses, and thus enhances T cell-mediated inflammation, whereas IL-18 increases the barrier function and regeneration of epithelial cells and protects the host from inflammatory stimuli. Although the functional role of IL-18 in regulation of inflammation remains controversial, accumulating evidence indicates the contribution of IL-18 to the pathogenesis of inflammatory bowel diseases (IBD). For example, levels of serum and/or mucosal IL-18 and IL-18 binding protein are elevated in the patients with IBD. Furthermore, polymorphisms in IL-18 and IL-18 related molecules, such as the IL-18 receptor and/or an IL-18 activator NLRP3, genes are found in the patients with IBD. Thus, these preclinical data imply that IL-18 can be a novel therapeutic target for the treatment of IBD. In this review, we focus on IL-18 biology and physiological roles in animal models and human IBD, to provide an outline for development of IL-18 blockade strategies. PMID- 23651167 TI - Langmuir and Langmuir-Blodgett films of hybrid amphiphiles with a polyoxometalate headgroup. AB - A hybrid was at first synthesized by a postfunctionalization of an aminomethane trisalkoxo-functionalized Anderson-type polyoxometalate (POM) encapsulated by three tetrabutylammonium ions using a 3,5-bis(tetradecyloxy)benzoic acid by amidation. Then the three TBA(+) counter cations were programmatically replaced by protons (H(+)) following a molecule-to-amphiphile conversion. In this way one hybrid and three POM-containing hybrid amphiphiles (PCHAs) were acquired by adjusting the number (n) of TBA(+) ions and number (3 - n) of H(+) ions (n = 3, 2, 1, and 0). These compounds can be spread onto a water surface to form a Langmuir monolayer film at the air-water interface. Surface pressure-molecular area measurements exhibit the TBA(+) (H(+)) number playing an important role in the forming ability and stability of Langmuir monolayer films. Also, the Langmuir Blodgett (LB) technique has been used to transfer the monolayer film onto solid supports to fabricate solid multilayer films. It was found that the PCHA with three H(+) ions had the best Langmuir film-forming ability and thus formed stable LB films with a two-dimensional ordered structure. Our findings are instructive in fabricating and using solid films of the amphiphiles with POM headgroups. PMID- 23651168 TI - Flexible, transparent, and noncytotoxic graphene electric field stimulator for effective cerebral blood volume enhancement. AB - Enhancing cerebral blood volume (CBV) of a targeted area without causing side effects is a primary strategy for treating cerebral hypoperfusion. Here, we report a new nonpharmaceutical and nonvascular surgical method to increase CBV. A flexible, transparent, and skin-like biocompatible graphene electrical field stimulator was placed directly onto the cortical brain, and a noncontact electric field was applied at a specific local blood vessel. Effective CBV increases in the blood vessels of mouse brains were directly observed from in vivo optical recordings of intrinsic signal imaging. The CBV was significantly increased in arteries of the stimulated area, but neither tissue damage nor unnecessary neuronal activation was observed. No transient hypoxia was observed. This technique provides a new method to treat cerebral blood circulation deficiencies at local vessels and can be applied to brain regeneration and rehabilitation. PMID- 23651169 TI - Nanoporous metal oxides with tunable and nanocrystalline frameworks via conversion of metal-organic frameworks. AB - Nanoporous metal oxide materials are ubiquitous in the material sciences because of their numerous potential applications in various areas, including adsorption, catalysis, energy conversion and storage, optoelectronics, and drug delivery. While synthetic strategies for the preparation of siliceous nanoporous materials are well-established, nonsiliceous metal oxide-based nanoporous materials still present challenges. Herein, we report a novel synthetic strategy that exploits a metal-organic framework (MOF)-driven, self-templated route toward nanoporous metal oxides via thermolysis under inert atmosphere. In this approach, an aliphatic ligand-based MOF is thermally converted to nanoporous metal oxides with highly nanocrystalline frameworks, in which aliphatic ligands act as the self templates that are afterward evaporated to generate nanopores. We demonstrate this concept with hierarchically nanoporous magnesia (MgO) and ceria (CeO2), which have potential applicability for adsorption, catalysis, and energy storage. The pore size of these nanoporous metal oxides can be readily tuned by simple control of experimental parameters. Significantly, nanoporous MgO exhibits exceptional CO2 adsorption capacity (9.2 wt %) under conditions mimicking flue gas. This MOF-driven strategy can be expanded to other nanoporous monometallic and multimetallic oxides with a multitude of potential applications. PMID- 23651170 TI - Is daily headache related to asthma? Results from a population-based survey. AB - OBJECTIVE: Despite the high worldwide prevalence of asthma and headache, little is known about the association between these conditions. The objective of our study was to evaluate the association between asthma and daily headache in a representative sample of the general population of South Korea. METHODS: We retrospectively analyzed 7984 individuals included in the Second Korean National Health and Nutrition Examination Survey (KNHANES II), a prospectively administered survey performed in 2001 by a government organization within the Ministry of Health and Welfare. After adjustment of risk factors for daily headache, multivariate logistic regression analysis was performed to evaluate the association between asthma and daily headache. RESULTS: Of 7984 individuals, 69 (0.9%) had daily headache and 429 (5.4%) had asthma symptoms. Daily headache was significantly more prevalent in subjects with asthma symptoms (14/429, 3.3%) than in those without (55/7555, 0.7%; p < 0.001). Of the 4833 nonsmokers, 46 (1.0%) had daily headache and 287 (5.9%) had asthma symptoms, with daily headache being significantly more prevalent in subjects with asthma symptoms (11/231, 4.8%) than in those without (35/4602, 0.8%; p < 0.001). Multivariate logistic regression showed that the odds ratios for daily headache were 2.3 (95% CI: 1.21-4.33, p = 0.01) in all individuals with asthma symptoms and 3.4 (95% CI: 1.65-7.12, p = 0.001) in nonsmokers with asthma symptoms. CONCLUSION: Individuals with asthma symptoms are at higher risk of daily headache than those without the symptoms, suggesting a link between these conditions. PMID- 23651172 TI - Human T-lymphotropic virus type 1 non-structural proteins: Requirements for latent infection. AB - It has been more than 30 years since the discovery of human T-lymphotropic virus type 1 (HTLV-1), the first human retrovirus identified. Human T-lymphotropic virus type 1 infects 15-20 million people worldwide causing two major diseases: adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis. Human T-lymphotropic virus type 1 establishes several decades of latent infection, during which viral-host interaction determines disease segregation. This review highlights non-structural proteins that are encoded on the viral genome and manage latent infection. Latent infection is a key in HTLV pathology, so that effective inhibition of these proteins might lead to successful disease management. PMID- 23651171 TI - Measurement invariance of DSM-IV alcohol, marijuana and cocaine dependence between community-sampled and clinically overselected studies. AB - AIMS: To examine whether DSM-IV symptoms of substance dependence are psychometrically equivalent between existing community-sampled and clinically overselected studies. PARTICIPANTS: A total of 2476 adult twins born in Minnesota and 4121 unrelated adult participants from a case-control study of alcohol dependence. MEASUREMENTS: Life-time DSM-IV alcohol, marijuana and cocaine dependence symptoms and ever use of each substance. DESIGN: We fitted a hierarchical model to the data, in which ever use and dependence symptoms for each substance were indicators of alcohol, marijuana or cocaine dependence which were, in turn, indicators of a multi-substance dependence factor. We then tested the model for measurement invariance across participant groups, defined by study source and participant sex. FINDINGS: The hierarchical model fitted well among males and females within each sample [comparative fit index (CFI) > 0.96, Tucker Lewis index (TLI) > 0.95 and root mean square error of approximation (RMSEA) < 0.04 for all], and a multi-group model demonstrated that model parameters were equivalent across sample- and sex-defined groups (DeltaCFI = 0.002 between constrained and unconstrained models). Differences between groups in symptom endorsement rates could be expressed solely as mean differences in the multi substance dependence factor. CONCLUSIONS: Life-time substance dependence symptoms fitted a dimensional model well. Although clinically overselected participants endorsed more dependence symptoms, on average, than community-sampled participants, the pattern of symptom endorsement was similar across groups. From a measurement perspective, DSM-IV criteria are equally appropriate for describing substance dependence across different sampling methods. PMID- 23651173 TI - A combination of two electrophoretical approaches for detailed proteome-based characterization of SCLC subtypes. AB - CONTEXT: Small cell lung cancers (SCLC) are heterogeneous and tumours differ in growth characteristics and treatment resistance. OBJECTIVE: To get insight into the underlying protein profiles responsible for this heterogeneity, two subtypes of SCLC cells mutually differing in chemo resistance properties and growth characteristics are analysed. MATERIALS AND METHODS: Two different electrophoresis approaches in combination with mass spectrometry were used to detect differences between the SCLC cell lines GLC1 and GLC1M13: IEF/SDS-PAGE as well as cetyltrimethylammonium bromide (CTAB)-SDS-PAGE. RESULTS: Altogether 60 non redundant differentially expressed proteins were found of which 5 were verified by Western Blot analysis. DISCUSSION: Most of these proteins identified are involved in processes of tumour progression. Therefore, these proteins are interesting candidates for further functional analysis. CONCLUSION: Additional CTAB-SDS page is a complementary method to IEF-SDS page revealing a complete new subset of proteins differentially expressed between GLC1 and GLC1 M13 cells SCLC subtypes. PMID- 23651174 TI - Epidemiological profiles of patients with chronic migraine and chronic tension type headache. AB - BACKGROUND: We evaluated risk factors associated with chronic headache (CH) such as age, gender, smoking, frequent drinking of alcoholic beverages (drinking), obesity, education and frequent intake of acute pain drugs to test their usefulness in clinical differentiation between chronic migraine (CM) and chronic tension-type headache (CTTH). METHODS: We used baseline data from the population based German Headache Consortium Study including 9,944 participants aged 18-65 years, screened 2003-2005, using validated questionnaires. CM and CTTH were defined according to IHS criteria. Multinominal logistic regression analyses were used to investigate the association of CM or CTTH with risk factors by estimating odds ratios (OR) and 95% confidence intervals (95%CI). RESULTS: The prevalence of CH was 2.6% (N = 255, mean age 46 +/- 14.1 years, 65.1% women), CM 1.1% (N = 108, 45 +/- 12.9 years, 73.1%), CTTH 0.5% (N = 50, 49 +/- 13.9 years, 48.0%). Participants with CM compared to CTTH were more likely to be female (OR: 2.34, 95%CI: 1.00-5.49) and less likely to drink alcohol (0.31, 0.09-1.04). By trend they seemed more likely to smoke (1.81, 0.76-4.34), to be obese (1.85, 0.54 6.27), to report frequent intake of acute pain drugs (1.68, 0.73-3.88) and less likely to be low educated (0.72, 0.27-1.97). CONCLUSIONS: We concluded that the careful assessment of different risk factors might aid in the clinical differentiation between CM and CTTH. PMID- 23651175 TI - How does the functional mobility scale relate to capacity-based measures of walking ability in children and youth with cerebral palsy? AB - This study examined the relationship between walking performance rated on the Functional Mobility Scale (FMS) and measures of walking capacity in children with cerebral palsy (CP). A total of 143 participants with spastic CP (GMFCS levels I to III) were rated on the FMS and had assessment of self-selected walking speed (WS), fast 1 minute walk test (1MWT) and six minute walk test (6MWT). For each FMS distance, children rated 6 had significantly better 6MWT than children scored 5; children rated FMS 2, 3, or 4 had lower walking capacity measures but were not clearly distinguishable from each other. The 6MWT was an independent predictor of variation in FMS score, accounting for 20% to 27% of the variance across the three FMS distances. While walking capacity impacts on community mobility in children with CP much of the variance remains unexplained, suggesting that other factors play an important role. PMID- 23651176 TI - Renal diseases in haemophilic patients: pathogenesis and clinical management. AB - Haemophilia A and B are genetic X-linked bleeding disorders, caused by mutations in genes encoding factors VIII and IX, respectively. Clinical manifestations of haemophilia are spontaneous haemorrhage or acute bleeding caused by minor trauma, resulting in severe functional consequences that can culminate in a debilitating arthropathy. Life expectancy and quality of life of patients with haemophilia have dramatically improved over the last years, mainly for new therapeutic options and the awareness to the risk of HCV and HIV infections. Different clinical problems arise from this important change in history of patients with haemophilia. In particular, ageing-related diseases, such as diabetes, hypertension and cancer, and chronic viral infections are emerging as new challenges in this patient population. Among the different types of chronic illnesses, renal diseases are of special interest as they involve some difficult management issues. In fact, decisions regarding adequate preventive strategies and viral infection treatment, the choice of the dialytic modality, placement of vascular access and prescription of dialytic treatments are particularly complicated, because only few data are available. In this review, we discuss the pathogenesis of renal damage in patients with haemophilia, especially in those with blood-transmitted viral infections, and the major issues about the management of renal diseases, including problems related to dialytic treatment and kidney transplantation, providing practical algorithms to guide the clinical decision-making process. PMID- 23651177 TI - Inflammatory marker profiles in an avian experimental model of aspergillosis. AB - Aspergillosis is a common infection in avian species, but can be a challenge to diagnose. Inflammatory markers have been successfully used in mammals for diagnostic and monitoring purposes of various diseases. The aim of this study was to identify inflammatory markers that could aid in the diagnosis of aspergillosis in an avian species. Five-week-old Japanese quail were infected experimentally with Aspergillus fumigatus, and inflammatory markers were measured in plasma. In addition, lung tissues were cultured to quantify the fungal burden. Infected quail had higher plasma levels of ceruloplasmin, unsaturated iron-binding capacity (UIBC), iron, and total iron-binding capacity (TIBC), and lower levels of haptoglobin, compared with uninfected controls. There were positive linear relationships between A. fumigatus colony-forming units cultured from the lungs of infected quail, and levels of ceruloplasmin, UIBC, and TIBC. Quail that died prior to the end of the experiment (day 10 post-infection) had higher ceruloplasmin, UIBC, and TIBC, and lower haptoglobin levels than infected quail that survived. The inflammatory marker profile in quail infected with aspergillosis in this study differs from that seen in mammals, and from the pattern of inflammatory markers seen in birds with bacterial infections. Inflammatory markers could prove useful for diagnosing aspergillosis in birds, and for monitoring disease progression in infected avian species. PMID- 23651178 TI - Species of Candida as a component of the nasal microbiota of healthy horses. AB - Respiratory infections are a common problem among equines and occur with variable rates of morbidity and mortality. Although some fungal species are considered primary agents of respiratory tract infections in several mammals, their relevance in respiratory diseases of equines is frequently neglected. In the present study, we performed an active search for Candida spp. in the nasal cavity of horses. The presence of Candida spp. was investigated through the use of nasal swabs that were streaked on culture media. These yeasts were identified through physiological testing and their in vitro antifungal susceptibility were also characterized. The analysis of the material from the nasal cavity of 97 randomly chosen horses resulted in the isolation of Candida spp. from 35 animals (36.08%), out of which 18 (32.14%) were C. famata, 14 (25%) C. parapsilosis, 12 (21.42%) Meyerozyma guilliermondii (C. guilliermondii), 11 (19.64%) C. tropicalis and 1 (1.78%) Wickerhamomyces anomalus (C. pelliculosa). The minimum inhibitory concentration (MIC) values ranged from 0.03125-1 MUg/ml for amphotericin B; and from 0.03125-> 16 MUg/ml and 0.125 to > 64 MUg/ml for itraconazole and fluconazole, respectively. Resistance to fluconazole and itraconazole was observed among C. tropicalis (n = 3) and C. guilliermondii (n = 1). The data show a predominance of non-C. albicans Candida species in the nasal microbiota of healthy equines, including antifungal resistant isolates, reiterating the importance of monitoring fungal pathogens in these animals. PMID- 23651179 TI - Candida cerebral abscesses: a case report and review of the literature. AB - Cerebral abscess caused by Candida spp. is a rare disease, with a nonspecific presentation, little data on treatment, and generally poor outcomes. We present a case of this type of Candida infection in a 57-year-old man with a history of uncontrolled diabetes mellitus and intravenous drug abuse, and review the literature on this disease. Our patient had a good treatment outcome with liposomal amphotericin B and flucytosine, followed by oral fluconazole. Comorbidities include prior antibiotic use (52%), prior surgery (28%), malignancy (28%), stem cell or solid organ transplant (20%), prior corticosteroid use (16%), central venous catheter (CVC) insertion (10%), and burns (7%). Diagnosis requires a high index of suspicion, as clinical presentations and laboratory data can be nonspecific and difficult to differentiate from bacterial cerebral abscesses. In reviewed cases, 55% of blood cultures and 23% of cerebrospinal fluid (CSF) cultures were positive for Candida spp. and outcomes were poor, as the mortality rate of the non-autopsy cases reviewed was 69%. PMID- 23651180 TI - Modified culture method detects a high diversity of fungal species in cystic fibrosis patients. AB - Cystic fibrosis (CF) is one of the most common genetic lung diseases worldwide. The production of sticky viscous mucus leads to enhanced bacterial colonization and infection, but yeasts and filamentous fungi are also found abundantly in the mucus of patients suffering from CF. The role of fungi in the airways of CF patients is still not understood completely. Furthermore, recent investigations have shown that the spectrum of fungi isolated from the airways of CF patients depends strongly on the methods used. In this study, different mycological culture methods were compared: culture with a native inoculum, culture with homogenization of CF sputum, and culture after homogenization and serial dilutions of CF sputum. Altogether, 934 sputum samples from 113 patients were examined from July 2009 through December 2011. A total of 1,744 fungal isolates was recovered; 20 different yeasts and 14 filamentous fungal species were identified. Candida albicans, C. dubliniensis, and C. parapsilosis were the most common species of yeast. For the filamentous fungi, Aspergillus fumigatus was the most common, followed by Scedosporium apiospermum/Pseudallescheria boydii group and A. terreus. Many fungal, species such as Exophiala dermatitidis, Rasamsonia (Geosmithia) argillacea, and others, were isolated only from homogenized sputum samples. The longitudinal data also show that fungal colonization of CF patients is quite stable, even when treated with itraconazole. In conclusion, we recommend homogenizing CF sputa with a mucolyticum, to prepare serial dilutions, and to use appropriate fungal culture media with added antibiotics. PMID- 23651181 TI - Effects of seasonality and a diet of brassicas on the shedding of Escherichia coli O157 in sheep. AB - Sheep flocks were tested for Escherichia coli O157 from pooled fecal samples while they grazed on pasture in winter, brassicas in spring, and on pasture during the summer. The winter pasture study reported an average individual prevalence of 3.1% (95% confidence interval [CI]: 0.6-5.6%) and an average farm level prevalence of 10.4% (95% CI: 2.1-18.8%) over the 3-year study period. The spring brassica study reported a prevalence of 0% and the summer pasture study had an individual prevalence of 6.3% (95% CI: 2.1-12.1%) and a farm prevalence of 36.8% (95% CI: 15.8-57.8%). Analysis showed significant differences between the shedding of E. coli O157 in sheep grazing on brassicas in spring when compared to sheep grazing on pasture in the summer (p<0.01) and in winter (p=0.044; odds ratio [OR]=0.106). Furthermore, sheep excreted a lower prevalence of E. coli O157 in winter while grazing on pasture (p=0.017; OR=0.199). E. coli O157 isolates were characterized using polymerase chain reaction for the presence of known virulence factors; all carried the eae and stx2 gene and 10/11 positive flocks possessed the stx2c gene, suggesting that sheep are a potential source of human infection. PMID- 23651182 TI - Drug-induced lupus and autoimmune hepatitis secondary to infliximab for psoriasis. AB - We describe a case of previously unreported autoimmune hepatitis and lupus-like syndrome induced by infliximab treatment for chronic plaque psoriasis. The condition resolved after withdrawal of infliximab, with the liver injury having been reversed and minimal periportal fibrosis. In a two-part discussion we review the current literature on the pharmacology of infliximab and provide recommendations for management of infliximab side effects. PMID- 23651183 TI - The impact of workplace relationships on engagement, well-being, commitment and turnover for nurses in Australia and the USA. AB - AIMS: We examined the impact of workplace relationships (perceived organizational support, supervisor-nurse relationships and teamwork) on the engagement, well being, organizational commitment and turnover intentions of nurses working in Australian and USA hospitals. BACKGROUND: In a global context of nurse shortages, knowledge about factors impacting nurse retention is urgently sought. We postulated, using the Social Exchange Theory, that nurses' turnover intentions would be affected by several factors and especially their relationships at work. DESIGN: Based on the literature review, data were collected via a self-report survey to test the hypotheses. METHODS: A self-report survey was used to gather data in 2010-2012 from 510 randomly chosen nurses from Australian hospitals and 718 nurses from US hospitals. A multi-group structural equation modelling analysis identified significant paths and compared the impact between countries. RESULTS: The findings indicate that this model was more effective in predicting the correlations between variables for nurses in Australia compared with the USA. Most paths predicted were confirmed for Australia, except for the impact of teamwork on organizational commitment and turnover, plus the impact of engagement on turnover. In contrast, none of the paths related to supervisor-subordinate relationships was significant for the USA; neither were the paths from teamwork to organizational commitment or turnover. CONCLUSION: Our findings suggest that well-being is a predictor of turnover intentions, meaning that healthcare managers need to consider nurses' well-being in everyday decision-making, especially in the cost-cutting paradigm that pervades healthcare provision in nearly every country. This is important because nurses are in short supply and this situation will continue to worsen, because many countries have an ageing population. PMID- 23651184 TI - One-dimensional porphyrin nanoassemblies assisted via graphene oxide: sheetlike functional surfactant and enhanced photocatalytic behaviors. AB - Surfactant-assisted self-assembly (SAS) has received much attention for supramolecular nanoassemblies, due to its simplicity and easiness in realizing a controllable assembly. However, in most of the existing SAS protocols, the employed surfactants work only as a regulator for a controllable assembly but not as active species for function improvement. In this paper, we report that a porphyrin, zinc 5,10,15,20-tetra(4-pyridyl)-21H,23H-porphine (ZnTPyP), could be assembled to form one-dimensional (1D) supramolecular nanostructures via a SAS method, wherein graphene oxide (GO) plays a fascinating role of sheetlike surfactant. We show that, when a chloroform or tetrahydrofuran solution of ZnTPyP is injected into an aqueous dispersion of GO, 1D supramolecular nanoassemblies of ZnTPyP with well-defined internal structures could be easily formulated in a controllable manner. Our experimental facts disclose that the complexation of ZnTPyP with the two-dimensional GO nanosheets plays an important role in this new type of SAS. More interestingly, compared with the 1D ZnTPyP nanoassemblies formulated via a conventional SAS, wherein cetyltrimethylammonium bromide is used as surfactant, those constructed via our GO-assisted SAS display distinctly enhanced photocatalytic activity for the photodegradation of rhodamine B under visible-light irradiation. Our new findings suggest that GO could work not only as an emergent sheetlike surfactant for SAS in terms of supramolecular nanoassembly but also as functional components during the performance of the assembled nanostructures. PMID- 23651185 TI - Balance self-efficacy in relation to balance and activities of daily living in community residents with stroke. AB - PURPOSE: This study attempts to determine a causal relationship among balance self-efficacy, balance, and activities of daily living (ADL) in community residents with stroke. METHOD: A cross-sectional descriptive correlation study was conducted with a convenience sample comprising 105 stroke patients living in the community. Data were collected using self-reporting questionnaires, including the Activities-specific Balance Confidence (ABC) scale and the Korean version of the Modified Barthel Index (K-MBI). The Berg Balance Scale was used to measure balance ability. A path model was tested to investigate the causal relations between variables, using the AMOS 17.0 statistical program to analyze the models, to obtain maximum-likelihood estimates of model parameters and to provide goodness-of-fit indices. RESULTS: The proposed path model showed good fit indices. The direct path was significant between balance self-efficacy and balance (0.583), between balance and ADL (0.455). The indirect path was significant between balance self-efficacy and ADL (0.015). CONCLUSION: Our results support the link between balance efficacy, balance, and ADL in stroke patients. The proposed conceptual model was a good fit for the data and provided a plausible framework for understanding the relationship among these factors in stroke patients. Our model may also guide the intervention of functional rehabilitation for stroke patients. IMPLICATIONS FOR REHABILITATION: Balance self efficacy, a psychological factor, should not be overlooked in attempting to improve functional outcomes in stroke survivors because balance self-efficacy impact ADL through the mediation of balance ability It would be appropriate to assess the balance efficacy as well as balance ability for maximizing performing tasks such as ADLs for individual with stroke Interventions that use a combination of balance training and balance self-efficacy enhancement could be the most effective for improving ADL in the case of community-dwelling stroke patients. PMID- 23651186 TI - Cancer immunoediting: antigens, mechanisms, and implications to cancer immunotherapy. AB - Accumulated data from animal models and human cancer patients strongly support the concept that the immune system can identify and control nascent tumor cells in a process called cancer immunosurveillance. In addition, the immune system can also promote tumor progression through chronic inflammation, immunoselection of poorly immunogenic variants, and suppressing antitumor immunity. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. The current framework of cancer immunoediting is a dynamic process comprised of three distinct phases: elimination, equilibrium, and escape. Recently, we demonstrated that immunoselection by CD8(+) T cells of tumor variants lacking strong tumor-specific antigens represents one mechanism by which cancer cells escape tumor immunity and points toward the future of personalized cancer therapy. PMID- 23651187 TI - Cell-extrinsic effects of the tumor unfolded protein response on myeloid cells and T cells. AB - Tumor-infiltrating myeloid cells, macrophages, and dendritic cells (DCs) are key regulators of tumor immunity and growth. The origin of tumor-derived signals that instruct myeloid cells in the tumor microenvironment is only partially understood. The endoplasmic reticulum (ER) stress response, or unfolded protein response (UPR), provides survival advantages to tumor growth. However, the cell extrinsic effects of the tumor UPR on immune cells have not been explored. Our laboratory recently showed that the tumor UPR can be transmitted by yet unidentified factor(s) to myeloid cells, macrophages, and DCs. ER stress transmission to receiver myeloid cells upregulates the production of proinflammatory cytokines, and contextually of arginase I, leading to a proinflammatory/suppressive phenotype. DCs imprinted by tumor-borne ER stress transmissible factor(s) have decreased cross-presentation of antigen and defective cross-priming, causing T cell activation without proliferation. When DCs imprinted by transmissible ER stress are admixed with tumor cells and injected in vivo, facilitation of tumor growth is observed. Thus, tumor-borne ER stress plays a hitherto unappreciated role at the tumor/immune interface that ultimately facilitates tumor growth. PMID- 23651188 TI - Immunotherapy in preneoplastic disease: targeting early procarcinogenic inflammatory changes that lead to immune suppression and tumor tolerance. AB - Recent advances in immunotherapy have demonstrated that single agent vaccines can be effective when given as primary prevention before exposure to the causative agent, and partially effective in some patients with existing cancer. However, as tumors develop and progress, tumor-induced immune suppression and tolerance present the greatest barrier to therapeutic success. Preneoplastic disease represents an important opportunity to intervene with tumor antigen-targeted vaccines before these mechanisms of immune evasion outpace efforts by the immune system to destroy precancerous cells. However, as we discuss in this review, emerging evidence suggests that procarcinogenic inflammatory changes occur early in cancer development, in both patients and mouse models of cancer progression. Defining early inhibitory signals within tumor microenvironments will yield insights that can eventually be used in the clinic to target these events and deliver treatments that can be used in addition to cancer vaccines to prevent premalignant and early invasive cancers. PMID- 23651190 TI - Human dendritic cells subsets as targets and vectors for therapy. AB - The skin immune system includes a complex network of dendritic cells (DCs). In addition to generating cellular and humoral immunity against pathogens, skin DCs are involved in tolerogenic mechanisms that maintain immune homeostasis and in pathogenic chronic inflammation in which immune responses are unrestrained. Harnessing DC function by directly targeting DC-derived molecules or by selectively modulating DC subsets is a novel strategy for ameliorating inflammatory diseases. In this short review, we discuss recent advances in understanding the functional specialization of skin DCs and the potential implication for future DC-based therapeutic strategies. PMID- 23651189 TI - Integration of epidemiology, immunobiology, and translational research for brain tumors. AB - We recently identified a pivotal role for the host type I interferon (IFN) pathway in immunosurveillance against de novo mouse glioma development, especially through the regulation of immature myeloid cells (IMCs) in the glioma microenvironment. The present paper summarizes our published work in a number of areas. We have identified single-nucleotide polymorphisms (SNPs) in human IFN genes that dictate altered prognosis of patients with glioma. One of these SNPs (rs12553612) is located in the promoter of IFNA8 and influences its activity. Conversely, recent epidemiologic data show that chronic use of nonsteroidal anti inflammatory drugs lowers the risk of glioma. We translated these findings back to our de novo glioma model and found that cyclooxygenase-2 inhibition enhances antiglioma immunosurveillance by reducing glioma-associated IMCs. Taken together, these findings suggest that alterations in myeloid cell function condition the brain for glioma development. Finally, in preliminary work, we have begun applying novel immunotherapeutic approaches to patients with low-grade glioma with the aim of preventing malignant transformation. Future research will hopefully better integrate epidemiological, immunobiological, and translational techniques to develop novel, preventive approaches for malignant gliomas. PMID- 23651191 TI - Dendritic cell immunotherapy. AB - The U.S. Food and Drug Administration's approval of the first cell-based immunotherapy has rejuvenated interest in the field. Early clinical trials have established the ability of dendritic cell (DC) immunotherapy to exploit a patient's own immune system to induce antitumor immune responses. However, suboptimal conditions for generating potent immunostimulatory DCs, in addition to the suppression mediated by the tumor microenvironment, have contributed to limited clinical success in vivo. Therefore, combining DC vaccines with new approaches that enhance immunogenicity and overcome the regulatory mechanisms underlying peripheral tolerance may be key to achieving effective, durable, antitumor immune responses that translate to better clinical outcomes. PMID- 23651192 TI - Molecular programming of steady-state dendritic cells: impact on autoimmunity and tumor immune surveillance. AB - Dendritic cells are master regulators of immunity. Immature dendritic cells are essential for maintaining self-tolerance, while mature dendritic cells initiate a variety of specialized immune responses. Dendritic cell quiescence is often viewed as a default state that requires exogenous stimuli to induce maturation. However, recent studies have identified dendritic cell quiescence factors that actively program dendritic cells to an immature state. In the absence of these factors, dendritic cells spontaneously become immunogenic and can induce autoimmune responses. Herein we discuss two such factors, NF-kappaB1 and A20, that preserve dendritic cell immaturity through their regulation of NF-kappaB signaling. Loss of either of these factors increases dendritic cell immunogenicity, suggesting that they may be important targets for enhancing dendritic cell-based cancer immunotherapies. Alternatively, defects in molecules critical for maintaining steady-state DCs may provide novel biomarkers that identify patients who have enhanced natural antitumor immunity or that correlate with better responses to various immunotherapies. PMID- 23651193 TI - Preventing cancer by targeting abnormally expressed self-antigens: MUC1 vaccines for prevention of epithelial adenocarcinomas. AB - Prophylactic vaccines based on tumor-associated antigens (TAAs) have elicited concerns due to their potential toxicity. Because TAAs are considered self antigens, the prediction is that such vaccines will induce autoimmunity. While this has been observed in melanoma, where an antitumor immune response leads to vitiligo, autoimmunity has almost never been seen following vaccination with numerous other TAAs. We hypothesized that antigen choice determines outcome and have been working to identify TAAs whose expression differs between normal and tumor tissue, and thus could elicit antitumor immunity without autoimmunity. Studies on the epithelial TAA MUC1 have revealed that, compared to MUC1 on normal cells, tumors, premalignant lesions, and noncancerous pathologies affecting epithelial cells express abnormal MUC1, which is not a self-antigen but rather an abnormal disease-associated antigen (DAA). This distinction, which can be made for many known TAAs, has broad implications for the design and acceptance of preventative cancer vaccines. PMID- 23651194 TI - Immunological control of cell cycle aberrations for the avoidance of oncogenesis: the case of tetraploidy. AB - Tetraploid cells--cells that contain twice the normal amount of DNA--are more prone to neoplastic transformation than their normal, diploid counterparts since they are genomically unstable and frequently undergo asymmetric, multipolar cell divisions. Similar to many other genomic aberrations, tetraploidization is normally avoided by multiple, nonredundant cell-intrinsic mechanisms that are tied to cell cycle checkpoints. Unexpectedly, tetraploidization is also under the control of a cell-extrinsic mechanism determined by the immune system. Indeed, oncogene- or carcinogen-induced cancers developing in immunodeficient mice contain cells with a higher DNA content than similar tumors growing in immunocompetent hosts. Moreover, cancer cell lines that have been rendered tetraploid in vitro grow normally in immunodeficient mice, yet almost fail to generate tumors in immunocompetent animals. One of the mechanisms whereby the immune system recognizes tetraploid cells originates from tetraploidy causing an endoplasmic reticulum (ER) stress response that culminates in the exposure of the ER protein calreticulin on the cell surface. Hence, tetraploidy exemplifies a potentially oncogenic alteration that is repressed by a combination of cell autonomous mechanisms and immunosurveillance. Oncogenesis and tumor progression require the simultaneous failure of both such control systems. PMID- 23651195 TI - Ongoing adaptive immune responses in the microenvironment of melanoma metastases. AB - A large body of evidence supports the idea that the tumor environment is immunosuppressive, notably for T lymphocytes. Yet, in some tumor types, the presence of tumor-infiltrating T cells has favorable prognostic value. In order to better understand the functional value of T cells in human tumors, we focused on cutaneous metastases of melanoma and observed that some of them host ectopic lymphoid structures in which B cell, and possibly T cell, responses take place. This observation is discussed in the context of current views on immunosuppression in tumors. PMID- 23651196 TI - Main features of human T helper 17 cells. AB - In addition to T helper type 1 (Th1) and Th2 cells, Th17 cells are a third arm of effector CD4(+) T cells. Human Th17 cells express RORC and CD161 and originate from RORC-expressing CD161(+) precursors, which migrate to lymphoid tissue and differentiate into mature Th17 cells in response to interleukin (IL)-1beta and IL 23. Human Th17 cells are rare in inflammed tissues for two reasons: (1) Th17 cells do not produce IL-2 and, therefore, do not proliferate in response to TCR signaling, mainly because of RORC-dependent IL-4I1-mediated mechanisms that interfere with IL-2 gene activation; and (2) Th17 cell shift to a Th1 phenotype in the presence of IL-12; such Th17-derived Th1 cells are considered to be nonclassical Th1 cells and can be distinguished from classical Th1 cells. The possible role of Th17 cells in human tumors is still unclear and even controversial. PMID- 23651197 TI - In silico modeling of cancer cell dissemination and metastasis. AB - Metastasis is the main cause of cancer-related death. It is surprising then that the exact nature of metastasis-the process by which cancer cells leave the primary tumor to reach distant organs, and resume proliferation-is not fully understood. Moreover, the different conditions under which the immune system can either promote or suppress metastasis are only now beginning to be uncovered. In recent years, our understanding of metastasis as a genocentric, cell-autonomous process has shifted toward a systemic model in which interactions between cancer cells and their surrounding microenvironments lead to dissemination and metastasis. In silico modeling of the various steps involved in metastasis can help provide an understanding of how tumor properties emerge from the complex interplays between tumor cells and their microenvironment. In silico models can also be useful in identifying the selective forces that favor the outcomes of cancer cells with metastatic potential. PMID- 23651198 TI - Common pathways to tumor rejection. AB - The control of tumor growth by the host's immunosurveillance is centered on the activation of interferon (IFN) pathways. In particular, direct study of tumors by various groups has uncovered an IFN-gamma-related signature whose presence is consistently associated with better prognosis, predisposition to respond to immunotherapy, and, in its extreme manifestation, the acute phases of tumor rejection. Together, and related to the IFN-gamma-associated signature, a cluster of genes are coordinately expressed that we refer to as the immunologic constant of rejection (ICR). Activation of ICR components is observed in all forms of immune-mediated, tissue-specific destruction, including autoimmunity, allograft rejection, graft-versus-host disease, and killing of affected cells during the acute phases of infection that leads to clearance of pathogens. Thus, tumor rejection is a facet of a general and conserved mechanism that favors (tumor rejection, clearance of pathogen) or encumbers (graft rejection, autoimmunity) the organism. Here, we summarize progress in the understanding of its genesis, outline the difficulties, and propose a strategy for understanding the causes of tumor rejection. PMID- 23651199 TI - Cancer-induced immunosuppressive cascades and their reversal by molecular targeted therapy. AB - Immunological status in tumor tissues varies among patients. Infiltration of memory-type CD8(+) T cells into tumors correlates with prognosis of patients with various cancers. However, the mechanism of the differential CD8(+) T cell infiltration has not been well investigated. In general, tumor-associated microenvironments, including tumor and sentinel lymph nodes, are under immunosuppressive conditions such that the immune system is not able to eliminate cancer cells without immune-activating interventions. Constitutive activation of various signaling pathways in human cancer cells triggers multiple immunosuppressive cascades that involve various cytokines, chemokines, and immunosuppressive cells. Signaling pathway inhibitors could inhibit these immunosuppressive cascades by acting on either cancer or immune cells, or both. In addition, common signaling mechanisms are often utilized for multiple hallmarks of cancer (e.g., cell proliferation/survival, invasion/metastasis, and immunosuppression). Therefore, targeting these common signaling pathways may be an attractive strategy for cancer therapy including immunotherapy. PMID- 23651200 TI - Introduction to The Renaissance of Cancer Immunotherapy. PMID- 23651201 TI - 'Just talking about it opens your heart': meaning-making among Black African migrants and refugees living with HIV. AB - Meaning-making has emerged as a core construct in addressing trauma, loss or crisis. This paper considers how diasporic Black Africans living with HIV, who come from interdependent collectivist cultures where the norm is one of implicit support, extend their meaning-making strategies when faced with a diagnosis of HIV. In this qualitative study, 13 Black African migrants and refugees living with HIV in New Zealand were interviewed and the transcripts analysed. After their diagnosis, participants began a journey of reconceptualising situational and global meaning. They extended their meaning-making strategies to include a community of like others to gain explicit support. Caregivers in host countries must understand the meaning-making processes of HIV-positive Black African migrants in order to provide competent services that lead to good social and health outcomes. All healthcare and social services workers should regularly assess Black African migrants and refugees living with HIV for positive social connectedness as well as medication adherence and more specific health concerns. PMID- 23651203 TI - Evolutionary synthetic biology. AB - Signaling networks process vast amounts of environmental information to generate specific cellular responses. As cellular environments change, signaling networks adapt accordingly. Here, I will discuss how the integration of synthetic biology and directed evolution approaches is shedding light on the molecular mechanisms that guide the evolution of signaling networks. In particular, I will review studies that demonstrate how different types of mutations, from the replacement of individual amino acids to the shuffling of modular domains, lead to markedly different evolutionary trajectories and consequently to diverse network rewiring. Moreover, I will argue that intrinsic evolutionary properties of signaling proteins, such as the robustness of wild type functions, the promiscuous nature of evolutionary intermediates, and the modular decoupling between binding and catalysis, play important roles in the evolution of signaling networks. Finally, I will argue that rapid advances in our ability to synthesize DNA will radically alter how we study signaling network evolution at the genome-wide level. PMID- 23651204 TI - Engineered networks of synthetic and natural proteins to control cell migration. AB - Mammalian cells reprogrammed with engineered transgenes have the potential to be useful therapeutic platforms because they can support large genetic networks, can be taken from a host or patient, and perform useful functions such as migration and secretion. Successful engineering of mammalian cells will require the development of modules that can perform well-defined, reliable functions, such as directed cell migration toward a chemical or physical signal. One inherently modular cellular pathway is the Ca(2+) signaling pathway: protein modules that mobilize and respond to Ca(2+) are combined across cell types to create complexity. We have designed a chimera of Rac1, a GTPase that controls cell morphology and migration, and calmodulin (CaM), a Ca(2+)-responsive protein, to control cell migration. The Rac1-CaM chimera (named RACer) controlled lamellipodia growth in response to Ca(2+). RACer was combined with LOVS1K (a previously engineered light-sensitive Ca(2+)-mobilizing module) and cytokine receptors to create protein networks where blue light and growth factors regulated cell morphology and, thereby, cell migration. To show the generalizability of our design, we created a Cdc42-CaM chimera that controls filopodia growth in response to Ca(2+). The insights that have been gained into Ca(2+) signaling and cell migration will allow future work to combine engineered protein systems to enable reprogrammed cell sensing of relevant therapeutic targets in vivo. PMID- 23651205 TI - Landscape topography determines global stability and robustness of a metabolic network. AB - Metabolic networks have gained broad attention in recent years as a result of their important roles in biological systems. However, how to quantify the global stability of the metabolic networks is still challenging. We develop a probabilistic landscape approach to investigate the global natures of the metabolic system under external fluctuations. As an example, we choose a model of the carbohydrate metabolism and the anaplerotic synthesis of oxalacetate in Aspergillus niger under conditions of citric acid accumulation to explore landscape topography. The landscape has a funnel shape, which guarantees the robustness of system under fluctuations and perturbations. Robustness ratio (RR), defined as the ratio of gap between lowest potential and average potential versus roughness measured by the dispersion or square root of variations of potentials, can be used to quantitatively evaluate the global stability of metabolic networks, and the larger the RR value, the more stable the system. Results of the entropy production rate imply that nature might evolve such that the network is robust against perturbations from environment or network wirings and performs specific biological functions with less dissipation cost. We also carried out a sensitivity analysis of parameters and uncovered some key network structure factors such as kinetic rates or wirings connecting the protein species nodes, which influence the global natures of the system. We found there is a strong correlation between the landscape topography and the input-output response. The more stable and robust the metabolic network is, the sharper the response is. PMID- 23651206 TI - A basis set of de novo coiled-coil peptide oligomers for rational protein design and synthetic biology. AB - Protein engineering, chemical biology, and synthetic biology would benefit from toolkits of peptide and protein components that could be exchanged reliably between systems while maintaining their structural and functional integrity. Ideally, such components should be highly defined and predictable in all respects of sequence, structure, stability, interactions, and function. To establish one such toolkit, here we present a basis set of de novo designed alpha-helical coiled-coil peptides that adopt defined and well-characterized parallel dimeric, trimeric, and tetrameric states. The designs are based on sequence-to-structure relationships both from the literature and analysis of a database of known coiled coil X-ray crystal structures. These give foreground sequences to specify the targeted oligomer state. A key feature of the design process is that sequence positions outside of these sites are considered non-essential for structural specificity; as such, they are referred to as the background, are kept non descript, and are available for mutation as required later. Synthetic peptides were characterized in solution by circular-dichroism spectroscopy and analytical ultracentrifugation, and their structures were determined by X-ray crystallography. Intriguingly, a hitherto widely used empirical rule-of-thumb for coiled-coil dimer specification does not hold in the designed system. However, the desired oligomeric state is achieved by database-informed redesign of that particular foreground and confirmed experimentally. We envisage that the basis set will be of use in directing and controlling protein assembly, with potential applications in chemical and synthetic biology. To help with such endeavors, we introduce Pcomp, an on-line registry of peptide components for protein-design and synthetic-biology applications. PMID- 23651207 TI - Encapsulation of milk beta-lactoglobulin by chitosan nanoparticles. AB - Naturally occurring polymers, such as chitosan, have been extensively studied as carriers for therapeutic protein and gene delivery systems. beta-Lactoglobulin (beta-LG) is a member of the lipocalin superfamily of transporters for small hydrophobic molecules. We examine the binding of milk beta-lactoglobulin with chitosan of different sizes such as chitosan 15, 100, and 200 KD in aqueous solution at pH 5-6, using FTIR, CD, and fluorescence spectroscopic methods. Structural analysis showed that chitosan binds beta-LG via both hydrophilic and hydrophobic contacts with overall binding constants of K(beta-LG-ch-15) = 4.1 (+/ 0.4) * 10(2) M(-1), K(beta-LG-ch-100) = 7.2 (+/-0.6) * 10(4) M(-1), and K(beta-LG ch-200) = 3.9 (+/-0.5) * 10(3) M(-1) with the number of bound protein per chitosan (n) 0.9 for ch-15, 0.6 for ch-100, and 1.6 for ch-200. Chitosan 100 KD forms stronger complexes with beta-LG than chitosans 200 and 15 KD. Polymer binding did not alter protein conformation inducing structural stabilization. Chitosan 100 is a stronger protein transporter than chitosan 15 and 200 KD. PMID- 23651208 TI - Tracking change in children with severe and persisting speech difficulties. AB - Standardised tests of whole-word accuracy are popular in the speech pathology and developmental psychology literature as measures of children's speech performance. However, they may not be sensitive enough to measure changes in speech output in children with severe and persisting speech difficulties (SPSD). To identify the best ways of doing this, we compared a range of commonly used procedures for perceptual phonological and phonetic analysis of developmental speech difficulties. Data are drawn from four children with SPSD, recorded at 4 years and again at 6 years old performing naming and repetition tasks. Measures of speech output included percentage of whole words correct (PWC), percentage of consonants correct (PCC), proportion of whole-word proximity (PWP), phonological pattern (process) analysis and phonetic inventory analysis. Results indicate that PWC captures change only when identical stimuli are used across time points. PCC is a more robust indicator of change, being less affected by the choice of stimuli. PWP also captures change across time and tasks, while appearing to be more sensitive than PCC to psycholinguistic variables. PCC and PWP are thus both potentially useful tools for evaluating speech outcomes. PMID- 23651210 TI - Effects of the electrode size and modification protocol on a label-free electrochemical biosensor. AB - In the present work, the effect of a surface modification protocol along with the electrode size has been investigated for developing an efficient, label-free electrochemical biosensing method for diagnosis of traumatic brain injury (TBI) biomarkers. A microdisk electrode array (MDEA) and a macroelectrode with a comb structure (MECS) were modified with an anti-GFAP (GFAP = glial fibrillary acidic protein) antibody using two protocols for optimum and label-free detection of GFAP, a promising acute-phase TBI biomarker. For the MDEA, an array of six microdisks with a 100 MUm diameter and, for the MECS, a 3.2 mm * 5.5 mm electrode 5 MUm wide with 10 MUm spaced comb fingers were modified using an optimized protocol for dithiobis(succinimidyl propionate) (DSP) self-assembled monolayer formation. Anti-GFAP was covalently bound, and the remaining free DSP groups were blocked using ethanolamine (Ea). Sensors were exposed to solutions with different GFAP concentrations, and a label-free electrochemical impedance spectroscopy (EIS) technique was used to determine the concentration. EIS results confirmed that both types of Ea/anti-GFAP/DSP/Au electrodes modified with an optimized DSP based protocol can accurately detect GFAP in the range of 1 pg mL(-1) to 100 ng mL(-1) with a detection limit of 1 pg mL(-1). However, the cross-use of the MDEA protocol on the MECS and vice versa resulted in very low sensitivity or poor signal resolution, underscoring the importance of proper matching of the electrode size and type and the surface modification protocol. PMID- 23651209 TI - Sleep: a synchrony of cell activity-driven small network states. AB - We posit a bottom-up sleep-regulatory paradigm in which state changes are initiated within small networks as a consequence of local cell activity. Bottom up regulatory mechanisms are prevalent throughout nature, occurring in vastly different systems and levels of organization. Synchronization of state without top-down regulation is a fundamental property of large collections of small semi autonomous entities. We posit that such synchronization mechanisms are sufficient and necessary for whole-organism sleep onset. Within the brain we posit that small networks of highly interconnected neurons and glia, for example cortical columns, are semi-autonomous units oscillating between sleep-like and wake-like states. We review evidence showing that cells, small networks and regional areas of the brain share sleep-like properties with whole-animal sleep. A testable hypothesis focused on how sleep is initiated within local networks is presented. We posit that the release of cell activity-dependent molecules, such as ATP and nitric oxide, into the extracellular space initiates state changes within the local networks where they are produced. We review mechanisms of ATP induction of sleep-regulatory substances and their actions on receptor trafficking. Finally, we provide an example of how such local metabolic and state changes provide mechanistic explanations for clinical conditions, such as insomnia. PMID- 23651211 TI - Upregulation of T-cell factor-4 isoform-responsive target genes in hepatocellular carcinoma. AB - BACKGROUND: The Wnt/beta-catenin signalling pathway regulates genes involved in cell proliferation, survival, migration and invasion through regulation by T-cell factor (TCF)-4 transcription factor proteins. However, the role of TCF-4 isoforms generated by alternative splicing events in hepatocellular carcinoma (HCC) is unknown. AIM: Here, we investigated TCF-4 isoforms (TCF-4J and K)-responsive target genes that are important in hepatic oncogenesis and tumour development. METHODS: Gene expression microarray was performed on HCC cells overexpressing TCF 4J and K isoforms. Expression level of selected target genes was evaluated and correlations were made between their expression level and that of TCF-4 isoform in 47 pairs of human HCC tumours. RESULTS: Comparison by gene expression microarray revealed that 447 genes were upregulated and 343 downregulated more than 2.0-fold in TCF-4J compared with TCF-4K expressing cells. We validated expression of 18 selected target genes involved in Wnt/beta-catenin, insulin/IGF 1/IRS1 and Notch signalling pathways in 47 pairs of human HCCs and adjacent uninvolved liver tissues. It was observed that 13 genes (CLDN2, STK17B, SPP1, AXIN2, WISP2, MMP7, IRS1, ANXA1, CAMK2N1, ASPH, GPR56, CD24 and JAG1) activated by TCF-4J isoform in HCC cells, were also upregulated in HCC tumours compared with adjacent peritumour tissue; more importantly, 10 genes exhibited a significant correlation with the TCF-4J expression level in tumour. CONCLUSION: TCF-4 isoforms (TCF-4J and K) activated different downstream target genes in HCC. The biological consequence of TCF-4J isoform expression was upregulation of genes associated with tripartite Wnt/beta-catenin, insulin/IGF-1/IRS1 and Notch signal transduction pathway activation, which contribute to the pathogenesis of HCC. PMID- 23651212 TI - SV40 late protein VP4 forms toroidal pores to disrupt membranes for viral release. AB - Nonenveloped viruses are generally released from the cell by the timely lysis of host cell membranes. SV40 has been used as a model virus for the study of the lytic nonenveloped virus life cycle. The expression of SV40 VP4 at later times during infection is concomitant with cell lysis. To investigate the role of VP4 in viral release and its mechanism of action, VP4 was expressed and purified from bacteria as a fusion protein for use in membrane disruption assays. Purified VP4 perforated membranes as demonstrated by the release of fluorescent markers encapsulated within large unilamellar vesicles or liposomes. Dynamic light scattering results revealed that VP4 treatment did not cause membrane lysis or change the size of the liposomes. Liposomes encapsulated with 4,4-difluoro-5,7 dimethyl-4-bora-3a,4a-diaza-3-indacene-labeled streptavidin were used to show that VP4 formed stable pores in membranes. These VP4 pores had an inner diameter of 1-5 nm. Asymmetrical liposomes containing pyrene-labeled lipids in the outer monolayer were employed to monitor transbilayer lipid diffusion. Consistent with VP4 forming toroidal pore structures in membranes, VP4 induced transbilayer lipid diffusion or lipid flip-flop. Altogether, these studies support a central role for VP4 acting as a viroporin in the disruption of cellular membranes to trigger SV40 viral release by forming toroidal pores that unite the outer and inner leaflets of membrane bilayers. PMID- 23651213 TI - Interconnected carbon nanosheets derived from hemp for ultrafast supercapacitors with high energy. AB - We created unique interconnected partially graphitic carbon nanosheets (10-30 nm in thickness) with high specific surface area (up to 2287 m(2) g(-1)), significant volume fraction of mesoporosity (up to 58%), and good electrical conductivity (211-226 S m(-1)) from hemp bast fiber. The nanosheets are ideally suited for low (down to 0 degrees C) through high (100 degrees C) temperature ionic-liquid-based supercapacitor applications: At 0 degrees C and a current density of 10 A g(-1), the electrode maintains a remarkable capacitance of 106 F g(-1). At 20, 60, and 100 degrees C and an extreme current density of 100 A g( 1), there is excellent capacitance retention (72-92%) with the specific capacitances being 113, 144, and 142 F g(-1), respectively. These characteristics favorably place the materials on a Ragone chart providing among the best power energy characteristics (on an active mass normalized basis) ever reported for an electrochemical capacitor: At a very high power density of 20 kW kg(-1) and 20, 60, and 100 degrees C, the energy densities are 19, 34, and 40 Wh kg(-1), respectively. Moreover the assembled supercapacitor device yields a maximum energy density of 12 Wh kg(-1), which is higher than that of commercially available supercapacitors. By taking advantage of the complex multilayered structure of a hemp bast fiber precursor, such exquisite carbons were able to be achieved by simple hydrothermal carbonization combined with activation. This novel precursor-synthesis route presents a great potential for facile large-scale production of high-performance carbons for a variety of diverse applications including energy storage. PMID- 23651215 TI - Establishment of a novel rat model for deep tissue injury deterioration. AB - Deep tissue injuries (DTIs) can become significant problems because of their rapid deterioration into deep pressure ulcers. Presently, no animal model of DTI deterioration has been developed. By concentrating pressure and shear stress in deep tissues while minimising pressure and shear stress in the overlying skin, we produced an effective rat model of DTI deterioration. Two-dimensional finite element method (FEM) simulated the distribution of pressure and shear stress under several pressure-loading conditions. FEM showed that concentrated shear stress in deep tissue with minimum shear stress in the overlying skin could be created by using a prominence and a cushion, respectively. On the basis of the results of FEM analysis, we selected suitable conditions for testing the rat DTI deterioration model. The compressed area was macroscopically observed until day 13, and histopathologic analysis via haematoxylin and eosin (H&E) staining was performed on days 3, 7 and 13. H&E staining showed that the distribution of tissue damage was similar to the predicted FEM results. Deep ulceration and tissue damage extending from deep tissues to the overlying skin and surrounding tissues were observed in the DTI deterioration model, which are similar to the clinical manifestations of DTI deterioration. In conclusion, a representative DTI deterioration model was established by concentrating high shear stress in deep tissues while minimising shear stress in the overlying skin. This model will allow a better understanding of the mechanisms behind DTI deterioration and the development of preventative strategies. PMID- 23651214 TI - Nuclear translocation and accumulation of glyceraldehyde-3-phosphate dehydrogenase involved in diclazuril-induced apoptosis in Eimeria tenella (E. tenella). AB - In mammalian cells, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) has recently been shown to be implicated in numerous apoptotic paradigms, especially in neuronal apoptosis, and has been demonstrated to play a vital role in some neurodegenerative disorders. However, this phenomenon has not been reported in protists. In the present study, we report for the first time that such a mechanism is involved in diclazuril-induced apoptosis in Eimeria tenella (E. tenella). We found that upon treatment of parasites with diclazuril, the expression levels of GAPDH transcript and protein were significantly increased in second-generation merozoites. Then, we examined the subcellular localization of GAPDH by fluorescence microscopy and Western blot analysis. The results show that a considerable amount of GAPDH protein appeared in the nucleus within diclazuril treated second-generation merozoites; in contrast, the control group had very low levels of GAPDH in the nucleus. The glycolytic activity of GAPDH was kinetically analyzed in different subcellular fractions. A substantial decrease (48.5%) in glycolytic activity of GAPDH in the nucleus was displayed. Moreover, the activities of caspases-3, -9, and -8 were measured in cell extracts using specific caspase substrates. The data show significant increases in caspase-3 and caspase-9 activities in the diclazuril-treated group. PMID- 23651216 TI - Reasons for recall following conditional discharge: explanations given by male patients suffering from dual diagnosis in a London Forensic Unit. AB - Patients who have been discharged from forensic services often have conditions they have to abide by as part of their discharge, and failure to do so leads to recall. We interviewed six men who had been conditionally discharged from forensic services and then been recalled into hospital to find out what they thought went wrong. The reasons they gave for why things went wrong included feeling that the system was unfair and made them feel like criminals even though they did not feel they had put anyone at risk. Some of them were not fully aware of the conditions they needed to adhere to, and some of them had breached the conditions but did not take responsibility for what had happened. In addition, supervision was felt to be very controlling and disruptive rather than supportive when patients were often lonely, bored and needing support. Most participants reported that they experienced poor standards of aftercare in hostels they were required to reside in. In the future, care of patients after conditional discharge should include better communication between patients and their supervisory team, recognition of the need for more support and improvements in the standards of care in hostels, as well as a collaborative approach to risk assessment that might reduce the frequency of relapse and readmission. This study explores how male patients suffering from dual diagnosis in a forensic unit perceive being recalled and readmitted following conditional discharge and their views about how services might be improved. A qualitative approach was used drawing on grounded theory techniques. Audiotaped semistructured interviews collected data from a purposefully selected sample of six participants who had been recalled and met the inclusion criteria of the study. Data were analysed using the constant comparative method. Most participants perceived the recall system as unfair, inappropriately criminalized their behaviour and was based on an assessment of risk that they did not understand or accept. Participants were not fully aware of the conditions of their discharge, and most did not accept responsibility for their role in being recalled and blamed the system. Care following discharge was rarely seen as positive, and poor standards in hostels were reported by most participants. Supervision was often seen as disruptive and controlling, and focused more on surveillance rather than support. Better communication might have helped them understand and adhere to the conditions of their discharge. Participants identified the importance of family and friends to their recovery, the importance of having their own accommodation, and the need to be more independent. PMID- 23651217 TI - Mutation design and strain background influence the phenotype of Escherichia coli luxS mutants. AB - Previous analyses of luxS in Escherichia coli have used different strain backgrounds and design formats to produce the luxS mutation, resulting in luxS mutants with confusingly dissimilar phenotypes. This study therefore investigates the roles that strain background and mutational design strategy have upon the phenotype of the pathogenic E. coli luxS mutant. We inactivated luxS in three E. coli backgrounds: enteropathogenic E. coli E2348-69, and enterohaemorrhagic strains Sakai and NCTC12900. To investigate the influence of mutational design strategy, four mutation formats were used: antibiotic resistance insertion methodologies as previously employed, using tetracycline and chloramphenicol resistance cassettes, and non-polar strategies creating deletion and premature termination mutations. Our study showed that the E. coli luxS phenotype was markedly dependent on strain background: in some strains disruption of luxS caused significant metabolic stress or no stress at all. How the luxS mutation was constructed also shaped its phenotype: non-polar mutants were very similar to wild type, while mutations made using the antibiotic insertion methodologies produced phenotypes defective in growth and virulence. Proteomic profiling of our luxS mutants showed only a few proteins were differentially expressed and those that were altered suggested a metabolic rather than communication role for the E. coli luxS gene product. PMID- 23651218 TI - Porous titania with heavily self-doped Ti3+ for specific sensing of CO at room temperature. AB - Semiconductor-based sensors have played an important role in efficient detection of combustible, flammable, and toxic gases, but they usually need to operate at elevated temperatures (200 degrees C or higher). Although reducing the operation temperature down to room temperature is of practical significance, it is still a huge challenge to fabricate room temperature sensors with a low cost. Here we show a novel "self-doping" strategy to overcome simultaneously both difficulties of "high resistance" and "low reaction rate", which have always been encountered for room-temperature operation of semiconductor-based sensors. In particular, a porous crystalline titania with heavily self-doped Ti(3+) species has been prepared by using a porous amorphous TiO2 and urea as the starting materials. The resulting Ti(3+) self-doped TiO2 material serves as an efficient room-temperature gas-sensing material for specific CO detection with fast response/recovery. The self-dopant (Ti(3+)) in the titania material has proved to decrease the resistance of TiO2 significantly on the one hand and to increase the chemisorbed oxygen species substantially, thus enhancing the surface reaction activity on the other. Such a self-doping concept is anticipated to give a fresh impetus to rational design of room-temperature sensing devices with low costs. PMID- 23651219 TI - The association of asthma with BMI and menarche in the 1958 British Birth Cohort. AB - BACKGROUND: Obesity and early menarche have been associated with asthma. In this report, we assess the association of asthma with BMI and with changes in BMI from childhood to early adulthood. In addition, we determine if, in girls, any observed association of asthma with menarche can be explained by BMI. METHODS: In a large national birth cohort, the associations of asthma at age 7, 11, 16 and 33 years with BMI, and of, asthma at age 33 years with changes in BMI from age 7 to age 33 years was assessed using logistic and mixed effects models as appropriate. Associations of asthma with age of menarche in girls were similarly assessed with and without adjustment for BMI. RESULTS: Information on asthma, BMI, onset of menarche and confounders at all assessments was available for 1968 girls and 2223 boys. Obesity was relatively uncommon (<2%) in childhood. Overweight (BMI 25+) girls had more asthma. Girls with early menarche were more likely to be overweight. At age 11 years, asthma was associated with early menarche (OR = 1.70, 95% CI 1.17-2.47, after adjustment for BMI OR = 1.60, 95% CI 1.10-2.34). Across all ages, asthma was significantly associated with BMI (OR = 1.50, 95% CI 1.18-1.90) but not with early menarche (OR = 1.24, 95% CI 0.95-1.63). CONCLUSION: Asthma is more common in overweight girls. Early menarche is more common in overweight girls but this does not explain its association with asthma at age 11 years. Early menarche is not a risk factor for asthma at age 33 years in this cohort. PMID- 23651220 TI - Training program for overweight prevention in the child's first year: compilation and results. AB - The current local overweight-prevention protocols are not applied as intended by Dutch child healthcare physicians and nurses. The development of a training program for these practitioners, based on the Intervention Mapping framework, with the aim of improving overweight-prevention in a child's first year, is described in this study. The needs assessment showed three program objectives to be relevant, namely improving: (i) awareness of the importance of early overweight-prevention; (ii) the competence to discuss (the risk of) overweight with parents; and (iii) working systematically according to the overweight prevention protocol. A matrix was then created specifying the program objectives in terms of personal learning objectives and environmental change objectives, and appropriate strategies were identified. The results suggested that a more active tailored and structured change strategy improves knowledge and skills, in particular, which results in a better overall implementation of the overweight prevention protocol. This training program should help providers understand how the implementation of a protocol, such as the overweight-prevention protocol, can be improved. Using the Intervention Mapping framework for systematic protocol implementation seems a valuable option. PMID- 23651221 TI - 'Ecstasy' and the use of sleep medications in a general community sample: a 4 year follow-up. AB - AIMS: Animal models show that a single dose of 3,4-methylenedioxymethamhetamine (MDMA; 'ecstasy') can result in long-term disruption of sleep. We evaluated the relationship between ecstasy consumption and the use of sleep medications in humans after controlling for key factors. DESIGN: The Personality and Total Health Through Life project uses a longitudinal cohort with follow-up every 4 years. This study reports data from waves 2 and 3. SETTING: Participants were recruited from the electoral roll in the Australian Capital Territory and Queanbeyan, New South Wales, Australia. PARTICIPANTS: Participants were aged 20 24 years at wave 1 (1999-2000). MEASURES: The study collected self-reported data on ecstasy, meth/amphetamine, cannabis, alcohol, tobacco and use of sleeping medications (pharmaceutical or other substances). Depression was categorized using the Brief Patient Health Questionnaire (BPHQ). Other psychosocial measures included life-time traumas. We used generalized estimating equations to model outcomes. FINDINGS: Ecstasy data were available from 2128 people at wave 2 and 1977 at wave 3: sleeping medication use was reported by 227 (10.7%) respondents at wave 2 and 239 (12.1%) at wave 3. Increased odds ratios (OR) for sleeping medication use was found for those with depression [OR = 1.88, 95% confidence interval (CI): 1.39, 2.53], women (OR = 1.44, 95% CI: 1.13, 1.84), and increased by 19% for each life-time trauma. Ecstasy use was not a significant predictor, but >=monthly versus never meth/amphetamine use increased the odds (OR = 3.03, 95% CI 1.30, 7.03). CONCLUSION: The use of ecstasy appears to be associated with the use of sleeping medications but this association can be accounted for by other factors. PMID- 23651222 TI - Resonant photocurrent generation in dye-sensitized periodically nanostructured photoconductors by optical field confinement effects. AB - Herein we show experimental evidence of resonant photocurrent generation in dye sensitized periodically nanostructured photoconductors, which is achieved by spectral matching of the sensitizer absorption band to different types of localized photon modes present in either periodic or broken symmetry structures. Results are explained in terms of the calculated spatial distribution of the electric field intensity within the configurations under analysis. PMID- 23651224 TI - Generational changes in the meanings of sex, sexual identity and stigma among Latino young and adult men. AB - In this paper we examine the sexual identities of Latino men who have sex with men and women, in which an analysis was made of 150 sexual histories of Latino men aged 18-60. This study asks how the bisexual identity and experience of stigma is different for Latino men along the generational spectrum and how do these differences relate to kinship support and gender ideology? In the process of analysis, two main clusters of characteristics were identified to reflect this population: young men aged 18-25, whose open bisexual identity correlated positively with kinship/peer support and flexible gender and sexual roles, and men aged 26-60, who refused or were reluctant to identify as bisexual despite the fact that they were sexually active with both men and women. This group as a whole had less kinship and peer support, were more likely to identify with traditional gender roles and were less sexually versatile. Finally, a third group reflected Latino men across the generational divide who were less concerned with same-sex stigma, but who nevertheless felt the bisexual label to be confining, illegitimate or otherwise negative. PMID- 23651223 TI - A potent bivalent Smac mimetic (SM-1200) achieving rapid, complete, and durable tumor regression in mice. AB - We have designed, synthesized, and evaluated a series of new compounds based upon our previously reported bivalent Smac mimetics. This led to the identification of compound 12 (SM-1200), which binds to XIAP, cIAP1, and cIAP2 with Ki values of 0.5, 3.7, and 5.4 nM, respectively, inhibits cell growth in the MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines with IC50 values of 11.0 and 28.2 nM, respectively. Compound 12 has a much improved pharmacokinetic profile over our previously reported bivalent Smac mimetics and is highly effective in induction of rapid and durable tumor regression in the MDA-MB-231 xenograft model. These data indicate that compound 12 is a promising Smac mimetic and warrants extensive evaluation as a potential candidate for clinical development. PMID- 23651225 TI - Breastfeeding mitigates a disaster. PMID- 23651226 TI - The orbitofrontal cortex regulates outcome-based decision-making via the lateral striatum. AB - The orbitofrontal cortex (oPFC) sends substantial projections to the ventrolateral striatum and aspects of the nucleus accumbens that are, functionally, poorly understood. This is despite probable cortico-striatal involvement in multiple diseases such as addiction and obsessive-compulsive disorder. Here we surgically disconnected the oPFC from the ventrolateral striatum using unilateral asymmetric lesions in mice and classified instrumental decision-making strategies. Mice with symmetric lesions that spared one oPFC striatal network served as controls. As a complementary approach, we selectively knocked down Brain-derived neurotrophic factor (Bdnf) bilaterally in the oPFC and ascertained behavioral and neurobiological consequences within the downstream striatum. oPFC-striatal disconnection and oPFC Bdnf knockdown blocked sensitivity to outcome-predictive relationships in both food-reinforced and cocaine associated settings. Bdnf knockdown simultaneously regulated striatal BDNF expression, and striatal c-Fos predicted sensitivity to action-outcome associative contingencies. Previous evidence strongly implicates the dorsolateral striatum in stimulus-response habit formation. Our findings thus provide novel evidence for functional compartmentalisation within the lateral striatum, with the dorsal compartment subserving classical stimulus-response habit systems and a ventral compartment coordinating outcome-based decision-making via oPFC interactions. This compartmentalisation may apply to both 'natural', as in the case of food-reinforced behavior, and 'pathological', as in the case of cocaine seeking, contexts. PMID- 23651227 TI - High performance of silicon nanowire-based biosensors using a high-k stacked sensing thin film. AB - High performance silicon nanowire (SiNW) sensors with SiO2/HfO2/Al2O3 (OHA) engineered sensing thin films were fabricated. A lower interface state density, a larger capacitance and a stronger chemical immunity, which are essential for enhancing the performance of devices, were accomplished by stacking thin SiO2, HfO2, and Al2O3 layers, respectively, in sequence on the SiNW channel. Compared with the conventional single SiO2 thin film, the staked OHA thin films demonstrated improved sensing performances; a higher sensitivity, a lower hysteresis voltage, and a smaller drift rate, as well as a higher output current. Therefore, the SiNW sensors with OHA stacked sensing thin films are very promising to biological and chemical sensor applications. PMID- 23651229 TI - Repression of G protein-coupled receptor family C group 5 member A is associated with pathologic differentiation grade of oral squamous cell carcinoma. AB - BACKGROUND: G protein-coupled receptor family C group 5 member A (GPRC5A), a member of G protein-coupled receptor family, has been shown to function as a tumor suppressor in lung tissue. The biological functions of GPRC5A have therefore been linked to lung tissue. However, the biological significance of this gene product remains obscure. In this study, we investigated the expression of GPRC5A proteins in normal oral tissue and oral squamous cell carcinoma (OSCC), and we characterized its biological activity in OSCC cell lines. METHODS: Western blot analysis and immunohistochemical staining were used to investigate the expression of GPRC5A in both OSCC cell lines and clinical samples. GPRC5A stable transfectants and their parental OSCC cells were characterized for their biological activities in anchorage-independent growth. RESULTS: High levels of immunohistochemical GPRC5A expression were detected in normal oral tissue, especially differentiated area. In contrast, GPRC5A expression was dramatically repressed in OSCCs (P < 0.01). The immunohistochemical GPRC5A expression was moderately well differentiated, but greatly repressed in moderately differentiated OSCCs and completely repressed in poorly differentiated OSCCs. Overexpression of GPRC5A in OSCC CAL27 cells resulted in a suppressed anchorage independent growth activity, a transforming phenotype. CONCLUSIONS: GPRC5A is expressed in normal oral epithelium. Repression of GPRC5A is associated with poorly differential grade of OSCCs. Overexpression of GPRC5A in OSCC cell line reversed the malignant phenotype. Thus, GPRC5A is important for homeostasis in oral tissue, and deletion or repression of this gene may involve in tumorigenesis of OSCCs and may serve as a prognostic marker for malignant type of OSCCs. PMID- 23651230 TI - Measurement of antioxidant activity and antioxidant compounds under versatile extraction conditions: II. The immuno-biochemical antioxidant properties of black sour cherry (Prunus cerasus) extracts. AB - Retrospectively, we have measured the antioxidant activity and a variety of antioxidant compounds under versatile extraction conditions of sweet cherry (Prunus avium) extracts. Further in this study, in order to understand the biochemical constituents and antioxidant activities of a variety of extracts of black sour cherries (P. cerasus), a related species, antioxidant compounds, including L-ascorbic acid (vitamin C), phenols, flavonoids, and anthocyanins, and the total antioxidant activity were simultaneously measured under varying extraction conditions (mild heating and brief microwave exposure) for: i) whole juice extracts (WJE), ii) methanol-extracted juice (MEJ), iii) ddH2O-extracted pomace (dPOM), and iv) methanol-extracted pomace (mPOM). The antioxidant activity for WJE was substantially increased with mild and prolonged exposure to either heating or microwave, such that the % inhibition against 2,2-diphenyl-1 bspicrylhydrazyl (DPPH) followed a positive correlation (heating, 5-20 min.; microwave, 1-2 min.), insignificant with MEJ and dPOM, whereas with mPOM there was sharp downregulation. L-Ascorbic acid content was not affected with mild to prolonged heating or microwave exposure (WEJ and mPOM), except a mild increase with MEJ and dPOM. Similarly, total phenols assessed showed no significant variations, as compared with control extracts, except a mild decrease with exposure for mPOM. In a manner similar to L-ascorbic acid, total flavonoid content was increased under varying conditions for WEJ and MEJ, and slightly decreased for dPOM and mPOM. On the other hand, anthocyanins showed differential variations with exposure (up- and downregulation). Assessment of extraction means as compared with WJE revealed sharp increase in the antioxidant activity for MEJ, dPOM and mPOM, significant increase in L-ascorbic acid, total phenol, and flavonoid contents for MEJ, dPOM and mPOM, and mild decrease in anthocyanin contents for MEJ, dPOM, and mPOM. These results substantiate the measurable antioxidant activities and contents of P. cerasus extracts under versatile conditions of mild exposure, an effect bearing significant fluctuation with biochemical properties. Since many of those molecules are known to have immuno biochemical constituencies, antioxidant compounds in sour cherries may have putative antiinflammatory potential and applications in medicinal chemistry, corroborating the observation of regulating and attenuating the growth of microorganisms of medical importance in vitro. PMID- 23651228 TI - Ever closer to a prophylactic vaccine for HCV. AB - INTRODUCTION: With 3 - 4 million new infections occurring annually, hepatitis C virus (HCV) is a major global health problem. There is increasing evidence to suggest that HCV will be highly amenable to a vaccine approach, and despite advances in treatment, a vaccine remains the most cost-effective and realistic means to significantly reduce the worldwide mortality and morbidity associated with persistent HCV infection. AREAS COVERED: In this review we discuss immune responses to HCV during natural infection, and describe how they may inform vaccine design. We introduce the current candidate vaccines for HCV and compare how these fare against the expected requirements of an effective prophylactic HCV vaccine in relation to the breadth, functionality, magnitude and phenotype of the vaccine-induced immune response. EXPERT OPINION: Although the correlates of immune protection against HCV are not completely defined, we now have vaccine technologies capable of inducing HCV-specific adaptive immune responses to an order of magnitude that are associated with protection during natural infection. The challenge next is to i) establish well-characterised cohorts of people at risk of HCV infection for vaccine efficacy testing and ii) to better understand the correlates of protection in natural history studies. If these can be achieved, a vaccine against HCV appears a realistic goal. PMID- 23651231 TI - N-acetylcysteine versus placebo for treating nail biting, a double blind randomized placebo controlled clinical trial. AB - Nail biting is a common behavioral problem. While there are established behavioral interventions for management, they are of modest efficacy, and there is minimal evidence for effective pharmacotherapy. This study investigated the role of N-acetylcysteine (NAC) a potent glutathione and glutamate modulator for the treatment of pathological nail biting in children and adolescents. This pilot randomized, double-blind, placebo-controlled clinical trial of NAC (800 mg/day) or placebo enrolled 42 children and adolescents with chronic nail biting. Nail length was the objective outcome. Evaluations were carried out three times; before treatment, one month after enrollment in the study, and two months after enrollment. The duration (chronicity) of nail biting in the NAC and placebo groups was 3.63(2.45) and 5.09(3.74) years (P=0.14). The mean nail length gradually increased in both the NAC and placebo groups during this trial. There was a statistically significant difference between the two groups regarding increased nail length after the first month of trial [(5.21(5.75) and 1.18(3.02) millimeters], however no difference after two months was observed. Two patients in the NAC group discontinued medication due to adverse events. One patient experienced headache, agitation, and social withdrawal, and another patient expressed severe aggression after taking medication and was withdrawn from the study. This study supports the hypothesis that NAC decreases nail biting behavior in children and adolescents over the short term. NAC is relatively well tolerated and severe adverse effects are rare. However, there was a high rate of dropout. Further studies with longer durations that build on these preliminary data are recommended. This study is registered at the Iranian Registry of Clinical Trials (Irct registration number: IRCT201103023930N3). PMID- 23651232 TI - Five year anniversary of the North American section of Rural and remote health: "Timing is everything!". PMID- 23651233 TI - Detection of abalone shrivelling syndrome-associated virus using loop-mediated isothermal amplification. PMID- 23651234 TI - Osteology and radiographic anatomy of the pelvis and hind limb of healthy ring tailed lemurs (Lemur catta). AB - In family Lemuridae, anatomical variations exist. Considering its conservation status (near threatened) and presence of similarities between strepsirrhines and primitive animals, it was thought to be beneficial to describe the gross osteology and radiographic anatomy of the pelvis and hind limb of ring-tailed lemurs (Lemur catta) as a reference for clinical use and species identification. Radiography was performed in 14 captive adult ring-tailed lemurs. The radiographic findings were correlated with bone specimens from two adult animals. Additionally, computed tomography of the hind limbs was performed in one animal. The pelvic bone has a well-developed caudal ventral iliac spine. The patella has a prominent tuberosity on the cranial surface. The first metatarsal bone and digit 1 are markedly stouter than the other metatarsal bones and digits with medial divergence from the rest of the metatarsal bones and digits. Ossicles were seen in the lateral meniscus, inter-phalangeal joint of digit 1 and in the infrapatellar fat pad. Areas of mineral opacity were seen within the external genitalia, which are believed to be the os penis and os clitoris. Variations exist in the normal osteology and radiographic appearance of the pelvis and hind limb of different animal species. The use of only atlases from domestic cats and dogs for interpretative purposes may be misleading. PMID- 23651235 TI - Carbohydrate-decorated PCL fibers for specific protein adhesion. AB - Ultrafine biocompatible fibers decorated with carbohydrates were prepared by electrospinning. Both bulk- and surface-modification approaches have been investigated and compared in terms of practicability and grafting density along the fibrous mats. On one hand, bulk-functionalized fibers were prepared by electrospinning of native and galactose-modified PCL polymers. The size and morphology of the resulting fibers was strongly influenced by the galactose-PCL content as observed by electron microscopy. Successful surface modification was evidenced by water contact angle measurements, but a rather low carbohydrate density was attained, as indicated by a colorimetric quantification. On the other hand, efficient and versatile surface-glycosylation was achieved after modification of azido-functionalized electrospun fibers by CuAAC click-chemistry. Homogeneous ultrafine PCL fibers, decorated with azide functions, have been made completely hydrophilic upon coupling with propargyl-alpha-d-mannoside and propargyl-beta-d-galactoside. Specific adhesion of lectins further attested good bioavailability of the surface carbohydrate residues, suggesting interesting perspectives of the latter approach in the development of bioactive materials for tissue engineering. PMID- 23651236 TI - Self-assembly in poly(dimethylsiloxane)-poly(ethylene oxide) block copolymer template directed synthesis of Linde type A zeolite. AB - We describe the hydrothermal synthesis of zeolite Linde type A (LTA) submicrometer particles using a water-soluble amphiphilic block copolymer of poly(dimethylsiloxane)-b-poly(ethylene oxide) as a template. The formation and growth of the intermediate aggregates in the presence of the diblock copolymer have been monitored by small-angle X-ray scattering (SAXS) above the critical micellar concentration at a constant temperature of 45 degrees C. The early stage of the growth process was characterized by the incorporation of the zeolite LTA components into the surface of the block copolymer micellar aggregates with the formation of primary units of 4.8 nm with a core-shell morphology. During this period, restricted to an initial time of 1-3 h, the core-shell structure of the particles does not show significant changes, while a subsequent aggregation process among these primary units takes place. A shape transition of the SAXS profile at the late stage of the synthesis has been connected with an aggregation process among primary units that leads to the formation of large clusters with fractal characteristics. The formation of large supramolecular assemblies was finally verified by scanning electron microscopy, which evidenced the presence of submicrometer aggregates with size ranging between 100 and 300 nm, while X-ray diffraction confirmed the presence of crystalline zeolite LTA. The main finding of our results gives novel insight into the mechanism of formation of organic inorganic mesoporous materials based on the use of a soft interacting nanotemplate as well as stimulates the investigation of alternative protocols for the synthesis of novel hybrid materials with new characteristics and properties. PMID- 23651237 TI - Association of cytokine gene polymorphisms with oral lichen planus in Malayalam speaking ethnicity from South India (Kerala). AB - Oral lichen planus (OLP) is a chronic mucocutaneous condition that affects the oral mucous membrane as well as skin. It is a chronic cell-mediated autoimmune condition where the T-cell-mediated immune response plays an important part in the pathogenesis by causing damage to basal keratinocytes in oral mucosa. Cytokine gene polymorphisms have an unquestionable role in the orchestration of the immune response, leading to different functional scenarios, which in turn influence the outcome of the disease establishment and evolution. The purpose of this study was to understand the role of these cytokine gene polymorphisms in the tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 genes with OLP in 101 individuals of Malayalam-speaking ethnicity from South India (Kerala). We further investigated the role of these polymorphisms in patients suffering from OLP with other comorbid factors. Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism. The results demonstrate that the A allele in the TNF-alpha -308 polymorphism could play an important role in the susceptibility to OLP. IL-1beta +3954 in OLP was associated with other comorbid factors in both allelic and genotypic combinations. However, when patients suffering from OLP were stratified to understand the involvement of other comorbid factors, we observed that the T and C alleles were independent risk factors for chronic periodontitits and diabetes mellitus. On the other hand, IL-6 -597 did not show any disease association with OLP in the study population. This study indicates that proinflammatory cytokines are an important factor in understanding the disease burden of OLP and their comorbid factors. PMID- 23651238 TI - Indomethacin in combination with exercise leads to muscle and brain inflammation in mice. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used by athletes to reduce exercise-induced inflammation and pain. However, NSAID use has been linked to side effects, including mucosal damage in the gastrointestinal tract resulting in endotoxemia and inflammation. Incidentally, when NSAID use is combined with exercise there is some evidence that this effect may be exacerbated; however, this hypothesis has not been directly tested in a controlled experiment. We examined the combined effect of indomethacin (IND) and exercise on muscle and brain inflammation in mice. Male C57BL/6 mice were randomly assigned to: Exercise 0 mg/Kg IND (Ex-0), Sedentary 0 mg/Kg IND (Sed-0), Exercise 2.5 mg/Kg IND (Ex 2.5), or Sedentary 2.5 mg/Kg IND (Sed-2.5) (n=8-11/group). Mice were given IND (gavage) 1 h before exercise (treadmill run at 25 m/min, 8% grade for 90 min) or rest for 5 consecutive days. Run times and body weight were recorded daily. Muscle and brain were examined for gene expression of inflammatory mediators after 5 days of treatment. While IND and exercise alone had little effect on inflammation, the combination treatment produced substantial increases in the muscle (IL-1beta, MCP-1 & TNF-alpha) and brain (IL-1beta & MCP-1) (P<0.05). Hematocrit and hemoglobin were decreased along with body weight (days 3-5), and run time to fatigue (days 3-5) (P<0.05) and in general, these were correlated with the increased expression of muscle and brain inflammatory mediators. The combination of IND and exercise can lead to inflammation in both the muscle and brain that is associated with serious side effects and impaired performance in mice. PMID- 23651240 TI - Nutrition and health during mid-life: searching for solutions and meeting challenges for the aging population. AB - Interactions between genetic (genome) and environmental factors (epigenome) operate during a person's entire lifespan. The aging process is associated with several cellular and organic functional alterations that, at the end, cause multi organic cell failure. Epigenetic mechanisms of aging are modifiable by appropriate preventive actions mediated by sirtuins, caloric input, diet components, adipose tissue-related inflammatory reactions, and physical activity. The Mediterranean lifestyle has been for many millennia a daily habit for people in Western civilizations living around the Mediterranean sea who worked intensively and survived with very few seasonal foods. A high adherence to the traditional Mediterranean diet is associated with low mortality (higher longevity) and reduced risk of developing chronic diseases, including cancer, the metabolic syndrome, depression and cardiovascular and neurodegenerative diseases. Reports indicate that some dietary components, such as olive oil, antioxidants, omega-3 and -6 polyunsaturated acids, polyphenols and flavonoids, mediate beneficial anti-aging effects (anti-chronic diseases and increased longevity). Equally, physical activity displays a positive effect, producing caloric consumption and regulation of adipose and pancreatic function. The predictive strength of some food patterns may be a way of developing recommendations for food and health policies. This paper will discuss several ways of improving health during mid-life, focusing on certain groups of functional foods and healthy habits which may reduce or prevent age-related chronic diseases. PMID- 23651239 TI - Vasohibin-1 expression is regulated by transforming growth factor-beta/bone morphogenic protein signaling pathway between tumor-associated macrophages and pancreatic cancer cells. AB - Vasohibin-1 has been detected in endothelial cells as an intrinsic angiogenesis inhibitor. Both tumor-associated macrophages (TAMs) and transforming growth factor-beta (TGF-beta)/bone morphogenic protein (BMP) signaling have been reported to promote angiogenesis in cancer. However, whether vasohibin-1 expression is regulated by TGF-beta/BMP signaling between TAMs and cancer cells remains unclear. The expression of TGF-beta1, TGF-beta2, BMP-4, and BMP-7 in TAMs and the expression of vasohibin-1, vascular endothelial growth factor-A (VEGF-A), and VEGF-C in two pancreatic cancer cell lines (a nonmetastatic cell line Panc-1 and a distant metastatic cell line HPAF-II) were measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). The TGF-beta receptor 1 and BMP receptor 1 were inhibited by the inhibitor SB-431542 and LDN193189, respectively. Thereafter, vasohibin-1, VEGF-A, and VEGF-C expression was detected by real-time RT-PCR. We found that the expression of TGF-beta1, TGF-beta2, BMP-4, and BMP-7 was upregulated in TAMs cocultured with pancreatic cancer cells. Vasohibin-1, VEGF-A, and VEGF-C mRNA expression in pancreatic cancer cells was upregulated by TAMs. Vasohibin-1 expression in pancreatic cancer cells cocultured with TAMs was upregulated significantly when TGF-beta receptors or BMP receptors were inhibited, but VEGF-C expression was downregulated. Therefore, Vasohibin-1 expression is regulated by the TGF-beta/BMP signaling between TAMs and pancreatic cancer cells. These results might shed a new light on the antiangiogenesis therapy in the pancreatic cancer. PMID- 23651241 TI - Erectile dysfunction, testosterone deficiency, and risk of coronary heart disease in a cohort of men living with HIV in Belgium. AB - INTRODUCTION: Erectile dysfunction (ED) is more prevalent in men living with HIV (MLHIV) when compared with age-matched HIV-negative men. This may be related to a premature decline in testosterone levels. In the general population, ED has been associated with an increased risk for coronary heart disease (CHD). AIM: The aim of this study is to determine the prevalence of ED, testosterone deficiency, and risk of CHD in a cohort of young to middle-aged MLHIV in Belgium. METHODS: A cross-sectional, observational study among 244 MLHIV attending the outpatient clinic of the Institute of Tropical Medicine in Antwerp. MAIN OUTCOME MEASURES: The short version of the international index of erectile function (IIEF-5) questionnaire diagnosed ED (cutoff score <= 21). The 10-year risk score for CHD was calculated. In a subset of men reporting ED, the calculated free testosterone (CFT) was determined using Vermeulen's formula. Testosterone deficiency was defined as CFT <0.22 nmol/L. RESULTS: One hundred fifty-one men (61.9%) self reported ED (median IIEF-5 score: 16 [interquartile range (IQR) 12-19]). In multivariate analysis, only increasing age, but none of the HIV-related parameters, nor any of the individual cardiovascular-risk related parameters, was statistically significantly associated with ED. Eighteen out of the 49 (36.7%) men with ED who received a blood test to assess testosterone levels were diagnosed with testosterone deficiency. The 10-year risk of CHD in the cohort was 4.3% (IQR 3.6-5.7) and was significantly higher in men with ED (5.1%, IQR 4.4 6.6) compared with men without ED (3.1%, IQR 2.5-4.2). CONCLUSIONS: This study showed that ED and testosterone deficiency are highly prevalent in young to middle-aged MLHIV and that ED might be associated with an increased risk of CHD. Therefore, healthcare professionals should screen for clinical ED and should consider testing for underlying testosterone deficiency. A clinical diagnosis of ED should trigger a full evaluation of the patient's cardiovascular risk factors, even at younger age. PMID- 23651242 TI - Three-pulse photon echo of finite numbers of molecules: single-molecule traces. AB - In conventional bulk nonlinear spectroscopy, the contribution from molecules with different environmental conditions sometimes conceals the properties of interest and prevents the assessment of the heterogeneity of complex systems. This is especially true when exploring mechanisms of coherence loss in multicomponent systems [Ishizaki and Fleming, J. Phys. Chem. B 2011, 115, 6227]. To avoid this drawback of ensemble measurements and evaluate single-molecule behavior, a quantum theory is proposed to study the three-pulse photon echo signal of a two level system in a bath and reveal the fluctuations inherent to single molecules. The current method takes advantage of the coherent state representation to understand the photon echo experiment in a wave function formalism rather than the reduced density matrix. Information regarding the environmental degrees of freedom (DoF) is explicitly encoded in the initial state of the system plus bath. The thermal fluctuations of the initial states induce variation of the photon echo signal, which is clearly different from the ensemble average echo signal. We use our formalism to demonstrate the recovery of the conventional ensemble response signal from the single-molecule signal. PMID- 23651243 TI - 5% fluorouracil chemowraps in the management of widespread lower leg solar keratoses and squamous cell carcinoma. AB - Elderly patients with extensive hypertrophic solar keratoses and squamous cell carcinoma on the lower legs can pose significant management challenges. Typically these patients require surgical treatment which is complicated by comorbidities and poor background lower leg skin. 5% fluorouracil chemowraps provides a useful alternative technique for the management of diffuse hypertrophic solar keratoses and as an adjuvant, and in some situations as a palliative treatment, for squamous cell carcinomas on the lower legs. PMID- 23651245 TI - Synthetic biology: research perspectives from China. PMID- 23651247 TI - Designing the scientific cradle for quantitative biologists. PMID- 23651244 TI - Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) represents a significant cause of global morbidity and mortality, with a substantial economic impact. Recent changes in the Global initiative for chronic Obstructive Lung Disease (GOLD) guidance refined the classification of patients for treatment using a combination of spirometry, assessment of symptoms, and/or frequency of exacerbations. The aim of treatment remains to reduce existing symptoms while decreasing the risk of future adverse health events. Long-acting bronchodilators are the mainstay of therapy due to their proven efficacy. GOLD guidelines recommend combining long acting bronchodilators with differing mechanisms of action if the control of COPD is insufficient with monotherapy, and recent years have seen growing interest in the additional benefits that combination of long-acting muscarinic antagonists (LAMAs), typified by tiotropium, with long-acting beta(2)-agonists (LABAs), such as formoterol and salmeterol. Most studies have examined free combinations of currently available LAMAs and LABAs, broadly showing a benefit in terms of lung function and other patient-reported outcomes, although evidence is limited at present. Several once- or twice-daily fixed-dose LAMA/LABA combinations are under development, most involving newly developed monotherapy components. This review outlines the existing data for LAMA/LABA combinations in the treatment of COPD, summarizes the ongoing trials, and considers the evidence required to inform the role of LAMA/LABA combinations in treatment of this disease. PMID- 23651248 TI - ePathBrick: a synthetic biology platform for engineering metabolic pathways in E. coli. AB - Harnessing cell factories for producing biofuel and pharmaceutical molecules has stimulated efforts to develop novel synthetic biology tools customized for modular pathway engineering and optimization. Here we report the development of a set of vectors compatible with BioBrick standards and its application in metabolic engineering. The engineered ePathBrick vectors comprise four compatible restriction enzyme sites allocated on strategic positions so that different regulatory control signals can be reused and manipulation of expression cassette can be streamlined. Specifically, these vectors allow for fine-tuning gene expression by integrating multiple transcriptional activation or repression signals into the operator region. At the same time, ePathBrick vectors support the modular assembly of pathway components and combinatorial generation of pathway diversities with three distinct configurations. We also demonstrated the functionality of a seven-gene pathway (~9 Kb) assembled on one single ePathBrick vector. The ePathBrick vectors presented here provide a versatile platform for rapid design and optimization of metabolic pathways in E. coli. PMID- 23651249 TI - Assembly of large, high G+C bacterial DNA fragments in yeast. AB - The ability to assemble large pieces of prokaryotic DNA by yeast recombination has great application in synthetic biology, but cloning large pieces of high G+C prokaryotic DNA in yeast can be challenging. Additional considerations in cloning large pieces of high G+C DNA in yeast may be related to toxic genes, to the size of the DNA, or to the absence of yeast origins of replication within the sequence. As an example of our ability to clone high G+C DNA in yeast, we chose to work with Synechococcus elongatus PCC 7942, which has an average G+C content of 55%. We determined that no regions of the chromosome are toxic to yeast and that S. elongatus DNA fragments over ~200 kb are not stably maintained. DNA constructs with a total size under 200 kb could be readily assembled, even with 62 kb of overlapping sequence between pieces. Addition of yeast origins of replication throughout allowed us to increase the total size of DNA that could be assembled to at least 454 kb. Thus, cloning strategies utilizing yeast recombination with large, high G+C prokaryotic sequences should include yeast origins of replication as a part of the design process. PMID- 23651250 TI - Characterization and modeling of transcriptional cross-regulation in Acinetobacter baylyi ADP1. AB - Synthetic biology involves reprogramming and engineering of regulatory genes in innovative ways for the implementation of novel tasks. Transcriptional gene regulation systems induced by small molecules in prokaryotes provide a rich source for logic gates. Cross-regulation, whereby a promoter is activated by different molecules or different promoters are activated by one molecule, can be used to design an OR-gate and achieve cross-talk between gene networks in cells. Acinetobacter baylyi ADP1 is naturally transformable, readily editing its chromosomal DNA, which makes it a convenient chassis for synthetic biology. The catabolic genes for salicylate, benzoate, and catechol metabolism are located within a supraoperonic cluster (-sal-are-ben-cat-) in the chromosome of A. baylyi ADP1, which are separately regulated by LysR-type transcriptional regulators (LTTRs). ADP1-based biosensors were constructed in which salA, benA, and catB were fused with a reporter gene cassette luxCDABE under the separate control of SalR, BenM, and CatM regulators. Salicylate, benzoate, catechol, and associated metabolites were found to mediate cross-regulation among sal, ben, and cat operons. A new mathematical model was developed by considering regulator-inducer binding and promoter activation as two separate steps. This model fits the experimental data well and is shown to predict cross-regulation performance. PMID- 23651251 TI - Automated design of genetic toggle switches with predetermined bistability. AB - Synthetic biology aims to rationally construct biological devices with required functionalities. Methods that automate the design of genetic devices without post hoc adjustment are therefore highly desired. Here we provide a method to predictably design genetic toggle switches with predetermined bistability. To accomplish this task, a biophysical model that links ribosome binding site (RBS) DNA sequence to toggle switch bistability was first developed by integrating a stochastic model with RBS design method. Then, to parametrize the model, a library of genetic toggle switch mutants was experimentally built, followed by establishing the equivalence between RBS DNA sequences and switch bistability. To test this equivalence, RBS nucleotide sequences for different specified bistabilities were in silico designed and experimentally verified. Results show that the deciphered equivalence is highly predictive for the toggle switch design with predetermined bistability. This method can be generalized to quantitative design of other probabilistic genetic devices in synthetic biology. PMID- 23651252 TI - Cloning large gene clusters from E. coli using in vitro single-strand overlapping annealing. AB - Despite recent advances in genomic sequencing and DNA chemical synthesis, construction of large gene clusters containing DNA fragments is still a difficult and expensive task. To tackle this problem, we developed a gene cluster extraction method based on in vitro single-strand overlapping annealing (SSOA). It starts with digesting the target gene cluster in an existing genome, followed by recovering digested chromosome fragments. Subsequently, the single-strand DNA overhangs formed from the digestion process would be specifically annealed and covalently joined together with a circular and a linear vector, respectively. The SSOA method was successfully applied to clone a 18 kb DNA fragment encoding NADH:ubiquinone oxidoreductase. Genomic DNA fragments of different sizes including 11.86, 18.33, 28.67, 34.56, and 55.99 kb were used to test the cloning efficiency. Combined with genetic information from KEGG and the KEIO strain collection, this method will be useful to clone any specific region of an E. coli genome at sizes less than ~28 kb. The method provides a cost-effective way for genome assembly, alternative to chemically synthesized gene clusters. PMID- 23651253 TI - Click-like reactions with the inert HCB11Cl11(-) anion lead to carborane-fused heterocycles with unusual aromatic character. AB - The chlorinated carba-closo-dodecaborate anion HCB11Cl11(-) is an exceptionally stable molecule and has previously been reported to be substitutionally inert at the B-Cl vertices. We present here the discovery of base induced cycloaddition reactions between this carborane anion and organic azides that leads to selective C and B functionalization of the cluster. A single crystal X-ray diffraction study reveals bond lengths in the heterocyclic portion of the ring that are shortened, which suggests electronic delocalization. Molecular orbital analysis of the ensuing heterocycles reveals that two of the bonding orbitals of these systems resemble two of the doubly occupied pi-MOs of a simple 5-membered Huckel aromatic, even though they are entangled in the carborane skeleton. Nucleus independent chemical shift analysis indicates that both the carborane cluster portion of the molecule and the carborane fused heterocyclic region display aromatic character. Computational methods indicate that the reaction likely follows a stepwise addition cyclization pathway. PMID- 23651254 TI - Inhibition of Dengue virus 2 replication by artificial micrornas targeting the conserved regions. AB - Dengue virus (DENV), a mosquito-borne flavivirus, causes serious diseases and threatens public health in tropical and subtropical areas worldwide. RNA interference (RNAi) is a prevailing strategy for antiviral therapy. In this paper, 6 single artificial microRNAs (amiRNAs) targeting the highly conserved regions of the DENV-2 genome were identified and inhibited virus replication efficiently. Then, effective tandem amiRNAs targeting 2 different DENV-2 genome regions were constructed and expressed simultaneously from a single microRNA-like polycistron to avoid virus variation or mutation escape. Finally, the most high performance tandem amiRNA was embedded in a lenti-viral vector and inhibited DENV 2 virus replication stably and dose-dependently. Overall, these results indicated that RNAi based on multiple amiRNAs targeting viral conserved regions was an effective approach for improvements of nucleic acid inhibitors of DENV and provided a new therapeutic strategy for DENV infection in humans. PMID- 23651255 TI - Internet addiction assessment tools: dimensional structure and methodological status. AB - AIMS: Excessive internet use is becoming a concern, and some have proposed that it may involve addiction. We evaluated the dimensions assessed by, and psychometric properties of, a range of questionnaires purporting to assess internet addiction. METHODS: Fourteen questionnaires were identified purporting to assess internet addiction among adolescents and adults published between January 1993 and October 2011. Their reported dimensional structure, construct, discriminant and convergent validity and reliability were assessed, as well as the methods used to derive these. RESULTS: Methods used to evaluate internet addiction questionnaires varied considerably. Three dimensions of addiction predominated: compulsive use (79%), negative outcomes (86%) and salience (71%). Less common were escapism (21%), withdrawal symptoms (36%) and other dimensions. Measures of validity and reliability were found to be within normally acceptable limits. CONCLUSIONS: There is a broad convergence of questionnaires purporting to assess internet addiction suggesting that compulsive use, negative outcome and salience should be covered and the questionnaires show adequate psychometric properties. However, the methods used to evaluate the questionnaires vary widely and possible factors contributing to excessive use such as social motivation do not appear to be covered. PMID- 23651256 TI - Interplay of Aro80 and GATA activators in regulation of genes for catabolism of aromatic amino acids in Saccharomyces cerevisiae. AB - Aro80, a member of the Zn(2)Cys(6) family proteins, activates expression of the ARO9 and ARO10 genes involved in catabolism of aromatic amino acids in response to aromatic amino acids that act as inducers. ARO9 and ARO10 are also under the control of nitrogen catabolite repression, but the direct roles for GATA factors, Gat1 and Gln3, in this regulation have not yet been elucidated. Here, we demonstrate that Aro80 is constitutively bound to its target promoters and activated by inducers at the level of transactivation. Although Aro80 also binds to its own promoter, ARO80 expression is induced only by rapamycin, but not by tryptophan. We show that Aro80 is absolutely required for Gat1 binding to the ARO9, ARO10 and ARO80 promoters upon rapamycin treatment. Gln3 binding to these promoters shows a partial requirement for Aro80. Rapamycin-dependent Gat1 and Gln3 binding to the Aro80 target promoters is not affected by tryptophan availability, suggesting that transactivation activity of Aro80 is not necessary for the recruitment of GATA factors. Rapamycin-dependent induction of Aro80 target genes also requires PP2A phosphatase complex, but not Sit4 phosphatase, acting downstream of TORC1. PMID- 23651257 TI - Health promotion behavior in middle-aged Koreans: a cross sectional survey. AB - This cross-sectional study was conducted to verify self-efficacy, self-esteem, and social support as characteristics of health promotion behavior in middle-aged Koreans, and the influence of social support on self-efficacy and self-esteem with respect to health promotion behavior. Data were collected from 310 subjects in South Korea using a self-administered questionnaire. We found a significant finding that self-efficacy positively influences health promotion behavior, focusing on the moderating effect of social support. Self-efficacy affected health promotion behavior (P < 0.01) as did social support. Mean self-efficacy, self-esteem, health promotion behavior, and social support scores were 50.27, 29.35, 124.39, and 76.51, respectively. This finding provides strong evidence that social support can be used as a model to understand health promotion behavior. Individualized nursing interventions based on social support and self efficacy theory should be utilized in high-risk middle-aged patients so as to assist and improve health promotion behavior. Also, in community practice settings, nurses should consider that increased social support and self-efficacy are required to improve health promotion behaviors. PMID- 23651258 TI - Reduced enthalpy of metal hydride formation for Mg-Ti nanocomposites produced by spark discharge generation. AB - Spark discharge generation was used to synthesize Mg-Ti nanocomposites consisting primarily of a metastable body-centered-cubic (bcc) alloy of Mg and Ti. The bcc Mg-Ti alloy transformed upon hydrogenation into the face-centered-cubic fluorite Mg1-yTiyHx phase with favorable hydrogen storage properties. Both metal and metal hydride nanocomposites showed a fractal-like porous morphology, with a primary particle size of 10-20 nm. The metal content of 70 atom % (at %) Mg and 30 at % Ti, consistently determined by XRD, TEM-EDS, and ICP-OES, was distributed uniformly across the as-prepared sample. Pressure-composition isotherms for the Mg-Ti-H nanocomposites revealed large differences in the thermodynamics relative to bulk MgH2, with a much less negative enthalpy of formation of the hydride as small as -45 +/- 3 kJ/molH2 as deduced from van't Hoff plots. The plateau pressures of hydrogenation were substantially higher than those for bulk MgH2 in the low temperature range from 150 to 250 degrees C. The reaction entropy was simultaneously reduced to values down to 84 +/- 5 J/K mol H2, following a linear relationship between the enthalpy and entropy. Plausible mechanisms for the modified thermodynamics are discussed, including the effect of lattice strains, the presence of interfaces and hydrogen vacancies, and the formation of excess free volume due to local deformations. These mechanisms all rely on the finely interdispersed nanocomposite character of the samples which is maintained by grain refinement. PMID- 23651259 TI - Romanowsky-Giemsa as a counterstain for immunohistochemistry: optimizing a traditional reagent. AB - We describe a detailed protocol for using Romanowsky-Giemsa (RG) counterstaining on formalin fixed, paraffin embedded tissue sections that are stained immunohistochemically (IHC) after antigen retrieval using hot acidic citrate buffer. RG staining is easy to perform and provides consistent results that are similar to hematoxylin and eosin (HE) staining. The counterstaining was applied after a variety of antibodies that used the DAB chromogen and the intensity of IHC stained structures was preserved. Moreover, RG counterstaining provided finer cell detail than HE, methyl green or nuclear fast red. A detailed troubleshooting guide is provided for the RG staining protocol. PMID- 23651260 TI - Immunohistochemical expression of TLR4 and TLR9 in various grades of oral epithelial dysplasia and squamous cell carcinoma, and their roles in tumor progression: a pilot study. AB - Toll-like receptors (TLRs) play an essential role in the activation of innate immunity. TLRs are expressed in B-lymphocytes, monocytes, dendritic cells and epithelial cells. We examined the immunohistochemical expressions of TLR4 and TLR9 in various grades of oral epithelial dysplasia (OED), oral squamous cell carcinoma (OSCC) and normal oral mucosa (NOM) to determine the association between TLR4 and TLR9 in the progression of lesions from dysplasia to carcinoma. Expressions of TLR4 and TLR9 were assessed using immunohistochemistry (IHC) on paraffin embedded tissue blocks of various grades of OED (28 cases), OSCC (27 cases) and NOM (10 cases). Expression of TLR4 was high in all grades of OED and OSCC. Expression of TLR9 was high in well differentiated squamous cell carcinoma and moderately differentiated squamous cell carcinomas, and moderate to low in poorly differentiated squamous cell carcinomas. Although expression was high in case of TLR4, it was not statistically significant. Expression of TLR9 was statistically significant. In OED, expression of TLR9 was less than that of TLR4. Our results indicated that the pattern of expression of TLR4 and TLR9 increased significantly from mild to severe dysplasia compared to controls. Expression of TLR4 and TLR9 reflects progression of OED to OSCC, which suggests that TLR may play a role in tumorigenesis and that it could be used as a target for OSCC prevention and therapy in the future. PMID- 23651261 TI - Olfactory bulb-derived cells seeded on 3D scaffolds exhibit neurotrophic factor expression and pro-angiogenic properties. AB - Olfactory bulb (OB)-derived cells include fibroblasts, astrocytes, and olfactory ensheathing cells (OECs). OECs are a distinctive type of glia that secrete neurotrophic factors and form myelin sheaths around axons projecting from the olfactory mucosa into the OB of the central nervous system. Their unique properties make them candidates for cell therapy of spinal cord injury (SCI). Current SCI cellular repair techniques suffer from massive cell loss post implantation. To overcome this difficulty, we propose to seed and propagate OB derived cells on biodegradable scaffolds to form a stable tissue construct. Upon implantation, scaffolds may serve as carriers to introduce the tissue into the lesion site. In this study, we characterized OB-derived cells cultured on biodegradable poly-l-lactic acid/polylactic-co-glycolic acid scaffolds in vitro. We showed that cells remained viable and proliferative for up to 2 weeks on the scaffolds. We have shown that OB-derived cells induce neuronal differentiation of pheochromocytoma cells (PC12) on scaffolds, and that a purified population of OECs is sufficient for the differentiation. Selective inhibition of nerve growth factor (NGF) on PC12 cells blocks the differentiation. We have shown that the expression of BDNF and NGF genes in OB-derived cells grown on 3D scaffolds compared to 2D monolayer cultures was significantly upregulated. In addition, OB derived cells stimulated network formation of endothelial cells grown on the same scaffolds. Taken together, these results clearly demonstrate the vast potential of 3D scaffolds in maintaining and strengthening the unique therapeutic properties of embedded OB-derived cells. This strategy will enable more efficient therapeutic usage of OB-derived cells for treatment of SCI. PMID- 23651262 TI - Considering Aboriginal palliative care models: the challenges for mainstream services. AB - This review discusses palliative care and end-of-life models of care for Aboriginal people in the Australian state New South Wales, and considers Aboriginal palliative care needs by reflecting on recent literature and lessons derived from Aboriginal consultation. Aboriginal people in Australia account for a very small proportion of the population, have poorer health outcomes and their culture demonstrates a clear resistance to accessing mainstream health services which are viewed as powerful, isolating and not relevant to their culture, way of life, family and belief systems. Aboriginal people regard their land as spiritual and their culture dictates that an Aboriginal person needs to know their origins, emphasising the value placed on kin and also demonstrating a strong desire to remain within their own country. Currently Aboriginal people tend to not access palliative care services in mainstream facilities; and there is very little data on Aboriginal admissions to palliative care centres. Over the last two decades only two models of palliative care focusing on and developed in Aboriginal communities have been implemented. The seminal contribution to Aboriginal Palliative Care was in the form of a resource kit developed to support palliative care providers to examine their practice for cultural appropriateness for Aboriginal and Torres Strait Islanders. The 'living model' coming from this project is adaptive and flexible, enabling implementation in different Aboriginal country as a participative process with community input. The Australian government's National Indigenous Palliative Care Needs Study similarly indicated that Australian empirical research on Aboriginal palliative care service provision is in its infancy, and comprehensive data on the rates of Aboriginal access to palliative care services did not exist. What literature does exist is drawn together in an argument for the development and need for culturally specific Aboriginal palliative care models, which are culturally appropriate, locally accessible and delivered in collaboration and partnership with Aboriginal controlled health services. This is essential because Aboriginal people are a minority cultural group who are disconnected from mainstream health service delivery, and have a sense of cultural isolation when accessing mainstream services. It is preferable that palliative care is delivered in a collaboration between Aboriginal Controlled Health Service and mainstream palliative care services to ensure a dignified end of life for the Aboriginal person. These collaborations and partnerships are fundamental to ensure that a critical mass of Aboriginal clinicians are trained and experienced in end of life care and palliation. Developing palliative care programs within Aboriginal communities and training Aboriginal Health Workers, promoted and developed in partnership with the Aboriginal community, are important strategies to enhance palliative care service provision. Further partnerships should be championed in this collaborative process, acknowledging a need for palliative care models that fit with Aboriginal peoples' community values, beliefs, cultural/ spiritual rituals, heritage and place. PMID- 23651263 TI - Normalization of the psychometric hepatic encephalopathy score in Polish population. A prospective, quantified electroencephalography study. AB - BACKGROUND: The psychometric hepatic encephalopathy score (PHES) is recommended as a gold standard in evaluation of minimal hepatic encephalopathy (HE). Normative databases have been collected in few countries, clearly showing differences among studied groups. Thus, the standardization of PHES for selected populations remains necessary. AIMS: To standardize PHES in a large cohort of Polish healthy subjects and to evaluate the normograms in patients with cirrhosis with quantified electroencephalography (EEG). METHODS: Three hundred and sixteen (142 males/174 females, aged 44.5 +/- 12.1) normal individuals and 50 (31 males/19 females, aged 52.8 +/- 12.4) patients with cirrhosis without overt HE were included. Key correction variables of psychometric tests were performed. The multivariate linear regression was used to calculate PHES normograms. RESULTS: Age and education levels were identified as predictors of all tests, therefore age- and education-adjusted normograms were developed. A weighted time-errors regression model for line tracing test (LTT) scoring was used. The PHES ranged between +5 and -15 points and the cut-off between normal and pathological PHES was set on <=-5 points. By this cut-off level, PHES had a sensitivity of 57% and specificity of 97% to diagnose minimal HE (AUC = 0.866 +/- 0.028). In patients with cirrhosis, PHES correlated with severity of liver disease (MELD, r = -0.475, P < 0.001 and Child-Pugh classification, r = -0.452, P < 0.002) and EEG (r = 0.547, P < 0.002). In patients with impaired EEG, PHES was lower than in individuals with unaltered EEG (P < 0.02); however, agreement between these two modalities was limited. CONCLUSIONS: Valid Polish PHES normograms, which incorporates w-LTT scoring system have been developed. Future multi-centre international studies are needed to validate widely applicable norms. PMID- 23651264 TI - Self-reports of faulty parental attachments in childhood and criminal psychopathy in an adult-incarcerated population: an integrative literature review. AB - This study examined self-reports of psychopathic offenders' childhood interactions with their parents to better understand what variables influence adult criminal psychopathy. The findings showed that childhood separations, physical abuse and indifferent parenting styles were more prominent in self reports of incarcerated male psychopaths than with incarcerated males who were not psychopathic. To better understand the worldview of the criminal psychopath, and the trajectory of psychopathy, there is a need for more studies that examine childhood interactions with parental figures as reported by the adult criminal psychopath. ABSTRACT: Despite the high percentage of incarcerated psychopaths, few studies attempt to assess the past parent-child bonds of these individuals by asking them to report childhood attachments with their parents. Currently, there is limited data regarding common variables that contribute to a break in parent child attachment and later adult criminal psychopathy. The data that presently exist concentrate on juvenile or community samples and do not explore the attachment variables that continue into adult criminal psychopathy. This paper presents the current literature regarding self-reports of childhood attachment to parents as indicated by male-incarcerated adult psychopaths compared with self reports of childhood attachment to parents as indicated by male-incarcerated adult non-psychopaths. Variables that influence a break in attachment between the offenders and their parents and suggestions for future clinical research are provided. PMID- 23651265 TI - A blue-absorbing photolabile protecting group for in vivo chromatically orthogonal photoactivation. AB - The small and synthetically easily accessible 7-diethylamino-4 thiocoumarinylmethyl photolabile protecting group has been validated for uncaging with blue light. It exhibits a significant action cross-section for uncaging in the 470-500 nm wavelength range and a low light absorption between 350 and 400 nm. These attractive features have been implemented in living zebrafish embryos to perform chromatic orthogonal photoactivation of two biologically active species controlling biological development with UV and blue-cyan light sources, respectively. PMID- 23651266 TI - Separation of hemicellulose and cellulose from wood pulp by means of ionic liquid/cosolvent systems. AB - Pulp of high cellulose content, also known as dissolving pulp, is needed for many purposes, including the production of cellulosic fibers and films. Paper-grade pulp, which is rich in hemicellulose, could be a cheap source but must be refined. Hitherto, hemicellulose extraction procedures suffered from a loss of cellulose and the non-recoverability of unaltered hemicelluloses. Herein, an environmentally benign fractionation concept is presented, using mixtures of a cosolvent (water, ethanol, or acetone) and the cellulose dissolving ionic liquid 1-ethyl-3-methylimidazolium acetate (EMIM OAc). This cosolvent addition was monitored using Kamlet-Taft parameters, and appropriate stirring conditions (3 h at 60 degrees C) were maintained. This allowed the fractionation of a paper grade kraft pulp into a separated cellulose and a regenerated hemicellulose fraction. Both of these exhibited high levels of purity, without any yield losses or depolymerization. Thus, this process represents an ecologically and economically efficient alternative in producing dissolving pulp of highest purity. PMID- 23651267 TI - Au nanorod design as light-absorber in the first and second biological near infrared windows for in vivo photothermal therapy. AB - Photothermal cancer therapy using near-infrared (NIR) laser radiation is an emerging treatment. In the NIR region, two biological transparency windows are located in 650-950 nm (first NIR window) and 1000-1350 nm (second NIR window) with optimal tissue transmission obtained from low scattering and energy absorption, thus providing maximum radiation penetration through tissue and minimizing autofluorescence. To date, intensive effort has resulted in the generation of various methods that can be used to shift the absorbance of nanomaterials to the 650-950 nm NIR regions for studying photoinduced therapy. However, NIR light absorbers smaller than 100 nm in the second NIR region have been scant. We report that a Au nanorod (NR) can be designed with a rod-in-shell (rattle-like) structure smaller than 100 nm that is tailored to be responsive to the first and second NIR windows, in which we can perform hyperthermia-based therapy. In vitro performance clearly displays high efficacy in the NIR photothermal destruction of cancer cells, showing large cell-damaged area beyond the laser-irradiated area. This marked phenomenon has made the rod-in-shell structure a promising hyperthermia agent for the in vivo photothermal ablation of solid tumors when activated using a continuous-wave 808 m (first NIR window) or a 1064 nm (second NIR window) diode laser. We tailored the UV-vis-NIR spectrum of the rod-in-shell structure by changing the gap distance between the Au NR core and the AuAg nanoshell, to evaluate the therapeutic effect of using a 1064 nm diode laser. Regarding the first NIR window with the use of an 808 nm diode laser, rod-in-shell particles exhibit a more effective anticancer efficacy in the laser ablation of solid tumors compared to Au NRs. PMID- 23651270 TI - The likelihood of sunburn in sunscreen users is disproportionate to the SPF. AB - BACKGROUND/OBJECTIVE: Sunburn is a common feature in sunscreen users. The purpose of this paper is to estimate the expected frequency and magnitude of sunburn resulting from typical use of sunscreens labelled SPF15 and SPF30 by people spending long periods outdoors in strong summer sunshine. METHODS: By combining the probability distribution of the measured sun protection factor (SPF) in vivo with those for the average application thickness and the uniformity of application over the skin surface, a simulation model was developed to estimate the variation in delivered protection over the exposed skin surface from consumer use of sunscreens. RESULTS: While either sunscreen, if delivering the nominal SPF over the entire exposed skin, would be sufficient to prevent any erythema, the simulation indicates that the combination of the average quantity applied with the variability in thickness over the skin surface will lead to erythema, especially in SPF15 sunscreen users. CONCLUSION: People who intend spending long periods outside in strong sunshine would be better advised to use SPF30 labelled sunscreens than SPF15 sunscreens, and to apply the product carefully over exposed skin if they wish to minimize their risk of sunburn and, by implication, skin cancer. PMID- 23651271 TI - Photopatch testing in Asians: a 5-year experience in Singapore. AB - BACKGROUND: Photopatch testing is important for diagnosing photoallergic contact dermatitis. We aimed to evaluate the use of photopatch test at the National Skin Centre, Singapore. METHODS: All patients who had photopatch tests done between 2007 and 2011 at the National Skin Centre were included. RESULTS: Twenty-two patients were included. The mean age was 40.2. Female : male ratio was 3.4. The ethnic groups were Chinese (68%), Malay (4%), Indian (14%) and others (14%). Ten out of 22 patients (45.5%) had a positive photopatch test. There were 20 positive photopatch test reactions found in these 10 patients, and all 20 positive reactions were of current relevance. The frequencies of the positive photopatch test reactions were 2-hydroxy-4-methoxybenzophenone (oxybenzone) (n = 6), 2 hydroxymethoxymethylbenzophenone (mexenone) (n = 3), 2-ethylhexyl-4 dimethylaminobenzoate (n = 1), ketoprofen gel (n = 1) and the patient's own product (n = 9). CONCLUSIONS: Our study suggests that sunscreen is the most common photoallergen to date as opposed to musk ambrette, which was the most common photoallergen in our earlier study in 1991-1993. This finding is similar to the recent European Multicentre Photopatch Test Study. PMID- 23651272 TI - UV responses in Native Hawaiians and Pacific Islanders, and Asians residing in Hawai'i and in Maryland. AB - BACKGROUND: UV exposure causes a wide range of skin damage including cutaneous melanoma. The mechanisms of cellular and molecular damage, as well as those of erythemal and pigmentation responses to UV exposure, have largely been studied in the White population. METHODS: This study systematically investigates responses to UV exposure in the Native Hawaiian and Pacific Islander (NHPI) and Asian populations living in Hawai'i (A/HI) as well as in Asians living in Maryland (A/MD). RESULTS: Our analyses indicate that the NHPI population is less sensitive to UV exposure than the A/HI population. Comparisons between the two Asian groups suggest that, despite slightly but not statistically different baseline constitutive pigmentation (pre-UV exposure), the A/HI and A/MD had similar UV sensitivity, measured as minimal erythemal dose (MED). However, the A/MD population had higher levels of oxyhemoglobin at doses of 2.0, 2.8 and 4.0 MED. Unexpectedly, the A/MD subjects retained higher levels of pigmentation 2 weeks post-UV exposure. CONCLUSION: This study provides insight into UV responses of the inhabitants of Hawai'i and shows that such responses are statistically significant for relatively small samples of NHPI and for A/HI and A/MD. PMID- 23651273 TI - Three school-age cases of xeroderma pigmentosum variant type. AB - BACKGROUND: Xeroderma pigmentosum (XP) is a photosensitive genodermatosis with increased susceptibility to skin cancers. Patients are typically diagnosed with XP when they consult a dermatologist for skin cancers. CASE/METHODS: The genetic analysis and 2-8 years of follow-up for three school-age patients with XP-V is described. The patients were referred to us because of increased pigmented freckles; they had not experienced abnormal sunburn or developed skin cancer at their first visit. All patients harbored a genetic mutation in the POLH gene. XPV9KO was diagnosed at age 13 with a homozygous del1661A that creates a stop codon in the non-catalytic domain of POLH. The patient practiced sun protection, effectively preventing the development of skin cancer by age 21. XPV19KO was diagnosed at age 11 with a compound heterozygous mutation of G490T and C1066T, causing POLH truncation in the catalytic domain. This patient developed basal cell carcinoma at ages 12 and 13. XPV18KO was referred to us at age 11 and diagnosed with compound heterozygous variants of c.1246_1311del66 (exon 9 skipping), a novel mutation, and c.661_764 del104 (exon 6 skipping). CONCLUSION: Freckle-like pigmentation on sun-exposed skin is sometimes the only sign of XP-V, and early diagnosis is extremely important for children. PMID- 23651274 TI - Does artificial UV use prior to spring break protect students from sunburns during spring break? AB - BACKGROUND: Dark-skinned individuals are less likely than light-skinned individuals to become sunburned or develop skin cancer. Some have extrapolated this relationship and surmised that developing and maintaining a tan will reduce the risk of sunburns and melanoma. In order to examine whether this strategy indeed protects against sunburns, we surveyed college students about both their tanning habits prior to spring break and their spring break activities. METHODS: Sorority and fraternity students were recruited after spring break. Analyses examined associations between potential risk factors and the development of one or more sunburns during spring break. RESULTS: As expected, the risk of obtaining a sunburn increased with: time spent in the sun during spring break; light complexion, as assessed by various sun-sensitivity factors; and lack of sunscreen use. We also found that tanning using an artificial UV source during the 10 weeks prior to spring break was not associated with reduced risk of sunburns during spring-break, but rather with a marginal increase in this risk. CONCLUSIONS: These data provide evidence that maintaining a tan may not provide protection from sunburns. Public health messages need to address this misconception, stating clearly that a tan does not protect against or reduce the chances of developing a sunburn. PMID- 23651275 TI - 5-aminolevulinic acid-based photodynamic therapy for the treatment of condylomata acuminata in Chinese patients: a meta-analysis. AB - OBJECTIVE: This meta-analysis was designed to assess the efficacy of topical 5 aminolaevulinic acid (ALA) photodynamic therapy (PDT) in Chinese patients with condylomata acuminata (CA). METHODS: Electronic literature databases (Medline, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang database) were searched for relevant randomized controlled trials (RCTs) published prior to October 2012. Only RCTs that compared ALA-PDT to non-ALA-PDT for patients with genital condylomata were selected. The outcomes included the recurrence rate and adverse events. The risk ratios (RRs) and 95% confidence intervals (CIs) were calculated as the ALA-PDT vs. without ALA-PDT. RESULTS: Twenty RCTs composed of 1903 patients (ALA-PDT, n = 1106; non-ALA-PDT, n = 797) were included in the meta-analysis. ALA-PDT decreased the recurrence rate within 12 week after treatment (vs. without ALA-PDT, RR: 0.28, 95% CI: 0.22-0.35) and 24 week after treatment (vs. without ALA-PDT, RR: 0.24, 95% CI: 0.17-0.34) in a fixed-effect model. The common adverse events related ALA-PDT included a mild burning and/or stinging sensation, erythema, mild edema, erosion, and hyperpigmentation. CONCLUSION: Local application of ALA-PDT reduced recurrence rate vs. without ALA-PDT. The use of ALA-PDT should be considered as a feasible therapy for the treatment of CA. PMID- 23651276 TI - A case of cutaneous lichen sclerosus et atrophicus effectively treated by extracorporeal photochemotherapy. AB - Lichen sclerosus et atrophicus (LSA) is an inflammatory disease that affects the genitals, which was first described by Hallopeau in 1887 and is of unknown etiology. Only 15% of patients have an associated extra-genital form, and 2.5% have an isolated extra-genital form. LSA treatment remains poorly codified and mostly empirical. Here, we report a case of LSA, of mainly cutaneous form, which was effectively treated using extracorporeal photochemotherapy (ECP). Remission was achieved quickly, after the fourth session, with excellent treatment tolerance. ECP is now recognized as an effective treatment for erosive lichen planus, graft-versus-host disease (GVHD), and scleroderma. Thus, we began ECP treatment for our cases of LSA based on clinical and/or anatomopathological similarities between LSA and these commonly ECP-treated disorders. The fact that ECP is effective in LSA, GVHD, erosive lichen planus, and scleroderma strengthen the hypothesis that there is a common link between these four conditions. PMID- 23651277 TI - Chemical analysis and in vitro UV-protection characteristics of clays traditionally used for sun protection in South Africa. AB - Clays have been used in southern Africa as photoprotectants by the indigenous people. Typically, two types of clay are used: one white in colour and the other red. In this work, the two clays were identified and characterized, and their in vitro SPF values measured. The clays afford a low SPF but offer broad-spectrum protection. No cutaneous side effects from the use of these clays are known. Further consideration should be given to the potential use of clays in sunscreen preparations. PMID- 23651278 TI - Vibrio splendidus, Vibrio ichthyoenteri and Vibrio pacinii isolated from the digestive tract microflora of larval ballan wrasse, Labrus bergylta Ascanius, and goldsinny wrasse, Ctenolabrus rupestris (L.). PMID- 23651279 TI - Role of murine models in psychiatric illness drug discovery: a dimensional view. AB - INTRODUCTION: The extensive comorbidity among psychiatric disorders underscores the need for a fundamental change in the way psychopathology is classified. An alternative 'dimensional' system classifies disorders based on relationships with respect to heritability patterns and comorbidity. It is from this 'dimensional view' that mouse modeling of neuropsychiatric disorders is presently discussed. AREAS COVERED: This review describes three proposed dimensions of psychopathology: internalizing (disorders of negative emotions), externalizing (disorders of impulsivity) and schizophrenic. The article, furthermore, presents and explains the concept of endophenotype and discusses the possible endophenotypes relevant to each of these dimensions. Finally, the article also describes mouse behavioral tests that are used for quantifying these endophenotypes and presents examples of recent studies that have used these tests. EXPERT OPINION: Considering animal models within the context of endophenotypes associated with psychopathological 'dimensions', rather than focusing on modeling specific disorders, might facilitate the discovery of new pharmacotherapies. Mouse models will be powerful tools for exploring how environmental factors interact with genetic vulnerability to cause psychopathology, possibly leading to novel preventative treatment strategies. Future pharmacotherapies for neuropsychiatric disorders such as depression might comprise drugs or drug combinations that target key components of multiple systems, including neurotransmitter systems, cytokine production, oxidative stress and the HPA axis. PMID- 23651280 TI - The influence of restricted feeding on glucagon-like peptide-1 (GLP-1)-containing cells in the chicken small intestine. AB - The influence of restricted feeding on the distribution of glucagon-like peptide 1 (GLP-1)-containing endocrine cells in the chicken small intestine was investigated using immunohistochemical and morphometrical techniques. This study demonstrated that the restricted feeding had an influence on the activity of GLP 1-immunoreactive cells in the chicken small intestine. There were differences in the localization and the frequency of occurrence of GLP-1-immunoreactive cells in the small intestine between control and restricted groups, especially 25% feed supply group provided with 25% of the intake during the adapting period. GLP-1 immunoreactive cells in the control chickens were mainly located in epithelium from crypts to the lower part of intestinal villi. Those in restricted groups, however, tended to be located from crypts to the middle part of intestinal villi. The frequency of occurrence of GLP-1-immunoreactive cells was lowest in the control group, medium in 50% feed supply group and highest in 25% feed supply group at each intestinal region examined in this study, that is, increased with the advancement of restricting the amount of feed supply. These data show that the quantity of food intake is one of signals that have an influence on the secretion of GLP-1 from L cells in the chicken small intestine. PMID- 23651281 TI - Are progestins really necessary as part of a combined HRT regimen? AB - For many years it has been perceived wisdom that hormone replacement therapy for women with a uterus should include a progestin to prevent the proliferative effects of estrogen on the endometrium and endometrial cancer. But, with the reports from the Women's Health Initiative (WHI) and Million Women Study indicating that such regimens are associated with an increased risk of breast cancer, whereas unopposed estrogen may not increase this risk, or even reduce it, it is pertinent to reassess the merits of adding a progestin. In addition, the suggestion from the WHI that the effects of estrogen and progestins are a 'class effect' are clearly inaccurate, as there is particular evidence from the French E3N cohort studies of differential effects of progestins, with progesterone and dydrogesterone additions showing no increase in risk of breast cancer. The data are presented but an answer to the posed question remains unclear and as usual dependent on the circumstances and views of each individual woman and her medical adviser. PMID- 23651282 TI - Anchored LH2 complexes in 2D polarization imaging. AB - Protein is a soft material with inherently large structural disorder. Consequently, the bulk spectroscopies of photosynthetic pigment protein complexes provide averaged information where many details are lost. Here we report spectroscopy of single light-harvesting complexes where fluorescence excitation and detection polarizations are both independently rotated. Two samples of peripheral antenna (LH2) complexes from Rhodopseudomonas acidophila were studied. In one, the complexes were embedded in polyvinyl alcohol (PVA) film; in the other, they were anchored on the glass surface and covered by the PVA film. LH2 contains two rings of pigment molecules-B800 and B850. The B800 excitation polarization properties of the two samples were found to be very similar, indicating that orientation statistics of LH2s are the same in these two very different preparations. At the same time, we found a significant difference in B850 emission polarization statistics. We conclude that the B850 band of the anchored sample is substantially more disordered. We argue that both B800 excitation and B850 emission polarization properties can be explained by the tilt of the anchored LH2s due to the spin-casting of the PVA film on top of the complexes and related shear forces. Due to the tilt, the orientation statistics of two samples become similar. Anchoring is expected to orient the LH2s so that B850 is closer to the substrate. Consequently, the tilt-related strain leads to larger deformation and disorder in B850 than in B800. PMID- 23651283 TI - Bio-design automation: nobody said it would be easy. PMID- 23651285 TI - Ensemble Bayesian analysis of bistability in a synthetic transcriptional switch. AB - An overarching goal of synthetic and systems biology is to engineer and understand complex biochemical systems by rationally designing and analyzing their basic component interactions. Practically, the extent to which such reductionist approaches can be applied is unclear especially as the complexity of the system increases. Toward gradually increasing the complexity of systematically engineered systems, programmable synthetic circuits operating in cell-free in vitro environments offer a valuable testing ground for principles for the design, characterization, and analysis of complex biochemical systems. Here we illustrate this approach using in vitro transcriptional circuits ("genelets") while developing an activatable transcriptional switch motif and configuring it as a bistable autoregulatory circuit, using just four synthetic DNA strands and three essential enzymes, bacteriophage T7 RNA polymerase, Escherichia coli ribonuclease H, and ribonuclease R. Fulfilling the promise of predictable system design, the thermodynamic and kinetic constraints prescribed at the sequence level were enough to experimentally demonstrate intended bistable dynamics for the synthetic autoregulatory switch. A simple mathematical model was constructed based on the mechanistic understanding of elementary reactions, and a Monte Carlo Bayesian inference approach was employed to find parameter sets compatible with a training set of experimental results; this ensemble of parameter sets was then used to predict a test set of additional experiments with reasonable agreement and to provide a rigorous basis for confidence in the mechanistic model. Our work demonstrates that programmable in vitro biochemical circuits can serve as a testing ground for evaluating methods for the design and analysis of more complex biochemical systems such as living cells. PMID- 23651286 TI - An end-to-end workflow for engineering of biological networks from high-level specifications. AB - We present a workflow for the design and production of biological networks from high-level program specifications. The workflow is based on a sequence of intermediate models that incrementally translate high-level specifications into DNA samples that implement them. We identify algorithms for translating between adjacent models and implement them as a set of software tools, organized into a four-stage toolchain: Specification, Compilation, Part Assignment, and Assembly. The specification stage begins with a Boolean logic computation specified in the Proto programming language. The compilation stage uses a library of network motifs and cellular platforms, also specified in Proto, to transform the program into an optimized Abstract Genetic Regulatory Network (AGRN) that implements the programmed behavior. The part assignment stage assigns DNA parts to the AGRN, drawing the parts from a database for the target cellular platform, to create a DNA sequence implementing the AGRN. Finally, the assembly stage computes an optimized assembly plan to create the DNA sequence from available part samples, yielding a protocol for producing a sample of engineered plasmids with robotics assistance. Our workflow is the first to automate the production of biological networks from a high-level program specification. Furthermore, the workflow's modular design allows the same program to be realized on different cellular platforms simply by swapping workflow configurations. We validated our workflow by specifying a small-molecule sensor-reporter program and verifying the resulting plasmids in both HEK 293 mammalian cells and in E. coli bacterial cells. PMID- 23651287 TI - Automated selection of synthetic biology parts for genetic regulatory networks. AB - Raising the level of abstraction for synthetic biology design requires solving several challenging problems, including mapping abstract designs to DNA sequences. In this paper we present the first formalism and algorithms to address this problem. The key steps of this transformation are feature matching, signal matching, and part matching. Feature matching ensures that the mapping satisfies the regulatory relationships in the abstract design. Signal matching ensures that the expression levels of functional units are compatible. Finally, part matching finds a DNA part sequence that can implement the design. Our software tool MatchMaker implements these three steps. PMID- 23651288 TI - Computational modeling of synthetic microbial biofilms. AB - Microbial biofilms are complex, self-organized communities of bacteria, which employ physiological cooperation and spatial organization to increase both their metabolic efficiency and their resistance to changes in their local environment. These properties make biofilms an attractive target for engineering, particularly for the production of chemicals such as pharmaceutical ingredients or biofuels, with the potential to significantly improve yields and lower maintenance costs. Biofilms are also a major cause of persistent infection, and a better understanding of their organization could lead to new strategies for their disruption. Despite this potential, the design of synthetic biofilms remains a major challenge, due to the complex interplay between transcriptional regulation, intercellular signaling, and cell biophysics. Computational modeling could help to address this challenge by predicting the behavior of synthetic biofilms prior to their construction; however, multiscale modeling has so far not been achieved for realistic cell numbers. This paper presents a computational method for modeling synthetic microbial biofilms, which combines three-dimensional biophysical models of individual cells with models of genetic regulation and intercellular signaling. The method is implemented as a software tool (CellModeller), which uses parallel Graphics Processing Unit architectures to scale to more than 30,000 cells, typical of a 100 MUm diameter colony, in 30 min of computation time. PMID- 23651289 TI - Hierarchical modeling for synthetic biology. AB - One of the characteristics of synthetic biology is that it often combines mathematical modeling with experimental work. The link between modeling and experiments is carried out by human researchers who have a conceptual understanding of the underlying biological system. At present, there is no method for representing a conceptual description that can be used to connect mathematical models and experimental data, especially sequence annotations, pertaining to the same underlying biological system. One reason for this limitation is that there can exist different mathematical models of the same biological system. In such cases, the same annotation in a DNA sequence would map differently to different models of the same system. In order to enable software support for synthetic biology, a software framework is needed such that it is able to capture a conceptual description of a biological system, including quantitative values, without confining itself to one mathematical model. The novel use of hierarchical modeling inside TinkerCell (www.tinkercell.com) provides one potential software solution for representing a "conceptual diagram" of a biological system. The conceptual diagram does not assume any underlying model. Rather, the diagram is mapped automatically to one of several models. The diagram can then contain information relevant for both modeling and experimental work. Computer-aided design (CAD) can be very useful to synthetic biology. CAD allows engineers to spend more effort at the design stage and less at the construction stage by automatically performing many tasks that are currently performed by human researchers. The ability to automatically link models and experimental results will be one step in the development of practical CAD systems for synthetic biology. PMID- 23651290 TI - Specification and simulation of synthetic multicelled behaviors. AB - Recent advances in the design and construction of synthetic multicelled systems in E. coli and S. cerevisiae suggest that it may be possible to implement sophisticated distributed algorithms with these relatively simple organisms. However, existing design frameworks for synthetic biology do not account for the unique morphologies of growing microcolonies, the interaction of gene circuits with the spatial diffusion of molecular signals, or the relationship between multicelled systems and parallel algorithms. Here, we introduce a framework for the specification and simulation of multicelled behaviors that combines a simple simulation of microcolony growth and molecular signaling with a new specification language called gro. The framework allows the researcher to explore the collective behaviors induced by high level descriptions of individual cell behaviors. We describe example specifications of previously published systems and introduce two novel specifications: microcolony edge detection and programmed microcolony morphogenesis. Finally, we illustrate through example how specifications written in gro can be refined to include increasing levels of detail about their bimolecular implementations. PMID- 23651291 TI - A data-driven framework for identifying nonlinear dynamic models of genetic parts. AB - A key challenge in synthetic biology is the development of effective methodologies for characterization of component genetic parts in a form suitable for dynamic analysis and design. In this investigation we propose the use of a nonlinear dynamic modeling framework that is popular in the field of control engineering but is novel to the field of synthetic biology: Nonlinear AutoRegressive Moving Average model with eXogenous inputs (NARMAX). The framework is applied to the identification of a genetic part BBa_T9002 as a case study. A concise model is developed that exhibits accurate representation of the system dynamics and a structure that is compact and consistent across cell populations. A comparison is made with a biochemical model, derived from a simple enzymatic reaction scheme. The NARMAX model is shown to be comparably simple but exhibits much greater prediction accuracy on the experimental data. These results indicate that the data-driven NARMAX framework is an attractive technique for dynamic modeling of genetic parts. PMID- 23651292 TI - Bridging the gap between science and public health: taking advantage of tobacco control experience in Brazil to inform policies to counter risk factors for non communicable diseases. AB - AIMS AND DESIGN: The historical and economic involvement of Brazil with tobacco, as a major producer and exporter, was considered an insurmountable obstacle to controlling the consumption of this product. Nevertheless, the country was able to achieve significant progress in implementing public policies and to take an international leadership position, meeting its constitutional commitment to protect public health. In this paper we provide a brief historical overview of tobacco control (TC) in Brazil, and analyse the factors that contributed to the major decline in tobacco consumption in the country over the last 20 years, as well as identify the challenges that had to be overcome and those still at play. FINDINGS: The Brazilian case demonstrates how cross-sectorial collaborations among health-related groups that capitalize on their respective strengths and capacities can help to influence public policy and overcome industry and population resistance to change. Although Brazil still lags behind some leading TC nations, the country has an extensive collaborative TC network that was built over time and continues to focus upon this issue. CONCLUSIONS: The tobacco experience can serve as an example for other fields, such as alcoholic beverages, of how networks can be formed to influence the legislative process and the development of public policies. Brazilian statistics show that problems related to non-communicable diseases are a pressing public health issue, and advocacy groups, policy-makers and government departments can benefit from tobacco control history to fashion their own strategies. PMID- 23651293 TI - Tris chelating phosphate complexes of bis(thio)urea ligands. AB - Two bisurea (L(1), L(2)) and one bisthiourea (L(3)) ligands were synthesized and their anion coordination behavior was studied. These ligands can readily form the tris chelates [PO4(L)3](3-) (1, 5, and 6) with phosphate ion (PO4(3-)) in the solid state, in which the anion is coordinated by six urea groups through 12 hydrogen bonds. Solution binding studies by (1)H NMR and UV-vis spectroscopy revealed different binding properties of the ligands toward phosphate ion. While the bis(p-nitrophenyl)-substituted bisurea L(1) retains the 3:1 (host to guest) binding ratio in solution, the diethyl derivative L(2) only forms 1:1 complex with phosphate ion. The more acidic thiourea L(3) undergoes deprotonation/decomposition in the presence of phosphate ion. Moreover, the sulfate complex (2) of L(1) and bicarbonate (3) and carbonate (4) complexes of L(2) have also been obtained, which show lower coordination numbers both in the solid state and in solution. PMID- 23651294 TI - The prospective associations between depression and sexual satisfaction among female medical students. AB - INTRODUCTION: The direction of the relationships between depression and sexual dissatisfaction is unclear. Possibly, these relationships are influenced by different elements/components of depression represented by different measures (i.e., Center for Epidemiologic Studies Depression Scale [CES-D], which highlights mood, vs. Beck Depression Inventory version II [BDI-II], which focuses on cognition and physical symptoms). High-achieving women--such as female medical students, interns, and residents--might be particularly prone to both depression and sexual dissatisfaction. AIM: The aim of this study is to examine the direction of the longitudinal associations between depressive symptoms and sexual dissatisfaction in high-achieving, romantically involved female Israeli medical students and interns/residents using both CES-D and BDI-II. METHODS: One hundred ninety-four female medical students from the first, fourth, and seventh (internship) years from all medical schools in Israel who were currently involved in romantic relationships were assessed twice over a 1-year interval using both CES-D and BDI-II. Cross-lagged structural equation modeling analyses were employed. MAIN OUTCOME MEASURES: Depressive symptoms were measured by the CES-D and the BDI-II. Sexual satisfaction was assessed by the "partner-satisfaction" factor of the Pinney Sexual Satisfaction Inventory. RESULTS: Elevated levels of CES-D-measured depression were found (26% at T1 and 13% at T2 above the stricter cutoff point). The direction of the longitudinal association between depressive symptoms and sexual dissatisfaction changed according to the depression measure used: baseline CES-D-measured depression predicted an increase in sexual dissatisfaction over time (beta = 0.148, P = 0.016). Baseline sexual satisfaction predicted an increase in BDI-II-measured depression (beta = 0.136, P = 0.045). CONCLUSION: High-achieving, "fully-functioning" female medical students suffer from elevated levels of CES-D-measured depressed mood. Depressed mood might lead to sexual dissatisfaction, which in turn is likely to bring about "clinical," BDI II-measured depression. We recommend a routine assessment of depressed mood and sexual dissatisfaction in this population, as well as increased access to tailored intervention for both clinical challenges. PMID- 23651295 TI - Copper-catalyzed highly enantioselective cyclopentannulation of indoles with donor-acceptor cyclopropanes. AB - A highly diastereo- and enantioselective BOX/Cu(II)-catalyzed C2,C3 cyclopentannulation of indoles with donor-acceptor cyclopropanes has been developed on the basis of asymmetric formal [3 + 2] cycloaddition of indoles. This reaction provides rapid and facile access to a series of enantioenriched cyclopenta-fused indoline products and can be further extended to the construction of tetracyclic pyrroloindolines. The synthetic potential of the reaction was demonstrated in a four-step synthesis of the core structure of borreverine. PMID- 23651297 TI - Cutaneous sarcoidosis and infliximab: evidence for efficacy in refractory disease. AB - Biological therapy with tumour necrosis factor alpha antibodies continues to offer a life-changing option for a range of autoimmune and inflammatory skin conditions. We present three cases of sarcoidosis, with refractory cutaneous disease successfully treated with infliximab. A review of the literature shows increased numbers of cases of refractory cutaneous sarcoidosis successfully cleared with infliximab therapy. PMID- 23651296 TI - Supplementation of exogenous adenosine 5'-triphosphate enhances mechanical properties of 3D cell-agarose constructs for cartilage tissue engineering. AB - Formation of tissue-engineered cartilage is greatly enhanced by mechanical stimulation. However, direct mechanical stimulation is not always a suitable method, and the utilization of mechanisms underlying mechanotransduction might allow for a highly effective and less aggressive alternate means of stimulation. In particular, the purinergic, adenosine 5'-triphosphate (ATP)-mediated signaling pathway is strongly implicated in mechanotransduction within the articular cartilage. We investigated the effects of transient and continuous exogenous ATP supplementation on mechanical properties of cartilaginous constructs engineered using bovine chondrocytes and human mesenchymal stem cells (hMSCs) encapsulated in an agarose hydrogel. For both cell types, we have observed significant increases in equilibrium and dynamic compressive moduli after transient ATP treatment applied in the fourth week of cultivation. Continuous ATP treatment over 4 weeks of culture only slightly improved the mechanical properties of the constructs, without major changes in the total glycosaminoglycan (GAG) and collagen content. Structure-function analyses showed that transiently ATP-treated constructs, and in particular those based on hMSCs, had the highest level of correlation between compositional and mechanical properties. Transiently treated groups showed intense staining of the territorial matrix for GAGs and collagen type II. These results indicate that transient ATP treatment can improve functional mechanical properties of cartilaginous constructs based on chondrogenic cells and agarose hydrogels, possibly by improving the structural organization of the bulk phase and territorial extracellular matrix (ECM), that is, by increasing correlation slopes between the content of the ECM components (GAG, collagen) and mechanical properties of the construct. PMID- 23651298 TI - Enantioselective inhibition of microbial lipolytic enzymes by nonracemic monocyclic enolphosphonate analogues of cyclophostin. AB - Four nonracemic enolphosphonate analogues of Cyclophostin were obtained by asymmetric synthesis, and their absolute configurations at both phosphorus and C 5 carbon chiral centers were unambiguously assigned. The influence of chirality was studied by testing the inhibitory effects of these four stereoisomers toward the lipolytic activity of three microbial lipases: Fusarium solani cutinase, Rv0183, and LipY from Mycobacterium tuberculosis . Cutinase was highly diastereoselective for the (Sp) configuration using (Sc) inhibitors, whereas no obvious stereopreference at phosphorus was observed with (Rc) compounds. Conversely, Rv0183 exhibited strong enantioselective discrimination for (Sp) configuration regardless of the chirality at the asymmetric carbon atom. Lastly, LipY discriminated only the unusual diastereoisomeric configuration (Rc, Rp) leading to the most potent inhibitor. This work, which provides a fundamental premise for the understanding of the stereoselective relationships between nonracemic enolphosphonates and their inhibitory activity, also opens new prospects on the design and synthesis of highly specific enantioselective antimicrobial agents. PMID- 23651299 TI - A missense mutation in CHS1, a TIR-NB protein, induces chilling sensitivity in Arabidopsis. AB - Low temperature is an environmental factor that affects plant growth and development and plant-pathogen interactions. How temperature regulates plant defense responses is not well understood. In this study, we characterized chilling-sensitive mutant 1 (chs1), and functionally analyzed the role of the CHS1 gene in plant responses to chilling stress. The chs1 mutant displayed a chilling-sensitive phenotype, and also displayed defense-associated phenotypes, including extensive cell death, the accumulation of hydrogen peroxide and salicylic acid, and an increased expression of PR genes: these phenotypes indicated that the mutation in chs1 activates the defense responses under chilling stress. A map-based cloning analysis revealed that CHS1 encodes a TIR-NB type protein. The chilling sensitivity of chs1 was fully rescued by pad4 and eds1, but not by ndr1. The overexpression of the TIR and NB domains can suppress the chs1-conferred phenotypes. Interestingly, the stability of the CHS1 protein was positively regulated by low temperatures independently of the 26S proteasome pathway. This study revealed the role of a TIR-NB-type gene in plant growth and cell death under chilling stress, and suggests that temperature modulates the stability of the TIR-NB protein in Arabidopsis. PMID- 23651300 TI - Local silencing controls the oxidative stress response and the multidrug resistance in Candida glabrata. AB - In Candida glabrata, the sirtuins Sir2 and Hst1 control the expression of a wide number of genes including adhesins required for host colonization and niacin transporters needed for growth. Given that these sirtuins can be inactivated during infection, we asked if their inhibition could modify the response of C. glabrata to other stressful conditions. Here, we found that deletion of HST1 decreases susceptibility of C. glabrata to fluconazole and hydrogen peroxide. The transcription factor Pdr1 and the ABC transporter Cdr1 mediated the fluconazole resistance phenotype of the hst1Delta cells, whereas the transcriptional activator Msn4 and the catalase Cta1 are necessary to provide oxidative stress resistance. We show that the transcription factor Sum1 interacts with Hst1 and participate in the regulation of these genes. Interestingly, even though C. glabrata and Saccharomyces cerevisiae are closely related phylogenetically, deletion of HST1 decreased susceptibility to fluconazole and hydrogen peroxide only in C. glabrata but not in S. cerevisiae, indicating a different transcriptional control by two similar sirtuins. Our findings suggest that Hst1 acts as a regulator of stress resistance associated-genes. PMID- 23651301 TI - Increased pregnancy after reduced male abstinence. AB - This study was conducted to test the hypothesis that continuous epididymal sperm depletion after recurrent ejaculations (REC) in contrast to a period of abstinence (ABS) results in a decreased level of sperm DNA fragmentation (SDF) and a consequent increased rate of pregnancy. Forty couples undergoing intra cytoplasmic injection (ICSI) were asked to abstain from ejaculation for a period of 4 days and then ejaculate once per day for a period of 4 days, followed by a period of abstinence for 12 hours; sperm samples obtained after ABS and REC were assessed for volume, concentration, motility, and SDF and compared in 25 of the patients. Additionally, and in a different experiment, the pregnancy rate of this experimental group (40 couples) was compared to a control group of 150 couples in which the males had abstained from ejaculation for 4 days prior to ejaculation. Sperm selection was performed using density gradient centrifugation prior to ICSI. Semen quality in the REC group that was assessed over the course of the ejaculation schedule showed a decrease in semen volume (67%) and SDF (27%) following sperm selection; there was no difference for sperm motility or sperm concentration. When the pregnancy rate between the 40 couples in the REC group and 150 couples in the control ABS group were compared, the REC group had a pregnancy rate of 56.4% (25/40), whereas the ABS rate was only 43.3% (65/150) (p = 0.030). We conclude that recurrent ejaculation every 24 hours for four days with a final abstinence of 12 hours, combined with sperm selection using density gradient centrifugation, produces a significant increase in pregnancy rate when using ICSI. As ICSI was the strategy selected for fertilization, we propose that the observed reduction in SDF was the primary factor leading to improved reproductive outcome. PMID- 23651302 TI - Virtual screening strategies in drug discovery: a critical review. AB - Virtual screening (VS) is a powerful technique for identifying hit molecules as starting points for medicinal chemistry. The number of methods and softwares which use the ligand and target-based VS approaches is increasing at a rapid pace. What, however, are the real advantages and disadvantages of the VS technology and how applicable is it to drug discovery projects? This review provides a comprehensive appraisal of several VS approaches currently available. In the first part of this work, an overview of the recent progress and advances in both ligand-based VS (LBVS) and structure-based VS (SBVS) strategies highlighting current problems and limitations will be provided. Special emphasis will be given to in silico chemogenomics approaches which utilize annotated ligand-target as well as protein-ligand interaction databases and which could predict or reveal promiscuous binding and polypharmacology, the knowledge of which would help medicinal chemists to design more potent clinical candidates with fewer side effects. In the second part, recent case studies (all published in the last two years) will be discussed where the VS technology has been applied successfully. A critical analysis of these case studies provides a good platform in order to estimate the applicability of various VS strategies in the new lead identification and optimization. PMID- 23651303 TI - Targeting PI3K/Akt/mTOR cascade: the medicinal potential, updated research highlights and challenges ahead. AB - Nowadays, cancer treatment is moving away from conventional cytotoxic drugs to target-based agents. This is primarily attributed to some remarkable leaps made in deciphering the tumor-relevant signaling pathways. Among them, PI3K/Akt/mTOR cascade presently elicits a substantial amount of pharmaceutical interests owing to its intimate role in tumor initiation and progression. Additionally, its medicinal potential lies in some protein kinases along the cascade, embracing PI3K, Akt and mTOR, which regulate crucial cellular activities. During the pursuit of PI3K axis inhibitors, medicinal chemistry efforts have diverged into three separate directions for addressing the issues associated with pioneering PI3K axis inhibitors, including poor pharmacokinetic (PK) profiles, low kinase specificity and lack of multiple inhibitory activities. Distinguished from other reviews in the literature, this article will outline these issues in sequence and give an account of recent medicinal chemistry efforts along with updated strides in surmounting them. Particularly, some candidates developed upon these efforts will be highlighted for their design rationale, preclinical performance or clinical status. Rather than merely focus on stunning breakthroughs, the review will critically remind us of the underlying challenges in developing PI3K axis modulators to direct the future research in this field. PMID- 23651304 TI - Role of microRNA deregulation in breast cancer cell chemoresistance and stemness. AB - Studies with breast cancer cells, showed that microRNAs (miRNAs) act as regulators of signaling pathways playing a key role in tumor progression and being targeted in chemotherapy. Deregulation of these pathways by altered miRNA expression or single nucleotide polymorphisms (SNPs) found in certain miRNA genes have been shown to lead tumor growth, metastasis, angiogenesis, and drug resistance. miRNAs have also been indicated to act on stem cell selfrenewal and alter signal transduction in cancer stem-like cells (CSC), which are resistant to many conventional therapies and account for the inability of these therapies to cure cancers. By considering these findings, miRNAs are proposed as potential novel biomarkers as well as therapeutic targets in new anti-cancer strategies. In this review, the miRNAs found to be involved in breast cancer chemoresistance will be covered together with breast CSC and their contribution to chemotherapy resistance. PMID- 23651305 TI - Deep penetration of nanoparticulate drug delivery systems into tumors: challenges and solutions. AB - In recent decades, nanoparticulate drug delivery systems have attracted extensive attention in cancer therapy for such appealing properties as small particle size, huge surface area, narrow size distribution and prolonged circulation time. Although several nanomedicines have successfully reached the clinical, evidences have proved that therapeutic efficacy isn't improved significantly, except for better toleration and less side effects. Given that the physiological abnormalities in tumors, multiple biobarriers need to be overcome before nanomedicines are delivered to the target site. Passive targeting nanoparticles ensure nanomedicines' extensive extravasation from tumor vessels via enhanced permeation and retention effect, but the diffusion distance is limited to 2-3 cell layer thicknesses. Active targeting nanoparticles tend to bind the peripheral cells of the tumor mass, hindering nanoparticles further penetration into the tumor core region. Therefore, how to improve the deep penetration of nanomedicines into tumors is a formidable task for achieving the desired anticancer therapeutic efficacy. This review demonstrates the penetration obstacles existing in tumor region for nanoparticles, summarizes the important properties of nanomedicines affecting tumor deep penetration and highlights the solutions to improve tumor deep penetration of nanoparticles. PMID- 23651306 TI - Recent advances in fluorescent probes for monitoring of hydrogen sulfide. AB - Hydrogen sulfide (H2S), known for its unpleasant rotten egg smell and its high toxicity, has recently emerged as an important mediator of human physiological and pathological processes, such as the regulation of cell growth, cardiovascular protection, the stimulation of angiogenesis, gastric mucosal injury and Alzheimer's disease. Due to its significant actions in the physiology, H2S has attracted the abundant concern of numerous researchers in the cutting edge of chemistry, biology and medicine. Recently, several fluorescent probes have been developed for detecting and elucidating the role played by H2S in biological systems. This review highlights recent advances that have been made on the mechanism and applications of fluorescent probes for the detection of H2S, demonstrating a new field in which remarkable improvements have been accomplished over the last two years. PMID- 23651307 TI - Nuclear estrogen receptors co-activation mechanisms. AB - Estrogens play very important role in opening the transcription event, which is a final step of activation of the first order mediators as receptors or channels in the cell wall by information coming from the outside of the cell. For the long time the exact step by step mechanism of cellular transfer of information to the cell nuclei was not known. Currently many new informations are available. Very important seems the step of phosphorylation and therefore desensitization of the target proteins. All peptide kinases, especially serine and threonine, like protein kinases A and C, RAS and MAP kinases, cycline kinases are potential or confirmed biological targets. Except them elements of the transcription complexes like p160.SRC-1, histon acetyltransferase and histon deacetylase, CBP/p300, TRAP/DRIP, NSD1, PPARgamma/PGC-1, NCOR1, SMRT, REA were also found useful. Finally estrogens are able to activate other receptors, namely aryl hydrocarbon receptors (AhR) and estrogen receptor related proteins (ERR). It is well known that many types of cancer are related to the direct or indirect excessive activation of nuclear estrogen receptors, therefore their inhibition could be crucial in many estrogen-related cancers. Understanding the interactions in such complexes would help in developing new and better multi-target cures and finding new ligands with better pharmacological and pharmacokinetic properties. PMID- 23651308 TI - Are plant extracts a potential therapeutic approach for genital infections? AB - More than 40% of the new drugs registered from 1981 to 2006 were obtained, derived or inspired from natural compounds. The influence of natural products in the anti-infective area is quite marked, being a great percentage of drugs derived or extracted from natural products. Vaginal infections are one of the most common reasons a women visits a gynecologist. Given the high popularity of natural therapies among women who suffer from chronic infections, it is urgent for women's healthcare providers to be knowledgeable about such therapies. Additionally, many phytotherapeutic products have been suggested as natural sources of antimicrobial compounds. The increased resistance to conventional antibiotics is one of the main factors justifying the search and development of new antimicrobial agents, especially those of natural origin. Currently, phytochemicals are considered by the scientific community as very attractive targets for potential drug discovery and therapy. In this review, we will focus on the most relevant reports published during the last twenty years about the antimicrobial activity of plant extracts upon microorganisms most frequently involved in genital infections, such as Candida spp., Gardnerella vaginalis, Trichomonas vaginalis and Human papillomavirus. The relationship between their composition and the antimicrobial effects will be highlighted and vaginal therapeutic delivery systems that vehicle plant extracts both commercialized and under investigation will be included. PMID- 23651309 TI - Traditional chinese medicine remedy to jury: the pharmacological basis for the use of shikonin as an anticancer therapy. AB - Shikonin is the major constituent of the root of Lithospermum erythrorhizon, which has been used in traditional Chinese medicine to treat external wounds, burns, or dermatitis for centuries. Nowadays, this root is commonly used as an herbal medicine against cancer. Studies carried out over the past 30 years have demonstrated that many of the effects historically associated with the use of this root have a scientific basis, with shikonin and its derivatives being responsible for its pharmacological properties. These include both anti inflammatory and anticancer effects. While previous summaries have focused on the pharmacokinetics and toxicity of shikonin, the aim of this review is to report on the most current findings with regard to shikonin's antitumor activity by summarizing and comparing the various studies published in the last ten years and discussing the pharmacological aspects that make shikonin a promising anticancer agent. PMID- 23651311 TI - Oxygen defects and surface chemistry of ceria: quantum chemical studies compared to experiment. PMID- 23651310 TI - Tuning self-assembled nanostructures through enzymatic degradation of a peptide amphiphile. AB - The enzymatic cleavage of a peptide amphiphile (PA) is investigated. The self assembly of the cleaved products is distinct from that of the PA substrate. The PA C16-KKFFVLK is cleaved by alpha-chymotrypsin at two sites leading to products C16-KKF with FVLK and C16-KKFF with VLK. The PA C16-KKFFVLK forms nanotubes and helical ribbons at room temperature. Both PAs C16-KKF and C16-KKFF corresponding to cleavage products instead self-assemble into 5-6 nm diameter spherical micelles, while peptides FVLK and VLK do not adopt well-defined aggregate structures. The secondary structures of the PAs and peptides are examined by FTIR and circular dichroism spectroscopy and X-ray diffraction. Only C16-KKFFVLK shows substantial beta-sheet secondary structure, consistent with its self-assembly into extended aggregates, based on PA layers containing hydrogen-bonded peptide headgroups. This PA also exhibits a thermoreversible transition to twisted tapes on heating. PMID- 23651312 TI - Uptake of 210Po by aquatic plants of a fresh water ecosystem around the uranium mill tailings management facility of Jaduguda, India. AB - PURPOSE: The present study was designed to investigate the uptake of Polonium-210 ((210)Po) by aquatic plants growing in a fresh water ecosystem around the tailings management facility of the uranium industry of Jaduguda, India. Evaluation of the activity concentration of (210)Po in aquatic plants, the concentration ratio of (210)Po from substrate to plants and the relationship of (210)Po with other stable elements were major objectives of the investigation. MATERIALS AND METHODS: Based on the habitat, three types of plant were collected and analyzed for (210)Po activity estimation. Along with aquatic plants, effluent, surface water and bottom sediment were also collected and analyzed for (210)Po activity content. From the acid solution (210)Po was electrodeposited on brightly polished silver discs and counted for alpha activity in an alpha counter. RESULTS: The highest (210)Po activity concentration (4884 Bq kg(-1) fresh weight) was found in filamentous algae from residual water of the tailings pond. For sediment-rooted plants, a significant positive correlation (r = 0.91, p < 0.0001) was observed between plant and sediment activity concentration of (210)Po. CONCLUSIONS: For all of the three different groups of plants studied, highly significant correlations were observed between activity concentration of (210)Po and Cu with the significance level variation between 0.00-0.05 (both for linear and log transformed data). PMID- 23651313 TI - Results from a large multinational clinical trial (guardianTM3) using prophylactic treatment with turoctocog alfa in paediatric patients with severe haemophilia A: safety, efficacy and pharmacokinetics. AB - Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open-label, non controlled trial investigated the safety, efficacy and pharmacokinetics (PK) of turoctocog alfa, a new rFVIII product, in a paediatric population. The primary objective was to evaluate safety. A total of 31 younger children (0-5 years) and 32 older children (6-11 years), with >= 50 exposure days to any factor VIII (FVIII) product and no history of inhibitors, received prophylaxis with turoctocog alfa (25-50 IU kg(-1) every second day or 25-60 IU kg(-1) three times weekly). PK assessments of turoctocog alfa and the patients' previous FVIII product were performed in 28 patients. Mean exposure to turoctocog alfa was 60 exposure days per patient. This corresponds to approximately 4.5 months in the trial. None of the patients developed inhibitors (>= 0.6 BU) and no safety concerns were raised. A total of 120 bleeding episodes (95%) were controlled with 1-2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as 'excellent' or 'good' haemostatic response) for treatment of bleeding episodes was 92%. Overall, the median annualized bleeding rate was 3.0 (interquartile range: 8.5) bleeds patient(-1) year(-1) . PK parameters were comparable between the two age groups. In conclusion, the present large global clinical trial showed that turoctocog alfa was safe, effective in treatment of bleeding episodes and had a prophylactic effect in paediatric patients. PMID- 23651314 TI - Wafer-scale production of uniform InAs(y)P(1-y) nanowire array on silicon for heterogeneous integration. AB - One-dimensional crystal growth allows the epitaxial integration of compound semiconductors on silicon (Si), as the large lattice-mismatch strain arising from heterointerfaces can be laterally relieved. Here, we report the direct heteroepitaxial growth of a mixed anion ternary InAsyP1-y nanowire array across an entire 2 in. Si wafer with unprecedented spatial, structural, and special uniformity across the entire 2 in. wafer and dramatic improvements in aspect ratio (>100) and area density (>5 * 10(8)/cm(2)). Heterojunction solar cells consisting of n-type InAsyP1-y (y = 0.75) and p-type Si achieve a conversion efficiency of 3.6% under air mass 1.5 illumination. This work demonstrates the potential for large-scale production of these nanowires for heterogeneous integration of optoelectronic devices. PMID- 23651315 TI - Effects of tobacco smoking on the survival rate of dental implants placed in areas of maxillary sinus floor augmentation: a systematic review. AB - OBJECTIVES: The objective of this systematic review was to evaluate the effects of smoking on the survival rate of dental implants placed in areas of maxillary sinus floor augmentation. MATERIAL AND METHODS: The Cochrane Oral Health Group's Trials Register (CENTRAL), MEDLINE and EMBASE were searched in duplicate up to, and including, October 2012 without language restrictions. Studies were considered eligible for inclusion if they involved the treatment of smokers and non-smokers with titanium implants and sinus floor elevation procedures. The Newcastle-Ottawa Scale and the Cochrane Collaboration's quality assessment tool were used for the assessment of the risk of bias in included studies. Random effects meta-analyses were used to assess the number of implants lost in smokers vs. number of implants lost in non-smokers. RESULTS: Of 3360 potentially eligible papers, eight studies were included. More than half (62.5%) of the studies found that smoking adversely affects implant survival in sites of sinus floor augmentation. Similarly, the pooled analysis indicated a statistically significantly increased risk of implant failure in smokers when the outcomes of all studies available to be included into meta-analysis were evaluated [RR: 1.87 (95% CI: 1.35, 2.58), P = 0.0001]. Conversely, a subgroup analysis including only prospective studies (3 studies) did not reveal significant differences in implant failure between smokers and non-smokers [RR: 1.55 (95% CI: 0.91, 2.65), P = 0.11]. CONCLUSIONS: Although smoking was associated with implant failure in most of individual studies and in the overall meta-analysis, the detrimental effect of smoking was not confirmed when only prospective data were assessed. PMID- 23651316 TI - Anti-H5N1 virus flavonoids from Capparis sinaica Veill. AB - Methanolic extract of Capparis sinaica Veill was tested for its in vitro antiviral activity against highly pathogenic avian influenza strain H5N1 using plaque inhibition assay in Madin-Darby canine kidney. The results indicated that the extract possessed potent antiviral activity (100% inhibition at the concentration of 1 MUg/ml). Based on this result, C. sinaica Veill was selected for further study by applying bioactivity-guided fractionation to isolate its antiviral principles. The fractions eluted with EtOAc and 25% MeOH in EtOAc were found to hold the antiviral activity. Further chromatographic separation of the fractions holding the antiviral activity led to the isolation of quercetin (1), isoquercetin (2) and rutin (3) for the first time from this species. The isolates showed reduction in the virus titre by 68.13%, 79.66% and 73.22% inhibition at a concentration of 1 ng/ml, respectively. PMID- 23651317 TI - Specific binding of aluminium and iron ions to a cation-selective cell wall channel of Microthrix parvicella. AB - Heavy metal salts containing aluminium or iron are used in wastewater treatment to control excessive growth of the Gram-positive bacterium Microthrix parvicella, frequently observed in wastewater plants suffering from bulking, foaming and scum. Microthrix parvicella belongs to the class Actinobacteria but not to mycolata, although its taxonomic position in this class is not identified. Investigations using the microspheres adhesion to cells method (MAC) suggested that M. parvicella is as strongly hydrophobic as the mycolic acid containing actinomycetes. The cell wall of M. parvicella was investigated for the presence of water-filled channels using the lipid bilayer assay. An ion-permeable channel called MppA with a conductance of 600 pS in 1 M KCl was identified in cell wall extracts and purified to homogeneity. The cation-selective channel showed no voltage-dependent closure at higher voltages. Interestingly, MPPA could be blocked by heavy metal ions. Binding of polyvalent cations such as iron and aluminium was studied in titration experiments and revealed stability constants for their binding to MppA up to 700 M(-1). The cell wall channel of M. parvicella contains a binding site for polyvalent cations which may play a crucial role for the effect of heavy metals salts on M. parvicella-dominated activated sludge. PMID- 23651318 TI - Spectral-to-temporal amplitude mapping polarization spectroscopy of rotational transients. AB - A new implementation of pump-probe polarization spectroscopy is presented where the revivals of an impulsively excited rotational wavepacket are mapped onto a broad-band, chirped continuum pulse to measure a long temporal window without the need for delay scanning. Experimental measurements and a theoretical framework for spectral-temporal amplitude mapping polarization spectroscopy (STAMPS) as applied to impulsive rotational motion are presented. In this technique, a femtosecond laser pulse is used to prepare a rotational wavepacket in a gas-phase sample at room temperature. The rotational revivals of the wavepacket are then mapped onto a chirped continuum (400-800 nm) pulse created by laser filamentation in argon. Nearly single-shot time-resolved rotational spectra are recorded over a 65 ps time window. The transient birefringence spectra are simulated by including terms for polarization rotation of the probe as well as cross-phase modulation. Measurements and simulations are presented for the cylindrically symmetric N2, O2, and CO2 molecules. The long time window of the method allows measurement of rotational spectra for asymmetric top molecules, and here we present measurements for ethylene and methanol. PMID- 23651319 TI - Overexpression of microRNA319 impacts leaf morphogenesis and leads to enhanced cold tolerance in rice (Oryza sativa L.). AB - MicroRNA319 (miR319) family is one of the conserved microRNA (miRNA) families among diverse plant species. It has been reported that miR319 regulates plant development in dicotyledons, but little is known at present about its functions in monocotyledons. In rice (Oryza sativa L.), the MIR319 gene family comprises two members, Osa-MIR319a and Osa-MIR319b. Here, we report an expression pattern analysis and a functional characterization of the two Osa-MIR319 genes in rice. We found that overexpressing Osa-MIR319a and Osa-MIR319b in rice both resulted in wider leaf blades. Leaves of osa-miR319 overexpression transgenic plants showed an increased number of longitudinal small veins, which probably accounted for the increased leaf blade width. In addition, we observed that overexpressing osa miR319 led to enhanced cold tolerance (4 degrees C) after chilling acclimation (12 degrees C) in transgenic rice seedlings. Notably, under both 4 and 12 degrees C low temperatures, Osa-MIR319a and Osa-MIR319b were down-regulated while the expression of miR319-targeted genes was induced. Furthermore, genetically down-regulating the expression of either of the two miR319-targeted genes, OsPCF5 and OsPCF8, in RNA interference (RNAi) plants also resulted in enhanced cold tolerance after chilling acclimation. Our findings in this study demonstrate that miR319 plays important roles in leaf morphogenesis and cold tolerance in rice. PMID- 23651320 TI - Early effect of vomerine flap closure of the hard palate at the time of lip repair on the alveolar gap and other maxillary dimensions. AB - OBJECTIVE: Comparison of the effects of vomerine flap (VF) closure of the hard palate at the time of lip repair with non-closure of the hard palate in subjects with unilateral cleft lip and palate (UCLP). DESIGN: Retrospective, single blinded, cohort study. SETTING: Study model sets of 40 consecutive, non syndromic, infants with complete UCLP operated on between 1988 and 1998. PATIENTS: All subjects were operated on by a single consultant plastic surgeon immediately before and after the unit's change of protocol (1993), when VF closure of the hard palate was incorporated at the time of lip repair. Subjects were divided into two groups: VF ( n = 18) and non-VF (n = 22), which acted as a control group. Each subject had maxillary impressions taken before lip repair at 3 months (VF mean age = 11.7 weeks; non-VF mean age = 13.4 weeks) and before palate repair at 6 months (VF mean age = 22.8 weeks; non-VF mean age = 24.0 weeks). MAIN OUTCOME MEASURES: Seven predetermined landmarks and four maxillary dimensions were computed following single-blinded analysis using a reflex microscope. RESULTS: Repeatability tests showed good measurement precision. The operator measurement errors were 0.00018 mm in a horizontal plane (X and Y) and 0.00028 in the vertical plane (Z). The VF group showed significant changes in the alveolar cleft width. There were no statistically significant changes in any arch form variable between the VF and non-VF groups. CONCLUSION: The decrease of alveolar arch gap width at palate repair (6 months) in the VF group was significantly more than the decrease observed in the non-VF group, and there was no significant decrease in the, anterior and posterior arch width or anteroposterior length of the hard palate in the VF group compared with the non VF group. PMID- 23651321 TI - Complex Archimedean tiling self-assembled from DNA nanostructures. AB - Archimedean tilings are periodic polygonal tessellations that are created by placing regular polygons edge-to-edge around a vertex to fill the plane. Here we show that three- and four-arm DNA junction tiles with specifically designed arm lengths and intertile sticky-end interactions can be used to form sophisticated two-dimensional (2D) and three-dimensional (3D) tessellation patterns. We demonstrate two different complex Archimedean patterns, (3(3).4(2)) and (3(2).4.3.4), and the formation of 2D lattices, 3D tubes, and sealed polygon shaped pockets from the tessellations. The successful growth of hybrid DNA tile motif arrays suggests that it maybe possible to generate 2D quasi-crystals from DNA building blocks. PMID- 23651322 TI - The occurrence of bleaching stripe disease in Gracilaria corticata and controlling of the disease using quorum quenching approach. AB - In the present study, the Gram-negative bacteria Vibrio and Pseudoalteromonas species associated with Gracilaria corticata found to be opportunistic pathogens that caused bleaching stripe disease on its host. Consortium of these pathogens induced maximum disease symptoms with 27.3 mm long bleaching stripe. Presence of Gram-positive bacteria Bacillus reduced the disease appearances in the co-culture of Gram-negative bacteria. Each Gram-negative bacteria had capability to produce two different types of AHLs. For the first time found that in the addition of (Z ) - 4- Bromo- 5- (bromomethylene) - 2(5H)- furanone with co-culture of pathogenic bacteria and host fronds significantly minimized the bleaching stripe symptoms. Incubating of pathogenic bacteria with 8 and 10 MUm ml(-1) of furanone did not able to induce disease symptoms. The present study will help to understand the chemical interaction between Gram- positive and negative bacteria in marine environment. This article is protected by copyright. All rights reserved. PMID- 23651323 TI - Ions-induced nanostructuration: effect of specific ionic adsorption on hydrophobic polymer surfaces. AB - The effect of surface charges on the ionic distribution in close proximity to an interface has been extensively studied. On the contrary, the influence of ions (from dissolved salts) on deformable interfaces has been barely investigated. Ions can adsorb from aqueous solutions on hydrophobic surfaces, generating forces that can induce long-lasting deformation of glassy polymer films, a process called ion-induced polymer nanostructuration, IPN. We have found that this process is ion-specific; larger surface modifications are observed in the presence of water ions and hydrophobic and amphiphilic ions. Surface structuration is also observed in the presence of certain salts of lithium. We have used streaming potential and atomic force microscopy to study the effect of dissolved ions on the surface properties of polystyrene films, finding a good correlation between ionic adsorption and IPN. Our results also suggest that the presence of strongly hydrated lithium promotes the interaction of anions with polystyrene surfaces and more generally with hydrophobic polymer surfaces, triggering then the IPN process. PMID- 23651324 TI - Reticulated acanthoma with sebaceous differentiation: another sebaceous neoplasm associated with Muir-Torre syndrome? AB - Reticulated acanthoma with sebaceous differentiation (RASD) represents a rare benign cutaneous epithelial neoplasm with sebaceous differentiation. There has been much speculation about the relationship between RASD and Muir-Torre syndrome (MTS). We report a 53 year-old man who presented with RASD in addition to a prior history of sebaceous adenomas. Immunohistochemically, the tumour cells in the RASD and sebaceous adenomas showed a significantly reduced MSH6 protein expression, whereas there was no loss of MLH1, MSH2 and PMS2. This benign neoplasm, which can be mistaken for various other cutaneous lesions with sebaceous differentiation, deserves wider recognition for its possible association with MTS. PMID- 23651325 TI - Peptide radicals and cation radicals in the gas phase. PMID- 23651326 TI - Haloferax volcanii archaeosortase is required for motility, mating, and C terminal processing of the S-layer glycoprotein. AB - Cell surfaces are decorated by a variety of proteins that facilitate interactions with their environments and support cell stability. These secreted proteins are anchored to the cell by mechanisms that are diverse, and, in archaea, poorly understood. Recently published in silico data suggest that in some species a subset of secreted euryarchaeal proteins, which includes the S-layer glycoprotein, is processed and covalently linked to the cell membrane by enzymes referred to as archaeosortases. In silico work led to the proposal that an independent, sortase-like system for proteolysis-coupled, carboxy-terminal lipid modification exists in bacteria (exosortase) and archaea (archaeosortase). Here, we provide the first in vivo characterization of an archaeosortase in the haloarchaeal model organism Haloferax volcanii. Deletion of the artA gene (HVO_0915) resulted in multiple biological phenotypes: (a) poor growth, especially under low-salt conditions, (b) alterations in cell shape and the S layer, (c) impaired motility, suppressors of which still exhibit poor growth, and (d) impaired conjugation. We studied one of the ArtA substrates, the S-layer glycoprotein, using detailed proteomic analysis. While the carboxy-terminal region of S-layer glycoproteins, consisting of a putative threonine-rich O glycosylated region followed by a hydrophobic transmembrane helix, has been notoriously resistant to any proteomic peptide identification, we were able to identify two overlapping peptides from the transmembrane domain present in the DeltaartA strain but not in the wild-type strain. This clearly shows that ArtA is involved in carboxy-terminal post-translational processing of the S-layer glycoprotein. As it is known from previous studies that a lipid is covalently attached to the carboxy-terminal region of the S-layer glycoprotein, our data strongly support the conclusion that archaeosortase functions analogously to sortase, mediating proteolysis-coupled, covalent cell surface attachment. PMID- 23651327 TI - Children's and parents' perceptions of postoperative pain management: a mixed methods study. AB - AIMS AND OBJECTIVES: To explore children's and parents' perceptions about the quality of postoperative pain management. BACKGROUND: Children continue to experience moderate to severe pain postoperatively. Unrelieved pain has short- and long-term undesirable consequences. Thus, it is important to ensure pain is managed effectively. Little research has explored children's and parents' perceptions of pain management. DESIGN: Exploratory study. METHODS: Children (n = 8) were interviewed about their perceptions of pain care using the draw-and-write technique or a semi-structured format and asked to rate the worst pain experienced postoperatively on a numerical scale. Parents (n = 10) were asked to complete the Information About Pain questionnaire. Data were collected in 2011. RESULTS: Most children experienced moderate to severe pain postoperatively. Children reported being asked about their pain, receiving pain medication and using nonpharmacological methods of pain relief. A lack of preoperative preparation was evident for some children. Most parents indicated they had received information on their child's pain management. Generally, participants were satisfied with care. CONCLUSION: Participants appeared satisfied with the care provided despite experiencing moderate to severe pain. This may be attributable to beliefs that nurses would do everything they could to relieve pain and that some pain is to be expected postsurgery. RELEVANCE TO CLINICAL PRACTICE: Children are still experiencing moderate to severe pain postoperatively. Given the possible short- and long-term consequences of unrelieved pain, this is of concern. Knowledge translation models may support the use of evidence in practice, and setting a pain goal with parents and children may help improve care. PMID- 23651328 TI - Mechanism of hypocoagulability in proton-irradiated ferrets. AB - PURPOSE: To determine the mechanism of proton radiation- induced coagulopathy. MATERIAL AND METHODS: Ferrets were exposed to either solar particle event (SPE) like proton radiation at a predetermined dose rate of 0.5 Gray (Gy) per hour (h) for a total dose of 0 or 1 Gy. Blood was collected pre- and post-irradiation for a complete blood cell count or a soluble fibrin concentration analysis, to determine whether coagulation activation had occurred. Tissue was stained with an anti-fibrinogen antibody to confirm the presence of fibrin in blood vessels. RESULTS: SPE-like proton radiation exposure resulted in coagulation cascade activation, as determined by increased soluble fibrin concentration in blood from 0.7-2.4 at 3 h, and 9.9 soluble fibrin units (p < 0.05) at 24 h post-irradiation and fibrin clots in blood vessels of livers, lungs and kidneys from irradiated ferrets. In combination with this increase in fibrin clots, ferrets had increased prothrombin time and partial thromboplastin time values post-irradiation, which are representative of the extrinsic/intrinsic coagulation pathways. Platelet counts remained at pre-irradiation values over the course of 7 days, indicating that the observed effects were not platelet-related, but instead likely to be due to radiation-induced effects on secondary hemostasis. White blood cell (WBC) counts were reduced in a statistically significant manner from 24 h through the course of the seven-day experiment. CONCLUSIONS: SPE-like proton radiation results in significant decreases in all WBC counts as well as activates secondary hemostasis; together, these data suggest severe risks to astronaut health from exposure to SPE radiation. PMID- 23651329 TI - The key regulatory roles of the PI3K/Akt signaling pathway in the functionalities of mesenchymal stem cells and applications in tissue regeneration. AB - Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into various cell types and have been widely used in tissue engineering application. In tissue engineering, a scaffold, MSCs and growth factors are used as essential components and their interactions have been regarded to be important for regeneration of tissues. A critical problem for MSCs in tissue engineering is their low survival ability and functionality. Most MSCs are going to be apoptotic after transplantation. Therefore, increasing MSC survival ability and functionalities is the key for potential applications of MSCs. Several approaches have been studied to increase MSC tissue forming capacity including application of growth factors, overexpression of stem cell regulatory genes, and improvement of biomaterials for scaffolds. The effects of these approaches on MSCs have been associated with activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. The pathway plays central regulatory roles in MSC survival, proliferation, migration, angiogenesis, cytokine production, and differentiation. In this review, we summarize and discuss the literatures related to the roles of the PI3K/Akt pathway in the functionalities of MSCs and the involvement of the pathway in biomaterials-increased MSC functionalities. Biomaterials have been modified in their properties and surface structure and loaded with growth factors to increase MSC functionalities. Several studies demonstrated that the biomaterials-increased MSC functionalities are mediated by the activation of the PI3K/Akt pathway. PMID- 23651330 TI - Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design. AB - Constitutive activation of signal transducer and activator of transcription 3 (STAT3) has been validated as an attractive therapeutic target for cancer therapy. To stop both STAT3 activation and dimerization, a viable strategy is to design inhibitors blocking its SH2 domain phosphotyrosine binding site that is responsible for both actions. A new fragment-based drug design (FBDD) strategy, in silico site-directed FBDD, was applied in this study. A designed novel compound, 5,8-dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-sulfonamide (LY5), was confirmed to bind to STAT3 SH2 by fluorescence polarization assay. In addition, four out of the five chosen compounds have IC50 values lower than 5 MUM for the U2OS cancer cells. 8 (LY5) has an IC50 range in 0.5-1.4 MUM in various cancer cell lines. 8 also suppresses tumor growth in an in vivo mouse model. This study has demonstrated the utility of this approach and could be used to other drug targets in general. PMID- 23651331 TI - Laboratory-based scoring system for prediction of hepatic inflammatory activity in patients with autoimmune hepatitis. AB - BACKGROUND & AIMS: In autoimmune hepatitis (AIH), inflammation is closely related to fibrosis. Although transaminase levels are commonly used to assess hepatic inflammation, they may not relate directly to the histology. We developed a noninvasive diagnostic score as an alternative to liver biopsy to help optimize treatment for AIH and monitor disease progress. METHODS: Eighty-two participants with type 1 AIH who had undergone liver biopsy were included (44 in training and 38 in validation sets). Liver histology was assessed according to the histologic activity index (HAI; score 0-18) and Ishak's histologic fibrosis index (HFI; score 0-6). High inflammation was defined as HAI>4, and advanced fibrosis was defined as HFI>2. Routine laboratory test findings and stepwise linear regression were used to develop the best models predicting HAI and HFI. The best cut-off value to predict high inflammation and advanced fibrosis for these formulas was then calculated based on receiver-operating characteristic analysis. RESULTS: The cut-off value for a model predicting high inflammation was >=3.57 (AUROC = 0.93; 95% CI: 0.86-1.00), with 100% sensitivity and 85% specificity. High inflammation was confirmed with an 81% positive predictive value and excluded with a 100% negative predictive value. In the validation set, the sensitivity, specificity, positive predictive value and negative predictive values were 100, 56, 88 and 100% respectively. The diagnostic yield of the fibrosis score was unsatisfactory. CONCLUSIONS: The noninvasive inflammatory score based on four routine laboratory parameters discriminated patients with and without significant hepatic inflammation and may facilitate follow-up of type 1 AIH patients. PMID- 23651332 TI - Effects of molybdenum on sperm quality and testis oxidative stress. AB - In order to investigate the effects of molybdenum (Mo) on sperm parameters and testicular oxidative stress, the ICR strain of adult mice were exposed to different doses of molybdenum for a sub-acute toxicity test. Compared to the control, our results showed that the sperm parameters, including the epididymis index, sperm motility, sperm count, and morphology, increased by a moderate dose of Mo (25 mg/L), but were negatively affected at high doses (>= 100 mg/L). In addition, the changes of sperm parameters were accompanied with changes of the superoxide dismutase (SOD) activities, the glutathione peroxidase (GPx) activities, and the malondialdehyde (MDA) levels in testes. In conclusion, Mo affects the sperm quality through regulating the testicular oxidative stress in a complex manner. PMID- 23651333 TI - The effects of ErhBMP-2-/EGCG-coated BCP bone substitute on dehiscence around dental implants in dogs. AB - OBJECTIVES: The purpose was to evaluate the effect of Escherichia coli-derived recombinant human bone morphogenetic protein-2 (ErhBMP-2)-/epigallocatechin-3 gallate (EGCG)-coated biphasic calcium phosphate (BCP) and titanium barrier membrane on dehiscence defects in dogs. MATERIALS AND METHODS: In five mongrel dogs, the dehiscence bony defects around dental implants were surgically created and in total three implants were placed at edentulous ridge of which teeth had been extracted 12 weeks before. For the control group, BCP was applied to the dehiscence defect. For experimental groups, ErhBMP-2-coated BCP and ErhBMP-2 /EGCG-coated BCP were applied. The newly designed titanium barrier membrane was used to apply all the defects. The defects were evaluated histologically and histometrically after 12 weeks. The comparative statistics of the groups were obtained through Kruskal-Wallis test. RESULTS: In bone-to-implant contact (BIC), bone density (BD), bone regeneration height (BRH), and bone mineralization apposition rate (BMAR), differences among groups were not found. ErhBMP-2/EGCG group appeared to have higher value. In fluorescence analysis, bone remodeling around graft material was more active in the ErhBMP-2/EGCG group. CONCLUSION: Within the limit of this study, it is reasonable to assume that BMP-2-/EGCG coated biphasic BCP and the newly designed titanium membrane were more beneficial in dehiscence defect healing with increased bone remodeling. PMID- 23651334 TI - Dodecanuclear hexagonal-prismatic M12L18 coordination cages by subcomponent self assembly. AB - Dodecanuclear hexagonal-prismatic M12L18 cages were prepared by a subcomponent self-assembly process with commercially available pyridinecarboxaldehyde, m xylenediamine, and cadmium(II) perchlorate or manganese(II) perchlorate. The NMR spectrum of the Cd cage shows that there are three independent ligand sets, and the X-ray crystal structure of the Mn cage reveals that the structure has both fac-Delta- and mer-Lambda-configured metal centers in a 1:1 ratio. The cage structure also has a large cavity that contains five perchlorate anions. PMID- 23651337 TI - A combinatorial library of unsaturated lipidoids for efficient intracellular gene delivery. AB - A combinatorial library of unsaturated lipidoids was synthesized through the Michael addition of amines to oleyl acrylamide. Their capability in facilitating in vitro gene delivery was evaluated by transfecting HeLa cells with EGFP encoding plasmid DNA and mRNA. The preliminary screening results indicated that lipidoids with unsaturated oleyl tails are superior transfection agents compared to saturated lipidoids with n-octadecyl tails under the same conditions. The different transfection abilities of the unsaturated and saturated lipidioids were ascribed to the large, tightly packed lipoplexes of saturated lipidoids. The potential applications of the library of lipidoids were further expanded by looking at their ability to transfect fibroblasts as well as different cancerous cell lines. PMID- 23651338 TI - Genome replication, synthesis, and assembly of the bacteriophage T7 in a single cell-free reaction. AB - The synthesis of living entities in the laboratory is a standing challenge that calls for innovative approaches. Using a cell-free transcription-translation system as a molecular programming platform, we show that the bacteriophage T7, encoded by a 40 kbp DNA program composed of about 60 genes, can be entirely synthesized from its genomic DNA in a test tube reaction. More than a billion infectious bacteriophages T7 per milliliter of reaction are produced after a few hours of incubation. The replication of the genomic DNA occurs concurrently with phage gene expression, protein synthesis, and viral assembly. The demonstration that genome-sized viral DNA can be expressed in a test tube, recapitulating the entire chain of information processing including the replication of the DNA instructions, opens new possibilities to program and to study complex biochemical systems in vitro. PMID- 23651339 TI - Efficient orthogonal integration of the bacteriophage phi29 DNA-portal connector protein in engineered lipid bilayers. AB - The portal connector of bacteriophage viruses constitutes a robust molecular machine for DNA translocation. In this paper we propose an optimized reconstitution method for efficient orthogonal integration of native viral connectors into lipid bilayers, particularly of giant unilamellar vesicles. Our nanoengineering plan considers the hydrophilic connector protein of the bacteriophage virus phi29 integrated into a specifically engineered bilayer made of "hydrophylized" lipids. From the precise knowledge of the connector structure, the membrane chemistry was designed by tuning reactivity in the bilayer using specific functional lipids. We show details on the reconstitution methods and experimental evidence about the integration of the portal protein in the engineered membrane. The proposed route provides an efficient method for orthogonal integration of native viral connectors into lipid bilayers in conditions adequate for functional DNA translocation. This concept could be potentially exploited in advanced nanotechnological realizations, particularly for the integration of these powerful machines into giant lipid vesicles with the aim of building a cargo-device useful for gene delivery applications. PMID- 23651340 TI - Effects of compartment size on the kinetics of intracompartmental multimeric protein synthesis. AB - The cell contents are encapsulated within a compartment, the volume of which is a fundamental physical parameter that may affect intracompartmental reactions. However, there have been few studies to elucidate whether and how volume changes alone can affect the reaction kinetics. It is difficult to address these questions in vivo, because forced cell volume changes, e.g., by osmotic inflation/deflation, globally alters the internal state. Here, we prepared artificial cell-like compartments with different volumes but with identical constituents, which is not possible with living cells, and synthesized two tetrameric enzymes, beta-glucuronidase (GUS) and beta-galactosidase (GAL), by cell-free protein synthesis. Tetrameric GUS but not GAL was synthesized more quickly in smaller compartments. The difference between the two was dependent on the rate-limiting step and the reaction order. The observed acceleration mechanism would be applicable to living cells as multimeric protein synthesis in a microcompartment is ubiquitous in vivo. PMID- 23651341 TI - Kaye Middleton Fillmore, 1941-2013. PMID- 23651342 TI - Nanoscale infrared (IR) spectroscopy and imaging of structural lipids in human stratum corneum using an atomic force microscope to directly detect absorbed light from a tunable IR laser source. AB - An atomic force microscope (AFM) and a tunable infrared (IR) laser source have been combined in a single instrument (AFM-IR) capable of producing ~200-nm spatial resolution IR spectra and absorption images. This new capability enables IR spectroscopic characterization of human stratum corneum at unprecendented levels. Samples of normal and delipidized stratum corneum were embedded, cross sectioned and mounted on ZnSe prisms. A pulsed tunable IR laser source produces thermomechanical expansion upon absorption, which is detected through excitation of contact resonance modes in the AFM cantilever. In addition to reducing the total lipid content, the delipidization process damages the stratum corneum morphological structure. The delipidized stratum corneum shows substantially less long-chain CH2 -stretching IR absorption band intensity than normal skin. AFM-IR images that compare absorbances at 2930/cm (lipid) and 3290/cm (keratin) suggest that regions of higher lipid concentration are located at the perimeter of corneocytes in the normal stratum corneum. PMID- 23651343 TI - Serum levels and activity of indoleamine2,3-dioxygenase and tryptophanyl-tRNA synthetase and their association with disease severity in patients with chronic kidney disease. AB - OBJECTIVE: This study aims to test the serum levels and activity of indoleamine2,3-dioxygenase(IDO) and tryptophanyl-tRNA synthetase (TTS) in patients with chronic kidney disease (CKD) and to evaluate their association with disease severity. METHOD: Serum concentrations of IDO and TTS in 61 patients with CKD and 16 healthy volunteers were tested by ELISA. Tryptophan and kynurenine concentrations were measured by high-performance liquid chromatography (HPLC). RESULTS: Patients with CKD showed higher serum levels of IDO and TTS in comparison to healthy controls (p = 0.001). Patients with CKD showed lower serum levels of tryptophan and higher serum levels of kynurenine in comparison to healthy controls (p < 0.001). The kyn/Trp ratio significantly correlated with the disease severity in CKD patients (r = 0.721; p < 0.001). CONCLUSIONS: IDO and TTS may play critical roles in the immune pathogenesis of CKD. The activity of IDO correlated with the disease severity of CKD. PMID- 23651344 TI - Serial measurements of high-sensitivity cardiac troponin T after exercise stress test in stable coronary artery disease. AB - OBJECTIVE: The aim was to assess serial measurements of high-sensitivity cardiac troponin T (hs-cTNT) post-exercise in patients with stable coronary artery disease (CAD). METHODS: Twelve patients with positive coronary angiograms (CAD positives) and 12 controls performed an exercise stress test. RESULTS: CAD positive had higher baseline and peak concentrations of hs-cTNT than controls. Significant increases in hs-cTNT were seen in both groups after exercise. In two third of patients the peak in hs-cTNT was above the 99th percentile. CONCLUSION: hs-cTNT is higher in patients with stable coronary disease than in controls and exceeds the diagnostic cut-off value for myocardial infarction in a majority of patients with CAD after exercise. PMID- 23651345 TI - Composite alginate microspheres as the next-generation egg-box carriers for biomacromolecules delivery. AB - INTRODUCTION: Alginate microspheres are versatile tools for the delivery of a wide range of therapeutic biomacromolecules. This naturally occurring biopolymer has many unique properties making it an ideal candidate for tailoring with different composites of polymers leading to the formation of strong complexes for a broad range of applications. AREAS COVERED: This article overviews various types of composite alginate microspheres, methods of preparation, new technologies available, physico-chemical characteristics, controlled release profiles, applications and the future directions of composite alginate microsphere delivery system for biomacromolecules. EXPERT OPINION: Composite alginate microsphere systems are the ideal carriers for controlled delivery applications because of their ability to encapsulate a myriad of therapeutic drugs, proteins, enzymes, DNA, antisense oligonucleotides, vaccines, growth factors and chemokines as well as the ease of processing, mechanical properties, biocompatibility, high bioavailability, controlled release rates, stability, suitability for different administration modes, targeted/localized delivery of different agents and large-scale production with cost-effectiveness. This article presents updated information of applying microalginate-based technologies and tools in the biomedical field which will benefit research scientists and clinical physicians or biopharmaceutical industries keen in the development of application based new therapeutic and diagnostic strategies for various diseases. Furthermore, this technology will play more important roles in biosensors, vaccination, tissue engineering, cancer chemotherapeutics and stem cell research. PMID- 23651346 TI - Linear mesostructures in DNA--nanorod self-assembly. AB - The assembly of molecules and nanoscale objects into one-dimensional (1D) structures, such as fibers, tubules, and ribbons, typically results from anisotropic interactions of the constituents. Conversely, we found that a 1D structure can emerge via a very different mechanism, viz, the spontaneous symmetry breaking of underlying interparticle interactions during structure formation. For systems containing DNA-decorated nanoscale rods, this mechanism, driven by flexible DNA chains, results in the formation of 1D ladderlike mesoscale ribbons with a side-by-side rod arrangement. Detailed structural studies using electron microscopy and in situ small-angle X-ray scattering (SAXS), as well as analysis of assembly kinetics, reveal the role of collective DNA interactions in the formation of the linear structures. Moreover, the reversibility of DNA binding facilitates the development of hierarchical assemblies with time. We also observed similar linear structures of alternating rods and spheres, which implies that the discovered mechanism is generic for nanoscale objects interacting via flexible multiple linkers. PMID- 23651347 TI - Adrenomedullin and angiopoietin-1 additively restore erectile function in diabetic rats: comparison with the combination therapy of vascular endothelial growth factor and angiopoietin-1. AB - INTRODUCTION: Erectile dysfunction (ED) is a major health problem. We have shown that adrenomedullin (AM) restores erectile function in diabetic rats. AIM: The aim of this study is to explore a better treatment for ED, we examined whether combination of AM and angiopoietin-1 (Ang-1) was more effective to treat ED than treatment with AM alone or Ang-1 alone. We also compared the effect of the combination therapy with that of treatment with vascular endothelial growth factor-A (VEGF-A). METHODS: Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Adenoviruses expressing AM (AdAM), Ang-1 (AdAng-1), and VEGF-A (AdVEGF-A) were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology, and protein expression were analyzed 4 weeks after the injection of the adenoviruses. MAIN OUTCOME MEASURES: Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of alpha-smooth muscle actin (SMA), VE cadherin and type I collagen was assessed by Western blot analysis. RESULTS: Infection with AdAM plus AdAng-1 more effectively restored erectile function than infection with AdAM alone or AdAng-1 alone. This combination therapy restored erectile function to a level similar to that observed in the age-matched Wistar rats. Expression of SMA and VE-cadherin increased more significantly in the AdAM plus AdAng-1-treated group than in the AdAM- or AdAng-1-treated group. Although AdVEGF-A infection restored erectile function significantly, it also caused enlargement of the trabeculae of the cavernous body, aberrant angiogenesis, and overproduction of type I collagen. CONCLUSIONS: These results suggested that combination therapy with AM and Ang-1 potently restored erectile function and normal morphology of the cavernous body compared with VEGF-A administration. This combination therapy will be useful to treat ED patients with a severely damaged cavernous body. PMID- 23651348 TI - Novel insight into the inflammatory and cellular responses following experimental glaucoma surgery: a roadmap for inhibiting fibrosis. AB - Failure after glaucoma filtration surgery is attributed to fibrosis at the operated site. To understand the wound healing process after glaucoma filtration surgery, we have developed a mouse model for glaucoma filtration surgery which closely mimics the clinical response. In this study, we describe a systematic analysis of the wound healing response in vivo. Our data revealed that the post surgical tissue response was separable into two distinguishable phases. The early "acute inflammatory" phase was characterized by significantly increased transcript expression of Vegfa, Cxcl1, Cxcl5, Ccl2, Ccl3, Ccl4, Gmcsf and specific Mmps as well as greater infiltration of monocytes/macrophages and T cells. The late "fibrotic" phase was characterized by an increased expression of Tgfb2 and extracellular matrix genes as well as a notable reduction of infiltrating inflammatory cells. Significantly, more mitotic cells were observed at both time points post-surgery. Subconjunctival fibroblasts may be involved in both phases since they have the capacity to reiterate the in vivo gene expression profiles upon either pro-inflammatory or pro-fibrotic cytokine stimulation. Given that the cellular and molecular targets that govern the early and late phases of wound healing are distinct and time sensitive, a multi-targeted therapeutic approach to sequentially inhibit inflammation and fibrogenesis at the critical time point may lead to improved surgical outcomes in glaucoma filtration surgery. PMID- 23651349 TI - Anxiety experienced by individuals with cancer in remission. AB - For this qualitative research study, we interviewed 25 individuals who survived cancer regarding the sentiments they experienced in adjusting to having their condition in remission. Among other findings that we reported elsewhere, two themes emerged from the in-depth interviews relating to apprehensive percepts. One was that participants spoke of their tendency to battle worrisome thoughts. Although they used a variety of words in describing the construct, anxiety repeatedly appeared as a cogent emotion when facing cancer. Second, anniversaries were said to have continued cogence for the participants as they triggered memories and tended to generate degrees of anxiety. PMID- 23651350 TI - Current status of rectal cancer treatment in China. AB - AIM: Colorectal cancer (CRC) is the fourth most common carcinoma in China. For economic reasons, a national CRC registry has not been established and a large scale screening programme has not been implemented. METHOD: Clinical studies (since 2000) of CRC epidemiology which originated from China were summarized, and data was analyzed. RESULTS: In China, the majority of hospitals in central cities and even in county hospitals are able to provide medical care for CRC patients. Due to socio-economic disparities, medical conditions and skill level, there is a wide variation in the treatment. Most oncologists make their clinical decisions based on the National Comprehensive Cancer Network (NCCN) guidelines, although some domestic guidelines are now available. On 11 October 2011, the China Ministry of Health released national guidelines for CRC treatment. Owing to language difficulties, research on CRC in China has only had a limited exposure in the international literature, due in some part to lack of understanding of the current position in the country. CONCLUSION: The national guidelines for CRC treatment will give a degree of standardization of the treatment of CRC nationwide and will ensure that higher quality care will be available, especially in rural areas. Chinese colorectal surgeons urgently need to exchange their knowledge and experience with international colleagues. PMID- 23651352 TI - Taming the electronic structure of lead and eka-lead (flerovium) by the relativistic coupled cluster method. AB - Theoretical investigations of the superheavy elements (SHEs) are extremely challenging and are often the sole source of useful chemical information. Relativistic Fock-space multireference coupled cluster (RFS-MRCC) computations have been carried out for evaluating the ionization potential (IP), excitation energies (EE), nuclear magnetic hyperfine constant (A), lifetime (tau), and Lande g factor of singly ionized eka-lead (Fl II). To judge the accuracy of Fl II results, similar calculations are performed for Pb II, which shows a nice and consistent agreement with known experimental values. Thus, we believe that our predictions for Fl are reliable and useful for the simulation of experimental behavior. To the best of our knowledge, no prior theoretical and/or experimental information is available for A, tau, and g-factor of this SHE. The higher IPs and EEs of Fl II, with respect to Pb II, indicate the former to be more inert and less metallic than Pb. This is contingent on the effects of the relativistic stabilization of the 7s and 7p1/2 orbitals. The present analysis demonstrates the influence of higher-body cluster operators on atomic properties. The close agreement with the experiment (having an estimated error within 1-2%) indicates that the FS-MRCC method is a reliable predictive tool in cases where the experimental results are not readily available, such as the SHEs. The remaining source of error possibly stems out from the omission of the full-blown triple virtual excitations and the absence of Breit interaction. PMID- 23651351 TI - Prolactin receptor gene polymorphisms are associated with gestational diabetes. AB - AIMS: Human placental lactogen (hPL) acts via the prolactin receptor (PRLR) on maternal beta-cells to mediate increases in beta-cell mass and function during normal pregnancy. This interaction between hPL and PRLR is essential to maintain normal glucose homeostasis and to address the increased metabolic demands of pregnancy. Given the importance of the PRLR-hPL axis in pancreatic islet cell adaptation to pregnancy, we hypothesized that genetic variation in the PRLR gene could influence risk of development of gestational diabetes mellitus (GDM). DNA samples from 96 mothers affected by GDM and 96 unaffected cases were genotyped for 8 selected single nucleotide polymorphisms (SNPs) in PRLR. RESULTS: Significant associations were identified in two SNPs analyzed. The minor alleles of PRLR SNPs rs10068521 and rs9292578 were more frequently observed in GDM cases than controls and were associated with a 2.36-fold increased risk for GDM in those carrying the minor allele. CONCLUSION: SNPs of the PRLR gene 5' UTR and promoter region are associated with increased risk for GDM in a population of Chilean subjects. PMID- 23651353 TI - Application of BRED technology to construct recombinant D29 reporter phage expressing EGFP. AB - Bacteriophage Recombineering of Electroporated DNA (BRED) has been described for construction of gene deletion and point mutations in mycobacteriophages. Using BRED, we inserted a Phsp60-egfp cassette (1143 bp) into the mycobacteriophage D29 genome to construct a new reporter phage, which was used for detection of mycobacterial cells. The cassette was successfully inserted and recombinant mycobacteriophage purified. DNA sequencing of the cassette did not show any mutations even after several phage generations. Mycobacterium smegmatis mc(2) 155 cells were infected with D29::Phsp60-egfp (MOI of 10) and evaluated for EGFP expression by microscopy. Fluorescence was observed at around 2 h after infection, but dissipated in later times because of cell lysis. We attempted to construct a lysis-defective mutant by deleting the lysA gene, although we were unable to purify the mutant to homogeneity even with complementation. These observations demonstrate the ability of BRED to insert c. 1 kbp-sized DNA segments into mycobacteriophage genomes as a strategy for constructing new diagnostic reporter phages. PMID- 23651354 TI - Systemic responses of mice to dextran sulfate sodium-induced acute ulcerative colitis using 1H NMR spectroscopy. AB - The interplay between genetic mutation and environmental factors is believed to contribute to the etiology of inflammatory bowel disease (IBD). While focused attention has been paid to the aforementioned research, time-specific and organ specific metabolic changes associated with IBD are still lacking. Here, we induced acute ulcerative colitis in mice by providing water containing 3% dextran sulfate sodium (DSS) for 7 days and investigated the metabolic changes of plasma, urine, and a range of biological tissues by employing a (1)H nuclear magnetic resonance (NMR)-based metabonomics approach with complementary information on serum clinical chemistry and histopathology. We found that DSS-induced acute ulcerative colitis leads to significant elevations in the levels of amino acids in plasma and decreased levels in the membrane-related metabolites and a range of nucleotides, nucleobases, and nucleosides in the colon. In addition, acute colitis-induced elevations in the levels of nucleotides in the liver were observed, accompanied by reduced levels of glucose. DSS-induced acute colitis also resulted in increased levels of oxidized glutathione and attenuated levels of taurine in the spleen. Furthermore, acute colitis resulted in depletion in the levels of gut microbial cometabolites in urine along with an increase in citric acid cycle intermediates. These findings suggest that DSS-induced acute colitis causes a disturbance of lipid and energy metabolism, damage to the colon and liver, a promoted antioxidative and anti-inflammatory response, and perturbed gut microbiotal communities. The information obtained here provided details of the time-dependent and holistic metabolic changes in the development of the DSS induced acute ulcerative colitis, which could be useful in discovery of novel therapeutic targets for management of IBD. PMID- 23651355 TI - Cyanuric acid hydrolase: evolutionary innovation by structural concatenation. AB - The cyanuric acid hydrolase, AtzD, is the founding member of a newly identified family of ring-opening amidases. We report the first X-ray structure for this family, which is a novel fold (termed the 'Toblerone' fold) that likely evolved via the concatenation of monomers of the trimeric YjgF superfamily and the acquisition of a metal binding site. Structures of AtzD with bound substrate (cyanuric acid) and inhibitors (phosphate, barbituric acid and melamine), along with mutagenesis studies, allowed the identification of the active site. The AtzD monomer, active site and substrate all possess threefold rotational symmetry, to the extent that the active site possesses three potential Ser-Lys catalytic dyads. A single catalytic dyad (Ser85-Lys42) is hypothesized, based on biochemical evidence and crystallographic data. A plausible catalytic mechanism based on these observations is also presented. A comparison with a homology model of the related barbiturase, Bar, was used to infer the active-site residues responsible for substrate specificity, and the phylogeny of the 68 AtzD-like enzymes in the database were analysed in light of this structure-function relationship. PMID- 23651358 TI - Function allocation in complex systems: reframing an old problem. AB - In this article, we offer a new, macroergonomics perspective on the long-debated issue of function allocation. We believe thinking in this domain needs to be realigned, moving away from the traditional microergonomics conceptualisation, concerned predominantly with task-based decisions, and towards a macroergonomics approach, viewing function allocation choices as central to effective systems design. We frame our arguments within a systems perspective, advocating that function allocation issues need to be on the agenda of all individuals with a wider interest in the human and organisational aspects of complex work systems, including people who commission, sponsor, design, implement and use such systems. We also argue that allocation decisions should form a transparent, explicit stage early in the systems design and development process, involve multiple stakeholders (including end-users), be evidence-based, framed within the language of risk and utilise iterative methods (e.g. scenarios planning techniques). PRACTITIONER SUMMARY: This article presents a macroergonomics approach to function allocation, advocating its importance in effective systems design. Adopting a systems mindset, we argue function allocation should form an explicit stage early in the design process, involve multiple stakeholders, be evidence based, framed within the language of risk and utilise iterative methods. PMID- 23651359 TI - Synthesis, pharmacological characterization, and docking analysis of a novel family of diarylisoxazoles as highly selective cyclooxygenase-1 (COX-1) inhibitors. AB - 3-(5-Chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6), a known selective cyclooxygenase-1 (COX-1) inhibitor, was used to design a new series of 3,4 diarylisoxazoles in order to improve its biochemical COX-1 selectivity and antiplatelet efficacy. Structure-activity relationships were studied using human whole blood assays for COX-1 and COX-2 inhibition in vitro, and results showed that the simultaneous presence of 5-methyl (or -CF3), 4-phenyl, and 5-chloro( bromo or -methyl)furan-2-yl groups on the isoxazole core was essential for their selectivity toward COX-1. 3g, 3s, 3d were potent and selective COX-1 inhibitors that affected platelet aggregation in vitro through the inhibition of COX-1 dependent thromboxane (TX) A2. Moreover, we characterized their kinetics of COX-1 inhibition. 3g, 3s, and 3d were more potent inhibitors of platelet COX-1 and aggregation than P6 (named 6) for their tighter binding to the enzyme. The pharmacological results were supported by docking simulations. The oral administration of 3d to mice translated into preferential inhibition of platelet derived TXA2 over protective vascular-derived prostacyclin (PGI2). PMID- 23651360 TI - Perspectives of health personnel on how to preserve and promote the patients' dignity in a rehabilitation context. AB - AIMS AND OBJECTIVES: To explore how healthcare personnel comprehend the term dignity and what they do to attend to, preserve and promote the dignity of patients in the rehabilitation context. BACKGROUND: Literature reveals that knowledge exists concerning the nature of dignity. Literature is scant on how health personnel think the reasons may be when patients do not maintain their dignity or how caregivers might improve and strengthen their concern in preserving and promoting the patients' dignity in a rehabilitation context. DESIGN: The study was explorative and descriptive, with content analysis of gathered empirical data. METHODS: Qualitative focus group interviews with representatives from the staff at three different rehabilitation centres were carried out. Professionals within different occupations were represented at the meeting: nurses, ergonomists, physiotherapists, psychologists, medical doctors, social workers, auxiliary nurses and speech therapists. RESULTS: Dignity is promoted when the patient himself becomes an active agent, when the patient's feelings and thoughts are respected, when the family of the patient is included and listened to, when the patient is free to make critical comment, when members of staff are able to cope with the patient's disabilities and when the aesthetic environment is attended to and enhanced. Dignity is not promoted when health personnel override or dominate patients, when health personnel focus merely on the patient's diagnosis and not the sick person and when health personnel and/or relatives try to impose their own values. CONCLUSION: The staff working in institutions to rehabilitate patients with head injuries and multiple sclerosis must be aware and sensitive to the importance of maintaining and supporting the patient's dignity and self-respect. RELEVANCE FOR CLINICAL PRACTICE: The results from this project confirm the importance of acknowledging the patient's self worth as a human being, unconditionally. This might be essential in promoting and preserving the patients' dignity. PMID- 23651361 TI - Recurrent implantation success in consecutive embryo transfer cycles: a unique case report. AB - We describe here a unique case of a woman with an azoospermic male partner conceiving each time during ten consecutive in-vitro fertilization embryo transfer (IVF-ET) cycles. A 27 year old woman reported with primary infertility to our out-patient department at the Institute of Reproductive Medicine, Salt Lake, India in November 2001. Ten consecutive IVF-ET cycles including both, fresh and frozen embryos were performed over a span of ten years. Following each ET, the woman became pregnant; however, viable babies were not achieved. Finally, after the tenth consecutive IVF-ET cycle, a caesarean section (CS) was performed at 30 weeks and twin babies weighing 1.3 kg and 1.25 kg, respectively, were delivered and both the babies survived. It seems unlikely that the woman's conception with each embryo transfer was merely coincidental; a persistently receptive window of implantation with a high embryo implantation rate is evident. This case motivated us to introduce the term, repeated implantation success (RIS). We hypothesize that for successful implantation, expression of various factors during each cycle may be possible only in genetically pre-determined women. Identification of these genetically pre-determined set of marker(s) could help in predicting the chances of a successful pregnancy in women undergoing IVF. PMID- 23651362 TI - An estimating function approach to the analysis of recurrent and terminal events. AB - In clinical and observational studies, the event of interest can often recur on the same subject. In a more complicated situation, there exists a terminal event (e.g., death) which stops the recurrent event process. In many such instances, the terminal event is strongly correlated with the recurrent event process. We consider the recurrent/terminal event setting and model the dependence through a shared gamma frailty that is included in both the recurrent event rate and terminal event hazard functions. Conditional on the frailty, a model is specified only for the marginal recurrent event process, hence avoiding the strong Poisson type assumptions traditionally used. Analysis is based on estimating functions that allow for estimation of covariate effects on the recurrent event rate and terminal event hazard. The method also permits estimation of the degree of association between the two processes. Closed-form asymptotic variance estimators are proposed. The proposed method is evaluated through simulations to assess the applicability of the asymptotic results in finite samples and the sensitivity of the method to its underlying assumptions. The methods can be extended in straightforward ways to accommodate multiple types of recurrent and terminal events. Finally, the methods are illustrated in an analysis of hospitalization data for patients in an international multi-center study of outcomes among dialysis patients. PMID- 23651363 TI - Who may not benefit from continuous renal replacement therapy in acute kidney injury? AB - This study aimed to identify factors that may predict early kidney recovery (less than 48 hours) or early death (within 48 hours) after initiating continuous renal replacement therapy (CRRT) in acute kidney injury (AKI) patients. This is a multicenter retrospective observational study of 14 Japanese Intensive care units (ICUs) in 12 tertiary hospitals. Consecutive adult patients with severe AKI requiring CRRT admitted to the participating ICUs in 2010 (n=343) were included. Patient characteristics, variables at CRRT initiation, settings, and outcomes were collected. Patients were grouped into early kidney recovery group (CRRT discontinuation within 48 hours after initiation, n=52), early death group (death within 48 hours after CRRT initiation, n=52), and the rest as the control group (n=239). The mean duration of CRRT in the early kidney recovery group and early death group was 1.3 and 0.9 days, respectively. In multivariable regression analysis, in comparison with the control group, urine output (mL/h) (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01-1.03), duration between ICU admission to CRRT initiation (days) (OR: 0.65, 95% CI: 0.43-0.87), and the sepsis related organ failure assessment score (OR: 0.87, 95% CI; 0.78-0.96) were related to early kidney recovery. Serum lactate (mmol/L) (OR: 1.19, 95% CI: 1.11-1.28), albumin (g/dL) (OR: 0.52, 95% CI: 0.28-0.92), vasopressor use (OR: 3.68, 95% CI: 1.37-12.16), and neurological disease (OR: 9.64, 96% CI: 1.22-92.95) were related to early death. Identifying AKI patients who do not benefit from CRRT and differentiating such patients from the study cohort may allow previous and future studies to effectively evaluate the indication and role of CRRT. PMID- 23651364 TI - External negative electric potential accelerates exocytosis of lamellar bodies in human skin ex vivo. AB - Exocytosis of lamellar bodies at the uppermost nucleated layer of the epidermis is a crucial process for epidermal permeability barrier homoeostasis. We have previously suggested that skin surface electric potential might be associated with barrier homoeostasis. Thus, we hypothesized that the potential might drive exocytosis of lamellar bodies. In this study, we tested this idea by applying negative electric potential (-0.5 V) to human skin samples ex vivo for 2 h and observing the ultrastructure of the uppermost layer. The secretion of lamellar bodies was accelerated in the potential-applied skin, compared to that in untreated control skin. Multiphoton observation indicated that extracellular lipid domains were more extensive in treated skin than in control skin. Moreover, the calcium ion gradient was greater at the uppermost layer of the epidermis of treated skin, compared to that in control skin. These results indicate that electric potential may regulate lamellar body secretion in healthy human skin. PMID- 23651365 TI - Role of nuclear factor kappa-B in phenytoin-induced gingival overgrowth. AB - OBJECTIVE: This study investigates the expression of transcription factor nuclear factor-kappa B (NF-kappaB) and its relation to various cellular mediators that act in the pathogenesis of phenytoin-induced gingival overgrowth. MATERIALS AND METHODS: Eighteen epileptic patients had phenytoin-induced gingival overgrowth (PHT-GO), 20 patients with plaque-induced gingivitis (Gingivitis), and 20 periodontally and systemically healthy individuals (Control) were included in this study. The expression of activated NF-kappaB subunits (p50 and p65), IL 1beta, TNF-alpha and TGFbeta-1 levels were examined in the gingival sections obtained from each participant. RESULTS: The results demonstrated a significantly higher expression of p65 in fibroblasts in PHT-GO group with respect to Gingivitis (P < 0.05) and control groups (P < 0.01). However, we found no statistically significant differences between PHT-GO and Gingivitis groups according to the immunohistochemical staining in macrophages (P > 0.05). Immune reactive TGFbeta-1 levels in the gingival connective tissue cells were statistically higher in PHT-GO group with respect to Gingivitis group(P < 0.05). Statistically significant correlations were found between the HI and activated TGFbeta-1 and p65 levels in PHT-GO group. CONCLUSION: The results of this study showed that NF-kappaB is activated in PHT-related gingival overgrowth. This study may provide a basis for future research into specific NF-kappaB inhibition for preventing of the side effects of this drug. PMID- 23651366 TI - Solid state molecular device based on a rhenium(I) polypyridyl complex immobilized on TiO2 films. AB - The photochemical and photophysical behaviors of fac-[Re(CO)3(phen)(trans stpyCOOH)](+) (phen = 1,10-phenanthroline, trans-stpyCOOH = 4-[trans-(pyridin-4 yl-vinyl)]benzoic acid) in acetonitrile solution and adsorbed on a TiO2 film have been investigated. The trans-to-cis photoisomerization at 404 nm irradiation of coordinated stpyCOOH occurs efficiently in fluid solution as shown by quantum yield determined spectrophotometrically (Phi(UV-vis) = 0.37 +/- 0.04) and, more accurately, by (1)H NMR (Phi(NMR) = 0.48 +/- 0.04), following the photoproduct signals in the distinct region of the reactant. For the first time, the trans-to cis isomerization is also reported for the complex adsorbed on the TiO2 surface (Phi(UV-vis) = 0.23 +/- 0.03). The photoproduct, fac-[Re(CO)3(phen)(cis stpyCOOH)](+), is emissive in acetonitrile (phi = 0.032), but its radiative decay is highly quenched on the oxide surface by electron photoinjection into the semiconductor, leading to an increasing photocurrent as the trans-to-cis isomerization takes place. Therefore, the photoinduced trans-to-cis isomerization of coordinated ligand immobilized on TiO2 films acts as a trigger for the electron injection process. This system exemplifies the use of photoinduced molecular motion to yield electrical current, which can be used as a "proof of concept" for molecular machines/devices. PMID- 23651367 TI - Risks associated with the therapeutic use of fluoroquinolones. AB - INTRODUCTION: Quinolones are among the most often prescribed antimicrobial agents. Some types of toxicity observed during therapy with these drugs have gained much attention. AREAS COVERED: Here, we review the potential of the most widely used fluoroquinolones, ciprofloxacin, levofloxacin and moxifloxacin for adverse reactions. The rates of adverse events are similar for quinolones and other antibacterial agents. However, quinolone therapy can be associated with specific risks, which must be weighed against their benefit. In some studies, use of quinolones was associated with Clostridium difficile-associated diarrhea. Patients with impairments of the CNS (e.g., epilepsy or arteriosclerosis) should not be treated with quinolones. They should be avoided in patients with known prolongation of the QT interval or other risk factors for tachyarrhythmia. The risk for quinolone-associated tendinopathy is more pronounced among elderly persons, non-obese patients and individuals with concurrent use of glucocorticoids or chronic renal diseases. Quinolones are contraindicated in children because they cause destruction of the immature joint cartilage in animals. The use in paediatrics is restricted to life-threatening infections. EXPERT OPINION: Changes in the resistance situation and newly recognized adverse reactions require a continuing adjustment of therapeutic recommendations and constant educational efforts in the field of antimicrobial therapy. PMID- 23651388 TI - The nature and scope of gambling in Canada. AB - AIMS: This paper provides a historical review of gambling in Canada and examines the benefits and shortcomings of present-day Canadian gambling policies and practices. This includes a discussion of provincial and federal government roles in gambling regulation and an overview of problem gambling prevention and treatment initiatives. METHODS: The gambling studies literature was probed for pertinent information on factors such as historical development, legislative changes, economic conditions and cultural influences that have affected gambling participation and social responsibility strategies in Canada. RESULTS: Two major Criminal Code of Canada amendments (in 1969 and 1985) were pivotal in Canadian gambling expansion. The first decriminalized lotteries and casinos, while the second allowed electronic gambling devices and authorized provinces to operate and regulate gambling. These changes resulted in a radical gambling expansion which, in addition to raising provincial revenues, created public policy concerns. Varying provincial government interpretations of the ambiguous Criminal Code gambling statutes led to a lack of uniformity in how provinces regulate and operate gambling; when gambling expanded, there were no legislative safeguards in place to deal with the personal and societal effects of problem gambling. Subsequent programs designed to prevent and treat problem gambling have not been overly effective. CONCLUSIONS: Canadian provinces have a monopoly on gambling within their borders and treat the activity as a profit-driven business enterprise. Problems associated with widespread gambling such as addiction, increased crime, bankruptcy and suicide are seen as minor concerns and not addressed in an aggressive fashion. Given the Canadian federal government's detachment from gambling policy and Canadian provinces' heavy reliance on gambling revenues, little change in the Canadian gambling landscape is anticipated in the near future. PMID- 23651389 TI - Solvent based hydrogen bonding: impact on poly(3-hexylthiophene) nanoscale morphology and charge transport characteristics. AB - We demonstrate that supramolecular assembly and subsequent enhancement of charge transport characteristics of conjugated polymers can be facilitated simply by adding small amounts of a more volatile poor solvent, which can hydrogen bond with the majority solvent. Addition of up to 2 vol % acetone to a precursor solution of poly(3-hexylthiophene) (P3HT) in chloroform leads to approximately a 4-fold increase in P3HT field-effect mobility. The improvement is associated with hydrogen bonding interactions between acetone and chloroform which decrease the evaporation rate of the mixed solvent. P3HT is less soluble in the binary solvent than in the more readily vaporized chloroform component, and this characteristic enables the supramolecular assembly of P3HT chains at the nanoscale. Two dimensional molecular ordering of the polymer film was controlled by varying the quantity of poor solvent added to the precursor solution, and the correlation between field-effect mobility and molecular ordering was investigated. Hansen solubility parameters were used to systematically understand how the solvent mixture enhances the alignment and assembly of polymer chains and influences subsequent thin film properties. The value of the relative energy difference (RED) of the solvent with respect to P3HT increased from less than 1 to more than 1 during film formation, which indicates that the solvent characteristics are initially those of a good solvent but transform into those of a poor dissolution medium. A mechanistic illustration of the molecular ordering process during film formation is postulated. PMID- 23651390 TI - Filling in the gaps: the need for further investigation to understand the effects of oral contraceptives on female sexual satisfaction. PMID- 23651391 TI - Gender differences of mental health consumers accessing integrated primary and behavioral care. AB - Persons with severe mental illness and addiction are at higher risk for early morbidity and mortality than the general population, and are less likely to receive primary care and preventive health services. Primary and behavioral integrated care programs aim to reduce these health disparities by providing comprehensive health and wellness services. Gender in particular may play a significant role in individuals' engagement and outcomes in such programs. Hence, this study examines the salient characteristics of behavioral health consumers accessing an integrated care program at a large community mental health center. Baseline gender differences in consumer demographics, substance use, psychological distress and functioning, physical health indicators, and risk factors for serious medical conditions are examined. Our results demonstrate that key gender differences exist and may warrant distinct treatment needs for men and women receiving integrated care. PMID- 23651392 TI - Impact of vitamin D insufficiency on insulin homeostasis and beta cell function in nondiabetic male HIV-infected patients. AB - OBJECTIVES: Vitamin D is thought to play a role in glucose homeostasis and beta cell function. Our aim was to examine the impact of plasma 25-hydroxyvitamin D [25(OH)D] upon in vivo insulin sensitivity and beta cell function in HIV-infected male patients without diabetes. METHODS: A cross-sectional study was carried out involving a cohort of HIV-infected patients undergoing regular assessment in a tertiary hospital. Eighty-nine patients [mean (+/- standard deviation) age 42 +/- 8 years] were included in the study: 14 patients were antiretroviral therapy (ART)-naive, while 75 were on ART. Vitamin D insufficiency (VDI) was defined as 25(OH)D < 75 nmol/L; insulin sensitivity was determined using a 2-h continuous infusion of glucose model assessment with homeostasis (CIGMA-HOMA), using the trapezoidal model to calculate the incremental insulin and glucose areas under the curve (AUCins and AUGglu, respectively). Beta cell function was assessed using the disposition index (DI). Abdominal visceral adipose tissue (VAT) and hepatic triglyceride content (HTGC) were measured by magnetic resonance imaging (MRI) and 1-H magnetic resonance spectroscopy. Multivariate linear regression analysis was performed. RESULTS: VDI was associated with insulin resistance (IR), as indicated by a higher CIGMA-HOMA index (odds ratio 1.1) [1.01-1.2]. This association was independent of the main confounders, such as age, Centers for Disease Control and Prevention (CDC) stage, ART, lipodystrophy, body mass index, VAT:subcutaneous adipose tissue ratio and HTGC, as confirmed by multivariate analysis (B = 12.3; P = 0.01; r2 = 0.7). IR in patients with VDI was compensated by an increase in insulin response. However, beta cell function was lower in the VDI subpopulation (33% decrease in DI). CONCLUSIONS: VDI in nondiabetic HIV positive male patients is associated with impaired insulin sensitivity and a decrease in pancreatic beta cell function. PMID- 23651393 TI - Involvement of the ribose operon repressor RbsR in regulation of purine nucleotide synthesis in Escherichia coli. AB - Escherichia coli is able to utilize d-ribose as its sole carbon source. The genes for the transport and initial-step metabolism of d-ribose form a single rbsDACBK operon. RbsABC forms the ABC-type high-affinity d-ribose transporter, while RbsD and RbsK are involved in the conversion of d-ribose into d-ribose 5-phosphate. In the absence of inducer d-ribose, the ribose operon is repressed by a LacI-type transcription factor RbsR, which is encoded by a gene located downstream of this ribose operon. At present, the rbs operon is believed to be the only target of regulation by RbsR. After Genomic SELEX screening, however, we have identified that RbsR binds not only to the rbs promoter but also to the promoters of a set of genes involved in purine nucleotide metabolism. Northern blotting analysis indicated that RbsR represses the purHD operon for de novo synthesis of purine nucleotide but activates the add and udk genes involved in the salvage pathway of purine nucleotide synthesis. Taken together, we propose that RbsR is a global regulator for switch control between the de novo synthesis of purine nucleotides and its salvage pathway. PMID- 23651394 TI - Early diet impacts infant rhesus gut microbiome, immunity, and metabolism. AB - Epidemiological research has indicated a relationship between infant formula feeding and increased risk of chronic diseases later in life including obesity, type-2 diabetes, and cardiovascular disease. The present study used an infant rhesus monkey model to compare the comprehensive metabolic implications of formula- and breast-feeding practices using NMR spectroscopy to characterize metabolite fingerprints from urine and serum, in combination with anthropometric measurements, fecal microbial profiling, and cytokine measurements. Here we show that formula-fed infants are larger than their breast-fed counterparts and have a different gut microbiome that includes higher levels of bacteria from the Ruminococcus genus and lower levels of bacteria from the Lactobacillus genus. In addition, formula-fed infants have higher serum insulin coupled with higher amino acid levels, while amino acid degradation products were higher in breast-fed infants. Increases in serum and urine galactose and urine galactitol were observed in the second month of life in formula-fed infants, along with higher levels of TNFalpha, IFN-gamma, IL-1beta, IL-4, and other cytokines and growth factors at week 4. These results demonstrate that metabolic and gut microbiome development of formula-fed infants is different from breast-fed infants and that the choice of infant feeding may hold future health consequences. PMID- 23651395 TI - Delivery of poorly soluble compounds by amorphous solid dispersions. AB - Solid state manipulation by amorphous solid dispersion has been the subject of intensive research for decades due to their excellent potential for dissolution and bioavailability enhancement. The present review aims to highlight the latest advancement in this area, with focus on the fundamentals, characterization, formulation development and manufacturing of amorphous solid dispersions as well as the new generation amorphization technologies. Additionally, specific applications of amorphous solid dispersion in the formulation of herbal drugs or bioactive natural products are reviewed to reflect the growing interest in this relatively neglected area. PMID- 23651396 TI - Application of precipitation methods for the production of water-insoluble drug nanocrystals: production techniques and stability of nanocrystals. AB - This review focuses on using precipitation (bottom-up) method to produce water insoluble drug nanocrystals, and the stability issues of nanocrystals. The precipitation techniques for production of ultra-fine particles have been widely researched for last few decades. In these techniques, precipitation of solute is achieved by addition of a non-solvent for solute called anti-solvent to decrease the solvent power for the solute dissolved in a solution. The anti-solvent can be water, organic solvents or supercritical fluids. In this paper, efforts have been made to review the precipitation techniques involving the anti-solvent precipitation by simple mixing, impinging jet mixing, multi-inlet vortex mixing, the using of high-gravity, ultrasonic waves and supercritical fluids. The key to the success of yielding stable nanocrystals in these techniques is to control the nucleation kinetics and particle growth through mixing during precipitation based on crystallization theories. The stability issues of the nanocrystals, such as sedimentation, Ostwald ripening, agglomeration and cementing of crystals, change of crystalline state, and the approaches to stabilizing nanocrystals are also discussed in detail. PMID- 23651397 TI - Current advances and future trends in characterizing poorly water-soluble drugs using spectroscopic, imaging and data analytical techniques. AB - A common feature of many new analytical techniques that allows fast and non destructive analysis of poorly-water-soluble drug is that they generate a large amount of data with a multivariate character within a short time frame, which in turn highlights the need for advanced data analytical methods in extracting information from the complex data set. The current review critically examines how spectroscopy and imaging techniques can be utilized for fast and non-destructive characterization of solid state poorly water-soluble drug formulations. The first part of the present review describes the basics behind many of the currently used methods including Raman, near infrared (NIR), infrared (IR) spectroscopy and X ray powder diffractometry in characterizing poorly water soluble drugs. Key emphasis was placed on a critical review of the currently used spectral preprocessing methods, and the influence of selected preprocessing on spectral data sets is exemplified. Further the existing uni- and multivariate spectral data analytical methods in analyzing complex spectral data sets are reviewed, covering estimation of spectral peak moments, peak modeling, variations of Principal Component Analysis (PCA), variations of Partial Least Squares (PLS) analysis and Multivariate Curve Resolution (MCR). The second part of the present review discusses hyperspectral imaging, UV imaging, optical microscopy imaging and process imaging methods suitable for characterization of poorly water-soluble solid state drug formulations. Image analytical techniques suitable for analyzing hyperspectral image data set are described. Further, the application of various image analytical techniques leading to the estimation of nucleation and crystal growth rates from polarized light microscopy is described. PMID- 23651398 TI - Application of spray-drying and electrospraying/electospinning for poorly water soluble drugs: a particle engineering approach. AB - Solid dispersions have been widely studied as an attractive formulation strategy for the increasingly prevalent poorly water-soluble drug compounds, including herbal medicines, often leading to improvements in drug dissolution rate and bioavailability. However, several challenges are encountered with solid dispersions, for instance regarding their physical stability, and the full potential of these formulations has yet to be reached. Solid dispersions have mainly been used to produce immediate release systems using water-soluble polymers but an extended release system may provide equal or better performance due to enhancement in the pharmacokinetics and low variability in plasma concentration. Progress in processing technologies and particle engineering provides new opportunities to prepare particle-based solid dispersions with control of physical characteristics and tailored drug release kinetics. Spray drying and electrospraying are both technologies that allow production and continuous manufacturing of particle-based amorphous solid dispersions in a single step process and electrospinning further allows the production of fiber based systems. This review presents the use of spray drying and electrospraying/electrospinning as techniques for preparing particle-based solid dispersions, describes the particle formation processes via numerical and experimental models and discusses particle engineering using these techniques. Examples are given on the applications of these techniques for preparing solid dispersions and the challenges associated with the techniques such as stability, preparation of final dosage form and scale-up are also discussed. PMID- 23651399 TI - Nanotechnology versus other techniques in improving drug dissolution. AB - Many newly discovered drug molecules have low aqueous solubility, which results in low bioavailability. One way to improve their dissolution is to formulate them as nanoparticles, which have high specific surface areas, consequently increasing the dissolution rate and solubility. Nanoparticles can be produced via top-down or bottom-up methods. Top-down techniques such as wet milling and high pressure homogenisation involve reducing large particles to nano-sizes. Some pharmaceutical products made by these processes have been marketed. Bottom-up methods such as precipitation and controlled droplet evaporation form nanoparticles from molecules in solution. To minimise aggregation upon drying and promote redispersion of the nanoparticles upon reconstitution or administration, hydrophilic matrix formers are added to the formulation. However, the nanoparticles will eventually agglomerate together after dispersing in the liquid and hinders dissolution. Currently there is no pharmacopoeial method specified for nanoparticles. Amongst the current dissolution apparatus available for powders, the flow-through cell has been shown to be the most suitable. Regulatory and pharmacopoeial standards should be established in the future to standardise the dissolution testing of nanoparticles. More nanoparticle formulations of new hydrophobic drugs are expected to be developed in the future with the advancement of nanotechnology. However, the agglomeration problem is inherent and difficult to overcome. Thus the benefit of dissolution enhancement often cannot be fully realised. On the other hand, chemical strategies such as modifying the parent drug molecule to form a more soluble salt form, prodrug, or cyclodextrin complexation are well established and have been shown to be effective in enhancing dissolution. Thus the value of nanoformulations needs to be interpreted in the light of their limitations. Chemical approaches should also be considered in new product development. PMID- 23651400 TI - Nanosuspensions of poorly water soluble drugs prepared by top-down technologies. AB - In recent years, nanosuspensions have been accepted as a valuable drug delivery system for poorly water-soluble drugs. Topdown and bottom-up technologies are the two main approaches for generating nanosuspensions. Several products manufactured by the top-down technologies have been successfully commercialized demonstrating that the processing features of the technologies are adaptable to industrial scale operation and meeting high pharmaceutical quality control standards. Nanosuspensions of poorly soluble drugs have shown to achieve dramatic improvements on the in vivo performance of the drugs including the enhancement of bioavailability and elimination of food effect when administered orally. This review will focus on the preparation of nanosuspensions by the top-down technologies. The influence of drug physicochemical properties on the nanosuspension forming process and the subsequent conversion into a dry powder form will be discussed with proposed mechanisms. In addition, the criteria for selection of stabilizers will be reviewed. The characteristics of drugs and stabilizers as well as their interaction effects on the redispersion properties of a dry powder prepared from a nanosuspension will be highlighted. The different administration routes of nanosuspensions are also presented with their potential therapeutic benefits. PMID- 23651402 TI - Effects of nanosuspension formulations on transport, pharmacokinetics, in vivo targeting and efficacy for poorly water-soluble drugs. AB - A surprisingly large proportion of new chemical entities (NCE) is emerging from the drug discovery pipeline, and many active components extracted from herbal medicines are water insoluble, which represents a great challenge for their development. Nanosuspensions, which are submicron colloidal dispersions of pure drug particles that are stabilised by a small percentage of the excipients, could dramatically enhance the saturated solubility, dissolution rate and adhesion of drug particles to cell membranes. Nanosuspensions are the most suitable for drugs that require high dosing or have limited administrative volume. After 20 years of development, several oral products and one injectable product are commercially available. The aim of this review is to fill the gap between rational formulation designs and the in vivo performance of poorly water-soluble drug nanosuspensions. Specifically, this review will correlate characteristics of nanosuspension formulations, including drug property, particle size, crystallinity, stabiliser and surface property, with their transport, pharmacokinetics, bioactivity and toxicity after delivery by different administration routes. The elucidation of the mechanisms of targeted drug delivery, cellular transport and internalisation of nanosuspensions are also reviewed to interpret the in vivo performance of these nanosuspensions. Moreover, the recent application of nanosuspensions for poorly water-soluble herbal medicines is highlighted. PMID- 23651401 TI - Application of hot melt extrusion for poorly water-soluble drugs: limitations, advances and future prospects. AB - Hot melt extrusion (HME) is a powerful technology to enhance the solubility and bioavailability of poorly water-soluble drugs by producing amorphous solid dispersions. Although the number of articles and patents about HME increased dramatically in the past twenty years, there are very few commercial products by far. The three main obstacles limiting the commercial application of HME are summarized as thermal degradation of heat-sensitive drugs at high process temperature, recrystallization of amorphous drugs during storage and dissolving process, and difficulty to obtain products with reproducible physicochemical properties. Many efforts have been taken in recent years to understand the basic mechanism underlying these obstacles and then to overcome them. This article reviewed and summarized the limitations, recent advances, and future prospects of HME. PMID- 23651403 TI - Supercritical fluid particle design for poorly water-soluble drugs (review). AB - Supercritical fluid particle design (SCF PD) offers a number of routes to improve solubility and dissolution rate for enhancing the bioavailability of poorly water soluble drugs, which can be adopted through an in-depth knowledge of SCF PD processes and the molecular properties of active pharmaceutical ingredients (API) and drug delivery system (DDS). Combining with research experiences in our laboratory, this review focuses on the most recent development of different routes (nano-micron particles, polymorphic particles, composite particles and bio drug particles) to improve solubility and dissolution rate of poorly water soluble drugs, covering the fundamental concept of SCF and the principle of SCF PD processes which are typically used to control particle size, shape, morphology and particle form and hence enable notable improvement in the dissolution rate of the poorly water-soluble drugs. The progress of the industrialization of SCF PD processes in pharmaceutical manufacturing environment with scaled-up plant under current good manufacturing process (GMP) specification is also considered in this review. PMID- 23651404 TI - Editorial: Novel formulation strategies for poorly water-soluble drugs and herbal medicines. PMID- 23651405 TI - Synergistic promotion of blood vessel regeneration by astragaloside IV and ferulic acid from electrospun fibrous mats. AB - The promotion of blood vessel initiation and growth plays an important role in the realization of therapeutic vascularization and regeneration of functional tissues. Astragalus membranaceus and angelica sinensis are commonly used traditional Chinese medicines for enriching the blood. In the current study astragaloside IV (AT, the main active ingredient of astragalus) and ferulic acid (FA, the main ingredient of angelica) were loaded into electrospun fibrous scaffolds to provide abundant and sustained biological factors required to initiate vascularization and bring it to maturity. The cell viability after AT and FA treatment was dose-dependent with an optimal concentration of around 50 MUg/mL, and the most significant synergistic effect was demonstrated for the combined treatment with AT and FA with the ratio of 7/3 on both primary endothelial and smooth muscle cells. The in vitro release study showed that the amount of AT and FA release could be regulated by their loading amount and ratios in electrospun fibers. The localized and sustained codelivery of AT and FA indicated significantly high cell viability and secretion of extracellular matrices for both endothelial and smooth muscle cells, and induced significantly high densities of vascular structures after subcutaneous implantation. The most significant angiogenesis promotion with few inflammatory reactions was demonstrated for electrospun fibers containing AT and FA with the ratio of 7/3. It was suggested that the integration of the synergistic effect of Chinese medicine into electrospun fibrous scaffolds should provide clinical relevance for therapeutic vascularization, full vascularization in engineered tissues, and regeneration of blood vessel substitutes. PMID- 23651407 TI - Dissociative recombination of CH4(+). AB - CH4(+) is an important molecular ion in the astrochemistry of diffuse clouds, dense clouds, cometary comae, and planetary ionospheres. However, the rate of one of the common destruction mechanisms for molecular ions in these regions, dissociative recombination (DR), is somewhat uncertain. Here, we present absolute measurements for the DR of CH4(+) made using the heavy ion storage ring CRYRING in Stockholm, Sweden. From our collision-energy dependent cross-sections, we infer a thermal rate constant of k(Te) = 1.71(+/-0.02) * 10(-6)(Te/300)(-0.66(+/ 0.02)) cm3 s(-1) over the region of electron temperatures 10 <= Te <= 1000 K. At low collision energies, we have measured the branching fractions of the DR products to be CH4 (0.00 +/- 0.00); CH3 + H (0.18 +/- 0.03); CH2 + 2H (0.51 +/- 0.03); CH2 + H2 (0.06 +/- 0.01); CH + H2 + H (0.23 +/- 0.01); and CH + 2H2 (0.02 +/- 0.01), indicating that two or more C-H bonds are broken in 80% of all collisions. PMID- 23651406 TI - A preliminary investigation of the impact of oily skin on quality of life and concordance of self-perceived skin oiliness and skin surface lipids (sebum). AB - OBJECTIVE: This preliminary study investigated both the impact of oily skin on quality of life (QoL) and the agreement between subjective oily skin self assessment and objective skin surface sebum measurement in young to middle-aged Chinese women in Beijing. METHODS: A 18-item Chinese version of the Oily Skin Self-Image Questionnaire (OSSIQ) was used to assess the impact of oily skin on QoL in 300 healthy female subjects (age groups: 20-25; 26-30; 31-35,). The subjects were divided equally into the oily skin group and the non-oily skin group based on their self-perception of skin oiliness. The level of skin surface lipids (SSL) was measured on the middle of the forehead, and both cheeks using the Sebumeter((r)). In order to assess the agreement between self-perceived skin oiliness and measured SSL, we tentatively used the SSL median value as a dividing point to regroup all subjects. RESULTS: The results indicate that the Chinese version of the OSSIQ distinguished the oily skin group from the non-oily skin group. Subjects in the oily skin group had significant higher emotional status score and behavior score when compared with subjects in the non-oily skin group. Subjects in the oily skin group had higher SSL when compared with subjects in the non-oily skin group, especially in younger age groups. The agreement between self perceived skin oiliness and measured SSL was moderately strong in younger age groups, and declined with age. CONCLUSION: These results strongly suggest that having oily skin can cause a significant negative impact on QoL among Chinese women. The Chinese version of the OSSIQ is a reliable and valid tool for assessing the impact of oily skin on QoL. The accuracy of oily skin self assessment declines with age. PMID- 23651408 TI - Hb Grove City [beta38(C4)Thr->Ser, ACC>AGC; HBB: c.116C>G]: a new low oxygen affinity beta chain variant. AB - A previously unreported beta chain hemoglobin (Hb) variant, Hb Grove City [beta38(C4)Thr->Ser, ACC>AGC; HBB: c.116C>G], was discovered in a woman who presented with hypoxia and mild anemia. Her young daughter also tested positive for the variant and displayed similar symptoms. Hemoglobin-oxygen dissociation testing confirmed right-shifted oxygen dissociation curves. A corresponding Hb variant was detected by high performance liquid chromatography (HPLC) and intact mass spectrometry (MS) but was not detected by capillary electrophoresis (CE), isoelectrofocusing (IEF) or alkaline or acid electrophoresis. DNA sequencing analysis confirmed a beta-globin gene mutation. All three previous mutations at this locus affect oxygen affinity, as does this new variant. This newly described variant showed variable stability results and therefore may be mildly unstable but is not associated with microcytosis, significant hemolysis or clinically evident cyanosis. It is important to consider hemoglobinopathies in patients who are anemic and have unexplained hypoxia. Arterial blood gas and p50 evaluations may prevent unnecessary diagnostic interventions. Additionally, Hb variants with altered oxygen affinity can be electrophoretically silent; therefore, multiple methods including MS and/or DNA sequencing are warranted when clinical suspicion is high. PMID- 23651409 TI - Antifungal activity against plant pathogens of metabolites from the endophytic fungus Cladosporium cladosporioides. AB - Bioassay-guided fractionation of Cladosporium cladosporioides (Fresen.) de Vries extracts led to the isolation of four compounds, including cladosporin, 1; isocladosporin, 2; 5'-hydroxyasperentin, 3; and cladosporin-8-methyl ether, 4. An additional compound, 5',6-diacetylcladosporin, 5, was synthesized by acetylation of compound 3. Compounds 1-5 were evaluated for antifungal activity against plant pathogens. Phomopsis viticola was the most sensitive fungus to the tested compounds. At 30 MUM, compound 1 exhibited 92.7, 90.1, 95.4, and 79.9% growth inhibition against Colletotrichum acutatum , Colletotrichum fragariae , Colletotrichum gloeosporioides , and P. viticola, respectively. Compound 2 showed 50.4, 60.2, and 83.0% growth inhibition at 30 MUM against Co. fragariae, Co. gloeosporioides, and P. viticola, respectively. Compounds 3 and 4 were isolated for the first time from Cl. cladosporioides. Moreover, the identification of essential structural features of the cladosporin nuclei has also been evaluated. These structures provide new templates for the potential treatment and management of plant diseases. PMID- 23651411 TI - Age as a moderator in the relationship between work-related characteristics, job dissatisfaction and need for recovery. AB - Job dissatisfaction and need for recovery are associated with voluntary turnover, absenteeism and diminished health. In the light of encouraging working longer, this study investigated whether the relationships between various work characteristics and job dissatisfaction and need for recovery are dependent on age. Cross-sectional questionnaire data from 591 university employees were divided into four age groups: < 36, 36-44, 45-54 and >= 55 years. Multivariate regression analyses were used, including interaction variables to detect a moderating effect of age group. Limited age group effects were found: only the association of Feedback with job dissatisfaction and Task variety with need for recovery were influenced by age group. The salience of specific work characteristics within the age groups varied: for job dissatisfaction, Task variety ( < 55) and Changes in tasks ( >= 55) were most important. For need for recovery, this applied to Autonomy ( < 36) and Workload ( >= 45). To encourage working longer, age-specific measures could be considered, in addition to individual measures, to respond to individual needs. PRACTITIONER SUMMARY: Demographic changes increase the importance to stimulate working longer. Using questionnaire data, we investigated the relationship between work characteristics, job dissatisfaction and need for recovery in four age groups. Although the moderating effect of age group was rather limited, the salience of specific work characteristics within the age groups varied. PMID- 23651410 TI - PTS phosphorylation of Mga modulates regulon expression and virulence in the group A streptococcus. AB - The ability of a bacterial pathogen to monitor available carbon sources in host tissues provides a clear fitness advantage. In the group A streptococcus (GAS), the virulence regulator Mga contains homology to phosphotransferase system (PTS) regulatory domains (PRDs) found in sugar operon regulators. Here we show that Mga was phosphorylated in vitro by the PTS components EI/HPr at conserved PRD histidines. A DeltaptsI (EI-deficient) GAS mutant exhibited decreased Mga activity. However, PTS-mediated phosphorylation inhibited Mga-dependent transcription of emm in vitro. Using alanine (unphosphorylated) and aspartate (phosphomimetic) mutations of PRD histidines, we establish that a doubly phosphorylated PRD1 phosphomimetic (D/DMga4) is completely inactive in vivo, shutting down expression of the Mga regulon. Although D/DMga4 is still able to bind DNA in vitro, homo-multimerization of Mga is disrupted and the protein is unable to activate transcription. PTS-mediated regulation of Mga activity appears to be important for pathogenesis, as bacteria expressing either non phosphorylated (A/A) or phosphomimetic (D/D) PRD1 Mga mutants were attenuated in a model of GAS invasive skin disease. Thus, PTS-mediated phosphorylation of Mga may allow the bacteria to modulate virulence gene expression in response to carbohydrate status. Furthermore, PRD-containing virulence regulators (PCVRs) appear to be widespread in Gram-positive pathogens. PMID- 23651412 TI - Structure-activity relationship of N,N'-disubstituted pyrimidinetriones as Ca(V)1.3 calcium channel-selective antagonists for Parkinson's disease. AB - CaV1.3 L-type calcium channels (LTCCs) have been a potential target for Parkinson's disease since calcium ion influx through the channel was implicated in the generation of mitochondrial oxidative stress, causing cell death in the dopaminergic neurons. Selective inhibition of CaV1.3 over other LTCC isoforms, especially CaV1.2, is critical to minimize potential side effects. We recently identified pyrimidinetriones (PYTs) as a CaV1.3-selective scaffold; here we report the structure-activity relationship of PYTs with both CaV1.3 and CaV1.2 LTCCs. By variation of the substituents on the cyclopentyl and arylalkyl groups of PYT, SAR studies allowed characterization of the CaV1.3 and CaV1.2 LTCCs binding sites. The SAR also identified four important moieties that either retain selectivity or enhance binding affinity. Our study represents a significant enhancement of the SAR of PYTs at CaV1.3 and CaV1.2 LTCCs and highlights several advances in the lead optimization and diversification of this family of compounds for drug development. PMID- 23651413 TI - Nursing students' attitudes towards provision of sexual health care in clinical practice. AB - AIMS AND OBJECTIVES: To investigate nursing students' attitudes towards providing sexual health care in clinical practice and to identify associated factors. BACKGROUND: Sexual health care is an important component of holistic health care. Nurses' personal sexual knowledge and attitudes are shown to influence provision of sexual health care. DESIGN: This is a descriptive, cross-sectional study. METHODS: We selected 146 senior nursing students by convenience sampling from nursing schools in two medical universities in central Taiwan. Data were collected using the Nursing Attitudes on Sexual Health Care scale developed based on the 'Permission/Limited Information/Specific Suggestions/Intensive Therapy' model. Higher scores indicated more positive attitudes. RESULTS: Participants' mean age was 22.15 years. Mean total Nursing Attitudes on Sexual Health Care scores ranged from 45-75 (61.40 +/- 10.17). Nursing students' most positive attitudes towards Permission/Limited Information/Specific Suggestions/Intensive Therapy sexual healthcare interventions were at the Permission level, and least positive attitudes were at levels of Specific Suggestion and Intensive Therapy. The top three positive items were as follows: accept patients' expression of sexual concerns, initiate discussions and encourage patients to talk. Male nursing students had negative attitudes towards sexual healthcare interventions, which became more positive as age increased, especially at the Limited Information level. CONCLUSIONS: Nursing students had different attitudes towards different levels of sexual health care in the Permission/Limited Information/Specific Suggestions/Intensive Therapy model. Attitudes were associated with age and gender. The Nursing Attitudes on Sexual Health Care scale is useful and reliable for identifying nurses' attitudes towards providing sexual health care. RELEVANCE TO CLINICAL PRACTICE: The Permission/Limited Information/Specific Suggestions/Intensive Therapy-based Nursing Attitudes on Sexual Health Care scale helps to identify nurses' attitudes. A better understanding of nurses' attitudes towards provisional sexual health care will provide information needed to develop appropriate education programmes to improve delivery of sexual health care. PMID- 23651414 TI - Interview with L. Stephen Coles, MD, PhD by Vicki Glaser. PMID- 23651415 TI - Haptoglobin phenotypes and in vitro fertilization treatment outcomes. AB - The haptoglobin (Hp) protein has been implicated in various aspects of reproduction. One possible mechanism is through its effect on angiogenesis. Angiogenesis plays a major role in follicle production. The Hp insertion polymorphism results in the production of Hp proteins denoted Hp 1-1, 2-1, and 2 2, with markedly different angiogenic activities. We sought to determine if the number of oocytes aspirated during in vitro fertilization is related to the Hp type and to compare clinical data and treatment outcomes. We conducted a prospective non-interventional study in an academic in vitro fertilization center serving northern Israel. All patients undergoing in vitro fertilization who agreed to have their haptoglobin phenotype and clinical data evaluated anonymously were included. The main outcome measure was the number of oocytes harvested from each aspiration. The groups did not differ regarding ethnicity or BMI, though women with the Hp1-1 phenotype had a longer duration of infertility (p = 0.037) and a higher gonadotropin requirement (p = 0.024) to achieve the same treatment outcome. Women with mechanical factor infertility were more likely (p = 0.042) to have the Hp 1-1/2-1 phenotypes than the Hp2-2 phenotype. There were no differences in the number of oocytes aspirated or the pregnancy rate. In summary, we could not establish a correlation between Hp phenotype and oocyte number or IVF outcomes though the Hp2-2 phenotype may be protective against mechanical factor infertility. Further studies with a larger sample size, particularly concerning the Hp1-1 phenotype, are required in order to extend these results. PMID- 23651416 TI - Association of social determinants of health with self-rated health among Australian gay and bisexual men living with HIV. AB - Despite a vast improvement in the survival of people living with HIV (PLHIV) since the introduction of combination antiretroviral treatment (cART), little change in the self-rated health of PLHIV has been observed since the introduction of cART in Australia. Difficulties with attaining employment or achieving financial security have been noted as some of the key challenges still facing PLHIV in the post-cART era. As a result, we investigated the independent association of a number of key social determinants of health with self-rated health among HIV-positive gay and bisexual men in Australia. Data from two recent national, cross-sectional surveys of PLHIV (the HIV Futures 5 and 6 surveys) were used. Logistic regression was used to assess the independent association of ethnicity, region of residence, education level, employment status, after-tax income, experience of HIV-related discrimination, level of social support, relationship status and recent sexual activity with reporting good-excellent self rated health, after adjusting for clinical factors and other social determinants of health. Multiple imputation was used to estimate missing data for variables with >5% missing data. Of the 1713 HIV-positive gay/bisexual men who responded to the HIV Futures 5 and 6 surveys, information on self-rated health was available for 99.3%. Close to three-quarters of these respondents (72.1%) reported their self-rated health as good or excellent; the remainder (27.9%) reported their self rated health as poor or fair. In multivariable analysis involving 89.3% of respondents, being employed, reporting recent sexual activity, a greater number of sources of social support and a higher weekly after-tax income were found to be independently associated with reporting good-excellent self-rated health. Despite the inability of this study to detect causal associations, addressing barriers to employment and sexual activity, and mechanisms to increase social support, is likely to have positive health effects for PLHIV in Australia. PMID- 23651417 TI - Waldenstrom macroglobulinaemia: the key questions. AB - In this review, the key issues that pertain to Waldenstrom disease are discussed in a concise question-and-answer format. Diagnosis, prognosis, and indications for state-of-the-art therapy are updated. Current therapies presented at the 7th International Workshop for Waldenstrom Macroglobulinaemia are included. PMID- 23651418 TI - Bullous pemphigoid: role of complement and mechanisms for blister formation within the lamina lucida. AB - Bullous pemphigoid (BP), an autoimmune subepidermal blistering skin disease, demonstrates tense blisters with or without widespread erythema, blistering along the lamina lucida, immunoglobulin G and/or complement deposits at the basement membrane zone, and the presence of circulating autoantibodies against hemidesmosomal molecules. These autoantibodies usually react against 180-kDa and/or 230-kDa proteins, designated as BP180 and BP230, respectively. The precise blistering mechanisms after autoantibodies bind to antigens are not fully understood. Immune complexes are thought to initially activate the complement cascade, which may induce activation of proteases and/or cytokines and cause dermal-epidermal separation. However, why does separation run specifically within the lamina lucida in a space as narrow as 500 nm wide? This review mainly focuses on the possible mechanisms of BP-specific blistering and how separation occurs along the lamina lucida, based on existing evidence. PMID- 23651419 TI - An anti-c-Fms antibody inhibits osteoclastogenesis in a mouse periodontitis model. AB - OBJECTIVE: Bacterial lipopolysaccharide (LPS) can induce inflammatory bone loss such as periodontal disease. The formation of osteoclasts depends on macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kb ligand (RANKL). It has recently been reported that administration of an antibody of the M-CSF receptor c-Fms completely blocked osteoclastogenesis and bone erosion induced by LPS in mouse calvaria. In this study, the effect of antibody against c-Fms in the mouse periodontitis model by injection of LPS was investigated. MATERIALS AND METHODS: C57BL6/J mice were injected with LPS and anti-c-Fms antibody into the mesial gingiva of the first molar in the left mandible. Histological sections of periodontal tissue were stained for tartrate resistant acid phosphatase, and osteoclast numbers and ratio of alveolar bone resorption determined. RESULTS: The number of osteoclasts and ratio of alveolar bone resorption in mice administered both LPS and anti-c-Fms antibody was lower than those in mice administered LPS alone. The expression of RANKL receptor, RANK, was inhibited by the anti-c-Fms antibody in periodontal tissue. CONCLUSION: M-CSF and/or its receptor are potential therapeutic targets for the treatment of bone resorption, caused by LPS, in periodontitis. Injection of an anti-c-Fms antibody might be useful for inhibition of pathological bone resorption in periodontitis. PMID- 23651420 TI - Cardiovascular safety and hemodynamic considerations in oncology drug development - webinar highlights October 10th 2012. AB - INTRODUCTION: Development of new drugs in oncology may have implications for cardiovascular risk. This report describes some aspects of our growing knowledge in the area of evaluating benefit-risk and may be of direct importance to scientists working in drug discovery and development. AREAS COVERED: This report of webinar highlights entitled "Trends in CardiOncology: the evolution of blood pressure and electrocardiogram (ECG) Markers" covers the current state of pharmacology of selected drugs which induce blood pressure elevation and best practices in employing the measurement of blood pressure elevation and cardiac safety parameters for drug development in oncology. EXPERT OPINION: Oncology drug induced cardiotoxicity has recently been recognised as an important drug development and clinical issue. The recognition of the risks and opportunities has prompted intensive research into mechanisms of chemotherapy-induced cardiotoxicity and potential prevention strategies. Drug-induced blood pressure elevation has emerged as a key area of interest, both as a marker of efficacy of vascular targeted chemotherapies as well as a target for early intervention strategies. While further research is ongoing, current data strongly suggest that early intervention strategies may provide significant short- and long-term clinical benefits to cancer patients undergoing chemotherapy. PMID- 23651422 TI - Nanofibers with very fine core-shell morphology from anisotropic micelle of amphiphilic crystalline-coil block copolymer. AB - A novel and facile strategy, combining anisotropic micellization of amphiphilic crystalline-coil copolymer in water and reassembly during single spinneret electrospinning, was developed for preparing nanofibers with very fine core-shell structure. Polyvinyl alcohol (PVA) and polyethylene glycol-block-poly(p dioxanone) (PEG-b-PPDO) were used as the shell and the crystallizable core layer, respectively. The core-shell structure could be controllably produced by altering concentration of PEG-b-PPDO, and the chain length of the PPDO block. The morphology of the nanofibers was investigated by Transmission Electron Microscope (TEM) and Scanning Electron Microscope (SEM). X-ray rocking curve measurements were performed to investigate the degree of ordered alignment of the PPDO crystalline lamellae in the nanofiber. The results suggested that the morphology of nanoparticles in spinning solution plays very important role in determining the phase separation of nanofibers. The amphiphilic PEG-b-PPDO copolymer self assembled into star anise nanoaggregates in water solution induced by the crystallization of PPDO blocks. When incorporated with PVA, the interaction between PVA and PEG-b-PPDO caused a morphological transition of the nanoaggregates from star anise to small flake. For flake-like particles, their flat surface is in favor of compact stacking of PPDO crystalline lamellae and interfusion of amorphous PPDO in the core of nanofibers, leading to a relatively ordered alignment of PPDO crystalline lamellae and well-defined core-shell phase separation. However, for star anise-like nanoaggregates, their multibranched morphology may inevitably prohibit the compact interfusion of PPDO phase, resulting in a random microphase separation. PMID- 23651421 TI - Testing the effects of an empowerment-based leadership development programme: part 1 - leader outcomes. AB - AIM: To determine if a leadership development programme based on an empowerment framework significantly increased leaders' use of empowering behaviours. BACKGROUND: Leadership programmes are effective ways to prepare nurse leaders for their complex roles. Relational competencies, such as leader empowering behaviours, are associated with improved leader, staff and practice environment outcomes. METHODS: A quasi-experimental, pre-test-post-test design was used to compare perceptions and self-reported behaviours of leaders who participated in a year-long leadership programme with those of similar leaders who did not attend the programme. Multiple regression analyses were used to evaluate a conceptual framework of leader empowerment. RESULTS: The leadership programme was directly associated with leaders' perceptions of using more empowering behaviours. Leader empowering behaviours were also associated with feelings of being structurally empowered, mediated through feelings of being psychologically empowered, although the source of empowerment needs further investigation. CONCLUSIONS: Leaders' use of empowering behaviours can be increased through focused training and through a workplace empowerment process. IMPLICATIONS FOR NURSE MANAGEMENT: Leader empowering behaviours have been shown to be associated with more engaged staff and healthier work environments. Based on study results, we suggest that these behaviours are teachable, and they should be emphasized in leadership development programmes. PMID- 23651424 TI - Exploring quality of life in Italian patients with rare disease: a computer-aided content analysis of illness stories. AB - The present study used a narrative-based approach to identify common themes that characterized the illness experience and quality of life of patients affected by rare disease (RD). Textual data were comprised of illness stories written by 32 adult Italian patients (eight men and 24 women), with the following RD diagnoses: amyotrophic lateral sclerosis (n = 12), anorectal atresia (n = 4), Poland syndrome (n = 4), and idiopathic pulmonary hypertension (n = 12). Computer-aided content analysis was performed to detect the main themes (cluster analysis) and latent factors (correspondence analysis) emerging in patients' narratives, and to test their association with gender and diagnosis. Four thematic domains were detected in the textual corpus, which are respectively referred to as: hopelessness (12.74%), need for autonomy (38.43%), search for normalcy (11.89%), and expectations of recovery (36.94%). Three latent factors explained the overall data variance: the relationship with social and medical healthcare providers (F1), adjustment processes to disease and social limitations (F2), and self beliefs and coping (F3). Some differences were revealed with respect to patient gender and diagnosis. Illness stories highlight the significant relationship of RD patients with healthcare services and their need for a holistic approach because of the lack of effective treatment. Physical limitation and emotional distress do not necessarily seem to overlap for adjustment and quality of life (QoL). Overall, the perception of illness chronicity is likely to affect patients' self-beliefs and coping with more than their feeling of abnormalcy, that is the less salient theme. PMID- 23651423 TI - One patient out of four with newly diagnosed erectile dysfunction is a young man- worrisome picture from the everyday clinical practice. AB - INTRODUCTION: Erectile dysfunction (ED) is a common complaint in men over 40 years of age, and prevalence rates increase throughout the aging period. Prevalence and risk factors of ED among young men have been scantly analyzed. AIM: Assessing sociodemographic and clinical characteristics of young men (defined as <= 40 years) seeking first medical help for new onset ED as their primary sexual disorder. METHODS: Complete sociodemographic and clinical data from 439 consecutive patients were analyzed. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients completed the International Index of Erectile Function (IIEF). MAIN OUTCOME MEASURE: Descriptive statistics tested sociodemographic and clinical differences between ED patients <= 40 years and >40 years. RESULTS: New onset ED as the primary disorder was found in 114 (26%) men <= 40 years (mean [standard deviation [SD]] age: 32.4 [6.0]; range: 17-40 years). Patients <= 40 years had a lower rate of comorbid conditions (CCI = 0 in 90.4% vs. 58.3%; chi(2) , 39.12; P < 0.001), a lower mean body mass index value (P = 0.005), and a higher mean circulating total testosterone level (P = 0.005) as compared with those >40 years. Younger ED patients more frequently showed habit of cigarette smoking and use of illicit drug, as compared with older men (all P <= 0.02). Premature ejaculation was more comorbid in younger men, whereas Peyronie's disease was prevalent in the older group (all P = 0.03). At IIEF, severe ED rates were found in 48.8% younger men and 40% older men, respectively (P > 0.05). Similarly, rates of mild, mild-to moderate, and moderate ED were not significantly different between the two groups. CONCLUSIONS: This exploratory analysis showed that one in four patients seeking first medical help for new onset ED was younger than 40 years. Almost half of the young men suffered from severe ED, with comparable rates in older patients. Overall, younger men differed from older individuals in terms of both clinical and sociodemographic parameters. PMID- 23651428 TI - The sensor kinase KdpD of Escherichia coli senses external K+. AB - The Kdp system of Escherichia coli is composed of the high-affinity K(+) transporter KdpFABC and the two regulatory proteins KdpD (sensor kinase) and KdpE (response regulator), which constitute a typical two-component system. The kdpFABC operon is induced under K(+) -limiting conditions and, to a lesser extent, under high osmolality in the medium. In search for the stimulus sensed by KdpD, we studied the inhibitory effect of extracellular K(+) on the Kdp system at pH 6.0, which is masked by unspecific K(+) transport at higher pH values. Based on KdpD derivatives carrying single aspartate replacements in the periplasmic loops which are part of the input domain, we concluded that the inhibition of the Kdp system at extracellular K(+) concentrations above 5 mM is mediated via KdpD/KdpE and not due to inhibition of the K(+) -transporting KdpFABC complex. Furthermore, time-course analyses of kdpFABC expression revealed that a decline in the extracellular K(+) concentration efficiently stimulates KdpD/KdpE-mediated signal transduction. In this report we provide evidence that the extracellular K(+) concentration serves as one of the stimuli sensed by KdpD. PMID- 23651426 TI - Metabolomics as a potential new approach for investigating human reproductive disorders. AB - Metabolomics has been emerging for several years as a global chemical phenotyping approach offering fascinating descriptive capabilities for addressing life complexity. It facilitates the understanding of the mechanisms of biological and biochemical processes in complex systems and promises new insights into specific research questions. The objective of this study was to use for the first time a metabolomic approach based on liquid chromatography high resolution mass spectrometry for characterizing an alteration of the testicular function, namely impaired semen quality. Metabolomic fingerprints were generated from serum samples collected from Danish young men presenting low, intermediate, or high sperm concentrations. Serum metabolic profiles were found to be significantly different among the three groups of volunteers. The developed methodology permitted to correlate the studied clinical parameter (i.e., sperm concentration) with the metabolite profiles generated. Peptides related to the Protein Complement C3f were identified as putative markers associated with this clinical parameter. The biological interpretation and further robustness linked to this observation remain to be further investigated, in particular to address the inter and intraindividual variabilities. PMID- 23651425 TI - Efficacy and safety of long-acting intramuscular testosterone undecanoate in aging men: a randomised controlled study. AB - OBJECTIVE: To evaluate the efficacy and safety of long-acting i.m. testosterone undecanoate (TU) in Malaysian men with testosterone deficiency (TD). PATIENTS AND METHODS: A total of 120 men, aged 40-70 years, with TD (serum total testosterone [TT] <= 12 nmol/L) were randomised to receive either i.m. TU (1000 mg) or placebo. In all, 58 and 56 men in the placebo and treatment arm, respectively, completed the study. Participants were seen six times in the 48-week period and the following data were collected: physical examination results, haemoglobin, haematocrit, TT, lipid profile, fasting blood glucose, sex hormone-binding globulin, liver function test, prostate- specific antigen (PSA) and adverse events. RESULTS: The mean (sd) age of the participants was 53.4 (7.6) years. A significant increase in serum TT (P < 0.001), PSA (P = 0.010), haematocrit (P < 0.001), haemoglobin (P < 0.001) and total bilirubin (P = 0.001) were seen in the treatment arm over the 48-week period. Two men in the placebo arm and one man in the treatment arm developed myocardial infarction. Common adverse events observed in the treatment arm included itching/swelling/pain at the site of injection, flushing and acne. Overall, TU injections were well tolerated. CONCLUSIONS: TU significantly increases serum testosterone in men with TD. PSA, haemoglobin and haematocrit were significantly elevated but were within clinically safe limits. There was no significant adverse reaction that led to the cessation of treatment. PMID- 23651429 TI - Comparison between fibroblasts and mesenchymal stem cells derived from dermal and adipose tissue. AB - OBJECTIVE: Stem cells have the ability to renew themselves and differentiate into various cell types. For this reason, numerous research groups have been studying these cells for their therapeutic potential. Some of the therapies, however, are not producing the expected results because of contamination by other cell types, especially by fibroblasts. In the cosmetic industry, stem cells are used to test the efficacy of anti-ageing and rejuvenation products. The purpose of this work was to gain a better understanding of the differences in phenotype, in gene expression associated with stem cells, in the pattern of cell surface proteins and in the differentiation capacity of adipose-derived stem cells, of skin derived stem cells and of commercially available fibroblasts. METHODS: In this study, we compared fibroblasts with mesenchymal stem cells derived from bone marrow, skin (dermis) and adipose tissue, to assess the differentiation potential of fibroblasts. Dermal and adipose stem cells were isolated from aesthetic surgery patients, and fibroblasts were obtained from a commercial source. The following parameters were used in this study: immunophenotypic profile (positive: CD29, CD73, CD90 and CD105; negative: CD14, CD45 and HLA-DR); differentiation into osteoblastic, chondrogenic and adipogenic cell types; and PCR array to analyse the gene expression of cells isolated from different culture passages. RESULTS: Fibroblasts express the same cell immunophenotypic markers, as well as the genes that are known to be expressed in stem cells, and were shown to be expressed also in adipose and dermis stem cells. Fibroblasts are also able to differentiate into the three cell lineages mentioned above, that is, adipocytes, osteocytes and chondrocytes. CONCLUSION: Human dermal fibroblasts have a potential to adhere to plastic surfaces and differentiate into other cell types. However, for stem cells intended to be used in cosmetics, experiments conducted with contaminated fibroblasts may produce poor or even falsely negative results for the efficacy of the active ingredient or formulation and thus conceal their promising effects as anti-ageing and skin rejuvenation products. PMID- 23651427 TI - Ischemia/Reperfusion-inducible protein modulates the function of organic cation transporter 1 and multidrug and toxin extrusion 1. AB - The recently identified ischemia/reperfusion-inducible protein (IRIP) has been reported to negatively modulate the activities of several transporters in cell culture systems. The goal of this study is to determine whether IRIP regulates the activities of OCT1 and MATE1, and hence the disposition in vivo of their substrate metformin, a therapeutic drug for diabetes and other obesity-related syndromes. In the uptake studies in the human embryonic kidney 293 cells overexpressing IRIP with and without OCT1 or MATE1, IRIP overexpression was found to significantly inhibit the uptake of 1-methyl-4-phenylpyridinium mediated by OCT1 or MATE1. In contrast, knockdown of IRIP by small hairpin RNA (shRNA) increased the transporter activities in vitro. IRIP overexpression decreased the membrane localization of transporter proteins without any changes in transcript levels in cells. By overexpressing IRIP in mouse liver via hydrodynamic tail vein injection, we demonstrated that increased IRIP expression could cause a significant reduction in hepatic accumulation of metformin (P < 0.01). In addition, we observed that the expression of IRIP was approximately half (P < 0.01) in ob/ob mice when compared to their lean littermates, with significant increases in hepatic Oct1 protein expression and metformin accumulation. In conclusion, IRIP negatively modulates the function of OCT1 and MATE1 in cells. Importantly, we provide in vivo evidence for such modulation that may cause an alteration in drug disposition. The regulation by IRIP on transporter activities likely occurs at a post-transcriptional level, and future studies are needed to characterize the exact mechanism. PMID- 23651430 TI - alpha-Glucosidase inhibiton and antiglycation activity of laccase-catalyzed catechin polymers. AB - Catechin polymers were produced by laccase (12 U/mL) in a mixture of sodium acetate buffer (1% (+)-catechin, 100 mM, pH 5) and methanol (buffer:methanol = 95:5, v/v). The freeze-dried catechin polymers were recovered from the precipitate after dialysis followed by centrifugation. Catechin polymers extracted with 20% ethanol had potent inhibitory activity against alpha glucosidase with an IC50 value of 4 MUg/mL, and they were present as a mixture of dimers, trimers, and tetramers. The antihyperglycemic effect of the catechin polymers was confirmed by an oral maltose tolerance test. The catechin polymers also had significantly improved antiglycation and superoxide dismutase-like activities compared to those of (+)-catechin. Since formation of advanced glycation end products and oxidative stress are accelerated in hyperglycemic conditions, we suggest that enzymatic production of catechin polymers could have a potential protective effect in type 2 diabetes, diabetic complications, and other free radical related diseases. PMID- 23651432 TI - Transformation of Beauveria bassiana to produce EGFP in Tenebrio molitor for use as animal feed additives. AB - Efforts are underway to develop more effective and safer animal feed additives. Entomopathogenic fungi can be considered practical expression platforms of functional genes within insects which have been used as animal feed additives. In this work, as a model, the enhanced green fluorescent protein (egfp) gene was expressed in yellow mealworms, Tenebrio molitor by highly infective Beauveria bassiana ERL1170. Among seven test isolates, ERL1170 treatment showed 57.1% and 98.3% mortality of mealworms 2 and 5 days after infection, respectively. The fungal transformation vector, pABeG containing the egfp gene, was inserted into the genomic DNA of ERL1170 using the restriction enzyme-mediated integration method. This resulted in the generation of the transformant, Bb-egfp#3, which showed the highest level of fluorescence. Bb-egfp#3-treated mealworms gradually turned dark brown, and in 7-days mealworm sections showed a strong fluorescence. This did not occur in the wild-type strain. This work suggests that further valuable proteins can be efficiently produced in this mealworm-based fungal expression platform, thereby increasing the value of mealworms in the animal feed additive industry. PMID- 23651433 TI - Work in an intermediate unit: balancing between relational, practical and moral care. AB - AIMS AND OBJECTIVES: To explore the activities carried out and the conditions required to enable satisfactory work in an intermediate unit for patients aged 60 and older. BACKGROUND: In recent years, several intermediate units have been established to improve the clinical pathway from hospital to home for older patients. DESIGN: Qualitative study. METHODS: Data were obtained from interviews with eight patients and 16 healthcare providers working in the unit and from observations in six multidisciplinary meetings and six report meetings in the unit. Transcripts of interviews and field notes were analysed using a method for systematic text condensation. RESULTS: Care performed as a balance between relational, practical and moral aspects seems to be important to render good service to patients and to ensure the providers' job satisfaction. Most patients experienced their stay in the unit as positive. The providers highlighted 'suitable patients', an appropriate physical environment and communicating computer systems as significant factors for performing treatment and for providing nursing and rehabilitation in a caring manner. CONCLUSIONS: When environmental and organisational conditions exert pressure on the working situation, care as a practical activity seems to be prioritised at the expense of the two other aspects. The findings indicate that unfavourable environmental and organisational conditions impede patients' recovery process and thereby a good clinical pathway. RELEVANCE TO CLINICAL PRACTICE: To recruit, support and retain a multidisciplinary staff to the best interest of patients, it seems to be important to perform care work as a balance between relational, practical and moral activities. PMID- 23651436 TI - Improving resource allocation decisions for health and HIV programmes in South Africa: Bioethical, cost-effectiveness and health diplomacy considerations. AB - The escalating expenditure on patients with HIV/AIDS within an inadequately funded public health system is tending towards crowding out care for patients with non-HIV illnesses. Priority-setting decisions are thus required and should increasingly be based on an explicit, transparent and accountable process to facilitate sustainability. South Africa's public health system is eroding, even though the government has received extensive donor financing for specific conditions, such as HIV/AIDS. The South African government's 2007 HIV plan anticipated costs exceeding 20% of the annual health budget with a strong focus on treatment interventions, while the recently announced 2012-2016 National Strategic HIV plan could cost up to US$16 billion. Conversely, the total non-HIV health budget has remained static in recent years, effectively reducing the supply of health care for other diseases. While the South African government cannot meet all demands for health care simultaneously, health funders should attempt to allocate health resources in a fair, efficient, transparent and accountable manner, in order to ensure that publicly funded health care is delivered in a reasonable and non-discriminatory fashion. We recommend a process for resource allocation that includes ethical, economic, legal and policy considerations. This process, adapted for use by South Africa's policy-makers, could bring health, political, economic and ethical gains, whilst allaying a social crisis as mounting treatment commitments generated by HIV have the potential to overwhelm the health system. PMID- 23651438 TI - Female upper body and breast skin temperature and thermal comfort following exercise. AB - Breast support reduces breast pain and movement during exercise, however, an extra layer of clothing may affect thermoregulation. This preliminary study investigated female upper body and breast skin temperature and thermal comfort following short-duration exercise. Eight female participants with C-cup breasts had thermal images (infra-red camera, FLIR systems) of the bare breasts, the breasts in two sports bras (composite and polyester) and the abdomen, taken before and after 20 min of exercise at 28(o)C. Following exercise, bare-breast, bra and abdomen temperatures reduced by 0.61(o)C, 0.92(o)C and 2.06(o)C, respectively. The polyester sports bra demonstrated greater thermal comfort and enabled a greater change in skin temperature than the composite sports bra. It is concluded that following short-duration exercise, sports bras reduced the cooling ability of the breast. Material properties of the bras affect thermal comfort and post-exercise skin temperature; this should be an important consideration for sports bra manufacturers. PRACTITIONER SUMMARY: This study investigates the effect of sports bras on thermal regulation of the breast following exercise. Sports bras negatively affected the cooling ability of the skin on the breast, with the material properties of the bra affecting thermal comfort following exercise. These results present important considerations for sports bra manufacturers. PMID- 23651441 TI - Postnatal regulation of X,K-ATPases in rat skin and conserved lateroapical polarization of Na,K-ATPase in vertebrate epidermis. AB - Development of epidermis creates stratified epithelium with different sets of ion transporting enzymes in its layers. We have characterized expression of Na,K- and H,K-ATPase alpha and beta subunits and FXYD isoforms in rat skin. Maturation of rat skin from newborn to adult is associated with an increase in FXYD4 and a decrease of Na,K-ATPase alpha1-isoform, ATP1B4 and FXYD6 transcripts. Na,K-ATPase of rat epidermis is represented predominantly by alpha1 and beta3 isoforms. Keratinization is associated with the loss of the Na,K-ATPase alpha-subunit and an enrichment of alphang. Na,K-ATPase alpha1 is abundant in the innermost layer, stratum basale, where it is lacking in basal membranes, thus indicating lateroapical polarization of Na,K-ATPase. Immunocytochemical detection of Na,K ATPase in Xenopus laevis skin shows that cellular and subcellular localization of the enzyme has a pattern highly similar to that of mammals: basolateral in glandular epithelium and lateroapical in epidermis. PMID- 23651440 TI - The mean fluorescence intensities of anti-HLA antibodies detected using micro bead flow cytometry predict the risk of platelet transfusion refractoriness. AB - There are no accepted methods to predict the development of platelet transfusion refractoriness (PTR) due to human leucocyte antigen (HLA)-alloimmunization. Hence, matched platelets are usually given only to patients demonstrating PTR, necessarily resulting in some ineffective random donor platelets (RDPLT) transfusions. To assess its utility in predicting PTR, we retrospectively tested samples from 387 patients receiving chemotherapy for acute leukaemia or autologous transplantation using a micro-bead flow cytometry assay. The average of the mean fluorescence intensities (avgMFI) of the class I beads in the screening assay was correlated with outcomes of RDPLT transfusions during a 2 week period. Antibodies were detected in 57 patients; 66 developed PTR, of whom 28 were alloimmunized. avgMFI usefully predicted the development of PTR (area under the receiver operating curve 0.87, 95% confidence interval: 0.77-0.96). A logistic regression model estimated the probability of PTR to be >90% when avgMFI >5440. These results indicate that micro-bead flow cytometry assays could inform a risk-adapted strategy for managing thrombocytopaenic HLA allo-immunized patients. PMID- 23651435 TI - Mild beta(+)-thalassemia associated with two linked sequence variants: IVS-II-839 (T>C) and IVS-II-844 (C>A). AB - We report four unrelated families with a mild beta(+)-thalassemia (beta(+)-thal) allele consisting of two sequence variants at the 3' end of IVS-II: IVS-II-839 (T>C) (HBB: c.316-12T>C) and IVS-II-844 (C>A) (HBB: c.316-7C>A). These sequence variants alter the conserved polypyrimidine tract of the consensus splice acceptor sequence (Y11NYAG/G), which could reduce splicing efficiency. This may represent a common, yet under-diagnosed beta(+)-thal allele in African populations. PMID- 23651442 TI - A crossed molecular beam and ab-initio investigation of the reaction of boron monoxide (BO; X2Sigma+) with methylacetylene (CH3CCH; X1A1): competing atomic hydrogen and methyl loss pathways. AB - The gas-phase reaction of boron monoxide ((11)BO; X(2)Sigma(+)) with methylacetylene (CH3CCH; X(1)A1) was investigated experimentally using crossed molecular beam technique at a collision energy of 22.7 kJ mol(-1) and theoretically using state of the art electronic structure calculation, for the first time. The scattering dynamics were found to be indirect (complex forming reaction) and the reaction proceeded through the barrier-less formation of a van der-Waals complex ((11)BOC3H4) followed by isomerization via the addition of (11)BO(X(2)Sigma(+)) to the C1 and/or C2 carbon atom of methylacetylene through submerged barriers. The resulting (11)BOC3H4 doublet radical intermediates underwent unimolecular decomposition involving three competing reaction mechanisms via two distinct atomic hydrogen losses and a methyl group elimination. Utilizing partially deuterated methylacetylene reactants (CD3CCH; CH3CCD), we revealed that the initial addition of (11)BO(X(2)Sigma(+)) to the C1 carbon atom of methylacetylene was followed by hydrogen loss from the acetylenic carbon atom (C1) and from the methyl group (C3) leading to 1-propynyl boron monoxide (CH3CC(11)BO) and propadienyl boron monoxide (CH2CCH(11)BO), respectively. Addition of (11)BO(X(2)Sigma(+)) to the C1 of methylacetylene followed by the migration of the boronyl group to the C2 carbon atom and/or an initial addition of (11)BO(X(2)Sigma(+)) to the sterically less accessible C2 carbon atom of methylacetylene was followed by loss of a methyl group leading to the ethynyl boron monoxide product (HCC(11)BO) in an overall exoergic reaction (78 +/- 23 kJ mol(-1)). The branching ratios of these channels forming CH2CCH(11)BO, CH3CC(11)BO, and HCC(11)BO were derived to be 4 +/- 3%, 40 +/- 5%, and 56 +/- 15%, respectively; these data are in excellent agreement with the calculated branching ratios using statistical RRKM theory yielding 1%, 38%, and 61%, respectively. PMID- 23651431 TI - Allosteric communication in the KIX domain proceeds through dynamic repacking of the hydrophobic core. AB - The KIX domain of the transcriptional coactivator CREB binding protein (CBP) co operatively mediates interactions between transcription factors. Binding of the transcription factor mixed-lineage leukemia (MLL) induces the formation of a low populated conformer of KIX that resembles the conformation of the KIX domain in the presence of a second transcription factor molecule. NMR spin relaxation studies have previously shown that allosteric coupling proceeds through a network of hydrophobic core residues that bridge the two binding sites. Here we describe high-resolution NMR solution structures of the binary complex of KIX with MLL and the ternary complex of KIX formed with MLL and phosphorylated kinase inducible domain of CREB (pKID) as a second ligand. We show that binding of pKID to the binary complex of KIX with MLL is accompanied by a defined repacking of the allosteric network in the hydrophobic core of the protein. Rotamer populations derived from methyl group (13)C chemical shifts reveal a dynamic contribution to the repacking process that is not captured by the structural coordinates and exemplify the dynamic nature of allosteric communication in the KIX domain. PMID- 23651437 TI - Discovery of N-{4-[(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl-2 methylpropyl}-4-phenoxybenzamide analogues as selective kappa opioid receptor antagonists. AB - There is continuing interest in the discovery and development of new kappa opioid receptor antagonists. We recently reported that N-substituted 3-methyl-4-(3 hydroxyphenyl)piperazines were a new class of opioid receptor antagonists. In this study, we report the syntheses of two piperazine JDTic-like analogues. Evaluation of the two compounds in an in vitro [(35)S]GTPgammaS binding assay showed that neither compound showed the high potency and kappa opioid receptor selectivity of JDTic. A library of compounds using the core scaffold 21 was synthesized and tested for their ability to inhibit [(35)S]GTPgammaS binding stimulated by the selective kappa opioid agonist U69,593. These studies led to N [(1S)-1-{[(3S)-4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl]methyl}-2-methylpropyl] 4-phenoxybenzamide (11a), a compound that showed good kappa opioid receptor antagonist properties. An SAR study based on 11a provided 28 novel analogues. Evaluation of these 28 compounds in the [(35)S]GTPgammaS binding assay showed that several of the analogues were potent and selective kappa opioid receptor antagonists. PMID- 23651434 TI - Perinatal exposure to fluoxetine via placenta and lactation inhibits the testicular development in male rat offspring. AB - Due to the widespread use of fluoxetine to treat depression, including pregnant and nursing women, the present study aimed to investigate the effects of in utero and lactational exposure to fluoxetine in rat offspring at post natal day 22. Wistar rat dams were orally treated with fluoxetine (5, 10, and 20 mg/kg) from day 13 gestation to day 21 lactation. Exposure to 10 and 20 mg/kg fluoxetine reduced the body and testis weights. The volume of the seminiferous tubules and epithelium were also reduced following 20 mg/kg fluoxetine exposure. The length of the seminiferous tubules and the population of Sertoli cells changed in offspring exposed to fluoxetine. The amount of seminiferous tubules lacking tubular lumen was higher in rats exposed to 20 mg/kg fluoxetine. Plasma testosterone showed no significant change. In conclusion, fluoxetine exposure via the placenta and lactation may inhibit and delay testicular development, adversely affecting several testicular parameters important for the establishment of sperm production in adulthood. PMID- 23651439 TI - Assessing willingness to test for HIV among men who have sex with men using conjoint analysis, evidence for uptake of the FDA-approved at-home HIV test. AB - Men who have sex with men (MSM) in the USA, represent a vulnerable population with lower rates of HIV testing. There are various specific attributes of HIV testing that may impact willingness to test (WTT) for HIV. Identifying specific attributes influencing patients' decisions around WTT for HIV is critical to ensure improved HIV testing uptake. This study examined WTT for HIV by using conjoint analysis, an innovative method for systematically estimating consumer preferences across discrete attributes. WTT for HIV was assessed across eight hypothetical HIV testing scenarios varying across seven dichotomous attributes: location (home vs. clinic), price (free vs. $50), sample collection (finger prick vs. blood), timeliness of results (immediate vs. 1-2 weeks), privacy (anonymous vs. confidential), results given (by phone vs. in-person), and type of counseling (brochure vs. in-person). Seventy-five MSM were recruited from a community-based organization providing HIV testing services in Los Angeles to participate in conjoint analysis. WTT for HIV score was based on a 100-point scale. Scores ranged from 32.2 to 80.3 for eight hypothetical HIV testing scenarios. Price of HIV testing (free vs. $50) had the highest impact on WTT (impact score = 31.4, SD = 29.2, p<0.0001), followed by timeliness of results (immediate vs. 1-2 weeks) (impact score = 13.9, SD = 19.9, p<=0.0001) and testing location (home vs. clinic) (impact score = 10.3, SD = 22.8, p=0.0002). Impacts of other HIV testing attributes were not significant. Conjoint analysis method enabled direct assessment of HIV testing preferences and identified specific attributes that significantly impact WTT for HIV among MSM. This method provided empirical evidence to support the potential uptake of the newly FDA-approved over-the counter HIV home test kit with immediate results, with cautionary note on the cost of the kit. PMID- 23651445 TI - Sr2FeO3 with stacked infinite chains of FeO4 square planes. AB - The synthesis of Sr2FeO3 through a hydride reduction of the Ruddlesden-Popper layered perovskite Sr2FeO4 is reported. Rietveld refinements using synchrotron and neutron powder diffraction data revealed that the structure contains corner shared FeO4 square-planar chains running along the [010] axis, being isostructural with Sr2CuO3 (Immm space group). Fairly strong Fe-O-Fe and Fe-Fe interactions along [010] and [100], respectively, make it an S = 2 quasi two dimensional (2D) rectangular lattice antiferromagnet. This compound represents the end-member (n = 1) of the serial system Sr(n+1)FenO(2n+1), together with previously reported Sr3Fe2O5 (n = 2) and SrFeO2 (n = infinity), thus giving an opportunity to study the 2D-to-3D dimensional crossover. Neutron diffraction and Mossbauer spectroscopy show the occurrence of G-type antiferromagnetic order below 179 K, which is, because of dimensional reduction, significantly lower than those of the other members, 296 K in Sr3Fe2O5 and 468 K in SrFeO2. However, the temperature dependence of magnetic moment shows a universal behavior. PMID- 23651443 TI - Inhibition of CK2alpha down-regulates Notch1 signalling in lung cancer cells. AB - Protein kinase CK2 is frequently elevated in a variety of human cancers. The Notch1 signalling pathway has been implicated in stem cell maintenance and its aberrant activation has been shown in several types of cancer including lung cancer. Here, we show, for the first time, that CK2alpha is a positive regulator of Notch1 signalling in lung cancer cell lines A549 and H1299. We found that Notch1 protein level was reduced after CK2alpha silencing. Down-regulation of Notch1 transcriptional activity was demonstrated after the silencing of CK2alpha in lung cancer cells. Furthermore, small-molecule CK2alpha inhibitor CX-4945 led to a dose-dependent inhibition of Notch1 transcriptional activity. Conversely, forced overexpression of CK2alpha resulted in an increase in Notch1 transcriptional activity. Finally, the inhibition of CK2alpha led to a reduced proportion of stem-like CD44 + /CD24- cell population. Thus, we report that the inhibition of CK2alpha down-regulates Notch1 signalling and subsequently reduces a cancer stem-like cell population in human lung cancer cells. Our data suggest that CK2alpha inhibitors may be beneficial to the lung cancer patients with activated Notch1 signalling. PMID- 23651444 TI - Factors affecting residual platelet aggregation in prasugrel treated patients. AB - Identification of factors affecting platelet reactivity (PR) and high PR (HPR) or high platelet inhibition (HPI) rates while on prasugrel maintenance dose (MD) might be helpful in avoiding ischemic or bleeding complications. We retrospectively analyzed all patients (n=233) treated in our institution between April 2010 and November 2012 who had platelet function assessment pre-prasugrel and following prasugrel 10 mg MD for at least 5 days, using the Verify Now P2Y12 platelet function assay. Multiple linear regression and logistic regression models were applied to identify independent factors affecting post-prasugrel PR level, HPR and HPI status. The amount of variance in PR under prasugrel MD that could be explained by the model was 25.9% (adjusted R2), p<0.001. Pre-prasugrel treatment PR, acute coronary syndrome (ACS), prasugrel loading and smoking uniquely accounted for 10.8%, 1.3%, 3.5% and 1.2% of the observed variance, respectively. HPR and HPI were observed in 7.7% and 13.7% of the cases, respectively. On multivariate analysis, pre-prasugrel PR in the upper quartile (>313 PRU) was the only independent factor associated with HPR under prasugrel MD. In contrast, pre-prasugrel PR in the lower quartile (<242 PRU) and prasugrel loading emerged as the only independent predictors of HPI. In patients under different clinical settings receiving prasugrel 10 mg MD a significant amount of the PR variability in response to prasugrel may be explained by pre- treatment PR level, ACS, prasugrel loading and smoking status. A high pre- treatment PR is associated with HPR, while a low pre-treatment PR and prasugrel loading predict HPI. PMID- 23651446 TI - An analysis of patients with T2 renal cell carcinoma (RCC) according to tumour size: a population-based analysis. AB - OBJECTIVE: To examine the discriminant properties of the most contemporary version of the Tumour-Node-Metastasis (TNM) staging for renal cell carcinoma (RCC) sub-classification of T2 lesions according to a threshold size of 10 cm. Other thresholds were also assessed. PATIENTS AND METHODS: Between 1988 and 2006, within the Surveillance, Epidemiology, and End Results database, patients with T2 N0-2 M0-1 RCC treated with a nephrectomy were abstracted. Tumour size was evaluated according to several thresholds: >=8, >=9, >=10, >=11, and >=12 cm. Kaplan-Meier and life tables for cancer-specific mortality (CSM) were computed. Several Cox regression modes were fitted for prediction of CSM, using different thresholds. The predictive accuracy of various thresholds was compared using the area under the curve and methods of calibration. RESULTS: In all, 4963 patients were identified. Kaplan-Meier analyses showed statistically significant CSM-free survival differences between all examined thresholds. In multivariable Cox regression models, all tested tumour size thresholds emerged as independent predictors of CSM. Of all thresholds, the values of 9 (0.55) and 11 cm (0.55) achieved the highest discrimination in univariable analysis, followed by 10 (0.539), 12 (0.539), and 8 cm (0.531). When the thresholds were combined with all other variables, the 11 cm (0.688) achieved the highest discrimination. CONCLUSION: The discriminant properties of all examined thresholds showed very similar discriminant properties, which brings into questioning whether a dichotomization of pT2 tumours is really necessary. PMID- 23651447 TI - Dysregulation of miR-31 and miR-375 expression is associated with clinical outcomes in oral carcinoma. AB - OBJECTIVES: To identify differentially expressed miRNA between oral squamous cell carcinoma (OSCC) and non-cancer (NC) and to associate these with clinico pathological parameters. MATERIALS AND METHODS: miRNA microarray profiling was utilized to obtain the expression profile of miRNAs in four OSCC and four NC samples. The expression of miR-31 and miR-375 was further validated in 26 OSCC and three NC samples using real-time-PCR. The association between miRNA expression and clinico-pathological parameters was tested by univariate and multivariate analyses. RESULTS: Microarray profiling demonstrated that 15 and four miRNAs were up-regulated and down-regulated, respectively, in OSCC as compared with NC. miR-31 and miR-375 were validated as up- and down-regulated miRNAs, respectively. In univariate analyses, expression of miR-31 was significantly elevated in early stage, tumours with no metastatic nodes and those from the buccal mucosa. By contrast, low miR-375 expression was significantly associated with late stage disease, larger tumour size and the non-cohesive type of pattern of invasion in OSCC. The association between miR-31 expression with tumour staging and site and miR-375 with tumour staging remained significant in multivariate analyses. CONCLUSIONS: This study has identified 19 miRNAs significantly associated with OSCC, and expressions of miR-31 and miR-375 were significantly related with clinico-pathological parameters suggesting they could be important in driving oral tumourigenesis. PMID- 23651448 TI - Investigation of the impact of low cost traffic engineering measures on road safety in urban areas. AB - This paper investigates the impact of low cost traffic engineering measures (LCTEMs) on the improvement of road safety in urban areas. A number of such measures were considered, such as speed humps, woonerfs, raised intersections and other traffic calming measures, which have been implemented on one-way, one-lane roads in the Municipality of Neo Psychiko in the Greater Athens Area. Data were analysed using the before-and-after safety analysis methodology with large control group. The selected control group comprised of two Municipalities in the Athens Greater Area, which present similar road network and land use characteristics with the area considered. The application of the methodology showed that the total number of crashes presented a statistically significant reduction, which can be possibly attributed to the introduction of LCTEMs. This reduction concerns passenger cars and single-vehicle crashes and is possibly due to the behavioural improvement of drivers of 25 years old or more. The results of this research are very useful for the identification of the appropriate low cost traffic engineering countermeasures for road safety problems in urban areas. PMID- 23651449 TI - Potential of human gammaD-crystallin for hair damage repair: insights into the mechanical properties and biocompatibility. AB - OBJECTIVES: The objective of this work was to develop a new strategy to physically 'repair' chemically damaged hair. Hence the human eye gammaD crystallin, a protein from the superfamily characterized structurally by the Greek key motif, was studied. The human gammaD-crystallin was chosen based on the ability of proteins belonging to this superfamily to be involved in the coating of specific structures. Two crystallins were used on the study, the wild type (Protein Data Bank ID: 1HK0) and the mutant protein. The mutant form was intended to induce a strong and quick protein polymerization as well to have new possible points of anchorage to hair. METHODS: The ability of both crystallins to bind to damaged hair and even penetrate into its cortex was checked by fluorescence microscopy, confocal microscopy and scanning electron microscopy. Furthermore the reinforcement of hair mechanical resistance, the potential cytotoxic/inflammatory effect of crystallins were studied in order to have a fully comprehension about the protein based formulation. RESULTS: Although the chemical over-bleaching treatment induced a decrease of 20% on the resistance of the hair, the crystallins which bind and penetrate the hair fibre were able to recover and even to improve its mechanical properties when compared to the virgin hair. Moreover none of the crystallins displayed a toxic effect in fibroblasts for all the range of tested concentrations upon 72 h of exposure. The active aggregation process of mutant crystallin induced an inflammatory response in fibroblasts in the first 24 h of contact, measured by the amount of released pro-inflammatory cytokine IL-6 to the medium. In contrast contact with wild type crystallin did not lead to significant inflammation. CONCLUSION: Outcome from protein formulation characterization supports the hypothesis that the gammaD-crystallin it is able to recover and improve the mechanical properties of chemical damaged hair. Therefore it can be considered as a very promising strengthening agent for the development of new restorative hair care products. PMID- 23651450 TI - Major depressive disorder symptoms in male and female young adults. AB - This research aimed to compare the prevalence rates of major depressive disorder (MDD) and to differentiate the presence and severity of depressive symptoms between women and men aged 18-24 years. In this population-based, cross-sectional study (n = 1560), young adults were screened with the Mini International Neuropsychiatric Interview for MDD (n = 137). Participants then completed a self report questionnaire to gather sociodemographic data, and the presence of each symptom of depression was assessed with the Beck Depression Inventory. The proportion of women (12.2%) with MDD was higher than that of men (5.3%). The symptoms of depression found to be significantly more prevalent in women were sadness, crying, difficulty making decisions, and lack of energy, as well as self criticism, irritability, changes in self-image, work difficulty, and loss of interest in sex. Sadness and self-criticism were significantly more severe in women than in men. The presentation of depressive symptoms in young adults with MDD differed between men and women. PMID- 23651451 TI - Prevalence and factors associated with the complaint of premature ejaculation and the four premature ejaculation syndromes: a large observational study in China. AB - INTRODUCTION: Although the new classification of premature ejaculation (PE) has been proposed by Waldinger et al., there have been few studies investigating the four PE syndromes in China. AIMS: We investigated the prevalence and factors associated with the complaint of PE and the four PE syndromes in Anhui province, China. METHODS: Between September 2011 and September 2012, subjects were selected from five cities in Anhui province, China. They participated in this survey by completing a detailed verbal questionnaire regarding their demographic data and medical and sexual history. Men with PE complaint were diagnosed as lifelong PE (LPE), acquired PE (APE), natural variable PE (NVPE), or premature-like ejaculatory dysfunction (PLED). MAIN OUTCOME MEASURES: PE complaint was divided into four PE syndromes. Anxiety, depression, and erectile dysfunction were independently assessed by the self-rating anxiety/depression scale and the international index of erectile function-5, respectively. RESULTS: Of the 3,016 men evaluated, 25.80% complained of PE. The distribution of the four PE syndromes in men with PE complaint was in the order of NVPE (44.09%), PLPE (24.81%), APE (18.77%), and LPE (12.34%). Patients with PE complaint were older and more likely to smoke, had more comorbidities, and a higher body mass index (BMI) than patients without the complaint (P < 0.001 for all). Similar findings were also observed in patients with APE compared with other PE patients (depression P = 0.012, cardiovascular P = 0.003, others P < 0.001). In addition, the rates of counseling by a doctor in men with LPE and APE were higher than those in men with NVPE and PLED (P < 0.001). CONCLUSION: The prevalence of PE complaint in male population of Anhui province, China, was 25.80%, with the highest PE syndromes being NVPE and PLPE. Patients with PE complaint or APE were older and more likely to smoke, had more comorbidities, and a higher BMI. PMID- 23651452 TI - Reconstituting protein interaction networks using parameter-dependent domain domain interactions. AB - BACKGROUND: We can describe protein-protein interactions (PPIs) as sets of distinct domain-domain interactions (DDIs) that mediate the physical interactions between proteins. Experimental data confirm that DDIs are more consistent than their corresponding PPIs, lending support to the notion that analyses of DDIs may improve our understanding of PPIs and lead to further insights into cellular function, disease, and evolution. However, currently available experimental DDI data cover only a small fraction of all existing PPIs and, in the absence of structural data, determining which particular DDI mediates any given PPI is a challenge. RESULTS: We present two contributions to the field of domain interaction analysis. First, we introduce a novel computational strategy to merge domain annotation data from multiple databases. We show that when we merged yeast domain annotations from six annotation databases we increased the average number of domains per protein from 1.05 to 2.44, bringing it closer to the estimated average value of 3. Second, we introduce a novel computational method, parameter dependent DDI selection (PADDS), which, given a set of PPIs, extracts a small set of domain pairs that can reconstruct the original set of protein interactions, while attempting to minimize false positives. Based on a set of PPIs from multiple organisms, our method extracted 27% more experimentally detected DDIs than existing computational approaches. CONCLUSIONS: We have provided a method to merge domain annotation data from multiple sources, ensuring large and consistent domain annotation for any given organism. Moreover, we provided a method to extract a small set of DDIs from the underlying set of PPIs and we showed that, in contrast to existing approaches, our method was not biased towards DDIs with low or high occurrence counts. Finally, we used these two methods to highlight the influence of the underlying annotation density on the characteristics of extracted DDIs. Although increased annotations greatly expanded the possible DDIs, the lack of knowledge of the true biological false positive interactions still prevents an unambiguous assignment of domain interactions responsible for all protein network interactions.Executable files and examples are given at: http://www.bhsai.org/downloads/padds/ PMID- 23651453 TI - Human sperm and other seminal constituents in male infertile patients from arsenic and cadmium rich areas of Southern Assam. AB - In the present study the occurrence of two heavy metals, arsenic and cadmium, have been reported in the drinking water and seminal plasma of infertile male patients as compared to a control group. The study originated from a survey of geogenic groundwater contamination with the heavy metals arsenic and cadmium in Southern Assam, India as an increase in the incidence of male infertility was being reported from these areas. According to WHO protocol, patients with sperm concentration < 20 x 10(6)/ml were selected as cases (oligozoospermic and azoospermic), and those with > 20 x 10(6)/ml, without any extreme pathological disorders and having fathered a child within 1-2 years of marriage were the control (normozoospermic) group. The study reports an inverse relationship between total sperm count and heavy metal content in drinking water as well as seminal plasma of the subjects. Moreover, a high correlation between altered semenological parameters and lower expression of accessory sex gland markers like fructose, acid phosphatase, and neutral alpha-glucosidase in the seminal plasma of patients is reported. The study also highlights significant differences of the sperm function parameters like hypo-osmotic swelling, acrosome reaction, and nuclear chromatin decondensation in the patient group as compared to controls. These findings are significant as they address a likely association between heavy metal stress and altered sperm function as well as seminal enzyme inhibition. PMID- 23651454 TI - Fetal head circumference, operative delivery, and fetal outcomes: a multi-ethnic population-based cohort study. AB - BACKGROUND: Operative delivery procedures, such as primary cesarean section, vacuum-assisted, and forceps-assisted vaginal delivery increase maternal and fetal morbidity, and the cost of care. We evaluated whether large fetal head circumference (FHC) independently increases risk of such interventions, as well as fetal distress or low Apgar score, in anatomically normal infants. METHODS: We conducted a population-based retrospective cohort study using Washington State birth certificate data. We included singleton, term infants born to nulliparous mothers from 2003-2009. We compared mode of delivery and fetal outcomes in 10,750 large-FHC (37-41 cm) infants relative to 10,750 average-FHC (34 cm) infants, frequency matched by birth-year. RESULTS: Large-FHC infants were nearly twice as likely to be delivered by primary cesarean section as average-FHC infants (unadjusted relative risk [RR] 1.84, 95% confidence interval [CI]: 1.77, 1.92). The RR for primary cesarean section associated with large-FHC was largest for mothers aged 19 years or less (RR 2.28; 95% CI: 1.99, 2.61), and smallest for mothers aged 35 years or greater (RR 1.51; 95% CI: 1.37, 1.66) [test of homogeneity, p < 0.001]. Large-FHC infants were at increased risk of vacuum assisted vaginal delivery (RR 1.55; 95% CI: 1.43, 1.69), and forceps-assisted vaginal delivery (RR 1.61; 95% CI: 1.32, 1.97). There was no difference in risk of fetal distress (RR 0.97; 95% CI: 0.89, 1.07) for large-FHC versus average-FHC infants. Risk estimates were unaffected by adjustment for potential confounders. CONCLUSIONS: Nulliparous mothers of large-FHC infants are at increased risk of primary cesarean section, vacuum-assisted and forceps-assisted vaginal delivery relative to mothers of average-FHC infants. Maternal age modifies the association between FHC and primary cesarean section. PMID- 23651456 TI - Flotillins functionally organize the bacterial membrane. AB - Proteins and lipids are heterogeneously distributed in biological membranes. The correct function of membrane proteins depends on spatiotemporal organization into defined membrane areas, called lipid domains or rafts. Lipid microdomains are therefore thought to assist compartmentalization of membranes. However, how lipid and protein assemblies are organized and whether proteins are actively involved in these processes remains poorly understood. We now have identified flotillins to be responsible for lateral segregation of defined membrane domains in the model organism Bacillus subtilis. We show that flotillins form large, dynamic assemblies that are able to influence membrane fluidity and prevent condensation of Laurdan stained membrane regions. Absence of flotillins in vivo leads to coalescence of distinct domains of high membrane order and, hence, loss of flotillins in the bacterial plasma-membrane reduces membrane heterogeneity. We show that flotillins interact with various proteins involved in protein secretion, cell wall metabolism, transport and membrane-related signalling processes. Importantly, maintenance of membrane heterogeneity is critical for vital cellular processes such as protein secretion. PMID- 23651455 TI - Design and selection parameters to accelerate the discovery of novel central nervous system positron emission tomography (PET) ligands and their application in the development of a novel phosphodiesterase 2A PET ligand. AB - To accelerate the discovery of novel small molecule central nervous system (CNS) positron emission tomography (PET) ligands, we aimed to define a property space that would facilitate ligand design and prioritization, thereby providing a higher probability of success for novel PET ligand development. Toward this end, we built a database consisting of 62 PET ligands that have successfully reached the clinic and 15 radioligands that failed in late-stage development as negative controls. A systematic analysis of these ligands identified a set of preferred parameters for physicochemical properties, brain permeability, and nonspecific binding (NSB). These preferred parameters have subsequently been applied to several programs and have led to the successful development of novel PET ligands with reduced resources and timelines. This strategy is illustrated here by the discovery of the novel phosphodiesterase 2A (PDE2A) PET ligand 4-(3 [(18)F]fluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine, [(18)F]PF-05270430 (5). PMID- 23651457 TI - An ultrafast look at Au nanoclusters. AB - In the past 20 years, researchers studying nanomaterials have uncovered many new and interesting properties not found in bulk materials. Extensive research has focused on metal nanoparticles (>3 nm) because of their potential applications, such as in molecular electronics, image markers, and catalysts. In particular, the discovery of metal nanoclusters (<3 nm) has greatly expanded the horizon of nanomaterial research. These nanosystems exhibit molecular-like characteristics as their size approaches the Fermi-wavelength of an electron. The relationships between size and physical properties for nanomaterials are intriguing, because for metal nanosystems in this size regime both size and shape determine electronic properties. Remarkably, changes in the optical properties of nanomaterials have provided tremendous insight into the electronic structure of nanoclusters. The success of synthesizing monolayer protected clusters (MPCs) in the condensed phase has allowed scientists to probe the metal core directly. Au MPCs have become the "gold" standard in nanocluster science, thanks to the rigorous structural characterization already accomplished. The use of ultrafast laser spectroscopy on MPCs in solution provides the benefit of directly studying the chemical dynamics of metal nanoclusters (core), and their nonlinear optical properties. In this Account, we investigate the optical properties of MPCs in the visible region using ultrafast spectroscopy. Based on fluorescence up-conversion spectroscopy, we propose an emission mechanism for these nanoclusters. These clusters behave differently from nanoparticles in terms of emission lifetimes as well as two-photon cross sections. Through further investigation of the transient (excited state) absorption, we have found many unique phenomena of nanoclusters, such as quantum confinement effects and vibrational breathing modes. In summary, based on the differences in the optical properties, the distinction between nanoclusters and nanoparticles appears at a size near 2.2 nm. This is consistent with simulations from a free-electron model proposed for MPCs. The use of ultrafast techniques on these nanoclusters can answer many of the fundamental questions about the nature of these exciting nanomaterials and their applications. PMID- 23651458 TI - Eigenstates of thiophosgene near the dissociation threshold: deviations from ergodicity. AB - A subset of the highly excited eigenstates of thiophosgene (SCCl2) near the dissociation threshold are analyzed using sensitive measures of quantum ergodicity. We find several localized eigenstates, suggesting that the intramolecular vibrational energy flow dynamics is nonstatistical even at such high levels of excitations. The results are consistent with recent observations of sharp spectral features in the stimulated emission spectra of SCCl2. PMID- 23651459 TI - Greedy feature selection for glycan chromatography data with the generalized Dirichlet distribution. AB - BACKGROUND: Glycoproteins are involved in a diverse range of biochemical and biological processes. Changes in protein glycosylation are believed to occur in many diseases, particularly during cancer initiation and progression. The identification of biomarkers for human disease states is becoming increasingly important, as early detection is key to improving survival and recovery rates. To this end, the serum glycome has been proposed as a potential source of biomarkers for different types of cancers.High-throughput hydrophilic interaction liquid chromatography (HILIC) technology for glycan analysis allows for the detailed quantification of the glycan content in human serum. However, the experimental data from this analysis is compositional by nature. Compositional data are subject to a constant-sum constraint, which restricts the sample space to a simplex. Statistical analysis of glycan chromatography datasets should account for their unusual mathematical properties.As the volume of glycan HILIC data being produced increases, there is a considerable need for a framework to support appropriate statistical analysis. Proposed here is a methodology for feature selection in compositional data. The principal objective is to provide a template for the analysis of glycan chromatography data that may be used to identify potential glycan biomarkers. RESULTS: A greedy search algorithm, based on the generalized Dirichlet distribution, is carried out over the feature space to search for the set of "grouping variables" that best discriminate between known group structures in the data, modelling the compositional variables using beta distributions. The algorithm is applied to two glycan chromatography datasets. Statistical classification methods are used to test the ability of the selected features to differentiate between known groups in the data. Two well-known methods are used for comparison: correlation-based feature selection (CFS) and recursive partitioning (rpart). CFS is a feature selection method, while recursive partitioning is a learning tree algorithm that has been used for feature selection in the past. CONCLUSIONS: The proposed feature selection method performs well for both glycan chromatography datasets. It is computationally slower, but results in a lower misclassification rate and a higher sensitivity rate than both correlation-based feature selection and the classification tree method. PMID- 23651460 TI - p-Hydroxycinnamic acid production directly from cellulose using endoglucanase- and tyrosine ammonia lyase-expressing Streptomyces lividans. AB - BACKGROUND: p-Hydroxycinnamic acid (pHCA) is an aromatic compound that serves as a starting material for the production of many commercially valuable chemicals, such as fragrances and pharmaceuticals, and is also used in the synthesis of thermostable polymers. However, chemical synthesis of pHCA is both costly and harmful to the environment. Although pHCA production using microbes has been widely studied, there remains a need for more cost-effective methods, such as the use of biomass as a carbon source. In this study, we produced pHCA using tyrosine ammonia lyase-expressing Streptomyces lividans. In order to improve pHCA productivity from cellulose, we constructed a tyrosine ammonia lyase- and endoglucanase (EG)-expressing S. lividans transformant and used it to produce pHCA from cellulose. RESULTS: A Streptomyces lividans transformant was constructed to express tyrosine ammonia lyase derived from Rhodobacter sphaeroides (RsTAL). The transformant produced 786 or 736 mg/L of pHCA after 7 days of cultivation in medium containing 1% glucose or cellobiose as the carbon source, respectively. To enhance pHCA production from phosphoric acid swollen cellulose (PASC), we introduced the gene encoding EG into RsTAL-expressing S. lividans. After 7 days of cultivation, this transformant produced 753, 743, or 500 mg/L of pHCA from 1% glucose, cellobiose, or PASC, respectively. CONCLUSIONS: RsTAL-expressing S. lividans can produce pHCA from glucose and cellobiose. Similarly, RsTAL- and EG-expressing S. lividans can produce pHCA from glucose and cellobiose with excess EG activity remaining in the supernatant. This transformant demonstrated improved pHCA production from cellulose. Further enhancements in the cellulose degradation capability of the transformant will be necessary in order to achieve further improvements in pHCA production from cellulose. PMID- 23651461 TI - Childhood drowning in Malaysia. AB - This study aimed to collate data on childhood drowning in Malaysia and review existing drowning prevention measures. This study used secondary data from governmental and non-governmental agencies. All reported fatal drownings from 2000 to 2007 and all reported non-fatal drownings from 2000 to 2008 were included. Data were analysed to provide understanding of the epidemiology of drowning incidents, risk factors and available preventive efforts. On average 286 (range 248-344) children died yearly due to drowning with a death rate of 3.05 per 100,000 annually. An additional average of 207 children drowned but survived annually (1.99 per 100,000). The estimated burden of drowning in children (death and non-death) is 5 per 100,000. There was no reduction in annual drowning fatalities over time. Most drowning took place in east coast regions during the annual monsoon season. It was 3.52 (2.80-4.41) times more common in boys and most prevalent among 10-14 years. Most prevalent sites of all-age drowning were seas and rivers. Limited water safety regulations are currently available in the country. This is the first comprehensive national study in Malaysia on paediatric drowning and highlights the magnitude of the problem. It calls for concerted effort to devise effective national drowning prevention measures. PMID- 23651462 TI - A short form of the Speech, Spatial and Qualities of Hearing scale suitable for clinical use: the SSQ12. AB - OBJECTIVE: To develop and evaluate a 12-item version of the Speech, Spatial and Qualities of Hearing scale for use in clinical research and rehabilitation settings, and provide a formula for converting scores between the full (SSQ49) and abbreviated (SSQ12) versions. DESIGN: Items were selected independently at the three centres (Eriksholm Research Centre, MRC Institute of Hearing Research, University of New England) to be representative of the complete scale. A consensus was achieved after discussion. STUDY SAMPLE: The data set (n = 1220) used for a factor analysis (Akeroyd et al, submitted) was re-analysed to compare original SSQ scores (SSQ49) with scores on the short version (SSQ12). RESULTS: A scatter-plot of SSQ12 scores against SSQ49 scores showed that SSQ12 score was about 0.6 of a scale point lower than the SSQ49 (0-10 scale) in the re-analysis of the Akeroyd et al data. SSQ12 scores lay on a slightly steeper slope than scores on the SSQ49. CONCLUSIONS: The SSQ12 provides similar results to SSQ49 in a large clinical research sample. The slightly lower average SSQ12 score and the slightly steeper slope reflect the composition of this short form relative to the SSQ49. PMID- 23651463 TI - Rethinking health research capacity strengthening. AB - Health research capacity strengthening (HRCS) is a strategy implemented worldwide to improve the ability of developing countries to tackle the persistent and disproportionate burdens of disease they face. Drawing on a review of existing HRCS literature and our experiences over the course of an HRCS project in Vietnam, we summarise major challenges to the HRCS enterprise at the interpersonal, institutional and macro levels. While over the course of several decades of HRCS initiatives many of these challenges have been well documented, we highlight several considerations that remain underarticulated. We advance critical considerations of the HRCS enterprise by discussing (1) how the organisation of US public health funding shapes the ecology of knowledge production in low- and middle-income country contexts, (2) the barriers US researchers face to effectively collaborate in capacity strengthening for research-to-policy translation, and (3) the potential for unintentional negative consequences if HRCS efforts are not sufficiently reflexive about the limitations of dominant paradigms in public health research and intervention. PMID- 23651464 TI - Roles of two large serine recombinases in mobilizing the methicillin-resistance cassette SCCmec. AB - Methicillin-resistant Staphylococcus aureus (MRSA) emerged via acquisition of a mobile element, staphylococcal cassette chromosome mec (SCCmec). Integration and excision of SCCmec is mediated by an unusual site-specific recombination system. Most variants of SCCmec encode two recombinases, CcrA and CcrB, that belong to the large serine family. Since CcrA and CcrB are always found together, we sought to address their specific roles. We show here that CcrA and CcrB can carry out both excisive and integrative recombination in Escherichia coli in the absence of any host-specific or SCCmec-encoded cofactors. CcrA and CcrB are promiscuous in their substrate choice: they act on many non-canonical pairs of recombination sites in addition to the canonical ones, which may explain tandem insertions into the SCCmec attachment site. Moreover, CcrB is always required, but CcrA is only required if one of the four half-sites is present. Recombinational activity correlates with DNA binding: CcrA recognizes only that half-site, which overlaps a conserved coding frame on the host chromosome. Therefore, we propose that CcrA serves as a specificity factor that emerged through modular evolution to enable recognition of a bacterial recombination site that is not an inverted repeat. PMID- 23651465 TI - Neurogenic differentiation of human dental pulp stem cells using different induction protocols. AB - OBJECTIVE: An investigation on neuronal differentiation capacity of human dental pulp stem cells (DPSCs) was still lacking. In this study, two different neuronal induction protocols were investigated and compared. METHODS: The neuronal differentiation was induced using chemical or growth factor induction protocol. The differentiation was confirmed by the neurogenic mRNA and protein expression using polymerase chain reaction and immunocytochemistry, respectively. RESULTS: Chemical-induced neuronal differentiation protocol promoted morphological change and beta3-TUBULIN protein expression. Though, SOX2, SOX9, and beta3-TUBULIN mRNA levels were not different compared with the control, indicating a defective differentiation. For growth factor induction protocol, the cells were exhibited neurite-like cellular process and positively stained with beta3-TUBULIN. In addition, the increase in intracellular calcium was noted upon NMDA stimulation, implying the neuronal function. A dramatic increased mRNA expression of neurogenic markers [SOX2, SOX9, beta3-TUBULIN, and gamma-aminobutyric acid (GABA receptors)] was noted as compared to the control. In addition, a remarkable increased expression of Notch signaling target gene, HEY1, was observed in growth factor-induced DPSCs derived neuronal-like cells compared with the control. CONCLUSION: These data indicate that growth factor induction method is a preferable protocol for neuronal differentiation by DPSCs. PMID- 23651466 TI - Commentary from the Editorial Board to Vitiligo: interplay between oxidative stress and immune system (Laddha et al.). AB - Vitiligo pathogenesis is very puzzling, and novel mechanisms possibly involved in the development of this disorder are frequently explored. Recently, some authors proposed an interplay between oxidative stress and immune system at the basis of melanocyte loss. According to the experimental evidence, they suggest that exposition to environmental agents might lead to an association between vitiligo and other autoimmune diseases. Accordingly, it is proposed that increased reactive oxygen species due to environmental agents could induce a modification of both melanocytic structures and other tissue proteins, or might disregulate the immune system, influencing the appearance of vitiligo and autoimmune comorbidities. PMID- 23651467 TI - Is diameter-axial-polar scoring predictive of renal functional damage in patients undergoing partial nephrectomy? An evaluation using technetium Tc 99m (99Tcm) diethylene-triamine-penta-acetic acid (DTPA) glomerular filtration rate. AB - OBJECTIVE: To identify the effects of diameter-axial-polar (DAP) scoring and other clinical variables on renal functional outcomes after partial nephrectomy (PN). MATERIAL AND METHODS: A total of 59 patients with complete radiographic, clinical and follow-up information were included for analysis. Technetium Tc 99m ((99) Tc(m) )-diethylene-triamine-penta-acetic acid (DTPA) renal scintigraphy was used to determine the glomerular filtration rate (GFR) of both kidneys and each kidney individually. All cross-sectional images were reviewed by a single radiologist and a DAP score was assigned. RESULTS: The median decline in total GFR after PN was 13% at a median follow-up of 12 months (from 86.8 to 76.2 mL/min per 1.73 m(2) , P < 0.001). The median GFR of the operated kidney showed a significant decrease peri-operatively (42.4 to 27.1 mL/min per 1.73 m(2) , P < 0.001). The function of the contralateral kidney showed a significant increase (43.5 to 48.8 mL/min per 1.73 m(2) , P < 0.001). On multivariate analysis, preoperative total GFR, ischaemia time and DAP sum score were independent predictors of absolute functional decline of the affected kidney (all P < 0.001), while only preoperative total GFR and DAP sum score were significantly associated with the total absolute GFR reduction (all P < 0.001). CONCLUSION: Preoperative renal function status and DAP score of renal tumours are the primary determinants of long-term functional outcomes after PN, but renal ischaemia damage to the operated kidney after PN is possibly masked by functional compensation of the contralateral healthy kidney if only overall renal function is assessed. PMID- 23651468 TI - Direct analysis of lipsticks by Sorptive tape-like extraction laser desorption/ionization mass spectrometry imaging. AB - OBJECTIVE: The objective of this study is to create and establish a simple and rapid method for lipid evaluation in daily-use female products, namely lipsticks. METHODOLOGY: This approach uses STE-LDI-MSI for fast fingerprinting of complex lipids, such as triacylglycerols, phosphoglycerols and simpler structures as free fatty acids. RESULTS: This work has focused on lipsticks of several brands globally marketed. With no sample preparation, it has demonstrated to readily identify compounds of interest by integrating both full scan and MS/MS data. CONCLUSION: A novel and rapid technique for lipid evaluation in lipsticks is presented. PMID- 23651469 TI - Acetate metabolism and Escherichia coli biofilm: new approaches to an old problem. AB - Current antibiotics continue to lose effectiveness for infectious diseases, especially in cases where the bacteria from a biofilm. This review article summarizes control mechanisms for bacterial biofilm, with an emphasis on the modification of signal transduction pathways, such as quorum sensing and two component signaling, by externally added metabolic intermediates. As a link between central metabolism and signal transduction, we discuss the activation of two-component response regulators by activated acetate intermediates in response to signals from the environment. These signals constitute 'nutrients' for the bacteria in most cases. Depending on the identity of the nutrient, biofilm amounts may be reduced. The nutrient may then be used for the development of both novel prevention and treatment options for biofilm-associated infectious diseases. PMID- 23651470 TI - Broadband Ge/SiGe quantum dot photodetector on pseudosubstrate. AB - : We report the fabrication and characterization of a ten-period Ge quantum dot photodetector grown on SiGe pseudosubstrate. The detector exhibits tunable photoresponse in both 3- to 5- MUm and 8- to 12- MUm spectral regions with responsivity values up to about 1 mA/W at a bias of -3 V and operates under normal incidence radiation with background limited performance at 100 K. The relative response in the mid- and long-wave atmospheric windows could be controlled through the applied voltage. PMID- 23651471 TI - Parenting styles and emotional intelligence of HIV-affected children in Thailand. AB - The purpose of this study was to examine the impact of parenting styles on emotional intelligence of HIV-affected children in Thailand. This study uses data from 205 HIV-affected children in northern and northeastern Thailand. Correlation and regression analyses were used to examine the predictors of emotional intelligence. Children reporting higher levels of stress reported less caring parenting style (standardized beta [B]=-0.18, p=0.050). Children with higher self esteem were also more likely to perceive their parents as caring (B=0.48, p=0.002). Children who scored lower on their self-esteem reported their parents to be more overprotective (B=-0.30, p=0.030), and children reporting higher levels of stress reported their parents to be more overprotective (B=0.12, p=0.010). Children reporting caring parenting style were significantly more likely to report higher emotional intelligence (B=0.66, p=0.001). Parenting styles play an important role in the emotional intelligence. Identifying and testing interventions to help parents improve their parenting styles, while helping their HIV-affected children cope with stress and self-esteem, are essential in promoting mental health of HIV-affected children in Thailand. PMID- 23651472 TI - Comparative transcriptome analysis to investigate the high starch accumulation of duckweed (Landoltia punctata) under nutrient starvation. AB - BACKGROUND: Duckweed can thrive on anthropogenic wastewater and produce tremendous biomass production. Due to its relatively high starch and low lignin percentage, duckweed is a good candidate for bioethanol fermentation. Previous studies have observed that water devoid of nutrients is good for starch accumulation, but its molecular mechanism remains unrevealed. RESULTS: This study globally analyzed the response to nutrient starvation in order to investigate the starch accumulation in duckweed (Landoltia punctata). L. punctata was transferred from nutrient-rich solution to distilled water and sampled at different time points. Physiological measurements demonstrated that the activity of ADP-glucose pyrophosphorylase, the key enzyme of starch synthesis, as well as the starch percentage in duckweed, increased continuously under nutrient starvation. Samples collected at 0 h, 2 h and 24 h time points respectively were used for comparative gene expression analysis using RNA-Seq. A comprehensive transcriptome, comprising of 74,797 contigs, was constructed by a de novo assembly of the RNA-Seq reads. Gene expression profiling results showed that the expression of some transcripts encoding key enzymes involved in starch biosynthesis was up-regulated, while the expression of transcripts encoding enzymes involved in starch consumption were down-regulated, the expression of some photosynthesis-related transcripts were down-regulated during the first 24 h, and the expression of some transporter transcripts were up-regulated within the first 2 h. Very interestingly, most transcripts encoding key enzymes involved in flavonoid biosynthesis were highly expressed regardless of starvation, while transcripts encoding laccase, the last rate-limiting enzyme of lignifications, exhibited very low expression abundance in all three samples. CONCLUSION: Our study provides a comprehensive expression profiling of L. punctata under nutrient starvation, which indicates that nutrient starvation down-regulated the global metabolic status, redirects metabolic flux of fixed CO2 into starch synthesis branch resulting in starch accumulation in L. punctata. PMID- 23651473 TI - The higher diabetogenic risk of tacrolimus depends on pre-existing insulin resistance. A study in obese and lean Zucker rats. AB - Insulin resistance may interact with calcineurin inhibitors, enhancing the diabetogenic effect of tacrolimus compared with cyclosporine-A. We studied both drugs in insulin-resistant animals: obese Zucker rats (n = 45), and insulin sensitive animals: lean Zucker rats (n = 21). During 11 days, animals received saline-buffer, cyclosporine-A (2.5 mg/kg/day) or tacrolimus (0.3 mg/kg/day). At Days 0 and 12 animals underwent intraperitoneal glucose tolerance test (0-30-60 120 min). Islet morphometry, beta-cell proliferation, apoptosis and Ins2 gene expression were analyzed. By Day 12, no lean animal had developed diabetes, while all obese animals on tacrolimus and 40% on cyclosporine-A had. In obese animals, tacrolimus reduced beta-cell proliferation and Ins2 gene expression compared with cyclosporine-A. Five days after treatment discontinuation, partial recovery was observed, with only 10% and 60% of the animals on cyclosporine and tacrolimus remaining diabetic respectively. Beta-cell proliferation increased in animals on tacrolimus while Ins2 gene expression remained unaltered. In conclusion, insulin resistance exacerbated the diabetogenic effect of tacrolimus compared with cyclosporine-A. This may be explained by greater inhibition of Ins2 gene and beta cell proliferation by tacrolimus in the insulin resistant state. Discontinuation of the drugs may allow the recovery of the metabolic alterations. PMID- 23651474 TI - Efficacy and bleeding profile of a combined oral contraceptive containing oestradiol valerate/dienogest: a pooled analysis of three studies conducted in North America and Europe. AB - OBJECTIVE: To summarise all clinical data on the contraceptive efficacy and bleeding profile associated with an oestradiol valerate (E2V) and dienogest (DNG) [E2V/DNG] combined oral contraceptive (COC) derived from Phase III trials. METHODS: Pooled analysis of three large-scale multicentre trials conducted in healthy women who received oral E2V/DNG for 7 to 28 cycles (28-day cycles). RESULTS: A total of 2266 women were included in this analysis. Overall, 19 pregnancies occurred over 13 cycles during 880,950 days of relevant exposure (Pearl Index [PI] of 0.79; upper limit of the two-sided 95% confidence interval [CI]: 1.23). Ten pregnancies attributed to method failure came about during 871,091 days of relevant exposure (adjusted PI of 0.42; upper limit of the two sided 95% CI: 0.77). In women aged 18 to 35 years (n = 1687), the corresponding PI and adjusted PI were 1.01 (upper limit of the two-sided 95% CI: 1.59) and 0.51 (upper limit of the two-sided 95% CI: 0.97), respectively. In the first 13 cycles of treatment, 76 to 81% of women experienced scheduled withdrawal bleeding, and 13 to 23% experienced intracyclic bleeding. CONCLUSIONS: E2V/DNG provides reliable contraceptive efficacy in women aged 18 to 50 years. PMID- 23651476 TI - The complex binding of PRDM9. AB - A recent study investigates the in vitro DNA binding behavior of PRDM9, a zinc finger protein involved in the localization of recombination hotspots in mammals. PMID- 23651475 TI - Polymorphisms in xenobiotic metabolizing genes (EPHX1, NQO1 and PON1) in lymphoma susceptibility: a case control study. AB - BACKGROUND: The interplay between genetic susceptibility and carcinogenic exposure is important in the development of haematopoietic malignancies. EPHX1, NQO1 and PON1 are three genes encoding proteins directly involved in the detoxification of potential carcinogens. METHODS: We have studied the prevalence of three functional polymorphisms affecting these genes rs1051740 EPHX1, rs1800566 NQO1 and rs662 PON1 in 215 patients with lymphoma and 214 healthy controls. RESULTS: Genotype frequencies for EPHX and NQO1 polymorphisms did not show any correlation with disease. In contrast, the GG genotype in the PON1 polymorphism was found to be strongly associated with the disease (15.3% vs. 4.7%; OR = 3.7 CI (95%): 1.8-7.7; p < 0.001). According to the pathological diagnosis this association was related to follicular (p = 0.004) and diffuse large B-cell (p = 0.016) lymphomas. CONCLUSIONS: Despite the fact that further confirmation is needed, this study shows that the PON1 GG genotype in rs662 polymorphism could be a risk factor for B-cell lymphomas. PMID- 23651477 TI - Editorial (Hot topic: Pharmacophore mapping and high throughput screening in drug discovery). PMID- 23651478 TI - A novel integrated framework and improved methodology of computer-aided drug design. AB - Computer-aided drug design (CADD) is a critical initiating step of drug development, but a single model capable of covering all designing aspects remains to be elucidated. Hence, we developed a drug design modeling framework that integrates multiple approaches, including machine learning based quantitative structure-activity relationship (QSAR) analysis, 3D-QSAR, Bayesian network, pharmacophore modeling, and structure-based docking algorithm. Restrictions for each model were defined for improved individual and overall accuracy. An integration method was applied to join the results from each model to minimize bias and errors. In addition, the integrated model adopts both static and dynamic analysis to validate the intermolecular stabilities of the receptor-ligand conformation. The proposed protocol was applied to identifying HER2 inhibitors from traditional Chinese medicine (TCM) as an example for validating our new protocol. Eight potent leads were identified from six TCM sources. A joint validation system comprised of comparative molecular field analysis, comparative molecular similarity indices analysis, and molecular dynamics simulation further characterized the candidates into three potential binding conformations and validated the binding stability of each protein-ligand complex. The ligand pathway was also performed to predict the ligand "in" and "exit" from the binding site. In summary, we propose a novel systematic CADD methodology for the identification, analysis, and characterization of drug-like candidates. PMID- 23651479 TI - Protein interface pharmacophore mapping tools for small molecule protein: protein interaction inhibitor discovery. AB - Protein:protein interactions are becoming increasingly significant as potential drug targets; however, the rational identification of small molecule inhibitors of such interactions remains a challenge. Pharmacophore modelling is a popular tool for virtual screening of compound libraries, and has previously been successfully applied to the discovery of enzymatic inhibitors. However, the application of pharmacophore modelling in the field of protein:protein interaction inhibitors has historically been considered more of a challenge and remains limited. In this review, we explore the interaction mimicry by known inhibitors that originate from in vitro screening, demonstrating the validity of pharmacophore mapping in the generation of queries for virtual screening. We discuss the pharmacophore mapping methods that have been successfully employed in the discovery of first-in-class inhibitors. These successful cases demonstrate the usefulness of a "tool kit" of diverse strategies for application across a range of situations depending on the available structural information. PMID- 23651480 TI - Pharmacophore modeling for antitargets. AB - The pharmacophore modeling in modern drug research has been applied for both bioactivity profiling and early stage of risk assessment of potential side effects and toxicity due to interactions of drug candidates with antitargets namely P-glycoprotein, hERG, cytochrome P450 and pregnane X-receptor. In this article, an existing state concerning with pharmacophore modeling applied for promiscuous proteins in drug research were updated and reviewed. In an attempt to create new safe medicines faster, the partial overlap of substrate properties of hERG, P-glycoprotein, pregnane X-receptor and cytochrome P450 has to be considered and drug safety has to be dealt on a system level on the off-targets. PMID- 23651481 TI - p38 Mitogen-activated protein kinase inhibitors: a review on pharmacophore mapping and QSAR studies. AB - p38 mitogen-activated protein (MAP) kinases are the serine/threonine protein kinases, which play a vital role in cellular responses to external stress signals. p38 MAP kinase inhibitors have shown anti-inflammatory effects in the preclinical disease models, primarily through inhibition of the expression of inflammatory mediators. A number of structurally diverse p38 MAP kinase inhibitors have been developed as potential anti-inflammatory agents. Most of the inhibitors have failed in the clinical trials either due to poor pharmacokinetic profile or selectivity issue, which makes p38 MAP kinase a promising target for molecular modelling studies. Several quantitative structure activity relationships (QSAR) and pharmacophore models have been developed to identify the structural requirements essential for p38 MAP kinase inhibitory activity. In this review, we provide an overview of the presently known p38 MAP kinase inhibitors and how QSAR analyses among series of compounds have led to the development of molecular models and pharmacophores, allowing the design of novel inhibitors. PMID- 23651482 TI - Methods and applications of structure based pharmacophores in drug discovery. AB - A pharmacophore model does not describe a real molecule or a real association of functional groups but illustrates a molecular recognition of a biological target shared by a group of compounds. Pharmacophores also represent the spatial arrangement of essential interactions in a receptor-binding pocket. Structure based pharmacophores (SBPs) can work both with a free (apo) structure or a macromolecule-ligand complex (holo) structure. The SBP methods that derive pharmacophore from protein-ligand complexes use the potential interactions observed between ligand and protein, whereas, the SBP method that aims to derive pharmacophore from ligand free protein, uses only protein active site information. Therefore SBPs do not encounter to challenging problems such as ligand flexibility, molecular alignment as well as proper selection of training set compounds in ligand based pharmacophore modeling. The current review deals with Hot Spot' analysis of binding site to feature generation, several approaches to feature reduction, and considers shape and excluded volumes to SBP model building. This review continues to represent several applications of SBPs in virtual screening especially in parallel screening approach and multi-target drug design. Also it reports the applications of SBPs in QSAR. This review emphasizes that SBPs are valuable tools for hit to lead optimization, virtual screening, scaffold hopping, and multi-target drug design. PMID- 23651483 TI - Recent advances on QSAR-based profiling of agonist and antagonist A3 adenosine receptor ligands. AB - Adenosine receptors (ARs) are signaling molecules ubiquitously expressed in a wide variety of tissues in the human body. ARs mediate physiological functions by interacting with four subtypes of G-protein-coupled receptors, namely A1, A2A, A2B and A3. The A3 AR, probably the most studied subtype, is also ubiquitously expressed, with high levels in peripheral organs and low levels in the brain. This type of AR is involved in a variety of important pathophysiological processes, ranging from modulation of cerebral and cardiac ischemic damage to regulation of immunosuppression and inflammation. Consequently, the development of potent and selective A3 AR ligands as promising therapeutic options for a variety of diseases has been a prime subject of medicinal chemistry research for more than two decades. Among the plethora of approaches applied quantitative structure activity relationships (QSAR) stands out for being largely employed due to their potential to increase the efficiency at initial stages of the drug discovery process. So, we provide a review of the main QSAR studies devoted to the design, discovery and development of agonist and antagonist A3 adenosine receptor ligands. Common pitfalls of these QSAR applications and the current trends in this area are also analyzed. PMID- 23651484 TI - Recent trends and future prospects in computational GPCR drug discovery: from virtual screening to polypharmacology. AB - Extending virtual screening approaches to deal with multi-target drug design and polypharmacology is an increasingly important aspect in drug design. In light of this, the concept of accessible chemical space and its exploration should be reviewed. The great advantages of re-using drugs with safe pharmacological profiles with favourable pharmacokinetic properties highlights drug repositioning as a valid alternative to rational drug design, massive drug development efforts, and high-throughput screening, especially when supported by in silico techniques. Here, we discuss some of the advantages of multi-target approaches, and we review some significant examples of their application in the last decade to that well known class of pharmaceutical targets, the G-protein coupled receptors. PMID- 23651485 TI - The role of 3D pharmacophore mapping based virtual screening for identification of novel anticancer agents: an overview. AB - In recent years, numerous changes have been made in the field of cancer research with the progresses of molecular biology, chemoinformatics and chemogenomics. Several new biomolecular targets have been identified, and investigated for new drug discovery. In the current article, we discuss the role of pharmacophore mapping and pharmacophorebased virtual screening (PBVS) approaches for identification of novel anticancer hits. It showed that pharmacophorebased studies were performed for almost every type of anticancer agents. However, such applications are clustered on finding novel hits for a few targets like cancer related hormones, kinase enzymes and other less investigated targets. Some reports were found with virtual hits experimentally validated against respective targets. These were thoroughly described and the novel hits were pointed out. Others with PBVS of anticancer targets were also discussed and the identified features were highlighted. Present review showed that PBVS may serve as a true lead generator if it is performed in a unified fashion that combines in silico techniques with experimental validation. With enormous progresses in computational methods as well as molecular biology, it is expected that pharmacophore-based drug discovery strategy will aid in significant upsurge in the field of cancer chemotherapy in near future. PMID- 23651486 TI - Assessing the performance of 3D pharmacophore models in virtual screening: how good are they? AB - Pharmacophore approaches have evolved to be one of the most successful tools in drug discovery, especially since the past two decades. 3D pharmacophore methods are now commonly used as part of more complex workflows in drug discovery campaigns, and have been successfully and extensively applied in virtual screening (VS) approaches. This review provides a perspective of how to assess the performance of 3D pharmacophore models to be used in VS. Since 3D VS protocols are in general assessed by their ability to discriminate between active and inactive compounds, we summarize the impact of the composition and preparation of modeling and external sets on the outcome of evaluations. Moreover, we highlight the significance of both classic enrichment parameters and advanced descriptors for the performance of 3D pharmacophore-based virtual screening methods. PMID- 23651487 TI - Real-time interactive data mining for chemical imaging information: application to automated histopathology. AB - BACKGROUND: Vibrational spectroscopic imaging is now used in several fields to acquire molecular information from microscopically heterogeneous systems. Recent advances have led to promising applications in tissue analysis for cancer research, where chemical information can be used to identify cell types and disease. However, recorded spectra are affected by the morphology of the tissue sample, making identification of chemical structures difficult. RESULTS: Extracting features that can be used to classify tissue is a cumbersome manual process which limits this technology from wide applicability. In this paper, we describe a method for interactive data mining of spectral features using GPU based manipulation of the spectral distribution. CONCLUSIONS: This allows researchers to quickly identify chemical features corresponding to cell type. These features are then applied to tissue samples in order to visualize the chemical composition of the tissue without the use of chemical stains. PMID- 23651488 TI - Diagnostic significance of nitrates and nitrites and L-arginine, in development of hepatorenal syndrome in patients with end stage alcoholic liver cirrhosis. AB - Hepatorenal syndrome (HRS) represents a complication of the end-stage liver cirrhosis. The aim of the present study was to analyze concentrations of nitrates and nitrites (NO2 + NO3) and L-arginine in patients with liver cirrhosis and HRS as a possible predictive marker for the development of HRS. The research was performed in a group of 28 patients with cirrhosis and HRS, a group of 22 patients suffering from cirrhosis without HRS and a control group comprised of 42 healthy voluntary blood donors. In patients with end-stage alcoholic liver cirrhosis, with HRS, the concentrations of NO2 + NO3 increased and correlated with the degree of cirrhosis progression, compared to patients without HRS and significantly higher compared to the control group. The level of NO2 + NO3 was in a positive correlation with the degree of liver damage de Ritis coefficient (HRS = 0.72; cirrhosis: = 0.55; control = -0.10). Significant positive correlation was found between NO2 + NO3 concentration and inflammatory marker C-reactive protein (HRSC = 0.75; cirrhosis = 0.70, control = -0.25). The correlation between NO2 + NO3 concentration and creatinine concentration in patients with HRS was significantly higher compared to patients without HRS (HRS = 0.82; cirrhosis = 0.32; control = -0.25). By using binary regression analysis, on the basis of clinical criteria of HRS diagnosis, the strongest independent positive predictor for HRS development was NO2 + NO3, associated with 45.02 times higher incidence of HRS, compared to arginine (12.7 times higher incidence), creatinine (13.1 times higher incidence), and AST/ALT ratio (10.55 higher incidence of HRS). Since the determination of NO2 + NO3 represents a reliable and easily applicable method, it may be used as an early predictive marker for HRS development. PMID- 23651489 TI - Ion-channels: goals for function-oriented synthesis. AB - Ion channels provide a conductance pathway for the passive transport of ions across membranes. These functional molecules perform key tasks in biological systems such as neuronal signaling, muscular control, and sensing. Recently, function-oriented synthesis researchers began to focus on ion channels with the goal of modifying the function of existing ion channels (ion selectivity, gating) or creating new channels with novel functions. Both approaches, ion channel engineering and de novo design, have involved synthetic chemists, biochemists, structural biologists, and neurochemists. Researchers characterize the function of ion channels by measuring their conductance in samples of biological membranes (patch clamp) or artificial membranes (planar lipid bilayers). At the single molecule level, these measurements require special attention to the purity of the sample, a challenge that synthetic chemists should be aware of. Ideally, researchers study the function of channels while also acquiring structural data (X-ray, NMR) to understand and predict how synthetic modifications alter channel function. Long-term oriented researchers would like to apply synthetic ion channels to single molecule sensing and to implantat these synthetic systems in living organisms as tools or for the treatment of channelopathies. In this Account, we discuss our own work on synthetic ion channels and explain the shift of our research focus from a de novo design of oligo-THFs and oligo-THF-amino acids to ion channel engineering. We introduce details about two biological lead structures for ion channel engineering: the gramicidin beta(6,3) helix as an example of a channel with a narrow ion conductance pathway and the outer membrane porins (OmpF, OmpG) with their open beta-barrel structure. The increase and the reversal of ion selectivity of these systems and the hydrophobic match/mismatch of the channel with the phospholipid bilayer are of particular interest. For engineering ion channels, we need to supplement the single-point attachment of a synthetic modulator with the synthesis of a more challenging two-point attachment. The successful function-oriented synthesis of ion channels will require interdisciplinary efforts that include new electrophysiology techniques, efficient synthesis (peptide/protein/organic), and good structural analysis. PMID- 23651490 TI - Five years of malaria control in the continental region, Equatorial Guinea. AB - BACKGROUND: A successful malaria control programme began in 2004 on Bioko Island, Equatorial Guinea. From 2007, the same multiple malaria interventions, though reduced in scope for funding reasons, were introduced to the four mainland provinces of Equatorial Guinea (the continental region) aiming to recreate Bioko's success. Two provinces received long-lasting insecticidal nets (LLINs) and two provinces received biannual indoor residual spraying (IRS). Enhanced case management and communications were introduced throughout. METHODS: Estimates of intervention coverage and indicators of malaria transmission for 2007 to 2011 were derived from annual malaria indicator surveys (MIS). Results were complemented by health information system (HIS) and entomological data. The personal protection offered by LLINs and IRS against Plasmodium falciparum infection was estimated with logistic regression. RESULTS: The estimated proportion of children aged 1-4 using either an LLIN the previous night or living in a house sprayed in the last six months was 23% in 2007 and 42% in 2011. The estimated prevalence of P. falciparum in children aged 1-4 was 68% (N=1,770; 95% confidence interval [CI]: 58-76%) in 2007 and 52% (N=1,602; 95% CI: 44-61%) in 2011. Children 1-4 years had lower prevalence if they used an LLIN the previous night (N=1,124, 56%; adjusted odds ratio [aOR] 0.64, 95% CI: 0.55-0.74) or if they lived in a sprayed house (N=1,150, 57%; aOR 0.80, 95% CI: 0.62-1.03) compared to children with neither intervention (N=4,131, 66%, reference group). The minority of children who both used an LLIN and lived in a sprayed house had the lowest prevalence of infection (N=171, 45%; aOR 0.52, 95% CI: 0.35-0.78). High site-level intervention coverage did not always correlate with lower site level P. falciparum prevalence. The malaria season peaked in either June or July, not necessarily coinciding with MIS data collection. CONCLUSIONS: Though moderate impact was achieved after five years of vector control, case management, and communications, prevalence remained high due to an inability to sufficiently scale-up coverage with either IRS or LLINs. Both LLINs and IRS provided individual protection, but greater protection was afforded to children who benefitted from both. PMID- 23651491 TI - Vasculogenesis of decidua side population cells of first-trimester pregnancy. AB - INTRODUCTION: Sufficient uterine blood supply is essential for the fetus to develop normally in the uterus. Several mechanisms are involved in the process of vessel development in deciduas and villus. We focus on whether first-trimester decidua side population (SP) cells contain cells capable of differentiating into endothelial cells. METHODS: Eight decidua samples were collected from healthy women, 22- to 30-years old, undergoing elective terminations of early pregnancy (six to eight gestational weeks). The cell suspensions from human deciduas were stained by Hoechst 33342 and sorted by flow cytometry, further cultured under differentiation conditions and analyzed for specific markers. These cells were implanted into ischemic limbs of nude mice to test the capacity of angiogenesis in vivo by DiI tracers and immunohistochemistry. RESULTS: Decidua CD31(-)CD146(-) SP cells of first-trimester human pregnancy can differentiate into endothelial cells, express the corresponding specific markers of endothelial cells, such as CD31 and CD146, and form tube-like structures on Matrigel and part of newly formed vessels in the ischemic limbs of nude mice. Vascular endothelial growth factor was more effective in promoting proliferation of CD31(-)CD146(-)SP cells compared with other growth factors, and estrogen and progesterone at a final concentration of 10 MUmol/L and 30 MUmol/L, respectively, promoted the migration of CD31()-CD146(-)SP cells in a dose-dependent manner. CONCLUSIONS: CD31(-)CD146( ) SP cells may be involved in the formation of new vessels in the maternal aspect of the placenta in the first trimester. PMID- 23651492 TI - Women respondents report higher household food insecurity than do men in similar Canadian households. AB - OBJECTIVE: We investigated factors accounting for the consistently higher levels of household food insecurity reported by women in Canada. DESIGN: Two cycles of the Canadian Community Health Survey for the years 2005/2006 and 2007/2008 were pooled to examine the association between household food insecurity, measured using the Household Food Security Survey Module and other metrics, and respondent sex. We stratified households as married/cohabiting (in which case, the household respondent was chosen randomly) or non-married (single/widowed/separated/divorced) and adjusted for differences in household characteristics, including the presence of children. SETTING: Canada. SUBJECTS: Analysis was restricted to households dependent on employment/self-employment and whose reported annual household income was below $CAN 100,000. Exclusions included respondents less than 18 years of age, any welfare receipt, and missing food insecurity, marital status, income source and amount, or household composition data. RESULTS: For non-married households, increased food insecurity in female- v. male-led households was accounted for by significant differences in household socio-economic characteristics. In contrast, in married/cohabiting households with or without children, higher food insecurity rates were reported when the respondent was female and neither respondent characteristics nor socio economic factors accounted for the differences. CONCLUSIONS: Higher rates of food insecurity in non-married households in Canada are largely attributable to women's socio-economic disadvantage. In married households, women appear to report higher levels of food insecurity than men. These findings suggest a possible bias in the measurement of population-level household food insecurity in surveys that do not account for the sex of the respondent in married/cohabiting households. PMID- 23651493 TI - Relationship between total antioxidant capacities of cereals measured before and after in vitro digestion. AB - Total antioxidant capacity (TAC), which is the cumulative capacity of different antioxidants to reduce oxidative stress, proved to be very useful to correlate the antioxidant capacity of the diet with the incidence of some disease or with modification of disease biomarkers. Therefore, it is important to estimate the real antioxidant potential of cereals. Most methods are based mainly on extractive methods which may largely underestimate the TAC of cereals. Several recent articles have reported a direct approach, the Quencher procedure, which produces a higher TAC compared to extractive methods. However, both the extractive methods and the Quencher procedure are performed prior to digestion. In this article, an in vitro approach using enzymatic digestion, designed to mimic digestion in the gastrointestinal tract (physiological conditions), had been used to release antioxidants from cereals. Seven whole cereals were employed for the determination of DPPH as well as ABTS radical scavenging activity before and after simulated digestion. The objective was to compare the in vitro procedure of antioxidant extraction with the Quencher procedure and water extraction. The values of the TAC's from the cereal grains obtained from the in vitro procedure were 1.8-10.3 times higher than the Quencher procedure and 3.5 10.5 times higher than water extraction. Correlation between the results of the TAC obtained using the three different procedures was also investigated. The in vitro gastrointestinal digestion procedure is more useful in the screening of grains, assessing their beneficial health effects compared to the Quencher procedure or water extraction. PMID- 23651494 TI - Human resource assessment for scaling up VL active case detection in Bangladesh, India and Nepal. AB - OBJECTIVES: To determine whether medical staff at PHC level would have the time to take up additional activities such as 1-day fever camps for active VL case detection. METHODS: This article assessed the workload of health staff of different professional categories working at health facilities in Bangladesh, India and Nepal. Data were collected from different sites in high endemic VL areas. The study population was the health staff of government health facilities at all levels. Workload indicators of staffing need (WISN) software were adopted to carry out the analysis of staff workload and their availability in the selected health facility. The WISN difference and WISN ratio for a particular health facility were calculated from actual staffing available and calculated staffing requirement. RESULTS: The results showed a mixed picture of the availability of health workers. In most settings of Bangladesh and India, physicians with or without laboratory technicians would have time for active case detection. In Nepal, this would be performed by trained nurses and paramedical personnel. CONCLUSION: If all vacant posts were filled, active case detection could be performed more easily. The elimination programme can be scaled up with the current staffing levels in the endemic areas with some short training if and when necessary. PMID- 23651495 TI - Fall-related sub-acute and non-acute care and hospitalised rehabilitation episodes of care: what is the injury burden? AB - BACKGROUND: Falls are the leading cause of injury in older people. Rehabilitation services can assist individuals to improve mobility and function after sustaining a fall-related injury. However, the true effect of fall-related injury resulting in hospitalisation is often underestimated because of failure to consider sub acute and non-acute care provided following the acute hospitalisation episode. AIM: This study aims to describe the sub-acute and non-acute health service use of individuals hospitalised in New South Wales (NSW), Australia for a fall related injury during 2000-01 to 2008-09, to examine the burden of fall-related inpatient rehabilitation hospital admissions from 1998-99 to 2010-11 and to estimate future demand for fall-related inpatient rehabilitation admissions in NSW to 2020. METHOD: Retrospective review of sub-acute and non-acute records linked to hospital admission records during 2001-02 to 2008-09 in NSW. Analysis of temporal trends from 1998-99 to 2010-11 and projections to 2020 for rehabilitation-related (ICD-10-AM: Z47, Z48, Z50, Z75.1) inpatient hospital admissions. RESULTS: There were 4317 individuals with a fall-related injury admitted to hospital and subsequently admitted for sub-acute and non-acute care; 84% of these were aged 65+ years; 70.4% were female and 27.2% had femur fractures. For the rehabilitation-related admissions, total mean functional independence measure (FIM) scores improved significantly (from 78.4 to 94.6; P<0.0001) between admission and discharge. Fall-related inpatient rehabilitation episodes increased by 9.1% each year between 1998 and 2011 for individuals aged 65 years and older and are projected to rise to 50000 admissions annually by 2020. CONCLUSION: This is the first study to provide an epidemiological profile of individuals using sub-acute and non-acute care in NSW using linked data. Improvements in data validity and reliability would enhance the quality of the sub-acute and non-acute care data and its ability to be used to inform resource use in this sector. The examination of temporal trends using only the inpatient hospital admissions provides a guide for resource implications for inpatient rehabilitation services. What is known about this topic? Fall-related injuries that result in inpatient hospital admissions are increasing in Australia. However, the extent of the effect of fall-related injuries in the sub-acute and non-acute sector remains unknown, due to data limitations. What does this paper add? Provides the first epidemiological profile of individuals who fall and go on to use sub-acute and non-acute care in NSW using linked data. It highlights where improvements in data quality in the sub-acute and non-acute care data could be made to improve their usefulness to inform resource use in this sector. What are the implications for clinicians? Fall injury prevention and healthy ageing strategies for older individuals remain a priority for clinicians. The current and projected future resource implications for inpatient rehabilitation and follow-up services provide an indication for clinicians of future demand in this area as the population ages. However, data quality needs to improve to provide clinicians with strongly relevant guidance to inform clinical practice. PMID- 23651496 TI - GaAs-based resonant tunneling diode (RTD) epitaxy on Si for highly sensitive strain gauge applications. AB - As a highly sensitive strain gauge element, GaAs-based resonant tunneling diode (RTD) has already been applied in microelectromechanical system (MEMS) sensors. Due to poor mechanical properties and high cost, GaAs-based material has been limited in applications as the substrate for MEMS. In this work, we present a method to fabricate the GaAs-based RTD on Si substrate. From the experimental results, it can be concluded that the piezoresistive coefficient achieved with this method reached 3.42 * 10-9 m2/N, which is about an order of magnitude higher than the Si-based semiconductor piezoresistors. PMID- 23651497 TI - A signaling cascade mediated by ceramide, src and PDGFRbeta coordinates the activation of the redox-sensitive neutral sphingomyelinase-2 and sphingosine kinase-1. AB - Stress-inducing agents, including oxidative stress, generate the sphingolipid mediators ceramide (Cer) and sphingosine-1-phosphate (S1P) that are involved in stress-induced cellular responses. The two redox-sensitive neutral sphingomyelinase-2 (nSMase2) and sphingosine kinase-1 (SK1) participate in transducing stress signaling to ceramide and S1P, respectively; however, whether these key enzymes are coordinately regulated is not known. We investigated whether a signaling link coordinates nSMase2 and SK1 activation by H2O2. In mesenchymal cells, H2O2 elicits a dose-dependent biphasic effect, mitogenic at low concentration (5MUM), and anti-proliferative and toxic at high concentration (100MUM). Low H2O2 concentration triggered activation of nSMase2 and SK1 through a nSMase2/Cer-dependent signaling pathway that acted upstream of activation of SK1. Further results implicated src and the trans-activation of PDGFRbeta, as supported by the blocking effect of specific siRNAs, pharmacological inhibitors, and genetically deficient cells for nSMase2, src and SK1. The H2O2-induced src/PDGFRbeta/SK1 signaling cascade was impaired in nSMase2-deficient fro/fro cells and was rescued by exogenous C2Cer that activated src/PDGFRbeta/SK1. Thus, the results define a nSMase2/SK1 signaling pathway implicated in the mitogenic response to low oxidative stress. On the other hand, high oxidative stress induced inhibition of SK1. The results also showed that the toxicity of high H2O2 concentration was comparable in control and nSMase2-deficient cells. Taken together the results identify a tightly coordinated nSMase2/SK1 pathway that mediates the mitogenic effects of H2O2 and may sense the degree of oxidative stress. PMID- 23651498 TI - Imaging of integrin alpha(V)beta(3) expression using (68)Ga-RGD positron emission tomography in pediatric cerebral infarct. AB - Enhanced expression of integrin alphavbeta3 is commonly used as a biomarker for angiogenesis, which is one of the key pathophysiologic processes in cerebral infarct. Integrin alphavbeta3 can be imaged with arginine-glycine-aspartic acid (RGD) peptide agents. In this study, characteristics of positron emission tomography (PET) using a 68Ga-labeled RGD were investigated in pediatric cerebral infarct. Pediatric patients with moyamoya disease underwent 68Ga-RGD PET in a research protocol for neovascularization evaluation. In these patients, 17 cerebral infarct lesions of 10 patients were included in the analysis. On 68Ga RGD PET, the infarct lesion to contralateral brain ratio (LCR) of the infarct lesion was measured and analyzed with regard to postinfarct time interval (PTI) and perfusion single-photon emission computed tomography (SPECT) findings. An increase in 68Ga-RGD uptake was observed in cerebral infarct, particularly in recent lesions. The LCR was significantly higher in the recent than in the chronic lesions, and a significant correlation existed between the LCR and PTI. Additionally, the LCR was significantly higher in the lesions with hyperperfusion on SPECT. This study, as the first human study using an RGD agent for in vivo cerebral infarct imaging, demonstrated that 68Ga-RGD PET has a potential for molecular imaging of integrin alphavbeta3 expression in cerebral infarct as a biomarker of angiogenesis. PMID- 23651499 TI - Electron paramagnetic resonance spectrometry and imaging in melanomas: comparison between pigmented and nonpigmented human malignant melanomas. AB - It has been known for a long time that the melanin pigments present in normal skin, hair, and most of malignant melanomas can be detected by electron paramagnetic resonance (EPR) spectrometry. In this study, we used EPR imaging as a tool to map the concentration of melanin inside ex vivo human pigmented and nonpigmented melanomas and correlated this cartography with anatomopathology. We obtained accurate mappings of the melanin inside pigmented human melanoma samples. The signal intensity observed on the EPR images correlated with the concentration of melanin within the tumors, visible on the histologic sections. In contrast, no EPR signal coming from melanin was observed from nonpigmented melanomas, therefore demonstrating the absence of EPR-detectable pigments inside these particular cases of skin cancer and the importance of pigmentation for further EPR imaging studies on melanoma. PMID- 23651500 TI - In vivo visualization and monitoring of viable neural stem cells using noninvasive bioluminescence imaging in the 6-hydroxydopamine-induced mouse model of Parkinson disease. AB - Transplantation of neural stem cells (NSCs) has been proposed as a treatment for Parkinson disease (PD). The aim of this study was to monitor the viability of transplanted NSCs expressing the enhanced luciferase gene in a mouse model of PD in vivo. The PD animal model was induced by unilateral injection of 6 hydroxydopamine (6-OHDA). The behavioral test using apomorphine-induced rotation and positron emission tomography with [18F]N-(3-fluoropropyl)-2'-carbomethoxy-3' (4-iodophenyl)nortropane ([18F]FP-CIT) were conducted. HB1.F3 cells transduced with an enhanced firefly luciferase retroviral vector (F3-effLuc cells) were transplanted into the right striatum. In vivo bioluminescence imaging was repeated for 2 weeks. Four weeks after transplantation, [18F]FP-CIT PET and the rotation test were repeated. All 6-OHDA-injected mice showed markedly decreased [18F]FP-CIT uptake in the right striatum. Transplanted F3-effLuc cells were visualized on the right side of the brain in all mice by bioluminescence imaging. The bioluminescence intensity of the transplanted F3-effLuc cells gradually decreased until it was undetectable by 10 days. The behavioral test showed that stem cell transplantation attenuated the motor symptoms of PD. No significant change was found in [18F]FP-CIT imaging after cell transplantation. We successfully established an in vivo bioluminescence imaging system for the detection of transplanted NSCs in a mouse model of PD. NSC transplantation induced behavioral improvement in PD model mice. PMID- 23651501 TI - Feasibility of vascular endothelial growth factor imaging in human atherosclerotic plaque using (89)Zr-bevacizumab positron emission tomography. AB - Intraplaque angiogenesis is associated with the occurrence of atherosclerotic plaque rupture. Cardiovascular molecular imaging can be used for the detection of rupture-prone plaques. Imaging with radiolabeled bevacizumab, a monoclonal anti vascular endothelial growth factor (VEGF)-A, can depict VEGF levels corresponding to the angiogenic status in tumors. We determined the feasibility of 89Zr bevacizumab imaging for the detection of VEGF in carotid endarterectomy (CEA) specimens. Five CEA specimens were coincubated with 89Zr-bevacizumab and aspecific 111In-labeled IgG to determine the specificity of bevacizumab accumulation. In 11 CEA specimens, 89Zr-bevacizumab micro-positron emission tomography (PET) was performed following 2 hours of incubation. Specimens were cut in 4 mm wide segments and were stained for VEGF and CD68. In each segment, the mean percent incubation dose per gram of tissue (%Inc/g) and tissue to background ratio were determined. A 10-fold higher accumulation of 89Zr bevacizumab compared to 111In-IgG uptake was demonstrated by gamma counting. The mean %Inc/ghot spot was 2.2 +/- 0.9 with a hot spot to background ratio of 3.6 +/ 0.8. There was a significant correlation between the segmental tissue to background uptake ratio and the VEGF score (rho = .74, p < .001). It is feasible to detect VEGF tissue concentration within CEA specimens using 89Zr bevacizumab PET. 89Zr-bevacizumab accumulation in plaques is specific and correlates with immunohistochemistry scores. PMID- 23651502 TI - Measuring response to therapy by near-infrared imaging of tumors using a phosphatidylserine-targeting antibody fragment. AB - Imaging tumors and their response to treatment could be a valuable biomarker toward early assessment of therapy in patients with cancer. Phosphatidylserine (PS) is confined to the inner leaflet of the plasma membrane in normal cells but is externalized on tumor vascular endothelial cells (ECs) and tumor cells, and PS exposure is further enhanced in response to radiation and chemotherapy. In the present study, we evaluated the potential of a PS-targeting human F(ab')2 antibody fragment, PGN650, to detect exposure of PS in tumor-bearing mice. Tumor uptake of PGN650 was measured by near-infrared optical imaging in human tumor xenografts in immunodeficient mice. PGN650 specifically targeted tumors and was shown to target CD31-positive ECs and tumor cells. Tumor uptake of PGN650 was significantly higher in animals pretreated with docetaxel. The peak tumor to normal tissue (T/N) ratio of probe was observed at 24 hours postinjection of probe, and tumor binding was detected for at least 120 hours. In repeat dose studies, PGN650 uptake in tumors was significantly higher following pretreatment with docetaxel compared to baseline uptake prior to treatment. PGN650 may be a useful probe to detect PS exposed in tumors and to monitor enhanced PS exposure to optimize therapeutic agents to treat tumors. PMID- 23651503 TI - Optimization of [(11)C]raclopride positron emission tomographic rat studies: comparison of methods for image quantification. AB - The goal of this study was to compare different quantification approaches and reconstruction methods to estimate the binding potential in [11C]raclopride studies in rats. The final aim was to determine if the results obtained with short-acquisition scanning were comparable to the results obtained with long acquistion (conventional) scanning. We analyzed two rat data sets: a baseline versus a pretreatment study (with cold raclopride) and a young versus an old animal group comparison. The study results support the contention that optimization of [11C]raclopride positron emission tomographic studies in rats by shortening the acquisition time is feasible. In addition, filtered backprojection is recommended as a reconstruction algorithm, although iterative methods may be more sensitive to detect within-group differences. PMID- 23651504 TI - Imaging tumor vasculature noninvasively with positron emission tomography and RGD peptides labeled with copper 64 using the bifunctonal chelates DOTA, oxo-DO3a. and PCTA. AB - Two novel bifunctional chelates, 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca 1(15),11,13-triene-3,6,9-triacetic acid (PCTA) and 1-oxa-4,7,10 triazacyclododecane-4,7,10-triacetic acid (Oxo-DO3A), were found to radiolabel antibodies with copper 64 (64Cu) well for positron emission tomography (PET). In this study, the same chelators were used to radiolabel peptides with 64Cu for PET imaging of angiogenesis. PCTA, Oxo-DO3A, and 1,4,7,10-tetraazacyclododecane N,N',N'',N'''-tetraacetic acid (DOTA) were conjugated to cyclic-(RGDyK), and their binding affinities were confirmed. Conditions for 64Cu radiolabeling were optimized for maximum yield and specific activity. The in vitro stability of the radiolabeled compounds was challenged with serum incubation. PET studies were carried out in a non-alphavbeta3-expressing tumor model to evaluate the compounds' specificity for proliferating tumor vasculature and their in vivo pharmacokinetics. The PCTA and Oxo-DO3A bioconjugates were labeled with 64Cu at higher effective specific activity and radiochemical yield than the DOTA bioconjugate. In the imaging studies, all the 64Cu bioconjugates could be used to visualize the tumor and the radiotracer uptake was blocked with cyclic-(RGDyK). Target uptake of each bioconjugate was similar, but differences in other tissues were observed. 64Cu-PCTA-RGD showed the best clearance from nontarget tissue and the highest tumor to nontarget ratios. PCTA was the most promising bifunctional chelate for 64Cu peptide imaging and warrants further investigation. PMID- 23651506 TI - An overview of the recent outbreaks of the avian-origin influenza A (H7N9) virus in the human. AB - Since the first human infection with influenza A (H7N9) viruses have been identified in Shanghai on March 31, 2013, the latest variant of the avian flu virus has spread across four Chinese provinces recently. Human infections with avian influenza are rare and this is the first time that human infection with a low pathogenic avian influenza A virus has been associated with fatal outcome. To date (May 5(th), 2013), China had reported 128 confirmed H7N9 infections in human, among 27 died. Most reported cases have severe respiratory illness resulting in severe pneumonia and in some cases have died. No evidence of sustained human-to -humans at this time, however, there is one family cluster with two confirmed cases for which human-to-human transmission cannot be ruled out. Recent evidence showed that the gene sequences of this novel H7N9 virus is primarily zoonotic and may be better adapted than other avian influenza viruses to infect human. Effective global infection control is urgently needed, and further surveillance and analyses should be undertaken to identify the source and mode of transmission of these viruses. PMID- 23651505 TI - Resistance to BH3 mimetic S1 in SCLC cells that up-regulate and phosphorylate Bcl 2 through ERK1/2. AB - BACKGROUND AND PURPOSE: B cell lymphoma 2 (Bcl-2) is a central regulator of cell survival that is overexpressed in the majority of small-cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. The purpose of this work was to study the key factors that determine the sensitivity of SCLC cells to Bcl-2 homology domain-3 (BH3) mimetic S1 and the mechanism underlying the resistance of BH3 mimetics. EXPERIMENTAL APPROACHES: Western blot was used to evaluate the contribution of Bcl-2 family members to the cellular response of SCLC cell lines to S1. Acquired resistant cells were derived from initially sensitive H1688 cells. Quantitative PCR and gene silencing were performed to investigate Bcl-2 up-regulation. KEY RESULTS: A progressive increase in the relative levels of Bcl-2 and phosphorylated Bcl-2 (pBcl-2) characterized the increased de novo and acquired resistance of SCLC cell lines. Furthermore, acute treatment of S1 induced Bcl-2 expression and phosphorylation. We showed that BH3 mimetics, including S1 and ABT-737, induced endoplasmic reticulum (ER) stress and then activated MAPK/ERK pathway. The dual function of MAPK/ERK pathway in defining BH3 mimetics was illustrated; ERK1/2 activation leaded to Bcl-2 transcriptional up-regulation and sustained phosphorylation in naive and acquired resistant SCLC cells. pBcl-2 played a key role in creating resistance of S1 and ABT-737 not only by sequestrating pro-apoptotic proteins, but also sequestrating a positive feedback to promote ERK1/2 activation. CONCLUSIONS AND IMPLICATIONS: These results provide significant novel insights into the molecular mechanisms for crosstalk between ER stress and endogenously apoptotic pathways in SCLC following BH3 mimetics treatment. PMID- 23651508 TI - Probe design rules and effective enzymes for endonuclease-based detection of nucleic acids. AB - Junction probe (JP) platform is an isothermal endonuclease-based detection assay for both RNA and DNA. Herein, we screen 31 REAse and identify effective restriction endonucleases that can be used for JP detection. Secondly, we investigate how different probe architectures affect JP cleavage rates and conclude that although molecular beacon (MB) JP probes give less background noise than linear JP probes, the cleavage of MB JP probes are slower than linear JP probes. PMID- 23651507 TI - Tranexamic acid and the reduction of blood loss in total knee and hip arthroplasty: a meta-analysis. AB - BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic drug used as a blood sparing technique in many surgical specialties. The principal objective of our meta-analysis was to review randomized, controlled trials (RCT) comparing total blood loss and the number of patients receiving allogeneic blood transfusions with and without the use of TXA for knee (TKA) and hip (THA) arthroplasty. METHODS: Studies were included if patients underwent primary unilateral TKA or THA; the study involved the comparison of a TXA treatment group to a control group who received either a placebo or no treatment at all; outcome measures included total blood loss TBL, number of patients receiving allogeneic blood transfusions, and/or incidence of thromboembolic complications; the study was a published or unpublished RCT from 1995 - July 2012. RESULTS: Data were tested for publication bias and statistical heterogeneity. Combined weighted mean differences in blood loss favoured TXA over control for TKA and THA patients respectively [ -1.149 (p < 0.001; 95% CI -1.298, -1.000), -0.504 (p < 0.001; 95% CI, -0.672, -0.336)]. Combined odds ratios favoured fewer patients requiring allogeneic transfusions for TKA and THA with the use of TXA respectively [0.145 (p < 0.001; 95% CI, 0.094, 0.223), 0.327 (p < 0.001; 95% CI, 0.208, 0.515)]. Combined odds ratios indicated no increased incidence of DVT with TXA use in TKA and THA respectively [1.030 (p = 0.946; 95% CI, 0.439, 2.420), 1.070 (p = 0.895; 95% CI, 0.393, 2.911)]. CONCLUSIONS: TXA should be considered for routine use in primary knee and hip arthroplasty to decrease blood loss. PMID- 23651509 TI - Synthesis and biological evaluation of C-glucosides with azulene rings as selective SGLT2 inhibitors for the treatment of type 2 diabetes mellitus: discovery of YM543. AB - Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus. PMID- 23651510 TI - Development of human hip joint in the second and the third trimester of pregnancy; a cadaveric study. AB - BACKGROUND: The purpose of the study was an evaluation of fetal hip joint morphology during the second and the third trimester of pregnancy. Serial sections were performed on 23 cadaver infants. RESULTS: The mean lunar age was 6.6 months. Femoral shaft length (FSL) and width of the proximal and distal epiphysis were x-rayed to determine fetal age. The neck shaft angle (NSA), the femoral antetorsion angle (FAA), the acetabulum anteversion angle (AAA) and the acetabulum slope angle (ASA) were measured. Hip development ratios were plotted for all cadaveric species and revealed: flat FSL/NSA slope pattern, upward FSL/FAA slope pattern and downward slope pattern for FSL/ASA and FSL/AAA ratios. The changes, observed during the developmental period, were not statistically significant. NSA did not change during the second or the third pregnancy trimester. FAA increased during pregnancy but the changes were not statistically significant. AA, as well as ASA, showed a decreasing trend during the second and the third pregnancy trimester, however, with no correlations to age. CONCLUSION: Despite an increasing depth and growing dimensions of the acetabulum in the uterus, its orientation does not change in any significant way. PMID- 23651511 TI - Amnion-derived multipotent progenitor cells support allograft tolerance induction. AB - Donor-specific immunological tolerance using high doses of bone marrow cells (BMCs) has been demonstrated in mixed chimerism-based tolerance induction protocols; however, the development of graft versus host disease remains a risk. Here, we demonstrate that the co-infusion of limited numbers of donor unfractionated BMCs with human amnion-derived multipotent progenitor cells (AMPs) 7 days post-allograft transplantation facilitates macrochimerism induction and graft tolerance in a mouse skin transplantation model. AMPs + BMCs co-infusion with minimal conditioning led to stable, mixed, multilineage lymphoid and myeloid macrochimerism, deletion of donor-reactive T cells, expansion of CD4(+)CD25(+)Foxp3(+) regulatory T cells (T(regs)) and long-term allograft survival (>300 days). Based on these findings, we speculate that AMPs maybe a pro tolerogenic cellular therapeutic that could have clinical efficacy for both solid organ and hematopoietic stem cell transplant applications. PMID- 23651512 TI - A novel reproducible model of neonatal stroke in mice: comparison with a hypoxia ischemia model. AB - Neonatal stroke occurs in 1/4000 live births and leaves life-long neurological impairments, such as cerebral palsy and epilepsy. Currently, the rodent models of neonatal stroke that are available exhibit significant inter-animal variability, which makes it difficult to accurately assess the mechanisms of brain injury and the efficacy of candidate treatments. We aimed to introduce a novel, highly reproducible model of stroke, middle cerebral artery occlusion (MCAO), in immature mice, and to evaluate the reproducibility of this model compared with a conventional hypoxia-ischemia (HI) model. Postnatal day 12 CB-17 mice underwent left MCAO by direct electrocoagulation. The MCAO model exhibited excellent long term survival; 85% up to 8 weeks after the insult. Infarct was evident in every animal with MCAO (n=27) and was confined to the cortex, with the exception of some mild thalamic injury. While the % stroke volume 48 h after the insult was consistent in the MCAO group, range: 17.8-30.4% (minimum-maximum), it was substantially less consistent in the HI group, range: 3.0-70.1%. This contrasting variability between the two models was also evident in the cerebral blood flow, 24h after the insult, and in the ipsilateral hemispheric volume, as assessed at 8 weeks after the insult. Mice with MCAO exhibited significant neurofunctional deficits in the rotarod and open-field tests. Preclinical studies for neonatal stroke could become more reliable using this model, with even a potential reduction in the number of pups required for statistical significance. The contrasting variability between the two models may provide insights into the factors that contribute to inter-animal variability in brain injury. PMID- 23651513 TI - Retinol palmitate prevents ischemia-induced cell changes in hippocampal neurons through the Notch1 signaling pathway in mice. AB - Retinol palmitate, an analog of vitamin A, plays multiple roles in the nervous system, including neural differentiation, axon outgrowth, and neural patterning, and is also an antioxidative agent and thereby potential neuroprotectant for brain ischemia. The present study aimed at investigating the protective effects of retinol palmitate against ischemia-induced brain injury in a bilateral common carotid artery occlusion (BCCAO) model in mice. Ischemia induced by 20-min BCCAO resulted in significant neuronal morphological changes and reactive astrocyte proliferation in the hippocampus, particularly in the CA1 region, and these changes were accompanied by increased Notch1 expression. Intraperitoneal retinol palmitate administration before ischemia reduced ischemic neurons with Notch1 expression; the differences were statistically significant in both the 1.2mg/kg group and 12 mg/kg group. These results show that retinol palmitate prevents brain ischemia-induced neuronal injury with Notch1 expression and that Notch1 signaling could be involved in the neuroprotective mechanism. Retinol palmitate could be a treatment option for human brain infarction. PMID- 23651515 TI - Industrial activated sludge exhibit unique bacterial community composition at high taxonomic ranks. AB - Biological degradation of domestic and industrial wastewater by activated sludge depends on a common process of separation of the diverse self-assembled and self sustained microbial flocs from the treated wastewater. Previous surveys of bacterial communities indicated the presence of a common core of bacterial phyla in municipal activated sludge, an observation consistent with the concept of ecological coherence of high taxonomic ranks. The aim of this work was to test whether this critical feature brings about a common pattern of abundance distribution of high bacterial taxa in industrial and domestic activated sludge, and to relate the bacterial community structure of industrial activated sludge with relevant operational parameters. We have applied 454 pyrosequencing of 16S rRNA genes to evaluate bacterial communities in full-scale biological wastewater treatment plants sampled at different times, including seven systems treating wastewater from different industries and one plant that treats domestic wastewater, and compared our datasets with the data from municipal wastewater treatment plants obtained by three different laboratories. We observed that each industrial activated sludge system exhibited a unique bacterial community composition, which is clearly distinct from the common profile of bacterial phyla or classes observed in municipal plants. The influence of process parameters on the bacterial community structure was evaluated using constrained analysis of principal coordinates (CAP). Part of the differences in the bacterial community structure between industrial wastewater treatment systems were explained by dissolved oxygen and pH. Despite the ecological relevance of floc formation for the assembly of bacterial communities in activated sludge, the wastewater characteristics are likely to be the major determinant that drives bacterial composition at high taxonomic ranks. PMID- 23651514 TI - Effects of blending of desalinated and conventionally treated surface water on iron corrosion and its release from corroding surfaces and pre-existing scales. AB - This study examined effects of blending desalinated water with conventionally treated surface water on iron corrosion and release from corroding metal surfaces and pre-existing scales exposed to waters having varying fractions of desalinated water, alkalinities, pH values and orthophosphate levels. The presence of desalinated water resulted in markedly decreased 0.45 MUm-filtered soluble iron concentrations. However, higher fractions of desalinated water in the blends were also associated with more fragile corroding surfaces, lower retention of iron oxidation products and release of larger iron particles in the bulk water. SEM, XRD and XANES data showed that in surface water, a dense layer of amorphous ferrihydrite phase predominated in the corrosion products. More crystalline surface phases developed in the presence of desalinated water. These solid phases transformed from goethite to lepidocrocite with increased fraction of desalinated water. These effects are likely to result from a combination of chemical parameters, notably variations of the concentrations of natural organic matter, calcium, chloride and sulfate when desalinated and conventionally treated waters are blended. PMID- 23651516 TI - Identification of cellular factors required for the budding of koala retrovirus. AB - Koala retrovirus (KoRV) is a unique gammaretrovirus that is currently endogenizing into its host and considered to be associated with leukemia, lymphoma and immunosuppression in koalas (Phascolactos cinereus). In this study, it was demonstrated that WWP2 or WWP2-like E3 ubiquitin ligases possessing the WW domain closely related to WWP2 and Vps4A/B are involved in KoRV budding. These data suggest that KoRV Gag recruits the cellular endosomal sorting complex required for transport machinery through interaction of the PPPY L-domain with the WW domain(s) of WWP2 and that progeny virions are released from cells by utilizing the multivesicular body sorting pathway. PMID- 23651517 TI - Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells. AB - BACKGROUND: Vascular endothelial growth factor-a (VEGF)-targeted therapies have become an important treatment for a number of human malignancies. The VEGF inhibitors are actually effective in several types of cancers, however, the benefits are transiently, and the vast majority of patients who initially respond to the therapies will develop resistance. One of possible mechanisms for the acquired resistance may be the direct effect(s) of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGFR). Thus, we investigated here the direct effect of chronic VEGF inhibition on phenotype changes in human colorectal cancer (CRC) cells. METHODS: To chronically inhibit cancer cell-derived VEGF, human CRC cell lines (HCT116 and RKO) were chronically exposed (2 months) to an anti-VEGF monoclonal antibody (mAb) or were disrupted the Vegf gene (VEGF-KO). Effects of VEGF family members were blocked by treatment with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI). Hypoxia-induced apoptosis under VEGF inhibited conditions was measured by TUNEL assay. Spheroid formation ability was assessed using a 3-D spheroid cell culture system. RESULTS: Chronic inhibition of secreted/extracellular VEGF by an anti-VEGF mAb redundantly increased VEGF family member (PlGF, VEGFR1 and VEGFR2), induced a resistance to hypoxia-induced apoptosis, and increased spheroid formation ability. This apoptotic resistance was partially abrogated by a VEGFR-TKI, which blocked the compensate pathway consisted of VEGF family members, or by knockdown of Vegf mRNA, which inhibited intracellular function(s) of all Vegf gene products. Interestingly, chronic and complete depletion of all Vegf gene products by Vegf gene knockout further augmented these phenotypes in the compensate pathway-independent manner. These accelerated phenotypes were significantly suppressed by knockdown of hypoxia inducible factor-1alpha that was up-regulated in the VEGF-KO cell lines. CONCLUSIONS: Our findings suggest that chronic inhibition of tumor cell-derived VEGF accelerates tumor cell malignant phenotypes. PMID- 23651519 TI - SUMO-1 conjugation blocks beta-amyloid-induced astrocyte reactivity. AB - Astrocyte reactivity is implicated in the neuronal loss underlying Alzheimer's disease. Curcumin has been shown to reduce astrocyte reactivity, though the exact pathways underlying these effects are incompletely understood. Here we investigated the role of the small ubiquitin-like modifier (SUMO) conjugation in mediating this effect of curcumin. In beta-amyloid (Abeta)-treated astrocytes, morphological changes and increased glial fibrillary acidic protein (GFAP) confirmed reactivity, which was accompanied by c-jun N-terminal kinase activation. Moreover, the levels of SUMO-1 conjugated proteins, as well as the conjugating enzyme, Ubc9, were decreased, with concomitant treatment with curcumin preventing these effects. Increasing SUMOylation in astrocytes, by over expression of constitutively active SUMO-1, but not its inactive mutant, abrogated Abeta-induced increase in GFAP, suggesting astrocytes require SUMO-1 conjugation to remain non-reactive. PMID- 23651518 TI - Sixty years of genome biology. AB - Sixty years after Watson and Crick published the double helix model of DNA's structure, thirteen members of Genome Biology's Editorial Board select key advances in the field of genome biology subsequent to that discovery. PMID- 23651520 TI - Racial/ethnic and immigrant differences in early childhood diet quality. AB - OBJECTIVE: To assess racial/ethnic differences in the diet in young children and the explanatory role of maternal BMI, immigrant status and perception of child's weight. DESIGN: Among white, black and Hispanic 3-year-olds, we used negative binomial and linear regression to examine associations of race/ethnicity with foods and nutrients assessed by a validated FFQ. SETTING: Project Viva, Boston (MA), USA. SUBJECTS: Children aged 3 years (n 898). RESULTS: Mean age was 38.3 (sd 2.8) months; 464 (52 %) were boys and 127 mothers (14 %) were immigrants. After adjustment for sociodemographic factors, black and Hispanic children (v. white) had a higher intake of sugar-sweetened beverages (rate ratio (RR) = 2.59 (95 % CI 1.95, 3.48) and RR = 1.59 (95 % CI 1.07, 2.47), respectively) and lower intakes of skimmed/1 % milk (RR = 0.42 (95 % CI 0.33, 0.53) and RR = 0.43 (95 % CI 0.31, 0.61), respectively) and trans-fat (-0.10 (95 % CI -0.18, -0.03) % of energy and -0.15 (95 % CI -0.26, -0.04) % of energy, respectively). Among Hispanics only, a lower intake of snack food (RR = 0.83 (95 % CI 0.72, 0.98)) was found and among blacks only, a higher intake of fast food (RR = 1.28 (95 % CI 1.05, 1.55)) and lower intakes of saturated fat (-0.86 (95 % CI -1.48, -0.23) % of energy), dietary fibre (0.85 (95 % CI 0.08, 1.62) g/d) and Ca (-120 (95 % CI 175, -65) mg/d) were found. Being born outside the USA was associated with more healthful nutrient intakes and less fast food. CONCLUSIONS: Three-year-old black and Hispanic (v. white) children ate more sugar-sweetened beverages and less low fat dairy. Total energy intake was substantially higher in Hispanic children. Snack food (Hispanic children) and fat intakes (black children) tended to be lower. Children of immigrants ate less fast food and bad fats and more fibre. PMID- 23651521 TI - Access to artemisinin-based anti-malarial treatment and its related factors in rural Tanzania. AB - BACKGROUND: Artemisinin-based combination treatment (ACT) has been widely adopted as one of the main malaria control strategies. However, its promise to save thousands of lives in sub-Saharan Africa depends on how effective the use of ACT is within the routine health system. The INESS platform evaluated effective coverage of ACT in several African countries. Timely access within 24 hours to an authorized ACT outlet is one of the determinants of effective coverage and was assessed for artemether-lumefantrine (Alu), in two district health systems in rural Tanzania. METHODS: From October 2009 to June 2011 we conducted continuous rolling household surveys in the Kilombero-Ulanga and the Rufiji Health and Demographic Surveillance Sites (HDSS). Surveys were linked to the routine HDSS update rounds. Members of randomly pre-selected households that had experienced a fever episode in the previous two weeks were eligible for a structured interview. Data on individual treatment seeking, access to treatment, timing, source of treatment and household costs per episode were collected. Data are presented on timely access from a total of 2,112 interviews in relation to demographics, seasonality, and socio economic status. RESULTS: In Kilombero-Ulanga, 41.8% (CI: 36.6-45.1) and in Rufiji 36.8% (33.7-40.1) of fever cases had access to an authorized ACT provider within 24 hours of fever onset. In neither of the HDSS site was age, sex, socio-economic status or seasonality of malaria found to be significantly correlated with timely access. CONCLUSION: Timely access to authorized ACT providers is below 50% despite interventions intended to improve access such as social marketing and accreditation of private dispensing outlets. To improve prompt diagnosis and treatment, access remains a major bottle neck and new more innovative interventions are needed to raise effective coverage of malaria treatment in Tanzania. PMID- 23651522 TI - Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. AB - The role of very-low-carbohydrate ketogenic diets (VLCKD) in the long-term management of obesity is not well established. The present meta-analysis aimed to investigate whether individuals assigned to a VLCKD (i.e. a diet with no more than 50 g carbohydrates/d) achieve better long-term body weight and cardiovascular risk factor management when compared with individuals assigned to a conventional low-fat diet (LFD; i.e. a restricted-energy diet with less than 30% of energy from fat). Through August 2012, MEDLINE, CENTRAL, ScienceDirect,Scopus, LILACS, SciELO, ClinicalTrials.gov and grey literature databases were searched, using no date or language restrictions, for randomised controlled trials that assigned adults to a VLCKD or a LFD, with 12 months or more of follow-up. The primary outcome was bodyweight. The secondary outcomes were TAG, HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), systolic and diastolic blood pressure,glucose, insulin, HbA1c and C-reactive protein levels. A total of thirteen studies met the inclusion/exclusion criteria. In the overall analysis,five outcomes revealed significant results. Individuals assigned to a VLCKD showed decreased body weight (weighted mean difference 20.91 (95% CI 21.65, 20.17) kg, 1415 patients), TAG (weighted mean difference 20.18 (95% CI 20.27, 20.08) mmol/l, 1258 patients)and diastolic blood pressure (weighted mean difference 21.43 (95% CI 22.49, 20.37) mmHg, 1298 patients) while increased HDL C(weighted mean difference 0.09 (95% CI 0.06, 0.12) mmol/l, 1257 patients) and LDL-C (weighted mean difference 0.12 (95% CI 0.04,0.2) mmol/l, 1255 patients). Individuals assigned to a VLCKD achieve a greater weight loss than those assigned to a LFD in the longterm; hence, a VLCKD may be an alternative tool against obesity. PMID- 23651523 TI - Conducting retrospective impact analysis to inform a medical research charity's funding strategies: the case of Asthma UK. AB - BACKGROUND: Debate is intensifying about how to assess the full range of impacts from medical research. Complexity increases when assessing the diverse funding streams of funders such as Asthma UK, a charitable patient organisation supporting medical research to benefit people with asthma. This paper aims to describe the various impacts identified from a range of Asthma UK research, and explore how Asthma UK utilised the characteristics of successful funding approaches to inform future research strategies. METHODS: We adapted the Payback Framework, using it both in a survey and to help structure interviews, documentary analysis, and case studies. We sent surveys to 153 lead researchers of projects, plus 10 past research fellows, and also conducted 14 detailed case studies. These covered nine projects and two fellowships, in addition to the innovative case studies on the professorial chairs (funded since 1988) and the MRC-Asthma UK Centre in Allergic Mechanisms of Asthma (the 'Centre') which together facilitated a comprehensive analysis of the whole funding portfolio. We organised each case study to capture whatever academic and wider societal impacts (or payback) might have arisen given the diverse timescales, size of funding involved, and extent to which Asthma UK funding contributed to the impacts. RESULTS: Projects recorded an average of four peer-reviewed journal articles. Together the chairs reported over 500 papers. All streams of funding attracted follow-on funding. Each of the various categories of societal impacts arose from only a minority of individual projects and fellowships. Some of the research portfolio is influencing asthma-related clinical guidelines, and some contributing to product development. The latter includes potentially major breakthroughs in asthma therapies (in immunotherapy, and new inhaled drugs) trialled by university spin-out companies. Such research-informed guidelines and medicines can, in turn, contribute to health improvements. The role of the chairs and the pioneering collaborative Centre is shown as being particularly important. CONCLUSIONS: We systematically demonstrate that all types of Asthma UK's research funding assessed are making impacts at different levels, but the main societal impacts from projects and fellowships come from a minority of those funded. Asthma UK used the study's findings, especially in relation to the Centre, to inform research funding strategies to promote the achievement of impact. PMID- 23651524 TI - Chemistry and biological activities of thioacridines/thioacridones. AB - Over the last few decades, numerous articles dealing with acridine have been reported providing solid background for drug design. Interest in thioacridine/thioacridone derivatives is demonstrated by their use against varied pharmacological activities. The article summarizes the synthetic routes of thioacridine/thioacridone and wide range of their uses including receptor interaction, enzyme inhibition, anti-proliferative effects, anti-microbial activity, etc. The first synthetic route for thioacridone includes the use of acridone with sulfur at high temperature. In order to improve the yield and the laborious reaction conditions other new synthetic methodologies were developed. It has been multi substituted with variety of functional groups which have a substantial impact on their biological activities. The diversity in the biological response has prompted researchers to explore this skeleton to its potential against several activities. Our aim is to review the most promising therapeutic developments dealing with thioacridine/thioacridone derivatives by pinpointing the new trends and the promising therapeutic directions. PMID- 23651526 TI - Short term in-patient rehabilitation in axial spondyloarthritis - the results of a 2-week program performed in daily clinical practice. AB - BACKGROUND: From a health service perspective, society, with its limited resources, needs to be reassured that evidence-based medicine is also effective when carried out in the frame of ordinary clinical practice. The effectiveness of rehabilitation programs in ankylosing spondylitis (AS) has been proven to be effective in clinical trials. However, less is known when this is carried out in clinical practice. The aim of this study was to evaluate the effect of a 2-weeks rehabilitation program on self-reported outcome and physical function in patients with axial spondyloarthritis (ax-SpA) including AS patients carried out in ordinary clinical practice. The program contained of daily water exercises, exercises for flexibility, muscle strength, and cardio-respiratory fitness. RESULTS: A total of 87 ax-SpA patients (60 men, 27 women), aged >= 18 years were identified to have participated in the 2-weeks in-patient rehabilitation program. Mean age was 49 years and disease duration was 14 years. 92.5% were HLA-B27 positive, 62% were current users of non-steroidal anti-inflammatory drugs, and 17% were current users of tumour necrosis factor inhibitors. After 2-weeks, a statistical significant improvement (p < 0.001) was observed for patient-reported outcomes (Bath Ankylosing Spondylitis (BAS) Disease Activity Index 4.3 vs. 3.1, BAS Functional Index 3.1 vs. 2.4) and physical measured outcomes (BAS Metrology Index 3.23 vs. 2.29, Gait Velocity 2.2 vs. 2.6 m/s, timed-stands test 22.5 vs. 16.3 s, finger-floor distance 17.9 vs. 8.9 cm, chest expansion 3.9 vs. 4.6 cm). CONCLUSION: Data, from our retrospective case series report, support that patient with ax-SpA benefit from short-term rehabilitation when it is carried out in ordinary clinical care. Data from ordinary clinical care may be important when discussing the effectiveness of a treatment and allocating resources in the health care system. PMID- 23651528 TI - Raymond Gosling: the man who crystallized genes. AB - On April 25th 1953, three publications in Nature forever changed the face of the life sciences in reporting the structure of DNA. Sixty years later, Raymond Gosling shares his memories of the race to the double helix. PMID- 23651529 TI - Nutrition capacity development: a practice framework. AB - OBJECTIVE: To outline a framework and a process for assessing the needs for capacity development to achieve nutrition objectives, particularly those targeting maternal and child undernutrition. DESIGN: Commentary and conceptual framework. SETTING: Low- and middle-income countries. Result A global movement to invest in a package of essential nutrition interventions to reduce maternal and child undernutrition in low- and middle-income countries is building momentum. Capacity to act in nutrition is known to be minimal in most low- and middle income countries, and there is a need for conceptual clarity about capacity development as a strategic construct and the processes required to realise the ability to achieve population nutrition and health objectives. The framework for nutrition capacity development proposed recognises capacity to be determined by a range of factors across at least four levels, including system, organisational, workforce and community levels. This framework provides a scaffolding to guide systematic assessment of capacity development needs which serves to inform strategic planning for capacity development. CONCLUSIONS: Capacity development is a critical prerequisite for achieving nutrition and health objectives, but is currently constrained by ambiguous and superficial conceptualisations of what capacity development involves and how it can be realised. The current paper provides a framework to assist this conceptualisation, encourage debate and ongoing refinement, and progress capacity development efforts. PMID- 23651527 TI - Detecting negative selection on recurrent mutations using gene genealogy. AB - BACKGROUND: Whether or not a mutant allele in a population is under selection is an important issue in population genetics, and various neutrality tests have been invented so far to detect selection. However, detection of negative selection has been notoriously difficult, partly because negatively selected alleles are usually rare in the population and have little impact on either population dynamics or the shape of the gene genealogy. Recently, through studies of genetic disorders and genome-wide analyses, many structural variations were shown to occur recurrently in the population. Such "recurrent mutations" might be revealed as deleterious by exploiting the signal of negative selection in the gene genealogy enhanced by their recurrence. RESULTS: Motivated by the above idea, we devised two new test statistics. One is the total number of mutants at a recurrently mutating locus among sampled sequences, which is tested conditionally on the number of forward mutations mapped on the sequence genealogy. The other is the size of the most common class of identical-by-descent mutants in the sample, again tested conditionally on the number of forward mutations mapped on the sequence genealogy. To examine the performance of these two tests, we simulated recurrently mutated loci each flanked by sites with neutral single nucleotide polymorphisms (SNPs), with no recombination. Using neutral recurrent mutations as null models, we attempted to detect deleterious recurrent mutations. Our analyses demonstrated high powers of our new tests under constant population size, as well as their moderate power to detect selection in expanding populations. We also devised a new maximum parsimony algorithm that, given the states of the sampled sequences at a recurrently mutating locus and an incompletely resolved genealogy, enumerates mutation histories with a minimum number of mutations while partially resolving genealogical relationships when necessary. CONCLUSIONS: With their considerably high powers to detect negative selection, our new neutrality tests may open new venues for dealing with the population genetics of recurrent mutations as well as help identifying some types of genetic disorders that may have escaped identification by currently existing methods. PMID- 23651530 TI - Hybrid PET/MR imaging of the heart: feasibility and initial results. AB - PURPOSE: To assess the feasibility of hybrid imaging of the heart with fluorine 18 fluorodeoxyglucose (FDG) on an integrated 3-T positron emission tomography (PET)/magnetic resonance (MR) imaging system. MATERIALS AND METHODS: The present study was approved by the local institutional review board. Written informed consent was obtained from all patients before imaging. Twenty consecutive patients with myocardial infarction (n = 20) underwent cardiac PET/MR imaging examination. Ten patients underwent additional cardiac PET/computed tomography (CT) before PET/MR. Two-dimensional half-Fourier acquisition single-shot turbo spin-echo sequences, balanced steady-state free precession cine sequences, two dimensional turbo inversion-recovery magnitude T2-weighted sequences, and late gadolinium-enhanced (LGE) segmented two-dimensional inversion-recovery turbo fast low-angle shot sequences were performed. According to the 17-segment model, PET tracer uptake, wall motion, and late gadolinium enhancement were visually assessed for each segment on a binary scale, and categorical intermethod agreement was calculated by using the Cohen kappa. The maximum standardized uptake value was measured in corresponding myocardial locations on PET/CT and PET/MR images. RESULTS: Agreement was substantial over all patients and segments between PET and LGE images (kappa = 0.76) and between PET and cine images (kappa = 0.78). In 306 segments, 97 (32%) were rated as infarcted on PET images, compared with 93 (30%) rated as infarcted on LGE images and with 90 (29%) rated as infarcted on cine images. In a subgroup of patients (n = 10) with an additional PET/CT scan, no significant difference in myocardial tracer uptake between PET/CT and PET/MR images was found (paired t test, P = .95). CONCLUSION: Cardiac PET/MR imaging with FDG is feasible and may add complementary information in patients with ischemic heart disease. PMID- 23651532 TI - Standard or hypofractionated radiotherapy in the postoperative treatment of breast cancer: a retrospective analysis of acute skin toxicity and dose inhomogeneities. AB - BACKGROUND: To identify predictive factors of radiation-induced skin toxicity in breast cancer patients by the analysis of dosimetric and clinical factors. METHODS: 339 patients treated between January 2007 and December 2010 are included in the present analysis. Whole breast irradiation was delivered with Conventional Fractionation (CF) (50 Gy, 2.0/day, 25 fractions) and moderate Hypofractionated Schedule (HS) (44 Gy, 2.75 Gy/day, 16 fractions) followed by tumour bed boost. The impact of patient clinical features, systemic treatments and, in particular, dose inhomogeneities on the occurrence of different levels of skin reaction has been retrospectively evaluated. RESULTS: G2 and G3 acute skin toxicity were 42% and 13% in CF patients and 30% and 7.5% in HS patients respectively. The retrieval and revaluation of 200 treatment plans showed a strong correlation between areas close to the skin surface, with inhomogeneities >107% of the prescribed dose, and the desquamation areas as described in the clinical records. CONCLUSIONS: In our experience dose inhomogeneity underneath G2 - G3 skin reactions seems to be the most important predictor for acute skin damage and in these patients more complex treatment techniques should be considered to avoid skin damage. Genetic polymorphisms too have to be investigated as possible promising candidates for predicting acute skin reactions. PMID- 23651531 TI - Red meat consumption is associated with the risk of type 2 diabetes in men but not in women: a Japan Public Health Center-based Prospective Study. AB - The relationship between different types of meat intake and the risk of type 2 diabetes remains unclear. We prospectively examined the association between total meat, total red meat, unprocessed red meat, processed meat and poultry intake and the incidence of type 2 diabetes. Subjects were 27 425 men and 36 424 women aged 45-75 years who participated in the second survey of the Japan Public Health Center-based Prospective Study, and had no history of type 2 diabetes, cancer, stroke, IHD, chronic liver disease or kidney disease. Meat intake was estimated using a validated 147-item FFQ. OR of self-reported, physician-diagnosed type 2 diabetes over 5 years were estimated using a multiple logistic regression. A total of 1178 newly diagnosed cases of type 2 diabetes were self-reported. Intakes of total meat and total red meat were associated with the increased risk of type 2 diabetes in men but not in women. The multivariate-adjusted OR for the highest quartile compared with the lowest quartile of total meat and total red meat intake were 1.36 (95% CI 1.07, 1.73; P for trend=0.006) and 1.48 (95% CI 1.15, 1.90; P for trend=0.003) for men, respectively, and 0.82 (95% CI 0.62, 1.09; P for trend=0.14) and 0.77 (95% CI 0.57, 1.02; P for trend=0.08) for women, respectively. Intakes of processed red meat and poultry were not associated with the increased risk of diabetes in either men or women. In conclusion, elevated intake of red meat is associated with the increased risk of type 2 diabetes in Japanese men but not in women. PMID- 23651533 TI - Community perceptions of a malaria vaccine in the Kintampo districts of Ghana. AB - BACKGROUND: Malaria remains the leading cause of morbidity and mortality in sub Saharan Africa despite tools currently available for its control. Making malaria vaccine available for routine use will be a major hallmark, but its acceptance by community members and health professionals within the health system could pose considerable challenge as has been found with the introduction of polio vaccinations in parts of West Africa. Some of these challenges may not be expected since decisions people make are many a time driven by a complex myriad of perceptions. This paper reports knowledge and perceptions of community members in the Kintampo area of Ghana where malaria vaccine trials have been ongoing as part of the drive for the first-ever licensed malaria vaccine in the near future. METHODS: Both qualitative and quantitative methods were used in the data collection processes. Women and men whose children were or were not involved in the malaria vaccine trial were invited to participate in focus group discussions (FGDs). Respondents, made up of heads of religious groupings in the study area, health care providers, traditional healers and traditional birth attendants, were also invited to participate in in-depth interviews (IDIs). A cross-sectional survey was conducted in communities where the malaria vaccine trial (Mal 047RTS,S) was carried out. In total, 12 FGDs, 15 IDIs and 466 household head interviews were conducted. RESULTS: Knowledge about vaccines was widespread among participants. Respondents would like their children to be vaccinated against all childhood illnesses including malaria. Knowledge of the long existing routine vaccines was relatively high among respondents compared to hepatitis B and Haemophilus influenza type B vaccines that were introduced more recently in 2002. There was no clear religious belief or sociocultural practice that will serve as a possible barrier to the acceptance of a malaria vaccine. CONCLUSION: With the assumption that a malaria vaccine will be as efficacious as other EPI vaccines, community members in Central Ghana will accept and prefer malaria vaccine to malaria drugs as a malaria control tool. Beliefs and cultural practices as barriers to the acceptance of malaria vaccine were virtually unknown in the communities surveyed. PMID- 23651535 TI - Community perceptions on the secondary health benefits established by malaria vaccine trials (RTS,S phase 2 and phase 3) at the Korogwe site in North Eastern Tanzania. AB - BACKGROUND: Studies conducted thus far have demonstrated that the malaria vaccine (RTS,S) has a promising safety profile. Within the context of planning for future vaccine trials and for the purpose of building on previous research that has been undertaken in sub-Saharan Africa with regard to community perceptions about clinical studies, this research aimed to explore the community perceptions on the secondary health benefits established by the malaria vaccine trials (RTS,S Phase 2 and Phase 3) at the Korogwe site in Tanzania. METHODS: An exploratory qualitative study design was used. Participants were recruited from the Korogwe site. Sampling techniques were purposive and random. A total of five focus group discussions and six in-depth interviews were conducted. Interview guides with open-ended questions were employed to collect data. Male and female parents whose infants participated and those whose infants did not participate in the trials, health workers and community leaders were interviewed. Thematic analysis framework was used to analyse the data. RESULTS: The activities of a malaria vaccine project appeared to be well known to the community. Respondents had largely positive views towards the secondary health benefits which have been established by malaria vaccine trials. The project has led to a massive investment in health care infrastructure and an improvement in health care services across the study areas. The project was perceived by the community to have established major secondary health benefits. Misconceptions amongst respondents, especially with regard to blood samples, were also observed in this study. CONCLUSION: Despite some misconceptions with regard to the conduct of malaria vaccine trials, especially on blood sampling, generally this study observed that most participants were positive about the secondary health benefits brought about by the malaria vaccine trials in Korogwe. PMID- 23651534 TI - Acute and subacute IL-1beta administrations differentially modulate neuroimmune and neurotrophic systems: possible implications for neuroprotection and neurodegeneration. AB - BACKGROUND: In Alzheimer's disease, stroke and brain injuries, activated microglia can release proinflammatory cytokines, such as interleukin (IL)-1beta. These cytokines may change astrocyte and neurotrophin functions, which influences neuronal survival and induces apoptosis. However, the interaction between neuroinflammation and neurotrophin functions in different brain conditions is unknown. The present study hypothesized that acute and subacute elevated IL-1beta differentially modulates glial and neurotrophin functions, which are related to their role in neuroprotection and neurodegeneration. METHOD: Rats were i.c.v. injected with saline or IL-1beta for 1 or 8 days and tested in a radial maze. mRNA and protein expressions of glial cell markers, neurotrophins, neurotrophin receptors, beta-amyloid precursor protein (APP) and the concentrations of pro- and anti-inflammatory cytokines were measured in the hippocampus. RESULTS: When compared to controls, memory deficits were found 4 days after IL-1 administrations, however the deficits were attenuated by IL-1 receptor antagonist (RA). Subacute IL-1 administrations increased expressions of APP, microglial active marker CD11b, and p75 neurotrophin receptor, and the concentration of tumor necrosis factor (TNF)-alpha and IL-1beta, but decreased expressions of astrocyte active marker glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and TrK B. By contrast, up-regulations of NGF, BDNF and TrK B expressions were found after acute IL-1 administration, which are associated with the increase in both glial marker expressions and IL-10 concentrations. However, TrK A was down-regulated by acute and up-regulated by subacute IL-1 administrations. Subacute IL-1-induced changes in the glial activities, cytokine concentrations and expressions of BDNF and p75 were reversed by IL-1RA treatment. CONCLUSION: These results indicate that acute and subacute IL-1 administrations induce different changes toward neuroprotection after acute IL-1 administrations but neurodegeneration after subacute ones. PMID- 23651536 TI - A semi-automated protocol for Archaea DNA extraction from stools. AB - BACKGROUND: The PCR-based detection of archaea DNA in human specimens relies on efficient DNA extraction. We previously designed one such protocol involving only manual steps. In an effort to reduce the workload involved, we compared this manual protocol to semi-automated and automated protocols for archaea DNA extraction from human specimens. FINDINGS: We tested 110 human stool specimens using each protocol. An automated protocol using the EZ1 Advanced XL extractor with the V 1.066069118 Qiagen DNA bacteria card and the EZ1(r) DNA Tissue Kit (Qiagen, Courtaboeuf, France) yielded 35/110 (32%) positives for the real-time PCR detection of the Methanobrevibacter smithii 16S rRNA gene, with average Ct values of 36.1. A semi-automated protocol combining glass-powder crushing, overnight proteinase K digestion and lysis in the buffer from the EZ1 kit yielded 90/110 (82%) positive specimens (P = 0.001) with an average Ct value of 27.4 (P = 0.001). The manual protocol yielded 100/110 (91%) positive specimens (P = 0.001) with an average Ct value of 30.33 (P = 0.001). However, neither the number of positive specimens nor the Ct values were significantly different between the manual protocol and the semi-automated protocol (P > 0.1 and P > 0.1). CONCLUSION: Proteinase K digestion and glass powder crushing dramatically increase the extraction yield of archaea DNA from human stools. The semi automated protocol described here was more rapid than the manual protocol and yielded significantly more archaeal DNA. It could be applied for extracting total stool DNA for further PCR amplification. PMID- 23651537 TI - Brief parenting intervention for parents of NICU graduates: a randomized, clinical trial of Primary Care Triple P. AB - BACKGROUND: Preterm-born or asphyxiated term-born children who received neonatal intensive care show more emotional and behavioral problems than term-born children without a medical condition. It is uncertain whether regular parenting intervention programs to which the parents of these children are usually referred, are effective in reducing child problem behavior in this specific population. Our objective was to investigate whether a regular, brief parenting intervention, Primary Care Triple P, is effective in decreasing emotional and behavioral problems in preterm-born or asphyxiated term-born preschoolers. METHODS: For this pragmatic, open randomized clinical trial, participants were recruited from a cohort of infants admitted to the neonatal intensive care units (NICU) of two Dutch hospitals. Children born with a gestational age <32 weeks or birth weight <1500 g and children born at a gestational age 37-42 weeks with perinatal asphyxia were included. After screening for a t-score >=60 on the Child Behavior Checklist (CBCL), children were randomly assigned to Primary Care Triple P (n = 34) or a wait-list control group (n = 33). The primary outcome was child emotional and behavioral problems reported by parents on the CBCL, 6 months after the start of the trial. RESULTS: There was no effect of the intervention on the CBCL at the trial endpoint (t64 = 0.54, P = .30). On secondary measurements of child problem behavior, parenting style, parenting stress, and parent perceived child vulnerability, groups either did not differ significantly or the intervention group showed more problems. In both the intervention and control group there was a significant decrease in emotional and behavioral problems during the trial. CONCLUSIONS: Primary Care Triple P, a brief parenting intervention, is not effective in reducing child emotional and behavioral problems in preterm-born children or term-born children with perinatal asphyxia. TRIAL REGISTRATION: Netherlands National Trial Register (NTR): NTR2179. PMID- 23651538 TI - Genotype imputation accuracy in a F2 pig population using high density and low density SNP panels. AB - BACKGROUND: F(2) resource populations have been used extensively to map QTL segregating between pig breeds. A limitation associated with the use of these resource populations for fine mapping of QTL is the reduced number of founding individuals and recombinations of founding haplotypes occurring in the population. These limitations, however, become advantageous when attempting to impute unobserved genotypes using within family segregation information. A trade off would be to re-type F(2) populations using high density SNP panels for founding individuals and low density panels (tagSNP) in F(2) individuals followed by imputation. Subsequently a combined meta-analysis of several populations would provide adequate power and resolution for QTL mapping, and could be achieved at relatively low cost. Such a strategy allows the wealth of phenotypic information that has previously been obtained on experimental resource populations to be further mined for QTL identification. In this study we used experimental and simulated high density genotypes (HD-60K) from an F(2) cross to estimate imputation accuracy under several genotyping scenarios. RESULTS: Selection of tagSNP using physical distance or linkage disequilibrium information produced similar imputation accuracies. In particular, tagSNP sets averaging 1 SNP every 2.1 Mb (1,200 SNP genome-wide) yielded imputation accuracies (IA) close to 0.97. If instead of using custom panels, the commercially available 9K chip is used in the F(2), IA reaches 0.99. In order to attain such high imputation accuracy the F(0) and F(1) generations should be genotyped at high density. Alternatively, when only the F(0) is genotyped at HD, while F(1) and F(2) are genotyped with a 9K panel, IA drops to 0.90. CONCLUSIONS: Combining 60K and 9K panels with imputation in F(2) populations is an appealing strategy to re-genotype existing populations at a fraction of the cost. PMID- 23651539 TI - Effect of photoperiod and temperature on the intensity of pupal diapause in the cotton bollworm, Helicoverpa armigera (Lepidoptera: Noctuidae). AB - The intensity of pupal diapause in the cotton bollworm, Helicoverpa armigera (Hubner) was investigated under both laboratory and natural conditions. By transferring diapausing pupae induced under LD 11:13, LD 12:12 and LD 13:11 at 20, 22 and 25 degrees C to 25 degrees C combined with LD 15:9 to terminate diapause the rearing day length of 11 h evoked greater intensity of diapause than did 12 and 13 h at 25 degrees C; whereas the rearing temperature of 25 degrees C evoked more intense diapause than did 20 and 22 degrees C under LD 11:13. By transferring diapausing pupae induced under LD 12:12 at 20 and 22 degrees C to six temperatures of 18, 20, 22, 25, 28 and 31 degrees C combined with LD 15:9 to terminate diapause, the duration of diapause was significantly shortened from 146 days at 18 degrees C to 24 days at 31 degrees C, showing that high temperatures significantly accelerate diapause development. Furthermore, the duration of diapause was significantly longer at the rearing temperature of 22 degrees C than that at 20 degrees C when the diapause-terminating temperatures were 20 and 22 degrees C. Chilling at 5 degrees C did not shorten the duration of diapause but lengthened it when chilling period was included. However, chilling plays an important role in synchronizing adult emergence. Rearing temperature of 22 degrees C also evoked more intense diapause than did 20 degrees C in most chilling treatments. When the overwintering pupae were transferred at different times from natural temperatures to 25 degrees C, it was found that the earlier the transfer took place, the earlier the adults emerged when the time spent under natural conditions was included. However, cool temperatures before March showed an enhanced effect on diapause development at 20 degrees C, suggesting that the high diapause-terminating temperature can offset the effect of chilling on diapause development. The result of diapause termination under natural conditions suggests that the developmental threshold for post-diapause development in H. armigera should be around 17.5 degrees C. PMID- 23651540 TI - Detection of protein structure of frozen ancient human remains recovered from a glacier in Canada using synchrotron fourier transform infrared microspectroscopy. AB - We previously used synchrotron infrared microspectroscopy to describe the biochemical signature of skeletal muscle (biceps brachii) from the frozen ancient remains of a young man. In this current paper, we use light microscopy to assess the state of preservation of cellular components in the trapezius muscle from these same ancient remains and then use mid-infrared analysis at the Canadian Light Source synchrotron facility to further analyze the tissue. We compare spectra between the trapezius samples from the ancient remains and a recently deceased cadaver (control). Infrared spectra indicate preservation of secondary structure, with the alpha-helix being the principal component, along with triple helical portions of the protein backbone. Our mid-infrared analysis indicates an energy reserve in the skeletal muscle in the ancient remains. PMID- 23651541 TI - Patients' worries before starting antiretroviral therapy and their association with treatment adherence and outcomes: a prospective study in rural Uganda, 2004 2009. AB - BACKGROUND: In HIV-infected persons, good adherence to antiretroviral therapy (ART) is essential for successful treatment outcomes. Patients' worries before starting ART may affect their ART adherence and treatment outcomes. METHODS: Between 2004 and 2009, HIV-infected individuals in a prospective cohort study in rural Uganda were assessed for ART eligibility. A counsellor explained the ART eligibility criteria, adherence and side effects, and recorded the patients' worries related to ART. Every quarter, patients who initiated ART had clinical, immunological (CD4 cell counts) and virological (viral loads) assessments, and data were collected on ART adherence using patients' self-reports and pill counts. We describe the patients' worries and examine their association with ART adherence, and immunological and virological outcomes. RESULTS: We assessed 421 patients, 271 (64%) were females, 318 (76%) were aged 30 years and above and 315 (75%) were eligible for ART. 277 (66%) reported any worry, and the proportions were similar by sex, age group and ART eligibility status. The baseline median CD4 counts and viral loads were similar among patients with any worry and those with no worry. The commonest worries were: fear of HIV serostatus disclosure; among 69 (16%) participants, lack of food when appetite improved after starting ART; 50 (12%), concurrent use of other medications; 33 (8%), adherence to ART; 28 (7%) and problems concerning condom use; 27 (6%). After 24 months or more on ART, patients who reported any worry had made more scheduled ART refill visits than patients who reported no worry (p<0.01), but the annual CD4 cell increases were similar (p=0.12). After one year on ART, patients who reported any worry had greater virological suppression than patients who reported no worry (p<0.05). CONCLUSIONS: Despite the lack of significant associations of worries with unfavourable ART outcomes, physicians and counsellors should assist patients in overcoming their worries that can cause stress and discomfort. Food supplements may be desirable for some patients initiating ART. PMID- 23651542 TI - Increased expression of OX40 is associated with progressive disease in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. AB - BACKGROUND: OX40 is a member of the tumor necrosis factor receptor family that is expressed primarily on activated CD4+ T cells and promotes the development of effector and memory T cells. Although OX40 has been reported to be a target gene of human T-cell leukemia virus type-1 (HTLV-1) viral transactivator Tax and is overexpressed in vivo in adult T-cell leukemia (ATL) cells, an association between OX40 and HTLV-1-associated inflammatory disorders, such as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), has not yet been established. Moreover, because abrogation of OX40 signals ameliorates chronic inflammation in animal models of autoimmune disease, novel monoclonal antibodies against OX40 may offer a potential treatment for HTLV-1-associated diseases such as ATL and HAM/TSP. RESULTS: In this study, we showed that OX40 was specifically expressed in CD4+ T cells naturally infected with HTLV-1 that have the potential to produce pro-inflammatory cytokines along with Tax expression. We also showed that OX40 was overexpressed in spinal cord infiltrating mononuclear cells in a clinically progressive HAM/TSP patient with a short duration of illness. The levels of the soluble form of OX40 (sOX40) in the cerebrospinal fluid (CSF) from chronic progressive HAM/TSP patients or from patients with other inflammatory neurological diseases (OINDs) were not different. In contrast, sOX40 levels in the CSF of rapidly progressing HAM/TSP patients were higher than those in the CSF from patients with OINDs, and these patients showed higher sOX40 levels in the CSF than in the plasma. When our newly produced monoclonal antibody against OX40 was added to peripheral blood mononuclear cells in culture, HTLV-1-infected T cells were specifically removed by a mechanism that depends on antibody-dependent cellular cytotoxicity. CONCLUSIONS: Our study identified OX40 as a key molecule and biomarker for rapid progression of HAM/TSP. Furthermore, blocking OX40 may have potential in therapeutic intervention for HAM/TSP. PMID- 23651544 TI - CoCl2 induces PC12 cells apoptosis through p53 stability and regulating UNC5B. AB - The receptor uncoordinated 5B (UNC5B) induces apoptosis in the absence of its cognate ligand netrin-1. However, the role of UNC5B in hypoxia-induced apoptosis is not known. Here, we have demonstrated the biological functions of UNC5B in hypoxia-induced apoptosis and related regulatory pathways and examined the effects of UNC5B on p53-dependent apoptosis in PC12 cells under hypoxic conditions. First, we characterized p53-dependent PC12 cell death induced by CoCl2. Our data showed that CoCl2 increased p53 stabilization and transcriptional activity. The downregulation of p53 expression with specific small interfering RNA (p53 siRNA) in CoCl2-treated PC12 cells caused reduction in apoptosis, UNC5B expression, and p21 expression. Moreover, in PC12 cells, ectopic expression of UNC5B significantly enhanced apoptosis, while silencing of UNC5B with siRNA significantly inhibited apoptosis. In addition, netrin-1 significantly inhibited CoCl2-induced p53 stability and UNC5B expression and CoCl2-induced caspase-3 activity and cell death. Collectively, these results demonstrate a novel role for p53 in the control of CoCl2-induced apoptosis through the regulation of UNC5B. PMID- 23651543 TI - Maternal-fetal transfer of selenium in the mouse. AB - Selenoprotein P (Sepp1) is taken up by receptor-mediated endocytosis for its selenium. The other extracellular selenoprotein, glutathione peroxidase-3 (Gpx3), has not been shown to transport selenium. Mice with genetic alterations of Sepp1, the Sepp1 receptors apolipoprotein E receptor-2 (apoER2) and megalin, and Gpx3 were used to investigate maternal-fetal selenium transfer. Immunocytochemistry (ICC) showed receptor-independent uptake of Sepp1 and Gpx3 in the same vesicles of d-13 visceral yolk sac cells, suggesting uptake by pinocytosis. ICC also showed apoER2-mediated uptake of maternal Sepp1 in the d-18 placenta. Thus, two selenoprotein-dependent maternal-fetal selenium transfer mechanisms were identified. Selenium was quantified in d-18 fetuses with the mechanisms disrupted. Maternal Sepp1 deletion, which lowers maternal whole-body selenium, decreased fetal selenium under selenium-adequate conditions but deletion of fetal apoER2 did not. Fetal apoER2 deletion did decrease fetal selenium, by 51%, under selenium-deficient conditions, verifying function of the placental Sepp1-apoER2 mechanism. Maternal Gpx3 deletion decreased fetal selenium, by 13%, but only under selenium-deficient conditions. These findings indicate that the selenoprotein uptake mechanisms ensure selenium transfer to the fetus under selenium-deficient conditions. The failure of their disruptions (apoER2 deletion, Gpx3 deletion) to affect fetal selenium under selenium-adequate conditions indicates the existence of an additional maternal-fetal selenium transfer mechanism. PMID- 23651545 TI - Dose response effect of methylphenidate on ventral tegmental area neurons and animal behavior. AB - Methylphenidate (MPD) is the drug of choice prescribed to treat ADHD patients. More recently, MPD is also used as a cognitive enhancement and recreationally by young adults and its therapeutic effects are not fully understood. One of the neuroanatomical sites is reported to be the ventral tegmental area (VTA). The ventral tegmental area neuronal activity was recorded from freely behaving non anesthetized rats implanted bilaterally with semi-permanent electrodes which were recorded from a wireless telemetric system. Thirty-three animals, divided randomly into four groups, were used: saline (n=10), 0.6 mg/kg (n=6), 2.5 mg/kg (n=7) and 10.0 mg/kg MPD (n=10). MPD caused an increase in locomotor activity with a dose response characteristic; 0.6 mg/kg MPD elicited some increase in locomotion, but not significantly, while 2.5 and 10.0 mg/kg MPD elicited significant increases in behavior of 191% and 870% respectively. A total of 209 ventral tegmental area units were recorded; 100% (36/36) units showed no response to saline; 89% (154/173) of the neurons responded to MPD, with the majority 66% (101/154) showing an increase in activity. In response to 0.6 mg/kg (n=52), the majority of units 54% (28/52) showed a decrease in activity. For both 2.5 (n=60) and 10.0 mg/kg (n=61), the majority of ventral tegmental area units responded with an increase in activity with 63% (38/60) and 70% (43/61) respectively. This study demonstrated that the majority of ventral tegmental area neurons respond to acute MPD in a dose response characteristic and are not related to the animal's locomotor activity. PMID- 23651546 TI - Bioengineered stem cells in neural development and neurodegeneration research. AB - The recent discovery of a simple method for making induced pluripotent stem cells (iPSC) from human somatic cells was a major scientific advancement that opened the way for many promising new developments in the study of developmental and degenerative diseases. iPSC have already been used to model many different types of neurological diseases, including autism, schizophrenia, Alzheimer's disease and Parkinson's disease. Because of their pluripotent property, iPSC offer the possibility of modeling human development in vitro. Their differentiation seems to follow the developmental timeline and obeys environmental cues. Clinically relevant phenotypes of neurodegenerative pathologies have also been observed using iPSC derived human neuronal cultures. Options for treatment are still some way off. Although some early research in mouse models has been encouraging, major obstacles remain for neural stem cell (NSC) transplantation therapy. However, iPSC now offer the prospect of an unlimited amount of human neurons or astrocytes for drug testing. The aim of this review is to summarize the recent progress in modeling neural development and neurological diseases using iPSC and to describe their applications for aging research and personalized medicine. PMID- 23651547 TI - Gene-based single nucleotide polymorphism discovery in bovine muscle using next generation transcriptomic sequencing. AB - BACKGROUND: Genetic information based on molecular markers has increasingly being used in cattle breeding improvement programmes, as a mean to improve conventionally phenotypic selection. Advances in molecular genetics have led to the identification of several genetic markers associated with genes affecting economic traits. Until recently, the identification of the causative genetic variants involved in the phenotypes of interest has remained a difficult task. The advent of novel sequencing technologies now offers a new opportunity for the identification of such variants. Despite sequencing costs plummeting, sequencing whole-genomes or large targeted regions is still too expensive for most laboratories. A transcriptomic-based sequencing approach offers a cheaper alternative to identify a large number of polymorphisms and possibly to discover causative variants. In the present study, we performed a gene-based single nucleotide polymorphism (SNP) discovery analysis in bovine Longissimus thoraci, using RNA-Seq. To our knowledge, this represents the first study done in bovine muscle. RESULTS: Messenger RNAs from Longissimus thoraci from three Limousin bull calves were subjected to high-throughput sequencing. Approximately 36-46 million paired-end reads were obtained per library. A total of 19,752 transcripts were identified and 34,376 different SNPs were detected. Fifty-five percent of the SNPs were found in coding regions and ~22% resulted in an amino acid change. Applying a very stringent SNP quality threshold, we detected 8,407 different high confidence SNPs, 18% of which are non synonymous coding SNPs. To analyse the accuracy of RNA-Seq technology for SNP detection, 48 SNPs were selected for validation by genotyping. No discrepancies were observed when using the highest SNP probability threshold. To test the usefulness of the identified SNPs, the 48 selected SNPs were assessed by genotyping 93 bovine samples, representing mostly the nine major breeds used in France. Principal component analysis indicates a clear separation between the nine populations. CONCLUSIONS: The RNA-Seq data and the collection of newly discovered coding SNPs improve the genomic resources available for cattle, especially for beef breeds. The large amount of variation present in genes expressed in Limousin Longissimus thoracis, especially the large number of non synonymous coding SNPs, may prove useful to study the mechanisms underlying the genetic variability of meat quality traits. PMID- 23651548 TI - Low-carbohydrate, high-protein diet score and risk of incident cancer; a prospective cohort study. AB - BACKGROUND: Although carbohydrate reduction of varying degrees is a popular and controversial dietary trend, potential long-term effects for health, and cancer in specific, are largely unknown. METHODS: We studied a previously established low-carbohydrate, high-protein (LCHP) score in relation to the incidence of cancer and specific cancer types in a population-based cohort in northern Sweden. Participants were 62,582 men and women with up to 17.8 years of follow-up (median 9.7), including 3,059 prospective cancer cases. Cox regression analyses were performed for a LCHP score based on the sum of energy-adjusted deciles of carbohydrate (descending) and protein (ascending) intake labeled 1 to 10, with higher scores representing a diet lower in carbohydrates and higher in protein. Important potential confounders were accounted for, and the role of metabolic risk profile, macronutrient quality including saturated fat intake, and adequacy of energy intake reporting was explored. RESULTS: For the lowest to highest LCHP scores, 2 to 20, carbohydrate intakes ranged from median 60.9 to 38.9% of total energy intake. Both protein (primarily animal sources) and particularly fat (both saturated and unsaturated) intakes increased with increasing LCHP scores. LCHP score was not related to cancer risk, except for a non-dose-dependent, positive association for respiratory tract cancer that was statistically significant in men. The multivariate hazard ratio for medium (9-13) versus low (2-8) LCHP scores was 1.84 (95% confidence interval: 1.05-3.23; p-trend = 0.38). Other analyses were largely consistent with the main results, although LCHP score was associated with colorectal cancer risk inversely in women with high saturated fat intakes, and positively in men with higher LCHP scores based on vegetable protein. CONCLUSION: These largely null results provide important information concerning the long-term safety of moderate carbohydrate reduction and consequent increases in protein and, in this cohort, especially fat intakes. In order to determine the effects of stricter carbohydrate restriction, further studies encompassing a wider range of macronutrient intakes are warranted. PMID- 23651549 TI - Determination of blank indication of active radon monitors. AB - The importance of determination of the blank indication for active radon monitors is discussed. Two new blank chambers were developed at ENEA-INMRI that allows such determination with an uncertainty lower than a few Bq/m(3). Results are reported and that show the large blank variability between radon active monitors and its growth with time when such monitors are used at high radon concentrations. PMID- 23651550 TI - Characterisation of clinical and newly fabricated meshes for pelvic organ prolapse repair. AB - Clinical meshes used in pelvic organ prolapse (POP) repair are predominantly manufactured from monofilament polypropylene (PP). Complications from the use of these meshes in transvaginal kits, including mesh exposure and pain, have prompted two public health notifications by the FDA. The aim of this study was to compare several clinical PP POP meshes to new fabricated POP meshes, knitted from alternative polymers, for their mechanical properties using standard and clinically relevant multi-axial testing methods. Five new meshes were warp knitted to different architectures and weights from polyamide and polyetheretherketone monofilaments. A composite mesh of a polyamide mesh incorporating a gelatin layer was also fabricated to enable the potential delivery of cells on these meshes. Meshes were assessed for their structural characteristics and mechanical properties, using uniaxial stiffness, permanent strain, bending rigidity and multi-axial burst strength methods. Results were compared to three clinical urogynaecological polypropylene meshes: Polyform(r), Gynemesh(TM)PS, and IntePro(r). New fabricated meshes were uniaxially less stiff (less than 0.24 N/mm and 1.20 N/mm in toe and linear regions, respectively) than the Gynemesh (0.48 N/mm and 2.08 N/mm in toe and linear regions, respectively) and IntePro (0.57 N/mm in toe region) clinical meshes, with the gelatin coated PA mesh exhibiting lower permanent strain than Polyform clinical mesh (8.1% vs. 23.5%). New meshes had lower burst stiffness than Polyform (less than 16.9 N/mm for new meshes and 26.6N/mm for Polyform). Within the new mesh prototypes, the PA meshes, either uncoated (4.7-5.7 MUN m) or with gelatin coating (16.7 MUN m) possessed lower bending rigidity than both Polyform and Gynemesh (46.2 MUN m and 36.4 MUN m, respectively). The new fabricated mesh designs were of similar architecture, but with some improved mechanical properties, compared to clinical POP meshes. Multi-axial analysis of new and clinical mesh designs provides greater discriminatory power in analysing mesh mechanical properties for clinical applications. PMID- 23651551 TI - Communication of genome regulatory elements in a folded chromosome. AB - The most popular model of gene activation by remote enhancers postulates that the enhancers interact directly with target promoters via the looping of intervening DNA fragments. This interaction is thought to be necessary for the stabilization of the Pol II pre-initiation complex and/or for the transfer of transcription factors and Pol II, which are initially accumulated at the enhancer, to the promoter. The direct interaction of enhancer(s) and promoter(s) is only possible when these elements are located in close proximity within the nuclear space. Here, we discuss the molecular mechanisms for maintaining the close proximity of the remote regulatory elements of the eukaryotic genome. The models of an active chromatin hub (ACH) and an active nuclear compartment are considered, focusing on the role of chromatin folding in juxtaposing remote DNA sequences. The interconnection between the functionally dependent architecture of the interphase chromosome and nuclear compartmentalization is also discussed. PMID- 23651552 TI - Expression and function of the dense-core vesicle membranes are governed by the transcription repressor REST. AB - The membrane of dense-core vesicles is present only in neural cells, where it is instrumental to the regulated discharge of important molecules such as the catecholamine neurotransmitters. The mechanism underlying the specificity of this membrane to certain cell types has so far been unclear. Studies of this problem have been carried out by employing the pheochromocytoma PC12 cell line and its clones defective of dense-core vesicles. REST, the transcription repressor expressed at high levels in non-neural and at very low levels in neural cells, was found to regulate the genes encoding almost all the proteins of both the core and the membrane of the dense-core vesicles, including the transporter for catecholamines and the SNAREs for their exocytosis. Moreover, REST appears to control the assembly of the vesicle membrane. The role of REST in the various steps of the expression and function of the dense-core vesicle membrane is critical during development and participates in the dynamic regulation of mature cell physiology. PMID- 23651553 TI - Simplified bone-anchored hearing aid insertion using a linear incision without soft tissue reduction. AB - BACKGROUND: Numerous techniques have been described to manage the skin and other soft tissues during bone-anchored hearing aid insertion. Previously, generally accepted techniques have sometimes led to distressing alopecia and soft tissue defects. Now, some surgeons are rejecting the originally described split skin flap in favour of a less invasive approach. OBJECTIVE: To investigate bone anchored hearing aid placement utilising a single, linear incision with either no or minimal underlying soft tissue reduction. PATIENTS AND METHODS: Thirty-four adults were prospectively enrolled to undergo single-stage bone-anchored hearing aid placement with this modified technique. A small, linear incision was used at the standard position and carried down through the periosteum. Standard technique was then followed with placement of an extended length abutment. Patients were reviewed regularly to assess wound healing, including evaluation with Holgers' scale. RESULTS: Only 14.7 per cent of patients had a reaction score of 2 or higher. Most complications were limited to minor skin reactions that settled with silver nitrate cautery and/or antibiotics. None required revision surgery for tissue overgrowth, and there were no implant failures. CONCLUSION: Our results suggest this to be a simple and effective insertion technique with favourable cosmesis and patient satisfaction. PMID- 23651555 TI - Individuals' half-lives for 2,3,4,7,8-penta-chlorodibenzofuran (PeCDF) in blood: correlation with clinical manifestations and laboratory results in subjects with Yusho. AB - BACKGROUND: In 1968, many people developed dioxin poisoning (Yusho) in Japan. Ingestion of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) was considered to be the cause of this poisoning. Although some patients had high concentrations of 2,3,4,7,8-PeCDF in their blood, individuals' half-lives of 2,3,4,7,8-PeCDF were long. OBJECTIVES: To evaluate the relationship between clinical and laboratory parameters and the individual half-life of 2,3,4,7,8-PeCDF in blood. METHODS: Clinical and laboratory data were collected during annual check-ups from 2001 to 2008. We enrolled 71 patients, who were measured more than 3 times, and who had 2,3,4,7,8-PeCDF concentrations in blood >50pgg(-1) lipid. The half-life of 2,3,4,7,8-PeCDF for each patient was estimated using linear regression. Moreover, relationships between clinical and laboratory parameters and individual half-life were investigated by linear regression. RESULTS: A shortened individual half-life for 2,3,4,7,8-PeCDF was significantly correlated with an increased red blood cell count, increased viscous secretions from the meibomian glands, existing black comedones, and severe cedar pollen allergy. CONCLUSIONS: Symptoms that accelerate excretion of lipids from the body, such as viscous secretions from the meibomian glands, may lead to a shorter half-life of 2,3,4,7,8-PeCDF. Red blood cells are related to the half-life of 2,3,4,7,8-PeCDF. However, further studies are required to investigate the excretory mechanism of 2,3,4,7,8-PeCDF. PMID- 23651554 TI - A case of ultrasound-guided prenatal diagnosis of prune belly syndrome in Papua New Guinea--implications for management. AB - BACKGROUND: Prune belly syndrome is a rare congenital malformation of unknown aetiology and is characterised by abnormalities of the urinary tract, a deficiency of abdominal musculature and bilateral cryptorchidism in males. We report a case of prune belly syndrome from Papua New Guinea, which was suspected on pregnancy ultrasound scan and confirmed upon delivery. CASE PRESENTATION: A 26 year-old married woman, Gravida 3 Para 2, presented to antenatal clinic in Madang, Papua New Guinea, at 21(+5) weeks' gestation by dates. She was well with no past medical or family history of note. She gave consent to participate in a clinical trial on prevention of malaria in pregnancy and underwent repeated ultrasound examinations which revealed a live fetus with persistent megacystis and anhydramnios. Both mother and clinicians agreed on conservative management of the congenital abnormality. The mother spontaneously delivered a male fetus weighing 2010 grams at 34 weeks' gestation with grossly abnormal genitalia including cryptorchidism, penile aplasia and an absent urethral meatus, absent abdominal muscles and hypoplastic lungs. The infant passed away two hours after delivery. This report discusses the implications of prenatal detection of severe congenital abnormalities in PNG. CONCLUSION: This first, formally reported, case of prune belly syndrome from a resource-limited setting in the Oceania region highlights the importance of identifying and documenting congenital abnormalities. Women undergoing antenatal ultrasound examinations must be carefully counseled on the purpose and the limitations of the scan. The increasing use of obstetric ultrasound in PNG will inevitably result in a rise in prenatal detection of congenital abnormalities. This will need to be met with adequate training, referral mechanisms and better knowledge of women's attitudes and beliefs on birth defects and ultrasound. National medicolegal guidance regarding induced abortion and resuscitation of a fetus with severe congenital abnormalities may be required. PMID- 23651556 TI - Degradation and mineralization of DDT by the ectomycorrhizal fungi, Xerocomus chrysenteron. AB - One strain of ectomycorrhizal fungi, Xerocomus chrysenteron, had been investigated for its ability to degrade 1,1,1-trichloro-2,2-bis(4-chlorophe-nyl) ethane (DDT) by measuring unlabeled DDT and identifying its metabolites, and determining the mineralization of [(13)C]DDT in pure cultures. After 45d incubation, about 55% of the added DDT disappeared from the culture system, less than 5% remained in the nutrient solution, and about 44% was retained in the mycelium. Inoculation with mycelium enhanced the degradation of DDT in soil, and alleviated enrichment of DDT in plants. The metabolites identified by gas chromatography-mass spectrometry were 1,1-dichloro-2,2-bis(4-chlorophenyl) ethane (DDD), 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (DDE), and 4,4' dichlorobenzophenone (DBP). There were significant differences in the delta(13)C of released CO2 between [(13)C]DDT and DDT cultures, which indicated X. chrysenteron was able to mineralize DDT to CO2. PMID- 23651557 TI - Trends in parameterization, economics and host behaviour in influenza pandemic modelling: a review and reporting protocol. AB - BACKGROUND: The volume of influenza pandemic modelling studies has increased dramatically in the last decade. Many models incorporate now sophisticated parameterization and validation techniques, economic analyses and the behaviour of individuals. METHODS: We reviewed trends in these aspects in models for influenza pandemic preparedness that aimed to generate policy insights for epidemic management and were published from 2000 to September 2011, i.e. before and after the 2009 pandemic. RESULTS: We find that many influenza pandemics models rely on parameters from previous modelling studies, models are rarely validated using observed data and are seldom applied to low-income countries. Mechanisms for international data sharing would be necessary to facilitate a wider adoption of model validation. The variety of modelling decisions makes it difficult to compare and evaluate models systematically. CONCLUSIONS: We propose a model Characteristics, Construction, Parameterization and Validation aspects protocol (CCPV protocol) to contribute to the systematisation of the reporting of models with an emphasis on the incorporation of economic aspects and host behaviour. Model reporting, as already exists in many other fields of modelling, would increase confidence in model results, and transparency in their assessment and comparison. PMID- 23651558 TI - The current development of CNS drug research. AB - In the past few years, several high profiled pharmaceutical companies have decided to shut down major research activities within the central nervous system (CNS) area. For example, in December 2011 Novartis announced that the company is closing its neuroscience facility in Basel, Switzerland, where Novartis is headquartered (Abbott, 2011). It follows similar moves by GlaxoSmithKline and AstraZeneca, both based in the UK, which in 2010 announced the closure of major parts of their neuroscience research divisions globally (Jack, Financial Times, 4 February 2010). Also companies primarily based in the USA, Pfizer and Merck, as well as the French company Sanofi, have pulled back on research into brain disorders. This development is still proceeding, as e.g. AstraZeneca closed their CNS/pain centres (Fiercebiotech, press release, 2 February 2012). Several of the companies have launched smaller new initiatives based on studies of genetics and biomarkers, but as mental disorders such as unipolar depression impose the largest disease burden worldwide, e.g. 6.2% disability-adjusted life year of total (WHO, 2008), and current treatments do not work particularly well for many patients, this has obviously raised a number of concerns related to how the future developments should be carried out, and whether the genetic approach may be sufficient. In June 2012, the International College of Neuropsychopharmacology (http://www.cinp.org) hosted an international workshop in order to discuss and consider the consequences and implications of the withdrawal of these research activities. This paper presents the problem background together with a summary of the viewpoints of the invited speakers and recommendations for future intervention. PMID- 23651559 TI - Quinolone alkaloids with antibacterial and cytotoxic activities from the fruits of Evodia rutaecarpa. AB - Five new quinolone alkaloids, euocarpines A-E (16-20), four new natural products (1, 4, 12, and 14), and eleven known natural products were isolated from the fruits of Evodia rutaecarpa (Juss.) Benth. The structures of the new compounds were elucidated based on spectroscopic evidence. All compounds were evaluated for their antibacterial activity against three strains and for their cytotoxic activity against four human tumor cell lines. The results revealed that 5, 7-11, 13, 14, and 16-20 exhibited moderate antibacterial activities (MIC values: 4-128 MUg/mL), and 9, 11, 14, and 17 exhibited moderate cytotoxic activities against HepG-2, Hela, BEL7402, and BEL7403 (IC50 values: 15.85-56.36 MUM). PMID- 23651560 TI - Pregnane alkaloids from Sarcococca hookeriana var. digyna. AB - Fourteen pregnane-type steroidal alkaloids were isolated from the ethanolic extracts of whole Sarcococca hookeriana var. digyna plants. Their structures were elucidated on the basis of spectral data. Three of them were identified as new steroidal alkaloids: (S)-20-(N,N-dimethylamino)-16alpha,17alpha-epoxy-3beta methoxy-pregn-5-ene (1), (20S)-20-(N,N-dimethylamino)-3beta-tigloylamino-5alpha pregn-11beta-ol (2), and (20S)-2alpha,4beta-bis(acetoxy)-20-(N,N-dimethylamino) 3beta-tigloylamino-5alpha-pregnane (3). Some of the isolated compounds showed estrogen biosynthesis-promoting effects in human ovarian granulosa-like KGN cells. The EC50 values for the most effective compounds, vagnine B (6) and funtumafrine C (12), were 71 MUM and 67 MUM, respectively. PMID- 23651561 TI - Transcriptome-wide comparison of sequence variation in divergent ecotypes of kokanee salmon. AB - BACKGROUND: High throughput next-generation sequencing technology has enabled the collection of genome-wide sequence data and revolutionized single nucleotide polymorphism (SNP) discovery in a broad range of species. When analyzed within a population genomics framework, SNP-based genotypic data may be used to investigate questions of evolutionary, ecological, and conservation significance in natural populations of non-model organisms. Kokanee salmon are recently diverged freshwater populations of sockeye salmon (Oncorhynchus nerka) that exhibit reproductive ecotypes (stream-spawning and shore-spawning) in lakes throughout western North America and northeast Asia. Current conservation and management strategies may treat these ecotypes as discrete stocks, however their recent divergence and low levels of gene flow make in-season genetic stock identification a challenge. The development of genome-wide SNP markers is an essential step towards fine-scale stock identification, and may enable a direct investigation of the genetic basis of ecotype divergence. RESULTS: We used pooled cDNA samples from both ecotypes of kokanee to generate 750 million base pairs of transcriptome sequence data. These raw data were assembled into 11,074 high coverage contigs from which we identified 32,699 novel single nucleotide polymorphisms. A subset of these putative SNPs was validated using high resolution melt analysis and Sanger resequencing to genotype independent samples of kokanee and anadromous sockeye salmon. We also identified a number of contigs that were composed entirely of reads from a single ecotype, which may indicate regions of differential gene expression between the two reproductive ecotypes. In addition, we found some evidence for greater pathogen load among the kokanee sampled in stream-spawning habitats, suggesting a possible evolutionary advantage to shore-spawning that warrants further study. CONCLUSIONS: This study provides novel genomic resources to support population genetic and genomic studies of both kokanee and anadromous sockeye salmon, and has the potential to produce markers capable of fine-scale stock assessment. While this RNAseq approach was successful at identifying a large number of new SNP loci, we found that the frequency of alleles present in the pooled transcriptome data was not an accurate predictor of population allele frequencies. PMID- 23651562 TI - Antibacterial effect of Manuka honey on Clostridium difficile. AB - BACKGROUND: Manuka honey originates from the manuka tree (Leptospermum scoparium) and its antimicrobial effect has been attributed to a property referred to as Unique Manuka Factor that is absent in other types of honey. Antibacterial activity of Manuka honey has been documented for several bacterial pathogens, however there is no information on Clostridium difficile, an important nosocomial pathogen. In this study we investigated susceptibility of C. difficile to Manuka honey and whether the activity is bactericidal or bacteriostatic. METHODS: Three C. difficile strains were subjected to the broth dilution method to determine minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) for Manuka honey. The agar well diffusion method was also used to investigate sensitivity of the C. difficile strains to Manuka honey. RESULTS: The MIC values of the three C. difficile strains were the same (6.25% v/v). Similarly, MBC values of the three C. difficile strains were the same (6.25% v/v). The activity of Manuka honey against all three C. difficile strains was bactericidal. A dose-response relationship was observed between the concentrations of Manuka honey and zones of inhibition formed by the C. difficile strains, in which increasing concentrations of Manuka honey resulted in increasing size of zone of inhibition formed. Maximum zone of inhibition was observed at 50% (v/v) Manuka honey and the growth inhibition persisted over 7 days. CONCLUSION: C. difficile is appreciably susceptible to Manuka honey and this may offer an effective way of treating infections caused by the organism. PMID- 23651563 TI - Proteomic approach to Pseudomonas aeruginosa adaptive resistance to benzalkonium chloride. AB - This study aimed to assess the membrane modifications in Pseudomonas aeruginosa after continuous exposure to increasing doses of benzalkonium chloride (BC). Two different concentrations were used, 0.9 and 12.0mM. Proteomic investigations revealed that the range of the outer membrane proteome alterations following continuous exposure is very low, i.e. about 10% and BC concentration dependent. Adapted cells revealed different expressions of key proteins frequently reported as involved in acquired resistance mechanisms. Porins (OprF and OprG) and lipoproteins (OprL and OprI) were underexpressed when the higher adaptation concentration (12 mM) was used. Some of these membrane alterations have been described as involved in the acquired resistance to antibiotics, suggesting possible common mechanisms between these two types of resistance. BIOLOGICAL SIGNIFICANCE: Results obtained after P. aeruginosa adaptation to benzalkonium chloride suggest that the bacterial adaptation to BC do not mobilize complete outer membrane systems. Though, we showed that adaptive resistance to BC promoted some changes in proteins previously described as involved in antibiotic resistance. These results contribute to the assumption that there are common resistance mechanisms, between adaptive and acquired resistance of P. aeruginosa. PMID- 23651564 TI - Proteomic analysis of glioblastomas: what is the best brain control sample? AB - Glioblastoma (GB) is the most frequent and aggressive tumor of the central nervous system. There is currently growing interest in proteomic studies of GB, particularly with the aim of identifying new prognostic or therapeutic response markers. However, comparisons between different proteomic analyses of GB have revealed few common differentiated proteins. The types of control samples used to identify such proteins may in part explain the different results obtained. We therefore tried to determine which control samples would be most suitable for GB proteomic studies. We used an isotope-coded protein labeling (ICPL) method followed by mass spectrometry to reveal and compare the protein patterns of two commonly used types of control sample: GB peritumoral brain zone samples (PBZ) from six patients and epilepsy surgery brain samples (EB) pooled from three patients. The data obtained were processed using AMEN software for network analysis. We identified 197 non-redundant proteins and 35 of them were differentially expressed. Among these 35 differentially expressed proteins, six were over-expressed in PBZ and 29 in EB, showing different proteomic patterns between the two samples. Surprisingly, EB appeared to display a tumoral-like expression pattern in comparison to PBZ. In our opinion, PBZ may be more appropriate control sample for GB proteomic analysis. BIOLOGICAL SIGNIFICANCE: This manuscript describes an original study in which we used an isotope-coded protein labeling method followed by mass spectrometry to identify and compare the protein patterns in two types of sample commonly used as control for glioblastoma (GB) proteomic analysis: peritumoral brain zone and brain samples obtained during surgery for epilepsy. The choice of control samples is critical for identifying new prognostic and/or diagnostic markers in GB. PMID- 23651565 TI - Proteome alterations monitored by DIGE analysis in Silybum marianum cell cultures elicited with methyl jasmonate and methyl B cyclodextrin. AB - Elicitation with methyl jasmonate (MeJA) or/and cyclodextrin (CD) strongly induced silymarin (Sm) accumulation in suspensions of Silybum marianum, with most of Sm isomers being detected in the culture medium. This induction provides a model platform to characterize the regulation of flavonolignan accumulation and release in response to elicitors and, with this aim, changes in the S. marianum cell proteome were investigated. The DIGE technique was used to detect statistically significant changes in the cell's proteome. A total number of 1269 unique spots were detected, 67 of which were de-regulated upon elicitation. Nineteen spots were identified by nLC-MS/MS database search analysis. Identified proteins belong to a few categories, including metabolism, stress and defense responses and transport processes. The most abundant group was represented by pathogenesis-related (PR) proteins and heat shock proteins. Two proteins related to transport process were identified and both were upregulated by elicitation. One was identified as Ras-related protein Rab11C of the Rab family of small ATPase superfamily. A second protein was identified as an ABC transporter. Some of the identified proteins are discussed with respect to their putative role in the extracellular flavonolignan accumulation in S. marianum cultures. BIOLOGICAL SIGNIFICANCE: Most approaches to increase secondary metabolite yields using plant cell cultures have been focused on the optimization of its biosynthesis. The study of other post biosynthetic events, like chemical or enzymatic modifications, transport, storage/secretion and catabolism/degradation are also biotechnologically relevant. Secretion is of particular interest since if cell cultures are to be used routinely for the commercial production, they must release the targeted metabolites into the extracellular medium. Elicitor-induced silymarin accumulation and release in S. marianum cell cultures provide a responsive model system to profile both alterations in proteins related to monolignol/flavonoid biosynthesis and to identify potential systems involved in secretion of secondary metabolites. The proteomic approach undertaken in this work has permitted identify some of the events occurring in elicited S. marianum cell cultures. One attainment of this study is that a vesicular transport mechanism could be involved in the release of this class of secondary metabolites to the extracellular compartment. This finding forms a baseline for future research on a non-sequenced medicinal plant S. marianum at molecular level. PMID- 23651566 TI - Special issue on epilepsy. PMID- 23651567 TI - Grafting of poly(2-methacryloyloxyethyl phosphorylcholine) on polyethylene liner in artificial hip joints reduces production of wear particles. AB - Despite improvements in the techniques, materials, and fixation of total hip arthroplasty, periprosthetic osteolysis, a complication that arises from this clinical procedure and causes aseptic loosening, is considered to be a major clinical problem associated with total hip arthroplasty. With the objective of reducing the production of wear particles and eliminating periprosthetic osteolysis, we prepared a novel hip polyethylene (PE) liner whose surface graft was made of a biocompatible phospholipid polymer-poly(2-methacryloyloxyethyl phosphorylcholine (MPC)). This study investigated the wear resistance of the poly(MPC)-grafted cross-linked PE (CLPE; MPC-CLPE) liner during 15*10(6) cycles of loading in a hip joint simulator. The gravimetric analysis showed that the wear of the acetabular liner was dramatically suppressed in the MPC-CLPE liner, as compared to that in the non-treated CLPE liner. Analyses of the MPC-CLPE liner surface revealed that it suffered from no or very little wear even after the simulator test, whereas the CLPE liners suffered from substantial wears. The scanning electron microscope (SEM) analysis of the wear particles isolated from the lubricants showed that poly(MPC) grafting dramatically decreased the total number, area, and volume of the wear particles. However, there was no significant difference in the particle size distributions, and, in particular, from the SEM image, it was observed that particles with diameters less than 0.50MUm were present in the range of the highest frequency. In addition, there were no significant differences in the particle size descriptors and particle shape descriptors. The results obtained in this study show that poly(MPC) grafting markedly reduces the production of wear particles from CLPE liners, without affecting the size of the particles. These results suggest that poly(MPC) grafting is a promising technique for increasing the longevity of artificial hip joints. PMID- 23651568 TI - On skin expansion. AB - This article discusses skin expansion without considering cellular growth of the skin. An in vivo analysis was carried out that involved expansion at three different sites on one patient, allowing for the observation of the relaxation process. Those measurements were used to characterize the human skin of the thorax during the surgical process of skin expansion. A comparison between the in vivo results and the numerical finite elements model of the expansion was used to identify the material elastic parameters of the skin of the thorax of that patient. Delfino's constitutive equation was chosen to model the in vivo results. The skin is considered to be an isotropic, homogeneous, hyperelastic, and incompressible membrane. When the skin is extended, such as with expanders, the collagen fibers are also extended and cause stiffening in the skin, which results in increasing resistance to expansion or further stretching. We observed this phenomenon as an increase in the parameters as subsequent expansions continued. The number and shape of the skin expanders used in expansions were also studied, both mathematically and experimentally. The choice of the site where the expansion should be performed is discussed to enlighten problems that can lead to frustrated skin expansions. These results are very encouraging and provide insight into our understanding of the behavior of stretched skin by expansion. To our knowledge, this study has provided results that considerably improve our understanding of the behavior of human skin under expansion. PMID- 23651569 TI - Volumetric three-dimensional intravascular ultrasound visualization using shape based nonlinear interpolation. AB - BACKGROUND: Intravascular ultrasound (IVUS) is a standard imaging modality for identification of plaque formation in the coronary and peripheral arteries. Volumetric three-dimensional (3D) IVUS visualization provides a powerful tool to overcome the limited comprehensive information of 2D IVUS in terms of complex spatial distribution of arterial morphology and acoustic backscatter information. Conventional 3D IVUS techniques provide sub-optimal visualization of arterial morphology or lack acoustic information concerning arterial structure due in part to low quality of image data and the use of pixel-based IVUS image reconstruction algorithms. In the present study, we describe a novel volumetric 3D IVUS reconstruction algorithm to utilize IVUS signal data and a shape-based nonlinear interpolation. METHODS: We developed an algorithm to convert a series of IVUS signal data into a fully volumetric 3D visualization. Intermediary slices between original 2D IVUS slices were generated utilizing the natural cubic spline interpolation to consider the nonlinearity of both vascular structure geometry and acoustic backscatter in the arterial wall. We evaluated differences in image quality between the conventional pixel-based interpolation and the shape-based nonlinear interpolation methods using both virtual vascular phantom data and in vivo IVUS data of a porcine femoral artery. Volumetric 3D IVUS images of the arterial segment reconstructed using the two interpolation methods were compared. RESULTS: In vitro validation and in vivo comparative studies with the conventional pixel-based interpolation method demonstrated more robustness of the shape-based nonlinear interpolation algorithm in determining intermediary 2D IVUS slices. Our shape-based nonlinear interpolation demonstrated improved volumetric 3D visualization of the in vivo arterial structure and more realistic acoustic backscatter distribution compared to the conventional pixel-based interpolation method. CONCLUSIONS: This novel 3D IVUS visualization strategy has the potential to improve ultrasound imaging of vascular structure information, particularly atheroma determination. Improved volumetric 3D visualization with accurate acoustic backscatter information can help with ultrasound molecular imaging of atheroma component distribution. PMID- 23651570 TI - The two directions of TNF-related apoptosis-inducing ligand in rheumatoid arthritis. AB - The TNF-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) superfamily that has been recognized for its specific pro apoptotic effect on cancer cells and has been therefore proposed as a treatment in cancer. Studies on animal models have shown that TRAIL could also have a beneficial effect in rheumatoid arthritis (RA). This includes reports suggesting that TRAIL could be used to control the synovial hyperplasia and hyperactivation of immune cells observed in RA, but recent reports suggest a disease promoting role of TRAIL in RA. Indeed, adverse effects and mechanism of resistance could counteract beneficial effect of TRAIL. This review focuses on the role of TRAIL in immune regulation, synovial hyperplasia and joint remodeling in RA. We will also discuss the potential use of TRAIL in RA treatment. PMID- 23651571 TI - A double signal amplification platform for ultrasensitive and simultaneous detection of ascorbic acid, dopamine, uric acid and acetaminophen based on a nanocomposite of ferrocene thiolate stabilized Fe3O4@Au nanoparticles with graphene sheet. AB - A double signal amplification platform for ultrasensitive and simultaneous detection of ascorbic acid (AA), dopamine (DA), uric acid (UA) and acetaminophen (AC) was fabricated by a nanocomposite of ferrocene thiolate stabilized Fe3O4@Au nanoparticles with graphene sheet. The platform was constructed by coating a newly synthesized phenylethynyl ferrocene thiolate (Fc-SAc) modified Fe3O4@Au NPs coupling with graphene sheet/chitosan (GS-chitosan) on a glassy carbon electrode (GCE) surface. The Fe3O4@Au-S-Fc/GS-chitosan modified GCE exhibits a synergistic catalytic and amplification effect toward AA, DA, UA and AC oxidation. The oxidation peak currents of the four compounds on the electrode were linearly dependent on AA, DA, UA and AC concentrations in the ranges of 4-400 MUM, 0.5-50 MUM, 1-300 MUM and 0.3-250 MUM in the individual detection of each component, respectively. By simultaneously changing the concentrations of AA, DA, UA and AC, their electrochemical oxidation peaks appeared at -0.03, 0.15, 0.24 and 0.35 V, and good linear current responses were obtained in the concentration ranges of 6 350, 0.5-50, 1-90 and 0.4-32 MUM with the detection limits of 1, 0.1, 0.2 and 0.05 MUM (S/N=3), respectively. PMID- 23651572 TI - DNA stabilized silver nanoclusters for ratiometric and visual detection of Hg2+ and its immobilization in hydrogels. AB - DNA oligomers are particularly interesting templates for making silver nanoclusters (AgNCs) as different emission colors can be obtained by varying the DNA sequence. Many AgNCs have been used as Hg2+ sensors since Hg2+ induces fluorescence quenching. From an analytical chemistry standpoint, however, these 'light off' sensors are undesirable. In this work, taking advantage of the fact that some AgNCs are not as effectively quenched by Hg2+, we design a sensor with AgNCs containing two emission peaks. The red peak is strongly quenched by Hg2+ while the green peak shows a concomitant increase, producing an orange-to-green visual fluorescence transformation. Using this AgNC, we demonstrate ratiometric detection with a detection limit of 4 nM Hg2+. This sensor is further immobilized in a hydrogel matrix and this gel is also capable of detecting Hg2+ with a visual response. PMID- 23651573 TI - Construction of near-infrared photonic crystal glucose-sensing materials for ratiometric sensing of glucose in tears. AB - Noninvasive monitoring of glucose in tears is highly desirable in tight glucose control. The polymerized crystalline colloidal array (PCCA) that can be incorporated into contact lens represents one of the most promising materials for noninvasive monitoring of glucose in tears. However, low sensitivity and slow time response of the PCCA reported in previous arts has limited its clinical utility. This paper presents a new PCCA, denoted as NIR-PCCA, comprising a CCA of glucose-responsive sub-micrometered poly(styrene-co-acrylamide-co-3 acrylamidophenylboronic acid) microgels embedded within a slightly positive charged hydrogel matrix of poly(acrylamide-co-2-(dimethylamino)ethyl acrylate). This newly designed NIR-PCCA can reflect near-infrared (NIR) light, whose intensity (at 1722 nm) would decrease evidently with increasing glucose concentration over the physiologically relevant range in tears. The lowest glucose concentration reliably detectable was as low as ca. 6.1 MUg/dL. The characteristic response time tau(sensing) was 22.1+/-0.2s when adding glucose to 7.5 mg/dL, and the higher the glucose concentration is, the faster the time response. Such a rationally designed NIR-PCCA is well suited for ratiometric NIR sensing of tear glucose under physiological conditions, thereby likely to bring this promising glucose-sensing material to the forefront of analytical devices for diabetes. PMID- 23651574 TI - Benefits of early tracheotomy: a meta-analysis based on 6 observational studies. AB - BACKGROUND: Whether early tracheotomy can improve the clinical outcomes of critically ill patients remains controversial. The current study aimed to discuss the potential benefits of early tracheotomy compared to late tracheotomy with meta-analysis of observational studies. METHODS: An electronic search (up to February 28, 2013) was conducted by a uniform requirement, and then clinical data satisfying the predefined inclusion criteria were extracted. RESULTS: Data from a total of 2,037 subjects were included from 6 observational retrospective studies. Meta-analysis suggested that early tracheotomy was associated with significant reductions in mortality (odds ratio 0.77, 95% CI 0.62-0.96), duration of mechanical ventilation (mean difference -10.04, 95% CI -15.15 to -4.92), ICU stay (mean difference -8.80 d, 95% CI -9.71 to -7.89 d), and hospital stay (mean difference -12.18 d, 95% CI -18.25 to -6.11 d). However, as compared with late tracheotomy, early tracheotomy did not reduce the incidence of ventilator associated pneumonia. CONCLUSIONS: Our meta-analysis of retrospective observational studies suggests that early tracheotomy performed between days 3 and 7 after intubation had some advantages, including decreased mortality and reduced ICU stay, hospital stay, and mechanical ventilation duration in ICU patients. PMID- 23651575 TI - Impact and predictors of prolonged chest tube duration in mechanically ventilated patients with acquired pneumothorax. AB - BACKGROUND: Prolonged chest tube duration is less well studied in patients who are supported by mechanical ventilation and have acquired pneumothorax. We investigated the impact of prolonged chest tube duration on patient outcomes and the risk factors associated with prolonged chest tube duration. METHODS: This retrospective observational study included 106 ventilated subjects who had been treated with thoracostomy for pneumothorax between May 2004 and December 2011. We analyzed 61 subjects and 63 events. The subjects were divided into a prolonged chest tube duration group (> 18 d) and a non-prolonged group (<= 18 d). RESULTS: Subjects with prolonged chest tube duration had significantly higher ICU mortality (P = .006), longer ICU stay (P = .001), longer hospitalization (P = .004), longer mechanical ventilation after development of pneumothorax (P = .003), higher maximum peak inspiratory pressure (P = .03), and a higher rate of surgical emphysema (P = .009). High peak inspiratory pressure and surgical emphysema remained independent predictors of prolonged chest tube duration after multivariate logistic regression analysis. The probability of chest tube removal within 28 days was significantly lower in subjects with both high peak inspiratory pressure and surgical emphysema, compared to subjects without any risk factors (log rank P = .001). CONCLUSIONS: High peak inspiratory pressure and surgical emphysema are independent predictors of prolonged chest tube duration and negatively impact clinical outcomes in this patient group. These findings may provide information for better chest tube management. PMID- 23651576 TI - Mechanisms of cisplatin ototoxicity: theoretical review. AB - INTRODUCTION: Cisplatin is an effective chemotherapeutic agent commonly used in the treatment of malignant tumours, but ototoxicity is a significant side effect. OBJECTIVES: To discuss the mechanisms of cisplatin ototoxicity and subsequent cell death, and to present the results of experimental studies. MATERIAL AND METHODS: We conducted a systematic search for data published in national and international journals and books, using the Medline, SciELO, Bireme, LILACS and PubMed databases. RESULTS: The nicotinamide adenine dinucleotide phosphate oxidase 3 isoform (also termed NOX3) seems to be the main source of reactive oxygen species in the cochlea. These reactive oxygen species react with other molecules and trigger processes such as lipid peroxidation of the plasma membrane and increases in expression of the transient vanilloid receptor potential 1 ion channel. CONCLUSION: Cisplatin ototoxicity proceeds via the formation of reactive oxygen species in cochlear tissue, with apoptotic cell death as a consequence. PMID- 23651577 TI - Epidemiological analysis of respiratory viral etiology for influenza-like illness during 2010 in Zhuhai, China. AB - BACKGROUND: Influenza-like illnesses (ILI), a subset of acute respiratory infections (ARI), are a significant source of morbidity and mortality worldwide. ILI can be caused by numerous pathogens, however; there is limited information on the etiology and epidemiology of ILI in China. METHODS: We performed a one-year surveillance study (2010) of viral etiology causing ILI and investigated the influence of climate on outbreaks of ILI attributed to viruses at the Outpatient Department of Zhuhai Municipal People's Hospital in Zhuhai, China. RESULTS: Of the 337,272 outpatients who sought attention in the Outpatient Department of Zhuhai Municipal People's Hospital in 2010, 3,747 (1.11%) presented with ILI. Of these patients presenting with ILI, 24.66% (924/3,747) had available samples and were enrolled in this study. At least one respiratory virus was identified in 411 patients (44.48%) and 42 (4.55%) were co-infected with two viruses. In patients co-infected with two viruses, respiratory syncytial virus (RSV) was detected in 50% (21/42). Among common viral pathogens detected, significant differences in age distributions were observed in seasonal influenza virus A (sFulA, H3N2) and B (sFluB), pandemic H1N1 2009 influenza viruses (H1N1pdm09), RSV, and adenovirus (ADV). Infections with sFluA (H3N2), sFluB, RSV, and human metapneumovirus (HMPV) had characteristic seasonal patterns. The incidences of sFluA (H3N2), ADV, and RSV correlated with air temperature. Alternatively, the incidence of sFluB correlated with relative air humidity. CONCLUSIONS: These results demonstrate that a wide range of respiratory viral pathogens are circulating in Zhuhai city. This information needs to be considered by clinicians when treating patients presenting with ILI. PMID- 23651578 TI - Strengths and weaknesses of parent-staff communication in the NICU: a survey assessment. AB - BACKGROUND: Parents of infants hospitalized in the neonatal intensive care unit (NICU) find themselves in a situation of emotional strain. Communication in the NICU presents special challenges due to parental stress and the complexity of the highly technologized environment. Parents' need for communication may not always be met by the NICU staff. This study aimed to describe strengths and weaknesses of parent-nurse and parent-doctor communication in a large level III NICU in Sweden in order to improve our understanding of parents' communication needs. METHODS: Parents were asked to complete a survey consisting of sixteen questions about their experiences of communication with nurses and doctors in the NICU. In each question the parents evaluated some aspect of communication on a five- or six-point Likert scale. They also had the opportunity on each question to comment on their experiences in their own words. Data were analyzed using IBM SPSS Statistics 20.0 and qualitative manifest content analysis. RESULTS: 270 parents (71.4%) completed the survey. Parents generally rated communication with the staff in the NICU positively and appreciated having received emotional support and regular information about their child's care. Although a large majority of the parents were satisfied with their communication with doctors and nurses, only about half of the parents felt the nurses and doctors understood their emotional situation very well. Some parents would have desired easier access to conversations with doctors and wanted medical information to be given directly by doctors rather than by nurses. Parents' communication with the staff was hampered when many different nurses were involved in caring for the infant or when the transfer of information in connection with shift changes or between the maternity ward and NICU was poor. Parents also desired to be present during doctors' rounds on their infant. CONCLUSIONS: Training both doctors and nurses in communication skills, especially in how to meet parents' emotional needs better, could make communication at the NICU more effective and improve parental well-being. Creating a framework for the parents of what to expect from NICU communication might also be helpful. In addition, our results support the use of primary nurse teams to improve continuity of care and thereby promote successful communication. PMID- 23651579 TI - Foot orthoses for the management of low back pain: a qualitative approach capturing the patient's perspective. AB - BACKGROUND: The onset of non specific low back pain is associated with heavy lifting, age, female gender, and poor general health, with psychological factors being predictors of it becoming chronic. Additionally, it is thought that altered lower limb biomechanics are a contributory factor, with foot orthoses increasingly being considered as an appropriate intervention by physiotherapists and podiatrists. However, research into the effect of foot orthoses is inconclusive, primarily focusing on the biomechanical effect and not the symptomatic relief from the patient's perspective. The aim of this study was to explore the breadth of patients' experiences of being provided with foot orthoses and to evaluate any changes in their back pain following this experience. METHOD: Following ethical approval, participants (n = 25) with non-specific low back pain associated with altered lower limb biomechanics were provided with customised foot orthoses. At 16 weeks after being provided with the foot orthoses, conversational style interviews were carried out with each patient. An interpretivistic phenomenological approach was adopted for the data collection and analysis. RESULTS: For these participants, foot orthoses appeared to be effective. However, the main influence on this outcome was the consultation process and a patient focussed approach. The consultation was an opportunity for fostering mutual understanding, with verbal and visual explanation reassuring the patient and this influenced the patient's beliefs, their engagement with the foot orthoses (physical) and their experience of low back pain (psychological). CONCLUSION: Clinicians need to adopt 'psychologically informed practice' in relation to the provision of foot orthoses. Likewise, researchers should consider all the influencing factors found in this study, both in relation to their study protocol and the outcomes they plan to measure. PMID- 23651580 TI - Sex steroid hormones modulate responses to social challenge and opportunity in males of the monogamous convict cichlid, Amatitliana nigrofasciata. AB - Steroid hormones play an important role in modulating behavioral responses to various social stimuli. It has been suggested that variation in the hormonal regulation of behavior across species is associated with social organization and/or mating system. In order to further elucidate the interplay of hormones and behavior in social situations, we exposed males of the monogamous convict cichlid Amatitliana nigrofasciata to three social stimuli: gravid female, intruder male, and a nonsocial stimulus. We used a repeated measure design to create behavioral profiles and explore how sex steroid hormones respond to and regulate social behavior. Results show distinct behavioral responses to different social situations, with circulating 11-ketotestosterone increasing in response to social stimuli. Pharmacological manipulations using specific androgen and estrogen receptor agonists and antagonists exposed complex control over digging behavior in the social opportunity context. In the social challenge context, aggressive behaviors decreased in response to blocking the androgen receptor pathway. Our results extend our understanding of sex steroid regulation of behavioral responses to social stimulation. PMID- 23651581 TI - Short and long-term genome stability analysis of prokaryotic genomes. AB - BACKGROUND: Gene organization dynamics is actively studied because it provides useful evolutionary information, makes functional annotation easier and often enables to characterize pathogens. There is therefore a strong interest in understanding the variability of this trait and the possible correlations with life-style. Two kinds of events affect genome organization: on one hand translocations and recombinations change the relative position of genes shared by two genomes (i.e. the backbone gene order); on the other, insertions and deletions leave the backbone gene order unchanged but they alter the gene neighborhoods by breaking the syntenic regions. A complete picture about genome organization evolution therefore requires to account for both kinds of events. RESULTS: We developed an approach where we model chromosomes as graphs on which we compute different stability estimators; we consider genome rearrangements as well as the effect of gene insertions and deletions. In a first part of the paper, we fit a measure of backbone gene order conservation (hereinafter called backbone stability) against phylogenetic distance for over 3000 genome comparisons, improving existing models for the divergence in time of backbone stability. Intra- and inter-specific comparisons were treated separately to focus on different time-scales. The use of multiple genomes of a same species allowed to identify genomes with diverging gene order with respect to their conspecific. The inter-species analysis indicates that pathogens are more often unstable with respect to non-pathogens. In a second part of the text, we show that in pathogens, gene content dynamics (insertions and deletions) have a much more dramatic effect on genome organization stability than backbone rearrangements. CONCLUSION: In this work, we studied genome organization divergence taking into account the contribution of both genome order rearrangements and genome content dynamics. By studying species with multiple sequenced genomes available, we were able to explore genome organization stability at different time-scales and to find significant differences for pathogen and non-pathogen species. The output of our framework also allows to identify the conserved gene clusters and/or partial occurrences thereof, making possible to explore how gene clusters assembled during evolution. PMID- 23651582 TI - Neurogenic potential of hESC-derived human radial glia is amplified by human fetal cells. AB - The efficient production of human neocortical neurons from human embryonic stem cells (hESC) is the primary requirement for studying early stages of human cortical development. We used hESC to obtain radial glial cells (hESC-RG) and then compared them with RG cells isolated from human fetal forebrain. Fate of hESC-RG cells critically depends on intrinsic and extrinsic factors. The expression of Pax6 (intrinsic factor) has a similar neurogenic effect on hESC-RG differentiation as reported for human fetal RG cells. Factors from the microenvironment also play a significant role in determining hESC-RG cell fate. In contrast to control cultures, wherein hESC-RG generate mainly astroglia and far fewer neurons, in co-cultures with human fetal forebrain cells, the reverse was found to be true. This neurogenic effect was partly due to soluble factors from human fetal brain cultures. The detected shift towards neurogenesis has significance for developing future efficient neuro-differentiation protocols. Importantly, we established that hESC-RG cells are similar in many respects to human fetal RG cells, including their proliferative capacity, neurogenic potential, and ability to generate various cortical neuronal sub-types. Unlike fetal RG cells, the hESC-RG cells are readily available and can be standardized, features that have considerable practical advantages in research and clinics. PMID- 23651583 TI - Resveratrol promotes proteasome-dependent degradation of Nanog via p53 activation and induces differentiation of glioma stem cells. AB - Glioblastoma is the most common and aggressive primary brain tumor. Glioma stem cells (GSCs) are relatively resistant to chemo-radiotherapy and are responsible for tumor progression and the recurrence of glioblastomas after conventional therapy. Thus, the control of the GSC population is considered key to realizing long-term survival of glioblastoma patients. Here, we identified that resveratrol significantly reduced the self-renewal and tumor-initiating capacity of patient derived GSCs. Furthermore, resveratrol promoted Nanog suppression via proteasomal degradation, which was inhibited by MG132, a proteasome inhibitor. p53 activation is an important factor in Nanog suppression and treatment with resveratrol was also found to activate the p53/p21 pathway. Importantly, inhibition of Nanog by siRNA provoked inhibitory effects on both the self-renewal and tumor-forming capacity of GSCs. Our findings indicate that Nanog is an essential factor for the retention of stemness and may contribute to the resveratrol-induced differentiation of GSCs. Our results also suggest that targeting GSCs via the p53 Nanog axis, with resveratrol for instance, could be a therapeutic strategy against glioblastoma. PMID- 23651584 TI - Adenosine A1 receptor stimulation enhances osteogenic differentiation of human dental pulp-derived mesenchymal stem cells via WNT signaling. AB - In this study, mesenchymal stem cells deriving from dental pulp (DPSCs) of normal human impacted third molars, previously characterized for their ability to differentiate into osteoblasts, were used. We observed that: i) DPSCs, undifferentiated or submitted to osteogenic differentiation, express all four subtypes of adenosine receptors (AR) and CD73, corresponding to 5'-ecto nucleotidase; and ii) AR stimulation with selective agonists elicited a greater osteogenic cell differentiation consequent to A1 receptor (A1R) activation. Therefore, we focused on the activity of this AR. The addition of 15-60nM 2 chloro-N(6)-cyclopentyl-adenosine (CCPA), A1R agonist, to DPSCs at each change of the culture medium significantly increased the proliferation of cells grown in osteogenic medium after 8days in vitro (DIV) without modifying that of undifferentiated DPSCs. Better characterizing the effect of A1R stimulation on the osteogenic differentiation capability of these cells, we found that CCPA increased the: i) expression of two well known and early osteogenic markers, RUNX 2 and alkaline phosphatase (ALP), after 3 and 7DIV; ii) ALP enzyme activity at 7DIV and iii) mineralization of extracellular matrix after 21DIV. These effects, abolished by cell pre-treatment with the A1R antagonist 8-cyclopentyl-1,3 dipropyl-xanthine (DPCPX), involved the activation of the canonical Wnt signaling as, in differentiating DPSCs, CCPA significantly increased dishevelled protein and inhibited glycogen synthase kinase-3beta, both molecules being downstream of Wnt receptor signal pathway. Either siRNA of dishevelled or cell pre-treatment with Dickkopf-1, known inhibitor of Wnt signaling substantially reduced either DPSC osteogenic differentiation or its enhancement promoted by CCPA. Summarizing, our findings indicate that the stimulation of A1R may stimulate DPSC duplication enhancing their osteogenic differentiation efficiency. These effects may have clinical implications possibly facilitating bone tissue repair and remodeling. PMID- 23651585 TI - Long-term repopulating hematopoietic stem cells and "side population" in human steady state peripheral blood. AB - This report brings the first experimental evidence for the presence of long-term (LT) repopulating hematopoietic stem cells (HSCs) and Side Population (SP) cells within human steady state peripheral blood CD34(+) cells. Ex vivo culture, which reveals the LT-HSC, also increases short-term (ST) HSC engraftment capacity and SP cell number (as well as the SP subpopulations defined on the basis of CD38, CD90 and CD133 expression) which are very low in freshly isolated cells. Thus, ex vivo incubation either allows the expansion of the small fraction of HSCs or reveals "Scid Repopulating Cells - SRC" that are present in the initial CD34(+) cell population but unable to engraft. In addition, among these CD34(+) cells, we confirm the presence of committed progenitors at frequencies similar to those found in cord blood CD34(+) cells. These cells, obtained from leukoreduction filters (LRFs) and rejected in the course of the preparation of red blood cell concentrates, are an abundant and reliable material for obtaining committed progenitors, short- and long-term HSCs of therapeutic interest, especially after the ex vivo expansion phase. Our results open a perspective to set up new therapeutic protocols using expanded LRFs-recovered CD34(+) cells as a source of HSCs for autologous or allogeneic transplantation. PMID- 23651586 TI - Material modifications for the alkaline differential extraction method for sexual assault evidence. PMID- 23651587 TI - Onset of puberty and normal histological appearances of the reproductive organs in peripubertal female Gottingen minipigs. AB - In preclinical studies, it is important to know whether the animals used are sexually mature or not. Precise data have not yet been published, however, about the histological features of the female reproductive organs during the peripubertal period or about the age of acquisition of sexual maturity in the minipig. The histological characteristics of the genital organs of female control minipigs from toxicology studies were described and, based on the presence of ovarian corpora lutea, used to assess the age at which maturity was reached. Only 50% of females can be considered mature at about 6.5 months old (a body weight of 11.8 kg), and 100% were not mature until about 7.5 months old (13.1 kg), although it is said that females reach sexual maturity at the age of approximately 5 months, by the time the body weight is about 10 to 12 kg. The uterine weights of mature females were higher than 94.4 g, whereas the maximum weight reached in the immature females was 55.2 g. In contrast, the differences between immature and mature ovarian weights were not significant. The histological appearance of the mature vagina in the various stages of the estrous cycle is also described. PMID- 23651588 TI - Intermittent oral coadministration of a gamma secretase inhibitor with dexamethasone mitigates intestinal goblet cell hyperplasia in rats. AB - Dexamethasone was given in 2 oral dosing regimens with repeat dose oral administration of the gamma secretase inhibitor (GSI), PF-03084014, in Sprague Dawley (SD) rats in order to evaluate the effects of coadministration of dexamethasone on GSI-induced goblet cell hyperplasia (GCH) in the intestinal tract. Safety end points were evaluated in 1 week and 1 month studies. The dosing regimens tested in the 1-month studies included a 1-week pretreatment with 1.0 mg/kg dexamethasone followed by a 3-week repeat dose treatment with 100 mg/kg GSI or concurrent intermittent treatment with 1.0 mg/kg dexamethasone on weeks 1 and 3 and repeat dose treatment with 100 mg/kg GSI for 4 weeks. Pretreatment with dexamethasone for 1 week transiently mitigated the severity of intestinal GCH for up to 1 week. Intermittent coadministration of dexamethasone on weeks 1 and 3 with GSI repeat dosing for 4 weeks mitigated intestinal GCH for up to 4 weeks post treatment. Treatment-related morbidity and mortality occurred on day 7 with 150 mg/kg GSI and 5 mg/kg dexamethasone coadministration, and on days 13, 14, and 23 with 100 mg/kg GSI and 1 mg/kg dexamethasone coadministration. PMID- 23651589 TI - Expression of HPV16 E5 down-modulates the TGFbeta signaling pathway. AB - BACKGROUND: Infection with high-risk human papillomavirus (HR-HPV) genotypes, mainly HPV16 and HPV18, is a major risk factor for cervical cancer and responsible for its progression. While the transforming role of the HPV E6 and E7 proteins is more characterized, the molecular mechanisms of the oncogenic activity of the E5 product are still only partially understood, but appear to involve deregulation of growth factor receptor expression. Since the signaling of the transforming growth factor beta (TGFbeta) is known to play crucial roles in the epithelial carcinogenesis, aim of this study was to investigate if HPV16 E5 would modulate the TGF-BRII expression and TGFbeta/Smad signaling. FINDINGS: The HPV16 E5 mRNA expression pattern was variable in low-grade squamous intraepithelial lesions (LSIL), while homogeneously reduced in high-grade lesions (HSIL). Parallel analysis of TGFBRII mRNA showed that the receptor transcript levels were also variable in LSILs and inversely related to those of the viral protein. In vitro quantitation of the TGFBRII mRNA and protein in human keratinocytes expressing 16E5 in a dose-dependent and time-dependent manner showed a progressive down-modulation of the receptor. Phosphorylation of Smad2 and nuclear translocation of Smad4 were also decreased in E5-expressing cells stimulated with TGFbeta1. CONCLUSIONS: Taken together our results indicate that HPV16 E5 expression is able to attenuate the TGFbeta1/Smad signaling and propose that this loss of signal transduction, leading to destabilization of the epithelial homeostasis at very early stages of viral infection, may represent a crucial mechanism of promotion of the HPV-mediated cervical carcinogenesis. PMID- 23651590 TI - De novo transcriptome sequencing and comparative analysis of differentially expressed genes in Gossypium aridum under salt stress. AB - Salinity stress is one of the most serious factors that impede the growth and development of various crops. Wild Gossypium species, which are remarkably tolerant to salt water immersion, are valuable resources for understanding salt tolerance mechanisms of Gossypium and improving salinity resistance in upland cotton. To generate a broad survey of genes with altered expression during various stages of salt stress, a mixed RNA sample was prepared from the roots and leaves of Gossypium aridum plants subjected to salt stress. The transcripts were sequenced using the Illumina sequencing platform. After cleaning and quality checks, approximately 41.5 million clean reads were obtained. Finally, these reads were eventually assembled into 98,989 unigenes with a mean size of 452 bp. All unigenes were compared to known cluster of orthologous groups (COG) sequences to predict and classify the possible functions of these genes, which were classified into at least 25 molecular families. Variations in gene expression were then examined after exposing the plants to 200 mM NaCl for 3, 12, 72 or 144 h. Sequencing depths of approximately six million raw tags were achieved for each of the five stages of salt stress. There were 2634 (1513 up-regulated/1121 down regulated), 2449 (1586 up-regulated/863 down-regulated), 2271 (946 up regulated/1325 down-regulated) and 3352 (933 up-regulated/2419 down-regulated) genes that were differentially expressed after exposure to NaCl for 3, 12, 72 and 144 h, respectively. Digital gene expression analysis indicated that pathways involved in "transport", "response to hormone stimulus" and "signaling" play important roles during salt stress, while genes involved in "protein kinase activity" and "transporter activity" undergo major changes in expression during early and later stages of salt stress, respectively. PMID- 23651591 TI - Association of polymorphisms in the interleukin-4 gene with response to hepatitis B vaccine and susceptibility to hepatitis B virus infection: a meta-analysis. AB - OBJECTIVE: The aim of this meta-analysis is to evaluate the associations between functional polymorphisms in the interleukin-4 (IL4) gene and individuals' responses to hepatitis B vaccine and their susceptibility to hepatitis B virus (HBV) infection. METHODS: A literature search on articles published before December 1st, 2012 was conducted in PubMed, Embase, Web of Science and China BioMedicine (CBM) databases. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistical analyses were performed using the STATA 12.0 software. RESULTS: Eight studies were eligible for inclusion in this meta-analysis, including five cross-sectional studies on individual's response to hepatitis B vaccine and three case-control studies on HBV infection risk. The meta-analysis results showed that the T allele of rs2243250, the T allele of rs2070874, and the C allele of rs2227284 in IL4 gene were associated with high responses to hepatitis B vaccine. Further subgroup analysis by ethnicity showed that there was a significant association between IL4 genetic polymorphisms and an individual's responses to hepatitis B vaccine among Asian populations, but similar association was not found among Caucasian populations. However, there was no evidence indicating a correlation between IL4 genetic polymorphism and susceptibility to HBV infection. CONCLUSION: Our current meta-analysis suggests that rs2243250, rs2070874 and rs2227284 polymorphisms in IL4 gene may play an important role in determining the response to hepatitis B vaccine, especially among Asian populations. However, further studies are still needed to evaluate the associations between IL4 genetic polymorphisms and HBV infection risk. PMID- 23651593 TI - Screening and expression of genes from metagenomes. AB - Microorganisms are the most abundant and widely spread organisms on earth. They colonize a huge variety of natural and anthropogenic environments, including very specialized ecological niches and even extreme habitats, which are made possible by the immense metabolic diversity and genetic adaptability of microbes. As most of the organisms from environmental samples defy cultivation, cultivation independent metagenomics approaches have been applied since more than one decade to access and characterize the phylogenetic diversity in microbial communities as well as their metabolic potential and ecological functions. Thereby, metagenomics has fully emerged as an own scientific field for mining new biocatalysts for many industrially relevant processes in biotechnology and pharmaceutics. This review summarizes common metagenomic approaches ranging from sampling, isolation of nucleic acids, construction of metagenomic libraries and their evaluation. Sequence-based screenings implement next-generation sequencing platforms, microarrays or PCR-based methods, while function-based analysis covers heterologous expression of metagenomic libraries in diverse screening setups. Major constraints and advantages of each strategy are described. The importance of alternative host-vector systems is discussed, and in order to underline the role of phylogenetic and physiological distance from the gene donor and the expression host employed, a case study is presented that describes the screening of a genomic library from an extreme thermophilic bacterium in both Escherichia coli and Thermus thermophilus. Metatranscriptomics, metaproteomics and single cell-based methods are expected to complement metagenomic screening efforts to identify novel biocatalysts from environmental samples. PMID- 23651594 TI - The Escherichia coli Nucleoid in Stationary Phase. AB - Compaction of DNA is an essential phenomenon that affects all facets of cellular biology. Surprisingly, given the abundance and apparent simplicity of bacteria, our understanding of chromosome organization in these ancient organisms is inadequate. In this chapter we will focus on arguably the best understood aspect of DNA folding in the model bacterium Escherichia coli: the supercondensation of the chromosome that occurs during periods of starvation and stress. PMID- 23651595 TI - Living with Stress: A Lesson from the Enteric Pathogen Salmonella enterica. AB - The ability to sense and respond to the environment is essential for the survival of all living organisms. Bacterial pathogens such as Salmonella enterica are of particular interest due to their ability to sense and adapt to the diverse range of conditions they encounter, both in vivo and in environmental reservoirs. During this cycling from host to non-host environments, Salmonella encounter a variety of environmental insults ranging from temperature fluctuations, nutrient availability and changes in osmolarity, to the presence of antimicrobial peptides and reactive oxygen/nitrogen species. Such fluctuating conditions impact on various areas of bacterial physiology including virulence, growth and antimicrobial resistance. A key component of the success of any bacterial pathogen is the ability to recognize and mount a suitable response to the discrete chemical and physical stresses elicited by the host. Such responses occur through a coordinated and complex programme of gene expression and protein activity, involving a range of transcriptional regulators, sigma factors and two component regulatory systems. This review briefly outlines the various stresses encountered throughout the Salmonella life cycle and the repertoire of regulatory responses with which Salmonella counters. In particular, how these Gram-negative bacteria are able to alleviate disruption in periplasmic envelope homeostasis through a group of stress responses, known collectively as the Envelope Stress Responses, alongside the mechanisms used to overcome nitrosative stress, will be examined in more detail. PMID- 23651596 TI - Chitin and glucan, the yin and yang of the fungal cell wall, implications for antifungal drug discovery and therapy. AB - The structural carbohydrate polymers glucan and chitin compliment and reinforce each other in a dynamic process to maintain the integrity and physical strength of the fungal cell wall. The assembly of chitin and glucan in the cell wall of the budding yeast Saccharomyces cerevisiae and the polymorphic human pathogen Candida albicans are essential processes that involve a range of fungal-specific enzymes and regulatory networks. The fungal cell wall is, therefore, an attractive target for novel therapies as host cells lack many cell wall-related proteins. The most recent class of antifungal drug approved for clinical use, the echinocandins, targets the synthesis of cell wall beta(1-3)glucan. The echinocandins are effective at treating invasive and bloodstream Candida infections and are now widely used in the clinic. However, there have been sporadic reports of breakthrough infections in patients undergoing echinocandin therapy. The acquisition of point mutations in the FKS genes that encode the catalytic beta(1-3)glucan synthase subunits, the target of the echinocandins, has emerged as a dominant resistance mechanism. Cells with elevated chitin levels are also less susceptible to echinocandins and in addition, treatment with sub-MIC echinocandin activates cell wall salvage pathways that increase chitin synthesis to compensate for reduced glucan production. The development of drugs targeting the cell wall has already proven to be beneficial in providing an alternative class of drug for use in the clinic. Other cell wall targets such as chitin synthesis still hold great potential for drug development but careful consideration should be given to the capacity of fungi to manipulate their walls in a dynamic response to cell wall perturbations. PMID- 23651597 TI - Risk factors associated with overweight and obesity among urban school children and adolescents in Bangladesh: a case-control study. AB - BACKGROUND: Childhood obesity has become an emerging urban health problem in urban cities in Bangladesh, particularly in affluent families. Risk factors for obesity in this context have not been explored yet. The objective of this study was to identify the risk factors associated with overweight and obesity among school children and adolescents in Dhaka, Bangladesh. METHODS: From October through November 2007, we conducted a case-control study among children aged 10 15 years in seven schools in Dhaka. We assessed body mass index (weight in kg/height in sq. meter) to identify the cases (overweight/obese) and controls (healthy/normal weight) following the Centers for Disease Control and Prevention age and sex specific growth chart. We used a structured questionnaire to collect demographic information and respondent's exposure to several risk factors such as daily physical activity at home and in school, hours spent on computer games and television watching, maternal education level and parents' weight and height. RESULTS: We enrolled 198 children: 99 cases, 99 controls. Multiple logistic regression analysis revealed that having at least one overweight parent (OR = 2.8, p = 0.001) and engaging in sedentary activities for >4 hours a day (OR = 2.0, p = 0.02) were independent risk factors for childhood overweight and/or obesity while exercising >= 30 minutes a day at home was a protective factor (OR = 0.4, p = 0.02). There were no significant associations between childhood overweight and sex, maternal education or physical activity at school. CONCLUSION: Having overweight parents along with limited exercise and high levels of sedentary activities lead to obesity among school children in urban cities in Bangladesh. Public health programs are needed to increase awareness on risk factors for overweight and obesity among children and adolescents in order to reduce the future burden of obesity-associated chronic diseases. PMID- 23651598 TI - A new electrochemically active bacterium phylogenetically related to Tolumonas osonensis and power performance in MFCs. AB - A facultative anaerobic bacterium (designated as P2-A-1) was isolated from microbial fuel cells (MFCs) inoculated with sludge from a sewage treatment plant. Based on 16S rDNA sequence analysis, the strain was identified as Tolumonas osonensis OCF 7(T) according to its biochemical, physiological and morphological characteristics. Through parameters optimization, the P2-A-1 MFC reached the maximum power density of 424 mW/m(2) in the substrate of 2g/L sodium acetate. Further, a facile bacteria treatment approach by chemically "perforating" pores and channels on bacterial membrane was developed to significantly improve the power density. And 1mM of EDTA-treated cell yielded the highest power density of 509.1 mW/m(2) because the membrane permeability of cell was enhanced by verification of coenzyme Q and fatty acid composition tests. It offers a novel facultative anaerobic Gram-positive bacterium that can utilize a wide variety of substrates for power production, making it highly valuable for application in MFCs. PMID- 23651599 TI - Gas phase bio-filter for the removal of triethylamine (TEA) from air: microbial diversity analysis with reference to design parameters. AB - Biotic (packed bio-filter; PBF) and abiotic (packed filter; PF) studies were carried out on two similar 2L gas phase filters for the removal of triethylamine (TEA) at inlet concentration in the range of 250-280 ppmV. Removal efficiency (RE) of PBF remained in the range of 90-99% during the stable period of operation (170 days) whereas RE of PF dropped gradually to 10% in a span of 90 days. Five different bacterial species viz; Aeromonas sp., Alcaligenes sp., Arthrobacter sp., Klebsiella sp., and Pseudomonas sp., were identified in PBF. It was observed that diethyl amine, ethylamine and nitrate were formed as metabolites during the degradation pathway. Empty bed residence time of 20s, mass loading rate of 202.26 g/m(3)/h, space velocity of 178.82 m(3)/m(3)/h and elimination capacity of 201.52 g/m(3)/h were found to be optimum design parameters for PBF to get RE in the range of 90-99%. PMID- 23651600 TI - Reaction kinetics of hydrothermal carbonization of loblolly pine. AB - Hydrothermal carbonization (HTC) is a pretreatment process to convert diverse feedstocks to homogeneous energy-dense solid fuels. Understanding of reaction kinetics is necessary for reactor design and optimization. In this study, the reaction kinetics and effects of particle size on HTC were investigated. Experiments were conducted in a novel two-chamber reactor maintaining isothermal conditions for 15s to 30 min reaction times. Loblolly pine was treated at 200, 230, and 260 degrees C. During the first few minutes of reaction, the solid product mass yield decreases rapidly while the calorific value increases rapidly. A simple reaction mechanism is proposed and validated, in which both hemicellulose and cellulose degrade in parallel first-order reactions. Activation energy of hemicellulose and cellulose degradation were determined to be 30 and 73 kJ/mol, respectively. For short HTC times, both reaction and diffusion effects were observed. PMID- 23651601 TI - Progress in Pediatrics in 2012: choices in allergy, endocrinology, gastroenterology, hematology, infectious diseases, neurology, nutrition and respiratory tract illnesses. AB - In this review, we summarize the progresses in allergy, endocrinology, gastroenterology, hematology, infectious diseases, neurology, nutrition and respiratory tract illnesses that have been published in The Italian Journal of Pediatrics in 2012. The induction of Treg activity by probiotics might be effective for promoting tolerance towards food allergens. Nasal cytology is useful in patients with rhinitis for diagnosing chronic non-allergic non infectious diseases. Atopic eczema is associated both with an aberrant skin matrix and impaired systemic immune response. Therefore, isolated topical treatment may have suboptimal effect. Diagnostic work-up of exercise-induced anaphylaxis, including exercise challenge test, is necessary to reach a diagnosis. Studies may support a role for nutrition on prevention of asthma and cardiovascular diseases. Clinicians need to early identify adolescent menstrual abnormalities to minimize sequelae, and to promote health information. In Multiple Endocrine Neoplasia type 2B investigations include acetylcholinesterase study of rectal mucosa followed by the molecular analysis of RET mutation. Low adherence to gluten-free diet and osteopenia are common problems in children with diabetes mellitus type 1 and celiac disease. In infantile colic, laboratory tests are usually unnecessary and the treatment is based on reassurance. Prevalence of obesity and stunting is elucidated by several studies. Evidences are growing that dietetic measures are needed to prevent obesity in children with acute leukemia. Treatment studies for infectious diseases show promise for probiotics along with standard triple therapy in children with Helicobacter pilori infection, while zinc has no effect on pneumonia. Educational programs about the proper management of the febrile child are warranted. A new hour-specific total serum bilirubin nomogram has been shown to be able to predict newborns without hyperbilirubinemia after 48 to 72 hours of life. Newborns with hypoxic-ischemic encephalopathy present ECG and cardiac enzymes alterations leading to reduced neonatal survival. Rehabilitation programs including sensory integration therapy and motor performance, may improve activities of daily life in children with developmental coordination disorder. Aerobic exercise training in addition to chest physiotherapy might be useful in children with cystic fibrosis. Studies on effectiveness of leukotriene receptor antagonists, alone or with other drugs in preschool wheezing are needed. PMID- 23651602 TI - Subclinical psychotic experiences and bipolar spectrum features in depression: association with outcome of psychotherapy. AB - BACKGROUND: Subthreshold psychotic and bipolar experiences are common in major depressive disorder (MDD). However, it is unknown if effectiveness of psychotherapy is altered in depressed patients who display such features compared with those without. The current paper aimed to investigate the impact of the co presence of subclinical psychotic experiences and subclinical bipolar symptoms on the effectiveness of psychological treatment, alone or in combination with pharmacotherapy. METHOD: In a naturalistic study, patients with MDD (n = 116) received psychological treatment (cognitive behavioural therapy or interpersonal psychotherapy) alone or in combination with pharmacotherapy. Depression and functioning were assessed six times over 2 years. Lifetime psychotic experiences and bipolar symptoms were assessed at the second time point. RESULTS: Subclinical psychotic experiences predicted more depression over time (beta = 0.20, p < 0.002), non-remission [odds ratio (OR) 7.51, p < 0.016] and relapse (OR 3.85, p < 0.034). Subthreshold bipolar symptoms predicted relapse (OR 1.16, p < 0.037). CONCLUSIONS: In general, subclinical psychotic experiences have a negative impact on the course and outcome of psychotherapy in MDD. Effects of subclinical bipolar experiences were less prominent. PMID- 23651603 TI - P268S in NOD2 associates with susceptibility to Parkinson's disease in Chinese population. AB - BACKGROUND: The cause of almost all cases of Parkinson's disease (PD) remains unknown. Recent years have seen an explosion in the rate of discovery of genetic defects linked to PD. Different racial and geographical populations may have different distributions of genetic variants. METHODS: In the current study, we screened the following genetic variants, including some rare mutations and single nucleotide polymorphisms (SNPs), in a pedigree and cases-controls. To best of our knowledge, we first screened these variants known to be associated with neurodegeneration disease, E46K (rs104893875) in SNCA, A1442P in LRRK2, IVS9 in PARK2, A350V in SLC41A1, P268S (rs2066842), R702W (rs2066844), G908R (rs2066845), 1007fs (rs2066847) in NOD2 and G2385R (rs34778348) in LRRK2 from southern China population. Genotyping was performed by jointly using primers overlapping polymerase chain reaction (PCR) site-directed mutagenesis, restriction fragment length polymorphism (RFLP), and capillary electrophoresis (CE). RESULTS: We didn't discover above 9 variants in the family members of the pedigree. Furthermore, of 237 patients with sporadic Parkinson's disease and 190 controls, no heterozygosity or homozygosity were found from E46K, A1442P, A350V, R702W, G908R, or 1007fs but heterozygosity onto G2385R, IVS9, and P268S. No significant difference between cases and controls was found in both allele frequency (P = 0.572) and genotype frequency (P = 0.348) of IVS9. However, significant differences in genotype frequency (P = 0.009) of G2385R were consistent with prior observation. Eight patients with Parkinson's disease (2 women and 6 men are over the age of 50 years at onset of PD) carried the P268S heterozygous variation in NOD2. There was no heterozygosity or homozygosity of P268S in the controls. Genotype frequency of P268S (P = 0.0450) had significant differences. CONCLUSIONS: Our results suggested that the P268S variant in NOD2 might be a risk factor for susceptibility to sporadic Parkinson's disease in Chinese populations. It also implied that the inflammatory response may play a role in PD. PMID- 23651604 TI - Feline anaplastic oligodendroglioma: long-term remission through radiation therapy and chemotherapy. AB - A 10-year-old spayed female Abyssinian cat was presented with cluster limbic focal seizures with secondary generalisation. From magnetic resonance imaging (MRI) findings, the cat was diagnosed clinically as having a glioma in the left piriform lobe, and hypofractionated radiation therapy (RT) was performed using a linear accelerator. Although the tumour size had reduced significantly at 4 months after RT, recurrence was observed at 11 months after RT. Additional RT was performed and was effective; however, recurrence was observed at 11 months after the additional RT. Chemotherapy was started using nimustine (ACNU; 30 mg/m(2), every 6 weeks). Tumour regression was confirmed by follow-up MRIs from 2 to 5 months after starting chemotherapy. Four years and 2 months after the first presentation the cat died as a result of tumour lysis syndrome following treatment of a high-grade lymphoma. Histopathological diagnosis of the brain tumour confirmed anaplastic oligodendroglioma. PMID- 23651605 TI - Investigating Coxiella burnetii infection in a breeding cattery at the centre of a Q fever outbreak. AB - The potential role of cats in transmitting Coxiella burnetii to humans was highlighted in a Q fever outbreak, linked to a caesarean section in a breeding queen, in an Australian small animal veterinary hospital. The objectives of this study were to evaluate the C burnetii seroreactivity of the breeding queen and other cats residing at the same breeding cattery (n = 27) and to evaluate C burnetii infection of the breeding queen by molecular and histological methods. Three assays [complement fixation test (CFT), indirect immunofluorescence assay (IFA) and enzyme-linked immunosorbent assay (ELISA)] were used for serological evaluation. Additionally, uterine and ovarian samples collected from the breeding queen 11 weeks post-parturition were assessed by routine and specialised histological methods and polymerase chain reaction. The breeding queen showed strong seropositivity using CFT (titre 1/32), IFA (titre phase I 1/8192 and phase II 1/8192) and ELISA; however, the reproductive tract showed no evidence of pathology or C burnetii infection. A number of cattery-confined cats were identified as seropositive to phase II and/or phase I C burnetii. Serological detection of C burnetii in a breeding cattery linked to a Q fever outbreak indicates likely infection by this bacterium in Australian feline populations, re confirming the relevance of this zoonosis. PMID- 23651606 TI - Cognitive vulnerability to anxiety in the stress generation process: further investigation of the interaction effect between the looming cognitive style and anxiety sensitivity. AB - BACKGROUND AND OBJECTIVES: The goal of the present study was to replicate and extend previous research on the relationship between stress generation and two well-documented anxiety related cognitive vulnerabilities, Looming Cognitive Style (LCS) and Anxiety Sensitivity (AS). We first sought to replicate findings that LCS and AS augment each other's stress generation effect. Next, we expanded upon these findings by conducting fine grained analyses not possible in the prior study, by using the third edition of the Anxiety Sensitivity Index (Taylor et al., 2007) and examined the individual facets of AS, which includes: Mental Incapacitation (fear of mental impairment), Physical (fear of catastrophic outcomes such as death), and Social (fear of being noticed for trembling, blushing) facets. METHODS: We followed 99 female undergraduates who were assessed twice over a six-week interval. RESULTS: First, the results replicated a previous study and showed that LCS and AS magnified each other's impact on stress generation. Second, analyses using the individual subscales of AS indicated significant interactions between LCS and the Mental Incapacitation and Physical facets of AS but not the Social facet. LIMITATIONS: Limitations of the present study include reliance on self-report measures and the use of a female only sample. Using such a sample is consistent with previous literature, but limits generalizability to males. CONCLUSIONS: The present findings are consistent with the emerging view that stress generation is an active, transactional process and that anxiety-related cognitive styles (much like depressive styles) contribute to stress generation. PMID- 23651607 TI - Characteristics of worry in generalized anxiety disorder. AB - BACKGROUND & OBJECTIVES: Groups of clients and community volunteers with Generalized Anxiety Disorder (GAD) and clients with Panic Disorder were compared to a group with elevated worry but without GAD on a range of measures, to identify individual differences beyond a high propensity to worry. METHOD: Participants completed standardised questionnaires and a behavioural worry task that assesses frequency and severity of negative thought intrusions. RESULTS: Relative to high worriers, clients with GAD had higher scores on trait anxiety, depression, more negative beliefs about worry, a greater range of worry topics, and more frequent and severe negative thought intrusions. Relative to community volunteers with GAD, clients in treatment reported poorer attentional control. Compared to clients with Panic Disorder, clients with GAD had higher trait anxiety, propensity to worry, negative beliefs and a wider range of worry content. CONCLUSIONS: Results confirmed expectations of group differences based on GAD diagnostic criteria, but also revealed other differences in mood, characteristics of worry, and perceived attentional control that may play a role in the decision to seek treatment. PMID- 23651608 TI - The impact of polymorphisms in STAT6 on treatment outcome in HCV infected Taiwanese Chinese. AB - Genetic polymorphisms observed in various disease states associated with sensitivity or resistance to specific treatments have been a robust area of investigation for decades, with the potential to allow clinicians to make evidence-based decisions on the appropriate course of treatment. This study aimed to evaluate whether genetic polymorphisms of the signal transducer and activator of transcription 6 gene (STAT6) could be associated with a sustained virological response (SVR) among patients infected with hepatitis C virus genotypes 1 and 2 (HCV-1 and HCV-2) who were treated with peginterferon plus ribavirin (PEG IFNalpha-RBV). We analyzed the associations between SVR to PEG-IFNalpha-RBV therapy and 4 single nucleotide polymorphisms (SNPs) in STAT6. This study included Taiwanese Chinese patients infected with either HCV-1 (n = 265) or HCV-2 (n = 195) in the presence or absence of an SVR. Among the STAT6 SNPs examined, the dosage effect of the A allele and allele frequency in rs1059513 were inversely correlated with SVR in patients infected with HCV-1 (P = 0.0179 and P = 0.0235, respectively). This effect was not observed in patients infected with HCV 2. The GG, GGG, and GGGC STAT6 haplotypes comprising 2, 3, and 4 SNPs (rs1059513, rs703817, rs324015, and rs3024974) were found to be associated with SVR, and their presence may increase the probability of a successful treatment outcome in patients infected with HCV-1 (P = 0.0273, 0.0352, and 0.0368, respectively). Moreover, a multivariate logistic regression model for predicting an SVR revealed that the presence of the GGGC haplotype carriers mutually affected the outcome of PEG-IFNalpha-RBV treatment. The presence of STAT6 SNPs and the association with SVR demonstrated that STAT6 polymorphisms might influence the therapeutic outcomes of patients infected with HCV-1 under standard-of-care (SOC) treatment. PMID- 23651609 TI - Real-life compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy. AB - BACKGROUND: Subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT) are safe and effective treatments of allergic rhinitis, but high levels of compliance and persistence are crucial to achieving the desired clinical effects. OBJECTIVE: Our objective was to assess levels and predictors of compliance and persistence among grass pollen, tree pollen, and house dust mite immunotherapy users in real life and to estimate the costs of premature discontinuation. METHODS: We performed a retrospective analysis of a community pharmacy database from The Netherlands containing data from 6486 patients starting immunotherapy for 1 or more of the allergens of interest between 1994 and 2009. Two thousand seven hundred ninety-six patients received SCIT, and 3690 received SLIT. Time to treatment discontinuation was analyzed and included Cox proportional hazard models with time-dependent covariates, where appropriate. RESULTS: Overall, only 18% of users reached the minimally required duration of treatment of 3 years (SCIT, 23%; SLIT, 7%). Median durations for SCIT and SLIT users were 1.7 and 0.6 years, respectively (P < .001). Other independent predictors of premature discontinuation were prescriber, with patients of general practitioners demonstrating longer persistence than those of allergologists and other medical specialists; single-allergen immunotherapy, lower socioeconomic status; and younger age. Of the persistent patients, 56% were never late in picking up their medication from the pharmacy. Direct medication costs per nonpersistent patient discontinuing in the third year of treatment were ?3800, an amount that was largely misspent. CONCLUSION: Real-life persistence is better in SCIT users than in SLIT users, although it is low overall. There is an urgent need for further identification of potential barriers and measures that will enhance persistence and compliance. PMID- 23651610 TI - A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer' disease. AB - Previous studies have shown that melatonin is implicated in modulating learning and memory processing. Melatonin also exerts neuroprotective activities against Abeta-induced injury in vitro and in vivo. Neu-P11 (piromelatine, N-(2-(5-methoxy 1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2-carboxamide) is a novel melatonin (MT1/MT2) receptor agonist and a serotonin 5-HT1A/1D receptor agonist recently developed for the treatment of insomnia. In the present study we firstly investigated whether Neu-P11 and melatonin enhance memory performance in the novel object recognition (NOR) task in rats, and then assessed whether Neu-P11 and melatonin improve neuronal and cognitive impairment in a rat model of Alzheimer' disease (AD) induced by intrahippocampal Abeta(1-42) injection. The results showed that a single morning or afternoon administration of Neu-P11 enhanced object recognition memory measured at 4 or 24h after training. Melatonin was effective in the memory facilitating effects only when administered in the afternoon. Further results showed that intrahippocampal Abeta(1-42) injection resulted in hippocampal cellular loss, as well as decreased learning ability and memory in the Y maze and NOR tasks in rats. Neu-P11 but not melatonin attenuated cellular loss and cognitive impairment in the rat AD model. The current data suggest that Neu-P11 may serve as a novel agent for the treatment of AD. PMID- 23651611 TI - Maternal testosterone influences a begging component that makes fathers work harder in chick provisioning. AB - In species with biparental care, parents disagree evolutionarily over the amount of care that each of them is willing to provide to offspring. It has recently been hypothesised that females may try to manipulate their mates by modifying offspring begging behaviour through yolk hormone deposition, shifting the division of labour in their own favour. To test this hypothesis we first investigated how yellow-legged gull (Larus michaellis) parents feed offspring in relation to each component of complex begging behaviour and if feeding behaviour varies between sexes. Then we investigated the effect of yolk testosterone on chicks' begging by experimentally increasing yolk testosterone levels. Our results revealed that yolk testosterone has a component-specific effect on chicks' begging, specifically increasing the number of chatter calls. Parental feeding effort was influenced by the number of chatter calls emitted by chicks, but most importantly, the influence was stronger in male than in female parents. Moreover, chick body mass increased with the number of paternal feeds. In conclusion, these results show that female gulls may use yolk testosterone deposition to exploit their partners as predicted by the 'Manipulating Androgen Hypothesis (MAH)'. PMID- 23651612 TI - Organizational effects of estrogen on male-type vulnerability to early weaning. AB - We previously reported that early-weaned (postnatal day 14) male ICR mice, compared to normally weaned animals, exhibited a persistent increase in anxiety related behavior in the elevated plus maze test. In this study, we examined whether steroid hormone manipulations on postnatal day 0 and at the ages of 2 or 3 weeks affected male-type vulnerability to early weaning. Neither castration nor ovariectomy at the age of 3 weeks affected male-type vulnerability. However, in males, castration at the age of 2 weeks attenuated the increased anxiety levels induced by early weaning, and the implantation of testosterone or estradiol, but not of dihydrotestosterone, restored the effects of early weaning. In contrast, in females, neonatal treatment with testosterone propionate together with testosterone at the age of 2 weeks, which reversed sexual behavior to the male type, did not affect anxiety levels in response to early weaning. When pregnant females were repeatedly treated with testosterone propionate on embryonic days 14, 17, and 19, in addition to testosterone treatment at the age of 2 weeks, the anxiety levels in female were increased by early weaning. Furthermore, the prenatal treatment of estradiol benzoate, but not dihydrotestosterone, induced enhanced anxiety levels by early weaning in females. These results suggest that neural systems are masculinized by estrogen from the embryonic phase to the early postnatal period and are responsible for the high levels of anxiety elicited by early weaning. PMID- 23651613 TI - IGF1R levels in the brain negatively correlate with longevity in 16 rodent species. AB - The insulin/insulin-like growth factor signaling (IIS) pathway is a major conserved regulator of aging. Nematode, fruit fly and mouse mutants with reduced IIS signaling exhibit extended lifespan. These mutants are often dwarfs leading to the idea that small body mass correlates with longevity within species. However, when different species are compared, larger animals are typically longer lived. Hence, the role of IIS in the evolution of life history traits remains unresolved. Here we used comparative approach to test whether IGF1R signaling changes in response to selection on lifespan or body mass and whether specific tissues are involved. The IGF1R levels in the heart, lungs, kidneys, and brains of sixteen rodent species with highly diverse lifespans and body masses were measured via immunoblot after epitope conservation analysis. We report that IGF1R levels display strong negative correlation with maximum lifespan only in brain tissue and no significant correlations with body mass for any organ. The brain IGF1R and lifespan correlation holds when phylogenetic non-independence of data points is taken into account. These results suggest that modulation of IGF1R signaling in nervous tissue, but not in the peripheral tissues, is an important factor in the evolution of longevity in mammals. PMID- 23651614 TI - Cost-effectiveness of a stepped-care intervention to prevent major depression in patients with type 2 diabetes mellitus and/or coronary heart disease and subthreshold depression: design of a cluster-randomized controlled trial. AB - BACKGROUND: Co-morbid major depression is a significant problem among patients with type 2 diabetes mellitus and/or coronary heart disease and this negatively impacts quality of life. Subthreshold depression is the most important risk factor for the development of major depression. Given the highly significant association between depression and adverse health outcomes and the limited capacity for depression treatment in primary care, there is an urgent need for interventions that successfully prevent the transition from subthreshold depression into a major depressive disorder. Nurse led stepped-care is a promising way to accomplish this. The aim of this study is to evaluate the cost effectiveness of a nurse-led indicated stepped-care program to prevent major depression among patients with type 2 diabetes mellitus and/or coronary heart disease in primary care who also have subthreshold depressive symptoms. METHODS/DESIGN: An economic evaluation will be conducted alongside a cluster randomized controlled trial in approximately thirty general practices in the Netherlands. Randomization takes place at the level of participating practice nurses. We aim to include 236 participants who will either receive a nurse-led indicated stepped-care program for depressive symptoms or care as usual. The stepped-care program consists of four sequential but flexible treatment steps: 1) watchful waiting, 2) guided self-help treatment, 3) problem solving treatment and 4) referral to the general practitioner. The primary clinical outcome measure is the cumulative incidence of major depressive disorder as measured with the Mini International Neuropsychiatric Interview. Secondary outcomes include severity of depressive symptoms, quality of life, anxiety and physical outcomes. Costs will be measured from a societal perspective and include health care utilization, medication and lost productivity costs. Measurements will be performed at baseline and 3, 6, 9 and 12 months. DISCUSSION: The intervention being investigated is expected to prevent new cases of depression among people with type 2 diabetes mellitus and/or coronary heart disease and subthreshold depression, with subsequent beneficial effects on quality of life, clinical outcomes and health care costs. When proven cost-effective, the program provides a viable treatment option in the Dutch primary care system. TRIAL REGISTRATION: Dutch Trial Register NTR3715. PMID- 23651615 TI - Direct evidence for RNA-RNA interactions at the 3' end of the Hepatitis C virus genome using surface plasmon resonance. AB - Surface plasmon resonance was used to investigate two previously described interactions analyzed by reverse genetics and complementation mutation experiments, involving 5BSL3.2, a stem-loop located in the NS5B coding region of HCV. 5BSL3.2 was immobilized on a sensor chip by streptavidin-biotin coupling, and its interaction either with the SL2 stem-loop of the 3' end or with an upstream sequence centered on nucleotide 9110 (referred to as Seq9110) was monitored in real-time. In contrast with previous results obtained by NMR assays with the same short RNA sequences that we used or SHAPE analysis with longer RNAs, we demonstrate that recognition between 5BSL3.2 and SL2 can occur in solution through a kissing-loop interaction. We show that recognition between Seq9110 and the internal loop of 5BSL3.2 does not prevent binding of SL2 on the apical loop of 5BSL3.2 and does not influence the rate constants of the SL2 5BSL3.2 complex. Therefore, the two binding sites of 5BSL3.2, the apical and internal loops, are structurally independent and both interactions can coexist. We finally show that the stem-loop SL2 is a highly dynamic RNA motif that fluctuates between at least two conformations: One is able to hybridize with 5BSL3.2 through loop-loop interaction, and the other one is capable of self associating in the absence of protein, reinforcing the hypothesis of SL2 being a dimerization sequence. This result suggests also that the conformational dynamics of SL2 could play a crucial role for controlling the destiny of the genomic RNA. PMID- 23651616 TI - Dual inhibitor of phosphoinositide 3-kinase/mammalian target of rapamycin NVP BEZ235 effectively inhibits cisplatin-resistant urothelial cancer cell growth through autophagic flux. AB - PURPOSE: Therapeutically induced autophagic cell death has been proven to be effective in cases of solid tumors. The dual phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 possesses antitumor activity against solid tumors. Inhibition of mTOR has been shown to elicit autophagy. In this study, we examined the antiproliferation and autophagic activities of NVP-BEZ235 in parental and cisplatin-resistant urothelial carcinoma (UC) cells. MATERIALS AND METHODS: Two UC cell lines, NTUB1 and a cisplatin resistant subline N/P(14), were applied to examine the cytotoxic effect of NVP BEZ-235. The cell death mechanism was also evaluated. RESULTS: NVP-BEZ235 was effective in inhibiting the growth of UC cells including parental and cisplatin resistant cells on flow cytometry assay and Western blot. Although NVP-BEZ235 did not induce LC3-II conversion, it did elicit acidic vesicular organelle (AVO) development on flow cytometry. On Western blot, NVP-BEZ235 decreased p62 and phospho-Rb expressions in a concentration-dependent manner. GFP-LC3 conversion and the appearance of cleaved-GFP following NVP-BEZ235 treatment were demonstrated on Western blot. In addition, lysosomotropic inhibition of autophagy by chloroquine (CQ), an agent that is currently in clinical use and a known antagonist of autophagy, resulted in proliferation of UC cells. Thus, inhibition of autophagic flux by CQ appears to be a survival mechanism that counteracts the anticancer effects of NVP-BEZ235. CONCLUSIONS: We demonstrated that NVP-BEZ235 inhibits UC cell proliferation by activating autophagic flux and cell cycle arrest, but does not induce apoptotic cell death. Our findings suggest that the anticancer efficacy of NVP-BEZ235 is due to autophagic flux and co-treatment with CQ counteracts the cytotoxic effect. PMID- 23651617 TI - Nephroprotective effect of GSK-3beta inhibition by lithium ions and delta-opioid receptor agonist dalargin on gentamicin-induced nephrotoxicity. AB - Nephrotoxicity and ototoxicity are the most considerable side effects of aminoglycoside antibiotics, such as gentamicin that seriously limits its application in medicine. The major mechanism of negative effect of gentamicin on kidney cells involves damage of mitochondria and induction of an oxidative stress that causes cell death resulting in kidney dysfunction. In this work we compared effects of the lithium ions and delta-opioid receptors agonist, dalargin on gentamicin-induced kidney injury. It was revealed that LiCl and dalargin treatment reduced renal tubular cell death and diminished kidney injury caused by gentamicin. Both LiCl and dalargin were found to enhance phosphorylation of glycogen synthase kinase 3beta in the kidney which points to induction of nephroprotective signaling pathways. Thus, we conclude that lithium ions and dalargin might be considered as novel promising agents for future use to prevent negative consequences of therapy with aminoglycoside antibiotics. PMID- 23651619 TI - Chlamydia screening interventions from community pharmacies: a systematic review. AB - BACKGROUND: Chlamydia (Chlamydia trachomatis) is the most commonly notified sexually transmissible infection in Australia. Increasing the number of people aged 16-25 years being tested for chlamydia has become a key objective. The strategy recommends that chlamydia screening sites should be easy to access. Community pharmacies are conveniently located and easily accessible. This review aimed to determine the different types of pharmacy-based chlamydia screening interventions, describe their uptake rates, and understand issues around the acceptability of and barriers to testing. METHODS: Seven electronic databases were searched for peer-reviewed articles published up to 30 October 2011 for studies that reported chlamydia screening interventions from community pharmacies, or had qualitative evidence on acceptability or barriers linked with interventions. RESULTS: Of the 163 publications identified, 12 met the inclusion criteria. Nine reported chlamydia screening interventions in a pharmacy setting, whereas three focussed on perspectives on chlamydia screening. Pharmacists could offer a chlamydia test to consumers attending the pharmacy for a sexual health related consultation, or consumers could request a chlamydia test as part of a population-based intervention. Participating consumers said pharmacies were accessible and convenient, and pharmacists were competent when offering a chlamydia test. Pharmacists reported selectively offering tests to women they thought would be most at risk, undermining the principles of opportunistic interventions. CONCLUSION: Chlamydia screening from community pharmacies is feasible, and can provide an accessible, convenient venue to get a test. Professional implementation support, alongside resources, education and training programs, and incentives may overcome the issue of pharmacists selectively offering the test. PMID- 23651618 TI - Comparative proteome analysis of Tumor necrosis factor alpha-stimulated human Vascular Smooth Muscle Cells in response to melittin. AB - BACKGROUND: Bee venom has been used to relieve pain and to treat inflammatory diseases, including rheumatoid arthritis, in humans. To better understand the mechanisms of the anti-inflammatory and anti-atherosclerosis effect of bee venom, gel electrophoresis and mass spectrometry were used to identify proteins whose expression was altered in human Vascular Smooth Muscle Cells (hVSMCs) stimulated by tumor necrosis factor alpha after 12 h in the presence of melittin. RESULTS: To obtain valuable insights into the anti-inflammatory and anti-atherosclerosis mechanisms of melittin, two-dimensional (2-D) gel electrophoresis and MALDI TOF/TOF were used. The proteome study, we showed 33 significant proteins that were differentially expressed in the cells treated with tumor necrosis factor alpha and melittin. Thirteen proteins were significantly increased in the cells treated with tumor necrosis factor alpha, and those proteins were reduced in the cells treated with melittin. Five of the proteins that showed increased expression in the cells treated with tumor necrosis factor alpha are involved in cell migration, including calreticulin, an essential factor of development that plays a role in transcription regulation. The proteins involved in cell migration were reduced in the melittin treated cells. The observed changes in the expression of GRP75, prohibitin, and a select group of other proteins were validated with reverse transcribed-PCR. It was confirmed that the observed change in the protein levels reflected a change in the genes level. In addition, the phosphorylation of EGFR and ERK was validated by analyzing the protein pathway. CONCLUSION: Taken together, these data established that the expression of some proteins was significantly changed by melittin treatment in tumor necrosis factor alpha stimulated the cells and provided insights into the mechanism of the melittin function for its potential use as an anti-inflammatory agent. PMID- 23651620 TI - Characterization of the anxiolytic and sedative profile of JM-20: a novel benzodiazepine-dihydropyridine hybrid molecule. AB - OBJECTIVES: The aim of this study was to investigate the effects of oral administration of a novel benzodiazepine derivative, JM-20, on the neurological behavior of different rodent models, focusing on the GABAergic effect. We have also investigated the acute toxicity of oral administration of JM-20 in mice. METHODS: Mice or rats received oral administration of JM-20 at 2, 4, 8, and 10 mg/kg to evaluate the sedative/hypnotic, anxiolytic, and anticonvulsant effects, as well as the influence on the stereotyped behavior induced by amphetamine. Diazepam (DZP) was used as a positive control. In addition, the mice received a single oral JM-20 dose of 2000 mg/kg to evaluate the acute toxicity. RESULTS: In a dose-dependent manner, JM-20 (i) increased the number of crossings and decreased the number of rearings in the open-field test; (ii) decreased the aggressive behavior of socially-isolated mice; and (iii) increased the latency period for tonic seizure's onset and the percentage of survival of animals with seizures. Moreover, JM-20 increased the sleeping time induced by barbiturates and the time spent and the number of entries in the open arms of the elevated plus maze test. In the JM-20 toxicity test, no mortality was observed and only minor signs of toxicity associated with sedation were detected. CONCLUSIONS: These results indicate that JM-20 has an anxiolytic profile similar to DZP and its dihydropyridine moiety did not appear to interfere with the GABAergic activity associated with benzodiazepine. Furthermore, JM-20 did not show significant acute toxic effects in mice. PMID- 23651621 TI - Sex-biased gene expression in the developing brain: implications for autism spectrum disorders. AB - Autism spectrum disorders affect significantly more males than females. Understanding sex differences in normal human brain development may provide insight into the mechanism(s) underlying this disparity; however, studies of sex differences in brain development at the genomic level are lacking. Here, we report a re-analysis of sex-specific gene expression from a recent large transcriptomic study of normal human brain development, to determine whether sex biased genes relate to specific mechanistic processes. We discovered that male biased genes are enriched for the processes of extracellular matrix formation/glycoproteins, immune response, chromatin, and cell cytoskeleton. We highlight that these pathways have been repeatedly implicated in autism and demonstrate that autism candidate genes are also enriched for these pathways. We propose that the overlap of these male-specific brain transcriptional modules with the same pathways in autism spectrum disorders may partially explain the increased incidence of autism in males. PMID- 23651623 TI - Letter to the Editor: haloperidol but not dopamine rapidly induces neuronal death: comments on 'A systematic review of the effects of antipsychotic drugs on brain volume'. PMID- 23651622 TI - High occurrence of functional new chimeric genes in survey of rice chromosome 3 short arm genome sequences. AB - In an effort to identify newly evolved genes in rice, we searched the genomes of Asian-cultivated rice Oryza sativa ssp. japonica and its wild progenitors, looking for lineage-specific genes. Using genome pairwise comparison of approximately 20-Mb DNA sequences from the chromosome 3 short arm (Chr3s) in six rice species, O. sativa, O. nivara, O. rufipogon, O. glaberrima, O. barthii, and O. punctata, combined with synonymous substitution rate tests and other evidence, we were able to identify potential recently duplicated genes, which evolved within the last 1 Myr. We identified 28 functional O. sativa genes, which likely originated after O. sativa diverged from O. glaberrima. These genes account for around 1% (28/3,176) of all annotated genes on O. sativa's Chr3s. Among the 28 new genes, two recently duplicated segments contained eight genes. Fourteen of the 28 new genes consist of chimeric gene structure derived from one or multiple parental genes and flanking targeting sequences. Although the majority of these 28 new genes were formed by single or segmental DNA-based gene duplication and recombination, we found two genes that were likely originated partially through exon shuffling. Sequence divergence tests between new genes and their putative progenitors indicated that new genes were most likely evolving under natural selection. We showed all 28 new genes appeared to be functional, as suggested by Ka/Ks analysis and the presence of RNA-seq, cDNA, expressed sequence tag, massively parallel signature sequencing, and/or small RNA data. The high rate of new gene origination and of chimeric gene formation in rice may demonstrate rice's broad diversification, domestication, its environmental adaptation, and the role of new genes in rice speciation. PMID- 23651624 TI - Nonhuman primates as models for transplantation of the uterus. PMID- 23651625 TI - Serum bisphenol-A concentration and sex hormone levels in men. AB - OBJECTIVE: To evaluate the association between serum bisphenol-A (BPA) concentration and sex hormone levels in men. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 290 men with or without BPA exposure in the workplace. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum sex hormone levels. RESULT(S): After adjustment for potential confounders using linear regression, increasing serum BPA concentration was statistically significantly associated with [1] decreased androstenedione levels, [2] decreased free testosterone levels, [3] decreased free androgen index, and [4] increased sex hormone-binding globulin levels. Comparison of hormone levels between workers exposed and unexposed to BPA showed similar associations. CONCLUSION(S): Exposure to a high BPA level may impact sex hormone levels in men. PMID- 23651626 TI - Effects of combined antioxidant supplementation on human sperm motility and morphology during sperm manipulation in vitro. AB - OBJECTIVE: To evaluate the effect of antioxidant combinations on human sperm motility and morphologic normality during preparation and in vitro incubation to improve sperm quality for assisted reproductive technology (ART). DESIGN: Prospective study. SETTING: Laboratory. PATIENT(S): Six fertile males, 21 to 25 years of age, after 3 days of sexual abstinence. INTERVENTION(S): Sperm retrieved from patients with normal fertility prepared and incubated in vitro in medium supplemented with taurine, cysteine, and/or glutathione. MAIN OUTCOME MEASURE(S): Motility indices, including motility (MOT), average path velocity (VAP), curvilinear velocity (VCL), straight-line velocity (VSL), and morphologic normality. RESULT(S): Taurine supplementation during sperm preparation had no significant effects on motility or morphologic normality. However, when sperm was incubated for 24 hours under taurine-supplemented conditions, the rates of reduction in MOT, VAP, VCL, and VSL were statistically significantly decreased compared with taurine-free conditions. Morphologic normality was maintained, regardless of taurine treatment. The optimal taurine concentration for improving sperm motility and morphologic normality during preparation and in vitro incubation was 1 mM. Subsequently, combined treatment with 1 mM taurine, 1 mM cysteine, and 1 mM glutathione induced statistically significant synergistic effects on MOT, VAP, VCL, and VSL without any alteration of morphologic normality. CONCLUSION(S): Combined treatment with taurine, cysteine, and glutathione statistically significantly ameliorated the reduction in sperm motility during in vitro manipulation of human sperm. PMID- 23651627 TI - Sperm banking is of key importance in patients with prostate cancer. AB - OBJECTIVE: To assess the need for sperm banking among patients with prostate cancer (PCa) who are candidates for radical prostatectomy (RP). DESIGN: Cross sectional study. SETTING: Urologic department. PATIENT(S): Cohort of 510 Caucasian-European candidates for RP. INTERVENTION(S): A 10-item self administered questionnaire to assess opinions on sperm banking before RP, to which descriptive statistics and logistic regression models were applied. MAIN OUTCOME MEASURE(S): PCa patients' wishes for preoperative sperm banking. RESULT(S): Data collection was completed for 495 patients (97.1%). Ninety-nine (20%) expressed a wish for preoperative sperm banking. Men who wanted to bank sperm were younger (mean 62.2 vs. 65.1 years), were more frequently childless (21.2% vs. 8.8%), and more frequently had a more intense desire for fatherhood (64.7% vs. 9.3%) than the patients not interested in banking sperm. Willingness to bank sperm was not affected by the patient's educational or relationship status. Moreover, the interest for sperm banking was maintained regardless of cost issues. Overall, 84% of the patients considered it necessary to have a dedicated service of preoperative sperm cryopreservation. CONCLUSION(S): One out of five PCa patients would bank sperm before RP. Most patients considered it necessary to establish a dedicated service for preoperative sperm cryopreservation, regardless of their own motivation to bank sperm. PMID- 23651628 TI - Influence of arthritis-related protein (BBF01) on infectivity of Borrelia burgdorferi B31. AB - BACKGROUND: Lyme borreliosis, caused by tick-borne Borrelia burgdorferi, is a multi-phasic, multi-system disease in humans. Similar to humans, C3H mice develop arthritis and carditis, with resolution and periodic bouts of recurrence over the course of persistent infection. Borrelia burgdorferi arthritis-related protein (Arp/BBF01), a highly conserved protein among B. burgdorferi s.s. isolates, has been shown to be antigenic in humans with Lyme borreliosis, and a target for antibody-mediated disease resolution in the mouse model. RESULTS: A mutant strain of B. burgdorferi s.s. deficient of the arp gene and a complemented version of that mutant were created and examined for phenotypic effects in mice compared to wild-type B. burgdorferi. Deletion of arp did not abolish infectivity, but did result in a higher infectious dose compared to wild-type B. burgdorferi, which was restored by complementation. Spirochete burdens in tissues of C3H-scid mice were lower when infected with the arp mutant, compared to wild-type, but arthritis was equally severe. Spirochete burdens were also lower in C3H mice infected with the arp mutant, but disease was markedly reduced. Ticks that fed upon infected C3H mice were able to acquire infection with both wild-type and arp mutant spirochetes. Arp mutant spirochetes were marginally able to be transmitted to naive hosts by infected ticks. CONCLUSION: These results indicated that deletion of BBF01/arp did not abrogate, but diminished infectivity and limited spirochete burdens in tissues of both immunocompetent and immunodeficient hosts, and attenuated, but did not abolish the ability of ticks to acquire or transmit infection. PMID- 23651629 TI - Mesonephric adenocarcinoma with a sarcomatous component, a notable subtype of cervical carcinosarcoma: a case report and review of the literature. AB - Carcinosarcoma of the uterine cervix is less common than its counterpart in the uterine corpus. On the other hand, mesonephric adenocarcinoma is also a rare neoplasm in the uterine cervix, and it has been reported that mesonephric adenocarcinomas are often accompanied by sarcomatous components. We present a case of mesonephric adenocarcinoma with a sarcomatous component which arose in a 63-year-old postmenopausal woman. The hysterectomy specimen grossly showed an exophytic mass measuring 1.8 cm in the uterine cervix. Histologically, diffuse mesonephric hyperplasia and adenocarcinoma with malignant spindle cell proliferation was recognized, and therefore the tumor was diagnosed as "mesonephric adenocarcinoma with a sarcomatous component." The review of the literature of cervical carcinosarcoma and cervical mesonephric adenocarcinoma revealed that 16% of cervical carcinosarcoma is of mesonephric duct origin, and that mesonephric adenocarcinoma seems to be more likely to have sarcomatous change. We think the presence of a sarcomatous component in the cervical biopsy specimen could be helpful in the diagnosis of mesonephric duct origin. PMID- 23651630 TI - Linked-in: design and efficacy of antibody drug conjugates in oncology. AB - The use of antibody drug conjugates (ADCs) as targeted chemotherapies has successfully entered clinical practice and holds great promise. ADCs consist of an antibody and toxin-drug combined together via a chemical linker. While the antibody and drug are of vital importance in the direct elimination of cancer cells, more advanced linker technology was instrumental in the delivery of more potent drugs with fewer side effects. Here, we discuss the preclinical experience as well as clinical trials, with a specific emphasis on the clinical outcomes and side effects, in addition to linker strategies for five different ADCs, in order to describe different approaches in the development of this new class of anticancer agents. Brentuximab vedotin is approved for use in Hodgkin's lymphoma and Trastuzumab emtansine is approved for breast cancer. Combotox, Inotuzumab Ozogamicin, and Moxetumomab Pasudotox are in various stages of clinical development and are showing significant efficacy in lymphoid malignancies. These ADCs illustrate the promise and future potential of targeted therapy for presently incurable malignancies. PMID- 23651632 TI - The effect of deuteration on the structure of bacterial cellulose. AB - In vivo generated deuterated bacterial cellulose, cultivated from 100% deuterated glycerol in D2O medium, was analyzed for deuterium incorporation by ionic liquid dissolution and (2)H and (1)H nuclear magnetic resonance (NMR). A solution NMR method of the dissolved cellulose was used to determine that this bacterial cellulose had 85% deuterium incorporation. Acetylation and (1)H and (2)H NMR of deuterated bacterial cellulose indicated near equal deuteration at all sites of the glucopyranosyl ring except C-6 which was partly deuterated. Despite the high level of deuterium incorporation no significant differences in the molecular and morphological properties were observed for the deuterated and protio bacterial cellulose samples. The highly deuterated bacterial cellulose presented here can be used as a model substrate for studying cellulose biopolymer properties via future small angle neutron scattering (SANS) studies. PMID- 23651631 TI - New evidence for coupled clock regulation of the normal automaticity of sinoatrial nodal pacemaker cells: bradycardic effects of ivabradine are linked to suppression of intracellular Ca2+ cycling. AB - Beneficial clinical bradycardic effects of ivabradine (IVA) have been interpreted solely on the basis of If inhibition, because IVA specifically inhibits If in sinoatrial nodal pacemaker cells (SANC). However, it has been recently hypothesized that SANC normal automaticity is regulated by crosstalk between an "M clock," the ensemble of surface membrane ion channels, and a "Ca(2+) clock," the sarcoplasmic reticulum (SR). We tested the hypothesis that crosstalk between the two clocks regulates SANC automaticity, and that indirect suppression of the Ca(2+) clock further contributes to IVA-induced bradycardia. IVA (3 MUM) not only reduced If amplitude by 45 +/- 6% in isolated rabbit SANC, but the IVA-induced slowing of the action potential (AP) firing rate was accompanied by reduced SR Ca(2+) load, slowed intracellular Ca(2+) cycling kinetics, and prolonged the period of spontaneous local Ca(2+) releases (LCRs) occurring during diastolic depolarization. Direct and specific inhibition of SERCA2 by cyclopiazonic acid (CPA) had effects similar to IVA on LCR period and AP cycle length. Specifically, the LCR period and AP cycle length shift toward longer times almost equally by either direct perturbations of the M clock (IVA) or the Ca(2+) clock (CPA), indicating that the LCR period reports the crosstalk between the clocks. Our numerical model simulations predict that entrainment between the two clocks that involves a reduction in INCX during diastolic depolarization is required to explain the experimentally AP firing rate reduction by IVA. In summary, our study provides new evidence that a coupled-clock system regulates normal cardiac pacemaker cell automaticity. Thus, IVA-induced bradycardia includes a suppression of both clocks within this system. PMID- 23651633 TI - Keeping adolescents busy with extracurricular activities. AB - Adolescent participation in academic/extracurricular activities is related to fewer diagnoses of sexually transmitted infections during adolescence. The role parents play in motivating participation in such activities is unclear. This mixed-methods study explored parental influences on academic/extracurricular activity participation, and the relationship of such participation to adolescents' future aspirations and sexual behavior, over a 4-year period. We utilized semistructured interviews with 28 White and Asian American adolescents (age 17-19) and event history calendar self-reports of activities, part-time jobs, and sexual behaviors. Data triangulation was used to integrate qualitative and quantitative data. Increased participation was correlated with abstinence and later sexual onset. Many adolescents reported that parents were reluctant to talk with them about sexual risks and instead preferred to keep them busy and ensure that they had the "right" friends. Adolescents endorsed the parental strategy of keeping them busy with activities. Findings and implications for school nursing practice are discussed. PMID- 23651634 TI - Evaluation of the association between persistent organic pollutants (POPs) and diabetes in epidemiological studies: a national toxicology program workshop review. AB - BACKGROUND: Diabetes is a major threat to public health in the United States and worldwide. Understanding the role of environmental chemicals in the development or progression of diabetes is an emerging issue in environmental health. OBJECTIVE: We assessed the epidemiologic literature for evidence of associations between persistent organic pollutants (POPs) and type 2 diabetes. METHODS: Using a PubMed search and reference lists from relevant studies or review articles, we identified 72 epidemiological studies that investigated associations of persistent organic pollutants (POPs) with diabetes. We evaluated these studies for consistency, strengths and weaknesses of study design (including power and statistical methods), clinical diagnosis, exposure assessment, study population characteristics, and identification of data gaps and areas for future research. CONCLUSIONS: Heterogeneity of the studies precluded conducting a meta-analysis, but the overall evidence is sufficient for a positive association of some organochlorine POPs with type 2 diabetes. Collectively, these data are not sufficient to establish causality. Initial data mining revealed that the strongest positive correlation of diabetes with POPs occurred with organochlorine compounds, such as trans-nonachlor, dichlorodiphenyldichloroethylene (DDE), polychlorinated biphenyls (PCBs), and dioxins and dioxin-like chemicals. There is less indication of an association between other nonorganochlorine POPs, such as perfluoroalkyl acids and brominated compounds, and type 2 diabetes. Experimental data are needed to confirm the causality of these POPs, which will shed new light on the pathogenesis of diabetes. This new information should be considered by governmental bodies involved in the regulation of environmental contaminants. PMID- 23651635 TI - A survivin-associated adaptive response in radiation therapy. AB - Adaptive responses can be induced in cells by very low doses of ionizing radiation resulting in an enhanced resistance to much larger exposures. The inhibitor of apoptosis protein, survivin, has been implicated in many adaptive responses to cellular stress. Computerized axial tomography used in image-guided radiotherapy to position and monitor tumor response uses very low radiation doses ranging from 0.5 to 100 mGy. We investigated the ability of these very low radiation doses administered along with two 2 Gy doses separated by 24 hours, a standard conventional radiotherapy dosing schedule, to initiate adaptive responses resulting in the elevation of radiation resistance in exposed cells. Human colon carcinoma (RKO36), mouse sarcoma (SA-NH), along with transformed mouse embryo fibroblasts, wild type or cells lacking functional tumor necrosis factor receptors 1 and 2 were used to assess their relative ability to express an adaptive response when grown either to confluence in vitro or as tumors in the flank of C57BL/6 mice. The survival of each of these cells was elevated from 5% to 20% (P <= 0.05) as compared to cells not receiving a 100 mGy or lesser dose. In addition, the cells exposed to 100 mGy exhibited elevations in survivin levels, reductions in apoptosis frequencies, and loss of an adaptive response if transfected with survivin siRNA. This survivin-mediated adaptive response has the potential for affecting outcomes if regularly induced throughout a course of image guided radiation therapy. PMID- 23651637 TI - Mental health literacy about depression: a survey of portuguese youth. AB - BACKGROUND: Depression is a common disorder in adolescents and young adults, but help seeking is low. Mental health literacy about depression is a key concept to plan interventions for improving help seeking. This study aimed to evaluate youth mental literacy about depression in order to design school-based interventions. METHODS: During 2012, a survey was conducted with a stratified cluster sample of 4938 Portuguese young people between 14 and 24 years of age. Following the presentation of a vignette describing depression, a series of questions was asked concerning: recognition of the disorder; knowledge of professional help and treatments available; knowledge of effective self-help strategies; knowledge and skills to give first aid and support to others; and knowledge of how to prevent this disorder. RESULTS: In response to an open-ended question, around a quarter of the participants failed to recognize depression in the vignette. When asked about the potential helpfulness of various people, most of the participants considered mental health professionals, family and friends to be helpful. However, teachers, social workers and a helpline were less likely to be considered as helpful. With regard to medications, vitamins received more positive views than psychotropics. Some interventions were frequently rated as likely to be helpful, whereas for others there was a lack of knowledge about their effectiveness. A positive finding is that alcohol and tobacco consumption were seen as harmful. When asked about mental health first aid strategies, participants supported the value of listening to the person in the vignette and advising professional help, but some unhelpful strategies were commonly endorsed as well. CONCLUSION: Deficits were found in some aspects of depression literacy in Portuguese youth. Therefore intervention in this area is needed. PMID- 23651636 TI - Therapeutic destruction of insulin receptor substrates for cancer treatment. AB - Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and antiapoptotic signaling from insulin-like growth factor 1 receptor (IGF-IR), insulin receptor (IR), and other oncoproteins. IRS1 plays a central role in cancer cell proliferation, its expression is increased in many human malignancies, and its upregulation mediates resistance to anticancer drugs. IRS2 is associated with cancer cell motility and metastasis. Currently, there are no anticancer agents that target IRS1/2. We present new IGF-IR/IRS-targeted agents (NT compounds) that promote inhibitory Ser-phosphorylation and degradation of IRS1 and IRS2. Elimination of IRS1/2 results in long-term inhibition of IRS1/2-mediated signaling. The therapeutic significance of this inhibition in cancer cells was shown while unraveling a novel mechanism of resistance to B-RAF(V600E/K) inhibitors. We found that IRS1 is upregulated in PLX4032-resistant melanoma cells and in cell lines derived from patients whose tumors developed PLX4032 resistance. In both settings, NT compounds led to the elimination of IRS proteins and evoked cell death. Treatment with NT compounds in vivo significantly inhibited the growth of PLX4032-resistant tumors and displayed potent antitumor effects in ovarian and prostate cancers. Our findings offer preclinical proof-of concept for IRS1/2 inhibitors as cancer therapeutics including PLX4032-resistant melanoma. By the elimination of IRS proteins, such agents should prevent acquisition of resistance to mutated-B-RAF inhibitors and possibly restore drug sensitivity in resistant tumors. PMID- 23651638 TI - College women's experiences with rape disclosure: a national study. AB - Disclosure of a rape to informal support sources (e.g., friends) is a relatively common experience, but it is not well understood. This study expands our limited knowledge of the characteristics and life experiences of disclosure recipients among a national sample of 2,000 female college students. Over 40% of respondents reported having received a rape disclosure, and more than two thirds of these recipients encouraged victims to formally report their rapes to the police or other authorities. Correlates of disclosure receipt and encouragement of reporting, including personal assault history, mental health history, and substance use, are presented and discussed. PMID- 23651639 TI - The impact of sexual enhancement alcohol expectancies and risky behavior on alcohol-involved rape among college women. AB - A structural equation model examined sexual enhancement alcohol expectancies, heavy episodic drinking (HED), and risky sexual behavior as correlates of alcohol involved rape in a sample of 353 college women. Prevalence of alcohol-involved rape was 15.6%. Sexual enhancement alcohol expectancies were indirectly associated with alcohol-involved rape via increased levels of HED, greater likelihood of sex while intoxicated, and number of sex partners. All forms of risky behavior were associated with alcohol-involved rape although HED had the strongest relationship. Findings suggest continued focus on women's positive alcohol expectancies and HED as risk factors for alcohol-involved rape. Implications for intervention will be discussed. PMID- 23651640 TI - In-line quantification of two active ingredients in a batch blending process by near-infrared spectroscopy: influence of physical presentation of the sample. AB - The aim of this study was to apply near-infrared (NIR) spectroscopy to the simultaneous in-line monitoring of two active pharmaceutical ingredients (APIs) in a pharmaceutical batch blending process. The formulation under study consisted of a high load API (A1), one polymer, a second API (A2) and one lubricant. Additionally, the effects of the presentation of A1 on the spectral data were evaluated. For this purpose, the high load active was blended either as a cohesive powder or as a free flowing material. For improving the flow behavior of the high load active a melt-granulation (MG) step was performed. The NIR spectra of the high load API (A1) before and after MG showed that the polymer wavelength absorption band was the most affected, this wavelength range was also associated with the water band region. Thus, these frequencies carried information from the melt-granulation process and could be influenced by the water content. For the APIs quantification, independent partial least squares (PLS-1) models for each API were generated. Furthermore, a PLS-2 model was also developed for the simultaneous quantification of each API. The PLS models were used for the in-line blend uniformity monitoring of both APIs. PMID- 23651641 TI - Solubility enhancement of paclitaxel using a linear-dendritic block copolymer. AB - The solubilising capacities of micelles of a linear-dendritic copolymer (BE PAMAM), formed by conjugating the poly(butylene oxide) (B)-poly(ethylene oxide) (E) block copolymer B16E42 (BE) with a G2 PAMAM dendrimer, have been compared with those of the diblock copolymer B16E42 for the anti-cancer drug paclitaxel. The BE-PAMAM copolymer showed a greater solubility enhancement than BE under equivalent conditions. Drug-loading efficiency was improved using a solvent loading method compared with the conventional solution-loading method. The solubility of paclitaxel was increased 3700-fold by micellar encapsulation in a 2% (w/v) BE-PAMAM copolymer solution at 37 degrees C using this solubilisation technique. Dynamic light scattering and transmission electron microscopy studies indicated a transition of spherical to worm-like micelles of the BE copolymer induced by the encapsulation of drug molecules. A sustained release of encapsulated drug was observed, with approximately 80% and 60% paclitaxel being released from 2% (w/v) solutions of BE and BE-PAMAM respectively after 24h of dialysis at 37 degrees C. PMID- 23651642 TI - Development of amorphous solid dispersion formulations of a poorly water-soluble drug, MK-0364. AB - The goal of this study was to demonstrate that MK-0364 solid dispersions can be developed as a means to increase the solubility and bioavailability of a poorly water-soluble drug, MK-0364. The potential solid dispersions would enable an oral solid dosage form as a monotherapy or combination product of MK-0364. Preliminary screening included sample preparation via a solvent casting method, physical characterization, and in vitro dissolution testing. Lead formulations were subsequently manufactured using hot melt extrusion (HME) and spray-drying (SD). All HME (without polyvinyl pyrrolidone) and SD formulations exhibit characteristics of a single phase glass including an amorphous halo when analyzed with X-ray powder diffraction (XRPD), a single glass transition temperature (Tg) measured with differential scanning calorimetry (DSC), and supersaturation when dissolved in dissolution media. The oral absorption of MK-0364 from selected HME and SD formulations in monkeys results in marginally greater exposure with a consistently longer Tmax relative to a liquid filled capsule reference. Based on the processability, physical characterization, in vitro dissolution, and animal pharmacokinetic results, copovidone- and hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based solid dispersion formulations are viable product concepts. The physical stability of both the solid dispersion formulations was also evaluated for 54 weeks under different conditions. The copovidone-based solid dispersion requires protection from moisture. PMID- 23651643 TI - Porous orthopedic steel implant as an antibiotic eluting device: prevention of post-surgical infection on an ovine model. AB - Traumatology and orthopedic surgery can benefit from the use of efficient local antibiotic-eluting systems to avoid bacterial contamination of implanted materials. In this work a new percutaneous porous-wall hollow implant was successfully used as a local antibiotic-eluting device both in vitro and in vivo. The implant is a macroporous 316 L stainless steel filter tube with a nominal filtration cut-off size of 200 nm with one open end which was used to load the synthetic antibiotic linezolid and an opposite blind end. The antibiotic release kinetics from the device on a simulated biological fluid under in vitro conditions demonstrated an increased concentration during the first five days that subsequently was sustained for at least seven days, showing a kinetic close to a zero order release. Antibiotic-loaded implants were placed in the tibia of four sheep which were trans-surgically experimentally infected with a biofilm forming strain of Staphylococcus aureus. After 7 and 9 days post infection, sheep did not show any evidence of infection as demonstrated by clinical, pathological and microbiological findings. These results demonstrate the capability of such an antibiotic-loaded implant to prevent infection in orthopedic devices in vivo. Further research is needed to assess its possible use in traumatology and orthopedic surgery. PMID- 23651644 TI - Characterization and optimization of GMO-based gels with long term release for intraarticular administration. AB - Osteoarthritis is characterized by slow degenerative processes in the articular cartilage within synovial joints. It could be interesting to develop a sustained release formulation that could be effective on both pain/inflammation and restoration of mechanical integrity of the joint. Recently, an injectable system based on glycerol monooleate (GMO), containing clonidine as a model hydrophilic analgesic/anti-inflammatory drug and hyaluronic acid as a viscoelastic scaffold, showed promising potential as a biodegradable and biocompatible preparation to sustain the drug activity. However, drug release from the system is relatively fast (complete within 1 week) and the underlying drug release mechanisms not fully understood. The aims of this study were: (i) to significantly improve this type of local controlled drug delivery system by further sustaining clonidine release, and (ii) to elucidate the underlying mass transport mechanisms. The addition of FDA-approved inactive ingredients such as sodium oleate or purified soybean oil was found to be highly effective. The release rate could be substantially reduced (e.g., 50% release after 10 days), due to the increased hydrophobicity of the systems, resulting in slower and reduced water uptake and reduced drug mobility. Interestingly, Fick's second law of diffusion could be used to quantitatively describe drug release. PMID- 23651645 TI - Development of a pulmonary peptide delivery system using porous nanoparticle aggregate particles for systemic application. AB - As a non-invasive administration route, pulmonary peptide delivery for systemic application has shown great promise. However, many barriers exist that prevent effective peptide delivery. The use of porous nanoparticle-aggregate particles (PNAPs) is an excellent option because of their proper aerodynamic size and maximal deposition. However, in most cases, the spray drying heating process for PNAPs has been challenging in regard to maintaining peptide stability and activity. To overcome these issues, we developed a spray freeze-drying method for PNAP preparation. To solve the low entrapment efficiency problem of nanostructured lipid carriers, we used hydrophobic ion pair complexes to increase the lipophilicity of the peptide, thus increasing entrapment efficiency and drug loading. Here, we used a model peptide, octreotide acetate, for PNAP preparation, which has a high entrapment efficiency (>95%) and proper aerodynamic size (~3 MUm). In addition, after intrapulmonary administration, we evaluated the pharmacokinetics and pharmacodynamics in a rat preventive hepatic ischemia reperfusion injury model. Our in vivo data showed significantly increased area under the curve and improved plasma aspartate aminotransferase levels for our PNAP intrapulmonary delivery system vs. the clinically used octreotide acetate delivery via subcutaneous injection. Together, PNAPs may have great potential for carrying peptide drugs for pulmonary delivery. PMID- 23651647 TI - Silk lutein extract and its combination with vitamin E reduce UVB-mediated oxidative damage to retinal pigment epithelial cells. AB - Increased exposure to solar ultraviolet B (UVB) radiation may promote age related macular degeneration (AMD). Lutein can protect retinal pigment epithelial (RPE) cells from various oxidative insults but its direct protection against UVB has not been reported. This study aimed to demonstrate protective effects of silk lutein extract against UVB-induced oxidative damage to RPE cells and compared with standard lutein and Trolox, a vitamin E analog. ARPE-19 cells were treated with luteins with and without Trolox prior to UVB exposure. Cell viability and apoptosis were determined by trypan blue staining and caspase-3 activity, respectively. Oxidative damage was evaluated by measuring intracellular reactive oxygen species (ROS), lipid peroxidation, and activities of antioxidant enzymes (superoxide dismutase, glutathione peroxidase and catalase). Levels of lutein remained in culture medium was determined by HPLC. Both luteins reduced cellular ROS levels and lipid peroxidation mediated by UVB, and subsequently increased cell viability and reduced apoptosis. They also restored activities of most tested antioxidant enzymes. Enhancement of lutein antioxidant efficacy was observed in the presence of Trolox. In all these effects, the two lutein preparations had similar effectivenesses. In cell free media, Trolox enhanced the protective effect of lutein probably by reducing its degradation and repairing the oxidized derivatives. Yellow silk cocoon is a potential candidate of lutein for further development as dietary supplement for the prevention of AMD. PMID- 23651646 TI - Hepatitis C treatment access and uptake for people who inject drugs: a review mapping the role of social factors. AB - BACKGROUND: Evidence documents successful hepatitis C virus (HCV) treatment outcomes for people who inject drugs (PWID) and interest in HCV treatment among this population. Maximising HCV treatment for PWID can be an effective HCV preventative measure. Yet HCV treatment among PWID remains suboptimal. This review seeks to map social factors mediating HCV treatment access. METHOD: We undertook a review of the social science and public health literature pertaining to HCV treatment for PWID, with a focus on barriers to treatment access, uptake and completion. Medline and Scopus databases were searched, supplemented by manual and grey literature searches. A two step search was taken, with the first step pertaining to literature on HCV treatment for PWID and the second focusing on social structural factors. In total, 596 references were screened, with 165 articles and reports selected to inform the review. RESULTS: Clinical and individual level barriers to HCV treatment among PWID are well evidenced. These include patient and provider concerns regarding co-morbidities, adherence, and side effect management. Social factors affecting treatment access are less well evidenced. In attempting to map these, key barriers fall into the following domains: social stigma, housing, criminalisation, health care systems, and gender. Key facilitating factors to treatment access include: combination intervention approaches encompassing social as well as biomedical interventions, low threshold access to opiate substitution therapy, and integrated delivery of multidisciplinary care. CONCLUSION: Combination intervention approaches need to encompass social interventions in relation to housing, stigma reduction and systemic changes in policy and health care delivery. Future research needs to better delineate social factors affecting treatment access. PMID- 23651648 TI - Sex differences matter in the gut: effect on mucosal immune activation and inflammation. AB - BACKGROUND: Women and men have diverse responses to many infectious diseases. These differences are amplified following menopause. However, despite extensive information regarding the effects of sex hormones on immune cells, our knowledge is limited regarding the effects of sex and gender on the function of the mucosal immune system. Sex differences also manifest in the prevalence of gut associated inflammatory and autoimmune disorders, including Crohn's disease, ulcerative colitis and Celiac disease. It is thus hypothesized that a baseline sex associated difference in immune activation may predispose women to inflammation associated disease. METHODS: Peripheral blood samples and small intestinal biopsies were obtained from 34 healthy men and women. Immunophenotypic analysis of isolated lymphocytes was performed by flow cytometry. Oligonucleotide analysis was used to study the transcriptional profile in the gut mucosal microenvironment while real-time PCR analysis was utilized to identify differential gene expression in isolated CD4+ T cells. Transcriptional analysis was confirmed by protein expression levels for genes of interest using fluorescent immunohistochemistry. Data was analyzed using the GraphPad software package. RESULTS: Women had higher levels of immune activation and inflammation-associated gene expression in gut mucosal samples. CD4+ and CD8+ T cells had a significantly higher level of immune activation-associated phenotype in peripheral blood as well as in gut associated lymphoid tissue along with higher levels of proliferating T cells. CD4+ T cells that showed upregulation of IL1beta as well as the TH17 pathway-associated genes contributed a large part of the inflammatory profile. CONCLUSION: In this study, we demonstrated an upregulation in gene expression related to immune function in the gut microenvironment of women compared to men, in the absence of disease or pathology. Upon closer investigation, CD4+ T cell activation levels were higher in the LPLs in women than in men. Sex differences in the mucosal immune system may predispose women to inflammation-associated diseases that are exacerbated following menopause. Our study highlights the need for more detailed analysis of the effects of sex differences in immune responses at mucosal effector sites. PMID- 23651649 TI - Examining HIV-related stigma and discrimination in Ghana: what are the major contributors? AB - BACKGROUND: Although AIDS-related stigma and discrimination are considered detrimental to HIV prevention activities, not many studies have attempted to understand stigma and discrimination in sub-Saharan Africa, particularly Ghana. METHODS: Using the 2008 Ghana Demographic and Health Survey and applying the ordinary least-squares technique, this study examined what influences AIDS related stigma and discrimination among men and women in Ghana. RESULTS: The results indicate that Ghanaian men and women with relatively high knowledge about HIV/AIDS had low stigmatising and discriminatory attitudes (b=-0.097, P<0.01; b= 0.083, P<0.01), respectively. On the other hand, respondents who endorsed more myths about HIV transmission had high stigma and discriminatory attitudes. Women who had ever tested for their HIV serostatus reported significantly lower levels of stigma and discrimination (b=-0.085, P<0.01) compared with those who had not tested for HIV. Individuals who are highly educated, employed and in wealthy households all reported significantly lower levels of stigma and discrimination compared with those who are uneducated, unemployed and in poorer households. CONCLUSION: AIDS-related stigma and discrimination can be reduced by encouraging HIV testing, and ensuring that Ghanaians understand and have factual knowledge regarding the transmission of the disease. PMID- 23651650 TI - Polystyrene-divinylbenzene stationary phases agglomerated with quaternized multi walled carbon nanotubes for anion exchange chromatography. AB - This work explores the potential of multi-walled carbon nanotubes as an agglomerated material for ion chromatography stationary phases for the separation of inorganic anions. Polyelectrolytes with quaternary ammonium groups were introduced onto the carbon nanotube surface, based on condensation polymerization of 1,4-butanediol diglycidyl ether (BDDE) and methylamine (MA). Quaternized multi walled carbon nanotubes (Q-MWCNTs) were electrostatically adsorbed onto the surface of sulfonated polystyrene-divinylbenzene (PS-DVB) beads to generate the anion exchanger, which were confirmed by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). A 100mm*4.0mm i.d. column was packed with Q-MWCNTs agglomerated PS-DVB particles, with a capacity of 56MUequiv./column. Separation of inorganic anions, such as F(-), Cl(-), NO2(-), Br(-), NO3(-), SO4(2-) and PO4(3-) were performed. The stationary phase was rigid, chemically stable and showed good ion-exchange characteristics. PMID- 23651651 TI - Young children's flexible use of semantic cues to word meanings: converging evidence of individual and age differences. AB - A new test of children's flexible use of semantic cues for word learning extended previous results. In Experiment 1, three- to five-year-olds (N = 51) completed two tests of interpreting several novel words for the same stimulus arrays. Within-sentence phrasal cues implied different stimulus referent properties. Children's cue-using flexibility in the new Flexible Induction of Meanings [Words for Animates] test (FIM-An) was strongly correlated with an established test (Flexible Induction of Meanings [Words for Objects]; Deak, 2000). Individual children showed between-test consistency in using cues to flexibly assign words to different referent properties. There were large individual differences, as well as limited age differences, in the distribution of flexible and inflexible response patterns. The comprehensibility of specific cues, and perceptual salience of specific properties, explained much of the variance. Proportions of flexible and inflexible patterns shifted with age. Experiment 2 replicated these results in N=36 three- and four-year-olds, using a modified FIM-An with more distinctive cues. PMID- 23651652 TI - Reversal of multidrug resistance by magnetic chitosan-Fe3O4 nanoparticle encapsulated MDR1 siRNA in glioblastoma cell line. AB - OBJECTIVE: To investigate the reversal effects of MDR1 gene on multidrug resistance in the glioblastoma cell line BT325 by magnetic chitosan-Fe3O4 nanoparticle-encapsulated MDR1 siRNA. METHODS: The shRNA expression vector was constructed and the recombinant plasmids were cloned. Magnetic chitosan-Fe3O4 nanoparticles were prepared and the encapsulation rate was determined. After transfection, the BT325 cells were cultured to assay the transfection efficiency. The changing of MDR1 mRNA level and P-gp protein was evaluated. And the sensitivity to different chemotherapeutic drugs was assessed in BT325-siRNA transfected cell and untransfected cell by IC50 values. RESULTS: The MDR1 RNAi plasmid was successfully designed and preparation. The encapsulation efficiency of the magnetic chitosan-Fe3O4 nanoparticle was 98-99%. The transfection efficiency of the siRNA-nanoparticles in BT325 cells was 70-80%. And the MDR1 mRNA levels were downregulated by reverse transcription (RT)-PCR assay. Furthermore, the results of P-gp protein expression decreased on immunocytochemical assay, Western blot and flow cytometry compared with control group. The IC50 values of DOX and VCR were decreased between the transfected cell and normal BT325 cell. CONCLUSION: After targeted transfection of the glioblastoma cell line with magnetic chitosan-Fe3O4 nanoparticle-encapsulated MDR1 siRNA, the expression of MDR1 at both the mRNA and protein level decreased, which increased sensitivity to chemotherapy in vitro. It might provide a basis for investigation of the mechanism involved in multidrug resistance in glioma. PMID- 23651653 TI - Assessment of bacterial diversity during composting of agricultural byproducts. AB - BACKGROUND: Composting is microbial decomposition of biodegradable materials and it is governed by physicochemical, physiological and microbiological factors. The importance of microbial communities (bacteria, actinomycetes and fungi) during composting is well established. However, the microbial diversity during composting may vary with the variety of composting materials and nutrient supplements. Therefore, it is necessary to study the diversity of microorganisms during composting of different agricultural byproducts like wheat bran, rice bran, rice husk, along with grass clippings and bulking agents. Here it has been attempted to assess the diversity of culturable bacteria during composting of agricultural byproducts. RESULTS: The culturable bacterial diversity was assessed during the process by isolating the most prominent bacteria. Bacterial population was found to be maximum during the mesophilic phase, but decreased during the thermophilic phase and declined further in the cooling and maturation phase of composting. The bacterial population ranged from 10(5) to 10(9) cfu g(-1) compost. The predominant bacteria were characterized biochemically, followed by 16S rRNA gene sequencing. The isolated strains, both Gram-positive and Gram negative groups belonged to the order Burkholderiales, Enterobacteriales, Actinobacteriales and Bacillales, which includes genera e.g. Staphylococcus, Serratia, Klebsiella, Enterobacter, Terribacillus, Lysinibacillus Kocuria, Microbacterium, Acidovorax and Comamonas. Genera like Kocuria, Microbacterium, Acidovorax, Comamonas and some new species of Bacillus were also identified for the first time from the compost made from agricultural byproducts. CONCLUSION: The use of appropriate nitrogen amendments and bulking agents in composting resulted in good quality compost. The culture based strategy enabled us to isolate some novel bacterial isolates like Kocuria, Microbacterium, Acidovorax and Comamonas first time from agro-byproducts compost. These bacteria can be used as potential compost inoculants for accelerating composting process. PMID- 23651654 TI - Functional analyses of nanoparticle toxicity: a comparative study of the effects of TiO2 and Ag on tomatoes (Lycopersicon esculentum). AB - Engineered nanoparticles (NPs), increasingly used in industry, enter and migrate through biological ecosystems. NPs may create some acute toxicity, but their overall effects on living organisms remain largely unknown. In particular, the behavior of NPs in natural conditions and their consequent ecological effects are still poorly understood. In this study, we developed methods to test the phytotoxicity of two distinctly different NPs, one aerosol (nano-TiO2), and the other colloidal silver (AgNP), by specifically considering their tendencies to agglomerate and form precipitates. First we examined effects of these NPs on germination and root elongation. While exposure to neither of these NPs resulted in acute toxicity on germination, silver NPs caused significantly decreased root elongation at every concentration we tested. We found that the hydrodynamic diameters of AgNPs were much smaller than those of nano-TiO2, which induced higher uptake and phytotoxicity. Based on the agglomeration behavior of the NPs, greenhouse trials were run using commercial soil, for nano-TiO2, and Hoagland's solution, for AgNP. Phytotoxicity of silver NPs in the mature plants was demonstrated by lower chlorophyll contents, higher superoxide dismutase activity and less fruit productivity, while nano-TiO2 resulted in higher superoxide dismutase activity at the highest concentration (5000mg/kg). Both nano-TiO2 and AgNPs were taken up into plant stems, leaves and fruits. Our results suggest that further studies of the ecological effects of nanoparticles and steps to mitigate appropriate management strategies are required. PMID- 23651655 TI - Establishing local and regional DRLs by means of electronic radiographical X-ray examination records. AB - The objective of the paper is to demonstrate that patient dose audits may be undertaken at the local and regional levels by employing electronic examination records contained in Radiology Information Systems (RISs) that have been collected, analysed and managed by modern IT systems. The resulting mean and third quartile values obtained may then be used to establish local and regional dose reference levels (DRLs) as part of an optimisation strategy. The method involved the collection of roughly 1.3 million radiographical examination records stored in hospital RIS over a 3-y period from 10 hospital sites in the north of England. These were analysed according to the process employed in the national patient dose (NPD) audits undertaken every 5 y in the UK. Data processing and analysis methods are described that are suitable for handling very large data sets quickly and efficiently. Because RIS data involve manual data entry it may be susceptible to data entry errors. Therefore, a comparison of results obtained from both RIS and DICOM generated data was first of all undertaken in order to 'calibrate' the RIS-based method and demonstrate its accuracy. The results obtained from this comparison indicate that the RIS-based examination records provide patient dose distributions with an equivalent statistical accuracy compared with those employing DICOM data and, therefore, may be employed in patient dose audits in order to establish both local and regional DRLs for use in patient dose management and optimisation strategies. PMID- 23651656 TI - Compatibility characteristics of five radiographic films utilised in Brazilian diagnostic radiology. AB - To evaluate the quality of the radiographic films in Brazil, according to the recommendations of ISO 9236-1, a radiographic images simulator was used. A study of the control of the quality in radiographic films was implemented. With regard to this study, the results of five films of different manufacturers are presented. The characteristic curves for the ISO qualities of 55, 70, 90 and 120 kV are presented. The PTW REX simulator was used to determine the image quality parameters. Film 2 presents problems due to high sensitivity. Film 1 has a higher energy dependence than the other films. Film 5 yields the best results for almost all the sensitometric parameters. In conclusion, existing films in the Brazilian market vary considerably with relation to image quality. PMID- 23651657 TI - The activity concentration of 210Po in Romanian commercial cigarettes and the radiation exposure estimation derived from their regular consumption. AB - Due to the relatively high activity concentrations of (210)Po that are found in tobacco, cigarette smoking has been found to be the principal pathway of the intake of this radionuclide. The (210)Po concentrations in the lung tissues may contribute significantly to an increase in the internal radiation dose and in the number of instances of lung cancer observed among smokers. The study of (210)Po in tobacco is required due to its potential for human radiation exposure through ingestion and inhalation. The risk factor caused by (210)Po in Romanian commercial cigarettes is not yet evaluated. Ten of the most frequently smoked brands of cigarettes sold in Romania were investigated in this work for this purpose. The activity concentration of (210)Po was determined by alpha spectrometry using a PIPS detector after chemical leaching and spontaneous deposition of (210)Po on a stainless steel disc from diluted HCl solution. The samples were spiked with (209)Po for chemical recovery calculation. The (210)Po activity concentrations of the measured types of cigarettes ranged from 4.65 to 10.22 mBq sample(-1) and the resulted average concentration of (210)Po isotopes is 8.35+/-0.80 mBq cigarette(-1) (the errors form a 2sigma interval of confidence). When comparing the results of this study with the activity concentration values reported by other countries it was found that the results of this study are in the lower end of the world range. The estimation of this study shows that cigarette smokers, who are smoking one pack (20 cigarettes) per day, are exposed to an effective dose of 75.51 MUSv y(-1). PMID- 23651658 TI - Measures of thyroid function among Belarusian children and adolescents exposed to iodine-131 from the accident at the Chernobyl nuclear plant. AB - BACKGROUND: Thyroid dysfunction after exposure to low or moderate doses of radioactive iodine-131 (131I) at a young age is a public health concern. However, quantitative data are sparse concerning 131I-related risk of these common diseases. OBJECTIVE: Our goal was to assess the prevalence of thyroid dysfunction in association with 131I exposure during childhood (<= 18 years) due to fallout from the Chernobyl accident. METHODS: We conducted a cross-sectional analysis of hypothyroidism, hyperthyroidism, autoimmune thyroiditis (AIT), serum concentrations of thyroid-stimulating hormone (TSH), and autoantibodies to thyroperoxidase (ATPO) in relation to measurement-based 131I dose estimates in a Belarusian cohort of 10,827 individuals screened for various thyroid diseases. RESULTS: Mean age at exposure (+/- SD) was 8.2 +/- 5.0 years. Mean (median) estimated 131I thyroid dose was 0.54 (0.23) Gy (range, 0.001-26.6 Gy). We found significant positive associations of 131I dose with hypothyroidism (mainly subclinical and antibody-negative) and serum TSH concentration. The excess odds ratio per 1 Gy for hypothyroidism was 0.34 (95% CI: 0.15, 0.62) and varied significantly by age at exposure and at examination, presence of goiter, and urban/rural residency. We found no evidence of positive associations with antibody-positive hypothyroidism, hyperthyroidism, AIT, or elevated ATPO. CONCLUSIONS: The association between 131I dose and hypothyroidism in the Belarusian cohort is consistent with that previously reported for a Ukrainian cohort and strengthens evidence of the effect of environmental 131I exposure during childhood on hypothyroidism, but not other thyroid outcomes. PMID- 23651659 TI - Therapeutic activity of inhibition of the soluble epoxide hydrolase in a mouse model of scrapie. AB - AIMS: The misfolding and the aggregation of specific proteins are key features of neurodegenerative diseases, specifically Transmissible Spongiform Encephalopathies (TSEs). In TSEs, neuronal loss and inflammation are associated with the accumulation of the misfolded isoform (PrP(sc)) of the cellular prion protein (PrP(c)). Therefore we tested the hypothesis that augmenting a natural anti-inflammatory pathway mediated by epoxygenated fatty acids (EpFAs) will delay lethality. EpFAs are highly potent but enzymatically labile molecules produced by the actions of a number of cytochrome P450 enzymes. Stabilization of these bioactive lipids by inhibiting their degradation mediated by the soluble epoxide hydrolase (sEH) results in potent anti-inflammatory effects in multiple disease models. MAIN METHODS: Mice were infected with the mouse-adapted RML strain of scrapie by intracerebral or intraperitoneal routes. Animals received the sEH inhibitor, by oral route, administrated in drinking water or vehicle (PEG400). Infected mice were euthanized at a standard clinical end point. Histopathological, immunohistochemical and Western blot analyses of brain tissue confirmed the presence of pathology related to prion infection. KEY FINDINGS: Oral administration of the sEHI did not affect the very short survival time of the intracerebral prion infection group. However, mice infected by intraperitoneal route and treated with t-AUCB survived significantly longer than the control group mice (p<0.001). SIGNIFICANCE: These findings support the idea that inhibition of sEH or augmentation of the natural EpFA signaling in the brain offers a potential and different route to understand prion diseases and may become a therapeutic strategy for diseases involving neuroinflammation. PMID- 23651660 TI - Relationship between noradrenaline release in the locus coeruleus and antiallodynic efficacy of analgesics in rats with painful diabetic neuropathy. AB - AIMS: In animal models of neuropathic pain, the noradrenergic descending pain inhibitory pathways from the locus coeruleus (LC) may be suppressed. However, no study has investigated the correlation between noradrenaline (NA) release in the LC and efficacy of analgesics in rats with painful diabetic neuropathy. Using microdialysis and analysis of mechanical hypersensitivity, we investigated the correlation between NA release in the LC and efficacy of morphine, tramadol, and clomipramine in rats with diabetic mellitus (DM). MAIN METHODS: In freely moving rats, basal NA concentrations in LC perfusate were quantitated 72 to 96 h after microdialysis probe implantation. Following intravenous administration of each drug, NA concentrations were expressed as a percentage of basal values. We concurrently measured the threshold to elicit a paw withdrawal response every 20 min for 80 min. KEY FINDINGS: NA concentrations in the LC perfusate were significantly higher in the tramadol and clomipramine groups compared to the morphine group. Naloxone administration did not significantly affect NA concentrations. In the morphine group, NA release in the LC was not significantly correlated with the pain threshold. In contrast, in the tramadol and clomipramine groups, NA release in the LC was significantly correlated with the pain threshold. The correlation coefficient was higher in the clomipramine group than in the tramadol group. SIGNIFICANCE: Our results suggest that the descending noradrenergic pathway can play an important role in analgesia for DM neuropathy and that there is a significant correlation between NA release in the LC and the efficacy of tramadol and clomipramine. PMID- 23651661 TI - Bio-production of lactobionic acid: current status, applications and future prospects. AB - Lactobionic acid has appeared on the commercial scene as a versatile polyhydroxy acid with numerous promising applications in the food, medicine, pharmaceutical, cosmetics and chemical industries. This high value-added bio-product has recently received growing attention as a bioactive compound, providing an excellent chemical platform for the synthesis of novel potentially biocompatible and biodegradable drug delivery vehicles. Recent advances in tissue engineering and nanomedicine have also underlined the increased importance of this organic acid as a key biofunctionalization agent. The growing commercial relevance of lactobionic acid has therefore prompted the development of novel systems for its biotechnological production that are both sustainable and efficient. The present review explores recent advances and studies related to lactobionic acid bio production, whether through microbial or enzymatic approaches, highlighting the key bioprocessing conditions for enhanced bio-production. Detailed overviews of the current microbial cell factories as well as downstream processing methodologies for lactobionic acid production are also presented. Furthermore, the potential prospects and current applications of this polyhydroxy acid are also discussed, with an emphasis on the role of lactobionic acid as a key platform in the development of novel drugs, biomaterials, nanoparticles and biopolymer systems. PMID- 23651662 TI - Pleomorphic carcinoma of the breast associated with cyst formation: a unique surgical case focusing on cytological and immunohistochemical findings. Cystic breast PC. AB - A mammary nodular lesion was recognized one month before the surgery in the right upper breast of a 55-year-old female. The fine needle aspiration cytology specimens contained many individual bizarre, multi-nucleated, and/or giant cells having hyperchromatic pleomorphic nuclei, prominent nucleoli, and relatively abundant cytoplasm, admixed with numerous mitotic figures in a hemorrhagic or inflammatory background. A small amount of sheet-like or three-dimensional clusters of malignant cells coexisted. We first interpreted it as high-grade malignancy, such as invasive carcinoma, not otherwise specified. A right breast conserving surgery was performed, and gross examination revealed a cystic cavity formed and solid tumor lesion, measuring 35 * 35 * 25 mm and looking gray yellowish to -whitish. On microscopic examination, the tumor was composed of a diffuse proliferation of highly atypical cells devoid of adhesive characteristics, including many multi-nucleated giant bizarre cells, in a haphazard fashion with stromal invasion, alternating with sarcomatoid features of spindle tumor cells. The cystic cavity was surrounded by hemorrhagic and inflammatory granulation tissue and lined by mostly denuded but atypical tumor cells or bland-looking flattened epithelial cells. Immunohistochemically, these tumor cells are specifically positive for all epithelial markers. Therefore, we made a conclusive diagnosis of pleomorphic carcinoma of the breast with cyst formation. We should be aware that, owing to its characteristic findings, cytopathologists can diagnose correctly, based on careful cytological examination of adequate samplings. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9290689448998782. PMID- 23651663 TI - Predictors of psychiatric disorders in combat veterans. AB - BACKGROUND: Most previous research that has examined mental health among Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) combatants has relied on self-report measures to assess mental health outcomes; few studies have examined predictors of actual mental health diagnoses. The objective of this longitudinal investigation was to identify predictors of psychiatric disorders among Marines who deployed to combat in Iraq and Afghanistan. METHODS: The study sample consisted of 1113 Marines who had deployed to Iraq or Afghanistan. Demographic and psychosocial predictor variables from a survey that all Marines in the sample had completed were studied in relation to subsequent psychiatric diagnoses. Univariate and multivariate logistic regression were used to determine the influence of the predictors on the occurrence of psychiatric disorders. RESULTS: In a sample of Marines with no previous psychiatric disorder diagnoses, 18% were diagnosed with a new-onset psychiatric disorder. Adjusting for other variables, the strongest predictors of overall psychiatric disorders were female gender, mild traumatic brain injury symptoms, and satisfaction with leadership. Service members who expressed greater satisfaction with leadership were about half as likely to develop a mental disorder as those who were not satisfied. Unique predictors of specific types of mental disorders were also identified. CONCLUSIONS: Overall, the study's most relevant result was that two potentially modifiable factors, low satisfaction with leadership and low organizational commitment, predicted mental disorder diagnoses in a military sample. Additional research should aim to clarify the nature and impact of these factors on combatant mental health. PMID- 23651664 TI - Thyroid hormone signaling. PMID- 23651665 TI - Ability to access community-based needle-syringe programs and injecting behaviors among drug users: a cross-sectional study in Hunan Province, China. AB - BACKGROUND: Needle-syringe exchange programs (NSPs) have been substantially rolled-out in China since 2002. Limited studies reported effectiveness of NSPs in a Chinese setting. This study aimed to assess the association between accessibility to NSPs and drug-use risk behaviors of IDUs by investigating primary (self-reported) data of IDUs recruited from NSP sites, community settings and mandatory detoxification centers (MDCs) in Hunan province, China. METHODS: A cross-sectional survey was conducted in Hunan province in 2010. IDU recruits participated in a face-to-face interview to provide information related to their ability to access NSPs, demographic characteristics, and injecting behaviors in the past 30 days. RESULTS: Of the total 402 participants, 35%, 14% and 51% participants indicated low, medium and high ability to access NSPs in the past 30 days, respectively. A significantly higher proportion of IDUs (77.3%) from the high-access group reported <=2 injecting episodes per day compared with medium- (46.3%) and low-access (58.8%) groups. Only 29.0% of high-access IDUs re-used syringes before disposal in the past 30 days, significantly lower than those in the medium- (43.1%) and low-access (41.3%) groups. Reported levels of needle/syringe sharing decreased significantly as the ability to access NSPs increased (16.3%, 12.7% and 2.5% in the low, medium and high access groups, respectively). Ninety percent of IDUs recruited from MDCs had low ability to access NSPs. CONCLUSIONS: Increased NSP accessibility is associated with decreased levels of injecting frequency, repetitive use and sharing of injecting equipment among Chinese IDUs. Mandatory detention of IDUs remains as a major barrier for IDUs to access NSPs in China. PMID- 23651667 TI - Degree and correlates of sexual mixing in female sex workers in Karnataka, India. AB - Background The degree of sexual mixing plays an important role in understanding disparities in sexually transmissible infections and HIV across social groups. This study examines the degree of sexual age mixing, and explores its individual and partnership level correlates among female sex workers (FSWs) in Karnataka, India. METHODS: Data were drawn from special behavioural surveys conducted in 2006-07 among 577 FSWs in two districts of Karnataka: Belgaum and Bangalore. Sexual mixing in age was assessed as the difference in age between FSWs and their sexual partners, and the degree of assortativeness in sexual mixing was assessed using Newman's assortativity coefficient. RESULTS: A total of 577 FSWs were interviewed; 418 of whom reported two or more partnerships, resulting in 942 partnerships. In about half (52%) of these partnerships, the age difference between the FSW and her sexual partner was 5 years or more. The degree of assortativity in age mixing was 0.098, indicating minimally assortative mixing. The disassortativeness in age mixing was positively associated with young age and no formal education, and negatively with duration in sex work. Partnerships which were of a commercial nature were more likely to be disassortative than noncommercial partnerships. CONCLUSION: The minimally assortative age mixing indicates sexually transmissible infections can transfer from members of one age group to another. Efforts are required to limit the transmission of infection from one group to other by promoting safer sexual behaviour. PMID- 23651666 TI - Adipocytokines, inflammation, and breast cancer risk in postmenopausal women: a prospective study. AB - Obesity is a known risk factor for postmenopausal breast cancer; it has been postulated that adipocytokines may mediate this association. We explored the relationship between three markers altered by obesity: leptin, adiponectin, and soluble tumor necrosis factor receptor 2 (sTNF-R2), an inflammatory marker, with breast cancer risk in postmenopausal women. A nested case-control study of postmenopausal women was conducted within CLUE II, a prospective population-based cohort. Baseline plasma levels of leptin, adiponectin, and sTNF-R2 were assayed in 272 female breast cancer cases and 272 controls matched on age, date, and hour of blood draw. Conditional logistic regression was used to estimate matched odds ratios (OR) and 95% confidence intervals (CI). sTNF-R2 and leptin were independently positively associated with breast cancer risk in adjusted models. The OR for breast cancer comparing the highest to lowest tertile was 2.44 (95% CI: 1.30-4.58) for sTNF-R2 and 1.98 (95% CI: 1.20-3.29) for leptin. While higher levels of adiponectin were protective (OR for the lowest tertile = 1.63; 95% CI: 1.02-2.60), there was no dose response. A 20% reduction in the breast cancer risk associated with overweight/obesity was observed when sTNF-R2 alone was included in multivariable models. Including both sTNF-R2 and adiponectin in the models resulted in a 29% reduction in the OR. Adipocytokines and sTNF-R2 are important factors in the etiology of postmenopausal breast cancer due to adiposity. This study informs our understanding of the relationship between obesity, inflammation, and postmenopausal breast cancer and identifies potential biomarkers. PMID- 23651668 TI - Protein adsorption and cell adhesion controlled by the surface chemistry of binary perfluoroalkyl/oligo(ethylene glycol) self-assembled monolayers. AB - This work reports a study of protein adsorption and cell adhesion on binary self assembled monolayers (SAMs) of alkanethiols with terminal perfluoroalkyl (PFA) and oligo(ethylene glycol) (OEG) chains in varying ratios. The surface chemistry of the SAMs was characterized by contact angle measurement, grazing angle infrared spectroscopy (GIR), X-ray photoelectron spectroscopy, and the effect on protein adsorption was investigated by surface plasmon resonance, GIR, and immunosorbent assay. Hela cell adhesion on these surfaces was also studied by fluorescence microscopy. Results reveal that, compared to OEG, PFA tended to be a higher fraction of the composition in SAM than in the assembly solution. More interestingly, the nearly 38% PFA SAM had a strong antifouling property whereas the 74% PFA SAM showed a high adsorption capacity to protein and cell. The binary PFA/OEG SAMs were favorable for maintaining the fibrinogen conformation, hence its high activity. The findings may have important implications for constructing PFA-containing surfaces with the distinct properties that is highly resistant or highly favorable toward protein adsorption and cell adhesion. PMID- 23651669 TI - Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations. AB - The persistence leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) despite tyrosine kinase inhibition (TKI) may explain relapse after TKI withdrawal. Here we performed genome-wide transcriptome analysis of highly refined CML and normal stem and progenitor cell populations to identify novel targets for the eradication of CML LSCs using exon microarrays. We identified 97 genes that were differentially expressed in CML versus normal stem and progenitor cells. These included cell surface genes significantly upregulated in CML LSCs: DPP4 (CD26), IL2RA (CD25), PTPRD, CACNA1D, IL1RAP, SLC4A4, and KCNK5. Further analyses of the LSCs revealed dysregulation of normal cellular processes, evidenced by alternative splicing of genes in key cancer signaling pathways such as p53 signaling (e.g. PERP, CDKN1A), kinase binding (e.g. DUSP12, MARCKS), and cell proliferation (MYCN, TIMELESS); downregulation of pro-differentiation and TGF-beta/BMP signaling pathways; upregulation of oxidative metabolism and DNA repair pathways; and activation of inflammatory cytokines, including CCL2, and multiple oncogenes (e.g., CCND1). These data represent an important resource for understanding the molecular changes in CML LSCs, which may be exploited to develop novel therapies for eradication these cells and achieve cure. PMID- 23651670 TI - Expression of non-replicating persistence associated genes of Mycobacterium bovis in lymph nodes from skin test-reactor cattle. AB - Upon oxygen shift-down, Mycobacterium tuberculosis complex bacteria can induce a genetic program characterized by halted duplication, which is called Non replicating persistence (NRP). During this phase, at least 48 genes, collectively named Dormancy survival regulator (DosR) regulon, are important for the long-term survival of bacilli under a non-respiring state, a condition that bacilli encounter inside granulomatous lesions. It remains unclear whether expression of NRP genes occurs within the tissue of Mycobacterium bovis naturally infected cattle. In order to start dissecting this question, total RNA from bovine lymph node tissues of sacrificed tuberculin reacting animals was isolated and transcription of genes required for in vivo duplication (esxB and fbpB) and in vitro NRP (hspX, pfkB, and mb2660c) were analyzed by RT-PCR approaches. Detection of transcripts was positive in bovine tissue samples for genes hspX, pfkB, and mb2660c in 84, 32, and 21%, respectively. NRP genes were upregulated even in animals with a negative IFN-gamma in vitro test, and the expression of NRP genes occurred more often than expression of the esxB gene. PMID- 23651671 TI - Secondhand tobacco smoke exposure in open and semi-open settings: a systematic review. AB - BACKGROUND: Some countries have recently extended smoke-free policies to particular outdoor settings; however, there is controversy regarding whether this is scientifically and ethically justifiable. OBJECTIVES: The objective of the present study was to review research on secondhand smoke (SHS) exposure in outdoor settings. DATA SOURCES: We conducted different searches in PubMed for the period prior to September 2012. We checked the references of the identified papers, and conducted a similar search in Google Scholar. STUDY SELECTION: Our search terms included combinations of "secondhand smoke," "environmental tobacco smoke," "passive smoking" OR "tobacco smoke pollution" AND "outdoors" AND "PM" (particulate matter), "PM(2.5)" (PM with diameter <= 2.5 um), "respirable suspended particles," "particulate matter," "nicotine," "CO" (carbon monoxide), "cotinine," "marker," "biomarker" OR "airborne marker." In total, 18 articles and reports met the inclusion criteria. RESULTS: Almost all studies used PM(2.5) concentration as an SHS marker. Mean PM(2.5) concentrations reported for outdoor smoking areas when smokers were present ranged from 8.32 to 124 ug/m(3) at hospitality venues, and 4.60 to 17.80 ug/m(3) at other locations. Mean PM(2.5) concentrations in smoke-free indoor settings near outdoor smoking areas ranged from 4 to 120.51 ug/m(3). SHS levels increased when smokers were present, and outdoor and indoor SHS levels were related. Most studies reported a positive association between SHS measures and smoker density, enclosure of outdoor locations, wind conditions, and proximity to smokers. CONCLUSIONS: The available evidence indicates high SHS levels at some outdoor smoking areas and at adjacent smoke-free indoor areas. Further research and standardization of methodology is needed to determine whether smoke-free legislation should be extended to outdoor settings. PMID- 23651672 TI - Communicative abilities in children: an assessment through different phenomena and expressive means. AB - Previous studies on children's pragmatic abilities have tended to focus on just one pragmatic phenomenon and one expressive means at a time, mainly concentrating on comprehension, and overlooking the production side. We assessed both comprehension and production in relation to several pragmatic phenomena (simple and complex standard communication acts, irony, and deceit) and several expressive means (linguistic, extralinguistic, paralinguistic). Our study involved 390 Italian-speaking children divided into three age groups: 5;0-5;6, 6;6-7;0, and 8;0-8;6. Children's performance on all tasks improved with their age. Within each age group, children responded more accurately to tasks involving standard communication than to those involving deceit and irony, across all expressive means and for both comprehension and production. Within each pragmatic phenomenon, children responded more accurately to simple acts than to complex ones, regardless of age group and expressive means, i.e., linguistic or extralinguistic. Overall results fit well with the Cognitive Pragmatics theory (Bara, 2010). PMID- 23651673 TI - Screening and analysis of PoAkirin1 and two related genes in response to immunological stimulants in the Japanese flounder (Paralichthys olivaceus). AB - A member of the NF-kappaB signaling pathway, PoAkirin1, was cloned from a full length cDNA library of Japanese flounder (Paralichthys olivaceus). The full length cDNA comprises a 5'UTR of 202 bp, an open reading frame of 564 bp encoding a 187-amino-acid polypeptide and a 521-bp 3'UTR with a poly (A) tail. The putative protein has a predicted molecular mass of 21 kDa and an isoelectric point (pI) of 9.22. Amino acid sequence alignments showed that PoAkirin1 was 99% identical to the Scophthalmus maximus Akirin protein (ADK27484). Yeast two-hybrid assays identified two proteins that interact with PoAkirin1: PoHEPN and PoC1q. The cDNA sequences of PoHEPN and PoC1q are 672 bp and 528 bp, respectively. Real time quantitative reverse-transcriptase polymerase chain reaction analysis showed that bacteria could induce the expressions of PoAkirin1, PoHEPN and PoC1q. However, the responses of PoHEPN and PoC1q to the bacterial challenge were slower than that of PoAkirin1. To further study the function of PoAkirin1, recombinant PoAkirin1 and PoHEPN were expressed in Escherichia coli and would be used to verify the PoAkirin1-PoHEPN binding activity. These results identified two proteins that potentially interact with PoAkirin1 and that bacteria could induce their expression. PMID- 23651674 TI - Short-latency artifacts associated with concurrent TMS-EEG. AB - BACKGROUND: Concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) is an emerging method for studying cortical network properties. However, various artifacts affect measurement of TMS-evoked cortical potentials (TEPs), especially within 30 ms of stimulation. OBJECTIVE/HYPOTHESIS: The aim of this study was to assess the origin and recovery of short-latency TMS-EEG artifacts (<30 ms) using different stimulators and under different experimental conditions. METHODS: EEG was recorded during TMS delivered to a phantom head (melon) and 12 healthy volunteers with different TMS machines, at different scalp positions, at different TMS intensities, and following paired pulse TMS. Recovery from the TMS artifact and other short-latency artifacts were compared between conditions. RESULTS: Following phantom stimulation, the artifact resulting from different TMS machines (Magstim 200, Magventure MagPro R30 and X100) and pulse shapes (monophasic and biphasic) resulted in different artifact profiles. After accounting for differences between machines, TMS artifacts recovered within ~12 ms. This was replicated in human participants, however a large secondary artifact (peaks at 5 and 10 ms) became prominent following stimulation over lateral scalp positions, which only recovered after ~25-40 ms. Increasing TMS intensity increased secondary artifact amplitude over both motor and prefrontal cortex. There was no consistent modulation of the secondary artifact following inhibitory paired-pulse TMS (interstimulus interval = 100 ms) over motor cortex. CONCLUSIONS: The secondary artifact observed in humans is consistent with activation of scalp muscles following TMS. TEPs can be recorded within a short period of time (10-12 ms) following TMS, however measures must be taken to avoid muscle stimulation. PMID- 23651675 TI - Patient navigation in cancer care. Introduction. PMID- 23651676 TI - The history, principles, and future of patient navigation: commentary. PMID- 23651677 TI - Patient navigation in the oncology care setting. AB - OBJECTIVES: To review the evolution and current status of patient navigation in cancer care settings, discuss challenges as navigation evolves, and suggest education and research needs to optimize outcomes associated with navigation processes and nurse navigator roles. DATA SOURCES: Literature review, association publications, and government and non-governmental documents. CONCLUSION: Since its inception over two decades ago, navigation programs have been established in hospitals in the United States, Canada, Australia, and other nations. Despite wide-spread implementation, challenges remain in defining the navigator processes and navigator roles, preparation, qualifications, and job descriptions. Scientific efforts are needed to craft and codify these definitions. IMPLICATIONS FOR NURSING PRACTICE: Nurses and organized nursing must identify the needs reflected by the navigation processes and support role delineation, identification, and validation of educational curriculum and competencies. PMID- 23651678 TI - Patient navigation and the American Cancer Society. AB - OBJECTIVES: To review the evolution, implementation, and development of the American Cancer Society's Navigator program. DATA SOURCES: American Cancer Society reports and published articles CONCLUSION: The American Cancer Society has a long history of supporting the growth and development of navigation, from provision of funding for Dr Freeman's pilot program, to developing a program that includes training, policy development, and research. The Society continues to play a key role in providing leadership to advance patient navigation as a means to improve patients' access to care, movement through the health care system while furthering patient centered care, patients' quality of life and eliminating health outcome disparities. IMPLICATIONS FOR NURSING PRACTICE: With the American Cancer Society navigation model, navigators are trained to meet with patients, identify barriers to care, and work with institutional health care teams to support patients and assist staff with aspects of care that can be managed by non medical personnel. PMID- 23651679 TI - Development of a breast navigation program. AB - OBJECTIVES: To review the development of a navigation program in a major US academic health care institution, and provide guidance for navigation programmatic development in other settings. DATA SOURCES: The Johns Hopkins Breast Center Steering Committee minutes, Hospital Cancer Registry; administrative data, and literature. CONCLUSION: Incorporating navigation services throughout the cancer continuum, from diagnosis to survivorship, provides guidance for patients with cancer. Navigation processes and programs must remain dynamic, reflecting patient and community needs. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses have traditionally performed many tasks associated with navigation, including patient education, psychosocial support, and addressing barriers to care. This article provides an exemplar for nurses developing or enhancing comprehensive breast programs. PMID- 23651680 TI - Oncology nurse navigators and the continuum of cancer care. AB - OBJECTIVES: To discuss the role and challenges of the oncology nurse navigator working within a multidisciplinary team caring for patients with various types of cancers. DATA SOURCES: Published empirical research and critical analysis articles. CONCLUSION: The experienced oncology nurse in the role of navigator has the disease-specific knowledge necessary to provide patient-centered care throughout the cancer continuum and promote positive patient outcomes. The role of the oncology nurse navigator has a positive impact on both the patient and the cancer team by providing continuity of care and improved communication. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurse navigators need a concrete definition of their role and function as they serve not only the patient but the cancer care system in which they work. Acknowledging foundational concepts as a guide, programs can then develop and expand. The role needs to be flexible as the health care system changes. Future development of the role can be guided by oncology nurse navigators who evaluate their programs and identify common challenges and system barriers. PMID- 23651681 TI - Navigation as an intervention to eliminate disparities in American Indian communities. AB - OBJECTIVES: To identify the role of patient navigation in decreasing health care disparities through an exemplar of a successful patient navigation program for American Indian populations living in the Northern and Southern Plains of the United States. DATA SOURCES: Published literature and data from the Native Navigators and the Cancer Continuum study. CONCLUSION: Native Patient Navigators successfully collaborated with local American Indian organizations to provide cancer education through a series of 24-hour workshops. These workshops increased community knowledge about cancer, influenced cancer screening behaviors, and increased the visibility and availability of the navigators to provide navigation services. IMPLICATIONS FOR NURSING PRACTICE: Reaching those with health care disparities requires multiple strategies. Collaborating with patient navigators who are embedded within and trusted by their communities helps to bridge the gap between patients and providers, increases adherence to care recommendations, and improves quality of life and survival. PMID- 23651682 TI - Evaluation and outcome measures in patient navigation. AB - OBJECTIVES: To review evaluation and outcome measures, including patient-reported outcomes, for assessing the impact of patient navigation. DATA SOURCES: Published peer-reviewed papers, systematic reviews, clinical reports, research and clinical experience. CONCLUSION: Research is demonstrating that patient navigation has beneficial outcomes across the cancer care continuum. More research is needed on outcomes of patient navigation by oncology nurses, to include baseline assessments that identify the areas of program focus, ongoing evaluation, and achievement of desired outcomes. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses who provide patient navigation as care coordinators, navigators, case managers, or team members have the potential to affect many positive outcomes in oncology care. Nursing research is needed to define oncology nursing patient navigation interventions and associated outcomes. PMID- 23651683 TI - Community cancer center administration and support for navigation services. AB - OBJECTIVES: To address the value of patient navigation (PN) to a community cancer center and suggest ways to measure PN outcomes to justify it as a critical component of cancer care. DATA SOURCES: Literature review and unpublished data from the DC Citywide Patient Navigation Network. CONCLUSION: Economic challenges in health care necessitate justification and appropriate utilization of all specialties and roles in cancer care. Demonstrating the value of PN programs is critical for sustaining these programs in community cancer centers. Having a clear business plan helps to define appropriate return-on-investment measures and an evaluation plan is important to assess program impact. IMPLICATIONS FOR NURSING PRACTICE: Nurses play a key role in working with administrators to define value metrics, track these measures, and report the results. Nurses should also seek out training and resources to enhance knowledge and skills for navigating patients. PMID- 23651684 TI - Legal services: a necessary component of patient navigation. AB - OBJECTIVES: Access to legal advocacy is an essential tool to help cancer patients and survivors through the continuum of care. This article examines delivery models that can seamlessly integrate into patient navigation programs. DATA SOURCES: Technical reports, books, journal articles, and Web sites. CONCLUSION: Psychosocial obstacles are common barriers of low-income individuals facing a cancer diagnosis. Legal solutions can help to minimize these obstacles, yet patients rarely have access to these services. Training patient navigators to appropriately screen for legal issues and collaborate with attorneys can be used to help prevent, rather than just react to, legal issues by addressing them as a part of a treatment plan. IMPLICATIONS FOR NURSING PRACTICE: Attorneys working with patient navigators, particularly nurse navigators, can impact oncology nursing practice by providing an innovative collaboration that is consistent with emerging trends in patient-centered treatment. PMID- 23651685 TI - Performance of the Dutch SF-36 version 2 as a measure of health-related quality of life in patients with rheumatoid arthritis. AB - BACKGROUND: The aim of this study was to examine the measurement properties of the Dutch SF-36 version 2 (SF-36v2) health survey in patients with rheumatoid arthritis (RA). METHODS: Scaling assumptions, internal reliability, and internal construct validity were examined using available data from 1884 RA patients included in the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. External construct validity and responsiveness to change were examined using baseline and 6-month follow-up data from a subset of 387 early RA patients participating in the DREAM remission induction cohort. RESULTS: The individual items of the SF 36v2 adequately met scaling assumptions, although four items correlated too highly with items from different scales. Internal consistency was high for all eight scales and the physical and mental health components underlying the scales were replicated, supporting the use of the standard scoring algorithms. The SF 36v2 scales demonstrated minimal floor effects and ceiling effects were noteworthy only for the role-physical, social functioning, and role-emotional scales. Correlations with other core measures were as expected and the SF-36v2 showed excellent known-groups validity in distinguishing between patients with low or moderate-high disease activity. All scales related to physical health showed moderate to large responsiveness to change in patients that achieved low disease activity at six months. CONCLUSION: The SF-36v2 appears to be a psychometrically sound tool for the assessment of health-related quality of life of Dutch patients with RA. PMID- 23651686 TI - Microvascular morphometrics of the hypophysis and pituitary tumors: from bench to operating theatre. AB - The idea that microvasculature might be a histopathological biomarker in the prognosis and treatment of tumors is garnering even more attention in the scientific community. The roles of neovascularity in tumor progression and metastasis, have become a hot-topic of investigation in cancer research. A number of methods of quantitatively analyzing pituitary adenoma microvasculature have been applied, and fractal analysis is emerging as a potential effective model for this aim. Additionally, new and more specific immunological techniques have been developed for the detection of microvessels. CD105 (Endoglin) has been proposed as a valuable antigen that marks only newly formed vessels, rather than the entire tumor microvascular system. The combination of different types of immunostaining techniques for the detection of microvessels in pituitary adenomas with fractal analysis as an objective and computer-aided technique to quantify and describe morphological aspects of microvessels has potential implications in future clinical and surgical applications. Tumor treatments, such as anti angiogenic therapy, as well as intraoperative tools, stand to be enhanced by increasing advances in microvascular research. We here review the methods used for the quantitative analysis of microvessels of the pituitary in its physiopathological states, with the aim to show the pituitary adenoma as a model for the study of neoplastic angioarchitecture and the importance of the introduction of new techniques for the study of angiogenesis, with the relative scientific, medical and surgical implications. PMID- 23651687 TI - Effects of luteolin on spatial memory, cell proliferation, and neuroblast differentiation in the hippocampal dentate gyrus in a scopolamine-induced amnesia model. AB - OBJECTIVES: Luteolin, a common flavonoid from many plants, has various pharmacological activities, including a memory-improving effect. In this study, we investigated the effects of luteolin on spatial memory, cell proliferation, and neuroblast differentiation in the hippocampal dentate gyrus in a rat model of scopolamine (SCO)-induced amnesia. METHODS: Scopolamine was subcutaneously administered for 28 days via an Alzet minipump (44 mg/ml delivered at 2.5 MUl/h) along with a daily intraperitoneal administration of vehicle (saline) 10 mg/kg luteolin or 5 mg/kg galantamine (GAL) (a control drug for acetylcholinesterase (AChE) inhibitor) for 28 days. RESULTS: The administration of SCO significantly decreased the spatial alteration percentage in the Y-maze test compared to that in the vehicle (saline)-treated group. The administration of luteolin or GAL significantly improved the spatial alteration percentage compared to that in the SCO-treated group. Similarly, the administration of SCO significantly decreased the cell proliferation (Ki67-positive cells) and neuroblast differentiation (doubleocortin-positive cells) in the dentate gyrus. The administration of luteolin or GAL significantly mitigated the SCO-induced reduction of Ki67- and doublecortin-immunoreactive cells in the dentate gyrus. In addition, the administration of luteolin significantly decreased the lipid peroxidation (malondialdehyde (MDA) levels) and increased the brain-derived neurotrophic factor (BDNF) and AChE levels in the hippocampal homogenates compared to the SCO treated group. CONCLUSION: These results suggest that the luteolin treatment improves the SCO-induced reduction of cell proliferation and neuroblast differentiation in the dentate gyrus. The mechanism underlying the amelioration of SCO-induced amnesia by luteolin may be associated with the increase in BDNF, acetylcholine, and the decrease in lipid peroxidation. PMID- 23651688 TI - Maternal perceptions of partner support during breastfeeding. AB - BACKGROUND: Many women find breastfeeding challenging to sustain beyond the first three postpartum months. Women rely on a variety of resources to aid and encourage breastfeeding, including 'partner support'. Women's perception of partner support during breastfeeding may influence maternal satisfaction and confidence but it remains understudied. We asked women about their perceptions of partner support during breastfeeding and measured the effect on maternal confidence, commitment, and satisfaction with respect to breastfeeding. METHODS: Using a descriptive, cross sectional design, we recruited 76 mothers from community health clinics in Calgary, Alberta. Participants completed a questionnaire addressing perceptions of partner support, the Breastfeeding Self Efficacy Scale (BSES) measuring maternal confidence and ability to breastfeed, and the Hill and Humenick Lactation Scale (HHLS) measuring commitment, perceived infant satiety, and breastfeeding satisfaction. Descriptive analysis was performed on socio-demographic and survey responses. Multiple regression modeling was used to examine the association between partner support and breastfeeding outcomes. RESULTS: Women who reported active/positive support from their partners scored higher on the BSES (p < 0.019) than those reporting ambivalent/negative partner support when we controlled for previous breastfeeding experience and age of infant. There were no significant differences between the two groups of women on total score of HHLS or any of the subscales with respect to perceptions of partner support. CONCLUSION: Mothers feel more capable and confident about breastfeeding when they perceive their partners are supportive by way of verbal encouragement and active involvement in breastfeeding activities. Mothers with partners who seemed ambivalent, motivated only by "what's best for baby," or provided negative feedback about breastfeeding, felt less confident in their ability to breastfeed. It is important that health care professionals appreciate the influence that positive and active partner support has upon the development of maternal confidence in breastfeeding, a known predictor for maintaining breastfeeding. Common support strategies could be communicated to both the partner and mother in the prenatal and postpartum periods. Health professionals can provide information, invite partners to become active learners and discuss supportive partner functions. Further research should address those functions that are perceived as most supportive by mothers and that partners are willing to perform. PMID- 23651689 TI - Facilitating partner notification through an online messaging service: Let Them Know. AB - Let Them Know (www.letthemknow.org.au) is an Australian internet based service designed to support individuals diagnosed with an STI to notify sexual partners using anonymous or personal text messages. A review of user activity and acceptability of the website was performed. Between 17 March 2010 and 31 March 2011, of 13?024 website visits, 4863 (37%) visits resulted in a text message being sent. From 3 December 2010, of 1383 consecutive users, 963 (70%) indicated they were more likely to contact a partner because of the website. A short period of misuse was identified and controlled, and additional measures to monitor for and prevent misuse were subsequently implemented. Web-based notification systems such as the Let Them Know website can help to facilitate partner notification for individuals who may be reluctant to do this in person. PMID- 23651690 TI - Radiofluorination using aluminum-fluoride (Al18F). AB - Targeted agents are increasingly used for treating cancer and other diseases, but patients may need to be carefully selected to maximize the potential for therapeutic benefit. One way to select patients is to bind an imaging radionuclide to a targeting agent of interest, so that its uptake in specific sites of disease can be visualized by positron-emission tomography (PET) or single-photon emission computed tomography.18F is the most commonly used radionuclide for PET imaging. Its half-life of approximately 2 h is suited for same-day imaging of many compounds that clear quickly from the body to allow visualization of uptake in the intended target. A significant impediment to its use, however, is the challenging coupling of 18F to a carbon atom of the targeting agent. Because fluorine binds to aluminum, we developed a procedure where the Al18F complex could be captured by a chelate, thereby greatly simplifying the way that imaging agents can be fluorinated for PET imaging. This article reviews our experience with this technology. PMID- 23651692 TI - Endometrial polyps in the bitch: a retrospective study of 21 cases. AB - Endometrial polyps (EPs) are tumour-like lesions reported frequently in domestic carnivores. The present report describes the clinical and pathological features of EPs in 21 bitches. Most affected bitches had a regular reproductive history. Five bitches had no clinical signs and eleven showed clinical signs of pyometra. Four bitches had a large EP which resulted in compression of the abdominal viscera. One bitch had an acute uterine torsion. A clinical diagnosis of EPs was only made when the lesions were large and identified by abdominal palpation or ultrasound. Grossly, the EPs were 5-25 cm in diameter and were single, sessile or pedunculated. They were often associated with cystic endometrial hyperplasia. Microscopically, the EPs were fibroglandular with the stroma sometimes being haemorrhagic and infiltrated by inflammatory cells. In one case, there were areas of stromal smooth muscle and epithelial squamous metaplasia, which may have been consistent with preneoplastic change. PMID- 23651691 TI - Coordinate regulation of noradrenergic and serotonergic brain regions by amygdalar neurons. AB - Based on the importance of the locus coeruleus-norepinephrine (LC-NE) system and the dorsal raphe nucleus-serotonergic (DRN-5-HT) system in stress-related pathologies, additional understanding of brain regions coordinating their activity is of particular interest. One such candidate is the amygdalar complex, and specifically, the central nucleus (CeA), which has been implicated in emotional arousal and is known to send monosynaptic afferent projections to both these regions. Our present data using dual retrograde tract tracing is the first to demonstrate a population of amygdalar neurons that project in a collateralized manner to the LC and DRN, indicating that amygdalar neurons are positioned to coordinately regulate the LC and DRN, and links these brain regions by virtue of a common set of afferents. Further, we have also characterized the phenotype of a population of these collaterally projecting neurons from the amygdala as containing corticotropin releasing factor or dynorphin, two peptides heavily implicated in the stress response. Understanding the co-regulatory influences of this limbic region on 5HT and NE regions may help fill a gap in our knowledge regarding neural circuits impacting these systems and their adaptations in stress. PMID- 23651693 TI - Adrenohepatic fusion in domestic ferrets (Mustela putorius furo). AB - We describe two cases of adrenohepatic fusion (AHF) in domestic ferrets (Mustela putorius furo). This condition is defined as the union of hepatic tissue with the adrenal gland with close fusion of the respective parenchymal cells and lack of a fibrous capsule between the two cell populations. AHF is believed to be a congenital anomaly caused by failure of retroperitoneal mesenchyme to stimulate capsule formation, promoting the fusion of the structures. Two male domestic ferrets had a mass adherent to the liver, comprising adrenal gland with areas of fusion between the liver parenchyma and adrenal cortex. There was no evidence of a capsule separating the hepatic and adrenal cell populations. Clinical signs related to either the liver or adrenal gland were not observed, so this was considered to be an incidental finding. PMID- 23651694 TI - Endocardial fibroelastosis in a quarterhorse mare. AB - A 4-year-old crossbred Quarterhorse mare was submitted to the Clemson Veterinary Diagnostic Center for necropsy examination with a chronic history of inappetence, weight loss and lethargy. Prior to death the horse had developed mild diarrhoea and began showing evidence of colic. Necropsy examination revealed a markedly enlarged heart due predominantly to marked dilation of the right atrium, tortuous congested mesenteric blood vessels, marked ascites, pleural effusion and pulmonary oedema. Further examination of the heart showed the endocardium of the left side of the heart, including the mitral valve leaflets, to be diffusely thickened. Microscopically, the endocardial thickening was due to deposition of fibrous connective tissue and elastin fibres. These findings are consistent with a diagnosis of endocardial fibroelastosis. PMID- 23651695 TI - Outcomes and quality of life after platelet-rich plasma therapy in patients with recalcitrant hindfoot and ankle diseases: a preliminary report of 12 patients. AB - The present study aimed to determine the outcomes and quality of life after platelet-rich plasma therapy in patients with chronic recalcitrant diseases of the hindfoot and ankle and to identify the crucial clinical variables. The records of 12 adult patients with diseases of the hindfoot and ankle were included in the present study. These patients had been treated with platelet-rich plasma from September 2010 to April 2011 after 3 to 6 months or more of conservative treatment had been unsuccessful. They had attended the follow-up visits, were consecutively enrolled, and retrospectively studied. A total of 3 mL of autologous platelet-rich plasma was injected under fluoroscopic or ultrasound guidance into the affected areas. All patients had been evaluated using visual analog scale foot and ankle scoring before treatment and at set intervals after treatment. According to their scores at the final follow-up visit (mean 16 months), the patients were allocated to the satisfactory (score >= 80; n = 8) and unsatisfactory (score < 80; n = 4) groups. The health-related quality of life was assessed using the Medical Outcomes Study short-form, 36-item survey at the final follow-up visit, because the study was retrospective, and the information was not available before treatment. The mean visual analog score at the final follow-up visit (79.71 +/- 17.81) was significantly greater than the mean pretreatment score (57.89 +/- 20.77; p = .002). Four patients (33%) had unsatisfactory results. The mean short-form, 36-item score for the satisfactory group (85.23 +/- 11.30) was significantly greater than that (57.33 +/- 12.91) of the unsatisfactory group (p = .003). No definitive factors influencing the outcome of this treatment were found. The substantial number of patients with an unsatisfactory outcome indicates that platelet-rich plasma injection might be an option but might not be a mainstay of nonoperative treatment of problematic conditions of the hindfoot and ankle. The actual benefit of this treatment, including the factors influencing its outcome, are still inconclusive. PMID- 23651696 TI - A prospective study of 20 foot and ankle wounds treated with cryopreserved amniotic membrane and fluid allograft. AB - We reviewed the background information and previous clinical studies that considered the use of allogeneic amniotic tissue and fluid (granulized amniotic membrane and amniotic fluid) in the treatment of chronic diabetic foot wounds. This innovation represents a relatively new approach to wound management by delivering a unique allograft of live human cells in a nonimmunogenic structural tissue matrix. Developed to fill soft tissue defects and bone voids and to convey antimicrobial and anti-inflammatory capabilities, granulized amniotic membrane and amniotic fluid does not require fetal death, because its procurement is performed with maternal consent during birth. In the present investigation, 20 chronic wounds (20 patients) that had been treated with standard wound therapy for a mean of 36.6 +/- 31.58 weeks and with a mean baseline area of 10.15 +/- 19.54 cm(2) were followed up during a 12-week observation period or until they healed. A total of 18 of the wounds (90%) healed during the 12-week observation period, and none of the wounds progressed to amputation. From our experience with the patients in the present case series, we believe that granulized amniotic membrane and amniotic fluid represents a useful option for the treatment of chronic diabetic foot wounds. PMID- 23651697 TI - Outcome after metatarsal osteotomy for hallux valgus: a study of postoperative foot function using revised foot function index short form. AB - The aim of the present study was to evaluate patients' perception of their functional outcome at 6 and 12 months after surgical correction for hallux valgus using the Foot Function Index Revised short form. A total of 59 patients underwent 68 osseous and soft tissue procedures for the correction of hallux valgus deformity from January 2009 through December 2010. The outcome analysis was based on the validated patient questionnaire, the Foot Function Index Revised. The preoperative data were collected on the day of the patient's surgery using the Foot Function Index Revised short-form questionnaire. The postoperative data were collected at 6 and 12 months after the patient's initial surgical date using the same validated questionnaire. The cumulative Foot Function Index Revised score and the scores in each subscale demonstrated statistically significant data at both 6 and 12 months of follow-up. On average, the Foot Function Index Revised scores had improved by 39% at 6 months and 50% at 12 months. The improvement in all scores indicated an improvement in health-related foot function after hallux valgus surgery, evidencing effective surgical intervention. Expectations are the best predictors of patient satisfaction, and the present study has provided statistically significant data to allow physicians to establish realistic outcomes after surgical correction for hallux valgus deformity. PMID- 23651698 TI - In situ aortobiiliac reconstruction of infected aneurysm using a single superficial femoral vein. AB - OBJECTIVE: To demonstrate successful in situ aortoiliac reconstruction of an infected infrarenal aneurysm using one single superficial femoral vein (SFV). METHODS: In situ reconstruction using the right SFV sutured in end-to-end anastomosis with the aorta and distally with the right common iliac artery and in end-to-side anastomosis with the left common iliac artery. RESULTS: The operating time was less than reported for aortic in situ reconstruction with bilateral SFV harvesting. The duplex scan 3 months postoperatively showed permeability of the bypass without any anastomotic stenosis or pseudoaneurysm. The right common femoral, popliteal, and greater saphenous veins were patent without thrombus, and the patient did not complain about peripheral edema. CONCLUSIONS: The use of only one instead of both the SFVs for aortobiiliac in situ reconstruction might be a way to reduce operating time and allow autogenous venous reconstruction even in patients with limited availability of venous material. PMID- 23651699 TI - Characterization and outcomes of iliac vessel injury in the 21st century: a review of the National Trauma Data Bank. AB - INTRODUCTION: Iliac vessel trauma (IVT) is traditionally associated with high mortality. We evaluated a modern series of patients with IVT to assess current outcomes and endovascular therapy use. METHODS: We performed a retrospective review of the National Trauma Data Bank. Patients with IVT were stratified by blunt and penetrating mechanism and arterial and venous injury. RESULTS: In blunt IVT, there was no significant difference in mortality between those with and without pelvic fractures (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.36 1.06). In penetrating IVT, combined arterial and venous IVT was associated with higher mortality (OR 1.70, 95% CI 1.06-2.70) compared to isolated arterial IVT. Isolated venous IVT was associated with lower mortality (OR 0.55, 95% CI 0.35 0.85) compared to isolated arterial IVT. Endovascular stenting was utilized in 11.3% of blunt IVT with pelvic fractures, 6.3% of blunt IVT without pelvic fractures, and 1.8% of penetrating IVT. CONCLUSION: Iliac Vessel Trauma has significant mortality. Endovascular intervention for IVT is applied sparingly. PMID- 23651700 TI - Integration of pediatric mental health care: an evidence-based workshop for primary care providers. AB - INTRODUCTION: Pediatric primary care providers (PCPs) are being asked to care for children with mental health (MH) disorders but cite inadequate training as a barrier. An intensive workshop may improve the PCPs' level of knowledge and lead to an increase in quality care for children with MH disorders. We compared pediatric PCPs' knowledge, comfort, and practice in the evaluation and management of pediatric patients with attention deficit-hyperactivity disorder, depression, anxiety, and autism spectrum disorders before and after a 2-day educational workshop. METHOD: Study participants (n = 30) were recruited from rural areas of Pennsylvania. A pre- and posttest design was used. A 15-question multiple choice knowledge test and a 19-question survey of comfort and practice were administered before and after the workshop. RESULTS: The mean knowledge test number correct increased from 9.19 before the workshop to 12.23 after the workshop (p < .0001). Survey scores increased from 34.6 before the workshop to 44.14 after the workshop (p < .0001). DISCUSSION: Intensive workshops may be an effective method of training PCPs on provision of MH care in pediatric primary care practice. PMID- 23651701 TI - Prevalence of behavior changing strategies in fitness video games: theory-based content analysis. AB - BACKGROUND: Fitness video games are popular, but little is known about their content. Because many contain interactive tools that mimic behavioral strategies from weight loss intervention programs, it is possible that differences in content could affect player physical activity and/or weight outcomes. There is a need for a better understanding of what behavioral strategies are currently available in fitness games and how they are implemented. OBJECTIVE: The purpose of this study was to investigate the prevalence of evidence-based behavioral strategies across fitness video games available for home use. Games available for consoles that used camera-based controllers were also contrasted with games available for a console that used handheld motion controllers. METHODS: Fitness games (N=18) available for three home consoles were systematically identified and play-tested by 2 trained coders for at least 3 hours each. In cases of multiple games from one series, only the most recently released game was included. The Sony PlayStation 3 and Microsoft Xbox360 were the two camera-based consoles, and the Nintendo Wii was the handheld motion controller console. A coding list based on a taxonomy of behavioral strategies was used to begin coding. Codes were refined in an iterative process based on data found during play-testing. RESULTS: The most prevalent behavioral strategies were modeling (17/18), specific performance feedback (17/18), reinforcement (16/18), caloric expenditure feedback (15/18), and guided practice (15/18). All games included some kind of feedback on performance accuracy, exercise frequency, and/or fitness progress. Action planning (scheduling future workouts) was the least prevalent of the included strategies (4/18). Twelve games included some kind of social integration, with nine of them providing options for real-time multiplayer sessions. Only two games did not feature any kind of reward. Games for the camera-based consoles (mean 12.89, SD 2.71) included a greater number of strategies than those for the handheld motion controller console (mean 10.00, SD 2.74, P=.04). CONCLUSIONS: Behavioral strategies for increasing self-efficacy and self-regulation are common in home console fitness video games. Social support and reinforcement occurred in approximately half of the studied games. Strategy prevalence varies by console type, partially due to greater feedback afforded by camera-based controllers. Experimental studies are required to test the effects of these strategies when delivered as interactive tools, as this medium may represent an innovative platform for disseminating evidence-based behavioral weight loss intervention components. PMID- 23651702 TI - Prisons and mental health: introductory editorial: hospitalizing mentally ill patients. PMID- 23651703 TI - The impact of phonological neighborhood density on typical and atypical emerging lexicons*. AB - According to the Extended Statistical Learning account (ExSL; Stokes, Kern & dos Santos, 2012) late talkers (LTs) continue to use neighborhood density (ND) as a cue for word learning when their peers no longer use a density learning mechanism. In the current article, LTs expressive (active) lexicon ND values differed from those of their age-matched, but not language-matched, TD peers, a finding that provided support for the ExSL account. Stokes (2010) claimed that LTs had difficulty abstracting sparse words, but not dense, from the ambient language. If true, then LTs' receptive (passive), as well as active lexicons should be comprised of words of high ND. However, in the current research only active lexicons were of high ND. LTs' expressive lexicons may be small not because of an abstraction deficit, but because they are unable to develop sufficiently strong phonological representations to support word production. PMID- 23651704 TI - Modeling predictors of risky drug use behavior among male street laborers in urban Vietnam. AB - BACKGROUND: The application of theoretical frameworks for modeling predictors of drug risk among male street laborers remains limited. The objective of this study was to test a modified version of the IMB (Information-Motivation-Behavioral Skills Model), which includes psychosocial stress, and compare this modified version with the original IMB model in terms of goodness-of-fit to predict risky drug use behavior among this population. METHODS: In a cross-sectional study, social mapping technique was conducted to recruit 450 male street laborers from 135 street venues across 13 districts of Hanoi city, Vietnam, for face-to-face interviews. Structural equation modeling (SEM) was used to analyze data from interviews. RESULTS: Overall measures of fit via SEM indicated that the original IMB model provided a better fit to the data than the modified version. Although the former model was able to predict a lesser variance than the latter (55% vs. 62%), it was of better fit. The findings suggest that men who are better informed and motivated for HIV prevention are more likely to report higher behavioral skills, which, in turn, are less likely to be engaged in risky drug use behavior. CONCLUSIONS: This was the first application of the modified IMB model for drug use in men who were unskilled, unregistered laborers in urban settings. An AIDS prevention program for these men should not only distribute information and enhance motivations for HIV prevention, but consider interventions that could improve self-efficacy for preventing HIV infection. Future public health research and action may also consider broader factors such as structural social capital and social policy to alter the conditions that drive risky drug use among these men. PMID- 23651706 TI - Investigating the role of the general practitioner in cancer prevention: a mixed methods study. AB - BACKGROUND: Despite evidence of the effectiveness of cancer preventive services and the increasing development of guidelines, actual rates of delivery of cancer prevention activities remain low. Due to their frequent front-line contact with the public, family physicians (GPs) have the potential to play an important role in the primary prevention of cancer. However, there is a lack of information about their actual role in cancer prevention. The aim of this study was to investigate the actual and potential roles of general practitioners (GP) in the prevention of cancer. METHODS: A sequential exploratory mixed methods approach was used. The sample included all the General Practice (GP) practices in a region in the UK (n=345). Postal questionnaires were administered to GPs (n=1249); following 290 returns (response rate 23%), semi-structured interviews were undertaken with GPs (n=14). RESULTS: The majority of the GP respondents (66.4%, n=184) considered that they routinely provided cancer prevention information. This was specifically focusing on smoking cessation as almost all GPs (96.8%, n=270) enquired about a patient's smoking status. Overall, 47.2% (n=128) of GP respondents indicated that they felt they did not have time to perform a cancer prevention role; however, 88.3% (n=242) still felt that they had the 'opportunity' to do so. Over half the sample (61.3%, n=168) indicated that imposed health priorities and targets militated against providing cancer prevention activities. Almost all the GP respondents (98.9%, n=273) agreed with empowering individuals to take responsibility for their health issues. The GPs identified the need for alternative models for cancer prevention beyond current face to face patient care, including other health and non-health professionals. Whilst lack of time was identified as a critical factor, the GPs indicated that significant efforts were made to encourage patients to take personal responsibility for lifestyle choices. CONCLUSIONS: The GPs indicated a need for training around behavioural change and theories of motivation and action. This has implications for primary care and family physicians worldwide. While doctor patient consultations and the physicians' credibility offer great potential for cancer prevention, time pressures and imposed government targets often mean that their actual cancer prevention role is reduced. PMID- 23651705 TI - Linear association between social anxiety symptoms and neural activations to angry faces: from subclinical to clinical levels. AB - Social anxiety disorder (SAD), which is characterized by the fear of being rejected and negatively evaluated, involves altered brain activation during the processing of negative emotions in a social context. Although associated temperament traits, such as shyness or behavioral inhibition, have been studied, there is still insufficient knowledge to support the dimensional approach, which assumes a continuum from subclinical to clinical levels of social anxiety symptoms. This study used functional magnetic resonance imaging (fMRI) to examine the neural bases of individual differences in social anxiety. Our sample included participants with both healthy/subclinical as well as clinical levels of social anxiety. Forty-six participants with a wide range of social anxiety levels performed a gender decision task with emotional facial expressions during fMRI scanning. Activation in the left anterior insula and right lateral prefrontal cortex in response to angry faces was positively correlated with the level of social anxiety in a regression analysis. The results substantiate, with a dimensional approach, those obtained in previous studies that involved SAD patients or healthy and subclinical participants. It may help to refine further therapeutic strategies based on markers of social anxiety. PMID- 23651707 TI - Accelerated long-term forgetting in transient epileptic amnesia: an acquisition or consolidation deficit? AB - Accelerated Long-term Forgetting (ALF) is the rapid loss of newly acquired memories over days to weeks despite normal retention at standard (~30 min) intervals. It has recently been described in association with epilepsy, particularly the syndrome of Transient Epileptic Amnesia (TEA). The cognitive mechanisms underlying ALF remain uncertain, but disruption either of memory acquisition or consolidation processes has been postulated. To arbitrate between these accounts, we reanalysed data from an existing word-list recall data set to investigate whether ALF can be observed for words learned under precisely matched conditions in TEA patients and controls. We reanalysed the data of 24 patients with TEA and 24 matched healthy controls who learnt a 15-item word list to a learning criterion of 90% with a minimum of five learning trials. Free recall of the words was probed at delays of 30 min and 1 week and 3 weeks after learning. In addition, a 'yes-no' recognition test was conducted after the 3-week free recall. Forgetting rates across the first 30 min delay and the subsequent 1 week and 3 week delay were compared between patients and controls. To ensure that learning conditions were closely matched between patients and control participants, we excluded exceptionally fast (N(TEA)=1, N(controls)=4) and slow (N(TEA)=6, N(controls)=2) learners. Furthermore, we analysed only words that were presented five or six times during learning and retrieved successfully on four or five occasions during learning. Recall performance on the last learning trial and 30 min after acquisition were indistinguishable between TEA patients and controls. Over the delay interval of 30 min to 1 week, however, accelerated forgetting of this newly learned verbal material was observed in TEA patients. This severe forgetting is also reflected in the three-week recognition test, where TEA patients performed significantly worse than controls. Moreover, whereas recall on the last learning trial correlated significantly with the 30 min delayed recall in both groups, recall on the last learning trial correlated significantly with 1 week and 3 week delayed recall only in the controls. In both groups, the three-week free recall performance correlated with the three-week recognition test. Patients with TEA demonstrate ALF even for verbal material that is learned under precisely matched conditions. These results are consistent with the hypothesis that ALF represents a disruption of memory consolidation rather than an acquisition deficit. PMID- 23651708 TI - The ups and downs of repetition: modulation of the perirhinal cortex by conceptual repetition predicts priming and long-term memory. AB - In order to better understand how concepts might be represented in the brain, we used a cross-modal conceptual priming paradigm to examine how repetition-related activity changes in the brain are related to conceptual priming. During scanning, subjects made natural/manmade judgments on a continuous stream of spoken nouns, written nouns and pictures of objects. Each stimulus either repeated in the same or a different modality with 1-4 intervening trials between repetitions. Behaviorally, participants showed significant perceptual and conceptual priming effects. The fMRI data showed that the conditions associated with the greatest behavioral priming exhibited the largest decreases in BOLD activity in left perirhinal cortex (PRc), as well as a few other regions. Furthermore, the PRc was the only region to show this relationship for the cross-modal conditions alone, where the concept but not the percept repeated. Conversely, repetition-related increases in PRc activity predicted better subsequent memory as assessed by a post-scan recognition test. These results suggest that repetition-related activity changes in the PRc are related both to the speed of access to a repeated concept and to that concept's later memorability. PMID- 23651709 TI - The classical progesterone receptor mediates the rapid reduction of fallopian tube ciliary beat frequency by progesterone. AB - BACKGROUND: The transport of gametes as well as the zygote is facilitated by motile cilia lining the inside of the fallopian tube. Progesterone reduces the ciliary beat frequency within 30 minutes in both cows and mice. This rapid reduction suggest the involvement of a non-genomic signaling mechanism, although it is not known which receptors that are involved. Here we investigated the possible involvement of the classical progesterone receptor in this process. METHOD: The ciliary beat frequency of mice fallopian tube was measured ex vivo using an inverted bright field microscope and a high speed camera. The effects of the agonists progesterone and promegestone and an antagonist, mifeprestone, were investigated in wildtype mice. The effect of progesterone was also investigated in mice lacking the classical progesterone receptor. RESULTS: Progesterone, as well as the more specific PR agonist promegestone, significantly reduced the CBF at concentrations of 10-100 nanomolar within 10-30 minutes. In the absence of progesterone, the PR antagonist mifeprestone had no effect on the ciliary beat frequency at a concentration of 1 micromolar. When ciliated cells were pre incubated with 1 micromolar mifeprestone, addition of progesterone did not reduce the ciliary beat frequency. Accordingly, in ciliated cells from mice not expressing the classical progesterone receptor, exposure to 100 nanomolar progesterone did not reduce the ciliary beat frequency. CONCLUSIONS: This is the first study to provide comprehensive evidence that the classical progesterone receptor mediates the rapid reduction of the tubal ciliary beat frequency by progesterone. PMID- 23651710 TI - Evidence of effective scrapie transmission via colostrum and milk in sheep. AB - BACKGROUND: Evidence for scrapie transmission from VRQ/VRQ ewes to lambs via milk was first reported in 2008 but in that study there were concerns that lateral transmission may have contributed to the high transmission rate observed since five control lambs housed with the milk recipients also became infected. This report provides further information obtained from two follow-up studies, one where milk recipients were housed separately after milk consumption to confirm the validity of the high scrapie transmission rate via milk and the second to assess any difference in infectivity from colostrum and subsequent milk. Protein misfolding cyclic amplification (PMCA) was also used to detect prion protein in milk samples as a comparison with the infectivity data and extended to milk samples from ewes without a VRQ allele. RESULTS: Seven pairs of lambs fed colostrum and milk individually from seven scrapie-affected sheep (pre-clinical or clinical) presented with disease-associated prion protein, PrPd, in rectal lymphoid tissue at 4-5 months of age. Five further pairs of lambs fed either colostrum or subsequent milk from five pre-clinical scrapie-affected sheep equally presented with PrPd in lymphoid tissue by 9 months of age. Nine sheep were lost due to intercurrent diseases but all remaining milk or colostrum recipients, including those in the original study with the lateral transmission controls, developed clinical signs of scrapie from 19 months of age and scrapie was confirmed by brain examination. Unexposed control sheep totalling 19 across all three studies showed no evidence of infection.Scrapie PrP was amplified repeatedly by PMCA in all tested milk samples from scrapie-affected VRQ/VRQ sheep, and in one scrapie-affected ARQ/ARQ sheep. By contrast, milk samples from five VRQ/VRQ and 11 ARQ/ARQ scrapie-free sheep did not have detectable scrapie PrP on repeated tests. CONCLUSIONS: Feeding of milk from scrapie-affected sheep results in a high transmission rate in VRQ/VRQ sheep and both colostrum and milk transmit scrapie. Detection of scrapie prion protein in individual milk samples from scrapie-affected ewes confirms PMCA as a valuable in vitro test. PMID- 23651711 TI - Leaving the street and reconstructing lives: impact of DOTS in empowering homeless people in Tokyo, Japan. AB - SETTING: Since 2000, the Public Health Centre (PHC) in Shinjuku, an area of Tokyo with one of the largest homeless populations in Japan, has been implementing PHC based DOTS treatment for homeless tuberculosis (TB) patients, with much epidemiological success. Anecdotal evidence indicates that homeless patients treated under DOTS have experienced various positive changes. However, this experience has not yet been systematically analysed. OBJECTIVE: To explore the changes experienced by homeless TB patients, and to discuss the possible role of PHC-based DOTS treatment in effecting these changes. DESIGN: A qualitative study via in-depth interviews with 18 ex-homeless patients who completed DOTS-based treatment at Shinjuku City PHC. The data were analysed using the interpretive content analysis method. RESULTS: The various changes experienced by the participants were categorised into five sub-categories of empowerment, including improved mental health and interpersonal relationships. Some of these changes were attributable to the participants undergoing PHC-based DOTS, which, by addressing their various emotional needs, helped to trigger patient empowerment. Based on our findings, a model of empowerment using PHC-based DOTS was constructed. CONCLUSION: PHC-based DOTS not only successfully controlled TB, it also empowered homeless patients by addressing their emotional needs. The interpersonal skills of the nurses played a critical role in this process. PMID- 23651712 TI - Ultrasound-guided drainage of subcutaneous abscesses on the trunk is feasible. AB - INTRODUCTION: Subcutaneous trunk abscesses are frequent, and current treatment options generally involve incision. By contrast, the standard care for breast abscesses is ultrasound-guided drainage. The aim of this study was to evaluate the feasibility of ultrasound-guided drainage combined with antibiotics in the treatment of subcutaneous abscesses on the trunk. MATERIAL AND METHODS: In this prospective study, 27 patients were treated with ultrasound-guided needle aspiration and oral antibiotics. Follow-up was performed at a 3-6-day interval, and the procedure was repeated if the abscess was not obliterated. RESULTS: Treatment was initially successful in 25 of the 27 participants (93%); two patients went on to surgery. The median time from first treatment to the final control visit was nine days. The 25 patients with initial successful treatment were contacted after a median of 84 days, and six (24%) of these reported recurrence of an abscess at the puncture site. 88% of the patients reported that they were satisfied or very satisfied with ultrasound-guided drainage. CONCLUSION: Our results indicate that ultrasound-guided drainage combined with antibiotics is feasible in the treatment of small subcutaneous abscesses on the trunk. Ultrasound-guided drainage was well-tolerated, had a high degree of success and short healing times. Additional randomised studies are needed to verify our findings. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23651713 TI - Renal and cardiovascular effects of irbesartan in dialysis patients--a randomized controlled trial protocol (SAFIR study). AB - INTRODUCTION: Cardiovascular (CV) events are a major cause of morbidity and mortality in haemodialysis (HD) patients. Hypertension, increased arterial stiffness and left ventricular (LV) hypertrophy are highly prevalent and are often poorly controlled. Volume overload is an important factor and survival could be improved by treatment strategies that preserve residual renal function (RRF), reduce blood pressure, and decrease arterial stiffness and LV hypertrophy. Angiotensin II receptor blocker (ARB) treatment can prevent CV events in patients with hypertension and heart failure. However, few data exist in patients with chronic renal failure and it is not known whether ARB treatment improves clinical outcome in HD patients. MATERIAL AND METHODS: This is a randomized, controlled and double-blinded intervention study. A total of 82 HD patients from six Danish HD centres will be treated for a year with an ARB (irbesartan) or placebo. The inclusion criteria are urine output > 300 ml/day, dialysis vintage < 1 year and LV ejection fraction > 30%. The primary outcomes are change in RRF, LV hypertrophy, arterial stiffness and intra-dialytic haemodynamics. CONCLUSION: If ARB-treatment improves RRF and intermediate CV endpoints in a group of newly started HD patients, it may improve the survival for this high risk population. FUNDING: The trial is investigator-initiated, investigator-driven and supported by the Danish Agency for Science, Technology and Innovation and several private foundations. PMID- 23651714 TI - Promising results after endoscopic vacuum treatment of anastomotic leakage following resection of rectal cancer with ileostomy. AB - INTRODUCTION: In colorectal surgery, the most feared complication is anastomotic leakage (AL), which is associated with a high morbidity and mortality. In this study, we focus on treatment of perianastomotic abscess following AL after low anterior resection (LAR) of rectal cancer. In the literature, conservative irrigation regimes are reported to perdure for months and some even years and to be associated with a poor stoma closure rate. In the present paper, we evaluated endoscopic vacuum treatment of the perianastomotic abscess. MATERIAL AND METHODS: Patients who had LAR due to rectal cancer with total mesorectal excision (TME) performed in Slagelse and Naestved Hospitals in the 2008-2012 (1st February) period were identified in the Danish Colorectal Cancer Group database. We included patients who had AL and who did not require emergency reoperation and were treated with endoscopic vacuum in the study period. Patients who initiated treatment more than one month after the leakage were excluded. All patients had primary ileostomy. RESULTS: A total of 13 patients were included. All patients had successful closure of the perianastomotic abscess for a median of 18 (3-40) days in a median of eight (1-18) sessions. The median length of hospital stay was 25 (7-39) days. Mortality was zero, and the stoma closure rate was 12/13 (97%). CONCLUSION: Our data support the positive findings previously reported by other studies. Endoscopic vacuum treatment seems to be a safe approach for selected patients in the treatment of perianastomotic abscess after LAR with TME of rectal cancer. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23651715 TI - Medication reconciliation is a prerequisite for obtaining a valid medication review. AB - INTRODUCTION: The objective of this study was to compare medication reconciliation and medication review based on number, type and severity of discrepancies and drug-related problems (DRPs), denoted errors. MATERIAL AND METHODS: This was a retrospective study conducted at the Department of Cardiology, Hillerod Hospital. Medication reconciliation compared the prescriptions in patient records, an electronic medication system (EMS) and in discharge summaries (DS). The medication review was based on the EMS. The two methods were performed on the same data material. To assess the clinical importance of the errors, a four-point scale was applied. RESULTS: A total of 75 patient records were included. In all, 198 discrepancies were identified by medication reconciliation, 2.6 per patient. The most frequent discrepancies were omission of a drug in the DS and discrepancy between the drugs noted in the patient record and the EMS. 15% of the discrepancies were potentially serious or fatal, 62% were potentially significant and 23% were potentially non-significant. A total of 129 DRPs were identified by medication review, 1.7 per patient. The most frequent DRPs were sub therapeutic dosage, inappropriate dosage regimen and untreated medical condition. 35% of the DRPs were potentially serious or fatal, 29% were potentially significant and 36% were potentially non-significant. CONCLUSION: Medication reconciliation identified a higher number of errors than medication review, but the number of serious errors identified by medication review was higher than that identified by medication reconciliation. The two methods identified different types of errors and should be used concurrently to supplement each other. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23651716 TI - The majority of patients in septic shock are transfused with fresh-frozen plasma. AB - INTRODUCTION: Fresh-frozen plasma (FFP) transfusion may be widely used in patients in septic shock, but the use is not well-described. Our aim was to describe the current use of FFP transfusion in medical patients with septic shock. MATERIAL AND METHODS: This was a prospective cohort study of medical patients with septic shock (n = 60) admitted to two general intensive care units (ICUs) during a three-month period. Patients were divided into two groups, one received FFP transfusion, the other did not. Baseline characteristics, transfusions and outcome were compared between the groups. Episodes of bleeding, procedures and coagulation parameters were compared between days with and without FFP transfusion. RESULTS: 57% of the patients received a median of six (interquartile range: 3-10) units of FFP during their ICU stay. The FFP transfused patients had higher sequential organ failure assessment scores at admission (13 (9-15) versus 10 (7-11), p = 0.02) than the untransfused patients, but there were no differences in simplified acute physiology score II or mortality. On days of FFP transfusion, international normalized ratio levels (1.8 (1.4-2.3) versus 1.3 (1.2-1.6), p < 0.0001) were higher, and invasive procedures (p < 0.0001), episodes of bleeding (p < 0.0001), transfusion of red blood cells (p < 0.0001) and platelets (p < 0.0001) more frequent than on days without transfusion. Two thirds of FFP transfusions were given to patients with clinical evidence of bleeding and/or as prophylaxis before invasive procedures. CONCLUSION: The majority of medical ICU patients with septic shock received FFP transfusion. One third of the FFPs were given unrelated to invasive procedures or bleeding. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23651717 TI - Late group-based rehabilitation has no advantages compared with supervised home exercises after total knee arthroplasty. AB - INTRODUCTION: This study aimed to test whether group-based rehabilitation focusing on strength training, education and self-management is more effective than individual, supervised home-training after fast-track total knee arthroplasty (TKA). MATERIAL AND METHODS: We allocated 80 participants undergoing primary TKA to either group-based rehabilitation or individual, supervised home training (40 participants in each group). The group-based rehabilitation consisted of 12 outpatient visits during six weeks including strength and endurance exercises, education and self-management combined with home exercises. The primary outcome was Oxford Knee Score; secondary outcomes were EuroQoL-5 Dimensions QoL and Physical Function of the Medical Outcomes Short Form 36. Tertiary outcomes were pain, knee range of motion, tandem test, Leg Extensor Power, 10-m walking test, 30-sec. and five-times sit-to-stand. Outcomes were assessed four weeks, three months and six months after surgery. In addition, the questionnaires were completed before surgery. RESULTS: We found no difference in gain of function or quality of life between the two groups at three and six months follow-up. CONCLUSION: Individual, supervised home-training and group based rehabilitation programmes improved patients' quality of life and physical function equally six months after TKA. FUNDING: This study was funded by Holstebro Municipality, Region of Central Jutland, and Lundbeck Centre for Fast Track Hip and Knee Surgery. TRIAL REGISTRATION: The study was registered in the Danish Data Protection Agency (Registration no.: 1-16-02-41-10) and Clinical Trials (Registration no.: KL24621). PMID- 23651718 TI - Standardised test protocol (Constant Score) for evaluation of functionality in patients with shoulder disorders. AB - INTRODUCTION: The Constant Score (CS), developed as a scoring system to evaluate overall functionality of patients with shoulder disorders, is widely used but has been criticised for relying on an imprecise terminology and for lack of a standardised methodology. A modified guideline was therefore published in 2008 with several new recommendations, but a standardised test protocol was not included. Also, this new version has not been translated into Danish. The aims of the present study were to develop a standardised English test protocol for the newly modified CS, and to translate and cross-culturally adapt this version into Danish. MATERIAL AND METHODS: An English test protocol was developed and translated into Danish at two independent centres according to international recommendations. Consensus on a preliminary version was achieved. The subjective part was tested on six patients, while two physiotherapists gave feedback on the objective part. Relevant items were culturally adapted and rephrased, and a simple standardised test protocol was developed. RESULTS: Only minor inconsistencies in the translations were found. A few questions and words had to be rephrased due to cultural and linguistic differences. One of the authors of the modified CS approved both the English and the Danish test protocol. CONCLUSION: A simple test protocol of the modified CS was developed in both English and Danish. With precise terminology and definitions, the test protocol is the first of its kind. We suggest its use internationally for standardised assessment of the CS. Testing of validity, reliability and responsiveness of both versions needs to be done in future research. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23651719 TI - Patients undergoing radical prostatectomy have a better survival than the background population. AB - INTRODUCTION: The objective of this study was to investigate standardised relative survival and mortality ratio for patients undergoing radical prostatectomy for localized prostate cancer at our institution. MATERIAL AND METHODS: Between 1995 and 2010, a total of 1,350 consecutive patients underwent radical prostatectomy. Patients were followed prospectively per protocol. No patients were lost to follow-up. Overall and cause-specific survival were described using Kaplan-Meier plots. Standardized relative survival and mortality ratio were calculated based on expected survival in the age-matched Danish population using the methods and macros described by Dickmann. The country specific population mortality rates used for calculation of the expected survival were based on data from The Human Mortality Database. RESULTS: The median follow up was 3.4 years (range: 0-14.3 years). A total of 59 (4.4%) patients died during follow-up. In all, 17 (1.3%) patients died of prostate cancer. The estimated ten year overall survival was 89.3%. The cancer-specific survival was estimated to 96.6% after ten years. Relative survival was 1.04 after five years and 1.14 after ten years. The standardized mortality ratio, i.e. observed mortality/expected mortality, was 0.61 and 0.39 at five and ten years, respectively. CONCLUSION: The overall and cancer-specific ten-year survival in a consecutive series of patients in a non-screened Danish population is >= 89%. The survival and mortality ratio is significantly better than expected in the age-matched background population. This finding is likely explained by selection bias. Although the results indicate an excellent outcome in terms of cancer control, the efficacy of prostatectomy for localized prostate cancer remains at debate. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23651720 TI - No clinical value of post-operative routine X-ray following uncomplicated cementless primary total hip arthroplasty. AB - INTRODUCTION: There is no consensus among hip surgeons in Denmark on how to follow up patients after total hip arthroplasty (THA). Agreement on the need for radiographic examinations is also lacking. The purpose of this study was to evaluate if routine outpatient post-operative radiographs, obtained three and 12 months after uncomplicated cementless primary THA influenced patient treatment. MATERIAL AND METHODS: A retrospective chart review was performed for 249 cases who had received THA during a four-month period. Patient data, indication for surgery and type of prosthesis were noted. The radiographic descriptions in the medical record made by the operating surgeon at the three- and 12-month outpatient follow-up visits were examined. RESULTS: At three months, the radiograph showed subsidence ranging from "barely detectable" to ten millimetres in eight of 216 cases. One patient was treated with crutches. The remaining three patients were given another follow-up visit. At 12 months, two cases had signs of stress shielding with cortical thickening. This had no consequence in one patient and the other was given additional follow-up. CONCLUSION: We conclude that routine radiographs can be omitted from the outpatient follow-up within the first year following primary elective cementless THA as it does not affect treatment. We believe radiographs should be reserved for patients with subjective complaints such as pain and to those who are referred outside the routine follow-up plan due to complications. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23651721 TI - Advances in autologous chondrocyte implantation and related techniques for cartilage repair. AB - Articular cartilage is a specialized tissue exhibiting low intrinsic capabilities of regeneration or healing after injury. Autologous chondrocyte implantation (ACI) and scaffold-supported ACI are often used for treatment of larger chondral defects (> 2 cm2). These utilize open surgery re-implantation of ex vivo cultured autologous chondrocytes harvested as a biopsy arthroscopically in a prior surgery. This two-step procedure is an advanced and expensive treatment that despite high expectations have failed to regenerate articular cartilage in a consistent and predictable fashion, and as many as 25% the operated of patients have dissatisfactory outcomes. The objective of the present thesis was to address and investigate methods for optimizing the steps involved in the ACI and scaffold supported ACI treatment including chondrocyte culture environment, chondrocyte labeling and tracking, improved biomaterials, and cell seeding densities. We hypothesized that these areas were eligible for targeted optimization, which has been addressed in the five papers constituting the work performed in the present thesis. The first two studies address the in vitro cell expansion of chondrocytes before re-implantation. After validation of hypoxia-suitable housekeeping genes for quantitative gene expression analysis using previously validated algorithms (study 1) the effect of combined hypoxic- and 3D culture on human chondrocytes gene expression was investigated (study 2). An in vitro experiment was performed to determine the effect on gene expression of an intracellular superparamagnetic labeling agent for 1.5T MRI-tracking of alginate-embedded human chondrocytes (study 3). We further performed a literature study, reviewing the cell seeding densities of the implanted chondrocytes used in clinically available cell transplantation-based treatments for cartilage repair (study 4). Finally, we tested the addition of dermatan sulfate to a clinically approved methoxy polyethen-glycol (MPEG) substituted polylactide-co-glycolic acid (PLGA) scaffold by implantation of cell-free scaffolds in an osteochondral rabbit model (study 5). We determined a set of hypoxia-stable reference genes in study 1 that were then used in study 2. We observed that there was a positive effect on chondrogenic gene expression in human chondrocytes when culturing in 3D compared to monolayer and in hypoxia compared to normoxia and that there was an additional positive combined effect of 3D and hypoxia. Using a clinical MRI-system we were able to track labeled chondrocytes for up to 4 weeks, but we found that the labeling agent had significant effects on chondrocyte gene expression, which could potentially confound results when used in vivo. In our review of chondrocyte seeding densities we found large variability between commercial products and a very limited preclinical basis for the applied densities. Lastly, we found that there was no positive effect in vivo of adding dermatan sulfate to MPEG-PLGA scaffold in osteochondral repair. We conclude that while the outcome of ACI-related treatments certainly is multifactorial it may be improved by optimizing the in vitro culture by hypoxic and 3D culture and by adjusting the chondrocyte seeding density. Our studies on biomaterials and potential system for cell tracking in vivo did not show results that justified further studies and clinical trials. PMID- 23651722 TI - Mammography screening. Benefits, harms, and informed choice. AB - The rationale for breast cancer screening with mammography is deceptively simple: catch it early and reduce mortality from the disease and the need for mastectomies. But breast cancer is a complex problem, and complex problems rarely have simple solutions. Breast screening brings forward the time of diagnosis only slightly compared to the lifetime of a tumour, and screen-detected tumours have a size where metastases are possible. A key question is if screening can prevent metastases, and if the screen-detected tumours are small enough to allow breast conserving surgery rather than mastectomy. A mortality reduction can never justify a medical intervention in its own right, but must be weighed against the harms. Overdiagnosis is the most important harm of breast screening, but has gained wider recognition only in recent years. Screening leads to the detection and treatment of breast cancers that would otherwise never have been detected because they grow very slowly or not at all and would not have been detected in the woman's lifetime in the absence of screening. Screening therefore turns women into cancer patients unnecessarily, with life-long physical and psychological harms. The debate about the justification of breast screening is therefore not a simple question of whether screening reduces breast cancer mortality. This dissertation quantifies the primary benefits and harms of screening mammography. Denmark has an unscreened "control group" because only two geographical regions offered screening over a long time-period, which is unique in an international context. This was used to study breast cancer mortality, overdiagnosis, and the use of mastectomies. Also, a systematic review of overdiagnosis in five other countries allowed us to show that about half of the screen-detected breast cancers are overdiagnosed. An effect on breast cancer mortality is doubtful in today's setting, and overdiagnosis causes an increase in the use of mastectomies. These findings are discussed in the context of tumour biology and stage at diagnosis. The information provided to women in invitations and on the Internet exaggerates benefits, participation is directly recommended, and the harms are downplayed or left out, despite agreement that the objective is informed choice. This raises an ethical discussion concerning autonomy versus paternalism, and the difficulty in weighing benefits against harms. Finally, financial, political, and professional conflicts of interest are discussed, as well as health economics. PMID- 23651723 TI - Use of infliximab and anti-infliximab antibody measurements to evaluate and optimize efficacy and safety of infliximab maintenance therapy in Crohn's disease. AB - BACKGROUND: Infliximab (IFX) is a therapeutic monoclonal antibody (Ab) against TNF-alpha, which is used to induce and maintain remission in patients with moderate to severe Crohn's disease. Despite its effectiveness, approximately one third of patients experience primary treatment failure, and another one third later lose effect of maintenance therapy. IFX is well tolerated but may result in potentially life-threatening side effects such acute severe infusion reactions. Determining optimal therapy after therapeutic failure is complicated. Recent studies have indicated, that measurements of IFX and anti-IFX Ab concentrations in individual patients may be helpful in this process. AIM: The aim of this PhD thesis was to investigate the clinical utility of measuring IFX and anti-IFX Ab by novel radioimmunoassay (RIA) techniques. Specifically, the aim was to investigate if these measurements could aid in evaluating and optimizing efficacy and safety of IFX therapy in patients with Crohn's disease. METHODS: An experimental study for comparison of analytical properties of assays for measuring IFX and anti-IFX Ab was applied. In addition, three observational, retrospective, single centre cohort studies of all patients with Crohn's disease treated with IFX were carried out. RESULTS: Serum levels of IFX and anti-IFX Ab measured by RIA strongly associated with clinical response types to IFX maintenance therapy. Cut-off values providing optimal discrimination of patients with loss of response or maintained remission were established. An algorithm for evaluating and optimizing therapy in individual patients with loss of treatment response based on IFX and anti-IFX Ab levels was proposed. Acute severe infusion reactions appeared not to be true IgE-mediated anaphylactic reactions, but rather associated with development of anti-IFX IgG Ab. Risk was increased during episodic therapy, but absence of anti-IFX Ab prior to a reinitiation series did not exclude reactions and assessments hereof could not be used for risk stratification. Several factors may potentially interfere with associations of IFX and anti-IFX Ab with clinical outcome including use of different analytical techniques, different cut-off values for reporting of positive test results, differences in timing of measurements, and transiency of anti-IFX Ab. CONCLUSIONS: Monitoring serum levels of IFX and anti-IFX Ab by novel RIA techniques appears promising for evaluating and optimizing efficacy and safety of IFX therapy in Crohn's disease. Previous conflicting reports on the importance of tests are potentially biased by use of different types of assays, different cut off values for binary classification of test results, and inconsistent timing of measurements. Prospective validation of proposed treatment algorithms in larger cohorts is warranted. PMID- 23651724 TI - Regulation of urea synthesis during the acute phase response in rats. AB - Catabolism is a serious clinical problem in patients with active inflammation. Under such stressful conditions, the catabolism and loss of tissue nitrogen (N) result from proteolysis and are augmented by an up-regulation of the hepatic capacity to eliminate amino-N via urea-N. Our earlier studies suggest that this is part of the acute phase response to inflammation despite the increased need for amino-N for incorporation into acute phase proteins synthesised by the liver. It is, therefore, patho-physiologically and potentially therapeutically important to identify regulators of urea synthesis which, in this way, aggravate the inflammatory loss of body N; this study aimed at identifying such mediators, quantifying their effects, and unravelling their mode of action. The cytokines tumour necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) play key roles in inflammation, and they both induce protein breakdown and catabolism. Therefore, they are both potential mediators of the up-regulation of urea synthesis. Our first experiments showed that TNF-alpha administration in rats acutely, i.e. after 3 h, up-regulated the in vivo capacity of urea-N synthesis (CUNS) by 30%, whereas IL-6 was observed not to acutely change CUNS. Furthermore, our experiments aimed at characterising the regulation of hepatic N elimination via urea during different phases of the TNF-alpha-induced acute phase response and to identify the steps between gene expression and physiological function that might be involved. We did so by using four different methods 1, 3, 24, and 72 h after TNF-alpha injection in rats: examination of urea cycle enzyme mRNA levels in liver tissue, the hepatocyte urea cycle enzyme proteins, CUNS, and known hormonal regulators of CUNS. The major serum acute phase proteins and their liver mRNA levels were also measured. Despite a progressive down-regulation of the urea cycle genes and a fully established acute phase response 24 h after TNF-alpha administration, no change in the in vivo capacity for the disposal of amino-N by urea synthesis was observed 1, 24, and 72 h after TNF-alpha injection. Moreover, TNF-alpha actually up-regulated urea synthesis 3 h after administration (cf. above). The dissociation of the effects of TNF-alpha on the urea genes and on physiological functions remains unexplained. The lack of down-regulation of whole body urea synthesis may promote the loss of N from the body and contribute towards inflammatory catabolism. This indicates the presence of an independent hepatic component of the inflammation response that is of primary importance for the stress-catabolic state. PMID- 23651725 TI - Chronic intestinal ischaemia: measurement of the total splanchnic blood flow. AB - A redundant collateral network between the intestinal arteries is present at all times. In case of ischaemia in the gastrointestinal tract, the collateral blood supply can develop further, thus accommodating the demand for oxygen even in the presence of significant stenosis or occlusion of the intestinal arteries without clinical symptoms of intestinal ischaemia. Symptoms of ischemia develop when the genuine and collateral blood supply no longer can accommodate the need for oxygen. Atherosclerosis is the most common cause of obliteration in the intestinal arteries. In chronic intestinal ischaemia (CII), the fasting splanchnic blood flow (SBF) is sufficient, but the postprandial increase in SBF is inadequate and abdominal pain will therefore develop in relation to food intake causing the patient to eat smaller meals at larger intervals with a resulting weight loss. Traditionally, the CII-diagnosis has exclusively been based upon morphology (angiography) of the intestinal arteries; however, substantial discrepancies between CII-symptoms and the presence of atherosclerosis/stenosis in the intestinal arteries have been described repeatedly in the literature impeding the diagnosis of CII. This PhD thesis explores a method to determine the total SBF and its potential use as a diagnostic tool in patients suspected to suffer from CII. The SBF can be measured using a continuous infusion of a tracer and catheterisation of a hepatic vein and an artery. By measuring the SBF before and after a standard meal it is possible to assess the ability or inability to enhance the SBF and thereby diagnosing CII. In Study I, measurement of SBF was tested against angiography in a group of patients suspected to suffer from CII due to pain and weight loss. A very good agreement between the postprandial increase in SBF and angiography was found. The method was validated against a well-established method independent of the hepatic extraction of tracer using pAH in a porcine model (study II). An excellent agreement was found between the two methods for the measurement of SBF. In the same set-up metabolism and recirculation in the intestines of the 99mTechnetium labelled tracer was rejected based on the consistency between the portal and arterial contents of tracer. Based on this study we concluded that an arterial blood sample can be used instead of a portal blood sample, making the method applicable to patients. In study III, 20 healthy volunteers and 29 patients with weight loss and abdominal pain but normal morphology of the intestinal arteries were investigated. A reference value for the meal induced SBF-increase and the relation to bodyweight was established designating that bodyweight should be taken into account when diagnosing CII based on measurement of SBF. The clinical method for measuring the SBF based on hepatic 99mTc-MBF extraction is a robust method. It allows determination of the postprandial increase in SBF providing knowledge about the circulatory physiology in intestines in patients with weight loss and abdominal pain with or without intestinal arterial stenosis. Future studies within this field could include measurement of the SBF before and after revascularisation in order to quantify the effect of revascularisation or investigate whether arterial blood sampling could be avoided or the amount of blood samples (and thus the time spend) could be reduced. The three studies were presented at eleven national and international congresses and Helle Damgaard Zacho has been awarded three prizes for the presentations. PMID- 23651726 TI - Thymic function in HIV-infection. AB - This thesis is based on seven previously published articles. The work was performed during my employment at The Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, as a scholarship student from 2000-2001 and as a research assistant in the period 2004-2010. HIV-infection is characterized by CD4+ cell depletion. The differences between patients in the degree of CD4+ cell recovery upon treatment with highly active antiretroviral therapy (HAART) may in part be due to differences in the supply of naive CD4+ cells from the thymus. The thymus atrophies with increasing age for which reason the adult thymus was previously assumed to be without function. The aim of these investigations was to examine the role of the thymus in different aspects of HIV infection: In adult HIV-infected patients, during HIV-positive pregnancy, and in HIV-exposed uninfected (HIV-EU) children born to HIV-infected mothers. Thymic size and output were determined in 25 adult HIV-infected patients receiving HAART and in 10 controls. Larger thymic size was associated with higher CD4 counts and higher thymic output. Furthermore, patients with abundant thymic tissue seemed to have broader immunological repertoires, compared with patients with minimal thymic tissue. The study supports the mounting evidence of a contribution by the adult thymus to immune reconstitution in HIV-infection. In a follow-up study conducted till 5 years of HAART, the importance of the thymus to the rate of cellular restoration was found to primarily lie within the first two years of HAART. The effect of recombinant human growth hormone (rhGH) was then investigated in a randomized, double-blinded placebo controlled trial in 46 adult HIV-infected patients on HAART. Daily treatment with a low dose of rhGH of 0.7mg for 40 weeks stimulated thymopoiesis as expressed by thymic size, density, and output strongly supporting the assumption that rhGH possesses the potential to stimulate the ageing thymus, holding promise as a future means to complete CD4 restoration and renew the TCR repertoire in patients who respond insufficiently to HAART. Apart from naive T cells, regulatory T cells (Tregs) are developed in the thymus. Tregs play a critical role in peripheral tolerance and suppress inappropriate immune activation such as induced by HIV. We studied levels of Tregs in adult HIV-infected patients with known thymic output. Our studies demonstrate increased levels of Tregs in HIV-infected patients despite long-term treatment with HAART, suppressed viral loads, and normalized CD4 counts and immune activation suggesting that Tregs expand irreversibly in HIV-infection independently of viral load, CD4 depletion or level of immune activation. Our data further suggest that elevated levels of Tregs in HIV-infected adults may in part be due to increased thymic production of naive Tregs. During pregnancy, establishing fetal-maternal tolerance is essential to pregnancy success. In a prospective study on HIV-positive and HIV-negative pregnant women we found alterations in thymic output and Treg levels in HIV-negative pregnant women compatible with such an establishment. HIV-infected women, however, displayed different immunological profiles from HIV-negative women, and this immune unbalance may interfere with the prevention of fetal rejection and may partly explain the increased risk of abortion in HIV-infected women. We finally examined thymic function in 20 HIV-EU children at 15 months of age. The thymus was reduced in size in HIV-EU children compared with children born to HIV-negative mothers, but no evidence of impaired thymic function, immune regulation, or antibody vaccination response was detected, suggesting that no qualitative immune deficits persist in HIV-EU children beyond infancy. In conclusion, the thymus is functional in adults, and it contributes to immunological recovery in HIV infected patients primarily during the first two years of HAART. Treg levels are increased in HIV-infected patients independent of viral load, CD4 cell depletion or level of immune activation, and this may be due to increased thymic production of naive Tregs. Alteration of thymic function in adults is possible, both by stimulation of thymopoiesis with rhGH therapy and as a result of pregnancy. Finally, immunological abnormalities detected in HIV-EU infants are recovered at 15 months of age, and even if diminished in size, thymic function is normalized at this age. PMID- 23651727 TI - Intracranial meningiomas, the VEGF-A pathway, and peritumoral brain oedema. AB - Meningiomas are the second-most common intracranial tumours in adults. They are derived from the arachnoid cells, and although approximately 90% of meningiomas are benign, more than half of all meningiomas develop peritumoral brain oedema (PTBE), which increases morbidity. The PTBE can be treated with steroid therapy, but this treatment is not specific, is not always effective, and involves long term side-effects. Meningiomas are treated with radiation therapy, stereotactic radio-surgery or surgical resection. At the moment surgical resection is the only definite treatment, and the removal of the tumour also removes the PTBE. Based on the localization of the meningioma, surgery can be complicated. Although PTBE around meningiomas is frequent, the mechanisms behind its development are not clearly understood. It is believed that due to tumour growth and local tissue hypoxia, angiogenesis is increased and leads to the formation of PTBE. The angiogenic protein vascular endothelial growth factor A (VEGF-A) is believed to be involved in the formation of PTBE around meningiomas, as several studies have found that it is increased in meningiomas with PTBE. VEGF-A is also known as vascular permeability factor due to its ability to increase the permeability of capillaries. Paper I examines the VEGF-A protein and mRNA levels in 101 intracranial meningiomas. The PTBE is quantified on MRI, and capillary length and tumour water content are measured and compared to control brain tissue. Possible co-factors to PTBE like meningioma localization and subtypes are also examined. Forty-three of the patients have primary, solitary, supratentorial meningiomas with PTBE. The correlation between PTBE or edema index with the VEGF-A protein and mRNA, capillary length, and tumour water content is investigated in these patients. A novel method is used for mRNA quantification. It involves direct amplification of the mRNA with probes and branched DNA in order to produce a chemiluminescence signal that can be measured using a luminometer. The paper shows that the oedema index is correlated to the VEGF-A protein and mRNA, and that capillary length is correlated to the PTBE. It also finds that VEGF-A protein and mRNA, capillary length and water content is increased in meningiomas compared to control tissue, suggesting that VEGF-A is produced in, and possibly secreted from the meningiomas. In addition, supratentorial meningiomas are shown to have larger PTBE compared to infratentorial meningiomas, suggesting that infratentorial meningiomas are diagnosed and removed earlier, due to earlier symptom development based on the anatomical features of the fossa posterior. Finally, a gender-specific difference in tumour water content and VEGF-A protein is revealed (higher and lower in females, respectively). Paper II is a method comparison study pitting the chemiluminescence assay against the often used quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) assay. In RT-qPCR, RNA is isolated, measured, reverse transcribed, purified, amplified via real-time PCR, and analyzed. The method is robust and reliable, albeit laborious to some extent. The chemiluminescence assay detects RNA directly without the need for RNA purification, complement DNA synthesis or cyclic amplification. By comparing the output of the two protocols to a dilution series ranging from 1 to 128 times of the homogenized samples, the precision of the protocols is measured. Furthermore, VEGF-A/GAPDH ratios are quantified for 15 tissue samples and the results compared between the two protocols, showing significant correlation. The study finds that the chemiluminescence assay is competitive to RT-qPCR, and reflects a similar pattern in gene expression measurement with a similar precision. Whether one method or the other should be used depends on the variability of the samples, budget, and time. RT-qPCR has a much wider dynamic range, and is preferable in case of significant sample inter variability. It is also less expensive, and gives the user more flexibility as homemade reagents can be used. On the other hand, the chemiluminescence assay is straight forward, requires less hands-on-time, and can be used on formalin-fixed and paraffin-embedded (FFPE) tissue. Paper III continues the investigations in paper I. The sample size is increased so that 22 angiomatous and secretory meningiomas are compared to 40 non-angiomatous meningiomas and 10 control brain tissue samples. Angiomatous and secretory meningiomas are chosen because they are known to have larger PTBE compared to other meningiomas. In addition to VEGF-A, capillary length, and PTBE, the VEGF-A tyrosine kinase receptor VEGFR-2 mRNA and protein levels are also examined. VEGFR-2 is a transmembrane receptor found on endothelial cells. It binds VEGF-A and thereby increases angiogenesis. VEGFR-2's co-receptor neuropilin-1 is also examined. Neuropilin-1 is an agonist of angiogenesis through complex-binding of VEGF-A, but it can also work as an inhibitor through competitive binding of semaphorin-3A. The complex binding of semaphorin-3A to neuropilin-1 can also induce endothelial cell apoptosis, thus working as an antagonist of angiogenesis. The study finds that VEGF-A mRNA, VEGF A protein, and neuropilin-1 mRNA are higher in angiomatous and non-angiomatous meningiomas compared to controls. VEGFR-2 protein is higher, and neuropilin-1 protein lower in angiomatous meningiomas compared to controls. The mean capillary length is 3614 mm/mm3 in angiomatous, 605 mm/mm3 in non-angiomatous meningiomas, and 229 mm/mm3 in the controls. Non-angiomatous and angiomatous meningioma patients have equally sized tumours. The mean PTBE around the angiomatous meningiomas is 695 cm3, i.e. 477 cm3 larger than the non-angiomatous meningiomas (p = 0.0045), and the mean oedema index is twice the size compared to the non angiomatous meningiomas. Further comparison between the two meningioma groups shows that mean VEGF-A mRNA, VEGFR-2 protein, and neuropilin-1 mRNA is significantly higher and neuropilin-1 protein is lower in the angiomatous meningiomas. We believe that the VEGF-A pathway participates in the formation of PTBE in meningiomas by inducing formation of "leaky" capillaries, resulting in secretion of VEGF-A and plasma to the peritumoural brain tissue. It may therefore be worth pursuing therapies targeted directly against VEGF-A and its receptors through drugs like bevacizumab, sorafenib, sunitifib, and cediranib. PMID- 23651728 TI - Testing impact of perinatal inflammation on cerebral autoregulation in preterm neonates: evaluation of a noninvasive method. AB - Increased preterm delivery rate and survival of preterm infants of whom a considerable proportion survive with neurodevelopmental impairment calls for better knowledge of mechanisms associated with brain injury. This thesis focuses on cerebral autoregulation and is based on clinical studies of very preterm infants and experimental studies in newborn piglets. Maintaining adequate cerebral perfusion is critical to avoid brain injury. In healthy neonates, cerebral autoregulation ensures an almost unchanged cerebral perfusion within a narrow range of arterial blood pressures. When autoregulation is impaired, cerebral blood flow follows changes in arterial blood pressure passively. Both impaired cerebral autoregulation and perinatal inflammation have been associated with perinatal brain injury in preterm neonates. We hypothesized that impaired cerebral autoregulation might represent a hemodynamic link between inflammation and brain injury. We used an apparently well established non-invasive method based on frequency analysis between spontaneous changes in arterial blood pressure and cerebral oxygenation as measured with near-infrared spectroscopy. It turned out that the methodology was weak. This led us to evaluate the precision and validity of this method. We monitored 22 preterm neonates and demonstrated that reliable detection of impaired cerebral autoregulation requires several hours of monitoring. However, weighting measurements with large variations in blood pressure in favour of those with small increases the precision. This reduces the required monitoring time in each infant (study I). Furthermore, we used a piglet model to validate the method against a conventional measure of cerebral autoregulation and demonstrated a significant correlation with degree of impaired autoregulation (study II). To study a possible link between cerebral autoregulation and perinatal inflammation, cerebral autoregulation was measured in 60 infants in their first postnatal day. Foetal vasculitis was used as a marker of antenatal (preceding) inflammation. Level of interleukin-6 in postnatal blood samples was used as a marker of postnatal (concurrent) inflammation. Neither ante- nor postnatal inflammation affected cerebral autoregulation significantly. There was, however, a trend towards a more severely impaired autoregulation in infants with signs of antenatal inflammation. Postnatal inflammation was significantly associated with hypotension, and blood pressure was inversely associated with degree of impaired cerebral autoregulation (study III). Also, we made use of our piglet model to study (i) if hypovolaemia affects cerebral autoregulation, and (ii) a possible direct cerebrovascular effect of dopamine therapy. Hypovolaemia without hypotension did not seem to affect autoregulation significantly. Dopamine, the most frequently used antihypotensive drug in neonates, elicited an unexplained mismatch between cerebral oxygenation and perfusion, as perfusion increased while oxygenation was unaffected (study IV). This mismatch has formed the basis for an ongoing explanatory study. Based on the findings in the present thesis we conclude the following: Our non-invasive method has potential use in clinical research. However, low precision hampers its clinical application. In preterm infants with perinatal inflammation, cerebral blood flow is at most moderately affected by variations in arterial blood pressure, provided inflammation induced hypotension is prevented. In newborn piglets, hypovolaemia alone did not affect cerebral autoregulation significantly, and dopamine therapy elicited an unexplained mismatch between cerebral perfusion and oxygenation. PMID- 23651729 TI - Associations between sedation, delirium and post-traumatic stress disorder and their impact on quality of life and memories following discharge from an intensive care unit. AB - In the intensive care units (ICUs) sedation strategies have changed in the past decade towards less sedation and daily wake-up calls. Recent studies indicate that no sedation (after intubation) is most beneficial for patients. A smaller number of these patients have been assessed for post-traumatic stress disorder (PTSD) after ICU discharge, but none of them were assessed for delirium while in the ICU. In other studies, delirium in the ICU is described as distressing for the patients and increasing morbidity, i.e. dementia after discharge and mortality. The associations between sedation, delirium, and PTSD have not previous been described. The aim of this PhD study was to investigate: 1) how sedation is associated with delirium in the ICU, 2) the consequences of delirium in relation to PTSD, anxiety, and depression, 3) the consequences of delirium for the patients' memories from ICU and the health-related quality of life after discharge. In a prospective observation study with patients admitted a minimum of 48 hours to the ICUs in Aarhus or Hillerod, we included all patients aged > 17 years. Non-Danish-speaking, patients transferred from other ICUs and patients with brain injury that made delirium-assessment impossible were excluded. Patients were interviewed face-to-face after 1 week, and at 2 months and 6 months by telephone using six different questionnaires. Among 3,066 patients admitted to the ICUs, 942 fulfilled the inclusion criteria. Primarily due to the inability to test for delirium, 302 patients were later excluded. Of the remaining 640 patients, 65% were delirious on 1 or more days. Fluctuations in sedation levels increased the risk of delirium statistically significantly with or without adjustments for age, gender, severity of illness, surgical/medical patient, or ICU site. After 2 months vs. 6 months, 297 patients vs. 248 patients were interviewed. PTSD was found in 7% vs. 5%, anxiety in 6% vs. 4%, and depression in 10% at both interviews. Delirium had no association with any of the psychometric results. Memories of delusion and memories of feelings were statistically significantly associated with delirium and with the psychometric outcomes, whereas memories of facts had no association with the psychometric outcomes. Health-related quality of life (SF-36) was statistically significantly decreased in most of the domains if patients had PTSD, anxiety, or depression but was not associated with delirium or the type of memories. CONCLUSION: Fluctuations in the level of sedation of patients in the ICU increased the incidence of delirium, but the delirium did not affect the risk of PTSD, anxiety, or depression. These were, however, affected by the type of memories the patients had. Health-related quality of life (SF-36) was decreased if patients had PTSD, anxiety, or depression but was unaffected by memories of the ICU and the presence of delirium while in the ICU. PMID- 23651730 TI - Vitamin B12 deficiency among patients with diabetes mellitus: is routine screening and supplementation justified? AB - Vitamin B12 is an essential micronutrient required for optimal hemopoetic, neuro cognitive and cardiovascular function. Biochemical and clinical vitamin B12 deficiency has been demonstrated to be highly prevalent among patients with type 1 and type 2 diabetes mellitus. It presents with diverse clinical manifestations ranging from impaired memory, dementia, delirium, peripheral neuropathy, sub acute combined degeneration of the spinal cord, megaloblastic anemia and pancytopenia. This review article offers a current perspective on the physiological roles of vitamin B12, proposed pathophysiological mechanisms of vitamin B12 deficiency, screening for vitamin B12 deficiency and vitamin B12 supplementation among patients with diabetes mellitus. PMID- 23651731 TI - Activation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase during high fat diet feeding. AB - The liver plays a central role in regulating cholesterol homeostasis. High fat diets have been shown to induce obesity and hyperlipidemia. Despite considerable advances in our understanding of cholesterol metabolism, the regulation of liver cholesterol biosynthesis in response to high fat diet feeding has not been fully addressed. The aim of the present study was to investigate mechanisms by which a high fat diet caused activation of liver 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) leading to increased cholesterol biosynthesis. Mice were fed a high fat diet (60% kcal fat) for 5weeks. High fat diet feeding induced weight gain and elevated lipid levels (total cholesterol and triglyceride) in both the liver and serum. Despite cholesterol accumulation in the liver, there was a significant increase in hepatic HMG-CoA reductase mRNA and protein expression as well as enzyme activity. The DNA binding activity of sterol regulatory element binding protein (SREBP)-2 and specific protein 1 (Sp1) were also increased in the liver of mice fed a high fat diet. To validate the in vivo findings, HepG2 cells were treated with palmitic acid. Such a treatment activated SREBP-2 as well as increased the mRNA and enzyme activity of HMG-CoA reductase leading to intracellular cholesterol accumulation. Inhibition of Sp1 by siRNA transfection abolished palmitic acid-induced SREBP-2 and HMG-CoA reductase mRNA expression. These results suggest that Sp1-mediated SREBP-2 activation contributes to high fat diet induced HMG-CoA reductase activation and increased cholesterol biosynthesis. This may play a role in liver cholesterol accumulation and hypercholesterolemia. PMID- 23651732 TI - Mutation at the folate receptor 4 locus modulates gene expression profiles in the mouse uterus in response to periconceptional folate supplementation. AB - Periconceptional supplementation of folic acid to the diet of women is considered a great success for a public health intervention. Higher folate status, either by supplementation, or via the mandatory fortification of grain products in the United States, has led to significant reduction in the incidence of neural tube defects. Besides birth defects, folate deficiency has been linked to a variety of morbidities, most notably to increased risk for cancer. However, recent evidence suggests that excess folate may be detrimental - for birth defect incidence or in the progression of cancer. How folate mediates beneficial or detrimental effects is not well understood. It is also unknown what molecular responses are elicited in women taking folate supplements, and thus experience a bolus of folate on top of the status achieved by fortification. To characterize the response to a periconceptional regimen of supplementation with folinic acid, we performed gene expression profiling experiments on uterus tissue of pregnant mice with either wildtype alleles or targeted disruption at the folate receptor 4 locus. We observed that, depending on the genetic background, folinic acid supplementation affects expression of genes that contribute to lipid metabolism, protein synthesis, mitochondrial function, cell cycle, and cell activation. The extent of the response is strongly modulated by the genetic background. Finally, we provide evidence that folinic acid supplementation in the mutant paradigm affects histone methylation status, a potential mechanism of gene regulation in this model. PMID- 23651733 TI - Caregiver rating bias in mild cognitive impairment and mild Alzheimer's disease: impact of caregiver burden and depression on dyadic rating discrepancy across domains. AB - BACKGROUND: Caregivers of individuals with dementia are biased in their rating of mental health measures of the care receiver. This study examines caregiver burden and depression as predictors of this bias for mild cognitive impairment and mild Alzheimer's disease in different domains. METHODS: The sample consisted of 202 persons: 60 with mild cognitive impairment, 41 with mild Alzheimer's disease, and 101 caregivers. Discrepancy scores were calculated by subtracting the mean caregiver score from the respective mean patient score on the following assessment instruments: the Geriatric Depression Scale, Apathy Evaluation Scale, Bayer-Activities of Daily Living Scale, and Quality of Life-AD scale. Caregiver burden and depression were assessed by the Zarit Burden Interview and the Center for Epidemiologic Studies Depression Scale. RESULTS: Intraclass correlation coefficients were low for apathy (0.38), daily functioning (0.38), and quality of life (0.30) and moderate for depression (0.49). These domains showed negative rating discrepancies, which indicates caregiver rating bias for all four domains. Regression analyses revealed that caregiver burden significantly contributed to explaining these discrepancies in the domains apathy, daily functioning, and quality of life. CONCLUSION: Caregiver rating bias can be attributed to caregiver burden. When caregiver burden is present, data based on caregiver ratings should therefore be interpreted with caution. PMID- 23651734 TI - Do residents' perceptions of being well-placed and objective presence of local amenities match? A case study in West Central Scotland, UK. AB - BACKGROUND: Recently there has been growing interest in how neighbourhood features, such as the provision of local facilities and amenities, influence residents' health and well-being. Prior research has measured amenity provision through subjective measures (surveying residents' perceptions) or objective (GIS mapping of distance) methods. The latter may provide a more accurate measure of physical access, but residents may not use local amenities if they do not perceive them as 'local'. We believe both subjective and objective measures should be explored, and use West Central Scotland data to investigate correspondence between residents' subjective assessments of how well-placed they are for everyday amenities (food stores, primary and secondary schools, libraries, pharmacies, public recreation), and objective GIS-modelled measures, and examine correspondence by various sub-groups. METHODS: ArcMap was used to map the postal locations of 'Transport, Health and Well-being 2010 Study' respondents (n = 1760), and the six amenities, and the presence/absence of each of them within various straight-line and network buffers around respondents' homes was recorded. SPSS was used to investigate whether objective presence of an amenity within a specified buffer was perceived by a respondent as being well-placed for that amenity. Kappa statistics were used to test agreement between measures for all respondents, and by sex, age, social class, area deprivation, car ownership, dog ownership, walking in the local area, and years lived in current home. RESULTS: In general, there was poor agreement (Kappa <0.20) between perceptions of being well-placed for each facility and objective presence, within 800 m and 1000 m straight-line and network buffers, with the exception of pharmacies (at 1000 m straight-line) (Kappa: 0.21). Results varied between respondent sub groups, with some showing better agreement than others. Amongst sub-groups, at 800 m straight-line buffers, the highest correspondence between subjective and objective measures was for pharmacies and primary schools, and at 1000 m, for pharmacies, primary schools and libraries. For road network buffers under 1000 m, agreement was generally poor. CONCLUSION: Respondents did not necessarily regard themselves as well-placed for specific amenities when these amenities were present within specified boundaries around their homes, with some exceptions; the picture is not clear-cut with varying findings between different amenities, buffers, and sub-groups. PMID- 23651735 TI - A systems change: leading the way to meeting health needs. AB - Demonstrating the efficacy of our practice requires a paradigm shift. Becoming an effective leader and clinician can facilitate opportunities for program development and clinical research. The use of strategic planning strategies, such as needs assessment and SWOT analysis, can help lead the way to such change. The following illustrates the use of strategic planning to develop The Carpal and Cubital Tunnel Syndrome Program (CCTSP) within a growing orthopedic practice. PMID- 23651736 TI - Th1-, Th2-, and Th17-related cytokine and chemokine receptor mRNA and protein expression in the brain tissues, T cells, and macrophages of dogs with necrotizing and granulomatous meningoencephalitis. AB - Necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE), and granulomatous meningoencephalomyelitis (GME) are idiopathic inflammatory diseases in the central nervous system (CNS) of dogs. In our previous study, the proportion of inflammatory cells, except for CD3-positive T cells, were not different in parenchymal and perivascular lesions in the brain. However, breed specificities, clinical courses, and specific lesions were distinct among these diseases. Thus, similarities and differences in the pathologies of these diseases have been implied. In this study, the messenger RNA (mRNA) and/or protein expression levels of cytokines and chemokine receptors were investigated in NME (n = 2), NLE (n = 4), and GME (n = 2) cases, and their relationship in the formation of specific lesions was discussed. The mRNA and protein expression levels of interferon (IFN)-gamma and interleukin (IL)-17 were marked in NME and GME, respectively. The mRNA expression levels of CXCR3 and CCR2 were also marked in NME and GME, respectively. The results of double-labeling immunofluorescence, used to identify cells producing IL-17 in these lesions, showed that most CD163 positive macrophages/microglia but fewer CD3-positive T cells were IL-17 positive in GME. These results indicate that IFN-gamma plays a key role in NME lesions and that the macrophages/microglia that infiltrate brain lesions producing IL-17 are more important in GME than T cells. PMID- 23651737 TI - Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans. AB - It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. PMID- 23651738 TI - Resveratrol inhibits LXRalpha-dependent hepatic lipogenesis through novel antioxidant Sestrin2 gene induction. AB - Liver X receptor-alpha (LXRalpha), a member of the nuclear receptor superfamily of ligand-activated transcription factors, regulates de novo fatty acid synthesis that leads to stimulate hepatic steatosis. Although, resveratrol has beneficial effects on metabolic disease, it is not known whether resveratrol affects LXRalpha-dependent lipogenic gene expression. This study investigated the effect of resveratrol in LXRalpha-mediated lipogenesis and the underlying molecular mechanism. Resveratrol inhibited the ability of LXRalpha to activate sterol regulatory element binding protein-1c (SREBP-1c) and thereby inhibited target gene expression in hepatocytes. Moreover, resveratrol decreased LXRalpha-RXRalpha DNA binding activity and LXRE-luciferase transactivation. Resveratrol is known to activate Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK), although its precise mechanism of action remains controversial. We found that the ability of resveratrol to repress T0901317-induced SREBP-1c expression was not dependent on AMPK and Sirt1. It is well established that hepatic steatosis is associated with antioxidant and redox signaling. Our data showing that expression of Sestrin2 (Sesn2), which is a novel antioxidant gene, was significantly down-regulated in the livers of high-fat diet-fed mice. Moreover, resveratrol up-regulated Sesn2 expression, but not Sesn1 and Sesn3. Sesn2 overexpression repressed LXRalpha activated SREBP-1c expression and LXRE-luciferase activity. Finally, Sesn2 knockdown using siRNA abolished the effect of resveratrol in LXRalpha-induced FAS luciferase gene transactivation. We conclude that resveratrol affects Sesn2 gene induction and contributes to the inhibition of LXRalpha-mediated hepatic lipogenesis. PMID- 23651739 TI - Low prevalence of 'classical' microscopic colitis but evidence of microscopic inflammation in Asian irritable bowel syndrome patients with diarrhoea. AB - BACKGROUND: There is increasing evidence for the role of microscopic inflammation in patients with IBS. We aimed to examine the prevalence of microscopic colitis and inflammation in Malaysian IBS patients with diarrhoea (IBS-D). METHODS: Consecutive patients who met the Rome III criteria for IBS-D and asymptomatic controls were prospectively recruited. Colonoscopy was performed in all study subjects and systematic biopsies taken from all segments of the colon. The diagnosis of lymphocytic colitis and collagenous colitis was made using previously defined criteria. Patients with post infectious IBS were excluded. RESULTS: 120 subjects (74 IBS-D, 46 controls) were recruited during the study period. In the IBS-D group, the colonoscopic (macroscopic) findings were as follows; normal findings n = 58 (78.4%), diverticula disease n = 5 (6.8%), diminutive polyps n = 9 (12.2%) and haemorrhoids n = 2(2.7%). No subject under the age of 40 had any significant findings. Microscopically, there was only one case (1.3%) with histology consistent with collagenous colitis. However, the IBS D patients had a higher prevalence of moderate microscopic inflammation (n = 11, 14.9%) compared to controls (n = 1, 2.2%) (p = 0.005). CONCLUSIONS: 'Classical' microscopic colitis is uncommon in Malaysian patients with IBS-D but a significant number of adults showed evidence of microscopic inflammation. PMID- 23651740 TI - Signal transduction in primary human T lymphocytes in altered gravity - results of the MASER-12 suborbital space flight mission. AB - We investigated the influence of altered gravity on key proteins of T cell activation during the MASER-12 ballistic suborbital rocket mission of the European Space Agency (ESA) and the Swedish Space Cooperation (SSC) at ESRANGE Space Center (Kiruna, Sweden). We quantified components of the T cell receptor, the membrane proximal signaling, MAPK-signaling, IL-2R, histone modifications and the cytoskeleton in non-activated and in ConA/CD28-activated primary human T lymphocytes. The hypergravity phase during the launch resulted in a downregulation of the IL-2 and CD3 receptor and reduction of tyrosine phosphorylation, p44/42-MAPK phosphorylation and histone H3 acetylation, whereas LAT phosphorylation was increased. Compared to the baseline situation at the point of entry into the microgravity phase, CD3 and IL-2 receptor expression at the surface of non-activated T cells were reduced after 6 min microgravity. Importantly, p44/42-MAPK-phosphorylation was also reduced after 6 min microgravity compared to the 1g ground controls, but also in direct comparison between the in-flight MUg and the 1g group. In activated T cells, the reduced CD3 and IL-2 receptor expression at the baseline situation recovered significantly during in-flight 1g conditions, but not during microgravity conditions. Beta tubulin increased significantly after onset of microgravity until the end of the microgravity phase, but not in the in-flight 1g condition. This study suggests that key proteins of T cell signal modules are not severely disturbed in microgravity. Instead, it can be supposed that the strong T cell inhibiting signal occurs downstream from membrane proximal signaling, such as at the transcriptional level as described recently. However, the MASER-12 experiment could identify signal molecules, which are sensitive to altered gravity, and indicates that gravity is obviously not only a requirement for transcriptional processes as described before, but also for specific phosphorylation / dephosphorylation of signal molecules and surface receptor dynamics. PMID- 23651741 TI - Epicardial unipolar radiofrequency ablation for left ventricular aneurysm related ventricular arrhythmia. AB - We report a case of a 62-year-old Chinese man with typical triple-vessel lesions and apical left ventricular aneurysm accompanied with ventricular tachycardia. Off-pump coronary artery bypass (OPCAB) grafting was performed in combination with epicardial unipolar radiofrequency ablation and linear closure of left ventricular aneurysm. The patient recovered well without postoperative complications. Holter monitoring showed no recurrence of the ventricular arrhythmia and the attack frequency of arrhythmia decreased significantly. The patient has been angina-free for 25 months since the operation and shows increasing exercise tolerance. Thus, left ventricular aneurysm plication combined with epicardial unipolar radiofrequency ablation during OPCAB may be beneficial for patients with ventricular aneurysm and preoperative malignant ventricular arrhythmia. PMID- 23651742 TI - Simultaneous determination of 2-naphthoxyacetic acid and indole-3-acetic acid by first derivation synchronous fluorescence spectroscopy. AB - A simple, rapid, sensitive and selective method for simultaneously determining 2 naphthoxyacetic acid (BNOA) and Indole-3-Acetic Acid (IAA) in mixtures has been developed using derivation synchronous fluorescence spectroscopy based on their synchronous fluorescence. The synchronous fluorescence spectra were obtained with Deltalambda=100 nm in a pH 8.5 NaH2PO4-NaOH buffer solution, and the detected wavelengths of quantitative analysis were set at 239 nm for BNOA and 293 nm for IAA respectively. The over lapped fluorescence spectra were well separated by the synchronous derivative method. Under optimized conditions, the limits of detection (LOD) were 0.003 MUg/mL for BNOA and 0.012 MUg/mL for IAA. This method is simple and expeditious, and it has been successfully applied to the determination of 2-naphthoxyacetic acid and indole-3-acetic acid in fruit juice samples with satisfactory results. The samples were only filtrated through a 0.45 MUm membrane filter, which was free from the tedious separation procedures. The obtaining recoveries were in the range of 83.88-87.43% for BNOA and 80.76-86.68% for IAA, and the relative standard deviations were all less than 5.0%. Statistical comparison of the results with high performance liquid chromatography Mass Spectrometry (HPLC-MS) method revealed good agreement and proved that there were no significant difference in the accuracy and precision between these two methods. PMID- 23651744 TI - [Multimorbidity in a health care system which is adapted to individual diseases]. PMID- 23651743 TI - Isoniazid preventive treatment: predictors of adverse events and treatment completion. AB - SETTING: Villa Marelli Institute (VMI), Niguarda Ca'Granda Hospital, Milan, Italy. BACKGROUND: A recent report on the fatal side effects of isoniazid preventive therapy (IPT) from the United States has re-ignited discussion on the safety of this intervention. OBJECTIVE: To evaluate IPT feasibility, treatment completion and adverse events (AE) and their determinants under field conditions. METHODS: Data from consecutive subjects undergoing IPT at the VMI were recorded in an electronic database from 1992 to 2009. Logistic regression analysis was performed to detect completion and AE determinants. RESULTS: A total of 11,963 patients were included in the study. AE (odds ratio [OR] 2.70, 95%CI 2.22-3.28) and human immunodeficiency virus positive status (OR 5.20, 95%CI 2.10-12.93) were the main determinants of treatment interruption among Italians, while social weakness (no housing/job; OR 2.88, 95%CI 2.43-3.42), AEs (OR 1.33, 95%CI 1.15 1.53, 2.22-3.28) and screening in undocumented subjects (OR 1.20, 95%CI 1.01 1.44) prevailed among foreigners. Age was the main determinant of transaminase increase (OR 1.03, 95%CI 1.03-1.04), as were AEs of the gastrointestinal (OR 1.02, 95%CI 1.02-1.03), central nervous (OR 1.02, 95%CI 1.02-1.05) and peripheral nervous systems (OR 1.04, 95%CI 1.02-1.05). CONCLUSION: This analysis demonstrates the feasibility and safety of IPT, with determinants of interruption and AEs being predictable and addressable. PMID- 23651745 TI - [Further minimization of minimally invasive surgery for colorectal disease may have a future]. PMID- 23651746 TI - [Limited evidence for negative pressure wound treatment of skin transplants and closed surgical wounds]. AB - The indications for negative pressure wound treatment (NPWT) are increasing, e.g. for fixation of skin transplant and primary closed surgical wounds. The evidence for indications and positive effects are limited. NPWT should exclusively be used for fixation of split thickness skin transplants when immobilisation is otherwise difficult and for primary closed surgical wounds in selected patients at risk. Future high-quality investigations are necessary to pinpoint indications for topical negative pressure therapy, the effect of the different NPWT-modalities, and the overall economy compared to conventional bandages. PMID- 23651747 TI - [Use of multiple intervention progammes in community health projects]. AB - An organising framework for multiple interventions in community health is described. The framework provides a foundation for programmatic research on multiple interventions. Multiple intervention programmes are characterised by the use of multiple strategies targeted at multiple levels of the socio-ecological system. A short description is given of the framework and an identification of gaps and challenges based on the international literature and critical questions are posed that need to be considered if this framework should be implemented in Danish communities. PMID- 23651748 TI - [Chronic obstructive pulmonary disease]. AB - The new version of the GOLD document on chronic obstructive pulmonary disease (COPD), introduces a profound change in the stratification of the patients. In addition to the level of forced expiratory volume in the first second (FEV1), the new stratification also includes the level of daily symptoms, in particular dyspnoea, and the history of exacerbations. This review describes this stratification and the treatment of stable COPD according to the GOLD document. It focuses on early diagnosis, smoking cessation, rehabilitation and medical treatment. PMID- 23651749 TI - [Diagnosis and treatment of genetic haemochromatosis]. AB - Genetic haemochromatosis is a complex disorder/disease, which can be caused by a multiplicity of mutations in genes involved in iron metabolism being located on different chromosomes. In Caucasians, mutations in the HFE-gene account for the most common form of haemochromatosis (type 1). Non-HFE-haemochromatoses are less frequent and consist of juvenile haemochromatosis (type 2A and 2B) and TRF2 related haemochromatosis (type 3), which all respond to phlebotomies. The others comprise ferroportin disease (type 4A) atypical ferroportin disease (type 4B), acoeruloplasminaemia, atransferrinaemia and DMT1-associated haemochromatosis. PMID- 23651750 TI - [Juvenile haemochromatosis caused by a homozygous Gly320Val mutation in the haemojuvelin gene]. AB - Juvenile haemochromatosis caused by a homozygous Gly320Val mutation in the haemojuvelin (HJV) gene was diagnosed in a 12-year-old Danish girl and her 10 year-old sister. Both appeared healthy without clinical or biochemical signs of organ damage. They had iron overload (plasma transferrin saturation 81 and 80%, plasma ferritin 3,671 and 1,356 microgram/l, liver iron content of 375 and 361 micromol/g dry weight, normal myocardial iron content. Their parents were both HJV heterozygous with normal iron status. The girls began phlebotomy treatment with favourable effect. PMID- 23651751 TI - [Sudden unexpected cardiac death in an 18-year-old female with familial hypercholesterolaemia]. AB - Familial hypercholesterolaemia (FH) is a well-defined but underdiagnosed dyslipidaemia occurring in 1:500 persons. We report a case where an 18-year-old woman with an untreated FH dies a sudden cardiac death due to acute myocardial infarction. In patients with FH atherosclerotic manifestations are common at a young age and FH should always be suspected in patients with P-low-density lipoprotein cholesterol level above 5 mmol/l (4 mmol/l for persons < 16 years of age). Patients with FH should be referred to specialized units so that family members with FH systematically are identified. PMID- 23651752 TI - [Fulminant perimyocarditis following tonsillitis]. AB - Fulminant perimyocarditis is a rare and potentially fatal condition that may mimick myocardial infarction. The long-term prognosis is favourable, once the patient has survived the index admission, and recurrence is extremely rare. This case describes a 35-year-old man, who experienced recurrence twice within six months. Due to the risk of a potentially fatal outcome, patients should be followed closely with clinical controls of infection parameters and echocardiography. PMID- 23651753 TI - [Glioblastoma multiforme with intra- and extramedullary dissemination to the spinal cord]. AB - Metastases to the spinal cord from glioblastoma multiforme (GBM) are uncommon, but important to have in mind when patients with a history of GBM present with symptoms that do not correlate with the primary disease pattern. We report a rare case, where a male with GBM, six months after tumour excision followed by concomitant radio- and chemotherapy, presented with gait disturbance and unspecific neurological symptoms of the lower right limb. Magnetic resonance imaging of columna totalis revealed both intra- and extramedullary metastases in the spinal cord. The patient died one month later. PMID- 23651754 TI - [Successful conservative treatment of coecal perforation in a patient with Ogilvie's syndrome]. AB - The case report describes a 37-year-old woman who was diagnosed with Ogilvie's syndrome after caesarean section. Conservative treatment was initiated with minimal effect, and the patient was subsequently treated with IV neostigmine. A computed tomography of the abdomen revealed enlarged peritoneal cavity. However the patient was clinically unaffected without fever or signs of peritonitis. The perforation was managed with a conservative approach including antibiotics and close observation of the patient. After nine days the patient was discharged with normal gastrointestinal function and without further reported complications. PMID- 23651755 TI - [Orf parapoxvirus can infect humans after relevant exposure]. AB - Orf virus occurs worldwide among sheep and goats. Transmission to humans is seen by close contact with infected animals, but the incidence in Denmark is unknown. We present a typical case in a sheep farmer with an orf infection of his hands. Upon conservative treatment the infected areas healed without sequelae. We shortly discuss the epidemiology, the natural history, the treatment and the complications of orf virus. PMID- 23651756 TI - The effects of in vivo B-cell depleting therapy on ex-vivo cytokine production. AB - In renal transplantation, IL-17 production by T-cells might be dependent on the presence of B-cells. Therefore, the effect of in vivo B-cell depletion on ex-vivo IL-17 production was investigated. Twenty patients undergoing living-donor renal transplantation were recruited from a larger cohort of patients participating in a randomized, double-blind trial. All patients were allocated to a single intra operative dose of either placebo or rituximab (375 mg/m(2)) added to the standard immunosuppressive therapy. Blood was collected at baseline, at one day, and at one month after surgery. The healthy kidney donors also gave blood at baseline. Peripheral blood mononuclear cells were stimulated ex-vivo in different manners (heat killed Candida albicans yeast, heat killed Staphylococcus aureus, or alphaCD3alphaCD28 coated beads), to address the role of B-cells in ex-vivo cytokine responses. The concentration of monocyte- and T-cell-derived cytokines (IL-1beta, IL-6, TNF-alpha, IFN-gamma, IL-17 and IL-22) was measured in supernatants. Of the 20 recruited patients, 13 received treatment with rituximab and 7 received placebo. In all patients, IL-17 was produced by CD4-positive, gammadeltaTCR-negative cells. After stimulation, there was no difference between patients and healthy controls in ex-vivo production of IL-17 or other cytokines. In all patients there was a general decrease of monocyte- and T-cell-derived cytokines after transplantation, except for IL-17. There was no difference between patients who received rituximab and patients who received placebo. A single dose of rituximab treatment added to standard immunosuppressive therapy in renal transplant patients did not influence the production of IL-17 or other monocyte- or T-cell derived cytokines after ex-vivo stimulation. PMID- 23651758 TI - New lessons on DXA-based measurement of regional body composition in athletes. PMID- 23651759 TI - The passionate life of Simon Chan. PMID- 23651760 TI - The neuropsychological sequelae of delirium in elderly patients with hip fracture three months after hospital discharge. AB - BACKGROUND: Delirium is a risk factor for long-term cognitive impairment and dementia. Yet, the nature of these cognitive deficits is unknown as is the extent to which the persistence of delirium symptoms and presence of depression at follow-up may account for the association between delirium and cognitive impairment at follow-up. We hypothesized that inattention, as an important sign of persistent delirium and/or depression, is an important feature of the cognitive profile three months after hospital discharge of patients who experienced in-hospital delirium. METHODS: This was a prospective cohort study. Fifty-three patients aged 75 years and older were admitted for surgical repair of acute hip fracture. Before the surgery, baseline characteristics, depressive symptomatology, and global cognitive performance were documented. The presence of delirium was assessed daily during hospital admission and three months after hospital discharge when patients underwent neuropsychological assessment. RESULTS: Of 27 patients with in-hospital delirium, 5 were still delirious after three months. Patients with in-hospital delirium (but free of delirium at follow up) showed poorer performance than patients without in-hospital delirium on tests of global cognition and episodic memory, even after adjustment for age, gender, and baseline cognitive impairment. In contrast, no differences were found on tests of attention. Patients with in-hospital delirium showed an increase of depressive symptoms after three months. However, delirium remained associated with poor performance on a range of neuropsychological tests among patients with few or no signs of depression at follow-up. CONCLUSION: Elderly hip fracture patients with in-hospital delirium experience impairments in global cognition and episodic memory three months after hospital discharge. Our results suggest that inattention, as a cardinal sign of persistent delirium or depressive symptomatology at follow-up, cannot fully account for the poor cognitive outcome associated with delirium. PMID- 23651761 TI - Aphicidal efficacy of scorpion- and spider-derived neurotoxins. AB - Insect-specific neurotoxins that act within the insect hemocoel (body cavity) represent an untapped resource for insect pest management. On the basis of recent advances made in development of appropriate delivery systems for transport of these toxins from the insect gut, across the gut epithelium to their target site, we screened neurotoxins derived from scorpion or spider venom for efficacy against the pea aphid, Acyrthosiphon pisum, and the green peach aphid, Myzus persicae. Toxins were selected to represent different modes of electrophysiological action, including activity on voltage-gated calcium channels (omega-TRTX-Gr1a, omega-agatoxin Aa4a, omega-hexatoxin-Hv1a), calcium- and voltage-activated potassium channels (charybdotoxin, maurotoxin), chloride channels (chlorotoxin) and voltage-gated sodium channels (LqhalphaIT). The Bacillus thuringiensis-derived toxin Cyt1Aa was also tested as a positive control for toxicity. In per os bioassays with both aphid species, toxicity was only seen for omega-TRTX-Gr1a and Cyt1Aa. On injection into the hemocoel of A. pisum, LD50 values ranged from 1 to 8 ng/mg body weight, with omega-hexatoxin-Hv1a being the most toxic (1.02 ng/mg body weight). All neurotoxins caused rapid paralysis, with charybdotoxin, maurotoxin and chlorotoxin also causing melanization of injected aphids. These data represent the first comprehensive screen of neurotoxins against aphids, and highlight the potential for practical use of the insect specific toxin omega-hexatoxin-Hv1a in aphid management. PMID- 23651762 TI - MU-Theraphotoxin-An1a: primary structure determination and assessment of the pharmacological activity of a promiscuous anti-insect toxin from the venom of the tarantula Acanthoscurria natalensis (Mygalomorphae, Theraphosidae). AB - Tarantulas are included in the mygalomorph spider family Theraphosidae. Although the pharmacological diversity of theraphosid toxins (theraphotoxins) is broad, studies dedicated to the characterization of biologically active molecules from the theraphosid genus Acanthoscurria have been restricted to the investigation of antimicrobial peptides and polyamines produced by the hemocytes of Acanthoscurria gomesiana. The present study reports the purification, primary structure determination and electrophysiological effects of an anti-insect toxin, named MU theraphotoxin-An1a (MU-TRTX-An1a), from the venom of Acanthoscurria natalensis - a tarantula species occurring in the Brazilian biomes caatinga and cerrado. The analysis of the primary structure of MU-TRTX-An1a revealed the similarity of this toxin to theraphosid toxins bearing a huwentoxin-II-like fold. Electrophysiological experiments showed that MU-TRTX-An1a (100 nM) induces membrane depolarization, increases the spontaneous firing frequency and reduces spike amplitude of cockroach dorsal unpaired median (DUM) neurons. In addition, under voltage-clamp conditions, MU-TRTX-An1a (100 nM) only partially blocks voltage-dependent sodium current amplitudes in DUM neurons without any effect on their voltage dependence. This effect correlates well with the reduction of the spontaneous action potential amplitudes. Altogether, these last results suggest that MU-TRTX-An1a affects insect neuronal voltage-dependent sodium channels, which are among possible channels targeted by this promiscuous toxin. PMID- 23651763 TI - A framework for the analysis of heterogeneity of treatment effect in patient centered outcomes research. AB - Individuals vary in their response to a treatment. Understanding this heterogeneity of treatment effect is critical for evaluating how well a treatment can be expected to work for an individual or a subgroup of individuals. An overemphasis on hypothesis testing has resulted in a dichotomy of all heterogeneity of treatment effect analyses into confirmatory (hypothesis testing) and exploratory (hypothesis finding) analyses. This limited view of heterogeneity of treatment effect is inadequate for creating evidence that is useful for informing patient-centered decisions. An expanded framework for heterogeneity of treatment effect assessment is proposed. It recognizes four distinct goals of heterogeneity of treatment effect analyses: hypothesis testing, hypothesis finding, reporting subgroup effects for meta-analysis, and individual-level prediction. Accordingly, two new types of heterogeneity of treatment effect analyses are proposed: descriptive and predictive. Descriptive heterogeneity of treatment effect analyses report treatment effects for prespecified subgroups in accordance with prospectively specified analytic strategy. They need not be powered to detect heterogeneity of treatment effect. They emphasize estimation and reporting of subgroup effects rather than hypothesis testing. Sampling properties (e.g., standard error) of descriptive analysis can be characterized, thus facilitating meta-analysis of subgroup effects. Predictive heterogeneity of treatment effect analyses estimate probabilities of beneficial and adverse responses of individuals to treatments and facilitates optimal treatment decisions for different types of individuals. Procedures are also suggested to improve reliability of heterogeneity of treatment effect assessment from observational studies. Heterogeneity of treatment effect analysis should be identified as confirmatory, descriptive, exploratory, or predictive analysis. Evidence should be interpreted in a manner consistent with the analytic goal. PMID- 23651764 TI - Interviewer effects when investigating abuse were not compatible with effect modification but instead with confounding. AB - OBJECTIVES: To describe interviewer-related variability in abuse estimates and assess the nature of the interviewer effects on the associations between elder abuse and covariates. STUDY DESIGN AND SETTING: After intensive training, six interviewers administered structured questionnaires through face-to-face interviews to assess abuse in a population-based sample of 641 Portuguese individuals aged 60-84 years. RESULTS: The overall prevalence of abuse victimization during the previous year was 28.1%, but it differed significantly according to the interviewer, ranging from 16.9% to 36.8%. There was no statistical effect modification introduced by the interviewer on the association of abuse and its determinants. Additionally, interviewer-level variables (empathy and violence beliefs) showed no significant contribution to explain the variance attributable to potential interviewer effects. Adjusting for the interviewer had little or no effect on the odds ratio of abuse for gender, age, education, and quality of life. However, the interviewer introduced relevant confounding of the associations between abuse and other sensitive topics, such as somatic complaints. CONCLUSION: Although no relevant effect modification was observed, this study emphasizes the importance of the interviewer as a relevant confounder when estimating associations between sensitive variables, as it is the case of elder abuse. PMID- 23651766 TI - Not PEDro's bias: summary quality scores can be used in meta-analysis. PMID- 23651765 TI - Individual participant data meta-analyses should not ignore clustering. AB - OBJECTIVES: Individual participant data (IPD) meta-analyses often analyze their IPD as if coming from a single study. We compare this approach with analyses that rather account for clustering of patients within studies. STUDY DESIGN AND SETTING: Comparison of effect estimates from logistic regression models in real and simulated examples. RESULTS: The estimated prognostic effect of age in patients with traumatic brain injury is similar, regardless of whether clustering is accounted for. However, a family history of thrombophilia is found to be a diagnostic marker of deep vein thrombosis [odds ratio, 1.30; 95% confidence interval (CI): 1.00, 1.70; P = 0.05] when clustering is accounted for but not when it is ignored (odds ratio, 1.06; 95% CI: 0.83, 1.37; P = 0.64). Similarly, the treatment effect of nicotine gum on smoking cessation is severely attenuated when clustering is ignored (odds ratio, 1.40; 95% CI: 1.02, 1.92) rather than accounted for (odds ratio, 1.80; 95% CI: 1.29, 2.52). Simulations show models accounting for clustering perform consistently well, but downwardly biased effect estimates and low coverage can occur when ignoring clustering. CONCLUSION: Researchers must routinely account for clustering in IPD meta-analyses; otherwise, misleading effect estimates and conclusions may arise. PMID- 23651767 TI - Baseline predictors of treatment outcome in Internet-based alcohol interventions: a recursive partitioning analysis alongside a randomized trial. AB - BACKGROUND: Internet-based interventions are seen as attractive for harmful users of alcohol and lead to desirable clinical outcomes. Some participants will however not achieve the desired results. In this study, harmful users of alcohol have been partitioned in subgroups with low, intermediate or high probability of positive treatment outcome, using recursive partitioning classification tree analysis. METHODS: Data were obtained from a randomized controlled trial assessing the effectiveness of two Internet-based alcohol interventions. The main outcome variable was treatment response, a dichotomous outcome measure for treatment success. Candidate predictors for the classification analysis were first selected using univariate regression. Next, a tree decision model to classify participants in categories with a low, medium and high probability of treatment response was constructed using recursive partitioning software. RESULTS: Based on literature review, 46 potentially relevant baseline predictors were identified. Five variables were selected using univariate regression as candidate predictors for the classification analysis. Two variables were found most relevant for classification and selected for the decision tree model: 'living alone', and 'interpersonal sensitivity'. Using sensitivity analysis, the robustness of the decision tree model was supported. CONCLUSIONS: Harmful alcohol users in a shared living situation, with high interpersonal sensitivity, have a significantly higher probability of positive treatment outcome. The resulting decision tree model may be used as part of a decision support system but is on its own insufficient as a screening algorithm with satisfactory clinical utility. TRIAL REGISTRATION: Netherlands Trial Register (Cochrane Collaboration): NTR TC1155. PMID- 23651768 TI - Repeat antenatal steroid exposure and later blood pressure, arterial stiffness, and metabolic profile. AB - OBJECTIVE: To determine the relationship between repeat courses of antenatal corticosteroids (ACS) and risk factors for cardiovascular disease in adolescents and young adults. STUDY DESIGN: We assessed body mass index, blood pressure, arterial stiffness, blood lipids, and insulin resistance (IR) in a Swedish population-based cohort (n = 100) at a median age of 18 (range 14-26) years. Fifty-eight subjects (36 males) had been exposed to 2-9 weekly courses of antenatal betamethasone and 42 (23 males) were unexposed subjects matched for age, sex, and gestational age (GA). RESULTS: There were no significant differences between the groups regarding body mass index, systolic or diastolic blood pressures, arterial stiffness measured by augmentation index, blood lipids, IR, or morning cortisol levels either in simple regression or in multivariable models. However, more subjects with elevated augmentation index had been exposed to repeat courses of ACS (n = 7) compared with unexposed subjects (n =1, P = .06), and glucose, insulin, and IR correlated inversely to GA at start of ACS (P < .01). CONCLUSIONS: Repeat courses of ACS did not correlate to adverse cardiovascular risk profile in adolescence and young adulthood, but long-standing effects on the arterial tree and glucose metabolism, the latter dependent on GA at ACS exposure, cannot be excluded. These observations have clinical implications for the ongoing discussion on short-term benefits and long-term safety of repeat ACS treatment. PMID- 23651770 TI - Infantile bromoderma. PMID- 23651769 TI - Copper deficiency in patients with cystinosis with cysteamine toxicity. AB - OBJECTIVES: To assess whether copper deficiency plays a role in the recently described cysteamine toxicity in patients with cystinosis, and to examine whether polymorphisms in copper transporters, lysyl oxidase, and/or type I procollagen genes could be responsible for the occurrence of cysteamine toxicity in a small subset of patients with cystinosis. STUDY DESIGN: Thirty-six patients with cystinosis were included: 22 with Fanconi syndrome (including 7 with cysteamine toxicity), 12 after renal transplantation, 1 receiving hemodialysis, and 1 with ocular cystinosis. Serum copper and ceruloplasmin levels and urinary copper/creatinine ratio were measured. Genes ATP7A and CTR1 (encoding copper transporters), LOX (encoding lysyl oxidase), and COL1A1 and COL1A2 (encoding type I procollagen) were analyzed in patients with (n = 6) and without (n = 5) toxicity. Fibroblast (pro)collagen synthesis was compared in patients with (n = 3) and those without (n = 2) cysteamine toxicity. RESULTS: All 22 patients with Fanconi syndrome had increased urinary copper excretion. Serum copper and ceruloplasmin levels were decreased in 9 patients, including all 7 patients with cysteamine toxicity. No specific sequence variations were associated with toxicity. All fibroblasts exhibited normal (pro)collagen synthesis. CONCLUSION: Patients with cystinosis with cysteamine toxicity demonstrate copper deficiency. This can cause decreased activity of lysyl oxidase, the enzyme that generates the aldehydes required for collagen cross-linking. Thus, copper supplementation might prevent cysteamine toxicity. PMID- 23651771 TI - Self-reported sitting time is not associated with incidence of cardiovascular disease in a population-based cohort of mid-aged women. AB - BACKGROUND: In Westernised societies adults are increasingly spending many hours each day in sedentary, low energy expenditure activities such as sitting. Although there is growing evidence on the relationship between television/screen time and increased cardiovascular disease mortality, very little is known about the association between total sitting time (in different domains) and cardiovascular disease incidence. We investigated this in a population-based cohort of mid-aged women in Australia. FINDINGS: Data were from 6154 participants in the 1946-51 birth cohort of the Australian Longitudinal Study on Women's Health who were free of cardiovascular disease at baseline. Survival analysis was used to determine the association between self-reported sitting time and cardiovascular disease incidence, determined through hospital diagnoses and cause of death data. During a mean (+/- SD) follow-up time of 9.9 +/- 1.2 years, 177 cases of cardiovascular disease occurred. Mean sitting time (+/- SD) was 5.4 +/- 2.6 hours a day. Sitting time was not associated with incident cardiovascular disease (adjusted hazard ratio 0.97, 95% CI 0.92 to 1.03). We found no interaction between physical activity and sitting time and cardiovascular disease. CONCLUSIONS: In mid-aged women sitting time does not appear to be associated with cardiovascular disease incidence. These findings are contrary to expectations, given the growing evidence of a relationship between sitting time and cardiovascular disease mortality. Research in this area is scarce and additional studies are needed to confirm or refute these findings. PMID- 23651772 TI - Age-related self-overestimation of step-over ability in healthy older adults and its relationship to fall risk. AB - BACKGROUND: Older adults could not safely step over an obstacle unless they correctly estimated their physical ability to be capable of a successful step over action. Thus, incorrect estimation (overestimation) of ability to step over an obstacle could result in severe accident such as falls in older adults. We investigated whether older adults tended to overestimate step-over ability compared with young adults and whether such overestimation in stepping over obstacles was associated with falls. METHODS: Three groups of adults, young-old (age, 60-74 years; n, 343), old-old (age, >74 years; n, 151), and young (age, 18 35 years; n, 71), performed our original step-over test (SOT). In the SOT, participants observed a horizontal bar at a 7-m distance and estimated the maximum height (EH) that they could step over. After estimation, they performed real SOT trials to measure the actual maximum height (AH). We also identified participants who had experienced falls in the 1 year period before the study. RESULTS: Thirty-nine young-old adults (11.4%) and 49 old-old adults (32.5%) failed to step over the bar at EH (overestimation), whereas all young adults succeeded (underestimation). There was a significant negative correlation between actual performance (AH) and self-estimation error (difference between EH and AH) in the older adults, indicating that older adults with lower AH (SOT ability) tended to overestimate actual ability (EH > AH) and vice versa. Furthermore, the percentage of participants who overestimated SOT ability in the fallers (28%) was almost double larger than that in the non-fallers (16%), with the fallers showing significantly lower SOT ability than the non-fallers. CONCLUSIONS: Older adults appear unaware of age-related physical decline and tended to overestimate step over ability. Both age-related decline in step-over ability, and more importantly, overestimation or decreased underestimation of this ability may raise potential risk of falls. PMID- 23651773 TI - Study of DNA interactions with bifenthrin by spectroscopic techniques and molecular modeling. AB - The interaction between bifenthrin (BF) and calf thymus DNA (ctDNA) in physiological buffer (pH 7.4) was investigated by UV-vis absorption, fluorescence, circular dichroism (CD), and Fourier transform infrared (FT-IR) spectroscopy, coupled with viscosity measurements and molecular docking techniques. It was found that BF molecular could intercalate into the base pairs of ctDNA as evidenced by significant increases in absorption intensity, fluorescence polarization and relative viscosity of ctDNA, decrease in iodide quenching effect, and induced CD spectral changes. The association constant of BF with ctDNA was evaluated to be in the order of 10(4) L mol(-1). Thermodynamic analysis of the binding data obtained at different temperatures suggested that the binding process was primarily driven by hydrogen bonds and van der Waals forces, as the values of the enthalpy change (DeltaH) and the entropy change (DeltaS) were calculated to be -31.13+/-1.89 kJ mol(-1) and -22.79+/-1.21 J mol( 1) K(-1), respectively. The results of FT-IR spectra and molecular docking showed that a specific binding mainly existed between BF and adenine and guanine bases. PMID- 23651774 TI - Influences of urea and pH on the interaction of cinchonidine with bovine serum albumin by steady state fluorescence spectroscopy. AB - The binding of cinchonidine to bovine serum albumin (BSA) in aqueous solution in the absence and presence of urea has been studied by fluorescence spectroscopic techniques at pH 7.40. Denaturation of BSA in the presence of urea is almost complete at [urea] >=8.0 M. Upon unfolding, two fluorescence peaks of BSA were observed. One peak was assigned to the fluorescence of Trp residue in a polar environment, and the other peak was assigned to the fluorescence of Tyr residues. In addition, the fluorescence quenching effects of cinchonidine were shown not only on the native but also on the unfolded form of BSA. The quenching rate constants and binding constants calculated in the absence and presence of the denaturant urea indicates that the binding capacity of cinchonidine to the denatured BSA deceases dramatically. In addition, influence of pH on the interaction between cinchonidine and BSA was investigated and the binding abilities of the drug to BSA deceased under lower pH conditions (pH 3.5 and 1.8) and higher pH conditions (pH 9.0). PMID- 23651775 TI - Effect of trivalent metal ion impurities (Al3+, Cr3+ and Fe3+) on the growth, structural and physical properties of potassium acid phthalate (KAP) crystals. AB - Trivalent metal ion (Al, Cr, Fe) doped potassium hydrogen phthalate (KAP) crystals have been grown from aqueous solution at room temperature. Powder XRD and ICP-OES studies confirmed the metal ion doping into KAP crystals. The presence of functional groups in the crystal has been observed by FTIR analysis. Optical transmission studies were carried out by allowing the UV-NIR ray of wavelength between 190 and 1000 nm to pass through the (010) face of the grown KAP crystals. Dielectric constant value of Fe-doped KAP at 100 Hz was found to be significantly higher than that of undoped and Cr and Al-doped KAP. TG-DTA studies show the decomposition temperatures to be 255, 270, 258 and 287 degrees C for pure, Al(3+), Cr(3+) and Fe(3+) doped KAP crystals respectively. Microhardness studies reveal that the Cr(3+) and Fe(3+) doped crystals have higher hardness values than that of undoped and Al-doped KAP. The grown crystals were also subjected to second harmonic generation (SHG) efficiency tests. PMID- 23651776 TI - Human exposure to p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) in urban and semi-rural areas in southeast Spain: a gender perspective. AB - p,p'-Dichlorodiphenyldichloroethylene (p,p'-DDE) is the main metabolite of pesticide dichlorodiphenyltrichloroethane and a marker of past exposure to this organochlorine pesticide. p,p'-DDE is considered a persistent organic pollutant with potential adverse effects on human health. The aims of the present study were to assess p,p'-DDE levels in serum and adipose tissue from a cohort of adults in southern Spain and to explore the predictors of exposure from a gender perspective. Chemical analyses were performed using gas chromatography-coupled mass spectrometry in tandem mode. The study population (n=387) was intraoperatively recruited in two areas of Granada Province (southern Spain), and data on potential predictors of these concentrations were gathered by questionnaire. The statistical analysis was performed by means of multivariable linear regression models. All participants showed detectable concentrations of p,p'-DDE in both serum and adipose tissue, with median concentrations of 175.7 and 93.0 ng/g lipid, respectively (p<0.001), and the two measurements showed positive correlations. Women showed higher concentrations than men (115.8 and 66.2 ng/g lipid, respectively, p<0.001). Concentrations in both matrices were positively associated with fatty food consumption, as well as with age and BMI, the latter only in adipose tissue. The multivariate model showed that, among women, adipose tissue concentrations were approximately 40% higher in those residing in the semi-rural area and 2-fold higher in those whose mothers had participated in agricultural activities during the pregnancy. In this study population, gender and place of residence play a key role in human exposure to p,p'-DDE and can be used to identify subjects at special risk of long-term exposure. PMID- 23651777 TI - Quantifying temporal trends in ground level ozone concentration in the UK. AB - There is a high interest in quantifying temporal trends in surface ozone concentrations as they serve to quantify the impacts of the anthropogenic precursor reductions and to assess the effects of emission control strategies. In this paper ozone trends for nearly 2 decades (1993 to 2011) at both rural and urban sites have been analysed, using ground level ozone data from 5 urban and 15 rural sites, which are part of the UK AURN. This study analyses ozone trends at various percentiles, in addition to traditional mean trends using quantile regression, TheilSen function, and changepoint analysis. Ozone trends show significant variability at different statistical metrics (e.g., mean, median, maximum and selected quantiles). Maximum trends were negative, whereas median and mean trends were positive during the study period (1993-2011) at both rural and urban sites. Urban and rural trends show different rates of change and indicate that urban decrement (the difference in ozone concentration between rural and urban areas) has been decreasing over the period. Ozone trends were negative during the last 8 years (2004-2011), which could have been caused by the stabilisation of NOx concentration during this period. Furthermore, 3 changepoints were detected in the temporal trend using Pruned Exact Linear Time (PELT) search algorithm, which provides further insight into the ozone temporal trends. PMID- 23651778 TI - Impact of forested fallows on fertility and mercury content in soils of the Tapajos River region, Brazilian Amazon. AB - Recent research on slash-and-burn agriculture conducted in the Amazonian basin has suggested that soils must be left under forested fallows for at least 10 to 15 years to regain fertility levels comparable to non-disturbed forests in order to allow for short cycle crop cultivation. However, small scale farmers tend nowadays to re-burn secondary forests as soon as after 3 to 5 years, thus could contribute to further reduce soil fertility and could enhance the transfer of mercury (Hg) naturally present in soils of the region towards water courses. The present research project sets out to characterize the impact of forested fallows of differing age and land-use history on soils properties (fertility and Hg contents) in the region of the Tapajos River, an active pioneer front of the Brazilian Amazon. To do this, soil samples in forested fallows of variable age and in control primary forests were retrieved. In general, soil fertility of grouped forested fallows of different ages was similar to that of the primary forests. But when discriminating soils according to their texture, forested fallows on coarse grained soils still had much higher NH4/NO3 ratios, NH4 and Ca contents than primary forests, this even 15 years after burning. The impact of repeated burnings was also assessed. Fallows on coarse grained soils showed an impoverishment for all variables related to fertility when the number of burnings was 5 or more. For fallows on fine grained soils that underwent 5 or more burnings, NO3 contents were low although a cation enrichment was observed. Total soil Hg content was also sensitive to repeated burnings, showing similar losses for forested fallows established on both types of soil. However, Hg linked to coarse particles appeared to migrate back towards fine particles at the surface of coarse grained soils in fallows older than 7 years. PMID- 23651779 TI - [What happened to the structured interviews after coercive measures?]. PMID- 23651780 TI - [Legal demands for structured interviews after coercive measures are not followed]. AB - In 2010, a programme intended to increase the number of structured interviews after coercive measures (IC) was implemented in a psychiatric ward. The IC forms were collected before and after the implementation of the programme. The number of ICs was compared to the total amount of compulsion. A significant rise in the number of effectuated ICs was demonstrated. The patients' contentment underwent no change. The majority of the coercive measures were not followed by an IC. At the next audit of the psychiatric legislation we will suggest an adjustment of the paragraphs concerning ICs. PMID- 23651781 TI - [Diagnosis and treatment of acute colonic pseudo-obstruction]. AB - Acute colonic pseudo-obstruction (ACPO), also known as Ogilvie's syndrome, is a clinical condition with acute dilatation of the colon without a provable mechanical cause. Early recognition and treatment of the condition is important in order to improve the outcome. The diagnosis is based on clinical and radiographic findings. Supportive therapy should be the initial management. If no improvement occurs after 24 hours, medical treatment with neostigmine administered i.v. is instituted and repeated if necessary. Colonoscopic decompression is the next step, but if ischaemia or perforation appear surgery should be performed. PMID- 23651782 TI - [Treatment of adrenocortical carcinomas is challenging]. AB - Adrenocortical carcinomas (ACC) are rare tumours responsible for only 0.02% of the total number of malignant diseases. However the ACC are aggressive with a mean fiveyears survival of 20-50% and are often associated with increased production of adrenocortical hormones. The effect of the treatment is controversial and often based on small retrospective series or expert opinions. Centralization, international attention and collaboration in the treatment of ACC are mandatory. Randomized clinical trials are needed to determine the best treatment strategy in order to increase survival in patients with ACC. PMID- 23651783 TI - [Neuromuscular electrical stimulation improves the functional level in patients with severe chronic obstructive pulmonary disease]. AB - Muscle atrophy and exertional dyspnoea are common in patients with severe chronic obstructive pulmonary disease (COPD). Neuromuscular electrical stimulation (NMES) is a new type of training for these patients. A number of randomized trials show that NMES has a positive physiological and clinical effect of muscle strength and endurance in patients with advanced COPD and in patients with acute COPD exacerbations. However, this positive effect is not seen in patients with moderate COPD. We suggest that NMES should be integrated in rehabilitation programmes for patients with severe COPD. PMID- 23651784 TI - [Frequent dialogues may help in patients who are HIV-positive and have massive adherence problems and treatment failure]. AB - This pilot study investigates the feasibility and effect of an intervention based on coaching and directly observed therapy (DOT), aimed at patients who are HIV positive and have massive adherence problems and treatment failure. Participants were followed six months with coaching, homework and DOT. Eleven were enrolled and seven completed at least six sessions. All seven were satisfied with the intervention. DOT was not usable; six of the seven had more than half of their viral load counts below 500 copies/ml one year after the intervention. Only two of the seven had so before the intervention. PMID- 23651785 TI - [Perivascular epithelioid cell tumours of the uterus]. AB - Perivascular epithelioid cell tumours (PEComas) are rare tumours with unknown malignant potential. We report a case of a 48-year-old woman, who had had many tumours, initially diagnosed as leiomyomas, removed from her uterus and vagina over 16 years. A recurrent tumour and revision of prior specimens revealed PEComa. As free surgical margins could not be obtained, the woman is regularly controlled by magnetic resonance imaging. So far recurrence has not been detected. This case shows that knowledge of PEComas is important to ensure relevant follow-up as these are low malignant tumours that tend to reoccur. PMID- 23651786 TI - [Acute, severe liver insufficiency caused by extrahepatic biliary atresia in a newborn]. AB - A newborn female was hospitalized due to metabolic acidosis and conjugated hyperbilirubinaemia. Extrahepatic biliary atresia (EHBA) was suspected why a (99m)Tc-mebrofenin cholescintigraphy was performed. It showed poor hepatocyte tracer uptake and no drainage to the gut. The hepatocyte dysfunction was caused by an obstructing adrenal gland neuroblastoma later visualised by ultrasound and MRI. The cholescintigraphy is a non-invasive modality to exclude or confirm the suspicion of EHBA. Furthermore neonatal conjugated hyperbilirubinaemia demands the use of a multimodality imaging strategy for differential diagnosis to EHBA. PMID- 23651787 TI - [Identification of the epileptic focus by the use of magnetoencephalography in a patient with refractory focal epilepsy]. AB - Magnetoencephalography (MEG) is increasingly used in the non-invasive presurgical evaluation of patients with refractory focal epilepsy. Combination of MEG and magnetic resonance imaging of the brain can estimate the location of the epileptiform discharges. We report a case of a patient with paroxysmal sensory symptoms. All previous investigations where normal, but by the use of MEG we were able to identify the epileptic focus in the insular region. MEG has a better spatial resolution than electroencefalography, and it is more sensitive to tangentially oriented dipoles. MEG should be considered in the workup of patients with refractory focal epilepsy. PMID- 23651788 TI - The integrated design and optimization of a WEEE collection network in Shanghai, China. AB - An integrated formal collection and recycling network is a significant concern to achieve efficient management of waste electrical and electronic equipment (WEEE). This study, which aimed to investigate the present problems of WEEE recycling in China, proposes the application of a comprehensive solution approach to address a complete WEEE collection and transportation network in Shanghai, China. The methodologic steps regard three things: identification of WEEE collection sites and transit sites with quadratic optimizing models solved by exact algorithm; vehicle routing planning with a modified ant colony algorithm; and defining of minimum transportation cycles and proper shipping arrangements. The rounded WEEE collection network is presented as technical support and a demonstration of further planning and construction of the WEEE recycling system in China. PMID- 23651789 TI - Topical diacerein for epidermolysis bullosa: a randomized controlled pilot study. AB - Blistering in epidermolysis bullosa simplex type Dowling-Meara (EBS-DM) is associated with an inflammatory phenotype, which can be disrupted by diacerein in vitro. In this pilot study we hypothesized, that a topical formulation of diacerein 1% reduces blistering. Five patients initially applied diacerein underneath both armpits. Then, each participant received 1% diacerein-cream for one armpit, and placebo for the other (randomized withdrawal). The number of blisters was reduced significantly (left: -78%; right: -66% of baseline) within two weeks and remained significantly below the initial level even during withdrawal in four patients. These findings point to a relevant effect of diacerein and provide important information for a confirmative study. PMID- 23651790 TI - The molecular basis of targeting protein kinases in cancer therapeutics. AB - In this paper, we provide an overview of targeted anticancer therapies with small molecule kinase inhibitors. First, we discuss why a single constitutively active kinase emanating from a variety of aberrant genetic alterations is capable of transforming a normal cell, leading it to acquire the hallmarks of a cancer cell. To draw attention to the fact that kinase inhibition in targeted cancer therapeutics differs from conventional cytotoxic chemotherapy, we exploit a conceptual framework explaining why suppressed kinase activity will selectively kill only the so-called oncogene 'addicted' cancer cell, while sparing the healthy cell. Second, we introduce the protein kinase superfamily in light of its common active conformation with precisely positioned structural elements, and the diversified auto-inhibitory conformations among the kinase families. Understanding the detailed activation mechanism of individual kinases is essential to relate the observed oncogenic alterations to the elevated constitutively active state, to identify the mechanism of consequent drug resistance, and to guide the development of the next-generation inhibitors. To clarify the vital importance of structural guidelines in studies of oncogenesis, we explain how somatic mutations in EGFR result in kinase constitutive activation. Third, in addition to the common theme of secondary (acquired) mutations that prevent drug binding from blocking a signaling pathway which is hijacked by the aberrant activated kinase, we discuss scenarios of drug resistance and relapse by compensating lesions that bypass the inactivated pathway in a vertical or horizontal fashion. Collectively, these suggest that the future challenge of cancer therapy with small molecule kinase inhibitors will rely on the discovery of distinct combinations of optimized drugs to target individual subtypes of different cancers. PMID- 23651791 TI - Multitasking in nanotechnology. PMID- 23651792 TI - Antiplatelet or anticoagulant therapy might not increase the risk of haemoptysis in patients with bronchiectasis. AB - The aim of this study was to assess whether the use of antiplatelets and anticoagulants increased haemoptysis in patients with bronchiectasis. Cases (n = 242) with a history of haemoptysis were compared with controls (n = 242) without a history of haemoptysis. Of the 242 case patients, 16.5% took antiplatelets compared with 19.8% of controls (P = 0.346). The proportion of warfarin users did not differ between cases and controls (3.3% vs. 2.5%, P = 0.588). The use of these agents might not be associated with increased risk of haemoptysis in patients with bronchiectasis. PMID- 23651793 TI - Pegvisomant bioavailability of single 30 mg/mL subcutaneous injection compared to two 15 mg/mL subcutaneous injections: a pharmacokinetic, safety and tolerability study. AB - OBJECTIVE: The study was conducted to evaluate the pharmacokinetics (PK), relative bioavailability (relBA), safety and tolerability of two single-dose pegvisomant subcutaneous (SC) administrations: one injection of 30 mg/mL (1 * 30 mg/mL) versus two injections of two 15 mg/mL (2 * 15 mg/mL). DESIGN: This was a 2 period, single-dose, crossover study in 14 healthy male and female subjects. All subjects received both administrations during the two treatment periods separated by a two-week washout. Serum samples were collected intensively up to 360 h post injection and were assayed by a validated enzyme linked immunosorbent assay (ELISA) for pegvisomant. PK parameters including AUC and Cmax were derived by noncompartmental analyses. Mixed effects model was used to obtain bioavailability estimates. Safety and tolerability were assessed by clinical monitoring, including adverse events, laboratory assessments and injection site reactions. RESULTS: All subjects completed the study. The relBA of 1 * 30 mg/mL relative to 2 * 15 mg/mL was 123.89% with a 90% CI (112.91-135.93%). Adjusted for the difference in actual pegvisomant amounts in both formulations the dose-adjusted relBA reduced to 112.97% with a 90% CI (103.09-123.80%). Single injection with a higher drug concentration in injection solution might have a role in this 13% higher bioavailability for 1 * 30 mg/mL administration. Other PK parameters for the two administrations were comparable. No laboratory abnormalities, vital signs, ECG, or injection site reactions of clinical concern were observed in either treatment. CONCLUSIONS: Comparable BA, safety and tolerability of the new 30 mg/mL strength to the currently marketed 15 mg/mL strength were established in this study. PMID- 23651794 TI - Crew and patient safety in ambulances: results of a personnel survey and experimental side impact crash test. AB - INTRODUCTION: Ambulance drivers often travel under stressful conditions at high speed while using vehicles with poor high-speed maneuverability. The occupant safety of ambulance vehicles has not yet been addressed by the automotive safety paradigm; particularly for the rear patient compartment. This study had two objectives: (1) to assess by survey the French Emergency Medical Services (EMS) to determine the layout of the vehicle most often used and the EMS personnel's behavior during transport; and (2) to conduct a crash test to analyze the injuries which may affect EMS personnel and patients in the rear patient compartment. METHOD: Firstly, a survey was distributed to the 50 largest metropolitan French EMS programs. Secondly, a crash test was performed with a Mobile Intensive Care Unit (MICU) in conditions closest to reality. RESULTS: Forty-nine of the 50 biggest metropolitan French EMS programs responded to the survey. This represents 108 French MICUs. During the last three years, 12 of 49 EMS programs (24%) identified at least one accident with an MICU, and six of these 12 (50%) suffered at least one death in those accidents. A crash test using a typical French EMS MICU showed that after impact of a collision, the ambulance was moved more than five meters with major consequences for all passengers. A study-approved human cadaver placed in the position of a potential patient was partially thrown from the stretcher with a head impact. The accelerometric reaction of the anthropomorphic manikin head was measured at 48G. CONCLUSION: The crash test demonstrated a lack of safety for EMS personnel and patients in the rear compartment. It would be preferable if each piece of medical equipment were provided with a quick release system resistant to three-dimensional 10G forces. The kinetic changes undergone by the "patient" substitute on the stretcher would probably have an effect of causing injury pathology. This study highlights the need for more research and development in this area. PMID- 23651796 TI - Shikonin exerts anti-inflammatory effects in a murine model of lipopolysaccharide induced acute lung injury by inhibiting the nuclear factor-kappaB signaling pathway. AB - Shikonin, an analog of naphthoquinone pigments isolated from the root of Lithospermum erythrorhyzon, was recently reported to exert beneficial anti inflammatory effects both in vivo and in vitro. The present study aimed to investigate the potential therapeutic effect of shikonin in a murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Dexamethasone was used as a positive control to evaluate the anti-inflammatory effect of shikonin in the study. Pretreatment with shikonin (intraperitoneal injection) significantly inhibited LPS-induced increases in the macrophage and neutrophil infiltration of lung tissues and markedly attenuated myeloperoxidase activity. Furthermore, shikonin significantly reduced the concentrations of TNF-alpha, IL-6 and IL-1beta in bronchoalveolar lavage fluid induced by LPS. Compared with the LPS group, lung histopathologic changes were less pronounced in the shikonin-pretreated mice. Additionally, Western blotting results showed that shikonin efficiently decreased nuclear factor-kappaB (NF-kappaB) activation by inhibiting the degradation and phosphorylation of IkappaBalpha. These results suggest that shikonin exerts anti inflammatory properties in LPS-mediated ALI, possibly through inhibition of the NF-kappaB signaling pathway, which mediates the expression of pro-inflammatory cytokines. Shikonin may be a potential agent for the prophylaxis of ALI. PMID- 23651795 TI - Morphine dependence and withdrawal induced changes in cholinergic signaling. AB - Cholinergic signaling is thought to be involved in morphine dependence and withdrawal, but the specific mechanisms involved remain unclear. The current study aimed to identify alterations in the cholinergic system that may contribute to the development of morphine dependence and withdrawal. Acetylcholinesterase (AChE) activity and [3H]-epibatidine binding were evaluated in order to determine if morphine dependence and withdrawal induces alterations in cholinergic signaling or expression of high affinity nicotinic acetylcholine receptors (nAChRs) in the midbrain (MB), medial habenula (MHb) and interpeduncular nucleus (IPN). The effect of cholinergic signaling through nAChRs on morphine-withdrawal induced jumping behavior was then determined. Lastly, the contribution of beta4 containing nAChRs receptors in the MHb to morphine-withdrawal induced jumping behavior and neuronal activity as indicated by c-fos expression was assessed. Chronic morphine administration decreased AChE activity in MB and MHb, an effect that was no longer present following precipitated withdrawal. Morphine dependent mice showed increased nicotinic acetylcholine receptor (nAChR) levels in MB. Further, nicotine (0.4 mg/kg) and lobeline (3 mg/kg) decreased jumping behavior while mecamylamine (1 mg/kg) had no effect. Knock-down of beta4 subunit containing nAChRs in the MHb attenuated c-fos activation, but did not decrease morphine withdrawal-induced jumping. Thus, morphine withdrawal induces cholinergic signaling in the MHb, but this does not appear to be responsible for the effects of cholinergic drugs on somatic signs of opiate withdrawal, as measured by jumping behavior. PMID- 23651798 TI - [COPD yesterday, today and tomorrow]. PMID- 23651797 TI - [Early detection of COPD must be a priority]. PMID- 23651799 TI - [Early diagnosis of COPD is important and possible]. AB - Chronic obstructive pulmonary disease (COPD) is substantially underdiagnosed and under treated. The present review paper discusses the possibilities of early diagnosis by means of spirometry in the setting of Danish general practice. It is concluded that case finding of undiagnosed COPD is feasible by applying opportunistic spirometry in patients with relevant exposures and relevant respiratory symptoms. The potential barriers of this approach and possible solutions are discussed. PMID- 23651800 TI - [Occupational exposure for dust and gases is an important risk factor for developing COPD]. AB - Some patients with chronic obstructive pulmonary disease (COPD) are never smokers, which suggests that there must be other important risk factors. This paper describes the evidence for an association between occupational exposure and COPD. In several studies a consistent and predominantly significant association between occupational exposures and COPD is found, even though the studies vary in design, enrolled populations and in measures of exposure and outcome. Strong evidence supports a causal association between multiple categories of occupational exposure and COPD, both within and across industry groups. PMID- 23651801 TI - [New guidelines for diagnosis and staging of chronic obstructive pulmonary disease]. AB - A clinical diagnosis of chronic obstructive pulmonary disease (COPD) should be considered in any individual who has dyspnoea, chronic cough or sputum production and/or a history of exposure to risk factors for the disease. Spirometry is essential for the definite diagnosis of the disease. Differential diagnosis and co-morbidities such as osteoporosis, heart failure and lung cancer are important to consider and treat. The combined results of symptoms (few/many), lung function and the amount of exacerbations make up the risk of future exacerbations and risk of death of any given patient. PMID- 23651802 TI - [Medical treatment of COPD]. AB - Chronic obstructive pulmonary disease (COPD) is treated with bronchodilator and antiinflammatory drugs along with smoking cessation and pulmonary rehabilitation. The pharmacological treatment of COPD is based on the assessment of current symptoms and future risk as first proposed in the GOLD 2011 strategy document. Long-acting bronchodilatators are the cornerstone of treatment of COPD and inhaled drugs are always preferred. Inhaled corticosteroids can be added for reducing exacerbations where also roflumilast has proven efficacy. This review covers recommendations for treating COPD according to the latest recommendations from the Danish Respiratory Society. PMID- 23651803 TI - [The effects of smoking cessation related to COPD]. AB - This article summarizes the effects of smoking cessation on the risk of morbidity and mortality related to chronic obstructive pulmonary disease (COPD) and describes methods of achieving smoking abstinence in this group of patients. If smoking cessation occurs before the age of 30-35 years almost all of the excess risk of smoking can be avoided. There is convincing evidence that smoking cessation at all ages slows the otherwise accelerated lung function decline. Smokers with COPD should be offered more intensive and often repeated smoking cessation treatments, as they are likely to be more addicted to nicotine than healthy smokers. PMID- 23651804 TI - [COPD treatment in general practice in Denmark is into a rapid development]. AB - In this article the change towards pro-activity in the treatment of chronic obstructive pulmonary disease (COPD) is reviewed. Implementing International Classification of Primary Care and COPD indicators registration provide opportunity for quality assurance by quality reports and follow-up. Changing practice organization supports teamwork for the benefit of the patients. Municipal COPD rehabilitation has become available. Cooperation is improved by an overview of municipal services on www.sundhed.dk and by a correspondence module. Tracing COPD and applying data must be enhanced. In the years to come we will benefit from the collected data for research in general practice. PMID- 23651805 TI - [Rehabilitation and palliative care of patients with severe COPD must be integrated]. AB - Treatment elements of rehabilitation and palliative care are described in relation to the main clinical manifestations of severe and very severe chronic obstructive pulmonary disease (COPD). With increasing loss of function the need for multidisciplinary effort increases. Physiotherapy, occupational therapy and medical treatment are adjusted to the improvement of the current quality of life with new treatment goals and decision on cessation of treatment including oxygen without subjective effect. Palliation with end-of-life discussion must be integrated in COPD rehabilitation programmes especially for patients with frequent exacerbations. PMID- 23651806 TI - Achieving pH control in microalgal cultures through fed-batch addition of stoichiometrically-balanced growth media. AB - BACKGROUND: Lack of accounting for proton uptake and secretion has confounded interpretation of the stoichiometry of photosynthetic growth of algae. This is also problematic for achieving growth of microalgae to high cell concentrations which is necessary to improve productivity and the economic feasibility of commercial-scale chemical production systems. Since microalgae are capable of consuming both nitrate and ammonium, this represents an opportunity to balance culture pH based on a nitrogen feeding strategy that does not utilize gas-phase CO2 buffering. Stoichiometry suggests that approximately 36 weight%NH4+ (balance nitrogen as NO3-) would minimize the proton imbalance and permit high-density photoautotrophic growth as it does in higher plant tissue culture. However, algal media almost exclusively utilize nitrate, and ammonium is often viewed as 'toxic' to algae. RESULTS: The microalgae Chlorella vulgaris and Chlamydomonas reinhardtii exclusively utilize ammonium when both ammonium and nitrate are provided during growth on excess CO2. The resulting proton imbalance from preferential ammonium utilization causes the pH to drop too low to sustain further growth when ammonium was only 9% of the total nitrogen (0.027 gN-NH4+/L). However, providing smaller amounts of ammonium sequentially in the presence of nitrate maintained the pH of a Chlorella vulgaris culture for improved growth on 0.3 gN/L to 5 gDW/L under 5% CO2 gas-phase supplementation. Bioreactor pH dynamics are shown to be predictable based on simple nitrogen assimilation as long as there is sufficient CO2 availability. CONCLUSIONS: This work provides both a media formulation and a feeding strategy with a focus on nitrogen metabolism and regulation to support high-density algal culture without buffering. The instability in culture pH that is observed in microalgal cultures in the absence of buffers can be overcome through alternating utilization of ammonium and nitrate. Despite the highly regulated array of nitrogen transporters, providing a nitrogen source with a balanced degree of reduction minimizes pH fluctuations. Understanding and accommodating the behavior of nitrogen utilization in microalgae is key to avoiding 'culture crash' and reliance on gas phase CO2 buffering, which becomes both ineffective and cost prohibitive for commercial-scale algal culture. PMID- 23651807 TI - Evaluation of Clostridium ljungdahlii DSM 13528 reference genes in gene expression studies by qRT-PCR. AB - Clostridium ljungdahlii DSM 13528 is a promising platform organism for biofuel production from syngas. Gene expression analysis permits a better understanding of the important molecular biological characteristics of this organism, such as carbon fixation and solvent adaptation. Normalization is a prerequisite for accurate gene expression analysis, but until now, no valid reference genes have been proposed for quantitative real-time polymerase chain reaction (qRT-PCR) analysis of C. ljungdahlii DSM 13528. In this study, seven candidate reference genes (gyrA, rho, fotl, rpoA, gukl, recA, 16S rRNA) were selected for qRT-PCR quantification of their expression levels in various culture conditions that corresponded to different carbon sources and stresses. Two analytical programs, geNorm and NormFinder, were used to evaluate reference gene stability. The results showed that gyrA, rho and fotl exhibited the most stable expression levels across all tested samples and can be confidently used as reference genes to normalize the transcriptional data of target genes in qRT-PCR analyses of C. ljungdahlii DSM 13528. This study presents the first attempt to explore the validity of candidate reference genes and provide a set of valid reference genes for normalizing C. ljungdahlii DSM 13528 target gene expression and transcriptome analysis. PMID- 23651808 TI - Subterminal oxidation of n-alkanes in achlorophyllous alga Prototheca sp. AB - Some Prototheca sp. are known to be involved in n-hexadecane degradation. Two derivatives derived from n-hexadecane in such Prototheca sp. were identified as 5 hexadecanone and 5-hexadecanol. n-Hexadecane was assumed to be converted to 5 hexadecanol and then to 5-hexadecanone through a unique subterminal oxidation pathway in such Prototheca sp. PMID- 23651809 TI - Cocktail delta-integration of xylose assimilation genes for efficient ethanol production from xylose in Saccharomyces cerevisiae. AB - Cocktail delta-integration was applied to improve ethanol production from xylose in Saccharomyces cerevisiae. Two hundred of recombinant S. cerevisiae strains possessing various copies of XYL1, XYL2, and XKS1 genes were constructed by cocktail delta-integration. Efficient strains with efficient ethanol production from xylose were successfully obtained by the fermentation test. PMID- 23651810 TI - VPAC1 receptor expression in peripheral blood mononuclear cells in a human endotoxemia model. AB - BACKGROUND: Vasoactive intestinal peptide (VIP) exerts immune-modulatory actions mainly via VPAC1 receptor stimulation. VPAC1 may be a treatment target of inflammatory diseases, but little is known about the receptor expression profile in immune-competent cells in vivo. MATERIAL AND METHODS: 20 male healthy subjects received a single intravenous bolus of 2 ng/kg body weight Escherichia coli endotoxin (LPS). Receptor status was evaluated in peripherial blood cells before and 3, 6 and 24 h after LPS by FACS analysis and q-PCR. VIP plasma concentrations were measured by ELISA. RESULTS: Granulocytes accounted for 51% of leukocytes at baseline and 58 +/- 37% were positive for VPAC1. The granulocyte population increased 2.6 fold after LPS, and a transient down-regulation of VPAC1 to 28 +/- 23% was noted at 3 h (p < 0.001), which returned to baseline at 24 hours. Baseline VPAC1 expression was low in lymphocytes (6.3 +/- 3.2%) and monocytes (11 +/- 9.6%). In these cells, LPS up-regulated VPAC1 at 6 h (13.2 +/- 4.9%, p < 0.001) and 24 h (31.6 +/- 20.5%, p = 0.001), respectively. Consistent changes were noted for the VIP-receptors VPAC2 and PAC1. VPAC1, VPAC2 and PAC1 mRNA levels were unchanged in peripheral blood mononuclear cells (PBMC). VIP plasma concentration increased from 0.5 +/- 0.3 ng/ml to 0.7 +/- 0.4 ng/ml at 6 h after LPS (p < 0.05) and returned to baseline within 24 h. CONCLUSION: The time profile of VPAC receptor expression differs in granulocytes, monocytes and lymphocytes after LPS challenge in humans. Changes in circulating VIP concentrations may reflect innate immune responses. PMID- 23651811 TI - Botulinum toxin A and B raise blood flow and increase survival of critically ischemic skin flaps. AB - BACKGROUND: Botulinum toxin (BTX) A and B are commonly used for aesthetic indications and in neuromuscular disorders. New concepts seek to prove efficacy of BTX for critical tissue perfusion. Our aim was to evaluate BTX A and B in a mouse model of critical flap ischemia for preoperative and intraoperative application. METHODS: BTX A and B were applied on the vascular pedicle of an axial pattern flap in mice preoperatively or intraoperatively. Blood flow, tissue oxygenation, tissue metabolism, flap necrosis rate, apoptosis assay, and RhoA and eNOS expression were endpoints. RESULTS: Blood-flow measurements 1 d after the flap operation revealed a significant reduction to 53% in the control group, while flow was maintained or increased in all BTX groups (103%-129%). Over 5 d all BTX groups showed significant increase in blood flow to 166-187% (P < 0.01). Microdialysis revealed an increase of glucose and reduced lactate/pyruvate ratio and glycerol levels in the flap tissue of all BTX groups. This resulted in significantly improved tissue survival in all BTX groups compared with the control group (62% +/- 10%; all P < 0.01): BTX A preconditioning (84% +/- 5%), BTX A application intraoperatively (88% +/- 4%), BTX B preconditioning (91% +/- 4%), and intraoperative BTX B treatment (92% +/- 5%). This was confirmed by TUNEL assay. Immunofluorescence demonstrated RhoA and eNOS expression in BTX groups. All BTX applications were similarly effective, despite pharmacologic dissimilarities and different timing. CONCLUSIONS: In conclusion, we were able to show on a vascular, tissue, cell, and molecular level that BTX injection to the feeding arteries supports flap survival through ameliorated blood flow and oxygen delivery. PMID- 23651812 TI - Sequestration: inadvertently killing biomedical research to score political points. PMID- 23651813 TI - Associations of inflammatory biomarkers to body mass index among patients with acute coronary syndrome. PMID- 23651814 TI - Nighttime heart rate variability, overnight urinary norepinephrine, and glycemic status in apparently healthy human adults. PMID- 23651815 TI - Aborting STEMI: what treatment opportunities may Smart-Phone ECGs give us prior to first medical contact to facilitate primary PCI? PMID- 23651817 TI - Value of right ventricular strain in predicting functional capacity in patients with mitral stenosis. PMID- 23651816 TI - A critical challenge: dosage-related efficacy and acute complication intracoronary injection of autologous bone marrow mesenchymal stem cells in acute myocardial infarction. AB - BACKGROUND: Previous studies showed improvement in heart function by injecting bone marrow mesenchymal stem cells (BMSCs) after AMI. Emerging evidence suggested that both the number and function of BMSCs decline with ageing. We designed a randomized, controlled trial to further investigate the safety and efficacy of this treatment. METHODS: Patients with ST-elevation AMI undergoing successful reperfusion treatment within 12 hours were randomly assigned to receive an intracoronary infusion of BMSCs (n=21) or standard medical treatment (n=22) (the numbers of patients were limited because of the complication of coronary artery obstruction). RESULTS: There is a closely positive correlation of the number and function of BMSCs vs. the cardiac function reflected by LVEF at baseline (r=0.679, P=0.001) and at 12-month follow-up (r=0.477, P=0.039). Six months after cell administration, myocardial viability within the infarct area by 18-FDG SPECT was improved in both groups compared with baseline, but no significant difference in the BMSCs compared with control groups (4.0+/-0.4% 95%CI 3.1-4.9 vs. 3.2+/ 0.5% 95%CI 2.1-4.3, P=0.237). 99mTc-sestamibi SPECT demonstrated that myocardial perfusion within the infarct area in the BMSCs did not differ from the control group (4.4+/-0.5% 95%CI 3.2-5.5 vs. 3.9+/-0.6% 95%CI 2.6-5.2, P=0.594). Similarly, LVEF after 12 and 24 months follow-up did not show any difference between the two groups. In the BMSCs group, one patient suffered a serious complication of coronary artery occlusion during the BMSCs injection procedure. CONCLUSIONS: The clinical benefits of intracoronary injection of autologous BMSCs in acute STEMI patients need further investigation and reevaluation. PMID- 23651818 TI - An unusual complication of coronarography: delayed catheter migration to the vertebral artery. PMID- 23651819 TI - Successful cardiac resynchronization therapy in a 1.5-year-old girl with dilated cardiomyopathy and functional mitral regurgitation. PMID- 23651820 TI - Comparison of magnetocardiography and electrocardiography in diagnosis of cardiac ischemia: a simulation study. PMID- 23651821 TI - Cerebral hemorrhage under rivaroxaban. PMID- 23651822 TI - Balloon-assisted tracking of guide catheter dealing with radial artery perforation and subclavian loop during percutaneous coronary intervention by transradial approach. PMID- 23651823 TI - Improving heart disease knowledge and research participation in adults with congenital heart disease (the Health, Education and Access Research Trial: HEART ACHD). AB - OBJECTIVE: The objective of this prospective multi-center study was to evaluate heart disease knowledge within the adult congenital heart disease (ACHD) population, pilot an educational intervention and assess interest in research participation among new patients at ACHD clinics. BACKGROUND: Many adults with congenital heart disease lack knowledge about their heart condition that may contribute to undesirable outcomes. METHODS: Patients >=18 years of age were recruited upon their first presentation to an ACHD clinic and underwent an educational intervention consisting of creation of a personal health information 'passport' and an introduction to web-based resources. Subjects were asked to complete initial and follow-up surveys documenting their perceived knowledge. RESULTS: Nine hundred twenty-two subjects were recruited from 12 ACHD centers, and 520 (57%) completed follow-up surveys. Patients who completed the follow-up survey were more likely to be women, have more education, and have mild heart disease. At follow-up, the ability of the subjects to name their heart condition improved (78% to 83%, p=0.002). Improvements were seen in mean Likert items regarding perceived knowledge of appropriate exercise (p<0.0001), symptoms of heart rhythm problems or endocarditis (p<0.0001), reasons for cardiac tests (p<0.007), and birth control options and pregnancy safety (p<0.0001). On follow up, subjects reported a better understanding of medical research (p<0.01), and higher interest in research participation (p<0.003). CONCLUSION: This joint clinician-patient pilot program will help inform future efforts toward patient education and participation in research with a focus on standardization of protocols for life-long longitudinal follow-up and continued multi-center collaboration in the ACHD population. PMID- 23651824 TI - Heart failure entails significant changes in human nucleocytoplasmic transport gene expression. AB - BACKGROUND: Heart failure (HF) induces alterations in nucleocytoplasmic transport, which is essential to the cardiomyocyte biology. The objective of this study was to analyze the changes in gene expression in human HF, particularly focusing on nucleocytoplasmic transport-related genes. METHODS AND RESULTS: 29 RNA heart samples from dilated cardiomyopathy (DCM, n = 12) and ischemic cardiomyopathy (ICM, n = 12) patients undergoing heart transplantation and control donors (CNT, n = 5) were extracted to perform a microarray profiling using Affymetrix Human Gene(r) 1.0 ST arrays. We focused on the study of 5 nucleocytoplasmic transport-related genes, since this functional category has not previously been studied in HF. XPO1, GABPB2, and RANBP17 were upregulated, while KALRN was downregulated in both DCM and ICM, and XPO5 only in DCM. Validation of the results by RT-qPCR increasing the total heart samples up to 41 showed a high degree of consistency with microarray results. Moreover, we observed a strong relationship between the XPO1 mRNA and robust left ventricular function parameters in ICM: left ventricular end-systolic (r = 0.81, p<0.0001) and end diastolic diameters (r = 0.80, p<0.0001), and ejection fraction (r = -0.57, p<0.05). CONCLUSIONS: We show that the expression of nucleocytoplasmic transport related genes is altered in HF. Furthermore, XPO1 mRNA level is closely related with robust left ventricular function parameters in ICM patients. These changes may help to distinguish DCM and ICM in HF at the level of the transcriptome and provide a base for novel therapeutic approaches. PMID- 23651825 TI - Percutaneous treatment of acute axillary artery occlusion after chopping wood. PMID- 23651826 TI - Erythropoietin induces angiogenesis in a manner dependent on the intrinsic auto/paracrine production of interleukin-6 in vitro. PMID- 23651828 TI - Enhanced therapeutic effects on acute myocardial infarction with multiple intravenous transplantation of human cord blood mononuclear cells. AB - BACKGROUND: Cell transplantation of human cord blood mononuclear progenitor cells (HCBMCs) is a new treatment that could restore cardiac functions after acute myocardial infarction (AMI). We hypothesize that multiple doses of HCBMCs might increase homing of transplanted cells to infarcted region, and improve outcome of AMI via inhibition of ischemic-induced inflammatory responses. METHODS AND RESULTS: HCBMCs were injected intravenously to rabbits that previously underwent ligation of left anterior coronary artery (LAD). Single dose of HCBMCs was intravenously delivered on the 7th day or multiple doses of HCBMCs were delivered on the 7th, 9th, 11th and 13th day after AMI. Homing of HCBMCs was determined by 5-bromodeoxyuridine (BrdU) labeling. The amount of grafted cells homed and retained in the infarcted area was significantly increased in the rabbits that received multiple doses. More viable cardiomyocytes and less collagen deposition were observed also in the group with more injections. Cardiac functions were assessed by echocardiography and hemodynamics. Multiple doses of HCBMCs showed significant benefits in preservation of cardiac functions. In infarcted myocardium, multiple transplantations of HCBMCs showed a significant increase in the myocardial level of anti-inflammatory IL-10 and a marked decrease in the level of the pro-inflammatory IL-6. CONCLUSIONS: Multiple injections of HCBMCs markedly increased the amount of grafted cells, beneficially improving cardiac functions after AMI. The findings suggest that multiple doses of HCBMCs might be a novel strategy in the cell therapy for AMI. PMID- 23651827 TI - Cholesterol-adjusted vitamin E serum levels are associated with cardiovascular events in patients with non-valvular atrial fibrillation. AB - BACKGROUND: Non-valvular atrial fibrillation is associated with an increase in thromboembolism, i.e. stroke, and atherosclerotic events, i.e. myocardial infarction. Vitamin E possesses anti-coagulant as well as anti-atherosclerotic properties. Our aim was to assess whether vitamin E is associated with cardiovascular events in patients with non-valvular atrial fibrillation. METHODS: Serum levels of cholesterol-adjusted vitamin E were measured in 1012 patients with non-valvular atrial fibrillation. Patients were followed for a mean time of 27.0 months, and cardiovascular events, such as cardiovascular death and fatal and nonfatal stroke or myocardial infarction, were recorded. RESULTS: During the follow-up period, cardiovascular events occurred in 109 (11%) patients (18 fatal and 14 nonfatal myocardial infarction; 13 fatal and 19 nonfatal ischemic strokes; 45 cardiovascular deaths). Lower vitamin E serum levels were found in patients who experienced cardiovascular events compared to those who did not (3.8+/-1.2 vs. 4.4+/-1.8 MUmol/mmol cholesterol; p<0.001). Using a Cox proportional hazard model, age, diabetes, history of stroke and myocardial infarction and vitamin E serum levels (HR 0.77; 95% CI: 0.67-0.89; p=0.001) independently predicted cardiovascular events. Patients with vitamin E<4.2 MUmol/mmol cholesterol (median values) had an increased risk of cardiovascular events (HR 1.87; 95% CI: 1.25 2.80: p=0.002). CONCLUSIONS: Low vitamin E serum levels are associated with an increased risk of cardiovascular events in patients with non-valvular atrial fibrillation. PMID- 23651829 TI - Urgent endovascular repair of upper gastrointestinal bleeding from an arterio biliary fistula with a covered coronary stent. PMID- 23651830 TI - Association of TNF-alpha with left ventricular diastolic dysfunction in patients with hepatitis C virus infection. PMID- 23651831 TI - Red cell distribution width as a novel, simple, inexpensive predictor of mortality in patients with chronic heart failure. PMID- 23651832 TI - Additional side branch stent placement in patients with long side branch lesions treated with the Tryton dedicated bifurcation side branch stent. PMID- 23651833 TI - Alcohol consumption and the heart. PMID- 23651834 TI - Systolic blood pressure during exercise testing and the risk of sudden cardiac death. PMID- 23651835 TI - A food desert in Detroit: associations with food shopping and eating behaviours, dietary intakes and obesity. AB - OBJECTIVE: Currently 67 % of the US population is overweight or obese and obesity is associated with several chronic medical conditions. Geographic areas where individuals lack access to healthy foods have been termed 'food deserts'. The study aim was to examine if area of residence within Metro Detroit was associated with dietary intake, food and shopping behaviours, and BMI. DESIGN: Cross sectional study. SETTINGS: Participants were recruited in the waiting area of four primary-care clinics. SUBJECTS: Individuals (n 1004) completed a questionnaire comprising four sections: demographics; personal health status including self-reported height and weight; a modified diet, transportation and shopping survey; and a subscale from the Diet and Health Knowledge Survey. RESULTS: Seventy-four per cent of participants were female and the mean age was 46.7 (sd 15.0) years. In univariate analyses, living in Detroit was associated with being African American, unemployment, less education, no regular exercise, worse health self-rating and obesity (P < 0.0005 for all). Participants living in Detroit had a 3.06 (95 % CI 1.91, 4.21) kg/m2 larger BMI compared with people living outside the city (P < 0.0005) in univariate analyses, but the effect was attenuated when adjusted for demographics, disease status, shopping and eating behaviours, dietary intakes and diet knowledge (beta = -0.46 kg/m2, 95 % CI 2.23, 1.30 kg/m2, P = 0.60). CONCLUSIONS: Overweight and obesity are highly prevalent both inside (82.9 %) and outside (72.8 %) the city of Detroit, presenting a major public health problem. However, living in this food desert was not significantly associated with BMI after potential covariates were considered. PMID- 23651836 TI - Associations between blood persistent organic pollutants and 25-hydroxyvitamin D3 in pregnancy. AB - Persistent organic pollutants (POPs) are suggested to contribute to lower vitamin D levels; however, studies in humans are scarce and have never focused on pregnancy, a susceptibility period for vitamin D deficiency. We investigated whether serum levels of POPs were associated with circulating 25-hydroxyvitamin D3 [25(OH)D3] concentration in pregnancy. Cross-sectional associations of serum concentrations of eight POPs with plasma 25(OH)D3 concentration were analyzed in 2031 pregnant women participating in the Spanish population-based cohort INfancia y Medio Ambiente (INMA) Project. Serum concentrations of POPs were measured by gas chromatography and plasma 25(OH)D3 concentration was measured by high performance liquid chromatography in pregnancy (mean 13.3+/-1.5weeks of gestation). Multivariable regression models were performed to assess the relationship between blood concentrations of POPs and 25(OH)D3. An inverse linear relationship was found between serum concentration of PCB180 and circulating 25(OH)D3. Multivariate linear regression models showed higher PCB180 levels to be associated with lower 25(OH)D3 concentration: quartile Q4 vs. quartile Q1, coefficient=-1.59, 95% CI -3.27, 0.08, p trend=0.060. A non-monotonic inverse relationship was found between the sum of predominant PCB congeners (PCB 180, 153 and 138) and 25(OH)D3 concentration: coefficient (95% CI) for quartile Q2 vs. Q1 [-0.50 (-1.94, 0.94)], quartile Q3 vs. Q1 [-1.56 (-3.11, -0.02)] and quartile Q4 vs. Q1 [-1.21 (-2.80, 0.38)], p trend=0.081. No significant associations were found between circulating 25(OH)D3 and serum levels of p,p'-DDE, p,p'-DDT, HCB, and beta-HCH. Our results suggest that the background exposure to PCBs may result in lower 25(OH)D3 concentration in pregnant women. PMID- 23651837 TI - Detection of fluorotelomer alcohols in indoor environments and their relevance for human exposure. AB - Fluorotelomer alcohols (FTOH) are important precursors of perfluorinated carboxylic acids (PFCA). These neutral and volatile compounds are frequently found in indoor air and may contribute to the overall human exposure to per- and polyfluorinated alkyl substances (PFAS). In this study air samples of ten workplace environments and a car interior were analysed. In addition, extracts and emissions from selected outdoor textiles were analysed in order to establish their potential contribution to the indoor levels of the above-mentioned compounds. Concentrations of FTOHs measured in air ranged from 0.15 to 46.8, 0.25 to 286, and 0.11 to 57.5ng/m(3) for 6:2, 8:2 and 10:2 FTOHs, respectively. The highest concentrations in air were identified in shops selling outdoor clothing, indicating outdoor textiles to be a relevant source of FTOH in indoor workplace environments. Total amounts of FTOH in materials of outdoor textiles accounted for <0.8-7.6, 12.1-180.9 and 4.65-105.7MUg/dm(2) for 6:2, 8:2 and 10:2 FTOHs, respectively. Emission from selected textiles revealed emission rates of up to 494ng/h. The measured data show that a) FTOHs are present in indoor textiles (e.g. carpets), b) they are released at ambient temperatures and c) indoor air of shops selling outdoor textiles contains the highest levels of FTOH. Exposure of humans to perfluorooctanoic acid (PFOA) through absorption of FTOH and subsequent degradation is discussed on the basis of indoor air levels. Calculation of indoor air-related exposure using the median of the measured air levels revealed that exposure is on the same order of magnitude as the recently reported dietary intakes for a background-exposed population. On the basis of the 95th percentile, indoor air exposure to PFOA was estimated to exceed dietary exposure. However, indoor air-related intakes of FTOH are far below the tolerable daily intake (TDI) of PFOA, indicating that there is no risk to health, even when assuming an unrealistic complete degradation of FTOH into PFOA. PMID- 23651839 TI - Cortical effects of user training in a motor imagery based brain-computer interface measured by fNIRS and EEG. AB - The present study aims to gain insights into the effects of training with a motor imagery (MI)-based brain-computer interface (BCI) on activation patterns of the sensorimotor cortex. We used functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG) to investigate long-term training effects across 10 sessions using a 2-class (right hand and feet) MI-based BCI in fifteen subjects. In the course of the training a significant enhancement of activation pattern emerges, represented by an [oxy-Hb] increase in fNIRS and a stronger event related desynchronization in the upper beta-frequency band in the EEG. These effects were only visible in participants with relatively low BCI performance (mean accuracy <= 70%). We found that training with an MI-based BCI affects cortical activation patterns especially in users with low BCI performance. Our results may serve as a valuable contribution to the field of BCI research and provide information about the effects that training with an MI-based BCI has on cortical activation patterns. This might be useful for clinical applications of BCI which aim at promoting and guiding neuroplasticity. PMID- 23651838 TI - Toxoplasma gondii cathepsin proteases are undeveloped prominent vaccine antigens against toxoplasmosis. AB - BACKGROUND: Toxoplasma gondii, an obligate intracellular apicomplexan parasite, infects a wide range of warm-blooded animals including humans. T. gondii expresses five members of the C1 family of cysteine proteases, including cathepsin B-like (TgCPB) and cathepsin L-like (TgCPL) proteins. TgCPB is involved in ROP protein maturation and parasite invasion, whereas TgCPL contributes to proteolytic maturation of proTgM2AP and proTgMIC3. TgCPL is also associated with the residual body in the parasitophorous vacuole after cell division has occurred. Both of these proteases are potential therapeutic targets in T. gondii. The aim of this study was to investigate TgCPB and TgCPL for their potential as DNA vaccines against T. gondii. METHODS: Using bioinformatics approaches, we analyzed TgCPB and TgCPL proteins and identified several linear-B cell epitopes and potential Th-cell epitopes in them. Based on these results, we assembled two single-gene constructs (TgCPB and TgCPL) and a multi-gene construct (pTgCPB/TgCPL) with which to immunize BALB/c mice and test their effectiveness as DNA vaccines. RESULTS: TgCPB and TgCPL vaccines elicited strong humoral and cellular immune responses in mice, both of which were Th-1 cell mediated. In addition, all of the vaccines protected the mice against infection with virulent T. gondii RH tachyzoites, with the multi-gene vaccine (pTgCPB/TgCPL) providing the highest level of protection. CONCLUSIONS: T. gondii CPB and CPL proteases are strong candidates for development as novel DNA vaccines. PMID- 23651840 TI - Spatial attention increases high-frequency gamma synchronisation in human medial visual cortex. AB - Visual information processing involves the integration of stimulus and goal driven information, requiring neuronal communication. Gamma synchronisation is linked to neuronal communication, and is known to be modulated in visual cortex both by stimulus properties and voluntarily-directed attention. Stimulus-driven modulations of gamma activity are particularly associated with early visual areas such as V1, whereas attentional effects are generally localised to higher visual areas such as V4. The absence of a gamma increase in early visual cortex is at odds with robust attentional enhancements found with other measures of neuronal activity in this area. Here we used magnetoencephalography (MEG) to explore the effect of spatial attention on gamma activity in human early visual cortex using a highly effective gamma-inducing stimulus and strong attentional manipulation. In separate blocks, subjects tracked either a parafoveal grating patch that induced gamma activity in contralateral medial visual cortex, or a small line at fixation, effectively attending away from the gamma-inducing grating. Both items were always present, but rotated unpredictably and independently of each other. The rotating grating induced gamma synchronisation in medial visual cortex at 30 70 Hz, and in lateral visual cortex at 60-90 Hz, regardless of whether it was attended. Directing spatial attention to the grating increased gamma synchronisation in medial visual cortex, but only at 60-90 Hz. These results suggest that the generally found increase in gamma activity by spatial attention can be localised to early visual cortex in humans, and that stimulus and goal driven modulations may be mediated at different frequencies within the gamma range. PMID- 23651841 TI - Does skull shape mediate the relationship between objective features and subjective impressions about the face? AB - In our previous work, we described facial features associated with a successful recognition of the sex of the face (Mareckova et al., 2011). These features were based on landmarks placed on the surface of faces reconstructed from magnetic resonance (MR) images; their position was therefore influenced by both soft tissue (fat and muscle) and bone structure of the skull. Here, we ask whether bone structure has dissociable influences on observers' identification of the sex of the face. To answer this question, we used a novel method of studying skull morphology using MR images and explored the relationship between skull features, facial features, and sex recognition in a large sample of adolescents (n=876; including 475 adolescents from our original report). To determine whether skull features mediate the relationship between facial features and identification accuracy, we performed mediation analysis using bootstrapping. In males, skull features mediated fully the relationship between facial features and sex judgments. In females, the skull mediated this relationship only after adjusting facial features for the amount of body fat (estimated with bioimpedance). While body fat had a very slight positive influence on correct sex judgments about male faces, there was a robust negative influence of body fat on the correct sex judgments about female faces. Overall, these results suggest that craniofacial bone structure is essential for correct sex judgments about a male face. In females, body fat influences negatively the accuracy of sex judgments, and craniofacial bone structure alone cannot explain the relationship between facial features and identification of a face as female. PMID- 23651842 TI - Of blades and branches: understanding and expanding the Arabidopsis ad/abaxial regulatory network through target gene identification. AB - HD-ZIPIII and KANADI transcription factors have opposing and dramatic affects on plant development. Analysis of mutants shows these proteins to be master regulators of ad/abaxial (i.e., upper/lower) leaf polarity, leaf blade outgrowth, and branch formation. Because these factors do their work by regulating other genes, we have focused our attention on defining their targets. We have found overlap between the ad/abaxial regulatory pathway and hormone signaling pathways, especially pathways of abscisic acid and auxin signaling. This has led to the discovery that abscisic acid signaling acts upstream of HD-ZIPIII and KANADI in the control of germination and may ultimately explain how environmental stress pathways control new growth at the shoot apex. Auxin signaling conversely is downstream from HD-ZIPIII and KANADI action with these factors controlling targets at all steps of auxin action-biosynthesis, transport, regulation of transport, and signaling. Based on these findings, we propose a model in which the HD-ZIPIII and KANADI factors pattern auxin response in the embryo. Finally, many genes targeted for control by HD-ZIPIII and KANADI proteins are themselves transcription factors-indicating these master regulators call up tissue specific subprograms of transcriptional control to affect the many polar differences observed across tissues. PMID- 23651843 TI - Grafts of porcine small intestinal submucosa seeded with cultured homologous smooth muscle cells for bladder repair in dogs. AB - BACKGROUND: Due to numerous complications associated to gastrointestinal augmented cystoplasty, this study aimed to analyze the anatomic repair of the bladder of 10 female dogs using grafts of porcine small intestinal submucosa (SIS) seeded with cultured homologous smooth muscle cells, and compare them with the acellular SIS grafts. RESULTS: We assessed the possible side effects and complications of each type of graft by clinical examination, abdominal ultrasound and laboratory findings. Anatomic repair of neoformed bladder was assessed by histological staining for H/E and Masson's Trichrome, analyzed with a Nikon Photomicroscope connected to the system of image analysis Image J. CONCLUSIONS: We propose that SIS associated to homologous smooth cells can improve the quality of tissue repair, and consequently decrease the potential complications inherent to acellular SIS. PMID- 23651844 TI - Enhanced insulin clearance in mice lacking TRPM8 channels. AB - Blood glucose concentration is tightly regulated by the rate of insulin secretion and clearance, a process partially controlled by sensory neurons serving as metabolic sensors in relevant tissues. The activity of these neurons is regulated by the products of metabolism which regulate transmitter release, and recent evidence suggests that neuronally expressed ion channels of the transient receptor potential (TRP) family function in this critical process. Here, we report the novel finding that the cold and menthol-gated channel TRPM8 is necessary for proper insulin homeostasis. Mice lacking TRPM8 respond normally to a glucose challenge while exhibiting prolonged hypoglycemia in response to insulin. Additionally, Trpm8-/- mice have increased rates of insulin clearance compared with wild-type animals and increased expression of insulin-degrading enzyme in the liver. TRPM8 channels are not expressed in the liver, but TRPM8 expressing sensory afferents innervate the hepatic portal vein, suggesting a TRPM8-mediated neuronal control of liver insulin clearance. These results demonstrate that TRPM8 is a novel regulator of serum insulin and support the role of sensory innervation in metabolic homeostasis. PMID- 23651845 TI - Cooperative effect of E2 and FGF2 on lactotroph proliferation triggered by signaling initiated at the plasma membrane. AB - In the present work, we investigated the effect of 17beta-estradiol (E2) and basic fibroblast growth factor 2 (FGF2) on the lactotroph cell-proliferative response and the related membrane-initiated signaling pathway. Anterior pituitary mixed-cell cultures of random, cycling 3-mo-old female rats were treated with 10 nM E2, E2 membrane-impermeable conjugated BSA (E2-BSA), PPT (ERalpha agonist), and DPN (ERbeta agonist) alone or combined with FGF2 (10 ng/ml) for 30 min or 4 h. Although our results showed that the uptake of BrdU into the nucleus of lactotrophs was not modified by E2 or FGF2 alone, a significant increase in the lactotroph uptake of BrdU was observed after E2/FGF2 coincubation, with this effect being mimicked by PPT/FGF2. These proliferative effects were blocked by ICI 182,780 or PD-98059. The involvement of membrane ER in the proliferative response of prolactin cells induced by the steroid and FGF2 coincubation was confirmed using E2-BSA, and the association between ERalpha and FGF receptor was observed after E2/FGF2 treatment by immunoprecipitation. A significant increase in the ERK1/2 expression was noted after E2, E2-BSA, PPT, and FGF2 alone, which was more noticeable after E2-BSA/FGF2, E2/FGF2, or PPT/FGF2 treatments. This study provides evidence that E2 and FGF2 exert a cooperative effect on the lactotroph proliferation principally by signaling initiated at the plasma membrane triggering a genomic effect mediated by MEK/ERK1/2, a common signaling pathway, that finally regulates the lactotroph population, thus contributing to pituitary plasticity. PMID- 23651846 TI - Nutrient infusion bypassing duodenum-jejunum improves insulin sensitivity in glucose-tolerant and diabetic obese subjects. AB - The mechanisms of type 2 diabetes remission after bariatric surgery is still not fully elucidated. In the present study, we tried to simulate the Roux-en-Y gastric bypass with a canonical or longer biliary limb by infusing a liquid formula diet into different intestinal sections. Nutrients (Nutrison Energy) were infused into mid- or proximal jejunum and duodenum during three successive days in 10 diabetic and 10 normal glucose-tolerant subjects. Plasma glucose, insulin, C-peptide, glucagon, incretins, and nonesterified fatty acids (NEFA) were measured before and up to 360 min following. Glucose rate of appearance (Ra) and insulin sensitivity (SI), secretion rate (ISR), and clearance were assessed by mathematical models. SI increased when nutrients were delivered in mid-jejunum vs. duodenum (SI * 104 min-1.pM-1: 1.11 +/- 0.44 vs. 0.62 +/- 0.22, P < 0.015, in controls and 0.79 +/- 0.34 vs. 0.40 +/- 0.20, P < 0.05, in diabetic subjects), whereas glucose Ra was not affected. In controls, Sensitivity of NEFA production was doubled in mid-jejunum vs. duodenum (2.80 +/- 1.36 vs. 1.13 +/- 0.78 * 106, P < 0.005) and insulin clearance increased in mid-jejunum vs. duodenum (2.05 +/- 1.05 vs. 1.09 +/- 0.38 l/min, P < 0.03). Bypass of duodenum and proximal jejunum by nutrients enhances insulin sensitivity, inhibits lipolysis, and increases insulin clearance. These results may further our knowledge of the effects of bariatric surgery on both insulin resistance and diabetes. PMID- 23651847 TI - Exercise training improves cutaneous microvascular function in nonalcoholic fatty liver disease. AB - The leading causes of mortality in nonalcoholic fatty liver disease (NAFLD) relate to cardiovascular disease (CVD). The contribution of nitric oxide (NO) to endothelial function, a surrogate of CVD risk, is currently unknown in NAFLD. We hypothesize that NO-mediated cutaneous microvessel function would be impaired in NAFLD compared with controls and that exercise would enhance microvessel function compared with conventional care. Thirteen NAFLD patients (aged 50 +/- 3 yr, BMI 31 +/- 1 kg/m2) and seven controls (48 +/- 4 yr, 30 +/- 2 kg/m2) were studied. NAFLD patients were randomized to either 16 wk of exercise or conventional care. Cutaneous microvessel function was examined using laser Doppler flowmetry combined with intradermal microdialysis of N(G)-monomethyl-l-arginine to assay the NO dilator response to local forearm heating. Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively, and cardiorespiratory fitness was assessed. Differences in NO contribution to cutaneous blood flow between NAFLD and control individuals and between interventions were analyzed using general linear modeling. NO contribution to cutaneous blood flow was similar between NAFLD and controls (P = 0.47). Cardiorespiratory fitness was greater following exercise training compared with conventional care. NO contribution to cutaneous blood flow in response to heating at 42 degrees C was 20.4% CVCmax (95% CI = 4.4, 36.4) greater following exercise training compared with conventional care (P = 0.02). Exercise training improves cutaneous microvascular NO function in NAFLD patients. The benefit of exercise training compared with conventional care strongly supports a role for exercise in the prevention of CVD in NAFLD. PMID- 23651848 TI - TWEAK prevents TNF-alpha-induced insulin resistance through PP2A activation in human adipocytes. AB - Visceral fat is strongly associated with insulin resistance. Obesity-associated adipose tissue inflammation and inflammatory cytokine production are considered key mediators of insulin signaling inhibition. TWEAK is a relatively new member of the TNF cytokine superfamily, which can exist as full length membrane associated (mTWEAK) and soluble (sTWEAK) isoforms. Although TWEAK has been shown to have important functions in chronic inflammatory diseases its physiological role in adipose tissue remains unresolved. In this study, we explore the molecular mechanisms involved in the modulation of TNF-alpha-induced effects on insulin sensitivity by sTWEAK in a human visceral adipose cell line and also in primary human adipocytes obtained from visceral fat depots. Our data reveal that sTWEAK ameliorates TNF-alpha-induced insulin resistance on glucose uptake, GLUT4 translocation and insulin signaling without affecting other metabolic effects of TNF-alpha such as lipolysis or apoptotis. Co-immunoprecipitation experiments in adipose cells revealed that pretreatment with sTWEAK specifically inhibits TRAF2 association with TNFR1, but not with TNFR2, which mediates insulin resistance. However, sTWEAK does not affect other downstream molecules activated by TNF alpha, such as TAK1. Rather, sTWEAK abolishes the stimulatory effect of TNF-alpha on JNK1/2, which is directly involved in the development of insulin resistance. This is associated with an increase in PP2A activity upon sTWEAK treatment. Silencing of the PP2A catalytic subunit gene overcomes the dephosphorylation effect of sTWEAK on JNK1/2, pointing to PP2A as a relevant mediator of sTWEAK induced JNK inactivation. Overall, our data reveal a protective role of TWEAK in glucose homeostasis and identify PP2A as a new driver in the modulation of TNF alpha signaling by sTWEAK. PMID- 23651849 TI - Overexpression of intraislet ghrelin enhances beta-cell proliferation after streptozotocin-induced beta-cell injury in mice. AB - Previously, we reported that exogenous administration of ghrelin ameliorates glucose metabolism in a neonate streptozotocin (STZ)-induced diabetic rat model through enhancement of beta-cell proliferation. However, it was not clear whether the observed beta-cell proliferation was a direct or indirect effect (e.g., via orexigenic or growth hormone-stimulated pathways) of ghrelin activity. Here, we aimed to investigate whether ghrelin directly impacts beta-cell proliferation after STZ-induced injury in mice. Seven-week-old male rat insulin II promoter ghrelin internal ribosomal sequence ghrelin O-acyltransferase transgenic (RIP-GG Tg) mice, which have elevated pancreatic ghrelin levels, but only minor changes in plasma ghrelin levels when fed a medium-chain triglyceride-rich diet, were treated with STZ. Then, serum insulin, pancreatic insulin mRNA expression, and islet histology were evaluated. We found that the serum insulin levels, but not blood glucose levels, of RIP-GG Tg mice were significantly ameliorated 14 days post-STZ treatment. Pancreatic insulin mRNA expression was significantly elevated in RIP-GG Tg mice, and beta-cell numbers in islets were increased. Furthermore, the number of phospho-histone H3+ or Ki67+ proliferating beta-cells was significantly elevated in RIP-GG Tg mice, whereas the apoptotic indexes within the islets, as determined by TUNEL assay, were not changed. These results indicate that ghrelin can directly stimulate beta-cell proliferation in vivo after beta-cell injury even without its orexigenic or GH-stimulating activities, although it did not have enough impact to normalize the glucose tolerance in adult mice. PMID- 23651851 TI - The family that eats together stays together: new p53 family transcriptional targets in autophagy. AB - Autophagy is a biological process that is crucial to maintain cellular homeostasis and is regulated by several metabolic pathways, including the p53 tumor suppressor pathway. In this issue of Genes & Development, Kenzelmann Broz and colleagues (pp. 1016-1031) show how the p53 family as a whole, including p63 and p73, collaborate in controlling autophagy to support tumor suppression. PMID- 23651850 TI - Thyroid hormone receptor-beta agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. AB - Liver-specific thyroid hormone receptor-beta (TRbeta)-specific agonists are potent lipid-lowering drugs that also hold promise for treating nonalcoholic fatty liver disease and hepatic insulin resistance. We investigated the effect of two TRbeta agonists (GC-1 and KB-2115) in high-fat-fed male Sprague-Dawley rats treated for 10 days. GC-1 treatment reduced hepatic triglyceride content by 75%, but the rats developed fasting hyperglycemia and hyperinsulinemia, attributable to increased endogenous glucose production (EGP) and diminished hepatic insulin sensitivity. GC-1 also increased white adipose tissue lipolysis; the resulting increase in glycerol flux may have contributed to the increase in EGP. KB-2115, a more TRbeta- and liver-specific thyromimetic, also prevented hepatic steatosis but did not induce fasting hyperglycemia, increase basal EGP rate, or diminish hepatic insulin sensitivity. Surprisingly, insulin-stimulated peripheral glucose disposal was diminished because of a decrease in insulin-stimulated skeletal muscle glucose uptake. Skeletal muscle insulin signaling was unaffected. Instead, KB-2115 treatment was associated with a decrease in GLUT4 protein content. Thus, although both GC-1 and KB-2115 potently treat hepatic steatosis in fat-fed rats, they each worsen insulin action via specific and discrete mechanisms. The development of future TRbeta agonists must consider the potential adverse effects on insulin sensitivity. PMID- 23651852 TI - RB goes mitochondrial. AB - The retinoblastoma tumor suppressor RB is well known for its capacity to restrict cell cycle progression at the G1/S transition of the cell cycle by controlling the transcription of cell cycle genes. In this issue of Genes & Development, Hilgendorf and colleagues (pp. 1003-1015) have identified a novel tumor suppressor function for RB independent of its role as a transcriptional regulator, in which RB directly activates the apoptosis regulator Bax at the mitochondria to promote cell death. PMID- 23651854 TI - The DEAH-box helicase DHX36 mediates dendritic localization of the neuronal precursor-microRNA-134. AB - Specific microRNAs (miRNAs), including miR-134, localize to neuronal dendrites, where they control synaptic protein synthesis and plasticity. However, the mechanism of miRNA transport is unknown. We found that the neuronal precursor miRNA-134 (pre-miR-134) accumulates in dendrites of hippocampal neurons and at synapses in vivo. Dendritic localization of pre-miR-134 is mediated by the DEAH box helicase DHX36, which directly associates with the pre-miR-134 terminal loop. DHX36 function is required for miR-134-dependent inhibition of target gene expression and the control of dendritic spine size. Dendritically localized pre miR-134 could provide a local source of miR-134 that can be mobilized in an activity-dependent manner during plasticity. PMID- 23651853 TI - Protein segregase meddles in remodeling of mRNA-protein complexes. AB - Remodeling of RNA-protein complexes (mRNPs) plays a critical role in mRNA biogenesis and metabolism. However, relatively little is known about the underlying mechanism and regulation of the mRNP remodeling. In this issue of Genes & Development, Zhou and colleagues (pp. 1046-1058) report that a protein remodeling machine, the p97-UBXD8 complex, disassembles mRNPs containing the AU rich elements (AREs) bound by HuR proteins in a nondegradative, ubiquitin signaling-dependent manner, revealing a novel mechanism to regulate mRNA turnover. PMID- 23651855 TI - The T-box transcription factor Eomesodermin is essential for AVE induction in the mouse embryo. AB - Reciprocal inductive interactions between the embryonic and extraembryonic tissues establish the anterior-posterior (AP) axis of the early mouse embryo. The anterior visceral endoderm (AVE) signaling center emerges at the distal tip of the embryo at embryonic day 5.5 and translocates to the prospective anterior side of the embryo. The process of AVE induction and migration are poorly understood. Here we demonstrate that the T-box gene Eomesodermin (Eomes) plays an essential role in AVE recruitment, in part by directly activating the homeobox transcription factor Lhx1. Thus, Eomes function in the visceral endoderm (VE) initiates an instructive transcriptional program controlling AP identity. PMID- 23651856 TI - Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses. AB - The mechanisms by which the p53 tumor suppressor acts remain incompletely understood. To gain new insights into p53 biology, we used high-throughput sequencing to analyze global p53 transcriptional networks in primary mouse embryo fibroblasts in response to DNA damage. Chromatin immunoprecipitation sequencing reveals 4785 p53-bound sites in the genome located near 3193 genes involved in diverse biological processes. RNA sequencing analysis shows that only a subset of p53-bound genes is transcriptionally regulated, yielding a list of 432 p53-bound and regulated genes. Interestingly, we identify a host of autophagy genes as direct p53 target genes. While the autophagy program is regulated predominantly by p53, the p53 family members p63 and p73 contribute to activation of this autophagy gene network. Induction of autophagy genes in response to p53 activation is associated with enhanced autophagy in diverse settings and depends on p53 transcriptional activity. While p53-induced autophagy does not affect cell cycle arrest in response to DNA damage, it is important for both robust p53 dependent apoptosis triggered by DNA damage and transformation suppression by p53. Together, our data highlight an intimate connection between p53 and autophagy through a vast transcriptional network and indicate that autophagy contributes to p53-dependent apoptosis and cancer suppression. PMID- 23651858 TI - Dynamic binding of RBPJ is determined by Notch signaling status. AB - Notch signaling plays crucial roles in mediating cell fate choices in all metazoans largely by specifying the transcriptional output of one cell in response to a neighboring cell. The DNA-binding protein RBPJ is the principle effector of this pathway in mammals and, together with the transcription factor moiety of Notch (NICD), regulates the expression of target genes. The prevalent view presumes that RBPJ statically occupies consensus binding sites while exchanging repressors for activators in response to NICD. We present the first specific RBPJ chromatin immunoprecipitation and high-throughput sequencing study in mammalian cells. To dissect the mode of transcriptional regulation by RBPJ and identify its direct targets, whole-genome binding profiles were generated for RBPJ; its coactivator, p300; NICD; and the histone H3 modifications H3 Lys 4 trimethylation (H3K4me3), H3 Lys 4 monomethylation (H3K4me1), and histone H3 Lys 27 acetylation (H3K27ac) in myogenic cells under active or inhibitory Notch signaling conditions. Our results demonstrate dynamic binding of RBPJ in response to Notch activation at essentially all sites co-occupied by NICD. Additionally, we identify a distinct set of sites where RBPJ recruits neither NICD nor p300 and binds DNA statically, irrespective of Notch activity. These findings significantly modify our views on how RBPJ and Notch signaling mediate their activities and consequently impact on cell fate decisions. PMID- 23651857 TI - Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A. AB - To identify key regulators of human brain tumor maintenance and initiation, we performed multiple genome-wide RNAi screens in patient-derived glioblastoma multiforme (GBM) stem cells (GSCs). These screens identified the plant homeodomain (PHD)-finger domain protein PHF5A as differentially required for GSC expansion, as compared with untransformed neural stem cells (NSCs) and fibroblasts. Given PHF5A's known involvement in facilitating interactions between the U2 snRNP complex and ATP-dependent helicases, we examined cancer-specific roles in RNA splicing. We found that in GSCs, but not untransformed controls, PHF5A facilitates recognition of exons with unusual C-rich 3' splice sites in thousands of essential genes. PHF5A knockdown in GSCs, but not untransformed NSCs, astrocytes, or fibroblasts, inhibited splicing of these genes, leading to cell cycle arrest and loss of viability. Notably, pharmacologic inhibition of U2 snRNP activity phenocopied PHF5A knockdown in GSCs and also in NSCs or fibroblasts overexpressing MYC. Furthermore, PHF5A inhibition compromised GSC tumor formation in vivo and inhibited growth of established GBM patient-derived xenograft tumors. Our results demonstrate a novel viability requirement for PHF5A to maintain proper exon recognition in brain tumor-initiating cells and may provide new inroads for novel anti-GBM therapeutic strategies. PMID- 23651859 TI - Systemic lupus erythematosus due to C1q deficiency with progressive encephalopathy, intracranial calcification and acquired moyamoya cerebral vasculopathy. AB - We report a female with infantile onset of systemic lupus erythematosus secondary to C1q deficiency, in whom we identified a novel homozygous mutation in C1qB. The patient developed a progressive encephalopathy associated with spasticity, and suffered several arterial ischaemic strokes. Cerebral imaging demonstrated acquired intracranial calcification and a cerebral vasculopathy reminiscent of moyamoya. This case demonstrates overlap with some features of Aicardi-Goutieres syndrome which, like C1q deficiency, is a monogenic cause of inflammation involving dysregulation of the innate immune system and stimulation of a type I interferon response. PMID- 23651860 TI - Therapeutic drug monitoring of mycophenolate mofetil for the treatment of severely active lupus nephritis. AB - BACKGROUND: Plasma mycophenolic acid (MPA) concentrations may predict therapeutic response in active lupus nephritis (LN). We determined the efficacy and safety of a concentration-controlled MPA regime in the treatment of severely active LN. METHODS: In this prospective study, 19 biopsy-proven class III/IV LN patients were treated with mycophenolate mofetil (MMF) for 48 weeks. The MMF dosage was based on maximal plasma MPA concentration at 1-hour post dose (MPA-C1). All patients had plasma MPA-C1 levels monitored weekly until achieving the targeted level of >13 mg/L. A low-dose steroid protocol was started at 0.5 mg/kg/day and rapidly tapered to 5 mg/day. Therapeutic response was evaluated at week 24 and week 48. MPA area-under-the curve (MPA-AUC0-12h) was measured at week 12 to verify the optimum dosage. RESULTS: No death or end-stage kidney disease occurred in this study. Seventeen patients (89%) responded to therapy at week 24 with four (21%) patients having complete response. There was no renal relapse at week 48 and four more patients had converted from partial response to complete response. Seventy eight percent of patients achieved the recommended MPA-AUC0-12h level. No association between plasma MPA concentrations and adverse reactions or infections was found. CONCLUSIONS: MPA-C1 may be a practical monitoring of MPA levels in patients with LN. It is convenient to monitor and may facilitate an optimum estimate of MPA exposure. PMID- 23651861 TI - Cross-sectional and longitudinal associations of lifestyle factors with depressive symptoms in >= 53-year old Taiwanese - results of an 8-year cohort study. AB - OBJECTIVE: The objective of this study is to determine the concurrent and longitudinal associations of lifestyle factors including smoking, alcohol drinking, betel quid chewing, tea (Camellia sinensis) drinking and physical activity with depressive symptoms in older Taiwanese. METHODS: The study analyzed Taiwan Longitudinal Study on Aging (TLSA) datasets to determine the association of lifestyle variables with concurrent depressive symptoms in 4122 >= 50-year-old Taiwanese at baseline (1999) and with the new development of depressive symptoms 8 years later. RESULTS: Heavy/problem alcohol drinking increased the association with concurrent depressive symptoms (OR=1.85, 95%CI=1.02-3.36); frequent tea drinking (OR=0.63, 95%CI=0.50-0.79) and frequent physical activity (OR=0.59, 95%CI=0.48-0.71) reduced the association; whereas smoking and betel quid chewing showed no significant associations. Smoking (OR=1.56, 95%CI=1.06-2.30) increased the development of depressive symptoms 8 years later; past smoking and current betel quid chewing showed similar trends (OR=1.47, 95%CI=0.93-2.31); exercising >= 3 times/wk reduced the development (OR=0.77, 95%CI=0.60-0.99) while alcohol drinking showed no impact. CONCLUSION: Lifestyle variables can impact the mental wellbeing of older Taiwanese. Interventions to reduce the risk of depressive symptoms in older adults should include strategies aimed at improving these modifiable risk factors. PMID- 23651864 TI - Assessing anxiety levels and empathic tendency in blood and platelet donors. AB - In spite of a constantly-increasing requirement for blood transfusion in the world, blood donation does not exhibit an increase at the same rate. In Turkey with a population of 74 million, only 15 per 10,000 people donate blood regularly and rate of voluntary blood donation is very low compared to developed countries. The aim of this study is to determine empathic level of donors and anxiety levels of blood and platelet donors and also to enable comfort and motivation of donors by taking precautions for reducing their anxieties. This prospective and descriptive study was conducted with 100 voluntary donors (50 blood donors, 50 platelet donors) who admitted to Blood Centre of Cumhuriyet University Hospital between 15 March 2012 and 30 April 2012. Average age of these donors was 27 (19 48)years. The mean scores of donors from Empathic Tendency Scale (ETS), State Anxiety Invertory (SAI) and Trait Anxiety Inventory (TAI) were 70 (49-83), 40 (33 45) and 34 (30-44), respectively. ETS score of those donating blood/platelet for the first time was low, >1 is higher in those who donated previously. SAI and TAI scores of blood donors were higher than those of platelet donors (p<0.001) and TAI score was higher in those who donate for the first time (p<0.007) compared to previously donated precipitants. In conclusion, this study underscores that the request of the donor to help others is the most important factor for donation. People frequently donate blood to unfamiliar people and recurring blood donations increase the level of empathy. Donation made during the continuous disclosure is an important factor for being a donor. PMID- 23651865 TI - Apheresis-inducible cytokine pattern change in children with homozygous familial hypercholesterolemia. AB - Familial hypercholesterolemia is a genetic disorder that leads to severe atherosclerosis related cardiovascular complications in young adults. Extracorporeal elimination is a method of LDL-lowering procedures effective in patients with homozygous or severe heterozygous FH utilized in cases. The recruitment of leucocytes into the arterial intima is dependent on a cascade of events mediated through a diverse family of adhesion molecules. Several pro inflammatory adhesion molecules are cleared by various lipid apheresis methods. This study showed that, LDL-apheresis led to several changes in circulating inflammatory factors which induced antiinflammatory and antiatherogenic changes in the plasma profile in homozygous familial hypercholesterolemic patients. PMID- 23651866 TI - Predictors of weight loss during conformal radiotherapy for head and neck cancers - how important are planning target volumes? AB - AIMS: Nutritional compromise is common during high dose radiotherapy (RT) or chemoradiotherapy (CRT) for head and neck cancers. We aimed to identify the factors that determine nutritional outcome for head and neck cancer patients during radiotherapy. METHODS: Data from 103 patients with head and neck cancer treated with highly conformal radiotherapy to doses of 60 Gy or more in 30-33 fractions in the adjuvant or definitive setting was analyzed. All patients received complex 3D conformal radiotherapy (3DCRT) or intensity modulated radiotherapy (IMRT). Patients received regular nutritional counseling and need based interventions. Their weight was recorded at the beginning and end of radiotherapy. Using univariate and multivariate models we tested possible predictors of weight loss of >5% and NG tube requirement. RESULTS: The mean weight loss was 3.8%. The incidence of weight loss >5% was 37.9% and NG tube placement was 24.3%. The factors significantly associated with >5% weight loss in the univariate analysis were tumor site (oro-hypopharyngeal vs. others), definitive vs. adjuvant RT; prescription dose of >60 Gy vs. 60 Gy; CRT vs. RT alone; prescription dose planning target volume (PTV) volume >235 cc and total PTV volume >615 cc. Age, sex, T stage, N stage and modality (3DCRT/IMRT) were not significant. In multivariate analysis, the total PTV volume, prescription dose PTV volume and use of chemotherapy were significant after controlling for other factors. Patients could be risk stratified based on the use of CRT and large PTV volumes. Patients with none, one or both factors had a likelihood of >5% weight loss of 0%, 30.3%, and 56.9% (p < 0.001) and likelihood of NG tube placement of 5.3%, 15.2% and 37.3% (p = 0.007). CONCLUSIONS: It is possible to predict weight loss and NG tube requirements from disease and treatment related factors. PTV volumes are important predictors of nutritional compromise. Risk stratification may enable more focused counseling and identification of patients who require preventive interventions. PMID- 23651867 TI - A qualitative review of the neurophysiological underpinnings of fatigue in multiple sclerosis. AB - Fatigue is debilitating in multiple sclerosis (MS) and may have multiple causes. Recent investigations into objectively measurable correlates of fatigue have used transcranial magnetic stimulation (TMS) to examine a range of neurophysiological measures of neural excitability that may be altered in patients with MS. This qualitative review was conducted to test the hypothesis that changes in neural excitability are a contributing factor in MS-related fatigue. A search of the English language literature led to the compilation and synthesis of original research papers in which various aspects of neural excitability and neural transmission were measured using TMS in patients with MS. The resulting papers were classified into three categories of study relevant to fatigue: abnormalities in excitability and their correlation with self-reported fatigue; effects of exercise-induced fatigue on neural excitability; and effects of fatigue medications on neural excitability. Evidence of an association between fatigue and intracortical inhibition is both limited and conflicting, and no evidence suggests associations of fatigue with corticomotor excitability or neuronal conduction. Pharmacologically-induced changes in fatigue were found to correlate with changes in intracortical excitability. No conclusions could be drawn regarding neural excitability and exercise-induced fatigue, due to variability in study populations, outcome measures, and exercise protocols across different studies. Suggestions for future studies in this area are proposed with a view to identifying potentially modifiable factors contributing to fatigue in MS. PMID- 23651868 TI - Month of birth in multiple sclerosis with and without longitudinally extensive spinal cord lesions: a study of a Japanese national survey. AB - OBJECTIVES: Month of birth has been associated with the environmental factors for multiple sclerosis (MS). This study aimed to investigate whether individuals with MS had significantly different frequencies of birth in a particular month of the year, and whether month-of-birth patterns were influenced by the longitudinally extensive spinal cord lesions (LESCL) status relative to the general population in the same Japanese birth cohort. METHODS: In this study, performed as a part of the fourth Japanese nationwide survey of MS, patients were divided into two groups according to the presence (n=307) or absence (n=906) of LESCLs that were diagnosed on the basis of magnetic resonance imaging findings. The number of births in every month was counted for both groups. Control data were obtained from birth records of the Japanese general population of the median years of birth of each group. Differences in the month-of-birth distributions between the patients and the general population were assessed using the chi-square test. RESULTS: In MS patients without LESCLs, significantly more patients were born in January and June, whereas significantly fewer patients were born in May, compared to the general population. The seasonal patterns of birth were not in association with those of ambient ultraviolet (UV) radiation. No significant differences were found for the month-of-birth distributions between MS patients with LESCLs and the general population. CONCLUSIONS: A different distribution of month of birth in Japanese MS patients without LESCLs from the general population, but not in those with LESCLs, suggests some role for environmental factors in the pathogenesis of the former group. Environmental factors other than UV radiation should be further elucidated in Japanese and other Asian MS cohorts. PMID- 23651869 TI - Effectiveness of national evidence-based medicine competition in Taiwan. AB - BACKGROUND: Competition and education are intimately related and can be combined in many ways. The role of competition in medical education of evidence-based medicine (EBM) has not been investigated. In order to enhance the dissemination and implementation of EBM in Taiwan, EBM competitions have been established among healthcare professionals. This study was to evaluate the impact of competition in EBM learning. METHODS: The EBM competition used PICO (patient, intervention, comparison, and outcome) queries to examine participants' skills in framing an answerable question, literature search, critical appraisal and clinical application among interdisciplinary teams. A structured questionnaire survey was conducted to investigate EBM among participants in the years of 2009 and 2011. Participants completed a baseline questionnaire survey at three months prior to the competition and finished the same questionnaire right after the competition. RESULTS: Valid questionnaires were collected from 358 participants, included 162 physicians, 71 nurses, 101 pharmacists, and 24 other allied healthcare professionals. There were significant increases in participants' knowledge of and skills in EBM (p<0.001). Their barriers to literature searching and forming answerable questions significantly decreased (p<0.01). Furthermore, there were significant increases in their access to the evidence-based retrieval databases, including the Cochrane Library (p<0.001), MD Consult (p<0.001), ProQuest (p<0.001), UpToDate (p=0.001), CINAHL (p=0.001), and MicroMedex (p=0.024). CONCLUSIONS: The current study demonstrates a method that successfully enhanced the knowledge of, skills in, and behavior of EBM. The data suggest competition using PICO queries may serve as an effective way to facilitate the learning of EBM. PMID- 23651870 TI - Kinase inhibitors: a new tool for the treatment of rheumatoid arthritis. AB - Despite aggressive immunosuppression with biologics and traditional DMARDs, achieving disease remission remains an unmet goal for most rheumatoid arthritis (RA) patients. In this context, there is a demand for novel treatment strategies, with kinase inhibitors expected to enrich the existing therapeutic armamentarium. In RA some kinases participate in the generation of pathogenic signaling cascades. Pharmacologic inhibition of kinases that mediate pathogenic signal transduction heralds a new era for RA therapeutics. Oral inhibitors of JAKs, Syk, PI3Ks, MAPKs and Btk are under development or in clinical trials in patients with RA. In this review, we discuss the scientific rationale for the use of kinase inhibitors in RA and summarize the experience from clinical trials. PMID- 23651871 TI - In vitro protein selection. PMID- 23651872 TI - Pushing the (nuclear) envelope into meiosis. AB - A recent study shows that a short isoform of a mammalian nuclear lamin is important for homologous chromosome interactions during meiotic prophase in mice. PMID- 23651873 TI - The role of home-based records in the establishment of a continuum of care for mothers, newborns, and children in Indonesia. AB - BACKGROUND: The provision of appropriate care along the continuum of maternal, newborn, and child health (MNCH) service delivery is a challenge in developing countries. To improve this, in the 1990s, Indonesia introduced the maternal and child health (MCH) handbook, as an integrated form of parallel home-based records. OBJECTIVE: This study aimed to identify the roles of home-based records both before and after childbirth, especially in provinces where the MCH handbook (MCHHB) was extensively promoted, by examining their association with MNCH service uptake. DESIGN: This was a cross-sectional study using nationally representative data sets, the Indonesia Demographic and Health Surveys (IDHSs) from 1997, 2002-2003, and 2007. The IDHS identifies respondents' ownership of home-based records before and after childbirth. Multivariate logistic regression was used to examine associations between record ownership and service utilisation in national data and data from two provinces, West Sumatra and North Sulawesi, where ownership of pre- and post-natal records served as a proxy for MCHHB ownership. RESULTS: Pre- and post-natal record ownership increased from 1997 to 2007. Provincial data from 2007 showed that handbook ownership was associated with having delivery assisted by trained personnel [adjusted odds ratio (aOR): 2.12, 95% confidence interval (CI): 1.05-4.25], receiving maternal care (aOR: 3.92, 95% CI: 2.35-6.52), completing 12 doses of child immunisation for seven diseases (aOR: 4.86, 95% CI: 2.37-9.95), and having immunisation before and after childbirth (aOR: 5.40, 95% CI: 2.28-12.76), whereas national data showed that service utilisation was associated with ownership of both records compared with owning a single record or none. CONCLUSION: Our results suggest that pre- and post-natal home-based record use may be effective for ensuring service utilisation. In addition, since the handbook is an efficient home-based record for use throughout children's life courses, it could be an effective tool for promoting the continuum of MNCH care in Indonesia. PMID- 23651874 TI - The role of globular heads of the C1q receptor in HPV 16 E2-induced human cervical squamous carcinoma cell apoptosis is associated with p38 MAPK/JNK activation. AB - BACKGROUND: Human papillomavirus type 16 (HPV 16) E2 protein is a multifunctional DNA-binding protein. HPV 16 E2 regulates many biological responses, including DNA replication, gene expression, and apoptosis. The purpose of this study was to investigate the relationship among the receptor for globular heads of the human C1q (gC1qR) gene expression, HPV 16 E2 transfection and apoptosis regulation in human cervical squamous carcinoma cells (C33a and SiHa). METHODS: gC1qR expression was examined in C33a and SiHa cells using real-time PCR and Western blot analysis. Apoptosis of C33a and SiHa cells was assessed by flow cytometry. C33a and SiHa cell viability, migration and proliferation were detected using the water-soluble tetrazolium salt (WST-1) assay, a transwell assay and 3H-thymidine incorporation into DNA (3H-TdR), respectively. RESULTS: C33a and SiHa cells that were transfected with a vector encoding HPV 16 E2 displayed significantly increased gC1qR gene expression and p38 mitogen-activated protein kinase (p38 MAPK)/c-jun N-terminal kinase (JNK) activation as well as up-regulation of cellular apoptosis, which was abrogated by the addition of gC1qR small interfering RNA (siRNA). Furthermore, the changes in C33a and SiHa cell viability, migration and proliferation that were observed upon HPV 16 E2 transfection were abrogated by SB203580 (a p38 MAPK inhibitor) or SP600125 (a JNK inhibitor) treatment. CONCLUSION: These data support a mechanism whereby HPV 16 E2 induces apoptosis by silencing the gC1qR gene or inhibiting p38 MAPK/JNK signalling in cervical squamous cell carcinoma. PMID- 23651876 TI - Dietary patterns and breast cancer risk among women. AB - OBJECTIVE: Breast cancer is the most common type of cancer in women worldwide. Several studies have examined the role of single nutrients and food groups in breast cancer pathogenesis but fewer investigations have addressed the role of dietary patterns. Our main objective was to identify the relationship between major dietary patterns and breast cancer risk among Iranian women. DESIGN: Hospital-based case-control study. SETTING: Shohada Teaching Hospital, Tehran, Iran. SUBJECTS: Overall, 100 female patients aged 30-65 years with breast cancer and 174 female hospital controls were included in the present study. Dietary intake was assessed using a valid and reliable semi-quantitative FFQ consisting of 168 food items. RESULTS: Two dietary patterns were identified explaining 24.31 % of dietary variation in the study population. The 'healthy' food pattern was characterized by the consumption of vegetables, fruits, low-fat dairy products, legumes, olive and vegetable oils, fish, condiments, organ meat, poultry, pickles, soya and whole grains; while the 'unhealthy' food pattern was characterized by the consumption of soft drinks, sugars, tea and coffee, French fries and potato chips, salt, sweets and desserts, hydrogenated fats, nuts, industrial juice, refined grains, and red and processed meat. Compared with the lowest tertile, women in the highest tertile of the 'healthy' dietary pattern score had 75 % decreased risk of breast cancer (OR = 0.25, 95 % CI 0.08, 0.78), whereas women in the highest tertile of the 'unhealthy' dietary pattern had a significantly increased breast cancer risk (OR = 7.78, 95 % CI 2.31, 26.22). CONCLUSIONS: A healthy dietary pattern may be negatively associated with breast cancer risk, while an unhealthy dietary pattern is likely to increase the risk among Iranian women. PMID- 23651875 TI - Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment. AB - INTRODUCTION: Unwanted drug interactions with ionic currents in the heart can lead to an increased pro-arrhythmic risk to patients in the clinic. It is therefore a priority for safety pharmacology teams to detect block of cardiac ion channels, and new technologies have enabled the development of automated and high throughput screening assays using cell lines. As a result of screening multiple ion-channels there is a need to integrate information, particularly for compounds affecting more than one current, and mathematical electrophysiology in-silico action potential models are beginning to be used for this. METHODS: We quantified the variability associated with concentration-effect curves fitted to recordings from high-throughput Molecular Devices IonWorks(r) QuattroTM screens when detecting block of I(Kr) (hERG), I(Na) (NaV1.5), I(CaL) (CaV1.2), I(Ks) (KCNQ1/minK) and I(to) (Kv4.3/KChIP2.2), and the Molecular Devices FLIPR(r) Tetra fluorescence screen for I(CaL) (CaV1.2), for control compounds used at AstraZeneca and GlaxoSmithKline. We examined how screening variability propagates through in-silico action potential models for whole cell electrical behaviour, and how confidence intervals on model predictions can be estimated with repeated simulations. RESULTS: There are significant levels of variability associated with high-throughput ion channel electrophysiology screens. This variability is of a similar magnitude for different cardiac ion currents and different compounds. Uncertainty in the Hill coefficients of reported concentration-effect curves is particularly high. Depending on a compound's ion channel blocking profile, the uncertainty introduced into whole-cell predictions can become significant. DISCUSSION: Our technique allows confidence intervals to be placed on computational model predictions that are based on high-throughput ion channel screens. This allows us to suggest when repeated screens should be performed to reduce uncertainty in a compound's action to acceptable levels, to allow a meaningful interpretation of the data. PMID- 23651877 TI - Organocatalysis in heterocyclic synthesis: DABCO as a mild and efficient catalytic system for the synthesis of a novel class of quinazoline, thiazolo [3,2 a]quinazoline and thiazolo[2,3-b] quinazoline derivatives. AB - BACKGROUND: There are only limited publications devoted to the synthesis of especially thiazolo[3,2-a]quinazoline which involved reaction of 2 mercaptopropargyl quinazolin-4-one with various aryl iodides catalyzed by Pd-Cu or by condensation of 2-mercapto-4-oxoquinazoline with chloroacetic acid, inspite of this procedure was also reported in the literature to afford the thiazolo [2,3 b] quinazoline. So the multistep synthesis of the thiazolo[3,2-a]- quinazoline suffered from some flaws and in this study we have synthesized a novel class of thiazoloquinazolines by a simple and convenient method involving catalysis by 1,4 diazabicyclo[2.2.2]octane (DABCO). RESULTS: A new and convenient one-pot synthesis of a novel class of 2-arylidene-2H-thiazolo[3,2-a]quinazoline-1,5 diones 9a-i was established through the reaction between methyl-2-(2-thio cyanatoacetamido)benzoate (4) and a variety of arylidene malononitriles 8a-i in the presence of DABCO as a mild and efficient catalytic system via a Michael type addition reaction and a mechanism for formation of the products observed is proposed. Moreover 4 was converted to ethyl-2-[(4-oxo-3,4-dihydroquinazolin-2 yl)thio]acetate (10) upon reflux in ethanol containing DABCO as catalyst. The latter was reacted with aromatic aldehydes and dimethylformamide dimethylacetal (DMF-DMA) to afford a mixture of two regioselectively products with identical percentage yield, these two products were identified as thiazolo[3,2 a]quinazoline 9,13 and thiazolo[2,3-b]quinazoline 11,12 derivatives respectively. The structure of the compounds prepared in this study was elucidated by different spectroscopic tools of analyses also the X-ray single crystal technique was employed in this study for structure elucidation, Z/E potential isomerism configuration determination and to determine the regioselectivity of the reactions. CONCLUSION: A simple and efficient one-pot synthesis of a novel class of 2-arylidene-2H-thiazolo[3,2-a]quinazoline-1,5-diones 9a-i was established through DABCO catalyzed Michael type addition reaction. In addition many fused quinazoline and quinazoline derivatives were synthesized which appeared as valuable precursors in synthetic and medicinal chemistry. PMID- 23651878 TI - Motor and cognitive placebo-/nocebo-responses in Parkinson's disease patients with deep brain stimulation. AB - Expectation contributes to placebo and nocebo responses in Parkinson's disease (PD). Subthalamic nucleus (STN) deep brain stimulation (DBS) improves proximal more than distal movements whereas it impairs executive cognitive function such as verbal fluency (VF). We investigated how expectation modulates the pattern of motor improvement in STN-DBS and its interaction with VF. In a within-subject design, expectation of 24 hypokinetic-rigid PD patients regarding the impact of STN-DBS on motor symptoms was manipulated by verbal suggestions (positive [placebo], negative [nocebo], neutral [control]). Patients participated with (MedON) and without (MedOFF) antiparkinsonian medication. Motor function was assessed by Unified Parkinson's Disease Rating Scale and quantitative kinematic analysis of proximal alternating hand and distal finger tapping. VF was quantified by lexical and semantic tests. In MedOFF, expectation significantly affected proximal but not distal movements resulting in better performance in the placebo than in the nocebo condition. Placebo responders with improvement of >=25% were characterized by a trend for impaired lexical VF. These results indicate that positive motor expectations exert both motor placebo and cognitive nocebo responses by further enhancing the STN-DBS-effect on proximal movements and by impairing VF. The placebo response on motor performance resembles the clinically known STN-DBS-effect with stronger improvement in proximal than distal movements. The nocebo response on VF is likely due to implicit learning mechanisms associated with an expectation-induced placebo response on motor performance. PMID- 23651879 TI - One-trial object recognition memory in the domestic rabbit (Oryctolagus cuniculus) is disrupted by NMDA receptor antagonists. AB - The spontaneous response to novelty is the basis of one-trial object recognition tests for the study of object recognition memory (ORM) in rodents. We describe an object recognition task for the rabbit, based on its natural tendency to scent mark ("chin") novel objects. The object recognition task comprised a 15min sample phase in which the rabbit was placed into an open field arena containing two similar objects, then removed for a 5-360min delay, and then returned to the same arena that contained one object similar to the original ones ("Familiar") and one that differed from the original ones ("Novel"), for a 15min test phase. Chin marks directed at each of the objects were registered. Some animals received injections (sc) of saline, ketamine (1mg/kg), or MK-801 (37MUg/kg), 5 or 20min before the sample phase. We found that chinning decreased across the sample phase, and that this response showed stimulus specificity, a defining characteristic of habituation: in the test phase, chinning directed at the Novel, but not Familiar, object was increased. Chinning directed preferentially at the novel object, which we interpret as novelty-induced sensitization and the behavioral correlate of ORM, was promoted by tactile/visual and spatial novelty. ORM deficits were induced by pre-treatment with MK-801 and, to a lesser extent, ketamine. Novel object discrimination was not observed after delays longer than 5min. These results suggest that short-term habituation and sensitization, not long-term memory, underlie novel object discrimination in this test paradigm. PMID- 23651880 TI - Low doses of the NMDA receptor antagonists, MK-801, PEAQX, and ifenprodil, induces social facilitation in adolescent male rats. AB - Adolescents display high levels of interactions with peers relative to other age groups, with these interactions further enhanced by ethanol under some circumstances. Understanding of the neural mechanisms underlying these high levels of social interactions is important given that alcohol use is initiated during adolescence and adolescents tend to report drinking for social reasons. Given that ethanol's effects are associated in part with functional antagonism of the NMDA receptor system, the current experiment explored the role of NMDA antagonists for facilitating adolescent social behavior. Adolescent male Sprague Dawley rats were challenged acutely with either the non-competitive NMDA antagonist, MK-801 (0.01, 0.03mg/kg), the NR2A antagonist, PEAQX (1.25, 3.75mg/kg) or the NR2B antagonist, ifenprodil (0.75, 2.25mg/kg) 30min prior to a 10-min social interaction test. All compounds generally increased overall social activity (i.e., sum of social investigation, contact behavior, and play), with ifenprodil also significantly enhancing play and social contact behaviors. Although the frequencies of peer-directed social behaviors were typically greater following administration with these NMDA antagonists, social preference, indexed via the number of crossovers to the side with the partner relative to crossovers away, was significantly reduced in MK-801 and PEAQX-treated rats. None of these changes were associated with concomitant alterations in overall locomotor activity under these test circumstances. These data support the suggestion that the increases in social interactions observed in adolescents following acute ethanol may be driven in part by NMDA receptor antagonism - particularly of the NR2B subunit - given that ifenprodil stimulated social behavior in a manner similar to that produced by low doses of ethanol. PMID- 23651881 TI - Committed action: an application of the psychological flexibility model to activity patterns in chronic pain. AB - Whether a person with chronic pain avoids activity, persists with activity, or overexerts himself or herself is considered important to the quality of his or her daily functioning. However, results from studies of these activity patterns have not always yielded clear and consistent findings. It is suggested that applying the psychological flexibility model to activity patterns may clarify and integrate research in this area. Psychological flexibility is defined as the ability to persist or to change behavior in a setting of competing psychological influences, guided by goals and dependent on what the situation at hand affords. One aspect of psychological flexibility that appears pertinent to chronic pain is called committed action. Committed action is essentially goal-directed, flexible persistence. The purpose of the current study was to develop a measure of committed action, the committed action questionnaire (CAQ), in people seeking treatment for chronic pain (N = 216), to examine preliminary reliability and validity, and to test how well a summary score from the measure is able to predict patient health and functioning. Results generally support the internal consistency of the CAQ and show that it is correlated with another established component of psychological flexibility. In regression analyses the CAQ was able to account for significant variance in depression, social functioning, mental health, vitality, and general health, beyond the contributions of pain and acceptance of pain. PERSPECTIVE: The psychological flexibility model may be useful for understanding patterns of behavior in relation to chronic pain. It appears possible to assess a process in this model called committed action, and this process appears related to important aspects of functioning. PMID- 23651882 TI - How good is the neurophysiology of pain questionnaire? A Rasch analysis of psychometric properties. AB - The Neurophysiology of Pain Questionnaire (NPQ) was devised to assess how an individual conceptualizes the biological mechanisms that underpin his or her pain. Despite its widespread use, its psychometric properties have not been comprehensively interrogated. Rasch analysis was undertaken on NPQ data from a convenience sample of 300 spinal pain patients, and test-retest reliability was assessed in a sample of 45 low back pain patients. The NPQ effectively targeted the ability of the sample and had acceptable internal consistency and test-retest reliability. However, some items functioned erratically for persons of differing abilities or were psychometrically redundant. The NPQ was reanalyzed with 7 questionable items excluded, and superior psychometric properties were observed. These findings suggest that the NPQ could be improved, but future prospective studies including qualitative measures are needed. In summary, the NPQ is a useful tool for assessing a patient's conceptualization of the biological mechanisms that underpin his or her pain and for evaluating the effects of cognitive interventions in clinical practice and research. These findings suggest that it has adequate psychometric properties for use with chronic spinal pain patients. PERSPECTIVE: Rasch analysis was used to analyze the NPQ. Despite several limitations, these results suggest that it is a useful tool with which to assess a patient's conceptualization of the biological mechanisms that underpin his or her pain and to evaluate the effects of cognitive interventions in clinical practice and research. PMID- 23651883 TI - National estimates of central line-associated bloodstream infections in critical care patients. AB - OBJECTIVE. Recent studies have demonstrated that central line-associated bloodstream infections (CLABSIs) are preventable through implementation of evidence-based prevention practices. Hospitals have reported CLABSI data to the Centers for Disease Control and Prevention (CDC) since the 1970s, providing an opportunity to characterize the national impact of CLABSIs over time. Our objective was to describe changes in the annual number of CLABSIs in critical care patients in the United States. DESIGN: Monte Carlo simulation. Setting. U.S. acute care hospitals. PATIENTS: Nonneonatal critical care patients. METHODS: We obtained administrative data on patient-days for nearly all US hospitals and applied CLABSI rates from the National Nosocomial Infections Surveillance and the National Healthcare Safety Network systems to estimate the annual number of CLABSIs in critical care patients nationally during the period 1990-2010 and the number of CLABSIs prevented since 1990. RESULTS: We estimated that there were between 462,000 and 636,000 CLABSIs in nonneonatal critical care patients in the United States during 1990-2010. CLABSI rate reductions led to between 104,000 and 198,000 fewer CLABSIs than would have occurred if rates had remained unchanged since 1990. There were 15,000 hospital-onset CLABSIs in nonneonatal critical care patients in 2010; 70% occurred in medium and large teaching hospitals. CONCLUSIONS: Substantial progress has been made in reducing the occurrence of CLABSIs in U.S. critical care patients over the past 2 decades. The concentration of critical care CLABSIs in medium and large teaching hospitals suggests that a targeted approach may be warranted to continue achieving reductions in critical care CLABSIs nationally. PMID- 23651884 TI - When counting central line infections counts. PMID- 23651885 TI - Use of a computer decision support system and antimicrobial therapy appropriateness. AB - OBJECTIVE: To determine whether antimicrobial (AM) courses ordered with an antimicrobial computer decision support system (CDSS) were more likely to be appropriate than courses ordered without the CDSS. DESIGN: Retrospective cohort study. Blinded expert reviewers judged whether AM courses were appropriate, considering drug selection, route, dose, and duration. SETTING: A 279-bed university-affiliated Department of Veterans Affairs (VA) hospital. PATIENTS: A 500-patient random sample of inpatients who received a therapeutic AM course between October 2007 and September 2008. Intervention. An optional CDSS, available at the point of order entry in the VA computerized patient record system. RESULTS: CDSS courses were significantly more likely to be appropriate (111/254, 44%) compared with non-CDSS courses (81/246, 33%, P = .013). Courses were more likely to be appropriate when the initial provider diagnosis of the condition being treated was correct (168/273, 62%) than when it was incorrect, uncertain, or a sign or symptom rather than a disease (24/227, 11%, P < .001. In multivariable analysis, CDSS-ordered courses were more likely to be appropriate than non-CDSS-ordered courses (odds ratio [OR], 1.83; 95% confidence interval [CI], 1.13-2.98). Courses were also more likely to be judged appropriate when the initial provider diagnosis of the condition being treated was correct than when it was incorrect, uncertain, or a sign or symptom rather than a disease (OR, 3.56; 95% CI, 1.4-9.0). CONCLUSIONS: Use of the CDSS was associated with more appropriate AM use. To achieve greater improvements, strategies are needed to improve provider diagnoses of syndromes that are infectious or possibly infectious. PMID- 23651886 TI - Antimicrobial stewardship and automated pharmacy technology improve antibiotic appropriateness for community-acquired pneumonia. AB - BACKGROUND: The Centers for Medicare and Medicaid Services' (CMS's) Hospital Inpatient Quality Reporting program includes the initial selection of antibiotics for adult community-acquired pneumonia (CAP) patients as a performance measure. A multidisciplinary team defined opportunities for improving performance in appropriate antibiotic use among CAP patients. The team consisted of personnel from the emergency department (ED), the antimicrobial stewardship program (infectious disease, pharmacy), and performance improvement. DESIGN: Quasi experimental before-after study. SETTING: A large, urban, multicampus academic medical center. Interventions. Interventions included an algorithm for ED providers identifying appropriate antibiotic selections, development of a CAP kit consisting of appropriate antibiotics and dosing regimens bundled with the treatment algorithm, and preloading an automated ED medication dispensing and management system. A quality improvement methodology ("plan, do, check, act") was used to pilot stewardship interventions at one ED campus and later at a second ED campus. RESULTS: In the pilot ED, appropriate antibiotic selection for CAP improved from 54.9% before the intervention in 2008 to 93.4% after the intervention in 2011 (P = .001). Subsequently, in the second ED appropriate antibiotic regimens for CAP improved from 64.6% before the intervention in 2008 to 91.3% after the intervention in 2011 (P = .004)). The rates of another CMS measure, antibiotic administration within 6 hours, were not statistically different before and after the interventions. In an interrupted time series logistic regression analysis, the intervention was found to be significantly associated with the improved prescribing ([Formula: see text]). DISCUSSION: The combination of interdisciplinary teamwork, antibiotic stewardship, education, and information technology is associated with replicable and sustained prescribing improvements. PMID- 23651887 TI - Sustained savings from a longitudinal cost analysis of an internet-based preapproval antimicrobial stewardship program. AB - OBJECTIVE: To evaluate an internet-based preapproval antimicrobial stewardship program for sustained reduction in antimicrobial prescribing and resulting cost savings. DESIGN: Retrospective cohort study and cost analysis. METHODS: Review of all doses and charges of antimicrobials dispensed to patients over 6 years (July 1, 2005-June 30, 2011) at a tertiary care pediatric hospital. RESULTS: Restricted antimicrobials account for 26% of total doses but 81% of total antimicrobial charges. Winter months (November-February) and the oncology and infant and toddler units were associated with the highest antimicrobial charges. Five restricted drugs accounted for the majority (54%) of charges but only 6% of doses. With an average approval rate of 91.5% (95% confidence interval [CI], 91.1%-91.9%), the preapproval antibiotic stewardship program saved $103,787 (95% CI, $98,583-$109,172) per year, or $14,156 (95% CI, $13,446-$14,890) per 1,000 patient-days. CONCLUSIONS: A preapproval antimicrobial stewardship program effectively reduces the number of doses and subsequent charges due to restricted antimicrobials years after implementation. Hospitals with reduced resources for implementing postprescription review may benefit from a preapproval antimicrobial stewardship program. Targeting specific units, drugs, and seasons may optimize preapproval programs for additional cost savings. PMID- 23651889 TI - Attributable burden of hospital-onset Clostridium difficile infection: a propensity score matching study. AB - OBJECTIVE: To determine the attributable in-hospital mortality, length of stay (LOS), and cost of hospital-onset Clostridium difficile infection (HO-CDI). DESIGN: Propensity score matching. SETTING: Six Pennsylvania hospitals (2 academic centers, 1 community teaching facility, and 3 community nonteaching facilities) contributing data to a clinical research database. PATIENTS: Adult inpatients between 2007 and 2008. METHODS: We defined HO-CDI in adult inpatients as a positive C. difficile toxin assay result from a specimen collected more than 48 hours after admission and more than 8 weeks following any previous positive result. We developed an HO-CDI propensity model and matched cases with noncases by propensity score at a 1?3 ratio. We further restricted matching within the same hospital, within the same principal disease group, and within a similar length of lead time from admission to onset of HO-CDI. RESULTS: Among 77,257 discharges, 282 HO-CDI cases were identified. The propensity score-matched rate was 90%. Compared with matched noncases, HO-CDI patients had higher mortality (11.8% vs. 7.3%; P < .05), longer LOS (median [interquartile range (IQR)], 12 [9 21] vs. 11 [8-17] days; P < .01), and higher cost (median [IQR], $20,804 [$11,059 $38,429] vs. $16,634 [$9,413-$30,319]; P < .01). The attributable effect of HO CDI was 4.5% (95% confidence interval [CI], 0.2%-8.7%; P < .05) for mortality, 2.3 days (95% CI, 0.9-3.8; P < .01) for LOS, and $6,117 (95% CI, $1,659-$10,574; P < .01) for cost. CONCLUSIONS: Patients with HO-CDI incur additional attributable mortality, LOS, and cost burden compared with patients with similar primary clinical condition, exposure risk, lead time of hospitalization, and baseline characteristics. PMID- 23651888 TI - Predictors of hospitals with endemic community-associated methicillin-resistant Staphylococcus aureus. AB - OBJECTIVE: We sought to identify hospital characteristics associated with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) carriage among inpatients. DESIGN: Prospective cohort study. SETTING: Orange County, California. PARTICIPANTS: Thirty hospitals in a single county. METHODS: We collected clinical MRSA isolates from inpatients in 30 of 31 hospitals in Orange County, California, from October 2008 through April 2010. We characterized isolates by spa typing to identify CA-MRSA strains. Using California's mandatory hospitalization data set, we identified hospital-level predictors of CA-MRSA isolation. RESULTS: CA-MRSA strains represented 1,033 (46%) of 2,246 of MRSA isolates. By hospital, the median percentage of CA-MRSA isolates was 46% (range, 14%-81%). In multivariate models, CA-MRSA isolation was associated with smaller hospitals (odds ratio [OR], 0.97, or 3% decreased odds of CA-MRSA isolation per 1,000 annual admissions; P < .001, hospitals with more Medicaid-insured patients (OR, 1.2; P = .002), and hospitals with more patients with low comorbidity scores (OR, 1.3; P < .001). Results were similar when restricted to isolates from patients with hospital-onset infection. CONCLUSIONS: Among 30 hospitals, CA-MRSA comprised nearly half of MRSA isolates. There was substantial variability in CA MRSA penetration across hospitals, with more CA-MRSA in smaller hospitals with healthier but socially disadvantaged patient populations. Additional research is needed to determine whether infection control strategies can be successful in targeting CA-MRSA influx. PMID- 23651891 TI - Has improved hand hygiene compliance reduced the risk of hospital-acquired infections among hospitalized patients in Ontario? Analysis of publicly reported patient safety data from 2008 to 2011. AB - DESIGN: Prospective, observational, ecological, time series, cross-sectional study examining the association between hand hygiene compliance (HHC) rates and the incidence of hospital-acquired infections. SETTING: Acute care hospitals (N = 166) located in the province of Ontario, Canada. METHODS: All data were extracted from the Ontario patient safety indicator database ( http://www.hqontario.ca/public-reporting/patient-safety). Complete data were available for 166 acute care hospitals from October 1, 2008, to December 31, 2011. The rates of Clostridium difficile infection (CDI) are reported monthly, methicillin-resistant Staphylococcus aureus (MRSA) bacteremia quarterly, and HHC rates yearly. Trends and associations for each indicator were evaluated by ordinary least squares regression (HHC), zero-inflated Poisson regression (MRSA bacteremia), or Poisson regression (CDI). Dependent variables included in the regression analyses were extracted from the same database and included year, healthcare region, and type of hospital (teaching or small or large community). RESULTS: Compared to those in 2008, reported HHC rates improved every year both before and after environment/patient contact (range, 10.6%-25.3%). Compared to those in 2008, there was no corresponding change in the rates of MRSA bacteremia; however, the rates of CDI decreased in 2009 but were not statistically significantly decreased from baseline in either 2010 or 2011. No consistent association was demonstrated between changes in the rates of HHC and these two healthcare-associated infections (HAIs). CONCLUSIONS: Despite significant improvements in reported rates of HHC among healthcare personnel in Ontario's hospitals, we could not demonstrate a positive ecological impact on rates of these two HAIs. PMID- 23651892 TI - The current state of validating the accuracy of clinical data reporting: lessons to be learned from quality and process improvement scientists. AB - We believe that the current practice in HAI reporting of using estimation approaches rather than quality control approaches to data supply chain validation might be supportable for research. However, we believe that it should not be the standard recommended practice for program managers who need to ensure that their data supply chain produces data of sustainably reliable quality over time to ensure maximum protection of the public's health. Therefore, we strongly recommend an immediate, synergistic alignment of the state-of-the-art validation acceptance-sampling methods and science currently used widely in industry with the needs and logistics of the tasks involved in collecting, sampling, evaluating, and reporting HAI data. We believe that the American public deserves to have its best technology and its "A Team" on the field in this effort and that involving the ASQ, its Healthcare Division, its quality scientists, and its intellectual capital resources could dramatically improve the HAI quality reporting system. Our people and our healthcare system deserve no less! PMID- 23651893 TI - Safety-engineered devices in 2012: the critical role of healthcare workers in device selection. PMID- 23651894 TI - A summary of the Third Global Interferon-gamma Release Assay Symposium. AB - Studies over the past several decades have dramatically increased our understanding of the immune response to Mycobacterium tuberculosis infection, and advances in proteomics and genomics have led to a new class of immune-diagnostic tests, termed interferon-gamma (IFN-gamma) release assays (IGRAs), which appear to obviate many of the problems encountered with the tuberculin skin test (TST). Worldwide, 2 IGRAs are currently commercially available. QuantiFERON-TB Gold In Tube (Cellestis) is a third-generation product that uses an enzyme-linked immunosorbent assay to measure IFN-gamma generated in whole blood stimulated with M. tuberculosis-specific antigens. T-Spot-TB (Oxford Immunotec) employs enzyme linked immunosorbent spot technology to enumerate the number of purified lymphocytes that respond to M. tuberculosis-specific antigens by producing IFN gamma. These in vitro tests measure the host immune response to M. tuberculosis specific antigens, which virtually eliminates false-positive cross reactions caused by bacillus Calmette-Guerin vaccination and/or exposure to environmental nontuberculous mycobacteria that plague the interpretation and accuracy of the tuberculin skin test (TST). The high specificity of IGRAs, together with sensitivity commensurate with or better than that of the TST, promises an accurate diagnosis and the ability to focus tuberculosis-control activities on those who are actually infected with M. tuberculosis. The Third Global Symposium was held over a 3-day period and was presented by the University of California, San Diego, Continuing Medical Education department; slides and sound recordings of each presentation are available at http://cme.ucsd.edu/igras/syllabus.html . A moderated discussion is also available at http://cme.ucsd.edu/igrasvideo . This document provides a summary of the key findings of the meeting, specifically focusing on the use of IGRAs in screening healthcare worker populations. PMID- 23651895 TI - A summary of meeting proceedings on addressing variability around the cut point in serial interferon-gamma release assay testing. AB - On June 13, 2012, a group of key stakeholders, leaders, and national experts on tuberculosis (TB), occupational health, and laboratory science met in Atlanta, Georgia, to focus national discussion on the higher than expected positive results occurring among low-risk, unexposed healthcare workers undergoing serial testing with interferon-gamma release assays (IGRAs). The objectives of the meeting were to present the latest clinical and operational research findings on the topic, to discuss evaluation and treatment algorithms that are emerging in the absence of national guidance, and to develop a consensus on the action steps needed to assist programs and physicians in the interpretation of serial testing IGRA results. This report summarizes its proceedings. PMID- 23651896 TI - A multimodal intervention to reduce urinary catheter use and associated infection at a Veterans Affairs Medical Center. AB - We assessed the impact of a quality improvement intervention to reduce urinary catheter use and associated urinary tract infections (UTIs) at a single hospital. After implementation, UTIs were reduced by 39% ([Formula: see text]). Additionally, we observed a slight decrease in catheter use and the number of catheters without an appropriate indication. PMID- 23651890 TI - Surgical site infections, International Nosocomial Infection Control Consortium (INICC) report, data summary of 30 countries, 2005-2010. AB - OBJECTIVE: To report the results of a surveillance study on surgical site infections (SSIs) conducted by the International Nosocomial Infection Control Consortium (INICC). DESIGN: Cohort prospective multinational multicenter surveillance study. SETTING: Eighty-two hospitals of 66 cities in 30 countries (Argentina, Brazil, Colombia, Cuba, Dominican Republic, Egypt, Greece, India, Kosovo, Lebanon, Lithuania, Macedonia, Malaysia, Mexico, Morocco, Pakistan, Panama, Peru, Philippines, Poland, Salvador, Saudi Arabia, Serbia, Singapore, Slovakia, Sudan, Thailand, Turkey, Uruguay, and Vietnam) from 4 continents (America, Asia, Africa, and Europe). PATIENTS: Patients undergoing surgical procedures (SPs) from January 2005 to December 2010. METHODS: Data were gathered and recorded from patients hospitalized in INICC member hospitals by using the methods and definitions of the Centers for Disease Control and Prevention National Healthcare Safety Network (CDC-NHSN) for SSI. SPs were classified into 31 types according to International Classification of Diseases, Ninth Revision, criteria. RESULTS: We gathered data from 7,523 SSIs associated with 260,973 SPs. SSI rates were significantly higher for most SPs in INICC hospitals compared with CDC-NHSN data, including the rates of SSI after hip prosthesis (2.6% vs. 1.3%; relative risk [RR], 2.06 [95% confidence interval (CI), 1.8-2.4]; P < .001), coronary bypass with chest and donor incision (4.5% vs. 2.9%; RR, 1.52 [95% CI, 1.4-1.6]; [P < .001); abdominal hysterectomy (2.7% vs. 1.6%; RR, 1.66 [95% CI, 1.4-2.0]; P < .001); exploratory abdominal surgery (4.1% vs. 2.0%; RR, 2.05 [95% CI, 1.6-2.6]; P < .001); ventricular shunt, 12.9% vs. 5.6% (RR, 2.3 [95% CI, 1.9 2.6]; P < .001, and others. CONCLUSIONS: SSI rates were higher for most SPs in INICC hospitals compared with CDC-NHSN data. PMID- 23651897 TI - Antimicrobial stewardship programs in Florida's acute care facilities. AB - We surveyed acute care facilities in Florida to assess components of and barriers to sustained antimicrobial stewardship programs (ASPs). Most respondents with and without ASPs are doing some stewardship-related activities to improve antimicrobial use. Collaborative efforts between facilities and health departments are important to providing better resources for ASPs. PMID- 23651898 TI - Trichosporon asahii among intensive care unit patients at a medical center in Jamaica. AB - We investigated an increase in Trichosporon asahii isolates among inpatients. We identified 63 cases; 4 involved disseminated disease. Trichosporon species was recovered from equipment cleaning rooms, washbasins, and fomites, which suggests transmission through washbasins. Patient washbasins should be single-patient use only; adherence to appropriate hospital disinfection guidelines was recommended. PMID- 23651899 TI - Cost of annual tuberculosis screening of healthcare workers with negative tuberculin skin test results. PMID- 23651900 TI - Hospital basins used to administer chlorhexidine baths are unlikely microbial reservoirs. PMID- 23651901 TI - Predicting the impact of contact precautions on methicillin-resistant Staphylococcus aureus outcomes: caution up ahead. PMID- 23651902 TI - Reply to Crnich and Drinka. PMID- 23651903 TI - Impact of cohorting for multidrug-resistant organisms with and without real-time feedback. PMID- 23651904 TI - Patient isolation in the high-prevalence setting: challenges with regard to multidrug-resistant gram-negative bacilli. PMID- 23651905 TI - Unnecessary antimicrobial use in the context of Clostridium difficile infection: a call to arms for the Veterans Affairs Antimicrobial Stewardship Task Force. PMID- 23651906 TI - Clostridium difficile surveillance: a multicenter comparison of LabID events and use of standard definitions. PMID- 23651907 TI - Hospital flood preparedness and flood-related psychological consequences in 15 provinces in central Thailand after implementation of a national guideline. PMID- 23651908 TI - Engineered drought-induced biosynthesis of alpha-tocopherol alleviates stress induced leaf damage in tobacco. AB - Tocopherols are members of the vitamin E complex and essential antioxidant compounds synthesized in chloroplasts that protect photosynthetic membranes against oxidative damage triggered by most environmental stresses. Tocopherol deficiency has been shown to affect germination, retard growth and change responses to abiotic stress, suggesting that tocopherols may be involved in a number of diverse physiological processes in plants. Instead of seeking constitutive synthesis of tocopherols to improve stress tolerance, we followed an inducible approach of enhancing alpha-tocopherol accumulation under dehydration conditions in tobacco. Two uncharacterized stress inducible promoters isolated from Arabidopsis and the VTE2.1 gene from Solanum chilense were used in this work. VTE2.1 encodes the enzyme homogentisate phytyltransferase (HPT), which catalyzes the prenylation step in tocopherol biosynthesis. Transgenic tobacco plants expressing ScVTE2.1 under the control of stress-inducible promoters showed increased levels of alpha-tocopherol when exposed to drought conditions. The accumulation of alpha-tocopherol correlated with higher water content and increased photosynthetic performance and less oxidative stress damage as evidenced by reduced lipid peroxidation and delayed leaf senescence. Our results indicate that stress-induced expression of VTE2.1 can be used to increase the vitamin E content and to diminish detrimental effects of environmental stress in plants. The stress-inducible promoters introduced in this work may prove valuable to future biotechnological approaches in improving abiotic stress resistance in plants. PMID- 23651909 TI - Diarrheogenic Escherechia coli in potable water sources of West Bengal, India. AB - Diarrheal diseases are a major cause of morbidity and mortality in developing countries. Among the bacterial pathogens, diarrheagenic Escherichia coli are most frequently connected in cases with epidemic and endemic diarrhea worldwide. Environmental surveillance for monitoring of E.coli is very rare. In the present study, we have applied a modified technique to quantify coliform and E. coli in different potable water sources and their subsequent characterization (in relation to diarrheal pathogenicity) in the diarrhea endemic foci of West Bengal. More than one-fifth of the targeted sources (21.4%) have been identified harboring E. coli. Serotyping and molecular analysis reveals multidrug resistant EPEC, EIEC and ETEC among 9% of positive sources. Rainy season seems to be the most conducive period for E. coli induced diarrhea. While non-diarrheogenic E.coli were sensitive to most of the drugs, diarrheogenic E. coli, possessing toxicity, showed resistance against tetracycline, kanamycin, furazolidone, amoxicillin, ampicillin, norfloxacin, ciprofloxacin. Presence of multidrug resistant diarrheogenic E.coli justifies the potentiality of potable water sources as its vehicle and as a potent diarrheal inducer in diarrhea prone area along with increasing concern of drug resistance. Presence of diarrheogenic E. coli stresses the urgent need of its environmental surveillance like diarrheogenic Vibrios. PMID- 23651910 TI - The effect of activity-based financing on hospital length of stay for elderly patients suffering from heart diseases in Norway. AB - BACKGROUND: Whether activity-based financing of hospitals creates incentives to treat more patients and to reduce the length of each hospital stay is an empirical question that needs investigation. This paper examines how the level of the activity-based component in the financing system of Norwegian hospitals influences the average length of hospital stays for elderly patients suffering from ischemic heart diseases. During the study period, the activity-based component changed several times due to political decisions at the national level. METHODS: The repeated cross-section data were extracted from the Norwegian Patient Register in the period from 2000 to 2007, and included patients with angina pectoris, congestive heart failure, and myocardial infarction. Data were analysed with a log-linear regression model at the individual level. RESULTS: The results show a significant, negative association between the level of activity based financing and length of hospital stays for elderly patients who were suffering from ischemic heart diseases. The effect is small, but an increase of 10 percentage points in the activity-based component reduced the average length of each hospital stay by 1.28%. CONCLUSIONS: In a combined financing system such as the one prevailing in Norway, hospitals appear to respond to economic incentives, but the effect of their responses on inpatient cost is relatively meagre. Our results indicate that hospitals still need to discuss guidelines for reducing hospitalisation costs and for increasing hospital activity in terms of number of patients and efficiency. PMID- 23651911 TI - Development of a patient-centered aggregate score to predict survival after lung resection for non-small cell lung cancer. AB - OBJECTIVE: The objective of this analysis was to develop a survival aggregate score (SAS), including objective and subjective patient-based parameters, and assess its prognostic role after major anatomic resection for non-small cell lung cancer. METHODS: A total of 245 patients underwent major lung resections for non small cell lung cancer with preoperative evaluation of quality of life (Short Form 36v2 survey) and complete follow-up. The Cox multivariable regression and bootstrap analyses were used to identify prognostic factors of overall servival, which were weighted to construct the scoring system and summed to generate the SAS. RESULTS: Cox regression analysis showed that the factors negatively associated with overall survival and used to construct the score were 36-item short-form health survey physical component summary score less than 50 (hazard ratio [HR], 1.7; P = .008), aged older than 70 years (HR, 1.9; P = .002), and carbon monoxide lung diffusion capacity less than 70% (HR, 1.7; P = .01). Patients were grouped into 4 risk classes according to their SAS. The 5-year overall survival was 78% in class SAS0, 59% in class SAS1, 42% in class SAS2, and 14% in class SAS3 (log-rank test, P < .0001). SAS maintained its association with overall survival in patients with stages pT1 (log-rank test, P = .01), pT2 (log rank test, P = .02), or pT3-4 (log-rank test, P = .001), and in those with stages pN0 (log-rank test, P = .0005) or pN1-2 (log-rank test, P = .02). The 5-year cancer-specific survival was 83% in class SAS0, 71% in class SAS1, 63% in class SAS2, and 17% in class SAS3 (log-rank test, P < .0001). CONCLUSIONS: This system may be used to refine stratification of prognosis for clinical and research purposes. PMID- 23651912 TI - Optical assessment of silicon nanowire arrays fabricated by metal-assisted chemical etching. AB - Silicon nanowire (SiNW) arrays were prepared on silicon substrates by metal assisted chemical etching and peeled from the substrates, and their optical properties were measured. The absorption coefficient of the SiNW arrays was higher than that for the bulk silicon over the entire region. The absorption coefficient of a SiNW array composed of 10-MUm-long nanowires was much higher than the theoretical absorptance of a 10-MUm-thick flat Si wafer, suggesting that SiNW arrays exhibit strong optical confinement. To reveal the reason for this strong optical confinement demonstrated by SiNW arrays, angular distribution functions of their transmittance were experimentally determined. The results suggest that Mie-related scattering plays a significant role in the strong optical confinement of SiNW arrays. PMID- 23651913 TI - 'Is tinnitus accompanied by hemifacial spasm in normal-hearing patients also a type of hyperactive neurovascular compression syndrome? : A magnetoencephalography study. AB - BACKGROUND: Traditionally, tinnitus accompanied by hemifacial spasm has been considered a type of hyperactive neurovascular compression syndrome that is similar to hemifacial spasm alone because of the anatomically close relationship between the facial nerve and cochlear nerve as well as the hyperactive clinical nature. METHODS: Participants were 29 subjects who presented with hemifacial spasm and neuroradiological evidence of vascular compression of the cranial (facial/cochlear) nerve. We used magnetoencephalography (MEG) to estimate the activity of the cochlear nerve in patients with and without tinnitus on the ipsilateral side. We compared the difference in the latency and the ratio of the equivalent current dipole (ECD) strength between the ipsilateral and contralateral sides of the spasm and tinnitus. RESULTS: Cochlear nerve activity in patients with tinnitus was increased with a shorter latency (p = 0.016) and stronger ECD strength (p = 0.028) compared with patients without tinnitus. CONCLUSION: The MEG results from normal-hearing patients who had tinnitus accompanied by hemifacial spasm suggest that the hyperactivity of the auditory central nervous system may be a crucial pathophysiological factor in the generation of tinnitus in these patients. The neurovascular compression that causes sensory input from the pathologic facial nerve activity may contribute to this hyperactivity of the central auditory nervous system. PMID- 23651914 TI - Treatments for patients with comorbid epilepsy and depression: a systematic literature review. AB - Depression is recognized as a serious comorbidity of epilepsy, but treatment of depression and anxiety in people with epilepsy is challenging. The aim of this article was to review published controlled clinical treatment studies of depression and anxiety in patients with epilepsy. The PubMed, Cochrane and PsycINFO databases were searched for controlled clinical trials, or controlled psychosocial or behavioral trials published in English before June 2012. Search terms were: seizures, epilepsy, depression, psychotherapy, cognitive therapy/treatment, behavioral therapy/treatment and nonpharmacologic therapy/treatment, education and stress management. Seven studies were included in this review. Interventions included antidepressant medications, antiepileptic medications, and cognitive behavioral therapy. Despite the methodological limitations in the studies identified by this review, both medications and psychotherapy improved depression and anxiety in patients with epilepsy. However, further research is needed in the form of randomized controlled clinical trials to establish appropriate pharmacological and psychosocial co-management of depression and epilepsy. PMID- 23651915 TI - Hyperactive behavior in a family with autosomal dominant lateral temporal lobe epilepsy caused by a mutation in the LGI1/epitempin gene. AB - Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is characterized by focal seizures with auditory features or aphasia. Mutations in the leucine-rich glioma-inactivated 1 (LGI1) gene have been reported in up to 50% of families with ADLTE. Attention-deficit/hyperactivity disorder (ADHD) symptoms have not yet been reported in these families. Clinical data were collected from a family with five affected members. Leucine-rich glioma-inactivated 1 exons and boundaries were sequenced by standard methods. Attention-deficit/hyperactivity disorder symptoms were scored based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Affected members had seizures with auditory features and psychic auras, and some experienced nightmares. A heterozygous c.431+1G>A substitution in LGI1 was detected in all members. Significantly more hyperactivity symptoms were found in family members carrying the LGI1 mutation. This study expands the phenotypic spectrum associated with ADLTE due to LGI1 mutation and underlines the need for more systematic evaluation of ADHD and related symptoms. PMID- 23651916 TI - Sodium and nutrition labelling: a qualitative study exploring New Zealand consumers' food purchasing behaviours. AB - OBJECTIVE: Dietary sodium reduction is an important public health intervention that would reduce blood pressure and chronic disease. An understanding of how New Zealand consumers' food purchasing behaviour is influenced by perceptions of dietary sodium will inform future sodium-reduction strategies. DESIGN: The present qualitative study used in-depth interviews of adult consumers to explore consumer knowledge, understanding of food labels and food purchasing behaviour with respect to dietary sodium. SETTING: New Zealand. SUBJECTS: A convenience sample of sixteen adult grocery shoppers. RESULTS: A thematic analysis of the transcripts showed New Zealand consumers lacked the background knowledge necessary to understand and regulate their own salt intake and were unable to interpret existing food labels with respect to dietary salt. CONCLUSIONS: The findings add further weight to calls for food labels that do not require background knowledge or numerical skills and highlight the need for population based public health interventions. Education of New Zealand consumers on the health benefits of sodium reduction and how this may be achieved would complement this approach. PMID- 23651917 TI - Framework for combining REACH and national regulations to obtain equal protection levels of human health and the environment in different countries - comparative study of Denmark and Korea. AB - The aim of this paper is to present a conceptual framework for a systems approach to protect the environment and human health by taking into account differences in the cumulative risks of total human exposure in a territorial context. To this end the measures that are available and that can be included in REACH exposure scenarios in order to obtain territorially relevant chemical safety assessments (CSAs) were explored. The advantage of linking the REACH exposure scenarios with background environmental quality data reported under other national regulations is discussed. The main question is how REACH may be improved to protect the environment and human health inside and outside the EU. This question is exemplified in a comparative case study of two countries, Denmark and Korea, each with its own set of different environmental qualities and national regulations. As a member of the EU Denmark is obliged to adopt REACH, while Korea implemented REACH to improve the competitiveness of Korean industry within the EU market. It is presented how differences in national regulations and environmental qualities in these two countries affect background human exposure concentrations. Choosing lead as a model compound, the territorial differences in background exposure to endocrine and neurological interfering stressors were modelled. It is concluded that the different territorial soil and air lead pollution levels contribute differently to the total childhood lead exposure in the two countries. As such, the probability of the total exposure from air and soil exceeding 10% of the provisional Total Daily Intake (PTDI) is estimated to be 55.3% in Denmark and 8.2% in Korea. The relative contribution from air inhalation and soil ingestion to childhood lead exposure is estimated to be 1-99% in Denmark while it is 83-17% in Korea. PMID- 23651918 TI - Determining optimal conditions to produce activated carbon from barley husks using single or dual optimization. AB - When producing activated carbons from agricultural by-products, certain properties, such as yield and specific surface area, are very important for obtaining an economical and promising adsorbent material. Nevertheless, many researchers have not simultaneously optimized these properties and have obtained different optimal conditions for the production of activated carbon that either increases specific surface area but decreases yield or vice versa. In this research, the production of activated carbon from barley husks (BH) by chemical activation with zinc chloride was optimized by using a 2(3) factorial design with replicates at the central point, followed by a central composite design with two responses (the yield and iodine number) and three factors (the activation temperature, activation time, and impregnation ratio). Both responses were simultaneously optimized by using the desirability functions approach to determine the optimal conditions of this process. The findings reveal that after the simultaneous dual optimization, the maximal response values were obtained at an activation temperature of 436 degrees C, an activation time of 20 min, and an impregnation ratio of 1.1 g ZnCl2/g BH, although the results after the single optimization of each response were quite different. At these conditions, the predicted values for the iodine number and yield were 829.58 +/- 78.30 mg/g and 46.82 +/- 2.64%, respectively, whereas experimental tests produced values of 901.86 mg/g and 48.48%, respectively. Moreover, activated carbons from BH obtained at the optimal conditions primarily developed a porous structure (mesopores > 71% and micropores > 28%), achieving a high surface area (811.44 m(2)/g) that is similar to commercial activated carbons and lignocellulosic-based activated carbons. These results imply that the pore width and surface area are large enough to allow the diffusion and adsorption of pollutants inside the adsorbent particles. In summary, two responses were optimized to determine the optimal conditions for the production of activated carbons because it is possible to increase both the specific surface area and yield. PMID- 23651919 TI - CEACAM1 expression in oligodendrocytes of the developing rat brain shows a spatiotemporal relation to myelination and is altered in a model of encephalopathy of prematurity. AB - CEACAM1 is the founder molecule of the family of 'carcinoembryonic antigen related cell adhesion molecules' and part of the immunoglobulin superfamily. Due to its role as a coreceptor to many other receptors (e.g. Toll-like receptor 2, Toll-like receptor 4, T-cell receptor, B-cell receptor, epidermal growth factor receptor and vascular endothelial growth factor receptor) and its different isoforms, CEACAM1 is a multifunctional protein with an impact on proliferation and differentiation of multiple cell types. Although different modes of action in other tissues are described, the role of CEACAM1 in the developing brain remains elusive. Here we report for the first time that CEACAM1 is expressed ontogenetically in oligodendrocytes of the developing rat brain, and that CEACAM1 expression has a spatiotemporal relation to myelination. In addition, CEACAM1 expression is altered in a model of hyperoxia- and inflammation-induced encephalopathy of prematurity, a myelination disorder of children born preterm. Furthermore, primary oligodendrocytes stimulated with CEACAM1 show increased myelination. Therefore, we postulate that CEACAM1 is, at least in part, involved in hyperoxia- and inflammation-induced disruption of myelination, but may also play a role in intact myelination as it is ontogenetically expressed in myelinating oligodendrocytes. PMID- 23651920 TI - Giving up the keys: how driving cessation affects engagement in later life. AB - PURPOSE: Many older adults consider driving vital to maintaining their preferred lifestyle and engagement with society, yet it is normative for individuals to eventually stop driving. This study examined the impact of driving cessation on older adults' productive and social engagement and whether their mental and physical health mediated this relationship. DESIGN AND METHODS: Multilevel modeling was used to analyze longitudinal data (N = 4,788 adults age 65 and over) from the Health and Retirement Study (1998-2010). RESULTS: Productive engagement (paid work, formal volunteering, and informal volunteering) was negatively affected when older adults stopped driving, but social engagement was not immediately compromised by their transition to nondriver status. The role of physical health and mental health as mediators in explaining this relationship was negligible. IMPLICATIONS: The results suggest that interventions aimed at maintaining nondrivers' participation in productive roles should focus on factors other than enhancement of health and well-being to spur greater engagement (e.g., availability of and barriers to use of public transportation). Also important in the intervention process is planning for mobility transitions. Future research should test for geographic (e.g., urban vs. rural) differences in the impact of driving cessation on productive and social engagement. PMID- 23651921 TI - Investigation of ginkgo biloba leave extracts as corrosion and Oil field microorganism inhibitors. AB - Ginkgo biloba (Ginkgoaceae), originating from China, now distributes all over the world. Wide application of Ginkgo biloba extracts is determined by the main active substances, flavonoids and terpenoids, which indicates its extracts suitable to be used as an effective corrosion inhibitor. The extracts of Ginkgo biloba leave have been investigated on the corrosion inhibition of Q235A steel with weight loss and potentiodynamic polarisation techniques. The inhibition efficiency of the extracts varies with extract concentration. The extracts inhibit corrosion mainly by adsorption mechanism. Potentiodynamic polarisation studies show that extracts are mixed type inhibitors. The antibacterial activity of the extracts against oil field microorganism (SRB, IB and TGB) was also investigated. PMID- 23651922 TI - The extra-cellular signal regulated kinases ERK1 and ERK2 segregate displaying distinct spatiotemporal characteristics in activated mast cells. AB - ERK1 and ERK2 are highly homologous isoforms that often play redundant roles in regulating cellular functions. We analyzed the spatiotemporal patterns of ERK1 and ERK2 in resting and activated mast cells. Strikingly, we identified distinct pathways for these kinases. ERK1 localized to the cytosol and translocated to the nucleus upon cell activation and kinase phosphorylation. In contrast, ERK2 distributed between the cytosol and near the microtubule organizing center (MTOC) in resting cells and accumulated further at a pericentrosomal region upon cell trigger. Pericentrosomal accumulation of ERK2 was phosphorylation independent, required an intact microtubule network and was significantly enhanced by the overexpression of Neuronal Calcium Sensor-1 (NCS-1). We also identified gamma tubulin and phosphatidylinositol 4 kinasebeta (PI4Kbeta), a downstream effector of NCS-1, as novel partner proteins of ERK2. Taken together, our results imply non-redundant functions of ERK1 and ERK2 in mast cells and implicate NCS-1 and PIota4Kappabeta as regulators of ERK2 trafficking. PMID- 23651923 TI - 4F2hc-silencing impairs tumorigenicity of HeLa cells via modulation of galectin-3 and beta-catenin signaling, and MMP-2 expression. AB - 4F2hc is a type-II glycoprotein whose covalent-bound association with one of several described light chains yields a heterodimer mainly involved in large neutral amino acid transport. Likewise, it is well known that the heavy chain interacts with beta-integrins mediating integrin-dependent events such as survival, proliferation, migration and even transformation. 4F2hc is a ubiquitous protein whose overexpression has been related to tumor development and progression. Stable silencing of 4F2hc in HeLa cells using an artificial miRNA impairs in vivo tumorigenicity and leads to an ineffective proliferation response to mitogens. 4F2hc colocalizes with beta1-integrins and CD147, but this interaction does not occur in lipid rafts in HeLa cells. Moreover, silenced cells present defects in integrin- (FAK, Akt and ERK1/2) and hypoxia-dependent signaling, and reduced expression/activity of MMP-2. These alterations seem to be dependent on the inappropriate formation of CD147/4F2hc/beta1-integrin heterocomplexes on the cell surface, arising when CD147 cannot interact with 4F2hc. Although extracellular galectin-3 accumulates due to the decrease in MMP-2 activity, galectin-3 signaling events are blocked due to an impaired interaction with 4F2hc, inducing an increased degradation of beta-catenin. Furthermore, cell motility is compromised after protein silencing, suggesting that 4F2hc is related to tumor invasion by facilitating cell motility. Therefore, here we propose a molecular mechanism by which 4F2hc participates in tumor progression, favoring first steps of epithelial-mesenchymal transition by inhibition of beta-catenin proteasomal degradation through Akt/GSK-3beta signaling and enabling cell motility. PMID- 23651924 TI - Identification of a small molecule targeting annexin A7. AB - Autophagy involves multiple membrane trafficking and fusion events. Annexin A7 (ANXA7) is postulated to play a role in membrane fusion during exocytosis, while the contribution of ANXA7 to autophagy is poorly understood. Our recent studies demonstrated that ABO could promote autophagy via elevation of ANXA7 and triggering ANXA7 subcellular redistribution. However, little is known about the molecular mechanisms how ANXA7 regulates autophagy. As molecular disruption of ANXA7 in mice results in several unwished phenotypes, small molecule modulators may be efficacious in defining the mechanisms of ANXA7 action. However, so far no compounds that selectively target ANXA7 have been identified. So, we hypothesize that ABO might be a potent modulator of ANXA7. We also have detected the colocalization of ANXA7 and microtubule-associated protein 1 light chain 3 (LC3), and ANXA7 was essential for LC3 accumulation in VEC autophagy. As a GTPase, whether ANXA7 affects the phosphorylation of LC3 or other proteins needs further investigation. In this study, we performed site-directed mutagenesis and found that ABO directly bound to Thr(286) of ANXA7 and inhibited its phosphorylation. By yeast two-hybrid screening, we found that ANXA7 could interact with grancalcin (GCA). ABO promoted the interaction and inhibited GCA phosphorylation, leading to the decrease of intracellular Ca(2+) concentration. At the same time, ABO inhibited the phosphorylation of LC3. Hence, by identifying ABO as an unprecedented modulator of ANXA7 as well as GCA and LC3 as interacting proteins of ANXA7, we demonstrated the possible mechanisms how ANXA7 regulates autophagy for the first time. PMID- 23651925 TI - Clinical applications of sequencing take center stage. AB - A report on the Advances in Genome Biology and Technology (AGBT) meeting, Marco Island, Florida, USA, February 20-23, 2013. PMID- 23651927 TI - Emerging alternative model for cardiothoracic surgery training in India. AB - BACKGROUND: In India, cardiothoracic (CT) surgery training follows a 3+3-year model, where 3 years of general surgery residency with certification (MS/DNB) is required for entering 3 years of thoracic surgery residency (MCh/DNB). There are two certifying boards at the national level. One being the Medical Council of India (MCI), which oversees the major accreditation process involving the undergraduate and postgraduate medical education in India, and the other being the National Board of Examinations (NBE), which was formed for the purpose of establishing a uniform standard of postgraduate medical education. Recently, the latter body has come up with an alternative model for thoracic surgery residency in India. This model includes an integrated 6-year residency, with lesser emphasis on general surgical skills and greater exposure to CT surgery. CONCLUSIONS: Changes to the current model of training for CT surgery is the need of the hour and should be initiated very soon by the MCI to meet the future demand for CT surgeons in India. An integrated training program is essential to create a new generation of cardiovascular specialists. Future directions to achieve this goal must include modifications to the undergraduate programs so as to infuse interest for CT surgery in the young minds of medical students. PMID- 23651926 TI - Identification of comorbidities that place men at highest risk of death from androgen deprivation therapy before brachytherapy for prostate cancer. AB - PURPOSE: To determine which specific comorbidities predispose men to excess mortality by androgen deprivation therapy (ADT) given before and during brachytherapy for prostate cancer. METHODS AND MATERIALS: We analyzed 5972 men with T1c-T3b prostate cancer treated with brachytherapy-based radiation with or without neoadjuvant ADT. Cox multivariable analysis with propensity scoring was used to determine if ADT was associated with increased all-cause mortality (ACM) in men divided into groups stratified by cardiac comorbidities. Tests for interaction between risk group and outcome were performed. RESULTS: ADT was associated with increased ACM in men with a history of myocardial infarction or congestive heart failure, regardless of whether they underwent revascularization (adjusted hazard ratio [AHR], 2.1 [95% confidence interval {CI}, 1.02-4.17; p=0.04]) or not (AHR, 1.8 [95% CI, 1.05-3.20; p = 0.03]), but this effect was not seen in men with less severe comorbidity. However, among men with diabetes, there was a significant interaction with risk group (p=0.01) such that ADT was associated with excess mortality in men with low-risk disease (AHR = 2.21 [1.04 4.68]; p=0.04) but not in men with intermediate or high-risk disease (AHR, 0.64 [0.33-1.22]; p=0.17). CONCLUSIONS: ADT was associated with excess ACM in all patients with a history of congestive heart failure or myocardial infarction, regardless of whether they were revascularized, and in diabetics with low-risk disease. ADT for gland downsizing before brachytherapy should be avoided in these men. PMID- 23651928 TI - Branchial O(2) chemoreceptors in Nile tilapia Oreochromis niloticus: Control of cardiorespiratory function in response to hypoxia. AB - This study examined the distribution and orientation of gill O(2) chemoreceptors in Oreochromis niloticus and their role in cardiorespiratory responses to graded hypoxia. Intact fish, and a group with the first gill arch excised (operated), were submitted to graded hypoxia and their cardiorespiratory responses (oxygen uptake - VO(2) , breathing frequency - fR, ventilatory stroke volume - VT, gill ventilation - VG, O(2) extraction from the ventilatory current - EO(2) , and heart rate - fH) were compared. Their responses to bolus injections of NaCN into the bloodstream (internal) or ventilatory water stream (external) were also determined. The VO(2) of operated fish was significantly lower at the deepest levels of hypoxia. Neither reflex bradycardia nor ventilatory responses were completely abolished by bilateral excision of the first gill arch. EO(2) of the operated group was consistently lower than the intact group. The responses to internal and external NaCN included transient decreases in fH and increases in fR and Vamp (ventilation amplitude). These cardiorespiratory responses were attenuated but not abolished in the operated group, indicating that chemoreceptors are not restricted to the first gill arch, and are sensitive to oxygen levels in both blood and water. PMID- 23651929 TI - Protein tyrosine phosphatase encoded in Cotesia plutellae bracovirus suppresses a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella. AB - Parasitization by an endoparasitoid wasp, Cotesia plutellae, inhibits a larva-to pupa metamorphosis of the diamondback moth, Plutella xylostella. This study tested an inhibitory effect of C. plutellae bracovirus (CpBV) on the metamorphosis of P. xylostella. Parasitized P. xylostella exhibited significantly reduced prothoracic gland (PTG) development at the last instar compared to nonparasitized larvae. Expression of the ecdysone receptor (EcR) was markedly suppressed during the last instar larvae parasitized by C. plutellae. By contrast, expression of the insulin receptor (InR) significantly increased in the parasitized larvae. Microinjection of CpBV significantly inhibited the larva-to pupa metamorphosis of nonparasitized larvae in a dose-dependent manner. Injection of CpBV also inhibited the expression of the EcR and increased the expression of the InR. Individual CpBV segments were transiently expressed in its encoded genes in nonparasitized larvae and screened to determine antimetamorphic viral gene(s). Out of 21 CpBV segments, two viral segments (CpBV-S22 and CpBV-S27) were proved to inhibit larva-to-pupa metamorphosis by transient expression assay. RNA interference of each gene encoded in the viral segments was applied to determine antimetamorphic gene(s). Protein tyrosine phosphatase, early expressed gene, and four hypothetical genes were selected to be associated with the antimetamorphic activity of CpBV. These results suggest that antimetamorphosis of P. xylostella parasitized by C. plutellae is induced by inhibiting PTG development and subsequent ecdysteroid signaling with viral factors of CpBV. PMID- 23651931 TI - Identification of amphiphysin 1 as an endogenous substrate for CDKL5, a protein kinase associated with X-linked neurodevelopmental disorder. AB - Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase predominantly expressed in brain and mutations of its gene are known to be associated with neurodevelopmental disorders such as X-linked West syndrome and Rett syndrome. However, the physiological substrates of CDKL5 that are directly linked to these neurodevelopmental disorders are currently unknown. In this study, we explored endogenous substrates for CDKL5 in mouse brain extracts fractionated by a liquid phase isoelectric focusing. In conjunction with CDKL5 phosphorylation assay, this approach detected a protein band with an apparent molecular mass of 120kDa that is remarkably phosphorylated by CDKL5. This 120-kDa protein was identified as amphiphysin 1 (Amph1) by LC-MS/MS analysis, and the site of phosphorylation by CDKL5 was determined to be Ser-293. The phosphorylation mimic mutants, Amph1(S293E) and Amph1(S293D), showed significantly reduced affinity for endophilin, a protein involved in synaptic vesicle endocytosis. Introduction of point mutations in the catalytic domain of CDKL5, which are disease-causing missense mutations found in Rett patients, resulted in the impairment of kinase activity toward Amph1. These results suggest that Amph1 is the cytoplasmic substrate for CDKL5 and that its phosphorylation may play crucial roles in the neuronal development. PMID- 23651932 TI - The paradox of teaching responsible conduct of research. PMID- 23651930 TI - Impact of post-challenge hyperglycemia on clinical outcomes in Japanese patients with stable angina undergoing percutaneous coronary intervention. AB - BACKGROUND: Post-challenge hyperglycemia (PH) is well-established as one of risk factors for coronary artery disease. However, it remains unclear whether PH affects clinical outcomes in patients with stable angina undergoing percutaneous coronary intervention (PCI). METHODS: A total of 828 patients with stable angina undergoing PCI were retrospectively analyzed. Of these, 452 patients with previously diagnosed diabetes mellitus (DM) or fasting plasma glucose (PG) >=126 mg/dl and HbA1c >=6.5% were defined as known DM. The remaining 376 patients were divided into the two groups according to 2-h PG: PH (2-h PG >=140 mg/dl, n=236) and normal glucose tolerance (NGT, 2-h PG <140 mg/dl, n=140). We assessed the rate of major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, myocardial infarction, stroke, and clinically-driven revascularization. RESULTS: During the median follow-up of 4.3 years, the MACE rate was significantly higher in the DM and PH groups than the NGT group (39.3% vs. 20.7%, P <0.001; 31.4% vs. 20.7%, P=0.044, respectively). Compared with the NGT group, the cumulative incidence of revascularization was significantly higher in the DM group (35.1% vs. 18.5%, P <0.001) and tended to be higher in the PH group (27.1% vs. 18.5%, P=0.067). In the multivariate analysis, known DM (Hazard ratio [HR]: 2.16, 95% confidence interval (CI): 1.49-3.27, P < 0.001), PH (HR: 1.62, 95% CI: 1.07-2.53, P = 0.023), LDL-C >100 mg/dl (HR: 1.62, 95% CI: 1.26 to 2.10, P < 0.001), and previous stroke (HR: 1.47, 95% CI: 1.03-2.04, P = 0.034) were predictors of MACE. CONCLUSION: PH is associated with future cardiovascular events in patients with stable angina undergoing PCI. PMID- 23651933 TI - Reported goals of instructors of responsible conduct of research for teaching of skills. AB - The National Institutes of Health (NIH) training grant requirement to provide training in the responsible conduct of research (RCR) is now more than 20 years old. Implicit in the requirement is that this training will have an impact not only on what trainees know, but on what they know how to do. There is, however, a range of responses about what skills are seen to be necessary for the ethical practice of science. As part of a larger, earlier study examining RCR instructors' overall goals in teaching RCR, we asked 50 RCR instructors from 37 different institutions what their goals were for teaching skills in their RCR courses. The responses about what constituted necessary skills were wide ranging, from a focus on teaching the skill of ethical decision making to the perceived importance of ensuring that trainees understand the importance of the community in some research relationships. This diversity in responses about what skills should be taught in RCR courses is not especially surprising, given the variation in instructors, formats, instruction, goals, and outcome measures for RCR courses, but it does reinforce the necessity of giving more thought to what goals are to be achieved. This is true not only of skills to be learned, but of any other objectives one might have for research ethics teaching and learning. PMID- 23651934 TI - The social and policy contexts of the New Brunswick Declaration on Research Ethics, Integrity, and Governance: a commentary. AB - This paper explores the social and policy implications of the "New Brunswick Declaration on Research Ethics, Integrity, and Governance" developed at the Ethics Rupture Summit in Fredericton, N.B., Canada, October 2012. It discusses the Declaration and the Summit in relation to the usual criticism and analysis of research ethics regimes, and considers reasons why the immense prior literature has had little impact on regulatory bodies. Because the Declaration, like the Illinois White Paper, has quickly achieved considerable attention relative to most other such documents, and because much further deliberation has evolved since the Summit, we offer here a commentary on each of the eight principles contained in the Declaration in the hope of further stimulating discussion and consolidating the progress that now seems underway. PMID- 23651935 TI - Ethical challenges and lessons learned from Inuulluataarneq - "Having the Good Life" study: a community-based participatory research project in Greenland. AB - We present the ethical challenges and lessons learned over the course of a four year community-based participatory research (CBPR) project conducted on sexually transmitted infections (STIs) in Greenland. Specifically discussed is Inuulluataarneq-the "Having the Good Life" study. Inuulluataarneq is an interdisciplinary international, collaborative CBPR study involving the University of Toronto in Canada, the Greenlandic Medical Research Council, the Centre for Primary Care in Nuuk, the University of Greenland, local health partners and communities in Greenland, the Statens Serum Institut in Denmark, and Montana State University in the United States. Inuulluataarneq is the first CBPR project implemented in Greenland. Ethical issues discussed are: (1) the complexity of working with multiple institutional review boards on an international health research project using a CBPR framework; (2) unexpected influences on health policy; and (3) the dynamic of balancing community decision making and practices with academic research requirements and expectations. Inuulluataarneq's primary contribution to understanding ethical issues when conducting research in the Arctic involves an acceptance of the time, patience, and dedication of researchers and community partners it takes to discuss, understand, and process differing ethical viewpoints and procedures. PMID- 23651936 TI - Developing a family-based HIV prevention intervention in rural Kenya: challenges in conducting community-based participatory research. AB - Community-Based Participatory research (CBPR) introduces new ethical challenges for HIV prevention studies in low-resource international settings. We describe a CBPR study in rural Kenya to develop and pilot a family-based HIV prevention and mental health promotion intervention. Academic partners (APs) worked with a community advisory committee (CAC) during formative research, intervention development, and a pilot trial. Ethical challenges emerged related to: negotiating power imbalances between APs and the CAC; CAC members' shifting roles as part of the CAC and wider community; and anticipated challenges in decision making about sustainability. Factors contributing to ethical dilemmas included low access to education, scarcity of financial resources, and the shortage of HIV related services despite high prevalence. PMID- 23651937 TI - Community-based participatory research (CBPR) with indigenous communities: producing respectful and reciprocal research. AB - The health disparities between Indigenous and non-Indigenous peoples in Canada continue to grow despite an expanding body of research that attempts to address these inequalities, including increased attention from the field of health geography. Here, we draw upon a case study of our own community-based approach to health research with Anishinabe communities in northern Ontario as a means of advocating the growth of such participatory approaches. Using our own case as an example, we demonstrate how a collaborative approach to respectful and reciprocal research can be achieved, including some of the challenges we faced in adopting this approach. PMID- 23651938 TI - Peer research assistantships and the ethics of reciprocity in community-based research. AB - A major component of community-based research (CBR) in the field of HIV is the Meaningful Involvement of People Living with HIV/AIDS (MIPA) through hiring, training, and supporting peer research assistants (PRAs). CBR researchers and PRAs have begun to dialogue about the successes and challenges associated with peer research assistantships as they attempt to address the range of ethical issues that impact the PRAs' experience at different stages throughout the research process. I discuss some of the ethical tensions related to the PRA/researcher relationship, the relationship of the PRA to the research itself, and suggestions for how to move forward in addressing these tensions. PMID- 23651939 TI - Assessing the quality of VA Human Research Protection Programs: VA vs. affiliated University Institutional Review Board. AB - We compared the Human Research Protection Program (HRPP) quality indicator data of the Department of Veterans Affairs (VA) facilities using their own VA institutional review boards (IRBs) with those using affiliated university IRBs. From a total of 25 performance metrics, 13 did not demonstrate statistically significant differences, while 12 reached statistically significance differences. Among the 12 with statistically significant differences, facilities using their own VA IRBs performed better on four of the metrics, while facilities using affiliate IRBs performed better on eight. However, the absolute difference was small (0.2-2.7%) in all instances, suggesting that they were of no practical significance. We conclude that it is acceptable for facilities to use their own VA IRBs or affiliated university IRBs as their IRBs of record. PMID- 23651941 TI - PhD students' awareness of research misconduct. PMID- 23651942 TI - Enhanced characteristics of genetically modified switchgrass (Panicum virgatum L.) for high biofuel production. AB - BACKGROUND: Lignocellulosic biomass is one of the most promising renewable and clean energy resources to reduce greenhouse gas emissions and dependence on fossil fuels. However, the resistance to accessibility of sugars embedded in plant cell walls (so-called recalcitrance) is a major barrier to economically viable cellulosic ethanol production. A recent report from the US National Academy of Sciences indicated that, "absent technological breakthroughs", it was unlikely that the US would meet the congressionally mandated renewable fuel standard of 35 billion gallons of ethanol-equivalent biofuels plus 1 billion gallons of biodiesel by 2022. We here describe the properties of switchgrass (Panicum virgatum) biomass that has been genetically engineered to increase the cellulosic ethanol yield by more than 2-fold. RESULTS: We have increased the cellulosic ethanol yield from switchgrass by 2.6-fold through overexpression of the transcription factor PvMYB4. This strategy reduces carbon deposition into lignin and phenolic fermentation inhibitors while maintaining the availability of potentially fermentable soluble sugars and pectic polysaccharides. Detailed biomass characterization analyses revealed that the levels and nature of phenolic acids embedded in the cell-wall, the lignin content and polymer size, lignin internal linkage levels, linkages between lignin and xylans/pectins, and levels of wall-bound fucose are all altered in PvMYB4-OX lines. Genetically engineered PvMYB4-OX switchgrass therefore provides a novel system for further understanding cell wall recalcitrance. CONCLUSIONS: Our results have demonstrated that overexpression of PvMYB4, a general transcriptional repressor of the phenylpropanoid/lignin biosynthesis pathway, can lead to very high yield ethanol production through dramatic reduction of recalcitrance. MYB4-OX switchgrass is an excellent model system for understanding recalcitrance, and provides new germplasm for developing switchgrass cultivars as biomass feedstocks for biofuel production. PMID- 23651943 TI - From soil to leaves--aluminum fractionation by single step extraction procedures in polluted and protected areas. AB - The paper presents the fractionation of aluminum in the samples of soil and plants of different species using a selective single-step extraction method. The study was conducted in the area located near a chemical plant, which for many years served as a post-crystallization leachate disposal site storing chemical waste (sector I), and in the area around the site: in Wielkopolski National Park, Rogalin Landscape Park and toward the infiltration ponds at the "Debina" groundwater well-field for the city of Poznan (Poland) (sector II). The results of aluminum fractionation in samples of soil, leaves and plants showed heavy pollution with aluminum, especially in the water soluble aluminum fraction - Alsw (maximum concentration of aluminum in soil extract was 234.8 +/- 4.8 mg kg(-1), in the leaves of Betula pendula it was 107.4 +/- 1.8 mg kg(-1) and in the plants of Artemisia vulgaris (root) and Medicago sativa (leaves) it amounted to 464.7 +/ 10.7 mg kg(-1)and 146.8 +/- 1.2 mg kg(-1) respectively). In addition, the paper presents the problem of organic aluminum fractionation in biological samples and it shows the relationship between aluminum concentration in soil and the analysed woody and herbaceous species. PMID- 23651944 TI - Another family with a euchromatic duplication variant of 9q13-q21.1 derived from segmentally duplicated pericentromeric euchromatin. AB - Microscopically visible copy number variations within the proximal short arm heterochromatin and proximal long arm of chromosome 9 have been described as euchromatic variants (EVs) and are derived from extensive segmental duplications (SDs) that map to both the proximal short and long arms of chromosome 9. Recently, 3-4 additional copies of an SD cassette were found in 2 families with duplication EVs of 9q13-q21. Here, we report a third family with a duplication EV of 9q13-q21.1 that was ascertained at prenatal diagnosis for advanced maternal age and found in the fetus and her phenotypically normal mother. Dual-colour fluorescence in situ hybridization with bacterial artificial chromosomes RP11 246P17 and RP11-211E19 was consistent with the EV chromosome having 1-2 additional copies of a similar SD cassette, except that the SD-boundary clone RP11-88I18 was not apparently included. It is important to distinguish the 9q13 q21.1 EVs from possible pathogenic imbalances of chromosome 9, especially at prenatal diagnosis, as these EVs have no established phenotypic or reproductive consequences. The nature of the G-dark bands in 9q13-q21 EVs is briefly discussed. PMID- 23651945 TI - Single-domain amnestic mild cognitive impairment identified by cluster analysis predicts Alzheimer's disease in the european prospective DESCRIPA study. AB - BACKGROUND/AIMS: To identify prodromal Alzheimer's disease (AD) subjects using a data-driven approach to determine cognitive profiles in mild cognitive impairment (MCI). METHODS: A total of 881 MCI subjects were recruited from 20 memory clinics and followed for up to 5 years. Outcome measures included cognitive variables, conversion to AD, and biomarkers (e.g. CSF, and MRI markers). Two hierarchical cluster analyses (HCA) were performed to identify clusters of subjects with distinct cognitive profiles. The first HCA included all subjects with complete cognitive data, whereas the second one selected subjects with very mild MCI (MMSE >=28). ANOVAs and ANCOVAs were computed to examine whether the clusters differed with regard to conversion to AD, and to AD-specific biomarkers. RESULTS: The HCAs identified 4-cluster solutions that best reflected the sample structure. One cluster (aMCIsingle) had a significantly higher conversion rate (19%), compared to subjective cognitive impairment (SCI, p < 0.0001), and non-amnestic MCI (naMCI, p = 0.012). This cluster was the only one showing a significantly different biomarker profile (Abeta42, t-tau, APOE epsilon4, and medial temporal atrophy), compared to SCI or naMCI. CONCLUSION: In subjects with mild MCI, the single-domain amnestic MCI profile was associated with the highest risk of conversion, even if memory impairment did not necessarily cross specific cut-off points. A cognitive profile characterized by isolated memory deficits may be sufficient to warrant applying prevention strategies in MCI, whether or not memory performance lies below specific z-scores. This is supported by our preliminary biomarker analyses. However, further analyses with bigger samples are needed to corroborate these findings. PMID- 23651946 TI - 89Zr-bevacizumab PET imaging in primary breast cancer. AB - Vascular endothelial growth factor (VEGF)-A is overexpressed in most malignant and premalignant breast lesions. VEGF-A can be visualized noninvasively with PET imaging and using the tracer (89)Zr-labeled bevacizumab. In this clinical feasibility study, we assessed whether VEGF-A in primary breast cancer can be visualized by (89)Zr-bevacizumab PET. METHODS: Before surgery, breast cancer patients underwent a PET/CT scan of the breasts and axillary regions 4 d after intravenous administration of 37 MBq of (89)Zr-bevacizumab per 5 mg. PET images were compared with standard imaging modalities. (89)Zr-bevacizumab uptake was quantified as the maximum standardized uptake value (SUV max). VEGF-A levels in tumor and normal breast tissues were assessed with enzyme-linked immunosorbent assay. Data are presented as mean +/- SD. RESULTS: Twenty-five of 26 breast tumors (mean size +/- SD, 25.1 +/- 19.8 mm; range, 4-80 mm) in 23 patients were visualized. SUV max was higher in tumors (1.85 +/- 1.22; range, 0.52-5.64) than in normal breasts (0.59 +/- 0.37; range, 0.27-1.69; P < 0.001). The only tumor not detected on PET was 10 mm in diameter. Lymph node metastases were present in 10 axillary regions; 4 could be detected with PET (SUV max, 2.66 +/- 2.03; range, 1.32-5.68). VEGF-A levels in the 17 assessable tumors were higher than in normal breast tissue in all cases (VEGF-A/mg protein, 184 +/- 169 pg vs. 10 +/- 21 pg; P = 0.001), whereas (89)Zr-bevacizumab tumor uptake correlated with VEGF-A tumor levels (r = 0.49). CONCLUSION: VEGF-A in primary breast cancer can be visualized by means of (89)Zr-bevacizumab PET. PMID- 23651948 TI - Transcriptomic analysis of clonal growth rate variation during CHO cell line development. AB - The selection of clones displaying a high rate of cell growth is an essential component of Chinese hamster ovary (CHO) cell line development. In recent years various "omics" technologies have been utilised to understand the mechanisms underlying bioprocess phenotypes. In this study, gene expression analysis using a CHO-specific microarray was conducted for a panel of CHO-K1 MAb-secreting cell lines spanning a range of growth rates that were derived from a single cell line development project. In-silico functional analysis of the resulting transcriptomic data revealed the overrepresentation of biological processes such as cell cycle and translation within those genes upregulated during fast growth, while genes associated with cellular homeostasis were downregulated. Using differential expression and correlation analysis we identified a high priority group of 416 transcripts (190 upregulated; 226 downregulated) associated with growth rate. Expression changes of eight of these genes were independently confirmed by qPCR. Finally, we demonstrate the enrichment of predicted mRNA targets of miR17-92, a microRNA (miRNA) cluster known to be upregulated during rapid proliferation, within downregulated transcripts. PMID- 23651947 TI - VPAC1 receptors for imaging breast cancer: a feasibility study. AB - VPAC1 encodes G-protein-coupled receptors expressed on all breast cancer (BC) cells at the onset of the disease, but not on benign lesions. Our extensive preclinical studies have shown that (64)Cu-TP3805 has a high affinity for VPAC1, is stable in vivo, and has the ability to distinguish spontaneously grown malignant BC masses from benign lesions. Our long-term goal is to develop (64)Cu TP3805 as an agent to perform in vivo histology, to distinguish malignant lesions from benign masses noninvasively and thereby avoid patient morbidity and the excess economic costs of benign biopsies. METHODS: (18)F-FDG obtained commercially served as a control. (64)Cu-TP3805 was prepared using a sterile kit containing 20 MUg of TP3805. Radiochemical purity and sterility were examined. Nineteen consenting women with histologically proven BC were given 370 MBq of (18)F-FDG. One hour later, 6 of these patients were imaged with PET/CT and 13 with positron emission mammography (PEM). Two to 7 d later, 6 PET/CT patients received 111 MBq (+/- 10%) (n = 2), 127 MBq (+/- 10%) (n = 2), or 148 MBq (+/- 10%) (n = 2) of (64)Cu-TP3805 and were imaged 2 and 4 h later. Thirteen PEM patients received 148 MBq (+/- 10%) of (64)Cu-TP3805 and were imaged 15 min, 1 h, 2 h, and 4 h later. Standardized uptake value (SUV) was calculated for PET/CT patients, and PUV/BGV (PEM uptake value/background value) was calculated for PEM patients. Tumor volume was also calculated. RESULTS: The radiochemical purity of (64)Cu-TP3805 was 97% +/- 2%, and specific activity was 44.4 GBq (1.2 Ci)/MUmol. In 19 patients, a total of 24 lesions were imaged (15 invasive ductal carcinoma, 1 high-grade mammary carcinoma, 3 lobular carcinoma, 1 invasive papilloma, and 4 sentinel lymph nodes). All lesions were unequivocally detected by (64)Cu-TP3805 and by (18)F-FDG. The average tumor volume as determined by PET/CT with (64)Cu TP3805 was 90.6% +/- 16.1% of that with (18)F-FDG PET/CT, and the average SUV was 92% +/- 26.4% of that with (18)F-FDG. For PEM, the tumor volume with (64)Cu TP3805 was 113% +/- 37% of that with (18)F-FDG and the PUV/BGV ratio was 97.7% +/ 24.5% of that with (18)F-FDG. CONCLUSION: (64)Cu-TP3805 is worthy of further investigation in patients requiring biopsy of suggestive imaging findings, to further evaluate its ability to distinguish malignant lesions from benign masses noninvasively. PMID- 23651949 TI - Engineering Clostridium acetobutylicum for alcohol production. AB - While Clostridium acetobutylicum has been used for large-scale butanol production (ABE fermentation), its by-product acetone cannot be used as a biofuel. In this study, C. acetobutylicum was engineered for alcohol titers (butanol plus ethanol). The adc gene was inactivated to eliminate acetone production, and glutathione biosynthetic capability was introduced into C. acetobutylicum to improve the strain's robustness by expressing Escherichia coli's gshAB genes in the adc locus. Acetone production was reduced from 2.64+/-0.22 g/L to 0.15+/-0.08 g/L in the engineered strain 824adc::gsh, whereas butanol production was increased from 5.17+/-0.26 g/L to 8.27+/-0.27 g/L. To further improve the alcohol titers, the metabolic flux in the alcohol biosynthesis pathways was enhanced. Overlapping PCR was used to generate expression cassette EC, which expresses the hbd, thl, crt, and bcd genes, and the Sol operon was amplified to express the adhE and ctfAB genes. Butanol and alcohol production reached 14.86+/-0.26 g/L and 18.11+/-0.66 g/L, respectively, in 824adc::gsh Sol-EC. Furthermore, the butanol and alcohol yields were 0.336 g/g and 0.409 g/g, respectively, in 824adc::gsh Sol EC. This study provided a combined strategy for enhancing alcohol production in C. acetobutylicum. PMID- 23651950 TI - Application of polyhydroxyalkanoate (PHA) synthesis regulatory protein PhaR as a bio-surfactant and bactericidal agent. AB - Polyhydroxyalkanoates (PHA), a family of diverse bio-polyesters, are produced by many bacteria as an energy and carbon storage material. PHA synthesis regulatory protein PhaR was reported to attach on the surface of intracellular PHA granules for convenience of synthesis regulation. PhaR was found to have an amphiphilic property. However, no study was conducted to exploit this property for applications as bio-surfactant and bactericide agent. Purified PhaR showed a higher emulsification ability than that of the widely used chemical surfactants including SDS, Tween 20, sodium oleate, and liquefied detergent (LD). PhaR also showed a higher emulsification ability than bio-surfactants rhamnose and PHA granules associated protein termed phasin or PhaP. Non-purified PhaR, namely, the native inclusion bodies and cell lysates, also demonstrated to be an excellent surfactant. PhaR was found highly stable even at 95 degrees C. In addition, PhaR was revealed to be a promising bactericidal agent against Gram positive and negative bacteria. PhaR can be conveniently produced by recombinant Escherichia coli. It has shown to be a bio-surfactant with excellent emulsification ability and strong bactericidal capacity at elevated temperature as high as 95 degrees C. Therefore, PhaR could be used in areas including food, beverage, pharmaceutical and cosmetics industries. PMID- 23651951 TI - Heart failure management and the war between evidence-based guidelines and common sense. PMID- 23651952 TI - Is frequency of family meals associated with parental encouragement of healthy eating among ethnically diverse eighth graders? AB - OBJECTIVE: The purpose of the present study was to explore the relationship between family meals and parental encouragement of healthy eating overall and by ethnicity. DESIGN: Family meal frequency was measured with one item asking how many times in the past 7 d all or most of the family ate a meal together, which was then categorized to represent three levels of family meals (<=2 times, 3-6 times and >=7 times). Parental encouragement of healthy eating assessed how often parents encouraged the student to eat fruits and vegetables, drink water, eat wholegrain bread, eat breakfast and drink low-fat milk (never to always). An overall scale of parental encouragement of healthy eating was created. Mixed effect regression analyses were run controlling for gender, ethnicity, age and socio-economic status. Moderation by ethnicity was explored. SETTING: Middle schools. SUBJECTS: Participants included 2895 US eighth grade students participating in the Central Texas CATCH (Coordinated Approach To Child Health) Middle School Project (mean age 13.9 years; 24.5 % White, 52.7 % Hispanic, 13.0 % African-American, 9.8 % Other; 51.6 % female). RESULTS: Eating more family meals was significantly associated with having parents who encouraged healthy eating behaviours (P for trend <0.001). The number of family meals was positively associated with encouragement of each of the healthy eating behaviours (P for trend <0.0001). There were no differences in the relationships by ethnicity of the students. CONCLUSIONS: Families who eat together are more likely to encourage healthy eating in general. Interventions which promote family meals may include tips for parents to increase discussions about healthy eating. PMID- 23651953 TI - Rapid improvement of hepatic steatosis after initiation of leptin substitution in a leptin-deficient girl. AB - BACKGROUND: Leptin deficiency is associated with severe obesity and metabolic disturbances. Increased liver fat content has been reported in only one case beforehand, even though hepatic steatosis is a typical comorbidity of common obesity. It is also frequent in patients with lipodystrophy where it resolves under leptin therapy. SUBJECT AND METHODS: In 2010, we reported a leptin deficient patient with a novel homozygous mutation in the leptin gene and severe hepatic steatosis. We have now studied serum changes and changes in liver fat content during the substitution with recombinant methionyl human leptin. RESULTS: After 23 weeks of leptin substitution, elevated transaminases, total cholesterol and low-density lipoprotein levels normalized. After 62 weeks, homeostasis model assessment of insulin resistance improved from 10.7 to 6.0 and body fat mass dropped from 50.2 to 37.8%. Liver fat content was drastically reduced from 49.7 to 9.4%. The first changes in liver fat content were detectable after 3 days of therapy. CONCLUSION: Our patient showed a remarkable reduction of liver fat content during the treatment with recombinant methionyl human leptin. These changes occurred rapidly after initiation of the substitution, which implies that leptin has a direct effect on hepatic lipid metabolism in humans as it is seen in rodents. PMID- 23651954 TI - Additional data on Helicobacter pylori and hepatitis C virus infections and lymphoma association. PMID- 23651956 TI - Molecular understanding of curcumin in diabetic nephropathy. AB - Diabetic nephropathy is characterized by a plethora of signaling abnormalities. Recent trials have suggested that intensive glucose-lowering treatment leads to hypoglycemic events, which can be dangerous. Curcumin is the active ingredient of turmeric, which has been widely used in many countries for centuries to treat numerous diseases. The preventive and therapeutic properties of curcumin are associated with its antioxidant and anti-inflammatory properties. Here, we highlight the renoprotective role of curcumin in diabetes mellitus (DM) with an emphasis on the molecular basis of this effect. We also briefly discuss the numerous approaches that have been undertaken to improve the pharmacokinetics of curcumin. PMID- 23651957 TI - The future of genomic medicine is here. AB - A report on the 6th annual Future of Genomic Medicine conference, held at the Scripps Seaside Forum, La Jolla, CA, USA, March 7-8, 2013. PMID- 23651955 TI - Mobile genetic elements of the human gastrointestinal tract: potential for spread of antibiotic resistance genes. AB - The human intestine is an important location for horizontal gene transfer (HGT) due to the presence of a densely populated community of microorganisms which are essential to the health of the human superorganism. HGT in this niche has the potential to influence the evolution of members of this microbial community and to mediate the spread of antibiotic resistance genes from commensal organisms to potential pathogens. Recent culture-independent techniques and metagenomic studies have provided an insight into the distribution of mobile genetic elements (MGEs) and the extent of HGT in the human gastrointestinal tract. In this mini review, we explore the current knowledge of mobile genetic elements in the gastrointestinal tract, the progress of research into the distribution of antibiotic resistance genes in the gut and the potential role of MGEs in the spread of antibiotic resistance. In the face of reduced treatment options for many clinical infections, understanding environmental and commensal antibiotic resistance and spread is critical to the future development of meaningful and long lasting anti-microbial therapies. PMID- 23651958 TI - [Medical humanities and scientific development]. PMID- 23651959 TI - [The effect of catheter based renal synthetic denervation on renin-angiotensin aldosterone system in patients with resistant hypertension]. AB - OBJECTIVE: to explore the effect of catheter based renal synthetic denervation on renin-angiotensin-aldosterone system (RAAS) and blood pressure reduction in patients with resistant hypertension. and assess the validity and security of the treatment. METHODS: Ten patients with resistant hypertension from June 2011 to December 2011 were retrospectively reviewed, and then all of 10 patients screened for eligibility were allocated to renal denervation. Primary endpoints were changes of office blood pressure at 1 week, 1, 3 and 6 months after procedure. We assessed the effectiveness of renal sympathetic denervation with heart rate (HR), renin activity (PRA), angiotensin II (AngII), aldosterone (Ald), and creatinine (Cr) before and 2 weeks after procedure. RESULTS: Office blood pressure after catheter-based renal denervation decreased by 22.8/9.1 mm Hg (1 mm Hg = 0.133 kPa), 34.8/14.7 mm Hg, 42.6/20.7 mm Hg, 43.2/21.6 mm Hg, at 1 week, 1, 3 and 6 months, respectively (P < 0.001). Meanwhile, the level of PRA, AngII, Ald decreased by (1.11 +/- 0.89) ng*ml(-1)*h(-1) (P = 0.003), (17.06 +/- 13.82) ng/L (P = 0.004), (404.5 +/- 285.8) ng/L (P = 0.002), respectively; and heart rate decreased by 5.1 bpm (P = 0.002). However, the Cr level and eGFR did not change significantly (P > 0.05). CONCLUSION: Catheter-based renal sympathetic denervation can reduce the level of renin activity, angiotensin II and aldosterone, and causes substantial and sustained blood-pressure reduction. PMID- 23651960 TI - [KCNQ1 mutation in patients with lone atrial fibrillation]. AB - OBJECTIVE: Recent studies suggest that mutation of the slow delayed rectifier potassium channel [I(Ks)] contributes to familial atrial fibrillation (FAF). In the current study, we explored the potential association between KCNQ1 polymorphism with lone AF (LAF). METHODS: Clinical data and blood samples were collected from 95 Han Chinese patients with LAF and matched healthy controls. Variants of the KCNQ1 gene were identified using single-strand conformational polymorphism (SSCP) analysis. A case-control association study in KCNQ1 identified four known single-nucleotide polymorphisms (SNPs) during SSCP screening of the 95 LAF patients and 190 healthy controls. RESULTS: Three new variations were identified in KCNQ1 from 95 sporadic LAF including 1 in 5'UTR(c. 22T > C), 1 in exon9 synonymous mutation (c.1008C > T) and 1 in intron region (c.1590 + 31A > T). These variations were heterozygous and not presented in 190 healthy controls. Highly significant difference was detected between LAF group and control groups in rs760419 polymorphism. Logistic regression revealed that rs760419 was independent risk factor for LAF(OR = 2.056, P = 0.001). CONCLUSIONS: KCNQ1 mutation is associated with LAF and rs760419 polymorphism is a susceptible marker for LAF. PMID- 23651961 TI - [Preferential conduction to right ventricular outflow track leads to left bundle branch block morphology in patient with premature ventricular contraction originating from the aortic sinus cusp]. AB - OBJECTIVE: The purpose of this study was to explore the relationship between originate and breakout and radiofrequency catheter ablation strategy in patients undergoing radiofrequency ablation for premature ventricular contractions originating from the aortic sinus cusp (ASC) using 3-dimensional electro anatomic mapping. METHODS: This study included 21 consecutive patients (10 male) underwent ablation for frequent PVCs originating from ASC in our hospital between May 2009 and February 2012. Electro anatomic mapping and ablation of right ventricular outflow track (RVOT) and left ventricular outflow track (LVOT) were performed with the 7F 4-mm-tip ablation catheter from right femoral vein and artery. Activation mapping and pacing mapping were performed in all patients. RESULTS: Ablation was successful in all 21 patients successful ablation target in left coronary sinus cusp (LCC, n = 17), in right coronary sinus cusp (RCC, n = 2) and in noncoronary sinus cusp (NCC, n = 2). Seven patients showed a RBBB morphology (group A) and 14 patients showed a LBBB morphology (group B). In group A, earliest ventricular activation (EVA) was recorded 22 - 34 (27.4 +/- 4.6) ms earlier before QRS at the site of catheter ablation in ASC. In group B, EVA was later in RVOT than that in ASC in 5 patients and EVA at the site of catheter ablation in RVOT and ASC was 22 - 28 (25.2 +/- 2.7) ms and 26 - 40 (32.8 +/- 5.2) ms, respectively (t = -3.6, P = 0.024) while EVA was earlier in the remaining 9 patients and EVA recorded in RVOT and ASC was 22 - 38 (28.7 +/- 5.9) ms and 18 - 28 (22.7 +/- 3.6) ms, respectively (t = 3.8, P = 0.005). CONCLUSION: Patients with premature ventricular contractions originating from the ASC often show preferential conduction to the RVOT, which may explain the LBBB morphology of ECG in these patients. PMID- 23651962 TI - [ACEI/ARB use among high risk patients with coronary heart disease in China: a cross-sectional study]. AB - OBJECTIVE: This study investigated current use of ACEI/ARB among high risk patients with coronary heart disease (CHD) in China and factors affecting ACEI/ARB use in these patients. METHODS: This cross-sectional survey was performed between June to December 2007 and May to November 2009 in 51 hospitals from 14 cities. The characteristics of patients with established CHD were collected by electronic questionnaire. RESULTS: Only 45.8% high risk CHD patients were taking ACEI/ARB and the ACEI/ARB medication decreased significantly with time after initial CHD diagnosis. ACEI/ARB was taken in 46.1% CHD patients complicated with diabetes mellitus and in 56.3% CHD patients complicated with hypertension. Logistic regression analysis showed that comorbid hypertension was the strongest factor associated with ACEI/ARB use. In addition, male gender, history of myocardial infarction (MI), PCI and the time after initial CHD diagnosis were independent factors affecting the use of ACEI/ARB. Captopril was the most commonly prescribed ACEI in this cohort. CONCLUSION: ACEI/ARB is underused in secondary prevention among high risk CHD patients in China. It remains a major challenge for healthcare professionals and policy makers to make efforts on narrowing the gap between evidence and practice. PMID- 23651963 TI - [Implication of elevated expression of receptor for activated C kinase 1 in mononuclear cells and coronary atherosclerotic plaques from patients with coronary artery disease]. AB - OBJECTIVE: To observe the expression and clinical implication of receptor for activated C kinase 1 (RACK1) in mononuclear cells and coronary atherosclerotic plaques from patients with coronary artery disease. METHODS: mRNA and protein expressions of RACK1 were detected in mononuclear cells from 29 patients with stable angina pectoris (SAP), 41 patients with acute coronary syndrome (ACS) and 30 healthy volunteers. RACK1 protein expression was also detected by immunohistochemistry in 17 coronary atherosclerotic plaques and 6 normal autopsy coronary samples. RESULTS: (1) mRNA expression of RACK1 was significantly upregulated in mononuclear cells from patients with ACS compared with those from patients with SAP (18.71 +/- 5.45 vs. 12.18 +/- 4.14, P < 0.05), and the latter was also significantly higher than in healthy controls (12.18 +/- 4.14 vs. 3.65 +/- 1.57, P < 0.05). (2) Similar changes were observed for protein expression of RACK1 for the three groups. (3) Increased expression of RACK1 was found in atherosclerotic plaques, especially in unstable plaques, positive RACK1 stain was evidenced in foam cells, inflammatory cells, smooth muscle cells and endothelial cells. CONCLUSIONS: The expression of RACK1 is significantly upregulated in mononuclear cells from patients with coronary artery disease, especially in patients with ACS, and in coronary atherosclerotic plaques, especially in unstable plaques. Our results thus suggest that RACK1 might play an important role in the development and progression of coronary artery disease. PMID- 23651964 TI - [Viable myocardium evaluation by two dimensional speckle tracking imaging combined with adenosine stress echocardiography]. AB - OBJECTIVE: Regional left ventricular (LV) function could be detected by measuring peak-systolic strain by speckle tracking imaging (STI). We evaluated the value of STI combined with adenosine stress echocardiography on assessing myocardial viability in patients with myocardial infarction (MI). METHODS: Two dimensional echocardiography was performed at rest and after adenosine stress echocardiography (infused at 140 ug*kg(-1)*min(-1) over a period of 6 min) in 39 stable patients with previous MI. Peak-systolic (Speak-sys) circumferential strain, radial strain and longitudinal strain were assessed by STI. Radionuclide myocardial perfusion/metabolic imaging served as the "gold standard" to detection of myocardial viability. RESULTS: (1) There were 215 viable and 153 non-viable regions among 368 abnormal motion segments out of 624 segments in 39 MI patients according to radionuclide imaging results. (2) Speak-sys was similar between viable and nonviable myocardium at rest (all P > 0.05). After adenosine infusion, radial Speak-sys [(37.98 +/- 5.45)% vs. (30.22 +/- 5.47)%], longitudinal Speak sys [(-23.71 +/- 4.53)% vs. (-17.52 +/- 4.34)%] increased significantly (P < 0.05)in viable segments compared to baseline levels and were significantly higher than in nonviable segments radial Speak-sys [(37.98 +/- 5.45)% vs. (30.12 +/- 5.37)%] and longitudinal Speak-sys [(-23.71 +/- 4.53)% vs. (-16.95 +/- 4.62)%] (P < 0.05), while remained unchanged in nonviable segments before and after adenosine infusion. Circumferential Speak-sys was similar before and after adenosine infusion in both viable and nonviable segments (all P > 0.05). (3) Delta radial strain change > 9.8% has a sensitivity of 82.3% and a specificity of 81.1% whereas a delta change of longitudinal strain > 16.5% has a sensitivity of 83.5% and a specificity of 92.3% for detecting viable segments. CONCLUSIONS: Speckle tracking imaging combined with adenosine stress echocardiography could serve as a new and reliable method of assessing myocardial viability. PMID- 23651965 TI - [Value of left atrial area index for diagnosing left ventricular diastolic dysfunction in hypertensive patients with preserved left ventricular systolic function]. AB - OBJECTIVE: To investigate the correlation between left atrial size and left ventricular filling pressure (LVFP) and the value of left atrial size assessment on detecting diastolic dysfunction in hypertensive patients with preserved LVEF by echocardiography. METHODS: Echocardiography was performed in 346 hypertensive patients with preserved LVEF(>= 50%), left atrial size including left atrial diameter (LAD) and left atrial area (LAA) was measured and indexed to body surface area (LADI, LAAI). The ratio of early diastolic transmitral velocity to early diastolic mitral annular velocity (E/Em) was determined and LVFP was calculated with the formula: LVFP = 1.24*E/Em + 1.9. Patients were divided into diastolic dysfunction group [DD group, LVFP > 15 mm Hg (1 mm Hg = 0.133 kPa), n = 81] and normal diastolic function group (NDF group, LVFP <= 15 mm Hg, n = 265). RESULTS: As compared to patients in NDF group, the patients in DD group had larger LA [LADI: (21.4 +/- 2.6) mm/m(2) vs. (19.6 +/- 2.4) mm/m(2); LAAI: (12.1 +/- 2.6) cm(2)/m(2) vs. (10.4 +/- 1.7)cm(2)/m(2); all P < 0.01]. LA size parameters were positively correlated with LVFP (r = 0.211-0.450, all P < 0.01), LAAI was best correlated with LVFP (r = 0.450, P < 0.01). ROC analysis showed that LAAI >= 11.4 cm(2)/m(2) diagnosed DD with a sensitivity of 63%, specificity of 74% and accuracy of 72%. CONCLUSION: Left atrium dilation correlates positively with LVFP in hypertensive patients with preserved LVEF. The LAAI is a more accurate parameter for identifying patients with diastolic dysfunction in this cohort. PMID- 23651966 TI - [Imaging and clinical characteristics of patients with coronary artery stenosis located proximally to myocardial bridging]. AB - OBJECTIVE: To explore the imaging and clinical characteristics and related risk factors of patients with coronary artery stenosis located proximally to myocardial bridging. METHODS: This study enrolled 603 patients with angiography evidenced myocardial bridging-mural coronary artery between May 2004 to May 2009. Angiographic and clinic data were collected according to uniform protocol and standard questionnaires were used to obtain patients' demographic and clinical information. Univariate and multivariate analysis were performed to explore related risk factors. RESULTS: Chest pain was present in 247 cases (41.0%). Dynamic ST-T changes were found in 229 cases (38%). A total of 644 myocardial bridging-mural coronary arteries were detected including 382 (62.4%) segments located proximally to myocardial bridging. Diastolic vessel diameters in the myocardial bridging segment were significantly smaller than reference segments (all P < 0.01). Stepwise multiple regression analysis suggested that vascular bifurcation lesions, the degree of narrowing and the number of diseased coronary vessels of non- myocardial bridging-mural coronary arteries, age, LDL-C/HDL-C, male gender, diabetes, and systolic narrow rate of myocardial bridging-mural coronary arteries were positively related with the narrowing degree of the first coronary artery stenosis located proximally to myocardial bridging (P < 0.05 or P < 0.01). Vascular bifurcation lesions, the degree of narrowing and the number of diseased coronary vessels of non- myocardial bridging-mural coronary arteries, age, LDL-C/HDL-C, male, diabetes and dyslipidemia were positively related with the narrowing degree of the most severe coronary artery stenosis located proximally to myocardial bridging (P < 0.05 or P < 0.01). CONCLUSIONS: Myocardial ischemia is common in patients with myocardial bridging and the artery segments located proximally to myocardial bridging are prone to stenosis. Systolic narrow rate of myocardial bridging-mural coronary arteries is one of major determinants of coronary artery stenosis located proximally to myocardial bridging. Whereas the other coronary heart disease risk factors are likely to play more important roles. PMID- 23651967 TI - [Reduced circulating endothelial progenitor cells is a risk factor of coronary slow flow]. AB - OBJECTIVE: To explore if reduced number of circulating endothelial progenitor cells (EPCs) is a risk factor for patients with coronary slow flow (CSF). METHODS: Thirty patients with CSF and 30 age and gender matched control subjects with normal coronary angiography were included in the study. Mononuclear cells were isolated from peripheral blood by Ficoll density gradient centrifugation and plated on fibronectin-coated culture dishes. EPCs were characterized as adherent cells double positive for DiI-AcLDL-uptake and lectin-binding by converted fluorescence microscope (*200). RESULTS: Smoking, diabetes mellitus, hypertension and the levels of plasma lipoprotein profile were similar between the two groups (all P > 0.05). The number of EPCs was significantly lower in patients with CSF compared with control subjects (35.7 +/- 5.9 vs.53.2 +/- 5.9, P < 0.01). TIMI frame counts was correlated with circulating EPCs number (OR = 0.424, 95%CI 0.358 - 0.621, P < 0.01) and not associated with gender, age, smoking, diabetes mellitus, hypertension and the levels of plasma lipoprotein profile. CONCLUSION: Decreased circulating EPCs is an independent risk factor for CSF. PMID- 23651968 TI - [Cilostazol inhibits proliferation and induces apoptosis in rat vascular smooth muscle cells through Rb-p53-p21 pathways]. AB - OBJECTIVE: To explore the effects and related mechanisms of cilostazol on rat vascular smooth muscle cells (VSMCs)proliferation. METHODS: VSMCs were treated with DMEM (control) and various doses of cilostazol (1.0*10(-7), 2.5*10(-7), 5.0*10(-7), 7.5*10(-7) and 1.0*10(-6) mol/L) for 13 d (cell counting) or 72 h. Proliferation of VSMCs was investigated by cell-counting, MTT and flow cytometry analysis. Cell apoptosis was determined by TUNEL staining. mRNA and protein expressions of cell cycle regulatory proteins, such as Rb, p53 and p21 were detected by RT-PCR and Western blot, respectively. RESULTS: Cilostazol inhibited VSMCs proliferation and induced VSMCs arrest at G1 phase in a dose-dependent manner. High dose of cilostazol (7.5*10(-7) and 1.0*10(-6) mol/L) induced VSMCs apoptosis. p53 mRNA expression in 2.5*10(-7) mol/L to 7.5*10(-7) mol/L groups as well as 1.0*10(-6) mol/L group (3.22 +/- 0.45 vs. 1.75 +/- 0.32) and p53 protein expression in 7.5*10(-7) mol/L group and 1.0*10(-6) mol/L group (0.53 +/- 0.11 vs. 0.18 +/- 0.06) were significantly upregulated after 72 h culture (all P < 0.05 vs. control). Low dose of cilostazol (1.0*10(-7), 2.5*10(-7) and 5.0*10(-7) mol/L) significantly upregulated p21 mRNA expression compared to control group (1.86 +/- 0.19, 2.20 +/- 0.24 and 2.10 +/- 0.18 vs. 1.210 +/- 0.18, all P < 0.05). Similarly, Rb mRNA expression was significantly upregulated in 1.0*10(-7), 2.5*10(-7) and 5.0*10(-7) mol/L groups (0.89 +/- 0.07 vs. 0.38 +/- 0.04)compared with control group (all P < 0.05). However, high dose cilostazol (7.5*10(-7) and 1.0*10(-6) mol/L) significantly downregulated p21 mRNA expression (0.81 +/- 0.09 vs. 1.21 +/- 0.18, 0.36 +/- 0.10 vs. 1.21 +/- 0.18, all P < 0.05 vs. control) and Rb mRNA expression (0.12 +/- 0.02 and 0.11 +/- 0.02 vs. 0.38 +/- 0.04, all P < 0.05 vs. control). p21 and Rb protein expressions also upregulated at low concentrations of cilostazol and downregulated at high concentrations of cilostazol. CONCLUSION: Cilostazol could inhibit the proliferation of rat VSMCs through modulating Rb-p53-p21 pathway and induce VSMCs apoptosis through upregulating p53. PMID- 23651969 TI - [Impact of Pax-8 gene interference on mitochondrial function and cardiomyocyte apoptosis]. AB - OBJECTIVE: To observe the effects of paired box gene 8 (Pax-8) silencing by RNA interference on mitochondrial function and cardiomyocytes apoptosis. METHODS: The cultured H9C2 (2-1) myocytes were divided into 3 groups: short interference RNA targeting Pax-8 (Pax-8 siRNA) group, non-specific siRNA group as the negative control (NC siRNA), and blank control group (BC siRNA). Fluorescence spectrophotometry was used to detect the activity of caspase-3. RT-PCR was performed to detect mRNA expression of Bcl2 and Bax. The protein expression of Bcl2, Bax and cytoplasm of Cytochrome was examined by Western blot. Changes of DeltaPsim were detected by flow cytometry.DeltaPsim with JC-1 monomer/polymer ratio was calculated for measuring mitochondrial depolarization proportion. RESULTS: Compared to NC siRNA and BC siRNA group (0.075 +/- 0.021, 0.072 +/- 0.019), the activity of caspase-3 in Pax-8 siRNA group (0.167 +/- 0.012) was significantly increased (P < 0.05); Bcl2 mRNA and protein expression in Pax-8 siRNA group (0.61 +/- 0.06, 0.94 +/- 0.11) were significantly downregulated compared with NC siRNA group (0.90 +/- 0.070, 1.39 +/- 0.15) and BC siRNA group (0.94 +/- 0.087, 1.49 +/- 0.20) (P < 0.05); Bax mRNA and protein expression in Pax-8 siRNA group (1.05 +/- 0.10, 1.25 +/- 0.12) were markedly upregulated compared with NC siRNA group (0.72 +/- 0.03, 0.99 +/- 0.12) and BC siRNA group (0.64 +/- 0.03, 0.92 +/- 0.06), P < 0.05; cytosolic cytochrome expression in Pax 8 siRNA group (0.75 +/- 0.14) was significantly upregulated compared with NC siRNA group (0.51 +/- 0.06) and BC siRNA group (0.48 +/- 0.07) (P < 0.05); JC-1 monomer/polymer ratio in Pax-8 siRNA group (0.163 +/- 0.011) was significantly increased compared with NC siRNA group (0.092 +/- 0.015) and BC siRNA group (0.072 +/- 0.025) (P < 0.05) indicating mitochondrial membrane potential was significantly reduced in Pax-8 siRNA group. Above parameters were similar between NC siRNA group and BC siRNA group (P > 0.05). CONCLUSION: Inhibiting Pax-8 results in enhanced cardiomyocytes apoptosis through the mitochondrial pathway. PMID- 23651970 TI - [Risk factors for hyperuricemia in active and retired employees underwent physical examination]. AB - OBJECTIVE: To observe serum uric acid (UA) level distribution and explore risk factors of hyperuricemia (HUA) in a large cohort of active and retired employees underwent physical examination. METHODS: Physical examination was arranged for 21 700 active and retired employees from May 2010 to September 2011, 16 416 employees were examined and complete examination data were obtained in 14 044 subjects. The distribution characteristics of UA level and correlations of UA level and HUA prevalence rate with gender, age, body mass index (BMI), systolic pressure (SBP), diastolic pressure (DBP), fasting blood-glucose (FPG), serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) were analyzed. RESULTS: HUA prevalence rate was 11.2% in this cohort, which was significantly higher in males (15.8%) than in females (4.1%, P < 0.05). The UA level and the HUA prevalence rate presented a "J" curve relationship with aging and positively correlated with BMI, SBP, DBP, TG, LDL-C, TC and FPG while negatively correlated with HDL-C. Multiple linear regression analysis showed that SBP, BMI, FPG, TG, and LDL-C were independent risk factors while HDL-C and female gender were the protective factors of HUA(all P < 0.01). Aging and high DBP were independent risk factors of HUA for females (all P < 0.05) and LDL-C was risk factor of HUA for males (P < 0.05). CONCLUSIONS: Serum UA level presents a "J" wave relationship with aging. The risk factors of HUA are increased SBP, BMI, FPG, TG, LDL-C while the protective factors of HUA are female gender and high HDL-C. PMID- 23651971 TI - [Application experience of attain (r) select II catheter delivery system for left ventricular lead implantation in cardiac resynchronization therapy]. AB - OBJECTIVE: To summarize application experience of attain (r) select II catheter delivery system for left ventricular lead implantation in cardiac resynchronization therapy (CRT). METHODS: CRT/CRT-D was applied for 86 patients with congestive heart failure and left bundle-branch block. Left ventricular lead implantation was applied without use of attain (r) select II catheter delivery system in 42 patients without coronary vein anatomy variation (group A). Coronary sinus and cardiac vein angiography detected coronary vein anatomy variations in 44 patients and attain (r) select II catheter delivery system was not used in 21 patients (group B) and used in 23 patients (group C). Total procedure time, LV lead implantation time, X-ray exposure time and complications were compared among groups. The optimal LV lead location were observed at the end of procedure. RESULTS: Patients were followed up to 245 days (160 - 368 days). Total procedure time [(119 +/- 18) min vs. (142 +/- 17) min; (119 +/- 18) min vs. (143 +/- 17) min], LV lead implantation time [(32 +/- 7) min vs. (49 +/- 8) min;(32 +/- 7) min vs. (51 +/- 7) min]and X-ray exposure time [(27 +/- 6) min vs. (46 +/- 84) min;(27 +/- 6) min vs. (45 +/- 7) min] were significant reduced in group C compared to group A and B. Procedure-related complications were similar among the 3 groups. The rate of optimal LV lead location was significantly higher in group C than in group B (96% vs. 71%). CONCLUSIONS: It is feasible and safe to implant LV lead through coronary sinus with attain (r) select II catheter delivery system. Applying Attain (r) select II catheter delivery system can improve the rate of optimal LV lead location with coronary venous anatomy variation. PMID- 23651972 TI - [One case of torsades de pointes with Aase's syndrome induced by moxifloxacin]. PMID- 23651973 TI - [A case report of pulmonary arteriovenous malformations treated by Amplatzer duct occluder II]. PMID- 23651974 TI - [Super-responders to cardiac resynchronization therapy]. PMID- 23651975 TI - [Research on iron metabolism in pulmonary hypertension]. PMID- 23651976 TI - Cerebral Amyloidal Angiopathy--a disease with implications for neurology and psychiatry. AB - Cerebral Amyloidal Angiopathy (CAA), which occurs sporadically in most cases but can also occur hereditarily, belongs to the group amyloidoses and is characterized by the deposition and accumulation of beta-amyloid (Abeta) in smaller arterial vessels of the brain. The deposition of Abeta leads to degenerative changes in the cerebral vessel system (thickening of the vessel wall, microaneurysm, constriction of vascular lumen, dissection), which favour the development of the clinical symptomatology most often associated with CAA. Besides haemorrhages, cerebral ischaemia, transient neurological symptoms, leukoencephalopathy as well as cognitive decline and even dementia may appear in connection with CAA. A definite diagnosis of CAA can only be made on the basis of a pathological assessment, even though diagnostic findings of cerebral neuroimaging and clinical symptoms allow the diagnosis of a probable CAA. At present, no causal therapy options are available. Although CAA is placed within the range of neurological illnesses, psychiatric symptoms such as cognitive impairment, personality change or behavioural problems as well as depression are plausible clinical manifestations of CAA and may even dominate the clinical picture. Apart from epidemiological, pathogenetical, clinical and diagnostical aspects, possible psychiatric implications of CAA are discussed in the review article. PMID- 23651977 TI - CXCL12-gamma expression is inhibited in neuroinflammation. AB - CXCL12 plays a protective role in CNS autoimmunity. Expression of CXCL12-gamma, which has distinct structural and functional properties than the other isoforms of CXCL12, was determined in spinal cords of rats immunized to develop experimental autoimmune encephalomyelitis (EAE). CNS expression of CXCL12-gamma was markedly lower in EAE-prone Dark Agouti rats than in EAE-resistant Albino Oxford rats, both in spinal cord homogenates and micro-blood vessels isolated from spinal cords. Inhibition of nitric oxide (NO) synthesis in DA rats upregulated, while donation of NO in AO rats downregulated CNS expression of CXCL12-gamma. NO inhibited CXCL12-gamma expression in astrocytes in vitro. A splice variant of CXCL12-gamma which migrates into nucleolus was not detected in spinal cord or astrocytes. Thus, CXCL12-gamma is expressed in the CNS after EAE induction, but its expression is markedly suppressed in spinal cord affected with full blown inflammation. NO is an important regulator of CXCL12-gamma expression in neuroinflammation. PMID- 23651978 TI - Repetitive transcranial magnetic stimulation increases excitability of hippocampal CA1 pyramidal neurons. AB - Repetitive transcranial magnetic stimulation (rTMS) is able to induce alteration in cortical activity and excitability that outlast the period of stimulation, which is long-term depre-ssion (LTD) or long-term potentiation (LTP)-like. Accumulating evidence shows that Na(+), Ca(2+) and K(+) channels are important for the regulation of neuronal excitability. To investigate the possible mechanisms of rTMS on regulation of intrinsic excitability in hippocampal neurons, the male or female Sprague-Dawley rats aged 2-3 d or 7-8 d were treated with 14 or 7-d's low frequency (1 Hz) rTMS (400 stimuli/d), respectively. After that, the effects of rTMS on ion channels such as Na(+)-channel, A-type K(+) channel and Ca(2+)-channel in rat hippocampal CA1 pyramidal neurons were performed by standard whole-cell patch-clamp technique. The results showed that the peak amplitude and maximal rise slope of evoked single action potential (AP) were significantly increased after 14-d's rTMS treatment. Meanwhile, the AP threshold was significantly more depolarized in neurons after 14-d's rTMS treatment than neurons in control group that without rTMS treatment. The spontaneous excitatory post-synaptic currents (sEPSCs) frequency and amplitude of CA1 pyramidal neurons in groups with rTMS treatment (both 7 d and 14 d) were obviously increased compared with the age-matched control group. Furthermore, we found that electrophysiological properties of Na(+)-channel were markedly changed after rTMS treatment, including negative-shifted activation and inactivation curves, as well as fasten recovery rate. After rTMS application, the IA amplitude of K(+)-channel was reduced; the activation and inactivation curves of K(+) channel were significantly shifted to right. Time constant of recovery from inactivation was also more rapid. Moreover, rTMS induced an obvious increment in the maximal current peak amplitude of Ca(2+)-channel. At the same time, there was a significant rightward shift in the activation curve and inactivation curves of Ca(2+)-channel. These data suggest that rTMS can enhance the AP and sEPSCs of hippocampal CA1 neurons. Altered electrophysiological properties of Na(+) channel, A-type K(+) channels and Ca(2+) channels contribute to the underling mechanisms of rTMS-induced up-regulation of neural excitability. PMID- 23651979 TI - Molecular characterization of X-linked adrenoleukodystrophy in a Tunisian family: identification of a novel missense mutation in the ABCD1 gene. AB - BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a recessive neurodegenerative disorder that affects the brain's white matter and is associated with adrenal insufficiency. It is characterized by an abnormal function of the peroxisomes, which leads to an accumulation of very long-chain fatty acids (VLCFA) in plasma and tissues, especially in the cortex of the adrenal glands and the white matter of the central nervous system, causing demyelinating disease and adrenocortical insufficiency (Addison's disease). X-ALD is caused by a mutation in the ABCD1 gene (ATP-binding cassette, subfamily D, member 1), which encodes the adrenoleukodystrophy protein involved in the transport of fatty acids into the peroxisome for degradation. OBJECTIVE: We report here a disease-related variant in the ABCD1 gene in a 19-year-old Tunisian boy with childhood cerebral adrenoleukodystrophy. METHODS: The diagnosis was based on clinical symptoms, high levels of VLCFA in plasma, typical MRI pattern and molecular analysis. RESULTS: Molecular analysis by direct sequencing of the ABCD1 gene showed the presence of a novel missense mutation c.284C>A (p.Ala95Asp) occurring in the transmembrane domain in the proband, his mother and his sister. CONCLUSION: Using bioinformatic tools we suggest that this novel variant may have deleterious effects on adrenoleukodystrophy protein structure and function. PMID- 23651981 TI - A new chromosome translocation t(7;16)(q31,q22) change during an acute promyelocytic leukemia relapse. AB - The translocation t(15;17), which results in the PML-RARalpha fusion gene, is a characteristic chromosomal translocation in acute promyelocytic leukemia (APL). But additional chromosome aberrations in APL are increasingly recognized. Here, we report on a 16-year-old APL patient who had an fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) and a 46,XY,t(15;17)(q22;q21)-16+mar karyotype at diagnosis. The patient achieved complete remission after induction therapy with all-trans retinoic acid and chemotherapy. But he soon relapsed presenting distinctive APL features in the bone marrow and leptomeninges and showing a chromosome translocation change involving chromosomes 7 and 16 besides t(15;17)(q22;q21). The new karyotype 46,XY,t(7;16)(q31;q22),t(15;17)(q22;q21) was determined. To the best of our knowledge, this is the first report of a de novo APL with a chromosome translocation t(7;16)(q31,q22) together with a t(15;17)(q22;q21) and FLT3-ITD mutation. PMID- 23651982 TI - Long-term follow-up of lesion-specific outcomes comparing drug-eluting stents and bare metal stents in diseased saphenous vein grafts. AB - Saphenous vein grafts (SVGs) are a common choice for bypassing obstructed coronary arteries. Repeat coronary artery bypass grafting has been found to have substantial rates of morbidity and mortality; therefore, SVG percutaneous intervention has emerged as a positive alternative for revascularization. Stenting of SVGs has been shown to be more beneficial than medical management or balloon angioplasty alone. The literature is conflicting with regard to which type of stent-bare metal stent (BMS) or drug-eluting stent (DES)-is best suited for treating graft failure. The authors provide long-term follow-up data of lesion-specific outcomes when comparing DES versus BMS in SVGs. PMID- 23651983 TI - Venous disease: the missing link in cardiovascular medicine. AB - Until recently, medical literature and the practice of vascular medicine focused on the cosmetic aspects of venous disease and the advanced stages of venous insufficiency such as painful varicose veins and venous ulcers. The systemic effects of venous insufficiency resulting from a reduction of venous return and increased transit time of blood from the lower extremities that can mimic heart failure are only recently being recognized. This article reviews the diagnosis and treatment options for the patients with venous insufficiency, and increases awareness about the systemic effects of venous disease and its role in the practice of cardiovascular medicine. PMID- 23651984 TI - New vistas for the treatment of obesity: turning the tide against the leading cause of morbidity and cardiovascular mortality in the developed world. AB - Excess adiposity and obesity are the root cause of at least 27 diseases that cause considerable lifelong morbidity and, in many scenarios, eventual cardiovascular mortality. The human body has the ability to increase the number and size of its adipocytes by approximately 10-fold over the course of a lifetime. As fat mass increases, its blood supply, supporting cells, tissue structure, and local and systemic hormonal control also increase. This results in excess adiposity, leading to progressive obesity and the resistance to weight loss attempts. There have been numerous trials of food diets combined with exercise that, in general, have a 50% dropout rate at 1 year and lead to very modest (~ 5%) reductions in body weight. Thus, many with obesity require interventions beyond casual diet and exercise advice. Meal replacement diets and bariatric surgery offer considerably greater degrees of weight loss, but both can be plagued by weight regain. Because the ability to control food urges has been shown to be a key psychological factor for success, medicinal approaches that work in this domain are attractive adjuncts to diet, exercise, and weight-loss surgery. This article reviews the emerging role of medical therapy in the treatment of excess adiposity with the goal of reducing comorbidities and possibly improving cardiovascular survival. PMID- 23651985 TI - Failing the failing heart: a review of palliative care in heart failure. AB - Heart failure (HF) is the most common reason for hospital admission for patients older than 65 years. With an aging population and improving survival in heart failure patients, the number of people living with HF continues to grow. As this population increases, the importance of treating symptoms of fatigue, dyspnea, pain, and depression that diminish the quality of life in HF patients becomes increasingly important. Palliative care has been shown to help alleviate these symptoms and improve patients' satisfaction with the care they receive. Despite this growing body of evidence, palliative care consultation remains underutilized and is not standard practice in the management of HF. With an emphasis on communication, symptom management, and coordinated care, palliative care provides an integrated approach to support patients and families with chronic illnesses. Early communication with patients and families regarding the unpredictable nature of HF and the increased risk of sudden cardiac death enables discussions around advanced care directives, health care proxies, and deactivation of permanent pacemakers or implantable cardioverter defibrillators. Cardiologists and primary care physicians who are comfortable initiating these discussions are encouraged to do so; however, many fear destroying hope and are uncertain how to discuss end of-life issues. Thus, in order to facilitate these discussions and establish an appropriate relationship, we recommend that patients and families be introduced to a palliative care team at the earliest appropriate time after diagnosis. PMID- 23651986 TI - Systemic vasculitis: an underestimated cause of heart failure - assessment by cardiovascular magnetic resonance. AB - Cardiovascular manifestations in systemic vasculitis include initially silent cardiomyopathy due to either ischemic or inflammatory causes. The combination of vasculitis and cardiomyopathy is associated with a poor prognosis. Early treatment with immunosuppressants in conjunction with appropriate cardiac pharmacotherapy is considered important and has dramatically improved prognosis. Cardiovascular magnetic resonance, due to its nonionizing, noninvasive evaluation of the cardiovascular system, can be of great value in the diagnosis, follow-up, and treatment of patients with systemic vasculitis. PMID- 23651987 TI - Diagnosis and risk stratification in acute pulmonary embolism: the role of echocardiography. AB - Pulmonary embolism (PE) is a frequently encountered clinical condition with a high mortality rate that is affected by various factors such as age, hemodynamics, and other comorbidities. Early diagnosis and risk stratification are crucial to achieving a favorable clinical outcome. New risk stratification algorithms have been proposed in order to identify high-risk patients who will benefit from early thrombolytic treatment. Among the various validated diagnostic methods, the role of echocardiography is increasingly accepted. Recent advances in studying right ventricular function have made echocardiography an attractive tool for establishing or excluding the diagnosis of acute PE in the emergency setting and initiating optimal therapy. PMID- 23651988 TI - Health care reform: what's wrong with 17.6% GDP? PMID- 23651989 TI - Hypertension. Left ventricular hypertrophy and cardiac function in patients with resistant hypertension. PMID- 23651990 TI - Comparative analysis of kisspeptin-immunoreactivity reveals genuine differences in the hypothalamic Kiss1 systems between rats and mice. AB - Kiss1 mRNA and its corresponding peptide products, kisspeptins, are expressed in two restricted brain areas of rodents, the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC). The concentration of mature kisspeptins may not directly correlate with Kiss1 mRNA levels, because mRNA translation and/or posttranslational modification, degradation, transportation and release of kisspeptins could be regulated independently of gene expression, and there may thus be differences in kisspeptin expression even in species with similar Kiss1 mRNA profiles. We measured and compared kisspeptin-immunoreactivity in both nuclei and both sexes of rats and mice and quantified kisspeptin-immunoreactive nerve fibers. We also determined Kiss1 mRNA levels and measured kisspeptin immunoreactivity in colchicine pretreated rats. Overall, we find higher levels of kisspeptin-immunoreactivity in the mouse compared to the rat, independently of brain region and gender. In the female mouse AVPV high numbers of kisspeptin immunoreactive neurons were present, while in the rat, the female AVPV displays a similar number of kisspeptin-immunoreactive neurons compared to the level of Kiss1 mRNA expressing cells, only after axonal transport inhibition. Interestingly, the density of kisspeptin innervation in the anterior periventricular area was higher in female compared to male in both species. Species differences in the ARC were evident, with the mouse ARC containing dense fibers, while the rat ARC contains clearly discernable cells. In addition, we show a marked sex difference in the ARC, with higher kisspeptin levels in females. These findings show that the translation of Kiss1 mRNA and/or the degradation/transportation/release of kisspeptins are different in mice and rats. PMID- 23651992 TI - Abstinence versus agonist maintenance treatment: an outdated debate? PMID- 23651991 TI - Mechanisms of glucagon degradation at alkaline pH. AB - Glucagon is unstable and undergoes degradation and aggregation in aqueous solution. For this reason, its use in portable pumps for closed loop management of diabetes is limited to very short periods. In this study, we sought to identify the degradation mechanisms and the bioactivity of specific degradation products. We studied degradation in the alkaline range, a range at which aggregation is minimized. Native glucagon and analogs identical to glucagon degradation products were synthesized. To quantify biological activity in glucagon and in the degradation peptides, a protein kinase A-based bioassay was used. Aged, fresh, and modified peptides were analyzed by liquid chromatography with mass spectrometry (LCMS). Oxidation of glucagon at the Met residue was common but did not reduce bioactivity. Deamidation and isomerization were also common and were more prevalent at pH 10 than 9. The biological effects of deamidation and isomerization were unpredictable; deamidation at some sites did not reduce bioactivity. Deamidation of Gln 3, isomerization of Asp 9, and deamidation with isomerization at Asn 28 all caused marked potency loss. Studies with molecular-weight-cutoff membranes and LCMS revealed much greater fibrillation at pH 9 than 10. Further work is necessary to determine formulations of glucagon that minimize degradation and fibrillation. PMID- 23651993 TI - Advanced zinc-air batteries based on high-performance hybrid electrocatalysts. AB - Primary and rechargeable Zn-air batteries could be ideal energy storage devices with high energy and power density, high safety and economic viability. Active and durable electrocatalysts on the cathode side are required to catalyse oxygen reduction reaction during discharge and oxygen evolution reaction during charge for rechargeable batteries. Here we developed advanced primary and rechargeable Zn-air batteries with novel CoO/carbon nanotube hybrid oxygen reduction catalyst and Ni-Fe-layered double hydroxide oxygen evolution catalyst for the cathode. These catalysts exhibited higher catalytic activity and durability in concentrated alkaline electrolytes than precious metal Pt and Ir catalysts. The resulting primary Zn-air battery showed high discharge peak power density ~265 mW cm(-2), current density ~200 mA cm(-2) at 1 V and energy density >700 Wh kg(-1). Rechargeable Zn-air batteries in a tri-electrode configuration exhibited an unprecedented small charge-discharge voltage polarization of ~0.70 V at 20 mA cm( 2), high reversibility and stability over long charge and discharge cycles. PMID- 23651994 TI - Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer. AB - Although human papillomavirus was identified as an aetiological factor in cervical cancer, the key human gene drivers of this disease remain unknown. Here we apply an unbiased approach integrating gene expression and chromosomal aberration data. In an independent group of patients, we reconstruct and validate a gene regulatory meta-network, and identify cell cycle and antiviral genes that constitute two major subnetworks upregulated in tumour samples. These genes are located within the same regions as chromosomal amplifications, most frequently on 3q. We propose a model in which selected chromosomal gains drive activation of antiviral genes contributing to episomal virus elimination, which synergizes with cell cycle dysregulation. These findings may help to explain the paradox of episomal human papillomavirus decline in women with invasive cancer who were previously unable to clear the virus. PMID- 23651995 TI - Establishment of a robust single axis of cell polarity by coupling multiple positive feedback loops. AB - Establishment of cell polarity--or symmetry breaking--relies on local accumulation of polarity regulators. Although simple positive feedback is sufficient to drive symmetry breaking, it is highly sensitive to stochastic fluctuations typical for living cells. Here, by integrating mathematical modelling with quantitative experimental validations, we show that in the yeast Saccharomyces cerevisiae a combination of actin- and guanine nucleotide dissociation inhibitor-dependent recycling of the central polarity regulator Cdc42 is needed to establish robust cell polarity at a single site during yeast budding. The guanine nucleotide dissociation inhibitor pathway consistently generates a single-polarization site, but requires Cdc42 to cycle rapidly between its active and inactive form, and is therefore sensitive to perturbations of the GTPase cycle. Conversely, actin-mediated recycling of Cdc42 induces robust symmetry breaking but cannot restrict polarization to a single site. Our results demonstrate how cells optimize symmetry breaking through coupling between multiple feedback loops. PMID- 23651996 TI - Free-electron gas at charged domain walls in insulating BaTiO3. AB - Hetero interfaces between metal-oxides display pronounced phenomena such as semiconductor-metal transitions, magnetoresistance, the quantum hall effect and superconductivity. Similar effects at compositionally homogeneous interfaces including ferroic domain walls are expected. Unlike hetero interfaces, domain walls can be created, displaced, annihilated and recreated inside a functioning device. Theory predicts the existence of 'strongly' charged domain walls that break polarization continuity, but are stable and conduct steadily through a quasi-two-dimensional electron gas. Here we show this phenomenon experimentally in charged domain walls of the prototypical ferroelectric BaTiO3. Their steady metallic-type conductivity, 10(9) times that of the parent matrix, evidence the presence of stable degenerate electron gas, thus adding mobility to functional interfaces. PMID- 23651998 TI - Characterization of salt-adapted secreted lignocellulolytic enzymes from the mangrove fungus Pestalotiopsis sp. AB - Fungi are important for biomass degradation processes in mangrove forests. Given the presence of sea water in these ecosystems, mangrove fungi are adapted to high salinity. Here we isolate Pestalotiopsis sp. NCi6, a halotolerant and lignocellulolytic mangrove fungus of the order Xylariales. We study its lignocellulolytic enzymes and analyse the effects of salinity on its secretomes. De novo transcriptome sequencing and assembly indicate that this fungus possesses of over 400 putative lignocellulolytic enzymes, including a large fraction involved in lignin degradation. Proteomic analyses of the secretomes suggest that the presence of salt modifies lignocellulolytic enzyme composition, with an increase in the secretion of xylanases and cellulases and a decrease in the production of oxidases. As a result, cellulose and hemicellulose hydrolysis is enhanced but lignin breakdown is reduced. This study highlights the adaptation to salt of mangrove fungi and their potential for biotechnological applications. PMID- 23651997 TI - Interspecific bacterial sensing through airborne signals modulates locomotion and drug resistance. AB - Bacteria use chemical signals to sense each other and to regulate various physiological functions. Although it is known that some airborne volatile organic compounds function as bacterial signalling molecules, their identities and effects on global gene expression and bacterial physiological processes remain largely unknown. Here we perform microarray analyses of Escherichia coli exposed to volatile organic compounds emitted from Bacillus subtilis. We find that 2,3 butanedione and glyoxylic acid mediate global changes in gene expression related to motility and antibiotic resistance. Volatile organic compound-dependent phenotypes are conserved among bacteria and are regulated by the previously uncharacterized ypdB gene product through the downstream transcription factors soxS, rpoS or yjhU. These results strongly suggest that bacteria use airborne volatile organic compounds to sense other bacteria and to change master regulatory gene activity to adapt. PMID- 23651999 TI - Broadband high photoresponse from pure monolayer graphene photodetector. AB - Graphene has attracted large interest in photonic applications owing to its promising optical properties, especially its ability to absorb light over a broad wavelength range, which has lead to several studies on pure monolayer graphene based photodetectors. However, the maximum responsivity of these photodetectors is below 10 mA W(-1), which significantly limits their potential for applications. Here we report high photoresponsivity (with high photoconductive gain) of 8.61 A W(-1) in pure monolayer graphene photodetectors, about three orders of magnitude higher than those reported in the literature, by introducing electron trapping centres and by creating a bandgap in graphene through band structure engineering. In addition, broadband photoresponse with high photoresponsivity from the visible to the mid-infrared is experimentally demonstrated. To the best of our knowledge, this work demonstrates the broadest photoresponse with high photoresponsivity from pure monolayer graphene photodetectors, proving the potential of graphene as a promising material for efficient optoelectronic devices. PMID- 23652000 TI - Transmission-blocking interventions eliminate malaria from laboratory populations. AB - Transmission-blocking interventions aim to reduce the prevalence of infection in endemic communities by targeting Plasmodium within the insect host. Although many studies have reported the successful reduction of infection in the mosquito vector, direct evidence that there is an onward reduction in infection in the vertebrate host is lacking. Here we report the first experiments using a population, transmission-based study of Plasmodium berghei in Anopheles stephensi to assess the impact of a transmission-blocking drug upon both insect and host populations over multiple transmission cycles. We demonstrate that the selected transmission-blocking intervention, which inhibits transmission from vertebrate to insect by only 32%, reduces the basic reproduction number of the parasite by 20%, and in our model system can eliminate Plasmodium from mosquito and mouse populations at low transmission intensities. These findings clearly demonstrate that use of transmission-blocking interventions alone can eliminate Plasmodium from a vertebrate population, and have significant implications for the future design and implementation of transmission-blocking interventions within the field. PMID- 23652001 TI - An isoform of retinoid-related orphan receptor beta directs differentiation of retinal amacrine and horizontal interneurons. AB - Amacrine and horizontal interneurons integrate visual information as it is relayed through the retina from the photoreceptors to the ganglion cells. The early steps that generate these interneuron networks remain unclear. Here we show that a distinct retinoid-related orphan nuclear receptor beta1 (RORbeta1) isoform encoded by the retinoid-related orphan nuclear receptor beta gene (Rorb) is critical for both amacrine and horizontal cell differentiation in mice. A fluorescent protein cassette targeted into Rorb revealed RORbeta1 as a novel marker of immature amacrine and horizontal cells and of undifferentiated, dividing progenitor cells. RORbeta1-deficient mice lose expression of pancreas specific transcription factor 1a (Ptf1a) but retain forkhead box n4 factor (Foxn4), two early-acting factors necessary for amacrine and horizontal cell generation. RORbeta1 and Foxn4 synergistically induce Ptf1a expression, suggesting a central role for RORbeta1 in a transcriptional hierarchy that directs this interneuron differentiation pathway. Moreover, ectopic RORbeta1 expression in neonatal retina promotes amacrine cell differentiation. PMID- 23652002 TI - A sex-specific transcription factor controls male identity in a simultaneous hermaphrodite. AB - Evolutionary transitions between hermaphroditic and dioecious reproductive states are found in many groups of animals. To understand such transitions, it is important to characterize diverse modes of sex determination utilized by metazoans. Currently, little is known about how simultaneous hermaphrodites specify and maintain male and female organs in a single individual. Here we show that a sex-specific gene, Smed-dmd-1 encoding a predicted doublesex/male-abnormal 3 (DM) domain transcription factor, is required for specification of male germ cells in a simultaneous hermaphrodite, the planarian Schmidtea mediterranea. dmd 1 has a male-specific role in the maintenance and regeneration of the testes and male accessory reproductive organs. In addition, a homologue of dmd-1 exhibits male-specific expression in Schistosoma mansoni, a derived, dioecious flatworm. These results demonstrate conservation of the role of DM domain genes in sexual development in lophotrochozoans and suggest one means by which modulation of sex specific pathways can drive the transition from hermaphroditism to dioecy. PMID- 23652003 TI - Relation between the nodal and antinodal gap and critical temperature in superconducting Bi2212. AB - An energy gap is, in principle, a dominant parameter in superconductivity. However, this view has been challenged for the case of high-Tc cuprates, because anisotropic evolution of a d-wave-like superconducting gap with underdoping has been difficult to formulate along with a critical temperature Tc. Here we show that a nodal-gap energy 2DeltaN closely follows 8.5 kBTc with underdoping and is also proportional to the product of an antinodal gap energy Delta(*) and a square root superfluid density ?Ps for Bi2Sr2CaCu2O8+delta, using low-energy synchrotron radiation angle-resolved photoemission. The quantitative relations imply that the distinction between the nodal and antinodal gaps stems from the separation of the condensation and formation of electron pairs, and that the nodal-gap suppression represents the substantial phase incoherence inherent in a strong-coupling superconducting state. These simple gap-based formulae reasonably describe a crucial part of the unconventional mechanism governing Tc. PMID- 23652005 TI - A reversible long-life lithium-air battery in ambient air. AB - Electrolyte degradation, Li dendrite formation and parasitic reactions with H2O and CO2 are all directly correlated to reversibility and cycleability of Li-air batteries when operated in ambient air. Here we replace easily decomposable liquid electrolytes with a solid Li-ion conductor, which acts as both a catholyte and a Li protector. Meanwhile, the conventional solid air cathodes are replaced with a gel cathode, which contacts directly with the solid catholyte to form a closed and sustainable gel/solid interface. The proposed Li-air cell has sustained repeated cycling in ambient air for 100 cycles (~78 days), with discharge capacity of 2,000 mAh g(-1). The recharging is based largely on the reversible reactions of Li2CO3 product, originating from the initial discharge product of Li2O2 instead of electrolyte degradation. Our results demonstrate that a reversible long-life Li-air battery is attainable by coordinated approaches towards the focal issues of electrolytes and Li metal. PMID- 23652004 TI - A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases. AB - It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. Here we show that transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein (VCP)/p97 directly binds to multiple polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequence. Although normal and mutant polyglutamine proteins interact with TERA/VCP/p97, only mutant proteins affect dynamism of TERA/VCP/p97. Among multiple functions of TERA/VCP/p97, we reveal that functional defect of TERA/VCP/p97 in DNA double-stranded break repair is critical for the pathology of neurons in which TERA/VCP/p97 is located dominantly in the nucleus in vivo. Mutant polyglutamine proteins impair accumulation of TERA/VCP/p97 and interaction of related double-stranded break repair proteins, finally causing the increase of unrepaired double-stranded break. Consistently, the recovery of lifespan in polyglutamine disease fly models by TERA/VCP/p97 corresponds well to the improvement of double-stranded break in neurons. Taken together, our results provide a novel common pathomechanism in multiple polyglutamine diseases that is mediated by DNA repair function of TERA/VCP/p97. PMID- 23652006 TI - A versatile source of single photons for quantum information processing. AB - The generation of high-quality single-photon states with controllable narrow spectral bandwidths and central frequencies is key to facilitate efficient coupling of any atomic system to non-classical light fields. Such an interaction is essential in numerous experiments for fundamental science and applications in quantum communication and information processing, as well as in quantum metrology. Here we implement a fully tunable, narrow-band and efficient single photon source based on a whispering gallery mode resonator. Our disk-shaped, monolithic and intrinsically stable resonator is made of lithium niobate and supports a cavity-assisted spontaneous parametric down-conversion process. The generated photon pairs are emitted into two highly tunable resonator modes. We verify wavelength tuning over 100 nm of both modes with controllable bandwidth between 7.2 and 13 MHz. Heralding of single photons yields anti-bunching with g(2)(0)<0.2. PMID- 23652007 TI - Polytype control of spin qubits in silicon carbide. AB - Crystal defects can confine isolated electronic spins and are promising candidates for solid-state quantum information. Alongside research focusing on nitrogen-vacancy centres in diamond, an alternative strategy seeks to identify new spin systems with an expanded set of technological capabilities, a materials driven approach that could ultimately lead to 'designer' spins with tailored properties. Here we show that the 4H, 6H and 3C polytypes of SiC all host coherent and optically addressable defect spin states, including states in all three with room-temperature quantum coherence. The prevalence of this spin coherence shows that crystal polymorphism can be a degree of freedom for engineering spin qubits. Long spin coherence times allow us to use double electron-electron resonance to measure magnetic dipole interactions between spin ensembles in inequivalent lattice sites of the same crystal. Together with the distinct optical and spin transition energies of such inequivalent states, these interactions provide a route to dipole-coupled networks of separately addressable spins. PMID- 23652009 TI - Regulation of adipose oestrogen output by mechanical stress. AB - Adipose stromal cells are the primary source of local oestrogens in adipose tissue, aberrant production of which promotes oestrogen receptor-positive breast cancer. Here we show that extracellular matrix compliance and cell contractility are two opposing determinants for oestrogen output of adipose stromal cells. Using synthetic extracellular matrix and elastomeric micropost arrays with tunable rigidity, we find that increasing matrix compliance induces transcription of aromatase, a rate-limiting enzyme in oestrogen biosynthesis. This mechanical cue is transduced sequentially by discoidin domain receptor 1, c-Jun N-terminal kinase 1, and phosphorylated JunB, which binds to and activates two breast cancer associated aromatase promoters. In contrast, elevated cell contractility due to actin stress fibre formation dampens aromatase transcription. Mechanically stimulated stromal oestrogen production enhances oestrogen-dependent transcription in oestrogen receptor-positive tumour cells and promotes their growth. This novel mechanotransduction pathway underlies communications between extracellular matrix, stromal hormone output, and cancer cell growth within the same microenvironment. PMID- 23652011 TI - A universal description of ultraslow glass dynamics. AB - The dynamics of glass is of importance in materials science but its nature has not yet been fully understood. Here we report that a verification of the temperature dependencies of the primary relaxation time or viscosity in the ultraslowing/ultraviscous domain of glass-forming systems can be carried out via the analysis of the inverse of the Dyre-Olsen temperature index. The subsequent analysis of experimental data indicates the possibility of the self-consistent description of glass-forming low-molecular-weight liquids, polymers, liquid crystals, orientationally disordered crystals and Ising spin-glass-like systems, as well as the prevalence of equations associated with the 'finite temperature divergence'. All these lead to a new formula for the configurational entropy in glass-forming systems. Furthermore, a link to the dominated local symmetry for a given glass former is identified here. Results obtained show a new relationship between the glass transition and critical phenomena. PMID- 23652010 TI - Proteolysis of MOB1 by the ubiquitin ligase praja2 attenuates Hippo signalling and supports glioblastoma growth. AB - Human glioblastoma is the most frequent and aggressive form of brain tumour in the adult population. Proteolytic turnover of tumour suppressors by the ubiquitin proteasome system is a mechanism that tumour cells can adopt to sustain their growth and invasiveness. However, the identity of ubiquitin-proteasome targets and regulators in glioblastoma are still unknown. Here we report that the RING ligase praja2 ubiquitylates and degrades Mob, a core component of NDR/LATS kinase and a positive regulator of the tumour-suppressor Hippo cascade. Degradation of Mob through the ubiquitin-proteasome system attenuates the Hippo cascade and sustains glioblastoma growth in vivo. Accordingly, accumulation of praja2 during the transition from low- to high-grade glioma is associated with significant downregulation of the Hippo pathway. These findings identify praja2 as a novel upstream regulator of the Hippo cascade, linking the ubiquitin proteasome system to deregulated glioblastoma growth. PMID- 23652012 TI - SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs. AB - Ataxia telangiectasia is a devastating neurodegenerative disease caused primarily by loss of function mutations in ATM, a hierarchical DNA repair gene and tumour suppressor. So far, murine models of ataxia telangiectasia have failed to accurately recapitulate many aspects of the disease, most notably, the progressive cerebellar ataxia. Here we present a model of human ataxia telangiectasia using induced pluripotent stem cells, and show that small molecule read-through compounds, designed to induce read-through of mRNA around premature termination codons, restore ATM activity and improve the response to DNA damage. This platform allows for efficient screening of novel compounds, identification of target and off-target effects, and preclinical testing on relevant cell types for the pathogenic dissection and treatment of ataxia telangiectasia. PMID- 23652013 TI - Select interneuron clusters determine female sexual receptivity in Drosophila. AB - Female Drosophila with the spinster mutation repel courting males and rarely mate. Here we show that the non-copulating phenotype can be recapitulated by the elimination of spinster functions from either spin-A or spin-D neuronal clusters, in the otherwise wild-type (spinster heterozygous) female brain. Spin-D corresponds to the olfactory projection neurons with dendrites in the antennal lobe VA1v glomerulus that is fruitless-positive, sexually dimorphic and responsive to fly odour. Spin-A is a novel local neuron cluster in the suboesophageal ganglion, which is known to process contact chemical pheromone information and copulation-related signals. A slight reduction in spinster expression to a level with a minimal effect is sufficient to shut off female sexual receptivity if the dominant-negative mechanistic target of rapamycin is simultaneously expressed, although the latter manipulation alone has only a marginal effect. We propose that spin-mediated mechanistic target of rapamycin signal transduction in these neurons is essential for females to accept the courting male. PMID- 23652014 TI - Engineering fluid flow using sequenced microstructures. AB - Controlling the shape of fluid streams is important across scales: from industrial processing to control of biomolecular interactions. Previous approaches to control fluid streams have focused mainly on creating chaotic flows to enhance mixing. Here we develop an approach to apply order using sequences of fluid transformations rather than enhancing chaos. We investigate the inertial flow deformations around a library of single cylindrical pillars within a microfluidic channel and assemble these net fluid transformations to engineer fluid streams. As these transformations provide a deterministic mapping of fluid elements from upstream to downstream of a pillar, we can sequentially arrange pillars to apply the associated nested maps and, therefore, create complex fluid structures without additional numerical simulation. To show the range of capabilities, we present sequences that sculpt the cross-sectional shape of a stream into complex geometries, move and split a fluid stream, perform solution exchange and achieve particle separation. A general strategy to engineer fluid streams into a broad class of defined configurations in which the complexity of the nonlinear equations of fluid motion are abstracted from the user is a first step to programming streams of any desired shape, which would be useful for biological, chemical and materials automation. PMID- 23652015 TI - Genomic islands of divergence are not affected by geography of speciation in sunflowers. AB - Genomic studies of speciation often report the presence of highly differentiated genomic regions interspersed within a milieu of weakly diverged loci. The formation of these speciation islands is generally attributed to reduced inter population gene flow near loci under divergent selection, but few studies have critically evaluated this hypothesis. Here, we report on transcriptome scans among four recently diverged pairs of sunflower (Helianthus) species that vary in the geographical context of speciation. We find that genetic divergence is lower in sympatric and parapatric comparisons, consistent with a role for gene flow in eroding neutral differences. However, genomic islands of divergence are numerous and small in all comparisons, and contrary to expectations, island number and size are not significantly affected by levels of interspecific gene flow. Rather, island formation is strongly associated with reduced recombination rates. Overall, our results indicate that the functional architecture of genomes plays a larger role in shaping genomic divergence than does the geography of speciation. PMID- 23652016 TI - The oldest North American pachycephalosaurid and the hidden diversity of small bodied ornithischian dinosaurs. AB - Taphonomic biases dictate how organisms are represented in the fossil record, but their effect on studies of vertebrate diversity dynamics is poorly studied. In contrast to the high diversity and abundance of small-bodied animals in extant ecosystems, small-bodied dinosaurs are less common than their large-bodied counterparts, but it is unclear whether this reflects unique properties of dinosaurian ecosystems or relates to taphonomic biases. A new, fully domed pachycephalosaurid dinosaur, Acrotholus audeti, from the Santonian of Alberta predates incompletely domed taxa, and provides important new information on pachycephalosaur evolution and the completeness of the ornithischian fossil record. Here we provide the first empirical evidence that the diversity of small bodied ornithischian dinosaurs is strongly underestimated based on ghost lineages and the high proportion of robust and diagnostic frontoparietal domes compared with other pachycephalosaur fossils. This suggests preservational biases have a confounding role in attempts to decipher vertebrate palaeoecology and diversity dynamics through the Mesozoic. PMID- 23652017 TI - The gut microbiota suppresses insulin-mediated fat accumulation via the short chain fatty acid receptor GPR43. AB - The gut microbiota affects nutrient acquisition and energy regulation of the host, and can influence the development of obesity, insulin resistance, and diabetes. During feeding, gut microbes produce short-chain fatty acids, which are important energy sources for the host. Here we show that the short-chain fatty acid receptor GPR43 links the metabolic activity of the gut microbiota with host body energy homoeostasis. We demonstrate that GPR43-deficient mice are obese on a normal diet, whereas mice overexpressing GPR43 specifically in adipose tissue remain lean even when fed a high-fat diet. Raised under germ-free conditions or after treatment with antibiotics, both types of mice have a normal phenotype. We further show that short-chain fatty acid-mediated activation of GPR43 suppresses insulin signalling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of unincorporated lipids and glucose in other tissues. These findings establish GPR43 as a sensor for excessive dietary energy, thereby controlling body energy utilization while maintaining metabolic homoeostasis. PMID- 23652018 TI - GANP regulates recruitment of AID to immunoglobulin variable regions by modulating transcription and nucleosome occupancy. AB - Somatic hypermutation in B cells is initiated by activation-induced cytidine deaminase-catalyzed C->U deamination at immunoglobulin variable regions. Here we investigate the role of the germinal centre-associated nuclear protein (GANP) in enhancing the access of activation-induced cytidine deaminase (AID) to immunoglobulin variable regions. We show that the nuclear export factor GANP is involved in chromatin modification at rearranged immunoglobulin variable loci, and its activity requires a histone acetyltransferase domain. GANP interacts with the transcription stalling protein Spt5 and facilitates RNA Pol-II recruitment to immunoglobulin variable regions. Germinal centre B cells from ganp-transgenic mice showed a higher AID occupancy at the immunoglobulin variable region, whereas B cells from conditional ganp-knockout mice exhibit a lower AID accessibility. These findings suggest that GANP-mediated chromatin modification promotes transcription complex recruitment and positioning at immunoglobulin variable loci to favour AID targeting. PMID- 23652019 TI - Deletion of cavin genes reveals tissue-specific mechanisms for morphogenesis of endothelial caveolae. AB - Caveolae are abundant in endothelial cells and are thought to have important roles in endothelial cell biology. The cavin proteins are key components of caveolae, and are expressed at varied amounts in different tissues. Here we use knockout mice to determine the roles of cavins 2 and 3 in caveolar morphogenesis in vivo. Deletion of cavin 2 causes loss of endothelial caveolae in lung and adipose tissue, but has no effect on the abundance of endothelial caveolae in heart and other tissues. Changes in the morphology of endothelium in cavin 2 null mice correlate with changes in caveolar abundance. Cavin 3 is not required for making caveolae in the tissues examined. Cavin 2 determines the size of cavin complexes, and acts to shape caveolae. Cavin 1, however, is essential for normal oligomerization of caveolin 1. Our data reveal that endothelial caveolae are heterogeneous, and identify cavin 2 as a determinant of this heterogeneity. PMID- 23652020 TI - Absence of A673T amyloid-beta precursor protein variant in Alzheimer's disease and other neurological diseases. AB - The rare variant A673T in the amyloid-beta precursor protein (APP) gene has been shown to reduce the risk of cognitive impairment. We genotyped the variant in 8721 Asian individuals comprising 552 with Alzheimer's disease and vascular dementia, 790 with Parkinson's disease, and 7379 controls. The A673T variant was absent in all of the subjects. Our finding suggests that the A673T protective variant is not relevant in our Asian population. Studies in other ethnic populations would clarify whether this variant is specific to specific races/ethnicities. PMID- 23652022 TI - Radiation-induced stress response in peripheral blood of breast cancer patients differs between patients with severe acute skin reactions and patients with no side effects to radiotherapy. AB - The aim of the study was to compare the radiation-induced oxidative stress response in blood samples from breast cancer patients that developed severe acute skin reactions during the radiotherapy, with the response in blood samples from patients with no side effects. Peripheral blood was collected from 12 breast cancer patients showing no early skin reactions after radiotherapy (RTOG grade 0) and from 14 breast cancer patients who developed acute severe skin reactions (RTOG grade 3-4). Whole blood was irradiated with 0, 5 and 2000mGy gamma radiation and serum was isolated. The biomarker for oxidative stress, 8-oxo-dG, was analyzed in the serum by a modified ELISA. While a significant radiation induced increase of serum 8-oxo-dG levels was observed in serum of the RTOG 0 patients, no increase was seen in serum of the RTOG 3-4 patients. The radiation induced increase in serum 8-oxo-dG levels after 5mGy did not differ significantly from the increase observed for 2000mGy in the RTOG 3-4 cohort, thus no dose response relation was observed. A receiver operating characteristic (ROC) value of 0.97 was obtained from the radiation-induced increase in 8-oxo-dG indicating that the assay could be used to identify patients with severe acute adverse reactions to radiotherapy. The results show that samples of whole blood from patients, classified as highly radiosensitive (RTOG 3-4) based on their skin reactions to radiotherapy, differ significantly in their oxidative stress response to ionizing radiation compared to samples of whole blood from patients with no skin reactions (RTOG 0). Extracellular 8-oxo-dG is primarily a biomarker of nucleotide damage and the results indicate that the patients with severe acute skin reactions differ in their cellular response to ionizing radiation at the level of induction of oxidative stress or at the level of repair or both. PMID- 23652021 TI - Toxicology and carcinogenesis studies of Ginkgo biloba extract (CAS No. 90045-36 6) in F344/N rats and B6C3F1/N mice (Gavage studies). AB - Ginkgo biloba extract has been used primarily as a medicinal agent in the treatment or prevention of cardiovascular and cerebrovascular dysfunction. Ginkgo biloba extract was nominated for study by the National Cancer Institute because of its widespread use as an herbal supplement to promote mental function and the limited availability of toxicity and carcinogenicity data. Furthermore, one of the major ingredients in Ginkgo biloba extract, quercetin, is a known mutagen. The Ginkgo biloba extract used in the current studies was procured from a supplier known to provide material to United States companies and contained 31.2% flavonol glycosides, 15.4% terpene lactones (6.94% bilo-balide, 3.74% ginkgolide A, 1.62% ginkgolide B, 3.06% ginkgolide C), and 10.45 ppm ginkgolic acid. Male and female F344/N rats and B6C3F1/N mice were administered Ginkgo biloba extract in corn oil by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 62.5, 125, 250, 500, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses, 5 days per week for 23 days. All rats survived to the end of the study. Mean body weights of all dosed groups were similar to those of the vehicle control groups. Liver weights of all dosed groups of males and females were significantly greater than those of the vehicle control groups. The incidences of hepatocyte hypertrophy in all dosed groups of males and in 500 and 1,000 mg/kg females were significantly greater than those in the vehicle control groups; there was a dose-related increase in severity of this lesion in males. Hepatocyte fatty change occurred in all dosed males. The incidences of thyroid gland follicular cell hypertrophy were significantly increased in 500 and 1,000 mg/kg males and in 1,000 mg/kg females. The incidences of pigmentation in the olfactory epithelium of the nose were significantly increased in 500 and 1,000 mg/kg males and in females administered 125 mg/kg or greater. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 125, 250, 500, 1,000, or 2,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. One female mouse in the 1,000 mg/kg group died of a dosing accident during week 11. Mean body weights of 2,000 mg/kg females were significantly less than those of the vehicle control group. Ruffled fur was observed in two 1,000 mg/kg males between weeks 7 and 8 and all 2,000 mg/kg males between weeks 5 and 9. Liver weights of 250 mg/kg or greater males and all dosed groups of females were significantly greater than those of the vehicle control groups. Kidney weights of 2,000 mg/kg males were significantly less than those of the vehicle control group. The Markov transition matrix analyses indicate female mice in the 2,000 mg/kg group had a significantly higher probability of extended estrus than did the vehicle control females. The incidences of hepatocytic hypertrophy were significantly increased in males and females in the 250 mg/kg or greater groups. Significantly increased incidences of focal hepatocytic necrosis occurred in 1,000 and 2,000 mg/kg males. The incidences of hyaline droplet accumulation in the respiratory epithelium of the nose were significantly increased in 500 mg/kg males and 1,000 and 2,000 mg/kg females. In the olfactory epithelium of the nose, the incidences of hyaline droplet accumulation were significantly increased in the 125 (female only), 500, and 1,000 mg/kg groups. Incidences of atrophy of the olfactory epithelium were significantly increased in the 1,000 mg/kg groups. The incidences of pigment accumulation in macrophages in the olfactory epithelium were significantly increased in males in the 500 mg/kg or greater groups and in 1,000 and 2,000 mg/kg females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 100, 300, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 104 or 105 (females) weeks. Additional groups of 10 male and 10 female rats (special study) were administered the same doses, 5 days per week for 14 weeks. Survival of 1,000 mg/kg males was significantly less than that of the vehicle controls. At week 14, all dosed groups of males and 1,000 mg/kg females had increased levels of thyroid stimulating hormone compared to those of the vehicle control groups. There were no significant decreases in the levels of triiodothyronine or total thyroxine. Mean body weights of 300 mg/kg males and females were less (10% or more) than those of the vehicle controls after week 93, and those of 1,000 mg/kg males and females were less after week 89. Clinical findings included ruffled fur in seven, eight, and 10 males in the 100, 300, and 1,000 mg/kg groups, respectively, beginning at week 89; four vehicle control males also had ruffled fur. Liver weights were significantly increased in all dosed groups of special study rats at 14 weeks. In the liver at 2 years, incidences of hepatocellular adenoma were slightly increased in 100 and 300 mg/kg males. Significantly increased incidences of nonneoplastic lesions at 2 years included hepatocyte hypertrophy and bile duct hyperplasia in all dosed groups of males and females, focal fatty change in all dosed groups of females, cystic degeneration in 100 and 1,000 mg/kg males, and oval cell hyperplasia and necrosis in 1,000 mg/kg males. In the thyroid gland, incidences of follicular cell adenoma were slightly increased in 300 and 1,000 mg/kg males and 300 mg/kg females. Single incidences of follicular cell carcinoma occurred in the 300 and 1,000 mg/kg female groups. There were significantly increased incidences of follicular cell hypertrophy in all dosed groups of males and females and follicle hyperplasia in all dosed groups of males. In the nose, adenoma of the respiratory epithelium occurred in two females receiving 300 mg/kg. Except for respiratory epithelium hyperplasia in 100 mg/kg females, the incidences of transitional epithelium and respiratory epithelium hyperplasia were significantly increased in all dosed groups of males and females. Except for olfactory epithelium respiratory metaplasia in 100 mg/kg females, the incidences of atrophy, respiratory metaplasia, nerve atrophy, and pigmentation were significantly increased in the olfactory epithelium of all dosed groups of males and females. Incidences of goblet cell hyperplasia in the respiratory epithelium were significantly increased in 300 and 1,000 mg/kg males and females, and incidences of chronic active inflammation were significantly increased in 1,000 mg/kg males and females. The incidence of submucosa fibrosis was significantly increased in 1,000 mg/kg males. The incidences of mononuclear cell leukemia in 300 and 1,000 mg/kg males were significantly greater than that in the vehicle controls. Dose-related increased severity of kidney nephropathy was noted in all dosed groups of males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 0, 200, 600, or 2,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 104 weeks. Survival of 600 and 2,000 mg/kg males was significantly less than that of the vehicle controls; survival of 600 mg/kg females was significantly greater than that of the vehicle controls. Mean body weights of 600 and 2,000 mg/kg males were less (10% or more) than those of the vehicle controls after weeks 85 and 77, respectively; mean body weights of 2,000 mg/kg females were generally less than those of the vehicle controls between weeks 17 and 69 and after week 93. In the liver, there were significantly increased incidences of hepatocellular adenoma in all dosed groups of females, hepatocellular carcinoma in all dosed groups of males and 2,000 mg/kg females, and hepatoblastoma in all dosed groups of males and 600 and 2,000 mg/kg females. The increased incidences of these neoplasms were primarily due to increased incidences of multiple adenoma, carcinoma, and hepatoblastoma. Except for the incidences of hepatocellular carcinoma or hepatoblastoma (combined) in 200 and 600 mg/kg females, the incidences of hepatocellular adenoma or carcinoma (combined), hepatocellular carcinoma or hepatoblastoma (combined), and hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) were significantly increased in all dosed groups of males and females. Significantly increased incidences of nonneoplastic liver lesions included hypertrophy in all dosed groups of males and females, erythrophagocytosis in all dosed groups of males and in 600 and 2,000 mg/kg females, hematopoietic cell proliferation, inflammation, and necrosis in 600 and 2,000 mg/kg males, and cytoplasmic vacuolization, eosinophilic focus, and mixed cell focus in all dosed groups of females. In the thyroid gland, two incidences each of follicular cell adenoma occurred in the 600 and 2,000 mg/kg male groups. The incidence of follicle hyperplasia was significantly increased in 2,000 mg/kg males, and the incidences of follicular cell hypertrophy were significantly increased in 2,000 mg/kg males and 600 and 2,000 mg/kg females. In the forestomach, the incidences of inflammation, epithelium hyperplasia, and epithelium hyperkeratosis were significantly increased in all dosed groups of males and in 2,000 mg/kg females; the incidences of epithelium ulcer were significantly increased in 2,000 mg/kg males and females. GENETIC TOXICOLOGY Ginkgo biloba extract was mutagenic in S. typhimurium strains TA98 and TA100, and in E. coli strain WP2 uvrA/pKM101, with and without exogenous metabolic activation. (ABSTRACT TRUNCATED) PMID- 23652023 TI - Anaesthetic management of a giant encephalocele: size does matter. AB - Encephalocele is a form of neural tube defect, characterized by protrusion out of the meninges and brain tissue through a bony skull defect. As per the site of origin, these encephaloceles have been classified into different types, out of which the frontoethmoidal one is exclusively common in Southeast Asia with a reported incidence of 1 in 5,000. Neurological outcome of such malformations depends on the size of the sac, neural tissue content, hydrocephalus, associated infection, and other pathologies that accompany this condition. Here we describe the anaesthetic concerns and perioperative management of a giant occipital encephalocele. PMID- 23652024 TI - Cost effectiveness of neoadjuvant chemotherapy in locally advanced operable head and neck cancer followed by surgery and postoperative radiotherapy: a Markov model-based decision analysis. AB - INTRODUCTION: Head and neck carcinomas are among the most frequent tumor diseases and, because of different multimodal therapy options, cause enormous costs. For this reason, we examined whether in operable advanced head and neck carcinomas, neoadjuvant induction chemotherapy is cost effective in comparison with surgery followed by postoperative radio(chemo)therapy. MATERIAL AND METHODS: A Markov model was developed with paclitaxel, cisplatin and fluorouracil as induction therapy. The legal health insurance in Germany was chosen for cost perspectives, and a willingness-to-pay limit at EUR 38,000 was set. RESULTS: Total costs for surgery with postoperative radiochemotherapy amounted to EUR 13,999. Prior induction chemotherapy raised the costs to EUR 17,377, with a higher effectiveness by 0.1 years of life. Costs per year of life gained are EUR 33,780. The incremental cost effectiveness ratio (ICER) with variations in side effects for surgery and postoperative chemotherapy amounted to between EUR 31,520 and 36,050. With variations in side effects for induction chemotherapy, the ICER amounted to EUR 30,060-37,520. The Monte Carlo simulation disclosed cost effectiveness for 55.4% of the patients; for 44.6%, there was no cost effectiveness. CONCLUSION: The Markov-modeled cost effectiveness analysis indicates that with operable head and neck tumors, induction therapy with paclitaxel, cisplatin and fluorouracil is cost effective. PMID- 23652025 TI - Opportunities and challenges in social pharmacy and pharmacy practice research. AB - Pharmacy practice and social pharmacy are two important research areas within pharmaceutical and health sciences. As the disciplines have undergone and are still undergoing changes, it is useful to reflect on the current state of their research as the basis for discussing further development. The two areas are currently beset by a lack of consensus and charged all too often with evaluating narrowly focused pharmacy services. With the added challenge of diminished funding for research and the pressures to publish results, these fields have to accommodate a much broader research framework than ever before. In this article, the challenges and opportunities in current research are reviewed, and suggestions provided on how to further research in these areas. A systematic content analysis is important to benchmark trends in the types of studies conducted, and to map the collaboration and funding within these areas. PMID- 23652026 TI - Race concordance and healthcare. PMID- 23652027 TI - Residual symptoms related to physical and panic symptoms at baseline predict remission of depression at follow-up. AB - AIMS: The study aimed to investigate whether common residual symptoms at baseline were able to predict full remission of depression at 6-month and 2-year follow-up examinations in patients with major depressive disorder (MDD). METHODS: This study enrolled 135 outpatients with MDD. The depression (DS) and somatic subscales (SS) of the Depression and Somatic Symptoms Scale and the depression and anxiety (HADS-A) subscales of the Hospital Anxiety and Depression Scale were used to investigate residual symptoms, which were divided into the common residual part (CRP) and the other residual part (ORP). Multivariate logistic regression was used to compare the ability to predict full remission between the CRP and ORP scores at baseline. RESULTS: One hundred and nineteen and 106 outpatients completed the two follow-up examinations. The CRP of the DS and the ORP of the SS and HADS-A at baseline had a good ability to predict full remission among patients without pharmacotherapy. The three residual parts included physical and anxiety symptoms of depression and panic symptoms. CONCLUSIONS: Physicians should pay attention to physical, anxiety, and panic symptoms, because these symptoms are related to remission of depression. Future studies should explore how these symptoms affect the prognosis of depression. PMID- 23652028 TI - Primordial germ cells in an oligochaete annelid are specified according to the birth rank order in the mesodermal teloblast lineage. AB - The primordial germ cells (PGCs) in the oligochaete annelid Tubifex tubifex are descentants of the mesodermal (M) teloblast and are located in the two midbody segments X and XI in which they serve as germline precursors forming the testicular gonad and the ovarian gonad, respectively. During embryogenesis, vasa expressing cells (termed presumptive PGCs or pre-PGCs) emerge in a variable set of midbody segments including the genital segments (X and XI); at the end of embryogenesis, pre-PGCs are confined to the genital segments, where they become PGCs in the juvenile. Here, using live imaging of pre-PGCs, we have demonstrated that during Tubifex embryogenesis, pre-PGCs (defined by Vasa expression) stay in segments where they have emerged, suggesting that it is unlikely that pre-PGCs move intersegmentally during embryogenesis. Thus, it is apparent that pre-PGCs derived from the 10th and 11th M teloblast-derived primary m blast cells (designated m10 and m11) that give rise, respectively, to segments X and XI are specified in situ as PGCs and that those born in other segments become undetectable at the end of embryogenesis. To address the mechanisms for this segment-specific development of PGCs, we have performed a set of cell transplantation experiments as well as cell-ablation experiments. When m10 and m11 that are normally located in the mid region of the embryo were placed in positions near the anterior end of the host embryo, these cells formed two consecutive segments, which exhibited Vasa-positive PGC-like cells at early juvenile stage. This suggests that in terms of PGC generation, the fates of m10 and m11 remain unchanged even if they are placed in ectopic positions along the anteroposterior axis. Nor was the fate of m10 and m11 changed even if mesodermal blast cell chains preceding or succeeding m10 and m11 were absent. In a previous study, it was shown that PGC development in segments X and XI occurs normally in the absence of the overlying ectoderm. All this strongly suggests that irrespective of their surrounding cellular environments, m10 and m11 autonomously generate PGCs. We propose that m10 and m11 are exclusively specified as precursors of PGCs at the time of their birth from the M teloblast and that the M teloblast possesses a developmental program through which the sequence of mesodermal blast cell identities is determined. PMID- 23652030 TI - A systematic review of the association between pulmonary tuberculosis and the development of chronic airflow obstruction in adults. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major public health concern, accounting for 3 million deaths annually, 90% of which occur in low- and middle-income countries. Pulmonary tuberculosis (PTB) as a contributory factor in the aetiology of COPD is under debate, with most epidemiologic evidence suggesting a positive association. OBJECTIVES: To compile a systematic review of evidence for an association between PTB and the development of chronic airflow obstruction (CAO). METHODS: We performed a systematic review of original English language, peer-reviewed literature using the PubMed/MEDLINE database. CAO was defined by spirometry [FEV1:FVC ratio <0.70 or = 2.50 mm. IVUS of intermediate coronary lesions were performed before intervention. Pressure-derived fractional flow reserve (FFR) was measured at maximal hyperemia induced by adenosine infusion. An FFR < 0.80 was considered as abnormal functional significance. RESULTS: For the overall 165 lesions, the mean FFR value was 0.84 +/- 0.09. The diameter of the stenosis by visual estimation on angiogram was (59.63 +/- 11.29)%. Minimum lumen diameter (MLD), minimum lumen area (MLA) and plaque burden (PB) were (2.00 +/- 0.36) mm, (3.88 +/- 1.34) mm(2), (67.28 +/- 9.89)% respectively by IVUS measurements. An FFR < 0.80 was seen in 43 lesions (30.5%). There was a moderate correlation between IVUS parameters and FFR, including MLD (r = 0.372, P < 0.001), MLA (r = 0.442, P < 0.001) and PB (r = -0.172, P < 0.05). MLA was a predictor for FFR as a continuous variable independent of possible confounding variables (P < 0.05), and MLA and PB, were predictors for FFR < 0.80 as binary variables (P < 0.05). The best cutoff value of MLA to predict FFR < 0.80 was < 3.15 mm(2), with a 73.6% diagnostic accuracy; sensitivity 71.4%, specificity 67.0%, AUC = 0.709, and P < 0.001. The cutoff value of the PB to predict FFR < 0.80 was 65.45%; sensitivity 82.6%, specificity 41.2%, AUC = 0.644, and P < 0.01. If both MLA and PB were taken into account, the negative predictive value and the positive predictive value were 88.7% and 64.8% respectively. CONCLUSIONS: Anatomic measurements of intermediate coronary lesions obtained by IVUS showed a moderate correlation to FFR values. IVUS-derived MLA >= 3.15 mm(2) may be useful to exclude FFR < 0.80, but poor specificity limits its applicability for physiological assessment of lesions < 3.15 mm(2). MLA was one of many factors affecting coronary flow hemodynamics. Both MLA and PB should be taken into account when determining functional ischemia. PMID- 23652038 TI - Can "Hybrid stent implantation" improve long-term safety without adversely affecting efficacy when treating multilesion coronary artery disease in the drug eluting stent era? AB - BACKGROUND: Though drug-eluting stent (DES) almost solved a problem of restenosis, safety issues related to stent thrombosis are still the major concern of DES. We hypothesized that hybrid stent implantation may decrease the use of DES, probably improving the long-term safety but not affecting efficacy adversely when treating multilesion coronary artery disease in the DES era. METHODS: From April 2004 to October 2006, 848 patients with multilesion disease underwent hybrid stent implantation. During the same period 5647 patients with multilesion coronary heart disease were treated by exclusive DES implantation in Fu Wai Hospital. According to propensity score matching, we chose 823 pairs of patients with multileison coronary artery disease for inclusion into our study. We obtained the 24-month clinical outcome including death, myocardial infarction (MI), thrombosis, target lesion revascularization (TLR), target vessel revascularization (TVR), and major adverse cardiac events (MACE, the composite of death, MI, and TVR). We used Cox's proportional-hazard models to assess relative risks of all the outcome measures after propensity match. RESULTS: At 24 months, patients in the hybrid stent implantation group showed a significantly higher risk of TLR (8.39% vs. 3.28%, HR 2.38, 95%CI: 1.50 - 3.70), TVR (11.07% vs. 6.32%, HR 1.61, 95%CI: 1.15 - 2.27) and MACE (13.75% vs. 8.75%, HR 1.37, 95%CI: 1.02 - 1.85). No significant difference was apparent in terms of mortality (1.22% vs. 1.70%, HR 0.55, 95%CI: 0.24 - 1.25), MI (1.95% vs. 2.31%, HR 0.73, 95%CI: 0.37 - 1.42), or thrombosis (definite + probable) (0.73% vs. 1.58%, HR 0.40, 95%CI: 0.15 - 1.05). CONCLUSIONS: In patients with multilesion coronary artery disease, the exclusive DES implantation was associated with significantly lower risks of TLR, TVR and MACE, and the hybrid stent implantation did not result in any significant improvements regarding safety issues. Prospective studies are needed to confirm our results. PMID- 23652039 TI - Change in cholesterol absorption and synthesis markers in patients with coronary heart disease after combination therapy with simvastatin plus ezetimibe. AB - BACKGROUND: Statins and ezetimibe have been reported to change the balance of cholesterol metabolism, but few studies have been performed on Chinese patients. The aim of this study was to evaluate changes in cholesterol metabolism markers in patients with coronary heart disease. METHODS: Forty-five patients with coronary heart disease were treated with 20 mg/d of simvastatin for four weeks. Subjects were then divided into two different therapy groups according to whether they reached the target values for total cholesterol and low density lipoprotein cholesterol level. Patients who reached the target values remained on simvastatin and those who did not reach the target values took a combination of simvastatin plus 10 mg/d ezetimibe until the 12th week. The concentrations of cholesterol synthesis markers (lathosterol and desmosterol) and absorption markers (campesterol and sitosterol) were measured on the 1st, 4th, and 12th week of the study by gas chromatography. RESULTS: After treatment with simvastatin for four weeks, the levels of total cholesterol and low density lipoprotein cholesterol decreased significantly compared to levels measured during the 1st week (P < 0.05). On the 12th week the levels of total cholesterol and low density lipoprotein cholesterol had decreased significantly (P < 0.001) compared to levels during the 4th week. By the 12th week the levels of campesterol and sitosterol in the combination group had decreased significantly (P < 0.05) compared with levels measured during the 4th week. CONCLUSIONS: Coronary heart disease patients with high cholesterol synthesis at baseline might gain a greater benefit from simvastatin treatment. Combination therapy with simvastatin plus ezetimibe in patients with low cholesterol synthesis at baseline might increase the success rate of lipid-lowering through decreasing the absorption of cholesterol. PMID- 23652040 TI - Impact of the origin of sinus node artery on recurrence after pulmonary vein isolation in patients with paroxysmal atrial fibrillation. AB - BACKGROUND: Major atrial coronary arteries, including the sinus node artery (SNA), were commonly found in the areas involved in atrial fibrillation (AF) ablation and could cause difficulties in achieving linear block at the left atrial (LA) roof. The SNA is a major atrial coronary artery of the atrial coronary circulation. This study aimed to determine impact of the origin of SNA on recurrence of AF after pulmonary vein isolation (PVI) in patients with paroxysmal AF. METHODS: Seventy-eight patients underwent coronary angiography for suspected coronary heart disease, followed by catheter ablation for paroxysmal AF. According to the origin of SNA from angiographic findings, they were divided into right SNA group (SNA originating from the right coronary artery) and left SNA group (SNA originating from the left circumflex artery). Guided by an electroanatomic mapping system, circumferential pulmonary vein ablation (CPVA) was performed in both groups and PVI was the procedural endpoint. All patients were followed up at 1, 3, 6, 9 and 12 months post-ablation. Recurrence was defined as any episode of atrial tachyarrhythmias (ATAs), including AF, atrial flutter or atrial tachycardia, that lasted longer than 30 seconds after a blanking period of 3 months. RESULTS: The SNA originated from the right coronary artery in 34 patients (43.6%) and the left circumflex artery in 44 patients (56.4%). Freedom from AF and antiarrhythmic drugs (AADs) at 1 year was 67.9% (53/78) for all patients. After 1 year follow-up, 79.4% (27/34) in right SNA group and 59.1% (26/44) in left SNA group (P = 0.042) were in sinus rhythm. On multivariate analysis, left atrium size (HR = 1.451, 95%CI: 1.240 - 1.697, P < 0.001) and a left SNA (HR = 6.22, 95%CI: 2.01 - 19.25, P = 0.002) were the independent predictors of AF recurrence. CONCLUSIONS: The left SNA is more frequent in the patients with paroxysmal AF. After one year follow-up, the presence of a left SNA was identified as an independent predictor of AF recurrence after CPVA in paroxysmal AF. PMID- 23652041 TI - Four-year clinical outcome in asymptomatic patients undergoing coronary computed tomography angiography. AB - BACKGROUND: Percutaneous coronary intervention (PCI) is indicated for angina with coronary stenosis. However, PCI for asymptomatic coronary stenosis remains controversial. We prospectively followed a group of patients for four years who underwent coronary computed tomography angiography (CCTA) for major adverse cardiac events (MACE). We hypothesized that the results of this trial would reliably reflect the natural outcome of the coronary disease. METHODS: Consecutive patients who underwent CCTA from June 2008 to May 2009 were selected. Those who could not be reached by telephone, had significant angina, had CT images that were not interpretable, or poor kidney and left ventricular (LV) function were excluded. The patients were divided into five groups: group A normal CCTA without stenosis, group B mild stenosis (1% - 49%), group C moderate stenosis (50% - 74%), group D severe stenosis (= 75%) and they were treated with optimal medical therapy (OMT) or PCI. The group E had PCI before the CCTA examination. The patients were then followed for MACE after different treatments. MACE included acute myocardial infarction (MI), heart failure (HF) and death. RESULTS: The patient population consisted of 419 patients. The follow-up time was (51 +/- 5) months. The age was (60 +/- 31) years. Male made up 67.78% of the population (n = 284). A total of 51 cases of MACE occurred including 25 MI, eight HF and 18 all-cause deaths. There was no MACE in group A. Although MACE occurred in two patients in group B, they were not attributed to cardiac death. We further compared the MACE in groups C-E and no significant difference was found (P > 0.05). However, a difference was detected among patients with unstable angina pectoris (UAP), stable angina pectoris (SAP), re-hospitalization, and cerebrovascular events from groups A-E (P < 0.05). The plaque scores were used to predict MACE. The scores progressively increased significantly with lesion severity (P < 0.05). Receiver operating curve (ROC) was performed to determine the sensitivity and specificity in predicting MACE. Our scores predicted MI with area of 0.76, predicted HF with area of 0.77, and predicted death with area of 0.70. CONCLUSIONS: Normal and mild lesions had very few events. With increased stenosis the MACE rate increased progressively. PCI did not significantly reduce the MACE in comparison with OMT in asymptomatic patients. Furthermore, UAP, re hospitalization, and re-PCI were significantly increased in patients who were treated with PCI. PMID- 23652042 TI - Beyond retinocytomas: clinical benefit of topotecan in the management of other intra-cranial tumors especially glioblastomas. PMID- 23652043 TI - Perioperative aortic dissection rupture after endovascular stent graft placement for treatment of type B dissection. AB - BACKGROUND: The perioperative aortic dissection (AD) rupture is a severe event after endovascular stent graft placement for treatment of type B AD. However, this life-threatening complication has not undergone systematic investigation. The aim of the study is to discuss the reasons of AD rupture after the procedure. METHODS: The medical record data of 563 Stanford type B AD patients who received thoracic endovascular repair from 2004 to December 2011 at our institution were collected and analyzed. Double entry and consistency checking were performed with Epidata software. RESULTS: Twelve patients died during the perioperation after thoracic endovascular repair, with an incidence of 2.1%, 66.6% were caused by aortic rupture and half of the aortic rupture deaths were caused by retrograde type A AD. In our study, 74% of the non-rupture surviving patients had the free flow bare spring proximal stent implanted, compared with 100% of the aortic rupture patients (74% vs. 100%, P = 0.213). The aortic rupture patients are more likely to have ascending aortic diameters = 4 cm (62.5% vs. 9.0%, P = 0.032), involvement the aortic arch concavity (62% vs. 27%, P = 0.041) and have had multiple stents placed (P = 0.039). CONCLUSIONS: Thoracic AD endovascular repair is a safe and effective treatment option for AD with relative low in-hospital mortality. AD rupture may be more common in arch stent-graft patients with an ascending aortic diameter = 4 cm and with severe dissection that needs multi stent placement. Attention should be paid to a proximal bare spring stent that has a higher probability of inducing an AD rupture. Post balloon dilation should be performed with serious caution, particularly for the migration during dilation. PMID- 23652044 TI - An open-labeled, randomized, multicenter phase IIa study of gambogic acid injection for advanced malignant tumors. AB - BACKGROUND: Gambogic acid is a pure active compound isolated from the traditional Chinese medicinal plant gamboge (Garcinia morella Desv.). Based on the preliminary results of a phase I study, this phase IIa study compared the efficacy and safety of different dosage schedules of gambogic acid in patients with advanced malignant tumors. METHODS: Patients with advanced or metastases cancer who had not received any effective routine conventional treatment or who had failed to respond to the existing conventional treatment were randomly assigned to receive either 45 mg/m(2) gambogic acid intravenously from Days 1 to 5 of a 2-week cycle (Group A), or 45 mg/m(2) every other day for a total of five times during a 2-week cycle (Group B). The primary endpoint was objective response rate (ORR). RESULTS: Twenty-one patients assigned to Group A and 26 to Group B were included in the final analysis. The ORRs were 14.3% in Group A and 0% in Group B. It was not possible to analyze the significant difference because one of the values was zero. The disease control rates (DCRs) were 76.2% in Group A and 61.5% in Group B (P = 0.0456). The observed adverse reactions were mostly Grades I and II, and occurred in most patients after administration of the trial drug. There was no significant difference in the incidence of adverse reactions between the two arms. CONCLUSIONS: The preliminary results of this phase IIa exploratory study suggest that gambogic acid has a favorable safety profile when administered at 45 mg/m(2). The DCR was greater in patients receiving gambogic acid on Days 1 - 5 of a 2-week cycle, but the incidence of adverse reactions was similar irrespective of the administration schedule. PMID- 23652045 TI - Effects of triterpenic acid from Prunella vulgaris L. on glycemia and pancreas in rat model of streptozotozin diabetes. AB - BACKGROUND: The effects of triterpenic acid from Prunella vulgaris L. (TAP) on diabetes and its mechanism are uncertain. The aim of this study was to investigate the effects of TAP on antihyperglycemic, antioxidant, and pancreas protective in streptozotozin (STZ)-diabetic rats. METHODS: The diabetic model was produced by injection of 60 mg/kg STZ. Blood was drawn from the tail vein of rats after 72 hours. Rats with blood glucose >= 16.7 mmol/L were considered diabetic. Diabetic rats were randomly divided into four groups: (1) Diabetes rat (STZ), (2) Diabetic rats treated with 50 mg/kg of triterpenic acid from Prunella vulgaris L (STZ + TAP50), (3) Diabetic rats treated with 100 mg/kg TAP (STZ + TAP100), and (4) Diabetic rats treated with 200 mg/kg TAP (STZ + TAP200). Normal rats (n = 10) acted as the control group (NC). TAP was administered by the intragastric route once each day for six weeks. Body weight and the concentration of blood glucose (BG) were measured after three and six weeks. Fructosamine (FMN), malondialdehyde (MDA), and nitric oxide (NO), and the activities of nitric oxide synthase (NOS) and superoxide dismutase (SOD) in serum were determined after six weeks using commercially available kits following the manufacturer's instructions. Pathologic changes in pancreatic beta-cells were also investigated by microscopic examination after hematoxylin-eosin (HE) staining. The level of SOD mRNA in pancreatic beta-cells was measured by polymerase chain reaction (PCR). RESULTS: The levels of BG, FMN, NO, and MDA and the activities of NOS in serum in the four diabetes groups were significantly increased compared with the control group (P < 0.01). The activity of SOD in serum and the body weight was significantly decreased compared with the control group (P < 0.01). After administration of TAP to diabetic rats for six weeks, the body weight and the levels of BG, FMN, MDA, NO and the activity of NOS in serum decreased significantly compared with the STZ group in a dose-dependent manner. The activity of SOD in serum and body weight increased significantly compared with the STZ group in a dose-dependent manner. In addition, diabetic rats showed a significant decrease in SOD mRNA expression in pancreatic beta cells. However, these changes were reversed by TAP. Histopathological examination also showed the protective effect of TAP on pancreatic beta cells. CONCLUSIONS: Triterpenic acid from Prunella vulgaris L. has an anti-diabetic effect, by controlling blood glucose and antioxidants, and has a protective effect on the pancreas. PMID- 23652046 TI - Volumetric magnetic resonance imaging classification for Alzheimer's disease based on kernel density estimation of local features. AB - BACKGROUND: The classification of Alzheimer's disease (AD) from magnetic resonance imaging (MRI) has been challenged by lack of effective and reliable biomarkers due to inter-subject variability. This article presents a classification method for AD based on kernel density estimation (KDE) of local features. METHODS: First, a large number of local features were extracted from stable image blobs to represent various anatomical patterns for potential effective biomarkers. Based on distinctive descriptors and locations, the local features were robustly clustered to identify correspondences of the same underlying patterns. Then, the KDE was used to estimate distribution parameters of the correspondences by weighting contributions according to their distances. Thus, biomarkers could be reliably quantified by reducing the effects of further away correspondences which were more likely noises from inter-subject variability. Finally, the Bayes classifier was applied on the distribution parameters for the classification of AD. RESULTS: Experiments were performed on different divisions of a publicly available database to investigate the accuracy and the effects of age and AD severity. Our method achieved an equal error classification rate of 0.85 for subject aged 60 - 80 years exhibiting mild AD and outperformed a recent local feature-based work regardless of both effects. CONCLUSIONS: We proposed a volumetric brain MRI classification method for neurodegenerative disease based on statistics of local features using KDE. The method may be potentially useful for the computer-aided diagnosis in clinical settings. PMID- 23652047 TI - Changes in main causes of death in Macao residents from 1986 - 2006. AB - BACKGROUND: Since Macao's return of sovereignty to China in December 1999, the life style of Macao residents has changed. The aim of this study was to investigate changes of death patterns in Macao residents from 1986 to 2006 in order to identify the trends and patterns of major public health problems, which could provide the guidance for developing public health policies. METHODS: A retrospective study was conducted for this investigation. Research data were collected from official websites and statistical yearbooks and classified by the International Classification of Diseases (ICD)-9. RESULTS: It was observed that mortality from the three major causes of (1) infectious, maternal and childhood diseases, (2) chronic non-communicable diseases, and (3) injury and poisoning were 17.7, 298.2 and 26.0 per 100 000, respectively. The largest decrease in death rate over the 21-year study-period was from infectious, maternal and childhood diseases (62.5%). The highest mortality rate was ischemic heart diseases (37.0%). The largest increase in mortality rate was lung cancer (46.9%). CONCLUSIONS: Mortality rate of Macao residents progressively decreased, but the constituent ratio of death from chronic non-communicable diseases was increasing. The mortality rate of lung cancer was clearly ascending, so emphasis should be put on tertiary prevention in future. PMID- 23652048 TI - Water and sodium restriction on cardiovascular disease in young chronic hemodialysis patients. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is an independent predictor of morbidity and mortality in chronic hemodialysis (CHD) patients. It remains unclear whether efforts to correct fluid overload in young CHD can reverse LVH. This prospective single-center cohort study evaluated left ventricular masses index (LVMI) evolution in fluid overloaded young CHD patients with or without water-sodium control. METHODS: A total of 106 young patients aged between 22 and 44 years on CHD were enrolled in this prospective, control study. Patients were divided into three groups according to the percentage of interdialytic weight gain (PIDWG (%) = 100% * (predialysis weight-dry weight)/dry weight) at baseline. Thirty-six patients with PIDWG more than 5% received health education to restrict water-sodium intake strictly (Group I). Other 36 patients with comparable fluid status levels (the PIDWG more than 5%) did not receive health education to restrict water-sodium intake strictly (Group II) and those with PIDWG less than 5% (Group III, n = 34) were served as controls. Echocardiographic studies were performed to evaluate LVMI at baseline and then after 1, 3 and 6 months. The total follow-up time was 6 months. RESULTS: There was no significant difference in clinical data (such as age, gender, aetiology of renal failure and nutritional state, etc.) among the three groups at baseline. At baseline, the prevalence of LVH in Group I, II and III was 75.0%, 72.2% and 55.9%, respectively. LVMI was directly correlated with PIDWG (r = 0.779, P < 0.01). After 6 months, the PIDWG in Group I decreased in mean by (3.77 +/- 1.09)%, and LVMI decreased in mean by (27.59 +/- 12.15) g/m(2). The prevalence of LVH decreased in mean by 25.0%, and the blood pressure decreased in mean by (14.69 +/- 11.50) mmHg/ (7.14 +/- 7.51) mmHg. The medication category and total medication frequency of hypotensive drugs significantly decreased in Group I at 6 months. However the urine volume and the levels of serum creatinine and serum albumin in Group I were not significantly different compared to the baseline. The level of LVMI in Group II was significantly increased after 6 months compared with the baseline. After 6 months, the level of LVMI in Group III were not significantly different compared with the baseline. CONCLUSIONS: A high prevalence of LVH was present in young CHD patients, and was associated with fluid overload. Reduction fuild overload with water-sodium control can reverse LVH in young CHD patients. PMID- 23652049 TI - Resection and repair of large abdominal wall lesions in gynecologic patients. AB - BACKGROUND: The techniques of resection and repair of large lesions in the abdominal wall are very challenging in the area of gynecology. We explored the techniques of resection and plastic surgical repair of large abdominal wall lesions in gynecologic patients. METHODS: Twenty-six patients with large lesions in the abdominal wall underwent resection by the gynecologists and repair through abdominal plasty and V-Y plasty with or without fascia patch grafting by the gynecologists or plastic surgeons from March 2003 to October 2010. RESULTS: All patients had a history of cesarean section. One patient had an infected sinus tract after cesarean section, one patient had an inflammatory nodule, and the others had lesions of endometriosis, including one cancer. The average largest lesion diameter was (4.79 +/- 4.18) cm according to the ultrasonography results. The lesions of all patients were completely resected with pretty abdominal contour. A polypropylene biological mesh was added to the fascia in 20 patients. One patient underwent groin flap repair, and one underwent V-Y advanced skin flap repair on the left of the incision to relieve the suture tension. CONCLUSIONS: Multi-department cooperation involving the gynecology and plastic surgery departments, and even the general surgery department, is essential for patients with large lesions in the abdominal wall. This cooperative effort enabled surgeons to completely resect large lesions. Abdominal wall plastic surgical repair can ameliorate large wounds of the abdominal wall. PMID- 23652050 TI - Clinical results of combined palliative procedures for cyanotic congenital heart defects with intractable hypoplasia of pulmonary arteries. AB - BACKGROUND: Congenital heart defects with intractable hypoplasia of the pulmonary arteries without intercourse or with intercourse stenosis is unsuitable for surgical correction or regular palliative procedures. We reported our experience with combined palliative procedures for congenital heart defects with intractable hypoplasia pulmonary arteries. METHODS: From 2001 to 2012, a total of 41 patients with cyanotic congenital heart defects and intractable hypoplasia of the pulmonary arteries underwent surgical procedures. From among them, 31 patients had pulmonary atresia with ventricular septal defect (VSD) and the other 10 cases had complicated congenital heart defects with pulmonary stenosis. Different kinds of palliative procedures were performed according to the morphology of the right and left pulmonary arteries in every patient. If the pulmonary artery was well developed, a Glenn procedure was performed. A modified Blalock-Taussig shunt or modified Waterston shunt was performed if pulmonary arteries were hypoplastic. If the pulmonary arteries were severely hypoplastic, a Melbourne shunt was performed. Systemic pulmonary artery shunts were performed bilaterally in 25 cases. A systemic-pulmonary shunt was performed on one side and a Glenn procedure was performed contralaterally in 16 cases. Major aortopulmonary collateral arteries were unifocalized in six cases, ligated in two cases and interventionally embolized in two cases. There was one early death because of cardiac arrest and the hospital mortality was 2.4%. RESULTS: Five patients suffered from postoperative low cardiac output syndrome, three had perfusion of the lungs, and two pulmonary infections. Systemic pulmonary shunts were repeated after the original operation in three cases due to the occlusion of conduits. The mean follow-up time was 25 months. The pre- and the post-operation left pulmonary indices were (8.13 +/- 3.68) vs. (14.9 +/- 6.21) mm(2)/m(2). The pre- and post operation right pulmonary indices were (12.7 +/- 8.13) vs. (17.7 +/- 7.78) mm(2)/m(2). The pre- and post-operational pulmonary indices were (20.87 +/- 9.43) vs. (32.6 +/- 11.7) mm(2)/m(2). They were all significantly increased (P < 0.001). The diameter of the pulmonary artery increased after the modified Blalock Taussig shunt ((5.51 +/- 0.94) mm(2)/m(2) pre-operation vs. (7.01 +/- 1.97) mm(2)/m(2) post-operation), the modified Waterston shunt ((5.70 +/- 3.96) mm(2)/m(2) pre-operation vs. (9.17 +/- 3.62) mm(2)/m(2) post-operation) and the Melbourne shunt ((2.17 +/- 0.41) mm(2)/m(2) pre-operation vs. (7.35 +/- 2.49) mm(2)/m(2) post-operation) (all P < 0.05). Bilateral pulmonary arteries developed well as compared to their pre-operation development. Hemoglobin decreased from (194 +/- 27) to (174 +/- 24) g/L (P < 0.05) and peripheral oxygen saturation increased from (65 +/- 11)% to (84 +/- 6)% (P < 0.001). During the follow-up of 27 to 49 months, ultimate complete repair was performed in four cases and one patient underwent a Glenn procedure. CONCLUSIONS: The procedures should be considered on a case to case basis in patients having hypoplasia of the pulmonary arteries with cyanotic congenital heart defects. Combined palliative operations could be an adequate strategic treatment. PMID- 23652051 TI - Osteopontin knockdown suppresses non-small cell lung cancer cell invasion and metastasis. AB - BACKGROUND: Osteopontin (OPN) was identified as one of the leading genes that promote the metastasis of malignant tumor. However, the mechanism by which OPN mediates metastasis in non-small cell lung cancer (NSCLC) remains unknown. The aim of the study is to investigate the biological significance and the related molecular mechanism of OPN expression in lung cancer cell line. METHODS: Lentiviral-mediated RNA interference was applied to inhibit OPN expression in metastatic human NSCLC cell line (A549). The invasion, proliferation, and metastasis were evaluated OPN-silenced in A549 cells in vitro and in vivo. The related mechanism was further investigated. RESULTS: Interestingly, OPN knockdown significantly suppressed the invasiveness of A549 cells, but had only a minor effect on the cellular migration and proliferation. Moreover, we demonstrated that OPN knockdown significantly reduced the levels of matrix metalloproteinase (MMP)-2 and urokinase plasminogen activator (uPA), and led to an obvious inhibition of both in vitro invasion and in vivo lung metastasis of A549 cells (P < 0.001). CONCLUSIONS: Our data demonstrate that OPN contributes to A549 cell metastasis by stimulating cell invasion, independent of cellular migration and proliferation. OPN could be a new treatment target of NSCLC. PMID- 23652052 TI - Clinical and pathological features of acute optic neuritis in Chinese patients. AB - BACKGROUND: The incentives and the factors that affect the onset and outcome of optic neuritis (ON) are not very clear. The aim of this study is to define and get a comprehensive understanding of the clinical profile of ON, and to identify the factors that were related to the prognosis of the patients. METHODS: Medical records of patients with diagnosis of ON at Huashan Hospital, Fudan University between March 2008 and June 2011 were reviewed. Clinical features, ophthalmologic and neurologic assessments, neuroimaging studies, laboratory examinations, visual recovery, and final outcome of the patients were evaluated by the authors. RESULTS: Records of 50 patients (32 females and 18 males), aged 15 - 56 years, were reviewed, in which 22% patients had a previous onset of ON. Maximal visual deficit was severe in 72.5% (< 20/200). Abnormal rates of hormone levels and rheumatoid indicators were found in 54.2% and 25.0%. ANA test returned positive in 40%, oligoclonal banding (OCB) was identified in 31.3%, and Serum neuromyelitis optica (NMO)-IgG studies were abnormal in 25% of the patients. Neuroimaging abnormalities associated with ON were documented in six patients. Three of the 50 patients have been diagnosed with multiple sclerosis, and two with NMO. Visual acuity was 20/20 or better in 26.1% and 20/100 or worse in 39.1% affected eyes at the last visit. Poor visual acuity at onset is the main factor that would affect the final outcome of vision (P < 0.05). CONCLUSIONS: Vision defects of this group of patients were severe. Females had a higher incidence of ON than males. Hormone levels, rheumatoid indicators and immune parameters may be related to the onset of ON. The severe reduction of visual acuity at onset may be related to the poor outcome of vision in ON patients. PMID- 23652053 TI - Effect of the regimen of Gaoshan Hongjingtian on the mechanism of poly (ADP ribose) polymerase regulation of nuclear factor kappa B in the experimental diabetic retinopathy. AB - BACKGROUND: Poly(ADP-ribose) polymerase (PARP) plays an important role in the death of retinal capillary cells in diabetic retinopathy (DR) partly via its regulation of nuclear factor kappa B (NF-kappaB). The current study investigated the effect of the regimen of Gaoshan Hongjingtian (RG) on the mechanism of PARP regulation of NF-kappaB, and demonstrated the possible impact of the RG and Gaoshan Hongjingtian (Rhodiola sachalinensis, RS) on diabetic retinopathy. METHODS: Wistar rats were made diabetic by administering streptozotocin. They were then assigned to three groups at random. After 2 months, the three groups of these diabetic rats were treated with RS or RG, or untreated. Analyses of expression levels of PARP, NF-kappaB, and intercellular adhesion molecule-1 (ICAM 1) in the retinas of rats in different groups were performed by Western blotting and immunohistochemical assays, and mRNA levels of NF-kappaB and ICAM-1 were determined by real-time polymerase chain reaction (PCR). In addition, the basement membranes of capillaries in the rats' retinas were observed using electron microscopy, and diabetes-induced capillary degeneration (ghost pericytes and acellular capillaries) were quantitated. RESULTS: From the third month after the injection of streptozotocin, the diabetic rats were given daily RG, RS or tap water separately. The diabetic rats failed to gain weight compared with normal age-matched rats, whereas their glycated hemoglobin levels were significantly increased. After 5 months, the mRNA levels of NF-kappaB and ICAM-1 and the protein expression of PARP, NF-kappaB, and ICAM-1 were significantly increased in the retinas of diabetic rats in the untreated group compared with the nondiabetic controls. After 8 months, the number of degenerated retinal capillaries (ghost pericytes and acellular capillaries) was significantly increased in the diabetic rats in the untreated group compared with normal age-matched rats. RG and RS inhibited diabetes-induced over-expression of PARP, NF-kappaB, and ICAM-1 in the retinas of diabetic rats at the end of 5-month diabetic duration. Treatment using RG and RS significantly inhibited increases in the number of acellular capillaries and pericyte ghosts and suppressed the basement membrane thickening in the retinas of rats with diabetes for 8 months compared with the control diabetic rats. CONCLUSIONS: These results indicate that PARP plays an important role in the pathogenesis of diabetic retinopathy. RS and RG may have acted on the mechanism of PARP regulation of NF-kappaB, which suppressed the expression of NF kappaB and ICAM-1, and led to the inhibition of retinal capillary degeneration. PMID- 23652054 TI - Effect of pomegranate peel polyphenol gel on cutaneous wound healing in alloxan induced diabetic rats. AB - BACKGROUND: Pomegranate (punica granatum) belongs to the family Punicaceae, and its peel has been used as a traditional Chinese medicine because of its efficacy in restraining intestine, promoting hemostasis, and killing parasites. Pomegranate peel has been reported to possess wound-healing properties which are mainly attributed to its polyphenol extracts. The purpose of this study was to investigate the effect of pomegranate peel polyphenols (PPP) gel on cutaneous wound healing in diabetic rats. METHODS: Alloxan-induced diabetic rats were given incisional wounds on each side of the mid-back and then treated daily with PPP gel (polyphenol mass fraction = 30%) post-wounding. Rats were sacrificed on days 4, 7, 14, and 21 post-wounding to assess the rates of wound closure, histological characteristics; and to detect the contents of hydroxyproline, production of nitric oxide (NO), and activities of NO synthase (NOS), as well as the expressions of transforming growth factor-beta1 (TGF-beta1), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) in wound tissue. RESULTS: Wound closure was significantly shortened when PPP gel was applied to the wounds of diabetic rats. Histological examination showed the ability of PPP gel to increase fibroblast infiltration, collagen regeneration, vascularization, and epithelialization in the wound area of diabetic rats. In addition, PPP gel treated diabetic rats showed increased contents of hydroxyproline, production of NO, and activities of NOS and increased expressions of TGF-beta1, VEGF, and EGF in wound tissues. CONCLUSION: PPP gel may be a beneficial method for treating wound disorders associated with diabetes. PMID- 23652055 TI - Anatomical study of endoscope-assisted far lateral keyhole approach to the ventral craniocervical region with neuronavigational guidance. AB - BACKGROUND: Image-guided neurosurgery, endoscopic-assisted neurosurgery and the keyhole approach are three important parts of minimally invasive neurosurgery and have played a significant role in treating skull base lesions. This study aimed to investigate the potential usefulness of coupling of the endoscope with the far lateral keyhole approach and image guidance at the ventral craniocervical junction in a cadaver model. METHODS: We simulated far lateral keyhole approach bilaterally in five cadaveric head specimens (10 cranial hemispheres). Computed tomography-based image guidance was used for intraoperative navigation and for quantitative measurements. Skull base structures were observed using both an operating microscope and a rigid endoscope. The jugular tubercle and one-third of the occipital condyle were then drilled, and all specimens were observed under the microscope again. We measured and compared the exposure of the petroclivus area provided by the endoscope and by the operating microscope. Statistical analysis was performed by analysis of variance followed by the Student-Newman Keuls test. RESULTS: With endoscope assistance and image guidance, it was possible to observe the deep ventral craniocervical junction structures through three nerve gaps (among facial-acoustical nerves and the lower cranial nerves) and structures normally obstructed by the jugular tubercle and occipital condyle in the far lateral keyhole approach. The surgical area exposed in the petroclival region was significantly improved using the 0 degrees endoscope (1147.80 mm(2)) compared with the operating microscope ((756.28 +/- 50.73) mm(2)). The far lateral retrocondylar keyhole approach, using both 0 degrees and 30 degrees endoscopes, provided an exposure area ((1147.80 +/- 159.57) mm(2) and (1409.94 +/ 155.18) mm(2), respectively) greater than that of the far lateral transcondylar transtubercular keyhole approach ((1066.26 +/- 165.06) mm(2)) (P < 0.05). CONCLUSIONS: With the aid of the endoscope and image guidance, it is possible to approach the ventral craniocervical junction with the far lateral keyhole approach. The use of an angled-lens endoscope can significantly improve the exposure of the petroclival region without drilling the jugular tubercle and occipital condyle. PMID- 23652056 TI - Cytotoxic effects of mono-(2-ethylhexyl) phthalate on human embryonic stem cells. AB - BACKGROUND: Mono-(2-ethylhexyl) phthalate (MEHP), the metabolite of di-(2 ethylhexyl) phthalate (DEHP), was suspected to be toxic to human embryos. This study contributes to investigating its toxic effects by an embryonic stem cell test (EST) based on two human embryonic stem cell (hESCs) lines. METHODS: CH1 established in our own lab and H1, a federally registered cell line were two human embryonic stem cell lines used in this test. Four endpoint measurements were performed consisting of cell viability, proliferation ability, apoptosis as well as changes of gene expression patterns after spontaneous differentiation were determined. For measuring effects on the first three endpoints, the cells were treated with various concentrations of MEHP dissolved in dimethyl sulfoxide (DMSO) and only with DMSO which served as control and harvested after 5 days. For measuring effects during spontaneous differentiation, the RNA of embryoid bodies (EBs) formed after 8 days' MEHP exposure was collected and changes in differentiation specific gene expression patterns were analyzed by quantitative real time RT-PCR. RESULTS: As a result the viability and proliferation ability of both cell lines decreased significantly at 1000 umol/L MEHP, while there was no effect on apoptosis or cell morphology. In addition MEHP also changed the gene expression pattern in the EBs of both cell lines. CONCLUSION: MEHP in a high dose was cytotoxic and affected the development of hESCs, which indicates its embryo toxicity in human embryos. PMID- 23652057 TI - Tumstatin transfected into human glioma cell line U251 represses tumor growth by inhibiting angiogenesis. AB - BACKGROUND: Angiogenesis is a prerequisite for tumor growth and plays an important role in rapidly growing tumors, such as malignant gliomas. A variety of factors controlling the angiogenic balance have been described, and among these, the endogenous inhibitor of angiogenesis, tumstatin, has drawn considerable attention. The current study investigated whether expression of tumstatin by glioma cells could alter this balance and prevent tumor formation. METHODS: We engineered stable transfectants from human glioma cell line U251 to constitutively secrete a human tumstatin protein with c-myc and polyhistidine tags. Production and secretion of the tumstatin-c-myc-His fusion protein by tumstatin-transfected cells were confirmed by Western blotting analysis. In the present study, we identify the anti-angiogenic capacity of tumstatin using several in vitro and in vivo assays. Student's t-test and one-way analysis of variance (ANOVA) test were used to determine the statistical significance in this study. RESULTS: The tumstatin transfectants and control transfectants (stably transfected with a control plasmid) had similar in vitro growth rates compared to their parental cell lines. However, the conditioned medium from the tumstatin transfected tumor cells significantly inhibits proliferation and causes apoptosis of endothelial cells. It also inhibits tube formation of endothelial cells on Matrigel. Examination of armpit tumors arising from cells overexpressing tumstatin repress the growth of tumor, accompanying the decreased density of CD31 positive vessels in tumors ((5.62 +/- 1.32)/HP), compared to the control transfectants group ((23.84 + 1.71)/HP) and wild type U251 glioma cells group ((29.33 + 4.45)/HP). CONCLUSION: Anti-angiogenic gene therapy using human tumstatin gene may be an effective strategy for the treatment of glioma. PMID- 23652058 TI - Gene polymorphisms of interleukin-28, p21-activated protein kinases 4, and response to interferon-alpha based therapy in Chinese patients with chronic hepatitis B. AB - BACKGROUND: Peg-Interferon-alpha treatment is expensive and associated with considerable adverse effects, selection of patients with the highest probability of response is essential for clinical practice. The objective of this study was to assess the relationship between the gene polymorphisms of interleukin-28 (IL 28), p21-activated protein kinase 4 (PAK4) and the response to interferon treatment in chronic hepatitis B patients. METHODS: Two hundred and forty interferon-naive treatment HBeAg seropositive chronic hepatitis B patients were enrolled in the present prospective nested case-control study. Peripheral blood samples were collected, including 92 with favorable response and 148 without response to the interferon treatment. Rs8099917, rs12980602, and rs9676717 SNP was genotyped using matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). RESULTS: IL-28 genotype was not associated with response to interferon treatment (OR for GT/GG vs. TT, 0.881 (95%CI 0.388 - 2.002); P = 0.762; OR for CT/CC vs. TT, 0.902 (95%CI 0.458 - 1.778); P = 0.766). Rs9676717 in PAK4 genotype was independently associated with the response (OR for CT/CC vs. TT, 0.524 (95%CI 0.310 - 0.888); P = 0.016). When adjusting for age, gender, smoking, drinking, levels of hepatitis B virus DNA, and alanine aminotransferase (ALT), rs9676717 genotype TT appeared to be associated with a higher probability of response for interferon treatment (OR, 0.155 (95%CI 0.034 - 0.700); P = 0.015). CONCLUSION: Genotype TT for rs9676717 in PAK4 gene and no drinking may be predictive of the interferon-a treatment success. PMID- 23652059 TI - Comparison of the effect of posterior lumbar interbody fusion with pedicle screw fixation and interspinous fixation on the stiffness of adjacent segments. AB - BACKGROUND: Adjacent segment degeneration could seriously affect the long-term prognosis of lumbar fusion. Dynamic fixation such as the interspinous fixation, which is characterized by retaining the motion function of the spinal segment, has obtained satisfactory short-term effects in the clinical setting. But there are few reports about the biomechanical experiments on whether dynamic fixation could prevent adjacent segment degeneration. METHODS: The surgical segments of all 23 patients were L4/5. Thirteen patients with disc herniation of L4/5 underwent Wallis implantation surgery, and 10 patients with spinal stenosis of L4/5 underwent posterior lumbar interbody fusion (PLIF). L3-S1 segmental stiffness and displacement were measured by a spine stiffness gauge (SSG) device during surgery when the vertebral plate was exposed or during spinal decompression or internal fixation. Five fresh, frozen cadavers were used in the self control experiment, which was carried out in four steps: exposure of the vertebral plate, decompression of the spinal canal, implantation of a Wallis fixing device, and PLIF of L4/5 after removing the Wallis fixing device. Then, L3 S1 segment stiffness was measured by an SSG device. RESULTS: The experiments showed that the average stiffness of the L4/5 segment was (37.1 +/- 8.9) N/mm after exposure of the vertebral plate, while after spinal decompression, the average stiffness fell to (26.2 +/- 7.1) N/mm, decreasing by 25.8% (P < 0.05). For the adjacent segments L3/4 and L5/S1, their stiffness showed no significant difference between the L4/5 segment decompression and the exposure of the vertebral plate (P > 0.05). After Wallis implantation of L4/5, the stiffness of the cephalic adjacent segment L3/4 was (45.8 +/- 10.7) N/mm, which was 20.5% more than that after the exposure of the vertebral plate (P < 0.05); after L4/5 PLIF surgery, the stiffness of L3/4 was (35.3 +/- 10.7) N/mm and was decreased by 12.4% more than that after the exposure of the vertebral plate (P < 0.05). The stiffness of the cephalic adjacent segment L3/4 after fixation in the Wallis group was significantly higher than that of the PLIF group (P < 0.05). Cadaver experiments showed that the stiffness of the cephalic adjacent segment in the Wallis group was significantly higher than that of the PLIF group after L4/5 segment fixation (P < 0.05); the stiffness of the L5/S1 segment showed no significant difference between PLIF surgery and Wallis implantation (P > 0.05). CONCLUSIONS: After interspinous (Wallis) fixation, the stiffness of the cephalic adjacent segment increased. After PLIF with pedicle screw fixation, the stiffness of the cephalic adjacent segment decreased. An interspinous fixation system (Wallis) has a protective effect for cephalic adjacent segments for the immediate post-operative state. PMID- 23652060 TI - Factors potentially affecting the function of kidney grafts. AB - BACKGROUND: Donor and recipient risk factors on graft function have been well characterized. The contribution of demographic factors, such as age, gender, and other potential factors of donor and recipient at the time of transplantation on the function of a graft is much less well understood. In this study, we analyzed the effects of factors such as age, gender, etc., on the short-term and long-term graft function in kidney transplant recipients from living donor. METHODS: A total of 335 living donors and their recipients, who had kidney transplantation in our center from May 2004 to December 2009, were included. Serum creatinine level was used as the assessment criterion (serum creatinine level lower than 115 mmol/L is normal). Factors related to graft function such as age, gender, blood relation by consanguinity, human leukocyte antigen (HLA) mismatch, ABO type, etc., were analyzed separately. RESULTS: Donor age is the key factor affecting both the short-term and long-term function of a grafted kidney from a living donor. The group with donors younger than 48 years showed the best kidney function post transplantation. Match of gender and age is another important factor that influences the function of grafted kidney from a living donor. The older donor to younger recipient group had the worst outcome after kidney transplantation. After 36 months post transplantation, female donor to male recipient group had worse kidney function compared to other groups. We also found that calcinerin inhibitor used in the maintenance period may influence the function of a grafted kidney. No significant statistical differences were found in consanguinity, blood type, and mismatch of HLA. CONCLUSIONS: Donor age is an important factor affecting the function of a grafted kidney from a living donor. We also recommend taking nephron, immunology factor, infection, and demographic information all into consideration when assessing the outcome of kidney transplantation. PMID- 23652061 TI - Quadrilobed superior gluteal artery perforator flap for sacrococcygeal defects. AB - BACKGROUND: Perforator flaps are used extensively in repairing soft tissue defects. Superior gluteal artery perforator flaps are used for repairing sacral defects, but the tension required for direct closure of the donor area after harvesting of relatively large flaps carries a risk of postoperative dehiscence. This research was to investigate a modified superior gluteal artery perforator flap for repairing sacrococcygeal soft tissue defects. METHODS: From June 2003 to April 2010, we used our newly designed superior gluteal artery perforator flap for repair of sacrococcygeal soft tissue defects in 10 patients (study group). The wound and donor areas were measured, and the flaps were designed accordingly. Wound healing was assessed over a follow-up period of 6 - 38 months. From January 1998 to February 2003, twelve patients with sacrococcygeal pressure sores were treated with traditional methods, VY advancement flaps or oblong flaps, as control group. RESULTS: After debridement, the soft tissue defects ranged from 12 cm * 10 cm to 26 cm * 22 cm (mean 16.3 cm * 13.5 cm). Four patients were treated using right-sided flaps ranging from 15 cm * 11 cm to 25 cm * 20 cm (mean 18.2 cm * 14 cm). Four patients were treated using left-sided flaps, and two were treated using both right- and left-sided flaps. Suction drains were removed on postoperative Days 3 - 21 (mean 5.9) and sutures were removed on postoperative Days 12 - 14. Each flap included 1 - 2 perforators for each of the donor and recipient sites. Donor sites were closed directly. All flaps survived. In eight patients, the wounds healed after single-stage surgery. After further debridement, the wounds of the remaining two patients were considered healed on postoperative Days 26 and 33, respectively. The rate of first intention in the study group (80%, 8/10) significantly increased than that of control group ((25%, 3/12), chi(2) = 4.583, P = 0.032). Follow-up examinations found that the flaps had a soft texture without ulceration. In the two patients without paraplegia, the range of motion of the hip joints was not affected. CONCLUSION: The use of the quadrilobed superior gluteal artery perforator flap can overcome the disadvantages of traditional perforator flaps and represents an improved approach for repairing soft tissue defects in the sacrococcygeal region. PMID- 23652062 TI - Efficacy and safety of triple-antiplatelet therapy after percutaneous coronary intervention: a meta-analysis. AB - BACKGROUND: The combination of cilostazol, aspirin and clopidogrel (triple antiplatelet therapy, TAT) after a percutaneous coronary intervention has been used as an alternative therapy. We performed a meta-analysis to evaluate the efficacy and safety of TAT for patients after percutaneous coronary intervention (PCI). METHODS: We systematically searched Pubmed, Embase and Web of Science databases to identify all randomized controlled trials (RCTs) that compared dual antiplatelet therapy (DAT) with and without cilostazol after PCI. All analyses were conducted using Review Manager 5.0. RESULTS: The final analysis consisted of 4474 patients from ten studies. The combined results suggested that there was a lower risk of cardiac death (relative risk (RR) = 0.55, 95% confidence interval (CI): 0.31 - 0.98, P < 0.05) and major adverse cardiac events (MACEs) (RR = 0.63, 95% CI: 0.54 - 0.74, P < 0.05) in patients treated with TAT as compared to those with DAT follow-ups after six months to one year; no significant difference was observed in bleeding and non-fatal myocardial infarction (MI) (RR = 1.14, 95% CI: 0.80 - 1.64, P > 0.05; RR = 0.87, 95% CI: 0.42 - 1.83, P > 0.05). However, the rate of adverse drug reaction was higher in patients receiving TAT than in patients receiving DAT (RR = 2.21, 95% CI: 1.84 - 2.66, P < 0.05). Moreover, there was a lower risk of stent thrombosis in patients treated with TAT as compared to those treated with DAT (RR = 0.44, 95% CI: 0.21 - 0.94, P < 0.05). The TAT group had a reduced risk of target lesion revascularization (TLR) (RR = 0.60, 95% CI: 0.43 - 0.82, P = 0.001) and target vessel revascularization (TVR) than the DAT group (RR = 0.56, 95% CI: 0.45 - 0.71, P < 0.05). The number of MACEs was lower for patients in the TAT group than in the DAT group with diabetes mellitus sub-analysis (RR = 0.41, 95% CI: 0.28 - 0.61, P < 0.05). But no significant difference was observed between the two groups regarding MACEs in patients with drug-eluting stent implantations (RR = 0.82, 95% CI: 0.65 - 1.03, P > 0.05). CONCLUSION: TAT could significantly reduce the rates of MACEs and cardiac death in comparison to DAT, but more attention should be paid to adverse side effects of the drugs. PMID- 23652063 TI - Effect of pre-procedural statin therapy on myocardial no-reflow following percutaneous coronary intervention: a meta analysis. AB - BACKGROUND: Successful revascularization of coronary artery disease, especially ST-elevation myocardial infarction (STEMI), does not always mean optimal myocardial reperfusion in a portion of patients because of no-reflow phenomenon. We hypothesized that statins might attenuate the incidence of myocardial no reflow when used before percutaneous coronary intervention (PCI). The purpose of this study was to summarize the evidence of pre-procedural statin therapy to reduce myocardial no-reflow after PCI. METHODS: We searched the MEDLINE, Cochrane, and clinicaltrials.gov databases from inception to October 2012 for clinical trials that examined statin therapy before PCI. We required that studies initiated statins before PCI and reported myocardial no-reflow. A DerSimonian Laird model was used to construct random-effects summary risk ratios. RESULTS: In all, 7 studies with 3086 patients met our selection criteria. The use of pre procedural statins significantly reduced post-procedural no-reflow by 4.2% in all PCI patients (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.35 to 0.90, P = 0.016), and attenuated by 5.0% in non-STEMI patients (RR 0.41, 95% CI 0.18 to 0.94, P = 0.035). This benefit was mainly observed in the early or acute intensive statin therapy populations (RR 0.43, 95% CI 0.26 to 0.71, P = 0.001). CONCLUSIONS: Acute intensive statin therapy before PCI significantly reduces the hazard of post-procedural no-reflow phenomenon. The routine use of statins before PCI should be considered. PMID- 23652064 TI - Holmium laser versus conventional transurethral resection of the bladder tumor. AB - BACKGROUND: Transurethral resection of the bladder tumor (TURBT) remains the gold standard for non-muscle-invasive bladder cancer (NMIBC). Laser techniques have been widely used in urology. This analysis aimed to assess the safety and efficacy of holmium resection of the bladder tumor (HoLRBT) vs. TURBT. METHODS: A systemic search of MEDLINE, Embase, Web of Science, and The Cochrane Library as well as manual bibliography searches were performed to identify the relevant studies. The pooled estimates of operation time, obturator nerve reflex rate, bladder perforation rate, bladder irrigation rate, catheterization time, hospital stay, and one- and two-year recurrence free survivals were calculated. RESULTS: Five studies were enrolled into our meta-analysis. No significant difference was observed in the operation time between groups (weighted mean difference (WMD) 1.01, 95% confidential interval (95% CI) -3.52 - 5.54, P = 0.66). The significant difference in the obturator nerve reflex (OR 0.05, 95% CI 0.01 - 0.04, P = 0.004), bladder perforation (OR 0.14, 95% CI 0.03 - 0.61, P = 0.009), bladder irrigation (OR 0.13, 95% CI 0.04 - 0.45, P = 0.001), catheterization time (WMD 0.96, 95% CI -1.11 to -0.82, P < 0.00001), and hospital stay (WMD -1.46, 95% CI 1.65 to -1.27, P < 0.00001) showed advantages of HoLRBT over TURBT. The 2-year recurrence free survival rate favors the HoLRBT group (OR 1.46, 95% CI 1.02 - 2.11, P = 0.04). CONCLUSIONS: As a promising technique, HoLRBT is safe and efficient, and showed several advantages over TURBT. HoLRBT can be used as an alternative procedure for TURBT in terms of low-grade papillary urothelial carcinoma or low-grade early TNM-stage urothelial carcinoma. PMID- 23652065 TI - Development in mechanisms of ischemic mitral regurgitation. AB - OBJECTIVE: The clinical diagnosis and treatment of ischemia mitral regurgitation (IMR) remained difficult because of its unclear mechanisms. This paper reviews studies on the mechanisms of IMR during the last 20 years, and discusses the relevance of the various mechanisms. DATA SOURCES: Data used in this review were mainly from CNKI and Pubmed in English. The search terms were "ischemia mitral regurgitation mechanism", "myocardial infarction" AND "mitral regurgitation". STUDY SELECTION: Articles were selected if they involved mechanisms of IMR. RESULTS: IMR is one of the common complications of coronary artery disease. But currently, the clinical diagnosis and treatment of IMR remained difficult because of its unclear mechanisms. CONCLUSIONS: For now, dominating theory of ischemic mitral regurgitation mechanisms are left ventricular remodeling, imbalance of leaflet tethering and the closing force, left ventricular dysfunction, changes in spatial structure of the annulus and the dyssynchrony of the left ventricular electromechanical activity. PMID- 23652066 TI - Intestinal microcirculatory dysfunction and neonatal necrotizing enterocolitis. AB - OBJECTIVE: Based on the observation that coagulation necrosis occurs in the majority of neonatal necrotizing enterocolitis (NEC) patients, it is clear that intestinal ischemia is a contributing factor to the pathogenesis of NEC. However, the published studies regarding the role of intestinal ischemia in NEC are controversial. The aim of this paper is to review the current studies regarding intestinal microcirculatory dysfunction and NEC, and try to elucidate the exact role of intestinal microcirculatory dysfunction in NEC. DATA SOURCES: The studies cited in this review were mainly obtained from articles listed in Medline and PubMed. The search terms used were "intestinal microcirculatory dysfunction" and "neonatal necrotizing enterocolitis". STUDY SELECTION: Mainly original milestone articles and critical reviews written by major pioneer investigators in the field were selected. RESULTS: Immature regulatory control of mesentery circulation makes the neonatal intestinal microvasculature vulnerable. When neonates are subjected to stress, endothelial cell dysfunction occurs and results in vasoconstriction of arterioles, inflammatory cell infiltration and activation in venules, and endothelial barrier disruption in capillaries. The compromised vasculature increases circulation resistance and therefore decreases intestinal perfusion, and may eventually progress to intestinal necrosis. CONCLUSION: Intestinal ischemia plays an important role through the whole course of NEC. New therapeutic agents targeting intestinal ischemia, like HB-EGF, are promising therapeutic agents for the treatment of NEC. PMID- 23652067 TI - Role of microRNAs in endothelial function. PMID- 23652068 TI - Retroperitoneoscopic resection of a lower posterior mediastinal benign schwannoma using a transdiaphragmatic approach. PMID- 23652069 TI - Epithelioid angiosarcoma of esophagus. PMID- 23652070 TI - An occult inguinal hernia in a patient on continuous ambulatory peritoneal dialysis: preoperative CT peritoneography diagnosis. PMID- 23652071 TI - Metastatic renal cell carcinoma to vagina and review of literature. PMID- 23652072 TI - Is it inflammatory linear verrucous epidermal nevus or linear psoriasis? PMID- 23652074 TI - Risk factors analysis of postoperative intracranial infection in patients with recurrent glioma. PMID- 23652073 TI - Evolution of sequential bortezomib-dexamethasone treatment followed by autologous hematopoietic stem cell transplantation in hemodialysis treatment. PMID- 23652075 TI - Interdigitating dendritic cell sarcoma complicated with paraneoplastic pemphigus after surgery of resection. PMID- 23652076 TI - Pyoderma gangrenosum associated with ulcerative colitis and psoriasis. PMID- 23652077 TI - Brain abscess surgery-associated recurrent epilepsy in an end stage renal disease patient. PMID- 23652078 TI - Tracheoesophageal fistula treated with esophageal exclusion and cervical esophago gastric anastomosis via a retrosternal approach. PMID- 23652080 TI - The science police. PMID- 23652079 TI - Localized Statistics for DW-MRI Fiber Bundle Segmentation. AB - We describe a method for segmenting neural fiber bundles in diffusion-weighted magnetic resonance images (DWMRI). As these bundles traverse the brain to connect regions, their local orientation of diffusion changes drastically, hence a constant global model is inaccurate. We propose a method to compute localized statistics on orientation information and use it to drive a variational active contour segmentation that accurately models the non-homogeneous orientation information present along the bundle. Initialized from a single fiber path, the proposed method proceeds to capture the entire bundle. We demonstrate results using the technique to segment the cingulum bundle and describe several extensions making the technique applicable to a wide range of tissues. PMID- 23652082 TI - Japan to offer fast-track approval path for stem cell therapies. PMID- 23652083 TI - Delays in updates to ethics guidelines for research spark concern. PMID- 23652084 TI - Biomedical journal and publisher hope to bring preprints to life. PMID- 23652086 TI - After food and drug scandals, China's regulator gets a makeover. PMID- 23652087 TI - Inhibitors of rogue enzyme near trials for brain and blood tumors. PMID- 23652088 TI - Drug development for progeria yields insights into normal aging. PMID- 23652089 TI - With little research training, geriatricians pick clinic over the lab. PMID- 23652090 TI - Frailty research strengthens with biomarker and treatment leads. PMID- 23652091 TI - Old mice require new experimental tricks to study aging process. PMID- 23652092 TI - Sequencing of superagers offers drug targets, but fewer than hoped. PMID- 23652093 TI - New findings rejuvenate age-old drug development field. PMID- 23652094 TI - Living labs open door to retirees who want to join studies. PMID- 23652096 TI - Straight talk with... Mandana Arabi. Interview by Alisa Opar. AB - Malnutrition affects more than 2 billion people worldwide today, making them more prone to disease and cognitive development problems and more likely to die young. To address this massive health threat, the New York Academy of Sciences created the Sackler Institute for Nutrition Science in 2011. At its helm is Mandana Arabi, a physician-scientist born in Iran who previously worked as a nutrition scientist for UNICEF, the United Nations agency devoted to helping children, where she traveled the world developing large-scale programs to address infant and child malnutrition. Arabi may now be more rooted to her office in lower Manhattan, but she has certainly kept things moving at the newly established institute. This past December, she hosted a two-day conference, attended by World Health Organization (WHO) officials and many global experts, dedicated to creating a forward-looking research agenda for nutrition science. And last month the institute awarded its first research grants to investigate the intersection of nutrition and disease prevention. Arabi spoke with Alisa Opar about how the Sackler Institute hopes to put nutrition research on the scientific map. PMID- 23652097 TI - Rethinking the formula. PMID- 23652098 TI - Establish good genomic practice to guide medicine forward. PMID- 23652100 TI - Meat-metabolizing bacteria in atherosclerosis. PMID- 23652101 TI - A gut-heart connection in cardiometabolic regulation. PMID- 23652102 TI - Peli1 sets the CNS on fire. PMID- 23652103 TI - Targeting RAF-MEK-ERK kinase-scaffold interactions in cancer. PMID- 23652104 TI - How brown is brown fat? It depends where you look. PMID- 23652105 TI - Bad versus good cholesterol in the bone marrow. PMID- 23652106 TI - How antibiotics kill bacteria: new models needed? PMID- 23652124 TI - An empirical typology of hospital nurses' individual learning paths. AB - BACKGROUND: A relatively new theoretical concept is proposed in this paper, namely, the individual learning path. Learning paths are created by individual employees and comprise a set of learning-relevant activities that are both coherent as a whole and meaningful to them. OBJECTIVES: To explore the empirical basis of this theoretical concept. DESIGN: A qualitative study involving semi structured interviews. SETTINGS: Two academic medical centers (university hospitals) and two general hospitals in the Netherlands. PARTICIPANTS: A total of 89 nurses were involved in the study. METHODS: Semi-structured interviews were analyzed qualitatively; cluster analysis was then performed on quantified data from the interviews. RESULTS: Four types of learning path emerged, namely, the formal-external, self-directed, social-emotional, and information-oriented learning paths. CONCLUSIONS: The relatively new theoretical concept of an individual learning path can be observed in practice and a number of different learning-path types can be distinguished. Nurses were found to create their own learning paths, that is, select a theme that is relevant primarily to themselves, conduct a variety of learning activities around this theme, participate in social contexts that might help them, and mobilize learning facilities provided by their organization. These activities go way beyond the notion of employees as self directed learners merely in a didactic sense (establishing learning goals, choosing the right learning activities for these goals, evaluating to what extent their goals have been met as a result). The findings can be interpreted as evidence of employees acting strategically when it comes to their professional development. Providers of continuing professional education/development need to take this into account. PMID- 23652115 TI - Fetomaternal immune cross-talk and its consequences for maternal and offspring's health. AB - An improved mechanistic understanding of the adaptational processes mounted during mammalian reproduction is emerging. Intricate pathways occurring at the fetomaternal interface, such as the formation of a functional synapse between invading fetal trophoblast cells, and the involvement of various maternal immune cell subsets and epigenetically modified decidual stromal cells have now been identified. These complex pathways synergistically create a tolerogenic niche in which the semiallogeneic fetus can develop. New insights into fetomaternal immune cross-talk may help us to understand the pathogenesis of pregnancy complications as well as poor postnatal health. Moreover, the effects of maternal immune adaptation to pregnancy on autoimmune disease activity are becoming increasingly evident. Thus, insights into fetomaternal immune cross-talk not only advance our understanding of pregnancy-related complications but also may be informative on how immune tolerance can be modulated in clinical settings outside the context of reproduction. PMID- 23652125 TI - Are 72% of all Norwegian doctors depressed? PMID- 23652126 TI - [Patient information in the drug package inserts]. PMID- 23652116 TI - PPARgamma signaling and metabolism: the good, the bad and the future. AB - Thiazolidinediones (TZDs) are potent insulin sensitizers that act through the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) and are highly effective oral medications for type 2 diabetes. However, their unique benefits are shadowed by the risk for fluid retention, weight gain, bone loss and congestive heart failure. This raises the question as to whether it is possible to build a safer generation of PPARgamma-specific drugs that evoke fewer side effects while preserving insulin-sensitizing potential. Recent studies that have supported the continuing physiologic and therapeutic relevance of the PPARgamma pathway also provide opportunities to develop newer classes of molecules that reduce or eliminate adverse effects. This review highlights key advances in understanding PPARgamma signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy. PMID- 23652127 TI - Priorities in the borderlands. PMID- 23652128 TI - [Specialization of physicians when short term thinking rules]. PMID- 23652129 TI - [No research without planning and approval]. PMID- 23652130 TI - [Hypothesis-testing and exploratory studies]. PMID- 23652132 TI - [E. Skovlund replies]. PMID- 23652133 TI - [Important facts!]. PMID- 23652134 TI - [Misleading reference]. PMID- 23652135 TI - [Unnecessary confusion about health expenses]. PMID- 23652136 TI - [Terje L. Berstad replies]. PMID- 23652137 TI - [Should physicians provide care?]. PMID- 23652138 TI - [When should thyroid scintigraphy be performed?]. PMID- 23652139 TI - [Take the lead back!]. PMID- 23652140 TI - [The physician's place in critical media]. PMID- 23652141 TI - [Dialogue as an alternative to referral]. PMID- 23652143 TI - [Drug package inserts--varying information for the same medicines]. AB - BACKGROUND: Package inserts should convey important information and promote correct, safe and effective use of medicines. The purpose of this study was to investigate possible differences in the information on package inserts between a selection of generic medicines on the substitution list of the Norwegian Medicines Agency. MATERIAL AND METHOD: We based our investigation on the 25 most commonly used drugs in Norway. Eight of these drugs were excluded since they were not listed or did not have generic equivalents on the substitution list. For the remaining 17 drugs we procured the package inserts for a total of 71 medicines and compared the texts. Differences which we judged to be a possible source of worry or confusion for the patient were included. RESULTS: There was only one drug for which the package inserts for all the medicines were almost identical. For three other drugs there were consistently few differences. For the remaining 13 drugs (76%) there were cosiderable differences between the package inserts. There were generally fewest differences in the information on indications for use and most in the information on side effects. In many cases medical expressions without further explanation and unclear and vague words and expressions were used. CONCLUSION: There are significant differences in the information in package inserts for generic medicines. This may lead to confusion, uncertainty and poorer patient compliance. The treating doctor should inform patients who are prescribed a generic medicine that the information on the package insert may vary, but that the medicines nevertheless have equal therapeutic value. PMID- 23652144 TI - Evoked potential tests in clinical diagnosis. AB - BACKGROUND: Evoked potentials are used to detect conduction disturbances in the central nervous system. This paper provides an overview of the areas in which evoked potentials are used in clinical neurophysiological diagnostics, with the emphasis on coma and demyelinating disease. METHOD: The article is based on a literature search in PubMed and the authors' long experience of neurological and neurophysiological diagnostics. RESULTS: Somatosensory evoked potential (SEP) can be a reliable predictor of failure to regain consciousness as early as 24 hours after anoxic coma has occurred. If coma is caused by a brain trauma, cerebrovascular episode or other neurological disease, information about which sensory brainstem pathways are damaged can be obtained from somatosensory evoked potentials and brainstem auditory evoked potentials (BAEP), which can also be useful for planning rehabilitation. Normal SEP and BAEP findings in cases of coma caused by trauma are associated with a favourable prognosis. Visually evoked potential (VEP) can often reveal signs of a history of optic neuritis. SEP and BAEP can also reveal subclinical lesions in the central nervous system and be a supplementary diagnostic test for multiple sclerosis. INTERPRETATION: The clinical value of SEP and BAEP is high in coma cases. Evoked potentials are also important in intraoperative monitoring. The clinical value of VEP is high when a history of optic neuritis is a deciding factor for a multiple sclerosis diagnosis. Some selected patients who are being assessed for demyelinating disease will benefit from a full EP study. PMID- 23652145 TI - [Intoxation with paramethoxymethamphetamine]. AB - BACKGROUND: Since the summer of 2010, there has been an epidemic of deaths related to paramethoxymethamphetamine (PMMA) in Norway. We present a review of the pharmacology and toxicology of the substance. MATERIAL AND METHOD: The review is based on a literature search in the databases PubMed, Ovid and MEDLINE. A discretionary selection was made of relevant articles. RESULTS: Paramethoxymethamphetamine and paramethoxyamphetamine (PMA) are two so-called designer amphetamines which appear from time to time on the illegal narcotics market in many countries. They are frequently sold as ecstasy or amphetamine, often mixed with amphetamine or methamphetamine. The substances, known on the street as "Death", have potent serotonergic effects and are associated with significant toxicity. Many deaths have been reported worldwide, even after intake of an "ordinary user dose". The narcotic effect is not very pronounced and the onset is slow, which may lead to unintentional overdosing. INTERPRETATION: In cases of severe intoxation that are apparently related to intake of amphetamine or ecstasy, PMMA/PMA intoxation should be suspected. PMID- 23652146 TI - [Skeletal disorders in sarcoidosis]. PMID- 23652147 TI - [Medical treatment of neuropathic pain]. AB - Neuropathic pain represents a diagnostic challenge and is difficult to treat. In recent years, clinical trials have led to the development of a number of new treatment guidelines. The guidelines recommend drugs for the most important types of neuropathic pain and suggest alternatives in the event of lack of effect or intolerable adverse effects. Patients with this condition often suffer from anxiety, depression and insomnia, which influences the choice of drug. This article presents the most important drugs on which these guidelines concur. PMID- 23652148 TI - [Activity-based financing and ambulatory surgery]. PMID- 23652149 TI - Should patients who use illicit drugs be offered a second heart-valve replacement? AB - Intravenous drug users (IVDUs) have an elevated risk of contracting infectious endocarditis. Most of them have good effect from medical treatment, but some will need valve replacement. Until a few years ago, our hospital withheld valve surgery if patients with intravenous drug dependency and infectious endocarditis came to need a second valve replacement. However, there are no consensus guidelines for treatment of this group of patients, and a dearth of data on the effects and benefits of interventions. Using a method of ethical analysis, we here discuss whether it is appropriate to offer valve surgery to drug users for a second time. PMID- 23652150 TI - [Chlamydia and urethritis]. PMID- 23652152 TI - Involvement of DNA polymerase beta overexpression in the malignant transformation induced by benzo[a]pyrene. AB - OBJECTIVE: To explore the relationship between DNA polymerase beta (pol beta) overexpression and benzo[a]pyrene (BaP) carcinogenesis. METHODS: Firstly, mouse embryonic fibroblasts that express wild-type level of DNA polymerase beta (pol beta cell) and high level of pol beta (pol beta oe cell) were treated by various concentrations of BaP to determine genetic instability induced by BaP under differential expression levels of pol beta. Secondly, malignant transformation of pol beta cells by low concentration of BaP (20 MUM) was determined by soft agar colony formation assay and transformation focus assay. Thirdly, the mRNA and protein levels of BaP-transformed pol beta cells (named pol beta-T cells) was measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot, and the genetic instability of these cells were examined by HPRT gene mutation assay and random amplified polymorphic DNA (RAPD) assay. RESULTS: Pol beta cells were successfully transformed into malignant pol beta-T cells by an exposure to low concentration of BaP for 6 months. Pol beta-T cells exhibited increased levels of pol beta gene expression, HPRT gene mutation frequency and polymorphisms of RAPD products that were comparable to those of pol beta oe cells. CONCLUSION: Pol beta overexpression and its-associated genetic instability may play a key role in BaP carcinogenesis. PMID- 23652156 TI - Sequence representation during response preparation in the serial reaction time task. AB - The type of representations involved in implicit learning during the response preparation stage of sequence learning was studied using the response-locked lateralized readiness potential (LRP-R) as an index. Participants performed a modified serial reaction time task on an eight-letter sequence; half were informed to look for patterns in the sequence and half were not. The standard sequence was occasionally replaced by one of two deviant sequences and the LRP-R elicited was analyzed. When comparing across three sequence conditions, namely, a perceptual deviant sequence, a motor deviant sequence, and a standard sequence (as control), the onset latency and the mean amplitude of the LRP-R were similar for all three conditions and for both explicit and implicit learners. The perceptual deviant sequence group showed a longer response preparation time than the motor deviant group and the standard sequence group, but the latter two were not significantly different. The perceptual deviant sequence group showed more negative LRP-R amplitude than the other two groups that did not differ from each other. The finding of similar LRP-R profiles between implicit and explicit learners suggests that stimulus representation (S-S association) is the main form of representation supporting sequence learning in the response preparation stage. PMID- 23652155 TI - Do canonical transient receptor potential channels mediate cholinergic excitation of cortical pyramidal neurons? AB - Activation of M1-type muscarinic acetylcholine receptors excites neocortical pyramidal neurons, in part by gating a nonselective cation conductance that produces calcium-dependent 'afterdepolarizing potentials' (ADPs) following short trains of action potentials. Although the identity of the cation conductance mediating the ADP is not known, previous work has implicated canonical transient receptor potential (TRPC) channels, specifically the TRPC5 and TRPC6 subtypes. Using pharmacological and genetic approaches, we tested the role of TRPC channels in generating cholinergic ADPs in layer 5 pyramidal neurons in the mouse medial prefrontal cortex (mPFC). A variety of compounds that block TRPC channels, including 2-aminoethoxydiphenyl borate, flufenamic acid, lanthanum, SKF-96365, and Pyr-3, had little, if any, impact on cholinergic ADPs. Similarly, genetic deletion of several TRPC subunits, including TPRC1, TRPC5, and TRPC6 (single knockouts), or both TRPC5 and TRPC6 together (double knockout), failed to reduce the amplitude of cholinergic ADPs. These data suggest that TRPC5 and TRPC6 subunits are not required for cholinergic excitation of layer 5 pyramidal neurons in the mouse mPFC and that the focus of future work should be expanded to test the involvement of other potential ionic effectors. PMID- 23652157 TI - Topographic changes in event-related potentials because of learning of meaningful Kanji characters. AB - Japanese Kanji constitutes meaningful logograms, and its processing shows interhemispheric features. In the present study, human semantic learning of Kanji characters in 18 healthy native German adults was examined. Twenty Kanji characters were presented before and after a learning phase of about 20 min, and the electroencephalographic activity was recorded from 30 electrodes and averaged for each condition. Twenty different Kanji characters served as control stimuli. Successful learning was observed in all participants. The evoked potential maps showed the largest component occurring over occipital areas at latencies between 100 and 130 ms. Significant differences in the field strength (global field power) were observed for this component before and after learning. After learning, the distribution between the left and the right hemispheres significantly changed the negative centroid location from the left to the right hemisphere and from the posterior to the anterior area in each hemisphere. These effects were observed only after successful learning, and our findings suggest that the acquisition of meaning of Kanji characters following intensive short term learning is related to neurophysiological changes at an early stage of processing. The topographical changes in electrical brain activity reflect plasticity presumably in primary sensory areas during learning of meaningful materials that is related to top-down information processing. PMID- 23652158 TI - Lithium normalizes amphetamine-induced changes in striatal FoxO1 phosphorylation and behaviors in rats. AB - Administration of the psychostimulant drug amphetamine (AMPH) to animals causes hyperactivity and deficit in prepulse inhibition (PPI) of startle, behaviors that are often observed in neuropsychiatric disorders such as schizophrenia and bipolar disorder. Enhanced central dopamine (DA) transmission is believed to mediate AMPH-induced behavioral alterations. Lithium, a drug used primarily in the treatment of bipolar disorder, is reported to interact with the DA system and antagonize some DA-related behaviors. Here, we provide evidence that AMPH and lithium reciprocally regulate the activity of the transcription factor forkhead box, class O1 (FoxO1), a downstream target of Akt. Administration of d-AMPH (3 mg/kg, intraperitoneally) to Sprague-Dawley rats resulted in a concomitant decrease in levels of phosphorylated (p) Akt as well as p-FoxO1 in the striatum, whereas lithium chloride (LiCl,100 mg/kg, intraperitoneally) exerted the opposite effect, that is, it increased levels of p-Akt and p-FoxO1. Pretreatment of animals with lithium prevented an AMPH-induced decrease in striatal p-Akt and p FoxO1 levels. Pretreatment of animals with lithium also attenuated AMPH-induced locomotor activity and decreased prepulse inhibition. These in-vivo data suggest that the Akt-FoxO1 pathway may be a common target for the action of dopaminergic and antidopaminergic drugs, and its modulation may be relevant to the treatment of neuropsychiatric disorders. PMID- 23652159 TI - The experience of long-term opiate maintenance treatment and reported barriers to recovery: a qualitative systematic review. AB - BACKGROUND/AIM: To inform understanding of the experience of long-term opiate maintenance and identify barriers to recovery. METHODS: A qualitative systematic review. RESULTS: 14 studies in 17 papers, mainly from the USA (65%), met inclusion criteria, involving 1,088 participants. Studies focused on methadone prescribing. Participants reported stability; however, many disliked methadone. Barriers to full recovery were primarily 'inward focused'. CONCLUSION: This is the first review of qualitative literature on long-term maintenance, finding that universal service improvements could be made to address reported barriers to recovery, including involving ex-users as positive role models, and increasing access to psychological support. Treatment policies combining harm minimisation and abstinence-orientated approaches may best support individualised recovery. PMID- 23652160 TI - Effectiveness of Beauveria bassiana sensu lato strains for biological control against Rhipicephalus (Boophilus) microplus (Acari: Ixodidae) in China. AB - Owing to the need to combat the spread of acaricide-resistant ticks, the development of long-term biological control has become a hot topic for tick control. In this study, we investigated the pathogenicity of three Beauveria bassiana isolates on the engorged female Rhipicephalus (Boophilus) microplus ticks using different conidial concentrations. The results showed that B. bassiana B.bAT17 was highly pathogenic against engorged R. (B.) microplus females, resulting in lethal time (LT50 and LT90) of 7.14 and 9.33 days at a concentration of 10(9)conidia/ml. R. (B.) microplus females treated with B. bassiana B.bAT17 significantly reduced the amount of ovipositioning; and most ticks died before they could begin to oviposit. Proteases and chitinases were analyzed in order to establish a screening method for identification of high virulent strains. This study has confirmed the significant pathogenic effect of entomopathogenic fungi against engorged R. (B.) microplus females in China, and further studies on the efficiency of the fungus against ticks in the field are required. PMID- 23652161 TI - Neuroprotective and behavioural assessments of an imidazolium compound (DBZIM) in a rat model of Parkinson's disease induced by 6-OHDA. AB - The neuroprotective effect of DBZIM, a novel imidazolium compound, has previously been documented to slow down neurodegeneration in a mouse model of Parkinson's disease. In this study, we conducted behavioural studies and further investigated the neuroprotection in a rat Parkinsonian model induced by 6-hydroxydopamine (6 OHDA). DBZIM was found to significantly reduce the 6-OHDA-induced asymmetrical rotation and preferential usage of contralateral forelimbs. Furthermore, the degeneration of tyrosine hydroxylase immunopositive (TH+) dopaminergic neurones in the substantia nigra par compacta (SNc) was illustrated by immunohistochemistry. The significant loss of TH+ neurones by 6-OHDA administration was ameliorated by three different doses of DBZIM treatment in a bell-shape manner. Such neuroprotection was also observed in the 6-OHDA-lesioned striata. High-performance liquid chromatography (HPLC) analysis of the striatal tissues revealed that DBZIM beneficially maintained the dopamine level by slowing down its metabolism. In addition, DBZIM attenuated the activation of astrocytes and microglia. This suggests that anti-inflammation may be an additional mechanism underlying the DBZIM-mediated neuroprotection. These findings warrant further investigation of DBZIM as a promising and potent agent for the future treatment of Parkinson's disease. PMID- 23652162 TI - Sexual dimorphism in cerebral ischemia injury. AB - Stroke is a leading cause of permanent disability and death. A complex series of biochemical and molecular mechanisms (e.g. the release of ROS/NOS, proapoptotic proteins and proinflammatory cytokine; neuronal depolarization, Ca2+ accumulation and so on) impair the neurologic functions of cerebral ischemia and stroke. We have known for some time that the epidemiology of human stroke is sexually dimorphic until late in life, well beyond the years of reproductive senescence and menopause. The principal mammalian estrogen (17beta estradiol or E2) is neuroprotective in many types of brain injury and has been the major focus of investigation over the past several decades. However the incidence of stroke in women is lower than in men until decades past menopause, suggesting that factors beyond sex hormone contribute to these epidemiological sex differences. So a new concept is emerging: both sex steroids and biologic sex are important factors in clinical and experimental strokes. In this review, we will address sex steroids and gender differences in influencing the mechanisms and outcomes of brain ischemia stroke. These sex differences need to be identified which could help future translation to human neuroprotection. PMID- 23652163 TI - A near-infrared and ratiometric fluorescent chemosensor for palladium. AB - A near-infrared chemosensor for palladium based on the Tsuji-Trost reaction was developed. It displayed specific and ratiometric fluorescent responses toward palladium with a distinct color change from green to blue in aqueous media. PEG400 was employed as the reducing agent and palladium ligand instead of water insoluble triphenylphosphine. The chemosensor's bioimaging potential was demonstrated by in vitro and in vivo experiments. PMID- 23652165 TI - Chart-confirmed guillain-barre syndrome after 2009 H1N1 influenza vaccination among the Medicare population, 2009-2010. AB - Given the increased risk of Guillain-Barre Syndrome (GBS) found with the 1976 swine influenza vaccine, both active surveillance and end-of-season analyses on chart-confirmed cases were performed across multiple US vaccine safety monitoring systems, including the Medicare system, to evaluate the association of GBS after 2009 monovalent H1N1 influenza vaccination. Medically reviewed cases consisted of H1N1-vaccinated Medicare beneficiaries who were hospitalized for GBS. These cases were then classified by using Brighton Collaboration diagnostic criteria. Thirty one persons had Brighton level 1, 2, or 3 GBS or Fisher Syndrome, with symptom onset 1-119 days after vaccination. Self-controlled risk interval analyses estimated GBS risk within the 6-week period immediately following H1N1 vaccination compared with a later control period, with additional adjustment for seasonality. Our results showed an elevated risk of GBS with 2009 monovalent H1N1 vaccination (incidence rate ratio = 2.41, 95% confidence interval: 1.14, 5.11; attributable risk = 2.84 per million doses administered, 95% confidence interval: 0.21, 5.48). This observed risk was slightly higher than that seen with previous seasonal influenza vaccines; however, additional results that used a stricter case definition (Brighton level 1 or 2) were not statistically significant, and our ability to account for preceding respiratory/gastrointestinal illness was limited. Furthermore, the observed risk was substantially lower than that seen with the 1976 swine influenza vaccine. PMID- 23652164 TI - ABO blood group and risk of pancreatic cancer: a study in Shanghai and meta analysis. AB - Studies over 5 decades have examined ABO blood groups and risk of pancreatic cancer in Western, Asian, and other populations, though no systematic review has been published. We studied data from 908 pancreatic cancer cases and 1,067 population controls collected during December 2006-January 2011 in urban Shanghai, China, and reviewed the literature for all studies of this association. Random-effects meta-analysis provided summary odds ratio estimates according to blood group and by populations endemic versus nonendemic for cytotoxin-associated gene A (CagA)-positive Helicobacter pylori. In our Shanghai study, versus group O, only ABO group A was associated with risk (odds ratio (OR) = 1.60, 95% confidence interval (CI): 1.27, 2.03). In 24 pooled studies, group A showed increased risk in both CagA-nonendemic and -endemic populations (ORpooled = 1.40, 95% CI: 1.32, 1.49). In nonendemic populations, groups B and AB were also associated with higher risk (OR = 1.38, 95% CI: 1.16, 1.64; and OR = 1.52, 95% CI: 1.24, 1.85, respectively). However, in CagA-endemic populations, groups B and AB were not associated with risk (OR = 1.05, 95% CI: 0.92, 1.19; and OR = 1.13, 95% CI: 0.92, 1.38, respectively). These population differences were significant. One explanation for contrasts in associations of blood groups B and AB between CagA-endemic and -nonendemic populations could involve gastric epithelial expression of A versus B antigens on colonization behaviors of CagA-positive and CagA-negative H. pylori strains. PMID- 23652166 TI - Dietary flavonoid intake and esophageal cancer risk in the European prospective investigation into cancer and nutrition cohort. AB - We prospectively investigated dietary flavonoid intake and esophageal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The study included 477,312 adult subjects from 10 European countries. At baseline, country-specific validated dietary questionnaires were used. During a mean follow-up of 11 years (1992-2010), there were 341 incident esophageal cancer cases, of which 142 were esophageal adenocarcinoma (EAC), 176 were esophageal squamous cell carcinoma (ESCC), and 23 were other types of esophageal cancer. In crude models, a doubling in total dietary flavonoid intake was inversely associated with esophageal cancer risk (hazard ratio (HR) (log2) = 0.87, 95% confidence interval (CI): 0.78, 0.98) but not in multivariable models (HR (log2) = 0.97, 95% CI: 0.86, 1.10). After covariate adjustment, no statistically significant association was found between any flavonoid subclass and esophageal cancer, EAC, or ESCC. However, among current smokers, flavonols were statistically significantly associated with a reduced esophageal cancer risk (HR (log2) = 0.72, 95% CI: 0.56, 0.94), whereas total flavonoids, flavanols, and flavan-3-ol monomers tended to be inversely associated with esophageal cancer risk. No associations were found in either never or former smokers. These findings suggest that dietary flavonoid intake was not associated with overall esophageal cancer, EAC, or ESCC risk, although total flavonoids and some flavonoid subclasses, particularly flavonols, may reduce the esophageal cancer risk among current smokers. PMID- 23652167 TI - Reactive and infective dermatoses associated with adult-onset immunodeficiency due to anti-interferon-gamma autoantibody: Sweet's syndrome and beyond. AB - Immunodeficiency due to anti-interferon-gamma autoantibody (anti-IFN-gamma autoAb) is an emerging adult-onset immunodeficiency syndrome predominantly found in Southeast Asians. It is associated with severe or disseminated infections caused by non-tuberculous mycobacteria (NTM) and other opportunistic pathogens. We describe 3 patients with anti-IFN-gamma autoAb who developed reactive and infective dermatoses, and thoroughly review the existing literature on dermatoses associated with the immunodeficiency syndrome. Case 1 developed Sweet's syndrome associated with Mycobacterium chelonae lymphadenitis and penicilliosis. Case 2 suffered from multiple episodes of lobular panniculitis during recurrent infections by NTM, Penicillium marneffei and Burkholderia pseudomallei. Both cases responded to immunomodulating agents including corticosteroid and non steroidal anti-inflammatory drugs. Case 3 had direct skin invasion by M. chelonae and responded to prolonged anti-mycobacterial therapy. A novel working algorithm is proposed for the diagnosis and treatment of these patients who may be encountered by the dermatologist and histopathologist in clinical practice. PMID- 23652169 TI - Effects of intraoperative colloid administration on outcome in a population-based general surgical cohort: a propensity score analysis. AB - BACKGROUND: Many studies on colloids have recently been retracted, leaving us with uncertain evidence of their safety. We aimed to analyze whether intraoperative colloid administration is associated with postoperative complications. METHODS: The prospectively compiled database of the ARISCAT study of a large, representative cohort of general surgical patients was reanalyzed to compare outcomes according to whether intraoperative colloids were administered or not; a propensity score was used to adjust for potential confounders. The primary outcomes were major postoperative complications. Secondary outcomes were postoperative hospital-free days within 90 days and mortality at 30 and 90 days. In a retrospective survey we asked each center's data collectors to estimate the proportions of the different colloids administered during the study period. RESULTS: Of 2462 patients analyzed, 556 (22.6%) received some type of colloid intraoperatively. The median (25th-75th percentile) of total fluids administered was significantly higher in patients receiving colloids (10.0 [6.9-14.1] mL.kg 1.h-1 vs. 8.8 [6.0-12.8] mL.kg-1.h-1 for patients not receiving colloids; P<0.01). The median volume of colloids administered was 7.5 (6.3-10.4) mL.kg-1. An estimated 75.7% of the patients received third-generation hydroxyethyl starches (130/0.4). Significantly associated complications, after propensity score adjustment, were atelectasis, respiratory infection, bronchospasm, arrhythmia, sepsis, paralytic ileum, and hyperglycemia. Patients receiving colloids had 1.9 fewer postoperative hospital-free days (P<0.006). There were no significant differences in 30- and 90-day mortality. CONCLUSION: Our study suggests an association of intraoperative colloid administration, mainly of 130/0.4 hydroxyethyl starches, with diverse major postoperative complications and longer hospital stay. Controlled studies are urgently needed to assess the safety profile of colloid use in surgical patients. PMID- 23652170 TI - Tracheal amylase dosage as a marker for microaspiration: a pilot study. AB - BACKGROUND: Devices that limit microaspiration through the cuffs of endotracheal tubes could help prevent ventilator-associated pneumonia (VAP). The amount of tracheal microaspirations could be a relevant study endpoint. The aim of our study was to assess whether amylase measured in tracheal secretions constituted a relevant marker for microaspiration. METHODS: Twenty-six patients, intubated for at least 48 h and supplied with a subglottic secretion-suctioning device, constituted a group with a high risk of microaspiration. Twelve non-ventilated patients that required a bronchoscopy procedure constituted a group with a low risk of microaspiration (the control group). Tracheal (T) amylase was compared between the groups. In the intubated group, a series of oral (O), subglottic (Sg) and tracheal (T) suction samples were collected and T/O, T/Sg, Sg/O amylase ratios were determined. RESULTS: Amylase was measured in 277 (89 Sg, 96 B, 92 T) samples from the intubated group and in 12 T samples from the control group. Tracheal amylase was lower in the control group than the intubated group (191 [10 917] vs. 6661 [2774-19,358] IU/L, P<0.001). Amylase gradually increased from tracheal (6661 [2774-19,358] IU/L), to subglottic (130,750 [55,257-157,717] IU/L), to oral samples (307,606 [200,725-461,300] IU/L), resulting in a median 5.5% T/O ratio. In a subset of intubated patients, T amylase samples were assessed in two different laboratories, and gave reproducible results. CONCLUSION: Tracheal amylase was easy to collect, transport, and measure. The T/O amylase ratio is a first step towards quantifying oropharyngeal to tracheal microaspiration in mechanically-ventilated patients. PMID- 23652171 TI - Evaluation of continuous monitoring of stroke volume and cardiac output in patients supported by an intra-aortic balloon pump. AB - BACKGROUND: Currently available minimally invasive devices cannot provide continuous determination of stroke volume (SV) or cardiac output (CO) in patients supported with an intra-aortic balloon pump (IABP). Our aim was to evaluate the accuracy of Dat-conTM monitor for continuous SV and CO determination in such patients. METHODS: SV (SVdat-con) and CO (COdat-con) were determined by Dat-conTM monitor in 35 patients supported by IABP, at baseline and after 103 therapeutic interventions. Echocardiography was used to measure SV (SVecho) and CO (COecho) from velocity time integral and cross-sectional area of left ventricular outflow tract. Monitored and echocardiographic values were compared using Bland-Altman's statistics. RESULTS: Bias in baseline SVdat-con compared to SVecho was 0.2 mL, with 1.96 limits of agreement (SD) of +/-4.8 mL and with percentage error of 11%. Bias of baseline COdat-con compared to COecho was 0.03 l/min, with 1.96 SD of +/ 0.435 l/min with percentage error of 10.9%. After therapeutic interventions, bias of SVdat-con compared to SVecho was -0.3 mL, with 1.96 SD of +/-4.8 mL and with percentage error of 10.5%. Agreement for SV changes was >95% (exclusion zone: changes <10%). Bias of COdat-con compared to COecho after therapeutic interventions was -0.03 L/min, with 1.96 SD of +/-0.45 L/min. CONCLUSION: The accuracy and trending of continuous determination of SV and CO with Dat-conTM monitor in patients supported by IABP is equivalent to echocardiography. PMID- 23652172 TI - Management of the patient with diabetic peripheral neuropathy presenting for peripheral regional anesthesia: a European survey and review of literature. AB - BACKGROUND: Diabetic peripheral neuropathy (DPN) is a frequent complication of longstanding diabetes mellitus. There is no evidence-based consensus whether neuropathic patients undergoing peripheral regional anesthesia are at increased risk of neurologic damage. It is unknown whether these controversial results have been incorporated into clinical practice. We conducted a survey to test the hypothesis that the majority of respondents would consider DPN a potential risk factor for nerve damage in regional anesthesia, and would adapt their technique when performing regional anesthesia. In parallel, we sought to summarize the current knowledge-base regarding regional anesthesia and DPN. METHODS: We therefore performed 1) a literature search to review current literature and 2) an online computer-based survey among members of the European Society of Regional Anesthesia and Pain Therapy (ESRA). RESULTS: The overall response rate was 19% (584 responders/3107 invitations). About a quarter of participants would avoid regional anesthesia in patients with diabetic neuropathy, and 59% of respondents would counsel patients with diabetic neuropathy about increased risk of regional anesthesia. When techniques were modified, most participants would decrease or omit epinephrine, while fewer respondents would decrease dose of local anesthetic or perform other adjustments. More than 80% agreed with the statement that nerve blocks could be performed safely in diabetic neuropathic patients. CONCLUSION: In conclusion, we report the results of the first survey analyzing attitudes and standards of care among European anesthesiologists with regards to regional anesthesia in DPN. While literature is divided on the question whether pre existing diabetic neuropathy is a risk factor for new neurological deficit after regional anesthesia, most of the responders of this survey take measures to reduce risks, counsel patients on a possible greater risk of neurologic complications, but only a minority of responders would avoid peripheral regional anesthesia altogether. PMID- 23652173 TI - Informed consent for tracheostomy procedures in Intensive Care Unit: an Italian national survey. AB - BACKGROUND: Critically ill patients in Intensive Care Unit (ICU), due to their temporary or permanent incompetence, are often not capable to provide informed consent (IC), although required, for not emergency invasive procedures, like elective tracheostomy. By Italian law, a person with partially/temporarily physical/mental impairment needs a legal tutorship appointed by the court (Support Administrator, SA). We performed a national survey in Italy to investigate IC practice for elective tracheostomy procedure in critically ill conscious and unconscious patients in ICU. METHODS: Questions about IC were included in a survey concerning the clinical practice of tracheostomy in ICU. The survey was approved by the Italian Society of Anesthesia, Analgesia and Intensive Care (SIAARTI, n degrees 434 - 28 March 2012) and sent by e-mail to all members included in its mailing list. The duration of the survey was three months from April to June 2012. All required information was referred to the year 2011. RESULTS: The mailed questionnaire correctly fulfilled was sent back by 131/427 (30%) national ICUs. Our data showed 1) in conscious patients, IC was obtained by 82.4% of ICUs; 2) in unconscious patients, IC was obtained in only 61.8% with different procedures not following the current Italian law, 3) for surgical tracheostomy performed in operating room, IC was obtained in conscious and unconscious patients in only 69.8% and 47.2% of ICUs, respectively, 4) risk/benefit informative document was provided in 61.1% ICUs, but available only in 47.2% of ICUs performing tracheostomy in operating room. CONCLUSION: In Italian ICUs, participating to this study, the procedures related to IC for conscious and unconscious critically ill patients requiring surgical or percutaneous tracheostomy are not in line with current legal rules and procedures. PMID- 23652174 TI - Absent right superior vena cava. PMID- 23652175 TI - Fusarium species: an evolving challenges to critically ill patients. PMID- 23652176 TI - Key points for intraoperative management of percutaneous endoscopic lumbar discectomy (PELD) for anesthesiologists. PMID- 23652177 TI - Current developments in the treatment of neuropathic pain in AIDS patients. PMID- 23652178 TI - [Gaceta Medica de Mexico at the 150 years of the National Academy of Medicine of Mexico]. PMID- 23652179 TI - [Interpersonal relationships: perception of the communication, treatment and adverse experiences encountered by users of medical units that belong to the Coordinating Commission of the National Institutes of Health and High Specialty Hospitals (CCINSHAE)]. AB - INTRODUCTION: User's perception with regard to the attention they received in healthcare units is increasingly being taken into account by the health service providers in order to improve the quality of their service. AIM: Describe how the users perceive the health services provided by the CCINSHAE with regard to the communication with the physicians, the attention of the staff and the adverse personal and institutional experiences and to explore their relation with user's demographic characteristics, health condition, physical limitations to carry out daily activities and service area. METHODS: A questionnaire was designed to collect information about the user and his/her opinion with regard to the healthcare units, the communication with the physicians, the attention of the staff and the adverse personal and institutional experiences. The data were analyzed with STATA using sample weights. RESULTS: A total of 2,176 individuals were interviewed after they had received attention and represent a population of 1,457,964 users, over 6 months, of the CCINSAHE. We then calculated four binary variables that reflect the perception of the users. These four variables were significantly associated with the type of health unit where the user received attention, schooling, limitations to carry out daily activities, facilities provided to the relatives, family income, the use of alternative medicine, and the area of attention. DISCUSSION: A fundamental aspect of the service provided by the healthcare institutions is the communication between the physicians and the users. We found that the perception of the users with regard to the communication with the physician, the attention of the staff, and the adverse personal and institutional experiences was associated with the type of healthcare unit. The federal reference hospitals produced the most unfavorable perception while the regional hospitals produced the most favorable impression. This study enables the decision-making personnel to determine what needs to be modified in order to improve the service provided by the health units. PMID- 23652180 TI - [Intracranial electrode recording prognostic value in anterior temporal lobectomy and hypocampectomy]. AB - The experience obtained in the Epilepsy Clinic of the General Hospital of Mexico in regard to the use of intracraneal electrodes to determine the epileptic tissue that must be resected in an anterior temporal lobectomy with amygdalo hippocampectomy in patients with intractable mesial temporal lobe seizures is described. The data obtained while recording the electroencephalographic activity with these electrodes to learn about its impact in the postsurgical result (seizure reduction and complications) both in the first year and long-term (up to 17 years) follow-up was analyzed. Fifty seven patients implanted between years 1993-2008 were included. Forty eight patients (84%) were seizure and medication free in the first year of postsurgical follow-up. Five patients relapsed after five years of being seizure free. There were no serious complications caused by the use of intracraneal electrodes per se and neurological deficits were barely noticeable in one patient due to the lobectomy. CONCLUSION: the use of intracraneal electrodes is a safe and effective diagnostic method that contributes to the good postsurgical long-term outcome in those patients previously excluded for a possible surgery. PMID- 23652181 TI - [Behavior of hypertensive renal diseases in Mexico between 1998-2009. A growing problem]. AB - INTRODUCTION: High blood pressure (HBP) is a risk factor for chronic diseases. Worldwide, 20-25% of adults have hypertension, with 70% of them living in developing countries. Hypertensive renal disease (HRD) is a complication of insufficiently controlled hypertension. This study aims to analyze the behavior of HRD mortality in Mexico between 1998 and 2009. METHODS: Longitudinal study with secondary analysis of HRD records from the databases provided by INEGI, which analyzes the specific rates by age and sex and standardized mortality ratio (SMR) by states and regions. Georeferencing methods are used statewide. RESULTS: In Mexico from 1998 to 2009 there were 48,823 deaths from HRD. The standardized mortality rate rose from 3.35/100,000 inhabitants to 6.74 (p < 0.01). The specific rates by age and sex showed an increase in incidence after 50 years of age. States with higher SMR by HDR were DF, Estado de Mexico, Morelos, Jalisco, and Colima. CONCLUSIONS: HRD is a major microvascular complication of hypertension and its prevalence is increasing. We should strengthen the processes of early detection, care, and appropriate follow-up of people with hypertension to control this potentially preventable complication. PMID- 23652182 TI - [Factors associated with nutritional status of iodine in Mexican preschool children]. AB - BACKGROUND: Iodine deficiency is a public health problem in many developing countries where pregnant women and children are the more susceptible populations. OBJECTIVE: To evaluate the association of iodine nutritional status with the weather, availability of iodine in salt, and degree of social exclusion in preschool children of the state of Hidalgo, Mexico. METHODS: Cross-sectional study in 1,333 children < 5 years; in these, urinary iodine and iodine in the salt was measured, and annual average of humidity, type of location and degree of social marginalization in the localities where they lived was recorded. RESULTS: 24.5% of children evaluated had < 100 ug/l of urinary iodine excretion, and 28.6% of salt samples contained < 20 ppm of iodine; iodine urine average of wet weather children was lower (209.09 +/- 6.8 ug/l) than in dry climates (274.7 +/- 5.86 ug/l; p < 0.05); the iodine content of salt in children living communities with high levels of marginalization was less than with low marginalization (23.5 +/- 1.2 and 32.9 +/- 2.7 ppm, respectively; p < 0.01). CONCLUSIONS: The humidity and the degree of social marginalization of the locations were associated with lower iodine content of salt and urinary iodine in children evaluated. PMID- 23652183 TI - [HumGen in Spanish: a comparative description of human genetics regulatory framework in Latin America]. AB - OBJECTIVE: To provide a research database of normative documents in Spanish related to human genetics (HG). METHODS: This is a researchable database, where normative texts are related to HG. The ELSI issues are compiled, combining documents with national, regional, and international influence. The selection of these laws is done through a process of rigorous qualitative research. The portal is aimed at the general public, but with an emphasis on decision makers who possess the capacity to formulate policies on matters related to HG. Several normative documents, issued by international and regional organizations, are included, as well as documents of local government agencies of different countries. RESULTS: From the laws and policies available in the database, 39% are decrees of international organizations, 12% are regional normative texts, and 49% are national laws and policies. From all the national legal texts, 48% are laws or policies that belong to Spain. CONCLUSIONS: Latin American countries are not adopting a futuristic perspective because they do not regulate or legislate the technology resulting from research in HG. The HumGen Portal is a tool that will help the development of regulatory frameworks in Spanish-speaking countries, which will be suitable to current scientific progress. PMID- 23652184 TI - [Some observations on high specialty medical care in Mexico]. AB - OBJECTIVES: To put forth the concept of highly specialized medical care, in agreement with the nature of its practice, and evaluate the feasibility of creating a support service network. METHODS: Qualitative study of the current practice and requirements for 39 selected medical specialties, using the technique of focused groups of experts in each specialty. In accordance with the "Grounded Theory", variables were systematized and categorized and then compared in order to identify relationships between categories and link them to consensus testimonial references. On the basis of the characteristics of each kind of practice, one key expert integrated and validated service portfolios. RESULTS: We developed an integrated a concept for highly specialize medical care with 39 operational catalogs of those diagnoses that belong to each specialty, along with catalogs of the resources required by each specialty. CONCLUSIONS: Highly specialized care is a desirable model for clinical practice, but does not constitute a different level of care. Currently, medical practice is constrained by the lack of well-defined boundaries and scarcity of resources in order to be conceptualized as high specialty. It is therefore more convenient to strengthen the concept of third level of care in order to identify opportunities for the establishment of high specialty areas that will in turn serve as the focal points for medical innovation. PMID- 23652185 TI - [Coping with medical residency: depression burnout]. AB - Among the most prevalent psychiatric disorders, major depressive disorder is related with high incapacity levels, affecting also physical and mental health, and social, family, and work activities (burnout). OBJECTIVES: This study assessed possible damage and emotional changes in a cohort of recently incoming medical residents to the postgraduate courses of the National Institute of Neurology and Neurosurgery of Mexico City. MATERIALS AND METHODS: We collected information on sociodemographic data, and we applied two instruments: the scale of Maslach Burnout Inventory (MBI-HS) and the Beck Depression Inventory (BDI). Candidates were followed over time, at six and 12 months afterwards. RESULTS: When the authors analyzed depressive symptoms, they found that the percentage of medical residents without depression at baseline was 97.7% and at the second application, this percentage decreased statistically (p = 0.008) and yet there was an increase in mild depressive symptoms (p = 0.017). With respect to MBI-HS, there was high emotional exhaustion with a significant increase at six months after arrival. The psychiatry residents were those more affected. CONCLUSIONS: Exploratory research is needed to be performed among residents to detect depressive symptoms and burnout syndrome, to act in a timely manner and prevent the progression of these diseases. PMID- 23652186 TI - [Association between adiposity, inflammation and cardiovascular risk factors in school-aged Mexican children]. AB - OBJECTIVE: To evaluate the differences in inflammation markers and cardiovascular risk factors in a group of school-aged children with and without excessive adiposity. To examine the relationship between adiposity, inflammation, and cardiovascular risk factors. METHODS: Cross-sectional study of 285 school children (8-12 years old). Adiposity (body mass index, BMI, total body fat, TBF, and waist circumference), inflammatory markers (C-reactive protein [CRP], interleukin 1beta [IL-1beta], interleukin 6 [IL-6], and tumor necrosis factor-a [TNF-alpha]) and cardiovascular risk factors were analyzed. Mean differences were calculated and multiple regression models were made. RESULTS: Obese children had higher concentrations of CRP and IL-1beta; children with abdominal obesity also had higher CRP levels. A higher BMI was associated with higher blood pressure, and higher total cholesterol, triglycerides-TAG, and insulin concentrations, and with lower HDL-cholesterol. The CRP and IL-1beta concentrations correlated significantly with the three adiposity indices. The IL-6 concentrations were associated with TAG, and IL-1beta with HDL-cholesterol concentration, after adjustment by BMI. DISCUSSION: In a group of school-aged Mexican children, obesity increases cardiovascular risk and inflammation. Both IL-6 and IL-1beta appear to be factors involved in lipid alterations in these children. More research is needed in order to explore the role of subclinical inflammation in the development of cardiovascular alterations that have already been described in Mexican children with obesity. PMID- 23652187 TI - [Bone cancer pain: from preclinical pharmacology to clinical trials]. AB - Worldwide over 12 million people were diagnosed with cancer (excluding non melanoma skin cancer) and 8 million individuals died from cancer in 2008. Recent data indicate that 75-90% of patients with advanced stage diseases or metastatic cancer will experience significant cancer pain. Bone cancer pain is common in patients with advanced breast, prostate, and lung cancer as these tumors have a marked affinity to metastasize to bone. Once tumors metastasize to bone, they are a major cause of morbidity and mortality as the tumor induces significant skeletal remodeling, fractures, pain and anemia; all of which reduce the functional status, quality of life and survival of the patient. Currently, the factors that drive cancer pain are poorly understood, however, several recently introduced models of bone cancer pain that mirror the human condition, are providing insight into the mechanisms that drive bone cancer pain and guiding the development of novel therapies to treat the cancer pain. Several of these therapies have recently been approved by the FDA to treat bone cancer pain (bisphosphonates, denosumab) and others are currently being evaluated in human clinical trials (tanezumab). These new mechanism-based therapies are enlarging the repertoire of modalities available to treat bone cancer pain and improving the quality of life and functional status of patients with bone cancer. PMID- 23652188 TI - [Changing the paradigm of congenital heart disease: from the anatomy to the molecular etiology]. AB - Heart development consists in a group of complex and specific morfogenetic interactions, that requires the proper activity of each factor implicated in this process. Congenital heart defects (CHD) are a group of multifactorial complex diseases with environmental and genetic factors playing important roles. There is not an exact relation between molecular mechanisms and morphological defects in CHD, because in most of the cases the proper development of an anatomical structure implies the adequate function of several pathways that may depend of the action of different genes. This review summarizes the genetic factors implied in the normal heart development and the most common gene mutations associated with CHD. PMID- 23652189 TI - [Single nucleotide polymorphisms (SNPs): functional implications of regulatory SNP (rSNP) and structural RNA (srSNPs) in complex diseases]. AB - Single nucleotide polymorphisms (SNPs) represent to the genetics variant most common founded in the human genome. These polymorphisms have a wide distribution and can found in any region of gene or mRNA, the SNPs that have functional implications on the levels of gene expression are called regulatory SNPs (rSNPs), while those that affect translation, splicing, efficiency to enhance or inhibit the alternative, mRNA stability and protein function (without altering its structure), they are called structural RNA SNPs (srSNPs). Several studies have identified to these polymorphisms associated with different common diseases e.g. hypertension, obesity, rheumatoid arthritis and coronary artery disease. The aim of this review is to discuss the functional implication of rSNPs and srSNPs in the common diseases. PMID- 23652190 TI - [Hypophysitis autoimmune. Case series and literature review]. AB - Autoimmune hypophysitis is a rare condition that must be considered in the differential diagnosis of any pituitary tumor. We present a series of nine patients with clinical and radiologic diagnosis of autoimmune hypophysitis that were admitted to the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (INCMNSZ) in Mexico City between 2000-2012. Clinical, biochemical, imaging features (on MRI), treatment, and follow-up are described, and a review on this disease is presented. PMID- 23652191 TI - [National Academy of Medicine of Mexico President's message at the opening ceremony in the 150 academic years - February 6th 2013]. PMID- 23652192 TI - [Peredo's Inferno: a Mexican physician-translator in the XIX century]. AB - Manuel Peredo (1830-1890) participated fully in Mexico's national literary circles during the second half of the 19th century. Besides being recognized for his translation of Basch's Memories of Mexico, Peredo also translated the first tercets of Inferno's Canto XXXIII. Although forgotten today, his contribution is significant since it is the second Mexican translation of Dante, and particularly, the first Mexican translation of Canto XXXIII. PMID- 23652193 TI - Pathogen-induced autophagy signaling in innate immunity. AB - Innate immunity induces rapid responses to fight invading pathogens. To eliminate intracellular bacteria or viruses, innate cellular responses lead to the production of nuclear factor-kappaB-dependent inflammatory cytokines, inflammasome activation, type I interferon synthesis, and/or eventually death of the infected cells. Autophagy emerged as another component of innate immunity, as it offers an immediate autonomous cell defense mechanism by degrading intracellular pathogens. In addition, autophagy participates in the regulation of immune and inflammatory cell responses. Instead of providing a comprehensive status of the art that has already been addressed elsewhere, we chose to highlight some recent issues brought up in the field. PMID- 23652194 TI - Acute abdominal pain due to intussusception of the small intestine in a 17-year old patient. PMID- 23652195 TI - Pancreatic hamartoma. PMID- 23652196 TI - Treatment of traumatic corneal abrasions: a three-arm, prospective, randomized study. AB - PURPOSE: To compare three different treatment modalities for traumatic corneal abrasions. METHODS: We conducted a prospective, randomized, masked, three-arm clinical study of patients presenting with superficial corneal foreign bodies. Treatment modalities were: (1) pressure patching with ofloxacin ointment (patch group, PG, n = 18), (2) therapeutic contact lens with ofloxacin eye drops (contact lens group, CLG, n = 20) and (3) ofloxacin ointment alone (ointment group, OG, n = 28). Primary outcome measure was the difference of the mean corneal abrasion area between the three groups at 3 different time points (baseline, day 1 and day 7). RESULTS: A total of 66 patients were included in the study over a period of 2 years. Mean initial corneal abrasion area was 3.6 +/- 3.4 mm2 in the PG, 4.2 +/- 4.0 mm2 in the CLG and 3.7 +/- 3.1 mm2 in the OG (p = 0.875). Differences in corneal abrasion area at any time point were not statistically significant (abrasion area decrease from presentation to day 1 was 3.4 +/- 3.3 mm2 in the PG, 4.1 +/- 4.0 mm2 in the CLG and 3.5 +/- 3.1 mm2 in the OG, p = 0.789). The epithelium was healed in all patients at day 7. CONCLUSIONS: Treating traumatic corneal abrasions by pressure patching, a bandage contact lens or ointment alone was equal in reducing the abrasion area or reducing pain. According to our results the treatment of choice for traumatic abrasions may be adapted to the needs and preferences of the patient. PMID- 23652197 TI - Low glucose promotes CD133mAb-elicited cell death via inhibition of autophagy in hepatocarcinoma cells. AB - CD133 on cancer stem cells is a potential therapeutic target. In this study, CD133 antibody (CD133mAb) treatment resulted in cell death in hepatoma LM3, HepG2, Hep3B and Huh-7 cells, especially under low glucose condition. The treatment also inhibited formation of spheroids, colonies, and xenograft tumors. Ectopic CD133 enabled hepatocyte L02 to be suppressed by CD133mAb and increased spheroid formation. CD133mAb caused cell death in primary HCC cells and sensitized them to Doxorubicin and Cisplatin. The antibody effect was attributed to suppressing autophagy and promoting necrotic cell death. Therefore, targeting CD133 under low glucose condition is a potential therapeutic approach for hepatocarcinomas. PMID- 23652198 TI - Metabolic circadian rhythms in embryonic turtles. AB - Oviparous species are model organisms for investigating embryonic development of endogenous physiological circadian rhythms without the influence of maternal biorhythms. Recent studies have demonstrated that heart rates and metabolic rates of embryonic turtles are not constant or always maximal and can be altered in response to the presence of embryos at a more advanced stage of development within the nest. A first step in understanding the physiological mechanisms underpinning these responses in embryonic ectothermic organisms is to develop metabolic profiles (e.g., heart rate) at different temperatures throughout incubation. Heart beat and rhythmic patterns or changes in development may represent important signals or cues within a nest and may be vital to coordinate synchronous hatching well in advance of the final stages of incubation. We developed baseline embryonic heart-rate profiles of embryos of the short-necked Murray River turtle (Emydura macquarii) to determine the stage of embryogenesis that metabolic circadian rhythms become established, if at all. Eggs were incubated at constant temperatures (26 degrees C and 30 degrees C) and heart rates were monitored at 6-h intervals over 24 h every 7-11 days until hatching. Circadian heart rate rhythms were detected at the mid-gestation period and were maintained until hatching. Heart rates throughout the day varied by up to 20% over 24 h and were not related to time of day. This study demonstrated that endogenous metabolic circadian rhythms in developing embryos in turtle eggs establish earlier in embryogenesis than those documented in other vertebrate taxa during embryogenesis. Early establishment of circadian rhythms in heart rates may be critical for communication among embryos and synchrony in hatching and emergence from the nest. PMID- 23652199 TI - Evasion of predators contributes to the maintenance of male eyes in sexually dimorphic Euphilomedes ostracods (Crustacea). AB - Sexual dimorphisms have long drawn the attention of evolutionary biologists. However, we still have much to learn about the evolutionary, genetic, and developmental drivers of sexual dimorphisms. Here, we introduce ostracods of the genus Euphilomedes (Myodocopida, Ostracoda, and Crustacea) as a promising new system in which to investigate why and how sexual dimorphisms evolve. First, we ask whether male-skewed selective pressure from pelagic predators may help explain a dramatic sexual dimorphism in which male Euphilomedes have compound eyes, but females do not. Manipulative experiments demonstrate that blindfolding reduces the survival rate of male Euphilomedes when they are exposed to predatory fish. Blindfolding of the female rudimentary eyes (rudiments) does not, however, similarly influence the survival rate of brooding females. Further, numerical estimates of sighting distances, based on reasonable extrapolations from Euphilomedes's eye morphology, suggest that the eyes of male Euphilomedes are useful for detecting objects roughly the size of certain pelagic predators, but not conspecifics. We conclude that eyes do not mediate direct interactions between male and female Euphilomedes, but that differences in predation pressure perhaps associated with different reproductive behaviors-contribute to maintaining the sexually dimorphic eyes of these ostracods. Second, through transcriptome sequencing, we examined potential gene regulatory networks that could underlie sexual dimorphism in Euphilomedes' eyes. From the transcriptome of juvenile male Euphilomedes' eyes, we identified phototransduction genes and components of eye-related developmental networks that are well characterized in Drosophila and other species. The presence of suites of eye regulatory genes in our Euphilomedes juvenile male transcriptome will allow us, in future studies, to test how ostracods regulate the development of their sexually dimorphic eyes. PMID- 23652200 TI - Managing and sharing the escalating number of sponge "unknowns": the SpongeMaps project. AB - Contemporary collections of sponges in the Indo-west Pacific have escalated substantially due to pharmaceutical discovery, national bioregional planning, and compliance with international conventions on the seabed and its marine genetic resources beyond national jurisdictions. These partially processed operational taxonomic unit (OTU) collections now vastly outweigh the expertise available to make them better "known" via complete taxonomy, yet for many bioregions they represent the most significant body of currently available knowledge. Increasing numbers of cryptic species, previously undetected morphologically, are now being discovered by molecular and chemical analyses. The uncoordinated and fragmented nature of many previous collections, however, means that knowledge and expertise gained from a particular project are often lost to future projects without a biodiversity informatics legacy. Integrating these diverse data (GIS; OTUs; images; molecular, chemical, and other datasets) required a two-way iterative process so far unavailable for sponges with existing biodiversity informatics tools. SpongeMaps arose from the initial need for online collaboration to integrate morphometric data with molecular barcodes, including the Porifera Tree of Life (PorTol) project. It provides interrogation of existing data to better process new collections; capacity to create new OTUs; publication of online pages for individual species, so as to interpret GIS and other data for online biodiversity databases and services; and automatic links to external datasets for taxonomic hierarchy, specimen GIS and mapping, DNA sequence data, chemical structures, and images. PMID- 23652201 TI - Decoding the language of phosphorylation site dynamics. AB - Immune defenses depend on the ability of immunoreceptors to recognize foreign antigens and initiate intracellular signaling when a pathogen is detected. Signal initiation requires spatial reorganization of proteins and site-specific receptor phosphorylation, which leads to engagement of feedback loops. This Journal Club discusses recent work using combined experimental and computational approaches to investigate these processes in B cell antigen receptor (BCR) signaling. Specifically, the roles of different kinases in the presence and absence of BCR clustering were evaluated. Results indicated that spleen tyrosine kinase (SYK) can compensate for loss of Src-family kinase activity when receptors are spatially clustered, in part because receptor clustering enables SYK to trigger a positive feedback loop. This study and its implications suggest additional uses for computational models in studies of immunoreceptor signaling and highlight areas where extensions of current methodology are needed to better understand the complexities of biomolecular interactions. PMID- 23652202 TI - Old dance with a new partner: EGF receptor as the phenobarbital receptor mediating Cyp2B expression. AB - The decades-long quest for the phenobarbital (PhB) receptor that mediates activation of Cyp2B would appear fulfilled with the discovery by Mutoh et al., who found that PhB binds with pharmacological affinity to the epidermal growth factor receptor (EGFR). This finding provides a molecular basis for the suppression of hepatocyte EGFR signaling observed with PhB treatment, as previously noted in the context of tumor promotion. Although the PhB-mediated induction of Cyp2B expression through the association of a canonical nuclear receptor with the 5'-enhancer PBREM of Cyp2B is well known, direct binding of PhB to constitutive active androstane receptor (CAR, also known as NR1I3) typical of other xenobiotic-activated nuclear receptors has eluded detection. One EGF activated pathway affected by the PhB-EGFR interaction is the loss of tyrosine phosphorylation of the scaffold protein RACK1. Dephosphorylated RACK1 provides the mechanistic link between the binding of PhB to EGFR and its effects on CAR by facilitating the interaction of serine/threonine phosphatase PP2A with inactive phosphorylated CAR. The dephosphorylation of CAR enables its translocation to the nucleus and activation of Cyp2B expression. Because EGFR and transducers RACK1, PP2A, and other partners are highly networked in numerous cellular pathways, this newly discovered partnership will surely reveal new fundamental roles for PhB beyond the regulation of drug metabolism. PMID- 23652203 TI - Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling. AB - Phenobarbital is a central nervous system depressant that also indirectly activates nuclear receptor constitutive active androstane receptor (CAR), which promotes drug and energy metabolism, as well as cell growth (and death), in the liver. We found that phenobarbital activated CAR by inhibiting epidermal growth factor receptor (EGFR) signaling. Phenobarbital bound to EGFR and potently inhibited the binding of EGF, which prevented the activation of EGFR. This abrogation of EGFR signaling induced the dephosphorylation of receptor for activated C kinase 1 (RACK1) at Tyr(52), which then promoted the dephosphorylation of CAR at Thr(38) by the catalytic core subunit of protein phosphatase 2A. The findings demonstrated that the phenobarbital-induced mechanism of CAR dephosphorylation and activation is mediated through its direct interaction with and inhibition of EGFR. PMID- 23652204 TI - A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53. AB - In the intrinsic pathway of apoptosis, cell-damaging signals promote the release of cytochrome c from mitochondria, triggering activation of the Apaf-1 and caspase-9 apoptosome. The ubiquitin E3 ligase MDM2 decreases the stability of the proapoptotic factor p53. We show that it also coordinated apoptotic events in a p53-independent manner by ubiquitylating the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. HUWE1 ubiquitylates the antiapoptotic factor Mcl-1, and we found that HUWE1 also ubiquitylated PP5 (protein phosphatase 5), which indirectly inhibited apoptosome activation. Breast cancers that are positive for the tyrosine receptor kinase HER2 (human epidermal growth factor receptor 2) tend to be highly aggressive. In HER2-positive breast cancer cells treated with the HER2 tyrosine kinase inhibitor lapatinib, MDM2 was degraded and HUWE1 was stabilized. In contrast, in breast cancer cells that acquired resistance to lapatinib, the abundance of MDM2 was not decreased and HUWE1 was degraded, which inhibited apoptosis, regardless of p53 status. MDM2 inhibition overcame lapatinib resistance in cells with either wild-type or mutant p53 and in xenograft models. These findings demonstrate broader, p53-independent roles for MDM2 and HUWE1 in apoptosis and specifically suggest the potential for therapy directed against MDM2 to overcome lapatinib resistance. PMID- 23652205 TI - Requirement for nuclear calcium signaling in Drosophila long-term memory. AB - Calcium is used throughout evolution as an intracellular signal transducer. In the mammalian central nervous system, calcium mediates the dialogue between the synapse and the nucleus that is required for transcription-dependent persistent neuronal adaptations. A role for nuclear calcium signaling in similar processes in the invertebrate brain has yet to be investigated. Here, we show by in vivo calcium imaging of adult brain neurons of the fruit fly Drosophila melanogaster, that electrical foot shocks used in olfactory avoidance conditioning evoked transient increases in cytosolic and nuclear calcium concentrations in neurons. These calcium signals were detected in Kenyon cells of the flies' mushroom bodies, which are sites of learning and memory related to smell. Acute blockade of nuclear calcium signaling during conditioning selectively and reversibly abolished the formation of long-term olfactory avoidance memory, whereas short term, middle-term, or anesthesia-resistant olfactory memory remained unaffected. Thus, nuclear calcium signaling is required in flies for the progression of memories from labile to transcription-dependent long-lasting forms. These results identify nuclear calcium as an evolutionarily conserved signal needed in both invertebrate and vertebrate brains for transcription-dependent memory consolidation. PMID- 23652206 TI - Physicochemical forms of (90)Sr and (137)Cs in components of Glyboke Lake ecosystem in the Chornobyl exclusion zone. AB - Lake ecosystems are efficient 'collectors' for a wide range of radionuclides, which are accumulated by abiotic and biotic components after their input to the aquatic environment. Aquatic vegetation accumulates radionuclides, while annual atrophy of vegetative mass for the most species, in the absence of drainage, leads to an increase of radionuclide accumulation in bottom sediments. This leads to the preservation of a rather high level of radionuclides in the components of stagnant water ecosystems. As a result of global fallout and of the Chornobyl disaster, significant areas of Ukraine are contaminated with (90)Sr and (137)Cs, both of which present a significant radiological risk. Therefore, research into the way these radionuclides behave in freshwater ecosystems is of current interest, particularly following the Fukushima disaster. The present paper covers the study of physicochemical forms of radionuclides in the components of Glyboke Lake, located within the Chornobyl exclusion zone and considered to be one of the most contaminated lakes in the area. Physicochemical forms of radionuclides influence their distribution and solubility among the components of aquatic ecosystems, as well as biological availability for aquatic vegetation and intensity of migration processes. The study of chemical forms was conducted in bottom sediments and typical representatives of aquatic vegetation. The ratio of activity concentrations of (90)Sr and (137)Cs in water, aquatic plants and bottom sediments of Glyboke Lake was quantified. A diversity in distribution of physicochemical forms of radionuclides depending on a nutrition type of the studied aquatic plants was observed. PMID- 23652207 TI - Correlation between morphological and functional liver volume in each sector using integrated SPECT/CT imaging by computed tomography and technetium-99m galactosyl serum albumin scintigraphy in patients with various diseases who had undergone hepatectomy. AB - OBJECTIVES: The aim of the study was to accurately examine the functional volume (RI-vol) of the hepatic segments on single photon emission computed tomography/computed tomography (CT) fusion imaging by technetium-99m galactosyl human serum albumin scintigraphy and compare it with the RI-vol and morphological volume obtained on computed tomography (CT-vol). METHODS: In 60 patients with various liver background statuses who had undergone hepatectomy, the RI-vol and CT-vol were examined in each sector using imaging analysis. The values from a control group (n=91) were used as reference data. RESULTS: The mean RI-vol and CT vol of the right liver were 64 +/- 10 and 63 +/- 6%, respectively, whereas the values for the left liver were 36 +/- 10 and 37 +/- 6%, respectively. Compared with the control group, the ratios in each hemiliver were similar. The mean RI vol and CT-vol for each sector were also similar, and significant positive correlations were identified between the two volumes (P<0.01). In four patients with hepatic tumors involving the main hepatic vessels or the bile duct and in 10 patients who had undergone portal vein embolization, the actual RI-vol in the injured sector was significantly decreased compared with CT-vol (P<0.05). There were marked changes in functional volume in segment 6+7 and segment 2+3 after portal vein embolization (P<0.05). CONCLUSION: Volumetric measurement using single photon emission computed tomography/CT imaging with technetium-99m galactosyl human serum albumin scintigraphy is useful for evaluating the functional volume in separated livers and offers a good reflection of the background liver status. PMID- 23652208 TI - 18F-radiolabeled GLP-1 analog exendin-4 for PET/CT imaging of insulinoma in small animals. AB - BACKGROUND: Insulinoma is a neuroendocrine tumor derived from the beta cells of pancreatic islets. They are usually relatively inaccessible for surgical intervention. High expression levels of glucagon-like peptide-1 (GLP-1) receptor have been detected in insulinoma. AIM: The aim of the study was to evaluate the potential of F-radiolabeled GLP-1 analog exendin-4 for the diagnosis of insulinoma using PET/computed tomography imaging. MATERIALS AND METHODS: The GLP 1 receptor-specific molecular probe [F]FB-exendin-4 was prepared by the conjugation of exendin-4 and N-succinimidyl-4-[F] fluorobenzoate ([F]SFB). High expression of GLP-1 by the RIN-m5f insulinoma line and GLP-1 receptor specificity were evaluated by determining the saturation curve for in-vitro binding of I radiolabeled exendin-4 and by investigation of the competitive binding between I radiolabeled and unlabeled exendin-4. Further, the in-vivo biodistribution and micro-PET/computed tomography images of insulinoma-bearing mice were studied. RESULTS: An overall radiochemical yield of 35.6+/-2.3% (decay corrected, n=5) and specific radioactivity of around 30 GBq/umol were achieved for [F]FB-exendin-4, and the radiochemical purity was over 98%. Both in-vitro and in-vivo studies confirmed the specificity of [F]FB-exendin-4 to insulinoma cells. CONCLUSION: [F]FB-exendin-4 has been found to be an effective molecular imaging probe for detecting insulinomas. PMID- 23652209 TI - Biodistribution and imaging of [99mTc]-HYNIC-RGD in MDA-MB-231 and NTERA-2 cancer cell xenografts. AB - PURPOSE: Increased expression of alphavbeta3 integrins is involved in tumour angiogenesis. Targeting these receptors with a dedicated peptide containing the RGD sequence may provide information about the receptor status in and around the tumour and about the angiogenesis process involved. The aim of this study was to compare the uptake of [Tc]-HYNIC-RGD in two types of tumours that either express or do not express the alphavbeta3 receptor (NTERA-2 and MDA-MB-231, respectively) and discuss the use of this tracer in experimental models of angiogenesis. PROCEDURES: Uptake of intravenously injected [Tc]-HYNIC-RGD was studied ex vivo and in vivo. Histological analysis of excised tumours was carried out. Percentages of the injected dose uptake per gram of tissue were compared between the two types of tumours and in the periphery and centre of each tumour. RESULTS: [Tc]-HYNIC-RGD was rapidly cleared from blood circulation and excreted through the kidneys. Residual activity was retained in the intestine. Tumour uptake of [Tc]-HYNIC-RGD was high and homogeneous for alphavbeta3-positive cell lines (1.94+/-0.26%ID/g). Tumour uptake was weak and distributed only in the tumour periphery for alphavbeta3-negative cell lines (0.10+/-0.02%ID/g, tumour periphery; 0.06+/-0.01%ID/g, tumour core; P=0.01). These results correlated with vessel distribution. CONCLUSION: Uptake of [Tc]-HYNIC-RGD was more intense in alphavbeta3-positive cell lines than in alphavbeta3-negative cell lines, but tracer distribution was more representative of angiogenic locations in alphavbeta3-negative cell lines. Further clinical and preclinical studies are needed on the use of RGD-related tracers. PMID- 23652210 TI - Thyroid lobe ablation with iodine- 131I in patients with differentiated thyroid carcinoma: a randomized comparison between 1.1 and 3.7 GBq activities. AB - PURPOSE: The present study was undertaken to evaluate the ablation rate after administration of 1.1 or 3.7 GBq of iodine- (131I) to patients with low-risk differentiated thyroid carcinoma (DTC) primarily treated by lobectomy. PATIENTS AND METHODS: Enrolled were 136 consecutive patients affected by histologically proven low-risk DTC previously treated by lobectomy. Patients were randomized to receive a single dose of 1.1 or 3.7 GBq of 131I in an equivalence trial. Successful thyroid ablation was defined as a negative diagnostic whole-body scan and stimulated thyroglobulin levels lower than 2 ng/ml in the absence of thyroglobulin antibodies. RESULTS: The patient demographic and clinical data were well balanced at baseline. The ablation rate was significantly (P<0.01) higher in patients treated with 3.7 GBq (75%) than in those treated with 1.1 GBq (54%) of radioiodine. No relevant side effects occurred in either group. CONCLUSION: Radioiodine lobe ablation with a single administration of 3.7 GBq is a simple and safe mode of treatment, achieving an ablation rate higher than that of 1.1 GBq. This procedure may be offered as an alternative to completion thyroidectomy in highly selected DTC patients who had experienced complications during initial surgery or for whom completion thyroidectomy is contraindicated. PMID- 23652211 TI - A Langmuir-Hinshelwood approach to the kinetic modelling of catalytic ammonia decomposition in an integral reactor. AB - The increasing interest in ammonia decomposition is due to the fact that this compound can be used advantageously as a hydrogen carrier, allowing the development of single-step hydrogen generation systems. With the aim of developing efficient reactors for ammonia decomposition, e.g. for fuel cell applications, it is imperative to investigate the kinetics and reaction mechanism in depth. The main goal of this work is to develop reliable kinetic models that are able to predict the performance obtained using integral reactors, e.g. monoliths. In this case, an almost complete NH3 conversion is obtained, with a high H2 concentration at the exit of the reactor. The operating conditions, mainly the gas composition, are very different along the reactor. In addition, the temperatures needed to attain such large conversions are usually high. The kinetic models developed in this contribution are based on the Langmuir isotherm, considering that all the adsorbed species can be kinetically relevant, that the slow step or steps can be partially reversible, and that the surface can be considered as energetically uniform, i.e. ideal. Among other conclusions, the results obtained indicate that the variable kinetic orders and apparent activation energies frequently reported in the literature can be direct consequences of the data analysis and can therefore also be explained without considering any change in the controlling step with the reaction temperature or in the hydrogen or ammonia concentration. PMID- 23652212 TI - A logical fallacy: commentary on Moss et al. PMID- 23652213 TI - Demographic and clinical factors associated with changes in employment in multiple sclerosis. AB - OBJECTIVE: The objective of this paper is to investigate demographic and disease factors associated with changes in employment role and status in multiple sclerosis (MS). METHODS: Questionnaires on current symptoms, employment status and factors associated with changes in employment were sent to a community sample of 566 MS patients. RESULTS: A total of 221 completed questionnaires were analysed. Of 169 employed at diagnosis, 43.3% had left employment at a mean of 11.9 years after disease onset. Of those still employed, 55% had changed their role or working hours to accommodate symptoms relating to their disease. These patients reported greater fatigue (p = 0.001), pain (p = 0.033) and memory problems (p = 0.038) than those whose employment had remained unaffected. Multinomial logistic regression revealed the factors most strongly predictive of employment status were disability level, years of education, disease duration and fatigue (p = 0.032). CONCLUSIONS: Despite changes to public perceptions and legislative protection over the last 20 years, high rates of MS patients still leave the workforce prematurely, reduce working hours or change employment roles. These data have significant implications when considering social and economic impacts of MS, support the value of employment metrics as long-term outcome measures, and demonstrate the need to improve employment requirements and flexibility of working practices in individuals with MS. PMID- 23652214 TI - The effects of long-term interferon-beta-1b treatment on cognitive functioning in multiple sclerosis: a 16-year longitudinal study. AB - BACKGROUND: Multiple sclerosis (MS) is a progressive disease of the central nervous system that affects cognition. Short-term treatment with interferon-beta 1b (IFN-b-1b) has been shown to have beneficial effects on cognition. OBJECTIVE: The objective of this paper is to evaluate the effects of IFN-b-1b on cognitive functioning in patients with MS over the course of 16 years. METHODS: Sixteen subjects with relapsing-remitting MS participated in the study. Nine of these subjects received IFN-b-1b, while seven received placebo treatment in the pivotal MS trial. After five years, all subjects were switched to IFN-b-1b treatment. At two and four years into the study, all subjects underwent a brief neuropsychological test battery, magnetic resonance imaging (MRI), and neurologic ratings; measures were repeated at 16 years. RESULTS: Across the total cohort, cognitive functioning remained relatively stable over the course of 16 years. The placebo/IFN-b-b group exhibited increased visual memory performance relative to the IFN-b-1b treatment group, but had a greater decline in verbal memory. Initial MRI lesion load demonstrated a significant, negative correlation with overall cognitive performance at 16 years (p = 0.00). CONCLUSION: We conclude that IFN-b 1b has beneficial effects on long-term cognition outcomes in MS. PMID- 23652215 TI - Clinical impact of early brain atrophy in clinically isolated syndromes. AB - BACKGROUND: The impact of global and tissue-specific brain atrophy on conversion to multiple sclerosis (MS) after a clinically isolated syndrome (CIS) is not fully gauged. OBJECTIVES: We aimed to determine the magnitude and clinical relevance of brain volume dynamics in the first year after a CIS. METHODS: We assessed 176 patients with CIS within 3 months of onset, clinically and by conventional magnetic resonance imaging (MRI) scans, at baseline and 1 year after clinical onset. We determined the percentage of brain volume change (PBVC) and the brain parenchymal (BPF), grey matter (GMF) and white matter (WMF) fractions. RESULTS: The mean follow-up time was 53 months (SD = 16.8): 76 patients (43%) experienced a second attack, 32 (18%) fulfilled MRI-only 2005 McDonald criteria and 68 (39%) remained as CIS. Statistically significant decreases in the volume measures tested were observed in patients with a second attack, for BPF and PBVC; in both MS groups for GMF; whereas in all groups, the WMF was unchanged. Patients with a second attack had larger PBVC decreases (- 0.65% versus + 0.059%; p < 0.001). PBVC decreases below - 0.817% independently predicted shorter times to a second attack. CONCLUSIONS: Global brain and grey matter volume loss occurred within the first year after a CIS; brain volume loss predicted conversion to MS. PMID- 23652216 TI - The economic impact of multiple sclerosis in Australia in 2010. AB - BACKGROUND: Multiple sclerosis (MS) has a major impact on health and is a substantial burden on patients and society. We estimated the annual costs of MS in Australia from individual and societal perspectives using data from the Australian MS Longitudinal Study (AMSLS) and prevalence figures from 2010. METHODS: Direct and indirect costs were estimated from a subsample of 712 AMSLS subjects who completed baseline and follow-up economic impact surveys. All costs are in 2010 Australian dollars (AUD). RESULTS: Annual costs per person with MS were AUD48,945 (95% CI: 45,138 to 52,752). Total costs were AUD1.042 (0.9707 to 1.1227) billion based on a prevalence of 21,283. The largest component was indirect costs due to loss of productivity (48%). Costs increased with increasing disability: AUD36,369, AUD58,890 and AUD65,305 per patient per year for mild, moderate and severe disability, respectively. Total costs of MS to Australian society have increased 58% between 2005 and 2010. CONCLUSIONS: This study confirms that MS imposes a substantial burden on Australian society, particularly impacting on productivity. The burden increases with worsening disability associated with the disease. Investment in interventions that slow progression, as well as resources, services and environments that assist people with MS to retain employment, is supported. PMID- 23652217 TI - Assessing the validity of a computer-generated cognitive screening instrument for patients with multiple sclerosis. AB - BACKGROUND: Neuropsychological testing requires considerable time, expense, and expertise to administer. These factors can limit patient access. Computerized cognitive testing has been proposed as an alternative. OBJECTIVES: The objective of this paper is to validate a brief, simple-to-use computer-generated cognitive assessment screening battery for multiple sclerosis (MS) patients that has minimal motor involvement. METHODS: A sample of 96 MS patients and 98 healthy controls completed a computer-generated battery that included the Stroop, Symbol Digit Modalities Test (C-SDMT), a two- and four-second visual analog of the Paced Auditory Serial Addition Test (PVSAT-2, PVSAT-4), and simple and choice reaction time tests. The Minimal Assessment of Cognitive Function in MS was used to define cognitive impairment in the MS sample. RESULTS: Each newly developed test successfully distinguished between cognitively impaired patients and healthy controls as well as cognitively intact patients. A combination of three computerized tests (C-SDMT, PVSAT-2, PVSAT-4) with a mean administration time of 10 minutes had a sensitivity of 82.5% and specificity of 87.5% in detecting cognitive impairment. Good test-retest reliability was obtained for each measure. CONCLUSIONS: Good sensitivity and specificity, brevity, ease of administration, and a limited motor component highlight the feasibility of introducing this computer-generated cognitive screening instrument in a busy MS clinic. PMID- 23652218 TI - High prevalence of sickness absence and disability pension among multiple sclerosis patients: a nationwide population-based study. AB - INTRODUCTION: Although multiple sclerosis (MS) often implies substantial disability, there is little knowledge about sick leave and disability pension among MS patients. OBJECTIVES: The purpose of this study was to estimate the prevalence rates of sick leave and disability pension among MS patients and to explore how socio-demographics are associated with such rates. METHODS: The register data of all people who lived in Sweden in 2005 and were 16-64 years old was used to identify 9721 MS patients and matched controls. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and effect modifications were evaluated with Wald X(2) tests. RESULTS: In 2005, 61.7% of the MS patients were on partial or full disability pension compared to 14.2% among the controls. Of the others, 36.8% had >= 1 sick-leave spell for >14 days during that year. Socio-demographics were similarly associated with sick leave and disability pension among MS patients and controls, with the noteworthy exceptions that female gender and immigration status were less potent risk factors in the MS population (p<0.05). CONCLUSION: In spite of widespread access to modern health care including disease-modifying drugs, the majority of MS patients of working ages were on a disability pension. Strategies enabling MS patients to retain their footing in the labour market are needed. PMID- 23652219 TI - Quality attributes and color characteristics in three-piece boneless hams. AB - One hundred and fifty hams were selected on visual assessment of quality into normal (C) and two-tone (TT) groups. CIE LAB color and pH measurements were collected at the plant 48h postmortem on the gluteus medius (GM), gluteus profundus (GP), and rectus femoris (RF), and again at 72h on the semimembranosus (SM), biceps femoris (BF), semitendinosus (ST), and RF. Data were analyzed using GLM procedures of SAS, and correlations between color scores, pH, and drip loss were calculated. Plant and fabrication pH were lower (P<0.01) in GM from TT hams compared with C. Muscles from TT hams had lower (P<0.01) L* and a* values compared with C. The GM L* and GM pH values were correlated (P<0.05) with L* values for all other muscles and drip loss in SM. These data show that GM color and pH are accurate predictors of pork quality attributes in the muscles of a three-piece boneless ham. PMID- 23652220 TI - A thirty-four-year-old woman with chronic dyspnea and pulmonary interlobular septal thickening. Erdheim-Chester Disease. PMID- 23652221 TI - A novel benzazepinone sodium channel blocker with oral efficacy in a rat model of neuropathic pain. AB - A series of benzazepinones were synthesized and evaluated for block of Nav1.7 sodium channels. Compound 30 from this series displayed potent channel block, good selectivity versus other targets, and dose-dependent oral efficacy in a rat model of neuropathic pain. PMID- 23652223 TI - Rising environmental cadmium levels in developing countries: threat to genome stability and health. AB - Cadmium (Cd) is a ubiquitous environmental pollutant of increasing worldwide concern. It is thought to be of greater concern to rapidly industrializing developing countries because of the increasing pace of industrial activities in these countries with increasing consumption and release into the environment. Traditionally, health concerns in exposed human populations have revolved around the association of Cd with bone disease, emphysema and possibly hypertension. Accumulating evidence suggest that Cd is involved in the disruption of many genomic processes, the mechanisms of which are being gradually understood. Changes in DNA Methylation may be induced by cadmium leading to epigenetic alterations. Additionally, though Cd is not thought to induce reactive oxygen species (ROS) directly because it is not capable of accepting or donating electrons under physiological conditions, 8-hydroxy deoxyguanosine (8-OHdG) (a marker of oxidative stress to DNA and a risk factor for cancer among others) has been shown to be elevated in the DNA of testes from rats treated with cadmium chloride, at least in part because Cd inhibits DNA repair mechanisms. Cadmium is also a metabolic antagonist to Zinc (Zn), an important micronutrient involved in numerous molecular activities. This antagonism alters the physiological stoichiometric relationship between Cd and Zn leading to high Cd/Zn ratio, one consequence of which is high error rate and lack of efficient DNA repair systems leading to high mutation and genome instability culminating in many carcinogenic states, particularly prostate carcinogenesis. Cadmium has also been shown to replace Zn in the tumor suppressor protein, p53 thereby impairing p53's DNA binding activity and associated repair processes. The expression of the p53 protein is significantly depressed by cadmium. Although the rising level of Cd in the environment is widely acknowledged, the occult threat it poses to genome stability largely through inhibition of normal DNA damage repair, oxidative stress and apoptosis and health is poorly recognized. This paper examines the involvement of Cd in the molecular pathways of human disease, providing insight for the prevention of genome instability and associated disease susceptibility particularly cancer across populations through micronutrient intervention, aiding upregulation of the antioxidant defense and DNA repair systems. PMID- 23652224 TI - Differential responses to endothelial-dependent relaxation of the thoracic and abdominal aorta from male Sprague-Dawley rats. AB - Regional heterogeneity exists in reactivity of different vascular beds to vasoactive substances. Experiments were designed to determine if there are differences between thoracic and abdominal aorta response to acetylcholine induced relaxation. Ten male Sprague-Dawley rats with a weighing between 200g 250g were used. The aorta was isolated and 3mm aortic rings were cut and suspended in organ baths containing physiological salt saline (PSS). Contractile and relaxation responses to noradrenaline (NA) and ACh, in the presence or absence of L-NNA and high K+ concentration were studied. Contractile response to NA was similar along the aorta. At the higher doses, ACh elicited a greater (p < 0.05) relaxation in the abdominal aorta when compared with the thoracic aorta. However, inhibition of eNOS was more effective (p<0.05) in preventing ACh-induced relaxation in the thoracic aorta when compared with the abdominal aorta. Conversely, inhibition of endothelial hyperpolarizing factor (EDHF) by high K+ concentration blocked ACh-induced relaxation to a greater extent in the abdominal aorta (p<0.05) when compared with the thoracic aorta. ACh-induced relaxation differs in the thoracic and abdominal aorta. Differences in the EDHF activity along the aorta underlie the differential response of the thoracic and abdominal aorta to ACh-induced relaxation. PMID- 23652222 TI - Effects of spinally administered bifunctional nociceptin/orphanin FQ peptide receptor/MU-opioid receptor ligands in mouse models of neuropathic and inflammatory pain. AB - Nociceptin/orphanin FQ peptide receptor (NOP) agonists produce antinociceptive effects in animal models after spinal administration and potentiate MU-opioid receptor (MOP)-mediated antinociception. This study determined the antinociceptive effects of spinally administered bifunctional NOP/MOP ligands and the antinociceptive functions of spinal NOP and MOP receptors in mice. Antinociceptive effects of bifunctional NOP/MOP ligands BU08028 [(2S)-2 [(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6 methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol] and SR16435 [1-(1 (2,3,3alpha,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one] were pharmacologically compared with the putative bifunctional ligand buprenorphine, selective NOP agonist SCH221510 [3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8 azabicyclo[3.2.1]octan-3-ol] and selective MOP agonist morphine in neuropathic and inflammatory pain models. Additionally, the degree of tolerance development to the antiallodynic effects of SR16435 and buprenorphine were determined after repeated intrathecal administration. Our data indicated that BU08028 and SR16435 were more potent than morphine and SCH221510 in attenuating nerve injury-induced tactile allodynia and inflammation-induced thermal hyperalgesia. Coadministration of receptor-selective antagonists further revealed that both NOP and MOP in the spinal cord mediated the antiallodynic effects of BU08028 and SR16435, but intrathecal buprenorphine-induced antiallodynic effects were primarily mediated by MOP. Repeated intrathecal administration of SR16435 resulted in reduced and slower development of tolerance to its antiallodynic effects compared with buprenorphine. In conclusion, both NOP and MOP receptors in the spinal cord independently drive antinociception in mice. Spinally administered bifunctional NOP/MOP ligands not only can effectively attenuate neuropathic and inflammatory pain, but also have higher antinociceptive potency with reduced tolerance development to analgesia. Such ligands therefore display a promising profile as spinal analgesics. PMID- 23652225 TI - DE71 suppresses thyroid hormone-mediated dendritogenesis and neuritogenesis in the developing cerebellum. AB - Polybrominated diphenylethers (PBDEs) are synthesized chemicals essential to minimize accidents and deaths resulting from fire-outbreaks. Despite their usefulness, public health concern is on the increase over their use. PBDE is global in use, persistent in the environment, and possess the ability to bio accumulate. Previous studies have suggested that they may interfere with thyroid hormone homeostasis, and are neurotoxic. We therefore investigated the effects of DE71 (a PBDE mixture) on thyroid hormone (TH)-mediated developments in the cerebellum. Employing primary cerebellar culture from new born rats, our study revealed that low dose DE71 significantly suppressed TH-mediated Purkinje cell dendrite arborization. Also, low dose DE71 remarkably impaired neurite extension of granule cells obtained from reaggregate culture of new born rat cerebella. Taken together, our study clearly reveals that DE71 can impair TH-mediated neuronal development in the cerebellum and may therefore interfere with normal TH induced brain growth and function. PMID- 23652226 TI - Clinicopathological observations in experimental peste des petit ruminants virus and Mannheimia haemolytica A:2 co-infection in goats. AB - The experiment describes for the first time the clinicopathological features of the co-infection of Peste des petit Ruminants (PPR) virus and Mannheimia haemolytica,in goats. Twenty clinically healthy goats, six months of age were used. 15 goats were infected by intratracheal inoculation of 1ml of pure cultured 106.5 TCID50 PPR virus grown in Baby hamster kidney cell lines, and a week later,1 ml of pure culture (109 CFU) of Mannheimia haemolytica (MH)A2 to study its clinico-pathological features and five goats served as controls. The clinical signs were observed and two goats were euthanized at predetermined intervals for gross examinations, bacteriological, virological and histopathological investigations on tissues collected using standard techniques. The clinical signs were severe and the order of manifestation was anorexia, pyrexia, dyspnea, oculo nasal discharge, recumbency and death. The lesions observed were severe fibrinous bronchointerstitial pneumonia and pleurisy with thickened alveolar septa, edema and neutrophilic infiltrations of the interstitium with giant cells. There was also marked erosive stomatitis and acute enteritis. The average percentage lung consolidation for the infection was 7.01% and the right lung was more affected (p<0.05) while the overall mortality was 33.3%. MHA:2 and PPR virus were re isolated from the lungs. The clinicopathological features observed showed that goats were susceptible to co- infection of PPR and Mannheimiosis which was severe and fatal. The data should help veterinarians and other medical experts to recognize cases of bacterial complicated viral infection and be informed of the approach to the treatment of such conditions. PMID- 23652227 TI - Evaluation of toxic effects of metformin hydrochloride and glibenclamide on some organs of male rats. AB - Metformin hydrochloride (MET) and glibenclamide (GB) are used in the management of Type 2 Diabetes (T2D). This study was designed to investigate the toxic effect of MET and GB in the Liver, kidney and testis of rats. Twenty one rats were divided into three groups of seven rats each; group 1 served as control, groups 2 and 3 received GB and MET at doses of 5 and 30 mg/kg, respectively, for 21 days by oral gavage. Results indicate that MET and GB treatment did not affect body weight-gain in the rats. Also, there were no treatment-related changes in the absolute and relative weights of liver, kidney, and testis in MET and GB-treated rats relative to controls. However, significant increase (p<0.05) in testicular lipid peroxidation levels were accompanied by reduction in epididymal sperm count and motility in MET and GB-treated rats, whereas sperm live/dead ratio was unaffected. Specifically, MET and GB decreased sperm count and motility by 34%, 31% and 25%, 28%, respectively. Activities of hepatic and renal superoxide dismutase (SOD) and catalase (CAT), serum alkaline phosphatase, lactate dehydrogenase and alanine aminotransferase were not significantly (p>0.05) affected in MET and GB-treated rats, whereas testicular SOD, CAT, glutathione, serum aspartate aminotransferase and conjugated bilirubin were markedly affected by MET treatment. Histopathological results showed marked necrosis, degeneration of seminiferous tubules and defoliation of spermatocytes in testis of MET-treated rats. Taken together, MET and GB induced lipid peroxidation, affected seminal qualities and decreased antioxidant status. These drugs may interfere with normal biochemical processes in testis and liver of the rats. PMID- 23652228 TI - Comparison and prediction of preclinical students' performance in the MBBS stage I examination at the University of the West Indies, Mona Campus. AB - This retrospective study involved the analysis of the grades of ninety-four preclinical students who took the Bachelor of Medicine and Bachelor of Surgery (MBBS) Stage I Examination in Anatomy, Biochemistry, Physiology, Social and Preventive Medicine, and Pharmacology between December 1997 and May 1999 at the Mona Campus of The University of the West Indies (UWI). A statistically significant correlation was observed among the basic science subjects. Additionally, a statistically significant prediction was found between the performances of the students in one discipline and the others, with Physiology being the most predicted. The data support the hypothesis that students who performed well in one discipline were likely to perform well in the other disciplines; and also that the performance in some subjects could predict the performance in others. This result may also justify further investigation as to whether the performance in certain basic sciences disciplines at the preclinical stage can be used to predict performance in the clinical disciplines. PMID- 23652229 TI - Comparative morphophysiological evaluation of the testis of adult Wistar rats fed low protein-energy diet and dosed with aqueous extracts of Cuscuta australis. AB - Cuscuta australis (C. australis) seed and stem are historically used by the local population as dietary supplement for the management of infertility. This study, therefore, evaluated the effect of orally administered aqueous extracts of C. australis seed and stem, 300 mg/kg body weight/day for seven days, on the testis of the adult Wistar rat fed either low or normal protein-energy diets. The control group received water. The relative weight of the testis was non significantly increased (p>0.05) in the Low Protein-energy diet-Water-treated (LPWA), Low Protein-energy diet-Seed-treated (LPSE) and Normal Protein-energy diet-Seed-treated (NPSE) groups relative to the Normal Protein-energy diet-Water treated (NPWA). The weight of the testis was also non-significantly increased (p?0.05) in the Low Protein-energy diet-Stem-treated (LPST), but decreased in the Normal Protein-energy diet-Stem-treated (NPST), relative to LPWA and NPWA. Heights of germinal epithelium were significantly decreased (p<0.05) in the LPWA, LPSE and LPST relative to the NPWA, NPSE and NPST. Diet significantly influenced (p<0.001) the effect of stem extract on the height of germinal epithelium. The NPSE, LPSE, NPST, LPST and LPWA showed significantly decreased (p<0.001) plasma levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) relative to NPWA. The LPWA, LPSE and NPST also showed significantly decreased (p<0.001) levels of testosterone relative to NPWA and LPST. Diet significantly influenced (p<0.001) the effect of seed on the level of LH. Seed-diet interactions significantly affected the levels of FSH (p<0.001) and LH (p<0.05), but not testosterone. Diet significantly influenced (p<0.001) the effects of stem extract on the levels of FSH, LH and testosterone. Stem-diet interactions significantly affected (p<0.001) the levels of FSH, LH and testosterone. Our data suggest that the aqueous extract of C. australis stem is more potent than the seed extract and that dietary protein-energy intake may influence the efficacy of orally administered aqueous extracts of C. australis. PMID- 23652230 TI - Effect of road transport stress on erythrocyte osmotic fragility (EOF) of healthy young adult Nigerians during the harmattan season. AB - Road transportation and harmattan season have been reported to be stressful to live stock species. This study was conducted with the aim of investigating the effect of two and half hours of road transportation on the erythrocyte osmotic fragility of 23 healthy young adults Nigerians (15 males and 8 females) during the harmattan season. After an overnight fast, venous blood was collected from each subject for the determination of serum cortisol, glucose concentration and erythrocyte osmotic fragility. The subjects were then transported at a speed of 65-75Km/h covering a distance of 180km. Thereafter venous blood was again collected (within 10 minutes) for the determination of serum cortisol concentration, glucose concentration and erythrocyte osmotic fragility using standard methods. There was a statistically significant decrease (P < 0.05) in percent haemolysis recorded at Nacl concentration of 0.50% after transportation. There was also significant decrease (P < 0.001) in percent haemolysis at Nacl concentration of 0.60 and 0.70% in the male subject after road transportation as compared to values obtained before transportation. There was a statically significant difference (P < 0.05) between the serum concentrations of cortisols in the subjects before and after road transportation. The results of this study indicated that road transportation was stressful to the subjects and measurement of erythrocyte osmotic fragility (EOF) could be used as a biomarker of stress in humans. PMID- 23652231 TI - Preliminary study on the effects of Buchholzia coriacea seed extract on male reproductive parameters in rats. AB - The effects of methanol extract of Buchholzia coriacea seed was studied on male reproductive system of albino rats. Administration of 200mg/kg b.w.(p.o.) of the extract for 6 weeks resulted in significant reduction (P?0.05) in the weight of the epididymis and seminal vesicle, but not the testes and prostate gland. Also the weight of the visceral organs- lungs, liver, heart and kidney were unaffected. A marked decrease (P<0.05) in sperm motility and volume was also observed in sperm collected from the caudal epididymis of the treated animals. Sperm count and morphology were not significantly affected (P<0.05). Total tissue protein of the epididymis and testes of the treated rats was significantly increased (P<0.05) and fertility was zero in the treated rats. Histological section showed that the epididymal ducts were mostly empty, though the epithelial lining appeared normal. There were fewer spermatozoa and late stage spermatids in the testes, with normal testicular epithelium. The results suggest that the extract of Buchholzia coriacea may have antifertility effects in male rats, the site of action most probably the epididymis. PMID- 23652232 TI - Streptozotocin diabetes and insulin resistance impairment of spermatogenesis in adult rat testis: central vs. local mechanism. AB - Mammalian reproduction is dynamically regulated by the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones are synthesized in the pituitary gland following stimulation by the gonadotropin releasing hormone (GnRH) and act by stimulating steroid production and gametogenesis in both males and females. Male adult Sprague-Dawley rats (120 - 140 g) were randomly divided into 7 groups. Group 1 > Control group; fed on normal rat pellets. Group 2 > Streptozotocin group; received a single dose IP injection of streptozotocin 45 mg/kg BW in Na+ citrate buffer pH 4.5. Group 3 > Streptozotocin-insulin treated group; received a single dose IP injection of streptozotocin as in group 2 above and treated with insulin sub-cutaneously. Group 4 > Streptozotocin-ginger treated group; received a single dose IP injection of streptozotocin as in group 2 above and treated with 500 mg/Kg Ginger extract orally. Group 5 > Insulin resistant group; fed ad libitum on a special diet containing 25% fructose mixed with 75% normal rat chow (w/w). Group 6 > Insulin resistant-pioglitazone treated group; fed ad libitum on a special diet as in group 5 above and treated with Pioglitazone 15 mg/kg orally. Group 7 > Insulin resistant-ginger treated group; fed ad libitum on a special diet as in group 4 above, and also treated with 500 mg/Kg Ginger extract orally. Hormonal and tissue biochemistry analyses revealed that both central and local mechanisms are implicated in the impairment of spermatogenesis by diabetes but the hypothalamo pituitary testicular axis alteration might not likely have a major impact as the local defect on steroidogenesis in the testis. This local defect could also predispose to male hypogonadism, i.e. failure of gonadal function. PMID- 23652233 TI - Bioassay using the water soluble fraction of a Nigerian light crude oil on Clarias gariepinus fingerlings. AB - A 96-hour bioassay was conducted using the water soluble fraction of a Nigerian light crude oil sample on Clarias gariepinus fingerlings. 0, 2.5, 5.0, 7.5 and 10 mls of water soluble fractions (WSF) of the oil were added to 1000 litres of de chlorinated tap water to form 0, 25, 50 , 75 and 100 parts per million representing treatments 1 to 5 respectively. Each treatment had two replicates with fifteen fish per replicate. At the end of the 96-hour period of exposure, the fish were transferred into separate bowls containing fresh water without oil for recovery for ten more days. Heavy metal and total hydrocarbon contents of the water and fish were analyzed at 96 hour and 14 days which marked the end of the recovery period. No mortalities were recorded on all treatments during the 96 hour period. Mortalities were observed between 120 and 144 hours after the onset of the experiment with the maximum number of dead fish (p<0.05) from treatment 5(100 ppm WSF) during the recovery period indicating a delayed response to the WSF by the fish. No mortalities were recorded after 144 hours till the termination of the experiment at 14 days . The 96-hour LC50 could not be calculated since no deaths occurred during the period. The Total hydrocarbon contents of the water were 0, 0.026 ,0.316 ,0.297, 0.253 mg/l for treatments 1(0 ppmWSF)) to 5(100ppm WSF) respectively. Lead , iron and cadmium were not detected in water during the study, lead was also not detected in fish muscles from all treatments. The iron contents of all the treatments were lower than the control except for treatment 3(50 ppm WSF). THC concentrations in fish were higher at 96 hours and 14 days than in the water indicating bioconcentration in fish and a retention in the fish long after exposure. PMID- 23652234 TI - Effects of honey, glutamine and their combination on canine small bowel epithelial cell proliferation following massive resection. AB - The effects of honey, glutamine and honey/glutamine combination on the healing and adaptive process of the bowel following massive small bowel resection were studied in some Nigerian nondescript breeds of dogs. 24 dogs (3-4 months old) of mixed sexes with mean body weight of 4.42+/-0.70 kg were studied. They were randomized into four treatment groups following 70% small bowel resection. Group A dogs were placed on glutamine treatment, Group B on oral glutamine/honey and group C on honey and group D normal saline (control). Their body weights were evaluated for 15 days and the pre- and post-treatment gut biopsy samples were obtained and processed for morphometric evaluation. All groups exhibited signs of small bowel adaptation (Glutamine/honey>glutamine > honey > control) at the end of the experiment (4 weeks). Glutamine/honey combination, glutamine and honey had gradual increase in body weight from days 3-15 of weight evaluation. The control group, however, had a remarkable drop in body weight compared with other groups. Oral glutamine/honey combination showed the best overall effect based on body weight gain, intestinal mucosal growth and adaptation, evidenced by increased in residual bowel Villi height (27.71um), Villi weight (14.51um), Crypt depth (11.25um), and Villi density (3.40um). Glutamine showed a better result than honey with a significant increase in villi height (38.08um), width (8.48um) and crypt depth (40um). Histologically, an improved villi branching was observed with glutamine/honey combination. Our results showed that honey/glutamine combination had comparative therapeutic advantage over glutamine or honey and may be a preferred treatment for short bowel syndrome patients. PMID- 23652235 TI - Attenuation of salt-induced hypertension by aqueous calyx extract of Hibiscus sabdariffa. AB - The aqueous calyx extract of Hibiscus sabdariffa (HS) has a folk reputation as an antihypertensive agent. On account of its antioxidant properties and probably high K+ concentration, we hypothesized that HS may attenuate the development of salt-induced hypertension. Sprague-Dawley rats (n=8 each) were treated for 12 weeks as follows: control (normal diet + water), salt-loaded (8% salt diet + water), HS (normal diet + 6 mg/ml HS), salt+HS (8% salt diet + 6 mg/ml HS) and furosemide (normal diet+ 0.25mg/Kg furosemide). Their blood pressure and heart rates were measured and responses to noradrenalin and acetylcholine (0.01 mg/kg respectively) were estimated. The cationic concentration of 6 mg/ml HS was determined. The Na+ and K+ concentrations of 6 mg/ml HS were 3.6 and 840 mmol/l respectively. The mean arterial pressure (MAP+/-SEM; mmHg) of salt loaded rats (184.6+/-29.8) was significantly higher than control (113.2+/-3.0; P<0.05), HS (90.0+/-7.4; P<0.001) salt+HS (119.4+/-8.9; P<0.05) and furosemide (94.9+/-11.5; P<0.01). The MAP of salt+HS and control rats did not differ significantly and the effect of HS was comparable to furosemide. The pressor response to noradrenalin or vasodilator response to acetylcholine remained similar in all groups. These results suggest that HS attenuated the development of salt-induced hypertension and this attenuation may be associated with its high K+ content or high potassium: sodium ratio and not with altered pressor/depressor response to noradrenalin or acetylcholine. Also the effects of HS and furosemide on blood pressure are comparable. PMID- 23652237 TI - Zinc oxide nanoparticles: chemical mechanisms and classical and non-classical crystallization. AB - Among all the functional materials, ZnO plays an outstanding role in terms of chemical and physical properties, but also in terms of morphological variety and the number of reported synthesis approaches. Complex shapes and hierarchical architectures make ZnO a perfect example to study chemical and crystallization mechanisms. In this review article, we will discuss the nucleation and growth of ZnO nanostructures in liquid media by classical and non-classical (i.e., particle based) crystallization pathways. We elaborate the chemical conditions and parameters that are responsible for the occurrence of one or the other pathway. PMID- 23652238 TI - Evaluation of inhomogeneity correction factors for 6 MV flattening filter-free beams with brass compensators. AB - The 6 MV flattening filter-free (FFF) beam has been commissioned for use with compensators at our institution. This novel combination promises advantages in mitigating tumor motion due to the reduced treatment time made possible by the greatly increased dose rate of the FFF beam. Given the different energy spectrum of the FFF beam and the beam hardening effect of the compensator, the accuracy of the treatment planning system (TPS) model in the presence of low-density heterogeneities cannot be assumed. Therefore, inhomogeneity correction factors (ICF) for an FFF beam attenuated by brass slabs were measured and compared to the TPS calculations in this work. The ICF is the ratio of the point dose in the presence of inhomogeneity to the dose in the same point in a homogeneous medium. The ICFs were measured with an ion chamber at a number of points in a flat water equivalent slab phantom containing a 7.5 cm deep heterogeneity (air or 0.27 g/cm3 wood). Comparisons for the FFF beam were carried out for the field sizes from 5* 5 to 20 * 20 cm2 with the brass slabs ranging from 0 to 5 cm in thickness. For a low-density wood heterogeneity in a slab phantom, with the exception of the point 1cm beyond the proximal buildup interface, the TPS handles the inhomogeneity correction with the brass-filtered 6 MV FFF beam at the requisite 2% error level. The combinations of field sizes and compensator thicknesses when the error exceeds 2% (2.6% maximum) are not likely to be experienced in clinical practice. In terms of heterogeneity corrections, the beam model is adequate for clinical use. PMID- 23652239 TI - Coronary calcium quantification using contrast-enhanced dual-energy computed tomography scans. AB - The purpose of this study is to evaluate a direct measure of calcium burden by using dual-energy computed tomography (DECT) during contrast-enhanced coronary imaging, potentially eliminating the need for an extra noncontrast X-ray acquisition. The ambiguity of separation of calcium from contrast material on contrast-enhanced images was solved by using virtual noncontrast images obtained by DECT. A new threshold CT number was required to detect the calcium carrying potential risk for adverse coronary events on virtual noncontrast images. Two methods were investigated to determine the 130 HU threshold for DECT scoring. An in vitro anthropomorphic phantom with 29 excised patient calcium plaques inserted was used for both a linear and a logistic regression analysis. An IRB approved in vivo prospective study of six patients was also performed to be used for logistic regression analysis. The threshold found by logistic regression model to define the calcium burden on virtual noncontrast images detects the calcium carrying potential risk for adverse coronary events correctly (2.45% error rate). DECT calcium mass and volume scores obtained by using the threshold correlates with both conventional Agatston and volume scores (r = 0.98, p < 0.001). A conventional CT cardiac exam requires two scans, including a noncontrast scan for calcium quantification and a contrast-enhanced scan for coronary angiography. With the ability to quantify calcium on DECT contrast-enhanced images, a DECT cardiac exam could be accomplished with one contrast-enhanced scan for both calcium quantification and coronary angiography. PMID- 23652240 TI - Prostate volumetric-modulated arc therapy: dosimetry and radiobiological model variation between the single-arc and double-arc technique. AB - This study investigates the dosimetry and radiobiological model variation when a second photon arc was added to prostate volumetric-modulated arc therapy (VMAT) using the single-arc technique. Dosimetry and radiobiological model comparison between the single-arc and double-arc prostate VMAT plans were performed on five patients with prostate volumes ranging from 29-68.1 cm3. The prescription dose was 78 Gy/39 fractions and the photon beam energy was 6 MV. Dose-volume histogram, mean and maximum dose of targets (planning and clinical target volume) and normal tissues (rectum, bladder and femoral heads), dose-volume criteria in the treatment plan (D99% of PTV; D30%, D50%, V17Gy and V35Gy of rectum and bladder; D5% of femoral heads), and dose profiles along the vertical and horizontal axis crossing the isocenter were determined using the single-arc and double-arc VMAT technique. For comparison, the monitor unit based on the RapidArc delivery method, prostate tumor control probability (TCP), and rectal normal tissue complication probability (NTCP) based on the Lyman-Burman-Kutcher algorithm were calculated. It was found that though the double-arc technique required almost double the treatment time than the single-arc, the double-arc plan provided a better rectal and bladder dose-volume criteria by shifting the delivered dose in the patient from the anterior-posterior direction to the lateral. As the femoral head was less radiosensitive than the rectum and bladder, the double-arc technique resulted in a prostate VMAT plan with better prostate coverage and rectal dose-volume criteria compared to the single-arc. The prostate TCP of the double-arc plan was found slightly increased (0.16%) compared to the single-arc. Therefore, when the rectal dose-volume criteria are very difficult to achieve in a single-arc prostate VMAT plan, it is worthwhile to consider the double-arc technique. PMID- 23652241 TI - Relationship of segment area and monitor unit efficiency in aperture-based IMRT optimization. AB - In step-and-shoot IMRT plans, aperture-based optimization (or one-step optimization) has been considered as a means of improving monitor unit (MU) efficiency compared to fluence-based optimization (or two-step optimization). However, the extent of improvement on MU efficiency varies, depending on the implementation and design of one-step optimization. In this paper, we attempted to investigate MU efficiency issue in two methods of one-step optimization implemented in two commercial treatment planning systems (TPSs). Five patients with nasopharyngeal cancer and five patients with advanced prostate cancer were selected for this study. For these patients, clinically used IMRT plans were generated using the Direct Machine Parameter Optimization (DMPO) in the Pinnacle TPS. New IMRT plans were created using the Direct Aperture Optimization (DAO) method in the Panther TPS. For the purpose of this study, we used the similar planning dose objectives and beam configurations with a similar total number of segments in each pair of DMPO and DAO plans. With similar plan quality, DMPO plans required more MUs than DAO plans. The average number of MUs (expressed in mean +/- 1 SD) for the DMPO and DAO plans was 1,169 +/- 186 and 671 +/- 135 for the nasopharynx cases, and 711 +/- 48 and 400 +/- 65 for the prostate cases, respectively. The average segment areas (expressed in mean +/- 1 SD) for the DMPO plans were smaller than those for the DAO plans: 46.0 +/- 7.6 cm2 vs. 100.9 +/- 32.3 cm2 for the nasopharynx cases, and 58.3 +/- 17.2 cm2 vs. 97.4 +/- 35.0 cm2 for the prostate cases, respectively. In conclusion, two one-step optimization algorithms, DMPO and DAO, resulted in much different MU efficiency with the similar number of segments and optimization parameters. This MU difference is largely attributed to the fact that large area segments are used more often in DAO plans than in DMPO plans. PMID- 23652242 TI - Abdominal and pancreatic motion correlation using 4D CT, 4D transponders, and a gating belt. AB - The correlation between the pancreatic and external abdominal motion due to respiration was investigated on two patients. These studies utilized four dimensional computer tomography (4D CT), a four dimensional (4D) electromagnetic transponder system, and a gating belt system. One 4D CT study was performed during simulation to quantify the pancreatic motion using computer tomography images at eight breathing phases. The motion under free breathing and breath-hold were analyzed for the 4D electromagnetic transponder system and the gating belt system during treatment. A linear curve was fitted for all data sets and correlation factors were evaluated between the 4D electromagnetic transponder system and the gating belt system data. The 4D CT study demonstrated a modest correlation between the external marker and the pancreatic motion with R-square values larger than 0.8 for the inferior-superior (inf-sup). Then, the relative pressure from the belt gating system correlated well with the 4D electromagnetic transponder system's motion in the anterior-posterior (ant-post) and the inf-post directions. These directions have a correlation value of -0.93 and 0.76, while the lateral only had a 0.03 correlation coefficient. Based on our limited study, external surrogates can be used as predictors of the pancreatic motion in the inf sup and the ant-post directions. Although there is a low correlation on the lateral direction, its motion is significantly shorter. In conclusion, an appropriate treatment delivery can be used for pancreatic cancer when an internal tracking system, such as the 4D electromagnetic transponder system, is unavailable. PMID- 23652243 TI - An investigation of image guidance dose for breast radiotherapy. AB - Cone-beam computed tomography (CBCT) is used for external-beam radiation therapy setup and target localization. As with all medical applications of ionizing radiation, radiation exposure should be managed safely and optimized to achieve the necessary image quality using the lowest possible dose. The present study investigates doses from standard kilovoltage kV radiographic and CBCT imaging protocol, and proposes two novel reduced dose CBCT protocols for the setup of breast cancer patients undergoing external beam radiotherapy. The standard thorax kV and low-dose thorax CBCT protocols available on Varian's On-Board Imaging system was chosen as the reference technique for breast imaging. Two new CBCT protocols were created by modifying the low-dose thorax protocol, one with a reduced gantry rotation range ("Under breast" protocol) and the other with a reduced tube current-time product setting ("Low dose thorax 10ms" protocol). The absorbed doses to lungs, heart, breasts, and skin were measured using XRQA2 radiochromic film in an anthropomorphic female phantom. The absorbed doses to lungs, heart, and breasts were also calculated using the PCXMC Monte Carlo simulation software. The effective dose was calculated using the measured doses to the included organs and the ICRP 103 tissue weighting factors. The deviation between measured and simulated organ doses was between 3% and 24%. Reducing the protocol exposure time to half of its original value resulted in a reduction in the absorbed doses of the organs of 50%, while the reduced rotation range resulted in a dose reduction of at least 60%. Absorbed doses obtained from "Low dose thorax 10ms" protocol were higher than the doses from our departments orthogonal kV-kV imaging protocol. Doses acquired from "Under breast" protocol were comparable to the doses measured from the orthogonal kV-kV imaging protocol. The effective dose per fraction using the CBCT for standard low-dose thorax protocol was 5.00 +/- 0.30 mSv; for the "Low dose thorax 10ms" protocol it was 2.44 +/- 0.21 mSv; and for the "Under breast" protocol it was 1.23 +/- 0.25 mSv when the image isocenter was positioned at the phantom center and 1.17 +/- 0.30 mSv when the image isocenter was positioned in the middle of right breast. The effective dose per fraction using the orthogonal kV-kV protocol was 1.14 +/- 0.16 mSv. The reduction of the scan exposure time or beam rotation range of the CBCT imaging significantly reduced the dose to the organs investigated. The doses from the "Under breast" protocol and orthogonal kV-kV imaging protocol were comparable. Simulated organ doses correlated well with measured doses. Effective doses from imaging techniques should be considered with the increase use of kV imaging protocols in order to support the use of IGRT. PMID- 23652244 TI - Performance evaluation of respiratory motion-synchronized dynamic IMRT delivery. AB - The purpose of this study was to evaluate the capabilities of DMLC to deliver the respiratory motion-synchronized dynamic IMRT (MS-IMRT) treatments under various dose rates. In order to create MS-IMRT plans, the DMLC leaf motions in dynamic IMRT plans of eight lung patients were synchronized with the respiratory motion of breathing period 4 sec and amplitude 2 cm (peak to peak) using an in-house developed leaf position modification program. The MS-IMRT plans were generated for the dose rates of 100 MU/min, 400 MU/min, and 600 MU/min. All the MS-IMRT plans were delivered in a medical linear accelerator, and the fluences were measured using a 2D ion chamber array, placed over a moving platform. The accuracy of MS-IMRT deliveries was evaluated with respect to static deliveries (no compensation for target motion) using gamma test. In addition, the fluences of gated delivery of 30% duty cycle and non- MS-IMRT deliveries were also measured and compared with static deliveries. The MS-IMRT was better in terms of dosimetric accuracy, compared to gated and non-MS-IMRT deliveries. The dosimetric accuracy was observed to be significantly better for 100 MU/min MS-IMRT. However, the use of high-dose rate in a MS-IMRT delivery introduced dose-rate modulation/beam hold-offs that affected the synchronization between the DMLC leaf motion and target motion. This resulted in more dose deviations in MS-IMRT deliveries at the dose rate of 600 MU/min. PMID- 23652245 TI - Monitor unit optimization in RapidArc plans for prostate cancer. AB - Intensity-modulated radiation therapy (IMRT) has become a standard treatment for prostate cancer based on the superior sparing of the bladder, rectum, and other surrounding normal tissues compared to three-dimensional conformal radiotherapy, despite the longer delivery time and the increased number of monitor units (MU). The novel RapidArc technique represents a further step forward because of the lower number of MUs per fraction and the shorter delivery time, compared to IMRT. This paper refers to MU optimization in RA plans for prostate cancer, using a tool incorporated in Varian TPS Eclipse. The goal was to get the lowest MU RA plan for each patient, keeping a well-defined level of PTV coverage and OAR sparing. Seven prostate RA plans (RA MU-Optimized) were retrospectively generated using the MU optimization tool in Varian Eclipse TPS. Dosimetric outcome and nontarget tissue sparing were, compared to those of RA clinical plans (RA Clinical) used to treat patients. Compared to RA Clinical, RA MU-Optimized plans resulted in an about 28% (p = 0.018) reduction in MU. The total integral dose (ID) to each nontarget tissue (but not the penile bulb) showed a consistent average relative reduction, statistically significant only for the femoral heads. Within the intermediate dose region (40-60 Gy), ID reductions (4%-17% p < 0.05) were found for the rectum, while a slight but significant (0.4%-0.9%, p < 0.05) higher ID was found for the whole body. Among the remaining data, the mean dose to the bladder was also reduced (-12%, p = 0.028). Plans using MU optimization are clinically applicable and more MU efficient, ameliorating the exposure of the rectum and the bladder to intermediate doses. PMID- 23652246 TI - Flattening filter-free linac improves treatment delivery efficiency in stereotactic body radiation therapy. AB - Stereotactic body radiation therapy (SBRT) employs precision target tracking and image-guidance techniques to deliver ablative doses of radiation to localized malignancies; however, treatment with conventional photon beams requires lengthy treatment and immobilization times. The use of flattening filter-free (FFF) beams operating at higher dose rates can shorten beam-on time, and we hypothesize that it will shorten overall treatment delivery time. A total of 111 lung and liver SBRT cases treated at our institution from July 2008 to July 2011 were reviewed and 99 cases with complete data were identified. Treatment delivery times for cases treated with a FFF linac versus a conventional dose rate linac were compared. The frequency and type of intrafraction image guidance was also collected and compared between groups. Three hundred and ninety-one individual SBRT fractions from 99 treatment plans were examined; 36 plans were treated with a FFF linac. In the FFF cohort, the mean (+/- standard deviation) treatment time (time elapsed from beam-on until treatment end) and patient's immobilization time (time from first alignment image until treatment end) was 11.44 (+/- 6.3) and 21.08 (+/- 6.8) minutes compared to 32.94 (+/- 14.8) and 47.05 (+/- 17.6) minutes for the conventional cohort (p < 0.01 for all values). Intrafraction-computed tomography (CT) was used more often in the conventional cohort (84% vs. 25%; p < 0.05), but use of orthogonal X-ray imaging remained the same (16% vs. 19%). For lung and liver SBRT, a FFF linac reduces treatment and immobilization time by more than 50% compared to a conventional linac. In addition, treatment with a FFF linac is associated with less physician-ordered image guidance, which contributes to further improvement in treatment delivery efficiency. PMID- 23652247 TI - Effects on the photon beam from an electromagnetic array used for patient localization and tumor tracking. AB - One of the main components in a Calypso 4D localization and tracking system is an electromagnetic array placed above patients that is used for target monitoring during radiation treatment. The beam attenuation and beam spoiling properties of the Calypso electromagnetic array at various beam angles were investigated. Measurements were performed on a Varian Clinac iX linear accelerator with 6 MV and 15 MV photon beams. The narrow beam attenuation properties were measured under a field size of 1 cm * 1 cm, with a photon diode placed in a cylindrical graphite buildup cap. The broad beam attenuation properties were measured under a field size of 10 cm * 10 cm, with a 0.6 cc cylindrical Farmer chamber placed in a polystyrene buildup cap. Beam spoiling properties of the array were studied by measuring depth-dose change from the array under a field size of 10 cm * 10 cm in a water-equivalent plastic phantom with an embedded Markus parallel plate chamber. Change in depth doses were measured with the array placed at distances of 2, 5, and 10 cm from the phantom surface. Narrow beam attenuation and broad beam attenuation from the array were found to be less than 2%-3% for both 6 MV and 15 MV beams at angles less than 40 degrees , and were more pronounced at more oblique angles. Spoiling effects are appreciable at beam buildup region, but are insignificant at depths beyond dmax. Dose measurements in a QA phantom using patient IMRT and VMAT treatment plans were shown to have less than 2.5% dose difference with the Calypso array. The results indicate that the dose difference due to the placement of Calypso array is clinically insignificant. PMID- 23652248 TI - Assessing the role of volumetric-modulated arc therapy in hepatocellular carcinoma. AB - The role of volumetric-modulated arc therapy (VMAT) in hepatocellular carcinoma (HCC) remains controversial. The purpose of this study was to determine the potential clinical role of VMAT compared with three-dimensional conformal radiotherapy (3D CRT) for liver irradiation. Four-dimensional CT scans of 24patients with unresectable HCC were included and divided into two groups: (1) adjacent group (n = 11), with planning target volumes overlapping or within 1 cm adjacent to the alimentary tract; (2) nonadjacent group (n = 13), in which the normal liver itself was the dose-limiting structure. Target coverage, organs-at risk (OARs) doses, delivery parameters, and treatment accuracy were evaluated. Superior target coverage, conformity, and homogeneity were achieved with VMAT compared with 3D CRT. In the adjacent group, VMAT provided superior sparing of serial functioning OARs including the stomach, small intestine, and spinal cord. In the nonadjacent group, VMAT provided inferior sparing of most OARs including the liver, stomach, and small intestine. For the whole group, the effective treatment time was 2.1 +/- 0.3 min for 3D CRT and 3.1 +/- 0.2 min for VMAT. For liver lesions adjacent to the alimentary tract, this study indicates that VMAT should be selected due to the plan quality, delivery efficiency, and superior sparing of stomach and small intestine. However, for liver lesions away from the alimentary tract, VMAT is not superior to 3D CRT for normal tissue protection. PMID- 23652249 TI - A technique to use CT images for in vivo detection and quantification of the spatial distribution of radiation-induced esophagitis. AB - The purpose of the study was to examine whether CT imaging can be used to quantify radiation-induced injury to the esophagus. Weekly CT images for 14 patients receiving proton therapy for thoracic tumors were retrospectively reviewed. The images were registered with the original treatment planning CT image using deformable registration techniques, and the esophageal contours from the treatment plan were automatically mapped to the weekly images. The relative change in the size of the esophagus was calculated for each CT slice as the ratio of the cross-sectional area of the esophagus (minus air) in the weekly CT image to the same area in the planning CT image. The maximum relative change in cross sectional area for each CT image was calculated and examined for correlation with the clinical toxicity score for all the patients. The average maximum relative expansion of the esophagus at the end of treatment was 1.41 +/- 0.26, 1.68 +/- 0.36, and 2.10 +/- 0.18 for patients with grade 0, 2, and 3 esophagitis, respectively. An unpaired t-test, with the level of significance corrected with a Bonferroni correction, showed that the difference between grade 3 and 0 was significant, but the differences between grade 0 and 2, and 2 and 3 were not. The timing of changes in esophageal expansion closely matched that of clinically noted changes in patient symptoms. Expansion of the esophagus on CT images has potential as an objective measure of toxicity. The ability to quantify objectively the spatial distribution of radiation-induced injury will be a useful tool in understanding the impact of partial esophageal sparing on the probability of esophagitis. PMID- 23652250 TI - Utilization of cone beam CT for reconstruction of dose distribution delivered in image-guided radiotherapy of prostate carcinoma - bony landmark setup compared to fiducial markers setup. AB - The purpose of this study was to compare two different styles of prostate IGRT: bony landmark (BL) setup vs. fiducial markers (FM) setup. Twenty-nine prostate patients were treated with daily BL setup and 30 patients with daily FM setup. Delivered dose distribution was reconstructed on cone-beam CT (CBCT) acquired once a week immediately after the alignment. Target dose coverage was evaluated by the proportion of the CTV encompassed by the 95% isodose. Original plans employed 1 cm safety margin. Alternative plans assuming smaller 7 mm margin between CTV and PTV were evaluated in the same way. Rectal and bladder volumes were compared with initial ones. While the margin reduction in case of BL setup makes the prostate coverage significantly worse (p = 0.0003, McNemar's test), in case of FM setup with the reduced 7 mm margin, the prostate coverage is even better compared to BL setup with 10 mm margin (p = 0.049, Fisher's exact test). Moreover, partial volumes of organs at risk irradiated with a specific dose can be significantly lowered (p < 0.0001, unpaired t-test). Reducing of safety margin is not acceptable in case of BL setup, while the margin can be lowered from 10 mm to 7 mm in case of FM setup. PMID- 23652251 TI - Hippocampal-sparing whole-brain radiotherapy using Elekta equipment. AB - The purpose of this study was to evaluate the feasibility of hippocampal-sparing whole-brain radiotherapy (HS WBRT) using the Elekta Infinity linear accelerator and Monaco treatment planning system (TPS). Ten treatment plans were created for HS-WBRT to a dose of 30 Gy (10 fractions). RTOG 0933 recommendations were applied for treatment planning. Intensity-modulated radiotherapy (IMRT) plans for the Elekta Infinity linear accelerator were created using Monaco 3.1 TPS-based on a nine-field arrangement and step-and-shoot delivery method. Plan evaluation was performed using D2% and D98% for the whole-brain PTV (defined as whole brain excluding hippocampus avoidance region), D100% and maximum dose to the hippocampus, and maximum dose to optic nerves and chiasm. Homogeneity index (HI) defined as (D2%-D98%)/Dmedian was used to quantify dose homogeneity in the PTV. The whole-brain PTV D2% mean value was 37.28 Gy (range 36.95-37.49Gy), and D98% mean value was 25.37 Gy (range 25.40-25.89 Gy). The hippocampus D100% mean value was 8.37 Gy (range 7.48-8.97 Gy) and the hippocampus maximum dose mean value was 14.35 Gy (range 13.48-15.40 Gy). The maximum dose to optic nerves and optic chiasm for all patients did not exceed 37.50 Gy. HI mean value was 0.36 (range 0.34-0.37). Mean number of segments was 105 (range 88-122) and mean number of monitor units was 1724 (range 1622-1914). Gamma evaluation showed that all plans passed 3%, 3 mm criteria with more than 99% of the measured points. These results indicate that Elekta equipment (Elekta Infinity linac and Monaco TPS) can be used for HS WBRT planning according to compliance criteria defined by the RTOG 0933 protocol. PMID- 23652252 TI - A comparison of the dosimetric effects of intrafraction motion on step-and-shoot, compensator, and helical tomotherapy-based IMRT. AB - Intrafraction motion during intensity-modulated radiation therapy can cause differences between the planned and delivered patient dose. The magnitude of these differences is dependent on a number of variables, including the treatment modality. This study was designed to compare the relative susceptibility of plans generated with three different treatment modalities to intrafraction motion. The dosimetric effects of motion were calculated using computational algorithms for seven lung tumor patients. Three delivery techniques - MLC-based step-and-shoot (SNS), beam attenuating compensators, and helical tomotherapy (HT) - were investigated. In total 840 motion-encoded dose-volume histograms (DVHs) were calculated for various combinations of CTV margins and sinusoidal CTV motion including CTV offsets. DVH-based metrics (e.g., D95% and D05%) were used to score plan degradations. For all three modalities, dosimetric degradations were typically smaller than 3% if the CTV displacement was smaller than the CTV margin. For larger displacements, technique and direction-specific sensitivities existed. While the HT plans show similar D95% degradations for motion in the SI and AP directions, SNS and compensator plans showed larger D95% degradations for motion in the SI direction than for motion in the AP direction. When averaged over all motion/margin combinations, compensator plans resulted in 0.9% and 0.6% smaller D95% reductions compared to SNS and HT plans, respectively. These differences were statistically significant. No statistically significant differences in D95% degradations were found between SNS and HT for data averaged over all margin and motion track combinations. For CTV motion that is larger than the CTV margin, the dosimetric impact on the CTV varies with treatment technique and the motion direction. For the cases presented here, the effect of motion on CTV dosimetry was statistically smaller for compensator deliveries than SNS and HT, likely due to the absence of the interplay effect which is present for the more dynamic treatment deliveries. The differences between modalities were, however, small and might not be clinically significant. As expected, margins that envelop the CTV motion provide dosimetric protection against motion for all three modalities. PMID- 23652253 TI - Fast Monte Carlo simulation for total body irradiation using a (60)Co teletherapy unit. AB - Our institution delivers TBI using a modified Theratron 780 60Co unit. Due to limitations of our treatment planning system in calculating dose for this treatment, we have developed a fast Monte Carlo code to calculate dose distributions within the patient. The algorithm is written in C and uses voxel density information from CT images to calculate dose in heterogeneous media. To test the algorithm, film-based dose measurements were made separately in a simple water phantom with a high-density insert and a RANDO phantom and then compared to doses calculated by the Monte Carlo algorithm. In addition, a separate simulation in GEANT4 was run for the RANDO phantom and compared to both film and the in house simulation. All results were analyzed using RIT113 film analysis software. Simulations in the water phantom accurately predict the depth of maximum dose in the phantom at 0.5 cm. The measured PDD along the central axis of the beam closely matches the PDD generated from the Monte Carlo code, deviating on average by only 3% along the depth of the water phantom. Dose measured at planes inside the high-density insert had a mean difference of 4.9% on cross-profile measurement. In the RANDO phantom, gamma pass rates vary between 91% and 99% at 3 mm, 3%, and were >99% at 5 mm, 5% for the four film planes measured. Profiles taken across the film and both simulations resulted in mean relative differences of < 2% for all profiles in each slice measured. The Monte Carlo algorithm presented here is potentially a viable method for calculating dose distributions delivered in TBI treatments at our center. While not yet refined enough to be the primary method of treatment planning, the algorithm at its current resolution determines the dose distribution for one patient within a few hours, and provides clinically useful information in planning TBI. With appropriate optimization, the Monte Carlo method presented here could potentially be implemented as a first line treatment planning option for 60Co TBI. PMID- 23652254 TI - An analytical model to determine interseed attenuation effect in low-dose-rate brachytherapy. AB - Brachytherapy treatment planning systems (BTPS) are employing the American Association of Physicists in Medicine (AAPM) Task Group 43 (TG-43)-recommended dosimetric parameters of sources, which are measured in water. The majority of brachytherapy implant volumes are not homogeneous media. Particularly, an implant with multiple seeds significantly changes homogeneity of the implant volume. Heterogeneities, such as attenuation by adjacent seeds or interseed attenuation (ISA), are neglected to this day in all BTPS. The goal of this project is to determine a novel analytical method to evaluate the impact of the dose perturbations (P-value) and/or interseed attenuation effect (ISA-value). This method will be validated for low- and high-energy brachytherapy seeds such as 125I and 192Ir using Monte Carlo (MC) simulation techniques. In this analytical model, determination of dose perturbation and interseed attenuation in a multisource brachytherapy implant is based on MC-simulated 3D kernels of P-values and ISA data for single active and single dummy configurations, arranged at different distances and orientations relative to each other. The accuracy of the final model in multisource implant configurations has been examined by a comparison of the calculated P-values and ISA-values with full Monte Carlo water simulations (FMCWS). This model enabled us to determine the total perturbation and ISA values for any multisource implant, and the results are in excellent agreement with the FMCWS data. The advantage of this model to FMCWS for daily clinical application is the speed of the calculations and ease of the implementation. The new perturbation and ISA formulism have shown a better accuracy for 192Ir than 125I due to Compton scattering and its independence of the atomic number of the chemical composition of the phantom materials. The maximum difference between the ISA model and FMCWS for all cases was less than 5%. This new model can provide inputs for brachytherapy planning software to consider the ISA effect in dose calculations based on TG-43U1 algorithm. This approach is applicable for energy range of 125I to192Ir sources. PMID- 23652255 TI - Perturbation of TG-43 parameters of the brachytherapy sources under insufficient scattering materials. AB - In the recommendations of Task Group #43 from American Association of Physicists in Medicine (AAPM TG43), methods of brachytherapy source dosimetry are recommended, under full scattering conditions. However, in actual brachytherapy procedures, sources may not be surrounded by full scattering tissue in all directions. Clinical examples include high-dose-rate (HDR) brachytherapy of the breast or low-dose-rate (LDR) brachytherapy of ocular melanoma using eye plaque treatment with 125I and 103Pd. In this work, the impact of the missing tissue on the TG-43-recommended dosimetric parameters of different brachytherapy sources was investigated. The impact of missing tissue on the TG-43-recommended dosimetric parameters of 137Cs, 192Ir, and 103Pd brachytherapy sources was investigated using the MCNP5 Monte Carlo code. These evaluations were performed by placing the sources at different locations inside a 30 * 30 * 30 cm3 cubical water phantom and comparing the results with the values of the source located at the center of the phantom, which is in a full scattering condition. The differences between the thickness of the overlying tissues for different source positions and the thickness of the overlying tissue in full scattering condition is referred to as missing tissue. The results of these investigations indicate that values of the radial dose function and 2D anisotropy function vary as a function of the thickness of missing tissue, only in the direction of the missing tissue. These changes for radial dose function were up to 5%, 11%, and 8% for 137Cs, 192Ir, and 103Pd, respectively. No significant changes are observed for the values of the dose rate constants. In this project, we have demonstrated that the TG-43 dosimetric parameters may only change in the directions of the missing tissue. These results are more practical than the published data by different investigators in which a symmetric effect of the missing tissue on the dosimetric parameters of brachytherapy source are being considered, regardless of the implant geometry in real clinical cases. PMID- 23652256 TI - Effective dose to patients and staff when using a mobile PET/SPECT system. AB - The purpose of this study was to determine the number of weekly acquisitions permissible using a mobile PET/SPECT scanner for myocardial perfusion/viability imaging in an intensive care unit (ICU) based on the effective dose to patients and staff. The effective dose to other patients and staff in an ICU was calculated following recommendations from the American Association of Physicists in Medicine Task Group 108 report (AAPM TG-108). The number of weekly acquisitions using 555 MBq (15 mCi) Tc-99m for myocardial perfusion or F-18 for myocardial viability was determined using the regulatory limits described in the Code of Federal Regulations 10 CFR 20. To increase the number of weekly acquisitions allowed, a reduction in administered dose and portable shielding was considered. A single myocardial perfusion image can be acquired with Tc-99m each week with a dose reduction to 455 MBq (12.3 mCi) without additional shielding. To acquire a myocardial viability image with F-18, an activity reduction to 220 MBq (5.9 mCi) is required to meet the regulatory effective dose limit without additional shielding. More than one weekly acquisition can be performed if additional shielding or activity reduction is utilized. A method for calculating dose to patients and staff in an ICU has been developed using conservative assumptions and following AAPM TG-108. This calculation must be repeated for each individual clinic before any acquisition is performed. PMID- 23652257 TI - Prostate rotation detected from implanted markers can affect dose coverage and cannot be simply dismissed. AB - With implanted markers, daily prostate displacements can be automatically detected with six degrees of freedom. The reported magnitudes of the rotations, however, are often greater than the typical range of a six-degree treatment couch. The purpose of this study is to quantify geometric and dosimetric effects if the prostate rotations are not corrected (ROT_NC) and if they can be compensated with translational shifts (ROT_C). Forty-three kilovoltage cone-beam CTs (KV-CBCT) with implanted markers from five patients were available for this retrospective study. On each KV-CBCT, the prostate, bladder, and rectum were manually contoured by a physician. The prostate contours from the planning CT and CBCT were aligned manually to achieve the best overlaps. This contour registration served as the benchmark method for comparison with two marker registration methods: (a) using six degrees of freedom, but rotations were not corrected (ROT_NC); and (b) using three degrees of freedom while compensating rotations into the translational shifts (ROT_C). The center of mass distance (CMD) and overlap index (OI) were used to evaluate these two methods. The dosimetric effects were also analyzed by comparing the dose coverage of the prostate clinical target volume (CTV) in relation to the planning margins. According to our analysis, the detected rotations dominated in the left-right axis with systematic and random components of 4.6 degrees and 4.1 degrees , respectively. When the rotation angles were greater than 10 degrees , the differences in CMD between the two registrations were greater than 5 mm in 85.7% of these fractions; when the rotation angles were greater than 6 degrees , the differences of CMD were greater than 4 mm in 61.1% of these fractions. With 6 mm/4 mm posterior planning margins, the average difference between the dose to 99% (D99) of the prostate in CBCTs and the planning D99 of the prostate was -8.0 +/- 12.3% for the ROT_NC registration, and -3.6 +/- 9.0% for the ROT_C registration (p = 0.01). When the planning margin decreased to 4 mm/2 mm posterior, the average difference in D99 of the prostate was -22.0 +/- 16.2% and 15.1 +/- 15.2% for the ROT_NC and ROT_C methods, respectively (p < 0.05). In conclusion, prostate rotation cannot be simply dismissed, and the impact of the rotational errors depends on the distance between the isocenter and the centroid of implanted markers and the rotation angle. PMID- 23652258 TI - Volumetric-modulated arc therapy for the treatment of a large planning target volume in thoracic esophageal cancer. AB - Recently, volumetric-modulated arc therapy (VMAT) has demonstrated the ability to deliver radiation dose precisely and accurately with a shorter delivery time compared to conventional intensity-modulated fixed-field treatment (IMRT). We applied the hypothesis of VMAT technique for the treatment of thoracic esophageal carcinoma to determine superior or equivalent conformal dose coverage for a large thoracic esophageal planning target volume (PTV) with superior or equivalent sparing of organs-at-risk (OARs) doses, and reduce delivery time and monitor units (MUs), in comparison with conventional fixed-field IMRT plans. We also analyzed and compared some other important metrics of treatment planning and treatment delivery for both IMRT and VMAT techniques. These metrics include: 1) the integral dose and the volume receiving intermediate dose levels between IMRT and VMATI plans; 2) the use of 4D CT to determine the internal motion margin; and 3) evaluating the dosimetry of every plan through patient-specific QA. These factors may impact the overall treatment plan quality and outcomes from the individual planning technique used. In this study, we also examined the significance of using two arcs vs. a single-arc VMAT technique for PTV coverage, OARs doses, monitor units and delivery time. Thirteen patients, stage T2-T3 N0-N1 (TNM AJCC 7th edn.), PTV volume median 395 cc (range 281-601 cc), median age 69 years (range 53 to 85), were treated from July 2010 to June 2011 with a four field (n = 4) or five-field (n = 9) step-and-shoot IMRT technique using a 6 MV beam to a prescribed dose of 50 Gy in 20 to 25 F. These patients were retrospectively replanned using single arc (VMATI, 91 control points) and two arcs (VMATII, 182 control points). All treatment plans of the 13 study cases were evaluated using various dose-volume metrics. These included PTV D99, PTV D95, PTV V9547.5Gy(95%), PTV mean dose, Dmax, PTV dose conformity (Van't Riet conformation number (CN)), mean lung dose, lung V20 and V5, liver V30, and Dmax to the spinal canal prv3mm. Also examined were the total plan monitor units (MUs) and the beam delivery time. Equivalent target coverage was observed with both VMAT single and two-arc plans. The comparison of VMATI with fixed-field IMRT demonstrated equivalent target coverage; statistically no significant difference were found in PTV D99 (p = 0.47), PTV mean (p = 0.12), PTV D95 and PTV V9547.5Gy (95%) (p = 0.38). However, Dmax in VMATI plans was significantly lower compared to IMRT (p = 0.02). The Van't Riet dose conformation number (CN) was also statistically in favor of VMATI plans (p = 0.04). VMATI achieved lower lung V20 (p = 0.05), whereas lung V5 (p = 0.35) and mean lung dose (p = 0.62) were not significantly different. The other OARs, including spinal canal, liver, heart, and kidneys showed no statistically significant differences between the two techniques. Treatment time delivery for VMATI plans was reduced by up to 55% (p = 5.8E-10) and MUs reduced by up to 16% (p = 0.001). Integral dose was not statistically different between the two planning techniques (p = 0.99). There were no statistically significant differences found in dose distribution of the two VMAT techniques (VMATI vs. VMATII) Dose statistics for both VMAT techniques were: PTV D99 (p = 0.76), PTV D95 (p = 0.95), mean PTV dose (p = 0.78), conformation number (CN) (p = 0.26), and MUs (p = 0.1). However, the treatment delivery time for VMATII increased significantly by two-fold (p = 3.0E-11) compared to VMATI. VMAT based treatment planning is safe and deliverable for patients with thoracic esophageal cancer with similar planning goals, when compared to standard IMRT. The key benefit for VMATI was the reduction in treatment delivery time and MUs, and improvement in dose conformality. In our study, we found no significant difference in VMATII over single-arc VMATI for PTV coverage or OARs doses. However, we observed significant increase in delivery time for VMATII compared to VMATI. PMID- 23652261 TI - The emerging vision of the JACMP - part 2. PMID- 23652262 TI - The efficiency and stability of bubble formation by acoustic vaporization of submicron perfluorocarbon droplets. AB - Submicron droplets of liquid perfluorocarbon converted into microbubbles with applied ultrasound have been studied, for a number of years, as potential next generation extravascular ultrasound contrast agents. In this work, we conduct an initial ultra-high-speed optical imaging study to examine the vaporization of submicron droplets and observe the newly created microbubbles in the first microseconds after vaporization. It was estimated that single pulses of ultrasound at 10 MHz with pressures within the diagnostic range are able to vaporize on the order of at least 10% of the exposed droplets. However, only part of the newly created microbubbles survives immediately following vaporization - the bubbles may recondense back into the liquid droplet state within microseconds of nucleation. The probability of bubble survival within the first microseconds of vaporization was shown to depend on ultrasound excitation pressure as well as on bubble coalescence during vaporization, a behavior influenced by the presence of coating material on the newly created bubbles. The results of this study show for the first time that although initial vaporization of droplets is necessary to create echogenic bubbles, additional factors, such as coalescence and bubble shell properties, are important and should be carefully considered for the production of microbubbles for use in medical imaging. PMID- 23652263 TI - Minimum 10-year follow-up of patients after an acute, isolated posterior cruciate ligament injury treated nonoperatively. AB - BACKGROUND: Few studies report long-term subjective or objective results for acute, isolated posterior cruciate ligament (PCL) injuries in patients followed prospectively. HYPOTHESIS: Subjective or objective results will not differ based on PCL laxity. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Sixty eight patients with an acute, isolated PCL injury were treated nonoperatively and followed prospectively with yearly subjective surveys and periodic objective evaluations. Physical examination included evaluation of range of motion, effusion, and quadriceps strength; radiographic grading of osteoarthritis; and measurements of joint space width. Subjective follow-up included the International Knee Documentation Committee (IKDC) and modified Cincinnati Knee Rating System (CKRS) surveys. RESULTS: A total of 44 patients were available for both objective and subjective evaluations at a mean of 14.3 years (range, 10-21 years) after injury. All 68 patients underwent subjective follow-up at a mean of 17.6 years after injury. The mean quadriceps muscle strength was 97% of the noninvolved leg; all patients maintained normal knee range of motion. The overall grade of radiographs was rated as normal in 26 patients (59%), nearly normal in 13 patients (30%), abnormal in 4 patients (9%), and severely abnormal in 1 patient (2%). The grade of osteoarthritis on radiographs was not different in any knee compartment based on PCL laxity grade. Five patients (11%) had medial joint space narrowing greater than 2 mm. Mean IKDC and modified CKRS subjective scores at a mean of 17 years after injury were 73.4 +/- 21.7 and 81.3 +/- 17.4, respectively; there was no difference in subjective scores between PCL laxity grades. There was no difference in subjective scores between patients who completed a minimum 10-year objective follow-up and patients who completed surveys only. CONCLUSION: Long-term results after an isolated PCL injury show that patients remain active, have good strength and full knee range of motion, and report good subjective scores. The prevalence of moderate to severe osteoarthritis was 11%. Results were not different based on PCL laxity grade. This natural history study of nonoperatively treated PCL injuries can serve as a baseline for comparison with patients treated with PCL reconstruction. PMID- 23652264 TI - A young man with anemia and recurrent tachyarrhythmic episodes. PMID- 23652265 TI - An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. AB - Despite the global impact and advances in understanding the pathophysiology of cerebrovascular diseases, the term "stroke" is not consistently defined in clinical practice, in clinical research, or in assessments of the public health. The classic definition is mainly clinical and does not account for advances in science and technology. The Stroke Council of the American Heart Association/American Stroke Association convened a writing group to develop an expert consensus document for an updated definition of stroke for the 21st century. Central nervous system infarction is defined as brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging, and/or clinical evidence of permanent injury. Central nervous system infarction occurs over a clinical spectrum: Ischemic stroke specifically refers to central nervous system infarction accompanied by overt symptoms, while silent infarction by definition causes no known symptoms. Stroke also broadly includes intracerebral hemorrhage and subarachnoid hemorrhage. The updated definition of stroke incorporates clinical and tissue criteria and can be incorporated into practice, research, and assessments of the public health. PMID- 23652266 TI - Decreased corticospinal tract fractional anisotropy predicts long-term motor outcome after stroke. AB - BACKGROUND AND PURPOSE: Nearly 50% of patients have residual motor deficits after stroke, and long-term motor outcome is difficult to predict. We assessed the predictive value of axonal damage to the corticospinal tract indexed by diffusion tensor imaging fractional anisotropy for long-term motor outcome. METHODS: Consecutive patients with middle cerebral artery stroke underwent multimodal MRI, including diffusion tensor imaging <=12 hours, 3 days, and 30 days after onset. Clinical severity, infarct volume, location of corticospinal tract damage on diffusion tensor tractography, and ratios of fractional anisotropy (rFA) between affected and unaffected sides of the corticospinal tract at the pons were evaluated. Severity of motor deficit at 2 years was categorized using the Motricity Index as no deficit (Motricity Index, 100), slight-moderate deficit (Motricity Index, 99-50), or severe deficit (Motricity Index, <50). RESULTS: We evaluated 70 patients (28 women; 72+/-12 years). rFA values at day 30 correlated with the degree of motor deficit at 2 years (P<0.001). rFA at day 30 was the only independent predictor of long-term motor outcome (odds ratio, 1.60; 95% confidence interval, 1.26-2.03; P<0.001). The sensitivity, specificity, and positive and negative predictive values of the cutoffs rFA<0.982 for predicting slight-moderate deficit and rFA<0.689 for severe deficit were 94.4%, 84.6%, 73.9%, and 97.1%, respectively, and 100%, 83.3%, 81.3%, and 100%, respectively. CONCLUSIONS: rFA at day 30 is an independent predictor of long-term motor outcome after stroke. PMID- 23652267 TI - External validation of the iScore for predicting ischemic stroke mortality in patients in China. AB - BACKGROUND AND PURPOSE: The iScore is a prediction tool developed to estimate the risk of death in patients after hospitalization for an acute ischemic stroke. Our aim was to determine the accuracy of the iScore in patients with ischemic stroke in China. METHODS: The iScore was used to predict 30-day mortality rate in 11 656 patients and 1-year mortality rate in 11 051 patients with acute ischemic stroke. These patients were identified from the China National Stroke Registry (CNSR) data set. Model discrimination was quantified by calculating the C statistic. The calibration was assessed using Pearson correlation coefficient. RESULTS: The 30 day and 1-year mortality rates were 5.4% and 14.3%, respectively. The C statistics were 0.825 (95% confidence interval, 0.807-0.843) for 30-day mortality and 0.822 (95% confidence interval, 0.810-0.833) for 1-year mortality. The plots of observed versus predicted mortality rates showed excellent model calibration in the external validation samples from the CNSR (Pearson correlation coefficient, 0.925 for 30-day and 0.998 for 1-year mortality; both P<0.0001). CONCLUSIONS: The iScore reliably predicts 30-day and 1-year mortality in Chinese patients with ischemic stroke. PMID- 23652268 TI - Impact of completeness of ascertainment of minor stroke on stroke incidence: implications for ideal study methods. AB - BACKGROUND AND PURPOSE: Reliable comparisons of stroke incidence are important. To determine the impact of systematic assessment of patients referred with transient ischemic attack on the measured incidence and severity of stroke, we compared 2 population-based studies. METHODS: Patients with first-ever stroke ascertained during 2006 through 2010 from the Dijon Stroke Registry and the Oxford Vascular (OXVASC) Study were studied. Both studies comply with the criteria for ideal incidence studies, but the OXVASC Study also systematically assessed all patients referred with transient ischemic attack. Stroke severity was measured by the National Institutes of Health Stroke Scale. RESULTS: Among 902 incident strokes in Dijon and 748 cases in the OXVASC Study, age and gender distribution were comparable, but severity was lower in the OXVASC Study (median National Institutes of Health Stroke Scale, 2 versus 6; P<0.001). Although overall incidence of ischemic stroke was higher in the OXVASC Study (157 versus 98 of 100 000/y; incidence rate ratio, 1.59; 95% confidence interval, 1.24-2.05; P<0.001), this was accounted for by a 3-fold excess incidence of stroke with National Institutes of Health Stroke Scale <=2 in the OXVASC Study (90 versus 29/100 000/y; P<0.001), with no difference in incidence of more severe ischemic stroke (incidence rate ratio, 0.95; 95% confidence interval, 0.68-1.33). Of all 660 incident ischemic strokes in the OXVASC Study, 375 (56.8%) cases had an National Institutes of Health Stroke Scale <=2, of which 232 had been ascertained in the transient ischemic attack clinic. Of these 232 minor strokes, only 71 cases had a diagnosis of definite stroke documented in the medical records by the referring physician. CONCLUSIONS: Reliance on routine clinical coding underestimates the incidence of minor stroke. To improve comparability of incidence studies, researchers should assess patients referred with transient ischemic attack, and all studies should stratify incidence rates by stroke severity. PMID- 23652269 TI - Dalfampridine improves sensorimotor function in rats with chronic deficits after middle cerebral artery occlusion. AB - BACKGROUND AND PURPOSE: Stroke survivors often have permanent deficits that are only partially addressed by physical therapy. This study evaluated the effects of dalfampridine, a potassium channel blocker, on persistent sensorimotor deficits in rats with treatment initiated 4 or 8 weeks after stroke. METHODS: Rats underwent permanent middle cerebral artery occlusion. Sensorimotor function was measured using limb-placing and body-swing symmetry tests, which normally show a partial recovery from initial deficits that plateaus ~4 weeks after permanent middle cerebral artery occlusion. Dalfampridine was administered starting at 4 or 8 weeks after permanent middle cerebral artery occlusion in 2 blinded, vehicle controlled studies. Plasma samples were collected and brain tissue was processed for histologic assessment. RESULTS: Dalfampridine treatment (0.5-2.0 mg/kg) improved forelimb- and hindlimb-placing responses and body-swing symmetry in a reversible and dose-dependent manner. Plasma dalfampridine concentrations correlated with dose. Brain infarct volumes showed no differences between treatment groups. CONCLUSIONS: Dalfampridine improves sensorimotor function in the rat permanent middle cerebral artery occlusion model. Dalfampridine extended release tablets (prolonged release fampridine outside the United States) are used to improve walking in patients with multiple sclerosis, and these preclinical data provide a strong rationale for examining the potential of dalfampridine to treat chronic stable deficits in stroke patients. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01605825. PMID- 23652270 TI - Impact of acute cocaine use on aneurysmal subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: Acute cocaine use has been temporally associated with aneurysmal subarachnoid hemorrhage (aSAH). This study analyzes the impact of cocaine use on patient presentation, complications, and outcomes. METHODS: Data of patients admitted with aSAH between 1991 and 2009 were reviewed to determine impact of acute cocaine use (C). These patients were compared with aSAH patients without recent cocaine exposure (NC) in relation to their presentation, complications such as aneurysmal rerupture and delayed cerebral ischemia, and outcomes including hospital mortality and functional outcome. RESULTS: Data of 1134 aSAH patients were reviewed; 142 patients (12.5%) had associated cocaine use. Cocaine users were more likely to be younger (mean age: C, 49+/-11; NC, 53+/ 14; P<0.001). There were no differences in rates of poor-grade Hunt and Hess (4 5); (C, 21%; NC, 26%; P>0.05), associated intraventricular hemorrhage (C, 56%; NC, 51%; P>0.05), or hydrocephalus on admission Head CT (C, 49%; NC, 52%; P>0.05). Aneurysm rerupture incidence was higher among cocaine users (C, 7.7%; NC, 2.7%; P<0.05). The association of cocaine use with higher risk of delayed cerebral ischemia (C, 22%; NC, 16%; P<0.05) was not significant after correcting for other factors. Cocaine users were less likely to survive hospitalization compared with nonusers (mortality: C, 26%; NC, 17%; P<0.05); the adjusted odds of hospital mortality were 2.9 times higher among cocaine users (P<0.001). There were no differences in functional outcomes between the 2 groups. CONCLUSIONS: Acute cocaine use was associated with a higher risk of aneurysm rerupture and hospital mortality after aSAH. PMID- 23652272 TI - Long-term cognitive impairment after first-ever ischemic stroke in young adults. AB - BACKGROUND AND PURPOSE: Up to 14% of all ischemic strokes occur in young adults (<50 years). Poststroke cognitive performance is a decisive determinant of their quality of life. However, virtually no studies report on cognition after young stroke, especially not on the long term. This long-term perspective is important because young patients have a long life expectancy during which they start forming a family, have an active social life, and make decisive career moves. We aimed to evaluate the long-term cognitive outcome. METHODS: All consecutive patients between January 1, 1980, and November 1, 2010, with a first-ever young ischemic stroke were recruited for cognitive assessment, using a matched stroke free population as a reference. Composite Z scores for 7 cognitive domains were calculated and the ANCOVA model was used (Bonferroni correction). A below average performance was defined as >1.0 SD below the age-adjusted mean of the controls and cognitive impairment as >1.5 SD. RESULTS: Two hundred seventy-seven patients and 146 matched controls completed cognitive assessment (mean follow-up, 11.0 years, SD, 8.2; age, 50.9 years, SD, 10.3). Long-term cognitive outcome after an ischemic stroke was worse in most cognitive domains compared with a nonstroke population. Up to 50% of the patients had a below average performance or cognitive impairment. Deficits in processing speed, working memory, and attention were most common. CONCLUSIONS: Even 11 years after ischemic stroke in young adults, a substantial proportion of patients must cope with permanent cognitive deficits. These results have implications for information given to patients and rehabilitation services. PMID- 23652271 TI - Moyamoya disease in a primarily white, midwestern US population: increased prevalence of autoimmune disease. AB - BACKGROUND AND PURPOSE: Moyamoya disease is an uncommon, cerebrovascular occlusive disease of unknown pathogenesis. Previously described Moyamoya cohorts include predominantly Asian populations or ethnically diverse North American cohorts. To gain further insight into the pathogenesis of moyamoya, we examined clinical characteristics of a primarily white, Midwestern US population METHODS: Retrospective analysis of patients with angiographically confirmed moyamoya disease evaluated at our institution was performed. Prevalence of comorbidities, cerebrovascular risk factors, and autoimmune diseases were compared with the general population. RESULTS: Ninety-four patients with moyamoya were evaluated; 72.3% were female. Ethnic composition was primarily white (85%). A significantly higher prevalence of autoimmune disease was seen, particularly type 1 diabetes mellitus (8.5% versus 0.4% in the general population) and thyroid disease (17.0% versus 8.0% in the institutional general patient population). Hyperlipidemia was also increased (27.7% versus 16.3% in the general population). CONCLUSIONS: This study of a unique, primarily white, Midwestern population of moyamoya patients demonstrates a significantly higher prevalence of autoimmune disease than in the general population. This supports a possible autoimmune component to the pathogenesis of moyamoya disease. PMID- 23652273 TI - Clinical significance of fluid-attenuated inversion recovery vascular hyperintensities in transient ischemic attack. AB - BACKGROUND AND PURPOSE: Fluid-attenuated inversion recovery vascular hyperintensity (FVH) is often identified in patients with acute ischemic stroke. The purpose of this study was to determine the clinical significance of FVH in patients with transient ischemic attack (TIA). METHODS: Consecutive inpatients with TIA who underwent MRI within 24 hours of symptom onset were studied. The frequency, relative factors, and time course of FVH were determined. RESULTS: Of the 202 patients who were enrolled (76 women, mean age, 69.0 +/- 13.2 years), FVH was identified in 41 patients (20%). Multivariate analysis showed that atrial fibrillation (odds ratio, 7.14; 95% confidence interval [CI], 2.69-18.1), arterial occlusive lesion (odds ratio, 4.89; 95% CI, 3.03-12.2), and hemiparesis (odds ratio, 2.81; 95% CI, 1.17-7.48) was independently associated with FVH. Of 23 recurrence-free patients with FVH positive undergoing follow-up MRI at a median of 7 days after the onset, FVH was no longer positive in 15 patients (65%). Atrial fibrillation was more common (P=0.027) and arterial occlusive lesion was less common (P<0.001) in patients with transient FVH compared with those with persistent FVH. Within 90 days after the onset, 13 patients developed recurrent TIA or ischemic stroke. After Cox proportional hazard analysis, FVH (hazard ratio, 3.65; 95% CI, 1.09-12.7), arterial occlusive lesion (hazard ratio, 4.15; 95% CI, 1.18-17.1), and coexistence of FVH and arterial occlusive lesion (hazard ratio, 13.9; 95% CI, 3.36-71.0) were significantly associated with recurrent TIA or ischemic stroke. CONCLUSIONS: The presence of FVH early after symptom onset may help to diagnosis TIA, to identify the potential mechanisms of TIA and to predict recurrence risk after a TIA. PMID- 23652274 TI - Effects of intermittent hypoxia on cognitive performance and quality of life in elderly adults: a pilot study. AB - BACKGROUND: Physical exercise has a positive effect on cognitive performance and quality of life (QoL). One reason for this is the upregulation of brain-derived neurotrophic factor, which improves brain plasticity. Intermittent hypoxia promotes first the proliferation of endogenous neuroprogenitors which leads to an increased number of newborn neurons and second the expression of brain-derived neurotrophic factor in the adult hippocampus. Intermittent hypoxia may, therefore, support synaptic plasticity, the process of learning and provoke antidepressant-like effects. Hence, intermittent hypoxia might also lead to improved cognitive functioning and QoL. OBJECTIVE: This study aims to evaluate to what extent physical activity with preceded intermittent hypoxic training is more effective than solely strength-endurance training on cognitive performance and QoL. METHODS: 34 retired people aged between 60 and 70 years were randomly assigned to a control group or intervention group. Contrarily to the control group, which was supplied with a placebo air mixture, the intervention group was supplied with an intermittent hypoxic training prior to a strength-endurance exercise program. The cognitive performance of individuals was examined using the d2 test and the Number Combination Test (ZVT) both before and after the exercise program. We assessed QoL with the Medical Outcomes Study Short-Form 36-Item Health Survey (SF-12) and Pittsburgh Sleep Quality Index (PSQI) and the strength endurance capacity using the Spring test. RESULTS: Regarding the d2 test, a time * group effect was observed. Speed of cognitive performance in seconds was measured using ZVT. Here, no interaction effect was discovered. An interaction effect was not found in the Physical Component Summary scores (SF-12). Regarding the Mental Component Summary, an interaction effect just failed to become statistically significant. Furthermore, we determined sleep quality with the PSQI. Here, an interaction effect was observed. The analysis of the strength endurance test revealed no interaction effects. CONCLUSION: The data of the current study suggest that an additional intermittent hypoxic training combined with physical exercise augments the positive effects of exercise on cognitive performance and QoL in elderly humans. PMID- 23652275 TI - Gold-nanopatterned single interleukin-6 sandwich immunoassay chips with zeptomolar detection capability based on evanescent field-enhanced fluorescence imaging. AB - We developed a gold-nanopatterned immunoassay chip for single-molecule detection of interleukin-6 based on evanescent field-enhanced fluorescence imaging. The detection limit (496 zM) means that only four molecules need to be present per spot for detection. The sensitivity of this chip is ~5.4 * 10(4)-fold greater than that of a commercial ELISA for IL-6. PMID- 23652276 TI - Generation of antitumor peptides by connection of matrix metalloproteinase-9 peptide inhibitor to an endostatin fragment. AB - Previous applications of matrix metalloproteinase (MMP) inhibitors in cancer treatment have resulted in disappointing outcomes. Therefore, it is necessary to develop more active or better targeted MMP inhibitors. In this study, Inhibitor2, a heptapeptide MMP inhibitor, was connected to the N-terminus or C-terminus of ES 2, an 11-amino-acid antiangiogenic peptide, and two designed peptides, P2 and P4, were generated. P2 inhibited MMP-2, MMP-8, MMP-9, and tumor necrosis factor-alpha converting enzyme (TACE) activity with IC50 values of 1.40, 0.35, 1.36, and 1.95 MUmol/l, whereas those for P4 were 19, 20, 18, and 18 MUmol/l. P2 showed a higher affinity with integrin alpha5beta1 in a human umbilical vein endothelial cell (HUVEC) adhesion assay than P4. In the HUVEC migration assay, P2 showed a better inhibitory effect on HUVEC migration than P4 and Inhibitor2 and the inhibitory ratio at 2 MUg/ml was 77%. In a chorioallantoic membrane assay, at a concentration of 3.28 MUg/ml, P2 and P4 showed 69.8 and 56.8% inhibition of formation of new blood vessels on the embryo membrane. Furthermore, P2 significantly inhibited B16F10 growth in a syngeneic mouse model with an inhibition ratio of 57.92% by tumor weight at a dose of 20 mg/kg/day, whereas P4 and Inhibitor2 exerted no such in-vivo effect. The antiangiogenic effect of P2 was confirmed by CD31 staining of the tumor tissue sections. The Inhibitor2 part of P2 may function both as an MMP inhibitor and as a targeting motif. These studies represented an example of how to better apply the potent and peptidomimetic MMP inhibitors in cancer treatment. PMID- 23652278 TI - OSU-03012, a non-Cox inhibiting celecoxib derivative, induces apoptosis of human esophageal carcinoma cells through a p53/Bax/cytochrome c/caspase-9-dependent pathway. AB - OSU-03012 is a celecoxib derivative devoid of cyclooxygenase-2 inhibitory activity. It was previously reported to inhibit the growth of some tumor cells through the AKT-signaling pathway. In the current study, we assessed the ability of OSU-03012 to induce apoptosis in human esophageal carcinoma cells and the mechanism by which this occurs. A cell proliferation assay indicated that OSU 03012 inhibited the growth of human esophageal carcinoma cell lines with an IC50 below 2 MUmol/l and had the most effective cytotoxicity against Eca-109 cells. Terminal deoxynucleotidyl transferase-mediated nick-end labeling assay and flow cytometry analysis showed that OSU-03012 could induce the apoptosis in Eca-109 cells. After treatment of Eca-109 cells with 2 MUmol/l OSU-03012 for 24 h, the apoptosis index increased from 14.07 to 53.72%. OSU-03012 treatment resulted in a 30-40% decrease in the mitochondrial membrane potential and caused cytochrome c release into the cytosol. Further studies with caspase-9-specific and caspase-8 specific inhibitors (z-LEHDfmk and z-IETDfmk, respectively) pointed toward the involvement of the caspase-9 pathway, but not the caspase-8 pathway, in the execution of OSU-03012-induced apoptosis. Immunoblot analysis demonstrated that OSU-03012-induced cellular apoptosis was associated with upregulation of Bax, cleaved caspase-3, and cleaved caspase-9. Ser-15 of p53 was phosphorylated after 24 h of treatment of the cancer cells with OSU-03012. This increase in p53 was associated with the decrease in Bcl-2 and increase in Bax. An inhibitor of p53, pifithrin-alpha, attenuated the anticancer effects of OSU-03012 and downregulated the expression of Bax and cleaved caspase-9. Altogether, our results show that OSU-03012 could induce apoptosis in human esophageal carcinoma cells through a p53/Bax/cytochrome c/caspase-9-dependent pathway. PMID- 23652277 TI - A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy. AB - There is a need for efficacious therapies for metastatic castration-resistant prostate cancer (mCRPC) after disease progression on docetaxel. The SRC tyrosine kinase and its related family members may be important drivers of prostate cancer and can be inhibited by dasatinib. mCRPC patients, after one previous chemotherapy, started dasatinib at 70 mg twice daily, amended to 100 mg daily. The primary endpoint was the disease control (DC) rate, defined as complete response (CR), partial response (PR), or stable disease (SD) in prostate specific antigen (PSA), RECIST, bone scan, and FACT-P score. Up to 41 patients were to be accrued (two-stage design, 21+20) to rule out a null-hypothesized effect of 5 versus 20% (alpha=0.05, beta=0.1). Secondary endpoints included progression-free survival, toxicity, and pharmacokinetic and pharmacodynamic correlatives. Of 38 patients, 27 were evaluable for response or toxicity. The median duration of therapy was 55 days (6-284). Five patients showed DC after 8 weeks of therapy (18.5% DC, 95% CI: 6.3-38.1%). One PR (3.7% response rate, 95% CI: 0.1-19.0%) was observed in a patient treated for 284 days. Twelve patients (43%) discontinued treatment for toxicity. Dasatinib induced a decrease in phytohemagglutinin stimulated CSF2, CD40L, GZMB, and IL-2 mRNAs in blood cells, indicating target engagement. Decreases in plasma IL-6 and bone alkaline phosphatase, and in urinary N-telopeptide, were associated with DC. Dasatinib has definite but limited activity in advanced mCRPC, and was poorly tolerated. The observation of a patient with prolonged, objective, clinically significant benefit warrants molecular profiling to select the appropriate patient population. PMID- 23652279 TI - Application of novel biomaterials in clinical surgery. PMID- 23652280 TI - 'The ideal mesh?'. AB - Currently, more than 200 different textile constructions, so-called 'meshes', are available for use world-wide in the more than 20 million operations performed annually for the reinforcement of tissues. As any reintervention at the mesh tissue compound is a surgical challenge, sometimes resulting in almost untreatable defects, huge efforts are being made to improve the biological and functional performance of the meshes. Based on numerous experimental and clinical studies in the past 20 years, our understanding of them has improved markedly. This includes the biomechanical aspects and the histopathological evaluation of the recipient tissue. Sufficiently large pores as well as structural stability in case of mechanical strain have been identified to be crucial to reduce excessive inflammation and fibrosis. Furthermore, large pores prevent bridging of the foreign body reaction through the pore and thereby help to reduce clinical adverse events as erosion, shrinkage or pain. However, with regard to the many different indications for meshes, there will never be one single ideal mesh for all purposes. To achieve an optimal performance, every construction should be designed according to the specific functional requirements, charging the surgeon to identify the best mesh for his purpose. PMID- 23652281 TI - In vivo tissue engineering: mimicry of homing factors for self-endothelialization of blood-contacting materials. AB - Thrombogenicity of foreign surfaces is the major obstacle in cardiovascular interventions. Despite enormous advances in biomaterials research, the hemocompatibility of blood-contacting materials is still not satisfactory and the native endothelium still represents the ideal surface for blood contact. Circulating adult endothelial progenitor cells (EPCs) in the human blood provide an excellent source of autologous stem cells for the in vivo self endothelialization of blood-contacting materials. For this purpose, material surfaces can be coated with capture molecules mimicking natural homing factors to attract circulating EPCs. Hitherto, several ligands, such as aptamers, monoclonal antibodies, peptides, selectins and their ligands, or magnetic molecules, are used to biofunctionalize surfaces for the capturing of EPCs directly from patient's bloodstream onto blood-contacting materials. Subsequently, attracted EPCs can differentiate into endothelial cells and generate an autologous endothelium. The in vivo self-endothelialization of blood-contacting materials prevents the recognition of them as a foreign body; this opens up revolutionary new prospects for future clinical stem-cell and tissue engineering strategies. PMID- 23652282 TI - Biliary stent therapy for dominant strictures in patients affected by primary sclerosing cholangitis. AB - The diagnosis and the treatment of dominant strictures (DS) in patients with primary sclerosing cholangitis (PSC) is challenging and the scientific literature on the subject is quite limited. Only level II and level III evidence is available to guide physicians managing patients with DS and PSC. For the diagnosis, intraductal endoscopic ultrasound is the most sensitive (64%) and specific (95%) test. However, the majority of cases require a combination of several different diagnostic tests, as there is no single investigation that can rule out malignancy in this group of patients. For the treatment, serial endoscopic or percutaneous dilatations provide 1- and 3-year biliary duct patency in 80 and 60% of patients, respectively. Dilatation and stenting are the most common interventions, although the optimal duration of treatment has still not been clearly defined. Bile duct resection and/or bilioenteric bypass are currently indicated only for patients with preserved liver function. For all other patients, benign DS can be treated with endoscopic dilatation with short term stenting. This approach is effective and safe and does not increase the risk of malignant transformation or complications for liver transplant candidates. During the last decade, the use of self-expandable metallic stents for benign diseases has become an innovative option. The aim of this article is to review the diagnostic and therapeutic strategies for patients affected by PSC and DS with specific emphasis on the outcomes of patients treated with temporary stents. PMID- 23652284 TI - Therapeutic strategies for tendon healing based on novel biomaterials, factors and cells. AB - The repair of tendon injuries still presents a major clinical challenge to orthopedic medicine. Tendons, like some other tissues, are poorly vascularized and heal slowly. In addition, healing often leads to the formation of fibrous tissue and scar tissue which lack flexibility and biomechanical properties. So the treatment of tendon injuries is challenging. We give an overview of the structure and composition of tendons, pathological states of tendon and natural healing, as well as therapeutic options. We focus in particular on biomaterials that have been specifically developed or suggested for the successful repair of tendon injuries. In addition, we also review factor- and cell-dependent strategies to heal tendon and ligament disorders. Although brief, we hope that this review will be helpful, particularly for those readers who are new to the field of tendon tissue engineering. PMID- 23652283 TI - Design of a bioartificial pancreas. AB - Islet transplantation has been shown to be a viable treatment option for patients afflicted with type 1 diabetes. However, the lack of availablity of human pancreases and the need to use risky immunosuppressive drugs to prevent transplant rejection remain two major obstacles to the routine use of islet transplantation in diabetic patients. Successful development of a bioartificial pancreas using the approach of microencapsulation with perm-selective coating of islets in hydrogels for graft immunoisolation holds tremendous promise for diabetic patients because it has great potential to overcome these two barriers. In this review article, we will discuss the need for a bioartificial pancreas, provide a detailed description of the microencapsulation process, and review the status of the technology in clinical development. We will also critically review the various factors that will need to be taken into consideration in order to achieve the ultimate goal of routine clinical application. PMID- 23652285 TI - Perspectives on resorbable osteosynthesis materials in craniomaxillofacial surgery. AB - Since introduction to the clinics in the 1990s, resorbable osteosynthesis systems have undergone extensive improvements in order to establish their use as a standard treatment, especially in craniomaxillofacial surgery. However, the development of osteosynthesis systems made of poly(alpha-hydroxy acid) polymers has been hindered by the lack of information on the mechanical properties and biocompatibility of these materials. Moreover, magnesium-based degredable osteosynthesis materials have not yet been integrated into clinical practice owing to biocompatibility problems. Osteosynthesis systems made from nonresorbable titanium alloys have shown excellent biocompatibility, stability and individual fitting to the implant bed, so these materials are currently considered the 'gold standard'. The procedure of plate removal has been subjected to intense scrutiny and controversy. Bioresorbable materials are indicated for special conditions, such as osteosynthesis of the growing skull or orbital floor reconstructions. This paper presents an overview of the currently available and investigated resorbable osteosynthesis materials in comparison with the nonresorbable 'gold standard' titanium. The main problem areas such as sterilization, biocompatibility and stability are highlighted and perspectives for further improvements are provided. PMID- 23652288 TI - Breast feeding among Brazilian adolescents: practice and needs. AB - OBJECTIVES: to characterise breast feeding practices among Brazilian adolescents and identify their breast feeding needs. METHODS: the study was undertaken in Ribeirao Preto, Brazil in two stages. The first stage analysed data from the Second National Survey of Breast-feeding Prevalence, held in August 2008, which included 229 adolescent mothers. The second stage was a qualitative approach, and involved interviews with 10 adolescent mothers in a primary care unit. The data from the first stage were analysed in June 2010 based on descriptive statistics. The data obtained from the interviews were transcribed and organised using thematic content analysis. FINDINGS: breast feeding was reported by 75% of the adolescent mothers. Of the 144 mothers with infants aged <180 days, 84% reported that they were breast feeding: 19% were breast feeding exclusively, 17% were breast feeding predominantly, 49% were providing complementary feeding, and 16% had weaned their infants. Analysis of the interviews led to the identification of three thematic units: concern for the child's health; breast feeding difficulties; and health team and family support. CONCLUSIONS: the majority of the adolescent mothers presented conditions that were favourable to breast feeding (e.g. did not work outside the home, only had one child, breast fed in the first hour post partum). However, the practice of breast feeding still failed to meet the recommendations of the World Health Organization. The interviews led to identification of the breast feeding needs and demands of adolescent mothers, many of which were related to the needs of their infants. It is important to know what adolescent mothers think about breast feeding, in order to encourage the establishment of practices to keep breastfeeding as longer as possible in a satisfactory way for both mothers and infants. PMID- 23652286 TI - Abnormal stress responsivity in a rodent developmental disruption model of schizophrenia. AB - Although numerous studies have implicated stress in the pathophysiology of schizophrenia, less is known about how the effects of stress interact with genetic, developmental, and/or environmental determinants to promote disease progression. In particular, it has been proposed that in humans, stress exposure in adolescence could combine with a predisposition towards increased stress sensitivity, leading to prodromal symptoms and eventually psychosis. However, the neurobiological substrates for this interaction are not fully characterized. Previous work in our lab has demonstrated that rats born to dams administered with the DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 17 exhibit as adults behavioral and anatomical abnormalities consistent with those observed in patients with schizophrenia. Here, we examined behavioral and neuroendocrine responses to stress in the MAM model of schizophrenia. MAM-treated male rats were exposed to acute and repeated footshock stress at prepubertal, peripubteral, and adult ages. Ultrasonic vocalizations (USVs), freezing, and corticosterone responses were quantified. We found that juvenile MAM-treated rats emitted significantly more calls, spent more time vocalizing, emitted calls at a higher rate, and showed more freezing in response to acute footshock stress when compared with their saline (SAL) treated counterparts, and that this difference is not present in older animals. In addition, adolescent MAM-treated animals displayed a blunted HPA axis corticosterone response to acute footshock that did not adapt after 10 days of stress exposure. These data demonstrate abnormal stress responsivity in the MAM model of schizophrenia and suggest that these animals are more sensitive to the effects of stress in youth. PMID- 23652289 TI - Optic pit presentation with coexistent orbital cyst. PMID- 23652290 TI - Re: "The 18-gauge needle: an innovative simple tool for frontalis sling surgery". PMID- 23652291 TI - Reply Re: "The 18-gauge needle: an innovative simple tool for frontalis sling surgery". PMID- 23652292 TI - A technique for visualizing tear meniscus in patients with lower eyelid sagging or retraction. PMID- 23652293 TI - A technique for hemostasis from the cortical bone using an ultrasonic bone aspirator. PMID- 23652294 TI - Re: "Drug-induced Graves disease from CTLA-4 receptor suppression". PMID- 23652295 TI - Reply Re: "Drug-induced Graves disease from CTLA-4 receptor suppression". PMID- 23652296 TI - Surface structure of Pd(111) with less than half a monolayer of Zn. AB - We have characterized the structural properties of submonolayer amounts of Zn on Pd(111) using scanning tunneling microscopy (STM) and spot-profile analysis low energy electron diffraction (SPA-LEED). Following room temperature deposition of ~0.06 monolayers (ML) Zn onto Pd(111), we observe the substitution of Zn for Pd in the surface layer. At ~0.20 ML of deposited Zn, STM reveals a locally ordered phase with a (2/?3 * 2/?3)R30 degrees unit cell located near Zn substitutions; SPA-LEED patterns reveal the same periodicity. We attribute this phase to the metastable bonding of atoms or clusters predominantly in hollow sites surrounding Zn substitutions in the surface layer. At ~0.4 ML, STM images reveal local (?3 * ?3)R30 degrees and (2 * 1) ordering on surfaces annealed to 350 K. At coverages near 0.5 ML, both STM and SPA-LEED show the onset of the formation of the (2 * 1) ordering associated with the Zn : Pd 1 : 1 alloy phase. At all coverages, the surface is dominated by island growth; the islands' size and density is shown to depend critically on annealing at temperatures as low as 350 K. These results provide insight into the structural features of a Zn/Pd(111) coverage regime that has been much debated in recent years. PMID- 23652297 TI - Trends in performance on the psychiatry resident-in-training examination (PRITE(r)): 10 years of data from a single institution. AB - OBJECTIVE: The purpose of this study was to examine trends in the Psychiatry Resident-In-Training Examination (PRITE(r)) scores at one institution from 2001 to 2010. The authors hypothesized that two factors, the 2003 implementation of the Accreditation Council for Graduate Medical Education (ACGME) duty-hour restrictions and the residency program's 2008 restructuring of its curriculum to a half-day per week of didactics, would lead to improved scores. METHOD: Residents in the general psychiatry program at the University of Florida College of Medicine from 2001 to 2010 were included in this study. To examine the effect of the 2003 ACGME duty-hours change, the authors compared test results from 2001 2002 and 2003-2010. To examine the effect of the 2008 didactic restructuring, they compared test results from 2001-2007 and 2008-2010. RESULTS: There were 288 PRITE test scores from 2001 to 2010. The authors did not find a statistical difference between test results before and after the 2003 implementation of ACGME duty-hour restrictions or between test results before and after the 2008 restructuring of residency didactics. CONCLUSION: The hypothesis was rejected. The results of the literature review propose that examination scores are affected by other elements of residency training. PMID- 23652298 TI - Anomalous reactivity of supported V2O5 nanoparticles for propane oxidative dehydrogenation: influence of the vanadium oxide precursor. AB - The oxidative dehydrogenation (ODH) of propane to propylene by supported vanadia catalysts has received much attention in recent years, but different reactivity trends have been reported for this catalytic reaction system. In the present investigation, the origin of these differing trends are investigated with synthesis of supported V/SiO2, V/TiO2, and V/Al2O3 catalysts prepared with three different vanadium oxide precursors (2-propanol/vanadyl triisopropoxide [VO(O Pri)3] (VTI), oxalic acid/ammonium metavanadate [NH4VO3] (AMV), and toluene/vanadyl acetylacetonate [VO(C5H7O2)2] (VAA)) in order to elucidate the influence of the precursor on supported vanadia phase and propane ODH activity. In situ Raman spectroscopy revealed that the choice of vanadium precursor does not affect the dispersion of the supported vanadium oxide phase below 4 V nm(-2) (0.5 monolayer coverage), where only isolated and oligomeric surface VO4 species are present, and only the AMV precursor favors crystalline V2O5 nanoparticle (NP) formation below monolayer coverage (8 V nm(-2)). The propane ODH specific reactivity trend demonstrated that there is no significant difference in TOF for the isolated and oligomeric surface VO4 sites. Surprisingly, V2O5 NPs in the ~1-2 nm range exhibit anomalously high propane ODH TOF values for the supported vanadia catalysts. This was found for all supported vanadium oxide catalysts examined. This comparative study with different V-precursors and synthesis methods and oxide supports finally resolves the debate in the catalysis literature about the dependence of TOF on the surface vanadium density that is related to the unusually high reactivity of small V2O5 NPs. PMID- 23652299 TI - An effective treatment for penile strangulation. AB - The aim of this study was to present our experience of patients with penile strangulation. The clinical data of 6 patients (mean age, 36 years; range, 18-72 years) with penile strangulation caused by a metal hoop are provided, where the duration of strangulation was between 3 h and 1 month. Among these patients, the case of a 22-year-old patient with a steel hoop entrapment on his penis for 5 days is described; due to serious injury of the skin at the root of penis, an intermediate split-thickness thigh skin graft was used to repair the skin loss. A review of the literature is also provided in this study, and current treatment options and outcomes are evaluated. In all the cases described, the metal hoops were successfully removed, without gangrene of the penis. These patients were discharged 2-27 days later with a satisfactory outcome. Penile strangulation is an unusual clinical condition and the consequences may be severe. The choice of method for removal depends on the type and size of metal hoop, incarceration time, trauma grade and availability of equipment. Early treatment is essential to avoid potential complications, including ischemic necrosis and autoamputation. PMID- 23652300 TI - Integrin alpha3 is overexpressed in glioma stem-like cells and promotes invasion. AB - BACKGROUND: Glioma stem-like cell (GSC) properties are responsible for gliomagenesis and recurrence. GSCs are invasive but its mechanism remains to be elucidated. Here, we attempted to identify the molecules that promote invasion in GSCs. METHODS: Neurospheres and CD133+ cells were collected from glioblastoma (GBM) specimens and glioma cell lines by sphere-formation method and magnetic affinity cell sorting, respectively. Differential expression of gene candidates, its role in invasion and its signaling pathway were evaluated in glioma cell lines. RESULTS: Neurospheres from surgical specimens attached to fibronectin and laminin, the receptors of which belong to the integrin family. Integrin alpha3 was overexpressed in CD133+ cells compared with CD133- cells in all the glioma cell lines (4 out of 4). Immunohistochemistry demonstrated the localisation of integrin alpha3 in GBM cells, including invading cells, and in the tumour cells around the vessels, which is believed to be a stem cell niche. The expression of integrin alpha3 was correlated with migration and invasion. The invasion activity of glioma cells was linked to the phosphorylation of extracellular signal regulated kinase (ERK) 1/2. CONCLUSION: Our results suggest that integrin alpha3 contributes to the invasive nature of GSCs via ERK1/2, which renders integrin alpha3 a prime candidate for anti-invasion therapy for GBM. PMID- 23652301 TI - Socioeconomic variation in survival from childhood leukaemia in northern England, 1968-2010. AB - BACKGROUND: Despite marked improvements in childhood leukaemia survival, 20% still die within 5 years of diagnosis. The aim of this study was to evaluate the relationship between socioeconomic status, as assessed by paternal occupation at birth, and survival from childhood leukaemia in children, using data from the Northern Region Young Persons Malignant Disease Registry. METHODS: All 1007 cases of leukaemia in children aged 0-14 years, diagnosed between 1968 and 2010 and registered with the Registry were studied. Paternal occupational social class at the time of the child's birth was obtained and analysed in relation to survival using Cox-proportional regression. RESULTS: Compared with the most advantaged group (I/II), those in the middle group (IIIN/M) had a 68% increased risk of death, while those in the least advantaged group (IV/V) had 86% higher risk for acute lymphoblastic leukaemia. While the survival advantage of children in class I/II was apparent from the time of diagnosis, survival for children in groups IIIN/M and IV/V were comparable until 3-4 years after diagnosis, when they began to minimally diverge. CONCLUSION: The existence of such socioeconomic disparities cannot be attributed to accessibility to health care in the United Kingdom. Further research into the likely factors underlying these disparities is required. PMID- 23652302 TI - Hepatitis B virus reactivation risk varies with different chemotherapy regimens commonly used in solid tumours. AB - BACKGROUND: Hepatitis B virus (HBV) reactivation may occur with chemotherapy and has significant morbidity and mortality. The United States Centre for Disease Control and Prevention recommends pre-chemotherapy hepatitis B screening for all cancer patients, while the American Society of Clinical Oncology finds that there is insufficient evidence currently to support such a recommendation. Apart from anthracyclines, HBV reactivation rates from other commonly used chemotherapy regimens in solid tumours are not well described. METHODS: We compared HBV reactivation risk in patients receiving several commonly used chemotherapy regimens for solid tumours associated with different immunosuppression risk at a tertiary cancer centre in an HBV endemic region. RESULTS: A total of 1149 patients were identified, including 434, 196, 245 and 274, respectively, who received doxorubicin-based, oxaliplatin- or irinotecan-based, carboplatin/gemcitabine, and capecitabine chemotherapy. HBV screening rate was 39% overall. Thirty out of 448 (7%) screened patients were HBsAg positive and 28 out of 30 received prophylactic antiviral therapy with no reactivation. Three out of 1149 patients overall (0.3%) developed HBV reactivation, all from the unscreened doxorubicin group (3 out of 214, 1.4%). No unscreened patients (0 out of 487) in the other three treatment groups developed reactivation (P<0.001). CONCLUSION: Not all chemotherapy regimens result in HBV reactivation. Routine hepatitis B screening for low- or moderate-risk regimens may not be warranted. PMID- 23652303 TI - Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors. AB - BACKGROUND: Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk. METHODS: We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case-control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages <36 during 1956-2003. RESULTS: Two-hundred and sixty women had been diagnosed with breast cancer. Breast cancer risk was significantly increased in patients treated within 6 months of menarche (odds ratio (OR) 5.52, 95% confidence interval (CI) (1.97-15.46)), and increased significantly with proximity of sRT to menarche (Ptrend<0.001). It was greatest when sRT was close to a late menarche, but based on small numbers and needing reexamination elsewhere. Risk was not significantly affected by full-term pregnancies before or after treatment. Risk was significantly reduced by early menopause (OR 0.55, 95% CI (0.35-0.85)), and increased with number of premenopausal years after treatment (Ptrend=0.003). CONCLUSION: In summary, this paper shows for the first time that sRT close to menarche substantially increases breast cancer risk. Careful consideration should be given to follow-up of these women, and to measures that might reduce their future breast cancer risk. PMID- 23652304 TI - Myofibroblast activation in colorectal cancer lymph node metastases. AB - BACKGROUND: Myofibroblasts have an important role in regulating the normal colorectal stem cell niche. While the activation of myofibroblasts in primary colorectal cancers has been previously described, myofibroblast activation in lymph node metastases has not been described before. METHODS: Paraffin-embedded lymph node sections from patients with macrometastases, micrometastases and isolated tumour cells were stained to identify myofibroblasts and to characterise the distribution of different cell types in tumour-containing lymph nodes. The extent of myofibroblast presence was quantified and compared with the size of the metastasis and degree of proliferation and differentiation of the cancer cells. RESULTS: We show substantial activation of myofibroblasts in the presence of colorectal metastases in lymph nodes, which is intimately associated with glandular structures, both in micro- and macrometastases. The degree of activation is positively associated with the size of the metastases and the proportion of Ki67+ve cancer cells, and negatively associated with the degree of enterocyte differentiation as measured by CK20 expression. CONCLUSION: The substantial activation of myofibroblasts in tumour-containing lymph nodes strongly suggests that these metastatic cancer cells are still significantly dependent on their microenvironment. Further understanding of these epithelial mesenchymal interactions could lead to the development of new therapies in metastatic disease. PMID- 23652305 TI - Assessment of DNA methylation status in early stages of breast cancer development. AB - BACKGROUND: Molecular pathways determining the malignant potential of premalignant breast lesions remain unknown. In this study, alterations in DNA methylation levels were monitored during benign, premalignant and malignant stages of ductal breast cancer development. METHODS: To study epigenetic events during breast cancer development, four genomic biomarkers (Methylated-IN-Tumour (MINT)17, MINT31, RARbeta2 and RASSF1A) shown to represent DNA hypermethylation in tumours were selected. Laser capture microdissection was employed to isolate DNA from breast lesions, including normal breast epithelia (n=52), ductal hyperplasia (n=23), atypical ductal hyperplasia (n=31), ductal carcinoma in situ (DCIS, n=95) and AJCC stage I invasive ductal carcinoma (IDC, n=34). Methylation Index (MI) for each biomarker was calculated based on methylated and unmethylated copy numbers measured by Absolute Quantitative Assessment Of Methylated Alleles (AQAMA). Trends in MI by developmental stage were analysed. RESULTS: Methylation levels increased significantly during the progressive stages of breast cancer development; P-values are 0.0012, 0.0003, 0.012, <0.0001 and <0.0001 for MINT17, MINT31, RARbeta2, RASSF1A and combined biomarkers, respectively. In both DCIS and IDC, hypermethylation was associated with unfavourable characteristics. CONCLUSION: DNA hypermethylation of selected biomarkers occurs early in breast cancer development, and may present a predictor of malignant potential. PMID- 23652306 TI - Expression of steroid receptor coactivator 3 in ovarian epithelial cancer is a poor prognostic factor and a marker for platinum resistance. AB - BACKGROUND: Steroid receptor coactivator 3 (SRC3) is an important coactivator of a number of transcription factors and is associated with a poor outcome in numerous tumours. Steroid receptor coactivator 3 is amplified in 25% of epithelial ovarian cancers (EOCs) and its expression is higher in EOCs compared with non-malignant tissue. No data is currently available with regard to the expression of SRC-3 in EOC and its influence on outcome or the efficacy of treatment. METHODS: Immunohistochemistry was performed for SRC3, oestrogen receptor-alpha, HER2, PAX2 and PAR6, and protein expression was quantified using automated quantitative immunofluorescence (AQUA) in 471 EOCs treated between 1991 and 2006 with cytoreductive surgery followed by first-line treatment platinum based therapy, with or without a taxane. RESULTS: Steroid receptor coactivator 3 expression was significantly associated with advanced stage and was an independent prognostic marker. High expression of SRC3 identified patients who have a significantly poorer survival with single-agent carboplatin chemotherapy, while with carboplatin/paclitaxel treatment such a difference was not seen. CONCLUSION: Steroid receptor coactivator 3 is a poor prognostic factor in EOCs and appears to identify a population of patients who would benefit from the addition of taxanes to their chemotherapy regimen, due to intrinsic resistance to platinum therapy. PMID- 23652307 TI - Autoantibodies to MUC1 glycopeptides cannot be used as a screening assay for early detection of breast, ovarian, lung or pancreatic cancer. AB - BACKGROUND: Autoantibodies have been detected in sera before diagnosis of cancer leading to interest in their potential as screening/early detection biomarkers. As we have found autoantibodies to MUC1 glycopeptides to be elevated in early stage breast cancer patients, in this study we analysed these autoantibodies in large population cohorts of sera taken before cancer diagnosis. METHODS: Serum samples from women who subsequently developed breast cancer, and aged-matched controls, were identified from UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and Guernsey serum banks to formed discovery and validation sets. These were screened on a microarray platform of 60mer MUC1 glycopeptides and recombinant MUC1 containing 16 tandem repeats. Additional case-control sets comprised of women who subsequently developed ovarian, pancreatic and lung cancer were also screened on the arrays. RESULTS: In the discovery (273 cases, 273 controls) and the two validation sets (UKCTOCS 426 cases, 426 controls; Guernsey 303 cases and 606 controls), no differences were found in autoantibody reactivity to MUC1 tandem repeat peptide or glycoforms between cases and controls. Furthermore, no differences were observed between ovarian, pancreatic and lung cancer cases and controls. CONCLUSION: This robust, validated study shows autoantibodies to MUC1 peptide or glycopeptides cannot be used for breast, ovarian, lung or pancreatic cancer screening. This has significant implications for research on the use of MUC1 in cancer detection. PMID- 23652308 TI - Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma, a phase II study. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is a rare disease with a poor response to chemotherapy. Cisplatin is the most widely investigated drug in the treatment of ACC and in vitro studies have indicated activity of taxanes. The objectives of this study were to evaluate the efficacy and toxicity of cisplatin combined with docetaxel as first-line treatment of advanced ACC. METHODS: Patients with advanced ACC were included in this phase II trial investigating the response to a combination of cisplatin (50 mg m(-2)) and docetaxel (60 mg m(-2)) administered with a 3-week interval. RESULTS: Nineteen patients were included in this study. The response rate was 21% (95% CI: 3-39%). No patients obtained a complete response, 32% had stable disease, and 37% progressed while on treatment. The median progression-free survival (PFS) was 3 months (95% CI: 0.7-5.3 months) and 1 year PFS was 21% (95% CI: 3-39%). Median survival was 12.5 months (95% CI: 6-19 months). The predominant grade 3/4 toxicity was neutropenia (35%); febrile neutropenia occurred in 5% of cycles. CONCLUSION: This study could not demonstrate that the combination of cisplatin and docetaxel has higher efficacy than other regimens reported in previous studies. PMID- 23652309 TI - Patterns of exposure to infectious diseases and social contacts in early life and risk of brain tumours in children and adolescents: an International Case-Control Study (CEFALO). AB - BACKGROUND: Infectious diseases and social contacts in early life have been proposed to modulate brain tumour risk during late childhood and adolescence. METHODS: CEFALO is an interview-based case-control study in Denmark, Norway, Sweden and Switzerland, including children and adolescents aged 7-19 years with primary intracranial brain tumours diagnosed between 2004 and 2008 and matched population controls. RESULTS: The study included 352 cases (participation rate: 83%) and 646 controls (71%). There was no association with various measures of social contacts: daycare attendance, number of childhours at daycare, attending baby groups, birth order or living with other children. Cases of glioma and embryonal tumours had more frequent sick days with infections in the first 6 years of life compared with controls. In 7-19 year olds with 4+ monthly sick day, the respective odds ratios were 2.93 (95% confidence interval: 1.57-5.50) and 4.21 (95% confidence interval: 1.24-14.30). INTERPRETATION: There was little support for the hypothesis that social contacts influence childhood and adolescent brain tumour risk. The association between reported sick days due to infections and risk of glioma and embryonal tumour may reflect involvement of immune functions, recall bias or inverse causality and deserve further attention. PMID- 23652311 TI - Evaluation of a new panel of six mononucleotide repeat markers for the detection of DNA mismatch repair-deficient tumours. AB - BACKGROUND: Microsatellite instability (MSI) is a molecular phenotype due to defective DNA mismatch repair (MMR) system. It is used to predict outcome of colorectal tumours and to screen tumours for Lynch syndrome (LS). A pentaplex panel composed of five mononucleotide markers has been largely recommended for determination of the MSI status. However, its sensitivity may be taken in default in occasional situations. The aim of the study was to optimise this panel for the detection of MSI. METHODS: We developed an assay allowing co-amplification of six mononucleotide repeat markers (BAT25, BAT26, BAT40, NR21, NR22, NR27) and one polymorphic dinucleotide marker (D3S1260) in a single reaction. Performances of the new panel were evaluated on a cohort of patients suspected of LS. RESULTS: We demonstrate that our assay is technically as easy to use as the pentaplex assay. The hexaplex panel shows similar performances for the identification of colorectal and non-MSH6-deficient tumours. On the other hand, the hexaplex panel has higher sensitivity for the identification of MSH6-deficient tumours (94.7% vs 84.2%) and MMR-deficient tumours other than colorectal cancer (92.9% vs 85.7%). CONCLUSION: The hexaplex panel could thus be an attractive alternative to the pentaplex panel for the identification of patients with LS. PMID- 23652310 TI - Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy. AB - BACKGROUND: There have been controversies in prognostic impact of mucinous histology on colorectal cancer, and its implication in patients treated with adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is unclear. METHODS: Stage II and III colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Patients were grouped according to the mucinous content: >50%, mucinous adenocarcinoma (MAC); <50%, adenocarcinoma with intermediated mucinous component (AIM); and without any mucinous component, non-MAC (NMA). Clinicopathological features and disease-free survival (DFS) were compared. RESULTS: Among a total of 521 patients, 27 patients (5.2%) had MAC, 41 patients (7.9%) had AIM, and 453 patients (86.9%) had NMA. Mucinous adenocarcinoma and AIM had higher frequency of proximal location and microsatellite instability, but lower frequency of angiolymphatic invasion. Disease-free survival was significantly worse in the MAC compared with NMA (3 year DFS 57% and 86%, respectively; P<0.001) and AIM (3-year DFS 87%, P=0.01 vs MAC). Multivariate analysis revealed MAC as an independent negative prognostic factor of DFS (adjusted hazard ratio 7.96, 95% confidence interval 3.76-16.8). CONCLUSION: Adenocarcinoma with intermediated mucinous component and MAC have distinct clinicopathological features compared with NMA. Mucinous adenocarcinoma has an adverse prognostic impact on stage II or III colorectal cancer treated with adjuvant FOLFOX. PMID- 23652312 TI - Patients' and oncologists' views on the treatment and care of advanced ovarian cancer in the U.K.: results from the ADVOCATE study. AB - BACKGROUND: Most patients presenting with advanced ovarian cancer (AOC) eventually relapse. Symptom palliation, maintenance of quality of life (QoL) and prolongation of life are primary therapeutic goals. METHODS: Sixty-six U.K. oncologists completed an online survey about AOC management. Two hundred and two patients were interviewed about care, treatment experiences and expectations. RESULTS: Prior to diagnosis, 34% (69 out of 202) of women had > or =3 symptoms associated with AOC. Twenty-one per cent (43 out of 202) thought poor symptom recognition by general practitioners (GPs) delayed diagnosis. Amelioration of side effects experienced was variable, for example, only 54% (68 out of 127) distressed by alopecia had received sufficient information about it. Clinicians were asked 'What minimum gain in progression-free survival (PFS) would make you feel it worthwhile to offer maintenance therapy?'; 48% (24 out of 50) indicated 5 6 months, but 52% (26 out of 50) believed patients would find PFS of 3-4 months acceptable. When patients were presented with hypothetical scenarios, 33% (52 out of 160) would require 1-2 months extra life, 6% (10 out of 160) 3-4 months, 31% (49 out of 160) 5-6 months, and 31% (49 out of 160) > or =7 months. However, 86% (173 out of 202) would accept treatment that improved QoL without prolongation of life. When asked what was most important, 33% (67 out of 201) said QoL, 9% (19 out of 201) length of life and 57% (115 out of 201) said both were equally important. CONCLUSION: Clinicians' and patients' experiences, expectations and priorities about OC management may differ. PMID- 23652313 TI - Association between tuberculosis infections and non-pulmonary malignancies: a nationwide population-based study. AB - BACKGROUND: In addition to lung cancers, tuberculosis infections have been associated with increased risk of non-pulmonary malignancies in case reports. Our population-based study employed standardized incidence ratios (SIRs) to systemically survey non-pulmonary cancer risks after tuberculosis infections. METHODS: Data of patients who had newly diagnosed tuberculosis, were aged 20 years or older, and had no prior cancer or tuberculosis were sampled from the Taiwan National Health Insurance database between 2000 and 2010. SIRs compared cancer incidence in patients with tuberculosis infections to the general population. SIRs of specific cancers were further analyzed with respect to gender and time after tuberculosis infections. RESULTS: After a follow-up period of 28 866 person-years, 530 tuberculosis cases developed cancers compared with 256 cases in the general populations (2.07, 95% confidence interval (CI), 1.90-2.26). The SIR of non-pulmonary malignancies was also increased (1.71, 95% CI, 1.54 1.90). For males, SIRs were increased within 1 year after tuberculosis diagnosis for the following cancers: head and neck, esophageal, colorectal, liver, lung, melanomas, and Hodgkin's disease. SIRs were increased for liver, biliary, lung, and bladder cancers beyond the first year after tuberculosis diagnosis. For females, SIRs were increased for leukemia, esophageal, and lung cancers within the first year, and only for leukemia beyond 1 year post diagnosis. CONCLUSION: Having found increased risks of several cancers that differ with gender and time after tuberculosis diagnosis, physicians may consider these factors in patients following tuberculosis diagnosis. PMID- 23652314 TI - Phase I study of tremelimumab (CP-675 206) plus PF-3512676 (CPG 7909) in patients with melanoma or advanced solid tumours. AB - BACKGROUND: Tremelimumab, a fully human cytotoxic T-lymphocyte antigen 4 monoclonal antibody, and PF-3512676, a Toll-like receptor-9 agonist, are targeted immune modulators that elicit durable single-agent antitumour activity in advanced cancer. METHODS: To determine the maximum tolerated dose (MTD) of these agents combined during this phase I study, patients received intravenous tremelimumab (6.0, 10.0, or 15.0 mg kg(-1)) every 12 weeks plus subcutaneous PF 3512676 (0.05, 0.10, or 0.15 mg kg(-1)) weekly. Primary end points were safety and tolerability; secondary end points included pharmacokinetics and antitumour activity. RESULTS: Twenty-one patients with stage IV melanoma (n=17) or advanced solid tumours (n=4) were enrolled. Injection-site reactions (n=21; 100%), influenza-like illness (n=18; 86%), and diarrhoea (n=13; 62%) were the most common treatment-related adverse events (TAEs). Grade >=3 TAEs were reported (n=7; 33%). Dose-limiting toxicities (prespecified 6-week observation) occurred in one of the six patients in the 10 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 cohort (grade 3 hypothalamopituitary disorder) and two of the six patients in the 15 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 cohort (grade 3 diarrhoea). Consequently, 15 mg kg(-1) tremelimumab plus 0.05 mg kg(-1) PF-3512676 exceeded the MTD. Two melanoma patients achieved durable (>=170 days) partial response. No human antihuman antibody responses to tremelimumab were observed. CONCLUSION: Weekly PF-3512676 (<=0.15 mg kg(-1)) plus tremelimumab (<=10 mg kg(-1) every 12 weeks) was tolerable. PMID- 23652316 TI - Inhalation as a source of iron in secondary iron overload. PMID- 23652315 TI - Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer. AB - BACKGROUND: Membranous expression of the anti-adhesive glycoprotein podocalyxin like (PODXL) has previously been found to correlate with poor prognosis in several major cancer forms. Here we examined the prognostic impact of PODXL expression in urothelial bladder cancer. METHODS: Immunohistochemical PODXL expression was examined in tissue microarrays with tumours from two independent cohorts of patients with urothelial bladder cancer: n=100 (Cohort I) and n=343 (Cohort II). The impact of PODXL expression on disease-specific survival (DSS; Cohort II), 5-year overall survival (OS; both cohorts) and 2-year progression free survival (PFS; Cohort II) was assessed. RESULTS: Membranous PODXL expression was significantly associated with more advanced tumour (T) stage and high-grade tumours in both cohorts, and a significantly reduced 5-year OS (unadjusted HR=2.25 in Cohort I and 3.10 in Cohort II, adjusted HR=2.05 in Cohort I and 2.18 in Cohort II) and DSS (unadjusted HR=4.36, adjusted HR=2.70). In patients with Ta and T1 tumours, membranous PODXL expression was an independent predictor of a reduced 2-year PFS (unadjusted HR=6.19, adjusted HR=4.60) and DSS (unadjusted HR=8.34, adjusted HR=7.16). CONCLUSION: Membranous PODXL expression is an independent risk factor for progressive disease and death in patients with urothelial bladder cancer. PMID- 23652317 TI - Native Cu(A) redox sites are largely resilient to pH variations within a physiological range. AB - Previous studies on engineered CuA centres have shown that one of the histidine ligands is protonated and dissociated from the metal site at physiological pH values, thus suggesting a role in regulating proton-coupled electron transfer of cytochrome c oxidases in vivo. Here we report that for native CuA such protonation does not take place at physiologically relevant pH values and, furthermore, no significant changes in the spectroscopic and redox properties of the metal site occur at low pH. PMID- 23652318 TI - Commentary on Moss et al. PMID- 23652319 TI - Characterization of platelet concentrates using dynamic light scattering. AB - BACKGROUND: Each year, millions of platelet transfusions save the lives of cancer patients and patients with bleeding complications. However, between 10 and 30% of all platelet transfusions are clinically ineffective as measured by corrected count increments, but no test is currently used to identify and avoid these transfusions. ThromboLUX((r)) is the first platelet test intended to routinely characterize platelet concentrates prior to transfusion. METHODS: ThromboLUX is a non-invasive, optical test utilizing dynamic light scattering to characterize a platelet sample by the relative quantity of platelets, microparticles, and other particles present in the sample. ThromboLUX also determines the response of platelets to temperature changes. From this information the ThromboLUX score is calculated. Increasing scores indicate increasing numbers of discoid platelets and fewer microparticles. ThromboLUX uses calibrated polystyrene beads as a quality control standard, and accurately measures the size of the beads at multiple temperatures. RESULTS: Results from apheresis concentrates showed that ThromboLUX can determine the microparticle content in unmodified samples of platelet concentrates which correlates well with the enumeration by flow cytometry. ThromboLUX detection of microparticles and microaggregates was confirmed by microscopy. CONCLUSION: ThromboLUX provides a comprehensive and novel analysis of platelet samples and has potential as a noninvasive routine test to characterize platelet products to identify and prevent ineffective transfusions. PMID- 23652321 TI - Paracrine effects and heterogeneity of marrow-derived stem/progenitor cells: relevance for the treatment of respiratory diseases. AB - Stem cell-based treatment may represent a hope for the treatment of acute lung injury and pulmonary fibrosis, and other chronic lung diseases, such as cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). It is well established in preclinical models that bone marrow-derived stem and progenitor cells exert beneficial effects on inflammation, immune responses and repairing of damage in virtually all lung-borne diseases. While it was initially thought that the positive outcome was due to a direct engraftment of these cells into the lung as endothelial and epithelial cells, paracrine factors are now considered the main mechanism through which stem and progenitor cells exert their therapeutic effect. This knowledge has led to the clinical use of marrow cells in pulmonary hypertension with endothelial progenitor cells (EPCs) and in COPD with mesenchymal stromal (stem) cells (MSCs). Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells, MSCs, EPCs and fibrocytes, encompass a wide array of cell subsets with different capacities of engraftment and injured tissue-regenerating potential. The characterization/isolation of the stem cell subpopulations represents a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine and applied to lung disorders. PMID- 23652320 TI - Histamine enhances HIV-1-induced modulation of dendritic cells to skew naive T cell differentiation toward regulatory T cells. AB - Altered cytokine profiles and imbalanced frequencies of CD4(+) T helper cell subsets are thought to be linked with HIV-1/AIDS pathogenesis, but the causes need to be further clarified. Histamine, a biogenic amine with many functions, shows enhancement in HIV-1 infected individuals, which are considered to link with disease progression, but is poorly understood. This study investigated histamine-assisted HIV-1 modulation of dendritic cell (DC) functions. Histamine and HIV-1 showed a synergistic role in induction of interleukin-10; histamine inhibited HIV-1-induced IL-12 production from MDDCs (monocyte-derived DCs); notably, histamine augmented HIV-1-induced MDDC functional polarization and skewed naive T cell differentiation toward regulatory T cells (Tregs). The results indicate the novel role of histamine in HIV-1-induced DC functional regulation, which promoted Treg cell differentiation and up-regulated immunosuppressive factors. These findings help to bridge the correlation between elevated histamine and increased Treg cell frequency in HIV-1 infected individuals, and add to our understanding of HIV-1-induced immunosuppression. PMID- 23652322 TI - Effect of prolonged tacrolimus treatment in idiopathic membranous nephropathy with nephrotic syndrome. AB - OBJECTIVE: Tacrolimus has been used for idiopathic membranous nephropathy (IMN) therapy, but most patients who achieved remission showed a high relapse rate when tacrolimus was withdrawn after 6-12 months of therapy. We proposed that a prolonged therapeutic course should help reduce the relapse rate. METHODS: A total of 42 patients with nephrotic syndrome caused by IMN were randomly divided into short-term (n = 20) and long-term (n = 22) groups. All patients received initial treatment with tacrolimus and prednisone for 6 months, and afterward only the long-term patient group was tapered with low-dose tacrolimus until 24 months. RESULTS: Over 85% of the patients achieved proteinuria reduction, serum albumin improvement and serum lipid recovery; the probability of remission in both groups was over 80% at 6 months. The remission rate was steady at over 80% after 12 and 24 months in the long-term group, but only 50 and 45%, respectively, in the short term group. Nine patients (45%) relapsed in the short-term group after tacrolimus withdrawal, while not a single patient suffered recurrence in the long-term group. The concentration of tacrolimus remained similar between the two groups at 5-8 ng/ml during the initial 6 months, and was significantly decreased at 12 months compared to 6 months (p < 0.05), along with reduction of oral administration in the long-term group. CONCLUSION: Combined therapy of tacrolimus with prednisone can relieve IMN significantly; prolonged tacrolimus treatment at a low blood concentration can alleviate the illness persistently, with a low recurrence rate and gratifying safety. PMID- 23652323 TI - Barriers to preclinical investigations of anti-dengue immunity and dengue pathogenesis. AB - Dengue virus (DENV) is a human pathogen that causes severe and potentially fatal disease in millions of individuals each year. Immune-mediated pathology is thought to underlie many of the complications of DENV infection in humans, but the notable limitations of the available animal models have impeded our knowledge of the interactions between DENV and the immune system. In this Opinion article, we discuss some of the controversies in the field of dengue research relating to the interaction between DENV and the mammalian host. We highlight key barriers hindering our understanding of the molecular pathogenesis of DENV and offer suggestions for the most effective ways in which the role of the immune system in the protection from, and pathology of, DENV infection can be addressed experimentally. PMID- 23652325 TI - Bacterial physiology: Unfit expression. PMID- 23652326 TI - Bacterial pathogenesis: Legionella makes its mark on histones. PMID- 23652327 TI - Hearing performance with 2 different high-power sound processors for osseointegrated auditory implants. AB - OBJECTIVE: To compare speech understanding of the BAHA BP110 and BAHA Intenso sound processors. STUDY DESIGN: Prospective experimental study. SETTING: Tertiary referral center. PATIENTS: Twenty experienced user of osseointegrated auditory implants with conductive or mixed hearing loss. INTERVENTIONS: In a first session, half of the participants were fitted with an Intenso, the other half with a BP110. After 1 month of use, aided speech understanding in quiet and in noise was measured, and the other test processor was fitted. One month later, speech understanding with the second sound processor was assessed. MAIN OUTCOME MEASURES: Speech understanding in quiet and in noise, with noise arriving either from the front, the rear, or the side of the user with the osseointegrated bone conductor. RESULTS: Significant improvements were found for both processors for speech understanding in quiet (+9.6 to +34.8 percent points; p = 0.02 to 0.001) and in noise (+6.2 to +13.8 dB, p < 0.001). No significant differences were found between the 2 devices for speech in quiet. For noise from the rear, subjects were able to understand speech at signal-to-noise ratios which were lower (less favorable) by -5.1 dB (p < 0.001) when compared with the Intenso. CONCLUSION: Speech understanding is substantially improved by both devices, with no significant differences between the sound processors in quiet. In noise, speech understanding is significantly better with the BP110 when compared to the Intenso for noise from the rear. PMID- 23652324 TI - Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori. AB - The bacterial pathogen Helicobacter pylori has co-evolved with humans and colonizes approximately 50% of the human population, but only causes overt gastric disease in a subset of infected hosts. In this Review, we discuss the pathogenesis of H. pylori and the mechanisms it uses to promote persistent colonization of the gastric mucosa, with a focus on recent insights into the role of the virulence factors vacuolating cytotoxin (VacA), cytotoxin-associated gene A (CagA) and CagL. We also describe the immunobiology of H. pylori infection and highlight how this bacterium manipulates the innate and adaptive immune systems of the host to promote its own persistence. PMID- 23652328 TI - Can myringoplasty close the air-bone gap? AB - OBJECTIVE: The aim of this study is to evaluate whether closure of a tympanic membrane perforation with an intact ossicular chain results in a closure of the air-bone gap. STUDY DESIGN: Prospectively collected data from 154 patients undergoing temporalis fascia myringoplasty for chronic otitis media simplex were identified. SETTING: Tertiary referral center. PATIENTS: Between 2001 and 2009, overall, 106 patients with a central tympanic membrane perforation and, an intact ossicular chain were further analyzed. INTERVENTIONS: All patients underwent myringoplasty using temporalis fascia in an underlay technique. MAIN OUTCOME MEASURES: Comparison of the preoperative and postoperative hearing results in patients undergoing myringoplasty for chronic otitis media simplex. RESULTS: The mean postoperative air-bone gap (ABG) was 8.2 dB for the frequencies 0.5 to 4 kHz. Eighty-three patients (78%) showed postoperatively a mean ABG of 10 dB or lower. The ABG difference (improvement) was statistically significant for each single frequency (0.5, 1, 2, 3, and 4 kHz) (p < 0.0001). There is a linear correlation between the preoperative tympanic membrane perforation size and the postoperative ABG (p = 0.0017) for the frequencies 0.5 to 4 kHz. No statistical significant correlation was seen between the state of the middle-ear mucosa, temporal bone pneumatization, tympanometric middle-ear/mastoid volume, and the postoperative ABG. CONCLUSION: Complete ABG closure by myringoplasty could be achieved in only approximately 20% of the cases. 80% respectively presented with a mean residual ABG of 8 dB. We found a significant linear correlation between the preoperative size of the tympanic membrane perforation and the postoperative ABG, whereas mastoid volume, temporal bone pneumatization, and the condition of the mucosa did not affect the outcome. PMID- 23652329 TI - Postoperative validation of bone-anchored implants in the single-sided deafness population. PMID- 23652330 TI - Intratympanic and systemic steroids for sudden hearing loss. AB - OBJECTIVE: To investigate the therapeutic efficacy of intratympanic dexamethasone combined with systemic prednisolone in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). STUDY DESIGN: Prospective, quasirandomized, multicenter clinical trial. SETTING: One university hospital and 2 affiliated hospitals. PATIENTS: A total of 92 eligible patients with ISSNHL were allocated into 2 groups. Patients in the control group were treated with systemic prednisolone alone. Patients of the combined treatment group received additionally 3 intratympanic dexamethasone injections within 5 days. MAIN OUTCOME MEASURES: The main outcome measures used were the differences between pretreatment and posttreatment pure-tone audiometry averages (PTAs) and speech discrimination scores (SDSs). Successful treatment was defined as a greater than 10 dB improvement in PTA and 15% in SDS. The final assessment of hearing was performed 3 months after completion of treatment. RESULTS: Significant hearing recovery was observed in 31 (67.39%) of 46 cases, and in 24 (52.17%) of 46 control patients. Patients receiving combination therapy had a median improvement in PTA of 23.12 dB and a median increase in SDS of 32%. In the control group, the median hearing gain was 16.87 dB and 18%, respectively. The differences between the 2 groups were not statistically significant (p = 0.10 and p = 0.13). However, after performing a post hoc analysis by excluding individuals with profound hearing loss (PTA, >90 dB), the combined treatment group showed significant improvement compared with the control group (p = 0.04). No serious complications or adverse reactions were reported. CONCLUSION: The addition of intratympanic steroids to the conventional systemic steroid therapy may provide a safe and potentially effective therapeutic option in patients with mild-to-severe ISSNHL. PMID- 23652331 TI - Pediatric hearing loss and radiographic pericochlear hypoattenuation. AB - OBJECTIVE: To assess the relationship of sensorineural hearing loss to pericochlear radiographic hypoattenuation in the pediatric population. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Children, younger than 5 years, with both computed tomographic imaging of the temporal bone and audiometric analysis between 2004 and 2008 at the University of Michigan. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURE(S): The prevalence of pericochlear hypoattenuation in ears with and without hearing loss. RESULTS: One hundred seventy-six patients (98 male and 78 female patients) were completely reviewed. The prevalence of cochlear hypoattenuation was 39.2% (107/273) in ears with hearing loss, compared with 40.5% (32/79) in ears without hearing loss (p = 0.83). Similarly, the prevalence of hypoattenuation was not different in ears with sensorineural hearing loss (36.8%, 70/190) and those without hearing loss (40.3%, 31/79, p = 0.60). Patients with hypoattenuation (mean, 24 mo) were significantly younger than patients without hypoattenuation (mean, 30 mo). The prevalence of hypoattenuation was higher in the ears of children born prematurely (35/64, 54.7%) compared with the ears of children born at full term (90/230, 39.1%, p = 0.026; 95% confidence interval, 1.88%-29.3%). CONCLUSION: There does not seem to be a relationship between sensorineural hearing loss and the presence of decreased density of the bony cochlea in the pediatric population. The density of pericochlear bone increases with age. Prematurity is associated with a higher risk of hypoattenuation. This radiographic finding is common and may represent a normal developmental process. PMID- 23652332 TI - Selenoprotein P and selenoprotein M block Zn2+ -mediated Abeta42 aggregation and toxicity. AB - Aggregation and cytotoxicity of the amyloid-beta (Abeta) peptide with transition metal ions in neuronal cells have been suggested to be involved in the progression of Alzheimer's disease (AD). A therapeutic strategy to combat this incurable disease is to design chemical agents to target metal-Abeta species. Selenoproteins are a group of special proteins that contain the 21st amino acid Sec in their sequence. Due to the presence of Sec, studies of this group of proteins are basically focused on their roles in regulating redox potential and scavenging reactive oxygen species. Here, we reported that the His-rich domain of selenoprotein P (SelP-H) and the Sec-to-Cys mutant selenoprotein M (SelM') are capable of binding transition metal ions and modulating the Zn(2+)-mediated Abeta aggregation, ROS production and neurotoxicity. SelM' (U48C) and SelP-H were found to coordinate 0.5 and 2 molar equivalents of Zn(2+)/Cd(2+) with micromolar and submicromolar affinities, respectively. Metal binding induced the structural changes in SelP-H and SelM' according to the circular dichorism spectra. Zn(2+) binding to Abeta42 almost completely suppressed Abeta42 fibrillization, which could be significantly restored by SelP-H and SelM', as observed by thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM). Interestingly, both SelP-H and SelM' inhibited Zn(2+)-Abeta42-induced neurotoxicity and the intracellular ROS production in living cells. These studies suggest that SelP and SelM may play certain roles in regulating redox balance as well as metal homeostasis. PMID- 23652333 TI - Laparoscopy-assisted pylorus-preserving gastrectomy is better than laparoscopy assisted distal gastrectomy for middle-third early gastric cancer. AB - OBJECTIVE: The purpose of this study is to compare the surgical, oncologic safety and the nutritional, functional benefit of laparoscopy-assisted pylorus preserving gastrectomy (LAPPG) with laparoscopy-assisted distal gastrectomy (LADG) for middle-third early gastric cancers (EGC). BACKGROUND: Of those patients with middle-third EGC, it is still difficult to determine which procedure is better between LADG and LAPPG despite alleged advantages of LAPPG. METHODS: For middle-third EGC, a retrospective analysis was performed comparing those who underwent LADG and those who underwent LAPPG. To evaluate surgical and oncologic safety, clinicopathologic differences including the postoperative morbidity, the pattern of lymph node metastasis and recurrence were analyzed. Postoperative protein, albumin, quantification of abdominal fat area using abdomen computed tomography, and the incidence of postoperative gallstone were compared for the evaluation of functional advantages. RESULTS: The overall postoperative morbidity rate was similar between LADG (n = 176) and LAPPG (n = 116). Delayed gastric emptying was less frequent in LADG than in LAPPG (1.7% vs 7.8%); however, the rates of all the other complications were significantly higher in LADG than in LAPPG (17.0% vs 7.8%). The number of examined lymph nodes and metastatic lymph nodes at each lymph node station was not significantly different and 3-year recurrence-free survival rates were also similar between LADG and LAPPG (98.8% vs 98.2%). Decreases in serum protein and albumin in postoperative 1 to 6 months and abdominal fat area in postoperative 1 year were significantly greater in LADG than in LAPPG. The 3-year cumulative incidence of gallstone was significantly higher in LADG than in LAPPG (6.5% vs 0.0%). CONCLUSIONS: For middle-third EGC, LAPPG can be considered as a better treatment option than LADG in terms of nutritional advantage and lower incidence of gallstone. PMID- 23652334 TI - Multiprofessional team simulation training, based on an obstetric model, can improve teamwork in other areas of health care. AB - This interrupted time-series study evaluated the impact of multiprofessional scenario-based training on the safety culture and teamwork climate of 3 surgical wards during a time of reduced financial resources. The authors ran 22 team training sessions for teams of 4 to 5 medical and nursing staff over a 4-month period on 3 surgical wards, using 2 scenarios based on a previously successful obstetric training program. Safety culture was measured before and after training using a validated psychometric questionnaire. After training there was a statistically significant improvement in safety culture (P = .036) on the wards. Teamwork climate improved, but the evidence was not as strong (P = .052). Perceptions of hospital management and adequacy of staffing levels showed significant deterioration. Simple, low-resource interventions can have a significant positive impact on safety culture and possibly teamwork climate on surgical wards. This could be of great value in maintaining patient safety at times of financial constraint. PMID- 23652335 TI - Board oversight of patient care quality in large nonprofit health systems. AB - In hospitals and health systems, ensuring that organizational standards for patient care quality are adopted and that processes for monitoring and improving clinical services are in place are among governing boards' most important duties. A recent study examined board oversight of patient care quality in 14 of the country's 15 largest private nonprofit health systems. The findings show that 13 of the 14 boards have standing committees with oversight responsibility for patient quality and safety within their system; 11 of the 14 system boards formally adopt systemwide quality measures and standards; and all 14 regularly receive written reports on systemwide and hospital performance. In recent months, most of these boards had adopted action plans directed at improving their system's performance with respect to patient care quality. PMID- 23652337 TI - Insight into the mechanism of carbon steel corrosion under aerobic and anaerobic conditions. AB - We particularly focused our study on identifying the corrosion products formed at 30 degrees C on carbon steel under aerobic and anaerobic conditions and on following their evolution with time due to enhanced microbial activity under environmental and geological conditions. The nature and structural properties of corrosion products were investigated by scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDS), X-ray diffraction (XRD) and confocal micro-Raman spectroscopy. Structural characterisation clearly showed the formation of iron oxides (magnetite and maghemite) under aerobic conditions. Under anaerobic conditions, the first corrosion product formed on the steel surface was nanocrystalline mackinawite, which was then followed by a fast transformation process into the pyrrhotite phase, and the Raman spectrum of monoclinic pyrrhotite was proposed for the first time. Finally, this study also shows that in the context of geological disposal of radioactive waste, the corrosion of carbon steel containers in anoxic and sulphidogenic environments sustained by sulphate-reducing bacteria may not be a problem notably due to the formation of a passive layer on the steel surface. PMID- 23652336 TI - Doing well by doing good: assessing the cost savings of an intervention to reduce central line-associated bloodstream infections in a Hawaii hospital. AB - A complete understanding of the financial impact of patient safety interventions must consider the economic incentives of both payers and providers within the current fee-for-service payment model. This study evaluated the impact of a central line-associated bloodstream infection (CLABSI) initiative on costs, reimbursements, and margins for 1 Hawaii hospital and its payers. Intensive care unit patients (January 2009-December 2011) who developed a CLABSI were compared to matched controls. Mean hospital cost, reimbursement, and margin was $222 692 versus $80 144 (P = .01), $259 433 versus $72 543 (P < .01), and $54 906 versus $6506 (P < .01), respectively. Although hospitals and payers reduce costs by preventing CLABSIs, hospitals also would decrease their margins, which creates a perverse incentive to have more line infections. An optimal reimbursement system must reward hospitals and payers for preventing harm rather than treating illness. This study highlights the critical role that health care payers have as patient safety advocates, financial sponsors, and facilitators. PMID- 23652338 TI - Comparative outcomes of open versus laparoscopic sacrocolpopexy among Medicare beneficiaries. AB - INTRODUCTION AND HYPOTHESIS: Since the first reported laparoscopic sacrocolpopexy in 1991, a limited number of single-center studies have attempted to assess the procedure's effectiveness and safety. Therefore, we analyzed a national Medicare database to compare real-world short-term outcomes of open and laparoscopically assisted (including robotic) sacrocolpopexy in a United States sample of patients. METHODS: Public Use File data for a 5% random national sample of all Medicare beneficiaries aged 65 and older were obtained from the Centers for Medicare and Medicaid Services for the years 2004-2008. Women with pelvic organ prolapse were identified using ICD-9 diagnosis codes. CPT-4 procedure codes were used to identify women who underwent open (code 57280) or laparoscopic (code 57425) sacrocolpopexy. Individual subjects were followed for 1 year post operatively. Outcomes measured, using ICD-9 and CPT-4 codes, included medical and surgical complications and re-operation rates. RESULTS: Seven hundred and ninety four women underwent open and 176 underwent laparoscopic (including robotic) sacrocolpopexy. Laparoscopic sacrocolpopexy was associated with a significantly increased rate of re-operation for anterior vaginal wall prolapse (3.4% vs 1.0%, p = 0.018). However, more medical (primarily cardiopulmonary) complications occurred post-operatively in the open group (31.5% vs 22.7%, p = 0.023). When sacrocolpopexy was performed with concomitant hysterectomy, mesh-related complications were significantly higher in the laparoscopic group (5.4% vs 0%, p = 0.026). CONCLUSION: Laparoscopic sacrocolpopexy resulted in an increased rate of reoperation for prolapse in the anterior compartment. When hysterectomy was performed at the time of sacrocolpopexy, the laparoscopic approach was associated with an increased risk of mesh-related complications. PMID- 23652340 TI - Red blood cells decorated with functionalized core-shell magnetic nanoparticles: elucidation of the adsorption mechanism. AB - The decoration of red blood cells (RBCs) with aminated and carboxylated core shell magnetic nanoparticles (CSMNs) was studied and elucidated. It was demonstrated that only aminated CSMNs could decorate the RBCs and their adsorption interaction is mainly ruled by electrostatic attraction between the positively charged amino groups on CSMNs and the abundant sialic acid groups on the outer surface of RBCs. PMID- 23652342 TI - Crystal structure diversity in the bis[hydrotris(3,5 dimethylpyrazolyl)borate]iodouranium(III) complex: from neutral to cationic forms. AB - The iodouranium(III) complex with two hydrotris(3,5-dimethylpyrazolyl)borate ligands is shown to adopt three closely related forms in the solid state. In addition to the previously reported structure for [U(Tp(Me2))2I], in which one of the pyrazolyl rings coordinates side-on to the U atom, another structure incorporating solvent molecules presents undistorted pyrazol rings, and a third one is the ionic compound [U(Tp(Me2))2]I. The implications of this structural diversity for the recently reported single ion magnet behaviour in this complex are discussed, namely on the basis of quantum chemistry calculations. The main effect of the bonding of the iodine atom to uranium is the increase of the size of the first coordination sphere and lowering of the symmetry of the molecule, resulting in a smaller crystal field splitting. PMID- 23652343 TI - Modeling of light scattering by biconcave and deformed red blood cells with the invariant imbedding T-matrix method. AB - The invariant imbedding T-matrix method (II-TM) is employed to simulate the optical properties of normal biconcave and deformed red blood cells (RBCs). The phase matrix elements of a RBC model computed with the II-TM are compared with their counterparts computed with the discrete-dipole approximation (DDA) method. As expected, the DDA results approach the II-TM results with an increase in the number of dipoles per incident wavelength. Computationally, the II-TM is faster than the DDA when multiple RBC orientations are considered. For a single orientation, the DDA is comparable with or even faster than the II-TM because the DDA efficiently converges for optically soft particles; however, the DDA method demands significantly more computer memory than the II-TM. After the applicability of the II-TM is numerically confirmed, a comparison is conducted of the optical properties of oxygenated and deoxygenated RBCs and of normal and deformed RBCs. The spectral variations of RBCs' optical properties are investigated in the wavelength range from 0.25 to 1.0 MUm. Furthermore, the statistically averaged phase matrix of spheres and biconcave RBCs are compared. Conducted numerical simulations suggest the applicability of the II-TM for the inverse light scattering analysis and radiative transfer simulations in blood. PMID- 23652344 TI - Modulation of photoacoustic signal generation from metallic surfaces. AB - The ability to image metallic implants is important for medical applications ranging from diagnosis to therapy. Photoacoustic (PA) imaging has been recently pursued as a means to localize metallic implants in soft tissue. The work presented herein investigates different mechanisms to modulate the PA signal generated by macroscopic metallic surfaces. Wires of five different metals are tested to simulate medical implants/tools, while surface roughness is altered or physical vapor deposition (PVD) coatings are added to change the wires' overall optical absorption. PA imaging data of the wires are acquired at 970 nm. Results indicate that PA signal generation predominately occurs in a wire's metallic surface and not its aqueous surroundings. PA signal generation is similar for all metals tested, while addition of PVD coatings offers significant modulations (i.e., 4-dB enhancement and 26-dB reduction achieved) in PA signal generation. Results also suggest that PA signal increases with increasing surface roughness. Different coating and roughness schemes are then successfully utilized to generate spatial PA signal patterns. This work demonstrates the potential of surface modifications to enhance or reduce PA signal generation to permit improved PA imaging of implants/tools (i.e., providing location/orientation information) or to allow PA imaging of surrounding tissue. PMID- 23652345 TI - Fast digital lock-in amplifier for dynamic spectrum extraction. AB - An appropriate method for spectrum extraction for better signal-to-noise ratio (SNR) and lower computational cost is essential in noninvasive detection. We have first studied two existing extraction methods for dynamic spectrum (DS) comparatively: frequency domain analysis and single trial estimation; after analyzing the advantages and disadvantages theoretically, a new method based on a fast digital lock-in amplifier (FDLIA) was developed to overcome the limitations of these two existing methods. The feasibility of the new method was verified by experiments and the results demonstrated that the FDLIA method based on DS had greatly simplified the computation of frequency domain analysis without the method error; moreover, the continuous signal was cut into several short segments in FDLIA and the gross errors from an episode of pulse wave were eliminated, and thus SNR improved. Therefore, the FDLIA method utilizing the advantages of both existing methods can be effectively realized in a general embedded system in real time for its simple algorithm. PMID- 23652346 TI - Inferring phylogeny and introgression using RADseq data: an example from flowering plants (Pedicularis: Orobanchaceae). AB - Phylogenetic relationships among recently diverged species are often difficult to resolve due to insufficient phylogenetic signal in available markers and/or conflict among gene trees. Here we explore the use of reduced-representation genome sequencing, specifically in the form of restriction-site associated DNA (RAD), for phylogenetic inference and the detection of ancestral hybridization in non-model organisms. As a case study, we investigate Pedicularis section Cyathophora, a systematically recalcitrant clade of flowering plants in the broomrape family (Orobanchaceae). Two methods of phylogenetic inference, maximum likelihood and Bayesian concordance, were applied to data sets that included as many as 40,000 RAD loci. Both methods yielded similar topologies that included two major clades: a "rex-thamnophila" clade, composed of two species and several subspecies with relatively low floral diversity, and geographically widespread distributions at lower elevations, and a "superba" clade, composed of three species characterized by relatively high floral diversity and isolated geographic distributions at higher elevations. Levels of molecular divergence between subspecies in the rex-thamnophila clade are similar to those between species in the superba clade. Using Patterson's D-statistic test, including a novel extension of the method that enables finer-grained resolution of introgression among multiple candidate taxa by removing the effect of their shared ancestry, we detect significant introgression among nearly all taxa in the rex-thamnophila clade, but not between clades or among taxa within the superba clade. These results suggest an important role for geographic isolation in the emergence of species barriers, by facilitating local adaptation and differentiation in the absence of homogenizing gene flow. PMID- 23652347 TI - A semantic model for species description applied to the ensign wasps (hymenoptera: evaniidae) of New Caledonia. AB - Taxonomic descriptions are unparalleled sources of knowledge of life's phenotypic diversity. As natural language prose, these data sets are largely refractory to computation and integration with other sources of phenotypic data. By formalizing taxonomic descriptions using ontology-based semantic representation, we aim to increase the reusability and computability of taxonomists' primary data. Here, we present a revision of the ensign wasp (Hymenoptera: Evaniidae) fauna of New Caledonia using this new model for species description. Descriptive matrices, specimen data, and taxonomic nomenclature are gathered in a unified Web-based application, mx, then exported as both traditional taxonomic treatments and semantic statements using the OWL Web Ontology Language. Character:character state combinations are then annotated following the entity-quality phenotype model, originally developed to represent mutant model organism phenotype data; concepts of anatomy are drawn from the Hymenoptera Anatomy Ontology and linked to phenotype descriptors from the Phenotypic Quality Ontology. The resulting set of semantic statements is provided in Resource Description Framework format. Applying the model to real data, that is, specimens, taxonomic names, diagnoses, descriptions, and redescriptions, provides us with a foundation to discuss limitations and potential benefits such as automated data integration and reasoner-driven queries. Four species of ensign wasp are now known to occur in New Caledonia: Szepligetella levipetiolata, Szepligetella deercreeki Deans and Miko sp. nov., Szepligetella irwini Deans and Miko sp. nov., and the nearly cosmopolitan Evania appendigaster. A fifth species, Szepligetella sericea, including Szepligetella impressa, syn. nov., has not yet been collected in New Caledonia but can be found on islands throughout the Pacific and so is included in the diagnostic key. PMID- 23652348 TI - The impact of neoadjuvant chemotherapy on the histopathological assessment of thymomas: a clinicopathological correlation of 28 cases treated with a similar regimen. AB - BACKGROUND: Twenty-eight patients treated with neoadjuvant chemotherapy for invasive thymoma are presented. METHODS: The patients were 16 men and 12 women between the ages of 23 and 75 years (mean = 50.8 years). All patients were treated with a similar modality consisting of three courses of cyclophosphamide, doxorubicin, cisplatin, and prednisone prior to their surgical resection. RESULTS: Grossly, all tumors were ill-defined invasive masses ranging in size from 5 to 18 cm in greatest dimension. Histological evaluation of the resected tumors showed a gamut of histological features, including necrosis, cystic changes, hemorrhage, histiocytic proliferation, calcifications, and cholesterol cleft granulomas in varying proportions. In addition, we found that some histological types of thymoma appeared to be affected less by neoadjuvant chemotherapy, while others, mainly those tumors with a more prominent lymphocytic component, showed more extensive histological changes. CONCLUSIONS: Based on the results of this study, it appears that the response to induction chemotherapy in thymomas may be determined by the histological characteristics of the tumor, with treatment-related changes being present predominantly in cases in which the tumor had a prominent lymphocytic component (WHO type B1 and B2), while tumor viability was highest in cases where the histological type corresponded to spindle cell and atypical thymomas (WHO types A and B3, respectively). In addition, it has to be noted that the histological changes attributed to treatment effect may also be seen in untreated tumors thereby not allowing for definitive separation of treated from nontreated thymomas. PMID- 23652349 TI - Interstitial lung disease in a child with antisynthetase syndrome. AB - INTRODUCTION: Antisynthetase Syndrome is associated with interstitial lung disease in adult patients, but this has not been described in children. MATERIALS AND METHODS: A 13-year-old with interstitial lung disease due to Antisynthetase Syndrome and pulmonary arterial hypertension underwent emergent bilateral lung transplantation after a rapid clinical decline. CONCLUSION: We present the clinical, radiographic, and histological findings of a child with interstitial lung disease due to Antisynthetase Syndrome. PMID- 23652351 TI - Overexpression of mitofusin 2 improves translocation of glucose transporter 4 in skeletal muscle of high-fat diet-fed rats through AMP-activated protein kinase signaling. AB - Mitofusin 2 (Mfn2) is a mitochondrial membrane protein that plays a role in mitochondrial fusion and metabolism in mammalian cells. Previous studies have reported a positive correlation between Mfn2 expression and insulin sensitivity in non-diabetic and type 2 diabetic subjects. Thus, the aim of the present study was to investigate whether Mfn2 overexpression improves insulin sensitivity of high-fat diet (HFD) rats and the possible underlying mechanisms. Male SD rats were randomly divided into four groups: negative control; HFD; HFD plus adenoviral vectors; and HFD plus adenoviral vectors encoding Mfn2. Following an 11-week treatment protocol, the euglycemic-hyperinsulinemic clamp technique was applied to evaluate insulin sensitivity in rats. The skeletal muscles from rats in each group were analyzed by real-time PCR and western blot analysis to determine glucose transporter 4 (GLUT4) expression, translocation and relative translocation signaling. Consistent with Mfn2 repression and glucose intolerance, HFD downregulates GLUT4 expression at the mRNA and protein levels, while Mfn2 overexpression activates AMP-activated protein kinase (AMPK), increases GLUT4 expression and translocation and improves insulin resistance in the skeletal muscles of HFD rats. Results of the present study indicate that Mfn2 overexpression improves insulin sensitivity and may regulate GLUT4 translocation in an AMPK-dependent manner in the skeletal muscles of HFD rats. This study is likely to provide insight into the unique role of Mfn2 in promoting glucose uptake, leading to modulation of GLUT4 translocation signaling and maintenance of glucose homeostasis in vivo. PMID- 23652350 TI - ACE2 activation confers endothelial protection and attenuates neointimal lesions in prevention of severe pulmonary arterial hypertension in rats. AB - BACKGROUND: Angiotensin-converting enzyme 2 (ACE2), an ACE homolog, hydrolyzes angiotensin II and opposes its actions, and plays a protective role in the pathogenesis of pulmonary arterial hypertension (PAH). However, the underlying mechanisms involved in the effect of ACE2 on PAH are still uncertain. In this study, we observed the effects of ACE2 activation on endothelial dysfunction and vascular remodeling in the development of severe PAH in rats. METHODS: Severe PAH was induced by monocrotaline injection 1 week following left pneumonectomy, and ACE2 was activated by continuous injection of resorcinolnaphthalein. The PAH related hemodynamics, pathological changes, and endothelium-dependent vasorelaxation were examined to assess the effects of ACE2 activation. In addition, the changes of the main components of the renin-angiotensin system were identified by ELISA or Western blotting. RESULTS: Severe PAH was established at 3 weeks and was characterized by high pulmonary arterial pressure (45 mmHg), significant right ventricular hypertrophy, neointimal occlusive lesions, and impaired endothelium-dependent relaxation in pulmonary arteries. Coadministration of resorcinolnaphthalein reduced pulmonary arterial pressure, right ventricular hypertrophy, and neointimal formation and shifted the endothelial-dependent responses toward values measured in normal rats. Theses changes were associated with an increase in ACE2 and angiotensin-(1-7) levels and a decrease in ACE and angiotensin II levels, in addition to a decrease in the ACE/ACE2 ratio and the angiotensin II/angiotensin-(1-7) ratio. The beneficial effects of resorcinolnaphthalein were abolished by A-779. CONCLUSIONS: These findings suggested that ACE2 activation by resorcinolnaphthalein improved endothelial function and suppressed neointimal formation in the prevention of severe PAH by the mechanism of mediating the levels of the components of the renin-angiotensin system. PMID- 23652352 TI - Development of JAK2V617F-positive polycythemia vera after chemotherapy-induced remission of primary central nervous system diffuse large B cell non-Hodgkin's lymphoma: a case report and review of the literature. AB - The coexistence or the development of Philadelphia chromosome-negative myeloproliferative neoplasms after a lymphoproliferative disease in the same patient is an extremely rare event. We report the case of a 72-year-old man who developed JAK2V617F polycythemia vera 3 years after the diagnosis and treatment of primary diffuse large B cell non-Hodgkin's lymphoma of the central nervous system. We also review the literature regarding the pathogenesis underlying the association of myeloproliferative and lymphoproliferative chronic disorders. PMID- 23652353 TI - The DSM-5 personality disorder proposal and future directions in the diagnostic classification of personality disorder. AB - BACKGROUND: The compilation of DSM-5 presented a substantial opportunity to develop a coherent, evidence-based classification of personality disorder. The irremediable problems with DSM-IV are widely recognized, the field seemed ready for change, and the data and methods for constructing a scientific classification are readily available. Rather than seize this opportunity, DSM-5 advanced an incoherent proposal lacking in evidential support and too poorly organized for clinical use. METHODS: This article examines the problems with the proposal based on a consideration of the basic requirements of a satisfactory classification. It is suggested that an adequate system should have an explicit and coherent conceptual structure, be based on the best available scientific evidence, possess clinical utility, and be as parsimonious as possible. RESULTS: The DSM-5 proposal fails to meet these criteria. Problems with the product and process suggest the need for a radical reconsideration of how personality disorders are classified and how classifications are compiled. CONCLUSIONS: The article proposes that greater emphasis be placed on developing a classification that provides the diagnostic information clinicians need to treat personality disorder and that future classifications should be constructed through an explicit process that is open to public scrutiny. PMID- 23652355 TI - Trauma in Canada: a spirit of equity & collaboration. AB - BACKGROUND: The delivery of equitable trauma care in Canada is not without challenges within our universal health care system. Notably, the tyranny of geography is intermittently at odds with adequate access for our rural, indigenous, and impoverished populations. Other differences exist when compared with neighbouring trauma systems, for example in the United States. METHODS: As a critical review, we chose to compare and critique the overall system of trauma organization and perceived societal expectations of a high-income, North American country (Canada) to assist with discussions on trauma systems for the future. RESULTS: Tele-technology is providing some early solutions. Trauma systems and delivery of care in Canada differ from the United States due to our single-payer system, regionalization and universal provision. Care for injured Canadians has a long history of being multidisciplinary, with collaborative research programs. Canada also has a history of global surgical endeavours, beginning with Dr. Norman Bethune and his recognition of the political causes of trauma and continuing as a global public health concern for all. CONCLUSIONS: While challenges continue to exist for the provision of equitable trauma care in Canada, unique multidisciplinary, collaborative and technology-based solutions continue to be developed, both locally and globally, to address this critical public health issue. PMID- 23652356 TI - HIV testing and epidemiology in a hospital-based surgical cohort in Malawi. AB - BACKGROUND: Despite the high prevalence of HIV in adults (11 %) in Malawi, testing among surgical patients is not routine. We examined the feasibility of universal opt-out HIV testing and counseling (HTC) on the surgical wards of Kamuzu Central Hospital in Lilongwe, Malawi, and sought to further delineate the role of HIV in surgical presentation and outcome. METHODS: We reviewed HTC and surgical admission records from May to October 2011 and compared these data to data collected prospectively on patients admitted from November 2011 through April 2012, after universal HTC implementation. RESULTS: Prior to universal HTC, 270 of the 2,606 (10.4 %) surgical admissions were tested; 13 % were HIV infected. After universal HTC implementation, HTC counselors reviewed 1,961 of the 2,488 admissions (79 %): 310 (16 %) had known status (157 seropositive, 153 seronegative) and 1,651 had unknown status (81 %). Among those with unknown status, 97 % (1,598, of 64 % of all admissions) accepted testing, of whom 9 % were found to be HIV-infected. Patients with longer lengths of stay (LOS) (mean = 11 vs. 5 days, p < 0.01) and those who underwent surgical intervention (odds ratio [OR] 2.5; confidence interval [CI] 2.0-3.1) were more likely to have a known status on discharge. HIV was more prevalence in patients with infection and genital/anal warts or ulcers and lower in trauma patients. HIV-positive patients received less surgical intervention (OR 0.69; CI 0.52-0.90), but there was no association between HIV status and length of stay or mortality. CONCLUSIONS: Universal opt-out HTC on the surgical wards was well accepted and increased the proportion of patients tested. High HIV prevalence in this setting merits implementation of universal HTC. PMID- 23652354 TI - Extended lymphadenectomy in colon cancer is debatable. AB - Extended lymphadenectomy has gained considerable attention as an adjunct to conventional colon cancer surgery with the hope that it may potentially decrease local recurrence rates and improve cancer-specific outcome measures. Despite the enthusiasm surrounding these techniques, it is difficult to establish any additional survival benefit associated with more comprehensive lymphadenectomy strategies when these are performed in addition to conventional colon cancer surgery. Furthermore, these techniques remain unproven by large randomized clinical trials. The appropriate indications for performing extended lymphadenectomy also remain unclear, and there is a lack of standardization with regard to surgical technique. Moreover, there are a number of confounding factors that frequently receive little attention when oncological outcome measures are reported following extended lymphadenectomy in the setting of colon cancer. The purpose of this review is to outline these confounding issues and discuss their impact on reports describing cancer-specific outcome measures following the use of extended lymphadenectomy techniques. Furthermore, this review proposes that in light of the available published evidence, the role of radical lymphadenectomy is currently unproven, with large randomized clinical trials required in the future to determine whether there is a survival benefit for colon cancer patients. PMID- 23652358 TI - Hot off the press. AB - A personal selection of 33 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as asperterpenoid A, a metabolite of an endophytic Aspergillus species. PMID- 23652357 TI - Effects of enamel matrix proteins in combination with a bovine-derived natural bone mineral for the repair of bone defects. AB - OBJECTIVES: Previously, the use of enamel matrix derivative (EMD) in combination with a natural bone mineral (NBM) was able to stimulate periodontal ligament cell and osteoblast proliferation and differentiation. Despite widespread use of EMD for periodontal applications, the effects of EMD on bone regeneration are not well understood. The aim of the present study was to test the ability of EMD on bone regeneration in a rat femur defect model in combination with NBM. MATERIALS AND METHODS: Twenty-seven rats were treated with either NBM or NBM + EMD and assigned to histological analysis at 2, 4, and 8 weeks. Defect morphology and mineralized bone were assessed by MUCT. For descriptive histology, hematoxylin and eosin staining and Safranin O staining were performed. RESULTS: Significantly more newly formed trabecular bone was observed at 4 weeks around the NBM particles precoated with EMD when compared with NBM particles alone. The drilled control group, in contrast, achieved minimal bone regeneration at all three time points (P < 0.05). CONCLUSIONS: The present results may suggest that EMD has the ability to enhance the speed of new bone formation when combined with NBM particles in rat osseous defects. CLINICAL RELEVANCE: These findings may provide additional clinical support for the combination of EMD with bone graft for the repair of osseous and periodontal intrabony defects. PMID- 23652359 TI - Stereochemical effects on the aggregation and biological properties of the fibril forming peptide [KIGAKI]3 in membranes. AB - Single D-amino acid substitutions can be used to suppress or slow down the aggregation of peptides into beta-sheeted assemblies compared to the respective L amino acids. Here, we investigate the influence of local stereochemistry in the model peptide [KIGAKI]3-NH2, which is known to form amyloid-like fibrils. To find out whether aggregation plays a role in various biologically relevant functions that involve peptide-lipid interactions, we studied the antimicrobial, hemolytic and fusogenic activities of this amphiphilic membrane-active molecule. The stiff and sterically constrained amino acid CF3-Bpg [3-(trifluoromethyl)-bicyclopent [1,1,1]-1-ylglycine] was incorporated either as an L- or a D-enantiomer at different hydrophobic positions of the KIGAKI sequence. D-Epimers have a higher aggregation threshold than the L-epimers, yet the aggregation of both was confirmed using electron microscopy and circular dichroism. Solid-state (19)F-NMR analysis showed that the peptide aggregated in native membranes from human erythrocytes and bacterial protoplasts in the same way as in synthetic lipid bilayers. We then monitored the effect of the single L- or D-CF3-Bpg substitutions in KIGAKI on its distinct biological activities, which have to be measured at low peptide concentrations where the aggregation threshold cannot be directly assessed. These functional assays showed that the aggregation propensity of KIGAKI does not play a role in its antimicrobial action, but an increased tendency to aggregate promotes other undesirable effects such as hemolysis and membrane fusion. These results confirm the membranolytic and thereby toxic nature of amyloidogenic peptides, and emphasize the unpredictable role of peptide aggregation in the different assays used to study biological activities. PMID- 23652360 TI - Impaired lipopolysaccharide responsiveness of cord blood mononuclear cells and the risk of asthma: a longitudinal study. AB - BACKGROUND: We previously demonstrated that the proliferative response to lipopolysaccharide (LPS) in cord blood mononuclear cells (CBMCs) is negatively correlated with the induced expression of interleukin (IL)-4. Our aim, therefore, was to examine whether an impaired cellular response to LPS in infancy is associated with the risk for asthma. METHODS: In a prospective cohort study, the relationship between the CBMC response to LPS and the risk of atopy and wheezing after the age of 4 y was evaluated. RESULTS: LPS-induced CBMC proliferative responses varied markedly among the 102 infants studied (range, one- to fivefold increase over cells with diluent alone). Ninety-five infants (93%) were followed longitudinally. A higher CBMC proliferative response to LPS was noted in offspring born to nonatopic parents compared with those with at least one atopic parent (P = 0.008). Using a proliferative index cutoff of 2 separated patients into high and low induced IL-4 mRNA responders (P = 0.001). Significantly more children who never wheezed had a greater than twofold LPS-induced CBMC proliferative response compared to those with persistent atopic wheezing (P = 0.046). CONCLUSION: These results demonstrate that CBMC proliferative responses to LPS is impaired in infants born to atopic parents and may be a risk factor for asthma later in life. PMID- 23652361 TI - Association between neuropeptide Y gene polymorphisms and alcohol dependence: a case-control study in two independent populations. AB - BACKGROUND: Alcohol dependence is a chronic, progressive neurobiological brain disorder. Previous research reported an inverse association between ethanol drinking and cerebral neuropeptide Y (NPY) levels. There are conflicting results of studies on NPY gene polymorphisms in association with alcohol dependence in humans. METHODS: To assess the role of the NPY gene in alcohol dependence, we genotyped three polymorphisms--in a sample of 195 subjects from the Kota population (80 alcohol dependence and 115 controls) and 141 subjects from the Badaga population (80 alcohol dependence and 61 controls). Phenotype was defined based on the DSM-IV criteria. Genotyping was performed using sequencing. Association of the NPY gene with alcohol dependence was tested by using logistic regression and haplotype analyses and linkage disequilibrium. RESULTS: All three polymorphisms were found to be in the Hardy-Weinberg equilibrium in both populations. The results of our study reveal a significant association between G1258A and alcohol dependence in both the Kota and Badaga populations. The linkage disequilibrium between the markers is not strong or significant. Haplotype analysis also did not show significant association between the NPY gene and alcohol dependence. CONCLUSION: These data support the hypothesis that alcohol dependence is influenced by the NPY G1258A polymorphism in Indian populations. PMID- 23652362 TI - Impact of access to hospitals with catheterization facilities in the second Gulf Registry of Acute Coronary Events (Gulf RACE-2). AB - OBJECTIVES: It is currently unclear whether acute coronary syndrome patients who access hospitals with catheterization facilities, with or without an on-site percutaneous coronary intervention (PCI), have better outcomes in real-life clinical practice. METHODS AND RESULTS: This 9-month prospective study was carried out in six Arabian Gulf countries. Patients in hospitals with catheterization facilities [20/65 hospitals; 3615/6847 (52.8%) patients] were more likely to show evidence of cardiovascular risk factors (P<0.001) and more likely to undergo revascularization procedures that were mostly performed (>=80%) in low-risk and intermediate-risk patients. Patients in these centres experienced significantly higher rates of medical therapies and shorter door-to-needle times [median (IQR): 33 (40) vs. 43.5 (43) min, P<0.001]; 14.1% had primary PCI. They also had less in-hospital recurrent ischaemia, recurrent myocardial infarction, congestive heart failure and stroke, but more cardiogenic shock and major bleeding, and they had similar adjusted mortality rates in-hospital [odds ratio (OR): 1.06, 95% confidence interval (CI): 0.88-1.27] and at 30-day (OR: 1.11, 95% CI: 0.91-1.36) and 1-year (OR: 1.06, 95% CI: 0.89-1.27) follow-ups. CONCLUSION: Access to hospitals with catheterization facilities, with or without on-site PCI, was associated with a reduction in recurrent myocardial infarction and recurrent ischaemia, but not mortality. Further efforts are required to target revascularization procedures for higher risk patients as well as to widely implement primary PCI programmes. PMID- 23652363 TI - A Pro 12 Ala substitution in the PPARgamma2 polymorphism may decrease the number of diseased vessels and the severity of angiographic coronary artery. AB - AIMS: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated transcription factor that regulates the gene expression of the key proteins involved in lipid metabolism, vascular inflammation, and proliferation. PPARgamma may contribute toward attenuation of atherogenesis. We investigated the relationship of the Pro 12 Ala PPARgamma2 polymorphism with the presence and severity of coronary artery disease (CAD) assessed by Gensini score (Gs). MATERIALS AND METHODS: A total of 239 patients and 244 control individuals were investigated for clinical, biochemical, anthropometric, and angiographic information. Standard definitions were used to diagnose patients with acute coronary syndrome. The Gs system was used to calculate the severity of CAD. The computer model Homeostatic Model Assessment (HOMA) 2 was used to determine beta cell function (HOMA-beta), insulin sensitivity (HOMA-S), and insulin resistance (HOMA-IR). PCR-RFLP was performed for DNA genotyping for Pro 12 Ala in the PPARgamma2 polymorphism. RESULTS: Allele frequencies were 0.842 for the Pro allele and 0.158 for the Ala allele. The diseased vessel number was lower in patients with the Ala allele than others. The Gs tended to be lower in patients with the Ala allele than in others [10 (8-16) vs. 24 (16-32), P<0.001]. Patients with Pro/Pro had a significantly higher glycemia, insulinemia, and HOMA-IR, and reduced HOMA-beta and HOMA-S than Pro/Ala and Ala/Ala individuals. CONCLUSION: The Ala 12 Ala genotype of the PPARgamma2 gene may decrease the number of diseased vessels and the severity of CAD, which could be because of a direct antiatherogenic effect of this polymorphism as well as an indirect effect through its association with a lower level of inflammatory parameters and insulin resistance. PMID- 23652364 TI - Sphingomyelin in erythrocyte membranes increases the total cholesterol content of erythrocyte membranes in patients with acute coronary syndrome. AB - OBJECTIVES: To investigate whether the sphingomyelin content of erythrocyte membranes (SEM) is changed in patients with acute coronary syndrome (ACS) and determine the correlation between SEM and the total cholesterol content of erythrocyte membranes (CEM). METHODS: The SEM and CEM levels were measured in 354 patients undergoing coronary artery angiography in three different groups: ACS patients (n=199), patients with stable angina pectoris (SAP) (n=82), and controls (n=73). RESULTS: The SEM levels in the ACS group were significantly higher than those of the SAP group. The SEM levels were correlated positively with the CEM levels in patients with coronary artery disease. Multivariable logistic regression analysis showed that patients with higher levels of both SEM and CEM had an 8.569-fold greater risk of developing ACS than other patients, after adjusting for all potential confounding variables. CONCLUSION: Elevated SEM and CEM levels showed both independent and combined correlations with the occurrence of ACS and were positively correlated with each other in patients with coronary artery disease. These data suggest that the increased levels of SEM may play a role in the progression to plaque instability in ACS and may be the mechanisms underlying elevated levels of CEM in patients with ACS. PMID- 23652365 TI - Efficacy and safety of transcatheter coil embolization in congenital coronary artery fistulas guided by preinterventional cardiac computed tomography. AB - OBJECTIVE: Transcatheter coil embolization of coronary artery fistulas (CAFs) has emerged as an alternative to surgical closure despite limited data in the current literature. The aim of this study was to show the efficacy of CAF closure and the benefit of the combined preinterventional use of cardiac computed tomography and coronary angiography to evaluate the feasibility and enhance the safety of this procedure by obtaining precise information about the CAF anatomy. PATIENTS AND METHODS: Five consecutive patients (three men, two women, age 51-68 years) with symptomatic angiographically proven CAFs were screened for transcatheter treatment and underwent preinterventional cardiac multidetector computed tomography (MDCT). RESULTS: On the basis of CAF-associated clinical symptoms, exercise-induced ischemia, coronary angiography, and cardiac MDCT, four of five patients with a CAF draining into the pulmonary artery system were considered eligible for transcatheter coil embolization, whereas in MDCT the fifth patient had multiple draining sites of the CAF and a relevant drainage into the right ventricular myocardium and was thus excluded from the procedure. Coil embolization was successfully performed in the remaining four cases without any complications. There was no residual flow through the CAF after the procedure. Clinical symptoms resolved almost completely in all four patients during a median 15.6-month follow-up. CONCLUSION: Transcatheter coil embolization is a feasible and effective method for the treatment of symptomatic CAFs in selected cases. The adjunctive preinterventional use of cardiac MDCT with conventional angiography can identify vessels that are anatomically applicable for transcatheter closure, defer therapy in morphologically unsuitable complex cases, and thus optimize the safety of the procedure. PMID- 23652366 TI - Lipoprotein(a) is an important factor to determine coronary artery plaque morphology in patients with acute myocardial infarction. AB - BACKGROUND: Lipoprotein(a) [Lp(a)] can influence the development and disruption of atherosclerotic plaques through its effect on lipid accumulation. The purpose of this study was to evaluate the relationship between serum Lp(a) levels and plaque morphology of an infarct-related lesion and non-infarct-related lesion of the coronary artery in acute myocardial infarction (AMI). METHODS AND RESULTS: Coronary plaque morphology was evaluated in 68 patients (age 62.1+/-12.1 years, mean+/-SD; men n=58, women n=10) with AMI by intravascular ultrasound with radiofrequency data analysis before coronary intervention and by 64-slice computed tomography angiography within 2 weeks. Patients were divided into a group with an Lp(a) level of 25 mg/dl or more (n=20) and a group with an Lp(a) level of less than 25 mg/dl (n=48). Intravascular ultrasound with radiofrequency data analysis identified four types of plaque components at the infarct-related lesion: fibrous, fibrofatty, dense calcium, and necrotic core. The necrotic core component was significantly larger in the group with an Lp(a) level of 25 mg/dl or more than in the group with an Lp(a) level of less than 25 mg/dl (27.6+/-8.0 vs. 15.7+/-10.0%, P=0.0001). Coronary plaques were classified as calcified plaques, noncalcified plaques, mixed plaques, and low-attenuation plaques on 64 slice computed tomography angiography. Computed tomography indicated that the group with an Lp(a) level of 25 mg/dl or more had a greater number of total plaques, noncalcified plaques, and low-attenuation plaques in whole coronary arteries than did the group with an Lp(a) level of less than 25 mg/dl (5.3+/-1.8 vs. 3.7+/-2.2, P=0.0061; 4.0+/-2.0 vs. 1.2+/-1.3, P=0.0001; 2.2+/-2.1 vs. 0.5+/ 0.7, P=0.0001, respectively). CONCLUSION: Elevated serum Lp(a) levels are associated with the number of plaques and plaque morphology. Patients with a high Lp(a) level during AMI require more intensive treatment for plaque stabilization. PMID- 23652367 TI - Long-term efficacy of stereotactic bilateral anterior cingulotomy and bilateral anterior capsulotomy as a treatment for refractory obsessive-compulsive disorder. AB - OBJECTIVE: To investigate the long-term efficacy and adverse effects of stereotactic bilateral anterior cingulotomy (BACI) and bilateral anterior capsulotomy (BACA) as a treatment for refractory obsessive-compulsive disorder (OCD) patients. METHODS: Seven patients suffering from refractory OCD underwent stereotactic surgery and were followed for 12 months. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to assess the efficacy. The test was taken before and 6 and 12 months after surgery. RESULTS: The mean Y-BOCS scores decreased significantly from 32.9 +/- 4.7 at baseline to 20.6 +/- 5.3 after 12 months. Five out of the 7 patients showed a decrease of more than 35%. During the 12-month follow-up, the effective rate had increased from 28.6 to 71.4%. There were no significant adverse effects observed after surgery. CONCLUSIONS: The BACI and BACA were effective for the treatment of refractory OCD, and no significant adverse effects on long-term follow-up were found. PMID- 23652368 TI - A microporous metal-organic framework with both open metal and Lewis basic pyridyl sites for high C2H2 and CH4 storage at room temperature. AB - A new microporous metal-organic framework, Cu2(PDDI) (ZJU-5; H4PDDI = 5,5' (pyridine-2,5-diyl)diisophthalic acid), was solvothermally synthesized and structurally characterized. With open metal sites, Lewis basic pyridyl sites and suitable pore space, the acetylene uptake in ZJU-5a reaches the highest value of 290 cm(3) g(-1) at 273 K and 1 bar. Furthermore, ZJU-5a exhibits high absolute methane storage of 190 cm(3) (STP) cm(-3) at 35 bar and 224 cm(3) (STP) cm(-3) at 60 bar at room temperature. PMID- 23652371 TI - The 786-0 renal cancer cell-derived exosomes promote angiogenesis by downregulating the expression of hepatocyte cell adhesion molecule. AB - The aims of the current study were to determine whether 786-0 renal cancer cell derived exosomes promote human umbilical vein endothelial cells (HUVECs) to form tubular structures and to uncover the underlying mechanisms associated with this process. Exosomes were extracted and purified using ultrafiltration and sucrose gradient centrifugation and characterized by transmission electron microscopy. Tubular structure formation was observed using the matrigel tubular assay. In addition, an adenovirus vector was used to transfect the hepatocyte cell adhesion molecule (hepaCAM) gene into renal cancer 786-0 cells. The expression of hepaCAM and vascular endothelial growth factor (VEGF) mRNA and protein was determined by reverse transcription-polymerase chain reaction and western blot analysis, respectively. Tumor cell-derived exosomes were observed to significantly increase tubular formation in HUVECs. Following transfection with the hepaCAM gene, VEGF expression in 786-0 cells was markedly decreased. In HUVECs, exosome treatment increased VEGF mRNA and protein expression, while hepaCAM expression was only decreased at the protein level. In the present study, renal cancer 786-0 cell derived exosomes significantly promoted angiogenesis via upregulation of VEGF expression in HUVECs, which may be induced by the downregulation of hepaCAM. PMID- 23652373 TI - The effects of aerobic exercise on estrogen metabolism in healthy premenopausal women. AB - BACKGROUND: It is well accepted that exercise can decrease breast cancer risk. Limited clinical evidence suggests that this risk could be mediated through changes in estrogen metabolism in premenopausal women. Our objective was to investigate the effects of exercise on premenopausal estrogen metabolism pertinent to breast cancer risk. METHODS: Sedentary, healthy, young eumenorrheic women were randomized into an intervention of 30 minutes of moderate-to-vigorous aerobic exercise five times a week for approximately 16 weeks (n = 212), or into a usual-lifestyle sedentary control group (n = 179). Urinary levels of estrogens [estrone [E1], estradiol, and estriol] and nine estrogen metabolites were measured at baseline and at study end by liquid chromatography/tandem mass spectrometry. The ratios of 2-hydroxyestrone to 16alpha-hydroxyestrone (2 OHE1/16alpha-OHE1) and 2-OHE1 to 4-hydroxyestrone (2- OHE1/4-OHE1) were also calculated. RESULTS: The exercise intervention resulted in significant increases in aerobic fitness and lean body mass and a significant decrease in percent body fat. For exercisers who completed the study (n = 165), 2-OHE1/16alpha-OHE1 increased significantly (P = 0.043), whereas E1 decreased significantly (P = 0.030) in control participants (n = 153). The change from baseline in 2 OHE1/16alpha-OHE1 was significantly different between groups (P = 0.045), even after adjustment for baseline values. CONCLUSIONS: The exercise intervention resulted in a significant increase in the 2-OHE1/16alpha-OHE1 ratio but no differences in other estrogen metabolites or ratios. IMPACT: Our results suggest that changes in premenopausal estrogen metabolism may be a mechanism by which increased physical activity lowers breast cancer risk. PMID- 23652374 TI - Sleep disruption among older men and risk of prostate cancer. AB - BACKGROUND: Although positive associations have consistently been reported between sleep disruption and breast cancer, less is known about its potential role in prostate cancer. METHODS: Within the prospective AGES-Reykjavik cohort study, we followed 2,102 men recruited in 2002-2006 until the end of 2009. Participants answered questions on sleep disruption. Information on the occurrence of prostate cancer was obtained through record linkages across the Icelandic Cancer Registry. We used Cox regression models with 95% confidence intervals (CI) to estimate HRs of prostate cancer by symptoms of sleep disruption. RESULTS: During follow-up, 135 men (6.4%) were diagnosed with prostate cancer. Compared with men without sleep disruption, those with problems falling and staying asleep were at significantly increased risk of prostate cancer [HR, 1.7 (95% CI, 1.0-2.9) and 2.1 (95% CI, 1.2-3.7)], respectively, with increasing sleep disruption severity. When restricted to advanced prostate cancer (>= stage T3 or lethal disease), these associations became even stronger [HR 2.1 (95% CI, 0.7-6.2) and 3.2 (95% CI, 1.1-9.7)]. The results did not change after excluding from the analyses men who woke up during the night, indicative of nocturia, suggesting limited risk of reverse association. CONCLUSIONS: Our data suggest that certain aspects of sleep disruption may confer an increased risk of prostate cancer and call for additional, larger studies with longer follow-up times. IMPACT: Prostate cancer is one of the leading public health concerns in men; if confirmed in future studies, the association between sleep disruption and prostate cancer risk may open new avenues for prevention. PMID- 23652375 TI - CHEK2*1100delC homozygosity in the Netherlands--prevalence and risk of breast and lung cancer. AB - The 1100delC mutation in the CHEK2 gene has a carrier frequency of up to 1.5% in individuals from North-West Europe. Women heterozygous for 1100delC have an increased breast cancer risk (odds ratio 2.7). To explore the prevalence and clinical consequences of 1100delC homozygosity in the Netherlands, we genotyped a sporadic breast cancer hospital-based cohort, a group of non-BRCA1/2 breast cancer families, and breast tumors from a tumor tissue bank. Three 1100delC homozygous patients were found in the cohort of 1434 sporadic breast cancer patients, suggesting an increased breast cancer risk for 1100delC homozygotes (odds ratio 3.4, 95% confidence interval 0.4-32.6, P=0.3). Another 1100delC homozygote was found in 592 individuals from 108 non-BRCA1/2 breast cancer families, and two more were found after testing 1706 breast tumors and confirming homozygosity on their wild-type DNA. Follow-up data was available for five homozygous patients, and remarkably, three of them had developed contralateral breast cancer. A possible relationship between 1100delC and lung cancer risk was investigated in 457 unrelated lung cancer patients but could not be confirmed. Due to the small number of 1100delC homozygotes identified, the breast cancer risk estimate associated with this genotype had limited accuracy but is probably higher than the risk in heterozygous females. Screening for CHEK2 1100delC could be beneficial in countries with a relatively high allele frequency. PMID- 23652376 TI - A novel ALMS1 splice mutation in a non-obese juvenile-onset insulin-dependent syndromic diabetic patient. AB - Insulin-dependent juvenile-onset diabetes may occur in the context of rare syndromic presentations suggesting monogenic inheritance rather than common multifactorial autoimmune type 1 diabetes. Here, we report the case of a Lebanese patient diagnosed with juvenile-onset insulin-dependent diabetes presenting ketoacidosis, early-onset retinopathy with optic atrophy, hearing loss, diabetes insipidus, epilepsy, and normal weight and stature, who later developed insulin resistance. Despite similarities with Wolfram syndrome, we excluded the WFS1 gene as responsible for this disease. Using combined linkage and candidate gene study, we selected ALMS1, responsible for Alstrom syndrome, as a candidate gene. We identified a novel splice mutation in intron 18 located 3 bp before the intron exon junction (IVS18-3T>G), resulting in exon 19 skipping and consequent frameshift generating a truncated protein (V3958fs3964X). The clinical presentation of the patient significantly differed from typical Alstrom syndrome by the absence of truncal obesity and short stature, and by the presence of ketoacidotic insulin-dependent diabetes, optic atrophy and diabetes insipidus. Our observation broadens the clinical spectrum of Alstrom syndrome and suggests that ALMS1 mutations may be considered in patients who initially present with an acute onset of insulin-dependent diabetes. PMID- 23652377 TI - Human X-chromosome inactivation pattern distributions fit a model of genetically influenced choice better than models of completely random choice. AB - In eutherian mammals, one X-chromosome in every XX somatic cell is transcriptionally silenced through the process of X-chromosome inactivation (XCI). Females are thus functional mosaics, where some cells express genes from the paternal X, and the others from the maternal X. The relative abundance of the two cell populations (X-inactivation pattern, XIP) can have significant medical implications for some females. In mice, the 'choice' of which X to inactivate, maternal or paternal, in each cell of the early embryo is genetically influenced. In humans, the timing of XCI choice and whether choice occurs completely randomly or under a genetic influence is debated. Here, we explore these questions by analysing the distribution of XIPs in large populations of normal females. Models were generated to predict XIP distributions resulting from completely random or genetically influenced choice. Each model describes the discrete primary distribution at the onset of XCI, and the continuous secondary distribution accounting for changes to the XIP as a result of development and ageing. Statistical methods are used to compare models with empirical data from Danish and Utah populations. A rigorous data treatment strategy maximises information content and allows for unbiased use of unphased XIP data. The Anderson-Darling goodness-of-fit statistics and likelihood ratio tests indicate that a model of genetically influenced XCI choice better fits the empirical data than models of completely random choice. PMID- 23652378 TI - A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document. AB - The European Union (EU) Council Recommendation on rare diseases urged the member states to implement national and EU collaborative actions to improve the health care of rare disease patients. Following this recommendation, the European Commission launched a tender on newborn screening (NBS) to report on current practices of laboratory testing, form a network of experts and provide guidance on how to further implement NBS screening in a responsible way, the latter of which was provided in an Expert Opinion document. After consultation of experts from EU member states, (potential) candidate member states and European Free Trade Association countries, in a consensus meeting in June 2011, 70 expert opinions were finalized. They included the need to develop case definitions for all disorders screened for to facilitate assessment and international outcome studies. Decision whether a screening program should be performed can be based on screening criteria updated from the traditional Wilson and Jungner (1968) criteria, relating to disease, treatment, test and cost. The interest of the child should be central in the assessment of pros and cons. A European NBS body should assess evidence on (new) screening candidate disorders. For rare conditions, best level evidence should be used. The health system should ensure treatment to cases diagnosed by screening, controlled and revised by follow-up outcome studies. Screening methodology should aim to avoid unintended findings, such as mild forms and carrier status information, as much as possible. Activities to improve NBS in Europe, such as training and scientific evaluation, could benefit from collaboration at EU level and beyond. PMID- 23652379 TI - Clinical utility gene card for: Johanson-Blizzard syndrome. PMID- 23652380 TI - First-line treatment patterns and clinical outcomes in patients with HER2 positive and hormone receptor-positive metastatic breast cancer from registHER. AB - BACKGROUND: Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting. METHODS: registHER is a prospective, observational cohort of 1,023 patients with HER2 positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2 positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors. RESULTS: HER2-positive, HR-positive patients receiving first-line trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22-0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27 1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42-0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36-0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54-1.21; adjusted OS HR: 0.48, 95% CI: 0.26-0.89). CONCLUSIONS: These real-world data in patients with HER2-positive/HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting of HRs and HER2 receptors is associated with significantly prolonged PFS and OS times. PMID- 23652381 TI - A qualitative seminested PCR assay as an alternative to urine cytology for BK polyomavirus screening after renal transplantation. AB - OBJECTIVE: Polyomavirus-associated nephropathy (PVAN) is a major cause of graft dysfunction after kidney transplantation. Therefore, routine screening for BK polyomavirus (BKV) infection with urine cytology or quantitative PCR-based assays has been recommended. Although less expensive than quantitative tests, qualitative PCR assays are not recommended for screening based on the assumption that their diagnostic accuracy is inferior to urine cytology. However, studies comparing the performance of both methods are scarce. METHODS: We compared the accuracy between a qualitative seminested PCR (snPCR) assay and urine cytology for the screening of BKV viruria in 104 renal transplant recipients. RESULTS: The snPCR assay was more sensitive than cytology (100 and 61%, respectively), yielding better negative predictive value (100 vs. 90%). In 7 (39%) of the 18 PVAN cases, BKV infection was detected exclusively by snPCR. Although the specificity of snPCR (63%) was lower than cytology (74%), their positive predictive values were similar (36 vs. 33%, respectively). In ROC curve analysis, the accuracy of snPCR was significantly higher (p = 0.03). CONCLUSION: This qualitative snPCR assay was more accurate than urine cytology for the detection of BKV viruria in renal transplant patients. PMID- 23652382 TI - Boron azides in Staudinger oxidations and cycloadditions. AB - Staudinger reactions of Cy2BN3 with tri-substituted phosphines (R3P) yielded the boron-nitrogen-phosphorus linked systems Cy2BN=PR3 (R = Et, (t)Bu, Cy, Ph) (1a-1d respectively). Similarly, reaction of (C6F5)2BN3 with the phosphines P(t)Bu3, PPh3, Ph2PC=CPh and Ph2PC=CPPh2 yielded (C6F5)2BN=PR3 (2a-d respectively). In contrast, the reaction of (C6F5)2BN3 with Ph2P-C=Cp-tol in the presence of excess Me3SiN3 afforded the bicyclic product 3 [1-(C6F5)2B-4-(p-tol)-1H-1,2,3-triazole-5 P(NH)Ph2] in which both a Staudinger and a cycloaddition reaction has taken place. However, if the Staudinger reaction is prohibited via phosphine oxidation as in the case of (EtO)2P(O)C=CP(O)(OEt)2 then the unusual dimeric product 4 [2 (C6F5)2B-4-(P(O)OEt2)-2H-1,2,3-triazole-5-P(O)(OEt)(OB(C6F5)2)] is generated. The structures of 1b-d, 2b-d, 3 and 4 have been determined by X-ray diffraction. PMID- 23652384 TI - Cu(In(1-x)Ga(x))S2 nanocrystals and films: low-temperature synthesis with size and composition control. AB - We demonstrate a single-step X-ray irradiation process that yields high-quality Cu(In1-xGax)S2 nanocrystals in colloidal solutions, with complete control of size and composition. Thin films produced by drop-casting exhibit high-quality photoresponse, confirming that our process is suitable for microelectronics applications. PMID- 23652383 TI - Functional polymorphism in the neuropeptide Y gene promoter (rs16147) is associated with serum leptin levels and waist-hip ratio in women. AB - OBJECTIVE: The neuropeptide-Y (NP-Y) gene is a strong candidate gene in the pathophysiology of obesity-linked behavior, and several single-nucleotide polymorphisms of NP-Y have already been linked to body weight and appetite. However, the results from current studies remain inconclusive. The aim of the present study was to test whether a certain functional genetic variant (SNP rs16147) in the NP-Y promoter gene is associated with serum leptin levels and body fat distribution. METHOD: We genotyped and measured the serum leptin levels of the NP-Y rs16147 polymorphism in 1,097 Caucasian subjects in the context of a population-based, case-control multicenter study. We measured weight, height and waist circumference, from which we then calculated BMI and waist-to-hip ratio (WHR). RESULTS: We found the CT-genotype of the SNP rs16147 to be significantly associated with lower WHRs and higher serum leptin levels in women, compared to homozygote gene carriers. No association between rs16147, WHR and serum leptin levels was found in men. CONCLUSION: Our results provide evidence that the functionally relevant SNP in the NP-Y promoter gene affects body fat distribution and serum leptin levels in women, pointing towards possible behavioral effects of NPY in obesity. PMID- 23652385 TI - Fatigue and occupational functioning in major depressive disorder. PMID- 23652386 TI - Ghrelin discovery: a decade after. AB - Since its discovery 12 years ago, intensive research has been performed on ghrelin. The significance of ghrelin as a growth hormone-releasing hormone, appetite regulator, energy conservator and sympathetic nerve suppressor has now been well established. In this short essay, we summarize the history of the discovery of ghrelin. PMID- 23652387 TI - The ghrelin receptors (GHS-R1a and GHS-R1b). AB - The growth hormone (GH) secretagogue receptor (GHS-R1a) is a G protein-coupled receptor (GPCR) expressed in the brain as well as other areas of the body. In the early 1990s, this receptor was expression cloned in MERCK laboratories by using a group of synthesized small molecules known to increase GH release in humans and other animals. Since its discovery, hundreds of studies have shown the importance of this receptor and its endogenous ligand, ghrelin, in metabolism, neurotransmission, and behavior. Even more relevant are the prospective benefits that will result from pharmacologic manipulation of GHS-R1a. Multiple GHS-R1a agonists and antagonists are available for experimentation, and some have been used in patients with promising results. Studies in rodents have revealed intriguing potential roles for GHS-R1a modulation. Our goal in this chapter is to connect these studies with the inherent advantages of targeting this receptor pharmacologically. PMID- 23652388 TI - Discovery of ghrelin o-acyltransferase. AB - Ghrelin is a gut hormone with potent orexigenic and growth hormone release stimulatory effects, and is the first known endogenous ligand of the growth hormone secretagogue receptor. A notable feature of ghrelin is that it carries an acyl group, in most cases an octanoyl group, in the third serine. While it has been shown that the acylation is critical for the majority of ghrelin functions, the mechanisms of acylation of ghrelin remained poorly understood. In 2008, it was discovered that ghrelin O-acyltransferase (GOAT) is the enzyme responsible for acylating ghrelin. GOAT is highly conserved from zebrafish to humans. It is most abundant in the stomach and pancreas. GOAT mRNA expression is regulated by energy balance, being upregulated by energy restriction and downregulated by energy abundance. GOAT attenuation using synthetic inhibitors enhances insulin secretion and reduces body weight. GOAT inhibitors are currently being developed for the treatment of metabolic disorders. In addition to its ghrelin mediated effects, GOAT is also known to directly regulate bile acid secretion. The discovery of GOAT helped to redefine the ghrelin research field and enabled the development of another target molecule for potential therapies aimed to prevent/treat diabetes and obesity. PMID- 23652389 TI - Genetics of the ghrelin system. AB - Ghrelin was originally identified as a growth hormone secretagogue, but later studies suggested that it plays an important role in the regulation of appetite and body weight. The implication of genetic variants of the ghrelin-ghrelin receptor axis in the determination of stature, appetite, body weight, glucose metabolism and eating disorders has been the focus of numerous small and larger studies. More recently, several studies have shown some involvement of ghrelin and growth hormone secretagogue receptor (GHSR) genetic variants in some cancers, or their role in the genetics of immune diseases or addictive behaviour. The overall results suggest that the effects of common genetic variants are lacking or modest, while rare sequence alteration may lead to disease status in individual patients. In this review we summarize the available data on the genetics of ghrelin axis in humans. PMID- 23652390 TI - Ghrelin and the gut. AB - Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHS-R) which was identified in the pituitary gland and is now named the ghrelin receptor. However, the peptide is most abundant in the stomach and ghrelin receptors are present in all major organ systems and tissues. Ghrelin forms with motilin, a new gut peptide family and the sequence similarities of peptides and receptors suggest they evolved by gene duplication. Nevertheless, no cross reactivity exits between both peptides. Ghrelin shares with motilin motor effects in the gut, in particular gastric emptying and the induction of the migrating motor complex, but ghrelin also affects gastric acid secretion, offers gastroprotection and may modulate intestinal inflammation. The effects of ghrelin result from the activation of central, vagal and enteric neural receptors and receptors on immune cells. Ghrelin agonists have been developed for the treatment of hypomotility disorders and the peptidomimetic TZP-102 is in phase 2 clinical trials for diabetic gastroparesis. PMID- 23652391 TI - Ghrelin as a GH-releasing factor. AB - Growth hormone (GH) is secreted by the pituitary gland in a pulsatile manner. It is accepted that this pulsatility is primarily controlled by the hypothalamus, although this secretion can also be modulated by factors from GH-targeted organs, the pituitary and other regions of the central nervous systems, or by factors arriving from peripheral organs. In mammals, hypothalamic control of GH pulsatility is classically regulated by the interplay of two opposing hormones, stimulatory GHRH and inhibitory somatostatin (SS). Recognition of the gastric ghrelin peptide as the natural ligand for GH secretagogue receptor type 1a (GHS R1a) added a new element to the complex physiological regulation of GH secretion and clarified some of its aspects that were previously not fully understood. In this review, we examine data that suggest that ghrelin may regulate GH secretion, as well as ghrelin's possible use as a therapeutic agent. PMID- 23652392 TI - Other than growth hormone neuroendocrine actions of ghrelin. AB - Besides its growth hormone-releasing effect, ghrelin has been demonstrated to influence other hormonal systems, such as the hypothalamo-pituitary-adrenal axis, prolactin secretion, the thyroid axis as well as the gonadal axis. Ghrelin and its analogues stimulate the hypothalamo-pituitary-adrenal axis independent of the pituitary, via the hypothalamus, involving both corticotrophin-releasing hormone, arginine-vasopressin and neuropeptide Y stimulation. In adrenocortocotropic hormone (ACTH)-secreting tumors, the ghrelin receptor is pathologically expressed, thus accounting for especially high ACTH and cortisol responses to ghrelin and GH secretagogues in patients with Cushing's disease. Ghrelin stimulates prolactin release most probably from the somatomammotroph cells of the pituitary gland. The effect of ghrelin on the pituitary regulation of the thyroid axis is controversial and its role in the physiological control of thyroid function is still matter of investigation. On the other hand, ghrelin has been reported to exert an inhibitory effect on follicle-stimulating hormone and, in particular, on luteinizing hormone, probably via an inhibitory effect exerted at the hypothalamic level on gonadotropin-releasing hormone secretion. PMID- 23652393 TI - Ghrelin, the gonadal axis and the onset of puberty. AB - Puberty onset and reproduction are metabolically gated; conditions of energy insufficiency are associated to perturbations in the timing of puberty and subfertility. The neuroendocrine basis for this phenomenon relies on the regulatory actions of a diversity of nutritional and metabolic cues as well as hormones controlling energy homeostasis at different levels of the reproductive axis. Among these, experimental evidence from different species, including rodents and primates, has accumulated in recent years to strongly suggest that the gut hormone, ghrelin, which operates as signal of energy insufficiency and functional antagonist of leptin, may play a physiological, and eventual pathophysiological role in the regulation of puberty onset and gonadal function. Such a 'reproductive' dimension of ghrelin is likely to include, among others, its ability to modulate gonadotropin secretion, to influence the timing of puberty and to directly regulate gonadal (both testicular and ovarian) functions. In keeping with its proposed role as signal for energy deficit, most of the reported actions of ghrelin upon the reproductive axis appear to be inhibitory, thus suggesting that ghrelin may convey at least part of the suppressive effects of low body fuel stores and energy insufficiency on puberty and fertility. PMID- 23652394 TI - Ghrelin and the cardiovascular system. AB - Although ghrelin was initially associated with regulation of appetite, the cardiovascular system has also been recognized as a potentially important target for its effects. Moreover, experimental and a limited number of clinical studies suggest a potential role for ghrelin in the treatment of congestive heart failure. So far, reported cardiovascular effects of growth hormone secretagogues and/or ghrelin include lowering of peripheral resistance, either direct at the vascular level and/or by modulating sympathetic nervous activity. Other observed effects indicate possible improvement of contractility and cardioprotective and anti-inflammatory effects both in vivo and in vitro. Taken together, these results offer an interesting perspective on the future where further studies aiming at evaluating a role of growth hormone secretagogues and ghrelin in the treatment of cardiovascular disease are warranted. PMID- 23652395 TI - Ghrelin - a key pleiotropic hormone-regulating systemic energy metabolism. AB - The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand for the growth hormone secretagogue receptor (GHSR-1a). Since its discovery tremendous research efforts have been directed at unraveling ghrelin's mechanisms of action, revealing that ghrelin is a pleiotropic hormone implicated in myriad of molecular signaling mechanisms. Accordingly, ghrelin is the only known circulating peripheral hormone with the ability to promote a positive energy balance by stimulating food intake while decreasing energy expenditure and body fat utilization. Moreover, beyond its ability to promote the release of growth hormone from the anterior pituitary, ghrelin stimulates gut motility and gastric acid secretion, modulates sleep, taste sensation and behavior, and regulates glucose metabolism. Due to ghrelin's ability to promote body weight gain and adiposity via centrally mediated signaling mechanisms, modulation of the endogenous ghrelin system is considered a promising strategy to treat individuals with pathologically reduced body weight, such as patients with anorexia nervosa or cachexia. The aim of this chapter is to summarize the current knowledge of how ghrelin affects systemic energy metabolism. PMID- 23652396 TI - Ghrelin, reward and motivation. AB - Almost all circulating gut peptides contribute to the control of food intake by signalling satiety. One important exception is ghrelin, the only orexigenic peptide hormone thus far described. Ghrelin secretion increases before meals and behavioural and electrophysiological evidence shows that ghrelin acts in the hypothalamus via homeostatic pathways to signal hunger and increase food intake and adiposity. These findings strongly suggest that ghrelin is a dynamically regulated peripheral hunger signal. However, ghrelin also interacts with the brain reward pathways to increase food intake, alter food preference and enhance food reward. Here we discuss ghrelin's role as an endocrine gut-brain reward signal in relation to homeostatic and hedonic feeding control. PMID- 23652397 TI - Des-acyl ghrelin: a metabolically active peptide. AB - Unacylated ghrelin (UAG), or des-acyl ghrelin, is slowly fighting its way up into the field of interest that studies preproghrelin gene-encoded peptides. Long considered to be an inert degradation product of (acylated) ghrelin (AG), UAG nowadays emerges as an important hormone, separate from the other proghrelin derived peptides, AG and obestatin. UAG appears to have its own receptor, and it can share this receptor with AG, under experimental conditions at least. An increasing number of studies suggest that UAG can act as a potent functional inhibitor of ghrelin. It can even strongly suppress ghrelin levels in obese human diabetic subjects. Moreover, UAG can improve postprandial glycemia, especially in those subjects in whom preprandial acylated ghrelin levels are high, which makes UAG, or UAG analogs strong potential candidates for the development of drugs for the treatment of metabolic disorders or other conditions in which elevated AG/UAG ratios occur, such as diabetes, obesity and Prader-Willi syndrome. PMID- 23652398 TI - Ghrelin and tumors. AB - Since the original discovery of ghrelin and, subsequently, obestatin (the alternative product of the ghrelin gene), a major interest has been devoted to the investigation of their central and peripheral activities in physiological conditions as well as on their role in metabolic diseases. However, several studies with different methodological approaches variably identified ghrelin and obestatin synthesis and secretion in several neoplastic conditions, including neuroendocrine and non-neuroendocrine cancers of various sites. Moreover, in vitro studies showed the capability of ghrelin to modulate tumor cell functions such as cell proliferation, apoptosis and invasiveness, although with variable and even paradoxical effects in different cell models. Interestingly, in most studies, it was demonstrated that ghrelin exerts its pro- or antineoplastic properties by means of receptors other than GHSR1a, that still need to be identified. However, the possible usefulness of the modulation of the ghrelin/obestatin axis in neoplastic conditions using either synthetic agonists or antagonists, though interesting in perspective, is still far from clinical applicability, and probably more related to the regulation of specific metabolic pathways in tumor cells, including lipid and carbohydrate use, than to the specific modulation of cell proliferation. PMID- 23652399 TI - Ghrelin function in insulin release and glucose metabolism. AB - Given its wide spectrum of biological activities such as growth hormone (GH) release, feeding stimulation, adiposity and cardiovascular actions, the discovery of ghrelin opened many new perspectives within neuroendocrine, metabolic and cardiovascular research, thus suggesting its possible clinical application. Circulating ghrelin is produced predominantly in the stomach, and its receptor GH secretagogue receptor (GHS-R) is expressed in a variety of central and peripheral tissues. Ghrelin, GHS-R and ghrelin O-acyltransferase (GOAT), the enzyme that promotes the acylation of the third serine residue of ghrelin, are all expressed in pancreatic islets, and this peptide is released into pancreatic microcirculations. Ghrelin inhibits insulin release in mice, rats and humans. The signal transduction mechanisms of ghrelin receptor in islet beta-cells are very unique, being distinct from those utilized for GH release. Pharmacological and genetic blockade of islet-derived ghrelin markedly augments glucose-induced insulin release in vitro. Ablation of ghrelin, GHS-R or GOAT enhances insulin release and prevents impaired glucose tolerance in high-fat, diet-induced and leptin-deficient obese models. Thus, manipulation of the insulinostatic function of the ghrelin-GHS-R system, particularly that in islets, could optimize the amount of insulin release to meet the systemic demand. Ghrelin antagonism provides a novel strategy to treat type 2 diabetes with dysregulated insulin release. PMID- 23652400 TI - Products of the ghrelin gene, the pancreatic beta-cell and the adipocyte. AB - The ghrelin system comprises acylated ghrelin (AG), unacylated ghrelin (UAG) and obestatin, besides the receptor for AG, the growth hormone (GH) secretagogue receptor type 1a (GHS-R1a), and the enzyme-promoting ghrelin acylation, ghrelin O acyltransferase (GOAT). The ghrelin peptides exert a variety of biological actions, including regulation of energy homeostasis and glucose metabolism, as well as survival and proliferative effects in different cell types. Besides the stomach, its main site of production, ghrelin is expressed in pancreatic islets, where it represents an independent islet cell population. AG exerts insulinostatic actions, UAG has been shown to oppose the AG inhibitory effects on insulin secretion, and obestatin has demonstrated insulinotropic activities. Although differences exist in the regulation of glucose homeostasis, all peptides display survival and antiapoptotic actions in pancreatic beta-cells, preserving beta-cell mass and function both in vitro and in vivo. The ghrelin system is also expressed in adipose tissue, and ghrelin effects have been demonstrated in both white and brown adipocytes. Indeed, AG, UAG and obestatin promote adipogenesis and glucose uptake, and inhibit adipocyte lipolysis. Interestingly, despite similar effects at the cellular level, results from ghrelin, GHS-R and GOAT knockout mice have indicated that AG display diabetogenic effects in vivo. Conversely, UAG and obestatin positively regulate glucose metabolism, and a new role has been recently proposed for obestatin on adipocyte function and insulin sensitivity. PMID- 23652401 TI - Clinical perspectives for ghrelin-derived therapeutic products. AB - Because of its orexigenic, adipogenic and diabetogenic activities, acylated ghrelin (AG) has emerged as an attractive target for the treatment of obesity and type 2 diabetes. Pharmacological tools have been designed in order to antagonize or block the hormone's activity, or inhibit ghrelin O-acyltransferase (GOAT), the enzyme that catalyzes its acylation. AG antagonists, shown to be potent inhibitors of growth hormone (GH) secretion, were not able to consistently induce the desirable metabolic effects. Some of them, on the contrary, acted as AG agonists. Similarly, AG-blocking agents including Spiegelmers, vaccines, and monoclonal antibodies, gave mixed results. More encouraging yet very preliminary data were obtained with a novel GOAT inhibitor. However, although significant, the observed decrease in circulating AG levels was partial and improvement work remains to be done. Unacylated ghrelin (UAG) and analogs were shown to potently and rapidly inhibit plasma AG levels, and to improve glucose metabolism in addition to displaying beneficial effects on a variety of cells. These data support the rationale for further development of this new therapeutic class in type 2 diabetes and the Prader-Willi syndrome. A development program is underway with AZP-531, a cyclized UAG(6-13) analog with improved pharmacokinetic properties. PMID- 23652404 TI - Title page / table of contents / preface. PMID- 23652405 TI - Platelet Activation Test in Unprocessed Blood (Pac-t-UB) to Monitor Platelet Concentrates and Whole Blood of Thrombocytopenic Patients. AB - BACKGROUND: Platelet concentrate transfusion is the standard treatment for hemato oncology patients to compensate for thrombocytopenia. We have developed a novel platelet activation test in anticoagulated unprocessed blood (pac-t-UB) to determine platelet function in platelet concentrates and in blood of thrombocytopenic patients. METHODS: We have measured platelet activity in a platelet concentrate and in anticoagulated unprocessed blood of a post transfusion thrombocytopenic patient. RESULTS: Our data show time-dependent platelet activation by GPVI agonist (collagen related peptide; CRP), PAR-1 agonist (SFLLRN), P2Y12 agonist (ADP), and thromboxane receptor agonist (U46619) in a platelet concentrate. Furthermore, pac-t-UB showed time-dependent platelet activation in unprocessed blood of a post-transfusion patient with thrombocytopenia. Testing platelet function by different agonists in relation to storage show that 3-day-old platelet concentrates are still reactive to the studied agonists. This reactivity rapidly drops for each agonists during longer storage. DISCUSSION: Pac-t-UB is a novel tool to estimate platelet function by different agonists in platelet concentrates and in unprocessed blood of thrombocytopenic patients. In the near future, we will validate whether pac-t-UB is an adequate test to monitor the quality of platelet concentrates and whether pac-t-UB predicts the bleeding risk of transfused thrombocytopenic patients. PMID- 23652406 TI - A pooled analysis of diagnostic value of (99m)Tc-ubiquicidin (UBI) scintigraphy in detection of an infectious process. AB - PURPOSE: Although the data are promising from limited studies with technetium-99m ubiquicidin (Tc-UBI) scintigraphy in detection of infection in humans, these studies have had a limited sample size. This study was conducted to provide a systematic review and meta-analysis of the reported diagnostic accuracy of Tc-UBI scintigraphy in detection of an infectious process. MATERIALS AND METHODS: The PubMed/MEDLINE, Web of Science, EMBASE, and Google Scholar literature databases were systematically searched to find the relevant human studies on Tc-UBI scintigraphy. For each eligible study, the true-positive, false-positive, true negative, and false-negative findings at Tc-UBI scintigraphy were recorded, and the overall statistical parameters were acquired. RESULT: Ten studies carried out from 2004 to 2010 were included in the analysis. The pooled data sensitivity was 94.5 % and with a 95% confidence interval of 91.2%-96.8%. The pooled specificity was still as high as about 92.7%. The range of reported specificity was from 80% to 100%. The overall accuracy was 93.7% (95% CI: 91.2%-95.7%). CONCLUSION: The study demonstrated that Tc-UBI scintigraphy can be used to identify an infectious process with admirable accuracy in early views; however, further investigations are recommended. PMID- 23652408 TI - Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics. AB - OBJECTIVE: Human multidrug and toxin extrusion member 2 (MATE2-K, SLC47A2) plays an important role in the renal elimination of various clinical drugs including the antidiabetic drug metformin. The goal of this study was to characterize genetic variants of MATE2-K and determine their association with the pharmacokinetics of metformin. METHODS: We screened DNA samples from 48 healthy Koreans for variants in the promoter and coding regions of MATE2-K and examined the function of common haplotypes in the promoter region using in-vitro luciferase assays. Then, the metformin pharmacokinetic study was carried out to determine the association between MATE2-K promoter haplotypes and metformin pharmacokinetics. RESULTS: Nine variants in the promoter region of MATE2-K and one nonsynonymous variant, p.G211V, were identified. The MATE2-K promoter haplotype 1 containing a known functional polymorphism, g.-130G>A and haplotype 2 containing two polymorphisms, g.-609G>A and g.-396G>A showed a significant increase in reporter activity. Among the 45 individuals who participated in the metformin pharmacokinetic study, 12 healthy Koreans who were homozygous for haplotype 1 or 2 showed a significant increase in renal clearance [539 +/- 76 (reference group) vs. 633 +/- 102 (variant group) ml/min; P=0.006] and secretion clearance [439 +/- 81 (reference group) vs. 531 +/- 102 (variant group) ml/min; P=0.007] of metformin compared with that shown by the reference group. CONCLUSION: Our study suggests that common promoter haplotypes of MATE2-K are associated with the pharmacokinetics of metformin. PMID- 23652410 TI - Reincarnating the oxford cingulectomy in the epoch of stereotaxy and resurrecting lesions in the era of deep brain stimulation. PMID- 23652407 TI - OATP1B1-related drug-drug and drug-gene interactions as potential risk factors for cerivastatin-induced rhabdomyolysis. AB - OBJECTIVE: Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin. METHODS: This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1. RESULTS: The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P<0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin. CONCLUSION: Reduced function of OATP1B1 related to genetic variation and drug-drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1. PMID- 23652411 TI - Quantitative studies of adsorbate dynamics at noble metal electrodes by in situ Video-STM. AB - The surface diffusion of adsorbates at electrochemical interfaces is studied by in situ scanning tunneling microscopy with high temporal resolution, using sulfur and methyl thiolate on c(2 * 2) Cl covered Cu(100), Ag(100), and Au(100) electrode surfaces in 0.01 M HCl solution as an example. While on Au(100) quantitative studies were not possible because of the slow dynamics and high surface defect density, on Cu(100) and Ag(100) a pronounced exponential increase of the jump rates of isolated adsorbates toward more negative potentials was found, indicating a linear decrease of the tracer diffusion barriers with potential. The potential dependence is independent of the adsorbate species, but differs for Cu(100) and Ag(100) substrates. These trends can be explained by electrostatic contributions to the diffusion barrier, caused by the interaction of the adsorbates with the field of the electrochemical double layer, if the presence of the chloride coadsorbate layer is taken into account. PMID- 23652412 TI - Anti-inflammatory effects of essential oils from Chamaecyparis obtusa via the cyclooxygenase-2 pathway in rats. AB - Essential oils are concentrated hydrophobic liquids containing volatile aromatic compounds from plants. In the present study, the essential oil of Chamaecyparis obtusa (C. obtusa), which is commercially used in soap, toothpaste and cosmetics, was extracted. Essential oil extracted from C. obtusa contains several types of terpenes, which have been shown to have anti-oxidative and anti-inflammatory effects. In the present study, we examined the anti-inflammatory effects of C. obtusa essential oil in vivo and in vitro following the induction of inflammation by lipopolysaccharides (LPS) in rats. While LPS induced an inflammatory response through the production of prostaglandin E2 (PGE2) in the blood and peripheral blood mononuclear cells (PMNCs), these levels were reduced when essential oil was pre-administered. Additionally, the mechanism of action underlying the anti inflammatory effects of C. obtusa essential oil was investigated by measuring the mRNA expression of inflammation-associated genes. LPS treatment significantly induced the expression of transforming growth factor alpha (TNFalpha) and cyclooxygenase-2 (COX-2) in rats, while C. obtusa essential oil inhibited this effect. Taken together, our results demonstrate that C. obtusa essential oil exerts anti-inflammatory effects by regulating the production of PGE2 and TNFalpha gene expression through the COX-2 pathway. These findings suggest that C. obtusa essential oil may constitute a novel source of anti-inflammatory drugs. PMID- 23652413 TI - Synthesis of superior fast charging-discharging nano-LiFePO4/C from nano-FePO4 generated using a confined area impinging jet reactor approach. AB - LiFePO4/C nanocomposites with excellent electrochemical performance is synthesized from nano-FePO4, generated by a novel method using a confined area impinging jet reactor (CIJR). When discharged at 80 C (13.6 Ag(-1)), the LiFePO4/C delivers a discharge capacity of 95 mA h g(-1), an energy density of 227 W h kg(-1) and a power density of 34 kW kg(-1). PMID- 23652415 TI - Abstracts of the 38th Annual IUGA (International Urogynecological Association) Meeting. Dublin, Ireland. May 28-June 1, 2013. PMID- 23652416 TI - Vertebral augmentation with nitinol endoprosthesis: clinical experience in 40 patients with 1-year follow-up. AB - PURPOSE: This study was designed to assess the clinical outcomes of patients treated by vertebral augmentation with nitinol endoprosthesis (VNE) to treat painful vertebral compression fractures. METHODS: Forty patients with one or more painful osteoporotic VCF, confirmed by MRI and accompanied by back-pain unresponsive to a minimum 2 months of conservative medical treatment, underwent VNE at 42 levels. Preoperative and postoperative pain measured with Visual Analog Scale (VAS), disability measured by Oswestry Disability Index (ODI), and vertebral height restoration (measured with 2-dimensional reconstruction CT) were compared at last follow-up (average follow-up 15 months). Cement extravasation, subsequent fractures, and implant migration were recorded. RESULTS: Long-term follow-up was obtained in 38 of 40 patients. Both VAS and ODI significantly improved from a median of 8.0 (range 5-10) and 66 % (range 44-88 %) to 0.5 (range 0-8) and 6 % (range 6-66 %), respectively, at 1 year (p < 0.0001). Vertebral height measurements comparing time points increased in a statistically significant manner (ANOVA, p < 0.001). Overall cement extravasation rate was 9.5 %. Discal and venous leakage rates were 7.1 and 0 % respectively. No symptomatic extravasations occurred. Five of 38 (13.1 %) patients experienced new spontaneous, osteoporotic fractures. No device change or migration was observed. CONCLUSIONS: VNE is a safe and effective procedure that is able to provide long lasting pain relief and durable vertebral height gain with a low rate of new fractures and cement leakages. PMID- 23652417 TI - Percutaneous vertebroplasty for pain management in patients with multiple myeloma: is radiofrequency ablation necessary? AB - PURPOSE: This study was designed to investigate the added role of radiofrequency ablation (RFA) to vertebroplasty on the pain management of patients with multiple myeloma (MM). METHODS: Thirty-six patients (51-82 years) with vertebral localization of MM were randomly divided into two groups: 18 patients (group A) who underwent RFA and then vertebroplasty, and 18 patients (group B) who underwent only vertebroplasty. Primary endpoints were technical success and pain relief score rate measured by the visual analogue pain scores (VAS) and Roland Morris Questionnaire (RMQ); secondary endpoint was the amount of administered analgesia. Survival and complications were compared. RESULTS: Technical success was 100 % in both groups. The VAS score (at 24 h and 6 weeks postprocedure) decreased in equal manner for both groups from a mean of 9.1-3.4 and 2.0 for group A and from a mean of 9.3-3.0 and 2.3 for group B; RMQ mean score was 19.8 for group A and 19.9 for group B and decreased to a mean of 9.6 and 8.2 for group A and 9.5 and 8.7 for group B. The amount of medication was equally decreased in the two groups. No statistically significant difference was noted. No major complication occurred and two patients died from other causes. CONCLUSIONS: The use of percutaneous vertebroplasty alone appears to be effective for the pain management of the patients with vertebral involvement of multiple myeloma. The use of RFA that includes cost and time does not offer any clear added benefit on the midterm pain management of such patients. PMID- 23652418 TI - Is a swine model of arteriovenous malformation suitable for human extracranial arteriovenous malformation? A preliminary study. AB - OBJECTIVE: A chronic arteriovenous malformation (AVM) model using the swine retia mirabilia (RMB) was developed and compared with the human extracranial AVM (EAVM) both in hemodynamics and pathology, to see if this brain AVM model can be used as an EAVM model. METHODS: We created an arteriovenous fistula between the common carotid artery and the external jugular vein in eight animals by using end-to-end anastomosis. All animals were sacrificed 1 month after surgery, and the bilateral retia were obtained at autopsy and performed hematoxylin and eosin staining and immunohistochemistry. Pre- and postsurgical hemodynamic evaluations also were conducted. Then, the blood flow and histological changes of the animal model were compared with human EAVM. RESULTS: The angiography after operation showed that the blood flow, like human EAVM, flowed from the feeding artery, via the nidus, drained to the draining vein. Microscopic examination showed dilated lumina and disrupted internal elastic lamina in both RMB of model and nidus of human EAVM, but the thickness of vessel wall had significant difference. Immunohistochemical reactivity for smooth muscle actin, angiopoietin 1, and angiopoietin 2 were similar in chronic model nidus microvessels and human EAVM, whereas vascular endothelial growth factor was significant difference between human EAVM and RMB of model. CONCLUSIONS: The AVM model described here is similar to human EAVM in hemodynamics and immunohistochemical features, but there are still some differences in anatomy and pathogenetic mechanism. Further study is needed to evaluate the applicability and efficacy of this model. PMID- 23652419 TI - Impaired information-processing speed and working memory in leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL) and DARS2 mutations: a report of three adult patients. AB - Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL) is clinically characterized by progressive pyramidal and cerebellar dysfunction, dorsal column dysfunction and sometimes with axonal neuropathy. Magnetic resonance imaging of brain and the spinal cord reveals characteristic findings. LBSL is caused by mutations in the DARS2 gene that encodes the mitochondrial aspartyl-tRNA synthetase. The presentation and clinical course of LBSL is not uniform, and there is lack of longitudinal data on these patients. In addition, the existing data on the prevalence and characteristics of cognitive abnormalities in patients with LBSL are scarce and somewhat conflicting. Here we report long-term data of neurological and cognitive functioning in three non-related adult patients with LBSL. Cognitive impairment seems to be common among patients with LBSL and DARS2 mutations. The cognitive profile in LBSL shares similarities with that reported in multiple sclerosis, as information-processing speed and working memory are especially affected. In addition, our results and the previously reported carrier frequencies of common pathogenic DARS2 mutations suggest that LBSL may be underdiagnosed in the population. PMID- 23652420 TI - Abnormal ghrelin secretion contributes to gastrointestinal symptoms in multiple system atrophy patients. AB - Patients with multiple system atrophy (MSA) often have evidence of compromised gastrointestinal motility. Ghrelin is a gut hormone that influences gastrointestinal motility in humans. The aim of this study was to determine whether ghrelin secretion is affected in MSA patients, and to investigate the relation between ghrelin secretion and gastrointestinal symptoms. Plasma levels of active ghrelin and unacylated ghrelin were measured in patients with MSA (n = 30), other atypical parkinsonian disorders including progressive supranuclear palsy-Richardson syndrome and corticobasal syndrome (n = 24), and control subjects (n = 24) using enzyme-linked immunosorbent assays. Gastrointestinal symptoms were quantified in all subjects using a self-report questionnaire. The ratio of active ghrelin to total ghrelin in the plasma (active ghrelin ratio) was lower in patients with MSA (mean: 8.0 %) than in patients with other atypical parkinsonian disorders (mean: 13.7 %, P = 0.001) and control subjects (mean: 13.9 %, P = 0.001). The active ghrelin ratio was correlated with the severity of gastrointestinal symptoms in MSA (r = -0.5, P = 0.004). Our observations indicate that ghrelin secretion is affected in patients with MSA. The low active ghrelin ratio may contribute to gastrointestinal symptoms in MSA. PMID- 23652421 TI - A case of rapid conversion to psychosis of delusional misidentification associated with derealisation, verbal memory impairment and FDG-PET imaging abnormalities. AB - The delusional misidentification syndromes, occurring within the context of different nosological settings, such as schizophrenia, are psychopathological phenomena related to the experience of depersonalisation/derealisation. Extensive research indicates that individuals meeting specific "prodromal" criteria, such as attenuated psychotic symptoms, brief intermittent psychotic symptoms, or functional decline and family history of schizophrenia have increased risk for impending psychosis. Despite depersonalisation and/or derealisation often precede psychotic onset, they are not included among the prodromal criteria of the Australian-American approach. A 17-year-old boy with acute agitation, violent behaviour and aggression, and dissociative amnesia had a mild verbal memory impairment and temporo-limbic hypometabolism on the positron-emission tomography. The patient was assessed with both the ultra-high risk (UHR) and the basic symptom approaches and was not found to be prodromal with imminent risk of transition to psychosis. He was hospitalised briefly and 2 weeks after discharge he developed delusional misidentification. This case shows that even the integration of both UHR and basic symptoms criteria may give false negatives in the prediction of psychosis, especially in those cases in which a long prodromal phase is absent. PMID- 23652422 TI - Quantifying temporal and spatial variations in sediment, nitrogen and phosphorus transport in stream inflows to a large eutrophic lake. AB - High-frequency sampling of two major stream inflows to a large eutrophic lake (Lake Rotorua, New Zealand) was conducted to measure inputs of total suspended sediment (TSS), and fractions of nitrogen and phosphorus (P). A total of 17 rain events were sampled, including three during which both streams were simultaneously monitored to quantify how concentration-discharge (Q) relationships varied between catchments during similar hydrological conditions. Dissolved inorganic nitrogen (DIN) concentrations declined slightly during events, reflecting dilution of groundwater inputs by rainfall, whereas dissolved inorganic P (PO4-P) concentrations were variable and unrelated to Q, suggesting dynamic sorptive behaviour. Event loads of total nitrogen (TN) were predominantly DIN, which is available for immediate uptake by primary producers, whereas total phosphorus (TP) loads predominantly comprised particulate P (less labile). Positive correlations between Q and concentrations of TP (and to a lesser extent TN) reflected increased particulate nutrient concentrations at high flows. Consequently, load estimates based on hourly Q during storm events and concentrations of routine monthly samples (mostly base flow) under-estimated TN and TP loads by an average of 19% and 40% respectively. Hysteresis with Q was commonly observed and inclusion of hydrological variables that reflect Q history in regression models improved predictions of TN and TP concentrations. Lorenz curves describing the proportions of cumulative load versus cumulative time quantified temporal inequality in loading. In the two study streams, 50% of estimated two-year loads of TN, TP and TSS were transported in 202-207, 76-126 and 1-8 days respectively. This study quantifies how hydrological and landscape factors can interact to influence pollutant flux at the catchment scale and highlights the importance of including storm transfers in lake loading estimates. PMID- 23652423 TI - Toxin-antitoxin Systems: Classification, Biological Function and Application in Biotechnology. AB - The toxin-antitoxin (TA) systems are systems in which an unstable antitoxin inhibits a stable toxin. This review aims to introduce the TA system and its biological application in bacteria. For this purpose, first we introduce a new classification for the TA systems based on how the antitoxin can neutralize the toxin, we then describe the functions of TA systems and finally review the application of these systems in biotechnology. PMID- 23652424 TI - Isolated central hypothyroidism in young siblings as a manifestation of PROP1 deficiency: clinical impact of whole exome sequencing. AB - BACKGROUND/AIMS: Central hypothyroidism (CH) in children is rare and may be due to a variety of genetic defects. Most of these defects, but not all, are associated with additional pituitary hormone deficits. In a young child presenting with CH, it is important to determine whether additional pituitary hormone deficiencies are present, but this may be difficult to establish clinically. METHODS: We describe the clinical characteristics of two young siblings, aged 6 months and 2 years, presenting with isolated CH. Whole exome sequencing was performed to determine the genetic basis of isolated CH. RESULTS: A homozygous frameshift mutation of PROP1 (296delGA) was identified in both probands. Defects in PROP1 cause progressive deficiency of multiple pituitary hormones. Based on this genetic diagnosis, further clinical testing was performed that demonstrated growth hormone deficiency in one sibling. CONCLUSIONS: PROP1 deficiency may present as isolated CH at a very young age. In disorders with multiple potential causative genes, whole exome sequencing may facilitate rapid genetic diagnosis and lead to important changes in clinical management. PMID- 23652425 TI - pyGenClean: efficient tool for genetic data clean up before association testing. AB - Genetic association studies making use of high-throughput genotyping arrays need to process large amounts of data in the order of millions of markers per experiment. The first step of any analysis with genotyping arrays is typically the conduct of a thorough data clean up and quality control to remove poor quality genotypes and generate metrics to inform and select individuals for downstream statistical analysis. We have developed pyGenClean, a bioinformatics tool to facilitate and standardize the genetic data clean up pipeline with genotyping array data. In conjunction with a source batch-queuing system, the tool minimizes data manipulation errors, accelerates the completion of the data clean up process and provides informative plots and metrics to guide decision making for statistical analysis. AVAILABILITY AND IMPLEMENTATION: pyGenClean is an open source Python 2.7 software and is freely available, along with documentation and examples, from http://www.statgen.org. PMID- 23652426 TI - InterEvScore: a novel coarse-grained interface scoring function using a multi body statistical potential coupled to evolution. AB - MOTIVATION: Structural prediction of protein interactions currently remains a challenging but fundamental goal. In particular, progress in scoring functions is critical for the efficient discrimination of near-native interfaces among large sets of decoys. Many functions have been developed using knowledge-based potentials, but few make use of multi-body interactions or evolutionary information, although multi-residue interactions are crucial for protein-protein binding and protein interfaces undergo significant selection pressure to maintain their interactions. RESULTS: This article presents InterEvScore, a novel scoring function using a coarse-grained statistical potential including two- and three body interactions, which provides each residue with the opportunity to contribute in its most favorable local structural environment. Combination of this potential with evolutionary information considerably improves scoring results on the 54 test cases from the widely used protein docking benchmark for which evolutionary information can be collected. We analyze how our way to include evolutionary information gradually increases the discriminative power of InterEvScore. Comparison with several previously published scoring functions (ZDOCK, ZRANK and SPIDER) shows the significant progress brought by InterEvScore. AVAILABILITY: http://biodev.cea.fr/interevol/interevscore CONTACT: guerois@cea.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23652427 TI - Evidence for the dissemination of cryptic non-coding RNAs transcribed from intronic and intergenic segments by retroposition. AB - MOTIVATION: Insertion of DNA segments is one mechanism by which genomes evolve. The bulk of genomic segments are now known to be transcribed into long and short non-coding RNAs (ncRNAs), promoter-associated transcripts and enhancer-templated transcripts. These various cryptic ncRNAs are thought to be dispersed in the human and other genomes by retroposition. RESULTS: In this study, I report clear evidence for dissemination of cryptic ncRNAs transcribed from intronic and intergenic segments by retroposition. I used highly stringent conditions to find recently retroposed ncRNAs that had a poly(A) tract and were flanked by target site duplication. I identified 73 instances of retroposition in the human, mouse, and rat genomes (12, 36 and 25 instances, respectively). The inserted segments, in some cases, served as a novel exon or promoter for the associated gene, resulting in novel transcript variants. Some disseminated sequences showed sequence conservation across animals, implying a possible regulatory role. My results indicate that retroposition is one of the mechanisms for dispersion of ncRNAs. I propose that these newly inserted segments may play a role in genome evolution by potentially functioning as novel exons, promoters or enhancers. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23652428 TI - Comparative analysis of changes in membrane currents in neurons and astrocytes in rat hippocampal slices after stimulation of glutamatergic transmission. PMID- 23652429 TI - The eye of the opossum shrimp Mysis relicta (Crustacea, Mysidae) contains two visual pigments located in different photoreceptor cells. PMID- 23652430 TI - Revealing of T-type low-voltage activated calcium channels (CaV3) in frog neuromuscular junctions. PMID- 23652431 TI - Antidiabetic activity of a novel dipeptide mimetic of nerve growth factor. PMID- 23652432 TI - The influence of oligopeptides on spontaneous carcinogenesis in mice. PMID- 23652434 TI - The effects of new nociceptin analogs on the behavior of white rats. PMID- 23652433 TI - Specific inhibitory effects of the alkylammonium derivative 6-methyluracil on acetylcholinesterase of smooth and striated muscles in rats. PMID- 23652435 TI - Somnogenic effect of exogenous heat shock protein 70 kDa is mediated by GABA(A) receptors in the preoptic area of the hypothalamus. PMID- 23652436 TI - The influence of 9-anthracene carbonic acid on the contractile and electric parameters of the frog (Rana temporaria) skeletal muscle fibers. PMID- 23652437 TI - A unique find of the earliest multicellular algae in the lower proterozoic (2.45 Ga) of the Kola Peninsula. PMID- 23652438 TI - The structure of tactile organs of the Russian desman (Desmana moschata L. 1758) and their role in orientation. PMID- 23652439 TI - New finds of early cretaceous mammals in Mongolia. PMID- 23652440 TI - Hydrogen peroxide generation in the vacuoles of red beet root cells. PMID- 23652441 TI - Stability of Semax acetyl to proteolysis in various biological media. PMID- 23652442 TI - Dietary liposoluble antioxidants protect mouse immune cells from the toxic effects of atmospheric ammonia. PMID- 23652444 TI - Inhibition of the renin-angiotensin-aldosterone system for cerebrorenal protection. AB - Blood pressure is a strong risk factor for ischemic and atherosclerotic events such as stroke. Blood pressure is often elevated in patients with chronic kidney disease. Consequently, chronic kidney disease patients are at high risk of developing cardiovascular and cerebrovascular damage. Blood pressure reduction by means of inhibiting the renin-angiotensin-aldosterone system (RAAS) reduces the risk of stroke. There is evidence available in the primary and secondary prevention of stroke that RAAS blockade exerts cerebrovascular protective effects independent of blood pressure lowering. This chapter discusses the role of RAAS blockade for the prevention and treatment of stroke in chronic kidney disease. The role of dual RAAS blockade will be reviewed and alternative strategies to enhance the effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers will be provided. PMID- 23652443 TI - Ecdysone triggered PGRP-LC expression controls Drosophila innate immunity. AB - Throughout the animal kingdom, steroid hormones have been implicated in the defense against microbial infection, but how these systemic signals control immunity is unclear. Here, we show that the steroid hormone ecdysone controls the expression of the pattern recognition receptor PGRP-LC in Drosophila, thereby tightly regulating innate immune recognition and defense against bacterial infection. We identify a group of steroid-regulated transcription factors as well as two GATA transcription factors that act as repressors and activators of the immune response and are required for the proper hormonal control of PGRP-LC expression. Together, our results demonstrate that Drosophila use complex mechanisms to modulate innate immune responses, and identify a transcriptional hierarchy that integrates steroid signalling and immunity in animals. PMID- 23652445 TI - Obesity and heart failure as a mediator of the cerebrorenal interaction. AB - The obesity epidemic is contributing substantially to the burden of cardiovascular disease including heart disease and congestive heart failure, in the United States and the rest of the world. Overnutrition as a driver of obesity, promotes alterations in fatty acid, lipid, and glucose metabolism that influence myocardial function and progression of heart failure from diastolic to systolic failure. The association of progressive heart failure and progressive chronic kidney disease is well documented and often referred to as the cardiorenal syndrome, as well as a prognosticator for cerebrovascular disease (e.g. stroke). Whether the relationship between obesity, heart disease/failure and risk for chronic kidney disease and stroke is direct or a confluence of risk factors is poorly understood. PMID- 23652446 TI - Subclinical cerebral abnormalities in chronic kidney disease. AB - BACKGROUND AND PURPOSE: Impaired kidney function or chronic kidney disease (CKD), as measured by estimated glomerular filtration rate (eGFR), is associated with incident stroke risk. However, few studies have examined the relationship between CKD and subclinical cerebral abnormalities. METHODS: We examined 675 elderly subjects (mean age 69.9 years), who were living independently at home without apparent dementia, using magnetic resonance imaging. Serum creatinine values, measured by the enzymatic method, were used for the Japanese equation of eGFR. RESULTS: Subclinical lacunar infarction, deep white matter lesions, and periventricular hyperintensities were detected in 88 (13.0%), 240 (35.6%) and 158 (23.4%) of the 675 participants, respectively. In the forward stepwise method of logistic analysis, age (OR 2.081/10, 95% CI 1.541-2.810), hypertension (OR 3.656, 95% CI 2.184-6.119), diabetes mellitus (OR 1.961, 95% CI 1.007-3.820), alcohol intake (OR 2.130, 95% CI 1.283-3.535), and eGFR <45 ml/min/1.73 m(2) were significant factors concerning subclinical lacunar infarction. CKD defined as eGFR <60 ml/min/1.73 m(2) was not significantly associated with subclinical lacunar infarction. Decreased eGFR was not a significant factor associated with white matter lesions (WMLs). Age (OR 2.781/10, 95% CI 2.252-3.435), hypertension (OR 1.746, 95% CI 1.231-2.477), diabetes mellitus (OR 1.854, 95% CI 1.070-3.213), but not eGFR were significant factors concerning WMLs. CONCLUSIONS: The present study showed that community-dwelling elderly subjects with late stage 3 CKD were at high risk for prevalent subclinical lacunar infarction. The identification of CKD-specific modifiable risk factors for SBI and WMLs is of increased importance for prevention of subclinical brain ischemic lesions. PMID- 23652447 TI - Carotid atherosclerosis in kidney disease. AB - Recently, chronic kidney disease (CKD) has become a major public health problem and a risk factor for all-cause mortality, cardiovascular disease (CVD). To prevent cardiovascular disease as early as possible, subclinical studies for CKD are essential. Recently, carotid atherosclerosis has been evaluated by measurement of the intima-media thickness (IMT) of the carotid artery wall, which is a good predictor of incidence of CVD. In this manuscript, I reviewed subclinical studies on the relationship between the carotid atherosclerosis and kidney dysfunction in a general population. Cross-sectional studies for general populations have shown an inverse association of carotid IMT with renal function. In one large cross-sectional study in a US population, the cystatin C level had no independent association with carotid IMT. However, in cross-sectional studies for outpatients, a significant association was observed between the two in subjects with kidney dysfunction. The association between CKD and carotid IMT tends to be weaker in apparently healthy populations than in patients. A higher level of blood pressure decreases renal function, and a decreased GFR raises blood pressure. In other words, increases in blood pressure and decreases of renal function exacerbate each other. Therefore, an investigation of the incidence of CVD and subclinical analyses of both renal dysfunction and blood pressure categories is called for. The impact of high-normal blood pressure and hypertension on stenosis were more evident in subjects with CKD. Carotid atherosclerosis tended to be more severe in subjects with CKD and high blood pressure. These findings pointed to the importance of early detection of subjects with decreased renal function and the strict management of blood pressure in general populations. PMID- 23652448 TI - Kidney disease and cognitive function. AB - We provide a brief review of research on chronic kidney disease and cognitive performance, including dementia. We touch briefly on the literature relating end stage-renal disease to cognitive function, but focus on studies of modest and moderate forms of chronic kidney disease (CKD) that precede dialysis and transplantation. We summarize previous reviews dealing with case control studies of patients but more fully examine community-based studies with large samples and necessary controls for demographic risk factors, cardiovascular variables, and other confounds such as depression. In addition we suggest potential biological and social-psychological mediators between CKD and cognition. Studies follow in two categories of design: (1) cross-sectional studies, and (2) longitudinal studies. In each, CKD is related to a wide range of deficits in cognitive functioning including verbal and visual memory and organization, and components of executive functioning and fluid intellect. In general, prior to the need to treat with hemodialysis (HD) or kidney transplant (KT), magnitude of effect with relation to CKD and function are small or modest in persons free from acute stroke and dementia. However, HD and KT can result in major impairment. We discuss needed controls, the greater demand on controls after the start of HD and KT, and suggest that mechanisms intervening relations between hypertension, or diabetes, and cognitive performance may be similar to those intervening between hypertension and cognitive performance and the hypertension and diabetes literature on cognition provides a good model for the study of early stage kidney disease and cognitive ability. We posit that the mechanisms linking CKD and cognition may be similar to those linking hypertension or diabetes to cognition. We identify the need for more studies with multiple cognitive test batteries, measures of every-day cognitive abilities relevant to patient understanding of the disease and treatments, and more studies with prevalent and incident dementia outcomes. DESCRIPTORS: kidney disease, chronic kidney disease, cognitive function, dementia and cardiovascular risk factors. PMID- 23652449 TI - Risk of stroke in kidney disease. AB - Stroke is a leading cause of mortality and morbidity worldwide. Traditional cardiovascular risk factors - hypertension, diabetes and dyslipidemia - are related to the incidence of stroke. Chronic kidney disease has also been recognized to be a major public health problem as a cardiovascular risk factor. Growing evidence has suggested that chronic kidney disease is associated with an increased risk of cardiovascular disease including stroke in general populations. Those with chronic kidney disease have a greater prevalence of traditional cardiovascular risk factors. Several meta-analyses assessing the association between chronic kidney disease and stroke have found that the magnitude of the risk estimates adjusted for known traditional cardiovascular risk factors were reduced as compared with the age-adjusted risk estimates. While these findings on the surface seem to downplay the effect of chronic kidney disease on stroke, they may actually suggest that an accumulation of traditional cardiovascular risk factors in those with chronic kidney disease increases the risk of stroke, and that applying appropriate treatments to those with chronic kidney disease is important for reducing the risk of stroke. Additionally, other large-scale meta analyses demonstrated that chronic kidney disease was a significant risk factor for stroke independent of known cardiovascular risk factors. Chronic kidney disease may also be associated with an increase in nontraditional risk factors such as hyperhomocysteinemia, inflammation, asymmetric dimethylarginine, oxidative stress, and anemia, and thrombogenic factors such as left ventricular hypertrophy, endothelial dysfunction, and arterial stiffness. Herein, we review the results of meta-analyses of published cohort studies for a better understanding of the precise nature of the relationship between chronic kidney disease and stroke, important to both the clinical and public health fields. Further studies are warranted to determine whether interventions to prevent the progression of kidney impairment are effective at reducing the risk of stroke. PMID- 23652450 TI - Role of 24-hour blood pressure management in preventing kidney disease and stroke. AB - Apart from the well-known role of hypertension in cerebrovascular disease, chronic kidney disease is emerging as an independent risk factor for stroke. Although the mechanism underlying the relationship between blood pressure variability, diurnal blood pressure variation disruption (e.g. nondipping) and kidney dysfunction is not fully understood, these factors are closely associated with each other. This review article summarizes the recent literature on these topics. Cerebral small vessel disease is considered to serve as a common pathophysiology in the relationship of hypertension and chronic kidney disease with cognitive impairment and stroke. Strict 24-hour blood pressure control is necessary to prevent the progression of kidney dysfunction, dementia and stroke. PMID- 23652452 TI - Stroke features and management in patients with chronic kidney disease. AB - Chronic kidney disease (CKD) is an independent risk factor for cardiovascular diseases, including stroke. Patients with CKD are susceptible to ischemic as well as hemorrhagic stroke. The impairments in the small vessel vasculature, atherosclerotic changes of the large vessels, and coagulation abnormalities in CKD probably underlie the specific characteristics of stroke in these patients. The clinical outcomes, including the functional outcomes and short- as well as long-term mortality after stroke, are poor in patients with CKD. CKD is defined as a decreased glomerular filtration rate (GFR) and/or increased urine albumin excretion. A number of studies have shown that either or both of these two markers were significantly associated with poor functional outcomes and mortality after stroke. Recent studies have suggested that proteinuria/albuminuria is more deeply involved in the clinical outcomes than GFR. Although the mechanisms responsible for their association are currently unclear, glomerular barrier and/or filtration dysfunction are probably related to the small vessel diseases, hypercoagulability and inflammation, which may affect the clinical outcomes in CKD patients after stroke. The evidence for the most effective management of acute stroke in CKD patients is lacking, and thus, the current treatment for stroke is optimized for individual patients based on their background. Further studies are thus needed to elucidate the specific features of stroke and also the management of stroke in patients with CKD. PMID- 23652451 TI - Preventing stroke and systemic embolism in renal patients with atrial fibrillation: focus on anticoagulation. AB - Chronic kidney disease and atrial fibrillation (AF) commonly coexist, and data suggest that renal patients have AF rates in excess of double that encountered in the general population. These patients are at increased risk of stroke, regardless of the presence or absence of AF. Furthermore, a lower GFR causes increased thromboembolic risk in patients with AF - independent of other risk factors. The dilemma facing clinicians treating this cohort of patients is that renal insufficiency confers both a thromboembolic and a bleeding risk. Renal disease also commonly coexists with other risk factors for stroke and bleeding such as hypertension and advanced age. Furthermore, bleeding risk tracks stroke risk and many risk factors are common to both thromboembolism and haemorrhage. Patients with severe renal impairment are also actively excluded from the majority of trials for stroke prevention in AF, including those trials which informed the development of stroke risk factor scoring schemes. Therefore, patients with renal disease and AF present a unique management challenge. The available data suggests that the benefit from warfarin in terms of stroke reduction is not as clear as in the general population, and there is an increased risk of bleeding complications and even ectopic vascular calcification. Thus, it is problematic to extrapolate the benefits of warfarin in the general population to a subgroup that has been actively excluded from clinical trials. The new oral anticoagulants have relatively little data in patients with severe renal impairment, and all have an element of renal excretion. There is a need for large randomised control trials in patients with renal insufficiency and on haemodialysis to provide a bank of high-quality scientific data on which clinicians can base their management decisions. Until then, we must adopt a pragmatic approach which involves careful consideration of the relative risk of stroke and bleeding in each individual patient. PMID- 23652453 TI - Stroke feature and management in dialysis patients. AB - Strokes remain the major complication among dialysis population as the number of diabetes and elderly is increasing. In chronic hemodialysis patients, prevalence and incidence of stroke is higher than that of the general population. According to the annual registry data of the Japanese Society for Dialysis Therapy, prevalence of stroke death has been declining, yet the incidence of nonfatal incidence of stroke is not known. Underlying mechanisms of stroke are multiple. Among them, control of hypertension is important for the primary prevention; however, the ideal target level of blood pressure is not determined. Other than hypertension, maintaining good nutritional status is utmost important. Most observational studies suggested that the target was 140/90 mm Hg at prehemodialysis session. However, blood pressure levels are variable in both at office (before and after dialysis session) and at home. It is advisable to measure blood pressure multiple occasions and also at home. In case of acute cerebral hemorrhage, glycerol is indicated to prevent cerebral edema. Blood pressure is recommended to control as systolic <180 mm Hg or mean arterial pressure <130 mm Hg, and lower blood pressure gradually to 80% of the baseline level. In case of acute cerebral infarction hypertension is not treated unless severely hypertensive, systolic >220 mm Hg or diastolic >120 mm Hg and lower blood pressure gradually to 85-90% of the baseline level. Use of warfarin is controversial in case of acute cerebral infarction. Modification of dialysis modality is needed to prevent the increase in intracranial pressure and/or recurrence of stroke. PMID- 23652454 TI - Thrombolysis and hyperacute reperfusion therapy for stroke in renal patients. AB - Thrombolytic therapy using recombinant tissue plasminogen activator (rt-PA) is established as an effective treatment for patients with acute ischemic stroke. No distinction to the presence of chronic kidney disease (CKD) was made in previous clinical trials. In this chapter, three clinical studies that investigated renal dysfunction on the effect of rt-PA were reviewed and a meta-analysis was performed. In total, 344 patients with CKD and 504 patients without were treated within 3 h of symptom onset. Patients with CKD showed decreased odds of being alive and independent compared to patients with normal renal function (OR 0.60, 95% CI 0.45-0.81). Symptomatic intracranial hemorrhage occurred more in patients with CKD than without (OR 3.38, 95% CI 1.60-7.15). Risk of fatal outcome was also significantly higher in patients with CKD (OR 3.15, 95% CI 1.82-5.45). PMID- 23652455 TI - Antiplatelet therapy for preventing stroke in patients with chronic kidney disease. AB - Chronic kidney disease (CKD), defined as reduced glomerular filtration rate and/or proteinuria, is a serious worldwide health problem. The incidence and prevalence of CKD are increasing with age, and patients with CKD are a population at very high risk for developing stroke. CKD may increase the risk for incident stroke independent of conventional stroke risk factors. A common pathological process including anemia, homocysteine, nitric oxide, oxidative stress, inflammation, and conditions promoting coagulation may be related to the development of stroke in the course of CKD. CKD can also serve as a marker of brain injury, because the cerebral microvascular system has similar hemodynamic features with the vascular beds of the kidney. CKD has been linked with markers of cerebral small artery disease including white matter lesions, lacunar infarctions, and cerebral microbleeds. CKD has been implicated with neurological deterioration during hospitalization, poor functional outcome, and hemorrhagic transformation in patients with acute stroke. Recurrence of stroke may also be higher in CKD patients compared with those having normal kidney function. However, there have been no specific recommendations for antiplatelet therapy in patients with ischemic stroke plus CKD. As CKD patients have distinct characteristics including high bleeding complications and poor response to antiplatelet agents, selecting and adjusting platelet aggregation inhibitors should be individualized. In addition, it should be noted that aspirin may aggravate renal dysfunction. Phosphodiesterase inhibitors restore endothelial dysfunction and may serve as a target for preventing stroke in CKD patients. Aside from antiplatelet therapy, other treatments including lipid control, blood pressure lowering, and renal transplantation are also important. Further studies are warranted for optimal treatment in stroke prevention in CKD patients. PMID- 23652459 TI - An ab-initio computational method to determine dielectric properties of biological materials. AB - Frequency dependent dielectric properties are important for understanding the structure and dynamics of biological materials. These properties can be used to study underlying biological processes such as changes in the concentration of biological materials, and the formation of chemical species. Computer simulations can be used to determine dielectric properties and atomic details inaccessible via experimental methods. In this paper, a unified theory utilizing molecular dynamics and density functional theory is presented that is able to determine the frequency dependent dielectric properties of biological materials in an aqueous solution from their molecular structure alone. The proposed method, which uses reaction field approximations, does not require a prior knowledge of the static dielectric constant of the material. The dielectric properties obtained from our method agree well with experimental values presented in the literature. PMID- 23652460 TI - Dual enzyme responsive microcapsules simulating an "OR" logic gate for biologically triggered drug delivery applications. AB - Hollow microcapsules capable of disintegrating in response to dual biological stimuli have been synthesized from two FDA approved drug molecules. The capsules fabricated from protamine and chondroitin sulphate disintegrate in the presence of either trypsin or hyaluronidase enzymes, which are documented to be simultaneously over-expressed under some pathological conditions. PMID- 23652461 TI - 'Distorteidolias' - fantastic perceptive distortion. A new, pure dorsomedial thalamic syndrome. AB - The role of the thalamus in the pathogenesis of the visual and auditory hallucinations has been reported under the name of peduncular hallucinosis, usually with coexisting midbrain involvement. These hallucinations typically take the form of dreamy de novo productions (phanteidolias), less often that of transformations of perceptions into new items (such as seeing faces in clouds) called pareidolias. However, hallucinations taking the form of a complex distortion of perception is a different phenomenon, which to our knowledge has not been reported. We studied 2 patients with complex, 'fantastic', perceptive distortion involving the visual and auditory systems after thalamic stroke limited to the region of the dorsomedial nucleus, sparing the intralaminar nuclei and the midbrain (explaining the lack of disorders of consciousness and confusional state). Our patients reported the modification of usual stimuli (face, body, voices) into unreal, fantastically distorted perceptions (monstrous change of shapes or sounds without appearance of new items). While the exact mechanism leading to such perceptive distortions remains unknown, a release phenomenon due to damage to the dorsomedial thalamus (probably affecting cholinergic system) responsible for a disinhibition of cortical function involved in familiarity of perception seems likely. We suggest that these hallucinations should be called 'distorteidolias'. PMID- 23652462 TI - SIRT1 prevents atherosclerosis via liver-X-receptor and NF-kappaB signaling in a U937 cell model. AB - Atherosclerosis is a chronic immunoinflammatory disease associated with blood lipid disorders. Previous studies in mice have demonstrated that liver X receptor (LXR)-ATP-binding cassette (ABC) A1/ABCG1/C-C chemokine receptor type 7 (CCR7) and nuclear factor kappaB (NF-kappaB) signaling pathways are important for atherosclerotic plaque formation. In addition, Sirtuin 1 (SIRT1) has been reported as a key regulator in the protection from risk of atherosclerosis. However, the exact mechanism by which SIRT1 prevents atherosclerosis remains largely unknown. To explore the possible mechanisms, the expression of SIRT1 and the association between SIRT1, LXR and NF-kappaB in the process of foam cell formation was investigated in an in vitro human mononuclear U937 cell line. Monocyte-derived foam cells were induced by palmitate and Ox-LDL treatment. Oil Red O staining revealed an accumulation of a large number of lipid droplets in foam cells. Results of reverse transcription polymerase chain reaction (RT-PCR) revealed that SIRT1 expression was downregulated during foam cell formation. In addition, the expression of LXRalpha and its targets, ABCA1, ABCG1 and CCR7, were downregulated. However, NF-kappaB and its targets, tumor necrosis factor alpha (TNFalpha) and interleukin (IL)-1beta, were upregulated in foam cells. Following activation of SIRT1 by SRT1720, the expression of LXRalpha and its targets increased, whereas expression of NF-kappaB and its targets decreased. Furthermore, the formation of foam cells was blocked. The SIRT1 inhibitor, nicotinamide, was found to eliminate the effects of SRT1720. Results of the present study indicate that SIRT1 may prevent the formation and progression of atherosclerosis by enhancing the LXR-ABCA1/ABCG1/CCR7 and inhibiting the NF kappaB pathways. PMID- 23652465 TI - Synthesis, physical properties and self-assembly behavior of azole-fused pyrene derivatives. AB - A novel selenadiazole-fused pyrene derivative PySe was successfully synthesized and characterized. Its single structure is almost planar and adopts a sandwich herringbone packing model. The self-assembly behaviors based on compound PySe and its analogue thiadiazole-fused pyrene derivative PyS were studied in detail and the as-formed nanostructures were fully characterized by means of UV-vis absorption, emission spectra, X-ray diffraction, field emission SEM and TEM. We attribute the bathochromic shift absorption and emission spectra of PyS and PySe in aqueous solution to the formation of J-type aggregation. In addition, our investigation demonstrated that the shape and size of the as-prepared nanostructures could be tuned by different chalcogen analogues and the volume ratio of water to organic solvent. PMID- 23652464 TI - Hip fracture prevention with a multifactorial educational program in elderly community-dwelling Finnish women. AB - Guidelines suggest identification of women at fracture risk by bone density measurement and subsequently pharmacotherapy. However, most women who sustain a hip fracture do not have osteoporosis in terms of bone density. The present non pharmacological intervention among elderly women unselected for osteoporosis reduced hip fracture risk by 55 % providing an alternative approach to fracture prevention. INTRODUCTION: Hip fractures are expensive for society and cause disability for those who sustain them. We studied whether a multifactorial non pharmacological prevention program reduces hip fracture risk in elderly women. METHODS: A controlled trial concerning 60- to 70-year-old community-dwelling Finnish women was undertaken. A random sample was drawn from the Population Information System and assigned into the intervention group (IG) and control group (CG). Of the 2,547 women who were invited to the IG, 1,004 (39 %) and of the 2,120 invited to the CG, 1,174 (55 %) participated. The IG participated in a fracture prevention program for 1 week at a rehabilitation center followed by review days twice. The CG received no intervention. During the 10-year follow-up, both groups participated in survey questionnaire by mail. Outcome of interest was occurrence of hip fractures and changes in bone-health-related lifestyle. RESULTS: During the follow-up, 12 (1.2 %) women in the IG and 29 (2.5 %) in the CG sustained a hip fracture (P = 0.039). The determinants of hip fractures by stepwise logistic regression were baseline smoking (odds ratio (OR) 4.32 (95 % confidence interval [CI] 2.14-8.71), age OR 1.15/year (95 % CI 1.03-1.28), fall history OR 2.7 (95 % CI 1.24-5.9), stroke history OR 2.99 (95 % CI 1.19-7.54) and participating in this program OR 0.45 (95 % CI 0.22-0.93). Starting vitamin D and calcium supplement use was more common in the IG compared with the CG. CONCLUSIONS: The results suggest that this non-pharmacological fracture prevention program may reduce the risk of hip fractures in elderly Finnish women. PMID- 23652463 TI - Additive association of vitamin D insufficiency and sarcopenia with low femoral bone mineral density in noninstitutionalized elderly population: the Korea National Health and Nutrition Examination Surveys 2009-2010. AB - Vitamin D insufficiency and sarcopenia are crucial risk factors for osteoporosis. In a study of noninstitutionalized elderly subjects, we investigated the simultaneous effect of vitamin D and sarcopenia on bone mineral density (BMD) and found that sarcopenia was associated with low BMD in the femur, especially in those with suboptimal vitamin D levels. INTRODUCTION: Although vitamin D insufficiency and sarcopenia are prevalent in the elderly population worldwide, their possible influence on BMD has not been determined. We aimed to investigate the different effect of vitamin D insufficiency and sarcopenia on BMD in the elderly Korean population. METHODS: Individuals aged 60 or older were selected from those who participated in the Fourth and Fifth Korea National Health and Nutrition Examination Surveys conducted in 2009 and 2010; 1,596 males and 1,886 females were analyzed. Appendicular skeletal muscle mass (ASM) and BMD were assessed by dual-energy X-ray absorptiometry; serum 25-hydroxyvitamin D [25(OH)D] and a panel of clinical and laboratory parameters were also measured. RESULTS: The study population was divided into four groups according to their vitamin D and sarcopenic status. BMD in total femur and in the femoral neck but not the lumbar spine was markedly decreased in sarcopenic subjects with vitamin D insufficiency [25(OH)D < 20 ng/ml] comparing to other groups, regardless of gender. Multivariable linear regression models showed that BMD was significantly associated with ASM and high daily calcium intake as well as conventional risk factors such as age, body mass index (BMI), and history of fracture. Independent predictors for low femur BMD included sarcopenia, low daily calcium intake, low 25(OH)D levels, age, and BMI. CONCLUSIONS: These data showed that an association between vitamin D insufficiency and low BMD was more prominent in elderly subjects with sarcopenia. PMID- 23652466 TI - No excuse for not looking. PMID- 23652467 TI - Comparison of optical quality parameters and ocular aberrations after wavefront guided laser in-situ keratomileusis versus wavefront-guided laser epithelial keratomileusis for myopia. AB - BACKGROUND: To compare optical quality, ocular scattering, and higher-order aberrations (HOAs) after laser in-situ keratomileusis (LASIK) versus laser epithelial keratomileusis (LASEK). METHODS: A total of 47 eyes from 47 participants who had undergone LASIK (group I) or LASEK (group II) procedure at least 6 months prior were enrolled. Ocular aberrations and modulation transfer function (MTF) values measured using iTrace, a ray-tracing type aberrometer, were compared to MTF (modulation transfer function) cut-off values, Strehl ratio, and objective indices of scattering obtained using the Objective Quality Analysis System II (OQAS II). RESULTS: There was no significant correlation between the postoperative optical quality parameters and the HOAs between both groups. In group I, the MTF cut-off value was significantly correlated with cylinder refraction (p = 0.037), and the objective scattering index (OSI) was positively correlated with spherical equivalent (p = 0.023). In group II, there was a statistically significant correlation between the OSI and achieved refractive correction (p = 0.001). Regression analysis showed that the OSI was the most significant predictor of MTF cut-off values after refractive surgery. Additionally, MTF values measured by OQAS were significantly lower than those measured by iTrace without correlation. CONCLUSION: Optical quality after refractive surgery may be influenced by not only ocular aberrations but also by scattering. Even though the accuracies of the machines used in this study to measure optical quality have yet to be proven, this study showed limited correlation among the values measured using the two different machines after refractive surgery. Therefore, for more generalized evaluation of visual function after refractive surgery, more advanced optical devices still need to be developed. PMID- 23652468 TI - KGF, FGFb, VEGF, HGF and TGFbeta1 secretion of human keratocytes following photodynamic inactivation (PDI) in vitro. AB - PURPOSE: With increasing resistance of microorganisms to antibiotics, photodynamic inactivation (PDI) may be a potential treatment alternative for infectious keratitis. Growth factors have the function to regulate proliferation, apoptosis and motility of the cells, and thereby affect wound healing. The purpose of this study was to evaluate the possible impact of PDI on the secretion of keratinocyte growth factor (KGF), fibroblast growth factor beta (FGFb), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and transforming growth factor beta1 (TGFbeta1) of human keratocytes, in vitro. METHODS: Primary human keratocytes were isolated by digestion in collagenase A (1.0 mg/ml) from human corneal buttons, and cultured in DMEM/Ham's F12 medium supplemented with 10% FCS. Keratocyte cell cultures underwent illumination using red (670 nm) light for 13 min following exposure to 100 nM concentration of the photosensitizer chlorin e6 (Ce6) in culture medium. Five hours and 24 hours after PDI, secretion of KGF, FGFb, VEGF, HGF and TGFbeta1 was measured by enzyme-linked immunoabsorbent assay (ELISA). RESULTS: Compared to untreated controls, FGFb secretion of keratocytes increased (p < 0.0001) and HGF expression decreased (p < 0.01) significantly 5 hours after PDI, whereas KGF, VEGF, and TGFbeta1 secretion remained unchanged. Twenty-four hours following PDI, KGF secretion decreased (p < 0.0001) significantly, while FGFb, HGF, VEGF and TGFbeta1 concentrations did not differ markedly from untreated controls. CONCLUSIONS: Photodynamic inactivation triggers FGFb and inhibits HGF secretion of keratocytes transiently (5 hours) and inhibits KGF secretion 24 hours following treatment. In the short term, PDI does not have an impact on VEGF and TGFbeta1 secretion of keratocytes, in vitro. PMID- 23652469 TI - Vitreous fluid and circulating levels of soluble lr11, a novel marker for progression of diabetic retinopathy. AB - BACKGROUND: To evaluate the vitreous fluid levels of soluble LR11 (sLR11), a novel circulating marker for proliferative diabetic retinopathy (PDR), in patients with PDR and non-PDR (NPDR) in comparison to those in patients with non diabetic ocular diseases. METHOD: Twenty NPDR and 60 PDR cases were included. Twenty-four subjects with a macular hole were served as a control group. The sLR11 levels of vitreous fluid and serum were determined by sandwich enzyme linked immunosorbent assay. RESULTS: The serum sLR11 levels in the PDR and NPDR groups were 12.3 +/- 5.0 ng/ml and 10.0 +/- 2.7 ng/ml, respectively. The sLR11 levels in the vitreous fluid in the PDR (17.8 +/- 6.2 ng/ml) and NPDR (17.4 +/- 7.1 ng/ml) groups were significantly higher than those in the control subjects (12.3 +/- 4.5 ng /ml) (P = 0.0003 and P = 0.006, respectively). The vitreous fluid levels of sLR11 were not significantly different between the PDR and NPDR groups, and the levels were not significantly correlated with the serum levels of sLR11 in the patients with PDR or NPDR. CONCLUSION: Vitreous fluid sLR11 level may be a novel risk factor for the early development of PDR prior to the increase in circulating levels in diabetic patients. PMID- 23652470 TI - PCSK9 inhibitors. AB - PURPOSE OF REVIEW: To summarize the therapeutic strategies to inhibit PCSK9 and to describe the main results obtained in phase I and II trials with monoclonal antibodies targeting PCSK9. RECENT FINDINGS: Among the various approaches for PCSK9 inhibition, human data are only available for inhibition of PCSK9 binding to LDL receptor by monoclonal antibodies. Promising preclinical studies have also been reported with other strategies, including inhibition of PCSK9 synthesis by gene silencing agents. The two most advanced monoclonal antibodies in development are SAR236553/REGN727 and AMG145. In phase II, these two monoclonal antibodies administered subcutaneously are well tolerated and effective to decrease atherogenic lipoproteins. A dramatic decrease in LDL cholesterol up to 70% can be obtained. The efficacy has been evaluated so far in addition to statins in hypercholesterolemic patients with or without familial hypercholesterolemia, in patients with intolerance to statin therapy and in monotherapy. SUMMARY: The short-term efficacy, safety and tolerability of two monoclonal antibodies to PSCK9 have been demonstrated in several phase II trials. These PCSK9 inhibitors are now tested in larger phase III studies to provide insights into the long-term safety and clinical efficacy of this very promising approach. PMID- 23652471 TI - Current world literature. Lipid metabolism. PMID- 23652472 TI - Emerging role of cellular cholesterol in the pathogenesis of nonalcoholic fatty liver disease. PMID- 23652473 TI - Winner by points?--LDL cholesterol as a target for therapeutic intervention. PMID- 23652474 TI - Atherosclerosis: cell biology and lipoproteins. PMID- 23652475 TI - Therapy and clinical trials. PMID- 23652477 TI - Comment on the study 'Long-term efficacy of stereotactic bilateral anterior cingulotomy and bilateral anterior capsulotomy as a treatment for refractory obsessive-compulsive disorder' by Zhang et al. PMID- 23652478 TI - In vivo screening of extracellular matrix components produced under multiple experimental conditions implanted in one animal. AB - Animal experiments help to progress and ensure safety of an increasing number of novel therapies, drug development and chemicals. Unfortunately, these also lead to major ethical concerns, costs and limited experimental capacity. We foresee a coercion of all these issues by implantation of well systems directly into vertebrate animals. Here, we used rapid prototyping to create wells with biomaterials to create a three-dimensional (3D) well-system that can be used in vitro and in vivo. First, the well sizes and numbers were adjusted for 3D cell culture and in vitro screening of molecules. Then, the functionality of the wells was evaluated in vivo under 36 conditions for tissue regeneration involving human mesenchymal stem cells (hMSCs) and bovine primary chondrocytes (bPCs) screened in one animal. Each biocompatible well was controlled to contain MUl-size volumes of tissue, which led to tissue penetration from the host and tissue formation under implanted conditions. We quantified both physically and biologically the amounts of extracellular matrix (ECM) components found in each well. Using this new concept the co-culture of hMSCs and bPCs was identified as a positive hit for cartilage tissue repair, which was a comparable result using conventional methods. The in vivo screening of candidate conditions opens an entirely new range of experimental possibilities, which significantly abates experimental animal use and increases the pace of discovery of medical treatments. PMID- 23652479 TI - Desired vancomycin trough serum concentration for treating invasive methicillin resistant Staphylococcal infections. AB - Vancomycin area under the curve/minimal inhibitory concentration (AUC/MIC) >400 best predicts the outcome when treating invasive methicillin-resistant Staphylococcus aureus infection; however, trough serum concentrations are used clinically to assess the appropriateness of dosing. We used pharmacokinetic modeling and simulation to examine the relationship between vancomycin trough values and AUC/MIC in children receiving vancomycin 15 mg/kg every 6 hours and methicillin-resistant Staphylococcus aureus MIC of 1 MUg/mL. A trough of 7-10 MUg/mL predicted achievement of AUC/MIC >400 in >90% of children. PMID- 23652480 TI - Bony structures related to snapping scapula: correlation to gender, side and age. AB - PURPOSE: This study aimed at summarizing the non-pathologic bony structures which are involved in the pathogenesis of snapping scapula and evaluate their incidence, morphology and correlation to gender, side and age. METHODS: The angulation in the sagittal plane between the supraspinatus and infraspinatus portion of the medial border was measured in 140 dried scapulae. In 264 dried scapulae the medial scapular border morphology was classified into three types and the presence of the Luschka's tubercle and the teres major tubercle or process was recorded. Correlation to gender, side and age was examined using SPSS. RESULTS: The mean angulation between the supraspinatus and infraspinatus portion of the medial border was 154.6 degrees +/- 8.8 degrees . Tauhe medial scapular border was straight in 99 (37.5 %), convex in 135 (51.1 %) and concave in 30 bones (11.4 %). The Luschka's tubercle was present in eight bones (3 %), while teres major tubercle was found in 114 scapulae (43.2 %). A teres major process was present in 18 bones (6.8 %). The process was curved towards the chest wall in nine bones (3.4 %), while in the other nine scapulae (3.4 %) it had no curvature. CONCLUSIONS: The non-pathologic bony structures which predispose to snapping scapula are not rare and include the concave medial scapular border, the Luschka's tubercle and the teres major process curved towards the chest wall. Orthopaedic surgeons should bear in mind these non-pathologic bony structures in order not to be overlooked during the diagnostic procedure of a snapping scapula since they usually require surgical treatment. PMID- 23652481 TI - An extremely uncommon variant of left hepatic artery arising from the superior mesenteric artery. AB - We report a new variation of the left hepatic artery arising from the superior mesenteric artery. The variant was discovered during radiological examinations in a patient presenting with ruptured hepatocellular carcinoma of the left liver lobe. Anatomical description was based on CT-scan and angiographic analysis. When present the left hepatic artery originates from the left gastric artery, with an incidence of 12-34 %. Knowledge of left hepatic artery anatomy is mandatory to optimize surgical and radiological management in complex clinical situations. PMID- 23652482 TI - Metal ions in sugar binding, sugar specificity and structural stability of Spatholobus parviflorus seed lectin. AB - Spatholobus parviflorus seed lectin (SPL) is a heterotetrameric lectin, with two alpha and two beta monomers. In the crystal structure of SPL alpha monomer, two residues at positions 240 and 241 are missing. This region was modeled based on the positional and sequence similarities. The role of metal ions in SPL structure was analyzed by 10 ns molecular dynamics simulation. MD simulations were performed in the presence and absence of metal ions to explain the loss of haemagglutinating property of the lectin due to demetallization. Demetallized structure was found to deviate drastically at the metal binding loop region. Affinity of different sugars like N-acetyl galactosamine (GalNAc), D-galactose and lactose towards the native and demetallized protein was calculated by molecular docking studies. It was found that the sugar binding site got severely distorted in demetallized lectin. Consequently, sugar binding ability of lectin might be decreasing in the demetallized condition. Isothermal titration calorimetric (ITC) analysis of the sugars in the presence of native and demetallized protein confirmed the in silico results. It was observed after molecular dynamics simulations, that significant structural deviations were not caused in the quaternary structure of demetallized lectin. It was confirmed that the structural changes modified the sugar binding ability, as well as sugar specificity of the present lectin. The role of metal ions in sugar binding is described based on the in silico studies and ITC analysis. A comprehensive analysis of the ITC data suggests that the sugar specificity of the metal bound lectin and the loss of sugar specificity due to metal chelation are not linear. PMID- 23652483 TI - A theoretical investigation on the proton transfer tautomerization mechanisms of 2-thioxanthine within microsolvent and long range solvent. AB - A relative complete study on the mechanisms of the proton transfer reactions of 2 thioxanthine was carried out with density functional theory. The models were designed with monohydrated and dihydrated microsolvent catalyses either with or without the presence of water solvent considered with the polarized continuum model (PCM). A total number of 114 complexes and 67 transition states were found with the B3LYP/6-311+G** calculations. The energies were refined with both B3LYP/aug-cc-pVTZ and PCM-B3LYP/aug-cc-pVTZ methods. The activation energies were reported with respect to the Gibbs free energies obtained in conjunction with the standard statistical thermodynamics. Possible reaction pathways were confirmed with the intrinsic reaction coordinates. Pathways via C8 atom on the imidazole ring, via the bridged C4 and C5 atoms between pyrimidine and imidazole rings and via N, O and S atom on the pyrimidine ring were examined. The results show that the most feasible pathway is the proton transfers within the long range solvent surrounding via the N, O and S atoms in the pyrimidine ring with di-hydrated catalysis: N(7)H + 2H2O -> IM89 -> IM90 -> P13 + 2H2O -> IM91 -> IM92 -> P6 + 2H2O -> IM71 -> IM72 -> P7 + 2H2O -> IM107 -> IM108 -> P18 + 2H2O -> IM111 -> IM112 -> P19 + 2H2O -> IM113 -> IM114 -> P17 + 2H2O -> IM105 -> IM106 -> N(9)H + 2H2O that has the highest energy barrier of 44.0 kJ mol(-1) in the transition of IM89 to IM90 via TS54. The small energy barrier is in good agreement with the experimental observation that 2-TX tautomerizes at room temperature in water. In the aqueous phase, the most stable intermediate is found to be IM21 [N(7)H + 2H2O] and the possible co-existing species are the monohydrated IM1, IM9, IM39 and IM46, and the di-hydrated IM5, IM8, IM13, IM16, IM81, IM89, IM90, IM91 and IM106 complexes that have a relative concentration larger than 10(-6) (1 ppm) with respect to IM21. PMID- 23652484 TI - Theoretical investigation of the gas-phase reactions of CF2ClC(O)OCH3 with the hydroxyl radical and the chlorine atom at 298 K. AB - A Theoretical study on the mechanism of the reactions of CF2ClC(O)OCH3 with the OH radical and Cl atom is presented. Geometry optimization and frequency calculations have been performed at the MPWB1K/6-31+G(d,p) level of theory and energetic information is further refined by calculating the energy of the species using G2(MP2) theory. Transition states are searched on the potential energy surface involved during the reaction channels and each of the transition states are characterized by presence of only one imaginary frequency. The existence of transition states on the corresponding potential energy surface is ascertained by performing intrinsic reaction coordinate (IRC) calculation. Theoretically calculated rate constants at 298 K and atmospheric pressure using the canonical transition state theory (CTST) are found to be in good agreement with the experimentally measured ones. Using group-balanced isodesmic reactions as working chemical reactions, the standard enthalpies of formation for CF2ClC(O)OCH3, CF2ClC(O)OCH2 and CF3C(O)OCH3 are also reported for the first time. PMID- 23652485 TI - Choroidal thickness in childhood. AB - PURPOSE: We examined choroidal thickness (ChT) and its spatial distribution across the posterior pole in pediatric subjects with normal ocular health and minimal refractive error. METHODS: ChT was assessed using spectral domain optical coherence tomography (OCT) in 194 children aged 4 to 12 years, with spherical equivalent refractive errors between +1.25 and -0.50 diopters sphere (DS). A series of OCT scans were collected, imaging the choroid along 4 radial scan lines centered on the fovea (each separated by 45 degrees ). Frame averaging was used to reduce noise and enhance chorioscleral junction visibility. The transverse scale of each scan was corrected to account for magnification effects associated with axial length. Two independent masked observers segmented the OCT images manually to determine ChT at foveal center, and averaged across a series of perifoveal zones over the central 5 mm. RESULTS: The average subfoveal ChT was 330 +/- 65 MUm (range, 189-538 MUm), and was influenced significantly by age (P = 0.04). The ChT of the 4- to 6-year-old age group (312 +/- 62 MUm) was significantly thinner compared to the 7- to 9-year-olds (337 +/- 65 MUm, P < 0.05) and bordered on significance compared to the 10- to 12-year-olds (341 +/- 61 MUm, P = 0.08). ChT also exhibited significant variation across the posterior pole, being thicker in more central regions. The choroid was thinner nasally and inferiorly compared to temporally and superiorly. Multiple regression analysis revealed age, axial length, and anterior chamber depth were associated significantly with subfoveal ChT (P < 0.001). CONCLUSIONS: ChT increases significantly from early childhood to adolescence. This appears to be a normal feature of childhood eye growth. PMID- 23652486 TI - Blue-light reflectance imaging of macular pigment in infants and children. AB - PURPOSE: While the role of the macular pigment carotenoids in the prevention of age-related macular degeneration has been extensively studied in adults, comparatively little is known about the physiology and function of lutein and zeaxanthin in the developing eye. We therefore developed a protocol using a digital video fundus camera (RetCam) to measure macular pigment optical density (MPOD) and distributions in premature infants and in children. METHODS: We used blue light reflectance to image the macular pigment in premature babies at the time of retinopathy of prematurity (ROP) screening and in children aged under 7 years who were undergoing examinations under anesthesia for other reasons. We correlated the MPOD with skin carotenoid levels measured by resonance Raman spectroscopy, serum carotenoids measured by HPLC, and dietary carotenoid intake. RESULTS: We enrolled 51 infants and children ranging from preterm to age 7 years. MPOD correlated significantly with age (r = 0.36; P = 0.0142), with serum lutein + zeaxanthin (r = 0.44; P = 0.0049) and with skin carotenoid levels (r = 0.42; P = 0.0106), but not with dietary lutein + zeaxanthin intake (r = 0.13; P = 0.50). All premature infants had undetectable macular pigment, and most had unusually low serum and skin carotenoid concentrations. CONCLUSIONS: Our most remarkable finding is the undetectable MPOD in premature infants. This may be due in part to foveal immaturity, but the very low levels of serum and skin carotenoids suggest that these infants are carotenoid insufficient as a consequence of low dietary intake and/or severe oxidative stress. The potential value of carotenoid supplementation in the prevention of ROP and other disorders of prematurity should be a fruitful direction for further investigation. PMID- 23652487 TI - Racial differences in retinal vessel geometric characteristics: a multiethnic study in healthy Asians. AB - PURPOSE: To investigate potential racial/ethnic differences in retinal vascular geometric parameters in a multiethnic Asian population (Chinese, Malay, and Indian) free of clinical diseases. METHODS: A series of retinal vascular parameters were measured from retinal photographs using a computer-assisted program following a standardized protocol. Healthy participants were defined as nonsmokers, the absence of diabetes mellitus, uncontrolled hypertension, obesity, stroke, heart disease, glaucoma, and retinopathy. RESULTS: THERE WERE SIGNIFICANT DIFFERENCES IN MEASUREMENTS OF RETINAL VASCULAR CALIBER, TORTUOSITY, AND FRACTAL DIMENSION AMONG THE THREE ETHNIC GROUPS. IN MULTIPLE LINEAR REGRESSION MODEL CONTROLLING FOR AGE, SEX, BODY MASS INDEX, SYSTOLIC BLOOD PRESSURE, CHOLESTEROL, AND GLUCOSE LEVELS, INDIANS HAD THE LARGEST ARTERIOLAR AND VENULAR CALIBERS (ARTERIOLES [SE]: 158.94 MUm [1.00]; venules: 228.26 MUm [1.53]), followed by Malays (arterioles: 138.31 MUm [0.74]; venules: 204.26 MUm [1.13]), and then Chinese (arterioles: 131.20 MUm [0.84]; venules: 195.09 MUm [1.28]). Chinese had the largest arteriolar and venular tortuosity (arterioles [* $${10}^{5}$$]: 7.20 [0.08] VENULES [ $${10}^{5}$$]: 9.09 [0.10]), and venular fractal dimension (1.244 [0.003]). There were no statistically significant differences in other retinal vascular parameters after correcting multiple comparisons by the method of modified false discovery rate. CONCLUSIONS: We found that among ethnic groups composed of healthy Chinese, Malay, and Indians, there were statistically significant differences in several retinal parameters. There exist racial influences in retinal vascular parameters and other yet unknown or unmeasured environmental factor or lifestyle habits and genetic variations not related to race that may also contribute to these differences. PMID- 23652489 TI - Precursors of age-related macular degeneration: associations with physical activity, obesity, and serum lipids in the inter99 eye study. AB - PURPOSE: To investigate associations of small, hard macular drusen and larger macular drusen with obesity-related risk factors. METHODS: Cross-sectional study of 888 subjects aged 30 to 60 years characterized using anthropometric measurements and blood sample analyses. Physical activity was assessed by questionnaire. Digital grayscale fundus photographs were recorded in red-free illumination and graded for the presence of macular drusen > 63 MUm in either eye and the presence of 20 or more small, hard macular drusen as a mean of both eyes. RESULTS: Macular drusen > 63 MUm were associated with the level of physical activity, the age- and sex-adjusted odds ratio being 0.33 (95% confidence interval 0.13-0.82, P = 0.016) for participants who were physically active more than 7 hours/week compared with participants active 0 to 2 hours/week. In women, macular drusen > 63 MUm were associated with higher serum triglycerides (P = 0.0005). A waist circumference in the top quartile increased the odds for drusen > 63 MUm in men whereas in women, having a waist circumference in the middle quartiles reduced these odds. The presence of 20 or more small, hard macular drusen was associated with lower levels of serum high-density lipoprotein cholesterol (HDL; P = 0.029) and with moderately elevated triglycerides. CONCLUSIONS: Precursors of AMD were associated with modifiable obesity-related risk factors; notably low physical activity with drusen > 63 MUm; and lower serum HDL and moderately elevated serum triglycerides with 20 or more small, hard macular drusen per eye. These findings support that a physically active, heart healthy lifestyle prevents the earliest manifestation of AMD. (ClinicalTrials.gov number, NCT00289237.). PMID- 23652488 TI - Choroid development and feasibility of choroidal imaging in the preterm and term infants utilizing SD-OCT. AB - PURPOSE: To determine whether choroidal imaging is feasible in preterm and term infants using an 840-nm portable spectral domain optical coherence tomography (SD OCT) system without the use of enhanced-depth imaging techniques and to assess choroidal development by comparing choroidal thickness of preterm infants, term infants, and adults. METHODS: SD-OCT images were obtained from 86 preterm infants, 59 term infants, and nine adults using a portable SD-OCT system plus nine adults using a tabletop system. An unprocessed image across the macula from one randomly selected eye of each participant was selected for determination of whether the choroidal-scleral junction (CSJ) could be visualized and for measurement of choroidal thickness. RESULTS: Subfoveal CSJ was visualized in 96% of young-preterm infants (imaged from 30-36 weeks postmenstrual age [PMA]); 78% of term-aged preterm infants (imaged from 37-42 weeks PMA); 49% of term infants; and 39% of adult subjects. Racial pigmentation did not affect CSJ visibility in young-preterm infants (P = 0.57). Subfoveal choroidal thickness (SFCT) in young preterm infants, term-aged preterm infants, term infants, and adults was 176 +/- 53 MUm, 289 +/- 92 MUm, 329 +/- 66 MUm, and 258 +/- 66 MUm, respectively, and these were all statistically significantly different from one another except term aged preterms to adults. CONCLUSIONS: Infant choroid can be imaged with a portable SD-OCT system without enhanced depth imaging. Melanin in the RPE and choroid does not hinder outer choroidal imaging in young-preterm infants without advanced retinopathy of prematurity (ROP). In preterm infants, choroidal thickness increased with age but was thinner when compared to term infants suggesting delayed development due to ROP. PMID- 23652490 TI - A systematic review on zinc for the prevention and treatment of age-related macular degeneration. AB - PURPOSE: The objective of this systematic review was to examine the evidence on zinc intake from foods and supplements in the primary prevention and treatment of AMD. METHODS: Randomized controlled trials (RCTs), prospective cohort, retrospective cohort, and case-control studies that investigated zinc intake from foods and/or supplements, and AMD in men and women with a mean age of 50 years or older were included. Medline and Cochrane Central were searched from inception to February 2012 and November 2012, respectively. Data extraction and quality appraisal were done on all eligible studies. RESULTS: TEN STUDIES WERE INCLUDED: four RCTs, four prospective cohort, and two retrospective cohort studies. Age related Eye Disease Study (AREDS) showed zinc treatment to significantly reduce the risk of progression to advanced AMD. The risk of visual acuity loss was of similar magnitude, but not statistically significant. Two RCTs reported statistically significant increases in visual acuity in early AMD patients and one RCT showed no effect of zinc treatment on visual acuity in advanced AMD patients. Results from six cohort studies on associations between zinc intake and incidence of AMD were inconsistent. CONCLUSIONS: Current evidence on zinc intake for the prevention of AMD is inconclusive. Based on the strength of AREDS, we can conclude that zinc treatment may be effective in preventing progression to advanced AMD. Zinc supplementation alone may not be sufficient to produce clinically meaningful changes in visual acuity. PMID- 23652491 TI - Influence of incisional vitreous incarceration in sclerotomy closure competency after transconjunctival sutureless vitrectomy. AB - PURPOSE: To evaluate the influence that vitreous incarceration may exert on the presence of postoperative conjunctival blebs over sclerotomies after transconjunctival sutureless vitrectomy (TSV). Blebs are formed by incisional leakage due to incompetent closure. METHODS: Experimental study in which 23-gauge TSV was performed in 146 cadaveric pig eyes. Once the vitrectomy was finished, triamcinolone was injected inside the vitreous cavity for staining residual vitreous, one of the superior cannulas was extracted over the light probe, and the other cannula was removed with the plug inserted. Postoperative conjunctival blebs in superior sclerotomies were assessed by anterior-segment optical coherence tomography (AS-OCT) in a masked fashion; nondetectable blebs were classified as grade 0 (B0), thin bleb (<=half scleral thickness) as grade 1 (B1), and thick bleb (>half scleral thickness) as grade 2 (B2). Postoperative incisional vitreous entrapment was evaluated by slit-lamp photographs in a masked way; no incarceration was classified as grade 0 (V0), thin incarceration as grade 1 (V1), and thick incarceration as grade 2 (V2). RESULTS: Conjunctival blebs were found in 13.7% of the sclerotomies (11.3% bleb-B1, 2.4% bleb-B2). Vitreous incarceration was found in 96.5% of the sclerotomies without bleb (B0), 81.8% of the incisions with bleb-B1, and 14.3% of the wounds with bleb-B2. Vitreous incarceration was significantly associated with the absence of conjunctival bleb (P < 0.001). CONCLUSIONS: Vitreous incarceration in sclerotomies is related to less incisional leakage in our experimental model. Maneuvers that reduce vitreous entrapment, such as the interposition of a nonhollow probe during the cannula extraction, could decrease the sclerotomy closure competency. PMID- 23652492 TI - Short-term effects of overnight orthokeratology on corneal epithelial permeability and biomechanical properties. AB - PURPOSE: To investigate the effects of 30 nights of overnight orthokeratology (OOK) on corneal epithelial permeability (Pdc) and corneal biomechanical properties. METHODS: BE Retainer and Paragon CRT lenses were used. Visits were scheduled approximately 4 hours after awakening at baseline and after 1, 5, 10, 14, and 30 days of treatment. Pdc was measured at baseline and at day 30, whereas corneal biomechanical properties and visual acuities (VAs) were measured at all visits. RESULTS: Thirty-nine neophytes and soft contact lens wearers completed the study. There was no difference in Pdc between baseline (ln[Pdc] [95% confidence interval (CI)] = -2.65 [-2.80 to -2.50]) and day 30 (ln[Pdc][CI] = 2.68 [-2.85 to -2.50]) (P = 0.88). Corneal hysteresis (CH) and corneal resistance factor (CRF) reduced significantly from baseline (CH [CI] = 10.89 [10.59-11.19] mm Hg and CRF [CI] = 10.35 [9.99-10.72] mm Hg) to day 30 (CH [CI] = 10.59 [10.31 10.87] mm Hg and CRF [CI] = 9.58 [9.26-9.89] mm Hg) (P = 0.001 for CH and P < 0.001 for CRF). Posttreatment VA did not reach baseline targets, and the difference was worse with low-contrast letters. Asian individuals (n = 18) had significantly worse VA than non-Asian individuals (n = 21) under most conditions through day 5, and the difference extended through day 14 with low-contrast letters under mesopic conditions. The percentage of participants who achieved 20/20 uncorrected was 17% Asian and 40% non-Asian individuals after day 1 and reached 69% Asian and 83% non-Asian individuals at day 30. CONCLUSIONS: Thirty nights of OOK did not alter Pdc when measured 4 hours after awakening. OOK caused CH and CRF to decrease, but the changes were not clinically significant compared with diseased and postsurgical cases. Asian individuals, who had lower baseline CH in this study, responded slower to OOK based on early uncorrected VA and overrefraction measurements. PMID- 23652493 TI - A magnetic bead-based method for mouse trabecular meshwork cell isolation. AB - PURPOSE: Mice have been used widely for glaucoma research. However, due to the small size of the mouse eye, it is difficult to dissect mouse trabecular meshwork (MTM) tissues and establish MTM cell strains. To circumvent this problem, we took advantage of the phagocytic property of trabecular meshwork (TM) cells, and developed a novel magnetic bead-based method that enables us to isolate pure MTM cells. METHODS: After anesthesia, up to 2 MUL of fluorescent or magnetic microbeads were injected intracamerally into the mouse eyes. To study the distribution and localization of the beads, mice were sacrificed 1 to 7 days after injection, and eyes were enucleated for fluorescent or transmission electron microscopy (TEM) study, respectively. To isolate MTM cells, anterior segments injected with magnetic beads were dissected from 10 to 15 sterilized mouse eyes 7 days after injection. The tissues were digested with collagenase A and purified by using a magnetic field as well as repeated washing. RESULTS: TEM studies showed that the magnetic beads were located in the mouse TM, but not in corneal or scleral fibroblast cells. Cultured MTM cells were similar morphologically to human TM cells. MTM cells expressed TM markers, including collagen IV, laminin, and alpha-smooth muscle actin. Also, MTM cells treated with 100 nM dexamethasone showed increased formation of cross-linked actin networks and induction of myocilin expression. CONCLUSIONS: The magnetic bead-based method is efficient for isolating MTM cells with minimal microdissection techniques required. It will be a useful approach for isolating TM cells from small animals for glaucoma research. PMID- 23652494 TI - Redox and electrochemical water splitting catalytic properties of hydrated metal oxide modified electrodes. AB - This paper presents a review of the redox and electrocatalytic properties of transition metal oxide electrodes, paying particular attention to the oxygen evolution reaction. Metal oxide materials may be prepared using a variety of methods, resulting in a diverse range of redox and electrocatalytic properties. Here we describe the most common synthetic routes and the important factors relevant to their preparation. The redox and electrocatalytic properties of the resulting oxide layers are ascribed to the presence of extended networks of hydrated surface bound oxymetal complexes termed surfaquo groups. This interpretation presents a possible unifying concept in water oxidation catalysis bridging the fields of heterogeneous electrocatalysis and homogeneous molecular catalysis. PMID- 23652497 TI - The cover. Ocean Park #54. PMID- 23652499 TI - The prevalence of the morphin and cocain habits. PMID- 23652500 TI - The Cochrane Collaboration turns 20: assessing the evidence to inform clinical care. PMID- 23652501 TI - Dengue more prevalent than previously thought. PMID- 23652502 TI - Scientists mine web search data to identify epidemics and adverse events. PMID- 23652503 TI - Evidence lacking for benefit from oral cancer screening. PMID- 23652513 TI - Prehospital airway management for out-of-hospital cardiac arrest. PMID- 23652514 TI - Prehospital airway management for out-of-hospital cardiac arrest. PMID- 23652515 TI - Prehospital airway management for out-of-hospital cardiac arrest--reply. PMID- 23652516 TI - Development of trustworthy practice guidelines. PMID- 23652517 TI - Development of trustworthy practice guidelines--reply. PMID- 23652518 TI - Incidence of fall-related traumatic brain injuries among older Finnish adults between 1970 and 2011. PMID- 23652519 TI - Investments in infrastructure for diverse research resources and the health of the public. PMID- 23652520 TI - Developing quality measures to address overuse. PMID- 23652521 TI - A piece of my mind. Status update: whose photo is that? PMID- 23652522 TI - Effect of long-detection interval vs standard-detection interval for implantable cardioverter-defibrillators on antitachycardia pacing and shock delivery: the ADVANCE III randomized clinical trial. AB - IMPORTANCE: Using more intervals to detect ventricular tachyarrhythmias has been associated with reducing unnecessary implantable cardioverter-defibrillator (ICD) therapies. OBJECTIVE: To determine whether using 30 of 40 intervals to detect ventricular arrhythmias (VT) (long detection) during spontaneous fast VT episodes reduces antitachycardia pacing (ATP) and shock delivery more than 18 of 24 intervals (standard detection). DESIGN, SETTING, AND PARTICIPANTS: Randomized, single-blind, parallel-group trial that enrolled 1902 primary and secondary prevention patients (mean [SD] age, 65 [11] years; 84% men; 75% primary prevention ICD) with ischemic and nonischemic etiology undergoing first ICD implant at 1 of 94 international centers (March 2008-December 2010). INTERVENTIONS: Patients were randomized 1:1 to programming with long- (n = 948) or standard-detection (n = 954) intervals. MAIN OUTCOMES AND MEASURES: Total number of ATPs and shocks delivered for all episodes (primary outcomes) and inappropriate shocks, mortality, and syncopal rate (secondary outcomes). RESULTS: During a median follow-up of 12 months (interquartile range, 11-13), long detection group had 346 delivered therapies (42 therapies per 100 person-years, 95% CI, 38-47) vs 557 in the standard-detection group (67 therapies per 100 person-years [95% CI, 62-73]; incident rate ratio [IRR], 0.63 [95% CI, 0.51 0.78]; P < .001). The long- vs the standard-detection group experienced 23 ATPs per 100 person-years (95% CI, 20-27) vs 37 ATPs per 100 person-years (95% CI, 33 41; IRR, 0.58 [95% CI, 0.47-0.72]; P < .001); 19 shocks per 100 person-years (95% CI, 16-22) vs 30 shocks per 100 person-years (95% CI, 26-34; IRR, 0.77 [95% CI, 0.59-1.01]; P = .06), with a significant difference in the probability of therapy occurrence (P < .001); and a reduction in first occurrence of inappropriate shock (5.1 per 100 patient-years [95% CI, 3.7-6.9] vs 11.6 [95% CI, 9.4-14.1]; IRR, 0.55 [95% CI, 0.36-0.85]; P = .008). Mortality (5.5 [95% CI, 4.0-7.2] vs 6.3 [95% CI, 4.8-8.2] per 100 patient-years; HR, 0.87; P = .50) and arrhythmic syncope rates (3.1 [95% CI, 2.6-4.6] vs 1.9 [95% CI, 1.1-3.1] per 100 patient-years; IRR, 1.60 [95% CI, 0.76-3.41]; P = .22) did not differ significantly between groups. CONCLUSIONS AND RELEVANCE: Among patients receiving an ICD, the use of a long- vs standard-detection interval resulted in a lower rate of ATP and shocks, and inappropriate shocks. This programming strategy may be an appropriate alternative. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00617175. PMID- 23652523 TI - Identification of genetic loci associated with Helicobacter pylori serologic status. AB - IMPORTANCE: Helicobacter pylori is a major cause of gastritis and gastroduodenal ulcer disease and can cause cancer. H. pylori prevalence is as high as 90% in some developing countries but 10% of a given population is never colonized, regardless of exposure. Genetic factors are hypothesized to confer H. pylori susceptibility. OBJECTIVE: To identify genetic loci associated with H. pylori seroprevalence in 2 independent population-based cohorts and to determine their putative pathophysiological role by whole-blood RNA gene expression profiling. DESIGN, SETTING, AND PARTICIPANTS: Two independent genome-wide association studies (GWASs) and a subsequent meta-analysis were conducted for anti-H. pylori IgG serology in the Study of Health in Pomerania (SHIP) (recruitment, 1997-2001 [n = 3830]) as well as the Rotterdam Study (RS-I) (recruitment, 1990-1993) and RS II (recruitment, 2000-2001 [n = 7108]) populations. Whole-blood RNA gene expression profiles were analyzed in RS-III (recruitment, 2006-2008 [n = 762]) and SHIP-TREND (recruitment, 2008-2012 [n = 991]), and fecal H. pylori antigen in SHIP-TREND (n = 961). MAIN OUTCOMES AND MEASURES: H. pylori seroprevalence. RESULTS: Of 10,938 participants, 6160 (56.3%) were seropositive for H. pylori. GWASs identified the toll-like receptor (TLR) locus (4p14; top-ranked single nucleotide polymorphism (SNP), rs10004195; P = 1.4 * 10(-18); odds ratio, 0.70 [95% CI, 0.65 to 0.76]) and the FCGR2A locus (1q23.3; top-ranked SNP, rs368433; P = 2.1 * 10(-8); odds ratio, 0.73 [95% CI, 0.65 to 0.81]) as associated with H. pylori seroprevalence. Among the 3 TLR genes at 4p14, only TLR1 was differentially expressed per copy number of the minor rs10004195-A allele (beta = -0.23 [95% CI, -0.34 to -0.11]; P = 2.1 * 10(-4)). Individuals with high fecal H. pylori antigen titers (optical density >1) also exhibited the highest 25% of TLR1 expression levels (P = .01 by chi2 test). Furthermore, TLR1 exhibited an Asn248Ser substitution in the extracellular domain strongly linked to the rs10004195 SNP. CONCLUSIONS AND RELEVANCE: GWAS meta-analysis identified an association between TLR1 and H. pylori seroprevalence, a finding that requires replication in nonwhite populations. If confirmed, genetic variations in TLR1 may help explain some of the observed variation in individual risk for H. pylori infection. PMID- 23652524 TI - Elective cesarean delivery on maternal request. AB - IMPORTANCE: Some pregnant women prefer cesarean delivery and request it without maternal or fetal indication rather than proceeding with a plan for vaginal delivery. OBJECTIVE: To review approaches for counseling women who ask for cesarean delivery without maternal or fetal indication (known as cesarean delivery on maternal request [CDMR]). EVIDENCE REVIEW: An Agency for Healthcare Research and Quality evidence report of studies published after 1990, a 2006 National Institutes of Health state-of-the-science conference report, and published literature were examined. FINDINGS: The prevalence of CDMR in the United States is not precisely known but probably occurs in less than 3% of all deliveries. Most practicing obstetricians have received requests for CDMR from patients. Compared with a plan for vaginal delivery, CDMR may be associated with lower rates of hemorrhage, maternal incontinence, and rare but serious neonatal outcomes. However, CDMR is associated with a higher risk of neonatal respiratory morbidity. Adverse consequences of CDMR may be manifested only in future pregnancies. Repeated cesarean deliveries have higher rates of operative complications, placental abnormalities such as placenta previa and accreta, and consequent gravid hysterectomy. CONCLUSIONS AND RELEVANCE: There is no immediate expectation for CDMR to reduce the health risks of mothers or infants. Accordingly, counseling and decisions regarding CDMR should be made after considering a woman's full reproductive plans. PMID- 23652525 TI - Reducing shocks and improving outcomes with implantable defibrillators. PMID- 23652526 TI - Helicobacter pylori susceptibility in the GWAS era. PMID- 23652527 TI - JAMA patient page. Lung cancer screening. PMID- 23652528 TI - Infection prevention in the cancer center. AB - Cancer patients are frequently immunosuppressed and at risk for a wide range of opportunistic and healthcare-associated infections. A good infection prevention program is extremely important to reduce risk of infection. This review focuses on infection prevention measures specific to patients, healthcare personnel, and visitors in the cancer center. PMID- 23652529 TI - Prenatal imaging of caudal regression syndrome with postnatal correlation: novel insights. PMID- 23652530 TI - Dry needling as a method of tendinopathy treatment. AB - Tendinopathy is a broad concept that describes any painful condition that occurs in or around a tendon.The ideal treatment for tendinopathy is still nebulous. Dry needling is a treatment method in which a special needle is placed into the focus of tendinosis. The aim of this procedure is to form fenestrations which may initiateadvantageous bleeding and thus bring about the influx of growth factors (activating healing and regeneration). Relevant clinical studies have often combineddry needling with autologous blood injection therapy. Results from these studies are encouraging. This review of English-language literature aims to present this noteworthy method of tendino- and enthesopathytreatmentm by describing the results of several trials, hypotheses explaining the underlying mechanism and the application of dry needling in other fields of medicine. PMID- 23652531 TI - Correlations between BMP-4 gene expression, heterotopic ossification and function after uncemented total hip replacement. AB - BACKGROUND: Heterotopic ossification (HO) is the abnormal, non-neoplastic presence of lamellar bone in soft tissue. Bone morphogenetic proteins (BMP) are among factors that may lead to HO. The purpose of the study was to evaluate correlations between BMP-4 gene expression and HO and the influence of those factors on outcomes of cementless total hip replacement (THR). PATIENTS AND METHODS: A series of sixty-four (64) patients were enrolled. The patients were at a mean age of 52.3 years and all of them had undergone unilateral THR. Mean duration of follow-up was 56.74 months. At the last follow-up visit, 1 ml blood samples were collected and BMP-4 gene expression was measured by the RT-PCR technique. Hip radiographs were also obtained and a clinical examination was performed during that visit. RESULTS: A strong statistical correlation was observed between HO grades according to Brooker's scale and BMP-4 expression levels (rho=0.946, p<0.0001), while there was no correlation between clinical outcomes according to the Harris Hip Score (HHS) and Brooker's grades (rho= 0.188, p=0.3) as well as between Harris hip scores and BMP-4 expression levels (rho=0.1, p=0.6). CONCLUSIONS: BMP-4 expression strongly correlates with HO as measured by Brooker's scale and may play a role in the aetiology of this condition. The over-expression of BMP-4 may exert a certain influence on ectopic bone formation after total hip arthroplasty. PMID- 23652533 TI - Reliability of clinical evaluation of meniscus repair with the all-inside technique. AB - INTRODUCTION: The study aimed to compare questionnaire data and clinical evaluation with an assessment of meniscal morphology conducted at arthroscopic anterior cruciate ligament (ACL) reconstruction following meniscal repair. MATERIAL AND METHODS: The study involved a selected group of 17 subjects (5 women and 12 men) aged 14-33 years, who underwent meniscal repair with the Fast-Fix system followed by ACL reconstruction. The mean interval between the procedures was 9 months. Prior to each procedure, the patients were requested to fill in the Lysholm Knee Questionnaire. RESULTS: At review, 14 patients met the criteria of a healed meniscal repair, whereas the remaining 3 subjects presented with signs of meniscal injury. These observations were confirmed at repeat arthroscopy. The Lysholm score for the entire study group increased from a baseline value of 57.3 to 92.2 points postoperatively, with the patients with reruptured menisci also improving, from 58 to 75.3 points. CONCLUSIONS: 1) Our results show that clinical examination is reliable to evaluate the healing of meniscal lesions following all inside repair, as confirmed by repeat arthroscopy. 2) A far greater increase in the Lysholm score seen in patients whose menisci were confirmed to have healed by repeat arthroscopy indicates that such questionnaires may be of help in the evaluation of treatment outcomes. PMID- 23652532 TI - A comparison of complications requiring return to theatre in hip and knee arthroplasty patients taking enoxaparin versus rivaroxaban for thromboprophylaxis. AB - BACKGROUND: There is no consensus on the optimal form of venous thromboembolic prophylaxis treatment in hip and knee arthroplasty patients, or on the safety and complication profile of the available chemical prophylaxis modalities. In this study we aimed to measure the return to theatre rate for any cause related to wound complications in patients undergoing total hip replacement and total knee replacement, and compare these rates between patients on oral Rivaroxaban 10mg OD and subcutaneous Enoxaparin 40mg OD in our department. MATERIAL AND METHODS: There were a total of 387 patients included in the study; 227 patients in group 1, who received Enoxaparin 40mg OD, and 160 patients in group 2, who received Rivaroxaban 10mg OD. RESULTS: The primary outcome measure was re-operation rate due to wound complications. Secondary outcome measures were infection rate, incidence of deep vein thrombosis, pulmonary emboli, duration of hospital stay, change in haemoglobin and haematocrit and blood transfusion rate. In this retrospective cohort study we found that patients who received Rivaroxaban were more than twice as likely to return to theatre for wound complications compared to patients receiving Enoxaparin. Although not statistically significant, this increase is in line with previous studies. Infection rates increased from 0.9% to 1.9% after the introduction of Rivaroxaban and microbiologically confirmed superficial infections rose from 1.3% to 3.1% after Rivaroxaban was introduced in our unit. These rises were not statistically significant. CONCLUSION: Our study highlights the need for large randomised controlled trials to assess post operative complications following the introduction of Rivaroxaban for post arthroplasty thromboprophylaxis. PMID- 23652534 TI - Thoracolumbar compression fractures - experimental study and clinical case analysis. AB - BACKGROUND: Epiphyseal stabilisation and reduction with the use of ligamentotaxis are employed in the surgical treatment of compression fractures of the spine. The mechanism of ligamentotaxis has not been fully elucidated. Therefore, it is fundamental to analyse various clinical data to determine the study area relevant to the elucidation of this mechanism. MATERIAL AND METHODS: We developed criteria for data selection from patient medical records for a newly-created database regarding cases of thoracolumbar vertebral body fractures. We also developed rules for assigning cases to a specific group according to the AO/Magerl classification. The methodology of fracture assessment involved the results of visualization of the spinal segment including the injured vertebral bodies and their virtual and material models. To this end, preoperative CT images were processed with specialised computer software. RESULTS: A biomechanically-oriented classification of clinical cases in the database was carried out based on 3D-CAD virtual models of spinal segments and models of individual injured vertebral bodies and RP material models in FDM technology. We indicated cases in which ligamentotaxis could be of use. CONCLUSIONS: Our analysis of ligamentotaxis research shows that the focus should be on cases of comminuted and nonosteoporotic fractures. Supporting work-up with 3D-CAD virtual and RP material models of spinal structures appears to be useful not only for the purposes of the present study but also in medical practice. PMID- 23652535 TI - Lumbosacral pain in ballet school students. Pilot study. AB - BACKGROUND: The unique biomechanical demands placed on ballet students predispose to injury and pain. The aim of this study was to evaluate the prevalence of lumbosacral pain in ballet school students and to identify possible risk factors for the pain. MATERIAL AND METHODS: The study group comprised 71 ballet school students, including 45 females and 26 males, aged 15-18 years (mean 16.5 years). In order to identify possible risk factors for pain, a survey was conducted, the angle of sacral bone inclination was measured using a mechanical inclinometer and the BMI was calculated. A VAS scale was used for a subjective assessment of pain intensity. RESULTS: Low back pain was reported by 44 patients (62%). A comparison of sacral inclination angles in a position with the feet placed parallel and in the turnout position showed statistically significant changes in the angle among respondents reporting pain (p <0.05). CONCLUSIONS: 1. Compensation in the turnout position by increas ed anterior tilt of the pelvis may increase the risk of low back pain. 2. An angle of sacral bone inclination in turnout above or equal to 30 degrees can increase the intensity of low back pain. 3. A BMI below 18.5 in female ballet school stu dents can increase the risk of lumbosacral pain. PMID- 23652536 TI - The effect of limitation in ankle dorsiflexion on knee joint function. A pilot study. AB - BACKGROUND: A restriction in ankle dorsiflexion is a common complication of ankle fractures. This kind of dysfunction, if severe, can significantly influence gait. A restriction in ankle dorsiflexion (forward movement of the shin relative to the foot) can cause, among others, hyperextension of the knee during the stance phase. The length of leading leg step is shortened and alternant walk downstairs is very difficult. The aim of this study was to examine the correlation between the range of dorsiflexion in the ankle joint and the range of extension (hyperextension) in the knee joint. MATERIAL AND METHODS: The study enrolled 17 patients after ankle joint fractures treated conservatively or surgically. The extension ranges of motion in the ankle and knee joints were assessed by goniometry to compare these values in injured vs. healthy limbs. Non-parametric methods (the Wilcoxon signed-rank test) were used for the analysis. RESULTS: The results showed limitation in ankle dorsiflexion in the fractured limb, which amounted to 4.40 vs. 16.00 in healthy limbs in all patients. This difference was statistically significant (p<0.001). There was also a significantly (p<0.001) greater range of knee hyperextension on the side of injury (5.00 vs. 1.90 in healthy limbs). CONCLUSIONS: 1. Post-traumatic restriction of ankle dorsiflexion can cause knee joint overload. 2. Examinations of knee function during walking should be carried out in patients with trauma-related dysfunctions of the ankle joint in order to prevent secondary musculoskeletal abnormalities. PMID- 23652537 TI - Percutaneous K-wire buttress technique for displaced radial neck fracture. AB - Radial neck fractures are uncommon injuries in adults and more often found in children, where they account for 5-8.5% of elbow injuries. It is generally agreed that an angulation of less than 30 degrees is acceptable. However, anything greater than this should be improved in an attempt to restore normal anatomy and maximize the range of movement. We describe our management of a radial neck fracture in a young lady which was significantly angulated, resulting in a restriction of movements. Attempts at a closed reduction failed and hence we proceeded with percutaneous reduction and buttressing with a K-wire. Post operatively the patient regained a full range of movements with normal elbow function. We outline our surgical technique, which has not been previously described. We suggest that it is a safe and easy option in cases of failed closed reduction and should be considered prior to proceeding with an open reduction. PMID- 23652539 TI - Erosivity, surface runoff, and soil erosion estimation using GIS-coupled runoff erosion model in the Mamuaba catchment, Brazil. AB - This study evaluates erosivity, surface runoff generation, and soil erosion rates for Mamuaba catchment, sub-catchment of Gramame River basin (Brazil) by using the ArcView Soil and Water Assessment Tool (AvSWAT) model. Calibration and validation of the model was performed on monthly basis, and it could simulate surface runoff and soil erosion to a good level of accuracy. Daily rainfall data between 1969 and 1989 from six rain gauges were used, and the monthly rainfall erosivity of each station was computed for all the studied years. In order to evaluate the calibration and validation of the model, monthly runoff data between January 1978 and April 1982 from one runoff gauge were used as well. The estimated soil loss rates were also realistic when compared to what can be observed in the field and to results from previous studies around of catchment. The long-term average soil loss was estimated at 9.4 t ha(-1) year(-1); most of the area of the catchment (60%) was predicted to suffer from a low- to moderate-erosion risk (<6 t ha(-1) year(-1)) and, in 20% of the catchment, the soil erosion was estimated to exceed > 12 t ha(-1) year(-1). Expectedly, estimated soil loss was significantly correlated with measured rainfall and simulated surface runoff. Based on the estimated soil loss rates, the catchment was divided into four priority categories (low, moderate, high and very high) for conservation intervention. The study demonstrates that the AvSWAT model provides a useful tool for soil erosion assessment from catchments and facilitates the planning for a sustainable land management in northeastern Brazil. PMID- 23652538 TI - Clinical improvement after 2 years one stage bilateral open reduction of chronic anterior shoulder dislocations with internal fixation of greater tuberosity fractures. Case study. AB - We report an unusual case of clinical improvement after 2 years from one stage bilateral open reduction of chronic anterior shoulder dislocations with internal fixation of greater tuberosity fractures. The chronic bilateral anterior shoulder dislocations with greater tuberosity fractures were caused by electric shock. After the injury the patient was hospitalized on a medical ward and the dislocations were not diagnosed. Four weeks later the diagnosis of both anterior shoulders dislocations with greater tuberosity fractures was confirmed by X-ray. The patient was treated with one stage bilateral open reduction of chronic shoulder dislocations with internal fixation of greater tuberosity fractures by means of a deltopectoral approach. The shoulders were kept immobilized for six week, next the patient was rehabilitated. He underwent a thorough first evaluation 1 year after the procedure and second ewaluation after 2 years. He had a very good and comfortable range of motion in both shoulders at a follow-up. The modified Constant score was very good in both shoulders (95 points). To the best of our knowledge, such a case has not yet been described in the literature. Our case proved the chronic anterior bilateral humeral head dislocation may be successfully treated in one stage procedure provided the patient is carefully selected and his consent obtained. Moreover, the clinical improvement may be expected even two years after the surgery. PMID- 23652541 TI - Noninvasive pH Monitoring in Platelet Concentrates. AB - BACKGROUND: New technology introduces the option to measure pH in platelet concentrates noninvasively. Findings that in one out of 25 apheresis concentrates the pH decreased significantly during storage motivated us to evaluate apheresis concentrates from 307 platelet donors. METHODS: Small (15 ml) BSCI storage containers for noninvasive pH measurement were used in parallel with Fenwal PL2400 bags for storage of 5 days. Noninvasive pH measurement was compared to pH determination in samples from the storage container. Decrease of pH during storage was calculated as DeltapH d2-d5. RESULTS: The coefficient of correlation for noninvasive pH measurement (n = 256) versus standard methods was R(2) = 0.964 (pH electrode) or 0.952 (ABL 510). pH values in BSCI bags were slightly lower than in Fenwal PL2400 containers. Concentrates collected from 8 of the 307 donors showed a significant drop in pH. Repeated collection did not confirm these findings with a single exception. CONCLUSION: Noninvasive pH measurement demonstrates a high reproducibility. Our study could not confirm the frequency of 1 out of 25 plateletpheresis donors with concentrates developing a significant drop in pH during storage. This may be due to a substantially lower platelet concentration in our preparations. PMID- 23652542 TI - Optimisation of patient dose for the horizontal beam technique in lateral lumbar spine radiographic examinations. AB - In the emergency department, patients undergoing lateral lumbar spine radiography examinations are positioned either lying on their side on an X-ray table with the X-ray beam vertical or lying supine on a trolley with the X-ray beam horizontal. The measured dose-area product (DAP) values were found to differ significantly, typically 1.3 Gy cm(2) for those patients examined on the X-ray table and 2.7 Gy cm(2) for those on a trolley. This work investigates the reason for higher DAP values with the horizontal beam technique. The UK's current recommended national diagnostic reference level (NDRL) for the lateral lumbar spine is 2.5 Gy cm(2). The measurements of body diameter on volunteers showed that rotating the patients from their side to their back resulted in an increase in tissue thickness of between 2 cm and 9 cm for the lumbar region. X-ray absorption increases exponentially with increasing tissue thickness. An increase of 5 cm in body diameter for a lateral lumbar spine at 93 kV will increase the DAP by more than two-fold. Mathematical modelling and measurements with polymethyl methacrylate provided data to predict the tube potential increase necessary to reduce the DAP. For the horizontal beam technique, the tube potential was increased from 93 kV to 102 kV and the average DAP reduced to 2.3 Gy cm(2). Radiographic technique should be understood when auditing the dose. Tube potential must be increased to optimise the horizontal beam technique. The 2.5-Gy cm(2) NDRL relates predominantly to the more common vertical beam technique. Separate local diagnostic reference levels for horizontal and vertical beam techniques are recommended. PMID- 23652543 TI - Statistical evaluation of toxicological assays: Dunnett or Williams test-take both. AB - The US National Toxicology Program recommends the use of the parametric multiple comparison procedures of Dunnett and Williams for the evaluation of repeated toxicity studies. For endpoints where either increasing or decreasing effects are of toxicological relevance, we recommend the use of the two-sided Dunnett test exclusively. For the many other endpoints, where a priori only one direction is of toxicological relevance, however, we recommend the combination of Dunnett and Williams test. In particular, we recommend the so-called Umbrella-protected Williams test which offers insights for all interesting monotone and non-monotone alternatives while only suffering a marginal loss in power compared to the Dunnett test. We illustrate the power difference analytically and compare the approach for different endpoint types using three real data examples to alternative tests available. Nonparametric tests, which are suitable for the evaluation of skewed distributed or scores data, are also considered. Particular attention is given to the different interpretations of the findings revealed by the different test. R programs used for the analyses are provided. PMID- 23652544 TI - Assessment of ABCG2-mediated transport of xenobiotics across the blood-milk barrier of dairy animals using a new MDCKII in vitro model. AB - The ATP-binding cassette (ABC) efflux transporter ABCG2 represents the main route for active secretion of drugs and toxins across the blood-milk barrier, thereby producing a potential health risk for dairy consumers through formation of relevant residues in milk. However, no suitable in vitro model is as yet available to systematically investigate ABCG2-mediated transport of xenobiotics into milk of dairy animals. We recently cloned ABCG2 from the lactating mammary gland of dairy cows (bABCG2) and goats (cABCG2). Thus, the objective of this study was to generate a suitable blood-milk barrier in vitro model using polarized MDCKII monolayers stably expressing mammary bABCG2 or cABCG2. ABCG2 protein was localized by confocal microscopy to the apical and lateral plasma membrane of polarized MDCKII cells. Intact barrier function of MDCKII-bABCG2 and MDCKII-cABCG2 monolayers was confirmed by determination of cell permeability of transcellular marker propranolol and paracellular marker atenolol which was <=1 %. In flux assays, ABCG2 substrate 2-amino-1-methyl-6-phenylimidazo[4,5 b]pyridine (PhIP) showed preferential basolateral to apical (B > A) transport in ABCG2-MDCKII cells. This apically directed PhIP transport was significantly inhibited by ABCG2 inhibitor fumitremorgin C (FTC) or the flavonoid equol. PhIP B > A transport in MDCKII-bABCG2 monolayers was additionally decreased by ABCG2 inhibitor Ko143. The fluoroquinolone antibiotic enrofloxacin was identified as a substrate of ruminant mammary ABCG2. The analgesic drug sodium salicylate was shown to be substrate of bABCG2 but not of cABCG2. Thus, the generated mammary ABCG2-expressing MDCKII cells represent a valuable tool to study active secretion of drugs and toxins into milk. PMID- 23652545 TI - Highly selective fluorescent recognition of histidine by a crown ether terpyridine-Zn(II) sensor. AB - A Zn(II) complex was found to exhibit greatly enhanced fluorescence in the presence of histidine but not in the presence of any other amino acids including cysteine. This sensor could also distinguish histidine from other imidazole derivatives. PMID- 23652546 TI - Osteo-renal cross-talk and phosphate metabolism by the FGF23-Klotho system. AB - Phosphate is widely distributed in the body and an adequate balance is required for maintaining essential cellular and organ functions. Dysregulation of phosphate balance, either in the form of hypophosphatemia or hyperphosphatemia can induce disorders ranging from rickets/osteomalacia to cardiovascular calcification. A physiologic phosphate balance is delicately maintained by multiorgan cross-talks among the intestine, kidney, and bone. Sodium-dependent phosphate (Na/Pi) cotransporters present in the intestine and kidney play a major role in phosphate absorption and reabsorption, according to the body's demand. Some of the calcium regulating factors, including parathyroid hormone and vitamin D can influence the activities of Na/Pi cotransporters, and thereby can affect phosphate balance. In addition, molecular analysis of the unexplained hypophosphatemic diseases, including autosomal-dominant hypophosphatemic rickets and tumor-induced osteomalacia has led to the identification of fibroblast growth factor 23 (FGF23). Subsequent studies have documented that bone-derived FGF23 and kidney-derived klotho can form an endocrine network to control urinary phosphate excretion. Studies have also documented negative effect of FGF23/klotho system on vitamin D metabolism and Na/Pi cotransporter activities. This article will summarize how the FGF23/klotho system might influence systemic phosphate metabolism, and consequences of its abnormal regulation will be briefly described. PMID- 23652547 TI - Extracellular phosphate as a signaling molecule. AB - Phosphorus is involved in various biological processes including membrane integrity, maintenance and inheritance of genetic materials, energy metabolism, intracellular signaling and skeletal mineralization. In addition, accumulating evidences have indicated that alteration in the levels of extracellular inorganic phosphate (Pi) itself triggers signaling to regulate gene expression and cellular functions in some cell types. In bone cells such as osteoblasts and chondrocytes, extracellular Pi modulates cell proliferation, differentiation, mineralization and apoptosis. In extraskeletal tissues, extracellular Pi also exerts various effects. For example, increased extracellular Pi results in the calcification associated with the upregulation of osteoblast marker genes in vascular smooth muscle cells. As to the mechanistic aspects, it is suggested that an increase in extracellular Pi triggers signal transduction via the PiT1 type III sodium/phosphate (Na(+)/Pi) cotransporter and ERK1/2 pathway. Unicellular organisms such as bacteria and yeast sense the environmental Pi with a protein complex located in the plasma membrane, which regulates the expression of multiple genes involved in Pi uptake and metabolism to adapt to its availability. In mammals that are multicellular organisms, Pi availability should be sensed both at a cellular level to regulate the function of each cell and as a whole body to maintain the Pi homeostasis of the extracellular fluid. Although the responsiveness to the increased extracellular Pi suggests the existence of Pi sensing mechanism in mammalian cells as well, it is unknown whether the sensing of Pi availability at a cellular level and that at a whole-body level share the same pathway or not. This chapter will review the findings regarding the regulation of various cellular functions by extracellular Pi, and also discuss the current concept on the mechanism for Pi-sensing. PMID- 23652548 TI - Complex regulation and diverse functions of alpha-klotho. AB - It has been understood that the alpha-klotho gene, first identified as an aging related gene, is actually necessary for regulating mineral homeostasis in vertebrates. All vertebrates, including humans, actively maintain calcium and phosphate ions in bones, circulating blood, and cerebrospinal fluid. Therefore, disruptions in homeostasis cause osteoporosis, ectopic calcification, and epilepsy. Vitamin D and parathyroid hormone are well-known hormones for maintaining calcium and phosphate balance. Synthesis of vitamin D, secretion of parathyroid hormone, and absorption of calcium and phosphate ions are all finely controlled by alpha-Klotho-dependent machineries. However, the precise molecular mechanisms and functions of alpha-Klotho are still unclear. In this article, we present an overview of recent progress in alpha-klotho research, with a main focus on molecular aspects. PMID- 23652551 TI - Phosphate toxicity and vascular mineralization. AB - Vascular calcification or mineralization is a major complication seen in patients with advanced stages of chronic kidney disease (CKD), and it is associated with markedly increased morbidity and mortality. Most of the CKD-related vascular mineralization is attributable to abnormal mineral ion metabolism. Elevated serum calcium and phosphate levels, along with increased calcium-phosphorus byproduct, and the use of active vitamin D metabolites are thought to be the predisposing factors for developing vascular mineralization in patients with CKD. Recent experimental studies have shown that vascular mineralization can be suppressed by reducing serum phosphate levels, even in the presence of extremely high serum calcium and 1,25-dihydroxyvitamin D levels, indicating that reducing 'phosphate toxicity' should be the important therapeutic priority in CKD patients for minimizing the risk of developing vascular mineralization and the disease progression. PMID- 23652550 TI - Nuclear receptor LXR: a new partner for sodium-dependent phosphate cotransporters. AB - New pharmaceutical research approaches are focusing on trying to alleviate the perturbed phosphate (Pi) homeostasis associated with the onset of chronic kidney disease; this includes activation of some of the nuclear receptors. We have recently reported the down regulation of the intestinal and renal sodium phosphate (NaPi) cotransporters by the liver X receptor (LXR) agonists, and the consequent decrease of the serum Pi levels. In this review, we describe our current knowledge of the different proteins involved in the renal and intestinal actions of LXR. PMID- 23652549 TI - Klotho and chronic kidney disease. AB - Through alternative splicing, Klotho protein exists both as a secreted and a membrane form whose extracellular domain could be shed from the cell surface by secretases and released into the circulation to act as endocrine factor. Unlike membrane Klotho which functions as a coreceptor for fibroblast growth factor-23 (FGF23) to modulate FGF23 signal transduction, soluble Klotho is a multifunction protein present in the biological fluids including blood, urine and cerebrospinal fluid and plays important roles in antiaging, energy metabolism, inhibition of Wnt signaling, antioxidation, modulation of ion transport, control of parathyroid hormone and 1,25(OH)2VD3 production, and antagonism of renin-angiotensin aldosterone system. Emerging evidence from clinical and basic studies reveal that chronic kidney disease is a state of endocrine and renal Klotho deficiency, which may serve as an early biomarker and a pathogenic contributor to chronic progression and complications in chronic kidney disease including vascular calcification, cardiac hypertrophy, and secondary hyperparathyroidism. Supplementation of exogenous Klotho and/or upregulation of endogenous Klotho production by using rennin angiotensin system inhibitors, HMG CoA reductase inhibitors, vitamin D analogues, peroxisome proliferator-activated receptors gamma agonists, or anti-oxidants may confer renoprotection from oxidation and suppression of renal fibrosis, and also on prevention or alleviation of complications in chronic kidney disease. Therefore, Klotho is a highly promising candidate on the horizon as an early biomarker, and as a novel therapeutic agent for chronic kidney disease. PMID- 23652552 TI - Vitamin D and type II sodium-dependent phosphate cotransporters. AB - The type II sodium-dependent Pi (NaPi) cotransporters (NaPi-IIa, NaPi-IIb and NaPi-IIc) contribute to renal and intestinal Pi absorption. 1,25-Dihydroxyvitamin D [1,25(OH)2D3] is an important factor for NaPi-II transporters in the small intestine and kidney. In a previous study, low levels of 1,25(OH)2D3 appeared to suppress the expression of renal NaPi cotransporters. We identified a functional vitamin D receptor-responsive element in the human NaPi-IIa and NaPi-IIc genes in renal epithelial cells. In an analysis of vitamin D receptor (VDR)-null mice, we observed early onset of hypophosphatemia. The cause of the hypophosphatemia in VDR-null mice before weaning appeared to be increased plasma parathyroid hormone (PTH) levels during the suckling periods. A rescue diet (high calcium diet) decreased plasma PTH levels in VDR-null mice. The reduced plasma PTH levels normalized the renal Npt2a and Npt2c protein levels in weanling animals. Thus, the dietary intervention completely normalized the expression of the renal Pi transporters (Npt2a/Npt2c) in VDR-null mice, suggesting that the lack of VDR activity was not the cause of the impaired renal Pi reabsorption. In suckling animals, 1,25(OH)2D3 may be essential for the prevention of the phosphaturic action of PTH. In adult animals, 1,25(OH)2D3 is thought to be an important factor for posttranscriptional regulation of the Npt2b gene in the small intestine. Fibroblast growth factor 23 (FGF23) is a novel phosphaturic factor that influences vitamin D metabolism and renal reabsorption of Pi. We characterized the role of the VDR in the action of FGF23 using VDR-null mice. FGF23 reduced renal Pi transport and 25-hydroxyvitamin D 1a-hydroxylase levels by a mechanism that was independent of the VDR. By contrast, the induction of 25-hydroxyvitamin D 24-hydroxylase and the reduction in serum 1,25(OH)2D3 levels induced by FGF23 were dependent on the VDR. Thus, the VDR is not essential for the phosphaturic action of FGF23, but is essential for control of the plasma 1,25(OH)2D3 level. Moreover, FGF23 reduces intestinal NaPi transport activity and Npt2b protein levels by a mechanism that is dependent on the VDR. Klotho functions as a co receptor for FGF23 and is increased by 1,25(OH)2D3. Klotho induces phosphaturia by inhibiting the renal NaPi-IIa transporter. In this review, we discuss the roles of 1,25(OH)2D3/VDR in the regulation of renal type II NaPi cotransporters in the kidney and small intestine. PMID- 23652553 TI - Vitamin D in chronic kidney disease. AB - Vitamin D deficiency is highly prevalent in patients with chronic kidney disease (CKD). The low vitamin D status is, to a large extent, caused by dysregulation of vitamin D metabolism as a result of renal insufficiency. Recent studies indicate that vitamin D-deficiency may promote or accelerate the progression of CKD, whereas treatment with low calcemic vitamin D analogs can reduce proteinuria and ameliorate renal damage in animal models of kidney disease and in patients with CKD. The renoprotective activity of vitamin D regulates multiple signaling pathways known to play important roles in renal injury. These findings underscore the importance of correcting vitamin D deficiency with vitamin D supplementation or with activated vitamin D analogs in the management of CKD. PMID- 23652554 TI - Parathyroid function in chronic kidney disease: role of FGF23-Klotho axis. AB - The parathyroid gland plays a central role in the regulation of mineral metabolism. In patients with chronic kidney disease (CKD), circulating levels of parathyroid hormone (PTH) are progressively increased as kidney function declines, as a result of phosphate retention, hypocalcemia, decreased production of 1,25-dihydroxyvitamin D [1,25(OH)2D], endogenous changes within the parathyroid gland, and skeletal resistance to the actions of PTH. In addition, the identification of fibroblast growth factor 23 (FGF23) and its cofactor Klotho offers important implications for the deeper understanding of disordered mineral metabolism in CKD. In early CKD, increased FGF23 to maintain neutral phosphate balance results in suppression of renal 1,25(OH)2D production and thereby triggers the early development of secondary hyperparathyroidism. FGF23 also acts directly on the parathyroid to decrease PTH synthesis and secretion, but this effect is blunted in advanced stages of CKD, due to decreased expression of the Klotho-FGF receptor 1 complex and increased concentrations of C-terminal FGF23 that competes with full-length FGF23 for binding to the receptor complex. Recent clinical studies also reported that high levels of FGF23 are associated with morbidity and mortality as well as treatment resistance to active vitamin D, suggesting the potential of FGF23 as a novel biomarker to guide treatment of disordered phosphate metabolism in CKD. This review will discuss the pathogenesis of secondary hyperparathyroidism, particularly focusing on the emerging role of the FGF23-Klotho axis in patients with CKD. PMID- 23652555 TI - FGF23-induced hypophosphatemia persists in Hyp mice deficient in the WNT coreceptor Lrp6. AB - Deregulated phosphate homeostasis can lead to a wide range of disorders, including myopathy, cardiac dysfunction, and skeletal abnormalities. Therefore, characterization of the molecular regulation of phosphate metabolism is of pathophysiological and clinical significance. Hyp mouse is the model for human X linked hypophosphatemia which is due to mutations that inactivate the endopeptidases of the X chromosome (PHEX). PHEX inactivation leads to increased serum levels of fibroblast growth factor 23 (FGF23), a phosphaturic hormone that induces excessive renal phosphate excretion and severe hypophosphatemia. The expression of WNT signaling components is increased in Hyp mice. To determine the potential role of WNT signaling in FGF23-mediated hypophosphatemia, we cross-bred Hyp mice with mice deficient in the WNT coreceptor low-density lipoprotein receptor-related protein 6 (Lrp6) to generate Hyp and Lrp6 double mutant mice (Hyp/Lrp6). Like Hyp mice, Hyp/Lrp6 double mutants maintained high serum levels of FGF23, and accordingly exhibited hypophosphatemia to the same degree as the Hyp mice did, indicating that genetically reducing WNT signaling does not impact FGF23-induced phosphaturia. Moreover, similar to Hyp mice, the Hyp/Lrp6 double mutants also exhibited reduced mineralization of the bone, further supporting that reduced WNT signaling does not affect the chronic phosphate wasting caused by excess FGF23 in these mice. In further support of our finding, injection of bioactive FGF23 protein into Lrp6 mutant mice reduced serum phosphate levels to a similar degree as FGF23 injection into wild-type mice. Our in vivo studies provide genetic and pharmacological evidence for a WNT-independent function of FGF23 in the regulation of phosphate homeostasis. PMID- 23652556 TI - Can salivary phosphate levels be an early biomarker to monitor the evolvement of obesity? AB - Phosphate is an essential nutrient required for important biological reactions that maintain the normal homoeostatic control of the cell. The adverse effects of phosphate metabolism in obesity have not been studied in detail, chiefly because such an association is thought to be uncommon. However, in some animal models of obesity, serum phosphate levels were noted to be higher than the nonobese controls. For example, leptin-deficient (ob/ob) mice become severely obese and have high serum phosphate levels. In this study, we analyzed the phosphate content in saliva collected from children (n = 77; 10.5 +/- 1.8) to evaluate association with body mass index; there is a significant increase of salivary phosphate content in obese compared to normal-weight children (ANOVA p < 0.001). The correlation coefficient (r) between BMI and phosphate was 0.33 (p = 0.0032). Our results suggest that the human salivary phosphate level may be an early biomarker of the genesis of obesity in children. The diagnostic importance lies in the fact that the salivary phosphate level could provide a noninvasive predictive marker in the development of obesity. Further studies will be required to understand the underlying mechanism of increased salivary phosphate accumulation in obese and overweight children. Nevertheless, its occurrence without systemic changes could be of diagnostic value, particularly in monitoring evolvement of obesity. PMID- 23652560 TI - Genetic polymorphisms of interleukin 17A and interleukin 17F and their association with inflammatory bowel disease in a Chinese Han population. AB - OBJECTIVE: Interleukin-17A and interleukin-17F (IL-17A and IL-17F) are candidate genes for chronic inflammatory disease. We investigated the association between IL17A/F gene polymorphisms and susceptibility to and clinical features of inflammatory bowel disease (IBD). METHODS: A total of 270 ulcerative colitis (UC) patients, 82 Crohn's disease (CD) patients and 268 healthy controls were recruited in this study. Genomic DNA was extracted and analyzed for IL17A/F gene polymorphisms using ligase detection reaction allelic technology. RESULTS: Compared to the controls, the mutant allele C for IL17F rs763780 was significantly more common in CD patients [14.0 vs 8.4 %, P = 0.033, odds ratio (OR) 1.18, 95 % confidence interval (CI) 1.41-3.04] and was associated with the disease lesion location. This variant of IL17F rs763780 also had a weak correlation with the age of UC onset (P = 0.05, OR 0.97, 95 % CI 0.94-1.00). The IL17A (rs2275913, G-197A) variant had a weak association with the severity of disease: patients with the mutant allele A tended to suffer mild active UC. The haplotype (GGTT) of IL17A formed with four single nucleotide polymorphisms (rs2275913, rs8193037, rs8193038, and rs3804513) was associated with an increased risk of UC (P = 0.034, OR 4.58, 95 % CI 1.54-13.64). CONCLUSIONS: The IL17F (rs763780, 7488T/C) variant was associated with an increased risk for the development of CD, and affected some clinical features of UC and CD. The IL17A (rs2275913, G-197A) variant had a weak association with the severity of UC. There was a risk haplotype in IL17A which could increase the risk of UC. PMID- 23652561 TI - Estimation of effective population size in continuously distributed populations: there goes the neighborhood. AB - Use of genetic methods to estimate effective population size (Ne) is rapidly increasing, but all approaches make simplifying assumptions unlikely to be met in real populations. In particular, all assume a single, unstructured population, and none has been evaluated for use with continuously distributed species. We simulated continuous populations with local mating structure, as envisioned by Wright's concept of neighborhood size (NS), and evaluated performance of a single sample estimator based on linkage disequilibrium (LD), which provides an estimate of the effective number of parents that produced the sample (Nb). Results illustrate the interacting effects of two phenomena, drift and mixture, that contribute to LD. Samples from areas equal to or smaller than a breeding window produced estimates close to the NS. As the sampling window increased in size to encompass multiple genetic neighborhoods, mixture LD from a two-locus Wahlund effect overwhelmed the reduction in drift LD from incorporating offspring from more parents. As a consequence, never approached the global Ne, even when the geographic scale of sampling was large. Results indicate that caution is needed in applying standard methods for estimating effective size to continuously distributed populations. PMID- 23652562 TI - Mediation of seed provisioning in the transmission of environmental maternal effects in Maritime pine (Pinus pinaster Aiton). AB - Although maternal environmental effects are increasingly recognized as an important source of phenotypic variation with relevant impacts in evolutionary processes, their relevance in long-lived plants such as pine trees is largely unknown. Here, we used a powerful sample size and a strong quantitative genetic approach to analyse the sources of variation of early seedling performance and to identify seed mass (SM)-dependent and -independent maternal environmental effects in Maritime pine. We measured SM of 8924 individual seeds collected from 10 genotypes clonally replicated in two environments of contrasting quality (favourable and stressful), and we measured seedling growth rate and biomass allocation to roots and shoots. SM was extremely variable (up to 14-fold) and strongly determined by the maternal environment and the genotype of the mother tree. The favourable maternal environment led to larger cones, larger seeds and reduced SM variability. The maternal environment also determined the offspring phenotype, with seedlings coming from the favourable environment being 35% larger and with greater root/shoot ratio. Transgenerational plasticity appears, thus, to be a relevant source of phenotypic variation in the early performance of this pine species. Seed provisioning explained most of the effect of the maternal environment on seedling total biomass. Environmental maternal effects on seedling biomass allocation were, however, determined through SM-independent mechanisms, suggesting that other epigenetic regulation channels may be involved. PMID- 23652564 TI - Multigenerational hybridisation and its consequences for maternal effects in Atlantic salmon. AB - Outbreeding between segregating populations can be important from an evolutionary, conservation and economical-agricultural perspective. Whether and how outbreeding influences maternal effects in wild populations has rarely been studied, despite both the prominent maternal influence on early offspring survival and the known presence of fitness effects resulting from outbreeding in many taxa. We studied several traits during the yolk-feeding stage in multigenerational crosses between a wild and a domesticated Atlantic salmon (Salmo salar) population up to their third-generation hybrid in a common laboratory environment. Using cross-means analysis, we inferred that maternal additive outbreeding effects underlie most offspring traits but that yolk mass also underlies maternal dominant effects. As a consequence of the interplay between additive and dominant maternally controlled traits, offspring from first generation hybrid mothers expressed an excessive proportion of residual yolk mass, relative to total mass, at the time of first feeding. Their residual yolk mass was 23-97% greater than those of other crosses and 31% more than that predicted by a purely additive model. Offspring additive, epistatic and epistatic offspring-by-maternal outbreeding effects appeared to further modify this largely maternally controlled cross-means pattern, resulting in an increase in offspring size with the percentage of domesticated alleles. Fitness implications remain elusive because of unknown phenotype-by-environment interactions. However, these results suggest how mechanistically co-adapted genetic maternal control on early offspring development can be disrupted by the effects of combining alleles from divergent populations. Complex outbreeding effects at both the maternal and offspring levels make the prediction of hybrid phenotypes difficult. PMID- 23652563 TI - Antennapedia is involved in the development of thoracic legs and segmentation in the silkworm, Bombyx mori. AB - Homeotic genes, which are associated closely with body patterning of various species, specify segment identity. The Wedge eye-spot (Wes) is a new homeotic mutant located on the sixth linkage group. Homozygous Wes/Wes embryos are lethal and display a pair of antenna-like appendages under the mouthparts as well as fused thoracic segments. These mutants also exhibit a narrower eye-spot at the larval stage compared with the wild type. By positional cloning, we identified the candidate gene of the Wes locus, Bombyx mori Antennapedia (BmAntp). Two BmAntp transcripts were identified in the homozygote of the Wes mutant, including a normal form and an abnormal form with a 1570-bp insertion. Our data showed that the insertion element was a long interspersed nuclear element (LINE)-like transposon that destroyed the original open reading frame of BmAntp. Quantitative RT-PCR analysis showed that the expression levels of normal BmAntp transcripts were increased markedly in the Wes heterozygous larvae compared with the wild type. Furthermore, we performed RNAi of BmAntp and observed fused thoracic segments and defective thoracic legs in the developing embryos. Our results indicated that BmAntp is responsible for the Wes mutant and has an important role in determining the proper development of the thoracic segments. Our identification of a homeotic mutation in the silkworm is an important contribution to our understanding of the regulation of Hox genes at different levels of expression. PMID- 23652566 TI - Editorial introduction. Human lipoprotein metabolism and therapeutic options for coronary heart disease (CHD) reduction. PMID- 23652565 TI - The genetic basis of speciation in the Giliopsis lineage of Ipomopsis (Polemoniaceae). AB - One of the most powerful drivers of speciation in plants is pollinator-mediated disruptive selection, which leads to the divergence of floral traits adapted to the morphology and behavior of different pollinators. Despite the widespread importance of this speciation mechanism, its genetic basis has been explored in only a few groups. Here, we characterize the genetic basis of pollinator-mediated divergence of two species in genus Ipomopsis, I. guttata and I. tenuifolia, using quantitative trait locus (QTL) analyses of floral traits and other variable phenotypes. We detected one to six QTLs per trait, with each QTL generally explaining small to modest amounts of the phenotypic variance of a backcross hybrid population. In contrast, flowering time and anthocyanin abundance (a metric of color variation) were controlled by a few QTLs of relatively large effect. QTLs were strongly clustered within linkage groups, with 26 of 37 QTLs localized to six marker-interval 'hotspots,' all of which harbored pleiotropic QTLs. In contrast to other studies that have examined the genetic basis of pollinator shifts, our results indicate that, in general, mutations of small to modest effect on phenotype were involved. Thus, the evolutionary transition between the distinct pollination modes of I. guttata and I. tenuifolia likely proceeded incrementally, rather than saltationally. PMID- 23652567 TI - Effects of cholesteryl ester transfer protein inhibitors on human lipoprotein metabolism: why have they failed in lowering coronary heart disease risk? AB - PURPOSE OF REVIEW: To examine the recent advances in our knowledge of cholesteryl ester transfer protein (CETP) inhibitors, heart disease risk reduction, and human lipoprotein metabolism. RECENT FINDINGS: CETP inhibitors block the transfer of cholesteryl ester from HDLs to triglyceride-rich lipoproteins (TRLs), thereby raising HDL cholesterol and lowering TRL cholesterol, and in some cases LDL cholesterol. Two CETP inhibitors, dalcetrapib and torcetrapib, have been tested in large clinical trials in statin-treated coronary heart disease patients and have shown no clinical benefit compared to placebo. Anacetrapib and evacetrapib, two potent CETP inhibitors, are now being tested in large clinical trials. Torcetrapib has been shown to decrease the fractional catabolic rate (FCR) of HDL apolipoproteins (apo) A-I and A-II, enhance the FCR of TRL apoB-100 and apoE, and decrease TRL apoB-48 production, but has no significant effects on fecal cholesterol excretion in humans. Anacetrapib also delays the FCR of HDL apoA-I. SUMMARY: CETP inhibitors form a complex between themselves, CETP, and HDL particles, which may interfere with the many physiologic functions of HDL, including reverse cholesterol transport. Available data would suggest that CETP inhibitors will fail as lipid-altering medications to reduce coronary heart disease risk because of interference with normal human HDL metabolism. PMID- 23652568 TI - Apolipoprotein M: bridging HDL and endothelial function. AB - PURPOSE OF REVIEW: The review will address the potential roles of apolipoprotein M (apoM) as a carrier protein and modulator of sphingosine-1-phosphate (S1P) bioactivity. RECENT FINDINGS: Recombinant apoM can bind small lipids such as retinoic acid, oxidized phospholipids, and S1P. Thus, the effects of apoM may be pleiotrophic. The S1P binding ability of apoM has biological impact. ApoM-bound S1P can activate S1P1 receptors on endothelial cells and deficiency of apoM abolishes the presence of S1P in HDL. In mice, the lack of apoM causes dysfunctional endothelial barrier function in the lungs. In humans, sepsis that is characterized by impaired endothelial function is associated with low plasma apoM. SUMMARY: Plasma apoM is mainly bound to HDL. The roles of apoM in atherosclerosis and lipoprotein metabolism have been given much attention. New in the field is the discovery of apoM as a chaperone for S1P. S1P is a bioactive lipid with effects on angiogenesis, lymphocyte trafficking, endothelial cell migration, and inflammation. A drug targeting the S1P-system (fingolimod) is now used for treatment of multiple sclerosis. It improves the blood-brain barrier and inhibits migration of lymphocytes into the brain. Further exploration of the apoM/S1P axis may uncover its potential as a biomarker and target for new treatments. PMID- 23652569 TI - Lysosomal acid lipase A and the hypercholesterolaemic phenotype. AB - PURPOSE OF REVIEW: Mutations in lysosomal acid lipase A (LIPA) result in two phenotypes depending on the extent of lysosomal acid lipase (LAL) deficiency: the severe, early-onset Wolman disease or the less severe cholesteryl ester storage disease (CESD). In CESD, the severity of the symptoms, hepatomegaly and hypercholesterolaemia, can be highly variable, presenting in childhood or adulthood. Therefore, it is likely that many patients are undiagnosed or misdiagnosed. Nevertheless, LAL deficiency has been recognized for more than 25 years, but adequate therapeutic strategies are limited. RECENT FINDINGS: CESD has an estimated prevalence of one in 90,000 to 170,000 individuals in the general population, confirming the likelihood that this disease is currently underdiagnosed. A number of studies have shown that in LIPA deficient patients the hypercholesterolaemic phenotype can be attenuated using statin therapy, and favourable effects on reduction of lipid accumulation in lysosomes have been reported. Targeting lysosomal exocytosis with LAL replacement therapy was shown to be successful in animal models and recently a phase I/II study demonstrated its safety and its potential metabolic efficacy on transaminase levels. SUMMARY: The hypercholesterolaemic phenotype in CESD can be difficult to distinguish from other known hypercholesterolaemic disorders. In the majority of CESD cases with hypercholesterolaemia favourable responses on statin treatment are observed, but the effect on reduction of lipid accumulation in lysosomes needs to be further evaluated. Combining statins with LAL replacement therapy may provide a promising approach for optimal treatment of LIPA deficiencies in the future. PMID- 23652570 TI - HDL quality or cholesterol cargo: what really matters--spotlight on sphingosine-1 phosphate-rich HDL. AB - PURPOSE OF REVIEW: The absolute level of HDL cholesterol (HDL-C) may not be the only criterion contributing to their antiatherothrombotic effects. This review focuses on evidence in support of the concept that HDL-bound sphingosine-1 phosphate (S1P) plays a role in different HDL atheroprotective properties and may represent a potential target for therapeutic interventions. RECENT FINDINGS: Recent large randomized clinical trials testing the hypothesis of raising HDL-C with niacin and dalcetrapib in statin-treated patients failed to improve cardiovascular outcomes. Emerging evidence suggests that many of the cardioprotective functions of HDL, such as vasodilation, angiogenesis and endothelial barrier function, protection against ischemia/reperfusion injury, and inhibition of atherosclerosis, may be attributable to its S1P cargo. HDL associated S1P may represent a future therapeutic target. SUMMARY: HDL functionality is affected by its composition and there is evidence to suggest S1P plays a role in some of HDL's functions and atheroprotective properties. PMID- 23652572 TI - Tuning structural motifs and alloying of bulk immiscible Mo-Cu bimetallic nanoparticles by gas-phase synthesis. AB - Nowadays bimetallic nanoparticles (NPs) have emerged as key materials for important modern applications in nanoplasmonics, catalysis, biodiagnostics, and nanomagnetics. Consequently the control of bimetallic structural motifs with specific shapes provides increasing functionality and selectivity for related applications. However, producing bimetallic NPs with well controlled structural motifs still remains a formidable challenge. Hence, we present here a general methodology for gas phase synthesis of bimetallic NPs with distinctively different structural motifs ranging at a single particle level from a fully mixed alloy to core-shell, to onion (multi-shell), and finally to a Janus/dumbbell, with the same overall particle composition. These concepts are illustrated for Mo Cu NPs, where the precise control of the bimetallic NPs with various degrees of chemical ordering, including different shapes from spherical to cube, is achieved by tailoring the energy and thermal environment that the NPs experience during their production. The initial state of NP growth, either in the liquid or in the solid state phase, has important implications for the different structural motifs and shapes of synthesized NPs. Finally we demonstrate that we are able to tune the alloying regime, for the otherwise bulk immiscible Mo-Cu, by achieving an increase of the critical size, below which alloying occurs, closely up to an order of magnitude. It is discovered that the critical size of the NP alloy is not only affected by controlled tuning of the alloying temperature but also by the particle shape. PMID- 23652573 TI - A prospective study on 132 cases of ocular palsy. AB - OBJECTIVES: In this prospective study, we used one diagnostic protocol to establish an early diagnosis in patients with ocular palsies in absence of other neurological findings. MATERIALS AND METHODS: The study was performed on a consecutive series of 132 patients who visited our Neurological Department for ptosis and/or diplopia in absence of other neurological signs, using the same diagnostic protocol. RESULTS: An etiological diagnosis was made in 74% of cases during a mean time of 17 +/- 23 months from symptom onset. Myasthenia gravis was the most common diagnosis (n = 60, 45.5%). Thirty-four cases (26%) remained undiagnosed in spite of a follow-up lasting 32 +/- 33 months on average. CONCLUSIONS: Identifying the cause of an isolated ocular palsy can be difficult, and an extended follow-up time does not aid in further establishment of the diagnosis. PMID- 23652571 TI - Mass spectrometry imaging with high resolution in mass and space. AB - Mass spectrometry (MS) imaging links molecular information and the spatial distribution of analytes within a sample. In contrast to most histochemical techniques, mass spectrometry imaging can differentiate molecular modifications and does not require labeling of targeted compounds. We have recently introduced the first mass spectrometry imaging method that provides highly specific molecular information (high resolution and accuracy in mass) at cellular dimensions (high resolution in space). This method is based on a matrix-assisted laser desorption/ionization (MALDI) imaging source working at atmospheric pressure which is coupled to an orbital trapping mass spectrometer. Here, we present a number of application examples and demonstrate the benefit of 'mass spectrometry imaging with high resolution in mass and space.' Phospholipids, peptides and drug compounds were imaged in a number of tissue samples at a spatial resolution of 5-10 MUm. Proteins were analyzed after on-tissue tryptic digestion at 50-MUm resolution. Additional applications include the analysis of single cells and of human lung carcinoma tissue as well as the first MALDI imaging measurement of tissue at 3 MUm pixel size. MS image analysis for all these experiments showed excellent correlation with histological staining evaluation. The high mass resolution (R = 30,000) and mass accuracy (typically 1 ppm) proved to be essential for specific image generation and reliable identification of analytes in tissue samples. The ability to combine the required high-quality mass analysis with spatial resolution in the range of single cells is a unique feature of our method. With that, it has the potential to supplement classical histochemical protocols and to provide new insights about molecular processes on the cellular level. PMID- 23652574 TI - Chromatography paper as a low-cost medium for accurate spectrophotometric assessment of blood hemoglobin concentration. AB - Anemia affects a quarter of the world's population, and a lack of appropriate diagnostic tools often prevents treatment in low-resource settings. Though the HemoCue 201+ is an appropriate device for diagnosing anemia in low-resource settings, the high cost of disposables ($0.99 per test in Malawi) limits its availability. We investigated using spectrophotometric measurement of blood spotted on chromatography paper as a low-cost (<$0.01 per test) alternative to HemoCue cuvettes. For this evaluation, donor blood was diluted with plasma to simulate anemia, a micropipette spotted blood on paper, and a bench-top spectrophotometer validated the approach before the development of a low-cost reader. We optimized impregnating paper with chemicals to lyse red blood cells, paper type, drying time, wavelengths measured, and sensitivity to variations in volume of blood, and we validated our approach using patient samples. Lysing the blood cells with sodium deoxycholate dried in Whatman Chr4 chromatography paper gave repeatable results, and the absorbance difference between 528 nm and 656 nm was stable over time in measurements taken up to 10 min after sample preparation. The method was insensitive to the amount of blood spotted on the paper over the range of 5 MUL to 25 MUL. We created a low-cost, handheld reader to measure the transmission of paper cuvettes at these optimal wavelengths. Training and validating our method with patient samples on both the spectrometer and the handheld reader showed that both devices are accurate to within 2 g dL(-1) of the HemoCue device for 98% and 95% of samples, respectively. PMID- 23652575 TI - Primary headache associated with sexual activity: case report. AB - OBJECTIVES: To present a rare case of primary headache associated with sexual activity. CLINICAL PRESENTATION AND INTERVENTION: A 48-year-old man presented with a severe headache during sexual intercourse, particularly at the time of orgasm. A diagnosis of type 2 primary headache associated with sexual activity was made, and he was started on indomethacin 25 mg to be taken 30 min before intercourse and propranolol 40 mg twice a day, following which he noted a dramatic improvement within in a week. CONCLUSIONS: The case highlights the importance of paying attention to the differential diagnosis. For this patient, prophylactic treatment with beta-blockers and/or preemptive therapy with indomethacin was successful. PMID- 23652576 TI - Cervical myelopathy due to an epidural cervical mass after chronic cervical spinal cord stimulation. AB - BACKGROUND: Spinal cord stimulation (SCS) is an established treatment for neuropathic pain. Severe long-term complications are rare. Only recently secondary mass lesions associated with chronic stimulation were noted to occur. OBJECTIVES: To report the rare occurrence of cervical myelopathy secondary to an epidural cervical spinal mass after chronic cervical SCS. METHODS: Implantation of a paddle electrode at C2-C4 for chronic neuropathic pain resulted in improvement of pain for several years but it lost its efficacy after 8 years. Myelography and postmyelographic CT detected an epidural mass surrounding the electrode and compressing the spinal cord when cervical myelopathy had developed 17 years after electrode implantation. RESULTS: The mass which consisted of dense fibrous scar tissue was removed via hemilaminectomy. At postoperative follow-up at 8 months there was no further progression of gait disorder. CONCLUSION: Long term cervical SCS in a rare case may lead to fibrous epidural mass lesions which may not only cause loss of efficacy but which may also result in new neurological deficits. PMID- 23652577 TI - Special cannula to use 20-gauge instruments while performing a 23-gauge vitreous surgery in complicated cases. PMID- 23652578 TI - Prospective evaluation of the incidence and risk factors for the development of RPE tears after high- and low-dose ranibizumab therapy. AB - PURPOSE: To prospectively determine the incidence and risk factors for retinal pigment epithelial (RPE) tears in eyes with vascularized pigment epithelial detachments (PED) and exudative age-related macular degeneration receiving antivascular endothelial growth factor therapy. METHODS: Eyes were prospectively randomized into 1 of 4 arms: 1) 0.5 mg of ranibizumab monthly for 12 months; 2) 0.5 mg of ranibizumab monthly for 3 months and then pro re nata on the basis of clinical and optical coherence tomography-guided indications; 3) high-dose 2.0 mg of ranibizumab monthly for 12 months; or 4) 2.0 mg of ranibizumab monthly for 3 months and then pro re nata thereafter. All PEDs were measured for height, greatest linear diameter, and surface area at baseline. The incidence of RPE tears in the entire 4-arm cohort was determined at the end of 12 months. Eyes were divided into two groups (tear vs. nontear) and statistically compared to determine risk factors for the development of RPE tear. RESULTS: Of 37 eyes, a total of 5 developed postranibizumab RPE tears during the course of the study (incidence 14%). Four of the 5 tears occurred in the high-dose 2.0-mg groups. Baseline PED height, surface area, and greatest linear diameter were significantly greater in the group that developed RPE tears versus the nontear group (P = 0.018, 0.031, and 0.048, respectively). There were significantly more eyes with PED height >550 microns in the RPE tear group (4 of 5, 80%) compared with the nontear group (9 of 32, 18%) (P = 0.042). The presence of PED height >550 microns was associated with an increased tear rate from 14% to 31%. Furthermore, retrospective identification of a ring sign or Grade 1 tear at baseline, in addition to PED height >550 microns, was associated with a further increase in the tear rate to 67%. CONCLUSION: In this study, the prospective incidence of RPE tears was ~14%. A baseline PED height >550 microns and presence of a Grade 1 tear, or positive ring sign, were identified as high-risk factors for the subsequent development of an RPE tear. PMID- 23652579 TI - Silicone oil sequestration under epiretinal membrane. PMID- 23652580 TI - Expression of vascular endothelial growth factor and intravitreal anti-VEGF therapy with bevacizumab in vasoproliferative retinal tumors. AB - PURPOSE: To examine whether vasoproliferative retinal tumors (VPRTs) express vascular endothelial growth factor and respond to intravitreal bevacizumab injection. METHODS: Retrospective interventional case series. Intravitreal bevacizumab 1.25 mg was administered to 9 patients with VPRT-associated neovascularization or exudative retinal changes. The changes of the tumor size, best-corrected visual acuity, and central retinal thickness were evaluated before and after treatment. Immunohistochemistry with anti-vascular endothelial growth factor antibody in an excised tissue of VPRT during pars plana vitrectomy was performed. RESULTS: In two patients with small tumors (within two disk diameters), the tumors disappeared or regressed with only one injection of intravitreal bevacizumab injection. Larger tumors regressed after additional laser photocoagulation and/or cryotherapy without recurrence of exudative retinal changes in six eyes, although these did not regress by intravitreal bevacizumab injection alone. The mean logarithm of the minimal angle of resolution value of best-corrected visual acuity and central retinal thickness at the final visit were significantly improved compared with those of pretreatment (P = 0.02 and P = 0.03, respectively). Immunoreactivity for vascular endothelial growth factor was strongly detected in the resected tumor tissue. CONCLUSION: These results suggest that vascular endothelial growth factor derived from VPRTs causes retinal neovascularization or exudative retinal changes associated with VPRTs. Intravitreal bevacizumab may be a useful therapeutic option for these complications secondary to VPRTs. PMID- 23652581 TI - Intravitreal dexamethasone 0.7-mg implant for radiation macular edema after proton beam therapy for choroidal melanoma. AB - PURPOSE: To evaluate the efficacy of dexamethasone 0.7-mg intravitreal implant in patients with radiation macular edema after proton beam therapy for choroidal melanoma. METHODS: Five patients' charts were retrospectively reviewed. The main outcome measures were visual acuity and mean central retinal thickness. RESULTS: All patients received a radiation dose of 60 cobalt gray equivalent. Radiation macular edema occurred within a mean time of 26 months after irradiation. Mean preinjection visual acuity was 41 Early Treatment Diabetic Retinopathy Study letters. Mean central retinal thickness was 487.1 MUm. Two months after injection, mean visual acuity was 47 Early Treatment Diabetic Retinopathy Study letters. It improved for 3 patients (+4, +9 and, +15 letters) and remained unchanged for 2. Mean central retinal thickness was 331 MUm. It decreased for 4 patients (-111, -134, -336, and -187 MUm). Two patients underwent a second injection of dexamethasone performed 5 months after the first injection. The gain of visual acuity was +8 and +23 letters with a decrease in central retinal thickness of 158 and 262 MUm, respectively. Intraocular pressure increased for 1 patient over a mean follow-up period of 6.4 months. CONCLUSION: Intravitreal dexamethasone implant can improve visual acuity in radiation macular edema. The observed beneficial effect lasted up to 5 months. PMID- 23652583 TI - DDA3 associates with microtubule plus ends and orchestrates microtubule dynamics and directional cell migration. AB - Cell motility and adhesion involve orchestrated interaction of microtubules (MTs) with their plus-end tracking proteins (+TIPs). However, the mechanisms underlying regulations of MT dynamics and directional cell migration are still elusive. Here, we show that DDA3-EB1 interaction orchestrates MT plus-end dynamics and facilitates directional cell migration. Biochemical characterizations reveal that DDA3 interacts with EB1 via its SxIP motif within the C-terminal Pro/Ser-rich region. Time-lapse and total internal reflection fluorescence (TIRF) microscopic assays demonstrate that DDA3 exhibits EB1-dependent, MT plus-end loading and tracking. The EB1-based loading of DDA3 is responsible for MT plus-ends stabilization at the cell cortex, which in turn orchestrates directional cell migration. Interestingly, the DDA3-EB1 interaction is potentially regulated by EB1 acetylation, which may account for physiological regulation underlying EGF elicited cell migration. Thus, the EB1-based function of DDA3 links MT dynamics to directional cell migration. PMID- 23652584 TI - Assessment of cardiac inflammation and remodeling during the development of streptozotocin-induced diabetic cardiomyopathy in vivo: a time course analysis. AB - In this study, we examined cardiac inflammation, fibrosis and left ventricular (LV) function during the development of streptozotocin (STZ)-induced diabetic cardiomyopathy using an animal model of diabetes mellitus (DM). Diabetes was induced in 22 Sprague-Dawley rats by an intraperitoneal single injection of STZ (70 mg/kg). Non-diabetic animals served as the controls (n=6). LV function was documented using the conductance catheter technique 2 and 6 weeks after the induction of diabetes. Cardiac tissue was analyzed for cardiac immune cell infiltration, oxidative stress and remodeling in rats with STZ-induced diabetes at 2 different time points by immunohistochemistry. Cardiac function was significantly impaired in the diabetic animals. After 2 weeks, the induction of diabetes resulted in impaired cardiac function indexed by a decrease in systolic and diastolic LV function. This impairment of LV performance continued for up to 6 weeks after the STZ injection. This was associated with an increase in cardiac CD3+ and CD8a+ immune cell invasion and fibrosis, indexed by an increase in collagen content (p<0.05). Furthermore, oxidative stress response and matrix remodeling were increased after 2 weeks and this continued for up to 6 weeks after the induction of diabetes. In conclusion, cardiac dysfunction is associated with cardiac inflammation and adverse remodeling in experimental diabetic cardiomyopathy. Our results suggest that the model of STZ-induced diabetic cardiomyopathy is a robust model for investigating cardiac immune response and LV remodeling processes under diabetic conditions. PMID- 23652585 TI - Allogeneic hematopoietic cell transplantation with reduced-intensity conditioning following FLAMSA for primary refractory or relapsed acute myeloid leukemia. AB - Patients with primary refractory or relapsed acute myeloid leukemia (AML) have a dismal prognosis. We report a retrospective single center analysis of aplasia inducing chemotherapy using fludarabine, cytarabine, and amsacrine (FLAMSA) followed by reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (HCT) in 62 consecutive primary refractory or relapsed AML patients. Two-year event-free survival and overall survival (OS) were 26 and 39%, respectively. Risk stratification according to cytogenetic and molecular genetic markers showed superior survival in patients in the intermediate-1 risk group (2 year OS 70%) compared to the intermediate-2 risk (2-year OS 34%, p = 0.03) and adverse risk (2-year OS 38%, p = 0.06) group. The use of HLA-matched versus HLA mismatched donors had no significant influence on survival (p = 0.98). Two-year OS in the elderly subgroup defined by age >=60 years was 31% compared to 46% in the group of younger patients <60 years (p = 0.19). Cumulative incidence of non relapse mortality at 2 years adjusted for relapse as competing risk was 20% for patients <60 years and 26% for older patients (p = 0.55). Chronic graft-versus host disease was associated with a statistically significant superior survival (p < 0.01). FLAMSA-RIC followed by allogeneic HCT enables long-term disease-free survival in primary refractory or relapsed AML even in the elderly patient population. PMID- 23652586 TI - Assessing DcR3 expression in relation to survivin and other prognostic factors in B cell non-Hodgkin's lymphoma. AB - The soluble decoy receptor 3 (DcR3) is a member of the tumor necrosis factor receptor superfamily whose overexpression has been observed in several human malignancies. Survivin is one of the inhibitors of apoptosis proteins that are thought to play an important role in the pathogenesis of malignancies. We aimed to evaluate the expression of DcR3 in relation to survivin in B cell non Hodgkin's lymphoma (NHL) and then we focused on patients with diffuse large B cell non-Hodgkin's lymphoma (DLBCL) (50 cases) and correlated DcR3 expression with survivin expression and other prognostic parameters. Fifteen subjects with reactive lymphoid hyperplasia were included as controls. The expression of DcR3 and survivin were analyzed by immunohistochemistry on formalin-fixed paraffin embedded lymph node sections from 80 cases of B cell NHL and 15 controls. Bone marrow biopsy sections of patients were also immunostained with the previous markers. RESULTS: DcR3 expression was found in 32.5% of B cell NHL patients versus 6.7% of controls (p <0.001) and was associated with the aggressive/highly aggressive subtypes. DcR3 was strongly expressed in 30% of DLBCL patients, where it was associated with survivin expression, high international prognostic index (IPI), the presence of extra nodal disease, ECOG performance status >1, reduced remission rates and shorter event-free survival. The expression of survivin was 40% in B cell NHL patients versus 13.3% in the control group (p <0.001). The expression of survivin in aggressive/highly aggressive B cell NHL was significantly higher than that in indolent B cell NHL. Survivin expression has been detected in 44% of the DLBCL patients and was associated with their clinical stage and shorter event-free survival (p = 0.026). Bone marrow biopsy sections from DLBCL patients showed significant DcR3 and survivin over expressions in sections with infiltration by lymphoma cells than sections with no infiltration. CONCLUSION: DcR3 expression was associated with other prognostic factors including survivin, reduced remission rates, and shorter event-free survival. Survivin is closely related to aggressive/highly aggressive subtypes of B cell NHL and is associated with shorter event-free survival. Both DcR3 and survivin expressions on bone marrow sections can be of help in diagnosing bone marrow infiltration. PMID- 23652587 TI - Collaborative learning using nursing student dyads in the clinical setting. AB - Formal pairing of student nurses to work collaboratively on one patient assignment is a strategy for improving the quality and efficiency of clinical instruction while better utilizing the limited resources at clinical agencies. The aim of this qualitative study was to explore the student nurse and patient experiences of collaborative learning when peer dyads are used in clinical nursing education. Interviews were conducted with 11 students and 9 patients. Students described the process of collaborative learning as information sharing, cross-checking when making clinical decisions, and group processing when assessing the outcomes of nursing interventions. Positive outcomes reported by students and patients included reduced student anxiety, increased confidence and task efficiency. Students' primary concern was reduced opportunity to perform hands-on skills which had to be negotiated within each dyad. Meeting the present and future challenges of educating nurses will require innovative models of clinical instruction such as collaborative learning using student peer dyads. PMID- 23652588 TI - The cannabinoid CB2 receptor is necessary for nicotine-conditioned place preference, but not other behavioral effects of nicotine in mice. AB - RATIONALE: Whereas cannabinoid CB1 receptors have long been known to contribute to the rewarding effects and dependence liability of many drugs of abuse, recent studies have implicated the involvement of cannabinoid CB2 receptors. OBJECTIVE: Here, we evaluated the role of CB2 receptors in the rewarding properties of nicotine, as assessed in the conditioned place preference (CPP) paradigm and mecamylamine-precipitated withdrawal in nicotine dependent mice. METHODS: Using complementary pharmacological and genetic approaches, we investigated the involvement of CB2 receptors in nicotine- and cocaine-induced CPP in mice and mecamylamine-precipitated withdrawal in nicotine-dependent mice. We also determined whether deletion of CB2 receptors affects nicotine-induced hypothermia and hypoalgesia. RESULTS: Nicotine-induced (0.5 mg/kg) CPP was completely blocked by selective CB2 antagonist, SR144528 (3 mg/kg) in wild-type mice, and was absent in CB2 (-/-) mice. Conversely, the CB2 receptor agonist, O-1966 (1, 3, 5, 10, 20 mg/kg) given in combination with a subthreshold dose of nicotine (0.1 mg/kg) elicited a place preference. In contrast, O-1966 (20 mg/kg) blocked cocaine (10 mg/kg)-induced CPP in wild type mice, while CB2 (-/-) mice showed unaltered cocaine CPP. CB2 (+/+) and (-/-) nicotine-dependent mice showed almost identical precipitated withdrawal responses and deletion of CB2 receptor did not alter acute somatic effects of nicotine. CONCLUSIONS: Collectively, these results indicate that CB2 receptors are required for nicotine-induced CPP in the mouse, while it is not involved in nicotine withdrawal or acute effects of nicotine. Moreover, these results suggest that CB2 receptors play opposing roles in nicotine- and cocaine-induced CPP. PMID- 23652589 TI - Firing of antagonist small-diameter muscle afferents reduces voluntary activation and torque of elbow flexors. AB - During muscle fatigue, firing of small-diameter muscle afferents can decrease voluntary activation of the fatigued muscle. However, these afferents may have a more widespread effect on other muscles in the exercising limb. We examined if the firing of fatigue-sensitive afferents from elbow extensor muscles in the same arm reduces torque production and voluntary activation of elbow flexors. In nine subjects we examined voluntary activation of elbow flexors by measuring changes in superimposed twitches evoked by transcranial magnetic stimulation of the motor cortex during brief (2-3 s) maximal voluntary contractions (MVC). Inflation of a blood pressure cuff following a 2-min sustained MVC blocked blood flow to the fatigued muscle and maintained firing of small-diameter afferents. After a fatiguing elbow flexion contraction, maximal flexion torque was lower (26.0 +/- 4.4% versus 67.9 +/- 5.2% of initial maximal torque; means +/- s.d.; P < 0.001) and superimposed twitches were larger (4.1 +/- 1.1% versus 1.8 +/- 0.2% ongoing MVC, P = 0.01) with than without ischaemia. After a fatiguing elbow extensor contraction, maximal flexion torque was also reduced (82.2 +/- 4.9% versus 91.4 +/- 2.3% of initial maximal torque; P = 0.007), superimposed twitches were larger (2.7 +/- 0.7% versus 1.3 +/- 0.2% ongoing MVC; P = 0.02) and voluntary activation lower (81.6 +/- 8.2% versus 95.5 +/- 6.9%; P = 0.04) with than without ischaemia. After a fatiguing contraction, voluntary drive to the fatigued muscles is reduced with continued input from small-diameter muscle afferents. Furthermore, fatigue of the elbow extensor muscles decreases voluntary drive to unfatigued elbow flexors of the same arm. Therefore, firing of small-diameter muscle afferents from one muscle can affect voluntary activation and hence torque generation of another muscle in the same limb. PMID- 23652590 TI - Muscle glycogen stores and fatigue. AB - Studies performed at the beginning of the last century revealed the importance of carbohydrate as a fuel during exercise, and the importance of muscle glycogen on performance has subsequently been confirmed in numerous studies. However, the link between glycogen depletion and impaired muscle function during fatigue is not well understood and a direct cause-and-effect relationship between glycogen and muscle function remains to be established. The use of electron microscopy has revealed that glycogen is not homogeneously distributed in skeletal muscle fibres, but rather localized in distinct pools. Furthermore, each glycogen granule has its own metabolic machinery with glycolytic enzymes and regulating proteins. One pool of such glycogenolytic complexes is localized within the myofibrils in close contact with key proteins involved in the excitation contraction coupling and Ca2+ release from the sarcoplasmic reticulum (SR). We and others have provided experimental evidence in favour of a direct role of decreased glycogen, localized within the myofibrils, for the reduction in SR Ca2+ release during fatigue. This is consistent with compartmentalized energy turnover and distinctly localized glycogen pools being of key importance for SR Ca2+ release and thereby affecting muscle contractility and fatigability. PMID- 23652591 TI - A 'toothache tree' alkylamide inhibits Adelta mechanonociceptors to alleviate mechanical pain. AB - In traditional medicine, the 'toothache tree' and other plants of the Zanthoxylum genus have been used to treat inflammatory pain conditions, such as toothache and rheumatoid arthritis. Here we examined the cellular and molecular mechanisms underlying the analgesic properties of hydroxy-alpha-sanshool, the active alkylamide produced by Zanthoxylum plants. Consistent with its analgesic effects in humans, sanshool treatment in mice caused a selective attenuation of mechanical sensitivity under naive and inflammatory conditions, with no effect on thermal sensitivity. To elucidate the molecular mechanisms by which sanshool attenuates mechanical pain, we performed single fibre recordings, calcium imaging and whole-cell electrophysiology of cultured sensory neurons. We found that: (1) sanshool potently inhibits Adelta mechanonociceptors that mediate both sharp acute pain and inflammatory pain; (2) sanshool inhibits action potential firing by blocking voltage-gated sodium currents in a subset of somatosensory neurons, which express a unique combination of voltage-gated sodium channels; and (3) heterologously expressed Nav1.7 is most strongly inhibited by sanshool as compared to other sodium channels expressed in sensory neurons. These results suggest that sanshool targets voltage-gated sodium channels on Adelta mechanosensory nociceptors to dampen excitability and thus induce 'fast pain' analgesia. PMID- 23652592 TI - Glucocorticoid exerts its non-genomic effect on IPSC by activation of a phospholipase C-dependent pathway in prefrontal cortex of rats. AB - In response to stressor, the brain activates a comprehensive stress system. Among others, this stress system causes release of glucocorticoids that also feed back to the brain. Glucocorticoids affect brain function by activation of both delayed, genomic and rapid, non-genomic mechanisms in rodents. Here we report that application of the potent glucocorticoid receptor agonist dexamethasone (DEX) caused a rapid increase of spontaneous and miniature inhibitory postsynaptic currents (IPSCs) and elicited intermittent burst activities through a non-genomic pathway, involving membrane-located receptors. The onset of the rapid effect in prefrontal cortex (PFC, <15 min) was much slower than in hippocampus (<5 min). The intermittent burst activities were abolished in the presence of TTX. Furthermore, the nitric oxide (NO) pathway was present and endogenously activated in PFC. Part of the rapid DEX effect in PFC remained after blocking NO-sensitive guanylyl cyclase that was due to activation of a phospholipase C-diacylglycerol-dependent signalling pathway. Thus, our data demonstrated that glucocorticoids could rapidly enhance IPSCs and evoke burst activities by activation of at least two different signalling pathways in hippocampus and PFC of rats. PMID- 23652593 TI - Voltage sensitivity of M2 muscarinic receptors underlies the delayed rectifier like activation of ACh-gated K(+) current by choline in feline atrial myocytes. AB - Choline (Ch) is a precursor and metabolite of the neurotransmitter acetylcholine (ACh). In canine and guinea pig atrial myocytes, Ch was shown to activate an outward K(+) current in a delayed rectifier fashion. This current has been suggested to modulate cardiac electrical activity and to play a role in atrial fibrillation pathophysiology. However, the exact nature and identity of this current has not been convincingly established. We recently described the unique ligand- and voltage-dependent properties of muscarinic activation of ACh activated K(+) current (IKACh) and showed that, in contrast to ACh, pilocarpine induces a current with delayed rectifier-like properties with membrane depolarization. Here, we tested the hypothesis that Ch activates IKACh in feline atrial myocytes in a voltage-dependent manner similar to pilocarpine. Single channel recordings, biophysical profiles, specific pharmacological inhibition and computational data indicate that the current activated by Ch is IKACh. Moreover, we show that membrane depolarization increases the potency and efficacy of IKACh activation by Ch and thus gives the appearance of a delayed rectifier activating K(+) current at depolarized potentials. Our findings support the emerging concept that IKACh modulation is both voltage- and ligand-specific and reinforce the importance of these properties in understanding cardiac physiology. PMID- 23652594 TI - The role of alpha-adrenergic receptors in mediating beat-by-beat sympathetic vascular transduction in the forearm of resting man. AB - Sympathetic vascular transduction is commonly understood to act as a basic relay mechanism, but under basal conditions, competing dilatory signals may interact with and alter the ability of sympathetic activity to decrease vascular conductance. Thus, we determined the extent to which spontaneous bursts of muscle sympathetic nerve activity (MSNA) mediate decreases in forearm vascular conductance (FVC) and the contribution of local alpha-adrenergic receptor mediated pathways to the observed FVC responses. In 19 young men, MSNA (microneurography), arterial blood pressure and brachial artery blood flow (duplex Doppler ultrasound) were continuously measured during supine rest. These measures were also recorded in seven men during intra-arterial infusions of normal saline, phentolamine (PHEN) and PHEN with angiotensin II (PHEN+ANG). The latter was used to control for increases in resting blood flow with alpha adrenergic blockade. Spike-triggered averaging was used to characterize beat-by beat changes in FVC for 15 cardiac cycles following each MSNA burst and a peak response was calculated. Following MSNA bursts, FVC initially increased by +3.3 +/- 0.3% (P = 0.016) and then robustly decreased to a nadir of -5.8 +/- 1.6% (P < 0.001). The magnitude of vasoconstriction appeared graded with the number of consecutive MSNA bursts; while individual burst size only had a mild influence. Neither PHEN nor PHEN+ANG infusions affected the initial rise in FVC, but both infusions significantly attenuated the subsequent decrease in FVC (-2.1 +/- 0.7% and -0.7 +/- 0.8%, respectively; P < 0.001 vs. normal saline). These findings indicate that spontaneous MSNA bursts evoke robust beat-by-beat decreases in FVC that are exclusively mediated via alpha-adrenergic receptors. PMID- 23652595 TI - Enhanced inhibitory neurotransmission in the cerebellar cortex of Atp1a3 deficient heterozygous mice. AB - Dystonia is characterized by excessive involuntary and prolonged simultaneous contractions of both agonist and antagonist muscles. Although the basal ganglia have long been proposed as the primary region, recent studies indicated that the cerebellum also plays a key role in the expression of dystonia. One hereditary form of dystonia, rapid-onset dystonia with parkinsonism (RDP), is caused by loss of function mutations of the gene for the Na pump alpha3 subunit (ATP1A3). Little information is available on the affected brain regions and mechanism for dystonia by the mutations in RDP. The Na pump is composed of alpha and beta subunits and maintains ionic gradients of Na(+) and K(+) across the cell membrane. The gradients are utilized for neurotransmitter reuptake and their alteration modulates neural excitability. To provide insight into the molecular aetiology of RDP, we generated and analysed knockout heterozygous mice (Atp1a3(+/-)). Atp1a3(+/-) showed increased symptoms of dystonia that is induced by kainate injection into the cerebellar vermis. Atp1a3 mRNA was highly expressed in Purkinje cells and molecular-layer interneurons, and its product was concentrated at Purkinje cell soma, the site of abundant vesicular gamma-aminobutyric acid transporter (VGAT) signal, suggesting the presynaptic localization of the alpha3 subunit in the inhibitory synapse. Electrophysiological studies showed that the inhibitory neurotransmission at molecular-layer interneuron-Purkinje cell synapses was enhanced in Atp1a3(+/-) cerebellar cortex, and that the enhancement originated via a presynaptic mechanism. Our results shed light on the role of Atp1a3 in the inhibitory synapse, and potential involvement of inhibitory synaptic dysfunction for the pathophysiology of dystonia. PMID- 23652596 TI - Do t-tubules play a role in arrhythmogenesis in cardiac ventricular myocytes? AB - The transverse (t-) tubules of mammalian ventricular myocytes are invaginations of the surface membrane. The function of many of the key proteins involved in excitation-contraction coupling is located predominantly at the t-tubules, which thus form a Ca(2+)-handling micro-environment that is central to the normal rapid activation and relaxation of the ventricular myocyte. Although cellular arrhythmogenesis shares many ion flux pathways with normal excitation-contraction coupling, the role of the t-tubules in such arrhythmogenesis has not previously been considered. In this brief review we consider how the location and co location of proteins at the t-tubules may contribute to the generation of arrhythmogenic delayed and early afterdepolarisations, and how the loss of t tubules that occurs during heart failure may alter the generation of such arrhythmias, as well as contributing to other types of arrhythmia as a result of changes of electrical heterogeneity within the whole heart. PMID- 23652599 TI - The conversion of protonated cytosine-SO3(-) to uracil-SO3(-): insights into the novel induced hydrolytic deamination through bisulfite catalysis. AB - The induced ability of bisulfite to facilitate the hydrolytic deamination of the protonated cytosine-SO3(-) has been studied at the MP2/6-311++G(3df,3pd)//B3LYP/6 311++G(d,p) level and CBS-QB3 approach, respectively. In the gas phase, two distinct groups of mechanisms were explored, the direct hydrolytic deamination (path A) and HSO3(-)-induced hydrolytic deamination (paths B-D), and it indicates that the direct hydrolytic deamination of protonated cytosine-SO3(-) (path A) is unlikely because of the high activation free energy involved in the rate-limiting step, whereas the presence of bisulfite (paths B-D) significantly contributes to decreasing the activation free energy. In the aqueous phase, although the solvent effects of water significantly decrease the activation free energy of path A, the direct hydrolysis reaction remains unfavorable and the HSO3(-)-induced mechanism is still more favorable, which is in agreement with previous experimental data. The pseudo-first-order rate constant (k') for direct hydrolysis is obviously smaller than that of HSO3(-)-induced hydrolytic deamination, which is the most plausible mechanism, where the calculated the k' (1.99-3.81 * 10(-5) s(-1)) is in close proximity to the experimentally determined the pseudo-first-order rate constant (26.2 * 10(-5) s(-1)). Furthermore, the results also manifest that there is a positive correlation between the k' and temperature, and the ratio of reaction rates between direct hydrolysis reaction and HSO3(-)-induced hydrolytic deamination increases with the increase of the bisulfite concentration at a given temperature. PMID- 23652597 TI - Opposing HDAC4 nuclear fluxes due to phosphorylation by beta-adrenergic activated protein kinase A or by activity or Epac activated CaMKII in skeletal muscle fibres. AB - Class IIa histone deacetylases (HDACs) move between skeletal muscle fibre cytoplasm and nuclei in response to various stimuli, suppressing activity of the exclusively nuclear transcription factor Mef2. Protein kinase A (PKA) phosphorylates class IIa HDACs in cardiac muscle, resulting in HDAC nuclear accumulation, but this has not been examined in skeletal muscle. Using HDAC4 green fluorescent protein (HDAC4-GFP) expressed in isolated skeletal muscle fibres, we now show that activation of PKA by the beta-receptor agonist isoproterenol or dibutyryl (Db) cAMP causes a steady HDAC4-GFP nuclear influx. The beta-receptor blocker propranolol or PKA inhibitor Rp-cAMPS blocks the effects of isoproterenol on the nuclear influx of HDAC4-GFP, and Rp-cAMPS blocks the effects of Db cAMP. The HDAC4-GFP construct having serines 265 and 266 replaced with alanines, HDAC4 (S265/266A)-GFP, did not respond to beta-receptor or PKA activation. Immunoprecipitation results show that HDAC4-GFP is a substrate of PKA, but HDAC4 (S265/266A)-GFP is not, implicating HDAC4 serines 265/266 as the site(s) phosphorylated by PKA. During 10 Hz trains of muscle fibre electrical stimulation, the nuclear efflux rate of HDAC4-GFP, but not of HDAC4 (S265/266) GFP, was decreased by PKA activation, directly demonstrating antagonism between the effects of fibre stimulation and beta-adrenergic activation of PKA on HDAC4 nuclear fluxes. 8-CPT, a specific activator of Epac, caused nuclear efflux of HDAC4-GFP, opposite to the effect of PKA. Db cAMP increased both phosphorylated PKA and GTP-bound Rap1. Our results demonstrate that the PKA and CaMKII pathways play important opposing roles in skeletal muscle gene expression by oppositely affecting the subcellular localization of HDAC4. PMID- 23652601 TI - Editor's Note. PMID- 23652600 TI - Relationship between ST-segment recovery and clinical outcomes after primary percutaneous coronary intervention: the HORIZONS-AMI ECG substudy report. AB - BACKGROUND: In patients with ST-segment elevation myocardial infarction undergoing thrombolytic therapy, the degree of ST-segment resolution (STR) correlates with long-term cardiovascular mortality. The long-term predictive value of STR after primary percutaneous coronary intervention (PCI) is less well understood. We sought to determine the long-term prognostic value of STR after primary PCI in ST-segment-elevation myocardial infarction. METHODS AND RESULTS: In a formal substudy from the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, 2484 patients with ST segment-elevation myocardial infarction undergoing primary PCI with interpretable baseline and 60-minute post-PCI electrocardiograms had at least 1 mm of baseline ST-segment elevation in >=2 contiguous leads. Patients were categorized by the degree of STR at 60 minutes: (1) complete (>70%); (2) partial (30%-70%); and (3) absent (<30%). Absent, incomplete, and complete STR were achieved in 514 (20.7%), 712 (28.7%), and 1258 (50.5%) patients, respectively. STR <30% was associated with a greater likelihood of hypertension, diabetes mellitus, longer symptom onset to balloon time, lower left ventricular ejection fraction, and final thrombolysis in myocardial infarction flow <3. At 3 years, patients with STR<30% experienced a higher rate of major adverse cardiovascular events (death, reinfarction, ischemia-driven target vessel revascularization or stroke; 29.9% versus 20.1% versus 19.6%; P<0.0001), ischemia-driven target vessel revascularization (20.4% versus 14.0% versus 11.7%; P<0.001), and mortality (8.4% versus 5.0% versus 5.6%; P=0.03) than those with partial and complete STR, respectively. By multivariable analysis, STR<30% was an independent predictor of 3-year major adverse cardiovascular events (hazard ratio, 1.58; 95% confidence interval, 1.24-2.00; P=0.0002) and 3-year ischemia-driven target vessel revascularization (hazard ratio, 1.87; 95% confidence interval, 1.41-2.48; P<0.0001). CONCLUSIONS: In this large international study, absent STR 60 minutes after primary PCI was present in ~1 in 5 patients with ST-segment-elevation myocardial infarction and was a significant independent predictor of major adverse cardiovascular events and target vessel revascularization at 3 years. PMID- 23652602 TI - Modified fixation free plug technique using a new 3D multilamellar implant for inguinal hernia repair: a retrospective study of a single operator case series. AB - AIM: Implant fixation, mesh shrinkage and poor quality of tissue ingrowth are unresolved issues in modern hernia repair. Many complications reported in the literature such as bleeding, nerve entrapment, hematoma, pain, discomfort, and testicular complications, are considered to be a direct results of implant fixation. This article describes the outcomes of a procedure carried out using a handcrafted implant that addresses the issues consequent to point fixation. METHODS: This was a retrospective study on the short, medium and long-term results of placing a-modified, fixation free three-dimensional polypropylene implant in 61 patients who underwent inguinal hernia repair using a novel delivery technique. The follow up length was at least 36 months postop. RESULTS: Only minor adverse events and a low complication rate of the procedure were observed in this patient sample. There were no long- term complications. Postoperative pain was very low in both the short and long term. No chronic pain was reported. No recurrences occurred. CONCLUSION: The results of this retrospective study on a new method of inguinal hernia repair using a three dimensional handcrafted multilamellar implant delivered with a modified placement technique are promising. The short-, medium- and long-term complications were notably low. No recurrences were noticed but, more importantly, no chronic pain and extremely low discomfort rates were observed even in the long term. PMID- 23652603 TI - Isolation and characterization of spliceostatin B, a new analogue of FR901464, from Pseudomonas sp. No. 2663. PMID- 23652604 TI - Synthesis and structure-activity relationships studies of brartemicin analogs as anti-invasive agents. AB - Brartemicin is a trehalose-based inhibitor of tumor cell invasion produced by the actinomycete of the genus Nonomuraea. In order to find more potent anti-invasive agents and study the structure-activity relationships, a series of 19 brartemicin analogs were prepared via two synthetic routes from alpha,alpha-D-trehalose and evaluated for their anti-invasive activities. Compound 4f, 6,6'-bis(2,3 dimethoxybenzoyl)-alpha,alpha-D-trehalose, was more potent than the natural brartemicin. It inhibited the invasion of murine colon 26-L5, colon carcinoma SW620, melanoma B16-BL6 and breast MDA-MB-231 cells with IC50 values of 0.15, 2.35, 4.12 and 2.61 MUM, respectively. Analog 4p, 6,6'-bis(3,4 dimethoxycinnamoyl)-alpha,alpha-D-trehalose, was as potent as brartemicin against invasion of murine colon 26-L5 carcinoma cells in vitro. The structure-activity relationships of these novel trehalose-based compounds were summarized. PMID- 23652605 TI - Correction of the structure of cuevaene A and its identity with MBJ-0020 from Streptomyces sp. 30503. PMID- 23652606 TI - Cytotoxic sesquiterpenoids MBJ-0009 and MBJ-0010 from a saprobic fungus Nectria sp. f26111. PMID- 23652607 TI - A bright and responsive europium probe for determination of pH change within the endoplasmic reticulum of living cells. AB - A ratiometric Eu(III) complex has been developed that localises selectively within the endoplasmic reticulum of living cells. Careful calibration, using a time-gated spectral imaging microscope, allows the intensity ratio of emission bands and the variation of excited state lifetime to be used for pH determination, with a pKa of 7.15. PMID- 23652608 TI - Intracerebral administration of heat-inactivated Staphylococcus epidermidis enhances oncolysis and prolongs survival in a 9L orthotopic gliosarcoma model. AB - BACKGROUND/AIMS: The association between postoperative infection and prolonged survival in high-grade glioma is still a matter of debate. Previously we demonstrated that the intracerebral (i.c.) injection of heat-inactivated staphylococcal epitopes (HISE) resulted in a well-defined infux of immunocompetent cells across the blood-brain barrier. The present study investigated the potential antitumoral effect of HISE-immunostimulation in an experimental glioma model. METHODS: Wistar rats were intracerebrally implanted with 9L gliosarcoma cells (n=6), 9L cells mixed with HISE (n=12), or phosphate buffered saline (n=4). Tumor growth was measured by serial magnetic resonance imaging (MRI). After death due to the tumor burden, the brains were histopathologically assessed for inflammation and oncolysis. A toxicity assay was performed to quantify potential impairment of HISE on tumor cell growth in vitro. RESULTS: Animals treated by HISE showed a significant increase in average survival and even complete regression of an already established mass in one case. Naive 9L gliosarcomas failed to recruit significant numbers of systemic immune cells. In contrast, concomitant intracerebral HISE inoculation lead to a oncolysis and a distinct peri- and intratumoral infiltration of macrophages, CD8 and CD4 co-expressing T-lymphocytes in two thirds of the tumor-bearing animals. The toxicity screening showed HISE-mediated oncolysis to be ineffective ex vivo. CONCLUSION: This study describes a novel approach for combatting malignant glioma using inactivated staphylococci as potent immunomodulators. Our results provide an outline for investigating the strategic potential of bacteria as emerging future therapeutics. PMID- 23652609 TI - Results of pretransplant treatment of hepatorenal syndrome with terlipressin. AB - PURPOSE OF REVIEW: Hepatorenal syndrome (HRS) is a dreaded complication of end stage liver disease. The best treatment option for HRS is liver transplantation (LT) in suitable candidates. Pretransplant care of HRS is of utmost importance in order to secure a good posttransplant outcome. We review the advances during the last year in the diagnosis and management of HRS in candidates who are awaiting liver transplantation. RECENT FINDINGS: New attempts at defining renal failure in cirrhosis using the Acute Kidney Injury (AKI) definition have been proposed, as this definition has the potential advantage of detecting earlier phases of kidney dysfunction. Patients who undergo liver transplantation with acute tubular necrosis recover renal function more slowly than those with HRS and have a higher incidence of chronic kidney disease at all time points after liver transplantation. Vasoconstrictor drugs, particularly terlipressin, are effective for the management of HRS; however, noradrenaline is a good choice if terlipressin is not available. Long-term treatment of HRS with vasoconstrictors until liver transplantation in those patients with HRS recurrence after the first treatment is beneficial as a bridge to liver transplantation. Data from the cohorts of patients treated with vasoconstrictors (terlipressin and midodrine) indicate that liver transplantation offers a clear survival benefit to patients with HRS regardless of prior therapy with these drugs. SUMMARY: Ongoing advances in the management of patients with HRS before liver transplantation indicate that vasoconstrictors plus albumin should be offered to all suitable candidates. Liver transplantation remains the best treatment option for HRS. PMID- 23652610 TI - Evolving aspects of liver transplantation for nonalcoholic steatohepatitis. AB - PURPOSE OF REVIEW: Nonalcoholic steatohepatitis (NASH), obesity, and the metabolic syndrome are highly prevalent. NASH, a rare indication for liver transplantation in the early 1990s, is now the third most common indication. This review considers key aspects of the liver transplantation for NASH. RECENT FINDINGS: NASH is one consequence of obesity, almost always occurring in the context of metabolic syndrome and oxidative stress. Recurrence of NASH can be severe. The components of metabolic syndrome are often exacerbated following liver transplantation by factors such as immunosuppression, and are important predictors of patient morbidity and mortality. Many aspects of the metabolic syndrome are modifiable. The roles bariatric surgery, nutritional and pharmacotherapy of NASH, and the impact of established and new immunosuppressive agents have recently evolved. SUMMARY: A nuanced approach is needed in management of obesity, metabolic syndrome, and immunosuppression in liver transplant recipients. PMID- 23652612 TI - Differences in physical workload between military helicopter pilots and cabin crew. AB - PURPOSE: The 1-year prevalence of regular or continuous neck pain in military helicopter pilots of the Dutch Defense Helicopter Command (DHC) is 20%, and physical work exposures have been suggested as risk factors. Pilots and cabin crew perform different tasks when flying helicopters. The aims of the current study were to compare the exposures to physical work factors between these occupations and to estimate the 1-year prevalence of neck pain in military helicopter cabin crew members. METHODS: A survey was completed by almost all available helicopter pilots (n = 113) and cabin crew members (n = 61) of the DHC. The outcome measures were self-reported neck pain and exposures to nine physical work factors. Differences in the proportions of helicopter pilots and cabin crew members reporting being often exposed to the particular physical factor were assessed with the chi(2) test. RESULTS: The 1-year prevalence of regular or continuous neck pain among cabin crew was 28%. Significantly more cabin crew members than pilots reported being often exposed to manual material handling, performing dynamic movements with their torsos, working in prolonged bent or twisted postures with their torsos and their necks, working with their arms raised and working in awkward postures. Often exposure to prolonged sitting and dynamic movements with the neck were equally reported by almost all the pilots and cabin crew members. CONCLUSION: Flight-related neck pain is prevalent in both military helicopter pilots and cabin crew members. The exposures to neck pain related physical work factors differ between occupations, with the cabin crew members subjected to more factors. These results have implications for preventative strategies for flight-related neck pain. PMID- 23652613 TI - Basilar artery atherosclerosis and hypertensive small vessel disease in isolated pontine infarctions: a study based on high-resolution MRI. AB - BACKGROUND: Isolated pontine infarctions are classified as paramedian pontine infarction (PPI) and lacunar pontine infarction (LPI), usually attributed to basilar artery (BA) atherosclerosis and small vessel disease (SVD), respectively. Recently, researchers found BA atherosclerotic plaques in LPI and made the pathogenesis of LPI confusing. METHODS: We evaluated the presence and location of BA plaques with high-resolution MRI and SVD burden with presence of hypertension, leukoaraiosis and silent brain infarction. RESULTS: The prevalence of BA plaques and SVD was similar between PPI and LPI, with most plaques relevant to corresponding infarctions. Some PPI had no plaques; some LPI had no obvious SVD. CONCLUSION: SVD and BA plaques with or without lumen stenosis were both possible causes of PPI and LPI. PMID- 23652614 TI - Amorphous silicon-carbon nanospheres synthesized by chemical vapor deposition using cheap methyltrichlorosilane as improved anode materials for Li-ion batteries. AB - We report the preparation and characterization of amorphous silicon-carbon (Si-C) nanospheres as anode materials in Li-ion batteries. These nanospheres were synthesized by a chemical vapor deposition at 900 degrees C using methyltrichlorosilane (CH3SiCl3) as both the Si and C precursor, which is a cheap byproduct in the organosilane industry. The samples were characterized by X-ray diffraction, transmission electron microscopy, scanning electron microscopy, nitrogen adsorption, thermal gravimetric analysis, Raman spectroscopy, and X-ray photoelectron spectroscopy. It was found that the synthesized Si-C nanospheres composed of amorphous C (about 60 wt%) and Si (about 40 wt%) had a diameter of 400-600 nm and a surface area of 43.8 m(2) g(-1). Their charge capacities were 483.6, 331.7, 298.6, 180.6, and 344.2 mA h g(-1) at 50, 200, 500, 1000, and 50 mA g(-1) after 50 cycles, higher than that of the commercial graphite anode. The Si C amorphous structure could absorb a large volume change of Si during Li insertion and extraction reactions and hinder the cracking or crumbling of the electrode, thus resulting in the improved reversible capacity and cycling stability. The work opens a new way to fabricate low cost Si-C anode materials for Li-ion batteries. PMID- 23652617 TI - Comparison of different anesthetic regimens in patients undergoing laparoscopic adjustable gastric banding operations: a prospective randomized trial. AB - BACKGROUND AND OBJECTIVE: Obesity is a multisystem disorder, particularly involving the respiratory and cardiovascular systems; therefore, a multidisciplinary approach is required. In spite of widespread performance of weight reduction (bariatric) surgeries, information regarding the anesthetic care of morbidly obese patients is scarce. The aim of this study was to compare the impact of fentanyl and remifentanil on the time of recovery, breathing parameters, and postoperative pain in morbidly obese patients undergoing laparoscopic adjustable gastric banding operations. MATERIAL AND METHODS: In this prospective randomized study, 66 morbidly obese patients (BMI>35 kg/m(2)), aged between 24 and 70 years, scheduled for a laparoscopic adjustable gastric banding operation were divided into 2 groups based on the opioid used for anesthesia: group 1 whose who received remifentanil; and group 2, fentanyl). The following parameters were recorded: peripheral blood oxygenation (SpO2) while breathing room air at baseline and 5 minutes after preoxygenation (100%); end-tidal carbon dioxide pressure at designated time points during the procedure; time to extubation; SpO2 in the postanesthesia care unit; and pain intensity (using the visual analogue scale); and the presence of nausea and vomiting. RESULTS: The time to extubation was shorter in the remifentanil group, but there was no significant difference in the time to discharge from the postanesthesia care unit. The recovery of respiratory parameters to the baseline values was better and faster in the remifentanil group. The intensity of postoperative pain was similar in both groups (VAS, <3) CONCLUSIONS: Remifentanil showed good analgesic properties during laparoscopic gastric banding surgery. Postanesthesia recovery and return of respiratory parameters to the baseline values was faster when remifentanil was used. Postoperative pain and the rate of opioid-induced side effects after analgesia with remifentanil were similar as after anesthesia with a longer acting opioid, fentanyl. Despite the problem widely discussed in literature about remifentanil-induced hyperalgesia, no cases of analgesic overconsumption were registered in our study. PMID- 23652618 TI - Nonsteroidal anti-inflammatory drug-induced severe hyponatremia. AB - Hyponatremia (serum sodium level, <135 mmol/L) occasionally may develop in the course of treatment with nonsteroidal anti-inflammatory drugs, which are usually used in daily clinical practice. Nonsteroidal anti-inflammatory drugs diminish the normal inhibitory effect of prostaglandins on the activity of antidiuretic hormone and can therefore reduce free water excretion, leading to water retention and induction or exacerbation of hyponatremia. In this report, we present a case of hyponatremia in a 78-year-old man who had received meloxicam, a nonsteroidal anti-inflammatory drug. PMID- 23652619 TI - Disc impediment in medtronic-Hall aortic valve prosthesis followed by successful reoperation. AB - This case report describes the diagnostic and treatment challenges of the combined disc impediment caused by pannus ingrowth in combination with thrombus formation in a 21-mm Medtronic-Hall aortic valve prosthesis. A combined obstruction of a Medtronic-Hall prosthesis in the aortic position is a rare, but potentially fatal clinical condition for the first time reported in Vilnius University Hospital Santariskiu Klinikos. Despite the difficulties in determining a correct diagnosis, our critically ill patient was clinically stabilized by partially successful thrombolysis and then successfully treated by a surgical thrombectomy together with pannus excision during the rotation of the disc within the valve housing 3 years after the valve implantation. PMID- 23652620 TI - Effect of visual feedback information on isometric contraction of forearm flexor muscles in men and women after ischemic stroke. AB - The aim of this study was to determine the effect of visual feedback information (VFI) on the isometric contraction of the forearm flexor muscles in men and women after an ischemic stroke when doing a physical load at 20% of strength. MATERIAL AND METHODS: The study included healthy subjects (n=20) and subjects after ischemic stroke (n=20). The study was conducted in Lithuanian Sports University. The measurements of maximum voluntary strength (MVS) and accurate isometric contraction were performed using an isokinetic dynamometer Biodex System Pro 3. RESULTS: The absolute errors of isometric contraction of the right arm muscles at 20% of MVS were similar in all the groups during the attempt with visual feedback information. The smallest absolute errors of the healthy subjects were 1.42+/ 0.35 Nm when the task was performed with visual feedback and the greatest absolute errors were 4.69+/-0.95 Nm (P<0.01) while performing the task without visual feedback. Meanwhile, the smallest and greatest absolute errors of the subjects after ischemic stroke were 1.32+/-0.45 Nm and 5.05+/-0.63 Nm, respectively, while performing the task without visual feedback (P<0.01). CONCLUSIONS: Maximum voluntary strength was greater in all the groups of men. The absolute errors of isometric contractions of the right and left arm muscles tended to increase in both the men and the women when there was no visual feedback information. The women and the men after an ischemic stroke produced greater absolute errors when performing the task with the right and left arm without visual feedback information than the healthy subjects. PMID- 23652611 TI - Histone variants: emerging players in cancer biology. AB - Histone variants are key players in shaping chromatin structure, and, thus, in regulating fundamental cellular processes such as chromosome segregation and gene expression. Emerging evidence points towards a role for histone variants in contributing to tumor progression, and, recently, the first cancer-associated mutation in a histone variant-encoding gene was reported. In addition, genetic alterations of the histone chaperones that specifically regulate chromatin incorporation of histone variants are rapidly being uncovered in numerous cancers. Collectively, these findings implicate histone variants as potential drivers of cancer initiation and/or progression, and, therefore, targeting histone deposition or the chromatin remodeling machinery may be of therapeutic value. Here, we review the mammalian histone variants of the H2A and H3 families in their respective cellular functions, and their involvement in tumor biology. PMID- 23652621 TI - Estimation of all-cause and cardiovascular mortality risk in relation to leisure time physical activity: a cohort study. AB - BACKGROUND AND OBJECTIVE: Epidemiologists agree that physical activity has a protective role in morbidity and mortality mainly through its positive impact on risk factors. So far, most studies have confirmed that CVD risk decreases with an increasing physical activity level, but it is not known what level of physical activity is already sufficient for mortality risk reduction. Thus, the aim of this study was to explore long-term associations between leisure-time physical activity and mortality risk in the Lithuanian urban population. MATERIAL AND METHODS: The MONICA study (1992-1993) and the repeated health examination survey in 2001-2002 were organized as a cohort study of 2642 middle-aged inhabitants from the general Lithuanian population of Kaunas. Two random samples aged 35-64 years were examined in 1992-2002. Leisure-time physical activity was assessed by an interview method, asking about physically demanding activities at leisure time measured in hours. The study sample was pooled into 2 groups: inactive (first quartile) and active (second to fourth quartiles). Follow-up was carried out in terms of the endpoints reached from the baseline until December 31, 2010. Mortality data from the National Death Register were obtained. RESULTS: Multivariate adjusted Cox proportional hazards analyses revealed an HR of 1.46 (95% CI, 1.15-1.85) for all-cause mortality and 1.73 (95% CI, 1.23-2.45) for CVD mortality in the lowest quartile of leisure-time physical activity compared with the higher ones. As much as 16.2% of all-cause mortality and 22.2% of CVD mortality was attributable to the lowest quartile of leisure-time physical activity. CONCLUSIONS: This study demonstrated a beneficial effect of leisure time physical activity on predicting all-cause and CVD mortality risk. PMID- 23652622 TI - Effect of high temperatures on daily counts of mortality from diseases of circulatory system in Astana, Kazakhstan. AB - BACKGROUND AND OBJECTIVE: Associations between hot temperatures and both overall and cardio- and cerebrovascular mortality have been observed in many European, North American, and Southeastern Asian cities. However, the effects varied among the settings with limited evidence from the countries with arid and semiarid climates. The aim of this study was to assess the effect of air temperature on deaths from the selected diseases of the circulatory system in the city of Astana, Kazakhstan. MATERIAL AND METHODS: The daily counts of deaths from hypertensive diseases (ICD-10 codes, I10-I15), cerebrovascular diseases (ICD-10 codes, I60-I69), and ischemic heart disease (ICD-10 codes, I20-I25) during the warm seasons (April-September) of 2000-2001 and 2006-2010 were obtained from the City Registry Office. The associations between the maximum apparent temperature (average of lags 0-3) and mortality were assessed by a first-order autoregressive Poisson regression with the adjustment for barometric pressure (average of lags 0 3), wind speed, and effects of month, year, holidays, and weekends. RESULTS: Altogether, there were 282, 1177, and 2994 deaths from hypertensive diseases, cerebrovascular diseases, and ischemic heart disease, respectively. The maximum effective temperature varied between -2.2 degrees C and 44.5 degrees C. An increase in temperature by 1 degrees C was associated with a 1.9% (95% CI, 0.3 3.5) increase in the daily number of deaths from cerebrovascular diseases and with a 3.1% (95% CI, 0.2-6.1) decrease in the number of deaths from hypertensive diseases among women. CONCLUSIONS: The results suggest a positive association between the maximum apparent temperature and the daily counts of deaths from cerebrovascular diseases and an inverse association between temperature and mortality from hypertensive diseases, but only among women. PMID- 23652623 TI - Maternal request is not to blame for an increase in the rate of Cesarean section. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to establish whether Lithuanian women would request an elective cesarean section in a low-risk pregnancy and to compare how the women's opinion changed during the 5-year period. MATERIAL AND METHODS: A study was conducted at the Hospital of Lithuanian University of Health Sciences from November 1 to December 31, 2006, and from January 1 to February 28, 2011. A total of 204 and 239 women were enrolled in 2006 and 2011, respectively. Self-administered anonymous questionnaires collected information on women's knowledge about the advantages of the different modes of delivery and their preferred type of birth in a low-risk pregnancy. RESULTS: Overall, 82.4% of the participants in 2006 and 74.5% in 2011 thought that women should be able to choose the mode of delivery in a low-risk pregnancy. If they had had such an opportunity, 15.2% of women in 2006 and 14.9% in 2011 would have chosen cesarean section without any medical indication. The most frequently mentioned advantage of vaginal delivery was that it is natural, while safety for the newborn and the possibility of avoiding delivery pain were the mentioned advantages of cesarean section. CONCLUSIONS: Approximately 15% of Lithuanian women would request an elective cesarean section, and this percentage did not change during the 5-year period. While the national cesarean section rate is increasing with every year, it seems that "maternal request" cannot be blamed for this phenomenon. Despite all the available information about the different modes of delivery, women still lack professional and reliable knowledge about it. PMID- 23652624 TI - Recent advances in endovascular treatment of aortoiliac occlusive disease. AB - The rate of endovascular interventions for iliac occlusive lesions is continuously growing. The evolution of the technology supporting these therapeutic measures improves the results of these interventions. We performed a review of the literature to report and appreciate short- and long-term results of endovascular stenting of iliac artery occlusive lesions. The Medline database was searched to identify all the studies reporting iliac artery stenting for aortoiliac occlusive disease (Trans Atlantic Inter-Society Consensus [TASC] type A, B, C, and D) from January 2006 to July 2012. The outcomes were technical success, long-term primary and secondary patency rates, early mortality, and complications. Technical success was achieved in 91% to 99% of patients as reported in all the analyzed articles. Early mortality was described in 5 studies and ranged from 0.7% to 3.6%. The most common complications were access site hematomas, distal embolization, pseudoaneurysms, and iliac artery ruptures. The complications were most often treated conservatively or using percutaneous techniques. The 5-year primary and secondary patency rates ranged from 63% to 88% and 86% to 93%, respectively; and the 10-year primary patency rates ranged from 68% to 83%. In this article, combined percutaneous endovascular iliac stenting and infrainguinal surgical reconstructions and new techniques in the treatment of iliac stent restenosis are discussed. Iliac stenting is a feasible, safe, and effective method for the treatment of iliac occlusive disease. Initial technical and clinical success rates are high; early mortality and complication rates are low. Long-term patency is comparable with that after bypass surgery. PMID- 23652626 TI - Failure of collateral blood flow is associated with infarct growth in ischemic stroke. AB - Changes in collateral blood flow, which sustains brain viability distal to arterial occlusion, may impact infarct evolution but have not previously been demonstrated in humans. We correlated leptomeningeal collateral flow, assessed using novel perfusion magnetic resonance imaging (MRI) processing at baseline and 3 to 5 days, with simultaneous assessment of perfusion parameters. Perfusion raw data were averaged across three consecutive slices to increase leptomeningeal collateral vessel continuity after subtraction of baseline signal analogous to digital subtraction angiography. Changes in collateral quality, Tmax hypoperfusion severity, and infarct growth were assessed between baseline and days 3 to 5 perfusion-diffusion MRI. Acute MRI was analysed for 88 patients imaged 3 to 6 hours after ischemic stroke onset. Better collateral flow at baseline was associated with larger perfusion-diffusion mismatch (Spearman's Rho 0.51, P<0.001) and smaller baseline diffusion lesion volume (Rho -0.70, P<0.001). In 30 patients without reperfusion at day 3 to 5, deterioration in collateral quality between baseline and subacute imaging was strongly associated with absolute (P=0.02) and relative (P<0.001) infarct growth. The deterioration in collateral grade correlated with increased mean Tmax hypoperfusion severity (Rho 0.68, P<0.001). Deterioration in Tmax hypoperfusion severity was also significantly associated with absolute (P=0.003) and relative (P=0.002) infarct growth. Collateral flow is dynamic and failure is associated with infarct growth. PMID- 23652625 TI - The APOE E4/E4 genotype potentiates vascular fibrin(ogen) deposition in amyloid laden vessels in the brains of Alzheimer's disease patients. AB - Evidence indicates a critical role for cerebrovascular dysfunction in Alzheimer's disease (AD) pathophysiology. We have shown that fibrin(ogen), the principal blood-clotting protein, is deposited in the AD neurovasculature and interacts with beta-amyloid (Abeta), resulting in increased formation of blood clots. As apolipoprotein E (ApoE), a lipid-transporting protein with three human isoforms (E2, E3, and E4), also binds to Abeta, we hypothesized that ApoE and fibrin(ogen) may have a combined effect on the vascular pathophysiology in AD. We assessed whether APOE genotype differentially influences vascular fibrin(ogen) deposition in postmortem brain tissue using immunohistochemistry. An increased deposition of fibrin(ogen) was observed in AD cases compared with non-demented controls, and there was a strong correlation between cerebral amyloid angiopathy (CAA) severity and fibrin(ogen) deposition. Moreover, brains from AD cases homozygous for APOE E4 showed increased deposition of fibrin(ogen), specifically in CAA- and oligomeric Abeta-positive vessels compared with AD APOE E2 and E3 allele carriers, an effect that was not directly linked to CAA severity and cerebrovascular atherosclerosis. These data further support a role for fibrin(ogen) in AD pathophysiology and link the APOE E4/E4 genotype with increased thrombosis and/or impaired fibrinolysis in the human AD brain. PMID- 23652627 TI - Modeling of brain metabolism and pyruvate compartmentation using (13)C NMR in vivo: caution required. AB - Two variants of a widely used two-compartment model were prepared for fitting the time course of [1,6-(13)C2]glucose metabolism in rat brain. Features common to most models were included, but in one model the enrichment of the substrates entering the glia and neuronal citric acid cycles was allowed to differ. Furthermore, the models included the capacity to analyze multiplets arising from (13)C spin-spin coupling, known to improve parameter estimates in heart. Data analyzed were from a literature report providing time courses of [1,6 (13)C2]glucose metabolism. Four analyses were used, two comparing the effect of different pyruvate enrichment in glia and neurons, and two for determining the effect of multiplets present in the data. When fit independently, the enrichment in glial pyruvate was less than in neurons. In the absence of multiplets, fit quality and parameter values were typical of those in the literature, whereas the multiplet curves were not modeled well. This prompted the use of robust statistical analysis (the Kolmogorov-Smirnov test of goodness of fit) to determine whether individual curves were modeled appropriately. At least 50% of the curves in each experiment were considered poorly fit. It was concluded that the model does not include all metabolic features required to analyze the data. PMID- 23652628 TI - Detection and characterization of two novel mutations in the HNF4A gene in maturity-onset diabetes of the young type 1 in two Japanese families. AB - BACKGROUND: Maturity-onset diabetes of the young (MODY) is a subgroup of monogenic diabetes mellitus, of which MODY1, caused by HNF4A mutations, accounts for only 5% or less and has been rarely reported in East Asian countries. Here we report two novel HNF4A mutations in two Japanese families with MODY1. METHODS: Proband 1 is an 8-year-old girl and proband 2 is a 14-year-old girl. Both were nonobese, demonstrated elevated HbA1c and negative serum anti-glutamic acid decarboxylase antibodies, and had a family history of diabetes. We directly sequenced HNF4A and performed functional analysis of the detected missense mutation. RESULTS: Proband 1 had a heterozygous missense mutation, c.824A>G (p.Asn275Ser). Luciferase assay demonstrated a significant reduction in transcriptional activity. A heterozygous frame shift mutation, c.692-695delAGGA (p.Lys231ThrfsX5), was detected in proband 2. Affected family members shared the same mutations, showing high penetrance. Both mutations reside in the HNF4alpha dimerization domain and the corresponding amino acids are well conserved between species. CONCLUSIONS: These two mutations are most likely the cause of MODY1 in these families. Considering the effectiveness of sulfonylureas, it is important to correctly diagnose MODY1. PMID- 23652629 TI - NeuroD regulates neuronal migration. AB - NeuroD is required for the survival of many subtypes of developing neurons in the vertebrate central nervous system. Because NeuroD-deficient neurons in the hippocampus, cerebellum, and inner ear die prematurely in the early stage of neurogenesis, the role of NeuroD during the later stages of neurogenesis of these cell subtypes is not well understood. In addition, the mechanism of NeuroDdeficient neuronal death has not been investigated. It was hypothesized that NeuroD-dependent neuronal death occurs through a Bax-dependent apoptotic pathway. Based on this hypothesis, this study attempted to rescue neuronal cell death by deleting the Bax gene in NeuroD null mice to investigate the role of NeuroD in surviving neurons. The NeuroD and Bax double null mice displayed a decrease in the number of apoptotic cells in the hippocampus and the cerebellum and the rescue of vestibulocochlear ganglion (VCG) neurons that failed to migrate and innervate. In addition, at E13.5, the NeuroD(-/-)Bax(-/-) VCG neurons failed to express TrkB and TrkC, which are known to be essential for the survival of those neurons. These data suggest that neuronal death in NeuroD null mice is mediated by Bax-dependent apoptosis and that NeuroD is required for the migration of VCG neurons. Finally, these data show that TrkB and TrkC expression in E13.5 VCG neurons requires NeuroD and that TrkB and TrkC expression may be necessary for the normal migration and innervations of those neurons. PMID- 23652630 TI - CT imaging as a prognostic indicator for patients with pulmonary injury from acute paraquat poisoning. AB - OBJECTIVE: CT imaging may be an effective diagnostic method for assessing the extent and progression of pulmonary injury in patients with acute paraquat (PQ) poisoning. METHODS: A retrospective review of 78 patients with acute PQ poisoning (survivor group, n=42; non-survivor group, n=36) was conducted to examine the lung segment involvement and CT image characteristics from baseline (first CT scan at a mean of 2.4 days after poisoning) to treatment time (second CT scan 3 days after the first). We examined the association between prognosis and pulmonary lesions indicated by characteristic effusion, fibrosis and consolidation in CT images. RESULTS: Significant differences were apparent in CT images at baseline and after 3 days between the survivor and the non-survivor groups, with higher levels of pulmonary segment involvement, effusion, consolidation and fibrosis observed in the non-survivor group at baseline (p<0.05). The non-survivor group also showed rapid lesion progression. The receiver operating characteristic curve indicated that the best prognostic value of baseline CT scanning was achieved when performed 2-3 days following the initial exposure. CONCLUSION: Prognosis correlated with increasing lung segment involvement, extent of disease characteristics visualised using CT and speed of lesion progression from baseline. Prognostic evaluation using CT scanning can be used to effectively provide earlier treatment for patients at risk for severe complications associated with PQ toxicity, such as acidosis; leukocytosis; and renal, hepatic and pancreatic failures. ADVANCES IN KNOWLEDGE: Chest CT scan can be used 2-3 days following acute PQ poisoning to determine prognosis. PMID- 23652631 TI - Sann-Joong-Kuey-Jian-Tang decreases the protein expression of Mcl-1 and TCTP and increases that of TNF-alpha and Bax in BxPC-3 pancreatic carcinoma cells. AB - Sann-Joong-Kuey-Jian-Tang (SJKJT), a traditional Chinese medicinal prescription, has been used for the treatment of lymphadenopathy and solid tumors, and has shown therapeutic potential in several human malignant tumor cell lines. However, the efficacy and molecular mechanisms of action of SJKJT in human pancreatic cancer have not yet been elucidated. In the present study, we evaluated the cytotoxic effects of SJKJT on BxPC-3 human pancreatic carcinoma cells by MTT assay. The protein expression levels of myeloid cell leukemia 1 protein (Mcl-1), translationally controlled tumor protein (TCTP), tumor necrosis factor-alpha (TNF alpha), caspase-8, caspase-3, Bax and Bcl-2 family in the BxPC-3 cells were measured by western blot analysis. The cell cycle was analyzed by flow cytometry. The protein expression of caspase-3 was also detected by immunocytochemistry (ICC). The results revealed that SJKJT inhibited the proliferation of BxPC-3 cells in a time- and dose-dependent manner. The protein expression levels of TNF alpha, caspase-8, caspase-3 and Bax increased in the BxPC-3 cells treated with SJKJT; however, the levels of Mcl-1, TCTP and Bcl-xL decreased. The results also demonstrated that SJKJT increased the percentage of BxPC-3 cells in the sub-G1 phase. In addition, ICC staining indicated that the protein expression of caspase 3 was upregulated in the BxPC-3 cells treated with SJKJT. These findings indicate that SJKJT inhibits the proliferation of BxPC-3 cells through the extrinsic and intrinsic pathway, inducing apoptosis in vitro. Our study, using BxPC-3 human pancreatic cancer cells, demonstrates that SJKJT has potential as a chemotherapeutic agent for the treatment of pancreatic cancer. Further sutdies are warranted to fully elucidate its mechanisms of action. PMID- 23652632 TI - Paper-based microfluidic point-of-care diagnostic devices. AB - Dipstick and lateral-flow formats have dominated rapid diagnostics over the last three decades. These formats gained popularity in the consumer markets due to their compactness, portability and facile interpretation without external instrumentation. However, lack of quantitation in measurements has challenged the demand of existing assay formats in consumer markets. Recently, paper-based microfluidics has emerged as a multiplexable point-of-care platform which might transcend the capabilities of existing assays in resource-limited settings. However, paper-based microfluidics can enable fluid handling and quantitative analysis for potential applications in healthcare, veterinary medicine, environmental monitoring and food safety. Currently, in its early development stages, paper-based microfluidics is considered a low-cost, lightweight, and disposable technology. The aim of this review is to discuss: (1) fabrication of paper-based microfluidic devices, (2) functionalisation of microfluidic components to increase the capabilities and the performance, (3) introduction of existing detection techniques to the paper platform and (4) exploration of extracting quantitative readouts via handheld devices and camera phones. Additionally, this review includes challenges to scaling up, commercialisation and regulatory issues. The factors which limit paper-based microfluidic devices to become real world products and future directions are also identified. PMID- 23652634 TI - Approximate Bayesian computation (ABC) gives exact results under the assumption of model error. AB - Approximate Bayesian computation (ABC) or likelihood-free inference algorithms are used to find approximations to posterior distributions without making explicit use of the likelihood function, depending instead on simulation of sample data sets from the model. In this paper we show that under the assumption of the existence of a uniform additive model error term, ABC algorithms give exact results when sufficient summaries are used. This interpretation allows the approximation made in many previous application papers to be understood, and should guide the choice of metric and tolerance in future work. ABC algorithms can be generalized by replacing the 0-1 cut-off with an acceptance probability that varies with the distance of the simulated data from the observed data. The acceptance density gives the distribution of the error term, enabling the uniform error usually used to be replaced by a general distribution. This generalization can also be applied to approximate Markov chain Monte Carlo algorithms. In light of this work, ABC algorithms can be seen as calibration techniques for implicit stochastic models, inferring parameter values in light of the computer model, data, prior beliefs about the parameter values, and any measurement or model errors. PMID- 23652633 TI - PrfA led to reduced biofilm formation and contributed to altered gene expression patterns in biofilm-forming Listeria monocytogenes. AB - The foodborne pathogen Listeria monocytogenes has the ability to develop biofilm in the food-processing environment, which becomes a major concern for food safety. PrfA, a key transcriptional activator that regulates most of the known listerial virulence gene expression, has been shown to promote L. monocytogenes biofilm formation. In this study, the whole-genome microarray was used to identify differentially expressed genes associated with the putative interaction between biofilm formation and PrfA in L. monocytogenes. Comparative transcriptome analyses indicated that over 21.9 % of the L. monocytogenes EGDe genes (627 out of 2,857 predicted) were altered in their expression of biofilm compared to the planktonic phase. These genes were classified into different functional categories which cover most of the biochemical functions encountered in bacterial cells, indicating that L. monocytogenes biofilm formation is probably controlled by a complex regulation network involved in variable genes required for the different biological pathways. Further comparison of gene expression profiles of biofilms between L. monocytogenes EGDe and its PrfA deletion mutant revealed 185 genes associated with PrfA and biofilm formation. Except for 10 genes, transcription levels of 175 genes were completely opposite between DeltaprfA and wild-type during the biofilm formation, i.e., up-regulated genes in DeltaprfA were down-regulated in the wild-type strain, and vice versa, indicating that loss of PrfA dramatically altered gene expression patterns in L. monocytogenes biofilm and resulted in reduced ability of the biofilm formation. PMID- 23652635 TI - An extension of the Wilcoxon-Mann-Whitney test for analyzing RT-qPCR data. AB - Classical approaches for analyzing reverse transcription quantitative polymerase chain reaction (RT-qPCR) data commonly require normalization before assessing differential expression (DE). Normalization often has a substantial effect on the interpretation and validity of the subsequent analysis steps, but at the same time it causes a reduction in variance and introduces dependence among the normalized outcomes. These effects can be substantial, however, they are typically ignored. Most normalization techniques and methods for DE focus on mean expression and are sensitive to outliers. Moreover, in cancer studies, for example, oncogenes are often only expressed in a subsample of the populations during sampling. This primarily affects the skewness and the tails of the distribution and the mean is therefore not necessarily the best effect size measure within these experimental setups. In our contribution, we propose an extension of the Wilcoxon-Mann-Whitney test which incorporates a robust normalization, and the uncertainty associated with normalization is propagated into the final statistical summaries for DE. Our method relies on semiparametric regression models that focus on the probability P{Y <= Y'}, where Y and Y' denote independent responses for different subject groups. This effect size is robust to outliers, while remaining informative and intuitive when DE affects the shape of the distribution instead of only the mean. We also extend our approach for assessing DE for multiple features simultaneously. Simulation studies show that the test has a good performance, and that it is very competitive with standard methods for this platform. The method is illustrated on two neuroblastoma studies. PMID- 23652636 TI - Is yoga an effective treatment in the management of patients with chronic low back pain compared with other care modalities - a systematic review. AB - OBJECTIVE: The aim of the study was to assess randomized-control trials (RCTs) to ascertain whether yoga is an effective treatment in the management of patients with chronic low back pain (cLBP) compared with other care modalities. METHODS: A search strategy was formulated with key concepts identified using the PICO process. Four databases were searched in June 2012. Appropriate eligibility criteria were set and implemented. RESULTS: Four randomized control trials met the inclusion criteria. All four papers found that yoga lead to a significant improvement in back function, and three demonstrated a significant improvement in back pain when compared with certain care modalities. All papers had significant limitations identified, however. CONCLUSIONS: Given the limitations identified within the studies, the conclusions drawn must be considered conservatively. Although early results appear promising, but further well-designed RCTs are warranted, with multiple, specified comparator care modalities before firm conclusions can be gained. PMID- 23652637 TI - Omega-3 fatty acid for the treatment and remission of Crohn's disease. AB - This integrative literature review focused on the use of omega-3 fatty acid supplementation for the treatment of Crohn's disease (CD). A systematic review of studies investigating the use of omega-3 in individuals with CD was performed. OVID MEDLINE, the Cochrane Database, and CINAHL were searched for pertinent research. Experiments were limited to double-blind placebo controlled trials. Five studies observing CD relapse rates and three studies examining biochemical changes were evaluated. The studies reviewed show contradicting information regarding the efficacy of omega-3 for CD. While some studies have shown supplementation with omega-3 results in sustained remission from disease, other studies concluded no correlation between omega-3 supplementation and improved remission rates. Studies investigating biochemical variables suggest favorable changes in immunological milieu, including modifications of lipid profiles and cytokine production. The studies reviewed are adversely limited by low number of participants, short duration of study and other significant deficits. Limited data remain available and current literature indicated mixed conclusions regarding the efficacy of omega-3 for treatment of CD. Further large-scale studies of longer duration are necessary. PMID- 23652638 TI - Decreasing cardiovascular risk factors in obese individuals using a combination of PGX(r) meal replacements and PGX(r) granules in a 12-week clinical weight modification program. AB - In this open, clinically based, weight modification program, we determined in six sedentary obese adults (five women; one male; age range 30-62 years) that the combination of a modified calorie diet plus PGX(r) meal replacement and PGX(r) supplementation resulted in a significant reduction in several cardiovascular risk factors over a 12-week time period. This included a significant improvement in lipids (-0.98 mmol/l LDL-C), reduction in average weight (-9.2 kg), mean reduction in fat (-4.1%) and an increase in fat-free mass (2.8%). PMID- 23652639 TI - Phytochemical screening and toxicity studies on the methanol extract of the seeds of moringa oleifera. AB - The seeds of Moringa oleifera were collected, air-dried, pulverized, and subjected to cold extraction with methanol. The methanol extract was screened phytochemically for its chemical components and used for acute and sub-acute toxicity studies in rats. The phytochemical screening revealed the presence of saponins, tannins, terpenes, alkaloids, flavonoids, carbohydrates, and cardiac glycosides but the absence of anthraquinones. Although signs of acute toxicity were observed at a dose of 4,000 mg kg-1 in the acute toxicity test, and mortality was recorded at 5,000 mg kg-1, no adverse effect was observed at concentrations lower than 3,000 mg kg-1. The median lethal dose of the extract in rat was 3,873 mg kg-1. Sub-acute administration of the seed extract caused significant (p<0.05) increase in the levels of alanine and aspartate transferases (ALT and AST), and significant (p<0.05) decrease in weight of experimental rats, at 1,600 mg kg-1. The study concludes that the extract of seeds of M. oleifera is safe both for medicinal and nutritional uses. PMID- 23652640 TI - Tea toxicity and cholinesterase inhibition of Huilliche herbal medicine. AB - Eleven species of Huilliche medicinal plants used traditionally against infections and for wound healing were tested for their cholinesterase inhibition activity. Two different teas (a 5-7 min infusion and a 1 h decoction, both in water) were tested for their toxicity against Artemia salina. The results from the present study clearly show that teas boiled for 1 h is much more toxic than teas infused for 5-7 min. These results support the different traditional use of the two teas, where the 1h tea is for external use only. Additionally, significant inhibition of cholinesterase has been observed for MeOH extracts of Acaena argentea, Amomyrtas meli and Pseudopanax laetevirens, with that of A. argentea being the most potent. All findings call for further investigations. PMID- 23652641 TI - Antimalarial potential of China 30 and Chelidonium 30 in combination therapy against lethal rodent malaria parasite: Plasmodium berghei. AB - Homeopathy is a therapeutic method based on the application of similia principle, utilizing ultra-low doses of medicinal substances made from natural products. The present study has been designed to evaluate the efficacy of Cinchona officinalis (Chin.) 30C and Chelidonium majus (Chel.) 30C in combination therapy against lethal murine malaria. Five groups having twelve BALB/c mice each were administered orally with 0.2 ml/mouse/day of different drugs, and their antimalarial potential was evaluated by Peter's 4-day test. The combination of Chin. 30 and Chel. 30 exhibited complete parasite clearance by the 28th day post inoculation which was similar to the positive control [artesunate (4 mg/kg)+sulphadoxine-primethamine (1.2 mg/kg)] group. Both the groups exhibited enhanced mean survival time (MST) 28+/-0 days,whereas, the mice of infected control group survived up to 7.6+/-0.4 days only. The preventive and curative activities of the combination in comparison to the positive controls [pyrimethamine (1.2 mg/Kg) and chloroquine (20 mg/Kg), respectively] were also evaluated. The combination had a significant preventive activity (p<0.0005), with 89.2% chemosuppression which was higher than the standard drug, pyrimethamine (83.8%). It also showed a moderate curative activity with complete clearance of parasite in 50% of surviving mice, and enhancing the MST of mice up to 26.8+/-2.8 days. These findings point to the significant antiplasmodial efficacy of the combination of these homeopathic drugs against Plasmodium berghei. PMID- 23652642 TI - Developing an in-patient acupuncture treatment in a pediatric hospital. AB - Little is known about the broad application of acupuncture as adjuvant treatment for in-patient pediatric populations. We review a series of cases involving acupuncture for conditions ranging from insomnia to cyclic vomiting. The details of the protocol for each are included. This case series illustrates the benefits of an in-patient acupuncture treatment service, as well as the subtleties of an acupuncture protocol when treating children and adolescents. PMID- 23652643 TI - Aloe vera gel protects liver from oxidative stress-induced damage in experimental rat model. AB - Aloe vera is a semi-tropical plant of Liliaceae family which has a wide range of applications in traditional medicine. In the present study, we sought to investigate the heptaoprotective potential of Aloe vera gel as a diet supplement. To achieve this goal, we have designed in vitro and in vivo experimental models of chemical-induced liver damage using male Sprague-Dawley rat. In the in vitro model, its effect was evaluated on Fenton's reaction-induced liver lipid peroxidation. Co-incubation with gel significantly reduced the generation of liver lipid peroxide (LPO). Next, to see the similar effect in vivo, gel was orally administered to rats once daily for 21 successive days. Following 1 hour of the last administration of gel, rats were treated with intra-peritoneal injection of CCl4. Dietary gel showed significant hepatoprotection against CCl4 induced damage as evident by restoration of liver LPO, serum transaminases, alkaline phosphatase, and total bilirubin towards near normal. The beneficial effects were pronounced with the doses used (400 and 800 mg/kg body weight). Besides, we did not observe any significant drop in serum albumin, globulin as well as total protein levels of gel-administered rats. Histopathology of the liver tissue further supported the biochemical findings confirming the hepatoprotective potential of dietary gel. PMID- 23652644 TI - Light-inducible molecular beacons for spatio-temporally highly defined activation. AB - We have developed a new molecular beacon design that requires an additional UV pulse for fluorescence activation. This improves the signal-to-noise ratio tremendously compared to previous approaches and allows for a precise control of the time point and location of RNA labelling. PMID- 23652645 TI - Plasmon based biosensor for distinguishing different peptides mutation states. AB - Periodic and reproducible gold nanocuboids with various matrix dimensions and with different inter-particle gaps were fabricated by means of top-down technique. Rhodamine 6G was used as a probe molecule to optimize the design and the fabrication of the cuboid nanostructures. The electric field distribution for the nanocuboids with varying matrix dimensions/inter-particle gap was also investigated. These SERS devices were employed as biosensors through the investigation of both myoglobin and wild/mutated peptides. The results demonstrate the probing and the screening of wild/mutated BRCA1 peptides, thus opening a path for the fabrication of simple and cheap SERS device capable of early detection of several diseases. PMID- 23652646 TI - Proteomic analysis of the cerebrospinal fluid of Parkinson's disease patients pre and post-deep brain stimulation. AB - AIMS: To investigate alterations in protein expression associated with deep brain stimulation (DBS) in an attempt to elucidate possible mechanisms of action . METHODS: Cerebrospinal fluid (CSF), obtained from six Parkinson's disease (PD) patients (pre- and post-DBS) and from six normal healthy controls, was studied for differentially expressed proteins. 2-D DIGE, in combination with MALDI-TOF and TOF-TOF Mass Spectrometry (MS) or ESI-MS, was used to identify the changed proteins (3 PD patients and 3 controls). Selected proteins were further studied using western blotting (6 PD patients and 6 controls). RESULTS: Twenty-one proteins were identified after MS and protein database interrogation. Apart from apolipoprotein A-I (apoA-I), the expression levels of complement C4 (C4), IgA, tetranectin, and extracellular superoxide dismutase (EC-SOD), detected by western blotting, correlated well with the 2-D DIGE results. In the follow-up period, the expression levels of C4, apoA-I and IgA were stable whereas EC-SOD and tetranectin were significantly elevated. In addition, when DBS was ceased in one patient due to a suicide attempt, the levels of EC-SOD and tetranectin significantly decreased. CONCLUSION: Our preliminary results suggest that variations in the expression levels of EC-SOD and tetranectin in CSF is related to DBS. PMID- 23652647 TI - Individual Characteristics Associated with Blood Donation: A Cross-National Comparison of the German and Swiss Population between 1994 and 2010. AB - OBJECTIVE: The aim of this study is to compare individual characteristics associated with blood donation in the German and Swiss population between 1994 and 2010. METHODS: Population-based survey data from the Eurobarometer 1994 and 2009, the Swiss Health Survey 1997, and the Swiss Blood Donation Survey 2010 were used to compare age-adjusted percentages of German and Swiss adults ever having donated blood (n = 8,746). A multivariate logistic regression was applied to the pooled data to estimate odds ratios (OR). RESULTS: Donor rates between 1994 and 2010 increased by 8.6% in Germany (p = 0.0045) and remained stable in Switzerland. The likelihood to report donating increased with age. Gender differences (OR = 2.85; p = 0.0000) and differences between education levels were more pronounced in Switzerland as compared to Germany (OR = 2.56; p = 0.0000 and OR = 2.73; p = 0.0010). Furthermore education differences were more marked in men in both countries (OR = 1.99; p = 0.0000 and OR = 1.68; p = 0.0140). CONCLUSION: The blood establishments should intensify their efforts to motivate women and lower educated people to give blood. Our data suggest that population-based surveys could be a helpful tool to describe donor rates in different countries and to guide future recruitment strategies. PMID- 23652648 TI - Struggling Between Strength and Vulnerability, a Patients' Counter Story. AB - Currently, patients are expected to take control over their health and their life and act as independent users and consumers. Simultaneously, health care policy demands patients are expected to self manage their disease. This article critically questions whether this is a realistic expectation. The paper presents the auto-ethnographic narrative of the first author, which spans a period of 27 years, from 1985 to 2012. In total nine episodes were extracted from various notes, conversations and discussions in an iterative process. Each of these episodes was condensed around a 'critical moment' as perceived by the "self". The critical moments in the illness process vary between newly encountered problems with basic needs and mourning, to renewed strength and the desire to grow, embracing new situations. Being confronted with and living with a chronic illness involves periods of anxiety and self centredness alternating with strength and advocating the interests of peer-patients. These episodes of emotion, confusion and refinding a balance have a cyclic pattern. The narrative illustrates the vulnerability and dependency of a patient with a chronic disease. The discussion relates this to mainstream dominant views on patients 'in control of their own life'. The narrative illustrates, that the vulnerability and dependency of the patient are key factors to take into account in health care policy. The narrative provides a counter story, challenging current thinking in terms of strength, selfmanagement, patients' own control and independent role. PMID- 23652649 TI - The birth of human stereotactic surgery. AB - Stereotactic surgery began with the Horsley-Clarke apparatus which has been used in animal research since 1908. In 1947, Spiegel and Wycis introduced stereotactic surgery in human patients. Their initial choice of target involved the extrapyramidal system, which Russell Meyers had recently performed with craniotomy and manual lesions that might alleviate symptoms of movement disorders, albeit with significant morbidity and mortality, a problem not seen with stereotactic surgery. PMID- 23652650 TI - Functional neurosurgery in Parkinson's disease: a long journey from destruction over modulation towards restoration. AB - Neurosurgical treatment of Parkinson's disease (PD) has re-gained considerable attention over the last two decades due to a better understanding of the pathophysiology of the basal ganglia, the long-term complications of medical treatment, and advances in neuroimaging and neurosurgical techniques. The introduction of deep brain stimulation (DBS) has created new perspectives for the surgical management of PD patients, due to the low morbidity, reversibility and improvement of both motor function and quality of life as compared to the lesioning techniques. We present an overview of basic principles, history, indications, and results of current neurosurgical techniques available in PD. PMID- 23652651 TI - Improving MRT image quality in patients with movement disorders. AB - OBJECTIVE: In order to improve image quality in a simultaneous fMRI-EEG study with patients suffering from the involuntary movements typical for Huntington's disease, the aim was to develop a technique for immobilizing the heads of our patients inside an MRI head coil. METHODS: We modified a mask technique previously used for reliable repositioning in temporally fractionated radiotherapy. The mask was tested in three patients with Huntington's disease, acquiring structural and functional MR images with simultaneous EEG with and without the mask. RESULTS: Image as well as EEG signal quality were significantly improved in patients wearing the mask. However, the image quality with mask was comparable to acquisitions from patients without movement disorders only in patients with light to moderate dyskinesia. Although image quality was also significantly improved in a patient suffering from severe dyskinesia with quasi continuous involuntary movements, the quality of both the MR images as well as the EEG signal was lower than what would be expected in a healthy control person. CONCLUSION: We have succeeded in developing a mask that fits into the MRI head coil, does not disturb the MRI signal, and significantly improves both fMRI and EEG signal quality. PMID- 23652652 TI - STN stimulation in general anaesthesia: evidence beyond 'evidence-based medicine'. AB - Awake surgery is regarded mandatory for optimal electrode implantation into the subthalamic nucleus (STN) for deep brain stimulation (DBS) in Parkinson's disease (PD). However, this is questionable since general anaesthesia (GA) does not preclude intraoperative microrecordings and clinical evaluation of, for example, current spread to the corticospinal tract. In addition, even in the awake state, clinical testing is not without limitations. We report on intra- and postoperative findings in 11 patients suffering from advanced PD who were operated under GA (propofol/remifentanil). The activity of STN neurons under GA was characterized by excessive burst discharges that differed fundamentally from the irregular tonic patterns observed in the STN of awake patients. In all patients, we obtained improved motor symptoms and reduced levodopa-induced dyskinesias and motor fluctuations, which was associated with a reduction in the levodopa equivalent daily dose. Therapeutic DBS was not limited by current spread to the corticospinal tract in any of the patients. The trajectories chosen for electrode implantation in GA compared well to awake surgery. Our results indicate that STN surgery in GA can be performed in a safe manner. It can be offered to anxious patients, and represents a viable option when awake surgery bears a risk for the patient. PMID- 23652653 TI - The impact of multichannel microelectrode recording (MER) in deep brain stimulation of the basal ganglia. AB - Deep brain stimulation (DBS) of the basal ganglia (Ncl. subthalamicus, Ncl. ventralis intermedius thalami, globus pallidus internus) has become an evidence based and well-established treatment option in otherwise refractory movement disorders. The Ncl. subthalamicus (STN) is the target of choice in Parkinson's disease.However, a considerable discussion is currently ongoing with regard to the necessity for micro-electrode recording (MER) in DBS surgery.The present review provides an overview on deep brain stimulation and (MER) of the STN in patients with Parkinson's disease. Detailed description is given concerning the multichannel MER systems nowadays available for DBS of the basal ganglia, especially of the STN, as a useful tool for target refinement. Furthermore, an overview is given of the historical aspects, spatial mapping of the STN by MER, and its impact for accuracy and precision in current functional stereotactic neurosurgery.The pros concerning target refinement by MER means on the one hand, and cons including increased bleeding risk, increased operation time, local or general anesthesia, and single versus multichannel microelectrode recording are discussed in detail. Finally, the authors favor the use of MER with intraoperative testing combined with imaging to achieve a more precise electrode placement, aiming to ameliorate clinical outcome in therapy-resistant movement disorders. PMID- 23652654 TI - A comparison between stereotactic targeting methods of the subthalamic nucleus in cases with Parkinson's disease. AB - BACKGROUND: Several methods are used for targeting of the subthalamic nucleus (STN) for the surgical treatment of Parkinson's disease (PD). The goal of this study is to determine the most suitable morphological method for localizing the STN in order to perform deep brain stimulation (DBS) in the treatment of PD. METHODS: Twelve cases with PD underwent bilateral STN-DBS and followed up for 5 years. Indirect calculation of the STN using AC-PC coordinates, and direct targeting of the STN using stereotactic CT/MRI fusion, were used for targeting. A microelectrode recording method was used to localize the STN. RESULTS: Direct targeting of the STN using CT/MRI fusion was very precise in every case, based upon evaluation of the intraoperative microelectrode recordings, postoperative MRI scans, and clinical follow-up of the cases. The coordinate differences obtained from these two methods were statistically significant. CONCLUSION: Direct targeting method of the STN using CT/MRI fusion provided higher precision than the indirect calculation method. This method may be used as a standard targeting technique, and may obviate the need for using complicated technologies such as microelectrode recording, which may sometimes be risky and counterproductive. PMID- 23652655 TI - Behind the screen: pseudobulbar symptoms after deep brain stimulation. AB - BACKGROUND: Thalamotomy was formerly used to treat different tremor syndromes. Nowadays, deep brain stimulation has become an established technique to treat different movement disorders. The combination of these two stereotactic interventions is rare. CLINICAL PRESENTATION: We present a patient in which a right-sided tremor -syndrome with an underlying pathology of combined essential tremor and Parkinsonian tremor was successfully treated initially with a left sided thalamotomy and subsequently with -bilateral deep brain stimulation in the subthalamic nucleus. RESULTS: Deep brain stimulation in the subthalamic nucleus resulted in hemidystonia, pathological laughing and crying, dysarthria and dysphagia, all due to dislocation of the stimulation electrodes contacting the internal capsule. After discontinuation of the high-frequency stimulation these side-effects disappeared, but were then reactivated by an LCD television in stand by mode. CONCLUSION: In this report we discuss the pathophysiology of pseudobulbar symptoms and pathological laughing and crying in context of thalamotomy and dislocated DBS electrodes. Furthermore, we report on the occurrence that magnetic fields in the household have an impact on deep brain stimulation, even if they are in stand-by mode. PMID- 23652656 TI - Psychiatric side-effects of bilateral deep brain stimulation for movement disorders. AB - INTRODUCTION: The effects of deep brain stimulation (DBS) on cognitive functions, and its psychiatric side-effects, are still controversial. The present study investigated psychiatric comorbidity and postoperative effects of DBS of different targets on mood and psychological functions in 81 patients with a mean follow-up of 37 months. METHODS: A total of 109 patients underwent implantation of DBS electrodes between 2001 and 2006; it was possible to evaluate 81 patients by a psychiatric test battery using the "Neuropsychiatric Inventory". To evaluate the possible influence of the target, we analyzed the data without 16 patients with DBS surgery for other diseases (e.g., epilepsia, cluster headache) or unilateral implantation only. The resulting population (n = 65, mean age 61 years, range 23-78 years, male:female 42:23) consisted of 43 Parkinson's disease patients stimulated in the subthalamic nucleus, ten dystonia patients stimulated in the globus pallidus internus, and 12 tremor patients in the ventral intermediate nucleus. RESULTS: There was a high rate of preoperative psychiatric comorbidity, which is reflected by a high rate of patients with preoperative medication of neuroleptic drugs (18.4 %, especially clozapin 14.7 %) and antidepressive drugs (16.5 %). Depression was the most common psychiatric side effect after DBS, occurring in 47.7 % of all patients (31/65 patients), without significant preference to a specific target (STN: 42 %, Gpi: 60 %, VIM: 58 %). Delusion (n = 5 out of 43 PD patients, 11.6 %), euphoria (n = 1, 2.3 %) and disinhibition (n = 3, 7.0 %) were seen in the PD patients only. CONCLUSION: A wide range of behavioural changes may be seen following DBS. Depression was the most common side-effect after DBS, and occurred independently of the target. PD patients, in contrast to dystonia and tremor patients, developed complications in all tested subgroups, with varying frequencies. Preoperative evaluation for psychiatric and cognitive dysfunction is crucial to identify patients who are at specific risk for psychiatric complications. PMID- 23652657 TI - Active stimulation site of nucleus accumbens deep brain stimulation in obsessive compulsive disorder is localized in the ventral internal capsule. AB - Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder characterized by persistent thoughts and repetitive ritualistic behaviours. Despite optimal cognitive-behavioral and pharmacological therapy, approximately 10 % of patients remain treatment-resistant. Deep brain stimulation (DBS) is being investigated as experimental therapy for treatment-refractory OCD. In the current study, we determined the relationship between anatomical location of active electrode contacts and clinical outcome in 16 OCD patients undergoing bilateral nucleus accumbens (NAc) DBS. We found that most patients actually do not receive active stimulation in the NAc but in the more laterally, anteriorly and dorsally located ventral part of the anterior limb of the internal capsule, ventral ALIC (vALIC). Our nine patients receiving bilateral vALIC DBS improved on average 73 % on their Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores, whereas the six patients with their centers of stimulation located otherwise improved on average only 42 %. We therefore propose bilateral vALIC as a promising new DBS target for patients with treatment-refractory OCD. Future studies employing a direct vALIC targeting approach in larger patient numbers are needed to test whether this proposal holds true. PMID- 23652658 TI - Functional neurosurgery for secondary dystonia: indications and long-term results. AB - Dystonia is a movement disorder characterized by patterned, repetitive, phasic, or tonic sustained muscle contractions that produce abnormal, often twisting, postures or repetitive movements. When the disorder is genetic or the cause is unknown and dystonia is the sole feature, the disease is called primary or idiopathic, conversely secondary dystonia (SD) may be caused by various brain insults. Both primary dystonia and SD have been notorious for their poor response to medical treatment. Today, stereotactic neurosurgical procedures are offered to improve the disability and quality of life of patients who do not respond to medical therapy. However, SD shows less and more variable results than primary dystonia to neurosurgical procedures, the benefits of ablative or deep brain stimulation (DBS) procedures in basal structures being still subject to debate and much harder to fully appreciate. In this work, the authors show a 33-patient series with secondary dystonia, separating the statistic and clinical analysis into several etiology groups: perinatal insults, tardive syndromes, genetic syndromes, and posttraumatic. In these groups, we show the mean BFM score improvement in the different patient series, comparing our results with world literature, and finally propose a classification system for bettering the clinical approach in surgery decision when this is indicated. PMID- 23652659 TI - Deep brain stimulation of the ventrolateral thalamic base and posterior subthalamic area in dystonic head tremor. AB - Dystonic head tremor (DHT) is characterized by head tremor associated with cervical dystonia (CD). Deep brain stimulation (DBS) can be considered when local treatment with botulinum toxin or oral medication has failed. However, there is lack of data regarding the optimal target structure for surgery in DHT.DBS of the ventrolateral (VL) thalamus is an established treatment option for medically refractory tremor. Tremor suppression is described as being most effective when stimulating at the inferior thalamic base and within the posterior subthalamic area (PSA). Moreover, there is surgical evidence from the pre-DBS era that both lesions and high-frequency stimulation of the PSA improve CD. Based on these observations, we performed DBS in three patients with DHT, placing the proximal contacts of the electrodes into the inferior base of VL thalamic nuclei and the distal contacts into the adjacent PSA. Chronic stimulation improved not only head tremor but also CD. These findings suggest that DBS at the base of VL thalamus and the adjacent PSA should undergo further investigation as a potential target for patients with DHT. PMID- 23652660 TI - Intra-operative transdural electric stimulation in awake patient: target refining for motor cortex stimulation. AB - INTRODUCTION: Most authors perform the implantation of epidural electrodes for motor cortex stimulation (MCS) under general anesthesia, using navigation merely based on anatomic landmarks or in combination with intra-operative sensory evoked potentials (SEP) for functional localization. However, intra-operative SEP can only provide the localization of central sulcus in patients who present sensory pathways which are at least partially preserved. Conversely, there are massive deafferentation pain syndromes (e.g., brachial plexus avulsion or amputation) in which the peripheral sensory pathways are severely or totally injured, precluding the use of intra-operative SEP. Objective. The authors present a simple technique for functional localization and intra-operative mapping of motor cortex by the implementation of transdural electrical stimulation of cerebral cortex for target refining of motor cortex during cortical electrode implantation procedures. METHODS: Thirteen patients with complete brachial plexus root avulsion suffering from severe neuropathic pain in the affected limb were included in this report. First, the anatomical location of the motor cortex of the hand was stereotactically determined by the hand knob within the central sulcus. Functional mapping of cortex was performed by transdural bipolar electrical stimulation under local anesthesia, so patients were fully awake during the whole time of cortical mapping. The cortical mapping oriented the placement of epidural electrodes for chronic cortical stimulation for treatment of neuropathic pain. RESULTS: Stereotactic MR images of the hand knob were considered a satisfactory landmark for the motor area of the hand in all patients. On top of the anatomical landmark, transdural electrical stimulation (4.0-6.0 mA, 30-60 Hz and pulse width of 1 ms) gave vivid sensations of movement in the deafferented hand, forearm, and arm. The phantom sensation was elicited with lower current than usual motor mapping in patients with intact limbs. It was possible to delineate the spatial map of the phantom hand on the cortical surface with acceptable resolution. The sensation of wrist flexion was elicited in all; most of the patients had clear distinction of the thumb and index. The remaining fingers were not perceived individually. The cortical area responsive to the thumb tended to occupy a lateral position related to the areas of the other fingers, following the maps of the normal homunculus. The evoked sensation was restricted to the period of stimulation, and it stopped as soon as that was discontinued. The stimulation also evoked emotional responses related to sensation of limb movement. CONCLUSION: The proposed technique was useful for target refining in implantation of epidural electrode for motor cortex stimulation. Further studies are required to investigate if target refining by intra-operative mapping will significantly improve the results in the treatment of refractory pain. PMID- 23652661 TI - Restorative strategies for the dopaminergic nigrostriatal projection pathway. AB - New insights into the mechanism of dopaminergic (DA) nigrostriatal neuron degeneration and regeneration in experimental studies in animal models of Parkinson's disease (PD) have opened up the discussion about novel therapeutic strategies such as cell-based therapies and neuroprotection of DA neurons. These cellular and molecular approaches aim at preventing or slowing down the progressive degeneration of DA neurons and/or replacing the lost ones. Here, a brief overview of basic principles and current strategies of these novel restorative approaches is discussed in light of experimental results and possible clinical applications. PMID- 23652662 TI - Some recent trends and further promising directions in functional neurosurgery. AB - The field of functional neurosurgery has developed a number of recent innovative neuromodulatory approaches to treat disease that remains resistant to the best medical therapy. These include novel surgical techniques to intervene in motor and cognitive sequelae of refractory epilepsy, neurodegenerative disease, and certain psychiatric conditions. To a large extent, much of the innovation in our field continues to be driven by a systems-level understanding of the impact of disease on the brain. For example, several groups have exploited findings from neuroimaging work to identify a number of new potential neuromodulatory targets for the treatment of refractory depression. Ongoing discoveries at the cellular and molecular level promise targeted gene or drug delivery aimed at curing disease. Neurosurgeons will certainly remain at the forefront of translating these strategies into practical clinical applications. Several randomized trials are now underway to assess the safety and efficacy of a number of new approaches, and we will continue to acquire better knowledge of optimal patient selection, identification of the most effective neuromodulatory targets, and recognition of adverse effects as these studies progress. PMID- 23652663 TI - Impact of automated hotspot detection for (18)FET PET-guided stereotactic biopsy. AB - OBJECTIVE: The aim of this study was to explore the impact of automated hotspot detection on surgical planning of (18)FET PET-guided stereotactic serial biopsy. METHOD: Imaging of ten patients with brain lesions detected by MRI and showing increased (18)FET uptake on PET who were retrospectively and randomly assigned to compose the study. Stereotactic biopsy plans (PET-guided and MR-guided) were performed by two neurosurgeons for each patient, independently and blinded. For PET-guided plans, biopsy target was achieved by means of an automated hotspot detection system. MR-guided plans targeted contrast enhancement areas or hyperintense areas in T2-weighted sequences. FET uptake ratio (UR) was determined in the biopsy trajectory across the lesion. Highest UR (HUR) from both planning techniques was compared. RESULTS: Each single HUR obtained through PET-guided technique was higher than correspondent values from MR-guided technique. Mean HUR of 2.41 (SE +/- 0.23) for PET-guided plans and 1.85 (+/-0.16) for MR-guided plans were respectively obtained. This difference was statistically significant (p = 0.002). CONCLUSION: The use of an automated hotspot detection system was able to provide higher FET HUR along stereotactic biopsy trajectories in comparison to those from MR-guided plans. The use of specially designed computational tools may refine surgical planning by improving biopsy targeting. PMID- 23652664 TI - Interstitial radiosurgery with iodine-125 seeds in the treatment of brain metastases, glial tumours and benign intracranial lesions. AB - In a retrospective single-centre study, we analysed data of 1,378 patients (55 % male, 45 % female) who underwent interstitial radiotherapy with 1,596 implanted Iodine-125 seeds in the Department of Stereotactic and Functional Neurosurgery in Freiburg from January 1990 to December 2011. The medical prerequisites and physical parameters of the treatment with Iodine-125 seeds are given. The method used in Freiburg relying on temporary Iodine-125 seed implants is described in detail and analysed. The survival rates and the peri-operative risk are evaluated. We conclude that interstitial radiosurgery with Iodine-125 seeds is a safe and useful tool, offering a wide range of treatment options for benign and also malignant intracranial lesions, especially if they are small, deep-seated, in eloquent areas, or not suitable for micro-surgery. PMID- 23652665 TI - Bistable memory devices with lower threshold voltage by extending the molecular alkyl-chain length. AB - Three organic small molecules with alkyl chains of different lengths based on an azobenzene scaffold were designed and synthesized. The indium-tin oxide (ITO)-Azo Al sandwich memory devices showed write-once-read-many-times (WORM) characteristics. The switch threshold voltage of Azo-based memory devices significantly decreased as the end-capping alkyl chain extends, which is totally consistent with the AFM and X-ray diffraction results that the thin films showed smoother morphologies and closer intermolecular packing with the molecular alkyl chain length prolonging. These results demonstrated that variation in the alkyl chain length at the end of the conjugated molecules is a powerful strategy for tuning film microstructure and intermolecular packing to enable high performance of the fabricated sandwiched devices. PMID- 23652666 TI - Salivary duct carcinoma of the accessory parotid gland. PMID- 23652667 TI - Multiple endocrine neoplasia type 1. AB - Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant tumor syndrome characterized by the occurrence of tumors in multiple endocrine tissues and nonendocrine tissues. The three main endocrine tissues most frequently affected by tumors are parathyroid (95%), enteropancreatic neuroendocrine (50%) and anterior pituitary (40%). Tumors are caused by a heterozygous germline inactivating mutation in the MEN1 gene (1st hit) followed by somatic inactivating mutation or loss of the normal copy of the gene (2nd hit), leading to complete loss of function of the encoded protein menin. Most of the disease features and tumors are recapitulated in mouse models with heterozygous germline loss of the Men1 gene. Also, tissue-specific tumors are observed in mouse models with homozygous somatic loss of the Men1 gene specifically in MEN1-associated endocrine tissues. Hence, mouse models could serve as possible surrogates for studying MEN1 and related states. To gain insights into MEN1 pathophysiology, menin-interacting partners and pathways have been identified to investigate its tumor suppressor and other functions. Also, the 3D crystal structure of menin has been deciphered which could be useful to reveal the relevance of MEN1 gene mutations and menin's interactions. This chapter covers clinical, genetic and basic findings about the MEN1 syndrome, MEN1 gene and its product protein menin. PMID- 23652668 TI - Multiple endocrine neoplasia type 2. AB - Multiple endocrine neoplasia type 2 (MEN2) is an autosomal-dominant cancer syndrome characterized by variable penetrance of medullary thyroid carcinoma(MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPT). MEN2 consists of two clinical subtypes, MEN2A and MEN2B. Familial medullary thyroid cancer is now viewed as a phenotypic variant of MEN2A with decreased penetrance for PHEO and PHPT rather than a distinct entity. All subtypes are caused by gain-of-function mutations of the RET proto-oncogene. Genotype phenotype correlations exist that help predict the presence of other associated endocrine neoplasms as well as the timing of thyroid cancer development. Recognition of the clinical entity in individuals and families at risk of harboring a germline RET mutation is crucial for the management and prevention of associated malignancies. Recent guidelines released by the American Thyroid Association regarding the management of MTC will be summarized in this chapter. PMID- 23652669 TI - von Hippel-Lindau syndrome. AB - von Hippel-Lindau (VHL) disease is an autosomal-dominant familial cancer syndrome associated with mutations of the VHL tumor suppressor gene (3p25-26). Its estimated incidence ranges from 1 in 36,000 to 1 in 53,000 with a penetrance of up to 95% by age 60. Genotype-phenotype correlation divides VHL into two broad clinical subtypes. Type 1 VHL is predominantly associated with large deletion or truncation mutations which result in an encoded protein with very little or no activity. It is associated with retinal and CNS hemangioblastoma and renal cell carcinoma but not pheochromocytoma. Type 2 is usually associated with missense mutations encoding a protein with limited activity and includes pheochromocytoma. It is further classified into three other subtypes (2A, 2B, 2C) based on the presence of hemangioblastoma and renal cell carcinoma. Visceral cysts in the kidney, pancreas and epididymis, nonfunctioning pancreatic neuroendocrine tumors which often show distinctive clear cell cytology, endolymphatic sac tumors and head and neck paragangliomas are well recognized but less common presenting features. Surveillance of carriers can reduce the burden of disease and is best performed in specialist referral centers with due consideration given to both the complex molecular pathogenesis and psychosocial aspects of the disease. PMID- 23652670 TI - Carney complex. AB - Carney complex is a rare, dominantly inherited multiple endocrine neoplasia syndrome, affecting endocrine glands as the adrenal cortex (causing Cushing's syndrome), the pituitary and the thyroid. It is associated with many other nonendocrine tumors, including cardiac myxomas, testicular tumors, melanotic schwannoma, breast myxomatosis, and abnormal pigmentation (lentiginosis) or myxomas of the skin. The gene located on the CNC1 locus was identified 12 years ago as the regulatory subunit 1A (R1A) of the protein kinase A (PRKAR1A) located at 17q22-24. Inactivating heterozygous germline mutations of PRKAR1A are observed in about two thirds of Carney complex patients with some genotype-phenotype correlation useful for follow-up and prognosis. More rarely, mutations of phosphodiesterase genes have been reported in patients presenting mainly with Cushing's syndrome. In vitro and in vivo studies help to understand how R1A inactivation leads to tumorigenesis. PRKAR1A appears to be a relatively weak tumorigenic signal which can cooperate with other signaling pathways and tumor suppressors. PMID- 23652671 TI - Multiple endocrine neoplasia type 4. AB - A few years ago a novel multiple endocrine neoplasia syndrome, named multiple endocrine neoplasia type 4 (MEN4), was discovered thanks to studies conducted on a MEN syndrome in the rat (named MENX). The rat and the human syndromes are both caused by germline mutations in the Cdkn1b/CDKN1B gene, respectively. This gene encodes p27Kip1, a putative tumor suppressor which binds to and inhibits cyclin/cyclin-dependent kinase complexes, thereby preventing cell cycle progression. MEN4 patients carry heterozygous mutations at various residues of p27Kip1 and present with endocrine lesions mainly belonging to a MEN1-like spectrum: their most common phenotypic features are parathyroid and pituitary adenomas. Recently, germline mutations in p27kip1 were also identified in patients with a sporadic parathyroid disease presentation. In vitro functional analysis of several CDKN1B sequence changes identified in MEN4 patients detected impaired activity of the encoded p27Kip1 variant proteins (e.g. reduced expression, mislocalization or poor binding to interaction partners), thereby highlighting the characteristics of the protein which are critical for tumor suppression. Although the number of MEN4 patients is low, the discovery of this syndrome has demonstrated a novel role for CDKN1B as a tumor susceptibility gene for neuroendocrine tumors. Here, we review the clinical characteristics of the MEN4 syndrome and the molecular phenotype of the associated p27Kip1 mutations. PMID- 23652672 TI - Novel hereditary forms of pheochromocytomas and paragangliomas. AB - Pheochromocytomas and paragangliomas are catecholamine-secreting tumors of neural crest origin that arise from the adrenal medulla or extra-adrenal sympathetic paraganglia, respectively. Over the last decade, the extensive genetic heterogeneity of these tumors came to light with the identification of multiple susceptibility genes. These mutations account for at least one-third of pheochromocytomas and paragangliomas, the highest inheritable proportion of any known human tumor. This chapter will present an overview of genetic and molecular features of the most recently identified hereditary forms of pheochromocytoma and paraganglioma: those caused by mutations in five genes of the succinate dehydrogenase (SDH) complex, the transmembrane-encoding gene TMEM127 and the MYC binding partner, MAX. Initial genotype-phenotype correlations, as well as emerging functional data, have aligned the new mutants either with defects in hypoxic-angiogenic signaling (SDH-related) or kinase receptor/mTOR pathways (TMEM127 and MAX). These findings, in combination with those of the more well established syndromes, have been relevant for guiding clinical follow-up. The progress of recent years in understanding the pathogenesis of pheochromocytomas and paragangliomas is expected to continue to improve patient screening and to become, in the long term, the catalyst for development of new therapeutic options for surgically untreatable tumors. PMID- 23652673 TI - Carney triad. AB - Carney triad is a rare multitumoral syndrome of unknown etiology that was first described in 1977. The neoplasms affect the stomach, lungs, paraganglionic system, adrenal cortex, and esophagus. Approximately 150 cases have been identified. The disorder occurs in young women primarily and is not familial. Multifocal tumors develop in the organs affected. No patient has had tumors in all 5 organs. One patient had tumor in 4 organs; most patients have them in 2. Thus, the syndrome is usually only partially expressed. The gastric tumors are malignant and metastasize to the liver, peritoneum, and lymph nodes. The lung, adrenal, and esophageal tumors are benign. The paraganglionic tumors are usually benign. Long-term follow-up shows that the syndrome is a chronic, persistent, and generally indolent condition whose outcome is largely dependent on the behavior of the metastases of the gastric sarcoma. Among the 79 affected patients described in 1999 (average follow-up 8 years, 64 were alive, 19 were apparently free of tumors, 45 had residual or metastatic disease, and 15 were dead (10 died of causes related to the syndrome). PMID- 23652674 TI - Genetics of pituitary adenomas. AB - Pituitary adenomas are common tumors of the adenohypophysis which can cause considerable morbidity, due to excessive hormonal secretion or compression and local invasion of surrounding structures. The vast majority of pituitary adenomas occur sporadically. Altered gene expression is commonly detected but somatic mutations, epigenetic changes and abnormal microRNAs have also been described. Occurrence of GNAS mutations at a postzygotic stage lead to McCune-Albright syndrome (MAS), a disease causing endocrine hyperfunction and tumors in several organs, including the pituitary. Familial pituitary adenomas occur as part of a syndrome affecting other organs, such as in MEN1 or Carney complex, or occur with pituitary adenomas only as in familial isolated pituitary adenoma (FIPA). FIPA, an autosomal-dominant disease with variable penetrance, is explained in 20% of patients by germline mutations in the tumor suppressor aryl hydrocarbon receptor interacting protein(AIP), while no gene abnormality has been identified to date in the majority of the FIPA families. AIP mutation-positive patients have a characteristic clinical phenotype with usually young- or childhood-onset growth hormone (GH) and/or prolactin (PRL)-secreting adenomas and can be seen in cases with no apparent family history as well. Understanding the tumorigenic process in AIP-positive and AIP-negative FIPA patients could result in better diagnostic and treatment options for both familial and sporadic cases. PMID- 23652675 TI - Clinical behavior and genetics of nonsyndromic, familial nonmedullary thyroid cancer. AB - Nonmedullary thyroid cancer (NMTC) is one of the most inheritable forms of all cancers with an 8- to 10-fold risk of a first-degree relative developing disease. Familial nonmedullary thyroid cancer (FNMTC) describes this familial aggregation and is comprised of two distinct subgroups; syndromic and nonsyndromic. Greater than 85% of thyroid tumors in nonsyndromic FNMTC are papillary thyroid cancer, followed by FTC (~10%), poorly differentiated, and anaplastic thyroid cancer (~5%). Compared to sporadic NMTC, FNMTC presents at a younger age and is associated with a higher incidence of multifocal disease and metastasis. The transmission pattern most frequently follows an autosomal dominant mode of inheritance. While there has been extensive investigation to find a high penetrant, single locus as the causative genetic factor, more recent data suggest that FNMTC is a polygenic disorder with variable penetrance likely associated with a low-to-moderate number of low-penetrant alleles. A number of case controlled, familial and population-based studies using genomewide association single-nucleotide polymorphism arrays have begun to unravel the complex genetic environment of FNMTC. These studies highlight the significant challenges in identifying markers predictive of disease onset and progression. Continued efforts will hopefully lead to identification of a panel of genetic markers used to identify family members at risk. Until this time, clinical factors appear to be the most efficient and accurate method for surveillance and diagnosis. PMID- 23652677 TI - Endocrine tumors associated with neurofibromatosis type 1, Peutz-Jeghers syndrome and other familial neoplasia syndromes. AB - Endocrine tumors are a less common but important component of the clinical spectrum of a number of hereditary tumor syndromes such as neurofibromatosis type 1, Peutz-Jeghers syndrome, Beckwith-Wiedemann syndrome, the tuberous sclerosis complex, Li-Fraumeni syndrome, PTEN hamartoma tumor syndrome, and APC-associated polyposis. It is important to recognize the often unique clinical presentations of these tumors and possible strategies for presymptomatic screening and early diagnosis. PMID- 23652676 TI - Genetic defects associated with familial and sporadic hyperparathyroidism. AB - Primary hyperparathyroidism (PHPT) occurs sporadically, but occasionally it may be a feature of a familial condition, such as multiple endocrine neoplasia type 1 (MEN1), MEN2A, or the HPT-jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia/neonatal severe hyperparathyroidism (FHH/NSHPT). PHPT may also occur as familial isolated hyperparathyroidism (FIHP), and has been observed as a consequence of mutations in the CDKN1B gene (MEN4). Tumorigenesis in these conditions may be the result of protooncogene activation (e.g. RET in MEN2) or two-hit losses of a tumor suppressor (e.g. MEN1, HPT-JT). In patients with MEN1, HPT-JT or FHH/NSHPT, the hyperparathyroidism manifests at a younger age and affects both sexes equally. In MEN1, mutations of the MEN1 gene also cause enteropancreatic and anterior pituitary tumors. In MEN2, activating mutations in the RET protooncogene also cause medullary thyroid carcinoma and pheochromocytoma. In HPT-JT, mutations of CDC73/HRPT2 are associated with parathyroid carcinoma, but tumors of the kidneys and uterus are additional features. In some FIHP families, a CASR mutation may be identified. In parathyroid carcinoma, even if sporadic, molecular diagnostics for CDC73/HRPT2 should be considered, as it should be for younger patients. Further exploration of these hereditary syndromes may shed light on the molecular mechanisms giving rise to nonhereditary PHPT. PMID- 23652681 TI - Noninvasive ventilation in pediatric intensive care. AB - PURPOSE OF REVIEW: The use of noninvasive ventilation (NIV) has become increasingly popular in the pediatric intensive care unit (PICU) over the last decade. This review intends to assess our current knowledge on the utilization of noninvasive support in children, especially focusing on its efficacy and safety profile. RECENT FINDINGS: Recent studies endorse the use of this therapy in the pediatric intensive care setting. NIV appears to be associated with a decrease in the intubation rate in children. Children who are responsive to NIV will usually show improvement in their physiologic parameters shortly after the initiation of this therapy and this improvement is often sustained. NIV is proving to be a well tolerated alternative to endotracheal intubation, in particular in those patients with primary respiratory failure, postsurgical patients or with postextubation respiratory distress. Most studies represent single-center experience and therefore caution must be exerted when attempting to generalize their results. SUMMARY: NIV appears to be a well-tolerated alternative for use in the pediatric population. Its use is associated with decreased intubation rates, which may lead to a decrease in the intubation-related complications. More investigation is needed to fully evaluate the ramifications of increased use of this technology in the PICU. PMID- 23652682 TI - Update on urinary tract infections in the emergency department. AB - PURPOSE OF REVIEW: To review recent changes in the diagnostic and therapeutic approach to pediatric urinary tract infection in the emergency department. RECENT FINDINGS: Updated guidelines from the American Academy of Pediatrics have significantly changed the approach to UTI, risk-stratifying patients according to their likelihood of UTI, and re-defining criteria for diagnosis of UTI. New studies have delineated important risk factors for concomitant bacteremia and adverse events. Procalcitonin has emerged as the inflammatory marker most predictive of upper versus lower urinary tract infection and renal scarring. Delays in empiric antibiotic therapy are associated with increased rates of renal scarring. Corticosteroids are a potential adjunctive therapy to antibiotics. SUMMARY: Timely diagnosis and therapy of UTI are essential. New guidelines may alter the traditional approach to evaluation and management. Future studies will likely focus on the impact of the new guidelines, further delineate the role of procalcitonin in predicting UTI, and explore the role of corticosteroids as an adjunct to antibiotic therapy. PMID- 23652683 TI - Cystic fibrosis in the era of genomic medicine. AB - PURPOSE OF REVIEW: The field of cystic fibrosis (CF) is changing dramatically as the scientific knowledge accumulated since the cloning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is being translated into effective therapies to correct the basic defect and provide better disease models and in-depth understanding of the basic mechanisms of disease. RECENT FINDINGS: This review focuses on three main aspects of the recent advances in the field: understanding the lung disease pathophysiology (in particular, the early events that condition its onset), better definition of the complex microbiology of the CF airway, and therapeutic developments. Although the most recently developed therapies, whether approved or under study, do not constitute a definitive cure, the benefit to patients is already becoming clearly apparent. SUMMARY: As the field continues to change rapidly and new therapies are being identified, CF has become a paradigm for the application of concepts such as translational medicine, genomic medicine, and personalized care, with measurable clinical benefit for the patients affected by this disease. PMID- 23652684 TI - Stem cell transplantation and lung dysfunction. AB - PURPOSE OF REVIEW: To identify factors that impact the incidence and severity of lung dysfunction after haematopoietic stem cell transplantation (HSCT) for preventive and therapeutic purposes. RECENT FINDINGS: Respiratory failure from lung dysfunction after HSCT is a serious and often fatal transplant-related complication, but recent data reveal decreasing incidence and improving outcome over time. Idiopathic pneumonia syndrome (IPS) and bronchiolitis obliterans are now recognized as part of a spectrum of post-HSCT lung diseases involving both aspects of innate and adaptive immune responses, but may differ in the main lung structure affected: alveolar versus airway epithelium. There exists a strong association between acute graft-versus-host disease (GVHD) and IPS, and bronchiolitis obliterans is pathognomonic of chronic GVHD. Experimental models of IPS and bronchiolitis obliterans have proven useful to test strategies designed to limit lung injury including the effects of allogeneity, chemoradiotherapy and stem cell therapy. Recent advances in critical care practices, early diagnosis and utilizing ARDS Network ventilatory and conservative fluid management recommendations have also contributed to better outcome from lung dysfunction after HSCT. SUMMARY: Understanding the factors that contribute to post-HSCT lung injury should lead to safer transplant practices that will allow the broader use of HSCT for sicker children with comorbidities. PMID- 23652685 TI - Congenital hyperinsulinism. AB - PURPOSE OF REVIEW: Congenital hyperinsulinism (CHI) is a multifaceted disease and continues to be the most common cause of persistent hypoglycemia in infants. The purpose of the review is to highlight important recent developments regarding CHI. RECENT FINDINGS: Several recent studies have highlighted the advances in medical genetics, imaging techniques, histological variety, and surgical decision making regarding CHI. The advancements have resulted in the ability to often distinguish between diffuse and focal disease, thus allowing a more focused medical and surgical approach to the patient. When genetic information is combined with advanced imaging and intraoperative histological analysis, surgical results have improved. Despite medical and surgical advancements, recent studies also reveal the need for better medical options for patients and that aggressive surgery may lead to the onset of diabetes. SUMMARY: Current advances have improved the overall care of the patient with CHI, although there are still improvements to be achieved. The ability to apply these advancements is best accomplished with an experienced team consisting of geneticists, radiologists, endocrinologists, pathologists, and surgeons. Utilizing a team approach results in a complete evaluation and allows a customized care plan for each patient. PMID- 23652686 TI - Common presentations of pediatric rheumatologic diseases: a generalist's guide. AB - PURPOSE OF REVIEW: To present a case-based approach of three common scenarios which often present to the primary care physician. The approach to these cases and the differential diagnosis are discussed for these common rheumatologic diseases. RECENT FINDINGS: Numerous healthy children and adolescents are referred to pediatric rheumatologists for the evaluation of suspected rheumatologic diseases. Often, general rheumatologic laboratory tests are sent which are not necessarily specific to the clinical situation. There is a high false-positive rate associated with many of these tests and undue anxiety and referrals result from these. Directed laboratory studies based on history and exam findings are more prudent and useful in the evaluation of these children. Routine antinuclear antibody testing, for example, is not recommended without supportive symptoms or signs. SUMMARY: A practical approach for primary care physicians is described for the evaluation of patients suspected of having some of the more common pediatric rheumatologic symptoms and diseases. PMID- 23652687 TI - Update on adolescent immunizations: selected review of US recommendations and literature. AB - PURPOSE OF REVIEW: To provide a clinically relevant synopsis of recent research findings as well as updated recommendations from the American Academy of Pediatrics (AAP) and Advisory Committee on Immunization Practices (ACIP) regarding adolescent immunizations. RECENT FINDINGS: Coverage rates for the adolescent vaccinations continue to lag behind those of the childhood vaccinations, despite their importance. Recent research has focused on the reasons for suboptimal adolescent vaccination rates as well as strategies for improvement. By more fully understanding the barriers to immunization, efforts can be implemented to address these concerns and to ensure that all eligible adolescents receive their vaccinations. In addition, much work has focused on the duration of protection induced by childhood and adolescent vaccinations and the need for booster doses in older adolescents. Because immunity has been found to wane after vaccination, these booster doses can serve to more fully protect adolescents. This article reviews selected recent publications on human papillomavirus, meningococcal conjugate, and tetanus and diphtheria toxoids and acellular pertussis vaccines. SUMMARY: Adolescent vaccinations will continue to be studied and this research will serve to shape future recommendations. Through this work, we can learn the best methods to optimize the protection of all adolescents against these very serious diseases. PMID- 23652688 TI - Clinical approach to known and emerging tick-borne infections other than Lyme disease. AB - PURPOSE OF REVIEW: We review latest developments in knowledge of established and emerging tick-borne infections in the United States other than Lyme borreliosis, emphasizing a clinical and geographic approach to diagnosis and management. RECENT FINDINGS: The incidence of tick-borne diseases in the United States has increased. New tick-borne diseases have emerged and will likely continue to be identified. SUMMARY: Clinicians should maintain suspicion for tick-borne diseases in children with acute infectious illnesses, and consider treating such patients presumptively to prevent complications. Knowledge of common tick vectors in the United States and the infections they transmit will allow pediatricians to appropriately assess and manage patients with tick-borne diseases. PMID- 23652689 TI - Bipolar disorder in children: assessment in general pediatric practice. AB - PURPOSE OF REVIEW: Pediatricians are increasingly confronted with the mental health needs of children. Given the unanticipated role, well-described diagnostic guidelines and treatment protocols are essential: but often lacking. Identification of bipolar disorder in children, a condition which lacks diagnostic criteria consensus, presents a particular challenge. Despite this, it is generally regarded as a condition associated with considerable morbidity and mortality. Extended delays to treatment, typical for the condition, contribute to significantly reduced adult functionality. RECENT FINDINGS: Most children with bipolar disorder exhibit a subsyndromal course of illness. This has prompted many investigative groups to explore whether such a presentation is developmental or unique. Despite the ongoing debate, there has been a rapid increase in the rate of diagnoses. Concurrently, breakthroughs in neurology, neuroimaging, and genetics have called into question the existing conceptually based psychiatric constructs altogether. New research approaches which reflect these advances are more likely to lead to evidence-based diagnosis and treatment. Such an example is a novel phenotype called Fear of Harm (FOH). A new research perspective resulted in the unification of a broad range of symptoms from bipolar disorder as well as many of the co-occurring disorders. When considered as a whole, the syndrome maps on to a known neural pathway and has led investigators to a putative biomarker. SUMMARY: If given the right information and tools, pediatricians are uniquely positioned to interrupt the decline caused by mental illnesses. Importantly, the newly defined FOH syndrome includes clinical symptoms which are frequently first brought to the attention of pediatricians. Although these symptoms are not exclusive to the mood disorder, they could alert pediatricians to the need for further evaluation. PMID- 23652690 TI - Current world literature. Emergency and critical care medicine. PMID- 23652692 TI - Context for WOC practice: improving clinical practice and generating research that goes beyond current best evidence. PMID- 23652693 TI - The CAET salutes JWOCN's 40th anniversary: "A Canadian LINK". PMID- 23652694 TI - Initial experiences with Store Forward software in telemedicine. PMID- 23652695 TI - Review of pressure ulcer risk assessment scales. PMID- 23652696 TI - Challenges in classification of gluteal cleft and buttocks wounds: consensus session reports. AB - The damaging effects of moisture, pressure, friction, and shear on human tissue are well-known among wound care experts. Nevertheless, accurate classification of these lesions is frequently challenging, even for experienced wound clinicians. The authors gathered clinical illustrations of gluteal cleft wounds and conducted a literature search as a basis for presentation to conference attendees, with the goal of gaining consensus regarding guidelines for accurate classification of these wounds. The aim of this article was to summarize results of the consensus sessions that occurred at the Wound Ostomy Continence Nurses' Society National conferences in 2011 and 2012, and to highlight areas where consensus has been achieved as well as areas in which consensus has not yet been reached. PMID- 23652697 TI - Canadian Association for Enterostomal Therapy evidence-based recommendations for conservative sharp wound debridement: an executive summary. AB - The Canadian Association for Enterostomal Therapy Conservative sharp wound debridement evidence-based recommendations are a result of the decision and commitment to advance clinical nursing practice to improve the provision of care to patients via development of an open source guide. The recommendations were developed by a volunteer group of ET nurses who work in clinical practice, policy development, consultation, and education in wound care. The document was developed over the course of 2 years (2009-2011); it is a distillation of existing literature, guidelines, and expert opinion. The development and dissemination of the recommendations were sponsored by the Canadian Association for Enterostomal Therapy. These recommendations should be considered in the context of the organization or care setting as well as available resources and supports. Resources and supports take the form of access to emergency care, physicians and allied health care professionals, education, administrative support, funding, supplies, equipment, and policy. The recommendations should also be applied with consideration of the evolving evidence that will further define practices in Conservative Sharp Wound Debridement. Refer to the supplemental digital content associated with this article at (supplemental digital content 1, http://links.lww.com/JWOCN/A16) for the complete document. PMID- 23652698 TI - Turning and repositioning the critically ill patient with hemodynamic instability: a literature review and consensus recommendations. AB - In the critical care population, heart rate and rhythm, blood pressure, respiratory rate, and oxygen saturation are monitored continuously, providing immediate feedback regarding any changes in patient status. Hemodynamic instability is a term commonly used by clinicians to describe labile changes in cardiopulmonary status, although this term is poorly defined in the literature. The clinician's perception of hemodynamic instability may cause a delay or omission in turning, repositioning, and other interventions to advance patient mobility and may contribute to pressure ulcer formation. The intensive care unit's practice culture and individual clinician perceptions regarding hemodynamic instability may lead to staff not turning patients out of fear that they are "too unstable to turn." This article provides a discussion of the link between pressure ulcers and immobility, provides a review of current literature on progressive mobility and hemodynamic instability, and presents the results of a critical care consensus panel on safe and effective turning of critical care patients. PMID- 23652699 TI - Procedure for obtaining a urine sample from a urostomy, ileal conduit, and colon conduit: a best practice guideline for clinicians. AB - The purpose of this document was to define the correct technique for obtaining a urine sample from a urostomy, ileal, or colon conduit. While healthcare providers do not commonly encounter patients with a urostomy, knowledge of the correct procedure to obtain a urine specimen is essential. Urine samples obtained incorrectly from a urostomy can lead to inaccurate cultures, resulting in an improper diagnosis and treatment, which can endanger the life of a patient. This column presents patient preparation, the procedure to obtain a specimen with and without a catheter, and aftercare of the patient and specimen. This best practice guideline has been developed by a panel of certified ostomy nurses serving on the Wound, Ostomy and Continence Nurses (WOCN) Society's Clinical Practice Ostomy Committee. The guideline has undergone content validation through a consensus building process by the WOCN Society, which was managed by the Center for Clinical Investigation. PMID- 23652700 TI - Perceptions of phantom rectum syndrome and health-related quality of life in patients following abdominoperineal resection for rectal cancer. AB - PURPOSE: The aim of the study was to investigate how patients described their perceptions of phantom rectum syndrome after abdominoperineal resection and ostomy creation, and its influence on daily living and health-related quality of life. A further aim was to find out strategies patients use to alleviate phantom rectum syndrome sensations. SUBJECTS AND SETTING: Twenty-five patients who underwent abdominoperineal resection and a colostomy (18 men and 7 women; median age 5 63 years; range, 40-78 years) at Sahlgrenska University Hospital, Goteborg, Sweden, participated in the study. METHODS: At follow-up 8 months postsurgery, a WOC nurse interviewed patients with a structured questionnaire about the experience of nonpainful and painful sensations in the perineal area. Health related quality of life was evaluated using a general cancer-specific instrument (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0). RESULTS: Twenty-four patients (96%) experienced painful or nonpainful phantom rectum syndrome at some point during the first 8 postoperative months. The nonpainful sensations (20 patients) occurred in connection with emptying of feces via the stoma, when performing colostomy irrigation, at rest, or in various positions. Fifteen patients experienced painful sensations, characterized as pins and needles, pain in the perineal area, stinging, and burning occurring mostly in sitting positions. Patients with painful sensations had statistically significant higher scores regarding pain and lower scores for social function than those without painful sensations (P < .031). Phantom rectum symptoms caused worries and concerns and influenced daily life in 29% (n = 5). CONCLUSIONS: Phantom rectum syndrome is prevalent in patients undergoing abdominoperineal resection and ostomy creation. Information about phantom rectum syndrome should be shared preoperatively and during follow up in order to promote optimal quality of life and alleviate bothersome symptoms and concerns associated with phantom rectum syndrome. PMID- 23652701 TI - Urinary bag decontamination for long-term use: a systematic review. AB - A systematic review of research on urinary drainage bag decontamination methods was conducted to evaluate existing evidence for practice related to long-term urinary catheter users. Six trials were found that met inclusion criteria. In addition, 9 clinical practice guidelines about urinary catheter care from 3 English-speaking countries were examined. Two studies were of modest quality; they included a randomized trial of 54 persons in a rehabilitation hospital and a laboratory comparison of 5 decontamination products. Three other articles included in the review were case series. All were published between 1985 and 1994. Bleach (NaClO) solutions of varying concentrations (0.06%-1%) were most often tested, and results were similar in controlling microbial contamination in the drainage bags. However, the studies often lacked definitions or standardization of key outcome measures such as safety and ease of the procedure and integrity of the drainage bag. The clinical practice guidelines differed in advice on bag decontamination, and some did not address it. Further research is recommended to evaluate the efficacy of decontamination procedures in patients with long-term indwelling catheters and drainage bags. PMID- 23652702 TI - Impact of a nurse-run clinic on prevalence of urinary incontinence and everyday life in men undergoing radical prostatectomy. AB - PURPOSE: To determine the prevalence of urinary incontinence (UI) in patients undergoing prostatectomy and to evaluate the impact of UI on the everyday life in order to select the patients eligible to enter a pelvic floor rehabilitation program. SUBJECTS AND SETTINGS: The sample comprised 114 consecutive men undergoing laparoscopic or open radical prostatectomy between April 2007 and April 2008. Participants' mean age was 59 years (range, 46-67 years). The research setting was a hospital-based clinic in Barcelona, Spain. Patients who required an indwelling urinary catheter due to other factors were excluded from the trial. During admission, nursing staff explained the study and obtained informed consent from patients willing to participate in the trial. METHODS: The impact of UI on daily living was evaluated via administration of the International Consultation on Incontinence Questionnaire-Short Form. Impact of UI was evaluated before surgery, and after 1 and 12 months following indwelling catheter removal. RESULTS: A total of 95.5% patients developed UI 1 month following bladder catheter removal. Slightly less than 1 in 4 patients (24.8%) indicated that UI had no effect on activities of daily living. In contrast, 27.5% indicated that UI had a moderate impact and 47.7% indicated a severe impact. Ninety-one patients reported performing pelvic floor muscle exercises to improve UI, but only 45% were found to be performing them correctly. When evaluated at 1 year following catheter removal, 52.64% of the patients continued to experience UI. The majority (79.8%) indicated that UI did not impact their daily lives, 8.8% indicated a moderate impact, and 20.4% reported that UI had a severe impact on daily life. Seventy patients (61.4%) continued to perform pelvic floor muscle exercises; after 1 year, 93% were deemed to be correctly identifying, contracting, and relaxing their pelvic floor muscles. CONCLUSIONS: Urinary incontinence remains prevalent as long as 12 months following catheter removal. Incontinence exerts a moderate to severe impact on daily life in 27.5% to 20.4% of respondents. In order to minimize the negative impact as much as possible, we advocate a pelvic floor muscle training program overseen by RNs. PMID- 23652703 TI - Study hints-How to use the content outline to study for the WOCNCB Exam. PMID- 23652704 TI - Mechanically powered ambulatory negative pressure wound therapy device for treatment of a colostomy takedown site. AB - BACKGROUND: The management of postostomy takedown surgical wound sites can be challenging. Complications from these contaminated wounds can lead to serious complications such as hernia formation and increased healthcare costs. Negative pressure wound therapy (NPWT) has been shown to be potentially helpful in managing these heavily colonized wound sites. We report the case of a mechanically powered ambulatory NPWT device (SNaP Wound Care System; Spiracur Inc, Sunnyvale, California) for treating these postcolostomy takedown wounds. CASE: A young 9-year-old boy in Port-Au-Prince, Haiti, had under gone colostomy as a protective measure after pelvic fracture 5 months prior. Having healed the pelvic fracture and being fully ambulatory, he underwent takedown of his colostomy with reanastomosis of the bowel. At the completion of surgery, the ostomy wound site was managed by a mechanically powered NPWT device. This allowed the patient to remain ambulatory without the need for attachment to a heavier electrically powered NPWT device during healing. Dressing changes were limited to twice weekly instead of 3 times daily. CONCLUSION: This case demonstrates the feasibility of an underdescribed application for a new mechanically powered ambulatory negative pressure device. Findings from this case study suggest that this device may be clinically applicable for patients undergoing ostomy takedown in the United States and in developing nations such as Haiti. PMID- 23652707 TI - Initial stages of benzotriazole adsorption on the Cu(111) surface. AB - Benzotriazole (BTAH) has been used as a copper corrosion inhibitor since the 1950s; however, the molecular level detail of how inhibition occurs remains a matter of debate. The onset of BTAH adsorption on a Cu(111) single crystal was investigated via scanning tunnelling microscopy (STM), vibrational spectroscopy (RAIRS) and supporting DFT modelling. BTAH adsorbs as anionic (BTA(-)), CuBTA is a minority species, while Cu(BTA)2, the majority of the adsorbed species, form chains, whose sections appear to diffuse in a concerted manner. The copper surface appears to reconstruct in a (2 * 1) fashion. PMID- 23652708 TI - Ipsi- and contralateral H-reflexes and V-waves after unilateral chronic Achilles tendon vibration. AB - Chronic Achilles tendon vibration has previously shown its effectiveness in improving plantar flexor's strength and activation capacities. The present study investigated the related neural mechanisms by analyzing H-reflexes and V-waves of the soleus (SOL) and gastrocnemii (GM gastrocnemius medialis; GL gastrocnemius lateralis) muscles under maximal isometric plantar flexion. Moreover, recordings were conducted bilaterally to address potential crossed effects. 11 subjects were engaged in this study. Maximal voluntary contraction and superimposed H-reflexes and V-waves were quantified in both legs at baseline (PRE) and 2 weeks later to verify repeatability of data (CON). Then, subjects were retested after 14 days of daily unilateral Achilles tendon vibration (VIB; 1 h per day; frequency: 50 Hz). No changes were reported between PRE and CON data. In the VIB condition, there was an increase in MVC for both the vibrated (+9.1 %; p = 0.016) and non-vibrated (+10.2 %; p = 0.009) legs. The H-reflex increased by a mean 25 % in the vibrated SOL (p < 0.001), while it remained unchanged for the contralateral side (p = 0.531). The SOL V-wave also increased in the vibrated limb (+43.3 %; p < 0.001), as well as in the non-vibrated one (+41.9 %; p = 0.006). Furthermore, the GM V wave increased by 37.8 % (p = 0.081) in the vibrated side and by 39.4 % (p = 0.03) in the non-vibrated side. However, no changes were reported for the GL muscles. While the present study confirmed the strength gains induced by chronic Achilles tendon vibration, the results indicated a cross-education phenomenon with differences in neural adaptations between the vibrated leg and non-vibrated leg. PMID- 23652709 TI - Noisy fluctuation of heart rate indicates cardiovascular system instability. AB - Heart rate spontaneously fluctuates despite homeostatic regulatory mechanisms to stabilize it. Harmonic and fractal fluctuations have been described. Non-harmonic non-fractal fluctuation has not been studied because it is usually thought that it is caused by apparatus noise. We hypothesized that this fluctuation looking like apparatus noise (that we call "noisy fluctuation") is linked to challenged blood pressure stabilization and not to apparatus noise. We assessed noisy fluctuation by quantifying the small and fastest beat-to-beat fluctuation of RR interval by means of spectral analysis (Nyquist power of heart rate variability: nyHRV) after filtering out its fractal component. We observed nyHRV in healthy supine subjects and in patients with vasovagal symptoms. We challenged stabilization of blood pressure by upright posture (by means of a head-up tilt table test). Head-up position on the tilt table dramatically decreased nyHRV (0.128 +/- 0.063 vs. 0.004 +/- 0.002, p < 0.01) in healthy subjects (n = 12). Head-up position also decreased nyHRV in patients without vasovagal symptoms (n = 24; 0.220 +/- 0.058 vs. 0.034 +/- 0.015, p < 0.05), but not in patients with vasovagal symptoms during a head-up tilt table test (age and sex paired, 0.103 +/ 0.041 vs. 0.122 +/- 0.069, not significant). Heart rate variability includes a physiological non-harmonic non-fractal noisy fluctuation. This noisy fluctuation indicates low engagement of regulatory mechanisms because it disappears when the cardiovascular system is challenged (upright posture). It also indicates cardiovascular instability because it does not disappear in upright patients before vasovagal syncope, a transient failure of cardiovascular regulation. PMID- 23652710 TI - A systematic review of phacoemulsification cataract surgery in virtual reality simulators. AB - The aim of this study was to review the capability of virtual reality simulators in the application of phacoemulsification cataract surgery training. Our review included the scientific publications on cataract surgery simulators that had been developed by different groups of researchers along with commercialized surgical training products, such as EYESI(r) and PhacoVision(r). The review covers the simulation of the main cataract surgery procedures, i.e., corneal incision, capsulorrhexis, phacosculpting, and intraocular lens implantation in various virtual reality surgery simulators. Haptics realism and visual realism of the procedures are the main elements in imitating the actual surgical environment. The involvement of ophthalmology in research on virtual reality since the early 1990s has made a great impact on the development of surgical simulators. Most of the latest cataract surgery training systems are able to offer high fidelity in visual feedback and haptics feedback, but visual realism, such as the rotational movements of an eyeball with response to the force applied by surgical instruments, is still lacking in some of them. The assessment of the surgical tasks carried out on the simulators showed a significant difference in the performance before and after the training. PMID- 23652712 TI - Susac's Syndrome: A Case Presentation and Radiological Approach to this Rare Autoimmune Endotheliopathy. AB - Susac's syndrome is an uncommon neurologic disorder, consisting of the clinical triad of encephalopathy, branch retinal artery occlusions, and hearing loss. We report a case of a sudden vision and hearing impairment in a 35-year-old female patient. Magnetic resonance imaging of the brain revealed multiple lesions in the white matter and the corpus callosum, typical of Susac's syndrome. PMID- 23652711 TI - Comparison of changes in blood glucose, insulin resistance indices, and adipokine levels in diabetic and nondiabetic subjects with morbid obesity after laparoscopic adjustable gastric banding. AB - OBJECTIVE: The aim of the study was to evaluate blood glucose, insulin resistance indices, and adipokine (leptin and adiponectin) levels in morbidly obese individuals with and without type 2 diabetes mellitus and to compare the changes in these parameters 1 year after laparoscopic adjustable gastric banding surgery. MATERIAL AND METHODS: In total, 103 patients (37 subjects with and 66 subjects without type 2 diabetes mellitus) were studied preoperatively and again 1 year after laparoscopic adjustable gastric banding. RESULTS: One year after laparoscopic adjustable gastric banding, the leptin concentrations decreased significantly in both treatment groups, while the adiponectin levels increased significantly in the nondiabetic patients (11.19 ug/mL [SD 7.20] vs. 15.58 ug/mL [SD 7.8], P=0.003) and tended to increase in the group of the patients with type 2 diabetes mellitus (8.98 ug/mL [SD 6.80] vs. 13.01 ug/mL [SD 12.14], P>0.05). A considerable decrease in the insulin resistance indices was noted in the patients with type 2 diabetes mellitus 1 year after the intervention, and it was followed by a partial or complete remission of type 2 diabetes mellitus in 23 (85.19%) of the 27 investigated diabetic patients. The postoperative insulin resistance indices in the patients with type 2 diabetes mellitus became similar to the values in the nondiabetic subjects. CONCLUSIONS: Weight loss after laparoscopic adjustable gastric banding is associated with a significant increase in adiponectin secretion in nondiabetic morbidly obese patients and with improvement in adiponectin secretion in type 2 diabetes individuals. In subjects with type 2 diabetes, this surgical intervention results in a significant reduction in blood glucose and insulin resistance. PMID- 23652713 TI - Dependence of reaction time and movement speed on task complexity and age. AB - The aim of this study was to determine the differences in reaction time, reaction complexity, and movement speed depending on age. MATERIAL AND METHODS: The study included 40 healthy subjects (20 young and 20 older women and men). The study was conducted at the Human Motorics Laboratory, Lithuanian Sports University. An analyzer DPA-1 of dynamic upper and lower limb movements was used for the research purposes. RESULTS: The reaction time of the right arm of the young subjects was 0.26 s (SD, 0.01) and that of the left arm was 0.25 s (SD, 0.02), when an accuracy task was performed. The reaction time of the older subjects was 0.29 s (SD, 0.03) and 0.28 s (SD, 0.03) for the right and left arms, respectively. The reaction time of the right leg of the young subjects was 0.26 s (SD, 0.02) and that of the left leg was 0.27 s (SD, 0.03). The reaction time of the right and left legs of the older subjects was 0.33 s (SD, 0.02) and 0.35 s (SD, 0.04), respectively. The reaction of the young subjects was almost two times faster compared with the older persons after the accuracy task with each limb was accomplished. CONCLUSIONS: In case of movements with arms and legs, reaction time and movement speed directly depend on the complexity of a task. Reaction time and movement speed are slower for the older subjects in comparison with the young ones; the results worsen in proportion to the increasing complexity of a task. PMID- 23652714 TI - What are the predictors of self-assessed health in Lithuanian health professionals? AB - BACKGROUND AND OBJECTIVE: Scientific evidence indicates that patient safety and access to health care is linked to the well-being of health professionals. The self-assessed health status has been widely used as a health measure in different surveys. The aim of this study was to examine and determine the factors related to the self-assessed health status of health professionals. MATERIAL AND METHODS: The cross-sectional questionnaire surveys of nurses and physicians were carried out in randomly selected hospitals. A total of 1025 health professionals (739 nurses and 286 physicians) from 3 hospitals of different size located in 1 geographical region of Lithuania participated in the survey. The response rate among the nurses and the physicians was 89.2% and 52.5%, respectively. The overall response rate was 74.7%. The data on self-assessed health, demographic factors, anthropometric data, blood pressure, cholesterol level in blood, personal history of diseases, smoking, and alcohol consumption were gathered with the help of the questionnaire. RESULTS: About two-thirds (64.1%) of the health professionals reported good or quite good health, and only 1.5% of the respondents reported quite poor or poor health. Multivariate logistic regression analysis revealed that the SAH status of health professionals was dependent on age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.02-1.05 [Model 1]; OR, 1.04; 95% CI, 1.02-1.06 [Model 2]), diseases (OR, 7.32; 95%, 5.18-10.35), heart diseases (OR, 12.09; 95% CI, 2.9-50.35), hypertension (OR, 2.53; 95% CI, 1.55-4.14), cancer (OR, 6.19; 95% CI, 1.27-30.13), gastrointestinal (OR, 3.54; 95% CI, 1.59-7.86) and musculoskeletal diseases (OR, 3.21; 95% CI, 1.71-6.02), smoking (OR, 2.1; 95% CI, 1.28-3.45 [Model 1]; OR, 2.00; 95% CI, 1.26-3.16 [Model 2]), and occupation (OR, 1.47; 95% CI, 1.04-2.07 [ Model 1]; OR, 1.54; 95% CI, 1.11-2.16 [Model 2]). CONCLUSIONS: Diseases are the main predictors of self assessed health in health professionals. Advancing age and smoking also contribute to poorer self-assessed health. PMID- 23652716 TI - Mortality of Lithuanian population over 2 decades of independence: critical points and contribution of major causes of death. AB - The aim of the study was to analyze trends in overall mortality and mortality from major causes of death, detect differences in cut points, and estimate the contribution of the major causes of death to the changes in overall mortality throughout 2 decades of independence in Lithuania (1991-2000 and 2001-2010). MATERIAL AND METHODS: Overall mortality and mortality from cardiovascular diseases, cancer, and external causes were analyzed for the periods of 1991-2000 and 2001-2010. Joinpoint analysis was used to identify the best-fitting points wherever a statistically significant change in mortality occurred, and analysis of components was applied for the assessment of the contribution of major causes of death. RESULTS: The 1991-1994 period was identified as the most negative in terms of increasing mortality from all major causes of death, while the 2007-2010 period was most favorable, when the most significant decline in overall mortality was observed (4.84% per year for males and 4.41% per year for females). External causes contributed most to the growing overall mortality in 1991-1994 both for males and females (37.20% and 25.29%, respectively). Since 2007, all major causes contributed positively to the declining overall mortality of the Lithuanian population. The most significant contribution was made by cardiovascular diseases and external causes. CONCLUSIONS: Despite the considerable transformations of socioeconomic situation and economic crisis, it is likely that Lithuania is entering into the stage of positive health development. For assuring this trend in the future, investments in sustainable health and social developments are inevitable. PMID- 23652715 TI - Maternal age-associated congenital anomalies among newborns: a retrospective study in Latvia. AB - BACKGROUND AND OBJECTIVE: In Latvia, the mean age of women giving birth increased from 27.3 in 2000 to 29.0 years in 2010 during the last 11 years. The aim of this study was to report on major congenital anomalies of newborns at birth by the maternal age and to compare the mean maternal age by different diagnosis subgroups and maternal and neonatal characteristics. MATERIAL AND METHODS: A cross-sectional retrospective study with the data from the Medical Birth Register (2000-2010) was carried out. The live birth prevalence rate was calculated for the subgroups of major congenital anomalies per 10 000 live births by the maternal age. RESULTS: The live birth prevalence rate of major congenital anomalies during the period 2000-2010 was 211.4 per 10 000 live births. The prevalence rate increased depending on the maternal age. Congenital heart defects, limb defects, and urinary system anomalies were the most common anomalies. The study results showed an age-related risk of abdominal wall defects, orofacial clefts, and chromosomal anomalies. There were significantly higher proportions of preterm births, newborns with low birth weight, and complications during pregnancy among mothers aged 35 years and more. CONCLUSIONS: The data on congenital anomalies from the Latvian Medical Birth Register can be used for the assessment of epidemiology of congenital anomalies. The results of this retrospective study showed a decrease in the live birth prevalence rate of major congenital anomalies despite an increase in the mean age of mothers in Latvia. PMID- 23652717 TI - Ultrasonography and magnetic resonance imaging of the brain in hypoxic full-term newborns. AB - The aim of this article was to review the studies on diagnostic and prognostic value of radiological investigations (cranial sonography, Doppler ultrasonography, and magnetic resonance imaging) in the detection of hypoxic ischemic brain injuries in full-term newborns. MATERIALS AND METHODS: A systematic search of studies on the diagnostic and prognostic possibilities of radiological investigations for the detection of hypoxic-ischemic injuries in full-term newborns was performed. RESULTS: A total of 13 prospective and 4 retrospective studies that analyzed the incidence of hypoxic-ischemic cerebral injuries, determined by means of cranial sonography, Doppler sonography, and magnetic resonance imaging, and associations with the stages of hypoxic-ischemic encephalopathy and long-term neurodevelopmental outcomes were included in this systematic review. CONCLUSIONS: Magnetic resonance imaging detects lesions in 75% 100% of cases. Magnetic resonance imaging performed at the age of 7-11 days demonstrated a high sensitivity (100%) and negative predictive value (100%) to predict unfavorable outcomes at 4 years of age. In newborns with hypoxic-ischemic encephalopathy, substantial cerebral hemodynamic alterations are detected after birth. The sensitivity and negative predictive value of cerebral blood flow velocities (peak systolic flow velocity, end-diastolic flow velocity) changes at 12+/-2 hours of age to predict the severity of hypoxic-ischemic encephalopathy and unfavorable outcomes at 18 months of age were found to be high (90% and 94%, respectively). A low resistive index (<0.56) at the age of 1-3 days had a specificity of 95% to predict unfavorable outcomes at 3 years of age. The data on the diagnostic and prognostic potential of cranial sonography are limited scarce and contrary. PMID- 23652718 TI - Morphological change of inner retinal layer on spectral-domain optical coherence tomography following macular hole surgery. AB - BACKGROUND/AIMS: To investigate the morphological changes of the inner retinal layer by spectral-domain optical coherence tomography (OCT) after idiopathic full thickness macular hole (MH) surgery. METHODS: In a retrospective study, the authors evaluated 52 eyes of 49 patients with MH closed following vitrectomy. All patients were followed postoperatively for more than 6 months. Cross-sectional and retinal surface images were obtained using Cirrus high-definition OCT before and after surgery. In 24 of the 52 eyes, fundus autofluorescence (FAF) was analyzed. RESULTS: The incidence of dissociated optic nerve fiber layer (DONFL) increased gradually over time after surgery. 57.7% had defects of only the retinal nerve fiber layer (RNFL) and 30.8% had defects in the inner plexiform layer at 6 months after surgery. Postoperative best-corrected visual acuity did not differ significantly based on the depth of the DONFL (p = 0.299). There were no changes in FAF in the area with DONFL. CONCLUSIONS: DONFL is characterized by progressive defects that are not limited to RNFL thickness. The healing process after vitrectomy for MH is not limited in the RNFL affecting deeper structural changes. Further investigations are required to evaluate the pathophysiological mechanism of inner retinal change after MH surgery. PMID- 23652719 TI - Evaluation of a mail-delivered, print-format, self-management program for persons with systemic sclerosis. AB - Patient self-management programs usually require participants to attend group sessions, which can be difficult for individuals with mobility issues. In addition, many programs are not disease specific. The purpose of this study was to evaluate the effects of a mail-delivered self-management program for individuals with scleroderma (SSc). The program consisted of a workbook and exercise DVD that provided information on medical aspects of the disease, dysphagia, fatigue management, advocacy, activities of daily living, oral hygiene, skin and wound care, psychosocial changes, exercises, and other features of the condition. Participants provided feedback on the effects of the self management program by responding to questions on demographic and six self-report questionnaires, keeping a health log, and participating in a program evaluation interview. A total of 49 participants completed the program and returned the postintervention questionnaires. Participants consistently reported that the program was easy to use. Depression, fatigue, and pain decreased, and hand function, self-efficacy for controlling pain, and self-efficacy "other" improved; however, the only statistically significant change was in self-efficacy for pain. This is the first study to develop and assess the effects of a mail-delivered format for self-management for people with SSc. A self-management program should help individuals with SSc develop self-management strategies to manage this complex disease and advocate for themselves to promote better health. PMID- 23652720 TI - Exposure to ultrafine particles in hospitality venues with partial smoking bans. AB - Fine particles in hospitality venues with insufficient smoking bans indicate health risks from passive smoking. In a random sample of Viennese inns (restaurants, cafes, bars, pubs and discotheques) effects of partial smoking bans on indoor air quality were examined by measurement of count, size and chargeable surface of ultrafine particles (UFPs) sized 10-300 nm, simultaneously with mass of particles sized 300-2500 nm (PM2.5). Air samples were taken in 134 rooms unannounced during busy hours and analyzed by a diffusion size classifier and an optical particle counter. Highest number concentrations of particles were found in smoking venues and smoking rooms (median 66,011 pt/cm(3)). Even non-smoking rooms adjacent to smoking rooms were highly contaminated (median 25,973 pt/cm(3)), compared with non-smoking venues (median 7408 pt/cm(3)). The particle number concentration was significantly correlated with the fine particle mass (P<0.001). We conclude that the existing tobacco law in Austria is ineffective to protect customers in non-smoking rooms of hospitality premises. Health protection of non-smoking guests and employees from risky UFP concentration is insufficient, even in rooms labeled "non-smoking". Partial smoking bans with separation of smoking rooms failed. PMID- 23652721 TI - A novel cognitive-neurophysiological state biomarker in premanifest Huntington's disease validated on longitudinal data. AB - In several neurodegenerative diseases, like Huntington's disease (HD), treatments are still lacking. To determine whether a treatment is effective, sensitive disease progression biomarkers are especially needed for the premanifest phase, since this allows the evaluation of neuroprotective treatments preventing, or delaying disease manifestation. On the basis of a longitudinal study we present a biomarker that was derived by integrating behavioural and neurophysiological data reflecting cognitive processes of action control. The measure identified is sensitive enough to track disease progression over a period of only 6 month. Changes tracked were predictive for a number of clinically relevant parameters and the sensitivity of the measure was higher than that of currently used parameters to track prodromal disease progression. The study provides a biomarker, which could change practice of progression diagnostics in a major basal ganglia disease and which may help to evaluate potential neuroprotective treatments in future clinical trials. PMID- 23652722 TI - Dorsal hippocampal involvement in conditioned-response timing and maintenance of temporal information in the absence of the CS. AB - Involvement of the dorsal hippocampus (DHPC) in conditioned-response timing and maintaining temporal information across time gaps was examined in an appetitive Pavlovian conditioning task, in which rats with sham and DHPC lesions were first conditioned to a 15-s visual cue. After acquisition, the subjects received a series of non-reinforced test trials, on which the visual cue was extended (45 s) and gaps of different duration, 0.5, 2.5, and 7.5 s, interrupted the early portion of the cue. Dorsal hippocampal-lesioned subjects underestimated the target duration of 15 s and showed broader response distributions than the control subjects on the no-gap trials in the first few blocks of test, but the accuracy and precision of their timing reached the level of that of the control subjects by the last block. On the gap trials, the DHPC-lesioned subjects showed greater rightward shifts in response distributions than the control subjects. We discussed these lesion effects in terms of temporal versus non-temporal processing (response inhibition, generalisation decrement, and inhibitory conditioning). PMID- 23652723 TI - Laterality affects spontaneous recovery of contralateral hand motor function following motor cortex injury in rhesus monkeys. AB - The purpose of this study was to test whether brain laterality influences spontaneous recovery of hand motor function after controlled brain injuries to arm areas of M1 and lateral premotor cortex (LPMC) of the hemisphere contralateral to the preferred hand in rhesus monkeys. We hypothesized that monkeys with stronger hand preference would exhibit poorer recovery of skilled hand use after such brain injury. Degree of handedness was assessed using a standard dexterity board task in which subjects could use either hand to retrieve small food pellets. Fine hand/digit motor function was assessed using a modified dexterity board before and after the M1 and LPMC lesions in ten monkeys. We found a strong negative relationship between the degree of handedness and the recovery of manipulation skill, demonstrating that higher hand preference was associated with poorer recovery of hand fine motor function. We also observed that monkeys with larger lesions within M1 and LPMC had greater initial impairment of manipulation and poorer recovery of reaching skill. We conclude that monkeys with a stronger hand preference are likely to show poorer recovery of contralesional hand fine motor skill after isolated brain lesions affecting the lateral frontal motor areas. These data may be extended to suggest that humans who exhibit weak hand dominance, and perhaps individuals who use both hands for fine motor tasks, may have a more favorable potential for recovery after a unilateral stroke or brain injury affecting the lateral cortical motor areas than individuals with a high degree of hand dominance. PMID- 23652726 TI - Fabrication of a rhythmic assembly system based on reversible formation of dynamic covalent bonds in a chemical oscillator. AB - A rhythmic assembly (RA) system driven by a pH oscillator was constructed through the reversible formation of dynamic covalent bonds. PMID- 23652725 TI - The effect of single-pulse transcranial magnetic stimulation and peripheral nerve stimulation on complexity of EMG signal: fractal analysis. AB - The aim of this study was to examine whether single-pulse transcranial magnetic stimulation (spTMS) affects the pattern of corticospinal activity once voluntary drive has been restored after spTMS-induced EMG silence. We used fractal dimension (FD) to explore the 'complexity' of the electromyography (EMG) signal, and median frequency of the spectra (MDF) to examine changes in EMG spectral characteristics. FD and MDF of the raw EMG epochs immediately before were compared with those obtained from epochs after the EMG silence. Changes in FD and MDF after spTMS were examined with three levels of muscle contraction corresponding to weak (20-40%), moderate (40-60%) and strong (60-80% of maximal voluntary contraction) and three intensities of stimulation set at 10, 20 and 30% above the resting motor threshold. FD was calculated using the Higuchi fractal dimension algorithm. Finally, to discern the origin of FD changes between the CNS and muscle, we compared the effects of spTMS with the effects of peripheral nerve stimulation (PNS) on FD and MDF. The results show that spTMS induced significant decrease in both FD and MDF of EMG signal after stimulation. PNS did not have any significant effects on FD nor MDF. Changes in TMS intensity did not have any significant effect on FD or MDF after stimulation nor had the strength of muscle contraction. However, increase in contraction strength decreased FD before stimulation but only between weak and moderate contraction. The results suggest that the effects of spTMS on corticospinal activity, underlying voluntary motor output, outlast the TMS stimulus. It appears that the complexity of the EMG signal is reduced after spTMS, suggesting that TMS alters the dynamics of the ongoing corticospinal activity most likely temporarily synchronizing the neural network activity. Further studies are needed to confirm whether observed changes after TMS occur at the cortical level. PMID- 23652727 TI - Inhibition of arginine ADP-ribosyltransferase 1 reduces the expression of poly(ADP-ribose) polymerase-1 in colon carcinoma. AB - Poly(ADP-ribose) polymerase-1 (PARP-1) which mediates poly-ADP-ribosylation, has been extensively investigated in carcinoma compared to arginine ADP ribosyltransferase 1 (ART1), which mediates mono-ADP-ribosylation. Previous studies have demonstrated that these enzymes promote proliferation and tumor development in colon carcinoma. However, whether there is any association between PARP-1 and ATR1 in colon carcinoma, remains unelucidated. In this study, using immunohistochemical analysis, we detected a higher expression of PARP-1 and ART1 in 63 samples from patients with colon carcinoma compared to 10 samples of normal colonic mucosa; our results revealed a positive correlation between the expression of PARP-1 and ART1 in the 63 human colon carcinoma tissue samples. To determine the correlation between PARP-1 and ART1, inhibitors of PARP-1 and ART1 and lentivirus vector-mediated ART1 short-hairpin RNA (shRNA) were used to culture CT26 murine colon adenocarcinoma cells separately. Using double-label immunofluorescence assay, we detected the expression of PARP-1 in the CT26 cells, which was decreased following treatment with 5-aminoisoquinolinone (5-AIQ, a PARP 1 inhibitor) or meta-iodobenzylguanidine (MIBG, an ART1 inhibitor). However, the expression of ART1 only decreased when the CT26 cells were treated with MIBG. Furthermore, our results demonstrated that silencing ART1 inhibited PARP-1 expression by decreasing the expression of nuclear factor-kappaB (NF-kappaB), inhibiting ras homolog A (RhoA). Hence, our data demonstrate the positive correlation between ART1 and PARP-1; the inhibition of ART1 activity downregulates PARP-1 expression by decreasing the activity of NF-kappaB in CT26 colon carcinoma cells. PMID- 23652728 TI - Electrically tunable optofluidic light switch for reconfigurable solar lighting. AB - We describe a reconfigurable lighting system for indoor solar illumination which provides a new way for solar energy conservation. We have experimentally demonstrated an electrically tunable optofluidic light switch which takes the key role for the reconfigurability. The working principle of the switch is based on applying a dielectrophoretic force on a thin oil film hence inducing a surface deformation and consequent leakage of the guided light propagating along the waveguide. A maximum modulation frequency of 2 Hz was achieved. The switch has the advantages of simple fabrication, compact size and low power consumption. The potential applications of such an optofluidic switch are also discussed. PMID- 23652729 TI - Voices of innovation: building a model for curriculum transformation. AB - Innovation in nursing education curriculum is critically needed to meet the demands of nursing leadership and practice while facing the complexities of today's health care environment. International nursing organizations, the Institute of Medicine, and; our health care practice partners have called for curriculum reform to ensure the quality and safety of patient care. While innovation is occurring in schools of nursing, little is being researched or disseminated. The purposes of this qualitative study were to (a) describe what innovative curricula were being implemented, (b) identify challenges faced by the faculty, and (c) explore how the curricula were evaluated. Interviews were conducted with 15 exemplar schools from a variety of nursing programs throughout the United States. Exemplar innovative curricula were identified, and a model for approaching innovation was developed based on the findings related to conceptualizing, designing, delivering, evaluating, and supporting the curriculum. The results suggest implications for nursing education, research, and practice. PMID- 23652730 TI - Theoretical insights into [PMo12O40](3-) grafted on single-walled carbon nanotubes. AB - Nano-hybrid materials based on a combination of polyoxometalate (POM) clusters and single-walled carbon nanotubes (SWNT) exhibit a great interesting application in molecular cluster batteries. The interactions between POM and SWNT and their detailed electronic properties have been investigated by employing first principles calculations. Various models were constructed to study the geometries, interactions (binding sites and energies), and charge transfer behavior. Analysis of charge distributions reveals two different charge transfer characteristic depending on the type of POM interaction with SWNT. The simulation provides insight into the optimal structures in lieu of interfacial stability. Finally, the implications of these results for understanding the properties of molecular cluster batteries are discussed. PMID- 23652731 TI - Expression of aquaporins in human embryos and potential role of AQP3 and AQP7 in preimplantation mouse embryo development. AB - BACKGROUND/AIMS: Water channels, also named aquaporins (AQPs), play crucial roles in cellular water homeostasis. METHODS: RT-PCR indicated the mRNA expression of AQPs 1-5, 7, 9, and 11-12, but not AQPs 0, 6, 8, and 10 in the 2~8-cell stage human embryos. AQP3 and AQP7 were further analyzed for their mRNA expression and protein expression in the oocyte, zygote, 2-cell embryo, 4-cell embryo, 8-cell embryo, morula, and blastocyst from both human and mouse using RT-PCR and immunofluorescence, respectively. RESULTS: AQP3 and AQP7 were detected in all these stages. Knockdown of either AQP3 or AQP7 by targeted siRNA injection into 2 cell mouse embryos significantly inhibited preimplantation embryo development. However, knockdown of AQP3 in JAr spheroid did not affect its attachment to Ishikawa cells. CONCLUSION: These data demonstrate that multiple aquaporins are expressed in the early stage human embryos and that AQP3 and AQP7 may play a role in preimplantation mouse embryo development. PMID- 23652732 TI - Maximum voluntary isometric pinch contraction and force-matching from the fourth to the eighth decades of life. AB - Understanding the effects of age and gender on pinch strength, variability, and accuracy and how one's hand function changes with age better enables those in the preventative and rehabilitative fields to combat these losses. The present study examined fine motor maximum pinch strength [maximum voluntary isometric contraction (MVIC)] as well as the ability to maintain 5% MVIC accurately and consistently in five decades. One hundred adults in five groups, 20 in each decade of life from 30 to 79 years old, were nonrandomly recruited from the community. A two-way analysis of variance applied to MVIC, and a two-way multivariate analysis of variance applied to the variability (coefficient of variability) and accuracy (root mean square error), plus correlation and regression analyses, were used to determine decade and gender effects on pinch force. The task involved using isometric pinch control of a computer cursor to match a 5% of MVIC force level represented by a horizontal line. MVIC and force matching steadiness and accuracy across all ages were not significantly different until the eighth decade (P<0.01). Men were stronger (P<0.001) but performed low level force-matching with greater error (P<0.001) than women. Strength was not correlated with steadiness but was weakly correlated with accuracy (r=0.293, P<0.01), and steadiness and accuracy were strongly correlated (r=0.783, P<0.001). Decade and gender were moderate and strong predictors of accuracy and steadiness, respectively. In conclusion, age and gender differences were evident in pinch force strength and control. PMID- 23652733 TI - Trends in vascular risk factor treatment and control in US stroke survivors: the National Health and Nutrition Examination Surveys (1999-2010). AB - BACKGROUND: Treatment and control of vascular risk factors reduce the likelihood of recurrent stroke. Present nationally representative data are sparse regarding secondary prevention treatment and control rates. METHODS AND RESULTS: We evaluated sex- and race-stratified blood pressure, cholesterol, and hemoglobin A1c levels and treatment and control rates in 1154 self-reported stroke survivors from the National Health and Nutrition Examination Surveys 1999 to 2010. We used weighted linear regression to estimate time trends. Participants were 54% to 61% women, 70% to 76% white, and had a mean age of 63 to 66 years. For blood pressure, treatment rates remained unchanged in men, but in women, treatment rates increased from 41% in 1999 to 2000 to 65% in 2009 to 2010 (P=0.03), and control rates increased from 23% to 79% (P=0.03). Treatment rates remained unchanged in non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, although control rates increased in non-Hispanic whites from 50% in 1999 to 2002 to 69% in 2007 to 2010 (P=0.04). For cholesterol, treatment rates increased from 30% to 40% in men (P=0.02) and from 28% to 36% (P<0.01) in women, but control rates increased only in men, from 62% to 87% (P<0.01). Cholesterol treatment rates increased only in non-Hispanic blacks, from 18% to 37% (P=0.02). By sex and race, there was no change in dysglycemia treatment and control. CONCLUSIONS: Despite improvements in blood pressure treatment and control and cholesterol treatment for women and cholesterol treatment and control for men, stroke secondary prevention through treatment and control of vascular risk factors remains suboptimal. Urgent action is needed to improve secondary prevention to reduce stroke morbidity and mortality in this high-risk group. PMID- 23652734 TI - Long-term outcomes after invasive management for older patients with non-ST segment elevation myocardial infarction. AB - BACKGROUND: Early invasive management is recommended for patients with non-ST segment elevation myocardial infarction (MI), but the incidence of long-term outcomes after early catheterization among older patients and the relationship of revascularization procedures with outcomes in this population have not been described. METHODS AND RESULTS: Using data from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) registry, we linked 19 336 older patients (>=65 years) with non-ST segment elevation MI found to have significant coronary disease during catheterization and who survived through 30 days posthospital discharge to Medicare/Medicaid data. All-cause mortality, readmission for MI, readmission for stroke, and use of repeat revascularization procedures were tracked for a median of 1181 days. Outcome comparisons were stratified by use of percutaneous coronary intervention (PCI; n=11 766, 60.8%) or coronary artery bypass grafting (n=3515, 18.2%) performed during the index hospitalization and through 30 days postdischarge, as well as by medical management without revascularization (n=4055, 21.0%). During follow-up, ~17% of patients underwent PCI (most commonly in patients initially treated with PCI), and only 3% of patients underwent coronary artery bypass grafting. Compared with an unadjusted long-term mortality cumulative incidence through 5 years of 50% in the medical management group, mortality was lower in the PCI group (33.5%; adjusted hazard ratio, 0.75; 95% confidence interval, 0.70-0.79) and lowest in the coronary artery bypass grafting group (24.2%; adjusted hazard ratio, 0.52; 95% confidence interval, 0.47-0.57; P<0.001 for 3-way comparisons). The unadjusted cumulative incidence of the composite of death, readmission for MI, or readmission for stroke at 5 years was 62.4%, 44.9%, and 33.0% for medical management, PCI, and coronary artery bypass grafting, respectively. CONCLUSIONS: Older patients with non-ST-segment elevation MI with significant coronary disease face high long-term risks for mortality and nonfatal cardiovascular outcomes after early catheterization that differ by type of revascularization procedure performed. These findings can help guide the design of studies evaluating long-term therapies among elderly post-MI patients. PMID- 23652735 TI - Perceived risk of ischemic and bleeding events in acute coronary syndromes. AB - BACKGROUND: Acute coronary syndrome registries report the use of incomplete guideline therapies, especially among the highest risk patients. Whether this treatment gap results from misperceptions of risk by physicians is uncertain. METHODS AND RESULTS: The Perceived Risk of Ischemic and Bleeding Events in Acute Coronary Syndrome Patients (PREDICT) study was a prospective acute coronary syndrome registry in Australia, China, India, and Russia, involving 58 hospitals between May 2009 and February 2011. In-hospital care and events up to 6 months were assessed. At least 2 clinicians involved in patient care estimated the untreated risk and change in risk with each therapy. Physician risk assessment and objective risk measures (eg, Global Registry of Acute Coronary Events [GRACE] score) for death, death/myocardial infarction, and bleeding events were compared using the c statistic and integrated discrimination improvement. In total, 1542 patients and 4230 patient-specific physician estimates were obtained. Of responding clinicians, 81.9% were cardiovascular specialists (years of practice: mean [SD], 11.5 [7.7] years). The median physician-perceived risk of 6-month death was 25% (interquartile range, 14%-35%). The GRACE score was superior to physician estimation (c statistic: GRACE score, 0.812 [95% confidence interval, 0.772-0.851] versus physician, 0.652 [95% confidence interval, 0.596-0.708]; P<0.0001). The GRACE score added to clinician intuition improved discrimination (integrated discrimination improvement, 0.0632 [SE, 0.012]; P<0.0001). Invasive management correlated with physician-estimated risk but not with GRACE risk. Among patients not at high risk by physician estimation, increased risk by GRACE score was associated with higher mortality (3.7% versus 0.8%; P<0.001). CONCLUSIONS: Objective risk assessment provides superior risk discrimination when compared with physician-estimated risk. Whether systematic use of objective risk stratification improves clinical outcomes should be studied in appropriately designed clinical trials. PMID- 23652736 TI - Incentivizing recruitment and retention to address enrollment challenges in clinical research. PMID- 23652737 TI - Primary prevention of acute rheumatic fever and rheumatic heart disease with penicillin in South African children with pharyngitis: a cost-effectiveness analysis. AB - BACKGROUND: Acute rheumatic fever and subsequent rheumatic heart disease remain significant in developing countries. We describe a cost-effective analysis of 7 strategies for the primary prevention of acute rheumatic fever and rheumatic heart disease in children presenting with pharyngitis in urban primary care clinics in South Africa. METHODS AND RESULTS: We used a Markov model to assess the cost-effectiveness of treatment with intramuscular penicillin using each of the following strategies: (1) empirical (treat all); (2) positive throat culture (culture all); (3) clinical decision rule (CDR) score >=2 (CDR 2+); (4) CDR score >=3 (CDR 3+); (5) treating those with a CDR score >=2 plus those with CDR score <2 and positive cultures (CDR 2+, culture CDR negatives); (6) treating those with a CDR score >=3 plus those with CDR score <3 and positive cultures (CDR 3+, culture CDR negatives); and (7) treat none. The strategies ranked in order from lowest cost were treat all ($11.19 per child), CDR 2+ ($11.20); the CDR 3+ ($13.00); CDR 2+, culture CDR negatives ($16.42); CDR 3+, culture CDR negatives ($23.89); and culture all ($27.21). The CDR 2+ is the preferred strategy at less than $150/quality-adjusted life year compared with the treat all strategy. A strategy of culturing all children compared with the CDR 2+ strategy costs more than $125 000/quality-adjusted life year gained. CONCLUSIONS: Treating all children presenting with pharyngitis in urban primary care clinics in South Africa with intramuscular penicillin is the least costly. A strategy of using a clinical decision rule without culturing is overall the preferred strategy. A strategy of culturing all children may be prohibitively expensive. PMID- 23652738 TI - Peristomal moisture-associated skin damage in adults with fecal ostomies: a comprehensive review and consensus. AB - Approximately 1 million persons living in North America have an ostomy, and approximately 70% will experience stomal or peristomal complications. The most prevalent of these complications is peristomal skin damage, and the most common form of peristomal skin damage occurs when the skin is exposed to effluent from the ostomy, resulting in inflammation and erosion of the skin. Despite its prevalence, research-based evidence related to the assessment, prevention, and management of peristomal moisture-associated skin damage is sparse, and current practice is largely based on expert opinion. In order to address current gaps in clinical evidence and knowledge of this condition, a group of WOC and enterostomal therapy nurses with expertise in ostomy care was convened in 2012. This article summarizes results from the panel's literature review and summarizes consensus-based statements outlining best practices for the assessment, prevention, and management of peristomal moisture-associated dermatitis among patients with fecal ostomies. PMID- 23652739 TI - Class II division 2 treatment--does skeletal maturity influence success and stability? AB - AIM: To analyze the influence of skeletal maturity on Herbst multibracket (MB) treatment of Class II division 2 malocclusions and its stability. MATERIAL AND METHODS: A total of 37 patients fulfilled the inclusion criteria (Class II division 2, fully erupted premolars and canines, Class II molar relationship >=1/2 cusp widths bilaterally or 1 cusp width unilaterally, retention period >=24 months). According to pretreatment hand wrist skeletal maturity the subjects were assigned to the groups EARLY (n=9), LATE (n=14) and ADULT (n=14). Lateral headfilms (T1: before treatment, T2: after Herbst MB treatment, T3: after retention) were analyzed using the Sagittal-Occlusal analysis and standard cephalometrics. RESULTS: During Herbst MB treatment (T2-T1), significant (p<0.001) molar relationship improvement was seen in all groups (EARLY: 3.6 mm; LATE: 3.7 mm; ADULT: 3.2 mm). The amount of skeletal effects contributing to molar correction varied markedly between the groups (EARLY: 19%; LATE: 62%; ADULT: 31%). Improvement (p<0.01) was also seen for ssNB angle (EARLY: 1.8 degrees ; LATE: 1.8 degrees ; ADULT: 0.9 degrees ) and overbite (EARLY: 3.3 mm; LATE: 4.5 mm; ADULT: 4.3 mm). During retention (T3-T2), minimal changes of molar relationship (<0.2 mm) and ssNB angle (<0.5 degrees ) were seen in all groups. Also the overbite relapsed (EARLY: 0.5 mm; LATE: 1.0 mm; ADULT: 1.1 mm) only to a clinically irrelevant extent. CONCLUSION: Irrespective of skeletal maturity, Herbst MB treatment of Class II division 2 malocclusions showed to be successful and stable. However, the LATE group showed the highest amount of skeletal effects contributing to the correction of the molar relationship. PMID- 23652740 TI - Laparoscopic resection of rectal cancer results in higher lymph node yield and better short-term outcomes than open surgery: a large single-center comparative study. AB - BACKGROUND: Prognosis in rectal cancer is closely related to mesorectal integrity, margin status, and adequate lymph node dissection. The impact of laparoscopy on the pathologic and short-term outcomes remains controversial. OBJECTIVE: We aim to compare the pathologic and short-term outcomes of laparoscopic and open resections for rectal cancer. DESIGN: This is a large single-center retrospective comparative study using a prospective database. PATIENTS: All patients who underwent primary resections for rectal cancer from January 2007 to September 2011 were identified. MAIN OUTCOME MEASURES: Pathologic (nodal harvest, mesorectal integrity, circumferential, and distal margins) and operative outcomes were measured. RESULTS: Two hundred thirty-four (mean age, 61 years; 65% male) patients underwent resections for primary rectal cancer, including 118 laparoscopic (99 restorative proctectomies, 19 abdominoperineal resections) and 116 open (69 restorative proctectomies, 47 abdominoperineal resections) resections. Both groups were similar in demographics, comorbidities, and tumor characteristics. The laparoscopic group had significantly more lymph nodes (26 vs 21, p = 0.02) than the open group, with no differences in circumferential margins, proportion of distal resection margins = 30 kg/m) and nonobese patients were matched 1:2 for age, sex, ASA class, location, and stage of tumor. Demographics, use of neoadjuvant chemoradiotherapy, operative and perioperative outcomes, pathology, long-term outcomes including oncologic outcomes, and whether restoration of intestinal continuity was obtained were compared. RESULTS: One hundred fifty-seven obese patients and 314 nonobese patients were included in the study. The groups were similar for matched characteristics. The use of neoadjuvant chemoradiotherapy (p = 0.048) and anastomotic leak (p = 0.0003) rates were higher in obese patients. A similar proportion of nonobese and obese patients underwent sphincter-preserving resection (p > 0.99), and postoperative hospital stay (p = 0.23), 30-day postoperative reoperation (p = 0.83), mortality (p > 0.99), and readmissions (p = 0. 13) were similar. The obese and nonobese groups had similar overall (p = 0.61) and disease-free survival (p = 0.74) at a mean follow-up of 5 years for both groups. LIMITATIONS: This study was limited by its retrospective and nonrandomized nature. CONCLUSION: At a high-volume specialized colorectal unit, proctectomy can be performed in obese patients with similar long-term oncologic outcomes and ability to restore intestinal continuity in comparison with nonobese patients. Proctectomy in obese patients, however, is associated with an increased risk of anastomotic leak in comparison with nonobese patients. PMID- 23652742 TI - Clinical prediction of pathological complete response after preoperative chemoradiotherapy for rectal cancer. AB - BACKGROUND: The clinical pretreatment factors that accurately predict response to chemoradiation in rectal cancer are not currently known. OBJECTIVE: The aim of this study is to evaluate the clinical factors associated with a pathological complete response after preoperative chemoradiotherapy for rectal cancer. DESIGN: This study is a retrospective review of prospectively collected data. SETTING: This study was conducted at a tertiary care hospital/referral center in South Korea. PATIENTS: From December 2000 to September 2011, a total of 391 consecutive patients with rectal cancer who underwent neoadjuvant chemoradiotherapy followed by radical surgery were identified. The treatment consisted of concurrent chemoradiation, which included preoperative 5-fluorouracil-based chemotherapy and pelvic radiation (median, 5040 cGy); this was followed 8 weeks later (median, 57 days) by surgery with curative intent. MAIN OUTCOME MEASURES: The primary outcome measured was the clinicopathological comparison between pathological complete response (n = 57, 14.6%) and non-pathological complete response (n = 334, 85.4%) groups. RESULTS: The pathological complete response groups had a higher percentage of noncircumferential tumors, nonmacroscopic ulceration, well differentiation, small tumor diameter, early clinical T stage, early clinical N stage, or low levels of pretreatment CEA than the non-pathological complete response group. In multivariate regression analysis, independent predictors of a higher pathological complete response rate were noncircumferentiality (p = 0.007; OR, 3.214), nonmacroscopic ulceration (p = 0.002; OR, 6.702), and low pretreatment CEA level (p = 0.004; OR, 2.656). Significant differences in the pathological complete response rate existed among the 4 risk stratification groups (p < 0.001). For the prediction of pathological complete response by the clinical risk score model, the sensitivity was 64.1% and the specificity was 73.7% (area under the curve, 0.706; p < 0.001). LIMITATIONS: This study was limited because it was a single-institution study with a small sample size. CONCLUSIONS: Pretreatment clinical variables, including tumor circumferentiality, macroscopic ulceration, and CEA level, may be important determinants in achieving a pathological complete response. PMID- 23652743 TI - Population-based use of sphincter-preserving surgery in patients with rectal cancer: is there room for improvement? AB - BACKGROUND: Treatment of rectal cancer in North America has been associated with lower rates of sphincter-preserving surgery in comparison with other regions. It is unclear if these lower rates are due to patient, tumor, or treatment factors; thus, the potential to increase the use of sphincter-preserving surgery is unknown. OBJECTIVE: The aim of this study is to identify the factors associated with the use of sphincter-preserving surgery and to quantify the potential for an increase in sphincter preservation. DESIGN: This population-based retrospective cohort study used patient-level data collected through a comprehensive, standardized review of hospital inpatient and outpatient medical records and cancer center charts. SETTINGS: This study was conducted in all hospitals providing rectal cancer surgery in a Canadian province. PATIENTS: All patients with a new diagnosis of rectal cancer from July 1, 2002 to June 30, 2006 who underwent potentially curative radical surgery were included. MAIN OUTCOME MEASURES: Logistic regression was used to identify factors associated with receiving a permanent colostomy. Patients were categorized as having received an appropriate or potentially inappropriate colostomy based on a priori determined patient, tumor, operative, and pathologic criteria. RESULTS: Of 466 patients who underwent radical surgery, 48% received a permanent colostomy. There was significant variation in the rate of sphincter-preserving surgery among the 10 hospitals that provided rectal cancer care (12%-73%, p = 0.0001). On multivariate analysis, male sex, low tumor height, and increasing tumor stage were associated with the receipt of a permanent colostomy. Among patients who received a permanent stoma, 65 of 224 (29%) patients received a potentially inappropriate stoma. On multivariate analysis, male sex and treatment in a medium- or low volume hospital was associated with the receipt of a potentially inappropriate colostomy. LIMITATIONS: This study was limited by its retrospective design. CONCLUSIONS: These data suggest that the receipt of a permanent colostomy by many patients with rectal cancer may be inappropriate, and there is potential to increase the use of sphincter-preserving surgery in patients with rectal cancer. PMID- 23652744 TI - Surgery for locally advanced recurrent colorectal cancer involving the aortoiliac axis: can we achieve R0 resection and long-term survival? AB - BACKGROUND: Locally advanced, recurrent colorectal cancer involving the aortoiliac axis may be considered a contraindication for curative surgery because of the technical challenges of achieving a negative margin resection and an assumed poor prognosis. OBJECTIVE: The aim of this study was to assess oncologic outcomes and the ability to achieve an R0 resection in these patients. DESIGN: A retrospective review of a prospectively maintained colorectal cancer database identified 406 consecutive patients who underwent surgery for locally recurrent colorectal cancer between 1997 and 2007. SETTING: This study was conducted at an academic multidisciplinary tertiary center. PATIENTS: The demographic and clinicopathological features of patients undergoing resection for locally advanced disease involving the aortoiliac axis at our institution were reviewed. RESULTS: Twelve patients (7 women, median age 51 years) were identified. Major vessel involvement included internal iliac artery (n = 7), common iliac artery (n = 5), external iliac artery (n = 3), aorta (n = 3), internal iliac vein (n = 2), and external iliac vein (n = 1). R0 resection was achieved in 7 patients, and R1 resection in 5. Eleven patients received intraoperative radiation therapy. Vascular reconstruction (3 aorta, 5 common iliac, 3 external iliac) included synthetic interposition grafts, femoral-femoral bypasses, or primary anastomosis. One patient underwent venous reconstruction of the external iliac vein. No graft complications were encountered, and graft patency at 4 years was 100%. Thirty-day morbidity was seen in 9 patients, 8 of whom had Clavien grade <3. Thirty-day mortality was nil. Overall and disease-free survival at 4 years was 55% and 45%. LIMITATIONS: This study was limited by its sample size, retrospective design, and the number of outcome events. CONCLUSION: R0 resection of locally advanced recurrent colorectal cancer involving the aortoiliac axis was achieved in over 50% of patients. Overall and disease-free survival was comparable to outcomes seen with locally advanced disease to nonvascular structures. PMID- 23652745 TI - Clinical, MRI, and PET-CT criteria used by surgeons to determine suitability for pelvic exenteration surgery for recurrent rectal cancers: a Delphi study. AB - BACKGROUND: Surgical resection with clear margins is the major predictor of long term survival in recurrent rectal cancer. The extent of pelvic exenteration surgery depends on many factors including clinical and radiological criteria. OBJECTIVE: The aim of this study was to establish which clinical, MRI, and PET criteria were considered important by surgeons who perform pelvic exenteration surgery, when assessing a patient with recurrent rectal cancer for pelvic exenteration surgery. DESIGN: A 2-stage Delphi study was conducted among an international panel of 36 colorectal surgeons recruited via a snowball-sampling method. Surgeons rated the importance of 99 clinical and radiological criteria by using a 9-point scale. MAIN OUTCOME MEASURES: Consensus was attained when at least 85% of the panel rated criteria within 3 points. RESULTS: Clinical factors suggestive of systemic disease, symptoms of advanced local recurrence such as pain, surgical fitness, and cognitive impairment were considered important by the panel when considering suitability for surgery. Agreement regarding the indication for surgery was reached for 20 radiological factors. Strong agreement was achieved for factors associated with tumor involvement in the axial and anterior compartments. For only 16 of these 20 radiological factors was there an agreement that a clear resection margin was likely to be achieved. LIMITATIONS: Further rounds of Delphi may have yielded greater consensus. CONCLUSION: This study has identified a set of criteria considered by experts to be important in evaluating patients' suitability for pelvic exenteration surgery. Evaluation of these criteria is required to determine their clinical utility in predicting a negative resection margin at pelvic exenteration surgery. PMID- 23652747 TI - Fecal lactoferrin: a noninvasive fecal biomarker for the diagnosis and surveillance of pouchitis. AB - BACKGROUND: Fecal lactoferrin is a marker of intestinal inflammation and can be assessed with a simple qualitative immunochromatographic rapid test. OBJECTIVE: We aimed to assess the sensitivity and specificity of the test in the diagnosis of pouchitis and evaluate its clinical utility in the surveillance of inflammation of the pouch after antibiotic therapy. DESIGN: Between October 2005 and September 2009, we recruited a consecutive series of patients who had their ileal pouch examined under a general anesthetic. Distinctions between healthy and inflamed pouches were made by the use of the Pouch Disease Activity Index. Fecal samples were taken before biopsy of the pouch, and a clinician blinded to the examination findings performed the lactoferrin test. After antimicrobial treatment, a number of patients with pouchitis had a repeat examination and lactoferrin test. RESULTS: There were 85 (41 male) patients. Median age was 42 (interquartile range, 36-49) years. Twenty-four patients had pouchitis. The test was positive in all 24 patients with pouchitis and 5 patients with a healthy pouch. The sensitivity and specificity of the test for pouchitis was 100% and 92%. The positive predictive value was 82%. In 7 patients who received antibiotic treatment for their pouchitis, the test was able to accurately predict the resolution and/or persistence of pouchitis. CONCLUSION: The qualitative fecal lactoferrin rapid test is a sensitive method for the diagnosis and confirmation of resolution of pouchitis. The test provides clinicians with greater confidence in the prescription of antibiotics for suspected pouchitis and its surveillance. PMID- 23652746 TI - Detailed stratification of TNM stage III rectal cancer based on the presence/absence of extracapsular invasion of the metastatic lymph nodes. AB - BACKGROUND: The presence/absence of extracapsular invasion in metastatic lymph nodes has been reported as being significantly correlated with the prognosis in a wide variety of cancers. However, the influence of extracapsular invasion in the metastatic lymph nodes on the prognosis in patients with stage III rectal cancer has not yet been investigated. OBJECTIVE: We investigated the presence/absence of extracapsular invasion in the metastatic nodes of the relevant main/lateral lymph node group in patients with rectal cancer to determine the usefulness of this parameter for stratifying the prognosis of patients with stage III rectal cancer. DESIGN: This was a single-institution study. SETTINGS: This study was conducted at a single institution. PATIENTS: We enrolled 101 consecutive patients with stage III rectal cancer who had undergone curative surgery with extended lymph node dissection and investigated the presence/absence of extracapsular invasion in the regional metastatic lymph nodes to determine the usefulness of such stratification for a more precise prediction of the patient prognosis. MAIN OUTCOME MEASURES: The main outcomes measured were the disease-free and overall survival rates. RESULTS: Univariate analysis revealed a significantly poorer prognosis, in terms of both the disease-free survival rate (p = 0.003) and overall survival rate (p = 0.008), of the pN3-extracapsular invasion-positive cases in comparison with the pN3-extracapsular invasion-negative cases. Multivariate analysis revealed the presence/absence of extracapsular invasion in the metastatic lymph nodes as the only variable that was statistically significantly associated with the disease-free survival rate (p = 0.011). LIMITATIONS: This was a retrospective study in a small number of patients from a single institution. There were no comparator groups. CONCLUSIONS: Detailed stratification of pN3 cases based on the presence/absence of extracapsular invasion in metastatic lymph nodes has the potential to contribute significantly to more available prediction of the prognosis of patients with stage III colorectal cancer. PMID- 23652748 TI - Predictors of postoperative urinary retention after colorectal surgery. AB - BACKGROUND: National quality initiatives have mandated the earlier removal of urinary catheters after surgery to decrease urinary tract infection rates. A potential unintended consequence is an increased postoperative urinary retention rate. OBJECTIVE: The aim of this study was to determine the incidence and risk factors for postoperative urinary retention after colorectal surgery. DESIGN: This was a prospective observational study. SETTINGS: A colorectal unit within a single institution was the setting for this study. PATIENTS: Adults undergoing elective colorectal operations were included. INTERVENTIONS: Urinary catheters were removed on postoperative day 1 for patients undergoing abdominal operations, and on day 3 for patients undergoing pelvic operations. Postvoid residual and retention volumes were measured. MAIN OUTCOME MEASURES: The primary outcomes measured were urinary retention and urinary tract infection. RESULTS: The overall urinary retention rate was 22.4% (22.8% in the abdominal group, 21.9% in the pelvic group) and was associated with longer operative time and increased perioperative fluid administration. Mean operative time for those with retention was 2.8 hours and, for those without retention, the mean operative time 2.2 hours (abdominal group 2 hours vs 1.4 hours, pelvic group 3.9 hours vs 3.1 hours, p <= 0.02). Patients with retention received a mean of 2.7L during the operation, whereas patients without retention received 1.8L (abdominal group 1.9L vs 1.4L, pelvic group 3.6L vs 2.2L, p < 0.01). In the abdominal group, patients with and without retention also received different fluid volumes on postoperative days 1 (2.2L vs 1.7L, p = 0.004) and 2 (1.6L vs 1L, p = 0.05). Laparoscopic abdominal group had a 40% retention rate in comparison with 12% in the open abdominal group (p = 0.004). Age, sex, preoperative radiation therapy, preoperative prostatism, preoperative diagnosis, and level of anastomosis were not associated with retention. The urinary tract infection rate was 4.9%. LIMITATION: The lack of documentation of preoperative urinary function was a limitation of this study. CONCLUSIONS: The practice of earlier urinary catheter removal must be balanced with operative time and fluid volume to avoid high urinary retention rates. Also important is increased vigilance for the early detection of retention. PMID- 23652749 TI - Postoperative and long-term outcomes after redo surgery for failed colorectal or coloanal anastomosis: retrospective analysis of 50 patients and review of the literature. AB - INTRODUCTION: Redo surgery for failed colorectal or coloanal anastomosis is a surgical challenge, but despite its technical difficulties and the high associated morbidity risk, it may represent the only valuable option to improve patients' quality of life by avoiding a permanent stoma and decreasing chronic pelvic symptoms. OBJECTIVES: This study aimed to analyze postoperative and long term outcomes, with particular focus on functional results, in patients undergoing redo surgery in comparison with previously published studies. DESIGN: This was a retrospective review of prospectively collected data in an institutional database. SETTING: The study was conducted in the colorectal unit of a tertiary referral teaching hospital in France. PATIENTS: Consecutive patients who underwent redo surgery for failed colorectal or coloanal anastomosis from 1998 to 2011 were included. RESULTS: A total of 50 patients (23 men, 27 women) were included. The median age at redo surgery was 62 years (range, 40-84). Twenty-six patients (52%) underwent a redo colorectal anastomosis and 24 patients a redo coloanal anastomosis (48%). Indications were anastomotic stricture (n = 20), chronic pelvic sepsis (n = 14), rectovaginal fistula (n = 3), prior Hartmann's procedure for complication of initial anastomosis (n = 8), and anastomotic cancer recurrence (n = 5). The median operative time was 435 minutes. Postoperative mortality was 0% and morbidity was 26%. No anastomotic leakage occurred. After a median follow-up of 21 (range, 1-137) months, 44 patients (88%) were evaluated for functional results. The median number of bowel movements per day was 2 (range, 1-10), with 70% of patients having fewer than 3 per day. LIMITATION: The study was limited by its retrospective nature and lack of data on quality of life. CONCLUSIONS: Redo surgery for failed colorectal or coloanal anastomosis is a valuable surgical option which allows avoidance of a permanent stoma in nearly 90% of patients. It remains a major undertaking with high intraoperative and postoperative morbidity. PMID- 23652750 TI - The value of preoperative biopsy in the management of solid presacral tumors. AB - BACKGROUND: Surgical decision making and the use of neoadjuvant therapy in the management of solid presacral tumors rely greatly on an accurate preoperative diagnosis. The utility of preoperative biopsy has been questioned because of potential complications and the increasing accuracy of modern imaging. OBJECTIVE: The aim of this study was to analyze biopsy-related morbidity and to compare the accuracy of imaging versus biopsy in making a preoperative diagnosis. DESIGN: This study is a retrospective review of all patients who underwent biopsy of presacral tumors at Mayo Clinic Rochester between 1990 and 2010. The demographics, pathology, complications of biopsy, and imaging were reviewed. Biopsy results and radiologic findings were matched with the final pathology and analyzed. SETTINGS: This study was conducted at a tertiary care center. PATIENTS: Adult patients with solid presacral tumors who underwent preoperative biopsy were evaluated. MAIN OUTCOME MEASURES: The primary outcomes measured were the biopsy related complications and the accuracy of preoperative imaging and biopsy in comparison with final pathology. RESULTS: Seventy-six biopsies were performed in 73 patients. Fifty-six patients underwent percutaneous biopsies, 14 underwent open biopsies, and 3 underwent both. Biopsy-specific complications included 2 hematomas (1 open, 1 percutaneous). Preoperative biopsy correlated with the postoperative pathologic diagnosis in 63 patients (91%). Of the 6 solid presacral tumors diagnosed incorrectly on biopsy, 1 was falsely reported as benign. Sensitivity, specificity, and positive and negative predictive values of biopsy to detect malignant disease was 96%, 100%, 100%, and 98%. Ten of 35 patients (29%) with a definitive imaging diagnosis were given incorrect diagnoses. Sensitivity, specificity, and positive and negative predictive values of imaging to diagnose malignant disease was 83%, 81%, 83%, and 81%. LIMITATIONS: This investigation was designed as a retrospective study. CONCLUSION: Preoperative biopsy of presacral tumors is safe and highly concordant with postoperative pathology in comparison with imaging. Given the significant differences in therapeutic approach for benign versus malignant solid presacral tumors, as well as the current limitations of imaging, a percutaneous preoperative biopsy should be obtained to guide management decisions. PMID- 23652751 TI - Increased risk for complications after colorectal surgery with selective cyclo oxygenase 2 inhibitor etoricoxib. AB - BACKGROUND: Cyclo-oxygenase 2 inhibitors can be used for pain treatment after colorectal surgery. OBJECTIVE: The aim of this study was to investigate whether the use of etoricoxib has negative effects on the perioperative outcome in colorectal surgery. DESIGN: Complication data from an advanced medical database system were sampled prospectively, and patient records were reviewed retrospectively. PATIENTS: All patients with elective colorectal surgery within an enhanced recovery after surgery protocol from 2008 to 2009 were selected. INTERVENTION: The nonrandomized use of perioperative etoricoxib treatment was compared with a control group. MAIN OUTCOME MEASURES: The primary outcome measured was the number of patients with postoperative complications according to the Dindo-Clavien classification. RESULTS: One hundred one patients received etoricoxib treatment, whereas 104 did not. The patient groups were very comparable. We observed a significant increase in the number of patients with postoperative complications with etoricoxib treatment (43 vs 30 patients; 42.6% vs 28.8%, p = 0.041) due to an increase in patients with a major complication (Dindo-Clavien complication grade III-V: 22.8% vs 9.6%, p = 0.01). Patients with etoricoxib treatment and a complication needed a longer recovery period than patients with a complication in the control group (18 (17; 20) vs 14 (13; 15) days, p = 0.05). We observed an increased level of postoperative serum creatinine with etoricoxib treatment (105 (98; 112) vs 82 (78; 85), p = 0.003), which was more pronounced in patients with a complication (141 (127; 155) vs 91 (83; 98), p = 0.002; 25 vs 8 patients with serum creatinine >100 MUmol/L, p = 0.008). In multivariate analysis, etoricoxib was identified as an independent risk factor for experiencing a major complication with a risk increase of approximately 2.5 fold (p = 0.03). LIMITATIONS: This study was limited by the nonrandomized use of perioperative etoricoxib and the retrospective nature of its review of patient records. CONCLUSIONS: Etoricoxib increased the number of patients with postoperative complications and should be considered carefully in colorectal surgery. PMID- 23652752 TI - Topical glyceryl trinitrate ointment for pain related to anal hypertonia after stapled hemorrhoidopexy: a randomized controlled trial. AB - BACKGROUND: Postoperative pain after stapled hemorrhoidopexy is cause for considerable concern and may be related to contracture of continence muscles. OBJECTIVE: We compared glyceryl trinitrate 0.4% ointment with lidocaine chlorohydrate 2.5% gel as topical therapy to relieve the pain of anorectal muscular spasm after stapled hemorrhoidopexy. DESIGN: This was a single-blind, parallel-group, randomized controlled trial. SETTING: The study was conducted at a university teaching hospital in Rome, Italy. PATIENTS: Patients with severe postoperative anal pain after stapled hemorrhoidopexy, clinical evidence of anal hypertonia, and elevated anal resting pressure on manometric assessment were enrolled. Patients treated for concomitant anorectal disease were excluded. INTERVENTIONS: Participants were randomly assigned to receive twice-daily, local topical application of glyceryl trinitrate or lidocaine for a total of 14 days. MAIN OUTCOME MEASURES: Pain intensity was measured on a visual analog scale at baseline and after 2, 7, and 14 days of therapy. Anal resting pressure was measured pre- and postoperatively and after 14 days of therapy. RESULTS: Of 480 patients undergoing stapled hemorrhoidopexy, 121 had severe postoperative pain (score >3) and underwent clinical examination; 45 patients (13 women, 28 men) had clinically evident anal hypertonia and underwent anorectal manometry; 41 patients had elevated anal resting pressure and entered the study. Mean pain scores were significantly lower with glyceryl trinitrate than with lidocaine on day 2 (2.5 +/ 1.0 vs 4.0 +/- 1.1, p < 0.0001); day 7 (1.4 vs 2.8, p < 0.0001); and day 14 (0.4 vs 1.4, p = 0.003). Anal resting pressure was significantly lower with glyceryl trinitrate than with lidocaine on day 14 (75.4 +/- 7.4 mmHg vs 85.6 +/- 7.9 mmHg, p < 0.0001). LIMITATIONS: GTN-induced reduction in sphincter tone could not be evaluated during the initial period, when pain was most intense. Because anorectal manometry was performed only in patients with severe pain and clinical evidence of anal hypertonia, firm conclusions cannot be drawn as to frequency of hypertonia after SH. Bias may have been introduced because the surgical team could not be blinded. CONCLUSION: Topical 0.4% glyceryl trinitrate is effective in relieving pain and reducing anal resting pressure in patients with anal hypertonia after stapled hemorrhoidopexy. PMID- 23652753 TI - Bioabsorbable synthetic plug in the treatment of anal fistulas. AB - BACKGROUND: Management of anal fistulas is challenging, because surgeons must aim to obtain complete healing while sparing the sphincter and avoiding fecal incontinence. The optimal treatment method remains unknown. OBJECTIVE: This study assessed the safety and effectiveness of the use of a new synthetic fistula plug made of bioabsorbable polymers in the treatment of cryptoglandular anal fistulas. DESIGN: This study is a retrospective review of a database of patient records. SETTING: : Patients were treated at a general hospital in Italy. PATIENTS: Forty eight patients (39 men and 9 women; mean age, 49.9 years) with 49 fistulas were treated with the synthetic plug between November 2009 and March 2012. Types of fistula were as follows: 24 superficial transsphincteric, 18 medium transsphincteric, 5 deep transsphincteric, and 1 medium intersphincteric. INTERVENTIONS: The fistula tract was cleaned by using curettage, and a synthetic plug was sized to fit the tract and inserted. A draining seton was used preoperatively in 1 patient. MAIN OUTCOME MEASURES: The outcome measures were complete closure of the fistula, with no discharge/residual fistula (verified by endoanal ultrasonography), perineal pain level (assessed with a visual analog scale), and fecal continence. Follow-up was conducted at 1 week and 1, 3, 6, and 12 months postoperatively. RESULTS: The overall healing rate was 69.3% (34/49 fistulas, 33/48 patients). Eight patients (24.2%) had healing by 3 months after surgery, 21 patients (63.6%) had healed by 6 months, and 4 patients (12.1%) had healed by 12 months. By 3 months, no patient had perineal pain or fecal incontinence. No plug became dislodged, and no patient had the onset of anal stenosis, bleeding, local infection, or any other complication. LIMITATIONS: The number of patients and the retrospective nonrandomized nature of the investigation are limitations of this study. CONCLUSIONS: In patients with cryptoglandular anal fistulas, the use of a bioabsorbable synthetic plug provided a high rate of healing without causing fecal incontinence or other major adverse effects. Larger and randomized studies of this treatment are warranted. PMID- 23652754 TI - Assessment of female patients with rectal intussusception and prolapse: is this a progressive spectrum of disease? AB - BACKGROUND: Rectal intussusception may be the initial abnormality of a progressive pelvic floor disorder culminating in external prolapse. The evidence, however, is unclear, and the pathophysiological mechanisms underlying this condition are unknown. OBJECTIVE: The aim of this study is to identify the relationship between age, symptom duration, anorectal physiology parameters, and type of intussusception/prolapse in order to appreciate the natural history of the condition. DESIGN: All female patients diagnosed proctographically with rectorectal/rectoanal intussusception or external prolapse between 1994 and 2007 were studied. Demographics, symptom duration, and anorectal physiology results were compared between these proctographic groups. Patients with repeat proctographic evaluation were also analyzed separately. SETTINGS: This investigation was conducted at a tertiary academic colorectal center. PATIENTS: A total of 1014 women (median age, 51; range, 16-96), including 32 who underwent repeat proctography, were analyzed. MAIN OUTCOME MEASURES: The primary outcomes measured were the differences in median age, symptom duration, and anorectal physiology parameters between the proctographic groups. RESULTS: The cohort exhibited a statistically significant difference (p = 0.0001) in the median age of the proctographic groups with older patients diagnosed with rectoanal rather than rectorectal intussusception, which was supported by uni- and multivariate modeling. Symptom duration was statistically different (p = 0.0002) between the rectorectal intussusception (60 months; range, 1-936) and external rectal prolapse patient groups (36 months; range, 2-732). Patients with external rectal prolapse had statistically lower anal resting (median, 41 versus 77 cmH2O) and squeeze pressures (median 40 versus 56 cmH2O) than patients with rectorectal intussusception. Within 2 years, 19.2% and 3.8% of patients with rectorectal intussusception on the initial proctogram demonstrated progression to rectoanal intussusception and external prolapse. LIMITATIONS: This study was limited by its retrospective nature. CONCLUSION: Rectal intussusception may be an initial abnormality leading to external prolapse, but this appears to happen infrequently. Long-term observational studies are required to fully understand its natural history. PMID- 23652755 TI - Robotic colonic surgery: is it advisable to commence a new learning curve? AB - BACKGROUND: Robotic surgery has potential advantages in rectal and pelvic surgery, in which the dissection is performed within a confined operative field. However, the position of robotic colonic surgery remains largely undefined with limited insight of whether it offers any potential advantages over open or laparoscopic colon surgery. OBJECTIVES: The aim of this systematic review was to compare the short-term outcomes of the published robotic colonic surgery with those of laparoscopic colonic surgery. DATA SOURCES: The search was performed in September 2012 with the use of PubMed, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. The search terms used were "colorectal," "colon," "colectomy," and "robotic/robot." DATA SELECTION: All studies reporting outcomes on robotic colonic resection were included in the review process. Colonic robotic data were compared with data on the short-term outcomes of laparoscopic colonic surgery from a Cochrane review and 4 main randomized controlled trials. INTERVENTIONS: A comparison was conducted of robotic colonic surgery vs standard laparoscopic colonic surgery. MAIN OUTCOME MEASURES: Short-term outcomes and the complication profile of colonic robotic surgery were compared with conventional multiple-port laparoscopic colonic surgery. RESULTS: Fifteen robotic colonic surgery articles with 351 patients (173 males, 178 females) were considered for analysis. The operative time and financial cost of robotic colonic surgery was greater than standard laparoscopic colonic surgery with comparable short-term outcomes and early postoperative complications profile. CONCLUSIONS: The present evidence on robotic colonic surgery has shown both feasibility and a safety profile comparable to standard laparoscopic colonic surgery. However, operative time and cost were greater in robotic colonic surgery, with no difference in the length of postoperative stay in comparison with standard laparoscopic colonic surgery. Whether the general surgical community should embark on a new learning curve for robotic colonic surgery can only be answered in the light of future studies. PMID- 23652756 TI - Application of laser-assisted indocyanine green fluorescent angiography for the assessment of tissue perfusion of anodermal advancement flaps. PMID- 23652758 TI - Perianal versus endoanal application of glyceryl trinitrate 0.4% ointment in the treatment of chronic anal fissure: results of a randomized controlled trial. Is this the solution to the headaches? Retraction. PMID- 23652759 TI - Midterm results after perineal stapled prolapse resection for external rectal prolapse. PMID- 23652760 TI - Transtar rectal prolapse excision. PMID- 23652761 TI - Percutaneous posterior tibial nerve stimulation for fecal incontinence: are we all reading from the same page? PMID- 23652762 TI - The authors reply. PMID- 23652765 TI - Si/PEDOT hybrid core/shell nanowire arrays as photoelectrodes for photoelectrochemical water-splitting. AB - Si/poly(3,4-ethylenedioxythiophene) (PEDOT) core/shell nanowire arrays have been prepared by chemical etching of Si nanowires followed by vapor-phase polymerization of PEDOT as hybrid photoanodes for photoelectrochemical water splitting. The PEDOT layer is employed as a multi-functional coating to prevent photocorrosion of Si nanowires, collect photogenerated holes and catalyze the water oxidation reaction. The amino silane modified Si nanowire surface improves PEDOT layer adhesion, and the resulting photoanode exhibits better photoresponse and improved stability. By tuning the length of the nanowires, we identify that the competition between the carrier recombination and catalytic water oxidation reaction is the primary factor determining the photoelectrocatalytic activity of the hybrid photoanode. PMID- 23652766 TI - Fast induction of biosynthetic polysaccharide genes lpxA, lpxE, and rkpI of Rhizobium sp. strain PRF 81 by common bean seed exudates is indicative of a key role in symbiosis. AB - Rhizobial surface polysaccharides (SPS) are, together with nodulation (Nod) factors, recognized as key molecules for establishment of rhizobia-legume symbiosis. In Rhizobium tropici, an important nitrogen-fixing symbiont of common bean (Phaseolus vulgaris L.), molecular structures and symbiotic roles of the SPS are poorly understood. In this study, Rhizobium sp. strain PRF 81 genes, belonging to the R. tropici group, were investigated: lpxA and lpxE, involved in biosynthesis and modification of the lipid-A anchor of lipopolysaccharide (LPS), and rkpI, involved in synthesis of a lipid carrier required for production of capsular polysaccharides (KPS). Reverse transcription quantitative PCR (RT-qPCR) analysis revealed, for the first time, that inducers released from common bean seeds strongly stimulated expression of all three SPS genes. When PRF 81 cells were grown for 48 h in the presence of seed exudates, twofold increases (p < 0.05) in the transcription levels of lpxE, lpxA, and rkpI genes were observed. However, higher increases (p < 0.05) in transcription rates, about 50-fold for lpxE and about 30-fold for lpxA and rkpI, were observed after only 5 min of incubation with common bean seed exudates. Evolutionary analyses revealed that lpxA and lpxE of PRF81 and of the type strain of R. tropici CIAT899(T)clustered with orthologous Rhizobium radiobacter and were more related to R. etli and Rhizobium leguminosarum, while rkpI was closer to the Sinorhizobium sp. group. Upregulation of lpxE, lpxA, and rkpI genes suggests that seed exudates can modulate production of SPS of Rhizobium sp. PRF81, leading to cell wall changes necessary for symbiosis establishment. PMID- 23652768 TI - Transmission dynamics of West Nile virus in mosquitoes and corvids and non corvids. AB - There are more than 300 avian species that can transmit West Nile virus (WNv). In general, the corvid and non-corvid families of birds have different responses to the virus, with corvids suffering a higher disease-induced mortality rate. By taking both corvids and non-corvids as the primary reservoir hosts and mosquitoes as vectors; we formulate and study a system of ordinary differential equations to model a single season of the transmission dynamics of WNv in the mosquito-bird cycle. We calculate the basic reproduction number and analyze the existence and stability of the equilibria. The existence of a backward bifurcation gives a further sub-threshold condition beyond the basic reproduction number for the spread of the virus. We also discuss the role of corvids and non-corvids in spreading the virus. We conclude that knowledge of the relative abundance of corvid bird species and other mammals assist us in accurate estimation of the epidemic of WNv. PMID- 23652769 TI - Severe and long-lasting hypotension occuring immediately after parathyroidectomy in hypertensive hemodialysis patients: a case series. PMID- 23652767 TI - N-acetyl-Ser-Asp-Lys-Pro inhibits interleukin-1beta-mediated matrix metalloproteinase activation in cardiac fibroblasts. AB - Myocardial matrix turnover involves a dynamic balance between collagen synthesis and degradation, which is regulated by matrix metalloproteinases (MMPs). N-acetyl Ser-Asp-Lys-Pro (Ac-SDKP) is a small peptide that inhibits cardiac inflammation and fibrosis. However, its role in MMP regulation is not known. Thus, we hypothesized that Ac-SDKP promotes MMP activation in cardiac fibroblasts and decreases collagen deposition via this mechanism. To that end, we tested the effects of Ac-SDKP on interleukin-1beta (IL-1beta; 5 ng/ml)-stimulated adult rat cardiac fibroblasts. We measured total collagenase activity, MMP-2, MMP-9, and MMP-13 expressions, and activity along with their inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. In order to examine the effects of Ac-SDKP on the signaling pathway that controls MMP transcription, we also measured nuclear factor-kappaB (NFkappaB) and p42/44 mitogen-activated protein kinase (MAPK) activation. Ac-SDKP did not alter collagenase or gelatinase activity in cardiac fibroblasts under basal conditions, but blunted the IL-1beta-induced increase in total collagenase activity. Similarly, Ac-SDKP normalized the IL 1beta-mediated increase in MMP-2 and MMP-9 activities and MMP-13 expression. Inhibition of MMPs by Ac-SDKP was associated with increased TIMP-1 and TIMP-2 expressions. Collagen production was not affected by Ac-SDKP, IL-1beta, or a combination of both agents. Ac-SDKP blocked IL-1beta-induced p42/44 phosphorylation and NFkappaB activation in cardiac fibroblasts. We concluded that the Ac-SDKP-inhibited collagenase expression and activation was associated with increased expression of TIMP-1 and TIMP-2. These pharmacological effects of Ac SDKP may be linked to the inhibition of MAPK and NFkappaB pathway. PMID- 23652770 TI - Chromosome studies of European cyprinid fishes: cross-species painting reveals natural allotetraploid origin of a Carassius female with 206 chromosomes. AB - A single female with 206 chromosomes and another 26 females with 156 chromosomes identified as Prussian carp, Carassius gibelio, and 5 individuals with 100 chromosomes identified as crucian carp, C. carassius, were sampled during field survey in one locality in the upper Elbe River. To identify the origin of females with high chromosome numbers, comparative karyotype analysis, GISH, with whole C. carassius DNA as probe and phylogenetic positions of sampled individuals revealed by cytochrome b mitochondrial marker were performed. GISH showed consistently bright labeling of 50 chromosomal elements out of 206, corresponding to the haploid chromosome number of C. carassius. The position of these females with high chromosome numbers in a reconstructed phylogenetic tree was within the clade of C. gibelio, documenting its affiliation to C. gibelio mitochondrial, i.e. maternal lineage. Our findings indicated that the mother of the female with high chromosome numbers was a gynogenetically reproducing 156-chromosome C. gibelio female and the father a bisexually reproducing C. carassius male. We, therefore, hypothesized that the C. gibelio * C. carassius allopolyploid female with 206 chromosomes arose by a mechanism of sperm genome addition to an unreduced egg of the mother. PMID- 23652771 TI - Tuning the electronic properties of an N-heterocyclic carbene by charge and mesomeric effects. AB - N-Methylation of a pyridoimidazolium salt and subsequent deprotonation afford a cationic NHC ligand. The spectroscopic characteristics of its Rh and Ir metal complexes reveal the reduced donor and enforced pi-acceptor behaviour of this ligand system. PMID- 23652773 TI - The association between osteoporosis and hypertension: the role of a low dairy intake. AB - Hypertension and related cardiovascular diseases are reported to be associated with osteoporosis. A nutritional pathway related to dairy intake has been postulated for both diseases. The aim of this study was to assess calcium intake from dairy sources as a possible pathogenic link between osteoporosis and hypertension. This was a cross-sectional observational study performed on 3,301 postmenopausal women referred for a densitometry screening. Osteoporosis was diagnosed by lumbar dual-energy X-ray absorptiometry and hypertension was defined by blood pressure data and/or the use of antihypertensive medication. Dairy food consumption was evaluated using a weekly food-frequency questionnaire. The odds of being affected by osteoporosis, hypertension, or both diseases were calculated for quartiles of dairy intake by logistic regression analyses. Women with hypertension were affected more frequently by osteoporosis (33.2 vs. 23.3 %; p = 0.000), and there was a higher prevalence of hypertension among women with osteoporosis (32.2 vs. 22.5 %; p = 0.000). The proportion of women with hypertension, osteoporosis, and both diseases significantly increased across decreasing quartiles of dairy intake. A dairy intake in the lowest quartile was a significant predictor of osteoporosis [OR (95 % CI): 1.43 (1.12, 1.82)] and hypertension [OR (95 % CI): 1.46 (1.15, 1.85)] when compared to the highest quartile. Similarly, a low dairy intake was associated with increased odds to have both the diseases [OR (95 % CI): 1.60 (1.10, 2.34)]. From these results we conclude that osteoporosis and hypertension are associated in postmenopausal women, and a low dairy intake may increase the risk of both diseases, acting as a possible pathogenic link. PMID- 23652772 TI - Gut microbiota, tight junction protein expression, intestinal resistance, bacterial translocation and mortality following cholestasis depend on the genetic background of the host. AB - Failure of the intestinal barrier is a characteristic feature of cholestasis. We have previously observed higher mortality in C57BL/6J compared with A/J mice following common bile duct ligation (CBDL). We hypothesized the alteration in gut barrier function following cholestasis would vary by genetic background. Following one week of CBDL, jejunal TEER was significantly reduced in each ligated mouse compared with their sham counterparts; moreover, jejunal TEER was significantly lower in both sham and ligated C57BL/6J compared with sham and ligated A/J mice, respectively. Bacterial translocation to mesenteric lymph nodes was significantly increased in C57BL/6J mice vs. A/J mice. Four of 15 C57BL/6J mice were bacteremic; whereas, none of the 17 A/J mice were. Jejunal IFN-gamma mRNA expression was significantly elevated in C57BL/6J compared with A/J mice. Western blot analysis demonstrated a significant decrease in occludin protein expression in C57BL/6J compared with A/J mice following both sham operation and CBDL. Only C57BL/6J mice demonstrated a marked decrease in ZO-1 protein expression following CBDL compared with shams. Pyrosequencing of the 16S rRNA gene in fecal samples showed a dysbiosis only in C57BL/6J mice following CBDL when compared with shams. This study provides evidence of strain differences in gut microbiota, tight junction protein expression, intestinal resistance and bacterial translocation which supports the notion of a genetic predisposition to exaggerated injury following cholestasis. PMID- 23652775 TI - Chrysanthemum zawadskii extract protects osteoblastic cells from highly reducing sugar-induced oxidative damage. AB - In this study, Chrysanthemum zawadskii extract (CZE) was investigated to determine its effects on 2-deoxy-D-ribose (dRib)-induced oxidative damage and cellular dysfunction in the MC3T3-E1 mouse osteoblastic cell line. Osteoblastic cells were treated with the highly reducing sugar, dRib, in the presence or absence of CZE. Cell viability, apoptosis and reactive oxygen species (ROS) production were subsequently examined. It was observed that dRib reduced cell survival, while it markedly increased the intracellular levels of ROS and apoptosis. However, pre-treatment of the cells with CZE attenuated all the dRib induced effects. The antioxidant, N-acetyl-L-cysteine (NAC), also prevented dRib induced oxidative cell damage. In addition, treatment with CZE resulted in a significant increase in alkaline phosphatase (ALP) activity and collagen content, as well as in the expression of genes associated with osteoblast differentiation [ALP, collagen, osteopontin (OPN), osteoprotegerin (OPG), bone sialoprotein (BSP), osteocalcin (OC) and bone morphogenetic protein (BMP)2, BMP4 and BMP7]. In mechanistic studies of the antioxidative potential of CZE, we found that CZE reversed the dRib-induced decrease in the expression of phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT)1 and AKT2 genes, which are master regulators of survival-related signaling pathways. CZE also upregulated the gene expression of the antioxidant enzymes, superoxide dismutase (SOD)2, SOD3 and glutathione peroxidase 4 (GPx4), which was inhibited by dRib. Taken together, these results suggest that CZE attenuates dRib-induced cell damage in osteoblastic cells and may be useful for the treatment of diabetes-associated bone disease. PMID- 23652776 TI - Impact of a dedicated enteral feeding system in an Italian NICU. AB - The inadvertent connection between an enteral feeding system and a nonenteral system such as a vascular line may occur. Intravenous administration of an enteral admixture may lead to severe, sometimes lethal, complications. We report our experience with a new set of enteral devices that may prevent any risk of misconnection. PMID- 23652777 TI - Why critically ill patients are protein deprived. PMID- 23652778 TI - Low-dose furosemide administered with adequate hydration reduces contrast-induced nephropathy in patients undergoing coronary angiography. AB - OBJECTIVE: We investigated the effects of low-dose furosemide, administered with adequate hydration on contrast-induced nephropathy (CIN). METHODS: A total of 859 patients scheduled to undergo coronary angiography or angioplasty were enrolled and randomly assigned to a furosemide treatment or control group. All patients received supplemental hydration. Immediately after surgery, patients in the furosemide group received intravenous furosemide injection (20 mg); those in the control group received no treatment. Total fluid intake and urine output were recorded. Pre- and postsurgical changes in serum creatinine levels (SCr), glomerular filtration rate (GFR) and creatinine clearance rate (CCr) were assessed, and the incidence of CIN was also evaluated between the two groups. Logistic regression analysis was used to study risk factors for CIN. RESULTS: General baseline conditions were similar between the two groups. Patients who received furosemide had significantly less increase in SCr and a more marked increase in GFR and CCr than those who did not. The incidence of CIN was significantly higher in the control group. Logistic regression analysis revealed that female gender and angiotensin-converting enzyme inhibitor were risk factors for CIN, whereas furosemide acted as a protective agent. CONCLUSIONS: With full hydration, small doses of furosemide can reduce CIN better than hydration alone. PMID- 23652779 TI - Tissue Factor Expression on Platelet Surface during Preparation and Storage of Platelet Concentrates. AB - BACKGROUND: Tissue factor (TF), the main activator of blood coagulation, is expressed on platelet surface and, together with procoagulant phospholipids, contributes to the global coagulation potential of these blood components. The present study evaluated, for the first time, the expression of TF on platelet surface during preparation and storage of platelet concentrates (PC) for transfusional use. METHODS: Platelet TF was measured by flow cytometry in healthy donor whole blood (WB) and in pooled buffy-coat-derived PC on the day of preparation and up to 4 days of storage in parallel with classical markers of platelet activation, i.e., fibrinogen, P-selectin, and glycoprotein GPIIb. Data were analyzed according to donor age and blood ABO group. RESULTS: TF was detected on whole blood platelets and was found highest in O donors. Compared to whole blood, platelet surface TF was higher upon PC preparation and further increased during storage. The rise in TF levels positively correlated with the elevations of the other platelet markers. CONCLUSIONS: Our findings show that platelet surface TF is maintained in PC obtained by the pooled buffy coat method. Further studies are warranted to investigate a possible correlation between TF levels and the hemostatic response of the platelet transfusion recipient. PMID- 23652780 TI - Fill factor in organic solar cells. AB - The fill factor (FF) is an important parameter that determines the power conversion efficiency of an organic solar cell. There are several factors that can significantly influence FF, and these factors interact with each other very intricately. Due to this reason, a deep understanding of FF is quite difficult. Based on the three fundamental elements in the solar cell equivalent circuit, namely series resistance, shunt resistance and diode, we reviews the research progress in understanding on FF in organic solar cells. Physics lying behind the often-observed undesirable S-shaped J-V curves is also summarized. This paper aims to give a brief and comprehensive summary on FF from a fundamental point of view. PMID- 23652781 TI - Treatment of psychotic and behavioral symptoms with clozapine, aripiprazole, and reboxetine in a patient with Huntington's disease. AB - We report on the successful use of a combined psychopharmacological treatment in a patient with Huntington's disease, at age 39, suffering from severe psychotic and behavioral symptoms. He presented with a schizophreniform psychosis accompanied by aggressive behavior leading to admission to the locked ward of our hospital. After unsatisfactory control of the psychiatric symptoms with olanzapine, risperidone, and amisulpride, we introduced aripiprazole. This did not affect the psychotic symptoms; however, led to an improvement in aggressive behavior, motivation, and even chorea. Accordingly, we choose not to switch medication but to add clozapine. Nevertheless, his delusions improved slightly, and further add-on treatment with reboxetine brought a further beneficial effect on motivation and activities of daily living. As chorea was not disabling in our patient, tetrabenazine has not yet been tried. Treatment was safe without any relevant side effects. PMID- 23652782 TI - The use of haplotypes in the identification of interaction between SNPs. AB - Although haplotypes can provide great insight into the complex relationships between functional polymorphisms at a locus, their use in modern association studies has been limited. This is due to our inability to directly observe haplotypes in studies of unrelated individuals, but also to the extra complexity involved in their analysis and the difficulty in identifying which is the truly informative haplotype. Using a series of simulations, we tested a number of different models of a haplotype carrying two functional single nucleotide polymorphisms (SNPs) to assess the ability of haplotypic analysis to identify functional interactions between SNPs at the same locus. We found that, when phase is known, analysis of the haplotype is more powerful than analysis of the individual SNPs. The difference between the two approaches becomes less either as an increasing number of non-informative SNPs are included, or when the haplotypic phase is unknown, while in both cases the SNP association becomes progressively better at identifying the association. Our results suggest that when novel genotyping and bioinformatics methods are available to reconstruct haplotypic phase, this will permit the emergence of a new wave of haplotypic analysis able to consider interactions between SNPs with increased statistical power. PMID- 23652783 TI - Haplotype analysis of PPARgamma C681G and intron CT variants. Positive association with essential hypertension. AB - BACKGROUND: There is strong evidence suggesting an association between the peroxisome-activated receptor gamma (PPARgamma) gene and multimetabolic disorders. The association of PPARgamma genetic variants with essential hypertension (EH) has not yet been investigated. The aim of this study was to investigate the association between the PPARgamma gene (C681G and intron CT) and EH, examining the polymorphism and haplotype in a Han Chinese population. METHODS: Participants were recruited within the framework of the PMMJS cohort population survey in an urban community of Jiangsu Province, China. Two single nucleotide polymorphisms (SNPs) previously reported to be associated with multimetabolic disorders and the reasonable coverage of the PPARgamma gene region were analyzed with TaqMan SNP genotyping assays. RESULTS: C681G and intron CT were significantly associated with an increased risk of EH both in the codominant model and the dominant model after adjusting for potential nongenetic risk factors. Analysis of the haplotype association revealed that the risk of EH was significantly increased among individuals carrying the GC (odds ratio, 95 % CI: 1.60, 1.21-2.11), CT (1.45, 1.03-2.11), and GT haplotypes (1.95, 1.17-3.23) compared with those carrying the CC haplotype. CONCLUSION: The polymorphisms of C681G and intron CT were significantly associated with the risk of EH, and the GC, CT, and GT haplotypes established by C681G and intron CT are likely to be genetic markers of EH in the Han Chinese population. PMID- 23652784 TI - Linking traffic noise, noise annoyance and life satisfaction: a case study. AB - The primary purpose of this study was to explore the link between rail and road traffic noise and overall life satisfaction. While the negative relationship between residential satisfaction and traffic noise is relatively well established, much less is known about the effect of traffic noise on overall life satisfaction. Based on results of previous studies, we propose a model that links objective noise levels, noise sensitivity, noise annoyance, residential satisfaction and life satisfaction. Since it is not clear whether a bottom-up or top-down relationship between residential satisfaction and life satisfaction holds, we specify models that incorporate both of these theoretical propositions. Empirical models are tested using structural equation modeling and data from a survey among residents of areas with high levels of road traffic noise (n1 = 354) and rail traffic noise (n2 = 228). We find that traffic noise has a negative effect on residential satisfaction, but no significant direct or indirect effects on overall life satisfaction. Noise annoyance due to road and rail traffic noise has strong negative effect on residential satisfaction rather than on overall life satisfaction. These results are very similar for the road and railway traffic contexts and regardless of whether the model assumes the top-down or bottom-up direction of the causation between life satisfaction and residential satisfaction. PMID- 23652785 TI - A microfluidic origami chip for synthesis of functionalized polymeric nanoparticles. AB - This report demonstrates a microfluidic origami chip to synthesize monodisperse, doxorubicin-loaded poly(lactic-co-glycolic acid) nanoparticles with diameters of ~100 nm, a size optimized for cellular uptake and anticancer efficacy, but difficult to achieve with existing approaches. This three-dimensional design in a microchannel may allow for the fabrication of polymeric nanoparticles in this size regime with ease. PMID- 23652787 TI - The conformational landscape of tartrate-based inhibitors of the TACE enzyme as revealed by Hamiltonian Replica Exchange simulation. AB - The inhibitors of the Tumor Necrosis Factor-alpha Converting Enzyme represent promising tools for the treatment of Rheumatoid Arthritis, Multiple Sclerosis and other autoimmune diseases. In this work, using Hamiltonian Replica Exchange Molecular Dynamics simulations and atomistic force field we perform an accurate structural characterization of a group of tartrate-based inhibitors. The simulations highlight a correlation between the conformational landscape in bulk solvent and inhibition potency. Since the structures in bulk solvent are much more compact than the crystallographic bound state, we formulate the hypothesis of a two-step docking mechanism: (i) formation of an intermediate between the compact, hydroxyl exposing conformations in solution and the catalytic zinc ion; (ii) structural rearrangement in the active site of TACE of the zinc-tethered drug in the final binding conformation. PMID- 23652786 TI - Recent advances in reconstructive surgery for bone and soft tissue sarcomas. AB - We present the current perspective on reconstructive surgery for soft tissue tumors, especially in the extremities, based on our large series. A total of 1,813 patients with bone and soft tissue sarcomas underwent surgery at our hospital between 1978 and 2011. Reconstructive operations were performed by plastic surgeons. In such reconstructive surgery, to achieve better quality of life for the patient, great effort was made not only for limb salvage but also for functional reconstruction. Although a few surgeries resulted in limb amputation due to multiple tumors, recurrence, or advanced age of the patient, the rate of limb salvage and/or functional recovery has been increasing dramatically using the method of flap surgery and vascular reconstruction. In fact, over more than 30 years, the limb salvage rate at our hospital has increased from 71.6 % around 1980 to 90.5 % around 2010. In this article, we describe our experience in plastic and reconstructive surgeries after operation for bone and soft tissue sarcomas. PMID- 23652788 TI - Effect of temozolomide on male gametes: an epigenetic risk to the offspring? AB - INTRODUCTION: Temozolomide is an oral alkylating agent with proven efficacy in recurrent high-grade glioma. The antitumour activity of this molecule is attributed to the inhibition of replication through DNA methylation. However, this methylation may also perturb other DNA-dependent processes, such as spermatogenesis. The ability to father a child may be affected by having this treatment. Here we report a pregnancy and a baby born after 6 cures of temozolomide. METHODS: The quality of gametes of the father has been studied through these cures and after the cessation of treatment. Sperm parameters, chromosomal content and epigenetic profiles of H19, MEST and MGMT have been analysed. RESULTS: Sperm counts decrease significantly and hypomethylation of the H19 locus increase with time even staying in the normal range. CONCLUSION: This is the first report of an epigenetic modification in sperm after temozolomide treatment suggesting a potential risk for the offspring. A sperm cryopreservation before the initiation of temozolomide treatment should be recommended. PMID- 23652789 TI - Product qualification: a barrier to point-of-care microfluidic-based diagnostics? AB - One of the most exciting applications of microfluidics-based diagnostics is its potential use in next generation point-of-care (POC) devices. Many prototypes are already in existence, but, as of yet, few have achieved commercialisation. In this article, we consider the issue surrounding product qualification as a potential barrier to market success. The study discusses, in the context of POC microfluidics-based diagnostics, what the generic issues are and potential solutions. Our findings underline the need for a community-based effort that is necessary to speed up the product qualification process. PMID- 23652791 TI - Ammonia does not interfere with the Diazyme adenosine deaminase test. PMID- 23652792 TI - What is a biomarker? It's time for a renewed definition. PMID- 23652790 TI - Bisphosphonate-related osteonecrosis of the jaw in non-malignant bone disease. AB - Bisphosphonates such as alendronate, risedronate and zoledronate have revolutionised the treatment for osteoporosis and Paget's disease. These drugs reduce fracture risk and probably mortality in patients with osteoporosis. However, they have a long in vivo half-life following cessation and may be associated with delayed dental healing and even the devastating complication of osteonecrosis of the jaw (ONJ). Extensive media attention highlighting this issue has caused much concern among patients and healthcare professionals. This paper seeks to provide treating clinicians with a balanced multi-disciplinary review of the available evidence pertaining to this issue and practical advice regarding prevention and management of ONJ. PMID- 23652793 TI - InterMOD: integrated data and tools for the unification of model organism research. AB - Model organisms are widely used for understanding basic biology, and have significantly contributed to the study of human disease. In recent years, genomic analysis has provided extensive evidence of widespread conservation of gene sequence and function amongst eukaryotes, allowing insights from model organisms to help decipher gene function in a wider range of species. The InterMOD consortium is developing an infrastructure based around the InterMine data warehouse system to integrate genomic and functional data from a number of key model organisms, leading the way to improved cross-species research. So far including budding yeast, nematode worm, fruit fly, zebrafish, rat and mouse, the project has set up data warehouses, synchronized data models, and created analysis tools and links between data from different species. The project unites a number of major model organism databases, improving both the consistency and accessibility of comparative research, to the benefit of the wider scientific community. PMID- 23652794 TI - Isometric contraction of Dupuytren's myofibroblasts is inhibited by blocking intercellular junctions. AB - Myofibroblasts (MFs) are responsible for both physiological wound and scar contraction. However, it is not known whether these cells act individually to contract the surrounding matrix or whether they behave in a coordinated manner. Therefore, we studied intercellular junctions of primary human MFs derived from patients with Dupuytren's disease, a fibrotic disorder of the dermis and subdermal tissues of the palm. The cells were maintained in anchored three dimensional collagen lattices to closely mimic conditions in vivo. We found that selective blockade of adherens, mechanosensitive, or gap junctions effectively inhibited contraction of the collagen matrices and downregulated the MF phenotype. Our data indicate that MFs in part function as a coordinated cellular syncytium, and disruption of intercellular communication may provide a therapeutic target in diseases characterized by an overabundance of these contractile cells. PMID- 23652795 TI - The Aryl hydrocarbon receptor is involved in UVR-induced immunosuppression. AB - UVR suppresses the immune system through the induction of regulatory T cells (Tregs). UVR-induced DNA damage has been recognized as the major molecular trigger involved, as reduction of DNA damage by enhanced repair prevents the compromise to the immune system by UVR. Nevertheless, other signaling events may also be involved. The aryl hydrocarbon receptor (AhR) was identified as another target for UVR, as UVR activates the AhR and certain UVR effects were not detected in AhR-deficient cells. We studied whether the AhR is involved in UVR induced local immunosuppression and whether similar effects can be induced by AhR agonists. The AhR antagonist 3-methoxy-4-nitroflavone reduced UVR-mediated immunosuppression and the induction of Tregs in murine contact hypersensitivity (CHS). Conversely, activation of the AhR by the agonist 4-n-nonylphenol (NP) suppressed the induction of CHS and induced antigen-specific Tregs similar to UVR. This was further confirmed in AhR knockout mice in which UVR- and NP-induced immunosuppression were significantly reduced. Together, this indicates that the AhR is involved in mediating UVR-induced immunosuppression. Activation of the AhR might represent an alternative to modulate the immune system in a similar manner like UVR but without causing the adverse effects of UVR, including DNA damage. PMID- 23652796 TI - Plakoglobin as a regulator of desmocollin gene expression. AB - Desmosomes are cell adhesion junctions required for the normal development and maintenance of mammalian tissues and organs such as the skin, skin appendages, and the heart. The goal of this study was to investigate how desmocollins (DSCs), transmembrane components of desmosomes, are regulated at the transcriptional level. We hypothesized that differential expression of the Dsc2 and Dsc3 genes is a prerequisite for normal development of skin appendages. We demonstrate that plakoglobin (Pg) in conjunction with lymphoid enhancer-binding factor 1 (Lef-1) differentially regulates the proximal promoters of these two genes. Specifically, we found that Lef-1 acts as a switch activating Dsc2 and repressing Dsc3 in the presence of Pg. Interestingly, we also determined that NF-kappaB pathway components, the downstream effectors of the ectodysplasin-A (EDA)/ ectodysplasin A receptor (EDAR)/NF-kappaB signaling cascade, can activate Dsc2 expression. We hypothesize that Lef-1 and EDA/EDAR/NF-kappaB signaling contribute to a shift in Dsc isoform expression from Dsc3 to Dsc2 in placode keratinocytes. It is tempting to speculate that this shift is required for the invasive growth of placode keratinocytes into the dermis, a crucial step in skin appendage formation. PMID- 23652798 TI - Myosin-Va contributes to manifestation of malignant-related properties in melanoma cells. PMID- 23652797 TI - Indoleamine 2,3-dioxygenase activity contributes to local immune suppression in the skin expressing human papillomavirus oncoprotein e7. AB - Chronic infection of anogenital epithelium with human papillomavirus (HPV) promotes development of cancer. Many pathogens evoke immunosuppressive mechanisms to enable persistent infection. We have previously shown that grafted skin expressing HPV16 E7 oncoprotein from a keratin-14 promoter (K14E7) is not rejected by a syngeneic, immunocompetent host. In this study we show that indoleamine 2,3-dioxygenase (IDO) 1, an IFN-gamma-inducible immunoregulatory molecule, is more highly expressed by langerin(-ve) dermal dendritic cells (DCs) from K14E7 skin than nontransgenic control skin. Furthermore, inhibiting IDO activity using 1-methyl-dl-tryptophan (1-D/L-MT) promotes K14E7 skin graft rejection. Increased IDO1 expression and activity in K14E7 skin requires IFN gamma and invariant natural killer T (iNKT) cells, both of which have been shown to negatively regulate T-cell effector function and suppress K14E7 graft rejection. Furthermore, DCs from K14E7 skin express higher levels of IFN-gamma receptor (IFN-gammaR) than DCs from control skin. K14E7 transgenic skin recruits significantly higher numbers of DCs, independent of IFN-gamma and IFN-gammaR expression. Consistent with these observations in a murine model, we found higher expression of IDO1 and IFN-gamma but not IDO2 in the cervical epithelium of patients with HPV-associated cervical intraepithelial neoplasia (CIN) 2/3. Our data support a hypothesis that induction of IDO1 in HPV-infected skin contributes to evasion of host immunity. PMID- 23652799 TI - Analysis of nucleotide diversity among alleles of the major bacterial blight resistance gene Xa27 in cultivars of rice (Oryza sativa) and its wild relatives. AB - Xa27 is one of the important R-genes, effective against bacterial blight disease of rice caused by Xanthomonas oryzae pv. oryzae (Xoo). Using natural population of Oryza, we analyzed the sequence variation in the functionally important domains of Xa27 across the Oryza species. DNA sequences of Xa27 alleles from 27 rice accessions revealed higher nucleotide diversity among the reported R-genes of rice. Sequence polymorphism analysis revealed synonymous and non-synonymous mutations in addition to a number of InDels in non-coding regions of the gene. High sequence variation was observed in the promoter region including the 5'UTR with 'pi' value 0.00916 and 'theta w ' = 0.01785. Comparative analysis of the identified Xa27 alleles with that of IRBB27 and IR24 indicated the operation of both positive selection (Ka/Ks > 1) and neutral selection (Ka/Ks ~ 0). The genetic distances of alleles of the gene from Oryza nivara were nearer to IRBB27 as compared to IR24. We also found the presence of conserved and null UPT (upregulated by transcriptional activator) box in the isolated alleles. Considerable amino acid polymorphism was localized in the trans-membrane domain for which the functional significance is yet to be elucidated. However, the absence of functional UPT box in all the alleles except IRBB27 suggests the maintenance of single resistant allele throughout the natural population. PMID- 23652800 TI - Fibronectin is essential for reparative cardiac progenitor cell response after myocardial infarction. AB - RATIONALE: Adoptive transfer of cardiac progenitor cells (CPCs) has entered clinical application, despite limited mechanistic understanding of the endogenous response after myocardial infarction (MI). Extracellular matrix undergoes dramatic changes after MI and therefore might be linked to CPC-mediated repair. OBJECTIVE: To demonstrate the significance of fibronectin (Fn), a component of the extracellular matrix, for induction of the endogenous CPC response to MI. METHODS AND RESULTS: This report shows that presence of CPCs correlates with the expression of Fn during cardiac development and after MI. In vivo, genetic conditional ablation of Fn blunts CPC response measured 7 days after MI through reduced proliferation and diminished survival. Attenuated vasculogenesis and cardiogenesis during recovery were evident at the end of a 12-week follow-up period. Impaired CPC-dependent reparative remodeling ultimately leads to continuous decline of cardiac function in Fn knockout animals. In vitro, Fn protects and induces proliferation of CPCs via beta1-integrin-focal adhesion kinase-signal transducer and activator of transcription 3-Pim1 independent of Akt. CONCLUSIONS: Fn is essential for endogenous CPC expansion and repair required for stabilization of cardiac function after MI. PMID- 23652801 TI - Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension. AB - RATIONALE: Mitochondrial signaling regulates both the acute and the chronic response of the pulmonary circulation to hypoxia, and suppressed mitochondrial glucose oxidation contributes to the apoptosis-resistance and proliferative diathesis in the vascular remodeling in pulmonary hypertension. Hypoxia directly inhibits glucose oxidation, whereas endoplasmic reticulum (ER)-stress can indirectly inhibit glucose oxidation by decreasing mitochondrial calcium (Ca2+m levels). Both hypoxia and ER stress promote proliferative pulmonary vascular remodeling. Uncoupling protein 2 (UCP2) has been shown to conduct calcium from the ER to mitochondria and suppress mitochondrial function. OBJECTIVE: We hypothesized that UCP2 deficiency reduces Ca2+m in pulmonary artery smooth muscle cells (PASMCs), mimicking the effects of hypoxia and ER stress on mitochondria in vitro and in vivo, promoting normoxic hypoxia inducible factor-1alpha activation and pulmonary hypertension. METHODS AND RESULTS: Ucp2 knockout (KO)-PASMCs had lower mitochondrial calcium than Ucp2 wildtype (WT)-PASMCs at baseline and during histamine-stimulated ER-Ca2+ release. Normoxic Ucp2KO-PASMCs had mitochondrial hyperpolarization, lower Ca2+-sensitive mitochondrial enzyme activity, reduced levels of mitochondrial reactive oxygen species and Krebs' cycle intermediates, and increased resistance to apoptosis, mimicking the hypoxia-induced changes in Ucp2WT-PASMC. Ucp2KO mice spontaneously developed pulmonary vascular remodeling and pulmonary hypertension and exhibited a pseudohypoxic state with pulmonary vascular and systemic hypoxia inducible factor-1alpha activation (increased hematocrit), not exacerbated further by chronic hypoxia. CONCLUSIONS: This first description of the role of UCP2 in oxygen sensing and in pulmonary hypertension vascular remodeling may open a new window in biomarker and therapeutic strategies. PMID- 23652802 TI - A distinct evolution of the T-cell repertoire categorizes treatment refractory gastrointestinal acute graft-versus-host disease. AB - Steroid refractory gastrointestinal (GI) acute graft-versus-host disease (aGVHD) is a major cause of mortality in hematopoietic stem cell transplantation (HCT) without immune markers to establish a diagnosis or guide therapy. We found that T cell receptor beta (TCRbeta) complementarity-determining region 3 repertoire sequencing reveals patterns that could eventually serve as a disease biomarker of T-cell alloreactivity in aGVHD. We identified T-cell clones in GI biopsies in a heterogeneous group of 15 allogeneic HCT patients with GI aGVHD symptoms. Seven steroid-refractory aGVHD patients showed a more conserved TCRbeta clonal structure between different biopsy sites in the GI tract than 8 primary therapy responsive patients. Tracking GI clones identified longitudinally at endoscopy in the blood also revealed an increased clonal expansion in patients with steroid refractory disease. Immune repertoire sequencing-based methods could enable a novel personalized way to guide diagnosis and therapy in diseases where T-cell activity is a major determinant. PMID- 23652803 TI - Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia. AB - The pharmacogenetics of methotrexate (MTX) was investigated in a large cohort of pediatric patients with acute lymphoblastic leukemia (ALL). Four hundred ninety nine children with ALL from the ALL-BFM (Berlin-Frankfurt-Munster) 2000 trial who received 1996 courses of MTX at 5 g/m(2) were genotyped for 8 single nucleotide polymorphisms in 5 candidate genes of the MTX/folate pathway. Patients' MTX pharmacokinetics, MTX toxicities, and outcomes were correlated with the genotypes. The interindividual variability in MTX kinetics had a substantial genetic component between 68% and 75%. The SLCO1B1 rs4149056 variant was significantly associated with MTX kinetics. In a multiple regression model, MTX area under the concentration time curve (AUC)0-48h increased by 26% (P < .001) per SLCO1B1 rs4149056 C allele. MTX AUC0-48h was a significant predictor of overall toxic adverse events during MTX courses (R(2) = 0.043; P < .001), whereas the thymidylate synthase rs34743033 tandem repeat polymorphism was predictive of stomatitis (R(2) = 0.018; P = .009), a frequent side effect of high-dose MTX. Multiple Cox regression analyses revealed an association of minimal residual disease (hazard ratio 7.3; P < .001) and methylenetetrahydrofolate reductase rs1801131 (hazard ratio 3.1; P = .015) with event-free survival in the ALL-BFM 2000 study population. Genetic variations substantially influence the kinetics and response to high-dose MTX therapy in childhood ALL. PMID- 23652805 TI - How I treat NK/T-cell lymphomas. AB - Natural killer (NK)/T-cell lymphomas and NK-cell leukemias are aggressive malignancies. Occurring worldwide, they show a predilection for Asian and South American populations. Neoplastic cells are surface CD3-, cytoplasmic CD3epsilon+, CD56+, cytotoxic-molecule positive, Epstein-Barr virus (EBV) positive, with germline T-cell receptor gene. Lymphomas occur commonly in the nasal and upper aerodigestive region. Occasional cases present in the skin, salivary gland, testis, and gastrointestinal tract. Rare cases are disseminated with lymphadenopathy, hepatosplenomegaly, and a leukemic phase. Positron emission tomography computed tomography is useful in staging, as lymphomas are 18 fluorodeoxyglucose avid. Quantification of circulating EBV DNA is an accurate biomarker of tumor load. Nasal NK/T-cell lymphomas present mostly with stage I/II disease. Concomitant/sequential chemotherapy and radiotherapy is standard treatment. Radiotherapy alone is inadequate because of high systemic failure rate. For stage III/IV nasal, nonnasal, and disseminated lymphomas, systemic chemotherapy is indicated. Regimens containing l-asparaginase and drugs unaffected by P-glycoprotein are most effective. Hematopoietic stem cell transplantation (HSCT) is not indicated for early-stage nasal lymphomas. HSCT for lymphomas not in remission has poor results. In advanced-stage nasal, nonnasal, disseminated, or relapsed lymphomas, HSCT may be considered when remission is achieved. Prognostic modeling and EBV DNA monitoring may be useful in risk stratification for HSCT. PMID- 23652804 TI - The microenvironment of AIDS-related diffuse large B-cell lymphoma provides insight into the pathophysiology and indicates possible therapeutic strategies. AB - Despite the use of highly active antiretroviral therapy (HAART), AIDS-related lymphoma remains common. We investigated the tumor, microenvironment, and viral components in 41 AIDS-related diffuse large B-cell lymphomas (AR-DLBCLs) in the pre- and post-HAART era. The outcome has improved and the frequency of the prognostically unfavorable immunoblastic histology has decreased after HAART. Compared with sporadic cases, AR-DLBCL demonstrated increased hyperproliferation (P < .001) and c-Myc rearrangements, reduced CD4(+) (P < .001) and FOXP3(+) T cells (P < .001), increased activated cytotoxic cells (P < .001), but no difference in tumor-associated macrophages. Our analysis showed that AR-DLBCL is highly angiogenic with higher blood-vessel density than sporadic cases (P < .001) and highlighted the role of Epstein-Barr virus in angiogenesis. We recognized viral profiles and as a second step examined the reactive cytotoxic cell infiltrates. Our observation of markedly higher numbers of cytotoxic cells in AR DLBCL with LMP1 and/or p24 compared with cases lacking viral antigens (P < .001) has important clinical implications, implicitly linked to the immunosurveillance theory. Whereas early initiation of HAART should improve immunosurveillance and reduce the incidence of LMP1-positive AR-DLBCL, cases without viral antigens appear able to avoid immunologic reaction and likely require additional strategies to improve surveillance. PMID- 23652806 TI - Activated platelets can deliver mRNA regulatory Ago2*microRNA complexes to endothelial cells via microparticles. AB - Platelets play a crucial role in the maintenance of hemostasis, as well as in thrombosis. Upon activation, platelets release small membrane-bound microparticles (MPs) containing bioactive proteins and genetic materials from their parental cells that may be transferred to, and exert potent biological effects in, recipient cells of the circulatory system. Platelets have been shown to contain an abundant and diverse array of microRNAs, and platelet-derived MPs are the most abundant microvesicles in the circulation. Here we demonstrate that human platelets activated with thrombin preferentially release their miR-223 content in MPs. These MPs can be internalized by human umbilical vein endothelial cells (HUVEC), leading to the accumulation of platelet-derived miR-223. Platelet MPs contain functional Argonaute 2 (Ago2)*miR-223 complexes that are capable of regulating expression of a reporter gene in recipient HUVEC. Moreover, we demonstrate a role for platelet MP-derived miR-223 in the regulation of 2 endogenous endothelial genes, both at the messenger RNA and protein levels. Our results support a scenario by which platelet MPs may act as intercellular carriers of functional Ago2*microRNA complexes that may exert heterotypic regulation of gene expression in endothelial cells, and possibly other recipient cells of the circulatory system. PMID- 23652807 TI - Directed neuronal differentiation of mouse embryonic and induced pluripotent stem cells and their gene expression profiles. AB - Embryonic stem cells (ESCs) may be useful as a therapeutic source of cells for the production of healthy tissue; however, they are associated with certain challenges including immunorejection as well as ethical issues. Induced pluripotent stem cells (iPSCs) are a promising substitute since a patient's own adult cells would serve as tissue precursors. Ethical concerns prevent a full evaluation of the developmental potency of human ESCs and iPSCs, therefore, mouse iPSC models are required for protocol development and safety assessments. We used a modified culturing protocol to differentiate pluripotent cells from a mouse iPS cell line and two mouse ES cell lines into neurons. Our results indicated that all three pluripotent stem cell lines underwent nearly the same differentiation process when induced to form neurons in vitro. Genomic expression microarray profiling and single-cell RT-qPCR were used to analyze the neural lineage differentiation process, and more than one thousand differentially expressed genes involved in multiple molecular processes relevant to neural development were identified. PMID- 23652808 TI - Clinically relevant effect of a new intranasal therapy (MP29-02) in allergic rhinitis assessed by responder analysis. AB - BACKGROUND: It is unclear what constitutes a clinically meaningful response for allergic rhinitis (AR) outcomes. The objectives of these post hoc analyses were (1) to define a clinically meaningful response using novel efficacy analyses (including a responder analysis), and (2) to compare the efficacy of MP29-02 [a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP)] with commercially available FP, AZE and placebo in seasonal AR (SAR) patients, using these novel analyses. METHODS: 610 moderate-to-severe SAR patients (>=12 years old) were randomized into a double-blind, placebo controlled, 14-day, parallel-group trial. Change from baseline in the reflective total nasal symptom score (rTNSS) over 14 days was the primary outcome. Post hoc endpoints included the sum of nasal and ocular symptoms (rT7SS), efficacy by disease severity and by predominant nasal symptom, and a set of responder analyses. RESULTS: MP29-02 most effectively reduced rT7SS (relative greater improvement: 52% to FP; 56% to AZE) and both nasal and ocular symptoms irrespective of severity. More MP29-02 patients achieved a >=30, >=50, >=60, >=75 and >=90% rTNSS reduction, which occurred days faster than with either active comparator; MP29-02 alone was superior to placebo at the >=60% (or higher) threshold. One in 2 MP29-02 patients achieved a >=50% rTNSS reduction and 1 in 6 achieved complete/near-to-complete response. Only MP29-02 was consistently superior to placebo for all patients, whatever their predominant symptom. CONCLUSIONS: MP29-02 provided faster and more complete symptom control than first line therapies. It was consistently superior irrespective of severity, response criteria or patient-type, and may be considered the drug of choice for moderate to-severe AR. These measures define a new standard for assessing relevance in AR. PMID- 23652809 TI - Attenuating gene expression (AGE) for vaccine development. AB - Live attenuated vaccines are adept in stimulating protective immunity. Methods for generating such vaccines have largely adopted strategies used with Salmonella enterica. Yet, when similar strategies were tested in other gram-negative bacteria, the virulence factors or genes responsible to incapacitate Salmonella often failed in providing the desired outcome. Consequently, conventional live vaccines rely on prior knowledge of the pathogen's virulence factors to successfully attenuate them. This can be problematic since such bacterial pathogens normally harbor thousands of genes. To circumvent this problem, we found that overexpression of bacterial appendages, e.g., fimbriae, capsule, and flagella, could successfully attenuate wild-type (wt) Salmonella enterica serovar Typhimurium. Further analysis revealed these attenuated Salmonella strains conferred protection against wt S. Typhimurium challenge as effectively as genetically defined Salmonella vaccines. We refer to this strategy as attenuating gene expression (AGE), a simple efficient approach in attenuating bacterial pathogens, greatly facilitating the construction of live vaccines. PMID- 23652810 TI - In vitro targeted gene electrotransfer to endothelial cells with plasmid DNA containing human endothelin-1 promoter. AB - Development of recombinant DNA technologies has allowed us to create new delivery systems that target specific cell types and that can be used in gene therapy. One of these targets is vascular endothelium because of its important role in tumor angiogenesis. For tumor endothelium-specific targeting, we prepared plasmid DNA encoding green fluorescent protein under the control of human endothelin-1 promoter (pENDO-EGFP), which is specific for endothelial cells. First we determined gene electrotransfer parameters for improved transfection of endothelial cells evaluating different osmolarity of electroporation buffer, voltages of applied electric pulses, and addition of fetal bovine serum immediately after electroporation to the cells for improved transfection and survival. Transfection efficacy of pENDO-EGFP in different endothelial and nonendothelial cell lines was determined next. Gene electrotransfer efficacy was evaluated using three different methods: fluorescence microscopy, fluorescence microplate reader, and flow cytometry. Our results showed that transfection efficacy was higher when cells were prepared in hypoosmolar compared to isoosmolar electroporation buffer. Furthermore, immediate addition of fetal bovine serum to the cells after pulsing also improved gene electrotransfer into target cells. We proved expression of EGFP under the control of human endothelin 1 promoter in endothelial cells, which was also significantly higher compared to nonendothelial cells. Taken together, we successfully constructed pENDO-EGFP, which was specifically expressed in endothelial cells using improved gene electrotransfer parameters. PMID- 23652811 TI - Statistical assessment of change point detectors for single molecule kinetic analysis. AB - Change point detectors (CPDs) are used to segment recordings of single molecules for the purpose of kinetic analysis. The assessment of the accuracy of CPD algorithms has usually been based on testing them with simulated data. However, there have not been methods to assess the output of CPDs from real data independent of simulation. Here we present one method to do this based on the assumption that the elementary kinetic unit is a stationary period (SP) with a normal distribution of samples, separated from other SPs by change points (CPs). Statistical metrics of normality can then be used to assess SPs detected by a CPD algorithm (detected SPs, DSPs). Two statistics in particular were found to be useful, the z-transformed skew (S(Z)) and z-transformed kurtosis (K(Z)). K(Z)(S(Z)) plots of DSP from noise, simulated data and single ion channel recordings showed that DSPs with false negative CP could be distinguished. Also they showed that filtering had a significant effect on the normality of data and so filtering should be taken into account when calculating statistics. This method should be useful for analyzing single molecule recordings where there is no simple model for the data. PMID- 23652812 TI - Enzymeless multi-sugar fuel cells with high power output based on 3D graphene Co3O4 hybrid electrodes. AB - Biofuel cells (BFCs), which use enzymes as catalysts to harvest energy from green and sustainable fuels abundantly producible from biological systems, are promising next-generation energy devices. However, the poor stability and high specificity to only one fuel type of these bio-catalysts largely limits the practical use of current BFCs. In this contribution, we demonstrate a unique fuel cell which, equipped with two identical enzyme-free electrodes based on Co3O4 coated 3D graphene, is able to efficiently harvest electricity from various sweet biofuels (glucose, sucrose, or lactose). Taking advantage of the dual catalytic ability of nanostructured Co3O4 for both glucose oxidation and oxygen reduction as well as the exceptional electrical and structural properties of 3D graphene, our glucose-powered fuel cell, with good long-term stability, offers high open circuit voltage (~1.1 V) and power density output (2.38 +/- 0.17 mW cm(-2)). PMID- 23652813 TI - Water infusion versus air insufflation for colonoscopy: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The aim of this meta-analysis was to determine whether water infusion colonoscopy (WIC) is a more effective diagnostic tool than standard air insufflation colonoscopy (AIC). METHODS: All articles pertinent to a comparison of water-related methods and air insufflation to facilitate insertion of the colonoscope were retrieved from PubMed, Web of Science, Embase, and Cochrane databases. Pooling results were derived by using the Review Manager Software. Outcomes were assessed using the weighted mean difference (MD) with 95 % confidence intervals (CI) for continuous variables and the odds ratios (OR) with 95 % CI for dichotomous variables. RESULTS: Eighteen studies involving 2,797 patients were included. WIC was associated with a significantly higher cecal intubation rate than AIC (OR = 1.90; 95 % CI 1.21-2.99; p = 0.005). The intubation time was similar for the two types of colonoscopy, but in WIC there was a significantly lower visual analog scale score for abdominal pain than in AIC (MD = -1.30; 95 % CI -2.03 to -0.58; p < 0.001) without sacrificing the polyp detection rate (OR = 1.17; 95 % CI 0.78-1.77; p = 0.44). Statistically, the patient's willingness to repeat colonoscopy was significantly greater for WIC than for AIC (OR = 1.74; 95 % CI 1.14-2.67; p < 0.01). Furthermore, in the subgroup for trainees, the WIC group achieved a higher cecal intubation rate (OR = 1.83; 95 % CI 1.15-2.93; p = 0.01) and a shorter intubation time (MD = -1.72 min; 95 % CI -3.34 to -0.11; p = 0.04) than the AIC group. CONCLUSIONS: In contrast to AIC, WIC improved cecal intubation, alleviated abdominal pain, and increased patients' willingness to repeat the procedure. PMID- 23652814 TI - Interdependence of linguistic and indexical speech perception skills in school age children with early cochlear implantation. AB - OBJECTIVES: This study documented the ability of experienced pediatric cochlear implant (CI) users to perceive linguistic properties (what is said) and indexical attributes (emotional intent and talker identity) of speech, and examined the extent to which linguistic (LSP) and indexical (ISP) perception skills are related. Preimplant-aided hearing, age at implantation, speech processor technology, CI-aided thresholds, sequential bilateral cochlear implantation, and academic integration with hearing age-mates were examined for their possible relationships to both LSP and ISP skills. DESIGN: Sixty 9- to 12-year olds, first implanted at an early age (12 to 38 months), participated in a comprehensive test battery that included the following LSP skills: (1) recognition of monosyllabic words at loud and soft levels, (2) repetition of phonemes and suprasegmental features from nonwords, and (3) recognition of key words from sentences presented within a noise background, and the following ISP skills: (1) discrimination of across-gender and within-gender (female) talkers and (2) identification and discrimination of emotional content from spoken sentences. A group of 30 age matched children without hearing loss completed the nonword repetition, and talker- and emotion-perception tasks for comparison. RESULTS: Word-recognition scores decreased with signal level from a mean of 77% correct at 70 dB SPL to 52% at 50 dB SPL. On average, CI users recognized 50% of key words presented in sentences that were 9.8 dB above background noise. Phonetic properties were repeated from nonword stimuli at about the same level of accuracy as suprasegmental attributes (70 and 75%, respectively). The majority of CI users identified emotional content and differentiated talkers significantly above chance levels. Scores on LSP and ISP measures were combined into separate principal component scores and these components were highly correlated (r = 0.76). Both LSP and ISP component scores were higher for children who received a CI at the youngest ages, upgraded to more recent CI technology and had lower CI aided thresholds. Higher scores, for both LSP and ISP components, were also associated with higher language levels and mainstreaming at younger ages. Higher ISP scores were associated with better social skills. CONCLUSIONS: Results strongly support a link between indexical and linguistic properties in perceptual analysis of speech. These two channels of information appear to be processed together in parallel by the auditory system and are inseparable in perception. Better speech performance, for both linguistic and indexical perception, is associated with younger age at implantation and use of more recent speech processor technology. Children with better speech perception demonstrated better spoken language, earlier academic mainstreaming, and placement in more typically sized classrooms (i.e., >20 students). Well-developed social skills were more highly associated with the ability to discriminate the nuances of talker identity and emotion than with the ability to recognize words and sentences through listening. The extent to which early cochlear implantation enabled these early implanted children to make use of both linguistic and indexical properties of speech influenced not only their development of spoken language, but also their ability to function successfully in a hearing world. PMID- 23652815 TI - Catalyst-controlled switchable phosphination of alpha-diazoesters. AB - Organocatalyst and metal provide different products: a catalyst-controlled switchable phosphination of alpha-diazoesters has been developed by using DBU and copper as catalysts. It provided an efficient synthetic method for the construction of various phosphorus compounds via the formation of N-P and C-P bonds. PMID- 23652816 TI - Tracking chromosome evolution in southern African gerbils using flow-sorted chromosome paints. AB - Desmodillus and Gerbilliscus (formerly Tatera) comprise a monophyletic group of gerbils (subfamily Gerbillinae) which last shared an ancestor approximately 8 million years ago; diploid chromosome number variation among the species ranges from 2n = 36 to 2n = 50. In an attempt to shed more light on chromosome evolution and speciation in these rodents, we compared the karyotypes of 7 species, representing 3 genera, based on homology data revealed by chromosome painting with probes derived from flow-sorted chromosomes of the hairy footed gerbil, Gerbillurus paeba (2n = 36). The fluorescent in situ hybridization data revealed remarkable genome conservation: these species share a high proportion of conserved chromosomes, and differences are due to 10 Robertsonian (Rb) rearrangements (3 autapomorphies, 3 synapomorphies and 4 hemiplasies/homoplasies). Our data suggest that chromosome evolution in Desmodillus occurred at a rate of ~1.25 rearrangements per million years (Myr), and that the rate among Gerbilliscus over a time period spanning 8 Myr is also ~1.25 rearrangements/Myr. The recently diverged Gerbillurus (G. tytonis and G. paeba) share an identical karyotype, while Gerbilliscus kempi, G. afra and G. leucogaster differ by 6 Rb rearrangements (a rate of ~1 rearrangement/Myr). Thus, our data suggests a very slow rate of chromosomal evolution in Southern African gerbils. PMID- 23652817 TI - Analysis of the molecular interactions governing the polymorphism of benzamide--a guide to syntheses? AB - Dispersion-corrected density functional calculations are used to rationalize the subtle differences in the molecular interactions in benzamide crystals. The potential energy of the different polymorph structures is dominated by the interplay between intermolecular attraction and molecular torsion/deformation to accommodate favourable molecular packing. Using suitable proxies arranged in pseudo-crystalline setups we discriminate the contribution of hydrogen bonding, pi-pi interactions and intra-molecular interactions to the lattice energies of the most relevant (P1 and P3) benzamide polymorphs. Strikingly, these commonly anticipated binding/packing concepts cannot account for the observed ranking of benzamide structures, thus hinting at the importance of the interactions between the benzene rings and the polar amide groups. Moreover, individual structural motifs that account for the competition between the two crystal structure types are elaborated. On the basis of such in-depth understanding of molecular interactions - in terms of both structure and chemistry - we suggest nucleation scenarios as guides to a more controlled synthesis of the stable P1 form or to direct nucleation in favour of the P3 polymorph. PMID- 23652818 TI - Molecular cloning and expression of five glutathione S-transferase (GST) genes from Banana (Musa acuminata L. AAA group, cv. Cavendish). AB - KEY MESSAGE: Three tau class MaGSTs responded to abiotic stress, MaGSTF1 and MaGSTL1 responded to signaling molecules, they may play an important role in the growth of banana plantlet. Glutathione S-transferases (GST) are multifunctional detoxification enzymes that participate in a variety of cellular processes, including stress responses. In this study, we report the molecular characteristics of five GST genes (MaGSTU1, MaGSTU2, MaGSTU3, MaGSTF1 and MaGSTL1) cloned from banana (Musa acuminate L. AAA group, cv. Cavendish) using a RACE-PCR-based strategy. The predicted molecular masses of these GSTs range from 23.4 to 27.7 kDa and their pIs are acidic. At the amino acid level, they share high sequence similarity with GSTs in the banana DH-Pahang (AA group) genome. Phylogenetic analysis showed that the deduced amino acid sequences of MaGSTs also have high similarity to GSTs of other plant species. Expression analysis by semi quantitative RT-PCR revealed that these genes are differentially expressed in various tissues. In addition, their expression is regulated by various stress conditions, including exposure to signaling molecules, cold, salinity, drought and Fusarium oxysporum f specialis(f. Sp) cubense Tropical Race 4 (Foc TR4) infection. The expression of the tau class MaGSTs (MaGSTU1, MaGSTU2 and MaGSTU3) mainly responded to cold, salinity and drought while MaGSTF1 and MaGSTL1 expressions were upregulated by signaling molecules. Our findings suggest that MaGSTs play a key role in both development and abiotic stress responses. PMID- 23652819 TI - Ectopic expression of bacterial amylopullulanase enhances bioethanol production from maize grain. AB - KEY MESSAGE: Heterologous expression of amylopullulanase in maize seeds leads to partial starch degradation into fermentable sugars, which enhances direct bioethanol production from maize grain. Utilization of maize in bioethanol industry in the United States reached +/-13.3 billion gallons in 2012, most of which was derived from maize grain. Starch hydrolysis for bioethanol industry requires the addition of thermostable alpha amylase and amyloglucosidase (AMG) enzymes to break down the alpha-1,4 and alpha-1,6 glucosidic bonds of starch that limits the cost effectiveness of the process on an industrial scale due to its high cost. Transgenic plants expressing a thermostable starch-degrading enzyme can overcome this problem by omitting the addition of exogenous enzymes during the starch hydrolysis process. In this study, we generated transgenic maize plants expressing an amylopullulanase (APU) enzyme from the bacterium Thermoanaerobacter thermohydrosulfuricus. A truncated version of the dual functional APU (TrAPU) that possesses both alpha amylase and pullulanase activities was produced in maize endosperm tissue using a seed-specific promoter of 27-kD gamma zein. A number of analyses were performed at 85 degrees C, a temperature typically used for starch processing. Firstly, enzymatic assay and thin layer chromatography analysis showed direct starch hydrolysis into glucose. In addition, scanning electron microscopy illustrated porous and broken granules, suggesting starch autohydrolysis. Finally, bioethanol assay demonstrated that a 40.2 +/- 2.63 % (14.7 +/- 0.90 g ethanol per 100 g seed) maize starch to ethanol conversion was achieved from the TrAPU seeds. Conversion efficiency was improved to reach 90.5 % (33.1 +/- 0.66 g ethanol per 100 g seed) when commercial amyloglucosidase was added after direct hydrolysis of TrAPU maize seeds. Our results provide evidence that enzymes for starch hydrolysis can be produced in maize seeds to enhance bioethanol production. PMID- 23652821 TI - Trabectedin in metastatic soft tissue sarcomas: Role of pretreatment and age. AB - Trabectedin has mostly been studied in metastatic leiomyosarcoma and liposarcomas. Only limited data are available in other sarcoma subtypes, heavily pretreated and elderly patients. We retrospectively analyzed 101 consecutive sarcoma patients treated with trabectedin at our center. We recorded progression free survival (PFS), clinical benefit rate (CBR, defined as complete or partial response or stable disease for at least 6 weeks) and toxicity. Covariates were sarcoma subtype, age and pretreatment. On average, trabectedin was administered for 2nd relapse/progression (range 1st to 12th line). A median of 2 cycles and a dose of 1.5 mg/m2 (range 1-21 cycles; 1.3-1.5 mg/m2) was administered. The median PFS under treatment with trabectedin was 2.1 months in the overall population. Different clinical outcomes were observed with respect to sarcoma subtypes: in patients with L-sarcoma [defined as leiosarcoma and liposarcoma (n=25)] the CBR was 55%. Notably, long lasting remissions were even observed in 7th-line treatment. In contrast, the majority of patients with non-L-sarcomas quickly progressed (median PFS 1.6 months). Nevertheless, a CBR of 34% was achieved, including long-lasting disease stabilization in subtypes such as rhabdomyosarcoma. Patients treated with trabectedin at 1st or 2nd line (n=16) achieved an improved PFS (median 5.7 months, range) and a CBR of 59%. No differences in terms of toxicity or efficacy were observed between patients older than 65 years (n=23) and younger patients (n=78). In this non-trial setting, port associated complications were more frequent (14%) with trabectedin compared to other continuous infusion protocols administered at our outpatient therapy center. The majority of patients with relapsing L-sarcomas and a substantial fraction of patients with non-L-sarcomas derive a clinically meaningful benefit from trabectedin. Outpatient treatment is well tolerated also in elderly and heavily pretreated patients. Port-associated complications were observed at an unusually high rate. This suggests a drug-specific local toxicity that merits further investigation. PMID- 23652820 TI - Transcriptome profiling reveals differential transcript abundance in response to chilling stress in Populus simonii. AB - KEY MESSAGE: We report global gene expression patterns of poplar in response to chilling stress. A total of 1,085 significantly differentially expressed genes, involved in photosynthesis, signal transduction, and regulation of transcription, were identified. To understand the gene network underlying the response to chilling stress in the poplar, Populus simonii, we determined the genome transcript expression profile using an Affymetrix GeneChip with 56,000 genes. Our results revealed 11,626 cold-responsive genes, with 5,267 upregulated and 6,359 downregulated. In terms of biological processes, gene ontology (GO) analysis indicated that cold-induced genes were enriched in response to temperature stimulus, reactive oxygen species, and hormone stimulus. GO terms including cellular nitrogen compound metabolic processes, photosynthesis, and generation of precursor metabolites and energy were enriched in the cold-repressed genes. The functional annotation of differentially expressed genes revealed genes involved in photosynthesis, calcium/calmodulin-mediated signal transduction, abscisic acid (ABA) homeostasis and transport, and antioxidant defense systems. Gene expression analysis showed that the majority of genes involved in photosynthesis were repressed, but the THF1 gene was induced, suggesting that it may play an important role in the production of vesicles for leaf development under low temperature conditions. Several genes involved in calcium/calmodulin-mediated signal transduction, ABA homeostasis and transport, and antioxidant defense systems were significantly induced under chilling stress, suggesting that they may act as positive regulators in the enhanced low-temperature tolerance of poplar. Several transcription factors had divergent expression patterns, suggesting they have variable functional responses to abiotic stress. This profile of global gene expression patterns during chilling stress will be valuable for future studies on the molecular mechanisms of chilling tolerance in woody plants. PMID- 23652823 TI - Re: Variations in the origin of the vertebral artery and its level of entry into the transverse foramen diagnosed by CT angiography. PMID- 23652824 TI - Life events and stress: do older men and women in Malaysia cope differently as consumers? AB - The study of major life events and their effects on well-being has considerable relevance for scientific disciplines and policy making in understanding the consumer behaviour of older people. There is evidence of differences in reactions to and coping with stress between males and females but relatively little knowledge about such gender differences amongst older people, especially in middle-income countries. This study of older Malaysians looked at both coping strategies and gender differences in reactions to stress when people are confronted with certain life events. Seventeen major life events were used in interviews with 645 respondents aged 50 years or older in five major urban areas in Peninsular Malaysia. The analysis showed older women tended to experience higher levels of chronic stress than older men. They also had more health problems, had lower levels of self-esteem and were less satisfied with life. Whilst the results showed little support for gender differences in coping behaviours, stress had a significant influence on the way older men and women change store preferences. A hypothesis that older women would use more emotion focused coping strategies was not supported. Knowledge of how older Malaysians cope with life events and stress and especially in this instance with regard to consumption behaviour, is likely to be of considerable academic and policy related interest. PMID- 23652825 TI - Cross-cultural understandings of festival food-related activities for older women in Chiang Mai, Thailand, Eastern Kentucky, USA and Auckland, New Zealand. AB - This cross-country, cross-cultural study explored the meaning of older women's food-related activities for the annual festivals of Songkran (Thai New Year) in Chiang Mai, Thailand; and Christmas in Richmond, Kentucky, USA; and Auckland, New Zealand. A derived etic method was used. The community-dwelling participants were 33 Thai women, aged 60 and older, and 16 New Zealand and 23 eastern Kentucky women, aged 65 and older. This article focuses on the final cross-cultural analysis of the data. Emic, or within-country, findings are presented, followed by the derived etic, or cross-cultural, interpretations for two themes of meaning; older women's 'protecting what matters' and 'leading the way'. Applying derived etic methods helped reveal how, despite the highly different food-related practices, preparing and sharing celebratory foods at Songkran or Christmas held related meanings for older women in Thailand, Kentucky USA, and New Zealand. PMID- 23652826 TI - The effects of ezetimibe/simvastatin versus simvastatin monotherapy on platelet and inflammatory biomarkers in patients with metabolic syndrome. AB - In a randomized, double-blind, crossover study of 15 aspirin-naive patients (mean age 48.8 +/- 10.2 years) with the metabolic syndrome, statin monotherapy (simvastatin 40 mg daily) was compared to combination therapy (simvastatin 40 mg and ezetimibe 10 mg daily) on biomarkers of inflammation and platelet activity. The addition of ezetimibe to simvastatin over a 4-week period was associated with reduced expression of CD141 (thrombomodulin; p = 0.02), platelet endothelial cell adhesion molecule (p < 0.0001) and CD51/61 (vitronectin receptor; p = 0.048) compared to statin monotherapy. Ezetimibe added to simvastatin improves several indices of platelet reactivity beyond statin monotherapy. However, the clinical relevance of these findings await results of the IMPROVE-IT trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). PMID- 23652827 TI - Understanding electronic and optical properties of anatase TiO2 photocatalysts co doped with nitrogen and transition metals. AB - This paper describes an investigation into the general trend in electronic properties of anatase TiO2 photocatalysts co-doped with transition metals and nitrogen employing first-principles density functional theory. Fourteen different transition metals (M), including Sc, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, and Cd, have been considered. The characteristic band structures of the co doping systems involving the transition metal series are presented. Our results indicate that the absorption edges of TiO2 are shifted to the visible-light region upon introduction of dopants, due to the reduced conduction band minimum (CBM) and the formation of impurity energy levels (IELs) in the band gap. These IELs are primarily formed from (a) the anti-bonding orbitals of the M-O (M indicates the doped transition metal) bonds, (b) the unsaturated nonbonding d orbitals of the doped transition metal (mainly d(xy), d(yz), and d(xz)), and (c) the Ti-O bonding/Ti-N anti-bonding orbitals of the bond next to the doped transition metal. When the valence d electrons of the doped metal are between 3 and 7, all three types of IELs appear in the band gap of the (M, N) co-doped systems. For systems doped with a metal of more than 7 valence electrons, only types (a) and (c) of IELs as well as the unoccupied pz state of N are observed. Based on our analysis, we propose that the co-doping systems such as (V, N), (Cr, N), and (Mn, N), which have the IELs with a significant bandwidth, are of great potential as candidates for photovoltaic applications in the visible light range. PMID- 23652828 TI - On the stability of [(uracil)2-Cu]2+ complexes in the gas phase. Different pathways for the formation of [(uracil-H)(uracil)-Cu]+ monocations. AB - The association of uracil dimers and copper(II) has been studied through the use of B3LYP/6-311+G(3df,2p)//6-31+G(d,p) calculations. Although uracil-Cu(2+) complexes have never been experimentally detected, our results show that [(uracil)2-Cu](2+) is thermodynamically stable with regard to both the proton loss and the fragmentation into (uracil)2(+) + Cu(+), although it is metastable with respect to the coulomb explosion yielding [uracil-Cu](+) + uracil(+). Importantly, a proton transfer from [(uracil)2-Cu](2+) to a third neutral uracil molecule is very exothermic. This is consistent with the fact that when electrospray mass spectrometry techniques are used [(uracil-H)(uracil)-Cu](+) and uracil-H(+) monocations are detected, but not the [(uracil)2-Cu](2+) doubly charged species. In the most stable conformers of [(uracil)2-Cu](2+) the two uracil monomers are held together through the metal cation which forms a linear bridge between two carbonyl groups each belonging to a different monomer. This is at variance with what has been found for complexes involving alkaline-earth dications, such as (uracil)2Ca(2+), in which the metal dication association preserves the network of hydrogen bonds which stabilize the free (uracil)2 dimers. The formation of [(uracil-H)(uracil)-Cu](+) complexes is accompanied by the enolization of the uracil units. All possible mechanisms to reach the experimentally detected [(uracil-H)(uracil)-Cu](+) singly charged ions, either by direct association of Cu(2+) to uracil dimers and posterior deprotonation of the formed complex or through the interaction of Cu(2+) with uracil followed by its deprotonation and subsequent association with a second uracil molecule, have been investigated. PMID- 23652829 TI - U-shaped association between body mass index and proteinuria in a large Japanese general population sample. AB - BACKGROUND: There is little data on the association between body mass index (BMI) and proteinuria. METHODS: This was a cross-sectional cohort study assessing the association between BMI and proteinuria in a large Japanese population. Using a nationwide health check-up database of 212,251 Japanese aged >20 years with no pre-existing cardiovascular diseases (185,183 men, median age 66 years; 127,068 women, median age 65 years), we examined the association between BMI and proteinuria (>= 1+ on dipstick). RESULTS: Subjects were divided into 11 subgroups by BMI grading in 1 kg/m(2) intervals from 18.5-27.5 kg/m(2). A BMI of approximately 22 +/- 0.5 kg/m(2) was considered optimal for Japanese; therefore, this subgroup was set as a reference when logistic analysis was applied. Age, waist circumference, height, weight, smoking and drinking habits, use of medications such as antihypertensive, antidiabetic, or antihyperlipidemic, as well as proteinuria, estimated glomerular filtration rate (eGFR), chemistry data, and blood pressure levels were significantly different between subgroups in both genders. The odds ratio for proteinuria showed a U-shape in men and women, even after adjustment for significant covariates such as age, waist circumference, systolic blood pressure, eGFR, fasting plasma glucose, triglyceride, low-density lipoprotein, antihypertensive use, antidiabetic use, antihyperlipidemic use, and lifestyle factors (smoking and drinking). Gender differences were also prominent- a BMI <20.4 kg/m(2) was significantly associated with proteinuria in men compared to a BMI <18.4 kg/m(2) in women. On the other hand, a BMI >= 25.5 kg/m(2) was also significantly associated with proteinuria in men compared to a BMI >= 22.5 kg/m(2) in women. CONCLUSIONS: We found that BMI levels were associated with proteinuria in a U-shaped manner and showed marked gender differences. Health guidance should not only focus on higher BMI subjects, but also on thin subjects, in terms of the prevention of chronic kidney disease. PMID- 23652830 TI - Heavy chain deposition disease: an overview. AB - Heavy chain deposition disease (HCDD) is one of three entities of monoclonal immunoglobulin deposition disease, characterized histopathologically by the presence of nodular glomerulosclerosis and glomerular and tubular deposition of monoclonal heavy chains without associated light chains. Although HCDD is an extremely rare disease, >30 cases have been reported to date in the literature. Of these cases, only three cases have been reported in Japan. The majority of the patients presents with nephrotic syndrome, hematuria, and hypertension, and develop progressive renal failure with or without the complication of multiple myeloma. Some cases have been treated successfully using chemotherapy. Because of its rarity, a thorough understanding of HCDD is essential for both accurate diagnosis and adequate subsequent treatment. PMID- 23652831 TI - All we ever wanted to know about perioperative bleeding. PMID- 23652832 TI - Ultrasound targeted microbubble destruction stimulates cellular endocytosis in facilitation of adeno-associated virus delivery. AB - The generally accepted mechanism for ultrasound targeted microbubble destruction (UTMD) to enhance drug and gene delivery is through sonoporation. However, passive uptake of adeno-associated virus (AAV) into cells following sonoporation does not adequately explain observations of enhanced transduction by UTMD. This study investigated alternative mechanisms of UTMD enhancement in AAV delivery. UTMD significantly enhanced transduction efficiency of AAV in a dose-dependent manner. UTMD stimulated a persistent uptake of AAV into the cytoplasm and nucleus. This phenomenon occurred over several hours, suggesting that some viral particles are endocytosed by cells rather than exclusively passing through pores created by sonoporation. Additionally, UTMD enhanced clathrin expression and accumulation at the plasma membrane suggesting greater clathrin-mediated endocytosis following UTMD. Transmission electron microscopy (TEM) revealed that UTMD stimulated formation of clathrin-coated pits (CPs) and uncoated pits (nCPs). Furthermore, inhibition of clathrin-mediated endocytosis partially blocked the enhancement of AAV uptake following UTMD. The results of this study implicate endocytosis as a mechanism that contributes to UTMD-enhanced AAV delivery. PMID- 23652833 TI - Resistin promotes the expression of vascular endothelial growth factor in ovary carcinoma cells. AB - Resistin is a novel hormone that is secreted by human adipocytes and mononuclear cells and is associated with obesity, insulin resistance and inflammation. Recently, resistin has been postulated to play a role in angiogenesis. Here, we investigated the hypothesis that resistin regulates ovary carcinoma production of vascular endothelial growth factor (VEGF) and the angiogenic processes. We found that in human ovarian epithelial carcinoma cells (HO-8910), resistin (10-150 ng/mL) enhanced both VEGF protein and mRNA expression in a time- and concentration-dependent manner, as well as promoter activity. Furthermore, resistin enhanced DNA-binding activity of Sp1 with VEGF promoter in a PI3K/Akt dependent manner. PI3K/Akt activated by resistin led to increasing interaction with Sp1, triggering a progressive phosphorylation of Sp1 on Thr453 and Thr739, resulting in the upregulation of VEGF expression. In an in vitro angiogenesis system for endothelial cells (EA.hy926) co-cultured with HO-8910 cells, we observed that the addition of resistin stimulated endothelial cell tube formation, which could be abolished by VEGF neutralizing antibody. Our findings suggest that the PI3K/Akt-Sp1 pathway is involved in resistin-induced VEGF expression in HO-8910 cells and indicates that antiangiogenesis therapy may be beneficial treatment against ovarian epithelial carcinoma, especially in obese patients. PMID- 23652834 TI - Oenothein B suppresses lipopolysaccharide (LPS)-induced inflammation in the mouse brain. AB - Oenothein B has been recently evaluated for its ability to affect inflammatory responses in peripheral tissues. In this study, we examined its effect on the damage to the central nervous system due to systemic inflammation. For this purpose, ICR mice were injected with an intraperitoneal (i.p.) dose of lipopolysaccharide (LPS; 1 mg/kg mouse). When oenothein B was administered per os (p.o.), it suppressed (1) LPS-induced abnormal behavior in open field; (2) LPS induced microglial activation in the hippocampus and striatum; and (3) LPS induced cyclooxygenase (COX)-2 production in the hippocampus and striatum of these mice. These results suggest that oenothein B had the ability to reduce neuroinflammation in the brain during systemic inflammation. PMID- 23652835 TI - Effects of (-)-gallocatechin-3-gallate on tetrodotoxin-resistant voltage-gated sodium channels in rat dorsal root ganglion neurons. AB - The (-)-gallocatechin-3-gallate (GCG) concentration in some tea beverages can account for as much as 50% of the total catechins. It has been shown that catechins have analgesic properties. Voltage-gated sodium channels (Nav) mediate neuronal action potentials. Tetrodotoxin inhibits all Nav isoforms, but Nav1.8 and Nav1.9 are relatively tetrodotoxin-resistant compared to other isoforms and functionally linked to nociception. In this study, the effects of GCG on tetrodotoxin-resistant Na+ currents were investigated in rat primary cultures of dorsal root ganglion neurons via the whole-cell patch-clamp technique. We found that 1 MUM GCG reduced the amplitudes of peak current density of tetrodotoxin resistant Na+ currents significantly. Furthermore, the inhibition was accompanied by a depolarizing shift of the activation voltage and a hyperpolarizing shift of steady-state inactivation voltage. The percentage block of GCG (1 MUM) on tetrodotoxin-resistant Na+ current was 45.1% +/- 1.1% in 10 min. In addition, GCG did not produce frequency-dependent block of tetrodotoxin-resistant Na+ currents at stimulation frequencies of 1 Hz, 2 Hz and 5 Hz. On the basis of these findings, we propose that GCG may be a potential analgesic agent. PMID- 23652836 TI - Galleria mellonella larvae as an infection model for group A streptococcus. AB - Group A streptococcus is a strict human pathogen that can cause a wide range of diseases, such as tonsillitis, impetigo, necrotizing fasciitis, toxic shock, and acute rheumatic fever. Modeling human diseases in animals is complicated, and rapid, simple, and cost-effective in vivo models of GAS infection are clearly lacking. Recently, the use of non-mammalian models to model human disease is starting to re-attract attention. Galleria mellonella larvae, also known as wax worms, have been investigated for modeling a number of bacterial pathogens, and have been shown to be a useful model to study pathogenesis of the M3 serotype of GAS. In this study we provide further evidence of the validity of the wax worm model by testing different GAS M-types, as well as investigating the effect of bacterial growth phase and incubation temperature on GAS virulence in this model. In contrast to previous studies, we show that the M-protein, among others, is an important virulence factor that can be effectively modeled in the wax worm. We also highlight the need for a more in-depth investigation of the effects of experimental design and wax worm supply before we can properly vindicate the wax worm model for studying GAS pathogenesis. PMID- 23652837 TI - Genetic analysis of Italian patients with congenital hyperinsulinism of infancy. AB - BACKGROUND/AIMS: Congenital hyperinsulinism of infancy is a rare disease that needs prompt treatment to avoid brain damage. There are currently no data regarding the clinical and molecular features of Italian patients. METHODS: Thirty-three patients with HI and their parents were included. Consanguinity was reported in six patients. Half of patients were macrosomic at birth. None had raised 3-hydroxybutyrylcarnitine or hyperammonemia. Molecular analysis of ABCC8 and KCNJ11 genes was performed in all patients, and subjects with no mutation underwent analysis of HNF4A and GCK. GLUD1 and HADH genes were analyzed in a patient with leucine sensitivity. RESULTS: Mutations in the ABCC8 and KCNJ11 genes were found in 45% of the patients (6 novel). No mutations in HNF4A, GLUD1 and GCK genes were found. Recessive mode of inheritance was found in 21% of patients. A single heterozygous mutation was identified in 24% of probands. 72% of the patients were responsive to medical treatment, and 44% of the 17 patients with no identified mutation achieved spontaneous remission. Nine children, unresponsive to medical therapy, underwent pancreatectomy. CONCLUSION: This is the first report on hyperinsulinism of infancy in Italy, confirming the complexity of the clinical forms and the heterogeneity of the genetic causes of the disease. PMID- 23652838 TI - Monitoring of platelet activation in platelet concentrates using transmission electron microscopy. AB - OBJECTIVE: The quality of platelet concentrates (PC) is important for the in vivo recovery of thrombostasis in patients suffering from bleeding disorders and in tumor patients after chemotherapy. In this respect, activated platelets (PLT) cannot display their full functionality in the recipient and even can cause adverse effects. Therefore, we developed a transmission electron microscopy (TEM) method for quality assessment of PC. METHODS: Score values taken from panorama TEM images describe the progress of PLT activation. To exemplify this method, i) 19 apheresis PC isolated with the Baxter Amicus system (BA) were compared with 14 PC obtained from pooled buffy coats (BC). ii) The score values of 33 PC derived from BA as well from BC were compared with flow-cytometric CD62P determinations by cross correlation. iii) Changes in the score value profiles during storage of a single pathogen-reduced BA PC were monitored over a period of 7 days. RESULTS: The TEM evaluation described allows for demonstrating particular PLT activation stages. i) Significant differences between the percentages of the score values 0, 1 and 2 could be demonstrated in both processing groups. No significant differences were found comparing these two groups. ii) A weak correlation could be shown when comparing the percentages of score values 2 plus 3 with the percentage of CD62P-positive PLT. iii) The pathogen reduction affected slightly the score profiles during storage due to an increase of dead PLT. CONCLUSION: Our investigations demonstrate the unique detailed quality information of PC obtained by the TEM method. This method can be performed in every routine electron microscopy laboratory. PMID- 23652839 TI - Generation of full dimensional potential energy surfaces for atmospherically important charge transfer tetratomic complexes: the case of the OMgOO+ radical cation. AB - The weakly bound charge transfer OMgOO(+)((2)Pi) ion is a quasi-linear-bent Renner-Teller system with a non-zero spin-orbit contribution. The six-dimensional potential energy surfaces (6D-PESs) for the two Renner-Teller components have been generated in internal coordinates. After benchmarking calculations, we show that the newly implemented explicitly correlated coupled cluster approach (RCCSD(T)-F12) in connection with the cc-pVTZ-F12 basis set provides an accurate description of the full 6D-PESs of this molecular system. Both components are bent with low barriers to linearity along the in-plane angles. The potentials are also very flat along the out-of-plane torsional mode. Hence, this confers a pronounced quasi linear character to OMgOO(+). Moreover, the parts of the potentials relative to the middle bond are shallow and strongly coupled to the bending motions. The parts of the PESs corresponding to the OO and MgO external diatom stretch coordinates differ strongly from those relative to the four other internal coordinates. Special care was taken to correctly account for such behaviors during the generation of the grid and fitting procedures. The present theoretical methodology can be used for mapping the 6D-PESs of other atmospherically important charge transfer complexes presenting similar features such as ONNO(+), O4(+), OOCO(+) or M-CO2(+) (where M is an alkali, magnesium or aluminum metal). PMID- 23652840 TI - The Liverpool Care Pathway for cancer patients dying in hospital medical wards: a before-after cluster phase II trial of outcomes reported by family members. AB - BACKGROUND: Hospital is the most common place of cancer death but concerns regarding the quality of end-of-life care remain. AIM: Preliminary assessment of the effectiveness of the Liverpool Care Pathway on the quality of end-of-life care provided to adult cancer patients during their last week of life in hospital. DESIGN: Uncontrolled before-after intervention cluster trial. SETTINGS/PARTICIPANTS: The trial was performed within four hospital wards participating in the pilot implementation of the Italian version of the Liverpool Care Pathway programme. All cancer patients who died in the hospital wards 2-4 months before and after the implementation of the Italian version of Liverpool Care Pathway were identified. A total of 2 months after the patient's death, bereaved family members were interviewed using the Toolkit After-Death Family Interview (seven 0-100 scales assessing the quality of end-of-life care) and the Italian version of the Views of Informal Carers - Evaluation of Services (VOICES) (three items assessing pain, breathlessness and nausea-vomiting). RESULTS: An interview was obtained for 79 family members, 46 (73.0%) before and 33 (68.8%) after implementation of the Italian version of Liverpool Care Pathway. Following Italian version of Liverpool Care Pathway implementation, there was a significant improvement in the mean scores of four Toolkit scales: respect, kindness and dignity (+16.8; 95% confidence interval = 3.6-30.0; p = 0.015); family emotional support (+20.9; 95% confidence interval = 9.6-32.3; p < 0.001); family self efficacy (+14.3; 95% confidence interval = 0.3-28.2; p = 0.049) and coordination of care (+14.3; 95% confidence interval = 4.2-24.3; p = 0.007). No significant improvement in symptom' control was observed. CONCLUSIONS: These results provide the first robust data collected from family members of a preliminary clinically significant improvement, in some aspects, of quality of care after the implementation of the Italian version of Liverpool Care Pathway programme. The poor effect for symptom control suggests areas for further innovation and development. PMID- 23652841 TI - Comparison of survival analysis and palliative care involvement in patients aged over 70 years choosing conservative management or renal replacement therapy in advanced chronic kidney disease. AB - BACKGROUND: There are limited data on the outcomes of elderly patients with chronic kidney disease undergoing renal replacement therapy or conservative management. AIMS: We aimed to compare survival, hospital admissions and palliative care access of patients aged over 70 years with chronic kidney disease stage 5 according to whether they chose renal replacement therapy or conservative management. DESIGN: Retrospective observational study. SETTING/PARTICIPANTS: Patients aged over 70 years attending pre-dialysis clinic. RESULTS: In total, 172 patients chose conservative management and 269 chose renal replacement therapy. The renal replacement therapy group survived for longer when survival was taken from the time estimated glomerular filtration rate <20 mL/min (p < 0.0001), <15 mL/min (p < 0.0001) and <12 mL/min (p = 0.002). When factors influencing survival were stratified for both groups independently, renal replacement therapy failed to show a survival advantage over conservative management, in patients older than 80 years or with a World Health Organization performance score of 3 or more. There was also a significant reduction in the effect of renal replacement therapy on survival in patients with high Charlson's Comorbidity Index scores. The relative risk of an acute hospital admission (renal replacement therapy vs conservative management) was 1.6 (p < 0.05; 95% confidence interval = 1.14-2.13). A total of 47% of conservative management patients died in hospital, compared to 69% undergoing renal replacement therapy (Renal Registry data). Seventy-six percent of the conservative management group accessed community palliative care services compared to 0% of renal replacement therapy patients. CONCLUSIONS: For patients aged over 80 years, with a poor performance status or high co-morbidity scores, the survival advantage of renal replacement therapy over conservative management was lost at all levels of disease severity. Those accessing a conservative management pathway had greater access to palliative care services and were less likely to be admitted to or die in hospital. PMID- 23652842 TI - Recommendations for managing missing data, attrition and response shift in palliative and end-of-life care research: part of the MORECare research method guidance on statistical issues. AB - BACKGROUND: Statistical analysis in palliative and end-of-life care research can be problematic due to high levels of missing data, attrition and response shift as disease progresses. AIM: To develop recommendations about managing missing data, attrition and response shift in palliative and end-of-life care research data. DESIGN: We used the MORECare Transparent Expert Consultation approach to conduct a consultation workshop with experts in statistical methods in palliative and end-of-life care research. Following presentations and discussion, nominal group techniques were used to produce recommendations about attrition, missing data and response shift. These were rated online by experts and analysed using descriptive statistics for consensus and importance. RESULTS: In total, 20 participants attended the workshop and 19 recommendations were subsequently ranked. There was broad agreement across recommendations. The top five recommendations were as follows: A taxonomy should be devised to define types of attrition. Types and amount of missing data should be reported with details of imputation methods. The pattern of missing data should be investigated to inform the imputation approach. A statistical analysis plan should be pre-specified in the protocol. High rates of attrition should be assumed when planning studies and specifying analyses. The leading recommendation for response shift was for more research. CONCLUSIONS: When designing studies in palliative and end-of-life care, it is recommended that high rates of attrition should not be seen as indicative of poor design and that a clear statistical analysis plan is in place to account for missing data and attrition. PMID- 23652843 TI - The effect of a tuberculosis chest X-ray image reference set on non-expert reader performance. AB - OBJECTIVES: In low-resource settings, limitations in diagnostic accuracy of chest X-rays (CXR) for pulmonary tuberculosis (PTB) relate partly to non-expert interpretation. We piloted a TB CXR Image Reference Set (TIRS) to improve non expert performance in an operational setting in Malawi. METHODS: Nineteen doctors and clinical officers read 60 CXR of patients with suspected PTB, at baseline and using TIRS. Two officers also used the CXR Reading and Recording System (CRRS). Correct treatment decisions were assessed against a "gold standard" of mycobacterial culture and expert performance. RESULTS: TIRS significantly increased overall non-expert sensitivity from 67.6 (SD 14.9) to 75.5 (SD 11.1, P = 0.013), approaching expert values of 84.2 (SD 5.2). Among doctors, correct decisions increased from 60.7 % (SD 7.9) to 67.1 % (SD 8.0, P = 0.054). Clinical officers increased in sensitivity from 68.0 % (SD 15) to 77.4 % (SD 10.7, P = 0.056), but decreased in specificity from 55.0 % (SD 23.9) to 40.8 % (SD 10.4, P = 0.049). Two officers made correct treatment decisions with TIRS in 62.7 %. CRRS training increased this to 67.8 %. CONCLUSION: Use of a CXR image reference set increased correct decisions by doctors to treat PTB. This tool may provide a low cost intervention improving non-expert performance, translating into improved clinical care. Further evaluation is warranted. KEY POINTS: * Tuberculosis treatment decisions are influenced by CXR findings, despite improved laboratory diagnostics. * In low-resource settings, CXR interpretation is performed largely by non-experts. * We piloted the effect of a simple reference training set of CXRs. * Use of the reference set increased the number of correct treatment decisions. This effect was more marked for doctors than clinical officers. * Further evaluation of this simple training tool is warranted. PMID- 23652844 TI - Diffusion-weighted MRI in pretreatment prediction of response to neoadjuvant chemotherapy in patients with breast cancer. AB - PURPOSE: To evaluate the accuracy of the apparent diffusion coefficient (ADC) provided by diffusion-weighted imaging (DWI) in predicting the response to neoadjuvant chemotherapy (NACT) at baseline in patients according to their breast tumour phenotypes. MATERIALS & METHODS: This retrospective study was approved by our institutional review board. One hundred eighteen consecutive women with locally advanced breast cancer who had undergone NACT followed by breast surgery were included. DWI was performed at 1.5 T less than 2 weeks before NACT. We studied the correlation between pretreatment ADC and response in pathology after surgery according to immunohistochemical features and intrinsic subtypes (luminal A, luminal B, HER2-enriched, and triple-negative tumours). RESULTS: After surgery, the pathologist recognized 24 complete responders (CRps) and 94 non complete responders (NCRps). No difference was identified between the pretreatment ADCs of the CRp and NCRp patients. There were differences in pretreatment ADCs among the luminal A (1.001 +/- 0.143 * 10(-3) mm(2)/s), luminal B (0.983 +/- 0.150 * 10(-3) mm(2)/s), HER2-enriched (1.132 +/- 0.216 * 10(-3) mm(2)/s), and triple-negative (1.168 +/- 0.245 * 10(-3) mm(2)/s; P = 0.0003) tumour subtypes. In triple-negative tumours, the pretreatment ADC was higher in NCRp (1.060 +/- 0.143 * 10(-3) mm(2)/s) than in CRp patients (1.227 +/- 0.271 * 10(-3) mm(2)/s; P = 0.047). CONCLUSION: Pretreatment ADC can predict the response of breast cancer to NACT if tumour subtypes are considered. Key Points * Apparent diffusion coefficient helps clinicians to assess patients with breast cancer. * Pretreatment ADC is related to tumour grade and hormone receptor status. * Pretreatment ADC is lower in luminal A and B than in triple-negative tumours. * Pretreatment ADC is higher in complete than in non-complete responders to neoadjuvant chemotherapy. PMID- 23652845 TI - Diagnostic accuracy of unenhanced, contrast-enhanced perfusion and angiographic MRI sequences for pulmonary embolism diagnosis: results of independent sequence readings. AB - OBJECTIVES: To independently evaluate unenhanced, contrast-enhanced perfusion and angiographic MR sequences for pulmonary embolism (PE) diagnosis. METHODS: Prospective investigation, including 274 patients who underwent perfusion, unenhanced 2D steady-state-free-precession (SSFP) and contrast-enhanced 3D angiographic MR sequences on a 1.5-T unit, in addition to CTA (CT angiography). Two independent readers evaluated each sequence independently in random order. Sensitivity, specificity, predictive values and inter-reader agreement were calculated for each sequence, excluding sequences judged inconclusive. Sensitivity was also calculated according to PE location. RESULTS: Contrast enhanced angiographic sequences showed the highest sensitivity (82.9 and 89.7 %, reader 1 and reader 2, respectively), specificity (98.5 and 100 %) and agreement (kappa value 0.77). Unenhanced angiographic sequences, although less sensitive overall (68.7 and 76.4 %), were sensitive for the detection of proximal PE (92.7 and 100 %) and showed high specificity (96.1 and 99.1 %) and good agreement (kappa value 0.62). Perfusion sequences showed lower sensitivity (75.0 and 79.3 %), specificity (84.8 and 89.7 %) and agreement (kappa value 0.51), and a negative predictive value of 84.8 % at best. CONCLUSIONS: Compared with contrast enhanced angiographic sequences, unenhanced sequences demonstrate lower sensitivity, except for proximal PE, but high specificity and agreement. The negative predictive value of perfusion sequences was insufficient to safely rule out PE. KEY POINTS: * Unenhanced angiographic MR sequences are very specific and can identify proximal PE. * Contrast-enhanced MR angiographic sequences show high sensitivity for PE diagnosis. * A normal MR perfusion result does not exclude PE. * Inter-reader agreement is better for angiographic than perfusion MR sequences. PMID- 23652846 TI - Acute myocardial infarction: early CT aspects of myocardial microcirculation obstruction after percutaneous coronary intervention. AB - OBJECTIVE: To evaluate the capabilities of delayed enhanced multidetector CT (DE MDCT), performed immediately after percutaneous coronary intervention (PCI), in predicting myocardial microvascular obstruction (MVO) formation assessed by delayed enhanced MRI (DE-MRI). METHODS: Thirty-two patients presenting with a primary acute myocardial infarction, successfully recanalised by PCI, underwent a DE-MDCT immediately after PCI and a DE-MRI within 1 week. The left ventricle was split into 64 subsegments, rated as "healthy", "infarcted" or "MVO" on DE-MRI. Their mean density was measured on DE-MDCT and calculated relative to the patient's mean healthy myocardium density. Hypoenhanced DE-MDCT subsegments, termed "CT early MVO", were also recorded. Sensitivity and specificity of DE-MDCT for MRI-assessed "MVO" subsegments detection was calculated for mean CT relative density (threshold determined from a ROC analysis), "CT early MVO" and both. RESULTS: Mean CT relative density was higher in MRI-assessed "MVO" than in "infarcted" and "healthy" subsegments (1.82 +/- 0.46, 1.43 +/- 0.36 and 1.0 +/- 0.13 respectively; P < 0.001) leading to a sensitivity and specificity of 94.3 % and 89.2 % for a cutoff of 1.36. Sensitivity and specificity were respectively 16.9 % and 99.8 % for "CT early MVO" and 95.3 % and 89.3 % when considering the two patterns. CONCLUSION: DE-MDCT, performed immediately after PCI, allows for an accurate prediction of MVO formation. KEY POINTS: * Myocardial microvascular obstruction (MVO) is an important prognostic sequel following myocardial infarction. * MVO can be accurately predicted by multidector CT (MDCT). * Both hypo- and hyperenhanced myocardial areas can be analysed by MDCT. * MDCT may become a useful prognostic tool for acute MI outcome. PMID- 23652847 TI - Increase in left liver lobe function after preoperative right portal vein embolisation assessed with gadolinium-EOB-DTPA MRI. AB - OBJECTIVES: To prospectively evaluate the early development of regional liver function after right portal vein embolisation (PVE) with Gd-EOB-DTPA-enhanced MRI in patients scheduled for extended right hemihepatectomy. METHODS: Ten patients who received a PVE before an extended hemihepatectomy were examined before and 14 days after PVE using Gd-EOB-DTPA-enhanced MRI of the liver. In these sequences representative region of interest measurements were performed in the embolised right (RLL) and the non-embolised left liver lobe (LLL). The volume as well as hepatic uptake index (HUI) was calculated independently for each lobe. RESULTS: Relative enhancement 14 days after PVE decreased in the RLL and increased significantly in the LLL (P < 0.05). Average hepatic uptake index (HUI) for RLL was significantly lower 14 days after PVE than before PVE (P < 0.05) and significantly higher for LLL (P < 0.05). CONCLUSIONS: A significant shift of contrast uptake from the right to the left liver lobe can be depicted as early as 14 days after right PVE by using Gd-EOB-DTPA-enhanced MRI, which could reflect the redirected portal venous blood flow and the rapid utilisation of a hepatic functional reserve. KEY POINTS: * Preoperative portal vein embolisation (PVE) is widely performed before right-sided hepatic resection. * PVE increases intravenous contrast medium uptake in the left lobe of liver. * The hepatic uptake index for the left liver lobe increases rapidly after PVE. * Left liver lobe function increase may be visualised by Gd-EOB-DTPA-enhanced MRI. PMID- 23652848 TI - Real-time ultrasound elastography: an assessment of enlarged cervical lymph nodes. AB - OBJECTIVES: To determine the efficacy of real-time elastography (RTE), compared with our previously proposed prediction model, in the detection of malignancy in cervical lymph nodes (LNs). METHODS: One hundred and thirty-one patients underwent ultrasound-guided fine needle aspiration biopsy (ultrasound FNAB) after ultrasound and RTE evaluation. The formula of the RTE scoring system was a four point visual scale, based on a previously determined model. The formula of the prediction model was: [Formula: see text]. An extended model was constructed with four previous predictors and elasticity scores, using a logistic regression model. RESULTS: Final histology revealed 77 benign and 54 malignant LNs. In the elasticity score system, sensitivity was 66.7 %, specificity was 57.1 %, the positive predictive value (PPV) was 52.2 % and the negative predictive value (NPV) was 71.0 %. In the prediction model system, sensitivity was 79.6 %, specificity was 92.2 %, the PPV was 87.8 % and the NPV was 86.6 %. When the extended and the original model were compared, the areas under the receiver operating characteristic curve (c-statistic) was 0.94 and 0.95, respectively (P > 0.05). CONCLUSIONS: Qualitative RTE offers no additional value over conventional ultrasound in predicting malignancy in cervical LNs. KEY POINTS: * An ultrasound system can help in the assessment of cervical lymph nodes. * Grey-scale and power Doppler ultrasound remain fundamental for neck nodal evaluation. * Qualitative real-time elastography provided no additional value compared with current prediction models. PMID- 23652849 TI - Endovascular treatment of brain arteriovenous malformations using a liquid embolic agent: results of a prospective, multicentre study (BRAVO). AB - OBJECTIVES: To evaluate the safety and efficacy of a new liquid embolic agent in brain arteriovenous malformation (bAVMs) embolisation. METHODS: A prospective, multicentre series was conducted at 11 interventional centres in Europe to evaluate embolisation of bAVMs with the new liquid embolic agent. Technical conditions, complications, clinical outcome and anatomical results were independently analysed. RESULTS: From December 2005 to December 2008, 117 patients (72 male; 45 female, aged 18-75 years) were included. Clinical presentation was mostly haemorrhage (34.2 %) and seizures (28.2 %). Most AVMs were located in the brain hemispheres (85.5 %). AVMs were <3 cm in 52.1 % of patients and >= 3 cm in 47.9 %. Morbidity was observed in 6/117 patients (5.1 %), related to haemorrhagic events in 2 cases and non-haemorrhagic complications in 4 cases. Five patients (4.3 %) died in relation to the treatment (bleeding in 4 patients and extensive venous thrombosis in 1). Complete occlusion of the AVM by embolisation alone was obtained in 23.5 % of patients. Complementary treatment was performed in 82.3 % of patients with partial AVM occlusion, mostly radiosurgery. CONCLUSIONS: In this prospective, multicentre, European, observational series, the new liquid embolic agent proved to be suitable for BAVM embolisation, with acceptable morbidity and mortality and good efficacy. KEY POINTS: * Numerous interventional techniques have been used to embolise brain arteriovenous malformations (AVMs). * This prospective multicentre study demonstrates the suitability of a liquid embolic agent. * The safety of treatment using Onyx is acceptable. * Such embolisation leads to complete AVM occlusion in 23.5 % of patients. PMID- 23652850 TI - Diagnostic value of commercially available shear-wave elastography for breast cancers: integration into BI-RADS classification with subcategories of category 4. AB - OBJECTIVES: To evaluate the diagnostic performance of shear-wave elastography (SWE) for breast cancer and to determine whether the integration of SWE into BI RADS with subcategories of category 4 improves the diagnostic performance. METHODS: A total of 389 breast masses (malignant 120, benign 269) in 324 women who underwent SWE before ultrasound-guided core biopsy or surgery were included. The qualitative SWE feature was assessed using a four-colour overlay pattern. Quantitative elasticity values including the lesion-to-fat elasticity ratio (Eratio) were measured. Diagnostic performance of B-mode ultrasound, SWE, or their combined studies was compared using the area under the ROC curve (AUC). RESULTS: AUC of Eratio (0.952) was the highest among elasticity values (mean, maximum, and minimum elasticity, 0.949, 0.939, and 0.928; P = 0.04) and AUC of colour pattern was 0.947. AUC of combined studies was significantly higher than for a single study (P < 0.0001). When adding SWE to category 4 lesions, lesions were dichotomised according to % of malignancy: 2.1 % vs. 43.2 % (category 4a) and 0 % vs. 100 % (category 4b) for Eratio and 2.4 % vs. 25.8 % (category 4a) for colour pattern (P < 0.05). CONCLUSIONS: Shear-wave elastography showed a good diagnostic performance. Adding SWE features to BI-RADS improved the diagnostic performance and may be helpful to stratify category 4 lesions. KEY POINTS: * Quantitative and qualitative shear-wave elastography provides further diagnostic information during breast ultrasound. * The elasticity ratio (E ratio ) showed the best diagnostic performance in SWE. * E ratio and four-colour overlay pattern significantly differed between benign and malignant lesions. * SWE features allowed further stratification of BI-RADS category 4 lesions. PMID- 23652851 TI - Thickening of the inferior glenohumeral capsule: an ultrasound sign for shoulder capsular contracture. AB - OBJECTIVES: The aim of this retrospective study was to measure the inferior glenohumeral capsule thickness of shoulders clinically affected by capsular contracture by comparison to the contralateral asymptomatic side. METHODS: Bilateral shoulder ultrasound (US) examinations of 20 patients with clinically or MRI proven unilateral capsular contracture were retrospectively assessed. Inferior capsule evaluation was performed with a transducer placed within the axilla in maximally abducted shoulders. Measurements were symmetrically performed orthogonally to the inferior glenohumeral ligament (IGHL) in the axial plane; the coronal plane was used to ensure the tension of the IGHL. The significance of any difference in thickening was assessed with the Mann-Whitney test. RESULTS: The average thickness was 4.0 mm in shoulders with capsular contracture vs. 1.3 mm in asymptomatic contralateral shoulders (P < 0.0001). Twenty per cent of patients with capsular contracture and inferior capsule thickness increase showed US features of other painful diseases of the rotator cuff. CONCLUSION: The thickness of the inferior capsule is measurable through ultrasound examination and appears to be increased in shoulders with capsular contracture. Exploration of the inferior aspect of the shoulder joint could be added to shoulder US examination protocols for capsular contracture assessment even if other rotator cuff abnormalities are diagnosed by US. KEY POINTS: * Ultrasound is increasingly used to diagnose shoulder problems. * The thickness of the inferior glenohumeral ligament is measurable in the axilla. * The inferior glenohumeral ligament appears thickened in shoulders with capsular contracture. * Capsular contracture ultrasound features can be associated with other rotator cuff problems. PMID- 23652852 TI - Role of preoperative MR imaging in the evaluation of patients with persistent or recurrent gynaecological malignancies before pelvic exenteration. AB - PURPOSE: To determine the diagnostic performance of MRI in assessing local tumour extent and evaluate associations between MRI features and survival in patients undergoing MRI before pelvic exenteration for persistent or recurrent gynaecological cancers. METHODS AND MATERIALS: The study included 50 patients with persistent or recurrent gynaecological malignancies who underwent pelvic exenteration between January 1999 and December 2011 and had MRI at most 90 days before surgery. Two radiologists independently assessed invasion of adjacent organs (on a 5-point scale). Diagnostic accuracy, inter-reader agreement, and associations between organ invasion on MRI and patient survival were evaluated. RESULTS: Areas under receiver operating characteristic curves (AUCs) for invasion of the bladder, rectum and pelvic sidewall were 0.96, 0.90 and 0.98 for reader 1 and 0.95, 0.88 and 0.90 for reader 2. Corresponding sensitivities/specificities were 87.0 %/92.6 %, 81.3 %/97.0 % and 87.5 %/97.2 % for reader 1, and 87.0 %/100.0 %, 75.0 %/97.0 % and 75.0 %/94.4 % for reader 2. Inter-reader agreement was excellent for organ invasion (kappa = 0.81-0.85). Pelvic sidewall invasion on MRI was associated with overall and recurrence-free survival (P = 0.01-0.04 for the two readers). CONCLUSION: Preoperative MRI is accurate in predicting organ invasion. It may guide surgical planning and serve as a predictive biomarker in patients undergoing pelvic exenteration for gynaecological malignancies. KEY POINTS: * MRI can accurately assess bladder and rectal wall invasion before major surgery. * MRI identifies patients requiring extended pelvic exenteration by detecting sidewall invasion. * Inter-reader agreement for detecting organ invasion and tumor size is excellent. * Pelvic sidewall invasion on MRI is associated with shorter overall and recurrence-free survival. PMID- 23652853 TI - Hypoxia promotes radioresistance of CD133-positive Hep-2 human laryngeal squamous carcinoma cells in vitro. AB - Hypoxia promotes the radioresistance of laryngeal carcinomas and CD133 is one of the markers expressed by tumor-initiating, human laryngeal carcinoma cells. In order to investigate whether CD133-positive Hep-2 cells exhibit a radioresistant phenotype and to determine whether hypoxia promotes this phenotype, we performed a series of experiments. Hep-2 cells, and Hep-2 cells stably expressing hypoxia inducible factor (HIF)-targeted small interfering RNA (siRNA) were cultured under hypoxic and normoxic conditions and were treated with varying doses of gamma-rays (0, 5, 10, 15 and 20 Gy). MTT and cell cycle assays were subsequently performed. Using fluorescence-activated cell sorting (FACS), CD133-positive Hep-2 cells and CD133-positive HIF-siRNA Hep-2 cells were isolated. These cells were grown as spheres under hypoxic and normoxic conditions for MTT and soft agar colony formation assays. The expression levels of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), survivin, p53 and ataxia-telangiectasia mutated (ATM) were also assayed using flow cytometry. The data showed that the growth of Hep-2 cells exposed to hypoxic conditions and treated with 10 Gy radiation (group A) was less compared to that of groups B-D (P<0.05). In addition, more cells in group A were arrested in the G1 phase of the cell cycle compared to groups B-D (P<0.05). The percentage of CD133+ cells detected after radiation increased and was the highest for group A (P<0.05). In sphere formation assays, significantly more CD133+ cells grew in spheres than CD133- cells (P<0.001). Moreover, sphere formation was the highest for CD133+ Hep-2 cells grown under hypoxic conditions and exposed to irradiation (group E) (P<0.05). Lastly, expression of DNA-PKcs and survivin for group E was the highest (P<0.05), while ATM and p53 levels remained largely unchanged (P>0.05). In conclusion, CD133-positive Hep-2 cells exhibited a radioresistant phenotype that was enhanced with hypoxia. Furthermore, an increase in DNA-PK activity was associated with this enhancement. PMID- 23652854 TI - Large-scale reorganization of the somatosensory cortex of adult macaque monkeys revealed by fMRI. AB - Somatosensory cortex of adult primates undergoes topographic reorganization following spinal cord or peripheral nerve injuries. Electrophysiological studies in monkeys show that after chronic lesions of dorsal columns of the spinal cord at cervical levels, there is an expansion of face representation into the deafferented hand region of area 3b of cortex. However, these techniques can sample only a limited portion of the brain. In order to help understand mechanisms of brain reorganization use of noninvasive tools in non-human primate experimental model is important. Use of blood oxygen level dependent-functional magnetic resonance imaging (BOLD-fMRI) to study brain reorganization in non-human primates has been extremely limited. Here, we show that in monkeys with long-term unilateral lesions of the dorsal columns at cervical levels, tactile stimulation of the chin showed BOLD activation in the deafferented hand region of contralesional area 3b in the post-central gyrus. In a monkey with a partial lesion of the dorsal columns, stimulations of both hand and chin activated the partially deafferented hand region. We also show that the somatotopic organization in the non-deafferented ipsilesional somatosensory cortex remained normal. PMID- 23652855 TI - Destruction of tissue, cells and organelles in type 1 diabetic rats presented at macromolecular resolution. AB - Finding alternatives for insulin therapy and making advances in etiology of type 1 diabetes benefits from a full structural and functional insight into Islets of Langerhans. Electron microscopy (EM) can visualize Islet morphology at the highest possible resolution, however, conventional EM only provides biased snapshots and lacks context. We developed and employed large scale EM and compiled a resource of complete cross sections of rat Islets during immuno destruction to provide unbiased structural insight of thousands of cells at macromolecular resolution. The resource includes six datasets, totalling 25.000 micrographs, annotated for cellular and ultrastructural changes during autoimmune diabetes. Granulocytes are attracted to the endocrine tissue, followed by extravasation of a pleiotrophy of leukocytes. Subcellullar changes in beta cells include endoplasmic reticulum stress, insulin degranulation and glycogen accumulation. Rare findings include erythrocyte extravasation and nuclear actin like fibers. While we focus on a rat model of autoimmune diabetes, our approach is general applicable. PMID- 23652857 TI - Subacute sclerosing panencephalitis case presenting with cortical blindness: early diagnosis with MRI and MR spectroscopy. PMID- 23652856 TI - How reliable are pseudocontact shifts induced in proteins and ligands by mobile paramagnetic metal tags? A modelling study. AB - The anisotropic component of the magnetic susceptibility tensor (Deltachi tensor) associated with various paramagnetic metal ions can induce pseudocontact shifts (PCSs) and residual dipolar couplings (RDCs) in proteins, yielding valuable restraints in structural studies. In particular, PCSs have successfully been used to study ligands that bind to proteins tagged with a paramagnetic metal ion, which is of great interest in fragment-based drug design. To create easy-to interpret PCSs, the metal ion must be attached to the protein in a rigid manner. Most of the existing methods for site-specific attachment of a metal tag, however, result in tethers with residual flexibility. Here we present model calculations to quantify the extent, to which mobility of the metal-binding tag can compromise the quality of the Deltachi tensor that can be determined from the PCSs observed in the protein. Assuming that the protein can be approximated by a sphere and the tag is attached by a single tether, the results show that a single effective ?chi tensor can describe the PCSs and RDCs of the protein spins very well even in the presence of substantial tag mobility, implying that PCSs of ligands in binding pockets of the protein can be predicted with similar accuracy. In contrast, the quality of the PCS prediction for nuclear spins positioned above the surface of the protein is significantly poorer, with implications for studies of protein-protein complexes. The simulations probed the sensitivity of the effective Deltachi tensor to different parameters, including length of the tether between protein and metal ion, protein size, type and amplitude of tag motion, tensor orientation relative to the protein and direction of tag motion. Tether length and amplitude of motion were identified as two key parameters. It is shown that the amplitude of tag motions cannot be quantified by simple comparisons of the effective Deltachi tensor with the alignment tensor determined from RDCs. PMID- 23652858 TI - Tungsten coil disappearance and SAH recurrence 12 years after endovascular embolisation. PMID- 23652859 TI - Caries prevalence in non-syndromic patients with cleft lip and/or palate: a meta analysis. AB - AIM: To evaluate caries prevalence in non-syndromic patients with cleft lip and/or palate (CLP) in comparison with a matched non-CLP population. METHODS: A literature search was conducted in order to identify articles reporting on the prevalence of caries in CLP versus non-CLP individuals. The related citations function in PubMed and reference lists of retrieved articles were used to expand the search. Only studies with a suitable matched control group were included. From each included study, study and sample characteristics were extracted, as were results. The main outcome was the score given for caries prevalence in each study, using a well-defined index. The data were entered into meta-analysis software and a meta-analysis performed using the random-effects model. RESULTS: From the 592 articles initially identified, 7 were chosen according to preset inclusion and exclusion criteria. All of the studies were cross-sectional in nature, and used the decayed, missing, and filled (DMF/dmf) indices as the final outcomes. The included studies involved a total of 474 CLP patients aged 1.5-29 years. When looking at permanent teeth, data from 5 studies suggest that CLP patients have a higher number of DMF teeth than the controls (mean difference 1.38; p = 0.003). For deciduous teeth, data from 4 studies suggest that CLP patients have a higher number of dmf teeth than the controls (mean difference 1.51; p = 0.03). CONCLUSION: Non-syndromic patients with CLP tend to have higher caries prevalence, both in the permanent and the deciduous dentition, in comparison with matched non-CLP controls. PMID- 23652860 TI - Histopathology of embolic debris captured during transcatheter aortic valve replacement. AB - BACKGROUND: Recent transcatheter aortic valve replacement studies have raised concerns about adverse cerebrovascular events. The etiopathology of the embolized material is currently unknown. METHODS AND RESULTS: A total of 40 patients underwent transcatheter aortic valve replacement with the use of a dual filter based embolic protection device (Montage Dual Filter System, Claret Medical, Inc). Macroscopic material liberated during the transcatheter aortic valve replacement procedure was captured in the device filter baskets in 30 (75%) patients and sent for histopathologic analysis. The captured material varied in size from 0.15 to 4.0 mm. Amorphous calcified material (size, 0.55-1.8 mm) was identified in 5 patients (17%). In 8 patients (27%), the captured material (size, 0.25-4.0 mm) contained valve tissue composed of loose connective tissue (collagen and elastic fibers) with focal areas of myxoid stroma, with or without coverage by endothelial cells and intermixed with fibrin. In another 13 (43%) patients, collagenous tissue, which may represent elements of vessel wall and valvelike structures, was identified. In 9 patients (30%), thrombotic material was intermixed with neutrophils (size, 0.15-2.0 mm). Overall, thrombotic material was found in 52% of patients, and tissue fragments compatible with aortic valve leaflet or aortic wall origin were found in 52% (21/40) of patients. CONCLUSIONS: Embolic debris traveling to the brain was captured in 75% of transcatheter aortic valve replacement procedures where a filter-based embolic protection device was used. The debris consisted of fibrin, or amorphous calcium and connective tissue derived most likely from either the native aortic valve leaflets or aortic wall. PMID- 23652862 TI - Cilostazol: the "poor man's" replacement of drug-eluting stents and balloons? PMID- 23652861 TI - Cilostazol reduces angiographic restenosis after endovascular therapy for femoropopliteal lesions in the Sufficient Treatment of Peripheral Intervention by Cilostazol study. AB - BACKGROUND: It remains unclear whether cilostazol, which has been shown to improve the clinical outcomes of endovascular therapy for femoropopliteal lesions, also reduces angiographic restenosis. METHODS AND RESULTS: The Sufficient Treatment of Peripheral Intervention by Cilostazol (STOP-IC) study investigated whether cilostazol reduces the 12-month angiographic restenosis rate after percutaneous transluminal angioplasty with provisional nitinol stenting for femoropopliteal lesions. Two hundred patients with femoropopliteal lesions treated from March 2009 to April 2011 at 13 cardiovascular centers were randomly assigned 1:1 to receive oral aspirin with or without cilostazol. The primary end point was 12-month angiographic restenosis rate. Secondary end points were the restenosis rate on duplex ultrasound, the rate of major adverse cardiac events, and target lesion event-free survival. Researchers evaluated all follow-up data and assessed the end points in a blinded fashion. The mean lesion length and reference vessel diameter at the treated segment were 128+/-86 mm and 5.4+/-1.4 mm, respectively. The frequency of stent used was similar between groups (88% versus 90% in the cilostazol and noncilostazol group, respectively, P=0.82). During the 12-month follow-up period, 11 patients died and 152 patients (80%) had evaluable angiographic data at 12 months. The angiographic restenosis rate at 12 months was 20% (15/75) in the cilostazol group versus 49% (38/77) in the noncilostazol group (P=0.0001) by intention-to-treat analysis. The cilostazol group also had a significantly higher event-free survival at 12 months (83% versus 71%, P=0.02), although cardiovascular event rates were similar in both groups. CONCLUSIONS: Cilostazol reduced angiographic restenosis after percutaneous transluminal angioplasty with provisional nitinol stenting for femoropopliteal lesions. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00912756; and URL: https://www.umin.ac.jp. Unique identifier: UMIN000002091. PMID- 23652863 TI - Near-infrared phosphorescence: materials and applications. AB - Room-temperature phosphorescent materials that emit light in the visible (red, green, and blue; from 400 to 700 nm) have been a major focus of research and development during the past decades, due to their applications in organic light emitting diodes (OLEDs), light-emitting electrochemical cells, photovoltaic cells, chemical sensors, and bio-imaging. In recent years, near-infrared (NIR) phosphorescence beyond the visible region (700-2500 nm) has emerged as a new, promising, and challenging research field with potential applications toward NIR OLEDs, telecommunications, night vision-readable displays. Moreover, NIR phosphorescence holds promise for in vivo imaging, because cells and tissues exhibit little absorption and auto-fluorescence in this spectral region. This review describes the overall progress made in the past ten years on NIR phosphorescent transition-metal complexes including Cu(I), Cu(II), Cr(III), Re(I), Re(III), Ru(II), Os(II), Ir(III), Pt(II), Pd(II), Au(I), and Au(III) complexes, with a primary focus on material design complemented with a selection of optical, electronic, sensory, and biologic applications. A critical comparison of various NIR phosphorescent materials reported in the literature and a blueprint for future development in this field are also provided. PMID- 23652864 TI - Noncarboplatin-induced Sensorineural Hearing Loss in a Patient With an Intracranial Nongerminomatous Germ Cell Tumor. AB - Treatment for intracranial germ cell tumors includes platinum-based chemotherapy and external beam radiation therapy, which are risk factors for hearing loss. In patients who experience significant sensorineural ototoxicity due to cochlear hair cell injury, dose reduction of chemotherapy may be necessary. This report describes an adolescent male, with excellent treatment response for an intracranial nongerminomatous germ cell tumor, who developed sensorineural hearing loss, which was central rather than cochlear in origin and unrelated to carboplatin. This patient highlights the need to carefully differentiate the type and etiology of sensorineural hearing loss in patients with brain tumors receiving ototoxic chemotherapy. PMID- 23652865 TI - A case of macrophage activation syndrome developing in a patient with chronic granulomatous disease-associated colitis. AB - Although macrophage activation syndrome (MAS) develops in some patients with chronic granulomatous disease (CGD), all of the reported cases have been associated with pathogenic microbial infections. We report a 2-year-old boy with CGD-associated colitis who suffered from MAS without any clinical signs of a microbial infection. He was treated with 1 course of methylprednisolone pulse therapy and the clinical symptoms improved; however, the colitis was difficult to control even with immunosuppressive drugs, and he eventually required hematopoietic stem cell transplantation 1 year after the onset of MAS. It is likely that MAS develops in patients with CGD colitis independent of microbial infections. PMID- 23652866 TI - The use of an intrathecal pump to manage intractable cancer pain in a pediatric patient: a case report. AB - A 15-year-old girl with combined immune deficiency syndrome, diagnosed with metastatic squamous cell cancer of the anus, had significant pain secondary to vulvar-perianal condyloma. Conventional treatment with oral and intravenous analgesics was limited by significant side effects of mental status changes and urinary retention leading to clinical deterioration that precluded attempts at chemotherapy. An intrathecal pump was implanted in the challenging setting of neutropenia. There was a drastic improvement in her quality of life and the ability to tolerate further chemotherapy. The option of an intrathecal pump for pain control extended our patient's ability to enjoy important quality time with family by several months. PMID- 23652867 TI - Gastric metastasis from an alveolar soft part sarcoma in a child: case report and review of the literature. AB - The authors report a child with alveolar soft part sarcoma who developed significant anemia due to gastrointestinal blood loss. Evaluation revealed the source of bleeding as a gastric metastasis, which was successfully removed. A brief review of gastrointestinal involvement by alveolar soft part sarcoma is discussed. PMID- 23652869 TI - A rare occurrence of hairy cell leukemia in a congolese child: a presentation and challenge of diagnosis in low resource settings. AB - BACKGROUND: Hairy cell leukemia is a rare form of leukemia and has been rarely reported in African and pediatric population. OBSERVATION: We are reporting a 4 year-old child who was received for investigation for persistent anemia, prolonged fever, and thrombocytopenia. Bone marrow aspiration showed hypercellular marrow with cells characterized by irregular windblown-appearing cell borders with pseudopod-like projections. Our patient presented with hairy cell leukemia. CONCLUSION: The diagnosis was thought to be most consistent with hairy cell leukemia based on the distinctive morphology of the cells. PMID- 23652870 TI - Translocation t(5;15)(p15;q11-q13) childhood acute lymphoblastic leukemia with heterogeneous prognosis implications. PMID- 23652868 TI - The ability of lumbar spine DXA and phalanx QUS to detect previous fractures in young thalassemic patients with hypogonadism, hypothyroidism, diabetes, and hepatitis-B: A 2-year subgroup analysis from the Taranto Area of Apulia Region. AB - BACKGROUND: Osteoporosis is a leading cause of morbidity in patients affected by beta-thalassemia major or intermediate; we aimed to assess the association between demineralization observed in young thalassemic patients. METHODS: A total of 88 patients with beta-thalassemia were recruited at Microcitemia Center of Taranto Hospital under the Prevention Osteoporosis and Fractures research project from 2008 to 2010. All the patients were screened with both dual energy x-ray absorptiometry (DXA) and quantitative ultrasound (QUS). T score and Z score values were obtained for each subject. RESULTS: The overall prevalence of demineralization was 84% with DXA and 70% with QUS, whereas normality was found in 16% of patients screened with DXA and in 30% of cases with QUS. Hypogonadism, hypothyroidism, diabetes mellitus, hepatitis-B, and the presence of previous fragility fractures were significantly associated with the demineralization status (lower T scores values) both with DXA and QUS. CONCLUSION: Our data confirm that DXA and QUS examinations are both useful for detecting bone demineralization in thalassemic patients. PMID- 23652871 TI - Neurological paraneoplastic syndrome as presentation of leukemia. AB - Acute disseminated encephalomyelitis (ADEM) has been reported in acute leukemia and after stem cell transplantation, but ADEM as a presenting feature in pediatric acute lymphoblastic leukemia is rare. We report an 8-year-old child with acute lymphoblastic leukemia who presented with features of ADEM. The diagnosis was confirmed by neuroimaging and the lesions disappeared with chemotherapy. PMID- 23652872 TI - Colonic malignant peripheral nerve sheath tumor in a child. PMID- 23652873 TI - Chylothorax at presentation in T-cell acute lymphoblastic leukemia: the milky puzzle. PMID- 23652874 TI - Proton pump inhibitor therapy in chemotherapy-induced pancreatitis. PMID- 23652875 TI - Prospective surveillance study of blood stream infections associated with central venous access devices (port-type) in children with acute leukemia: an intervention program. AB - The use of intensive chemotherapy and central devices has improved patients survival, but it is associated with catheter-related blood-stream infections (CRBSI). An educational program was instituted for preventing CRBSI occurrence in acute leukemia pediatric patients having totally implanted central devices. The Centers of Disease Control and Prevention criteria were used as definition for CRBSI. Data collected were age, sex, diagnosis, chemotherapy, inpatient versus outpatient, microbiological data, risk factors, social risk score, and treatment performed. CRBSI rate decreased from 6.7 to 3.7/1000 catheter-days with preventive measures (P=0.05). A further decrease to 1.5/1000 catheter-days was reached after the intensification of the educational program (P=0.01). Severe neutropenia at the time of catheter insertion was related to CRBSI and to infection recurrence (P<0.05). Most of the episodes occurred during induction chemotherapy. Thirty-six CRBSI episodes occurred in 25 of 73 patients. The most frequent microorganism isolated was Staphylococcus spp. Antibiotherapy was successful in 83.3% of episodes. Six patients needed a central venous access device replacement. Our intervention program was successful to decrease the CRBSI rates and its intensification allowed a further decrease, approaching reported rates in this setting. Severe neutropenia at the time of central venous access device insertion was related to CRBSI occurrence and recurrence. PMID- 23652876 TI - Congenital neuroblastoma in a neonate with isotretinoin embryopathy. AB - We describe a neonate with isotretinoin embryopathy and an incidental finding of congenital neuroblastoma. Diffuse liver metastases led to the decision to provide oncologic therapy followed by tumor resection. Despite the possible need for chronic care related to the comorbidities of the isotretinoin embryopathy and oncologic management, the patient remains disease-free. Because of the uncertain etiology of neuroblastoma, it remains unclear whether exposure to isotretinoin during embryogenesis and fetal development had an oncogenic effect on this patient. PMID- 23652877 TI - Significant response to oral Etoposide in the treatment of an unresectable cardiac sarcoma. AB - Primary cardiac sarcomas are rare and carry a poor prognosis. The standard of care is complete resection. Outcomes for patients without complete resection are dismal, and the benefit of adjuvant therapy is uncertain. A 9-year-old girl presented with a large right-sided cardiac mass. After biopsy, the tumor was classified as an undifferentiated sarcoma. Resection was not feasible due to apparent invasion of the right ventricle and atrioventricular groove. Treatment with oral etoposide resulted in a 97% reduction in tumor volume and allowed for complete resection of residual tumor. She is alive with no evidence of disease 25 months from diagnosis. PMID- 23652878 TI - Outcome of children and adolescents with a second or third relapse of acute lymphoblastic leukemia (ALL): a population-based analysis of the Austrian ALL-BFM (Berlin-Frankfurt-Munster) study group. AB - We analyzed outcome of a population-based cohort of 74 children with second and third acute lymphoblastic leukemia (ALL) relapse and aimed to identify prognostic factors. Duration of previous remission and site of relapse appeared of prognostic relevance as patients with a second remission duration >1.5 years and isolated extramedullary relapse did better. Neither patient with a second bone marrow relapse who underwent previous allogeneic transplantation nor patients with T-cell ALL survived. Overall, 7 of 74 (9%) patients are in long-term remission. Stem cell transplantation seemed to be the only curative option for systemic relapse of B-cell precursor ALL as all 4 surviving patients with a second/third relapse involving the bone marrow received a transplant. Conclusively, patients with a second ALL relapse are ideal candidates for phase I/II trials exploring new innovative drugs. PMID- 23652879 TI - Magnetic resonance imaging versus histopathology in Wilms tumor and nephroblastomatosis: 3 examples of noncorrelation. AB - Magnetic resonance imaging (MRI) has become the principal tool for Wilms tumor (WT) assessment and follow-up. MRI and histopathologic findings were not congruent in 2 of the q30 scanned patients with renal masses (2008 to 2011). Three lesions thought to be WT on MRI were found to be a sclerotic nephrogenic rest (1), cystic renal dysplasia (1), and focal chronic pyelonephritis (1). The "typical" features suggesting nephroblastomatosis and WT on MRI are unreliable and such lesions require biopsy for histopathologic diagnosis, especially when nephron-sparing surgery is necessary to preserve renal function. PMID- 23652880 TI - Variants of cardiomyopathy and hypertension in neuroblastoma. AB - Catecholamine-associated cardiomyopathies caused by neuroblastoma have rarely been reported. We are reporting 2 cases of neuroblastoma associated with hypertension and severe cardiomyopathic changes in different extremes. One case was dilated cardiomyopathy with heart failure, and the other showed echocardiographic features simulating hypertrophic obstructive cardiomyopathy. Both girls had high levels of urine catecholamines on presentation. Anthracycline group of chemotherapy was avoided. Chemotherapy and tumor resection resulted in successful normalization of blood pressure and regression of cardiomyopathic changes. Blood pressure and cardiomyopathic changes should be monitored not only at presentation, but also during the treatment for neuroblastoma. PMID- 23652881 TI - Pancytopenia after allogeneic bone marrow transplant due to copper deficiency. AB - Pancytopenia occurring 1 year or later after allogeneic bone marrow transplantation typically prompts a primary consideration for relapse. We present the case of a 15-year old-girl who underwent transplantation for therapy-related myelodysplasia secondary to Ewing sarcoma treatment who developed pancytopenia with myelodysplasia 1 year after transplant due to copper deficiency. Copper deficiency is an important consideration in the evaluation of pancytopenia and myelodysplasia in pediatric patients. PMID- 23652883 TI - A shark liver gene-derived active peptide expressed in the silkworm, Bombyx mori: preliminary studies for oral administration of the recombinant protein. AB - Active peptide from shark liver (APSL) is a cytokine from Chiloscyllium plagiosum that can stimulate liver regeneration and protects the pancreas. To study the effect of orally administered recombinant APSL (rAPSL) on an animal model of type 2 diabetes mellitus, the APSL gene was cloned, and APSL was expressed in Bombyx mori N cells (BmN cells), silkworm larvae and silkworm pupae using the silkworm baculovirus expression vector system (BEVS). It was demonstrated that rAPSL was able to significantly reduce the blood glucose level in mice with type 2 diabetes induced by streptozotocin. The analysis of paraffin sections of mouse pancreatic tissues revealed that rAPSL could effectively protect mouse islets from streptozotocin-induced lesions. Compared with the powder prepared from normal silkworm pupae, the powder prepared from pupae expressing rAPSL exhibited greater protective effects, and these results suggest that rAPSL has potential uses as an oral drug for the treatment of diabetes mellitus in the future. PMID- 23652884 TI - Oral manifestation of Crohn's disease without concomitant gastrointestinal involvement. AB - Crohn's disease (CD) is a chronic relapsing inflammatory disorder of unknown etiology and uncertain pathogenesis with no known cure. CD can involve any segment of the gastrointestinal tract, and oral lesions consistent with granulomatous ulcers are considered an important extra-intestinal manifestation. Oral lesions in the absence of gastrointestinal involvement are rarely reported. We report a case of a 64-year-old man with a history of CD that was in remission for three decades, presenting with painful cobblestone-like ulcerations of the oral mucosa, but without gastrointestinal signs or symptoms. Surgical biopsy of the oral lesions revealed non-necrotizing chronic granulomatous ulcers on histopathologic examination, similar to results from a biopsy of his small intestine three decades previously which established his diagnosis of CD. The patient was successfully treated with potent topical corticosteroids which resulted in resolution of the oral lesions and associated symptoms. PMID- 23652885 TI - Dermatologic disorders in skin of color: moving toward a better understanding. PMID- 23652886 TI - A short educational intervention measurably benefits keloid-prone individuals' knowledge of prevention and treatment. AB - BACKGROUND: The Internet is a commonly utilized health information resource that provides access to information of varying quality. OBJECTIVE: We sought to evaluate the use of the Internet as a health information resource within a keloid patient population and the effects of an educational intervention on patient knowledge about keloids.
METHODS: A consecutive convenience sample of subjects completed a questionnaire on keloid-related Internet use and on personal and family history of keloids. Participants listened to a short educational intervention on keloid-related topics followed by assessment of relevant knowledge at baseline, immediately postintervention, and 3 months after the intervention. RESULTS: Among 40 participants, 55% reported having used the Internet to obtain keloid-related information. Subjects who had used the Internet to obtain keloid-related information had baseline knowledge similar to those who had not. When subjects were assessed immediately and 3 months postintervention, the intervention improved knowledge that not all raised scars are keloids, that keloids are not cancerous, and that certain areas of the body are more prone to keloid formation. The proportion of subjects who reported being less likely to obtain piercings or tattoos because of the intervention was 80% and 75%, respectively. LIMITATIONS: This study was performed at a single academic center. CONCLUSION: The Internet is a commonly used information resource for keloid-prone individuals, but keloid-related knowledge was not greater among Internet keloid related information seekers. A very short educational intervention benefits keloid-prone individuals by improving knowledge about keloid prevention and treatment and by discouraging them from obtaining piercings and tattoos. PMID- 23652887 TI - Keloids: an update on medical and surgical treatments. AB - Keloids are the result of an overgrowth of dense fibrous tissue that usually develops after healing of a skin injury. Despite their common occurrence, keloids remain one of the most challenging dermatologic conditions to successfully treat. They are often symptomatic, do not usually regress spontaneously, and tend to recur after excision. Prevention of keloids is essential. A previous history of keloid development should be elicited. Wound closure with minimal tension and application of adjunctive therapies before abnormal healing is paramount. Education regarding wound care should be given in order to prevent infection and foreign body reactions. Elective surgery should be avoided in patients predisposed to developing keloids. In this article, we review recent advances in medical and surgical treatment of keloids. PMID- 23652888 TI - Shave frequency and regimen variation effects on the management of pseudofolliculitis barbae. AB - BACKGROUND: Pseudofolliculitis barbae (PFB) is an inflammatory condition of the face with a clinical presentation of papules in the beard area with occasional pustules or hypertrophic scarring, all of which develop in response to shaving. Prevalent in African American men, a limited amount of data have been published on the shave outcomes as they relate to clinically measurable responses and patient satisfaction scoring. The primary purpose of this study is to evaluate the impact of a daily shaving regimen and advanced shaving products on exacerbation of lesions and symptoms in patients with PFB. METHODS: Ninety African American men were randomized to 1 of 3 treatment groups shaving 2 to 3 times per week with standard products (control group), shaving daily with standard products (daily standard group) or shaving daily with advanced products (daily advanced). The number of pustules, papules, ingrown hairs, and investigator's assessment of severity and subjective symptoms of itching and burning/stinging were assessed at baseline, week 6, and week 12. The response to treatment was also assessed by the investigator and the subject at weeks 6 and 12. Secondary measures including questionnaires regarding baseline shave practices were also correlated with outcomes variables. RESULTS: There were no significant differences noted between the 3 groups for papule (P=.32) or pustule (P=.46) count for the 12-week study. However, there was a significant mean papule reduction from baseline detected for both the control and daily advanced groups. In addition, compared to baseline, there was a significant reduction in ingrown hairs for the control group, and a directional reduction in ingrown hairs for the daily advanced group. There were significant group differences between the control group and both daily shaving groups, with the control group seeing significantly fewer ingrown hairs (P=.005 for control vs daily standard group and P=.04 for control vs daily advanced group). There were no significant group differences among the 3 groups for investigator-graded severity (P=.43) and response to treatment (P=.51). There was a significant perceived improvement in the response to treatment (P=.007) and itching (P=.002) for the daily advanced group vs the control group. PMID- 23652889 TI - Hair and scalp disorders in ethnic populations. AB - Human hair has been classified into 3 major groups, as determined by ethnic origin. In these populations, significant structural and biochemical variations of the hair follicle and shaft are seen, as well as unique hair grooming practices. These structural variations of the hair are closely linked to the common disorders of the hair and scalp, such as acquired trichorrhexis nodosa, seborrheic dermatitis, traction alopecia, central centrifugal cicatricial alopecia, dissecting cellulitis, frontal fibrosing alopecia, and pseudofolliculitis barbae. PMID- 23652890 TI - A retrospective chart review to assess the safety of nonablative fractional laser resurfacing in Fitzpatrick skin types IV to VI. AB - BACKGROUND: Laser resurfacing in patients with Fitzpatrick skin phototypes (SPT) IV to VI is associated with a higher risk of pigmentary alteration. There is a paucity of studies evaluating optimum treatment parameters for fractional lasers in darkly pigmented skin types. METHODS: This is a retrospective review of medical records for patients with SPT IV to VI who were treated with a 1,550 nm erbium-doped fractional nonablative laser (Fraxel Re:Store SR 1550; Solta Medical, Hayword, CA). Data were collected from patient charts and the clinic laser logbook from January 2008 to January 2012. The frequency of treatment associated postinflammatory hyperpigmentation (PIH) and treatment settings used were evaluated. RESULTS: A total of 115 total laser sessions (45 patients) were included in our analysis. Five of the sessions (4%) were accompanied by PIH, 2 of which occurred in a single patient. Only 1 episode of PIH lasted longer than 1 month (2 months). Two of the 5 cases had only transient PIH (<=7 days), one of which was reported by the patient and not clinically evident on examination. CONCLUSION: The 1,550 nm erbium-doped fractional laser is well tolerated in SPT IV to VI. Fractional laser resurfacing, with the settings used and pretreatment and posttreatment hydroquinone 4% cream, was associated with a low risk of PIH in darker skin types. PMID- 23652891 TI - Retinoids and azelaic acid to treat acne and hyperpigmentation in skin of color. AB - In this review, we examine published data reporting the efficacy of pharmaceutical agents to treat associated postinflammatory hyperpigmentation commonly seen in skin of color. Retinoids and azelaic acid have been widely used to treat acne. Now there are increasing data describing their use in skin of color for the treatment of both acne and the subsequent postinflammatory hyperpigmentation. Historically, some dermatologists have been hesitant to use retinoids in skin of color because of perceived hypersensitivity in this patient population. However, recent data support the use of retinoids and azelaic acid in skin of color as both safe and beneficial. PMID- 23652893 TI - A double-blind, placebo-controlled pilot study to estimate the efficacy and tolerability of a nonsteroidal cream for the treatment of cradle cap (seborrheic dermatitis). AB - This study was a multicenter, double-blind, placebo-controlled, parallel-group pilot study of efficacy and tolerability of a nonsteroidal cream (Promiseb(r) Topical Cream; Promius Pharma, LLC, Bridgewater, NJ) for treatment of cradle cap when applied topically twice daily for up to 14 days in 42 pediatric subjects. Both treatments were similarly effective in reducing disease severity, as measured by success with Investigator's Global Assessment scores at day 7 or end of treatment, with 96% of subjects achieving success in the nonsteroidal cream group and 92% of subjects achieving success in the placebo cream group. Both treatments resulted in significant reductions from baseline in terms of erythema, crusting, scaling, and oiliness (P<.05), with no significant difference between treatments. There was a significant difference (P=.03) between treatment groups for percent reduction in scaling at the end of treatment, with a 90% reduction in the nonsteroidal cream group compared with a 58% reduction in the placebo cream group. All subjects in both groups had an overall safety score of excellent, and there were no adverse events related to treatment for either group. PMID- 23652892 TI - The efficacy and tolerability of tazarotene foam, 0.1%, in the treatment of acne vulgaris in 2 multicenter, randomized, vehicle-controlled, double-blind studies. AB - BACKGROUND: Tazarotene 0.1% gel and cream are effective topical treatments for acne. Tazarotene foam, 0.1% was developed to provide an alternative, safe, and effective formulation. OBJECTIVE: To evaluate efficacy and tolerability of tazarotene foam, 0.1% in adults and adolescents with acne vulgaris. METHODS: Two randomized, double-blind, vehicle-controlled, parallel-group studies were conducted at 39 centers in the United States and Canada. The first study involved 744 participants and the second 742, aged 12 to 45 years, who were randomized to receive treatment with either tazarotene foam, 0.1% or vehicle foam once daily for 12 weeks. Lesion counts, Investigator's Static Global Assessments (ISGA), and Subject's Global Assessments (SGA) were evaluated at baseline and weeks 2, 4, 8, and 12. Tolerability was monitored throughout the study. RESULTS: At week 12 in both studies, treatment with tazarotene foam led to greater decreases from baseline in mean absolute and percentage change in lesion counts (noninflammatory, inflammatory, and total), greater proportion of participants with >=2-grade improvement in ISGA score, and greater proportion of participants with ISGA score of 0 or 1 than vehicle treatment (P<.001 for all). Only application-site skin irritation and dryness were reported by >5% of participants in active treatment groups in both studies. LIMITATIONS: The efficacy and tolerability of tazarotene foam were not compared directly with those of other formulations. CONCLUSION: Tazarotene foam, 0.1% significantly reduced the number and severity of acne lesions after 12 weeks and had a safe and acceptable tolerability profile. PMID- 23652894 TI - The effects of filtrate of the secretion of the Cryptomphalus aspersa on photoaged skin. AB - BACKGROUND: Growth factors (GFs) are chemical messengers that regulate specific cellular activities such as cell proliferation and formation of the extracellular matrix. GFs may be derived from a variety of sources, including animals. OBJECTIVE: Evaluate the safety and efficacy of a topical antiphotoaging product containing secretions of the snail Cryptomphalus aspersa (SCA) for the improvement of facial rhytides. MATERIALS AND METHODS: This was a 2-center, double-blind, randomized, 14-week study in which 25 patients with moderate to severe facial photodamage were treated with an emulsion (with 8% SCA) and liquid serum (with 40% SCA) on one side of the face and placebo on the contralateral side for 12 weeks. Silicone skin impressions of periocular rhytides were performed at baseline and after 12 weeks of treatment. Patient and physician assessments were also performed at 8, 12, and 14 weeks. RESULTS: Periocular rhytides on the active ingredient side showed significant improvement after 12 weeks (P=.03) and improved texture to a greater degree than placebo at 8 and 12 weeks, as well as 2 weeks after discontinuing the product (14 weeks). CONCLUSION: Daily application of topical products containing SCA proved effective and well tolerated for improvement in coarse periocular rhytides and fine facial rhytides. Subjects noted a significant degree of improvement in fines lines at the 8-week time point on the SCA-treated side (P<=.05) but did not report a significant difference in the quality of their skin. PMID- 23652895 TI - Vitamin A and its derivatives in experimental photocarcinogenesis: preventive effects and relevance to humans. AB - The 1925 classical observation that vitamin A deficiency leads to squamous metaplasia and epithelial keratinization, coupled with the later finding that excess vitamin A inhibits keratinization of chick embryo skin, set the foundation for the potential therapeutic use of retinoids in cutaneous conditions of keratinization. Significant progress has since been made understanding the molecular biology, biochemistry, pharmacology, and toxicology of vitamin A and its derivatives, collectively named retinoids. Natural and synthetic retinoids are now routinely used to treat acne, psoriasis, skin keratinization disorders, and photodamage. Retinoids also inhibit tumor formation and skin cancer development in experimental systems and in humans. Retinol and retinyl palmitate (RP) are found in cosmetic products and in foods and dietary supplements, which are all considered safe, by inclusion in the Generally Recognized as Safe Substances Database. However, the safety of topical retinoids was questioned in one publication and in a recent National Toxicology Program report of RP containing topical preparations, suggesting the possible earlier onset of ultraviolet-induced squamous cell carcinomas in the hairless mouse photocarcinogenesis model. This suggestion contradicts a large body of data indicating that topical retinoids are chemoprotective in humans, and it was immediately challenged by new reviews on the safety of RP in general and within sunscreens. This paper will review the preclinical and clinical data supporting the safety and chemopreventive activity of retinoids, with an emphasis on RP, and will examine the experimental systems used to evaluate the safety of topical vitamin A preparations in order to provide perspective relative to human skin. PMID- 23652896 TI - Protective effects of a topical antioxidant complex containing vitamins C and E and ferulic acid against ultraviolet irradiation-induced photodamage in Chinese women. AB - OBJECTIVE: The objective of the study was to investigate whether a topical antioxidant complex containing vitamins C and E and ferulic acid can protect solar-simulated ultraviolet irradiation (ssUVR)-induced acute photodamage in human skin. METHOD: Twelve healthy female Chinese subjects were enrolled in this study. Four unexposed sites on dorsal skin were marked for the experiment. The products containing antioxidant complex and vehicle were applied onto 2 sites, respectively, for 4 consecutive days. On day 4, the antioxidant complex-treated site, the vehicle-treated site, and the untreated site (positive control) received ssUVR (5 times the minimal erythema dose). The fourth site (negative control) received neither ssUVR nor treatment. Digital photographs were taken, and skin color was measured pre- and postirradiation. Skin biopsies were obtained 24 hours after exposure to ssUVR, for hematoxylin and eosin and immunohistochemical staining. RESULTS: A single, 5 times the minimal erythema dose of ssUVR substantially induced large amounts of sunburn cell formation, thymine dimer formation, overexpression of p53 protein, and depletion of CD1a+ Langerhans cells. The antioxidant complex containing vitamins C and E and ferulic acid conferred significant protection against biological events compared with other irradiated sites. CONCLUSION: A topical antioxidant complex containing vitamins C and E and ferulic acid has potential photoprotective effects against ssUVR-induced acute photodamage in human skin. PMID- 23652897 TI - A 12-month, prospective, evaluator-blinded study of small gel particle hyaluronic acid filler in the correction of temporal fossa volume loss. AB - OBJECTIVE: The primary objective of this study is to examine the use and persistency of small gel particle hyaluronic acid (SGP-HA) filler (Restylane(r); Medicis Aesthetics Inc, Scottsdale, AZ) in the treatment of temporal fossa volumization over a 12-month follow-up, and determine local adverse events (AEs). STUDY DESIGN: This is a US Food and Drug Administration-approved, blinded, prospective, single-center, open-label trial enrolling 20 subjects undergoing subcutaneous injection of SGP-HA for rejuvenation of the temples. Primary outcomes were measured using a standardized grading system—the Hollowness Severity Rating Scale (HSRS)—at each visit by the treating investigator, a blinded physician assessment of randomized photos using the HSRS, and patient questionnaires over a 12-month period. AEs were monitored by the investigator and via patient diaries. RESULTS: At weeks 4, 12, and 24, and month 12, all graders (ie, investigator, blinded physician assessor, and patients) reported improvement overall in hollowness. At baseline, temporal fossa hollowness was measured as moderate to severe. At week 4 to month 12, temporal fossa was graded at none or only mild hollowness. No touch-ups were necessary at week 4 on all subjects. All AEs were mild or moderate and resolved within 2 weeks. CONCLUSION: Our study demonstrates clinically significant efficacy and safety in the use of Restylane for temple augmentation and, thus, facial rejuventation. PMID- 23652898 TI - New world cutaneous leishmaniasis: obstacles in initiating treatment with sodium stibogluconate in 2 travelers from Texas. AB - New World cutaneous leishmaniasis (CL) is considered in the differential diagnosis for patients with nonhealing ulcers and a history of travel to high risk areas. For patients at risk for progression to mucocutaneous leishmaniasis, first-line treatment in the United States entails the use of sodium stibogluconate (SSG), which is obtained from the Centers for Disease Control and Prevention (CDC) under an investigational drug protocol. We report 2 cases of New World CL in travelers to endemic areas who were diagnosed and treated with SSG. These cases demonstrate the logistics of coordinating with the CDC to definitively diagnose New World CL and initiate the necessary treatment. PMID- 23652900 TI - Novel use of topical dapsone 5% gel for erythema elevatum diutinum: safer and effective. AB - We present a case of an otherwise healthy 81-year-old gentleman with multiple asymptomatic, erythematous, indurated papules and plaques, ranging in size from 0.5 to 1.5 cm, involving the dorsal, lateral, and palmar surfaces of the fingers bilaterally. A clinical suspicion of erythema elevatum diutinum (EED) led to initial treatment with topical dapsone 5% gel (ACZONE; Allergan Inc, Irvine, CA). Lesional biopsy demonstrated a dense perivascular infiltration of polymorphonuclear leukocytes and chronic inflammatory cells with perivascular fibrin deposition. Focal neutrophilic infiltration of superficial dermal blood vessel walls was present, suggesting a leukocytoclastic vasculitis. Stains for bacteria and fungi were negative. Clinicopathologic findings were consistent with EED, and in the interim, improvement with topical dapsone 5% gel was noted. Addition of oral dapsone led to complete resolution of the lesions. We present this case to illustrate the subtle, indolent clinical presentation of EED and demonstrate the uncomplicated use of topical dapsone 5% gel for rapid improvement and subsequent successful treatment of localized disease. PMID- 23652903 TI - Resident Rounds. Part III. Cutaneous Mycobacterium avium-intracellulare resembling sarcoidosis. PMID- 23652902 TI - Case experience of 308-nm excimer laser therapy compatibility with PUVA and oral bexarotene for the treatment of cutaneous lesions in mycosis fungoides. AB - Little is known about the safety and effectiveness of excimer laser therapy when used in conjunction with other therapies in the treatment of mycosis fungoides (MF) lesions. We describe the use of adjunctive excimer laser therapy in combination with psoralen plus ultraviolet A (PUVA) and oral bexarotene for the treatment of recalcitrant and sanctuary plaques in a patient with MF. In our patient, this regimen successfully induced clinical and histologic resolution in MF plaques with minimal side effects limited to mild, short-lived tenderness and, rarely, local erythema. Our experience suggests that adjunctive excimer laser therapy with PUVA and oral bexarotene has the potential to be a safe, well tolerated, and effective focal treatment regimen for cutaneous MF lesions. PMID- 23652904 TI - Tattoo removal: new laser options. PMID- 23652907 TI - Undesirable effects after treatment with dermal fillers. AB - BACKGROUND: Soft tissue augmentation is one of the most frequent techniques in cosmetic dermatology. Nowadays, there are a high number of available materials. Nonanimal hyaluronic acid (HA) is one of most useful fillers for lip augmentation and for treating nasolabial folds, marionette lines, and the dynamic wrinkles of the upper face. OBJECTIVE: To evaluate the type and management of undesirable effects of nonanimal reticulated or stabilized HA observed in our cosmetic unit in the past 3 years. MATERIALS AND METHODS: The consecutive patients using HA attending to our clinic in the past 3 years were divided into 3 categories, according to the time of presentation of the adverse reactions: immediate, early, and late-onset complications. All patients were treated. RESULTS: Twenty-three patients presented to our clinic complaining of complications after soft tissue augmentation with HA. Ten patients presented immediate-onset complications, 8 showed early-onset complications, and 5 cases complaint of late-onset complications. Treatment of the first group consisted of hyaluronidase injection, massage, and topical antibiotics. Early- and late-onset complications were treated with intralesional triamcinolone acetonide. All patients improved, with the exception of a woman with recurrent granulomas. CONCLUSION: Generally, undesirable effects of HA (immediate, early, or late onset) are not frequent, and when present, they improve if treated properly. Physicians need to be aware of these possible adverse events in order to establish proper treatment and prevent scarring or other sequelae. PMID- 23652908 TI - The therapeutic effects of a topical tretinoin and corticosteroid combination for vitiligo: a placebo-controlled, paired-comparison, left-right study. AB - BACKGROUND: Topical all-trans-retinoic acid (tretinoin) prevents skin atrophy induced by long-term use of topical corticosteroids, without abrogating their anti-inflammatory effects. OBJECTIVE: The goal of this study was to determine the efficacy of tretinoin plus topical corticosteroids (tretinoin plus) for repigmentation in patients with vitiligo. METHODS: A placebo-controlled, paired comparison, left-right study was conducted for a period of 6 months on tretinoin plus and the vehicle plus the same topical corticosteroid (vehicle plus) treatment in 50 patients diagnosed with generalized vitiligo. Clinical responses were assessed using the computerized analysis, and the results were compared with the visual analysis. RESULTS: The percentage agreement between the 2 analyses was 91.8%. Among 49 participants who successfully completed this study, 27 (55%) showed a better response to tretinoin plus than to vehicle plus. The improved response was noted at an early stage of treatment, during the first 3 months in 60% of patients. CONCLUSION: Combined therapy with tretinoin plus topical corticosteroids is safe and effective and provides another option for treatment of patients with vitiligo. PMID- 23652909 TI - The therapeutic role of isotretinoin in the management of Behcet's disease: a single-blinded, controlled therapeutic study. AB - OBJECTIVES: To evaluate the long-term remission efficacy and safety of isotretinoin in the treatment of Behcet's disease (BD). PATIENTS AND METHODS: This single-blind, controlled therapeutic study was conducted in the Department of Dermatology and Venereology at Baghdad Teaching Hospital from February 2011 to January 2012. Thirty patients with BD were included in this work. Each patient received isotretinoin 20 mg orally once daily for 3 months. They were assessed at week 2 and then monthly depending on the Clinical Manifestation Index (CMI) and to record any side effects. At week 12, isotretinoin was stopped and patients were given placebo therapy in a form of glucose capsules for another 3 months. RESULTS: Thirty patients were treated, 14 (46.6%) males and 16 (53.3%) females, with a male to female ratio of 1:1. Their ages ranged from 16 to 64 years (mean +/- standard deviation [SD], 38.4 +/- 10.9 years). During the first 3 months of therapy, the pathergy test, oral pathergy test, and C-reactive protein were significantly minimized. The CMI before isotretinoin therapy ranged between 2 and 8 (mean +/- SD, 4.933 +/- 1.91). After therapy, within the first 14 days, the mean CMI started to decline to a lower level, and it continued to decline significantly until week 12. It then started to increase through week 4 of placebo therapy, but remained statistically significant until the second month of placebo therapy. Isotretinoin therapy also had a statistically significant effect in reducing oral ulcers and skin manifestations. CONCLUSION: Isotretinoin is an effective therapeutic and prophylactic drug in the management of BD. PMID- 23652910 TI - Endoscopically assisted percutaneous transesophageal gastrotubing: a retrospective pilot study. AB - BACKGROUND: Percutaneous transesophageal gastrotubing (PTEG) was developed as an alternative route to access the gastrointestinal tract when percutaneous endoscopic gastrostomy is contraindicated. PTEG was originally performed without endoscopy. However, endoscopy may enhance safety. MATERIALS AND METHODS: A percutaneous rupture-free balloon is inserted under ultrasonographic control into an upper esophageal puncture site with a specialized needle. A guidewire is inserted through the needle into the rupture-free balloon, followed by a dilator and sheath. A placement tube is then inserted through the sheath. PTEG was performed in 85 patients (56 men and 29 women, mean age 70.5 years), 30 under fluoroscopic guidance and 55 under endoscopic guidance. These groups were subdivided into the nutrition subgroup (fluoroscopy, 20 patients; endoscopy, 23) and the decompression subgroup (fluoroscopy, 10 patients; endoscopy, 32) according to the purpose of PTEG. RESULTS: Nine (30%) of the 30 patients in the fluoroscopy group required endoscopic assistance to complete the procedure. None of the patients in the endoscopy group required fluoroscopy (P<0.05). The overall complication rate of PTEG was 16.4%. Complication rates in the nutrition and decompression subgroups were, respectively, 20.0 and 20.0% in the fluoroscopy group and 17.4 and 12.5% in the endoscopy group (NS). No patient required surgery or died because of the procedure. Survival rates did not differ significantly between the groups. CONCLUSION: Endoscopically assisted PTEG is a feasible, safe, and useful procedure. The use of endoscopy enhances visual information, may increase the safety of the procedure, and allows better confirmation of each step involved, without radiation exposure. PMID- 23652911 TI - Anorectal incontinence: a challenge in diagnostic and therapeutic approach. AB - Anorectal incontinence is a symptom of a complex multifactorial disorder involving the pelvic floor and anorectum, which is a severe disability and a major social problem. Various causes may affect the anatomical and functional integrity of the pelvic floor and anorectum, leading to the anorectal continence disorder and incontinence. The most common cause of anorectal incontinence is injury of the sphincter muscles following delivery or anorectal surgeries. Although the exact incidence of anorectal incontinence is unknown, various studies suggest that it affects ~2.2-8.3% of adults, with a significant prevalence in the elderly (>50%). The successful treatment of anorectal incontinence depends on the accurate diagnosis of its cause. This can be achieved by a thorough assessment of patients. The management of incontinent patients involves conservative therapeutic procedures, surgical techniques, and minimally invasive approaches. PMID- 23652912 TI - Mean platelet volume as a surrogate marker of inflammation in patients with chronic hepatitis B. PMID- 23652914 TI - Clinical and laboratory features and natural history of seronegative hepatitis in a nontransplant centre. AB - BACKGROUND: Seronegative hepatitis is a recognized cause of liver failure requiring transplantation. The aetiology is unknown, but might relate to an unidentified virus or immune dysregulation. There are few data on seronegative hepatitis presenting to nontransplant centres. OBJECTIVES: To describe the clinical/laboratory features and natural history of seronegative hepatitis and compare these with viral/autoimmune hepatitis. METHODS: Cases of seronegative, viral and autoimmune hepatitis were identified from 2080 consecutive patients attending a rapid-access jaundice clinic over a 14-year period. RESULTS: Of 881 patients with hepatocellular jaundice, 27 (3%) had seronegative hepatitis, 44 (5%) autoimmune and 62 (7%) viral hepatitis (acute hepatitis A, B, C and E viruses). Fifteen out of 27 (56%) patients with seronegative hepatitis were male, median age 60 years (range 14-74). Peak bilirubin was 63 MUmol/l (range 9-363), alanine aminotransferase 932 IU/l (range 503-3807). Duration of illness was 7 weeks (range 4-12). No patients developed liver failure or had further bouts of hepatitis. One patient developed acute lymphoblastic leukaemia shortly after presentation.There was no difference in age/sex of patients with seronegative hepatitis and those with viral hepatitis. Compared with autoimmune hepatitis (age 65 years, range 15-91), patients with seronegative hepatitis were younger (P=0.002) and more likely to be male (P=0.004). Patients with autoimmune hepatitis were more likely (P<0.0001) to have an albumin less than 35 g/l, international normalized ratio greater than 1.2, raised IgG and positive antinuclear/smooth muscle antibody, compared with patients with seronegative hepatitis. CONCLUSION: Seronegative hepatitis presenting to a nontransplant centre is generally a self-limiting illness. The aetiology is more likely to be viral than autoimmune. PMID- 23652913 TI - The comparison of the efficacy of pegylated interferon alpha-2a and alpha-2b in chronic hepatitis B patients. AB - BACKGROUND/AIM: Although 48-week therapy with pegylated-interferons has been shown to be effective for the treatment of chronic hepatitis B (CHB), comparison of the efficacy of pegylated-interferon alpha-2a (Peg-IFNalpha-2a) and Peg IFNalpha-2b in the therapy is not obvious. We aimed to compare the efficacy of Peg-IFNalpha-2a versus Peg-IFNalpha-2b in the treatment of CHB. PATIENTS AND METHODS: Fifty-one CHB patients treated with 48 weeks of Peg-IFNalpha-2a (n=24) and Peg-IFNalpha-2b (n=27) who had been followed up between 2009 and 2011 at the Liver Clinic of Adana Numune Training and Research Hospital, Turkey, were investigated retrospectively. Six (25%) patients in the Peg-IFNalpha-2a group and nine (33%) in the Peg-IFNalpha-2b group were HBeAg-positive. Serum HBV-DNA, HBeAg, and HBsAg values were assessed at baseline. Biochemical and virological responses were evaluated every 12 weeks during the course of the treatment, at the end of the treatment, and follow-up week 24. Sustained virological response (SVR) was defined as sustained inhibition of viral replication (HBV-DNA<10 000 copies/ml) and a normal alanine aminotransaminase level until 24 weeks after treatment. Undetectable HBV-DNA was considered as less than 400 copies/ml. RESULTS: Six of the 24 (25%) patients treated with Peg-IFNalpha-2a versus eight of the 27 (29.6%) patients treated with Peg-IFNalpha-2b achieved an SVR (P=0.75). HBeAg seroconversion occurred in three patients only in the Peg-IFNalpha-2b group. Rates of patients with undetectable HBV-DNA at 24 weeks after a 48-week course of therapy were 20.8% for Peg-IFNalpha-2a and 22.2% for Peg-IFNalpha-2b (P=0.82). CONCLUSION: In CHB, there were no significant differences between Peg IFNalpha-2a and Peg-IFNalpha-2b treatment groups in achieving an SVR and undetectable HBV-DNA levels. PMID- 23652915 TI - Comparison of the outcomes of patients who underwent deceased-donor or living donor liver transplantation after successful downstaging therapy. AB - BACKGROUND: Many controversies exist on the different outcomes of living-donor liver transplantation (LDLT) or deceased-donor liver transplantation (DDLT) for hepatocellular carcinoma (HCC) recipients. AIMS: We aimed to determine the difference in outcomes between HCC patients who underwent LDLT or DDLT after successful downstaging therapy. PATIENTS AND METHODS: Eighty-three adult patients were diagnosed with advanced HCC and received a liver transplantation after various successful downstaging therapies: 31 patients underwent LDLT and 52 patients underwent DDLT. We retrospectively collected and analyzed the data of these two groups. RESULTS: The LDLT and DDLT groups showed similar overall complication rates and mortality rates. The overall 1-, 3- and 5-year recurrence free rates were 77.4, 71, and 62.7% after LDLT and 80.7, 69.2, and 60.5% after DDLT (P=0.771). The overall patient survival rates at 1, 3, and 5 years were 90.3, 74.2, and 71% after LDLT and 90.4, 71.2, and 67.3% after DDLT (P=0.860). The 1-, 3-, and 5-year post-transplant hepatitis B virus recurrence rates were 4, 5, and 10.5%, respectively, for the patients who underwent LDLT and 2.6, 6.7, and 10.7%, respectively, for the patients who underwent DDLT (P=0.918). CONCLUSION: These data strongly suggest that no significant differences in postoperative complications, tumor recurrence rate, survival rate, and hepatitis B virus recurrence exist between DDLT and LDLT patients. PMID- 23652916 TI - Hepatitis C antiviral treatment outcomes are comparable between clinical trial participants and recipients of standard-of-care therapy: an analysis of trial effect. AB - BACKGROUND: Trial effect refers to the impact of clinical trial participation on treatment outcomes. Little literature exists evaluating the magnitude and direction of trial effect in hepatitis C virus (HCV). METHODS: A single-center, retrospective study on HCV antiviral therapy recipients was conducted. Sustained virologic response (SVR), virologic response at treatment weeks 4 and 12, dose interruptions, and adverse events were compared between clinical trial participants and standard-of-care antiviral recipients between September 2000 and November 2011. RESULTS: A total of 449 patients were evaluated (trial: 89, nontrial: 360). Patients were matched for age (trial: 47 years, nontrial: 45 years), sex (male: trial, 74%; nontrial, 72%), and ethnicity (white: trial, 87%; nontrial, 78%). The groups differed in the incidence of genotype 1 infection (trial: 83%, nontrial 53%; P<0.001), liver biopsy rates (trial: 98%, nontrial: 66%; P<0.001), and history of psychiatric illness (trial: 30%, nontrial: 53%; P<0.001). On intent-to-treat analysis, SVR rates were found to be similar (trial: 51%, nontrial: 54%; P=0.86), even when stratified for genotype (G1: trial, 47%; nontrial, 47%; P=0.78). Interferon dose reductions (trial: 18%, nontrial: 6%; P<0.01) were more likely in trial patients, whereas treatment discontinuation because of side effects (trial: 8%, nontrial: 18%; P<0.02) was less likely in them. No differences in safety issues were identified. CONCLUSION: Overall, a trial effect resulting in improved or diminished SVR rates was not identified. Other potential positive and negative variables should be focused upon for HCV patients deliberating between clinical trial participation and receiving standard of-care treatment. PMID- 23652917 TI - Role of the surface-subsurface interlayer interaction in enhancing oxygen hydrogenation to water in Pd3Co alloy catalysts. AB - Based on density functional theory calculations, we present mechanisms underlying the improvement in the catalytic performance of Pd-based alloys for oxygen hydrogenation to water. As a model case, we consider the Pd/Pd3Co system where one or two Pd overlayers are located on top of the bimetallic substrate. Our calculations clearly demonstrate that the subsurface Co atoms assist in facilitating the oxygen reduction reaction by lowering the activation barriers for O/OH hydrogenation with a slight increase in the O2 scission barrier; however, we also find that the Co atoms lying below the subsurface have no significant contribution in altering the surface reactivity towards oxygen hydrogenation. The analysis of intra- and interlayer orbital interactions in the near-surface region elucidates the synergetic interplay between the surface electronic structure modification due to the underlying Co atoms (interlayer ligand effect) and the compressive strain caused by the Pd3Co substrate. This result also brings to light the significant contribution of the out of plane (d(xz) and d(yz)) states in altering the surface reactivity towards O hydrogenation. PMID- 23652918 TI - Partial trisomy 2p and partial monosomy 2q arising from a paternal intrachromosomal 2q-into-2p between-arm insertion and paracentric inversion: molecular cytogenetic characterization of a four-break rearrangement. AB - We report on a 26-month-old boy with an interstitial duplication of 2p22.3p22.2 and an interstitial deletion of 2q14.1q21.2. The abnormality was derived from his father having a balanced paracentric inversion and pericentric insertion. The deletion in the child was identified by cytogenetic analysis and characterized in more detail by molecular cytogenetics and array comparative genomic hybridization. The latter revealed a 20-Mb deletion in the long arm and a 5.6-Mb duplication in the short arm of chromosome 2. Fluorescence in situ hybridization in paternal chromosomes characterized an intrachromosomal insertion of 2q14.1q21.2 into 2p23; additionally a paracentric inversion of 2p13p23 was observed. The boy with the unbalanced karyotype suffered from severe psychomotor retardation, thrombophilia due to protein C deficiency, and hypertrophic cardiomyopathy and also had phenotypic abnormalities. Most of these features have previously been described in individuals with interstitial deletion of 2q14.1. PMID- 23652919 TI - Test-retest reliability of the Swedish version of the Orthotics and Prosthetics Users' Survey. AB - BACKGROUND: The Orthotics and Prosthetics Users' Survey consists of five modules to assess outcomes of orthotic and prosthetic interventions: lower extremity functional status, upper extremity functional status, client satisfaction with device, client satisfaction with services and health-related quality of life. OBJECTIVES: To investigate the test-retest reliability and calculate the smallest detectable difference for all modules of the Swedish Orthotics and Prosthetics Users' Survey. STUDY DESIGN: Test-retest reliability study design. METHODS: A total of 69 patients at a Department of Prosthetics and Orthotics completed Orthotics and Prosthetics Users' Survey on two occasions separated by a 2-week interval, giving 18 answers on lower extremity functional status, 41 on upper extremity functional status, 53 on client satisfaction with device, 12 on client satisfaction with services and 67 answers on health-related quality of life. Raw scores were converted into Orthotics and Prosthetics Users' Survey units on a 0 100 scale. Intra-class correlation coefficients, Bland-Altman plots, common person linking plots and t-tests of person mean measures were used to investigate the reliability. The 95% confidence level smallest detectable differences were calculated. RESULTS: The intra-class correlation coefficients ranged from 0.77 to 0.96 for the modules, and no systematic differences were detected between the response occasions. The smallest detectable differences ranged from 7.4 to 16.6 units. CONCLUSIONS: The test-retest reliability was satisfactory for all Orthotics and Prosthetics Users' Survey modules. The smallest detectable difference was large on all modules except the health-related quality of life module. CLINICAL RELEVANCE: The Orthotics and Prosthetics Users' Survey modules are reliable and, thus, can be recommended for repeated measurements of patients over time. Relatively large changes are needed to achieve statistical significance when assessing individual patients. PMID- 23652920 TI - Biochemical heterogeneity and developmental varieties in T-cell leukemia. PMID- 23652921 TI - PP2A(Cdc55/B55), a possible therapeutic target in cyclin D1-dependent cancers. PMID- 23652923 TI - Discovering smoking-related pathway alterations in urothelial cell carcinoma pathogenesis. PMID- 23652922 TI - An expanded role for Caveolin-1 in brain tumors. PMID- 23652924 TI - More isn't always better: limiting centrosome size in interphase. PMID- 23652925 TI - Analyses of the combination of 6-MP and dasatinib in cell culture. AB - A major tenet of cancer therapeutics is that combinations of anticancer agents with different mechanisms of action and different toxicities may be effective treatment regimens. Evaluation of additivity/synergy in cell culture may be used to identify drug combination opportunities and to assess risk of additive/synergistic toxicity. The combination of 6-mercaptopurine and dasatinib was assessed for additivity/synergy using the combination index (CI) method and a response surface method in six human tumor cell lines including MCF-7 and MDA-MB 468 breast cancer, NCI-H23 and NCI-H460 non-small cell lung cancer, and A498 and 786-O renal cell cancer, based on two experimental end-points: ATP content and colony formation. Clonal colony formation by human bone marrow CFU-GM was used to assess risk of enhanced toxicity. The concentration ranges tested for each drug were selected to encompass the clinical Cmax concentrations. The combination regimens were found to be additive to sub-additive by both methods of data analysis, but synergy was not detected. The non-small cell lung cancer cell lines were the most responsive among the tumor lines tested and the renal cell carcinoma lines were the least responsive. The bone marrows CFU-GM were more sensitive to the combination regimens than were the tumor cell lines. Based upon these data, it appears that the possibility of enhanced efficacy from combining 6 mercaptopurine (6-MP) and dasatinib would be associated with increased risk of severe bone marrow toxicity, so the combination is unlikely to provide a therapeutic advantage for treating solid tumor patients where adequate bone marrow function must be preserved. PMID- 23652927 TI - [Treatment of severe tibial fractures with extensive soft tissue damage and/or contamination. Quality of life after use of the Ilizarov external fixator]. AB - BACKGROUND: The Ilizarov external fixator (IF) is an immediate and definitive treatment option for severe tibial fractures compromised by extensive soft tissue damage. The aim of this study was to assess the general performance of the IF and especially the impact on patient quality of life. METHOD: A postal questionnaire including an SF-12 health survey and questions about various other aspects of quality of life was sent to all patients who received an IF for primary fracture treatment at a level 1 trauma centre between January 2000 and June 2009. RESULTS: A total of 48 completed questionnaires were received from patients treated with IF for severe tibial fractures. The median time to removal of the IF was 154 days (range 70-614 days). The mean SF-12 mental component score (MCS) was 52 (SD+/-12) and the mean physical component score (PCS) was 38 (SD+/-11). Of the patients 100 % answered that they were either satisfied or very satisfied with the treatment and 91 % would choose the same method of treatment under similar circumstances. CONCLUSIONS: This study demonstrates a high performance of IF in the treatment of severe tibial fractures with compromised soft tissue where more standard forms of treatment are contraindicated. PMID- 23652926 TI - To combine or not combine: the role of radiotherapy and targeted agents in the treatment for renal cell carcinoma. AB - INTRODUCTION: Renal cell carcinoma is counted among the most resistant tumors to chemotherapy and radiotherapy, respectively. However, therapeutic options expanded since the introduction of molecular agents, targeting specific pathways such as the vascular endothelial growth factor (VEGF)-alpha, the VEGF receptor (VEGFR), or the mammalian target of rapamycin (mTOR) pathway. These new agents almost doubled the time to tumor progression and in some trials even improved overall survival. Against this background, the role of local treatment strategies in metastasized or inoperable primary renal cell carcinoma has to be redefined. With the onset of new technical developments in radiotherapy and the possibility to precisely deliver higher doses per fraction, encouraging response and control rates have been reported for kidney cancer, supporting a possible role for irradiation in this setting. This overview summarizes the preclinical data and clinical experiences of modern radiotherapy with focus on possible synergies and toxicities when combined with molecular targeted agents. METHODS: The available literature on preclinical and clinical data comprising prospective trials, retrospective analyses and case reports was reviewed. CONCLUSION: With the recent developments in stereotactic and image-guided radiotherapy, encouraging data concerning local control in the treatment for metastasized renal cell carcinoma have been generated and are therefore recommended whenever possible. It seems that with these high- precision irradiation schedules, the combination with targeted agents is feasible with no increase in severe adverse events. Nevertheless, the addition of molecular targeted drugs to radiotherapy outside of approved regimens or clinical trials warrants careful consideration for every single case. PMID- 23652928 TI - [Stress reactions in bones of the foot in sport: diagnosis, assessment and therapy]. AB - Stress reactions and stress fractures are defined as structural damage to bone caused by repetitive stress or stereotypical loading. The balance between loading and unloading of bone is disrupted in stress reactions and stress fractures through the sport-specific demands and by the exogenous or endogenous risk factors present. In sports orthopedics the localization of stress reactions and stress fractures are subdivided into high risk fractures and low risk fractures. Conventional diagnostic radiology can initially be inconclusive. With symptoms persisting over 2 weeks further diagnostics using magnetic resonance imaging (MRI) should be performed. In the area of the foot stress reactions and stress fractures can often occur bilaterally or multifocally and most commonly affect the second metatarsals followed by the third metatarsals. Fractures of the fifth metatarsal, second metatarsal base, medial malleolus as well as navicular and sesamoid fractures are high risk fractures requiring special clinical and radiological monitoring. Basically, conservative treatment using the 2-phase model is the treatment of choice. In delayed union or severe pain surgical treatment is indicated. PMID- 23652929 TI - [Neuromuscular deficits in chronic ankle instability. Frequency and significance multicenter study]. AB - The peroneal reaction time (PRT) is used in the assessment of neuromuscular deficits in chronic functional ankle instability. Powered by the Editorial Manager and Preprint Manager from Aries Systems Corporation the present study was conducted to determine the PRT in a large collective of patients with chronic ankle instability because it is unclear if this parameter of neuromuscular deficit is prolonged. In this study 186 patients underwent a diagnostic algorithm consisting of anamnesis, clinical examination, X-ray and determination of the PRT on a tilting platform. A prolonged PRT as a manifestation of a neuromuscular deficit could be detected in the majority of the patients (n = 143, 77%). Comparing the affected and healthy legs 77 patients (41%) showed a significant difference in talar shift (p = 0.002) and talar tilt (p = 0.04) in the radiological stress views. Of these 77 patients only 15 (8%) showed radiological evidence of a mechanical problem. As a consequence of recurring ankle sprains a post-traumatic deficit in proprioception has to be expected in most cases. In general a conservative therapy approach should be followed including specific training to improve neuromuscular and proprioceptive deficits. PMID- 23652930 TI - [Development of compartment syndrome after intravenous administration of an X-ray contrast medium. Recommendations on acute therapy regimens]. AB - The incidence of extravasation of contrast medium is reported in the literature to be between 0.2 % and 0.9 %. A rare consequence of this could be compartment syndrome of the affected limb which requires immediate treatment.We report the case of a patient who developed acute compartment syndrome of the forearm after intravenous injection of radiographic contrast medium in a radiovolar vein during a computed tomography (CT) scan for multiple trauma. The clinical symptoms with pain, loss of range of motion and sensitivity functions, measurement of compartment pressure and radiological images confirmed the diagnosis. After emergency dermatofasciotomy of the forearm the full range of motion and sensitivity functions could be restored. PMID- 23652931 TI - Effect of genetic polymorphisms in CA6 gene on the expression and catalytic activity of human salivary carbonic anhydrase VI. AB - Carbonic anhydrase isoenzyme VI (CA VI) plays an important role in the homeostasis of oral tissues participating in the processes of taste, protection of dental tissues against the loss of minerals, caries, and possibly in the formation of dental calculus in periodontal disease. This study aimed to verify the correlation between changes in the expression and activity of human salivary carbonic anhydrase VI and genetic polymorphisms in its gene (CA6). The study population consisted of 182 healthy volunteers (female and male, aged 18-22). Samples of total saliva were assayed for CA VI concentrations using a specific time-resolved immunofluorometric assay. CA VI catalytic activity was detected by a modified protocol of Kotwica et al. [J Physiol Pharmacol 2006;57(suppl 8):107 123], adapted to CA VI in saliva. Samples of genomic DNA were genotyped for polymorphisms rs2274327 (C/T), rs2274328 (A/C) and rs2274333 (A/G) by TaqMan(r) SNP Genotyping Assays. The concentration and catalytic activity of the salivary CA VI obtained for the different genotypes were analyzed using the Kruskal-Wallis nonparametric test and the Dunn test. The results showed that individuals with TT genotype (rs2274327) had significantly lower CA VI concentrations than the individuals with genotypes CT or CC (p < 0.05). There was also an association between polymorphism rs2274333 and salivary CA VI concentrations. There were no associations between the three polymorphisms analyzed and variations in CA VI activity. Our results suggest that polymorphisms in the CA6 gene are associated with the concentrations of secreted CA VI. PMID- 23652932 TI - Allele-specific programming of Npy and epigenetic effects of physical activity in a genetic model of depression. AB - Neuropeptide Y (NPY) has been implicated in depression, emotional processing and stress response. Part of this evidence originates from human single-nucleotide polymorphism (SNP) studies. In the present study, we report that a SNP in the rat Npy promoter (C/T; rs105431668) affects in vitro transcription and DNA-protein interactions. Genotyping studies showed that the C-allele of rs105431668 is present in a genetic rat model of depression (Flinders sensitive line; FSL), while the SNP's T-allele is present in its controls (Flinders resistant line; FRL). In vivo experiments revealed binding of a transcription factor (CREB2) and a histone acetyltransferase (Ep300) only at the SNP locus of the FRL. Accordingly, the FRL had increased hippocampal levels of Npy mRNA and H3K18 acetylation; a gene-activating histone modification maintained by Ep300. Next, based on previous studies showing antidepressant-like effects of physical activity in the FSL, we hypothesized that physical activity may affect Npy's epigenetic status. In line with this assumption, physical activity was associated with increased levels of Npy mRNA and H3K18 acetylation. Physical activity was also associated with reduced mRNA levels of a histone deacetylase (Hdac5). Conclusively, the rat rs105431668 appears to be a functional Npy SNP that may underlie depression-like characteristics. In addition, the achieved epigenetic reprogramming of Npy provides molecular support for the putative effectiveness of physical activity as a non-pharmacological antidepressant. PMID- 23652934 TI - Acute kidney injury after acute gastroenteritis in an infant with hereditary hypouricemia. AB - Hereditary hypouricemia is a rare disorder characterized by extremely low serum uric acid levels caused by excessive urinary excretion due to an inherited tubular defect in urate handling. Exercise-induced acute kidney injury (AKI) is the main complication of this disorder, though AKI may also be induced by other factors. A 7-month-old boy with hereditary hypouricemia developed AKI associated with severe dehydration caused by rotavirus gastroenteritis. He also showed severe hypernatremia and metabolic acidosis and received continuous renal replacement therapy for 3 days. He showed no signs of hydronephrosis or urolithiasis. However, hypouricemia was noted when his renal function recovered (serum uric acid <0.6 mg/dl). Analysis of the urate transporter 1 gene revealed a homozygous nonsense mutation in exon 4 (c.774G > A, p.W258X). Both parents were heterozygous for the mutation and his younger brother was later determined to have severe hypouricemia (0.6 mg/dl). CONCLUSION: Uric acid is an essential factor for scavenging oxidative stressors. In this patient, severe dehydration may have directly caused pre-renal AKI, but susceptibility to oxidative stressors under severe dehydration, as well as exercise, may also contribute to AKI. Careful attention should be paid to dehydration, especially in young children, to avoid the development of AKI in patients with hereditary hypouricemia. PMID- 23652935 TI - Childhood chronic physical condition, self-reported health, and life satisfaction in adolescence. AB - The present study investigates the prevalence and type of chronic conditions at 7 years of age-with special reference to atopic conditions-and their longitudinal associations with self-reported health and life satisfaction in adolescence. The data were obtained from Northern Finland Birth Cohort 1986 (NFBC 1986), which is a longitudinal 1-year birth cohort from an unselected, regionally defined population (n = 9,432). The present study investigated a sample of 8,036 children with data of chronic conditions at 7 years of age and a sample of 6,680 children with data of chronic conditions at 16 years of age. According to parents' report the prevalence of CC at 7 years of age was 14.8 % among boys and 13.2 % among girls, these figures being at 16 years of age 20.7 and 19.4 %, respectively. Atopic conditions were the most common chronic conditions at 7 years of age (12.7 % vs. other chronic conditions 4.7 %). Childhood chronic condition was associated with subsequent self-reported health in adolescence, but not with subsequent self reported life satisfaction. Chronic condition at 7 years of age increased the risk of reporting health as "poor" even if the chronic condition was no longer prevalent at 16 years of age. Atopic conditions seemed to be linked with self reported poor/moderate health more often than other chronic conditions among girls. Conclusion Childhood chronic conditions seem to affect adolescent's subjective health, but fortunately, they do not affect adolescents' subjective well-being to such an extent that it could lower their life satisfaction. PMID- 23652936 TI - Effects of birth size, post-natal growth and current size on insulin resistance in 9-year-old children: a prospective cohort study. AB - The influence of pre-natal conditions on later type 2 diabetes risk factors such as insulin resistance (IR) may be mediated by post-natal growth trajectory. We aimed to investigate the association of body size at birth and 9 years with IR at 9 years. Using data from a prospective Australian cohort study, we examined the influence of body size from birth to 9 years [z-score for weight or body mass index (BMI)] on IR at 9 years (estimated by homeostasis model assessment). At age 9 years, 151 children provided a fasting blood sample. z-BMI at age 9 was positively associated with IR. Birth z-BMI was inversely associated with IR only after adjustment for z-BMI at age 9 years. This may be interpreted as an effect of accelerated growth between birth and 9 years on IR. There was a statistically significant interaction between birth and 9-year z-BMI. Results from regression models including z-BMI at all available time points (birth, 6 and 12 months, and 2, 3.5 and 9 years) indicate a possible inverse association between body size at 3.5 years and HOMA-IR at 9 years. Results were similar when the analyses were repeated with z-weight substituted for z-BMI. These results add to the body of evidence concerning the importance of growth in early life for later IR, and highlight a possible interaction between pre- and post-natal growth. The potential influence of growth at around 3.5 years for HOMA-IR at 9 years warrants further investigation. PMID- 23652937 TI - Unexpected vertical transmission of HIV infection. AB - Mother-to-child transmission of HIV infection occurred in a child born from an HIV-infected mother with HIV-RNA undetectable during pregnancy. She was suffering from gastroenteritis in the last 3 weeks of gestation. PMID- 23652938 TI - Long-term follow-up of neurological manifestations in a boy with incontinentia pigmenti. AB - Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis confined to females. It is usually lethal in males. However, the survival of some males has been reported in literature. We describe a long follow-up case of a 12-year-old male with IP and a normal karyotype but a genomic deletion of the NEMO gene in the Xq28 position in the form of somatic mosaicism. The patient showed severe ophthalmic abnormalities and neurological manifestations characterised by very mild cerebellar ataxia and a history of epilepsy that was severe at the beginning with West syndrome, become moderate overtime and is now resolved. Despite these neurological manifestations, probably related to the presence of at least some mutated cells in his brain, the long-term follow-up in this patient demonstrated good neurological and cognitive outcome. PMID- 23652939 TI - Mixed gonadal dysgenesis in a patient with de novo tas(Y;19)(p11.3;q13.4) and 45,X mosaicism. AB - We report a patient with a de novo telomeric association between chromosomes 19 and Y in conjunction with mixed gonadal dysgenesis. The patient was first admitted to the clinic because of abnormal external genitalia. Laparoscopic evaluation revealed (1) a rudimentary uterus, one fallopian tube, and a small gonad resembling an ovary on the right side, and (2) an immature fallopian tube, a vas deferens, and a gonad resembling a testis on the left side. Conventional cytogenetic analysis performed on cultivated peripheral blood cells, and tissue obtained from the phallus and a gonadal structure which resembled a testis revealed two different cell lines with the 46,X,tas (Y;19)(p11.3;q13.4) and 45,X karyotype. Y chromosome microdeletion analysis showed that the patient did not have any genomic deletions in the AZFa, b, c, or SRY regions on the long arm of the Y chromosome. This is the first report of a patient with mixed gonadal dysgenesis that is accompanied by a telomeric association between chromosomes 19 and Y with 45,X mosaicism. PMID- 23652940 TI - Nursing home administrator self-assessed preparedness. AB - BACKGROUND: Nursing home administrators (NHAs) are in key positions to improve nursing home quality. NHAs require state-level licensure, which involves passing a national NHA licensure examination and fulfilling state-level licensure requirements that vary widely across states. With multiple pathways to NHA licensure, little is known about NHAs' preparation and training to meet the complex demands of this position. PURPOSE: The aim of this study was to explore NHAs' self-assessed person-job fit based on NHAs' self-rated preparedness and the importance of the activities that supported their preparation. METHODOLOGY/APPROACH: A descriptive cross-sectional design was used to collect data from NHAs (N = 175) randomly recruited from nursing homes in five states, with a mailed self-administered questionnaire. Data analysis included descriptive statistics, correlations, and t tests/ANOVA. FINDINGS: Thirty percent of respondents reported they were well prepared, overall, for their first NHA position. The findings suggest NHA preferences for more formalized ways to develop their entry-level competencies, with lower preference for On-the-job training, Previous job experience, and Self-study and higher preference for Administrator-in-training, Bachelor's degree programs, and Mentoring. PRACTICE IMPLICATIONS: There is an urgent need for NHAs who are well prepared to effectively address our nation's mandates for nursing home quality improvement. With multiple pathways to NHA licensure, this exploratory study provides initial insights about NHAs' self-assessed preparation and training. The findings suggest that NHAs prefer more formalized ways to prepare for the NHA position. Research is needed to identify specific teaching/learning practices and on-the-job training that maximize the NHAs' preparation to meet their job demands. PMID- 23652941 TI - Molecular skin research can impact systemic cancers. PMID- 23652942 TI - Periungual pyogenic granuloma following imatinib therapy in a patient with chronic myelogenous leukemia. PMID- 23652943 TI - Comorbidities associated with leptin and psoriasis. PMID- 23652944 TI - Cosmeceuticals for recurrence prevention after prior skin cancer: an overview. AB - INTRODUCTION: Skin cancer is the most common form of cancer in the United States. According to the World Health Organization, the incidence of both nonmelanoma and melanoma skin cancers has increased over the past few decades. OBJECTIVE: The objective of this article is to review studies about cosmeceuticals that can be used by people who previously had skin cancer and may work as agents that help in some way to prevent new skin cancer lesions. CONCLUSION: Cosmeceuticals are antiaging skin products that overlap cosmetics and pharmaceuticals and are commonly available over the counter. This article reviewed several substances used in cosmeceuticals formulations that could be useful for individuals who have had previous skin cancers and need to prevent possible new lesions. Further studies are needed to better evaluate these products and their skin cancer preventive properties. PMID- 23652946 TI - Nontraditional management of basal cell carcinoma. AB - This review discusses nontraditional modalities available for the treatment of basal cell carcinoma along with the existing evidence to support their respective uses in varying clinical situations. By definition, these modalities are nonsurgical, and in many cases, are not approved by the US Food and Drug Administration as treatments for basal cell carcinoma, including topical chemotherapies, photodynamic therapy, oral therapies, and complementary therapies. Nonetheless, as the population of patients with skin cancer increases at epidemic proportions, many of these modalities are, and will become, increasingly relevant in the dermatologist's armamentarium. PMID- 23652945 TI - Targeting the hedgehog pathway to treat basal cell carcinoma. AB - The discovery of mutations that activate hedgehog (Hh) signaling in basal cell carcinoma (BCC) and other cancers has spurred the development of small molecule inhibitors that target the Hh pathway. High-throughput screens have identified a number of drug candidates that antagonize smoothened (SMO), an essential protein in the Hh signaling pathway. Clinical studies of the oral SMO inhibitor vismodegib (GDC-0449) in patients with inoperable or metastatic BCC have led to its recent approval by the US Food and Drug Administration. This review aims to give the clinician an overview of vismodegib and other Hh pathway inhibitors in the treatment of patients with advanced BCC and basal cell nevus syndrome. Issues of drug mechanism, efficacy, safety, tolerability, and tumor resistance are addressed. PMID- 23652947 TI - Treatment of facial photodamage using a novel retinol formulation. AB - BACKGROUND: Photoaged skin is characterized by a variety of clinical, histologic, and biochemical features. OBJECTIVE: To determine the efficacy of a new topical formulation of 1% retinol and the effects of this same formulation using a 0.5% retinol concentration to minimize irritation. METHODS: Patients at 2 sites (n=6, n=5) with photodamaged skin applied a novel suspension of retinol (1%) daily to their faces for 8 to 12 weeks. Clinicians graded improvement in ultraviolet induced features at 4 to 6 weeks and at 8 to 12 weeks. Positive results of the observational pilot study warranted a follow-up study on the low concentration. At a third site, females (n=30) with facial photodamage applied the same formulation with or without retinol (0.5%) daily for 8 weeks. Twenty-two subjects applied the test product and 8 applied vehicle according to a randomized, double blinded, institutional review board-approved protocol. Improvements in photodamage features were graded at 4 and 8 weeks. RESULTS: In the observational pilot study, most participants showed improvement in overall photodamage, crow's feet, elasticity,wrinkles, brightness, and hyperpigmentation at 60 to 80 days. Improvements at 60 to 80 days were greater than at 30 to 46 days. In the low concentration study with 0.5% retinol, improvements were modest, most likely due to the lower retinol concentration. Burning, pruritus, dryness, and erythema were minimal with the 0.5% retinol concentration. CONCLUSIONS: The topical formulation of 1% retinol improves photodamaged skin for at least 8 to 12 weeks. Although improvements with the 0.5% retinol were more modest, side effects such as burning, dryness, pruritus, and erythema during the 8-week study period were minimal. These encouraging results justify a longer-term study to determine whether topically applied 0.5% retinol can provide benefits comparable with those seen with topically applied 1% retinol. PMID- 23652948 TI - The clinical effects of zinc as a topical or oral agent on the clinical response and pathophysiologic mechanisms of acne: a systematic review of the literature. AB - This article reviews the published literature about the efficacy of oral and topical zinc as treatments for acne vulgaris. The medical literature was systematically reviewed to identify relevant articles. Each published study was assessed for pathophysiologic results and the quality of the clinical evidence the study provided based on Strength of Recommendation Taxonomy (SORT) criteria. Finally, the body of evidence for using oral or topical zinc in the treatment of acne was assessed, again using SORT criteria. A SORT strength of recommendation of B (inconsistent or limited-quality patient-oriented evidence) appears to be appropriate for both oral and topical zinc. The preponderance of evidence suggests zinc has antibacterial and anti-inflammatory effects and that it may decrease sebum production. PMID- 23652949 TI - Combination therapy for psoriasis in the United States. AB - BACKGROUND: Psoriasis is treated with several classes of treatments that may be used in combination, but the ways combination therapies are used are not well characterized. PURPOSE: To determine the frequency of prescribing calcipotriene and other psoriasis drugs in combination. METHODS: Visits with a sole diagnosis of psoriasis were selected from 1990-2010 data from the National Ambulatory Medical Care Survey. The number of combination therapies used, the leading therapies in each class of medications, and the leading types used in combination were analyzed. RESULTS: About 10.2 million of 20.3 million psoriasis visits used multiple treatments. The mean number of prescribed medications increased over time (P=.0003). The top 10 treatments included 6 topical steroids, calcipotriene, 2 other topicals, and methotrexate. The most common combinations were topical steroid plus other topical (15.0%), multiple topical steroids (11.5%), topical steroid plus vitamin D analogue (9.7%), and topical steroid plus systemic treatment (6.9%). Vitamin D analogues and systemic treatments were prescribed with increasing frequency over time, while fewer topical steroids were used, and use of other topicals did not change significantly. LIMITATIONS: Visits with multiple diagnoses had to be excluded to ensure that the medications listed were for psoriasis. CONCLUSIONS: Combination therapy is the most common way to treat psoriasis in the United States. The wide range of combination therapies prescribed may reflect increased attention to individualization of treatment to match patients' diverse preferences. PMID- 23652950 TI - Inflammatory mediators are inhibited by a taurine metabolite in CpG oligodeoxynucleotide and IFN-r activated macrophage cell line. AB - Taurine plays an important role in brain and retinal development, and has an antiinflammatory and antioxidant function. Taurine chloramine (Tau-Cl) is produced in polymorphonuclear leukocytes via the myeloperoxidase/halide system. We previously demonstrated that Tau-Cl inhibits the production of nitric oxide (NO) and TNF-alpha in human and murine macrophages activated with IFN-gamma in combination with individual Toll-like receptor (TLR) ligands including those for TLR2 and/or TLR4. In the current study, we further explored the effects of Tau-Cl in RAW 264.7 cells stimulated with the TLR9 ligand CpG oligodeoxynucleotide (ODN). Specifically, we examined the effect of CpG ODN plus IFN-gamma on the production of NO and TNF-alpha, and the effect of Tau-Cl on this process. Our findings show that CpG ODN plus IFN-gamma-activated RAW 264.7 cells secrete high levels of NO and TNF-alpha, and that Tau-Cl (0.8 mM) inhibits this effect in a dose-dependent manner, more potently inhibiting the production of NO (99% inhibition) than that of TNF-alpha (48% inhibition). Nitric oxide synthase (iNOS) protein was also induced by CpG ODN plus IFN-gamma, and was also inhibited by Tau Cl. Furthermore, while CpG ODN plus IFN-gamma induced TNF-alpha and iNOS mRNAs, Tau-Cl transiently suppressed this effect. Taurine itself had no effects on any of these processes. Our findings in a macrophage cell line demonstrate that Tau Cl inhibits proinflammatory mediators resulting from TLR9 activation, and have implications for the utility of Tau-Cl in scenarios where such activation is deleterious such as in autoimmune conditions or infections in which overwhelming inflammation may occur. CpG ODNs and Tau-Cl both have potential for topical treatment of autoimmune conditions, including psoriasis, vitiligo, and alopecia areata. As CpG ODNs may, under some conditions, up-regulate Tregs, addition of Tau-Cl to CpG ODN topical formulations has potential for improving cancer immunotherapy. PMID- 23652951 TI - Allogeneic growth arrested keratinocytes and fibroblasts delivered in a fibrin spray accelerate healing in Mohs micrographic surgery wounds. AB - OBJECTIVES: To determine the effectiveness of HP802-247 compared with bacitracin ointment in healing wounds resulting from Mohs micrographic surgery. METHODS: Open-label, randomized pilot study conducted at a single center. Subjects were randomized to either HP802-247 (5M cells/mL) applied weekly or bacitracin ointment applied daily. Treatment continued for up to 12 weeks or complete wound closure. Primary efficacy was effectiveness as measured by the Investigator's Global Assessment of Healing (IGAH) scale. Secondary outcomes included median time to healing, investigator- and subject-scored signs and symptoms, and an assessment of scar by the investigator at 16 weeks postsurgery. RESULTS: All subjects achieved favorable outcomes within the study period; however, these were reached more quickly for the HP802-247 group than for bacitracin. At 3 weeks postsurgery, healing was assessed as very effective for 75% of subjects in the HP802-247 group compared with 50% for bacitracin. Median time to closure was 24.5 days for HP802-247 and 29 days for bacitracin. Scores for signs and symptoms and scar were similar for both groups but, in general, were numerically better for HP802-247. CONCLUSION: In this small pilot study, HP802-247 was found to provide a modest, incremental benefit in the healing of Mohs micrographic surgery wounds, suggesting that the healing of uncomplicated acute wounds may be slightly accelerated without enhancement of scarring. PMID- 23652952 TI - Treating hyperpigmentation in darker-skinned patients. AB - BACKGROUND: The treatment of hyperpigmentation in darker-skinned patients (Fitzpatrick skin phototypes III-VI) has remained challenging for dermatologists. No studies have been conducted on hyperpigmentation under the eyes, axilla, and neck in darker-skinned patients. This survey was designed to assess current treatments of hyperpigmentation in these areas. MATERIALS/METHODS: With approval from the institutional review board at the University of California, Irvine, an electronic survey was sent to practicing dermatologists that contained 18 questions regarding the approach to evaluating and treating hyperpigmentation under the eyes, in the axilla, and along the neck. RESULTS: Fifty dermatologists completed the survey, and 46 (92%) reported treating patients with darker skin. The ethnic groups treated were Latino (97.8%), African American (97.8%), Middle Eastern (77.6%), and Asian (88.9%). Thirty-six reported treating patients with hyperpigmentation under the eyes, and 22 (61.1%) thought the hyperpigmentation was a result of idiopathic increase in melanin deposition. Forty-two responded to treating hyperpigmentation in the axilla, most of whom thought it was related to acanthosis nigricans (69.0%) or contact dermatitis (59.5%). Forty responded to treating hyperpigmentation on the neck, most of whom treated the condition with hydroquinone (66%). Treatments for these 3 areas were not found to be effective. CONCLUSIONS: Hyperpigmentation under the eyes, under the arms, or on the neck is a significant problem in darker-skinned patients that is refractory to currently available treatments, highlighting the necessity of developing treatment approaches directed toward this population. Two cases of hyperpigmentation on the neck are presented, describing a new entity that primarily affects dark-skinned individuals. PMID- 23652953 TI - Nonmelanoma skin cancer in young women. AB - The increasing incidence of nonmelanoma skin cancer in young women is a growing public health concern. Varying environmental and lifestyle exposures in this specific population highlight the need for a broad understanding of the potential risk factors that may contribute to the early development of these tumors. Reducing the morbidity and mortality in this high-risk population is contingent on developing better strategies for prevention, education, and treatment. PMID- 23652954 TI - Iododerma following serial computed tomography scans in a lung cancer patient. AB - Iododerma is a rare cutaneous eruption occurring after iodine administration. Nine cases of iododerma following intravenous contrast have been reported in the English-language literature, typically in patients with renal insufficiency. We report a case of iododerma in a patient with relatively unimpaired renal function who underwent serial computer tomography (CT) scans with intravenous contrast. An 81-year-old woman with stage IV lung cancer developed fever and rash following serial CT scans with iodixanol contrast media. On examination, we noted conjunctival injection, enlarged glands, oral ulcers, and erythematous papules and plaques on her forehead, arms, and legs. Random urine iodine was elevated to 106,767 MUg/L (normal range, 26-705 MUg/L). Skin biopsy revealed diffuse predominantly neutrophilic dermal infiltrate. The patient's clinical presentation, laboratory findings, and biopsy results were consistent with iododerma. Iododerma can occur in patients with adequate kidney function, and its presentation can include ocular and glandular symptoms, as in this case. Withdrawal of the source of iodine typically leads to resolution of symptoms. PMID- 23652956 TI - Cutaneous clues to renal cell carcinoma: hereditary leiomyomatosis and renal cell carcinoma. AB - We present a case of a 33-year-old female who was incidentally found to have cutaneous leiomyomata during a routine skin examination. Further history revealed that she also suffered from uterine fibroids and that her mother had died at an early age from renal cell carcinoma. This case serves as a reminder of the often subtle cutaneous clues, as well as the importance of a multidisciplinary approach, for early diagnosis of potentially fatal conditions. PMID- 23652958 TI - Crusted scabies and multiple dosages of ivermectin. AB - We present the case of a bone marrow transplant patient who was diagnosed with crusted scabies but did not respond to the usual approach with topical permethrin and ivermectin. The Centers for Disease Control and Prevention were contacted and suggested a 7-dose regimen of ivermectin. The patient started to improve remarkably after the third dose, and the skin eruption was resolved after 7 doses. This case supports the use of a more prolonged course of oral ivermectin for crusted scabies in those who fail the conventional approach. PMID- 23652959 TI - Resident rounds. Part III. A case of Proteus syndrome. PMID- 23652960 TI - Hair loss in the dermatology office: an update on alopecia areata. PMID- 23652963 TI - Melanocytes transplantation in patients with vitiligo using needling micrografting technique. AB - BACKGROUND: Some cases of vitiligo require melanocyte transplantation, but these surgical techniques have varying degrees of success. OBJECTIVES: To perform melanocytes transplantion in patients with vitiligo using a new needling micrografting technique. PATIENTS AND METHODS: This interventional case study took place at the Department of Dermatology and Venereology at Baghdad Teaching Hospital from December 2010 to September 2011. Twelve patients with vitiligo were included. A split-thickness skin graft was taken from the normal area and cut into micropieces ranging from 0.1 mm to 0.3 mm in diameter. The recipient area was anesthetized, and the micrografts were then implanted into the dermis using the needling technique. The number of implanted micrografts depended on the size of the recipient area. Follow-up was conducted every 2 weeks for the first month and then every 4 weeks for a further 16 weeks. RESULTS: The intake rate of grafting at week 2 ranged from 90% to 100%. The micrografts started producing noticeable pigmentation at week 2, and pigmentation was obvious at week 4. At week 8, the rate of pigmentation ranged from 10% to 90% (25.24%), and at week 16 it ranged from 10% to 100% (61.36%). CONCLUSION: This new approach to the treatment of vitiligo delivers rapid and satisfactory pigmentation. PMID- 23652965 TI - The Emervel French survey: a prospective real-practice descriptive study of 1,822 patients treated for facial rejuvenation with a new hyaluronic acid filler. AB - BACKGROUND: Emervel consists of a range of 5 hyaluronic acid (HA) fillers (Touch, Classic, Lips, Deep, and Volume), with a fixed HA concentration (20 mg/mL), and various degrees of cross-linking and calibration. OBJECTIVES: To describe the current use of Emervel fillers in France. METHODS: Prospective multicenter, cross sectional, real-practice, descriptive survey, including 1,822 patients injected with Emervel fillers for face rejuvenation by 58 French physicians between September 2010 and July 2011. The injection modalities were left to the respective physician's discretion. RESULTS: The physicians were dermatologists (52.3%), surgeons (43.8%), or general practitioners (14.1%). Nasolabial folds (NLF) with a mean severity 2.4 were mainly injected with Emervel Deep (51.0%) and Emervel Classic (36.0%) (mean volume: 1.0 mL), and primarily with the linear retrograde (LR) technique (89.3%). Marionette lines (ML), with a mean severity 2.6 were mainly injected with Emervel Deep (52.5%) and Emervel Classic (34.6%) (mean volume: 0.8 mL), and mainly with the LR technique (79.5%). More than 90% of patients had scores of 0 or 1 for erythema, bruising, edema, and pain. No serious adverse events were reported up to 15 months after the injection. CONCLUSION: These data could contribute to upcoming international consensus on optimal injection modalities of the Emervel range of HA fillers. PMID- 23652964 TI - Sign and pseudo-sign of Leser-Trelat: case reports and a review of the literature. AB - BACKGROUND: Leser-Trelat is distinguished by a rare paraneoplastic sign that is characterized by the sudden eruption of multiple seborrheic keratoses (SKs), associated with underlying internal malignancies. Similar non-malignancy associated SK eruptions are referred to as the "pseudo-sign of Leser-Trelat" (PLT). OBJECTIVE: Two cases of rapid SK eruptions, one the sign of Leser-Trelat (SLT) and one PLT, are presented, and the literature on SLT and PLT is reviewed. METHODS: A literature review of SLT/PLT was performed by searching the PubMed database for all related English published cases. RESULTS: We identified 109 cases of SLT and 12 cases of PLT, with a mean patient age of 61.8 years. SK eruptions were observed before (68.3%), after (22.1%), and at the time of (9.6%) malignancy diagnosis. The malignancy most frequently associated with SLT was gastric adenocarcinoma. The most common anatomical location of SK eruptions was the trunk (18.9%). Frequently reported associated signs and symptoms included pruritus (52%) and acanthosis nigricans (38.7%). The most common treatment included surgery (35.8%), chemotherapy (26.9%), and radiation therapy (26.9%). Treatment resulted in clinical improvement (45%), no change (30%), exacerbation (15%), or initial improvement followed by exacerbation of SKs. Patient outcomes included disease stability/ improvement (48.4%), recurrence (9.7%), exacerbation/metastasis/new malignancy (4.8%), and death (37.1%). LIMITATIONS: This was a retrospective study and excluded non-English published cases. CONCLUSION: This review updates the existing SLT literature and emphasizes the presence of PLT. Clinicians should be aware that SK eruptions may be early manifestations of an internal malignancy or other pathology. To our knowledge, this is the first review examining both SLT and PLT. PMID- 23652966 TI - Multi-tiered analysis of brain injury in neonates with congenital heart disease. AB - Early brain injury occurs in newborns with congenital heart disease (CHD) placing them at risk for impaired neurodevelopmental outcomes. Predictors for preoperative brain injury have not been well described in CHD newborns. This study aimed to analyze, retrospectively, brain magnetic resonance imaging (MRI) in a heterogeneous group of newborns who had CHD surgery during the first month of life using a detailed qualitative CHD MRI Injury Score, quantitative imaging assessments (regional apparent diffusion coefficient [ADC] values and brain volumes), and clinical characteristics. Seventy-three newborns who had CHD surgery at 8 +/- 5 (mean +/- SD) days of life and preoperative brain MRI were included; 38 also had postoperative MRI. Thirty-four (34 of 73, 47 %) had at least one type of preoperative brain injury, and 28 of 38 (74 %) had postoperative brain injury. The 5-min APGAR score was negatively associated with preoperative injury, but there was no difference between CHD types. Infants with intraparenchymal hemorrhage, deep gray matter injury, and/or watershed infarcts had the highest CHD MRI Injury Scores. ADC values and brain volumes were not different in infants with different CHD types or in those with and without brain injury. In a mixed group of CHD newborns, brain injury was found preoperatively on MRI in almost 50 %, and there were no significant baseline characteristic differences to predict this early brain injury except 5-min APGAR score. We conclude that all infants, regardless of CHD type, who require early surgery should be evaluated with MRI because they are all at high risk for brain injury. PMID- 23652968 TI - The successful treatment of genu recurvatum as a complication following eight Plate epiphysiodesis in a 10-year-old girl: a case report with a 3.5-year follow up. AB - We report a case of genu recurvatum following eight-Plate epiphysiodesis and the successful treatment of this complication. A 10-year-old patient underwent epiphysiodesis of the knee with eight-Plates. She was followed up and genu recurvatum developed as a complication. At the 12-month follow-up after epiphysiodesis, the treated knee showed a flexion of 135 degrees and an extension of 35 degrees . Lateral radiograph evaluation showed an extension change of the femur. During reoperation, the eight-Plates were repositioned more posterior, which resulted in successful treatment of the hyperextension. Eight Plates can lead to (treatable) articular surface angle changes in the sagittal plane. PMID- 23652967 TI - Three-dimensional imaging of the spine using the EOS system: is it reliable? A comparative study using computed tomography imaging. AB - The aim of this study was to evaluate the precision of three-dimensional geometry compared with computed tomography (CT) images. This retrospective study included patients who had undergone both imaging of the spine using the EOS imaging system and CT scanning of the spine. The apical vertebral orientation was also measured using the EOS imaging system and by CT. Other measures such as the Cobb angle and apical vertebral rotation and translation were used as the control variables to evaluate the potential discrepancy between the standing position in EOS imaging and the supine position in CT scanning. The apical vertebral orientations were 8.7 degrees for the first measurement and 8.4 degrees for the second measurement made by the first author, and 10.3 degrees for the measurement made by the second author. The average of these measurements was 9.3 degrees compared with 6.6 degrees (P=0.65) obtained on CT scanning. The precision of EOS-based measurements of vertebral rotation has never been tested in clinical practice. Although it has limitations, this study suggests that the results obtained using EOS are comparable to those obtained on CT. PMID- 23652969 TI - Pediatric Maisonneuve: case report of a rare pattern of injury. AB - A 12-year-old boy presented to our emergency department complaining of pain and functional limitation on his right ankle after an indirect trauma. Plain radiographs were taken identifying a type II epiphysiolysis of the distal tibia and a proximal fibula fracture. An open reduction and internal fixation was performed without transyndesmal fixation. Maisonneuve fractures are an uncommon injury in the pediatric population. This fracture pattern has not been described by the Dias-Tachdjian classification. It is important to bear in mind that, based on the need for osteosynthesis for the epiphysiolysis, the treatment of these fractures in children usually differs from that in the adults as no transyndesmal screw fixation is required. PMID- 23652970 TI - Five gene products are required for assembly of the central pyrrole moiety of coumermycin A1. AB - Coumermycin A1 is an aminocoumarin antibiotic produced by Streptomyces rishiriensis. It exhibits potent antibacterial and anticancer activity. The coumermycin A1 molecule contains two terminal 5-methyl-pyrrole-2-carboxylic acid moieties and one central 3-methylpyrrole-2,4-dicarboxylic acid moiety (CPM). While the biosynthesis of the terminal moieties has been elucidated in detail, the pathway leading to the CPM remains poorly understood. In this work, the minimal set of genes required for the generation of the CPM scaffold was identified. It comprises the five genes couR1, couR2a, couR2b, couR3, and couR4 which are grouped together in a contiguous 4.7 kb region within the coumermycin A1 biosynthetic gene cluster. The DNA fragment containing these genes was cloned into an expression plasmid and heterologously expressed in Streptomyces coelicolor M1146. Thereupon, the formation of CPM could be shown by HPLC and by HPLC-MS/MS, in comparison to an authentic CPM standard. This proves that the genes couR1-couR4 are sufficient to direct the biosynthesis of CPM, and that the adjacent genes couR5 and couR6 are not required for this pathway. The enzyme CouR3 was expressed in Escherichia coli and purified to near homogeneity. The protein exhibited an ATPase activity similar to that reported for its close ortholog, the threonine kinase PduX. However, we could not show a threonine kinase activity of CouR3, and; therefore, the substrate of CouR3 in CPM biosynthesis is still unknown and may be different from threonine. PMID- 23652971 TI - Improved production of protease-resistant phytase by Aspergillus oryzae and its applicability in the hydrolysis of insoluble phytates. AB - Among three hundred isolates of filamentous fungi, Aspergillus oryzae SBS50 secreted higher phytase activity at pH 5.0, 35 degrees C and 200 rpm after 96 h of fermentation. Starch and beef extract supported the highest phytase production than other carbon and nitrogen sources. A nine-fold improvement in phytase production was achieved due to optimization. Supplementation of the medium with inorganic phosphate repressed the enzyme synthesis. Among surfactants tested, Tween 80 increased fungal growth and phytase production, which further resulted in 5.4-fold enhancement in phytase production. The phytase activity was not much affected by proteases treatment. The enzyme resulted in the efficient hydrolysis of insoluble phytate complexes (metal- and protein-phytates) in a time dependent manner. Furthermore, the hydrolysis of insoluble phytates was also supported by scanning electron microscopy. The enzyme, being resistant to trypsin and pepsin, and able to hydrolyze insoluble phytates, can find an application in the animal food/feed industry for improving nutritional quality and also in combating environmental phosphorus pollution and plant growth promotion. PMID- 23652972 TI - Rehabilitation: the important role of the interdisciplinary team in home care. PMID- 23652973 TI - Clipboard. Later end-of-life discussions may mean more aggressive treatment: study suggests earlier talks might contribute to care aimed at easing suffering. PMID- 23652974 TI - Effective pain management of older adult hospice patients with cancer. AB - Pain is subjective and a unique and individual experience. For those involved in the care of hospice patients, pain management can be challenging and is not always effectively managed. This case study explores an older adult cancer patient's pain experience at the end of her life with implementation of pain management strategies from hospice. PMID- 23652975 TI - Identifying urinary incontinence in the home setting: part 1-assessment, diagnosis, and strategies to treat incontinence. AB - Urinary incontinence is a prevalent but difficult dysfunction for many older adults. Living with urinary incontinence can have a profound impact on one's quality of life. The purpose of this case study and article is to identify and describe treatment techniques used to treat urinary incontinence. PMID- 23652977 TI - Wound care dressings and choices for care of wounds in the home. AB - Statistics from various resources report that many patients in home healthcare settings have wounds. These vary from surgical, pressure, neuropathic, trauma, stasis, and venous wounds. These require the assessment, knowledge, and expertise of a clinician to assist them with wound care management. The purpose of this article is to identify and categorize types of wound care products appropriate for the various types of wounds that clinicians care for and manage in the home. PMID- 23652979 TI - Online resources for culturally and linguistically appropriate services for home healthcare and hospice, part 5: resources for African patients. AB - Providing culturally and linguistically appropriate home healthcare and hospice care to patients who have emigrated from the African continent can be a challenge. This article reviews Web sites that provide introductions to some of the predominant cultures in Africa. Web sites providing patient education material in 13 African languages are also discussed. PMID- 23652981 TI - Possible change to prospective payment system payments based on therapy visits: can this new reimbursement structure assure that home health patients receive the therapy services they need? PMID- 23652982 TI - Determination of ATP and ADP Secretion from Human and Mouse Platelets by an HPLC Assay. AB - BACKGROUND: Secretion of ADP and ATP is an essential prerequisite for platelet aggregation. Impaired nucleotide secretion can cause aggregation defects and increased bleeding risk. Quantitative determination of platelet nucleotide content and exocytosis is thus of importance for the characterization and diagnosis of bleeding phenotypes. For transgenic animal models with hemostatic defects analysis of potential secretion defects is as well imperative. METHODS: Supernatants of washed platelets and platelet-rich plasma were analyzed by HPLC for ADP and ATP concentration. Calibration of the HPLC data was accomplished with an internal standard compensating for loss of analyte, detection sensitivity, and interference of the biomatrix. RESULTS: HPLC analysis of nucleotide secretion was carried out with human and mouse platelets. Detection limits were determined for washed platelet and platelet-rich plasma samples. In the physiological concentration range linearity with respect to the peak area is maintained. CONCLUSION: The method combines reasonable sensitivity with robustness. The internal standard ensures reliable quantification of nucleotide concentrations even in presence of otherwise interfering substances. The low sample consumption renders possible the application to analysis of small samples like in mouse experiments. PMID- 23652983 TI - Veno-right ventricular ECMO support in an infant. PMID- 23652984 TI - Physical mapping of 20 unmapped fragments of the btau_4.0 genome assembly in cattle, sheep and river buffalo. AB - The recent advances in sequencing technology and bioinformatics have revolutionized genomic research, making the decoding of the genome an easier task. Genome sequences are currently available for many species, including cattle, sheep and river buffalo. The available reference genomes are very accurate, and they represent the best possible order of loci at this time. In cattle, despite the great accuracy achieved, a part of the genome has been sequenced but not yet assembled: these genome fragments are called unmapped fragments. In the present study, 20 unmapped fragments belonging to the Btau_4.0 reference genome have been mapped by FISH in cattle (Bos taurus, 2n = 60), sheep (Ovis aries, 2n = 54) and river buffalo (Bubalus bubalis, 2n = 50). Our results confirm the accuracy of the available reference genome, though there are some discrepancies between the expected localization and the observed localization. Moreover, the available data in the literature regarding genomic homologies between cattle, sheep and river buffalo are confirmed. Finally, the results presented here suggest that FISH was, and still is, a useful technology to validate the data produced by genome sequencing programs. PMID- 23652986 TI - [Hemomediastinum caused by rupture of a bronchial artery aneurysm]. AB - Hemomediastinum caused by rupture of a bronchial artery aneurysm is a very infrequent pathology. Clinical presentation can be variable; it can resemble an aortic pathology and be diagnosed in emergency situations. Computerized tomography (CT) of the thorax is the initial test for diagnosis. We present the clinical case of a 70-year-old man with an initial clinical assessment of transfixive thoracic pain resembling an acute aortic pathology. TC was carried out with a diagnosis of suspected mediastinal neoplasia (Hounsfield Units/HU 38 - soft tissue), biopsy sampling was carried out by gastroscopy and broncoscopy with haemorrhagic pap smear, presenting light anemization on admission and remaining haemodynamically stable and asymptomatic. Facing a high clinical suspicion of arterial pathology, CT was repeated in which hemomediastinum was described in resolution, with subsequent confirmation of the existence of ruptured bronchial artery aneurysm through angiography and proceeding to therapeutic embolization. PMID- 23652985 TI - Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS. AB - Dynamic changes in microvascular endothelial structure and function are pivotal in the acute inflammatory response, the body's rapid, coordinated effort to localize, sequester, and eliminate microbial invaders at their portal of entry. To achieve this, the endothelium becomes leaky and inflamed, providing innate immune cells and humoral effector molecules access to the site of infection. During sepsis this locally adaptive response becomes manifest throughout the body, leading to dangerous host consequences. Increased leakiness in the pulmonary circulation contributes to acute respiratory distress syndrome (ARDS), a complication of sepsis associated with 40% mortality. Understanding the molecular governance of vascular leak and inflammation has major diagnostic, prognostic, and potentially therapeutic implications for this common and pernicious disease. This review summarizes results from cell-based experiments, animal models, and observational human studies; together, these studies suggest that an endothelial receptor called Tie2 and its ligands, called angiopoietins, form a signaling axis key to the vascular dyshomeostasis that underlies sepsis. PMID- 23652987 TI - The role of a ginseng saponin metabolite as a DNA methyltransferase inhibitor in colorectal cancer cells. AB - Hypermethylation of runt-related transcription factor 3 (RUNX3) promoter regions occurs in at least 65% of colorectal cancer cell lines. Compound K, the main metabolite of ginseng saponin, induced demethylation of a RUNX3 promoter in HT-29 human colorectal cancer cells, assessed by methylation-specific PCR and the quantitative pyrosequencing analysis. The demethylation of RUNX3 in compound K treated cells resulted in the re-expression of RUNX3 mRNA, protein and the localization into the nucleus. Demethylation of the RUNX3 gene by compound K occurred via inhibition of the expression and activity of DNA methyltransferase 1 (DNMT1). Compound K also significantly induced RUNX3-mediated expression of Smad4 and Bim. DNMT1 inhibitory activity by compound K was related to extracellular signal-regulated kinase (ERK) inhibition, assessed by siRNA transfection on DNMT1 and ERK. In conclusion, compound K significantly inhibits the growth of colorectal cancer cells by inhibiting DNMT1 and reactivating epigenetically silenced genes. Ginseng saponin is a potential candidate as DNMT1 inhibitor in the chemoprevention of cancer. PMID- 23652988 TI - The short-term effects of soybean intake on oxidative and carbonyl stress in men and women. AB - Beyond other beneficial effects, a soy-rich diet has been shown to reduce the risk of cardiovascular diseases and diabetic complications. Reduction of oxidative and carbonyl stress has been proposed as the underlying mechanism, but the evidence for this is lacking. The aim of our study was to evaluate the effects of short-term increased soy intake on oxidative and carbonyl stress parameters in young volunteers. Young healthy probands (omnivores) of both genders (55 women, 33 men) were given soybeans (2 g/kg bodyweight daily) for one week. Markers of oxidative and carbonyl stress were measured in plasma at the beginning and at the end of one week soybean intake and after another week of a wash-out period. Total antioxidant capacity was increased by soybean intake in both genders. This led to decreased levels of advanced oxidation protein products in women, but not in men. On the contrary, in men, soybean intake increased lipoperoxidation. No effects on carbonyl stress markers (advanced glycation end products-specific fluorescence and fructosamine) were found. Soybean intake has gender-specific effects on oxidative stress in young healthy probands potentially due to divergent action and metabolism of phytoestrogens in men and women. Effects of soybean intake on carbonyl stress should be evaluated in longer studies. PMID- 23652989 TI - A facile asymmetric synthesis of (s)-14-methyl-1-octadecene, the sex pheromone of the peach leafminer moth. AB - An asymmetric synthesis of 14-methyl-1-octadecene, the sex pheromone of the peach leafminer moth has been achieved. The target molecule was synthesized in six linear steps and in 30.3% overall yield from commercially available hexanoyl chloride, (S)-4-benzyloxazolidin-2-one and 1,9-nonanediol. The hexanoyl chloride was connected with (S)-4-benzyloxazolidin-2-one, and with the induction of the chiral oxazolidinone auxiliary, after chiral methylation, LAH reduction and then tosylation gave the chiral key intermediate 5 in high stereoselectivity. 1,9 Nonanediol, was selectively brominated, THP protected and subjected to Li2CuCl4 mediated C-C coupling to afford a C12 intermediate. The target molecule, (S)-14 methyl-1-octadecene, was obtained after the two parts were subjected to a second Li2CuCl4-mediated C-C coupling. Our synthetic approach represents the first time a substrate-control asymmetric synthesis of (S)-14-methyl-1-octadecene has been reported. PMID- 23652990 TI - Theoretical study of H/D isotope effects on nuclear magnetic shieldings using an ab initio multi-component molecular orbital method. AB - We have theoretically analyzed the nuclear quantum effect on the nuclear magnetic shieldings for the intramolecular hydrogen-bonded systems of sigma-hydroxy acyl aromatic species using the gauge-including atomic orbital technique combined with our multi-component density functional theory. The effect of H/D quantum nature for geometry and nuclear magnetic shielding changes are analyzed. Our study clearly demonstrated that the geometrical changes of hydrogen-bonds induced by H/D isotope effect (called geometrical isotope effect: GIE) is the dominant factor of deuterium isotope effect on 13C chemical shift. PMID- 23652991 TI - Changes in SeMSC, glucosinolates and sulforaphane levels, and in proteome profile in broccoli (Brassica oleracea var. Italica) fertilized with sodium selenate. AB - The aim of this work was to analyze the effect of sodium selenate fortification on the content of selenomethyl selenocysteine (SeMSC), total glucosinolates and sulforaphane, as well as the changes in protein profile of the inflorescences of broccoli (Brassica oleracea var. Italica). Two experimental groups were considered: plants treated with 100 MUmol/L sodium selenate (final concentration in the pot) and control plants treated with water. Fortification began 2 weeks after transplantation and was repeated once a week during 10 weeks. Broccoli florets were harvested when they reached appropriate size. SeMSC content in broccoli florets increased significantly with sodium selenate fortification; but total glucosinolates and sulforaphane content as well as myrosinase activity were not affected. The protein profile of broccoli florets changed due to fortification with sodium selenate. Some proteins involved in general stress responses were up-regulated, whereas down-regulated proteins were identified as proteins involved in protection against pathogens. This is the first attempt to evaluate the physiological effect of fortification with sodium selenate on broccoli at protein level. The results of this work will contribute to better understanding the metabolic processes related with selenium uptake and accumulation in broccoli. PMID- 23652992 TI - Simultaneous determination of structurally diverse compounds in different Fangchi species by UHPLC-DAD and UHPLC-ESI-MS/MS. AB - Two bisbenzylisoquinoline alkaloids, two morphine alkaloids, one aporphine alkaloid, syringaresinol and aristolochic acid I were selected as marker compounds and simultaneously analyzed using an ultra-high pressure liquid chromatography-diode array detection (UHPLC-DAD) method. These marker compounds were used for the quality control of Fangchi species of different origins, including Sinomenium acutum, Stephania tetrandra, Cocculus trilobus and Aristolochia fangchi. A reversed-phase UHPLC-DAD method was developed and validated for the simultaneous quantification of structurally diverse markers in different Fangchi species. In addition, an UHPLC-electrospray ionization tandem mass spectrometry (ESI-MS/MS) method was used for marker identification in Fangchi species, which provided diagnostic MS/MS spectral patterns that were dependent upon the marker structures. The UHPLC-MS/MS data were used to confirm and complement the UHPLC-DAD quality evaluation results. Additionally, magnoflorine and syringaresinol were observed for the first time in S. tetrandra and C. trilobus, respectively. Twenty different Fangchi species samples were analyzed for aristolochic acid I, syringaresinol and the alkaloids using the UHPLC-DAD and MS/MS method. Based on the levels of markers and principal component analysis (PCA), this method allowed for the clear classification of the samples into four different groups representing samples originating from the four species. PMID- 23652993 TI - Decoupling of conductivity relaxation from structural relaxation in protic ionic liquids and general properties. AB - The main focus of this work is the study of conductivity relaxation of amorphous lidocaine hemisuccinate near the glass transition at ambient pressure. Measurements have been made using broadband dielectric spectroscopy (BDS) and temperature-modulated differential scanning calorimetry. Our study shows that the ion conductivity relaxation becomes increasingly faster than the structural relaxation as the glass transition temperature Tg is approached. At Tg the structural relaxation time is longer than the conductivity relaxation times by three decades, i.e. the decoupling index Rtau is about 3. Decoupling is accompanied by the ion conductivity relaxation which narrows in its frequency dispersion with decreasing temperature. This abnormal behavior is identical to that found in two other protic ionic liquids (PILs), procaine HCl and procainamide HCl. Considering that the phenomenon has been found before in several inorganic ionic glass-formers and now in three protic ionic liquids, it could be a general property of ionically conducting glass-forming substances, although more cases have to be studied before a definitive conclusion can be made. We show that it can be rationalized within the framework of the Coupling Model. PMID- 23652994 TI - Hexokinase cellular trafficking in ischemia-reperfusion and ischemic preconditioning is altered in type I diabetic heart. AB - Diabetes mellitus (DM) has been reported to alter the cardiac response to ischemia-reperfusion (IR). In addition, cardioprotection induced by ischemic preconditioning (IPC) is often impaired in diabetes. We have previously shown that the subcellular localisation of the glycolytic enzyme hexokinase (HK) is causally related to IR injury and IPC protective potential. Especially the binding of HK to mitochondria and prevention of HK solubilisation (HK detachment from mitochondria) during ischemia confers cardioprotection. It is unknown whether diabetes affects HK localisation during IR and IPC as compared to non diabetes. In this study we hypothesize that DM alters cellular trafficking of hexokinase in response to IR and IPC, possibly explaining the altered response to IR and IPC in diabetic heart. Control (CON) and type I diabetic (DM) rat hearts (65 mg/kg streptozotocin, 4 weeks) were isolated and perfused in Langendorff-mode and subjected to 35 min I and 30 min R with or without IPC (3 times 5 min I). Cytosolic and mitochondrial fractions were obtained at (1) baseline, i.e. after IPC but before I, (2) 35 min I, (3) 5 min R and (4) 30 min R. DM improved rate pressure product recovery (RPP; 71 +/- 10 % baseline (DM) versus 9 +/- 1 % baseline (CON) and decreased contracture (end-diastolic pressure: 24 +/- 8 mmHg (DM) vs 77 +/- 4 mmHg (CON)) after IR as compared to control, and was associated with prevention of HK solubilisation at 35 min I. IPC improved cardiac function in CON but not in DM hearts. IPC in CON prevented HK solubilisation at 35 min I and at 5 min R, with a trend for increased mitochondrial HK. In contrast, the non effective IPC in DM was associated with solubilisation of HK and decreased mitochondrial HK at early reperfusion and a reciprocal behaviour at late reperfusion. We conclude that type I DM significantly altered cellular HK translocation patterns in the heart in response to IR and IPC, possibly explaining altered response to IR and IPC in diabetes. PMID- 23652995 TI - Heterogeneity of 11q13 region rearrangements in laryngeal squamous cell carcinoma analyzed by microarray platforms and fluorescence in situ hybridization. AB - We reinvestigated rearrangements occurring in region q13 of chromosome 11 aiming to: (i) describe heterogeneity of the observed structural alterations, (ii) estimate amplicon size and (iii) identify of oncogenes involved in laryngeal cancer progression as potential targets for therapy. The study included 17 cell lines derived from laryngeal cancers and 34 specimens from primary laryngeal tumors. The region 11q13 was analyzed by fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH) and gene expression microarray. Next, quantitative real time PCR was used for chosen genes to confirm results from aCGH and gene expression microarray. The observed pattern of aberrations allows to distinguish three ways, in which gain and amplification involving 11q13 region may occur: formation of a homogeneously staining region; breakpoints in/near 11q13, which lead to the three to sevenfold increase of the copy number of 11q13 region; the presence of additional copies of the whole chromosome 11. The minimal altered region of gain and/or amplification was limited to ~1.8 Mb (chr.11:69,395,184-71,209,568) and comprised mostly 11q13.3 band which contain 12 genes. Five, out of these genes (CCND1, ORAOV1, FADD, PPFIA1, CTTN) had higher expression levels in comparison to healthy controls. Apart from CCND1 gene, which has an established role in pathogenesis of head and neck cancers, CTTN, ORAOV1 and FADD genes appear to be oncogene-candidates in laryngeal cancers, while a function of PPFIA1 requires further studies. PMID- 23652996 TI - Dishevelled-2 silencing reduces androgen-dependent prostate tumor cell proliferation and migration and expression of Wnt-3a and matrix metalloproteinases. AB - To identify Dishevelled-2 (Dvl2) is a prostate cancer-associated gene and analyze the effects on the growth and invasive capacity of human prostate cancer (PCa) cells. Dvl2 mRNA expression was measured in PCa cell lines and tissue samples, by real-time reverse transcription PCR (qRT-PCR). Immunohistochemistry was used to examine the distribution of Dvl2 in PCa specimens. Silencing Dvl2 in LNCaP cells, proliferation was measured by the CCK-8 assay, cell motility and invasiveness by scratch wound and transwell migration assays, and Wnt-3a, AR, and matrix metalloproteinase (MMP) expression by western blotting. Dvl2 was overexpressed in LNCaP cells compared with the AI PCa lines DU-145 and PC-3, as well as in the majority of PCa tissue specimens examined by qRT-PCR (14/27, 51.9 %). Dvl2 expression was low in all 10 BPH specimens, weakly positive in 26/104 AD PCa specimens (23.8 %), positive in 60/104 AD PCa specimens (55 %), and strongly positive in all 5 AI PCa specimens. Dvl2 expression was significantly correlated with combined Gleason score (p = 0.02), lymph node metastasis (p = 0.005), and TNM stage (p = 0.015). Silencing of Dvl2 mRNA expression significantly reduced LNCaP cell proliferation, motility, invasiveness and Wnt-3a, AR, MMP-2, and MMP-9 expression. Dvl2 may increase PCa growth and metastasis potential, possibly by upregulating Wnt-3a, AR, and MMP expression. Silencing Dvl2 expression may be an effective treatment strategy for PCa. PMID- 23652998 TI - Genetic manipulation, a feasible tool to enhance unique characteristic of Chlorella vulgaris as a feedstock for biodiesel production. AB - Developing a reliable technique to transform unicellular green algae, Chlorella vulgaris, could boost potentials of using microalgae feedstock in variety of applications such as biodiesel production. Volumetric lipid productivity (VLP) is a suitable variable for evaluating potential of algal species. In the present study, the highest VLP level was recorded for C. vulgaris (79.08 mg l(-1 )day( 1)) followed by 3 other strains studied; C. emersonii, C. protothecoides, and C. salina by 54.41, 45 and 18.22 mg l(-1)day(-1), respectively. Having considered the high productivity of C. vulgaris, it was selected for the preliminary transformation experiment through micro-particle bombardment. Plasmid pBI 121, bearing the reporter gene under the control of CaMV 35S promoter and the kanamycin marker gene, was used in cells bombardment. Primary selection was done on a medium supplemented by 50 mg l(-1) kanamycin. After several passages, the survived cells were PCR-tested to confirm the stability of transformation and then were found to exhibit beta-glucuronidase (GUS) activity in comparison with the control cells. Southern hybridization of npt II probe with genomic DNA revealed stable integration of the cassette in three different positions in the genome. The whole process was successfully implemented as a pre-step to transform the algal cells by genes involved in lipid production pathway which will be carried out in our future studies. PMID- 23652997 TI - Biochemical characterization and functional analysis of fructose-1,6 bisphosphatase from Clonorchis sinensis. AB - Fructose-1,6-bisphosphatase (FBPase), a key regulatory enzyme of gluconeogenesis, plays an essential role in metabolism and development of most organisms. To the wealth of available knowledge about FBPase from Clonorchis sinensis (CsFBPase), in this study, the characteristics of CsFBPase and its potential role in pathogenesis of clonorchiasis were investigated. The Km value of CsFBPase was calculated to be 41.9 uM. The optimal temperature and pH of CsFBPase were 37 degrees C and pH 7.5-8.0, respectively. In addition, Mg(2+) or K(+) played a regulatory role in enzyme activity of CsFBPase. Both transcriptional and translational level of CsFBPase were higher in metacercariae (one of larva stages) than those in adult worm (P < 0.05). CsFBPase were observed to extensively express in the intestine, vitellaria and tegument of adult worms and ubiquitously in metacercariae. Moreover, CsFBPase was confirmed as a component of excretory/secretory products. Consequently, the translocation of CsFBPase could be detected on epithelial cells of bile duct in liver of C. sinensis infected rat. Recombinant CsFBPase can specifically bind to the membrane of human hepatic stellate cell line LX-2 by immunofluorescence analysis and stimulated proliferation and activation of LX-2 which demonstrated by Cell Counting Kit-8 and upregulation of key fibrosis-related factors, such as alpha-smooth muscle actin, collagen I and collagen III using qRT-PCR. Thus, we predicated that CsFBPase might be a multifunctional enzyme which played as both regulatory enzyme and virulence factor in pathogenesis of C. sinensis infection. PMID- 23652999 TI - Impaired muscarinic type 3 (M3) receptor/PKC and PKA pathways in islets from MSG obese rats. AB - Monosodium glutamate-obese rats are glucose intolerant and insulin resistant. Their pancreatic islets secrete more insulin at increasing glucose concentrations, despite the possible imbalance in the autonomic nervous system of these rats. Here, we investigate the involvement of the cholinergic/protein kinase (PK)-C and PKA pathways in MSG beta-cell function. Male newborn Wistar rats received a subcutaneous injection of MSG (4 g/kg body weight (BW)) or hyperosmotic saline solution during the first 5 days of life. At 90 days of life, plasma parameters, islet static insulin secretion and protein expression were analyzed. Monosodium glutamate rats presented lower body weight and decreased nasoanal length, but had higher body fat depots, glucose intolerance, hyperinsulinemia and hypertrigliceridemia. Their pancreatic islets secreted more insulin in the presence of increasing glucose concentrations with no modifications in the islet-protein content of the glucose-sensing proteins: the glucose transporter (GLUT)-2 and glycokinase. However, MSG islets presented a lower secretory capacity at 40 mM K(+) (P < 0.05). The MSG group also released less insulin in response to 100 MUM carbachol, 10 MUM forskolin and 1 mM 3 isobutyl-1-methyl-xantine (P < 0.05, P < 0.0001 and P < 0.01). These effects may be associated with a the decrease of 46 % in the acetylcholine muscarinic type 3 (M3) receptor, and a reduction of 64 % in PKCalpha and 36 % in PKAalpha protein expressions in MSG islets. Our data suggest that MSG islets, whilst showing a compensatory increase in glucose-induced insulin release, demonstrate decreased islet M3/PKC and adenylate cyclase/PKA activation, possibly predisposing these prediabetic rodents to the early development of beta-cell dysfunction. PMID- 23653000 TI - CXCL12 and TP53 genetic polymorphisms as markers of susceptibility in a Brazilian children population with acute lymphoblastic leukemia (ALL). AB - Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Genetic polymorphisms in the 3'UTR region of the CXCL12 (rs1801157) and TP53 codon 72 (rs1042522) genes may contribute to susceptibility to childhood ALL because they affect some important processes, such as metastasis regulation and tumor suppression. Thus the objective of the present study was to detect the frequency of two genetic polymorphisms in ALL patients and controls and to add information their impact on genetic susceptibility and prognosis. The CXCL12 and TP53 polymorphisms were tested in 54 ALL child patients and in 58 controls by restriction fragment length polymerase chain reaction and allelic specific chain reaction techniques, respectively. The frequencies of both allelic variants were higher in ALL patients than in the controls and indicated a positive association: OR = 2.44; 95 % CI 1.05-5.64 for CXCL12 and OR = 2.20; 95 % CI 1.03-4.70 for TP53. Furthermore, when the two genetic variants were analyzed together, they increased significantly more than fivefold the risk of this neoplasia development (OR = 5.24; 95 % CI 1.39-19.75), indicating their potential as susceptibility markers for ALL disease and the relevance of the allelic variant combination to increased risk of developing malignant tumors. Future studies may indicate a larger panel of genes involved in susceptibility of childhood ALL and other hematological neoplasias. PMID- 23653001 TI - CCND1 G870A polymorphism interaction with cigarette smoking increases lung cancer risk: meta-analyses based on 5008 cases and 5214 controls. AB - Evidence indicates CCND1 G870A polymorphisms as a risk factor for a number of cancers. Increasing studies have been conducted on the association of CCND1 G870A polymorphism with lung cancer risk. However, the results were controversial. The aim of the present study was to derive a more precise estimation of the relationship. Meta-analyses examining the association between CCND1 G870A polymorphism and lung cancer were performed. Subgroup analyses regarding ethnicity, smoking status, histological types and source of controls were also implemented. All eligible studies for the period up to May 2012 were identified. The overall data from ten case-control studies including 5,008 cases and 5,214 controls indicated that variant A allele may have an association with increased lung cancer risk (AA vs GG: OR = 1.21; 95 % CI = 1.08-1.36, dominant model: OR = 1.09; 95 % CI = 1.00-1.19, recessive model: OR = 1.23; 95 % CI = 1.01-1.49). In the subgroup analysis by ethnicity, A allele may elevate lung cancer risk among Asians but not Caucasians or Mixed ethnicities. In smoking status subgroup, A allele was shown to associate with increased lung cancer risk among smokers but not non-smokers. In the subgroup analysis by histological types, increased cancer risks were shown in adenocarcinoma but not squamous cell carcinoma, under the homozygote comparison and recessive models. Collectively, the results of the present study suggest that CCND1 G870A polymorphism might be a low-penetrant risk factor for lung cancer, particularly among Asians and smokers. Moreover, homozygous AA alleles might have a correlation with increased lung adenocarcinoma susceptibility. PMID- 23653002 TI - Isocitrate lyase encoding plasmids in BCG cause increased survival in ApoB100 only LDLR-/- mice. AB - We studied the role of isocitrate lyase in the interaction between Mycobacterium bovis BCG and mice. ApoB100-only LDLR-/- (B6;129S-ApoBtm2SgyLdlrtm1Her/J) mice were inoculated with M. bovis BCG harbouring plasmids carrying the gene for isocitrate lyase. The presence of ~29 times more copies of this gene resulted in a higher bacterial yield in the spleens and lungs of the infected mice. The spleen was 3-4 times heavier, and in the spleen the bacteria survived over 10 days longer than did the bacteria with the control plasmid. Propionate was less toxic for bacteria carrying icl plasmids in vitro. This recombinant BCG can be a possible vaccine candidate. PMID- 23653003 TI - Aberrant DNA methylation at Igf2-H19 imprinting control region in spermatozoa upon neonatal exposure to bisphenol A and its association with post implantation loss. AB - Bisphenol A (BPA) is an estrogenic compound commonly used in manufacture of various consumer products. Earlier studies from our group have demonstrated that neonatal exposure of male rats to BPA causes decrease in sperm count and motility, increase in post implantation loss, ultimately leading to subfertility during adulthood. One of the factors contributing for post implantation loss is altered methylation pattern of imprinted genes. The present study was undertaken to investigate the molecular effects of neonatal exposure of male rats to BPA (2.4 MUg/pup) (F0) on the methylation of H19 imprinting control region (ICR) in resorbed embryo (F1) and compared with spermatozoa of their respective sires (F0). We observed a significant down regulation in the transcript expression of Igf2 and H19 genes in BPA resorbed embryo (F1) as compared to control viable embryo. A significant hypomethylation was observed at the H19 ICR in the spermatozoa as well as in resorbed embryo sired by rats exposed neonatally to BPA. These results indicated that the aberrant methylation at ICR in spermatozoa was inherited by embryo which causes perturbation in the expression of Igf2 and H19, ultimately leading to post implantation loss. This could be one of the possible mechanisms of BPA induced adverse epigenetic effects on male fertility. PMID- 23653004 TI - Cloning, promoter analysis and expression of the tumor necrosis factor receptor associated factor 6 (TRAF6) in Japanese scallop (Mizuhopecten yessoensis). AB - Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a key adaptor molecule for the tumor necrosis factor superfamily and Toll-like/interleukin-1 receptor superfamily. It plays an important role in innate and adaptive immunity. The TRAF6 of Japanese scallop Mizuhopecten yessoensis (designated as MyTRAF6) was identified and characterized in this study. The full-length cDNA of MyTRAF6 was 2,407 bp, which consisted of 239-bp 5'-terminal untranslated region, 1,974-bp open reading frame encoding a polypeptide of 657 amino acids, 194-bp of 3' terminal untranslated region followed by a canonical polyadenylation signal sequence AATAAA and a poly (A) tail. The predicted amino acid sequence of MyTRAF6 contained the characteristic motifs of TRAF proteins, including a Zinc finger of RING-type, two Zinc fingers of TRAF-type, and a MATH (meprin and TRAF homology) domain. It had an overall identity of 43-96% with those of other TRAF6s, the highest identity (96%) with Chlamys farreri TRAF6, and the least identity (43%) with Meleagris gallopavo TRAF6. Phylogenetic analysis classified MyTRAF6 as a true TRAF6 ortholog. In addition, the promoter of MyTRAF6 was also identified by genome walking. It contained several potential transcription factor-binding sites and three single nucleotide polymorphisms. qRT-PCR analysis revealed that MyTRAF6 was highly expressed in hemocytes of adult M. yessoensis. MyTRAF6 transcript level in the hemocytes reached a maximum 6 h after Vibrio anguilarum challenge. The results indicated that MyTRAF6 may fulfill an important function during M. yessoensis bacterial infection. It could be a key effector molecule involved in the innate defense of molluscs. PMID- 23653005 TI - The cloning of the cdk2 transcript and the localization of its expression during gametogenesis in the freshwater giant prawn, Macrobrachium rosenbergii. AB - Cyclin-dependent kinases (cdks) are key regulators of the cell cycle. In mammals, cdk2 plays an essential role in the meiosis of spermatocytes and oocytes. To investigate the role of cdk2 kinase during gametogenesis in crustaceans, we cloned a complete cDNA sequence of cdk2 from the freshwater giant prawn, Macrobrachium rosenbergii, and examined its localization and expression in the developing gonads. The prawn cdk2 cDNA is 1,745 bp in length and encodes a putative protein of 305 amino acids. The deduced protein contains a conserved cyclin binding motif PSTAIRE and shares high homology with reported cdk2 kinases of other species. RT-PCR analysis showed a wide distribution of the cdk2 mRNA in all tested organs including the testis, ovary, heart, muscles, hepatopancreas and gills, and the highest level of expression in the ovary and testis. Localization by in situ hybridization of cdk2 mRNA in the ovary showed high expression in the ooplasm of previtellogenic and the nuclei of late vitellogenic oocytes. In testicular sections, cdk2 transcript is low in spermatogonia, high in spermatocytes, but reduced in spermatids and sperm. The high expression of the cdk2 transcripts in meiotic spermatocytes and oocytes indicated that the cdk2 gene has the conservative function in the germ cells meiosis during gametogenesis. PMID- 23653006 TI - Halplotypes of the ovine ADRB3 gene (ADRB3) and their association with post weaning growth in New Zealand Suffolk sheep. AB - The beta3-adrenergic receptor (ADRB3) regulates thermogenesis and lipolysis in brown and white adipose tissue. Previously, sixteen ovine ADRB3 haplotypes have been defined. In this study, the relationship between these ADRB3 haplotypes and variation in post-weaning growth was investigated in 797 New Zealand Suffolk lambs from 38 sire lines and eight studs, using PCR-SSCP and General Linear Mixed effects Models. Seven haplotypes were found in these sheep and they comprised five previously reported intron sequences and four previously reported 3'UT sequences. The frequencies of the various diplotypes ranged from 0.1 to 17.6% and individual haplotypes from 0.8 to 32.5%. The presence of haplotype A-b was associated with a decreased weaning-weight (P=0.001). Sheep with the B-c/F-e diplotype had a higher mean weaning-weight than those with A-b/B-c or A-b/E-e (P<0.05). The presence of C-a was found to be associated with increased post weaning growth (P=0.008), while the presence of B-c was associated with decreased post-weaning growth (P=0.005). Sheep with A-b/C-a had higher mean post-weaning growth than those with A-b/A-b, A-b/B-c, B-c/B-c, B-c/E-e or B-c/F-e (P<0.05). Sheep with B-c/B-c had lower mean post-weaning growth than those with A-b/C-a or B-c/C-a (P<0.05). Additive effects for the different forms of the B-c haplotypes on post-weaning growth were identified. The effects of the ovine ADRB3 haplotypes on weaning-weight and post-weaning growth confirm that they could be used as a candidate gene-marker for improving sheep growth. PMID- 23653007 TI - Screening and test of CD40 related signal transduction pathway in AGS cells and construction of gene silencing vector. AB - This study is designed to screen the CD40 related signal transduction pathway in AGS cells and construction of gene silencing vector. Analysis results showed 414 differential genes expression, including upregulation of 209 genes and downregulation of 205 genes. Basing on the ratio of signal in experimental group to signal in control group, 45 genes (38 genes upregulation and seven genes downregulation) with significant (P<0.01) change in expression levels were screened according to the screening standard (signal log ratio>=1 or <=-1). These genes involved into metabolism, cell cycle and apoptosis, signal transduction and stress response. Furthermore, PI3K mRNA expression level in PI3K siRNA transfected AGS cells was 0.2335+/-0.0116 72 h after transfection. This value was significantly (P<0.05) lower than that in blank and negative control groups. PI3K protein expression in PI3K siRNA transfected AGS cells was significantly (P<0.05) lower than that in blank and PI3K siRNA/N transfected groups. Therefore, PI3K siRNA gene silencing vector can significantly inhibit PI3K mRNA and protein expression in AGS cells. PMID- 23653008 TI - The novel human MRC1 gene polymorphisms are associated with susceptibility to pulmonary tuberculosis in Chinese Uygur and Kazak populations. AB - The MRC1 gene, encoding the human mannose receptor (MR), is a member of the C type lectin receptors family. MR can recognize and bind to Mycobacterium tuberculosis by the extracellular structure, and play a role in antigen presenting and maintaining a stable internal environment. This study aimed to investigate potential associations of SNPs in exon 7 of the MRC1 gene with pulmonary tuberculosis (TB). G1186A, G1195A, T1212C, C1221G, C1303T and C1323T were genotyped using PCR and DNA sequencing in 595 Chinese Uygur and 513 Kazak subjects. In the Uygur, the frequency of allele G (P=0.031, OR=1.29, 95% CI=1.02 1.62) and AA genotype (P=0.033, OR=1.64, 95% CI=1.04-2.60) for G1186A was lower in the pulmonary TB than healthy control and were significantly correlated with pulmonary TB. After adjustment for age and gender, G1186A was found to be additive models in association with pulmonary TB (P=0.04, OR=1.27, 95% CI=1.01 1.60). By calculating linkage disequilibrium, the frequency of haplotype GGTCCT (P=0.032, OR=0.75, 95% CI=0.57-0.97) and GGTCCC (P=0.044, OR=0.57, 95% CI=0.33 0.99) was significantly associated with pulmonary TB. No association was found between other SNPs and pulmonary TB. In the Kazak, all SNPs were not associated with pulmonary TB. Our results suggest that genetic factors play an important role in susceptibility to pulmonary TB at the individual level, and provide an experimental basis to clarify the pathogenesis of pulmonary TB. PMID- 23653009 TI - Toll-like receptor (TLR) and matrix metalloproteinase (MMP) polymorphisms and periodontitis susceptibility: a meta-analysis. AB - The aim of this study was to determine whether the toll-like receptor (TLR) and matrix metalloproteinase (MMP) polymorphisms confers susceptibility to periodontitis in ethnically different populations. A literature search using PubMed and Embase provided the data to conduct a meta-analysis on the associations between the TLR2 Arg753Gln, TLR4 Asp299Gly, Thr399Ile, MMP-1 -1607 G1/G2 and MMP-9 -1562 C/T polymorphisms and periodontitis. A total of 32 studies (14 on TLR polymorphisms and 18 on MMP polymorphisms) were considered in the meta analysis. The meta-analysis showed no association between periodontitis and the TLR2 753Arg allele (Odds ratio [OR]=0.962, 95% confidence interval [CI]=0.662 1.400, p=0.841). Meta-analysis of the TLR4 Asp299Gly and Thr399Ile polymorphisms showed no association between periodontitis and the TLR4 299Asp allele in all study subjects (OR=0.984, 95% CI=0.761-1.271, p=0.900; OR=1.030, 95% CI=0.748 1.418, p=0.854). Meta-analysis showed an association between the MMP-1 -1607 G2G2 genotype and periodontitis in Asians (OR=3.778, 95% CI=1.210-11.80, p=0.022). Meta-analysis containing only studies in Hardy-Weinberg equilibrium revealed no association between chronic periodontitis and the MMP-9 -1562TT genotype (OR=0.638, 95% CI=0.265-1.533, p=0.315). This meta-analysis demonstrates a lack of association between the TLR2 Arg753Gln, TLR4 Asp299Gly, Thr399Ile, MMP-9 -1562 C/T polymorphisms and periodontitis, but shows an association between the MMP-1 1607 G2G2 genotype and periodontitis in Asians. PMID- 23653010 TI - Sequence polymorphisms at the growth hormone GH1/GH2-N and GH2-Z gene copies and their relationship with dairy traits in domestic sheep (Ovis aries). AB - The purpose was to analyze the growth hormone GH1/GH2-N and GH2-Z gene copies and to assess their possible association with milk traits in Sarda sheep. Two hundred multiparous lactating ewes were monitored. The two gene copies were amplified separately and each was used as template for a nested PCR, to investigate single strand conformation polymorphism (SSCP) of the 5'UTR, exon-1, exon-5 and 3'UTR DNA regions. SSCP analysis revealed marked differences in the number of polymorphic patterns between the two genes. Sequencing revealed five nucleotide changes at the GH1/GH2-N gene. Five nucleotide changes occurred at the GH2-Z gene: one was located in exon-5 (c.556G > A) and resulted in a putative amino acid substitution G186S. All the nucleotide changes were copy-specific, except c.*30delT, which was common to both GH1/GH2-N and GH2-Z. Variability in the promoter regions of each gene might have consequences on the expression level, due to the involvement in potential transcription factor binding sites. Both gene copies influenced milk yield. A correlation with milk protein and casein content was also evidenced. These results may have implications that make them useful for future breeding strategies in dairy sheep breeding. PMID- 23653011 TI - Combination use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in diabetic kidney disease. AB - Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) have played a major role in slowing the progression of diabetic kidney disease, since they lower urine protein levels, lower blood pressure, and slow progression. Studies have suggested that the combination of ACE-I and ARB offered greater benefits for patients with diabetic kidney disease. In 2008, the large ONTARGET study reported no benefit with combination therapy, as compared with monotherapy. This study has changed practice patterns, but few patients in this study had diabetic kidney disease. In this review, the data in favor of the combination use of these agents in patients with diabetic kidney disease and data against the combination are reviewed. At this time, there is little support for using the combination in diabetic patients with no kidney disease or early stage diabetic kidney disease. But there are patients who may benefit from combination use. PMID- 23653012 TI - Insights into Chinese perspectives on do-not-resuscitate (DNR) orders from an examination of DNR order form completeness for cancer patients. AB - PURPOSE: Discussing end-of-life care with patients is often considered taboo, and signing a do-not-resuscitate (DNR) order is difficult for most patients, especially in Chinese culture. This study investigated distributions and details related to the signing of DNR orders, as well as the completeness of various DNR order forms. METHODS: Retrospective chart reviews were performed. We screened all charts from a teaching hospital in Taiwan for patients who died of cancer during the period from January 2010 to December 2011. A total of 829 patient records were included in the analysis. The details of the DNR order forms were recorded. RESULTS: The DNR order signing rate was 99.8%. The percentage of DNR orders signed by patients themselves (DNR-P) was 22.6%, while the percentage of orders signed by surrogates (DNR-S) was 77.2%. The percentage of signed DNR forms that were completely filled out was 78.4%. The percentage of DNR-S forms that were completed was 81.7%, while the percentage of DNR-P forms that were completely filled out was only 67.6%. CONCLUSION: Almost all the cancer patients had a signed DNR order, but for the majority of them, the order was signed by a surrogate. Negative attitudes of discussing death from medical professionals and/or the family members of patients may account for the higher number of signed DNR-S orders than DNR-P orders. Moreover, early obtainment of signed DNR orders should be sought, as getting the orders earlier could promote the quality of end of-life care, especially in non-oncology wards. PMID- 23653013 TI - Testosterone replacement for fatigue in hypogonadal ambulatory males with advanced cancer: a preliminary double-blind placebo-controlled trial. AB - BACKGROUND: Uncontrolled studies show fatigue, anorexia, depression, and mortality are associated with low testosterone in men with cancer. Testosterone replacement improves quality of life and diminishes fatigue in patients with non cancer conditions. The primary objective was to evaluate the effect of testosterone replacement on fatigue in hypogonadal males with advanced cancer, by the Functional Assessment of Chronic Illness Therapy-Fatigue subscale (FACIT Fatigue) at day 29. METHODS: This is a randomized, double-blinded placebo controlled trial. Outpatients with advanced cancer, bioavailable testosterone (BT) <70 ng/dL and fatigue score >3/10 on the Edmonton Symptom Assessment Scale were eligible. Intra-muscular testosterone or sesame seed oil placebo was administered every 14 days to achieve BT levels 70-270 ng/dL. RESULTS: Sixteen placebo and 13 testosterone-treated subjects were evaluable. No statistically significant difference was found for FACIT-fatigue scores between arms (-2 +/- 12 for placebo, 4 +/- 8 for testosterone, p = 0.11). Sexual Desire Inventory score (p = 0.054) and performance status (p = 0.02) improved in the testosterone group. Fatigue subscale scores were significantly better (p = 0.03) in those treated with testosterone by day 72. CONCLUSIONS: Four weeks of intramuscular testosterone replacement in hypogonadal male patients with advanced cancer did not significantly improve quality of life. Larger studies of longer duration are warranted. PMID- 23653014 TI - Congruence in symptom assessment between hepatocellular carcinoma patients and their primary family caregivers in China. AB - OBJECTIVES: The aims of this cross-sectional study were to explore the agreement in symptom evaluation results between patients and their family caregivers and to search for the possible factors influencing the agreement. METHODS: A convenience sample of 280 dyads consisting of hepatocellular carcinoma patients and their family caregivers was included in this study. All of them completed the symptom checklist of Chinese version of the M. D. Anderson symptom inventory and the evaluations of six common symptoms of hepatocellular carcinoma. RESULTS: The levels of agreement ranged from moderate to substantial. A number of factors associated with caregivers (particularly depression state, age, others helping to care for the patient or not, and the relationship with patient) and patients (traditional Chinese medicine treatment, religion, KPS scores, and educational levels) were significantly correlated with levels of disparity on some symptoms. CONCLUSION: The study illustrates that family caregivers of hepatocellular carcinoma patients can provide reasonable reports on patients' symptoms. Healthcare providers need to pay special and sufficient attention to the caregivers' depression. PMID- 23653015 TI - The reciprocal relationship between vigor and insomnia: a three-wave prospective study of employed adults. AB - Vigor is a positive affect experienced at work. It refers to feelings of possessing physical strength, emotional energy, and cognitive liveliness. Accumulated evidence suggests that vigor has a protective effect on health, but the mechanisms of this link remain to be discovered. This study focused on sleep quality as one possible mechanism. We used a full-panel, longitudinal design to investigate the hypothesis that changes in vigor over time have inverse effects on insomnia and vice versa. The study was conducted on a multi-occupational sample of working adults (N = 1,414, 70 % men) at three time points (T1, T2, and T3), over a period of about 3 years. Vigor was assessed by the Shirom-Melamed Vigor Measure, while insomnia was assessed by the Brief Athens Insomnia Scale. Results of SEM-analyses, controlling for neuroticism, and other potential confounding variables, offered a strong support for the study hypotheses, indicating cross-lagged reciprocal inverse relationships between vigor and insomnia. The results suggest that vigor has a protective effect on sleep quality and that vigor might positively influence health through this pathway. PMID- 23653016 TI - Polarotaxis and scototaxis in the supratidal amphipod Platorchestia platensis. AB - Talitrid amphipods use many cues for orientation during forays between temporary burrows and feeding areas, and for locating beaches when submerged, with visual cues being particularly important. Little evidence exists for polarized light among these visual cues despite extensive orientation by celestial and underwater polarized light in other crustaceans and in insects. We used electroretinography to assess spectral sensitivity in the eye of the beach flea Platorchestia platensis, and behavioral studies to test whether linearly polarized light serves as an orientation cue. Two spectral classes were present in the P. platensis eye with maxima at 431 and 520 nm. Non-uniform orientation of amphipods in the laboratory arena required either light/dark or polarized cues. Scototactic movements depended on arena conditions (day/night, wet/dry), while orientation under linearly polarized light was wavelength-dependent and parallel to the e vector. Subsequent tests presented conflicting and additive scototactic and polarotactic cues to differentiate among these responses. In dry conditions, orientation parallel to the polarization e-vector overcame a dominant negative scototaxis, confirming that polarotaxis and scototaxis are separate orientation responses in this species. These behavioral results demonstrate talitrid amphipods can perceive and orient to linearly polarized light, and may use it to orient toward preferred zones on beaches. PMID- 23653017 TI - Expression of Tim-1 and Tim-3 in Plasmodium berghei ANKA infection. AB - Cerebral malaria (CM) is a serious and often fatal complication of Plasmodium falciparum infections; however, the precise mechanisms leading to CM is poorly understood. Mouse malaria models have provided insight into the key events in pathogenesis of CM. T-cell immune response is known to play an important role in malaria infection, and members of the T-cell immunoglobulin- and mucin-domain containing molecule (Tim) family have roles in T-cell-mediated immune responses. Tim-1 and Tim-3 are expressed on terminally differentiated Th2 and Th1 cells, respectively, and participate in the regulation of Th immune response. Until now, the role of Tim family proteins in Plasmodium infection remains unclear. In the present study, the mRNA levels of Tim-1, Tim-3, and some key Th1 and Th2 cytokines in the spleen of Kunming outbred mice infected with Plasmodium berghei ANKA (PbANKA) were determined using real-time polymerase chain reaction (qRT PCR). Compared with uninfected controls, Tim-1 expression was significantly decreased in infected mice with CM at day 10 postinfection (p.i.) but significantly increased in infected mice with non-CM at day 22 p.i.; in contrast, Tim-3 expression was significantly increased in infected mice both with CM at day 10 p.i. and with non-CM at day 22 p.i. The expressions of IFN-gamma, TNF-alpha, IL-10, and IL-12 were significantly increased but IL-4 was significantly decreased in infected mice with CM at days 10 p.i., whereas the expressions of IFN-gamma, TNF-alpha, IL-4, IL-10, and TGF-beta were significantly increased but IL-12 was significantly decreased in infected mice with non-CM at days 22 p.i. Furthermore, the expression of Tim-1 and Tim-3 could reflect Th2 and Th1 immune response in the spleen of PbANKA-infected mice, respectively. Our data suggest that PbANKA infection could inhibit the differentiation of T lymphocytes toward Th2 cells, promote the Th1 cell differentiation, and induce Th1-biased immune response in the early infective stage, whereas the infection could promote Th2 cell differentiation and induce Th2-biased immune response in the late infective stage. Our data indicate that both Tim-1 and Tim-3 may play a role in the process of PbANKA infection, which may represent a potential therapeutic target. PMID- 23653018 TI - Thyroiditis de Quervain. Are there predictive factors for long-term hormone replacement? AB - BACKGROUND: Subacute thyroiditis is a usually self-limiting disease of the thyroid. However, approximately 0.5-15% of the patients require permanent thyroxine substitution. Aim was to determine predictive factors for the necessity of long-term hormone-replacement (LTH). PATIENTS, METHODS: We retrospectively reviewed the records of 72 patients with subacute thyroiditis. Morphological and serological parameters as well as type of therapy were tested as predictive factors of consecutive hypothyroidism. RESULTS: Mean age was 49 +/- 11 years, f/m ratio was 4.5 : 1. Thyroid pain and signs of hyperthyroidism were leading symptoms. Initial subclinical or overt hyperthyroidism was found in 20% and 37%, respectively. Within six months after onset 15% and 1.3% of the patients developed subclinical or overt hypothyroidism, respectively. At latest follow-up 26% were classified as liable to LTH. At onset the thyroid was enlarged in 64%, and at latest follow-up in 8.3%, with a significant reduction of the thyroid volume after three months. At the endpoint the thyroid volume was less in patients in the LTH group compared with the non-LTH group (41.7% vs. 57.2% of sex adjusted upper norm, p = 0.041). Characteristic ultrasonographic features occurred in 74% of the patients in both lobes. Serological and morphological parameters as well as type of therapy were not related with the need of LTH. CONCLUSIONS: In this study the proportion of patients who received LTH was 26%. At the endpoint these patients had a lower thyroid volume compared with euthyroid patients. No predictive factors for LTH were found. PMID- 23653019 TI - Chemical routes to top-down nanofabrication. AB - In fabricating materials at the nanometer scale, nanotechnologists typically employ two general strategies: bottom-up and top-down. While the bottom-up approach constructs nanomaterials from basic building blocks like atoms or molecules, the top-down approach produces nanostructures by deconstructing larger materials with the use of lithographic tools (i.e., physical top-down) or through chemical-based processes (i.e., chemical top-down). This tutorial review summarizes the various top-down nanofabrication methods, with great emphasis on the chemical routes that can generate nanoporous materials and ordered arrays of nanostructures with three-dimensional features. The chemical top-down routes that are discussed in detail include (1) templated etching, (2) selective dealloying, (3) anisotropic dissolution, and (4) thermal decomposition. These emerging nanofabrication tools open up new avenues in the creation of functional nanostructures with a wide array of promising applications. PMID- 23653020 TI - Subcapital correction osteotomy for malunited slipped capital femoral epiphysis. AB - BACKGROUND: Slipped capital femoral epiphysis (SCFE), causing posterior and inferior displacement and retroversion of the femoral head, is a well-recognized etiology for femoroacetabular impingement and can lead to premature arthritis in the young adult. The treatment of malunited SCFE remains controversial. Surgical dislocation and subcapital correction osteotomy (SCO) has been described as a powerful method to correct the proximal femoral deformity. METHODS: Between January 2003 and January 2010, 11 patients (12 hips) with closed femoral physes and symptomatic femoroacetabular impingement from malunited SCFE were treated with surgical dislocation and SCO. We performed a retrospective review of patient histories, physical examinations, operative findings, and preoperative and postoperative anteroposterior (AP) and groin-lateral (GLat) radiographs. Mean follow-up was 61 months. RESULTS: There were 4 female and 7 male patients with an average age of 15 years at the time of SCO. On the AP radiograph, the mean inferior femoral head displacement (AP epiphyseal-neck angle) was significantly improved (-26 to -6 degrees, P<0.001). On the GLat radiograph, the mean posterior femoral head displacement (lateral epiphyseal-neck angle) was significantly improved (-45 to -3 degrees, P<0.001). The mean alpha-angle was also significantly improved on both views (AP: 85 to 56 degrees, P<0.001; GLat: 85 to 46 degrees, P<0.001). Operative findings included 1 femoral osteochondral defect, 8 Outerbridge grade 3 to 4 acetabular cartilage lesions, and 10 labral lesions. Significant improvement of the mean Harris Hip Score was seen at latest follow-up (54 to 77, P=0.016). Complications occurred in 4 of the 12 cases with avascular necrosis in 2 patients, a worse postoperative Harris Hip Score in 1 patient, and failure of fixation treated successfully with revision open reduction internal fixation in 1 patient. CONCLUSIONS: SCO as an adjunct to surgical dislocation and osteochondroplasty can be used to correct the deformity of the proximal femur associated with malunited SCFE. Normalization of proximal femoral anatomy may postpone progression to severe osteoarthritis and thus delay the need for arthroplasty in this young patient population. However, surgeons and patients should be aware that the risks of this procedure in this population are significant. LEVEL OF EVIDENCE: Level IV-therapeutic study. PMID- 23653021 TI - Midterm results after subtrochanteric end-to-side valgization osteotomy in severe infantile coxa vara. AB - BACKGROUND: For the treatment of the severe infantile coxa vara it is mandatory for the orthopaedic surgeon to observe the mechanobiology of the growing hip before and after the surgical intervention. We hereby would like to present our experiences with the subtrochanteric end-to-side valgization osteotomy and to compare the procedure with the alternatively used Y-shaped osteotomy as described by Pauwels. METHODS: Thirteen patients (20 hips) who had undergone subtrochanteric end-to-side valgization were followed for a mean 6.2 years (range, 0.8 to 12.8 y). At the time of surgery the mean age was 7.1 years (range, 2.0 to 13.3 y), last follow-up examination was performed at a mean of 13.4 years of age (range, 5.1 to 18.3 y). The deformities were etiologically based on 5 entities: congenital coxa vara (n=1), osteochondrodysplasias (n=12), postosteomyelitic coxa vara (n=5), and avascular femoral head necrosis in the course of congenital dysplasia of the hip (n=2). The follow-up rate was 100%.In addition, we analyzed a total of 93 pelvic radiographies with a total of 139 hip joints. Thirty angles and distances were assessed according to parameters described in the literature. RESULTS: Although preoperatively 12 patients presented with a positive Trendelenburg's sign, it was only present postoperatively in 2 patients. Duchenne's limp reduced from 10 to 1. All of the 15 preoperatively apparent nonunions could be healed by means of surgery. Two hips redeveloped pathologically lowered collodiaphyseal angles postoperatively, one of which had to undergo revision surgery. Preoperatively 15 out of 20 patients (75%) showed nonunions all of which healed after surgery. No recurrence could be seen at the time of the last follow-up.The following angles were assessed on plain radiographies of the pelvis preoperatively and directly postoperatively as well as on the last follow-up at a mean of 85 months: CCD angle 98 degrees/156 degrees/144 degrees, EY-angle 55 degrees/5 degrees/15.7 degrees, AY-angle 32 degrees/75 degrees/66 degrees, CE-angle 20 degrees/25 degrees/18 degrees, AC-angle 20 degrees/18 degrees/20 degrees. The articulotrochanteric distance was 5 mm/26 mm/14 mm. CONCLUSIONS: The subtrochanteric end-to-side valgization osteotomy showed to be highly effective in the management of the infantile coxa vara, improving the clinical impairment of the patients postoperatively. All of the preoperatively present nonunions showed osseous consolidation at follow-up examination. Only minor revarization tendencies could be found. The procedure is technically less demanding, safer and more efficient regarding the lengthening of the affected limb in comparison to the Y-shaped intertrochanteric osteotomy as described by Pauwels. LEVEL OF EVIDENCE: Case-control study (EBM-level III). PMID- 23653022 TI - Internet search term affects the quality and accuracy of online information about developmental hip dysplasia. AB - BACKGROUND: The recent emphasis on shared decision-making has increased the role of the Internet as a readily accessible medical reference source for patients and families. However, the lack of professional review creates concern over the quality, accuracy, and readability of medical information available to patients on the Internet. METHODS: Three Internet search engines (Google, Yahoo, and Bing) were evaluated prospectively using 3 difference search terms of varying sophistication ("congenital hip dislocation," "developmental dysplasia of the hip," and "hip dysplasia in children"). Sixty-three unique Web sites were evaluated by each of 3 surgeons (2 fellowship-trained pediatric orthopaedic attendings and 1 orthopaedic chief resident) for quality and accuracy using a set of scoring criteria based on the AAOS/POSNA patient education Web site. The readability (literacy grade level) of each Web site was assessed using the Fleisch-Kincaid score. RESULTS: There were significant differences noted in quality, accuracy, and readability of information depending on the search term used. The search term "developmental dysplasia of the hip" provided higher quality and accuracy compared with the search term "congenital hip dislocation." Of the 63 total Web sites, 1 (1.6%) was below the sixth grade reading level recommended by the NIH for health education materials and 8 (12.7%) Web sites were below the average American reading level (eighth grade). CONCLUSIONS: The quality and accuracy of information available on the Internet regarding developmental hip dysplasia significantly varied with the search term used. Patients seeking information about DDH on the Internet may not understand the materials found because nearly all of the Web sites are written at a level above that recommended for publically distributed health information. CLINICAL RELEVANCE: Physicians should advise their patients to search for information using the term "developmental dysplasia of the hip" or, better yet, should refer patients to Web sites that they have personally reviewed for content and clarity. Orthopaedic surgeons, professional societies, and search engines should undertake efforts to ensure that patients have access to information about DDH that is both accurate and easily understandable. PMID- 23653023 TI - Osteopenia predicts curve progression of adolescent idiopathic scoliosis in girls treated with brace treatment. AB - BACKGROUND: Previous studies have shown a significant association between osteopenia and adolescent idiopathic scoliosis (AIS). And initial bone mineral density (BMD) was proposed to serve as a new prognostic factor of curve progression in AIS. However, it remains unknown whether there is a link between the initial bone mineral status and the outcome of brace treatment. This study aimed to investigate whether the initial bone mineral status could influence the final outcome of brace treatment in AIS. METHODS: Girls with AIS treated with brace treatment were recruited. These patients either completed brace treatment, or were indicated for correction surgery with a curve magnitude of >45 degrees. Patients with a progressed scoliosis (group A) and those with a nonprogressed scoliosis (group B) were identified. The associations between the bracing outcome and the indices before bracing, including growth status, anthropometric measurements, BMD status, curve magnitude, and curve pattern were evaluated using univariate analysis and regression analysis. RESULTS: Sixty-eight patients were included. There were 17 girls (25%) in group A and 51 girls (75%) in group B, respectively. The girls in group A had a significantly larger initial Cobb angle (32.3+/-6.6 vs. 29.1+/-5.3 degrees), a significantly lower BMD of lumbar spine from L2 to L4 value (0.80+/-0.11 vs. 0.88+/-0.12 g/cm), and a marginally significantly lower Risser grade (1.4+/-1.5 vs. 2.2+/-1.4), than in group B. In comparison with group B, more girls in group A were found to be premenarche (P=0.008), osteopenic (P=0.003), with a lower Risser grade (P=0.079), a greater curve magnitude (P=0.159), and a main thoracic pattern (P=0.122) before the initiation of bracing treatment. As revealed by the multiple logistic regression analysis, osteopenia (P=0.002) was identified as an independent risk factor in curve progression in AIS girls, during the total duration of bracing treatment. CONCLUSIONS: Osteopenia is identified to serve as a new independent risk factor in the curve progression during the duration of bracing treatment. The evaluation of initial BMD status before bracing may help to predict the outcome of brace treatment. LEVEL OF EVIDENCE: Level II. PMID- 23653024 TI - Predicting operative blood loss during spinal fusion for adolescent idiopathic scoliosis. AB - BACKGROUND: Patient and surgical factors are known to influence operative blood loss in spinal fusion for adolescent idiopathic scoliosis (AIS), but have only been loosely identified. To date, there are no established recommendations to guide decisions to predonate autologous blood, and the current practice is based primarily on surgeon preference. This study is designed to determine which patient and surgical factors are correlated with, and predictive of, blood loss during spinal fusion for AIS. METHODS: Retrospective analysis of 340 (81 males, 259 females; mean age, 15.2 y) consecutive AIS patients treated by a single surgeon from 2000 to 2008. Demographic (sex, age, height, weight, and associated comorbidities), laboratory (hematocrit, platelet, PT/PTT/INR), standard radiographic, and perioperative data including complications were analyzed with a linear stepwise regression to develop a predictive model of blood loss. RESULTS: Estimated blood loss was 907+/-775 mL for posterior spinal fusion (PSF, n=188), 323+/-171 mL for anterior spinal fusion (ASF, n=124), and 1277+/-821 mL for combined procedures (n=28). For patients undergoing PSF, stepwise analysis identified sex, preoperative kyphosis, and operative time to be the most important predictors of increased blood loss (P<0.05). For ASF, the mean arterial pressure at incision and the operative time were predictive (P<0.05). The following formula was developed to estimate blood loss in PSF: blood loss (mL)=C+Op-time (min)*(6.4)-pre-op T2-T12 kyphosis (degrees)*(8.7), C=233 if male and -270 if female. CONCLUSION: We find sex, operative time, and preoperative kyphosis to be the most important predictors of increased blood loss in PSF for AIS. Mean arterial pressure and operative time were predictive of estimated blood loss in ASF. For posterior fusions, we also present a model that estimates blood loss preoperatively and can be used to guide decisions regarding predonation of blood and the use of antifibrinolytic agents. LEVEL OF EVIDENCE: Retrospective study: Level II. PMID- 23653025 TI - Impact of pedicle screw fixation on loss of deformity correction in patients with adolescent idiopathic scoliosis. AB - BACKGROUND: Loss of coronal correction has been reported in the presence of a solid posterior fusion mass in patients who are skeletally immature. Significant increases in postoperative coronal curvature are typically attributed to the presence of pseudarthrosis, loss of instrumentation fixation, or adding-on. We evaluated the clinical and radiographic factors associated with a loss of correction that was not attributed to these etiologies as well as the impact of pedicle screw fixation on loss of correction. METHODS: A prospective, longitudinal study database was retrospectively queried for patients with at least 2 years of follow-up who underwent surgery for adolescent idiopathic scoliosis. Loss of correction was defined (1) clinically, as a >5 degree increase in the inclinometer reading at any time interval after surgery, excluding preoperative values; or (2) radiographically, as an increase of >= 10 degrees in the coronal Cobb angle of an instrumented curve. Patients with pseudarthrosis, adding-on, or loss of fixation were excluded. RESULTS: Ninety-three of 800 patients (11.6%) had loss of deformity correction. Twenty-one patients (2.5%) had >5 degrees of inclinometer change and 76 patients (9.5%) had >=10 degrees of Cobb change, with a mean loss of 10.85+/-4.2 degrees. When comparing pedicle screw constructs only, 10% of patients developed loss of correction as opposed to 20% of the patients with hybrid constructs (P=0.036). Factors associated with loss of correction were: age, hybrid construct, magnitude of thoracic curve, thoracic apical translation, and T1 tilt angle. CONCLUSION: This study reports a high percentage of loss of coronal correction (12%) after 2 years of follow-up that was not associated with infection, adding-on, or apparent pseudarthrosis. Larger magnitude thoracic curves with apical deviation and hybrid constructs were associated with an increased likelihood of loss of curve correction where use of pedicle screw fixation seems to decrease its incidence. LEVEL OF EVIDENCE: III. PMID- 23653026 TI - Detection of pars injury by SPECT in patients younger than age 10 with low back pain. AB - BACKGROUND: Evaluation of extension-based low back pain in young athletes with suspected pars injury may include a referral for skeletal single photon emission computed tomography (SPECT). However, the diagnostic yield of this technique in children with low back pain before the age of 10 years remains uncertain. We examined a series of consecutive SPECT scans to address this question. MATERIALS AND METHODS: A retrospective review of department databases revealed 107 consecutive skeletal Tc-99m MDP SPECT scans performed between January 1, 2007 and December 31, 2009 in children less than 10 years of age. Of these, 72 studies were performed for a referral diagnosis of back pain. There were 43 girls (44 studies) and 28 boys (28 studies). The mean age was 7.2 years (range, 1.9 to 9.9 y). All SPECT scans were reviewed and positive findings documented. In addition, all available anatomic imaging, imaging reports (computed tomography, magnetic resonance, and x-ray) and clinical notes were reviewed, and results were compared with those of SPECT studies. RESULTS: Of the 72 SPECT studies, 35 (49%) identified a focal area in the spine of abnormal increased uptake, with 17 in the region of the pars interarticularis. With additional imaging, 1 case was demonstrated not to be a pars injury (computed tomography showed a transverse process fracture) and 2 patients with negative SPECT scans were shown to have pars injuries that SPECT scan had not detected, for a total of 18 pars injuries (25%) in this cohort. Reported participation in gymnastics or football was related to pars injury (odds ratio 4.3, P=0.04). CONCLUSIONS: Pars injury was found in 25% of children referred for SPECT scan with back pain below 10 years of age. SPECT scan was highly sensitive for this injury as well as in identifying other potential sites of pathology, and should be considered in the workup of persistent low back pain in young children. LEVEL OF EVIDENCE: Level II, diagnostic study. PMID- 23653027 TI - Successful conservative treatment for neglected rotatory atlantoaxial dislocation. AB - BACKGROUND: Rotatory atlantoaxial subluxation (RAS) is a rare condition that is often misdiagnosed and therefore incorrectly managed. We describe our experience and propose an algorithm for treating neglected RAS nonoperatively. METHODS: All consecutive children with neglected (>6 wk) RAS were treated in our department between 2005 and 2010 by cervical traction using a Gleason traction device and nonsteroidal anti-inflammatory drugs and muscle relaxants. When reduction was not achieved, the Gleason device was replaced by a halo device without manipulative reduction, and weight was added as necessary until reduction was successful. Fixation of reduction was either by a sternooccipital mandibular immobilizer or a halo vest for 3 to 4 months. RESULTS: All 5 children (4 boys and 1 girl, aged 4 to 11 y) were successfully treated for neglected RAS. The mean duration from symptom onset (eg, limited neck range of motion, discomfort) to treatment initiation was 11.6 weeks (range, 6 to 16 wk). Closed reduction was achieved by a Gleason or a noninvasive halo device within 1 to 2 weeks in 4 cases. The fifth case was reduced after 5 weeks of traction using a halo with a 5 kg weight. All children had symmetrical full range of motion, normal neurological examination, and were fully engaged in educational and sports activities without recurrent dislocations at final follow-up (mean, 30 mo; range, 18 to 49 mo). CONCLUSIONS: Conservative treatment by gradual and prolonged traction without manipulative reduction in neglected RAS might be a successful method. Reduction can often be achieved within 2 weeks of treatment onset. LEVEL OF EVIDENCE: Level IV (retrospective case series). PMID- 23653028 TI - Associated injuries in children and adolescents with spinal trauma. AB - BACKGROUND: Over half of children and adolescents with spinal trauma have associated injuries, most commonly involving the appendicular skeleton, head and neck, and thorax. The incidence and characteristics of these associated injuries have been well described, but to our knowledge there has been no evaluation of the relationship between the injury characteristics and the patient age. METHODS: Data were obtained from the trauma registries of the local pediatric and adult level 1 trauma centers, and patients aged 0 to 19 years with spinal trauma were identified. For analysis, patients were divided into 3 age groups: 0 to 3, 4 to 12, and 13 to 19 years. Associated injuries were divided into 5 groups: head, thoracic, abdominal, appendicular skeletal fracture, and neurological. RESULTS: Overall, 25 patients had isolated dislocations and 307 patients had 366 spinal fractures or fracture-dislocations: 36% cervical, 31% thoracic, and 51% lumbar. Most (84%) of the injuries occurred in the 13- to 19-year-old group. Sixty-two percent of patients had associated injuries, most commonly thoracic injuries (pulmonary contusion, pneumothorax, rib fracture); 45% had multilevel spinal fractures, 39% of which were noncontiguous. Nearly three fourths of the noncontiguous fractures occurred in a different spinal region; cervical fracture with concomitant thoracic fracture was the most frequent pattern. CONCLUSIONS: This large series of consecutive patients highlights several important concepts concerning pediatric spinal fractures, including age-related patterns of injury, frequent associated injuries, and a high rate of multiple spinal injuries, especially noncontiguous injuries. It also emphasizes the importance of careful full-body examination and imaging of the entire spine in children and adolescents with a known spinal injury. LEVEL OF EVIDENCE: Level IV-case series. PMID- 23653029 TI - Management of missed Monteggia fractures with ulnar osteotomy, open reduction, and dual-socket external fixation. AB - BACKGROUND: Open reduction of the radial head is usually necessary in the treatment of a missed Monteggia fracture. However, the best way to stabilize the reduction remains controversial. The purpose of this study is to present our experience using the dual-socket external fixator to stabilize the ulna osteotomy and capture the reduction of the radial head. METHODS: We reviewed 33 patients with missed Monteggia fracture who underwent open reduction, ulnar osteotomy, and dual-socket external fixation from 2004 to 2010. The average age of this group was 7 years and the average time to surgical treatment after the fracture was 15 months. We treated all patients with open reduction of the radial head, fully releasing the capsular contracture, removing the fibrous scar tissue within the joint, performing ulnar osteotomy, and fixing the osteotomy with dual-socket external fixation. The clinical and radiographic follow-up averaged 38 months. Descriptive statistics utilized the Student test to compare the preoperative and postoperative functional movement of elbow and forearm. RESULTS: All patients had excellent clinical and radiographic outcomes without losing motion of the elbow and forearm, and all patients maintained reduction of the radial head at the final follow-up. There were no significant differences in the motion of the elbow and forearm between preoperative and postoperative examinations. Delayed union of the ulna occurred in 2 cases, both successfully treated with autologous iliac crest bone graft at 7 months after the operation. Three cases had early redislocation of the radial head, and these were treated successfully by changing the position of the ulnar osteotomy and readjusting the external fixators. CONCLUSIONS: Dual-socket external fixation has the major advantage of permitting and capturing the optimal position of the ulna osteotomy to achieve the best possible reduction of the radial head. A further advantage is the possibility of easily changing the position of the ulnar osteotomy by adjustment of the fixator should the radial head subluxate or redislocate in the early postoperative period as had occurred in 3 of our cases. We conclude that our procedure of fully releasing the capsular contractures, removing scar tissue, ulnar osteotomy, reduction of the radial head, and fixation of the osteotomy with dual-socket external fixation is a safe and effective way to manage children with a missed Monteggia fracture. LEVEL OF EVIDENCE: Therapeutic level IV. PMID- 23653030 TI - Flexible intramedullary nailing in children: nail to medullary canal diameters optimal ratio. AB - BACKGROUND: Postoperative axial deviations and delayed unions are possible complications after flexible intramedullary nailing (FIN). The goals of this study were to determine if a correlation exists between occurrence of the above complications and the ratio of the diameter between nail and medullary canal [nail diameter (ND)/MCD ratio], to study the interobserver variability in the measurement of MCD, and to define a threshold to be respected to optimize the results. METHODS: Eighty-one consecutive diaphyseal fractures treated by means of FIN were evaluated. The ND/MCD ratios were determined by 2 independent observers. Axial deviations were defined as 5-degree angulation or more observed before bone union. Absence of bone union at 3 months was considered as delayed union. Statistical analysis was made for interobserver variability of MCD, dependency between occurrence of complications and ND/MCD ratio and eventual confounding variables (age, weight, sex, and fracture location). RESULTS: Of the 81 fractures, 14 presented with an axial deviation and 3 with a delayed union. Interobserver variability of MCD diameter was excellent (intraclass correlation: 0.96). Occurrence of the above complications was significantly associated with a low ND/MCD ratio (P=0.0002) but with none of the examined confounding variables. Receiver operating characteristic analysis showed absence of complications with a ND/MCD ratio >35% with a sensitivity of 100% and specificity of 89%. Related with the MCD measurements variability, a safe threshold of 40% can be suggested. CONCLUSIONS: In FIN, ND>40% to the MCD should be chosen to avoid complications, besides respecting the technical principles. Measuring the medullary canal diameter in order to choose correct nail size is reproducible between different observers. In adolescents with a medullary canal diameter of >10 mm in femur or tibia fractures, alternative methods of osteosynthesis than FIN should be considered. SIGNIFICANCE: This work statistically confirms that a ND/MCD ratio of >40% must be respected to avoid some complications in FIN. LEVEL OF EVIDENCE: Level III. PMID- 23653031 TI - The use of biodegradable sutures for the fixation of tibial eminence fractures in children: a comparison using PDS II, Vicryl and FiberWire. AB - BACKGROUND: Arthroscopic suture fixation of tibial eminence fractures using FiberWire is a favorable therapeutic option. The application of biodegradable material may be of advantage especially during childhood. The aim of this study was to evaluate the biomechanical properties using the biodegradable suture materials PDS II and Vicryl compared with FiberWire. METHODS: Bone mineral density was evaluated by pqCT in 18 human knee specimens and 3 similar groups were formed. A standardized anterior tibial eminence fracture was created and suture fixation was performed using each suture material (PDS II, Vicryl, FiberWire) in 6 specimens. Cyclic testing and destructive loading to failure was conducted. RESULTS: Both testing modalities showed PDS II to be inferior to the other evaluated suture materials. Although significantly higher failure loads were seen with FiberWire sutures, Vicryl yielded comparable stiffness in load-to failure testing. No significant differences between Vicryl and FiberWire could be observed under nondestructive cyclic conditions. CONCLUSIONS: Even though FiberWire yields a superior ultimate failure load, Vicryl presented comparable results under cyclic conditions. CLINICAL RELEVANCE: For tibial eminence fractures in children, Vicryl should be considered as an alternative biodegradable suture material. The use of PDS II cannot be advocated. PMID- 23653033 TI - Transverse plane gait problems in children with cerebral palsy. AB - Transverse plane deviations are significant contributors to pathologic gait in children with cerebral palsy (CP). Due to limitations in neuromuscular control, balance, strength and coordination, transverse plane gait deviations are poorly tolerated in these children. Transverse plane malalignment results in lever arm dysfunction and can be seen with either intoeing or out-toeing. Frequent causes of transverse plane problems and lever arm dysfunction include long bone (femoral and/or tibial) torsion, pelvic rotation, and pes varus or valgus. Computerized motion analysis facilitates accurate identification of transverse plane abnormalities. This article addresses appropriate identification and treatment of transverse plane gait deviations in children with CP. PMID- 23653032 TI - Ketorolac administration does not delay early fracture healing in a juvenile rat model: a pilot study. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective at controlling pain in children, especially in the treatment of fractures. Adult animal and adult clinical studies demonstrate conflicting evidence for the inhibitory relationship between NSAIDs and fracture healing. Published pediatric orthopaedic clinical studies do not demonstrate an inhibitory effect of ketorolac on bone healing. Little is known about the effects of any NSAID on bone formation in juvenile animals. This study investigates the effects of the NSAID ketorolac on fracture healing in a juvenile rat model. METHODS: Unilateral surgically induced and stabilized tibial shaft fractures were created in 45 juvenile (3 to 4 wk old) male Sprague-Dawley rats. Either ketorolac (5 mg/kg; n=24) or saline (0.9% normal saline; n=21) was then administered to the rats 6 d/wk by intraperitoneal injections. Animals were then randomly assigned into time groups and euthanized at 7 days (n=8 ketorolac, n=7 saline), 14 days (n=8 ketorolac, n=7 saline), or 21 days (n=8 ketorolac, n=7 saline) postfracture. Biomechanical analysis was performed using a custom-designed 4-point bending loading apparatus. Statistics for tibial stiffness and strength data were performed using software package Systat 11. Specimens were also evaluated histologically using hematoxylin and eosin staining. RESULTS: Strength and stiffness of all fractured tibiae increased over time from day 7 to day 21 regardless of treatment type. No statistical difference was found between the fractured tibiae strength or stiffness in the ketorolac or control-treated specimens at the same time point. In addition, the quality of the fracture callus was similar in both groups at each of the time points. CONCLUSIONS: In this study of a juvenile rat model with a stabilized tibia fracture, fracture callus strength, stiffness, and histologic characteristics were not affected by the administration of ketorolac during the first 21 days of fracture healing. CLINICAL RELEVANCE: The absence of inhibitory effects of ketorolac on early juvenile rat fracture healing supports the clinical practice of utilizing NSAIDs for analgesia in children with long bone fractures. PMID- 23653034 TI - Subtalar fusion for pes valgus in cerebral palsy: results of a modified technique in the setting of single event multilevel surgery. AB - BACKGROUND: We studied the use of cortico-cancellous circular allograft combined with cannulated screw fixation for the correction of dorsolateral peritalar subluxation in a series of children with bilateral spastic cerebral palsy undergoing single event multilevel surgery. METHODS: Forty-six children who underwent bilateral subtalar fusion between January 1999 and December 2004 were retrospectively reviewed. Gait laboratory records, Gross Motor Function Classification System (GMFCS) levels, Functional Mobility Scale (FMS) scores, and radiographs were reviewed. The surgical technique used an Ollier type incision with a precut cortico-cancellous allograft press-fit into the prepared sinus tarsi. One or two 7.3 mm fully threaded cancellous screws were used to fix the subtalar joint. Radiographic analysis included preoperative and postoperative standing lateral radiographs measuring the lateral talocalcaneal angle, lateral talo-first metatarsal angle, and navicular cuboid overlap. Fusion rate was assessed with radiographs >12 months after surgery. RESULTS: The mean patient age was 12.9 years (range, 7.8 to 18.4 y) with an average follow-up of 55 months. Statistically significant improvement postoperatively was found for all 3 radiographic indices: lateral talocalcaneal angle, mean improvement 20 degrees (95% CI, 17.5-22.1; P<0.001); lateral talo-first metatarsal angle, mean improvement 21 degrees (95% CI, 19.2-23.4; P<0.001); and navicular cuboid overlap, mean improvement 29% (95% CI, 25.7%-32.6%; P<0.001). FMS improved across all patients, with Gross Motor Function Classification System III children experiencing a 70% improvement across all 3 FMS distances (5, 50, and 500 m). All 3 radiographic measures improved significantly (P<0.001). Fusion was achieved in 45 patients and there were no wound complications. CONCLUSIONS: With this study, we demonstrate significant improvement in radiographic segmental alignment and overall function outcome with this modified subtalar fusion technique. We conclude that this technique is an effective complement for children with dorsolateral peritalar subluxation undergoing single event multilevel surgery. LEVEL OF EVIDENCE: Level IV. PMID- 23653035 TI - Estimation of the recovery of physiological genu varum with linear mixed model. AB - BACKGROUND: Although previous studies have provided reference values for the lower limb alignment in children with physiological genu varum, those often have methodologic flaws, including problems with assumptions of statistical independence. In this study we intend to use appropriate statistical methods to determine reference values of the recovery of physiological genu varum by using a linear mixed model (LMM). METHODS: The database of our institution was searched and teleroentgenograms of patients up to 5 years of age with clinical diagnosis of physiological genu varum were selected. The mechanical tibiofemoral angle (mTFA), mechanical lateral distal femoral angle (mLDFA), and mechanical medial proximal tibial angle (mMPTA) were measured from each radiograph. These measures were then incorporated in LMM. The reference values for mTFA, mLDFA, and mMPTA were calculated by LMMs with age, sex, and side of the limbs, as the fixed effects with each subject as random effects. RESULTS: A total of 425 teleroentgenograms were evaluated from 161 patients with physiological genu varum. Age, sex, and limb side terms were found to be significant contributing factors to the measures. In the LMM, with the age as quadratic, mTFA was equal to -0.3-degree varus [95% confidence interval (CI), -5.9 to 5.3 degrees] at the age of 3 years. The mLDFA was equal to 87.8 degrees (95% CI, 82.8-92.8 degrees) at the age of 4.5 years. The mMPTA was equal to 88.8 degrees (95% CI, 80.4-97.2 degrees) at the age of 2.5 years. CONCLUSIONS: An LMM fitted well to estimate the natural recovery of physiological genu varum. Age, sex, and side of the limbs were found to be significant factors in the estimation of mTFA, and age and side of limbs were significant in estimation of mLDFA and mMPTA. LEVEL OF EVIDENCE: Level III-diagnostic study. PMID- 23653036 TI - Treatment of femoral lengthening-related knee stiffness with a novel quadricepsplasty. AB - BACKGROUND: Knee stiffness is common after femoral lengthening. Certain patients require a quadricepsplasty when therapy does not improve flexion. A small subset of such patients may also have obligate patellar dislocation with knee flexion due to contracture of the extensor mechanism. We describe our surgical approach for both clinical situations and our outcomes in a pediatric population. METHODS: Six patients, 2 with obligate patellar dislocation, were reviewed (9% of our femoral lengthening population). Indications for surgery included persistent symptomatic restriction of flexion after at least 3 months of therapy or obligate lateral patellar dislocation with knee flexion. Knee range of motion and clinical strength were assessed. Four patients were available for gait analysis and concentric quadriceps strength testing by isokinetic dynamometer. Patient satisfaction was surveyed by questionnaire. RESULTS: All patients had full flexion before lengthening. The mean length gained (by circular external fixation and/or intramedullary motorized nail) was 10.7 cm. The mean age at the time of quadricepsplasty was 16 years. The average active flexion preoperatively was only 48 degrees. Two patients with obligate patellar dislocation and relatively good knee flexion inflated the average preoperative knee flexion. Although both had knee flexion to 100 degrees, the patella dislocated with flexion beyond 30 degrees. At follow-up (mean, 6.2 y) active flexion averaged 120 degrees (P<0.004). All patients had 5/5 clinical strength and no significant quadriceps lag. No patients had patellar instability postoperatively. Isokinetic dynamometer revealed an average weakness of 63% compared with the nonoperative quadriceps. Gait analysis indicated patients had near-normal gait patterns. All patients were satisfied and would pursue the same treatment. CONCLUSIONS: Our quadricepsplasty can significantly increase knee flexion and treat obligate patellar dislocation in the setting of extension contracture after femoral lengthening when nonoperative measures fail. LEVEL OF EVIDENCE: Level IV. PMID- 23653037 TI - Adolescent runners: the effect of training shoes on running kinematics. AB - BACKGROUND: The modern running shoe typically features a large cushioned heel intended to dissipate the energy at heel strike to the knees and hips. The purpose of this study was to evaluate the effect that shoes have upon the running biomechanics among competitive adolescent runners. We wish to answer the question of whether running style is altered in these athletes because of footwear. METHODS: Twelve competitive adolescent athletes were recruited from local track teams. Each ran on a treadmill in large heel trainers, track flats, and barefoot. Four different speeds were used to test each athlete. The biomechanics were assessed with a motion capture system. Stride length, heel height during posterior swing phase, and foot/ground contact were recorded. RESULTS: Shoe type markedly altered the running biomechanics. The foot/ground contact point showed differences in terms of footwear (P<0.0001) and speed (P=0.000215). When wearing trainers, the athletes landed on their heels 69.79% of the time at all speeds (P<0.001). The heel was the first point of contact <35% of the time in the flat condition and <30% in the barefoot condition. CONCLUSIONS: Running biomechanics are significantly altered by shoe type in competitive adolescents. Heavily heeled cushioned trainers promote a heel strike pattern, whereas track flats and barefoot promote a forefoot or midfoot strike pattern. Training in heavily cushioned trainers by the competitive runner has not been clearly shown to be detrimental to performance, but it does change the gait pattern. It is not known whether the altered biomechanics of the heavily heeled cushioned trainer may be detrimental to the adolescent runner who is still developing a running style. PMID- 23653038 TI - Bovine xenograft failures in pediatric foot reconstructive surgery. AB - BACKGROUND: Structural bone grafting serves an important and necessary role during pediatric foot reconstruction. Different bone grafts have been used for such reconstructions including corticocancellous autografts, allografts, and synthetic grafts. Bovine xenografts represent a novel option with multiple potential advantages; however, there are limited clinical data on the efficacy and success of such grafts. This retrospective case series was performed to review the anecdotally recognized high failure rate of bovine xenograft transplantation in pediatric foot reconstruction at a tertiary institution. MATERIALS AND METHODS: Ten pediatric patients with 13 feet underwent reconstructive procedures involving implantation of bovine xenografts for various foot deformities. The mean age at time of surgery was 14.1 years with an average clinical follow-up of 21.6 months. All patients received lateral column lengthening with additional various other reconstructive procedures performed by 3 separate orthopaedic surgeons in a similar step-wise manner. Clinical outcomes were obtained through a retrospective chart review of standard preoperative and postoperative clinical and radiographic data. RESULTS: Seven of 13 (53.8%) bovine xenografts implanted resulted in clinical symptoms of failure with corresponding radiographic failed graft incorporation. The most common presenting symptom was foot pain with activity and each failure was easily identified on plain radiographs by lucency surrounding the graft sites. All 7 failures required a subsequent revision surgery to remove the bovine graft followed by placement of human iliac crest allograft. After revision surgery, each patient reported subjective improvement in pain and return to daily activity with radiographic evidence of complete incorporation of the graft. CONCLUSIONS: Bovine xenografts used as structural grafts in pediatric foot reconstruction resulted in unacceptably high rates of failure and the need for further revision surgery. For this reason, surgeons should be cautioned against the use of bovine xenograft material in the surgical management of pediatric foot deformity. LEVEL OF EVIDENCE: Level IV case series. PMID- 23653039 TI - Concurrent septic arthritis and osteomyelitis in children. AB - INTRODUCTION: Septic arthritis and osteomyelitis can both independently cause substantial morbidity. With concomitant septic arthritis and osteomyelitis, the septic arthritis may be treated without knowledge of the adjacent osteomyelitis resulting in delayed treatment. This study aims to identify factors that may help to diagnosis concurrent infections (CI) earlier. METHODS: A retrospective chart review of 200 patients with septic arthritis was performed. Patients with CI were compared with patients with septic arthritis alone using tests determined by the nature of the variable being analyzed (the chi test, the Fisher exact test, the Cochran-Armitage trend test, and the Kruskal-Wallis test.). RESULTS: Two hundred patients were eligible and analyzed, of which 43 (21.5%) had CI. On the basis of age, CI were most common in newborns and adolescents (P<0.0001). On the basis of location, 72% of shoulder infections (P<0.0001) were concurrent, whereas <50% of elbows, hips, knees, and ankle were CI. The most common infective organism was methicillin-sensitive Staphylococcus aureus (P<0.0001). CI were significantly associated with increased median (6) days of clinical symptoms before presentation (P<0.0001), increased duration of median (6) days of hospital stay (P<0.0001), increased number of operative procedures (P=0.005), and increased need for ICU admission (P=0.024). CONCLUSIONS: Utilizing advanced imaging (CT scan, bone scan, and/or MRI) in patients with septic arthritis who are younger than 4 months of age, between ages 13 and 20 years, with septic arthritis involving the shoulder, and with symptoms for more than 6 days may shorten hospital stays, decrease the number of operative procedures required, and possibly limit infection-related sequelae by identifying CI earlier. LEVEL OF EVIDENCE: III. PMID- 23653040 TI - The Bangladesh clubfoot project: the first 5000 feet. AB - BACKGROUND: Bangladesh is one of the most populous countries in the world at 160 million with 1/3 existing below the poverty line. With an annual birth rate of approximately 3.2 million, an estimated incidence of 1:900 live births, the country has approximately 5000 new cases of idiopathic congenital talipes equinovarus per annum. The Bangladesh sustainable clubfoot program, Walk for Life (WFL), was conceived to respond to this unmet need. METHODS: WFL started in 2009 and has rapidly grown to 35 clinics. Overseas experts initially increased local capacity by training a team of national paramedical staff. Government support enabled integration with the public hospital system and enhanced sustainability. WFL has supplied materials, educational, administrative, and clinical support throughout. All recruited cases underwent Ponseti casting. Demographic, Pirani scores, cast, tenotomy, and bracing data have been prospectively collected from all patients. Detailed review has been undertaken for 1040 patients after 12 months of treatment in 3 divisions of Bangladesh. RESULTS: Between 2009 and 2011, 6069 feet (3922 patients) were recruited to the project. Of these 1643 feet (1040 patients) have completed a minimum of 1-year follow-up. The male:female ratio was 2.7:1 with a mean age of 22 months at presentation (range, 0 to 36). Typical idiopathic congenital talipes equinovarus responded in a median of 5 casts (range, 1 to 25) with 76% undergoing tenotomy. Thirteen percent were atypical feet requiring a median of 5 casts. The percentage of patients missing at the 12 month point was 12%. Two percent of patients experienced complications. CONCLUSIONS: The Bangladesh clubfoot program demonstrates that rapid case ascertainment is possible in a developing world setting with appropriate logistical support. The use of local physiotherapists and paramedics yielded good clinical outcomes in an environment with full access to clinical review and ongoing training. A higher than expected number of atypical cases have been noted, requiring modified Ponseti treatment. Complications have been few at this early stage. LEVEL OF EVIDENCE: Level 2-therapeutic study. PMID- 23653041 TI - Neuroblastoma: a rare cause of a limping child. How to avoid a delayed diagnosis? AB - Neuroblastoma is the most common solid extracranial tumor of childhood. Even though >25% of presentations are orthopaedic in nature, ranging from a limp to lower limb paralysis, neuroblastoma is a rare cause of limping in childhood and can therefore be easily missed by the admitting orthopaedic surgeon. Four cases of metastatic neuroblastoma are reported who all presented with hip pain within the last 3 years at Royal Manchester Children's Hospital. They all posed a diagnostic dilemma and an alternative diagnosis was initially made. A simple screening examination of the abdomen after ultrasonographic hip examination for sepsis would have led to an earlier diagnosis in all 4 cases. We suggest that including the abdomen in children undergoing a hip sonographic examination in those who are slightly atypical in nature or have indications of malignancy may lead to an early diagnosis of this rare cause of hip pain. LEVEL OF EVIDENCE: IV. PMID- 23653042 TI - Solitary osseous capillary-type vascular malformation of the distal humerus in a child. AB - Vascular malformations are abnormal proliferations of the endothelial lining of the blood vessels that are most commonly found in skin and can penetrate the local soft tissue and muscle. Only 1% of all vascular malformations are found in the bone. Skeletal vascular malformations of the long bones, including the humerus, are extremely rare entities that are particularly uncommon in children. Only 4 reports involving the humerus have been described in children previously. We present the case of an intraosseous capillary vascular malformation of the right distal humerus in a 3-year-old boy. Definitive treatment was successful with a single operation using curettage and intramedullary decompression with grafting of an osteoconductive calcium sulfate pellet filler and autogenous bone graft. This is, to our knowledge, the youngest reported case of a solitary intraosseous capillary vascular malformation involving the distal humerus. PMID- 23653043 TI - Meta-analysis to determine if surgical resection of the primary tumour in the setting of stage IV breast cancer impacts on survival. AB - INTRODUCTION: The role of primary tumor excision in patients with stage IV breast cancer is unclear. Therefore, a meta-analysis of relevant studies was performed to determine whether surgical excision of the primary tumor enhances oncological outcome in the setting of stage IV breast cancer. METHODS: A comprehensive search for relevant published trials that evaluated outcomes following excision of the primary tumor in stage IV breast cancer was performed using MEDLINE and available data were cross-referenced. Data were extracted following review of appropriate studies by authors. The primary outcome was overall survival following surgical removal of the primary tumor. RESULTS: Data from ten studies included 28,693 patients with stage IV disease of whom 52.8% underwent excision of the primary carcinoma. Surgical excision of the primary tumor in the setting of stage IV breast cancer was associated with a superior survival at 3 years (40% (surgery) versus 22% (no surgery) (odds ratio 2.32, 95% confidence interval 2.08-2.6, p<0.01). Subgroup analyses for selection of patients for surgery or not, favored smaller primary tumors, less competing medical comorbidities and lower metastatic burden (p<0.01). There was no statistical difference between the two groups regarding location of metastatic disease, grade of tumor, or receptor status. CONCLUSIONS: Patients with stage IV disease undergoing surgical excision of the primary tumor achieve a superior survival rate then their nonsurgical counterparts. In the absence of robust evidence, this meta-analysis provides evidence base for primary resection in the setting of stage IV breast cancer for appropriately selected patients. PMID- 23653044 TI - Impact of anti-drug antibodies in preclinical pharmacokinetic assessment. AB - The administration of human biotherapeutics is often associated with a higher incidence of immunogenicity in preclinical species. The presence of anti-drug antibodies (ADAs) in the test samples can affect the accurate measurement of therapeutic protein (TP) in bioanalytical methods designed to support pharmacokinetic (PK) and toxicokinetic (TK) assessments. The impact can vary depending on the bioanalytical method platform and study dosing design. The goal of this study is to evaluate the impact of ADA response on the bioanalytical methods in support of PK/TK and the associated study data interpretation. Sprague Dawley rats were administered with four weekly doses of 50 mg/kg TP, a humanized monoclonal antibody. The TP in serum samples was measured using three bioanalytical methods that quantified bound and/or unbound TP to ADA. The ADA response in the animals was classified into negative, low, medium, and high based on the magnitude of the response. The presence of ADA in samples led to discrepant TP measurements between the methods, especially at time points where the TP concentrations were low. This could be due to ADA interference to the accurate measurement of ADA-bound TP concentrations. The TP concentration at last time point (C last) was reduced by 82.8%, 98.6%, and 99.8%, respectively, for samples containing low, medium, and high levels of ADA. The interfering effects of the ADA on bioanalytical methods and exposure were evident as early as 2 weeks post-dosing. This modeling approach can provide the better understanding of ADA impact on PK exposure in multiple doses. PMID- 23653045 TI - Comparison of a new cobinamide-based method to a standard laboratory method for measuring cyanide in human blood. AB - Most hospital laboratories do not measure blood cyanide concentrations, and samples must be sent to reference laboratories. A simple method is needed for measuring cyanide in hospitals. The authors previously developed a method to quantify cyanide based on the high binding affinity of the vitamin B12 analog, cobinamide, for cyanide and a major spectral change observed for cyanide-bound cobinamide. This method is now validated in human blood, and the findings include a mean inter-assay accuracy of 99.1%, precision of 8.75% and a lower limit of quantification of 3.27 uM cyanide. The method was applied to blood samples from children treated with sodium nitroprusside and it yielded measurable results in 88 of 172 samples (51%), whereas the reference laboratory yielded results in only 19 samples (11%). In all 19 samples, the cobinamide-based method also yielded measurable results. The two methods showed reasonable agreement when analyzed by linear regression, but not when analyzed by a standard error of the estimate or paired t-test. Differences in results between the two methods may be because samples were assayed at different times on different sample types. The cobinamide based method is applicable to human blood, and can be used in hospital laboratories and emergency rooms. PMID- 23653046 TI - Detection of methicillin-susceptible Staphylococcus aureus ST398 and ST133 strains in gut microbiota of healthy humans in Spain. AB - Fecal samples of 100 healthy humans were tested for Staphylococcus aureus recovery. Fifteen samples (15 %) contained S. aureus, all methicillin-susceptible (MSSA), being one isolate/sample further studied. These 15 isolates were characterized by spa and agr typing as well as multi-locus sequence typing. High diversity of spa types (n = 11) and sequences types (n = 8) was detected. Two S. aureus of lineages ST398 or ST133 were detected, and six isolates were ascribed to clonal complex 30 (CC30). Strains were susceptible to most of the 17 antimicrobial agents tested with exceptions: erythromycin/clindamycin (three strains, containing erm(C) and/or erm(A) + mph(C) genes) and tobramycin and mupirocin (one strain containing ant(4')-Ia + mup(A) genes). The presence of 18 staphylococcal enterotoxin genes was studied by PCR, and isolates were negative for lukF/lukS-PV genes, although strain ST133 harbored the lukD-lukE + lukM genes. Other virulence genes detected were (number of strains): tsst-1 (6), hla (15), hlb (9), hld (15), hlg (6), hlgv (9), cna (2), aur (14), and egc-like cluster (3). Analysis of immune evasion cluster genes showed six types, highlighting their absence in two strains of lineages ST133 and ST5. A high clonal diversity of MSSA strains was identified in the intestinal microbiota of healthy humans, being CC30 the most frequent one. This is the first report of MSSA ST133 and ST398 isolates in gut microbiota of healthy humans. PMID- 23653048 TI - Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan. AB - Poly(ADP-ribose) polymerase inhibitors (PARPi) are currently evaluated in clinical trials in combination with topoisomerase I (Top1) inhibitors against a variety of cancers, including colon carcinoma. Since the mismatch repair component MLH1 is defective in 10-15% of colorectal cancers we have investigated whether MLH1 affects response to the Top1 inhibitor irinotecan, alone or in combination with PARPi. To this end, the colon cancer cell lines HCT116, carrying MLH1 mutations on chromosome 3 and HCT116 in which the wild-type MLH1 gene was replaced via chromosomal transfer (HCT116+3) or by transfection of the corresponding MLH1 cDNA (HCT116 1-2) were used. HCT116 cells or HCT116+3 cells stably silenced for PARP-1 expression were also analysed. The results of in vitro and in vivo experiments indicated that MLH1, together with low levels of Top1, contributed to colon cancer resistance to irinotecan. In the MLH1-proficient cells SN-38, the active metabolite of irinotecan, induced lower levels of DNA damage than in MLH1-deficient cells, as shown by the weaker induction of gamma H2AX and p53 phosphorylation. The presence of MLH1 contributed to induce of prompt Chk1 phosphorylation, restoring G2/M cell cycle checkpoint and repair of DNA damage. On the contrary, in the absence of MLH1, HCT116 cells showed minor Chk1 phosphorylation and underwent apoptosis. Remarkably, inhibition of PARP function by PARPi or by PARP-1 gene silencing always increased the antitumor activity of irinotecan, even in the presence of low PARP-1 expression. PMID- 23653050 TI - Standardized sample preparation using a drop-on-demand printing platform. AB - Hazard detection systems must be evaluated with appropriate test material concentrations under controlled conditions in order to accurately identify and quantify unknown residues commonly utilized in theater. The existing assortment of hazard reference sample preparation methods/techniques presents a range of variability and reproducibility concerns, making it increasingly difficult to accurately assess optically- based detection technologies. To overcome these challenges, we examined the optimization, characterization, and calibration of microdroplets from a drop-on-demand microdispenser that has a proven capability for the preparation of energetic reference materials. Research presented herein focuses on the development of a simplistic instrument calibration technique and sample preparation protocol for explosive materials testing based on drop-on demand technology. Droplet mass and reproducibility were measured using ultraviolet-visible (UV-Vis) absorption spectroscopy. The results presented here demonstrate the operational factors that influence droplet dispensing for specific materials (e.g., energetic and interferents). Understanding these parameters permits the determination of droplet and sample uniformity and reproducibility (typical R2 values of 0.991, relative standard deviation or RSD <= 5%), and thus the demonstrated maturation of a successful and robust methodology for energetic sample preparation. PMID- 23653047 TI - A semiphysiological population pharmacokinetic model for dynamic inhibition of liver and gut wall cytochrome P450 3A by voriconazole. AB - BACKGROUND: Accurate predictions of cytochrome P450 (CYP) 3A-mediated drug-drug interactions (DDIs) account for dynamic changes of CYP3A activity at both major expression sites (liver and gut wall) by considering the full pharmacokinetic profile of the perpetrator and the substrate. Physiological-based in vitro-in vivo extrapolation models have become of increasing interest. However, due to discrepancies between the predicted and observed magnitude of DDIs, the role of models fully based on in vivo data is still essential. OBJECTIVE: The primary objective of this study was to develop a coupled dynamic model for the interaction of the CYP3A inhibitor voriconazole and the prototypical CYP3A substrate midazolam. METHODS: Raw concentration data were obtained from a DDI study. Ten subjects were given either no pretreatment (control) or voriconazole twice daily orally. Midazolam was given either intravenously or orally after the last voriconazole dose and during control phases. Data analysis was performed by the population pharmacokinetic approach using non-linear mixed effects modelling (NONMEM 7.2.0). Model evaluation was performed using visual predictive checks and bootstrap analysis. RESULTS: A semiphysiological model was able to describe the pharmacokinetics of midazolam, its major metabolite and voriconazole simultaneously. By considering the temporal disposition of all three substances in the liver and gut wall, a time-varying CYP3A inhibition process was implemented. Only the incorporation of hypothetical enzyme site compartments resulted in an adequate fit, suggesting a sustained inhibitory effect through accumulation. Novel key features of this analysis are the identification of (1) an apparent sustained inhibitory effect by voriconazole due to a proposed quasi accumulation at the enzyme site, (2) a significantly reduced inhibitory potency of intravenous voriconazole for oral substrates, (3) voriconazole as a likely uridine diphosphate glucuronosyltransferase (UGT) 2B inhibitor and (4) considerable sources of interindividual variability. CONCLUSION: The proposed semiphysiological modelling approach generated a mechanistic description of the complex DDI occurring at major CYP3A expression sites and thus may serve as a powerful tool to maximise information acquired from clinical DDI studies. The model has been shown to draw precise and accurate predictions. Therefore, simulations based on this kind of models may be used for various clinical scenarios to improve pharmacotherapy. PMID- 23653049 TI - Differences in metabolic and mitogenic signallingof insulin glargine and AspB10 human insulin in rats [corrected]. AB - AIMS/HYPOTHESIS: In vitro, insulin glargine (A21Gly,B31Arg,B32Arg human insulin) has an insulin receptor (IR) profile similar to that of human insulin, but a slightly higher affinity for the IGF-1 receptor (IGF1R). AspB10 human insulin (AspB10), [corrected] the only insulin analogue with proven carcinogenic activity, has a greater affinity for IGF1R and IR, and a prolonged IR occupancy time. The pharmacological and signalling profile of therapeutic and suprapharmacological doses of glargine were analysed in different tissues of rats, and compared with human insulin and AspB10. METHODS: Male Wistar rats were injected s.c. with human insulin or insulin analogue at doses of 1 to 200 U/kg, and the effects on blood glucose and the phosphorylation status of IR, IGF1R, Akt and extracellular signal-regulated protein kinase 1/2 in muscle, fat, liver and heart samples were investigated. RESULTS: Glargine, AspB10 and human insulin lowered blood glucose, with the onset of action delayed with glargine. Glargine treatment resulted in phosphorylation levels of IR and Akt that were comparable with those achieved with human insulin, although delayed in time in some tissues. AspB10 treatment resulted in at least twofold higher phosphorylation levels and significantly longer duration of IR and Akt phosphorylation in most tissues. None of the insulin treatments resulted in detectable IGF1R phosphorylation in muscle or heart tissue, whereas intravenous injection of IGF-1 increased IGF1R phosphorylation. CONCLUSIONS/INTERPRETATION: The IR signalling pattern of AspB10 in vivo is distinctly different from that of human insulin and insulin glargine, and might challenge the notion that activation of IGF1R plays a role in the observed carcinogenic effect of AspB10. PMID- 23653051 TI - Development of a micro-gripper using piezoelectric bimorphs. AB - Piezoelectric bimorphs have been used as a micro-gripper in many applications, but the system might be complex and the response performance might not have been fully characterized. In this study the dynamic characteristics of bending piezoelectric bimorphs actuators were theoretically and experimentally investigated for micro-gripping applications in terms of deflection along the length, transient response, and frequency response with varying driving voltages and driving signals. In addition, the implementation of a parallel micro-gripper using bending piezoelectric bimorphs was presented. Both fingers were actuated separately to perform mini object handling. The bending piezoelectric bimorphs were fixed as cantilevers and individually driven using a high voltage amplifier and the bimorph deflection was measured using a non contact proximity sensor attached at the tip of one finger. The micro-gripper could perform precise micro manipulation tasks and could handle objects down to 50 um in size. This eliminates the need for external actuator extension of the microgripper as the grasping action was achieved directly with the piezoelectric bimorph, thus minimizing the weight and the complexity of the micro-gripper. PMID- 23653052 TI - A ferrocene-porphyrin ligand for multi-transduction chemical sensor development. AB - 5,10,15,20-Tetraferrocenyl porphyrin, H2TFcP, a simple example of a donor acceptor system, was tested as ligand for the development of a novel multi transduction chemical sensors aimed at the determination of transition metal ions. The fluorescence energy transfer between ferrocene donor and porphyrin acceptor sub-units was considered. The simultaneously measured optical and potentiometric responses of solvent polymeric membranes based on H2TFcP permitted the detection of lead ions in sample solutions, in the concentration range from 2.7 * 10(-7) to 3.0 * 10(-3) M. The detection limit of lead determination was 0.27 MUM, low enough to perform the direct analysis of Pb2+ in natural waters. PMID- 23653053 TI - Position measurement/tracking comparison of the instrumentation in a droplet actuated-robotic platform. AB - This paper reports our work on developing a surface tension actuated micro robotic platform supported by three bubbles (liquid environment) or droplets (gaseous environment). The actuation principle relies on the force developed by surface tension below a millimeter, which benefits from scaling laws, and is used to actuate this new type of compliant robot. By separately controlling the pressure inside each bubble, three degrees of freedom can be actuated. We investigated three sensing solutions to measure the platform attitude in real time (z-position of each droplet, leading to the knowledge of the z position and Thetax and Thetay tilts of the platform). The comparison between optical, resistive, and capacitive measurement principles is hereafter reported. The optical technique uses SFH-9201 components. The resistive technique involves measuring the electrical resistance of a path flowing through two droplets and the platform. This innovative technique for sensing table position combines three pairs of resistances, from which the resistance in each drop can be deduced, thus determining the platform position. The third solution is a more usual high frequency (~200 MHz) capacitive measurement. The resistive method has been proven reliable and is simple to implement. This work opens perspectives toward an interesting sensing solution for micro-robotic platforms. PMID- 23653054 TI - Remote interrogation of WDM fiber-optic intensity sensors deploying delay lines in the virtual domain. AB - In this work a radio-frequency self-referencing WDM intensity-based fiber-optic sensor operating in reflective configuration and using virtual instrumentation is presented. The use of virtual delay lines at the reception stage, along with novel flexible self-referencing techniques, and using a single frequency, avoids all-optical or electrical-based delay lines approaches. This solution preserves the self-referencing and performance characteristics of the proposed WDM-based optical sensing topology, and leads to a more compact solution with higher flexibility for the multiple interrogation of remote sensing points in a sensor network. Results are presented for a displacement sensor demonstrating the concept feasibility. PMID- 23653055 TI - Update on tissue engineering in pediatric urology. AB - Pediatric urology patients often present with congenital or acquired tissue and organ dysfunction that requires surgical reconstruction to recreate the normal genitourinary systems functions. The traditional methods have varying degrees of donor site morbidity or inherent side effects. Tissue engineering is a developing field that aims to replace or regenerate these dysfunctional tissues and organs with cells, biomaterials, or a combination thereof. A tremendous amount of work has been done to these ends in terms of preclinical work, and some clinical trials have resulted. This review highlights the status of these studies in pediatric urology for the use of tissue engineering and reconstruction of the corporal bodies, urethra, and bladder. PMID- 23653057 TI - Fullerene C70 characterization by 13C NMR and the importance of the solvent and dynamics in spectral simulations. AB - The nuclear magnetic resonance (NMR) spectroscopy combined with theoretical calculations is an important tool for fullerene identification. However, the accuracy of available theoretical methods is often not adequate. Therefore, in this work, different computational aspects needed to simulate realistically chemical shifts in the C70 molecule are investigated by density functional theory (DFT) calculations. The importance of the functional choice, basis set, solvent, and molecular motions was assessed. The solvent was simulated using the implicit conductor-like polarized continuum model. The molecular motions were included via anharmonic corrections and averaging of snapshots obtained from classical and first-principles molecular dynamics (MD) simulations. Comparison to experiment revealed that density functional calculations typically overestimate the (13)C NMR chemical shifts. Hybrid functionals, such as BHandH and BHandHLYP, and long range corrected functionals, such as wB97xd and CAM-B3LYP, give the best results. While the solvent has a minor effect (chemical shift changes by ~1 ppm), the vibrational and dynamical effects are surprisingly large, causing changes up to 9 ppm. Consideration of the latter was also necessary to explain the observed temperature dependence. While the dynamical corrections for MD performed in vacuum were overestimated, inclusion of the solvent in simulations provided more realistic results. The study thus points out the importance of an appropriate solvent model and a complex approach to the modelling, balancing the static, dynamic and environmental factors. PMID- 23653058 TI - Buds of May. PMID- 23653056 TI - Clinical characteristics and effectiveness of lansoprazole in Japanese patients with gastroesophageal reflux disease and dyspepsia. AB - BACKGROUND: Patients with gastroesophageal reflux disease (GERD) frequently have symptoms of dyspepsia in addition to reflux symptoms. Treatment options for dyspepsia are not standardized. The aim of this study was to clarify the therapeutic effect of lansoprazole on dyspepsia in Japanese patients with GERD. METHODS: GERD patients with dyspepsia were enrolled and treated with lansoprazole 15 or 30 mg once daily for 4 weeks. Reflux and dyspeptic symptoms were assessed by questionnaires before treatment, and 2 and 4 weeks after the start of lansoprazole treatment. RESULTS: In the effectiveness analysis set (n = 12,653), heartburn was reported by 91.6 % of patients at study enrollment. Postprandial fullness was the most frequently reported dyspepsia symptom at the start of the study, reported by 79.0 % of enrolled patients. After 4 weeks of lansoprazole treatment, heartburn symptoms were improved in 75.7 % of patients and symptoms of postprandial fullness were improved in 68.7 % of patients. The therapeutic effect of low and high doses of lansoprazole on dyspepsia, as well as on reflux symptoms, was approximately 10 % higher in patients with endoscopy-confirmed erosive esophagitis (60.1-82.2 %), than in patients with non-erosive reflux diseases (53.0-73.3 %). Lansoprazole was well tolerated. CONCLUSION: In this large-scale clinical study, lansoprazole effectively relieved dyspepsia in addition to reflux symptoms in patients with GERD. PMID- 23653059 TI - 'Open for business': do open-access psychiatry journals provide value for money? PMID- 23653060 TI - Catatonia from Kahlbaum to DSM-5. PMID- 23653061 TI - Employment as a health intervention--the role of psychiatry in bridging the evidence to practice gap. PMID- 23653062 TI - A retrospective of publications addressing suicidal behaviour in the Australian and New Zealand Journal of Psychiatry, 1967-2012. AB - OBJECTIVE: To review publications addressing suicidal behaviour in the Australian and New Zealand Journal of Psychiatry, 1967-2012. METHOD: A PubMed/MEDLINE search using the words suicide, attempted suicide (and their synonyms) and Aust NZ J Psychiatr was carried out, and an examination of all tables of contents of the journal for the years 1967-2012 was performed. RESULTS: In 342 (7.4%) of 4599 articles there was reference to suicidal behaviour. This ratio was consistent over time, although the nature of their content changed from broader epidemiological and clinical review studies to more focused reports. CONCLUSIONS: Papers addressing suicidal behaviour have been published consistently in the Australian and New Zealand Journal of Psychiatry since its inception in 1967. Early clinical reviews remain pertinent to the present time. PMID- 23653063 TI - DSM-5 somatic symptom disorder mislabels medical illness as mental disorder. PMID- 23653064 TI - Strategies for improving employment outcomes for people with psychosis. Commentary on: Severe mental illness and work--what can we do to maximise employment opportunities for individuals with psychosis? PMID- 23653065 TI - Severe mental illness and work. PMID- 23653066 TI - Similar psychological distance reduces temporal discounting. AB - People often prefer inferior options in the present even when options in the future are more lucrative. Five studies investigated whether decision making could be improved by manipulating construal level and psychological distance. In Studies 1a, 1b, and 2, temporal discounting was reduced when future rewards (trips to Paris) were construed at a relatively concrete level, thus inducing a similar level of construal to present rewards. By contrast, Studies 3 and 4 reduced temporal discounting by making present financial rewards more psychologically distant via a social proximity manipulation, and thus linked to a similar high level of construal as future rewards. These results suggest that people prefer the more lucrative option when comparing two intertemporal choices that are construed on a similar level instead of on a different level. Thus, changes in construal level and mental representations can be used to promote more desirable choices in economic decision making. PMID- 23653067 TI - It had to be you (not me)!: Women's attributional rationalization of their contribution to successful joint work outcomes. AB - We investigated the tendency of women to undervalue their contributions in collaborative contexts. Participants, who believed they were working with another study participant on a male sex-typed task, received positive feedback about the team's performance. Results indicated that women and men allocated credit for the joint success very differently. Women gave more credit to their male teammates and took less credit themselves unless their role in bringing about the performance outcome was irrefutably clear (Studies 1 and 2) or they were given explicit information about their likely task competence (Study 4). However, women did not credit themselves less when their teammate was female (Study 3). Together these studies demonstrate that women devalue their contributions to collaborative work, and that they do so by engaging in attributional rationalization, a process sparked by women's negative performance expectations and facilitated by source ambiguity and a satisfactory "other" to whom to allocate credit. PMID- 23653068 TI - A review of the energetics of pollination biology. AB - Pollination biology is often associated with mutualistic interactions between plants and their animal pollen vectors, with energy rewards as the foundation for co-evolution. Energy is supplied as food (often nectar from flowers) or as heat (in sun-tracking or thermogenic plants). The requirements of pollinators for these resources depend on many factors, including the costs of living, locomotion, thermoregulation and behaviour, all of which are influenced by body size. These requirements are modified by the availability of energy offered by plants and environmental conditions. Endothermic insects, birds and bats are very effective, because they move faster and are more independent of environmental temperatures, than are ectothermic insects, but they are energetically costly for the plant. The body size of endothermic pollinators appears to be influenced by opposing requirements of the animals and plants. Large body size is advantageous for endotherms to retain heat. However, plants select for small body size of endotherms, as energy costs of larger size are not matched by increases in flight speed. If high energy costs of endothermy cannot be met, birds and mammals employ daily torpor, and large insects reduce the frequency of facultative endothermy. Energy uptake can be limited by the time required to absorb the energy or eliminate the excess water that comes with it. It can also be influenced by variations in climate that determine temperature and flowering season. PMID- 23653069 TI - Trait-mediated indirect effects, predators, and disease: test of a size-based model. AB - Increasing prevalence of wildlife disease accentuates the need to uncover drivers of epidemics. Predators can directly influence disease prevalence via density mediated effects (e.g., culling infected hosts leading to reduced disease prevalence). However, trait-mediated indirect effects (TMIEs) of predators can also strongly influence disease--but predicting a priori whether TMIEs should increase or decrease disease prevalence can be challenging, especially since a single predator may elicit responses that have opposing effects on disease prevalence. Here, we pair laboratory experiments with a mechanistic, size-based model of TMIEs in a zooplankton host, fungal parasite, multiple predator system. Kairomones can either increase or decrease body size of the host Daphnia, depending on the predator. These changes in size could influence key traits of fungal disease, since infection risk and spore yield increase with body size. For six host genotypes, we measured five traits that determine an index of disease spread (R 0). Although host size and disease traits did not respond to kairomones produced by the invertebrate predator Chaoborus, cues from fish reduced body size and birth rate of uninfected hosts and spore yield from infected hosts. These results support the size model for fish; the birth and spore yield responses should depress disease spread. However, infection risk did not decrease with fish kairomones, thus contradicting predictions of the size model. Exposure to kairomones increased per spore susceptibility of hosts, countering size-driven decreases in exposure to spores. Consequently, synthesizing among the relevant traits, there was no net effect of fish kairomones on the R 0 metric. This result accentuates the need to integrate the TMIE-based response to predators among all key traits involved in disease spread. PMID- 23653071 TI - Syntheses, characterization and energetic properties of closo-(B12H12)2- salts of imidazolium derivatives. AB - The diimidazolium derivative of acetylene and its salt 3,3'-(but-2-yne-1,4 diyl)bis(1-methyl-1H-imidazol-3-ium)chloride (1) was synthesized by a solvent free sonochemical method and then the counter chloride ions were replaced by closo-dodecaborate [(B12H12)(2-)] and perchlorate (ClO4(-)) anions respectively. Along with these two ionic salts, a series of salts with closo-dodecaborate and alkyl imidazolium cations were also synthesized. All the compounds were characterized by NMR and MASS spectral data, elemental analyses and thermogravimetric analyses. In addition to that enthalpy of combustion, enthalpy of formation and heat of explosion of all the compounds were experimentally determined. Based on the properties of these compounds, they can be used as insensitive energetic materials in various fields in propellant research and technology such as solid rocket propellants and burn rate accelerators. PMID- 23653070 TI - Latitudinal patterns in phenotypic plasticity: the case of seasonal flexibility in lizards' fat body size. AB - Several studies published over the last years suggest that the ability of many species to cope with global change will be closely related to the current amount of plasticity for fitness-related traits. Thus, disentangling general patterns in phenotypic flexibility, which could be then included in models aimed to predict changes in species distribution, represent a central goal in the current ecological agenda. The climatic variability hypothesis (CVH) could be considered a timely and promising hypothesis since it provides an explicit link between climatic and geographic variables and phenotypic plasticity. Specifically, the CVH states that as the range of climatic fluctuation experienced by terrestrial animals increases with latitude, individuals at higher latitudes should present greater levels of phenotypic flexibility. Within this framework, here we evaluate the existence of latitudinal patterns in fat body size flexibility--estimated as the difference between maximum and minimum fat body size values observed throughout a year--for 59 lizard species, comprising the first evaluation of the CVH for a trait, other than thermic or metabolic characters, in ectothermic species. Conventional and phylogenetic analyses indicated a positive relationship between fat body size flexibility and latitude, and also between flexibility and temperature variability indexes. Together with previous findings our results suggest that: (1) latitudinal pattern for fitness-related traits, other than thermal characters, are beginning to emerge; (2) latitude is usually a better predictor of phenotypic plasticity than putative climatic variables; (3) hemispheric differences in climatic variability appears to be correlated with hemispheric differences in phenotypic plasticity. PMID- 23653072 TI - Consensus-based definition of unfitness to intensive and non-intensive chemotherapy in acute myeloid leukemia: a project of SIE, SIES and GITMO group on a new tool for therapy decision making. PMID- 23653074 TI - Personality disorders and DSM-5. PMID- 23653073 TI - Differential endothelial coverage, response to injury and neointimal integration of CX3CR1/smooth muscle-like cells after carotid or femoral arterial injury. AB - BACKGROUND: Previously, we established the importance of the CX3CL1/CX3CR1 axis in the promotion of myeloid cell differentiation into neointimal smooth muscle like cells (SMLC). METHODS: In this study, acute (24 h) endothelial coverage and CX3CL1 expression as well as chronic (2 weeks) vascular remodeling was examined with respect to whether myeloid CX3CR1(+) SMLC number in the neointima differed between carotid and femoral artery wire injury. RESULTS AND CONCLUSION: Twenty four hours after injury, CX3CL1 expression was significantly elevated in injured carotid compared to femoral arteries. In mice with CX3CR1 promoter-driven expression of green fluorescent protein, neointima formation was significantly greater (p < 0.05) 2 weeks after injury in femoral versus carotid arteries as determined by the intima/media ratio. Although the percentage of F4/80/CX3CR1(+) cell integration was similar in both models, the carotid lesion had greater proportions of cells coexpressing CX3CR1 and both alpha-smooth muscle actin and calponin (p < 0.05). Wire injury of carotid arteries was associated with greater CX3CL1 expression in the acute phase followed by greater CX3CR1 coexpressing SMLC content in later lesions as well as less neointima formation than in femoral arteries. This may, in part, explain the variability in lesion composition after carotid versus femoral wire injury. PMID- 23653075 TI - Convergence between DSM-IV-TR and DSM-5 diagnostic models for personality disorder: evaluation of strategies for establishing diagnostic thresholds. AB - The Personality and Personality Disorders Work Group for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) recommended substantial revisions to the personality disorders (PDs) section of DSM-IV-TR, proposing a hybrid categorical-dimensional model that represented PDs as combinations of core personality dysfunctions and various configurations of maladaptive personality traits. Although the DSM-5 Task Force endorsed the proposal, the Board of Trustees of the American Psychiatric Association (APA) did not, placing the Work Group's model in DSM-5 Section III ("Emerging Measures and Models") with other concepts thought to be in need of additional research. This paper documents the impact of using this alternative model in a national sample of 337 patients as described by clinicians familiar with their cases. In particular, the analyses focus on alternative strategies considered by the Work Group for deriving decision rules, or diagnostic thresholds, with which to assign categorical diagnoses. Results demonstrate that diagnostic rules could be derived that yielded appreciable correspondence between DSM-IV-TR and proposed DSM-5 PD diagnoses-correspondence greater than that observed in the transition between DSM III and DSM-III-R PDs. The approach also represents the most comprehensive attempt to date to provide conceptual and empirical justification for diagnostic thresholds utilized within the DSM PDs. PMID- 23653076 TI - Cued panic attacks in body dysmorphic disorder. AB - BACKGROUND: Body dysmorphic disorder (BDD) is a common and often severe disorder. Clinical observations suggest that panic attacks triggered by BDD symptoms may be common. However, to our knowledge, no study has examined such panic attacks in BDD. We investigated the prevalence, clinical features, and correlates of BDD- triggered panic attacks in individuals with this disorder. METHODS: Panic attacks and other variables were assessed using reliable and valid measures in 76 individuals with lifetime DSM-IV BDD. RESULTS: 28.9% (95% CI, 18.5%-39.4%) of participants reported lifetime panic attacks triggered by BDD symptoms. The most common triggers of such attacks were feeling that others were looking at or scrutinizing the perceived appearance defects (61.9%), looking in the mirror at perceived defects (38.1%), and being in bright light where perceived defects would be more visible (23.8%). The most common panic attack symptoms were palpitations (86.4%), sweating (66.7%), shortness of breath (63.6%), trembling or shaking (63.6%), and fear of losing control or going crazy (63.6%). Compared to participants without such panic attacks, those with BDD-triggered panic attacks had more severe lifetime BDD, social anxiety, and depressive symptoms, as well as poorer functioning and quality of life on a number of measures. They were also less likely to be employed and more likely to have been psychiatrically hospitalized and to have had suicidal ideation due to BDD. CONCLUSIONS: Panic attacks triggered by BDD-related situations appear com- mon in individuals with this disorder. BDD-triggered panic attacks were associated with greater symptom severity and morbidity. PMID- 23653077 TI - Evidence-based recommendations for the prescription of exercise for major depressive disorder. AB - Major depressive disorder (MDD) is a source of great disease burden, due in part to the limited accessibility and effectiveness of current treatments. Although current treatments are efficacious in a segment of the population with MDD, there is a clear need for alternative and augmentation treatment strategies. Exercise is one such alternative treatment option. Research has shown exercise to be efficacious as both a stand-alone and an augmentation therapy. As a result, exercise is now included in the American Psychiatric Association's treatment recommendations. The purpose of this article is to provide clinicians with a knowledge base to prescribe exercise to their patients. The authors describe the evidence supporting the use of exercise in the treatment of MDD, provide evidence based recommendations for prescribing exercise, and address practical considerations related to prescribing exercise in real-world treatment settings. PMID- 23653078 TI - Treating the "unhealthy alcohol user" on medical wards: beyond withdrawal. AB - BACKGROUND: Alcohol use disorders (AUDs) are common among patients admitted to general hospitals. Unfortunately, AUDs often go undetected and untreated. Psychiatrists are frequently called upon to assist in the management of cases involving alcohol withdrawal. However, there is a dearth of knowledge regarding potential therapeutic approaches to AUDs beyond the acute withdrawal stage. OBJECTIVE: This article presents an overview of the epidemiology, clinical characteristics, and treatment of AUDs on medical wards, with a specific focus on the post alcohol-withdrawal phase. METHOD: This article is based on a survey of the published literature on AUDs and their treatment in the medical ward using the PubMed database. RESULTS: Various screening tools are available to facilitate the detection of AUDs. Among non-medically ill patients, brief psychological interventions have proven to be effective in primary care and emergency room settings, while pharmacotherapy has been shown to reduce the risk of relapse. Existing data on the implementation of these interventions in the general hospital setting remain scarce. CONCLUSION: Current evidence suggests the need for additional research in this area with a view toward clarifying AUD treatment guidelines for medically ill inpatients. The hospital stay could provide a valuable opportunity to initiate interventions for AUDs with medically ill patients, leading to significant changes in alcohol use behaviors and better health-related outcomes. PMID- 23653079 TI - Declining differences in response rates with antidepressants versus placebo: a modest proposal for another contributing cause. AB - This column discusses declining differences in response rates between sequentially introduced selective serotonin reuptake inhibitors (SSRI) and placebo. Although discussions of this phenomenon in the literature have largely focused on increasing placebo response rates, the author proposes that another factor may be responsible. That factor is an order effect, meaning that response rates have been declining as a function of the number of SSRIs on the market when the next SSRI is in development. The rationale is that the pool of potential clinical trial participants likely to respond to a drug with this mechanism of action (MOA) becomes progressively smaller with the introduction of each new agent with the same MOA, because many patients will already have been treat- ed and responded to an earlier member of the class. This phenomenon is not limited to the SSRIs but generalizes to any class of treatments that shares the same MOA. PMID- 23653080 TI - A psychoanalyst views inception. AB - The author, a psychoanalyst, discusses the 2010 film, Inception, discerning the parallels and differences between cinematic dreaming states as shown in the film and psychoanalytic processes. The movie presents the unknown and un psychoanalytic phenomena of group shared dreaming, manipulation of other people's dreams with criminal intent, and multiple structured layers of dreaming. In parallel, however, the lead character appears to work through a complicated state of derealization, mourning, guilt, rage, and loss in the course of dreaming. PMID- 23653081 TI - The DSM-5 and forensic psychiatry. AB - In his first Law and Psychiatry column for the Journal of Psychiatric Practice, the author discusses potential forensic consequences of the publication of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM 5). While the transition to DSM-5 may prove challenging for both patients and clinicians, the scrutiny and adversarial process associated with forensic psychiatric practice will entail a unique set of challenges. The philosophy of innovation behind the DSM-5, and the attendant changes, could lead to some unintended consequences, particularly in medicolegal settings. This column highlights some of the major changes in DSM-5 and explores points of particular concern for forensic psychiatric practice, such as the move toward a non multiaxial diagnostic system and dimensional severity ratings being superimposed on certain categorical diagnoses. The innovative changes featured in DSM-5, and the controversies surrounding some of them, could yield an environment of increased cynicism in courts of law, with renewed skepticism regarding mental health diagnoses and the forensic psychiatrists who testify about them. Fortunately, the best method for forensic psychiatric practice in this environment of change is to continue to adhere to a meticulous and transparent medicolegal process, with recognition that changes in the diagnostic manual will seldom alter essential medicolegal conclusions. Forensic psychiatrists may enhance their credibility and the strength of the opinions they offer by proactively illustrating how nuances in diagnosis do not change legally defined constructs such as insanity or incompetence. PMID- 23653082 TI - Wellness and recovery programs: a model of self-advocacy for people living with mental illness. AB - People living with mental illnesses, their family members, and advocacy groups have long encouraged the mental health system to adopt a greater focus on wellness and recovery. A superficial interpretation of wellness and recovery may cause some clinicians to devalue the possibility and importance of wellness and recovery for the people they serve, and this may inhibit or disrupt the development of a working therapeutic relationship. This column reviews definitions of wellness and recovery and their applicability to serious mental illnesses and provides an overview of several programs that promote wellness and recovery. In addition to peer-led courses, ongoing peer support and a range of applications for mobile devices can help consumers lead a self-directed and affirming life that facilitates symptom management and reduction and maximizes wellness. By understanding wellness and recovery and how people living with mental illnesses achieve these goals, psychiatrists may build rapport with their patients and improve outcomes. By familiarizing oneself with new resources available to people with serious mental illness, mental health clinicians may be able to suggest supports that extend far beyond the time constraints of our current treatment model. PMID- 23653083 TI - Court-mandated outpatient psychiatric care for a pregnant woman with psychosis: a unique bridge to alliance. AB - We describe the case of a young pregnant woman with refractory schizoaffective disorder and how we reached a decision to apply for court-mandated outpatient psychiatric treatment (Assisted Outpatient Treatment or AOT). The patient was stable when we made this application as a preventive measure, given her serious prior episodes of illness. While there has been court-mandated outpatient obstetrical treatment, as far as we know this is the first report of mandated outpatient psychiatric treatment in connection with pregnancy. The ultimate benefit of this AOT application was the development of a therapeutic alliance and improved voluntary adherence to treatment, and a safe outcome to the pregnancy. PMID- 23653084 TI - Psychiatrists' use of electronic communication and social media and a proposed framework for future guidelines. AB - BACKGROUND: Recent and ongoing advances in information technology present opportunities and challenges in the practice of medicine. Among all medical subspecialties, psychiatry is uniquely suited to help guide the medical profession's response to the ethical, legal, and therapeutic challenges- especially with respect to boundaries--posed by the rapid proliferation of social media in medicine. Ironically, while limited guidelines exist for other branches of medicine, guidelines for the responsible use of social media and information technology in psychiatry are lacking. OBJECTIVE: To collect data about patterns of use of electronic communications and social media among practicing psychiatrists and to establish a conceptual framework for developing professional guidelines. METHODS: A structured survey was developed to assess the use of email, texting, and social media among the active membership of the Group for the Advancement of Psychiatry (GAP) to gain insight into current practices across a spectrum of the field and to identify areas of concern not addressed in existing guidelines. This survey was distributed by mail and at an annual meeting of the GAP and a descriptive statistical analysis was conducted with SPSS. RESULTS: Of the 212 members, 178 responded (84% response rate). The majority of respondents (58%) reported that they rarely or never evaluated their online presence, while 35% reported that they had at some time searched for information online about patients. Only 20% posted content about themselves online and few of these restricted that information. Approximately 25% used email to communicate with patients, and very few obtained written consent to do so. CONCLUSION: Discipline specific guidelines for psychiatrists' interactions with social media and electronic communications are needed. Informed by the survey described here, a review of the literature, and consensus opinion, a framework for developing such a set of guidelines is proposed. The model integrates four key areas: treatment frame, patient privacy, medico-legal concerns, and professionalism. This conceptual model, applicable to many psychiatric settings, including clinical practice, residency training, and continuing medical education, will be helpful in developing discipline-wide guidelines for psychiatry and can be applied to a decision-making process by individual psychiatrists in day-to-day practice. PMID- 23653085 TI - More than four decades of medical informatics education for medical students in Germany. New recommendations published. AB - The publication of German competency-based learning objectives "Medical Informatics" for undergraduate medical education gives reason to report on more publications of the German journal GMS Medical Informatics, Biometry and Epidemiology ( MIBE ) in Methods. The publications in focus deal with support of medical education by health and biomedical informatics, hospital information systems and their relation to medical devices, transinstitutional health information systems and the need of national eHealth strategies, epidemiological research on predicting high consumption of resources, and with the interaction of epidemiologists and medical statisticians in examining mortality risks in diabetes, in genome wide association studies and in dealing with limits and thresholds. This report is the beginning of an annual series intending to support better international cooperation to achieve good information as a basis for good medicine and good healthcare. PMID- 23653086 TI - Development and characterization of propranolol selective molecular imprinted polymer composite electrospun nanofiber membrane. AB - Propranolol (PPL) imprinted microspheres (MIP) were successfully prepared via oil/water polymerization using a methyl methacrylate (MMA) monomer, PLL template, and divinylbenzene (DVB) cross-linker and favorably incorporated in a Eudragit RS100 nanofiber membrane. A non-PPL imprinted polymer (NIP), without a template, was used as a control. The morphology and particle size of the beads were investigated using scanning electron microscopy. The results revealed that both MIP and NIP had a spherical shape with a micron size of approximately 50-100 MUm depending on the amounts of DVB and PPL used. NIP2 (MMA/DVB, 75:2.5) and MIP8 (PPL/MMA/DVB, 0.8:75:2.5) were selected for reloading of PPL, and the result indicated that increasing the ratio of PPL to polymer beads resulted in increase PPL reloading (>80%). A total of 10-50% NIP2 or MIP8 was incorporated into a 40% (w/v) Eudragit-RS100 fiber membrane using an electrospinning technique. PPL could be bound to the 50% MIP8 composite fiber membrane with a higher extent and at a higher rate than the control (NIP2). Furthermore, the MIP8 composite fiber membrane showed higher selectivity to PPL than the other beta-blockers (atenolol, metoprolol, and timolol). Thus, the MIP8 composite fiber membrane can be further developed for various applications in pharmaceutical and other affinity separation fields. PMID- 23653087 TI - 25-Hydroxyvitamin D(3)-loaded PLA microspheres: in vitro characterization and application in diabetic periodontitis models. AB - This study aimed at the preparation of a sustained-release 25-hydroxyvitamin D(3) (25OHD) treatment for diabetic periodontitis, a known complication of diabetes. 25OHD-loaded polylactic acid (PLA) microspheres were prepared using oil-in-water emulsion-solvent evaporation method. The prepared microspheres exhibited intact surfaces, with average sizes ranging from 42.3 to 119.4 MUm. The encapsulation efficiency ranged from 79.2% (w/w) to 88.5% (w/w), and the drug content was between 15.8% (w/w) and 17.8% (w/w). Drug release from the produced microspheres followed a near-to-zero-order release pattern and lasted over 10 weeks. In an in vitro model of diabetic periodontitis, the abnormal morphological changes and the decrease in the cell viability of bone marrow stromal cells could be effectively attenuated after the 25OHD-loaded microsphere application. Additionally, in a rat model of diabetic periodontitis, alveolar bone loss was inhibited and osteoid formation in the periodontium was promoted upon 25OHD-loaded microsphere treatment. In conclusion, 25OHD-loaded PLA microspheres may provide an effective approach for the treatment of this disease. PMID- 23653089 TI - Cooling treatment transiently increases the permeability of brain capillary endothelial cells through translocation of claudin-5. AB - The blood-brain-barrier (BBB) is formed by different cell types, of which brain microvascular endothelial cells are major structural constituents. The goal of this study was to examine the effects of cooling on the permeability of the BBB with reference to tight junction formation of brain microendothelial cells. The sensorimotor cortex above the dura mater in adult male Wistar rats was focally cooled to a temperature of 5 degrees C for 1 h, then immunostaining for immunoglobulin G (IgG) was performed to evaluate the permeability of the BBB. Permeability produced by cooling was also evaluated in cultured murine brain endothelial cells (bEnd3) based on measurement of trans-epithelial electric resistance (TEER). Immunocytochemistry and Western blotting of proteins associated with tight junctions in bEnd3 were performed to determine protein distribution before and after cooling. After focal cooling of the rat brain cortex, diffuse immunostaining for IgG was observed primarily around the small vasculature and in the extracellular spaces of parenchyma of the cortex. In cultured bEnd3, TEER significantly decreased during cooling (15 degrees C) and recovered to normal levels after rewarming to 37 degrees C. Immunocytochemistry and Western blotting showed that claudin-5, a critical regulatory protein for tight junctions, was translocated from the membrane to the cytoplasm after cooling in cultured bEnd3 cells. These results suggest that focal brain cooling may open the BBB transiently through an effect on tight junctions of brain microendothelial cells, and that therapeutically this approach may allow control of BBB function and drug delivery through the BBB. PMID- 23653090 TI - HIV testing and intimate partner violence among non-pregnant women in 15 US states/territories: findings from behavioral risk factor surveillance system survey data. AB - Intimate partner violence (IPV) has been shown to be associated with higher rates of HIV infection among women, underscoring the importance of encouraging IPV victims to receive HIV testing. However, we do not know how much HIV testing behavior is influenced by IPV victimization. The current study characterized the association between individual types of IPV and HIV testing in a large sample of non-pregnant women in 15 US states/territories. The 2005 Behavioral Risk Factor Surveillance System data were analyzed after restricting the sample to non pregnant women. The dependent variable, whether a woman ever had an HIV test, was examined in relation to individual types of IPV victimization (threatened physical violence; attempted physical violence; completed physical violence; and unwanted sex). Associations between HIV testing and types of IPV were assessed using adjusted risk ratios (aRR) that controlled for demographics and HIV-related risk factors (intravenous drug use, sexually transmitted diseases, exchange sex, unprotected anal sex). Approximately 28.6 % of women reported ever having experienced IPV, and 52.8 % of these women reported being tested for HIV. Among women who had not experienced IPV, 32.9 % reported ever having been tested for HIV. HIV testing was associated with lifetime experience of threatened violence (aRR = 1.43; 95 % CI = 1.24-1.65), attempted violence (aRR = 1.43; 95 % CI = 1.20 1.69), completed physical violence (aRR = 1.30; 95 % CI = 1.13-1.48), and unwanted sex (aRR = 1.66; 95 % CI = 1.48-1.86). Women who experienced each type of IPV were more likely to have been ever tested for HIV compared to women with no IPV history. However, nearly half of those reporting IPV, even though at greater risk for HIV infection, had never been tested. Additional efforts are needed to address barriers to testing in this group. PMID- 23653088 TI - Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence. AB - Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. Thus, our aim was to provide a comprehensive narrative review of plant-based medicines that have clinical and/or preclinical evidence of anxiolytic activity. We present the article in two parts. In part one, we reviewed herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In this current article (part two), we review herbal medicines for which there have been both preclinical and clinical investigations of anxiolytic activity. A search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) for English language papers using the search terms 'anxiety' OR 'anxiety disorder' OR 'generalized anxiety disorder' OR 'social phobia' OR 'post-traumatic stress disorder' OR 'panic disorder' OR 'agoraphobia' OR 'obsessive compulsive disorder' in combination with the search terms 'Herb*' OR 'Medicinal Plants' OR 'Botanical Medicine' OR 'Chinese herb*', in addition to individual herbal medicines. This search of the literature revealed 1,525 papers, of which 53 plants were included in the review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed here in part two), with the other 32 having solely preclinical evidence (reviewed in part one). Support for efficacy was found for chronic use (i.e. greater than one day) of the following herbs in treating a range of anxiety disorders in human clinical trials: Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis and Echium amoenum. For several of the plants studied, conclusions need to be tempered due to methodological issues such as small sample sizes, brief intervention durations and non-replication. Current evidence does not support Hypericum perforatum or Valeriana spp. for any anxiety disorder. Acute anxiolytic activity was found for Centella asiatica, Salvia spp., Melissa officinalis, Passiflora incarnata and Citrus aurantium. Bacopa monnieri has shown anxiolytic effects in people with cognitive decline. The therapeutic application of psychotropic plant-based treatments for anxiety disorders is also discussed, specifically Psychotria viridis and Banisteriopsis caarti (ayahuasca), Psilocybe spp. and cannabidiol-enriched (low tetrahydrocannabinol (Delta(9)-THC)) Cannabis spp. PMID- 23653091 TI - HIV risk among substance-using men who have sex with men and women (MSMW): findings from South Florida. AB - Compared with men who have sex with men only (MSMO), men who have sex with men and women (MSMW) consistently report higher rates of two HIV risk behaviors: transactional sex (TS) and concurrent substance use and sex (CSS). Within MSMW, little is known about how synergistic epidemics ("syndemics") affect TS and CSS. Using a sample of substance-using MSM (n = 515) in South Florida, we compared TS and CSS among MSMO and MSMW; examined whether, within MSMW (n = 86), TS and CSS predict unprotected anal intercourse with partners of serodiscordant/unknown HIV status (SU-UAI); and tested whether syndemics predict TS and CSS. MSMW reported higher rates of engaging in both TS and CSS (AOR = 1.7; 95 % CI 1.0-3.0). Within MSMW, engagement in both TS and CSS predicted SU-UAI (AOR = 3.3; 95 % CI 1.2 9.6); and syndemics predicted TS and CSS involvement (p < 0.01). Substance-using MSMW may benefit from interventions targeting TS, CSS, and background syndemics. PMID- 23653092 TI - Trends, correlates, and disease patterns of antipsychotic use among children and adolescents in Taiwan. AB - PURPOSE: We used Taiwan's population-based National Health Insurance database to investigate the trends, correlates, and disease patterns of antipsychotic use among children and adolescents. METHODS: The National Health Research Institutes provided a database of 1,000,000 random subjects for study. We chose subjects who were aged 18 years or younger during 1997-2005. In this sample, subjects who were given at least one antipsychotic prescription, including first-generation antipsychotics (FGAs) or second-generation antipsychotics (SGAs), were identified. Trends, prevalence, and associated factors of antipsychotic use were determined. The proportion of antipsychotic use for psychiatric and medical disorders was also analyzed. RESULTS: The 1-year prevalence of SGA use increased from 0.00 % in 1997 to 0.09 % in 2005, whereas the 1-year prevalence of FGA use ranged from 2.24 to 3.43 % during this same period, with no significant change. Age and male gender were associated with higher SGA use. Among SGA users, the greatest proportion suffered from psychiatric disorders, including tics, hyperkinetic syndrome of childhood, schizophrenia, affective disorders, and autism. Among FGA users, a larger proportion was for medical conditions, including diseases of the digestive and respiratory systems. CONCLUSION: The prevalence of pediatric SGA use increased greatly from 1997 to 2005. Among pediatric subjects using antipsychotics, SGAs were mostly used for psychiatric disorders, whereas FGAs were mostly prescribed for medical conditions. Future research will focus on indication, dosage, frequency, duration, adverse effects, and off-label use of antipsychotics in the pediatric population. PMID- 23653093 TI - Stochastic contribution for the coding of agonist induced calcium oscillation in hepatocytes. AB - The influence of stochastic inositol-1,4,5-trisphosphate receptor (IP3R) dynamics and their clustering have been extensively investigated to explore the mechanism through which the stochastic molecular event finally shape the intracellular calcium signaling. Most of the previous works employed simplified models which take the concentration of IP3 instead of that of the agonist as the stimulation intensity. However, the IP3 level is not linearly dependent on the agonist concentration in stimulus induced signaling systems because there are feedback links in the transduction network. In this work, we include both the IP3R dynamics and the typical agonist induced signaling transduction cascade in the model to investigate the essential influence of stochastic IP3R dynamics on the coding of the stimulus induced calcium signal. Simulation results reveal two distinct oscillation areas under different stimulation levels. The signal is optimally modulate by the IP3R cluster number in the weak stimulated area while affected by the stimulus intensity in the strong stimulated area. Different dependences of coefficient of variance (CV) on the number of clusters are obtained in these two areas, which explains the disagreement in the previous reported results. Besides, the transition between these areas explains the significant CV reduction observed in experiments. PMID- 23653094 TI - Mechanical double layer model for Saccharomyces cerevisiae cell wall. AB - The elastic modulus of the Baker's yeast (Saccharomyces cerevisiae) cell wall reported in studies using atomic force microscopy (AFM) is two orders of magnitude lower than that obtained using whole cell compression by micromanipulation. Using finite element modelling, it is shown that Hertz-Sneddon analysis cannot be applied to AFM indentation data for single layer core-shell structures. In addition, the Reissner solution for shallow homogeneous spheres is not appropriate for thick walls such as those of yeast cells. In order to explain yeast compression measurements at different length scales, a double layer wall model is presented considering a soft external layer composed of mannoproteins, and a stiff inner layer of beta-glucan fibres and chitin. Under this model, previous AFM studies using sharp indenters provide reasonable estimates of the external layer elastic modulus, while micromanipulation provides the total stiffness of the cell wall. Data from both measurements are combined to estimate the mechanical properties of the inner stiff layer. PMID- 23653095 TI - Positive correlation between variants of lipid metabolism-related genes and coronary heart disease. AB - Four gene variants related to lipid metabolism (including the rs562338 and rs503662 variants of the APOB gene, the rs7767084 variant of the LPA gene and the rs2246942 variant of the LIPA gene) have been shown to be associated with coronary heart disease (CHD). The aim of the present study was to assess their association with CHD in the Han Chinese population and to assess the contribution of these gene variants to CHD. Using the standardized coronary angiography method, we enrolled 290 CHD patients and 193 non-CHD patients as non-CHD controls from Lihuili Hospital (Ningbo, China). In addition, we recruited 330 unrelated healthy volunteers as healthy controls from the Xi Men Community (Ningbo, China). Our results demonstrated that the rs503662 and rs562338 variants of the APOB gene were extremely rare in the Han Chinese population (minor allele frequency <1%). Genotype rs2246942-GG of the LIPA gene was associated with an increased risk of CHD [CHD cases versus healthy controls: P=0.04; odds ratio (OR)=1.63; 95% confidence interval (CI)=1.02-2.60). Genotype rs7767084-CC of the LPA gene was identified as a protective factor against CHD in females (CHD cases versus non CHD controls: P=0.04, OR=0.21; CHD cases versus healthy controls: P=0.02, OR=0.21). The results of our meta-analysis indicated that rs7767084 was not associated with a high risk of CHD (P=0.83; combined OR=0.93; 95% CI=0.47-1.85). In the present study, two single nucleotide polymorphisms (SNPs) of genes involved in lipid metabolism (rs2246942 and rs7767084) were identified to be significantly associated with CHD in the Han Chinese population. Specifically, rs2246942-GG of the LIPA gene was a risk factor for CHD, while rs7767084-CC of the LPA gene was a protective factor against CHD in females. However, our meta analysis indicated that rs7767084 is not associated with a higher risk of CHD. PMID- 23653096 TI - ERG overexpression and PTEN status predict capsular penetration in prostate carcinoma. AB - BACKGROUND: This study examines the combined effect of two common genetic alterations, ERG and PTEN, in prostate carcinoma progression. METHODS: Prostate tissue from 90 patients having unilateral capsular penetrating lesions, and a contra-lateral organ confined second lesion, were examined by immunohistochemistry for the expression of the TMPRSS2:ERG transformation product ERG and the loss of expression of PTEN, a powerful phosphatase inhibiting the PI3 kinase pathway. Multivariate logistic regression was carried out to analyze the data. RESULTS: After adjusting for Gleason score, the odds of having capsular penetration were 5.19 times higher (P = 0.015) for ERG+/PTEN- group as compared to the wild type (ERG-/PTEN+). CONCLUSIONS: This study presents the first evidence that ERG over expression and PTEN deletion is associated with greater risk of capsular penetration. Although further studies are needed, these results have the potential to change clinical assessment for prostate cancer. PMID- 23653097 TI - Results of treatment of femoroacetabular impingement in adolescents with a surgical hip dislocation approach. AB - BACKGROUND: The literature contains few studies of open treatment with an open surgical hip dislocation approach for treatment of femoroacetabular impingement (FAI) in adolescents. The average age and associated disorders in adolescents with FAI reveal a critical need to study younger patients whose hip disorder has not had time to progress. QUESTIONS: We assessed (1) how validated measures of patient-oriented assessment of hip function and quality of life change after surgical hip dislocation; (2) whether any patient-related or technique variables correlated with changes in the outcome scores; and (3) what the complications of treatment are and how many reoperations we performed on these patients. METHODS: We retrospectively reviewed a consecutive series of 71 hips in adolescents younger than 21 years who underwent surgical hip dislocation for FAI. The final cohort consisted of 44 patients (52 hips) with a mean age of 16 years. We analyzed changes in outcome variables after surgical hip dislocation and recorded reoperations during the study period. RESULTS: The minimum followup was 12 months (average, 27 months; range, 12-60 months). Modified Harris hip scores increased from a mean of 57.7 preoperatively to a mean of 85.8 postoperatively. Mean SF-12 scores increased from 42.3 to 50.6. Mean preoperative hip flexion increased from 97.5 degrees to 106.2 degrees . Mean internal rotation of the affected hip at 90 degrees flexion increased from 18.19 degrees to 34 degrees . CONCLUSIONS: Early results revealed improvements in hip function, patient quality of life, and ROM after surgical hip dislocation for the majority of this group of adolescents with FAI. However, 10% of the patients did not improve, and an additional 15% improved but still did not consider their hips good or excellent. This points toward the need for further studies in this population of patients. PMID- 23653098 TI - Weber osteotomy for large Hill-Sachs Defects: clinical and CT assessments. AB - BACKGROUND: The Weber derotation osteotomy is an uncommon procedure that typically is reserved for patients with engaging Hill-Sachs defects who have had other surgical treatments for shoulder instability fail. It is unknown whether the desired humeral derotation actually is achieved with the Weber osteotomy. QUESTIONS/PURPOSES: The purposes of this study were to answer the following questions: (1) What are the complication (including redislocation) and reoperation rates of the Weber osteotomy? (2) What are the American Shoulder and Elbow Surgeons (ASES) and functional (ROM in internal rotation, self care) results? (3) What fraction of the patients had humeral derotation within 10 degrees of the desired rotation? METHODS: A chart review of 19 Weber osteotomies and clinical assessment of 10 Weber osteotomies were performed by independent clinicians. The chart review, at a mean followup of 51 months (range, 13-148 months), focused on the complication rate and the frequency of redislocation. The clinical and CT assessments, at a mean followup of 54 months (range, 26-151 months), focused on ASES scores, ability of patients to perform self care with the affected arm, and CT scans to measure change in humeral retroversion. RESULTS: There were 25 complications and nine reoperations in 17 patients (19 shoulders), including pain (six patients, of whom one had complex regional pain syndrome), hematoma, infection, nonunion, delayed union, reoperations related to hardware and other noninstability-related causes (five patients), and internal rotation deficit. Redislocation occurred in one patient, who underwent repeat surgery, and subjective instability developed in two others. The mean ASES score was 78 points (of 100 points); six of the 10 patients (11 procedures) evaluated in person found it difficult or were unable to wash their backs with the affected arm. Humeral derotation varied from 7 degrees to 77 degrees ; only three of the nine patients for whom CT scans were available had derotation within 10 degrees of the desired rotation. CONCLUSIONS: Complication rates with the Weber osteotomy were much higher than previously reported. Because seven of 17 patients were lost to followup, the redislocation rate may be higher than we observed here. Given the unpredictable variability in humeral derotation achieved with a Weber osteotomy, an improved surgical technique is critical to avoid osteoarthritis and loss of internal rotation associated with overrotation. PMID- 23653099 TI - Is lateral pin fixation for displaced supracondylar fractures of the humerus better than crossed pins in children? AB - BACKGROUND: Closed reduction and percutaneous pin fixation is considered standard management for displaced supracondylar fractures of the humerus in children. However, controversy exists regarding whether to use an isolated lateral entry or a crossed medial and lateral pinning technique. QUESTIONS/PURPOSES: We performed a meta-analysis of randomized controlled trials (RCTs) to compare (1) the risk of iatrogenic ulnar nerve injury caused by pin fixation, (2) the quality of fracture reduction in terms of the radiographic outcomes, and (3) function in terms of criteria of Flynn et al. and elbow ROM, and other surgical complications caused by pin fixation. METHODS: We searched PubMed, Embase, the Cochrane Library, and other unpublished studies without language restriction. Seven RCTs involving 521 patients were included. Two authors independently assessed the methodologic quality of the included studies with use of the Detsky score. The median Detsky quality score of the included trials was 15.7 points. Dichotomous variables were presented as risk ratios (RRs) or risk difference with 95% confidence intervals (CIs) and continuous data were measured as mean differences with 95% CI. Statistical heterogeneity between studies was formally tested with standard chi square test and I(2) statistic. For the primary objective, a funnel plot of the primary end point and Egger's test were performed to detect publication bias. RESULTS: The pooled RR suggested that iatrogenic ulnar nerve injury was higher with the crossed pinning technique than with the lateral entry technique (RR, 0.30; 95% CI, 0.10-0.89). No publication bias was further detected. There were no statistical differences in radiographic outcomes, function, and other surgical complications. No significant heterogeneity was found in these pooled results. CONCLUSIONS: We conclude that the crossed pinning fixation is more at risk for iatrogenic ulnar nerve injury than the lateral pinning technique. Therefore, we recommend the lateral pinning technique for supracondylar fractures of the humerus in children. PMID- 23653100 TI - Does radiographic beam angle affect the radiocapitellar ratio measurement of subluxation in the elbow? AB - BACKGROUND: Radial head alignment is the key to determine elbow reduction after treatment of subluxations or Monteggia fractures. The radiocapitellar ratio (RCR) quantifies the degree of subluxation, by evaluating radial head alignment with the capitellum of the humerus; this ratio is reproducible when measured on true lateral radiographs of nonsubluxated elbows. However, the impact of beam angulation on RCR measurement is unknown. QUESTIONS/PURPOSES: Our hypotheses were that the RCR of the nonsubluxated elbow would remain in the normal range as the beam angle changed and that the RCR variability would increase for the subluxated elbow with small deviations in the beam angle. METHODS: Radiographs were taken of six healthy cadaveric extremities using beam angles ranging from -20 degrees to 20 degrees along the inferosuperior axis and from -20 degrees to 20 degrees along the dorsoventral axis. The same views then were taken of the six arms with anterior radiocapitellum subluxation followed by posterior radiocapitellum subluxation. RCRs were measured by one observer. As a reference value, the RCR was measured in the 0 degrees to 0 degrees position and the difference between each RCR in a nonreference position was subtracted from each RCR reference to obtain the delta-RCR. An ANOVA was performed to assess the main and interactive effects on the RCR measured in each C-arm position compared with the RCR measured on a true lateral radiograph. RESULTS: The RCR remained in the normal range even as the beam angle of the C-arm varied between -20 degrees and 20 degrees . The position of the beam did not affect the RCR in anteriorly subluxated elbows (p = 0.777), whereas RCR variation increased especially in the presence of posterior radial head subluxation when the C-arm position was 10 degrees or more out of plane (p = 0.006). The inferosuperior malposition of the C-arm had a greater impact on quantification of radial head alignment measurement. Despite that, the RCR measurement is reliable in reduced and subluxated elbows on lateral radiographs with a C-arm position deviation of as much as 20 degrees . CONCLUSIONS: Identification of a subluxated elbow could be made on any lateral radiograph with a beam angulation deviation of as much as 20 degrees . This suggests that the RCR is a useful diagnostic tool for clinical and research purposes, although for subluxated elbows, it is important to pay careful attention to the inferosuperior position of the C-arm. PMID- 23653101 TI - Maximizing tibial coverage is detrimental to proper rotational alignment. AB - BACKGROUND: Traditionally, the placement of the tibial component in total knee arthroplasty (TKA) has focused on maximizing coverage of the tibial surface. However, the degree to which maximal coverage affects correct rotational placement of symmetric and asymmetric tibial components has not been well defined and might represent an implant design issue worthy of further inquiry. QUESTIONS/PURPOSES: Using four commercially available tibial components (two symmetric, two asymmetric), we sought to determine (1) the overall amount of malrotation that would occur if components were placed for maximal tibial coverage; and (2) whether the asymmetric designs would result in less malrotation than the symmetric designs when placed for maximal coverage in a computer model using CT reconstructions. METHODS: CT reconstructions of 30 tibial specimens were used to generate three-dimensional tibia reconstructions with attention to the tibial anatomic axis, the tibial tubercle, and the resected tibial surface. Using strict criteria, four commercially available tibial designs (two symmetric, two asymmetric) were placed on the resected tibial surface. The resulting component rotation was examined. RESULTS: Among all four designs, 70% of all tibial components placed in orientation maximizing fit to resection surface were internally malrotated (average 9 degrees ). The asymmetric designs had fewer cases of malrotation (28% and 52% for the two asymmetric designs, 100% and 96% for the two symmetric designs; p < 0.001) and less malrotation on average (2 degrees and 5 degrees for the asymmetric designs, 14 degrees for both symmetric designs; p < 0.001). CONCLUSIONS: Maximizing tibial coverage resulted in implant malrotation in a large percentage of cases. Given similar amounts of tibial coverage, correct rotational positioning was more likely to occur with the asymmetric designs. CLINICAL RELEVANCE: Malrotation of components is an important cause of failure in TKA. Priority should be given to correct tibial rotational positioning. This study suggested that it is easier to balance rotation and coverage with asymmetric tibial baseplates; clinical research will need to determine whether the observed difference affects patellar tracking, loosening rates, or the likelihood of revisions after TKA. PMID- 23653102 TI - State of virtual reality based disaster preparedness and response training. AB - The advent of technologically-based approaches to disaster response training through Virtual Reality (VR) environments appears promising in its ability to bridge the gaps of other commonly established training formats. Specifically, the immersive and participatory nature of VR training offers a unique realistic quality that is not generally present in classroom-based or web-based training, yet retains considerable cost advantages over large-scale real-life exercises and other modalities and is gaining increasing acceptance. Currently, numerous government departments and agencies including the U.S. Department of Homeland Security (DHS), the Centers for Disease Control and Prevention (CDC) as well as academic institutions are exploring the unique advantages of VR-based training for disaster preparedness and response. Growing implementation of VR-based training for disaster preparedness and response, conducted either independently or combined with other training formats, is anticipated. This paper reviews several applications of VR-based training in the United States, and reveals advantages as well as potential drawbacks and challenges associated with the implementation of such training platform. PMID- 23653103 TI - Does intravenous landiolol, a beta1-adrenergic blocker, affect stroke volume variation? AB - PURPOSE: There are no reports about the effect of bradycardia on stroke volume variation (SVV), and we hypothesized that induced bradycardia alters the value of SVV. Landiolol, an ultra-short-acting adrenergic beta1-receptor blocking agent, was reported to induce bradycardia without decreasing blood pressure. The initial aim of this prospective study was to investigate changes in SVV values by induced bradycardia in patients with good cardiac function. METHODS: At 30 min after anesthesia induction, if heart rate (HR) was >80 bpm, the patient was chosen as a subject. Ten ASA physical status I-II patients aged 38-75 years who were scheduled for elective abdominal surgery were included in this study. Baseline values were recorded, and then administration of landiolol was started at 125 MUg/kg/min for 1 min and then continued at 40 MUg/kg/min. SVV and other parameters were recorded at baseline and 3 min after continuous landiolol injection. RESULTS: Landiolol significantly decreased systolic arterial pressure, and diastolic arterial pressure, contrary to our expectations, and also HR, SVV, cardiac output, stroke volume index, and pressure of end-tidal CO(2), whereas systemic vascular resistance values increased significantly. CONCLUSIONS: SVV decreased after continuous administration of a beta1-adrenergic blocker, probably because of a decrease in the difference of maximum stroke volume (SV) and minimum SV, or the downward shift of the Frank-Starling curve that occurred after landiolol administration. We believe that SVV values might be overestimated or misinterpreted when HR is decreased by landiolol and might not necessarily indicate that the patient is hypervolemic or normovolemic. PMID- 23653104 TI - Current attitudes of Turkish anesthesiologists to radiation exposure. AB - PURPOSE: The aim of this study was to investigate the attitudes of anesthesiologists to radiation exposure and current safety practice in Turkey. METHODS: The study enrolled anesthesiologists from all over Turkey, including all levels of academic degrees and all types of different institutions. Questionnaire forms were sent via e-mail to 505 anesthesiologists. The survey collected demographic data such as age, gender, position, and the institution at which the participant worked, and data about the frequency of radiation exposure during procedures and the participant's attitudes concerning radiation safety measures during these procedures. RESULTS: The questionnaire forms were delivered to 491 anesthesiologists, and 301 (61.3 %) of these were returned. Of these, 9 had not completed the questionnaire because of a lack of exposure to radiation. Among the remaining 292 personnel, the weekly frequencies of radiation exposure were more than five times (36.7 %), one to five times (50.3 %), and less than once (13 %) per week, respectively. Only a few anesthesiologists regularly wore a lead apron (30.11 %) and a thyroid shield (11.3 %) during procedures involving radiation exposure. CONCLUSIONS: This study demonstrated that nearly all anesthesiologists are regularly exposed to radiation and that few anesthesiologists in Turkey wear protective clothing, which is essential for radiation protection. Therefore, if it is not, increasing awareness about radiation protection should be an integral part of medical training and education. PMID- 23653105 TI - Design, synthesis, and application of a trifluoromethylated phenylalanine analogue as a label to study peptides by solid-state 19F NMR spectroscopy. PMID- 23653106 TI - Evaluation of the skin peptide defenses of the Oregon spotted frog Rana pretiosa against infection by the chytrid fungus Batrachochytrium dendrobatidis. AB - Population declines due to amphibian chytridiomycosis among selected species of ranid frogs from western North America have been severe, but there is evidence that the Oregon spotted frog, Rana pretiosa Baird and Girard, 1853, displays resistance to the disease. Norepinephrine-stimulated skin secretions were collected from a non-declining population of R. pretiosa that had been exposed to the causative agent Batrachochytrium dendrobatidis. Peptidomic analysis led to identification and isolation, in pure form, of a total of 18 host-defense peptides that were characterized structurally. Brevinin-1PRa, -1PRb, -1PRc, and 1PRd, esculentin-2PRa and -PRb, ranatuerin-2PRa, -2PRb, -2PRc, and -2PRe, temporin-PRb and -PRc were identified in an earlier study of skin secretions of frogs from a different population of R. pretiosa known to be declining. Ranatuerin-2PRf, -2PRg, -2PRh, temporin-PRd, -PRe, and -PRf were not identified in skin secretions from frogs from the declining population, whereas temporin-PRa and ranatuerin-2PRd, present in skin secretions from the declining population, were not detected in the current study. All purified peptides inhibited the growth of B. dendrobatidis zoospores. Peptides of the brevinin-1 and esculentin-2 families displayed the highest potency (minimum inhibitory concentration = 6.25 12.5 MUM). The study provides support for the hypothesis that the multiplicity and diversity of the antimicrobial peptide repertoire in R. pretiosa and the high growth-inhibitory potency of certain peptides against B. dendrobatidis are important in conferring a measure of resistance to fatal chytridiomycosis. PMID- 23653108 TI - AgS2O6CF3: the first trifluoromethylsulfonylsulfate(VI). AB - We describe the synthetic route towards a novel class of salts, trifluoromethylsulfonylsulfates, as exemplified by the silver(I) derivative (AgS2O6CF3). Formation proceeds via direct reaction between a triflate precursor, AgSO3CF3, and SO3. The title compound crystallizes in the P2(1)/c unit cell with a = 5.15746(14) A, b = 25.8563(9) A, c = 5.53970(14) A and beta = 101.1749(19) degrees . The structure is layered with the puckered [AgS2O6] 2D sheets; the terminal CF3 groups are separated by the van der Waals gap, as seen also for related metal triflates. The compound is very fragile thermally and it decomposes endothermally to AgSO3CF3 with concomitant evolution of SO3 even at 65 degrees C or upon grinding in an agate mortar; thus it may serve as a solid store of- otherwise volatile and corrosive--SO3. The IR and Raman spectra of AgS2O6CF3 have been tentatively assigned based on similarities to those of related Ag2S2O7 and AgSO3CF3 and phonon calculations. Synthesis and properties of KS2O6CF3 are also briefly described. PMID- 23653107 TI - Weekend versus weekday hospital admission and outcomes during hospitalization for patients due to worsening heart failure: a report from Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). AB - The day of the week of admission may influence the length of stay and in-hospital death. However, the association between the admission day of the week and in hospital outcomes has been inconsistent in heart failure (HF) patients among studies reported from Western countries. We thus analyzed this association in HF patients encountered in routine clinical practice in Japan. We studied the characteristics and in-hospital treatment in 1620 patients hospitalized with worsening HF by using the database of the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Patients were divided into two groups according to weekday (n = 1355; 83.6%) or weekend admission (n = 265; 16.4%). The mean age was 70.7 years and 59.4% were male. Etiology was ischemic in 34.0%, and mean left ventricular ejection fraction was 42.5%. Patients admitted on the weekend were significantly older and had more comorbidities, and more severe symptoms and signs of HF on admission. Length of stay was comparable between weekend and weekday admission (35.2 +/- 47.0 days vs 33.6 +/- 32.0 days, P = 0.591). Crude in-hospital mortality did not differ between patients admitted on the weekend and weekdays (7.5% vs 5.2%, P = 0.136). Even after adjustment for covariates in multivariable modeling with patients admitted on weekday as the reference, in-hospital death was comparable between patients admitted on the weekend and weekdays (adjusted odds ratio 1.125, 95% confidence interval 0.631 2.004, P = 0.691). Among patients hospitalized for worsening HF, admission day of the week did not affect in-hospital death and length of stay. PMID- 23653109 TI - "Collateral damages": preparing residents for coping with patient suicide. PMID- 23653110 TI - Membrane fluidity of halophilic ectoine-secreting bacteria related to osmotic and thermal treatment. AB - In response to sudden decrease in osmotic pressure, halophilic microorganisms secrete their accumulated osmolytes. This specific stress response, combined with physiochemical responses to the altered environment, influence the membrane properties and integrity of cells, with consequent effects on growth and yields in bioprocesses, such as bacterial milking. The aim of this study was to investigate changes in membrane fluidity and integrity induced by environmental stress in ectoine-secreting organisms. The halophilic ectoine-producing strains Alkalibacillus haloalkaliphilus and Chromohalobacter salexigens were treated hypo and hyper-osmotically at several temperatures. The steady-state anisotropy of fluorescently labeled cells was measured, and membrane integrity assessed by flow cytometry and ectoine distribution. Strong osmotic downshocks slightly increased the fluidity of the bacterial membranes. As the temperature increased, the increasing membrane fluidity encouraged more ectoine release under the same osmotic shock conditions. On the other hand, combined shock treatments increased the number of disintegrated cells. From the ectoine release and membrane integrity measurements under coupled thermal and osmotic shock conditions, we could optimize the secretion conditions for both bacteria. PMID- 23653111 TI - Arterial stiffness and walk time in patients with end-stage renal disease. AB - BACKGROUND: End-stage renal disease patients experience increased prevalence of cardiovascular disease. Heart-artery interaction may be shifted, impacting blood pressure lability, and exercise tolerance. The coupling ratio consists of the ratio of indexed arterial elastance (EaI, arterial load) to ElvI, a measure of cardiac contractility or stiffness. Our purpose was to explore the relationship between elastances and functional capacity. We hypothesized that arterial stiffness (central pulse wave velocity, PWV) and elastances would be correlated to shuttle walk time. METHODS: We used applanation tonometry, ultrasonography, and a shuttle walk test to evaluate our hypothesis. Spearman's correlations were used to assess relationships between variables. Block regression was also performed. RESULTS: Forty-two subjects on maintenance hemodialysis participated. Average age=44+/-5 years, body surface area=2.01 kg/m(2). Mean EaI=4.45 and mean ElvI=6.89; the coupling ratio=0.82. Mean aortic pulse pressure=51 mmHg and PWV=9.6 m/s. PWV(r=-0.385) and EaI (r=-0.424) were significantly and inversely related to walking time while stroke volume index (SVI) was positively correlated to shuttle walk time (r=0.337), p<0.05 for all. CONCLUSIONS: We conclude that, like other clinical populations, both arterial and heart function predict walking ability and represent potential targets for intervention; arterial stiffness and SVI are strongly related to shuttle walk time in patients with ESRD. PMID- 23653113 TI - MicroRNA-424-5p suppresses the expression of SOCS6 in pancreatic cancer. AB - MicroRNAs (miRNAs) are a group of small non-coding RNA molecules predicted to control the activity of about 30 % of all protein-coding genes in mammals. The expression of microRNA-424-5p (miR-424-5p) has been shown to vary in multiple hematological and solid organ malignancies, such as pancreatic cancer. This study aimed to characterize the function of upregulated miR-424-5p in pancreatic cancer and show how downstream suppressor of cytokine-induced signaling 6 (SOCS6) is negatively regulated by miR-424-5p. MiR-424-5p and SOCS6 expression was detected using quantitative real-time PCR (qRT-PCR) in pancreatic cancer tissues and adjacent non-tumorous ductal epithelium tissues. Luciferase reporter assays were used to assess SOCS6 as a target of miR-424-5p. The downstream effect of SOCS6 was measured by qRT-PCR after miR-424-5p inhibition and SOCS6 upregulation. The functions of miR-424-5p in vitro in pancreatic cancer cells were measured by migration and invasion assays and flow cytometry. Results suggested miR-424-5p was significantly upregulated in pancreatic cancer and suppress the expression of SOCS6, and miR-424-5p increased proliferation, migration and invasion of pancreatic cancer cells, while inhibited cell apoptosis. It was concluded that miR-424-5p is frequently upregulated in pancreatic cancer and modulates ERK1/2 signaling pathway by negatively regulating SOCS6. PMID- 23653112 TI - A collaborative nationwide lymphoma study in Lebanon: incidence of various subtypes and analysis of associations with viruses. AB - Incidence of various Hodgkin (HL) and non-Hodgkin lymphoma (NHL) subtypes and association with viruses in Lebanon are not known. We undertook a nationwide study of 272 patients diagnosed with lymphoma in 2007. HL comprised 32.7 % (n = 89) of cases while NHL represented 67.3 % (n = 183). Consistent with the literature, nodular sclerosis was the most predominant HL subtype (n = 57/89). Among NHL, B-cell NHL represented 88 % (n = 161/183), T-cell NHL 9 % (n = 17/183), whereas in 2.7 % it was not classifiable. The B-cell NHL comprised predominantly diffuse large B-cell lymphoma (46 %) and follicular lymphoma (23 %). 81 cases were reviewed by a panel of pathologists with 87.6 % concordance rate. Serology was negative for hepatitis C in 122 tested cases. HIV was positive in 2 cases. Two adult T-cell leukemia/lymphoma were HTLV-I positive. EBV IgG were positive in 88.5 % of cases. 38 EBV seropositive cases [27 NHL (24 B-cell, 3 T cell) and 11 HL] were studied for EBV genome expression using EBV-encoded RNA (EBER)-in situ hybridization. EBER expression was positive in 8 (21 %) cases (6 HL, 2 T-cell NHL). The distribution of lymphoma subtypes in Lebanon appears similar to that of Western countries. The high rate of EBV positivity in HL and T cell lymphoma by EBER deserves further investigation. PMID- 23653114 TI - Overexpression of CD73 in prostate cancer is associated with lymph node metastasis. AB - Prostate cancer is the most common malignancy in men in Europe and North America. At present, it is becoming an increasingly common cancer in China. CD73 (ecto-5' nucleotidase) is a glycosylphosphatidylinositol (GPI)-linked 70-kDa cell surface enzyme. It is also broadly expressed in many types of tissues. Recent studies have showed that CD73 is widely expressed on malignancies and is up-regulated in cancerous tissues. Consequently, we analyzed the expression of CD73 in prostate cancer tissue. The expression of the CD73 protein was evaluated by Immunohistochemistry staining in 116 tissue specimens. The expression was further examined by quantitative real-time PCR (qRT-PCR) and Western blot in the same set of patients. The intense cell membrane staining for the CD73 protein was observed. The expression of CD73 in lymph node non-metastasizing prostate cancer tissues can be seen at low levels, and is generally undetectable. RT-PCR and Western blot showed that the expression of CD73 in lymph node metastasizing prostate cancer was higher compared with non-metastasizing ones. These results suggest that CD73 could be considered as a relevant-specific target for molecular therapy of prostate cancer metastasis. PMID- 23653116 TI - Application of a rotating bioreactor consisting of low-cost and ready-to-use medical disposables for in vitro evaluation of the endothelialization efficiency of small-caliber vascular prostheses. AB - The incomplete endothelialization of especially small-caliber vascular prostheses after implantation in patients is a major disadvantage in cardiovascular interventions. The lack of an endothelium leads to the occurrence of thrombosis at the luminal surface of artificial vascular prostheses. Thus, the development of new graft materials and coatings for induction of complete endothelialization on the implant surfaces is a promising approach to improve hemocompatibility and maintain long-term graft patency. In this study, we designed a rotation model to evaluate the early endothelial cell (EC) seeding efficiency of different small caliber vascular devices, such as stents and vascular grafts. The suitability of the designed rotation model for endothelialization studies was investigated by seeding and cultivation of prostheses with ECs followed by scanning electron microscopy. Furthermore, the viability of attached ECs was determined by calcein acetoxymethyl ester (AM) staining. The rotation model consisting of low-cost medical disposables enabled sterile incubation and cultivation of ECs with vascular devices. Simultaneously, the rotation of the bioreactor ensured a uniform distribution and adhesion of cells to the devices. Calcein AM staining of adherent cells on prostheses revealed excellent cell viability. Moreover, using the designed rotation model, an influence of different coatings and materials on the adhesion and spreading of ECs was demonstrated. The rotating bioreactor described and used in this study not only saves time and money but is also eminently useful for the accelerated preclinical evaluation of the endothelialization efficiency of different materials and surface coatings of small-caliber vascular devices. PMID- 23653115 TI - Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. AB - Interleukin-22 (IL-22) is mainly produced at barrier surfaces by T cells and innate lymphoid cells and is crucial to maintain epithelial integrity. However, dysregulated IL-22 action leads to deleterious inflammation and is involved in diseases such as psoriasis, intestinal inflammation, and cancer. IL-22 binding protein (IL-22BP) is a soluble inhibitory IL-22 receptor and may represent a crucial regulator of IL-22. We show both in rats and mice that, in the steady state, the main source of IL-22BP is constituted by a subset of conventional dendritic cells (DCs) in lymphoid and non-lymphoid tissues. In mouse intestine, IL-22BP was specifically expressed in lamina propria CD103(+)CD11b(+) DC. In humans, IL-22BP was expressed in immature monocyte-derived DC and strongly induced by retinoic acid but dramatically reduced upon maturation. Our data suggest that a subset of immature DCs may actively participate in the regulation of IL-22 activity in the gut by producing high levels of IL-22BP. PMID- 23653117 TI - The efficacy of autologous platelet-rich plasma combined with erbium fractional laser therapy for facial acne scars or acne. AB - The aim of this study was to evaluate the efficacy of autologous platelet-rich plasma (PRP) combined with erbium fractional laser therapy for facial acne or acne scars. PRP combined with erbium fractional laser therapy was used for the treatment of 22 patients, including 16 patients who suffered from facial acne scars and 6 patients who suffered from acne scars concomitant with acne. Whole blood (40 ml) was collected from each patient, and following differential centrifugation, PRP was harvested. After using an erbium fractional laser, we applied PRP to the entire face of every patient. Digital photos were taken before and after the treatment for evaluation by dermatologists and the patients rated the efficacy on a 5-point scale. The erythema was moderate or mild, while its total duration was <3 days; after receiving the treatment three times, 90.9% of the patients showed an improvement of >50%, and 91% of the patients were satisfied; no acne inflammation was observed after treatment. PRP combined with erbium fractional laser therapy is an effective and safe approach for treating acne scars or acne, with minimal side-effects, and it simultaneously enhanced the recovery of laser-damaged skin. PMID- 23653118 TI - Heavy metal concentrations in surficial and core sediments from Izmir Bay: an assessment of contamination and comparison against sediment quality benchmarks. AB - The levels of heavy metals were determined in surface and core sediments from the Izmir Bay in 2009. The highest concentrations of As, Cr, Cu, Ni, Pb and Zn were found in the inner bay due to industrial activities. In contrast, maximum levels of Mn, Co, Fe and Al were observed in the outer bay, due to geochemical structure. Cu, Pb, Zn, Ni, As, Cr and Co levels in the upper layer of core sediments were higher than the mean background values of bottom sediments. The enrichment of Cr, Mn, Pb, Zn, Cu and As in the bay seems to be driven by anthropogenic sources. It was found that the sediments in Izmir Inner Bay were generally polluted heavily with Cu, As, Ni, Cr, Pb and moderately with Zn according to the numerical Sediment quality guidelines of the USEPA. PMID- 23653119 TI - Cryptococcus lacticolor sp. nov. and Rhodotorula oligophaga sp. nov., novel yeasts isolated from the nasal smear microbiota of Queensland koalas kept in Japanese zoological parks. AB - A total of 515 yeast strains were isolated from the nasal smears of Queensland koalas and their breeding environments in Japanese zoological parks between 2005 and 2012. The most frequent species in the basidiomycetous yeast biota isolated from koala nasal passages was Cryptococcus neoformans, followed by Rhodotorula minuta. R. minuta was the most frequent species in the breeding environments, while C. neoformans was rare. Seven strains representing two novel yeast species were identified. Analyses of the 26S rDNA (LSU) D1/D2 domain and nuclear ribosomal DNA internal transcribed spacer region sequences indicated that these strains represent new species with close phylogenetic relationships to Cryptococcus and Rhodotorula. A sexual state was not found for either of these two novel yeasts. Key phenotypic characters confirmed that these strains could be placed in Cryptococcus and Rhodotorula. The names Cryptococcus lacticolor sp. nov. (type strain TIMM 10013(T) = JCM 15449(T) = CBS 10915(T) = DSM 21093(T), DDBJ/EMBL/Genbank Accession No.; AB375774 (ITS) and AB375775 (26S rDNA D1/D2 region), MycoBank ID; MB 802688, Fungal Barcoding Database ID; 3174), and Rhodotorula oligophaga sp. nov. (type strain TIMM 10017(T) = JCM 18398(T) = CBS 12623(T) = DSM 25814(T), DDBJ/EMBL/Genbank Accession No.; AB702967 (ITS) and AB702967 (26S rDNA D1/D2 region), MycoBank ID; MB 802689, Fungal Barcoding Database ID; 3175) are proposed for these new species. PMID- 23653120 TI - Microlunatus cavernae sp. nov., a novel actinobacterium isolated from Alu ancient cave, Yunnan, South-West China. AB - A Gram-positive, coccoid, non-endospore-forming actinobacterium, designated YIM C01117(T), was isolated from a soil sample collected from Alu ancient cave, Yunnan province, south-west China. Based on the 16S rRNA gene sequence analysis, strain YIM C01117(T) was shown to belong to the genus Microlunatus, with highest sequence similarity of 97.4 % to Microlunatus soli DSM 21800(T). The whole genomic DNA relatedness as shown by the DNA-DNA hybridization study between YIM C01117(T) and M. soli DSM 21800(T) had a low value (47 +/- 2 %). Strain YIM C01117(T) was determined to contain LL-diaminopimelic acid with Gly, Glu and Ala amino acids (A3gamma' type) in the cell wall. Whole-cell hydrolysates were found to contain glucose, galactose, mannose and ribose. The major polar lipids were determined to be phosphatidylglycerol and diphosphatidylglycerol. The predominant menaquinone system present is MK-9(H4), while the major fatty acids were identified to be anteiso-C15:0 (24.1 %), iso-C16:0 (22.3 %) and iso-C15:0 (11.4 %). The G+C content of the genomic DNA was determined to be 65.9 mol%. The chemotaxonomic and genotypic data support the affiliation of the strain YIM C01117(T) to the genus Microlunatus. The results of physiological and biochemical tests allow strain YIM C01117(T) to be differentiated phenotypically from recognized Microlunatus species. Strain YIM C01117(T) is therefore considered to represent a novel species of the genus Microlunatus, for which the name Microlunatus cavernae sp. nov. is proposed. The type strain is YIM C01117(T) (= DSM 26248(T) = JCM 18536(T)). PMID- 23653121 TI - Paracoccus zhejiangensis sp. nov., isolated from activated sludge in wastewater treatment system. AB - A bacterial strain, designated J6(T), was isolated from activated sludge, collected from a chemical wastewater treatment system in Zhejiang Province of China. The cells stained Gram-negative, were aerobic, pale-yellow, and non-motile short rods. Phylogenetic analysis of the 16S rRNA gene sequence indicated that the closest relative of this organism was Paracoccus aminophilus KACC 12262(T) = JCM 7686(T) (97.4 % sequence similarity). Strain J6(T) grew at 10-37 degrees C (optimum 30 degrees C), at pH 6.0-8.0 (optimum pH 7.0) and with 0-5 % NaCl (optimum 3 %, w/v). The predominant cellular fatty acid found was summed feature 8(C18:1 omega7c and/or C18:1 omega6c; 82.8 %). The major respiratory quinone detected was Q-10 and the DNA G+C content was 61.9 mol %. The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine and several unknown polar lipids. Strain J6(T) showed low DNA-DNA relatedness values with P. aminophilus KACC 12262(T) (28 +/- 3 %). The phylogenetic analysis, DNA-DNA hybridization, whole cell fatty acid composition as well as biochemical characteristics allowed clear differentiation of the isolate from the other type strains of already described Paracoccus species. It is evident from the genotypic, phenotypic and chemotaxonomic analyses that strain J6(T) should be classified as a novel species of the genus Paracoccus, for which the name P. zhejiangensis sp. nov. is proposed. The type strain is J6(T) (KACC 16703(T) = CCTCC AB 2012031(T)). PMID- 23653122 TI - Assessment of key biological and engineering design parameters for production of Chlorella zofingiensis (Chlorophyceae) in outdoor photobioreactors. AB - For the design of a large field of vertical flat plate photobioreactors (PBRs), the effect of four design parameters-initial biomass concentration, optical path length, spacing, and orientation of PBRs-on the biochemical composition and productivity of Chlorella zofingiensis was investigated. A two-stage batch process was assumed in which inoculum is generated under nitrogen-sufficient conditions, followed by accumulation of lipids and carbohydrates in nitrogen deplete conditions. For nitrogen-deplete conditions, productivity was the most sensitive to initial biomass concentration, as it affects the light availability to individual cells in the culture. An initial areal cell concentration of 50 g m(-2) inoculated into 3.8-cm optical path PBR resulted in the maximum production of lipids (2.42 +/- 0.02 g m(-2) day(-1)) and carbohydrates (3.23 +/- 0.21 g m( 2) day(-1)). Productivity was less sensitive to optical path length. Optical path lengths of 4.8 and 8.4 cm resulted in similar areal productivities (biomass, carbohydrate, and lipid) that were 20 % higher than a 2.4-cm optical path length. Under nitrogen-sufficient conditions, biomass productivity was 48 % higher in PBRs facing north-south during the winter compared to east-west, but orientation had little influence on biomass productivity during the spring and summer despite large differences in insolation. An optimal spacing could not be determined based on growth alone because a tradeoff was observed in which volumetric and PBR productivity increased as space between PBRs increased, but land productivity decreased. PMID- 23653123 TI - Discovery of (hemi-) cellulase genes in a metagenomic library from a biogas digester using 454 pyrosequencing. AB - In this study, 341, 246, and 386 positive clones with endo-beta-1,4-glucanase, beta-glucosidase, and endo-beta-1,4-xylanase activities, respectively, were identified by screening from a metagenomic fosmid library constructed from a biogas digester. Subsequently, pools of 4, 10, and 16 positive clones were subjected to 454 pyrosequencing in different subruns. In total, 21 unique glycosyl hydrolase (GH) genes were predicted by bioinformatic analysis, which showed similarities to their nearest neighbors from 39 % to 72 %. In addition to bioinformatics prediction, nine GH genes were expressed and purified to identify their activity with four kinds of substrates. The activities of the most expressed proteins were consistent with their annotation based on bioinformatics prediction; however, three GH genes belonging to the GH5 family showed different activities from their annotation. An efficient acidic cellulase En1 had an optimal condition at 55 degrees C, pH 5.5, with a specific activity toward carboxymethylcellulose at 118 U/mg and K m at 12.8 g/L. This study demonstrated that there are diverse GHs in the biogas digester system with potential industrial application in lignocellulose hydrolysis, and their activities should be investigated with different substrates before their application. Additionally, pool sequencing of positive fosmid clones might be a cost-effective approach to obtain functional genes from metagenomic libraries. PMID- 23653124 TI - The quantity and quality of dissolved organic matter as supplementary carbon source impacts the pesticide-degrading activity of a triple-species bacterial biofilm. AB - Effects of environmental dissolved organic matter (eDOM) that consists of various low concentration carbonic compounds on pollutant biodegradation by bacteria are poorly understood, especially when it concerns synergistic xenobiotic-degrading consortia where degradation depends on interspecies metabolic interactions. This study examines the impact of the quality and quantity of eDOM, supplied as secondary C-source, on the structure, composition and pesticide-degrading activity of a triple-species bacterial consortium in which the members synergistically degrade the phenylurea herbicide linuron, when grown as biofilms. Biofilms developing on 10 mg L-1 linuron showed a steady-state linuron degradation efficiency of approximately 85 %. The three bacterial strains co localized in the biofilms indicating syntrophic interactions. Subsequent feeding with eDOM or citrate in addition to linuron resulted into changes in linuron degrading activity. A decrease in linuron-degrading activity was especially recorded in case of co-feeding with citrate and eDOM of high quality and was always associated with accumulation of the primary metabolite 3,4 dichloroaniline. Improvement of linuron degradation was especially observed with more recalcitrant eDOM. Addition of eDOM/citrate formulations altered biofilm architecture and species composition but without loss of any of the strains and of co-localization. Compositional shifts correlated with linuron degradation efficiencies. When the feed was restored to only linuron, the linuron-degrading activity rapidly changed to the level before the mixed-substrate feed. Meanwhile only minor changes in biofilm composition and structure were recorded, indicating that observed eDOM/citrate effects had been primarily due to repression/stimulation of linuron catabolic activity rather than to biofilm characteristics. PMID- 23653125 TI - Purification of recombinant catalase-peroxidase HPI from E. coli and its application in enzymatic polymerization reactions. AB - In this paper, a recombinant catalase-peroxidase HPI from Escherichia coli was prepared, purified, and used in enzymatic polymerization reactions for the production of several oligomeric products. We tested the enzyme on four different substrates, chosen as representative of phenols and anilines: phenol, 3 methoxyphenol, catechol, and aniline. The polymerization reactions were followed by SEC-HPLC analysis, and except for aniline, all the other substrates were completely converted into one or more polymerization products. Results showed that reactions performed with phenol and 3-methoxyphenol allowed the isolation of some oligomers of different weight: a 27-monomeric unit oligomer and a 23-U oligomer are the heaviest ones. Experiments performed with catechol showed the formation of oligomers of 7 U in the reaction with HPI. HPI polymerization reactions performed with aniline allowed the identification of two different oligomers, one of 4 U and one of 10 U. All the substrates have been also used in reactions catalyzed by HRP in the same reaction conditions. Several products were common to the two enzymes. This work suggests the use of HPI as an alternative enzyme in peroxidatic reactions for the production of different oligomers from phenols and other compounds. PMID- 23653126 TI - Highly luminescent material based on Alq3:Ag nanoparticles. AB - Tris (8-hydroxyquinoline) aluminum (Alq3) is an organic semiconductor molecule, widely used as an electron transport layer, light emitting layer in organic light emitting diodes and a host for fluorescent and phosphorescent dyes. In this work thin films of pure and silver (Ag), cupper (Cu), terbium (Tb) doped Alq3 nanoparticles were synthesized using the physical vapor condensation method. They were fabricated on glass substrates and characterized by X-ray diffraction, scanning electron microscope (SEM), energy dispersive spectroscopy, atomic force microscope (AFM), UV-visible absorption spectra and studied for their photoluminescence (PL) properties. SEM and AFM results show spherical nanoparticles with size around 70-80 nm. These nanoparticles have almost equal sizes and a homogeneous size distribution. The maximum absorption of Alq3 nanoparticles is observed at 300 nm, while the surface plasmon resonant band of Ag doped sample appears at 450 nm. The PL emission spectra of Tb, Cu and Ag doped Alq3 nanoparticles show a single broad band at around 515 nm, which is similar to that of the pure one, but with enhanced PL intensity. The sample doped with Ag at a concentration ratio of Alq3:Ag = 1:0.8 is found to have the highest PL intensity, which is around 2 times stronger than that of the pure one. This enhancement could be attributed to the surface plasmon resonance of Ag ions that might have increased the absorption and then the quantum yield. These remarkable result suggest that Alq3 nanoparticles incorporated with Ag ions might be quite useful for future nano-optoelectronic devices. PMID- 23653127 TI - Two highly sensitive and selective colorimetric "off-on" rhodamine-based fluorescent chemosensor for Hg(II) in aqueous media. AB - Two novel rhodamine derivatives were designed and synthesized. They were successfully characterized by HR-MS, (1)H NMR and (13)C NMR. They were found to exhibit a reversible colorimetric response and exhibit high selectivity and sensitivity for Hg(II) ion over other commonly coexistent metal ions. Their selectivity is excellent, and the detection of Hg(II) at ppb level is possible. The colorimetric and fluorescent response to Hg(II) can be conveniently detected even by the naked eye, which provides a facile method for visual detection of Hg(II). PMID- 23653128 TI - Foraging for thought: an inhibition-of-return-like effect resulting from directing attention within working memory. AB - Perceptual processing of a target stimulus may be inhibited if its location has just been cued, a phenomenon of spatial attention known as inhibition of return (IOR). In the research reported here, we demonstrated a striking effect, wherein items that have just been the focus of reflective attention (internal attention to an active representation) also are inhibited. Participants saw two items, followed by a cue to think back to (i.e., refresh, or direct reflective attention toward) one item, and then had to identify either the refreshed item, the unrefreshed item, or a novel item. Responses were significantly slower for refreshed items than for unrefreshed items, although refreshed items were better remembered on a later memory test. Control experiments in which we replaced the refresh event with a second presentation of one of the words did not show similar effects. These results suggest that reflective attention can produce an inhibition effect for attended items that may be analogous to IOR effects in perceptual attention. PMID- 23653129 TI - Maternal stress and infant mortality: the importance of the preconception period. AB - Although preconception and prenatal maternal stress are associated with adverse outcomes in birth and childhood, their relation to infant mortality remains uncertain. We used logistic regression to study infant mortality risk following maternal stress within a population-based sample of infants born in Sweden between 1973 and 2008 (N = 3,055,361). Preconception (6-0 months before conception) and prenatal (between conception and birth) stress were defined as death of a first-degree relative of the mother. A total of 20,651 offspring were exposed to preconception stress, 26,731 offspring were exposed to prenatal stress, and 8,398 cases of infant mortality were identified. Preconception stress increased the risk of infant mortality independently of measured covariates, and this association was timing specific and robust across low-risk groups. Prenatal stress did not increase risk of infant mortality. These results suggest that the period immediately before conception may be a sensitive developmental period with ramifications for infant mortality risk. PMID- 23653130 TI - Effect of total disc replacement on atypical symptoms associated with cervical spondylosis. AB - PURPOSE: To determine the efficacy of total disc replacement (TDR) for the treatment of cervical spondylosis associated with atypical symptoms. METHODS: In this retrospective study, patients with myelopathy and/or radiculopathy related to cervical spondylosis that were treated with TDR were contacted by phone. Atypical symptoms involved in the questionnaire included dizziness, headache, nausea, vomiting, blurred vision, tinnitus, palpitations, hypomnesia, and abdominal discomfort. The severity of each atypical symptom was evaluated separately based on an numerical rating scale. The radiographs and charts before and after the surgery were reviewed. Paired samples t tests were used to compare the severity of the symptoms before and after surgery. RESULTS: Between 2003 and 2010, 73 of 133 patients diagnosed with cervical spondylotic myelopathy and/or radiculopathy treated by TDR experienced atypical symptoms before surgery. The mean follow-up was 34.6 months. There were 47 males and 26 females (mean age 48.9 years). Of the 73 patients, 41 were diagnosed with myelopathy; 13 with radiculopathy; and 19 with mixed-type spondylosis. The incidence of each symptom before surgery was dizziness (46.6%), tinnitus (41.1 %), facial flushing and sweating (41.1 %), palpitations (39.7%), headache (35.6%), hypomnesia (30.1%), nausea and vomiting (20.5%), blurred vision (20.5%), and gastroenterologic discomfort (5.5%). The severity of the following symptoms improved after surgery: dizziness (p = 0.000, alpha = 0.05), headache (p = 0.000, alpha = 0.05), nausea and vomiting (p = 0.000, alpha = 0.05), blurred vision (p = 0.004, alpha = 0.05), tinnitus (p = 0.000, alpha = 0.05), palpitations (p = 0.000, alpha = 0.05), hypomnesia (p = 0.010, alpha = 0.05), and other symptoms (p = 0.030, alpha = 0.05). The gastroenterologic discomfort did not improve (p = 0.731, alpha = 0.05). CONCLUSIONS: TDR may have a positive effect on atypical symptoms associated with cervical spondylotic myelopathy and/or radiculopathy. PMID- 23653131 TI - Precision of estimates of local stability of repetitive trunk movements. AB - PURPOSE: Local dynamic stability of trunk movements quantified by means of the maximum Lyapunov exponent (lambdamax) can provide information on trunk motor control and might offer a measure of trunk control in low-back pain patients. It is unknown how many repetitions are necessary to obtain sufficiently precise estimates of lambdamax and whether fatigue effects on lambdamax can be avoided while increasing the number of repetitions. METHOD: Ten healthy subjects performed 100 repetitions of trunk movements in flexion, of trunk rotation and of a task combining these movement directions. lambdamax was calculated from thorax, pelvis and trunk (thorax relative to pelvis) kinematics. Data series were analyzed using a bootstrap procedure; ICC and coefficient of variation were used to quantify precision as a function of the number of cycles analyzed. ANOVA was used to compare movement tasks and to test for effects of time. RESULTS: Trunk local stability reached acceptable precision level after 30 repetitions. lambdamax was higher (indicating lower stability) in flexion, compared to rotation and combined tasks. There was no time effect (fatigue). lambdamax of trunk movement was lower and less variable than that of thorax and pelvis movements. CONCLUSIONS: The data provided allow for an informed choice of the number of repetitions in assessing local dynamic stability of trunk movements, weighting the gain in precision against the increase in measurement effort. Within the 100 repetitions tested, fatigue did not affect results. We suggest that increased stability during asymmetric movement may be explained by higher co activation of trunk muscles. PMID- 23653132 TI - Do physical activity level and body mass index predict recovery from persistent neck pain in men and women of working age? A population-based cohort study. AB - PURPOSE: The study sought to examine the gender-specific effects of physical activity level and body mass index on recovery from persistent neck pain (PNP) among citizens of working age in Stockholm, Sweden. METHODS: A population-based cohort of 1,730 subjects (18-65) with PNP answered surveys in 2002 and 2007. Prognostic factors were self-reported body mass index (BMI) and physical activity level (PAL) at baseline. Analyses were performed with odds ratios (OR) with corresponding 95 % confidence intervals (95 % CI). RESULTS: Women reporting higher physical activity level had higher odds of recovering from PNP than women with sedentary leisure time (OR of 1.5, 95 % CI 1.0-2.4), but no associations were found in men. No associations were found between BMI and recovery from PNP in any analyses. CONCLUSION: Physical activity seems to be associated with recovery from PNP in women and should therefore be encouraged. Future studies should continue investigating physical activity and lifestyle factors in relation to recovery from persistent neck pain, since these modifiable factors may be considered in interventions. PMID- 23653133 TI - Effect of pilot hole on biomechanical and in vivo pedicle screw-bone interface. AB - PURPOSE: To experimentally study the influence of pilot hole diameter (smaller than or equal to the internal (core) diameter of the screw) on biomechanical (insertion torque and pullout strength) and histomorphometric parameters of screw bone interface in the acute phase and 8 weeks after pedicle screw insertion. METHODS: Fifteen sheep were operated upon and pedicle screws inserted in the L1 L3 pedicles bilaterally. The pilot hole was smaller (2.0 mm) than the internal diameter (core) of the screw on the left side pedicle and equal (2.8 mm) to the internal diameter (core) of the screw on the right side pedicle. Ten animals were sacrificed immediately (five animals were assigned to pullout strength tests and five animals were used for histomorphometric bone-screw interface evaluation). Five animals were sacrificed 8 weeks after pedicle screw insertion for histomorphometric bone-screw interface evaluation. RESULTS: The insertion torque and pullout strength were significantly greater in pedicle screws inserted into pilot holes smaller than internal (core) diameter of the screw. Histomorphometric evaluation of bone-screw interface showed that the percentage of bone-implant contact, the area of bone inside the screw thread and the area of bone outside the screw thread were significantly higher for pilot holes smaller than the internal (core) diameter of the screw immediately after insertion and after 8 weeks. CONCLUSION: A pilot diameter smaller than the internal (core) diameter of the screw improved the insertion torque and pullout strength immediately after screw insertion as well the pedicle screw-bone interface contact immediately and 8 weeks after screw placement in sheep with good bone mineral density. PMID- 23653134 TI - Mechanism of the phospha-Wittig-Horner reaction. PMID- 23653135 TI - Run wild, run free. PMID- 23653136 TI - Who's to blame for overcrowding in accident and emergency departments? PMID- 23653137 TI - Have you heard the one about the man with Alzheimer's disease? PMID- 23653138 TI - Minimum alcohol pricing delivers health benefits without penalising moderate drinkers, finds analysis. PMID- 23653139 TI - Carbon nanotubes-based label-free affinity sensors for environmental monitoring. AB - Nanostructures, such as nanowires, nanobelts, nanosprings, and nanotubes, are receiving growing interest as transducer elements of bio/chemical sensors as they provide high sensitivity, multiplexing, small size, and portability. Single walled carbon nanotubes (SWNTs) are one such class of nanostructure materials that exhibit superior sensing behavior due to its large-surface carbon atoms that are highly responsive to surface adsorption events. Further, their compatibility with modern microfabrication technologies and facile functionalization with molecular recognition elements make them promising candidates for bio/chemical sensors applications. Here, we review recent results on nanosensors based on SWNTs modified with biological receptors such as aptamers, antibodies, and binding proteins, to develop highly sensitive, selective, rapid, and cost effective label-free chemiresistor/field-effect transistor nanobiosensors for applications in environmental monitoring. PMID- 23653140 TI - Engineering plant alternative oxidase function in mammalian cells: substitution of the motif-like sequence ENV for QDT diminishes catalytic activity of Arum concinnatum AOX1a expressed in HeLa cells. AB - Alternative oxidase (AOX) is a nonproton motive quinol-oxygen oxidoreductase which is a component of the mitochondrial respiratory chain in higher plants. In this study, we have characterized the catalytic activity and regulatory behaviors of Arum concinnatum AOX isoforms, namely AcoAOX1a and AcoAOX1b, and their artificial mutants in HeLa cells. We demonstrated that substitution of the motif like sequence ENV on the C-terminal half of AcoAOX1a for QDT diminishes its activity and proposed that the innate inactivity of AcoAOX1b in HeLa cells is, at least in part, attributable to its QDT motif. Furthermore, we show that introduction of F130L in the hydrophilic N-terminal extension of AcoAOX1a resulted in greater activity in the presence of pyruvate. This result indicates that functional significance of the N-terminal extension is not particular to the conventional regulatory cysteine. On the basis of these findings, we discuss new insights into the structural integrity of AOX in HeLa cells and the applicability of mammalian cells for functional analysis of this enzyme. PMID- 23653141 TI - Posterior cerebral artery involvement in moyamoya disease: initial infarction and angle between PCA and basilar artery. AB - PURPOSE: Moyamoya disease (MMD) is a chronic cerebrovascular occlusive disease, and progressive involvement of the posterior cerebral artery (PCA) has been reported. However, majority of MMD articles are presenting classic anterior circulation related issues. This study investigates the preoperative factors related to the long-term outcome of posterior circulation in MMD. METHODS: Retrospective review of 88 MMD patients (166 PCAs in either hemisphere) without symptomatic disease involvement of PCA at initial diagnosis was done. Data at initial diagnosis regarding age, presence of infarction, status of the PCA, type of posterior communicating artery, and the angle between PCA and basilar artery were reviewed. Progressive stenosis of PCA was evaluated by symptom or radiological imaging during follow up. RESULTS: During an average follow up of 8.3 years, 29 out of 166 (18 %) evaluated PCAs showed progressive disease involvement. The average time of progression from the initial operation was 4.9 years, with the latest onset at 10.8 years. The patients who showed progressive stenosis of the PCA tended to be younger, present with infarction, have smaller angle between PCA and basilar artery, and have asymptomatic stenosis of the PCA at initial presentation. However, multivariate analysis confirmed only the presence of initial infarction and a smaller angle between PCA and basilar artery to be significantly associated with progressive stenosis of PCA. CONCLUSIONS: Involvement of PCA in MMD may occur in a delayed fashion, years after the completion of revascularization of anterior circulation. Persistent long-term follow-up regarding the posterior circulation is recommended. PMID- 23653142 TI - Communicating syringomyelia associated with ventriculoperitoneal shunt malfunction verified with a cerebrospinal fluid dynamic study: case report. AB - HISTORY: A 20-year-old male presented with neck pain and motor impairment of the upper extremities because of recurrent syringomyelia caused by ventriculoperitoneal shunt malfunction. EXAMINATION AND OPERATION: A computed tomography scan after shuntgraphy demonstrated opacity in the intracranial ventricular system and cervical syrinx with contrast medium, which indicated communication between the fourth ventricle and syrinx. His symptoms resolved immediately after peritoneal catheter replacement, and magnetic resonance images obtained 1 week after surgery showed the complete resolution of hydrocephalus and syringomyelia. CONCLUSION: Syringomyelia associated with ventriculoparitoneal shunt malfunction is a well-known complication in myelodysplastic patients; however, this is the first case in which communicating syringomyelia was verified with a cerebrospinal fluid dynamic study. As the present case involved communicating syringomyelia, it could only be resolved by shunt revision surgery. PMID- 23653143 TI - Factors associated with caregiver readiness to use nonpharmacologic strategies to manage dementia-related behavioral symptoms. AB - BACKGROUND: Nonpharmacologic strategies to manage dementia-related behavioral symptoms depend upon caregiver implementation. Caregivers may vary in readiness to use strategies. We examined characteristics associated with readiness, extent readiness changed during intervention, and predictors of change in readiness. METHODS: Data came from a randomized trial involving 119 caregivers in a nonpharmacologic intervention for managing behavioral symptoms. Baseline measures included caregiver, patient, and treatment-related factors. At initial (2 weeks from baseline) and final (16 weeks) intervention sessions, interventionists rated caregiver readiness as pre-action (precontemplation = 1; contemplation = 2; preparation = 3) or action (= 4). Ordinal logistic regression identified baseline characteristics associated with initial readiness. Mc Nemar-Bowker test of symmetry described change in readiness; binary logistic regression identified baseline predictors of change in readiness (initial to final sessions). One-way multivariate analysis of variance identified treatment factors (dose/intensity, number of strategies used, perceived benefits, and therapeutic engagement) associated with change in readiness. RESULTS: At initial intervention session, 67.2% (N = 80) of caregivers were in pre-action and 32.8% (N = 39) in action. Initial high readiness was associated with better caregiver mood, less financial difficulty, lower patient cognition, and more behavioral symptoms. By final session, 72% (N = 79) were in action and 28% (N = 31) in pre-action; caregivers with less financial difficulty improved in readiness (B = -0.70, p = 0.017); those in action were more therapeutically engaged (F[2,107] = 3.61, p = 0.030) and perceived greater intervention benefits (F[2, 88] = 6.06, p = 0.003). CONCLUSION: Whereas patient and caregiver-related factors were associated with initial readiness, financial stability, therapeutic engagement, and perceived benefits enhanced probability of change. Understanding caregiver readiness and factors associated with its change may be important considerations in nonpharmacologic interventions. PMID- 23653144 TI - The future of U.S. psychiatric education (according to Sisyphus). PMID- 23653145 TI - Confirmation of reported aspirin use in community studies: utility of serum thromboxane B2 measurement. AB - Aspirin (ASA) is recommended for the prevention of cardiovascular disease; however, the compliance is low. Reported use may not reflect actual use. Serum thromboxane B2 (STxB2) measurement was evaluated to validate reported ASA use. Males aged 45 to 79 years and females aged 55 to 79 years completed a survey and STxB2 measurement (Thromboxane B2 EIA Kit; Cayman Chemical, Ann Arbor, Michigan). The 107 patients were grouped by use of ASA (56 ASA+ and 51 ASA-) and possible interfering medications (INT) such as nonsteroidal anti-inflammatory drugs. The STxB2 levels (ng/mL) were significantly lower in ASA users: ASA+ INT- 3.0 (0.7, 8.4), ASA+ INT+ 2.0 (0.8, 4.9), ASA- INT+ 176 (75, 390), and ASA- INT- 271 (199, 366). The INT use did not cause a significant difference in STxB2 levels. A STxB2 cut point of 25 ng/mL had high sensitivity (94.1%) and specificity (91.1%) for ASA use. The STxB2 was a reliable marker of ASA use and could be used to confirm ASA exposure in population-based health studies. PMID- 23653146 TI - Relationship between neutrophil-to-lymphocyte ratio and saphenous vein graft disease in patients with coronary bypass. AB - PURPOSE: In this study, we aimed to investigate the relationship between saphenous vein graft disease (SVGD) and neutrophil-to-lympocyte ratio (NLR) with other possible confounding factors. METHODS: A total of 120 patients were enrolled into the present study. Of all participants, 40 patients were with SVGD and 80 of them were with patent SVG. RESULTS: The NLR, white blood cell (WBC) count, age of SVG, red cell distribution width (RDW), and mean platelet volume were significantly higher in the SVGD group. In regression analysis, NLR, WBC, RDW, and age of SVG remained as independent predictors of SVGD. CONCLUSION: To our knowledge, we showed for the first time that NLR is independently associated with SVGD. It can be easily used in this era, because it is easily available, widely used, and relatively cheap. Besides NLR, WBC count, SVG age, and RDW can also be used to predict SVGD. PMID- 23653147 TI - Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study. AB - PURPOSE: Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction. EXPERIMENTAL DESIGN: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used. RESULTS: Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0-24)] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. CONCLUSIONS: In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day. PMID- 23653150 TI - Nonlinear optical response and biological applications of a series of pyrimidine based molecules for copper(II) ion probe. AB - Biological metal detecting, small molecule probes bearing nonlinear optical (NLO) response provide powerful alternatives due to their favorable photophysical properties (e.g. excitation wavelength in the near-IR region), cell permeability (due to their size), and chemical structure flexibility. Here, we present a series of pyrimidine-based NLO biological metal probes, especially a novel copper specific one which taken into account of the small volume-scaled and low cost scaled nonlinear optical response of TPP and TPP-Cu(2+) discussed in our present work. The photophysical properties of the probes were thoroughly investigated. (1)H NMR and theoretical computation prove the binding interaction between the probe and the copper ion, which supports the functions of the molecule as a fluorescence signaling unit showing strong fluorescence quenching upon copper metal ion binding. On the other hand, the two-photon absorption cross-section of the novel copper probe increased from 275 to 591 GM (lambda(ex) = 830 nm) after interacting with copper ion. It was further demonstrated that the NLO response for the copper(ii) ion probe could be used for biological copper detection in live cells. PMID- 23653149 TI - A randomized phase II trial of multiepitope vaccination with melanoma peptides for cytotoxic T cells and helper T cells for patients with metastatic melanoma (E1602). AB - PURPOSE: This multicenter randomized trial was designed to evaluate whether melanoma helper peptides augment cytotoxic T lymphocyte (CTL) responses to a melanoma vaccine and improve clinical outcome in patients with advanced melanoma. EXPERIMENTAL DESIGN: One hundred seventy-five patients with measurable stage IV melanoma were enrolled into 4 treatment groups, vaccinated with 12 MHC class I restricted melanoma peptides to stimulate CTL (12 MP, group A), plus a tetanus peptide (group B), or a mixture of 6 melanoma helper peptides (6 MHP, group C) to stimulate helper T lymphocytes (HTL), or with 6 melanoma helper peptide (6 MHP) alone (group D), in incomplete Freund's adjuvant plus granulocyte macrophage colony-stimulating factor. CTL responses were assessed using an in vitro stimulated IFN-gamma ELIspot assay, and HTL responses were assessed using a proliferation assay. RESULTS: In groups A to D, respectively, CTL response rates to 12 melanoma peptides were 43%, 47%, 28%, and 5%, and HTL response rates to 6 MHP were in 3%, 0%, 40%, and 41%. Best clinical response was partial response in 7 of 148 evaluable patients (4.7%) without significant difference among study arms. Median overall survival (OS) was 11.8 months. Immune response to 6 MHP was significantly associated with both clinical response (P = 0.036) and OS (P = 0.004). CONCLUSION: Each vaccine regimen was immunogenic, but MHPs did not augment CTL responses to 12 melanoma peptides. The association of survival and immune response to 6 MHP supports further investigation of helper peptide vaccines. For patients with advanced melanoma, multipeptide vaccines should be studied in combination with other potentially synergistic active therapies. PMID- 23653151 TI - Exercise in the prevention and rehabilitation of breast cancer. AB - Breast cancer is the most common type of cancer among women worldwide. Several epidemiological studies have shown an inverse relationship between the risk of breast cancer and physical activity levels, whereas exercise training has been recognized as a significant means in the rehabilitation process of breast cancer survivors. The relative risk reduction of breast cancer for women who engaged in moderate to vigorous physical activity for 3-5 days peek week ranged between 20 40 %. Furthermore, several studies demonstrated a 24-67 % reduction in the risk of total deaths and 50-53 % reduction in the risk of breast cancer deaths in women who are physically active after breast cancer diagnosis compared with sedentary women. Breast cancer survivors should be encouraged to participate in rehabilitation programs in order to obtain numerous physiological and psychological benefits. These include reductions in fatigue and improvements in immune function, physical functioning, body composition, and quality of life. Based on recent scientific evidence, a complete rehabilitation program for patients with breast cancer should combine both strength and aerobic exercise in order to maximize the expected benefits. PMID- 23653148 TI - Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. AB - PURPOSE: To determine the role of the CCL2/CCR2 axis and inflammatory monocytes (CCR2(+)/CD14(+)) as immunotherapeutic targets in the treatment of pancreatic cancer. EXPERIMENTAL DESIGN: Survival analysis was conducted to determine if the prevalence of preoperative blood monocytes correlates with survival in patients with pancreatic cancer following tumor resection. Inflammatory monocyte prevalence in the blood and bone marrow of patients with pancreatic cancer and controls was compared. The immunosuppressive properties of inflammatory monocytes and macrophages in the blood and tumors, respectively, of patients with pancreatic cancer were assessed. CCL2 expression by human pancreatic cancer tumors was compared with normal pancreas. A novel CCR2 inhibitor (PF-04136309) was tested in an orthotopic model of murine pancreatic cancer. RESULTS: Monocyte prevalence in the peripheral blood correlates inversely with survival, and low monocyte prevalence is an independent predictor of increased survival in patients with pancreatic cancer with resected tumors. Inflammatory monocytes are increased in the blood and decreased in the bone marrow of patients with pancreatic cancer compared with controls. An increased ratio of inflammatory monocytes in the blood versus the bone marrow is a novel predictor of decreased patient survival following tumor resection. Human pancreatic cancer produces CCL2, and immunosuppressive CCR2(+) macrophages infiltrate these tumors. Patients with tumors that exhibit high CCL2 expression/low CD8 T-cell infiltrate have significantly decreased survival. In mice, CCR2 blockade depletes inflammatory monocytes and macrophages from the primary tumor and premetastatic liver resulting in enhanced antitumor immunity, decreased tumor growth, and reduced metastasis. CONCLUSIONS: Inflammatory monocyte recruitment is critical to pancreatic cancer progression, and targeting CCR2 may be an effective immunotherapeutic strategy in this disease. PMID- 23653152 TI - Infective endocarditis caused by Cellulomonas spp. in an intravenous drug user: case report. AB - Cellulomonas spp. are often believed to be of low virulence. There are only a few reports of human infections. We report the first case of endocarditis caused by Cellulomonas in an intravenous drug abuser. The diagnosis of infective endocarditis (IE) in this case was definite using the Duke criteria. The course of the disease was complicated with a heart failure and possible mycotic aneurysm in the left leg. After the end of antimicrobial therapy aortic valve replacement was done because of severe heart failure. PMID- 23653153 TI - A combination of aprepitant, palonosetron, and dexamethasone prevents emesis associated with anthracycline-containing regimens for patients with breast cancer. A retrospective study. AB - BACKGROUND: Chemotherapy regimens for breast cancer containing anthracycline and cyclophosphamide are classified as highly emetogenic. Aprepitant (A), palonosetron (P), granisetron (G), or dexamethasone (D) are recommended antiemetic drugs. However, it is uncertain which combination is most effective. We retrospectively examined the efficacy of these antiemetic drugs. PATIENTS AND METHODS: We reviewed the medical records of 454 patients with breast cancer treated in our facility with regimens containing anthracycline and cyclophosphamide between August 2009 and September 2010. RESULT: The number of patients treated with GD, AGD, and APD was 147, 150, and 157, respectively. Complete response (CR) in the acute (0-24 h) and delayed (24-120 h) phases was 68.7 and 76.2 %, respectively, for GD, 90.0 and 92.7 %, respectively, for AGD, and 89.8 and 90.4 %, respectively, for APD. Complete control (CC) in the acute and delayed phases for each regimen was 60.5 and 64.6 %, respectively, for GD, 62.7 and 88.7 %, respectively, for AGD, and 84.1 and 87.3 %, respectively, for APD. In the acute and delayed phases CR for AGD or APD was significantly superior to that for GD (P < 0.01). It worth noting that CC for APD in the acute phase was significantly superior to that for AGD (P < 0.01). In the delayed phase CC for AGD or APD was significantly superior to that for GD. CONCLUSION: A combination of aprepitant, palonosetron, and dexamethasone is an antiemetic treatment of choice for patients treated with regimens containing anthracycline and cyclophosphamide. PMID- 23653154 TI - Vectofusin-1, a new viral entry enhancer, strongly promotes lentiviral transduction of human hematopoietic stem cells. AB - Gene transfer into hCD34(+) hematopoietic stem/progenitor cells (HSCs) using human immunodeficiency virus type 1 (HIV-1)-based lentiviral vectors (LVs) has several promising therapeutic applications. Yet, efficiency, safety, and cost of LV gene therapy could be ameliorated by enhancing target cell transduction levels and reducing the amount of LV used on the cells. Several transduction enhancers already exist such as fibronectin fragments and cationic compounds, but all present limitations. In this study, we describe a new transduction enhancer called Vectofusin-1, which is a short cationic peptide, active on several LV pseudotypes. Vectofusin-1 is used as a soluble additive to safely increase the frequency of transduced HSCs and to augment the level of transduction to one or two copies of vector per cell in a vector dose-dependent manner. Vectofusin-1 acts at the entry step by promoting the adhesion and the fusion between viral and cellular membranes. Vectofusin-1 is therefore a promising additive that could significantly ameliorate hCD34(+) cell-based gene therapy.Molecular Therapy Nucleic Acids (2013) 2, e90; doi:10.1038/mtna.2013.17; published online 7 May 2013. PMID- 23653155 TI - Evaluation of RNA Amplification Methods to Improve DC Immunotherapy Antigen Presentation and Immune Response. AB - Dendritic cells (DCs) transfected with total amplified tumor cell RNA have the potential to induce broad antitumor immune responses. However, analytical methods required for quantitatively assessing the integrity, fidelity, and functionality of the amplified RNA are lacking. We have developed a series of assays including gel electrophoresis, northern blot, capping efficiency, and microarray analysis to determine integrity and fidelity and a model system to assess functionality after transfection into human DCs. We employed these tools to demonstrate that modifications to our previously reported total cellular RNA amplification process including the use of the Fast Start High Fidelity (FSHF) PCR enzyme, T7 Powerswitch primer, post-transcriptional capping and incorporation of a type 1 cap result in amplification of longer transcripts, greater translational competence, and a higher fidelity representation of the starting total RNA population. To study the properties of amplified RNA after transfection into human DCs, we measured protein expression levels of defined antigens coamplified with the starting total RNA populations and measured antigen-specific T cell expansion in autologous DC-T cell co-cultured in vitro. We conclude from these analyses that the improved RNA amplification process results in superior protein expression levels and a greater capacity of the transfected DCs to induce multifunctional antigen-specific memory T cells.Molecular Therapy-Nucleic Acids (2013) 2, e91; doi:10.1038/mtna.2013.18; published online 7 May 2013. PMID- 23653156 TI - Haloperidol overdosing in the treatment of agitated hospitalized older people with delirium: a retrospective chart review from a community teaching hospital. AB - BACKGROUND: Practice guidelines recommend the use of low dose haloperidol when medication is needed to treat delirium with acute agitation in hospitalized older people. Despite this, high dose haloperidol may frequently be used and result in higher rates of complications. OBJECTIVE: To describe dosages and effects of haloperidol used in the initial treatment of delirium with acute agitation in hospitalized older people, and prescriber use of low and high dose haloperidol. METHODS: Retrospective chart reviews were performed from June 2008 to May 2009 in a community teaching hospital located in Upland, PA, USA. Patients aged 65 years and older with acute agitated delirium were included. Patients admitted to ICU and those with psychiatric conditions were excluded. Data were collected on haloperidol dosing, responses, sedation, length of stay, and concurrent use of lorazepam. RESULTS: A total of 261 charts of patients who received haloperidol were reviewed and 56 patients met inclusion criteria (14 males, 42 females). The mean age of subjects was 83 years. The recommended starting dose of haloperidol (0.5 mg) was administered to 35.7 % of the patients. An initial dose of more than 1 mg was received by 37.5 % of the patients. The remaining 26.8 % of patients received 1 mg. The relative risk of sedation was significantly greater for subjects receiving more than 1 mg of haloperidol in 24 h. The length of hospitalization was not predicted by haloperidol doses or lorazepam but by the number of days of agitation. CONCLUSIONS: Higher than recommended initial doses of haloperidol were frequently used in the treatment of delirium with acute agitation in hospitalized older people. We found no evidence to suggest that higher dosages were more effective in decreasing the duration of agitation or the length of hospital stay. Low dose haloperidol appears to be as effective as and safer than higher doses in the treatment of acute agitation in this older population. PMID- 23653157 TI - [Intermediate and long-term outcome after total joint replacement for hallux rigidus : a retrospective analysis]. AB - BACKGROUND: The treatment options for advanced hallux rigidus include arthrodesis, excision arthroplasty (Keller-Brandes) and joint arthroplasty and based on the literature, arthrodesis still appears to be the gold standard. In recent years, technical advances and higher patient demands have led to an increasing use of total joint replacement but comparative data on patient satisfaction and clinical outcome of different forms of treatment are rare. MATERIAL AND METHODS: Between 1995 and 2005 a total of 27 patients were treated with 28 joint replacements of the first metatarsophalangeal joint (MTPJ) in a surgical practice (Bio-Action Great Toe Implant, OsteoMed, Addison, TX). The mean age of the patients was 63.7 years. In a retrospective analysis patients were examined clinically and radiologically after a mean follow-up period of 8.8 years and asked about their satisfaction with surgical results using a questionnaire. RESULTS: After joint replacement 15 patients (53.6%) were free of pain, 8 (28.6%) reported marked improvement, 12 (42.9%) had no limitations in any activity and another 5 (17.9%) had no restrictions in activities of daily life. The maximum walking distance was improved in 21 patients (75%) and walking on rough ground in 24 (85.7%). Of the patients 11 (39.3%) had a good range of motion in the MTPJ, 13 (46.4%) reported a slight restriction, 24 (85.7%) were satisfied or very satisfied with the postoperative result and 22 stated that they would undergo joint replacement again. The results of the Wilcoxon test showed a significant increase in postoperative modified American Orthopaedic Foot and Ankle Society (AOFAS) scores compared with preoperative scores. There was loosening of the phalangeal component in 3 patients (11%), and 2 had to undergo revision. CONCLUSIONS: Many recent studies reported good to excellent long-term results of arthrodesis of the MTPJ for stage III and IV hallux rigidus. The results of this study suggest that similar results can be achieved by an experienced foot surgeon with total joint replacement in strictly selected patients. PMID- 23653158 TI - Development of a paper-and-pencil semi-adaptive questionnaire for 5 domains of health-related quality of life (PAT-5D-QOL). AB - OBJECTIVES: To develop a paper-and-pencil semi-adaptive test for 5 domains of health-related quality of life (PAT-5D-QOL) based on item response theory (IRT). METHODS: The questionnaire uses items from previously developed item banks for 5 domains: (1) walking, (2) handling objects, (3) daily activities, (4) pain or discomfort, and (5) feelings. For each domain, respondents are initially classified into 4 functional levels. Depending on the level, they are instructed to respond to a different set of 5 additional questions. IRT scores for each domain and overall health utility scores are obtained using a simple spreadsheet. The questions were selected using psychometric and conceptual criteria. The format of the questionnaire was developed through focus groups and cognitive interviews. Feasibility was tested in two population surveys. A simulation study was conducted to compare PAT-5D-QOL with a computerized adaptive test (CAT-5D QOL) and a fixed questionnaire, developed from the same item banks, in terms of accuracy, bias, precision, and ceiling and floor effects. RESULTS: Close to 90 % of the participants in feasibility studies followed the skip instructions properly. In a simulation study, scores on PAT-5D-QOL for all domains tended to be more accurate, more precise, less biased, and less affected by a ceiling effect than scores on a fixed IRT-based questionnaire of the same length. PAT-5D QOL was slightly inferior to a fully adaptive instrument. CONCLUSIONS: PAT-5D-QOL is a novel, semi-adaptive, IRT-based measure of health-related quality of life with a broad range of potential applications. PMID- 23653159 TI - Health-related quality of life and comorbidity among older women veterans in the United States. AB - PURPOSE: This paper examines the predictors of quality of life among older women (>=65 years of age) veterans in the United States focusing on the effect of comorbidity on health-related quality of life (HRQOL). METHODS: Data from the National Survey of Women Veterans, a cross-sectional nationally representative population-based, stratified random sample of women veterans, were used with an analytic sample size of 1,379 older women veterans. The SF12 physical and mental composite scores (PCS and MCS) were used as outcome measures, and a weighted comorbidity index was used as a covariate. RESULTS: Older women veterans who are married, employed, with higher income, and higher education have better physical health (PCS). For mental health, education is positively correlated, whereas depression and posttraumatic stress disorder are negatively correlated with MCS. After adjusting for socio-demographic, mental health, and chronic health indicators, the results showed that SF12 PCS varied by VA use status for each level of Seattle Index of Comorbidity. The same pattern was not found for MCS. CONCLUSION: For each level of comorbidity, VA users have worse HRQOL which might suggest that case mix adjustments comparing VA users and non-VA users must take into account more than comorbidity alone. PMID- 23653161 TI - Human Papillomavirus-mediated cervical cancer awareness and Gardasil vaccination: a pilot survey among North Indian women. AB - Human Papillomavirus (HPV)-mediated cervical cancer is a leading cause of morbidity and mortality in women worldwide, including Indian women. Cervical cancer control and prevention strategies are being adopted in developing nations to reduce the increasing burden of HPV infection in the vaccine era. The present study, therefore, aimed to evaluate cervical cancer awareness and knowledge of Gardasil vaccination in North Indian women. A pilot survey was conducted among 103 women of North Indian ethnicity residing in Lucknow/adjoining areas in state of Uttar Pradesh, during routine screening/clinic visits from June 2012 to December 2012. The study subjects were interviewed in either Hindi or English; subsequently the awareness of HPV-mediated cervical cancer and knowledge of Gardasil vaccination was assessed in terms of "yes", "no" and "no response". The study was approved by the Institutional Review Board. Written informed consent was taken from the participants. Overall, the response of participants (n = 103) in our single-centre survey-based pilot study was well-defined. The response regarding HPV-mediated cervical cancer awareness in terms of "yes", "no" and "no response" among the study subjects was 43.7, 44.7 and 11.6 %, respectively. Furthermore, in response to knowledge of HPV vaccine Gardasil, out of 103 subjects, 28.1 % answered "yes" while 37.9 and 34.0 % stated "no" and "no response", respectively. Our pilot survey may help in assessing knowledge of HPV mediated cervical cancer and Gardasil vaccination awareness in women, and accordingly develop cost-effective cervical cancer control and prevention/public health counseling sessions in a clinical setting. PMID- 23653160 TI - Analysis of the effect of estrogen/androgen perturbation on penile development in transgenic and diethylstilbestrol-treated mice. AB - Because both androgens and estrogens have been implicated in penile morphogenesis, we evaluated penile morphology in transgenic mice with known imbalance of androgen and estrogen signaling using scanning electron microscopy (SEM), histology, and immunohistochemistry of androgen and estrogen receptors alpha/beta. Penises of adult wild-type, estrogen receptor-alpha knockout (alphaERKO), estrogen receptor-beta knockout (betaERKO), aromatase knockout (Arom KO), and aromatase overexpression (Arom+) mice were evaluated, as well as adult mice treated with diethylstilbestrol (DES) from birth to day 10. Adult penises were examined because the adult pattern is the endpoint of development. The urethral orifice is formed by fusion of the MUMP (male urogenital mating protuberance) with the MUMP ridge, which consists of several processes fused to each other and to the MUMP. Similarly, the internal prepuce is completed ventrally by fusion of a ventral cleft. In adult murine penises the stromal processes that form the MUMP ridge are separated from their neighbors by clefts. alphaERKO, betaERKO, and Arom-KO mice have penises with a MUMP ridge clefting pattern similar to that of wild-type mice. In contrast, Arom+ mice and neonatally DES-treated mice exhibit profound malformations of the MUMP, MUMP ridge clefting pattern, and internal prepuce. Abnormalities observed in Arom+ and neonatally DES treated mice correlate with the expression of estrogen receptor-beta (ERbeta) in the affected structures. This study demonstrates that formation of the urethal orifice and internal prepuce is due to fusion of separate epithelial-surfaced mesenchymal elements, a process dependent upon both androgen and estrogen signaling, in which ERbeta signaling is strongly implicated. PMID- 23653163 TI - Vulnerabilities of Local Healthcare Providers in Complex Emergencies: Findings from the Manipur Micro-level Insurgency Database 2008-2009. AB - BACKGROUND: Research on healthcare delivery in zones of conflict requires sustained and systematic attention. In the context of the South Asian region, there has been an absence of research on the vulnerabilities of health care workers and institutions in areas affected by armed conflict. The paper presents a case study of the varied nature of security challenges faced by local healthcare providers in the state of Manipur in the North-eastern region of India, located in the Indo-Myanmar frontier region which has been experiencing armed violence and civil strife since the late 1960s. . The aim of this study was to assess longitudinal and spatial trends in incidents involving health care workers in Manipur during the period 2008 to 2009. METHODS: We conducted a retrospective database analysis of the Manipur Micro-level Insurgency Database 2008-2009, created by using local newspaper archives to measure the overall burden of violence experienced in the state over a two year period. Publicly available press releases of armed groups and local hospitals in the state were used to supplement the quantitative data. Simple linear regression was used to assess longitudinal trends. Data was visualized with GIS-software for spatial analysis. RESULTS: The mean proportion of incidents involving health care workers per month was 2.7% and ranged between 0 and 6.1% (table 2). There was a significant (P=0.037) month-to-month variation in the proportion of incidents involving health care workers, as well as a upward trend of about 0.11% per month. Spatial analysis revealed different patterns depending on whether absolute, population-adjusted, or incident-adjusted frequencies served as the basis of the analysis. CONCLUSIONS: The paper shows a small but steady rise in violence against health workers and health institutions impeding health services in Manipur's pervasive violence. More evidence-building backed by research along with institutional obligations and commitment is essential to protect the health systems Keywords: India, Manipur, insurgency, healthcare, security, ethnic strife. PMID- 23653164 TI - Chimpanzee nesting patterns in savanna habitat: environmental influences and preferences. AB - Data on chimpanzee (Pan troglodytes) nesting patterns were collected in Issa, Ugalla, western Tanzania. Ugalla is one of the driest, most open, and seasonal habitats inhabited by chimpanzees. We investigated the physical characteristics of nests and trees used for nesting to understand environmental influences on nest building and identify the characteristics preferred by the chimpanzees and the basis for such preferences. We analyzed 2,167 nests and 1,523 nesting trees. Most nests were built in the middle section of the tree crown and close to the tree trunk, and used a single tree in construction. Some physical characteristics of nests (e.g., distance from tree trunk) seemed to be the result of constraints imposed by tree structure. Issa chimpanzees preferred tall trees with high first branches for nesting supporting the hypothesis that elevated height of a sleeping place is a predator defense strategy. The height from the ground to the first branch showed less variation than either tree height or crown height and correlated weakly with tree height, suggesting that height from the ground to the first branch may be a more important factor than tree height alone in selecting a tree in which to nest. As in other study sites, the chimpanzees used tree species in proportions that did not correspond to their abundance suggesting tree species preference. We report for the first time that chimpanzees directionally oriented their nests and propose that this may be to maximize sunlight. We compare our data to those of other chimpanzee study sites. PMID- 23653165 TI - Stereoselective rearrangements with chiral hypervalent iodine reagents. PMID- 23653166 TI - Purification of beta-lactoglobulin with a high-capacity anion exchanger: high throughput process development and scale-up considerations. AB - BACKGROUND: beta-Lactoglobulin is the most abundant protein in bovine whey. It is a valuable nutriceutical with multiple physiological functions. There are many ongoing efforts to improve approaches by which this whey protein can be conveniently and economically purified in significant quantities. High-capacity resins for protein fractionation are currently available in the biotech industry. One such resin is evaluated in the present investigation. RESULTS: This work describes a high-capacity ion exchange chromatography method for one-column fractionation of beta-lactoglobulin from whey. It was obtained with a >90% purity. The dynamic binding capacity was measured in packed columns. Comparable value predicted on the basis of Langmuir isotherm analysis from batch adsorption data in a high-throughput 96-well format is shown. Scale-up considerations are discussed with respect to feed concentration and binding capacity. CONCLUSIONS: The feasibility of preparing purified beta-lactoglobulin with a single high capacity anion exchanger step was demonstrated. A capacity of >200 mg mL(-1) was obtained. A significant improvement in productivity can be realized by a simultaneous increase of binding capacity and feed concentration. PMID- 23653167 TI - The clinical results of transcervical carotid artery stenting and frequency chosen as the approach route of carotid artery stenting in 1,067 consecutive cases. AB - BACKGROUND: Carotid artery stenting (CAS) is generally performed via a transfemoral approach. A transbrachial approach is usually chosen as an alternative when CAS via a transfemoral approach is difficult. At our institutions, a transcervical approach is chosen when the previous two approach routes are not available. We reviewed CAS cases treated via the transcervical route in our 1,067 CAS series to investigate the safety, feasibility, and frequency of this procedure as an approach route of CAS. METHODS: We performed 1,067 CAS procedures in 1,067 consecutive cases between December 2002 and June 2011. Initially, a transfemoral route was chosen, and secondarily a transbrachial route, the last choice was a transcervical route. A transbrachial approach was chosen in 96 (9.0%) cases and a transcervical approach in ten (0.9%). We reviewed the characteristics and outcomes of CAS performed via a transcervical approach. RESULTS: CAS was successfully performed on all ten transcervical-approach patients. Eight procedures were performed under local anesthesia and two under general anesthesia. Perioperative morbidity and mortality were both 0%. The modified Rankin scale (mRS) showed no deterioration at 3 months except for one case whose mRS became five because of an embolic stroke after aortic valve replacement. CONCLUSIONS: CAS via a transcervical approach was safe and feasible, and its frequency chosen as an approach route was 0.9%. This procedure can be an alternative to transfemoral or transbrachial approaches when CAS via either of these approaches is too difficult. PMID- 23653168 TI - Metallic gold beads in hyaluronic acid: a novel form of gold-based immunosuppression? Investigations of the immunosuppressive effects of metallic gold on cultured J774 macrophages and on neuronal gene expression in experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is a neurodegenerative disease caused by recurring attacks of neuroinflammation leading to neuronal death. Immune-suppressing gold salts are used for treating connective tissue diseases; however, side effects occur from systemic spread of gold ions. This is limited by exploiting macrophage induced liberation of gold ions (dissolucytosis) from gold surfaces. Injecting gold beads in hyaluronic acid (HA) as a vehicle into the cavities of the brain can delay clinical signs of disease progression in the MS model, experimental autoimmune encephalitis (EAE). This study investigates the anti-inflammatory properties of metallic gold/HA on the gene expression of tumor necrosis factor (Tnf-alpha), Interleukin (Il)-1beta, Il-6, Il-10, Colony-stimulating factor (Csf) v2, Metallothionein (Mt)-1/2, Bcl-2 associated X protein (Bax) and B cell lymphoma (Bcl)-2 in cultured J774 macrophages and in rodents with early stages of EAE. Cells grew for 5 days on gold/HA or HA, then receiving 1,000 ng/mL lipopolysaccharide (LPS) as inflammatory challenge. In the EAE experiment, 12 Lewis rats received gold injections and control groups included 11 untreated and 12 HA-treated EAE rats and five healthy animals. The experiment terminated day 9 when the first ten animals showed signs of EAE, only one of which were gold treated (1p = 0.0367). Gene expression in the macrophages showed a statistically significant decrease in Il-6, Il-1beta and Il-10-response to LPS; interestingly HA induced a statistically significant increase of Il-10. In the EAE model gene expression of inflammatory cytokines increased markedly. Compared to EAE controls levels of Tnf-alpha, Il-1beta, Il-10, Il-6, IL-2, Ifn-gamma, Il-17, transforming growth factor (Tgf)-beta, superoxide dismutase (Sod)-2, Mt-2 and fibroblast growth factor (Fgf)-2 were lower in the gold-treated group. HA-treated animals expressed similar or intermediate levels. Omnibus testing for reduced inflammatory response following gold-treatment was not significant, but tendencies towards a decrease in the Sod-2, Fgf-2, Il-1beta response and a higher Bdnf and IL-23 gene expression were seen. In conclusion, our findings support that bio-liberation of gold from metallic gold surfaces have anti-inflammatory properties similar to classic gold compounds, warranting further studies into the pharmacological potential of this novel gold-treatment and the possible synergistic effects of hyaluronic acid. PMID- 23653170 TI - Small cerebellar hemorrhage in preterm infants: perinatal and postnatal factors and outcome. AB - The objective of the study is to determine perinatal and postnatal factors that may affect the occurrence of small cerebellar hemorrhage (CBH) and to evaluate the effect of small CBH on neurodevelopmental outcome in very preterm infants. This prospective study in an unselected cohort of very preterm infants was approved by the medical ethics committee, and informed parental consent was obtained. Presence of small CBH (<4 mm) was assessed with magnetic resonance imaging around term equivalent age in 108 preterm infants (<32 weeks gestation). We compared infants with and without small CBH for perinatal and postnatal factors, supratentorial brain injury, and for neurodevelopmental outcome at 2 years corrected age. Follow-up consisted of a neurological examination, mental and developmental assessment (Bayley Scales of Infant Development), and behavior checklist. Univariate and multivariate logistic regression analyses were performed to examine the relationships between variables. Small CBH was diagnosed in 16/108 very preterm infants. Univariate analyses identified gestational age, high-frequency oscillation (HFO) ventilation, and grade 3-4 intraventricular hemorrhage (IVH) as factors associated with small CBH. HFO ventilation and severe IVH were independent predictors of small CBH. We found no association between small CBH and neurodevelopmental outcome at 2 years of age. Small CBH is a frequent finding in preterm infants. These hemorrhages are independently associated with HFO ventilation and severe supratentorial hemorrhage and seem to have a favorable short-term prognosis. PMID- 23653171 TI - A 1-year drug utilization evaluation of protamine in hospitalized patients to identify possible future roles of heparin and low molecular weight heparin reversal agents. AB - Despite widespread use of unfractionated heparin (UFH) and low molecular weight heparin (LMWH), protamine sulfate remains the only reversal agent for UFH that is approved by the Food and Drug Administration within the US. Availability of new reversal agents for approved anticoagulants and those in development may improve patient safety and care. Delparantag (PMX-60056) is a novel small molecule that shows ability to neutralize the anticoagulation effects of UFH and LMWH in animals and humans. This study examined the 1-year utilization of protamine within an acute care hospital in order to determine the need for a novel reversing agent like delparantag. All patients having documented protamine administration within a 1-year period were included. Pharmacy automated dispensing machines and computerized medication management systems were queried for all doses of protamine withdrawn, billed for, or dispensed. Scanned medical records were reviewed and protamine and anticoagulant information was abstracted. Primary procedural group categorizations for protamine patients were coronary artery bypass graft, cardiac valve surgeries, abdominal aortic aneurysm and other open abdominal surgeries, fistula placement, non-cardiac vascular, cardiac catheter and electrophysiology lab, and "other." Average doses of protamine administered were 439, 423, 126, 26, 46, 36, and 35 mg in these groups, respectively. Four major bleeds and one serious adverse event occurred over the year period. Protamine is used in a wide array of procedures. Evaluating protamine's current use may be beneficial in identifying roles for future UFH and LMWH reversal agent use. PMID- 23653172 TI - Warfarin use in atrial fibrillation patients at low risk for stroke: analysis of the Michigan Anticoagulation Quality Improvement Initiative (MAQI(2)). AB - To more accurately quantify the proportion of anticoagulated patients with atrial fibrillation (AF) that may be inappropriately treated with warfarin for stroke prevention. Patients with AF have an increased risk of stroke, which is lowered by the use of warfarin. However there is likely more potential harm than benefit in patients that do not have additional stroke risk factors. Studies have described overuse of warfarin for stroke prophylaxis in lowest risk patients. However, many of those studies did not assess for electrical cardioversion (ECV) or radiofrequency ablation (RFA) as indications for warfarin therapy. Data from 1852 non-valvular AF patients treated with warfarin between October 2009 and October 2011 at seven anticoagulation centers participating in the Michigan Anticoagulation Quality Improvement Initiative registry were analyzed. Low risk AF patients were risk stratified using the CHADS2 scoring systems, with a score of zero representing lowest risk. 193 (10.4 %) of AF patients receiving warfarin were identified as having the lowest risk of stroke by the CHADS2 score. Of the patients with CHADS2 = 0, 130 (67.4 %) had undergone a recent ECV and/or RFA. Of all AF patients, only 63 (3.4 %) had a CHADS2 score of 0 and no recent ECV or RFA. The vast majority of AF patients receiving anticoagulation in this multi center registry are doing so in accordance with national and international guidelines. In contrast to prior population-based studies, very few low risk patients are receiving inappropriate warfarin therapy for stroke prophylaxis in AF, when procedure-based indications are also considered. PMID- 23653173 TI - New oral anticoagulants in non-valvular atrial fibrillation. AB - Atrial fibrillation (AF) is associated with an increased risk of embolic stroke. Dose-adjusted vitamin K antagonists (VKAs) to a target international normalized ratio (INR) range of 2.0-3.0 reduce the risk of ischemic stroke and are currently recommended in all patients with AF at moderate-high risk for stroke or systemic embolism. However, VKAs have several drawbacks, including unpredictable anticoagulant response, food and drug interactions, need for regular laboratory monitoring and dose adjustment. These limitations prompted the introduction of new oral anticoagulants (NOA) that target thrombin and factor Xa, key-enzymes in the coagulation pathway. NOA have predictable pharmacodynamics, allowing fixed dosing without the need of laboratory monitoring, and have few drug and food interactions. The present review focuses on pharmacological properties, safety, and appropriate clinical use of dabigatran, rivaroxaban and apixaban. PMID- 23653174 TI - Effectiveness of blood pressure educational and evaluation program for the improvement of measurement accuracy among nurses. AB - AIM: To assess the procedure for measuring blood pressure (BP) among hospital nurses and to assess if a training program would improve technique and accuracy. METHODS: 160 nurses from Molinette Hospital were included in the study. The program was based upon theoretical and practical lessons. It was one day long and it was held by trained nurses and physicians who have practice in the Hypertension Unit. An evaluation of nurses' measuring technique and accuracy was performed before and after the program, by using a 9-item checklist. Moreover we calculated the differences between measured and effective BP values before and after the training program. RESULTS: At baseline evaluation, we observed inadequate performance on some points of clinical BP measurement technique, specifically: only 10% of nurses inspected the arm diameter before placing the cuff, 4% measured BP in both arms, 80% placed the head of the stethoscope under the cuff, 43% did not remove all clothing that covered the location of cuff placement, did not have the patient seat comfortably with his legs uncrossed and with his back and arms supported. After the training we found a significant improvement in the technique for all items. We didn't observe any significant difference of measurement knowledge between nurses working in different settings such as medical or surgical departments. CONCLUSIONS: Periodical education in BP measurement may be required, and this may significantly improve the technique and consequently the accuracy. PMID- 23653175 TI - The use of the RESPeRATE device to lower blood pressure in inner city obese adolescents and children: a pilot feasibility study. AB - The RESPeRATE device was tested for feasibility of use in a population of overweight and obese children and adolescents (n = 10) in San Francisco, CA. After a 2-week and then a 2-month period, participants were interviewed on their frequency of use and attitudes towards the device. A high percentage stated that they enjoyed using the device at 2 months (90%) and 80% stated that they would recommend use to a friend or relative. Future studies are needed to assess the efficacy of the RESPeRATE device in lowering blood pressure and helping with weight loss/weight management in obese and overweight children. PMID- 23653176 TI - Onset of work restriction in employed adults with lower limb joint pain: individual factors and area-level socioeconomic conditions. AB - PURPOSE: To examine individual and area-level socioeconomic factors that predict the onset of work restriction in employed persons with lower limb joint pain. METHODS: Population-based prospective cohort study. Adults were aged 50-59, reported hip, knee, foot pain or a combination and maintained employment through 3 year follow-up (n = 716). Work restriction was measured as inability to participate in work as desired. Multi-level logistic regression was used to assess the associations of work restriction onset with baseline factors: health (severity of knee pain/functional limitation, comorbidity, anxiety, depression, cognitive impairment, abnormal weight), demographic socio-economic, environment and area-level employment deprivation. RESULTS: 108 (15.1 %) reported the onset of work restriction over 3 years. Severe lower limb joint pain and functional limitation, number of affected body sites and area employment deprivation were independently associated with onset. Significant interactions indicated a greater effect of area employment deprivation on older and more depressed workers. CONCLUSIONS: Results suggest that effectively preventing work disability in those with OA will require both condition-specific interventions to decrease pain and maintain function, and providing alternative employment opportunities for those with progressive functional limitations. Results in older workers are particularly concerning, as retirement ages are expected to increase in the general population. PMID- 23653177 TI - "Balancing on Skates on the Icy Surface of Work": a metasynthesis of work participation for persons with psychiatric disabilities. AB - PURPOSE: To explore how persons with psychiatric disabilities experience facilitators of and barriers to participation in paid work in transitional, supported, and open employment settings, in order to provide guidance for efforts to attract and retain these persons in gainful employment as a key dimension of recovery and community life. METHODS: A metasynthesis was conducted using 16 qualitative studies published between 1990 and 2011. RESULTS: Ten themes, two phases, and an overarching metaphor were identified. The first five themes describe facilitators of and impediments to getting a job (getting off the bench): (1) fighting inertia; (2) taking control; (3) encouraging peers; (4) disruptions related to the illness; (5) lack of opportunities and supports. The next five themes represent facilitators of and impediments to working (skating on the ice); (6) going mainstream; (7) social cohesion; (8) clarity in role and responsibilities; (9) environmental factors; (10) managing self-disclosure. We chose as our overarching metaphor "Balancing on Skates on the Icy Surface of Work," as we view both iceskaters and workers with psychiatric disabilities as needing to achieve and maintain their balance while being "on the edge" between various extremities. CONCLUSION: We have shown that, for persons with psychiatric disabilities to "get off the bench" and "onto the ice" of employment, they may need to be supported in finding and maintaining their balance in new situations through a combination of learning new skills and competencies (learning how to skate) while receiving in vivo assistance from empathic and knowledgeable supporters (being coached while on the ice). PMID- 23653178 TI - LovG: the thioesterase required for dihydromonacolin L release and lovastatin nonaketide synthase turnover in lovastatin biosynthesis. PMID- 23653179 TI - Morphology and biomechanics of the pinniped jaw: mandibular evolution without mastication. AB - Pinnipeds (seals, sea lions, and walruses) underwent a shift in jaw function away from typical carnivoran mastication to more novel marine behaviors during the terrestrial-aquatic transition. Here we test the effect of aquatic prey capture and male-male combat on the morphological evolution of a mammal jaw that does not masticate. Nine three-dimensional landmarks were taken along the mandible for 25 species (N = 83), and corpus and symphysis external and cortical breadths for a subset of five species (N = 33). Principal components analysis was performed on size-corrected landmark data to assess variation in overall jaw morphology across pinnipeds. Corpus breadths were input to a beam model to calculate strength properties and estimated bite force of specific species with contrasting behaviors (filter feeding, suction feeding, grip-and-tear feeding, and male-male combat). Results indicate that, although phylogenetic signal in jaw shape is strong, function is also important in determining morphology. Filter feeders display an elongate symphysis and a long toothrow that may play a role in filtering krill. Grip-and-tear feeders have a long jaw and large estimated bite force relative to non-biting species. However, the largest estimated bite forces were observed in males of male-male combative species, likely due to the high selection pressure associated with male success in highly polygynous species. The suction feeding jaw is weak in biting but has a different morphology in the two suction feeding taxa. In conclusion, familial patterns of pinniped jaw shape due to phylogenetic relatedness have been modified by adaptations to specialized behavior of individual taxa. PMID- 23653180 TI - Dietary phosphatidylinositol protects C57BL/6 mice from concanavalin A-induced liver injury by modulating immune cell functions. AB - SCOPE: Several recent studies have demonstrated that phospholipids (PLs) supplementation can modulate the function of cultured-immune cells. Furthermore, dietary PLs have been shown to ameliorate inflammatory processes and immune responses in arthritic and diabetic murine models, respectively. Thus, the aim of this study was to examine the immune-modulating activities of dietary soybean PLs in mice, with particular emphasis on the immune cell functions. METHODS AND RESULTS: Mice were fed semisynthetic diets for 6 weeks, which contained either 7% soybean oil or 5% soybean oil plus 2% of either PL: phosphatidylcholine (PC), phosphatidylinositol (PI), or phosphatidylserine (PS). Production of concanavalin A (Con A)-induced proinflammatory cytokines was significantly decreased in the splenocytes isolated from mice fed PI compared to other lipids. Supplementation of the diet with PI, but not with the other lipids, significantly suppressed the proinflammatory cytokine serum levels and the development of Con A-induced liver damages. CONCLUSION: These observations suggest that dietary PI influenced immune functions, resulting in the prevention of pathogenesis and development of the liver injury in mice. PMID- 23653181 TI - Changes in the mean systemic filling pressure during a fluid challenge in postsurgical intensive care patients. AB - PURPOSE: The difference between mean systemic filling (Pmsf) and central venous pressure (CVP) is the venous return gradient (dVR). The aim of this study is to assess the significance of the Pmsf analogue (Pmsa) and the dVR during a fluid challenge. METHODS: We performed a prospective observational study in postsurgical patients. Patients were monitored with a central venous catheter, a LiDCOTMplus and the NavigatorTM. A 250-ml intravenous fluid challenge was given over 5 min. A positive response to the fluid challenge was defined as either a stroke volume (SV) or cardiac output increase of greater than 10 %. RESULTS: A total of 101 fluid challenges were observed in 39 patients. In 43 events (42.6 %) the SV and CO increased by more than 10 %. Pmsa increased similarly during a fluid challenge in responders and non-responders (3.1 +/- 1.9 vs. 3.1 +/- 1.8, p = 0.9), whereas the dVR increased in responders (1.16 +/- 0.8 vs. 0.2 +/- 1, p < 0.001) as among non-responders CVP increased along with Pmsa (2.9 +/- 1.7 vs. 3.1 +/- 1.8, p = 0.15). Resistance to venous return did not change immediately after a fluid challenge. Heart performance (Eh) decreased significantly among non responders (0.41 +/- 0.15 vs. 0.34 +/- 0.13, p < 0.001) whereas among responders it did not change when compared with baseline value (0.35 +/- 0.15 vs. 0.34 +/- 0.12, p = 0.15). CONCLUSIONS: The changes in Pmsa and dVR measured at the bedside during a fluid challenge are consistent with the cardiovascular model described by Guyton. PMID- 23653182 TI - Treatment of acute hypernatremia in severely burned patients using continuous veno-venous hemofiltration with gradient sodium replacement fluid: a report of nine cases. PMID- 23653185 TI - Large-scale organic nanowire lithography and electronics. AB - Controlled alignment and patterning of individual semiconducting nanowires at a desired position in a large area is a key requirement for electronic device applications. High-speed, large-area printing of highly aligned individual nanowires that allows control of the exact numbers of wires, and their orientations and dimensions is a significant challenge for practical electronics applications. Here we use a high-speed electrohydrodynamic organic nanowire printer to print large-area organic semiconducting nanowire arrays directly on device substrates in a precisely, individually controlled manner; this method also enables sophisticated large-area nanowire lithography for nano-electronics. We achieve a maximum field-effect mobility up to 9.7 cm(2) V(-1) s(-1) with extremely low contact resistance (<5.53 Omega cm), even in nano-channel transistors based on single-stranded semiconducting nanowires. We also demonstrate complementary inverter circuit arrays comprising well-aligned p-type and n-type organic semiconducting nanowires. Extremely fast nanolithography using printed semiconducting nanowire arrays provide a simple, reliable method of fabricating large-area and flexible nano-electronics. PMID- 23653183 TI - Recommendations on the use of EEG monitoring in critically ill patients: consensus statement from the neurointensive care section of the ESICM. AB - OBJECTIVES: Recommendations for EEG monitoring in the ICU are lacking. The Neurointensive Care Section of the ESICM assembled a multidisciplinary group to establish consensus recommendations on the use of EEG in the ICU. METHODS: A systematic review was performed and 42 studies were included. Data were extracted using the PICO approach, including: (a) population, i.e. ICU patients with at least one of the following: traumatic brain injury, subarachnoid hemorrhage, intracerebral hemorrhage, stroke, coma after cardiac arrest, septic and metabolic encephalopathy, encephalitis, and status epilepticus; (b) intervention, i.e. EEG monitoring of at least 30 min duration; (c) control, i.e. intermittent vs. continuous EEG, as no studies compared patients with a specific clinical condition, with and without EEG monitoring; (d) outcome endpoints, i.e. seizure detection, ischemia detection, and prognostication. After selection, evidence was classified and recommendations developed using the GRADE system. RECOMMENDATIONS: The panel recommends EEG in generalized convulsive status epilepticus and to rule out nonconvulsive seizures in brain-injured patients and in comatose ICU patients without primary brain injury who have unexplained and persistent altered consciousness. We suggest EEG to detect ischemia in comatose patients with subarachnoid hemorrhage and to improve prognostication of coma after cardiac arrest. We recommend continuous over intermittent EEG for refractory status epilepticus and suggest it for patients with status epilepticus and suspected ongoing seizures and for comatose patients with unexplained and persistent altered consciousness. CONCLUSIONS: EEG monitoring is an important diagnostic tool for specific indications. Further data are necessary to understand its potential for ischemia assessment and coma prognostication. PMID- 23653186 TI - A synthetic route to ultralight hierarchically micro/mesoporous Al(III) carboxylate metal-organic aerogels. AB - Developing a synthetic methodology for the fabrication of hierarchically porous metal-organic monoliths that feature high surface area, low density and tunable porosity is imperative for mass transfer applications, including bulky molecule capture, heterogeneous catalysis and drug delivery. Here we report a versatile and facile synthetic route towards ultralight micro/mesoporous metal-organic aerogels based on the two-step gelation of metal-organic framework nanoparticles. Heating represents a key factor in the control of gelation versus crystallization of Al(III)-multicarboxylate systems. The porosity of the resulting metal-organic aerogels can be readily tuned, leading to the formation of well-ordered intraparticle micropores and aerogel-specific interparticle mesopores, thereby integrating the merits of both crystalline metal-organic frameworks and light aerogels. The hierarchical micro/mesoporosity of the Al-metal-organic aerogels is thoroughly evaluated by N2 sorption. The good accessibility of the micro/mesopores is verified by vapour/dye uptake, and their potential for utilization as effective fibre-coating absorbents is tested in solid-phase microextraction analyses. PMID- 23653187 TI - SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress. AB - Polo-like kinase 4 is essential for centrosome duplication, but its hyperactivation causes supernumerary centrosomes. Here we report that polo-like kinase 4 is directly phosphorylated and activated by stress-activated protein kinase kinase kinases (SAPKKKs). Stress-induced polo-like kinase 4 activation promotes centrosome duplication, whereas stress-induced SAPK activation prevents centrosome duplication. In the early phase of stress response, the balance of these opposing signals prevents centrosome overduplication. However, in the late phase of stress response, p53 downregulates polo-like kinase 4 expression, thereby preventing sustained polo-like kinase 4 activity and centrosome amplification. If both p53 and the SAPKK MKK4 are simultaneously inactivated, as is frequently found in cancer cells, persistent polo-like kinase 4 activity combined with the lack of SAPK-mediated inhibition of centrosome duplication conspire to induce supernumerary centrosomes under stress. Indeed, tumour-derived MKK4 mutants induced centrosome amplification under genotoxic stress, but only in p53-negative cells. Thus, our results reveal a mechanism that preserves the numeral integrity of centrosomes, and an unexplored tumour-suppressive function of MKK4. PMID- 23653188 TI - Top-down fabrication of sub-nanometre semiconducting nanoribbons derived from molybdenum disulfide sheets. AB - Developments in semiconductor technology are propelling the dimensions of devices down to 10 nm, but facing great challenges in manufacture at the sub-10 nm scale. Nanotechnology can fabricate nanoribbons from two-dimensional atomic crystals, such as graphene, with widths below the 10 nm threshold, but their geometries and properties have been hard to control at this scale. Here we find that robust ultrafine molybdenum-sulfide ribbons with a uniform width of 0.35 nm can be widely formed between holes created in a MoS2 sheet under electron irradiation. In situ high-resolution transmission electron microscope characterization, combined with first-principles calculations, identifies the sub-1 nm ribbon as a Mo5S4 crystal derived from MoS2, through a spontaneous phase transition. Further first-principles investigations show that the Mo5S4 ribbon has a band gap of 0.77 eV, a Young's modulus of 300GPa and can demonstrate 9% tensile strain before fracture. The results show a novel top-down route for controllable fabrication of functional building blocks for sub-nanometre electronics. PMID- 23653189 TI - Porous boron nitride nanosheets for effective water cleaning. AB - Effective removal of oils, organic solvents and dyes from water is of significant, global importance for environmental and water source protection. Advanced sorbent materials with excellent sorption capacity need to be developed. Here we report porous boron nitride nanosheets with very high specific surface area that exhibit excellent sorption performances for a wide range of oils, solvents and dyes. The nanostructured material absorbs up to 33 times its own weight in oils and organic solvents while repelling water. The saturated boron nitride nanosheets can be readily cleaned for reuse by burning or heating in air because of their strong resistance to oxidation. This easy recyclability further demonstrates the potential of porous boron nitride nanosheets for water purification and treatment. PMID- 23653190 TI - All-optical polariton transistor. AB - Although optical technology provides the best solution for the transmission of information, all-optical devices must satisfy several qualitative criteria to be used as logic elements. In particular, cascadability is difficult to obtain in optical systems, and it is assured only if the output of one stage is in the correct form to drive the input of the next stage. Exciton-polaritons, which are composite particles resulting from the strong coupling between excitons and photons, have recently demonstrated huge non-linearities and unique propagation properties. Here we show that polariton fluids moving in the plane of the microcavity can operate as input and output of an all-optical transistor, obtaining up to 19 times amplification and demonstrating the cascadability of the system. Moreover, the operation as an AND/OR gate is shown, validating the connectivity of multiple transistors in the microcavity plane and opening the way to the implementation of polariton integrated circuits. PMID- 23653191 TI - Ultraviolet-B-mediated induction of protein-protein interactions in mammalian cells. AB - Light-sensitive proteins are useful tools to control protein localization, activation and gene expression, but are currently limited to excitation with red or blue light. Here we report a novel optogenetic system based on the ultraviolet B-dependent interaction of the Arabidopsis ultraviolet-B photoreceptor UVR8 with COP1 that can be performed in visible light background. We use this system to induce nuclear accumulation of cytoplasmic green fluorescent protein fused to UVR8 in cells expressing nuclear COP1, and to recruit a nucleoplasmic red fluorescent protein fused to COP1 to chromatin in cells expressing UVR8-H2B. We also show that ultraviolet-B-dependent interactions between DNA-binding and transcription activation domains result in a linear induction of gene expression. The UVR8-COP1 interactions in mammalian cells can be induced using subsecond pulses of ultraviolet-B light and last several hours. As UVR8 photoperception is based on intrinsic tryptophan residues, these interactions do not depend on the addition of an exogenous chromophore. PMID- 23653192 TI - Rapid internal contraction boosts DNA friction. AB - Macroscopic objects are usually manipulated by force and observed with light. On the nanoscale, however, this is often done oppositely: individual macromolecules are manipulated by light and monitored with force. This procedure, which is the basis of single-molecule force spectroscopy, has led to much of our quantitative understanding of how DNA works, and is now routinely applied to explore molecular structure and interactions, DNA-protein reactions and protein folding. Here we develop the technique further by introducing a dynamic force spectroscopy set-up for a non-invasive inspection of the tension dynamics in a taut strand of DNA. The internal contraction after a sudden release of the molecule is shown to give rise to a drastically enhanced viscous friction, as revealed by the slow relaxation of an attached colloidal tracer. Our systematic theory explains the data quantitatively and provides a powerful tool for the rational design of new dynamic force spectroscopy assays. PMID- 23653193 TI - Ribosomal protein S1 functions as a termination factor in RNA synthesis by Qbeta phage replicase. AB - S1 is the largest ribosomal protein, and is vitally important for the cell. S1 is also a subunit of Qbeta replicase, the RNA-directed RNA polymerase of bacteriophage Qbeta. In both protein and RNA syntheses, S1 is commonly believed to bind to a template RNA at the initiation step, and not to be involved in later events. Here, we show that in Qbeta replicase-mediated RNA synthesis, S1 functions at the termination step by promoting release of the product strand in a single-stranded form. This function is fulfilled by the N-terminal fragment comprising the first two S1 domains. The results suggest that S1 might also have a role other than mRNA binding in the ribosome. PMID- 23653194 TI - Suppression of population transport and control of exciton distributions by entangled photons. AB - Entangled photons provide an important tool for secure quantum communication, computing and lithography. Low intensity requirements for multi-photon processes make them idealy suited for minimizing damage in imaging applications. Here we show how their unique temporal and spectral features may be used in nonlinear spectroscopy to reveal properties of multiexcitons in chromophore aggregates. Simulations demostrate that they provide unique control tools for two-exciton states in the bacterial reaction centre of Blastochloris viridis. Population transport in the intermediate single-exciton manifold may be suppressed by the absorption of photon pairs with short entanglement time, thus allowing the manipulation of the distribution of two-exciton states. The quantum nature of the light is essential for achieving this degree of control, which cannot be reproduced by stochastic or chirped light. Classical light is fundamentally limited by the frequency-time uncertainty, whereas entangled photons have independent temporal and spectral characteristics not subjected to this uncertainty. PMID- 23653195 TI - Using 20-million-year-old amber to test the super-Arrhenius behaviour of glass forming systems. AB - Fossil amber offers the opportunity to investigate the dynamics of glass-forming materials far below the nominal glass transition temperature. This is important in the context of classical theory, as well as some new theories that challenge the idea of an 'ideal' glass transition. Here we report results from calorimetric and stress relaxation experiments using a 20-million-year-old Dominican amber. By performing the stress relaxation experiments in a step-wise fashion, we measured the relaxation time at each temperature and, above the fictive temperature of this 20-million-year-old glass, this is an upper bound to the equilibrium relaxation time. The results deviate dramatically from the expectation of classical theory and are consistent with some modern ideas, in which the diverging timescale signature of complex fluids disappears below the glass transition temperature. PMID- 23653196 TI - A novel mechanism for fine-tuning open-state stability in a voltage-gated potassium channel. AB - Voltage-gated potassium channels elicit membrane hyperpolarization through voltage-sensor domains that regulate the conductive status of the pore domain. To better understand the inherent basis for the open-closed equilibrium in these channels, we undertook an atomistic scan using synthetic fluorinated derivatives of aromatic residues previously implicated in the gating of Shaker potassium channels. Here we show that stepwise dispersion of the negative electrostatic surface potential of only one site, Phe481, stabilizes the channel open state. Furthermore, these data suggest that this apparent stabilization is the consequence of the amelioration of an inherently repulsive open-state interaction between the partial negative charge on the face of Phe481 and a highly co-evolved acidic side chain, Glu395, and this interaction is potentially modulated through the Tyr485 hydroxyl. We propose that the intrinsic open-state destabilization via aromatic repulsion represents a new mechanism by which ion channels, and likely other proteins, fine-tune conformational equilibria. PMID- 23653197 TI - Description and first application of a new technique to measure the gravitational mass of antihydrogen. AB - Physicists have long wondered whether the gravitational interactions between matter and antimatter might be different from those between matter and itself. Although there are many indirect indications that no such differences exist and that the weak equivalence principle holds, there have been no direct, free-fall style, experimental tests of gravity on antimatter. Here we describe a novel direct test methodology; we search for a propensity for antihydrogen atoms to fall downward when released from the ALPHA antihydrogen trap. In the absence of systematic errors, we can reject ratios of the gravitational to inertial mass of antihydrogen >75 at a statistical significance level of 5%; worst-case systematic errors increase the minimum rejection ratio to 110. A similar search places somewhat tighter bounds on a negative gravitational mass, that is, on antigravity. This methodology, coupled with ongoing experimental improvements, should allow us to bound the ratio within the more interesting near equivalence regime. PMID- 23653199 TI - Linkage control between molecular and supramolecular chirality in 21-helical hydrogen-bonded networks using achiral components. AB - Chiral molecules preferentially form one-handed supramolecular assemblies that reflect the absolute configuration of the molecules. Under specific conditions, however, the opposite-handed supramolecular assemblies are also obtained because of flexibility in the bond length and reversibility of non-covalent interactions. The mechanism of the handedness selectivity or switching phenomenon remains ambiguous, and most phenomena are observed by chance. Here we demonstrate the construction of chiral hydrogen-bonded twofold helical assemblies with controlled handedness in the crystalline state based on crystallographic studies. Detailed investigation of the obtained crystal structures enabled us to clarify the mechanism, and the handedness of the supramolecular chirality was successfully controlled by exploiting achiral factors. This study clearly reveals a connection between molecular chirality and supramolecular chirality in the crystalline state. PMID- 23653200 TI - Pyroclastic passage zones in glaciovolcanic sequences. AB - Volcanoes are increasingly recognized as agents and recorders of global climate variability, although deciphering the linkages between planetary climate and volcanism is still in its infancy. The growth and emergence of subaqueous volcanoes produce passage zones, which are stratigraphic surfaces marking major transitions in depositional environments. In glaciovolcanic settings, they record the elevations of syn-eruptive englacial lakes. Thus, they allow for forensic recovery of minimum ice thicknesses. Here we present the first description of a passage zone preserved entirely within pyroclastic deposits, marking the growth of a tephra cone above the englacial lake level. Our discovery requires extension of the passage-zone concept to accommodate explosive volcanism and guides future studies of hundreds of glaciovolcanic edifices on Earth and Mars. Our recognition of pyroclastic passage zones increases the potential for recovering transient paleolake levels, improving estimates of paleo-ice thicknesses and providing new constraints on paleoclimate models that consider the extents and timing of planetary glaciations. PMID- 23653198 TI - Active cochlear amplification is dependent on supporting cell gap junctions. AB - Mammalian hearing relies upon active cochlear mechanics, which arises from outer hair cell electromotility and hair bundle movement, to amplify acoustic stimulations increasing hearing sensitivity and frequency selectivity. Here we describe the novel finding that gap junctions between cochlear supporting cells also have a critical role in active cochlear amplification in vivo. We find that targeted-deletion of connexin 26 in Deiters cells and outer pillar cells, which constrain outer hair cells standing on the basilar membrane, causes a leftward shift in outer hair cell electromotility towards hyperpolarization, and reduces active cochlear amplification with hearing loss. Coincident with large reduction in distortion product otoacoustic emission and severe hearing loss at high frequencies, the shift is larger in shorter outer hair cells. Our study demonstrates that active cochlear amplification in vivo is dependent on supporting cell gap junctions. These new findings also show that connexin 26 deficiency can reduce active cochlear amplification to induce hearing loss. PMID- 23653201 TI - Predatory cannibalism in Drosophila melanogaster larvae. AB - Hunting live prey is risky and thought to require specialized adaptations. Therefore, observations of predatory cannibalism in otherwise non-carnivorous animals raise questions about its function, adaptive significance and evolutionary potential. Here we document predatory cannibalism on larger conspecifics in Drosophila melanogaster larvae and address its evolutionary significance. We found that under crowded laboratory conditions younger larvae regularly attack and consume 'wandering-stage' conspecifics, forming aggregations mediated by chemical cues from the attacked victim. Nutrition gained this way can be significant: an exclusively cannibalistic diet was sufficient for normal development from eggs to fertile adults. Cannibalistic diet also induced plasticity of larval mouth parts. Finally, during 118 generations of experimental evolution, replicated populations maintained under larval malnutrition evolved enhanced propensity towards cannibalism. These results suggest that, at least under laboratory conditions, predation on conspecifics in Drosophila is a functional, adaptive behaviour, which can rapidly evolve in response to nutritional conditions. PMID- 23653202 TI - Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation. AB - How oncogenic signalling coordinates glycolysis and anabolic biosynthesis in cancer cells remains unclear. We recently reported that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate and product 2 phosphoglycerate. Here we report a novel mechanism in which Y26 phosphorylation enhances PGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor 2,3-bisphosphoglycerate binding and H11 phosphorylation. We also report the crystal structure of H11-phosphorylated PGAM1 and find that phospho-H11 activates PGAM1 at least in part by promoting substrate 3-phosphoglycerate binding. Moreover, Y26 phosphorylation of PGAM1 is common in human cancer cells and contributes to regulation of 3-phosphoglycerate and 2 phosphoglycerate levels, promoting cancer cell proliferation and tumour growth. As PGAM1 is a negative transcriptional target of TP53, and is therefore commonly upregulated in human cancers, these findings suggest that Y26 phosphorylation represents an additional acute mechanism underlying phosphoglycerate mutase 1 upregulation. PMID- 23653203 TI - The genome of a Mesozoic paleovirus reveals the evolution of hepatitis B viruses. AB - Paleovirology involves the identification of ancient endogenous viral elements within eukaryotic genomes. The evolutionary origins of the reverse-transcribing hepatitis B viruses, however, remain elusive, due to the small number of endogenized sequences present in host genomes. Here we report a comprehensively dated genomic record of hepatitis B virus endogenizations that spans bird evolution from >82 to <12.1 million years ago. The oldest virus relic extends over a 99% complete hepatitis B virus genome sequence and constitutes the first discovery of a Mesozoic paleovirus genome. We show that Hepadnaviridae are >63 million years older than previously known and provide direct evidence for coexistence of hepatitis B viruses and birds during the Mesozoic and Cenozoic Eras. Finally, phylogenetic analyses and distribution of hepatitis B virus relics suggest that birds potentially are the ancestral hosts of Hepadnaviridae and mammalian hepatitis B viruses probably emerged after a bird-mammal host switch. Our study reveals previously undiscovered and multi-faceted insights into prehistoric hepatitis B virus evolution and provides valuable resources for future studies, such as in-vitro resurrection of Mesozoic hepadnaviruses. PMID- 23653204 TI - Optimization of stress response through the nuclear receptor-mediated cortisol signalling network. AB - It is an accepted paradigm that extended stress predisposes an individual to pathophysiology. However, the biological adaptations to minimize this risk are poorly understood. Using a computational model based upon realistic kinetic parameters we are able to reproduce the interaction of the stress hormone cortisol with its two nuclear receptors, the high-affinity glucocorticoid receptor and the low-affinity pregnane X-receptor. We demonstrate that regulatory signals between these two nuclear receptors are necessary to optimize the body's response to stress episodes, attenuating both the magnitude and duration of the biological response. In addition, we predict that the activation of pregnane X receptor by multiple, low-affinity endobiotic ligands is necessary for the significant pregnane X-receptor-mediated transcriptional response observed following stress episodes. This integration allows responses mediated through both the high and low-affinity nuclear receptors, which we predict is an important strategy to minimize the risk of disease from chronic stress. PMID- 23653205 TI - Acoustic dynamics of network-forming glasses at mesoscopic wavelengths. AB - The lack of long-range structural order in amorphous solids induces well known thermodynamic anomalies, which are the manifestation of distinct peculiarities in the vibrational spectrum. Although the impact of such anomalies vanishes in the long wavelength, elastic continuum limit, it dominates at length scales comparable to interatomic distances, implying an intermediate transition regime still poorly understood. Here we report a study of such mesoscopic domains by means of a broadband version of picosecond photo-acoustics, developed to coherently generate and detect hypersonic sound waves in the sub-THz region with unprecedented sampling efficiency. We identify a temperature-dependent fractal v(3/2) frequency behaviour of the sound attenuation, pointing to the presence of marginally stable regions and a transition between the two above mentioned limits. The essential features of this behaviour are captured by a theoretical approach based on random spatial variation of the shear modulus, including anharmonic interactions. PMID- 23653206 TI - Resonant tunnelling and negative differential conductance in graphene transistors. AB - The chemical stability of graphene and other free-standing two-dimensional crystals means that they can be stacked in different combinations to produce a new class of functional materials, designed for specific device applications. Here we report resonant tunnelling of Dirac fermions through a boron nitride barrier, a few atomic layers thick, sandwiched between two graphene electrodes. The resonance occurs when the electronic spectra of the two electrodes are aligned. The resulting negative differential conductance in the device characteristics persists up to room temperature and is gate voltage-tuneable due to graphene's unique Dirac-like spectrum. Although conventional resonant tunnelling devices comprising a quantum well sandwiched between two tunnel barriers are tens of nanometres thick, the tunnelling carriers in our devices cross only a few atomic layers, offering the prospect of ultra-fast transit times. This feature, combined with the multi-valued form of the device characteristics, has potential for applications in high-frequency and logic devices. PMID- 23653207 TI - Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. AB - Tumours recruit mesenchymal stem cells to facilitate healing, which induces their conversion into cancer-associated fibroblasts that facilitate metastasis. However, this process is poorly understood on the molecular level. Here we show that CXCL16, a ligand for CXCR6, facilitates mesenchymal stem cell or very small embryonic-like cells recruitment into prostate tumours. CXCR6 signalling stimulates the conversion of mesenchymal stem cells into cancer-associated fibroblasts, which secrete stromal-derived factor-1, also known as CXCL12. CXCL12 expressed by cancer-associated fibroblasts then binds to CXCR4 on tumour cells and induces an epithelial-to-mesenchymal transition, which ultimately promotes metastasis to secondary tumour sites. Our results provide the molecular basis for mesenchymal stem cell recruitment into tumours and how this process leads to tumour metastasis. PMID- 23653208 TI - G-quadruplex structures are stable and detectable in human genomic DNA. AB - The G-quadruplex is an alternative DNA structural motif that is considered to be functionally important in the mammalian genome for transcriptional regulation, DNA replication and genome stability, but the nature and distribution of G quadruplexes across the genome remains elusive. Here, we address the hypothesis that G-quadruplex structures exist within double-stranded genomic DNA and can be explicitly identified using a G-quadruplex-specific probe. An engineered antibody is employed to enrich for DNA containing G-quadruplex structures, followed by deep sequencing to detect and map G-quadruplexes at high resolution in genomic DNA from human breast adenocarcinoma cells. Our high sensitivity structure-based pull-down strategy enables the isolation of genomic DNA fragments bearing single, as well as multiple G-quadruplex structures. Stable G-quadruplex structures are found in sub-telomeres, gene bodies and gene regulatory regions. For a sample of identified target genes, we show that G-quadruplex-stabilizing ligands can modulate transcription. These results confirm the existence of G-quadruplex structures and their persistence in human genomic DNA. PMID- 23653209 TI - Calix[n]imidazolium as a new class of positively charged homo-calix compounds. AB - Macrocycles based on neutral calixarenes and calixpyrroles have been extensively explored for ion binding, molecular assembly and related applications. Given that only these two types of calix compounds and their analogs are available, the introduction of new forms of widely usable calix macrocycles is an outstanding challenge. Here we report the quadruply/quintuply charged imidazole-based homo calix compounds, calix[4/5]imidazolium. The noncovalent (C-H)(+)/pi(+)-anion interactions of the imidazolium rings with anions inside and outside the cone are the stabilizing factors for crystal packing, resulting in self-assembled arrays of cone-shaped calix-imidazolium molecules. Calix[4]imidazolium senses fluoride selectively even in aqueous solutions. Calix[5]imidazolium recognizes neutral fullerenes through pi(+)-pi interactions and makes them soluble in water, which could be useful in fullerene chemistry. Not only derivatization and ring expansion of calix[n]imidazolium, but also their utilization in ionic liquids, carbene chemistry and nanographite/graphene exfoliation could be exploited. PMID- 23653211 TI - Observation of the nonlocal spin-orbital effective field. AB - The spin-orbital interaction in heavy nonmagnetic metal/ferromagnetic metal bilayer systems has attracted great attention and exhibited promising potentials in magnetic logic devices, where the magnetization direction is controlled by passing an electric current. It is found that the spin-orbital interaction induces both an effective field and torque on the magnetization, which have been attributed to two different origins: the Rashba effect and the spin Hall effect. It requires quantitative analysis to distinguish the two mechanisms. Here we show sensitive spin-orbital effective field measurements up to 10 nm thick ferromagnetic layer and find the effective field rapidly diminishes with the increase of the ferromagnetic layer thickness. We further show that this effective field persists even with the insertion of a copper spacer. The nonlocal measurement suggests that the spin-orbital effective field does not rely on the heavy normal metal/ferromagnetic metal interface. PMID- 23653210 TI - FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA. AB - N(6)-methyladenosine is a prevalent internal modification in messenger RNA and non-coding RNA affecting various cellular pathways. Here we report the discovery of two additional modifications, N(6)-hydroxymethyladenosine (hm(6)A) and N(6) formyladenosine (f(6)A), in mammalian messenger RNA. We show that Fe(II)- and alpha-ketoglutarate-dependent fat mass and obesity-associated (FTO) protein oxidize N(6)-methyladenosine to generate N(6)-hydroxymethyladenosine as an intermediate modification, and N(6)-formyladenosine as a further oxidized product. N(6)-hydroxymethyladenosine and N(6)-formyladenosine have half-life times of ~3 h in aqueous solution under physiological relevant conditions, and are present in isolated messenger RNA from human cells as well as mouse tissues. These previously unknown modifications derived from the prevalent N(6) methyladenosine in messenger RNA, formed through oxidative RNA demethylation, may dynamically modulate RNA-protein interactions to affect gene expression regulation. PMID- 23653212 TI - Non-hyperpolarizing GABAB receptor activation regulates neuronal migration and neurite growth and specification by cAMP/LKB1. AB - gamma-Aminobutyric acid is the principal inhibitory neurotransmitter in adults, acting through ionotropic chloride-permeable GABAA receptors (GABAARs), and metabotropic GABABRs coupled to calcium or potassium channels, and cyclic AMP signalling. During early development, gamma-aminobutyric acid is the main neurotransmitter and is not hyperpolarizing, as GABAAR activation is depolarizing while GABABRs lack coupling to potassium channels. Despite extensive knowledge on GABAARs as key factors in neuronal development, the role of GABABRs remains unclear. Here we address GABABR function during rat cortical development by in utero knockdown (short interfering RNA) of GABABR in pyramidal-neuron progenitors. GABABR short interfering RNA impairs neuronal migration and axon/dendrite morphological maturation by disrupting cyclic AMP signalling. Furthermore, GABABR activation reduces cyclic AMP-dependent phosphorylation of LKB1, a kinase involved in neuronal polarization, and rescues LKB1 overexpression induced defects in cortical development. Thus, non-hyperpolarizing activation of GABABRs during development promotes neuronal migration and morphological maturation by cyclic AMP/LKB1 signalling. PMID- 23653214 TI - Tomonaga-Luttinger physics in electronic quantum circuits. AB - In one-dimensional conductors, interactions result in correlated electronic systems. At low energy, a hallmark signature of the so-called Tomonaga-Luttinger liquids is the universal conductance curve predicted in presence of an impurity. A seemingly different topic is the quantum laws of electricity, when distinct quantum conductors are assembled in a circuit. In particular, the conductances are suppressed at low energy, a phenomenon called dynamical Coulomb blockade. Here we investigate the conductance of mesoscopic circuits constituted by a short single-channel quantum conductor in series with a resistance, and demonstrate a proposed link to Tomonaga-Luttinger physics. We reformulate and establish experimentally a recently derived phenomenological expression for the conductance using a wide range of circuits, including carbon nanotube data obtained elsewhere. By confronting both conductance data and phenomenological expression with the universal Tomonaga-Luttinger conductance curve, we demonstrate experimentally the predicted mapping between dynamical Coulomb blockade and the transport across a Tomonaga-Luttinger liquid with an impurity. PMID- 23653213 TI - Regulation of asymmetric cell division and polarity by Scribble is not required for humoral immunity. AB - The production of protective antibody requires effective signalling of naive B cells following encounter with antigen, and the divergence of responding B lymphocytes into distinct lineages. Polarity proteins have recently been proposed as important mediators of both the initial B cell response, and potentially of asymmetric cell division. Here we show that, although polarity proteins of the Scribble complex, Scribble, Dlg1 and Lgl1, are expressed and polarized during early B cell activation, their deficiency has no effect on the in vivo outcome of immunization or challenge with influenza infection. Furthermore, we find a striking correlation in the differentiation outcome of daughters of single founder B cells in vitro. Taken together, our results indicate that B cell differentiation does not require polarity proteins of the Scribble complex, and the findings do not support a role for asymmetric cell division in B cell activation and differentiation. PMID- 23653215 TI - Self-sustained oscillations of a torsional SQUID resonator induced by Lorentz force back-action. AB - For the study of nanomechanical resonators, ultra-sensitive measurement techniques are crucial. However, if the measurement sensitivity approaches quantum-mechanical limits, the back-action of the detector on the resonator cannot be neglected. If the back-action is strong enough, the corresponding instability can create self-sustained oscillators in the resonator. Here we demonstrate that a torsional mechanical resonator, which contains a direct current SQUID displacement detector, leads to this effect. We find that the Lorentz-force back-action can be so large that, in combination with complex nonlinear Josephson dynamics, it generates intrinsic self-sustained oscillations. The flux quantization limit of the maximum oscillation amplitude is exploited to calibrate the displacement resolution, which is shown to be below the standard quantum limit. The suspended torsional SQUID provides an interesting platform to study on-chip laser-like physics in an electromechanical system that can be controlled by both a flux and current bias. PMID- 23653217 TI - A K-nearest neighbors survival probability prediction method. AB - We introduce a nonparametric survival prediction method for right-censored data. The method generates a survival curve prediction by constructing a (weighted) Kaplan-Meier estimator using the outcomes of the K most similar training observations. Each observation has an associated set of covariates, and a metric on the covariate space is used to measure similarity between observations. We apply our method to a kidney transplantation data set to generate patient specific distributions of graft survival and to a simulated data set in which the proportional hazards assumption is explicitly violated. We compare the performance of our method with the standard Cox model and the random survival forests method. PMID- 23653216 TI - AtALMT9 is a malate-activated vacuolar chloride channel required for stomatal opening in Arabidopsis. AB - Water deficit strongly affects crop productivity. Plants control water loss and CO2 uptake by regulating the aperture of the stomatal pores within the leaf epidermis. Stomata aperture is regulated by the two guard cells forming the pore and changing their size in response to ion uptake and release. While our knowledge about potassium and chloride fluxes across the plasma membrane of guard cells is advanced, little is known about fluxes across the vacuolar membrane. Here we present the molecular identification of the long-sought-after vacuolar chloride channel. AtALMT9 is a chloride channel activated by physiological concentrations of cytosolic malate. Single-channel measurements demonstrate that this activation is due to a malate-dependent increase in the channel open probability. Arabidopsis thaliana atalmt9 knockout mutants exhibited impaired stomatal opening and wilt more slowly than the wild type. Our findings show that AtALMT9 is a vacuolar chloride channel having a major role in controlling stomata aperture. PMID- 23653218 TI - Gender-specific transcriptomic response to environmental exposure in Flemish adults. AB - Flanders, Belgium, is one of the most densely populated areas in Europe. The Flemish Environment and Health Survey (2002-2006) aimed at determining exposure to pollutants of neonates, adolescents, and older adults and to assess associated biological and health effects. This study investigated genome wide gene expression changes associated with a range of environmental pollutants, including cadmium, lead, PCBs, dioxin, hexachlorobenzene, p,p'-DDE, benzene, and PAHs. Gene expression levels were measured in peripheral blood cells of 20 adults with relatively high and 20 adults with relatively low combined internal exposure levels, all non-smokers aged 50-65. Pearson correlation was used to analyze associations between pollutants and gene expression levels, separately for both genders. Pollutant- and gender-specific correlation analysis results were obtained. For organochlorine pollutants, analysis within genders revealed that genes were predominantly regulated in opposite directions in males and females. Significantly modulated pathways were found to be associated with each of the exposure biomarkers measured. Pathways and/or genes related to estrogen and STAT5 signaling were correlated to organochlorine exposures in both genders. Our work demonstrates that gene expression in peripheral blood is influenced by environmental pollutants. In particular, gender-specific changes are associated with organochlorine pollutants, including gender-specific modulation of endocrine related pathways and genes. These pathways and genes have previously been linked to endocrine disruption related disorders, which in turn have been associated with organochlorine exposure. Based on our results, we recommend that males and females be considered separately when analyzing gene expression changes associated with exposures that may include chemicals with endocrine disrupting properties. PMID- 23653219 TI - Recurrent skeletal extra-axial chordoma confirmed with brachyury: imaging features and review of the literature. AB - A small number of tumors bearing histological resemblance to axial chordoma arising from the bone or soft tissue outside the axial skeleton have been reported. These lesions have historically been referred to as parachordoma, chordoma periphericum (CP), or extra-axial chordoma (EAC). With the introduction of the immunohistochemical stain brachyury, a sensitive and specific marker for notochordal origin, chordomas arising in extra-axial locations (i.e., CP, EAC), are now diagnosed with more accuracy and distinguished from parachordoma, which resembles chordoma on histology. The distinction between EAC and parachordoma is clinically important because EAC confirmed by immunoreactivity for brachyury tends to grow and recur with local bone destruction. Prior to the introduction of brachyury, the diagnosis of EAC was challenging and therefore the imaging features of EAC have not been comprehensively described. We report two cases of recurrent EAC confirmed by the expression of brachyury arising from the distal femur and distal tibia and describe the imaging findings from radiography and MRI at initial diagnosis and at recurrence. PMID- 23653220 TI - Is dynamic contrast-enhanced MRI useful for assessing proximal fragment vascularity in scaphoid fracture delayed and non-union? AB - OBJECTIVE: To assess dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) as a measure of vascularity in scaphoid delayed-union or non-union. MATERIALS AND METHODS: Thirty-five patients (34 male, one female; mean age, 27.4 +/- 9.4 years; range, 16-51 years) with scaphoid delayed-union and non-union who underwent DCE MRI of the scaphoid between September 2002 and October 2012 were retrospectively reviewed. Proximal fragment vascularity was classified as good, fair, or poor on unenhanced MRI, contrast-enhanced MRI, and DCE MRI. For DCE MRI, enhancement slope, Eslope comparison of proximal and distal fragments was used to classify the proximal fragment as good, fair, or poor vascularity. Proximal fragment vascularity was similarly graded at surgery in all patients. Paired t test and McNemar test were used for data comparison. Kappa value was used to assess level of agreement between MRI findings and surgical findings. RESULTS: Twenty-five (71 %) of 35 patients had good vascularity, four (11 %) had fair vascularity, and six (17 %) had poor vascularity of the proximal scaphoid fragment at surgery. DCE MRI parameters had the highest correlation with surgical findings (kappa = 0.57). Proximal scaphoid fragments with surgical poor vascularity had a significantly lower Emax and Eslope than those with good vascularity (p = 0.0043 and 0.027). The sensitivity, specificity, positive and negative predictive value and accuracy of DCE MRI in predicting impaired vascularity was 67, 86, 67, 86, and 80 %, respectively, which was better than that seen with unenhanced and post-contrast MRI. Flattened time intensity curves in both proximal and distal fragments were a feature of protracted non-union with a mean time interval of 101.6 +/- 95.5 months between injury and MRI. CONCLUSIONS: DCE MRI has a higher diagnostic accuracy than either non-enhanced MRI or contrast enhanced MRI for assessing proximal fragment vascularity in scaphoid delayed-union and non-union. For proper interpretation of contrast enhanced studies in scaphoid vascularity, one needs to incorporate the time frame between injury and MRI. PMID- 23653221 TI - The impairment of lysyl oxidase in keratoconus and in keratoconus-associated disorders. AB - Keratoconus (KC) is an eye disease characterized by the progressive thinning and protrusion of the cornea, which results in the loss of visual acuity. This disorder remains poorly understood, although recent studies indicate the involvement of genetic and environmental factors. Recently, we have found that the distribution of the cross-linking enzyme lysyl oxidase (LOX) is markedly decreased in about 63 % of keratoconic specimens. Similarly, LOX activity is significantly reduced by 38 % compared to control tissue. Nearly 70 systemic disorders have been reported in association with KC, most of them affecting the extracellular matrix. In this review we attempted to ascertain whether any KC associated diseases exhibit signs that may reflect LOX impairment. We hypothesized that very similar changes in the extracellular matrix, particularly at the level of collagen metabolism, including LOX impairment in mitral leaflets, may reflect an association between KC and mitral valve prolapse. Moreover, this putative association is supported by the high frequency of Down syndrome in both diseases. Among other disorders that have been found to coincide with KC, we did not find any in which the LOX enzyme may be directly or indirectly impaired. On the other hand, in cases where KC is present along with other connective tissue disorders (Marfan syndrome, Ehlers-Danlos syndrome and others), KC may not arise as a localized manifestation, but rather may be induced as the result of a more complex connective tissue disorder. PMID- 23653222 TI - Generation of hydrogen peroxide-resistant murine neuroblastoma cells: a target discovery platform for novel neuroprotective genes. AB - Oxidative stress has been suggested to play an important role in the pathogenesis of various neurodegenerative diseases including Alzheimer's disease (AD). Hydrogen peroxide (H2O2), one of the main reactive oxygen species, is converted into the highly toxic .OH radical in the presence of redox-active transition metals, which then oxidises nucleic acids, lipids and proteins, leading to neurodegeneration and cell death. There is an urgent need to gain more knowledge about relevant therapeutic targets to combat oxidative stress and it neurotoxic effects, and how this knowledge can be utilized to develop novel neuroprotective therapies for AD. One way to identify new mechanisms combating oxidative stress was via the creation of H2O2-resistant cell lines and identification of the mechanisms responsible for their resistance. However, in most cases catalase overexpression or increased glutathione content was identified as the primary mode of H2O2 resistance in these cell lines. In this study, we have generated six different resistant neuronal cell lines or populations (from the same original murine Neuro2a neuroblastoma line) by exposing cells to increasing concentrations of H2O2 and performing continuous selection for survivors over a period of several months, which appear to have acquired H2O2 resistance based on other, novel mechanisms. These six populations showed a significant, but differential resistance against H2O2 when compared with the parental cell line. Using combinations of catalase-, glutathione synthesis- and glutathione peroxidase inhibitors it was shown that the increased resistance of Neuro2a-HR cells is not solely based on an increased activity of catalase or the glutathione system, suggesting that their resistance might be based on yet unknown, novel defence mechanisms. PMID- 23653223 TI - Phytochemical properties and antioxidant capacities of various colored berries. AB - BACKGROUND: Berries are known to be rich in anthocyanins. These compounds give berries their distinctive colors and, more importantly, have several health benefits, such as contributing to the prevention of heart disease, cancer and inflammatory disease. In this study, anthocyanin-rich extracts from 12 colored berries found in northern China were analyzed by high-performance liquid chromatography coupled with diode array detection and electrospray ionization mass spectrometry (HPLC-DAD/ESI-MS). Total polyphenol content (TPC), total flavonoid content (TFC), total anthocyanin content (TAC) and antioxidant capacity (AOC) of the berries were assayed. The contribution of anthocyanins in the berries to their antioxidant capacity and bioactivity was also investigated. RESULTS: The 12 berries analyzed had typical profiles with different anthocyanin compositions, which can be considered as an indicator for differentiating berries. Cyanidin-3-xylosyl-galactoside and cyanidin-3-xylosyl-rutinoside were identified for the first time in Acanthopanax S. and Chinese dwarf cherry respectively. All berry extracts showed potent antioxidant activity, and TPC correlated well with AOC. Blue honeysuckle, blackcurrant and blueberry had higher TAC/TPC ratio, with anthocyanins contributing more to AOC. The higher flavonoid content in yellow raspberry and sea buckthorn might increase their antioxidant activity. In addition, wild raspberry had higher antioxidant activity than cultivated raspberries, but they all had lower anthocyanin content with less contribution to AOC. CONCLUSION: There is great potential to improve human health through consumption of these colored berries, especially those high in AOC. PMID- 23653224 TI - Carnitine levels in 26,462 individuals from the nationwide screening program for primary carnitine deficiency in the Faroe Islands. AB - BACKGROUND: Primary carnitine deficiency (PCD) is an autosomal recessive disorder of fatty acid oxidation and has been associated to episodes of sudden death in the Faroe Islands. Data are presented from the nationwide population based Faroese screening program to find people with low carnitine levels indicating PCD. METHODS: Whole blood samples from dried blood spots were analysed by tandem mass spectrometry with and without butylation. Genetic analyses were performed in all people with non-butylated free carnitine (fC0) below 7 MUmol/L. RESULTS: 55 % (n = 26,462) of the entire population was screened and 89 PCD patients were identified, yielding an overall prevalence of 1:297 of PCD in the Faroe Islands. Carnitine levels were positively correlated to age in both males and females (p < 0.003) although levels decreased in females when reaching fertile age. The gender difference in mean carnitine levels was significant during female fertile age (4.71 MUmol/L fC0 in the age group 25-30 years, p < 0.01). A lower cut-off of 5 MUmol/L in fC0 identified all homozygous for the severe genotype c.95A > G (p.N32S) (n = 20). CONCLUSION: Carnitine levels differ by gender and age. A lower cut-off of 5 MUmol/L in fC0 was appropriate to identify c.95A > G homozygotes. The prevalence of PCD in the Faroe Islands is the highest reported in the world (1:297). PMID- 23653225 TI - Human and mouse neuroinflammation markers in Niemann-Pick disease, type C1. AB - Niemann-Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post-mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C-X-C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL 3, IL-10 and IL-13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials. PMID- 23653227 TI - Does the PKU diet contribute to impaired renal function? PMID- 23653229 TI - Gold(I)-catalyzed cascade cycloadditions between allenamides and carbonyl tethered alkenes: an enantioselective approach to oxa-bridged medium-sized carbocycles. PMID- 23653228 TI - Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis. AB - Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and the epigenetic process of DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and cancers. However, reports on the association of MTHFR polymorphisms with autism spectrum disorders (ASD) are inconclusive. Therefore, we investigated the relationship of the MTHFR polymorphisms (C677T and A1298C) and the risk of ASD by meta-analysis. Up to December 2012, eight case-control studies involving 1672 patients with ASD and 6760 controls were included for meta-analysis. The results showed that the C677T polymorphism was associated with significantly increased ASD risk in all the comparison models [T vs. C allele (frequency of allele): odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.09-1.85; CT vs. CC (heterozygote): OR = 1.48, 95% CI: 1.09-2.00; TT vs. CC (homozygote): OR = 1.86, 95% CI: 1.08-3.20; CT+TT vs. CC (dominant model): OR = 1.56, 95% CI: 1.12-2.18; and TT vs. CC+CT (recessive model): OR = 1.51, 95% CI: 1.02-2.22], whereas the A1298C polymorphism was found to be significantly associated with reduced ASD risk but only in a recessive model (CC vs. AA+AC: OR = 0.73, 95% CI: 0.56-0.97). In addition, we stratified the patient population based on whether they were from a country with food fortification of folic acid or not. The meta-analysis showed that the C677T polymorphism was found to be associated with ASD only in children from countries without food fortification. Our study indicated that the MTHFR C677T polymorphism contributes to increased ASD risk, and periconceptional folic acid may reduce ASD risk in those with MTHFR 677C>T polymorphism. PMID- 23653226 TI - Mucopolysaccharide diseases: a complex interplay between neuroinflammation, microglial activation and adaptive immunity. AB - Mucopolysaccharide (MPS) diseases are lysosomal storage disorders (LSDs) caused by deficiencies in enzymes required for glycosaminoglycan (GAG) catabolism. Mucopolysaccharidosis I (MPS I), MPS IIIA, MPS IIIB and MPS VII are deficient in the enzymes alpha-L-Iduronidase, Heparan-N-Sulphatase, N-Acetylglucosaminidase and Beta-Glucuronidase, respectively. Enzyme deficiency leads to the progressive multi-systemic build-up of heparan sulphate (HS) and dermatan sulphate (DS) within cellular lysosomes, followed by cell, tissue and organ damage and in particular neurodegeneration. Clinical manifestations of MPS are well established; however as lysosomes represent vital components of immune cells, it follows that lysosomal accumulation of GAGs could affect diverse immune functions and therefore influence disease pathogenesis. Theoretically, MPS neurodegeneration and GAGs could be substantiating a threat of danger and damage to alert the immune system for cellular clearance, which due to the progressive nature of MPS storage would propagate disease pathogenesis. Innate immunity appears to have a key role in MPS; however the extent of adaptive immune involvement remains to be elucidated. The current literature suggests a complex interplay between neuroinflammation, microglial activation and adaptive immunity in MPS disease. PMID- 23653230 TI - Evaluation of a new formulation of epoprostenol sodium in Japanese patients with pulmonary arterial hypertension (EPITOME4). AB - INTRODUCTION: Pulmonary arterial hypertension (PAH) is associated with poor prognosis despite significant recent advances in its treatment. An intravenous formulation of epoprostenol sodium containing glycine and mannitol (epoprostenol GM; GlaxoSmithKline, London, UK) is widely used to treat PAH. A new formulation of epoprostenol sodium containing arginine and sucrose excipients (epoprostenol AS; Actelion Pharmaceuticals Japan Ltd., Tokyo, Japan) shows better stability at room temperature after preparing diluted solutions. The primary objective of this study was to evaluate the safety and tolerability of switching from epoprostenol GM to epoprostenol AS in Japanese patients with PAH. The authors also evaluated the efficacy and treatment satisfaction after switching formulations. METHODS: This was a two-site, open-label, single-arm, Phase 3b study. Eight adult Japanese PAH patients (seven females) treated with a stable dose of epoprostenol GM for >=30 days were switched to epoprostenol AS and followed for 12 weeks. Outcomes included safety, changes from baseline to 12 weeks in pulmonary hemodynamic factors (pulmonary vascular resistance, mean pulmonary arterial pressure, and cardiac output), and treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM-9). RESULTS: The mean (range) age and time since diagnosis of PAH were 48 (25-69) years and 6.2 (0.6-13.9) years, respectively. There were no unexpected safety or tolerability concerns after switching formulations. The epoprostenol dose was maintained after switching formulations. There were no significant changes in pulmonary hemodynamic factors from baseline to week 12. Regarding treatment satisfaction, there was a significant improvement in convenience, which is demonstrated in the score of the domain increased from 51.40 +/- 10.19 at baseline to 58.33 +/- 12.96 at week 12 (P < 0.05). CONCLUSIONS: Switching from epoprostenol GM to the same dose of epoprostenol AS was well tolerated over 12 weeks of treatment, and pulmonary hemodynamics were maintained. Switching to epoprostenol AS was also associated with improvements in treatment satisfaction (convenience). Clinical Trials: JapicCTI-122017. PMID- 23653231 TI - Effects of raftilose on serum biochemistry and liver morphology in rats fed with normal or high-fat diet. AB - Non-alcoholic fatty liver disease is the leading cause of chronic liver injury in developed countries. Oligofructose (OFS) is a prebiotic with proven benefits for health. The aim of the study is to evaluate the effect of 10% OFS on hepatic morphology and lipid metabolism in Wistar Kyoto rats submitted to normal diet (ND) or high-fat diet (FD). Animals were treated for 7 weeks. Lipid profile and serum alkaline phosphatase (ALP) activity were measured and liver histology evaluated at the end of the study. Ten percent OFS reduced triglyceride (TAG) levels when added to any of the diet regimens; 10% OFS decreased plasmatic urea in ND and plasmatic and urinary urea levels in FD; ND + 10% OFS treated rats showed lower ALP activity than controls. FD increased ALP activity, an effect not reversed by OFS. Animals submitted to FD have microscopic hepatic changes: marked steatosis with disarranged centrilobular zone structure; enlarged sinusoids; enlarged mitochondria and an increase in number and volume of adiposomes. Supplementation with 10% OFS in FD reversed those effects. In conclusion, 10% OFS supplementation prevented deleterious effects of FD such as alterations on lipid profile (TAG elevation) and hepatic morphologic changes. OFS decreased ALP activity in animals subjected to ND, which may have contributed to the differences on lipid metabolism. PMID- 23653232 TI - Entre-Parents: initial outcome evaluation of a preventive-parenting program for French-speaking parents. AB - Entre-Parents is the French adaptation of Parenting Our Children to Excellence, an eight-session group-parenting program for parents of preschoolers. An evaluation conducted in the French-speaking part of Switzerland with 132 parents provides initial evidence for the community acceptability and efficacy of Entre Parents. Program attendance was high (average of 6.6 out of the 8 sessions), and parents participated actively in sessions and expressed high levels of program satisfaction. Results indicate that, over time, the program contributed to more effective parenting practices, a reduction in parenting stress, an increase in family adaptability, and increases in children's social competence and reductions in their disruptive and anxious behaviors. Some of these benefits were stronger for parents who attended more sessions. PMID- 23653234 TI - Lessons from a flash flood in tehran subway, iran. PMID- 23653235 TI - Primary tumor vascularity in esophagus cancer. CD34 and HIF1-alpha expression correlate with tumor progression. AB - OBJECTIVE: Hypoxia inducible factor alpha (HIF1-alpha) is a key protein regulating the response of a variety of genes and pathways, including angiogenesis, to hypoxic stimuli. High vascularity in various carcinomas correlates with invasion and metastasis. Assessment of primary tumor vascularity and HIF1-alpha expression in esophageal carcinomas was an objective of this study. METHODS: The vascularity in esophageal carcinomas (n=52) was quantified by Chalkley method on CD34 immunostained sections. HIF1-alpha expression was examined by immunohistochemistry. The relationships between CD34 Chalkley count, HIF1-alpha and various clinico-pathological characteristics with clinical outcome were evaluated. RESULTS: High HIF1-alpha expression in squamous cell carcinoma (SCC) was significantly associated with the T3-4 group (p=0.02). A higher percentage of SCC with high HIF1-alpha expression compared to its expression in adenocarcinoma (AC) (p=0.005) was observed. In the SCC group, high CD34 Chalkley count and high HIF1-alpha expression implied a significantly reduced survival (p=0.003 and p=0.001). No such significant association was found in the AC group. CONCLUSIONS: HIF1-alpha expression is different in two separate tumor microenvironments: SCCs and ACs of the esophagus. This suggests that different mechanisms may be involved in HIF1-alpha expression- and activity between the two histological types of esophageal carcinoma. PMID- 23653236 TI - Diagnostic accuracy of preoperative alpha-fetoprotein as an ovarian tumor marker in children and adolescents: not as good as we thought? AB - PURPOSE: To evaluate the diagnostic accuracy of preoperative serum alpha fetoprotein (AFP) levels in predicting malignancy risk in children and adolescents presenting with ovarian neoplasms. METHODS: In 110 girls aged 18 and below diagnosed with ovarian neoplasms, we retrospectively correlated preoperative serum AFP levels with histological diagnosis of germ cell tumor or immature teratoma (GCT/IT) versus non-GCT/IT, and benign versus non-benign. We determined area under receiver-operating characteristic curves (AUC), sensitivity, specificity, and likelihood ratios. RESULTS: Twenty patients (18.2 %) had non-benign ovarian neoplasms, of which 12 had GCT/IT (10.9 %). In diagnosing GCT/IT versus non-GCT/IT, specificity of preoperative serum AFP was 87.8 %, sensitivity 66.7 %, and AUC 0.853. Excluding infants to remove the effects of increased variance in AFP in this group, specificity improved (92.0 %), but not sensitivity (66.7 %); AUC was 0.926. Increasing AFP cutoff to two times upper normal limit improved specificity (94.9 %), but not sensitivity (66.7 %). For benign versus non-benign tumors, AFP specificity was only 88.9 % and sensitivity 50.0 %. CONCLUSION: The diagnostic accuracy of preoperative serum AFP for detecting GCT/IT in girls was limited by poor sensitivity and positive predictive value. Excluding infants and raising cutoff levels improved specificity marginally. Clinicians should be aware of these limitations when using AFP in the preoperative evaluation of childhood ovarian neoplasms. PMID- 23653237 TI - Costal osteochondroma spicule associated with pleural effusion. AB - Costal osteochondromas are a rare cause of lung injury. We report a 7-year-old male who presented with chest pain, cough, and left-sided pleural effusion following a fall. Imaging identified a 2 cm costal osteochondroma, which was resected with a thoracoscopic-assisted segmental rib resection. PMID- 23653239 TI - Single electron transistor in aqueous media. AB - A gold nanoparticle necklace array spanning a ~30-micrometer-wide channel shows a robust coulomb blockade effect at room temperature with a threshold of 1V in air. When this device is operated in the aqueous solution, a gain of ~130 fold in conductance is obtained in electrochemical gating, significantly higher than other nanomaterial-based electrochemical transistors. PMID- 23653238 TI - Expressed sequence tags and molecular cloning and characterization of gene encoding pinoresinol/lariciresinol reductase from Podophyllum hexandrum. AB - Podophyllotoxin, an aryltetralin lignan, is the source of important anticancer drugs etoposide, teniposide, and etopophos. Roots/rhizome of Podophyllum hexandrum form one of the most important sources of podophyllotoxin. In order to understand genes involved in podophyllotoxin biosynthesis, two suppression subtractive hybridization libraries were synthesized, one each from root/rhizome and leaves using high and low podophyllotoxin-producing plants of P. hexandrum. Sequencing of clones identified a total of 1,141 Expressed Sequence Tags (ESTs) resulting in 354 unique ESTs. Several unique ESTs showed sequence similarity to the genes involved in metabolism, stress/defense responses, and signalling pathways. A few ESTs also showed high sequence similarity with genes which were shown to be involved in podophyllotoxin biosynthesis in other plant species such as pinoresinol/lariciresinol reductase. A full length coding sequence of pinoresinol/lariciresinol reductase (PLR) has been cloned from P. hexandrum which was found to encode protein with 311 amino acids and show sequence similarity with PLR from Forsythia intermedia and Linum spp. Spatial and stress-inducible expression pattern of PhPLR and other known genes of podophyllotoxin biosynthesis, secoisolariciresinol dehydrogenase (PhSDH), and dirigent protein oxidase (PhDPO) have been studied. All the three genes showed wounding and methyl jasmonate-inducible expression pattern. The present work would form a basis for further studies to understand genomics of podophyllotoxin biosynthesis in P. hexandrum. PMID- 23653240 TI - Diagnostic performance of 18F-fluorothymidine PET/CT for primary colorectal cancer and its lymph node metastasis: comparison with 18F-fluorodeoxyglucose PET/CT. AB - PURPOSE: To examine the diagnostic performance of (18)F-fluorothymidine (FLT) PET/CT in primary and metastatic lymph node colorectal cancer foci in comparison with (18)F-fluorodeoxyglucose (FDG) PET/CT. METHODS: The study population comprised 28 patients with 30 newly diagnosed colorectal cancers who underwent surgical resection of the primary lesion and regional lymph nodes after both FLT and FDG PET/CT. The associations between SUVmax levels and pathological factors were evaluated using the Mann-Whitney U or Kruskal-Wallis test. Differences in diagnostic indexes for detecting nodal metastasis between the two tracers were estimated using the McNemar exact or chi(2) test. RESULTS: All 30 primary cancers (43.0 +/- 20.0 mm, range 14 - 85 mm) were visualized by both tracers, but none of the FLT SUVmax values exceeded the FDG SUVmax values in any of the primary cancers (6.6 +/- 2.4 vs. 13.6 +/- 5.8, p < 0.001). The sensitivity, specificity and accuracy for detecting nodal metastasis were 41% (15/37), 98.8% (493/499) and 94.8% (508/536) for FDG PET/CT, and 32% (12/37), 98.8% (493/499) and 94.2% (505/536) for FLT PET/CT, respectively. The sensitivity (p = 0.45), specificity (p = 0.68) and accuracy (p = 0.58) were not different between the tracers. Nodal uptake of FLT and FDG was discordant in 7 (19%) of 37 metastatic nodes. There were ten concordant true-positive nodes of which six showed higher FDG SUVmax and four showed higher FLT SUVmax, but the difference between FDG and FLT SUVmax was not significant (5.56 +/- 3.55 and 3.62 +/- 1.45, respectively; p = 0.22). CONCLUSION: FLT has the same potential as FDG in PET/CT for the diagnosis of primary and nodal foci of colorectal cancer despite significantly lower FLT uptake in primary foci. PMID- 23653241 TI - Perfusion SPECT in patients with suspected pulmonary embolism. AB - PURPOSE: Ventilation/perfusion tomography (V/PSPECT), with new interpretation criteria and newer tracers for ventilation imaging, has markedly improved the diagnostic yield in acute pulmonary embolism (PE). Here, we evaluated the diagnostic performance of perfusion SPECT (PSPECT) without ventilation imaging. METHODS: We studied 152 patients with clinically suspected PE who had been examined with both V/PSPECT and multidetector computed tomographic angiography (MD-CTA). The diagnosis or exclusion of PE was decided by the referring clinician based on both the V/PSPECT and/or MD-CTA findings in combination with the clinical findings. PSPECT images were retrospectively examined by a physician with experience in the interpretation of planar perfusion scans who was blinded to clinical, V/PSPECT and MD-CTA data. PSPECT images were interpreted without the aid of chest radiography. All the patients who were deemed to have PE were given anticoagulant therapy. RESULTS: Of the 152 patients, 59 (39%) received a final diagnosis of PE, and 19 (32%) had associated cardiopulmonary diseases such as pneumonia, COPD, or left heart failure. PSPECT correctly identified 53 (90%) of the 59 patients with PE. The specificity was 88 of 93 (95%). None of the PSPECT images was rated nondiagnostic. PSPECT yielded an overall diagnostic accuracy of 93% (95% confidence interval, CI, 87-96%). At the observed PE prevalence of 39 %, the positive and negative predictive values of PSPECT were 91% (95% CI, 80-97%) and 94% (95% CI, 86-97%), respectively. CONCLUSION: In managing critically ill patients, PSPECT might be a valid alternative to V/PSPECT or MD-CTA since it was able to identify most patients with PE with a low false-positive rate and no inconclusive results. PMID- 23653242 TI - 18F-FDG PET/CT diagnosis of unexpected extracardiac septic embolisms in patients with suspected cardiac endocarditis. AB - PURPOSE: Acute infective endocarditis is a potentially life-threatening disease. Its outcome strongly depends on systemic embolization and extracardiac infections. When present, these conditions usually lead to a more aggressive therapeutic approach. However, the diagnosis of peripheral septic embolism is very challenging. (18)F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT has proven to be accurate for the detection of inflammatory diseases and occult infections. The aim of this study was to assess the added value of (18)F FDG PET/CT in the detection of extracardiac embolisms in the evaluation of patients with suspected valvular endocarditis (VE). METHODS: Seventy-one patients with suspected infective endocarditis, enrolled between June 2010 and December 2012, underwent (18)F-FDG PET/CT with the standard procedure on a dedicated PET/CT scanner. Extracardiac findings were subsequently evaluated with other imaging procedures. RESULTS: Of the 71 patients with suspicion of infective endocarditis, we found unexpected extracardiac findings in 17 patients (24%) without any clinical suspicion. Extracardiac findings were subsequently evaluated with other imaging procedures. CONCLUSION: PET/CT detected unexpected extra sites of infection in 24% of cases, leading to changes in therapeutic management in a very relevant percentage of patients. These findings may have important therapeutic implications. PMID- 23653243 TI - Phase I pharmacokinetic and biodistribution study with escalating doses of 223Ra dichloride in men with castration-resistant metastatic prostate cancer. AB - PURPOSE: 223Ra-Dichloride (223Ra) is a novel bone-seeking alpha-emitter that prolongs survival in patients with castration-resistant metastatic prostate cancer. We conducted a study to better profile the pharmacokinetics, pharmacodynamics, and biodistribution of this agent. METHODS: Ten patients received either 50, 100, or 200 kBq of 223Ra per kilogram of body weight. Subsequently, six of these ten patients received a second dose of 50 kBq/kg. Pharmacokinetics and biodistribution were assessed by serial blood sampling, planar imaging, and whole-body counting. Pharmacodynamic assessment was based on measurements of prostate-specific antigen, bone alkaline phosphatase, and serum N telopeptide. Safety was also assessed. RESULTS: Pharmacokinetic studies showed rapid clearance of 223Ra from the vasculature, with a median of 14% (range 9 34%), 2% (range 1.6-3.9%), and 0.5% (range 0.4-1.0%) remaining in plasma at the end of infusion, after 4 h, and after 24 h, respectively. Biodistribution studies showed early passage into the small bowel and subsequent fecal excretion with a median of 52% of administered 223Ra in the bowel at 24 h. Urinary excretion was relatively minor (median of 4% of administered 223Ra). Bone retention was prolonged. No dose-limiting toxicity was observed. Pharmacodynamic effects were observed (alkaline phosphatase and serum N-telopeptides) in a significant fraction of patients. CONCLUSION: 223Ra cleared rapidly from plasma and rapidly transited into small bowel, with fecal excretion the major route of elimination. Administered activities up to 200 kBq/kg were associated with few side effects and appeared to induce a decline in serum indicators of bone turnover. PMID- 23653244 TI - High FDG activity in focal fat necrosis: a pitfall in interpretation of posttreatment PET/CT in patients with non-Hodgkin lymphoma. AB - PURPOSE: PET/CT has a major role in lymphoma imaging, but glycolytic activity in inflammatory processes can reduce specificity. In this study we evaluated restaging PET/CT findings in patients with non-Hodgkin lymphoma (NHL) and fat necrosis. METHODS: We identified 16 patients from 8,819 restaging FDG PET/CT scans with suspicion of or biopsy-proven fat necrosis on PET/CT. RESULTS: All patients had NHL and demonstrated focal FDG-avid nodular change on CT with density higher than that of fat but lower than that of soft tissue. Histological confirmation was obtained in eight patients, with high GLUT-1 staining between necrotic tissue and organizing fat necrosis evident. Uptake resolved in four patients, and surveillance was continuing in four without relapse. CONCLUSION: Although rare, identification of fat necrosis in patients with a solitary FDG avid nodule after therapy is important and may lead to the avoidance of unnecessary interventions or treatment. Specific features on CT aid identification, whilst follow-up imaging can be helpful as the metabolic abnormality regresses with time. PMID- 23653245 TI - Imaging characteristics of cardiac dominant diffuse large B-cell lymphoma demonstrated with MDCT and PET/CT. AB - PURPOSE: To investigate the specific imaging findings of multidetector row CT (MDCT) and PET/CT with(18)F-FDG in cardiac dominant diffuse large B-cell lymphoma (DLBCL) in comparison with other cardiac tumours. METHODS: Five patients with DLBCL and 12 patients with other cardiac tumours including pericardial tumours were retrospectively reviewed. Among the patients with other cardiac tumours, seven had metastatic tumours, three had benign tumours, and two had other malignant cardiac tumours. The location of the cardiac mass, the encasement of the coronary artery surrounded by the mass, and pericardial effusion were evaluated using MDCT. The disease activity of the cardiac tumour was also evaluated by PET/CT. RESULTS: Four of the five DLBCL patients had primarily right sided cardiac lesions, which was seen significantly more frequently in DLBCL than in other cardiac tumours (p = 0.028). All cardiac DLBCL lesions were located around the atrioventricular groove and encased the coronary arteries. ECG-gated cardiac MDCT showed that there was no apparent stenosis of the coronary arteries. Large amounts of pericardial effusion were seen in all DLBCL patients. PET/CT revealed significantly higher FDG uptake in DLBCL than in other cardiac malignant tumours, with no overlap (p = 0.0007). CONCLUSION: The combination of a right sided cardiac mass with a large pericardial effusion and no apparent stenosis of the encased coronary artery revealed by MDCT and a high maximum standard uptake value were the specific findings in cardiac dominant DLBCL. PMID- 23653246 TI - Proteolytic activity from chicken intestine and pancreas: extraction, partial characterization and application for hyaluronic acid separation from chicken comb. AB - BACKGROUND: The potential utilization of viscera and combs, by-products from the chicken-processing industry, was investigated. Chicken combs have been reported to consist of hyaluronic acid (HA) bound to protein. Thus proteases extracted from broiler viscera were applied to digest combs to separate HA, a high-value ingredient widely used in pharmaceutical and medical products. RESULTS: The highest activity of crude protease extracted from chicken intestine and pancreas was 0.35 U mg(-1) enzyme at 60 degrees C and pH 7.5. pH stability of the enzyme was attained from pH 6 to 8, while its thermal stability declined from 30 to 50 degrees C, with complete activity loss occurring after 30 min at temperatures above 60 degrees C. Therefore the optimal conditions for broiler comb digestion by crude protease in this study were chosen as pH 7.5 and 50 degrees C. The results showed that the yield of crude enzyme-extracted HA was lower (P < 0.05) than that obtained by commercial papain digestion. Similar identity of extracted HA and HA standard was verified by cellulose acetate electrophoresis and Fourier transform infrared spectroscopy. CONCLUSION: The crude enzyme extract from chicken intestine and pancreas had high proteolytic activity and could be used successfully to separate HA from broiler combs. The method provides an appropriate means to add value to poultry-processing waste. PMID- 23653247 TI - Value of cardiac 320-multidetector computed tomography and cardiac magnetic resonance imaging for assessment of myocardial perfusion defects in patients with known chronic ischemic heart disease. AB - The challenge for therapies targeting perfusion abnormalities is to identify and evaluate the region of interest. The aim of this study was to compare rest and stress myocardial perfusion measured by cardiac multi-detector computed tomography (MDCT) and cardiac magnetic resonance (CMR) imaging in patients with invasive coronary angiography demonstrated occluded vessels. Twenty-four patients with refractory angina due to occluded coronary arteries underwent perfusion imaging obtained by 320-MDCT scanner and 1.5 T MR scanner. Rest and adenosine stress images were obtained and interpreted using the modified 17-segment American Heart Association model. For the qualitative analysis, each segment was graded according to the following scoring system: 0 = no defect, 1 = hypoperfusion transmural extent <1/3, 2 = 1/3-1/2, 3 = >1/2, and 4 = infarct stigmata. In the semiquantitative analysis the perfusion was either scored 0 (normal) or 1 (abnormal). The summed rest and stress scores were calculated. MDCT and CMR had a high probability to identify perfusion defects. An excellent correlation between MDCT and CMR summed rest (r = 0.916) and stress scores (r = 0.915) was found. The interobserver reproducibility was high for MDCT and CMR images. The qualitative and semiquantitative MDCT against CMR analysis of rest and stress images showed high concordance to detect perfusion defects per vascular territory and on a per myocardial segment basis. 320-MDCT and CMR perfusion imaging can be used clinically to identify myocardial perfusion defects and potentially evaluate the effect of therapy targeting perfusion abnormalities. PMID- 23653248 TI - Clinical and imaging parameters to predict cardiovascular outcome in asymptomatic subjects. AB - We aimed to compare the prognostic power of clinical parameters, biomarkers and imaging parameters in predicting cardiovascular outcome in asymptomatic healthy population. A total of 5,182 asymptomatic patients who visited Health Promotion Center at Seoul National University Bundang Hospital between January 2006 and September 2008 and had coronary computed tomography angiography were evaluated. All cardiovascular events including cardiac death, acute coronary syndrome and stroke were evaluated as outcome. In asymptomatic general Korean population, cardiovascular event was found in 1.3 % during median follow up period of 48 months. Various multivariate analyses including C-reactive protein, Framingham risk score (FRS), coronary artery calcium score and degree of coronary artery stenosis showed that FRS and degree of coronary artery stenosis were independent parameters for future adverse cardiovascular events in asymptomatic population (OR 1.068, 95 % CI 1.023-1.114, p = 0.003 for FRS, OR 1.041, 95 % CI 1.031-1.051, p < 0.001 for stenosis). The C-statistics of FRS, degree of stenosis and FRS with degree of stenosis were 0.72 (95 % CI 0.64-0.80), 0.80 (95 % CI 0.72-0.88) and 0.83 (95 % CI 0.75-0.91), respectively. Among the clinical parameters, biomarkers and imaging parameters of cardiovascular disease, both FRS and degree of coronary artery stenosis are independent parameters to predict adverse outcome in asymptomatic population. PMID- 23653249 TI - Analytical methods for the detection of undeclared synthetic drugs in traditional herbal medicines as adulterants. AB - Traditional herbal medicines (THMs) are gaining popularity worldwide as an alternative approach to prescription drugs for many reasons including a general perception that they are safe. But recently there have been number of reported studies that reveal adulteration of THMs with undeclared synthetic drugs, which may potentially cause serious toxic adverse effects. This paper reviews the various classes of synthetic drugs that were found to be adulterated in THMs worldwide. The main focus is to highlight newer analytical tools used to detect adulteration. Due to the advancement in hyphenated techniques like liquid chromatography tandem mass spectrometry (LC-MS/MS), gas chromatography-tandem mass spectrometry (GC-MS/MS) and other conventional tools, it has become possible to detect synthetic drugs and their structural analogues as adulterants even if they are present in small quantities. This review also gives an overview of health-related risks after consuming such spurious products and challenges for future perspectives to control such type of malpractices. PMID- 23653250 TI - Perceived social support levels among medical staff working at the medical faculty hospital of van following the 2011 Van-Turkey earthquake. AB - The aim of the study was to evaluate the "perceived social support levels" of the medical staff after the earthquake. The sample of this study is made up of 300 of the 490 medical staff of the Medical Faculty Hospital of Van. The data were collected using a survey that included the personal information and the "multidimensional perceived social support scale." It was observed that since the houses of the medical staff were being repaired or rebuilt, 55% of the medical staff were not residing in their homes. It was determined that 41.3% of the staff were residing in different cities away from their families. Among those, 52.4% was obliged to live apart from their families for more than 6 months. The medical staff whose families did not relocate, those who stayed with their spouses, and those who lived in containers were reported to have high social support. PMID- 23653251 TI - Clinical and molecular characterization of McArdle's disease in Brazilian patients. AB - McArdle's disease, a glycogen storage disease type V, is caused by a deficiency of the enzyme myophosphorylase, encoded by the PYGM gene. Worldwide distribution of mutations has revealed interesting data about the prevalence of mutations and population migrations. Currently, more than 100 mutations in the PYGM gene have been described, with some recurrent mutations in the different populations. However, no molecular studies of McArdle's disease were reported in Brazilian patients. Here, we describe the clinical phenotype and genotype of 10 patients from 8 unrelated Brazilian families. Among the 10 patients (3 females, 7 males), eight presented with the typical phenotype, with exercise intolerance, cramps, and myalgia; one patient showed permanent muscle weakness; and one patient showed a mild phenotype. Molecular analysis identified 5 different mutations in the 8 families, both in homozygosis or compound heterozygosis state. Four of them had already been described (p.R50X, p.T692kfs30, p.K609K, and p.G455R), and one, pI513V, is a novel heterozygous mutation. The common nonsense p.R50X mutation was found in 6 of the 8 families, being therefore the commonest mutation in the Brazilian population as well. Other mutations previously reported in European patients were also found in the patients in this study, which was expected considering the European ancestry of the Brazilian population. PMID- 23653252 TI - Transdermal delivery devices: fabrication, mechanics and drug release from silk. AB - Microneedles are a relatively simple, minimally invasive and painless approach to deliver drugs across the skin. However, there remain limitations with this approach because of the materials most commonly utilized for such systems. Silk protein, with tunable and biocompatibility properties, is a useful biomaterial to overcome the current limitations with microneedles. Silk devices preserve drug activity, offer superior mechanical properties and biocompatibility, can be tuned for biodegradability, and can be processed under aqueous, benign conditions. In the present work, the fabrication of dense microneedle arrays from silk with different drug release kinetics is reported. The mechanical properties of the microneedle patches are tuned by post-fabrication treatments or by loading the needles with silk microparticles, to increase capacity and mechanical strength. Drug release is further enhanced by the encapsulation of the drugs in the silk matrix and coating with a thin dissolvable drug layer. The microneedles are used on human cadaver skin and drugs are delivered successfully. The various attributes demonstrated suggest that silk-based microneedle devices can provide significant benefit as a platform material for transdermal drug delivery. PMID- 23653253 TI - Simultaneous phenotypic and genetic characterization of single circulating tumor cells from colon cancer patients. AB - Since circulating tumor cells (CTCs) have metastatic potential, their genetic and phenotypic characteristics could provide crucial information to establish the most effective therapy. We assessed the clinical utility of a methodology that allows the simultaneous analysis of CTC phenotype and genotype in colon cancer patients and, in addition, whether this methodology could provide complementary information to that obtained by the primary tumor biopsy. Thirty-three non metastatic (stages 0-III) colon cancer patients and 9 healthy donor samples were evaluated. All peripheral blood samples (10 ml) were analyzed by cytokeratin immunomagnetic enrichment. Eight samples were analyzed by immunocytochemistry and 25 samples were analyzed by FICTION technique for simultaneous cytokeratin expression and chromosome 17 and ERBB2 gene status. A further study was carried out in one patient who showed CTC heterogeneity in chromosomal abnormalities. We analyzed HER2 protein expression on CTCs and FISH and HER2 protein expression in primary tumor of this patient. Our results show that 9.09% of patients had cytokeratin-positive CTCs (CK+/CTCs in peripheral blood). One of the patients showed heterogeneity in chromosomal 17 abnormalities and two different CK expression patterns on CTCs: one CK+/CTCs and one CK-/CTCs. Furthermore, 63.33% of these CTCs overexpressed HER2 protein while the primary tumor of this patient was diploid and did not express HER2 protein. We describe a methodology that allows the simultaneous genetic and phenotypic analysis of CTCs in colon cancer patients, which may provide essential information to select patients who might benefit from specific therapy. PMID- 23653254 TI - Outcomes of correcting hyponatremia in patients with myocardial infarction. AB - BACKGROUND: Hyponatremia has significant prognostic implications in patients with heart, failure. However, little data are available regarding its significance in patients presenting with myocardial infarction. In addition, it is not known if correction of hyponatremia impacts outcomes in these patients. The aim of this study was to evaluate the prognostic value of hyponatremia in patients with myocardial infarction and the effect of its correction on all-cause mortality. METHODS: Patients with the discharge diagnosis of myocardial infarction at our institution between 2000 and 2010 with serum sodium levels measured within 24 h of admission were included in this retrospective analysis. Multivariate analysis was used to determine the predictors of all-cause mortality. Cox proportional hazard model was applied to determine the adjusted survival. RESULTS: A total of 11,562 patients (67.15 +/- 14.6 years, males 56.3 %) were included in the analysis. There were a total of 1,535 (13.3 %) deaths within mean follow-up duration of 5.5 +/- 3.3 years. There were 425 (27.9 %) deaths in patients with corrected hyponatremia and 155 (55.3 %) deaths in persistent hyponatremia patients. Multivariate analysis indicated that corrected hyponatremia and persistent hyponatremia were independent predictors of all cause mortality (p < 0.0001). When analyzing short-term (30 days) and long-term mortality, corrected hyponatremia group did not have associated long term mortality. Various methods to correct hyponatremia were also analyzed and use of vaptans was associated with decrease in mortality in patients with hyponatremia from 115 to 125 (HR 0.45; 95 % CI 0.26-0.78, p = 0.005). CONCLUSION: Our analysis showed that corrected and persistent hyponatremia in patients presenting with myocardial infarction is a predictor of all-cause mortality, major adverse cardiac events and heart failure related 30 day rehospitalization. In certain cases, correction of hyponatremia may actually improve survival of the patients. PMID- 23653256 TI - Capillary networks in tumor angiogenesis: from discrete endothelial cells to phase-field averaged descriptions via isogeometric analysis. AB - Tumor angiogenesis, the growth of new capillaries from preexisting ones promoted by the starvation and hypoxia of cancerous cell, creates complex biological patterns. These patterns are captured by a hybrid model that involves high-order partial differential equations coupled with mobile, agent-based components. The continuous equations of the model rely on the phase-field method to describe the intricate interfaces between the vasculature and the host tissue. The discrete equations are posed on a cellular scale and treat tip endothelial cells as mobile agents. Here, we put the model into a coherent mathematical and algorithmic framework and introduce a numerical method based on isogeometric analysis that couples the discrete and continuous descriptions of the theory. Using our algorithms, we perform numerical simulations that show the development of the vasculature around a tumor. The new method permitted us to perform a parametric study of the model. Furthermore, we investigate different initial configurations to study the growth of the new capillaries. The simulations illustrate the accuracy and efficiency of our numerical method and provide insight into the dynamics of the governing equations as well as into the underlying physical phenomenon. PMID- 23653257 TI - Regression modeling of the cumulative incidence function with missing causes of failure using pseudo-values. AB - Competing risks arise when patients may fail from several causes. Strategies for modeling event-specific quantities often assume that the cause of failure is known for all patients, but this is seldom the case. Several authors have addressed the problem of modeling the cause-specific hazard rates with missing causes of failure. In contrast, direct modeling of the cumulative incidence function has received little attention.We provide a general framework for regression modeling of this function in the missing cause setting, encompassing key models such as the Fine and Gray and additive models, by considering two extensions of the Andersen-Klein pseudo-value approach. The first extension is a novel inverse probability weighting method, whereas the second extension is based on a previously proposed multiple imputation procedure.We evaluated the gain in using these approaches with small samples in an extensive simulation study. We analyzed the data from an Eastern Cooperative Oncology Group breast cancer treatment clinical trial to illustrate the practical value and ease of implementation of the proposed methods. PMID- 23653255 TI - Neurodegenerative disease and obesity: what is the role of weight loss and bariatric interventions? AB - Neurodegenerative diseases are amongst the leading causes of worldwide disability, morbidity and decreased quality of life. They are increasingly associated with the concomitant worldwide epidemic of obesity. Although the prevalence of both AD and PD continue to rise, the available treatment strategies to combat these conditions remain ineffective against an increase in global neurodegenerative risk factors. There is now epidemiological and mechanistic evidence associating obesity and its related disorders of impaired glucose homeostasis, type 2 diabetes mellitus and metabolic syndrome with both AD and PD. Here we describe the clinical and molecular relationship between obesity and neurodegenerative disease. Secondly we outline the protective role of weight loss, metabolic and caloric modifying interventions in the context of AD and PD. We conclude that the application of caloric restriction through dietary changes, bariatric (metabolic) surgery and gut hormone therapy may offer novel therapeutic strategies against neurodegenerative disorders. Investigating the protective mechanisms of weight loss, metabolic and caloric modifying interventions can increase our understanding of these major public health diseases and their management. PMID- 23653258 TI - Design and fabrication of carbon nanotube field-emission cathode with coaxial gate and ballast resistor. AB - A low density vertically aligned carbon nanotube-based field-emission cathode with a ballast resistor and coaxial gate is designed and fabricated. The ballast resistor can overcome the non-uniformity of the local field-enhancement factor at the emitter apex. The self-aligned fabrication process of the coaxial gate can avoid the effects of emitter tip misalignment and height non-uniformity. PMID- 23653259 TI - Gold-catalyzed synthesis of iodofulvenes. AB - We report the gold-catalyzed synthesis of highly functionalized iodofulvenes from iododialkynes under mild conditions. The catalytic cycle involves the formation of gold acetylides and vinylgold intermediates. These intermediates can then undergo an unprecedented iodine/gold exchange. This new pathway for catalyst transfer in dual gold catalysis opens up the possibility of highly regioselective transformations directed by the gold in the organogold intermediates. The resulting products are well suited for further metal-mediated coupling reactions, allowing the synthesis of extended pi-systems. PMID- 23653260 TI - Commentary: China will change our teaching. PMID- 23653261 TI - Potential for the integration of biological and chemical control of sheath blight disease caused by Rhizoctonia solani on rice. AB - Biological control using antagonistic microbes to minimize the use of chemical pesticides has recently become more prevalent. In an attempt to find an integrated control system for sheath blight, caused by Rhizoctonia solani in rice, Streptomyces philanthi RM-1-138, commercial formulations of Bacillus subtilis as Larminar(r) and B. subtilis strain NSRS 89-24+MK-007 as Biobest(r) and chemical fungicides including carbendazim(r), validamycin(r), propiconazole(r) and mancozeb(r) were applied alone and in combination with S. philanthi RM-1-138. In vitro experiments showed that all treatments tested did provide some control against mycelial growth and sclerotia production by R. solani PTRRS-9. In addition, the four chemical fungicides had no detrimental effects on S. philanthi RM-1-138 even at high concentrations (up to 100 MUg/ml). The efficacy of S. philanthi RM-1-138, the commercial formulations of B. subtilis, chemical fungicides alone or in combination with S. philanthi RM-1-138 was also tested in a greenhouse experiment against sheath blight disease on rice plants. All treatments showed some protection of rice for sheath blight by 47-60 % when carbendazim(r) was applied alone and up to 74 % when combined with S. philanthi RM-1-138. PMID- 23653262 TI - Antimicrobial activity of Brazilian propolis extracts against rumen bacteria in vitro. AB - The antimicrobial activity of three Brazilian propolis extracts was evaluated on bacterial strains representing major rumen functional groups. The extracts were prepared using different concentrations of propolis and alcohol, resulting in different phenolic compositions. The propolis extracts inhibited the growth of Fibrobacter succinogenes S85, Ruminococcus flavefaciens FD-1, Ruminococcus albus 7, Butyrivibrio fibrisolvens D1, Prevotella albensis M384, Peptostreptococcus sp. D1, Clostridium aminophilum F and Streptococcus bovis Pearl11, while R. albus 20, Prevotella bryantii B14 and Ruminobacter amylophilus H18 were resistant to all the extracts. The inhibited strains showed also different sensitivity to propolis; the hyper-ammonia-producing bacteria (C. aminophilum F and Peptostreptococcus sp. D1) being the most sensitive. Inhibition of hyper-ammonia producing bacteria by propolis would be beneficial to the animal. The extract containing the lowest amount of phenolic compounds (LLOS C3) showed the lowest antimicrobial activity against all the bacteria. The major phenolic compounds identified in the propolis extracts (naringenin, chrysin, caffeic acid, p coumaric acid and Artepillin C) were also evaluated on four sensitive strains. Only naringenin showed inhibitory effect against all strains, suggesting that naringenin is one of the components participating to the antibacterial activity of propolis. PMID- 23653263 TI - Analysis of synonymous codon usage patterns in the genus Rhizobium. AB - The codon usage patterns of rhizobia have received increasing attention. However, little information is available regarding the conserved features of the codon usage patterns in a typical rhizobial genus. The codon usage patterns of six completely sequenced strains belonging to the genus Rhizobium were analysed as model rhizobia in the present study. The relative neutrality plot showed that selection pressure played a role in codon usage in the genus Rhizobium. Spearman's rank correlation analysis combined with correspondence analysis (COA) showed that the codon adaptation index and the effective number of codons (ENC) had strong correlation with the first axis of the COA, which indicated the important role of gene expression level and the ENC in the codon usage patterns in this genus. The relative synonymous codon usage of Cys codons had the strongest correlation with the second axis of the COA. Accordingly, the usage of Cys codons was another important factor that shaped the codon usage patterns in Rhizobium genomes and was a conserved feature of the genus. Moreover, the comparison of codon usage between highly and lowly expressed genes showed that 20 unique preferred codons were shared among Rhizobium genomes, revealing another conserved feature of the genus. This is the first report of the codon usage patterns in the genus Rhizobium. PMID- 23653264 TI - Luteibacter rhizovicinus MIMR1 promotes root development in barley (Hordeum vulgare L.) under laboratory conditions. AB - In order to preserve environmental quality, alternative strategies to chemical intensive agriculture are strongly needed. In this study, we characterized in vitro the potential plant growth promoting (PGP) properties of a gamma proteobacterium, named MIMR1, originally isolated from apple shoots in micropropagation. The analysis of the 16S rRNA gene sequence allowed the taxonomic identification of MIMR1 as Luteibacter rhizovicinus. The PGP properties of MIMR1 were compared to Pseudomonas chlororaphis subsp. aurantiaca DSM 19603(T), which was selected as a reference PGP bacterium. By means of in vitro experiments, we showed that L. rhizovicinus MIMR1 and P. chlororaphis DSM 19603(T) have the ability to produce molecules able to chelate ferric ions and solubilize monocalcium phosphate. On the contrary, both strains were apparently unable to solubilize tricalcium phosphate. Furthermore, the ability to produce 3 indol acetic acid by MIMR1 was approximately three times higher than that of DSM 19603(T). By using fluorescent recombinants of strains MIMR1 and DSM 19603(T), we also demonstrated that both bacteria are able to abundantly proliferate and colonize the barley rhizosphere, preferentially localizing on root tips and in the rhizoplane. Finally, we observed a negative effect of DSM 19603(T) on barley seed germination and plant growth, whereas MIMR1, compared to the control, determined a significant increase of the weight of aerial part (+22 %), and the weight and length of roots (+53 and +32 %, respectively). The results obtained in this work make L. rhizovicinus MIMR1 a good candidate for possible use in the formulation of bio-fertilizers. PMID- 23653265 TI - Genome characterization of a novel Burkholderia cepacia complex genomovar isolated from dieback affected mango orchards. AB - We characterized the genome of the antibiotic resistant, caseinolytic and non hemolytic Burkholderia sp. strain TJI49, isolated from mango trees (Mangifera indica L.) with dieback disease. This isolate produced severe disease symptoms on the indicator plants. Next generation DNA sequencing and short-read assembly generated the 60X deep 7,631,934 nucleotide draft genome of Burkholderia sp. TJI49 which comprised three chromosomes and at least one mega plasmid. Genome annotation studies revealed a total 8,992 genes, out of which 8,940 were protein coding genes. Comparative genomics and phylogenetics identified Burkholderia sp. TJI49 as a distinct species of Burkholderia cepacia complex (BCC), closely related to B. multivorans ATCC17616. Genome-wide sequence alignment of this isolate with replicons of BCC members showed conservation of core function genes but considerable variations in accessory genes. Subsystem-based gene annotation identified the active presence of wide spread colonization island and type VI secretion system in Burkholderia sp. TJI49. Sequence comparisons revealed (a) 28 novel ORFs that have no database matches and (b) 23 ORFs with orthologues in species other than Burkholderia, indicating horizontal gene transfer events. Fold recognition of novel ORFs identified genes encoding pertactin autotransporter like proteins (a constituent of type V secretion system) and Hap adhesion-like proteins (involved in cell-cell adhesion) in the genome of Burkholderia sp. TJI49. The genomic characterization of this isolate provided additional information related to the 'pan-genome' of Burkholderia species. PMID- 23653266 TI - Chemical composition and ruminal nutrient degradability of fresh and ensiled amaranth forage. AB - BACKGROUND: Amaranth is a crop with potential as a source of forage for ruminants that has not been well characterized. A study was conducted to determine the impact of ensiling on the nutritional quality and ruminal degradability of forage from two amaranth cultivars adapted to North America (i.e. Plainsman and D136). In particular, quantification and some microscopic characterization of oxalate found in amaranth were performed as it is an antiquality compound of concern. RESULTS: There were limited interactions between cultivars and ensiling for most variables. Differences in chemical composition between amaranth cultivars were also limited. Ensiling reduced non-structural carbohydrate and true protein contents. The proportion of acid detergent protein was high in fresh and ensiled forages of both cultivars (average of 177 g kg(-1) crude protein). Total oxalate content averaged 30 and 25 g kg(-1) in fresh and ensiled forages respectively. Ensiling reduced soluble oxalate content. Crystals observed in amaranth were calcium oxalate druses found mostly in idioblast cells in leaf mesophyll and parenchyma of primary and secondary veins. In situ ruminal degradability data indicated that both fresh and ensiled amaranth are highly degradable in the rumen. CONCLUSION: This study confirms that amaranth is a suitable forage for ruminant animals. Its chemical composition is comparable, for most variables, to that of other commonly used forage species. PMID- 23653267 TI - Continuous optical monitoring of cerebral hemodynamics during head-of-bed manipulation in brain-injured adults. AB - INTRODUCTION: Head-of-bed manipulation is commonly performed in the neurocritical care unit to optimize cerebral blood flow (CBF), but its effects on CBF are rarely measured. This pilot study employs a novel, non-invasive instrument combining two techniques, diffuse correlation spectroscopy (DCS) for measurement of CBF and near-infrared spectroscopy (NIRS) for measurement of cerebral oxy- and deoxy-hemoglobin concentrations, to monitor patients during head-of-bed lowering. METHODS: Ten brain-injured patients and ten control subjects were monitored continuously with DCS and NIRS while the head-of-bed was positioned first at 30 degrees and then at 0 degrees . Relative CBF (rCBF) and concurrent changes in oxy- (DeltaHbO2), deoxy- (DeltaHb), and total-hemoglobin concentrations (DeltaTHC) from left/right frontal cortices were monitored for 5 min at each position. Patient and control response differences were assessed. RESULTS: rCBF, DeltaHbO2, and DeltaTHC responses to head lowering differed significantly between brain-injured patients and healthy controls (P < 0.02). For patients, rCBF changes were heterogeneous, with no net change observed in the group average (0.3 +/- 28.2 %, P = 0.938). rCBF increased in controls (18.6 +/- 9.4 %, P < 0.001). DeltaHbO2, DeltaHb, and DeltaTHC increased with head lowering in both groups, but to a larger degree in brain-injured patients. rCBF correlated moderately with changes in cerebral perfusion pressure (R = 0.40, P < 0.001), but not intracranial pressure. CONCLUSION: DCS/NIRS detected differences in CBF and oxygenation responses of brain-injured patients versus controls during head-of bed manipulation. This pilot study supports the feasibility of continuous bedside measurement of cerebrovascular hemodynamics with DCS/NIRS and provides the rationale for further investigation in larger cohorts. PMID- 23653268 TI - Development of contrast-induced nephropathy in subarachnoid hemorrhage: a single center perspective. AB - BACKGROUND AND PURPOSE: The use of iodinated contrast-enhanced imaging studies is increasing in acute cerebrovascular diseases, especially in subarachnoid hemorrhage (SAH). In SAH, such studies are essential for both diagnosis and treatment of the cause and sequela of hemorrhage. These patients are often subjected to multiple contrast studies such as computed tomographic angiography, computed tomographic perfusion, and cerebral angiography. They are also predisposed to intravascular volume depletion as a part of the disease process from cerebral salt wasting (CSW) and as a result of multiple contrast exposure can develop contrast-induced nephropathy (CIN). Data regarding CIN in this population are scarce. We aimed to examine the incidence of CIN in SAH and identify potential associative risk factors. METHODS: We analyzed data from a prospectively collected patient database of patients with SAH admitted to the neurocritical intensive care unit in a single center over a period of 1 year. CIN was defined as an increase in serum creatinine by >1.5 times or >0.3 mg/dl greater than the admission value, or urine output <0.5 ml/kg/h during one 6-h block. RESULTS: In this cohort of 75 patients with SAH who had undergone at least one contrast study, the mean age was 57.3 +/- 15.6 years and 70.7% were women. Four percent developed CIN which resolved within 72 h and none required renal replacement therapy or dialysis. Patients older than 75 years (20%, p < 0.05), those with borderline renal function (14.3%, p = 0.26), diabetics (11.1%, p = 0.32), and those with lower recommended "maximum contrast dose" volume (33.3%, p = 0.12) had a trend toward development of CIN, although most were not statistically significant. Twenty-seven patients (36 %) were on 3% hypertonic saline (HTS) for CSW during the contrasted study but none developed CIN. CONCLUSIONS: The incidence of CIN in SAH patients is comparable to previously published reports on non-neurological cohorts. No definite association was noted with any predisposing factors postulated to be responsible for CIN, except for advanced age. Concurrent use of 3% HTS was not associated with CIN in this population. PMID- 23653270 TI - The reference values of sex hormones and SHBG serum levels in subjects over 65 years old - The PolSenior Study. AB - INTRODUCTION: Over the last decade, average life expectancy has continuously increased. There has been no data on normal sex hormone (SH) levels in a Polish elderly population. In this study, we assessed SH in the PolSenior cohort to determine normal reference ranges in relation to gender, age, and cardiovascular disease risk factors (CVDRFs). MATERIAL AND METHODS: The study was performed with 4,352 participants (2,168 men and 2,088 women), aged from 55 to over 90 years, stratified in five-year age groups. Pre-elderly subjects (55-59 years of age) served as the reference group. We assessed total testosterone (TT), estradiol (TE2) and DHEA-S (by RIA) SHBG and FSH (by IRMA) and calculated free androgen and free estrogen indices (FAI and FEI). Percentage body fat (%BF) was measured by bioelectric impedance analysis. The CVDRFs assessment included blood pressure and biochemical (blood glucose, high-density lipoproteins, triglycerides) and anthropometric (waist circumference) components of the metabolic syndrome. RESULTS: TT was low in 19.9%, normal in 78.2%, and high in 1.8% of men. TE2 was low in 94.6% of women. Age and CVDRFs significantly influenced values of SHBG, FSH, TT, FAI, FEI, and DHEA-S in men, while in women values of FSH, TT and TE2 did not change. BMI and %BF affected SH regardless of the age groups and CVDRFs. CONCLUSIONS: Our findings suggest that the reference ranges stratified by the five-year age bands seem more accurate than those given for the overall population over 60 years of age. The clinical relevance of these reference ranges increases when they are considered in relation to CVDRFs, BMI and %BF. PMID- 23653269 TI - Relationship between impaired cardiac sympathetic activity and spatial dyssynchrony in patients with non-ischemic heart failure: assessment by MIBG scintigraphy and tagged MRI. AB - BACKGROUND: Impairment of cardiac sympathetic activity has various detrimental effects on cardiac function. The purpose was to investigate the relationship between left ventricular (LV) dyssynchrony and cardiac sympathetic activity in non-ischemic heart failure (HF). METHODS: Twenty-seven patients with non-ischemic HF were enrolled. Cardiac sympathetic activity was assessed by heart-to mediastinum ratio (H/M ratio) on (123)I-Metaiodobenzylguanidine scintigraphy. LV dyssynchrony was assessed by cross-correlation analysis of time curves of myocardial circumferential strains delivered from cine-tagging MR images. Temporal dyssynchrony was defined as contraction delay between septal and lateral segments >110 milliseconds. Spatial dyssynchrony was defined as the negative value of the maximum correlation for the two strain time curves. RESULTS: H/M ratio was significantly lower for patients with spatial dyssynchrony compared to patients without (1.8 +/- 0.3 vs 2.1 +/- 0.3, P < .05). There was no difference between patients with and without temporal dyssynchrony (2.0 +/- 0.2 vs 2.0 +/- 0.3). The incidence of spatial dyssynchrony was significantly higher in patients with H/M ratio <2.0 than those whose ratios were >=2.0 (75% vs 20%, P = .001). There was no difference in the incidence of temporal dyssynchrony between the two groups (17% vs 20%). CONCLUSION: Impairment of cardiac sympathetic activity was found to be associated with spatial dyssynchrony in patients with non-ischemic HF. PMID- 23653271 TI - Body composition, glucose metabolism markers and serum androgens - association in women with polycystic ovary syndrome. AB - INTRODUCTION: To evaluate the association between abdominal and gynoid fat, glucose and lipid metabolism markers, and serum androgens in women with polycystic ovary syndrome (PCOS). MATERIAL AND METHODS: Anthropometric measurements were performed in 40 women with PCOS aged 19-49 years with body mass index (BMI) 18.7-53.8 kg/m2. Fasting serum glucose, lipids, insulin, leptin, LH, FSH, oestradiol, androgens, SHGB and TSH were estimated. Body composition was measured by DEXA scan. RESULTS: Four women (10%) were overweight, and 23 (57.5%) were obese. All subjects were hyperandrogenic (in 33 serum androgen levels were increased), and 16 of them were insulin resistant. All of the obese subjects had the abdominal type of obesity. Body weight, BMI, fat mass, fat mass of the trunk, abdominal and gynoidal fat mass correlated with serum triglyceride, glucose and insulin levels, and with HOMA index and blood pressure. Free androgen index (FAI) correlated with body weight (r = 0.43, p < 0.01), and BMI (r = 0.46, p < 0.05). CONCLUSIONS: Using the DEXA method, we demonstrated abdominal type of obesity in all our obese subjects. There were positive significant correlations between fatness, lipids and glucose metabolism indices and blood pressure. Direct positive correlations between free androgen index, body weight and BMI were found. PMID- 23653272 TI - Correlations between polymorphisms in genes coding elements of dopaminergic pathways and body mass index in overweight and obese women. AB - INTRODUCTION: Dopamine is considered to be crucial for food craving and intake, drug abuse and electrical brain stimulation. Increased levels of dopamine occur after energy intake in the dorsal striatum. In the ventral tagmental area, dopamine is responsible for motivation. There is a natural synaptic dopamine level, and as a result its activity is controlled by density of receptors, amount of released neurotransmitter, and defectiveness of re-uptake by specific transporters. In our study, we wanted to investigate if there is a correlation between mean BMI values and VNTR polymorphisms in SLC6A3 (rs28363170) and DRD4 genes. MATERIAL AND METHODS: Chosen gene fragments were amplified using polymerase chain reaction on the DNA template obtained from 506 women. The products of the reaction were electrophoresed and visualised in 3% agarose gel. The genotyping data was analysed with Kruskal-Wallis tests (p < 0.05). RESULTS: In the case of SLC6A3, statistically significant differences in mean BMI were found in the group of obese women (p < 0.05) but not for the whole population of women with normal weight or with overweight (p > 0.05). The mean BMI was higher for the SS genotype than for combined LL and LS genotypes. The difference in mean BMI values for variants of DRD4 was significant for the whole studied population and in the obese group (p > 0.05), and the higher value was correlated with the presence of a variant with seven or more repeats of 48 bp motif. CONCLUSIONS: When the two analysed polymorphisms were combined, the spread between the mean BMI values became greater than for single genes. This suggests that the effect on body mass of these two polymorphisms may combine and cause hypo-functionality of the dopaminergic reward system. PMID- 23653273 TI - Prognostic factors in patients surgically treated after hip fracture. AB - INTRODUCTION: By the impact of demographic changes and as the result of the 'incorrect' lifestyles pursued in developed societies, osteoporosis has become a serious social problem. Hip fracture is the most serious complication of osteoporosis and is associated with high mortality rates or permanent health impairment. The goal of this study was an evaluation of the impact of selected socio-economic factors and of the time period from fracture to surgical intervention on the patient's prognosis. MATERIAL AND METHODS: A group of 148 patients (114 women and 34 men) participated in the study, their age varying between 48 and 93 years, all of them after surgical treatment of hip fracture. A questionnaire study was carried out, encompassing all the participants. RESULTS: During a year-long follow up, thirty-four (34) patients, i.e. 23% of the whole group, passed away. Further comparisons were performed between two groups: Group A - 114 patients, who survived the follow up period, and Group B - those who died. The mean age of patients was 76.3 and 82.6 years in Groups A and B, respectively (p < 0.05). In Group A, 79.8% of the patients declared full self dependence prior to fracture episode vs. 44.1% of the patients in Group B (p < 0.05). Regular physical activity - in various forms - was undertaken by 39.5% of the patients in Group A and 11.8% of those in Group B (p < 0.05). Active ways of spending outdoor time were reported by 32.5% of the patients in Group A vs. 14.7% in Group B (p < 0.05). Fracture unfavourably influenced the material situation of affected patients. No relationship was found between the time period from fracture to surgery and the patient's prognosis. CONCLUSIONS: 1. Despite the currently available surgical treatment methods, hip fracture is still laden with a high risk of fatality. 2. High physical activity, especially outdoors, self dependence and having a partner positively influence patient's prognosis after hip fracture. 3. Hip fracture negatively changes the material situation of patients. 4. The length of time from hip fracture to operation has no effect on the survival rate. PMID- 23653274 TI - Influence of melatonin on symptoms of irritable bowel syndrome in postmenopausal women. AB - INTRODUCTION: Melatonin (MEL) exerts beneficial effects on the gut partly by myorelaxative properties upon the smooth muscle. Its secretion decreases with age, particularly in postmenopausal women. This study was aimed at evaluating the effect of MEL on the symptoms of irritable bowel syndrome (IBS) in this group of patients. MATERIAL AND METHODS: The investigations were carried out in 80 postmenopausal women, aged 48-65 years, divided into two equal groups, diagnosed according to Rome Criteria III: i.e. patients with IBS with constipation predominant (IBS-C), and patients with IBS with diarrhoea predominant (IBS-D). The control group (C) included healthy women aged 46-65 years. In all subjects, 6 sulfatoxymelatonin (6-HMS) concentration urine was measured using ELISA assay. Patients in both groups over the course of six months were given melatonin (at a dose of 3 mg fasting and 5 mg at bedtime) or a placebo (double blind trial). Disease activity was evaluated after two, four and six months, using a ten-point scale to assess the main somatic symptoms: visceral pain, abdominal bloating, etc. RESULTS: The amounts of 6-HMS urine excretion (MUg/24 h) were: C 11.4 +/- 3.0, IBS-C 10.2 +/- 3.2, IBS-D 14.0 +/- 6.3 (p < 0.05). Correlation between values of symptoms score and contrary excretion of 6-HMS: IBS-C r = -0.714, IBS-D r = 0.409. After six months in the IBS-C group, the intensity of visceral pain and abdominal bloating had decreased in 70% of patients (p < 0.01) and constipation in 50% of patients (p < 0.05). Beneficial changes in the IBS-D group were noted in 45% of patients, but this was not better compared to the placebo. CONCLUSIONS: Melatonin can be used as part of the treatment of IBS, particularly in patients with constipation-predominant IBS. PMID- 23653275 TI - Hyperandrogenism in adolescent girls with type 1 diabetes mellitus treated with intensive and continuous subcutaneous insulin therapy. AB - INTRODUCTION: Women with type 1 diabetes mellitus (T1DM) experience high prevalence of hyperandrogenic disorders. The aim of this study was to evaluate hormonal profile with respect to hyperandrogenic disorders in adolescents with T1DM. MATERIAL AND METHODS: Forty seven adolescent girls with T1DM were evaluated and compared to 19 healthy and 21 non-diabetic girls with polycystic ovary syndrome (PCOS). In all subjects, basal and GnRH analogue stimulated androgens, gonadotropins and SHBG were measured and ultrasonography of ovaries was performed. RESULTS: Girls with T1DM experienced first menses significantly later than healthy controls [13.1 (12.0-14.0) v. 12.0 (11.0-12.0) years, p = 0.02]. Nine (19.2%) of them fulfilled PCOS criteria (T1DM+PCOS). They had significantly mean HbA1c from the diagnosis of T1DM than T1DM girls with no PCOS [6.7 (6.6-7.2) v. 7.3(6.4-7.8)%, p = 0.049]. Hormonal profile, hirsutism score and ovarian volume did not differ significantly between the two groups. HbA1c at the study point and mean HbA1c for the last 12 months correlated negatively with SHBG level (r = -0.5, p = 0.006; r = -0.04, p = 0.02). T1DM+PCOS girls had significantly lower FAI [3.0 (2.6-4.3) v. 8.6 (6.5-10.8), p = 0.04] and ovarian volume than non diabetic PCOS girls [4.6 (2.7-5.2) v. 7.4 (4.3-10.0) mL, p = 0.007]. CONCLUSIONS: Clinical symptoms of PCOS in adolescent girls with T1DM are milder than in non diabetic peers, probably due to the protective role of higher SHBG resulting in lower free androgen level. PMID- 23653276 TI - Transplantation of autologous bone marrow mononuclear cells with VEGF gene improves diabetic critical limb ischaemia. AB - INTRODUCTION: The aim of this study was to assess the safety and efficacy of combined autologous bone marrow mononuclear cell and VEGF165 gene therapy in patients with diabetes mellitus suffering from critical limb ischaemia (CLI). MATERIAL AND METHODS: The administration of mononuclear cells (MNCs) and naked VEGF165 plasmid was performed in 16 limbs of 16 patients with rest pain and ischaemic ulcers due to diabetes. MNCs and plasmid were injected into the muscles of the ischaemic limbs. The levels of VEGF in serum and the ankle-brachial index (ABI) were measured before and after treatment. The Visual Analogue Scale (VAS) was used to evaluate pain sensation. CT angiography was performed before and after three months of therapy. RESULTS: Mean (+/- SD) plasma levels of VEGF increased non-significantly from 257 +/- 80 pg/L to 391 +/- 82 pg/L (p > 0.05) two weeks after therapy. The ABI improved significantly from 0.26 +/- 0.22 to 0.49 +/- 0.30 (p < 0.001) three months after therapy. A decrease in rest pain was observed in all patients; mean VAS decreased from 6.3 +/- 1.4 to 1.2 +/- 1.1 after three months (p < 0.002). Angiograms showed the development of collateral vessels in 12 limbs. Ischaemic ulcers healed in 12 limbs. Amputation was performed in four patients only, because of advanced wound infection. However, the level of amputations was lowered below knee level in these cases. Complications were limited to transient leg oedema in two patients and fever in two patients. CONCLUSIONS: Intramuscular bone marrow MNCs autotransplantation combined with the administration of phVEGF165 gene is safe, feasible and effective for patients with diabetes and CLI. PMID- 23653277 TI - Galanin modulates oxytocin release from rat hypothalamo-neurohypophysial explant in vitro - the role of acute or prolonged osmotic stimulus. AB - INTRODUCTION: Galanin (Gal) may be involved as the neuromodulator of different processes in the central nervous system in the regulation of neurohypophysial function. The aim of the present study was to examine the influence of Gal on oxytocin (OT) release in vitro: an acute or prolonged osmotic stimulus was used as the stimulatory agent. MATERIAL AND METHODS: Experiments were carried out on three-month old male rats which acted as donors of isolated rat hypothalamus (Hth), neurohypophysis (NH) or hypothalamo-neurohypophysial explants (Hth-NH). The effect of Gal on OT secretion was studied under conditions of non-osmotic (i.e. K(+)-evoked) (series 1), direct osmotic (i.e. Na(+)-evoked) (series 2) or indirect osmotic stimulation (series 3; neural tissues were obtained from animals drinking 2% NaCl). OT content was determined by radioimmunoassay. RESULTS: Galanin added into incubative media caused the inhibition of basal OT release from NH and Hth-NH explants prepared from euhydrated rats but stimulated basal and K(+)-stimulated OT release from the Hth tissue. Gal did not exert any influence on Na(+)-evoked OT secretion. We observed increased basal OT secretion from NH and K(+)-evoked respective OT release from Hth and Hth-NH explants taken from osmotically challenged rats under the influence of Gal. CONCLUSIONS: Present experiments in vitro show that: 1. Galanin plays the role of an inhibitory neuromodulator of OT release from the neurohypophysis; its effect is opposite at the hypothalamic level. 2. Galanin acts as the stimulatory neuromodulator of OT release in response to prolonged osmotic stimulus; an acute osmotic stimulus blocks OT-ergic neurons susceptible to Gal. PMID- 23653278 TI - Pathomechanisms of the development of obesity in some endocrinopathies - an overview. AB - Obesity is a disease in which the excess of accumulated body fat has an adverse effect on health and consequently leads to a reduced life expectancy. It is a typical 'disease of civilisation', and is a serious public health problem because of a significant increase in its prevalance. It is also a common symptom in a variety of endocrine disorders, but the factors responsible for the development of obesity in endocrinopathies have not been clearly identified. It is not known whether a common factor responsible for the development of obesity occurs in a number of endocrine diseases. On the other hand, adipose tissue is an important endocrine organ producing biologically active substances with local or systemic action that can lead to severe disorders of the endocrine system. This study presents data on the mechanisms of the development of obesity in the thyroid diseases, polycystic ovary syndrome, hypercortisolism and pituitary insufficiency. PMID- 23653279 TI - Thyroid cancer diagnosed and treated surgically during pregnancy - a case report. AB - Thyroid cancer has had an increasing prevalence over recent years and poses an extraordinary challenge when diagnosed during pregnancy. Although in the majority of cases in pregnant patients there occurs a well differentiated papillary carcinoma which has an excellent prognosis and for which surgery can be delayed until the postpartum period, in rare cases of advanced or rapidly growing tumour, and in a case of medullary or anaplastic cancer, surgery should be undertaken during pregnancy. Here, we present the case of a 30 year-old woman with Hurthle cell neoplasm recognised on cytology during the second trimester. Because of the neck lymph nodes metastases diagnosed on ultrasonography and cytology, which also could be seen as calcified foci on a chest X-ray examination performed three years earlier, she underwent surgery before the 22(nd) week of gestation. The course of surgery was successful and uneventful and she delivered a healthy child on term. An approach to pregnant patients with differentiated thyroid carcinoma is discussed. PMID- 23653280 TI - The management of Cushing's disease - from investigation to treatment. AB - Cushing's disease (CD) is caused by an adrenocorticotrophin (ACTH) secreting pituitary adenoma and it is the commonest cause of endogenous hypercortisolism. When high suspicion of Cushing's syndrome (CS) exists, recommended screening tests include the overnight dexamethasone suppression test, the low-dose dexamethasone suppression test, or late night salivary cortisol. If the initial test is positive on two occasions, the patient should be referred to a specialist endocrinologist for in-patient assessment, while elevated midnight serum cortisol and a low dose dexamethasone suppression test will confirm endogenous hypercortisolaemia. Plasma ACTH measurement at 9 am follows and, if elevated, MRI scan of the pituitary should be performed. Corticotrophin releasing hormone (CRH) test helps to distinguish pituitary from ectopic ACTH-dependent CS, though bilateral petrosal sinus sampling remains the gold standard. Transsphenoidal surgery is the recognised first-line treatment of CD, and can be repeated if unsuccessful. Second line therapy includes pituitary radiotherapy, bilateral adrenalectomy and medical treatment. Pituitary radiotherapy is very effective but it usually takes several years for its full effect to be seen. Bilateral adrenalectomy is useful in acutely unwell patients, who are unable to tolerate medical therapy. The most effective medical agents inhibit adrenal steroidogenesis and include metyrapone, ketoconazole, mitotane and etomidate. They are used in preparation for surgery, when an operation has been unsuccessful, or when the effects of radiotherapy are being awaited. Cabergoline and pasireotide decrease ACTH production, but are effective in only 30% and 25% of patients, respectively. It is crucial for patients with CD to be managed in specialist endocrine centres, as the expertise of multidisciplinary team members predicts the best outcome. PMID- 23653281 TI - Is a motor criterion essential for the diagnosis of clinical huntington disease? AB - While there has been a guideline for laboratory/genetic diagnosis of Huntington Disease (HD) since 1998, no such statement exists for the diagnosis of clinical HD. Informally, the most frequently used criteria for diagnosis of clinical HD is 'Motor 4' within the Unified Huntington Disease Rating Scale '99 (motor), made when the rater is highly confident that 'motor abnormalities observed are unequivocal signs of HD'. Recent studies involving pre-manifest individuals illustrated the shortcomings of this motor-only diagnostic approach. For instance, PREDICT-HD found cognitive changes decades before the expected date of motor diagnosis. Using a number of case studies, we highlight some of the subtleties involved in diagnosing clinical HD, in the absence of unequivocal motor signs for HD. New, broader, criteria for the diagnosis of clinical HD would be helpful in many ways. However its formulation will need to flexible rather than prescriptive, and will require extensive consultation with clinicians and families with HD. PMID- 23653282 TI - Protective effect of CV247 against cisplatin nephrotoxicity in rats. AB - CV247 (CV), an aqueous mixture of copper (Cu) and manganese (Mn) gluconates, vitamin C and sodium salicylate increased the antitumour effects of cisplatin (CDPP; cis-diamminedichloroplatinum) in vitro. We hypothesized that the antioxidant and cyclooxygenase-2 (COX-2; prostaglandin-endoperoxide synthase 2) inhibitory components of CV can protect the kidneys from CDPP nephrotoxicity in rats. CDPP (6.5 mg/kg, intraperitoneally) slightly elevated serum creatinine (Crea) and blood urea nitrogen (BUN) 12 days after treatment. Kidney histology demonstrated extensive tubular epithelial damage and COX-2 immunoreactivity increased 14 days after treatment. A large amount of platinum (Pt) accumulated in the kidney of CDPP-treated rats. Furthermore, CDPP decreased renal iron (Fe), molybdenum (Mo), zinc (Zn), Cu and Mn concentrations and increased plasma Fe and Cu concentrations. CDPP elevated plasma free radical concentration. Treatment with CV alone for 14 days (twice 3 ml/kg/day orally) did not influence these parameters. Chronic CV administration after CDPP reduced renal histological damage and slightly decreased COX-2 immunoreactivity, while failed to prevent the increase in Crea and BUN levels. Blood free radical concentration was reduced, that is, CV improved redox homeostasis. CV restored plasma Fe and renal Fe, Mo and Zn, while decreased Pt and elevated Cu and Mn concentrations in the kidney. Besides the known synergistic antitumour effects with CDPP, CV partially protected the kidneys from CDPP nephrotoxicity probably through its antioxidant effect. PMID- 23653283 TI - Classification of Plasmodium falciparum glucose-6-phosphate dehydrogenase inhibitors by support vector machine. AB - Plasmodium falciparum glucose-6-phosphate dehydrogenase (PfG6PD) has been considered as a potential target for severe forms of anti-malaria therapy. In this study, several classification models were built to distinguish active and weakly active PfG6PD inhibitors by support vector machine method. Each molecule was initially represented by 1,044 molecular descriptors calculated by ADRIANA.Code. Correlation analysis and attribute selection methods in Weka were used to get the best reduced set of molecular descriptors, respectively. The best model (Model 2w) gave a prediction accuracy (Q) of 93.88 % and a Matthew's correlation coefficient (MCC) of 0.88 on the test set. Some properties such as [Formula: see text] atom charge, [Formula: see text] atom charge, and lone pair electronegativity-related descriptors are important for the interaction between the PfG6PD and the inhibitor. PMID- 23653284 TI - Glycaemic index of meals affects appetite sensation but not energy balance in active males. AB - BACKGROUND: Foods with low glycaemic index (LGI) are reported to suppress appetite mainly in overweight population but have not been investigated in athletic adults. OBJECTIVE: The aim of this study was to compare the short-term effects of LGI and high GI (HGI) meals over a day on subsequent subjective appetite sensation, energy intake, energy expenditure, energy balance and resting metabolic rate in physically active males. METHODS: This cross-sectional randomized crossover study included 14 active males (mean +/- SD; age 34.5 +/- 8.9 years, body mass index 22.8 +/- 2.1 kg m(-2)) to consume LGI and HGI meals on two separate days. On each trial day, participants consumed a breakfast in the laboratory and then left with a packed lunch, dinner and snacks. Appetite scores, energy intake and expenditure were assessed. RESULTS: The area under the curve for appetite scores of the HGI trial was significantly smaller than that of the LGI trial during the laboratory period (p = 0.027) and throughout the day (p = 0.009). No significant differences in energy intake, energy expenditure, energy balance and resting metabolic rate were found between groups, between the trial days and between the corresponding post-trial days. CONCLUSIONS: These results show that frequent ingestion of the HGI meals, contrary to the previous reports, suppresses appetite more than that of LGI meals, but did not affect energy balance in physically active normal-weight males. PMID- 23653286 TI - Simulation-based uncertainty quantification of human arterial network hemodynamics. AB - This work aims at identifying and quantifying uncertainties from various sources in human cardiovascular system based on stochastic simulation of a one dimensional arterial network. A general analysis of different uncertainties and probability characterization with log-normal distribution of these uncertainties is introduced. Deriving from a deterministic one-dimensional fluid-structure interaction model, we establish the stochastic model as a coupled hyperbolic system incorporated with parametric uncertainties to describe the blood flow and pressure wave propagation in the arterial network. By applying a stochastic collocation method with sparse grid technique, we study systemically the statistics and sensitivity of the solution with respect to many different uncertainties in a relatively complete arterial network with potential physiological and pathological implications for the first time. PMID- 23653285 TI - Determination of anti-inflammatory activities of standardised preparations of plant- and mushroom-based foods. AB - PURPOSE: Chronic inflammatory processes contribute to the pathogenesis of many age-related diseases. In search of anti-inflammatory foods, we have systematically screened a variety of common dietary plants and mushrooms for their anti-inflammatory activity. METHODS: A selection of 115 samples was prepared by a generic food-compatible processing method involving heating. These products were tested for their anti-inflammatory activity in murine N11 microglia and RAW 264.7 macrophages, using nitric oxide (NO) and tumour necrosis factor alpha (TNF-alpha) as pro-inflammatory readouts. RESULTS: Ten food samples including lime zest, English breakfast tea, honey-brown mushroom, button mushroom, oyster mushroom, cinnamon and cloves inhibited NO production in N11 microglia, with IC50 values below 0.5 mg/ml. The most active samples were onion, oregano and red sweet potato, exhibiting IC50 values below 0.1 mg/ml. When these ten food preparations were retested in RAW 264.7 macrophages, they all inhibited NO production similar to the results obtained in N11 microglia. In addition, English breakfast tea leaves, oyster mushroom, onion, cinnamon and button mushroom preparations suppressed TNF-alpha production, exhibiting IC50 values below 0.5 mg/ml in RAW 264.7 macrophages. CONCLUSION: In summary, anti inflammatory activity in these food samples survived 'cooking'. Provided that individual bioavailability allows active compounds to reach therapeutic levels in target tissues, these foods may be useful in limiting inflammation in a variety of age-related inflammatory diseases. Furthermore, these foods could be a source for the discovery of novel anti-inflammatory drugs. PMID- 23653287 TI - Pyrolyzed bacterial cellulose: a versatile support for lithium ion battery anode materials. AB - A scalable, low-cost and environmentally benign strategy is developed for the facile construction of a unique kind of three-dimensional porous electrode architecture for high-performance lithium ion batteries. The methodology is based on the employment of pyrolyzed bacterial cellulose as a new three-dimensional porous scaffold to support various nanostructured active electrode materials, such as SnO2 and Ge. PMID- 23653288 TI - Blocking central galanin receptors attenuates insulin sensitivity in myocytes of diabetic trained rats. AB - Galanin (Gal), a bioactive neuropeptide, is widely distributed throughout the central nervous system and has diverse modulatory effects. To understand the central effect of this training-stimulatory peptide on insulin sensitivity, its antagonist M35 was injected into the cerebral ventricle in type 2 diabetic rats. A treadmill running of the rats was used to stimulate circulating Gal secretion and central Gal mRNA expression. The results showed that M35 significantly decreased glucose infusion rates in euglycemic-hyperinsulinemic clamp tests as well as 2-deoxy-[(3) H]D-glucose uptake and peroxisome proliferator-activated receptor-alpha expression levels in skeletal muscles. M35 also attenuated glucose transporter 4 (GLUT4) concentration in plasma membranes and total cell membranes of myocytes, and the ratios of the GLUT4 contents in the former to the latter in M35 groups were lower than those of each diabetic control. These results imply that endogenous Gal, acting through its central receptor, may facilitate GLUT4 translocation from cytoplasm vesicles to cellular surface of myocytes to accelerate glucose uptake and to enhance insulin sensitivity in healthy and type 2 diabetic rats. Gal and its relative agents are potential targets for treatment of type 2 diabetes mellitus and its complications. PMID- 23653289 TI - Problem-solving test: digestion of a plasmid with restriction endonucleases. AB - Terms to be familiar with before you start to solve the test: plasmid, restriction endonuclease, agarose gel electrophoresis, ethidium bromide staining, autoradiography, Coomassie staining, Southern blotting, linear and circular DNA, superhelical DNA, exonuclease, modification methylase, palindrome, sticky and blunt ends, nicked circular DNA. PMID- 23653290 TI - Descriptive sensory analysis of Aceto Balsamico Tradizionale di Modena DOP and Aceto Balsamico Tradizionale di Reggio Emilia DOP. AB - BACKGROUND: Aceto Balsamico Tradizionale (ABT) is a typical Italian vinegar available in two different forms: Aceto Balsamico Tradizionale di Modena DOP (ABTM) and Aceto Balsamico Tradizionale di Reggio Emilia DOP (ABTRE). ABT is obtained by alcoholic fermentation and acetic bio-oxidation of cooked grape must and aged at least 12 years in wooden casks and is known and sold around the world. Despite this widespread recognition, data on sensory characteristics of these products are very scarce. Therefore a descriptive analysis was conducted to define a lexicon for the ABT sensory profile and to create a simple, stable and reproducible synthetic ABT for training panellists. RESULTS: A lexicon of 20 sensory parameters was defined and validated and a synthetic ABT was prepared as standard reference. Simple standards for panellist training were also defined and the sensory profiles of ABTM and ABTRE were obtained. CONCLUSION: The obtained results confirm that descriptive analysis can be used for the sensory characterisation of ABT and that the sensory profiles of ABTM and ABTRE are very different. Furthermore, the results demonstrate that a lexicon and proper standard references are essential for describing the sensory qualities of ABT both for technical purposes and to protect the product from commercial fraud. PMID- 23653292 TI - Transient left ventricular systolic dysfunction mimicking myocardial infarction after pericardiocentesis. PMID- 23653293 TI - Remote magnetic catheter navigation: more than just bells and whistles ? PMID- 23653294 TI - Chiral hexa- and nonamethylene-bridged bis(L-Leu-oxalamide) gelators: the first oxalamide gels containing aggregates with a chiral morphology. AB - Chiral amino acid- and amino alcohol-oxalamides are well-known as versatile and efficient gelators of various lipophilic and polar organic solvents and water. To further explore the capacity of the amino acid/oxalamide structural fragment as a gelation-generating motif, the dioxalamide dimethyl esters 1(6)Me and 1(9)Me, and dicarboxylic acid 2(6)OH/2(9)OH derivatives containing flexible methylene bridges with odd (9; n=7) and even (6; n=4) numbers of methylene groups were prepared. Their self-assembly motifs and gelation properties were studied by using a number of methods (FTIR, (1)H NMR spectroscopy, CD, TEM, DSC, XRPD, molecular modeling, MMFF94, and DFT). In contrast to the previously studied chiral bis(amino acid or amino alcohol) oxalamide gelators, in which no chiral morphology was ever observed in the gels, the conformationally more flexible 1(6)Me, 1(9)Me, 2(6)OH, and 2(9)OH provide gelators that are capable of forming diverse aggregates of achiral and chiral morphologies, such as helical fibers, twisted tapes, nanotubules, straight fibers, and tapes, in some cases coexisting in the same gel sample. It is shown that the differential scanning calorimetry (DSC)-determined gelation enthalpies could not be correlated with gelator and solvent clogP values. Spectroscopic results show that intermolecular hydrogen-bonding between the oxalamide units provides the major and self-assembly directing intermolecular interaction in the aggregates. Molecular modeling studies reveal that molecular flexibility of gelators due to the presence of the polymethylene bridges gives three conformations (zz, p1, and p2) close in energy, which could form oxalamide hydrogen-bonded layers. The aggregates of the p1 and p2 conformations tend to twist due to steric repulsion between neighboring iBu groups at chiral centers. The X-ray powder diffraction (XRPD) results of 1(6)Me and 1(9)Me, xerogels prove the formation of p1 and p2 gel aggregates, respectively. The latter results explain the formation of gel aggregates with chiral morphology and also the simultaneous presence of aggregates of diverse morphology in the same gel system. PMID- 23653295 TI - Management of complications in long-term LVAD support. AB - INTRODUCTION: Management of complications in long-term LVAD support like aortic regurgitation, progressive decline of right ventricular function, or pump thrombosis are challenging.? METHODS AND RESULTS: After 2.5 years on a HeartMate II left ventricular assist device (LVAD) a 59-year-old patient was admitted to hospital due to severe hemolysis caused by a partial occlusion and thrombosis caused by a shift of the LVAD inflow cannula towards the lateral wall of the left ventricle (LV). Preoperative assessment revealed additional severe aortic regurgitation and impaired right ventricular (RV) function (severe tricuspid regurgitation, RV ejection fraction 25%, central venous pressure 14 mmHg). After LVAD device exchange and aortic valve replacement (AVR) RV failure occurred and a temporary right ventricular assist device (RVAD) was employed. RVAD explantation was feasible 21 days after surgery. The patient was discharged to a rehabilitation center.? DISCUSSION: In this case, LVAD exchange with concomitant AVR and temporary RVAD efforts saved the patient's life and restored a good quality of life. PMID- 23653296 TI - Mobile-bearing total knee arthroplasty: a full traumatic rotation of 180 degrees . AB - From February 2008 to September 2012 we implanted 204 mobile-bearing knee prostheses in 192 patients. All the prostheses were cemented (both femoral and tibial components), and the patella was not replaced. Only one early complication of the implants (1/204 = 0.004%) occurred after a traumatic event as a full 180 degrees rotation of the mobile-bearing polyethylene insert. A 78-year-old woman presented with swelling and severe pain at her right knee. This traumatic event was the only case among our mobile-bearing insert patients. ?The failed polyethylene inserts were retrieved and studied using a scanning electron microscope (SEM, ZEISS EVO 50 EP, Cambridge, UK) operating at 20 kV. ?Scratching and pitting were found on the UHMWPE insert perpendicular to the machining tracks for the concave surface. SEM micrographs of the insert showed burnishing on the concave surfaces and longitudinal scratches were clearly detectable and well marked on the analyzed surfaces. ?A traumatic, fully rotating, polyethylene insert is rare and our case is the first report describing a traumatic event with a complete 180 degree rotation mobile-bearing in a total knee prosthesis. ?In the literature few reports discuss clinical outcomes after total knee arthroplasty in patients with Parkinson's disease and they cite mixed results. However, some authors suggest that posterior-stabilized and cruciate-retaining TKA should work well while others prefer cruciate-retaining, condylar constrained kinetics, or hinged devices. Although we did not implant a posterior-stabilized mobile-bearing total knee prosthesis or a constrained prosthesis, we obtained good clinical and radiological results at the 2-year followup. PMID- 23653297 TI - Diagnostic value of NT-ProBNP for left ventricular hypertrophy in hemodialysis patients. PMID- 23653298 TI - Importance of linguistic details in alarm messages of ventricular assist devices. AB - PURPOSE: In the daily use of ventricular assist devices (VAD), and especially in emergency situations, an easy, self-explanatory handling of the peripheral components is essential to solving life-threatening situations, for non experienced bystanders as well as professional staff members. It has been proven that displaying messages can significantly improve proper reactions. However, in the case we report, an accidental pump cable disconnection could not be solved without the assistance of the VAD coordinator.? CASE REPORT: A long-term HeartWare(r) HVAD patient inadvertently disconnected himself from the pump, most probably due to a metabolically caused mental disorder, for which he had been readmitted to the hospital. Unluckily, the pump cable slipped beneath the bed sheet and the ward staff was not able to solve the problem. The staff who were involved claimed that the messages on the controller did not help them to resolve the difficulty. A comparison between the German and English texts revealed some ambivalence in the German wordings. ? RESULTS: Laypersons were asked to respond to this situation in a simulated scenario, starting with the original alarm messages "VAD stopped"-"VAD gestoppt" and "Connect Driveline"-"Verb-Kabel anschl." If they were unable to solve the problem within 3 minutes, another translation was offered orally: "Pumpe steht" and "Pumpenkabel anschliebetaen". None of the 5 test persons were able to respond correctly to the emergency situation with the original translation, but when provided with a modified translation, everybody solved the problem within 30 seconds.? CONCLUSIONS: Even small linguistic differences can lead to critical differences in the usability and, thus, the safety of VAD peripherals. Detailed discussions with professional translators and/or practical tests of failure scenarios may optimize usability. PMID- 23653299 TI - Reversal of pulmonary hypertension after diaphragm pacing in an adult patient with congenital central hypoventilation syndrome. AB - INTRODUCTION: Patients with the congenital central hypoventilation syndrome (CCHS) suffer from life-threatening hypoventilation when asleep, making them dependent on mechanical ventilation (MV) at night or during naps. State-of-art respiratory management consists of intermittent positive-pressure ventilation via a tracheotomy or mask. In some patients hypoventilation is permanent, in which case ventilatory support must be extended to the waking hours. Diaphragm pacing can prove useful in such situations. ? METHODS AND RESULTS: This report describes the case of a 26-year-old woman with CCHS in whom failure to achieve adequate MV led to life-threatening pulmonary hypertension (PH), with a systolic pulmonary artery pressure (PAP) of 80 mmHg and right ventricular hypertrophy, despite optimization of all possible measures and despite extensive therapeutic education efforts. Diaphragm pacing using laparoscopically implanted intradiaphragmatic phrenic nerve stimulation electrodes corrected alveolar hypoventilation and lastingly reversed PH (systolic PAP below 40 mmHg after 2 months, sustained after 2 years). Diaphragm pacing induced shoulder pain, however, involving the chronic use of analgesics. The pacing had to be stopped for tolerance reasons after two years, leading to PH worsening and the need for diurnal MV. ? CONCLUSIONS: Diaphragm pacing appears likely effective to restore alveolar ventilation and reverse PH in adult CCHS patients. PMID- 23653300 TI - Hemodialysis in patients requiring 131I treatment for thyroid carcinoma. AB - PURPOSE: Thyroid malignancies can be treated by surgery followed by ablation of the remnant tissue with 131I. As iodide removal from the body occurs by renal extraction, in patients suffering from end-stage renal disease it is necessary to properly evaluate both timing and method of the extracorporeal treatment.? METHODS: We present two patients on regular hemodialysis, admitted in isolation to the Nuclear Medicine Department and treated with 131I for thyroid carcinoma diagnosed during the check-up for transplantation. Both patients underwent two hemodialysis sessions with a portable machine for CRRT (continuous renal replacement therapy), 24 and 48 hours after the administration of 50 mCi of 131I. The nursing staff were monitored with a dosimeter. Radioactivity of the patients, dialysate and urines were measured during hemodialysis. ? RESULTS: The greater reduction was obtained with the first dialysis, but in both patients a further, though shorter, hemodialysis at 48 hours was necessary for reaching a patient's radioactivity compatible with discharge. Radioactivity measured in the dialysate demonstrated the almost total removal of radioiodine by dialysis alone. In both patients, follow-up exams revealed a complete ablation of thyroid tissue, without signs of local recurrence. The dose of radioactivity of the dialysis staff was below allowable limits. ? CONCLUSIONS: We conclude that a successful reduction of radioactivity, without dispersing its therapeutic efficacy, can be obtained with daily hemodialysis with a CRRT machine in patients in isolation treated with 131I. A therapeutic model is proposed. PMID- 23653301 TI - Cardiomyocyte differentiation of embryonic stem cells on the surface of organic semiconductors. AB - PURPOSE: Electrically active supports provide new horizons for bio-sensing and artificial organ design. Cell-based electrochemical biosensors can be used as bio microactuators, applied to the biorobotics. Microchip-based bioassay systems can provide real-time cell analysis for preclinical drug design or for intelligent drug delivery devices. In regenerative medicine, electrically active supports can be used as bio-reactors to monitor cell activity, optimize the stem cell differentiation and control cell and tissue morphology. Biocompatibility and direct interaction of the electrically active surface with the cell surface is a critical aspect of this technology.? METHODS: In this work embryonic stem cells (AK7 ES) have been cultivated on the surface of thin films achieved through the evaporation of two aromatic compounds (T6 and PDI-8CN2 ) of particular interest for the fabrication of organic field-effect transistors (OFET). One of the potential advantages offered by the application of OFETs as bio-electronic supports is that they represent a powerful tool for the detection of bio-signals because their electrically active surface is an organic film.? RESULTS: The cell morphology on T6 and PDI-8CN2 surface shows to be similar to the usual cell appearance, as obtained when standard culture support (petri dish) are employed. Moreover, our experimental results demonstrate that stem cells can be lead to differentiation up to "beating" cardiomyocytes even on these electrically-active organic films.? CONCLUSIONS: This investigation encourages the perspective to develop OFET-based biosensors in order to accurately characterize stem cells during the cardiac differentiation process and eventually increase their differentiation efficiency. PMID- 23653302 TI - The final frontier -- crossing the blood-brain barrier. PMID- 23653303 TI - Initial HIV mucosal infection and dendritic cells. PMID- 23653306 TI - Drain removal and aspiration to treat low output chylous fistula. AB - Chylous fistula following neck dissection is difficult to treat. We hypothesized that timely removal of the suction drain followed by daily aspiration might aid in resolution of the condition. The study model is prospective cohort study. Out of 170 consecutive neck dissections, 7 (4 %) developed chylous fistula postoperatively. Retaining the suction drain was associated with resolution of the fistula in only one case. The remaining six had peak 24 h outputs between 85 and 675 ml that showed no significant fall despite maximal conservative treatment. Suction drain removal followed by daily needle aspiration however led to cessation of the fistula in all six cases. No patient required surgical re exploration. Drain removal was associated with a significant fall in the volume of chylous output (p = 0.002). In selected cases of low output chylous fistula, suction drain removal and daily needle aspiration is an effective treatment option. PMID- 23653305 TI - Open mini-incision parathyroidectomy for solitary parathyroid adenoma. AB - Parathyroid surgery is the acceptable definitive treatment for primary hyperparathyroidism (pHPT) due to parathyroid adenoma. Open mini-incision parathyroidectomy (O-MIP) has an excellent cure rate and minimal morbidity. We aim to demonstrate the safety, efficacy and subjective patient satisfaction of O MIP and investigate the accuracy of pre-operative radiological localisation in relation to operative findings. A retrospective review of patients who underwent O-MIP for pHPT due to solitary parathyroid adenoma from April 2006 to August 2012 was performed. All patients were initially investigated by an endocrinologist to confirm pHPT with pre-operative localisation imaging using ultrasound scan (USS) and 99mTc-sestamibi (MIBI). One hundred and fifty consecutive patients were included with a median age of 62 years. Pre-operative USS and MIBI scans were concordant in 71 % of cases. In combined modality (USS and MIBI), localisation was 94.8 % accurate. There was 95.5 % identification of parathyroid tissue confirmed by intra-operative frozen section. Ninety-one percent of patients were treated as a day case. The median operative time was 60 min. The mean pre operative calcium level was 2.98 mmol/l, and the short-to-medium term mean calcium level was 2.49 (Paired t test, p < 0.001). There was no significant complication. O-MIP confers significant advantages over the traditional gold standard treatment of bilateral neck exploration. Accurate localisation is the key to successful O-MIP. In experienced hands, ultrasound and MIBI may be the only pre-operative investigations required for accurate localisation. PMID- 23653307 TI - Testosterone replacement therapy can increase circulating endothelial progenitor cell number in men with late onset hypogonadism. AB - Circulating endothelial progenitor cells (EPCs) are bone marrow-derived cells required for endothelial repair. A low EPC number can be considered as an independent predictor of endothelial dysfunction and future cardiovascular events. Recent evidence shows that patients with hypogonadal symptoms without other confounding risk factors have a low number of circulating progenitor cells (PCs) and EPCs, thus highlighting the role of testosterone in the proliferation and differentiation of EPCs. Here, we investigate if testosterone replacement therapy (TRT) can increase circulating EPC number in men with late onset hypogonadism. Forty-six men (age range, 40-73 years; mean age, 58.3 years) with hypogonadal symptoms were recruited, and 29 men with serum total testosterone (TT) levels less than 350 ng/dL received TRT using transdermal testosterone gel (Androgel; 1% testosterone at 5 g/day) for 12 months. Circulating EPC numbers (per 100 000 monocytes) were calculated using flow cytometry. There was no significant association between serum TT levels and the number of circulating EPCs before TRT. Compared with the number of mean circulating EPCs at baseline (9.5 +/- 6.2), the number was significantly higher after 3 months (16.6 +/- 11.1, p = 0.027), 6 months (20.3 +/- 15.3, p = 0.006) and 12 months (27.2 +/- 15.5, p = 0.017) of TRT. Thus, we conclude that serum TT levels before TRT are not significantly associated with the number of circulating EPCs in men with late onset hypogonadism. However, TRT can increase the number of circulating EPCs, which implies the benefit of TRT on endothelial function in hypogonadal men. PMID- 23653308 TI - Roles of T helper 17 cells and interleukin-17 in neuroautoimmune diseases with emphasis on multiple sclerosis and Guillain-Barre syndrome as well as their animal models. AB - The identification of T helper 17 (Th17) cells challenges the Th1/Th2 paradigm of the immune response and invites intensive exploration of their mechanisms and functions in the field of autoimmune diseases, host defense, allergy, etc. The collective data have shown that transforming growth factor-beta (TGF-beta), interleukin (IL)-6, IL-1beta, IL-21, and IL-23 are involved in the differentiation program of Th17 cells. The transcription factors RORgammaT, STAT3, RORgamma, RORalpha, and IRF4 exert regulatory effects on the development of Th17 cells. Among the Th17-related effector cytokines, such as IL-17, IL-17F, IL-21, and IL-22, IL-17 is regarded as a key cytokine to induce inflammatory responses. This review outlines the cytokines and transcription factors involved in the differentiation of Th17 cells and their effector functions, with specific focus on the roles of Th17 cells and IL-17 in neuroautoimmune diseases, especially in multiple sclerosis and Guillain-Barre syndrome, as well as in their animal models, experimental autoimmune encephalomyelitis and experimental autoimmune neuritis. PMID- 23653309 TI - Health behaviour change interventions for the promotion of physical activity in rheumatoid arthritis: a systematic review. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease with typical onset between the ages of 40 and 50 years. Increasing levels of physical activity (PA) have been shown to decrease inflammation, reduce pain, increase functional ability and improve self-esteem in people with RA. Health behaviour change (HBC) interventions have recently shown promise in facilitating the promotion of PA within a range of long-term conditions. There is currently no evidence synthesis relating to HBC interventions to increase PA in the RA population. OBJECTIVES: The aim of the present study was to determine whether HBC interventions can increase PA in people with RA and identify optimal interventions or promising constituent components of the HBC interventions. METHODS: A systematic literature search was conducted to identify randomized, controlled trials investigating the effect of HBC interventions on PA level in adults with RA. Four review authors independently assessed the methodological quality of studies and extracted data based upon predefined criteria. RESULTS: Following the application of inclusion/exclusion criteria, three studies remained for inclusion. Two studies reported significant short-term (<9 months) beneficial effects of HBC upon PA (p < 0.05). Individualized interventions were significantly more effective (p < 0.05). CONCLUSIONS: Due to methodological flaws and a lack of comparison with usual care, it is not possible to conclude whether HBC interventions can increase PA in the RA population. Although it is possible to highlight promising elements of HBC interventions, such as goal setting and feedback on performance, further research on all specific components, including information provision, behaviour contracts and problem solving, is required to establish conclusive clinical guidelines. PMID- 23653310 TI - Effect of whey protein hydrolysates with different molecular weight on fatigue induced by swimming exercise in mice. AB - BACKGROUND: In order to improve the antioxidant and anti-fatigue capacities of whey protein for wider utilization, it was hydrolyzed by chymotrypsin (EC 3.4.21.1) to produce whey protein hydrolysate (WPH). Fractions of WPH with different molecular weight (MW) were separated by ultrafiltration. Kunming mice in various treatment groups were orally administered (1.5 g kg(-1) body weight) whey protein isolate (WPI), WPH or WPHs with different MW (<5, 5-10, 10-30 or >30 kDa) for 6 weeks to explore whether different MW fractions of WPH affected mice fatigue. RESULTS: Compared with the control group (orally administered 9 g kg(-1) saline) or the WPI group, low-MW (<10 kDa) WPH groups showed prolonged swimming time (P < 0.05) and had higher concentrations (P < 0.05) of glucose, non esterfied fatty acid, liver glycogen, superoxide dismutase and glutathione peroxidase and lower concentration of lactate. Low-MW (<10 kDa) WPHs had higher hydroxyl- and alpha,alpha-diphenyl-beta-picrylhydrazyl-scavenging abilities and ferrous-chelating capacity than WPI. CONCLUSION: The results proved that low-MW (<10 kDa) WPHs with higher anti-fatigue capacity showed higher free radical scavenging and ferrous-chelating activities. PMID- 23653311 TI - Prolonged exposure to a low-dose of bisphenol A increases spontaneous motor activity in adult male rats. AB - We investigated the effects of bisphenol A (BPA), an environmental endocrine disrupting chemical, on spontaneous motor activity in adult male rats. The rats were implanted intraperitoneally with mini-osmotic pumps containing either BPA (50 MUg/kg body weight per day) in sesame oil (BPA-treated group) or sesame oil only (vehicle-treated group). Spontaneous motor activity during a 24-h period was measured over 5 days from day 9 to day 13 after implantation using an animal movement analysis system. Spontaneous motor activity during the last 2 h of the dark phase and during the first 1-h of the light phase was increased in the BPA treated group. Total spontaneous motor activity during the 12-h light phase, but not the 12-h dark phase, was higher in the BPA-treated group than in the vehicle treated group. These findings suggest that BPA may induce hyperactivity in adult male rats during the 12-h light phase, especially during the 2 h immediately preceding sleep-onset and 1 h immediately following sleep-onset. PMID- 23653312 TI - Social isolation and adult mortality: the role of chronic inflammation and sex differences. AB - The health and survival benefits of social embeddedness have been widely documented across social species, but the underlying biophysiological mechanisms have not been elucidated in the general population. We assessed the process by which social isolation increases the risk for all-cause and chronic disease mortality through proinflammatory mechanisms. Using the 18-year mortality follow up data (n = 6,729) from the National Health and Nutrition Examination Survey (1988-2006) on Social Network Index and multiple markers of chronic inflammation, we conducted survival analyses and found evidence that supports the mediation role of chronic inflammation in the link between social isolation and mortality. A high-risk fibrinogen level and cumulative inflammation burden may be particularly important in this link. There are notable sex differences in the mortality effects of social isolation in that they are greater for men and can be attributed in part to their heightened inflammatory responses. PMID- 23653313 TI - Quantification of rice blast disease progressions through Taqman real-time PCR. AB - Rice blast caused by Magnaporthe oryzae is a major disease in the paddy field and also a representative model system in the investigation of plant-microbe interactions. This study was undertaken to provide the quantitative evaluation method that specifically determines the amount of M. oryzae proliferation in planta. Real-time PCR was used as the detection strategy in combination with the primer pair and Taqman probe specific to MHP1, a unigene encoding HYDROPHOBIN that is indispensable for normal virulence expression. Based on the crossing point values from the PCR reactions containing a series of increasing concentration of cloned amplicon or fungal genomic DNA, correlation among the template's copy number or its amount and amplification pattern was calculated. Reliability of this equation was further confirmed using the DNA samples from the rice leaves infected with compatible or incompatible strains of M. oryzae. The primer pair used in the Taqman real-time PCR reaction can recognize the existence of fungal DNA as low as 1 pg. In sum, our quantitative evaluation system is applicable and reliable in the blast diagnosis and also in the estimation of objective blast disease progression. PMID- 23653314 TI - Assessing anthropogenic sources of mercury in soil in Wanshan Hg mining area, Guizhou, China. AB - Long-term mining and smelting activities brought a series of environmental issues into soils in Wanshan mercury (Hg) mining area (WMMA), Guizhou, China. Several studies have been published on the concentrations of Hg in local soils, but a comprehensive assessment of the mass of Hg in soil induced by anthropogenic activities, as presented in this paper, has not been previously conducted. Three districts of WMMA were chosen as the study areas. We summarized previous published data and sampled 14 typical soil profiles to analyze the spatial and vertical distributions of Hg in soil in the study areas. The regional geologic background, direct and indirect Hg deposition, and Hg-polluted irrigation water were considered as the main sources of Hg contaminations in local soils. Furthermore, the enrichment factor (EF) method was applied to assess the extent of anthropogenic input of Hg to soil. Titanium (Ti) was chosen to be the reference element to calculate the EF. Generally, the elevated values of EF were observed in the upper soil layers and close to mine wastes. The total budget of Hg in soil contributed from anthropogenic sources was estimated to be 1,227 t in arable soil and 75 t in natural soil. Our data showed that arable soil was the major sink of anthropogenic Hg in the study area. PMID- 23653316 TI - Electrocoagulation-integrated hybrid membrane processes for the treatment of tannery wastewater. AB - Three different combinations of treatment techniques, i.e. electrocoagulation combined with microfiltration (EMR), membrane bioreactor (MBR) and electrocoagulation integrated with membrane bioreactor (hybrid MBR, (HMBR)), were analysed and compared for the treatment of tannery wastewater operated for 7 days under the constant trans-membrane pressure of 5 kPa. HMBR was found to be most suitable in performance as well as fouling reduction, with 94 % of chemical oxygen demand (COD) removal, 100 % chromium removal and 8 % improvement in percentage reduction in permeate flux compared to MBR with only 90 % COD removal and 67 % chromium removal. The effect of mixed liquor suspended solids on fouling was also investigated and was found to be insignificant. EMR was capable of elevating the flux but was not as efficient as HMBR and MBR in COD removal. Fouling reduction by HMBR was further confirmed by SEM-EDX and particle size analysis. PMID- 23653315 TI - Application of zeolite-activated carbon macrocomposite for the adsorption of Acid Orange 7: isotherm, kinetic and thermodynamic studies. AB - In this study, the adsorption behavior of azo dye Acid Orange 7 (AO7) from aqueous solution onto macrocomposite (MC) was investigated under various experimental conditions. The adsorbent, MC, which consists of a mixture of zeolite and activated carbon, was found to be effective in removing AO7. The MC were characterized by scanning electron microscopy (SEM), energy dispersive X ray, point of zero charge, and Brunauer-Emmett-Teller surface area analysis. A series of experiments were performed via batch adsorption technique to examine the effect of the process variables, namely, contact time, initial dye concentration, and solution pH. The dye equilibrium adsorption was investigated, and the equilibrium data were fitted to Langmuir, Freundlich, and Tempkin isotherm models. The Langmuir isotherm model fits the equilibrium data better than the Freundlich isotherm model. For the kinetic study, pseudo-first-order, pseudo-second-order, and intraparticle diffusion model were used to fit the experimental data. The adsorption kinetic was found to be well described by the pseudo-second-order model. Thermodynamic analysis indicated that the adsorption process is a spontaneous and endothermic process. The SEM, Fourier transform infrared spectroscopy, ultraviolet-visible spectral and high performance liquid chromatography analysis were carried out before and after the adsorption process. For the phytotoxicity test, treated AO7 was found to be less toxic. Thus, the study indicated that MC has good potential use as an adsorbent for the removal of azo dye from aqueous solution. PMID- 23653317 TI - Applying Raman spectroscopy to the assessment of the biodegradation of industrial polyurethanes wastes. AB - Polyether-based polyurethanes (PBP) are extremely problematic polymers due to their long persistence in the environment. Moreover, the assessment of PBP biodegradation remains biased due to the inability of conventional methods to determine how their diverse subunits are degraded. To improve our knowledge of PBP biodegradation, we used Raman spectroscopy to identify patterns of PBP biodegradation. Specifically, PBP biodegradation was assessed using a microbial inoculum isolated from an industrial soil in which polyurethanes have been buried for 40 years. During a 28-day biodegradation assay, the PBP biodegradation level reached 27.5% (w/w), in addition to undergoing profound alteration of the PBP composition as identified by chemical analyses. After microbial degradation, Raman analyses revealed the disappearance of the polymer's amorphous region, which contains a high polyol content, whereas the isocyanate-rich crystalline regions were preserved. The use of Raman spectroscopy appears to be a particularly useful tool to enhance our assessment of polymer biodegradation. PMID- 23653318 TI - Antioxidant response of soybean seedlings to joint stress of lanthanum and acid rain. AB - Excess of rare earth elements in soil can be a serious environmental stress on plants, in particular when acid rain coexists. To understand how such a stress affects plants, we studied antioxidant response of soybean leaves and roots exposed to lanthanum (0.06, 0.18, and 0.85 mmol L(-1)) under acid rain conditions (pH 4.5 and 3.0). We found that low concentration of La3+ (0.06 mmol L(-1)) did not affect the activity of antioxidant enzymes (catalase and peroxidase) whereas high concentration of La3+ (>=0.18 mmol L(-1)) did. Compared to treatment with acid rain (pH 4.5 and pH 3.0) or La3+ alone, joint stress of La3+ and acid rain affected more severely the activity of catalase and peroxidase, and induced more H2O2 accumulation and lipid peroxidation. When treated with high level of La3+ (0.85 mmol L(-1)) alone or with acid rain (pH 4.5 and 3.0), roots were more affected than leaves regarding the inhibition of antioxidant enzymes, physiological function, and growth. The severity of oxidative damage and inhibition of growth caused by the joint stress associated positively with La3+ concentration and soil acidity. These results will help us understand plant response to joint stress, recognize the adverse environmental impact of rare earth elements in acidic soil, and develop measures to eliminate damage caused by such joint stress. PMID- 23653319 TI - Effects of allelochemical extracted from water lettuce (Pistia stratiotes Linn.) on the growth, microcystin production and release of Microcystis aeruginosa. AB - This study explored the optimisation of a method of extracting allelochemicals from Pistia stratiotes Linn., identified the optimal dose range for the allelochemicals' anti-algal effect and investigated their impact on the growth of Microcystis aeruginosa, as well as the production and release of microcystin-LR (MC-LR). Based on measured changes in algal cell density and chlorophyll a (Chl a) content, the allelochemicals were confirmed to have the strongest anti-algal effect with the lowest half-effect concentration of 65 mg L(-1) when they were extracted using ethyl acetate as the extraction solvent, 1:20 g mL(-1) as the extraction ratio and 1 h as the extraction time. The allelochemicals extracted from P. stratiotes using this optimal method exhibited the strongest inhibitory effect on the growth of algae when used within a dose range of 60-100 mg L(-1); the relative inhibitory ratio reached 50-90%, and Chl-a content reduced 50-75% in algae cell cultures within 3-7 days. In addition, the extracted allelochemical compounds demonstrated no significant impact on the extracellular release of MC LR during the culturing period. The amount of intracellular MC-LR per 10(6) algal cells increased depending on the increasing dose of allelochemicals from P. stratiotes after 7 days of culturing and maintained stability after 16 days. There was no increase in the total amount of MC-LR in the algal cell culture medium. Therefore, the application of allelochemicals from P. stratiotes to inhibit M. aeruginosa has a high degree of ecological safety and can be adopted in practical applications for treating water subjected to algae blooms because the treatment can effectively inhibit the proliferation of algal cells without increasing the release of cyanotoxin. PMID- 23653320 TI - Guest binding subtly influences spin crossover in an FeII4L4 capsule. AB - How much should we switch? Two FeII4L4 tetrahedral capsules were shown to undergo thermally induced spin crossover (SCO). Guest binding to one of these capsules was observed to affect the thermodynamics of its SCO in solution, leading to different spin transition temperatures between the empty host (blue) and the host guest complex (red). HS: high spin; LS: low spin. PMID- 23653321 TI - Ancient schwannoma. PMID- 23653323 TI - Clinical characteristics and insulin independence of Koreans with new-onset type 2 diabetes presenting with diabetic ketoacidosis. AB - BACKGROUND: We evaluated the incidence, characteristics and insulin independence of Koreans with new-onset type 2 diabetes (T2D) initially presenting with diabetic ketoacidosis (DKA). METHODS: We analysed clinical and biochemical data from diabetic patients presenting with DKA. They were classified into ketosis prone diabetes (KPD) type 1A (KPD-T1A) (A+beta-), type 1B (KPD-T1B) (A-beta-), type 2A (KPD-T2A) (A+beta+) or type 2B (KPD-T2B) (A-beta+) according to the presence or absence of an autoantibody and beta-cell reserve. Changes in therapy after insulin discontinuation were evaluated for up to 4 years. We also compared clinical and biochemical characteristics between newly diagnosed T2D patients presenting with DKA and previously diagnosed T2D patients presenting with DKA. RESULTS: Among 60 newly diagnosed KPD patients, 18, 21 and 21 patients were classified as KPD-T1A, KPD-T1B and KPD-T2B, respectively. In the KPD-T2B group, both fasting and stimulated C-peptide were recovered over 6 months. After 4 years of DKA development, 75% of KPD-T2B subjects no longer required insulin. Compared with previously diagnosed T2D patients presenting with DKA, newly diagnosed KPD T2B patients tended to be younger, more obese and showed better insulin secretory function after recovery from DKA. CONCLUSIONS: New-onset T2D patients presenting with DKA was not uncommon among the Korean population. In contrast to previously diagnosed T2D patients presenting with DKA, who showed a progressive decrease in insulin secretory function, new-onset KPD-T2B patients recovered insulin secretory function over time, and insulin independence could be expected. PMID- 23653322 TI - TIE2-expressing monocytes/macrophages regulate revascularization of the ischemic limb. AB - A third of patients with critical limb ischemia (CLI) will eventually require limb amputation. Therapeutic neovascularization using unselected mononuclear cells to salvage ischemic limbs has produced modest results. The TIE2-expressing monocytes/macrophages (TEMs) are a myeloid cell subset known to be highly angiogenic in tumours. This study aimed to examine the kinetics of TEMs in patients with CLI and whether these cells promote neovascularization of the ischemic limb. Here we show that there are 10-fold more circulating TEMs in CLI patients, and removal of ischemia reduces their numbers to normal levels. TEM numbers in ischemic muscle are two-fold greater than normoxic muscle from the same patient. TEMs from patients with CLI display greater proangiogenic activity than TIE2-negative monocytes in vitro. Using a mouse model of hindlimb ischemia, lentiviral-based Tie2 knockdown in TEMs impaired recovery from ischemia, whereas delivery of mouse macrophages overexpressing TIE2, or human TEMs isolated from CLI patients, rescued limb ischemia. These data suggest that enhancing TEM recruitment to the ischemic muscle may have the potential to improve limb neovascularization in CLI patients. PMID- 23653324 TI - Iran's Bushehr Earthquake at a Glance. AB - On 9 April 2013, an earthquake of 6.1 magnitude hit southwestern Iran near the city of Khvormuj and the towns of Kaki and Shonbeh in Bushehr province. The official disaster mitigation committee took immediate actions to coordinate rescue teams equipped with 24-hour medical air assistance. Overall, 160 victims were transferred to and treated in the Khvormuj hospital, while 139 survivors were transferred to the hospitals in Bushehr for specialized care. The survivors have been settled in temporary shelters with adequate primary supplies. Considering the hot climate of the area, immediate measures should be taken in order to avoid any further casualties particularly heatstroke, dehydration, diarrheal and vector-borne diseases. PMID- 23653325 TI - Parkinson's disease cybrids, differentiated or undifferentiated, maintain morphological and biochemical phenotypes different from those of control cybrids. AB - SH-SY5Y, control, and Parkinson's disease (PD) cybrids prepared from an Indian population were differentiated using retinoic acid (RA) for understanding their dopaminergic characteristics and neuritogenesis. Undifferentiated control and PD cybrids exhibited higher levels of TH mRNA, but lower c-RET expression, short neurites, low neuritic density, and low proportion of cells with neurites compared with the undifferentiated parent cell line, SH-SY5Y. The expression levels of DAT and Ptx3 were similar to SH-SY5Y. PD cybrids showed poor viability and lower differentiating potency than SH-SY5Y or control cybrids. RA treatment for 6 days elevated c-RET expression and corrected the neuritic morphology of the control, but not of PD cybrids. Cell viability was found to be reduced in differentiated control and PD cybrids. TH expression level was significantly elevated in SH-SY5Y following RA treatment, but not in both the cybrids. In differentiated control and PD cybrids, the TH immunofluorescence intensity was significantly lower compared with SH-SY5Y cells. MitoTracker Green fluorescence intensity of the mitochondria was higher in differentiated PD cybrids. Dopamine released into the medium was unaffected in the differentiated SH-SY5Y or in the control cybrids but was significantly elevated in PD cybrids. These results suggest that PD cybrids, differentiated or undifferentiated, maintained morphological and biochemical phenotypes significantly different from those of the control cybrids, or the differentiated SH-SY5Y cells, and therefore could be an ideal cellular model of the disease for pharmacological screening of drugs and for investigation of the pathophysiology of PD. PMID- 23653327 TI - Retraction note to: Cardiovascular responses to tracheal extubation or LMA removal in children. PMID- 23653326 TI - Microbiological quality and characteristics of probiotic products in China. AB - BACKGROUND: Probiotics are widely used in the food industry and medicine fields in China, but few studies have been conducted to evaluate the actual microbial amounts and species in probiotic products, which may conflict with the labels and mislead consumers to choose inappropriate foods or medicines. RESULTS: Twenty commercial dairy products and eight commercial 'healthcare' samples were collected from markets in China and tested using culture-dependent and culture independent methods. The results suggested that the total bacterial counts of most commercial products met the minimum quantitative requirement of the Chinese national standard (6.00 log colony-forming units g(-1) ). However, the bacterial counts of specific species were inconsistent with the labelling. In parallel, denaturing gradient gel electrophoresis analysis indicated that some probiotic containing products were wrongly labelled; no Bifidobacterium species were detected in the products claiming to contain bifidobacteria, and the probiotic characteristics (antimicrobial activity, acid resistance and bile resistance) of some isolates had degraded. Moreover, some contaminating bacteria, e.g. Enterobacter sp., Klebsiella sp. and Serratia sp., were also detected in these products. CONCLUSION: The combination of culture-dependent and culture independent methods was proven to quickly and conveniently detect the microbial diversity in probiotic products, and more effort is required to regulate the probiotic market in China. PMID- 23653328 TI - Anti-senescence efficacy of radio-electric asymmetric conveyer technology. AB - Recent evidence suggests that ageing-related diseases could result in an accelerated loss of self-renewal capability of adult stem cells, normally involved in replacing damaged cellular elements. In previous works, we highlighted that a specific treatment, named tissue optimization-regenerative (TO RGN), of radio-electric asymmetric conveyer (REAC) technology, influenced gene expression profiles controlling stem cell differentiation and pluripotency of human skin-derived fibroblasts in vitro. The purpose of the present work was to verify whether TO-RGN may also be effective in counteracting the expression of the senescence marker beta-galactosidase and of senescence-associated gene expression patterning, engaged during prolonged culture of human adipose-derived stem cells (hADSCs). Following TO-RGN exposure, we observed a significant downregulation in beta-galactosidase staining and in the expression of the senescence mediator genes p16INK4, ARF, p53, and p21(CIP1). Moreover, differently formed untreated cells, TO-RGN-exposed hADSCs maintained their typical fibroblast like morphology and exhibited a multilineage potential even at late passages, as shown by the remarkable preservation of commitment to osteogenic, adipogenic, chondrogenic, and vasculogenic fates, both at morphologic and gene expression levels. In conclusion, our study highlights a positive effect of TO-RGN in counteracting degenerative senescence processes in vitro. PMID- 23653329 TI - Activation of BKca channels mediates hippocampal neuronal death after reoxygenation and reperfusion. AB - Excessive K(+) efflux promotes central neuronal apoptosis; however, the type of potassium channel that mediates K(+) efflux in response to different apoptosis inducing stimuli is still unknown. It is hypothesized that the activation of large-conductance Ca(2+)-activated K(+) channels (BKCa) mediates hypoxia/reoxygenation (H/R)- and ischemia/reperfusion (I/R)-induced neuronal apoptosis. Rat hippocampal neuronal cultures underwent apoptosis after reoxygenation, as assessed by morphologic observation, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and caspase-3 activation. Single channel recordings revealed upregulation of BKCa channel activity 6 h after reoxygenation, which might be caused by elevated cytosolic Ca(2+). The K(+) ionophore valinomycin and the BKCa channel opener NS1619 induced neuronal apoptosis. Transfection of the BKCa channel alpha subunit into Chinese hamster ovary (CHO-K1) cells, which do not express endogenous K(+) channels, or into neurons will induce cell apoptosis, indicating that the opening of the BKCa channel serves as a pivotal event in mediating cell apoptosis. The specific BKCa channel blockers charybdotoxin and iberiotoxin and the nonselective K(+) channel blocker tetraethylammonium at concentrations more specific to the BKCa channel were neuroprotective. The A-type potassium channel blocker 4-aminopyridine and apamin, a small-conductance Ca(2+)-activated K(+) channel blocker, were not protective. This result suggests the involvement of the BKCa channel in H/R induced apoptosis. Similarly, specific BKCa channel blockers also showed neuroprotection in neurons subjected to oxygen-glucose deprivation/reoxygenation or animals subjected to forebrain ischemia-reperfusion. These results demonstrate that the over-activity of BKCa channels mediates hippocampal neuronal damage induced by H/R in vitro and I/R in vivo. PMID- 23653331 TI - Self-healing in tough graphene oxide composite hydrogels. AB - Polymer hydrogels that are capable of spontaneously healing injury are being developed at a rapid pace because of their great potential in biomedical applications. Here, the self-healing property of tough graphene nanocomposite hydrogels fabricated by using graphene peroxide as polyfunctional initiating and cross-linking centers is reported. The hydrogels show excellent self-healing ability at ambient temperature or even lower temperatures for a short time and very high recovery degrees (up to 88% tensile strength) can be achieved at a prolonged healing time. The healed gels exhibit very high tensile strengths (up to 0.35 MPa) and extremely high elongations (up to 4900%). The strong interactions between the polyacrylamide chains and the graphene oxide sheets are essential to the mechanical strengths of the healed gels. PMID- 23653330 TI - Differentially expressed epigenome modifiers, including aurora kinases A and B, in immune cells in rheumatoid arthritis in humans and mouse models. AB - OBJECTIVE: To identify epigenetic factors that are implicated in the pathogenesis of rheumatoid arthritis (RA), and to explore the therapeutic potential of the targeted inhibition of these factors. METHODS: Polymerase chain reaction (PCR) arrays were used to investigate the expression profile of genes that encode key epigenetic regulator enzymes. Mononuclear cells from RA patients and mice were monitored for gene expression changes, in association with arthritis development in murine models of RA. Selected genes were further characterized by quantitative reverse transcription-PCR, Western blot, and flow cytometry methods. The targeted inhibition of the up-regulated enzymes was studied in arthritic mice. RESULTS: A set of genes with arthritis-specific expression was identified by the PCR arrays. Aurora kinases A and B, both of which were highly expressed in arthritic mice and treatment-naive RA patients, were selected for detailed analysis. Elevated aurora kinase expression was accompanied by increased phosphorylation of histone H3, which promotes proliferation of T lymphocytes. Treatment with VX-680, a pan aurora kinase inhibitor, promoted B cell apoptosis, provided significant protection against disease onset, and attenuated inflammatory reactions in arthritic mice. CONCLUSION: Arthritis development is accompanied by changes in expression of a number of epigenome-modifying enzymes. Drug-induced down regulation of the aurora kinases, among other targets, seems to be sufficient to treat experimental arthritis. Development of new therapeutics that target aurora kinases can potentially improve RA management. PMID- 23653332 TI - "We inform the experience of health": perspectives on professionalism in nursing self-employment. AB - Nursing work has evolved tremendously over the last century, raising ongoing questions about nursing's professional status. Through various strategies, professionalization in nursing has to some extent been accomplished, although autonomy over nursing practice has been elusive. This is especially so in the contemporary health care system, in which managerial control is emphasized and physician dominance continues. In response to professional constraints in traditional work settings, nursing self-employment is growing. In this study I used focused ethnography to explore the professional experiences of Canadian self employed nurses and to reconsider nursing knowledge, ethics, and professionalism in this unique context. Despite the barriers they faced, these nurses offered a perspective on nursing professionalism that transcends classic professional traits, showing how the concept of professionalism can be invoked not as a way to "prove" status but as a way to describe a sense of commitment and the contribution to societal well-being. PMID- 23653334 TI - Phylogenetic examination of crude drugs derived from Yunnanese Swertia plants. AB - Aiming to examine whether the genetic background of the crude drugs derived from four Yunnanese Swertia plants and their chemical constituent profiles correlate, we analyzed the nucleotide sequences of their nuclear ribosomal DNA regions including ITS1, 5.8S ribosomal RNA gene, and ITS2, together with those of Japanese S. japonica and S. pseudochinensis from Hebei Province. The result that two of the Yunnanese Swertia plants, S. binchuanensis and S. punicea, were genetically similar may explain their similarity in chemical constituent profiles. On the other hand, in spite of differences in chemical profile, S. decora and S. pseudochinensis were genetically close. The other Yunnanese Swertia plants, S. delavayi, and S. japonica, stood at intermediate positions between these two genetically similar pairs. The result suggests that although genetic background would have an influence, environmental factors, e.g., soil and weather conditions, might be critical for their production of secondary metabolites. PMID- 23653333 TI - Metabolite sensing in eukaryotic mRNA biology. AB - All living creatures change their gene expression program in response to nutrient availability and metabolic demands. Nutrients and metabolites can directly control transcription and activate second-messenger systems. More recent studies reveal that metabolites also affect post-transcriptional regulatory mechanisms. Here, we review the increasing number of connections between metabolism and post transcriptional regulation in eukaryotic organisms. First, we present evidence that riboswitches, a common mechanism of metabolite sensing in bacteria, also function in eukaryotes. Next, we review an example of a double stranded RNA modifying enzyme that directly interacts with a metabolite, suggesting a link between RNA editing and metabolic state. Finally, we discuss work that shows some metabolic enzymes bind directly to RNA to affect mRNA stability or translation efficiency. These examples were discovered through gene-specific genetic, biochemical, and structural studies. A directed systems level approach will be necessary to determine whether they are anomalies of evolution or pioneer discoveries in what may be a broadly connected network of metabolism and post transcriptional regulation. PMID- 23653335 TI - AdipoQ polymorphisms are associated with type 2 diabetes mellitus: a meta analysis study. AB - OBJECTIVE: Adiponectin (AdipoQ) plays an important role in the pathogenesis of diabetes mellitus and is considered as an important candidate gene for type 2 diabetes mellitus (T2DM). So far, there have been many studies to investigate the association between the adiponectin polymorphisms and T2DM risk. However, the results are conflicting. To derive a more precise estimation, we performed a meta analysis to assess the association between five AdipoQ polymorphisms [-11426A > G (rs16861194), -11391G > A (rs17300539), -11377C > G (rs266729), +45T > G (rs2241766) and +276G > T (rs1501299)], and T2DM risk. METHODS: The fixed and random-effects model should be used to assess the summary odds ratios (ORs) of each study. ORs with 95% confidence intervals (CIs) were used to evaluate the strength of association. On the basis of the included criteria, we selected 39 papers, among which eight for -11426A > G, 14 for -11391G > A, 21 for -11377C > G, 28 for +45 T > G and 24 for +276G > T. Sensitivity analyses were conducted to assess the stability of the results. Both Begg's funnel plots and Egger's test are commonly used to evaluate publication bias. RESULTS: Overall, we found that individuals with the -11426G allele had a 0.15-fold significantly increased T2DM risk (additive model: 1.15, 1.04-1.27, 0.222). In the stratified analyses, we found that the -11426A > G, -11391G > A and -11377C > G polymorphisms could increase T2DM risk in European populations in the additive model. For Asian populations, we found that the -11377C > G polymorphism also could elevate T2DM risk. CONCLUSIONS: Our results suggested that the adiponectin -11426A > G polymorphism could contribute to the T2DM risk. PMID- 23653336 TI - Steric and electronic interactions controlling the cis/trans isomer equilibrium at X-Pro tertiary amide motifs in solution. AB - A systematic understanding of the noncovalent interactions that influence the structures of the cis conformers and the equilibrium between the cis and the trans conformers, of the X-Pro tertiary amide motifs, is presented based on analyses of (1)H-, (13)C-NMR and FTIR absorption spectra of two sets of homologous peptides, X-Pro-Aib-OMe and X-Pro-NH-Me (where X is acetyl, propionyl, isobutyryl and pivaloyl), in solvents of varying polarities. First, this work shows that the cis conformers of any X-Pro tertiary amide motif, including Piv Pro, are accessible in the new motifs X-Pro-Aib-OMe, in solution. These conformers are uniquely observable by FTIR spectroscopy at ambient temperatures and by NMR spectroscopy from temperatures as high as 273 K. This is made possible by the persistent presence of n(i-1) ->pi(i)* interactions at Aib, which also influence the disappearance of steric effects at these cis X-Pro rotamers. Second, contrary to conventional understanding, the energy contribution of steric effects to the cis/trans equilibrium at the X-Pro motifs is found to be nonvariant (0.54 +/- 0.02 kcal/mol) with increase in steric bulk on the X group. Third, the current studies provide direct evidence for the weak intramolecular interactions namely the n(i-1) ->pi(i)*, the N(Pro) ***H(i+1) (C5a), and the C7 hydrogen bond that operate and influence the structures, stabilities, and dynamics between different conformational states of X-Pro tertiary amide motifs. NMR and IR spectral data suggest that the cis conformers of X-Pro motifs are ensembles of short-lived rotamers about the C'(X)-N(Pro) bond. PMID- 23653338 TI - Consider Danon disease in dilated cardiomyopathy with noncompaction. PMID- 23653339 TI - Ascorbic acid is superior to silymarin in the recovery of ethanol-induced inflammatory reactions in hepatocytes of guinea pigs. AB - Both oxidative stress and inflammatory reactions play a major role in alcoholic liver fibrosis. We evaluated the efficacy of ascorbic acid (AA) and silymarin in the regression of alcohol-induced inflammation in hepatocytes of guinea pigs (Cavia porcellus). Animals were administered with ethanol at a daily dose of 4 g/kg body weight (b.wt) for 90 days. On the ninety-first day, ethanol administration was stopped and animals were divided into alcohol abstention group and silymarin- (25 mg/100 g b.wt) and AA- (25 mg/100 g b.wt) supplemented groups and maintained for 30 days. There was a significant increase in the activities of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transpeptidase in the serum of the ethanol group. The intracellular reactive oxygen species (ROS) and expressions of cytochrome P4502E1 and nuclear factor kappaB1, tumor necrosis factor-alpha, and transforming growth factor-beta(1) in hepatocytes were significantly increased in ethanol group. The fibrotic markers alpha-smooth muscle actin and alpha(1)(I) collagen and activity of cytotoxicity marker caspase-3 were significantly increased and AA content was significantly reduced in hepatocytes of alcohol-treated guinea pigs. But the AA and silymarin supplementation significantly reduced these changes in comparison with alcohol abstention group. AA could induce greater reduction of inflammatory and fibrotic markers in hepatocytes than silymarin. This indicates that AA is superior to silymarin in inhibiting intracellular ROS generation and thereby reducing the ethanol-induced inflammation in hepatocytes. PMID- 23653341 TI - How can we get high quality routine data to monitor the safety of devices and procedures? PMID- 23653340 TI - Commentary: Europe needs a central, transparent, and evidence based regulation process for devices. PMID- 23653342 TI - Rapid one-step inactivation of single or multiple genes in Escherichia coli. AB - Gene knockout experiments are frequently performed for both fundamental and applied biological research. We developed an integration helper plasmid-based knockout system for more efficient and rapid engineering of Escherichia coli. The integration helper plasmid, pCW611, contains two recombinases that are expressed in the reverse direction by two independent inducible systems. One is Red recombinase under the control of the arabinose-inducible system to induce a recombination event by using the linear gene knockout DNA fragment, while the other is Cre recombinase, which is controlled by the isopropyl beta-D-1 thiogalactopyranoside-inducible system to obtain markerless mutant strains. The time and effort required can be reduced with this system because iterative transformation and curing steps are not required. We could delete one target gene in three days by using pCW611. To verify the usefulness of this system, deletion experiments were performed to knock out four target genes individually (adhE, sfcA, frdABCD, and ackA) and two genes simultaneously for two cases (adhE-aspA and sfcA-aspA). Also, sequential deletion of four target genes (fumB, iclR, fumA, and fumC) was successfully performed to make a fumaric acid producing strain. This successfully developed and validated rapid and efficient gene manipulation system should be useful for the metabolic engineering of E. coli. PMID- 23653343 TI - Backbone and ILV methyl resonance assignments of E. coli thymidylate synthase bound to cofactor and a nucleotide analogue. AB - Thymidylate synthase (TSase) is a 62 kDa homodimeric enzyme required for de novo synthesis of thymidine monophosphate in most organisms. This makes the enzyme an excellent target for anticancer and microbial antibiotic drugs. In addition, TSase has been shown to exhibit negative cooperativity and half-the-sites reactivity. For these collective reasons, TSase is widely studied, and much is known about its kinetics and structure as it progresses through a multi-step catalytic cycle. Recently, nuclear magnetic resonance spin relaxation has been instrumental in demonstrating the critical role of dynamics in enzyme function in small model systems. These studies raise questions about how dynamics affect function in larger enzymes with more complex reaction coordinates. TSase is an ideal candidate given its size, oligomeric state, cooperativity, and status as a drug target. Here, as a pre-requisite to spin relaxation studies, we present the backbone and ILV methyl resonance assignments of TSase from Escherichia coli bound to a substrate analogue and cofactor. PMID- 23653348 TI - SCN1A Genetic Test for Dravet Syndrome (Severe Myoclonic Epilepsy of Infancy and its Clinical Subtypes) for use in the Diagnosis, Prognosis, Treatment and Management of Dravet Syndrome. AB - Classic Dravet syndrome is also termed severe myoclonic epilepsy of infancy (SMEI). There are subtle phenotypic variants of Dravet which may have all the features of the syndrome except one, such as without myoclonic seizures, onset in the second year or without generalized spike and wave on EEG. These have been termed borderline variants of SMEI. Rather than ascribing multiple different names to marginally different phenotypes, the term Dravet syndrome is now preferred to describe the group of severe infantile onset epilepsies (OMIM #607208, #182389, #604403) associated with mutations in SCN1A (OMIM *182389). SCN1A-related seizure disorders can be inherited in an autosomal dominant manner but most are due to de novo mutations. SCN1A testing can be done through bi directional DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) for: 1) individuals with electroclinical phenotype of Dravet Syndrome or clinical sub-types - several seizure types in one individual with onset in infancy, refractory to medication and with generalised spike and wave on EEG, or 2) infants less than 1 year old with 2 or more prolonged hemiclonic febrile seizures in early infancy. DISCLAIMER: This summary is based on a UK Genetic Testing Network (UKGTN) approved Gene Dossier application. PMID- 23653349 TI - p21-activated kinase 1 (PAK1) can promote ERK activation in a kinase-independent manner. AB - PAK1 plays an important role in proliferation and tumorigenesis, at least partially by promoting ERK phosphorylation of C-RAF (Ser-338) or MEK1 (Ser-298). We observed how that overexpression of a kinase-dead mutant form of PAK1 increased phosphorylation of MEK1/2 (Ser-217/Ser-221) and ERK (Thr-202/Tyr-204), although phosphorylation of B-RAF (Ser-445) and C-RAF (Ser-338) remained unchanged. Furthermore, increased activation of the PAK1 activator Rac1 induced the formation of a triple complex of Rac1, PAK1, and MEK1 independent of the kinase activity of PAK1. These data suggest that PAK1 can stimulate MEK activity in a kinase-independent manner, probably by serving as a scaffold to facilitate interaction of C-RAF. PMID- 23653350 TI - Epithelial to mesenchymal transition promotes breast cancer progression via a fibronectin-dependent STAT3 signaling pathway. AB - We previously established that overexpression of the EGF receptor (EGFR) is sufficient to induce tumor formation by otherwise nontransformed mammary epithelial cells, and that the initiation of epithelial-mesenchymal transition (EMT) is capable of increasing the invasion and metastasis of these cells. Using this breast cancer (BC) model, we find that in addition to EGF, adhesion to fibronectin (FN) activates signal transducer and activator of transcription 3 (STAT3) through EGFR-dependent and -independent mechanisms. Importantly, EMT facilitated a signaling switch from SRC-dependent EGFR:STAT3 signaling in pre-EMT cells to EGFR-independent FN:JAK2:STAT3 signaling in their post-EMT counterparts, thereby sensitizing these cells to JAK2 inhibition. Accordingly, human metastatic BC cells that failed to activate STAT3 downstream of EGFR did display robust STAT3 activity upon adhesion to FN. Furthermore, FN enhanced outgrowth in three dimensional organotypic cultures via a mechanism that is dependent upon beta1 integrin, Janus kinase 2 (JAK2), and STAT3 but not EGFR. Collectively, our data demonstrate that matrix-initiated signaling is sufficient to drive STAT3 activation, a reaction that is facilitated by EMT during BC metastatic progression. PMID- 23653351 TI - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) phosphorylation by protein kinase Cdelta (PKCdelta) inhibits mitochondria elimination by lysosomal-like structures following ischemia and reoxygenation-induced injury. AB - After cardiac ischemia and reperfusion or reoxygenation (I/R), damaged mitochondria propagate tissue injury by promoting cell death. One possible mechanism to protect from I/R-induced injury is the elimination of damaged mitochondria by mitophagy. Here we identify new molecular events that lead to mitophagy using a cell culture model and whole hearts subjected to I/R. We found that I/R induces glyceraldehyde-3-phosphate dehydrogenase (GAPDH) association with mitochondria and promotes direct uptake of damaged mitochondria into multiorganellar lysosomal-like (LL) structures for elimination independently of the macroautophagy pathway. We also found that protein kinase C delta (PKCdelta) inhibits GAPDH-driven mitophagy by phosphorylating the mitochondrially associated GAPDH at threonine 246 following I/R. Phosphorylated GAPDH promotes the accumulation of mitochondria at the periphery of LL structures, which coincides with increased mitochondrial permeability. Either inhibition of PKCdelta or expression of a phosphorylation-defective GAPDH mutant during I/R promotes a reduction in mitochondrial mass and apoptosis, thus indicating rescued mitophagy. Taken together, we identified a GAPDH/PKCdelta signaling switch, which is activated during oxidative stress to regulate the balance between cell survival by mitophagy and cell death due to accumulation of damaged mitochondria. PMID- 23653352 TI - In Silico screening on the three-dimensional model of the Plasmodium vivax SUB1 protease leads to the validation of a novel anti-parasite compound. AB - Widespread drug resistance calls for the urgent development of new antimalarials that target novel steps in the life cycle of Plasmodium falciparum and Plasmodium vivax. The essential subtilisin-like serine protease SUB1 of Plasmodium merozoites plays a dual role in egress from and invasion into host erythrocytes. It belongs to a new generation of attractive drug targets against which specific potent inhibitors are actively searched. We characterize here the P. vivax SUB1 enzyme and show that it displays a typical auto-processing pattern and apical localization in P. vivax merozoites. To search for small PvSUB1 inhibitors, we took advantage of the similarity of SUB1 with bacterial subtilisins and generated P. vivax SUB1 three-dimensional models. The structure-based virtual screening of a large commercial chemical compounds library identified 306 virtual best hits, of which 37 were experimentally confirmed inhibitors and 5 had Ki values of <50 MUM for PvSUB1. Interestingly, they belong to different chemical families. The most promising competitive inhibitor of PvSUB1 (compound 2) was equally active on PfSUB1 and displayed anti-P. falciparum and Plasmodium berghei activity in vitro and in vivo, respectively. Compound 2 inhibited the endogenous PfSUB1 as illustrated by the inhibited maturation of its natural substrate PfSERA5 and inhibited parasite egress and subsequent erythrocyte invasion. These data indicate that the strategy of in silico screening of three-dimensional models to select for virtual inhibitors combined with stringent biological validation successfully identified several inhibitors of the PvSUB1 enzyme. The most promising hit proved to be a potent cross-inhibitor of PlasmodiumSUB1, laying the groundwork for the development of a globally active small compound antimalarial. PMID- 23653353 TI - The mechanism by which a propeptide-encoded pH sensor regulates spatiotemporal activation of furin. AB - The proprotein convertase furin requires the pH gradient of the secretory pathway to regulate its multistep, compartment-specific autocatalytic activation. Although His-69 within the furin prodomain serves as the pH sensor that detects transport of the propeptide-enzyme complex to the trans-Golgi network, where it promotes cleavage and release of the inhibitory propeptide, a mechanistic understanding of how His-69 protonation mediates furin activation remains unclear. Here we employ biophysical, biochemical, and computational approaches to elucidate the mechanism underlying the pH-dependent activation of furin. Structural analyses and binding experiments comparing the wild-type furin propeptide with a nonprotonatable His-69 -> Leu mutant that blocks furin activation in vivo revealed protonation of His-69 reduces both the thermodynamic stability of the propeptide as well as its affinity for furin at pH 6.0. Structural modeling combined with mathematical modeling and molecular dynamic simulations suggested that His-69 does not directly contribute to the propeptide enzyme interface but, rather, triggers movement of a loop region in the propeptide that modulates access to the cleavage site and, thus, allows for the tight pH regulation of furin activation. Our work establishes a mechanism by which His-69 functions as a pH sensor that regulates compartment-specific furin activation and provides insights into how other convertases and proteases may regulate their precise spatiotemporal activation. PMID- 23653354 TI - Structural analysis of collagen type I interactions with human fibronectin reveals a cooperative binding mode. AB - Despite its biological importance, the interaction between fibronectin (FN) and collagen, two abundant and crucial tissue components, has not been well characterized on a structural level. Here, we analyzed the four interactions formed between epitopes of collagen type I and the collagen-binding fragment (gelatin-binding domain (GBD)) of human FN using solution NMR, fluorescence, and small angle x-ray scattering methods. Collagen association with FN modules (8 9)FnI occurs through a conserved structural mechanism but exhibits a 400-fold disparity in affinity between collagen sites. This disparity is reduced in the full-length GBD, as (6)FnI(1-2)FnII(7)FnI binds a specific collagen epitope next to the weakest (8-9)FnI-binding site. The cooperative engagement of all GBD modules with collagen results in four broadly equipotent FN-collagen interaction sites. Collagen association stabilizes a distinct monomeric GBD conformation in solution, giving further evidence to the view that FN fragments form well defined functional and structural units. PMID- 23653355 TI - Stability of the endosomal scaffold protein LAMTOR3 depends on heterodimer assembly and proteasomal degradation. AB - LAMTOR3 (MP1) and LAMTOR2 (p14) form a heterodimer as part of the larger Ragulator complex that is required for MAPK and mTOR1 signaling from late endosomes/lysosomes. Here, we show that loss of LAMTOR2 (p14) results in an unstable cytosolic monomeric pool of LAMTOR3 (MP1). Monomeric cytoplasmic LAMTOR3 is rapidly degraded in a proteasome-dependent but lysosome-independent manner. Mutational analyses indicated that the turnover of the protein is dependent on ubiquitination of several lysine residues. Similarly, other Ragulator subunits, LAMTOR1 (p18), LAMTOR4 (c7orf59), and LAMTOR5 (HBXIP), are degraded as well upon the loss of LAMTOR2. Thus the assembly of the Ragulator complex is monitored by cellular quality control systems, most likely to prevent aberrant signaling at the convergence of mTOR and MAPK caused by a defective Ragulator complex. PMID- 23653356 TI - Hsp70 targets a cytoplasmic quality control substrate to the San1p ubiquitin ligase. AB - Accumulation of misfolded proteins in cellular compartments can result in stress induced cell death. In the endoplasmic reticulum (ER), ER-associated degradation clears aberrant proteins from the secretory pathway. In the cytoplasm and nucleus, this job is left to the cytoplasmic quality control (CytoQC) machinery. Both processes utilize chaperones and the ubiquitin-proteasome system to aid in protein elimination. Previous studies in yeast have drawn comparisons between these processes using data from structurally and topologically different substrates. We sought to draw a direct comparison between ERAD and CytoQC by studying the elimination of a single misfolded domain that, depending on its residence, is disposed by either of these pathways. The truncated, second nucleotide binding domain (NBD2*) from a yeast ERAD substrate, Ste6p*, resides at the cytoplasmic face of the ER. We show that a soluble form of NBD2* is cytoplasmic and unlike wild-type NBD2 is targeted for proteasome-mediated degradation. In contrast to Ste6p*, which employs the ER-localized Doa10p ubiquitin ligase, NBD2* is ubiquitinated by a nuclear E3 ligase San1p, a factor that is also required for its degradation. Although the yeast cytoplasmic Hsp70 chaperone, Ssa1p, has been thought to facilitate the nuclear import or to maintain the solubility of most CytoQC substrates, we discovered that Ssa1p facilitates the interaction between San1p and NBD2*, demonstrating that chaperones can aid in substrate recognition and San1p-dependent protein degradation. These results emphasize the diverse action of molecular chaperones during CytoQC. PMID- 23653357 TI - Histone acetyltransferase 1 promotes homologous recombination in DNA repair by facilitating histone turnover. AB - Faithful repair of DNA double-strand breaks is vital to the maintenance of genome integrity and proper cell functions. Histone modifications, such as reversible acetylation, phosphorylation, methylation, and ubiquitination, which collectively contribute to the establishment of distinct chromatin states, play important roles in the recruitment of repair factors to the sites of double-strand breaks. Here we report that histone acetyltransferase 1 (HAT1), a classical B type histone acetyltransferase responsible for acetylating the N-terminal tail of newly synthesized histone H4 in the cytoplasm, is a key regulator of DNA repair by homologous recombination in the nucleus. We found that HAT1 is required for the incorporation of H4K5/K12-acetylated H3.3 at sites of double-strand breaks through its HIRA-dependent histone turnover activity. Incorporated histones with specific chemical modifications facilitate subsequent recruitment of RAD51, a key repair factor in mammalian cells, to promote efficient homologous recombination. Significantly, depletion of HAT1 sensitized cells to DNA damage compromised the global chromatin structure, inhibited cell proliferation, and induced cell apoptosis. Our experiments uncovered a role for HAT1 in DNA repair in higher eukaryotic organisms and provide a mechanistic insight into the regulation of histone dynamics by HAT1. PMID- 23653358 TI - Fusion of dioxygenase and lignin-binding domains in a novel secreted enzyme from cellulolytic Streptomyces sp. SirexAA-E. AB - Streptomyces sp. SirexAA-E is a highly cellulolytic bacterium isolated from an insect/microbe symbiotic community. When grown on lignin-containing biomass, it secretes SACTE_2871, an aromatic ring dioxygenase domain fused to a family 5/12 carbohydrate-binding module (CBM 5/12). Here we present structural and catalytic studies of this novel fusion enzyme, thus providing insight into its function. The dioxygenase domain has the core beta-sandwich fold typical of this enzyme family but lacks a dimerization domain observed in other intradiol dioxygenases. Consequently, the x-ray structure shows that the enzyme is monomeric and the Fe(III)-containing active site is exposed to solvent in a shallow depression on a planar surface. Purified SACTE_2871 catalyzes the O2-dependent intradiol cleavage of catechyl compounds from lignin biosynthetic pathways, but not their methylated derivatives. Binding studies show that SACTE_2871 binds synthetic lignin polymers and chitin through the interactions of the CBM 5/12 domain, representing a new binding specificity for this fold-family. Based on its unique structural features and functional properties, we propose that SACTE_2871 contributes to the invasive nature of the insect/microbial community by destroying precursors needed by the plant for de novo lignin biosynthesis as part of its natural wounding response. PMID- 23653359 TI - Exosome uptake depends on ERK1/2-heat shock protein 27 signaling and lipid Raft mediated endocytosis negatively regulated by caveolin-1. AB - The role of exosomes in cancer can be inferred from the observation that they transfer tumor cell derived genetic material and signaling proteins, resulting in e.g. increased tumor angiogenesis and metastasis. However, the membrane transport mechanisms and the signaling events involved in the uptake of these virus-like particles remain ill-defined. We now report that internalization of exosomes derived from glioblastoma (GBM) cells involves nonclassical, lipid raft-dependent endocytosis. Importantly, we show that the lipid raft-associated protein caveolin 1 (CAV1), in analogy with its previously described role in virus uptake, negatively regulates the uptake of exosomes. We find that exosomes induce the phosphorylation of several downstream targets known to associate with lipid rafts as signaling and sorting platforms, such as extracellular signal-regulated kinase 1/2 (ERK1/2) and heat shock protein 27 (HSP27). Interestingly, exosome uptake appears dependent on unperturbed ERK1/2-HSP27 signaling, and ERK1/2 phosphorylation is under negative influence by CAV1 during internalization of exosomes. These findings significantly advance our general understanding of exosome-mediated uptake and offer potential strategies for how this pathway may be targeted through modulation of CAV1 expression and ERK1/2 signaling. PMID- 23653360 TI - CCN3 protein participates in bone regeneration as an inhibitory factor. AB - CCN3, a member of the CCN protein family, inhibits osteoblast differentiation in vitro. However, the role of CCN3 in bone regeneration has not been well elucidated. In this study, we investigated the role of CCN3 in bone regeneration. We identified the Ccn3 gene by microarray analysis as a highly expressed gene at the early phase of bone regeneration in a mouse bone regeneration model. We confirmed the up-regulation of Ccn3 at the early phase of bone regeneration by RT PCR, Western blot, and immunofluorescence analyses. Ccn3 transgenic mice, in which Ccn3 expression was driven by 2.3-kb Col1a1 promoter, showed osteopenia compared with wild-type mice, but Ccn3 knock-out mice showed no skeletal changes compared with wild-type mice. We analyzed the bone regeneration process in Ccn3 transgenic mice and Ccn3 knock-out mice by microcomputed tomography and histological analyses. Bone regeneration in Ccn3 knock-out mice was accelerated compared with that in wild-type mice. The mRNA expression levels of osteoblast related genes (Runx2, Sp7, Col1a1, Alpl, and Bglap) in Ccn3 knock-out mice were up-regulated earlier than those in wild-type mice, as demonstrated by RT-PCR. Bone regeneration in Ccn3 transgenic mice showed no significant changes compared with that in wild-type mice. Phosphorylation of Smad1/5 was highly up-regulated at bone regeneration sites in Ccn3 KO mice compared with wild-type mice. These results indicate that CCN3 is up-regulated in the early phase of bone regeneration and acts as a negative regulator for bone regeneration. This study may contribute to the development of new strategies for bone regeneration therapy. PMID- 23653361 TI - The role of SIRT6 protein in aging and reprogramming of human induced pluripotent stem cells. AB - Aging is known to be the single most important risk factor for multiple diseases. Sirtuin 6, or SIRT6, has recently been identified as a critical regulator of transcription, genome stability, telomere integrity, DNA repair, and metabolic homeostasis. A knockout mouse model of SIRT6 has displayed dramatic phenotypes of accelerated aging. In keeping with its role in aging, we demonstrated that human dermal fibroblasts (HDFs) from older human subjects were more resistant to reprogramming by classic Yamanaka factors than those from younger human subjects, but the addition of SIRT6 during reprogramming improved such efficiency in older HDFs substantially. Despite the importance of SIRT6, little is known about the molecular mechanism of its regulation. We show, for the first, time posttranscriptional regulation of SIRT6 by miR-766 and inverse correlation in the expression of this microRNA in HDFs from different age groups. Our results suggest that SIRT6 regulates miR-766 transcription via a feedback regulatory loop, which has implications for the modulation of SIRT6 expression in reprogramming of aging cells. PMID- 23653362 TI - Up-regulation of ciliary neurotrophic factor in astrocytes by aspirin: implications for remyelination in multiple sclerosis. AB - Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor, and the mechanisms by which CNTF expression could be increased in the brain are poorly understood. Acetylsalicylic acid (aspirin) is one of the most widely used analgesics. Interestingly, aspirin increased mRNA and protein expression of CNTF in primary mouse and human astrocytes in a dose- and time-dependent manner. Aspirin induced the activation of protein kinase A (PKA) but not protein kinase C (PKC). H-89, an inhibitor of PKA, abrogated aspirin-induced expression of CNTF. The activation of cAMP-response element-binding protein (CREB), but not NF kappaB, by aspirin, the abrogation of aspirin-induced expression of CNTF by siRNA knockdown of CREB, the presence of a consensus cAMP-response element in the promoter of CNTF, and the recruitment of CREB and CREB-binding protein to the CNTF promoter by aspirin suggest that aspirin increases the expression of the Cntf gene via the activation of CREB. Furthermore, we demonstrate that aspirin induced astroglial CNTF was also functionally active and that supernatants of aspirin-treated astrocytes of wild type, but not Cntf null, mice increased myelin associated proteins in oligodendrocytes and protected oligodendrocytes from TNF alpha insult. These results highlight a new and novel myelinogenic property of aspirin, which may be of benefit for multiple sclerosis and other demyelinating disorders. PMID- 23653363 TI - Interaction of p190RhoGAP with C-terminal domain of p120-catenin modulates endothelial cytoskeleton and permeability. AB - p120-catenin is a multidomain intracellular protein, which mediates a number of cellular functions, including stabilization of cell-cell transmembrane cadherin complexes as well as regulation of actin dynamics associated with barrier function, lamellipodia formation, and cell migration via modulation of the activities of small GTPAses. One mechanism involves p120 catenin interaction with Rho GTPase activating protein (p190RhoGAP), leading to p190RhoGAP recruitment to cell periphery and local inhibition of Rho activity. In this study, we have identified a stretch of 23 amino acids within the C-terminal domain of p120 catenin as the minimal sequence responsible for the recruitment of p190RhoGAP (herein referred to as CRAD; catenin-RhoGAP association domain). Expression of the p120-catenin truncated mutant lacking the CRAD in endothelial cells attenuated effects of barrier protective oxidized phospholipid, OxPAPC. This effect was accompanied by inhibition of membrane translocation of p190RhoGAP, increased Rho signaling, as well as suppressed activation of Rac1 and its cytoskeletal effectors PAK1 (p21-activated kinase 1) and cortactin. Expression of p120 catenin-truncated mutant lacking CRAD also delayed the recovery process after thrombin-induced endothelial barrier disruption. Concomitantly, RhoA activation and downstream signaling were sustained for a longer period of time, whereas Rac signaling was inhibited. These data demonstrate a critical role for p120-catenin (amino acids 820-843) domain in the p120-catenin.p190RhoGAP signaling complex assembly, membrane targeting, and stimulation of p190RhoGAP activity toward inhibition of the Rho pathway and reciprocal up-regulation of Rac signaling critical for endothelial barrier regulation. PMID- 23653365 TI - Impact of type 1 diabetes mellitus on academic performance. AB - OBJECTIVE: To examine the effect of type 1 diabetes on academic performance. METHODS: Ethnically Saudi students with type 1 diabetes, and age, sex, ethnicity and socio-economic status-matched nondiabetic control students were recruited from eight schools. Overall academic grades were recorded, based on the scores obtained in written examinations in English, mathematics, physics, chemistry, biology and humanities. RESULTS: Students with type 1 diabetes (n = 36) obtained significantly lower academic grades compared with their nondiabetic control classmates (n = 36) (86.58 +/- 1.48 vs 90.62 +/- 1.36). CONCLUSIONS: Overall academic performance is significantly lower in students with type 1 diabetes compared with their nondiabetic classmates. This decline in academic performance may be explained by an association between diabetes and cognitive function. PMID- 23653364 TI - Importance of a Lys113-Glu195 intermonomer ionic bond in F-actin stabilization and regulation by yeast formins Bni1p and Bnr1p. AB - Proper actin cytoskeletal function requires actin's ability to generate a stable filament and requires that this reaction be regulated by actin-binding proteins via allosteric effects on the actin. A proposed ionic interaction in the actin filament interior between Lys(113) of one monomer and Glu(195) of a monomer in the apposing strand potentially fosters cross-strand stabilization and allosteric communication between the filament interior and exterior. We interrupted the potential interaction by creating either K113E or E195K actin. By combining the two, we also reversed the interaction with a K113E/E195K (E/K) mutant. In all cases, we isolated viable cells expressing only the mutant actin. Either single mutant cell displays significantly decreased growth in YPD medium. This deficit is rescued in the double mutant. All three mutants display abnormal phalloidin cytoskeletal staining. K113E actin exhibits a critical concentration of polymerization 4 times higher than WT actin, nucleates more poorly, and forms shorter filaments. Restoration of the ionic bond, E/K, eliminates most of these problems. E195K actin behaves much more like WT actin, indicating accommodation of the neighboring lysines. Both Bni1 and Bnr1 formin FH1-FH2 fragment accelerate polymerization of WT, E/K, and to a lesser extent E195K actin. Bni1p FH1-FH2 dramatically inhibits K113E actin polymerization, consistent with barbed end capping. However, Bnr1p FH1-FH2 restores K113E actin polymerization, forming single filaments. In summary, the proposed ionic interaction plays an important role in filament stabilization and in the propagation of allosteric changes affecting formin regulation in an isoform-specific fashion. PMID- 23653366 TI - Single-port access compared with three-port laparoscopic adnexal surgery in a randomized controlled trial. AB - OBJECTIVE: Scar-related cosmetic outcomes were compared prospectively between conventional three-port and single-port access laparoscopic adnexal gynaecological surgery. METHODS: Enrolled patients were randomly assigned to a single- or three-port surgery group. Scar-related outcomes were evaluated at 1 month, 6 months and 1 year. Scars were assessed by an independent observer using the modified Vancouver Scar Scale (mVSS). All patients were asked about pain related to the scar and scar satisfaction; results were recorded using a numerical rating scale. RESULTS: Seventy-three patients were enrolled between June 2010 and June 2011. Demographic and surgical outcomes did not differ between the groups. mVSS results were similar in the two groups at each follow-up point. The scar satisfaction profile measured at 1 month showed no significant difference between the groups, but the single-port access group had better results than the conventional group at all other follow-up timepoints. CONCLUSION: Cosmetic outcome was better for single-port than for three-port adnexal gynaecological surgery at 6-month and 1-year follow-up. PMID- 23653367 TI - Alveolar adenoma combined with multifocal cysts: case report and literature review. AB - Alveolar adenoma is an extremely rare and benign pulmonary neoplasm; it is always asymptomatic and is usually detected incidentally on routine chest X-radiography. Typically on imaging examinations, alveolar adenoma exhibits as a peripheral, solitary, cystic nodule in the lung, which may easily imitate other lung lesions, consequently leading to difficulties in the differential diagnosis of this condition. Surgical resection is the primary treatment option. The diagnosis of alveolar adenoma is mainly based on postoperative histopathology, with features of proliferative type 2 alveolar epithelial cells and septal mesenchyme. The present case was a 60-year-old woman with alveolar adenoma, combined with systemic mutifocal cystic lesions. She underwent surgery following the obvious enlargement of this mass and a cystic nodule 7 cm in maximum diameter was resected. Postoperative histopathology confirmed a diagnosis of alveolar adenoma; her prognosis was favourable. In addition to reporting a rare case of alveolar adenoma coexisting with multifocal cysts, the English-language literature was reviewed for similar cases of alveolar adenoma. PMID- 23653368 TI - Deep wound cultures correlate well with bone biopsy culture in diabetic foot osteomyelitis. AB - BACKGROUND: Osteomyelitis is a major complication in patients with diabetic foot ulceration. Accurate pathogenic identification of organisms can aid the clinician to a specific antibiotic therapy thereby preventing the need for amputation. METHODS: All diabetic patients with bone biopsy-confirmed osteomyelitis were included into the study: biopsies were performed either during surgical removal of infected bone or percutaneously under guided fluoroscopy through non-infected tissue. The depth and extent of the ulcer was assessed using a sterile blunt metal probe. Deep wound cultures were taken from the wound base after sharp debridement. RESULTS: Of 66 cases of suspected osteomyelitis in 102 joints, 34 patients had both bone biopsies and deep wound cultures over the study period. Thirty two of 34 (94%), had a history of preceding foot ulceration, and in 25 of the cases a positive probe to bone test was recorded. In a high proportion of patients, at least one similar organism was isolated from both the deep wound culture and bone biopsy procedures (25 of 34 cases, 73.5%, p<0.001). When organisms were isolated from both wound cultures and bone biopsies, the identical strain was identified in both procedures in a significant proportion of cases (16 of 25 cases, 64%, p<0.001, total sample analysis in 16 of 34 cases, 47%). CONCLUSIONS: Deep wound cultures correlate well with osseous cultures and provide a sensitive method in assessing and targeting likely pathogens that cause osseous infections. This will help aid the clinician in guiding antibiotic therapy in centers where bone biopsies may not be readily available. PMID- 23653369 TI - Differential effects of a 5% lidocaine medicated patch in peripheral nerve injury. AB - INTRODUCTION: We examined the effect of topical lidocaine on the function of small and large fibers in patients with peripheral neuropathic pain due to traumatic or postoperative nerve injury. METHODS: In an open-label study, 24 patients were treated with a 5% lidocaine patch for up to 12 weeks. We recorded contact heat evoked potentials (CHEPs) and performed quantitative sensory testing (QST) before and after treatment with the contralateral side as control. RESULTS: Twenty-one patients (mean age 47.6 +/- 13.5 years) completed the study. Lidocaine increased cold pain threshold (P = 0.04) and reduced CHEP amplitude (P = 0.007) with no effect on other QST parameters. Patients responding to treatment had less cold detection deficit on the affected side and had a larger increase in cold pain detection threshold following treatment than nonresponders. CONCLUSIONS: Controlled trials are warranted to further understand the mechanisms mediating the effects of topical lidocaine. PMID- 23653370 TI - The Asian Pharmacoepidemiology Network (AsPEN): promoting multi-national collaboration for pharmacoepidemiologic research in Asia. PMID- 23653371 TI - Time availability and preference for e-health communication channels for nutrition and physical activity. AB - The aim of this study was to examine the relationship between time availability and preference for computer-based (e-health) communication channels when receiving nutrition and physical activity information, two key behaviors related to cancer prevention. Students from a large, diverse, urban university (n = 397) completed a web-based survey indicating their usage patterns and preferences for multiple eHealth channels. Bivariate analyses were performed based on a measure of time availability, comprised of working status (25 h/week or more, 1-24 h/week, or not working) and enrollment status (full-time or part-time). Most e health channels were broadly used by students and did not differ according to time availability. Those with the most amount of time available preferred receiving nutrition and physical activity information via social networking more frequently compared to those with the least amount of time available (60 versus 43%, P <= 0.05). Our study suggests that time availability may be another important factor to consider when planning cancer prevention programs. PMID- 23653372 TI - Violence, teenage pregnancy, and life history : ecological factors and their impact on strategy-driven behavior. AB - Guided by principles of life history strategy development, this study tested the hypothesis that sexual precocity and violence are influenced by sensitivities to local environmental conditions. Two models of strategy development were compared: The first is based on indirect perception of ecological cues through family disruption and the second is based on both direct and indirect perception of ecological stressors. Results showed a moderate correlation between rates of violence and sexual precocity (r = 0.59). Although a model incorporating direct and indirect effects provided a better fit than one based on family mediation alone, significant improvements were made by linking some ecological factors directly to behavior independently of strategy development. The models support the contention that violence and teenage pregnancy are part of an ecologically determined pattern of strategy development and suggest that while the family unit is critical in affecting behavior, individuals' direct experiences of the environment are also important. PMID- 23653373 TI - Adamantyl arotinoids that inhibit IkappaB kinase alpha and IkappaB kinase beta. AB - A series of analogues of the adamantyl arotinoid (AdAr) chalcone MX781 with halogenated benzyloxy substituents at C2' and heterocyclic derivatives replacing the chalcone group were found to inhibit IkappaBalpha kinase alpha (IKKalpha) and IkappaBalpha kinase beta (IKKbeta) activities. The growth inhibitory capacity of some analogues against Jurkat T cells as well as prostate carcinoma (PC-3) and chronic myelogenous leukemia (K562) cells, which contain elevated basal IKK activity, correlates with the induction of apoptosis and increased inhibition of recombinant IKKalpha and IKKbeta in vitro, pointing toward inhibition of IKK/NFkappaB signaling as the most likely target of the anticancer activities of these AdArs. While the chalcone functional group present in many dietary compounds has been shown to mediate interactions with IKKbeta via Michael addition with cysteine residues, AdArs containing a five-membered heterocyclic ring (isoxazoles and pyrazoles) in place of the chalcone of the parent system are potent inhibitors of IKKs as well, which suggests that other mechanisms for inhibition exist that do not depend on the presence of a reactive alpha,beta unsaturated ketone. PMID- 23653374 TI - Smad3 binds Scleraxis and Mohawk and regulates tendon matrix organization. AB - TGFbeta plays a critical role in tendon formation and healing. While its downstream effector Smad3 has been implicated in the healing process, little is known about the role of Smad3 in normal tendon development or tenocyte gene expression. Using mice deficient in Smad3 (Smad3(-/-) ), we show that Smad3 ablation disrupts tendon architecture and has a dramatic impact on normal gene and protein expression during development as well as in mature tendon. In developing and adult tendon, loss of Smad3 results in reduced protein expression of the matrix components Collagen 1 and Tenascin-C. Additionally, when compared to wild type, tendon from adult Smad3(-/-) mice shows a down regulation of key tendon marker genes. Finally, we have established that Smad3 has the ability to physically interact with the critical transcriptional regulators Scleraxis and Mohawk. Together these results indicate a central role for Smad3 in normal tendon formation and in the maintenance of mature tendon. PMID- 23653375 TI - Outcomes for trainees vs experienced surgeons undertaking laparoscopic antireflux surgery - is equipoise achieved? AB - BACKGROUND: There is a learning curve associated with laparoscopic antireflux surgery which has an impact on patient outcomes. It is unclear, however, whether this can be eliminated by supervision of early cases by experienced surgeons. The aim of this study was to evaluate the impact of training under supervision on outcomes for laparoscopic fundoplication. METHOD: Patients undergoing primary laparoscopic antireflux surgery from 1995 to 2009 were identified from a prospective database. Patients were classified according to whether they were operated on by an experienced consultant or supervised trainee, and sub categorised according to the presence of a very large hiatus hernia. A standardised questionnaire was used to assess outcomes for heartburn, dysphagia and satisfaction at 1 and 5 years follow-up. Outcomes for the study groups were compared. RESULTS: One thousand seven hundred and ten patients underwent surgery; 1,112 were operated on by consultants and 598 by trainees. The peri-operative complication rate was not different between the groups, although in patients operated on by trainees, there were increased rates of endoscopic dilatation (9 vs. 5 % p = 0.014) and re-operation (9 vs. 6 %, p = 0.031), and a lower satisfaction rate (76 vs. 82 %, p = 0.044) within 5 years of surgery. All other outcomes were similar for trainees vs. consultants. CONCLUSION: The learning curve for laparoscopic fundoplication had a small, but statistically significant, impact on patient outcomes, with slightly lesser outcomes when surgery was undertaken by trainees, even when supervised by experienced surgeons. Although the differences were not large, they raise questions about equipoise and highlight ethical dilemmas with teaching new generations of surgeons. PMID- 23653376 TI - Laparoscopic versus open multivisceral resection for primary colorectal cancer: comparison of perioperative outcomes. AB - BACKGROUND: The role of laparoscopic surgery for locally advanced colorectal cancer invading or adhering to neighboring organs is controversial. This study evaluated the safety and feasibility of laparoscopic multivisceral resection for colorectal cancer. METHODS: This study included 126 patients who underwent multivisceral resection for primary colorectal cancer invading or adhering to neighboring organs or structures between July 2005 and November 2012 at our institution. Perioperative outcomes were compared between laparoscopic and open resections. RESULTS: Laparoscopic and open multivisceral resections were performed in 60 and 66 patients, respectively. Conversion to open surgery occurred in 6.7 % of patients. The median operative time was significantly longer (271 vs. 227 min), but the median blood loss was significantly less (40 vs. 205 mL), in the laparoscopic compared with the open group. The R0 resection rate of the primary tumor (95 vs. 98.5 %), number of lymph nodes harvested (18 vs. 18), and postoperative complications (28 vs. 24 %) were comparable between the groups. The median length of hospital stay was significantly shorter (13.5 vs. 18 days) in the laparoscopic compared with the open group. CONCLUSIONS: Laparoscopic multivisceral resection for colorectal cancer invading or adhering to neighboring organs is safe and feasible in selected patients. PMID- 23653377 TI - Circulating secreted frizzled-related protein 5 (Sfrp5) and wingless-type MMTV integration site family member 5a (Wnt5a) levels in patients with type 2 diabetes mellitus. AB - BACKGROUND: Secreted frizzled-related protein 5 (Sfrp5), an endogenous inhibitor of wingless-type MMTV integration site family (Wnt) signalling, is an anti inflammatory adipokine whose expression is perturbed in models of obesity and type 2 diabetes mellitus (T2DM). Wnt member 5a (Wnt5a) is a representative ligand, and recent reports suggest that Wnt5a is involved in inflammatory diseases and metabolic disorders. The aim of this study was to investigate whether plasma Wnt5a and Sfrp5 levels are altered in patients with T2DM. METHODS: Plasma Sfrp5 and Wnt5a concentrations were measured through enzyme-linked immunosorbent assay in type 2 diabetic and nondiabetic subjects. RESULTS: A total of 82 patients with T2DM and 42 nondiabetic subjects were studied. Plasma Sfrp5 levels were found to be elevated in patients with T2DM (9.4 +/- 9.0 vs 7.4 +/- 10.9 ng/mL, p = 0.006). In contrast, Wnt5a levels were decreased (6.8 +/- 12.6 vs 9.1 +/- 4.0 ng/dL, p < 0.001). Increasing concentrations of Sfrp5 were independently and significantly associated with T2DM. Multiple logistic regression analysis revealed Sfrp5 as an independent association factor for T2DM, even after full adjustment of known biomarkers. In a multiple linear regression analysis, only the fasting glucose level was positively associated with the plasma Sfrp5 level. CONCLUSIONS: Our results indicate that Sfrp5 may play a role in the pathogenesis of T2DM. PMID- 23653378 TI - X-ray repair cross-complementing group 1 Arg194Trp polymorphism is associated with increased risk of lung cancer in Chinese Han population. AB - There were many studies performed to assess the association between X-ray repair cross-complementing group 1 (XRCC1) Arg194Trp polymorphism and lung cancer risk in Chinese Han population, but contradictory results were reported. To provide a comprehensive and objective assessment of the association, a meta-analysis of all eligible case-control studies was carried out. After searching the databases and reading the abstracts, 12 case-control studies on the association between XRCC1 Arg194Trp polymorphism and lung cancer risk were finally included into this meta analysis. Those 12 studies included a total of 4,385 cases and 4,545 controls. XRCC1 Arg194Trp polymorphism was associated with increased risk of lung cancer in Chinese Han population under three main models (allele contrast model, odds ratio (OR) = 1.12, 95 % confidence interval (CI) 1.00-1.26, P = 0.049; homozygote model, OR = 1.27, 95 % CI 1.09-1.48, P = 0.003; recessive model, OR = 1.26, 95 % CI 1.09-1.46, P = 0.003). However, there was no obvious association between XRCC1 Arg194Trp polymorphism and lung cancer risk under the dominant model (OR = 1.06, 95 % CI 0.98-1.16, P = 0.146). Sensitivity analysis suggested the stability and liability of this meta-analysis. Therefore, this meta-analysis suggests that XRCC1 Arg194Trp polymorphism is associated with increased risk of lung cancer in Chinese Han population. PMID- 23653379 TI - TGF-beta1 -509C/T (or +869T/C) polymorphism might be not associated with hepatocellular carcinoma risk. AB - Many studies have reported the role of transforming growth factor-beta1 (TGF beta1) -509C/T or +869T/C polymorphism with hepatocellular carcinoma (HCC) risk. However, these studies have yielded conflicting results. Hence, we performed this meta-analysis to investigate the association between TGF-beta1 -509C/T or +869T/C polymorphism and HCC. A total of 11 studies including 2,577 HCC cases and 4,107 controls were included in the meta-analysis. Overall, TGF-beta1 -509C/T (or +869T/C) polymorphism was not associated with HCC risk (homogeneous co-dominant model: OR = 1.29, 95 % CI = 0.88-1.89; heterogeneous co-dominant model: OR = 1.15, 95 % CI = 0.91-1.45; dominant model: OR = 1.14, 95 % CI = 0.87-1.48; recessive model: OR = 1.15, 95 % CI = 0.89-1.49). In the subgroup analysis, TGF beta1 -509C/T (or +869T/C) polymorphism was significantly associated with HCC risk in Caucasians under the recessive model (OR = 1.65, 95 % CI = 1.07-2.55) but not in other genetic models. In addition, we did not observe significant association in Asians under all genetic models. In conclusion, our meta-analysis indicates that TGF-beta1 -509C/T (or +869T/C) polymorphism was not associated with risk of HCC, although a marginal association was found for Caucasians. However, a study with the larger sample size is needed to further evaluate gene environment interaction on the association. PMID- 23653381 TI - Aquaporin inhibition by gold(III) compounds: new insights. AB - Aquaporins (AQPs) are membrane water/glycerol channels with essential roles in biological systems, as well as being promising targets for therapy and imaging. Using a stopped-flow method, a series of gold(III), platinum(II) and copper(II) complexes bearing nitrogen donor ligands, such as 1,10-phenatroline, 2,2' bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4'-diamino-2,2'-bipyridine and 2,2';6',2"-terpyridine, were evaluated in human red blood cells expressing AQP1 and AQP3, responsible for water and glycerol movement, respectively. The results showed that the gold(III) complexes selectively modulate AQP3 over AQP1. Molecular modeling and density functional theory (DFT) calculations were subsequently performed to rationalize the observations and to investigate the possible molecular mechanism through which these gold compounds act on their putative target (AQP3). In the absence of any crystallographic data, a previously reported homology model was used for this purpose. Combined, the findings of this study show that potent and selective modulation of these solute channels is possible, however further investigation is required into the selectivity of this class of agents against all AQP isoforms and their potential therapeutic uses. PMID- 23653380 TI - Inhibition of SCAMP1 suppresses cell migration and invasion in human pancreatic and gallbladder cancer cells. AB - Lymph node (LN) metastasis is one of the most important risk factors for the prognosis of pancreatic cancer. This study aimed to identify novel LN metastasis associated markers and therapeutic targets for pancreatic and gallbladder cancers. DNA microarray analysis was carried out to identify genes differentially expressed between 17 pancreatic cancer tissues with LN metastasis and 17 pancreatic cancer tissues without LN metastasis. The expression of LZIC, FXR, SCAMP1, and SULT1E1 is significantly higher in pancreatic cancer tissues with LN metastasis than in pancreatic cancer tissues without LN metastasis. We recently reported that FXR plays an important role in LN metastasis of pancreatic cancer, and in this study, we selected the secretory carrier membrane protein 1 (SCAMP1) gene. To determine that function of the SCAMP1 gene, we examined the effects of SCAMP1 knockdown on pancreatic and gallbladder cancer proliferation, migration, and invasion using SCAMP1 small interfering RNA (siRNA) and the activity of vascular endothelial growth factor (VEGF) was measured by enzyme-linked immunosorbent assay. SCAMP1 overexpression is associated with LN metastasis in pancreatic cancer patients. The siRNA-mediated downregulation of SCAMP1 resulted in a marked reduction in cell migration and invasion, but not proliferation in MIA-PaCa2, PANC-1, TGBC-1, and TGBC-2 cells. In addition, downregulation of SCAMP1 inhibited VEGF levels of conditioned medium from SCAMP1 siRNA-transfected cells. These results suggest that downregulation of SCAMP1 could be a potential therapeutic target for patients with pancreatic and gallbladder cancer. PMID- 23653382 TI - Increasing the success of reverse sural flap from proximal part of posterior calf for traumatic foot and ankle reconstruction: patient selection and surgical refinement. AB - In this report, we present our experience on the use of the reverse sural flap for traumatic foot and ankle reconstruction. The patient selection and surgical refinement are discussed. From 2007 to 2010, 11 consecutive patients underwent modified reverse sural flap at the Chang Gung Memorial Hospital. The defects were located at the ankle (three cases), foot (two cases), and heel (six cases). Particular attention was paid to precise patient selection and surgical refinements. Patient selection was based on the lower limb vascular status by palpable distal pedal pulses and ankle brachial index ranging from 0.9 to 1.2. Surgical techniques were refined as precisely locating the perforators of peroneal artery, placing the skin paddle in upper third of leg for a distal region coverage, designing a 7-cm-wide adipofascial pedicle with a 2 cm skin paddle on it, preserving the mesentery structure of sural nerve and concomitant artery with or without including gastrocnemius muscles cuff, no tunneling when inset this flap and supercharging with lesser saphenous vein whenever needed. All the flaps survived completely. Only one patient required immediate anastomosis of lesser saphenous vein to local vein around defect in order to relieve the venous congestion during operation. Patients felt diminished but adequate recovery of sense of touch and temperature at the flap. Following the precise patient selection and surgical refinements, the modified reverse sural flap seemed to be a reliable and effective local flap for reconstruction of the soft tissue defects on ankle and foot. PMID- 23653383 TI - Upstream stimulatory factors 1 and 2 mediate the transcription of angiotensin II binding and inhibitory protein. AB - The angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP/Agtrap) promotes constitutive internalization of the AT1R so as to specifically inhibit the pathological activation of its downstream signaling yet preserve the base line physiological signaling activity of the AT1R. Thus, tissue-specific regulation of Agtrap expression is relevant to the pathophysiology of cardiovascular and renal disease. However, the regulatory mechanism of Agtrap gene expression has not yet been fully elucidated. In this study, we show that the proximal promoter region from -150 to +72 of the mouse Agtrap promoter, which contains the X-box, E-box, and GC-box consensus motifs, is able to elicit substantial transcription of the Agtrap gene. Among these binding motifs, we showed that the E-box specifically binds upstream stimulatory factor (Usf) 1 and Usf2, which are known E-box-binding transcription factors. It is indicated that the E-box-Usf1/Usf2 binding regulates Agtrap expression because of the following: 1) mutation of the E-box to prevent Usf1/Usf2 binding reduces Agtrap promoter activity; 2) knockdown of Usf1 or Usf2 affects both endogenous Agtrap mRNA and Agtrap protein expression, and 3) the decrease in Agtrap mRNA expression in the afflicted kidney by unilateral ureteral obstruction is accompanied by changes in Usf1 and Usf2 mRNA. Furthermore, the results of siRNA transfection in mouse distal convoluted tubule cells and those of unilateral ureteral obstruction in the afflicted mouse kidney suggest that Usf1 decreases but Usf2 increases the Agtrap gene expression by binding to the E-box. The results also demonstrate a functional E-box-USF1/USF2 interaction in the human AGTRAP promoter, thereby suggesting that a strategy of modulating the E-box-USF1/USF2 binding has novel therapeutic potential. PMID- 23653384 TI - Food ethics: issues of consumption and production : self-restraint and voluntaristic measures are not enough. PMID- 23653386 TI - Effect of lipopolysaccharide on the biological characteristics of human skin fibroblasts and hypertrophic scar tissue formation. AB - Burn injury-mediated destruction of the skin barrier normally induces microbial invasion, in turn leading to the development of systemic infection and occasional septic shock by the release of endotoxins. The objective of this work was to study the influence of lipopolysaccharide (LPS) on the biological characteristics of normal skin fibroblasts and to elucidate the influence of LPS in the initial stage of skin wound healing. Twenty patients with hypertrophic scar in proliferative stage were selected randomly and primary cultures were established from fibroblasts derived from their hypertrophic scar tissue and normal skin. Normal skin fibroblasts of passage 3 were stimulated with different concentrations of LPS. LPS stimulated the proliferation and collagen synthesis of fibroblasts within a certain extent of concentrations (0.005-0.5 MUg/mL) (P < 0.05), whereas at a concentration of 1 MUg/mL inhibited the proliferation and collagen synthesis of fibroblasts (P < 0.05). Collagen synthesis by normal skin fibroblasts after LPS stimulation mimicked those derived from hypertrophic scar tissue. LPS of 0.1 MUg/mL had significant effect on normal skin fibroblasts continuous passage of these fibroblasts resulted in ultrastructural pattern similar to fibroblasts derived from hypertrophic scar tissue, and the findings was substantiated by hematoxylin and eosin staining and immunohistochemistry detection of proliferation cell nuclear antigen, type I procollagen and alpha smooth muscle actin. Our results suggest that LPS might convert normal skin fibroblasts to hypertrophic scar tissue fibroblasts and participate in the formation of hypertrophic scar; hence, appropriate concentration of LPS may have no effect or be beneficial to skin wound healing, whereas excessive concentration of LPS may delay the time of wound healing. PMID- 23653385 TI - An updated review on drug-induced cholestasis: mechanisms and investigation of physicochemical properties and pharmacokinetic parameters. AB - Drug-induced cholestasis is an important form of acquired liver disease and is associated with significant morbidity and mortality. Bile acids are key signaling molecules, but they can exert toxic responses when they accumulate in hepatocytes. This review focuses on the physiological mechanisms of drug-induced cholestasis associated with altered bile acid homeostasis due to direct (e.g., bile acid transporter inhibition) or indirect (e.g., activation of nuclear receptors, altered function/expression of bile acid transporters) processes. Mechanistic information about the effects of a drug on bile acid homeostasis is important when evaluating the cholestatic potential of a compound, but experimental data often are not available. The relationship between physicochemical properties, pharmacokinetic parameters, and inhibition of the bile salt export pump among 77 cholestatic drugs with different pathophysiological mechanisms of cholestasis (i.e., impaired formation of bile vs. physical obstruction of bile flow) was investigated. The utility of in silico models to obtain mechanistic information about the impact of compounds on bile acid homeostasis to aid in predicting the cholestatic potential of drugs is highlighted. PMID- 23653387 TI - L-methionine placental uptake: characterization and modulation in gestational diabetes mellitus. AB - Our aim was to investigate the influence of gestational diabetes mellitus (GDM) and GDM-associated conditions upon the placental uptake of (14)C-l-methionine ((14)C-l-Met). The (14)C-l-Met uptake by human trophoblasts (TBs) obtained from normal pregnancies (normal trophoblast [NTB] cells) is mainly system l-type amino acid transporter 1 (LAT1 [L])-mediated, although a small contribution of system y(+)LAT2 is also present. Comparison of (14)C-l-Met uptake by NTB and by human TBs obtained from GDM pregnancies (diabetic trophoblast [DTB] cells) reveals similar kinetics, but a contribution of systems A, LAT2, and b(0+) and a greater contribution of system y(+)LAT1 appears to exist in DTB cells. Short-term exposure to insulin and long-term exposure to high glucose, tumor necrosis factor alpha, and leptin decrease (14)C-l-Met uptake in a human TB (Bewo) cell line. The effect of leptin was dependent upon phosphoinositide 3-kinase, extracellular signal-regulated kinase 1/2 (ERK/MEK 1/2), and p38 mitogen-activated protein kinase. In conclusion, GDM does not quantitatively alter (14)C-l-Met placental uptake, although it changes the nature of transporters involved in that process. PMID- 23653388 TI - Modulation of lipopolysaccharide-induced chorioamnionitis in fetal sheep by maternal betamethasone. AB - OBJECTIVE: We tested the hypothesis that the order of exposure to maternal betamethasone and intra-amniotic (IA) lipopolysaccharide (LPS) will differentially modulate inflammation in the chorioamnion. STUDY DESIGN: Time mated Merino ewes with singleton fetuses received saline alone, IA LPS alone, maternal betamethasone before LPS, or betamethasone after LPS. We assessed inflammatory markers in the chorioamnion and the amniotic fluid. RESULTS: Inflammatory cell infiltration, expression of myeloperoxidase, serum amyloid A3 (acute phase reactant) in the chorioamnion, and levels of interleukin (IL)-8 in the amniotic fluid increased 7 days after LPS exposure. Betamethasone prior to LPS decreased infiltration of the inflammatory cells, CD3+ T cells, and decreased the levels of IL-1beta and IL-8 in the amniotic fluid. CONCLUSIONS: Betamethasone 7 days prior to LPS exposure suppressed LPS-induced inflammation. The markers of inflammation largely had returned to the baseline 14 days after LPS exposure. PMID- 23653389 TI - The influence of maternal body mass index on myometrial oxytocin receptor expression in pregnancy. AB - Obese pregnant women have higher rates of dysfunctional labor patterns, need for oxytocin augmentation, labor induction, postdates pregnancy, and cesarean delivery compared to normal weight pregnant women. We tested the hypothesis that myometrial oxytocin receptor (OXTR) gene and protein expression are affected by obesity in pregnancy. Myometrial samples were obtained at the time of cesarean delivery from the upper aspect of the uterine hysterotomy incision and processed for real-time quantitative polymerase chain reaction and Western blot. There were 63 myometrial samples available for analysis. The median body mass index (BMI) at delivery was 31.0 kg/m(2) (interquartile range, 26.0, 40.0 kg/m(2)), and the median gestational age at delivery was 38.0 weeks (interquartile range, 33.0, 39.1 weeks). The OXTR gene expression did not correlate with maternal BMI at delivery by linear regression, and the median OXTR gene expression did not differ between women with a BMI <= 30 kg/m(2) and those with a BMI >= 40 kg/m(2). The OXTR protein expression was also not affected by maternal BMI. Myometrial OXTR gene expression appears to be independent of BMI at the time of delivery. Dysfunctional labor patterns and increased oxytocin utilization seen in obese women may not be due to differences in OXTR expression, though functional studies are required. PMID- 23653390 TI - Cigarette smoke-induced placental adrenomedullin expression and trophoblast cell invasion. AB - Smoking in pregnancy reduces preeclampsia risk, but the mechanism of this effect is unknown. Prior studies have demonstrated that women with preeclampsia have lower placental adrenomedullin (AM) expression, and cigarette smoke extract (CSE) treatment of placental trophoblast cells in culture increases AM cellular production. We hypothesized that CSE alters trophoblast invasion through an AM mediated mechanism, and that placental AM expression is greater among smokers. HTR-8/SVneo trophoblast cells were incubated for 24 hours in Matrigel-invasion chambers with 6 treatment groups: nonstimulated (NS), AM, AM inhibitor (AM22-52), 1% CSE, AM + AM22-52, and 1% CSE + AM22-52. Cells that penetrated the lower surface of the chambers were quantified, invasion indices were calculated, and compared using a 1-way analysis of variance with Bonferroni corrections for multiple comparisons. Trophoblast cells treated with both AM and 1% CSE demonstrated increased cellular invasion compared to NS controls (1.5-fold [P < .01] and 1.45-fold [P < .01], respectively). Cotreatment with the AM inhibitor significantly attenuated the increased invasion seen with both AM and CSE alone. Next, the placental tissue was obtained from 11 smokers and 11 nonsmokers at term and processed for immunohistochemistry (IHC) and real-time quantitative polymerase chain reaction (PCR) for AM. Placentas from smokers demonstrated more intense AM staining and increased AM gene (ADM) expression compared to placentas from nonsmokers (P = .004 for IHC, P = .022 for PCR). The CSE increases trophoblast cell invasion through an AM-mediated process, and placental AM expression is increased among term smokers compared to nonsmokers. These findings provide evidence that the AM pathway may play a role in the protection from preeclampsia seen in smokers. PMID- 23653391 TI - Metformin, at concentrations corresponding to the treatment of diabetes, potentiates the cytotoxic effects of carboplatin in cultures of ovarian cancer cells. AB - The use of the type 2 diabetics drug metformin has been correlated with enhanced progression-free survival in ovarian cancer. The literature has speculated that this enhancement is due to the high concentration of metformin directly causing cancer cell death. However, this explanation does not fit with clinical data reporting that the women exposed to constant micromolar concentrations of metformin, as present in the treatment of diabetes, respond better to chemotherapy. Herein, our aim was to examine whether micromolar concentrations of metformin alone could bring about cancer cell death and whether micromolar metformin could increase the cytotoxic effect of commonly used chemotherapies in A2780 and SKOV3 cell lines and primary cultured cancer cells isolated from the peritoneal fluid of patients with advanced ovarian cancer. Our results in cell lines demonstrate that no significant loss of viability or change in cell cycle was observed with micromolar metformin alone; however, we observed cytotoxicity with micromolar metformin in combination with chemotherapy at concentrations where the chemotherapy alone produced no loss in viability. We demonstrate that previous exposure and maintenance of metformin in conjunction with carboplatin produces a synergistic enhancement in cytotoxicity of A2780 and SKOV3 cells (55% and 43%, respectively). Furthermore, in 5 (44%) of the 11 ovarian cancer primary cultures, micromolar metformin improved the cytotoxic response to carboplatin but not paclitaxel or doxorubicin. In conclusion, we present data that support the need for a clinical study to evaluate the adjuvant maintenance or prescription of currently approved doses of metformin during the chemotherapeutic treatment of ovarian cancer. PMID- 23653392 TI - Possible involvement of CD10 in the development of endometriosis due to its inhibitory effects on CD44-dependent cell adhesion. AB - A reduced response to progesterone in the eutopic endometrium with endometriosis and in endometriotic tissues is considered to be the underlying factor for endometriosis. CD10 is known to be expressed by endometrial and endometriotic stromal cells and may be induced by progestins, although the function of CD10 is not fully revealed in endometrial or endometriotic tissues. In the current study, the expression of CD10 was significantly increased by treatment of the cells with progesterone, 17beta-estradiol, and dibutyryl cyclic adenosine monophosphate (cAMP) in the endometrial stromal cells. On the other hand, the expression of CD10 following treatment with progesterone, 17beta-estradiol, and dibutyryl cAMP was not significantly increased in endometriotic stromal cells. The adhesion assay for endometrial and endometriotic stromal cells to hyaluronan using 5- or 6 (N-succinimidyloxycarbonyl)-fluorescein 3', 6'-diacetate-labeled cells demonstrated that the CD44-dependent adhesion of stromal cells was inhibited by CD10. As far as the induction of CD10 is concerned, the effect of progesterone was different between endometrial stromal cells and endometriotic stromal cells. CD10 might be involved in the development of endometriosis due to its influence on CD44-dependent cell adhesion. PMID- 23653393 TI - A rapid membrane potential assay to monitor CFTR function and inhibition. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) protein is an important regulator of ion transport and fluid secretion in humans. Mutations to CFTR cause cystic fibrosis, which is a common recessive genetic disorder in Caucasians. Involvement of CFTR has been noted in other important diseases, such as secretory diarrhea and polycystic kidney disease. The assays to monitor CFTR function that have been described to date either are complicated or require specialized instrumentation and training for execution. In this report, we describe a rapid FlexStation-based membrane potential assay to monitor CFTR function. In this assay, agonist-mediated activation of CFTR results in membrane depolarization that can be monitored using a fluorescent membrane potential probe. Availability of a simple mix-and-read assay to monitor the function of this important protein might accelerate the discovery of CFTR ligands to study a variety of conditions. PMID- 23653394 TI - A timetable organizer for the planning and implementation of screenings in manual or semi-automation mode. AB - We have designed an Excel spreadsheet to facilitate the planning and execution of screenings performed manually or in semi-automation mode, following a sequential set of events. Many assays involve multiple steps, often including time-sensitive stages, thus complicating the proper implementation to ensure that all plates are treated equally to achieve reliable outcomes. The spreadsheet macro presented in this study analyzes and breaks down the timings for all tasks, calculates the limitation in the number of plates that suit the desired parameters, and allows for optimization based on tolerance of time delay and equal treatment of plates when possible. The generated Gantt charts allow for visual inspection of the screening process and provide timings in a tabulated form to assist the user to conduct the experiments as projected by the software. The program can be downloaded from http://sourceforge.net/projects/sams-hts/. PMID- 23653395 TI - Osmium(III) and osmium(V) complexes bearing a macrocyclic ligand: a simple and efficient catalytic system for cis-dihydroxylation of alkenes with hydrogen peroxide. AB - A simple protocol that uses [Os(III)(OH)(H2O)(L-N4Me2)](PF6)2 (1; L-N4Me2 = N,N' dimethyl-2,11-diaza[3.3](2,6)pyridinophane) as a catalyst and H2O2 as a terminal oxidant for efficient cis-1,2-dihydroxylation of alkenes is presented. Unfunctionalized (or aliphatic) alkenes and alkenes/styrenes containing electron withdrawing groups are selectively oxidized to the corresponding vicinal diols in good to excellent yields (46-99 %). In the catalytic reactions, the stoichiometry of alkene:H2O2 is 1:1, and thus the oxidant efficiency is very high. For the dihydroxylation of cyclohexene, the catalytic amount of 1 can be reduced to 0.01 mol % to achieve a very high turnover number of 5500. The active oxidant is identified as the Os(V)(O)(OH) species (2), which is formed via the hydroperoxide adduct, an Os(III)(OOH) species. The active oxidant 2 is successfully isolated and crystallographically characterized. PMID- 23653396 TI - Effect of white adipose tissue flap and insulin-like growth factor-1 on nerve regeneration in rats. AB - Adipose tissue-derived stem cells and insulin-like growth factor-1 (IGF-1) have shown potential to enhance peripheral nerve regeneration. The purpose of this study was to investigate the effect of an in vivo biologic scaffold, consisting of white adipose tissue flap (WATF) and/or IGF-1 on nerve regeneration in a crush injury model. Forty rats all underwent a sciatic nerve crush injury and then received: a pedicled WATF, a controlled local release of IGF-1, both treatments, or no treatment at the injury site. Outcomes were the normalized maximum isometric tetanic force (ITF) of the tibialis anterior muscle and histomorphometric measurements. At 4 weeks, groups with WATF had a statistically significant improvement in maximum ITF recovery, as compared to those without (P < 0.05), and there was an increase in myelin thickness and total axon count in the WATF-only group versus control (P < 0.01). Functional and histomorphometric data suggest that IGF-1 suppressed the effect of the WATF. Use of a pedicled WATF improved the functional and histomorphometrical results after axonotmesis in a rat model. IGF-1 does not appear to enhance nerve regeneration in this model. Utilizing the WATF may have a beneficial therapeutic role in peripheral nerve injuries. PMID- 23653397 TI - The role of cytoreductive surgery in advanced-stage ovarian cancer: a systematic review. AB - It has already been proven that ovarian cancer is the sixth most common cancer among women, and it is considered the leading cause of death by gynecologic cancer in developed countries. This article is a literature review based on the use of cytoreductive surgery matched with adjuvant chemotherapy in advanced-stage ovarian cancer. According to the statistics, the difficulty of obtaining an early diagnosis results in a delay in the disease treatment and as a consequence, in many cases, ovarian cancer is still diagnosed in the advanced stage of the disease. Primary surgery is performed, in addition to diagnosis and staging, to achieve optimal cytoreduction. The purpose of this article is to review the different surgical approaches in the management of epithelial ovarian cancer, specifically the high-stage disease, with a special concentration on the most recent therapeutic additions to our current knowledge, such as hyperthermic intraperitoneal chemotherapy and new therapeutic drugs. Surgical treatment still plays a pivotal role in the management of advanced-stage ovarian cancer. Complete cytoreduction continues to be, when feasible, the objective to be attempted in the surgical treatment of advanced ovarian cancer. Obviously, the success of the operation depends on numerous factors, including patient selection, the locations of tumors, and surgeon expertise. To offer patients the best possible outcome with the least accompanying morbidity, strong consideration should be given to the referral of such patients to expert care centers for primary surgery, because it may be the best means currently available for improving overall survival. PMID- 23653398 TI - The tree of life and a new classification of bony fishes. AB - The tree of life of fishes is in a state of flux because we still lack a comprehensive phylogeny that includes all major groups. The situation is most critical for a large clade of spiny-finned fishes, traditionally referred to as percomorphs, whose uncertain relationships have plagued ichthyologists for over a century. Most of what we know about the higher-level relationships among fish lineages has been based on morphology, but rapid influx of molecular studies is changing many established systematic concepts. We report a comprehensive molecular phylogeny for bony fishes that includes representatives of all major lineages. DNA sequence data for 21 molecular markers (one mitochondrial and 20 nuclear genes) were collected for 1410 bony fish taxa, plus four tetrapod species and two chondrichthyan outgroups (total 1416 terminals). Bony fish diversity is represented by 1093 genera, 369 families, and all traditionally recognized orders. The maximum likelihood tree provides unprecedented resolution and high bootstrap support for most backbone nodes, defining for the first time a global phylogeny of fishes. The general structure of the tree is in agreement with expectations from previous morphological and molecular studies, but significant new clades arise. Most interestingly, the high degree of uncertainty among percomorphs is now resolved into nine well-supported supraordinal groups. The order Perciformes, considered by many a polyphyletic taxonomic waste basket, is defined for the first time as a monophyletic group in the global phylogeny. A new classification that reflects our phylogenetic hypothesis is proposed to facilitate communication about the newly found structure of the tree of life of fishes. Finally, the molecular phylogeny is calibrated using 60 fossil constraints to produce a comprehensive time tree. The new time-calibrated phylogeny will provide the basis for and stimulate new comparative studies to better understand the evolution of the amazing diversity of fishes. PMID- 23653401 TI - Committee condemns Indian government for failing to withdraw 33 drugs that lack evidence. PMID- 23653399 TI - ACCF/AHA/SCAI 2013 Update of the Clinical Competence Statement on Coronary Artery Interventional Procedures: a Report of the American College of Cardiology Foundation/American Heart Association/American College of Physicians Task Force on Clinical Competence and Training (Writing Committee to Revise the 2007 Clinical Competence Statement on Cardiac Interventional Procedures). PMID- 23653402 TI - Small rise in rubella cases triggers warning. PMID- 23653403 TI - Government prioritises health checks for 15 million adults despite pre-election promise to scrap them. PMID- 23653404 TI - Dartmouth leads campaign for clinical trial transparency in the US. PMID- 23653405 TI - Protein fishing using magnetic nanobeads containing calmodulin site-specifically immobilized via an azido group. AB - We developed a novel method for capturing proteins that interact with a target protein. This method utilizes a protein containing a site-specifically incorporated 3-azidotyrosine (N3-Y) and FG beads for immobilization of the protein via an azido group. Using calmodulin (CaM) as the target protein, we introduced N3-Y at position 72 and conjugated it to FG beads by copper-free click chemistry. From the Ca(2+)/CaM-binding proteins captured from mouse brain cell lysate and analysis by mass spectrometry, we identified six proteins: alpha enolase (ENOA), glucose-6-phosphate isomerase (GPI), annexin A5 (ANXA5), malate dehydrogenase 1 (MDH1), glyceraldehyde-3-phosphate dehydrogenase and the well known CaM-binding protein phosphoglycerate kinase 1 (PGK1). The presence of photo crosslinking products via N3-Y for all the captured proteins except GPI indicated that they bound directly to CaM. In this study, ENOA, ANXA5 and MDH1 were identified as novel CaM-binding proteins, and PGK1 was bound to Ca(2+)/CaM and also Ca(2+)-free CaM. This method should prove useful for capturing novel interacting proteins and serve as a useful tool for proteomic analyses. PMID- 23653406 TI - Synergistic effect of SnO2/ZnWO4 core-shell nanorods with high reversible lithium storage capacity. AB - High reversible lithium storage capacity is obtained from novel SnO2/ZnWO4 core shell nanorods. At C/20 (20 h per half cycle) rate, the reversible capacity of SnO2/ZnWO4 core-shell nanorods is as high as 1000 mA h g(-1), much higher than that of pure ZnWO4, SnO2, or the traditional theoretical result of the simple mixture. Such performance can be attributed to the synergistic effect between the nanostructured SnO2 and ZnWO4. The distinct electrochemical activity of ZnWO4 nanorods probably activates the irreversible capacity of the SnO2 nanoparticles. These results indicate that high-performance lithium ion batteries can be realized by introducing the synergistic effect of one-dimensional core-shell nanocomposites. PMID- 23653408 TI - A probe to study the toxic interaction of tartrazine with bovine hemoglobin at the molecular level. AB - Tartrazine is an artificial azo dye commonly used in food products, but tartrazine in the environment is potentially harmful. The toxic interaction between tartrazine and bovine hemoglobin (BHb) was investigated using fluorescence, synchronous fluorescence, UV-vis absorption, circular dichroism (CD) and molecular modeling techniques under simulated physiological conditions. The fluorescence data showed that tartrazine can bind with BHb to form a complex. The binding process was a spontaneous molecular interaction, in which van der Waals' forces and hydrogen bonds played major roles. Molecular docking results showed that the hydrogen bonds exist between the oxygen atoms at position 31 of tartrazine and the nitrogen atom NZ7 on Lys99, and also between the oxygen atoms at position 15 of tartrazine and the nitrogen atom NZ7 on Lys104, Lys105. The results of UV-vis and CD spectra revealed that tartrazine led to conformational changes in BHb, including loosening of the skeleton structure and decreasing alpha helix in the secondary structure. The synchronous fluorescence experiment revealed that tartrazine binds into the hemoglobin central cavity, and this was verified using a molecular modeling study. PMID- 23653409 TI - Simply shapely: relative, not absolute shapes are primed in pop-out search. AB - Visual search is typically faster when the target from the previous trial is repeated than when it changes. This priming effect is commonly attributed to a selection bias for the target feature value or against the nontarget feature value that carries over to the next trial. By contrast, according to a relational account, what is primed in visual search is the target-nontarget relationship namely, the feature that the target has in relation to the features in the nontarget context (e.g., larger, darker, redder)-and switch costs occur only when the target-nontarget relations reverse across trials. Here, the relational account was tested against current feature-based views in three eye movement experiments that used different shape search tasks (e.g., geometrical figures varying in the number of corners). For all tested shapes, reversing the target nontarget relationships produced switch costs of the same magnitude as directly switching the target and nontarget features across trials ("full-switch"). In particular, changing only the nontargets produced large switch costs, even when the target feature was always repeated across trials. By contrast, no switch costs were observed when both the target and nontarget features changed, such that the coarse target-nontarget relations remained constant across trials. These results support the relational account over feature-based accounts of priming and indicate that a target's shape can be encoded relative to the shapes in the nontarget context. PMID- 23653410 TI - Short-lived effects of a visual inducer during egocentric space perception and manual behavior. AB - A pitched visual inducer has a strong effect on the visually perceived elevation of a target in extrapersonal space, and also on the elevation of the arm when a subject points with an unseen arm to the target's elevation. The manual effect is a systematic function of hand-to-body distance (Li and Matin Vision Research 45:533-550, 2005): When the arm is fully extended, manual responses to perceptually mislocalized luminous targets are veridical; when the arm is close to the body, gross matching errors occur. In the present experiments, we measured this hand-to-body distance effect during the presence of a pitched visual inducer and after inducer offset, using three values of hand-to-body distance (0, 40, and 70 cm) and two open-loop tasks (pointing to the perceived elevation of a target at true eye level and setting the height of the arm to match the elevation). We also measured manual behavior when subjects were instructed to point horizontally under induction and after inducer offset (no visual target at any time). In all cases, the hand-to-body distance effect disappeared shortly after inducer offset. We suggest that the rapid disappearance of the distance effect is a manifestation of processes in the dorsal visual stream that are involved in updating short lived representations of the arm in egocentric visual perception and manual behavior. PMID- 23653411 TI - Loss and persistence of implicit memory for sound: evidence from auditory stream segregation context effects. AB - An important question is the extent to which declines in memory over time are due to passive loss or active interference from other stimuli. The purpose of the present study was to determine the extent to which implicit memory effects in the perceptual organization of sound sequences are subject to loss and interference. Toward this aim, we took advantage of two recently discovered context effects in the perceptual judgments of sound patterns, one that depends on stimulus features of previous sounds and one that depends on the previous perceptual organization of these sounds. The experiments measured how listeners' perceptual organization of a tone sequence (test) was influenced by the frequency separation, or the perceptual organization, of the two preceding sequences (context1 and context2). The results demonstrated clear evidence for loss of context effects over time but little evidence for interference. However, they also revealed that context effects can be surprisingly persistent. The robust effects of loss, followed by persistence, were similar for the two types of context effects. We discuss whether the same auditory memories might contain information about basic stimulus features of sounds (i.e., frequency separation), as well as the perceptual organization of these sounds. PMID- 23653412 TI - Roughness perception across the hands. AB - It has previously been shown that the perceived roughness of a surface touched by one digit is influenced by the roughness of a different surface touched simultaneously by another digit on the same hand. The present study was designed to examine whether this is the case when surfaces of varying roughness are touched using digits on separate hands. Participants touched pairs of sandpaper surfaces, in sequence, using the same digit, and identified which of the two was rougher. Roughness discrimination was measured in the presence of distractor surfaces touched simultaneously with the target surface, but using a different digit either on the same or on the other hand. The overall perception of roughness of the attended surfaces was better on the left than on the right hand. Perceived roughness also varied systematically with the roughness of the distractor surfaces. Attended surfaces were more likely to be perceived as smoother when they were paired with smooth rather than rough distractors. Likewise, attended surfaces tended to be perceived as rougher with rough distractors. This pattern of results occurred whether the attended and distractor digits were on the same hand or different hands. These data confirm that it is difficult to restrict tactile attention for roughness to a single digit and show that this difficulty extends to restricting attention to a single hand. Furthermore, the effect of a stimulus at an unattended body location was not simply to impair perception in general, but to bias it in the roughness direction of the distractor surface. PMID- 23653413 TI - Prism adaptation in alternately exposed hands. AB - We assessed intermanual transfer of the proprioceptive realignment aftereffects of prism adaptation in right-handers by examining alternate target pointing with the two hands for 40 successive trials, 20 with each hand. Adaptation for the right hand was not different as a function of exposure sequence order or postexposure test order, in contrast with adaptation for the left hand. Adaptation was greater for the left hand when the right hand started the alternate pointing than when the sequence of target-pointing movements started with the left hand. Also, the largest left-hand adaptation appeared when that hand was tested first after exposure. Terminal error during exposure varied in cycles for the two hands, converging on zero when the right hand led, but no difference appeared between the two hands when the left hand led. These results suggest that transfer of proprioceptive realignment occurs from the right to the left hand during both exposure and postexposure testing. Such transfer reflects the process of maintaining spatial alignment between the two hands. Normally, the left hand appears to be calibrated with the right-hand spatial map, and when the two hands are misaligned, the left-hand spatial map is realigned with the right hand spatial map. PMID- 23653414 TI - Elevation easier than plan for sighted and early-blind adults in a perspective taking task. AB - Plans show shapes of objects from above, and represent both their left-right order and their order in the z-dimension (the distance of the objects). Elevations show only the vertical shapes of objects arranged from left to right. Plans, having more spatial information, may be more difficult for participants to construct. Results from a study with sighted, sighted-blindfolded, and early blind participants on Piaget's perspective-taking three-mountain task support this hypothesis. The plan task was judged more difficult than the elevation task even when participants performed with the same level of accuracy on both tasks. In visual and tactile tasks, amount of spatial-order information may determine difficulty, rather than plan versus elevation per se. PMID- 23653407 TI - Prophylaxis of venous thromboembolism in elderly patients with multimorbidity. AB - Pharmacological thromboprophylaxis (TP) is known to reduce venous thromboembolism (VTE) in medical inpatients, but the criteria for risk-driven prescription, safety and impact on mortality are still debated. We analyze data on elderly patients with multimorbidities admitted in the year 2010 to the Italian internal medicine wards participating in the REPOSI registry to investigate the rate of TP during the hospital stay, and analyze the factors that are related to its prescription. Multivariate logistic regression, area under the ROC curve and CART analysis were performed to look for independent predictors of TP prescription. Association between TP and VTE, bleeding and death in hospital and during the 3 month post-discharge follow-up were explored by logistic regression and propensity score analysis. Among the 1,380 patients enrolled, 171 (15.2 %) were on TP during the hospital stay (162 on low molecular weight heparins, 9 on fondaparinux). The disability Barthel index was the main independent predictor of TP prescription. Rate of fatal and non-fatal VTE and bleeding during and after hospitalization did not differ between TP and non-TP patients. In-hospital and post-discharge mortality was significantly higher in patients on TP, that however was not an independent predictor of mortality. Among elderly medical patients there was a relatively low rate of TP, that was more frequently prescribed to patients with a higher degree of disability and who had an overall higher mortality. PMID- 23653416 TI - Reply to letter--Eye oscillations in Parkinson's disease relate to the vestibulo ocular reflex. PMID- 23653417 TI - Synergistic manipulations of plant and insect defences. AB - BACKGROUND: It has been demonstrated previously that cis-jasmone acts as an elicitor of plant defence mechanism(s) by inducing secondary metabolism. It has also been demonstrated that temporal synergism can result in hypersensitive insect pests due to the inhibition of metabolic enzymes. RESULTS: Laboratory bioassays demonstrated that pre-exposure of insects by piperonyl butoxide followed by cis-jasmone treatment of crops, reduced Aphis gossypii on cotton by 80% and Myzus persicae on sweet pepper by 90%. By microencapsulating the cis jasmone and combining with piperonyl butoxide, Bemisia tabaci on tomatoes was reduced by 99%. A field trial with microencapsulated cis-jasmone combined with piperonyl butoxide resulted in a comparable reduction of whitefly egg numbers to that given by the registered rate of imidacloprid, with efficacy of 89% and 93%, respectively. CONCLUSIONS: If insect defence enzymes are compromised by piperonyl butoxide whilst plant defence is primed by cis-jasmone, there are possibilities of an insecticide-free method of controlling insect pests. The success seems largely dependent upon the toxicity of the plants' secondary chemistry. PMID- 23653415 TI - Concise review: pursuing self-renewal and pluripotency with the stem cell factor Nanog. AB - Pluripotent embryonic stem cells and induced pluripotent stem cells hold great promise for future use in tissue replacement therapies due to their ability to self-renew indefinitely and to differentiate into all adult cell types. Harnessing this therapeutic potential efficiently requires a much deeper understanding of the molecular processes at work within the pluripotency network. The transcription factors Nanog, Oct4, and Sox2 reside at the core of this network, where they interact and regulate their own expression as well as that of numerous other pluripotency factors. Of these core factors, Nanog is critical for blocking the differentiation of pluripotent cells, and more importantly, for establishing the pluripotent ground state during somatic cell reprogramming. Both mouse and human Nanog are able to form dimers in vivo, allowing them to preferentially interact with certain factors and perform unique functions. Recent studies have identified an evolutionary functional conservation among vertebrate Nanog orthologs from chick, zebrafish, and the axolotl salamander, adding an additional layer of complexity to Nanog function. Here, we present a detailed overview of published work focusing on Nanog structure, function, dimerization, and regulation at the genetic and post-translational levels with regard to the establishment and maintenance of pluripotency. The full spectrum of Nanog function in pluripotent stem cells and in cancer is only beginning to be revealed. We therefore use this evidence to advocate for more comprehensive analysis of Nanog in the context of disease, development, and regeneration. PMID- 23653418 TI - Classifying the reasons men consider to be important in prostate-specific antigen (PSA) testing decisions: evaluating risks, lay beliefs, and informed decisions. AB - BACKGROUND: Despite uncertainty regarding the benefits of prostate cancer screening, many men have had a prostate-specific antigen (PSA) test. PURPOSE: This study aims to identify classes of reasons guiding men's decisions about prostate cancer screening and predict reasoning approaches by family history and prior screening behaviour. METHODS: First-degree relatives of men with prostate cancer (n = 207) and men from the general population (n = 239) of Australia listed reasons they considered when deciding whether to have a PSA test. RESULTS: Responses were coded into 31 distinct categories. Latent class analysis identified three classes. The evaluation of risk information cues class (20.9 %) contained a greater number of men with a family history (compared with control and overcome cancer/risk class; 52.7 %). Informed decisions and health system class (26.5 %) included a lower proportion of men who had had a PSA test and greater proportions of highly educated and married men. CONCLUSION: Understanding the reasons underlying men's screening decisions may lead to a more effective information provision and decision support. PMID- 23653419 TI - Binding actions and scenes in visual long-term memory. AB - How does visual long-term memory store representations of different entities (e.g., objects, actions, and scenes) that are present in the same visual event? Are the different entities stored as an integrated representation in memory, or are they stored separately? To address this question, we asked observers to view a large number of events; in each event, an action was performed within a scene. Afterward, the participants were shown pairs of action-scene sets and indicated which of the two they had seen. When the task required recognizing the individual actions and scenes, performance was high (80%). Conversely, when the task required remembering which actions had occurred within which scenes, performance was significantly lower (59%). We observed this dissociation between memory for individual entities and memory for entity bindings across multiple testing conditions and presentation durations. These experiments indicate that visual long-term memory stores information about actions and information about scenes separately from one another, even when an action and scene were observed together in the same visual event. These findings also highlight an important limitation of human memory: Situations that require remembering actions and scenes as integrated events (e.g., eyewitness testimony) may be particularly vulnerable to memory errors. PMID- 23653420 TI - A list-length constraint on incidental item-to-item associations. AB - We investigated the possibility that item-to-item associations form between items concurrently included in a capacity-limited region of working memory, but not outside of that region. Many studies indicate a central capacity limit of three to five items (e.g., Cowan Neuropsychologia 49:1401-1406, 2001). Participants received lists of three, six, or nine words along with an orienting task, selecting the most interesting word from each list. Consistent with expectations, a subsequent, unexpected test showed that memory of whether two words came from the same list or not was superior for three-word lists, as compared with six- and nine-word lists, which did not differ. This effect occurred even though the separation between the list positions of the two probe words was controlled across list lengths. The study demonstrates a source of implicit learning that depends upon a limited-capacity working memory faculty, a finding that should inspire further research on the function of working memory in long-term learning. PMID- 23653421 TI - T cell subsets differently regulate osteogenic differentiation of human mesenchymal stromal cells in vitro. AB - T lymphocytes play a key role in the regulation of bone homeostasis and bone healing. The inflammatory response at the site of bone injury is essential to the initiation of the bone repair program; however, an uncontrolled exposure to inflammatory environment has a negative effect on tissue regeneration - indeed, activated T cells were shown to inhibit osteogenic differentiation on human mesenchymal stromal cells (MSCs). Whether resting T cells can induce osteogenic differentiation of MSCs and what role specific T cells subset play in this process is still elusive. In this study, we sought to analyse the osteogenic gene expression profile of whole T cells, CD4 and CD8 T cells isolated from healthy donors and investigated whether secreted factors from each group modulate osteogenic differentiation of human MSCs. Gene expression profiling identified a pool of 51 genes involved at various stages in bone growth which are expressed above detectable levels in CD4 and CD8 T cells. Most genes of this pool were expressed at higher levels in the CD4 subset. In vitro mineralization assays revealed that conditioned medium from CD4 T cells, but not from CD8 cells, significantly increased mineralization in osteogenic cultures of human MSCs; furthermore, mRNA expression of Runt-related transcription factor 2 (RUNX-2), osteocalcin (OC), bone sialoprotein (BSP) and alkaline phosphatase (ALP) in MSCs was significantly upregulated in the presence of CD4-conditioned medium but not with that obtained from CD8. The results show a differential role for CD4 and CD8 T cells in supporting bone formation and identify an osteogenic gene signature of each subset. PMID- 23653422 TI - Parkin disease and the Lewy body conundrum. PMID- 23653423 TI - Residual and pre-treatment application of starycide insect growth regulator (triflumuron) to control Aedes aegypti in containers. AB - BACKGROUND: Dengue is not endemic in Australia, although the vector mosquito Aedes aegypti is. In order to prevent dengue establishment, Australia maintains tight control of vector mosquitoes. Tight control programs often necessitate regular repeat application of treatments, and this is resource intensive. We sought to investigate the efficacy and longevity of triflurumon Starycide(r) Insect Growth Regulator under field conditions in tropical Australia against Aedes. We compared two doses (0.48 and 0.96 ppm), applied to water receptacles with delayed flooding by zero, two, and four weeks. RESULTS: We found greater than 90% inhibition of pupae development was achieved for up to 12 weeks. A dose of 0.96 ppm, when delayed for two or four weeks before flooding, provided 50 times inhibition relative to controls, for up to 22 weeks, suggesting triflumuron bound to the plastic substrate and offered a greater residual effect than applications without delayed flooding. CONCLUSION: We conclude that triflurumon offers excellent efficacy and longevity against Aedes in artificial containers. If deployed under standard conditions, re-application may not be required for up to 22 weeks, furthermore, initial applications could be performed under dry conditions, and this application method may improve the residual effects. PMID- 23653424 TI - Reason for optimism: a parent's perspective. AB - The ketogenic diet is increasing in popularity worldwide, as evidenced by this symposium. More child neurologists are prescribing it in more countries. However, the diet is still underutilized, only occasionally rising to the level of "last resort" among treatment options. Though much work remains to be done to make its use more widespread, recent developments provide reason to believe the future is promising. PMID- 23653425 TI - The ketogenic diet in Dravet syndrome. AB - Dravet syndrome is an infantile epilepsy syndrome with intractable pleomorphic seizures, cognitive impairment, and a number of comorbidities including ataxia/gait abnormalities and behavioral issues. Antiseizure medications are only partially effective in controlling seizures. Secondary to the intractable epilepsy, patients are often on multiple antiseizure medications with significant accumulative neurotoxic side effects. Specifically for Dravet syndrome, the medical literature includes both laboratory and clinical research that supports the use of the ketogenic diet. In addition, a review of the children with Dravet syndrome who were treated with the ketogenic diet at our center was undertaken. Thirteen of the 20 children (65%) with Dravet syndrome treated with the ketogenic diet experienced a greater than 50% reduction in seizure frequency. The ketogenic diet is a good alternative to medication for seizure management in children with Dravet syndrome. PMID- 23653426 TI - Acute mood effect of donepezil in young, healthy volunteers. AB - OBJECTIVE: Chronic use of the acetylcholinesterase inhibitor donepezil has been found to improve mood or to induce mania/hypomania in many neuropsychiatric patients with altered cholinergic and dopaminergic tone. Our aim was to determine whether acutely administered donepezil would alter mood in volunteers with no such alterations. METHODS: This investigation was a double-blind, crossover design study of 15 young, healthy male participants who were allocated in random order to three oral treatments: placebo and 5-mg and 7.5-mg donepezil (doses which exert clinical and acute cognitive effects without considerable peripheral side effects). At the theoretical peak-plasma concentrations of donepezil, volunteers rated how they felt on validated questionnaires, which included various dimensions of subjective feelings. We also assessed changes in brain derived neurotrophic factor (BDNF), which is increased by donepezil after chronic regimes and is related to modulation of mood. RESULTS: Donepezil significantly increased ratings of vigour and anxiety symptoms (medium effect sizes). No changes in bodily symptoms or BDNF were observed. CONCLUSIONS: Acute donepezil administration in participants with unaltered cholinergic and dopaminergic tone led to positive and negative changes in affect. These results call for further research on the direct mood effects of donepezil. PMID- 23653429 TI - Light-induced click reactions. AB - Spatial and temporal control over chemical and biological processes, both in terms of "tuning" products and providing site-specific control, is one of the most exciting and rapidly developing areas of modern science. For synthetic chemists, the challenge is to discover and develop selective and efficient reactions capable of generating useful molecules in a variety of matrices. In recent studies, light has been recognized as a valuable method for determining where, when, and to what extent a process is started or stopped. Accordingly, this Minireview will present the fundamental aspects of light-induced click reactions, highlight the applications of these reactions to diverse fields of study, and discuss the potential for this methodology to be applied to the study of biomolecular systems. PMID- 23653428 TI - Colistin is relatively safe in hematological malignancies and hematopoietic stem cell transplantation patients. AB - PURPOSE: Colistin is increasingly used as the last-resort treatment option against infections caused by multidrug-resistant (MDR) Gram-negative pathogens, but its nephrotoxicity is of concern, especially in severely ill patients. The aim of this study was to analyze the toxicity of colistin therapy in adults and children with hematological malignancies (HM) and hematopoietic stem cell transplantation (HSCT) recipients. METHODS: Data on HSCT recipients and HM patients, treated with intravenous colistin (2.5-5 mg/kg/day in children and 3-6 million international units (IU) in adults, adjusted to renal function) during the period 2008-2011 in our center, were retrospectively collected and analyzed. Nephrotoxicity was defined according to the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage kidney disease). RESULTS: Twenty-nine children and adults received 38 courses of intravenous colistin (2.5-5 mg/kg/day in children and 3-6 * 10(6) IU in adults, adjusted to renal function) [allogeneic HSCT (22 courses) and HM (16 courses)] for 3-28 days (median 10 days) for empirical therapy for nosocomial clinical sepsis (28) or local infection (6), and bacteremia with MDR Gram-negative rods (4). Nephrotoxicity was observed at the end of 4 (10.5%) courses. In 32 (84%) courses, nephrotoxic medications were concomitantly administered. Two patients had convulsions, probably unrelated to colistin. Seven patients (18%) died while on colistin therapy. No death was attributed to an adverse effect of colistin. CONCLUSIONS: Treatment with intravenous colistin, with dosage adjusted to renal function, was relatively safe for HM/HSCT patients, even with concomitantly administered nephrotoxic medications. Concern about nephrotoxicity should not justify a delay in initiating empirical colistin treatment in situations where infection with MDR Gram-negative rods is likely. PMID- 23653427 TI - Cell-cell interaction between vocal fold fibroblasts and bone marrow mesenchymal stromal cells in three-dimensional hyaluronan hydrogel. AB - Mesenchymal stromal cells (MSCs) are multipotential adult cells present in all tissues. Paracrine effects and differentiating ability make MSCs an ideal cell source for tissue regeneration. However, little is known about how interactions between implanted MSCs and native cells influence cellular growth, proliferation, and behaviour. By using an in vitro three-dimensional (3D) co-culture assay of normal or scarred human vocal fold fibroblasts (VFFs) and bone marrow-derived MSCs (BM-MSCs) in a uniquely suited hyaluronan hydrogel (HyStem-VF), we investigated cell morphology, survival rate, proliferation and protein and gene expression of VFFs and BM-MSCs. BM-MSCs inhibited cell proliferation of both normal and scarred VFFs without changes in VFF morphology or viability. BM-MSCs demonstrated decreased proliferation and survival rate after 7 days of co-culture with VFFs. Interactions between BM-MSCs and VFFs led to a significant increase in protein secretion of collagen I and hepatocyte growth factor (HGF) and a decrease of vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP 1) and interleukin-6 (IL-6). In particular, BM-MSCs significantly upregulated matrix metalloproteinase 1 (MMP1) and HGF gene expression for scarred VFFs compared to normal VFFs, indicating the potential for increases in extracellular matrix remodelling and tissue regeneration. Application of BM-MSCs-hydrogels may play a significant role in tissue regeneration, providing a therapeutic approach for vocal fold scarring. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 23653432 TI - Fast and accurate generation of ab initio quality atomic charges using nonparametric statistical regression. AB - We introduce a class of partial atomic charge assignment method that provides ab initio quality description of the electrostatics of bioorganic molecules. The method uses a set of models that neither have a fixed functional form nor require a fixed set of parameters, and therefore are capable of capturing the complexities of the charge distribution in great detail. Random Forest regression is used to build separate charge models for elements H, C, N, O, F, S, and Cl, using training data consisting of partial charges along with a description of their surrounding chemical environments; training set charges are generated by fitting to the b3lyp/6-31G* electrostatic potential (ESP) and are subsequently refined to improve consistency and transferability of the charge assignments. Using a set of 210 neutral, small organic molecules, the absolute hydration free energy calculated using these charges in conjunction with Generalized Born solvation model shows a low mean unsigned error, close to 1 kcal/mol, from the experimental data. Using another large and independent test set of chemically diverse organic molecules, the method is shown to accurately reproduce charge dependent observables--ESP and dipole moment--from ab initio calculations. The method presented here automatically provides an estimate of potential errors in the charge assignment, enabling systematic improvement of these models using additional data. This work has implications not only for the future development of charge models but also in developing methods to describe many other chemical properties that require accurate representation of the electronic structure of the system. PMID- 23653430 TI - Hip structural analysis in adolescent boys with anorexia nervosa and controls. AB - CONTEXT: We have reported lower hip bone mineral density (BMD) in adolescent boys with anorexia nervosa (AN) compared with controls. Although studies have described bone structure in girls with AN, these data are not available for boys. Hip structural analysis (HSA) using dual-energy x-ray absorptiometry is a validated technique to assess hip geometry and strength while avoiding radiation associated with quantitative computed tomography. OBJECTIVE: We hypothesized that boys with AN would have impaired hip structure/strength (assessed by HSA) compared with controls. DESIGN AND SETTING: We conducted a cross-sectional study at a clinical research center. SUBJECTS AND INTERVENTION: We used HSA techniques on hip dual-energy x-ray absorptiometry scans in 31 previously enrolled boys, 15 with AN and 16 normal-weight controls, 12 to 19 years old. RESULTS: AN boys had lower body mass index SD score (P < .0001), testosterone (P = .0005), and estradiol (P = .006) than controls. A larger proportion of AN boys had BMD Z scores <-1 at the femoral neck (60% vs 12.5%, P = 0008). Using HSA, at the narrow neck and trochanter region, boys with AN had lower cross-sectional area (P = .03, 0.02) and cortical thickness (P = .02, 0.03). Buckling ratio at the trochanter region was higher in AN (P = .008). After controlling for age and height, subperiosteal width at the femoral shaft, cross-sectional moment of inertia (narrow neck and femoral shaft), and section modulus (all sites) were lower in AN. The strongest associations of HSA measures were observed with lean mass, testosterone, and estradiol. On multivariate analysis, lean mass remained associated with most HSA measures. CONCLUSIONS: Boys with AN have impaired hip geometric parameters, associated with lower lean mass. PMID- 23653431 TI - Consumption of yogurts fortified in vitamin D and calcium reduces serum parathyroid hormone and markers of bone resorption: a double-blind randomized controlled trial in institutionalized elderly women. AB - CONTEXT: Nutritional prevention of bone deterioration with fortified foods seems particularly suitable in institutionalized elderly women at risk of vitamin D deficiency, secondary hyperparathyroidism, increased bone resorption, and osteoporotic fracture. OBJECTIVE: The objective was to evaluate whether fortification of yogurts with vitamin D and calcium exerts an additional lowering effect on serum PTH and bone resorption markers as compared with isocaloric and isoprotein dairy products in elderly women. DESIGN: A randomized double-blind controlled-trial, 56-day intervention was conducted in institutionalized women (mean age 85.5 years) consuming 2 125-g servings of either vitamin D- and calcium fortified yogurt (FY) at supplemental levels of 10 MUg/d vitamin D3 and 800 mg/d calcium or nonfortified control yogurt (CY) providing 280 mg/d calcium. MAIN OUTCOMES: The endpoints were serum changes from baseline (day 0) to day 28 and day 56 in 25-hydroxyvitamin-D (25OHD), PTH, and bone resorption markers tartrate resistant acid phosphatase isoform-5b (TRAP5b), the primary outcome, and carboxyl terminal cross-linked telopeptide of type I collagen (CTX). RESULTS: At day 56, serum 25OHD increased (mean +/- SEM) by 25.3 +/- 1.8 vs 5.2 +/- 2.5 nmol/L in FY (n = 29) and CY (n = 27), respectively (P < .0001). The corresponding changes in PTH were -28.6% +/- 7.2% vs -8.0% +/- 4.3% (P = .0003); in TRAP5b, -21.9% +/- 4.3% vs 3.0% +/- 3.2% (P < .0001); and in CTX, -11.0% +/- 9.7% vs -3.0% +/- 4.1% (P = .0146), in FY and CY, respectively. At day 28, these differences were less pronounced but already significant for 25OHD, PTH, and TRAP5b. CONCLUSIONS: This study in institutionalized elderly at high risk for osteoporotic fracture suggests that fortification of dairy products with vitamin D3 and calcium provides a greater prevention of accelerated bone resorption as compared with nonfortified equivalent foods. PMID- 23653433 TI - Emotional control, styles of coping with stress and acceptance of illness among patients suffering from chronic somatic diseases. AB - The purpose of this study was to analyse the associations of emotional control with sociodemographic and clinical variables in a sample of patients with a range of chronic somatic diseases. The relationships between emotional control, coping styles and adjustment to the disease were investigated. The sample consisted of 300 patients with the mean age of 54.60 +/- 17.57 years. Courtauld Emotional Control Scale was used to measure the patients' tendency to suppress negative emotions, Coping Inventory for Stressful Situations was used to measure coping styles and Acceptance of Illness Scale was applied to determine adjustment to the disease. Patients with neurological conditions showed significantly lower suppression of anger. Levels of emotional control were found to be related to gender, age and educational level but not to the place of residence. Task oriented style of coping with stress correlated positively with suppression of depression and anxiety, whereas acceptance of illness correlated negatively with suppression of anger. Levels of emotional control are only weakly related to the type of diagnosis; however, some clinical samples may show lower suppression of anger. Suppression of negative emotions is weakly related to adjustment indicators such as certain coping styles and acceptance of illness. PMID- 23653434 TI - Attention control in mood and anxiety disorders: evidence from the antisaccade task. AB - The antisaccade task (in which participants must suppress a reflexive saccade towards a sudden, peripheral stimulus and generate a volitional saccade in the opposite direction) is considered a measure of cognitive inhibition. The task has been used to examine cognitive control deficits in several neuropsychiatric conditions, most notably schizophrenia. This commentary summarizes recent evidence from antisaccade tasks in mood and anxiety disorders, with reference to neuropsychological models and psychopharmacological mechanisms. PMID- 23653435 TI - Would the real human embryonic stem cell please stand up? AB - Embryonic stem cells (ESCs) are now classified into two types of pluripotency: "naive" and "primed" based upon their differing characteristics. Conventional human ESCs have much more in common with mouse epiblast stem cells and are now deemed to be primed. Naive human ESCs that resemble mouse ESCs have recently been generated from their primed counterpart by cellular reprogramming. Isolation of naive hESCs from human embryos has proven to be difficult. Is the inability to capture naive hESCs the result of suboptimal derivation conditions or because they are so transient they cannot be "captured" in vitro? Prevailing evidence surrounding this issue are inconclusive and require additional human embryo research. However, negative public opinion regarding human embryo research, may make this an uphill battle. The solution may come from cellular reprogramming. PMID- 23653436 TI - [Teachers and attention deficit and/or hyperactivity disorder: a pilot study on the situation of teachers in Tyrol]. AB - BACKGROUND: Given the high prevalence of approximately 5% of Attention Deficit and/or Hyperactivity Disorder in children the level of knowledge of Tyrolean educators at selected educational institutions was examined. METHODS: As part of the thesis of A. Aglan 170 questionnaires were distributed at selected Tyrolean schools from May to October 2010. The questionnaires were completed voluntarily and anonymously by educators working there and then turned in. The questionnaire consisted of 43 items and was evaluated by means of conventional statistical methods. RESULTS: 98 (58%) of the questionnaires sent out were returned. 93 questionnaires (55%) were evaluated using standard statistical methods. Teachers were well informed about generic aspects of Attention Deficit and/or Hyperactivity Disorder. Knowledge gaps could be identified regarding the underlying causes of the disorder and available treatment options. Teachers demonstrated great willingness to actively cooperate and to learn more about Attention Deficit and/or Hyperactivity Disorder through further education in order to improve the situation of all parties involved. CONCLUSIONS: Lack of knowledge was found regarding the subtopics "causes of Attention Deficit and/or Hyperactivity Disorder" and "Treatment Options". The majority of the teachers would appreciate specialized training and is willing to adapt their lessons to the requirements of children, pupils and students affected by Attention Deficit and/or Hyperactivity Disorder. PMID- 23653437 TI - [In Process Citation]. PMID- 23653438 TI - Synergy between XANES spectroscopy and DFT to elucidate the amorphous structure of heterogeneous catalysts: TiO2-supported molybdenum oxide catalysts. PMID- 23653439 TI - Highly potent and stable capped siRNAs with picomolar activity for RNA interference. PMID- 23653440 TI - Retraction. Tsg101 interacts with herpes simplex virus 1 VP1/2 and is a substrate of VP1/2 ubiquitin-specific protease domain activity. PMID- 23653442 TI - Demonstration of the innate electrophilicity of 4-(3-(benzyloxy)phenyl)-2 (ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP), a small-molecule positive allosteric modulator of the glucagon-like peptide-1 receptor. AB - 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP) represents a novel small-molecule activator of the glucagon-like peptide-1 receptor (GLP-1R), and exhibits glucose-dependent insulin secretion in rats following i.v. (but not oral) administration. To explore the quantitative pharmacology associated with GLP-1R agonism in preclinical species, the in vivo pharmacokinetics of BETP were examined in rats after i.v. and oral dosing. Failure to detect BETP in circulation after oral administration of a 10-mg/kg dose in rats was consistent with the lack of an insulinotropic effect of orally administered BETP in this species. Likewise, systemic concentrations of BETP in the rat upon i.v. administration (1 mg/kg) were minimal (and sporadic). In vitro incubations in bovine serum albumin, plasma, and liver microsomes from rodents and humans indicated a facile degradation of BETP. Failure to detect metabolites in plasma and liver microsomal incubations in the absence of NADP was suggestive of a covalent interaction between BETP and a protein amino acid residue(s) in these matrices. Incubations of BETP with glutathione (GSH) in buffer revealed a rapid nucleophilic displacement of the ethylsulfoxide functionality by GSH to yield adduct M1, which indicated that BETP was intrinsically electrophilic. The structure of M1 was unambiguously identified by comparison of its chromatographic and mass spectral properties with an authentic standard. The GSH conjugate of BETP was also characterized in NADPH- and GSH-supplemented liver microsomes and in plasma samples from the pharmacokinetic studies. Unlike BETP, M1 was inactive as an allosteric modulator of the GLP-1R. PMID- 23653444 TI - Lysine trimethylation of EF-Tu mimics platelet-activating factor to initiate Pseudomonas aeruginosa pneumonia. AB - Pseudomonas aeruginosa is a ubiquitous microorganism and the most common Gram negative bacterium associated with nosocomial pneumonia, which is a leading cause of mortality among critically ill patients. Although many virulence factors have been identified in this pathogen, little is known about the bacterial components required to initiate infection in the host. Here, we identified a unique trimethyl lysine posttranslational modification of elongation factor Tu as a previously unrecognized bacterial ligand involved in early host colonization by P. aeruginosa. This modification is carried out by a novel methyltransferase, here named elongation factor Tu-modifying enzyme, resulting in a motif that is a structural mimic of the phosphorylcholine present in platelet-activating factor. This novel motif mediates bacterial attachment to airway respiratory cells through platelet-activating factor receptor and is a major virulence factor, expression of which is a prerequisite to pneumonia in a murine model of respiratory infection. IMPORTANCE: Phosphorylcholine is an interesting molecule from the microbiological and immunological point of view. It is a crucial epitope for the virulence of many important human pathogens, modulates the host immune response, and is involved in a wide number of processes ranging from allergy to inflammation. Our current work identifies a novel bacterial surface epitope structurally and functionally similar to phosphorylcholine. This novel epitope is crucial for initial colonization of the respiratory tract by Pseudomonas aeruginosa and for development of pneumonia. This opens up new targets for the development of novel drugs to prevent P. aeruginosa pneumonia, which is particularly important given the frequent emergence of multidrug-resistant strains. PMID- 23653445 TI - Factors required for activation of urease as a virulence determinant in Cryptococcus neoformans. AB - Urease in Cryptococcus neoformans plays an important role in fungal dissemination to the brain and causing meningoencephalitis. Although urea is not required for synthesis of apourease encoded by URE1, the available nitrogen source affected the expression of URE1 as well as the level of the enzyme activity. Activation of the apoenzyme requires three accessory proteins, Ure4, Ure6, and Ure7, which are homologs of the bacterial urease accessory proteins UreD, UreF, and UreG, respectively. A yeast two-hybrid assay showed positive interaction of Ure1 with the three accessory proteins encoded by URE4, URE6, and URE7. Metalloproteomic analysis of cryptococcal lysates using inductively coupled plasma mass spectrometry (ICP-MS) and a biochemical assay of urease activity showed that, as in many other organisms, urease is a metallocentric enzyme that requires nickel transported by Nic1 for its catalytic activity. The Ure7 accessory protein (bacterial UreG homolog) binds nickel likely via its conserved histidine-rich domain and appears to be responsible for the incorporation of Ni(2+) into the apourease. Although the cryptococcal genome lacks the bacterial UreE homolog, Ure7 appears to combine the functions of bacterial UreE and UreG, thus making this pathogen more similar to that seen with the plant system. Brain invasion by the ure1, ure7, and nic1 mutant strains that lack urease activity was significantly less effective in a mouse model. This indicated that an activated urease and not the Ure1 protein was responsible for enhancement of brain invasion and that the factors required for urease activation in C. neoformans resemble those of plants more than those of bacteria. IMPORTANCE: Cryptococcus neoformans is the major fungal agent of meningoencephalitis in humans. Although urease is an important factor for cryptococcal brain invasion, the enzyme activation system has not been studied. We show that urease is a nickel-requiring enzyme whose activity level is influenced by the type of available nitrogen source. C. neoformans contains all the bacterial urease accessory protein homologs and nickel transporters except UreE, a nickel chaperone. Cryptococcal Ure7 (a homolog of UreG) apparently functions as both the bacterial UreG and UreE in activating the Ure1 apoenzyme. The cryptococcal urease accessory proteins Ure4, Ure6, and Ure7 interacted with Ure1 in a yeast two-hybrid assay, and deletion of any one of these not only inactivated the enzyme but also reduced the efficacy of brain invasion. This is the first study showing a holistic picture of urease in fungi, clarifying that urease activity, and not Ure1 protein, contributes to pathogenesis in C. neoformans. PMID- 23653446 TI - Keto-mycolic acid-dependent pellicle formation confers tolerance to drug sensitive Mycobacterium tuberculosis. AB - ABSTRACT The chronic nature of tuberculosis (TB), its requirement of long duration of treatment, its ability to evade immune intervention, and its propensity to relapse after drug treatment is discontinued are reminiscent of other chronic, biofilm-associated bacterial diseases. Historically, Mycobacterium tuberculosis was grown as a pellicle, a biofilm-like structure, at the liquid-air interface in a variety of synthetic media. Notably, the most widely administered human vaccine, BCG, is grown as a pellicle for vaccine production. However, the molecular requirements for this growth remain ill defined. Here, we demonstrate that keto-mycolic acids (keto-MA) are essential for pellicle growth, and mutants lacking in or depleted of this MA species are unable to form a pellicle. We investigated the role of the pellicle biofilm in the reduction of antibiotic sensitivity known as drug tolerance using the pellicle-defective DeltammaA4 mutant strain. We discovered that the DeltammaA4 mutant, which is both pellicle defective and highly sensitive to rifampicin (RIF) under planktonic growth, when incorporated within the wild-type pellicle biofilm, was protected from the bactericidal activity of RIF. The observation that growth within the M. tuberculosis pellicle biofilm can confer drug tolerance to a drug-hypersensitive strain suggests that identifying molecular requirements for pellicle growth could lead to development of novel interventions against mycobacterial infections. Our findings also suggest that a class of drugs that can disrupt M. tuberculosis biofilm formation, when used in conjunction with conventional antibiotics, has the potential to overcome drug tolerance. IMPORTANCE Two of the most important questions in tuberculosis (TB) research are (i) how does Mycobacterium tuberculosis persist in the human host for decades in the face of an active immune response and (ii) why does it take six months and four drugs to treat uncomplicated TB. Both these aspects of M. tuberculosis biology are reminiscent of infections caused by organisms capable of forming biofilms. M. tuberculosis is capable of growing as a biofilm-like structure called the pellicle. In this study, we demonstrate that a specific cell wall component, keto-mycolic acid, is essential for pellicle growth. We also demonstrate that a strain of M. tuberculosis that is both drug sensitive and pellicle defective exhibits commensal behavior and becomes drug tolerant by becoming part of a heterogeneous pellicle, a characteristic of multispecies biofilms. These observations could have important implications for identifying novel pathways for M. tuberculosis drug tolerance and the design of new modalities to rapidly treat TB. PMID- 23653447 TI - Subcellular clustering of the phosphorylated WspR response regulator protein stimulates its diguanylate cyclase activity. AB - WspR is a hybrid response regulator-diguanylate cyclase that is phosphorylated by the Wsp signal transduction complex in response to growth of Pseudomonas aeruginosa on surfaces. Active WspR produces cyclic di-GMP (c-di-GMP), which in turn stimulates biofilm formation. In previous work, we found that when activated by phosphorylation, yellow fluorescent protein (YFP)-tagged WspR forms clusters that are visible in individual cells by fluorescence microscopy. Unphosphorylated WspR is diffuse in cells and not visible. Thus, cluster formation is an assay for WspR signal transduction. To understand how and why WspR forms subcellular clusters, we analyzed cluster formation and the enzymatic activities of six single amino acid variants of WspR. In general, increased cluster formation correlated with increased in vivo and in vitro diguanylate cyclase activities of the variants. In addition, WspR specific activity was strongly concentration dependent in vitro, and the effect of the protein concentration on diguanylate cyclase activity was magnified when WspR was treated with the phosphor analog beryllium fluoride. Cluster formation appears to be an intrinsic property of phosphorylated WspR (WspR-P). These results support a model in which the formation of WspR-P subcellular clusters in vivo in response to a surface stimulus is important for potentiating the diguanylate cyclase activity of WspR. Subcellular cluster formation appears to be an additional means by which the activity of a response regulator protein can be regulated. IMPORTANCE: Bacterial sensor proteins often phosphorylate cognate response regulator proteins when stimulated by an environmental signal. Phosphorylated response regulators then mediate an appropriate adaptive cellular response. About 6% of response regulator proteins have an enzymatic domain that is involved in producing or degrading cyclic di-GMP (c-di-GMP), a molecule that stimulates bacterial biofilm formation. In this work, we examined the in vivo and in vitro behavior of the response regulator-diguanylate cyclase WspR. When phosphorylated in response to a signal associated with surface growth, WspR has a tendency to form oligomers that are visible in cells as subcellular clusters. Our results show that the formation of phosphorylated WspR (WspR-P) subcellular clusters is important for potentiating the diguanylate cyclase activity of WspR-P, making it more active in c-di-GMP production. We conclude that oligomer formation visualized as subcellular clusters is an additional mechanism by which the activities of response regulator diguanylate cyclases can be regulated. PMID- 23653449 TI - Molecular dissection of bacterial nanowires. AB - The discovery of bacterial conductive structures, termed nanowires, has intrigued scientists for almost a decade. Nanowires enable bacteria to transfer electrons over micrometer distances to extracellular electron acceptors such as insoluble metal oxides or electrodes. Nanowires are pilus based and in Geobacter sulfurreducens are composed of the type IV pilin subunit PilA. Multiheme c-type cytochromes have been shown to attach to nanowire pili. Two hypotheses have been proposed for electron conduction in nanowires. The first (termed the metal-like conductivity or MLC hypothesis) claims that the pilus itself has the electron conductive properties and the attached cytochromes mediate transfer to the final electron acceptor, whereas the second hypothesis (termed the superexchange conductivity or SEC hypothesis) suggests that electrons are "hopping" between heme groups in cytochromes closely aligned with the pilus as a scaffold. In their recent article in mBio, Vargas et al. [M. Vargas, N. S. Malvankar, P.-L. Tremblay, C. Leang, J. A. Smith, P. Patel, O. Snoeyenbos-West, K. P. Nevin, and D. R. Lovley, mBio 4(2):e00210-13, 2013] address this ambiguity through an analysis of strain Aro-5, a G. sulfurreducens PilA mutant lacking aromatic residues in the nonconserved portion of PilA. These residues were suspected of involvement in electron transport according to the MLC hypothesis. The G. sulfurreducens mutant had reduced conductive properties, lending important support to the MLC hypothesis. The data also highlight the need for further and more conclusive evidence for one or the other hypothesis. PMID- 23653448 TI - Oral immunization with cholera toxin provides protection against Campylobacter jejuni in an adult mouse intestinal colonization model. AB - Immunity to Campylobacter jejuni, a major diarrheal pathogen, is largely Penner serotype specific. For broad protection, a vaccine should be based on a common antigen(s) present in all strains. In our previous study (M. J. Albert, S. Haridas, D. Steer, G. S. Dhaunsi, A. I. Smith, and B. Adler, Infect. Immun. 75:3070-3073, 2007), we demonstrated that antibody to cholera toxin (CT) cross reacted with the major outer membrane proteins (MOMPs) of all Campylobacter jejuni strains tested. In the current study, we investigated whether immunization with CT protects against intestinal colonization by C. jejuni in an adult mouse model and whether the nontoxic subunit of CT (CT-B) is the portion mediating cross-reaction. Mice were orally immunized with CT and later challenged with C. jejuni strains (48, 75, and 111) of different serotypes. Control animals were immunized with phosphate-buffered saline. Fecal shedding of challenge organisms was studied daily for 9 days. Serum and fecal antibody responses were studied by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. The cross reactivity of rabbit CT-B antibody to MOMP was studied by immunoblotting. The reactivity of 21 overlapping 30-mer oligopeptides (based on MOMP's sequence) against rabbit CT antibody was tested by ELISA. Test animals produced antibodies to CT and MMP in serum and feces and showed resistance to colonization, the vaccine efficacies being 49% (for strain 48), 37% (for strain 75), and 34% (for strain 111) (P, <=0.05 to <=0.001). One peptide corresponding to a variable region of MOMP showed significant reactivity. CT-B antibody cross-reacted with MOMP. Since CT-B is a component of oral cholera vaccines, it might be possible to control C. jejuni diarrhea with these vaccines. IMPORTANCE: Campylobacter jejuni is a major cause of diarrhea worldwide. Patients who recover from C. jejuni diarrhea develop immunity to the infecting serotype and remain susceptible to infection with other serotypes. A vaccine based on a common protective antigen(s) present in all C. jejuni serotypes is expected to provide broad protection. In our previous study, we showed that antibody to cholera toxin (CT) reacted with the major outer membrane proteins (MOMPs) from different strains of C. jejuni. We assumed that the B subunit of the toxin (CT-B), which is nontoxic and a component of licensed oral cholera vaccines, might be the component that cross-reacts with MOMP. In the current study, we showed that orally immunizing mice with CT protected them against colonization upon challenge with different serotypes of C. jejuni. We also showed that CT-B is the component mediating cross-reaction. Therefore, it might be possible to use cholera vaccines to prevent C. jejuni diarrhea. This could result in significant savings in vaccine development and treatment of the disease. PMID- 23653451 TI - CVD data to be standardized across Europe. PMID- 23653450 TI - Multiple protein analysis of formalin-fixed and paraffin-embedded tissue samples with reverse phase protein arrays. AB - Reverse-phase protein arrays (RPPAs) have become an important tool for the sensitive and high-throughput detection of proteins from minute amounts of lysates from cell lines and cryopreserved tissue. The current standard method for tissue preservation in almost all hospitals worldwide is formalin fixation and paraffin embedding, and it would be highly desirable if RPPA could also be applied to formalin-fixed and paraffin embedded (FFPE) tissue. We investigated whether the analysis of FFPE tissue lysates with RPPA would result in biologically meaningful data in two independent studies. In the first study on breast cancer samples, we assessed whether a human epidermal growth factor receptor (HER) 2 score based on immunohistochemistry (IHC) could be reproduced with RPPA. The results showed very good concordance between the IHC and RPPA classifications of HER2 expression. In the second study, we profiled FFPE tumor specimens from patients with adenocarcinoma and squamous cell carcinoma in order to find new markers for differentiating these two subtypes of non-small cell lung cancer. p21-activated kinase 2 could be identified as a new differentiation marker for squamous cell carcinoma. Overall, the results demonstrate the technical feasibility and the merits of RPPA for protein expression profiling in FFPE tissue lysates. PMID- 23653452 TI - Glutathione S-transferase mu2 suppresses cancer cell metastasis in non-small cell lung cancer. AB - Glutathione S-transferase mu2 (GST-M2) is a phase II detoxification enzyme. Low expression of GST-M2 in lung cancers is due to hypermethylation of its promoter. Lung cancer with the GST mu-null genotype is associated with shorter survival. However, a correlation between GST-M2 and important clinical parameters, as well as the migration of GST-M2-defective cells in lung cancer, has not been established. In the present study, we investigate the role of GST-M2 in cell migration and actin disassembly in lung cancer cells. GST-M2 and CCN2 mRNA levels were significantly reduced in non-small cell lung cancer (NSCLC) tumors when compared with matched normal lung tissues in 82 patients with NSCLC. We found that high expressions of both GST-M2 and CCN2 are correlated with favorable survival of patients with lung cancer when compared with similar patients without GST-M2 or CCN2 expression. GST-M2 can induce CCN2 expression by driving the CCN2 proximal promoter. Overexpression of GST-M2 decreases the formation of filopodia, resulting in remodeling of the reorganized cytoskeletons. Overexpression of GST M2 significantly suppressed cancer cell migration on wound-healing assay. In addition, overexpression of GST-M2 dramatically reduced tumor growth and metastasis in a xenograft mouse model. These data highlight the potential of GST M2 as a novel tumor suppressor. GST-M2 increases the expression of CCN2 in lung cancer cells, which inhibits cancer cell migration in lung cancer and animal models. PMID- 23653453 TI - The fat-soluble vitamins 100 years later: where are we now? PMID- 23653455 TI - Non-alcoholic fatty liver disease in common endocrine disorders. AB - Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease spanning from simple benign steatosis to steatohepatitis with fibrosis and scarring that can eventually lead to cirrhosis. Its prevalence is rising rapidly and is developing into the leading indication for liver transplantation worldwide. Abnormalities in endocrine axes have been associated with NALFD, including hypogonadism, hypothyroidism, GH deficiency and hypercortisolaemia. In some instances, correction of the endocrine defects has been shown to have a beneficial impact. While in patients with type 2 diabetes the association with NAFLD is well established and recognised, there is a more limited appreciation of the condition among common endocrine diseases presenting with hormonal excess or deficiency. In this review, we examine the published data that have suggested a mechanistic link between endocrine abnormalities and NAFLD and summarise the clinical data endorsing these observations. PMID- 23653458 TI - Costs of chronic obstructive pulmonary disease in relation to compliance with guidelines: a study in the primary care setting. AB - BACKGROUND: The aim of this study was to analyse the economic impact of nonadherence to the Global Initiative for Obstructive Lung Disease (GOLD) guidelines in patients with chronic obstructive pulmonary disease (COPD). METHODS: A retrospective analysis was carried out on a claim database. Patients aged at least 40 years with a diagnosis of COPD were eligible for this analysis. Demographics, medical data and use of resources were collected and direct and indirect costs were analysed (from January 2008 to June 2009). A probabilistic multivariate sensitivity analysis of avoided costs was carried out. All results are presented in annualized form and costs are expressed in Euros (2009). RESULTS: A total of 1365 patients were included, 79.5% were men. The mean age (+/ standard deviation) was 71.4 (+/-10.3) years, the mean forced expiratory volume in 1 s (FEV1) was 65.3% and they had a COPD history of 5.5 (+/-2.9) years. Patients were divided into an adherent group and a nonadherent group depending on whether therapeutic recommendations according to severity defined in the GOLD guidelines (2007) were followed. Patients in both groups were also classified as having stage II (FEV1 < 80% and < 50%) or stage III disease (FEV1 < 50% and >= 30%). The total annual drug cost per patient in the nonadherent group was ?771.5 while it was only ?426.4 for the adherent group. The average direct cost per patient per year in the nonadherent stage II group was ?1465 (+/-971) and it rose to ?2942 (+/-1918) for patients in the nonadherent group with stage III disease. The potential saving from the implementation of the GOLD guidelines in stage II COPD amounted to ?758 per patient per year (68% saving on drug cost). In contrast, the cost for patients with stage III disease was higher in the adherent group versus the nonadherent group (?2468). CONCLUSIONS: The cost of COPD may vary according to compliance with the GOLD guidelines. The cost observed for patients with stage II disease is higher than expected in patients who adhere to treatment, but patients with stage III disease treated according to the GOLD guidelines had significantly higher treatment costs. PMID- 23653459 TI - Progesterone antagonism of neurite outgrowth depends on microglial activation via Pgrmc1/S2R. AB - Neuronal plasticity is regulated by the ovarian steroids estradiol (E2) and progesterone (P4) in many normal brain functions, as well as in acute response to injury and chronic neurodegenerative disease. In a female rat model of axotomy, the E2-dependent compensatory neuronal sprouting is antagonized by P4. To resolve complex glial-neuronal cell interactions, we used the "wounding-in-a-dish" model of neurons cocultured with astrocytes or mixed glia (microglia to astrocytes, 1:3). Although both astrocytes and mixed glia supported E2-enhanced neurite outgrowth, P4 antagonized E2-induced neurite outgrowth only with mixed glia, but not astrocytes alone. We now show that P4-E2 antagonism of neurite outgrowth is mediated by microglial expression of progesterone receptor (Pgr) membrane component 1 (Pgrmc1)/S2R, a putative nonclassical Pgr mediator with multiple functions. The P4-E2 antagonism of neurite outgrowth was restored by add-back of microglia to astrocyte-neuron cocultures. Because microglia do not express the classical Pgr, we examined the role of Pgrmc1, which is expressed in microglia in vitro and in vivo. Knockdown by siRNA-Pgrmc1 in microglia before add-back to astrocyte-neuron cocultures suppressed the P4-E2 antagonism of neurite outgrowth. Conditioned media from microglia restored the P4-E2 activity, but only if microglia were activated by lipopolysaccharide or by wounding. Moreover, the microglial activation was blocked by Pgmrc1-siRNA knockdown. These findings explain why nonwounded cultures without microglial activation lack P4 antagonism of E2-induced neurite outgrowth. We suggest that microglial activation may influence brain responses to exogenous P4, which is a prospective therapy in traumatic brain injury. PMID- 23653460 TI - Dipeptidylpeptidase inhibition is associated with improvement in blood pressure and diastolic function in insulin-resistant male Zucker obese rats. AB - Diastolic dysfunction is a prognosticator for future cardiovascular events that demonstrates a strong correlation with obesity. Pharmacological inhibition of dipeptidylpeptidase-4 (DPP-4) to increase the bioavailability of glucagon-like peptide-1 is an emerging therapy for control of glycemia in type 2 diabetes patients. Accumulating evidence suggests that glucagon-like peptide-1 has insulin independent actions in cardiovascular tissue. However, it is not known whether DPP-4 inhibition improves obesity-related diastolic dysfunction. Eight-week-old Zucker obese (ZO) and Zucker lean rats were fed normal chow diet or diet containing the DPP-4 inhibitor, linagliptin (LGT), for 8 weeks. Plasma DPP-4 activity was 3.3-fold higher in ZO compared with Zucker lean rats and was reduced by 95% with LGT treatment. LGT improved echocardiographic and pressure volume derived indices of diastolic function that were impaired in ZO control rats, without altering food intake or body weight gain during the study period. LGT also blunted elevated blood pressure progression in ZO rats involving improved skeletal muscle arteriolar function, without reducing left ventricular hypertrophy, fibrosis, or oxidative stress in ZO hearts. Expression of phosphorylated- endothelial nitric oxide synthase (eNOS)(Ser1177), total eNOS, and sarcoplasmic reticulum calcium ATPase 2a protein was elevated in the LGT treated ZO heart, suggesting improved Ca(2+) handling. The ZO myocardium had an abnormal mitochondrial sarcomeric arrangement and cristae structure that were normalized by LGT. These studies suggest that LGT reduces blood pressure and improves intracellular Cai(2+) mishandling and cardiomyocyte ultrastructure, which collectively result in improvements in diastolic function in the absence of reductions in left ventricular hypertrophy, fibrosis, or oxidative stress in insulin-resistant ZO rats. PMID- 23653461 TI - Acute hypernatremia exerts an inhibitory oxytocinergic tone that is associated with anxiolytic mood in male rats. AB - Anxiety disorders are the most common psychiatric illnesses and are associated with heightened stress responsiveness. The neuropeptide oxytocin (OT) has garnered significant attention for its potential as a treatment for anxiety disorders; however, the mechanism mediating its effects on stress responses and anxiety is not well understood. Here we used acute hypernatremia, a stimulus that elevates brain levels of OT, to discern the central oxytocinergic pathways mediating stress responsiveness and anxiety-like behavior. Rats were rendered hypernatremic by acute administration of 2.0 M NaCl and had increased plasma sodium concentration, plasma osmolality, and Fos induction in OT-containing neurons relative to 0.15 M NaCl-treated controls. Acute hypernatremia decreased restraint-induced elevations in corticosterone and created an inhibitory oxytocinergic tone on parvocellular neurosecretory neurons within the paraventricular nucleus of the hypothalamus. In contrast, evaluation of Fos immunohistochemistry determined that acute hypernatremia followed by restraint increased neuronal activation in brain regions receiving OT afferents that are also implicated in the expression of anxiety-like behavior. To determine whether these effects were predictive of altered anxiety-like behavior, rats were subjected to acute hypernatremia and then tested in the elevated plus maze. Relative to controls given 0.15 M NaCl, rats given 2.0 M NaCl spent more time in the open arms of the elevated plus maze, suggesting that acute hypernatremia is anxiolytic. Collectively the results suggest that acute elevations in plasma sodium concentration increase central levels of OT, which decreases anxiety by altering neuronal activity in hypothalamic and limbic nuclei. PMID- 23653462 TI - mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids. AB - Bronchial carcinoids (BCs) are rare neuroendocrine tumors that are still orphans of medical treatment. Human BC primary cultures may display resistance to everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), in terms of cell viability reduction. Our aim was to assess whether the novel dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235 is effective in everolimus-resistant human BC tissues and cell lines. In addition, we searched for possible markers of the efficacy of mTOR inhibitors that may help in identifying the patients who may benefit from treatment with mTOR inhibitors, sparing them from ineffective therapy. We found that NVP-BEZ235 is twice as potent as everolimus in reducing cell viability and activating apoptosis in human BC tissues that display sensitivity to mTOR inhibitors, but is not effective in everolimus-resistant BC tissues and cell lines that bypass cyclin D1 downregulation and escape G0/G1 blockade. Rebound AKT activation was not observed in response to treatment with either mTOR inhibitor in the 'resistant' BC cells. In addition to total mTOR levels, putative markers of the sensitivity of BCs to mTOR inhibitors are represented by AKT, p70S6K (RPS6KB2), and ERK1/2 (MAPK3/1) protein levels. Finally, we validated these markers in an independent BC group. These data indicate that the dual PI3K/mTOR inhibitor NVP-BEZ235 is more potent than everolimus in reducing the proliferation of human BC cells. 'Resistant' cells display lower levels of mTOR, p70S6K, AKT, and ERK1/2, indicating that these proteins may be useful as predictive markers of resistance to mTOR and PI3K/mTOR inhibitors in human BCs. PMID- 23653463 TI - HIF2 and endocrine neoplasia: an evolving story. AB - In this issue of Endocrine-Related Cancer, Toledo et al. report the identification of activating mutations in the HIF2 (EPAS1) transcription factor in a subset of sporadic pheochromocytomas and paragangliomas. These findings add significantly to an evolving and complex story of the role of hypoxic gene response pathways in human endocrine neoplasia. PMID- 23653469 TI - Reconstruction of the Brassica rapa ancestral genome. PMID- 23653468 TI - Genomics of the fetal hypothalamic cellular response to transient hypoxia: endocrine, immune, and metabolic responses. AB - Fetuses respond to transient hypoxia (a common stressor in utero) with cellular responses that are appropriate for promoting survival of the fetus. The present experiment was performed to identify the acute genomic responses of the fetal hypothalamus to transient hypoxia. Three fetal sheep were exposed to 30 min of hypoxia and hypothalamic mRNA extracted from samples collected 30 min after return to normoxia. These samples were compared with those from four normoxic control fetuses by the Agilent 019921 ovine array. Differentially regulated genes were analyzed by network analysis and by gene ontology analysis, identifying statistically significant overrepresentation of biological processes. Real-time PCR of selected genes supported the validity of the array data. Hypoxia induced increased expression of genes involved in response to oxygen stimulus, RNA splicing, antiapoptosis, vascular smooth muscle proliferation, and positive regulation of Notch receptor target. Downregulated genes were involved in metabolism, antigen receptor-mediated immunity, macromolecular complex assembly, S-phase, translation elongation, RNA splicing, protein transport, and posttranscriptional regulation. We conclude that these results emphasize that the cellular response to hypoxia involves reduced metabolism, the involvement of the fetal immune system, and the importance of glucocorticoid signaling. PMID- 23653470 TI - Frenemies: antagonistic bHLH/bZIP transcription factors integrate light and reactive oxygen species signaling in Arabidopsis. PMID- 23653471 TI - Light-regulated hypocotyl elongation involves proteasome-dependent degradation of the microtubule regulatory protein WDL3 in Arabidopsis. AB - Light significantly inhibits hypocotyl cell elongation, and dark-grown seedlings exhibit elongated, etiolated hypocotyls. Microtubule regulatory proteins function as positive or negative regulators that mediate hypocotyl cell elongation by altering microtubule organization. However, it remains unclear how plants coordinate these regulators to promote hypocotyl growth in darkness and inhibit growth in the light. Here, we demonstrate that WAVE-DAMPENED 2-LIKE3 (WDL3), a microtubule regulatory protein of the WVD2/WDL family from Arabidopsis thaliana, functions in hypocotyl cell elongation and is regulated by a ubiquitin-26S proteasome-dependent pathway in response to light. WDL3 RNA interference Arabidopsis seedlings grown in the light had much longer hypocotyls than controls. Moreover, WDL3 overexpression resulted in overall shortening of hypocotyl cells and stabilization of cortical microtubules in the light. Cortical microtubule reorganization occurred slowly in cells from WDL3 RNA interference transgenic lines but was accelerated in cells from WDL3-overexpressing seedlings subjected to light treatment. More importantly, WDL3 protein was abundant in the light but was degraded through the 26S proteasome pathway in the dark. Overexpression of WDL3 inhibited etiolated hypocotyl growth in regulatory particle non-ATPase subunit-1a mutant (rpn1a-4) plants but not in wild-type seedlings. Therefore, a ubiquitin-26S proteasome-dependent mechanism regulates the levels of WDL3 in response to light to modulate hypocotyl cell elongation. PMID- 23653472 TI - Deciphering the diploid ancestral genome of the Mesohexaploid Brassica rapa. AB - The genus Brassica includes several important agricultural and horticultural crops. Their current genome structures were shaped by whole-genome triplication followed by extensive diploidization. The availability of several crucifer genome sequences, especially that of Chinese cabbage (Brassica rapa), enables study of the evolution of the mesohexaploid Brassica genomes from their diploid progenitors. We reconstructed three ancestral subgenomes of B. rapa (n = 10) by comparing its whole-genome sequence to ancestral and extant Brassicaceae genomes. All three B. rapa paleogenomes apparently consisted of seven chromosomes, similar to the ancestral translocation Proto-Calepineae Karyotype (tPCK; n = 7), which is the evolutionarily younger variant of the Proto-Calepineae Karyotype (n = 7). Based on comparative analysis of genome sequences or linkage maps of Brassica oleracea, Brassica nigra, radish (Raphanus sativus), and other closely related species, we propose a two-step merging of three tPCK-like genomes to form the hexaploid ancestor of the tribe Brassiceae with 42 chromosomes. Subsequent diversification of the Brassiceae was marked by extensive genome reshuffling and chromosome number reduction mediated by translocation events and followed by loss and/or inactivation of centromeres. Furthermore, via interspecies genome comparison, we refined intervals for seven of the genomic blocks of the Ancestral Crucifer Karyotype (n = 8), thus revising the key reference genome for evolutionary genomics of crucifers. PMID- 23653474 TI - How a nested framework illuminates the challenges of comparative environmental analysis. PMID- 23653473 TI - oiwa, a female gametophytic mutant impaired in a mitochondrial manganese superoxide dismutase, reveals crucial roles for reactive oxygen species during embryo sac development and fertilization in Arabidopsis. AB - Reactive oxygen species (ROS) can function as signaling molecules, regulating key aspects of plant development, or as toxic compounds leading to oxidative damage. In this article, we show that the regulation of ROS production during megagametogenesis is largely dependent on MSD1, a mitochondrial Mn-superoxide dismutase. Wild-type mature embryo sacs show ROS exclusively in the central cell, which appears to be the main source of ROS before pollination. Accordingly, MSD1 shows a complementary expression pattern. MSD1 expression is elevated in the egg apparatus at maturity but is downregulated in the central cell. The oiwa mutants are characterized by high levels of ROS detectable in both the central cell and the micropylar cells. Remarkably, egg apparatus cells in oiwa show central cell features, indicating that high levels of ROS result in the expression of central cell characteristic genes. Notably, ROS are detected in synergid cells after pollination. This ROS burst depends on stigma pollination but precedes fertilization, suggesting that embryo sacs sense the imminent arrival of pollen tubes and respond by generating an oxidative environment. Altogether, we show that ROS play a crucial role during female gametogenesis and fertilization. MSD1 activity seems critical for maintaining ROS localization and important for embryo sac patterning. PMID- 23653477 TI - QnAs with Randolph Blake. PMID- 23653476 TI - Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis. AB - Deregulated Toll-like receptor (TLR)-triggered inflammatory responses that depend on NF-kappaB are detrimental to the host via excessive production of proinflammatory cytokines, including TNF-alpha. Stat2 is a critical component of type I IFN signaling, but it is not thought to participate in TLR signaling. Our study shows that LPS-induced lethality in Stat2(-/-) mice is accelerated as a result of increased cellular transmigration. Blocking intercellular adhesion molecule-1 prevents cellular egress and confers survival of Stat2(-/-) mice. The main determinant of cellular egress in Stat2(-/-) mice is the genotype of the host and not the circulating leukocyte. Surprisingly, lethality and cellular egress observed on Stat2(-/-) mice are not associated with excessive increases in classical sepsis cytokines or chemokines. Indeed, in the absence of Stat2, cytokine production in response to multiple TLR agonists is reduced. We find that Stat2 loss leads to reduced expression of NF-kappaB target genes by affecting nuclear translocation of NF-kappaB. Thus, our data reveal the existence of a different mechanism of LPS-induced lethality that is independent of NF-kappaB triggered cytokine storm but dependent on cellular egress. PMID- 23653479 TI - Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease. AB - Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD. PMID- 23653481 TI - A Huygens principle for diffusion and anomalous diffusion in spatially extended systems. AB - We present a universal view on diffusive behavior in chaotic spatially extended systems for anisotropic and isotropic media. For anisotropic systems, strong chaos leads to diffusive behavior (Brownian motion with drift) and weak chaos leads to superdiffusive behavior (Levy processes with drift). For isotropic systems, the drift term vanishes and strong chaos again leads to Brownian motion. We establish the existence of a nonlinear Huygens principle for weakly chaotic systems in isotropic media whereby the dynamics behaves diffusively in even space dimension and exhibits superdiffusive behavior in odd space dimensions. PMID- 23653480 TI - Engineering bone tissue substitutes from human induced pluripotent stem cells. AB - Congenital defects, trauma, and disease can compromise the integrity and functionality of the skeletal system to the extent requiring implantation of bone grafts. Engineering of viable bone substitutes that can be personalized to meet specific clinical needs represents a promising therapeutic alternative. The aim of our study was to evaluate the utility of human-induced pluripotent stem cells (hiPSCs) for bone tissue engineering. We first induced three hiPSC lines with different tissue and reprogramming backgrounds into the mesenchymal lineages and used a combination of differentiation assays, surface antigen profiling, and global gene expression analysis to identify the lines exhibiting strong osteogenic differentiation potential. We then engineered functional bone substitutes by culturing hiPSC-derived mesenchymal progenitors on osteoconductive scaffolds in perfusion bioreactors and confirmed their phenotype stability in a subcutaneous implantation model for 12 wk. Molecular analysis confirmed that the maturation of bone substitutes in perfusion bioreactors results in global repression of cell proliferation and an increased expression of lineage-specific genes. These results pave the way for growing patient-specific bone substitutes for reconstructive treatments of the skeletal system and for constructing qualified experimental models of development and disease. PMID- 23653483 TI - The findings of the Mid-Staffordshire Inquiry do not uphold the use of hospital standardized mortality ratios as a screening test for 'bad' hospitals. AB - The Mid-Staffordshire Public Inquiry has published its findings. The initial investigations were triggered by an elevated hospital standardized mortality ratio (HSMR). This shows that the HSMR is being used as a screening test for substandard care; whereby hospitals that fail the test are scrutinized, whilst those that pass the test are not. But screening tests are often misunderstood and misused and so it is prudent to critically examine the HSMR before casting it in the role of a screening test for 'bad' hospitals. A screening test should be valid, have adequate performance characteristics and a clear post-test action plan. The HSMR is not a valid screening test (because the empirical relationship between clinically avoidable mortality and the HSMR is unknown). The HSMR has a poor performance profile (10 of 11 elevated HSMRs would be false alarms and 10 of 11 poorly performing hospitals would escape attention). Crucially, the aim of a post-test investigation into an elevated HSMR is unclear. The use of the HSMR as a screening test for clinically avoidable mortality and thereby substandard care, although well intentioned, is seriously flawed. The findings of the Mid Staffordshire Public Inquiry have no bearing on this conclusion because a 'bad' hospital cannot uphold a bad screening test. Nonetheless, HSMRs continue to pose a grave public challenge to hospitals, whilst the unsatisfactory nature of the HSMR remains a largely unacknowledged and unchallenged private affair. This asymmetric relationship is inappropriate, unhelpful, costly and potentially harmful. The use of process measures remains a valid way to measure quality of care. PMID- 23653484 TI - Cause of death in Alzheimer's disease: a cohort study. AB - BACKGROUND: Reporting of cause of death in patients with Alzheimer's disease (AD) has changed over the past few decades but concerns persist over the accuracy of death certificate completion in this setting. OBJECTIVES: To examine the causes of death in AD and examine how this compares with those affecting the normal population. METHODS: Death certificates were obtained for 85 AD patients and 52 control subjects from a cohort of 396 participants. Underlying causes of death and other conditions mentioned on the death certificates of the AD patients were analysed and compared with the Northern Ireland population age-and-sex adjusted mortality rates and subsequently to the death certificates of control subjects. RESULTS: AD and pneumonia were causes of significant excess mortality and the most common underlying causes of death in the AD patient group (23.53 and 17.65%, respectively). When compared with the control subjects, AD and gastrointestinal diseases were found to be more prevalent. AD was recorded on 63.5% of death certificates of AD subjects who died during follow-up. CONCLUSION: The cause of death documented for AD patients may be affected by the physician's knowledge of the patient or reflects the approach to management of patients with end-stage dementia. PMID- 23653485 TI - Long-lived frequency shifts observed in a magnetic resonance force microscope experiment following microwave irradiation of a nitroxide spin probe. AB - We introduce a spin-modulation protocol for force-gradient detection of magnetic resonance that enables the real-time readout of longitudinal magnetization in an electron spin resonance experiment involving fast-relaxing spins. We applied this method to observe a prompt change in longitudinal magnetization following the microwave irradiation of a nitroxide-doped perdeuterated polystyrene film having an electron spin-lattice relaxation time of [Formula: see text]. The protocol allowed us to discover a large, long-lived cantilever frequency shift. Based on its magnitude, lifetime, and field dependence, we tentatively attribute this persistent signal to deuteron spin magnetization created via transfer of polarization from nitroxide spins. PMID- 23653486 TI - Laser-enhanced cavitation during high intensity focused ultrasound: An in vivo study. AB - Laser-enhanced cavitation during high intensity focused ultrasound (HIFU) was studied in vivo using a small animal model. Laser light was employed to illuminate the sample concurrently with HIFU radiation. The resulting cavitation was detected with a passive cavitation detector. The in vivo measurements were made under different combinations of HIFU treatment depths, laser wavelengths, and HIFU durations. The results demonstrated that concurrent light illumination during HIFU has the potential to enhance cavitation effect by reducing cavitation threshold in vivo. PMID- 23653487 TI - The magnetic, relaxometric, and optical properties of gadolinium-catalyzed single walled carbon nanotubes. AB - We report the magnetic behavior, relaxometry, phantom magnetic resonance imaging (MRI), and near-infrared (NIR) photoluminescence spectroscopy of gadolinium (Gd) catalyzed single-walled carbon nanotubes (Gd-SWCNTs). Gd-SWCNTs are paramagnetic with an effective magnetic moment of 7.29 MUB . Gd-SWCNT solutions show high r1 and r2 relaxivities at very low (0.01 MHz) to clinically relevant (61 MHz) magnetic fields (r1 >= 130 mM-1 s-1, r2 >= 160 mM-1 s-1). Analysis of nuclear magnetic resonance dispersion profiles using Solomon, Bloembergen, and Morgan equations suggests that multiple structural and dynamic parameters such as rotational correlation time [Formula: see text], rate of water exchange [Formula: see text], and the number of fast-exchanging water molecules within the inner sphere q may be responsible for the increase in r1 and r2 relaxivity. The T1 weighted MRI signal intensity (gradient echo sequence; repetition time (TR) = 66 ms, echo time (TE) = 3 ms, flop angle = 108 degrees ) of Gd-SWCNT phantom solution is 14 times greater than the Gd-based clinical MRI contrast agent Magnevist. Additionally, these nanotubes exhibit near infrared fluorescence with distinct E11 transitions of several semiconducting SWCNTs. Taken together, these results demonstrate that Gd-SWCNTs have potential as a novel, highly efficacious, multimodal MRI-NIR optical imaging contrast agent. PMID- 23653488 TI - Magnetic Compton scattering studies of magneto-dielectric Ba(Co0.85Mn0.15)O3 delta AB - We revealed that the Ba(Co0.85Mn0.15)O3-delta ceramic samples exhibited ferromagnetic-dielectric behavior below the magnetic transition temperature of about 35 K. The origin of their magnetic ordering was expected to super-exchange coupling of Co4+(d5)-O2--Mn4+(d3) with bonding angle of 180 degrees and/or Mn4+(d3)-O2--Mn4+(d3) with bonding angle of 90 degrees . The magnetic spin momentum estimated by the magnetic Compton profiles (MCP) of the samples had similar temperature dependence as that determined by the temperature dependence of magnetic moment by superconducting quantum interference device, which meant that the observed magnetic moments could be ascribed to the spin moment. The shapes of the MCPs of the samples were completely same regardless of the temperature measured. This result indicates that there are no changes of the momentum space distribution of spin density between ferromagnetic and paramagnetic states. So, this magnetic transition is simply caused by a thermal fluctuation of the spin. PMID- 23653489 TI - PREDICTING LATENT CLASS SCORES FOR SUBSEQUENT ANALYSIS. AB - Latent class regression models relate covariates and latent constructs such as psychiatric disorders. Though full maximum likelihood estimation is available, estimation is often in three steps: (i) a latent class model is fitted without covariates; (ii) latent class scores are predicted; and (iii) the scores are regressed on covariates. We propose a new method for predicting class scores that, in contrast to posterior probability-based methods, yields consistent estimators of the parameters in the third step. Additionally, in simulation studies the new methodology exhibited only a minor loss of efficiency. Finally, the new and the posterior probability-based methods are compared in an analysis of mobility/exercise. PMID- 23653490 TI - Advanced endoscopic imaging. PMID- 23653491 TI - Two new genera of nematode (Oxyurida, Hystrignathidae) parasites of Passalidae (Coleoptera) from the Democratic Republic of Congo. AB - Two new genera and species parasitizing passalid beetles from the Democratic Republic of Congo are described. Kongonema meyeri gen. n. sp. n. is characterized by having females with the cervical cuticle unarmed, first cephalic annule cone like and truncate, sub-cylindrical procorpus and genital tract didelphic amphidelphic. The males of Kongonema meyeri gen. n. sp. n. have the procorpus sub cylindrical, the dorsal cuticle of the tail end thickened, a single large, median mammiform pre-cloacal papilla and a pair of small, pre-cloacal, sub-lateral papillae at a short distance before the level of the cloaca. Lubanema decraemerae gen. n. sp. n. is characterized by the body markedly fusiform, cuticle unarmed and strongly annulated, procorpus sub-cylindrical, isthmus as a constriction between procorpus and basal bulb, genital tract monodelphic-prodelphic and the posterior end rounded with a very short tail appendage. PMID- 23653492 TI - The genus Brulleia Szepligeti (Hymenoptera, Braconidae, Helconinae) from China, with descriptions of four new species. AB - The species of the genus Brulleia Szepligeti, 1904 (Hymenoptera, Braconidae, Helconinae) from China are revised. Four new species, namely Brulleia fanjingensis YanandChen, sp. n., Brulleia longipalpis YanandChen, sp. n., Brulleia noncarinata YanandChen, sp. n. andBrulleia punctata Yan andChen, sp. n. are described and illustrated. A key to the Chinese species of the genus Brulleia is included. PMID- 23653493 TI - Molecular systematics of the genus Troglophilus (Rhaphidophoridae, Orthoptera) in Turkey: mitochondrial 16S rDNA evidences. AB - This study focuses on the evolutionary relationships among Turkish species of the cave cricket genus Troglophilus.Fifteen populations were studied for sequence variation in a fragment (543 base pairs) of the mitochondrial DNA (mtDNA) 16S rDNA gene (16S) to reconstruct their phylogenetic relationships and biogeographic history. Genetic data retrieved three main clades and at least three divergent lineages that could not be attributed to any of the taxa known for the area. Molecular time estimates suggest that the diversification of the group took place between the Messinian and the Plio-Pleistocene. PMID- 23653494 TI - Checklist of the ants (Hymenoptera, Formicidae) of the Solomon Islands and a new survey of Makira Island. AB - The intent of this paper is to facilitate future research of the Solomon Islands ant fauna by providing the first comprehensively researched species inventory in over 75 years. The species list presented here includes the names of all ant species recorded from the islands that are available in the literature together with specimen records from several museum collections and new records from our 2008 Makira field expedition. All the names of described species presented are valid in accordance with the most recent Formicidae classification. In total, the checklist is composed of 237 species and subspecies (including 30 morphospecies) in 59 genera representing nine subfamilies. We report that the recent field expedition added 67 new species records to Makira and 28 new species records to the Solomon Islands. Our research recovered species occurrence records for 32 individual islands and five island groups. The five islands with the highest number of recorded species are: Makira (142 spp.), Guadalcanal (107 spp.), Malaita (70 spp.), Santa Isabel (68 spp.), and Rennell (66 spp.). Based on our results, we discuss the taxonomic composition of the archipelago's ant fauna, which islands are most in need of additional sampling, and the importance of establishing biodiversity baselines before environmental threats such as the invasive ant Wasmannia auropunctata cause irrevocable harm to the native biodiversity. PMID- 23653495 TI - A new species of Aeneator Finlay, 1926 (Mollusca, Gastropoda, Buccinidae) from northern Chile, with comments on the genus and a key to the Chilean species. AB - A new species of the genus Aeneator Finlay, 1926 is described from off the coast of Caldera (27 degrees S), northern Chile. Aeneator martae sp. n. has a small, broad, stout, angulated shell with more prominent axial ribs and a more obviously keeled periphery than all previously named Chilean species. Comparisons are provided with all other South American named species of Aeneator. PMID- 23653496 TI - Ovicides paralithodis (Nemertea, Carcinonemertidae), a new species of symbiotic egg predator of the red king crab Paralithodes camtschaticus (Tilesius, 1815) (Decapoda, Anomura). AB - Ovicides paralithodis sp. n. is described from the egg mass of the red king crab Paralithodes camtschaticus (Tilesius, 1815) from the Sea of Okhotsk, off Hokkaido, Japan, and Alaska, USA. Among four congeners, Ovicides paralithodis can be distinguished from Ovicides julieae Shields, 2001 and Ovicides davidi Shields and Segonzac, 2007 by having no eyes; from Ovicides jonesi Shields and Segonzac, 2007 by the presence of basophilic, vacuolated glandular lobes in the precerebral region; and from Ovicides jasoni Shields and Segonzac, 2007 by the arrangement of the acidophilic submuscular glands, which are not arranged in a row. Ovicides paralithodis represents the third described species of egg-predatory nemertean from Paralithodes camtschaticus, the second described carcinonemertid species from Japan, and the 21st described species in the family. The intensity of infestations may exceed 24,000 worms per a single egg-bearing pleopod of Paralithodes camtschaticus. A preliminary molecular phylogenetic analysis based on sequences of 28S rRNA and cytochrome c oxidase subunit I genes among selected monostiliferous hoplonemertean species supported the monophyly of Carcinonemertidae, suggesting that within the lineage of the family, evolution of the unique vas deferens, Takakura's duct, preceded loss of accessory stylets and accessory-stylet pouches. PMID- 23653497 TI - A redescription of Rhysida celeris (Humbert & Saussure, 1870), with a proposal of eight new synonyms (Scolopendromorpha, Scolopendridae, Otostigminae). AB - Seven species of the genus Rhysida Wood, 1862 from Venezuela and one subspecies from Peru described by Manuel Angel Gonzalez Sponga and Wolfgang Bucherl respectively, are revised. Rhysida caripensis Gonzalez-Sponga, 2002, Rhysida neoespartana Gonzalez-Sponga, 2002, Rhysida guayanica Gonzalez-Sponga, 2002, Rhysida maritima Gonzalez-Sponga, 2002, Rhysida monaguensis Gonzalez-Sponga, 2002, Rhysida porlamarensis Gonzalez-Sponga 2002, Rhysida sucupanensis Gonzalez Sponga, 2002 and Rhysida celeris andina Bucherl, 1953 are junior synonyms of Rhysida celeris (Humbert & Saussure, 1870), which is redescribed and illustrated for the first time. Its geographic distribution is updated and a map showing its distribution is presented. PMID- 23653498 TI - Initial responses of rove and ground beetles (Coleoptera, Staphylinidae, Carabidae) to removal of logging residues following clearcut harvesting in the boreal forest of Quebec, Canada. AB - Increased interest in biomass harvesting for bioenergetic applications has raised questions regarding the potential ecological consequences on forest biodiversity. Here we evaluate the initial changes in the abundance, species richness and community composition of rove (Staphylinidae) and ground beetles (Carabidae), immediately following 1) stem-only harvesting (SOH), in which logging debris (i.e., tree tops and branches) are retained on site, and 2) whole-tree harvesting (WTH), in which stems, tops and branches are removed in mature balsam fir stands in Quebec, Canada. Beetles were collected throughout the summer of 2011, one year following harvesting, using pitfall traps. Overall catch rates were greater in uncut forest (Control) than either stem-only or whole-tree harvested sites. Catch rates in WTH were greater than SOH sites. Uncut stands were characterized primarily by five species: Atheta capsularis, Atheta klagesi, Atheta strigosula, Tachinus fumipennis/frigidus complex (Staphylinidae) and to a lesser extent to Pterostichus punctatissimus(Carabidae). Increased catch rates in WTH sites, where post-harvest biomass was less, were attributable to increased catches of rove beetles Pseudopsis subulata, Quedius labradorensis and to a lesser extent Gabrius brevipennis. We were able to characterize differences in beetle assemblages between harvested and non-harvested plots as well as differences between whole tree (WTH) and stem only (SOH) harvested sites where logging residues had been removed or left following harvest. However, the overall assemblage response was largely a recapitulation of the responses of several abundant species. PMID- 23653499 TI - Hispaniolan hemilophini (coleoptera, cerambycidae, lamiinae). AB - The Tribe Hemilophini (Lamiinae) is reviewed for Hispaniola and an identification key is provided. Fifteen species are now known from the island, including one new species of Adesmus (Adesmus fortunei from Pedernales and La Vega Provinces, Dominican Republic), one new species of Oedudes (Oedudes anulatus from Peravia and La Vega Provinces, Dominican Republic), and five new species of Calocosmus (Calocosmus contortus from San Cristobal Province, Calocosmus punctatus from Peravia Province, Calocosmus rawlinsi from Elias Pina Province, Calocosmus robustus from La Vega Province, and Calocosmus thonalmus from La Altagracia Province, all in the Dominican Republic). Oedudes and Adesmus are new island and country records for Hispaniola and Dominican Republic, respectively. Calocosmus holosericeus Gahan is a new synonym of Calocosmus janus Bates. In addition to the new species, five new country records and four new island records are presented for Calocosmus. PMID- 23653500 TI - Cochylis Treitschke in China: one new species and five new records (Lepidoptera, Tortricidae, Cochylini). AB - Six species of Cochylis Treitschke, 1829 are recorded for China. Among them, Cochylis triangula sp. n. is described as new; Cochylis atricapitana (Stephens, 1852), Cochylis discerta Razowski, 1970, Cochylis dubitana (Hubner, [1799]), Cochylis faustana (Kennel, 1919) and Cochylis posterana hyrcana (Toll, 1948) are recorded for the first time for China. The female of Cochylis discerta Razowski, 1970 is described for the first time. Adults and genitaliaare illustrated, a key is given for the identification of Chinese species based on male genitalia. PMID- 23653501 TI - A taxonomic revision of the Cymindis (Pinacodera) limbata species group (Coleoptera, Carabidae, Lebiini), including description of a new species from Florida, U.S.A. AB - The Cymindis (Pinacodera) limbata species group (Coleoptera, Carabidae, Lebiini) is a precinctive New World taxon with ranges extended from portions of temperate southeastern Canada and the U.S.A. through the montane regions of Mexico, south to the Isthmus of Tehuantepec. The group is distinguishable from all other members of the subgenus Pinacodera by males possessing a distinctive sclerite (endophallic plate) at the apex of the endophallus. In the past, a lack of material and misunderstandings of range of variation within species have contributed to confusion about how many species there really are. This revision of the limbata species group includes a classification, a key to groups within the subgenus Pinacodera and species within the limbata group, descriptions of species, re-rankings and new synonymies. In total 10 taxa are treated, with 6 new synonyms proposed, 1 new combination introduced and 1 new species described: Cymindis (Pinacodera) rufostigma (type locality: Archbold Biological Station, Highlands County, Florida, U.S.A.). Each taxon is characterized in terms of structural features of adults, habitat, geographical distribution, and chorological affinities. Available ecological information and treatments of variation are included. PMID- 23653502 TI - First record of Acrocyrtus Yosii, 1959 (Collemobla, Entomobryidae) from Chinese mainland. AB - The genus Acrocrytus is reported from Chinese mainland for the first time, with description of two new species Acrocyrtus zhujiensis sp. n. and Acrocyrtus finis sp. n. from Zhejiang Province, East China. They can be separated from other species of this genus by colour pattern, unscaled appendages (antennae, legs and ventral tube), interocular chaetae, labial basal chaetae, bothriotrichal complex chaetae on Abd. II-IV, microchaeta a2 on Abd. II, im on Abd. III and C1p on Abd. IV. Illustrations and a table showing main differences with closest Acrocyrtus species are provided. PMID- 23653503 TI - Description of Lentistivalius philippinensis, a new species of flea (Siphonaptera, Pygiosyllomorpha, Stivaliidae), and new records of Ascodipterinae (Streblidae) on bats and other small mammals from Luzon, The Philippines. AB - During May 2009 and July 2011, we collected 357 mammals and examined each for ectoparasites. Among the ectoparasites collected, a new species of flea was discovered. This new species, Lentistivalius philippinensis, is described from the male sex only. Two males were recovered from two specimens of the soricid Crocidura grayi Dobson in Municipality Maria Aurora, Aurora Province, Luzon, Philippines. Additional fleas included Thaumapsylla breviceps orientalis Smit, Thaumapsylla longiforceps Traub, and Ischnopsyllus indicus Jordan. Although the latter species is common in Japan and documented in Guam (as well as mainland Southeast Asia) also on Pipistrellus javanicus (Gray), Ischnopsyllus indicus represents a new record in the Philippine Islands. The ascodipterinae (Streblidae) Maabella stomalata and Ascodipteron speiserianum Muir collected from Rhinolophus inops K. Andersen and Rhinolophus subrufus K. Andersen, respectively, also represent new host records. A key to the species of the flea genus Lentistivalius Traub is provided. PMID- 23653504 TI - A description of preimaginal stages of Pseudaspidapion botanicum Alonso-Zarazaga & Wang, 2011 (Apionidae, Curculionoidea). AB - The preimaginal stages including egg, mature larva and pupa of Pseudaspidapion botanicum Alonso-Zarazaga & Wang, 2011 were described and figured, diagnostic characters of larva and pupa were discussed, and corresponding biological information was supplied. The nomenclature of frontal setae in the larva compared with curculionid weevils, the absence of the hypopharyngeal bracon in the larva, and the metafemoral setae in the pupa were discussed. Common and different characters among the larvae of Pseudaspidapion botanicum, Aspidapion radiolus (Marsham, 1802) and Aspidapion aeneum (Fabricius, 1775) were also provided. PMID- 23653505 TI - New western Palaearctic Dinotrema species with mesoscutal pit and only medially sculptured propodeum (Hymenoptera, Braconidae, Alysiinae). AB - Descriptions of four new species of the genus Dinotrema Foerster with a mesoscutal pit and only medially sculptured propodeum are given. Dinotrema alysiae sp. n. (Denmark, England, Netherlands, Spain), Dinotrema paramicum sp. n. (Denmark, Finland), Dinotrema tirolense sp. n. (Italy) and Dinotrema valvulatum sp. n. (Denmark, Italy). PMID- 23653506 TI - Two new species of Membranacea Qin & Zhang from China (Hemiptera, Cicadellidae, Typhlocybinae, Empoascini). AB - Two new species of the empoascine leafhopper genus Membranacea Qin & Zhang are reported from China: Membranacea hubeiensis Yu & Yang, sp. n. and Membranacea stenoprocessa Yu & Yang, sp. n.. A key to distinguish all species of the genus is provided. PMID- 23653507 TI - Gastrocopta (Mollusca, Gastropoda, Pupillidae) in the Pilbara region of Western Australia. AB - Six species of Gastrocopta have been identified from the Pilbara region, Western Australia, by means of comparative analyses of shell and mtDNA variation. Three of these species, Gastrocopta hedleyi, Gastrocopta larapinta and Gastrocopta servilis, have been recorded in the Pilbara for the first time. Gastrocopta sp. CW1 is probably new to science and might be endemic to the region. By contrast, Gastrocopta hedleyi, Gastrocopta larapinta and Gastrocopta mussoni are shown to be widespread. PMID- 23653508 TI - The first euthemistid damsel-dragonfly from the Middle Jurassic of China (Odonata, Epiproctophora, Isophlebioptera). AB - Sinoeuthemis daohugouensis gen. et sp. n. is the first record of the isophlebiopteran family Euthemistidae from Middle Jurassic of northeast China, while previously this family was restricted to the early Late Jurassic Kazakhstan. This new finding allows us to emend the family diagnosis with hindwing characters. This new species shows a mixture of characters alternatively present in different genera of the two families Euthemistidae and Sphenophlebiidae. PMID- 23653509 TI - Two new species of Dacne Latreille (Coleoptera, Erotylidae) from China, with a key to Chinese species and subspecies of Dacne. AB - Two new species Dacne (Xenodacne) tangliangi sp. n. andDacne (Xenodacne) hujiayaoi sp. n. are described from China. A key to Chinese species and subspecies of genus Dacne Latreille is provided. PMID- 23653510 TI - An illustrated key to and diagnoses of the species of Histeridae (Coleoptera) associated with decaying carcasses in Argentina. AB - A key to 16 histerid species associated with decaying carcasses in Argentina is presented, including diagnoses and habitus photographs for these species. This article provides a table of all species associated with carcasses, detailing the substrate from which they were collected and geographical distribution by province. All 16 Histeridae species registered are grouped into three subfamilies: Saprininae (twelve species of Euspilotus Lewis and one species of Xerosaprinus Wenzel), Histerinae (one species of Hololepta Paykull and one species of Phelister Marseul) and Dendrophilinae (one species of Carcinops Marseul). Two species are new records for Argentina: Phelister rufinotus Marseuland Carcinops troglodytes (Paykull). A discussion is presented on the potential forensic importance of some species collected on human and pig carcasses. PMID- 23653513 TI - On newly and recently recorded species of the genus Lema Fabricius (Coleoptera, Chrysomelidae, Criocerinae) from Taiwan. AB - New records of four species (Lema lacertosa Lacordaire, 1845, Lema diversipes Pic, 1921, Lema cyanella (Linnaeus, 1758), Lema trivittata trivittata Say, 1824 and additional information on one recently recorded species (Lema solani Fabricius, 1798) are reported for Taiwan. Lema diversipes Pic, 1921 is removed from synonymy with Lema lacertosa Lacordaire, 1845; both species are redescribed. A lectotype is designated for Lema phungi Pic, 1924. The synonymies of Lema phungi Pic, 1924 and Lema jeanvoinei Pic, 1932 with Lema lacertosa Lacordaire, 1845 are supported. A revised key to the known species in Taiwan is provided. PMID- 23653512 TI - Hymenopteran parasitoids of the ant-eating spider Zodarion styliferum (Simon) (Araneae, Zodariidae). AB - Calymmochilus dispar Boucek & Andriescu (Hymenoptera, Eupelmidae) and Gelis apterus (Pontoppidan) (Hymenoptera, Ichneumonidae) are newly recorded as parasitoids of the ant-eating spider Zodarion styliferum (Simon) (Araneae, Zodariidae). The larvae of both parasitoid species fed on juvenile spiders. The final instar larva and pupa of Calymmochilus dispar and the male of Gelis apterus are described for the first time. Both species represent new distribution records for Portugal. The biology and host associations of the parasitoids are discussed. PMID- 23653514 TI - Larvae of five horticulturally important species of Chrysopodes (Neuroptera, Chrysopidae): shared generic features, descriptions and keys. AB - An expanded list of generic level larval characteristics is presented for Chrysopodes; it includes a reinterpretation of the mesothoracic and metathoracic structure and setation. Keys, descriptions and images of Semaphoront A (first instar) and Semaphoront B (second and third instars) are offered for identifying five species of Chrysopodes (Chrysopodes) that are commonly reported from horticultural habitats in the Neotropical region. PMID- 23653515 TI - Micro-computed tomography: Introducing new dimensions to taxonomy. AB - Continuous improvements in the resolution of three-dimensional imaging have led to an increased application of these techniques in conventional taxonomic research in recent years. Coupled with an ever increasing research effort in cybertaxonomy, three-dimensional imaging could give a boost to the development of virtual specimen collections, allowing rapid and simultaneous access to accurate virtual representations of type material. This paper explores the potential of micro-computed tomography (X-ray micro-tomography), a non-destructive three dimensional imaging technique based on mapping X-ray attenuation in the scanned object, for supporting research in systematics and taxonomy. The subsequent use of these data as virtual type material, so-called "cybertypes", and the creation of virtual collections lie at the core of this potential. Sample preparation, image acquisition, data processing and presentation of results are demonstrated using polychaetes (bristle worms), a representative taxon of macro-invertebrates, as a study object. Effects of the technique on the morphological, anatomical and molecular identity of the specimens are investigated. The paper evaluates the results and discusses the potential and the limitations of the technique for creating cybertypes. It also discusses the challenges that the community might face to establish virtual collections. Potential future applications of three dimensional information in taxonomic research are outlined, including an outlook to new ways of producing, disseminating and publishing taxonomic information. PMID- 23653516 TI - Two new species of Lecithoceridae (Lepidoptera, Gelechioidea), with a revised check list of the family in Taiwan. AB - Two species of Lecithoceridae (Lepidoptera, Gelechioidea), Caveana senuri sp. n. and Lecithocera dondavisi sp. n., are described from Taiwan. The monotypic Caveana Park was described from Thailand, based on Caveana diemseoki Park, 2011. Lecithocera Herrich-Schaffer, 1853 is the most diverse genus of the family, comprising more than 300 species worldwide. Lecithocera dondavisi sp. n. is the largest species of the genus so far, and closely resembles the Indian species, Lecithocera praeses Meyrick, 1919. A revised check list of the family in Taiwan is provided. PMID- 23653517 TI - Further notes on New Zealand Enantiobuninae (Opiliones, Neopilionidae), with the description of a new genus and two new species. AB - Mangatangi parvum gen. n. and sp. and Forsteropsalis pureroa sp. n. are described from the North Island of New Zealand. Pantopsalis listeri (White 1849) and Pantopsalis cheliferoides (Colenso 1882) are redescribed and no longer regarded as nomina dubia; Pantopsalis luna (Forster 1944) is identified as a junior synonym of Pantopsalis listeri. A key to Pantopsalis species is provided. PMID- 23653518 TI - The semi-aquatic freshwater earthworms of the genus Glyphidrilus Horst, 1889 from Thailand (Oligochaeta, Almidae) with re-descriptions of several species. AB - The semi-aquatic freshwater earthworm genus Glyphidrilus Horst, 1889 from Thailand was investigated based on extensive recent collecting. The species in this genus were characterized by their external and internal morphological characters of the location of wings, genital openings, genital organ structures and their locations, as well as the dimensions of body length and number of segments. Several type specimens were compared with both previous and newly collected materials. Ten new species are described from several river systems in Thailand; as Glyphidrilus borealis sp. n., Glyphidrilus chaophraya sp. n., Glyphidrilus chiensis sp. n., Glyphidrilus huailuangensis sp. n., Glyphidrilus kratuensis sp. n., Glyphidrilus quadratus sp. n., Glyphidrilus trangensis sp. n., Glyphidrilus wararamensis sp. n., Glyphidrilus vangthongensis sp. n. and Glyphidrilus vesper sp. n. Each species is endemic to a single river system. All 26 previously described species are re-described, and eight lectotypes have been designated. An identification key and a morphological comparison summary are provided. PMID- 23653519 TI - The amphibians and reptiles of Luzon Island, Philippines, VIII: the herpetofauna of Cagayan and Isabela Provinces, northern Sierra Madre Mountain Range. AB - We provide the first report on the herpetological biodiversity (amphibians and reptiles) of the northern Sierra Madre Mountain Range (Cagayan and Isabela provinces), northeast Luzon Island, Philippines. New data from extensive previously unpublished surveys in the Municipalities of Gonzaga, Gattaran, Lasam, Santa Ana, and Baggao (Cagayan Province), as well as fieldwork in the Municipalities of Cabagan, San Mariano, and Palanan (Isabela Province), combined with all available historical museum records, suggest this region is quite diverse. Our new data indicate that at least 101 species are present (29 amphibians, 30 lizards, 35 snakes, two freshwater turtles, three marine turtles, and two crocodilians) and now represented with well-documented records and/or voucher specimens, confirmed in institutional biodiversity repositories. A high percentage of Philippine endemic species constitute the local fauna (approximately 70%). The results of this and other recent studies signify that the herpetological diversity of the northern Philippines is far more diverse than previously imagined. Thirty-eight percent of our recorded species are associated with unresolved taxonomic issues (suspected new species or species complexes in need of taxonomic partitioning). This suggests that despite past and present efforts to comprehensively characterize the fauna, the herpetological biodiversity of the northern Philippines is still substantially underestimated and warranting of further study. PMID- 23653520 TI - Endemism of subterranean Diacyclops in Korea and Japan, with descriptions of seven new species of the languidoides-group and redescriptions of D. brevifurcus Ishida, 2006 and D. suoensis Ito, 1954 (Crustacea, Copepoda, Cyclopoida). AB - Copepods have been poorly studied in subterranean habitats in Korea. Previous records have indicated mostly the presence of species already described from Japan, with very few endemic elements. This commonality has usually been explained by repeated dispersal across the land bridges that connected the two countries several times during the Pleistocene glacial cycles. However, the Korean Peninsula is known for pockets of Cambrian and Ordovician carbonate rocks, with more than 1,000 caves already having been explored. The relative isolation of these carbonate pockets makes for an enormous speciation potential, and the development of a high level of short-range endemism of subterranean copepods should be expected. Representatives of the genus Diacyclops Kiefer, 1927 are here investigated from a range of subterranean habitats in South Korea, with comparative material sampled from central Honshu in Japan. Morphological analyses of microcharacters, many of which are used in cyclopoid taxonomy for the first time herein, reveal high diversity in both countries. No subterranean species is found in common, although the existence of four sibling species pairs in Korea and Japan may be indicative of relatively recent speciation. We describe seven new stygobiotic species, including three from Korea (Diacyclops hanguk sp. n., Diacyclops leeae sp. n., and Diacyclops parasuoensis sp. n.) and four from Japan (Diacyclops hisuta sp. n., Diacyclops ishidai sp. n., Diacyclops parahanguk sp. n., and Diacyclops pseudosuoensis sp. n.). Diacyclops hanguk, Diacyclops parasuoensis, Diacyclops ishidai, and Diacyclops parahanguk are described from newly collected material, while the other three new species are proposed for specimens previously identified as other, widely distributed species. Diacyclops brevifurcus Ishida, 2006 is redescribed from the holotype female, and Diacyclops suoensis Ito, 1954 is redescribed from material newly collected near the ancient Lake Biwa in Japan. This research provides evidence for the importance of subterranean habitats as reservoirs of biodiversity, and also demonstrates the inadequacy of current morphological methods of identifying closely related species of copepods. The disproportionately high diversity discovered around Lake Biwa provides further evidence in support of the hypothesis about the role of ancient lakes as biodiversity pumps for subterranean habitats. A key to the East Asian species of the languidoides-group is provided. PMID- 23653521 TI - Revision of the subfamily Opiinae (Hymenoptera, Braconidae) from Hunan (China), including thirty-six new species and two new genera. AB - The species of the subfamily Opiinae (Hymenoptera: Braconidae) from Hunan (Oriental China) are revised and illustrated. Thirty-six new species are described: Apodesmia bruniclypealis Li & van Achterberg, sp. n., Apodesmia melliclypealis Li & van Achterberg, sp. n., Areotetes albiferus Li & van Achterberg, sp. n., Areotetes carinuliferus Li & van Achterberg, sp. n., Areotetes striatiferus Li & van Achterberg, sp. n., Coleopioides diversinotum Li & van Achterberg, sp. n., Coleopioides postpectalis Li & van Achterberg, sp. n., Fopius dorsopiferus Li, van Achterberg & Tan, sp. n., Indiopius chenae Li & van Achterberg, sp. n., Opiognathus aulaciferus Li & van Achterberg, sp. n., Opiognathus brevibasalis Li & van Achterberg, sp. n., Opius crenuliferus Li & van Achterberg, sp. n., Opius malarator Li, van Achterberg & Tan, sp. n., Opius monilipalpis Li & van Achterberg, sp. n., Opius pachymerus Li & van Achterberg, sp. n., Opius songi Li & van Achterberg, sp. n., Opius youi Li & van Achterberg, sp. n., Opius zengi Li & van Achterberg, sp. n., Phaedrotoma acuticlypeata Li & van Achterberg, sp. n., Phaedrotoma angiclypeata Li & van Achterberg, sp. n., Phaedrotoma antenervalis Li & van Achterberg, sp. n., Phaedrotoma depressiclypealisLi & van Achterberg, sp. n., Phaedrotoma flavisoma Li & van Achterberg, sp. n., Phaedrotoma nigrisoma Li & van Achterberg, sp. n., Phaedrotoma protuberator Li & van Achterberg, sp. n., Phaedrotoma rugulifera Li & van Achterberg, sp. n., Li & van Achterberg,Phaedrotoma striatinota Li & van Achterberg, sp. n., Phaedrotoma vermiculifera Li & van Achterberg, sp. n., Rhogadopsis latipennis Li & van Achterberg, sp. n., Rhogadopsis longicaudifera Li & van Achterberg, sp. n., Rhogadopsis maculosa Li, van Achterberg & Tan, sp. n., Rhogadopsis obliqua Li & van Achterberg, sp. n., Rhogadopsis sculpturator Li & van Achterberg, sp. n., Utetes longicarinatus Li & van Achterberg, sp. n. and Xynobius notauliferus Li & van Achterberg, sp. n. Areotetes van Achterberg & Li, gen. n. (type species: Areotetes carinuliferus sp. n.) and Coleopioides van Achterberg & Li, gen. n. (type species: Coleopioides postpectalis sp. n. are described. All species are illustrated and keyed. In total 30 species of Opiinae are sequenced and the cladograms are presented. Neopius Gahan, 1917, Opiognathus Fischer, 1972, Opiostomus Fischer, 1972, and Rhogadopsis Brethes, 1913, are treated as a valid genera based on molecular and morphological differences. Opius vittata Chen & Weng, 2005 (not Opius vittatus Ruschka, 1915), Opius ambiguus Weng & Chen, 2005 (not Wesmael, 1835) and Opius mitis Chen & Weng, 2005 (not Fischer, 1963) are primary homonymsandarerenamed into Phaedrotoma depressa Li & van Achterberg, nom. n., Opius cheni Li & van Achterberg, nom. n. andOpius wengi Li & van Achterberg, nom. n., respectively. Phaedrotoma terga (Chen & Weng, 2005) comb. n.,Diachasmimorpha longicaudata (Ashmead, 1905) and Biosteres pavitita Chen & Weng, 2005, are reported new for Hunan, Opiostomus aureliae (Fischer, 1957) comb. n. is new for China and Hunan; Xynobius maculipennis(Enderlein, 1912) comb. n. is new for Hunan and continental China and Rhogadopsis longuria (Chen & Weng, 2005) comb. n. is new for Hunan. The following new combinations are given: Apodesmia puncta (Weng & Chen, 2005) comb. n., Apodesmia tracta (Weng & Chen, 2005) comb. n., Areotetes laevigatus (Weng & Chen, 2005) comb. n., Phaedrotoma dimidia (Chen & Weng, 2005) comb. n., Phaedrotoma improcera (Weng & Chen, 2005) comb. n., Phaedrotoma amputata (Weng & Chen, 2005) comb. n., Phaedrotoma larga (Weng & Chen, 2005) comb. n., Phaedrotoma osculas (Weng & Chen, 2005) comb. n., Phaedrotoma postuma (Chen & Weng, 2005) comb. n., Phaedrotoma rugulosa (Chen & Weng, 2005) comb. n., Phaedrotoma tabularis (Weng & Chen, 2005) comb. n., Rhogadopsis apii (Chen & Weng, 2005) comb. n., Rhogadopsis dimidia (Chen & Weng, 2005) comb. n., Rhogadopsis diutia (Chen & Weng, 2005) comb. n., Rhogadopsis longuria (Chen & Weng, 2005) comb. n., Rhogadopsis pratellae (Weng & Chen, 2005) comb. n., Rhogadopsis pratensis (Weng & Chen, 2005) comb. n., Rhogadopsis sculpta (Chen & Weng, 2005) comb. n., Rhogadopsis sulcifer (Fischer, 1975) comb. n., Rhogadopsis tabidula(Weng & Chen, 2005) comb. n., Xynobius complexus (Weng & Chen, 2005) comb. n., Xynobius indagatrix (Weng & Chen, 2005) comb. n., Xynobius multiarculatus (Chen & Weng, 2005) comb. n. THE FOLLOWING (SUB)GENERA ARE SYNONYMISED: Snoflakopius Fischer, 1972, Jucundopius Fischer, 1984, Opiotenes Fischer, 1998, and Oetztalotenes Fischer, 1998, with Opiostomus Fischer, 1971; Xynobiotenes Fischer, 1998, with Xynobius Foerster, 1862; Allotypus Foerster, 1862, Lemnaphilopius Fischer, 1972, Agnopius Fischer, 1982, and Cryptognathopius Fischer, 1984, with Apodesmia Foerster, 1862; Nosopoea Foerster, 1862, Tolbia Cameron, 1907, Brachycentrus Szepligeti, 1907, Baeocentrum Schulz, 1911, Hexaulax Cameron, 1910, Coeloreuteus Roman, 1910, Neodiospilus Szepligeti, 1911, Euopius Fischer, 1967, Gerius Fischer, 1972, Grimnirus Fischer, 1972, Hoenirus Fischer, 1972, Mimirus Fischer, 1972, Gastrosema Fischer, 1972, Merotrachys Fischer, 1972, Phlebosema Fischer, 1972, Neoephedrus Samanta, Tamili, Saha & Raychaudhuri, 1983, Adontopius Fischer, 1984, Kainopaeopius Fischer, 1986, Millenniopius Fischer, 1996, and Neotropopius Fischer, 1999, with Phaedrotoma Foerster, 1862. PMID- 23653522 TI - A new species of Callispa Baly (Coleoptera, Chrysomelidae, Cassidinae, Callispini) infesting coconut palm ( Cocos nucifera L.) in India. AB - Callispa keram sp. n. infesting coconut palm (Cocos nucifera L.) in Kerala, India is described and illustrated. Livistona chinensis R.Br. and Syagrus romanzoffiana (Cham.) Glassman are reported as additional host plants. PMID- 23653523 TI - Review of the palaearctic acomopterella zaitzev (Diptera, sciaroidea, mycetophilidae). AB - The distribution of Acomopterella species in the Palaearctic region has been re examined in this study, using recently collected material. The European species was found to be distributed in the eastern Palaearctic as well. A second Palaearctic species from Honshu (Japan) is herein described. The morphology of adult specimens was studied by light microscopy and scanning electron microscopy. The shape of functional specialized setae on mid tibiae in Acomopterella and seven further fungus gnat genera is described and the suitability of this character for systematic studies is discussed. Details of a "hind tibial organ" are described. The position of Acomopterella in the tribe Gnoristini is briefly discussed. Acomopterella is found to be more closely related to Speolepta Edwards, 1925, than to any other recent genus. PMID- 23653524 TI - Key for European species of the Cheilosia proxima group (Diptera, Syrphidae) with a description of a new species. AB - A new hoverfly species, Cheilosia barbafacies Vujic & Radenkovic sp. n. (Diptera, Syrphidae), is described and distinguished from the closely related species Cheilosia pascuorum Becker, 1894, based on material collected from the mountains of the Balkan Peninsula. Diagnostic characteristics and an identification key for the members of the proxima group of Cheilosia s. str., including the new taxon, are provided. PMID- 23653525 TI - New continental record and new species of Austromerope (Mecoptera, Meropeidae) from Brazil. AB - A new species of Meropeidae (Mecoptera) from Brazil, Austromerope brasiliensis sp. n., is described, representing only the 3rd extant species described in this family and the 1st record of the family from the Neotropical region. The distribution and biogeography of the family are discussed and we propose that Meropeidae originated before continental drift and then divided into two branches, northern and southern, with the breakup of Pangea. Identification keys for the Neotropical families of Mecoptera and for the species of Meropeidae are provided. PMID- 23653526 TI - A new species of Nicon Kinberg, 1866 (Polychaeta, Nereididae) from Ecuador, Eastern Pacific, with a key to all known species of the genus. AB - A new species of Nicon Kinberg, 1866 from the east Pacific coast of Ecuador is described. The new species is characterized by a long, thin dorsal ligule on median and posterior parapodia and infracicular sesquigomph falcigers in the neuropodia. A key to all species of Nicon is provided. PMID- 23653527 TI - The equilibria of vesicles adhered to substrates by short-ranged potentials. AB - In equilibrium, a vesicle that is adhered to a horizontal substrate by a long range attractive, short-range repulsive force traps a thin layer of fluid beneath it. In the asymptotic limit that this layer is very thin, there are quasi-two dimensional boundary-layer structures near the edges of the vesicle, where the membrane's shape is governed by a balance between bending and adhesive stresses. These boundary layers are analysed to obtain corrections to simpler models that instead represent the adhesive interaction by a contact potential, thereby resolving apparent discontinuities that arise when such models are used. Composite expansions of the shapes of two-dimensional vesicles are derived. When, in addition, the adhesive interaction is very strong, there is a nested boundary layer structure for which the adhesive boundary layers match towards sharp corners where bending stresses remain important but adhesive stresses are negligible. Outside these corners, bending stresses are negligible and the vesicle's shape is given approximately by the arc of a circle. Simple composite expansions of the vesicle's shape are derived that account for the shape of the membrane inside these corners. PMID- 23653528 TI - Archaeal viruses, not archaeal phages: an archaeological dig. AB - Viruses infect members of domains Bacteria, Eukarya, and Archaea. While those infecting domain Eukarya are nearly universally described as "Viruses", those of domain Bacteria, to a substantial extent, instead are called "Bacteriophages," or "Phages." Should the viruses of domain Archaea therefore be dubbed "Archaeal phages," "Archaeal viruses," or some other construct? Here we provide documentation of published, general descriptors of the viruses of domain Archaea. Though at first the term "Phage" or equivalent was used almost exclusively in the archaeal virus literature, there has been a nearly 30-year trend away from this usage, with some persistence of "Phage" to describe "Head-and-tail" archaeal viruses, "Halophage" to describe viruses of halophilic Archaea, use of "Prophage" rather than "Provirus," and so forth. We speculate on the root of the early 1980's transition from "Phage" to "Virus" to describe these infectious agents, consider the timing of introduction of "Archaeal virus" (which can be viewed as analogous to "Bacterial virus"), identify numerous proposed alternatives to "Archaeal virus," and also provide discussion of the general merits of the term, "Phage." Altogether we identify in excess of one dozen variations on how the viruses of domain Archaea are described, and document the timing of both their introduction and use. PMID- 23653529 TI - Secondary circulating prostate cells predict biochemical failure in prostate cancer patients after radical prostatectomy and without evidence of disease. AB - INTRODUCTION: Although 90% of prostate cancer is considered to be localized, 20% 30% of patients will experience biochemical failure (BF), defined as serum PSA >0.2 ng/mL, after radical prostatectomy (RP). The presence of circulating prostate cells (CPCs) in men without evidence of BF may be useful to predict patients at risk for BF. We describe the frequency of CPCs detected after RP, relation with clinicopathological parameters, and association with biochemical failure. METHODS AND PATIENTS: Serial blood samples were taken during followup after RP, mononuclear cells were obtained by differential gel centrifugation, and CPCs identified using standard immunocytochemistry using anti-PSA monoclonal antibodies. Age, pathological stage (organ confined, nonorgan confined), pathological grade, margin status (positive, negative), extracapsular extension, perineural, vascular, and lymphatic infiltration (positive, negative) were compared with the presence/absence of CPCs and with and without biochemical failure. Kaplan Meier methods were used to compare the unadjusted biochemical failure free survival of patients with and without CPCs. RESULTS: 114 men participated, and secondary CPCs were detected more frequently in patients with positive margins, extracapsular extension, and vascular and lymphatic infiltration and were associated with biochemical failure independent of these clinicopathological variables, and with a shorter time to BF. CONCLUSIONS: Secondary CPCs are an independent risk factor associated with increased BF in men with a PSA <0.2 ng/mL after radical prostatectomy, but do not determine if the recurrence is due to local or systemic disease. These results warrant larger studies to confirm the findings. PMID- 23653530 TI - Collagen scaffolds in bone sialoprotein-mediated bone regeneration. AB - Decades of research in bioengineering have resulted in the development of many types of 3-dimentional (3D) scaffolds for use as drug delivery systems (DDS) and for tissue regeneration. Scaffolds may be comprised of different natural fibers and synthetic polymers as well as ceramics in order to exert the most beneficial attributes including biocompatibility, biodegradability, structural integrity, cell infiltration and attachment, and neovascularization. Type I collagen scaffolds meet most of these criteria. In addition, type I collagen binds integrins through RGD and non-RGD sites which facilitates cell migration, attachment, and proliferation. Type I collagen scaffolds can be used for bone tissue repair when they are coated with osteogenic proteins such as bone morphogenic protein (BMP) and bone sialoprotein (BSP). BSP, a small integrin binding ligand N-linked glycoprotein (SIBLING), has osteogenic properties and plays an essential role in bone formation. BSP also mediates mineral deposition, binds type I collagen with high affinity, and binds alpha v beta 3 and alpha v beta 5 integrins which mediate cell signaling. This paper reviews the emerging evidence demonstrating the efficacy of BSP-collagen scaffolds in bone regeneration. PMID- 23653532 TI - Transforming a sequence of microbiology courses using student profile data. AB - A study was performed in the General Microbiology and Industrial Microbiology courses to increase research awareness at an early stage of the educational process and to establish collaboration between students in an Industrial Microbiology program and industry. In both courses, the professor helped students determine their learning styles and then used these data to design activities in order to accomplish the above objectives. In both the treatment and the control sections, students learned about strategies to optimize learning based on their learning styles. A cooperative learning format was introduced to promote active learning and team-building skills. The diverse learning styles data profile was used by students during cooperative learning activities for effective team integration. In the General Microbiology course, a mentor-mentee structure was introduced to expose students to research in microbiology by visiting research facilities on campus. This structure was an addition to the regular curriculum, which meets American Society for Microbiology curriculum recommendations. The results suggest an increase in interest in research by students. In the Industrial Microbiology course, a strategy was introduced to establish collaboration with industry in which students visit the workplace and identify microbial processes, microbiologist roles, and skills needed by microbiologists. Evaluation of these topics using pre- and posttest data indicates a significant increase in acquired knowledge relevant to daily workplace environments with the reformed course. In both courses, students gain information early in their academic experience to help them consider participation in research experiences while providing them with real-world experience toward the end of their academic careers, when they see the need for it. PMID- 23653531 TI - Increased risk of atrial and ventricular arrhythmia in long-lasting psoriasis patients. AB - BACKGROUND: Several reports have demonstrated an association between psoriasis and cardiovascular diseases. P wave dispersion (PWD) is the most important electrocardiographic (ECG) markers used to evaluate the risk of atrial arrhythmias. QT dispersion (QTD) can be used to assess homogeneity of cardiac repolarization and may be a risk for ventricular arrhythmias. AIM: To search PWD and QTD in patients with psoriasis. METHODS: Ninety-four outpatient psoriasis patients and 51 healthy people were evaluated by physical examination, 12-lead ECG, and transthoracic echocardiography. Severity of the psoriasis was evaluated by psoriasis area and severity index (PASI). RESULTS: Mean disease duration was 129.4 +/- 83.9 (range, 3-360) months and PASI ranged from 0 to 34.0 (mean +/- SD; 7.6 +/- 6.7). Compared to control group, psoriatic patients had significantly shorter Pmax and Pmin durations, longer QTcmax, and greater PWD and QTcD. Transmitral deceleration time (DT) and isovolumetric relaxation time (IVRT) were significantly longer among psoriasis patients. QTcD and PWD were significantly correlated with disease duration (r = 0.693, P < 0.001, and r = 0.368, P = 0.003, resp.). CONCLUSIONS: In this study, we found that both PWD and QTcD are increased in psoriasis patients compared to healthy subjects. In addition, they had longer DT and IVRT. PMID- 23653533 TI - Using computer technology to foster learning for understanding. AB - The literature shows that students typically use either a surface approach to learning, in which the emphasis is on memorization of facts, or a deep approach to learning, in which learning for understanding is the primary focus. This paper describes how computer technology, specifically the use of a multimedia CD-ROM, was integrated into a microbiology curriculum as part of the transition from focusing on facts to fostering learning for understanding. Evaluation of the changes in approaches to learning over the course of the term showed a statistically significant shift in a deep approach to learning, as measured by the Study Process Questionnaire. Additional data collected showed that the use of computer technology supported this shift by providing students with the opportunity to apply what they had learned in class to order tests and interpret the test results in relation to specific patient-focused case studies. The extent of the impact, however, varied among different groups of students in the class. For example, students who were recent high school graduates did not show a statistically significant increase in deep learning scores over the course of the term and did not perform as well in the course. The results also showed that a surface approach to learning was an important aspect of learning for understanding, although only those students who were able to combine a surface with a deep approach to learning were successfully able to learn for understanding. Implications of this finding for the future use of computer technology and learning for understanding are considered. PMID- 23653534 TI - An evaluation of computer-based instruction in microbiology. AB - There has been a tremendous increase in the availability of computer-based instructional (CBI) materials. Some studies have shown an improvement in learning when CBI is used. However, many researchers believe the current studies are inadequate. While CBI software should be thoroughly tested by developers, as educators, we should be concerned about whether or not the CBI materials we use are improving learning in our classrooms with our students. We present an evaluation of a computer-based hypermedia tutorial that was delivered over our General Microbiology website. We found that CBI was at least as effective as text based material. However, of all students who used CBI, only those who explored most of the site benefited from using the site. Tracking each student's use of the CBI was critical for understanding who was learning and why. PMID- 23653535 TI - Teaching emerging diseases: a strategy for succeeding with nonmajors. AB - A nonmajors course on emerging diseases served to introduce students to basic concepts in microbiology and to improve scientific literacy. The course used a range of learner-centered approaches to encourage students to take responsibility for their own learning. Evaluations demonstrated both student satisfaction and an increased understanding of important issues in microbiology. PMID- 23653536 TI - A Genetics Laboratory Module Involving Selection and Identification of Lysine Synthesis Mutants in the Yeast Saccharomyces cerevisiae. AB - We have developed a laboratory exercise, currently being used with college sophomores, which uses the yeast Saccharomyces cerevisiae to convey the concepts of amino acid biosynthesis, mutation, and gene complementation. In brief, selective medium is used to isolate yeast cells carrying a mutation in the lysine biosynthesis pathway. A spontaneous mutation in any one of three separate genetic loci will allow for growth on selective media; however, the frequency of mutations isolated from each locus differs. Following isolation of a mutated strain, students use complementation analysis to identify which gene contains the mutation. Since the yeast genome has been mapped and sequenced, students with access to the Internet can then research and develop hypotheses to explain the differences in frequencies of mutant genes obtained. PMID- 23653537 TI - The implementation of a new method of student assessment in a pathogenic bacteriology laboratory course. AB - A new case study method of assessment was developed to challenge advanced undergraduate biology majors interested in medical careers and allied health professions. This method is an alternative to traditional "unknown" identifications used in many microbiology laboratories. Students used various biochemical tests and selective media throughout the course to identify organisms cultured from their own bodies. In preparing a final assessment for the course, an assignment was developed to challenge the students to apply what they had learned in a medically relevant setting. Also of importance was the elimination of further biochemical testing by these students and prevention of contact with strict pathogens in this lab, due to budget and safety constraints, respectively. Each student was provided with a clinical specimen data record sheet and additional information about their "diseased patient". Students used analytical skills and critical thinking, as well as knowledge gained throughout the semester, to logically deduce the causative agent of disease in the mock patients. Students were required to: (i) describe the steps in this logical deduction, (ii) provide a brief overview of the characteristics and virulence factors of the organism(s), (iii) investigate all disease(s) caused by the organism, (iv) describe symptomology of the patient in detail, and (v) investigate disease treatment and prevention methods. The final assignment involved library and Internet research and culminated in a written report, which further developed writing and communication skills. Detailed descriptions of and materials for this assignment are provided along with an overall evaluation of this method after implementation. PMID- 23653538 TI - Successful application of active learning techniques to introductory microbiology. AB - While the traditional lecture format may be a successful way to teach microbiology to both medical and nursing students, it was not an effective means of learning for many prenursing and preprofessional students enrolled in either of the introductory microbiology courses at Ashland Community College, an open enrollment institution. The structure of both Medical Microbiology and Principles of Microbiology was redesigned to allow students to address the material in an active manner. Daily quizzes, student group discussions, scrapbooks, lab project presentations and papers, and extra credit projects were all added in order to allow students maximum exposure to the course material in a manner compatible with various methods of learning. Student knowledge, course evaluations, and student success rates have all improved with the active learning format. PMID- 23653539 TI - Expanding a learner-centered environment using group reports and constructivist portfolios. AB - A study was performed in the Microbial Physiology course to increase students' self-awareness of their misconceptions, promote sound research techniques, develop written and oral communication skills, stimulate metacognition, and improve teamwork and interpersonal relationship skills. The transformation in the teaching methodology included using cooperative learning, field trips, and portfolios that targeted diverse learning styles to challenge students in creative ways and to help prepare them for future careers. The entire structure of the class was modified by introducing in-class portfolios to form a constructivist environment in which the discussion and lecture topic of the day were built on prior student knowledge. Based on evaluations, students were very pleased with the new teaching and learning process and learned more content than in the more traditional class. They also felt better able to reflect on their learning. PMID- 23653540 TI - Learning support assessment study of a computer simulation for the development of microbial identification strategies. AB - This paper describes a study that examined how microbiology students construct knowledge of bacterial identification while using a computer simulation. The purpose of this study was to understand how the simulation affects the cognitive processing of students during thinking, problem solving, and learning about bacterial identification and to determine how the simulation facilitates the learning of a domain-specific problem-solving strategy. As part of an upper division microbiology course, five students participated in several simulation assignments. The data were collected using think-aloud protocol and video action logs as the students used the simulation. The analysis revealed two major themes that determined the performance of the students: Simulation Usage-how the students used the software features and Problem-Solving Strategy Development-the strategy level students started with and the skill level they achieved when they completed their use of the simulation. SEVERAL CONCLUSIONS EMERGED FROM THE ANALYSIS OF THE DATA: (i) The simulation affects various aspects of cognitive processing by creating an environment that makes it possible to practice the application of a problem-solving strategy. The simulation was used as an environment that allowed students to practice the cognitive skills required to solve an unknown. (ii) Identibacter (the computer simulation) may be considered to be a cognitive tool to facilitate the learning of a bacterial identification problem-solving strategy. (iii) The simulation characteristics did support student learning of a problem-solving strategy. (iv) Students demonstrated problem-solving strategy development specific to bacterial identification. (v) Participants demonstrated an improved performance from their repeated use of the simulation. PMID- 23653541 TI - Problem-solving skills among precollege students in clinical immunology and microbiology: classifying strategies with a rubric and artificial neural network technology. AB - Educators emphasize the importance of problem solving that enables students to apply current knowledge and understanding in new ways to previously unencountered situations. Yet few methods are available to visualize and then assess such skills in a rapid and efficient way. Using a software system that can generate a picture (i.e., map) of students' strategies in solving problems, we investigated methods to classify problem-solving strategies of high school students who were studying infectious and noninfectious diseases. Using maps that indicated items students accessed to solve a software simulation as well as the sequence in which items were accessed, we developed a rubric to score the quality of the student performances and also applied artificial neural network technology to cluster student performances into groups of related strategies. Furthermore, we established that a relationship existed between the rubric and neural network results, suggesting that the quality of a problem-solving strategy could be predicted from the cluster of performances in which it was assigned by the network. Using artificial neural networks to assess students' problem-solving strategies has the potential to permit the investigation of the problem-solving performances of hundreds of students at a time and provide teachers with a valuable intervention tool capable of identifying content areas in which students have specific misunderstandings, gaps in learning, or misconceptions. PMID- 23653542 TI - Using the theory of planned behavior as a framework for the evaluation of a professional development workshop. AB - This purpose of this study was to use a theoretical framework based on several decades of attitudinal research to assess the intentions of Microbial Discovery Workshop participants to incorporate the inquiry activities presented at the workshop into their curricula, to evaluate the participants actual use of these activities after the workshop, and to uncover the barriers and enablers the participants faced in doing so. As a framework, the theory of planned behavior was ascertained to be an appropriate means of assessment and it was revealed that participants' intention to use the workshop activities significantly correlated with their actual use. The participants' attitudes toward using the activities influenced their use more than the participants' perceptions of the social pressures that would influence their decision to use the activities or their belief as to how easy or difficult it would be to incorporate a given activity. The participants were found to be highly self-efficacious pertaining to their ability to implement the activities, but perceived self-efficacy was not a significant predictor of the participants' intentions to incorporate the activities into their teaching-learning repertoire. The study also uncovered other behaviors the participants displayed as a result of attending the workshop consistent with the goals and objectives of the workshop organizers. PMID- 23653543 TI - Bacteriophage: a model system for active learning. AB - Although bacteriophage provided a useful model system for the development of molecular biology, its simplicity, accessibility, and familiarity have not been fully exploited in the classroom. We describe a student-centered laboratory course in which student teams selected phage from sewage samples and characterized the phage in a semester-long project that modeled real-life scientific research. The course used an instructional approach that included active learning, collaboration, and learning by inquiry. Cooperative student teams had primary responsibility for organizing the content of the course, writing to learn using a journal article format, involving the entire group in shared laboratory responsibilities, and applying knowledge to the choice of new experiments. The results of student evaluations indicated a high level of satisfaction with the course. Our positive experience with this course suggests that phage provides an attractive model system for an active-learning classroom. PMID- 23653544 TI - An activity-based format increased student retention in a community college microbiology course. AB - Microbiology is offered each semester at the Allied Health Campus of Pearl River Community College. The evening course meets weekly for 16 sessions from 5 p.m. to 10 p.m. Most students enrolled in the course are in one of the seven associate degree allied health programs on the allied health campus. Among the challenges of teaching a course in this situation is retention of enrolled students. Although the course is required for most of the allied health programs on the campus, many students enrolled, attended class for a few weeks, and withdrew from the course. During the 1998-1999 school year the retention rates for students enrolled in the night microbiology classes for Fall and Spring semesters were 52% and 47%, respectively. The format for the 1998-1999 academic year was a conventional course with 21/2 hours of lecture material followed by 2 hours of laboratory. Little or no effort was made to correlate laboratory and lecture topics. The course format for Fall 1999 was modified to (i) provide the laboratory component at the beginning of the time slot, (ii) tailor the lecture topics to relate to the laboratory component each night, and (iii) add an outside reading component. The laboratory served as an introduction to the lecture topic, and the lecture became more significant since it related directly to the laboratory experience. Following this format change the retention rate for the Fall 1999 semester increased to 80%. PMID- 23653545 TI - Development of a microbiology course for diverse majors; longitudinal survey of the use of various active, problem-based learning assignments. AB - Educators are increasingly being encouraged to use more active- and problem-based learning techniques and assignments in the classroom to improve critical and analytical thinking skills. Active learning-based courses have been purported to be more time consuming than traditional lecture methods and for many instructors have therefore proven difficult to include in many one-semester science courses. To address this problem, a series of assignments was developed for use in a basic microbiology course involving sophomore-, junior-, and senior-level students from five different biology majors (environmental science, biology, biochemistry, premedicine, and physician assistant). Writing assignments included global, historical, and social themes for which a standardized grading format was established. Students also participated in a class debate in which the merits of the living microbial kingdoms were discussed, with only one kingdom being saved from an imaginary global catastrophe. Traditional lectures were facilitated by the use of a dedicated note packet developed by the instructor and specific for course content. Laboratories involved group analysis of mini-case history studies involving pathogenic microbes. Students' perceptions of the subject were assessed using an exit questionnaire sent to 100 of the 174 students who had taken the course during the 5-year time period. The majority of the 64 students who responded were sophomores (78%), in keeping with the target audience, and their perception of the course's challenge level was significantly higher (p < 0.03, 8.7) than their junior and senior counterparts (7.9). Students rated the most useful learning tools as case history studies (9.4) and the class debate (9.1), with the introduction of a dedicated microbiology links web page to the University website representing the sole component resulting in a statistically significant increase in students' perceptions of the importance of the course (p < 0.03). PMID- 23653546 TI - Bacterial Diversity Studies Using the 16S rRNA Gene Provide a Powerful Research Based Curriculum for Molecular Biology Laboratory. AB - We have developed a ten-week curriculum for molecular biology that uses 16S ribosomal RNA genes to characterize and compare novel bacteria from hot spring communities in Yellowstone National Park. The 16S rRNA approach bypasses selective culture-based methods. Our molecular biology course offered the opportunity for students to learn broadly applicable methods while contributing to a long-term research project. Specifically, students isolated and characterized clones that contained novel 16S rRNA inserts using restriction enzyme, DNA sequencing, and computer-based phylogenetic methods. In both classes, students retrieved novel bacterial 16S rRNA genes, several of which were most similar to Green Nonsulfur bacterial isolates. During class, we evaluated student performance and mastery of skills and concepts using quizzes, formal lab notebooks, and a broad project assignment. For this report, we also assessed student performance alongside data quality and discussed the significance, our goal being to improve both research and teaching methods. PMID- 23653547 TI - Learning Microbiology Through Cooperation: Designing Cooperative Learning Activities that Promote Interdependence, Interaction, and Accountability. AB - A microbiology course and its corresponding learning activities have been structured according to the Cooperative Learning Model. This course, The World According to Microbes, integrates science, math, engineering, and technology (SMET) majors and non-SMET majors into teams of students charged with problem solving activities that are microbial in origin. In this study we describe development of learning activities that utilize key components of Cooperative Learning-positive interdependence, promotive interaction, individual accountability, teamwork skills, and group processing. Assessments and evaluations over an 8-year period demonstrate high retention of key concepts in microbiology and high student satisfaction with the course. PMID- 23653548 TI - Team-based learning enhances long-term retention and critical thinking in an undergraduate microbial physiology course. AB - We used team-based learning to improve comprehension and critical thinking of students in an undergraduate microbial metabolism-physiology course. The course used well-known bacterial pathways to highlight themes of energy conservation and biodegradation. Prior to the introduction of team-based learning, student recall of this information was poor and students had difficulty extrapolating information to new organisms. Initially, individual and group quizzes were added to promote problem-solving and critical-thinking skills. This significantly improved student attitudes about the amount of information they learned and whether the instructor promoted critical thinking. However, retention of the material as judged by final examination scores was still poor. In the next year, two challenging projects were added to the course to complement the above themes: (i) postulating a pathway for the metabolism of a substrate by a bacterium, and (ii) modifying the current model for anaerobic sulfate reduction by incorporating recent genetic information. The inclusion of the team projects significantly improved final examination scores compared to the previous year without team projects. Overall, team-based learning with challenging projects improved the students' comprehension and retention of information, critical thinking, and attitudes about the course and focused student-instructor interactions on learning rather than grades. PMID- 23653549 TI - Effectiveness of an applied microbiology course specifically designed for chemical engineering majors. AB - In recent years, the disciplines of microbiology and chemical engineering have developed an increasing convergence. To meet the needs of their future employers, today's chemical engineering students must receive some background in microbiology. This report describes the development and content of "Biological Systems and Applications," a novel course specifically designed to provide basic biology and applied microbiology knowledge, skills, and experience to sophomore chemical engineering majors. Data collected from entrance and exit surveys of the students demonstrated that the course is successful. The importance of the "project-base" learning technique and of interdisciplinary faculty-student and faculty-faculty collaborations are proposed as elements essential to the success of this particular course. PMID- 23653550 TI - Promoting student involvement with environmental laboratory experiments in a general microbiology course. AB - This is a descriptive study of a series of laboratory exercises on environmental microbiology carried out by students in a general microbiology course during eight of the twelve weeks of the semester. The revised laboratory component is predicated upon seawater and sediment samples collected by student pairs using marine sampling equipment on a field trip aboard a research vessel. Two longitudinal studies were performed: assay for antibiotic production from isolated actinomycetes and construction and observation of Winogradsky columns. Two additional experiments: culturing microalgae and water testing for coliforms also used the samples collected by the students. The advantages of long-term, challenging laboratory experiences actively involving the students in group process, self-direction, and scientific practices are discussed. Also considered are development of laboratory skills, scientific competencies, and students' self confidence in carrying out such environmental investigations. Plans for future assessment of student learning are presented. PMID- 23653551 TI - Using the primary literature in an allied health microbiology course. AB - A strategy was adapted for using the primary literature to foster active learning in an allied health microbiology course. Recent journal articles were selected that underscored the fundamental microbiological principles to be learned in each course unit. At the beginning of the semester, students were taught the relationship between the layout of scientific articles and the scientific method. During the rest of the semester, students were oriented to the topic of each paper by viewing videos from Unseen Life on Earth: an Introduction to Microbiology, reading assigned pages from the text, and participating in mini lectures and discussions. After all preparatory material was completed, a paper was read and discussed in small groups and as a class. Students were assessed using daily reading quizzes and end-of-unit concept quizzes. While reading quizzes averaged approximately 93%, concept quiz grades averaged approximately 82%. Student recognition of the terms used in each unit's scientific article was assessed with pre-read and post-read wordlists. For the self-assessment, the percent change between pre-read and post-read word cognition was, as expected, highly significant. Approximately 80% of students agreed that reading the scientific articles was a valuable part of the class and that it provided meaning to their study of microbiology. Using the primary scientific literature facilitated active learning in and out of the classroom. This study showed that introducing the scientific literature in an allied health microbiology class can be an effective way of teaching microbiology by providing meaning through the current literature and understanding of the scientific method. PMID- 23653552 TI - Three-Dimensional Visualizations in Teaching Genomics and Bioinformatics: Mutations in HIV Envelope Proteins and Their Consequences for Vaccine Design. AB - This project addresses the need to provide a visual context to teach the practical applications of genome sequencing and bioinformatics. Present-day research relies on indirect visualization techniques (e.g., fluorescence-labeling of DNA in sequencing reactions) and sophisticated computer analysis. Such methods are impractical and prohibitively expensive for laboratory classes. More importantly, there is a need for curriculum resources that visually demonstrate the application of genome sequence information rather than the DNA sequencing methodology itself. This project is a computer-based lesson plan that engages students in collaborative, problem-based learning. The specific example focuses on approaches to Human Immunodeficiency Virus-1 (HIV-1) vaccine design based on HIV-1 genome sequences using a case study. Students performed comparative alignments of variant HIV-1 sequences available from a public database. Students then examined the consequences of HIV-1 mutations by applying the alignments to three-dimensional images of the HIV-1 envelope protein structure, thus visualizing the implications for applications such as vaccine design. The lesson enhances problem solving through the application of one type of information (genomic or protein sequence) into concrete visual conceptualizations. Assessment of student comprehension and problem-solving ability revealed marked improvement after the computer tutorial. Furthermore, contextual presentation of these concepts within a case study resulted in student responses that demonstrated higher levels of cognitive ability than was expected by the instructor. PMID- 23653553 TI - Efficacy of MedMyst: an Internet Teaching Tool for Middle School Microbiology. AB - Can web-based technology be used to effectively introduce or reinforce aspects of microbiology to middle school students? This central hypothesis examines whether brief exposure to a web adventure format containing virtual lab experiments and computer games within an engaging story line can impact student learning. An episodic adventure series, MedMyst (http://medmyst.rice.edu), focuses on infectious diseases and the microbes that cause them. The website is not intended to replace classroom instruction, but rather to engage students in problem solving activities not likely to be encountered elsewhere. It also provides scientists with a resource to introduce microbiology to adolescent audiences through outreach activities. In the online adventure, the player (student) enters a futuristic world in which he or she becomes a "Reconstructor," a member of an elite team charged with preventing the spread of infectious disease. The series consists of three "missions," each lasting approximately 30 to 40 minutes and designed to address a limited set of learning objectives. Middle school students participated in the creation of the characters and the stylized design through focus groups. Classroom teachers oversaw the alignment of the web adventure objectives with the National Science Content Standards. Scientists and clinicians reviewed the web adventure for content and accuracy. A field test involving over 700 students from nine different schools assessed the knowledge gains attributable to playing MedMyst. Gain scores from pretest to posttest indicated that middle school students retained important information by interacting with the online material for as little as 30 minutes per adventure; however, gains for high school students were less persuasive, perhaps indicating a different learning tool or content is required for this age audience. PMID- 23653554 TI - Learning partnerships between undergraduate biology students and younger learners. AB - In two upper-level elective biology courses and one beginning-level general biology course, college students participated in Learning Partnerships with middle or high school classes to study some aspect of biology. The goals were to enhance learning by providing resources to middle and high school students and teachers and by encouraging college students to consider teaching as a learning tool and a possible career goal. The college students designed lessons, activities, and laboratories that were done at the schools and at Bates College. Feedback and data suggest that the partnerships have helped teachers enrich their curricula, enhanced student learning, encouraged additional high school students to consider applying to college, and encouraged college students to consider teaching science. PMID- 23653555 TI - A web-based comparative genomics tutorial for investigating microbial genomes. AB - As the number of completely sequenced microbial genomes continues to rise at an impressive rate, it is important to prepare students with the skills necessary to investigate microorganisms at the genomic level. As a part of the core curriculum for first-year graduate students in the biological sciences, we have implemented a web-based tutorial to introduce students to the fields of comparative and functional genomics. The tutorial focuses on recent computational methods for identifying functionally linked genes and proteins on a genome-wide scale and was used to introduce students to the Rosetta Stone, Phylogenetic Profile, conserved Gene Neighbor, and Operon computational methods. Students learned to use a number of publicly available web servers and databases to identify functionally linked genes in the Escherichia coli genome, with emphasis on genome organization and operon structure. The overall effectiveness of the tutorial was assessed based on student evaluations and homework assignments. The tutorial is available to other educators at http://www.doe-mbi.ucla.edu/~strong/m253.php. PMID- 23653556 TI - Teaching phagocytosis using flow cytometry. AB - Investigative microbiology on protists in a basic teaching laboratory environment is limited by student skill level, ease of microbial culture and manipulation, instrumentation, and time. The flow cytometer is gaining use as a mainstream instrument in research and clinical laboratories, but has had minimal application in teaching laboratories. Although the cost of a flow cytometer is currently prohibitive for many microbiology teaching environments and the number of trained instructors and teaching materials is limited, in many ways the flow cytometer is an ideal instrument for teaching basic microbiology. We report here on a laboratory module to study phagocytosis in Tetrahymena sp. using flow cytometry in a basic microbiology teaching laboratory. Students and instructors found the flow cytometry data analysis program, Paint-AGate(PRO-TM), to be very intuitive and easy to learn within a short period of time. Assessment of student learning about Tetrahymena sp., phagocytosis, flow cytometry, and investigative microbiology using an inquiry-based format demonstrated an overall positive response from students. PMID- 23653557 TI - Alternative assessment strategy and its impact on student comprehension in an undergraduate microbiology course. AB - Medical Microbiology is a content-intensive course that requires a large time commitment from the students. Students are typically biology or prenursing majors, including students headed for professional schools, such as medical school and pharmacy school. This group is somewhat diverse in terms of background science coursework, so it can be difficult to teach in a way that benefits all the students. Numerous changes have been implemented in our microbiology curriculum to address the different abilities of our students by altering assessment and teaching strategies. It was hypothesized that changing the assessment strategy from the traditional scheme of two or three exams and one final to a new model of seven or eight shorter exams would have a positive impact on student comprehension and retention. The quantity of material taught or expected of the students to learn did not change, but there was definitely an impact on them. Although 30.0% of students routinely did not pass microbiology in previous semesters, the new method of assessment resulted in only 9.63% not completing the semester successfully, as determined by earning a grade of C or better. There is some evidence from conversations and interviews with students that indicates a positive impact of this methodology on student attitude. Implementation of these changes in other courses and their current effectiveness will be examined in the future, with an eye towards more broadly applicable successful teaching techniques in the sciences, especially for nonmajors. PMID- 23653558 TI - A "Hybrid" Bacteriology Course: The Professor's Design and Expectations; The Students' Performance and Assessment. AB - A basic bacteriology course was offered in two successive academic years, first in a conventional format and subsequently as a "hybrid" course. The latter combined (i) online presentation of content, (ii) an emphasis on online resources, (iii) thrice-weekly, face-to-face conversations to advance understanding, and (iv) frequent student postings on an electronic discussion board. We compared the two courses through statistical analysis of student performances on the final examinations and the course overall and student assessment of teaching. The data indicated that there was no statistical difference in performance on the final examinations or the course overall. Responses on an instrument of evaluation revealed that students less strongly affirmed the following measures in the hybrid course: (i) The amount of work was appropriate for the credit received, (ii) Interactions between students and instructor were positive, (iii) I learned a great deal in this course, and (iv) I would recommend this course to other students. We recommend clear direction about active learning tasks and relevant feedback to enhance learning in a hybrid course. PMID- 23653559 TI - Integrating statistics with a microbiology laboratory activity. AB - Statistics is an important tool for microbiologists but is virtually absent from undergraduate laboratory activities. The variables in a stringent protocol, the antibiotic disk diffusion assay described by the National Committee for Clinical Laboratory Standards, were examined by the authors as a means for introducing hypothesis testing and the application of elementary statistical tools. After several experiments, a lab activity was developed where students examine the effect of cell concentration on antibiotic activity and analyze data with the t test. They also collect data independently from the same samples and compare their measurements using analysis of variance (ANOVA). The outcome of the activity, including an assessment tool, indicated that students learned the appropriate use of the t test and ANOVA, gained an appreciation for standardized protocols, and enjoyed the experience. PMID- 23653560 TI - Assessment of student skills for critiquing published primary scientific literature using a primary trait analysis scale. AB - Instructor evaluation of progressive student skills in the analysis of primary literature is critical for the development of these skills in young scientists. Students in a senior or graduate-level one-semester course in Immunology at a Masters-level comprehensive university were assessed for abilities (primary traits) to recognize and evaluate the following elements of a scientific paper: Hypothesis and Rationale, Significance, Methods, Results, Critical Thinking and Analysis, and Conclusions. We tested the hypotheses that average recognition scores vary among elements and that scores change with time differently by trait. Recognition scores (scaled 1 to 5), and differences in scores were analyzed using analysis of variance (ANOVA), regression, and analysis of covariance (ANCOVA) (n = 10 papers over 103 days). By multiple comparisons testing, we found that recognition scores statistically fell into two groups: high scores (for Hypothesis and Rationale, Significance, Methods, and Conclusions) and low scores (for Results and Critical Thinking and Analysis). Recognition scores only significantly changed with time (increased) for Hypothesis and Rationale and Results. ANCOVA showed that changes in recognition scores for these elements were not significantly different in slope (F1,16 = 0.254, P = 0.621) but the Results trait was significantly lower in elevation (F1,17 = 12.456, P = 0.003). Thus, students improved with similar trajectories, but starting and ending with lower Results scores. We conclude that students have greatest difficulty evaluating Results and critically evaluating scientific validity. Our findings show extant student skills, and the significant increase in some traits shows learning. This study demonstrates that students start with variable recognition skills and that student skills may be learned at differential rates. Faculty can use these findings or the primary trait analysis scoring scale to focus on specific paper elements for which they desire to improve recognition. PMID- 23653561 TI - Development and evaluation of an electronic guide for introductory microbiology skills. AB - To increase the quality of instruction, enhance student learning, and decrease laboratory time spent on laboratory safety, basic skills, and the use of equipment, we developed the Micro eGuide website. We compared the performance of students who used the Micro eGuide to students provided more traditional instruction in both an upper-level introductory microbiology course for biology majors and in a lower-division introductory microbiology course for nonmajors. Assessment of student learning included written pretests and posttests, practical testing of laboratory skills, and for the major's class, a review of poster presentations of independent projects. Students who used the Micro eGuide showed a statistically significant increase in performance on written examination in the introductory microbiology courses for both biology majors and nonmajors. Use of the Micro eGuide in the sophomore-level course for nonbiology majors resulted in a statistically significant improvement in laboratory skills. Though the increase in laboratory skills in the majors courses was not statistically significant, instructors were able to use the site as an effective learning source and decrease the time spent in class on topics covered in the Micro eGuide. While the number of student independent research projects was too small for statistical analysis on the quality of the poster presentations, the improvement in student attitude and the increase in the diversity in topics selected suggests that students using the Micro eGuide had increased comfort with microbiology and increased interest in exploring microbiology. PMID- 23653562 TI - Evaluating the impact of a classroom response system in a microbiology course. AB - The use of a Classroom Response System (CRS) was evaluated in two sections, A and B, of a large lecture microbiology course. In Section B the instructor used the CRS technology at the beginning of the class period posing a question on content from the previous class. Students could earn extra credit if they answered the question correctly. In Section A, the class also began with an extra credit CRS question. However, CRS questions were integrated into the lecture during the entire class period. We compared the two classes to see if augmenting lectures with this technology increased student learning, confidence, attendance, and the instructor's ability to respond to student's misconceptions, over simply using the CRS as a quizzing tool. Student performance was compared using shared examination questions. The questions were categorized by how the content had been presented in class. All questions came from instructors' common lecture content, some without CRS use, and some questions where Instructor A used both lecture and CRS questions. Although Section A students scored significantly better on both types of examination questions, there was no demonstrable difference in learning based on CRS question participation. However, student survey data showed that students in Section A expressed higher confidence levels in their learning and knowledge and indicated that they interacted more with other students than did the students in Section B. In addition, Instructor A recorded more modifications to lecture content and recorded more student interaction in the course than did Instructor B. PMID- 23653563 TI - An evaluation of web-based case studies in microscopy. AB - It is often difficult to provide students in introductory science courses with opportunities that mimic the investigative learning experience of doing research. This is particularly true in microbiology courses where advanced microscopy techniques are expensive and difficult to do. To that end, we developed three computer-based case studies around real-life scenarios. Our goals were to: (i) improve students' understanding of advanced microscopic techniques, (ii) give students practice analyzing and interpreting data, and (iii) model a scientific approach to how these techniques are applied to current issues in microbiology. Each case requires students to use references and interpret actual microscopic images, thus giving them a more realistic experience than we could previously provide. We analyzed student learning and perceptions to these case studies. After doing the case studies, students were more able to apply microscopic methods to a realistic problem, thus demonstrating an understanding of how the methods are used. Students appreciated the intellectual challenges presented by having to interpret and analyze actual microscopic images. This approach has allowed us to introduce new areas of content to our course and to stimulate critical thinking skills, a difficult task in a large introductory microbiology course. PMID- 23653564 TI - The delta cooperative model: a dynamic and innovative team-work activity to develop research skills in microbiology. AB - The Delta Cooperative Model (DCM) is a dynamic and innovative teamwork design created to develop fundamentals in research skills. High school students in the DCM belong to the Upward Bound Science and Math (UBSM) program at the Inter American University, Ponce Campus. After workshops on using the scientific method, students were organized into groups of three students with similar research interests. Each student had to take on a role within the group as either a researcher, data analyst, or research editor. Initially, each research team developed hypothesis-driven ideas on their proposed project. In intrateam research meetings, they emphasized team-specific tasks. Next, interteam meetings were held to present ideas and receive critical input. Finally, oral and poster research presentations were conducted at the UBSM science fair. Several team research projects covered topics in medical, environmental, and general microbiology. The three major assessment areas for the workshop and DCM included: (i) student's perception of the workshops' effectiveness in developing skills, content, and values; (ii) research team self- and group participation evaluation, and (iii) oral and poster presentation during the science fair. More than 91% of the students considered the workshops effective in the presentation of scientific method fundamentals. The combination of the workshop and the DCM increased student's knowledge by 55% from pre- to posttests. Two rubrics were designed to assess the oral presentation and poster set-up. The poster and oral presentation scores averaged 83% and 75% respectively. Finally, we present a team assessment instrument that allows the self- and group evaluation of each research team. While the DCM has educational plasticity and versatility, here we document how the this model has been successfully incorporated in training and engaging students in scientific research in microbiology. PMID- 23653568 TI - The gears keep turning: current progress in platelet function testing. PMID- 23653565 TI - JAGGED controls Arabidopsis petal growth and shape by interacting with a divergent polarity field. AB - A flowering plant generates many different organs such as leaves, petals, and stamens, each with a particular function and shape. These types of organ are thought to represent variations on a common underlying developmental program. However, it is unclear how this program is modulated under different selective constraints to generate the diversity of forms observed. Here we address this problem by analysing the development of Arabidopsis petals and comparing the results to models of leaf development. We show that petal development involves a divergent polarity field with growth rates perpendicular to local polarity increasing towards the distal end of the petal. The hypothesis is supported by the observed pattern of clones induced at various stages of development and by analysis of polarity markers, which show a divergent pattern. We also show that JAGGED (JAG) has a key role in promoting distal enhancement of growth rates and influences the extent of the divergent polarity field. Furthermore, we reveal links between the polarity field and auxin function: auxin-responsive markers such as DR5 have a broader distribution along the distal petal margin, consistent with the broad distal organiser of polarity, and PETAL LOSS (PTL), which has been implicated in the control of auxin dynamics during petal initiation, is directly repressed by JAG. By comparing these results with those from studies on leaf development, we show how simple modifications of an underlying developmental system may generate distinct forms, providing flexibility for the evolution of different organ functions. PMID- 23653570 TI - Comment Concerning the Role of CD47 and Signal Regulatory Protein Alpha in Regulating the Clearance of Aged Red Blood Cells. PMID- 23653571 TI - Considering the Embryopathogenesis of VACTERL Association. AB - The nonrandom co-occurrence of vertebral, anorectal, cardiac, tracheoesophageal, genitourinary, and limb malformations, recognized as the VACTERL association, has not been satisfactorily explained from either a causation or embryopathogenesis standpoint. Few familial cases have been identified and maternal diabetes is the only environmental influence implicated to date. Mutations in single genes have been found in a number of syndromes with one or more of the VACTERL malformations, but these syndromes usually have other features which distinguish them from the VACTERL association. Animal models have provided clues to molecular pathways that may be involved in the embryogenesis of the VACTERL structures. What is lacking is the systematic study of individual genes and pathways in well composed cohorts of patients, which is now possible with high throughput molecular technologies. PMID- 23653569 TI - State of the art in platelet function testing. AB - Platelets perform many functions in hemostasis but also in other areas of physiology and pathology. Therefore, it is obvious that many different function tests have been developed, each one conceived and standardized for a special purpose. This review will summarize the different fields in which platelet function testing is currently in use; diagnostics of patients with bleeding disorders, monitoring patients' response to anti-platelet therapy, monitoring in transfusion medicine (blood donors, platelet concentrates, and after transfusion), and monitoring in perioperative medicine to predict bleeding tendency. The second part of the review outlines different methods for platelet function testing, spanning bleeding time, and platelet counting as well as determining platelet adhesion, platelet secretion, platelet aggregation, platelet morphology, platelet signal transduction, platelet procoagulant activity, platelet apoptosis, platelet proteomics, and molecular biology. PMID- 23653572 TI - VATER/VACTERL Association: Evidence for the Role of Genetic Factors. AB - The VATER/VACTERL association is typically defined by the presence of at least 3 of the following congenital malformations: Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities. The involvement of genetic factors in the development of this rare association is suggested by reports of familial occurrence, the increased prevalence of component features among first-degree relatives of affected individuals, high concordance rates among monozygotic twins, chromosomal (micro )aberrations or single gene mutations in individuals with the VATER/VACTERL phenotype, as well as murine knock-out models. Despite substantial efforts over the past decade, the genetic etiology of the VATER/VACTERL association in most instances remains elusive. The application of new genomic technologies such as high-resolution copy number variation studies or next-generation exome sequencing might lead to the identification of some of these causes. PMID- 23653573 TI - VACTERL Association Etiology: The Impact of de novo and Rare Copy Number Variations. AB - Copy number variations (CNVs), either DNA gains or losses, have been found at common regions throughout the human genome. Most CNVs neither have a pathogenic significance nor result in disease-related phenotypes but, instead, reflect the normal population variance. However, larger CNVs, which often arise de novo, are frequently associated with human disease. A genetic contribution has long been suspected in VACTERL (Vertebral, Anal, Cardiac, TracheoEsophageal fistula, Renal and Limb anomalies) association. The anomalies observed in this association overlap with several monogenetic conditions associated with mutations in specific genes, e.g. Townes Brocks (SALL1), Feingold syndrome (MYCN) or Fanconi anemia. So far VACTERL association has typically been considered a diagnosis of exclusion. Identifying recurrent or de novo genomic variations in individuals with VACTERL association could make it easier to distinguish VACTERL association from other syndromes and could provide insight into disease mechanisms. Sporadically, de novo CNVs associated with VACTERL are described in literature. In addition to this literature review of genomic variation in published VACTERL association patients, we describe CNVs present in 68 VACTERL association patients collected in our institution. De novo variations (>30 kb) are absent in our VACTERL association cohort. However, we identified recurrent rare CNVs which, although inherited, could point to mechanisms or biological processes contributing to this constellation of developmental defects. PMID- 23653574 TI - Exome Sequencing and High-Density Microarray Testing in Monozygotic Twin Pairs Discordant for Features of VACTERL Association. AB - Exome sequencing offers an efficient and affordable method to interrogate genetic factors involved in human disease. Performing exome sequencing of monozygotic twins discordant for VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities) association-type congenital malformations was hypothesized to potentially reveal discordant variants that could demonstrate disease cause(s). After demonstrating monozygosity, we applied high-density microarrays and exome sequencing to 2 twin pairs in which 1 twin had features of VACTERL association while the other was phenotypically normal (demonstrated through comprehensive clinical and radiological evaluation). No obvious discordant genotypic results were found that would explain phenotypic discordance. We conclude that VACTERL association is a complex disease, and while performing microarray analysis and exome sequencing on phenotypically discordant monozygotic twins may hypothetically reveal genetic causes of disorders, challenges remain in applying these methods in this circumstance. PMID- 23653575 TI - Sonic Hedgehog Signaling and VACTERL Association. AB - Hedgehog (Hh) signaling is vital for the patterning and organogenesis of almost every system. The specificity of these developmental processes is achieved through a tight spatio-temporal regulation of Hh signaling. Mice with defective Hh signal exhibit a wide spectrum of anomalies, including Vertebral defects, Anal atresia, Cardiovascular anomalies, Tracheoesophageal fistula, Renal dysplasia, and Limb defects, that resemble strikingly the phenotypes observed in VACTERL association in humans. In this review, we summarize our current understanding of mammalian Hh signaling and highlight the relevance of various mouse models for studying the etiology and pathogenesis of VACTERL association. In addition, recent advances in genetic study for unraveling the complexity of genetic inheritance of VACTERL and the implication of the Sonic hedgehog pathway in disease pathogenesis are also discussed. PMID- 23653576 TI - Adriamycin-Induced Models of VACTERL Association. AB - Animal models are of great importance for medical research. They have enabled analysis of the aetiology and pathogenesis of complex congenital malformations and have also led to major advances in the surgical and therapeutic management of these conditions. Animal models allow us to comprehend the morphological and molecular basis of disease and consequently to discover novel approaches for both surgical and medical therapy. The anthracycline antibiotic adriamycin was incidentally found to have teratogenic effects on rats, producing a range of defects remarkably similar to the VACTERL association of congenital anomalies in humans, providing a reproducible animal model of this condition. VACTERL association is a spectrum of birth defects which includes vertebral, anal, cardiovascular, tracheo-oesophageal, renal and limb anomalies. In recent years, adriamycin rodent models of VACTERL have provided valuable insights into the pathogenesis of this complex association, particularly in relation to tracheo oesophageal malformations. The adriamycin rat model and adriamycin mouse model are now well established in the investigation of the morphology of faulty organogenesis and the regulation of gene expression in tracheo-oesophageal anomalies. PMID- 23653577 TI - Mitochondrial Factors and VACTERL Association-Related Congenital Malformations. AB - VACTERL/VATER association is a group of congenital malformations characterized by at least 3 of the following findings: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. To date, no unifying etiology for VACTERL/VATER association has been established, and there is strong evidence for causal heterogeneity. VACTERL/VATER association has many overlapping characteristics with other congenital disorders that involve multiple malformations. In addition to these other conditions, some of which have known molecular causes, certain aspects of VACTERL/VATER association have similarities with the manifestations of disorders caused by mitochondrial dysfunction. Mitochondrial dysfunction can result from a number of distinct causes and can clinically manifest in diverse presentations; accurate diagnosis can be challenging. Case reports of individuals with VACTERL association and confirmed mitochondrial dysfunction allude to the possibility of mitochondrial involvement in the pathogenesis of VACTERL/VATER association. Further, there is biological plausibility involving mitochondrial dysfunction as a possible etiology related to a diverse group of congenital malformations, including those seen in at least a subset of individuals with VACTERL association. PMID- 23653578 TI - Diabetic embryopathy: a developmental perspective from fertilization to adulthood. AB - Maternal diabetes mellitus is one of the strongest human teratogens. Despite recent advances in the fields of clinical embryology, experimental teratology and preventive medicine, diabetes-related perturbations of the maternofetal unit maintain a considerable impact on the Healthcare System. Classic consequences of prenatal exposure to hyperglycemia encompass (early) spontaneous abortions, perinatal death and malformations. The spectrum of related malformations comprises some recurrent blastogenic monotopic patterns, i.e. holoprosencephaly, caudal dysgenesis and oculoauriculovertebral spectrum, as well as pleiotropic syndromes, i.e. femoral hypoplasia-unusual face syndrome. Despite this, most malformed fetuses display multiple blastogenic defects of the VACTERL type, whose (apparently) casual combination preclude recognizing recurrent patterns, but accurately testifies to their developmental stage at onset. With the application of developmental biology in modern medicine, the effects of diabetes on the unborn patient are expanded to include the predisposition to develop insulin resistance in adulthood. The mechanisms underlying the transgenerational correlation between maternal diabetes and proneness to adult disorders in the offspring remain unclear, and the epigenetic plasticity may represent the missing link. In this scenario, a development-driven summary of the multifaced consequences of maternal diabetes on fertility and child health may add a practical resource to the repertoire of available information on early stages of embryogenesis. PMID- 23653579 TI - VACTERL-H Association and Fanconi Anemia. AB - Patients with Fanconi anemia (FA) often have birth defects that suggest the diagnosis of VATER association. A review of 2,245 cases of FA reported in the literature from 1927 to 2012 identified 108 cases with at least 3 of the defining features of VATER association; only 29 had been so noted by the authors. The FA VATER signature was the significantly higher frequency of renal and limb (radial and/or thumb) anomalies (93% of cases had both) compared with less than 30% of VATER patients; the presence of one or both of these birth defects should lead to testing for FA. The relative frequencies of the genotypes of the patients with FA VATER were strikingly different from those expected from the general FA population; only 19% were FANCA, while 21% were FANCB, 14% FANCD1/BRCA2, and 12% FANCD2. Consistent with their genotypes, those with the FA VATER phenotype had a worse prognosis than FA patients with milder phenotypes, with shorter median survival and earlier onset of malignancies. The early identification of FA patients among infants with VATER association should lead to earlier more proactive management, such as cancer surveillance and genetic counseling. PMID- 23653580 TI - Clinical, genetic and environmental factors associated with congenital vertebral malformations. AB - Congenital vertebral malformations (CVM) pose a significant health problem because they can be associated with spinal deformities, such as congenital scoliosis and kyphosis, in addition to various syndromes and other congenital malformations. Additional information remains to be learned regarding the natural history of congenital scoliosis and related health problems. Although significant progress has been made in understanding the process of somite formation, which gives rise to vertebral bodies, there is a wide gap in our understanding of how genetic factors contribute to CVM development. Maternal diabetes during pregnancy most commonly contributes to the occurrence of CVM, followed by other factors such as hypoxia and anticonvulsant medications. This review highlights several emerging clinical issues related to CVM, including pulmonary and orthopedic outcome in congenital scoliosis. Recent breakthroughs in genetics related to gene and environment interactions associated with CVM development are discussed. The Klippel-Feil syndrome which is associated with cervical segmentation abnormalities is illustrated as an example in which animal models, such as the zebrafish, can be utilized to provide functional evidence of pathogenicity of identified mutations. PMID- 23653581 TI - Evaluation of Clinical Manifestations in Patients with Severe Lymphedema with and without CCBE1 Mutations. AB - The lymphedema-lymphangiectasia-intellectual disability (Hennekam) syndrome (HS) is characterised by a widespread congenital lymph vessel dysplasia manifesting as congenital lymphedema of the limbs and intestinal lymphangiectasia, accompanied by unusual facial morphology, variable intellectual disabilities and infrequently malformations. The syndrome is heterogeneous as mutations in the gene CCBE1 have been found responsible for the syndrome in only a subset of patients. We investigated whether it would be possible to predict the presence of a CCBE1 mutation based on phenotype by collecting clinical data of patients diagnosed with HS, with or without a CCBE1 mutation. We report here the results of 13 CCBE1 positive patients, 16 CCBE1 negative patients, who were clinically found to have classical HS, and 8 patients in whom the diagnosis was considered possible, but not certain, and in whom no CCBE1 mutation was identified. We found no statistically significant phenotypic differences between the 2 groups with the clinical HS phenotype, although the degree of lymphatic dysplasia tended to be more pronounced in the mutation positive group. We also screened 158 patients with less widespread and less pronounced forms of lymphatic dysplasia for CCBE1 mutations, and no mutation was detected in this group. Our results suggest that (1) CCBE1 mutations are present only in patients with a likely clinical diagnosis of HS, and not in patients with less marked forms of lymphatic dysplasia, and (2) that there are no major phenotypic differences between HS patients with or without CCBE1 mutations. PMID- 23653582 TI - X Chromosome-Inactivation Patterns in 31 Individuals with PHACE Syndrome. AB - Segmental hemangiomas of the head and neck can be associated with multiple congenital anomalies in the disorder known as PHACE syndrome (OMIM 606519) (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, and eye anomalies). All reported cases of PHACE syndrome to date have been sporadic, and the genetic basis of this disorder has not yet been established. PHACE syndrome has a striking female predominance which has raised the question of X-linked inheritance. In this study, the X chromosome-inactivation (XCI) patterns of 31 females with PHACE syndrome and their mothers were analyzed using blood-derived DNA and X-chromosome locus methylation assay. This study was performed to test the hypothesis that some cases of PHACE syndrome are due to X linked inheritance and favorable skewing in the mothers may protect against a severe phenotype, but the clinical phenotype may be unmasked in daughters with a random pattern of X-inactivation. XCI analysis was informative in 27/31 mothers. Our results identified skewed XCI in 5 of 27 (19%) informative mothers, which is not statistically significant with a p value of 0.41. None of the mothers reported significant medical problems, although a full PHACE work-up has not been performed in these individuals. Skewed XCI in the mothers of children with PHACE was identified in only a minority of cases. Based on these results, genetic heterogeneity is likely in PHACE syndrome, although it is possible a subset of cases are caused by a mutation in an X-linked gene. PMID- 23653583 TI - Hereditary Hemorrhagic Telangiectasia: Breakpoint Characterization of a Novel Large Deletion in ACVRL1 Suggests the Causing Mechanism. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Mutations in either ENG or ACVRL1 account for around 85% of cases, and 10% are large deletions and duplications. Here we present a large novel deletion in ACVRL1 gene and its molecular characterization in a 3 generation Italian family. We employed short tandem repeats (STRs) analysis, direct sequencing, multiplex ligation-dependant probe amplification (MLPA) analysis, and 'deletion specific' PCR methods. STRs Analysis at ENG and ACVRL1 loci suggested a positive linkage for ACVRL1. Direct sequencing of this gene did not identify any mutations, while MLPA identified a large deletion. These results were confirmed and exactly characterized with a 'deletion-specific' PCR: the deletion size is 4,594 bp and breakpoints in exon 3 and intron 8 show the presence of short direct repeats of 7 bp [GCCCCAC]. We hypothesize, as causative molecular mechanism, the replication slippage model. Understanding the fine mechanisms associated with genomic rearrangements may indicate the nonrandomness of these events, highlighting hot spots regions. The complete concordance among MLPA, STRs analysis and 'deletion-specific PCR' supports the usefulness of MLPA in HHT molecular analysis. PMID- 23653585 TI - Report on a patient with a 12q24.31 microdeletion inherited from an insulin dependent diabetes mellitus father. AB - We report a 2.3-year-old female patient with global developmental delay, infantile spasms, hypotonia, microcephaly, flat face, full cheeks, macroglossia, highly arched palate, retro-gnathia, narrow ear orifices, and cafe-au-lait spots. Molecular karyotyping revealed approximately a 1-Mb interstitial deletion of the long arm of one chromosome 12, del(12)(q24.31). The same deletion was identified in her father who presents insulin-dependent diabetes mellitus (IDDM) diagnosed at 14 years. Only one other patient with a similar de novo deletion has been reported previously [Mol Syndromol 2010;1:42-45]. A phenotype-genotype correlation is discussed, and the description of a novel rare microdeletion entity is raised. PMID- 23653584 TI - The c.7409G>A (p.Cys2470Tyr) Variant of FBN1: Phenotypic Variability across Three Generations. AB - Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the fibrillin gene FBN1, which encodes an extracellular matrix glycoprotein. Major features of Marfan syndrome occur in the ocular, cardiovascular, and skeletal systems as well as in the dura mater. Approximately 60% of known disease-causing mutations are missense mutations of single amino acid residues. Effects on the cardiovascular system are classically associated with mutations in exons 24-32 of the 65 FBN1 exons and many, though not all, reports associate missense mutations in exons 59-65 with a mild cardiovascular phenotype. Here we present 5 related individuals among whom a c.7409G>A (p.Cys2470Tyr) missense variant in exon 59 of FBN1 is associated with significant cardiovascular features. The index case also had an apparently de novo 46,XX,del(5)(q33.1q33.3) deletion on chromosome 5. This family demonstrates skeletal, dermatological and neurological features consistent with Marfan syndrome but lacks significant ophthalmological findings to date. These findings suggest that FBN1 C-terminal missense mutations may not confer the ophthalmological features of Marfan syndrome, but they also confer a more significant risk for cardiovascular pathology than that suggested by previous studies. Furthermore, clinical data from this family supports the previously reported association of dural ectasia with C-terminal mutations. PMID- 23653586 TI - A 1.3-mb 7q11.23 atypical deletion identified in a cohort of patients with williams-beuren syndrome. AB - Williams-Beuren syndrome is a rare multisystem neurodevelopmental disorder caused by a 1.55-1.84-Mb hemizygous deletion on chromosome 7q11.23. The classical phenotype consists of characteristic facial features, supravalvular aortic stenosis, intellectual disability, overfriendliness, and visuospatial impairment. So far, 26-28 genes have been shown to contribute to the multisystem phenotype associated with Williams-Beuren syndrome. Among them, haploinsufficiency of the ELN gene has been shown to cause the cardiovascular anomalies. Identification of patients with atypical deletions has provided valuable information for genotype phenotype correlation, in which other genes such as LIMK1,CLIP2, GTF2IRD1, or GTF2I have been correlated with specific cognitive profiles or craniofacial features. Here, we report the clinical and molecular characteristics of a patient with an atypical deletion that does not include the GTF2I gene and only partially includes the GTF2IRD1 gene. PMID- 23653587 TI - COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type. AB - Spondylometaphyseal dysplasia Algerian type (SMD-A) is an autosomal dominant disorder that was first reported in an Algerian family by Kozlowski et al. [Pediatr Radiol 1988;18:221-226]. Kozlowski's group reported a sporadic case in a 12-year-old Polish boy. They proposed SMD-A as a distinctive skeletal dysplasia and also suggested that a case of SMD reported by Schmidt et al. [J Pediatr 1963;63:106-112] might have had the same disorder. Afterwards, however, no additional report has emerged to date. In addition, the question whether SMD-A belongs to type II collagenopathy (a group of disorders due to a heterozygous mutation of COL2A1) has been continuously under debate. Here we report a 7-year old Japanese boy with a heterozygous missense mutation in COL2A1, 2582G>T (Gly861Val), whose phenotype matched that of SMD-A. Our observation supports the hypothesis that SMD-A is a variant of type II collagenopathy. PMID- 23653588 TI - Report of the First Clinical Case of a Moroccan Kabuki Patient with a Novel MLL2 Mutation. AB - Kabuki syndrome (also known as Niikawa-Kuroki syndrome) is a rare autosomal disorder, characterized by an unusual face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, mental retardation, and immunological defects. Point mutations and large intragenic deletions and duplications of the mixed lineage leukemia 2 (MLL2) and exons deletions of lysine demethylase 6A (-KDM6A) genes have been identified as its underlying causes. We report on the first description of a Moroccan Kabuki syndrome patient with typical facial features, developmental delay, finger pads, and other anomalies carrying a novel splice site mutation in the MLL2 gene that produces a truncated and likely pathogenetic form of MLL2 protein. PMID- 23653589 TI - An old test for new neurons: refining the Morris water maze to study the functional relevance of adult hippocampal neurogenesis. AB - The Morris water maze represents the de-facto standard for testing hippocampal function in laboratory rodents. In the field of adult hippocampal neurogenesis, however, using this paradigm to assess the functional relevance of the new neurons yielded surprisingly inconsistent results. While some authors found aspects of water maze performance to be linked to adult neurogenesis, others obtained different results or could not demonstrate any effect of manipulating adult neurogenesis. In this review we discuss evidence that the large diversity of protocols and setups used is an important aspect in interpreting the differences in the results that have been obtained. Even simple parameters such as pool size, number, and configuration of visual landmarks, or number of trials can become highly relevant for getting the new neurons involved at all. Sets of parameters are often chosen with implicit or explicit concepts in mind and these might lead to different views on the function of adult-generated neurons. We propose that the classical parameters usually used to measure spatial learning performance in the water maze might not be particularly well-suited to sensitively and specifically detect the supposedly highly specific functional changes elicited by the experimental modulation of adult hippocampal neurogenesis. As adult neurogenesis is supposed to affect specific aspects of information processing only in the hippocampus, any claim for a functional relevance of the new neurons has to be based on hippocampus-specific parameters. We also placed a special emphasis on the fact that the dentate gyrus (DG) facilitates the differentiation between contexts as opposed to just differentiating places. In conclusion, while the Morris water maze has proven to be one of the most effective testing paradigms to assess hippocampus-dependent spatial learning, new and more specific questions ask for new parameters. Therefore, the full potential of the water maze task remains to be tapped. PMID- 23653590 TI - Studying subcellular detail in fixed astrocytes: dissociation of morphologically intact glial cells (DIMIGs). AB - Studying the distribution of astrocytic antigens is particularly hard when they are localized in their fine, peripheral astrocyte processes (PAPs), since these processes often have a diameter comparable to vesicles and small organelles. The most appropriate technique is immunoelectron microscopy, which is, however, a time-consuming procedure. Even in high resolution light microscopy, antigen localization is difficult to detect due to the small dimensions of these processes, and overlay from antigen in surrounding non-glial cells. Yet, PAPs frequently display antigens related to motility and glia-synaptic interaction. Here, we describe the dissociation of morphologically intact glial cells (DIMIGs), permitting unambiguous antigen localization using epifluorescence microscopy. Astrocytes are dissociated from juvenile (p13-15) mouse cortex by applying papain treatment and cytospin centrifugation to attach the cells to a slide. The cells and their complete processes including the PAPs is thus projected in 2D. The entire procedure takes 2.5-3 h. We show by morphometry that the diameter of DIMIGs, including the PAPs is similar to that of astrocytes in situ. In contrast to cell culture, results derived from this procedure allow for direct conclusions relating to (1) the presence of an antigen in cortical astrocytes, (2) subcellular antigen distribution, in particular when localized in the PAPs. The detailed resolution is shown in an exemplary study of the organization of the astrocytic cytoskeleton components actin, ezrin, tubulin, and GFAP. The distribution of connexin 43 in relation to a single astrocyte's process tree is also investigated. PMID- 23653592 TI - Methylene blue induces macroautophagy through 5' adenosine monophosphate activated protein kinase pathway to protect neurons from serum deprivation. AB - Methylene blue has been shown to be neuroprotective in multiple experimental neurodegenerative disease models. However, the mechanisms underlying the neuroprotective effects have not been fully elucidated. Previous studies have shown that macroautophagy has multiple beneficial roles for maintaining normal cellular homeostasis and that induction of macroautophagy after myocardial ischemia is protective. In the present study we demonstrated that methylene blue could protect HT22 hippocampal cell death induced by serum deprivation, companied by induction of macroautophagy. We also found that methylene blue-mediated neuroprotection was abolished by macroautophagy inhibition. Interestingly, 5' adenosine monophosphate-activated protein kinase (AMPK) signaling, but not inhibition of mammalian target of rapamycin signaling, was activated at 12 and 24 h after methylene blue treatment in a dose-dependent manner. Methylene blue induced macroautophagy was blocked by AMPK inhibitor. Consistent with in vitro data, macroautophagy was induced in the cortex and hippocampus of mouse brains treated with methylene blue. Our findings suggest that methylene blue-induced neuroprotection is mediated, at least in part, by macroautophagy though activation of AMPK signaling. PMID- 23653593 TI - MANTA--an open-source, high density electrophysiology recording suite for MATLAB. AB - The distributed nature of nervous systems makes it necessary to record from a large number of sites in order to decipher the neural code, whether single cell, local field potential (LFP), micro-electrocorticograms (MUECoG), electroencephalographic (EEG), magnetoencephalographic (MEG) or in vitro micro electrode array (MEA) data are considered. High channel-count recordings also optimize the yield of a preparation and the efficiency of time invested by the researcher. Currently, data acquisition (DAQ) systems with high channel counts (>100) can be purchased from a limited number of companies at considerable prices. These systems are typically closed-source and thus prohibit custom extensions or improvements by end users. We have developed MANTA, an open-source MATLAB-based DAQ system, as an alternative to existing options. MANTA combines high channel counts (up to 1440 channels/PC), usage of analog or digital headstages, low per channel cost (<$90/channel), feature-rich display and filtering, a user-friendly interface, and a modular design permitting easy addition of new features. MANTA is licensed under the GPL and free of charge. The system has been tested by daily use in multiple setups for >1 year, recording reliably from 128 channels. It offers a growing list of features, including integrated spike sorting, PSTH and CSD display and fully customizable electrode array geometry (including 3D arrays), some of which are not available in commercial systems. MANTA runs on a typical PC and communicates via TCP/IP and can thus be easily integrated with existing stimulus generation/control systems in a lab at a fraction of the cost of commercial systems. With modern neuroscience developing rapidly, MANTA provides a flexible platform that can be rapidly adapted to the needs of new analyses and questions. Being open-source, the development of MANTA can outpace commercial solutions in functionality, while maintaining a low price-point. PMID- 23653594 TI - Different patterns of amygdala priming differentially affect dentate gyrus plasticity and corticosterone, but not CA1 plasticity. AB - Stress-induced activation of the amygdala is involved in the modulation of memory processes in the hippocampus. However, stress effects on amygdala and memory remain complex. The activation of the basolateral amygdala (BLA) was found to modulate plasticity in other brain areas, including the hippocampus. We previously demonstrated a differential effect of BLA priming on long-term potentiation (LTP) in the CA1 and the dentate gyrus (DG). While BLA priming suppressed LTP in CA1, it was found to enhance it in the DG. However, since the amygdala itself is amenable to experience-induced plasticity it is thus conceivable that when activity within the amygdala is modified this will have impact on the way the amygdala modulates activity and plasticity in other brain areas. In the current study, we examined the effects of different patterns of BLA activation on the modulation of LTP in the DG and CA1, as well as on serum corticosterone (CORT). In CA1, BLA-priming impaired LTP induction as was reported before. In contrast, in the DG, varying BLA stimulation intensity and frequency resulted in differential effects on LTP, ranging from no effect to strong impairment or enhancement. Varying BLA stimulation patterns resulted in also differential alterations in Serum CORT, leading to higher CORT levels being positively correlated with LTP magnitude in DG but not in CA1. The results support the notion of a differential role for the DG in aspects of memory, and add to this view the possibility that DG-associated aspects of memory will be enhanced under more emotional or stressful conditions. It is interesting to think of BLA patterns of activation and the differential levels of circulating CORT as two arms of the emotional and stress response that attempt to synchronize brain activity to best meet the challenge. It is foreseeable to think of abnormal such synchronization under extreme conditions, which would lead to the development of maladaptive behavior. PMID- 23653591 TI - Cholinergic connectivity: it's implications for psychiatric disorders. AB - Acetylcholine has been implicated in both the pathophysiology and treatment of a number of psychiatric disorders, with most of the data related to its role and therapeutic potential focusing on schizophrenia. However, there is little thought given to the consequences of the documented changes in the cholinergic system and how they may affect the functioning of the brain. This review looks at the cholinergic system and its interactions with the intrinsic neurotransmitters glutamate and gamma-amino butyric acid as well as those with the projection neurotransmitters most implicated in the pathophysiologies of psychiatric disorders; dopamine and serotonin. In addition, with the recent focus on the role of factors normally associated with inflammation in the pathophysiologies of psychiatric disorders, links between the cholinergic system and these factors will also be examined. These interfaces are put into context, primarily for schizophrenia, by looking at the changes in each of these systems in the disorder and exploring, theoretically, whether the changes are interconnected with those seen in the cholinergic system. Thus, this review will provide a comprehensive overview of the connectivity between the cholinergic system and some of the major areas of research into the pathophysiologies of psychiatric disorders, resulting in a critical appraisal of the potential outcomes of a dysregulated central cholinergic system. PMID- 23653595 TI - Optogenetic elevation of endogenous glucocorticoid level in larval zebrafish. AB - The stress response is a suite of physiological and behavioral processes that help to maintain or reestablish homeostasis. Central to the stress response is the hypothalamic-pituitary-adrenal (HPA) axis, as it releases crucial hormones in response to stress. Glucocorticoids (GCs) are the final effector hormones of the HPA axis, and exert a variety of actions under both basal and stress conditions. Despite their far-reaching importance for health, specific GC effects have been difficult to pin-down due to a lack of methods for selectively manipulating endogenous GC levels. Hence, in order to study stress-induced GC effects, we developed a novel optogenetic approach to selectively manipulate the rise of GCs triggered by stress. Using this approach, we could induce both transient hypercortisolic states and persistent forms of hypercortisolaemia in freely behaving larval zebrafish. Our results also established that transient hypercortisolism leads to enhanced locomotion shortly after stressor exposure. Altogether, we present a highly specific method for manipulating the gain of the stress axis with high temporal accuracy, altering endocrine and behavioral responses to stress as well as basal GC levels. Our study offers a powerful tool for the analysis of rapid (non-genomic) and delayed (genomic) GC effects on brain function and behavior, feedbacks within the stress axis and developmental programming by GCs. PMID- 23653596 TI - Neural dynamics and information representation in microcircuits of motor cortex. AB - The brain has to analyze and respond to external events that can change rapidly from time to time, suggesting that information processing by the brain may be essentially dynamic rather than static. The dynamical features of neural computation are of significant importance in motor cortex that governs the process of movement generation and learning. In this paper, we discuss these features based primarily on our recent findings on neural dynamics and information coding in the microcircuit of rat motor cortex. In fact, cortical neurons show a variety of dynamical behavior from rhythmic activity in various frequency bands to highly irregular spike firing. Of particular interest are the similarity and dissimilarity of the neuronal response properties in different layers of motor cortex. By conducting electrophysiological recordings in slice preparation, we report the phase response curves (PRCs) of neurons in different cortical layers to demonstrate their layer-dependent synchronization properties. We then study how motor cortex recruits task-related neurons in different layers for voluntary arm movements by simultaneous juxtacellular and multiunit recordings from behaving rats. The results suggest an interesting difference in the spectrum of functional activity between the superficial and deep layers. Furthermore, the task-related activities recorded from various layers exhibited power law distributions of inter-spike intervals (ISIs), in contrast to a general belief that ISIs obey Poisson or Gamma distributions in cortical neurons. We present a theoretical argument that this power law of in vivo neurons may represent the maximization of the entropy of firing rate with limited energy consumption of spike generation. Though further studies are required to fully clarify the functional implications of this coding principle, it may shed new light on information representations by neurons and circuits in motor cortex. PMID- 23653598 TI - On the similarities and differences of non-traumatic sound exposure during the critical period and in adulthood. AB - There is an almost dogmatic view of the different effects of moderate-level sound stimulation in neonatal vs. adult animals. It is often stated that exposure in neonates results in an expansion of the cortical area that responds to the frequencies present in the sound, being either pure tones or frequency modulated sounds. In contrast, recent findings on stimulating adult animals for a sufficiently long time with similar sounds show a contraction of the cortical region responding to those sounds. In this review I will suggest that most neonatal animal results have been wrongly interpreted (albeit generally not by the original authors) and that the changes caused in the critical period (CP) and in adulthood are very similar. Thus, the mechanisms leading to the cortical map changes appear to be similar in the CP and in adulthood. Despite this similarity, the changes induced in the CP are occurring faster and are generally permanent (unless extensive training paradigms to revert the changes are involved), whereas in adults the induction is slower and a slow recovery (months) to pre-exposure conditions takes place. PMID- 23653599 TI - Deciphering the role of CA1 inhibitory circuits in sharp wave-ripple complexes. AB - Sharp wave-ripples (SWRs) are population oscillatory patterns in hippocampal LFPs during deep sleep and immobility, involved in the replay of memories acquired during wakefulness. SWRs have been extensively studied, but their exact generation mechanism is still unknown. A computational model has suggested that fast perisomatic inhibition may generate the high frequency ripples (~200 Hz). Another model showed how replay of memories can be controlled by various classes of inhibitory interneurons targeting specific parts of pyramidal cells (PC) and firing at particular SWR phases. Optogenetic studies revealed new roles for interneuronal classes and rich dynamic interplays between them, shedding new light in their potential role in SWRs. Here, we integrate these findings in a conceptual model of how dendritic and somatic inhibition may collectively contribute to the SWR generation. We suggest that sharp wave excitation and basket cell (BC) recurrent inhibition synchronises BC spiking in ripple frequencies. This rhythm is imposed on bistratified cells which prevent pyramidal bursting. Axo-axonic and stratum lacunosum/moleculare interneurons are silenced by inhibitory inputs originating in the medial septum. PCs receiving rippling inhibition in both dendritic and perisomatic areas and excitation in their apical dendrites, exhibit sparse ripple phase-locked spiking. PMID- 23653597 TI - The CRISP theory of hippocampal function in episodic memory. AB - Over the past four decades, a "standard framework" has emerged to explain the neural mechanisms of episodic memory storage. This framework has been instrumental in driving hippocampal research forward and now dominates the design and interpretation of experimental and theoretical studies. It postulates that cortical inputs drive plasticity in the recurrent cornu ammonis 3 (CA3) synapses to rapidly imprint memories as attractor states in CA3. Here we review a range of experimental studies and argue that the evidence against the standard framework is mounting, notwithstanding the considerable evidence in its support. We propose CRISP as an alternative theory to the standard framework. CRISP is based on Context Reset by dentate gyrus (DG), Intrinsic Sequences in CA3, and Pattern completion in cornu ammonis 1 (CA1). Compared to previous models, CRISP uses a radically different mechanism for storing episodic memories in the hippocampus. Neural sequences are intrinsic to CA3, and inputs are mapped onto these intrinsic sequences through synaptic plasticity in the feedforward projections of the hippocampus. Hence, CRISP does not require plasticity in the recurrent CA3 synapses during the storage process. Like in other theories DG and CA1 play supporting roles, however, their function in CRISP have distinct implications. For instance, CA1 performs pattern completion in the absence of CA3 and DG contributes to episodic memory retrieval, increasing the speed, precision, and robustness of retrieval. We propose the conceptual theory, discuss its implications for experimental results and suggest testable predictions. It appears that CRISP not only accounts for those experimental results that are consistent with the standard framework, but also for results that are at odds with the standard framework. We therefore suggest that CRISP is a viable, and perhaps superior, theory for the hippocampal function in episodic memory. PMID- 23653600 TI - Robust training attenuates TBI-induced deficits in reference and working memory on the radial 8-arm maze. AB - Globally, it is estimated that nearly 10 million people sustain severe brain injuries leading to hospitalization and/or death every year. Amongst survivors, traumatic brain injury (TBI) results in a wide variety of physical, emotional and cognitive deficits. The most common cognitive deficit associated with TBI is memory loss, involving impairments in spatial reference and working memory. However, the majority of research thus far has characterized the deficits associated with TBI on either reference or working memory systems separately, without investigating how they interact within a single task. Thus, we examined the effects of TBI on short-term working and long-term reference memory using the radial 8-arm maze (RAM) with a sequence of four baited and four unbaited arms. Subjects were given 10 daily trials for 6 days followed by a memory retrieval test 2 weeks after training. Multiple training trials not only provide robust training, but also test the subjects' ability to frequently update short-term memory while learning the reference rules of the task. Our results show that TBI significantly impaired short-term working memory function on previously acquired spatial information but has little effect on long-term reference memory. Additionally, TBI significantly increased working memory errors during acquisition and reference memory errors during retention testing 2 weeks later. With a longer recovery period after TBI, the robust RAM training mitigated the reference memory deficit in retention but not the short-term working memory deficit during acquisition. These results identify the resiliency and vulnerabilities of short-term working and long-term reference memory to TBI in the context of robust training. The data highlight the role of cognitive training and other behavioral remediation strategies implicated in attenuating deficits associated with TBI. PMID- 23653601 TI - Shared neural substrates of emotionally enhanced perceptual and mnemonic vividness. AB - It is well-known that emotionally salient events are remembered more vividly than mundane ones. Our recent research has demonstrated that such memory vividness (Mviv) is due in part to the subjective experience of emotional events as more perceptually vivid, an effect we call emotionally enhanced vividness (EEV). The present study built on previously reported research in which fMRI data were collected while participants rated relative levels of visual noise overlaid on emotionally salient and neutral images. Ratings of greater EEV were associated with greater activation in the amygdala and visual cortex. In the present study, we measured BOLD activation that predicted recognition Mviv for these same images 1 week later. Results showed that, after controlling for differences between scenes in low-level objective features, hippocampus activation uniquely predicted subsequent Mviv. In contrast, amygdala and visual cortex regions that were sensitive to EEV were also modulated by subsequent ratings of Mviv. These findings suggest shared neural substrates for the influence of emotional salience on perceptual and mnemonic vividness, with amygdala and visual cortex activation at encoding contributing to the experience of both perception and subsequent memory. PMID- 23653602 TI - Correlations between brain activity and components of motor learning in middle aged adults: an fMRI study. AB - Implicit learning may be shown by improvements in motor performance, which occur unconsciously with practice and are typically restricted to the task that was practiced. The purpose of this study was to examine behaviorally relevant brain activation associated with change in motor behavior during sequence-specific motor learning of a perceptuomotor continuous tracking (CT) task in middle-aged adults. To gain further insight into the neural structures associated with change in motor behavior, overall improvement in tracking (root mean square error; RMSE) was decomposed into two components-temporal precision and spatial accuracy. We hypothesized that individual differences in CT task performance would be evident in unique networks of brain activation that supported overall tracking behavior as well-temporal and spatial tracking accuracy. A group of middle-aged healthy individuals performed the CT task, which contains repeated and random segments for seven days. Functional magnetic resonance imaging (fMRI) data was collected on the first and seventh day while the participants performed the task. Subjects did not gain explicit awareness of the sequence. To assess behaviorally-relevant changes in the blood oxygenation level-dependent (BOLD) response associated with individual sequence-specific tracking performance, separate statistical images were created for each participant and weighted by the difference score between repeated and random performance for days 1 and 7. Given the similarity of performance for random and repeated sequences during early practice, there were no unique networks evident at day 1. On Day 7 the resultant group statistical fMRI image demonstrated a positive correlation between RMSE difference score and bilateral cerebellar activation (lobule VI). In addition, individuals who showed greater sequence-specific temporal precision demonstrated increased activation in the precentral gyrus, middle occipital gyrus, and putamen of the right hemisphere and the thalamus, cuneus, and cerebellum of the left hemisphere. Activation of this neural network further confirms its involvement in timing of movements as it has been previously associated with task performance when individuals are instructed to emphasize speed over accuracy. In the present study, behavioral performance was associated with neural correlates of individual variation in motor learning that characterized the ability to implicitly learn a sequence specific CT task. PMID- 23653603 TI - Context-dependent generalization. AB - The pattern of generalization following motor learning can provide a probe on the neural mechanisms underlying learning. For example, the breadth of generalization to untrained regions of space after visuomotor adaptation to targets in a restricted region of space has been attributed to the directional tuning properties of neurons in the motor system. Building on this idea, the effect of different types of perturbations on generalization (e.g., rotation vs. visual translation) have been attributed to the selection of differentially tuned populations. Overlooked in this discussion is consideration of how the context of the training environment may constrain generalization. Here, we explore the role of context by having participants learn a visuomotor rotation or a translational shift in two different contexts, one in which the array of targets were presented in a circular arrangement and the other in which they were presented in a rectilinear arrangement. The perturbation and environments were either consistent (e.g., rotation with circular arrangement) or inconsistent (e.g., rotation with rectilinear arrangement). The pattern of generalization across the workspace was much more dependent on the context of the environment than on the perturbation, with broad generalization for the rectilinear arrangement for both types of perturbations. Moreover, the generalization pattern for this context was evident, even when the perturbation was introduced in a gradual manner, precluding the use of an explicit strategy. We describe how current models of generalization might be modified to incorporate these results, building on the idea that context provides a strong bias for how the motor system infers the nature of the visuomotor perturbation and, in turn, how this information influences the pattern of generalization. PMID- 23653604 TI - The influence of group membership on the neural correlates involved in empathy. AB - Empathy involves affective, cognitive, and emotion regulative components. The affective component relies on the sharing of emotional states with others and is discussed here in relation to the human Mirror System. On the other hand, the cognitive component is related to understanding the mental states of others and draws upon literature surrounding Theory of Mind (ToM). The final component, emotion regulation, depends on executive function and is responsible for managing the degree to which explicit empathic responses are made. This mini-review provides information on how each of the three components is individually affected by group membership and how this leads to in-group bias. PMID- 23653605 TI - Common muscle synergies for balance and walking. AB - Little is known about the integration of neural mechanisms for balance and locomotion. Muscle synergies have been studied independently in standing balance and walking, but not compared. Here, we hypothesized that reactive balance and walking are mediated by a common set of lower-limb muscle synergies. In humans, we examined muscle activity during multidirectional support-surface perturbations during standing and walking, as well as unperturbed walking at two speeds. We show that most muscle synergies used in perturbations responses during standing were also used in perturbation responses during walking, suggesting common neural mechanisms for reactive balance across different contexts. We also show that most muscle synergies using in reactive balance were also used during unperturbed walking, suggesting that neural circuits mediating locomotion and reactive balance recruit a common set of muscle synergies to achieve task-level goals. Differences in muscle synergies across conditions reflected differences in the biomechanical demands of the tasks. For example, muscle synergies specific to walking perturbations may reflect biomechanical challenges associated with single limb stance, and muscle synergies used during sagittal balance recovery in standing but not walking were consistent with maintaining the different desired center of mass motions in standing vs. walking. Thus, muscle synergies specifying spatial organization of muscle activation patterns may define a repertoire of biomechanical subtasks available to different neural circuits governing walking and reactive balance and may be recruited based on task-level goals. Muscle synergy analysis may aid in dissociating deficits in spatial vs. temporal organization of muscle activity in motor deficits. Muscle synergy analysis may also provide a more generalizable assessment of motor function by identifying whether common modular mechanisms are impaired across the performance of multiple motor tasks. PMID- 23653606 TI - Correlations of theory of mind deficits with clinical patterns and quality of life in schizophrenia. AB - BACKGROUND: Numerous studies have demonstrated the existence of theory of mind (ToM) impairments in patients with schizophrenia. The clinical consequences of these impairments are currently under debate. Accumulated evidence suggests that ToM deficits are linked to negative and disorganization symptoms, but direct correlations are lacking. Moreover, it is unclear whether ToM deficits are related to reduced quality of life (QoL). METHODS: To extend the understanding of objective (i.e., clinical symptoms) and subjective (QoL) correlates of impaired ToM, we assessed 206 patients with schizophrenia based on performance of an ecological task (Versailles-Situational Intention Reading, V-SIR), a Communication Disorders Scale (SCD), the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression rating, and a QoL questionnaire (S-QoL). Statistical inferences were drawn from correlations analyses considering both factors/subscales aggregates and single items. RESULTS: ToM performance was negatively correlated to disorganization and negative PANSS factors. Poor V-SIR performance was correlated with "conceptual disorganization," "difficulties in abstract thinking," and "apathy/social withdrawal." The SCD was correlated with "negative," "disorganization," and "anxiety/depression" PANSS factors. The S-QoL total score was not significantly correlated with ToM performance. Only the item "difficulties in expressing feelings" was significantly correlated with poorer V SIR performance. CONCLUSION: We discuss the intriguing paucity of the results and what they reveal about the difficulties faced by psychiatrists with patients not expressing complaints about lack of social skills. PMID- 23653607 TI - Addiction and choice: theory and new data. AB - Addiction's biological basis has been the focus of much research. The findings have persuaded experts and the public that drug use in addicts is compulsive. But the word "compulsive" identifies patterns of behavior, and all behavior has a biological basis, including voluntary actions. Thus, the question is not whether addiction has a biology, which it must, but whether it is sensible to say that addicts use drugs compulsively. The relevant research shows most of those who meet the American Psychiatric Association's criteria for addiction quit using illegal drugs by about age 30, that they usually quit without professional help, and that the correlates of quitting include legal concerns, economic pressures, and the desire for respect, particularly from family members. That is, the correlates of quitting are the correlates of choice not compulsion. However, addiction is, by definition, a disorder, and thereby not beneficial in the long run. This is precisely the pattern of choices predicted by quantitative choice principles, such as the matching law, melioration, and hyperbolic discounting. Although the brain disease model of addiction is perceived by many as received knowledge it is not supported by research or logic. In contrast, well established, quantitative choice principles predict both the possibility and the details of addiction. PMID- 23653608 TI - Persistence of internal representations of alternative voluntary actions. AB - We have investigated a situation in which externally available response alternatives and their internal representations could be dissociated, by suddenly removing some action alternatives from the response space during the interval between the free selection and the execution of a voluntary action. Choice reaction times in this situation were related to the number of initially available response alternatives, rather than to the number of alternatives available effectively available after the change in the external environment. The internal representations of response alternatives appeared to persist after external changes actually made the corresponding action unavailable. This suggests a surprising dynamics of voluntary action representations: counterfactual response alternatives persist, and may even be actively maintained, even when they are not available in reality. Our results highlight a representational basis for the counterfactual course of action. Such representations may play a key role in feelings of regret, disappointment, or frustration. These feelings all involve persistent representation of counterfactual response alternatives that may not actually be available in the environment. PMID- 23653609 TI - Editorial: Action effects in perception and action. PMID- 23653610 TI - Production is at the left edge of the PDC but still central: response to commentaries. PMID- 23653611 TI - What belongs together goes together: the speaker-hearer perspective. A commentary on MacDonald's PDC account. PMID- 23653612 TI - Production, comprehension, and synthesis: a communicative perspective on language. PMID- 23653613 TI - Early ERP Signature of Hearing Impairment in Visual Rhyme Judgment. AB - Postlingually acquired hearing impairment (HI) is associated with changes in the representation of sound in semantic long-term memory. An indication of this is the lower performance on visual rhyme judgment tasks in conditions where phonological and orthographic cues mismatch, requiring high reliance on phonological representations. In this study, event-related potentials (ERPs) were used for the first time to investigate the neural correlates of phonological processing in visual rhyme judgments in participants with acquired HI and normal hearing (NH). Rhyme task word pairs rhymed or not and had matching or mismatching orthography. In addition, the inter-stimulus interval (ISI) was manipulated to be either long (800 ms) or short (50 ms). Long ISIs allow for engagement of explicit, top-down processes, while short ISIs limit the involvement of such mechanisms. We hypothesized lower behavioral performance and N400 and N2 deviations in HI in the mismatching rhyme judgment conditions, particularly in short ISI. However, the results showed a different pattern. As expected, behavioral performance in the mismatch conditions was lower in HI than in NH in short ISI, but ERPs did not differ across groups. In contrast, HI performed on a par with NH in long ISI. Further, HI, but not NH, showed an amplified N2-like response in the non-rhyming, orthographically mismatching condition in long ISI. This was also the rhyme condition in which participants in both groups benefited the most from the possibility to engage top-down processes afforded with the longer ISI. Taken together, these results indicate an early ERP signature of HI in this challenging phonological task, likely reflecting use of a compensatory strategy. This strategy is suggested to involve increased reliance on explicit mechanisms such as articulatory recoding and grapheme-to-phoneme conversion. PMID- 23653615 TI - Additive conjoint measurement and the resistance toward falsifiability in psychology. PMID- 23653614 TI - A BOLD Perspective on Age-Related Neurometabolic-Flow Coupling and Neural Efficiency Changes in Human Visual Cortex. AB - Age-related performance declines in visual tasks have been attributed to reductions in processing efficiency. The neural basis of these declines has been explored by comparing the blood-oxygen-level-dependent (BOLD) index of neural activity in older and younger adults during visual task performance. However, neural activity is one of many factors that change with age and lead to BOLD signal differences. We investigated the origin of age-related BOLD changes by comparing blood flow and oxygen metabolic constituents of BOLD signal. Subjects periodically viewed flickering annuli and pressed a button when detecting luminance changes in a central fixation cross. Using magnetic resonance dual-echo arterial spin labeling and CO2 ingestion, we observed age-equivalent (i.e., similar in older and younger groups) fractional cerebral blood flow (DeltaCBF) in the presence of age-related increases in fractional cerebral metabolic rate of oxygen (DeltaCMRO2). Reductions in DeltaCBF responsiveness to increased DeltaCMRO2 in elderly led to paradoxical age-related BOLD decreases. Age-related DeltaCBF/DeltaCMRO2 ratio decreases were associated with reaction times, suggesting that age-related slowing resulted from less efficient neural activity. We hypothesized that reduced vascular responsiveness to neural metabolic demand would lead to a reduction in DeltaCBF/DeltaCMRO2. A simulation of BOLD relative to DeltaCMRO2 for lower and higher neurometabolic-flow coupling ratios (approximating those for old and young, respectively) indicated less BOLD signal change in old than young in relatively lower CMRO2 ranges, as well as greater BOLD signal change in young compared to old in relatively higher CMRO2 ranges. These results suggest that age-comparative studies relying on BOLD signal might be misinterpreted, as age-related BOLD changes do not merely reflect neural activity changes. Age-related declines in neurometabolic-flow coupling might lead to neural efficiency reductions that can adversely affect visual task performance. PMID- 23653616 TI - Low Spatial Frequency Bias in Schizophrenia is Not Face Specific: When the Integration of Coarse and Fine Information Fails. AB - Studies have shown that patients with schizophrenia exhibit visual processing impairments, particularly regarding the processing of spatial frequencies. In a previous work, we found that, compared to healthy volunteers, patients were biased toward low spatial frequencies (LSF) to identify facial expression at a glance. Given the ubiquity of faces in visual perception, it remains an open question whether the LSF bias is face specific or also occurs with other visual objects. Here, 15 patients with schizophrenia and 11 healthy control adults performed a categorization task with hybrid stimuli. These stimuli were single images consisting of two different objects, a fruit and an animal, each in a specific spatial frequency range, either low (LSF) or high (HSF). Observers were asked to report if they saw an animal or a fruit. The reported category demonstrated which spatial scale was preferentially perceived in each trial. In a control experiment, participants performed the same task but with images of only a single object, either a LSF or HSF filtered animal or fruit, to verify that participants could perceive both HSF or LSF when presented in isolation. The results on the categorization task showed that patients chose more frequently LSF with hybrid stimuli compared to healthy controls. However, both populations performed equally well with HSF and LSF filtered pictures in the control experiment, demonstrating that the LSF preference found with hybrid stimuli in patients was not due to an inability to perceive HSF. The LSF preference found in schizophrenia confirms our previous study conducted with faces, and shows that this LSF bias generalizes to other categories of objects. When a broad range of spatial frequencies are present in the image, as in normal conditions of viewing, patients preferentially rely on coarse visual information contained in LSF. This result may be interpreted as a dysfunction of the guidance of HSF processing by LSF processing. PMID- 23653617 TI - Deep Unsupervised Learning on a Desktop PC: A Primer for Cognitive Scientists. AB - Deep belief networks hold great promise for the simulation of human cognition because they show how structured and abstract representations may emerge from probabilistic unsupervised learning. These networks build a hierarchy of progressively more complex distributed representations of the sensory data by fitting a hierarchical generative model. However, learning in deep networks typically requires big datasets and it can involve millions of connection weights, which implies that simulations on standard computers are unfeasible. Developing realistic, medium-to-large-scale learning models of cognition would therefore seem to require expertise in programing parallel-computing hardware, and this might explain why the use of this promising approach is still largely confined to the machine learning community. Here we show how simulations of deep unsupervised learning can be easily performed on a desktop PC by exploiting the processors of low cost graphic cards (graphic processor units) without any specific programing effort, thanks to the use of high-level programming routines (available in MATLAB or Python). We also show that even an entry-level graphic card can outperform a small high-performance computing cluster in terms of learning time and with no loss of learning quality. We therefore conclude that graphic card implementations pave the way for a widespread use of deep learning among cognitive scientists for modeling cognition and behavior. PMID- 23653618 TI - The calcium wave model of the perception-action cycle: evidence from semantic relevance in memory experiments. AB - We present a general model of brain function (the calcium wave model), distinguishing three processing modes in the perception-action cycle. The model provides an interpretation of the data from experiments on semantic memory conducted by the authors. PMID- 23653619 TI - Inherently Analog Quantity Representations in Olive Baboons (Papio anubis). AB - Strong evidence indicates that non-human primates possess a numerical representation system, but the inherent nature of that system is still debated. Two cognitive mechanisms have been proposed to account for non-human primate numerical performance: (1) a discrete object-file system limited to quantities <4, and (2) an analog system which represents quantities comparatively but is limited by the ratio between two quantities. To test the underlying nature of non human primate quantification, we asked eight experiment-naive olive baboons (Papio anubis) to discriminate between number pairs containing small (<4), large (>4), or span (small vs. large) numbers of food items presented simultaneously or sequentially. The prediction from the object-file hypothesis is that baboons will only accurately choose the larger quantity in small pairs, but not large or span pairs. Conversely, the analog system predicts that baboons will be successful with all numbers, and that success will be dependent on numerical ratio. We found that baboons successfully discriminated all pair types at above chance levels. In addition, performance significantly correlated with the ratio between the numerical values. Although performance was better for simultaneous trials than sequential trials, evidence favoring analog numerical representation emerged from both conditions, and was present even in the first exposure to number pairs. Together, these data favor the interpretation that a single, coherent analog representation system underlies spontaneous quantitative abilities in primates. PMID- 23653620 TI - Interfaces between language and cognition. PMID- 23653621 TI - Time reproduction and numerosity interaction in the parietal cortex: some missing links. PMID- 23653622 TI - Ataxin-3 and its e3 partners: implications for machado-joseph disease. AB - Machado-Joseph disease (MJD) is the most common dominant inherited ataxia worldwide, caused by an unstable CAG trinucleotide expansion mutation within the SCA3 gene resulting in an expanded polyglutamine tract within the ataxin-3 protein. Ataxin-3 functions as a deubiquitinating enzyme (DUB), within the Ub system and whilst many DUBs are known to partner with and deubiquitinate specific E3-Ub ligases, ataxin-3 had no identified E3 partner until recent studies implicated parkin and CHIP, two neuroprotective E3 ligases. MJD often presents with symptoms of Parkinson disease (PD), which led to identification of parkin as a novel E3-Ub ligase whose activity was regulated by ataxin-3-mediated deubiquitination. Findings from these studies also revealed an unexpected convergence upon the E2-Ub-conjugating enzyme in the regulation of an E3/DUBenzyme pair. Moreover, mutant but not wild-type ataxin-3 promotes the clearance of parkin via the autophagy pathway, raising the intriguing possibility that increased turnover of parkin may contribute to the pathogenesis of MJD and help explain some of the Parkinsonian features in MJD. In addition to parkin, the U-box E3 ligase CHIP, a neuroprotective E3 implicated in protein quality control, was identified as a second E3 partner of ataxin-3, with ataxin-3 regulating the ability of CHIP to ubiquitinate itself. Indeed, ataxin-3 not only deubiquitinated CHIP, but also trimmed Ub conjugates on CHIP substrates, thereby regulating the length of Ub chains. Interestingly, when expanded ataxin-3 was present, CHIP levels were also reduced in the brains of MJD transgenic mice, raising the possibility that loss of one or both E3 partners may be a contributing factor in the pathogenesis of SCA3. In this review we discuss the implications from these studies and describe the importance of these findings in helping us understand the molecular processes involved in SCA3 and other neurodegenerative disorders. PMID- 23653623 TI - The YNP Metagenome Project: Environmental Parameters Responsible for Microbial Distribution in the Yellowstone Geothermal Ecosystem. AB - The Yellowstone geothermal complex contains over 10,000 diverse geothermal features that host numerous phylogenetically deeply rooted and poorly understood archaea, bacteria, and viruses. Microbial communities in high-temperature environments are generally less diverse than soil, marine, sediment, or lake habitats and therefore offer a tremendous opportunity for studying the structure and function of different model microbial communities using environmental metagenomics. One of the broader goals of this study was to establish linkages among microbial distribution, metabolic potential, and environmental variables. Twenty geochemically distinct geothermal ecosystems representing a broad spectrum of Yellowstone hot-spring environments were used for metagenomic and geochemical analysis and included approximately equal numbers of: (1) phototrophic mats, (2) "filamentous streamer" communities, and (3) archaeal-dominated sediments. The metagenomes were analyzed using a suite of complementary and integrative bioinformatic tools, including phylogenetic and functional analysis of both individual sequence reads and assemblies of predominant phylotypes. This volume identifies major environmental determinants of a large number of thermophilic microbial lineages, many of which have not been fully described in the literature nor previously cultivated to enable functional and genomic analyses. Moreover, protein family abundance comparisons and in-depth analyses of specific genes and metabolic pathways relevant to these hot-spring environments reveal hallmark signatures of metabolic capabilities that parallel the distribution of phylotypes across specific types of geochemical environments. PMID- 23653624 TI - Citrus tristeza virus p23: a unique protein mediating key virus-host interactions. AB - The large RNA genome of Citrus tristeza virus (CTV; ca. 20 kb) contains 12 open reading frames, with the 3'-terminal one corresponding to a protein of 209 amino acids (p23) that is expressed from an abundant subgenomic RNA. p23, an RNA binding protein with a putative zinc-finger domain and some basic motifs, is unique to CTV because no homologs have been found in other closteroviruses, including the type species of the genus Beet yellows virus (despite both viruses having many homologous genes). Consequently, p23 might have evolved for the specific interaction of CTV with its citrus hosts. From a functional perspective p23 has been involved in many roles: (i) regulation of the asymmetrical accumulation of CTV RNA strands, (ii) induction of the seedling yellows syndrome in sour orange and grapefruit, (iii) intracellular suppression of RNA silencing, (iv) elicitation of CTV-like symptoms when expressed ectopically as a transgene in several Citrus spp., and (v) enhancement of systemic infection (and virus accumulation) in sour orange and CTV release from the phloem in p23-expressing transgenic sweet and sour orange. Moreover, transformation of Mexican lime with intron-hairpin constructs designed for the co-inactivation of p23 and the two other CTV silencing suppressors results in complete resistance against the homologous virus. From a cellular point of view, recent data indicate that p23 accumulates preferentially in the nucleolus, being the first closterovirus protein with such a subcellular localization, as well as in plasmodesmata. These major accumulation sites most likely determine some of the functional roles of p23. PMID- 23653625 TI - Roles of autophagy in elimination of intracellular bacterial pathogens. AB - As a fundamental intracellular catabolic process, autophagy is important and required for the elimination of protein aggregates and damaged cytosolic organelles during a variety of stress conditions. Autophagy is now being recognized as an essential component of innate immunity; i.e., the recognition, selective targeting, and elimination of microbes. Because of its crucial roles in the innate immune system, therapeutic targeting of bacteria by means of autophagy activation may prove a useful strategy to combat intracellular infections. However, important questions remain, including which molecules are critical in bacterial targeting by autophagy, and which mechanisms are involved in autophagic clearance of intracellular microbes. In this review, we discuss the roles of antibacterial autophagy in intracellular bacterial infections (Mycobacteria, Salmonella, Shigella, Listeria, and Legionella) and present recent evidence in support of molecular mechanisms driving autophagy to target bacteria and eliminate invading pathogens. PMID- 23653626 TI - Interaction of the Capsular Polysaccharide A from Bacteroides fragilis with DC SIGN on Human Dendritic Cells is Necessary for Its Processing and Presentation to T Cells. AB - The zwitterionic capsular polysaccharide A (PSA) of Bacteroides fragilis is the first carbohydrate antigen described to be presented in major histocompatibility complex (MHC) class II for the induction of CD4(+) T cell responses. However, the identity of the receptor mediating binding and internalization of PSA in antigen presenting cells remains elusive. C-type lectins are glycan-binding receptors known for their capacity to target ligands for antigen presentation to T cells. Here, we investigated whether C-type lectins were involved in the internalization of PSA and identified dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) as the main receptor for PSA on human dendritic cells (DC). The induction of PSA-specific T cell proliferation appeared to be completely dependent on DC-SIGN. These data reveal a crucial role for DC-SIGN in the endocytosis and routing of PSA in human DC for the efficient stimulation of PSA-specific CD4(+) T cells. PMID- 23653627 TI - Interleukin-33: a mediator of inflammation targeting hematopoietic stem and progenitor cells and their progenies. AB - Inflammation is defined as a physiological response initiated by a variety of conditions that cause insult to the body, such as infection and tissue injury. Inflammation is triggered by specialized receptors in the innate immune system, which recognize microbial components known as pathogen-associated molecular patterns or endogenous signals produced by damaged cells (damage-associated molecular patterns). IL-33 is a cytokine that is released predominantly at the epithelial barrier when it is exposed to pathogens, allergens, or injury-inducing stimuli. IL-33 target cells are various, ranging from hematopoietic stem and progenitor cells (HSPCs) and essentially all types of their progeny to many non hematopoietic cells. The pleiotropic actions of IL-33 suggest that IL-33 is involved in every phase of the inflammatory process. In this review, we discuss recent advances in the understanding of how IL-33 orchestrates inflammatory responses by regulating HSPCs and innate immune cells. PMID- 23653628 TI - The potential of C4 grasses for cellulosic biofuel production. AB - With the advent of biorefinery technologies enabling plant biomass to be processed into biofuel, many researchers set out to study and improve candidate biomass crops. Many of these candidates are C4 grasses, characterized by a high productivity and resource use efficiency. In this review the potential of five C4 grasses as lignocellulosic feedstock for biofuel production is discussed. These include three important field crops-maize, sugarcane and sorghum-and two undomesticated perennial energy grasses-miscanthus and switchgrass. Although all these grasses are high yielding, they produce different products. While miscanthus and switchgrass are exploited exclusively for lignocellulosic biomass, maize, sorghum, and sugarcane are dual-purpose crops. It is unlikely that all the prerequisites for the sustainable and economic production of biomass for a global cellulosic biofuel industry will be fulfilled by a single crop. High and stable yields of lignocellulose are required in diverse environments worldwide, to sustain a year-round production of biofuel. A high resource use efficiency is indispensable to allow cultivation with minimal inputs of nutrients and water and the exploitation of marginal soils for biomass production. Finally, the lignocellulose composition of the feedstock should be optimized to allow its efficient conversion into biofuel and other by-products. Breeding for these objectives should encompass diverse crops, to meet the demands of local biorefineries and provide adaptability to different environments. Collectively, these C4 grasses are likely to play a central role in the supply of lignocellulose for the cellulosic ethanol industry. Moreover, as these species are evolutionary closely related, advances in each of these crops will expedite improvements in the other crops. This review aims to provide an overview of their potential, prospects and research needs as lignocellulose feedstocks for the commercial production of biofuel. PMID- 23653629 TI - Arabidopsis redox status in response to caterpillar herbivory. AB - Plant responses to insect herbivory are regulated through complex, hormone mediated interactions. Some caterpillar species have evolved strategies to manipulate this system by inducing specific pathways that suppress plant defense responses. Effectors in the labial saliva (LS) secretions of Spodoptera exigua caterpillars are believed to induce the salicylic acid (SA) pathway to interfere with the jasmonic acid (JA) defense pathway; however, the mechanism underlying this subversion is unknown. Since noctuid caterpillar LS contains enzymes that may affect cellular redox balance, this study investigated rapid changes in cellular redox metabolites within 45 min after herbivory. Caterpillar LS is involved in suppressing the increase in oxidative stress that was observed in plants fed upon by caterpillars with impaired LS secretions. To further understand the link between cellular redox balance and plant defense responses, marker genes of SA, JA and ethylene (ET) pathways were compared in wildtype, the glutathione-compromised pad2-1 mutant and the tga2/5/6 triple mutant plants. AtPR1 and AtPDF1.2 showed LS-dependent expression that was alleviated in the pad2 1 and tga2/5/6 triple mutants. In comparison, the ET-dependent genes ERF1 expression showed LS-associated changes in both wildtype and pad2-1 mutant plants and the ORA 59 marker AtHEL had increased expression in response to herbivory, but a LS-dependent difference was not noted. These data support the model that there are SA/NPR1-, glutathione-dependent and ET-, glutathione-independent mechanisms leading to LS-associated suppression of plant induced defenses. PMID- 23653630 TI - Induced resistance in tomato by SAR activators during predisposing salinity stress. AB - Plant activators are chemicals that induce disease resistance. The phytohormone salicylic acid (SA) is a crucial signal for systemic acquired resistance (SAR), and SA-mediated resistance is a target of several commercial plant activators, including Actigard (1,2,3-benzothiadiazole-7-thiocarboxylic acid-S-methyl-ester, BTH) and Tiadinil [N-(3-chloro-4-methylphenyl)-4-methyl-1,2,3-thiadiazole-5 carboxamide, TDL]. BTH and TDL were examined for their impact on abscisic acid (ABA)-mediated, salt-induced disease predisposition in tomato seedlings. A brief episode of salt stress to roots significantly increased the severity of disease caused by Pseudomonas syringae pv. tomato (Pst) and Phytophthora capsici relative to non-stressed plants. Root treatment with TDL induced resistance to Pst in leaves and provided protection in both non-stressed and salt-stressed seedlings in wild-type and highly susceptible NahG plants. Non-stressed and salt-stressed ABA-deficient sitiens mutants were highly resistant to Pst. Neither TDL nor BTH induced resistance to root infection by Phytophthora capsici, nor did they moderate the salt-induced increment in disease severity. Root treatment with these plant activators increased the levels of ABA in roots and shoots similar to levels observed in salt-stressed plants. The results indicate that SAR activators can protect tomato plants from bacterial speck disease under predisposing salt stress, and suggest that some SA-mediated defense responses function sufficiently in plants with elevated levels of ABA. PMID- 23653633 TI - Death of the genome paper. PMID- 23653631 TI - KNOX1 genes regulate lignin deposition and composition in monocots and dicots. AB - Plant secondary cell walls are deposited mostly in vascular tissues such as xylem vessels, tracheids, and fibers. These cell walls are composed of a complex matrix of compounds including cellulose, hemicellulose, and lignin. Lignin functions primarily to maintain the structural and mechanical integrity of both the transport vessel and the entire plant itself. Since lignin has been identified as a major source of biomass for biofuels, regulation of secondary cell wall biosynthesis has been a topic of much recent investigation. Biosynthesis and patterning of lignin involves many developmental and environmental cues including evolutionarily conserved transcriptional regulatory modules and hormonal signals. Here, we investigate the role of the class I Knotted1-like-homeobox (KNOX) genes and gibberellic acid in the lignin biosynthetic pathway in a representative monocot and a representative eudicot. Knotted1 overexpressing mutant plants showed a reduction in lignin content in both maize and tobacco. Expression of four key lignin biosynthesis genes was analyzed and revealed that KNOX1 genes regulate at least two steps in the lignin biosynthesis pathway. The negative regulation of lignin both in a monocot and a eudicot by the maize Kn1 gene suggests that lignin biosynthesis may be preserved across large phylogenetic distances. The evolutionary implications of regulation of lignification across divergent species are discussed. PMID- 23653634 TI - Biomarkers for gastroesophageal reflux in respiratory diseases. AB - Gastroesophageal reflux (GER) is commonly associated with respiratory symptoms, either through a vagal bronchoconstrictive reflex or through microaspiration of gastric contents. No diagnostic test is available, however, to diagnose when respiratory illnesses are caused by GER and when not, but research in this field has been moving forward. Various biomarkers in different types of biosamples have been studied in this context. The aim of this review is to summarize the present knowledge in this field. GER patients with respiratory diseases seem to have a different biochemical profile from similar patients without GER. Inflammatory biomarkers differ in asthmatics based on GER status, tachykinins are elevated in patients with GER-related cough, and bile acids are elevated in lung transplant patients with GER. However, studies on these biomarkers are often limited by their small size, methods of analysis, and case selections. The two pathogenesis mechanisms are associated with different respiratory illnesses and biochemical profiles. A reliable test to identify GER-induced respiratory disorders needs to be developed. Bronchoalveolar lavage is too invasive to be of use in most patients. Exhaled breath condensate samples need further evaluation and standardization. The newly developed particles in exhaled air measurements remain to be studied further. PMID- 23653632 TI - Neuronal inputs and outputs of aging and longevity. AB - An animal's survival strongly depends on its ability to maintain homeostasis in response to the changing quality of its external and internal environment. This is achieved through intracellular and intercellular communication within and among different tissues. One of the organ systems that plays a major role in this communication and the maintenance of homeostasis is the nervous system. Here we highlight different aspects of the neuronal inputs and outputs of pathways that affect aging and longevity. Accordingly, we discuss how sensory inputs influence homeostasis and lifespan through the modulation of different types of neuronal signals, which reflects the complexity of the environmental cues that affect physiology. We also describe feedback, compensatory, and feed-forward mechanisms in these longevity-modulating pathways that are necessary for homeostasis. Finally, we consider the temporal requirements for these neuronal processes and the potential role of natural genetic variation in shaping the neurobiology of aging. PMID- 23653635 TI - Duodenal tube feeding: an alternative approach for effectively promoting weight gain in children with gastroesophageal reflux and congenital heart disease. AB - We tested whether duodenal tube feeding effectively improves the clinical symptoms and body weight gain in children with congenital heart disease (CHD) and gastroesophageal reflux (GER). In the retrospective analysis of 17 consecutive children with CHD who were treated with duodenal tube feeding for symptomatic GER, we found that clinical symptoms of persistent emesis or respiratory wheezing after feeding disappeared with duodenal tube feeding in all patients. Duodenal tube feeding facilitated a stable nutritional supply, resulting in marked improvement of weight gain from 6 to 21 g/day (P < .0001). In a patient with trisomy 21 and persistent pulmonary hypertension after the closure of a ventricular septal defect, duodenal tube feeding ameliorated pulmonary hypertension, as evidenced by the improvement of the pressure gradient of tricuspid regurgitation from 77 to 41 mm Hg. In 14 of the 17 patients, the duodenal tube was successfully removed, with the spontaneous improvement of GER (median duration of duodenal tube feeding: 7 months). In conclusion, duodenal tube feeding improves the weight gain of infants with GER who need treatment for CHD-associated heart failure. It also allows for the improvement of pulmonary hypertension. PMID- 23653636 TI - Rifaximin versus Nonabsorbable Disaccharides for the Treatment of Hepatic Encephalopathy: A Meta-Analysis. AB - Background. Many studies have found that the antibiotic rifaximin is effective for the treatment of hepatic encephalopathy. However, there is no uniform view on the efficacy and safety of rifaximin. Methods. We performed a meta-analysis through electronic searches to evaluate the efficacy and safety of rifaximin in comparison with nonabsorbable disaccharides. Results. A total of 8 randomized controlled trials including 407 patients were included. The efficacy of rifaximin was equivalent to nonabsorbable disaccharides according to the statistical data (risk ratio (RR): 1.06, 95% CI: 0.94-1.19; P = 0.34). Analysis showed that patients treated with rifaximin had better results in serum ammonia levels (weighted mean difference (WMD): -10.63, 95% CI: -30.63-9.38; P = 0.30), mental status (WMD: -0.32, 95% CI: -0.67-0.03; P = 0.07), asterixis (WMD: -0.12, 95% CI: -0.31-0.08; P = 0.23), electroencephalogram response (WMD: -0.21, 95% CI: -0.34- 0.09; P = 0.0007), and grades of portosystemic encephalopathy (WMD: -2.30, 95% CI: -2.78--1.82; P < 0.00001), but only the last ones had statistical significance. The safety of rifaximin was better than nonabsorbable disaccharides (RR: 0.19, 95% CI: 0.10-0.34; P < 0.00001). Conclusion. Rifaximin is at least as effective as nonabsorbable disaccharides, maybe better for the treatment of hepatic encephalopathy. And the safety of rifaximin is better. PMID- 23653637 TI - The prevalence of functional gastrointestinal disorders in the chinese air force population. AB - Background. Functional gastrointestinal disorders (FGIDs) are common in the general population worldwide. However, there is paucity of large sale surveys for prevalence of FGID in the military personnel. Methods. It is a cross-sectional study, using Rome III criteria for the diagnosis of FGID among the Chinese Air Force (CAF) workers. Results. Of 4633 registered male subjects, there were 818 (16.4%) air crew and 4170 (83.6%) ground personnel. FGIDs were identified in 1088 (23.48%) of cases. It was more prevalent in the ground personnel than air crew (24.02% versus 20.33%; P = 0.022). Based on Rome III criteria, the commonest disease category was functional gastroduodenal disorder (37.4%), whereas functional nausea and vomiting disorder (FNV) was the most frequent overall diagnosis. Functional dyspepsia (FD) with irritable bowel syndrome (IBS) was the leading FGIDs' overlap (3.9%). Conclusion. FGIDs in CAF population are rather underestimated. This necessitates preventive strategies according to job characteristics. PMID- 23653638 TI - Changes in ghrelin-related factors in gastroesophageal reflux disease in rats. AB - To examine gastrointestinal hormone profiles and functional changes in gastroesophageal reflux disease (GERD), blood levels of the orexigenic hormone ghrelin were measured in rats with experimentally induced GERD. During the experiment, plasma acyl ghrelin levels in GERD rats were higher than those in sham-operated rats, although food intake was reduced in GERD rats. Although plasma levels of the appetite-suppressing hormone leptin were significantly decreased in GERD rats, no changes were observed in cholecystokinin levels. Repeated administration of rat ghrelin to GERD rats had no effect on the reduction in body weight or food intake. Therefore, these results suggest that aberrantly increased secretion of peripheral ghrelin and decreased ghrelin responsiveness may occur in GERD rats. Neuropeptide Y and agouti-related peptide mRNA expression in the hypothalamus of GERD rats was significantly increased, whereas proopiomelanocortin mRNA expression was significantly decreased compared to that in sham-operated rats. However, melanin-concentrating hormone (MCH) and prepro-orexin mRNA expression in the hypothalamus of GERD rats was similar to that in sham-operated rats. These results suggest that although GERD rats have higher plasma ghrelin levels, ghrelin signaling in GERD rats may be suppressed due to reduced MCH and/or orexin synthesis in the hypothalamus. PMID- 23653639 TI - Cough Test during Tension-Free Vaginal Tape Procedure in Preventing Postoperative Urinary Retention. AB - Objective. To discuss the practical value of the cough test during the tension free vaginal tape (TVT) procedure. Methods. In the first group, 41 patients of female stress incontinence received TVT operations which were performed according to the Ulmsten's method strictly, only that the stress of tape was adjusted in light of the cough test. In the second group, 44 patients of female stress incontinence received TVT operations in which the tape was put under the urethral tract without stress, not adjusted by cough test. Results. The cure rate was 38/41 (92.6%) in the cough test group and 41/44 (93.1%) in the noncough test group; detrusor pressure-uroflow study indicated that there were 11 cases in the obstruction zone in the cough test group while only 3 cases were in the obstruction zone in the noncough test group; 4 cases of urinary retention and 5 cases of voiding dysfunction were found in the cough test group, while difficulties of urination were not found in the non-cough test group. Conclusion. Adjusting the tape stress in accordance with the cough test during the TVT can increase the opportunity of urinary retention or difficulty of urination after operation. So there is no benefit of the cough test during tension-free vaginal tape procedure in preventing post-operative urinary retention. PMID- 23653640 TI - Efficient Serial and Parallel Algorithms for Selection of Unique Oligos in EST Databases. AB - Obtaining unique oligos from an EST database is a problem of great importance in bioinformatics, particularly in the discovery of new genes and the mapping of the human genome. Many algorithms have been developed to find unique oligos, many of which are much less time consuming than the traditional brute force approach. An algorithm was presented by Zheng et al. (2004) which finds the solution of the unique oligos search problem efficiently. We implement this algorithm as well as several new algorithms based on some theorems included in this paper. We demonstrate how, with these new algorithms, we can obtain unique oligos much faster than with previous ones. We parallelize these new algorithms to further improve the time of finding unique oligos. All algorithms are run on ESTs obtained from a Barley EST database. PMID- 23653641 TI - Association between Osteocalcin, Metabolic Syndrome, and Cardiovascular Risk Factors: Role of Total and Undercarboxylated Osteocalcin in Patients with Type 2 Diabetes. AB - Studies have demonstrated that total osteocalcin (TOC) is associated with metabolic syndrome (MetS) and therefore might influence the risk of cardiovascular disease in humans. Undercarboxylated osteocalcin (uOC) regulates insulin secretion and sensitivity in mice, but its relation to MetS in humans is unclear. We aimed to determine whether uOC is related to MetS and/or its individual components and other cardiovascular risk factors in patients with type 2 diabetes mellitus (T2DM), and whether TOC and uOC have utility in predicting the cardiovascular risk. We studied 203 T2DM patients with and without MetS. MetS was defined based on the NCEP-ATP III criteria. A correlation analysis was performed between the three outcome variables: (i) TOC, (ii) uOC, and (iii) carboxylated osteocalcin (cOC) and MetS components and other cardiovascular risk factors. Both TOC and uOC were significantly lower in patients with MetS compared to those without MetS, independent of body mass index. In patients with MetS, uOC was significantly and positively correlated with HDL cholesterol, while TOC was significantly and negatively correlated with serum triglycerides. We report for the first time that uOC is related to lipid indices in patients with T2DM. Further studies are necessary to determine whether uOC can be utilized for cardiovascular risk assessments in these patients. PMID- 23653642 TI - Nonalcoholic Fatty liver disease, diabetes mellitus and cardiovascular disease: newer data. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common, chronic liver disease worldwide. Within this spectrum, steatosis alone is apparently benign, while nonalcoholic steatohepatitis may progress to cirrhosis and hepatocellular carcinoma. NAFLD is strongly associated with obesity, dyslipidemia, type 2 diabetes mellitus, and cardiovascular disease. The pathogenesis of hepatic steatosis is not clearly known, but its main characteristics are considered insulin resistance, mitochondrial dysfunction, increased free fatty acids reflux from adipose tissue to the liver, hepatocyte lipotoxicity, stimulation of chronic necroinflammation, and fibrogenic response. With recent advances in technology, advanced imaging techniques provide important information for diagnosis. There is a significant research effort in developing noninvasive monitoring of disease progression to fibrosis and response to therapy with potential novel biomarkers, in order to facilitate diagnosis for the detection of advanced cirrhosis and to minimize the need of liver biopsy. The identification of NAFLD should be sought as part of the routine assessment of type 2 diabetics, as sought the microvascular complications and cardiovascular disease, because it is essential for the early diagnosis and proper intervention. Diet, exercise training, and weight loss provide significant clinical benefits and must be considered of first line for treating NAFLD. PMID- 23653644 TI - Glucose lowering therapeutic strategies for type 2 diabetic patients with chronic kidney disease in primary care setting in france: a cross-sectional study. AB - Aim. To understand glucose lowering therapeutic strategies of French general practitioners (GPs) in the management of type 2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD). Methods. A multicenter cross-sectional study was conducted from March to June 2011 among a sample of French GPs who contribute to the IMS Lifelink Disease Analyzer database. Eligible patients were those with T2DM and moderate-to-severe CKD who visited their GPs at least once during the study period. Data were collected through electronic medical records and an additional questionnaire. Results. 116 GPs included 297 patients: 86 with stage 3a (Group 1, GFR = 45-60 mL/min/1.73 m(2)) and 211 with stages 3b, 4, or 5 (Group 2, GFR < 45 mL/min/1.73 m(2)). Patients' mean age was approximately 75 years. Insulin was used in 19% of patients, and was predominant in those with severe CKD. More than two-thirds of patients were treated with glucose lowering agents which were either contraindicated or not recommended for CKD. Conclusion Physicians most commonly considered the severity of diabetes and not CKD in their therapeutic decision making, exposing patients to potential iatrogenic risks. The recent patient oriented approach and individualization of glycemic objectives according to patient profile rather than standard HbA1c would improve this situation. PMID- 23653643 TI - Action of Halowax 1051 on Enzymes of Phase I (CYP1A1) and Phase II (SULT1A and COMT) Metabolism in the Pig Ovary. AB - Polychlorinated naphthalenes (PCNs) are a group of organochlorinated compounds exhibiting dioxin-like properties. Previously published data showed the direct action of PCN-rich Halowax 1051 on ovarian follicular steroidogenesis. Taking into consideration that the observed biological effects of PCNs may be frequently side effects of metabolites generated by their detoxification, the aim of this study was to determine the activity and expression of enzymes involved in phase I (cytochrome P450, family 1 (CYP1A1)) and phase II (sulfotransferase (SULT1A) and catechol-O-methyltransferase (COMT)) detoxification metabolism. Cocultures of granulosa and theca interna cells collected from sexually mature pigs were exposed to 1 pg/mL to 10 ng/mL of Halowax 1051 for 1 to 48 hours, after which levels and activities of CYP1A1, SULT1A, and COMT were measured. Dose-dependent increases of CYP1A1 activity and expression were observed. High doses of Halowax 1051 were inhibitory to COMT and SULT1A activity and reduced their protein levels. In conclusion, fast activation of phase I enzymes with simultaneous inhibition of phase II enzymes indicates that the previously observed effect of Halowax 1051 on follicular steroidogenesis may partially result from metabolite action occurring locally in ovarian follicles. PMID- 23653645 TI - The role of fluorine-18-fluorodeoxyglucose positron emission tomography in aggressive histological subtypes of thyroid cancer: an overview. AB - Aggressive histological subtypes of thyroid cancer are rare and have a poor prognosis. The most important aggressive subtypes of thyroid cancer are Hurthle cell carcinoma (HCTC) and anaplastic and poorly differentiated carcinoma (ATC and PDTC). The American Thyroid Association recently published guidelines for the management of patients with ATC, but no specific guidelines have been done about HCTC. We performed an overview of the literature about the role of Fluorine-18 Fluorodeoxyglucose positron emission tomography or positron emission tomography/computed tomography (FDG-PET or PET/CT) in aggressive histological subtypes of thyroid cancer. Only few original studies about the role of FDG-PET or PET/CT in HCTC, PDTC, and ATC have been published in the literature. FDG-PET or PET/CT seems to be useful in staging or followup of invasive and metastatic HCTC. FDG-PET or PET/CT should be used in patients with ATC in initial staging and in the followup after surgery to evaluate metastatic disease. Some authors suggest the use of FDG-PET/CT in staging of PDTC, but more studies are needed to define the diagnostic use of FDG-PET/CT in this setting. Limited experience suggests the usefulness of FDG-PET or PET/CT in patients with more aggressive histological subtypes of DTC. However, DTC presenting as radioiodine refractory and FDG-PET positive should be considered aggressive tumours with poor prognosis. PMID- 23653648 TI - Prevention of localized osteitis in mandibular third-molar sites using platelet rich fibrin. AB - Purpose. To review our experience utilizing platelet rich fibrin (PRF), which is reported to aid in wound healing of extraction sites, for the prevention of localized osteitis following lower third-molar removal. Materials and Methods. PRF was placed in the mandibular third-molar extraction sites, 200 sites total, on 100 consecutive patients treated in our practice, by the authors. The patients were managed with standard surgical techniques, intraoperative IV antibiotic/steroid coverage, and routine postoperative narcotic analgesics/short term steroid coverage. All patients were reevaluated for localized osteitis within 7-10 days of the surgery. A comparison group consisted of 100 consecutive patients who underwent bilateral removal of indicated mandibular wisdom teeth and did not receive PRF placement within the lower third molar surgical sites. Results. The incidence of localized osteitis (LO) following removal of 200 lower third molars with simultaneous PRF placement within the extraction site was 1% (2 sites out of 200). The group of patients whose mandibular 3rd molar sockets were not treated with PRF demonstrated a 9.5% (19 sites out of 200) incidence of localized osteitis. The latter group also required 6.5 hours of additional clinical time to manage LO than the study group who received PRF. Conclusions. This retrospective review demonstrated that preventative treatment of localized osteitis can be accomplished using a low cost, autogenous, soluble, biologic material, PRF, that PRF enhanced third-molar socket healing/clot retention and greatly decreased the clinical time required for postoperative management of LO. PMID- 23653647 TI - The efficacy of strontium and potassium toothpastes in treating dentine hypersensitivity: a systematic review. AB - Objectives. The aim of the present paper was to review the published literature in order to identify all relevant studies for inclusion and to determine whether there was any evidence of the efficacy of strontium and potassium toothpastes in the treatment of dentine hypersensitivity (DH). Methods. Following a review of 94 relevant papers both from searching electronic databases (PUBMED) and hand searching of relevant written journals, 13 studies were identified, and 7 papers (1 for strontium-based toothpastes and 6 for potassium-based toothpastes) were finally accepted for inclusion. The main outcome measures were the methodology and assessment used by Investigators in studies designed to evaluate DH. Results. The results of the present paper would indicate that the reported efficacy of both strontium- and potassium-based toothpastes in relieving DH is questionable. Conclusions. The results from the present paper would appear to support the conclusions of previous investigators that there is only minimal evidence for the efficacy of both strontium- and potassium-based toothpastes in relieving symptoms of DH. PMID- 23653649 TI - Thrombin-accelerated quick clotting serum tubes: an evaluation with 22 common biochemical analytes. AB - Clot activator serum tubes have significantly improved turnaround times for result reporting compared to plain tubes. With increasing workload and service performance expectations confronting clinical laboratories with high-volume testing and with particular emphasis on critical analytes, attention has focussed on preanalytical variables that can be improved. We carried out a field study on the test performance of BD vacutainer rapid serum tubes (RSTs) compared to current institutional issued BD vacutainer serum separator tubes (SSTs) in its test result comparability, clotting time, and stability on serum storage. Data from the study population (n = 160) of patients attending outpatient clinics and healthy subjects showed that results for renal, liver, lipids, cardiac, thyroid, and prostate biochemical markers were comparable between RSTs and SSTs. Clotting times of the RSTs were verified to be quick with a median time of 2.05 min. Analyte stability on serum storage at 4 degrees C showed no statistically significant deterioration except for bicarbonate, electrolytes, and albumin over a period of 4 days. In conclusion, RSTs offered savings in the time required for the clotting process of serum specimens. This should translate to further trimming of the whole process from blood collection to result reporting without too much sacrifice on test accuracy and performance compared to the current widely used SSTs in most clinical laboratories. PMID- 23653650 TI - Viability Reagent, PrestoBlue, in Comparison with Other Available Reagents, Utilized in Cytotoxicity and Antimicrobial Assays. AB - This study compared different commercially available viability reagents. The growth indicator reagents include p-iodonitrotetrazolium violet (INT), PrestoBlue, and Alamar Blue which were used for antimicrobial analysis against Streptococcus mutans, Prevotella intermedia, Propionibacterium acnes, and Mycobacterium tuberculosis. PrestoBlue and Alamar Blue are resazurin based reagents that resulted in a quick and easily distinguishable colour change that allowed for visual readings. INT and Sodium 3'-[1-(phenyl amino-carbonyl)-3,4 tetrazolium]-bis-[4-methoxy-6-nitro] benzene sulfonic acid hydrate (XTT) are tetrazolium based reagents which are converted to a formazan dye in the presence of metabolically active mitochondria enzyme. For cell viability analysis, reagents XTT and PrestoBlue were compared. PrestoBlue was able to clearly indicate the minimum inhibitory concentration (MIC) of various positive drug controls on various microbial strains. PrestoBlue was also a good indicator of the 50% inhibitory concentration (IC50) of positive drug controls on various cell lines. PMID- 23653651 TI - Internal nasal valve incompetence is effectively treated using batten graft functional rhinoplasty. AB - Introduction. Internal nasal valve incompetence (INVI) has been treated with various surgical methods. Large, single surgeon case series are lacking, meaning that the evidence supporting a particular technique has been deficient. We present a case series using alar batten grafts to reconstruct the internal nasal valve, all performed by the senior author. Methods. Over a 7-year period, 107 patients with nasal obstruction caused by INVI underwent alar batten grafting. Preoperative assessment included the use of nasal strips to evaluate symptom improvement. Visual analogue scale (VAS) assessment of nasal blockage (NB) and quality of life (QOL) both pre- and postoperatively were performed and analysed with the Wilcoxon signed rank test. Results. Sixty-seven patients responded to both pre- and postoperative questionnaires. Ninety-one percent reported an improvement in NB and 88% an improvement in QOL. The greatest improvement was seen at 6 months (median VAS 15 mm and 88 mm resp., with a P value of <0.05 for both). Nasal strips were used preoperatively and are a useful tool in predicting patient operative success in both NB and QOL (odds ratio 2.15 and 2.58, resp.). Conclusions. Alar batten graft insertion as a single technique is a valid technique in treating INVI and produces good outcomes. PMID- 23653653 TI - Microscopic colitis with macroscopic endoscopic findings. AB - Microscopic Colitis (MC) is characterized by chronic watery diarrhea, grossly normal appearing colonic mucosa during conventional white light endoscopy, and biopsy showing microscopic inflammation. We report a case of collagenous colitis with gross endoscopic findings. PMID- 23653652 TI - Design of the tocilizumab in giant cell arteritis trial. AB - Overview. The GiACTA trial is a multicenter, randomized, double-blind, and placebo-controlled study designed to test the ability of tocilizumab (TCZ), an interleukin (IL)-6 receptor antagonist, to maintain disease remission in patients with giant cell arteritis (GCA). Design. Approximately 100 centers will enroll 250 patients with active disease. The trial consists of a 52-week blinded treatment phase followed by 104 weeks of open-label extension. Patients will be randomized into one of four groups. Group A (TCZ 162 mg weekly plus a 6-month prednisone-taper); group B (TCZ 162 mg every other week plus a 6-month prednisone taper); group C (placebo plus a 6-month prednisone-taper); and group D (placebo plus a 12-month prednisone taper). We hypothesize that patients assigned to TCZ in addition to a 6-month prednisone course are more likely to achieve the primary efficacy endpoint of sustained remission (SR) at 52 weeks compared with those assigned to a 6-month prednisone course alone, thus potentially minimizing the long-term adverse effects of corticosteroids. Conclusion. GiACTA will test the hypothesis that interference with IL-6 signaling exerts a beneficial effect on patients with GCA. The objective of this paper is to describe the design of the trial and address major issues related to its development. PMID- 23653654 TI - Isolation of Lodderomyces elongisporus from the Catheter Tip of a Fungemia Patient in the Middle East. AB - Lodderomyces elongisporus is phenotypically closely related to Candida parapsilosis and has recently been identified as an infrequent cause of bloodstream infections in patients from Asia and Mexico. We report here the isolation of Lodderomyces elongisporus from the catheter of a suspected case of fungemia. The identity of the isolate was confirmed by phenotypic characteristics and ribosomal DNA sequencing. PMID- 23653655 TI - The dilemma of pneumatosis intestinalis with pneumoperitoneum: nonoperative or surgical management-analysis of a case. AB - Pneumatosis intestinalis (PI) is an uncommon condition and can be associated with a wide spectrum of diseases, ranging from life-threatening to innocuous conditions. We report the case of a 46-year-old women coming to our attention for an acute abdominal pain, nausea, vomiting, constipation, and increased inflammatory marks, with a CT showing pneumoperitoneum and pneumatosis intestinalis. The previous diagnosis was advanced neoplasia of unknown origin. Despite the surgical intervention, which excluded an ischemic colitis, the patient died in the early postoperative period. The postmortem diagnosis was carcinoma of thymus gland, and the presence of pneumatosis was put down to metastasis nodes in the pulmonary parenchima. This case demonstrates the wide spectrum of presentation of pneumatosis intestinalis, the importance of a careful radiologic evaluation beside the clinical history, since the identification of correct pathogenesis and treatment can be very difficult. PMID- 23653656 TI - Successful treatment with bosentan of lower extremity ulcers in a scleroderma patient. AB - Digital ulcers are a well-known problem in patients with systemic sclerosis. Lower extremity ulcers are less prevalent but are also a challenging and underestimated complication of the disease causing important pain and morbidity. Bosentan, an oral dual endothelin receptor antagonist, has been shown to be effective in preventing digital ulcers in patients with systemic sclerosis. A few recent observations showed the efficacy of bosentan for accelerating the healing of nondigital ulcers in scleroderma patients. This report deals with a 48-year old patient with systemic sclerosis who developed painful ulcers on the left ankle and hallux. The ulcers were refractory to a combination of vasodilator therapy with a calcium antagonist and several courses of intravenous prostanoids, low molecular weight heparin, aspirin, simvastatin, and intensive local treatment. Bosentan treatment showed spectacular healing of the ulcers already after 4 months of therapy. This case supports the previous few observations of accelerating wound healing of lower extremity ulcers in systemic sclerosis patients with bosentan treatment. PMID- 23653657 TI - A case of the large cell neuroendocrine carcinoma of the urinary bladder. AB - Large cell neuroendocrine carcinoma (LCNEC) of the urinary bladder is very rare. Definite treatment strategy has not been established and prognosis of the disease is not clear yet. We report a case of primary LCNEC of the urinary bladder here with some review of the literature. The patient was a 84-year-old man. He underwent transurethral resection of bladder tumor (TURBT). Histological examination revealed a rosette arrangement of the tumor cells by HE staining and immunohistochemical study revealed positive CD 56, synaptophysin, and chromogranin A (LCNEC). After TURBT, he has no sign of recurrence for 8 months. We have to strictly observe the progress because LCNEC is very aggressive. PMID- 23653660 TI - Catechins and Sialic Acid Attenuate Helicobacter pylori-Triggered Epithelial Caspase-1 Activity and Eradicate Helicobacter pylori Infection. AB - The inflammasome/caspase-1 signaling pathway in immune cells plays a critical role in bacterial pathogenesis; however, the regulation of this pathway in the gastric epithelium during Helicobacter pylori infection is yet to be elucidated. Here, we investigated the effect of catechins (CAs), sialic acid (SA), or combination of CA and SA (CASA) on H. pylori-induced caspase-1-mediated epithelial damage, as well as H. pylori colonization in vitro (AGS cells) and in vivo (BALB/c mice). Our results indicate that the activity of caspase-1 and the expression of its downstream substrate IL-1 beta were upregulated in H. pylori infected AGS cells. In addition, we observed increased oxidative stress, NADPH oxidase gp91phox, CD68, caspase-1/IL-1 beta , and apoptosis, but decreased autophagy, in the gastric mucosa of H. pylori-infected mice. We have further demonstrated that treatment with CASA led to synergistic anti-H. pylori activity and was more effective than treatment with CA or SA alone. In particular, treatment with CASA for 10 days eradicated H. pylori infection in up to 95% of H. pylori-infected mice. Taken together, we suggest that the pathogenesis of H. pylori involves a gastric epithelial inflammasome/caspase-1 signaling pathway, and our results show that CASA was able to attenuate this pathway and effectively eradicate H. pylori infection. PMID- 23653658 TI - The impact of the myeloid response to radiation therapy. AB - Radiation therapy is showing potential as a partner for immunotherapies in preclinical cancer models and early clinical studies. As has been discussed elsewhere, radiation provides debulking, antigen and adjuvant release, and inflammatory targeting of effector cells to the treatment site, thereby assisting multiple critical checkpoints in antitumor adaptive immunity. Adaptive immunity is terminated by inflammatory resolution, an active process which ensures that inflammatory damage is repaired and tissue function is restored. We discuss how radiation therapy similarly triggers inflammation followed by repair, the consequences to adaptive immune responses in the treatment site, and how the myeloid response to radiation may impact immunotherapies designed to improve control of residual cancer cells. PMID- 23653659 TI - Age-dependent differences in systemic and cell-autonomous immunity to L. monocytogenes. AB - Host defense against infection can broadly be categorized into systemic immunity and cell-autonomous immunity. Systemic immunity is crucial for all multicellular organisms, increasing in importance with increasing cellular complexity of the host. The systemic immune response to Listeria monocytogenes has been studied extensively in murine models; however, the clinical applicability of these findings to the human newborn remains incompletely understood. Furthermore, the ability to control infection at the level of an individual cell, known as "cell autonomous immunity," appears most relevant following infection with L. monocytogenes; as the main target, the monocyte is centrally important to innate as well as adaptive systemic immunity to listeriosis. We thus suggest that the overall increased risk to suffer and die from L. monocytogenes infection in the newborn period is a direct consequence of age-dependent differences in cell autonomous immunity of the monocyte to L. monocytogenes. We here review what is known about age-dependent differences in systemic innate and adaptive as well as cell-autonomous immunity to infection with Listeria monocytogenes. PMID- 23653661 TI - Auricular acupressure combined with an internet-based intervention or alone for primary dysmenorrhea: a control study. AB - Background. Primary dysmenorrhea is prevalent in adolescents and young women. Menstrual pain and distress causes poor school performance and physiological damage. Auricular acupressure can be used to treat these symptoms, and Internet based systems are a flexible way of communicating and delivering the relevant information. Objective. This study investigates the effects of auricular acupressure (AA) alone and combined with an interactive Internet-based (II) intervention for the management of menstrual pain and self-care of adolescents with primary dysmenorrhea. Design. This study adopts a pretest/posttest control research design with a convenience sample of 107 participants. Results. The outcomes were measured using the short-form McGill pain questionnaire (SF-MPQ), visual analogue scale (VAS), menstrual distress questionnaire (MDQ), and adolescent dysmenorrheic self-care scale (ADSCS). Significant differences were found in ADSCS scores between the groups, and in SF-MPQ, VAS, MDQ, and ADSCS scores for each group. Conclusion. Auricular acupressure alone and a combination of auricular acupressure and interactive Internet both reduced menstrual pain and distress for primary dysmenorrhea. Auricular acupressure combined with interactive Internet instruction is better than auricular acupuncture alone in improving self-care behaviors. PMID- 23653662 TI - An Integrative Platform of TCM Network Pharmacology and Its Application on a Herbal Formula, Qing-Luo-Yin. AB - The scientific understanding of traditional Chinese medicine (TCM) has been hindered by the lack of methods that can explore the complex nature and combinatorial rules of herbal formulae. On the assumption that herbal ingredients mainly target a molecular network to adjust the imbalance of human body, here we present a-self-developed TCM network pharmacology platform for discovering herbal formulae in a systematic manner. This platform integrates a set of network-based methods that we established previously to catch the network regulation mechanism and to identify active ingredients as well as synergistic combinations for a given herbal formula. We then provided a case study on an antirheumatoid arthritis (RA) formula, Qing-Luo-Yin (QLY), to demonstrate the usability of the platform. We revealed the target network of QLY against RA-related key processes including angiogenesis, inflammatory response, and immune response, based on which we not only predicted active and synergistic ingredients from QLY but also interpreted the combinatorial rule of this formula. These findings are either verified by the literature evidence or have the potential to guide further experiments. Therefore, such a network pharmacology strategy and platform is expected to make the systematical study of herbal formulae achievable and to make the TCM drug discovery predictable. PMID- 23653663 TI - Why urban citizens in developing countries use traditional medicines: the case of suriname. AB - The use of traditional medicines (TMs) among urban populations in developing countries and factors underlying people's decision to use TMs are poorly documented. We interviewed 270 adults in Paramaribo, Suriname, using a stratified random household sample, semistructured questionnaires, and multivariate analysis. Respondents mentioned 144 medicinal plant species, most frequently Gossypium barbadense, Phyllanthus amarus, and Quassia amara. 66% had used TMs in the previous year, especially people who suffered from cold, fever, hypertension, headache, uterus, and urinary tract problems. At least 22% combined herbs with prescription medicine. The strongest explanatory variables were health status, (transfer of) plant knowledge, and health status combined with plant knowledge. Other predictive variables included religion, marital status, attitude of medical personnel, religious opinion on TMs, and number of children per household. Age, gender, nationality, rural background, education, employment, income, insurance, and opinion of government or doctors had no influence. People's main motivation to use TMs was their familiarity with herbs. Given the frequent use of self collected, home-prepared herbal medicine and the fact that illness and traditional knowledge predict plant use rather than poverty or a limited access to modern health care, the potential risks and benefits of TMs should be put prominently on the national public health agenda. PMID- 23653666 TI - Comparison of simple models of periodic protocols for combined anticancer therapy. AB - Several simple ordinary differential equation (ODE) models of tumor growth taking into account the development of its vascular network are discussed. Different biological aspects are considered from the simplest model of Hahnfeldt et al. proposed in 1999 to a model which includes drug resistance of cancer cells to chemotherapy. Some of these models can be used in clinical oncology to optimize antiangiogenic and cytostatic drugs delivery so as to ensure maximum efficacy. Simple models of continuous and periodic protocols of combined therapy are implemented. Discussion on the dynamics of the models and their complexity is presented. PMID- 23653664 TI - HIV-1 and the immune response to TB. AB - TB causes 1.4 million deaths annually. HIV-1 infection is the strongest risk factor for TB. The characteristic immunological effect of HIV is on CD4 cell count. However, the risk of TB is elevated in HIV-1 infected individuals even in the first few years after HIV acquisition and also after CD4 cell counts are restored with antiretroviral therapy. In this review, we examine features of the immune response to TB and how this is affected by HIV-1 infection and vice versa. We discuss how the immunology of HIV-TB coinfection impacts on the clinical presentation and diagnosis of TB, and how antiretroviral therapy affects the immune response to TB, including the development of TB immune reconstitution inflammatory syndrome. We highlight important areas of uncertainty and future research needs. PMID- 23653667 TI - A robust rerank approach for feature selection and its application to pooling based GWA studies. AB - Large-p-small-n datasets are commonly encountered in modern biomedical studies. To detect the difference between two groups, conventional methods would fail to apply due to the instability in estimating variances in t-test and a high proportion of tied values in AUC (area under the receiver operating characteristic curve) estimates. The significance analysis of microarrays (SAM) may also not be satisfactory, since its performance is sensitive to the tuning parameter, and its selection is not straightforward. In this work, we propose a robust rerank approach to overcome the above-mentioned diffculties. In particular, we obtain a rank-based statistic for each feature based on the concept of "rank-over-variable." Techniques of "random subset" and "rerank" are then iteratively applied to rank features, and the leading features will be selected for further studies. The proposed re-rank approach is especially applicable for large-p-small-n datasets. Moreover, it is insensitive to the selection of tuning parameters, which is an appealing property for practical implementation. Simulation studies and real data analysis of pooling-based genome wide association (GWA) studies demonstrate the usefulness of our method. PMID- 23653668 TI - Assessment of feasibility to use computer aided texture analysis based tool for parametric images of suspicious lesions in DCE-MR mammography. AB - Our aim was to analyze the feasibility of computer aided malignant tumor detection using the traditional texture analysis applied on two-compartment-based parameter pseudoimages of dynamic contrast-enhanced magnetic resonance (DCE-MR) breast image data. A major contribution of this research will be the through plane assessment capability. Texture analysis was performed on two-compartment based pseudo images of DCE-MRI datasets of breast data of eight subjects. The resulting texture parameter pseudo images were inputted to a feedforward neural network classification system which uses the manual segmentations of a primary radiologist as a gold standard, and each voxel was assigned as malignant or nonmalignant. The classification results were compared with the lesions manually segmented by a second radiologist. Results show that the mean true positive fraction (TPF) and false positive fraction (FPF) performance of the classifier vs. primary radiologist is statistically as good as the mean TPF and FPF performance of the second radiologist vs. primary radiologist with a confidence interval of 95% using a one-sample t-test with alpha = 0.05. In the experiment implemented on all of the eight subjects, all malignant tumors marked by the primary radiologist were classified to be malignant by the computer classifier. Our results have shown that neural network classification using the textural parameters for automated screening of two-compartment-based parameter pseudo images of DCE-MRI as input data can be a supportive tool for the radiologists in the preassessment stage to show the possible cancerous regions and in the postassessment stage to review the segmentations especially in analyzing complex DCE-MRI cases. PMID- 23653669 TI - Model independent MRE data analysis. AB - For the diagnosing modality called MRE (magnetic resonance elastography), the displacement vector of a wave propagating in a human tissue can be measured. The average of the local wavelength from this measured data could be an index for the diagnosing, because the local wave length becomes larger when the tissue is stiffer. By assuming that the local form of the wave is given approximately as multiple complex plane waves, we identify the real part of the complex linear phase of the strongest plane wave of this multiple complex plane waves, by first applying the FBI transform (Fourier-Bros-Iagolnitzer transform) with an appropriate size of Gaussian window and then taking the maximum of the modulus of the transform with respect to the Fourier variable. The real part of the linear phase is nothing but the real inner product of the wave vector and the position vector. Similarly the imaginary part of the linear phase describes the attenuation of the wave and it is given as a real inner product of a real vector and the position vector. This vector can also be recovered by our method. We also apply these methods to design some denoising and filtering for noisy MRE data. PMID- 23653665 TI - A review of the combination of experimental measurements and fibril-reinforced modeling for investigation of articular cartilage and chondrocyte response to loading. AB - The function of articular cartilage depends on its structure and composition, sensitively impaired in disease (e.g. osteoarthritis, OA). Responses of chondrocytes to tissue loading are modulated by the structure. Altered cell responses as an effect of OA may regulate cartilage mechanotransduction and cell biosynthesis. To be able to evaluate cell responses and factors affecting the onset and progression of OA, local tissue and cell stresses and strains in cartilage need to be characterized. This is extremely challenging with the presently available experimental techniques and therefore computational modeling is required. Modern models of articular cartilage are inhomogeneous and anisotropic, and they include many aspects of the real tissue structure and composition. In this paper, we provide an overview of the computational applications that have been developed for modeling the mechanics of articular cartilage at the tissue and cellular level. We concentrate on the use of fibril reinforced models of cartilage. Furthermore, we introduce practical considerations for modeling applications, including also experimental tests that can be combined with the modeling approach. At the end, we discuss the prospects for patient-specific models when aiming to use finite element modeling analysis and evaluation of articular cartilage function, cellular responses, failure points, OA progression, and rehabilitation. PMID- 23653670 TI - Postoperative simple biochemical markers for prediction of bone metastases in Egyptian breast cancer patients. AB - OBJECTIVE: The present study was undertaken to identify patient populations at high risk for bone metastases (BM) at any time after diagnosis of operable breast cancer. SUBJECTS AND METHODS: A total number of 59 cases with breast cancer after mastectomy was subdivided into two main groups that included 30 patients with radiologically confirmed BM and 29 patients with no bone metastasis (NBM). Patients with NBM were formerly observed for a one-year follow-up interval to monitor the development of bone metastasis (new BM). Parameters included a full blood picture, tumour markers (carcinoembryonic antigen and CA 15.3) and some biochemical markers (vascular endothelial growth factor and zinc levels, as well as tartrate-resistant acid phosphatase and alkaline phosphatase activities). RESULTS: A significant elevation was recorded in carcinoembryonic antigen level and alkaline phosphatase activity, as well as inflammation and vascularisation markers at the time of primary diagnosis in patients with BM, compared with those without BM. CA 15.3 was significantly higher in the new BM group as compared with the other two groups (patients free of bone metastasis [free BM] and BM). According to the likelihood ratio, a panel of single, calculated as well as combined markers was proposed to predict BM within one year in breast cancer patients. CONCLUSION: Vascularisation and inflammation markers, as well as CA 15.3 are predictive of bone recurrence within one year in breast carcinoma patients. We suggest that in cancer validation studies it is imperative to search for markers that link to the premetastatic process and to determine what type of mechanism is active in each stage. PMID- 23653671 TI - The tumour is not enough or is it? Problems and new concepts in the surgery of cerebral metastases. AB - Cerebral metastases are the most frequent cerebral tumours. Surgery of cerebral metastases plays an indispensible role in a multimodal therapy concept. Conventional white-light, microscopy assisted microsurgical and circumferential stripping of cerebral metastases is neurosurgical standard therapy, but is associated with an extraordinarily high recurrence rate of more than 50% without subsequent whole-brain radiotherapy. Therefore, neurosurgical standard therapy fails to achieve local tumour control in many patients. The present conceptual paper focuses on this issue and discusses the possible causes of the high recurrence rates such as intraoperative dissemination of tumour cells or the lack of sharp delimitation of metastases from the surrounding brain tissue resulting in incomplete resections. Adjuvant whole-brain radiotherapy reduces the risk of local and distant recurrences, but is associated with a well-documented impairment of neurocognitive function. New surgical strategies, such as supramarginal or fluorescence-guided resection, address the possibility of infiltrating tumour parts to achieve more complete resection of cerebral metastases. Supramarginal resection was shown to significantly reduce the risk of a local recurrence and prolongs two-year survival rates. Furthermore, radiosurgery in combination with surgery represents a promising approach. PMID- 23653672 TI - Primary extraosseous Ewing sarcoma of the lung in children. AB - We report a case of primary extraosseous Ewing sarcoma (EES) of the lung in a four-year-old child. In the literature, there are only a few case reports of EES located in the thorax. PMID- 23653673 TI - Plexiform neurofibroma in the submandibular gland along with small diffuse neurofibroma in the floor of the mouth but without neurofibromatosis-1: a rare case report. AB - Plexiform neurofibroma is more commonly seen in the orbit, neck, back, and inguinal region. It is extremely rare in the submandibular gland. These lesions rarely transform into malignancy but are locally infiltrative and can lead to haemorrhage. Therefore, plexiform neurofibroma should always be considered during differential diagnosis while excising a submandibular gland mass. We present here a case of plexiform neurofibroma in the submandibular gland and diffuse neurofibroma in the floor of the mouth in a 27-year-old female, not associated with neurofibromatosis-1. PMID- 23653674 TI - Primary adenocarcinoma of the upper oesophagus. AB - Upper oesophageal adenocarcinoma is a rare malignancy that occurs in the ectopic gastric mucosa, in the upper part of the oesophagus. Only 29 cases so far have been reported. We report the 30th case in a 50-year-old Asian female presenting with difficulty in swallowing. PMID- 23653675 TI - Appearance of malignant melanoma after a non-cutaneous cancer diagnosis. AB - BACKGROUND: The aim of this study is to find the associations between malignant melanoma (MM) and other non-cutaneous malignancies and to see whether there are possible correlations between them. METHODS: We analysed a sample of 1720 patients collected by our melanoma database, to identify patients with both MM and non-cutaneous primary cancer (NCC). The incidence rate (IR) included in our database was calculated as the ratio between the observed patients with NCC and those with MM. RESULTS: A total of 74 patients, with both NCC and MM, were included in our analysis, corresponding to 4.30% of patients with MM present in our melanoma database. After breast cancer (24.3%; IR = 1:4), the most common malignancies were lymphomas (14.8%; IR = 1:4), renal cell carcinoma (13.5%; IR = 1:7), thyroid cancer (9.4%; IR = 1:11), and prostatic carcinoma (8.1%; IR = 1:12), followed by other cancers. Among patients with lymphomas, most patients (72.7%) had a non-Hodgkin lymphoma. Our study shows a high coexistence of multiple malignancies in patients with MM. CONCLUSION: Although we cannot definitively confirm a true association between non-skin cancers and MM, we believe that there are sufficient links for further investigation in order to identify new aetiological factors and therapeutic targets for these cancers. PMID- 23653676 TI - A first new antimalarial pregnane glycoside from Gongronema napalense. AB - As a part of the UIC-based ICBG project in Laos, plants were collected based on ethnomedical interviews and evaluated for antimalarial activity. A CHCl3 extract from the vine of Gongronema napalense (Wall.) Decne. (Asclepiadaceae) showed promising anti-malarial activity while exhibiting low levels of cytotoxicity and was thus followed up with further fractionation and biological evaluation. Bioassay-guided fractionation led to the isolation of a new steroidal glycoside, gongroneside A, which showed antimalarial activity in vitro with an IC50 value of 1.60 and 1.39 MUM against the Plasmodium falciparum D6 and W2 clones, respectively. PMID- 23653679 TI - Antidepressant treatment outcome depends on the quality of the living environment: a pre-clinical investigation in mice. AB - Antidepressants represent the standard treatment for major depression. However, their efficacy is variable and incomplete. A growing number of studies suggest that the environment plays a major role in determining the efficacy of these drugs, specifically of selective serotonin reuptake inhibitors (SSRI). A recent hypothesis posits that the increase in serotonin levels induced by SSRI may not affect mood per se, but enhances neural plasticity and, consequently, renders the individual more susceptible to the influence of the environment. Thus, SSRI administration in a favorable environment would lead to a reduction of symptoms, while in a stressful environment might lead to a worse prognosis. To test this hypothesis, we treated C57BL/6 adult male mice with chronic fluoxetine while exposing them to either (i) an enriched environment, after exposure to a chronic stress period aimed at inducing a depression-like phenotype, or (ii) a stressful environment. Anhedonia, brain BDNF and circulating corticosterone levels, considered endophenotypes of depression, were investigated. Mice treated with fluoxetine in an enriched condition improved their depression-like phenotype compared to controls, displaying higher saccharin preference, higher brain BDNF levels and reduced corticosterone levels. By contrast, when chronic fluoxetine administration occurred in a stressful condition, mice showed a more distinct worsening of the depression-like profile, displaying a faster decrease of saccharin preference, lower brain BDNF levels and increased corticosterone levels. Our findings suggest that the effect of SSRI on depression-like phenotypes in mice is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions. PMID- 23653680 TI - Targeted brain derived neurotropic factors (BDNF) delivery across the blood-brain barrier for neuro-protection using magnetic nano carriers: an in-vitro study. AB - Parenteral use of drugs; such as opiates exert immunomodulatory effects and serve as a cofactor in the progression of HIV-1 infection, thereby potentiating HIV related neurotoxicity ultimately leading to progression of NeuroAIDS. Morphine exposure is known to induce apoptosis, down regulate cAMP response element binding (CREB) expression and decrease in dendritic branching and spine density in cultured cells. Use of neuroprotective agent; brain derived neurotropic factor (BDNF), which protects neurons against these effects, could be of therapeutic benefit in the treatment of opiate addiction. Previous studies have shown that BDNF was not transported through the blood brain barrier (BBB) in-vivo.; and hence it is not effective in-vivo. Therefore development of a drug delivery system that can cross BBB may have significant therapeutic advantage. In the present study, we hypothesized that magnetically guided nanocarrier may provide a viable approach for targeting BDNF across the BBB. We developed a magnetic nanoparticle (MNP) based carrier bound to BDNF and evaluated its efficacy and ability to transmigrate across the BBB using an in-vitro BBB model. The end point determinations of BDNF that crossed BBB were apoptosis, CREB expression and dendritic spine density measurement. We found that transmigrated BDNF was effective in suppressing the morphine induced apoptosis, inducing CREB expression and restoring the spine density. Our results suggest that the developed nanocarrier will provide a potential therapeutic approach to treat opiate addiction, protect neurotoxicity and synaptic density degeneration. PMID- 23653681 TI - Replication study in Chinese population and meta-analysis supports association of the 5p15.33 locus with lung cancer. AB - BACKGROUND: Common genetic polymorphisms on chromosome 5p15.33, including rs401681 in cleft lip and palate transmembrane 1-like gene (CLPTM1L), have been implicated in susceptibility to lung cancer through genome-wide association studies (GWAS); however, subsequent replication studies yielded controversial results. METHODOLOGY AND FINDINGS: A hospital-based case-control study in a Chinese population was conducted to replicate the association, and then a meta analysis combining our non-overlapping new data and previously published data was performed to clearly discern the real effect of lung cancer susceptibility. In our study with 611 cases and 1062 controls, the minor allele T carrier (TT plus CT) group conferred an OR of 0.801 (95% CI = 0.654-0.981) under the dominant model. The meta-analysis comprising 9111 cases and 11424 controls further confirmed the significant association in the dominant model (OR = 0.842, 95% CI = 0.795-0.891). By stratified analysis, we revealed that ethnicity and study design might constitute the source of between-study heterogeneity. Besides, the sensitivity and cumulative analyses indicated the high stability of the results. CONCLUSION: The results from our case-control study and meta-analysis provide convincing evidence that rs401681 is significantly associated with lung cancer risk. PMID- 23653682 TI - In vitro selection of mutant HDM2 resistant to Nutlin inhibition. AB - HDM2 binds to the p53 tumour suppressor and targets it for proteosomal degradation. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2 and abrogates its repressive function. Using a novel in vitro selection methodology, we simulated the emergence of resistance by evolving HDM2 mutants capable of binding p53 in the presence of Nutlin concentrations that inhibit the wild-type HDM2-p53 interaction. The in vitro phenotypes were recapitulated in ex vivo assays measuring both p53 transactivation function and the direct p53-HDM2 interaction in the presence of Nutlin. Mutations conferring drug resistance were not confined to the N-terminal p53/Nutlin-binding domain, and were additionally seen in the acidic, zinc finger and RING domains. Mechanistic insights gleaned from this broad spectrum of mutations will aid in future drug design and further our understanding of the complex p53-HDM2 interaction. PMID- 23653684 TI - The science of salsa: antimicrobial properties of salsa components to learn scientific methodology. AB - Most ethnic foods and cooking practices have incorporated the use of spices and other food additives. Many common spices have crossed cultural boundaries and appear in multiple ethnic cuisines. Recent studies have demonstrated that many of these ingredients possess antimicrobial properties against common food spoilage microorganisms. We developed a laboratory exercise that promotes the use of scientific methodology to evaluate the effectiveness of salsa components at inhibiting the growth of undesirable microorganisms. Tomato, onion, garlic, cilantro, and jalapeno were tested for antimicrobial properties against a representative fungus, Saccharomyces cerevisiae, and the common food spoilage bacteria Staphylococcus aureus, Bacillus cereus, and Escherichia coli. Each component was ethanol extracted and a modification of the Kirby-Bauer method of antimicrobial sensitivity was employed. Garlic demonstrated the greatest inhibitory effects against all organisms tested. Onion demonstrated a slight inhibition of all four organisms, while cilantro showed some inhibition of all three bacteria but no effect against the fungus. Jalapeno may have slightly inhibited E. coli and S. aureus, as evidenced by a consistently measured increase in the zone of inhibition that was not statistically significant when compared to that of the control. Following the initial exercise, students were given the opportunity to repeat the exercise using other spices such as cinnamon, clove, nutmeg, and coriander. Student learning outcomes were evaluated using preliminary and secondary surveys, mainly focusing on definitions of science and hypothesis as well as the process of science. Students enjoyed this exercise and met the learning goals of understanding the process and methodology of science, as well as the interdisciplinarity inherent in the sciences. Student learning was evidenced by an increase in the number of correct responses on the secondary survey in comparison to the preliminary. PMID- 23653685 TI - The Lichen-GIS Project, Teaching Students How to Use Bioindicator Species to Assess Environmental Quality. AB - A content-driven biology course for preservice K-8 teachers has been developed. This course uses the constructivist approach, where instructors engage students by organizing information around concept-based problems. To this end, a semester long, inquiry-based project was introduced where students studied lichen populations on trees located on their campus to monitor air quality. Data were incorporated into a geographical information systems (GIS) database to demonstrate how it can be used to map communities. Student teams counted the number of each lichen type within a grid placed on each tree trunk sampled and entered this information into a GIS database. The students constructed maps of lichen populations at each sample site and wrote abstracts about their research. Student performance was assessed by the preparation of these abstracts as well as by scores on pre- and posttests of key content measures. Students also completed a survey to determine whether the project aided in their comprehension as well as their interest in incorporating this activity into their own curricula. The students' pre- and posttest results showed an eightfold improvement in the total score after the semester project. Additionally, correct responses to each individual content measure increased by at least 35%. Total scores for the abstract ranged from 12 to 20 points out of 20 total points possible (60% to 100%), with a mean score of 15.8 points (78%). These results indicate that this exercise provided an excellent vehicle to teach students about lichens and their use as bioindicators and the application of geospatial technologies to map environmental data. PMID- 23653686 TI - Podcasts as tools in introductory environmental studies. AB - Technological tools have increasingly become a part of the college classroom, often appealing to teachers because of their potential to increase student engagement with course materials. Podcasts in particular have gained popularity as tools to better inform students by providing access to lectures outside of the classroom. In this paper, we argue that educators should expand course materials to include prepublished podcasts to engage students with both course topics and a broader skill set for evaluating readily available media. We present a pre- and postassignment survey evaluation assessing student preferences for using podcasts and the ability of a podcast assignment to support learning objectives in an introductory environmental studies course. Overall, students reported that the podcasts were useful tools for learning, easy to use, and increased their understanding of course topics. However, students also provided insightful comments on visual versus aural learning styles, leading us to recommend assigning video podcasts or providing text-based transcripts along with audio podcasts. A qualitative analysis of survey data provides evidence that the podcast assignment supported the course learning objective for students to demonstrate critical evaluation of media messages. Finally, we provide recommendations for selecting published podcasts and designing podcast assignments. PMID- 23653683 TI - RIG-I detects triphosphorylated RNA of Listeria monocytogenes during infection in non-immune cells. AB - The innate immune system senses pathogens by pattern recognition receptors in different cell compartments. In the endosome, bacteria are generally recognized by TLRs; facultative intracellular bacteria such as Listeria, however, can escape the endosome. Once in the cytosol, they become accessible to cytosolic pattern recognition receptors, which recognize components of the bacterial cell wall, metabolites or bacterial nucleic acids and initiate an immune response in the host cell. Current knowledge has been focused on the type I IFN response to Listeria DNA or Listeria-derived second messenger c-di-AMP via the signaling adaptor STING. Our study focused on the recognition of Listeria RNA in the cytosol. With the aid of a novel labeling technique, we have been able to visualize immediate cytosolic delivery of Listeria RNA upon infection. Infection with Listeria as well as transfection of bacterial RNA induced a type-I-IFN response in human monocytes, epithelial cells or hepatocytes. However, in contrast to monocytes, the type-I-IFN response of epithelial cells and hepatocytes was not triggered by bacterial DNA, indicating a STING-independent Listeria recognition pathway. RIG-I and MAVS knock-down resulted in abolishment of the IFN response in epithelial cells, but the IFN response in monocytic cells remained unaffected. By contrast, knockdown of STING in monocytic cells reduced cytosolic Listeria-mediated type-I-IFN induction. Our results show that detection of Listeria RNA by RIG-I represents a non-redundant cytosolic immunorecognition pathway in non-immune cells lacking a functional STING dependent signaling pathway. PMID- 23653687 TI - The use of interrupted case studies to enhance critical thinking skills in biology. AB - There has been a dramatic increase in the availability of case studies for use in the biology classroom, and perceptions of the effectiveness of case-study-based learning are overwhelmingly positive. Here we report the results of a study in which we evaluated the ability of interrupted case studies to improve critical thinking in the context of experimental design and the conventions of data interpretation. Students were assessed using further case studies designed to evaluate their ability to recognize and articulate problematic approaches to these elements of experimentation. Our work reveals that case studies have broad utility in the classroom. In addition to demonstrating a small but statistically significant increase in the number of students capable of critically evaluating selected aspects of experimental design, we also observed increased student engagement and documented widespread misconceptions regarding the conventions of data acquisition and analysis. PMID- 23653688 TI - The undergraduate teaching assistant experience offers opportunities similar to the undergraduate research experience. AB - There has been a growing concern in higher education about our failure to produce scientifically trained workers and scientifically literate citizens. Active learning and research-oriented activities are posited as ways to give students a deeper understanding of science. We report on an undergraduate teaching assistant (UTA) experience and suggest that students who participate as a UTA obtain benefits analogous to those who participate as an undergraduate research assistant (URA). We examined the experiences of 24 undergraduates acting as UTAs in a general microbiology course. Self-reported gains by the UTAs were supported by observational data from undergraduates in the course who were mentored by the UTAs and by the graduate teaching assistants (GTAs) with whom the UTAs worked. Specifically, data from the UTAs' journals and self-reported Likert scales and rubrics indicated that our teaching assistants developed professional characteristics such as self-confidence and communication and leadership skills, while they acquired knowledge of microbiology content and laboratory skills. Data from the undergraduate Likert scale as well as the pre- and post-GTA rubrics further confirmed our UTA's data interpretations. These findings are significant because they offer empirical data to support the suggestion that the UTA experience is an effective option for developing skills and knowledge in undergraduates that are essential for careers in science. The UTA experience provides a valuable alternative to the URA experience. PMID- 23653689 TI - Assessing student understanding of host pathogen interactions using a concept inventory. AB - As a group of faculty with expertise and research programs in the area of host pathogen interactions (HPI), we are concentrating on students' learning of HPI concepts. As such we developed a concept inventory to measure level of understanding relative to HPI after the completion of a set of microbiology courses (presently eight courses). Concept inventories have been useful tools for assessing student learning, and our interest was to develop such a tool to measure student learning progression in our microbiology courses. Our teaching goal was to create bridges between our courses which would eliminate excessive overlap in our offerings and support a model where concepts and ideas introduced in one course would become the foundation for concept development in successive courses. We developed our HPI concept inventory in several phases. The final product was an 18-question, multiple-choice concept inventory. In fall 2006 and spring 2007 we administered the 18-question concept inventory in six of our courses. We collected pre- and postcourse surveys from 477 students. We found that students taking pretests in the advanced courses retained the level of understanding gained in the general microbiology prerequisite course. Also, in two of our courses there was significant improvement on the scores from pretest to posttest. As we move forward, we will concentrate on exploring the range of HPI concepts addressed in each course and determine and/or create effective methods for meaningful student learning of HPI aspects of microbiology. PMID- 23653690 TI - Virtual lab demonstrations improve students' mastery of basic biology laboratory techniques. AB - Biology laboratory classes are designed to teach concepts and techniques through experiential learning. Students who have never performed a technique must be guided through the process, which is often difficult to standardize across multiple lab sections. Visual demonstration of laboratory procedures is a key element in teaching pedagogy. The main goals of the study were to create videos explaining and demonstrating a variety of lab techniques that would serve as teaching tools for undergraduate and graduate lab courses and to assess the impact of these videos on student learning. Demonstrations of individual laboratory procedures were videotaped and then edited with iMovie. Narration for the videos was edited with Audacity. Undergraduate students were surveyed anonymously prior to and following screening to assess the impact of the videos on student lab performance by completion of two Participant Perception Indicator surveys. A total of 203 and 171 students completed the pre- and posttesting surveys, respectively. Statistical analyses were performed to compare student perceptions of knowledge of, confidence in, and experience with the lab techniques before and after viewing the videos. Eleven demonstrations were recorded. Chi-square analysis revealed a significant increase in the number of students reporting increased knowledge of, confidence in, and experience with the lab techniques after viewing the videos. Incorporation of instructional videos as prelaboratory exercises has the potential to standardize techniques and to promote successful experimental outcomes. PMID- 23653691 TI - Promoting science for all by way of student interest in a transformative undergraduate microbiology laboratory for nonmajors. AB - In this study, we investigated a pedagogical innovation in an undergraduate microbiology course, Microbes and Society, for non-microbiology majors and education majors. The aim was to improve students' understanding by connecting their science experience to their areas of interest. Based on this idea of teaching, we redesigned the laboratory portion of a microbiology course. We had students in the laboratory component choose their areas of interest and use the areas as a framework for understanding science and how it influences and shapes the world around them. This course was part of a longitudinal project (Project Nexus) which prepares, supports, and sustains upper elementary and middle-level specialist science teachers. We used a battery of data collection instruments. We analyzed all data in several dimensions including using active-learning techniques, forming linkages between science and teaching, and connecting science and society. Our hypothesis was that we could promote science for all by connecting the diverse students' areas of interest in science to the laboratory's curriculum. We assessed the success of achieving our goal by using researchers' observations, the instructors' perspectives, and students' feedback. Our findings suggested that this course was appreciated by the students, especially education majors, who recognized the innovations as engaging and worthwhile. PMID- 23653692 TI - Letter to the editor. PMID- 23653693 TI - Stream water quality and service learning in an introductory biology class. AB - Northland College is a small environmental liberal arts college in northern Wisconsin near Lake Superior. In the fall of 2007 and 2008 students in a mixed science majors/non-majors introductory biology course engaged in a semester-long, service-learning project to monitor E. coli in city stormwater draining into Bay City Creek, a small stream that flows through campus and the town of Ashland before flowing into Lake Superior. Such monitoring is beyond the budget of most municipalities, but is an important public health and aesthetic issue for Ashland and Lake Superior. Our hypothesis was that this service-learning research project would have a positive impact on student learning and student perception of science, and the project would generate useful information for city leaders. Students collected and processed water samples using a standard protocol, analyzed the effect of stormwater on stream water quality, and presented their data in the form of posters to the mayor, a city administrator, and the Provost. Student learning was assessed by a poster-grading rubric, and by online and Northland College instruments. Student perceptions of science were found to be more positive than in the year preceding this project, even when clear answers were not found from their scientific investigation, and there appeared to be no distinction in responses between science majors and non-majors. PMID- 23653694 TI - Towards improving the integration of undergraduate biology and mathematics education. AB - Arguments have recently asserted the need for change in undergraduate biology education, particularly with regard to the role of mathematics. The crux of these protests is that rapidly developing technology is expanding the types of measurements and subsequent data available to biologists. Thus future generations of biologists will require a set of quantitative and analytic skills that will allow them to handle these types of data in order to tackle relevant questions of interest. In this spirit, we describe here strategies (or lessons learned) for undergraduate educators with regard to better preparing undergraduate biology majors for the new types of challenges that lay ahead. The topics covered here span a broad range, from classroom approaches to the administrative level (e.g., fostering inter-departmental communication, student advising) and beyond. A key theme here is the need for an attitude shift with regard to mathematics education by both students and faculty alike. Such a shift will facilitate the development and implementation of new teaching strategies with regard to improving integration of mathematics and biology pedagogy. PMID- 23653695 TI - It's All Their Fault? AB - Many students fail our introductory science courses and give up on science altogether. How much of this is their fault is debatable. But what is not debatable is that we can improve the situation by using active learning methods. Many faculty claim critical thinking is their highest priority. Their teaching seldom reflects this. They emphasize facts and lecture without context. Most of our students are not going to be scientists, but they are going to be citizens and need to be able to spot inaccuracies when they appear in the media. Case based and Problem-based Teaching are proven ways to achieve this goal. PMID- 23653696 TI - "Shovel-ready" Sequences as a Stimulus for the Next Generation of Life Scientists. AB - Genomics and bioinformatics are dynamic fields well-suited for capturing the imagination of undergraduates in both research laboratories and classrooms. Currently, raw nucleotide sequence is being provided, as part of several genomics research initiatives, for undergraduate research and teaching. These initiatives could be easily extended and much more effective if the source of the sequenced material and the subsequent focus of the data analysis were aligned with the research interests of individual faculty at undergraduate institutions. By judicious use of surplus capacity in existing nucleotide sequencing cores, raw sequence data could be generated to support ongoing research efforts involving undergraduates. This would allow these students to participate actively in discovery research, with a goal of making novel contributions to their field through original research while nurturing the next generation of talented research scientists. PMID- 23653697 TI - Studying gene expression: database searches and promoter fusions to investigate transcriptional regulation in bacteria. AB - A laboratory project was designed to illustrate how to search biological databases and utilize the information provided by these resources to investigate transcriptional regulation in Escherichia coli. The students searched several databases (NCBI Genomes, RegulonDB and EcoCyc) to learn about gene function, regulation, and the organization of transcriptional units. A fluorometer and GFP promoter fusions were used to obtain fluorescence data and measure changes in transcriptional activity. The class designed and performed experiments to investigate the regulation of genes necessary for biosynthesis of amino acids and how expression is affected by environmental signals and transcriptional regulators. Assessment data showed that this activity enhanced students' knowledge of databases, reporter genes and transcriptional regulation. PMID- 23653698 TI - Laboratory exploration of survival of probiotic cultures inside the human digestive tract using in vitro models. AB - Scientists often model complex biological phenomena in vitro, mimicking conditions found in living organisms. Understanding the power and limitations of biological models is an important topic in undergraduate science. In this activity, students develop their own in vitro model for testing the survival of bacteria from commercial probiotic supplements. Students work in groups to decide which factors are important for survival of bacteria in a chosen portion of the human digestive tract. Groups of students create their own in vitro models of organs such as stomach and/or intestines. Students expose a probiotic supplement to conditions mimicking the chosen portion of the human digestive tract, and measure the effect of those conditions on the survival of bacteria found in the supplement. Students choose to focus on conditions such as low pH found in stomach or pancreatic enzymes found in the upper intestine. Through this activity, students gain experience with serial dilutions and calculations of colony forming units (CFUs). This project also provides the students with the valuable experience of designing experiments in small groups. Students present their findings in a poster session, which provides a venue for discussing the validity and limitation of various models. PMID- 23653699 TI - Restriction Enzyme Digestion Exercise - An In-class Activity. PMID- 23653700 TI - Using concept maps in teaching microbiology. PMID- 23653701 TI - An Eco-friendly, Scaled-down Gram Stain Protocol. PMID- 23653702 TI - Want to inspire science students to consider a research career? Host a scientist in your classroom. PMID- 23653703 TI - Learn.Genetics from the Genetic Science Learning Center at the University of Utah:http://learn.genetics.utah.edu/. PMID- 23653704 TI - Teach.Genetics from the Genetic Science Learning Center at the University of Utah:http://teach.genetics.utah.edu/. PMID- 23653705 TI - Scientific Teaching Digital Library Website:http://scientificteaching.wisc.edu/materials. PMID- 23653707 TI - Multiple benefits derived from a peer teacher program in two undergraduate microbiology lab courses. AB - A peer teaching program was implemented to alleviate the problem of a limited number of lab instructors attempting to teach large numbers of students in two different undergraduate microbiology lab courses. The benefit of having peer teachers was immediately obvious to the lab instructors, faculty and staff who were responsible for conducting the labs, but it was soon evident that there were also benefits for everyone else involved in the program. The students enrolled in the labs reported that having peer teachers in the lab enhanced their learning, and they felt comfortable receiving help from a peer teacher who had recently completed the course. The peer teachers discovered that they gained valuable experience and confidence while teaching other students, and they appreciated the chance to gain hands-on experience. The lab instructors received the qualified help they needed in order to give more individual attention to the large numbers of students in the labs. The feedback from this program has been positive from everyone involved. PMID- 23653708 TI - The Use of Personal Narrative in Classroom Case Study Analysis to Improve Long term Knowledge Retention and Cultivate Professional Qualities in Allied Health Students. AB - This study evaluated the use of two different case study formats (clinically oriented cases versus personally-oriented cases) to determine which was most effective in promoting long-term retention of clinically significant microbiology concepts, developing patient empathy, improving comprehension of patient compliance problems, and facilitating student understanding of transcultural health care concerns. The analysis was conducted in multiple sections of three different introductory microbiology classes targeting specific cohorts: nursing students, pharmacy students and other allied health students (pre-med, pre-PA, CLS, etc.). Retention of course content was determined by evaluation of multiple choice and short answer examinations at least three weeks after completing case studies. Evaluation of patient empathy, understanding of patient compliance issues and transcultural health care concerns were determined via student surveys. The results of the study indicated that personalized cases significantly improved long-term retention of course content. In addition, student responses indicated that personalized case studies were more effective in developing patient empathy and aiding students in understanding issues patients have with complying with treatment recommendations. Finally, personalized case studies were effective tools for introducing students to the challenges of transcultural health care. PMID- 23653709 TI - Efficacy of role play in concert with lecture to enhance student learning of immunology. AB - Despite numerous reports that active learning increases student understanding, many barriers still exist that prevent faculty from shedding the traditional passive lecture and adopting active learning strategies in the classroom. This study looks at the use of role play as an active learning technique to convey new material, or as reinforcement to traditional lecture. A pre- and post-test survey was utilized to determine student learning gains, along with an anonymous survey to determine student attitudes about role play. Student learning gains are similar regardless of class size, role-playing participation or learning style, and reflect an increase in lower order cognition. Attitudes and learning gains indicate role play is preferable as a reinforcement technique, although the order does not matter if both lecture and role play are utilized to convey information. These data provide insight into the best practices of role-playing implementation in concert with traditional lecture format. PMID- 23653710 TI - Understanding undergraduates' problem-solving processes. AB - Fostering effective problem-solving skills is one of the most longstanding and widely agreed upon goals of biology education. Nevertheless, undergraduate biology educators have yet to leverage many major findings about problem-solving processes from the educational and cognitive science research literatures. This article highlights key facets of problem-solving processes and introduces methodologies that may be used to reveal how undergraduate students perceive and represent biological problems. Overall, successful problem-solving entails a keen sensitivity to problem contexts, disciplined internal representation or modeling of the problem, and the principled management and deployment of cognitive resources. Context recognition tasks, problem representation practice, and cognitive resource management receive remarkably little emphasis in the biology curriculum, despite their central roles in problem-solving success. PMID- 23653711 TI - Learning Outcomes with Linked Assessments - an Essential Part of our Regular Teaching Practice. AB - Setting up learning outcomes with linked assessments is a best practice in science education. In biology teaching, faculty are beginning to establish learning outcomes and assessments in the style of concept inventories. At a recent meeting of biology faculty who have designed concept inventories, the characteristics and uses of concept inventories were defined. Concept inventories used as pre- and post-measures of student learning provide a window into students' understanding of key concepts of a discipline and serve as a tool to motivate faculty toward evidence-based teaching habits. A movement for the development of a microbiology concept inventory is suggested. PMID- 23653712 TI - Research, collaboration, and open science using web 2.0. AB - There is little doubt that the Internet has transformed the world in which we live. Information that was once archived in bricks and mortar libraries is now only a click away, and people across the globe have become connected in a manner inconceivable only 20 years ago. Although many scientists and educators have embraced the Internet as an invaluable tool for research, education and data sharing, some have been somewhat slower to take full advantage of emerging Web 2.0 technologies. Here we discuss the benefits and challenges of integrating Web 2.0 applications into undergraduate research and education programs, based on our experience utilizing these technologies in a summer undergraduate research program in synthetic biology at Harvard University. We discuss the use of applications including wiki-based documentation, digital brainstorming, and open data sharing via the Web, to facilitate the educational aspects and collaborative progress of undergraduate research projects. We hope to inspire others to integrate these technologies into their own coursework or research projects. PMID- 23653713 TI - Clinical Microbiology in Pharmacy Education: A Practice-based Approach. AB - The increasing incidence of multi-drug resistant pathogenic bacteria, alongside viral and fungal human pathogens, supports the argument that skills in microbiology and infectious disease diagnosis, treatment and prevention are of growing global importance to be held among primary care clinicians. In Canada, inevitable future astronomical health care costs largely due to an aging population, have forced eyes upon pharmacists as one of (if not) the primary clinical professions to accommodate the growing need to accommodate patient access to health care while maintaining lower health care costs. As such, the role of pharmacists in health care is expanding, punctuating the need to enhance and improve Pharmacy education. Accurate assessment of the current gaps in Pharmacy education in Canada provides a unique opportunity for a new Pharmacy School at the University of Waterloo to establish a non-traditional, outcomes based model to curricular design. We are applying this iterative curriculum assessment and design process to the establishment of a Medical Microbiology program, deemed as a prominent gap in former Pharmacy educational training programs. A PILOT STUDY WAS CARRIED OUT DISTRIBUTING A COMPREHENSIVE SURVEY TO A LOCAL GROUP OF PHARMACISTS PRACTICING IN A VARIETY OF SETTINGS INCLUDING: hospital, clinic, community, independent, industry and government, to assess perceived gaps in Pharmacy microbiology and infectious disease education. Preliminary findings of the surveys indicate that practitioners feel under qualified in some areas of microbiology. The results are discussed with respect to a curricular redesign model and next steps in the process of curricular design are proposed. PMID- 23653714 TI - The impending crisis. AB - When you are ill and consult a physician for his or her expertise, many times laboratory testing is part of the clinical workup. This testing is critical to the physician's ability to diagnose the patient's condition. What if testing was not available ... because there was no one to do the testing? Although seemingly far-fetched, this scenario could play itself out in the next ten years due to an impending manpower crisis in laboratory medicine. The profession of Medical Technology, also known as Clinical Laboratory Science, is experiencing a shortage of qualified individuals for a variety of reasons - not the least of which is the closure of almost 70% of the schools teaching this critical profession. Health care workers (HCW) rely on accurate and timely clinical laboratory results in order to make decisions for their patients. Because ~ 70% of patient care decisions are based on clinical laboratory results, it is important to have a well-trained supply of laboratory professionals. This article will give an overview of the situation and the possible causes of this shortage, and pose challenges to our profession as to how this crisis can be averted. Visibility of this profession must be a prime focus of this effort in order for the population in general to be aware of the role Clinical Laboratory Scientists play in the health care consortium. This effort should begin early in the educational process, potentially as early as Middle School (junior high school), bringing awareness of the profession not only to students but to educators as well. PMID- 23653715 TI - Using flow cytometry to measure phagocytic uptake in earthworms. AB - This laboratory module familiarizes students with flow cytometry while acquiring quantitative reasoning skills during data analysis. Leukocytes, also known as coelomocytes (including hyaline and granular amoebocytes, and chloragocytes), from Eisenia hortensis (earthworms) are isolated from the coelomic cavity and used for phagocytosis of fluorescent Escherichia coli. Students learn how to set up in vitro cellular assays and become familiar with theoretical principles of flow cytometry. Histograms based on fluorescence and scatter properties combined with gating options permit students to restrict their analyses to particular subsets of coelomocytes when measuring phagocytosis, a fundamentally important innate immune mechanism used in earthworms. Statistical analysis of data is included in laboratory reports which serve as the primary assessment instrument. PMID- 23653716 TI - A small group activity about bacterial regulation and complementation. AB - As teachers, we well understand the need for activities that help develop critical-thinking skills in microbiology. In our experience, one concept that students have difficulty understanding is transcriptional regulation of bacterial genes. To help with this, we developed and evaluated a paper-based activity to help students understand and apply the concepts of bacterial transcriptional regulation. While we don't identify it as such, we use a complementation experiment to assess student understanding of how regulation changes when new DNA is introduced. In Part 1 of this activity, students complete an open-book, take home assignment that asks them to define common terminology related to regulation, and draw the regulatory components of different scenarios involving positive and negative regulation. In Part 2, students work in small groups of 3-4 to depict the regulatory components for a different scenario. They are asked to explain the results of a complementation experiment based on this scenario. They then predict the results of a slightly different experiment. Students who completed the Regulation Activity did significantly better on post-test questions related to regulation, compared to pre-test questions. PMID- 23653717 TI - Studying simple and complex traits using pedigrees produced from a large database. PMID- 23653718 TI - Coliforms everywhere! Using microbiology to teach the scientific method. PMID- 23653719 TI - Development of a DNA Bar-coding Project as a Biology Laboratory Module. PMID- 23653720 TI - MicroTracker: a Data Management Tool for Facilitating the Education of Undergraduate Students in Laboratory Research Environments. PMID- 23653721 TI - Learning can be all Fun and Games: Constructing and Utilizing a Biology Taboo Wiktionary to Enhance Student Learning in an Introductory Biology Course. PMID- 23653722 TI - The use of popular fiction to present a professional scientific career to high school students. PMID- 23653723 TI - Create a bacterium: an engaging semester-long assignment. PMID- 23653724 TI - A simple wooden ribosome model: helping students understand transpeptidation. PMID- 23653725 TI - The Sci-Fi Microbe: Reinforcing Understanding of Microbial Structures and their Significance Through a Creative Writing Exercise. PMID- 23653726 TI - Chemotaxis on the move - active learning teaching tool. PMID- 23653727 TI - Using an "unknown characterization" activity as the midterm lab practical in a large enrollment, multi-lab section microbiology course. PMID- 23653728 TI - Review of three DNA analysis applications for use in the microbiology or genetics classroom. PMID- 23653730 TI - Letters to the editor. PMID- 23653731 TI - Bassler and handelsman: letters to the editor. PMID- 23653732 TI - Gain in student understanding of the role of random variation in evolution following teaching intervention based on luria-delbruck experiment. AB - Undergraduate students in introductory biology classes are typically saddled with pre-existing popular beliefs that impede their ability to learn about biological evolution. One of the most common misconceptions about evolution is that the environment causes advantageous mutations, rather than the correct view that mutations occur randomly and the environment only selects for mutants with advantageous traits. In this study, a significant gain in student understanding of the role of randomness in evolution was observed after students participated in an inquiry-based pedagogical intervention based on the Luria-Delbruck experiment. Questionnaires with isomorphic questions regarding environmental selection among random mutants were administered to study participants (N = 82) in five separate sections of a sophomore-level microbiology class before and after the teaching intervention. Demographic data on each participant was also collected, in a way that preserved anonymity. Repeated measures analysis showed that post-test scores were significantly higher than pre-test scores with regard to the questions about evolution (F(1, 77) = 25.913, p < 0.001). Participants' pre-existing beliefs about evolution had no significant effect on gain in understanding of this concept. This study indicates that conducting and discussing an experiment about phage resistance in E. coli may improve student understanding of the role of stochastic events in evolution more broadly, as post test answers showed that students were able to apply the lesson of the Luria Delbruck experiment to other organisms subjected to other kinds of selection. PMID- 23653733 TI - A Retrospective Look at 20 Years of ASM Education Programs (1990-2010) and a Prospective Look at the Next 20 Years (2011-2030). AB - Professional societies provide visibility and legitimacy to the work of their post secondary educator members, advocate best practices in courses and sponsored student research, and establish deep networks and communities that catalyze members to collectively engage in undergraduate teaching and learning scholarship. Within the American Society for Microbiology (ASM), the Education Board, established in the mid-1970s, assumes this role. I have been fortunate enough to watch several pivotal programs support our growth and change the status quo by providing opportunities for biology educators to flourish. In this retrospective review, the background and details I offer about each initiative help explain ASM Education offerings, how our growth has been supported and how the status quo has changed. In this prospective look, I offer my vision of the future in post secondary education where classroom learning is student-centered and focused on global problems affecting our health and environment. For the profession to proliferate, the ASM must provide members as many opportunities in learning biology as they do with advancing biology to new frontiers. PMID- 23653734 TI - Redesigning introductory biology: a proposal. AB - With the increasing complexity and expansion of the biological sciences, there has been a corresponding increase in content in the first-year introductory biology course sequence for majors. In general this has resulted in courses that introduce students to large amounts of material and leave little time for practicing investigative science or skill development. Based on our analysis of data compiled from 742 biology faculty at a variety of institutions across the United States, we verified that there is strong agreement on the content appropriate for introductory biology courses for majors. Therefore, we propose that faculty teaching these courses focus primarily on the topics identified in this study, and redesign their courses to incorporate active learning strategies that emphasize the investigative nature of biology and provide opportunities for skill development. PMID- 23653735 TI - Antiviral drug research proposal activity. AB - The development of antiviral drugs provides an excellent example of how basic and clinical research must be used together in order to achieve the final goal of treating disease. A Research Oriented Learning Activity was designed to help students to better understand how basic and clinical research can be combined toward a common goal. Through this project students gained a better understanding of the process of scientific research and increased their information literacy in the field of virology. The students worked as teams to research the many aspects involved in the antiviral drug design process, with each student becoming an "expert" in one aspect of the project. The Antiviral Drug Research Proposal (ADRP) culminated with students presenting their proposals to their peers and local virologists in a poster session. Assessment data showed increased student awareness and knowledge of the research process and the steps involved in the development of antiviral drugs as a result of this activity. PMID- 23653736 TI - Implementation of a Service-learning Module in Medical Microbiology and Cell Biology Classes at an Undergraduate Liberal Arts University. AB - Here we discuss the implementation of a service-learning module in two upper division biology classes, Medical Microbiology and Cell Biology. This exciting hands-on learning experience provided our students with an opportunity to extend their learning of in-class topics to a real-life scenario. Students were required to volunteer their time (a minimum of 10 hours in a semester) at an under-served clinic in Houston, Texas. As they interacted with the personnel at the clinic, they were asked to identify the most prevalent disease (infectious for Medical Microbiology, and cellular-based for Cell) seen at the clinic and, working in groups, come up with educational material in the form of a display or brochure to be distributed to patients. The material was meant to educate patients about the disease in general terms, as well as how to recognize (symptoms), prevent and treat it. Students were required to keep a reflective journal in the form of a blog throughout the semester, and present their final materials to the class orally. Students were surveyed about their opinion of the experience at the end of the semester. The vast majority of student participants felt that the project was a positive experience and that it helped them develop additional skills beyond what they learn in the classroom and understand how lecture topics relate to every day life. PMID- 23653737 TI - "General Hospital": Using Skit-Writing and Role-playing to Teach Pathogenesis. PMID- 23653738 TI - Getting more from flashcards: examples from medical microbiology. PMID- 23653739 TI - A biology laboratory exercise using macromolecule assays to distinguish four types of milk. PMID- 23653740 TI - New teaching strategies to improve student performance in fundamentals of biotechnology. PMID- 23653741 TI - The recording of student performance in the microbiology laboratory as a training, tutorial, and motivational tool. AB - The laboratory component of a microbiology course consists of exercises which mandate a level of proficiency and manual dexterity equal to and often beyond that recognized among other biology courses. Bacterial growth, maintenance, identification (e.g., Gram stain, biochemical tests, genomics), as well as the continuous need to maintain laboratory safety and sterile technique, are only a few skills/responsibilities critical to the discipline of microbiology. Performance of the Gram stain remains one of the most basic and pivotal skills that must be mastered in the microbiology laboratory. However, a number of students continually have difficulty executing the Gram stain and preparative procedures associated with the test. In order to address this issue, we incorporated real-time digital recording as a supplemental teaching aid in the microbiology laboratory. Our use of the digital movie camera in the teaching setting served to enhance interest, motivate students, and in general, improve student performance. PMID- 23653742 TI - Use of Blue Agar CAS Assay for Siderophore Detection. PMID- 23653743 TI - A Sweet Vaccination - the Deadly Hershey's Kiss. PMID- 23653744 TI - Visualizing the cardiac cycle: a useful tool to promote student understanding. PMID- 23653745 TI - The use of current events as assessment tools. PMID- 23653746 TI - The MicroSafari: A Journey into Microbiology, an Expedition into Engagement. PMID- 23653747 TI - Covering all the bases in genetics: simple shorthands and diagrams for teaching base pairing to biology undergraduates. PMID- 23653748 TI - Collaborative creation of a lab rubric. PMID- 23653749 TI - Teaching bacterial arrangements and morphologies with candy. PMID- 23653750 TI - From the reviews editor. PMID- 23653752 TI - Suggested resources for scholarly teaching and for the scholarship of teaching and learning. PMID- 23653753 TI - Quick Quiz - Is it Really Recall? PMID- 23653754 TI - A review of scientific teaching. PMID- 23653755 TI - Summer workshop in metagenomics: one week plus eight students equals gigabases of cloned DNA. AB - We designed a week-long laboratory workshop in metagenomics for a cohort of undergraduate student researchers. During this course, students learned and utilized molecular biology and microbiology techniques to construct a metagenomic library from Puerto Rican soil. Pre-and postworkshop assessments indicated student learning gains in technical knowledge, skills, and confidence in a research environment. Postworkshop construction of additional libraries demonstrated retention of research techniques by the students. PMID- 23653756 TI - Manipulatives-based laboratory for majors biology - a hands-on approach to understanding respiration and photosynthesis. AB - The first course in our year-long introductory series for Biology majors encompasses four learning units: biological molecules and cells, metabolism, genetics, and evolution. Of these, the metabolism unit, which includes respiration and photosynthesis, has shown the lowest student exam scores, least interest, and lowest laboratory ratings. Consequently, we hypothesized that modeling metabolic processes in the laboratory would improve student content learning during this course unit. Specifically, we developed manipulatives-based laboratory exercises that combined paper cutouts, movable blocks, and large diagrams of the cell. In particular, our novel use of connecting LEGO blocks allowed students to move model electrons and phosphates between molecules and within defined spaces of the cell. We assessed student learning using both formal (content indicators and attitude surveys) and informal (the identification of misconceptions or discussions with students) approaches. On the metabolism unit content exam, student performance improved by 46% over pretest scores and by the end of the course, the majority of students rated metabolism as their most improved (43%) and favorite (33%) subject as compared with other unit topics. The majority of students rated manipulatives-based labs as very helpful, as compared to non-manipulatives-based labs. In this report, we will demonstrate that students made learning gains across all content areas, but most notably in the unit that covered respiration and photosynthesis. PMID- 23653757 TI - Designing cancer-killing artificial viruses to improve student understanding of microbiology. AB - Our objective was to assess the effectiveness of a "learning by designing" group project used in a lower-division Microbiology course. Students used knowledge gained from the course to design an artificial virus that would kill cancer cells. The assignment required groups to integrate the individual course topics into a unified, complex understanding of the field of microbiology. Throughout the course, students and the instructor collaborated in creating a rubric to evaluate the groups' final presentations. This paper reports the results of an assessment of the project by comparing the instructor's and the students' scores for the presentations. Students' and the instructor's scores were correlated; the Pearson coefficient of 0.52 was statistically significant. The results indicate that students gained sufficient knowledge to accurately evaluate proposed designs. Additionally, the overall course grade distribution improved compared to the semester before the project was introduced. Finally, in order to engage students in thinking about their own learning process, they completed a reflection assignment that required them to discuss the changes in their understanding of microbiology over the course of the semester. Our assessment indicates that a design project can serve as an effective and useful learning technique in undergraduate Microbiology courses, though modifications are suggested. PMID- 23653758 TI - Introductory biology textbooks under-represent scientific process. AB - Attrition of undergraduates from Biology majors is a long-standing problem. Introductory courses that fail to engage students or spark their curiosity by emphasizing the open-ended and creative nature of biological investigation and discovery could contribute to student detachment from the field. Our hypothesis was that introductory biology books devote relatively few figures to illustration of the design and interpretation of experiments or field studies, thereby de emphasizing the scientific process. To investigate this possibility, we examined figures in six Introductory Biology textbooks published in 2008. On average, multistep scientific investigations were presented in fewer than 5% of the hundreds of figures in each book. Devoting such a small percentage of figures to the processes by which discoveries are made discourages an emphasis on scientific thinking. We suggest that by increasing significantly the illustration of scientific investigations, textbooks could support undergraduates' early interest in biology, stimulate the development of design and analytical skills, and inspire some students to participate in investigations of their own. PMID- 23653759 TI - Authentic active learning activities demonstrating the use of serial dilutions and plate counts. AB - Serial dilution and plate counting is often taught in courses for both microbiology and allied health students. Lecture examples and examination questions addressing how the method is used can sometimes be contrived: artificial data sets may have little or no meaning other than to have students perform a calculation. Here we provide a set of activities employing data sets acquired from the primary literature. Our objective was to have the students think critically about a real scenario in which serial dilution and plate count was used. Each activity requires students to read a paragraph describing the study, predict the results, perform the appropriate calculations, and then evaluate the results in light of their predictions. To test the efficacy of these activities, a pretest quiz was given to approximately 100 students in an allied health/general microbiology course. After a lecture on how microbes are enumerated, students were given a different quiz. The class was then divided randomly into groups of three or four students and assigned one of the activities. A postactivity quiz was also administered. Approximately two weeks later, a serial dilution/plate count question was used on an examination and served as a final posttest. Standardized learning gains were calculated for the quiz administered after each learning activity. Even though learning gains were significantly higher after the lecture, there was also a significant improvement between the lecture and the activity. Using an exercise based on an authentic set of data significantly improved student learning gains, and is a useful practice for teaching microbiology. PMID- 23653760 TI - Improving Scientific Research and Writing Skills through Peer Review and Empirical Group Learning. AB - Here we describe a semester-long, multipart activity called "Read and wRite to reveal the Research process" (R(3)) that was designed to teach students the elements of a scientific research paper. We implemented R(3) in an advanced immunology course. In R(3), we paralleled the activities of reading, discussion, and presentation of relevant immunology work from primary research papers with student writing, discussion, and presentation of their own lab findings. We used reading, discussing, and writing activities to introduce students to the rationale for basic components of a scientific research paper, the method of composing a scientific paper, and the applications of course content to scientific research. As a final part of R(3), students worked collaboratively to construct a Group Research Paper that reported on a hypothesis-driven research project, followed by a peer review activity that mimicked the last stage of the scientific publishing process. Assessment of student learning revealed a statistically significant gain in student performance on writing in the style of a research paper from the start of the semester to the end of the semester. PMID- 23653761 TI - Microbes in mascara: hypothesis-driven research in a nonmajor biology lab. AB - In this laboratory exercise, students were taught concepts of microbiology and scientific process through an everyday activity - cosmetic use. The students' goals for the lab were to develop a hypothesis regarding microbial contamination in cosmetics, learn techniques to culture and differentiate microorganisms from cosmetics, and propose best practices in cosmetics use based on their findings. Prior to the lab, students took a pretest to assess their knowledge of scientific hypotheses, microbiology, and cosmetic safety. In the first week, students were introduced to microbiological concepts and methodologies, and cosmetic terminology and safety. Students completed a hypothesis-writing exercise before formulating and testing their own hypotheses regarding cosmetic contamination. Students provided a cosmetic of their own and, in consultation with their lab group, chose one product for testing. Samples were serially diluted and plated on a variety of selective media. In the second week, students analyzed their plates to determine the presence and diversity of microbes and if their hypotheses were supported. Students completed a worksheet of their results and were given a posttest to assess their knowledge. Average test scores improved from 5.2 (pretest) to 7.8 (posttest), with p-values < 0.0001. Seventy-nine percent (79%) of students correctly identified hypotheses that were not falsifiable or lacked variables, and 89% of students improved their scores on questions concerning safe cosmetic use. Ninety-one percent (91%) of students demonstrated increased knowledge of microbial concepts and methods. Based on our results, this lab is an easy, yet effective, way to enhance knowledge of scientific concepts for nonmajors, while maintaining relevance to everyday life. PMID- 23653762 TI - Investigating how streptococcus responds to their environment: bringing together current research, a case study and laboratory investigation. AB - Understanding the link between course work and unanswered authentic research questions being explored in the research lab is an important goal in undergraduate science teaching. The activity presented here focuses on current research regarding the virulence characteristics of Streptococcus pyogenes particularly targeting the control of sugar uptake regulated via catabolite repression. Students were challenged to formulate a research question and use higher-order thinking skills to analyze data, work collaboratively to solve problems, and pose and test a hypothesis in the laboratory setting. The activity employed an interrupted case study approach using both online and face-to-face settings. The case story and problems were distributed online and were followed by in-class discussions and lab work. Aspects of the activity required independent thinking, as well as collaborative work. Student learning gains were demonstrated via comparison of pre- and postscores on the Host Pathogen Interactions (HPI) concept inventory, results from an end of semester Student Perception Survey, and from analysis of students' work. PMID- 23653763 TI - Using a molecular-genetic approach to investigate bacterial physiology in a continuous, research-based, semester-long laboratory for undergraduates. AB - Designing investigative laboratory exercises that encourage critical thinking, problem solving, and independent thought for upper-division biology courses is a difficult but worthwhile task. In an effort to do so, we developed a semester long, continuous, research-based investigative laboratory that integrates numerous genetic and molecular biology methods into the investigation of a bacterial physiological process. In this lab, students use random Tn5 transposon mutagenesis to create prodigiosin pigment mutants in the bacterium, Serratia marcescens. This is followed by phenotypic characterization, cloning, and sequencing the Tn insertion site to identify genes involved in pigment biosynthesis. During this lab, students gain ample experience performing basic lab techniques while learning about - and applying - methods for elucidating gene function. The approach to the laboratory and the outcomes are intimately integrated into the teaching of many fundamental physiological processes underlying prodigiosin production in bacteria. The result is a cohesive course that integrates the theory and application of molecular genetic techniques with the study of bacterial physiology. Assessments of student learning objectives demonstrated that students greatly improved their understanding of both physiological processes and the genetic techniques used to investigate them. In addition, students felt that this semester-long exercise provided the necessary laboratory experience they needed and desired in preparation for careers in molecular biology, microbiology, and biochemistry. PMID- 23653764 TI - An investigation of bacterial protein interactions as a primary research project in a sophomore-level molecular biology course. AB - Longer term research activities that may be incorporated in undergraduate courses are a powerful tool for promoting student interest and learning, developing cognitive process skills, and allowing undergraduates to experience real research activities in which they may not otherwise have the opportunity to participate. The challenge to doing so in lower-level courses is that students may have not fully grasped the scientific concepts needed to undertake such research endeavors, and that they may be discouraged if activities are perceived to be too challenging. The paper describes how a bacterial protein:protein interaction detection system was adapted and incorporated into the laboratory component of a sophomore-level Molecular Cell Biology course. The project was designed to address multiple learning objectives connecting course content to the laboratory activities, as well as teach basic molecular biology laboratory skills and procedures in the context of a primary research activity. Pre- and posttesting and student surveys both suggest that the laboratory curriculum resulted in significant learning gains, as well as being well received and valued by the students. PMID- 23653765 TI - Assessment of microbiology students' progress with an audience response system. AB - The development of new approaches to teaching of large lecture courses is needed. Today's classroom has a wide range of students including high-achieving motivated learners, students struggling to understand basic concepts, and learning challenged students. Many of these students can be lost in large classes under the shadow of the high-achieving extroverted students who dominate classroom question-and-answer sessions. Measuring a student's understanding and achievement of content standards becomes difficult until an assessment has been done. To close this gap, an audience response system was introduced in an introductory Principles of Microbiology course. This technology specifically addressed the goal of individualizing instruction to the needs of the students. The evaluation of this project indicated an overall positive impact on student learning. PMID- 23653766 TI - Early embryonic development role-playing in a large introductory biology lecture. PMID- 23653767 TI - Perfecting your spread plate technique. PMID- 23653768 TI - Bugs and movies: using film to teach microbiology. AB - A YouTube channel has been created to watch commented video fragments from famous movies or TV series that can be used to teach microbiology. Although microbes are usually depicted in terms of their roles in causing infectious disease, numerous movies reflect other scientific aspects, such as biotechnological applications or bioethical issues. PMID- 23653770 TI - The big picture: a comparative review of several interactive web-based tools for problem analysis in public health. PMID- 23653771 TI - Using LabPaq Kits to Perform Science Labs at Home. PMID- 23653772 TI - A Review of EDVOTEK - The Biotechnology Education Company. PMID- 23653774 TI - The use of open-ended problem-based learning scenarios in an interdisciplinary biotechnology class: evaluation of a problem-based learning course across three years. AB - Use of open-ended Problem-Based Learning (PBL) in biology classrooms has been limited by the difficulty in designing problem scenarios such that the content learned in a course can be predicted and controlled, the lack of familiarity of this method of instruction by faculty, and the difficulty in assessment. Here we present the results of a study in which we developed a team-based interdisciplinary course that combined the fields of biology and civil engineering across three years. We used PBL scenarios as the only learning tool, wrote the problem scenarios, and developed the means to assess these courses and the results of that assessment. Our data indicates that PBL changed students' perception of their learning in content knowledge and promoted a change in students' learning styles. Although no statistically significant improvement in problem-solving skills and critical thinking skills was observed, students reported substantial changes in their problem-based learning strategies and critical thinking skills. PMID- 23653775 TI - Informing pedagogy through the brain-targeted teaching model. AB - Improving teaching to foster creative thinking and problem-solving for students of all ages will require two essential changes in current educational practice. First, to allow more time for deeper engagement with material, it is critical to reduce the vast number of topics often required in many courses. Second, and perhaps more challenging, is the alignment of pedagogy with recent research on cognition and learning. With a growing focus on the use of research to inform teaching practices, educators need a pedagogical framework that helps them interpret and apply research findings. This article describes the Brain-Targeted Teaching Model, a scheme that relates six distinct aspects of instruction to research from the neuro- and cognitive sciences. PMID- 23653776 TI - Does the transition to an active-learning environment for the introductory course reduce students' overall knowledge of the various disciplines in biology? AB - As biology education is being redesigned toward an interdisciplinary focus and as pedagogical trends move toward active-learning strategies and investigative experiences, a restructuring of the course content for the Introductory Biology course is necessary. The introductory course in biology has typically been a survey of all the biosciences. If the total number of topics covered is reduced, is the students' overall knowledge of biology also reduced? Our introductory course has been substantially modified away from surveying the biological sciences and toward providing a deep understanding of a particular biological topic, as well as focusing on developing students' analytical and communication skills. Because of this shift to a topic-driven approach for the introductory course, we were interested in assessing our graduating students' overall knowledge of the various biological disciplines. Using the Major Field Test - Biology (Educational Testing Service (ETS), Princeton, NJ), we compared the test performance of graduating students who had a traditional lecture-based introductory course to those who had a topic-driven active-learning introductory course. Our results suggest that eliminating the traditional survey of biology and, instead, focusing on quantitative and writing skills at the introductory level do not affect our graduating students' overall breadth of knowledge of the various biosciences. PMID- 23653777 TI - A call for a community of practice to assess the impact of emerging technologies on undergraduate biology education. AB - Recent recommendations for educational research encourage empirically tested, theory-based, completely transparent, and broadly applicable studies. In light of these recommendations, we call for a research standard and community of practice in the evaluation of technology use in the undergraduate life science classroom. We outline appropriate research methodology, review and critique the past research on technology usage and, lastly, suggest a new and improved focus for research on emerging technologies. PMID- 23653778 TI - Ethical and practical similarities between pedagogical and clinical research. AB - Clinical research and educational research face similar practical and ethical constraints that impact the rigor of both kinds of studies. Practical constraints facing undergraduate science education research include small sample sizes (largely a result of disproportionate incentives to conduct educational research at small colleges versus large universities), and the impossibility of randomizing individual students to separate arms of a study. Ethical constraints include gaining the informed consent and assuring the confidentiality of study participants, and the requirement of equipoise (i.e., that it is unethical to subject some study participants to an experimental treatment that researchers have good reason to believe to be inferior to another treatment). While these constraints have long been recognized for clinical research, their implications for educational research have not been fully recognized. Criticism that educational research lacks rigor should be tempered by the recognition that educational research is not parallel to laboratory research, but is parallel to clinical research. These parallels suggest solutions to some of the practical and ethical difficulties faced by educational researchers, as well. PMID- 23653779 TI - The Development of Curricular Guidelines for Introductory Microbiology that Focus on Understanding. AB - The number of students who leave majors in science, technology, engineering, and mathematics (STEM) due to a perception that courses are poorly taught is evidence that education reform in STEM is overdue. Despite decades of research that argues for student-centered teaching approaches, most introductory STEM courses are still taught in the large lecture format, focusing on rote memorization. While individual efforts in STEM educational reform are important, solutions will most certainly need to include institutional and cultural change. In biology, numerous national reports have called for educational reform to better prepare future scientists. We describe here a new, concept-based curriculum for Introductory Microbiology courses, designed to promote deep understanding of core concepts. Supported by the American Society for Microbiology (ASM) and based on the overarching concepts and competencies presented in the AAAS/NSF report Vision and Change in Undergraduate Biology Education: A Call to Action, we hope it will empower instructors to adapt student-centered approaches so that students in Introductory Microbiology courses can leave the course with a core set of enduring understandings of microbiology. PMID- 23653780 TI - Preparing Science-Trained Professionals for the Biotechnology Industry: A Ten Year Perspective on a Professional Science Master's Program. AB - The biotechnology industry has a need for business-savvy scientists; however, this is not the way scientists are traditionally trained at universities and colleges. To address this need, universities have developed Professional Science Master's (PSM) degree programs that offer advanced training in a technical field along with professional skills development through team-based projects and internships. Nearly ten years ago, the Department of Microbiology at NCSU started a PSM program in Microbial Biotechnology (MMB). This article provides an overview of the MMB program, and shares some of the lessons that we have learned. PMID- 23653781 TI - Increasing student understanding of microscope optics by building and testing the limits of simple, hand-made model microscopes. AB - The ability to effectively use a microscope to observe microorganisms is a crucial skill required for many disciplines within biology, especially general microbiology and cell biology. A basic understanding of the optical properties of light microscopes is required for students to use microscopes effectively, but this subject can also be a challenge to make personally interesting to students. To explore basic optical principles of magnification and resolving power in a more engaging and hands-on fashion, students constructed handmade lenses and microscopes based on Antony van Leeuwenhoek's design using simple materials paper, staples, glass, and adhesive putty. Students determined the power of their lenses using a green laser pointer to magnify a copper grid of known size, which also allowed students to examine variables affecting the power and resolution of a lens such as diameter, working distance, and wavelength of light. To assess the effectiveness of the laboratory's learning objectives, four sections of a general microbiology course were given a brief pre-activity assessment quiz to determine their background knowledge on the subject. One week after the laboratory activity, students were given the same quiz (unannounced) under similar conditions. Students showed significant gains in their understanding of microscope optics. PMID- 23653782 TI - Use of the sucrose gradient method for bacterial cell cycle synchronization. PMID- 23653783 TI - Role-based panel discussions to teach socio-economic consequences of wastewater treatment. PMID- 23653784 TI - Task books as an assessment tool for demonstrating basic lab skills in a microbiology course. PMID- 23653785 TI - The microbial contamination of mobile communication devices. PMID- 23653786 TI - Teaching the Central Dogma of Molecular Biology using Jewelry. PMID- 23653787 TI - Motivating students to learn biology vocabulary with wikipedia. PMID- 23653788 TI - Development of a myxomycete photoguide as a teaching tool for microbial taxonomy. PMID- 23653789 TI - Transdisciplinarity and microbiology education. PMID- 23653790 TI - Use of microthemes to increase writing content for introductory science laboratory. PMID- 23653791 TI - Development of a community-oriented parasitological survey as a teaching strategy for medical students. PMID- 23653792 TI - Models in movies: teaching abstract concepts in concrete models. PMID- 23653793 TI - Vision and Change-ing A First-Year Biology Classroom. PMID- 23653794 TI - Teaching with the macaulay library: an online archive of animal behavior recordings. PMID- 23653795 TI - Using a team structure for student-assisted facilitation of laboratories in an introductory allied health microbiology course. PMID- 23653798 TI - Advancing the Vision: New PubMed Indexing, Creative Commons Licensing, and December Highlights. PMID- 23653796 TI - A webinar case study by a clinical microbiologist to microbiology and physiology students: an integrative learning experience. PMID- 23653799 TI - Long-term retention of knowledge and critical thinking skills in developmental biology. AB - The primary goal of this project was to assess long-term retention of concepts and critical thinking skills in individuals who completed a Developmental Biology course. Undergraduates who had completed the course between 2006 and 2009 were recently contacted and asked to complete a professional goals survey and a multiple-choice developmental biology assessment test (DBAT) targeting four levels of learning. The DBAT was designed to assess students' retention of knowledge and skills related to factual recall, concept application, data analysis, and experimental design. Performance of the 2006-2009 cohorts was compared to that of students enrolled in 2010 who completed the DBAT at the beginning and the end of the semester. Participants from the 2010 course showed significant learning gains based on pre- and posttest scores overall and for each of the four levels of learning. No significant difference in overall performance was observed for students grouped by year from 2006-2010. Participants from the 2006-2009 cohorts scored slightly, but significantly, higher on average if they enrolled in graduate or professional training. However, performance on individual question categories revealed no significant differences between those participants with and without postundergraduate training. Scores on exams and a primary literature critique assignment were correlated with DBAT scores and thus represent predictors of long-term retention of developmental biology knowledge and skills. PMID- 23653800 TI - Learner-centered teaching in nonmajors introductory biology: the impact of giving students choices. AB - Learner-centered teaching represents more than creating a course where students are actively engaged. Rather it is articulated by a shift in the balance of power, function of content, role of the instructor, purpose of assessment, and/or responsibility for learning in a course. To make the learning environment in a large-enrollment nonmajors Biology course more learner-centered, students were given the responsibility to: 1) select course topics, 2) determine the types and weights of course assignments used to assess learning, and 3) individually decide, prior to being assigned work, the weight of exams and projects. Combined survey results from two learner-centered sections of the course (n = 137) indicate that a majority of the students found that choosing the topics enhanced their learning of course material. Students also reported that they put more effort into the parts of the course that they had weighted more heavily. In addition, results support that students are reflective of the learner-centered environment, confident in their ability to learn biological topics and more interested in biology than they thought they would be. Finally, course averages from the learner-centered courses were significantly higher than course grades from instructor-centered versions of the course. PMID- 23653801 TI - Towards a mastery understanding of critical reading in biology: the use of highlighting by students to assess their value judgment of the importance of primary literature. AB - An analysis of critical reading styles of freshmen and senior biology students was compared to that of biology faculty members through the use of highlighting a primary research article. Sentence-by-sentence comparisons were made within each group and the data were analyzed; the composite picture from each group was then compared to the other groups. There appears to be a close agreement of what is deemed important content as judged by faculty but less agreement by seniors and even less agreement by freshmen regarding the value of each line of the text. The results imply that experts in a field appear able to discriminate what is important and valuable in the primary literature and that the novice appears to develop some degree of scientific literacy during his or her undergraduate career. PMID- 23653802 TI - Educating medical laboratory technologists: revisiting our assumptions in the current economic and health-care environment. AB - Health care occupies a distinct niche in an economy struggling to recover from recession. Professions related to the care of patients are thought to be relatively resistant to downturns, and thus become attractive to students typically drawn to more lucrative pursuits. Currently, a higher profile for clinical laboratory technology among college students and those considering career change results in larger and better prepared applicant pools. However, after decades of contraction marked by closing of programs, prospective students encounter an educational system without the capacity or vigor to meet their needs. Here discussed are some principles and proposals to allow universities, partnering with health-care providers, government agencies, and other stake holders to develop new programs, or reenergize existing ones to serve our students and patients. Principles include academic rigor in biomedical and clinical science, multiple points of entry for students, flexibility in format, cost effectiveness, career ladders and robust partnerships. PMID- 23653803 TI - Using small group debates to actively engage students in an introductory microbiology course. AB - Debates stimulate critical thinking and can be a highly effective way to actively engage students in the classroom. This paper describes a small group debate format in which groups of four to six students debated preassigned topics in microbiology in front of the rest of the class. Rapid advancements in science, especially in microbiology, provide the scaffolding for students to locate and share evidence-based information from a plethora of complex and often conflicting sources. Student-generated debate presentations can be a welcome respite from the lecture format. Debates were scheduled throughout the course to coincide with topics being covered. Questionnaires distributed immediately after each debate revealed that the debates were well received by students and were effective in changing student attitudes and misconceptions. Debate preparation provided students the opportunity to gain proficiency in accessing information from electronic databases, to use resources from professional organizations, and to synthesize and analyze information. In addition, the debate process gave students experience in developing oral communication skills. PMID- 23653804 TI - Using Bioinformatics to Develop and Test Hypotheses: E. coli-Specific Virulence Determinants. AB - Bioinformatics, the use of computer resources to understand biological information, is an important tool in research, and can be easily integrated into the curriculum of undergraduate courses. Such an example is provided in this series of four activities that introduces students to the field of bioinformatics as they design PCR based tests for pathogenic E. coli strains. A variety of computer tools are used including BLAST searches at NCBI, bacterial genome searches at the Integrated Microbial Genomes (IMG) database, protein analysis at Pfam and literature research at PubMed. In the process, students also learn about virulence factors, enzyme function and horizontal gene transfer. Some or all of the four activities can be incorporated into microbiology or general biology courses taken by students at a variety of levels, ranging from high school through college. The activities build on one another as they teach and reinforce knowledge and skills, promote critical thinking, and provide for student collaboration and presentation. The computer-based activities can be done either in class or outside of class, thus are appropriate for inclusion in online or blended learning formats. Assessment data showed that students learned general microbiology concepts related to pathogenesis and enzyme function, gained skills in using tools of bioinformatics and molecular biology, and successfully developed and tested a scientific hypothesis. PMID- 23653805 TI - Species shout-outs from abdul to zebra: encouraging nonmajors to communicate in the biology classroom. PMID- 23653806 TI - Bacterial calligraphy: a memento for undergraduate research students. PMID- 23653807 TI - The use of the ames test as a tool for addressing problem-based learning in the microbiology lab. PMID- 23653808 TI - Determination of the antibiotic resistance profile of student cell phones. PMID- 23653809 TI - Printed identification key or web-based identification guide: an effective tool for species identification? PMID- 23653810 TI - Students in Differential Equations and Epidemiology Model a Campus Outbreak of pH1N1. PMID- 23653811 TI - Dynamic model visualizing the process of viral plaque formation. PMID- 23653813 TI - Enhancing engineering students' learning in an environmental microbiology course. PMID- 23653812 TI - The genome solver website: a virtual space fostering high impact practices for undergraduate biology. PMID- 23653814 TI - DNA microarrays in the undergraduate microbiology lab: experimentation and handling large datasets in as few as six weeks. AB - DNA microarrays have significantly impacted the study of gene expression on a genome-wide level but also have forced a more global consideration of research questions. As such, it has become critical to introduce undergraduate students to genomics approaches to research. A challenge with performing a DNA microarray experiment in the teaching lab is determining the time required for the study and how to handle the voluminous data generated. At an unexpectedly low cost, a 6 week, project-based lab module has been developed that provides 3 weeks for wet lab (hands-on work with the DNA microarrays) and 3 weeks for dry lab (analyzing data, using databases to help with data analysis, and considering the meaning of data within the large dataset). Options exist for extending the number of weeks dedicated to the project, but 6 weeks is sufficient for providing an introduction to both experimental genomics and data analysis. Students indicate that being able to both perform array experiments and thoroughly analyze data enriches their understanding of genomics and the complexity of biological systems. PMID- 23653815 TI - A discussion group program enhances the conceptual reasoning skills of students enrolled in a large lecture-format introductory biology course. AB - It has been well-established that discussion groups enhance student learning in large lecture courses. The goal of this study was to determine the impact of a discussion group program on the development of conceptual reasoning skills of students enrolled in a large lecture-format introductory biology course. In the discussion group, students worked on problems based on topics discussed in lecture. The program was evaluated using three assessment tools. First, student responses to pre- and posttests were analyzed. The test question asked the students to demonstrate the relationships between 10 different but related terms. Use of a concept map to link the terms indicated an advanced level of conceptual reasoning skills. There was a 13.8% increase in the use of concept maps from pre- to posttest. Second, the students took a Likert-type survey to determine the perceived impact of the program on their conceptual reasoning skills. Many of the students felt that the program helped them understand and use the main course concepts to logically solve problems. Finally, average exam grades increased as the semester progressed. The average final grade in the course was 75%. Students enrolled in the course the previous year (where the lecture component of the course did not assess or reflect student learning in the discussion group) had an average final grade of 69%. The results of this study demonstrate that the discussion group program improves the conceptual reasoning skills of students enrolled in a large lecture-format introductory biology course. PMID- 23653816 TI - Comparison of Online and Onsite Bioinformatics Instruction for a Fully Online Bioinformatics Master's Program. AB - The completely online Master of Science in Bioinformatics program differs from the onsite program only in the mode of content delivery. Analysis of student satisfaction indicates no statistically significant difference between most online and onsite student responses, however, online and onsite students do differ significantly in their responses to a few questions on the course evaluation queries. Analysis of student exam performance using three assessments indicates that there was no significant difference in grades earned by students in online and onsite courses. These results suggest that our model for online bioinformatics education provides students with a rigorous course of study that is comparable to onsite course instruction and possibly provides a more rigorous course load and more opportunities for participation. PMID- 23653817 TI - Learning geomicrobiology as a team using microbial mats, a multidisciplinary approach. AB - Microbial mats are one of the best suited laminar organo-sedimentary ecosystems for students from different educational backgrounds to visualize the direct relationship between microbes and minerals. We have used tropical hypersaline microbial mats from Puerto Rico as educational tools to promote active learning of geomicrobiology introductory concepts for undergraduate students organized in multidisciplinary teams with biological and geological backgrounds. Besides field trips and independent research projects focused on microbial mats, four intensive workshops and one capstone activity were designed to expose students to the different geomicrobiology subdisciplines (microbiology, molecular biology, geology, and geochemistry). The teaching-learning process was assessed using pre- and posttests, group discussions, activities including Gallery Walks and exquisite cadaver's, case studies, and focal interviews. While the posttest showed a significant difference in conceptual understanding, the Gallery Walk and the capstone activities demonstrated increase in the depth, coherence, and thoughtfulness in answering questions, including a clear integration of the different subdisciplines during their presentations. Finally, the main themes described by the students as important outcomes of their participation in the Research at Undergraduate Institutions: Microbial Observatory (RUI-MO) program were: (i) the opportunity to study and learn new and different science disciplines, (ii) the microbial mats were excellent tools to learn from and integrate different science disciplines, and (iii) working in multidisciplinary teams gave them the opportunity to learn from their peers' discipline backgrounds. To our knowledge this is the first educational initiative that uses tropical hypersaline microbial mats to teach geomicrobiology in a multidisciplinary fashion. PMID- 23653818 TI - Whole genome sequencing in the undergraduate classroom: outcomes and lessons from a pilot course. AB - The BIO2010 report challenged undergraduate institutions to prepare the next generation of researchers for the changing direction of biology that increasingly integrates advanced technologies, digital information, and large-scale analyses. In response, the Microbiology and Cell Science Department at the University of Florida developed a research-based course, "Bacterial Genome Sequencing." The objectives were to teach undergraduates about genomics and original research by sequencing a bacterial genome, to develop scientific communication skills by writing and submitting the project results as a class effort, and to promote an interest in biological research, particularly genomics. The students worked together to sequence, assemble, and annotate the Enterobacter cloacae P101 genome. We assessed student learning, scientific communication skills, and student attitudes by a variety of methods including exams, writing assignments, oral presentations, pre- and postcourse surveys, and a final exit survey. Assessment results demonstrate student learning gains and positive attitudes regarding the course. PMID- 23653819 TI - Development of higher-level cognitive skills in a learner-centered lab on extensions of mendelian inheritance using Drosophila. AB - Students can have difficulty comprehending complex concepts in science. They can memorize the definition but do not understand the underlying biological principles. In the Fundamentals of Genetics course at Arizona State University at the West campus, students grapple with the topic of "extensions of Mendelism." Additionally, in lab, students are challenged by scoring phenotypes that are not binary. Both of these concepts require that students understand not only inheritance but also the principles of protein structure and function. A genetics laboratory exercise was developed that combines study of some extensions of Mendelian inheritance with practice in manipulating Drosophila melanogaster and scoring subtle and variable phenotypes. Students analyze Drosophila with mutations that demonstrate some extensions of Mendelian inheritance: temperature sensitivity, variable expressivity, incomplete penetrance, multiple alleles, dosage compensation, and gene dosage effect. The phenotypes in some of these mutants differ from individual to individual and are difficult to discern; thus, students also gain experience in investigating challenging phenotypes. Pre- and postlab assessments indicate that performing this exercise increased students' mastery of the molecular basis of extensions of Mendelian inheritance and their abilities in scoring and manipulating flies. This is a discovery-based lab exercise in which students examine some extensions of Mendelian inheritance and gain experience in analyzing complex traits in Drosophila. PMID- 23653820 TI - Impact of online learning modules on medical student microbiology examination scores. AB - Medical students have a limited amount of time in which to acquire working knowledge of an enormous amount of information, and this is especially relevant for microbiology. One large midwestern medical school is unique in having medical microbiology taught at nine regional campuses using a single core curriculum. A committee of statewide course directors writes a licensure board-style final examination that is referenced to the core and used at all campuses. To prepare for the final examination, students traditionally utilize print-based board examination review books. The purpose of the present study was to determine whether students who train using web-based quizzes score differently as a group on this statewide examination than students who do not utilize the materials online for exam preparation. The study included 71 learners from two different campuses who were taught by the same instructor and were admitted to medical school with similar exemplary credentials. Results were aggregated for three consecutive years. A standard medical microbiology textbook was used to assign the same suggested readings for all students and similar laboratory sessions were provided for all learners. The independent variable was use of the web-based quizzes to prepare before examinations, as indicated by student web usage logs. The dependent variable was score on the statewide final examination. Results support the hypothesis that students who use preparation modules online score higher on the final examination than students who do not. Moreover, students who prepared online scored higher on questions designed to test synthesis of knowledge and analysis of data. The significant difference in final examination outcome (P < 0.002 using a two-tailed unpaired t test) indicates that online preparation for high-stakes examinations could improve student performance in medical microbiology. PMID- 23653821 TI - Construction and evaluation of an online microbiology course for nonscience majors. AB - The development of web-based technologies provides a new method for course delivery. As with any new technique, evaluation is a necessary tool to determine if the method is consistent with expectations. This study describes the conversion of a nonscience majors' microbiology lecture course to online delivery and evaluates the hypothesis that the online course can be as effective as the traditional course. Course examination scores are compared between the face-to face and online sections over a 3-year period. On all but one of the course examinations, no significant difference is found for those students in these two distinctly different course types. The success rate, as defined by those students earning grades of C or better, is high for both course types, although the traditional course success rate is slightly higher. Student evaluations of the courses are also positive, though some differences are noted. Overall, student performance in the online course is equivalent to that in the traditional course. PMID- 23653822 TI - CASE REPORT Reconstruction and Characterization of Composite Mandibular Defects Requiring Double Skin Paddle Fibular Free Flaps. AB - OBJECTIVE: Fibular free flaps are the preferred method for reconstruction of composite lateral mandibular defects. This reconstructive technique is limited by the skin paddle's inability to freely rotate when attempting to fill 2 poorly aligned defects. Reconstructive surgeons have been exploring multiple methods of creating 2 independent skin paddles based on the same peroneal blood supply. We present a variation of these techniques. METHOD: Our patient with a history of squamous cell carcinoma presented with a left retromolar recurrence and osteoradionecrosis of the mandible with a draining anterior sinus tract. The combination of these defects warranted further composite resection with fibular free flap reconstruction. RESULTS: A subperiosteal dissection was performed to create 2 separate septocutaneous skin paddles based on the same peroneal blood supply. This dissection and discard of proximal fibula provided the rotational freedom needed for the 2 skin islands to fill both a lateral oral defect and anterior cutaneous defect. CONCLUSION: Although similar reconstructive methods have been reported in the literature, the characterization of defects benefiting from these techniques is scarce and unclear. We describe clear and concise characteristics of these defects, which should be meaningful to the reconstructive surgeon when considering operative technique. PMID- 23653823 TI - Retrobulbar hematoma following orbital floor reconstruction. PMID- 23653824 TI - LNG-IUS treatment of non-atypical endometrial hyperplasia: Can Pipelle endometrial sampling be an accurate method of follow-up evaluation? PMID- 23653825 TI - Should studies of maintenance therapy be maintained in women with ovarian cancer? PMID- 23653826 TI - Concurrent chemoradiotherapy with low-dose daily cisplatin for high risk uterine cervical cancer: a long-term follow-up study. AB - OBJECTIVE: To evaluate the clinical efficacy of concurrent chemoradiotherapy (CCRT) using daily low-dose cisplatin for cervical cancer. METHODS: Fifty-one patients with locally advanced cervical cancer (FIGO stage IB2, bulky IIA, IIB IVA) who were treated with CCRT as primary therapy at Kurume University Hospital between 2000 and 2007 were retrospectively reviewed. CCRT consisted of 5 mg/m(2)/day of cisplatin 5 days per week, and external beam radiotherapy (EBRT) administrated to whole pelvis to 45-50.6 Gy. High-dose-rate intracavitary brachytherapy was delivered in a single dose of 4-5 Gy at point A, once a week after 20-30 Gy of EBRT. RESULTS: The median follow-up duration was 42 months (range, 5 to 116 months). The overall response rate was 94.1%. Five year overall survival rate was 71.5% and 46.2% in stage I or II, and stage III or IVA, respectively. During follow-up period, 30 recurrences (58.8%) were found, the local failure rate was 39%, and distant failure rate was 35.2%, and both (local and distant) were 15.7%. Hematological toxicities were the most frequent acute toxicities. Grade 3 and 4 neutropenia was observed in 37.3%. Late intestinal toxicities appeared in 7 cases (13.7%), which occurred between 6 and 114 months after treatment. Four cases required bowel surgery. CONCLUSION: CCRT using daily low-dose cisplatin was tolerable and showed favorable initial response as the primary therapy for locally advanced uterine cervical cancer. But there was no remarkable long-term benefit for patients' survival or local disease control in this study. The incidence of late intestinal toxicity still requires further investigation. PMID- 23653827 TI - Microscopic lesions of fallopian tubes in endometrioid carcinoma of the endometrium: How effective are the macroscopic tubal sampling techniques? AB - OBJECTIVE: Extrauterine involvement of endometrial carcinoma has a significant effect on the patients' prognosis and treatment decision. In classical method, macroscopic section is taken from the fallopian tube sparing the fimbrial ends. Fimbrial end of fallopian tube may be involved by tumors and precursor lesions. This study aims to determine the importance of sampling of fimbrial ends of fallopian tube in endometrioid endometrial carcinoma specimens. METHODS: We reevaluated the fallopian tubes of 200 cases of endometrioid endometrial carcinoma cases that have no macroscopic tubal lesion. A hundred cases were sampled with classical method, and the other 100 were sampled with a new method that includes the fimbrial ends. Statistical difference was examined by Fisher's exact test. RESULTS: No microscopic tubal lesion lesion was detected in cases that were sampled with the classical method. In contrast, there were 4 cases with tubal lesions in patients sampled with the new technique; 3 of them were located in the fimbrial end. Of the 3, there was one microscopic invasive carcinoma and two proliferative endometrial glandular lesions. Endometriosis was detected in two of the 4 cases with tubal lesions. CONCLUSION: Including the fimbrial end of fallopian tube to macroscopic sampling could detect more tubal lesions, which might provide additional prognostic and pathogenetic information of endometrioid endometrial carcinoma. PMID- 23653828 TI - A comparison of uterine papillary serous, clear cell carcinomas, and grade 3 endometrioid corpus cancers using 2009 FIGO staging system. AB - OBJECTIVE: This study was designed to compare survival outcomes of patients with uterine papillary serous carcinoma (UPSC) or clear cell carcinoma (CC) to those of patients with grade 3 endometrioid carcinoma (G3EC) according to 1988 and 2009 International Federation of Gynecology and Obstetrics (FIGO) staging systems. METHODS: We retrospectively reviewed all patients with endometrial cancer treated at a single institution between 1995 and 2009. Among the 647 patients with endometrial cancer, 51 with G3EC and 46 with UPSC and CC histology were confirmed. RESULTS: 1988 FIGO stage, 2009 FIGO stage, and extrauterine metastasis were significantly different between the UPSC and CC group and G3EC group (p=0.002, p=0.041, and p=0.020, respectively). Restaging from the 1988 FIGO to the 2009 FIGO criteria increased the number of stage I cases by 10 (11.0%). Overall, 8 in the UPSC and CC and 2 in the G3EC group were down-staged to stage I. In the UPSC and CC group, the 3-year overall survival for 1988 FIGO stage I was 92.9%. When UPSC and CC patients were restaged using the 2009 staging system, the 3-year overall survival of 2009 FIGO stage I dropped to 81.6%. UPSC and CC was associated with poor OS outcome compared with G3EC, after adjustment for 2009 FIGO stage and other clinicopathologic factors. CONCLUSION: We observed that UPSC and CC patients had different prognosis according to the old and new FIGO staging system. Our results suggest that UPSC and CC compared with the G3EC may retain the 1988 FIGO to be a slightly better discriminator than 2009 FIGO. PMID- 23653829 TI - LNG-IUS treatment of non-atypical endometrial hyperplasia in perimenopausal women: a randomized controlled trial. AB - OBJECTIVE: To compare the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) and oral norethisterone acetate (NET) for treatment of non atypical endometrial hyperplasia in perimenopausal women. METHODS: One hundred and twenty perimenopausal women with non-atypical endometrial hyperplasia were selected in this randomized controlled trial. Patients received LNG-IUS (n=59) or NET (n=61; 15 mg/day for 3 weeks/cycle) for 3-6 months. Outpatient follow-up with endometrial biopsies were undertaken at 3, 6, and 12 months intervals after treatment. Outcome measures were; the regression rate, the time to regression and hysterectomy rate. RESULTS: A significantly higher regression rate was noted in the LNG-IUS group than in NET group at the 3rd, 6th and 12th month follow-up visits using intention-to-treat analysis (67.8% vs. 47.5%, relative risk [RR], 1.42; 79.7% vs. 60.7%, RR, 1.31; and 88.1% vs. 55.7%, RR, 1.58, respectively). However, no significant difference was found regarding the median time to regression (3 months). The hysterectomy rate during the follow-up period was significantly higher in the NET group (57.4% vs.22%, p<0.001). CONCLUSION: LNG IUS treatment of non-atypical endometrial hyperplasia in perimenopausal women is more effective than NET for achieving disease regression for the majority within 1 year. Moreover, it can reduce the number of hysterectomies performed. PMID- 23653830 TI - Reproductive factors for ovarian cancer in southern Chinese women. AB - OBJECTIVE: To investigate the association between reproductive factors and the risk of ovarian cancer among southern Chinese women. METHODS: A hospital-based case-control study was undertaken in Guangzhou, Guangdong Province, between 2006 and 2008. A structured questionnaire was used to obtain information on parity, oral contraceptive use and other reproductive factors in a sample of 500 incident ovarian cancer patients and 500 controls (mean age, 59 years). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression models. RESULTS: High parity was inversely associated with ovarian cancer, with an adjusted OR 0.43 (95% CI, 0.30 to 0.62) for women who had given birth to 3 or more children compared to women who had given no more than one birth. Ever use of oral contraceptives was also protective against ovarian cancer; adjusted OR 0.56 (95% CI, 0.40 to 0.78). No association was found for hormone replacement therapy, menopausal status, hysterectomy and family history of ovarian and/or breast cancer. CONCLUSION: High parity and oral contraceptive use are associated with a lower risk of ovarian cancer in southern Chinese women. PMID- 23653831 TI - CA-125 cut-off value as a predictor for complete interval debulking surgery after neoadjuvant chemotherapy in patients with advanced ovarian cancer. AB - OBJECTIVE: In the present study, we evaluated changes in CA-125 cut-off values predictive of complete interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC) using receiver operating characteristic (ROC) analysis. METHODS: This retrospective single-institution study included patients with International Federation of Gynecology and Obstetrics (FIGO) stage III epithelial ovarian cancer and a pre-NAC serum CA-125 level of greater than 40 U/mL who were treated with neoadjuvant platinum-based chemotherapy followed by IDS between 1994 and 2009. Logistic regression analysis was used to evaluate univariate and independent multivariate associations with the effect of clinical, pathological, and CA-125 parameters on complete IDS, and ROC analysis was used to determine potential cut-off values of CA-125 for prediction of the possibility of complete IDS. RESULTS: Seventy-five patients were identified. Complete IDS was achieved in 46 (61.3%) patients and non-complete IDS was observed 29 (38.7%). Median pre-NAC CA-125 level was 639 U/mL (range, 57 to 6,539 U/mL) in the complete IDS group and 1,427 U/mL (range, 45 to 10,989 U/mL) in the non-complete IDS group. Median pre IDS CA-125 level was 15 U/mL (range, 2 to 60 U/mL) in the complete IDS group and 53 U/mL (range, 5 to 980 U/mL) in the non-complete IDS group (p<0.001). Multivariate analyses performed with complete IDS as the endpoint revealed only pre-IDS CA-125 as an independent predictor. The odds ratio of non-complete IDS was 10.861 when the pre-IDS CA-125 level was greater than 20 U/mL. CONCLUSION: The present data suggest that in the setting of IDS after platinum-based NAC for advanced ovarian cancer, a pre-IDS CA-125 level less than 20 U/mL is an independent predictor of complete IDS. PMID- 23653832 TI - Risk stratification of abdominopelvic failure for FIGO stage III epithelial ovarian cancer patients: implications for adjuvant radiotherapy. AB - OBJECTIVE: To analyze patterns of abdominopelvic failures and to define subgroups for the use of adjuvant radiotherapy in the International Federation of Gynecology and Obstetrics (FIGO) stage III epithelial ovarian cancer (EOC). METHODS: We reviewed 149 patients treated with debulking surgery followed by intravenous taxane and platinum chemotherapy between 1999 and 2008. Patient characteristics, patterns of failure, abdominopelvic failure APF-free survival (APFFS) and overall survival (OS) were analyzed. RESULTS: The median age of the patients was 51 years. Thirty-two patients (21.5%) were found to have residuum >2 cm after surgery. The median pretreatment CA-125 was 604 and 54.4% of patients had a decline in CA-125 >=90% between pretreatment and at postoperative 1 month. With a median follow-up of 50 months, 79 patients (53.0%) experienced abdominopelvic failure (APF). The 5-year APF-free survival rate was 41.1%. Lymph node metastasis, size of residual disease, and decline in CA-125 were found to be significant prognostic factors for APF upon multivariate analysis. The group of patients in whom abdominopelvic irradiation was indicated as definitive postoperative treatment comprised 55% of the overall patient population and their 5-year survival rate was 68%. CONCLUSION: The stratification was suggested to predict APF based on lymph node metastasis, size of residual tumor, and decline in CA-125. Adjuvant radiotherapy covering the whole abdominopelvis using the intensity modulation technique may be considered to reduce APF in FIGO stage III EOC patients with intermediate risk. PMID- 23653833 TI - A feasibility study on maintenance of docetaxel after paclitaxel-carboplatin chemotherapy in patients with advanced ovarian cancer. AB - OBJECTIVE: To test the concept of taxane sequencing, this feasibility trial evaluated maintenance of docetaxel after paclitaxel and carboplatin combination chemotherapy in patients with stage IC-IV ovarian cancer. METHODS: All patients received debulking surgery followed by paclitaxel and carboplatin chemotherapy. Attainment of clinically defined complete or partial response was confirmed by image scanning. Maintenance of docetaxel started at an initial dose of 70 mg/m(2) every 4 weeks for 6 cycles and was extended to 10 cycles unless disease progression and/or recurrence during the protocol therapy or unacceptable toxicities were seen. RESULTS: Stage subsets in 20 eligible patients were as follows: IIIB, 2 patients (10%); IIIC, 13 patients (65%); IV, 5 patients (25%). Neutropenia was common (40% with grade 3 or 4) and was most frequent during first or second cycle although the disabling peripheral neuropathy was not observed. Twelve patients completed protocol therapy (6<=cycles), while 8 patients failed to complete 6-cycle chemotherapy, because of progressive disease (5 patients) or grade 4 toxicities (3 patients). Median PFS was 20 months and 3-year PFS rate was 12%. Median overall survival was 39 months and 3-year OS rate was 69%. CONCLUSION: Six cycles of single-agent docetaxel maintenance chemotherapy is feasible and generally tolerable to women with advanced ovarian cancer who attained a clinically defined response to initial paclitaxel and carboplatin based chemotherapy. PMID- 23653834 TI - Comparison of advanced stage mucinous epithelial ovarian cancer and serous epithelial ovarian cancer with regard to chemosensitivity and survival outcome: a matched case-control study. AB - OBJECTIVE: The aim of this study was to compare clinicopathologic characteristics, surgery outcomes and survival outcomes of patients with stage III and IV mucinous epithelial ovarian cancer (mEOC) and serous epithelial ovarian carcinoma (sEOC). METHODS: Patients who had surgery for advanced stage (III or IV) mEOC were evaluated retrospectively and defined as the study group. Women with sEOC who were matched for age and stage of disease were randomly chosen from the database and defined as the control group. The baseline disease characteristics of patients and platinum-based chemotherapy efficacy (response rate, progression-free survival and overall survival [OS]) were compared. RESULTS: A total of 138 women were included in the study: 50 women in the mEOC group and 88 in the sEOC group. Patients in the mEOC group had significantly less grade 3 tumors and CA-125 levels and higher rate of para-aortic and pelvic lymph node metastasis. Patients in the mEOC group had significantly less platinum sensitive disease (57.9% vs. 70.8%; p=0.03) and had significantly poorer OS outcome when compared to the sEOC group (p=0.001). The risk of death for mEOC patients was significantly higher than for sEOC patients (hazard ratio, 2.14; 95% confidence interval, 1.34 to 3.42). CONCLUSION: Advanced stage mEOC patients have more platinum resistance disease and poorer survival outcome when compared to advanced stage sEOC. Therefore, novel chemotherapy strategies are warranted to improve survival outcome in patients with mEOC. PMID- 23653835 TI - Survival of women with ovarian carcinomas and borderline tumors is not affected by estrogen and progesterone receptor status. AB - OBJECTIVE: To examine the patterns of estrogen receptor (ER) and progesterone receptor (PR) expression in borderline ovarian tumors (BOTs) and ovarian carcinomas. We also assessed the disease-free survival (DFS) and overall survival (OS) in women with ovarian carcinoma, in relation to ER and/or PR expression. METHODS: We examined ER/PR expression in 38 BOTs and 172 ovarian carcinomas removed from patients treated at the State University of Campinas-UNICAMP (Brazil), from 1993 to 2008 and followed for up to 60 months using tissue microarray-based immunohistochemistry. RESULTS: Twenty-eight (73.7%) mucinous and 10 (26.3%) serous BOTs were included. Ovarian carcinomas consisted mainly of 79 (46.0%) serous, 44 (25.5%) mucinous, 17 (9.8%) endometrioid, 10 (5.8%) clear-cell types. There was no significant difference of the ER/PR expression between BOT and ovarian carcinoma (p=0.55 for ER alone, 0.90 for PR alone, and 0.12 for combined expression). The level of ER/PR expression in BOTs was significantly higher in serous than in mucinous tumors (p<0.01). In carcinomas, ER/PR was higher in serous tumors than in mucinous (p<0.01) and clear cell tumors (p=0.02), and higher in endometrioid tumors than in mucinous tumors (p<0.01). DFS was affected neither by the clinical characteristics nor by combined steroid receptor status. OS was found to be significantly worse (p<0.01) only in women with stages II-IV tumors and those with residual disease after surgery (p<0.01). CONCLUSION: Overall, serous and endometrioid tumors were predominantly ER/PR positive, whereas mucinous and clear-cell tumors were preponderantly ER/PR negative. DFS and OS were not affected by ER/PR expression. PMID- 23653836 TI - The mechanism of mesna in protection from cisplatin-induced ovarian damage in female rats. AB - OBJECTIVE: Cisplatin is a widely used chemotherapeutic agent in the treatment of cancers in clinic; but it often induces adverse effects on ovarian functions such as reduced fertility and premature menopause. Mesna could attenuate the cisplatin induced ovarian damages; however, the underlying mechanism is still unknown. This study aimed to figure out the underlying mechanism of the protection of mesna for ovaries against cisplatin therapy in cancers. METHODS: We performed female adult Sprague-Dawley rats into normal saline control (NS), low-dose cisplatin (CL), high-dose cisplatin (CH), CL plus mesna (CL+M), and CH plus mesna (CH+M) groups and detected anti-Mullerian hormone (AMH)-positive follicle, oxidative stress status and anti-oxidative capability in ovaries. RESULTS: AMH-positive follicles were significantly decreased after cisplatin administration, which was significantly reversed when mesna was co-administered with cisplatin. The end product of lipid peroxidation, malondialdehyde (MDA), was significantly increased, but the anti-oxidative enzymatic activity of superoxide dismutase (SOD) and glutathione (GSH) were significantly decreased in cisplatin groups when compared with NS group. In contrast, after co-administration of cisplatin with mesna, MDA was significantly decreased whereas the activity of SOD and the concentration of GSH were increased. Moreover, mesna did not decrease the anti tumor property of cisplatin in HePG2 cell lines. CONCLUSION: Cisplatin damages the granulosa cells by oxidative stress to deplete the ovarian reserve and mesna could protect ovarian reserve through anti-oxidation. These results might highlight the mechanism of the protection of mesna for ovarian reserve and open an avenue for the application of mesna as a protective additive in cisplatin chemotherapy in clinical practise. PMID- 23653838 TI - Maintenance of ovarian function in end-of-life cervical cancer patient following primary surgico-radiotherapy and ovarian transposition. AB - A 35-year-old woman underwent laparoscopic radical hysterectomy, pelvic lymphadenectomy and ovarian transposition for stage IB2 cervical adenocarcinoma. She received adjuvant concurrent chemoradiation for poor pathologic risk factors but had tumor recurrence 20 months after the surgery. Transposed ovaries were uninvolved in the recurrence and progression. Salvage chemotherapy and radiotherapy were given. Despite systemic chemotherapy and repeat pelvic radiotherapy, the patient was able to maintain ovarian function. Ovarian transposition in cervical cancer is an easily performed procedure that does not alter the prognosis of the disease in some cases. Present recommendations for its use should be reevaluated so that more premenopausal cancer patients may benefit from this underutilized procedure. PMID- 23653837 TI - Practice guidelines for the early detection of cervical cancer in Korea: Korean Society of Gynecologic Oncology and the Korean Society for Cytopathology 2012 edition. AB - The consensus guideline development committee of Korean Society of Gynecologic Oncology was reconvened in March 2012. The committee consisted of 36 experts representing 12 university hospitals and professional organizations. The objective of this committee was to develop standardized guidelines for cervical cancer screening tests for Korean women and to distribute these guidelines to every clinician, eventually improving the quality of medical care. Since the establishment of the consensus guideline development committee, evidence-based guidelines have either been developed de novo considering specific Korean situations or by adaptation of preexisting consensus guidelines from other countries. Recommendations for cervical cancer screening tests, management of atypical squamous and glandular cells, and management of low-grade and high-grade squamous intraepithelial lesions were developed. Additionally, recommendations for human papillomavirus DNA testing and recommendations for adolescent and pregnant women with abnormal cervical screening test results were also included. PMID- 23653840 TI - Evaluation of a genetic test for diagnose of primary hypolactasia in northeast of iran (khorasan). AB - OBJECTIVES: Primary or adult type hypolactasia, the most common enzyme deficiency in the world, is due to reduced lactase activity in the intestinal cell after weaning. Lactase non-persistence is inherited as an autosomal recessive trait. A DNA variant, single nucleotide polymorphism C/T-13910 which is located on 13910 base pairs (bp) upstream of the lactase gene (LCT) at chromosome 2 has been show to associate with the lactase persistence/non-persistence. The prevalence of the C/T-13910 variant is different for hypolactasia in European, Asian, African American and Northern African populations. In this study, we investigated, for the first time the allele frequent of the single nucleotide polymorphism C/T 13910 in the Iranian population in khorasan province with hypolactasia. MATERIALS AND METHODS: Peripheral blood was collected from 100 subjecs with primary hypolactasia and 100 healthy individuals as a control group. Genomic DNA was extracted. The genotype was analyzed with the PCR-RFLP method. A statistical analysis was performed by chi-square test using SPSS software. A P-value of <0.05 was considered statistically significant. RESULTS: In case group allelic frequency for SNP T-13910C (C, T) was respectively 95%, 5% vs. control group 86% and 14%. Genotype frequency (CC, CT, TT) in patient group was 90%, 10%, 0% vs. control group 74%, 24% and 2%. So according to our findings, there were significant differences between allelic frequencies (P=0.03), and in genotype frequency between case and control groups (P=0.006). CONCLUSION: Based on our results, analysis of C?T-13910 polymorphism can be used as a simple genetic test for diagnosis of primary type hypolactasia in the Iranian population. PMID- 23653839 TI - A review on angiogenesis and its assays. AB - Angiogenesis or formation of new blood vessels from preexisting vasculature is a key process in some physiological conditions such as wound healing, growth, and action of female reproductive organs. Moreover, disturbance of the mechanisms of physiological angiogenesis has a role in pathogenesis of some diseases in the form of overproliferation of blood vessels such as cancers, psoriasis, arthritis, retinopathies, obesity, asthma, and atherosclerosis or impaired angiogenesis participates in diseases such as heart and brain ischemia, neurodegeneration, hypertension, osteoporosis, respiratory distress, preeclampsia, endometriosis, postpartum cardiomyopathy, and ovarian hyperstimulation syndrome. Research and study in angiogenesis provide a potential to cure a variety of diseases such as cancers or cardiovascular diseases. Thus, in recent years, several methods for evaluation of angiogenesis have been introduced and selecting the most appropriate cure is very important. In this article, first, we briefly reviewed appropriate assays to evaluate therapeutic angiogenesis (clinical manipulation of angiogenesis) and its importance during some clinical diseases and then introduced in vitro, in vivo, and ex vivo assays of angiogenesis besides their benefits and disadvantages. Next, some quantitative techniques for assessing angiogenesis have been discussed. PMID- 23653841 TI - Para-nonylphenol impairs osteogenic differentiation of rat bone marrow mesenchymal stem cells by influencing the osteoblasts mineralization. AB - OBJECTIVES: Para-Nonylphenol (p-NP) is used in many industries and our previous study showed that p-NP causes a reduction in rats bone marrow mesenchymal stem cells (MSCs) viability. The aim of this study was to investigate the effect of p NP on osteogenic differentiation of MSCs. MATERIALS AND METHODS: MSCs were isolated and expanded to 3rd passage, then cultured in DMEM supplemented with osteogenic media as well as 0.5 or 2.5 uM of p-NP. After 5, 10, 15, and 21 days, the viability and the level of mineralization was determined using MTT assay and alizarin red, respectively. In addition, morphology and nuclear diameter of the cells were studied with the help of fluorescent dye. Furthermore, calcium content and alkalinphosphatase activity were also estimated using commercial kits. Data were statistically analyzed and the P<0.05 was taken as the level of significance. RESULTS: The viability and mineralization of the cells treated with 2.5 uM of p-NP reduced significantly after day 10 in comparison with the control group and administration of 0.5 uM. Moreover, chromatin condensation, reduction of nuclei diameter, and cytoplasm shrinkage was observed in the cell treated with 2.5 uM. The calcium concentration and alkalinphosphatase activity of the cells decreased significantly with 2.5 uM of p-NP when compared with 0.5 uM and control group. CONCLUSION: Adverse effect of p-NP was observed on osteogenic differentiation of MSCs at 2.5 uM due to disruption of mineralization. We strongly suggest more investigations on this chemical with respect to other stem cells, especially skin stem cells as p-NP is used in the formulation of cosmetics. PMID- 23653842 TI - Diagnostic value of lectins in differentiation of molar placentas. AB - OBJECTIVES: Distinction of hydatidiform moles from non-molar specimens and subclassification of hydatidiform moles as complete and partial are important for clinical practice, but diagnosis based solely on histomorphology suffers from poor interobserver reproducibility. Nowadays, pathologists rely on molecular techniques, however these methods are technically difficult, relatively expensive, and time consuming, and cannot be applied in all laboratories. Therefore, a relatively easy, time- and cost-effective ancillary tool, would be helpful. This study aimed to assess the role of lectins in differential diagnosis of molar placentas. MATERIALS AND METHODS: Lectin histochemistry with a panel of HRP-conjugated lectins comprising SBA, DBA, MPA, PNA, VVA, UEA-1, LTA, GS-I (B4), and WGA were performed in 20 non-molar (hydropic and non-hydropic spontaneous abortions) and 20 molar (partial and complete moles), formalin-fixed paraffin embedded tissue samples. On the basis of staining intensity, sections were graded and Kruskal-Wallis non-parametric statistical test was used to compare differences between samples. RESULTS: There was a significant difference between the reactivities of LTA and UEA-I with syncytiotrophoblasts of molar and non molar specimens (P<0.001). These lectins generally showed a moderate reactivity with syncytiotrophoblasts of molar group but did not react with this cell population in non-molar group. Furthermore, WGA showed relatively increased reaction with syncytiotrophoblasts of molar tissues compared with abortions, however, this did not reach to statistical significance (P=0.07). No major differences were seen in other lectins reactivities between the studied groups. CONCLUSION: The present study showed that UEA-1 and LTA lectins may be used as cytochemical probes in differentiating molar from non-molar placentas, but did not differentiate partial moles from complete moles. PMID- 23653843 TI - Consequences of Ischemic Preconditioning of Kidney: Comparing between Male and Female Rats. AB - OBJECTIVES: Ischemia-reperfusion injury (IRI) is a leading cause of kidney transplantation failure, and ischemic-preconditioning (IPC) is a protective method against the IRI. In the present study, the defensive effect of IPC on rats' kidney was investigated and more importantly the differences between two genders were appraised. MATERIALS AND METHODS: THIRTY TWO WISTAR RATS WERE RANDOMLY ALLOCATED TO FOUR GROUPS: group A (8 male IR), B (8 female IR), C (8 male IPC) and D (8 female IPC). Ischemia was induced by clamping of left renal arteries for 45 min in groups A and B. Rats in groups C and D experienced four cycles of 4 min arterial clamping followed by 11 min of de-clamping prior to the final 45 min of ischemia. 24 hr later, serum was provided to assess the blood urea nitrogen (BUN) and creatinine values. Also, renal tissues were obtained for histological measurements. RESULTS: Induction of IPC in both male and female rats led to significant decrease in creatinine levels in comparison with sham groups (P<0.01). The same results were seen in BUN levels (P<0.01). However, there were no significant difference between two genders. Besides, histological protective effects of IPC was proved especially in female rats (P<0.01). CONCLUSION: Findings of our study confirmed that renal IPC reduces the damages in both genders especially females. Thus, the IPC procedure seems to be a useful method mainly in females. PMID- 23653844 TI - Evaluating the expression of oct4 as a prognostic tumor marker in bladder cancer. AB - OBJECTIVES: The key transcriptional regulator Oct4 is one of the self-renewal and differentiation-related factors in cancer stem cells, where it maintains "stemness" state. Cancer stem cells have been identified in a variety of solid malignancies. They are a small population of tumor cells with stem cell characteristics, which are a likely cause of relapse in cancer patients. Due to high incidence, mortality, and recurrence rates of bladder cancer and the necessity of accurate prediction of malignant behavior of the tumors, we evaluated the prognostic value of Oct4 expression in formalin-fixed paraffin embedded (FFPE) tissues of bladder cancer. MATERIALS AND METHODS: In this study, Oct4 expression was evaluated in 52 (FFPE) tissues of bladder cancer. RNA extraction from samples of 30 patients from the archive of Labbafi-Nejad Medical Centre in Tehran was performed and Oct4 expression levels were examined by semi quantitative RT-PCR. The intracellular distribution of Oct4 protein was also determined by immunohistochemistry (IHC). RESULTS: The results revealed a significant correlation between the expression level of Oct4 and the tumors' grade and stage. A mostly cytoplasmic distribution of Oct4 protein was also confirmed by IHC. CONCLUSION: All together, our data indicate that the expression level of Oct4 gene is correlated with the clinical and histopathological prognostic indexes of tumors and thus can be considered as a potential prognostic tumor marker. PMID- 23653845 TI - Evaluation of curcumin effects on post-operative peritoneal adhesion in rats. AB - OBJECTIVES: The purpose of this study holds, for the first time, an evaluation of the intraperitoneal curcumin lavage on the development of post-operative intra abdominal adhesions. MATERIALS AND METHODS: Thirty male Wistar rats were randomized into five groups. The rats were administered anesthesia and underwent surgery in order to create intra-abdominal adhesions. Before the abdomen was closed, five lavage solutions of normal saline (control group), curcumin 1, 3, and 5% and hydrocortisone 1% were used for 1 min. After five days, the rats underwent laparatomy. Based on a histopathology evaluation and serum levels of hs CRP, TNFalpha and Isoprostane, peritoneal adhesion severity were compared in different groups. RESULTS: The groups that received curcumin 3% and 5% showed a significant decrease in TNFalpha, hs-CRP and Isoprostane serum concentrations compared to the normal saline group, however, these differences were not significant, between the other groups. The intensity of adhesions in the different groups of curcumin 1, 3 and 5% concentrations and hydrocortisone 1% were compared to the normal saline control group and no significant statistical difference was recorded. CONCLUSION: Curcumin was not effective in post-operative peritoneal adhesion; however, further studies on curcumin lavage in higher concentrations are recommended. PMID- 23653846 TI - Experimentally-Induced Metabolic Acidosis Does not Alter Aortic Fatty Streak Formation in High-Cholesterol Fed Rabbits. AB - OBJECTIVES: Cardiovascular disease causes a major clinical problem in patients with end stage renal disease. Since metabolic acidosis is very common in patients with end stage renal disease, we aimed to investigate the effect of experimentally-induced metabolic acidosis on serum lipid profile and aortic fatty streak (FS) formation in normal and high-cholesterol fed rabbits. MATERIALS AND METHODS: Twenty-four male rabbits were divided into four groups (n=6 each): (1) normal diet (ND): (2) hypercholesterolemic diet (HCD) (1%): (3) ND plus acidemic diet: (4) HCD plus acidemic diet. Metabolic acidosis was induced by adding 0.75% NH4Cl in drinking water. After 4 weeks, blood samples were taken and thoracic aortae were dissected for histological examinations. RESULTS: Results showed that in the animals who received NH4Cl, metabolic acidosis was successfully induced. Serum total cholesterol and low density lipoprotein (LDL) concentrations in HCD groups were significantly higher than ND groups (P<0.05) and acidosis did not significantly change serum lipid levels neither in ND nor in HCD animals (P>0.05). Histological examination of aortae showed higher mean average grades of pathological evaluation in HCD than ND groups (2.1+/-0.16 vs. 0+/-0; P<0.05). Acidosis did not further increase FS formation in HCD groups (P >0.05). CONCLUSION: In this model of experimentally-induced metabolic acidosis, acidosis could not increase FS formation in HCD animals and it seems that it does not interfere in progression of atherosclerosis process. PMID- 23653847 TI - Memory and motor coordination improvement by folic Acid supplementation in healthy adult male rats. AB - OBJECTIVES: Previous studies have shown that vitamin B as well as folate supplementation has been implicated in cognitive and neurodegenerative disorders including Alzheimer's and Parkinson's diseases. The aim of present study was to evaluate the effects of folic acid on passive avoidance task and motor coordination in healthy adult male rats. MATERIALS AND METHODS: Animals were randomly divided into five groups with 10 in each. 1) Sham treated (Veh); received same volume of normal saline as folate vehicle, 2-5) Test groups; each received a single dose of folate (5, 10 and 15 mg/ml/kg, IP daily for one week). At the end of the treatment with folic acid or vehicle, motor coordination in rotarod (after 24 hr) and passive avoidance memory in shuttle box (after 2 and 30 days) were evaluated, respectively. RESULTS: The results showed that folic acid (5, 10, and 15 mg/kg) increased short-term (P<0.05, P<0.001) memory while, long term memory affected significantly with doses 10 and 15 mg/kg (P<0.01, P<0.001). On the other hand, folic acid (5 and 10 mg/kg) had significant improving effect on motor coordination (P<0.001, P<0.01) but with 15 mg/kg dose didn't have any effect on motor coordination. CONCLUSION: Our results suggest that folic acid may improve both short- and long-term memories, dose dependently, although it affects motor balance at lower dose. The mechanism of folic acid effects on cognition and motor coordination is unknown and needs more investigations. PMID- 23653848 TI - Phase Angle Measurement in Healthy Human Subjects through Bio-Impedance Analysis. AB - OBJECTIVES: Bioelectrical impedance is the measure of impedance of the body. Impedance consists of electric resistance and reactance. Phase angle (PA) is the tan value of the ratio of reactance versus electric resistance. PA depends on cell membrane integrity and on body cell mass. There exists a correlation between PA values and body cell mass. The objective of this study was to compare the PA values of normal individuals and their anthropometric measurements. MATERIALS AND METHODS: Anthropometric measurements, Bioelectrical impedance analysis and PA measurements were done using Bodystat Quadscan 4000 machine on 42 healthy subjects between the age group of 18 to 50 yrs at a private hospital, Bangalore, Karnataka, India for eight months. Kolmogrov-Smirnov and Pearson's correlation tests were used for data analysis. RESULTS: The PA values were 7.321.17o in healthy subjects. PA values were significantly positively correlated with body mass index (BMI) (r= 0.011, P<0.001). The phase angle values for males and females were 7.43+/-0.98o and 7.05+/-1.1.58o, respectively. CONCLUSION: PA values positively correlated with BMI indicating the nutritional status of the study group. PA values were similar to the values to found in other studies. PMID- 23653849 TI - In vitro Assay of Human Gingival Scaffold in Differentiation of Rat's Bone Marrow Mesenchymal Stem Cells to Keratinocystes. AB - OBJECTIVES: Tissue engineering is an attractive science because it promises new therapeutic strategies for repairing organs that have lost functions due to damage. The purpose of this study was to evaluate induction effect of human gingival scaffold in tissue engineering for skin regeneration. MATERIALS AND METHODS: Tissue samples were obtained from crown-lengthening procedures and wisdom teeth removal. The samples were decellularized and used as a scaffold for loading of rat BM-MSCs. The human gingival scaffolds loaded by bone marrow mesenchymal stem cells were derived from Wistar rat. Finally, it was evaluated via electron micrographs, as well as immunohistochemical techniques at day 7, 14, and 28 after initial seeding. RESULTS: The histologic sections of human gingival scaffold -loaded rat BM-MSCs demonstrated formation of epithelial like layers at days 7, 14 and 28 after initial seeding. Scanning electron microscope (SEM) of the scaffolds indicated formed desmosomal adhesions, which revealed a degree of differentiation toward keratinocytes. The results of immunohistochemical staining were strongly positive for multi cytokeratin (CK) 14 days after initial seeding in epithelial differentiation. Rat BM-MSCs which loaded on human gingival scaffold is capable of differentiating toward keratinocytes. CONCLUSION: Gingival tissues were presented as a natural scaffold for attachment and differentiation of bone marrow mesenchymal stem cells towards keratinocytes, and might be used as suitable scaffold for reconstruction of the skin. PMID- 23653850 TI - Urine Monocyte Chemoattractant Protein-1(UMCP-1) as a Biomarker of Renal Involvement in Systemic Lupus Erythematosus. AB - OBJECTIVES: Lupus nephritis (LN) is frequently associated with a poor long-term prognosis. Renal biopsy is the diagnostic method of choice in this condition. Urine biomarkers have been mentioned in the diagnosis of LN. The study(,)s purpose was to evaluate the performance of urinary monocyte chemoattractant protein 1(UMCP-1) as a biomarker of renal involvement in systemic lupus erythematosus. MATERIALS AND METHODS: Forty-one recently diagnosed systemic lupus erythematosus patients (8 male and 33 female) without renal involvement (group 1) and twenty six patients (8 male and 18 female) with LN (group 2), proven by biopsy, were recruited to this study. UMCP-1 sensitivity and specificity for identifying biopsy-proven nephritis were calculated, and a receiver operating characteristic (ROC) curve was constructed to quantify how definitely UMCP-1 distinguishes between patients with and without LN. RESULTS: The mean value of UMCP-1 levels were 733.07 pg/ml +/- 1282.54 and 144.16 pg/ml +/- 137.90 in patients with and without LN respectively. The UMCP-1 level was significantly higher in group 2 than group 1. There was no significant correlation between UMCP 1 and 24-hour urine protein (r = 0.031, P= 0.874). The area under the ROC curve was 0.727 with a CI 95% of 0.597 to 0.857 (P=0.002). Using a cut-off value of 82 pg/ml,UMCP-1 had a sensitivity of 88.5% and a specificity of 46.3% for identifying LN. CONCLUSION: UMCP-1 can serve as a biomarker of LN although further longitudinal studies of these biomarkers are required in LN. PMID- 23653851 TI - Effect of Aerobic Exercise on Serum Concentration of Apelin, TNFalpha and Insulin in Obese Women. AB - OBJECTIVES: Apelin is novel adipokine acting on APJ receptor, regulated by insulin and tumor necrosis factor-alpha (TNF-alpha). Plasma apelin levels are increased in obese subjects. The aim of this study was to investigate whether or not the aerobic exercise modifies the elevated plasma apelin levels in obese women. MATERIALS AND METHODS: Twenty obese women (BMI 32.2 +/- 6.4 kg/m(2)) were selected by random sampling method among obese women. Twelve healthy women with a BMI of 31.7 +/- 0.6 kg/m(2) served as control group. The aerobic exercise was performed during 8 weeks, 3 sessions per week. The intensity of the training program proceeded form 50% to 70% in 8 weeks. RESULTS: Results showed that plasma levels of apelin and TNFalpha were higher in obese individuals compared with the control group. The exercise resulted in significant decrease (P<0.05) of BMI to 29.8+/- 6.3 kg/m(2) , plasma insulin (8.16 +/- 0.73 to 6.58 +/- 0.66 umol/l), apelin (369 +/- 25 pg/ml vs 257 +/- 12 pg/ml) and TNFalpha levels (0.66 +/- 0.04 pg/ml vs 0.56 +/- 0.04 pg/ml). P< 0.05 was considered statistically significant. CONCLUSION: Exercise can decrease plasma apelin, insulin and TNFalpha levels in obese women. Regular physical activity causes a decrease in plasma levels of apelin if body mass index and body fat mass simultaneously decreased. PMID- 23653852 TI - Anti-angiogenic Effects of Metformin, an AMPK Activator, on Human Umbilical Vein Endothelial Cells and on Granulation Tissue in Rat. AB - OBJECTIVES: Metformin is well known for activation of AMP-activated protein kinase (AMPK). AMPK activation inhibits mammalian target of rapamycin (mTOR) as a key signaling process in cell proliferation. Recent epidemiological studies demonstrate that metformin lowers the risk for several types of cancer in diabetic patients. Concerning the critical role of angiogenesis in the incidence and progression of tumors, we investigated the effect of metformin on human umbilical vein endothelial cells migration, as well as on vascular endothelial growth factor (VEGF) expressions in the cells and also on angiogenesis in air pouch model in rats. MATERIALS AND METHODS: A "wound" repair method was used to assess the cell migration (n=6). Real-time PCR was performed to quantify the mRNA expression of VEGF (n=5). In air pouch model, carrageenan was injected into the air pouches on the back of rats (n=6) and following an IV injection of carmine red dye granulomatous tissue was processed for the assessment of the dye content. An ordinary ANOVA with Student-Newman-Keuls post hoc test was used to compare groups. RESULTS: Metformin (orally, 50mg/kg) significantly (P<0.01) decreased angiogenesis in granulomatous tissue by 34% in pouch-bearing rats. Metformin at concentrations of 0.5-3 mM significantly (P<0.001) inhibited VEGF mRNA expression and endothelial cell migration. The inhibitory effects of metformin on the endothelial cell migration were reversed partially by compound C (P<0.01), an inhibitor of AMPK. CONCLUSION: The present study reported that metformin inhibited endothelial cell migration and angiogenesis in vitro and in vivo, and the effect was partially AMPK dependent. PMID- 23653853 TI - The effect of ramadan fasting on biochemical and performance parameters in collegiate wrestlers. AB - OBJECTIVES: This study was designed to evaluate the effect of Ramadan fasting on body composition, aerobic and anaerobic power, strength, plasma lipids profile and serum glucose among collegiate wrestlers. MATERIALS AND METHODS: Fourteen male collegiate wrestlers (age, 20.12+/-2.5 yrs) volunteered as subjects for the study. Subjects were tested one week before the beginning of Ramadan, the last two days of Ramadan and the last two days of the 4th week after the end of Ramadan. The paired sample t-test was used to assess the differences in pre and post-performance tests and repeated measures ANOVA and Bonferroni post hoc test to determine differences between three blood samplings. RESULTS: The results showed that except for anaerobic power and strength, body weight, body fat percentage and aerobic power at 4th week of Ramadan were significantly lower than pre-Ramadan values (P=0.05). Total cholesterol and low density lipoprotein levels decreased after Ramadan compared to pre-Ramadan (P= 0.011, P=0.001), however, a month after Ramadan, it reached to higher levels compared to pre-Ramadan period, which were not statistically significant. Similarly, significant decrease and increase were consequently observed in glucose and high density lipoprotein (P=0.001, P=0.045). Triacylglycerol and VLDL increased at the end of Ramadan compared to the period of time before Ramadan, and after Ramadan, it reached the lower levels compared to concentrations before Ramadan (P=0.133, P=0.133). CONCLUSION: This study also indicated that Ramadan fasting appears to have significant effect on body composition, aerobic power and lipid profile. PMID- 23653855 TI - Efficacy of Single-Pill Combination of Telmisartan 80 mg and Hydrochlorothiazide 25 mg in Patients with Cardiovascular Disease Risk Factors: A Prospective Subgroup Analysis of a Randomized, Double-Blind, and Controlled Trial. AB - Objective. Report of prespecified and post hoc subgroup analyses of a randomized, controlled trial comparing telmisartan 80 mg/hydrochlorothiazide 25 mg (T80/H25) combination therapy with T80 monotherapy, according to the presence of cardiovascular disease (CVD) risk factors. Methods. Hypertensive patients were randomized (2 : 1) to receive T80/H25 or T80 for 6 weeks, following a 1-week, low dose, and run-in period. Systolic blood pressure (SBP) and diastolic BP reductions and BP goal achievement were evaluated in patients with CVD risk factors: presence of diabetes mellitus (DM), renal impairment, increased body mass index (BMI), and 10-year estimated risk for coronary heart disease (CHD). Results. In total, 888 patients received treatment. Overall, T80/H25 therapy significantly reduced SBP more than T80 monotherapy, irrespective of patient subgroup. In patients with DM, renal impairment, high BMI, and high CHD risk, BP goal achievement rates (<140/90 mm Hg) at Week 7, among those treated with T80/H25, were 52.8%, 52.8%, 50.6%, and 38.5%, respectively. More patients with DM reached a guideline-based BP goal (<130/80 mm Hg) at 7 weeks with T80/H25 than with T80 monotherapy (16.7% versus 8.8%). Rates of treatment-related adverse events were low and comparable across patient subgroups. Conclusions. Antihypertensive treatment with T80/H25 single-pill combination is effective and generally well tolerated, irrespective of the presence of CVD risk factors. PMID- 23653856 TI - Hypertension and diabetes: entry points for prevention and control of the global cardiovascular epidemic. PMID- 23653854 TI - Depression and cardiac disease: epidemiology, mechanisms, and diagnosis. AB - In patients with cardiovascular disease (CVD), depression is common, persistent, and associated with worse health-related quality of life, recurrent cardiac events, and mortality. Both physiological and behavioral factors-including endothelial dysfunction, platelet abnormalities, inflammation, autonomic nervous system dysfunction, and reduced engagement in health-promoting activities-may link depression with adverse cardiac outcomes. Because of the potential impact of depression on quality of life and cardiac outcomes, the American Heart Association has recommended routine depression screening of all cardiac patients with the 2- and 9-item Patient Health Questionnaires. However, despite the availability of these easy-to-use screening tools and effective treatments, depression is underrecognized and undertreated in patients with CVD. In this paper, we review the literature on epidemiology, phenomenology, comorbid conditions, and risk factors for depression in cardiac disease. We outline the associations between depression and cardiac outcomes, as well as the mechanisms that may mediate these links. Finally, we discuss the evidence for and against routine depression screening in patients with CVD and make specific recommendations for when and how to assess for depression in this high-risk population. PMID- 23653858 TI - The Validation of a New Visual Anaemia Evaluation Tool HemoHue HH1 in Patients with End-Stage Renal Disease. AB - In chronic haemodialysis patients, anaemia is a frequent finding associated with high therapeutic costs and further expenses resulting from serial laboratory measurements. HemoHue HH1, HemoHue Ltd, is a novel tool consisting of a visual scale for the noninvasive assessment of anaemia by matching the coloration of the conjunctiva with a calibrated hue scale. The aim of the study was to investigate the usefulness of HemoHue in estimating individual haemoglobin concentrations and binary treatment outcomes in haemodialysis patients. A prospective blinded study with 80 hemodialysis patients comparing the visual haemoglobin assessment with the standard laboratory measurement was performed. Each patient's haemoglobin concentration was estimated by seven different medical and nonmedical observers with variable degrees of clinical experience on two different occasions. The estimated population mean was close to the measured one (11.06 +/- 1.67 versus 11.32 +/- 1.23 g/dL, P < 0.0005). A learning effect could be detected. Relative errors in individual estimates reached, however, up to 50%. Insufficient performance in predicting binary outcomes (ROC AUC: 0.72 to 0.78) and poor interrater reliability (Kappa < 0.6) further characterised this method. PMID- 23653857 TI - Adipose tissue dysfunction in nascent metabolic syndrome. AB - The metabolic syndrome (MetS) confers an increased risk for both type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Moreover, studies on adipose tissue biology in nascent MetS uncomplicated by T2DM and/or CVD are scanty. Recently, we demonstrated that adipose tissue dysregulation and aberrant adipokine secretion contribute towards the syndrome's low-grade chronic proinflammatory state and insulin resistance. Specifically, we have made the novel observation that subcutaneous adipose tissue (SAT) in subjects with nascent MetS has increased macrophage recruitment with cardinal crown-like structures. We have also shown that subjects with nascent MetS have increased the levels of SAT secreted adipokines (IL-1, IL-6, IL-8, leptin, RBP-4, CRP, SAA, PAI-1, MCP-1, and chemerin) and plasma adipokines (IL-1, IL-6, leptin, RBP-4, CRP, SAA, and chemerin), as well as decreased levels of plasma adiponectin and both plasma and SAT omentin-1. The majority of these abnormalities persisted following correction for increased adiposity. Our data, as well as data from other investigators, thus, highlight the importance of subcutaneous adipose tissue dysfunction in subjects with MetS and its contribution to the proinflammatory state and insulin resistance. This adipokine profile may contribute to increased insulin resistance and low-grade inflammation, promoting the increased risk of T2DM and CVD. PMID- 23653859 TI - Rhenium-188 production in hospitals, by w-188/re-188 generator, for easy use in radionuclide therapy. AB - Rhenium-188 (Re-188) is a high energy beta-emitting radioisotope obtained from the tungsten-188/rhenium-188 (W-188/Re-188) generator, which has shown utility for a variety of therapeutic applications in nuclear medicine, oncology, and interventional radiology/cardiology. Re-188 decay is accompanied by a 155 keV predominant energy gamma-emission, which could be detected by gamma-cameras, for imaging, biodistribution, or absorbed radiation dose studies. Its attractive physical properties and its potential low cost associated with a long-lived parent make it an interesting option for clinical use. The setup and daily use of W-188/Re-188 generator in hospital nuclear medicine departments are discussed in detail. The clinical efficacy, for several therapeutic applications, of a variety of Re-188-labeled agents is demonstrated. The high energy of the beta-emission of Re-188 is particularly well suited for effective penetration in solid tumours. Its total radiation dose delivered to tissues is comparable to other radionuclides used in therapy. Furthermore, radiation safety and shielding requirements are an important subject of matter. In the case of bone metastases treatment, therapeutic ratios are presented in order to describe the efficacy of Re-188 usage. PMID- 23653861 TI - Pathogenic Role of Iron Deposition in Reticuloendothelial Cells during the Development of Chronic Hepatitis C. AB - Aim. Chronic hepatitis C (CHepC) is frequently associated with hepatic iron overload, yet mechanisms underlying iron-induced liver injury have not been elucidated. We examined the significance of iron deposition in hepatocytes (HC) and reticuloendothelial cells (REC) in CHepC. Methods. Stainable hepatic iron was scored according to the iron deposition pattern in 373 patients. The levels of serum soluble TNF- alpha receptor (sTNFR2) and hepatic hepcidin mRNA and the efficacy of phlebotomy were compared among patients with different iron deposition patterns. Results. Serum transaminase levels and hepatic scores of stage, grade, and steatosis were higher in patients with REC iron staining than in those without. REC iron scores were independently associated with advanced stage. Serum sTNFR2 levels were significantly higher in patients with REC iron than in those without. REC iron scores were independently correlated with sTNFR2 levels. Compared with patients without stainable iron, those with iron overload had decreased ratios of hepcidin mRNA to serum ferritin. The efficacy of phlebotomy was greater in patients with REC iron than in those without REC iron. Conclusions. The present results show the importance of REC iron for the development of CHepC and the therapeutic effect of phlebotomy in CHepC. PMID- 23653860 TI - Gd-EOB-DTPA-Enhanced MRI for Detection of Liver Metastases from Colorectal Cancer: A Surgeon's Perspective! AB - Colorectal cancer affects over one million people worldwide annually, with the liver being the most common site of metastatic spread. Adequate resection of hepatic metastases is the only chance for a cure in a subset of patients, and five-year survival increases to 35% with complete resection. Traditionally, computed tomographic imaging (CT) was utilized for staging and to evaluate metastases in the liver. Recently, the introduction of hepatobiliary contrast enhanced magnetic resonance imaging (MRI) agents including gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Eovist in the United States, Primovist in Europe, or Gd-EOB-DTPA) has proved to be a sensitive method for detection of hepatic metastases. Accurate detection of liver metastases is critical for staging of colorectal cancer as well as preoperative planning. PMID- 23653862 TI - A novel approach to the surgical treatment of lumbar disc herniations: indications of simple discectomy and posterior transpedicular dynamic stabilization based on carragee classification. AB - Surgery of lumbar disc herniation is still a problem since Mixter and Barr. Main trouble is dissatisfaction after the operation. Today there is a debate on surgical or conservative treatment despite spending great effort to provide patients with satisfaction. The main problem is segmental instability, and the minimally invasive approach via microscope or endoscope is not necessarily appropriate solution for all cases. Microsurgery or endoscopy would be appropriate for the treatment of Carragee type I and type III herniations. On the other hand in Carragee type II and type IV herniations that are prone to develop recurrent disc herniation and segmental instability, the minimal invasive techniques might be insufficient to achieve satisfactory results. The posterior transpedicular dynamic stabilization method might be a good solution to prevent or diminish the recurrent disc herniation and development of segmental instability. In this study we present our experience in the surgical treatment of disc herniations. PMID- 23653863 TI - Obtaining glenoid positioning data from scapular palpable points in vitro. AB - Both clinical and biomechanical problems affecting the shoulder joint suggest that investigators should study force transmission into and out from the scapula. To analyze force transmission between the humeral head and the glenoid, one must know the position of the glenoid. Studies have analyzed the position of the scapula from the positions of three palpable points, but the position of the glenoid relative to three palpable points has not been studied. Dry scapulae (N = 13) were subjected to X-rays and a critical angle, Theta (which relates the plane determined by the three palpable points on the scapula to a plane containing the glenoid center and the first two palpable points) was calculated. The mean value for Theta was 28.5 +/- 5.60 degrees. The obtained Theta allows us to determine the position of the glenoid from three palpable points. This information could be used in calculation of forces across the shoulder joint, which in turn would allow optimizing the choice of strengthening exercises. PMID- 23653864 TI - Basal cell ameloblastoma of mandible: a rare case report with review. AB - Ameloblastoma is a slow-growing benign neoplasm that has a strong tendency to local invasion and that can grow to be quite large without metastasizing. Rare examples of distant metastasis of an ameloblastoma in lungs or regional lymph nodes do exist. It has an aggressive and recurrent course and is rarely metastatic. Radiographically it shares common features with other lesions such as the giant cell tumor, aneurysmal bone cyst, and renal cell carcinoma metastasis; a definitive diagnosis can only be made with histopathology. Basal cell ameloblastoma is believed to be the rarest histologic subtype in which the tumor is composed of more primitive cells and has even fewer features of peripheral palisading. Till date, only few cases of basal cell ameloblastoma have been reported in the literature. Considering the rarity of the lesion, we report here an interesting and unique case of basal cell ameloblastoma of the mandible occurring in a very old patient. PMID- 23653865 TI - Iodine-induced hyperthyroidism-an old clinical entity that is still relevant to daily ICU practice: a case report. AB - Objective. Hyperthyroidism has been described as elevated serum free T3 and/or free T4 levels with decreased thyrotropin (TSH) concentrations. The main causes are related to autoimmune and neoplastic pathology. However, it might be caused due to a long-term topical exposure (iodine solution dressing) or by intravenous administration of iodine-containing substances. Both clinical and laboratory features might be presented. The main management is based on interruption of all exposures with iodine solutions and also antithyroid medicine in case of severe laboratory and clinical disturbances. Data Sources. We present a case of iodine induced hyperthyroidism in a critically ill ICU patient caused by excessive iodine containing antiseptic solution washes and contrast agent administration. The patient was successfully treated by discontinuing iodine exposure and beta blocker administration. Conclusions. In patients with underlying thyroid gland pathology, thyroid-function tests and clinical observation in the ICU are of critical importance. PMID- 23653866 TI - Portal Hypertension in Childhood Bilateral Wilms' Tumor Survivor: An Excellent Indication for TIPS. AB - Introduction. Increased pressure in portal venous system is relatively a rare complication after chemoradiotherapy for Wilms' tumor (WT). In paediatric population, feasibility and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) in portal hypertension nonresponsive to medical or endoscopic treatment have been recently advocated. We report a case of TIPS positioning in a 15-year-old girl with portal hypertension as a long-term sequel of multimodality therapy in bilateral WT. Case Report. Two-year-old girl was diagnosed for bilateral WT. Right nephrectomy with left heminephrectomy and chemoradiotherapy were performed. At 7 years of age, the first gastrointestinal bleeding appeared, followed by another episode two years later, both were treated successfully with beta-blockers. At 15 years of age, severe unresponsive life-threatening gastroesophageal bleeding without hepatosplenomegaly was managed by TIPS. Reduction of the portosystemic pressure gradient was obtained. Conclusion. TIPS positioning for portal hypertension in long-term tumors' sequel is feasible and could be considered as an additional indication in paediatric patients. PMID- 23653867 TI - Celiac artery compression syndrome. AB - Celiac artery compression syndrome is a rare disorder characterized by episodic abdominal pain and weight loss. It is the result of external compression of celiac artery by the median arcuate ligament. We present a case of celiac artery compression syndrome in a 57-year-old male with severe postprandial abdominal pain and 30-pound weight loss. The patient eventually responded well to surgical division of the median arcuate ligament by laparoscopy. PMID- 23653868 TI - An Activin Receptor IA/Activin-Like Kinase-2 (R206H) Mutation in Fibrodysplasia Ossificans Progressiva. AB - Fibrodysplasia ossificans progressiva (FOP) is an exceptionally rare genetic disease that is characterised by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomical areas. This disease is caused by a mutation in activin receptor IA/activin-like kinase-2 (ACVR1/ALK2). A Mexican family with one member affected by FOP was studied. The patient is a 19-year-old female who first presented with symptoms of FOP at 8 years old; she developed spontaneous and painful swelling of the right scapular area accompanied by functional limitation of movement. Mutation analysis was performed in which genomic DNA as PCR amplified using primers flanking exons 4 and 6, and PCR products were digested with Cac8I and HphI restriction enzymes. The most informative results were obtained with the exon 4 flanking primers and the Cac8I restriction enzyme, which generated a 253 bp product that carries the ACVR1 617G>A mutation, which causes an amino acid substitution of histidine for arginine at position 206 of the glycine-serine (GS) domain, and its mutation results in the dysregulation of bone morphogenetic protein (BMP) signalling that causes FOP. PMID- 23653870 TI - Refractory anemia with ring sideroblasts associated with marked thrombocytosis complicated by massive splenomegaly treated with lenalidomide resulting in resolution of splenomegaly but severe and prolonged pancytopenia. AB - Refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) is a hematological malignancy that combines features of both a myeloproliferative and myelodysplastic disorder. There have been recent reports of the successful treatment of anemia in 2 patients with RARS-T with lenalidomide. Here we report the successful treatment of massive splenomegaly in a patient with a long history of RARS-T resulting in complete resolution of splenomegaly, but with prolonged severe cytopenias. We also report the acquisition of the t(3;12)(q26;p13) translocation previously described in cases of myelodysplasia and the potential for transformation to myelofibrosis. PMID- 23653869 TI - BRAF V600E-Negative Hairy Cell Leukaemia. AB - Since the initial report of the BRAF V600E mutation in hairy cell leukemia, numerous investigators have demonstrated the presence of this activating mutation in nearly all cases of this disease. A case of hairy cell leukemia is documented with a classical clinical, morphological, immunophenotypic, and cytochemical profile in which the BRAF V600E was not detected. The diagnostic and therapeutic implications are discussed. PMID- 23653871 TI - Diagnosing sporadic creutzfeldt-jakob disease in a patient with a suspected status epilepticus in the intensive care unit. AB - Objective. Several tests are available in the diagnostics of sporadic Creutzfeldt Jakob disease (sCJD); however, none of these is conclusive. We review the values of these tests, from an intensive care unit (ICU) perspective. Methods. Case report and review of the literature. Results. A 53-year-old woman initially presenting with psychiatric symptoms developed myoclonus and was admitted 1 month later to the ICU with a suspected nonconvulsive status epilepticus and respiratory insufficiency, probably due to extensive antiepileptic drug therapy. Typical MRI and EEG findings and a positive 14-3-3 protein led to the diagnosis of sCJD. All treatments were terminated, and autopsy confirmed sCJD. Conclusions. Clinical signs combined with MRI, EEG, and 14-3-3 and/or tau protein determination might be sufficient to diagnose or exclude sCJD and may therefore prevent the application of unnecessary diagnostic tests. PMID- 23653872 TI - Efficacy of t2*-weighted gradient-echo MRI in early diagnosis of cerebral venous thrombosis with unilateral thalamic lesion. AB - Cerebral venous thrombosis (CVT) is an uncommon cause of stroke with diverse etiologies and varied clinical presentations. Because of variability in clinical presentation and neuroimaging, CVT remains a diagnostic challenge. Recently, some studies have highlighted the value of T2*-weighted gradient-echo MRI (T2*WI) in the diagnosis of CVT. We report the case of a 79-year-old woman with CVT due to a hypercoagulable state associated with cancer. On the initial T2-weighted image (T2WI), there was a diffuse high-intensity lesion in the right thalamus, extending into the posterior limb of the internal capsule and midbrain. T2*WI showed diminished signal and enlargement of the right basilar vein and the vein of Galen. Even though there is a wide range of differential diagnoses in unilateral thalamic lesions, and a single thalamus lesion is a rare entity of CVT, based on T2*WI findings we could make an early diagnosis and perform treatment. Our case report suggests that T2*WI could detect thrombosed veins and be a useful method of early diagnosis in CVT. PMID- 23653873 TI - Not just another cause of dyspnea: common complaint leads to a rare diagnosis. AB - A 62-year-old man with past medical history of type 2 diabetes mellitus (DM-2) and hypertension presented with progressive shortness of breath since three months. He was diagnosed with diabetic polyradiculopathy with diaphragmatic involvement and was started on intravenous immunoglobulin (IVIg) therapy. Rapid improvement was seen as evidenced by increased vital capacity and other pulmonary function parameters. Considering the patient's positive response to intravenous immunoglobulins (IVIg), this case strengthens the fact that diaphragmatic involvement in Type 2 Diabetes Mellitus can be a part of focal or polyneuropathy and that the pathogenesis is immune mediated. PMID- 23653874 TI - Prenatal diagnosis of treacher-collins syndrome using three-dimensional ultrasonography and differential diagnosis with other acrofacial dysostosis syndromes. AB - Treacher-Collins syndrome (TCS) is a rare dominant autosomal anomaly resulting from malformation or disruption of the development of the first and second branchial arches. It is characterized by micrognathia, malar hypoplasia, and malformations of the eyes and ears. The prenatal diagnosis using two-dimensional ultrasonography (2DUS) is characterized by identification of facial malformations together with polyhydramnios. Three-dimensional ultrasonography (3DUS) has the capacity to spatially display these facial malformations, thus making it easy for the parents to understand them. We present a case of TCS diagnosed in the 33rd week using 3DUS, with postnatal confirmation using cranial computed tomography and anatomopathological analysis. PMID- 23653875 TI - Massive secondary postpartum hemorrhage with uterine artery pseudoaneurysm after cesarean section. AB - Uterine artery pseudoaneurysm is a rare but serious complication of cesarean section. If inadequately treated, it can lead to life-threatening postpartum hemorrhage. Herein, we report the case of a 28-year-old woman who developed secondary postpartum hemorrhage resulting from uterine artery pseudoaneurysm and cesarean scar dehiscence after cesarean section. Angiographic embolization is a safe and effective procedure for treating postpartum hemorrhage resulting from pseudoaneurysm in hemodynamically stable patients. However, uterine artery ligation may be the surgical procedure of choice for hemodynamically unstable patients when fertility preservation is desired. PMID- 23653876 TI - Verrucous carcinoma of the foot with bone invasion: a case report. AB - Verrucous carcinoma of the foot often affects deep structures such as tendons, muscles, or bones. A 74-year-old man presented with a foot lesion that had been diagnosed as a skin infection 7 years earlier. He was treated with multiple excisions and superficial biopsies associated with antibiotic therapy without success. In our department he underwent an aggressive and accurate debridement with marginal excision harvesting multiple biopsies. Pathological evaluation of tissue at the time of operation confirmed the diagnosis of verrucous carcinoma of the foot. Therefore, the patient underwent an amputation below knee, and there were no postoperative complications; the patient was able to walk with the aid of a prosthesis with no signs of recurrence. The lesion follows a chronic course evolving from a discrete focal lesion to a large fungating deeply penetrating mass often compromised by local infection. The slow growth and confusing early stage appearances can lead to delays in diagnosis of 8 to 15 years causing the extracutaneous involvement that requires a leg amputation. Many patients are initially treated with many topical medications without success, and most tumors have been treated as recalcitrant warts or corns for some time, whereas the basic approach is surgical. PMID- 23653877 TI - A case report and genetic characterization of a massive acinic cell carcinoma of the parotid with delayed distant metastases. AB - We describe the presentation, management, and clinical outcome of a massive acinic cell carcinoma of the parotid gland. The primary tumor and blood underwent exome sequencing which revealed deletions in CDKN2A as well as PPP1R13B, which induces p53. A damaging nonsynonymous mutation was noted in EP300, a histone acetylase which plays a role in cellular proliferation. This study provides the first insights into the genetic underpinnings of this cancer. Future large-scale efforts will be necessary to define the mutational landscape of salivary gland malignancies to identify therapeutic targets and biomarkers of treatment failure. PMID- 23653878 TI - Cell Based Autologous Immune Enhancement Therapy (AIET) after Radiotherapy in a Locally Advanced Carcinoma of the Cervix. AB - Radiotherapy is the primary form of treatment in patients with locally advanced cervical carcinoma. However for residual disease in the form of the persistent lymph nodes, surgery or chemotherapy is recommended. As surgery is not acceptable by every patient and chemotherapy has associated side effects, we hereby report the positive outcome of in vitro expanded natural killer cell and activated T lymphocyte based autologous immune enhancement therapy (AIET) for the residual lymphadenopathy in a patient with locally advanced cervical cancer after radiation. After six transfusions of AIET, there was complete resolution of residual lymph nodes and there was no evidence of local lesion. The patient also reported improvement in quality of life. As AIET has been reported as the least toxic among the available therapies for cancer, combining AIET with conventional forms of therapy in similar patients might not only improve the outcome but may also help the patients achieve a good quality of life. PMID- 23653879 TI - Spermaturia after radical prostatectomy: is surgical preservation of fertility possible? AB - Ease of sperm retrieval has not been previously described as a goal for patients undergoing radical prostatectomy for prostate cancer; however preservation of fertility is a known concern for some younger prostate cancer patients. We present the first known case of a patient with postejaculatory spermaturia following robotic assisted radical prostatectomy. We hypothesize that this is due to fistula formation between the vas deferens and the urinary tract. PMID- 23653880 TI - Intravesical Foreign Body via a Vesicoperineal Fistula. AB - Male urethral "play" has been described for centuries. There are serious potential complications in this. We present a bizarre case of a variant of such play. A 49-year-old man presented with abdominal pain and incontinence. He had created a "neovagina" at the perineum for self-pleasure. The handle of a toilet brush was placed in the neovagina for self-pleasure but retracted into the bladder via a vesicoperineal fistula. An open cystotomy was performed to remove the foreign body. PMID- 23653881 TI - Comparison of Predicted Exercise Capacity Equations and the Effect of Actual versus Ideal Body Weight among Subjects Undergoing Cardiopulmonary Exercise Testing. AB - Background. Oxygen uptake at maximal exercise (VO2 max) is considered the best available index for assessment of exercise capacity. The purpose of this study is to determine if the use of actual versus ideal body weight in standard regression equations for predicted VO2 max results in differences in predicted VO2 max. Methods. This is a retrospective chart review of patients who were predominantly in active military duty with complaints of dyspnea or exercise tolerance and who underwent cardiopulmonary exercise testing (CPET) from 2007 to 2009. Results. A total of 230 subjects completed CPET on a bicycle ergometer with a male predominance (62%) and an average age of 37 +/- 15 years. There was significant discordance between the measured VO2 max and predicted VO2 max when measured by the Hansen and Wasserman reference equations (P < 0.001). Specifically, there was less overestimation when predicted VO2 max was based on ideal body weight as opposed to actual body weight. Conclusion. Our retrospective analysis confirmed the wide variations in predicted versus measured VO2 max based on varying prediction equations and showed the potential advantage of using ideal body weight as opposed to actual body weight in order to further standardize reference norms. PMID- 23653882 TI - Inflammation in retinal vein occlusion. AB - Retinal vein occlusion is a common, vision-threatening vascular disorder. The role of inflammation in the pathogenesis and clinical consequences of retinal vein occlusion is a topic of growing interest. It has long been recognized that systemic inflammatory disorders, such as autoimmune disease, are a significant risk factor for this condition. A number of more recent laboratory and clinical studies have begun to elucidate the role inflammation may play in the molecular pathways responsible for the vision-impairing consequences of retinal vein occlusion, such as macular edema. This improved understanding of the role of inflammation in retinal vein occlusion has allowed the development of new treatments for the disorder, with additional therapeutic targets and strategies to be identified as our understanding of the topic increases. PMID- 23653883 TI - Neurosurgical developments on the horizon. PMID- 23653884 TI - Neurosurgery and the dawning age of Brain-Machine Interfaces. AB - Brain-machine interfaces (BMIs) are on the horizon for clinical neurosurgery. Electrocorticography-based platforms are less invasive than implanted microelectrodes, however, the latter are unmatched in their ability to achieve fine motor control of a robotic prosthesis capable of natural human behaviors. These technologies will be crucial to restoring neural function to a large population of patients with severe neurologic impairment - including those with spinal cord injury, stroke, limb amputation, and disabling neuromuscular disorders such as amyotrophic lateral sclerosis. On the opposite end of the spectrum are neural enhancement technologies for specialized applications such as combat. An ongoing ethical dialogue is imminent as we prepare for BMI platforms to enter the neurosurgical realm of clinical management. PMID- 23653885 TI - The future of spine surgery: New horizons in the treatment of spinal disorders. AB - BACKGROUND AND METHODS: As with any evolving surgical discipline, it is difficult to predict the future of the practice and science of spine surgery. In the last decade, there have been dramatic developments in both the techniques as well as the tools employed in the delivery of better outcomes to patients undergoing such surgery. In this article, we explore four specific areas in spine surgery: namely the role of minimally invasive spine surgery; motion preservation; robotic-aided surgery and neuro-navigation; and the use of biological substances to reduce the number of traditional and revision spine surgeries. RESULTS: Minimally invasive spine surgery has flourished in the last decade with an increasing amount of surgeries being performed for a wide variety of degenerative, traumatic, and neoplastic processes. Particular progress in the development of a direct lateral approach as well as improvement of tubular retractors has been achieved. Improvements in motion preservation techniques have led to a significant number of patients achieving arthroplasty where fusion was the only option previously. Important caveats to the indications for arthroplasty are discussed. Both robotics and neuro-navigation have become further refined as tools to assist in spine surgery and have been demonstrated to increase accuracy in spinal instrumentation placement. There has much debate and refinement in the use of biologically active agents to aid and augment function in spine surgery. Biological agents targeted to the intervertebral disc space could increase function and halt degeneration in this anatomical region. CONCLUSIONS: Great improvements have been achieved in developing better techniques and tools in spine surgery. It is envisaged that progress in the four focus areas discussed will lead to better outcomes and reduced burdens on the future of both our patients and the health care system. PMID- 23653886 TI - Anesthetic drug development: Novel drugs and new approaches. AB - The ideal sedative-hypnotic drug would be a rapidly titratable intravenous agent with a high therapeutic index and minimal side effects. The current efforts to develop such agents are primarily focused on modifying the structures of existing drugs to improve their pharmacodynamic and pharmacokinetic properties. Drugs currently under development using this rational design approach include analogues of midazolam, propofol, and etomidate, such as remimazolam, PF0713, and cyclopropyl methoxycarbonyl-etomidate (MOC-etomidate), respectively. An alternative approach involves the rapid screening of large libraries of molecules for activity in structural or phenotypic assays that approximate anesthetic and target receptor interactions. Such high-throughput screening offers the potential for identifying completely novel classes of drugs. Anesthetic drug development is experiencing a resurgence of interest because there are new demands on our clinical practice that can be met, at least in part, with better agents. The goal of this review is to provide the reader with a glimpse of the novel anesthetic drugs and new developmental approaches that lie on the horizon. PMID- 23653887 TI - Devices for cell transplantation into the central nervous system: Design considerations and emerging technologies. AB - Successful use of cell-based therapies for the treatment of neurological diseases is dependent upon effective delivery to the central nervous system (CNS). The CNS poses several challenges to the delivery of cell-based therapeutics, including the blood-brain barrier, anatomic complexity, and regional specificity. Targeted delivery methods are therefore required for the selective treatment of specific CNS regions. In addition, CNS tissues are mechanically and physiologically delicate and even minor injury to normal brain or spinal cord can cause devastating neurological deficits. Targeted delivery methods must therefore minimize tissue trauma. At present, direct injection into brain or spinal cord parenchyma promises to be the most versatile and accurate method of targeted CNS therapeutic delivery. While direct injection methods have already been employed in clinical trials of cell transplantation for a wide variety of neurological diseases, there are many shortcomings with the devices and surgical approaches currently used. Some of these technical limitations may hinder the clinical development of cell transplantation therapies despite validity of the underlying biological mechanisms. In this review, we discuss some of the important technical considerations of CNS injection devices such as targeting accuracy, distribution of infused therapeutic, and overall safety to the patient. We also introduce and discuss an emerging technology - radially branched deployment - that may improve our ability to safely distribute cell-based therapies and other therapeutic agents to the CNS. Finally, we speculate on future technological developments that may further enhance the efficacy of CNS therapeutic delivery. PMID- 23653888 TI - Developments on the horizon in the treatment of neurovascular problems. AB - The field of Interventional Neuroradiology and Endovascular Neurosurgery has seen much technical advancement in the past two decades, which has brought the specialty from its infancy as an alternative therapy to the current standing as near standard of care for many complex neurovascular pathologies. This past year is no exception with flow diverting stents and stent retriever devices aiming to make their mark on advanced treatments for intracranial aneurysms and ischemic stroke, respectively. This review article will focus on the development of these technologies, current data supporting their advantages and limitations, and a brief expert opinion on where these technologies may take the field in the next few years. PMID- 23653889 TI - New and improved ways to treat hydrocephalus: Pursuit of a smart shunt. AB - The most common treatment for hydrocephalus is placement of a cerebrospinal fluid shunt to supplement or replace lost drainage capacity. Shunts are life-saving devices but are notorious for high failure rates, difficulty of diagnosing failure, and limited control options. Shunt designs have changed little since their introduction in 1950s, and the few changes introduced have had little to no impact on these long-standing problems. For decades, the community has envisioned a "smart shunt" that could provide advanced control, diagnostics, and communication based on implanted sensors, feedback control, and telemetry. The most emphasized contribution of smart shunts is the potential for advanced control algorithms, such as weaning from shunt dependency and personalized control. With sensor-based control comes the opportunity to provide data to the physician on patient condition and shunt function, perhaps even by a smart phone. An often ignored but highly valuable contribution would be designs that correct the high failure rates of existing shunts. Despite the long history and increasing development activity in the past decade, patients are yet to see a commercialized smart shunt. Most smart shunt development focuses on concepts or on isolated technical features, but successful smart shunt designs will be a balance between technical feasibility, economic viability, and acceptable regulatory risk. Here, we present the status of this effort and a framework for understanding the challenges and opportunities that will guide introduction of smart shunts into patient care. PMID- 23653890 TI - Kinetic and thermodynamic analysis of the conformational folding process of SS reduced bovine pancreatic ribonuclease A using a selenoxide reagent with high oxidizing ability. AB - Redox-coupled folding pathways of bovine pancreatic ribonuclease A (RNase A) with four intramolecular disulfide (SS) bonds comprise three phases: (I) SS formation to generate partially oxidized intermediate ensembles with no rigid folded structure; (II) SS rearrangement from the three SS intermediate ensemble (3S) to the des intermediates having three native SS linkages; (III) final oxidation of the last native SS linkage to generate native RNase A. We previously demonstrated that DHS(ox), a water-soluble selenoxide reagent for rapid and quantitative SS formation, allows clear separation of the three folding phases. In this study, the main conformational folding phase (phase II) has been extensively analyzed at pH 8.0 under a wide range of temperatures (5-45 degrees C), and thermodynamic and kinetic parameters for the four des intermediates were determined. The free energy differences (DeltaG) as a function of temperature suggested that the each SS linkage has different thermodynamic and kinetic roles in stability of the native structure. On the other hand, comparison of the rate constants and the activation energies for 3S -> des with those reported for the conformational folding of SS-intact RNase A suggested that unfolded des species (desU) having three native SS linkages but not yet being folded are involved in very small amounts (<1%) in the 3S intermediate ensemble and the desU species would gain the native-like structures via X-Pro isomerization like SS-intact RNase A. It was revealed that DHS(ox) is useful for kinetic and thermodynamic analysis of the conformational folding process on the oxidative folding pathways of SS-reduced proteins. PMID- 23653891 TI - The vigor of defense against non-self: potential superiority of allorestricted T cells in immunotherapy of cancer? AB - Men and sharks are both jawed vertebrates at the top of the food chain. Sharks are the first extant to develop adaptive immunity preserved to man throughout jawed vertebrates. We hypothesize here, that T cell receptor/major histocompatibility complex (TCR/MHC) interactions developed as the defense mechanism of carnivors against takeover by their victims' cells derived pathogens. Germline encoded TCR segments have been conserved in evolution, providing the MHC bias of TCR. Ancestor genes of MHC polymorphisms may have first developed as a mating preference system, that later in evolution provided host immune responses destroying infectious non-self, yet maintaining tolerance to self. Pathogens may thus have simultaneously selected for alloimmunity. Allorejection has been observed in sharks and men. Cannibalism is a common ecological interaction in the animal kingdom, especially prevalent in aquatic communities; it favors selection of intraspecies allo responses for defense of self integrity. Alloreactive T cells do not undergo negative selection of strong TCR/MHC interactions; thus, they react stronger than self-MHC recognizing T cells. High levels of genetic diversity at MHC genes play a critical role in protecting populations of vertebrate species from contagious cells displaying stemness and homing features, including cancer cells. Recognition of self-MHC fails especially in diseases, which predominantly arise with age and after the peak of reproduction, e.g., cancer. So far, the treatment of malignant disease with autologous T cells has widely failed. Allorecognition constitutes an extremely powerful mechanism in evolution, which may be employed in immunotherapy of cancer by MHC-disparate, e.g., haploidentical transplantation and consecutive treatment with T cells from the donor parents recognizing tumor selective peptides presented by the non-inherited haplotype on the tumor. PMID- 23653892 TI - Development, implementation, and compliance of treatment pathways in radiation medicine. AB - INTRODUCTION: While much emphasis on safety in the radiation oncology clinic is placed on process, there remains considerable opportunity to increase safety, enhance outcomes, and avoid ad hoc care by instituting detailed treatment pathways. The purpose of this study was to review the process of developing evidence and consensus-based, outcomes-oriented treatment pathways that standardize treatment and patient management in a large multi-center radiation oncology practice. Further, we reviewed our compliance in incorporating these directives into our day-to-day clinical practice. METHODS: Using the Institute of Medicine guideline for developing treatment pathways, 87 disease specific pathways were developed and incorporated into the electronic medical system in our multi-facility radiation oncology department. Compliance in incorporating treatment pathways was assessed by mining our electronic medical records (EMR) data from January 1, 2010 through February 2012 for patients with breast and prostate cancer. RESULTS: This retrospective analysis of data from EMR found overall compliance to breast and prostate cancer treatment pathways to be 97 and 99%, respectively. The reason for non-compliance proved to be either a failure to complete the prescribed care based on grade II or III toxicity (n = 1 breast, 3 prostate) or patient elected discontinuance of care (n = 1 prostate) or the physician chose a higher dose for positive/close margins (n = 3 breast). CONCLUSION: This study demonstrates that consensus and evidence-based treatment pathways can be developed and implemented in a multi-center department of radiation oncology. And that for prostate and breast cancer there was a high degree of compliance using these directives. The development and implementation of these pathways serve as a key component of our safety program, most notably in our effort to facilitate consistent decision-making and reducing variation between physicians. PMID- 23653894 TI - Current aspects in the pathophysiology and treatment of chronic wounds in diabetes mellitus. AB - Impaired wound healing is a frequent and very severe problem in patients with diabetes mellitus, yet little is known about the underlying pathomechanisms. In this paper we review the biology of wound healing with particular attention to the pathophysiology of chronic wounds in diabetic patients. The standard treatment of diabetic ulcers includes measures to optimize glycemic control as well as extensive debridement, infection elimination by antibiotic therapy based on wound pathogen cultures, the use of moisture dressings, and offloading high pressure from the wound bed. In this paper we discuss novel adjuvant therapies with particular reference to the use of autologous skin transplants for the treatment of diabetic foot ulcers which do not respond to standard care. PMID- 23653893 TI - Monitoring regulatory immune responses in tumor immunotherapy clinical trials. AB - While immune monitoring of tumor immunotherapy often focuses on the generation of productive Th1-type inflammatory immune responses, the importance of regulatory immune responses is often overlooked, despite the well-documented effects of regulatory immune responses in suppressing anti-tumor immunity. In a variety of malignancies, the frequency of regulatory cell populations has been shown to correlate with disease progression and a poor prognosis, further emphasizing the importance of characterizing the effects of immunotherapy on these populations. This review focuses on the role of suppressive immune populations (regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages) in inhibiting anti-tumor immunity, how these populations have been used in the immune monitoring of clinical trials, the prognostic value of these responses, and how the monitoring of these regulatory responses can be improved in the future. PMID- 23653895 TI - Comparison of explant-derived and enzymatic digestion-derived MSCs and the growth factors from Wharton's jelly. AB - Wharton's jelly is not only one of the most promising tissue sources for mesenchymal stem cells (MSCs) but also a source of natural growth factors. To prove that we can get both natural growth factors and MSCs from Wharton's jelly, we compared cellular characteristics and the level of basic fibroblast growth factor (bFGF) from samples using the explant culture method to those derived from the traditional enzymatic culture method. The levels of bFGF were 27.0 +/- 11.7 ng/g on day 3, 15.6 +/- 11.1 ng/g on day 6, and decreased to 2.6 +/- 1.2 ng/g on day 14. The total amount of bFGF released was 55.0 +/- 25.6 ng/g on explant culture. Compared with the traditional enzymatic digestion method, the explant culture method showed a tendency to release higher levels of bFGF in supernatant media for the first week of culture, and the higher cellular yield at passage 0 (4.89 +/- 3.2 * 10(5)/g versus 1.75 +/- 2.2 * 10(5)/g, P = 0.01). In addition, the genes related to mitosis were upregulated in the explant-derived MSCs. PMID- 23653898 TI - GPU-based cloud service for Smith-Waterman algorithm using frequency distance filtration scheme. AB - As the conventional means of analyzing the similarity between a query sequence and database sequences, the Smith-Waterman algorithm is feasible for a database search owing to its high sensitivity. However, this algorithm is still quite time consuming. CUDA programming can improve computations efficiently by using the computational power of massive computing hardware as graphics processing units (GPUs). This work presents a novel Smith-Waterman algorithm with a frequency based filtration method on GPUs rather than merely accelerating the comparisons yet expending computational resources to handle such unnecessary comparisons. A user friendly interface is also designed for potential cloud server applications with GPUs. Additionally, two data sets, H1N1 protein sequences (query sequence set) and human protein database (database set), are selected, followed by a comparison of CUDA-SW and CUDA-SW with the filtration method, referred to herein as CUDA-SWf. Experimental results indicate that reducing unnecessary sequence alignments can improve the computational time by up to 41%. Importantly, by using CUDA-SWf as a cloud service, this application can be accessed from any computing environment of a device with an Internet connection without time constraints. PMID- 23653896 TI - The rabbit as a model for studying lung disease and stem cell therapy. AB - No single animal model can reproduce all of the human features of both acute and chronic lung diseases. However, the rabbit is a reliable model and clinically relevant facsimile of human disease. The similarities between rabbits and humans in terms of airway anatomy and responses to inflammatory mediators highlight the value of this species in the investigation of lung disease pathophysiology and in the development of therapeutic agents. The inflammatory responses shown by the rabbit model, especially in the case of asthma, are comparable with those that occur in humans. The allergic rabbit model has been used extensively in drug screening tests, and this model and humans appear to be sensitive to similar drugs. In addition, recent studies have shown that the rabbit serves as a good platform for cell delivery for the purpose of stem-cell-based therapy. PMID- 23653899 TI - Efficacy of surface treatments on the bond strength of resin cements to two brands of zirconia ceramic. AB - PURPOSE: To compare the shear bond strengths (SBS) of two cements to two Y-TZP ceramics subjected to different surface treatments. MATERIALS AND METHODS: Zirconia specimens were made from Lava (n = 36) and IPS e.max ZirCAD (n = 36), and their surfaces were treated as follows: no treatment (control), silica coating with 30-um silica-modified alumina (Al2O3) particles (CoJet Sand), or coating with liners Lava Ceram for Lava and Intensive ZirLiner for IPS e.max ZirCAD. Composite resin cylinders were bonded to zirconia with Panavia F or RelyX Unicem resin cements. All specimens were thermocycled (6000 cycles at 5 degrees C/55 degrees C) and subjected to SBS testing. Data were analyzed by three-way ANOVA and Tukey's (HSD) post-hoc test (alpha = 0.05). Failure mode was analyzed by stereomicroscope and SEM. RESULTS: CoJet Sand and liners promoted significantly higher SBS than their control groups, but had similar results to one another. Panavia F provided significantly higher SBS values than RelyX Unicem (p < 0.01) for nontreated zirconia specimens of both brands. When Lava and IPS e.max ZirCAD were abraded with CoJet Sand, RelyX Unicem promoted significantly higher SBS values than Panavia F (p < 0.001). There was no significant difference between the two cements when the zirconia specimens were treated with their respective liners. The nontreated specimens and those treated with CoJet Sand exhibited a high percentage of adhesive and mixed A failures, while the specimens treated with liners presented an increase in mixed A and mixed C failures as well as some cohesive failure in the bulk of Lava Ceram for both cements. CONCLUSION: CoJet Sand and liners provided the best surface treatment for Lava and IPS e.max ZirCAD. The best surface treatment/cement combinations were CoJet Sand/RelyX Unicem and liner/Panavia F. SBS of Panavia F and RelyX Unicem was not influenced by the zirconia brand. PMID- 23653897 TI - Cardioprotective effects of omega -3 PUFAs in chronic kidney disease. AB - The prevalence rate of chronic kidney disease (CKD) is increasing worldwide, and cardiovascular disease (CVD) is a main cause of death in patients with CKD. The high incidence of CVD in CKD patients is related to chronic inflammation, dyslipidemia, malnutrition, atherosclerosis, and vascular calcification. Omega-3 polyunsaturated fatty acids ( omega -3 PUFAs) have been shown to reduce the risk of CVD. In this paper, we review the beneficial effects of omega -3 PUFAs on CVD and the possible cardioprotective mechanisms of omega -3 PUFAs in CKD patients by determining the effect of omega -3 PUFAs in the general population. omega -3 PUFAs have several cardioprotective benefits, such as reducing inflammation, decreasing oxidative stress, inhibiting platelet activity, exerting antiarrhythmic effects, and improving triglyceride levels, in the general population and patients with CKD. Modifications of erythrocyte membrane fatty acid content, including an increased omega -3 index and decreased oleic acid, after omega -3 PUFAs supplementation are important changes related to CVD risk reduction in the general population and patients with CKD. Further basic and clinical studies are essential to confirm the effects of omega -3 PUFAs on vitamin D activation, vascular calcification prevention, cardiovascular events, and mortality in CKD patients. PMID- 23653900 TI - Effect of resin cements and aging on cuspal deflection and fracture resistance of teeth restored with composite resin inlays. AB - PURPOSE: To evaluate the influence of resin cements and aging on cuspal deflection, fracture resistance, and mode of failure of endodontically treated teeth restored with composite resin inlays. MATERIALS AND METHODS: Seventy-two maxillary premolars were divided into 6 groups: 1: sound teeth as control (C); 2: preparations without restoration (WR); 3: inlays luted with RelyX ARC (ARC); 4: inlays luted with RelyX Unicem (RLXU); 5: inlays luted with Maxcem Elite (MCE); 6: inlays luted with SeT (ST). Groups 2 to 6 received mesio-occlusal-distal preparations and endodontic treatment. Stone casts were made for groups 3 to 6. Composite resin inlays were built over each cast and luted with the resin cements. A 200-N load was applied on the occlusal aspect and the cuspal deflection was measured using a micrometer before and after 500,000 cycles of fatigue loading (200 N; 500,000 cycles). The specimens were then submitted to an axial load until failure. RESULTS: The median cuspal deflection (um) and median fracture resistance (N) were calculated and statistically analyzed using Kruskal Wallis and Mann-Whitney tests (p < 0.01). Values followed by the same letter represent no statistically significant difference. Cuspal deflection before cyclic loading: C = 3 uma; ARC = 4 umab; RLXU= 5 umab; MCE = 21 umb; ST = 51 umbc; WR = 69 umc. Cuspal deflection after cyclic loading: ARC = 6 uma; RLXU = 19 umab; MCE = 33 umb; ST = 62 umb. Fracture resistance in N: C = 1902a; ARC = 980b; RLXU = 670c; MCE = 533c; ST = 601c; WR = 526c. According to the Wilcoxon test, there was no statistical difference between the cuspal deflection before and after cyclic loading only for ARC (p = 0.015). There was a predominance of recovery fractures for the restored groups. CONCLUSION: Composite resin inlays luted with RelyX ARC maintained cuspal deflection stability and showed higher fracture resistance of the teeth than did inlays luted with the other cements tested. PMID- 23653901 TI - Experimental and clinical evaluation of a self-etching and an etch-and-rinse adhesive system. AB - PURPOSE: To assess the one-step self-etching adhesive iBond Gluma inside (1-SE) and the two-step etch-and rinse adhesive Gluma Comfort Bond (2-ER), both used in combination with the fine particle hybrid composite Venus, in a laboratory and in a prospective clinical study. MATERIALS AND METHODS: In the in vitro study, tooth composite interaction, microleakage, and adhesive failure of 8 Class V restorations per system were evaluated by light and scanning electron microscopy. In the in vivo study, 90 paired Class III/IV restorations were scored over 48 months (modified USPHS criteria). Cumulative failure rates (CFR) were calculated. RESULTS: In vitro, microleakage and adhesive failure at enamel margins were significantly increased with 1-SE in comparison with 2-ER. With 1-SE, micromechanical interlocking at enamel was reduced and pores within the adhesive layer arose. In vivo, after 48 months with 1-SE, decreased marginal integrity and an increased number of dark marginal color lines were observed. CONCLUSION: Because the results of the 4-year clinical study showed lower esthetics and marginal integrity for the 1-SE adhesive, its use should be viewed critically, which is in line with the reduced enamel-adhesive-composite interaction found in vitro. PMID- 23653902 TI - Effects of single-peak vs polywave light-emitting diode curing lights on the polymerization of resin cement. AB - PURPOSE: This study examined the effect of selecting a single-peak blue vs a polywave blue/violet emission LED curing light on the degree of conversion (DC) and Knoop microhardness (KHN) of resin cements when light cured through a ceramic disk. MATERIALS AND METHODS: Two shades (A1 and A4) of resin cement (Variolink II) were placed in a 0.5-mm-thick ring. The top surfaces were covered with a Mylar strip and further covered with a disk of 1-mm-thick Empress Esthetic ceramic, shade A2. The specimens were light cured by means of an Elipar-S10 (3M ESPE, single-peak blue LED) or BluePhase-G2 (Ivoclar Vivadent, polywave blue/violet LED) curing light, both for 20 s, directly on the surface of an attenuated total reflectance FT-IR plate at 30 degrees C. The DC of the resin was calculated after 100 s. The specimens were removed, and the Knoop microhardness was tested immediately and again after 24-h storage in the dark at 37 degrees C and 100% humidity. Five specimens were made in each group. The DC and Knoop microhardness results were analyzed with ANOVA and Fisher's PLSD at alpha = 0.05. RESULTS: The choice of curing light had no significant effect on the DC and only a small effect on the immediate and 24-h KHN values. Shade A4 of the resin cement was harder and had a higher DC than shade A1. CONCLUSION: When light cured for 20 s, Variolink II resin cement can be light cured with either the single-peak or the polywave curing light. Shade A4 of the cement was slightly harder than A1. PMID- 23653903 TI - A colorimetric method for H1N1 DNA detection using rolling circle amplification. AB - A highly sensitive and specific colorimetry-based rolling circle amplification (RCA) assay has been successfully developed as a method for the effective detection of H1N1 DNA. Specific oligonucleotide and reporter primer probes were designed together with a circular template, and the oligonucleotide probes were attached to the surfaces of magnetic beads (MBs) to form functional MB-DNA conjugates as capture probes for the target H1N1 DNA molecules. Together with the addition of DNA targets and reporter primer probes to the MB-DNA conjugates, sandwiched hybrids were formed. The initiation of RCA amplification using the circular template in the presence of phi29 polymerase allowed for the amplification of a large number of repeat sequences of the single-stranded (ss) DNA product. This RCA product accumulated gold nanoparticles (AuNPs), resulting in a colorimetric change that could be viewed by the naked eye or detected using UV-vis spectroscopy. According to this method, H1N1 DNA could be detected at the 1 pmol L(-1) level. This platform exhibited design convenience, simplicity, and cost-effectiveness, and could be used to provide a new diagnostic assay for H1N1, and other infectious diseases. PMID- 23653904 TI - Ultrasensitive electrochemiluminescence detection of lengthy DNA molecules based on dual signal amplification. AB - Aimed at the facile detection of lengthy DNA molecules, an easily operated sandwich-type electrochemiluminescence (ECL) DNA biosensor was constructed on a glassy carbon electrode (GCE) based on CdTe quantum dots coated hollow ZnO nanoparticles (CdTe-ZnO NPs)-S(2)O(8)(2-) ECL system in this work. To fabricate a high-performance protocol, the GCE surface was successively modified by graphene nanosheet (GS), carbon nanotube (CNT) and gold nanoparticles (AuNPs) to form AuNPs dotted CNT-GS composites (Au@CNT-GS) platform, which improved the electronic transmission rate as well as increased the amount of immobilized capture probe CMV-F (S(1)). For further ultrasensitive, stable and low-potential ECL detection, CdTe-ZnO NPs were synthesized, and employed to label signal probe T7 promoter (S(3)). Based on the hybridization effect, the immobilized capture probe S(1), target DNA and labeled signal probe S(3) formed a sandwich-type DNA complex, which produced the ECL emission in the presence with S(2)O(8)(2-) coreactant. Under optimal conditions, the DNA ECL biosensor showed a good linear range over 10(-14) M to 10(-19) M with a low detection limit of 0.61 * 10(-19) M. The proposed strategy demonstrates a reproducible, stable, and potent method that can be expanded to detect the genome which exists in living cells. PMID- 23653906 TI - Breaking through to youth: a preventive and holistic approach:Interview of Dr Philemon Choi with student reporters. Interviewed by Winnie Sung and Clara Tsui. PMID- 23653905 TI - Nanocapsule-based probe for evaluating the orientation of antibodies immobilized on a solid phase. AB - The orientation of sensing molecules on solid phase biosensors has to be optimized to facilitate efficient binding of analytes. Since conventional observation methods (e.g., electron microscopy, atomic force microscopy, time-of flight secondary ion mass spectrometry) require exaggerated machines and possess insufficient resolution for single molecule analyses, functional assays based on the reactivity to analytes have thus far been used for this optimization. However, it is not clear whether these assays can judge whether sensing molecules are fixed in an oriented-immobilization manner or not. Here, we describe that bio nanocapsules of about 30 nm diameter, displaying approximately 120 molecules of a tandem form of the immunoglobulin (Ig) G Fc-binding Z domain (ZZ-BNCs), can discriminate between the Fc regions of IgGs fixed in an oriented-immobilization manner and those fixed randomly, thus facilitating the evaluation of the orientation of IgGs in immunosensors. Furthermore, in sandwich immunoassays, ZZ BNCs can bind specifically to detection-IgGs fixed in an oriented-immobilization manner by antigen-capture IgG complexes, rather than to capture-IgGs fixed randomly onto a solid phase, allowing the simultaneous use of the same IgG as capture- and detection-IgGs. Thus, we demonstrate that ZZ-BNCs are a unique probe for evaluating the orientation of IgGs on a solid phase. PMID- 23653907 TI - Organic pollutant levels in an agricultural watershed: the importance of analyzing multiple matrices for assessing stream water pollution. AB - This study is aimed at analyzing the occurrence and transport of organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in the Quequen Grande river basin, as representative of a catchment under diffuse pollution sources. Pollutant levels in soils, river bottom sediments (RBS), streamwater (Sw), suspended particle materials (SPMs), macrophytes and muscle of silverside were determined by GC-ECD. Soil K(d) values for the current-used insecticides, endosulfans and cypermethrin, were established. Total levels (ng g(-1) dry weight) in soil ranged between 0.07-0.9 for OCPs, 0.03-0.37 for PCBs and 0.01-0.05 for PBDEs. Endosulfan insecticide (alpha- + b- + sulfate metabolite) represented up to 72.5% of OCPs. The low soil retention for alpha-endosulfan (K(d): 77) and endosulfan sulfate (K(d): 100) allows their transport to Sw, SPM and RBS. Levels of endosulfan in Sw in some cases exceeded the value postulated by international guidelines for aquatic biota protection (3 ng L(-1)). PCB and PBDE pollution was related to harbour, dumping sites and pile tire burning. Tri and hexa PCB congeners predominated in all matrices and exceeded the quality guideline value of 0.04 ng L(-1) in Sw. Considering levels in silverside muscle, none of the oral reference doses were exceeded, however, PCBs accounted for 18.6% of the total daily allowed ingest for a 70 kg individual. Although the levels of PCBs and OCPs in soil and RBS were low and did not go beyond quality guidelines, these compounds could still represent a risk to aquatic biota and humanbeings, and thus actions towards preventing this situation should be undertaken. PMID- 23653908 TI - Determination of nitrate isotopic signature in waters of different sources by analysing the nitrogen and oxygen isotopic ratio. AB - A reference study on both the nitrogen content in waters and nitrogen and oxygen isotopic signatures characterising nitrate from different sources was conducted within the San River catchment area. Three kinds of catchments were studied: (1) forested and uncultivated; (2) artificially fertilised with nitrate; and (3) fertilised with manure and sewage. Moreover, atmospheric water was studied. The obtained values were found to be similar to others in the literature, with the exception of nitrate from the atmosphere, in regard to which influence reflecting the local conditions was to be noted. The isotopic signature of nitrate in the studied water results from the biogeochemical transformation of nitrogen compounds rather than from the mixing of different sources. The obtained results were statistically distinct and can be used as end-member values in further modelling studies connected with the management of nitrate in river waters, especially under middle-eastern European conditions. PMID- 23653909 TI - Leachability of chemical constituents in soil-plant systems irrigated with synthetic graywater. AB - Over recent years, reuse of graywater for irrigation has become increasingly widespread internationally. While this practice is rapidly growing, there remain unanswered questions with respect to impacts to environmental quality and human health. The objective of this research was to determine the leachability of graywater constituents after applied to soil through a set of controlled greenhouse experiments. Four plant species including bermudagrass, tall fescue, Meyer Lemon and Emerald Gaiety Euonymus were included in the study. Three replicate columns for each species were set up and irrigated either with synthetic graywater or potable water for a 17 month duration. Leachate quality was assessed for dissolved organic carbon, nitrate, ammonium, total phosphorous, boron, sodium adsorption ratio, conductivity, surfactants, and total dissolved solids. The same constituents and also organic matter were measured in soil samples collected at the end of experiments. Phosphorus did not leach through the 50 cm deep soil columns. Salts, including boron, showed potential to leach through graywater irrigated soil. A portion of the applied nitrogen was assimilated by plants, but leaching of nitrogen was still observed as documented by statistically higher nitrogen in leachate collected from graywater-irrigated columns compared to potable water-irrigated columns (P <= 0.05). A low percentage of surfactants added to columns leached through (7 +/- 6% on average) and a mass balance on surfactant parent compounds showed that 92-96% of added surfactants were biodegraded. PMID- 23653910 TI - A randomized pahse I bioequivalence clinincal trial of a paediatric fixed-dose combination antiretroviral reconstitutable suspension in healthy adult volunteers. AB - BACKGROUND: This study aimed to test the hypothesis that the paediatric fixed dose combination granule for reconstitution (comprising lamivudine/zidovudine/nevirapine 30/60/50 mg per 5 ml) as a test product is bioequivalent to the coadministered single entities of the referenced products. Fixed-dose combination anti-retroviral therapy provides adequate suppression of HIV-1 replication, provides barrier to the development of resistance, simplifies dosage regimen and improves adherence. METHODS: An open label, randomized, two way crossover study was conducted on 24 health adults under fasted conditions, with a washout period of 14 days between treatments. A total of 15 blood samples were collected before dosing and up to 96 h post dosing. The drugs were extracted from plasma and anlaysed using a validated high performance liquid chromatography ultraviolet method. Non- compartmental pharmacokinetic (PK) analysis was performed to obtain the PK parameters, maximum plasma concentration (C max), area under the curve of plasma concentration-time curves from the time zero to last measurable concentration (AUC0-t) and the area under the curve extrapolated to infinity (AUC 0-infinity) ANOVA test was performed to determine the effect of model factors on the PK parameters. The two one-sided t-tests were performed on the log-transformed data to determine the 90% CL for the ratio of test to reference PK parameters. RESULTS: The drugs were well tolerated and safe with minimal adverse events. The ANOVA test indicated the absence of any significant effects ( P>0.05) due to the model parameters. The 90% Cl for the geometric mean ratio of the test/reference for the Cmax, AUC0-t and the AUC0-infinity for lamivudine, zidovudine and nevirapine were within 80-125% bioequivalence limits. CONCLUSIONS: This single dose randomized study found that the test and reference products met the criteria for bioequivalence in the fasting healthy adult volunteers. PMID- 23653912 TI - Unnatural dilemma: synthetic biology, DNA, and diagnostics. PMID- 23653911 TI - Second-line protease inhibitor-based antiretroviral therapy after non-nucleoside reverse transcriptase inhibitor failure: the effect of a nucleoside backbone. AB - BACKGROUND: Virological failures on combined antiretroviral therapy still occur. Boosted protease inhibitor ( Pl/r)- based therapy is a commonly used option after non-nucleoside reverse transcriptase inhibitor ( NNRTI) failure, but whether two fully active nucleoside reverse transciptase inhibitors (NRTIs) are required is unknown. We investigated the effect of an NRTI backbone in individuals receiving Pl/r after failing NNRTI-based combined antiretroviral therapy. METHODS: A longitudinal analysis of the UK Collaborative HIV Cohort (CHIC) and the UK HIV Drug Resistance Database to identify individuals who failed first-line NNRTI and two NRTIs, and switched to Pl/r-based therapy between January 1999 and December 2008 was conducted. We investigated the effect of NRTI on suppression. RESULTS: In total, 470 individuals met study criteria: 19.6%, 34.5% and 46.0% started 0, 1 or >= 2 NRTIs, respectively. Median CD4+ T-cell count was 223 cells/mm3 and HIV RNA was 4.3 log10 copies/ml; 246 (52.3%) underwent genotyping before switch. virological failure occurred in 10.9% and 13% after 48 and 96 weeks, respectively. In multivariable analysis, heterosexual risk group and HIV RNA were independently associated with virological failure; higher CD4+ T-cell count was protective (HR= 0.92). Number of new NRTIs or genotypic sensitivity score of backbone had no effect on treatment success rates when modelled as categorical or continuous variables. CONCLUSIONS: Successful treatment with a second-line Pl/r may not require two active NRTIs. If replicated in clinincal trials, these findings could guide future recommendations. PMID- 23653913 TI - Policies for handling residual newborn blood samples for human health research. PMID- 23653914 TI - Occipital headache. PMID- 23653915 TI - A 52-year-old woman with headache, ataxia and loss of consciousness. PMID- 23653916 TI - Will technology deliver for 'big neuroscience'? PMID- 23653917 TI - The author file: Emma Lundberg. PMID- 23653918 TI - Points of view: Labels and callouts. PMID- 23653919 TI - Beyond 2015: time to reposition Scandinavia in global health? PMID- 23653921 TI - Genetics: Mammalian genes interacting. PMID- 23653920 TI - Only an integrated approach across academia, enterprise, governments, and global agencies can tackle the public health impact of climate change. AB - BACKGROUND: Despite considerable global attention to the issues of climate change, relatively little priority has been given to the likely effects on human health of current and future changes in the global climate. We identify three major societal determinants that influence the impact of climate change on human health, namely the application of scholarship and knowledge; economic and commercial considerations; and actions of governments and global agencies. DISCUSSION: The three major areas are each discussed in terms of the ways in which they facilitate and frustrate attempts to protect human health from the effects of climate change. Academia still pays very little attention to the effects of climate on health in poorer countries. Enterprise is starting to recognise that healthy commerce depends on healthy people, and so climate change presents long-term threats if it compromises health. Governments and international agencies are very active, but often face immovable vested interests in other sectors. Overall, there tends to be too little interaction between the three areas, and this means that potential synergies and co-benefits are not always realised. CONCLUSION: More attention from academia, enterprise, and international agencies needs to be given to the potential threats the climate change presents to human health. However, there needs to also be much closer collaboration between all three areas in order to capitalise on possible synergies that can be achieved between them. PMID- 23653922 TI - Neuroscience: An enhanced view of the brain. PMID- 23653923 TI - Bioinformatics: Tumors have their differences. PMID- 23653924 TI - Proteomics: Marked for depth. PMID- 23653925 TI - Structural biology: Metalloenzyme structures in a shot. PMID- 23653926 TI - Model organisms: Mouse models challenged. PMID- 23653927 TI - Imaging: Peering at protons. PMID- 23653928 TI - Infectious diseases in Malian and Syrian conflicts. PMID- 23653929 TI - Talk of HIV cure goes viral. PMID- 23653930 TI - [New horizons of gluten sensitivity studies]. AB - Gluten sensitivity may be a cause of gluten-sensitivity celiac disease (GCD). Some gluten-sensitive subjects may have symptoms of GCD, but lack its characteristic changes in the small bowel mucosa (SBM) and a gluten-free diet results in the disappearance of clinical symptoms of GCD. If there is no gluten allergy, the concept "gluten intolerance (GI) unassociated with celiac disease" is applicable in these cases. There is an increase in the prevalence of GCD and GI, which is associated with the use of gluten in food industry to improve the taste and energy density of foods and with the damaging effect of viruses and bacteria on enterocyte membranes, thereby facilitating the penetration of gluten through SBM. The paper gives an update on progress in the diagnosis of GCD and GI and on prospects for designing gluten-free cereals. PMID- 23653931 TI - [The clinical and pathogenetic types of gastroesophageal reflux disease: risk factors and predictors]. AB - AIM: To study the clinical and pathogenetic types of gastroesophageal reflux disease (GERD) in terms of different types of reflux into the esophagus, their risk factors and predictors. MATERIALS AND METHODS: The clinical, morphological, motor tonic characteristics of the esophagogastroduodenal area, the phenotypic and visceral signs of existing undifferentiated connective tissue dysplasias (UDCTD), and the suprasegmental and segmental autonomic apparatus were studied in detail in 124 patients with GERD. RESULTS: Two clinical and pathogenetic types of GERD associated with the predominance of gastroesophageal or duodenogastroesophageal refluxes (GER and DGER) are identified. The type of the disease running in the predominance of GER develops in subjects with the high rate of visceral stigmas of UDCTD--cardiac failure and hiatal hernias, sympathetic autonomic tone in the digestive system. The feeding preference of piquant and spicy dishes and spices serves to realize the predictors of this type. The DGER-associated type develops in subjects with a concurrence of sympathetic and parasympathetic total autonomic tones in the digestive system in the presence of preexisting biliary tract diseases, including abnormalities in the structure of the gallbladder as visceral signs of UDCTD and it is realized in the feeding preference of high-calorie dishes. CONCLUSION: It is promising to study the autonomic status and the signs of UDCTD as structural and functional predictors of GERD and its types for the prediction of the disease, professional orientation, and the acquisition of eating behavior primarily in young people. PMID- 23653932 TI - [Calcium and phosphorus balance and its significance for the course of recurrent peptic ulcer disease]. AB - AIM: To evaluate calcium and phosphorus balances during recurrent peptic ulcer disease (PUD) and to estimate the impact of found changes on the course of an ulcerative process, secretory and motor functions in the stomach. SUBJECTS AND METHODS: Sixty patients with recurrent PUD were examined. They underwent determinations of blood and urinary calcium and phosphorus levels and gastric secretory and motor functions in addition to clinical and endoscopic examinations. RESULTS: Recurrent PUD was shown to be accompanied by significantly elevated blood calcium and substantially decreased blood phosphorus, insignificant hypercalciuria and hyperphosphaturia. These changes were attended by considerably increased acid- and pepsinogen-forming functions of the stomach, lower gastromucoprotein production, and gastric hypermotor dyskinesis. More pronounced shifts in calcium and phosphorus balance were revealed in the acute phase of a disease recurrence in young men with duodenal ulcers. CONCLUSION: A clear relationship between calcium and phosphorus metabolic disturbances, ulcerative process activity, and gastric functional changes may point to the significance of found shifts in ulcerogenesis and to the pathogenetic substantiation of correction of these disorders in the treatment of a disease recurrence. PMID- 23653933 TI - [A new system of specialized gastroenterological care to patients with inflammatory bowel diseases in St. Petersburg]. AB - AIM: To substantiate the effectiveness of the set-up center in the early detection of patients with inflammatory bowel diseases (IBD) and in its organization and implementation of current therapeutic programs. MATERIALS AND METHODS: The therapeutic activity of the specialized medical care system set up in St. Petersburg for patients with IBD (ulcerative colitis (UC) and Crohn's disease (CD)), which is based on a multifunctional inflammatory bowel disease center at City Clinical Hospital Thirty-One, was analyzed. RESULTS: The effective work of the center could reduce time for verification of the diagnosis of UC from 6.4 +/- 1.4 to 3.6 +/- 0.8 months and CD from 28.6 +/- 6.7 to 15.3 +/- 4.2 months, respectively; decline the annual number of patients with moderate and severe UC from 73.4 to 53.6 and CD from 66.7 to 47%, and also set up a centralized system for all required types of current therapeutic and diagnostic care for these patients. CONCLUSION: The establishment of the St. Petersburg Center for the diagnosis and treatment of inflammatory bowel diseases could develop and realize in practice a new closed-loop urban system for the early detection and notification of IBD patients, the organization and rendering of individual effective therapeutic-and-prophylactic care. PMID- 23653934 TI - [The role of small bowel microflora in the development of secondary lactase deficiency and the possibilities of its treatment with probiotics]. AB - AIM: To estimate the incidence of secondary lactase deficiency (SLD) in patients with postinfectious irritable bowel syndrome (PIBS) and the value of the small bowel microflora in its development and to elaborate treatment options for SLD. SUBJECTS AND METHODS: One hundred and thirty-eight patients with PIBS, including 112 (81.2%) women and 26 (18.8%) men, were examined. The patients' mean age was 33.9 +/- 9.1 years. The duration of the disease was 2.6 +/- 1.4 years. Lactase deficiency (LD) was diagnosed using the color scale to test biopsy specimens from the duodenal retrobulbar region. The bacterial overgrowth syndrome (BOS) was identified by a 2-hour lactulose (20 ml) hydrogen breath test. Sixty patients with moderate SLD were randomized to 2 groups: 1) 41 patients received basic therapy (mesim forte as one tablet t.i.d., no-spa, 40 mg, t.i.d.) and combined probiotic bifiform (Ferrosan) containing Bifidobacterium longum 107, Enterococcus faecium 107 as one capsule t.i.d. for 14 days. Group 2 patients (n = 19) had basic therapy in combination with placebo. RESULTS: SLD was detected in 59.4% of the patients with PIBS, including 43.5 and 15.9% with moderate and severe forms, respectively. In all cases, SLD was accompanied by BOS in the small bowel lumen, as confirmed by the results of a hydrogen breath test [101 +/- 37 ppm (a normal value of < 20 ppm)]. After a 14-day course of therapy with the combined probiotic bifiform, restoration of eubiosis in the small bowel lumen was achieved in 70.8% of the patients, as shown by the lesser degree of BOS (86.9 +/- 40.9 and 17.4 +/- 6.6 ppm before and after treatment, respectively; p < 0.01) and by normalization of the lactase test (p < 0.01). In the comparative placebo group, 68.4% showed no clear positive changes, SLD and BOS remained. CONCLUSION: The changes in the small bowel intraluminal microflora, which developed after prior intestinal infection, played a great role in the development of SLD. Bifiform belongs to the currently available probiotics and may be recommended to correct SLD in patients with PIBS resulting from the impaired microbiota of the small bowel and to prevent BOS. PMID- 23653935 TI - [Diagnostic value of serum markers of fibrosis in chronic liver diseases]. AB - AIM: To estimate the diagnostic value (DV) of direct markers of liver fibrosis, such as type IV collagen (C-IV), hyaluronic acid (HA), tissue inhibitor of metalloproteinases-1 (TIMP-1) in combination with indirect markers of fibrosis, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (gamma-GTP), alkaline phosphatase (ALP), platelets, tumor necrosis factor-alpha (TNF-alpha) in evaluating liver fibrosis. SUBJECTS AND METHODS: Sixty-seven patients with chronic diffuse liver diseases were examined. ALT, AST, gamma-GTP, and ALP were determined as indirect indicators of fibrosis. The levels of TIMP-1, HA, C-IV, and TNF-alpha were estimated by ELISA; the stage of fibrosis was determined by the results of indirect liver ultrasound fibroelastography (FE). RESULTS: According to the results of FE, the patients were divided into 2 groups: 1) (n = 25) F < or = 2 METAVIR and 2) (n = 42) F3-F4. While estimating DV of severe fibrosis stages (F3-F4), the area under the ROC curve (AUC) increased for platelets, HA, and C-IV. DV of ALT, AST declined with the higher degree of fibrosis. The highest ratio of test specificity and sensitivity (TSp and TSen) and AUC were observed for AST and HA. ALT and platelets showed low TSen, and TNF-alpha and TIMP-1 had no TSp. For evaluation of fibrosis (F4), a HA increase of over 57.7 ng/ml had 92.6% TSen and 67.5% TSp; for a C-IV elevation of above 133.1mkg/l, TSen was 85.2%, TSp was 57.5%; for a TIMP-1 rise from 24.4 ng/ml, TSen was 74.1% and TSp was 62.5%. For the diagnosis of fibrosis (F4) with a HA rise of more than 57.7 ng/ml, DV of a positive test was 65.8 (48.65-80.4; 95% CI) and that of a negative test was 93.1 (76.8-99.2; 95% CI). Thus, the negative rather than positive test results are of great diagnostic value for evaluation of the degree of fibrosis. CONCLUSION: The results of the investigation convincingly suggest that examination of the serum markers of fibrosis allows one to estimate with a high probability its presence and severity in patients with hepatic cirrhosis. The so-called direct markers (substances reflecting the biochemistry and regulation of fibrogenesis) are undoubtedly of great diagnostic value. PMID- 23653936 TI - [Cholagenic diarrhea is a type of postcholescystectomy syndrome]. AB - AIM: To study the role of biliary acids (BAs) in the pathogenesis of chronic diarrhea (CD) in patients undergoing cholecystectomy (CE). SUBJECTS AND METHODS: Twenty-five patients with post-CE diarrhea were examined. A comparison group consisted of 11 patients with diarrhea-predominant irritable bowel syndrome (IBS). The results of an examination of 15 healthy individuals were taken as normal values. Daily fecal BAs were determined by an enzyme spectrophotometric technique. RESULTS: In the patients after CE, daily fecal BA losses were found to be thrice as large as that in the healthy individuals. In the comparison group of patients with IBS, fecal bile excretion was not greater than the normal values. Stool normalization with a simultaneous decrease in fecal BA losses was seen in 92% of the post-CE patients receiving a course of therapy with adsorbents and astringents. CONCLUSION: Post-CE CD is a type of postcholescystectomy syndrome. PMID- 23653937 TI - [Gastrointestinal diseases and abdominal pain in combat veterans]. AB - AIM: To analyze the role of consequences of combat stress in the development of gastrointestinal tract (GIT) diseases. SUBJECTS AND METHODS: One hundred and sixty-one combat veterans aged 24 to 69 years were examined. All underwent a clinical and neurological examination using the McGill pain questionnaire (MPQ), Beck depression inventory, Kotenev trauma stress questionnaire, and visual analogue scale to determine pain intensity. Anxiety, impairments in memory and sleep, and depression were identified. The SF-36 questionnaire was used to estimate quality of life in the patients. Gastric secretory function was investigated; esophagogastroduodenoscopy, X-ray and ultrasound studies, clinical and biochemical blood tests, coprological examinations, fecal tests for dysbiosis, if indicated, occult blood were made. RESULTS: Combat stress and its consequences as posttraumatic stress disorder have been shown to play an important role in the pathogenesis of GIT diseases and in the development of chronic abdominal pain. GIT diseases in combat veterans are in larger measure a sequel of impaired processes of adjustment to combat stress. Chronic abdominal pains were heterogeneous. On the one hand, chronic GIT disease serves as a source of pain syndrome; on the other hand, the central nervous system is of importance in the development of chronic abdominal pain. CONCLUSION: In addition to therapy for GIT and hepatobiliary diseases, the treatment of GIT diseases in this category of patients involves psychotherapy and neuroprotection, aimed at reducing the consequences of combat stress in combat veterans. PMID- 23653938 TI - [Clinical characteristics of dyspepsia in patients with diabetes mellitus type 2]. AB - AIM: To estimate the prevalence of dyspepsia and to study its clinical manifestations and risk factors in patients with type 2 diabetes mellitus. SUBJECTS AND METHODS: One hundred and seven patients with type 2 DM and 33 with functional dyspepsia were examined. A clinical and laboratory study and testing were made to identify the symptoms of dyspepsia; dyspepsia-associated factors were studied. RESULTS: Dyspepsia was observed in 71.0% of the examined patients with type 2 DM. It may be attributed to organic gastrointestinal tract (GIT) diseases only in 42.3% of cases. In the type 2 DM patients, dyspepsia that could not be explained by organic GIT diseases was mainly manifested by a dyskinetic type while an ulcer-like type was prevalent in those with organic GIT diseases. In the patients with type 2 DM, dyspepsia that could not be accounted for GIT diseases was associated with the duration of carbohydrate metabolism disturbance, the presence of diabetic complications, Helicobacter pylori infection, and patient age. Some symptoms of dyspepsia (repletion and epigastric discomfort), which could not be explained by organic GIT diseases in patients with type 2 DM were associated with diabetic complications and carbohydrate metabolic parameters. CONCLUSION: Dyspepsia in type 2 DM was observed in 71% of cases; it can be due to organic GIT diseases in 42.3% and its association with digestive organ pathology was not revealed in 57.7%. PMID- 23653939 TI - [IgG4-related disease: patient group characterization and rituximab therapy]. AB - AIM: To characterize a group of patients with IgG4-related disease (IgG4-RD) in a Russian population and to evaluate the efficiency of rituximab therapy. SUBJECTS AND METHODS: In 2009 to 2011, at the Research Institute of Rheumatology, Russian Academy of Medical Sciences, 30 patients (16 men and 14 women; mean age 44 years) were diagnosed with IgG4-RD that was confirmed by determination of serum IgG4 levels and immunohistochemical study of biopsy samples stained for IgG4-positive plasma cells. Seven patients received rituximab therapy. RESULTS: It was assumed at baseline that there were different types of neoplasias in 12 (40%), non Hodgkin's and Hodgkin's lymphomas in 10 (33.3%), Sjogren's syndrome in 5 (16.7%), and Wegener's granulomatosis in 3 (10%). When 2 or more locations were involved, the condition was regarded as multifocal fibrosclerosis (33.3%). Localized forms were revealed in 20 (66.7%) patients. Among them, the largest number of patients was those who had orbital pseudotumor, Mikulicz's disease, or retroperitoneal fibrosclerosis. The most common sites of involvement were orbits (66.7%), salivary glands (70%) and lymph nodes (36.7%). Comparison of serum IgG4 levels in 28 patients with IgG4-RD, 22 patients with Sjogren's disease, salivary and lacrimal gland lymphomas, and 10 healthy controls showed that the concentration of IgG4 was significantly higher in Group 1 (median 2.6 g/I; IQR 1.22-4.65 (p < 0.001). Tissue IgG4/IgG ratio varied from 25 to 50% and averaged 38%. A moire like pattern of varying fibrosis was noted in 83% of cases. Analysis of laboratory data revealed elevated C-reactive protein concentrations (46.7% with a mean of 39.5 mg/l; normal values < 5.0 mg/l), increased erythrocyte sedimentation rate (60% with a mean of 37.6 mm/h), hypergammaglobulinemia (30% with a mean of 29.4%; normal range 13-22%), and rheumatoid factor (23.3%). After rituximab therapy, all the patients showed a decrease of IgG4 levels to the normal levels and positive changes evidenced by visualization techniques (computed tomography, magnetic resonance imaging). CONCLUSION: IgG4-RD is a novel problem in modern medicine, which requires a multidisciplinary approach and further study. Rituximab therapy is a promising treatment. PMID- 23653940 TI - [Gluten-sensitive celiac disease associated with recurrent aphthous stomatitis and schizophrenia]. AB - The paper describes a clinical case of celiac disease with grade 3 malabsorption, which is associated with recurrent aphthous stomatitis and schizophrenia. On readmission after 8 months of strict adherence to his gluten-free diet, the patient was observed to be in clinical remission and to have normalized laboratory indices and immunological tests. The signs of recurrent stomatitis disappeared. However, the symptoms of the mental disease remained. PMID- 23653941 TI - [New possibilities for overcoming the secondary inefficiency of anti-cytokine therapy in patients with inflammatory bowel diseases]. AB - A search for ways to overcome the secondary inefficiency of anti-cytokine therapy (ACT) with infliximab (IFX) in patients with inflammatory bowel diseases (IBD) remains relevant and determines the need for new approaches to solving this problem. The secondary inefficiency of ACT has been found to depend on the level of antibodies to IFX (anti-IFX Ab). The Department of Intestinal Pathology, Central Research Institute of Gastroenterology, is investigating the mechanisms for the occurrence of primary and secondary inefficiency of ACT, as well as ways to overcome them by cultured allogenic bone marrow mesenchymal stromal cells (MSC). In the framework of the searching investigation evaluating the efficiency and safety of MSC in patients with IBD, the investigators revealed that was a phenomenon of a decrease in anti-IFX Ab and came to the conclusion that the secondary inefficiency of ACT should be overcome in a patient with ulcerative colitis (UC). The elevated anti-IFX Ab levels were directly associated with the worsening clinical and endoscopic picture of UC and with the enhanced activity of an inflammatory process. The administration of cultures MSC contributed to lower anti-IFX Ab levels, overcome secondary inefficiency (an escape phenomenon) during ACT, and enhanced IFX sensitivity. The clinical observation indicated that MSC administration reduced anti-IFX concentrations and promoted UC remission during IFX therapy. Thus, MSC transplantation can be considered as a promising method for overcoming the secondary inefficiency of ACT, which aids in increasing the previously lost response to anti-inflammatory therapy. PMID- 23653943 TI - [Difficulties and errors in the management tactics of patients with chronic pancreatitis]. AB - The paper deals with the difficulties and errors that are most commonly used in clinical practice to manage patients with chronic pancreatitis (CP). The higher interest in CP is inspired by the wide prevalence of this disease with its constant upward trend. At the same time, a variety of the etiological forms of CP, from generically determined to infectious and autoimmune ones, in combination with a weak theoretical basis in a number of practitioners gives rise to a broad spectrum of tactical errors in the management of patients with CP. The paper summarizes and analyzes the most common defects and errors in the management tactics of patients with this nosological entity, including the aspects of diagnosis and medical treatment. Ways to solve the set optimization problems in management protocols for patients with CP are proposed in the context of evidence based medicine. PMID- 23653942 TI - [Diagnostic difficulties and remission criteria of autoimmune pancreatitis]. AB - The paper describes a clinical case in a 56-year-old female patient who has been suffering from chronic autoimmune pancreatitis, chronic recurrent cholangitis for 3 years. It demonstrates diagnostic difficulties at the early stage of the disease, the specific features of its course, the sequence of treatment in the patient, and problems in choosing a therapy option to achieve a remission. PMID- 23653944 TI - [Helicobacter pylori eradication: current status]. AB - The paper gives an update on the efficiency of Helicobacter pylori eradication. Triple therapy (a proton pump inhibitor + clarithromycin + amoxicillin) therapy is shown to hold top positions as first-line therapy for H. pylori eradication as before. The leading second-line therapy regimens are quadruple and 10-day triple schemes including levofloxacin. This point of view is supported by the Russian Gastroenterology Association. To reduce an increase in H. pylori resistance to clarithromycin, it is advisable to use Klacid (generic name: clarithromycin) in the eradication schemes. PMID- 23653945 TI - [Boceprevir: new possibilities for antiviral treatment of chronic hepatitis C]. AB - The given clinical review covers current antiviral therapy for chronic hepatitis C. Traditional antiviral therapy with pegylated interferon-alpha and ribavirin in patients with chronic hepatitis C virus genotype 1 allows a sustained virological response (SVR) to be achieved in no more than 40% of the treated patients. The practical introduction of the third component of the therapy as direct-acting antiviral agents makes it possible to substantially increase SVR, on the one hand, and to reduce treatment time, on the other hand. This review carefully analyzes the results of clinical trials of boceprevir (a new direct-acting antiviral agent and an NS3 serine protease inhibitor) that, when incorporated into an antiviral therapy regimen with pegylated interferons and ribavirin, considerably improves treatment results in patients with chronic hepatitis C virus genotype 1. Also, it discusses the safety and tolerance of drugs that belong to the class of hepatitis C virus serine protease inhibitors, as well as the problem of viral resistance. PMID- 23653946 TI - [Antibiotic-associated diarrhea in clinical practice]. AB - Antibiotic-associated diarrhea (AAD) is considered to mean at least 3 shapeless stool episodes within 2 or more consecutive days when using antibacterial agents. Due to the fact that antibiotics are used most commonly to treat many diseases, AAD is one of the topical problems for different clinical specialists. There has recently been increased interest in this condition due to its higher morbidity and mortality rates and the emergence of novel treatment-resistant virulent strains of Clostridium difficile 027 and 078/126. The paper discusses the possible risk of developing AAD depending on the class of the antibiotic used, as well as the mechanisms of its development. Infectious diarrhea most frequently results from bacterial overgrowth due to that the obligate intestinal microflora is suppressed by antibacterial drugs. C. difficile, Clostridium perfringers, Staphylococcus aureus, Salmonella spp., Klebsiella oxytoca, and Candida spp. are etiological factors in the development of this diarrhea. The severest intestinal lesions include pseudomembranous colitis (PMC) caused by C. difficile. The clinical and endoscopic picture and methods for the diagnosis and treatment of PMC are described. Therapy for this menacing condition is traditionally based on the use of metronidazole and vancomycin. In 2011, the US Food and Drug Administration approved the new drug fidaxomycin whose superiority over vancomycin has been demonstrated by a recurrence criterion. The paper discusses in detail other treatment options, including the use of probiotics. PMID- 23653947 TI - [Serotoninergic regulation of colonic motor function]. AB - The review deals with the serotoninergic regulation of colonic motor function. Serotonin (HT), its receptors and transporter, the enzymes of synthesis and degradation, play an important role in the regulation of colonic motor activity. Activation of 5-HT1, 5-HT2B, 5-HT3, and 5-HT4 receptors leads to increased colonic motor function. The elevation of serotonin levels determines the higher sensitivity of the colonic wall in irritable bowel syndrome. Serotonin plays a pathogenetic role in the development of ulcerative colitis and colostasis. PMID- 23653948 TI - [Progress in endoscopy-based diagnosis of small bowel diseases]. AB - The paper deals with new endoscopic imaging techniques for evaluating the mucosa of deep intestinal segments, mainly the small bowel. It shows the history of an enteroscopic method and its technical capabilities. Some pathological conditions for which deep enteroscopic techniques are best suited are characterized. PMID- 23653949 TI - [S.P. Botkin and his works in gastroenterology (on the occasion of the 180th anniversary of his birth]. PMID- 23653950 TI - [12th Congress of the Scientific Society of Gastroenterology of Russia, 38th session of the Central Research Institute of Gastroenterology]. PMID- 23653951 TI - Response to letter to the editor. PMID- 23653952 TI - Surgery, virtual reality, and the future. AB - MMVR has provided the leading forum for the multidisciplinary interaction and development of the use of Virtual Reality (VR) techniques in medicine, particularly in surgical practice. Here we look back at the foundations of our field, focusing on the use of VR in Surgery and similar interventional procedures, sum up the current status, and describe the challenges and opportunities going forward. PMID- 23653953 TI - The patient comes first. PMID- 23653954 TI - Alternative medicine needed in undergraduate medical education. PMID- 23653955 TI - Efficacy of preparation solutions and cleansing techniques on contamination of the skin in foot and ankle surgery: A systematic review and meta-analysis. AB - We report a systematic review and meta-analysis of published randomised and quasi randomised trials evaluating the efficacy of pre-operative skin antisepsis and cleansing techniques in reducing foot and ankle skin flora. The post-preparation culture number (Post-PCN) was the primary outcome. The data were evaluated using a modified version of the Cochrane Collaboration's tool. We identified eight trials (560 participants, 716 feet) that met the inclusion criteria. There was a significant difference in the proportions of Post-PCN between hallux nailfold (HNF) and toe web spaces (TWS) sites: 0.47 vs 0.22, respectively (95% confidence interval (CI) 0.182937 to 0.304097; p < 0.0001). Meta-analyses showed that alcoholic chlorhexidine had better efficacy than alcoholic povidone-iodine (PI) at HNF sites (risk difference 0.19 (95% CI 0.08 to 0.30); p = 0.0005); a two-step intervention using PI scrub and paint (S&P) followed by alcohol showed significantly better efficacy over PI (S&P) alone at TWS sites (risk difference 0.13 (95% CI 0.02 to 0.24); p = 0.0169); and a two-step intervention using chlorhexidine scrub followed by alcohol showed significantly better efficacy over PI (S&P) alone at the combined (HNF with TWS) sites (risk difference 0.27 (95% CI 0.13 to 0.40); p < 0.0001). No significant difference was found between cleansing techniques. PMID- 23653956 TI - Patients before targets. PMID- 23653957 TI - Complications of stomas: their aetiology and management. AB - The formation of a stoma is an essential part of many colorectal operations. Despite the frequency with which these surgeries are performed and the number of specialists involved in stoma care, complications are still common. This article investigates the most common complications, explains the reasons for their occurrence and suggests potential management options. Common stoma complications were identified by the colorectal/ stoma clinical nurse specialist (CSCNS) and a literature search was performed using a variety of online databases, including Medline and CINAHL using the keywords stoma, complications, prolapse, ischaemia, retraction, hernia and stenosis. Articles used were selected on the basis of relevance to the topic. The commonest complications of stomas included skin irritation, prolapse, retraction, ischaemia, hernia and stenosis. PMID- 23653958 TI - Profits before people? The risks of selling antibiotics. PMID- 23653959 TI - Managing asthma in the community: a guide for nursing staff. AB - Asthma is an inflammatory condition which affects all age groups and causes significant and unecessary morbidity and mortality. Appropriate management will depend on making the correct diagnosis and offering suitable medication through a device that the patient can use. Where indicated, self management through the use of asthma action plans should be encouraged. PMID- 23653960 TI - The Department of Health's model for district nursing: supporting practice. PMID- 23653961 TI - The impact of out-of-hours service provision on end-of-life care. PMID- 23653962 TI - A decision model for community nurses providing bereavement care. AB - Community (district) nurses play a significant role in assisting and supporting bereaved informal carers (family members and friends) of recently decease clients of palliative care. Bereavement care demands a wide range of competencies including clinical decision-making. To date, little has been known about the decision-making role of community nurses in Australia. The aim of this study was to conduct in-depth examination of an existing data set generated from semi structured interviews of 10 community nurses providing follow-up bereavement care home visits within an area health service of a metropolitan region of Sydney, Australia. A grounded theory approach to data analysis generated a model, which highlights an interaction between 'the relationship','the circumstances' (surrounding the bereavement),'the psychosocial variant', 'the mix of nurses', 'the workload', and 'the support' available for the bereaved and for community nurses, and elements of 'the visit' (central to bereavement care). The role of community nurses in bereavement care is complex, particularly where decision making is discretionary and contingent on multiple variables that effect the course of the family's grief. The decision model has the potential to inform community nurses in their support of informal carers, to promote reflective practice and professional accountability, ensuring continuing competence in bereavement care. PMID- 23653963 TI - Caseload management: an approach to making community needs visible. AB - AIM: To explore the process employed in the development of a population health framework and documentation for managing community nursing caseloads. BACKGROUND: No formal structure exists to validate and link local health information collected by Irish public health nurses to a wider epidemiological framework. Neglect of this bottom up information forfeits opportunities to resource and manage public health nursing services. DESIGN: Action research methods guided the development of the framework in one geographic area in Dublin and 34 participants engaged in Stringer's (1996) Look, Think and Act cycle. RESULTS: The framework identified four patient registers: family health, chronic sick/disability, older adults and acute care, which identify public health outcomes for discussion within the caseload analysis process and can predict risk factors in local populations. CONCLUSIONS: The use of the developed documentation identified a framework that describes caseloads in primary care and provides nurse managers with an evidence base to allocate resources, match skill mix to need, and estimate future workforce requirements. PMID- 23653964 TI - When to allow or deny adult access to children's health records. AB - The Data Protection Act 1998, section 7, has long granted patients the right of access to their health records. The right is exercised by a subject access request and a person with parental responsibility may exercise this right on behalf of a child. However, once the child is considered Gillick competent then a subject access request to a child's records must only be granted with the consent of the child. In this article the author sets out the requirements for a subject access request and why community nurses and specialist practitioners must proceed with caution when a request is received in respect of a child from the age of 12 years. PMID- 23653965 TI - Mobile technology in practice. PMID- 23653966 TI - Niche construction theory: a practical guide for ecologists. AB - Niche construction theory (NCT) explicitly recognizes environmental modication by organisms ("niche construction") and their legacy overtime ("ecological inheritance") to be evolutionary processes in their own right. Here we illustrate how niche construction theory provides usedl conceptual tools and theoretical insights for integrating ecosystem ecology and evolutionary theory. We begin by briefly describing NCT, and illustrating how it deifers from conventional evolutionary approaches. We then distinguish between two aspects ofniche construction--environment alteration and subsequent evolution in response to constructed environments--equating the first of these with "ecosystem engineering." We describe some of the ecological and evolutionary impacts on ecosystems of niche construction, ecosystem engineering and ecological inheritance, and illustrate how these processes trigger ecological and evolutionary feedbacks and leave detectable ecological signatures that are open to investigation. FIinally, we provide a practical guide to how NCT could be deployed by ecologists and evolutionary biologists to aeplore ecoeoolutionay dynamics. We suggest that, by highlighting the ecological and evolutionay ramifications of changes that organisms bring about in ecosystems, NCT helps link ecosystem ecology to evolutionary biology, potentially leading to a deeper understanding of how ecosystems change over time. PMID- 23653967 TI - Management of dental-oral procedures in patients with hereditary angioedema due to C1 inhibitor deficiency. AB - BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) has considerable implications for dental health care providers, since dental procedures may trigger severe and even life-threatening episodes. The aim of the present study was to analyze the efficacy and safety of premedication with attenuated androgens (AAs), plasma-derived human C1 esterase inhibitor concentrate (pdhC1INH), or both to prevent the development of upper airway angioedema after dental-oral procedures in patients with HAE-C1-INH. MATERIAL AND METHODS: All dental-oral procedures performed on patients with HAE-C1-INH who were followed up at La Paz University Hospital, Madrid, Spain were reviewed. Demographic data, maintenance treatment, preprocedure prophylaxis, disease severity, and occurrence of upper airway angioedema were recorded. RESULTS: Twenty-four patients (14 male/10 female; mean age, 42.6 years) underwent 66 procedures. Most procedures were performed on patients with severe HAE-C1-INH (20 procedures) or moderate HAE-C1-INH (26 procedures). Only 9 procedures were performed without short-term prophylaxis. Mild upper airway angioedema developed after 3 procedures performed without short-term prophylaxis in patients with minimal or asymptomatic HAE-C1-INH. A statistically significant association was found between development of mild postprocedure upper airway angioedema and lack of maintenance treatment with AA, lack of increased dose of preprocedure AA, and failure to administer preprocedure pdhC1INH (P = .002, Fisher exact test). CONCLUSIONS: Increased doses of prophylactic AA, administration of pdhC1INH, or both were good options for ambulatory management of dental-oral procedures in patients with HAE-C1-INH. Prophylaxis with pdC1INH or increased doses of AA is advisable before dental-oral procedures, even in patients with low disease severity. PMID- 23653968 TI - Markers of airway inflammation in the exhaled breath condensate of preschool wheezers. AB - BACKGROUND: Leukotrienes (LT), isoprostanes, and nitrites/nitrates are biomarkers of airway inflammation and oxidative stress that can be detected in exhaled breath condensate (EBC). The aim of this study was to evaluate LTB4, LTE4, 8 isoprostane, and nitrite/nitrate levels in the EBC of healthy and wheezing preschool children. METHODS: We included 21 healthy nonatopic children and 25 patients with recurrent wheezing episodes in a cross-sectional study. LTB4, LTE4, and 8-isoprostane concentrations were measured directly in EBC using a specific enzyme immunoassay; nitrite/nitrate concentrations were measured using a colorimetric assay. RESULTS: LTB4 concentrations were higher in children with wheezing episodes than in healthy controls (76 pg/mL vs 20 pg/mL, P < .001). LTE4 was increased in children with wheezing episodes than in healthy controls (68 pg/mL vs 35 pg/mL, P < .001). Nitrite concentrations were higher in children with wheezing episodes than in healthy controls (14 pg/mL vs 9.7 pg/mL, P < .03). We found no differences in 8-isoprostane and nitrate concentrations between the patients and the healthy controls. CONCLUSIONS: Our findings suggest that EBC is a suitable noninvasive method for the assessment of airway inflammation and oxidative stress in preschool children. Levels of LTB4, LTE4, and nitrites were higher in children with recurrent wheezing episodes than in healthy controls. PMID- 23653969 TI - ESPRINT-15 questionnaire (Spanish version): reference values according to disease severity using both the original and the modified ARIA classifications. AB - OBJECTIVE: ESPRINT-15 is a specific and validated instrument to measure health related quality of life in adults with allergic rhinitis. The aim of this study was to obtain new reference values based on disease severity using both the original and the modified versions of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines. METHODS: ESPRINT-15 was administered to a representative sample of adults with allergic rhinitis in Spain. As in a previous study by our group, means and percentiles were analyzed for 16 quotas based on gender, allergic rhinitis type (intermittent vs persistent), and 4 symptom intensity groups according to the total symptom score (TSS4). The novel aspect of the present study was our application the severity criteria proposed by both the original and the modified ARIA classifications. RESULTS: Of the 2756 patients in our previous dataset, 2580 were included in the present analysis. In terms of symptom severity, women ha relatively more intense symptoms than men with both ARIA classifications. In fact, using only the modified ARIA classification, we were abl to determine that severe rhinitis is moderately more frequent in women (27% vs 23%), although the difference is not statistically significant. CONCLUSIONS: The new set of reference values enables the ESPRINT-15 questionnaire to be adapted to the current severity classification Consequently, this quality of life tool (http://www.seaic.org/inicio/esprint) can be easily used and better interpreted in daily clinical practice. PMID- 23653970 TI - Immune responses to tyrophagus putrescentiae-induced airway inflammation in mice. AB - BACKGROUND: Storage mites are a source of aeroallergens that affect patients with allergic rhinitis and asthma. Tyrophagus putrescentiae is a causative factor of airway hypersensitivity, but the mechanisms and pathogenesis of Tputrescentiae induced allergy are not well understood. OBJECTIVE: This study aimed to develop a murine model of T putrescentiae-induced allergic asthma. METHODS: Immune responses and physiologic variations in immunoglobulins (Ig), leukocyte subpopulations, cytokines, gene expression, pulmonary function, and lung pathology were evaluated after intraperitoneal sensitization and intratracheal challenge with crude extract of T putrescentiae. RESULTS: After sensitization with aluminum hydroxide and challenge with T putrescentiae in mice, levels of T putrescentiae-specific IgE and IgG1 in sera increased significantly compared to the normal saline group (P < .01): Values for inflammatory leukocytes (neutrophils and eosinophils) and cytokines (interleukin [IL] 4, IL-5, and IL-13) increased significantly after sensitization. In terms of pulmonary function, pause values were significantly enhanced in T putrescentiae-sensitized mice after intratracheal challenge with T putrescentiae (P < .05). Expression of type 2 helper T cell (T(H)2)-related genes (IL4, IL5, IL13, and RANTES), T(H)2-specific transcription factor (GATA-3), and proinflammatory genes (IL6), and T(H)(H)17 related genes (IL17F) increased significantly after airway challenge. Sensitization with T putrescentiae crude extract led to inflammation of lung tissue, thickening of the tracheal wall, and tracheal rupture. CONCLUSIONS: Intraperitoneal sensitization followed by intratracheal challenge with crude extract of T putrescentiae can induce airway inflammation in BALB/c mice. The symptoms observed in a mouse model of allergic asthma, in terms of immune and clinical parameters, are reminiscent of the symptoms of allergic asthma in humans. A mouse model can be used to evaluate the therapeutic effectiveness of drugs on T putrescentiae-induced airway inflammation in humans. PMID- 23653971 TI - Serum tryptase concentrations in beekeepers with and without Hymenoptera venom allergy. AB - BACKGROUND: Increased tryptase concentrations are a risk marker for the severity of reactions to Hymenoptera stings or venom immunotherapy OBJECTIVE: To investigate serum tryptase concentrations in beekeepers with and without Hymenoptera venom allergy (HVA). METHODS: Serum tryptase concentrations were measured in adult patients with HVA (n = 91, 37 of whom were beekeepers), beekeepers without HVA (n = 152), and control individuals from the general adult population (n = 246). RESULTS: Multivariate analyses revealed that serum tryptase levels were positively associated with beekeeping activities (P < .001) and HVA (P < .001). Tryptase levels were also positively associated with age (P < .001) and male'sex (P = .02), and negatively associated with alcoho consumption (P = .002). CONCLUSIONS: Beekeeping and HVA are independently associated with increased concentrations of serum tryptase. PMID- 23653972 TI - Tomato allergy: clinical features and usefulness of current routinely available diagnostic methods. AB - BACKGROUND: Tomato contains many allergens but their clinical relevance is poorly defined and the usefulness of available diagnostic methods is unknown. OBJECTIVE: To assess the clinical usefulness of current diagnostic methods for tomato allergy. METHODS: Ninety-six adults with plant food allergy were grouped based on their reactivity to PR-10, profilin, and lipid transfer protein (LTP). Tomato allergy was ascertained by history and a positive skin prick test (SPT) to fresh tomato. SPT with a commercial extract and immunoglobulin (Ig) E measurements were carried out. RESULTS: In total, 36%, 8%, 28%, 18%, 8%, and 1% of patients were sensitized to PR-10, profilin, both PR-10 and profilin, LTP alone, LTP plus PR-10 or profilin, and genuine tomato allergens, respectively. Tomato allergy was detected in 32 (33%) of the 96 patients and was significantly associated with profilin hypersensitivity (P < .001). The sensitivity of SPT was good in all subgroups, but specificity was poor in many cases. ImmunoCAP sensitivity was acceptable in profilin reactors, but very poor in PR-10 reactors. IgE levels were not associated with tomato allergy in any of the subgroups. Similarly, birch and peach-specific IgE levels were not associated with tomato allergy in PR 10/profilin or in LTP reactors, respectively. Both SPT and ImmunoCAP worked well in the only patients with true tomato allergy. Birch- and tomato-specific IgE levels were not associated in patients monosensitized to PR-10, but they were correlated in profilin groups (P < .005). Peach- and tomato-specific IgE levels were correlated (P < .001) in LTP-allergic patients. CONCLUSIONS: Tomato allergy occurs via sensitization towards different proteins. Component-resolved diagnosis helps to define clinical subgroups with different risk levels. PMID- 23653973 TI - Profile of latex sensitization and allergies in children and adolescents with myelomeningocele in Sao Paulo, Brazil. AB - BACKGROUND: Latex allergy is an important cause of occupational allergy. In many countries the prevalence of latex allergy is still high and the profile of latex sensitization is unknown. OBJECTIVES: To evaluate the frequency of sensitization and allergy to latex in children and adolescents with myelomeningocele and to identify associated risk factors. METHODS: The study included 55 children and adolescents with myelomeningocele followed at a specialized center. In addition to a standard questionnaire and skin prick tests (SPTs) to aeroallergens and total latex, the patients underwent determination of total and specific serum IgE to latex and recombinant allergens. RESULTS: We observed a prevalence of 25% for latex sensitization and of 20% for latex allergy. Twenty-four patients (43.6%) were atopic and the average age for the first reaction to latex was 44.5 months. Cutaneous reactions were the most frequently reported reactions (72.7%). Specific immunoglobulin (Ig) E to rHev b 1, rHev b 3, rHev b 5, rHev b 6.1, and rHev b 6.2 was detected in over 50% of patients allergic to latex. Multivariate analysis showed current asthma, atopy, and having undergone 4 or more operations to be risk factors for latex sensitization. CONCLUSIONS: Our study documented a high prevalence of sensitization and allergy to latex in patients with myelomeningocele. Specific IgE to rHev b 1, rHev b 3, rHev b 5, rHev b 6.1, and rHev b 6.2 was detected in over 50% of children and adolescents with myelomeningocele who are allergic to latex. A history of current asthma, atopy, and having undergone 4 or more operations were independent risk factors for latex allergy. PMID- 23653974 TI - A novel CD40 ligand mutation in a patient with pneumonia, neutropenia, and hyperimmunoglobulin M phenotype. PMID- 23653975 TI - Changes in BAFF/APRIL levels in a 2-year-old girl with Kawasaki disease refractory to intravenous immunoglobulin therapy. PMID- 23653976 TI - Allergen stimulation induces simultaneous production of type 2 helper T cells and regulatory cytokines in patients with pollen allergy. PMID- 23653977 TI - DRESS syndrome involving 2 unrelated substances: imipenem and iodinated contrast media. PMID- 23653978 TI - Has sensitization to cockroach allergens changed during the last 17 years in the urban atopic population living in Naples (Southern Italy)? PMID- 23653979 TI - Perphenazine as a cause of mother-to-daughter contact dermatitis and photocontact dermatitis. PMID- 23653980 TI - Toxic epidermal necrolysis successfully treated with infliximab. PMID- 23653981 TI - Observational study of the safety of a cluster schedule for subcutaneous immunotherapy in a pediatric population. PMID- 23653982 TI - Novel mutation of IL2RG gene in a Korean boy with X-linked severe combined immunodeficiency. PMID- 23653983 TI - Food allergy to caper (Capparis spinosa). PMID- 23653984 TI - Early diagnosis of an allergic reaction to cisatracurium. PMID- 23653985 TI - Intravenous immunoglobulin in urticaria. PMID- 23653986 TI - Cypress-sensitized asymptomatic patients during the pollen season: sensitization or simply cross-reactivity? PMID- 23653987 TI - Epilepsy and agrression: prejudice and facts. PMID- 23653988 TI - Quadriceps tendon injuries. AB - INTRODUCTION: The aim of study was to analyze risk factors, mechanisms of injury, symptoms and time that elapsed from injury until operation of complete quadriceps tendon ruptures. MATERIAL AND METHODS: This retrospective multicenter study included 30 patients operated for this injury, of whom 28 (93.3%) were men. The average age was 53.7 years (18-73). Twenty-six patients had reconstruction of unilateral rupture and four of bilateral one. RESULTS: Eighty percent of them had some risk factors for rupture of the tendon with degenerative changes. Eight patients had diabetes, seven patients were on renal dialysis, two patients had secondary hyperparathyroidism, five patients were obese and two patients had former knee operations. These injuries occurred in 80% following minor trauma caused by falls on stairs, on flat surfaces and squatting. The most frequent symptoms were: pain, swelling, lack of extension of knee and defect above patella, and three cases were initially misdiagnosed. During the first 10 days after injury, acute and chronic ruptures were reconstructed in 22 (73.3%) and 8 patients, respectively. CONCLUSION: Quadriceps tendon injuries most often happen to male patients with predisposing conditions in their fifth and sixth decade of life due to trivial trauma. Patients on renal dialysis are the most vulnerable population group. PMID- 23653989 TI - Analysis of electrocardiogram in chronic obstructive pulmonary disease patients. AB - INTRODUCTION: Chronic obstructive pulmonary disease is the fourth leading cause of mortality worldwide. It is defined as a persistent airflow limitation usually progressive and not fully reversible to treatment. The diagnosis of chronic obstructive pulmonary disease and severity of disease is confirmed by spirometry. Chronic obstructive pulmonary disease produces electrical changes in the heart which shows characteristic electrocardiogram pattern. The aim of this study was to observe and evaluate diagnostic values of electrocardiogram changes in chronic obstructive pulmonary disease patients with no other comorbidity. MATERIAL AND METHODS: We analyzed 110 electrocardiogram findings in clinically stable chronic obstructive pulmonary disease patients and evaluated the forced expiratory volume in the first second, ratio of forces expiratory volume in the first second to the fixed vital capacity, chest radiographs and electrocardiogram changes such as p wave height, QRS axis and voltage, right bundle branch block, left bundle branch block, right ventricular hypertrophy, T wave inversion in leads V1-V3, S1S2S3 syndrome, transition zone in praecordial lead and QT interval. RESULTS: We found electrocardiogram changes in 64% patients, while 36% had normal electrocardiogram. The most frequent electrocardiogram changes observed were transition zone (76.36%) low QRS (50%) and p pulmonale (14.54%). Left axis deviation was observed in 27.27% patients. CONCLUSION: Diagnostic values of electrocardiogram in patients with chronic obstructive pulmonary disease suggest that chronic obstructive pulmonary disease patients should be screened electrocardiographically in addition to other clinical investigations. PMID- 23653990 TI - [Different response to human recombinant erythropoietin in patients undergoing hemodialysis treatment]. AB - INTRODUCTION: Treatment with recombinant human erythropoietin enabled the correction of anemia in the patients on regular hemodialysis but large individual differences in the dose required to achieve the target hemoglobin level were observed. In this study the erythropoietin resistance index was calculated in patients on hemodialysis in order to examine variations in the response to erythropoietin and factors that influence it. MATERIAL AND METHODS: The study included 48 patients (25 males) of mean age 67.5 years, who had been on regular hemodialysis in Samac for 43.9 months on average. All were treated with erythropoietin from the beginning of hemodialysis treatment. Their response to erythropoietin therapy was estimated by the erythropoietin resistance index. RESULTS: The use of erythropoietin enabled the correction of anemia but different doses were needed to achieve and maintain the target hemoglobin level. The individual weekly dose of erythropoietin ranged from 15 U/kg/week to 244 U/kg/week and the erythropoietin resistance index ranged from 0.13 U/kg/week/g/l to 2.46 U/kg/week/g/l. A satisfactory erythropoietin response with erythropoietin resistance index below 0.5 U/kg/week/g/l was found in 14 (30%) patients, while 19 (40%) patients had this index above 0.7 U/kg/week/g/l and 10 (21%) above 0.9 U/kg/week/g/l. Multivariate linear regression analysis detected C-reactive protein as a significant predictor of erythropoietin resistance index. CONCLUSION: Target hemoglobin levels were achieved and maintained by different doses of erythropoietin in individual patients, which resulted in great individual differences in response as estimated by the erythropoietin resistance index. Multivariate analysis indicated C-reactive protein as a variable significantly associated with this index. PMID- 23653991 TI - Vojvodinascore--local system for cardiac operative risk evaluation. AB - INTRODUCTION: The aim of the study was to investigate the prognostic value, sensitivity and specificity of both the logistic and additive European System for Cardiac Operative Risk Evaluation (as well as the European System for Cardiac Operative Risk Evaluation II and to assess the necessity for developing a local outcome prediction model in cardiac surgery. MATERIAL AND METHODS: The research included 406 consecutive patients who had undergone cardiac surgical procedures at Institute of Cardiovascular Diseases of Vojvodina from January 2012 to July 2012. The authors compared the predicted mortality according to the additive and logistic European Systems for Cardiac Operative Risk Evaluation, the new European System for Cardiac Operative Risk Evaluation II and the observed mortality (30 days after surgery). RESULTS: The difference between the predicted and observed mortality regarding the whole group of 406 operated cardiac patients was not statistically significant for the additive European System for Cardiac Operative Risk Evaluation (p = 0.081) and the European System for Cardiac Operative Risk Evaluation II (p = 0.164), but it was statistically significant for the logistic European System for Cardiac Operative Risk Evaluation (p = 0.031). The areas under the receiver operating characteristic curves are statistically different from 0.5 for both models (additive and logistic European System for Cardiac Operative Risk Evaluation), as well as for the European System for Cardiac Operative Risk Evaluation II. However, the proper classification of the patients has not been observed since their sensitivity and specificity are not satisfactory. CONCLUSION: The additive and logistic European Systems for Cardiac Operative Risk Evaluation overestimate while the European System for Cardiac Operative Risk Evaluation II underestimates the risk in cardiac surgery. We believe that a locally derived model would be of great use in the everyday clinical practice since it would faithfully illustrate the actual state of patient population of the region where it was developed. At the same time it would provide the accurate prediction of surgical outcome. PMID- 23653992 TI - [Nuchal translucency measurement--the effect of 3D/4D ultrasound]. AB - INTRODUCTION: Nuchal translucency thickness has undoubtedly been proven as an important marker in screening for chromosomal abnormalities. It is measured in the first trimester by ultrasound. This study was aimed at determining the effect of 3D/4D ultrasound on standard error of mean nuchal translucency measurements. MATERIAL AND METHODS: Having satisfied the inclusion criteria, 430 nuchal translucency measurements were analyzed (singleton pregnancies, 11(+0)-13(+6) weeks of gestation, crown rump length 45-84mm, postnatally confirmed absence of anomalies). The data were divided into two groups, depending on the method used (older generation 2D ultrasound or 3D/4D ultrasound). The reported nuchal translucency measurements were converted into multiple of median values of nuchal translucency and 95% confidence interval was calculated for the two sets of data. RESULTS: The standard error of mean values has decreased from 0.027, when nuchal translucency was mea-sured via 2D ultrasound, to 0.016 when 3D/4D ultrasound was used for the measurements. DISCUSSION: The detection rates of prenatal screening tests can be increased and the false positive rates can be decreased by lowering the standard error of mean value. CONCLUSION: Advanced technology and developed automated measuring ofnuchal translucency should result in further enhancements in early detection of fetal abnormalities. PMID- 23653994 TI - Influence of age and length of service on the level of stress and burnout syndrome. AB - INTRODUCTION: The burnout syndrome is a response to chronic emotional and interpersonal stressors which are related to workplace. Medicine is one of the professions at the greatest risk of suffering from burnout syndrome. The aim of this study was to assess the presence of stress and burnout syndrome in relation with age and length of service in the family medicine physicians in the Republic of Srpska. MATERIAL AND METHODS: The study was carried out on the basis of a questionnaire survey among family medicine physicians in seven Primary Health Care Centres in the Republic of Srpska from February 1st to April 30th 2010. The participants fulfilled the questionnaire for self-assessment of stress level and the Maslach Burnout Inventory, which were amended with data regarding age, sex, length of service and educational and vocational level. RESULTS: The study included 199 (83.3%) female and 40 (16.7%) male participants. The physicians aged over 46 years and with the length of service over 21 years had statistically significant higher level of stress and emotional exhaustion than younger participants and participants with shorter length of service. CONCLUSION: Age and length of service have important influence on the level of stress and burnout syndrome: the older the physicians and the higher the length of service the higher the level of stress and the higher the risk of burnout syndrome. PMID- 23653993 TI - Pulp vitality preservation after traumatic dental injuries to permanent teeth. AB - INTRODUCTION: The pulp vitality preservation after a trauma to permanent teeth is of great importance since dental injuries are common. The aim of our study was to investigate the pulp vitality preservation after tooth injuries. MATERIAL AND METHODS: A retrospective analysis of records of patients with a trauma was performed. The sample consisted of all patients who had been referred to the Department of Dentistry of Vojvodina for a trauma to permanent teeth during the period 2005-2010. We recorded the type of injury, treatment, state of vitality during the first visit and subsequent check-ups. RESULTS: The study included 162 children and adolescents aged 6-18 years having a trauma to 314 permanent teeth. The most frequent type of injuries in permanent teeth was fractures (54.5%), whereas luxation was a less common trauma (45.5%). Though different kinds of traumas have different optimal time for treatment, a period of 24 hours was taken as optimal; hence, 189 teeth were treated in optimal time and 55 complications occurred in them; while 105 complications occurred in 114 teeth which were treated 24 hours after the trauma. A year after the trauma the pulp vitality was preserved in 88 teeth (32%), pulp necrosis and other complications developed in 160 teeth (68%). CONCLUSION: The therapy of pulp vitality preservation in injured teeth was found successful in 32% and unsuccessful in 68% of cases at check-ups over one year. PMID- 23653995 TI - [Knowledge, attitudes and use of dietary supplement among students of the University of Nis (Serbia)]. AB - INTRODUCTION: Dietary supplements, being concentrated sources of vitamins, minerals and other substances with nutritional and physiological effects, are products that supplement the normal diet. The aim of this study was to determine the use, attitudes and knowledge on dietary supplements among students of the University of Nis, paying special attention to differences in responses between male and female students. MATERIAL AND METHODS: The study used the original questionnaire which was distributed to 330 students from the University of Nis. The sample was stratified by school, year of study and sex. Out of 330 questionnaires, 301 were classified as correct and they were further analyzed. RESULTS: Dietary supplements were used by 68.10% of the respondents. Females used dietary supplements more than males. Two or more products were most commonly used. Multivitamins were the most widely used products. The majority of respondents adhered to the declaration (77.07%). A small number had health damage (2.93%). More than half of the students stated that they were not properly informed about dietary supplements. The most common source of information was the media and friends. CONCLUSION: Health professionals and users of dietary supplements should be educated better on the use of these products in order to make the supplement use safe, controlled and rational. PMID- 23653996 TI - [Manufacturing process of high quality phytopreparation on example of herbal sedative]. AB - INTRODUCTION: Rational phytotherapy is a modern concept of using plant-originated drugs which has emerged from the need to improve phytotherapy in order to make the use of herbal remedies more efficient and safer. The aim of this study was to give the health-care workers more information on the manufacturing process of high quality phytopreparation following principles of Good Manufacturing Practice and Good Laboratory Practice on the example of herbal sedative, Odoval S capsules. MATERIAL AND METHODS: This study was designed to reflect the production process of a high-quality and safe herbal remedy, starting from defining the formulation and the production procedure to the quality control of raw materials, characterization of the final product, and testing stability of active ingredients in the capsules. RESULTS: Formulation of the phytopreparation, validation of the production process, quality control and stability testing, all together have resulted in the production of capsules with defined valeric acid content (1 mg valeric acid per capsule). DISCUSSION: The preparation is recommended to relieve the symptoms caused by chronic stress (anxiety, irritability, fatigue, lack of concentration, heart palpitations) and for mild insomnia. CONCLUSION: This paper presents the complete cycle of the production of a phytopreparation on the example of a new herbal sedative--Odoval S capsules. PMID- 23653997 TI - Carcinoma developing in a branchial cyst. AB - INTRODUCTION: The malignant transformation of the branchial cysts epithelium is rare and it represents separate entity called branchiogenic carcinoma. CASE REPORT: A 55-year-old male with fluctuating mass localized on the right side of the neck, was admitted to the Department of Maxillofacial Surgery, General hospital in Vrbas where cystic tumor 3 cm in its greatest dimension with friable, dark red wall below the front edge of the sternocleidomastoid muscle was revealed. The wall of the tumor was composed of lymphoid tissue with germinal centers. The internal surface of the cyst was lined with thin layered squamous epithelium that showed a transition from the normal, followed by the atypical epithelium, and the in situ carcinoma to the part corresponding to a poor differentiated invasive squamous carcinoma. Following the diagnosis of suspected branchiogenic carcinoma a radical neck dissection was performed. No elements of the tumor had been found in the sampled materials taken from striated muscle tissue, salivary gland tissue and reactive lymph nodes (n = 24). The patient was presented to Oncology Consilium, and radiotherapy was implemented. CONCLUSION: The definitive diagnosis must be based on histological features. A five-year monitoring of the patient is necessary to rule out cervical metastasis of this tumor. It is necessary for a five-year follow-up to rule out cervical metastasis of the tumor. PMID- 23653998 TI - [Mothers' resolution of their children's diagnosis of cerebral palsy]. AB - INTRODUCTION: The process of adaptation and acceptance of a child's diagnosis of cerebral palsy requires from parents to process the trauma caused by this knowledge cognitively and emotionally. Parents who manage to come to terms with their children's condition are labeled as resolved. As opposed to them, unresolved parents do not accept the reality of their children's condition and fail to overcome the crisis caused by knowledge of the child's diagnosis. Unresolved status has negative implications for the child, the parents and their relationship. CASE REPORTS: Two case reports of mothers whose children have been diagnosed to have cerebral palsy are given. The first case shows a resolved mother who managed to overcome the initial shock and started to feel a sense of relief from the period when she found out the child's diagnosis. In contrast, another case shows an unresolved mother with no significant changes in thoughts and feelings from the time since she learned the child's diagnosis. She was preoccupied with anger and attempted to minimize the child's problem. DISCUSSION: Interviews on reaction to diagnosis and reaction to diagnosis classification system allow identification of mothers' resolution of their children's diagnosis of cerebral palsy. The characteristics of resolved and unresolved maternal status are discussed. CONCLUSION: Parental resolution of diagnosis is essential for the successful adaptation to raising children with disabilities, as well as meeting the requirements of the parental role. It is important to recognize parental cognitions and feelings regarding the child's condition in order to direct psychotherapeutic interventions towards vulnerable population of parents. PMID- 23653999 TI - [Encapsulating peritoneal sclerosis--case report]. AB - INTRODUCTION: Encapsulating peritoneal sclerosis is a possible, serious, life threatening complication of peritoneal dialysis therapy. CASE 1: A female patient was hospitalized for clinical signs of encapsulating peritoneal sclerosis in the inflammatory stage with fever, intestinal occlusion, positive inflammatory syndrome (Le 20 K/microL,.CRP 217 mg/L) and highly turbid peritoneal effluent (Le 3.3 K/microL) with sterile culture. Risk factors for the development of encapsulating peritoneal sclerosis were nine previous episodes of peritonitis and long-term use of high osmolality dialysis solution. The diagnosis was confirmed by computed tomography findings. During the course of therapy, the patient had a good response to Tamoxifen and prednisone. Although encapsulating peritoneal sclerosis was well controlled, the patient died after eight months due to tuberculosis of the lungs with signs of heart failure. CASE 2: The clinical presentation also corresponded to encapsulating peritoneal sclerosis in the inflammation stage, and the identified risk factors were the long-term treatment with peritoneal dialysis (100 months) and an episode of peritonitis with tunnel infection. The first sign of encapsulating peritoneal sclerosis was hemorrhagic ascites, which was observed when the peritoneal catheter was being replaced. The diagnosis was confirmed by computed tomography findings. He was treated with Tamoxifen (10 mg 2x2 tbl). Except anemia, poor appetite and fatigue, the patient denied any other symptoms after 14 months of therapy. CONCLUSION: During peritoneal dialysis, one should always think about encapsulating peritoneal sclerosis which is not always easy to recognize. Timely diagnosis with the use of corticosteroids and Tamoxifen in the first and Tamoxifen in the second case were effective in controlling and preventing dise- ase progression. PMID- 23654000 TI - [Famous physicians from the past--Oribasisus from Pergamum]. AB - INTRODUCTION: Greek physician Oribasius from Pergamum (today's Bergama in western Turkey) (c. 320-400) was one of the most important physicians and personalities of his time. THE LIFE AND CAREER: Oribasisus studied medicine at Alexandria. Although he was the personal physician and friend of the Roman emperor Julian the Apostate, and a very important political figure of that period, he has been remembered as a most important medical writer and historian of medicine. MEDICAL WRITING: His major work, written in 70 books (only 25 of these survived), was the "Collectiones Medicae" which contains massive compilation of excerpts (epitomai) from the writings of older medical writers of the ancient world. Later on, he produced the "Synopsis for Eustathius" (Synopseos ad Eustathium) for his son Eustathius, who was also a physician. Oribasius dedicated a large work to his friend, the philosopher Eunapius: "Libri ad Eunapium", a kind of medical encyclopaedia in four volumes with a collection of easily procured medicines compiled for laymen. Several more of his writings are known to have been entirely lost. The works of Oribasius were translated in Latin as early as the fifth century, and later, in the medieval times his books were published in Europe (the "Synopsis for Eustathius" was published in 1554), while the critical edition of his works translated from Greek texts was published in Germany in 1926-1933. COMMENTARY AND CONCLUSION: The special importance of the Oribasius' works is that they have preserved a number of excerpts from many medical authors of antiquity whose writings would otherwise have been lost. Besides, these extracts (epitomai) were not entirely verbatim, they were looked upon critically and sorted out in an encyclopaedic manner. Because of that Oribasius is rightly considered to be the first writer of a medical encyclopaedia in the history of medicine. PMID- 23654001 TI - The development of internal fixation - historical overview. AB - Since the ancient times, man was faced with the problem of fracture treatment, which is first described in the records from ancient Egypt. Ever since, many treatment methods have been developed, but the real revolution in the fracture treatment was achieved by internal fixation. Since it was described for the first time, at the end of the 18th century, this method has continuously developed, but sterilization, radiographies, anaesthesiology, antibiotics made this surgery modern and safe. The great ideas and practical solutions of the new methods were done by Albin Lambotte, William Arbuthnot Lane, Robert Danis, William Hey Groves. They lead to the expansion of this method and truly made the principles for the future AO school. New methods, biological internal fixation, minimally invasive procedures, new technologies and devices for internal fixation are introduced in the surgical practice daily. PMID- 23654002 TI - The cardia: esophageal or gastric? Critical reviewing the anatomy and histopathology of the esophagogastric junction. AB - BACKGROUND: Discrepancy exists regarding the anatomical allocation of the cardia: esophageal or gastric. With this review we aimed to clarify this issue. METHODS: Using PUB MED, Scopus and Google we analyzed the recent literature (1889-2012) regarding the "esophageal" vs. the "gastric" cardia. RESULTS: The synonymous use of the term cardia to describe the anti reflux mechanism within the distal portion of the esophagus and the proximal segment of the stomach nourished the misunderstanding, that the cardia represents a normal anatomical structure interposed between the tubular esophagus and the body of the stomach. Anatomical, histopathological and physiological studies revealed that what has been taken for gastric cardia in fact represents reflux damaged dilated distal esophagus (DDE). Since DDE is covered by columnar lined esophagus (CLE) it cannot be differentiated from the proximal stomach during regular endoscopy. However, the histopathology of multi level biopsies obtained from the endoscopically suspected esophagogastric junction (EGJ) serves to allocate the origin of the columnar lined foregut, esophageal (cardiac, oxyntocardiac mucosa, intestinal metaplasia) vs. gastric (oxyntic mucosa). CONCLUSIONS: Neither the esophagus nor the stomach contains a "cardia". The recent misconceptions regarding the foregut anatomy explain, why the innermost coverage of the reflux damaged esophagus is termed "cardiac mucosa". Thus the term should be reserved to name the histopathology of cardiac and oxyntocardiac mucosa, which develop due to gastroesophageal reflux within the distal esophagus. PMID- 23654003 TI - [Effects of carbonic anhydrase inhibitors on pseudophakic corneal edema]. AB - INTRODUCTION: Acetazolamide as inhibitor of carbonic anhydrase, in glaucoma therapy, has an effect on lowering intraocular pressure. In addition to this primary effects, we attempted to determine the effect on the cornea after phacoemulsification. In our study, we determined the effects of systemically applied dose of 500 mg of acetazolamide on the edema, thickness, and corneal morphology after phacoemulsification ,with the Anterior Segment Optical Coherence Tomography (AS OCT). MATERIAL AND METHODS: The study included 53 patients who were divided into two groups. Groups were stratified by type of cataract (nuclear), age (62+/-1.5), preoperative visual acuity (5/60) Snellen table,and preoperative findings on AS-OCT. Phacoemulsification has done the same surgeon, with the same ultrasound probe length using ultrasonic force of the average value of 14 for a period of 72+/-2.5 seconds. Group of 33 patients were administered systemic acetazolamide at a dose of 250 mg per scheme 01 hours +24 hours after phacoemulsification (group I). Another group of 20 patients did not receive acetazolamide(group II). AS OCT recordings were performed before surgery, 6 hours and 24 hours after surgery. RESULTS: The mean value in both groups was 549+/-9 microm before surgery. Group I had average value of 648+/-6 microm after 6h, and the mean value was 612+/-4 microm after 24h. The group II,had a mean thickness of the cornea after 6 hours of 720+/-5 microm, and after 24 hours 708+/-4 microm. Morphological changes in the tomograms of the group I showed minimal creases Descemet's membrane. Postoperative visual acuity was 0,6,24h after the surgery in the I group of patients,and 0,3 in the II group. CONCLUSION: In our study the patients who administered systemic acetazolamide had significant reduction of central corneal thickness. The folds of Descemet's membrane and endothelial dysfunction in AS OCT tomograms showed less structural changes in group I. Significant better postoperative visual acuity in these patients is probably because of the smaller corneal edema after 24 h, which improves patients' comfort. PMID- 23654004 TI - Calcaneal fractures - the orthopaedic challenge. AB - Calcaneal fractures, since their description in 1843 by Malgaigne, still remain a challenge in orthopaedic surgery. They are significant from an epidemiological point of view - they represent 60% of all tarsal fractures, and of an increasing number of fractures due to traffic accidents and their outcome is unpredictable. In contrast to the disappointing results after nonoperative treatment and at the beginnings of calcaneal surgery, the outcome is promising nowadays. New imaging and fixation devices, with proper classification and indication for certain surgical procedures have led to the improved outcome. But, there are still controversies, and we emphasize the most rationale treatment for the calcaneal fractures, as well as best surgical options. PMID- 23654005 TI - Segment-oriented liver resections based on posterior intrahepatic glissonian approach. AB - BACKGROUND: Segment-oriented liver resections can be performed effective by posterior intrahepatic approach. A significance of such resection - is that they are oncologically radical as well as parenchyma-sparing. METHODOLOGY: Segmental liver resections were performed in 102 patients with liver tumors. Suprahilar control of the appropriate glissonean pedicle was achieved by the posterior intrahepatic approach. Liver parenchyma was transsected by ultrasonic dissector, under intermittent vascular occlusion (IVO). Pedicle was divided at the end of resection using "endo-GIA" vascular stapler. RESULTS: The overall transection time was 30,14+/-12,56 min. The amount of blood loss was 285,59+/-129,92 ml. The postoperative complication rate was 25,49%. R0 resection had 94 (92,16%) patients.There was no liver failure or perioperative death. CONCLUSIONS: Posterior intrahepatic approach for segmental resection is safe, can expedite the liver transection and reduce intraoperative hemorrhage. This approach provides adequate tumor clearance with preservation of normal parenchyma, as well as the vasculature or the biliary drainage of the contralateral liver. PMID- 23654006 TI - Introduction of new Tumor Marker Age Score in clinical practice: Validity evaluation for differentiation benign from malignant adnexal masses. AB - OBJECTIVE: The aim of the study was to examine several tumor markers and their correlation with pathohistological findings in patients with adnexal masses. METHODS: Study involved 139 patients, 84 of them with benign, 47 with malignant and 8 with borderline adnexal tumor. Levels of CA 125, CA 19-9, CEA and CA 15-3 were obtained preoperatively and assessed regarding the specific pathohistological diagnose and the patient's age. Obtaining these results led us to divide the patient's CA 125 levels with age and by doing that we have attained a new Tumor Marker Age score (TMA score). RESULTS: Patients with malignant adnexal tumors had significantly higher levels of CEA (p<0.05), CA 125, CA 19-9 and CA 15-3 tumor markers (p<0.01), in comparison with patients with benign tumors. TMA score highly statistically correlate with the tumor type (benignant/malignant). CONCLUSIONS: With the increase of tumor marker levels and the patient's age the malignant nature of adnexal tumors is more often. Results of our study highlight the importance of the use of combined tumor markers (at least CA-125 and CA 19-9) in women with adnexal masses. Those levels along with the patient's age and new TMA score could preoperatively predict malignant nature of the tumor. PMID- 23654007 TI - Impact of the injury pattern on the pedestrian fatalities in the city of Belgrade. AB - INTRODUCTION: In the city of Belgrade pedestrians are under the high risk to sustain injuries in the road traffic accidents, they are often with multiple injuries, with long-term treatment and significant consequences. Most of them are in the )senior or in the school age group. METHODS: We present the results of the epidemiological analysis of the mechanism of injury and treatment outcome of the pedestrians who sustained the lower limb injuries and additional, the injuries of the other organic systems. We also analysed the relevant data about the moment of the collision. RESULTS: Regarding the gender, male were significant more injured., in the senior age of life. Patients with multiple injuries, especially with the pelvic injuries or injuries of more than two systems were significant more likely to have a fatal outcome. CONCLUSION: The pedestrians are the most vulnerable group in road traffic accidents. Thus, we need to make actions on two levels: appropriate environment conditions and effective prehospital and hospital treatment. PMID- 23654008 TI - [Surgical treatment of degenerative cervical spine diseases: analyses of 90 patients clinical study]. AB - The effect of degenerative cervical spine surgery depends on good understanding of the pathogenesis and clinical course of disease with a detailed neurological and neuroradiological examination. Surgical approach should be considered separately for each pathological substrate in order to avoid additional morbidity. The aim of our study is to present the results of treatment through analysis of large clinical series focusing on anterior surgical approach with iliac crest graft fusion without cervical plating. The retrospective analysis of 90 patients operated on Neurosurgery of CHC Zemun, from 2008 to 2011, was done. In 81 patients cervical disc herniation was found in one or two levels, and 9 patients had spinal canal stenosis with polydiscopathy. Preoperatively 50 patients had cervical myelopathy, and 40 patients had radiculopathy as dominating clinical sign. Anterior cervical approach was performed in 79 patients, and 11 patients were operated by posterior approach. The treatment outcome was as follows: good outcome 16 (16.8%) patients, improved condition 65 (72.2%), without improvement 6 (6.7%), bad outcome 3 (4.3%). The anterior cervical approach with iliac crest autologous graft fusion, and without additional cervical plating, is reliable treatment option with results comparable to reported clinical series with sintetic graft placement and anterior cervical plate stabilisation. PMID- 23654009 TI - [Simultaneous carotid and coronary surgery without use of extracorporeal circulation--personal experience]. AB - OBJECTIVES: There is still a dilemma about best treatment option for patients with severe carotid and coronary artery disease. Reviving of beating heart revascularization technique and using of carotid stenting makes things even more difficult. Discussion about this subject is getting more and more profound. This is analysis of our initial experience with simultaneous carotid and off pump coronary procedures. MATERIALS AND METHODS: This is retrospective analysis of 18 patients operated using this technique in a period from 2001-2003 yrs. Follow up was done by telephone interview. For survivors specially designed questionaire was fulfilled. RESULTS: We operated total number of 18 patients with average age 60,6+/-9.32 years. Carotid recontruction was performed by eversion technique in all patients. Average number of coronary grafts was 2,67+/-0.88. During postoperative period 1 patient (5.55%) had verified perioperative infarction and 1 patient (5.55%) suffered from stroke. Average number of days in hospital was 9.95+/-4.74. During follow up period of 21 months two more patients died from cardiovascular causes. There was no need for repeat coronary angiogram or reintervention on carotid or coronary arteries. CONCLUSION: Simultaneous carotid and coronary operation performed on beating heart is safe and efficent method of treatment for patients with severe concomitant carotid and coronary artery disease. PMID- 23654010 TI - Ocular injuries caused by airsoft guns - ten-year experience. AB - INTRODUCTION: The study describes ocular injuries caused by airsoft guns pellets, type of these injuries and their incidence in different age groups. METHODS: This is a retrospective review of medical charts of patients who were hospitalized due to airsoft guns ocular injuries in ten-year period (from 2000 to 2009). Patient's age, gender, duration of hospitalization, type of treatment and initial and final visual acuity were analyzed. RESULTS: Overall 92 patients with ocular injuries caused by airsoft gun pellets were hospitalized in ten-year period. In all patients only one eye was injured and there were 72 (78.3%) male patients. Injuries involved ocular adnexa, anterior and posterior segment of the eye. On initial examination 41 (44.6%) patients were presented with subconjunctival hemorrhages, 42 (45.6%) with corneal abrasion, 42 (45.6%) patients had corneal edema, 6 (6.5%) had traumatic mydriasis, 90 (97.8%) patients exhibited hyphema, 10 (10.9%) iridodialysis, in 27 (29.3%) patients high intraocular pressure (IOP) was measured, one patient had subluxation of intraocular lens (IOL) and one patient had traumatic cataract. Posterior segment findings included vitreous hemorrhage in 3 (3.3%) patients, retinal hemorrhage in 15 (16.3%) patients, retinal edema in 35 (38.0%) patients and one patient had globe rupture. Average duration of hospitalization was 5.7 days (range from 1 to 18 days). Three patients (3.3%) required eye surgery, eight patients (8.7%) had anterior chamber washout while rest of the patients were conservatively managed. Visual acuity at hospital release was significantly improved comparing to initial visual acuity, ranging from counting fingers at 1 meter to 20/60 in 7 (8.6%) patients, from 20/50 to 20/30 in 13 (16.0%) patients and from 20/25 to 20/20 in 61 (75.3%) patients. In 11 patients testing the visual acuity was not possible because of their young age. CONCLUSION: Injuries attributed to airsoft guns were confined mostly to anterior segment. There was also high percentage of severe posterior segment trauma requiring hospital admission. The most important factors in preventing such injuries are restricting access to airsoft guns, especially to minors, as well as mandatory use of protective equipment such as protective eyeglasses. PMID- 23654011 TI - [Results of asymmetric bilateral medial rectus retroposition in unilateral Duane retraction syndrome type I]. AB - OBJECTIVE: To describe the results of asymmetric bilateral medial rectus retroposition in unilateral Duane retraction syndrome-this type I. METHOD: This is a retrospective study involving 18 patients, mean age 11.2 years (3-37 years) with unilateral Duane retraction syndrome's type who were operated in 2009 up to 2011 year. The aim was to investigate the existence of ocular torticollis, size deviation before and after surgery and presence of amblyopia, anisometropia, type of refractive errors and lateralization. RESULTS: All 18 patients were surgically treated by asymmetric retroposition of internal rectus (for 1-2mm more on the healthy eye). All patients preoperatively demonstrated ocular torticollis. Size of mean preoperative deviation was +22.2 pD of primary angle PD and +46 pD of secondary angle. Postoperative finding: deviation of > +10 PD is noted to the presence of mild torticollis in one patient. Intermediate follow-up period was 9.8 months. Unilateral Duane's syndrome is common among members of women (67%) compared to males (33%). Lateralization of Duane's syndrome is more common in the left eye compared to the right (83% vs. 17%). Amblyopia was present in two patients and anisometropia (11.1%). As for refractive errors: hyperopia was found in 9 patients (50%), hypermetric astigmatism in 7 cases (39%), myopia and 1 (5.5%) and emmetropia (5.5%). None of the patients had no pathological changes in the fundus and anterior segment. CONCLUSION: Asymmetric bilateral medial rectus retroposition is extremely effective in the treatment of ocular torticollis and esotropia in patients with unilateral Duane retraction syndrome-this type I. PMID- 23654012 TI - The effect of low frequency pulsing electromagnetic field in treatment of patients with knee joint osteoarthritis. AB - Pulsing electromagnetic field represents effective rocedure in treating of diverse diseases and p pathologic conditions, especially in rheumatology, orthopaedics and traumatology. The goal of this research is the objective evaluation of the treapeutic effect of low frequency pulsing electromagnetic field (LFEMF), in comparison with the effect of the other physical procedure: interfererence currents (IFC) and the medicamentous therapy, in treating of patients with knee joint osteoarthritis. This study was made as experimental, randomized, controlled clinical trial, opened type. The examination included 60 patients (40 females and 20 males) with osteoarthritis of the knee joint. All patients were divided in three groups. The first group of 20 persons, composed of patients treated with medicamentous therapy (Diklofenak of 100 mg, 2 tablets per day). The second group consisted of 20 patients treated by LFPEMF and the third group consisted of 20 patients treated by IFC. All procedures were implemented during 10 days All of patients had also the same duration therapeutic exercise. As observing parameter was used: Lattinen test for the evaluation of the pain sensitivity, before and after therapy. For the statistical analysis of the aquired data, was used Student's t-test. After therapy the pain was considerably reduced in each group, but this effect was the most significant in the II group of the examinees, treated by LFPEMF (p< 0.001), than the effects in other groups of patients: I group (p< 0.05) and III group (p< 0.01). According to the results of this study it can be concluded that LFPEMF is very effective therapeutic procedure in treatment of patients with knee joint osteoarthritis. PMID- 23654013 TI - Surgical management of macular holes - indications and complications. AB - Macular hole surgery is very demand surgery performed due to fullthickness macular rupture characterized by abscence of all retinal layers. Indications for surgery includes stages 3 and 4 regarding to Gass classification. Some authors sugest surgery for stage 2 but results are promissing only in anatomical reconstruction. Complications are evident such as cataract, late macular reopening, retinal tears and detachment, visual field defect etc. With improving surgical techniques, the rate of complications became lower. PMID- 23654014 TI - The effects of early rehabilitation in patients with surgically treated colorectal cancer. AB - Colorectal cancer is one of the most common cancer. Caught early, it is often curable. The important role in functional recovery of these patients, have enhanced recovery after surgery (ERAS) clinical care protocol and early rehabilitation. The goal of this research is the objective evaluation of the effects of early rehabilitation in patients after surgical treatment of colorectal cancer, respecting their functional recovery and quality of life, before and after rehabilitation. Tis study was made as experimental, randomized, controlled clinical trial, opened type.The examination included 58 patients (39 males and 19 females), age from 36 to 85 years, average 63.3, with surgically treated colorectal cancer. All patients had appropriate early multimodal accelerated rehabilitation program.The mean value of this program was 7,24 days. As observing parameter was used short form, 36 items health related questionnaire (SF-36), with two summary measures-Physical component summary (PCS) and Mental component summary (MCS), for the evaluation of quality of life, before and after treatment. For the statistical analysis of the aquired data, before and after therapy, was used Student's t-test. Afer therapy, the quality of life of patients was significantly improved, physical health (p< 0.01), as well as mental health (p<0,01). SF36 score after rehabilitation, show important improvement of quality of life in early treated patients. These results show exellent therapeutic possibilities of enhaced recovery clinical care protocol and early rehabilitation procedures. Acording to the results of this study, it can be concluded that early rehabilitation accelerated program is very effective in treatment of patients with surgically treated colorectal cancer. PMID- 23654015 TI - The dissolution of multiple renal uric acid stones via percutaneous nephrostomy in the patient with a solitary kidney. AB - INTRODUCTION: The dissolution of urinary stones could be performed in the patients with urinary obstruction caused by phosphate, or uric acid stones, through the percutaneous nephrostomy (PCN). CASE REPORT: A 27-year-old woman with complete obstruction of the solitary left kidney due to uric acid stones is presented. The woman was admitted in emergency unit due to anuria. Five days after PCN, irrigation with 1.6% sodium bicarbonate solution was initiated. Due to complete ureteral obstruction, the "Y" extension with the valve was connected to PCN and to the urinary bag, which enabled the patient to perform intermittent self-irrigation. After 12 days of irrigation, all the stones dissolute and ceased. CONCLUSION: In the era of ESWL, PCNL and ureterorenoscopy, PCN dissolution of urinary stones is rare procedure. However, this minimally invasive procedure could be successfully performed in selected cases. PMID- 23654016 TI - A 10-cm big stone formed in ileal conduit six years after cystectomy. AB - INTRODUCTION: Ileal conduit (IC) is the standard urinary diversion following radical cystectomy. The formation of stone in the IC is one of the relatively common late complications of the procedure. CASE REPORT: The case of 69-year-old man who developed 10-cm large stone in the IC, six years after cystectomy is presented. CONCLUSION: The majority of patients with the stone in IC can be treated with minimally invasive techniques, like manual extraction, or endoscopic procedures. PMID- 23654017 TI - Overlooked dislocation of C6/C7 vertebra with minimal neurologic deficit. AB - The beginning of 21 century was marked by an enormous increase in the number of traffic accidents, which led to an increasing number of multiple injured patients with associated injuries, especially injuries of cervical spine, because of its anatomical features. Even in the era of modern diagnostic procedures, cervical spine injuries are still often overlooked, especially in multiple injured patients and unconscious patients, and the consequences of undiagnosed injuries can be fatal. Very often there are ligamentous lesions, which can be detected only by using NMR, while the osteoarticular lesions can be diagnosed through careful clinical examination, X-rays and CT scan. This paper presents the case of female in the middle age with initially missed injury of the lower cervical spine segments, sustained in a car accident as a driver, with excellent results of treatment and complete recovery. PMID- 23654018 TI - Gigantic transitional cell carcinoma of the renal pelvis in the region of endemic nephropathy. AB - AIMS: To present the rare case of transitional cell carcinoma of the renal pelvic in the region of endemic nephropathy. PATIENT REPORT: A 64-year old man with gigantic urothelial carcinoma in renal pelvis and ureter. Patient underwent right nephrectomy. Hystopathological analysis after right nephrectomy revealed urothelial transitional cell carcinoma, grade III-IV with infiltration of right ureter. After one month, because of the hystopatological findings, patient underwent ureterectomy on the right side. RESULTS: Two years after surgery there are no signs of primary disease or metastasis and the cystoscopy findings are normal. CONCLUSION: Despite the poor prognosis, two years after surgery patient is without signs of primary disease or metastasis. PMID- 23654019 TI - Simultaneous ipsilateral testicular seminoma with pelvic ectopy and hematovesicula seminalis. AB - We present a rare case of 24 years old male who was diagnosed with simultaneous testicular tumor with pelvic ectopy and ipsilateral hematovesicula seminalis. Hemospermia was the only presented symptom. Patient underwent surgery and removal of the testicular tumor and right vesiculectomy were performed. Histopathological analysis revealed seminoma of the right testis and dilated right vesicula seminalis filled with hemorrhagic fluid and sings of chronic inflammation. Postoperatively irradiation of the abdomen was performed using standard protocol. Ten years after surgery there was no signs of decease recurrence. PMID- 23654020 TI - [The selection of best anesthesiological technique for hip fracture surgery in older high-risk patients]. AB - INTRODUCTION: Hip fracture is a pathological condition, more common in older age, i.e. in people over 65 years. The prevalence of this disorder is continuously increasing, simultaneously with higher age limit. In evaluation of risk for operation and anesthesia, older age itself represents higher risk and calls for special attention. In selection of anesthesiological technique, it is more usual to apply neuroaxial block or peripheral nerve block, which is more advantageous over general anesthesia. CASE REPORT: A female, 80-year old, patient B.D. was admitted to hospital for hip fracture, with the diagnosis of the right, lateral, basicervical femoral fracture. On admission, heart decompensation (decompensated dilated myocardiopathy), pulmonary edema and the left lateral pleural effusion were established. Due to high risk (ASA III) of intraoperative and postoperative complications, it was decided to apply combined peripheral nerve block. Using the neurostimulators, 3-in-1 block, lumbosacral block and sciatic nerve block were applied. During the operation, the patient was sedated by Propofol and had spontaneous respiration through the laryngeal mask. Intra- and postoperatively, the patient's hemodynamics was stable. CONCLUSION: Peripheral nerve blocks are safe and effective anesthesiological technique, which may reduce the mortality in patients with the hip fracture and maintain the hemodynamic stability, both during and after the surgical intervention. PMID- 23654021 TI - Belief in a day of judgment and death anxiety: a brief note. AB - The reliability of a scale to measure belief in a day of judgment was assessed using a sample of 162 undergraduate students. The scale had good reliability, and 12 of the 20 items constituted a homogenous subset of items. Scores on the scale were moderately associated with scores on a traditional religiosity scale, but were not associated with fears of death and dying. PMID- 23654022 TI - Factor structure of the Italian version of the religious fundamentalism scale. AB - The Religious Fundamentalism Scale was applied to an Italian group, composed of 250 participants, to assess if it could be considered a reliable measure of fundamentalism. All participants professed to be believers of the Catholic religion. The overall group was split randomly into two smaller groups. The data of the first group were analyzed with an exploratory factor analysis (EFA) to test the factor structure of the Italian version of the scale. The data of the second sample were analyzed with a confirmatory factor analysis, to test the factor structure that emerged from EFA. Results indicated a two-dimensional structure, composed of two correlated factors apparently representing believing and skeptical attitudes. PMID- 23654023 TI - Designating longevity hotspots: cautions concerning the instability of per capita centenarian estimates. AB - Estimates of per capita centenarians in a Utah population varied between one per 12,864 and one per 4,675, depending on the data that were used, the population assumptions that were made, and the boundary limits that were employed. In general, caution is warranted in claims about the existence of longevity hotspots. PMID- 23654024 TI - The speed of information processing of 9- to 13-year-old intellectually gifted children. AB - In general, intellectually gifted children perform better than non-gifted children across many domains. The present validation study investigated the speed with which intellectually gifted children process information. 184 children, ages 9 to 13 years old (91 gifted, M age = 10.9 yr., SD = 1.8; 93 non-gifted children, M age = 11.0 yr., SD = 1.7) were tested individually on three information processing tasks: an inspection time task, a choice reaction time task, an abstract matching task. Intellectually gifted children outperformed their non gifted peers on all three tasks obtaining shorter reaction time and doing so with greater accuracy. The findings supported the validity of the information processing speed in identifying intellectually gifted children. PMID- 23654025 TI - Effects of a multidisciplinary lifestyle intervention for obesity on mental and physical components of quality of life: the mediatory role of depression. AB - The current study investigates the effects of a multidisciplinary lifestyle intervention for obesity on Health Related Quality of Life (HRQoL). In this study, 92 adults with obesity were weighed and completed the Short Form Health Survey (SF-36) and the Center for Epidemiologic Studies Depression Scale (CES-D) at the baseline and at the end of a 3-month intervention. Repeated measures analysis of variance (ANOVA), a series of hierarchical regressions, and the statistical mediation analysis of Baron and Kenny were conducted. (a) Over 3 months, changes in weight and the mental and physical scales of the SF-36 and depression were all significant. (b) The results indicate a significant mediation of changes in depression scores for the association between weight loss and enhancement on the General Health scale of the SF-36. Improvements to HRQoL from a multidisciplinary lifestyle intervention seem to affect both the physical and mental components of the SF-36 score and to reduce depression, contributing to enhanced self-perceptions of well-being. PMID- 23654026 TI - Preliminary assessment of the behavioral activation model in Japanese undergraduate students. AB - Many studies have reported that behavioral activation is an effective intervention for depression. The behavioral activation model is based on several formulations. For example, depressive mood leads to avoidant behaviors, avoidance negatively affects social contacts, decreased socialization lessens opportunities for positive reinforcement, and a decrease in positive reinforcement results in more depressive mood. The purpose of this study was to examine relationships among avoidant behavior, social contact, frequency of positive reinforcement, and depressive mood by using structural equation modeling to assess support for aspects of this behavioral activation model. Participants were 630 Japanese undergraduate students and vocational school students. Results provided preliminary support for the model. Treating both avoidance and activating behavior might contribute to decreased impairment. PMID- 23654027 TI - Measurement equivalence of seven selected items of posttraumatic growth between black and white adult survivors of Hurricane Katrina. AB - This study examined the equivalence or comparability of the measurement properties of seven selected items measuring posttraumatic growth among self identified Black (n = 270) and White (n = 707) adult survivors of Hurricane Katrina, using data from the Baseline Survey of the Hurricane Katrina Community Advisory Group Study. Internal consistency reliability was equally good for both groups (Cronbach's alphas = .79), as were correlations between individual scale items and their respective overall scale. Confirmatory factor analysis of a congeneric measurement model of seven selected items of posttraumatic growth showed adequate measures of fit for both groups. The results showed only small variation in magnitude of factor loadings and measurement errors between the two samples. Tests of measurement invariance showed mixed results, but overall indicated that factor loading, error variance, and factor variance were similar between the two samples. These seven selected items can be useful for future large-scale surveys of posttraumatic growth. PMID- 23654028 TI - Empathy as related to motivations for medicine in a sample of first-year medical students. AB - Professionalism and empathy are crucial in clinical settings. An association would be expected between empathic attitudes and altruistic motivations for a medical education. However, data is scarce in first-year students, and a previous small-scale study did not fully confirm the hypothesis that person-oriented motives would have a strong relationship to empathy. The present study tested this association in a larger sample. 202 first-year medical students (M age = 19.0 yr., SD = 2.7; 67.3% women) were assessed cross-sectionally, using the Vaglum and colleagues' indexes on motives for choosing medicine (security/status, person-orientation, and interest in the natural sciences) and the Jefferson Scale of Physician Empathy for students. There was a weak association between empathy and person-orientation, but the evidence regarding links between empathy and the three motivation scores was low overall. In this Portuguese sample there was not a clear-cut association between empathy and motivations for medical school. PMID- 23654029 TI - Effects of daylight-saving time changes on stock market returns and stock market volatility: rebuttal. AB - In a 2011 reply to our 2010 comment in this journal, Berument and Dogen maintained their challenge to the existence of the negative daylight-saving effect in stock returns reported by Kamstra, Kramer, and Levi in 2000. Unfortunately, in their reply, Berument and Dogen ignored all of the points raised in the comment, failing even to cite the Kamstra, et al. comment. Berument and Dogen continued to use inappropriate estimation techniques, over parameterized models, and low-power tests and perhaps most surprisingly even failed to replicate results they themselves reported in their previous paper, written by Berument, Dogen, and Onar in 2010. The findings reported by Berument and Dogen, as well as by Berument, Dogen, and Onar, are neither well-supported nor well-reasoned. We maintain our original objections to their analysis, highlight new serious empirical and theoretical problems, and emphasize that there remains statistically significant evidence of an economically large negative daylight-saving effect in U.S. stock returns. The issues raised in this rebuttal extend beyond the daylight-saving effect itself, touching on methodological points that arise more generally when deciding how to model financial returns data. PMID- 23654030 TI - Testing Joiner's theory of suicide in jail inmates: an exploratory study. AB - Thomas Joiner has proposed an interpersonal theory of suicide in which thwarted belongingness, perceived burdensomeness, and an acquired capability to commit self-harm predict suicidal behavior. In an exploratory study, a questionnaire was administered to 38 jail inmates to test the applicability of this theory to these inmates. Only thwarted belongingness was associated with past suicidal behavior and the inmates' own prediction of the likelihood of future suicidal behavior. PMID- 23654031 TI - Depression and suicidal ideation in college students: a preliminary study of campus variables. AB - In a sample of 80 undergraduates, variables associated with the undergraduate experience (such as transfer student status, grade point average, working, and belonging to a fraternity/sorority) were not significantly associated with measures of depression, mania, or suicidal ideation. Students living on campus were more depressed and suicidal than those living with their parents. PMID- 23654032 TI - Exploring the relationships between fear-related xenophobia, perceptions of out group entitativity, and social contact in Norway. AB - An internet-related survey distributed to Norwegian students explored predictors of fear-related xenophobia toward immigrants. Specifically, this study examined a new social construct called "entitativity" (i.e., the extent to which out-group members are perceived as bonded together in a cohesive or organized unit), as well as frequency of informal social contact and valence of a recent encounter in relation to certain xenophobic attitudes. Correlational and multiple regression analyses indicated that perceived out-group entitativity was a moderate predictor of fear-related xenophobia. Voluntary informal contact was a weak predictor of fear-related xenophobia, whereas negative evaluation of an encounter in the recent past was a strong predictor. Further analysis indicated that the effect of entitativity on xenophobia was strongest when informal social contact was low. Moreover, analysis indicated that the effect of valenced contact was partly mediated through perception of entitativity. PMID- 23654033 TI - Replacement between conformity and counter-conformity in consumption decisions. AB - This study assessed, in a Chinese context, how self-esteem interacts with perceived similarity and uniqueness to yield cognitive dissonance, and whether the dissonance leads to self-reported conformity or counter-conformity behavior. Participants were 408 respondents from 4 major Chinese cities (M age = 33.0 yr., SD = 4.3; 48% men). Self-perceptions of uniqueness, similarity, cognitive dissonance, self-esteem and need to behave in conformity or counter-conformity were measured. A theoretical model was assessed in four situations, relating the ratings of self-esteem and perceived similarity/uniqueness to the way other people at a wedding were dressed, and the resultant cognitive dissonance and conformity/ counter-conformity behavior. Regardless of high or low self-esteem, all participants reported cognitive dissonance when they were told that they were dressed extremely similarly to or extremely differently from the other people attending the wedding. However, the conforming/counter-conforming strategies used by participants to resolve the cognitive dissonance differed. When encountering dissonance induced by the perceived extreme uniqueness of dress, participants with low self-esteem tended to say they would dress next time so as to conform with the way others were dressed, while those with high self-esteem indicated they would continue their counter-conformity in attire. When encountering dissonance induced by the perceived extreme similarity to others, both those with high and low self-esteem tended to say they would dress in an unorthodox manner to surprise other people in the future. PMID- 23654034 TI - The Duke University Religion Index (DUREL): validation and reliability of the Farsi version. AB - This study examined the validation and reliability of the Farsi version of the Duke University Religion Index (FDUREL), a brief measure designed to evaluate the primary dimensions of religiosity. The study was conducted in two phases. In the first phase, after translation of the original version of DUREL by using standard forward-backward translation, the FDUREL was administered to 427 medical students at different training levels. Reliability of the FDUREL was assessed by internal consistency and test-retest reliability. Principal components factor analysis was employed to assess the construct validity of the measure. In the second phase, 557 medical students were asked to fill out the FDUREL and Hoge Intrinsic Religiosity Scale to examine concurrent validity. The FDUREL was unidimensional and had good internal consistency and test-retest reliability. Results suggest that the FDUREL is a reliable and valid measure of religiosity in Farsi-speaking populations. PMID- 23654035 TI - Validating the Functions of Identity Scale: addressing methodological and conceptual matters. AB - Various studies have examined the validity of the Functions of Identity Scale; the current study addressed gaps in previous works. Its three main goals were to revise the Control subscale and establish its construct validity, to assess the structural validity of a five-factor model, and to establish the external validity of the subscales. Confirmatory factor analysis (CFA) was employed with a sample of 422 female and 107 male undergraduate students from two universities in Ontario, Canada. The analysis supported the construct validity of the revised five-factor measurement model and the new Personal Control factor. The external validity of each of the subscales was tested, and scale items were revised to increase clarity and readability (to a Grade 5.5 reading level). Rigorous validity testing, strong psychometric properties, low reading level, and a novel focus on the outer workings of identity formation make this scale an attractive addition to current identity measures. PMID- 23654036 TI - Taking purpose into account in experimental psychology: testing for controlled variables. AB - Experimental research in psychology is based on a causal model--the General Linear Model (GLM)--that assumes behavior has causes but not purposes. Powers (1978) used a control theory analysis to show that the results of psychological experiments based on such a model can be misleading if the organisms being studied are purposeful (control) systems. In the same paper, Powers presented evidence that organisms are such systems. Nevertheless, psychologists continue to use methods that ignore purpose because the behavior in most experiments appears to be non-purposeful (a caused result of variations in the independent variable). The experiments described in this paper show how purposeful behavior can appear to be caused by the independent variable when an organism's purposes are ignored. The results show how taking purpose into account using the control theory-based "Test for the Controlled Variable" can provide a productive new methodological direction for experimental research in psychology. PMID- 23654037 TI - Influence of item sequence on transient mood assessment. AB - The present study compared self-reported transient mood assessment using two different presentations of the sequence of mood scale items. A sample of 300 adults completed the standard Brunel Mood Scale and, after a distraction task, completed an experimental version composed of items grouped along the original subscales. A further 292 adults completed the scales in reverse order. After analysis, no significant differences in response patterns were observed. Results suggested that items sequenced non-randomly and according to mood subscales do not affect the accuracy of transient mood assessment. This suggests that for administration to large groups, the experimental version maintains the psychometric validity of the standard version while at the same time being more time-effective to score. PMID- 23654038 TI - Male abuser: type of violence and perception of the relationship with the victim. AB - This article explores violent behavior within a relationship from the male abuser's perspective. A systemic approach was used, combining qualitative and quantitative information in two parallel studies. The first (Study 1) is a descriptive analysis of a group of men (N = 220) who participated in a program to address violence within the couple. In the second (Study 2), a subgroup of 8 participants was interviewed in-depth for describing and analyzing their perceptions of violence. The data analysis suggest that relationship violence (a) begins in the early stages of the relationship, (b) is long-term, (c) rarely includes serious physical aggression, (d) is dominated by a growing hostility and isolation, (e) is characterized by a lack of awareness and responsibility for the violent behavior, and (f) includes intentional and strategic use of violent behavior. PMID- 23654039 TI - Compliments and receptivity to a courtship request: a field experiment. AB - 160 young women were solicited in the street to have a drink with a young male confederate. In the ingratiation condition, the solicitor complimented the woman regarding her physical appearance before making the request, while in the no compliment condition, the confederate asked his request directly. Results showed that complimenting was associated with greater compliance to the request. PMID- 23654040 TI - Inter-parental conflict and sibling warmth during adolescence: associations with female depression in emerging adulthood. AB - Grounded in Grych and Fincham's cognitive appraisal theory, this study examined whether female emerging adults' (N = 216) recalled sibling warmth moderated the relationship between exposure to inter-parental conflict in adolescence and their current depression. Findings indicated that sibling warmth moderated the relationship between the intensity and frequency of inter-parental conflict and depression, but not inter-parental conflict resolution. Compared to female emerging adults who reported lower sibling warmth, those who reported higher sibling warmth in the face of greater intensity and higher frequency of inter parental conflict during adolescence had lower depression. The important role of siblings for youth from conflicted homes was highlighted. PMID- 23654041 TI - The moderating role of attachment anxiety on social network site use intensity and social capital. AB - This study examined the moderating role of attachment anxiety on the relationship between intensity of social network site use and bridging, bonding, and maintained social capital. Data from 322 undergraduate Chinese students were collected. Hierarchical regression analyses showed positive relationships between online intensity of social network site use and the three types of social capital. Moreover, attachment anxiety moderated the effect of intensity of social network site use on social capital. Specifically, for students with lower attachment anxiety, the relationships between intensity of social network site use and bonding and bridging social capital were stronger than those with higher attachment anxiety. The result suggested that social network sites cannot improve highly anxiously attached individuals' social capital effectively; they may need more face-to-face communications. PMID- 23654042 TI - A comparison study of depression and quality of life in Turkish mothers of children with Down syndrome, cerebral palsy, and autism spectrum disorder. AB - This study aimed to compare the quality of life and depression levels in Turkish mothers of children with Down syndrome, cerebral palsy, and Autism Spectrum Disorder (ASD). An additional purpose is to identify whether the depression and quality of life levels of the mothers differ significantly based on demographic variables. Two hundred fifty-two mothers participated in the study. The World Health Organization's Quality of Life-BREF (WHOQOL-BREF-TR) assessment instrument was used to determine the mothers' quality of life and the Beck Depression Inventory (BDI) to characterize their depression. Mothers of children with cerebral palsy had significantly lower quality of life scores on the environment and national environment domains of the WHOQOL-BREF-TR than those of children with Down syndrome. No significant difference was observed in the depression of mothers. With increasing education and income, quality of life of the mothers increased whereas depression decreased. Moreover, depression increased and quality of life decreased in older mothers. Furthermore, the findings indicated significant negative correlations between mothers' depression and quality of life scores on all domains of the WHOQOL-BREF-TR. PMID- 23654043 TI - Emotional dispositions and substance use: mediating effect of alexithymia. AB - Substance consumption behaviors can range from use to abuse, the latter including addictive behaviors. Relationships between emotionality, alexithymia and substance-consumption behaviors among young adults were investigated through an explanatory model wherein alexithymia fulfills a mediating function by acting as an emotion-adjustment process. 256 students (62.1% women) with a mean age of 20.7 yr. (SD = 1.6), enrolled at two universities in southern France took part in the study. They filled out a substance-use questionnaire, the Emotionnalite positive et negative a 31 (EPN-31) emotionality scale, and the 20-item Toronto Alexithymia Scale (TAS-20). Mediation analyses validated the hypothesis that emotional dimensions of alexithymia act as mediators between emotionality (negative emotionality and emotional arousal) and substance use. As a mediating factor, alexithymia may be regarded as a type of operational process that regulates emotions. These results could have important implications for clinical and therapeutic applications focusing on emotion-regulation strategies and substance use. PMID- 23654044 TI - Cultivation and counter cultivation: does religiosity shape the relationship between television viewing and estimates of crime prevalence and assessment of victimization likelihood? AB - Religiosity may change the direction of the effect of TV viewing on assessment of the likelihood of personal victimization and estimates concerning crime prevalence. A content analysis of a representative sample of TV programming (56 hours of prime-time shows) was done to identify the most common crimes on television, followed by a survey of a representative sample of the adult public in a large urban district (778 respondents) who were asked to estimate the prevalence of these crimes and to assess the likelihood of themselves being victimized. People who defined themselves as non-religious increased their estimates of prevalence for crimes often depicted on TV, as they reported more time watching TV (ordinary cultivation effect), whereas estimates regarding the prevalence of crime and assessment of victimization likelihood among religious respondents were lower with reports of more time devoted to television viewing (counter-cultivation effect). PMID- 23654045 TI - Assessing empathy in antisocial youth: factor analytic and validation findings. AB - Relatively few researchers have examined empathy among antisocial youth, although adolescents may differ greatly in the nature and frequency of their offending behavior. In this investigation, exploratory and confirmatory factor analysis were used (1) to derive a brief empathy scale from the Psychopathic Personality Inventory-Short Version; (2) to assess the construct validity, internal consistency, and potential clinical utility of the derived empathy subscale; and (3) to identify key sociodemographic, psychosocial, and behavioral correlates of empathy in delinquent youth. The 707 adolescent residents of 27 Missouri Division of Youth Services rehabilitation facilities had a mean age of 15.5 yr. (SD = 1.2) and most (87%) were boys. Analysis suggested that the new measure possesses adequate psychometric properties and may be a useful addition to clinical assessments of antisocial youth. PMID- 23654046 TI - [Available in the clinic]. PMID- 23654047 TI - [Crowns and bridges]. PMID- 23654048 TI - [Lingual mandibular osteonecrosis]. AB - A 47-year-old man was referred to an oral and maxillofacial surgeon by his dentist because ofa painful ulcer with exposed bone at the lingual side of teeth 47 and 48. The lesion was diagnosed as lingual mandibular osteonecrosis. Characteristics of lingual mandibular osteonecrosis are exposed bone in the molar area and sequestration. The disorder can appear spontaneously or following damage to the mucous membrane. Treatment options are surgical smoothening of exposed bone, surgical removal of necrotic bone and awaiting spontaneous sequestration. PMID- 23654049 TI - [Self-perceived oral odour and social interaction]. AB - This study examined the influence of self-perceived oral odour on social interaction. A representative sample of 1,082 people from the Dutch population of 16 years and older, were surveyed. On average, the participants graded their oral odour as 66.8 on a scale 0-100; 4.2% judged their oral odour as 'not fresh' (score < or = 30). Approximately 65% indicated that they took into account the fact that, when meeting somebody for the first time, that person might smell their oral odour. Participants judging their oral odour to be not fresh were shown to keep significantly more distance when meeting somebody than participants judging their oral odour as fresh. Noteworthy was a subgroup of participants who judged their oral odour as fresh, but indicated that they always kept a certain distance to other people. The results suggest that self-perceived oral odour is a potential barrier in social interaction. PMID- 23654050 TI - [Dissertations 25 years after date 34. breakdown of collagen by fibroblasts and osteoclasts]. AB - The remodeling of soft and hard connective tissue is ssential for the proper functioning of an organism and also for the proper functioning of a tooth. An element of this remodeling is the disintegration mediated by fibroblasts or osteoclasts. The precise means by which the remodeling process takes place was and continues to be in part unknown. This doctoral research was able to show that collagen fibres are absorbed by fibroblasts from the surrounding tissue and consequently broken down in the lysosomal apparatus. Osteoclasts, the only cell type capable of breaking down mineralized bone, also appear to be capable of absorbing collagens. It was demonstrated that intracellular bone collagens in these cells can be found in patients who sufferfrom the rare disease pycnodysostosis. It is postulated that, in the osteoclasts of these patients, the activity of one or more enzymes which break down protein were reduced or absent. During the last 25 years, significant advances in the understanding of the processes which underlie the bone remodeling. PMID- 23654051 TI - [Oral medicine 5. Dietary counselling and psycho-social aspects of chemosensory disorders]. AB - Chemosensory disorders may result in loss of body weight and sometimes in gain of body weight. Therefore, dietary advice is an essential part of the counselling and treatment ofpatients with a chemosensory disorder. In cases involving a chemosensory disorder, a distinction has to be made between general dietary advice and advice during and after a patient's period of chemotherapy or radiotherapy. The aim of dietary advice is the improvement ofa patient's nutritional condition and the patient's well-being. In case of serious problems related to dealing with a chemosensory disorder, psycho-social counselling may be considered. PMID- 23654052 TI - [Dentistry and health care legislation 1. Professional standard for oral healthcare delivery]. AB - A dentist should deliver oral healthcare according to the professional standard. This legal determination is not very distinct and ought to be made more specific. Guidelines, protocols, and indicators play an important role in this respect, but are scarce in oral healthcare. Provisionally, judgements of discipline and complaints committees are heavily relied upon. Those judgements indicate what efforts, and in some cases even what results, a patient could have expected from a dentist in the specified conditions. PMID- 23654053 TI - Innovation for the 'bottom 100 million': eliminating neglected tropical diseases in the Americas. AB - An estimated 100 million people in the Latin American and Caribbean (LAC) region live on less than US$2 per day, while another 46 million people in the US live below that nation's poverty line. Almost all of the 'bottom 100 million' people suffer from at least one neglected tropical disease (NTD), including one-half of the poorest people in the region infected with hookworms, 10% with Chagas disease, and up to 1-2% with dengue, schistosomiasis, and/or leishmaniasis. In the US, NTDs such as Chagas disease, cysticercosis, toxocariasis, and trichomoniasis are also common among poor populations. These NTDs trap the poorest people in the region in poverty, because of their impact on maternal and child health, and occupational productivity. Through mass drug administration (MDA), several NTDs are on the verge of elimination in the Americas, including lymphatic filariasis, onchocerciasis, trachoma, and possibly leprosy. In addition, schistosomiasis may soon be eliminated in the Caribbean. However, for other NTDs including hookworm infection, Chagas disease, dengue, schistosomiasis, and leishmaniasis, a new generation of 'anti-poverty vaccines' will be required. Several vaccines for dengue are under development by multinational pharmaceutical companies, whereas others are being pursued through non-profit product development partnerships (PDPs), in collaboration with developing country manufacturers in Brazil and Mexico. The Sabin Vaccine Institute PDP is developing a primarily preventive bivalent recombinant human hookworm vaccine, which is about to enter phase 1 clinical testing in Brazil, as well as a new therapeutic Chagas disease vaccine in collaboration with several Mexican institutions. The Chagas disease vaccine would be administered to seropositive patients to delay or prevent the onset of Chagasic cardiomyopathy (secondary prevention). Together, MDA and the development of new anti-poverty vaccines afford an opportunity to implement effective control and elimination strategies for the major NTDs in the Americas. PMID- 23654054 TI - Non-typhoidal Salmonella in children: microbiology, epidemiology and treatment. AB - Non-typhoidal Salmonellae (NTS) are an important cause of infectious diarrhoea world-wide. In the absence of immune deficiency, gastroenteritis caused by NTS is usually mild, self limiting and rarely requires intervention. NTS are also an important cause of invasive disease, particularly in developing countries, likely secondary to the high prevalence of coexisting malnutrition, malaria and HIV infection. This review provides an overview of the microbiology, epidemiology and pathogenesis of NTS, and compares recommendations for the treatment of NTS gastroenteritis in children. PMID- 23654055 TI - Invasive fungal infections in patients with chronic granulomatous disease. AB - Invasive fungal infections are a major threat for chronic granulomatous disease (CGD) patients. The present study provides a comprehensive overview of published invasive fungal infections in the CGD host through an extensive review of epidemiological, clinical, diagnostic and therapeutic data. In addition to the often mild clinical presentation, the currently used diagnostics for invasive aspergillosis have low sensitivity in CGD patients and cannot be easily translated to this non-neutropenic host. Aspergillus fumigatus and A. nidulans are the most commonly isolated species. A. nidulans infections are seldom reported in other immunocompromised patients, indicating a unique interaction between this fungus and the CGD host. The occurrence of mucormycosis is mainly noted in the setting of treatment of inflammatory complications with immunosuppressive drugs. Candida infections are infrequently seen and do not cause mucocutaneous disease but do show an age-dependent clinical presentation. The CGD patient is susceptible to a wide range of fungal pathogens, indicating the need to determine the causative fungus, often by invasive diagnostics, to guide optimal and rational treatment. This review summarizes current understanding of invasive fungal infections in patients with CGD and will serve as a starting point to guide optimal treatment strategies and to direct further research aimed at improving outcomes. PMID- 23654056 TI - Clostridium difficile in children: a review of existing and recently uncovered evidence. AB - The clinical significance of the presence of Clostridium difficile in children's faeces remains uncertain using current diagnostic procedures. Clostridium difficile is a relatively common finding in infants with no symptoms of gastrointestinal disease, suggesting it may be an incidental finding and form part of the normal gut micro-flora in this age group. On the other hand, particularly in older children or those with significant co-morbidity, there are examples where C. difficile causes disease and exerts considerable morbidity and even mortality (C. difficile infection, CDI). Between these extremes lie a substantial group of children who have both diarrhoea and C. difficile in their stools but where the nature of the association is not clear: Clostridium difficile associated disease (CDAD). We review the significance of C. difficile in children presenting recently uncovered paediatric data from a large UK epidemiological study that informs some key unanswered questions. PMID- 23654057 TI - Diarrhea among children in developing countries. AB - Diarrhea continues to stand among the most important causes of global morbidity and mortality in children under 5 years of age. Although the introduction of oral rehydration and other case-management strategies have reduced acute diarrhea fatalities, many of the survivors develop persistent diarrhea and/or deficiencies of growth and cognition. Thus understanding the true global burden of diarrhea requires attention to acute diarrhea as well is its sequelae. To understand the etiology of moderate to severe diarrhea among children in high mortality areas of sub-Saharan Africa and south Asia we performed a comprehensive case-control study of children under 5 years of age at seven sites. Each site employed an identical case-control study design and each utilized a uniform comprehensive set of microbiological assays to identify the likely bacterial, viral and protozoal etiologies. Results of the studies will inform diarrhea prevention and management efforts worldwide. PMID- 23654058 TI - Building confidence in vaccines. AB - Despite significant efforts by governments, organizations and individuals to maintain public trust in vaccines, concerns persist and threaten to undermine the effectiveness of immunization programs. Vaccine advocates have traditionally focused on education based on evidence to address vaccine concerns and hesitancy. However, being informed of the facts about immunization does not always translate into support for immunization. While many are persuaded by scientific evidence, others are more influenced by cognitive shortcuts, beliefs, societal pressure and the media, with the latter group more likely to hesitate over immunization. Understanding evidence from the behaviour sciences opens new doors to better support individual decision-making about immunization. Drawing on heuristics, this overview explores how individuals find, process and utilize vaccine information and the role health care professionals and society can play in vaccine decision-making. Traditional, evidence-based approaches aimed at staunching the erosion of public confidence in vaccines are proving inadequate and expensive. Enhancing public confidence in vaccines will be complex, necessitating a much wider range of strategies than currently used. Success will require a shift in how the public, health care professionals and media are informed and educated about vaccine benefits, risks and safety; considerable introspection and change in current academic and vaccine decision-making practices; development of proactive strategies to broadly address current and potential future concerns, as well as targeted interventions such as programs to address pain with immunization. This overview outlines ten such opportunities for change to improve vaccine confidence. PMID- 23654059 TI - Chronic recurrent multifocal osteomyelitis. AB - Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disease occurring primarily in children and adolescents. Episodes of systemic inflammation occur due to immune dysregulation without autoantibodies, pathogens or antigen-specific T cells. CRMO is characterised by the insidious onset of pain with swelling and tenderness over the affected bones. Clavicular involvement was the classical description; however, the metaphyses and epiphyses of long bones are frequently affected. Lesions may occur in any bone, including vertebrae. Characteristic imaging includes bone oedema, lytic areas, periosteal reaction and soft tissue reaction. Biopsies from affected areas display polymorphonuclear leucocytes with osteoclasts and necrosis in the early stages. Subsequently, lymphocytes and plasma cells predominate followed by fibrosis and signs of reactive new bone forming around the inflammation. Diagnosis is facilitated by the use of STIR MRI scanning, potentially obviating the need for biopsy and unnecessary long-term antibiotics due to incorrect diagnosis. Treatment options include non-steroidal anti-inflammatory drugs and bisphosphonates. Biologics have been tried in resistant cases with promising initial results. Gene identification has not proved easy although research in this area continues. Early descriptions of the disease suggested a benign course; however, longer-term follow up shows that it can cause significant morbidity and longer-term disability. Although it has always been thought of as very rare, the prevalence is likely to be vastly underestimated due to poor recognition of the disease. PMID- 23654060 TI - Recognition and treatment of chlamydial infections from birth to adolescence. AB - The "silent epidemic" of Chlamydia trachomatis threatens to cause reproductive damage and infertility in many of the 50 million women who acquire it each year. Female reproductive tract infection has more recently been linked to stillbirth and premature delivery. Innate immune cells and mediators appear to be the primary players in pathogenesis, with neutrophils playing a prominent role in disease development. Although adaptive antibody and CD4 T cell responses appear primarily protective, these responses are inefficient. Infections are frequently chronic as a result, and when infection is diagnosed and treated with appropriate antibiotics, repeated infection is the rule. The lack of acute symptoms in many infected individuals contributes to the high prevalence of chlamydial infection. Although chronic sequelae are relatively rare in men, and many women sustain infection without developing pelvic inflammatory disease or chronic sequelae, the extremely high prevalence of chlamydial infection leads to significant morbidity and healthcare costs. A vaccine is urgently needed to prevent infection, but given the difficulties of inducing a CD4 T cell memory response that can home quickly to the genital tract, induction of sterilizing immunity may not be possible. A vaccine that prevents disease by lowering bacterial burden and dampening production of tissue-damaging responses may be possible. Until an efficacious vaccine is developed, screening and treatment programs appear to be the best method of disease prevention. PMID- 23654061 TI - Treatment of resistant bacterial infections in children: thinking inside and outside the box. AB - Antimicrobial resistance of bacteria causing pediatric infections has become more common and complicated in recent years. Although formerly confined to hospital settings, multi-drug resistant bacteria now also cause community-acquired infections. Treatment of infections caused by resistant pathogens is difficult, necessitating thinking both inside and outside the box. Determination of the precise minimal inhibitory concentration (MIC) is often crucial for selecting the most appropriate antibiotics, their doses, and use of prolonged infusions. For some multiply-resistant bacteria, off-label use of antibiotics, sometimes with no evidence from controlled studies ("salvage therapy") is unavoidable. PMID- 23654062 TI - An encephalitis primer. AB - For most clinicians managing a patient with encephalitis will be an infrequent event. The range of differential diagnoses in a child presenting with a clinical syndrome that could be encephalitis is broad. In addition, there are many pathogens that can cause encephalitis. In view of these facts, a systematic approach to clinical assessment, investigation and treatment, based on epidemiology and an understanding the limits of investigations, is crucial to effective management of this condition. This review focuses on encephalitis aetiology and investigation; HSV encephalitis; mycoplasma encephalitis; and flavivirus encephalitis as a globally important cause of disease. PMID- 23654063 TI - The evidence behind prophylaxis and treatment of wound infection after surgery. AB - Surgical site infections (SSIs) represent a serious post surgical complication. They are the leading cause of healthcare-related infections in developing countries and the second most common healthcare-related infection in developed countries. Here we discuss the epidemiology of and risk factors for SSIs together with the current evidence supporting the use of antibiotic prophylaxis for the prevention of wound infection after surgery. PMID- 23654064 TI - Infectious risks associated with biologics. AB - Biologics are generally either custom-designed monoclonal antibodies against specific target cells (e.g. B-cells) or target cytokines (e.g. tumour necrosis factor, TNF) or they are receptor constructs (fusion proteins) based on naturally occurring cytokine or cell receptors. Biologics are mostly used in adult rheumatology but are increasingly used in paediatrics. There are significant concerns about safety and also about cost. The main safety concerns are about increased risk of infection and malignancy. The use of TNF antagonists is associated with increased risk of serious infections with intracellular organisms, particularly mycobacteria, but also intracellular bacteria, fungi and Pneumocystis. B-cell antagonists like rituximab can cause progressive multifocal leukoencephalopathy. IL-6 antagonists are associated with increased rates of common bacterial infections and the complement pathway antagonist eculizumab with meningococcal infection. The risk of some infections associated with biologics can be reduced, by screening patients starting TNF antagonists for latent tuberculosis and giving them cotrimoxazole prophylaxis against Pneumocystis, and by immunising against VZV, hepatitis B, meningococci and pneumococci. However, the risk of the biologics causing serious infection in children is unknown and needs study. Children should not be started on the biologics without careful consideration of the risks and without fully informed consent. PMID- 23654065 TI - Cat scratch disease and other Bartonella infections. AB - First described in 1931, cat scratch disease remains the most commonly identified clinical syndrome associated with Bartonella infection. Over the last 20 years, however, the discovery and use of modern diagnostic tests has greatly expanded our understanding of the pathogenesis, clinical spectrum, and treatment options for Bartonella infections of all types. Indeed, each varies substantially depending on the infecting species and the immune status of the host. PMID- 23654066 TI - When to think of immunodeficiency? AB - Primary Immunodeficiencies (PIDs), although rare, are serious and heightened clinical suspicion leads to earlier diagnosis and improved outcome. Recognition of PIDs may be difficult as infections are common in young children in particular. Clues to the diagnosis of PID may be found in history, examination and initial basic investigations such as lymphocyte count. Age at presentation, type of infective organism and family history help focus on likely PIDs. Type of infective organism may indicate a specific PID, for example Aspergillus and Chronic Granulomatous Disease and Pneumocystis Jiroveci and SCID amongst others. Diagnostic aids such as 'The 10 Warning Signs of Primary Immunodeficiency' can be useful with failure to thrive, need for IV antibiotics, and family history of severe or unusual infections being the most discriminating. Systemic examination including the recognition of dysmorphic features may also support a particular diagnosis. PMID- 23654067 TI - Mycetoma caused by Madurella mycetomatis: a completely neglected medico-social dilemma. AB - Mycetoma is a debilitating disease with a highly particular geographical distribution. The mycetoma belt circles the entire world just above the equator and defines the region with the highest prevalence and incidence. Although the disease is seen in Central America, India and all across Africa, Sudan seems to be the homeland of mycetoma. Mycetoma is an infectious disease caused either by bacteria (actinomycetoma) or true fungi (eumycetoma). In Sudan most cases are caused by the fungal species Madurella mycetomatis. The precise natural habitat of this fungus is still an enigma, but its DNA can easily be found in soil and plant samples in endemic areas. Although the entire human population in these areas are in regular contact with the fungus, most individuals are unaffected. Thus mycetoma is an ideal clinical and experimental model system for the study of host-pathogen interactions. Also, given its relative importance locally, improvements in clinical and laboratory diagnostics and knowledge of the epidemiology of the disease are badly needed. This chapter describes the current state of affairs in the field of eumycetoma caused by M. mycetomatis. The value of laboratory research on this disease and future perspective for control and prevention of the infection are discussed. PMID- 23654068 TI - Elucidation and clinical role of emerging viral respiratory tract infections in children. AB - Acute respiratory viral infections (ARVI's) are the most common infectious disease in humans. With the appearance of molecular techniques the recovery of viruses has dramatically increased. Nowadays virologists can quickly discriminate virological families and related viruses from emerging viruses and consequently identify novel viruses. Many new respiratory viruses have been identified in children in the past 15 years. In this review we shortly discuss novel respiratory viruses and their pathogenic role in pediatric respiratory disease. Advantages and drawbacks of the technique and our current knowledge will be discussed. We will conclude this review with a general discussion on the future role of molecular diagnostic virology in the clinic. PMID- 23654069 TI - Urinary tract infections in children: microbial virulence versus host susceptibility. AB - Urinary tract infections (UTI) are common, dangerous and interesting. This review includes a general background on UTIs and molecular mechanisms of pathogenesis. In addition, we discuss UTI susceptibility and especially the effect of genetic variation on innate immunity. The symptoms of acute pyelonephritis are caused by the innate immune response and inflammation in the urinary tract decreases renal tubular function and may give rise to renal scarring, especially in childhood. The disease severity is explained by pathogens and their virulence factors triggering signaling through Toll-like receptors (TLRs), interferon regulatory factors (IRFs) and type 1 interferons, and the activation of a host response mediating disease or pathology or clearance of infection. In children with asymptomatic bacteriuria (ABU), in contrast, bacteria persist without causing symptoms or pathology. ABU strains mostly lack virulence factors, and the lack of symptoms has largely been attributed to their lack of virulence. Recently, rapid progress has been made in the understanding of host susceptibility mechanisms. For example, genetic alterations that reduce TLR4 function are associated with ABU while polymorphisms reducing IRF3 or CXCR1 expression are associated with acute pyelonephritis and an increased risk for renal scarring. Understanding bacterial virulence and host resistance promises new tools to improve the diagnostic accuracy in children with UTI. By combining information on bacterial virulence and the host response, it should be possible to start individualizing diagnosis and therapy. Finally, we propose that the prediction of future disease risk and decisions on prophylaxis and invasive diagnostic procedures might be improved by genetic analysis. PMID- 23654070 TI - Preventing urinary tract infections in early childhood. AB - Urinary tract infection (UTI) is common in children, causes them considerable discomfort, as well as distress to parents and has a tendency to recur. Approximately 20% of those children who experience one infection will have a repeat episode. Since 1975, 11 trials of long-term antibiotics compared with placebo or no treatment in 1,550 children have been published. Results have been heterogeneous, but the largest trial demonstrated a small reduction (6% absolute risk reduction, risk ratio 0.65) in the risk of repeat symptomatic UTI over 12 months of treatment. This effect was consistent across sub groups of children based upon age, gender, vesicoureteric reflux status and number of prior infections. Trials involving re-implantation surgery (and antibiotics compared with antibiotics alone) for the sub-group of children with vesicoureteric reflux have not shown a reduction in repeat UTI, with the possible exception of a very small benefit for febrile UTI. Systematic reviews have shown that circumcision reduces the risk of repeat infection but 111 circumcisions would need to be performed to prevent one UTI in unpredisposed boys. Given the need for anaesthesia and the risk of surgical complication, net clinical benefit is probably restricted to those who are predisposed (such as those with recurrent infection). Many small trials in complementary therapies have been published and many suggest some benefit, however inclusion of children is limited. Only three trials involving 394 children for cranberry products, two trials with a total of 252 children for probiotics and one trial with 24 children for vitamin A are published. Estimates of efficacy vary widely and imprecision is evident. Multiple interventions to prevent UTI in children exist. Of those, long-term low dose antibiotics has the strongest evidence base, but the benefit is small. Circumcision in boys reduces the risk substantially, but should be restricted to those at risk. There is little evidence of benefit of re-implantation alone, and the benefit of this procedure over antibiotics alone is very small. Cranberry concentrate is probably effective. PMID- 23654071 TI - How to get and get rid of gonorrhea. AB - Gonorrhea remains as a significant public health concern with an estimated 88 million new cases per year globally. Gonorrhea is a disease of sexual networks and is most prevalent in youth, men who have sex with men, and the socioeconomically disadvantaged. Highly adaptive through years of co-evolution, gonorrhea has developed multiple ways of evading the human immune system. Although new molecular-based strategies have opened avenues for less invasive testing, education and accessibility issues persist. Novel strategies, including use of the internet and social media, are required to better target high risk groups for education, testing, and treatment. Increasing the availability of youth-friendly health services will also help foster earlier gonorrhea diagnosis and management. The inappropriate and overuse of antibiotics and propensity of gonococcus for mutation has led to growing microbe resistance. Treatment failures now include both oral and intravenous formulations of third generation cephalosporins; key front line recommended gonococcal treatment in many countries. With treatment options dwindling, the need for better preventative strategies has never been more important. This overview highlights some of the major aspects of gonococcal infection, including the epidemiology of the disease with an emphasis on sexual networks, new diagnostic techniques, treatment options in the face of evolving gonococcal resistance, and notes potential new preventative strategies. PMID- 23654072 TI - Management of severe malaria: results from recent trials. AB - Globally, malaria remains a substantial public health burden with an estimated 349-552 million clinical cases of P. falciparum malaria each year--leading to 780,000 deaths directly attributable to the disease. Whilst the outcome from severe malaria in Africa children remains poor, recent developments in the management of malaria have come from two key sources--the introduction of new, safe and rapidly-effective anti-malarials and high quality evidence from two of the largest clinical trials ever conducted in African children with severe malaria. As a result, the time-honoured anti-malarial treatment for severe malaria, quinine, will now be replaced by artesunate, a water-soluble artemisinin derivative. Supportive care, specifically the management of shock, has been informed by a large late phase clinical trial which concluded that bolus resuscitation is harmful and therefore should be avoided in children with severe malaria, including the high risk group with severe metabolic acidosis and advanced shock. PMID- 23654073 TI - Phenotypes and endotypes of uncontrolled severe asthma: new treatments. AB - Severe asthma is a heterogeneous disease that affects only 5%-10% of asthmatic patients, although it accounts for a significant percentage of the consumption of health care resources. Severe asthma is characterized by the need for treatment with high doses of inhaled corticosteroids and includes several clinical and pathophysiological phenotypes. To a large extent, this heterogeneity restricts characterization of the disease and, in most cases, hinders the selection of appropriate treatment. In recent years, therefore, emphasis has been placed on improving our understanding of the various phenotypes of severe asthma and the identification of biomarkers for each of these phenotypes. Likewise, the concept of the endotype has been gaining acceptance with regard to the various subtypes of the disease, which are classified according to their unique functional or pathophysiological mechanism. This review discusses the most relevant aspects of the clinical and inflammatory phenotypes of severe asthma, including severe childhood asthma and the various endotypes of severe asthma. The main therapeutic options available for patients with uncontrolled severe asthma will also be reviewed. PMID- 23654074 TI - Association between the interleukin 6 genotype at position -174 and atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic skin disorder of unknown origin that usually manifests for the first time in early infancy. Different types of genetic predisposition and environmental factors seem to be associated with the disease. METHODS: This study was performed to evaluate the frequency of alleles, genotypes, and haplotypes of interleukin (IL) 6 single-nucleotide polymorphisms (SNPs) at positions -174 and nt565 in 89 Iranian children with AD and 139 healthy controls. RESULTS: The G allele was significantly more frequent at position -174 in IL6 in atopic patients than in the healthy controls (P < .001; OR, 2.82). Genotype GG was found at the same position in 71% of the patients; this frequency was significantly higher than the frequency of 30% recorded in the controls (P < .001; OR, 5.60). The GG haplotype of IL6 (-174, nt565) was significantly more frequent in the atopic patients than in the healthy controls (P < .001; OR, 2.99). CONCLUSIONS: A significant increase in the frequency of the G allele and GG genotype at position -174 of IL6 was found in patients with AD, thus suggesting that production of this cytokine is greater in atopic patients. PMID- 23654075 TI - B-cell subsets in patients with transient hypogammaglobulinemia of infancy, partial IgA deficiency, and selective IgM deficiency. AB - BACKGROUND: The pathogenesis of some primary humoral immunodeficiencies, such as transient hypogammaglobulinemia of infancy (THI) and immunoglobulin (Ig) A deficiency, remains unknown and can render diagnosis problematic. OBJECTIVE: In the present study, we used flow cytometry to analyze peripheral blood B-cell subsets in patients with THI and unclassified hypogammaglobulinemia (UCH), partial IgA deficiency, and selective IgM deficiency. METHODS: The study population comprised 41 patients with hypogammaglobulinemia (THI, 18; UCH, 23), 16 patients with partial IgA deficiency, and 16 patients with selective IgM deficiency who were admitted to Ankara University Department of Pediatric Immunology-Allergy between January 2010 and April 2011, as well as 29 healthy controls. B-cell subsets were examined according to the EUROclass classification. RESULTS: Age at diagnosis in the hypogammaglobulinemia group ranged between-14 months and 13 years (median, 26 months). Naive B-cell percentages were significantly higher and activated B-cell values lower in the THI patients than in the UCH patients and age-matched healthy controls. Nonswitched (IgM+CD27+IgD+) memory B-cell values were found to be significantly lower in patients with selective IgM deficiency than in healthy controls. No significant differences in B-cell subsets were found in patients with partial IgA deficiency. CONCLUSIONS: Previous reports show that reduced class-switched memory B cell values are associated with CVID, THI, and selective IgA deficiency. Our findings did not support these reports. Furthermore, we observed that naive B cell values were higher in patients with THI. A maturation defect could play a role in the pathogenesis of THI. PMID- 23654076 TI - Differences in the behavior of advanced glycation end products and advanced oxidation protein products in patients with allergic rhinitis. AB - BACKGROUND: The presence of oxidative stress in patients with asthma is well documented; however, the role of oxidative stress in allergic rhinitis has received less attention, although it is likely to be similar to that observed in patients with asthma. Advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs) are compounds formed by the transformation of macromolecules, including proteins, which can serve as densitometric markers of oxidative stress and inflammation in several diseases. OBJECTIVE: The aim of this study was to investigate the role of AGEs and AOPPs as new markers of oxidative stress and inflammation in patients affected by allergic rhinitis. METHODS: AGE and AOPP levels were determined in the sera of 25 patients with allergic rhinitis and 64 healthy controls. AGEs and AOPPs were detected using spectrofluorimetry and spectrophotometry, respectively. RESULTS: AGE levels in patients were significantly higher than those in controls (P < .0001). These levels were not affected by the presence of asthma. No statistically significant differences were found between AOPP levels in patients or controls (P = .38). CONCLUSIONS: Formation of AGEs and AOPPs may be accelerated in immunological and respiratory disorders such as asthma. Depending on the marker evaluated, the presence or absence of oxidative stress in allergic rhinitis is controversial. To our knowledge, this is the first study showing the possible involvement of AGEs in allergic rhinitis. The different behavior observed for these 2 biomarkers is very likely due to the activation of specific related biochemical pathways (eg, the myeloperoxidase pathway) associated with the condition under study. PMID- 23654077 TI - IL-4 gene polymorphisms and their association with atopic asthma and allergic rhinitis in Pakistani patients. AB - BACKGROUND AND OBJECTIVE: Interleukin (IL) 4 is a cytokine that mediates allergic responses. Different single nucleotide polymorphisms (SNPs) can influence the immune response mediated by cytokines. The aim of the present study was to investigate the possible association between IL-4 polymorphisms and allergic rhinitis and atopic asthma. METHODS: A total of 214 atopic patients (108 with asthma and 106 with allergic rhinitis) and 120 healthy controls from Pakistan were genotyped for IL-4 SNPs C-589T (rs2243250), T+2979G (rs2227284), and C-33T (rs2070874) using restriction fragment length polymorphism-polymerase chain reaction. Statistical analysis was performed using the statistical software package StatCalc, Epilnfo v.6. RESULTS: The SNP rs2243250 was significantly associated with both asthma (P = .004, chi2 = 11.0) and allergic rhinitis (P < .001, chi2 = 20.2), as was T-2979G (P < .001, chi2 = 22.51 for asthma and P < .001, chi2 = 57.6 for allergic rhinitis). The most frequent genotypes in the asthma and allergic rhinitis groups were TT for SNP rs2243250, and GG for SNP rs2227284. rs2070874 was not found to be associated with either of the 2 atopic respiratory diseases analyzed in the Pakistani cohort. CONCLUSIONS: rs2243250 and rs2227284 are significantly associated with asthma and allergic rhinitis. The results of this study indicate that in addition to environmental factors, genetic risk factors also play an important role in the development of atopic respiratory diseases. PMID- 23654078 TI - Nonadverse effects on allergenicity of isopentenyltransferase-transformed broccoli. AB - BACKGROUND: Genetically modified organisms (GMOs) provide modern agriculture with improvements in efficiency and the benefits of enhanced food production; however, the potential impact of GMOs on human health has not yet been clarified. OBJECTIVE: To investigate the allergenicity of isopentenyltransferase (ipt) transformed broccoli compared with non-GM broccoli. METHODS: Sera from allergic individuals were used to identify the allergenicity of GM and non-GM broccoli. Immunoglobulin (Ig) binding of different lines of GM and non-GM broccoli was identified using immunoblotting, enzyme-linked immunosorbent assay, and the histamin release assay. RESULTS: Positive reactions to broccoli (Brassica Oleracea) were observed in 7.02% of individuals. Specific IgE to broccoli and total IgE fro allergic individuals were well correlated. The different tests performed showed no significant differences in the allergenicity of conventionally raised and GM broccoli, indicating the absence of unexpected effects on allergenicity in ipt-transformed plants. Using Western blot analysis we detected heterogeneous IgE-reactive allergenic components in broccoli-allergic sera, but no significant differences between GM an non-GM broccoli were observed in serum from the same patients. CONCLUSIONS: Our study demonstrates that there are no differences between GM (ipt-transformed) broccoli and non-GM broccoli, as determined by specific IgE in sera from broccoli-allergic patients. This indicates that there were no unexpected effects on allergenicity in this GM broccoli. PMID- 23654079 TI - Soluble CD26 and CD30 levels in patients with common variable immunodeficiency. AB - BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by decreased serum immunoglobulin levels and increased susceptibility to recurrent bacterial infections. There is increasing evidence that the type 1 helper T cell (T(H)1)/T(H)2 cell balance is shifted towards a T(H) 1-type immune response in patients with CVID. This study was performed to measure levels of soluble CD26 (sCD26) and CD30 (sCD30) as plausible markers of a dysregulated immune response in a group of patients with CVID. METHODS: Twenty five patients with CVID and 20 age- and sex-matched controls were enrolled in this study. A sandwich enzyme-linked immunosorbent assay was used to measure serum sCD26 and sCD30 levels. RESULTS: The mean (SD) serum sCD26 level was significantly higher in patients with CVID than in controls (88.47 [59.82] ng/mL vs 28.31 [25.61] ng/mL, P = .001). Serum sCD30 levels were also significantly higher in patients with CVID than in controls (196.37 [169.71] ng/mL vs 30.72 [12.98] ng/mL, P < .001). Analysis of serum sCD30 levels in association with different clinical variables indicated that patients with splenomegaly and malignancy had significantly higher levels than patients without these disorders. However, serum sCD30 levels did not differ with bronchiectasis or autoimmunity. CONCLUSIONS: The presence of increased serum levels of sCD26 and sCD30 in patients with CVID suggests that CVID patients have a polarized immune response towards a T(H)1-like phenotype, whereas the association between high levels of these markers and disease severity suggests that the soluble form could be used as a prognostic tool in CVID. PMID- 23654080 TI - In vitro production of Ag-specific IFN-gamma in patients with delayed hypersensitivity to amoxicillin. PMID- 23654081 TI - Baseline tryptase levels are related to age, total IgE, and anti-rPru p 3 IgE levels in peach-allergic patients. PMID- 23654082 TI - Recurrent angioedema associated with secondary eosinophilia. PMID- 23654083 TI - Usefulness of oral food challenge and a visual analog scale in the etiologic diagnosis of eosinophilic esophagitis. PMID- 23654084 TI - Fixed drug eruption caused by piperacillin-tazobactam. PMID- 23654085 TI - Profilin may be a primary airborne sensitizer: a case report. PMID- 23654086 TI - Duck egg allergy in a patient who tolerates hen's eggs. PMID- 23654087 TI - Chronic granulomatous disease caused by a novel mutation in a 2-month-old boy with multifocal splenic abscesses. PMID- 23654088 TI - A case of DRESS syndrome induced by dipyrone. PMID- 23654089 TI - [Plasma proteomic research on obesity subtype and non-obesity subtype of T2DM]. AB - OBJECTIVE: With the increasingly serious epidemic situation of diabetes, plasma proteomic method and OFFGEL electrophoresis have been applied for screening different proteins between obese and non-obese T2DM patients, which may be used to further explain the mechanism of T2DM. METHODS: Twenty male T2DM volunteers (Obesity Subtype: 10; Non-obesity Subtype: 10) with the age of 18-44 years have been selected. The control group has been matched considering the factors of age, gender, etc. Albumin and IgG were removed from the plasma samples with highly specific immune-affinity method. Then the peptide-mixed samples were separated by pI with OFFGEL electrophoresis after solution digestion. Further separation and identification were performed by Nano HPLC-Chip-MS/MS system. Comparing the three groups, the differences were obtained and annotated on functions and its mechanism. RESULTS: 391, 415 and 371 proteins have been identified in the experimental groups and control group, respectively. The different proteins in groups and their annotations showed that adiponectin was down-regulated in obesity subtype of T2DM group, while STIM1 (stromal interaction molecule 1) was up-regulated. There were six protein kinases high expression in non-obesity DM patients, such as Serine-protein kinase ATM, Serine/threonine-protein kinase WNK1. CONCLUSION: Adiponectin, STIM1 and protein kinases may act in different roles on the pathogenesis of obesity subtype and non-obesity subtype of T2DM. PMID- 23654090 TI - [Genome DNA hypomethylation in HaCaT cells after short exposure to SiO2 nanoparticles]. AB - OBJECTIVE: To observe the effect of SiO2 nanoparticles on genome DNA methylation profile in cultured cells. METHODS: HaCaT cells were treated with nm-SiO2 at 2.5, 5 and 10 microg/ml and micro-SiO2 at 10 microg/ml for 24h and DAC treatment was given at 10 microg/ml group for 48h. The mC/(mC + C) percent was quantified by high performance capillary electrophoresis (HPCE) assay, and the expression level of mRNA and protein was detected by Real-time Q-PCR and westernblot assay. The activity of DNMTs was determined by DNA Methyltransferase Activity/Inhibition Assay Kit. RESULTS: HPCE assay showed that nm-SiO2-treated cells were decreased in some degree. An average proportion of methylated mC/ (mC + C) was 4.82% in control, 2.7% in 2.5 microg/ml and 2.17% in 10 microg/ml groups, while 3.1% in micro-SiO2 groups, which got the consistent downtrend of genome methylation level during increasing nm-SiO2 dose nanoparticles. The mRNA expression level for DNMT1 decreased gradually with increased dose of nm-SiO2 nanoparticles. The alterations at protein level were similar to those at the mRNA level. CONCLUSION: Genomic DNA methylation levels were decreased in HaCaT cells after short-term exposure to SiO2 nanoparticles. PMID- 23654091 TI - [Effects of soy protein supplement on overweight and obese population: meta analysis of randomized controlled trials]. AB - OBJECTIVE: To study the effects of soy protein supplement on overweight and obese population. METHODS: Randomized controlled trials (RCT) published from January 1988 to May 2012 observing the effect of soy protein supplement on overweight and obese population were collected. Meta-analysis was applied to estimate the standardized mean difference (WMD) and 95% confidence interval (95% CI). RESULTS: Among 13 RCTs, the number of the studies observing change of body weight, body mass index (BMI), fat mass and waist circumference were 12, 7, 7 and 11, respectively. Compared with the control group, the combined WMD (95% CI) of soy protein supplemented was - 1.04 kg [( -1.97) - ( -0.11)], -0.19 kg/m2 [(-0.41) - (0.02)], -0.99 kg [(-1.73) - (-0.24)] and - 0.94 cm [(-1.66) - (-0.21)], respectively. However, the protective effect of soy protein was only observed among studies conducted in Western population, but not in Asian population. CONCLUSION: Soy protein supplementation significantly decreased body weight, fat mass and waist circumference in overweight and obese population. PMID- 23654092 TI - [Effects of Chinese wild rice on lipid metabolism and lipotoxicity in rats fed with high fat/cholesterol diet]. AB - OBJECTIVE: To study the effects of four kinds of experimental diet, including high fat/cholesterol diet, Chinese wild rice diet, white rice-flour diet and basal diet on the lipotoxicity and disordered lipid metabolism in rats. METHODS: 44 male SD rats were divided into four groups, the basal group, high fat/cholesterol diet group, white rice-flour group and Chinese wild rice group. All rats of four groups were given different diets. Body weights were measured every week, serum total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), free fatty acids (FFA) and leptin concentrations were measured, and liver pathology were observed. RESULTS: When compared with the basal diet group, the hyperlipidemic rat model was successfully made in high fat/cholesterol diet group. When compared with the high fat/cholesterol diet group and white rice-flour diet group, the serum TG and TC contents were significantly decreased (P < 0.05), and HDL-C concentration significantly increased (P < 0.05) in Chinese wild rice group. Moreover, Chinese wild rice group had lower contents of serum and liver FFA than those of the high fat/cholesterol diet group and white rice-flour diet group (P < 0.05). Although Chinese wild rice group had a lower serum leptin level than the high fat/cholesterol diet group and white rice-flour diet group, there was no significant differences among the three groups (P > 0.05). The conditions of liver cell fatty degeneration in Chinese wild rice group were slight. CONCLUSION: Compared to the white rice-flour diet, Chinese wild rice could improve the lipid metabolism and liver lipotoxicity of hyperlipidemic rats induced by high fat/cholesterol diet. PMID- 23654094 TI - [Accumulative levels of organochlorine pesticides of HCHs, DDTs in breast milk and risk factors analysis in Shenzhen]. AB - OBJECTIVE: To first investigate the accumulative levels of DDTs and HCHs in human breast milk of primipara in Shenzhen area, analyze influencing factors and assess exposure risk of infant in Shenzhen. METHODS: From April in 2011 to April in 2012, 85 primiparas who have lived in Shenzhen over 3 years after parturition 4 - 6 weeks were recruited, and their breast milk were collected and questionnaires were filled out simultaneously. The samples were extracted five times with hexane, cleaned up by gel permeation chromatograph (GPC) and SPE, and quantified by gas chromatography-election capture detection (GC-ECD). Correlations between DDTs, HCHs and maternal age, weight, dietary, living time as well as infant birth weight and length were also analyzed with the SPSS 13.0 statistical software respectively. RESULTS: Among the several groups of DDTs and HCHs metabolites, p,p'-DDE were detected in total 85 samples and beta-HCH were detected in 58 samples, which accounted for 68.2% of the breast milk. The median levels of sigmaHCHs and sigma DDTs were 2.980 ng/g whole weight (80.200 ng/g fat) and 9.610 ng/g whole weight (268.390 ng/g fat). Both levels of sigmaHCHs and sigmaDDTs in the human milk had a positive association with maternal age among the demographic characteristics of primiparas. Furthermore, levels of sigma HCHs were positively correlated with freshwater fish consumption. However, sigma DDTs levels which were calculated in fat had a positive association only with the amount of poultry meat intake. CONCLUSION: Beta-HCH and p,p'-DDE were detected in human breast milk, and correlated with age and dietary intake. The average estimated daily intakes of HCHs and DDTs by infants are 0.468, 1.842 microg/(kg x BW x d) respectively, lower than acceptable daily intakes (ADI) proposed by the Ministry of Health of China and (the WHO/FAO) Joint Meeting of Pesticide Residues (JMPR). The average levels of HCHs, DDTs in the breast milk in Shenzhen general population are lower than those of Chinese average level. PMID- 23654093 TI - [Research of the whole grain-soybean compound package to regulate the cholesterol metabolism by SREBP-2, LDLR and visfatin]. AB - OBJECTIVE: To discuss the possible mechanism of the whole grain-soybean compound package on dyslipidaemia rats. METHODS: 44 SD rats were randomly divided into four groups: the hyperlipidaemic group, the rice-flour group, the whole grain soybean compound package group and the negative control group by lipid profiles, fed with corresponding feed for eight weeks. Serum total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were measured before and after the test. At the end of the experiment, blood samples were taken from the femoral artery, the rat organs were collected and weighted. Serum Visfatin levels and SREBP-2 mRNA and LDLR mRNA in the liver were measured. RESULTS: Compared with the hyperlipidaemic group and rice-flour group, the body weight, serum TC, TG and LDL-C of whole grain-soybean compound package group were significantly decreased (P < 0.05), HDL C was significantly increased (P < 0.05). Visfatin levels were significantly decreased (P < 0.05). Gene expressions of SREBP-2 and LDLR were significantly increased (P < 0.05). Gene expression of Visfatin in whole grain-soybean compound package group was significantly lower than that in hyperlipidaemia group and rice flour group (P < 0.05). CONCLUSION: Whole grain-soybean compound package can improve the serum lipid profiles and Visfatin of rats fed with a high fat diet. The possible mechanism is that the whole grain-soybean compound package can activate the expression of SREBP-2, LDLR and Visfatin. And then enhance the expressing activity of regulate the cholesterol metabolism by SREBP-2, LDLR and Visfatin. Ultimately, to reduce the level of rats' cholesterol, and then ameliorate the dyslipidaemia of rats. PMID- 23654095 TI - [A case-control study on tea consumption and the risk of lung cancer]. AB - OBJECTIVE: To investigate the association between tea consumption and lung cancer. METHODS: A case-control study was conducted, including 1225 newly diagnosed cases with lung cancer and 1234 healthy control subjects frequently matched by gender and age (+/- 3 year). Epidemiological data were collected by in person interviews using a standard questionnaire. The adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated by fitting multivariate unconditional logistic regression models that included potential confounding factors. RESULTS: A protective effect of tea drinking on risk of lung cancer was observed for non-smokers with adjusted OR was 0.465 (95% 0.345 - 0.625), and the risks decreased with increased years of tea drinking. The adjusted ORs for drinking green tea, black tea, oolong tea and others was 0.333 (95% CI 0.154 -0.720), 0.522 (95% CI 0.356 - 0.767), 0.735 (95% CI 0.424 - 1.274) and 0.267 (95% CI 0.143 - 0.497), respectively. The inverse associations were also observed between frequency, concentration, consumption and risk of lung cancer among non-smokers. Tea drinking was associated with decreased risk of lung cancer for those smokers with drinking tea < 3 times/week and low concentration, with the adjusted ORs of 0.453 (95% CI 0.286 - 0.717) and 0.518 (95% CI 0.346 - 0.778), respectively. CONCLUSION: The protective effect of tea drinking was observed on the risk of lung cancer, especially for non-smokers. PMID- 23654096 TI - [Influence of magnesium supplementation on insulin receptor affinity in erythrocytes of type 2 diabetes rats]. AB - OBJECTIVE: To observe the influence of oral magnesium supplementation on insulin receptor affinity in erythrocytes of type 2 diabetes rats. METHOD: diabetes rats were induced by high-fat-diet and intraperitoneal injection of streptozocin, and divided into 4 groups. Magnesium was supplemented in high-fat-diet at the dose of 2000, 1000, 200 and 0 mg/kg,respectively. Normal control rats were fed with ordinary diet. Rats were killed after four weeks. Erythrocytes insulin receptor number, combination constants, combined capacity, fasting insulin level and fasting glucose levels were measured, and insulin resistance index and insulin sensitivity index were calculated. RESULTS: High affinity insulin receptor combination constant, combined capacity and receptor number in high dosage group were (1.24 +/- 0.47) x 10(9) L/mol, (1.26 +/- 0.53) x 10(14)/L and 80.23 +/- 0.47 respectively, significantly higher than diabetes control group. Insulin resistance index decreased and insulin sensitivity index increased in high dosage group than diabetes control. CONCLUSION: Magnesium supplementation could improve erythrocyte insulin receptor affinity and improve insulin resistance in type 2 diabetic rats. PMID- 23654097 TI - [Comparison of four cytotoxicity assays for determining the acute toxicity of diesel exhaust particulate extracts]. AB - OBJECTIVE: To compare the determination ability of four in vitro cytotoxicity assays for acute toxicity of diesel exhaust particulate (DEP) extracts. METHOD: The cell viability of cultured 16HBE cells was measured by the MTT assay, the neutral red assay, the lactate dehydrogenase (LDH) leakage assay and the determination of total protein content after 12, 24 and 48h of being exposed to DEP extracts at different concentrations of 5, 10, 20, 40, 80 and 160 microg/ml. RESULTS: For measuring the acute cytotoxicity, the MTT assay was more delicate than the other three methods after 12h exposure. The sensitivity of both the MTT assay and the neutral red assay increased as the exposure time extended. The cell viability at each dosage decreased significantly after being exposed to DEP extracts for 24h compared to the control group (P < 0.05). When using the LDH assay, the cell viability reduced after 24h exposure to DEP extracts, but changed no more as time prolonged. Only the cell viabilities of the groups exposed to the high dosages of DEP extracts were observed with significant reduction by the protein assay after 12h and 24h exposure respectively. The cell viabilities measured by the same method at all dosages decreased after 48h exposure. CONCLUSION: The results of the four cytotoxicity assays showed differences in the present study. The MTT assay and the neutral red assay are more sensitive in detecting the adverse effect to 16HBE cells done by DEP extracts compared to the LDH assay and the protein assay. Taken the indicants of each toxicity assay into account, the DEP extracts may have major adverse effects on the functions of the organelles in 16HBE cells, such as mitochondria and lysosomes, however little influence to the cell anchorage dependence and the cell membrane damage. PMID- 23654098 TI - [Meta-analysis of studies on cut-off value of serum ferritin for identifying iron deficiency]. AB - OBJECTIVE: To synthesize evidence to discuss the appropriate cut-off value of serum ferritin (SF) for identifying iron deficiency. METHODS: A comprehensive electronic search and manual tracking were performed to collect potential studies on cut-off value of SF for identifying iron deficiency. Most relevant studies were identified according to the inclusion and exclusion criteria and data were extracted. All included studies were divided into three groups according to the cutoff value of SF: 12 -20 microg/L group, 25 microg/ L or 30 microg/L group and 36 - 60 microg/L group. Heterogeneity of the included studies was tested to select proper efficacy model for calculating pooled weighted diagnostic indicators and their 95% CI. Summary receiver operating characteristic (SROC) curve was made and the area under the curve (AUC) and Q * index were calculated respectively for the three groups. Finally, sensitivity analysis were performed. RESULTS: A total of 14 studies were included and were divided into three groups. After the pooled efficacy analysis, we found that the 12 - 20 microg/L group showed the lowest pooled sensitivity (0.767, 95 CI 0.705 -0.821) but highest specificity (0.959, 95 CI 0.934 -0.976). Compared with the other two groups, the pooled sensitivity of 25, 30 microg/L group (0.877, 95 CI 0.799 - 0.933) was highest, its pooled specificity was (0.944, 95 CI 0.888 - 0.977), the pooled sensitivity and pooled specificity of 36 - 60 microg/L group (0.836, 95 CI 0.797 0.870), (0.876, 95 CI 0.846 - 0.901)] were both relatively low. In terms of the integrated diagnostic capabilities, the 25, 30 microg/L group showed the highest diagnostic odds ratio (101.42, 95 CI 36.137 - 284.64), the largest AUC (0.9497 +/ 0.039) and the Q * index nearest 1 (0.8901 +/- 0.052) among the three groups. After we removed the studies with samples less than 50 and the studies from Chinese authors, the 25, 30 microg/L group still showed the best diagnostic efficiency. CONCLUSION: 25 or 30 microg/L of SF as the cut-off value of identifying iron deficiency shows high accuracy and good integrated diagnostic capability. PMID- 23654099 TI - [Influence of phthalates from Shaying river on children's intelligence and secretion of thyroid hormone]. AB - OBJECTIVE: To investigate the effect of phthalates exposure from drinking water on children's intelligence and secretion of thyroid hormone. METHODS: Two villages in S County were selected randomly as polluted area and control area according to the distance from the Shaying river basin. Phthalates including DEP, DBP, DMP, DEHP were measured both in the river water and drinking water using HPLC method. Children aged 8 to 13 years old studying in the village primary school were recruited by cluster sampling (n = 154). The combined Reven Test was used to test children intelligence and ELISA method was used to determined thyroid hormone levels. RESULTS: The concentrations of phthalates (DEP, DBP) were exceeding standards of surface water quality in any of the three sections of the river. Compared to the control area, the concentration of DEP and DBP in drinking water were significant higher in the polluted area than that in control area (P < 0.05). Children from polluted area had significant higher FT4 concentration compared to children from control area (P < 0.05). Intelligence level in children from polluted area was lower than that from control area (P < 0.05). CONCLUSION: The drinking water has been polluted by Shaying river and thyroid hormones levels of children were affected in the polluted areas. It is necessary to verify if this change is related to the phthalates. PMID- 23654100 TI - [Influence of water fluoride exposure on sex hormone binding globulin and testosterone in adult male]. AB - OBJECTIVE: To explore the influence of water fluoride exposure on sex hormone binding globulin (SHBG) and testosterone in adult male. METHODS: Cross-sectional study was conducted in three villages of Tongxu county including high fluoride group (HFG), defluoridation project group (DFPG) and control group (CG) based on the fluoride concentration in drinking water. Adult male who were born and raised in the village and aged 18 - 50 years old were recruited using cluster sampling. Fasting blood and morning urine samples were collected. The fluoride levels in drinking water and urine were detected by fluoride-ion selective electrode method. Serum SHBG level was determined using enzyme-linked immunosorbent assay (ELISA). The chemical luminescence immune analysis method was used to detect serum testosterone content. RESULTS: Serum SHBG level was 47.85 nmol/L in CG, 31.37 nmol/L in DFPG and 24.52 nmol/L in HFG respectively. There were significant difference among of three groups (P < 0.05). Serum testosterone level was 3.69 ng/ml in CG, 4.61 ng/ml in DFPG and 4.83 ng/ml in HFG respectively. Serum testosterone level in HFG was significantly higher than that in CG (P < 0.05). Serum SHBG level in HFG has positive correlation with serum testosterone (r = 0.230, P = 0.049), which has not been observed in DFPG and CG. CONCLUSIONS: Long time fluorine exposure may affect serum SHBG and testosterone level in adult male. PMID- 23654101 TI - [Effects of oleic acid on expression of adiponectin and its PPARgamma mechanism in 3T3-L1 adipocytes]. AB - OBJECTIVE: To explore the effects of oleic acid on the gene and protein expression of adiponectin and its PPARgamma mechanism in 3T3-l1 adipocytes. METHOD: L1 adipocytes were incubated with different concentration (25, 50, 100, 200, 400 micromol/L) for 24h, and the mRNA expression of adiponectin and PPARgamma was determined by real-time PCR (relative quantity). And then the 3T3 L1 adipocytes were treated for OA at concentration of 100 micromol/L for 24h with/without the affect of PPARgamma inhibitor GW9662, to determine the gene and protein expression of adiponectin. The protein expression changes of adiponectin were detected by immunoblotting. RESULT: The mRNA expression of adiponectin and PPARgamma increased at the dosages of 25, 50, and 100micromol /L. With the increase of OA, the mRNA expression of adiponectin and PPARgamma decreased in a dose-dependent manner. Incubating with GW9662 and OA, decreases in the mRNA and protein expression of adiponectin were 77% and 78.01% (P < 0.05), compared with the control respectively. CONCLUSION: OA could increase the gene expression of adiponectin and PPARgamma mRNA in dose-dependent manner in 3T3-L1 adipocytes,which could be specifically blocked by GW9662, OA indues the expression of adiponectin mRNA and protein in 3T3-L1 adipocytes, possibly by a mechanism involving PPARgamma. PMID- 23654102 TI - [Relationships between serum ghrelin and lipid profile and serum leptin, adiponectin, and insulin among children in Beijing, China]. AB - OBJECTIVE: To study the relationship between serum ghrelin and lipid profile and serum leptin, adiponectin, and insulin among children in Beijing. METHODS: A total of 879 pupils aged 8 - 10 years were randomly selected. Height, body weight, waist circumference, body mass index (BMI), body fat percentage (%BF), blood lipid, serum leptin, insulin, adiponectin and ghrelin were measured in all samples. RESULTS: Ghrelin associated negatively with body weight, waist circumference, BMI, %BF, serum leptin level and positively with HDL-C. Factor analysis has shown five factors which were sufficient to explain correlations between variables-body composition and leptin, dyslipidemia, glucose metabolism and adiponectin. CONCLUSION: Serum ghrelin level correlated strongly with body weight, waist circumference, BMI, %BF and leptin, Our finding suggested significantly increased leptin levels following decreased ghrelin levels could mostly disordered adipose metabolism at early obesity in children. PMID- 23654103 TI - [Reevaluation of the scale of psychological resilience for middle and primary school students]. AB - OBJECTIVE: To evaluate the feasibility of applying the self-rating scale of psychological resilience for middle school students among students of grade four to six in primary school and grade one to three in middle school in Changfeng county, Anhui province. To provide evidence for future study on mental health of middle and primary school students and left-behind children in Changfeng county. METHODS: The cluster sampling method were used to select three middle schools and five primary schools from Changfeng County in Hefei City. The psychological resilience among 2655 students of grade four to six were evaluated. The reliability and validity were analyzed. The self-rating scale of psychological resilience measures six dimensions included problem solving, cooperation and communication, self-efficacy, goals and aspirations, self-awareness, and empathy. RESULTS: The coefficient of Cronbach's a of the total scale scores was 0.944, that of grade four to six in primary school and grade one to three in middle school were from 0.932 to 0.947, and that of six factors were from 0.772 to 0.883. The correlation coefficient of split-half of the total scores was 0.874, and that of grade four to six in primary school and grade one to three in middle school were from 0.848 to 0.892. The test-retest reliability of the total scores was 0.894, and that of six factors were from 0.753 to 0.839, all correlations were significant statistically. Varimax rotation factor analysis was adopted and got six factors. Their accumulative contribution to total variance was 64.532%. The correlation coefficients between each item and the total scores were from 0.434 to 0.717, between each item and corresponding factors scores were from 0.683 to 0.876, between the total scores and six factors scores were from 0.692 to 0.846, among six factors scores were from 0.401 to 0.689, all correlations were significant statistically. The correlation coefficient between the total scores of the scale and depression was -0.493, and anxiety was -0.290, all correlations were significant statistically at the level of 0.01 with both side. CONCLUSION: The reliability and validity of the self-rating scale of psychological resilience for middle school students are well among students of grade four to six in primary school and grade one to three in middle school and it can be used to evaluate the psychological resilience level of these people including left-behind children. PMID- 23654104 TI - [Drinking behaviors of adults at different time of day in four cities of China in summer]. AB - OBJECTIVE: To investigate the drinking behaviors of adults at different time of day in four cities of China in summer. METHODS: A total of 1483 adults aged 18 - 60 years old from Beijing, Shanghai, Chengdu and Guangzhou were selected using multiple-stage random sampling method. The information of amounts and types of daily drinking water was recorded by subjects for seven consecutive days using a quantitative measurement. RESULTS: The proportion (97% - 99%) and mean (290 - 471 ml) of drinking water of subjects after breakfast, lunch and supper are higher than other time of day (P < 0.01). The distribution of plain water, tea, beverages at different time of day was the same as total drinking water. Among three periods a day, the amount of drinking water in the morning (719 ml/d) was the most, followed by in the afternoon (539 ml/d), and the least in the evening (417 ml/d), the difference was statistically significant (F = 972.55, P < 0.01). The highest consumption of plain water and beverages were in the morning. The consumption of tea in the morning was close to it in the afternoon and higher than that in the evening (t = -52.13, P < 0.01). The average daily drinking water in mealtime was 240 ml, while non-mealtime was 1436 ml, so the difference was statistically significant. Beverages in non-mealtime were higher than mealtime while plain water in non-meal time was higher than meal time (P < 0.05). CONCLUSION: The highest consumption of drinking was plain water among three periods a day, and beverages were higher in mealtime while plain water higher in non-mealtime. PMID- 23654105 TI - [Prevalence of overweight and obesity in primary school students from Wenzhou city and the analyses of the risk factors]. AB - OBJECTIVE: To investigate the prevalence of overweight and obesity in primary school students from Wenzhou City in Zhejiang Province, and to explore their relative risk factors. METHODS: Multi-stage stratified cluster sampling method was used to select 9035 children from the primary schools in Wenzhou City for the anthropometric measurements. 369 obesity cases and their paired controls of 389 children were chosen based on the large sample investigation. Diet and lifestyle factors were investigated in the nested case-control study for following logistic regression analyses. RESULTS: The overall prevalence of overweight and obesity was 11.2% and 6.4%, respectively. Male group had higher prevalence than female (P < 0.05). High frequency of vegetable intake, milk and dairy products intake, more physical activity were the benefit factors for preventing obesity (multi-variable logistic regression analysis, OR = 0.770, 0.821, 0.697 and 0.567, P = 0.033, 0.037, 0.017 and 0.008, respectively), whereas longer sedentary behavior was the risk factor of obesity (OR = 1.583, P = 0.003). CONCLUSIONS: The prevalence of both overweight and obesity in students from the primary schools were high in Wenzhou city, and were highly related to the diet habit and physical activity. PMID- 23654106 TI - [Pyroptosis induced by zinc oxide nanoparticles in A549 cells]. AB - OBJECTIVE: To explore whether exposure to zinc oxide nanoparticles (ZnO-NPs) induced pyroptosis in human alveolar type II epithelial cells (A549). METHODS: A549 cells were stimulated with different concentrations of ZnO-NPs (10 and 20 microg/ml) for 8 and 24h, respectively. The activity of lactic dehydrogenase (LDH) and the levels of interleukin-1beta (IL-1beta) in cell culture media were respectively measured by LDH activity kit and human IL-1beta ELISA kit. The activity of caspase-1 in A549 cells was detected by caspase-1 colorimetric assay kit. RESULTS: At 8h exposure to ZnO-NPs, there was no significant difference in the activity of LDH in the cell culture media among the ZnO-NPs-treated and control groups, but the activity of caspase-1 and the levels of IL-1beta in A549 cells were significantly increased in 20 microg/ml ZnO-NPs group compared to that in the control group (P < 0.05). Levels of IL-1beta and activity of LDH in the groups treated with ZnO-NPs (10 or 20 microg/ml) were significantly higher than that in the control group after 24 h exposure to ZnO-NPs, but there was no significant difference in the activity of caspase-1 among ZnO-NPs and control group. CONCLUSION: ZnO-NPs (20 microg/ml) treatment induces early increase in caspase-1 activity followed by the increase in LDH activity and IL-1 levels, indicative of pyroptosis in A549 cells. PMID- 23654107 TI - [Be based on the morphological and histological changes to study optimal dose of TCDD induced cleft palate in mice embryo]. AB - OBJECTIVE: To define the optimal 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) dose based on the morphological and histological changes of fetal mice cleft palate induced by different TCDD doses. METHODS: The pregnant mice were randomly divided into five groups and 6 in each grouop, and were gavaged on gestation day 10 (GD10). The control group were given 0.1 ml corn oil, and the experimental groups I, II , III, IV were given 32, 28, 24, 20 microg/kg TCDD respectively. To weight pregnant mice and embryos, record the number of live, cleft palate, dead and resorption fetal mice on GD 17.5. Another 15 pregnant mice were randomly divided into five groups (same as above) and 3 in each group. The coronal sections of the fetal mice heads were prepared at GD 13.5, 14.5 and 15.5 respectively, stained with haematoxylin-eosin staining (HE) and observed by microscopy. RESULTS: No significant differences in embryonic weight and live fetuses weight in each group. Compared with the control group,experimental groups I - III had small palate shelves (PS) and delayed palae shelves lift; the palate development and elevation in experimental group IV was similar to the control group. The incidence of cleft palate in the experimental groups I - IV were 97.37%, 93.02%, 65.12%, 56.82%, and no cleft palate in the control group. CONCLUSION: The optimal dose of TCDD to induce cleft palate in C57BL/6J mice is 28 microg/kg. PMID- 23654108 TI - [Study on synergistic effect of bactericidal effect of chlorine dioxide solution by surfactant]. AB - OBJECTIVE: To study the effect of gemini fluorocarbon, sodium p-perfluorous nonenoxybenzene sulfonate and sodium dodecyl sulfate on the chlorine dioxide solution sterilization to object surface. METHODS: Pure chlorine dioxide solution as the reference disinfectant, carrier quantitative bactericidal test and simulated test on-site were used to carry out laboratory observation according to The disinfection technical specifications (2002). RESULTS: Carrier quantitative bactericidal test showed that the addition dosage of gemini fluoronates, sodium dodecyl sulfate surfactant and perfluorinated the nonene oxy benzene sulfonate in disinfectant solution were 60, 60 and 40 mg/L respectively, the killing log value of Staphylococcus aureus exposed to the disinfectant solution containing chlorine dioxide 50 mg/L for 10 mm were all more than 3; and the addition dosage of gemini fluorinates, sodium dodecyl sulfate and perfluorinated the nonene oxy benzene sulfonate in disinfectant solution were 60 mg/L, the killing log value of Escherichia coli exposed to the disinfectant solution containing chlorine dixoxide 20 mg/L for 10 min were all more than 3. The bactericidal effect of the mixture use of surfactant and chlorine dioxide was better than the single use of chlorine dioxide. The simulated test on-site showed that the killing log value of Escherichia coli exposed to the disinfectant solution containing perfluorinated the nonene oxy benzene sulfonate 40 mg/L and chlorine dioxide 20 mg/L for 15 min was more than 3. CONCLUSION: Surface active agent on germicidal efficacy of chlorine dioxide solution had synergistic action. PMID- 23654109 TI - [Analysis on nutritional component of Cervus elaphus products]. AB - OBJECTIVE: To investigate nutrient values in the Cervus elaphus, so as to provide a scientific basis for choosing products by businesses and consumers. METHODS: According to the national standards required for various nutritional elements, the amount of protein, energy, fat, water, ash, amino acids, minerals, vitamin in different parts of the Cervus elaphus (venison, tail, penis cervi, sinew) were determined, carbohydrate and energy were calculated, and were compared with Cervus nippon. RESULTS: Nutritive characteristics of Cervus elaphus and Cervus nippon were similar. The respective portion of protion in Cervus elaphus venison, Cervus elaphus tail, Cervus elaphus penis cervi, Cervus elaphus sinew were 22.6, 70.7, 85.8 and 89.5 g/100 g; The respective Amino acid score portion in Cervus elaphus venison, Cervus elaphus tail, Cervus elaphus penis cervi, Cervus elaphus sinew were 97, 78, 45, 37. In all Cervus elaphus products, the highest contents of fat, cholesterol, calcium, potassium, iron, vitamin B2 and vitamin B12 were found in Cervus elaphus tail. The highest contents of protion and the lowest contents of potassium, iron and zinc were found in Cervus elaphus sinew. The INQ of protein, cholesterol, potassium, iron, zinc, vitamin B2 and vitamin B12 in Cervus elaphus venison were all above 2, and fat INQ was under 1. CONCLUSION: Cervus elaphus is a kind of high quality animal food which is rich in protein, potassium, iron, zinc, vitamin B2, vitamin B12 and essential amino acids, and low in fat. PMID- 23654110 TI - [Effect of L-arabinose on the postprandial blood glucose and body weight]. AB - OBJECTIVE: To study the effect of L-arabinose on the blood glucose level of adult, and to find out the optimal amount of daily L-arabinose intake for maintaining their health. METHODS: 50 adult were randomly selected and assigned to 5 group with different dose of L-arabinose or placebo, respectively. The preprandial blood glucose level and 1 h and 2h postprandial blood glucose were detected per 3 days. To investigate the variation of weight, 20 fat person was performed with daily L-arabinose or placebo intake for given daily for six months. Results After 30 days feeding, the decrease of postprandial blood glucose level was observed in group with 3% L-arabinose sample, and the groups with 5% - 10% have a significantly decreasing in the postprandial blood glucose level compared with control group result in (5.60 +/- 0.08) and (5.24 +/- 0.12), respectively (P < 0.05). The average body weight have a significantly reduce and after six months averagely reduced 5.5 kg, and the control group have no obviously variation. CONCLUSION: The daily consumption of L-arabinose would inhibit the postprandial blood glucose level and slimming down body which have a benefit for heath. PMID- 23654111 TI - [Reliability study on the infrared spectrometry for measuring the delta over baseline for breath 13C]. AB - OBJECTIVE: To assess the validity and reliability of the infrared spectrometry for measuring the delta over baseline for breath 13C. METHOD: Twenty-four healthy adults were selected, including twelve males and twelve females. 13C-Leucine was used as tracer in stable isotope metabolic experiments. One baseline breath was collected before the tracer protocol began. Other breath samples were collected at 60, 120, 180, 195, 210, 225, 240, 255, 270 and 300 min post-tracer challenge. The delta over baseline for breath 13C was measured by the infrared spectrometry and Heliview 13C breath analyzer. RESULTS: No significant differences were found between the infrared spectrometry and Heliview 13C breath analyzer in measuring the delta over baseline for breath 13C. The F value and p value of two-way ANOVA were 0.29 and 0.5874 respectively. The t and p value of consistency test were 0.48 and 0.6346 respectively. CONCLUSION: The 13C infrared spectrometry can reliably measure the delta over baseline for breath 13C. PMID- 23654112 TI - [Detection of phenolphthalein added illegally into anti-obesity and healthcare food by TLC-FTIR]. AB - OBJECTIVE: To establish a TLC-FTIR method for detection of western medicine phenolphthalein added illegally into anti-obesity and healthcare food. METHODS: The sample was extracted with anhydrous alcohol. The stationary phase was the GF254 aluminium alloy silica gel plates (10 cm x 20 cm) while the developing solvent was acetic ether: petroleum ether (60-90): methanol = 10: 6: 1. The sample volume was 2 microl. After primary screening by the UV lamp 254nm and self made 2% NaOH test paper, the preparative technique of TLC was used to separate the component. Then the component was detected by FTIR and compared with the FTIR spectrogram of standard substance. RESULTS: Five of the ten samples contained phenolphthalein with the same testing results by using the TLC scanning and HPLC. CONCLUSION: The established method is accurate and reliable and can be used for detection of phenolphthalein illegally added into the products. PMID- 23654113 TI - [UV-visible spectrum study on anti-UV damaging plants extraction]. AB - OBJECTIVE: To develop nature agent absorbing ultraviolet from plants for preventing UV damage. METHODS: Conduct ultraviolet visible spectrum scanning to aqueous extraction and alcohol extraction from polygonatum odoratum and onion. And compare the spectrum of Heilongjiang and Hunan polygonatum odoratum extraction. Dilute 5 times of the aqueous and alcohol extraction from 1g Heilongjiang, Hunan polygonatum odoratum to conduct UV visible spectrum scanning. Dilute 50 times of the aqueous and alcohol extraction of 20 g fresh onion and conduct ultraviolet visible spectra scanning. RESULTS: For the aqueous extraction of Heilongjiang and Hunan polygonatum odoratum by ultraviolet visible spectrum scan, both of them had strong absorption in the 290 nm to 400 nm while the absorption value of Heilongjiang's is slightly lower than the Hunan's in the ultraviolet region (290 nm to 320 nm) and the absorption value of Heilongjiang's was significantly better than Hunan's in the long-wavelength ultraviolet region (320 nm to 400 nm). For alcohol extraction, the absorption values were significantly different from 290 nm to 400 nm. Hunan's was stronger while Heilongjiang's was weaker in 290-320 nm. Onion aqueous extraction had strong absorption only at 358 nm while alcohol extraction has strong absorption from 290 nm to 400 nm. CONCLUSION: Absorption value of polygonatum odoratum aqueous extraction was stronger than alcohol extraction. Onion alcohol extraction in medium and long wave ultraviolet region had strong absorption spectrum. PMID- 23654114 TI - Lexical representation of Japanese vowel devoicing. AB - Vowel devoicing happens in Japanese when the high vowel is between voiceless consonants. The aim of this study is to investigate the lexical representation of vowel devoicing. A long-term repetition-priming experiment was conducted. Participants shadowed words containing either a devoiced or a voiced vowel in three priming paradigms, and their shadow responses were analyzed. It was found that participants produced the phonologically appropriate allophone most of the time based on the consonantal environments. Shadowing latencies for the voiced stimuli were faster than for the devoiced stimuli in the environment where the vowel should be voiced; while, no significant RT difference was observed between the two forms in the environment where vowel devoicing was expected. In addition, a priming effect between the devoiced and voiced stimuli emerged only in the devoicing environment. The results suggest that since vowel devoicing is very common in spoken Japanese, the devoiced form may be stored in the lexicon. The results also suggest a link between the two forms in the lexicon and a direct access between an input and a lexical representation without going through intermediate levels that usually cost extra processes. PMID- 23654115 TI - Perception and bias in the processing of compound versus phrasal stress: evidence from event-related brain potentials. AB - Previous research using picture/word matching tasks has demonstrated a tendency to incorrectly interpret phrasally stressed strings as compounds. Using event related potentials, we sought to determine whether this pattern stems from poor perceptual sensitivity to the compound/phrasal stress distinction, or from a post perceptual bias in behavioral response selection. A secondary aim was to gain insight into the role played by contrastive stress patterns in online sentence comprehension. The behavioral results replicated previous findings of a preference for compounds, but the electrophysiological data suggested a robust sensitivity to both stress patterns. When incongruent with the context, both compound and phrasal stress elicited a sustained left-lateralized negativity. Moreover, incongruent compound stress elicited a centro-parietal negativity (N400), while incongruent phrasal stress elicited a late posterior positivity (P600). We conclude that the previous findings of a preference for compounds are due to response selection bias, and not a lack of perceptual sensitivity. The present results complement previous evidence for the immediate use of meter in semantic processing, as well as evidence for late interactions between prosodic and syntactic information. PMID- 23654116 TI - Coarticulation in Catalan dark [l] and the alveolar trill: general implications for sound change. AB - Coarticulation data for Catalan reveal that, while being less sensitive to vowel effects at the consonant period, the alveolar trill [r] exerts more prominent effects than [l] on both adjacent [a] and [i]. This coarticulatory pattern may be related to strict manner demands on the production of the trill. Both consonants also differ regarding the relative prominence of the consonant-to-vowel anticipatory and carryover effects in VCV sequences: while [r] and [l] exert much anticipatory coarticulation on the preceding vowel, carryover effects on the following vowel turn out to be more salient for [r] than for [l]. These consonant dependent differences in coarticulatory direction parallel the directionality patterns observed in related vowel assimilatory and glide insertion processes occurring in the Romance languages, in Early Germanic, in Old, Middle and Modern English, and in Arabic when the target consonant is not [l] or [r] but a pharyngealized dentoalveolar. PMID- 23654117 TI - Contextual evidence for the representation of pitch accents in Standard Serbian. AB - This paper reports the results of an experiment that elicits contextual effects on Rising and Falling accents in Standard Serbian, with the goal of determining their acoustic correlates and their phonological representation. Materials systematically vary the distance between pitch accents, inducing "tone crowding," in order to identify the phonetic dimensions that consistently distinguish the two pitch accent types, to examine the association between accents and the segmental string, as well as the timing relationship between accent minima and maxima, and to investigate the interaction between lexical accents and boundary tones. On the basis of the phonetic findings, a unified analysis of the phonological distribution and phonetic realization of Falling and Rising accents in Standard Serbian is proposed. It is proposed that both Rising and Falling accents consist of a single lexical High (H). The restricted distribution of the two accents emerges from the interaction of stress and tone: Falling accents are monosyllabic, such that stress and pitch prominence coincide; Rising accents are bisyllabic, such that the stressed syllable precedes the pitch-accented syllable. The phonetic differences between the Falling and Rising accents follow from the place of lexically designated H, the location of stress, and the effects of boundary tones. The larger issue we address concerns the phonological characterization of tone/stress interactions. Given the two general types of interactions, one in which the place of stress is predictable from the place of tone, and the other with the reversed direction of influence, we analyze Standard Serbian as belonging to the former type. While both types can be characterized in systems of tonal phonology, which allow free interaction of tone and stress, the type exemplified by Standard Serbian, with contrastive tonal specifications governing the distribution of stress, cannot be captured in an Autosegmental Metrical (AM) framework, in which stress serves as anchor for tonal melodies. PMID- 23654118 TI - An analysis of noun definition in Cantonese. AB - This study investigated the noun definitions given by Cantonese speakers at different ages. Definitional responses on six concrete nouns from 1075 children aged 4;10 to 12;01 and 15 adults were analyzed with reference to the semantic content and the syntactic form. Results showed that conventional definitions produced by Cantonese adult speakers were realized with specific superordinates and more perceptual than functional attributes. The content was carried by a syntactic frame, "NP1, is NP2", where relative clause was not the predominant form of NP2 as in the English definition forms. Core attributes signifying the defining properties increased significantly with age while non-core attributes were observed relatively evenly throughout all groups. Preschoolers tended to drop the sentential-subject (i.e., NP1) and the copula is, and produce more functional than perceptual attributes. By Primary-2 (P2) (about 7;0), the taxonomic relation was coded with the frame of "NP1 is NP2". Beginning at P4 (about 9;0), children included a superordinate but the specificity of the adult like superordinate was not achieved even by P6 (about 11;0). In general, developmental trends accorded with the trends observed in other languages, but typological features played a role in framing the development of the syntactic form. PMID- 23654119 TI - Segmentation of written words in French. AB - Syllabification of spoken words has been largely used to define syllabic properties of written words, such as the number of syllables or syllabic boundaries. By contrast, some authors proposed that the functional structure of written words stems from visuo-orthographic features rather than from the transposition of phonological structure into the written modality. Thus, the first aim of the study was to assess whether the explicit segmentation of written words in French was consistent with syllabification patterns for spoken words previously reported. Second, given that spelling does not map perfectly with phonology, we examined how readers segmented printed words with grapheme/phoneme misalignments. The examination of the whole patterns of written segmentation produced by participants showed that, though written segmentation followed spoken segmentation for words matched for phonological/orthographic forms, discrepancies were found in cases of mismatch, therefore suggesting that readers rely on orthographic cues to parse printed strings of letters. This conclusion was confirmed with an on-line letter detection task. PMID- 23654120 TI - [Blood bath in a private setting. Deep cuts in the buttocks]. PMID- 23654121 TI - [Can healthy eating be a illness? (interview by Dr. Beate Schumacher)]. PMID- 23654122 TI - [Universities are producing too few general practitioners!]. PMID- 23654123 TI - [An ever increasing incidence of violence against physicians]. PMID- 23654124 TI - [Immune to nicotine addiction?]. PMID- 23654125 TI - [Which substances when?]. PMID- 23654126 TI - [Discontinuing the beta blocker before a stress test or not?]. PMID- 23654127 TI - [Healing through the skin and senses]. PMID- 23654128 TI - [Can swimming also be recommended?]. PMID- 23654129 TI - [Continuous right flank pain: what is compressing the kidney?]. PMID- 23654130 TI - [The sense and nonsense of diet programs]. PMID- 23654131 TI - [What weight loss methods could be recommended?]. PMID- 23654132 TI - [18 reasons why diet fail]. PMID- 23654133 TI - [Bite injuries]. PMID- 23654134 TI - [Patellar tendon rupture]. PMID- 23654135 TI - [Allergic rhinitis: burden of disease]. PMID- 23654136 TI - [Diabetes and sleep. What remains unrecognized by the patient]. PMID- 23654137 TI - [Hypertension in older patients]. PMID- 23654138 TI - [Targeted effect profile - proven effectiveness]. PMID- 23654139 TI - [Coughing attacks in children and adults reduced more rapidly]. PMID- 23654140 TI - [The diagnostic value of virus serology in patients with non-ischemic systolic heart failure and parvovirus B19 infection]. AB - INTRODUCTION: We determined retrospective analysis of the diagnostic value of virus serology in patients with non-ischemic systolic heart failure and parvovirus B19 infection. MATERIAL AND METHODS: Virus serology and endomyocardial biopsy were performed in 31 patients with non-ischemic systolic heart failure hospitalized from 2001 to 2006 in our clinic. RESULTS: The serum specimens from 31 patients were tested for IgM and IgG antibody against parvovirus B19. IgM antibodies were identified in 3 patients and IgG antibodies were identified in 23 patients. All of the patients underwent endomyocardial biopsy which revealed chronic active myocarditis in 10 patients (32.4%), chronic persistent myocarditis in 14 patients (45.1%) and no myocarditis in 7 patients (22.5%). CONCLUSIONS: Virus serology has no relevance for the diagnosis of non-ischemic systolic heart failure caused by parvovirus B19 infection. The result of serological tests are positive more frequently than the biopsy specimens results. PMID- 23654141 TI - [Ultrasonography in the diagnostics of reasons for the urinary incontinence at the postmenopausal woman. Part I--Two-dimensional ultrasonography]. AB - This article presents suitability of two-dimensional sonography in lower urinary tract diagnostics. Examination components, allowing for a detailed evaluation of anatomical changes in patients with urinary incontinence, were described. PMID- 23654142 TI - [Solitary rectal ulcer syndrome]. AB - Solitary rectal ulcer syndrome (SRUS) is a chronic, benign, polymorphic disease of the rectum, the final diagnosis of which is based on histopathologic criteria. Microscopic examination shows glandular changes, oedema and obliteration of the normal architecture in the region of the lamina propria, with muslce fibre penetrating into lamina. Although SRUS pathogenesis is bound up with defecation disorder, it still remains unclear. Disease symptoms are nonspecific--in most cases defecation disorders appear (incomplete defecation, blood and mucus in stool). In some patients emotional disorders can be observed. SRUS treatment is a complex and long-lasting process. Usually it is ineffective or gives only passing effects. SRUS can often be accompanied by rectal prolapse, sometimes a hidden one. In these cases there are more therapeutic possibilities and the prognosis is slightly better. There is no method of choice for SRUS treatment and the prognosis is hard to predict. The treatment should be selected individually, depending on the symptoms intensity and the occurrence of rectal prolapse. PMID- 23654143 TI - [The usefulness of the latest diagnostic and therapeutic criteria ACR/EULAR in the treatment of rheumatoid arthritis]. AB - In Poland nearly 400 thousand people are treated for rheumatoid arthritis and each year there are about 8 to 16 thousand new patients with this disease. Rheumatoid diseases constitute and enormous health problem which statistically encounters every the third person of the population. The condition for effective treatment of rheumatoid arthritis is early diagnosis and aggressive treatment of disease. So it became necessary to develop in 2010, the new ACR/ EULAR, much simpler than the ACR criteria of 1987, intended to enable the rapid implementation of appropriate intensive treatment, both conventional disease modifying drugs and biologicals. PMID- 23654144 TI - [Respiratory function impairment during treatment of chronic hepatitis C with peginterferon alfa2 and ribavirin. Two cases presentation]. AB - Pulmonary complications during standard therapy of chronic hepatitis C with pegylated interferon and ribavirin are rare but connected with wide spectrum of diseases from sarcoidosis to interstitial pneumonitis. The clinical course of that complications is often serious. In this paper, presentation of two patients with chronic hepatitis C with different anamnesis was shown. In the first case, without pulmonary burden, during therapy the features of pneumonitis were developed. In the second case, in patient with sarcoidosis, the antiviral therapy was carried out without important pulmonary aggravation. In reference to these observations and based on available literature, the pathogenetic mechanisms underlying pulmonary complications during this kind of therapy were discussed. Additionally, the scheme of pulmonary diagnostic proceeding in patients certified and then treated with peginterferon and ribawirin was proposed. PMID- 23654145 TI - [Drug-induced exacerbation of hypoaldosteronism in autoimmune polyglandular syndrome type 2]. AB - Hypoaldosteronism is a clinical condition resulting from inadequate stimulation of aIdosterone secretion (hyporeninemic hypoaIdosteronism), defects in adrenal synthesis of aldosterone (hyperreninemic hypoaldosteronism), or resistance to the peripheral action of this hormone (pseudohypoaldosteronism). The disease is characterized by a wide spectrum of clinical manifestations, ranging from asymptomatic hyperkalemia to life-threatening volume depletion, and, if unrecognized and untreated, it increases morbidity and mortality rates. In this paper, we report a case of a woman diagnosed with autoimmune polyglandular syndrome type 2. As a consequence of adrenal cortex destruction, the patient developed subclinical hypoaldosteronism which was effectively treated with small doses of fludrocortisone. Two and fours years later, she required ibuprofen and atenolol treatment and each of these treatments was accompanied by a transient deterioration in mineralocorticoid activity which resolved after drug withdrawal. This case shows for the first time that drugs reducing plasma renin activity may unmask subclinical hypoaldosteronism in subjects with autoimmune polyglandular syndromes, and that they should be avoided in patients with even small disturbances in the hormonal function of the zona glomerulosa. PMID- 23654146 TI - [Description of a patient with schizophrenia and coexisting megadose lorazepam dependence with slightly expressed withdrawl symptoms during drug reduction. A case report]. AB - The aim of this article is to present a patient with a megadose lorazepam dependence and slightly marked withdrawal symptoms during detoxication. The authors describe the case of 42 year old man who has been addicted to lorazepam (125 mg/d) for 2 years. On the ground of medical examination, anamnesis and hospital observation paranoid schizophrenia and lorazepam dependence syndrome was recognized. Despite relatively rapid reduction of lorazepam the withdrawal symptoms were slightly expressed. At the beginning of detoxication sleep disorders, feeling of "less looseness" and anxiety was observed. Review of medical database revealed other cases of megadose lorazepam dependence (95-300 mg/d). However in those cases withdrawal symptoms were distinct and the medical intervention was needed. PMID- 23654147 TI - [Cerebral salt wasting syndrome in a patient with posttraumatic brain injury]. AB - In patients with central nervous system disease, life-threatening hyponatremia can result from either the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or cerebral salt wasting syndrome (CSWS). Both clinical entities share many similar laboratory and clinical findings, and are characterized by low serum osmolality, inappropriately high urine osmolality, and high urine sodium levels. Despite outward similarities, the pathophysiology and treatment of these two conditions are very different. The former is treated with fluid restriction because of the increased level of free water and its dilutional effect causing hyponatremia, whereas the latter is treated with fluid and sodium resuscitation because of the increased loss of high urinary sodium. We present a 24-year-old man who developed CSWS after traumatic brain injury, showing diagnostic and treatment strategies undertaken in this patient and their impact on the course of CSWS. This case report illustrates the need for clinical awareness of CSWS in patients after head trauma. PMID- 23654148 TI - [Development of systemic lupus erythematosus after thymectomy performed in a patient with myasthenia gravis]. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, with not fully understood, complex origin. Several factors are suspected of involvement in the development of the disease. Genetic predisposition, environmental factors, some drugs, estrogens, cigarette smoking and ultra violet radiation seems to be the most important among them. The case of a patient with myasthenia gravis (MG) followed by thymectomy and lupus erythematosus (SLE) diagnosed one year later presented in this study. PMID- 23654149 TI - [Role of inflammation in etiology of atrial fibrillation--is lone arrhythmia really alone]. AB - We present the case study of recurrent AF episodes initially considered as a lone arrhythmia. Due to elevated C-reactive protein and fibrinogen serum levels with absence of other potential risk factors of arrhythmia and diseases underlying the genesis of inflammatory response we consider the plays a prominent role in etiology in perpetuation and maintenance of AF. Additional use of atorvastatin to a conventional therapy leads to significant reduction of C-reactive protein and fibrinogen and improves effect of long-term sinus rhythm maintenance. PMID- 23654150 TI - [The use of magnetic fields in the medical rehabilitation of patients after stroke]. AB - The article contains a literature review of the medical rehabilitation of post stroke patients using magnetic therapy. PMID- 23654151 TI - [Bach instead of midazolam?]. PMID- 23654152 TI - [Dapagliflozin. Lowering blood glucose levels by increasing glucosuria]. AB - The antidiabetic drug dapagliflozin lowers blood glucose levels by a novel mechanism: It increases the excretion of glucose via the kidneys. In clinical trials, HbA1c decreased by 0.5 to 0.7 percentage points if dapagliflozin was administered either in monotherapy or combined with other antidiabetic drugs. Common side effects are infections of the urogenital system. It is still unclear why patients in clinical trials suffered more often from cancer. Especially bladder cancer could be observed. However, the increase of cancer cases was not statistically significant. In contrast to the European Medicines Agency, the FDA has not yet approved dapagliflozin for safety reasons. PMID- 23654153 TI - [Micronutrients in oncology. Current data about vitamin D, selenium, L-carnitine and vitamin C]. AB - Many patients receiving cancer treatment use micronutrient supplements, with the intention to complement their cancer treatment, or help them cope with the therapy- and disease-associated side-effects. Up to 90% of the cancer patients are adding antioxidants without the knowledge of the treating physician. There are many concerns that antioxidants might decrease the effectiveness of chemotherapy, but increasing evidence suggests a benefit when antioxidants and other micronutrients, such as selenium, L-carnitine and vitamin D are added to conventional cytotoxic therapies. It is imperative that physicians discuss the use ofantioxidant and other micronutrient supplements with their cancer patients and educate them about potentially negative, but also potentially beneficial effects. PMID- 23654154 TI - [Measurement and data analysis of drug concentrations at the target site- potentials, limitations and fields of application]. AB - Drug measurements in the blood are only surrogates for drug concentrations in peripheral tissues, which often represent the target sites of the drug. Due to drug specific and physiological characteristics, however, blood and target site concentrations may differ. For this reason, methods to measure drug concentrations at the target site have been developed during the last years. During the last decade, microdialysis has become the method of choice for the continuous study of unbound tissue concentrations of drugs. In order to fully exploit these measurements to quantify the concentration-time profile of the investigated drug, different tools of data analysis can be applied. The aim is to contribute to decision-making in selecting the optimal dose 1) for dosing schedules during the development program of new drugs and 2) for therapeutic usage for physicians and pharmacists. For these aims, the so called ,,nonlinear mixed effect (NLME) modelling approach" presents the method of choice as it determines the typical concentration-time profile of a drug as well as the variability within the investigated study population. Additionally, between patient variability can be explained by patient-specific characteristics e.g. weight enabling dose individualisation within the whole investigated population. A systematic literature research in Pubmed for the use of antiinfectives in humans shows that the preferable methods of measuring concentrations at the target site (microdialysis) and data analysis (NLME) have rarely been used simultaneously. Hence, in future the benefit of linking both methods of choice should be further exploited in order to improve knowledge gain, to optimise antiinfective dosing regimens and to increase medication safety. PMID- 23654155 TI - [Bridging in anticoagulated patients. Bridging the anticoagulant gap in patients at risk]. PMID- 23654156 TI - Lessons in shiftinq the burden: #3. The critical moment for dental ethics. PMID- 23654157 TI - Someone guided your professional growth: do the same. PMID- 23654159 TI - 2012 American College of Dentistry awards. PMID- 23654158 TI - You will look good treating others with respect--I guarantee it. PMID- 23654160 TI - Position paper on digital communication in dentistry. AB - Digital communication offers advantages and challenges to dental practice. As dentistry becomes comfortable with this technology, it is essential that commercial and other values not be accepted on a par with professional ones and that the traditional dentist-patient relationship not be compromised by inserting third parties that introduce nonprofessional standards. The Officers and Regents of the American College of Dentist have prepared this background and position paper as a guide to the ethical use of digital communication in dental practice. PMID- 23654161 TI - People will talk. AB - The rise of the social media phenomenon and its impact on dentistry are discussed in the paper. The relationship between dentists and patients is growing wider and more indirect. Social media can be roughly characterized in five categories: social, reference, review, coupon, and information networks. Opportunities and threats posed by social media are explored. PMID- 23654162 TI - Introduction to social media. AB - This overview of social media categories some of the typical types and uses of this form of communication and suggests common courtesies and effective strategies for participation in the social media culture. PMID- 23654163 TI - Social media policy in other orqanizations. AB - Most professional organizations have developed policy for use of social media by their members and several have developed Web sites to help members with ethical media use. It is commmon among businesses, nonprofit organizations, and government agencies to have policies governing use of media by employees when communicating with the public and provide employee training. This article samples some of the best practices in social media policy. Development of such policy represents an attractive opportunity for dentistry. PMID- 23654164 TI - Being professional in the social media world. AB - What is at stake for dentists in the world of social media? Because it is unrealistic to completely avoid the new network, dentists should master some of these skills: risk management, crises management, and reputation management, as well as understanding that the playing field is not even. Guidelines for professional use of media are presented, along with some suggestions for effective participation. PMID- 23654165 TI - Different labs. AB - In this case a young dentist has signed onto a managed care plan that has several attractive features. Eventually, however, he notices that he makes little or no net revenue for some of the work that he does. A colleague recommends that he use different labs for different patients, with labs matched to each patient's dental plan and coverage. Offshore labs are used for managed care patients. Three knowledgeable experts comment on the case, two with many years of private practice experience, two who are dental educators holding master's degrees in philosophy and bioethics. PMID- 23654166 TI - Is general dentistry dead? How mid-level dental providers will affect the profession. AB - The rhetoric concerning mid-level providers and their impact on general dental practice is building in intensity. This is a complex issue and there is no clear picture of either the benefits or dangers to the public of such a delivery model, whether such plans are economically sustainable, or the role of general dentists in the configuration of future practices. The opinions of a representative sample of thinkers from various perspectives are sampled. PMID- 23654167 TI - Dentists demonstrating professionalism: Dentists in private practice settings provide free or reduced-fee care. AB - Access to oral health care is an issue that has received attention at the local, state, regional, and national levels. This study focuses on how dentists in private practice settings attempt to address problems regarding access to care through personal initiatives. These dentists donate or discount services in their own offices to individuals who face access barriers. These donated or discounted services may go unreported and unnoticed. The research question addressed in this study is: What was the amount and type of free and reduced-fee care that dentists in the community of Brookline, Massachusetts, provided during the 2008 calendar year. PMID- 23654168 TI - "Abuse of apprentice schemes risks safety". PMID- 23654169 TI - Fears over use of HCA apprentices. PMID- 23654170 TI - Staff must be free to raise safety concerns, says trust chief exec. PMID- 23654171 TI - All nurses should be improving public health, says DH director. PMID- 23654172 TI - "Beware the rituals - look for evidence behind your actions". PMID- 23654173 TI - Put nurses at the bedside, then work out how many are needed". PMID- 23654174 TI - After Francis: the government response. PMID- 23654175 TI - Is workplace culture an excuse for poor care? AB - This article looks at the issue of nurses' own responsibility for their actions. Negative behaviour can be explained by external factors, such as culture and the influence of others, or by internal ones, including a person's own moral compass. Within the context of the Francis report, this article raises questions about how we can ensure that nurses adhere to their code of conduct. PMID- 23654176 TI - Minimum training standards for HCAs. PMID- 23654177 TI - Minimising risk in the use of central lines. AB - Central lines are inserted for a number of clinical reasons, including to measure central venous pressure and the regular administration of intravenous drugs. One of their benefits is that several treatments can be given simultaneously. However, they are invasive and tend to leave patients prone to infection, so careful management is vital. This article focuses on the risk of infection, particularly of the bloodstream. PMID- 23654178 TI - Intravenous diuretic delivery in the home. AB - The British Heart Foundation is funding a two-year pilot programme at 12 UK sites to assess safe, effective ways for specialist nursing teams to administer intravenous diuretics at home or in day care. Initial findings suggest the service is effective, safe and preferred by patients and carers. It has the potential to reduce inpatient bed days, making significant savings. PMID- 23654179 TI - Can health visiting make the difference expected? PMID- 23654180 TI - 60 seconds with Elaine Maxwell. PMID- 23654181 TI - Just a perfect day. PMID- 23654182 TI - Have the courage to challenge others. PMID- 23654183 TI - [Paradigm shifts]. PMID- 23654184 TI - [Comparative study between 20 IU/ml heparin and 5% heparin/urokinase 5000 IU lock in hemodialysis central venous catheters with permeability problems]. AB - BACKGROUND: The central venous catheter prevalence as a permanent hemodialysis vascular access is growing in the last years. However, there is no consensus in the scientific community about what is the most appropriate lock solution to avoid complications. AIM: To compare the effectiveness and the cost between heparin 20 IU/ml (SH20) lock solution versus usual pattern (UP), consisted on 5% heparin/5000 IU urokinase lock solution in hemodialysis catheters with patency problems. METHODOLOGY: Experimental comparative study. Patients with a permanent hemodialysis central venous catheter with patency problems were included. Catheters were locked with SH20 during 6 sessions and with 5% heparin/5000 IU urokinase during another 6 sessions, depending on the patient. RESULTS: Of 50 patients in our unit, 7 fulfill the inclusion criteria. 42.9% had arterial branch resistance and 57% both branches resistance. Blood flow and venous pressure was similar in both periods. Blood lines reversal percentage was 15.85% using SH20 and 20.61% for UP, not statistically significant in all cases. The lock cost was 1 Euro/session with SH20 and 2.78 Euro/session with UP. CONCLUSIONS: 20 IU/ml heparin as a lock solution for hemodialysis catheters is as effective as the usual patterns but involves less systemic risk to the patient, reduced workload for nurses and lower cost per session. PMID- 23654185 TI - [Nursing care for psychiatric patients defined by NANDA-NIC-NOC terminology: a literature review]. AB - AIM: The purpose of this literature review is to provide a synthesis of the most relevant studies describing nursing work in mental health by means of NNN taxonomy. METHOD: Literature from 1990 to September 2011 was reviewed using the "scoping review" methodology. Three independent reviewers examined the articles which were found and selected those fulfilling the inclusion criteria for subsequent analysis. RESULTS: From the 220 articles obtained, 14 studies were finally included and divided into two groups. The aim of the first ten papers was examining the most frequent NANDA nursing diagnosis or/and NIC nursing interventions in different mental health care settings. The remaining four articles describe health care plans for psychiatric patients developed with NNN taxonomy. Combining results from both groups, the most prevalent diagnostic labels are: disturbed thought processes and impaired social interaction. CONCLUSIONS: This review has illustrated the lack of evidence in relation to NNN taxonomy in the field of mental health and the need of further research in this area. PMID- 23654186 TI - [Economic containment and satisfaction of nursing staff after the change of infusion sets at Hospital Santa Caterina of Salt (Girona)]. AB - INTRODUCTION: In situations such as the current economic crisis it is very important to consider the quality-price of healthcare materials. One of the most commonly used by nurses are the intravenous infusion sets. It is described the features of a new intravenous infusion set, that increases patient safety and improves the nursing care workload. OBJECTIVES: We suggested an analysis of the economic containment, as well as an appraisal of the nursing staff satisfaction, after the change of the intravenous infusion sets by new sets with different performances. METHODOLOGY: The study was conducted in the four hospital units at Hospital Santa Caterina of Salt (Girona): unit A (obstetrics and pediatrics), unit B (traumatology-surgery), unit F (internal medicine) and unit D (convalescence-palliative care). A cost study was developed comparing the costs in 2010 for the old intravenous infusion set with costs in 2011 for the new infusion set. A survey to assess the nursing staff satisfaction on the new infusion set was carried out in 2012 with 91 nurses (75.8% of nurses working in the four units). RESULTS: It has obtained an average decrease of 41.44% in consumption of infusion sets with Y and a 41.09% in infusion sets without Y This change of infusion sets has represented a financial saving of 8.003 Euros on sets with Y and 2.017 Euros on sets without Y And regarding the nursing satisfaction survey the results have mostly shown a high level of satisfaction in their management. In addition nurses surveyed considered that makes their task easier and improves the patient safety in hospital. CONCLUSIONS: The change by the new infusion set has reduced the consumption of infusion sets and meant considerable savings in costs of infusion sets, both sets with Y as in without Y. Nurses mostly manifest a high level of satisfaction. PMID- 23654187 TI - [Teens and sex education]. AB - It is widely debated among mental health professionals, among whom I include myself; the fact that not only teenagers who come to our clinics need good sex education, but that parents and/or legal guardians, often also it would be beneficial. I do not mean much to the sexual practice itself; the mechanics or completion of the act, as well as the training that is not received, when dealing with certain issues with young adolescents. Why can cost both accept that, well before age 17, have already fully developed sexuality? The answer could be as simple as saying that, it's not on focusing on the "do" but, from the "feel" and the latter field seems to be much more muddy and complex than the first. The management process of sexual development of our children and teens, begins when we are ready to grow ourselves in this respect, to overcome conflicts, needs, fears and insecurities of their own. Only then, when we will be able to become true and effective sexual educators and counselors of the young. PMID- 23654188 TI - [Pain may impact the affective and sexual life in women. Interview by Maria Jesus Nadal Nadal]. PMID- 23654189 TI - [Prevention of thromboembolism in bariatric surgery]. AB - Disease thromboembolic (ETEV) is one of the major complications that can occur after surgery, and is the leading cause of death in the postoperative period of Bariatric Surgery. Among other factors, should be aware that these patients are at additional risk of ETEV due to own obesity (IMC > 30). After Bariatric Surgery the risk of thromboembolic events varies according to the surveyed series. In general, it is estimated that danger EP (pulmonary embolism) is 0.8% and DVT (deep vein thrombosis) of 1.7%. ETEV global mortality estimates of 0.1 to 2%. PMID- 23654190 TI - [A vote of confidence in the future must be cast]. PMID- 23654191 TI - [About the last transit. Accompaniment of the soul and the personality]. AB - "Death and its approach represent a field of study for nurses": thus ended his article Montserrat Salvador Borrell in Revista ROL de Enfermeria in November 2010. Address it also from the point of view of the soul brings perspective and gives horizon in the sense of one greater understanding. Death, contemplated and lived exclusively from the material side, flees from as a not only traumatic event for which the experience but also unsurpassed for loved ones. Paradoxically, it's a more natural and frequent phenomenon. Why humans so hard that naturalness? Because we have not cultivated, sometimes not even recognized, other spiritual nature which forms us and who has the key to give sense to the decisive events. For many spiritual traditions, death is birth to another world that, from here, we call beyond. In accompaniment of soul seminars, based on the teachings transmitted by Elisabeth Kubler Ros and Marie Lise Labonte, patterns are learned to accompany the personality and soul--which does not always go according to the time of split--and to help the soul to rediscover his way toward the light, toward the origin. The soul knows it well, but the emotional ties forged during his earthly journey can retain it and hinder the process, which becomes slow and painful. The accompaniment of the soul is a "service" human, social and spiritual. Guides in a forgotten and often feared territory is a relief. You have guides to prepare the great journey allows, especially, make peace with himself with others I with the world. The Egyptians used the symbol of the solar boat, which waits for the deceased to cross the great waters. Nurses are, unknowingly, barqueras of small and large transits of existence. PMID- 23654192 TI - "Zoom-ln"--A targeted database search for identification of glycation modifications analyzed by untargeted tandem mass spectrometry. AB - Post-translational modifications (PTMs) are very important to biological function, however their identification and characterization is technically challenging. In this study, we have identified glycation modifications by nano LC MSE, a data independent acquisition work flow, followed by database search using the Protein Lynx Global Server (PLGSJ). PLGS search with a complete human protein database hardly identified glycation modifications in a glycated human serum albumin (HSA), which was detected to be glycated by western blotting with advanced glycation end products (AGE) antibody and fluorescence spectroscopy. To overcome this difficulty, "Zoom-In" approach, a targeted database search was used to identify glycation modifications in a glycated HSA, which were further manually validated. This approach was useful for identification of glycation modifications from untargeted tandem mass spectrometryworkflow such as MSE, but may require the development of a new algorithm or an upgrade of the existing software. PMID- 23654193 TI - Analysis of methyl-, chloro-, bromo- and trifluoromethyl-substituted 1,9-diphenyl 9H-fluorene and its isomers by gas chromatography-ion trap multistage tandem mass spectrometry. AB - This work presents a modified method to analyze methyL-, chloro-, bromo- and trifluoromethyl-substituted 1,9-diphenyt-9H-fluorene and their isomers by ion trap mass spectrometry with electron impact ionization (EI). Since MS spectra of 1,9-diphenyl-9H-fluorene with these four groups and their isomers are similar, it is difficult to distinguish them from its isomers. Multistage tandem mass spectrometry analysis involves selecting molecular ions obtained in MS spectra as precursor ions in the MS/MS process, and the fragment [C25H17]+ (m/z 317) obtained in MS/MS spectra as a precursor ion in MS3 processes. Collision-induced dissociation (CID) experiments at different activation energies were done to elucidate possible fragmentation pathways. Proposed fragmentation pathways including m/z 317 and structures of the product ions are acquired simultaneously. At a higher CID voltage, the isomers of C25H17-F3 can be distinguished in MS/MS, while the isomers of C25H17-CH3, C25H17-Cl and C25H17-Br can be distinguished in MS3. This work can provide new and valuable information needed for unambiguous characterization of such substances in complex sample matrices. PMID- 23654194 TI - Collision-induced dissociation of 40 flavonoid aglycones and differentiation of the common flavonoid subtypes using electrospray ionization ion-trap tandem mass spectrometry and quadrupole time-of-flight mass spectrometry. AB - Much Literature is available with respect to the collision-induced dissociation (CID) of different subtypes of flavonoid aglycones. However, a simultaneous comparison study of the common flavonoid subtypes under unified conditions is rarely reported, which is of crucial significance for their rapid structural elucidation. This study depicted the negative CID of 40 free flavonoids (comprising nine different subtypes) utilizing electrospray ionization ion-trap tandem mass spectrometry (ESI-IT-MSn). High-accuracy quadrupole time-of-flight mass spectrometry was employed to confirm the chemical formula of proposed key fragments. Specific fragmentation features were discovered among different flavonoid subtypes in terms of the essential collision energy, base peak, RDA fragmentation, and diversity of fragmentation pathways: CID of flavanones, chalcones and flavanonols was in need of lower Levels of collision energy [<40%) and exhibited simplified fragmentation pathways; overriding neutral loss of CO2 was detected for flavones, aurones and xanthones, while isoflavones preferred neutral loss of CO; 1,2A- and 1,3A- fragments were respectively dominant for flavonols and flavanones/chalcones, white homoisoflavones underwent specific radical elimination of ring B or methylene-ring B. These differentiated fragmentation characteristics integrating UV absorption resulted in the establishment of a decision tree to characterize and distinguish the common flavonoid subtypes. This study firstly revealed remarkable differentiations in the negative CID behavior of nine common flavonoid aglycone subtypes and the proposed determination strategy would much benefit the screening and rapid characterization of flavonoids from complicated matrixes by tandem mass spectrometry. PMID- 23654196 TI - Analysis of methanobactin from Methylosinus trichosporium OB3b via ion mobility mass spectrometry. AB - Methanobactins (mbs) are Low molecular mass copper binding chromopeptides analogous to pyoverdin class iron-binding siderophores. Mb produced by Methylosinus trichosporium OB3b (mb-oB3b) has been used as a model molecuLe for methanobactin although the amino acid sequence of mb-OB3b differs significantly from other characterized mbs. In particular, there is the presence of a pair of cystine residues which are absent in other characterized mbs. The role of the Cys3-Cys6 in copper binding, Cu(ll) reduction and its role on the mb-OB3b structure remains in debate. Here, we use a single-step dithiothreitol treatment as an effective method in reducing the disulfide bond allowing in-depth ion mobility-mass spectrometry (IM-MS) analysis. The IM-MS results show mb-oB3b exists in the gas-phase as three different negatively-charged states and exists in multiple conformational states, when introduced via electrospray ionization from aqueous solution near physiological pH. The disulfide bond serves a structural role and is not involved in the Cu(I/ll) binding capability of mb OB3b, with the binding of a second Cu(I/ll) related to a further deprotonation of mb-OB3b. Overall, these findings are in good correlation with expected solution phase behavior of mb-OB3b. The results suggest IM-MS is an effective tool for better understanding the complex nature of this intriguing peptide. PMID- 23654195 TI - Selective isolation of multiply charged peptides: a confident strategy for protein identification using a linear trap quadrupole mass spectrometer. AB - In this work, a method devised for the selective isolation of multiply-charged peptide applied to a complex protein mixture was evaluated for the first time using a mass spectrometer with low resolution (LTQ). In this procedure, all primary amino groups of tryptic peptides derived from human Liver tissue interstitial fluid (TIF) are blocked, restricting their positive charge, at acidic pH, to the presence of histidine and arginine residues. After strong cation exchange chromatography, multiply-charged peptides (#R+#H > 1) are retained in the column and separated with high selectivity from singly (#R+#H = 1) and neutral peptides (#R +#H = 0) which are collected together in the flow through. Using Liquid chromatography electrospray ionization tandem mass spectrometry analysis the retained fraction displayed a 95% enrichment of multiply charged peptides while in the flow-through; only 4% of multiply-charged peptides were identified. PMID- 23654197 TI - Dual enzyme activities assay by quantitative electrospray ionization quadrupole time-of-flight mass spectrometry. AB - A practical and rapid method based on electrospray ionization quadrupole-time of flight mass spectrometry (ESI-Q-ToF MS) was developed for detecting activities of both acetylcholinesterase IAChEI and glutathione S-transferase (GST). The simultaneous study of these two enzyme activities is significant for studying human bio-functions, especially for those who take in toxic compounds and have a risk of disease. Here, the enzyme activities were represented by the conversion of enzymatic substrates and determined by quantitatively analyzing enzymatic substrates. Different internal standards were used to quantify each enzymatic substrate and the good linearity of calibration curves demonstrated the feasibility of the internal standards. The Michaelis-Menten constants (Km) of both GST and AChE were measured by this method and were consistent with values previously reported. Furthermore, we applied this approach to detect GST and AChE activities of whole bloods from four deceased and healthy people. The variation in enzyme activity was in accord with information from gas chromatography mass spectrometry [GC/MS). The screening of AChE and GST provided reliable results and strong forensic evidence. This method offers an alternative choice for detecting enzyme activities and is anticipated to have wide applications in pharmaceutical research and prevention in toxic compounds. PMID- 23654198 TI - Proteins in aqueous humor from cataract patients with and without pseudoexfoliation syndrome. AB - The aim of this study was to investigate the protein content in aqueous humor in eyes with and without pseudoexfoliations (PEX) and to evaluate the quantitative proteomics method, isobaric tagging for relative and absolute protein quantification (iTRAQ), in combination with two separation methods followed by matrix-assisted Laser desorption/ionization (MALDI) mass spectrometry and tandem mass spectrometry (MS/MS). During cataract surgery, samples of aqueous humor were collected from 20 eyes with PEX and from 18 control eyes. The relative concentrations of proteins in the pooled samples of ten PEX eyes and eight controls were evaluated after trypsin digestion and Labeling of the peptides with (iTRAQ) reagent. Two separation methods, Liquid chromatography (LC) and capillary electrophoresis (CE) were used, followed by MALDI mass spectrometry and MS/MS. Furthermore, 1D gel electrophoresis was performed on the remaining ten pooled PEX samples and ten control samples. The gel material was separated by nano-liquid chromatography (nano-LC) followed by Linear-ion-trap quadrupole Fourier transformation ion cyclotron resonance (FT-ICR). Fifty four proteins were identified in the LC runs and 24 with CE. The relative concentrations of beta crystallines B2 and S were raised and those of angiotensinogen and osteopontin Lowered in the PEX sample compared to the control. The trends regarding beta crystallines B2, angiotensinogen and osteopontin were confirmed by the 1D gel electrophoresis. PMID- 23654199 TI - Enhancing the selectivity of enzyme detection by using tailor-made nanoparticles. AB - Development of effective ways to specifically and reversibly block the activity of an enzyme is highly desirable for enhancing the selectivity of enzyme assays. Here we demonstrate a novel approach for selective detection of enzyme activities in complex biological samples by using tailor-made nanoparticles. Employing deoxyribonuclease I (DNase I) as a model enzyme template, we prepared surface imprinted polymers over magnetic nanoparticles with monomers screened out of commonly used functional monomers. The resultant Fe3O4@MIP nanoparticles can not only block the activity of the target enzyme via selective adsorption but also quantitatively release the bound enzyme under mild conditions with the assistance of metal ion cofactors, which offers a very useful tool for enhancing the selectivity in enzyme detection. The approach enables sequential detection of the activities of 3'-5' exonuclease and DNase I in cell lysates. The strategy may be further extended to the detection of other enzyme proteins. PMID- 23654200 TI - Changes in total and individual crocetin esters upon in vitro gastrointestinal digestion of saffron aqueous extracts. AB - Changes that may be expected in crocetin esters (crocins) upon digestion were examined in saffron aqueous extracts for the first time. Chemical characterization of total and individual crocins and other bioactive compounds was achieved by UV-vis spectrophotometry, RP-HPLC-DAD, and LC-ESI-MS. Antioxidant activity was evaluated using in vitro assays and the comet assay. The observed loss for both total and trans-crocins was higher in saffron (~50%) than in gardenia extracts (~30%), which were also examined for comparison. Loss was lower than that reported for hydrophobic carotenoids. cis-Isomers were less affected, leading to the hypothesis that trans/cis isomerization may occur in parallel to degradation reactions. Monitoring changes in the extracts at oral, gastric, or intestinal phases, separately, verified this view pointing out the critical effect of pH, temperature, and duration of process but not of digestive enzymes. No isomerization and less degradation (<20% loss) was evidenced when pure trans crocetin (di-beta-D-gentiobiosyl) ester was subjected to gastric or intestinal conditions. PMID- 23654202 TI - The opportunity for microbiopsies for skin cancer. PMID- 23654201 TI - Evidence for a compulsive-like behavior in rats exposed to alternate access to highly preferred palatable food. AB - Converging evidence suggests that recurrent excessive calorie restriction causes binge eating by promoting behavioral disinhibition and overeating. This interpretation suggests that cognitive adaptations may surpass physiological regulations of metabolic needs after recurrent cycles of dieting and binging. Intermittent access to palatable food has long been studied in rats, but the consequences of such diet cycling procedures on the cognitive control of food seeking remain unclear. Female Wistar rats were divided in two groups matched for food intake and body weight. One group received standard chow pellets 7 days/week, whereas the second group was given chow pellets for 5 days and palatable food for 2 days over seven consecutive weeks. Rats were also trained for operant conditioning. Intermittent access to palatable food elicited binging behavior and reduced intake of normal food. Rats with intermittent access to palatable food failed to exhibit anxiety-like behaviors in the elevated plus maze, but displayed reduced locomotor activity in the open field and developed a blunted corticosterone response following an acute stress across the diet procedure. Trained under a progressive ratio schedule, both groups exhibited the same motivation for sweetened food pellets. However, in contrast to controls, rats with a history of dieting and binging exhibited a persistent compulsive-like behavior when access to preferred pellets was paired with mild electrical foot shock punishments. These results highlight the intricate development of anxiety like disorders and cognitive deficits leading to a loss of control over preferred food intake after repetitive cycles of intermittent access to palatable food. PMID- 23654203 TI - The possible use of inorganic phosphate in osteosarcoma therapy. PMID- 23654204 TI - Photogeneration of H2O2 in SPEEK/PVA aqueous polymer solutions. AB - Photolysis of air-saturated aqueous solutions containing sulphonated poly(ether etherketone) and poly(vinyl alcohol) results in the generation of hydrogen peroxide. Consumption of oxygen and H2O2 formation are initially concurrent processes with a quantum yield of peroxide generation of 0.02 in stirred or unstirred solutions within the range of 7 <= pH <= 9. The results are rationalized in terms of O2 reduction by photogenerated alpha-hydroxy radicals of the polymeric ketone in competition with radical-radical processes that consume the macromolecular reducing agents. Generation of H2O2 is controlled by the photochemical transformation that produces the polymer radicals, which is most efficient in neutral and slightly alkaline solutions. Quenching of the excited state of the polyketone by both H3O(+) and OH(-) affect the yields of the reducing macromolecular radicals and of H2O2. Deprotonation of the alpha-hydroxy polymeric radicals at pH > 9 accelerate their decay and contribute to suppressing the peroxide yields in basic solutions. Maxima in [H2O2] are observed when illuminations are performed with static systems, where O2 reduction is faster than diffusion of oxygen into the solutions. Under such conditions H2O2 can compete with O2 for the reducing radicals resulting in a consumption of the peroxide. PMID- 23654205 TI - Somatic mutation of SPOP tumor suppressor gene is rare in breast, lung, liver cancers, and acute leukemias. PMID- 23654206 TI - Positive display polarity is advantageous for both younger and older adults. AB - The effect of display polarity on visual acuity and proofreading performance was investigated for younger and older adults. An advantage of positive polarity (dark characters on light background) over negative polarity (light characters on dark background) was expected for younger adults, but the effects on older adults were ambiguous. Light scatter due to residues in the senescent lens and vitreous humour could reverse the typical advantage of positive polarity. However, age related changes lead to a decline in retinal illuminance. Brighter positive polarity displays should help to compensate for this decline and, accordingly, lead to better performance than darker negative polarity displays. Participants conducted a visual acuity test with black optotypes on white background or white optotypes on black background and performed a proofreading task in the same polarity. A positive polarity advantage was found for both age groups. The presentation in positive polarity is recommended for all ages. PRACTITIONER SUMMARY: In an ageing society, age-related vision changes need to be considered when designing digital displays. Visual acuity testing and a proofreading task revealed a positive polarity advantage for younger and older adults. Dark characters on light background lead to better legibility and are strongly recommended independent of observer's age. PMID- 23654208 TI - New strategies in assessing, treating, and relapse prevention of extramarital affairs. AB - Understanding, assessing, treating, and preventing relapse of extra-marital affairs has involved significant changes in the past 10 years. This conceptual/clinical article expands on the groundbreaking work of Snyder, Gordon, and Baucom (2007), and has a special focus placed on the process of sexual recovery from an extra-marital affair. Secondly, this article focuses on the importance of creating a relapse prevention agreement. Both traditional and non traditional agreements with regard to monogamy are described. Recognizing individual, couple, cultural, and value differences in norms and expectations exhibits a particular challenge in the study and treatment of extra-marital affairs. The clinician honors these complexities and differences by designing a treatment program that meets the needs of each couple. PMID- 23654209 TI - Unprecedented biomimetic homodimerization of oroidin and clathrodin marine metabolites in the presence of HMPA or phosphonate salt tweezers. AB - The first biomimetic homodimerization of oroidin and clathrodin was effected in the presence HMPA and diphosphonate salts, strong guanidinium and amide chelating agents. The intermolecular associations probably interfere with the entropically and kinetically favored intramolecular cyclizations. Use of oroidin.(1)/2HCl salt or clathrodin.(1)/2HCl was indicative in the presence of the ambident nucleophilic and electrophilic tautomers of the 2-aminoimidazolic oroidin and clathrodin precursors. Surprisingly, the homodimerization of oroidin led to the nagelamide D skeleton, while the homodimerization of clathrodin gave the benzene para-symmetrical structure 19. The common process was rationalized from tautomeric precursors I and III. PMID- 23654210 TI - Nonpharmacological nursing interventions for the management of patient fatigue: a literature review. AB - AIMS AND OBJECTIVES: To identify and describe nonpharmacological interventions for the management of fatigue that are within the scope of nursing practice. BACKGROUND: Fatigue is a complex multidimensional symptom experienced by patients with varying diagnoses. Limited details are available on the nature of nursing interventions to manage fatigue, which preclude fidelity of implementation in day to-day practice. DESIGN: Literature review. METHODS: Multiple databases were searched for publications reporting on the evaluation of nurse-delivered interventions for the management of fatigue. Data were extracted on study and intervention characteristics and results pertaining to the effects of the intervention on fatigue. RESULTS: The studies (n = 16) evaluated eight interventions: psycho-education, cognitive behavioural therapy, exercise, acupressure, relaxation, distraction, energy conservation and activity management, and a combination of exercise, education and support. CONCLUSION: Psycho-education was evaluated in several studies and demonstrated effectiveness when delivered in both acute and community settings. RELEVANCE TO CLINICAL PRACTICE: This review focused on interventions that are within the scope of nursing practice for the management of fatigue. The findings provide nurses with an overview of the effectiveness of interventions they may use in their day-to day practice to help patients manage fatigue. A detailed description of interventions found effective is provided to assist nurses in translating evidence into practice. PMID- 23654211 TI - Computational design of two-photon fluorescent probes for a zinc ion based on a Salen ligand. AB - A two-photon fluorescent probe has become a critical tool in biology and medicine owing to its capability of imaging intact tissue for a long period of time, such as in two-photon fluorescence microscopy (TPM). In this context, a series of Salen-based zinc-ion bioimaging reagents that were designed based on an intramolecular charge-transfer mechanism were studied through the quantum chemical method. The increase of one-photon absorption and fluorescence emission wavelength and the reduction of the oscillator strength upon coordination with a zinc ion reveal that they are fluorescent bioimaging reagents used for ratiometric detection. When the Salen ligand is incorporated with Zn(2+), the value of the two-photon absorption (TPA) cross-section (deltamax) will decrease, and most of the ligands and complexes exhibit a TPA peak in the near-infrared spectral region. That is, a substituent at the end of the ligand can influence the luminescence property, besides increasing solubility. In addition, the effect of an end-substituted position on the TPA property was considered, such as ortho and meta substitution. The detailed investigations will provide a theoretical basis to synthesize zinc-ion-responsive two-photon fluorescent bioimaging reagents as powerful tools for TPM and biological detection in vivo. PMID- 23654212 TI - Associations between arterial stiffness and platelet activation in normotensive overweight and obese young adults. AB - Obese individuals have elevated platelet activation and arterial stiffness, but the strength and temporality of the relationship between these factors remain unclear. We aimed to determine the effect of increased arterial stiffness on circulating platelet activity in overweight/obese young adults. This analysis included 92 participants (mean age 40 years, 60 women) in the Slow Adverse Vascular Effects of excess weight (SAVE) trial, a clinical trial examining the effects of a lifestyle intervention with or without sodium restriction on vascular health in normotensive overweight/obese young adults. Carotid-femoral (cf), brachial-ankle (ba) and femoral-ankle (fa) pulse wave velocity (PWV) served as measures of arterial stiffness and were measured at baseline and 6, 12 and 24 months follow-up. Platelet activity was measured as plasma beta-thromboglobulin (beta-TG) at 24 months. Higher plasma beta-TG was correlated with greater exposure to elevated cfPWV (p = 0.02) and baPWV (p = 0.04) during the preceding two years. After adjustment for serum leptin, greater exposure to elevated baPWV remained significant (p = 0.03) and exposure to elevated cfPWV marginally significant (p = 0.054) in predicting greater plasma beta-TG. Greater arterial stiffness, particularly central arterial stiffness, predicts greater platelet activation in overweight/obese individuals. This relationship might partly explain the association between increased arterial stiffness and incident atherothrombotic events. PMID- 23654213 TI - Predictive gene testing for Huntington disease and other neurodegenerative disorders. AB - BACKGROUND: Controversies exist around predictive testing (PT) programmes in neurodegenerative disorders. AIMS: This study sets out to answer the following questions relating to Huntington disease (HD) and other neurodegenerative disorders: differences between these patients in their PT journeys, why and when individuals withdraw from PT, and decision-making processes regarding reproductive genetic testing. METHODS: A case series analysis of patients having PT from the multidisciplinary Western Australian centre for PT over the past 20 years was performed using internationally recognised guidelines for predictive gene testing in neurodegenerative disorders. RESULTS: Of 740 at-risk patients, 518 applied for PT: 466 at risk of HD, 52 at risk of other neurodegenerative disorders - spinocerebellar ataxias, hereditary prion disease and familial Alzheimer disease. Thirteen percent withdrew from PT - 80.32% of withdrawals occurred during counselling stages. Major withdrawal reasons related to timing in the patients' lives or unknown as the patient did not disclose the reason. Thirty eight HD individuals had reproductive genetic testing: 34 initiated prenatal testing (of which eight withdrew from the process) and four initiated pre implantation genetic diagnosis. There was no recorded or other evidence of major psychological reactions or suicides during PT. CONCLUSIONS: People withdrew from PT in relation to life stages and reasons that are unknown. Our findings emphasise the importance of: (i) adherence to internationally recommended guidelines for PT; (ii) the role of the multidisciplinary team in risk minimisation; and (iii) patient selection. PMID- 23654214 TI - Observations of interstellar formamide: availability of a prebiotic precursor in the galactic habitable zone. AB - We conducted a study on interstellar formamide, NH2CHO, toward star-forming regions of dense molecular clouds, using the telescopes of the Arizona Radio Observatory (ARO). The Kitt Peak 12 m antenna and the Submillimeter Telescope (SMT) were used to measure multiple rotational transitions of this molecule between 100 and 250 GHz. Four new sources of formamide were found [W51M, M17 SW, G34.3, and DR21(OH)], and complementary data were obtained toward Orion-KL, W3(OH), and NGC 7538. From these observations, column densities for formamide were determined to be in the range of 1.1*10(12) to 9.1*10(13) cm(-2), with rotational temperatures of 70-177 K. The molecule is thus present in warm gas, with abundances relative to H2 of 1*10(-11) to 1*10(-10). It appears to be a common constituent of star-forming regions that foster planetary systems within the galactic habitable zone, with abundances comparable to that found in comet Hale-Bopp. Formamide's presence in comets and molecular clouds suggests that the compound could have been brought to Earth by exogenous delivery, perhaps with an infall flux as high as ~0.1 mol/km(2)/yr or 0.18 mmol/m(2) in a single impact. Formamide has recently been proposed as a single-carbon, prebiotic source of nucleobases and nucleic acids. This study suggests that a sufficient amount of NH2CHO could have been available for such chemistry. PMID- 23654215 TI - Beyond child soldiering: the interference of daily living conditions in former child soldiers' longer term psychosocial well-being in northern Uganda. AB - Given the various developments in former child soldiers' psychosocial well-being over time, the question arises as to which factors are associated with the prevalence of psychological distress. An ongoing debate points to the plausible importance of child soldiering-related and post-child soldiering factors. This study is an exploratory analysis of both types of association with former child soldiers' psychosocial well-being in the longer term. Follow-up data on a convenience sample of 424 northern Ugandan former child soldiers are analysed. Psychological symptoms are assessed by a review of the intake and assessment forms of the Rachele Rehabilitation Centre, which were not validated and did not include a standardised translation into the local language. These psychological symptoms and possible associated factors are analysed using binary logistic regression analysis. Thereby, both child soldiering-related and post-child soldiering variables are accounted for. The outcomes reveal almost no significant main effects of child soldiering-related variables, while a range of post-child soldiering variables (number of meals a day, school attendance, insults and professional support) are clearly associated with the prevalence of the measured psychological symptoms in the longer term. These exploratory conclusions should be further investigated in representative samples of former child soldiers using validated assessment tools. PMID- 23654216 TI - Disclosure of same-sex behavior by young Chinese migrant men: context and correlates. AB - The purpose of the study is to explore the disclosure of same-sex behavior by men who have sex with men (MSM) to different groups of people (i.e. family, friends, coworkers, and doctors) and the associated sociodemographic, behavioral, and psychosocial factors. A self-administered survey was conducted among 307 migrant MSM, aged 18-30, in Beijing in 2009. Most MSM disclosed their same-sex behavior to friends (69%), followed by family (25%), coworkers (25%), and doctors (24%). Factors associated with disclosure to friends included higher levels of perceived stigma, social capital and acculturation in Beijing, and suspecting partner to have a sexually transmitted disease (STD). Factors associated with disclosure to family included lower levels of internalized stigma, higher levels of acculturation in Beijing, and both risk and protective behavioral factors. MSM who disclosed to coworkers reported having worked in more cities, living with coworkers, and lower levels of social capital in Beijing. Disclosure to doctors was related to STD infection, sex partner, and sociodemographic factors. Results indicated that selective disclosure by MSM was situational and context-based. Future HIV/STD intervention needs to take into account factors relevant to their selective disclosure to different audiences. PMID- 23654217 TI - Large-scale screening of zeolite structures for CO2 membrane separations. AB - We have conducted large-scale screening of zeolite materials for CO2/CH4 and CO2/N2 membrane separation applications using the free energy landscape of the guest molecules inside these porous materials. We show how advanced molecular simulations can be integrated with the design of a simple separation process to arrive at a metric to rank performance of over 87,000 different zeolite structures, including the known IZA zeolite structures. Our novel, efficient algorithm using graphics processing units can accurately characterize both the adsorption and diffusion properties of a given structure in just a few seconds and accordingly find a set of optimal structures for different desired purity of separated gases from a large database of porous materials in reasonable wall time. Our analysis reveals that the optimal structures for separations usually consist of channels with adsorption sites spread relatively uniformly across the entire channel such that they feature well-balanced CO2 adsorption and diffusion properties. Our screening also shows that the top structures in the predicted zeolite database outperform the best known zeolite by a factor of 4-7. Finally, we have identified a completely different optimal set of zeolite structures that are suitable for an inverse process, in which the CO2 is retained while CH4 or N2 is passed through a membrane. PMID- 23654219 TI - Cardiovascular down-regulation in essential hypotension: relationships with autonomic control and sleep. AB - In this work, we aimed to clarify the autonomic involvement in the cardiovascular down-regulation in essential hypotension. The relationships between cardiovascular response and sleep quality were also examined. Thirteen female hypotensives and 13 female normotensives performed a stress task followed by polysomnography. Measures derived from blood pressure monitoring, impedance cardiography, and heart rate variability were collected. Hypotensives exhibited lower cardiovascular and autonomic activation than controls during the task. While a better sleep quality (i.e., higher sleep efficiency and lower nocturnal wakefulness) correlated with a reduced reactivity in normotensives, the opposite pattern occurred in hypotensives. The results suggest that a blunted response in both autonomic branches underlies the cardiovascular hypoactivation in hypotension. Further, good sleep seems to be associated with optimal levels of physiological reactivity. PMID- 23654218 TI - Evaluation of oxygen concentrators for use in countries with limited resources. AB - Seven different models of oxygen concentrators were purchased. The manufacturer's data were evaluated by a ranking method for operation at high temperature and high relative humidity, power consumption, warranty and cost. Measurements were then made of the oxygen concentration produced at maximum operating temperature. All the concentrators were CE marked and claimed compliance with the relevant Standard ISO 8359:1996. Only two models complied with their specification. On examination of the concentrators and the accompanying documents we found that compliance with 61 points listed in ISO 8359 ranged from 85% to 98%. Oxygen concentration was measured with the machines running simultaneously under both high temperature and high humidity. All models delivered low oxygen concentrations at 40 degrees C and 95% relative humidity. Only two models delivered >82% at 35 degrees C and 50% relative humidity. Concentrators intended for use in countries with limited resources should be evaluated before they are purchased, by independent experts, using the methods described herein. PMID- 23654220 TI - Orientation distribution of highly oriented type I collagen deposited on flat samples with different geometries. AB - The structural arrangement of type I collagen in vivo is critical for the normal functioning of tissues, such as bone, cornea, tendons, and blood vessels. At present, there are no established low-cost techniques for fabricating aligned collagen structures for applications in regenerative medicine. Here, we report on a straightforward approach to fabricate collagen films, with defined orientation distributions of collagen fibrillar aggregates within a matrix of oriented collagen molecules on flat sample surfaces. Langmuir-Blodgett (LB) technology was used to deposit thin films of oriented type I collagen onto flat substrates exhibiting various shapes. By varying the shapes of the substrates (e.g., rectangles, squares, circles, parallelograms, and various shaped triangles) as well as their sizes, a systematic study on collagen alignment patterns was conducted. It was found that the orientation and the orientation distribution of collagen along these various shaped substrates are directly depending on the geometry of the substrate and the dipping direction of that sample with respect to the collagen/water subphase. An important factor in tissue engineering is the stability, durability, and endurance of the constructed artificial tissue and thus its functioning in regenerative medicine applications. By testing these criteria, we found that the coated films and their alignments were stable for at least three months under different conditions and, moreover, that these films can withstand temperatures of up to 60 degrees C for a short time. Therefore, these constructs may have widespread applicability in the engineering of collagen-rich tissues. PMID- 23654221 TI - Stochastic resonance induced by exogenous noise in a model of a neuronal network. AB - This study investigates the possibility of using exogenous noise to restore the processing performances of neuronal systems where the endogenous noise is reduced due to the ageing or to degenerative diseases. This idea is based on the assumption, supported by theoretical studies, that the endogenous noise has a positive role in neuronal signal detection and that its reduction impairs the system function. Results, obtained on a two-layers feedforward network, show the onset of the Stochastic Resonance (SR) behavior, as long as the exogenous noise is properly tailored and filtered. The amount of noise to be furnished from the outside to optimize the system performance depends on the residual level of endogenous noise, indicating that both kinds of noise cooperate to the signal detection. These results support potentially new bioengineering applications where exogenous noise is furnished to enhance signal detectability. PMID- 23654222 TI - Optimization of neutral protease production from Bacillus subtilis: using agroindustrial residues as substrates and response surface methodology. AB - Statistically based experimental designs were applied to optimize the fermentation medium and cultural conditions for the maximization of neutral protease using three agroindustrial residues (cassava pulp, soybean meal, and wheat bran) and Bacillus subtilis DES-59. The Plackett-Burman design was used to evaluate the effects of variables such as the concentration of substrates, initial pH, shaker's rotating speed, temperature, inoculum size, and incubation time. Among the eight parameters, three significant variables (cassava pulp, soybean meal, and inoculum size) were selected for the optimization study, in which a central composite design was used to optimize the concentrations of cassava pulp and soybean meal and inoculum size and investigate the interactive effects of the three variables. The optimal parameters obtained from response surface methodology are 37.78 g/L of cassava pulp, 15 g/L of soybean meal, and 6.5% (v/v) of inoculum size, respectively, resulting in a maximum neutral protease activity of 4107 +/- 122 U/mL. PMID- 23654223 TI - High proficiency in a second language is characterized by greater involvement of the first language network: evidence from Chinese learners of English. AB - The assimilation hypothesis argues that second language learning recruits the brain network for processing the native language, whereas the accommodation hypothesis argues that learning a second language recruits brain structures not involved in native language processing. This study tested these hypotheses by examining brain activation of a group of native Chinese speakers, who were late bilinguals with varying levels of proficiency in English, when they performed a rhyming judgment to visually presented English word pairs (CE group) during fMRI. Assimilation was examined by comparing the CE group to native Chinese speakers performing the rhyming task in Chinese (CC group), and accommodation was examined by comparing the CE group to native English speakers performing the rhyming task in English (EE group). The CE group was very similar in activation to the CC group, supporting the assimilation hypothesis. Additional support for the assimilation hypothesis was the finding that higher proficiency in the CE group was related to increased activation in the Chinese network (as defined by the CC > EE), including the left middle frontal gyrus, the right inferior parietal lobule, and the right precuneus, and decreased activation in the English network (as defined by the EE > CC), including the left inferior frontal gyrus and the left inferior temporal gyrus. Although most of the results support assimilation, there was some evidence for accommodation as the CE group showed less activation in the Chinese network including the right middle occipital gyrus, which has been argued to be involved in holistic visuospatial processing of Chinese characters. PMID- 23654224 TI - The use of COLD-PCR, DHPLC and GeneScanning for the highly sensitive detection of c-KIT somatic mutations in canine mast cell tumours. AB - The conventional polymerase chain reaction (PCR)/sequencing methods may be poorly suited for the detection of somatic mutations in canine mast cell tumour (MCT) samples owing to limited sensitivity. This study was aimed at establishing novel and more sensitive methods, assessing their limit of detection and comparing their sensitivity with conventional methods.Two different 'driver' somatic mutations of c-KIT, together with the wild-type counterparts, were cloned in plasmids to prepare standard samples with known concentrations of mutated alleles in a background of wild-type alleles; the plasmids standards were assayed using either conventional or novel, highly sensitive technique. Conventional PCR/sequencing showed a sensitivity of 50-20%. Conversely, all the novel methods obtained higher sensitivities allowed reaching as low as 2.5-1.2% of the mutated DNA.The study demonstrates that early conventional methods could likely have underestimated the prevalence of KIT mutations of MCTs, therefore affecting the assessment of their relevance in prognosis and tyrosine kinase inhibitor (TKI) treatment effectiveness. PMID- 23654225 TI - Assessment of blood types of Ragdoll cats for transfusion purposes. AB - BACKGROUND: Transfusion of compatible blood types ensures the vitality of transfused erythrocytes and avoids transfusion reactions. Cats with types A, B, and AB blood should receive transfusions of the same blood type. In a feline blood donor program, it is therefore essential to have blood donors of all blood types available. OBJECTIVES: The objectives of this study were the identification of the 3 feline blood types in Ragdoll cats, the comparison of their frequencies with those of Domestic Shorthair (DSH) cats, and the determination of whether Ragdolls are suitable donors in a feline blood donor program. METHODS: The blood type was determined by gel column agglutination from Ragdoll cats. The relationships between phenotypic traits, the origin of the cats, and the different blood types were examined. The frequencies for potential transfusion reactions and the risk for neonatal isoerythrolysis (NI) were estimated. RESULTS: Of 61 typed Ragdolls, 77.1% had type A, 4.9% type B, and 18% type AB blood. The frequency of blood type A in Ragdolls was lower than in DSH cats (P = .02), while the frequency of blood type AB in Ragdolls was higher than in DSH cats (P = .0002). No relationship was found between blood type and origin of the cat or phenotypic traits. The estimated frequencies of major and minor transfusion reactions following an unmatched transfusion between Ragdolls (donors and recipients), Ragdoll donors and DSH recipients, and DSH donors and Ragdoll recipients were 4.7%, 6.7%, 4.6%, and 18.5%, 20.8%, 7.6%, respectively. The frequency of kittens at risk for NI was 5%. CONCLUSION: The presence of all 3 feline blood types and a relatively high incidence of AB type cats make Ragdolls an ideal donor breed to include in feline blood transfusion programs. PMID- 23654226 TI - Nonempirical energetic analysis of reactivity and covalent inhibition of fatty acid amide hydrolase. AB - Fatty acid amide hydrolase (FAAH) is a member of the amidase signature family and is responsible for the hydrolytic deactivation of fatty acid amide neuromodulators, such as anandamide. FAAH carries an unusual catalytic triad consisting of Lys-Ser-Ser, which uniquely enables the enzyme to cleave amides and esters at similar rates. The acylation of 9Z-octadecenamide (oleamide, a FAAH reference substrate) has been widely investigated by computational methods, and those have shown that conformational fluctuations of the active site affect the reaction barrier. Empirical descriptors have been devised to provide a possible mechanistic explanation for such conformational effects, but a first-principles understanding is still missing. A comparison of FAAH acylation with a reference reaction in water suggests that transition-state stabilization is crucial for catalysis because the activation energy barrier falls by 6 kcal/mol in the presence of the active site. With this in mind, we have analyzed the enzymatic reaction using the differential transition-state stabilization (DTSS) approach to determine key active-site residues for lowering the barrier. We examined several QM/MM structures at the MP2 level of theory and analyzed catalytic effects with a variation-perturbation partitioning of the interaction energy into electrostatic multipole and penetration, exchange, delocalization, and correlation terms. Three residues - Thr236, Ser218, and one water molecule - appear to be essential for the stabilization of the transition state, a conclusion that is also reflected by catalytic fields and agrees with site-directed mutagenesis data. An analogous analysis for URB524, URB618, and URB694 (three potent representatives of covalent, carbamate-based FAAH inhibitors) confirms the importance of the residues involved in oleamide acylation, providing insight for future inhibitor design. PMID- 23654227 TI - A fluoroimmunoassay based on quantum dot-streptavidin conjugate for the detection of chlorpyrifos. AB - A rapid and sensitive competitive fluorescence-linked immunosorbent assay (cFLISA) based on quantum dot-streptavidin conjugate (QDs-SA) was developed for the detection of chlorpyrifos in drinking water. The QDs-SA conjugate, which consists of 3-mercaptopropyl acid-stabilized CdTe nanoparticle QDs and streptavidin (SA) made through the active ester method, was employed to improve the sensitivity of QDs-SA-cFLISA. The 50% inhibition concentration (IC50) and the limit of detection (LOD) were 28.5 and 3.8 ng mL(-1), respectively. QDs-SA-cFLISA increased sensitivity 5.5-fold and reduced detection time by 1 h compared with conventional enzyme-linked immunosorbent assay (ELISA). With chlorpyrifos concentrations of 100, 50, and 20 ng mL(-1), recoveries ranged from 85.9% to 105.3% with coefficients of variation ranging from 6.3% to 13.5%. This study demonstrated that QDs-SA-cFLISA was more rapid and sensitive than conventional ELISA. Therefore, it can be used as a novel screening method for the detection of pesticide residues. PMID- 23654228 TI - Analytical method validation for the determination of meptyldinocap as 2,4 dinitrooctylphenol metabolite in mango and soil using LC-MS/MS and dissipation study of the fungicide in Indian mango field ecosystem. AB - An analytical method for the quantitative determination of meptyldinocap (2,4 DNOPC) as 2,4-dinitrooctylphenyl (2,4-DNOP) in mango and soil was developed as well as validated using liquid chromatography tandem mass spectrometry (LC MS/MS). The method comprised an extraction with an acetone:methanol:4 N HCl (100:10:5, v/v/v) mixture followed by hydrolytic conversion of parent 2,4-DNOPC to the corresponding phenol metabolite (2,4-DNOP), and cleanup was done by liquid:liquid partition using ethyl acetate. Final quantitation was performed by LC-MS/MS of 2,4-DNOP with negative electrospray ionization using gradient elution. The method was validated at concentrations ranging from 0.025 to 2 MUg/g, and the limit of quantification (LOQ) of meptyldinocap in mango and soil samples was 0.025 MUg/g. The recovery of meptyldinocap from mango and soil sample was found to be 93-98% spiked at different levels with analyte, and the relative standard deviation for repeatability (RSD(r)) and reproducibility (RSD(R)) were acceptable (2-6%). The method was rugged as evident from a low measurement uncertainty at 0.05 MUg/g. In order to evaluate its safety use in India a multilocational field dissipation study on meptyldinocap in mango was conducted by following the proposed analytical method. PMID- 23654229 TI - Separation and detection of cell wall-bound ferulic acid dehydrodimers and dehydrotrimers in cereals and other plant materials by reversed phase high performance liquid chromatography with ultraviolet detection. AB - Ferulate dehydrodimers and the more recently discovered dehydrotrimers play an important role in the cell wall architecture of plant-based foods and forages. High-performance liquid chromatography methods to determine ferulate dimers often lack specificity; methods for trimers did not exist yet. A method for the determination of 11 cell wall-bound ferulate dehydrodimers and -trimers was developed, including the crucial separation of the di/trimers from the often dominating phenolic monomers. Validation parameters for the basic calibration of the dimers and trimers met our acceptance criteria. However, the matrix calibration revealed that lignin-rich matrices lead to problems with precision and accuracy that likely can be addressed by using a more specific detection, that is, mass spectrometric detection, next to improved sample preparation procedures. The method was used to analyze low-lignin fibers from corn, wheat, and rye grains, wild rice, asparagus, and sugar beet. With the exception of wild rice, the 5-5/8-O-4-, 8-O-4/8-O-4-, and 8-8(aryltetralin)/8-O-4-dehydrotrimers were detected in all analyzed samples, however, often in amounts below the limit of quantitation. PMID- 23654230 TI - Rapid surface plasmon resonance immunoassay for the determination of deoxynivalenol in wheat, wheat products, and maize-based baby food. AB - A rapid screening assay (9 min/sample) has been developed and validated for the detection of deoxynivalenol in durum wheat, wheat products, and maize-based baby foods using an SPR biosensor. Through a single laboratory validation, the limits of detection (LOD) for wheat, wheat-based breakfast cereal, and maize-based baby food were 57, 9, and 6 MUg/kg, respectively. Intra-assay and interassay precisions were calculated for each matrix at the maximum and half-maximum European Union regulatory limits and expressed as the coefficient of variation (CV). All CVs fell below 10% with the exception of the between-run CV for breakfast cereal. Recoveries at the concentrations tested ranged from 92 to 115% for all matrices. Action limits of 161, 348, and 1378 MUg/kg were calculated for baby food, wheat-based breakfast cereal, and wheat, respectively, and the linear range of the assay was determined as 250-2000 MUg/kg. PMID- 23654231 TI - Direct electrochemical determination of methyl jasmonate in wheat spikelet at a nano-montmorillonite film modified electrode by derivative square wave voltammetry. AB - The direct electrochemical determination of methyl jasmonate (MeJA) at a nano montmorillonite modified glassy carbon electrode (nano-MMT/GCE) is reported. The modified electrode, prepared by a simple casting-drying method and characterized by scanning electron microscope (SEM) and electrochemical impedance spectra (EIS), was proved to process a uniform nanostructured surface with a large surface area and a fast electron transfer rate. This electrode exhibited a sensitive electrochemical response for the direct oxidation of MeJA in 0.1 mol L( 1) HClO4, which could be further improved by using a derivative square wave voltammetry technique. Thus, a simple and fast electrochemical method for the determination of MeJA is proposed. Under optimal working conditions, the oxidation current of MeJA linearly increased with its concentration in the range of 7.0 * 10(-7)-1.0 * 10(-3) mol L(-1) with a detection limit of 5.0 * 10(-7) mol L(-1). This method had been applied to the determination of MeJA content in wheat spikelet samples. PMID- 23654232 TI - Antioxidant capacity and in vitro inhibition of adipogenesis and inflammation by phenolic extracts of Vaccinium floribundum and Aristotelia chilensis. AB - Interest in berries from South America has increased due to their potential health benefits. The objective of this study was to characterize the anthocyanins and proanthocyanidins of Vaccinium floribundum and Aristotelia chilensis , total phenolics, and antioxidant capacity and to evaluate, in vitro, the ability of their phenolic extracts to reduce adipogenesis and lipid accumulation in 3T3-L1 adipocytes. The anti-inflammatory property of these extracts on RAW 264.7 macrophages was also investigated. Antioxidant capacity, measured as oxygen radical scavenging capacity and expressed as Trolox equivalents, was higher in the berries of A. chilensis. Phenolic extracts inhibited lipid accumulation by 4.0-10.8% when adipocytes were treated at maturity and by 5.9-37.9% when treated throughout differentiation. Furthermore, a proanthocyanidin-enriched fraction from V. floribundum significantly increased Pref-1 expression in preadipocytes. Phenolic extracts decreased the production of nitric oxide (3.7-25.5%) and prostaglandin E2 (9.1-89.1%) and the expression of inducible nitric oxide synthase (9.8-61.8%) and cycloxygenase-2 (16.6-62.0%) in lipopolysaccharide stimulated RAW 264.7 macrophages. V. floribundum and A. chilensis phytochemicals limit adipogenesis and inflammatory pathways in vitro, warranting further in vivo studies. PMID- 23654233 TI - 1-Deoxynojirimycin inhibits metastasis of B16F10 melanoma cells by attenuating the activity and expression of matrix metalloproteinases-2 and -9 and altering cell surface glycosylation. AB - 1-Deoxynojirimycin (1-DNJ), an iminosugar rich in mulberry, has been shown to possess antimetastatic potential. The antimetastatic mechanisms of 1-DNJ in melanoma B16F10 cells were studied, as were the antimetastatic activity (cell adhesion, migration, and invasion) of 1-DNJ, matrix metalloproteinases (MMP-2 and MMP-9), tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-2) mRNA, and flow cytometric analysis of cell surface in melanoma B16F10 cells. 1-DNJ significantly inhibited invasion, migration, and cell-matrix adhesion and markedly decreased MMP-2 and MMP-9 activity and mRNA expression. In contrast, 1-DNJ effectively enhanced the expression of TIMP-2 mRNA. In addition, 1-DNJ significantly decreased abnormal glycosylation and/or sialylation on B16F10 melanoma cell surface but increased the levels of alpha-mannose. Thus, the antimetastatic effects of 1-DNJ against B16F10 melanoma cells are likely associated with its attenuated activities and expression of MMP-2/9, enhancement of the TIMP-2 mRNA expression, and alterations of the cell surface-binding motif. These results suggest that 1-DNJ may be useful as an adjuvant of antimetastatic agents such as cisplatin. PMID- 23654234 TI - High molecular weight persimmon (Diospyros kaki L.) proanthocyanidin: a highly galloylated, A-linked tannin with an unusual flavonol terminal unit, myricetin. AB - MALDI-TOF MS suggested that the high molecular weight proanthocyanidin (condensed tannin) from persimmon (Diospyros kaki L.) pulp comprised a heteropolyflavanol series with flavan-3-O-galloylated extenders, flavan-3-ol and flavonol terminal units, and A-type interflavan linkages. Thiolysis-HPLC-ESI-MS with DAD, electrochemical, and ESI-MS detection confirmed a previously unreported terminal unit, the flavonol myricetin, in addition to the typical flavan-3-ols catechin and epigallocatechin gallate. The extender units were epicatechin, epigallocatechin, (epi)gallocatechin-3-O-gallate, and (epi)catechin-3-O-gallate. The crude tannin had a high prodelphinidin content (65%) and a high degree of 3-O galloylation (72%). The material was fractionated on Toyopearl TSK-HW-50-F to yield fractions distinguished by degree of polymerization (DP). Thiolysis suggested that the persimmon tannin was composed of polymers ranging from 7 to 20 kDa (DP 19-47), but sizes estimated by GPC were 50-70% smaller. The crude material was chemically degraded with acid to yield products that were amenable to NMR and ESI-MS analysis, which were used to establish for the first time that persimmon tannin has a mixture of B-type and A-type linkages. PMID- 23654235 TI - Ultraviolet light stimulates flavonol accumulation in peeled onions and controls microorganisms on their surface. AB - The effects of ultraviolet (UV) light on flavonol content in peeled onions (Allium cepa L.) and on microbial survival on their surface were investigated. The content of phenolic compounds showed a gradient within the onion bulb, with the highest level in the external dry "skin" (tunic) and the lowest level in the center. Peeled bulbs were treated with UV light comprising the bands of UV-C (more than half of the total UV output), UV-A, and UV-B. The response to UV depended upon the position of the scales within the bulb. In the outer fleshy scales, the UV doses of 1.2-6 kJ m(-2) approximately doubled the accumulation of flavonols and the total antioxidant capacity. When mid-depth (5th from the outside) scales were exposed to UV, the lowest dose tested (1.2 kJ m(-2)) had no significant effect on flavonols accumulation, whereas the higher doses decreased their levels. The low-dose UV treatment reduced the count of Escherichia coli on artificially contaminated peeled onions by 1.5-3 logs and alleviated the decay of Penicillium-inoculated bulbs. The present study has demonstrated a potential of UV light for simultaneous decontamination of peeled onions and their enrichment in health-enhancing phytonutrients. PMID- 23654236 TI - Biofortification and localization of zinc in wheat grain. AB - Zinc (Zn) deficiency associated with low dietary intake is a well-documented public health problem, resulting in serious health and socioeconomic problems. Field experiments were conducted with wheat to test the role of both soil and foliar application of ZnSO4 in Zn concentration of whole grain and grain fractions (e.g., bran, embryo and endosperm) in 3 locations. Foliar application of ZnSO4 was realized at different growth stages (e.g., stem elongation, boot, milk, dough stages) to study the effect of timing of foliar Zn application on grain Zn concentration. The rate of foliar Zn application at each growth stage was 4 kg of ZnSO4.7H2O ha(-1). Laser ablation (LA)-ICP-MS was used to follow the localization of Zn within grain. Soil Zn application at a rate of 50 kg of ZnSO4.7H2O ha(-1) was effective in increasing grain Zn concentration in the Zn deficient location, but not in the locations without soil Zn deficiency. In all locations, foliar application of Zn significantly increased Zn concentration in whole grain and in each grain fraction, particularly in the case of high soil N fertilization. In Zn-deficient location, grain Zn concentration increased from 11 mg kg(-1) to 22 mg kg(-1) with foliar Zn application and to 27 mg kg(-1) with a combined application of ZnSO4 to soil and foliar. In locations without soil Zn deficiency, combination of high N application with two times foliar Zn application (e.g., at the booting and milk stages) increased grain Zn concentration, on average, from 28 mg kg(-1) to 58 mg kg(-1). Both ICP-OES and LA ICP-MS data showed that the increase in Zn concentration of whole grain and grain fractions was pronounced when Zn was sprayed at the late growth stage (e.g., milk and dough). LA-ICP-MS data also indicated that Zn was transported into endosperm through the crease phloem. To our knowledge, this is the first study to show that the timing of foliar Zn application is of great importance in increasing grain Zn in wheat, especially in the endosperm part that is the predominant grain fraction consumed in many countries. Providing a large pool of Zn in vegetative tissues during the grain filling (e.g., via foliar Zn spray) is an important practice to increase grain Zn and contribute to human nutrition. PMID- 23654237 TI - Influence of postflowering temperature on fruit size and chemical composition of Glen Ample raspberry (Rubus idaeus L.). AB - The effects of postflowering temperature on the fruit chemical composition of Glen Ample raspberries were studied under controlled environment conditions. The berry weight decreased significantly with increasing temperature (12, 18, and 24 degrees C) and with progress of the harvest period. Because the moisture content increased in parallel with the berry weight, the antioxidant capacity (AOC) and the concentration of a range of bioactive compounds decreased with decreasing temperature and progress of the harvest season when expressed on a fresh weight basis in the conventional way. Under those circumstances, dry weight units are therefore preferable. However, despite the dilution effect of large berries, the concentration of ascorbic acid (vitamin C) increased with decreasing temperature, even on a fresh weight basis. Berry AOC was closely correlated with total phenolic concentration (r = 0.958), predominantly anthocyanins and ellagitannins. While a total of 10 anthocyanins were detected, cyanidin-3-sophoroside and cyanidin-3-(2(G)-glucosylrutinoside)-rutinoside accounted for 73% of the total, the former decreasing and the latter increasing with increasing growth temperature. By far, the most prevalent ellagitannins were lambertianin C and sanguiin H-6, both of which increased significantly with increasing temperature. It is concluded that the growth temperature has significant and contrasting effects on the concentration of a range of potentially bioactive compounds in raspberry. PMID- 23654238 TI - Separation and identification of phenolic compounds of extra virgin olive oil from Olea europaea L. by HPLC-DAD-SPE-NMR/MS. Identification of a new diastereoisomer of the aldehydic form of oleuropein aglycone. AB - The phenolic fraction of a monovarietal extra virgin olive oil (EVOO) from Olea europaea L. var. Cornezuelo was studied by the hyphenated HPLC-DAD-SPE-NMR/MS techniques. This survey led to the identification of 25 main compounds. One was identified as a new diastereoisomer of the aldehydic form of oleuropein aglycone (AOA) and characterized by 1D and 2D NMR techniques. The relative configuration of this new AOA was determined as 5R*,8S*,9S* on the basis of the results obtained from the combination of NOE experiments and Monte Carlo conformational search calculations. Assuming, as for the described diastereoisomers, that the new AOA comes from the natural oleuropein aglycone (OA), the absolute configuration was proposed as 5S,8R,9R. PMID- 23654239 TI - Effect of the commercial ripening stage and postharvest storage on microbial and aroma changes of 'Ambrunes' sweet cherries. AB - The purpose of this work was to investigate the effect of the commercial ripening stage and postharvest storage on microbial and aroma changes of 'Ambrunes' sweet cherries. The microbial counts and volatile profile of sweet cherry batches automatically sanitized and classified in three commercial ripening stages were studied for five postharvest storages. The batches were also evaluated sensorially, and the correlations between volatile compounds and aroma quality were determined. The microbial counts provided evidence that 21 days of cold storage is near the maximum extension of 'Ambrunes' sweet cherry storage in maintaining the minimal microbial quality during their shelf-life period. Relevant changes associated with longer cold storages were found in different aroma constituents with a negative impact on flavor. These changes were more evident in less ripened sweet cherries, including a decrease of (E)-2-hexenal and 1-hexanol and an increase of 2-methyl-propanal and 2-methyl-butanal. These compounds could constitute a good tool to predict flavor quality in 'Ambrunes' sweet cherries during the cold-storage process. PMID- 23654240 TI - Free fatty acids electronically bridge the self-assembly of a three-component nanocomplex consisting of amylose, protein, and free fatty acids. AB - The self-assembly of a ternary complex, which is formed through heating and cooling of a mixture of amylose (1.0 mg/mL), whey protein isolate (50 MUg/mL), and free fatty acids (FFAs, 250 MUg/mL) was investigated. High-performance size exclusion chromatography-multi-angle laser light scattering (HPSEC-MALLS) analysis showed that the complex is a water-soluble supramolecule (Mw = 6-7 * 10(6)), with a radius of gyration of 20-100 nm, indicating a nanoscale complex. Experimental results using 1-monostearyl-rac-glycerol (MSG) or cetyl alcohol that is similar to FFA in structure (except the headgroup) indicate that FFAs are the bridge between thermodynamically incompatible amylose and protein molecules and their functional carboxyl group is essential to the formation of the complex. Additionally, the effects of pH and salt treatments suggest that electrostatic interactions between negatively charged carboxyl groups of FFAs and polyionic protein are the foundation for the self-assembly of the complex. The fact that FFA is one important component in the self-assembled complex with an estimated molar ratio of 6:1:192 (amylose/protein/FFA, ~4-5% FFA) demonstrates that it might be used as a nanocarrier for the controlled release of lipophilic functional materials to maintain their stability, bioactivity, and more importantly water solubility. PMID- 23654241 TI - Heat-Induced changes occurring in oil/water emulsions stabilized by soy glycinin and beta-conglycinin. AB - Glycinin and beta-conglycinin are the two major proteins in soy protein isolate, and their emulsifying behavior was the subject of this study. These proteins form a thin layer of 30-40 nm when adsorbed at the interface. Microcalorimetric experiments showed that the thermal transitions of these proteins in the emulsion were very similar to those of the proteins in solution. The results also suggested that molecular rearrangements occurred during adsorption of beta conglycinin, as an endothermic transition peak appeared at high temperature when this protein was present at the interface. In general, beta-conglycinin exhibited greater emulsifying activity than glycinin, confirming previous reports. Heating at 95 degrees C for 15 min caused a decrease in solubility of glycinin, and interactions between the oil droplets, with an increase in the apparent viscosity, shear thinning behavior, and droplet particle size distribution of the emulsions. While, similar behavior was noted in b-conglycinin after heating at both 75 and 95 degrees C. Furthermore, the order of processing affected the subunits' composition at the interface. Heating the solution before emulsification caused a higher protein load at the interface and with all of the subunits present. On the other hand, when heating was carried out after homogenization, the basic glycinin polypeptide and the beta subunit of beta conglycinin were absent from the interface, suggesting that heat-induced complexes between these subunits formed and remained soluble in the unadsorbed phase. PMID- 23654242 TI - Influence of boron on carrot cell wall structure and its resistance to fracture. AB - Plant cell wall structure integrity and associated tissue mechanical properties is one of key determinants for the perceived texture of plant-based foods. Carrots (Daucus carota) were used to investigate the effect of mineral supply of boron (B) and/or calcium (Ca), during plant growth, on the plant cell wall structure and mechanical properties of matured root tissues. Five commercial cultivars of carrots, Kuroda (orange), Dragon Purple, Kuttiger White, Yellow, and Nutri-Red, were cultivated under controlled glasshouse conditions over two seasons. Significant increases in the accumulation of B and Ca were found for all cultivars of carrots when additional B and Ca were included in the nutrient feeding solutions throughout the plant growth period. Elevated levels of B in carrot root tissue reduced the uptake of Ca and other mineral nutrients and enhanced plant cell wall structural integrity, its resistance to fracture, and the weight and size (both diameter and length) of carrots. Although higher amounts of Ca were accumulated in the plant materials, the additional supply of Ca did not have a significant effect on the mechanical properties of mature plant tissues or on the uptake of B by the plant. The results suggest that B cross linking of pectin (rhamnogalacturonan II) has a greater influence on mature tissue mechanical properties than Ca cross-linking of pectin (homogalacturonan) when supplied during plant growth. PMID- 23654243 TI - Expression of recombinant AccMRJP1 protein from royal jelly of Chinese honeybee in Pichia pastoris and its proliferation activity in an insect cell line. AB - Major royal jelly protein 1 (MRJP1) is the most abundant member of the major royal jelly protein (MRJP) family of honeybee. Mature MRJP1 cDNA of the Chinese honeybee (Apis cerana cerana MRJP1, or AccMRJP1) was expressed in Pichia pastoris. SDS-PAGE showed that recombinant AccMRJP1 was identical in molecular weight to the glycosylated AmMRJP1 from the Western honeybee (Apis mellifera). Western blots probed with anti-AccMRJP1 antibody demonstrated that recombinant AccMRJP1 and soluble protein of the Western honeybee RJ (AmSPRJ) contained immunoreactive MRJP1. The 57 kDa protein in AmSPRJ contained an N-terminal amino sequence of N-I-L-R-G-E, which is identical to that previously characterized in AmMRJP1. The molecular weight of recombinant AccMRJP1 was decreased from 57 to 48 kDa after deglycosylation, indicating that AccMRJP1 was glycosylated. The recombinant AccMRJP1 significantly stimulated Tn-5B-4 cell growth, similar to AmSPRJ and fetal bovine serum, and affected cell shape and adhesion to the substrate. PMID- 23654244 TI - Individual and interactional effects of beta-glucan, starch, and protein on pasting properties of oat flours. AB - Seven experimental oat lines with high (6.2-7.2%), medium (5.5-5.9%), and low (4.4-5.3%) beta-glucan concentrations were evaluated for contributions of beta glucan, starch, protein, and their interactions, to pasting properties of oat flours by using a Rapid Visco Analyser (RVA, Newport Scientific, Warriewood, NSW, Australia). Significant correlations (P < 0.05) between beta-glucan concentration and pasting parameters of oat slurries were obtained under autolysis without 1 h of incubation, inhibition, and amylolysis. The relative decrease of viscosity after enzymatic hydrolysis of beta-glucan correlated with beta-glucan concentration (P < 0.05). These data demonstrated the important contribution of beta-glucan to pasting. The relative decrease of viscosity after either amylolysis or enzymatic removal of protein correlated with beta-glucan concentration (P < 0.1), which might be explained by the considerable contribution of the interaction of beta-glucan with starch and protein, to pasting. The viscosity decrease by hydrolysis of protein was much greater than the actual viscosity remaining after hydrolysis of both beta-glucan and starch, reconfirming the importance of interactions between protein and other oat components to pasting. Optimal multiple linear regression (MLR) models were generated to predict key pasting parameters in both buffer without 1 h of incubation and silver nitrate solution by using a stepwise procedure. The beta glucan concentration alone or together with the concentration of starch, rather than protein, was selected as the predictor under certain conditions. These results illustrated the major unit contribution of beta-glucan, secondary unit contribution of starch, and minimal unit contribution of protein to pasting. PMID- 23654245 TI - Genotype-by-environment interaction affects the essential mineral composition of peanut (Arachis hypogaea L.) kernels. AB - The concentrations of 15 essential minerals (B, Ca, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, P, Se, and Zn) in kernels of nine diverse peanut genotypes, which were cultivated in five distinct growing environments, were analyzed by inductively coupled plasma-optical emission spectroscopy (ICP-OES) and -mass spectrometry (ICP-MS). The effects of genotype, environment, and genotype-by environment (G * E) interactions were significant (P < 0.05) for all elements excluding Cr. Genetic control of mineral composition was demonstrated by large (P < 0.05) genotypic differences in Ca, Mo, K, Na, and P contents, and clustering of some genotypes in environment-centered principal components analysis (PCA) along axes comprising both macro (Ca, Mg, P, and K)- and microelements (Co, Cu, Fe, Mn, and Zn). Mo and Na concentrations were strongly influenced (P < 0.05) by the growing environment, with very high levels measured in samples from Bundaberg. The results confirm that that there is breeding potential for several important minerals in peanuts, although significant G * E interactions will complicate the response to selection. From a practical viewpoint, combining genetic improvement with agronomic management may be a useful strategy to consistently achieve desirable mineral concentrations in peanut kernels. PMID- 23654246 TI - Gastric emptying and short-term digestibility of thermally oxidized sunflower oil used for frying in fasted and nonfasted rats. AB - Four-hour in vivo digestibility of sunflower oil used in frying was tested in fasted and nonfasted rats. For three consecutive days, 12 male Wistar rats received 1 g of unused oil (controls, C), while 12 received 1 g of used oil (test group, T). On the night of day 3, 6 rats from each group were fasted (FC, FT) while the other 6 animals from each group had free access to food (NFC, NFT). On day 4, FC and NFC received 2 g of unused oil, while FT and NFT received 2 g of used oil. Luminal gastric and intestinal fats were studied by column and HPSE chromatography after endogenous corrections. Gastric emptying in FT was significantly slower than in NFT and FC. The luminal gastric fat profile differed from that of the oils administered, suggesting that nonoxidized triacylglycerols passed quickly into the intestines. All glyceridic compounds present in the luminal intestinal fat were affected by oil type (at least P < 0.01). Oil digestibility value order was FT < NFT < FC < NFC. FT and NFT presented lower (P < 0.001) triacylglycerol polymer and dimer digestibilities than NFC and FC. In conclusion, oil type determined luminal intestinal fat compounds and their digestibility more than nutritional status. PMID- 23654247 TI - Stabilization of soybean oil bodies by enzyme (laccase) cross-linking of adsorbed beet pectin coatings. AB - Soybean oil bodies are naturally coated by a layer of phospholipids and oleosin proteins, which protect them from in vivo environmental stresses. When oil bodies are incorporated into food products, they encounter new environmental stresses such as changes in pH, ionic strength, and temperature. Consequently, additional protection mechanisms are often needed to stabilize them. The purpose of this study was to determine whether soybean oil bodies could be stabilized by coating them with a layer of cross-linked anionic polysaccharide (beet pectin). The beet pectin layer was cross-linked via its ferulic acid groups using laccase (an enzyme that catalyzes the oxidation of phenolic groups). Oil body suspensions were prepared that contained 1 wt % oil and 0.06 wt % beet pectin at pH 7 and were then adjusted to pH 4.5 to promote electrostatic deposition of the beet pectin molecules onto the surfaces of the oil bodies. Laccase was then added to promote cross-linking of the adsorbed beet pectin layer. Cross-linked pectin coated oil bodies had similar or better stability than uncoated oil bodies to pH changes (3 to 7), NaCl addition (0 to 500 mM), and freeze-thaw cycling (-20 degrees C for 22 h; +40 degrees C for 2 h). These pectin-coated oil bodies may provide a convenient means of incorporating soybean oil into food and other products. PMID- 23654248 TI - Novel synthetic Medea selfish genetic elements drive population replacement in Drosophila; a theoretical exploration of Medea-dependent population suppression. AB - Insects act as vectors for diseases of plants, animals, and humans. Replacement of wild insect populations with genetically modified individuals unable to transmit disease provides a potentially self-perpetuating method of disease prevention. Population replacement requires a gene drive mechanism in order to spread linked genes mediating disease refractoriness through wild populations. We previously reported the creation of synthetic Medea selfish genetic elements able to drive population replacement in Drosophila. These elements use microRNA mediated silencing of myd88, a maternally expressed gene required for embryonic dorso-ventral pattern formation, coupled with early zygotic expression of a rescuing transgene, to bring about gene drive. Medea elements that work through additional mechanisms are needed in order to be able to carry out cycles of population replacement and/or remove existing transgenes from the population, using second-generation elements that spread while driving first-generation elements out of the population. Here we report the synthesis and population genetic behavior of two new synthetic Medea elements that drive population replacement through manipulation of signaling pathways involved in cellular blastoderm formation or Notch signaling, demonstrating that in Drosophila Medea elements can be generated through manipulation of diverse signaling pathways. We also describe the mRNA and small RNA changes in ovaries and early embryos associated from Medea-bearing females. Finally, we use modeling to illustrate how Medea elements carrying genes that result in diapause-dependent female lethality could be used to bring about population suppression. PMID- 23654249 TI - Opportunities for synthetic biology in antibiotics: expanding glycopeptide chemical diversity. AB - Synthetic biology offers a new path for the exploitation and improvement of natural products to address the growing crisis in antibiotic resistance. All antibiotics in clinical use are facing eventual obsolesce as a result of the evolution and dissemination of resistance mechanisms, yet there are few new drug leads forthcoming from the pharmaceutical sector. Natural products of microbial origin have proven over the past 70 years to be the wellspring of antimicrobial drugs. Harnessing synthetic biology thinking and strategies can provide new molecules and expand chemical diversity of known antibiotic scaffolds to provide much needed new drug leads. The glycopeptide antibiotics offer paradigmatic scaffolds suitable for such an approach. We review these strategies here using the glycopeptides as an example and demonstrate how synthetic biology can expand antibiotic chemical diversity to help address the growing resistance crisis. PMID- 23654250 TI - Real-time mRNA measurement during an in vitro transcription and translation reaction using binary probes. AB - In vitro transcription and translation reactions have become popular for a bottom up approach to synthetic biology. Concentrations of the mRNA intermediate are rarely determined, although knowledge of synthesis and degradation rates could facilitate rational engineering of in vitro systems. We designed binary probes to measure mRNA dynamics during cell-free protein synthesis by fluorescence resonance energy transfer. We tested different mRNA variants and show that the location and sequence environment of the probe target sites are important parameters for probe association kinetics and output signal. Best suited for sensitive real-time quantitation of mRNA was a target site located in the 3' untranslated region, which we designed to reduce secondary structure. We used this probe-target pair to refine our knowledge of mRNA dynamics in the commercially available PURE cell-free protein synthesis system and characterized the effect of TetR repressor on mRNA synthesis rates from a T7 promoter. PMID- 23654252 TI - Dynamic modeling of cellular populations within iBioSim. AB - As the complexity of synthetic genetic circuits increases, modeling is becoming a necessary first step to inform subsequent experimental efforts. In recent years, the design automation community has developed a wealth of computational tools for assisting experimentalists in designing and analyzing new genetic circuits at several scales. However, existing software primarily caters to either the DNA- or single-cell level, with little support for the multicellular level. To address this need, the iBioSim software package has been enhanced to provide support for modeling, simulating, and visualizing dynamic cellular populations in a two dimensional space. This capacity is fully integrated into the software, capitalizing on iBioSim's strengths in modeling, simulating, and analyzing single celled systems. PMID- 23654253 TI - AutoBioCAD: full biodesign automation of genetic circuits. AB - Synthetic regulatory networks with prescribed functions are engineered by assembling a reduced set of functional elements. We could also assemble them computationally if the mathematical models of those functional elements were predictive enough in different genetic contexts. Only after achieving this will we have libraries of models of biological parts able to provide predictive dynamical behaviors for most circuits constructed with them. We thus need tools that can automatically explore different genetic contexts, in addition to being able to use such libraries to design novel circuits with targeted dynamics. We have implemented a new tool, AutoBioCAD, aimed at the automated design of gene regulatory circuits. AutoBioCAD loads a library of models of genetic elements and implements evolutionary design strategies to produce (i) nucleotide sequences encoding circuits with targeted dynamics that can then be tested experimentally and (ii) circuit models for testing regulation principles in natural systems, providing a new tool for synthetic biology. AutoBioCAD can be used to model and design genetic circuits with dynamic behavior, thanks to the incorporation of stochastic effects, robustness, qualitative dynamics, multiobjective optimization, or degenerate nucleotide sequences, all facilitating the link with biological part/circuit engineering. PMID- 23654251 TI - Synthetic biology of antimicrobial discovery. AB - Antibiotic discovery has a storied history. From the discovery of penicillin by Sir Alexander Fleming to the relentless quest for antibiotics by Selman Waksman, the stories have become like folklore used to inspire future generations of scientists. However, recent discovery pipelines have run dry at a time when multidrug-resistant pathogens are on the rise. Nature has proven to be a valuable reservoir of antimicrobial agents, which are primarily produced by modularized biochemical pathways. Such modularization is well suited to remodeling by an interdisciplinary approach that spans science and engineering. Herein, we discuss the biological engineering of small molecules, peptides, and non-traditional antimicrobials and provide an overview of the growing applicability of synthetic biology to antimicrobials discovery. PMID- 23654254 TI - Modular construction of a functional artificial epothilone polyketide pathway. AB - Natural products of microbial origin continue to be an important source of pharmaceuticals and agrochemicals exhibiting potent activities and often novel modes of action. Due to their inherent structural complexity chemical synthesis is often hardly possible, leaving fermentation as the only viable production route. In addition, the pharmaceutical properties of natural products often need to be optimized for application by sophisticated medicinal chemistry and/or biosynthetic engineering. The latter requires a detailed understanding of the biosynthetic process and genetic tools to modify the producing organism that are often unavailable. Consequently, heterologous expression of complex natural product pathways has been in the focus of development over recent years. However, piecing together existing DNA cloned from natural sources and achieving efficient expression in heterologous circuits represent several limitations that can be addressed by synthetic biology. In this work we have redesigned and reassembled the 56 kb epothilone biosynthetic gene cluster from Sorangium cellulosum for expression in the high GC host Myxococcus xanthus. The codon composition was adapted to a modified codon table for M. xanthus, and unique restriction sites were simultaneously introduced and others eliminated from the sequence in order to permit pathway assembly and future interchangeability of modular building blocks from the epothilone megasynthetase. The functionality of the artificial pathway was demonstrated by successful heterologous epothilone production in M. xanthus at significant yields that have to be improved in upcoming work. Our study sets the stage for future engineering of epothilone biosynthesis and production optimization using a highly flexible assembly strategy. PMID- 23654256 TI - A novel and stable mouse artificial chromosome vector. AB - Human chromosome fragments (hCFs) and human artificial chromosomes (HACs) can be transferred into mouse ES cells to produce trans-chromosomic (Tc) mice. Although hCFs and HACs containing large genomic DNAs can be autonomously maintained in Tc mice, their retention rate is variable in mouse ES cell lines and Tc mouse tissues, possibly because of centromere differences between the species. To improve the retention rate of artificial chromosomes in mouse cells, we constructed novel mouse artificial chromosome (MAC) vectors by truncating a natural mouse chromosome at a site adjacent to the centromeric region. We obtained cell clones containing the MAC vectors that were stably maintained in mouse ES cells and various tissues in Tc mice. The MACs possess acceptor sites into which a desired gene or genes can be inserted. Thus, Tc mice harboring the MAC vectors may be valuable tools for functional analyses of desired genes, producing humanized model mice, and synthetic biology. PMID- 23654255 TI - Designed biosynthesis of 36-methyl-FK506 by polyketide precursor pathway engineering. AB - The polyketide synthase (PKS) biosynthetic code has recently expanded to include a newly recognized group of extender unit substrates derived from alpha,beta unsaturated acyl-CoA molecules that deliver diverse side chain chemistry to polyketide backbones. Herein we report the identification of a three-gene operon responsible for the biosynthesis of the PKS building block isobutyrylmalonyl-CoA associated with the macrolide ansalactam A from the marine bacterium Streptomyces sp. CNH189. Using a synthetic biology approach, we engineered the production of unnatural 36-methyl-FK506 in Streptomyces sp. KCTC 11604BP by incorporating the branched extender unit into FK506 biosynthesis in place of its natural C-21 allyl side chain, which has been shown to be critical for FK506's potent immunosuppressant and neurite outgrowth activities. PMID- 23654257 TI - PaR-PaR laboratory automation platform. AB - Labor-intensive multistep biological tasks, such as the construction and cloning of DNA molecules, are prime candidates for laboratory automation. Flexible and biology-friendly operation of robotic equipment is key to its successful integration in biological laboratories, and the efforts required to operate a robot must be much smaller than the alternative manual lab work. To achieve these goals, a simple high-level biology-friendly robot programming language is needed. We have developed and experimentally validated such a language: Programming a Robot (PaR-PaR). The syntax and compiler for the language are based on computer science principles and a deep understanding of biological workflows. PaR-PaR allows researchers to use liquid-handling robots effectively, enabling experiments that would not have been considered previously. After minimal training, a biologist can independently write complicated protocols for a robot within an hour. Adoption of PaR-PaR as a standard cross-platform language would enable hand-written or software-generated robotic protocols to be shared across laboratories. PMID- 23654258 TI - Combinatorial biosynthesis of cyclic lipopeptide antibiotics: a model for synthetic biology to accelerate the evolution of secondary metabolite biosynthetic pathways. AB - Nonribosomal peptide synthetases (NRPSs) are giant multi-enzymes that carry out sequencial assembly line couplings of amino acids to generate linear or cyclic peptides. NRPSs are composed of repeating enzyme domains with modular organization to activate and couple specific amino acids in a particular order. From a synthetic biology perspective, they can be considered as peptide assembly machines composed of devices to couple fatty acids to l-amino acids, l-amino acids to l-amino acids, and d-amino acids to l-amino acids. The coupling devices are composed of specific parts that contain two or more enzyme domains that can be exchanged combinatorially to generate novel peptide assembly machines to produce novel peptides. The potent lipopeptide antibiotics daptomycin and A54145E have identical cyclic depsipeptide ring structures and stereochemistry but have divergent amino acid sequences. As their biosynthetic gene clusters are derived from an ancient ancestral lipopetide pathway, these lipopeptides provided an attractive model to develop combinatorial biosynthesis to generate antibiotics superior to daptomycin. These studies on combinatorial biosynthesis have helped generate guidelines for the successful assembly of NRPS parts and devices that can be used to generate novel lipopeptide structures and have established a basis for future synthetic biology studies to further develop combinatorial biosynthesis as a robust approach to natural product drug discovery. PMID- 23654259 TI - Pigeon: a design visualizer for synthetic biology. AB - Pigeon is a Web-based tool that translates a textual description of a synthetic biology design into an image. It allows programmatic generation of design visualizations, is easy to learn, is easily extensible to new glyphs and notation, and can be connected to other software tools for visualizing their output. We present the Pigeon syntax, its current command set, and some examples of Pigeon programs and their output. PMID- 23654260 TI - Artificial conversion of the mating-type of Saccharomyces cerevisiae without autopolyploidization. AB - Crossbreeding is a classical yeast hybridization procedure, where the mating of haploid cells of opposite mating-type, MATa and MATalpha cells, produces a new heterozygous diploid. Here, we describe a method to generate haploid MATa and MATalpha cells using mating-type conversion caused by expression of the HO gene, which encodes an endonuclease. Importantly, our method prevents the autopolyploidization that typically arises during artificial mating-type conversion. This facilitates isolation of the desired mating-type of yeast cells with simple and easy procedure. In the current study, we designed a suitable genetic circuit for each haploid cell and converted MATalpha haploid cells into MATa haploid cells and vice versa, demonstrating the utility of constructed artificial regulation network to prevent autopolyploidization. Via forced expression of the a1 gene in MATalpha haploid cells or of alpha2 in MATa haploid cells, the undesirable mating ability of yeast cells was completely suppressed. We confirmed the success in prevention of autopolyploidization by ploidy analysis. This new approach provides a reliable and versatile tool for yeast crossbreeding, so that it will be useful for scientific research and industrial applications of yeast. PMID- 23654261 TI - Quantifying translational coupling in E. coli synthetic operons using RBS modulation and fluorescent reporters. AB - Translational coupling is the interdependence of translation efficiency of neighboring genes encoded within an operon. The degree of coupling may be quantified by measuring how the translation rate of a gene is modulated by the translation rate of its upstream gene. Translational coupling was observed in prokaryotic operons several decades ago, but the quantitative range of modulation translational coupling leads to and the factors governing this modulation were only partially characterized. In this study, we systematically quantify and characterize translational coupling in E. coli synthetic operons using a library of plasmids carrying fluorescent reporter genes that are controlled by a set of different ribosome binding site (RBS) sequences. The downstream gene expression level is found to be enhanced by the upstream gene expression via translational coupling with the enhancement level varying from almost no coupling to over 10 fold depending on the upstream gene's sequence. Additionally, we find that the level of translational coupling in our system is similar between the second and third locations in the operon. The coupling depends on the distance between the stop codon of the upstream gene and the start codon of the downstream gene. This study is the first to systematically and quantitatively characterize translational coupling in a synthetic E. coli operon. Our analysis will be useful in accurate manipulation of gene expression in synthetic biology and serves as a step toward understanding the mechanisms involved in translational expression modulation. PMID- 23654262 TI - Sequence, cloning, and analysis of the fluvirucin B1 polyketide synthase from Actinomadura vulgaris. AB - Fluvirucin B1 , produced by Actinomadura vulgaris, is a 14-membered macrolactam active against a variety of infectious fungi as well as influenza A. Despite considerable interest from the synthetic community, very little information is available regarding the biosynthetic origins of the fluvirucins. Herein, we report the identification and initial characterization of the fluvirucin B1 polyketide synthase and related enzymes. The cluster consists of five extender modules flanked by an N-terminal acyl carrier protein and C-terminal thioesterase domain. All but one of the synthase modules contain the full complement of tailoring domains (ketoreductase, dehydratase, and enoyl reductase) as determined by sequence homology with known polyketide synthases. Acitve site analyses of several key components of the cluster are performed to further verify that this gene cluster is associated with production of fluvirucin B1 . This work will both open doors toward a better understanding of macrolactam formation and provide an avenue to genetics-based diversification of fluvirucin structure. PMID- 23654263 TI - Analysis and design of a genetic circuit for dynamic metabolic engineering. AB - Recent advances in synthetic biology have equipped us with new tools for bioprocess optimization at the genetic level. Previously, we have presented an integrated in silico design for the dynamic control of gene expression based on a density-sensing unit and a genetic toggle switch. In the present paper, analysis of a serine-producing Escherichia coli mutant shows that an instantaneous ON-OFF switch leads to a maximum theoretical productivity improvement of 29.6% compared to the mutant. To further the design, global sensitivity analysis is applied here to a mathematical model of serine production in E. coli coupled with a genetic circuit. The model of the quorum sensing and the toggle switch involves 13 parameters of which 3 are identified as having a significant effect on serine concentration. Simulations conducted in this reduced parameter space further identified the optimal ranges for these 3 key parameters to achieve productivity values close to the maximum theoretical values. This analysis can now be used to guide the experimental implementation of a dynamic metabolic engineering strategy and reduce the time required to design the genetic circuit components. PMID- 23654264 TI - Discrete-time signal processing with DNA. AB - We present a methodology for implementing discrete-time signal processing operations, such as filtering, with molecular reactions. The reactions produce time-varying output quantities of molecules as a function of time-varying input quantities according to a functional specification. This computation is robust and independent of the reaction rates, provided that the rate constants fall within coarse categories. We describe two approaches: one entails synchronization with a clock signal, implemented through sustained chemical oscillations; the other is "self-timed" or asynchronous. We illustrate the methodology by synthesizing a simple moving-average filter, a biquad filter, and a Fast Fourier Transform (FFT). Abstract molecular reactions for these filters and transforms are translated into DNA strand displacement reactions. The computation is validated through mass-action simulations of the DNA kinetics. Although a proof of concept for the time being, molecular filters and transforms have potential applications in fields such as biochemical sensing and drug delivery. PMID- 23654266 TI - Reverse engineering validation using a benchmark synthetic gene circuit in human cells. AB - Multicomponent biological networks are often understood incompletely, in large part due to the lack of reliable and robust methodologies for network reverse engineering and characterization. As a consequence, developing automated and rigorously validated methodologies for unraveling the complexity of biomolecular networks in human cells remains a central challenge to life scientists and engineers. Today, when it comes to experimental and analytical requirements, there exists a great deal of diversity in reverse engineering methods, which renders the independent validation and comparison of their predictive capabilities difficult. In this work we introduce an experimental platform customized for the development and verification of reverse engineering and pathway characterization algorithms in mammalian cells. Specifically, we stably integrate a synthetic gene network in human kidney cells and use it as a benchmark for validating reverse engineering methodologies. The network, which is orthogonal to endogenous cellular signaling, contains a small set of regulatory interactions that can be used to quantify the reconstruction performance. By performing successive perturbations to each modular component of the network and comparing protein and RNA measurements, we study the conditions under which we can reliably reconstruct the causal relationships of the integrated synthetic network. PMID- 23654269 TI - A solid-phase platform for combinatorial and scarless multipart gene assembly. AB - With the emergence of standardized genetic modules as part of the synthetic biology toolbox, the need for universal and automatable assembly protocols increases. Although several methods and standards have been developed, these all suffer from drawbacks such as the introduction of scar sequences during ligation or the need for specific flanking sequences or a priori knowledge of the final sequence to be obtained. We have developed a method for scarless ligation of multipart gene segments in a truly sequence-independent fashion. The big advantage of this approach is that it is combinatorial, allowing the generation of all combinations of several variants of two or more modules to be ligated in less than a day. This method is based on the ligation of single-stranded or double-stranded oligodeoxynucleotides (ODN) and PCR products immobilized on a solid support. Different settings were tested to optimize the solid-support ligation. Finally, to show proof of concept for this novel multipart gene assembly platform a small library of all possible combinations of 4 BioBrick modules was generated and tested. PMID- 23654268 TI - Decaffeination and measurement of caffeine content by addicted Escherichia coli with a refactored N-demethylation operon from Pseudomonas putida CBB5. AB - The widespread use of caffeine (1,3,7-trimethylxanthine) and other methylxanthines in beverages and pharmaceuticals has led to significant environmental pollution. We have developed a portable caffeine degradation operon by refactoring the alkylxanthine degradation (Alx) gene cluster from Pseudomonas putida CBB5 to function in Escherichia coli. In the process, we discovered that adding a glutathione S-transferase from Janthinobacterium sp. Marseille was necessary to achieve N 7 -demethylation activity. E. coli cells with the synthetic operon degrade caffeine to the guanine precursor, xanthine. Cells deficient in de novo guanine biosynthesis that contain the refactored operon are "addicted" to caffeine: their growth density is limited by the availability of caffeine or other xanthines. We show that the addicted strain can be used as a biosensor to measure the caffeine content of common beverages. The synthetic N demethylation operon could be useful for reclaiming nutrient-rich byproducts of coffee bean processing and for the cost-effective bioproduction of methylxanthine drugs. PMID- 23654267 TI - Modularity of select riboswitch expression platforms enables facile engineering of novel genetic regulatory devices. AB - RNA-based biosensors and regulatory devices have received significant attention for their potential in a broad array of synthetic biology applications. One of the primary difficulties in engineering these molecules is the lack of facile methods to link sensory modules, or aptamers, to readout domains. Such efforts typically require extensive screening or selection of sequences that facilitate interdomain communication. Bacteria have evolved a widespread form of gene regulation known as riboswitches that perform this task with sufficient fidelity to control expression of biosynthetic and transport proteins essential for normal cellular homeostasis. In this work, we demonstrate that select riboswitch readout domains, called expression platforms, are modular in that they can host a variety of natural and synthetic aptamers to create novel chimeric RNAs that regulate transcription both in vitro and in vivo. Importantly, this technique does not require selection of device-specific "communication modules" required to transmit ligand binding to the regulatory domain, enabling rapid engineering of novel functional RNAs. PMID- 23654270 TI - Fluorescent proteins and in vitro genetic organization for cell-free synthetic biology. AB - To facilitate the construction of cell-free genetic devices, we evaluated the ability of 17 different fluorescent proteins to give easily detectable fluorescence signals in real-time from in vitro transcription-translation reactions with a minimal system consisting of T7 RNA polymerase and E. coli translation machinery, i.e., the PUREsystem. The data were used to construct a ratiometric fluorescence assay to quantify the effect of genetic organization on in vitro expression levels. Synthetic operons with varied spacing and sequence composition between two genes that coded for fluorescent proteins were then assembled. The resulting data indicated which restriction sites and where the restriction sites should be placed in order to build genetic devices in a manner that does not interfere with protein expression. Other simple design rules were identified, such as the spacing and sequence composition influences of regions upstream and downstream of ribosome binding sites and the ability of non-AUG start codons to function in vitro. PMID- 23654271 TI - SBROME: a scalable optimization and module matching framework for automated biosystems design. AB - The development of a scalable framework for biodesign automation is a formidable challenge given the expected increase in part availability and the ever-growing complexity of synthetic circuits. To allow for (a) the use of previously constructed and characterized circuits or modules and (b) the implementation of designs that can scale up to hundreds of nodes, we here propose a divide-and conquer Synthetic Biology Reusable Optimization Methodology (SBROME). An abstract user-defined circuit is first transformed and matched against a module database that incorporates circuits that have previously been experimentally characterized. Then the resulting circuit is decomposed to subcircuits that are populated with the set of parts that best approximate the desired function. Finally, all subcircuits are subsequently characterized and deposited back to the module database for future reuse. We successfully applied SBROME toward two alternative designs of a modular 3-input multiplexer that utilize pre-existing logic gates and characterized biological parts. PMID- 23654272 TI - Multichange isothermal mutagenesis: a new strategy for multiple site-directed mutations in plasmid DNA. AB - Multichange ISOthermal (MISO) mutagenesis is a new technique allowing simultaneous introduction of multiple site-directed mutations into plasmid DNA by leveraging two existing ideas: QuikChange-style primers and one-step isothermal (ISO) assembly. Inversely partnering pairs of QuikChange primers results in robust, exponential amplification of linear fragments of DNA encoding mutagenic yet homologous ends. These products are amenable to ISO assembly, which efficiently assembles them into a circular, mutagenized plasmid. Because the technique relies on ISO assembly, MISO mutagenesis is additionally amenable to other relevant DNA modifications such as insertions and deletions. Here we provide a detailed description of the MISO mutagenesis concept and highlight its versatility by applying it to three experiments currently intractable with standard site-directed mutagenesis approaches. MISO mutagenesis has the potential to become widely used for site-directed mutagenesis. PMID- 23654273 TI - Rational design of orthogonal libraries of protein coding genes. AB - Array-based oligonucleotide synthesis technologies provide access to thousands of custom-designed sequence variants at low cost. Large-scale synthesis and high throughput assays have become valuable experimental tools to study in detail the interplay between sequence and function. We have developed a methodology and corresponding algorithms for the design of diverse protein coding gene libraries, to exploit the potential of multiplex synthesis and help elucidate the effects of codon utilization and other factors in gene expression. Using our algorithm, we have computationally designed gene libraries with hundreds to thousands of orthogonal codon usage variants, uniformly exploring the design space of codon utilization, while demanding only a small fraction of the synthesis cost that would be required if these variants were synthesized independently. PMID- 23654274 TI - Retroactivity controls the temporal dynamics of gene transcription. AB - Just like in many engineering systems, impedance-like effects, called retroactivity, arise at the interconnection of biomolecular circuits, leading to unexpected changes in a circuit's behavior. In this paper, we provide a combined experimental and theoretical study to characterize the effects of retroactivity on the temporal dynamics of a gene transcription module in vivo. The response of the module to an inducer was measured both in isolation and when the module was connected to downstream clients. The connected module, when compared to the isolated module, responded selectively to the introduction of the inducer versus its withdrawal. Specifically, a "sign-sensitive delay" appeared, in which the connected module displayed a time delay in the response to induction and anticipation in the response to de-induction. The extent of these effects can be made larger by increasing the amounts of downstream clients and/or their binding affinity to the output protein of the module. Our experimental results and mathematical formulas make it possible to predict the extent of the change in the dynamic behavior of a module after interconnection. They can be employed to both recover the predictive power of a modular approach to understand systems or as an additional design tool to shape the temporal behavior of gene transcription. PMID- 23654275 TI - Modular design of a synthetic payload delivery device. AB - Predictable engineering of complex biological behaviors using characterized molecular functions remains a key challenge in synthetic biology. To explore the process of engineering biological behaviors, we applied a modular design strategy to the development of E. coli that deliver macromolecules to the cytoplasm of cancer cells in vitro. First, we specified five abstract, qualitative behaviors that would act in concert to achieve payload delivery. Drawing from disparate sources of previously described genetic components, we then designed, constructed, and tested individual genetic circuits to implement each module. Subsequent coupling of the modules and system optimization, aided by quantitative predictions, generated a system that delivers proteins to 80% of targeted cancer cells. Development of an effective delivery system provides strong evidence that advanced cellular behaviors, not just transcriptional circuits, can be rationally decomposed into a series of functional genetic modules and then constructed to achieve the target activity with the existing synthetic biology toolkit. PMID- 23654276 TI - Redirecting photosynthetic reducing power toward bioactive natural product synthesis. AB - In addition to the products of photosynthesis, the chloroplast provides the energy and carbon building blocks required for synthesis of a wealth of bioactive natural products of which many have potential uses as pharmaceuticals. In the course of plant evolution, energy generation and biosynthetic capacities have been compartmentalized. Chloroplast photosynthesis provides ATP and NADPH as well as carbon sources for primary metabolism. Cytochrome P450 monooxygenases (P450s) in the endoplasmic reticulum (ER) synthesize a wide spectrum of bioactive natural products, powered by single electron transfers from NADPH. P450s are present in low amounts, and the reactions proceed relatively slowly due to limiting concentrations of NADPH. Here we demonstrate that it is possible to break the evolutionary compartmentalization of energy generation and P450-catalyzed biosynthesis, by relocating an entire P450-dependent pathway to the chloroplast and driving the pathway by direct use of the reducing power generated by photosystem I in a light-dependent manner. The study demonstrates the potential of transferring pathways for structurally complex high-value natural products to the chloroplast and directly tapping into the reducing power generated by photosynthesis to drive the P450s using water as the primary electron donor. PMID- 23654277 TI - A genome-wide activity assessment of terminator regions in Saccharomyces cerevisiae provides a "terminatome" toolbox. AB - The terminator regions of eukaryotes encode functional elements in the 3' untranslated region (3'-UTR) that influence the 3'-end processing of mRNA, mRNA stability, and translational efficiency, which can modulate protein production. However, the contribution of these terminator regions to gene expression remains unclear, and therefore their utilization in metabolic engineering or synthetic genetic circuits has been limited. Here, we comprehensively evaluated the activity of 5302 terminator regions from a total of 5880 genes in the budding yeast Saccharomyces cerevisiae by inserting each terminator region downstream of the P TDH3 - green fluorescent protein (GFP) reporter gene and measuring the fluorescent intensity of GFP. Terminator region activities relative to that of the PGK1 standard terminator ranged from 0.036 to 2.52, with a mean of 0.87. We thus could isolate the most and least active terminator regions. The activities of the terminator regions showed a positive correlation with mRNA abundance, indicating that the terminator region is a determinant of mRNA abundance. The least active terminator regions tended to encode longer 3'-UTRs, suggesting the existence of active degradation mechanisms for those mRNAs. The terminator regions of ribosomal protein genes tended to be the most active, suggesting the existence of a common regulator of those genes. The "terminatome" (the genome wide set of terminator regions) thus not only provides valuable information to understand the modulatory roles of terminator regions on gene expression but also serves as a useful toolbox for the development of metabolically and genetically engineered yeast. PMID- 23654278 TI - Elimination of redundant and stop codons during the chemical synthesis of degenerate oligonucleotides. Combinatorial testing on the chromophore region of the red fluorescent protein mKate. AB - Although some strategies have been reported for the elimination of stop and redundant codons during the chemical synthesis of degenerate oligonucleotides, incorporating an expensive cocktail of 20 trimer-phosphoramidites is currently a commonly employed and straightforward approach. As an alternative option, we describe here a cheaper strategy based on standard monomer-phosphoramidites and a simplified resin-splitting procedure. The accurate division of the resin, containing the growing oligonucleotide, into four columns represents the key step in this approach. The synthesis of the degenerate codon NDT in column 1, loaded with 60% of the resin, produces 12 codons, while a degenerate codon VMA in column 2, loaded with 30% of the resin, produces 6 codons. Codons ATG and TGG, independently synthesized in columns 3 and 4, respectively, and loaded with 5% each, completes the 20 different codons. The experimental frequency of each mutant codon in the library was assessed by randomizing 12 contiguous codons that encode for amino acids located in the chromophore region of the enhanced red fluorescent protein mKate-S158A. Furthermore, randomization of three contiguous codons that encode for the amino acids Phe62, Met63, and Tyr64, which are equivalent to Phe64, Ser65, and Tyr66 in GFP, gave rise to some red and golden yellow fluorescent mutants displaying interesting phenotypes and spectroscopic properties. The absorption and emission spectra of two of these mutants also suggested that the complete maturation of the red and golden yellow chromophores in mKate proceeds via the formation of a green-type chromophore and a cyan-type chromophore, respectively. PMID- 23654279 TI - Designing and producing modified, new-to-nature peptides with antimicrobial activity by use of a combination of various lantibiotic modification enzymes. AB - Lanthipeptides are peptides that contain several post-translationally modified amino acid residues and commonly show considerable antimicrobial activity. After translation, the amino acid residues of these peptides are modified by a distinct set of modification enzymes. This process results in peptides containing one or more lanthionine rings and dehydrated Ser and Thr residues. Previously, an in vivo lanthipeptide production system based on the modification machinery of the model lantibiotic nisin was reported. Here, we present the addition of the modification enzymes LtnJ and GdmD to this production system. With these enzymes we can now produce lanthipeptides that contain d-alanines or a C-terminal aminovinyl-cysteine. We show experimentally that the decarboxylase GdmD is responsible for the C-terminal decarboxylation. Our results demonstrate that different lanthipeptide modification enzymes can work together in an in vivo production system. This yields a plug-and-play system that can be used to select different sets of modification enzymes to work on diverse, specifically designed substrates. PMID- 23654280 TI - Efficient behavior of photosynthetic organelles via Pareto optimality, identifiability, and sensitivity analysis. AB - In this work, we develop methodologies for analyzing and cross comparing metabolic models. We investigate three important metabolic networks to discuss the complexity of biological organization of organisms, modeling, and system properties. In particular, we analyze these metabolic networks because of their biotechnological and basic science importance: the photosynthetic carbon metabolism in a general leaf, the Rhodobacter spheroides bacterium, and the Chlamydomonas reinhardtii alga. We adopt single- and multi-objective optimization algorithms to maximize the CO 2 uptake rate and the production of metabolites of industrial interest or for ecological purposes. We focus both on the level of genes (e.g., finding genetic manipulations to increase the production of one or more metabolites) and on finding concentration enzymes for improving the CO 2 consumption. We find that R. spheroides is able to absorb an amount of CO 2 until 57.452 mmol h (-1) gDW (-1) , while C. reinhardtii obtains a maximum of 6.7331. We report that the Pareto front analysis proves extremely useful to compare different organisms, as well as providing the possibility to investigate them with the same framework. By using the sensitivity and robustness analysis, our framework identifies the most sensitive and fragile components of the biological systems we take into account, allowing us to compare their models. We adopt the identifiability analysis to detect functional relations among enzymes; we observe that RuBisCO, GAPDH, and FBPase belong to the same functional group, as suggested also by the sensitivity analysis. PMID- 23654281 TI - Synthetic gene circuit-mediated monitoring of endogenous metabolites: identification of GAL11 as a novel multicopy enhancer of s-adenosylmethionine level in yeast. AB - Monitoring levels of key metabolites in living cells comprises a critical step in various investigations. The simplest approach to this goal is a fluorescent reporter gene using an endogenous promoter responsive to the metabolite. However, such a promoter is often not identified or even present in the species of interest. An alternative can be a synthetic gene circuit based on a heterologous pair consisting of a promoter and a transcription factor known to respond to the metabolite. We exploited the met operator and MetJ repressor of Escherichia coli, the interaction between which depends on S-adenosylmethionine (SAM), to construct synthetic gene circuits that report SAM levels in Saccharomyces cerevisiae. Using a dual-input circuit that outputs selection marker genes in a doxycycline-tunable manner, we screened a genomic library to identify GAL11 as a novel multicopy enhancer of SAM levels. These results demonstrate the potential and utility of synthetic gene circuit-mediated metabolite monitoring. PMID- 23654283 TI - Asymmetric synthesis of indole homo-Michael adducts via dynamic kinetic Friedel Crafts alkylation with cyclopropanes. AB - An enantioconvergent Friedel-Crafts alkylation of indoles with donor-acceptor cyclopropanes is described. The reaction is catalyzed by pybox*MgI2 and proceeds via a type I dynamic kinetic asymmetric transformation (DyKAT). PMID- 23654282 TI - Engineered Streptomyces avermitilis host for heterologous expression of biosynthetic gene cluster for secondary metabolites. AB - An industrial microorganism, Streptomyces avermitilis, which is a producer of anthelmintic macrocyclic lactones, avermectins, has been constructed as a versatile model host for heterologous expression of genes encoding secondary metabolite biosynthesis. Twenty of the entire biosynthetic gene clusters for secondary metabolites were successively cloned and introduced into a versatile model host S. avermitilis SUKA17 or 22. Almost all S. avermitilis transformants carrying the entire gene cluster produced metabolites as a result of the expression of biosynthetic gene clusters introduced. A few transformants were unable to produce metabolites, but their production was restored by the expression of biosynthetic genes using an alternative promoter or the expression of a regulatory gene in the gene cluster that controls the expression of biosynthetic genes in the cluster using an alternative promoter. Production of metabolites in some transformants of the versatile host was higher than that of the original producers, and cryptic biosynthetic gene clusters in the original producer were also expressed in a versatile host. PMID- 23654285 TI - Beyond classical reactivity patterns: shifting from 1,4- to 1,6-additions in regio- and enantioselective organocatalyzed vinylogous reactions of olefinic lactones with enals and 2,4-dienals. AB - Organocatalysis is shown to expand the classical reactivity pattern for conjugate addition reactions. It is demonstrated that the site selectivity can be extended from 1,4- to 1,6-additions for the enantioselective vinylogous additions of methyl-substituted vinylogous lactones to enals and 2,4-dienals. This novel reactivity is demonstrated for methyl-substituted olefinic azlactones and butyrolactones. Their synthetic potential is first highlighted by the development of the organocatalytic regioselective vinylogous 1,4-addition to enals which proceeds with a very high level of double-bond geometry control and excellent enantioselectivity. The concept is developed further for the unprecedented intermolecular enantioselective organocatalyzed vinylogous 1,6-addition to linear 2,4-dienals, by which the site selectivity of the process is extended from the beta-position to the remote delta-position of the 2,4-dienal. The organocatalyst controls the newly generated stereocenter six bonds away from the stereocenter of the catalyst with a high level of enantiocontrol, and the products are obtained with full control of double-bonds configuration. The scope of these new reaction concepts is demonstrated for a series of aliphatic and aryl-substituted enals and 2,4-dienals undergoing enantioselective vinylogous reactions with methyl substituted olefinic azlactones and butyrolactones. Furthermore, mechanistic considerations are presented which can account for the change from 1,4- to 1,6 selectivity. Finally, a number of different transformations of the optically active 1,4- and 1,6-addition products are demonstrated. PMID- 23654284 TI - Expanding the scope of oligo-pyrrolinone-pyrrolidines as protein-protein interface mimics. AB - Oligo-pyrrolinone-pyrrolidines (generic structure 1) have the potential to interfere with protein-protein interactions (PPIs), but to reduce this to practice it is necessary to be able to synthesize these structures with a variety of different side chains corresponding to genetically encoded proteins. This paper describes expansion of the synthetic scope of 1, the difficulties encountered in this process, particularly issues with epimerization and slow coupling rates, and methods to overcome them. Finally, spectroscopic and physicochemical properties as well as proteolytic stabilities of molecules in this series were measured; these data highlight the suitability of oligo pyrrolinone-pyrrolidines for the development of pharmacological probes or pharmaceutical leads. PMID- 23654286 TI - High-pressure synthesis and superconductivity of the Laves phase compound Ca(Al,Si)2 composed of truncated tetrahedral cages Ca@(Al,Si))12. AB - The Zintl compound CaAl2Si2 peritectically decomposes to a new ternary cubic Laves phase Ca(Al,Si)2 and an Al-Si eutectic at temperatures above 750 degrees C under a pressure of 13 GPa. The ternary Laves phase compound can also be prepared as solid solutions Ca(Al(1-x)Si(x))2 (0.35 <= x <= 0.75) directly from the ternary mixtures under high-pressure and high-temperature conditions. The cubic Laves phase structure can be regarded as a type of clathrate compound composed of face-sharing truncated tetrahedral cages with Ca atoms at the center, Ca@(Al,Si)12. The compound with a stoichiometric composition CaAlSi exhibits superconductivity with a transition temperature of 2.6 K. This is the first superconducting Laves phase compound composed solely of commonly found elements. PMID- 23654287 TI - Interaction of imidazolium-based room-temperature ionic liquids with DOPC phospholipid monolayers: electrochemical study. AB - To test the biocompatible character of room-temperature ionic liquids (ILs), the interaction of various ILs with biological membrane (biomembrane) models was studied in this work. Dioleoyl phosphatidylcholine (DOPC) adsorbed on a mercury (Hg) electrode forms an impermeable defect-free monolayer which is a well established biomembrane model, prone to be studied by electrochemical techniques. We have monitored the modifications of the Hg supported monolayer caused by ILs using rapid cyclic voltammetry (RCV), alternating current voltammetry (ACV), and electrochemical impedance spectroscopy (EIS). A series of imidazolium-based ILs were investigated whose interaction highlighted the role of anion and lateral side chain of cation during the interaction with DOPC monolayers. It was shown that the hydrophobic and lipophilic character of the IL cations is a primary factor responsible for this interaction. Hg-supported monolayers provide an accurate analysis of the behavior of ILs at the interface of a biomembrane leading to a comprehensive understanding of the interaction mechanisms involved. At the same time, these experiments show that the Hg-phospholipid model is an effective toxicity sensing technique as shown by the correlation between literature in vivo toxicity data and the data from this study. PMID- 23654288 TI - 3(10)-Helical peptide acting as a dual relay for charge-hopping transfer in proteins. AB - We present a density functional calculational study to clarify that a 3(10)-helix peptide can serve as a novel dual-relay element to mediate long-range charge migrations via its C- and N-termini in proteins. The ionization potential of the 3(10)-helix C-terminus correlates inversely with the helix length, HOMO energy, and dipole moment. In particular, it decreases considerably with the increase in the number of peptide units, even to a smaller value than that of the easily oxidized amino acid residue, which implies the possibility of releasing an electron and forming a hole at the 3(10)-helical C-terminus. On the other hand, the electron affinity of the 3(10)-helical N-terminus correlates positively with the helix length and dipole moment but inversely with the LUMO energy. Clearly, the increasing positive electron-binding energy with the increase in the number of peptide units implies that the 3(10)-helical N-terminus can capture an excess electron and play an electron-relaying role. The relaying ability of the 3(10) helical C-terminus and N-terminus not only depends on the helix length but also varies subject to the capping effect, the collaboration and competition of proximal groups, and solvent environments. In contrast to the known hole relays such as the side chains of Tyr and Trp and electron relays such as the side chains of protonated Lys and Arg, either the hole relay (the 3(10)-helix C terminus) or the electron relay (the 3(10)-helix N-terminus) is property-tunable and could apply to different proteins in assisting or mediating long-range charge migrations. PMID- 23654289 TI - Engineering for the 21st century: synthetic biology. AB - For years, scientists have hoped that biology would find its engineering counterpart--a series of principles that could be used as reliably as chemical engineering is for chemistry. Thanks to major advances in synthetic biology, those hopes may soon be realized. PMID- 23654290 TI - Estimation of ligament strains and joint moments in the ankle during a supination sprain injury. AB - This study presents the ankle ligament strains and ankle joint moments during an accidental injury event diagnosed as a grade I anterior talofibular ligament (ATaFL) sprain. A male athlete accidentally sprained his ankle while performing a cutting motion in a laboratory setting. The kinematic data were input to a three dimensional rigid-body foot model for simulation analyses. Maximum strains in 20 ligaments were evaluated in simulations that investigated various combinations of the reported ankle joint motions. Temporal strains in the ATaFL and the calcaneofibular ligament (CaFL) were then compared and the three-dimensional ankle joint moments were evaluated from the model. The ATaFL and CaFL were highly strained when the inversion motion was simulated (10% for ATaFL and 12% for CaFL). These ligament strains were increased significantly when either or both plantarflexion and internal rotation motions were added in a temporal fashion (up to 20% for ATaFL and 16% for CaFL). Interestingly, at the time strain peaked in the ATaFL, the plantarflexion angle was not large but apparently important. This computational simulation study suggested that an inversion moment of approximately 23 N m plus an internal rotation moment of approximately 11 N m and a small plantarflexion moment may have generated a strain of 15-20% in the ATaFL to produce a grade I ligament injury in the athlete's ankle. This injury simulation study exhibited the potentially important roles of plantarflexion and internal rotation, when combined with a large inversion motion, to produce a grade I ATaFL injury in the ankle of this athlete. PMID- 23654291 TI - Retinal vascular features associated with risk of branch retinal vein occlusion. AB - PURPOSE/AIM: To identify retinal vascular features that precede the development of branch retinal vein occlusion (BRVO) by comparing case eyes and fellow eyes. MATERIALS AND METHODS: We identified 25 persons who attended an annual health screening program at Osaka Health Science Center, Osaka, Japan, and then developed BRVO in one eye between 1995 and 2009. We retrospectively reviewed retinal images of these subjects taken 1-5 years prior to the development of BRVO and compared the prevalence of retinal vascular features between case eyes and contralateral fellow eyes. Potential local retinal vascular features considered were (1) severe arterio-venous (AV) nicking, (2) a smaller angle at the crossing of the arteriole and venule, (3) double crossing, (4) crossing near venular bifurcation and (5) isolated retinopathy. The central retinal artery equivalent (CRAE), vein equivalent (CRVE) and AV ratio (CRAE divided by CRVE) were quantitatively estimated using a standardized imaging software (University of Wisconsin). RESULTS: Compared to the fellow eye, severe AV nicking (39.1% versus 2.6%, <0.001), isolated retinopathy (47.8% versus 7.69%, p < 0.001) and a smaller angle at the crossing site (82.6% versus 46.2%, p = 0.005) were more prevalent in eyes with BRVO compared with fellow eyes. Case eyes had a significantly smaller AV ratio at 1-5 years prior to the development of BRVO compared with fellow eyes (0.68 versus 0.73, p = 0.03). CONCLUSIONS: In addition to severe AV nicking, a well-known sign linked to BRVO, this study identified two new potential retinal vascular features--isolated retinopathy and a smaller angle at the crossing site- associated with BRVO development. We also found that a discrepancy in the AV ratio between eyes (i.e. a smaller AV ratio than the fellow eye) can be a quantitative indicator of a higher BRVO risk. These findings warrant further validation in longitudinal studies. PMID- 23654292 TI - Impact factors of nursing journals: what nurses need to know. AB - Impact factors (IFs) are scores based on the frequency with which articles in a journal have been cited in other journals during a 2-year or 5-year period. Impact factors vary across disciplines and even within fields because of differences in citing behaviors, types of publications, and other factors. Nurses need to understand IFs and the implications for them as authors, particularly in light of the small number of nursing journals with IFs. This article describes journal IFs, the current state of IFs for nursing journals, and considerations in selecting a journal for submission of an article. PMID- 23654293 TI - Overcoming barriers in online workshop development: an ELITE experience. AB - The Emerging Learning and Integrated Technologies Education (ELITE) Faculty Development Program created eight online workshops to assist nurse educators in using technology within their organization's nurse education program. Continuing education units were provided for completion of the individual online workshops. The ELITE program worked through several barriers to transform content that was previously presented during face-to-face workshops into standalone online offerings. Barriers and implementation strategies for the on-site to online transition included restructuring workshop objectives, keeping current with rapid technology changes, altering a course management system to meet the needs of the program and the learner, and crafting independent practice opportunities for the online learner. The online workshop development experience of the ELITE program may assist other continuing education and staff development professionals who are updating their program offerings or pursuing online education for the first time. PMID- 23654294 TI - Little shop of errors: an innovative simulation patient safety workshop for community health care professionals. AB - Continuing education for health care workers is an important mechanism for maintaining patient safety and high-quality health care. Interdisciplinary continuing education that incorporates simulation can be an effective teaching strategy for improving patient safety. Health care professionals who attended a recent Patient Safety Academy had the opportunity to experience firsthand a simulated situation that included many potential patient safety errors. This high fidelity activity combined the best practice components of a simulation and a collaborative experience that promoted interdisciplinary communication and learning. Participants were challenged to see, learn, and experience "ah-ha" moments of insight as a basis for error reduction and quality improvement. This innovative interdisciplinary educational training method can be offered in place of traditional lecture or online instruction in any facility, hospital, nursing home, or community care setting. PMID- 23654295 TI - From lecture to learning tasks: use of the 4C/ID model in a communication skills course in a continuing professional education context. AB - This article describes the use of four-component instructional design (4C/ID), a model to plan educational interventions for complex learning. This model was used to design a continuing education course on communication skills for health professionals in a context that is hierarchical and communal. The authors describe the 4C/ID model and provide an example of its application in designing the course. In the 4C/ID model, learning tasks serve as the backbone of the course, with lectures and other supportive information organized around them. The 4C/ID model is different from traditional models that base the course on lectures on different topics and connect part-task assignments to these topics. The use of the 4C/ID model to develop the educational intervention moves the paradigm from lectures to learning tasks to better prepare learners for real practice. PMID- 23654297 TI - Impact of Mn3+ upon structure and magnetism of the perovskite derivative Pb(2 x)Ba(x)FeMnO5 (x ~ 0.7). AB - On the basis of the Mn(3+) for Fe(3+) substitution in Pb(2-x)Ba(x)Fe2O5, a novel oxide Pb1.3Ba0.7MnFeO5 has been synthesized at normal pressure. Though it belongs to the same structural family, the mixed "MnFe" oxide exhibits a very different structural distortion of its framework compared to the pure "Fe2" oxide, due to the Jahn-Teller effect of Mn(3+). Combined neutron diffraction, high resolution electron microscopy/high angle annular dark field-scanning transmission electron microscopy (HAADF-STEM) investigations allow the origin of this difference to be determined. Here we show that the MO6 octahedra of the double perovskite layers in the "MnFe" structure exhibit a strong tetragonal pyramidal distortion "5 + 1", whereas the "Fe2" structure shows a tetrahedral distortion "4 + 2" of the FeO6 octahedra. Similarly, the MO5 polyhedra of the "MnFe" structure tend toward a tetragonal pyramid, whereas the FeO5 polyhedra of the "Fe2" structure are closer to a trigonal bipyramid. Differently from the oxide Pb(2-x)Ba(x)Fe2O5, which is antiferromagnetic, the oxide Pb1.3Ba0.7MnFeO5 exhibits a spin glass behavior with Tg ~ 50 K in agreement with the disordered distribution of the Mn(3+) and Fe(3+) species. PMID- 23654298 TI - Prevalence and genotype distribution of Chlamydia psittaci in feral Canada geese (Branta canadensis) in Belgium. AB - Chlamydia psittaci is a zoonotic pathogen with a wide range of avian hosts and worldwide geographical spread. Zoonotic transfer occurs by inhalation or direct contact and may cause psittacosis or parrot disease. Host reservoirs of particular epidemiological interest include gregarious or migratory species, as colonial behavior facilitates microbial spread amongst conspecifics and a migratory ecology permits disperse over a wide geographic region. The current study detected C. psittaci antibodies in 76 of 81 (93.8%) feral Canada geese (Branta canadensis) using a species-specific enzyme-linked immunosorbent assay. Viable C. psittaci were isolated from pharyngeal swabs of 47 of 81 (58%) birds, and subsequent ompA-based genotyping revealed genotypes E, B, and E/B. Absence of clinical symptoms in these geese could reflect a strong natural protection or a persistent infection. Canada geese are considered an important alien species in Europe. Current results denote that this avian reservoir poses a considerable risk to native wildlife as a potential source of C. psittaci. PMID- 23654299 TI - Mental workload measurement for emergency operating procedures in digital nuclear power plants. AB - Mental workload is a major consideration for the design of emergency operation procedures (EOPs) in nuclear power plants. Continuous and objective measures are desired. This paper compares seven mental workload measurement methods (pupil size, blink rate, blink duration, heart rate variability, parasympathetic/sympathetic ratio, total power and (Goals, Operations, Methods, and Section Rules)-(Keystroke Level Model) GOMS-KLM-based workload index) with regard to sensitivity, validity and intrusiveness. Eighteen participants performed two computerised EOPs of different complexity levels, and mental workload measures were collected during the experiment. The results show that the blink rate is sensitive to both the difference in the overall task complexity and changes in peak complexity within EOPs, that the error rate is sensitive to the level of arousal and correlate to the step error rate and that blink duration increases over the task period in both low and high complexity EOPs. Cardiac measures were able to distinguish tasks with different overall complexity. The intrusiveness of the physiological instruments is acceptable. Finally, the six physiological measures were integrated using group method of data handling to predict perceived overall mental workload. PRACTITIONER SUMMARY: The study compared seven measures for evaluating the mental workload with emergency operation procedure in nuclear power plants. An experiment with simulated procedures was carried out, and the results show that eye response measures are useful for assessing temporal changes of workload whereas cardiac measures are useful for evaluating the overall workload. PMID- 23654296 TI - Mitomycinoid alkaloids: mechanism of action, biosynthesis, total syntheses, and synthetic approaches. PMID- 23654301 TI - Injuries in Khartoum state, the Sudan: a household survey of incidence and risk factors. AB - Low- and middle-income countries have a higher burden of fatal and non-fatal injuries. The lack of evidence-based information hampers efforts for injury prevention. The aim of this study was to calculate non-fatal injury incidence rates and to investigate causes and risk factors for non-fatal injuries in Khartoum state. Information was gathered in a community-based survey using a stratified two-stage cluster sampling technique. Methods of data collection were face-to-face interviews during October and November 2010. The total number of individuals included was 5661, residing in 973 households. The overall injury incidence rate was 82.0/1000 person-years-at-risk. The three leading causes were falls, mechanical forces and road traffic crashes. Low socio-economic status was a risk factor for injuries in urban areas. Males had a significantly higher risk of being injured in both urban and rural areas. Our findings can contribute to the planning of prevention programmes. PMID- 23654302 TI - Common folds and transport mechanisms of secondary active transporters. AB - Secondary active transporters exploit the electrochemical potential of solutes to shuttle specific substrate molecules across biological membranes, usually against their concentration gradient. Transporters of different functional families with little sequence similarity have repeatedly been found to exhibit similar folds, exemplified by the MFS, LeuT, and NhaA folds. Observations of multiple conformational states of the same transporter, represented by the LeuT superfamily members Mhp1, AdiC, vSGLT, and LeuT, led to proposals that structural changes are associated with substrate binding and transport. Despite recent biochemical and structural advances, our understanding of substrate recognition and energy coupling is rather preliminary. This review focuses on the common folds and shared transport mechanisms of secondary active transporters. Available structural information generally supports the alternating access model for substrate transport, with variations and extensions made by emerging structural, biochemical, and computational evidence. PMID- 23654300 TI - Enediolate-dilithium amide mixed aggregates in the enantioselective alkylation of arylacetic acids: structural studies and a stereochemical model. AB - A combination of X-ray crystallography, (6)Li, (15)N, and (13)C NMR spectroscopies, and density functional theory computations affords insight into the structures and reactivities of intervening aggregates underlying highly selective asymmetric alkylations of carboxylic acid dianions (enediolates) mediated by the dilithium salt of a C2-symmetric chiral tetraamine. Crystallography shows a trilithiated n-butyllithium-dilithiated amide that has dimerized to a hexalithiated form. Spectroscopic studies implicate the non dimerized trilithiated mixed aggregate. Reaction of the dilithiated amide with the dilithium enediolate derived from phenylacetic acid affords a tetralithio aggregate comprised of the two dianions in solution and the dimerized octalithio form in the solid state. Computational studies shed light on the details of the solution structures and afford a highly predictive stereochemical model. PMID- 23654305 TI - Evolution in microbes. AB - This review presents a broad survey of experimental microbial evolution, covering diverse topics including trade-offs, epistasis, fluctuating conditions, spatial dynamics, cooperation, aging, and stochastic switching. Emphasis is placed on examples that highlight key conceptual points or address theoretical predictions. Experimental evolution is discussed from two points of view. First, population trajectories are described as adaptive walks on a fitness landscape, whose genetic structure can be probed by experiments. Second, populations are viewed from a physiological perspective, and their nongenetic heterogeneity is examined. Bringing together these two viewpoints remains a major challenge for the future. PMID- 23654303 TI - Entropy-enthalpy compensation: role and ramifications in biomolecular ligand recognition and design. AB - Recent calorimetric studies of interactions between small molecules and biomolecular targets have generated renewed interest in the phenomenon of entropy enthalpy compensation. In these studies, entropic and enthalpic contributions to binding are observed to vary substantially and in an opposing manner as the ligand or protein is modified, whereas the binding free energy varies little. In severe examples, engineered enthalpic gains can lead to completely compensating entropic penalties, frustrating ligand design. Here, we examine the evidence for compensation, as well as its potential origins, prevalence, severity, and ramifications for ligand engineering. We find the evidence for severe compensation to be weak in light of the large magnitude of and correlation between errors in experimental measurements of entropic and enthalpic contributions to binding, though a limited form of compensation may be common. Given the difficulty of predicting or measuring entropic and enthalpic changes to useful precision, or using this information in design, we recommend ligand engineering efforts instead focus on computational and experimental methodologies to directly assess changes in binding free energy. PMID- 23654304 TI - Molecular mechanisms of RNA interference. AB - Small RNA molecules regulate eukaryotic gene expression during development and in response to stresses including viral infection. Specialized ribonucleases and RNA binding proteins govern the production and action of small regulatory RNAs. After initial processing in the nucleus by Drosha, precursor microRNAs (pre-miRNAs) are transported to the cytoplasm, where Dicer cleavage generates mature microRNAs (miRNAs) and short interfering RNAs (siRNAs). These double-stranded products assemble with Argonaute proteins such that one strand is preferentially selected and used to guide sequence-specific silencing of complementary target mRNAs by endonucleolytic cleavage or translational repression. Molecular structures of Dicer and Argonaute proteins, and of RNA-bound complexes, have offered exciting insights into the mechanisms operating at the heart of RNA-silencing pathways. PMID- 23654306 TI - Structural studies of RNase P. AB - Ribonuclease P (RNase P) is one of the first ribozymes discovered and it is found in all phylogenetic groups. It is responsible for processing the 5' end of pre tRNAs as well as other RNA molecules. RNase P is formed by an RNA molecule responsible for catalysis and one or more proteins. Structural studies of the proteins from different organisms, the bacterial RNA component, and a bacterial RNase P holoenzyme/tRNA complex provide insights into the mechanism of this universal ribozyme. Together with the existing wealth of biochemical information, these studies provide atomic-level information on the mechanism of RNase P and continue to expand our understanding of the structure and architecture of large RNA molecules and ribonucleoprotein complexes, the nature of catalysis by ribozymes, the structural basis of recognition of RNA by RNA molecules, and the evolution of enzymes from the prebiotic, RNA-based world to the modern world. PMID- 23654307 TI - Nanoconfinement and the strength of biopolymers. AB - This review examines size effects observed in the mechanical strength of biopolymers that are organized in microstructures such as fibrils, layered composites, or particle nanocomposites. We review the most important aspects that connect nanoconfinement of basic material constituents at critical length scales to the mechanical performance of the entire material system: elastic modulus, strength, extensibility, and robustness. We outline theoretical and computational analysis as well as experimentation by emphasizing two strategies found in abundant natural materials: confined fibrils as part of fibers and confined mineral platelets that transfer load through a biopolymer interface in nanocomposites. We also discuss the application of confinement as a mechanism to tailor specific material properties in biological systems. PMID- 23654308 TI - Bully for you: workplace harassment of obstetrics and gynaecology trainees. PMID- 23654309 TI - HELLP syndrome: understanding and management of a pregnancy-specific disease. AB - HELLP, a syndrome characterised by haemolysis, elevated liver enzymes and low platelets, a variant of pre-eclampsia/eclampsia, is a multisystemic disorder with an incidence of up to 0.9% in all pregnancies and occurs in about one-quarter of pre-eclamptic patients. Most obstetricians presume that HELLP derives from an autoimmune reaction, leading to a materno- fetal imbalance, with accompanying aggregation of platelets, endothelial malfunction along with inborn errors of fatty acid oxidative metabolism. HELLP is characterised by high mortality and morbidity rates, leading to possibly life-threatening complications regarding both the mother and the fetus. Delivery is indicated if HELLP syndrome occurs after 34 gestational weeks or the fetal and/or maternal conditions deteriorate. Vaginal delivery is preferable. Standard corticosteroid treatment is of uncertain clinical value in maternal HELLP syndrome. Future observations and research results may shed more light on improving our understanding of the aspects of HELLP syndrome. PMID- 23654310 TI - Scrotal cooling and its benefits to male fertility: a systematic review. AB - The aim of this study was to systematically review the evidence for the impact of scrotal cooling on spermatogenesis. EMBASE (1980-2010) and MEDLINE (1950-Sept. 2010) databases were searched using the terms 'male infertility or subfertility or fertility', combined with a separate search of 'scrotal cooling', without any limits or restrictions. A total of eight articles met the criteria for inclusion in the study. There was insufficient evidence to draw any firm conclusions about the impact of scrotal cooling on male fertility. A positive trend of improved male fertility was however observed. There is therefore a need for well designed randomised controlled trials. PMID- 23654311 TI - Travelling after amniocentesis: answer to a frequent question. AB - The study investigated whether travelling after amniocentesis has an effect on outcomes of the procedure. A total of 57 patients who were referred to our tertiary centre from distant cities and who had to travel back by bus, by car or by plane, were evaluated for amniocentesis outcomes. The travelled distances were divided into 3 zones, which consisted of 50-100, 101-300 and over 300 km. Patients (n = 85) residing in our city (within 50 km) were identified as the control group. All of the procedures were done by the same perinatology team, following exactly the same procedure. It was found that there was one transient amniotic fluid leakage patient who had travelled 70 km by car after the amniocentesis. No other patients who had to travel after amniocentesis had a complication related to the procedure. It was concluded that although done on a limited number of patients, this study provides the first scientifically supported evidence that travelling by bus, by car or by plane after amniocentesis does not have adverse effects on the outcomes. PMID- 23654312 TI - Perinatal outcomes and risk factors in adolescent and advanced age pregnancies: comparison with normal reproductive age women. AB - The objective of the study was to analyse and compare demographic characteristics and clinical outcomes of pregnancies in adolescent, advanced age and normal reproductive age women. All completed pregnancies in a 6-month period, registered by the family practitioners in Denizli province, were included into the study. A face-to-face questionnaire was used to gather information. Participants were asked for demographic information, pregnancy outcome and obstetric history, obstetric and neonatal problems. Overall 5,882 pregnancies in different age groups: 296 (5%) adolescent (< 20-years-old); 4,957 (84.3%) normal reproductive age (20-35-years-old) and 629 (10.7%) advanced age (> 35-years-old ) (group III), were included into the study. Adolescent women had a lower educational status (p < 0.01), and family played a major role in decision of marriage (p < 0.01). Birth weight of the baby was lower in adolescents (p < 0.01). While adolescents tended to deliver vaginally (OR = 1.9, p < 0.01), elderly women were more prone to operative delivery (OR = 1.2, p < 0.05). Risk of caesarean section rate was higher in elderly nulliparous women (OR = 2.2, p 0.01). The number of spontaneous and induced abortions were increased with age (p < 0.01). Antenatal problems were seen least frequently in normal reproductive age women. Both antenatal (OR = 1.7, p < 0.01) and neonatal problems (OR = 1.5, p < 0.05), were significantly higher in advanced age pregnancy. It was concluded that with sufficient antenatal care, adolescent pregnancy is not associated with an increase in adverse pregnancy outcome, except low birth weights. Advanced maternal age is more likely to be associated with increased obstetric, maternal and neonatal complications. PMID- 23654313 TI - Low pregnancy associated plasma protein-A in the 1st trimester: is it a predictor of poor perinatal outcome? AB - The objective of the study was to examine the predictive value of pregnancy associated plasma protein-A (PAPP-A) as a marker of poor pregnancy outcome. Databases at the University Hospital Lewisham, were used retrospectively to identify singleton pregnancies, which underwent 1st trimester combined screening between July 2008 and April 2010 and were found to have PAPP-A levels <= 0.4 MoM. The perinatal courses of these pregnancies (n = 315) were evaluated for signs of adverse perinatal outcome and compared with a matched control group of pregnancies (n = 330) with normal PAPP-A levels. Results showed that women with low serum PAPP-A were at increased risk of adverse pregnancy outcome compared with the control group (OR 2.4, p = 000.1). They were also more likely to suffer fetal loss (OR 6.2, p = 0.001) in the form of miscarriage (OR 2.7, p = 0.110) and stillbirth (OR 2.4, p = 0.001). It was concluded that serum PAPP-A is a marker for poor pregnancy outcome and women with low serum PAPP-A levels would benefit from increased monitoring of their pregnancies. PMID- 23654314 TI - Vascular endothelial growth factor and endothelin-1 levels in normal pregnant women and pregnant women with pre-eclampsia. AB - The aim of the study was to estimate the levels of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) in maternal serum from normal pregnant women and women with pre-eclampsia. Serum concentrations of VEGF and ET-1 were measured in maternal blood in control group (n = 40) and in pregnancies complicated by pre-eclampsia (n = 40). Results showed that maternal VEGF levels were significantly raised in women with pre-eclampsia (p < 0.001). ET-1 concentration was not significantly different among women with pre-eclampsia compared with that in the control group. It was concluded that an increase in serum VEGF level was demonstrated in pre-eclampsia, suggesting that VEGF is involved in pathogenesis of pre-eclampsia. Further studies are needed to determine the serum concentrations of VEGF in pregnant women before the development of pre-eclampsia. PMID- 23654315 TI - Brain-derived neurotrophic factor and ciliary neurotrophic factor in maternal plasma and umbilical cord blood from pre-eclamptic and physiological pregnancies. AB - The aim of the study was to investigate the circulating levels of ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) in maternal serum and umbilical cord blood from respective pregnancies in pre eclampsia (PE) cases and a control cohort. A total of 12 pre-eclampsia cases and 34 healthy controls were enrolled and the maternal peripheral blood - umbilical cord blood duos, were examined for BDNF and CNTF levels. BNDF levels were significantly higher in umbilical cord blood from pre-eclamptic pregnancies; there was also significant difference between maternal plasma and umbilical cord blood levels of BDNF (p < 0.001) in the controls. The CNTF levels in umbilical cord blood (CNTF-UCB) were significantly higher in PE cases than in the controls (p = 0.03). Significant differences were observed in expression of BDNF and CNTF proteins in maternal peripheral blood and umbilical cord blood between pre eclampsia cases and healthy controls. PMID- 23654316 TI - Low accuracy of manual white blood cell count in amniotic fluid. AB - Intra-amniotic infection (IAI) is a common cause of pre-term labour. Manual WBC count on amniotic fluid (AF) has been suggested as a diagnostic test for IAI using a threshold of 50 cells/mm(3). However, no validation studies assessing the accuracy of this method have been performed. AF samples were selected for cell count analysis. WBCs were introduced to 47 AF samples. The results from two technologists' counts were compared with the calculated expected value for WBCs in these samples. Results showed that a comparison between the technologists' WBC count to the expected WBC count yielded R(2) coefficients of 0.62 and 0.78, indicating moderate accuracy. Percentage agreement between the technologists was 67%, indicating low reproducibility. It was concluded that there was moderate correlation between the manual and the expected WBC in the spiked AF samples. Clinicians should be aware of the inaccuracy and imprecision associated with this test when evaluating a patient for IAI. PMID- 23654317 TI - Obstetric outcome of ethnic Turkish women in London: a retrospective case-control study. AB - There is concern that the maternal mortality in ethnic minority women is significantly greater than that of Caucasian British women. The objective of this study was to compare the demographic and obstetric outcomes between these two groups. Data were collected retrospectively over a 2-year period from 148 index and 148 control cases. The study group had statistically similar maternal age, labour duration, blood loss and mode of delivery compared with Caucasian British women (p > 0.05). A total of 68% of Turkish women spoke little or no English; were more likely to be non-smokers and also more likely to be married to unemployed spouses (p = 0.0001). This is the first study comparing obstetric outcomes of immigrant Turkish women with their Caucasian British counterparts. There was no significant difference in maternal or fetal outcomes, which could be attributed to the 'healthy migrant' theory, coupled with increased vigilance in ethnic minority pregnancies. PMID- 23654318 TI - Fibronectin degradation by MMP-2/MMP-9 in the serum of pregnant women and umbilical cord with Toxoplasma gondii infection. AB - It has been suggested that in congenital Toxoplasma gondii infections, the parasite reaches the fetus by crossing the placental barrier. The purpose of this study was to determine the possible relationships between matrix metalloproteinases (MMPs) and dysfunction of the placental barrier in gravidas infected with T. gondii. We studied 26 umbilical cord sera; 20 and 6 were derived from gravidas seropositive for anti-T. gondii IgG and seropositive for anti-T. gondii IgM (low IgG avidity), respectively. Of 20 cord blood samples, 18 were seropositive for T. gondii IgG, whereas all cord blood samples were seronegative for T. gondii IgM. The other six sera were seronegative for T. gondii IgG, whereas three of six sera were seropositive for T. gondii IgM. Furthermore, T. gondii induced an increase in MMP-2 and -9 secretion in the sera of gravidas and umbilical cords. Moreover, MMP-2 and -9 were interacted with fibronectin. We propose that MMP-2 and -9 may be involved in ECM degradation and placental barrier dysfunction, which facilitates T. gondii transmission to the fetus. Future investigations of the effect of MMPs on migration across epithelial and endothelial barriers will be important to establish the mechanism of transit. PMID- 23654319 TI - Four cases of fetal intra-abdominal umbilical vein varix: a single centre's approach to management. AB - Fetal intra-abdominal umbilical vein (FIUV) varix is a rare prenatal abnormality characterised by a focal intrahepatic or extrahepatic dilatation of the intra abdominal portion of the umbilical vein. Usually, it is an isolated finding, but in some cases it can be associated to other fetal anomalies. Thrombosis is a possible complication of FIUV varix and it can lead to poor fetal or neonatal outcome. We describe four consecutive cases of FIUV varix diagnosed in our Unit and managed with low-dose aspirin (LDA) prophylaxis until the 35th week of gestation. None of the fetuses developed thrombosis of the varix and the neonatal outcomes were good in all the cases. PMID- 23654320 TI - Candida vaginitis in non-pregnant patients: a study of antifungal susceptibility testing and virulence factors. AB - Vulvovaginal candidosis (VVC) is a major problem for the female population worldwide, and considerably little is known about the difference between acute VVC (AVVC) and recurrent VVC (RVVC). We investigated the susceptibility to six antifungal agents and boric acid of Candida spp. isolated from vaginal cultures, as described in the CLSI document M27-A3, from 228 non-pregnant sexually active women (aged 18-49 years), and the virulence factors of these isolates. The isolates were derived from patients with AVVC (n = 64), those with RVVC (n = 125) and those without signs or symptoms (n = 39). In total, C. albicans was the most commonly isolated species (50%), followed by C. glabrata (35.5%) and other Candida spp. (14.5%). We observed slightly different minimum inhibitory concentration (MICs) for various antifungals among the species and study groups that could have potential therapeutic benefits for the treatment. Analysis of the virulence factors revealed that haemolytic activity is not involved in VVC pathogenesis but that germ-tube formation, adhesion to VECs, and proteinase and phospholipase production may be important in the pathogenesis of VVC. PMID- 23654321 TI - The association between serum progesterone and outcome of medical management of early fetal demise: a pilot study. AB - The study objective was to determine the relationship between serum progesterone level and the outcome of mifepristone-misoprostol regimen for medical management of missed miscarriage up to 12 weeks. A blood sample was collected just before mifepristone administration for serum progesterone assay. After 48 h, misoprostol 800 MUg was administered vaginally; further 400 MUg was administered 4 h later if necessary. Treatment was classed as a success if retained tissues were expelled within 72 h (Group 1), and a failure if this did not occur (Group 2). Of 52 analysed cases, complete medical evacuation occurred within 72 h in 40 (76.9%) women (serum progesterone ranged 13-90 nmol/l). Serum progesterone between the two groups were statistically significant (p < 0.001), by Mann-Whitney test. Of the 12 patients who did not respond, nine (75%) women had serum progesterone < 10 nmol/l. We found mifepristone-misoprostol regimen is less effective in missed miscarriage when serum progesterone is < 10 nmol/l. PMID- 23654322 TI - Evaluation of embryo transfer time (day 2 vs day 3) after imposed single embryo transfer legislation: when to transfer? AB - To determine whether the timing of embryo transfer (day 2 or day 3) affects pregnancy outcome in IVF patients, receiving single or double embryo transfer, 380 patients were included in this retrospective study. All patients underwent GnRH antagonist protocol. When stratified by number of transferred embryos, single embryo transfer (SET) patients undergoing a day 2 embryo transfer (ET) had similar biochemical pregnancy (25% vs 20.4%; p > 0.05) and clinical pregnancy (16.6% vs 14.6%; p > 0.05) rates to SET patients that were undergoing a day 3 ET. A similar observation was again noted in double embryo transfer (DET) patients undergoing a day 2 ET, with similar biochemical pregnancy (35% vs 29.8%; p > 0.05) and clinical pregnancy (25% vs 15.5%; p > 0.05) rates to DET patients undergoing a day 3 ET. Women, despite age, number of transferred embryos and ET timing, have similar reproductive outcomes. Shortening or lengthening the duration of in vitro culture provides no obvious benefit. PMID- 23654323 TI - The TRT Female Remeex System (r) for recurrent female stress urinary incontinence: a 5-year follow-up study. AB - Conventional surgery for female stress incontinence is usually successful but recurrent cases are difficult to treat. This study of 20 such cases treated by the Remeex TRT system shows symptomatic benefit up to 5 years following insertion of the device. The benefit of this procedure is that the sling can be adjusted to the correct tension in the optimum leak position and circumstances, and anytime thereafter without the need to repeat the entire operation. As a result, the voiding dysfunction rate and need to intermittent self-catheterise is reduced, even with a low pressure urethra. The cost per procedure and complication rate is higher that standard TVT, and the device may occasionally need removal due to persistent seroma. However, the improved quality of life makes this operation an attractive option in recurrent cases of female stress incontinence. PMID- 23654324 TI - Renal impairment as a complication of uterine fibroids: a retrospective hospital based study. AB - Leiomyomas can cause obstructive renal impairment and renal failure. This was a retrospective study of women with renal impairment seen at the University of the West Indies Hospital, Jamaica, between 2000 and 2004, looking at aetiology and severity (group 1). We also evaluated patients, in the same hospital, with fibroids who had ultrasonography during a later period (2006-2011), comparing those who had hydronephrosis and those without (group 2). In group 1, 274 women were coded as renal impairment. Case notes for 160 patients (59%) were analysed. Uterine fibroids accounted for 13/160 (8.1%) of cases. Comparing cases with and without fibroids, none of those with fibroids were over 50 years old compared with 59.3% of the others, OR 0.02 (CI 0.00-0.35) p = 0.0001. Hospital data for renal failure showed that most mean values were significantly better for those with fibroids. Urea, 8.59 mmol/l (SD 9.89) vs 17.00 mmol/l (SD 13.41) p = 0.003; Creatinine 300.15 MUmol/l (SD490.92) vs 424.05 MUmol/l (SD553.29) p = 0.022 and Creatinine clearance 73.21 ml/min (SD 38.92) vs 44.25 ml/min (SD 49.71) p = 0.017. However, mean potassium values were similar, 4.52 mmol/l (SD 0.61) vs 4.85 mmol/l (SD1.03) p = 0.2. In group 2, there were 216 patients and we found 31 (14.35%) patients at ultrasonography with hydronephrosis from fibroids. These patients had significantly larger uteri than those without hydronephrosis but renal function was similar, with only urea values significantly worse. Leiomyomas can cause renal impairment, however the prognosis appears good. PMID- 23654326 TI - An audit of interval female sterilisation by minilaparotomy at the University College Hospital, Ibadan, Nigeria. AB - Female sterilisation is a widely accepted and practiced family planning method. This study aimed at ascertaining the complications that followed interval minilaparotomy at the University College Hospital, Ibadan, over a 5-year period. Only women who requested sterilisation for family planning purposes were included in the study. There were 135 patients who had interval female sterilisation. Of these, 119 (88.1%) case files were available for analysis. The mean age at sterilisation was 38.2 +/- 3.8 years, mean parity of 7 +/- 2.0 and the mean number of living children at the time of the procedure was 6.5 +/- 1.4. The mean duration of the procedure was 42.35 +/- 13.07 min. The most receptive clientele for interval female sterilisation were 35 years or older and were grand multiparous. Women in the lowest Class (V) were least likely to accept female sterilisation in this study. Complications arising from the procedure were mostly minor, hence it is adjudged safe. There were no failed procedures in this study and only one of the patients had regrets about the procedure. PMID- 23654325 TI - Changes in the ovarian stromal blood flow in patients treated with laparoscopic salpingostomy for ectopic pregnancy. AB - This study is aimed to evaluate the impact of laparoscopic salpingostomy on ovarian stromal blood flow indices in patients with ectopic pregnancy, and to compare the ovarian stromal blood flow indices with matched paired healthy women. We included 37 patients who underwent laparoscopic salpingostomy and 37 age- and parity-matched women as controls. The main outcome was the differences in ovarian volume, antral follicle count (AFC), and ovarian stromal blood flow indices between the study group participants after the surgery and the healthy controls. Comparison of the ovarian parameters between the study group after the surgery and the control group revealed no significant differences in terms of ovarian volume (p = 0.783), AFC (p = 0.253), ovarian stromal S/D ratios (p = 0.054), pulsatility index (PI; p = 0.938) and resistance index (RI; p = 0.041). In addition, comparison of the ovarian parameters before and after the surgical treatment revealed no significant differences in the ovarian volume (p = 0.141), AFC (p = 0.084), ovarian stromal S/D ratios (p = 0.187), PI (p = 0.102) and RI (p = 0.108). In conclusion, laparoscopic salpingostomy does not affect ovarian function in terms of ovarian stromal blood flow indices, ovarian volume, and AFC. PMID- 23654328 TI - A rare case of conception 11 weeks following bariatric surgery without band adjustments and with a favourable outcome. PMID- 23654327 TI - The relationship of maternal age to molar pregnancy incidence, risks for chemotherapy and subsequent pregnancy outcome. AB - The national registration and treatment service for molar pregnancies in the UK allows for the collection of accurate data on this relatively rare diagnosis. In England and Wales, between 2000 and 2009, 5,793 patients with complete moles and 7,790 with partial moles were registered, compared with a total of 8,242,511 conceptions. The overall molar pregnancy incidence was 1 for every 607 conceptions (complete mole 1:1,423; partial mole 1:1,058), but with major variations with age. For complete moles, the risk varied from < 1:1,000 for ages 18-40, to 1:156 for women aged 45 and 1:8 for those aged 50 and above. The overall risk of requiring chemotherapy after a complete mole was 13.6% and 1.1% for partial mole, while the risk of a further molar pregnancy in the next conception was 1:68 but each of these figures have considerable variations with age. These modern statistics on molar pregnancy risks and outcomes should be of value to clinicians and their patients, while discussing this rare diagnosis. PMID- 23654329 TI - Aplastic anaemia and paroxysmal nocturnal haemoglobinuria during pregnancy. PMID- 23654330 TI - Longitudinal trend of quantitative fetal fibronectin in the prediction of delivery following insertion of a rescue cerclage. PMID- 23654331 TI - Cerebral venous sinus thrombosis in a pre-term neonate diagnosed by MR venography. PMID- 23654332 TI - Neonatal pneumococcal sepsis associated with maternal tubo-ovarian abscess. PMID- 23654333 TI - Ultrasound appearance of uterine wall prior to dehiscence. PMID- 23654334 TI - Maternal and fetal complications following treatment for cervical intraepithelial neoplasia. PMID- 23654335 TI - A novel device for prolapse reduction. PMID- 23654336 TI - Schistosomiasis, a neglected disease and 'flukey' finding at laparoscopy. PMID- 23654337 TI - Heterotopic pregnancy after spontaneous conception. PMID- 23654338 TI - Vaginal sarcoidosis. PMID- 23654339 TI - Pathogenesis and origin of extragenital Mullerian carcinosarcoma: evident or still vague? PMID- 23654340 TI - Cancer of cervical stump diagnosed in a woman with chronic myelogenous leukaemia. PMID- 23654341 TI - Trends in the average prescribed dose of methadone: more than a proxy for the evolution of severity of opioid dependence. PMID- 23654342 TI - Re: Letter from J. Trujols, N. Sinol & J. Perez De Los Cobos. PMID- 23654343 TI - Haemoperitoneum in the 3rd trimester of pregnancy: a rare cause. PMID- 23654344 TI - Elucidating the scapulo-humeral rhythm calculation: 3D joint contribution method. AB - The scapulo-humeral rhythm quantifies shoulder joint coordination during arm elevation. The common method calculates a ratio of gleno-humeral (GH) elevation to scapulo-thoracic upward rotation angles. However the other rotations also contribute to arm elevation. The objective is to propose a 3D dynamic scapulo humeral rhythm calculation method including all rotations of the shoulder joints and compare with the common method. Twenty-nine skin markers were placed on the trunk and dominant arm of 14 healthy males to measure shoulder kinematics. Two way repeated measures ANOVAs were applied to compare the two methods of calculation of joint contributions and scapulo-humeral rhythm during arm elevation. Significant main effects (p < 0.05) were observed between methods in joint contribution angles and scapulo-humeral rhythms. A systematic overestimation of the GH contribution was observed when only using the GH elevation angle because the scapula is moved outside a vertical plane. Hence, the proposed 3D method to calculate the scapulo-humeral rhythm allows an improved functional shoulder evaluation. PMID- 23654345 TI - Compound optimization through data set-dependent chemical transformations. AB - We have searched for chemical transformations that improve drug development relevant properties within a given class of active compounds, regardless of the compounds they are applied to. For different compound data sets, varying numbers of frequently occurring data set-dependent transformations were identified that consistently induced favorable changes of selected molecular properties. Sequences of compound pairs representing such transformations were determined that formed pathways leading from unfavorable to favorable regions of property space. Data set-dependent transformations were then applied to predict a series of compounds with increasingly favorable property values. By database searching the desired biological activity was detected for several designed molecules or compounds that were very similar to these molecules. Taken together our findings indicate that data set-dependent transformations can be applied to predict compounds that map to favorable regions of molecular property space and retain their biological activity. PMID- 23654347 TI - Simulating the postprandial stomach: biorelevant test methods for the estimation of intragastric drug dissolution. AB - Intragastric drug release from solid oral dosage forms can be affected by altered physicochemical and mechanical conditions in the upper gastrointestinal (GI) tract. Food effects may lead to changes of one or more pharmacokinetic parameters and, hence, influence drug plasma levels. This can result in severe consequences such as adverse drug reactions or even therapy failure. This review highlights different examples of drug performance under fed conditions. Various reasons such as delayed gastric emptying and pH-dependent solubility of the API as well as intragastric location and movement profiles of solid dosage forms can account for changed drug dissolution. Over the past years, several biorelevant media (e.g., fed state simulated gastric fluid) have been developed with the aim to approach the physiological situation regarding parameters such as pH, buffer capacity, surface tension, and osmolality. It was shown in different in vitro experiments that all of these factors can have an impact on drug dissolution. Besides the application of complex media such as milk or nutritional drinks, the dynamic changes of the gastric content were depicted in recent studies. The capabilities, limitations, and applicability of newly established test setups for the biorelevant simulation of intragastric drug delivery behavior are discussed. Simple test devices (e.g., rotating beaker or dissolution stress test) are mainly used for the biopharmaceutical evaluation of certain problems such as the impact of pressure or shear forces. On the other hand, complex biorelevant test devices (e.g., TNO TIM-1, Dynamic Gastric Model) have recently been introduced aiming at the simulation of multiple parameters characteristic for the postprandial upper GI tract. The different test methods are reviewed with respect to the spectrum of the simulated physiological factors and the degree of complexity. PMID- 23654346 TI - Evaluation of a national evidence-based health care course via teleconference in a developing country. AB - RATIONALE, AIMS AND OBJECTIVES: Continuing health education is essential but challenged. In 2006, the Brazilian Cochrane Center, in collaboration with the Ministry of Health, launched a mass teaching initiative in evidence-based health care (EBH) for public-sector professionals via teleconferencing. This 152-hour, interactive EBH course has enrolled over 4500 professionals. This study aimed to assess the acquisition EBH knowledge and skills, as well as the attitudes and perceptions of a sample of students enrolled in the 2009 course via teleconferencing. METHODS: This prospective cohort study analyzed three aspects of this 152-hour EBH course that recruited 1040 volunteer participants, all public health sector employees working in 131 different hospitals or health agencies. Pre- and post-course tests using a modified version of the Berlin questionnaire with 20 multiple-choice questions were used to examine knowledge acquisition in a sample of 297 students. Tests were completed upon registration and at course completion. The research projects submitted by 872 participants were evaluated to assess skill acquisition. Answers to an anonymous survey assessed the attitudes and perceptions of 914 participants. RESULTS: There was a significant increase in knowledge from baseline to course completion (mean scores 8.2 +/- 3.3 versus 13.7 +/- 3.0, P < 0.001). Over 90% of the research projects were judged to be of adequate quality (appropriate rationale for the study, well formulated research question and feasible execution); over 95% of the participants were satisfied with the course. CONCLUSION: The Brazilian EBH course via teleconference improved the knowledge and skills of public-sector health professionals and was approved by the vast majority of students. PMID- 23654348 TI - Analysis of the latest Austroads guidelines for fitness to drive as promulgated in March 2012. AB - After 9 years, Austroads has published new guidelines for fitness to drive. The guidelines have a preamble, which includes a legal disclaimer denying any culpability for those who designed the guidelines. They also warn of the legal responsibility for health professionals to satisfy their obligations, the need to be current with both relevant medical and legal expectations and if in doubt to seek guidance from Medical Defence Organisations. The guidelines are divided into Parts A and B, with A providing broad overview and background information while B deals with specific entities, such as blackouts, epilepsy or sleep disorders. This paper examines the guidelines and offers an appraisal of their content, their relevance to health practitioners and an assessment of their role in assisting to improve road safety. PMID- 23654349 TI - Anthropometric indicators of obesity are not hypercholesterolaemia predictors in the elderly. PMID- 23654351 TI - Structural analysis of a banana-liquid crystal in the B4 phase by solid-state NMR. AB - In this paper, we present a structural investigation of 1,3-phenylene bis[4-((4 10-decyloxyphenyl)iminomethyl)-benzoate], known as a banana-liquid crystal, in the B4 phase, which was performed by solid-state nuclear magnetic resonance (NMR) methodology combined with quantum chemical calculations. The present solid-state NMR measurements including (13)C CPMAS, 2D TOSS-deTOSS, dipole-dephase, 1D and 2D EXSY, and MAS-j-HMQC provided accurate spectral assignments and unambiguous NMR parameters such as (13)C chemical shift tensors, which were used for construction of the three-dimensional structure with the aid of density functional theory calculations. In the obtained molecular structure, two arms of the bent-core molecule are asymmetrically expanded such that the direction of the dipole moment is off alignment with respect to the middle line of the center benzene ring. It is this antisymmetric structure that is the origin of the twisted helical system in the B4 phase. PMID- 23654350 TI - Discrimination of single base mismatched oligonucleotides related to the rpoB gene of Mycobacterium tuberculosis using a surface plasmon resonance biosensor. AB - Single base mismatched oligonucleotides related to the rpoB gene of Mycobacterium tuberculosis, the mutations of which cause drug resistance of the infectious agent, were detected and discriminated using a surface plasmon resonance biosensor system. Thiol-modified oligonucleotides of the selected sequence (the probe) and 1-mercapto-6-hexanol were immobilized on a gold sensor surface. Hybridization between immobilized probe P2 and perfectly matched target T2 as well as a single base mismatched target TN was investigated in buffer solutions of various stringencies. Discrimination of perfectly matched and single base mismatched targets is achieved due to a difference in the level of their hybridization with the immobilized probe depending on stringency of the buffer solution. In 0.5*SSC buffer solution (7.5 mM sodium citrate, pH 7, containing 75 mM NaCl), sensor response at T2 injection into the measuring sensor cell was 16 times that at TN injection. The experimental results on surface hybridization between the studied oligonucleotides demonstrated a good correlation with theoretical calculations of thermodynamic parameters of these interactions in the solution. The described approach could be proposed as a basis for creating a biosensor for real-time label-free diagnostics of drug-resistant tuberculosis. PMID- 23654352 TI - Clinical significance of minimal residual disease in patients with acute leukaemia undergoing haematopoietic stem cell transplantation. AB - In patients with acute leukaemia, the relative risk of relapse influences the choice between chemotherapy and haematopoietic stem cell transplantation (HSCT). The demonstration that minimal residual disease (MRD) is the strongest overall prognostic indicator and can identify patients who are unlikely to be cured by standard chemotherapy has added a powerful new factor to consider when making this decision. There is substantial data indicating that the likelihood of relapse after transplant is directly correlated with levels of MRD before transplant. This knowledge can be used to adjust the timing of HSCT, and guide the selection of donor, conditioning regimen, and post-HSCT strategies to maximize the graft-versus-leukaemia effect. Because MRD emerging post-transplant carries a dire prognosis, its detection can trigger withdrawal of immunosuppression, additional cellular and molecular therapies, or preparations for a second HSCT. Although it is not yet clear whether any of these actions will significantly improve outcome, it is likely that they will be most effective for patients with a relatively low tumour burden, who can be identified only through MRD testing. In this article, we review the clinical significance of MRD in the context of autologous and allogeneic HSCT. PMID- 23654353 TI - Association of IL-1beta +3954 C/T and IL-10-1082 G/A cytokine gene polymorphisms with susceptibility to tuberculosis. AB - Tuberculosis (TB) constitutes the major cause of death due to infectious diseases. Cytokines play a major role in defence against Mycobacterium tuberculosis infection. Polymorphisms in the genes encoding various cytokines have been associated with tuberculosis susceptibility. Household contacts (HHC) are at increased risk of developing the disease. In this study, we examined the association of IL-1beta and IL-10 cytokine gene polymorphisms with risk of developing tuberculosis in TB patients, their HHC and healthy controls (HC) using JavaStat and SPSS. Multifactor dimensionality reduction (MDR) analyses were performed to explore the potential gene-gene interactions. The genotype and allele frequencies of IL-1beta +3954C/T polymorphism did not vary significantly between TB patients and HC. GG (P < 0.005, OR = 0.219 and 95% CI = 0.059-0.735) and GA (P < 0.0001, OR = 2.938 and 95% CI = 1.526-5.696) genotypes of IL-10-1082 G/A polymorphism were found to be significantly associated with patients versus HC. HHC with CC (P < 0.03, OR = 1.833 and 95% CI = 1.1-3.35) genotype in IL-1beta and GA (P < 0.0001, OR = 4.612 and 95% CI = 2.225-9.702) genotype in IL-10 were at increased risk of developing tuberculosis. MDR tests revealed high-risk genotypes in IL-1beta and IL-10 based on the association model. Our results demonstrate that the polymorphisms of IL-1beta and IL-10 genes may be valuable markers to predict the risk for the development of TB in household contacts. PMID- 23654355 TI - Antiproliferative and cytotoxic properties of moxifloxacin on rat retinal ganglion cells. AB - Abstract Purpose: To evaluate the antiproliferative and cytotoxic properties of moxifloxacin on cultured rat retinal ganglion cells (RGC5). MATERIALS AND METHODS: Rat retinal ganglion cells were exposed to various concentration of moxifloxacin (5-1500 MUg/mL). For antiproliferative properties, the 3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) test was performed. Cellular cytotoxicity was assessed by using the Live/Dead viability/cytotoxicity assay and analyzed by fluorescence microscopy after 24 and 72 h of incubation, respectively. RESULTS: Neither cytotoxic nor antiproliferative effect of moxifloxacin was observed below 50 MUg/mL on RGC5 cells after 24 and 72 h of incubation. At higher concentrations of moxifloxacin (150 MUg/mL, 500 MUg/mL, and 1500 MUg/mL (p < 0.001)) the number of viable cells and the proliferation rate of RGC5 were significantly reduced. CONCLUSIONS: These results suggest a dose-dependent cytotoxic and antiproliferative effect of moxifloxacin on RGC5. Therefore, intracameral application of moxifloxacin should be used cautiously in patients with increased risk of retinal ganglion cells damage, particularly in glaucoma patients. PMID- 23654354 TI - Influence of clinically significant portal hypertension on survival after hepatic resection for hepatocellular carcinoma in cirrhotic patients. AB - BACKGROUND: The role of clinically significant portal hypertension on the prognosis of cirrhotic patients undergoing hepatic resection for hepatocellular carcinoma (HCC) is debated. AIMS: In this study, our aim was to assess the role of clinically significant portal hypertension after hepatic resection for HCC in patients with cirrhosis. METHODS: We assessed the prognostic role of the presence of clinically significant portal hypertension (oesophageal/gastric varices/portal hypertensive gastropathy or a platelet count <100 * 10(9) /L associated with splenomegaly) in 152 patients with compensated cirrhosis who underwent hepatic resection for HCC at the Italian Liver Cancer centres. Survival rates were assessed in the whole series, in the subgroup of Child-Pugh score 5 patients with uninodular HCC <= 5 cm, and in Child-Pugh score 5 patients with uninodular HCC <= 2 cm and normal bilirubin. RESULTS: Median survival was similar in patients with and without clinically significant portal hypertension (79 vs 77 months, P = 0.686). Child-Pugh score 5 was the only variable significantly associated with survival by Cox multiple regression (P = 0.007). In Child-Pugh score 5 patients with single HCC <= 5 cm or in those with single HCC <= 2 cm and normal bilirubin, there was no survival difference between patients with and without clinically significant portal hypertension (median survival: 94 vs 78 months, P = 0.121 and >100 vs 86 months, P = 0.742). CONCLUSIONS: Presence of clinically significant portal hypertension has no influence on survival of patients with well compensated cirrhosis undergoing hepatic resection for HCC. PMID- 23654356 TI - Retinal venular calibre is increased in patients with autoimmune rheumatic disease: a case-control study. AB - AIM: To examine retinal vessel calibre in autoimmune rheumatic disease. MATERIALS AND METHODS: Patients with autoimmune rheumatic disease were recruited from a Rheumatology clinic. Retinal vessel calibre was measured from fundus photographs, and summarised as the central retinal artery and vein equivalents (CRAE and CRVE) using a semi-automated computer-assisted method. RESULTS: The 124 patients studied had rheumatoid arthritis (n = 76, 61%), systemic lupus erythematosus (n = 17, 14%), psoriatic arthritis (n = 11, 9%) or another rheumatological disease (n = 20, 16%). Retinal venular calibre was increased in patients with autoimmune rheumatic disease (+11.6 um, 95% Confidence interval [CI] 3.8 - 19.3, p = 0.01) compared with other hospital patients, after adjusting for baseline differences. This increase was also present in the subgroup with rheumatoid arthritis (p = 0.01). Patients with a rheumatic disease and elevated C-reactive protein (CRP) levels had wider retinal venules than those with a lower CRP (mean CRVE: 247.8 +/ 28.0 versus 216.6 +/- 25.3, p < 0.01), and than other hospital patients with increased CRP (mean CRVE: 247.8 +/- 28.0 versus 216.4 +/- 25.9, p < 0.01). CONCLUSIONS: Individuals with an autoimmune rheumatic disease have wider retinal venules than other hospital patients. This increase in calibre may be due to the underlying inflammatory activity. PMID- 23654357 TI - The influence of posture change on ocular blood flow in normal subjects, measured by laser speckle flowgraphy. AB - PURPOSE: To investigate, using laser speckle flowgraphy (LSFG), the autoregulation of ocular blood flow (BF) in response to posture change. METHODS: This study comprised 20 healthy volunteers (mean age 30.0 +/- 8.5). The mean blur rate (MBR) of the ocular circulation in the subjects was assessed in both a sitting and a supine position every 2 min over the course of 10 min. Baseline measurements of the MBR at the optic nerve head (ONH) and the choroid were taken in a sitting position. Increases in the MBR ratio in a supine position were calculated with reference to this baseline. Intraocular pressure (IOP), systemic blood pressure and heart rate in the brachial artery were also recorded. RESULTS: In the ONH, the MBR ratio increased significantly over the baseline after 2 min (104.8 +/- 5.0%, p = 0.001) and 4 min (104.4 +/- 5.6%, p = 0.005), in a supine position, but decreased to the initial level after only 6 min. In the choroid, on the other hand, while the MBR ratio also increased significantly after 2 min in a supine position (113.7 +/- 8.1%, p < 0.001), it kept this significant increase over the time course of 10 min. After 10 min in a supine position, IOP increased significantly (p < 0.001), systolic blood pressure decreased significantly (p < 0.001), but diastolic blood pressure did not change significantly compared to the baseline. (p = 0.07) CONCLUSIONS: ONH and choroidal circulation have significantly different hemodynamics in response to posture change in healthy volunteers. This finding suggests that LSFG enables us to assess the autoregulation of BF in the ONH. PMID- 23654358 TI - Reliable prediction of complex phenotypes from a modular design in free energy space: an extensive exploration of the lac operon. AB - The basic methodology for designing, altering, and constructing biological systems is increasingly relying on well-established engineering principles to move forward from trial and error approaches to reliably predicting the system behavior from the properties of the components and their interactions. The inherent complexity of even the simplest biological systems, however, often precludes achieving such predictive power. A prototypical example is the lac operon, one of the best-characterized genetic systems, which still poses serious challenges for understanding the results of combining its parts into novel setups. The reason is the pervasive complex hierarchy of events involved in gene regulation that extend from specific protein-DNA interactions to the combinatorial assembly of nucleoprotein complexes. Here, we integrate such complexity into a few-parameter model to accurately predict gene expression from a few simple rules to connect the parts. The model accurately reproduces the observed transcriptional activity of the lac operon over a 10,000-fold range for 21 different operator setups, different repressor concentrations, and tetrameric and dimeric forms of the repressor. Incorporation of the calibrated model into more complex scenarios accurately captures the induction curves for key operator configurations and the temporal evolution of the beta-galactosidase activity of cell populations. PMID- 23654359 TI - Colon cancer: association of histopathological parameters and patients' survival with clinical presentation. AB - Available data correlating symptoms of colon cancer patients with the severity of the disease are very limited. In a population-based setting, we correlated information on symptoms of colon cancer patients with several pathological tumor parameters and survival. Information on all patients diagnosed with colon cancer in Iceland in 1995-2004 for this retrospective, population-based study was obtained from the Icelandic Cancer Registry. Information on symptoms of patients and blood hemoglobin was collected from patients' files. Pathological parameters were obtained from a previously performed standardized tumor review. A total of 768 patients entered this study; the median age was 73 years. Tumors in patients presenting at diagnosis with visible blood in stools were significantly more likely to be of lower grade, having pushing border, conspicuous peritumoral lymphocytic infiltration, and lower frequency of vessel invasion. Patients with abdominal pain and anemia were significantly more likely to have vessel invasion. Logistic regression showed that visible blood in stools was significantly associated with protecting pathological factors (OR range 0.38-0.83, p < 0.05). Tumors in patients presenting with abdominal pain were strongly associated with infiltrative margin and scarce peritumoral lymphocytic infiltration (OR = 1.95; 2.18 respectively, p < 0.05). Changes in bowel habits were strongly associated with vessel invasion (OR = 2.03, p < 0.05). Cox regression showed that blood in stools predicted survival (HR = 0.54). In conclusion, visible blood in stools correlates significantly with all the beneficial pathological parameters analyzed and with better survival of patients. Anemia, general symptoms, changes in bowel habits, acute symptoms, and abdominal pain correlate with more aggressive tumor characteristics and adverse outcome for patients. PMID- 23654360 TI - Characterization of acoustic emissions resulting from particle collision with a stationary bubble. AB - The present work characterizes the acoustic emissions resulting from the collision of a particle driven under gravity with a captive bubble. Conventional methods to investigate the bubble particle collision interaction model measure a descriptive parameter known as the collision time. During such a collision, particle impact may cause a strong deformation and a following oscillation of the bubble-particle interface generates detectable passive acoustic emissions (AE). Experiments and models presented show that the AE frequency monotonically decreases with the particle radius and is independent of the impact velocity, whereas the AE amplitude has a more complicated relationship with impact parameters. PMID- 23654361 TI - Coarse-grid computation of the one-way propagation of coupled modes in a varying cross-section waveguide. AB - A one-way approximation is investigated for the computation of wave propagation in varying cross-section waveguides. The proposed method derives as a basic approximation of the extensively studied multimodal admittance method. When integrated with a Magnus scheme, this matrix one-way equation exhibits an unexpected behavior, as the deviation from the exact solution is minimum when only two discretization points per wavelength are taken. This peculiar property makes this method efficient to compute the wave propagation for a large variety of geometries, beyond the initially stated framework of weakly non-uniform waveguides. PMID- 23654362 TI - Experimental verification of transient nonlinear acoustical holography. AB - This paper presents an experimental study on nonlinear transient acoustical holography. The validity and effectiveness of a recently proposed nonlinear transient acoustical holography algorithm is evaluated in the presence of noise. The acoustic field measured on a post-focal plane of a high-intensity focused transducer is backward projected to reconstruct the pressure distributions on the focal and a pre-focal plane, which are shown to be in good agreement with the measurement. In contrast, the conventional linear holography produces erroneous results in this case where the nonlinearity involved is strong. Forward acoustic field projection was also carried out to further verify the algorithm. PMID- 23654363 TI - Interaction of torsional and longitudinal guided waves in weakly nonlinear circular cylinders. AB - The nonlinear forcing terms for the wave equation in general curvilinear coordinates are derived based on an isotropic homogeneous weakly nonlinear elastic material. The expressions for the nonlinear part of the first Piola Kirchhoff stress are specialized for axisymmetric torsional and longitudinal fundamental waves in a circular cylinder. The matrix characteristics of the nonlinear forcing terms and secondary mode wave structures are manipulated to analyze the higher harmonic generation due to the guided wave mode self interactions and mutual interactions. It is proved that both torsional and longitudinal secondary wave fields can be cumulative by a specific type of guided wave mode interactions. A method for the selection of preferred fundamental excitations that generate strong cumulative higher harmonics is formulated, and described in detail for second harmonic generation. Nonlinear finite element simulations demonstrate second harmonic generation by T(0,3) and L(0,4) modes at the internal resonance points. A linear increase of the normalized modal amplitude ratio A2/A1(2) over the propagation distance is observed for both cases, which indicates that mode L(0,5) is effectively generated as a cumulative second harmonic. Counter numerical examples demonstrate that synchronism and sufficient power flux from the fundamental mode to the secondary mode must occur for the secondary wave field to be strongly cumulative. PMID- 23654364 TI - Acoustic properties of low growing plants. AB - The plane wave normal incidence acoustic absorption coefficient of five types of low growing plants is measured in the presence and absence of soil. These plants are generally used in green living walls and flower beds. Two types of soil are considered in this work: a light-density, man-made soil and a heavy-density natural clay base soil. The absorption coefficient data are obtained in the frequency range of 50-1600 Hz using a standard impedance tube of diameter 100 mm. The equivalent fluid model for sound propagation in rigid frame porous media proposed by Miki [J. Acoust. Soc. Jpn. (E) 11, 25-28 (1990)] is used to predict the experimentally observed behavior of the absorption coefficient spectra of soils, plants, and their combinations. Optimization analysis is employed to deduce the effective flow resistivity and tortuosity of plants which are assumed to behave acoustically as an equivalent fluid in a rigid frame porous medium. It is shown that the leaf area density and dominant angle of leaf orientation are two key morphological characteristics which can be used to predict accurately the effective flow resistivity and tortuosity of plants. PMID- 23654365 TI - Influence of a forest edge on acoustical propagation: experimental results. AB - Acoustic propagation through a forest edge can produce complicated pressure time histories because of scattering from the trees and changes in the microclimate and ground parameters of the two regions. To better understand these effects, a field experiment was conducted to measure low-frequency acoustic pulses propagating in an open field, a forest, and passing through a forest edge in both directions. Waveforms measured in the open field were simple impulses with very low scattering, whereas waveforms at the edge and within the forest had stronger reverberations after the direct arrival. The direct wave pulse shapes increased in duration in accordance with the path length in the forest, which had an effective flow resistivity 12 to 13 that of the grassy open field. The measurements exhibit different rates of attenuation in the two regions, with relatively lower attenuation in the open field than higher rates in the forest. Decay of SEL transmitted into the forest was 4 dB more per tenfold distance than for outbound transmission. Stronger attenuation in the 1-2 kHz range occurs when propagating into the forest. While the measured meteorological profiles revealed three distinct microclimates, meteorological effects are not sufficient to explain the apparent non-reciprocal propagation. PMID- 23654366 TI - The depth-dependence of rain noise in the Philippine Sea. AB - During the Philippine Sea experiment in May 2009, Deep Sound, a free-falling instrument platform, descended to a depth of 5.1 km and then returned to the surface. Two vertically aligned hydrophones monitored the ambient noise continuously throughout the descent and ascent. A heavy rainstorm passed over the area during the deployment, the noise from which was recorded over a frequency band from 5 Hz to 40 kHz. Eight kilometers from the deployment site, a rain gauge on board the R/V Kilo Moana provided estimates of the rainfall rate. The power spectral density of the rain noise shows two peaks around 5 and 30 kHz, elevated by as much as 20 dB above the background level, even at depths as great as 5 km. Periods of high noise intensity in the acoustic data correlate well with the rainfall rates recovered from the rain gauge. The vertical coherence function of the rain noise has well-defined zeros between 1 and 20 kHz, which are characteristic of a localized source on the sea surface. A curve-fitting procedure yields the vertical directional density function of the noise, which is sharply peaked, accurately tracking the storm as it passed over the sensor station. PMID- 23654367 TI - Observations of shallow water marine ambient sound: the low frequency underwater soundscape of the central Oregon coast. AB - A year-long experiment (March 2010 to April 2011) measuring ambient sound at a shallow water site (50 m) on the central OR coast near the Port of Newport provides important baseline information for comparisons with future measurements associated with resource development along the inner continental shelf of the Pacific Northwest. Ambient levels in frequencies affected by surf-generated noise (f < 100 Hz) characterize the site as a high-energy end member within the spectrum of shallow water coastal areas influenced by breaking waves. Dominant sound sources include locally generated ship noise (66% of total hours contain local ship noise), breaking surf, wind induced wave breaking and baleen whale vocalizations. Additionally, an increase in spectral levels for frequencies ranging from 35 to 100 Hz is attributed to noise radiated from distant commercial ship commerce. One-second root mean square (rms) sound pressure level (SPLrms) estimates calculated across the 10-840 Hz frequency band for the entire year long deployment show minimum, mean, and maximum values of 84 dB, 101 dB, and 152 dB re 1 MUPa. PMID- 23654368 TI - Reconstructing surface wave profiles from reflected acoustic pulses. AB - Surface wave shapes are determined by analyzing underwater reflected acoustic signals. The acoustic signals (of nominal frequency 200 kHz) are forward scattered from the underside of surface waves that are generated in a wave tank and scaled to model smooth ocean swell. An inverse processing algorithm is designed and implemented to reconstruct the surface displacement profiles of the waves over one complete period. The inverse processing uses the surface scattered pulses collected at the receiver, an initial wave profile (two are considered), and a broadband forward scattering model based on Kirchhoff's diffraction formula to iteratively adjust the surface until it is considered optimized or reconstructed. Two physical length scales over which information can be known about the surface are confirmed. An outer length scale, the Fresnel zone surrounding each specular reflection point, is the only region where optimized surfaces resulting from each initial profile converge within a resolution set by the inner length scale, a quarter-wavelength of the acoustic pulse. The statistical confidence of each optimized surface is also highest within a Fresnel zone. Future design considerations are suggested such as an array of receivers that increases the region of surface reconstruction by a factor of 2 to 3. PMID- 23654369 TI - Probabilistic two-dimensional water-column and seabed inversion with self adapting parameterizations. AB - This paper develops a probabilistic two-dimensional (2D) inversion for geoacoustic seabed and water-column parameters in a strongly range-dependent environment. Range-dependent environments in shelf and shelf-break regions are of increasing importance to the acoustical-oceanography community, and recent advances in nonlinear inverse theory and sampling methods are applied here for efficient probabilistic range-dependent inversion. The 2D seabed and water column are parameterized using highly efficient, self-adapting irregular grids which intrinsically match the local resolving power of the data and provide parsimonious solutions requiring few parameters to capture complex environments. The self-adapting parameterization is achieved by implementing the irregular grid as a trans-dimensional hierarchical Bayesian model with an unknown number of nodes which is sampled with the Metropolis-Hastings-Green algorithm. To improve sampling, population Monte Carlo is applied with a large number of interacting parallel Markov chains with adaptive proposal distributions. The inversion is applied to simulated data for a vertical-line array and several source locations to several kilometers range. Complex acoustic-pressure fields are computed using a parabolic equation model and results are considered in terms of 2D ensemble parameter estimates and credibility intervals. PMID- 23654370 TI - Ultrasonic guided wave propagation across waveguide transitions: energy transfer and mode conversion. AB - Ultrasonic guided wave inspection of structures containing adhesively bonded joints requires an understanding of the interaction of guided waves with geometric and material discontinuities or transitions in the waveguide. Such interactions result in mode conversion with energy being partitioned among the reflected and transmitted modes. The step transition between an aluminum layer and an aluminum-adhesive-aluminum multi-layer waveguide is analyzed as a model structure. Dispersion analysis enables assessment of (i) synchronism through dispersion curve overlap and (ii) wavestructure correlation. Mode-pairs in the multi-layer waveguide are defined relative to a prescribed mode in a single layer as being synchronized and having nearly perfect wavestructure matching. Only a limited number of mode-pairs exist, and each has a unique frequency range. A hybrid model based on semi-analytical finite elements and the normal mode expansion is implemented to assess mode conversion at a step transition in a waveguide. The model results indicate that synchronism and wavestructure matching is associated with energy transfer through the step transition, and that the energy of an incident wave mode in a single layer is transmitted almost entirely to the associated mode-pair, where one exists. This analysis guides the selection of incident modes that convert into transmitted modes and improve adhesive joint inspection with ultrasonic guided waves. PMID- 23654371 TI - Dynamic surface acoustic response to a thermal expansion source on an anisotropic half space. AB - The surface displacement response to a distributed thermal expansion source is solved using the reciprocity principle. By convolving the strain Green's function with the thermal stress field created by an ultrafast laser illumination, the complete surface displacement on an anisotropic half space induced by laser absorption is calculated in the time domain. This solution applies to the near field surface displacement due to pulse laser absorption. The solution is validated by performing ultrafast laser pump-probe measurements and showing very good agreement between the measured time-dependent probe beam deflection and the computed surface displacement. PMID- 23654372 TI - Dynamical analysis of the nonlinear response of ultrasound contrast agent microbubbles. AB - The nonlinear response of spherical ultrasound contrast agent microbubbles is investigated to understand the effects of common shells on the dynamics. A compressible form of the Rayleigh-Plesset equation is combined with a thin-shell model developed by Lars Hoff to simulate the radial response of contrast agents subject to ultrasound. The responses of Albunex, Sonazoid, and polymer shells are analyzed through the application of techniques from dynamical systems theory such as Poincare sections, phase portraits, and bifurcation diagrams to illustrate the qualitative dynamics and transition to chaos that occurs under certain changes in system parameters. Corresponding calculations of Lyapunov exponents provide quantitative data on the system dynamics. The results indicate that Albunex and polymer shells sufficiently stabilize the response to prevent transition to the chaotic regime throughout typical clinical ranges of ultrasound pressure and frequency. By contrast, Sonazoid shells delay the onset of chaos relative to an unshelled bubble but do not prevent it. A contour plot identifying regions of periodic and chaotic behavior over clinical ranges of ultrasound pressure and frequency is provided for Sonazoid. This work characterizes the nonlinear response of various ultrasound contrast agents, and shows that shell properties have a profound influence on the dynamics. PMID- 23654373 TI - Measurements of the impedance matrix of a thermoacoustic core: applications to the design of thermoacoustic engines. AB - The successful design of a thermoacoustic engine depends on the appropriate description of the processes involved inside the thermoacoustic core (TAC). This is a difficult task when considering the complexity of both the heat transfer phenomena and the geometry of the porous material wherein the thermoacoustic amplification process occurs. An attempt to getting round this difficulty consists in measuring the TAC transfer matrix under various heating conditions, the measured transfer matrices being exploited afterward into analytical models describing the complete apparatus. In this paper, a method based on impedance measurements is put forward, which allows the accurate measurement of the TAC transfer matrix, contrarily to the classical two-load method. Four different materials are tested, each one playing as the porous element allotted inside the TAC, which is submitted to different temperature gradients to promote thermoacoustic amplification. The experimental results are applied to the modeling of basic standing-wave and traveling-wave engines, allowing the prediction of the engine operating frequency and thermoacoustic amplification gain, as well as the optimum choice of the components surrounding the TAC. PMID- 23654374 TI - Electromechanical properties of stripe-electroded tangentially polarized piezoelectric flexural bars. AB - Piezoelectric bar transducers are commonly used for generating low frequency flexural mode vibrations. The paper calculates the electromechanical properties including the effective electromechanical coupling coefficient of the stripe electroded tangentially polarized bar transducer vibrating in flexure under the simply supported boundary condition. A numerical analysis is used to model the curved electric field lines. Calculations take into account the internal energies due to the contributions of the transverse and longitudinal piezoelectric effects and the modal strain distribution in the bar. Results are presented as functions of distance between the electrodes and thickness of elements and are compared with traditional bimorph designs employing either transverse or longitudinal polarization. PMID- 23654375 TI - Modal decomposition of exterior acoustic-structure interaction. AB - A modal decomposition technique to analyze individual modal contributions to the sound power radiated from an externally excited structure submerged in a heavy fluid is presented. The fluid-loaded structural modes are calculated by means of a polynomial approximation and symmetric linearization of the underlying nonlinear eigenvalue problem. The eigenvalues and eigenfunctions of a fluid loaded sphere with and without internal structures are presented. The modal sound power contributions using both fluid-loaded structural modes and acoustic radiation modes are presented. The results for the resistive and reactive sound power obtained from the superposition of the individual modal sound power contributions are compared to the harmonic solution of the forced problem. PMID- 23654376 TI - Uncertainties in predicting structure-borne sound power input into buildings. AB - There has been a steady development of methods of measurement and prediction of structure-borne noise in buildings, particularly over the last two decades. In proposing and evaluating these methods, a major consideration has been the likely trade-off between accuracy and simplicity. Structure-borne sound transmission is a more complicated process than airborne sound transmission, but practitioners seek methods of prediction for the former, which are as straightforward as for the latter. In this paper a description is given of a study of multi-contact sources in buildings. The study concentrates on measurement and calculation procedures for sources and calculation procedures for receiver structures, particularly lightweight building elements. Although the study is not exhaustive, the findings point to the limitations of simplified methods, specifically the uncertainties likely as a result of reducing the data sets and computational effort, and the discrepancies resulting from simplifying assumptions. PMID- 23654377 TI - On the relationship between blast noise complaints and community annoyance. AB - Military installations typically rely on noise complaints to indicate adverse noise environments and often restrict the firing of certain weapons to reduce the number of noise complaints. Using complaints in this manner may also imply that the absence of complaints is an indicator of low community annoyance. The relationship between individual complaints and general community annoyance, however, is currently not established, and it is unknown whether implementing restrictions in reaction to individual complaints is an appropriate or necessary way to reduce community annoyance. This paper looks at whether there are significant differences in reported annoyance to complaint-referenced blast events and general military noise annoyance between those who complain and their non-complaining neighbors. Those who complained were significantly more annoyed to both complaint-referenced blast events and general military noise in comparison to their non-complaining neighbors. The implications of these findings are discussed in terms of range management. PMID- 23654378 TI - Measurement of acoustic characteristics of Japanese Buddhist temples in relation to sound source location and direction. AB - Although temples are important buildings in the Buddhist community, the acoustic quality has not been examined in detail. Buddhist monks change the location and direction according to the ceremony, and associated acoustical changes have not yet been examined scientifically. To discuss the desired acoustics of temples, it is necessary to know the acoustic characteristics appropriate for each phase of a ceremony. In this study, acoustic measurements were taken at various source locations and directions in Japanese temples. A directional loudspeaker was used as the source to provide vocal acoustic fields, and impulse responses were measured and analyzed. The speech transmission index was higher and the interaural cross-correlation coefficient was lower for the sound source directed toward the side wall than that directed toward the altar. This suggests that the change in direction improves speech intelligibility, and the asymmetric property of direct sound and complex reflections from the altar and side wall increases the apparent source width. The large and coupled-like structure of the altar of a Buddhist temple may have reinforced the reverberation components and the table in the altar, which is called the "syumidan," may have decreased binaural coherence. PMID- 23654379 TI - Spatial perception of sound fields recorded by spherical microphone arrays with varying spatial resolution. AB - The area of sound field synthesis has significantly advanced in the past decade, facilitated by the development of high-quality sound-field capturing and re synthesis systems. Spherical microphone arrays are among the most recently developed systems for sound field capturing, enabling processing and analysis of three-dimensional sound fields in the spherical harmonics domain. In spite of these developments, a clear relation between sound fields recorded by spherical microphone arrays and their perception with a re-synthesis system has not yet been established, although some relation to scalar measures of spatial perception was recently presented. This paper presents an experimental study of spatial sound perception with the use of a spherical microphone array for sound recording and headphone-based binaural sound synthesis. Sound field analysis and processing is performed in the spherical harmonics domain with the use of head-related transfer functions and simulated enclosed sound fields. The effect of several factors, such as spherical harmonics order, frequency bandwidth, and spatial sampling, are investigated by applying the repertory grid technique to the results of the experiment, forming a clearer relation between sound-field capture with a spherical microphone array and its perception using binaural synthesis regarding space, frequency, and additional artifacts. The experimental study clearly shows that a source will be perceived more spatially sharp and more externalized when represented by a binaural stimuli reconstructed with a higher spherical harmonics order. This effect is apparent from low spherical harmonics orders. Spatial aliasing, as a result of sound field capturing with a finite number of microphones, introduces unpleasant artifacts which increased with the degree of aliasing error. PMID- 23654380 TI - Impedance measurement of non-locally reactive samples and the influence of the assumption of local reaction. AB - In this paper, the measurement of the absorption coefficient of non-locally reactive sample layers of thickness d1 backed by a rigid wall is investigated. The investigation is carried out with the aid of real and theoretical experiments, which assume a monopole sound source radiating sound above an infinite non-locally reactive layer. A literature search revealed that the number of papers devoted to this matter is rather limited in comparison to those which address the measurement of locally reactive samples. Furthermore, the majority of papers published describe the use of two or more microphones whereas this paper focuses on the measurement with the pressure-particle velocity sensor (PU technique). For these reasons, the assumption that the sample is locally reactive is initially explored, so that the associated measurement errors can be quantified. Measurements in the impedance tube and in a semi-anechoic room are presented to validate the theoretical experiment. For samples with a high non local reaction behavior, for which the measurement errors tend to be high, two different algorithms are proposed in order to minimize the associated errors. PMID- 23654381 TI - Sparse recovery of the multimodal and dispersive characteristics of Lamb waves. AB - Guided waves in plates, known as Lamb waves, are characterized by complex, multimodal, and frequency dispersive wave propagation, which distort signals and make their analysis difficult. Estimating these multimodal and dispersive characteristics from experimental data becomes a difficult, underdetermined inverse problem. To accurately and robustly recover these multimodal and dispersive properties, this paper presents a methodology referred to as sparse wavenumber analysis based on sparse recovery methods. By utilizing a general model for Lamb waves, waves propagating in a plate structure, and robust l1 optimization strategies, sparse wavenumber analysis accurately recovers the Lamb wave's frequency-wavenumber representation with a limited number of surface mounted transducers. This is demonstrated with both simulated and experimental data in the presence of multipath reflections. With accurate frequency-wavenumber representations, sparse wavenumber synthesis is then used to accurately remove multipath interference in each measurement and predict the responses between arbitrary points on a plate. PMID- 23654382 TI - Per-survivor processing for underwater acoustic communications with direct sequence spread spectrum. AB - This paper proposes a receiver for direct-sequence spread spectrum transmissions in underwater acoustic channels, which combines a per-survivor processing (PSP) structure with sparse channel estimation. Specifically, the PSP structure establishes the trellis on the symbol level to render a small to moderate number of states, thus reducing the computational complexity. Meanwhile, the sparse channel estimation is performed on the chip level, where the orthogonal matching pursuit algorithm is used and a two-dimensional grid of path delay and Doppler scaling factor is incorporated in the dictionary construction. The effective combination of the PSP detection and sparse channel estimation achieves a good tradeoff between performance and complexity. Simulation and experiment results show that the proposed receiver outperforms the conventional RAKE receiver considerably, and most importantly, the proposed PSP receiver with an exact wideband dictionary maintains an excellent performance even for challenging underwater acoustic channels with large Doppler disparities on different paths. PMID- 23654383 TI - Near-field effects in Green's function retrieval from cross-correlation of elastic fields: experimental study with application to elastography. AB - In a lossless system, the causal and acausal Green's function for elastic waves can be retrieved by cross-correlating the elastic field at two positions. This field, composed of converging and diverging waves, is interpreted in the frame of a time-reversal process. In this work, the near-field effects on the spatio temporal focusing of elastic waves are analyzed through the elastodynamic Green's function. Contrary to the scalar field case, the spatial focusing is not symmetric preserving the directivity pattern of a simple source. One important feature of the spatial asymmetry is its dependency on the Poisson ratio of the solid. Additionally, it is shown that the retrieval of the bulk wave speed values is affected by diffraction. The correction factor depends on the relative direction between the source and the observed field. Experimental verification of the analysis is carried out on the volume of a soft-solid. A low-frequency diffuse-like field is generated by random impacts at the sample's free surface. The displacement field is imaged using ultrasound by a standard speckle tracking technique. One important application of this work is in the estimation of the shear elastic modulus in soft biological tissues, whose quantification can be useful in non-invasive diagnosis of various diseases. PMID- 23654384 TI - Binaural dereverberation based on interaural coherence histograms. AB - A binaural dereverberation algorithm is presented that utilizes the properties of the interaural coherence (IC) inspired by the concepts introduced in Allen et al. [J. Acoust. Soc. Am. 62, 912-915 (1977)]. The algorithm introduces a non-linear sigmoidal coherence-to-gain mapping that is controlled by an online estimate of the present coherence statistics. The algorithm automatically adapts to a given acoustic environment and provides a stronger dereverberation effect than the original method presented in Allen et al. [J. Acoust. Soc. Am. 62, 912-915 (1977)] in most acoustic conditions. The performance of the proposed algorithm was objectively and subjectively evaluated in terms of its impacts on the amount of reverberation and overall quality. A binaural spectral subtraction method based on Lebart et al. [Acta Acust. Acust. 87, 359-366 (2001)] and a binaural version of the original method of Allen et al. were considered as reference systems. The results revealed that the proposed coherence-based approach is most successful in acoustic scenarios that exhibit a significant spread in the coherence distribution where direct sound and reverberation can be segregated. This dereverberation algorithm is thus particularly useful in large rooms for short source-receiver distances. PMID- 23654385 TI - Exploiting randomness in acoustic impulse responses to achieve headphone compensation through deconvolution. AB - This paper presents a method of headphone/earphone equalization based upon deconvolution of the headphone impulse response from other acoustic filters in the processing chain. The methods presented are thus applicable to areas such as spatial audio, where input signals are processed with binaural impulse responses. The extraction of low order from higher order acoustic impulse responses is justified based upon an application of the theory pertaining to the clustering of the zeros of random coefficient polynomials about the unit circle. An argument is presented supporting the applicability of this theory to acoustic impulse responses. Such an equalization method guarantees a considerable reduction in computational effort over traditional separate compensating filters. A comparison is presented of the implementation of the equalization using the homomorphic method and least squares method with and without regularization to a traditional separate least squares inverse filter. The proposed approach is shown to have a performance comparable to a separate least squares designed compensator, often giving superior performance despite a large reduction in complexity. PMID- 23654386 TI - Spectral-envelope-group-delay models for transients. AB - Transient signals such as plosives in speech or Castanets in audio do not have a specific modulation or periodic structure in time domain. However, in the spectral domain they exhibit a prominent modulation structure, which is a direct consequence of their narrow time localization. Based on this observation, a spectral-domain AM-FM model for transients is proposed. The spectral AM-FM model is built starting from real spectral zero-crossings. The AM and FM correspond to the spectral envelope (SE) and group delay (GD), respectively. Taking into account the modulation structure and spectral continuity, a local polynomial regression technique is proposed to estimate the GD function from the real spectral zeros. The SE is estimated based on the phase function computed from the estimated GD. Since the GD estimation is parametric, the degree of smoothness can be controlled directly. Simulation results based on synthetic transient signals generated using a beta density function are presented to analyze the noise robustness of the SEGD model. Three specific applications are considered: (1) SEGD based modeling of Castanet sounds; (2) appropriateness of the model for transient compression; and (3) determining glottal closure instants in speech using a short-time SEGD model of the linear prediction residue. PMID- 23654387 TI - Latency of tone-burst-evoked auditory brain stem responses and otoacoustic emissions: level, frequency, and rise-time effects. AB - Simultaneous measurement of auditory brain stem response (ABR) and otoacoustic emission (OAE) delays may provide insights into effects of level, frequency, and stimulus rise-time on cochlear delay. Tone-burst-evoked ABRs and OAEs (TBOAEs) were measured simultaneously in normal-hearing human subjects. Stimuli included a wide range of frequencies (0.5-8 kHz), levels (20-90 dB SPL), and tone-burst rise times. ABR latencies have orderly dependence on these three parameters, similar to previously reported data by Gorga et al. [J. Speech Hear. Res. 31, 87-97 (1988)]. Level dependence of ABR and TBOAE latencies was similar across a wide range of stimulus conditions. At mid-frequencies, frequency dependence of ABR and TBOAE latencies were similar. The dependence of ABR latency on both rise time and level was significant; however, the interaction was not significant, suggesting independent effects. Comparison between ABR and TBOAE latencies reveals that the ratio of TBOAE latency to ABR forward latency (the level-dependent component of ABR total latency) is close to one below 1.5 kHz, but greater than two above 1.5 kHz. Despite the fact that the current experiment was designed to test compatibility with models of reverse-wave propagation, existing models do not completely explain the current data. PMID- 23654388 TI - On the balance of envelope and temporal fine structure in the encoding of speech in the early auditory system. AB - There is much debate on how the spectrotemporal modulations of speech (or its spectrogram) are encoded in the responses of the auditory nerve, and whether speech intelligibility is best conveyed via the "envelope" (E) or "temporal fine structure" (TFS) of the neural responses. Wide use of vocoders to resolve this question has commonly assumed that manipulating the amplitude-modulation and frequency-modulation components of the vocoded signal alters the relative importance of E or TFS encoding on the nerve, thus facilitating assessment of their relative importance to intelligibility. Here we argue that this assumption is incorrect, and that the vocoder approach is ineffective in differentially altering the neural E and TFS. In fact, we demonstrate using a simplified model of early auditory processing that both neural E and TFS encode the speech spectrogram with constant and comparable relative effectiveness regardless of the vocoder manipulations. However, we also show that neural TFS cues are less vulnerable than their E counterparts under severe noisy conditions, and hence should play a more prominent role in cochlear stimulation strategies. PMID- 23654389 TI - Estimating critical bandwidths of temporal sensitivity to low-frequency amplitude modulation. AB - Auditory filter bandwidths are measured for a temporal process using an amplitude modulation detection task. The signal is a 200 Hz wide, sinusoidally amplitude modulated band of noise centered within an unmodulated notched-noise masker. A modulation rate of 10 Hz is used to avoid possible information loss at more central processing levels for high modulation rates. Threshold functions are obtained for 10-14 notch widths for each of four different center frequencies (0.6, 1, 2, and 4 kHz) to determine the maximum notch width at which the masker has an effect. The ratio of center frequency to maximum notch width is ~2 at all center frequencies. It is proposed that the bandwidths observed in temporal tasks, which are consistently greater than expected from the viewpoint of critical band theory, be characterized as "temporal critical bands." This proposal does not oppose, but provides a complement to the traditional critical band obtained in tasks involving spectral discrimination. PMID- 23654390 TI - Human interaural time difference thresholds for sine tones: the high-frequency limit. AB - The smallest detectable interaural time difference (ITD) for sine tones was measured for four human listeners to determine the dependence on tone frequency. At low frequencies, 250-700 Hz, threshold ITDs were approximately inversely proportional to tone frequency. At mid-frequencies, 700-1000 Hz, threshold ITDs were smallest. At high frequencies, above 1000 Hz, thresholds increased faster than exponentially with increasing frequency becoming unmeasurably high just above 1400 Hz. A model for ITD detection began with a biophysically based computational model for a medial superior olive (MSO) neuron that produced robust ITD responses up to 1000 Hz, and demonstrated a dramatic reduction in ITD dependence from 1000 to 1500 Hz. Rate-ITD functions from the MSO model became inputs to binaural display models-both place based and rate-difference based. A place-based, centroid model with a rigid internal threshold reproduced almost all features of the human data. A signal-detection version of this model reproduced the high-frequency divergence but badly underestimated low-frequency thresholds. A rate-difference model incorporating fast contralateral inhibition reproduced the major features of the human threshold data except for the divergence. A combined, hybrid model could reproduce all the threshold data. PMID- 23654391 TI - The value of a kurtosis metric in estimating the hazard to hearing of complex industrial noise exposures. AB - A series of Gaussian and non-Gaussian equal energy noise exposures were designed with the objective of establishing the extent to which the kurtosis statistic could be used to grade the severity of noise trauma produced by the exposures. Here, 225 chinchillas distributed in 29 groups, with 6 to 8 animals per group, were exposed at 97 dB SPL. The equal energy exposures were presented either continuously for 5 d or on an interrupted schedule for 19 d. The non-Gaussian noises all differed in the level of the kurtosis statistic or in the temporal structure of the noise, where the latter was defined by different peak, interval, and duration histograms of the impact noise transients embedded in the noise signal. Noise-induced trauma was estimated from auditory evoked potential hearing thresholds and surface preparation histology that quantified sensory cell loss. Results indicated that the equal energy hypothesis is a valid unifying principle for estimating the consequences of an exposure if and only if the equivalent energy exposures had the same kurtosis. Furthermore, for the same level of kurtosis the detailed temporal structure of an exposure does not have a strong effect on trauma. PMID- 23654392 TI - Human sensitivity to differences in the rate of auditory cue change. AB - Measurement of sensitivity to differences in the rate of change of auditory signal parameters is complicated by confounds among duration, extent, and velocity of the changing signal. Dooley and Moore [(1988) J. Acoust. Soc. Am. 84(4), 1332-1337] proposed a method for measuring sensitivity to rate of change using a duration discrimination task. They reported improved duration discrimination when an additional intensity or frequency change cue was present. The current experiments were an attempt to use this method to measure sensitivity to the rate of change in intensity and spatial position. Experiment 1 investigated whether duration discrimination was enhanced when additional cues of rate of intensity change, rate of spatial position change, or both were provided. Experiment 2 determined whether participant listening experience or the testing environment influenced duration discrimination task performance. Experiment 3 assessed whether duration discrimination could be used to measure sensitivity to rates of changes in intensity and spatial position for stimuli with lower rates of change, as well as emphasizing the constancy of the velocity cue. Results of these experiments showed that duration discrimination was impaired rather than enhanced by the additional velocity cues. The findings are discussed in terms of the demands of listening to concurrent changes along multiple auditory dimensions. PMID- 23654393 TI - Sound source localization of filtered noises by listeners with normal hearing: a statistical analysis. AB - Several measures of sound source localization performance of 45 listeners with normal hearing were obtained when loudspeakers were in the front hemifield. Localization performance was not statistically affected by filtering the 200-ms, 2-octave or wider noise bursts (125 to 500, 1500 to 6000, and 125 to 6000 Hz wide noise bursts). This implies that sound source localization performance for noise stimuli is not differentially affected by which interaural cue (interaural time or level difference) a listener with normal hearing uses for sound source localization, at least for relatively broadband signals. This sound source localization task suggests that listeners with normal hearing perform with high reliability/repeatability, little response bias, and with performance measures that are normally distributed with a mean root-mean-square error of 6.2 degrees and a standard deviation of 1.79 degrees . PMID- 23654395 TI - Target identification using relative level in multi-talker listening. AB - Previous studies have suggested that listeners can identify words spoken by a target talker amidst competing talkers if they are distinguished by their spatial location or vocal characteristics. This "direct" identification of individual words is distinct from an "indirect" identification based on an association with other words (call-signs) that uniquely label the target. The present study assessed listeners' ability to use differences in presentation level between a target and overlapping maskers to identify target words. A new sentence was spoken every 800 ms by an unpredictable talker from an unpredictable location. Listeners reported color and number words in a target sentence distinguished by a unique call-sign. When masker levels were fixed, target words could be identified directly based on their relative level. Speech-reception thresholds (SRTs) were low (-12.9 dB) and were raised by 5 dB when direct identification was disrupted by randomizing masker levels. Thus, direct identification is possible using relative level. The underlying psychometric functions were monotonic even when relative level was a reliable cue. In a further experiment, indirect identification was prevented by removing the unique call-sign cue. SRTs did not change provided that other cues were available to identify target words directly. Thus, direct identification is possible without indirect identification. PMID- 23654394 TI - The precedence effect: fusion and lateralization measures for headphone stimuli lateralized by interaural time and level differences. AB - The present investigation assessed fusion and localization dominance aspects of the precedence effect under headphones across a variety of stimulus conditions in 10 normal-hearing listeners. Listeners were presented with "lead-lag" pairs of brief (123 MUs) impulses or trains of such pairs lateralized by interaural time or level differences (ITD or ILD). Listeners used a touch-sensitive display to indicate for the final lead-lag pair presented on each trial (1) whether one or two locations were perceived and (2) the location perceived. In the event two locations were perceived, subjects were further instructed to indicate the left most location perceived. Results demonstrated that lead-lag fusion was more robust for stimuli lateralized by ITD than ILD, particularly when cues of the test stimulus differed from cues of the preceding "buildup" stimulus, consistent with Krumbholz and Nobbe [(2002). J. Acoust. Soc. Am. 112, 654-663]. Unexpectedly, results also demonstrated reduced localization dominance with increasing lead-lag delay, suggesting that the fusion aspect of the precedence effect may be dissociated from the localization dominance aspect under buildup. It is thus argued that buildup of fusion might be understood more generally as an example of auditory object formation rather than a special facility for enhanced sound localization. PMID- 23654396 TI - Effect of spectral change enhancement for the hearing impaired using parameter values selected with a genetic algorithm. AB - Chen et al. [J. Acoust. Soc. Am. 131, 2987-2998 (2012)] evaluated the effectiveness of an algorithm for enhancing spectral changes over time in improving the intelligibility of speech in background sounds for hearing-impaired subjects. The processing improved intelligibility for speech in steady speech spectrum noise (SSN) but tended to impair intelligibility in a background of two talker speech (TTS). Large individual differences were found. The present study assessed whether the effectiveness of the algorithm was improved when the parameters that controlled the degree and type of enhancement were chosen individually for each subject, using a genetic algorithm based on subjective preferences for speech clarity. The parameter values selected by the genetic algorithm varied markedly across subjects. Speech intelligibility was measured for unprocessed stimuli and stimuli processed using the selected parameters, with SSN and TTS maskers and two signal-to-masker ratios (SMRs) for each subject. The intelligibility of speech in the SSN masker at the lower SMR was improved about 14 percentage points by the processing. The overall improvement produced by the processing was significantly larger than the improvement observed in the previous study when the parameter values were fixed across subjects, indicating that use of the genetic algorithm was beneficial. PMID- 23654397 TI - An episodic memory-based solution for the acoustic-to-articulatory inversion problem. AB - This paper presents an acoustic-to-articulatory inversion method based on an episodic memory. An episodic memory is an interesting model for two reasons. First, it does not rely on any assumptions about the mapping function but rather it relies on real synchronized acoustic and articulatory data streams. Second, the memory inherently represents the real articulatory dynamics as observed. It is argued that the computational models of episodic memory, as they are usually designed, cannot provide a satisfying solution for the acoustic-to-articulatory inversion problem due to the insufficient quantity of training data. Therefore, an episodic memory is proposed, called generative episodic memory (G-Mem), which is able to produce articulatory trajectories that do not belong to the set of episodes the memory is based on. The generative episodic memory is evaluated using two electromagnetic articulography corpora: one for English and one for French. Comparisons with a codebook-based method and with a classical episodic memory (which is termed concatenative episodic memory) are presented in order to evaluate the proposed generative episodic memory in terms of both its modeling of articulatory dynamics and its generalization capabilities. The results show the effectiveness of the method where an overall root-mean-square error of 1.65 mm and a correlation of 0.71 are obtained for the G-Mem method. They are comparable to those of methods recently proposed. PMID- 23654398 TI - Durational cues to fricative codas in 2-year-olds' American English: voicing and morphemic factors. AB - In the process of phonological development, fricatives are generally assumed to be later acquired than stops. However, most of the observational work on which this claim is based has concerned itself with word-initial onset consonants; little is known about how and when fricatives are mastered in word-final coda position (e.g., nose). This is all the more critical in a language like English, where word-final fricatives often carry important morphological information (e.g., toes, goes). This study examines the development of duration cues to the voicing feature contrast in coda fricatives, using longitudinal spontaneous speech data from CVC words (e.g., noise vs face) produced by three children (1;6 2;6 years) and six mothers. Results show that the children were remarkably adult like in the use of duration cues to voicing contrasts in fricatives even in this early age range. Furthermore the children, like the mothers, had longer frication noise durations for morphemic compared to non-morphemic fricatives (e.g., toes vs nose) when these segments occurred in utterance-final position. These results suggest that although children's fricatives tend to be overall longer and more voiced compared to those of adults, the voicing and morphological contrasts for fricative codas are acquired early in production. PMID- 23654399 TI - Eyebrow movements and vocal pitch height: evidence consistent with an ethological signal. AB - When asked to sing a high pitch, people produce a facial expression that is judged more friendly compared with singing a low pitch [Huron et al. (2009). Empirical Musicology Rev. 4(3), 93-100]. This effect was observed even when judges viewed only the face above the tip of the nose, and implies a relationship between pitch height and eyebrow height. In the current study, we examine the reverse relationship. Thirty-one participants were asked to read aloud standard texts while holding their eyebrows in a raised, neutral, or lowered position. Average F0 was found to correlate positively with eyebrow position, with higher vocal pitch associated with higher eyebrow placement. However, manipulating eyebrow placement produces a considerably smaller effect (on pitch) compared with the effect of manipulating pitch (on eyebrows). Results are discussed from the perspective of ethological signals [Lorenz (1939). Zool. Anz. 12, 69-102]. PMID- 23654400 TI - Toward a quantitative account of pitch distribution in spontaneous narrative: method and validation. AB - Pitch is well-known both to animate human discourse and to convey meaning in communication. The study of the statistical population distributions of pitch in discourse will undoubtedly benefit from methodological improvements. The current investigation examines a method that parameterizes pitch in discourse as musical pitch interval H measured in units of cents and that disaggregates the sequence of peak word-pitches using tools employed in time-series analysis and digital signal processing. The investigators test the proposed methodology by its application to distributions in pitch interval of the peak word-pitch (collectively called the discourse gamut) that occur in simulated and actual spontaneous emotive narratives obtained from 17 middle-aged African-American adults. The analysis, in rigorous tests, not only faithfully reproduced simulated distributions imbedded in realistic time series that drift and include pitch breaks, but the protocol also reveals that the empirical distributions exhibit a common hidden structure when normalized to a slowly varying mode (called the gamut root) of their respective probability density functions. Quantitative differences between narratives reveal the speakers' relative propensity for the use of pitch levels corresponding to elevated degrees of a discourse gamut (the "e-la") superimposed upon a continuum that conforms systematically to an asymmetric Laplace distribution. PMID- 23654401 TI - The influence of thyroarytenoid and cricothyroid muscle activation on vocal fold stiffness and eigenfrequencies. AB - The influence of the thyroarytenoid (TA) and cricothyroid (CT) muscle activation on vocal fold stiffness and eigenfrequencies was investigated in a muscularly controlled continuum model of the vocal folds. Unlike the general understanding that vocal fold fundamental frequency was determined by vocal fold tension, this study showed that vocal fold eigenfrequencies were primarily determined by vocal fold stiffness. This study further showed that, with reference to the resting state of zero strain, vocal fold stiffness in both body and cover layers increased with either vocal fold elongation or shortening. As a result, whether vocal fold eigenfrequencies increased or decreased with CT/TA activation depended on how the CT/TA interaction influenced vocal fold deformation. For conditions of strong CT activation and thus an elongated vocal fold, increasing TA contraction reduced the degree of vocal fold elongation and thus reduced vocal fold eigenfrequencies. For conditions of no CT activation and thus a resting or slightly shortened vocal fold, increasing TA contraction increased the degree of vocal fold shortening and thus increased vocal fold eigenfrequencies. In the transition region of a slightly elongated vocal fold, increasing TA contraction first decreased and then increased vocal fold eigenfrequencies. PMID- 23654402 TI - On the acoustic effects of the supraglottic structures in excised larynges. AB - The acoustic effects of the supraglottic laryngeal structures (SGSs), including the false vocal folds (FVFs) laryngeal ventricle, and the epiglottis were investigated in an excised canine larynx model with and without these anatomical structures. The purpose of this study was to better understand the acoustic contributions of these structures to phonation. Canine larynges were prepared and mounted over a 3/4 in. tube, which supplied pressurized, heated, and humidified air. Glottal adduction was accomplished by rotating the arytenoids with a suture passed behind the vocal folds to simulate the lateral cricoarytenoid muscle action. The SGSs were kept intact in the first part of the experiment and were removed in the second part. Results indicated that when the FVFs vibrated, a low frequency component was observed in the spectral data. The excised larynx with a SGS had a limited range of frequency with subglottal pressure, while the larynx without a SGS had a larger frequency range. The excised canine larynx with a SGS oscillated with a higher phonation threshold pressure and significantly louder. PMID- 23654403 TI - Language dependent vowel representation in speech production. AB - The representation of speech goals was explored using an auditory feedback paradigm. When talkers produce vowels the formant structure of which is perturbed in real time, they compensate to preserve the intended goal. When vowel formants are shifted up or down in frequency, participants change the formant frequencies in the opposite direction to the feedback perturbation. In this experiment, the specificity of vowel representation was explored by examining the magnitude of vowel compensation when the second formant frequency of a vowel was perturbed for speakers of two different languages (English and French). Even though the target vowel was the same for both language groups, the pattern of compensation differed. French speakers compensated to smaller perturbations and made larger compensations overall. Moreover, French speakers modified the third formant in their vowels to strengthen the compensation even though the third formant was not perturbed. English speakers did not alter their third formant. Changes in the perceptual goodness ratings by the two groups of participants were consistent with the threshold to initiate vowel compensation in production. These results suggest that vowel goals not only specify the quality of the vowel but also the relationship of the vowel to the vowel space of the spoken language. PMID- 23654404 TI - The interpretation of speech reception threshold data in normal-hearing and hearing-impaired listeners: II. Fluctuating noise. AB - Following previous work [Smits and Festen. (2011). J. Acoust. Soc. Am. 130, 2987 2998] involving the interpretation of speech reception threshold (SRT) data in steady-state noise, the present study considers fluctuating noise. Whereas the SIIsteady function [i.e., the speech intelligibility index (SII) against SNR in steady-state noise] can be approximated by a simple linear function going from 0 to 1 between SNR = -15 dB to +15 dB, the SIIfluc function is a function over a broader range than 30 dB and its maximum lies at a SNR higher than +15 dB. The difference in shape between the SIIsteady and SIIfluc functions has several implications. It predicts a reduction in fluctuating masker benefit (FMB), or even a negative FMB, for higher SNRs for normal-hearing listeners. Experimental data confirm this prediction. Much of the reduction in FMB for hearing-impaired listeners may be attributed to the higher SRTs in steady-state noise for these listeners. PMID- 23654405 TI - On-line perception of Mandarin Tones 2 and 3: evidence from eye movements. AB - Using the visual world paradigm, the present study investigated on-line processing of fine-grained pitch information prior to lexical access in a tone language; specifically how lexical tone perception of Mandarin Tones 2 and 3 was influenced by the pitch height of the tone at onset, turning point, and offset. Native speakers of Mandarin listened to manipulated tone tokens and selected the corresponding word from four visually presented words (objects in Experiment 1 and characters in Experiment 2) while their eye movements were monitored. The results showed that 87% of ultimate tone judgments were made according to offset pitch height. Tokens with high offset pitch were identified as Tone 2, and low offset pitch as Tone 3. A low turning point pitch served as a pivotal cue for Tone 3, and prompted more eye fixations on Tone 3 items, until the offset pitch directed significantly more fixations to the final tone choice. The findings support the view that lexical tone perception is an incremental process, in which pitch height at critical points serves as an important cue. PMID- 23654407 TI - The role of pitch and timing cues in the perception of phrasal grouping in Seoul Korean. AB - This paper reports two experiments in which listeners detected prosodic group boundaries in Seoul Korean speech, investigating how pitch and timing cues collaborate or compete with each other. Two types of timing cues, compensatory lengthening and group-final lengthening, were employed. The results show that both pitch and timing have demarcative functions which are exploited by listeners. However, listeners relied more on timing than pitch and this may be because in the experiments the pitch contour variations were limited to a small number of phonological categories, whereas temporal variations were more gradient. In addition, group-final lengthening was a more robust cue to the prosodic boundary than compensatory lengthening, and the integration of pitch and timing cues seems to be context-dependent. The results highlight the significance of local information in the universal grouping process and that the precise nature of the cues affect the way they integrate in perception. PMID- 23654406 TI - Effects of hearing loss on the subcortical representation of speech cues. AB - Individuals with sensorineural hearing loss often report frustration with speech being loud but not clear, especially in background noise. Despite advanced digital technology, hearing aid users may resort to removing their hearing aids in noisy environments due to the perception of excessive loudness. In an animal model, sensorineural hearing loss results in greater auditory nerve coding of the stimulus envelope, leading to a relative deficit of stimulus fine structure. Based on the hypothesis that brainstem encoding of the temporal envelope is greater in humans with sensorineural hearing loss, speech-evoked brainstem responses were recorded in normal hearing and hearing impaired age-matched groups of older adults. In the hearing impaired group, there was a disruption in the balance of envelope-to-fine structure representation compared to that of the normal hearing group. This imbalance may underlie the difficulty experienced by individuals with sensorineural hearing loss when trying to understand speech in background noise. This finding advances the understanding of the effects of sensorineural hearing loss on central auditory processing of speech in humans. Moreover, this finding has clinical potential for developing new amplification or implantation technologies, and in developing new training regimens to address this relative deficit of fine structure representation. PMID- 23654408 TI - Effect of glottal dynamics in the production of shouted speech. AB - In this paper characteristics of speech produced at different loudness levels are analyzed in terms of changes in the glottal excitation. Four loudness levels are considered in this study, namely, soft, normal, loud, and shout. The distinct changes in the excitation of the shout signal are analyzed using electroglottograph signals. The open and closed phases of the glottal vibration are distinctly different for shout signals, in comparison with those for normal speech. It is generally difficult to derive the glottal pulse information from the speech signal due to limitations in inverse filtering. Hence, the effects of changes in the excitation are examined by analyzing the speech signal using methods that can capture the temporal variations of the spectral features. In particular, the recently proposed methods of zero-frequency filtering and zero time liftering are used in this analysis. It is shown that the closed phase behavior of the excitation at different loudness levels can be seen in the temporal variation of spectral energy in the low frequency (LF) (<400 Hz) region. The ratio of the LF to high frequency energy clearly discriminates the speech produced at different loudness levels. These distinctions in the excitation features are also observed in different vowel contexts and across several speakers. PMID- 23654409 TI - Metrics for vector quantization-based parametric speech enhancement and separation. AB - Speech enhancement and separation algorithms sometimes employ a two-stage processing scheme, wherein the signal is first mapped to an intermediate low dimensional parametric description after which the parameters are mapped to vectors in codebooks trained on, for example, individual noise-free sources using a vector quantizer. To obtain accurate parameters, one must employ a good estimator in finding the parameters of the intermediate representation, like a maximum likelihood estimator. This leaves some unanswered questions, however, like what metrics to use in the subsequent vector quantization process and how to systematically derive them. This paper aims at answering these questions. Metrics for this are presented and derived, and their use is exemplified on a number of different signal models by deriving closed-form expressions. The metrics essentially take into account in the vector quantization process that some parameters may have been estimated more accurately than others and that there may be dependencies between the estimation errors. PMID- 23654410 TI - Synthesis of laughter by modifying excitation characteristics. AB - In this paper, a method to synthesize laughter by modifying the excitation source information is presented. The excitation source information is derived by extracting epoch locations and instantaneous fundamental frequency using zero frequency filtering approach. The zero frequency filtering approach is modified to capture the rapidly varying instantaneous fundamental frequency in natural laugh signals. The nature of variation of excitation features in natural laughter is examined to determine the features to be incorporated in the synthesis of a laugh signal. Features such as pitch period and strength of excitation are modified in the utterance of vowel /a/ or /i/ to generate the laughter signal. Frication is also incorporated wherever appropriate. Laugh signal is generated by varying parameters at both call level and bout level. Experiments are conducted to determine the significance of different features in the perception of laughter. Subjective evaluation is performed to determine the level of acceptance and quality of synthesis of the synthesized laughter signal for different choices of parameter values and for different input types. PMID- 23654412 TI - Nonlinear effects contributing to hand-stopping tones in a horn. AB - Hand stopping is a technique for playing the French horn while closing the bell relatively tightly using the right hand. The resulting timbre is called "penetrating" and "metallic." The effect of hand stopping on the horn input impedance has been studied, but the tone quality has hardly ever been considered. In the present paper, the dominant physical cause of the stopped-tone quality is discussed in detail. Numerical calculations of the transmission function of the stopped-horn model and the measurements of both sound pressure and wall vibration in hand stopping are carried out. They strongly suggest that the metallicness of the stopped tone is characterized by the generation of higher harmonics extending over 10 kHz due to the rapidly corrugating waveform and that the associated wall vibration on the bell may be responsible for this higher harmonic generation. However, excitation experiments and immobilization experiments performed to elucidate the relationship between sound radiation and wall vibration deny their correlation. Instead, the measurement result of the mouthpiece pressure in hand stopping suggests that minute wave corrugations peculiar to the metallic stopped tones are probably formed by nonlinear sound propagation along the bore. PMID- 23654411 TI - The role of binary mask patterns in automatic speech recognition in background noise. AB - Processing noisy signals using the ideal binary mask improves automatic speech recognition (ASR) performance. This paper presents the first study that investigates the role of binary mask patterns in ASR under various noises, signal to-noise ratios (SNRs), and vocabulary sizes. Binary masks are computed either by comparing the SNR within a time-frequency unit of a mixture signal with a local criterion (LC), or by comparing the local target energy with the long-term average spectral energy of speech. ASR results show that (1) akin to human speech recognition, binary masking significantly improves ASR performance even when the SNR is as low as -60 dB; (2) the ASR performance profiles are qualitatively similar to those obtained in human intelligibility experiments; (3) the difference between the LC and mixture SNR is more correlated to the recognition accuracy than LC; (4) LC at which the performance peaks is lower than 0 dB, which is the threshold that maximizes the SNR gain of processed signals. This broad agreement with human performance is rather surprising. The results also indicate that maximizing the SNR gain is probably not an appropriate goal for improving either human or machine recognition of noisy speech. PMID- 23654413 TI - A parametric model and estimation techniques for the inharmonicity and tuning of the piano. AB - Inharmonicity of piano tones is an essential property of their timbre that strongly influences the tuning, leading to the so-called octave stretching. It is proposed in this paper to jointly model the inharmonicity and tuning of pianos on the whole compass. While using a small number of parameters, these models are able to reflect both the specificities of instrument design and tuner's practice. An estimation algorithm is derived that can run either on a set of isolated note recordings, but also on chord recordings, assuming that the played notes are known. It is applied to extract parameters highlighting some tuner's choices on different piano types and to propose tuning curves for out-of-tune pianos or piano synthesizers. PMID- 23654414 TI - Nighttime foraging by deep diving echolocating odontocetes off the Hawaiian islands of Kauai and Ni'ihau as determined by passive acoustic monitors. AB - Remote autonomous ecological acoustic recorders (EARs) were deployed in deep waters at five locations around the island of Kauai and one in waters off Ni'ihau in the main Hawaiian island chain. The EARs were moored to the bottom at depths between 400 and 800 m. The data acquisition sampling rate was 80 kHz and acoustic signals were recorded for 30 s every 5 min to conserve battery power and disk space. The acoustic data were analyzed with the M3R (Marine Mammal Monitoring on Navy Ranges) software, an energy-ratio-mapping algorithm developed at Oregon State University and custom MATLAB programs. A variety of deep diving odontocetes, including pilot whales, Risso's dolphins, sperm whales, spinner and pan-tropical spotted dolphins, and beaked whales were detected at all sites. Foraging activity typically began to increase after dusk, peaked in the middle of the night and began to decrease toward dawn. Between 70% and 84% of biosonar clicks were detected at night. At present it is not clear why some of the known deep diving species, such as sperm whales and beaked whales, concentrate their foraging efforts at night. PMID- 23654415 TI - Variation in the production rate of biosonar signals in freshwater porpoises. AB - The biosonar (click train) production rate of ten Yangtze finless porpoises and their behavior were examined using animal-borne data loggers. The sound production rate varied from 0 to 290 click trains per 10-min time interval. Large individual differences were observed, regardless of body size. Taken together, however, sound production did not differ significantly between daytime and nighttime. Over the 172.5 h of analyzed recordings, an average of 99.0% of the click trains were produced within intervals of less than 60 s, indicating that during a 1-min interval, the number of click trains produced by each porpoise was typically greater than one. Most of the porpoises exhibited differences in average swimming speed and depth between day and night. Swimming speed reductions and usage of short-range sonar, which relates to prey-capture attempts, were observed more often during nighttime. However, biosonar appears to be affected not only by porpoise foraging, but also by their sensory environment, i.e., the turbid Yangtze River system. These features will be useful for passive acoustic detection of the porpoises. Calculations of porpoise density or abundance should be conducted carefully because large individual differences in the sound production rate will lead to large estimation error. PMID- 23654416 TI - The function of male sperm whale slow clicks in a high latitude habitat: communication, echolocation, or prey debilitation? AB - Sperm whales produce different click types for echolocation and communication. Usual clicks and buzzes appear to be used primarily in foraging while codas are thought to function in social communication. The function of slow clicks is less clear, but they appear to be produced by males at higher latitudes, where they primarily forage solitarily, and on the breeding grounds, where they roam between groups of females. Here the behavioral context in which these vocalizations are produced and the function they may serve was investigated. Ninety-nine hours of acoustic and diving data were analyzed from sound recording tags on six male sperm whales in Northern Norway. The 755 slow clicks detected were produced by tagged animals at the surface (52%), ascending from a dive (37%), and during the bottom phase (11%), but never during the descent. Slow clicks were not associated with the production of buzzes, other echolocation clicks, or fast maneuvering that would indicate foraging. Some slow clicks were emitted in seemingly repetitive temporal patterns supporting the hypothesis that the function for slow clicks on the feeding grounds is long range communication between males, possibly relaying information about individual identity or behavioral states. PMID- 23654418 TI - Mechanical clot damage from cavitation during sonothrombolysis. AB - Recent studies have shown that high intensity focused ultrasound (HIFU) accelerates thrombolysis for ischemic stroke. Although the mechanisms are not fully understood, cavitation is thought to play an important role. The goal of this paper is to investigate the potential for cavitation to cause mechanical damage to a blood clot. The amount of damage to the fiber network caused by a single bubble expansion and collapse is estimated by two independent approaches: One based on the stretch of individual fibers and the other based on the energy available to break individual fibers. The two methods yield consistent results. The energy method is extended to the more important scenario of a bubble outside a blood clot that collapses asymmetrically creating an impinging jet. This leads to significantly more damage compared to a bubble embedded within the clot structure. Finally, as an example of how one can apply the theory, a simulation of the propagation of HIFU waves through model calvaria of varying density is explored. The maximum amount of energy available to cause damage to a blood clot increases as the density of the calvaria decreases. PMID- 23654417 TI - The response of phospholipid-encapsulated microbubbles to chirp-coded excitation: implications for high-frequency nonlinear imaging. AB - The current excitation strategy for harmonic and subharmonic imaging (HI and SHI) uses short sine-bursts. However, alternate pulsing strategies may be useful for enhancing nonlinear emissions from ultrasound contrast agents. The goal of this study was to corroborate the hypothesis that chirp-coded excitation can improve the performance of high-frequency HI and SHI. A secondary goal was to understand the mechanisms that govern the response of ultrasound contrast agents to chirp coded and sine-burst excitation schemes. Numerical simulations and acoustic measurements were conducted to evaluate the response of a commercial contrast agent (Targestar-P((r))) to chirp-coded and sine-burst excitation (10 MHz frequency, peak pressures 290 kPa). The results of the acoustic measurements revealed an improvement in signal-to-noise ratio by 4 to 14 dB, and a two- to threefold reduction in the subharmonic threshold with chirp-coded excitation. Simulations conducted with the Marmottant model suggest that an increase in expansion-dominated radial excursion of microbubbles was the mechanism responsible for the stronger nonlinear response. Additionally, chirp-coded excitation detected the nonlinear response for a wider range of agent concentrations than sine-bursts. Therefore, chirp-coded excitation could be a viable approach for enhancing the performance of HI and SHI. PMID- 23654419 TI - Single-shot measurements of the acoustic field of an electrohydraulic lithotripter using a hydrophone array. AB - Piezopolymer-based hydrophone arrays consisting of 20 elements were fabricated and tested for use in measuring the acoustic field from a shock-wave lithotripter. The arrays were fabricated from piezopolymer films and were mounted in a housing to allow submersion into water. The motivation was to use the array to determine how the shot-to-shot variability of the spark discharge in an electrohydraulic lithotripter affects the resulting focused acoustic field. It was found that the dominant effect of shot-to-shot variability was to laterally shift the location of the focus by up to 5 mm from the nominal acoustic axis of the lithotripter. The effect was more pronounced when the spark discharge was initiated with higher voltages. The lateral beamwidth of individual, instantaneous shock waves were observed to range from 1.5 mm to 24 mm. Due to the spatial variation of the acoustic field, the average of instantaneous beamwidths were observed to be 1 to 2 mm narrower than beamwidths determined from traditional single-point measurements that average the pressure measured at each location before computing beamwidth. PMID- 23654420 TI - Experimental methods for the characterization of the frequency-dependent viscoelastic properties of soft materials. AB - A characterization method based on Rayleigh wave propagation was developed for the quantification of the frequency-dependent viscoelastic properties of soft materials at high frequencies; i.e., up to 4 kHz. Planar harmonic surface waves were produced on the surface of silicone rubber samples. The phase and amplitude of the propagating waves were measured at different locations along the propagation direction, which allowed the calculation of the complex Rayleigh wavenumbers at each excitation frequency using a transfer function method. An inverse wave propagation problem was then solved to obtain the complex shear/elastic moduli from the measured wavenumbers. In a separate, related investigation, dynamic indentation tests using atomic force microscopy (AFM) were performed at frequencies up to 300 Hz. No systematic verification study is available for the AFM-based method, which can be used when the dimensions of the test samples are too small for other existing testing methods. The results obtained from the Rayleigh wave propagation and AFM-based indentation methods were compared with those from a well-established method, which involves the generation of standing longitudinal compression waves in rod-shaped test specimens. The results were cross validated and qualitatively confirmed theoretical expectations presented in the literature for the frequency-dependence of polymers. PMID- 23656091 TI - Towards online maximum-likelihood-based speech clustering and separation. AB - This paper introduces an approach for online speech source clustering and separation, which is based on the utilization of the multichannel location information in a recursive expectation maximization (EM) algorithm. Specifically, the normalized multichannel speech-recording vector is employed as a feature vector and is modeled using Watson mixture model. The model parameters are determined by maximizing the data likelihood at every time-frequency slot in an online processing manner. Consequently, the proposed approach can continuously adjust the speech clusters. Promising results showing the advantage of the proposed approach over the batch EM algorithm in the case of two speakers with speaker movement are obtained. PMID- 23656092 TI - Evidence for a spatial bias in the perception of sequences of brief tones. AB - Listeners are unable to report the physical order of particular sequences of brief tones. This phenomenon of temporal dislocation depends on tone durations and frequencies. The current study empirically shows that it also depends on the spatial location of the tones. Dichotically testing a three-tone sequence showed that the central tone tends to be reported as the first or the last element when it is perceived as part of a left-to-right motion. Since the central-tone dislocation does not occur for right-to-left sequences of the same tones, this indicates that there is a spatial bias in the perception of sequences. PMID- 23656093 TI - Optimization of the array mirror for time reversal techniques used in a half space environment. AB - Time reversal (TR) utilizes an array of transducers, a time reversal mirror (TRM), to locate sources. Here TR is applied to simple sources using steady-state waveforms in a numerical, point source model in a half-space environment. It is found that TR can effectively localize a simple source broadcasting a continuous wave, depending on the angular spacing. Furthermore, the angular spacing and the aperture of the TRM are the most important parameters when creating a setup of receivers for imaging a source. This work optimizes a TRM when the source's location is known within a region of certainty. PMID- 23656094 TI - Experimental evaluation of inverse filtering using physical systems with known glottal flow and tract characteristics. AB - The technique presented here uses an impedance head to measure the input impedance spectrum of a physical model of a vocal tract, and then to inject a known glottal flow waveform into the tract. The sound measured outside the mouth is used to evaluate inverse filtering techniques by comparison with the known glottal flow and measured acoustical properties of the tract. The normalized least square errors in the glottal flow were typically a percent or less in the time domain and several percent in the frequency domain. Accurate determination of resonance frequencies and bandwidths required a suitable order of inverse filter. PMID- 23656095 TI - The vowel inherent spectral change of English vowels spoken by native and non native speakers. AB - The current study examined Vowel Inherent Spectral Change (VISC) of English vowels spoken by English-, Chinese-, and Korean-native speakers. Two metrics, spectral distance (amount of spectral shift) and spectral angle (direction of spectral shift) of formant movement from the onset to the offset, were measured for 12 English monophthongs produced in a /hvd/ context. While Chinese speakers showed significantly greater spectral distances of vowels than English and Korean speakers, there was no significant speakers' native language effect on spectral angles. Comparisons to their native vowels for Chinese and Korean speakers suggest that VISC might be affected by language-specific phonological structure. PMID- 23656096 TI - The effect of diffuse reflections on spatial discrimination in a simulated concert hall. AB - This letter presents results from a study on diffusive architectural surfaces and auditory perception. Spatial discrimination of multiple sources is investigated in a simulated performance venue with various diffusive surface treatments. Simulations were generated with closely spaced sound sources on the stage of a concert hall and a listener in the audience area. Subjects were asked to distinguish signals in which pairs of simultaneous talkers were presented at various lateral separations, in halls with flat or diffusive surfaces. The experiments reveal that discriminating differences in the lateral arrangement of sources is possible at narrower separation angles when reflections come from flat rather than diffusive surfaces. PMID- 23656097 TI - Infants' name recognition in on- and off-channel noise. AB - Previous work by Polka, Rvachew, and Molnar [Infancy 13(5), 421-439 (2008)] has reported that infants are poor at focusing their attention on a particular frequency range, and, as a result, are distracted by maskers that are outside of the target frequency range. The current study explores this effect of irrelevant distractors further and finds that 8-month-old infants are significantly less affected by maskers outside the frequency range (off-channel maskers) than by on channel maskers. Thus while infants may display difficulty ignoring irrelevant distractors, they are able to do so to at least some degree, suggesting some ability to perceive speech from spectrally remote maskers, despite the demonstrated presence of greater informational masking at this age. PMID- 23656098 TI - Preboundary lengthening and preaccentual shortening across syllables in a trisyllabic word in English. AB - This study demonstrates some new aspects of preboundary lengthening and preaccentual shortening on a test word banana in American English. Preboundary lengthening was found to be extended to the initial unstressed syllable beyond the main-stressed syllable, presenting more complexity than has previously been assumed. Preaccentual shortening was observed regardless of boundary strength or the stress pattern (trochaic vs iambic) of the following context word, suggesting that it operates globally at an utterance level. The locus of preaccentual shortening, however, was modulated by prosodic boundary: It is realized on the final vowel IP-finally but on the non-final stressed vowel IP-medially. PMID- 23656099 TI - English vowel identification in long-term speech-shaped noise and multi-talker babble for English and Chinese listeners. AB - The identification of 12 English vowels was measured in quiet and in long-term speech-shaped noise (LTSSN) and multi-talker babble for English-native (EN) listeners and Chinese-native listeners in the U.S. (CNU) and China (CNC). The signal-to-noise ratio was manipulated from -15 to 0 dB. As expected, EN listeners performed significantly better in quiet and noisy conditions than CNU and CNC listeners. Vowel identification in LTSSN was similar between CNU and CNC listeners; however, performance in babble was significantly better for CNU listeners than for CNC listeners, indicating that exposing non-native listeners to native English may reduce informational masking of multi-talker babble. PMID- 23656100 TI - Distributional training of speech sounds can be done with continuous distributions. AB - In previous research on distributional training of non-native speech sounds, distributions were always discontinuous: typically, each of only eight different stimuli was repeated multiple times. The current study examines distributional training with continuous distributions, in which all presented tokens are acoustically different. Adult Spanish learners of Dutch were trained on either a discontinuous or a continuous bimodal distribution of the Dutch vowel contrast /a/-/a?/. Both groups improved their perception of the contrast; this shows that continuous training works equally well as discontinuous training. Using the more natural continuous distributions is therefore recommended for future distributional learning experiments. PMID- 23656101 TI - Modifying the normalized covariance metric measure to account for nonlinear distortions introduced by noise-reduction algorithms. AB - In this study, two methods are proposed to modify the normalized covariance metric (NCM) measure to reduce the effects of gain-induced nonlinear distortions introduced by most noise-suppression algorithms. Considering that the gain induced distortions behave differently dependent on the signal-to-noise ratio between the noise-reduced speech and the noise, the first approach introduces a penalty factor involving this ratio in the modified NCM measure. The second approach deemphasizes segments marked with amplification distortions that contribute less to intelligibility via adaptive thresholding. Significantly higher correlations with intelligibility scores were obtained from the modified NCM measures compared with the original NCM measures. PMID- 23656102 TI - On a reference-free speech quality estimator for hearing aids. AB - A reference-free speech quality measure is proposed and assessed for hearing aid applications. The proposed speech quality metric is validated with subjective ratings obtained from hearing impaired listeners under a number of noisy and reverberant conditions. In addition, a comparison is drawn between the proposed measure and a state-of-the-art electroacoustic measure that relies on a clean reference signal. The results showed that the reference-free measure had a lower correlation with the subjective ratings of hearing aid speech quality in comparison to the correlations achieved by the measure utilizing a reference signal. Nevertheless, advantages of the reference-free approach are discussed. PMID- 23656103 TI - Wide-area assessment of topographical and meteorological effects on sound propagation by time-domain modeling. AB - Noise mapping with a three-dimensional finite-difference time-domain (FDTD) model over larger areas suffers from its high computational demand. This study shows that an FDTD model in combination with a meteorological model can be used for at least qualitative assessments of topographical and meteorological effects on sound propagation in domains of even some kilometers extension. This is achieved by restricting the acoustical simulations to low frequencies which allow the use of a rather large numerical grid spacing. PMID- 23656104 TI - Vibroacoustic response sensitivity due to relative alignment of two anisotropic poro-elastic layers. AB - The effects of relative alignment of two different types of anisotropic open cell porous materials are investigated in terms of the acoustic response of a multi layered configuration. Numerical experiments, where gradient based optimization techniques were used, are conducted to find possible extremal values. It is shown that, depending on the degree of anisotropy of the porous material properties, their angular orientations have a significant and frequency dependent influence on the measured response. The results highlight the importance of further advancing the knowledge of anisotropic porous material behavior. PMID- 23656105 TI - Adding thermal and granularity effects to the effective density fluid model. AB - Previously, an effective density fluid model (EDFM) was developed by the author [J. Acoust. Soc. Am. 110, 2276-2281 (2001)] for unconsolidated granular sediments and applied to sand. The model is a simplification of the full Biot porous media model. Here two additional effects are added to the EDFM model: heat transfer between the liquid and solid at low frequencies and the granularity of the medium at high frequencies. The frequency range studied is 100 Hz-1 MHz. The analytical sound speed and attenuation expressions obtained have no free parameters. The resulting model is compared to ocean data. PMID- 23656107 TI - Communication: Certifying the potential energy landscape. AB - It is highly desirable for numerical approximations to stationary points for a potential energy landscape to lie in the corresponding quadratic convergence basin. However, it is possible that an approximation may lie only in the linear convergence basin, or even in a chaotic region, and hence not converge to the actual stationary point when further optimization is attempted. Proving that a numerical approximation will quadratically converge to the associated stationary point is termed certification. Here, we apply Smale's alpha-theory to stationary points, providing a certification serving as a mathematical proof that the numerical approximation does indeed correspond to an actual stationary point, independent of the precision employed. As a practical example, employing recently developed certification algorithms, we show how the alpha-theory can be used to certify all the known minima and transition states of Lennard-Jones LJ(N) atomic clusters for N = 7, ..., 14. PMID- 23656106 TI - Perspective: Stochastic algorithms for chemical kinetics. AB - We outline our perspective on stochastic chemical kinetics, paying particular attention to numerical simulation algorithms. We first focus on dilute, well mixed systems, whose description using ordinary differential equations has served as the basis for traditional chemical kinetics for the past 150 years. For such systems, we review the physical and mathematical rationale for a discrete stochastic approach, and for the approximations that need to be made in order to regain the traditional continuous-deterministic description. We next take note of some of the more promising strategies for dealing stochastically with stiff systems, rare events, and sensitivity analysis. Finally, we review some recent efforts to adapt and extend the discrete-stochastic approach to systems that are not well-mixed. In that currently developing area, we focus mainly on the strategy of subdividing the system into well-mixed subvolumes, and then simulating diffusional transfers of reactant molecules between adjacent subvolumes together with chemical reactions inside the subvolumes. PMID- 23656108 TI - A general moment expansion method for stochastic kinetic models. AB - Moment approximation methods are gaining increasing attention for their use in the approximation of the stochastic kinetics of chemical reaction systems. In this paper we derive a general moment expansion method for any type of propensities and which allows expansion up to any number of moments. For some chemical reaction systems, more than two moments are necessary to describe the dynamic properties of the system, which the linear noise approximation is unable to provide. Moreover, also for systems for which the mean does not have a strong dependence on higher order moments, moment approximation methods give information about higher order moments of the underlying probability distribution. We demonstrate the method using a dimerisation reaction, Michaelis-Menten kinetics and a model of an oscillating p53 system. We show that for the dimerisation reaction and Michaelis-Menten enzyme kinetics system higher order moments have limited influence on the estimation of the mean, while for the p53 system, the solution for the mean can require several moments to converge to the average obtained from many stochastic simulations. We also find that agreement between lower order moments does not guarantee that higher moments will agree. Compared to stochastic simulations, our approach is numerically highly efficient at capturing the behaviour of stochastic systems in terms of the average and higher moments, and we provide expressions for the computational cost for different system sizes and orders of approximation. We show how the moment expansion method can be employed to efficiently quantify parameter sensitivity. Finally we investigate the effects of using too few moments on parameter estimation, and provide guidance on how to estimate if the distribution can be accurately approximated using only a few moments. PMID- 23656109 TI - Robust and efficient configurational molecular sampling via Langevin dynamics. AB - A wide variety of numerical methods are evaluated and compared for solving the stochastic differential equations encountered in molecular dynamics. The methods are based on the application of deterministic impulses, drifts, and Brownian motions in some combination. The Baker-Campbell-Hausdorff expansion is used to study sampling accuracy following recent work by the authors, which allows determination of the stepsize-dependent bias in configurational averaging. For harmonic oscillators, configurational averaging is exact for certain schemes, which may result in improved performance in the modelling of biomolecules where bond stretches play a prominent role. For general systems, an optimal method can be identified that has very low bias compared to alternatives. In simulations of the alanine dipeptide reported here (both solvated and unsolvated), higher accuracy is obtained without loss of computational efficiency, while allowing large timestep, and with no impairment of the conformational exploration rate (the effective diffusion rate observed in simulation). The optimal scheme is a uniformly better performing algorithm for molecular sampling, with overall efficiency improvements of 25% or more in practical timestep size achievable in vacuum, and with reductions in the error of configurational averages of a factor of ten or more attainable in solvated simulations at large timestep. PMID- 23656110 TI - Excitation energy transfer efficiency: equivalence of transient and stationary setting and the absence of non-Markovian effects. AB - We analyze efficiency of excitation energy transfer in photosynthetic complexes in transient and stationary setting. In the transient setting, the absorption process is modeled as an individual event resulting in a subsequent relaxation dynamics. In the stationary setting the absorption is a continuous stationary process, leading to the nonequilibrium steady state. We show that, as far as the efficiency is concerned, both settings can be considered to be the same, as they result in almost identical efficiency. We also show that non-Markovianity has no effect on the resulting efficiency, i.e., corresponding Markovian dynamics results in identical efficiency. Even more, if one maps dynamics to appropriate classical rate equations, the same efficiency as in quantum case is obtained. PMID- 23656111 TI - A linear- and sublinear-scaling method for calculating NMR shieldings in atomic orbital-based second-order Moller-Plesset perturbation theory. AB - An atomic-orbital (AO) based formulation for calculating nuclear magnetic resonance chemical shieldings at the second-order Moller-Plesset perturbation theory level is introduced, which provides a basis for reducing the scaling of the computational effort with the molecular size from the fifth power to linear and for a specific nucleus to sublinear. The latter sublinear scaling in the rate determining steps becomes possible by avoiding global perturbations with respect to the magnetic field and by solving for quantities that involve the local nuclear magnetic spin perturbation instead. For avoiding the calculation of the second-order perturbed density matrix, we extend our AO-based reformulation of the Z-vector method within a density matrix-based scheme. Our pilot implementation illustrates the fast convergence with respect to the required number of Laplace points and the asymptotic scaling behavior in the rate determining steps. PMID- 23656112 TI - A nonempirical scaling correction approach for density functional methods involving substantial amount of Hartree-Fock exchange. AB - A nonempirical scaling correction (SC) approach has been developed for improving bandgap prediction in density functional theory [X. Zheng, A. J. Cohen, P. Mori Sanchez, X. Hu, and W. Yang, Phys. Rev. Lett. 107, 026403 (2011)]. For finite systems such as atoms and molecules, the SC approach restores the Perdew-Parr Levy-Balduz condition [Phys. Rev. Lett. 49, 1691 (1982)] that the total electronic energy should scale linearly with number of electrons between integers. Although the original SC approach is applicable to a variety of mainstream density functional approximations, it gives zero correction to the Hartree-Fock method. This is because the relaxation of orbitals with the change in electron number is completely neglected. In this work, with an iterative scheme for the evaluation of Fukui function, the orbital relaxation effects are accounted for explicitly via a perturbative treatment. In doing so, the SC approach is extended to density functionals involving substantial amount of Hartree-Fock exchange. Our new SC approach is demonstrated to improve systematically the predicted Kohn-Sham frontier orbital energies, and alleviate significantly the mismatch between fundamental and derivative gaps. PMID- 23656113 TI - Hierarchical Nystrom methods for constructing Markov state models for conformational dynamics. AB - Markov state models (MSMs) have become a popular approach for investigating the conformational dynamics of proteins and other biomolecules. MSMs are typically built from numerous molecular dynamics simulations by dividing the sampled configurations into a large number of microstates based on geometric criteria. The resulting microstate model can then be coarse-grained into a more understandable macrostate model by lumping together rapidly mixing microstates into larger, metastable aggregates. However, finite sampling often results in the creation of many poorly sampled microstates. During coarse-graining, these states are mistakenly identified as being kinetically important because transitions to/from them appear to be slow. In this paper, we propose a formalism based on an algebraic principle for matrix approximation, i.e., the Nystrom method, to deal with such poorly sampled microstates. Our scheme builds a hierarchy of microstates from high to low populations and progressively applies spectral clustering on sets of microstates within each level of the hierarchy. It helps spectral clustering identify metastable aggregates with highly populated microstates rather than being distracted by lowly populated states. We demonstrate the ability of this algorithm to discover the major metastable states on two model systems, the alanine dipeptide and trpzip2 peptide. PMID- 23656114 TI - A comparison model between density functional and wave function theories by means of the Lowdin partitioning technique. AB - A comparison model is proposed based on the Lowdin partitioning technique to analyze the differences in the treatment of electron correlation by the wave function and density functional models. This comparison model provides a tool to understand the inherent structure of both theories and its discrepancies in terms of the subjacent mathematical structure and the necessary conditions for variationality required for the energy functional. Some numerical results on simple molecules are also reported revealing the known phenomenon of "overcorrelation" of density functional theory methods. PMID- 23656115 TI - Computational IR spectroscopy of water: OH stretch frequencies, transition dipoles, and intermolecular vibrational coupling constants. AB - The Hessian matrix reconstruction method initially developed to extract the basis mode frequencies, vibrational coupling constants, and transition dipoles of the delocalized amide I, II, and III vibrations of polypeptides and proteins from quantum chemistry calculation results is used to obtain those properties of delocalized O-H stretch modes in liquid water. Considering the water symmetric and asymmetric O-H stretch modes as basis modes, we here develop theoretical models relating vibrational frequencies, transition dipoles, and coupling constants of basis modes to local water configuration and solvent electric potential. Molecular dynamics simulation was performed to generate an ensemble of water configurations that was in turn used to construct vibrational Hamiltonian matrices. Obtaining the eigenvalues and eigenvectors of the matrices and using the time-averaging approximation method, which was developed by the Skinner group, to calculating the vibrational spectra of coupled oscillator systems, we could numerically simulate the O-H stretch IR spectrum of liquid water. The asymmetric line shape and weak shoulder bands were quantitatively reproduced by the present computational procedure based on vibrational exciton model, where the polarization effects on basis mode transition dipoles and inter-mode coupling constants were found to be crucial in quantitatively simulating the vibrational spectra of hydrogen-bond networking liquid water. PMID- 23656116 TI - Three new branched chain equations of state based on Wertheim's perturbation theory. AB - In this work, we present three new branched chain equations of state (EOS) based on Wertheim's perturbation theory. The first represents a slightly approximate general branched chain solution of Wertheim's second order perturbation theory (TPT2) for athermal hard chains, and the second represents the extension of first order perturbation theory with a dimer reference fluid (TPT1-D) to branched athermal hard chain molecules. Each athermal branched chain EOS was shown to give improved results over their linear counterparts when compared to simulation data for branched chain molecules with the branched TPT1-D EOS being the most accurate. Further, it is shown that the branched TPT1-D EOS can be extended to a Lennard-Jones dimer reference system to obtain an equation of state for branched Lennard-Jones chains. The theory is shown to accurately predict the change in phase diagram and vapor pressure which results from branching as compared to experimental data for n-octane and corresponding branched isomers. PMID- 23656118 TI - Quantum transport with two interacting conduction channels. AB - The transport properties of a conduction junction model characterized by two mutually coupled channels that strongly differ in their couplings to the leads are investigated. Models of this type describe molecular redox junctions (where a level that is weakly coupled to the leads controls the molecular charge, while a strongly coupled one dominates the molecular conduction), and electron counting devices in which the current in a point contact is sensitive to the charging state of a nearby quantum dot. Here we consider the case where transport in the strongly coupled channel has to be described quantum mechanically (covering the full range between sequential tunneling and co-tunneling), while conduction through the weakly coupled channel is a sequential process that could by itself be described by a simple master equation. We compare the result of a full quantum calculation based on the pseudoparticle non-equilibrium Green function method to that obtained from an approximate mixed quantum-classical calculation, where correlations between the channels are taken into account through either the averaged rates or the averaged energy. We find, for the steady state current, that the approximation based on the averaged rates works well in most of the voltage regime, with marked deviations from the full quantum results only at the threshold for charging the weekly coupled level. These deviations are important for accurate description of the negative differential conduction behavior that often characterizes redox molecular junctions in the neighborhood of this threshold. PMID- 23656117 TI - A simplified representation of anisotropic charge distributions within proteins. AB - Effective coarse-grained representations of protein-protein interaction potentials are vital in the modeling of large scale systems. We develop a method to fit an arbitrary number of effective charges to approximate the electrostatic potential of a protein at a given pH in an ionic solution. We find that the effective charges can reproduce an input potential calculated from a high resolution Poisson-Boltzmann calculation. Since the effective charges used in this model are not constrained to the locations of the original charged groups, the extra degrees of freedom allows us to reproduce the field anisotropy with fewer charges. The fitting procedure uses a number of approximations in the charge magnitudes, initial conditions, and multipoles to speed convergence. The most significant gains are found by fitting the multipole moments of the effective charge potential to the moments of the original field. We show that the Yukawa potential is not only sufficient as a pairwise summation in reproducing the potential, but comes naturally from the linearized expansion of the Poisson Boltzmann equation. We compute interaction energies and find excellent agreement to the original potential. From the effective charge model we compute the electrostatic contribution to the second virial coefficient. PMID- 23656119 TI - Monte Carlo simulation strategies to compute interfacial and bulk properties of binary fluid mixtures. AB - We introduce Monte Carlo simulation methods for determining interfacial properties of binary fluid mixtures. The interface potential approach, in which the interfacial properties of a system are related to the surface excess free energy of a thin fluid film in contact with a surface, is utilized to deduce the wetting characteristics of a fluid mixture. The strategy described here provides an effective means to obtain the evolution of interfacial properties with the chemical composition of the fluid. This task is accomplished by implementing an activity fraction expanded ensemble technique, which allows one to obtain elements of the interface potential as a function of composition. We also show how this technique can be utilized to calculate bulk coexistence properties of fluid mixtures in an efficient manner. The computational strategies introduced here are applied to three model systems. One includes an argon-methane fluid mixture that is known to display simple behavior in the bulk. The second fluid model contains a size asymmetric mixture that exhibits azeotropy. The third model fluid is the well-studied size symmetric mixture that displays liquid-liquid vapor phase coexistence. The techniques outlined here are used to compile the composition dependence of spreading and drying coefficients, liquid-vapor surface tension, and contact angle for these systems. We also compare our surface tension results with values estimated from predictive-style models that provide the surface tension of a fluid mixture in terms of pure component properties. Overall, we find that the general approach pursued here provides an efficient and precise means to calculate the bulk and wetting properties of fluid mixtures. PMID- 23656120 TI - Relativistic energy-consistent pseudopotentials for superheavy elements 119 and 120 including quantum electrodynamic effects. AB - Relativistic energy-consistent pseudopotentials for the superheavy elements with nuclear charges 119 and 120 replacing 92 electrons of a [Xe]4f(14)5d(10)5f(14) core were adjusted to relativistic multi-configuration Dirac-Coulomb-Breit finite nucleus all-electron reference data including lowest-order quantum electrodynamic effects, i.e., vacuum polarization and electron self-energy. The parameters were fitted by two-component multi-configuration Hartree-Fock calculations in the intermediate coupling scheme to the total valence energies of 131 to 140 relativistic states arising from 31 to 33 nonrelativistic configurations covering also anionic and highly ionized states, with mean absolute errors for the nonrelativistic configurations below 0.01 eV. Primitive basis sets for one- and two-component calculations with errors below 0.02 and 0.03 eV to the Hartree-Fock limit, respectively, as well as general contractions of these basis sets with double- to quadruple-zeta quality were obtained. Atomic highly correlated test calculations using the Fock-space coupled-cluster method yield for valence excitation energies and ionization potentials mean absolute errors of 26 cm(-1) and 59 cm(-1), respectively. Correlated and uncorrelated molecular test calculations show deficiencies below 0.005 A for the bond lengths and 3 N m(-1) for the force constants. PMID- 23656121 TI - Mean field QM/MM method: average position approximation. AB - The average position mean field combined quantum mechanical (QM) and molecular mechanical (MM) method, denoted as QM/, is described. This method can drastically reduce the QM/ molecular dynamics simulation time to a level similar to pure MM methods, enabling the sampling of millions of configurations. A rigorous analysis shows that there is a general and significant error (up to 7 kcal/mol) in mean field QM/ methods arising from the loss of instantaneous polarization of the QM electronic wavefunction. To reach high level of accuracy and efficiency, polarizable force field should be used to represent the QM region in mean field QM/ methods. PMID- 23656122 TI - Towards the blackbox computation of magnetic exchange coupling parameters in polynuclear transition-metal complexes: theory, implementation, and application. AB - We present a method for calculating magnetic coupling parameters from a single spin-configuration via analytic derivatives of the electronic energy with respect to the local spin direction. This method does not introduce new approximations beyond those found in the Heisenberg-Dirac Hamiltonian and a standard Kohn-Sham Density Functional Theory calculation, and in the limit of an ideal Heisenberg system it reproduces the coupling as determined from spin-projected energy differences. Our method employs a generalized perturbative approach to constrained density functional theory, where exact expressions for the energy to second order in the constraints are obtained by analytic derivatives from coupled perturbed theory. When the relative angle between magnetization vectors of metal atoms enters as a constraint, this allows us to calculate all the magnetic exchange couplings of a system from derivatives with respect to local spin directions from the high-spin configuration. Because of the favorable computational scaling of our method with respect to the number of spin-centers, as compared to the broken-symmetry energy-differences approach, this opens the possibility for the blackbox exploration of magnetic properties in large polynuclear transition-metal complexes. In this work we outline the motivation, theory, and implementation of this method, and present results for several model systems and transition-metal complexes with a variety of density functional approximations and Hartree-Fock. PMID- 23656123 TI - Delocalized Davydov D1 Ansatz for the Holstein polaron. AB - An efficient, yet very accurate trial wave function, constructed from projecting the well-known Davydov D1 Ansatz onto momentum eigenstates, is employed to study the ground state properties of the generalized Holstein Hamiltonian with simultaneous diagonal and off-diagonal coupling. Ground-state energies have been obtained with a precision matching that of the computationally much more demanding density-matrix renormalization group method. The delocalized D1 Ansatz lowers the ground-state energies at the Brillouin zone boundary significantly compared with the Toyozawa and Global-Local Ansatze in the weak coupling regime, while considerable improvement is demonstrated to have been achieved over the entire Brillouin zone in the strong coupling regime. Unique solutions are obtained with the delocalized D1 for different initial conditions when the transfer integral is 20 times the phonon frequency at the zone center, implying the absence of any self-trapping discontinuity. The scaled correlation variance is found to fit satisfactorily well with the predictions of the perturbation theories. PMID- 23656124 TI - Quantum critical point of spin-boson model and infrared catastrophe in bosonic bath. AB - An analytic ground state is proposed for the unbiased spin-boson Hamiltonian, which is non-Gaussian and beyond the Silbey-Harris ground state with lower ground state energy. The infrared catastrophe in Ohmic and sub-Ohmic bosonic bath plays an important role in determining the degeneracy of the ground state. We show that the infrared divergence associated with the displacement of the nonadiabatic modes in bath may be removed from the proposed ground state for the coupling alpha < alphac. Then alphac is the quantum critical point of a transition from non-degenerate to degenerate ground state and our calculated alphac agrees with previous numerical results. PMID- 23656125 TI - Vibrations of porphycene in the S0 and S1 electronic states: single vibronic level dispersed fluorescence study in a supersonic jet. AB - Supersonic jet-isolated porphycene has been studied using the techniques of laser induced fluorescence excitation, single vibronic level fluorescence, and spectral hole burning, combined with quantum mechanical calculations of geometry and vibrational structure of the ground and lowest electronically excited singlet states. Porphycene is a model for coherent double hydrogen tunneling in a symmetrical double well potential, as evidenced by tunneling splittings observed in electronic absorption and emission. The results led to reliable assignment of low frequency modes in S0 and S1 electronic states. The values of tunneling splitting were determined for ground state vibrational levels. In the case of tautomerization-promoting 2A(g) mode, tunneling splitting values significantly increase with the vibrational quantum number. Mode coupling was demonstrated by different values of tunneling splitting obtained for coexcitation of two or more vibrations. Finally, alternation of relative intensity patterns for the components of 2A(g) tunneling doublet observed for excitation and emission into different vibrational levels suggests that the energy order of levels corresponding to (+) and (-) combinations of nuclear wave functions is different for even and odd vibrational quantum numbers. PMID- 23656126 TI - Measuring dipolar and J coupling between quadrupolar nuclei using double-rotation NMR. AB - Among the interactions which govern NMR spectra, spin-spin coupling interactions provide the most direct form of structural information which is of interest to chemists. Dipolar coupling may be used to measure internuclear distances directly and J coupling may be used to identify bonding interactions and provide insights into the nature of the bonds. It is well known that the presence of a quadrupolar interaction reintroduces the dipolar interaction in spinning samples; however, similarly to the J coupling, this information is often lost if the observed nucleus is quadrupolar due to quadrupolar spectral broadening. Here we show for multiple spin pairs that double-rotation (DOR) NMR fully removes the effects of the quadrupolar interaction on the NMR spectrum leaving only the effects of dipolar and J couplings. We also demonstrate that the J coupling multiplets do not disappear for quadrupolar A2 spin pairs as they do for spin-1/2 nuclei. With DOR NMR, it is then straightforward to measure homonuclear J coupling constants between magnetically equivalent quadrupolar nuclei. A deeper understanding of the origins of the magnitudes and dominant mechanisms of J coupling for quadrupolar spin pairs in a series of related compounds is obtained by decomposing computed J coupling constants into their major molecular orbital contributions. PMID- 23656127 TI - Sideband separation experiments in NMR with phase incremented echo train acquisition. AB - A general approach for enhancing sensitivity of nuclear magnetic resonance sideband separation experiments, such as Two-Dimensional One Pulse (TOP), Magic Angle Turning (MAT), and Phase Adjust Spinning Sidebands (PASS) experiments, with phase incremented echo-train acquisition (PIETA) is described. This approach is applicable whenever strong inhomogeneous broadenings dominate the unmodulated frequency resonances, such as in non-crystalline solids or in samples with large residual frequency anisotropy. PIETA provides significant sensitivity enhancements while also eliminating spectral artifacts would normally be present with Carr-Purcell-Meiboom-Gill acquisition. Additionally, an intuitive approach is presented for designing and processing echo train acquisition magnetic resonance experiments on rotating samples. Affine transformations are used to relate the two-dimensional signals acquired in TOP, MAT, and PASS experiments to a common coordinate system. Depending on sequence design and acquisition conditions two significant artifacts can arise from truncated acquisition time and discontinuous damping in the T2 decay. Here we show that the former artifact can always be eliminated through selection of a suitable affine transformation, and give the conditions in which the latter can be minimized or removed entirely. PMID- 23656128 TI - Theoretical predictions of properties and gas-phase chromatography behaviour of carbonyl complexes of group-6 elements Cr, Mo, W, and element 106, Sg. AB - Fully relativistic, four-component density functional theory electronic structure calculations were performed for M(CO)6 of group-6 elements Cr, Mo, W, and element 106, Sg, with an aim to predict their adsorption behaviour in the gas-phase chromatography experiments. It was shown that seaborgium hexacarbonyl has a longer M-CO bond, smaller ionization potential, and larger polarizability than the other group-6 molecules. This is explained by the increasing relativistic expansion and destabilization of the (n - 1)d AOs with increasing Z in the group. Using results of the calculations, adsorption enthalpies of the group-6 hexacarbonyls on a quartz surface were predicted via a model of physisorption. According to the results, -DeltaHads should decrease from Mo to W, while it should be almost equal--within the experimental error bars--for W and Sg. Thus, we expect that in the future gas-phase chromatography experiments it will be almost impossible--what concerns DeltaHads--to distinguish between the W and Sg hexacarbonyls by their deposition on quartz. PMID- 23656129 TI - Infrared spectroscopy and tunneling dynamics of the vinyl radical in 4He nanodroplets. AB - The vinyl radical has been trapped in (4)He nanodroplets and probed with infrared laser spectroscopy in the CH stretch region between 2850 and 3200 cm(-1). The assigned band origins for the CH2 symmetric (nu3), CH2 antisymmetric (nu2), and lone alpha-CH stretch (nu1) vibrations are in good agreement with previously reported full-dimensional vibrational configuration interaction computations [A. R. Sharma, B. J. Braams, S. Carter, B. C. Shepler, and J. M. Bowman, J. Chem. Phys. 130, 174301 (2009)]. For all three bands, a-type and b-type transitions are observed from the lowest symmetry allowed roconvibrational state of each nuclear spin isomer, which allows for a determination of the tunneling splittings in both the ground and excited vibrational levels. Comparisons to gas phase millimeter wave rotation-tunneling [K. Tanaka, M. Toshimitsu, K. Harada, and T. Tanaka, J. Chem. Phys. 120, 3604-3618 (2004)] and high-resolution jet-cooled infrared spectra [F. Dong, M. Roberts, and D. J. Nesbitt, J. Chem. Phys. 128, 044305 (2008)] reveal that the He solvent effect is to reduce the ground and nu3 excited state tunneling splittings by ~20%. This solvent-induced modification of the tunneling dynamics can be reasonably accounted for by assuming either a ~2.5% increase in the effective barrier height along the tunneling coordinate or a ~5% increase in the effective reduced mass of the tunneling particles. PMID- 23656130 TI - Observation of linear to planar structural transition in sulfur-doped gold clusters: Au(x)S- (x = 2-5). AB - We report a joint experimental and theoretical study on the structures of a series of gold clusters doped with a sulfur atom, Au(x)S(-) (x = 2-5). Well resolved photoelectron spectra are obtained and compared with theoretical results calculated using several density functional methods to elucidate the structures and bonding of Au(x)S(-) (x = 2-5). Au2S(-) is found to have an asymmetric linear global minimum structure with C(infinityv) symmetry, while the most stable structure of neutral Au2S is bent with C(2v) symmetry, reminiscent of H2S. Au3S( ) is found to have an asymmetric bent structure with an Au-S-Au-Au connectivity. Two isomers are observed experimentally to co-exist for Au4S(-): a symmetric bent 1D structure (C(2v)) and a 2D planar low-lying isomer (C(s)). The global minimum of Au5S(-) is found to be a highly stable planar triangular structure (C(2v)). Thus, a 1D-to-2D structural transition is observed in the Au(x)S(-) clusters as a function of x at x = 4. Molecular orbital analyses are carried out to obtain insight into the nature of the chemical bonding in the S-doped gold clusters. Strong covalent bonding between S and Au is found to be responsible for the 1D structures of Au(x)S(-) (x = 2-4), whereas delocalized Au-Au interactions favor the 2D planar structure for the larger Au5S(-) cluster. PMID- 23656131 TI - Low energy (e,2e) coincidence studies of NH3: results from experiment and theory. AB - Experimental and theoretical triple differential cross sections (TDCS) from ammonia are presented in the low energy regime with outgoing electron energies from 20 eV down to 1.5 eV. Ionization measurements from the 3a1, 1e1, and 2a1 molecular orbitals were taken in a coplanar geometry. Data from the 3a1 and 1e1 orbitals were also obtained in a perpendicular plane geometry. The data are compared to predictions from the distorted wave Born approximation and molecular three-body distorted wave models. The cross sections for the 3a1 and 1e1 orbitals that have p-like character were found to be similar, and were different to that of the 2a1 orbital which has s-like character. These observations are not reproduced by theory, which predicts the structure of the TDCS for all orbitals should be similar. Comparisons are also made to results from experiment and theory for the iso-electronic targets neon and methane. PMID- 23656132 TI - Time-dependent quantum wave packet study of the Ar+H2+->ArH(+)+H reaction on a new ab initio potential energy surface for the ground electronic state (1(2)A'). AB - A new global potential energy surface for the ground electronic state (1(2)A') of the Ar+H2(+)->ArH(+)+H reaction has been constructed by multi-reference configuration interaction method with Davidson correction and a basis set of aug cc-pVQZ. Using 6080 ab initio single-point energies of all the regions for the dynamics, a many-body expansion function form has been used to fit these points. The quantum reactive scattering dynamics calculations taking into account the Coriolis coupling (CC) were carried out on the new potential energy surface over a range of collision energies (0.03-1.0 eV). The reaction probabilities and integral cross sections for the title reaction were calculated. The significance of including the CC quantum scattering calculation has been revealed by the comparison between the CC and the centrifugal sudden approximation calculation. The calculated cross section is in agreement with the experimental result at collision energy 1.0 eV. PMID- 23656133 TI - Fully quantal calculation of H2 translation-rotation states in (H2)4@5(12)6(4) clathrate sII inclusion compounds. AB - The quantal translation-rotation (TR) states of the (p-H2)4@5(12)6(4) and (o D2)4@5(12)6(4) hydrate clathrate sII inclusion compounds have been computed by nuclear-orbital/configuration-interaction methods. The model of these compounds in a rigid, high-symmetry 5(12)6(4) cage is treated in detail. The low-energy TR level structures of both isotopomers within this model are found to consist of states that can be readily described in terms of a small number of single-H2 and double-H2 excitation modes. The use of the high-symmetry results to facilitate the calculation and interpretation of (p-H2)4 and (o-D2)4 TR states in low symmetry physically realizable 5(12)6(4) cages is also reported. PMID- 23656134 TI - Electron collisions with the HCOOH...(H2O)n complexes (n = 1, 2) in liquid phase: the influence of microsolvation on the pi* resonance of formic acid. AB - We report momentum transfer cross sections for elastic collisions of low-energy electrons with the HCOOH...(H2O)n complexes, with n = 1, 2, in liquid phase. The scattering cross sections were computed using the Schwinger multichannel method with pseudopotentials in the static-exchange and static-exchange plus polarization approximations, for energies ranging from 0.5 eV to 6 eV. We considered ten different structures of HCOOH...H2O and six structures of HCOOH...(H2O)2 which were generated using classical Monte Carlo simulations of formic acid in aqueous solution at normal conditions of temperature and pressure. The aim of this work is to investigate the influence of microsolvation on the pi* shape resonance of formic acid. Previous theoretical and experimental studies reported a pi* shape resonance for HCOOH at around 1.9 eV. This resonance can be either more stable or less stable in comparison to the isolated molecule depending on the complex structure and the water role played in the hydrogen bond interaction. This behavior is explained in terms of (i) the polarization of the formic acid molecule due to the water molecules and (ii) the net charge of the solute. The proton donor or acceptor character of the water molecules in the hydrogen bond is important for understanding the stabilization versus destabilization of the pi* resonances in the complexes. Our results indicate that the surrounding water molecules may affect the lifetime of the pi* resonance and hence the processes driven by this anion state, such as the dissociative electron attachment. PMID- 23656135 TI - From light-scattering measurements to polarizability derivatives in vibrational Raman spectroscopy: the 2nu5 overtone of SF6. AB - The room-temperature isotropic spectrum of SF6 was recorded at the frequency of the 2nu5 overtone by running high-sensitivity incoherent Raman experiments for two independent polarizations of the incident beam and for gas densities varying from 2 to 27 amagat. Weak yet observable pressure effects were found. A transparent analysis of the Raman cross-section problem along with the first-ever prediction of the value of the mean polarizability second derivative ?(2)alpha/?q5(2) are made and the hitherto underestimated role of the hot bands of SF6 is brought to the wider public. The emergence of an analytic hotband factor is shown whose magnitude is dramatically increased with the order of the overtone and the gas temperature and all the more so upon considering low frequency molecular vibrations. Our formulas, which in the harmonic approximation are exact, are still applicable to real situations provided certain conditions are fulfilled. For nondegenerated modes, generalization to higher order overtones is made, an issue addressing the much challenging problem of the IR-allowed second overtone bands. The content of this paper is also an invitation towards ab initio derivative-calculations for sulfur hexafluoride, especially given the today's needs in interpreting spectra of significance for greenhouse atmospheric issues. PMID- 23656136 TI - Rovibronically selected and resolved two-color laser photoionization and photoelectron study of titanium monoxide cation. AB - Two-color visible-ultraviolet (VIS-UV) resonance-enhanced laser photoionization and pulsed field ionization-photoelectron (PFI-PE) study of gaseous titanium monoxide (TiO) in the total energy range of 55,000-57,320 cm(-1) has been conducted. The TiO molecules were selectively excited to single J' rotational levels of the intermediate TiO*(B(3)Pi1, nu' = 0) state by using a VIS dye laser and then ionized by using another UV laser. This two-color photoexcitation method has allowed the measurement of cleanly J(+)-resolved PFI-PE spectra for the TiO(+)(X (2)Delta(5/2,3/2); v(+) = 0, 1, and 2) vibrational bands. By simulating the rotationally resolved PFI-PE spectra, J(+) = 3/2 is determined to be the lowest rotational level of the ground electronic state, confirming that the symmetry of the TiO(+) ground state is (2)Delta(3/2). Irregular intensity patterns for rotational PFI-PE peaks that deviated from the regular patterns that favor the rotational transitions with small change of the core rotational angular momentum, are observed. This observation is indicative of strong perturbations of the PFI-PE rotational transitions, possibly by a channel-coupling mechanism. The analysis of the PFI-PE spectra yields highly precise values for the adiabatic ionization energy of TiO [IE(TiO) = 55 005.4 +/- 0.8 cm(-1) (6.81980 +/- 0.00010 eV)], and the vibrational frequency (omegae(+) = 1056.1 +/- 0.8 cm(-1)), the anharmonicity constant (omegae(+)chie(+) = 4.4 +/- 0.8 cm(-1)), the rotational constants (B(e)(+) = 0.5613 +/- 0.0009 cm(-1) and alphae(+) = 0.0029 +/- 0.0008 cm(-1)), and the equilibrium bond length (r(e)(+) = 1.583 A) for the TiO(+)(X (2)Delta(3/2)) ground state, the vibrational frequency (omegae(+) = 1058.4 +/- 0.8 cm(-1)), the anharmonicity constant (omegae(+)chie(+) = 5.1 +/- 0.8 cm(-1)), the rotational constants (B(e)(+) = 0.5715 +/- 0.0007 cm(-1) and alphae(+) = 0.0030 +/- 0.0004 cm(-1)) and the equilibrium bond length (r(e)(+) = 1.568 A) for the excited spin orbit state TiO(+)(X (2)Delta(5/2)), along with the spin-orbit coupling constant (A = 105.9 +/- 0.2 cm(-1)) for TiO(+)(X (2)Delta(5/2,3/2)). PMID- 23656137 TI - Spectroscopic observation of gold-dicarbide: photodetachment and velocity map imaging of the AuC2 anion. AB - Photoelectron spectra following photodetachment of the gold dicarbide anion, AuC2(-), have been recorded using the velocity map imaging technique at several excitation wavelengths. The binding energy spectra show well-defined vibrational structure which, with the aid of computational calculations and Franck-Condon simulations, was assigned to a progression in the Au-C stretching mode, nu3. The experimental data indicate that the features in the spectrum correspond to a (2)A' <- (3)A' transition, involving states which we calculate to have bond angles ~147 degrees but with a low barrier to linearity. PMID- 23656138 TI - Nature of the anomalies in the supercooled liquid state of the mW model of water. AB - The thermodynamic properties of the supercooled liquid state of the mW model of water show anomalous behavior. Like in real water, the heat capacity and compressibility sharply increase upon supercooling. One of the possible explanations of these anomalies, the existence of a second (liquid-liquid) critical point, is not supported by simulations for this model. In this work, we reproduce the anomalies of the mW model with two thermodynamic scenarios: one based on a non-ideal "mixture" with two different types of local order of the water molecules, and one based on weak crystallization theory. We show that both descriptions accurately reproduce the model's basic thermodynamic properties. However, the coupling constant required for the power laws implied by weak crystallization theory is too large relative to the regular backgrounds, contradicting assumptions of weak crystallization theory. Fluctuation corrections outside the scope of this work would be necessary to fit the forms predicted by weak crystallization theory. For the two-state approach, the direct computation of the low-density fraction of molecules in the mW model is in agreement with the prediction of the phenomenological equation of state. The non-ideality of the "mixture" of the two states never becomes strong enough to cause liquid-liquid phase separation, also in agreement with simulation results. PMID- 23656139 TI - A polarizable reactive force field for water to enable molecular dynamics simulations of proton transport. AB - A new polarizable water model is developed for molecular dynamics (MD) simulations of the proton transport process. The interatomic potential model has three important submodels corresponding to electrostatic interactions, making and breaking of covalent bonds, and treatment of electron exchange and correlation through a van der Waals potential. A polarizable diffuse charge density function was used to describe Coulombic interactions between atoms. Most of the model parameters were obtained from ab initio data for a lone water molecule. Molecules respond realistically to their electrochemical environment by the use of coupled fluctuating charge and fluctuating dipole dynamics, which controlled the charge density. The main purpose of the work is to develop a general model and framework for future studies, though some validation work was performed here. We applied the model to a MD simulation study of bulk properties of liquid water at room temperature and model gave good agreement with thermodynamic and transport properties at the same conditions. The model was then applied to a preliminary study of proton transfer, in which multiple proton transfer events were observed, though the rate of proton transfer was under-predicted by a factor of 5. PMID- 23656140 TI - Free energy barriers for homogeneous crystal nucleation in a eutectic system of binary hard spheres. AB - In this study, the free energy barriers for homogeneous crystal nucleation in a system that exhibits a eutectic point are computed using Monte Carlo simulations. The system studied is a binary hard sphere mixture with a diameter ratio of 0.85 between the smaller and larger hard spheres. The simulations of crystal nucleation are performed for the entire range of fluid compositions. The free energy barrier is found to be the highest near the eutectic point and is nearly five times that for the pure fluid, which slows down the nucleation rate by a factor of 10(-31). These free energy barriers are some of highest ever computed using simulations. For most of the conditions studied, the composition of the critical nucleus corresponds to either one of the two thermodynamically stable solid phases. However, near the eutectic point, the nucleation barrier is lowest for the formation of the metastable random hexagonal closed packed (rhcp) solid phase with composition lying in the two-phase region of the phase diagram. The fluid to solid phase transition is hypothesized to proceed via formation of a metastable rhcp phase followed by a phase separation into respective stable fcc solid phases. PMID- 23656141 TI - Determination of favorable inter-particle interactions for formation of substitutionally ordered solid phases from a binary mixture of oppositely charged colloidal suspensions. AB - The solid phase formed by a binary mixture of oppositely charged colloidal particles can be either substitutionally ordered or substitutionally disordered depending on the nature and strength of interactions among the particles. In this work, we use Monte Carlo molecular simulations along with the Gibbs-Duhem integration technique to map out the favorable inter-particle interactions for the formation of substitutionally ordered crystalline phases from a fluid phase. The inter-particle interactions are modeled using the hard core Yukawa potential but the method can be easily extended to other systems of interest. The study obtains a map of interactions depicting regions indicating the type of the crystalline aggregate that forms upon phase transition. PMID- 23656142 TI - The structure of liquid GeSe revisited: a first principles molecular dynamics study. AB - Early first-principles molecular dynamics results on liquid GeSe were characterized by shortcomings in the description of Ge-Ge (and to a lesser extent Se-Se) short range correlations. In that case the exchange-correlation functional adopted was the one devised by Perdew and Wang (PW91). In the search of improvements in the atomic-scale modelling of this liquid, we have produced new sets of data by employing two different schemes for the exchange-correlation part within the density functional theory approach. The two functionals selected are those proposed by Becke, Lee, Yang, and Parr (BLYP) and by Perdew, Burke, and Ernzerhof (PBE). The PBE results turned out to be quite similar to the PW91 ones. The BLYP results feature instead a better account of the Ge-Ge first shell of neighbors, correctly exhibiting two clear maxima separated by a deep minimum. Due to the increase in the number of the tetrahedral structural units, the atomic mobility of Ge and Se atoms in the network is reduced with respect to the PW91 case. This brings the diffusion coefficients of the two species down to values close to those of liquid Ge2Se3 and liquid GeSe2. PMID- 23656143 TI - Temperature measurements and an improved equation of state for shocked liquid benzene. AB - Time-resolved, Raman spectroscopy measurements were used to determine temperatures in multiply shocked liquid benzene to peak pressures of ~19 GPa. The previously reported equation of state (EOS) for benzene provides temperatures that are lower than the experimental measurements. To achieve improved temperature calculations, key thermodynamic parameters in the existing EOS were varied to examine and understand the sensitivity of temperatures to those parameters. Using the sensitivity studies, the benzene EOS parameters were refined to provide a good agreement between the calculated temperatures and the measured temperatures in multiply shocked benzene. Use of the improved EOS also leads to an increase in the decomposition temperature from 1315 K to 1485 K, for singly shocked liquid benzene. The present work underscores the importance of temperature measurements for developing accurate EOS for shocked liquids. PMID- 23656144 TI - Density dependence of dynamical heterogeneity in fluid methanol. AB - Brillouin and Raman scattering experiments on methanol through its glass transition under pressure are reported. The Brillouin scattering data were analyzed using viscoelastic theory and a fit to the Vinet equation of state. The variation in the linewidth of the longitudinal acoustic mode with pressure shows a broad maximum centered around 3 GPa. The pressure evolution of the relaxation time in the GHz range is obtained, and the Raman data are analyzed in terms of the Boson peak and its associated relaxation time in the THz range. The pressure evolution of these two relaxation processes extends previous determinations of relaxations at lower frequency based on dielectric measurements in supercooled methanol. The relaxation processes in glass-forming methanol have now been investigated over a wide frequency range and their evolution followed over a large variation of density. PMID- 23656145 TI - Thermodynamic anomaly of the sub-T(g) relaxation in hyperquenched metallic glasses. AB - Recently, we observed an unusual non-monotonic glass relaxation phenomenon, i.e., the three-step sub-T(g) relaxation in hyperquenched CuZrAl glass ribbons [L. N. Hu and Y. Z. Yue, Appl. Phys. Lett. 98, 081904 (2011)]. In the present work, we reveal the origin of this abnormal behavior by studying the cooling rate dependence of the sub-T(g) enthalpy relaxation in two metallic glasses. For the Cu46Zr46Al8 glass ribbons the sub-T(g) enthalpy relaxation pattern exhibits a three-step trend with the annealing temperature only when the ribbons are fabricated below a critical cooling rate. For the La55Al25Ni20 glass ribbons the activation energy for the onset of the sub-T(g) enthalpy relaxation also varies non-monotonically with the cooling rate of fabrication. These abnormal relaxation phenomena are explained in terms of the competition between the low and the high temperature clusters during the fragile-to-strong transition. By comparisons of chemical heterogeneity between Cu46Zr46Al8 and La55Al25Ni20, we predict that the abnormal relaxation behavior could be a general feature for the HQ metallic glasses. PMID- 23656146 TI - Pressure induced structural phase transition in solid oxidizer KClO3: a first principles study. AB - High pressure behavior of potassium chlorate (KClO3) has been investigated from 0 to 10 GPa by means of first principles density functional theory calculations. The calculated ground state parameters, transition pressure, and phonon frequencies using semiempirical dispersion correction scheme are in excellent agreement with experiment. It is found that KClO3 undergoes a pressure induced first order phase transition with an associated volume collapse of 6.4% from monoclinic (P2(1)/m) -> rhombohedral (R3m) structure at 2.26 GPa, which is in good accord with experimental observation. However, the transition pressure was found to underestimate (0.11 GPa) and overestimate (3.57 GPa) using local density approximation and generalized gradient approximation functionals, respectively. Mechanical stability of both the phases is explained from the calculated single crystal elastic constants. In addition, the zone center phonon frequencies have been calculated using density functional perturbation theory at ambient as well as at high pressure and the lattice modes are found to soften under pressure between 0.6 and 1.2 GPa. The present study reveals that the observed structural phase transition leads to changes in the decomposition mechanism of KClO3 which corroborates with the experimental results. PMID- 23656147 TI - Effect of local metal microstructure on adsorption on bimetallic surfaces: atomic nitrogen on Ni/Pt(111). AB - The adsorption of atomic nitrogen on Ni/Pt(111) surface bimetallics has been investigated as a function of the local microstructure of Ni and Pt atoms via density functional theory (DFT) calculations. Microstructures include surface and subsurface Ni atoms on Pt(111) as limiting cases, and also small clusters of Ni in the first and/or second layer of Pt. It is shown that the binding energy of N can be approximated as a perturbation from that on the host metal (Pt) with a linear short-ranged correction from the guest metal (Ni) that accounts for the coordination environment of nitrogen up to the 3rd nearest Ni neighbor. This model is rationalized with the d-band center theory. Coverage effects are also included. The model can be parameterized with a limited number of DFT calculations and applied to other bimetallic catalysts to estimate the coverage dependent binding energy on complex metal microstructures. PMID- 23656148 TI - Metal-organic frameworks with wine-rack motif: what determines their flexibility and elastic properties? AB - We present here a framework for the analysis of the full tensors of second-order elastic constants of metal-organic frameworks, which can be obtained by ab initio calculations. We describe the various mechanical properties one can derive from such tensors: directional Young's modulus, shear modulus, Poisson ratio, and linear compressibility. We then apply this methodology to four different metal organic frameworks displaying a wine-rack structure: MIL-53(Al), MIL-47, MIL 122(In), and MIL-140A. From these results, we shed some light into the link between mechanical properties, geometric shape, and compliance of the framework of these porous solids. We conclude by proposing a simple criterion to assess the framework compliance, based on the lowest eigenvalue of its second-order elastic tensor. PMID- 23656149 TI - Carbon monoxide adsorption on platinum-osmium and platinum-ruthenium-osmium mixed nanoparticles. AB - Density functional calculations (DFT) on carbon monoxide (CO) adsorbed on platinum, platinum-osmium, and platinum-ruthenium-osmium nanoclusters are used to elucidate changes on the adsorbate internal bond and the carbon-metal bond, as platinum is alloyed with osmium and ruthenium atoms. The relative strengths of the adsorbate internal bond and the carbon-metal bond upon alloying, which are related to the DFT calculated C-O and C-Pt stretching frequencies, respectively, cannot be explained by the traditional 5sigma-donation/2pi*-back-donation theoretical model. Using a modified pi-attraction sigma-repulsion mechanism, we ascribe the strength of the CO adsorbate internal bond to changes in the polarization of the adsorbate-substrate hybrid orbitals towards carbon. The strength of the carbon-metal bond is quantitatively related to the CO contribution to the adsorbate-substrate hybrid orbitals and the sp and d populations of adsorbing platinum atom. This work complements prior work on corresponding slabs using periodic DFT. Similarities and differences between cluster and periodic DFT calculations are discussed. PMID- 23656150 TI - The dissociative chemisorption of methane on Ni(111): the effects of molecular vibration and lattice motion. AB - We examine the dissociative chemisorption of methane on a Ni(111) surface, using a fully quantum approach based on the Reaction Path Hamiltonian that includes all 15 molecular degrees of freedom and the effects of lattice motion. The potential energy surface and all parameters in our model are computed from first principles. Vibrational excitation of the molecule is shown to significantly enhance the reaction probability, and the efficacy for this is explained in terms of the vibrationally non-adiabatic couplings, vibrational mode softening, and mode symmetry. Agreement with experimental data for molecules initially in the ground and 1nu3 state is good, and including lattice anharmonicity further improves our results. The variation of the dissociation probability with substrate temperature is well reproduced by the model, and is shown to result primarily from changes in the dissociation barrier height with lattice motion. The enhancement of dissociative sticking with substrate temperature is particularly strong for processes that would otherwise have insufficient energy to surmount the barrier. Our model suggests that vibrationally excited molecules are likely to dominate the "laser off" dissociative sticking at high nozzle temperatures. PMID- 23656151 TI - Adsorption induced transitions in soft porous crystals: an osmotic potential approach to multistability and intermediate structures. AB - Soft porous crystals are flexible metal-organic frameworks that respond to physical stimuli (temperature, pressure, and gas adsorption) by large changes in their structure and unit cell volume. We propose here a thermodynamic treatment, based on the osmotic ensemble, of the interplay between guest adsorption and host deformation, where the bare host material can undergo elastic deformation, as well as structural transitions between metastable phases in the case of a multistable material. We show that in addition to structural transitions between metastable phases of bistable or multistable host frameworks, a new guest stabilized host phase can be created when the size of the adsorbate is larger than the empty material's pore size. We then confront the findings of our approach with experimental data for systems exhibiting phenomena such as gate opening and breathing. PMID- 23656152 TI - Light-induced electronic non-equilibrium in plasmonic particles. AB - We consider the transient non-equilibrium electronic distribution that is created in a metal nanoparticle upon plasmon excitation. Following light absorption, the created plasmons decohere within a few femtoseconds, producing uncorrelated electron-hole pairs. The corresponding non-thermal electronic distribution evolves in response to the photo-exciting pulse and to subsequent relaxation processes. First, on the femtosecond timescale, the electronic subsystem relaxes to a Fermi-Dirac distribution characterized by an electronic temperature. Next, within picoseconds, thermalization with the underlying lattice phonons leads to a hot particle in internal equilibrium that subsequently equilibrates with the environment. Here we focus on the early stage of this multistep relaxation process, and on the properties of the ensuing non-equilibrium electronic distribution. We consider the form of this distribution as derived from the balance between the optical absorption and the subsequent relaxation processes, and discuss its implication for (a) heating of illuminated plasmonic particles, (b) the possibility to optically induce current in junctions, and (c) the prospect for experimental observation of such light-driven transport phenomena. PMID- 23656153 TI - The double-layer of penetrable ions: an alternative route to charge reversal. AB - We investigate a double-layer of penetrable ions near a charged wall. We find a new mechanism for charge reversal that occurs in the weak-coupling regime and, accordingly, the system is suitable for the mean-field analysis. The penetrability is achieved by smearing-out the ionic charge inside a sphere, so there is no need to introduce non-electrostatic forces and the system in the low coupling limit can be described by a modified version of the Poisson-Boltzmann equation. The predictions of the theory are compared with the Monte Carlo simulations. PMID- 23656154 TI - Polymer translocation dynamics in the quasi-static limit. AB - Monte Carlo (MC) simulations are used to study the dynamics of polymer translocation through a nanopore in the limit where the translocation rate is sufficiently slow that the polymer maintains a state of conformational quasi equilibrium. The system is modeled as a flexible hard-sphere chain that translocates through a cylindrical hole in a hard flat wall. In some calculations, the nanopore is connected at one end to a spherical cavity. Translocation times are measured directly using MC dynamics simulations. For sufficiently narrow pores, translocation is sufficiently slow that the mean translocation time scales with polymer length N according to ? (N - N(p))(2), where N(p) is the average number of monomers in the nanopore; this scaling is an indication of a quasi-static regime in which polymer-nanopore friction dominates. We use a multiple-histogram method to calculate the variation of the free energy with Q, a coordinate used to quantify the degree of translocation. The free energy functions are used with the Fokker-Planck formalism to calculate translocation time distributions in the quasi-static regime. These calculations also require a friction coefficient, characterized by a quantity N(eff), the effective number of monomers whose dynamics are affected by the confinement of the nanopore. This was determined by fixing the mean of the theoretical distribution to that of the distribution obtained from MC dynamics simulations. The theoretical distributions are in excellent quantitative agreement with the distributions obtained directly by the MC dynamics simulations for physically meaningful values of N(eff). The free energy functions for narrow pore systems exhibit oscillations with an amplitude that is sensitive to the nanopore length. Generally, larger oscillation amplitudes correspond to longer translocation times. PMID- 23656155 TI - The Lowe-Andersen thermostat as an alternative to the dissipative particle dynamics in the mesoscopic simulation of entangled polymers. AB - Dissipative Particle Dynamics (DPD) has shown a great potential in studying the dynamics and rheological properties of soft matter; however, it is associated with deficiencies in describing the characteristics of entangled polymer melts. DPD deficiencies are usually correlated to the time integrating method and the unphysical bond crossings due to utilization of soft potentials. One shortcoming of DPD thermostat is the inability to produce real values of Schmidt number for fluids. In order to overcome this, an alternative Lowe-Anderson (LA) method, which successfully stabilizes the temperature, is used in the present work. Additionally, a segmental repulsive potential was introduced to avoid unphysical bond crossings. The performance of the method in simulating polymer systems is discussed by monitoring the static and dynamic characteristics of polymer chains and the results from the LA method are compared to standard DPD simulations. The performance of the model is evaluated on capturing the main shear flow properties of entangled polymer systems. Finally the linear and nonlinear viscoelastic properties of such systems are discussed. PMID- 23656156 TI - Brownian dynamics method for simulation of binding kinetics of patterned colloidal spheres with hydrodynamic interactions. AB - We develop a Brownian dynamics simulation method with full hydrodynamic interactions (HI) to study the recognition kinetics between two patterned colloidal spheres. We use a general resistance matrix (12*12) to describe both the far and near-field hydrodynamics of translation, rotation, and translation rotation coupling between the two spheres, adopted from Jeffrey and Onishi [J. Fluid Mech. 139, 261 (1984)]. We apply the method to the specific binding of "patchy" spheres, including effects of depletion attraction and orientation specific binding, as are present in "Janus" spheres whose surfaces contain hydrophobic and hydrophilic faces [Q. Chen, S. C. Bae, and S. Granick, Nature (London) 469, 381 (2011)]. The binding times obtained between two non-patterned spheres (of equal or unequal diameter) with or without HI extrapolated to infinite dilution are shown to be in good agreement with theoretical predictions of the Smoluchowski equation. In addition, the binding times for pairs of spheres for three cases of surface patterning of the two spheres (uniform-uniform, uniform-Janus, and Janus-Janus) are compared with or without rotational motion. PMID- 23656157 TI - Homopolymer adsorption on periodically structured surfaces in systems with incommensurable lengths. AB - Surface-induced selective adsorption of homopolymers on a generic level is numerically analyzed for freely jointed chains (with a fixed bond length) whose monomers are attracted by the sites of regular periodic patterns. In particular, the behavior of the specific heat, the gyration tensor, and the bond order tensor are investigated as functions of the temperature. The properties of the transition are related to the interplay of the characteristic lengths. The adsorption proceeds in two steps for certain incommensurabilities of the bond length and the lattice constant. The corresponding adsorption mechanisms are elucidated by looking at the evolution of the inter bond angle distribution upon adsorption. Moreover, the origin of two steps in contrast to adsorption in one step is traced back to entropic restrictions caused by a strongly reduced phase space of the polymer for certain values of the incommensurability. PMID- 23656158 TI - Dynamics of exciton transfer in coupled polymer chains. AB - The dynamics of singlet and triplet exciton transfer in coupled polymer chains are investigated within the Su-Schrieffer-Heeger+Pariser-Parr-Pople model including both electron-phonon (e-p) coupling and electron-electron (e-e) interactions, using a multi-configurational time-dependent Hartree-Fock dynamic method. In order to explain the processes involved, the effects of on-site and long-range e-e interactions on the locality of the singlet and triplet excitons are first investigated on an isolated chain. It is found that the locality of the singlet exciton decreases, while the locality of the triplet exciton increases with an increase in the on-site e-e interactions. On the other hand, an increase in the long-range e-e interaction results in a more localized singlet exciton and triplet exciton. In coupled polymer chains, we then quantitatively show the yields of singlet and triplet exciton transfer products under the same interchain coupling. It is found that the yield of singlet interchain excitons is much higher than that of triplet interchain excitons, that is to say, singlet exciton transfer is significantly easier than that for triplet excitons. This results from the fact that the singlet exciton is more delocalized than the triplet exciton. In addition, hopping of electrons with opposite spins between the coupled chains can facilitate the transfer of singlet excitons. The results are of great significance for understanding the photoelectric conversion process and developing high-power organic optoelectronic applications. PMID- 23656159 TI - Probability of double-strand breaks in genome-sized DNA by gamma-ray decreases markedly as the DNA concentration increases. AB - By use of the single-molecule observation, we count the number of DNA double strand breaks caused by gamma-ray irradiation with genome-sized DNA molecules (166 kbp). We find that P1, the number of double-strand breaks (DSBs) per base pair per unit Gy, is nearly inversely proportional to the DNA concentration above a certain threshold DNA concentration. The inverse relationship implies that the total number of DSBs remains essentially constant. We give a theoretical interpretation of our experimental results in terms of attack of reactive species upon DNA molecules, indicating the significance of the characteristics of genome sized giant DNA as semiflexible polymers for the efficiency of DSBs. PMID- 23656160 TI - Kinetics of loop formation in worm-like chain polymers. AB - A common theoretical approach to calculating reaction kinetics is to approximate a high-dimensional conformational search with a one-dimensional diffusion along an effective reaction coordinate. We employed Brownian dynamics simulations to test the validity of this approximation for loop formation kinetics in the worm like chain polymer model. This model is often used to describe polymers that exhibit backbone stiffness beyond the monomer length scale. We find that one dimensional diffusion models overestimate the looping time and do not predict the quantitatively correct dependence of looping time on chain length or capture radius. Our findings highlight the difficulty of describing high-dimensional polymers with simple kinetic theories. PMID- 23656161 TI - On the role of thermal backbone fluctuations in myoglobin ligand gate dynamics. AB - We construct an energy function that describes the crystallographic structure of sperm whale myoglobin backbone. As a model in our construction, we use the Protein Data Bank entry 1ABS that has been measured at liquid helium temperature. Consequently, the thermal B-factor fluctuations are very small, which is an advantage in our construction. The energy function that we utilize resembles that of the discrete nonlinear Schrodinger equation. Likewise, ours supports topological solitons as local minimum energy configurations. We describe the 1ABS backbone in terms of topological solitons with a precision that deviates from 1ABS by an average root-mean-square distance, which is less than the experimentally observed Debye-Waller B-factor fluctuation distance. We then subject the topological multi-soliton solution to extensive numerical heating and cooling experiments, over a very wide range of temperatures. We concentrate in particular to temperatures above 300 K and below the Theta-point unfolding temperature, which is around 348 K. We confirm that the behavior of the topological multi-soliton is fully consistent with Anfinsen's thermodynamic principle, up to very high temperatures. We observe that the structure responds to an increase of temperature consistently in a very similar manner. This enables us to characterize the onset of thermally induced conformational changes in terms of three distinct backbone ligand gates. One of the gates is made of the helix F and the helix E. The two other gates are chosen similarly, when open they provide a direct access route for a ligand to reach the heme. We find that out of the three gates we investigate, the one which is formed by helices B and G is the most sensitive to thermally induced conformational changes. Our approach provides a novel perspective to the important problem of ligand entry and exit. PMID- 23656162 TI - Non-Markovianity during the quantum Zeno effect. AB - We examine the Zeno and anti-Zeno effects in the context of non-Markovian dynamics in entangled spin-boson systems in contact with noninteracting reservoirs. We identify enhanced non-Markovian signatures in specific two-qubit partitions of a Bell-like initial state, with results showing that the intra qubit Zeno effect or anti-Zeno effect occurs in conjunction with inter-qubit non Markovian dynamics for a range of system parameters. The time domain of effective Zeno or anti-Zeno dynamics is about the same order of magnitude as the non Markovian time scale of the reservoir correlation dynamics, and changes in decay rate due to the Zeno mechanism appears coordinated with information flow between specific two-qubit partitions. We extend our analysis to examine the Zeno mechanism-non-Markovianity link using the tripartite states arising from a donor acceptor-sink model of photosynthetic biosystems. PMID- 23656164 TI - Novel dual-mode immunomagnetic method for studying reactivation of nerve agent inhibited butyrylcholinesterase. AB - A novel immunomagnetic method has been developed for the simultaneous measurement of organophosphorus nerve agent (OPNA) adducts to butyrylcholinesterase (BuChE) and free OPNAs in serum. This new approach, deemed dual-mode immunomagnetic analysis (Dual-Mode IMA), combines immunomagnetic separation (IMS) and immunomagnetic scavenging (IMSc) and has been used to measure the effectiveness of cholinesterase reactivators on OPNA-inhibited BuChE in serum. BuChE inhibited by the nerve agent VX, uninhibited BuChE, and unbound VX were measured up to 1 h after the addition of oxime reactivators pralidoxime (2-PAM) and obidoxime. IMS experiments consisted of extracting BuChE and VX-BuChE serum adducts using antibutyrylcholinesterase monoclonal antibodies conjugated to protein-G ferromagnetic particles. In a parallel set of experiments using IMSc, BuChE coated magnetic beads were used to extract free VX from protein-depleted serum. Adducts from both IMS and IMSc were analyzed using a published IMS liquid chromatography tandem mass spectrometry (IMS-LC-MS/MS) protocol, which has also been demonstrated with other OPNAs. By applying this Dual-Mode IMA approach, 2 PAM was observed to be more potent than obidoxime in reactivating VX-adducted BuChE. VX-BuChE peptide concentrations initially measured at 19.7 +/- 0.7 ng/mL decreased over 1 h to 10.6 +/- 0.6 ng/mL when reactivated with 2-PAM and 14.4 +/- 1.2 ng/mL when reactivated with obidoxime. These experiments also show that previously published IMS-LC-MS/MS analyses are compatible with serum treated with oximes. Dual-Mode IMA is the first immunoaffinity method developed for the simultaneous measurement of OPNA adducted BuChE, unadducted BuChE, and free nerve agent in serum and is a promising new tool for studying reactivator effectiveness on cholinesterases inhibited by nerve agents. PMID- 23656165 TI - Mono- and polynuclear copper(II) complexes of alloferons 1 with point mutations (H6A) and (H12A): stability structure and cytotoxicity. AB - Mononuclear and polynuclear copper(II) complexes of the alloferons 1 (Allo1) with point mutations (H6A) H(1)GVSGA(6)GQH(9)GVH(12)G-COOH (Allo6A) and (H12A) H(1)GVSGH(6)GQH(9)GVA(12)G-COOH (Allo12A) have been studied by potentiometric, UV visible, CD, EPR spectroscopic, and mass spectrometry (MS) methods. Complete complex speciation at different metal-to-ligand ratios ranging from 1:1 to 3:1 was obtained. At physiological pH 7.4 and a 1:1 metal-to-ligand molar ratio, the Allo6A and Allo12A peptides form CuL complexes with the 4N {NH2, N(Im) H(1),2N(Im)} binding mode. The amine nitrogen donor and the imidazole nitrogen atoms (H(9)H(12) or H(6)H(9)) can be considered to be independent metal-binding sites in the species formed for the systems studied. As a consequence, di- and trinuclear complexes for the metal-to-ligand 2:1 and 3:1 molar ratios dominate in solution, respectively. The induction of apoptosis in vivo in Tenebrio molitor cells by the ligands and their copper(II) complexes at pH 7.4 was studied. The biological results show that copper(II) ions in vivo did not cause any apparent apoptotic features. The most active was the Cu(II)-Allo12A complex formed at pH 7.4 with a {NH2, N(Im)-H(1),N(Im)-H(6),N(Im)-H(9)} binding site. It exhibited 123% higher of caspase activity in hemocytes than the native peptide, Allo1. PMID- 23656166 TI - Impact of ballistic body armour and load carriage on walking patterns and perceived comfort. AB - This study investigated the impact of weight magnitude and distribution of body armour and carrying loads on military personnel's walking patterns and comfort perceptions. Spatio-temporal parameters of walking, plantar pressure and contact area were measured while seven healthy male right-handed military students wore seven different garments of varying weight (0.06, 9, 18 and 27 kg) and load distribution (balanced and unbalanced, on the front and back torso). Higher weight increased the foot contact time with the floor. In particular, weight placement on the non-dominant side of the front torso resulted in the greatest stance phase and double support. Increased plantar pressure and contact area observed during heavier loads entail increased impact forces, which can cause overuse injuries and foot blisters. Participants reported increasingly disagreeable pressure and strain in the shoulder, neck and lower back during heavier weight conditions and unnatural walking while wearing unbalanced weight distributed loads. This study shows the potentially synergistic impact of wearing body armour vest with differential loads on body movement and comfort perception. PRACTITIONER SUMMARY: This study found that soldiers should balance loads, avoiding load placement on the non-dominant side front torso, thus minimising mobility restriction and potential injury risk. Implications for armour vest design modifications can also be found in the results. PMID- 23656167 TI - Association of IL-17, IL-21, and IL-23R gene polymorphisms with HBV infection in kidney transplant patients. AB - Inflammatory cytokine gene polymorphisms may influence the hepatic and extrahepatic HBV-related disease in transplant patients. In this study, the association between IL-17, IL-23R, and IL-21 gene polymorphisms with hepatitis B virus (HBV) infection was evaluated in kidney transplant patients. In total, 220 kidney transplant patients were enrolled in this cross-sectional study between years 2007 and 2011. The genomic HBV DNA was identified using an HBV PCR detection Kit according to the manufacturer's instruction. The cytokine gene polymorphisms, including IL-17 197 A/G (rs2275913), IL-21 +1472 G/T (rs2055979), IL-21 5250 C/T (rs4833837), and IL-23R C/A (rs10889677) were evaluated by PCR RFLP and ARMS-PCR protocols. The serum levels of IL-17 and IL-21 were analyzed in HBV infected and noninfected transplant patients by ELISA methods according to manufacturer's instructions. 70 of 220 (35%) transplant patients experienced acute rejection. HBV DNA was detected in 52 of 220 (23.64%) transplant patients. 16 of 52 (30.8%) HBV-infected kidney transplant patients experienced acute rejection. A significant higher frequency of C allele of IL-23R (rs10889677) polymorphism, a higher frequency of AG heterozygote genotype and A allele of IL 17-G197A (rs2275913) polymorphism, a higher frequency of TT homozygote genotype and T allele of IL-21-G1472T (rs2055979) polymorphism, and a higher frequency of CC homozygote genotype and C allele of IL-21-C5250T (rs4833837) polymorphism were found in HBV-infected kidney transplant patients with acute rejection. Diagnosis of the higher frequency of the IL-17, IL-21, and IL-23R cytokine genotypes and allele polymorphisms in HBV-infected kidney transplant patients who experienced acute rejection, illustrates the importance of Th17-related cytokine genetic patterns. A better evaluation of HBV infection in kidney transplant patients is needed. PMID- 23656169 TI - Pediatric reference intervals: challenges and recent initiatives. AB - The clinical laboratory plays a critical role in healthcare delivery by providing objective data on specific biomarkers that directly aid in the diagnosis and monitoring of a wide range of clinical disorders. Reliable and accurate reference intervals for laboratory analyses are integral for correct interpretation of clinical laboratory test results and, therefore, for appropriate clinical decision-making. Ideally, reference intervals should be established based on a healthy population and stratified for key covariates including age, gender and ethnicity. However, establishing reference intervals can be challenging as it requires the collection of large numbers of samples from healthy individuals. This challenge is further augmented in pediatrics, where dynamic changes due to child growth and development markedly affect circulating levels of disease biomarkers. As a result, even larger reference populations are required to reliably calculate reference intervals. In this review, we outline the challenges specific to establishing pediatric reference intervals and highlight recent initiatives aimed at closing existing gaps in current knowledge. We also outline recommended approaches to the development of reference intervals and detail several alternative approaches. Finally, reference intervals for emerging and novel biomarkers of pediatric disease are discussed along with a number of potential alternative sample types. PMID- 23656168 TI - Altered lymphocyte proliferation and innate immune function in scrapie 139A- and ME7-infected mice. AB - Lymphoid organs play an important role in prion disease development and progression. While the role of lymphoid organs and changes in immune-related genes have been extensively investigated in scrapie-infected animals, innate immunity has not. Previous studies examined lymphocyte function in scrapie infected C3H/HeJ mice, which exhibit defects in lipopolysaccharide (LPS) response now known to result from a mutation in Toll-like receptor (TLR) 4. We examined immune function in scrapie-infected CD1 mice, which are LPS responders. Lymphocyte proliferation from CD1 mice infected with either 139A or ME7 scrapie was measured in response to concanavalin (Con) A or LPS at 1 and 3 months after infection. Following LPS exposure, mice infected 3 months with ME7, but not 139A, demonstrated significantly decreased lymphocyte proliferation compared to controls. After Con A exposure, lymphocyte proliferation in scrapie-infected mice did not differ from controls. Gender-specific comparison of lymphocyte proliferation showed significant decreases in mitogenic responses in females infected 3 months with either 139A or ME7, compared to controls. Males infected for 3 months with ME7, but not 139A, showed significantly decreased proliferation after lymphocyte exposure to LPS, but not Con A. Neither gender showed changes in lymphocyte proliferation after 1 month of scrapie infection. Innate immune activation of peritoneal macrophages was determined via production of nitric oxide (NO), IL-6, and TNF-alpha after exposure to TLR ligands. TNF-alpha and IL-6 production were reduced in macrophages from females infected with either scrapie strain for 3 months, while NO production after TLR agonist plus IFN-gamma exposure was decreased in both females and males infected for 3 months with 139A, compared to ME7. These data demonstrated altered innate immunity, suggesting hormonal and/or other gender-specific regulation may contribute to gender differences in some immune functions. Our data demonstrate lymphocyte proliferation and innate immune functioning in scrapie-infected mice deteriorate with disease progression. PMID- 23656170 TI - Mechanistic insights into C-H amination via dicopper nitrenes. AB - We examine important reactivity pathways relevant to stoichiometric and catalytic C-H amination via isolable beta-diketiminato dicopper alkylnitrene intermediates {[Cl2NN]Cu}2(MU-NR). Kinetic studies involving the stoichiometric amination of ethylbenzene by {[Cl2NN]Cu}2(MU-N(t)Bu) (3) demonstrate that the terminal nitrene [Cl2NN]Cu?N(t)Bu is the active intermediate in C-H amination. Initial rates exhibit saturation behavior at high ethylbenzene loadings and an inverse dependence on the copper species [Cl2NN]Cu, both consistent with dissociation of a [Cl2NN]Cu fragment from 3 prior to C-H amination. C-H amination experiments employing 1,4-dimethylcyclohexane and benzylic radical clock substrate support a stepwise H-atom abstraction/radical rebound pathway. Dicopper nitrenes [Cu]2(MU NCHRR') derived from 1 degrees and 2 degrees alkylazides are unstable toward tautomerization to copper(I) imine complexes [Cu](HN?CRR'), rendering 1 degrees and 2 degrees alkylnitrene complexes unsuitable for C-H amination. PMID- 23656171 TI - Beneficial effect of flax seeds in streptozotocin (STZ) induced diabetic mice: isolation of active fraction having islet regenerative and glucosidase inhibitory properties. AB - Diabetes mellitus is a metabolic disorder that affects millions of people worldwide. Present study highlights the antidiabetogenic property of Linum usitassimum active fraction (LU6) in streptozotocin (STZ) induced diabetic Swiss mice. Treatment with LU6 fraction showed improved glucose utilization with increase in liver glucose-6-phosphate dehydrogenase enzyme activity and normal glycogenesis in hepatic and muscle tissues. Reduction in pancreatic and intestinal glucosidase inhibitory activity was observed with LU6 treatment, indicating beneficial effects in reducing postprandial hyperglycemia (PPHG). Normalization of plasma insulin and C-peptide levels were observed in diabetic mice, indicating endogenous insulin secretion after the treatment with LU6. The histochemical and immunohistochemical analysis on pancreatic islets suggests the role of LU6 fraction in islet regeneration and insulin secretion as evident in increase functional pancreatic islets producing insulin. Furthermore, significant insulin producing islet formation was also observed in in vitro PANC-1 cells after LU6 treatment, indicating the cellular aggregates to be newly formed islets. This suggests the potential of LU6 fraction in the formation of new islets in vitro, as well as in vivo. Thus, LU6 can be used as a neutraceutical based first-line treatment for diabetes. PMID- 23656172 TI - Cardiac iron overload assessed by T2* magnetic resonance imaging and cardiac function in regularly transfused myelodysplastic syndrome patients. PMID- 23656173 TI - Cerebrolysin enhances cognitive recovery of mild traumatic brain injury patients: double-blind, placebo-controlled, randomized study. AB - In adults, mild traumatic brain injury (MTBI) frequently results in impairments of cognitive functions which would lead to psychological consequences in the future. Cerebrolysin is a nootropic drug, and can significantly improve cognitive function in patients with Alzheimer's disease and stroke. The purpose of this study was to investigate how Cerebrolysin therapy enhances cognitive recovery for mild traumatic brain injury patients using a double-blinded, placebo-controlled, randomized phase II pilot study. Patients having head injury within 24 h sent to our hospital were screened and recruited if patients were alert and conscious, and had intracranial contusion haemorrhage. From July 2009 to June 2010, totally, thirty-two patients were recruited in the double-blinded, placebo-controlled, and randomized study. Patients were randomized to receive Cerebrolysin (Group A, once daily intravenous infusion of 30 mL Cerebrolysin over a 60-min period for 5 days) or placebo (Group B, same dosage and administration of normal saline as Group A). The primary outcome measures were differences of cognitive function including Mini-Mental Status Examination (MMSE), and Cognitive Abilities Screening Instrument (CASI) scores between baseline and week 1, between baseline and week 4, and between baseline and week 12. Thirty-two patients completed the trial. For Group A, the CASI score difference between baseline and week 12 was 21.0 +/- 20.4, a significantly greater change than that of Group B (7.6 +/- 12.1) (p = 0.0461). Besides, drawing function (one of the domains of CASI; p = 0.0066) on week 4 and both drawing function (p = 0.0472) and long-term memory (one of the domains of CASI; p = 0.0256) on week 12 were also found to be significantly improved in the patients receiving Cerebrolysin treatment. Our results suggest that Cerebrolysin improves the cognitive function of the MTBI in patients at 3rd month after injury, especially for long-term memory and drawing function. PMID- 23656175 TI - Comment on "A theory of macromolecular chemotaxis" and "Phenomena associated with gel-water interfaces. Analyses and alternatives to the long-range ordered water hypothesis". PMID- 23656174 TI - The natural history of periodontal attachment loss during the third and fourth decades of life. AB - AIM: To describe changes in the occurrence of periodontal attachment loss (AL) through ages 26, 32 and 38 in a complete birth cohort. MATERIALS AND METHODS: Systematic periodontal examinations conducted at ages 26, 32 and 38 in a longstanding New Zealand cohort study (N = 1037). Periodontitis extent data were used to assign participants to periodontitis trajectories using group-based trajectory analysis. RESULTS: Eight hundred and thirty-one individuals were periodontally examined at all three ages; the prevalence and extent of AL increased as the cohort aged. Between 26 and 32, one in nine participants had 1+ sites showing new or progressing AL; that proportion almost doubled between ages 32 and 38. Four periodontitis trajectory groups were identified, comprising 55.2%, 31.5%, 10.7% and 2.5% of the cohort; these were termed the "Very low", "Low", "Moderately increasing" and "Markedly increasing" trajectory groups respectively. Those who had smoked tobacco at all ages from 15 through 38 were at higher risk of being in the "Moderately increasing" or "Markedly increasing" trajectory groups. There was a similar risk gradient for those who were in the highest 20% of cannabis usage. CONCLUSIONS: Periodontitis commences relatively early in adulthood, and its progression accelerates with age, particularly among smokers. PMID- 23656176 TI - Comparing effects of intravenous patient-controlled analgesia and intravenous injection in patients who have undergone total hysterectomy. AB - AIMS AND OBJECTIVES: To compare the effects of two pain management methods, intravenous patient-controlled analgesia and conventional intravenous injection, in terms of pain level, adverse reactions experienced, nursing care time spent for pain management, satisfaction with pain management and total cost of pain management for patients who underwent total abdominal hysterectomy. BACKGROUND: Patient-controlled intravenous analgesia has been used most commonly for management of postoperative pain. Although it can be very effective in management of postoperative pain, patients still complained of many adverse reactions. DESIGN: A quasi-experimental study design was used. METHODS: Seventy female participants were recruited for each group and were randomly assigned to one of the pain management methods. Data regarding pain level, adverse reactions experienced and level of satisfaction with pain management methods during a 48 hour postoperative period were collected. Calculation of cost for each pain management method was based on the cost of the device, drugs for both analgesics and antiemetics, and time spent by nurses for both pain management methods. Frequencies, percentages and means of the data were calculated, and chi-squared test and t-test were performed for homogeneity. RESULTS: Mean postoperative pain levels at 2, 6 and 12 hour were significantly lower in patients who used patient controlled analgesic compared with patients who received intravenous injection; however, after that, there was no significant difference between the two methods. The cost for pain management was much higher for patients who used patient controlled analgesic; however, satisfaction level with pain control was lower than that for patients who received intravenous injection. CONCLUSIONS: For patients who underwent total hysterectomy, patient-controlled analgesia was not cost-effective for management of postoperative pain for 48 hour, compared with conventional intravenous injection. RELEVANCE TO CLINICAL PRACTICE: For nurses caring for patients with pain, adaptation of diverse methods of pain management that will increase patients' satisfaction with pain management as well as lower the cost and occurrence of adverse reactions should be considered. PMID- 23656177 TI - Non-alcoholic fatty liver disease independently predicts prediabetes during a 7 year prospective follow-up. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is suspected to confer an increased risk for developing type 2 diabetes (DM). However, only a few prospective studies evaluated NAFLD as a predictor for DM, most did not adjust for the full range of potential cofounders and none used an objectively quantified degree of steatosis. Our aim was to evaluate the independent role of NAFLD in predicting the development of pre-DM in a 7-year prospective follow-up of healthy volunteers. METHODS: A prospective cohort of a subsample of the Israeli National Health Survey evaluated at baseline and after 7 years by identical protocols. Metabolic parameters and ultrasonographic evidence of NAFLD were evaluated in 213 subjects, without known liver disease or history of alcohol abuse. Exclusion criteria were pre-DM at the baseline survey. Steatosis was quantified by ultrasound with the hepato-renal ultrasound index (HRI). RESULTS: The study included 141 volunteers (mean age 48.78 +/- 9.68, 24.82% with NAFLD) without pre-DM/DM at baseline. Both NAFLD on regular US (OR=2.93, 1.02-8.41 95%CI) and HRI (OR=7.87, 1.83-33.82) were independent predictors for the development of pre-DM, adjusting for age, gender, BMI, family history of DM, baseline insulin, adiponectin and glucose. Further adjustment for physical activity and dietary intake did not weaken the association. Furthermore, NAFLD was a stronger predictor for pre-DM than the metabolic syndrome. Subjects with both NAFLD and glucose >=89 had 93.3% incidence rate of pre-DM. CONCLUSION: Non alcoholic fatty liver disease is a strong and independent risk factor for pre-DM in the general adult population; thus, NAFLD patients should be classified as a population at risk. PMID- 23656178 TI - Pedestrian worker fatalities in workplace locations, Australia, 2000-2010. AB - Pedestrian deaths of workers in Australian workplaces (1 July 2000-31 December 2010) are described using coronial and safety authority fatality databases. One hundred and fifteen deaths were identified, with the majority male (93%) and aged over 50 years (59%). Four industries predominated (85% of deaths): Agriculture, Forestry and Fishing (31%), Construction (29%), Transport, Postal and Warehousing (16%) and Manufacturing (10%). Similarly, three occupations dominated: Farmers (28%), Labourers (27%) and Machinery Operators and Drivers (25%). Common circumstantial factors (reversing machines or vehicles, driver also the pedestrian, driver's vision impeded and working accompanied) occurred in the Construction, Transport and Manufacturing industries, providing collaborative opportunities for prevention. Deaths occurring in the Agriculture industry showed different circumstantial factors, likely needing different solutions. While some effective countermeasures are known, workplace pedestrian fatalities continue to occur. Prevention strategies are needed to share known information across industries and to produce data enhancements and new knowledge. PMID- 23656180 TI - Engineered microbes for therapeutic applications. PMID- 23656179 TI - Automated large-scale file preparation, docking, and scoring: evaluation of ITScore and STScore using the 2012 Community Structure-Activity Resource benchmark. AB - In this study, we use the recently released 2012 Community Structure-Activity Resource (CSAR) data set to evaluate two knowledge-based scoring functions, ITScore and STScore, and a simple force-field-based potential (VDWScore). The CSAR data set contains 757 compounds, most with known affinities, and 57 crystal structures. With the help of the script files for docking preparation, we use the full CSAR data set to evaluate the performances of the scoring functions on binding affinity prediction and active/inactive compound discrimination. The CSAR subset that includes crystal structures is used as well, to evaluate the performances of the scoring functions on binding mode and affinity predictions. Within this structure subset, we investigate the importance of accurate ligand and protein conformational sampling and find that the binding affinity predictions are less sensitive to non-native ligand and protein conformations than the binding mode predictions. We also find the full CSAR data set to be more challenging in making binding mode predictions than the subset with structures. The script files used for preparing the CSAR data set for docking, including scripts for canonicalization of the ligand atoms, are offered freely to the academic community. PMID- 23656183 TI - Stable maintenance of multiple plasmids in E. coli using a single selective marker. AB - Plasmid-based genetic systems in Escherichia coli are a staple of synthetic biology. However, the use of plasmids imposes limitations on the size of synthetic gene circuits and the ease with which they can be placed into bacterial hosts. For instance, unique selective markers must be used for each plasmid to ensure their maintenance in the host. These selective markers are most often genes encoding resistance to antibiotics such as ampicillin or kanamycin. However, the simultaneous use of multiple antibiotics to retain different plasmids can place undue stress on the host and increase the cost of growth media. To address this problem, we have developed a method for stably transforming three different plasmids in E. coli using a single antibiotic selective marker. To do this, we first examined two different systems with which two plasmids may be maintained. These systems make use of either T7 RNA polymerase-specific regulation of the resistance gene or split antibiotic resistance enzymes encoded on separate plasmids. Finally, we combined the two methods to create a system with which three plasmids can be transformed and stably maintained using a single selective marker. This work shows that large scale plasmid-based synthetic gene circuits need not be limited by the use of multiple antibiotic resistance genes. PMID- 23656184 TI - Engineered E. coli that detect and respond to gut inflammation through nitric oxide sensing. AB - Advances in synthetic biology now allow for the reprogramming of microorganisms to execute specific tasks. Here, we describe the development of an engineered strain of E. coli capable of sensing and responding to the presence of a mammalian inflammatory signal. The synthetic gene regulatory circuit is designed to permanently alter gene expression in response to the well characterized inflammatory signal nitric oxide. The detection of nitric oxide initiates the expression of a DNA recombinase, causing the permanent activation of a DNA switch. We demonstrate that E. coli containing this synthetic circuit respond to nitric oxide from both chemical and biological sources, with permanent DNA recombination occurring in the presence of nitric oxide donor compounds or inflamed mouse ileum explants. In the future, this synthetic genetic circuit will be optimized to allow E. coli to reliably detect and respond to inflammation in vivo. PMID- 23656185 TI - Engineering integrated digital circuits with allosteric ribozymes for scaling up molecular computation and diagnostics. AB - Here we describe molecular implementations of integrated digital circuits, including a three-input AND logic gate, a two-input multiplexer, and 1-to-2 decoder using allosteric ribozymes. Furthermore, we demonstrate a multiplexer decoder circuit. The ribozymes are designed to seek-and-destroy specific RNAs with a certain length by a fully computerized procedure. The algorithm can accurately predict one base substitution that alters the ribozyme's logic function. The ability to sense the length of RNA molecules enables single ribozymes to be used as platforms for multiple interactions. These ribozymes can work as integrated circuits with the functionality of up to five logic gates. The ribozyme design is universal since the allosteric and substrate domains can be altered to sense different RNAs. In addition, the ribozymes can specifically cleave RNA molecules with triplet-repeat expansions observed in genetic disorders such as oculopharyngeal muscular dystrophy. Therefore, the designer ribozymes can be employed for scaling up computing and diagnostic networks in the fields of molecular computing and diagnostics and RNA synthetic biology. PMID- 23656186 TI - Rapid synthesis of defined eukaryotic promoter libraries. AB - Current gene synthesis methods allow the generation of long segments of dsDNA. We show that these techniques can be used to create synthetic regulatory elements and describe a method for the creation of completely defined, synthetic variants of the PHO5 promoter from the budding yeast Saccharomyces cerevisae. Overall, 128 promoters were assembled by high-temperature ligation, cloned into plasmids by isothermal assembly, maintained in E. coli, and consequently transformed into yeast by homologous recombination. Synthesis errors occurred at frequencies comparable to or lower than those achieved with current gene synthesis methods. The promoter synthesis method reported here is robust, fast, and readily accessible. Synthetically engineered promoter libraries will be useful tools for dissecting the intricacies of promoter input-output functions and may serve as tunable components for synthetic genetic networks. PMID- 23656187 TI - Survival times of women with metastatic breast cancer starting first-line chemotherapy in routine clinical practice versus contemporary randomised trials. AB - BACKGROUND: Survival times of women starting first-line chemotherapy for metastatic breast cancer (MBC) in routine clinical practice were determined and compared with those from a systematic review of randomised clinical trials. METHODS: We identified women with MBC starting first-line chemotherapy from June 2003 to February 2011 and recorded their demographics, tumour and treatment characteristics, and survival times from the start of chemotherapy. Their survival distribution was summarised by the following percentiles (represented scenarios for survival): 90th (worst-case), 75th (lower-typical), 25th (upper typical) and 10th (best-case), which were compared with the same percentiles from our systematic review of first-line chemotherapy trials. RESULTS: The 273 women had a median age of 56 years, and a median time from diagnosis of MBC of 3 months. Eastern Cooperative Oncology Group performance status was 0-1 in 80%. Tumours were hormone receptor positive in 69%, human epidermal growth factor receptor 2 (HER2)-positive in 27% and triple negative in 13%. Survival times in months in routine clinical practice (vs the systematic review) were: 90th percentile 4 (6); 75th percentile 9 (12); median 20 (22); 25th percentile 36 (36) and 10th percentile 61 (56). Independent predictors of overall survival included HER2-positive disease (hazard ratio (HR) 0.49, P = 0.0002), hormone receptor positive disease (HR 0.51, P = 0.0004), Eastern Cooperative Oncology Group performance status 0-1 (HR 0.36, P < 0.0001) and adjuvant chemotherapy (HR 1.86, P = 0.0002). CONCLUSION: Median and better survival times in routine practice were similar to those from randomised clinical trials; however, survival times worse than the median were shorter, likely reflecting patient selection in trials. Oncologists should adjust trial-based survival estimates for patients not meeting typical trial eligibility criteria. PMID- 23656188 TI - Differences in biological maturation, anthropometry and physical performance between playing positions in youth team handball. AB - It was the goal of this cross-sectional study to examine differences in maturity, anthropometry and physical performance between youth handball players across different playing positions (i.e. goalkeeper, back, pivot and wing). Multivariate analysis of covariance (MANCOVA), accounting for biological maturation, was used to assess positional differences in 472 male youth handball players from three age groups: U14, U15 and U16. Differences in age at peak height velocity were found in all age groups. Backs were significantly more mature than wings in U14 and U15 and than wings and pivots in U16. Furthermore, backs are overall taller, have a bigger arm span and perform best on tests for strength, agility and speed, especially in the U15 age group. Therefore, it can be concluded that youth players with the most advanced maturation status and the most favourable anthropometry and physical fitness scores, are consistently positioned in the back position. Players with a less advanced maturity status and an overall smaller stature are placed on the wing or pivot positions. In conclusion, it seems that anthropometrical and maturational characteristics are used by coaches to directly and/or indirectly select players for specific field positions. This strategy is risky since anthropometry and maturity status change over the years. PMID- 23656189 TI - Traumatic brachiocephalic trunk pseudoaneurysm. AB - The surgical approach to a large pseudoaneurysm of the brachiocephalic trunk may be hazardous because of its high risk of rupture. An adequate vascular control is vital before attempting to manage the pseudoaneurysm. We describe a surgical technique using deep hypothermic circulatory arrest to repair a giant pseudoaneurysm of the brachiocephalic trunk with impending rupture and severe respiratory distress and superior vena cava compression secondary to multisystem trauma. PMID- 23656191 TI - Clinical and radiographic outcomes of a combined resective and regenerative approach in the treatment of peri-implantitis: a prospective case series. AB - AIM: To assess the clinical and radiographic outcomes applying a combined resective and regenerative approach in the treatment of peri-implantitis. MATERIALS AND METHODS: Subjects with implants diagnosed with peri-implantitis (i.e., pocket probing depth (PPD) >=5 mm with concomitant bleeding on probing (BoP) and >=2 mm of marginal bone loss or exposure of >=1 implant thread) were treated by means of a combined approach including the application of a deproteinized bovine bone mineral and a collagen membrane in the intrabony and implantoplasty in the suprabony component of the peri-implant lesion, respectively. The soft tissues were apically repositioned allowing for a non submerged healing. Clinical and radiographic parameters were evaluated at baseline and 12 months after treatment. RESULTS: Eleven subjects with 11 implants were treated and completed the 12-month follow-up. No implant was lost yielding a 100% survival rate. At baseline, the mean PPD and mean clinical attachment level (CAL) were 8.1 +/- 1.8 mm and 9.7 +/- 2.5 mm, respectively. After 1 year, a mean PPD of 4.0 +/- 1.3 mm and a mean CAL of 6.7 +/- 2.5 mm were assessed. The differences between the baseline and the follow-up examinations were statistically significant (P = 0.001). The mucosal recession increased from 1.7 +/- 1.5 at baseline to 3.0 +/- 1.8 mm at the 12-month follow-up (P = 0.003). The mean% of sites with BoP+ around the selected implants decreased from 19.7 +/- 40.1 at baseline to 6.1 +/- 24.0 after 12 months (P = 0.032). The radiographic marginal bone level decreased from 8.0 +/- 3.7 mm at baseline to 5.2 +/- 2.2 mm at the 12-month follow-up (P = 0.000001). The radiographic fill of the intrabony component of the defect amounted to 93.3 +/- 13.0%. CONCLUSION: Within the limits of this study, a combined regenerative and resective approach for the treatment of peri-implant defects yielded positive outcomes in terms of PPD reduction and radiographic defect fill after 12 months. PMID- 23656192 TI - Possible contamination with clenbuterol from treated veal calves to untreated pen mates. AB - To investigate whether clenbuterol-treated calves could contaminate untreated pen mates, three animal experiments were performed. (1) One calf of a pen of five was treated with clenbuterol by injection (Ventipulmin injection, REG NL 2532, 2.5 mL/100 kg) twice a day for 10 days. (2) In two pens, one animal was treated with clenbuterol via oral administration (Ventipulmin syrup, REG NL 2532, 4 mL/125 kg) for 4 weeks. (3) In two pens, one animal was treated with clenbuterol via the milk (Ventipulmin, REG NL 2532, 2.5 mL/100 kg body weight) twice a day for 10 days. Here, the animal was set apart during treatment, cleaned and put back into the group. Levels of clenbuterol were analysed in hair and urine with LC-MS/MS. Clenbuterol administered by injection could not be transferred from treated to untreated calves. In the second experiment, all pen mates were found positive for clenbuterol in the hair. This contamination was probably due to licking the mouth of the treated animal or saliva from the treated animal spoiling the floor. In the third experiment, no pen mates were found positive for clenbuterol in the hair. Clenbuterol was found in the urine and hair of only treated animals. PMID- 23656190 TI - Role of differential adhesion in cell cluster evolution: from vasculogenesis to cancer metastasis. AB - Cell-cell and cell-matrix adhesions are fundamental to numerous physiological processes, including angiogenesis, tumourigenesis, metastatic spreading and wound healing. We use cellular potts model to computationally predict the organisation of cells within a 3D matrix. The energy potentials regulating cell-cell (JCC) and cell-matrix (JMC) adhesive interactions are systematically varied to represent different, biologically relevant adhesive conditions. Chemotactically induced cell migration is also addressed. Starting from a cluster of cells, variations in relative cell adhesion alone lead to different cellular patterns such as spreading of metastatic tumours and angiogenesis. The combination of low cell cell adhesion (high JCC) and high heterotypic adhesion (low JMC) favours the fragmentation of the original cluster into multiple, smaller cell clusters (metastasis). Conversely, cellular systems exhibiting high-homotypic affinity (low JCC) preserve their original configuration, avoiding fragmentation (organogenesis). For intermediate values of JCC and JMC (i.e. JCC/JMC ~ 1), tubular and corrugated structures form. Fully developed vascular trees are assembled only in systems in which contact-inhibited chemotaxis is activated upon cell contact. Also, the rate of secretion, diffusion and sequestration of chemotactic factors, cell deformability and motility do not significantly affect these trends. Further developments of this computational model will predict the efficacy of therapeutic interventions to modulate the diseased microenvironment by directly altering cell cohesion. PMID- 23656193 TI - Controlled formation of carbon nanotube junctions via linker-induced assembly in aqueous solution. AB - Here we present a simple approach for the controlled formation of one-dimensional and multiterminal nanotube junctions. We describe a facile bottom-up strategy for joining the ends of single-walled carbon nanotubes. The geometry of the junctions can be varied and controlled by linker-induced assembly of DNA-wrapped nanotubes. PMID- 23656194 TI - Peripheral blood CD34+ cell monitoring after cyclophosphamide and granulocyte colony-stimulating factor: an algorithm for the pre-emptive use of plerixafor. AB - Plerixafor "on demand" after chemotherapy plus granulocyte-colony-stimulating factor (G-CSF) is efficient in peripheral stem cell mobilization, but the timing of administration and criteria for patient selection are under investigation. To devise an algorithm for the "on demand" use of plerixafor at the first mobilization attempt, we analyzed the kinetics of hematopoietic recovery and peripheral blood CD34+ cells in 107 patients treated with high-dose cyclophosphamide plus G-CSF. Fifty-one patients with myeloma were treated with cyclophosphamide 3-4 g/m(2) on day 0 followed by G-CSF 10 MUg/kg from day + 6, and 56 patients with lymphoma received cyclophosphamide 6-7 g/m(2) followed by G CSF 5 MUg/kg from day + 1. Peripheral blood CD34+ cell monitoring was started on day + 8 in patients with myeloma and day + 10 in patients with lymphoma. The outcome of interest was a collection of <= 2 * 10(6) CD34+/kg. By a multivariate logistic regression model, CD34+ cell count < 10/MUL at leukocyte recovery (> 1000/MUL) or leukocyte count < 1000/MUL after day + 12 in myeloma and day + 14 in lymphoma predicted the failure of mobilization by 2.7 and 2.8 times (p = 0.001 and p = 0.02) with a sensitivity of 89% and specificity of 88%, respectively. Plerixafor "on demand" may be considered in patients with myeloma and lymphoma with delayed hematopoietic recovery and < 10/MUL CD34+ cells, as a first-line mobilization strategy. PMID- 23656195 TI - Down-regulation of microRNA-29c is associated with renal failure in multiple myeloma. PMID- 23656196 TI - 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography examination in patients with chronic lymphocytic leukemia may reveal Richter transformation. AB - The significance of positron emission tomography/computed tomography (PET/CT) in chronic lymphocytic leukemia (CLL) has not yet been systematically studied. This prospective study was aimed at assessing the benefit of PET/CT in patients with newly diagnosed or relapsed CLL and Richter transformation (RT). PET/CT examination was performed in 23 patients with newly diagnosed disease, 13 with relapsed disease and eight with suspected or histopathologically confirmed RT. In all patients, the maximum standardized uptake value (SUV(max)) was calculated. The median SUV(max) was 3.4 (range: 1.5-6.3) and 3.1 (range: 1.2-5.9) in newly diagnosed and relapsed patients, respectively. The median SUV(max) of patients with suspected or confirmed RT reached 16.5 (range: 7.2-25.3), a value different from that of the previous groups (p < 0.001). 2-[18F]fluoro- 2-deoxy-D-glucose ((18)F-FDG) PET/CT revealed inflammatory lesions in seven patients (16%) and synchronous tumors in two newly diagnosed patients. (18)F-FDG PET/CT may be a beneficial imaging method when used in individuals with CLL and suspected RT. PMID- 23656197 TI - Chronic neutrophilic leukemia with plasma cell dyscrasia: friends or relatives? PMID- 23656198 TI - Evidence for long-term hypercoagulopathy, but normalization of markers of extracellular matrix turnover, in patients with non-Hodgkin lymphoma. PMID- 23656199 TI - Uncoupling endoplasmic reticulum stress and autophagy: a potential implication for chronic lymphocytic leukemia therapy. PMID- 23656200 TI - Ibrutinib in chronic lymphocytic leukemia and B cell malignancies. AB - Recent clinical data suggest remarkable activity of ibrutinib, the first-in-class covalent inhibitor of Bruton's tyrosine kinase (BTK), in chronic lymphocytic leukemia (CLL), as well as excellent activity in other B cell malignancies, including in particular mantle cell lymphoma and Waldenstrom macroglobulinemia. This review evaluates the data from ongoing clinical and correlative studies of ibrutinib in B cell malignancies with a particular focus on CLL, and considers these data in the context of other B cell receptor pathway inhibitors. PMID- 23656201 TI - Unrelated and alternative donor allogeneic stem cell transplant in patients with relapsed or refractory Hodgkin lymphoma: a systematic review. AB - Abstract Allogeneic stem cell transplant (allo-SCT) is considered a clinical option for patients with Hodgkin lymphoma (HL) who have experienced at least two chemosensitive relapses. The aim of this systematic review was to determine the benefits and harms of allo-SCT with an unrelated donor (UD) versus related donor (RD) allo-SCT for adult patients with HL. Alternative donor sources such as haploidentical donor cells (Haplo) and umbilical cord blood (UCB) were also included. The available evidence was limited. Ten studies were included in this assessment. Four studies provided sufficient data to compare UD with RD allo-SCT. None of these studies was a randomized controlled trial. Additionally, three non comparative studies, such as registry analyses, which considered patients with UD transplants were included. The risk of bias in the studies was high. Results on overall and progression-free survival (PFS) showed no consistent tendency in favor of a donor type. Results on therapy-associated mortality and acute (grade II-IV) and chronic graft-versus-host disease were also inconsistent. The study comparing UCB with RD transplants and two non-comparative studies with UCB transplants showed similar results. One of the studies comparing additionally Haplo with RD transplants indicated a benefit in PFS for the Haplo transplant group. In summary, our findings do not indicate a substantial outcome disadvantage of UD and alternative donor sources versus RD allo-SCT for adult patients with advanced HL. PMID- 23656203 TI - Efficacy and safety of oral tranexamic acid in women with heavy menstrual bleeding and fibroids. AB - AIM: To evaluate the efficacy and safety of oral, modified-release tranexamic acid in women with heavy menstrual bleeding and fibroids. MATERIALS & METHODS: This was a pooled analysis of two pivotal Phase III studies. Fibroids were evaluated by transvaginal ultrasonography. Menstrual blood loss (MBL) was measured via a validated alkaline hematin method. RESULTS: In women with and without fibroids, mean MBL was reduced compared with placebo across all treatment cycles (p < 0.001). Within the tranexamic acid group, more statistically significant (p < 0.001) reductions in MBL compared with placebo occurred in women with fibroids than in those without fibroids. Adverse events were similar between treatment groups. CONCLUSION: Tranexamic acid was well tolerated and reduced MBL in women with and without fibroids. PMID- 23656204 TI - Chronic intermittent hypobaric hypoxia prevents cardiac dysfunction through enhancing antioxidation in fructose-fed rats. AB - High-fructose intake induces metabolic syndrome and cardiac dysfunction. Chronic intermittent hypobaric hypoxia (CIHH) preserves cardiac function during ischemia. We hypothesized that CIHH restores the impaired cardiac function in fructose-fed rats. Sprague-Dawley rats were randomly subject to treatment with fructose (10% fructose in drinking water for 6 weeks), CIHH (simulated 5000 m altitude, 6 h/day for 6 weeks in a hypobaric chamber), and CIHH plus fructose groups. In addition to an increase in blood pressure, fructose feeding caused elevated serum levels of glucose, fasting insulin and insulin C peptide, triglyceride, cholesterol, and mass ratio of heart to body. CIHH treatment decreased the arterial blood pressure, serum levels of biochemical markers, and cardiac hypertrophy in fructose-fed rats. Furthermore, CIHH treatment improved the recovery of left ventricular function after ischemia-reperfusion procedure (30 min global no-flow ischemia followed by 60 min of reperfusion) in rats with or without fructose feeding. In addition, CIHH treatment caused a significant increase in superoxide dismutase (SOD) activity and decrease in malondialdehyde level in cardiac myocardium experiencing ischemia-reperfusion in control and fructose-fed rats. Collectively, these data suggest that CIHH improve impaired cardiac function in fructose-fed rats through enhancing antioxidation in the myocardium. PMID- 23656205 TI - Phenomena associated with gel-water interfaces. Analyses and alternatives to the long-range ordered water hypothesis. AB - Interfacial regions between certain gels and their surrounding solutions were observed by Pollack and co-workers to exhibit several unexpected phenomena: (1) long-range exclusion of charged microspheres out to typical distances of ~100-200 MUm from the gel surface; (2) significant electrostatic potentials extending over comparable distances; (3) a reduced intensity of upward spontaneous thermal IR emission over a region 300-500 MUm wide at or near the gel-solution interface; and (4) a significantly lower proton T2 and an apparently reduced H2O self diffusion coefficient over a zone ~60 MUm wide at or near the gel-solution interface in high resolution NMR imaging experiments. To account for such observations, they proposed that a region of long-range ordered water bearing a net negative charge, but lacking mobile charge carriers, extended ~100-200 MUm outward from the gel surface. In this paper, various problems associated with the ordered water hypothesis, including contradictions by experiments from many other laboratories, are briefly discussed, and testable alternative explanations for the observed phenomena are proposed. Exclusion zones are suggested to arise from chemotaxis of the microspheres in long-range diffusion gradients of OH(-) (or H(+)) and salt, the theory of which was developed and compared with the observations on non-ionic gels in a companion paper. The same theory together with the expected directions of ion transfers between gel and solution are now used to predict qualitatively the exclusion/attraction behavior of microspheres in the presence of ionic gels and ionomers. The electrostatic potentials are interpreted as long-range liquid-junction potentials arising from the same long range diffusion gradients of OH(-) (or H(+)) and salt in the unstirred solutions of Pollack and co-workers. Alternative explanations in terms of plausible experimental artifacts are suggested for both the reduced intensity of IR thermal emission and the lower proton T2 and apparent H2O diffusion coefficient in the NMR imaging experiments. PMID- 23656206 TI - Control charts for accident frequency: a motivation for real-time occupational safety monitoring. AB - This paper quantitatively motivates the need for active monitoring of occupational safety incident data through the use of cumulative sum (CUSUM) control charts. The frequency of incidents within a subset of historical accident data is analysed. The performance of Poisson CUSUM and exponential CUSUM (time between-events) charts is compared in an illustrative example to show that shorter periods of aggregation and time-between-events monitoring lead to more timely indications of increased accident frequency. An extension showing the anticipated performance of these charts with real-time data is given. Various adjustments to the monitoring system are also simulated to show that quick implementation of hazard controls can significantly impact safety performance. Decreases in the frequency of safety incidents as a result of implemented hazard controls can also be monitored. PMID- 23656207 TI - 'Be our guest': challenges and benefits of using 'family conversations' to collect qualitative data about infant feeding and parenting. AB - AIMS AND OBJECTIVES: To describe the use of family conversations as a data collection strategy in a study that aimed to explore how 'social context' impacts on the infant feeding and early parenting choices of first-time mothers. Specifically, the authors aim to describe the challenges and benefits of facilitating 'family conversations' and the importance of considering the needs of the researcher and the research participants in the data collection process. BACKGROUND: Breastfeeding is endorsed by the World Health Organisation as a key health promotion strategy, and yet many women in Australia cease breastfeeding (either fully or partially) before the recommended time frame of six months. Engaging with and interviewing families is a well-established research strategy, but interviewing the family as a whole has rarely been used as a part of breastfeeding research. DESIGN: A component of a study, conducted in Sydney, Australia, was to use 'family conversations' to ascertain the views and beliefs that are held by those in the first-time mother's social network and how these impact on her experience of mothering and associated decision-making. CONCLUSIONS: Being able to balance the needs of the researcher and the research participants is an important challenge that is a core component of conducting ethical research. RELEVANCE TO CLINICAL PRACTICE: This paper highlights the viability of 'family conversations' as a data collection method for midwifery and nursing research and the need for midwives and child and family health nurses to more actively engage with a woman's support network with education and other strategies to assist in creating an environment for new mothers that is conducive to the continuation of breastfeeding and thriving as a mother. PMID- 23656209 TI - Efficacy of single buccal infiltrations for maxillary first molars in patients with irreversible pulpitis: a randomized controlled clinical trial. AB - AIM: To evaluate the efficacy of a single buccal infitration using 4% articaine hydrochloride (HCl) with 1 : 100,000 epinephrine or 4% articaine HCl with 1 : 100 000 epinephrine bitartrate for obtaining adequate pulpal anaesthesia in the palatal roots of maxillary first molars associated with irreversible pulpitis. METHODOLOGY: In this single-blind randomized clinical trial, fifty subjects were randomly allocated to receive maxillary buccal injections of 1.5 mL 4% articaine with 1 : 100,000 epinephrine (n = 25) or 1.5 mL 4% articaine with 1 : 100,000 epinephrine bitartrate (n = 25). Visual analogue scale (VAS) scores and pulse rate measurements were recorded during access cavity preparation and initial file placement into the mesiobuccal, distobuccal and palatal canals. Data were analysed using Duncan and t-tests. RESULTS: There was no significant difference between the two anaesthetic solutions regarding the VAS scores and pulse rate measurements during endodontic procedures. The mean VAS ratings of the 50 patients during file placement into the palatal canals were significantly higher compared with the other three root canal procedures (P < 0.0001). The heart rates during negotiation of palatal canals were significantly higher than when negotiating the mesiobuccal and distobuccal canals (P < 0.0001). CONCLUSION: Single buccal infiltration did not achieve adequate pulpal anaesthesia in the palatal root canal of the maxillary first molars associated with irreversible pulpitis. PMID- 23656210 TI - Association of doxycycline use with the development of gastroenteritis, irritable bowel syndrome and inflammatory bowel disease in Australians deployed abroad. AB - BACKGROUND: The risks are unknown for developing chronic gastrointestinal illness when personnel are relocated short term to other countries and when taking antibiotic prophylaxis in areas where malaria is endemic. AIM: To examine the associations of deployment to developed or developing countries and exposure to doxycycline with the new onset of acute gastroenteritis, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). METHODS: A cross-sectional web-based survey of all current and past members of the Australian Federal Police Association was undertaken. Independent predictors of gastrointestinal illness were examined by logistic regression analysis relative to those not deployed without exposure to doxycycline. RESULTS: Of 1300 respondents (response rate 34%), 133 were excluded due to pre-existing chronic gastrointestinal illness. Five hundred and ninety had episodes of overseas deployment for a median duration of 6.5 (range 0.1-149) months. Eighteen (3%) of those not deployed took doxycycline compared with 171 (30%) of those deployed. The risk of acute gastroenteritis was associated with deployment itself without clear association with doxycycline. Doxycycline exposure was associated with increased onset of IBS in those deployed to developing (odds ratio [OR], 6.99; 95% confidence interval [CI], 3.19-15.31) and developed country (OR, 6.93; 95% CI, 1.40-34.39). New onset of IBD (1.5%) was associated with deployment to developed countries and with doxycycline exposure (OR, 8.75; 95% CI, 1.67-45.86)). CONCLUSIONS: The use of doxycycline is a risk factor for developing IBS and possibly IBD when deployed to developing and developed countries respectively. Doxycycline as a risk factor for chronic gastrointestinal illness warrants a prospective large-scale study. PMID- 23656211 TI - Reliability and stability of anthropometric and performance measures in highly trained young soccer players: effect of age and maturation. AB - The purpose of this study was to assess both short-term reliability and long-term stability of anthropometric and physical performance measures in highly-trained young soccer players in relation to age and maturation. Data were collected on 80 players from an academy (U13-U18, pre- (n = 14), circum- (n = 32) and post- (n = 34) estimated peak height velocity, PHV). For the reliability analysis, anthropometric and performance tests were repeated twice within a month. For the stability analysis, these tests were repeated 12 times over a 4-year period in 10 players. Absolute reliability was assessed with the typical error of measurement, expressed as a coefficient of variation (CV). Relative reliability and long-term stability were assessed using the intraclass correlation coefficient (ICC). There was no clear age or maturation effect on either the CVs or ICCs: e.g., Post-PHV vs. Pre-PHV: effect size = -0.37 (90% confidence limits (CL):-1.6;0.9), with chances of greater/similar/lower values of 20/20/60%. For the long-term stability analysis, ICCs varied from 0.66 (0.50;0.80) to 0.96 (0.93;0.98) for 10-m sprint time and body mass, respectively. The short-term reliability of anthropometry and physical performance measures is unlikely to be affected by age or maturation. However, some of these measures are unstable throughout adolescence, which questions their usefulness in a talent identification perspective. PMID- 23656212 TI - Use of viscoelastic coagulation testing to monitor low molecular weight heparin administration to healthy horses. AB - OBJECTIVES: To evaluate the utility of thromboelastography (TEG) and Sonoclot analyses to monitor the effects of low molecular weight heparin (LMWH) administration to healthy horses. DESIGN: Randomized crossover study. SETTING: Large animal veterinary teaching hospital. ANIMALS: Six adult mixed breed healthy mares. INTERVENTIONS: LMWH (dalteparin) was administered (50 U/kg subcutaneously) either every 12 or 24 h for 3 consecutive days. Blood samples were collected before LMWH administration and then at selected time points for analysis. Thromboelastography derived R-time (R), K-time (K), angle (ANG), and maximum amplitude (MA), and Sonoclot activated clot time (ACT), clot rate (CR), and platelet function (PF) were measured in whole blood 30 min after sample collection. Change (Delta) and percentage change (%Delta) from baseline of each TEG and Sonoclot variable were subsequently calculated. Anti-factor Xa activity and activated partial thromboplastin time (aPTT) were assayed in harvested plasma. The association between anti-factor Xa activity and TEG and Sonoclot (measured and calculated) variables was assessed by calculating correlation coefficients and multiple regression analysis. The ability of measured and calculated TEG and Sonoclot variables to predict when anti-factor Xa activity fell below suggested thromboprophylactic levels was assessed using receiver operating characteristic curve analysis. MEASUREMENTS AND MAIN RESULTS: The correlation between aPTT and anti-factor Xa activity was weak (r = 0.343). Changes in TEG and Sonoclot variables following LMWH administration were consistent with hypocoagulation. All measured and calculated TEG variables were significantly correlated with anti-factor Xa activity. Sonoclot ACT, DeltaACT, CR, DeltaCR, and %DeltaCR were also significantly correlated with anti-factor Xa activity. TEG DeltaR and %DeltaR best predicted anti-factor Xa activity below the suggested thromboprophylactic level. CONCLUSIONS: Although correlations were modest, serial measurement of TEG variables may be used to monitor LMWH therapy in horses; however, further research is required in sick horses. PMID- 23656213 TI - Verruciform xanthoma of the upper-extremity in the absence of chronic skin disease or syndrome: a case report and review of the literature. AB - Verruciform xanthoma is a rare, benign lesion classically presenting on the oral mucosa or genital area. The etiology is not yet completely understood; however, verruciform xanthoma is often associated with (a) conditions of chronic inflammation or trauma, such as lichen sclerosis, recessive dystrophic epidermolysis bullosa, and pemphigus vulgaris, as well as in a setting of (b) chronic lymphedema, (c) chronic graft versus host disease, or (d) congenital epidermal nevi, such as those associated with the Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects (CHILD) syndrome. We report a case of a solitary verruciform xanthoma on the forearm of an 82-year-old man without history of chronic dystrophic skin disease or syndrome. In addition, a thorough literature review of extra-oral and extra-genital verruciform xanthomas is presented. On the basis of this review, we believe this case is an extremely rare presentation of a solitary verruciform xanthoma on the upper-extremity of an otherwise healthy individual. PMID- 23656214 TI - Cochlear dead region and word recognition of Mandarin Chinese in Taiwan. AB - In a tonal language, the identity of a word depends largely on the tonal identification of the contour of vocal fundamental frequency energy of which usually centers in a low frequency of less than 600 Hz. However, cochlear dead region (DR) is present mostly in the frequency range of 2000 Hz to 4000 Hz, and the effect of DR on a tonal language is worth investigating. Thirty-two native Mandarin speakers with moderate-to-severe degree of sensorineural hearing loss were included in this study. The pure-tone audiometry, speech recognition threshold (SRT) and word recognition score (WRS) were used to evaluate the degree of hearing loss and word recognition. The threshold equalizing noise (TEN) tests were used to identify the presence of DR. The results showed that most DRs were present in high frequencies. The hearing thresholds of the ears with a DR were not significantly different from those without DR. However, the WRS was significantly worse for the DR ears, especially for those whose DR included three or more audiometric frequencies. A DR caused a significantly worse word recognition for the tonal language speakers of Mandarin in Taiwan, although the DR frequency occurred in the high frequency of 2000 Hz to 4000 Hz. PMID- 23656215 TI - Comparison of training and anthropometric characteristics between recreational male half-marathoners and marathoners. AB - Participation in endurance running such as half-marathon (21-km) and marathon (42 km) has increased over the last decades. We compared 147 recreational male half marathoners and 126 recreational male marathoners to investigate similarities or differences in their anthropometric and training characteristics. The half marathoners were heavier (P < 0.05), had longer legs (P < 0.001), thicker upper arms (P < 0.05), a thicker thigh (P < 0.01), a higher sum of skinfold thicknesses (P < 0.01), a higher body fat percentage (P < 0.05) and a higher skeletal muscle mass (P < 0.05) than the marathoners. They had fewer years of experience (P < 0.05), completed fewer weekly training kilometers (P < 0.001), and fewer weekly running hours (P < 0.01) compared to the marathoners. For half-marathoners, body mass index (P = 0.011), percent body fat (P = 0.036) and speed in running during training (P < 0.0001) were related to race time (r2 = 0.47). For marathoners, percent body fat (P = 0.001) and speed in running during training (P < 0.0001) were associated to race time (r2 = 0.47). When body mass index was excluded for the half-marathoners in the multi-variate analysis, r2 decreased to 0.45, therefore body mass index explained only 2% of the variance of half-marathon performance. Percent body fat was significantly and negatively related to running speed during training in both groups. To summarize, half-marathoners showed differences in both anthropometry and training characteristics compared to marathoners that could be related to their lower training volume, most probably due to the shorter race distance they intended to compete. Both groups of athletes seemed to profit from low body fat and a high running speed during training for fast race times. PMID- 23656216 TI - Reduction of motor disorder in 6-OHDA-induced severe parkinsonism rats by post treatment with granulocyte-colony stimulating factor. AB - Granulocyte-colony stimulating factor (G-CSF) induced regeneration of dopaminergic neurons and improved behavior deficit in moderate Parkinson's disease (PD) model mice. Post treatment of G-CSF in severe PD model has not been addressed. A very severe PD model in rats was induced by a high dose 6 hydroxydopamine (6-OHDA) injected into the right medial forebrain bundle to evaluate therapeutic effects of G-CSF. G-CSF (50 microg/kg/day for five days) was given on the 9th day after the 6-OHDA injection. Rotational behavior was examined on the 9th and 28th days. Rats were killed on the 28th day and survival dopaminergic neurons in the substantia nigra, dopaminergic axons and dopaminergic receptor 2 in the striatum were examined. We, for the first time, demonstrated that post treatment with G-CSF reduced abnormal rotational behavior and increased the lesion to non-lesion ratio of dopaminergic fibers in the striatum, but the treatment promoted neither the increase in survival dopaminergic neurons nor the increase in dopaminergic receptor 2 expression. We conclude that post treatment with G-CSF can reduce the abnormal rotational behavior of severe PD rats primarily through relative increases in dopaminergic fibers of the lesion side in the striatum. Results of our study suggest therapeutic potentials of G-CSF for treating severe PD patients. PMID- 23656217 TI - Role of KCa3.1 channels in proliferation and migration of vascular smooth muscle cells by diabetic rat serum. AB - Proliferation and migration of vascular smooth muscle cells (VSMCs) are important events in the development of diabetic atherosclerosis. Previous studies have suggested that K(Ca)3.1 channels participate in atherosclerosis and coronary artery restenosis. In the present study, we attempted to clarify the roles of K(Ca)3.1 channels in the proliferation and migration of VSMCs using experimental type-2 diabetes rat serum and aortic smooth muscle cells (SMC) prepared from non diabetic rats. mRNA and protein levels and current density of K(Ca)3.1 channels were greatly enhanced in cultured VSMCs treated with diabetic serum. In addition, diabetic serum promoted cell proliferation and migration in cultured VSMCs, and the effects were fully reversed in the cells treated with the K(Ca)3.1 channels blocker TRAM-34. In conclusion, serum from diabetic rats increases the expression of K(Ca)3.1 channels and promotes proliferation and migration of VSMCs to possibly participate in vascular remodeling in diabetes. PMID- 23656218 TI - Comparative proteomic analysis of rodent plasma and mesenteric lymph. AB - The lymph has long been considered as the plasma filtrate and the proteomes of the lymph have received scanty attention. Currently, mesenteric lymph is reported to play an important role in the pathogenesis of multiple organ dysfunction syndrome in some critical illnesses. A better understanding of the composition and proteomes of mesenteric lymph becomes imperative to disclose the mechanistic role of mesenteric lymph. Seven male Sprague-Dawley rats were fasted overnight, and anesthetized to collect plasma and mesenteric lymph. The specimens were subjected to proteomic analysis using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). An average of 434 and 412 protein spots were found in the gels of the plasma and mesenteric lymph respectively. Peptide mass fingerprint analysis identified 77 proteins for 212 protein spots. The 2-DE proteomic pattern of mesenteric lymph was largely similar to that of the plasma. As in the plasma, large protein spots of albumin dominated the protein pattern in mesenteric lymph. Other major proteins identified in 2-DE gels included immunoglobulin heavy and light chains, fibrinogen alpha-, beta- and gamma-chains, serotransferrin, protease inhibitors, kininogens, macroglobulins, haptoglobin, and apolipoproteins. Meanwhile, mesenteric lymph contained an array of proteins that differentiated it from the plasma. The most differentially expressed proteins in mesenteric lymph were gamma-fibrinogen, protease inhibitors, and proteins related to lipid transport/metabolism. The study presents a detailed description of mesenteric lymph proteomes of a common experimental animal in physiological status using a common proteomic approach. These results provide the basis for future research. PMID- 23656219 TI - Suppression of TLR-4-related inflammatory pathway and anti-fibrosis effects of probiotic-fermented purple sweet potato yogurt in hearts of spontaneously hypertensive rats. AB - Inflammation plays an important role in triggering fibrosis of cardiovascular disease and hypertension. Gamma-aminobutyric acid (GABA) has hypotensive effect; GABA concentration could be enhanced in milk fermented with lactic acid bacteria (LAB). This study evaluated the effect of probiotic-fermented purple sweet potato yogurt (PSPY) on the toll-like receptor 4 (TLR-4)-related inflammatory components, and on fibrosis in the heart of spontaneously hypertensive rat (SHR). TLR4-related pathway and fibrosis-associated proteins TGFbeta and FGF2 were significantly increased in SHR hearts, but were highly suppressed in 10% PSPY-fed rats. Microscopic examination with Masson trichrome staining of left ventricle further demonstrated that 10% and 100% PSPY both significantly reduced interstitial fibrosis in SHR hearts. These findings indicated that oral administration of 10% probiotic-fermented PSPY was strong enough to lower cardiac fibrosis in SHR rats through the suppression of TLR-4-related inflammatory pathway. Therefore, PSPY may be included in diets to help prevent cardiac fibrosis in patients with hypertension. PMID- 23656220 TI - Effects of vitexin on scopolamine-induced memory impairment in rats. AB - Various synthetic derivatives of natural flavonoids are known to have neuroactive properties. The present study aimed to investigate the effects of vitexin (5, 7, 4-trihydroxyflavone-8-glucoside), a flavonoid found in such plants as tartary buckwheat sprouts, wheat leaves phenolome, Mimosa pudica Linn and Passiflora spp, on scopolamine-induced memory impairment in rats. To achieve this goal, we assessed the effects of vitexin on memory retrieval in the presence or absence of scopolamine using a step-through passive avoidance trial. In the first part of the study, vitexin (25, 50, and 100 microM) was administered intracerebroventricularly (i.c.v.) before acquisition trials. In the second part, vitexin, at the same doses, was administered before scopolamine (10 microg, i.c.v.) and before the acquisition trials. During retention tests, vitexin (100 microM) in the absence of scopolamine significantly increased the step-through latencies compared to scopolamine. In addition, vitexin (100 microM) significantly reversed the shorter step-through latencies induced by scopolamine (P < 0.05). These results indicate that vitexin has a potential role in enhancing memory retrieval. A possible mechanism is modulation of cholinergic receptors; however, other mechanisms may be involved in its effects in acute exposure. PMID- 23656221 TI - Late postcardiotomy sternal dehiscence: a simple approach using Stratos(r) system. AB - Management of late sternal dehiscence is challenging and time consuming. Although numerous techniques exist including rewiring and titanium plates screwing to stabilize the sternum, we describe an alternative technique by using four titanium clips and one connecting bar. PMID- 23656222 TI - Discussing Occupy Wall Street on Twitter: longitudinal network analysis of equality, emotion, and stability of public discussion. AB - To evaluate the quality of public discussion about social movements on Twitter and to understand the structural features and evolution of longitudinal discussion networks, we analyze tweets about the Occupy Wall Street movement posted over the course of 16 days by investigating the relationship between inequality, emotion, and the stability of online discussion. The results reveal that (1) the discussion is highly unequal for both initiating discussions and receiving conversations; (2) the stability of the discussion is much higher for receivers than for initiators; (3) the inequality of online discussions moderates the stability of online discussions; and (4) on an individual level, there is no significant relationship between emotion and political discussion. The implications help evaluate the quality of public discussion, and to understand the relationship between online discussion and social movements. PMID- 23656223 TI - Sulfur-doped graphene via thermal exfoliation of graphite oxide in H2S, SO2, or CS2 gas. AB - Doping of graphene with heteroatoms is an effective way to tailor its properties. Here we describe a simple and scalable method of doping graphene lattice with sulfur atoms during the thermal exfoliation process of graphite oxides. The graphite oxides were first prepared by Staudenmaier, Hofmann, and Hummers methods followed by treatments in hydrogen sulfide, sulfur dioxide, or carbon disulfide. The doped materials were characterized by scanning electron microscopy, high resolution X-ray photoelectron spectroscopy, combustible elemental analysis, and Raman spectroscopy. The zeta-potential and conductivity of sulfur-doped graphenes were also investigated in this paper. It was found that the level of doping is more dramatically influenced by the type of graphite oxide used rather than the type of sulfur-containing gas used during exfoliation. Resulting sulfur-doped graphenes act as metal-free electrocatalysts for an oxygen reduction reaction. PMID- 23656224 TI - Metabolic engineering and synthetic biology in strain development. PMID- 23656227 TI - From fields to fuels: recent advances in the microbial production of biofuels. AB - Amid grave concerns over global climate change and with increasingly strained access to fossil fuels, the synthetic biology community has stepped up to the challenge of developing microbial platforms for the production of advanced biofuels. The adoption of gasoline, diesel, and jet fuel alternatives derived from microbial sources has the potential to significantly limit net greenhouse gas emissions. In this effort, great strides have been made in recent years toward the engineering of microorganisms to produce transportation fuels derived from alcohol, fatty acid, and isoprenoid biosynthesis. We provide an overview of the biosynthetic pathways devised in the strain development of biofuel-producing microorganisms. We also highlight many of the commonly used and newly devised engineering strategies that have been employed to identify and overcome pathway bottlenecks and problems of toxicity to maximize production titers. PMID- 23656228 TI - Synthetic biology and metabolic engineering. AB - Metabolic engineering emerged 20 years ago as the discipline occupied with the directed modification of metabolic pathways for the microbial synthesis of various products. As such, it deals with the engineering (design, construction, and optimization) of native as well as non-natural routes of product synthesis, aided in this task by the availability of synthetic DNA, the core enabling technology of synthetic biology. The two fields, however, only partially overlap in their interest in pathway engineering. While fabrication of biobricks, synthetic cells, genetic circuits, and nonlinear cell dynamics, along with pathway engineering, have occupied researchers in the field of synthetic biology, the sum total of these areas does not constitute a coherent definition of synthetic biology with a distinct intellectual foundation and well-defined areas of application. This paper reviews the origins of the two fields and advances two distinct paradigms for each of them: that of unit operations for metabolic engineering and electronic circuits for synthetic biology. In this context, metabolic engineering is about engineering cell factories for the biological manufacturing of chemical and pharmaceutical products, whereas the main focus of synthetic biology is fundamental biological research facilitated by the use of synthetic DNA and genetic circuits. PMID- 23656229 TI - Modification-free photocontrol of beta-lactam conversion with spatiotemporal resolution. AB - beta-Lactams can be converted into beta-amino acids by beta-lactamase, a bacterial enzyme, leading to significant change in the biological function of the substrate molecules. Here we describe a method for photocontrol of beta-lactam conversion without gene nor enzyme modification. This is achieved by the addition of a cationic photosensitive surfactant, AzoTAB, to a gene expression medium containing DNA coding for beta-lactamase, the enzyme capable of the desired conversion. In the absence of UV (365 nm) or after illumination by blue light (480 nm) for 4 min, conversion of beta-lactam is strongly reduced while the application of UV for 4 min results in a strong enhancement of substrate conversion. Several cycles of activation/inhibition are obtained upon successive UV/blue light illuminations. When both reconstituted photoresponsive gene expression medium and beta-lactamase substrate are encapsulated in independent microfluidic chambers, selective UV illumination results in spatially resolved activation of substrate conversion. PMID- 23656230 TI - Rational design of Escherichia coli for L-isoleucine production. AB - Metabolic engineering of Escherichia coli was performed to construct a 100% rationally engineered strain capable of overproducing L-isoleucine, an important branched-chain amino acid. The thrABC (encoding L-threonine biosynthetic enzymes), ilvA (encoding feedback-resistant threonine dehydratase), ilvIH (encoding feedback-resistant acetohydroxy acid synthase III), and ygaZH (encoding branched-chain amino acid exporter) genes were amplified by plasmid-based overexpression. The ilvCED (encoding L-isoleucine biosynthetic enzymes) and lrp (encoding global regulator Lrp) genes were also amplified by chromosomal promoter replacement in order to further increase the flux toward L-isoleucine. The final engineered E. coli strain was able to produce 9.46 g/L of L-isoleucine with a yield of 0.14 g/g of glucose by fed-batch culture. The overall design principles described here for the production of highly regulated product should be useful in designing strains for the production of other similar bioproducts. PMID- 23656231 TI - A synthetic biology approach to engineer a functional reversal of the beta oxidation cycle. AB - While we have recently constructed a functional reversal of the beta-oxidation cycle as a platform for the production of fuels and chemicals by engineering global regulators and eliminating native fermentative pathways, the system-level approach used makes it difficult to determine which of the many deregulated enzymes are responsible for product synthesis. This, in turn, limits efforts to fine-tune the synthesis of specific products and prevents the transfer of the engineered pathway to other organisms. In the work reported here, we overcome the aforementioned limitations by using a synthetic biology approach to construct and functionally characterize a reversal of the beta-oxidation cycle. This was achieved through the in vitro kinetic characterization of each functional unit of the core and termination pathways, followed by their in vivo assembly and functional characterization. With this approach, the four functional units of the core pathway, thiolase, 3-hydroxyacyl-CoA dehydrogenase, enoyl-CoA hydratase/3 hydroxyacyl-CoA dehydratase, and acyl-CoA dehydrogenase/trans-enoyl-CoA reductase, were purified and kinetically characterized in vitro. When these four functional units were assembled in vivo in combination with thioesterases as the termination pathway, the synthesis of a variety of 4-C carboxylic acids from a one-turn functional reversal of the beta-oxidation cycle was realized. The individual expression and modular construction of these well-defined core components exerted the majority of control over product formation, with only highly selective termination pathways resulting in shifts in product formation. Further control over product synthesis was demonstrated by overexpressing a long chain thiolase that enables the operation of multiple turns of the reversal of the beta-oxidation cycle and hence the synthesis of longer-chain carboxylic acids. The well-defined and self-contained nature of each functional unit makes the engineered reversal of the beta-oxidation cycle "chassis neutral" and hence transferrable to the host of choice for efficient fuel or chemical production. PMID- 23656233 TI - Unusual patterns in 15N blood values after a diet switch in red knot shorebirds. AB - When a diet switch results in a change in dietary isotopic values, isotope ratios of the consumer's tissues will change until a new equilibrium is reached. This change is generally best described by an exponential decay curve. Indeed, after a diet switch in captive red knot shorebirds (Calidris canutus islandica), the depletion of (13)C in both blood cells and plasma followed an exponential decay curve. Surprisingly, the diet switch with a dietary (15)N/(14)N ratio (delta(15)N) change from 11.4 to 8.8 0/00 had little effect on delta(15)N in the same tissues. The diet-plasma and diet-cellular discrimination factors of (15)N with the initial diet were very low (0.5 and 0.2 0/00, respectively). delta(15)N in blood cells and plasma decreased linearly with increasing body mass, explaining about 40 % of the variation in delta(15)N. delta(15)N in plasma also decreased with increasing body-mass change (r (2)=.07). This suggests that the unusual variation in delta(15)N with time after the diet switch was due to interferences with simultaneous changes in body-protein turnover. PMID- 23656232 TI - Genetic circuit performance under conditions relevant for industrial bioreactors. AB - Synthetic genetic programs promise to enable novel applications in industrial processes. For such applications, the genetic circuits that compose programs will require fidelity in varying and complex environments. In this work, we report the performance of two synthetic circuits in Escherichia coli under industrially relevant conditions, including the selection of media, strain, and growth rate. We test and compare two transcriptional circuits: an AND and a NOR gate. In E. coli DH10B, the AND gate is inactive in minimal media; activity can be rescued by supplementing the media and transferring the gate into the industrial strain E. coli DS68637 where normal function is observed in minimal media. In contrast, the NOR gate is robust to media composition and functions similarly in both strains. The AND gate is evaluated at three stages of early scale-up: 100 mL shake flask experiments, a 1 mL MTP microreactor, and a 10 L bioreactor. A reference plasmid that constitutively produces a GFP reporter is used to make comparisons of circuit performance across conditions. The AND gate function is quantitatively different at each scale. The output deteriorates late in fermentation after the shift from exponential to constant feed rates, which induces rapid resource depletion and changes in growth rate. In addition, one of the output states of the AND gate failed in the bioreactor, effectively making it only responsive to a single input. Finally, cells carrying the AND gate show considerably less accumulation of biomass. Overall, these results highlight challenges and suggest modified strategies for developing and characterizing genetic circuits that function reliably during fermentation. PMID- 23656234 TI - Radiographic outcomes of transcrestal sinus floor elevation performed with a minimally invasive technique in smoker and non-smoker patients. AB - OBJECTIVES: To evaluate the association between smoking status and the outcomes of transcrestal sinus floor elevation (tSFE) performed with a minimally invasive technique (Smart Lift). METHODS: Forty-five implants were placed in 25 non-smoker (NS) and 20 smoker (S) patients in conjunction with the tSFE procedure. In all cases, an additional graft, chosen among different hydroxyapatite-based or beta tricalcium phosphate-based biomaterials, was pushed into the sinus by gradual increments. Immediately after surgery, residual bone height, implant penetration into the sinus, extent of sinus lift (SL) and the height of the graft apical to the implant apex (aGH) were assessed on periapical radiographs. At 6 months after surgery, SL and aGH were reassessed. RESULTS: (i) The Smart Lift procedure resulted in substantial 6-month SL and aGH in both treatment groups; (ii) smoking status did not significantly affect the 6-month radiographic outcomes; (iii) a similarly low incidence of intra- and postoperative complications was observed in NS and S patients. CONCLUSIONS: Smoking has a limited impact on the outcomes of tSFE performed with the Smart Lift technique. PMID- 23656235 TI - Reporting medical research. AB - Accurate, complete and timely publication of research studies is an integral part of a responsible research conduct. Following the reporting guidelines helps in preparing high quality research papers, facilitates peer review, and increases the chances of paper acceptance by a suitable journal. The EQUATOR Network website (www.equator-network.org) provides a collection of reporting guidelines and other resources helping researchers to publish their research studies. PMID- 23656236 TI - Monitoring of ractopamine concentration in the mixture of this feed additive with vitamin mineral complex and with swine feed by HPLC. AB - Ractopamine (RAC) analysis at all stages in the feed chain until its final mixing into swine feed is necessary to ensure the safety of all meat consumers and to decrease waste and the cost of supplementation of feed. Two suitable HPLC methods were developed and validated for RAC determination in vitamin mineral complex (VMC) and in swine feed. Both methods employed reverse-phase (C18 column at 40 degrees C) and isocratic elution, but with some modifications to the methods. Validation parameters, such as selectivity, linearity, precision, trueness and robustness, were shown to be within the acceptable range. Therefore, the developed methods can be successfully applied for the monitoring of RAC concentrations in samples of VMC and swine feed ensuring economy to producers and security to consumers of swine meat. PMID- 23656237 TI - Simulation and continued competence: getting better at what we need to be. PMID- 23656238 TI - Evaluating continuing education: options abound. AB - Many providers of continuing education activities perceive that there is a required evaluation form that must be completed by learners at the end of the learning activity. Although this is one approach to collecting evaluation data, it is by no means the only way. This column suggests several strategies that can be used to evaluate learning activities. PMID- 23656239 TI - Fostering healthy work environments through nursing education initiatives. AB - In this era of value-based health care, the knowledge, competence, and professionalism of the front-line nurse and other clinical staff are paramount. Everyone involved in patient care must maximize their skill set and drive high performance in the clinical arena. Healthy work environments will be key to achieving and sustaining quality outcomes and developing and retaining high performing teams. PMID- 23656240 TI - Improving cultural knowledge through a culturally themed nursing skills day. AB - A culturally themed nursing skills day is a fun, engaging way for nurses to learn how to provide culturally sensitive patient care. PMID- 23656242 TI - Donor-specific tolerance induction in organ transplantation via mixed splenocytes chimerism. AB - We have shown previously that donor-derived splenocytes can replace recipients' bone marrow and induce donor-specific tolerance (DST). We have also shown the usefulness of the chimeric state for the induction of DST. Further analysis of mixed splenocytes chimera, especially the role of each T cells in mixed splenocytes chimera, is indispensable issue for its clinical use. A chimeric state has been shown to achieve long-term survival in major histocompatibility complex (MHC)-mismatched grafts. The donor-derived splenocytes can replace recipients' bone marrow and induce DST. The long-term survival of allogeneic skin grafts was achieved without immunosuppressants. In this study we show the role of each T cell type in a splenocyte mixed chimera. This review provides a short summary of our original work, adding some supplemental interpretations. Mixed chimerism is thus considered an attractive approach for the induction of DST without the use of immunosuppressants. In this paper, we summarize some of the findings on mixed splenocyte chimeras and review mixed chimerism in recent organ transplantation. PMID- 23656243 TI - PPAR-gamma and tollip are associated with toll-like receptors in colitis rats. AB - To elucidate the significance of Toll-like receptors and their negative regulating factors PPAR-gamma and Tollip on the pathogenesis of colitis. Colitis model was induced by TNBS in rat. The expression of TLR2, TLR4, NF-kappaBp65, PPAR-gamma and Tollip was examined by immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR). RT-PCR revealed a significant increased expression of TLR2, TLR4, and NF-kappaBp65 in the colitis group compared with the normal group (TLR2: 1.057 +/- 0.092, 0.463 +/- 0.101, t = 4.125, P = 0.001; TLR4: 0.376 +/- 0.029, 0.215 +/- 0.049, t = 2.731, P = 0.013; NF-kappaBp65: 0.746 +/- 0.049, 0.206 +/- 0.063, t = 6.055, P = 0.000). The expression was positively correlated with the generally damage score and the histological injury score correspondingly (TLR2: r = 0.573, r = 0.559; TLR4: r = 0.754, r = 0.866; NF-kappaBp65: r = 0.548, r = 0.919). The Tollip mRNA wasn't obviously diversity between the normal and colitis groups by RT-PCR (Tollip: 0.288 +/- 0.050, 0.140 +/- 0.046, t = 1.993, P = 0.061). While the Tollip protein was mainly assembled in the lamina propriaand higher in the colitis group compared with the normal group by IHC. The expression of PPAR-gamma in the colitis group was obviously lower than that in the normal group (PPAR-gamma: 0.255 +/- 0.065, 0.568 +/- 0.072, t = 2.882, P = 0.010). The expression of Tollip and PPAR-gamma was negative correlated with the generally damage score and histological injury score correspondingly (Tollip: r = -0.497, r = -0.551; PPAR gamma: r = -0.683, r = -0.853). The disbalance between TLRs and their negative regulating factors PPAR-gamma and Tollip was closely associated with the course of colitis. PMID- 23656244 TI - Muc1/Cd227 immunohistochemistry in routine practice is a useful biomarker in breast cancers. AB - Over-expression of MUC1/CD227 is observed in 90% of breast tumors. Classical morphologic description and semi-quantitative digital measurement of MUC1 were performed from immunohistochemical stained slides of 123 routine histological samples. Measures of MUC1 expression showed statistical differences between non tumoral (NT) breast tissue and Ductal Carcinoma In Situ (DCIS) or infiltrating carcinoma (IC), p < 0.0001. Loss of MUC1 was correlated with high Ki67 index (p = 0.001) and loss of hormonal receptors (p = 0.03), whereas no correlations were found with HER2 expression. High-grade DCIS or IC showed increasing loss of apical polarised and cytoplasmic expression of MUC1. PMID- 23656245 TI - Immunoextraction of testosterone and epitestosterone from human urine sample based on polyamidoamine modified silica. AB - Polyamidoamine dendrimer (PAMAM) is one of a number of dendritic polymers with precise molecular structure, highly geometric symmetry, and a large number of terminal groups. The polyamidoamine modified silica was synthesized with microwave assisted protocol. Anti-epitestosterone monoclonal antibodies were immobilized onto the PAMAM grafted silica and prepared an off-line immunoextraction column that applied in the extraction of testosterone and epitestosterone. The results showed that the affinity activity of the anti epitestosterone monoclonal antibodies was remained at high level after immobilization. It was satisfactory to apply this new type of immunoextraction column to analyze testosterone and epitestosterone in spiked urine sample. PMID- 23656246 TI - Detection of anticardiolipin antibody igm by sm(3+)-labeled time-resolved fluoroimmunoassay. AB - In an effort to improve the quantitative detection of aCL IgM, we develop a new immunoassay to improve aCL IgM detection based on TRFIA using the complex of cardiolipin plus bovine beta2GPI as antigen and Sm(3+)-labeled rabbit anti-human IgM as conjugate. The precision, sensitivity, specificity, coefficient of recovery, and stability of the assay were evaluated and comparison with the classical ELISA was also made. The aCL IgM TRFIA kit we established had a wider detectable range than commercial ELISA ones when diluted a specimen with strong positive from 1:2.5-1:40960. We observed that for the established TRFIA kit there was a good liner range within 1:2.5-1:40960, whereas it was within 1:20-1:1280 when using ELISA kits. The intraassay precision rate and the interassay precision rate were <5% for 3 different concentrations. The sensitivity was 0.1MPL U/mL and the clinical diagnostic specificity was 98%. Average recovery rate was 101.13%. The established assay kit also behaved better in stability. Additionally, the immunoassay we established correlated well with the ELISA and the correlation coefficient was 0.956. We thus conclude that the TRFIA we developed for aCL IgM detection gives promise to a more sensitivity and reliable diagnosis of APS and has potential value for large-scale screening programs. PMID- 23656247 TI - Influence of different cell storage/culture conditions on spontaneous proliferation and level of tyrosine kinase receptor inhibition in two feline injection-site sarcoma cell lines. AB - Optimizing cell culture conditions is important when studying cell proliferation and viability, particularly in response to cytotoxic compounds. Altered cell storage conditions can adversely impact proliferation and viability in mortal cell lines. However, little is known regarding the effects on immortal feline cell lines. In the present study, two feline injection-site sarcoma (ISS) cell lines were evaluated under standard culture conditions and three alternative storage/culture conditions for spontaneous proliferation rate and sensitivity to masitinib, a highly selective tyrosine kinase inhibitor with activity against primary and metastatic ISS cell lines. Cell viability was assessed by 7 aminoactinomycin D and cytology. Spontaneous proliferation did not significantly differ across the FBS concentrations (10% vs. 1%) for one cell line, however, with the other cell line spontaneous proliferation was significantly decreased in the 1% FBS 1-step technique, and the cold step technique at both 1% and 10% FBS. When normalized to untreated control cells, the IC50 values for masitinib were comparable across all culture techniques. Furthermore, apoptosis appeared to be the primary mechanism of this proliferation inhibition. Our preliminary findings suggest that select feline sarcoma cell lines cultured in 10% FBS yield comparable cytotoxicity data even when subjected to varying storage/culture conditions. PMID- 23656248 TI - Characterization of serum immunoglobulin in channa striata (BLOCH) and kinetics of its response to Aeromonas hydrophila antigen. AB - The immunoglobulin (Ig) from the serum of Channa striata was isolated by gel electroelution and characterized further to understand its nature and subsequent applications in studying the immune response. The purity of the sample was confirmed with the presence of a single band on native gradient PAGE and the molecular weight of ~897 kDa was determined from the gel. In SDS-PAGE, C. striata Ig was reduced to produce two bands corresponding to H (heavy) (~72 kDa) and L (light) (~27 kDa) chain subunits. Polyclonal antiserum against the purified Ig was raised in a rabbit and adsorbed with 10% liver tissue homogenate of C. striata to enhance its specificity. By an indirect ELISA standardized using the adsorbed rabbit antiserum, the normal serum Ig concentration in C. striata was estimated to be 3.48 mg/mL. Further, a kinetic study of specific immunoglobulin response to formalin-killed Aeromonas hydrophila antigen was undertaken using another indirect ELISA, which showed a significant increase in serum immunoglobulin titer from day 2 onwards and reached its peak at day 14. Subsequently, the Ig titer was dropped from day 21 onwards till the completion of the experiment at day 42, although it was at a significantly higher level than the control. PMID- 23656249 TI - Serum programmed cell death protein 5 (PDCD5) levels is upregulated in liver diseases. AB - Intracellular protein molecules are detected in the blood following release from damaged cells. PDCD5 is widely expressed in most types of normal human tissue and is unregulated in cells undergoing apoptosis. It is therefore hypothesized that release of PDCD5 into the circulation might be a specific marker of apoptosis. In this study, a sandwich ELISA was developed for quantification of soluble PDCD5 protein and used to investigate serum PDCD5 levels in liver diseases. The highest levels of PDCD5 were detected in acute icteric hepatitis (AIH) patients compared with normal subjects and other detected liver diseases, such as chronic active hepatitis B (CAHB), chronic persistent hepatitis B (CPHB) and and liver cirrhosis (LC). Increased PDCD5 levels correlated well with ALT and AST in AIH and CAHB patients. In patients with CPHB, increased PDCD5 levels correlated well with AST, TBI, DBIL, and IBIL. In LC patients, PDCD5 levels correlated well with AST/ALT and DBIL. More importantly, increased PDCD5 levels were also observed in patients with normal ALT or AST levels. These data demonstrate a correlation between increased levels of PDCD5 in serum and liver disease progression and indicate the potential utility of serum PDCD5 as a biomarker for monitoring liver injury. PMID- 23656250 TI - Comparison of in-house developed ELISA with HPLC for measurement of hba1c. AB - In-house developed ELISA for HbA1c was evaluated in comparison with Bio-Rad D-10 Dual Program (HPLC). % HbA1c was estimated using said methods in 40 blood samples. Intra and inter assay coefficient of variation (CV) were in acceptable range i.e., <3%. HbA1c results obtained by two methods showed good correlation, (y = 0.8942x + 0.7229 R2 = 0.877). Sensitivity, specificity, positive, and negative predictive value for in-house ELISA classifying patients as controlled and uncontrolled diabetes against HPLC were recorded as 87%, 94.1%, 95.0%, and 93.8%, respectively, while accuracy of the test was 90.0%. In-house ELISA for HbA1c is not only accurate, cost effective and simple but also precise comparable to HPLC in deciding glycemic status of patients. PMID- 23656252 TI - A theory of macromolecular chemotaxis. AB - A macromolecule in a gradient of a cosolute that is preferentially (relative to the solvent) either attracted to or excluded from the domain of the macromolecule should experience a thermodynamic force and move, respectively, up or down the gradient. A theory of chemotactic forces arising from such preferential interactions, especially short-range ligand binding and excluded volume interactions, is developed via an extension of Kirkwood-Buff theory. The ligand binding result is confirmed for both non-ionic and ionic cosolutes by standard solution thermodynamics. The effect of increasing the electrolyte concentration to diminish the electrostatic free energy of a charged macromolecule is also treated formally via an electrostatic macromolecule-electrolyte preferential interaction coefficient. For short-range interactions, the induced chemotactic velocity is attributed entirely to tangential tractions at the interface between the macromolecule and its surrounding solution. The velocity of a spherical macromolecule driven by such tractions is derived by a hydrodynamic calculation for steady-state creepy flow with a partial slip boundary condition. Qualitative comparisons of theoretical predictions with experimental observations of Zheng and Pollack pertaining to charged microspheres near the surfaces of non-ionic gels suggest that the reported exclusion zones are due to chemotaxis induced by gradients of base (NaOH) (or acid (HCl)) and salt. With a single adjustable parameter, namely, the ratio of slip length to area per surface carboxyl (or amidine) group, this theory yields nearly quantitative agreement with many observations. The estimated slip length for the microspheres is comparable to that obtained for bovine serum albumen by fitting the chemotactic theory to two reported cross-diffusion coefficients. When a solution with a gradient of NaOH is placed in contact with a smooth glass wall, chemotactic surface tractions are predicted to cause convection of the solution toward the acidic end of the gradient, as observed in preliminary experiments. PMID- 23656251 TI - Maximizing the impact of HIV prevention efforts: interventions for couples. AB - Despite efforts to increase access to HIV testing and counseling services, population coverage remains low. As a result, many people in sub-Saharan Africa do not know their own HIV status or the status of their sex partner(s). Recent evidence, however, indicates that as many as half of HIV-positive individuals in ongoing sexual relationships have an HIV-negative partner and that a significant proportion of new HIV infections in generalized epidemics occur within serodiscordant couples. Integrating couples HIV testing and counseling (CHTC) into routine clinic- and community-based services can significantly increase the number of couples where the status of both partners is known. Offering couples a set of evidence-based interventions once their HIV status has been determined can significantly reduce HIV incidence within couples and if implemented with sufficient scale and coverage, potentially reduce population-level HIV incidence as well. This article describes these interventions and their potential benefits. PMID- 23656253 TI - Physiological focus on the erythropoietin-hepcidin-ferroportin axis. AB - To analyze the interconnection between erythropoiesis and iron metabolism, one of the issues raised in this study was to know iron bioavailability under physiopathological conditions. Our aim was to understand the functional axis response composed of erythropoietin (Epo)-hepcidin-ferroportin (FPN), when 2 dysfunctional states coexist, using an animal model of iron overload followed by hypoxia. FPN and prohepcidin were assessed by immunohistochemistry using rabbit anti-mouse FPN polyclonal and prohepcidin monoclonal antibodies. Goat-labeled polymer - horseradish peroxidase anti-rabbit EnVision + System (DAB) was used as the secondary antibody. Epo levels were measured by ELISA. Tissue iron was studied by Prussian blue iron staining. Erythropoietic response was assessed using conventional hematological tests. Iron overload increased prohepcidin that remained high in hypoxia, coexisting with high levels of Epo in hypoxia, with or without iron overload. In hypoxia, FPN was clearly evident in reticuloendothelial macrophages, more than in hypoxia with iron overload. Interestingly, duodenal FPN was clearly identified on the basolateral membrane in hypoxia, with or without iron overload. Our data indicate that 2 signals could induce the cell-specific response as follows: (i) iron signal, induced prohepcidin, which reduced reticuloendothelial FPN and reduced iron availability; and (ii) hypoxia signal, stimulated Epo, which affected iron absorption by stabilizing duodenal FPN and allowed iron supply to erythropoiesis independently of store size. PMID- 23656254 TI - Factors contributing to posttraumatic growth and its buffering effect in adult children of cancer patients undergoing treatment. AB - This study examined relationships among demographic, clinical, and psychosocial variables in adult children of cancer patients. Two hundred and fourteen participants completed measures of posttraumatic growth (PTG), distress, posttraumatic stress disorder (PTSD) symptoms, social support, and family functioning. Significant gender differences in all PTG dimensions were found, as well as associations among PTG, gender, parental dependency, distress, PTSD, and family functioning. Social support was not a mediator in the relationship between gender and PTG. Gender, education, disease duration, dependency, distress, and family flexibility predicted PTG. Finally, PTG had a moderating effect in the relationship between distress and PTSD/social support. These results may guide psychosocial interventions in this population. PMID- 23656255 TI - Cognitive adaptation theory and quality of life in late-stage cancer patients. AB - In this study, the question of whether using slightly illusionary, positive attributions of self, control, and meaning (e.g., cognitive adaptation theory), in the face of disconfirmatory evidence, facilitates quality of life in late stage cancer patients was examined. Eighty late-stage cancer patients (Mean age = 59.7, SD = 12.5; 48.8% male, 51.2% female; varying cancer diagnoses) who recently failed or refused first line anti-neoplastic treatment completed questionnaires assessing meaning, control, self-esteem, and optimism, as well as physical and psychological quality of life. Findings suggest that greater self-esteem, control, and meaning predicted physical and psychological quality of life, with physical quality of life being influenced by control beliefs and psychological quality of life influenced by self-esteem. Optimism independently predicted physical quality of life and neither mediated nor moderated the relationship between cognitive adaptation and quality of life. Findings suggest that slightly positive, illusionary beliefs of self, control, and meaning predicted quality of life even in the presence of clear, disconfirmatory environmental evidence. PMID- 23656256 TI - Psychosocial adjustment and marital intimacy among partners of patients with breast cancer: a comparison study with partners of healthy women. AB - This cross-sectional study investigated the psychosocial adjustment of 70 partners of patients with breast cancer by comparing their emotional adjustment and quality of life (QoL) with 70 partners of women without cancer. The role of marital intimacy in their adjustment and the moderating effect of group type were analyzed. The partners of patients with breast cancer presented higher levels of anxious and depressive symptomatology; poor social, psychological, general and physical QoL; and higher levels of intimacy. The moderation analysis showed that higher levels of intimacy predicted lower levels of depression and anxiety and greater QoL only among the partners of cancer patients. PMID- 23656258 TI - Psychosocial needs of rural survivors of cancer and their partners. AB - It is important to understand the psychosocial needs of rural survivors of cancer to better serve this group. Survivors and partners filled out a pre-tested survey addressing general and mental health, quality of life and demographics. Twenty nine survivors and 15 partners responded. Over 50% of both groups were at-risk for depression; 34% of the cancer survivors had some type of psychosocial problem requiring assistance. Areas to be targeted for psychosocial interventions for rural survivors include: management of side effects/complications of treatment; adjustment to changes in quality of life; emotional support; cancer impact on social relationships; uncertainty reduction. PMID- 23656257 TI - Racial differences in social support and coping among family caregivers of patients with prostate cancer. AB - More than 60 million Americans are informal caregivers to adults, which can negatively affect their health. Data from 126 White and 62 African American female caregivers in North Carolina were analyzed to describe social support and coping among family caregivers of patients with prostate cancer and to assess for racial differences. Social support amount and some coping methods differed by race. There was no racial difference in social support satisfaction. Borderline significant difference in social support by health status was found and this differed by race. These racial differences should be explored further to better understand the availability of caregiving resources and their health effects. PMID- 23656259 TI - Conditions that are significant for advanced cancer patients' coping with their suffering-as experienced by relatives. AB - As long as life could be lived as before patients could cope with their problems. But the progression of the illness challenged feelings and filled life with increasing levels of chaos and feelings of powerlessness. Relatives became involved quite late in the patients' interaction with the professionals, an interaction that was characterized by lack of continuity and the professionals' focus on the patient's sick body. It was therefore seldom that professionals had insight into the family's resources and need for professional support. This made it more difficult for the family to evaluate, control and cope with their suffering. Instead, patients gradually adapted to the professionals' and relatives' priorities and sometimes their control over the increasingly failing and dying body. PMID- 23656260 TI - Antiangiogenic nanotherapy for the control of obesity. PMID- 23656261 TI - Nanotechnology: a versatile aid in our fight against AIDS. PMID- 23656262 TI - Polymeric nanoparticulates for cancer immunotherapy. PMID- 23656263 TI - New circulating tumor cell technology could advance personalized medicine in prostate cancer. PMID- 23656264 TI - Nanoparticles and the blood coagulation system. Part I: benefits of nanotechnology. AB - Nanotechnology is proven to provide certain benefits in drug delivery by improving solubility, increasing uptake to target sites and changing pharmacokinetics profiles of traditional drugs. Since properties of many materials change tremendously at the nanoscale levels, nanotechnology is also being explored in various industrial applications. As such, nanoparticles are rapidly entering various areas of industry, biology and medicine. The benefits of using nanotechnology for industrial and biomedical applications are often tempered by concerns about the safety of these new materials. One such area of concern includes their effect on the immune system. While nanoparticle interactions with various constituents of the immune system have been reviewed before, little attention was given to nanoparticle effects on the blood coagulation system. Nanoparticle interface with the blood coagulation system may lead to either benefits to the host or adverse reactions. This article reviews recent advances in our understanding of nanoparticle interactions with plasma coagulation factors, platelets, endothelial cells and leukocytes. Part I is focused on desirable interactions between nanoparticles and the coagulation system, and discusses benefits of using nanotechnology to intervene in coagulation disorders. Undesirable interactions posing safety concerns are covered in part II, which will be published in the June issue of Nanomedicine. PMID- 23656265 TI - Nanomaterial-based sensors for detection of disease by volatile organic compounds. AB - The importance of developing new diagnostic and detection technologies for the growing number of clinical challenges is rising each year. Here, we present a concise, yet didactic review on a new diagnostics frontier based on the detection of disease-related volatile organic compounds (VOCs) by means of nanomaterial based sensors. Nanomaterials are ideal for such sensor arrays because they are easily fabricated, chemically versatile and can be integrated into currently available sensing platforms. Following a general introduction, we provide a brief description of the VOC-related diseases concept. Then, we focus on detection of VOC-related diseases by selective and crossreactive sensing approaches, through chemical, optical and mechanical transducers incorporating the most important classes of nanomaterials. Selected examples of the integration of nanomaterials into selective sensors and crossreactive sensor arrays are given. We conclude with a brief discussion on the integration possibilities of different types of nanomaterials into sensor arrays, and the expected outcomes and limitations. PMID- 23656266 TI - Nanotechnology tools for antibacterial materials. AB - The understanding of the interactions between biological systems and nanoengineered devices is crucial in several research fields, including tissue engineering, biomechanics, synthetic biology and biomedical devices. This review discusses the current knowledge of the interactions between bacteria and abiotic nanostructured substrates. First, the effects of randomly organized nanoscale topography on bacterial adhesion and persistence are described. Second, the interactions between microorganisms and highly organized/ordered micro- and nano patterns are discussed. Finally, we survey the most promising approaches for the fabrication of silver polymeric nanocomposites, which have important applications as antimicrobial materials. The advantages, drawbacks and limitations of such nanotechnologies are critically discussed in view of potential future applications. PMID- 23656267 TI - Biomimetic self-assembling peptides as scaffolds for soft tissue engineering. AB - Tissue engineered therapies are emerging as solutions to several of the medical challenges facing aging societies. To this end, a fundamental research goal is the development of novel biocompatible materials and scaffolds. Self-assembling peptides are materials that have undergone rapid development in the last two decades and they hold promise in meeting some of these challenges. Using amino acids as building blocks enables a great versatility to be incorporated into the structures that peptides form, their physical properties and their interactions with biological systems. This review discusses several classes of short self assembling sequences, explaining the principles that drive their self-assembly into structures with nanoscale ordering, and highlighting in vitro and in vivo studies that demonstrate the potential of these materials as novel soft tissue engineering scaffolds. PMID- 23656268 TI - Next-generation nanomedicines and nanosimilars: EU regulators' initiatives relating to the development and evaluation of nanomedicines. AB - Over the last three decades many first-generation nanomedicines have successfully entered routine clinical use and it is now important for medicines regulatory agencies to consider the mechanisms needed to ensure safe introduction of 'follow on' nanomedicine products, 'nanosimilars'. Moreover, drug regulators need to ensure that 'next'-generation nanomedicines enter clinical development and consequently the market in a safe and timely way for the benefit of public health. Here we review recent European Medicines Agency activities that relate to the effective development and evaluation of nanomedicine products while keeping patient and consumer safety at the forefront. PMID- 23656270 TI - Protocol variations in arm position influence the magnitude of waist girth. AB - Waist girth is recognised as a better predictor of obesity, particularly abdominal obesity, compared to other measures. Although several protocols for waist girth exist, arm position is either ignored, or not specified in unambiguous terms. Therefore, the purpose of this study was to determine if arm position influenced anthropometric waist girth measurement. Waist girth was measured in 92 adults (19 males, 73 females) with arms relaxed, abducted, horizontal, folded across the chest (three variations) and raised vertically. Duplicate measures, in all positions, were recorded by a single International Society for the Advancement of Kinanthropometry (ISAK)-trained technician to a precision of 0.2% technical error of measurement (TEM). Arm position had a significant effect (P < 0.001) on waist girth. Male participants had greater waist girth than females (P < 0.001) and the waist girth differences across the varying arm positions exhibited a significant position-by-gender interaction (P < 0.001). The arm position-by-body mass index (BMI) category interaction was also significant (P = 0.016) with greater differences observed at higher BMI. These findings suggest caution in comparing results of different studies where arm position is not specified and indicate that the arm position corresponding to the ISAK protocol has the lowest error and is therefore recommended. PMID- 23656271 TI - Long-term outcomes in patients with duodenal adenocarcinoma. AB - BACKGROUND: Because of the rarity of duodenal adenocarcinoma, little is known regarding its natural history or prognostic factors for survival. We therefore evaluated surgical treatment, and prognostic factors for survival in patients with duodenal adenocarcinoma. METHODS: We retrospectively reviewed the medical records of patients who were diagnosed with duodenal adenocarcinoma at Asan Medical Center between December 1999 and December 2009. RESULTS: Of the 76 patients, 47 (61%) underwent surgery with curative intent and 29 (39%) underwent palliative operation. Of the former, 25 underwent pancreaticoduodenectomy (PD), 19 underwent pylorus-preserving PD, 2 underwent segmental duodenectomy and 1 underwent transduodenal excision. The median survival of the 41 patients who achieved R0 resection was 25.1 months (range 4-134 months), with overall 1-, 3- and 5-year survival rates of 80.4%, 63.4% and 60.9%, respectively. Median survival was significantly longer in patients who underwent curative resection than in those who underwent palliative surgery (28.2 versus 6.6 months, P < 0.001). Univariate analysis showed that transfusion and lymph node metastasis were related to survival, and multivariate analysis revealed that lymph node metastasis was independently associated with survival (P = 0.036). Survival differences were observed between stages of the seventh edition of the American Joint Committee on Cancer staging system. CONCLUSION: In the absence of distant metastasis, curative resection enhances the long-term survival of patients with duodenal adenocarcinoma. Lymph node metastasis is prognostic factor of overall survival. PMID- 23656272 TI - Association of interleukin 18, interleukin 2, and tumor necrosis factor polymorphisms with subacute sclerosing panencephalitis. AB - Subacute sclerosing panencephalitis (SSPE) is a progressive inflammatory and degenerative disorder of the central nervous system. The measles virus (MV) and host and environmental factors are involved in the development of SSPE, but the precise mechanism by which the MV causes SSPE is still unknown. Studies have indicated that in SSPE patients, specific polymorphisms of certain genes are most likely involved in impairing the host's ability to eradicate the MV. The purpose of our study was to elucidate the role of polymorphisms in the genes encoding interleukin (IL)-2, IL-18, and tumor necrosis factor alpha (TNF-alpha) in the development of SSPE. Using the polymerase chain reaction with sequence-specific primers, the single-nucleotide polymorphisms (SNPs) of the promoter regions of IL 2 (-330), TNF-alpha (-308), and IL-18 (-137 and -607) were studied in 54 patients with SSPE and 72 healthy controls. The frequency of SSPE patients with the AA genotype of IL-18 at position -607 was significantly higher than the frequency of those with the CC genotype (p<0.001, odds ratio [OR]: 5.76), and a significantly higher proportion of patients had the C allele at -137 compared with the controls (p=0.002, OR: 2.72). In a haplotype analysis of two SNPs in the IL-18 gene, the frequency of the CA haplotype was significantly higher in SSPE patients (p<0.001, OR: 3.99) than in the controls. The IL-2 (-330) and TNF-alpha (-308) polymorphisms revealed no significant differences. In conclusion, these data suggest that the IL-18 gene polymorphisms at position -607 and -137 might be genetic risk factors for the SSPE disease. PMID- 23656273 TI - Fabrication of CuInTe2 and CuInTe(2-x)Se(x) ternary gradient quantum dots and their application to solar cells. AB - We report the first synthesis of colloidal CuInTe2, CuInTe2-xSex gradient alloyed quantum dots (QDs) through a simple hot injection method. We confirmed the composition of synthesized QDs to cationic rich phase of CuIn1.5Te2.5 and Cu0.23In0.36Te0.19Se0.22 with XPS and ICP analysis, and we have also found that the gradient alloyed Cu0.23In0.36Te0.19Se0.22 QDs exhibit greatly improved stability over the CuIn1.5Te2.5 QDs. The solution-processed solar cell based on the gradient alloyed Cu0.23In0.36Te0.19Se0.22 QDs exhibited 17.4 mA/cm(2) of short circuit current density (Jsc), 0.40 V of open circuit voltage (Voc), 44.1% of fill factor (FF), and 3.1% of overall power conversion efficiency at 100 mW/cm(2) AM 1.5G illumination. PMID- 23656274 TI - Speech, communication and use of augmentative communication in young people with cerebral palsy: the SH&PE population study. AB - BACKGROUND: Communication is frequently impaired in young people (YP) with bilateral cerebral palsy (CP). Important factors include motoric speech problems (dysarthria) and intellectual disability. Augmentative and Alternative Communication (AAC) techniques are often employed. The aim was to describe the speech problems in bilateral CP, factors associated with speech problems, current AAC provision and use, and to explore the views of both the parent/carer and young person about communication. METHODS: A total population of children with bilateral CP (n = 346) from four consecutive years of births (1989-1992 inclusive) with onset of CP before 15 months were reassessed at age 16-18 years. Motor skills and speech were directly assessed and both parent/carer and the young person asked about communication and satisfaction with it. RESULTS: Sixty had died, eight had other conditions, 243 consented and speech was assessed in 224 of whom 141 (63%) had impaired speech. Fifty-two (23% of total YP) were mainly intelligible to unfamiliar people, 22 (10%) were mostly unintelligible to unfamiliar people, 67 (30%) were mostly or wholly unintelligible even to familiar adults. However, 89% of parent/carers said that they could communicate 1:1 with their young person. Of the 128 YP who could independently complete the questions, 107 (83.6%) were happy with their communication, nine (7%) neither happy nor unhappy and 12 (9.4%) unhappy. A total of 72 of 224 (32%) were provided with one or more types of AAC but in a significant number (75% of 52 recorded) AAC was not used at home, only in school. Factors associated with speech impairment were severity of physical impairment, as measured by Gross Motor Function Scale level and manipulation in the best hand, intellectual disability and current epilepsy. CONCLUSIONS: In a population representative group of YP, aged 16-18 years, with bilateral CP, 63% had impaired speech of varying severity, most had been provided with AAC but few used it at home for communication. PMID- 23656275 TI - The use of high-dose insulin therapy and intravenous lipid emulsion to treat severe, refractory diltiazem toxicosis in a dog. AB - OBJECTIVE: To describe the novel use of high-dose insulin (HDI) therapy and intravenous lipid emulsion (ILE) to treat refractory, severe diltiazem toxicosis in a dog. CASE SUMMARY: A 4-year-old Pomeranian was presented for treatment 2.5 hours following ingestion of a diltiazem extended-release capsule. Toxic ingestion was calculated at a maximum exposure of 79 mg/kg, with a reported canine LD50 of 50 mg/kg. Clinical signs of progressive hypotension and severe bradycardia with atrial standstill were observed, which persisted despite treatment with atropine, calcium, glucagon, and dopamine. The novel use of HDI and ILE as part of therapy for diltiazem toxicosis resulted in clinical resolution of life-threatening signs. Within 1 hour of initiating HDI therapy, the clinical signs improved, and with continued treatment, the patient remained normotensive and survived to discharge. NEW OR UNIQUE INFORMATION PROVIDED: To the authors' knowledge, this is the first reported clinical case describing the use of both HDI and ILE therapy in the treatment of severe refractory diltiazem toxicosis in veterinary medicine. No significant adverse effects were observed from the treatment. In veterinary patients with severe refractory calcium channel blocker toxicosis, the use of HDI and ILE should be considered for life threatening clinical signs. PMID- 23656278 TI - Dimerization-dependent green and yellow fluorescent proteins. AB - Dimerization-dependent fluorescent proteins (ddFP) are a recently introduced class of genetically encoded reporters that can be used for the detection of protein interactions in live cells. The progenitor of this class of tools was a red fluorescent ddFP (ddRFP) derived from a homodimeric variant of Discosoma red fluorescent protein. Here, we describe the engineering and application of an expanded palette of ddFPs, which includes green (ddGFP) and yellow (ddYFP) variants. These optimized variants offer several advantages relative to ddRFP including increased in vitro contrast and brightness for ddGFP and increased brightness and a lowered pK a for ddYFP. We demonstrate that both variants are useful as biosensors for protease activity in live cells. Using the ddGFP tool, we generated a highly effective indicator of endomembrane proximity that can be used to image the mitochondria-associated membrane (MAM) interface of endoplasmic reticulum (ER) and mitochondria. PMID- 23656279 TI - Refactored M13 bacteriophage as a platform for tumor cell imaging and drug delivery. AB - M13 bacteriophage is a well-characterized platform for peptide display. The utility of the M13 display platform is derived from the ability to encode phage protein fusions with display peptides at the genomic level. However, the genome of the phage is complicated by overlaps of key genetic elements. These overlaps directly couple the coding sequence of one gene to the coding or regulatory sequence of another, making it difficult to alter one gene without disrupting the other. Specifically, overlap of the end of gene VII and the beginning of gene IX has prevented the functional genomic modification of the N-terminus of p9. By redesigning the M13 genome to physically separate these overlapping genetic elements, a process known as "refactoring," we enabled independent manipulation of gene VII and gene IX and the construction of the first N-terminal genomic modification of p9 for peptide display. We demonstrate the utility of this refactored genome by developing an M13 bacteriophage-based platform for targeted imaging of and drug delivery to prostate cancer cells in vitro. This successful use of refactoring principles to re-engineer a natural biological system strengthens the suggestion that natural genomes can be rationally designed for a number of applications. PMID- 23656280 TI - Scalable plasmid transfer using engineered P1-based phagemids. AB - Dramatic improvements to computational, robotic, and biological tools have enabled genetic engineers to conduct increasingly sophisticated experiments. Further development of biological tools offers a route to bypass complex or expensive mechanical operations, thereby reducing the time and cost of highly parallelized experiments. Here, we engineer a system based on bacteriophage P1 to transfer DNA from one E. coli cell to another, bypassing the need for intermediate DNA isolation (e.g., minipreps). To initiate plasmid transfer, we refactored a native phage element into a DNA module capable of heterologously inducing phage lysis. After incorporating known cis-acting elements, we identified a novel cis-acting element that further improves transduction efficiency, exemplifying the ability of synthetic systems to offer insight into native ones. The system transfers DNAs up to 25 kilobases, the maximum assayed size, and operates well at microliter volumes, enabling manipulation of most routinely used DNAs. The system's large DNA capacity and physical coupling of phage particles to phagemid DNA suggest applicability to biosynthetic pathway evolution, functional proteomics, and ultimately, diverse molecular biology operations including DNA fabrication. PMID- 23656281 TI - Hyperacute rejection in the xenogenic transplanted rat liver is triggered by the complement system only in the presence of leukocytes and free radical species. AB - BACKGROUND: Reactive oxygen species (ROS) and nitric oxide species (NOS) are pivotal after ischemia-reperfusion. However, the role of different cells on the formation of free radical species after xenotransplantation remains elusive. We hypothesized that ROS and NOS formed during hyperacute rejection are dependent on leukocytes, erythrocytes, activated thrombocytes, and Kupffer cells (KCs). To address this issue, we developed a model of xenoperfused rat liver and assessed the relationship between free radical production and graft dysfunction. METHODS: Livers from Sprague-Dawley rats were isolated, flushed with cold Ringer solution, and perfused at physically flow rates for 120 min after 1 h of ischemia. The control group was perfused with rat whole blood (n = 9). In the study groups, the livers were perfused with human whole blood, human plasma with erythrocytes, and plasma with erythrocytes and isolated thrombocytes (n = 9/group). In an additional group, gadolinium chloride (GdCl3), a selective Kupffer cell (KC) toxic agent, was applied. Liver damage, hyperacute rejection, and the depletion of KCs were monitored histologically. Liver damage and function were determined by means of liver enzymes, portal pressure, and bile production. Malondialdehyde (MDA), nitric oxide formation, and peroxynitrite concentration, as well as total glutathione (tGSH) level, were measured as indicators for free radical formation and anti-oxidative status. RESULTS: Significant differences in the MDA, NO, peroxynitrite levels, and GSH levels after reperfusion with various cell populations were observed. Markedly high ROS/RNS production was evident in the KCs and the xenogeneic whole-blood group. The oxidative stress was mainly caused by leukocytes and to lower extent by KCs, but only in combination with leukocytes. Neither erythrocytes, thrombocytes, nor hepatocytes had an effect on the release of ROS and RNS, as we could not observe significant differences in the MDA, peroxynitrite, and NO levels in these groups compared with control. Tissue injury and hyperacute rejection were more evident in the KC and whole blood livers. No sign of damage was observed for the control, erythrocyte, and thrombocyte group. Removal of leukocytes from the perfusate by filtration had a major protective effect on the liver function and the grade of hyperacute rejection, whereas KC depletion reduced the ROS production, but did not have an impact on the hyperacute rejection and liver damage. In all xenogeneic perfused groups, the activation of the complement was histologically observed by positive C3c and C9b. Neither KC depletion nor the removal of leukocytes or thrombocytes from the perfusate had an effect on the activation of the complement system. Damage of the rat liver by the complement system was only observed in association with leukocytes. CONCLUSION: Our data revealed that various cell populations contribute to the formation of free radicals in our model. The production of free radicals was mainly linked to leukocytes and to a minor extent to KCs, but only in combination with leukocytes. Free radicals critically contribute to injury, rejection, and dysfunction of the xenotransplanted liver. Furthermore, hyperacute rejection in the xenogeneic perfused liver is triggered by the complement system only in the presence of leukocytes and free radical formation. PMID- 23656282 TI - Mauritic acid: a new dammarane triterpene from the roots of Mauritia flexuosa L.f. (Arecaceae). AB - A new dammarane triterpene named mauritic acid (1) was isolated from the roots of Mauritia flexuosa L.f. The complete structural assignment of this new compound was elucidated from spectroscopic methods. Moreover, this compound was evaluated for its cytotoxicity against human cancer cell lines (OVCAR-8, PCM3, NCIH358M and different leukaemia cell strains). The mauritic acid presented significant cytotoxicity against OVCAR-8, PCM3 and NCIH358M cell lines with IC50 3.02, 2.39 and 6.19 MUM, respectively. The triterpenes 1 and 2 were also tested for their antimicrobial activity against 15 strains of microorganisms, including fungi and bacteria, with the best minimal inhibitory concentration values ranging from 50.8 to 203.5 MUM. PMID- 23656283 TI - In-vivo stimulation of macaque natural killer T cells with alpha galactosylceramide. AB - Natural killer T cells are a potent mediator of anti-viral immunity in mice, but little is known about the effects of manipulating NKT cells in non-human primates. We evaluated the delivery of the NKT cell ligand, alpha galactosylceramide (alpha-GalCer), in 27 macaques by studying the effects of different dosing (1-100 MUg), and delivery modes [directly intravenously (i.v.) or pulsed onto blood or peripheral blood mononuclear cells]. We found that peripheral NKT cells were depleted transiently from the periphery following alpha GalCer administration across all delivery modes, particularly in doses of >=10 MUg. Furthermore, NKT cell numbers frequently remained depressed at i.v. alpha GalCer doses of >10 MUg. Levels of cytokine expression were also not enhanced after alpha-GalCer delivery to macaques. To evaluate the effects of alpha-GalCer administration on anti-viral immunity, we administered alpha-GalCer either together with live attenuated influenza virus infection or prior to simian immunodeficiency virus (SIV) infection of two macaques. There was no clear enhancement of influenza-specific T or B cell immunity following alpha-GalCer delivery. Further, there was no modulation of pathogenic SIVmac251 infection following alpha-GalCer delivery to a further two macaques in a pilot study. Accordingly, although macaque peripheral NKT cells are modulated by alpha-GalCer in vivo, at least for the dosing regimens tested in this study, this does not appear to have a significant impact on anti-viral immunity in macaque models. PMID- 23656285 TI - The impact structured patient assessment frameworks have on patient care: an integrative review. AB - AIMS AND OBJECTIVES: To evaluate structured patient assessment frameworks' impact on patient care. BACKGROUND: Accurate patient assessment is imperative to determine the status and needs of the patient and the delivery of appropriate patient care. Nurses must be highly skilled in conducting timely and accurate patient assessments to overcome environmental obstacles and deliver quality and safe patient care. A structured approach to patient assessment is widely accepted in everyday clinical practice, yet little is known about the impact structured patient assessment frameworks have on patient care. DESIGN: Integrative review. METHODS: An electronic database search was conducted using Cumulative Index to Nursing and Allied Health Literature, Medical Literature Analysis and Retrieval System, PubMed and ProQuest Dissertations and Theses. The reference sections of textbooks and journal articles on patient assessment were manually searched for further studies. A comprehensive peer review screening process was undertaken. Research studies were selected that evaluated the impact structured patient assessment frameworks have on patient care. Studies were included if frameworks were designed for use by paramedics, nurses or medical practitioners working in prehospital or acute in-hospital settings. RESULTS: Twelve studies met the inclusion criteria. There were no studies that evaluate the impact of a generic nursing assessment framework on patient care. The use of a structured patient assessment framework improved clinician performance of patient assessment. Limited evidence was found to support other aspects of patient care including documentation, communication, care implementation, patient and clinician satisfaction, and patient outcomes. CONCLUSION: Structured patient assessment frameworks enhance clinician performance of patient assessment and hold the potential to improve patient care and outcomes; however, further research is required to address these evidence gaps, particularly in nursing. RELEVANCE TO CLINICAL PRACTICE: Acute care clinicians should consider using structured patient assessment frameworks in clinical practice to enhance their performance of patient assessment. PMID- 23656284 TI - Confirmatory factor analysis reveals a latent cognitive structure common to bipolar disorder, schizophrenia, and normal controls. AB - OBJECTIVE: We sought to determine whether a single hypothesized latent factor structure would characterize cognitive functioning in three distinct groups. METHODS: We assessed 576 adults (340 community controls, 126 adults with bipolar disorder, and 110 adults with schizophrenia) using 15 measures derived from nine cognitive tests. Confirmatory factor analysis (CFA) was conducted to examine the fit of a hypothesized six-factor model. The hypothesized factors included attention, psychomotor speed, verbal memory, visual memory, ideational fluency, and executive functioning. RESULTS: The six-factor model provided an excellent fit for all three groups [for community controls, root mean square error of approximation (RMSEA) <0.048 and comparative fit index (CFI) = 0.99; for adults with bipolar disorder, RMSEA = 0.071 and CFI = 0.99; and for adults with schizophrenia, RMSEA = 0.06 and CFI = 0.98]. Alternate models that combined fluency with processing speed or verbal and visual memory reduced the goodness of fit. Multi-group CFA results supported factor invariance across the three groups. CONCLUSIONS: Confirmatory factor analysis supported a single six-factor structure of cognitive functioning among patients with schizophrenia or bipolar disorder and community controls. While the three groups clearly differ in level of performance, they share a common underlying architecture of information processing abilities. These cognitive factors could provide useful targets for clinical trials of treatments that aim to enhance information processing in persons with neurological and neuropsychiatric disorders. PMID- 23656286 TI - Local understandings of conservation in southeastern Mexico and their implications for community-based conservation as an alternative paradigm. AB - Since the 1990s national and international programs have aimed to legitimize local conservation initiatives that might provide an alternative to the formal systems of state-managed or otherwise externally driven protected areas. We used discourse analysis (130 semistructured interviews with key informants) and descriptive statistics (679 surveys) to compare local perceptions of and experiences with state-driven versus community-driven conservation initiatives. We conducted our research in 6 communities in southeastern Mexico. Formalization of local conservation initiatives did not seem to be based on local knowledge and practices. Although interviewees thought community-based initiatives generated less conflict than state-managed conservation initiatives, the community-based initiatives conformed to the biodiversity conservation paradigm that emphasizes restricted use of and access to resources. This restrictive approach to community based conservation in Mexico, promoted through state and international conservation organizations, increased the area of protected land and had local support but was not built on locally relevant and multifunctional landscapes, a model that community-based conservation is assumed to advance. PMID- 23656287 TI - Determination of eight synthetic dyes in foodstuffs by green liquid chromatography. AB - Eight synthetic food colours were analysed by green liquid chromatography. Green liquid chromatography is an environmentally friendly technique which does not use organic solvents in the extraction procedure or in the chromatographic method. Analysis was carried out for the following colours: tartrazine (E102), indigotine (E132), Quinoline Yellow (E104), Ponceau 4R (E124), Sunset Yellow (E110), Brilliant Blue (E133), Allura Red (E129) and carmoisine (E122) in four different foods: cookies, coloured rice, saffron and fruit juice. The method was performed on an Eurospher-100 C8 (5 MUm, 4.6 * 250 mm) column with ultraviolet (UV)-VIS detection and validated by determining the calibration lines, measurement of recovery, precision, and limits of quantification and detection (LODs and LOQs). LOD ranged from 0.04 mg kg-1 for E102 to 1.00 mg kg-1 for E122; LOQ ranged from 0.06 mg kg-1 for E102 to 1.12 mg kg-1 for E122. The levels of colours in foods were compared with Iranian National Standards, but only 7.5% of cookies, 30% of coloured rice, 8% of saffron and 12% of juice samples were in compliance with these standards. Tartrazine is prohibited in Iran, but it was found as the most prevalent food colour in the samples analysed. The results of these tests confirmed that HPLC avoiding the use of organic solvents is a suitable method and can be used for quantitative analyses or screening of food samples for synthetic food colours. PMID- 23656288 TI - Challenging compounds for calculating hyperpolarizabilities: p-quinodimethane derivatives. AB - The hyperpolarizabilities of three p-quinodimethane derivatives with low diradical character have been evaluated. As electron correlation effects rule the electric field response properties, wave function and density functional theory based methods have been compared to benchmark values calculated with the coupled cluster method including single and double excitations as well as perturbative estimate of the triples [CCSD(T)]. The basis set effects have been further assessed. This study shows that the determination of the second hyperpolarizability with the CCSD method provides results in closest agreement with the CCSD(T) reference values. The use of MP2 level of theory performs well for the closed-shell compound but not for open-shell ones. Spin-projection UMP3 and UMP4 methods reproduce well UCCSD(T) values for the p-quinodimethane but not for the charged compound. Without spin projection correction, density functional theory with a large range of exchange-correlation functionals does not perform well for these systems. Similar effects have been observed for the polarizability and first hyperpolarizability, although these effects are smaller. PMID- 23656289 TI - Genetic variability of Baylisascaris schroederi from the Qinling subspecies of the giant panda in China revealed by sequences of three mitochondrial genes. AB - The present study examined the variations in three mitochondrial (mt) DNA sequences, namely cytochrome b (cytb), cytochrome c oxidase subunit 3 (cox3) and NADH dehydrogenase subunit 5 (nad5), among Baylisascaris schroederi isolates from the Qinling subspecies of the giant panda in Shaanxi province, northwestern China. No differences in length were detected in the three mt fragments from different isolates. The intra-specific sequence variations within all B. schroederi samples were 0-2.6% for pcytb, 0-1.8% for pcox3 and 0-2.1% for pnad5, while the inter-specific sequence differences among members of the genus Baylisascaris were 8.2-15.2%, 6.2-15.9% and 8.4-16.0% for pcytb, pcox3, pnad5, respectively. A phylogenetic analysis of the combined sequences of pcytb, pcox3 and pnad 5 showed that all B. schroederi samples in the present study were located in two large clusters, with one cluster containing samples from giant pandas in Sichuan province. These findings provide basic information for further study of molecular epidemiology and control of B. schroederi infection in the Qinling subspecies of the giant panda and throughout China. PMID- 23656290 TI - Complete mitochondrial genome organization of Schizothorax richardsonii (Gray, 1832). AB - The complete mitochondrial genome of Schizothorax richardsonii, an endemic coldwater fish of Himalayas, was determined for the first time. The genome is 16,592 bp in length and consists of 13 protein coding genes, 22 tRNAs, 2 rRNA genes and one putative control region. The gene organization and its order were similar to other vertebrates. The overall base composition was as follows: A: 29.9%, G: 17.7%, C: 26.9%, T: 25.5%, A + T content 55.4% and the G + C content 44.6%. The control region contains a microsatellite; (TA)13 exists between 16,469 and 16,494 bp. This study will provide the rationale for the management and conservation of the snow trout. PMID- 23656291 TI - Complete mitochondrial DNA genome of Pseudobagrus brevicaudatus (Siluriformes: Bagridae). AB - The complete mitochondrial genome of Pseudobagrus brevicaudatus (Siluriformes: Bagridae) was sequenced in this study. The total length of the mitogenome is 16,533 bp, with the base composition of 31.6% A, 26.8% T, 15.0%G, 26.6% C. The gene order and genes were the same as that found in other previously reported catfishes, including 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 1 non-coding control region. Except for ND6 gene and 8 tRNA genes, all other mitochondrial genes were encoded on the heavy strand. This complete mitogenome data provides the basis for taxonomic and conservation research of this and closely related species. PMID- 23656292 TI - The complete mitochondrial genome of Chinese Shinjang wolf. AB - In this study, the complete mitochondrial genome of Chinese Shinjang wolf (Canis lupus desertorum) was sequenced for the first time using blood samples obtained from a female wolf captured from Altay in Shinjang, China. Sequence analysis showed that the genome structure was in accordance with other Canidae species and it contains 12S rRNA gene, 16S rRNA gene, 22 tRNA genes, 13 protein-coding genes and 1 control region. PMID- 23656293 TI - Mitochondrial DNA reveals population structuring in Macrodon atricauda (Perciformes: Sciaenidae): a study covering the whole geographic distribution of the species in the southwestern Atlantic. AB - We investigated the genetic structure and diversity of M. atricauda, based on 266 specimens collected off the coast of southern Brazil and Argentina at seven locations, covering the whole geographic distribution of this species. A DNA sequence alignment of 904 base pairs of the mitochondrial Control Region revealed a total of 85 haplotypes. F(ST) analyses suggest that M. atricauda does not comprise a single demographic stock. Two different genetic units are identified, which possibly are related to ecological adaptations of the species within its range. Genetic diversity, Bayesian analysis of population structure, and significant negative results for the D and FS tests indicate that M. atricauda populations have undergone recent expansion. The spatial distribution of genetic variation seems to be related to historical colonization from south to north, followed by expansion. PMID- 23656294 TI - Mitochondrial D-loop mutations and polymorphisms are connected with canine malignant cancers. AB - Abstract The aim of the conducted investigations was to identify differences in the D-loop nucleotide sequence between neoplastic tissue, normal tissue, and blood and to determine their correlation with the type of cancer in dogs. In 62.5% of the analyzed tumors of epithelial origin and 25% tumors of mesenchymal origin, substitution was detected within the D-loop sequence between the neoplastic tissue, normal tissue, and blood. Two mutations occurring in the carcinogenic process in position T15620C have been identified in epithelioma glandulae sebacei and carcinoma planoepithelialae keratodes. Blood and cancer heteroplasmy was diagnosed for carcinoma planoepithelialae keratodes and "Comedo" carcinoma. The results of the study indicate that polymorphic changes in the D loop sequence promote carcinogenesis in dogs. Heteroplasmy diagnosed in blood and tumor cells and absence thereof in normal tissue may imply mtDNA recombination. High prevalence of mtDNA mutations in canine tumors may suggest mtDNA genetic instability, which is likely to play a role in carcinogenesis. PMID- 23656295 TI - Capability of Thailand to implement newborn male circumcision: a nation-wide survey. AB - This study was designed to gain baseline information on the capability of the hospitals of Thailand to provide newborn male circumcision (NC) and on the opinions of health-care personnel towards NC. Two questionnaires were sent to every hospital in Thailand that might have obstetrical services. One questionnaire requested information about the degree to which NC was provided by the hospital. The second questionnaire targeted health-care providers' opinions about NC. The response rate was 55.1% (747/1355). Of the 562 hospitals that had deliveries in 2010, 8.2% (46) provided at least one NC. Thirty-eight percent (35/92) of private hospitals and 2.3% (11/470) of government hospitals provided the service. The primary reason for performing NC was parental request (82.6%). Some providers (31.3%) said that NC was easy to perform and 39.1% thought NC was safe. Most respondents (91.8%) stated that physicians should perform the procedure instead of nurses, and choices about undergoing NC should be left to parents (55.0%). NC was rarely performed in government hospitals, and its staffs seemed to not recognize the health benefits of NC. A massive education program for health-care providers would be necessary before implementing a national program for NC. More information on the opinions of health authorities, health care personnel and parents as well as cost-effectiveness studies are needed before a proper policy can be implemented. PMID- 23656296 TI - Optimized chemical probes for REV-ERBalpha. AB - REV-ERBalpha has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBalpha agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. (1) Potent REV-ERBalpha agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRalpha. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing. PMID- 23656297 TI - Exposure to extremely low-frequency magnetic field restores spinal cord injury induced tonic pain and its related neurotransmitter concentration in the brain. AB - Spinal cord injury (SCI) is unequivocally reported to produce hyperalgesia to phasic stimuli, while both hyper- and hypoalgesia to tonic stimuli. The former is spinally mediated and the latter centrally. Besides, its management is unsatisfactory. We report the effect of magnetic field (MF; 17.96 MUT, 50 Hz) on tonic pain behavior and related neurotransmitters in the brain of complete thoracic (T13) SCI rats at week 8. Adult male Wistar rats were divided into Sham, SCI and SCI+MF groups. Formalin-pain behavior was compared utilizing 5 min block pain rating (PR), 60 min session-PR, time spent in various categories of increasing pain (T0-T3) and flinch incidences. Serotonin (5-HT), dopamine (DA), norepinepherine (NE), gamma-aminobutyric acid (GABA), glutamate and glycine were estimated in brain tissue by liquid chromatography-mass spectrometry. Session-PR, block-PR and number of flinches were significantly lower, while time spent in categories 0-1 was higher in the SCI versus Sham group. These parameters were comparable in the SCI+MF versus Sham group. 5-HT concentration in cortex, remaining forebrain areas and brain stem (BS), was lower while GABA and NE were higher in BS of SCI, which were comparable with Sham in the SCI+MF group. The concentration of DA, glutamate and glycine was comparable amongst the groups. The data indicate significant hypoalgesia in formalin pain while increased in GABA, NE and decreased in 5-HT post-SCI, which were restored in the SCI+MF group. We suggest beneficial effect of chronic (2 h/day * 8 weeks) exposure to MF (50 Hz, 17.96 MUT) on tonic pain that is mediated by 5-HT, GABA and NE in complete SCI rats. PMID- 23656298 TI - Zebrafish Expression Ontology of Gene Sets (ZEOGS): a tool to analyze enrichment of zebrafish anatomical terms in large gene sets. AB - The zebrafish (Danio rerio) is an established model organism for developmental and biomedical research. It is frequently used for high-throughput functional genomics experiments, such as genome-wide gene expression measurements, to systematically analyze molecular mechanisms. However, the use of whole embryos or larvae in such experiments leads to a loss of the spatial information. To address this problem, we have developed a tool called Zebrafish Expression Ontology of Gene Sets (ZEOGS) to assess the enrichment of anatomical terms in large gene sets. ZEOGS uses gene expression pattern data from several sources: first, in situ hybridization experiments from the Zebrafish Model Organism Database (ZFIN); second, it uses the Zebrafish Anatomical Ontology, a controlled vocabulary that describes connected anatomical structures; and third, the available connections between expression patterns and anatomical terms contained in ZFIN. Upon input of a gene set, ZEOGS determines which anatomical structures are overrepresented in the input gene set. ZEOGS allows one for the first time to look at groups of genes and to describe them in terms of shared anatomical structures. To establish ZEOGS, we first tested it on random gene selections and on two public microarray datasets with known tissue-specific gene expression changes. These tests showed that ZEOGS could reliably identify the tissues affected, whereas only very few enriched terms to none were found in the random gene sets. Next we applied ZEOGS to microarray datasets of 24 and 72 h postfertilization zebrafish embryos treated with beclomethasone, a potent glucocorticoid. This analysis resulted in the identification of several anatomical terms related to glucocorticoid-responsive tissues, some of which were stage-specific. Our studies highlight the ability of ZEOGS to extract spatial information from datasets derived from whole embryos, indicating that ZEOGS could be a useful tool to automatically analyze gene expression pattern features of any large zebrafish gene set. PMID- 23656300 TI - How frequently are words used on naming tests used in spoken conversation? AB - Naming, or word-finding ability, is typically assessed using measures that require a patient to name a pictured object. Words used less frequently tend to be more difficult to find when speaking; thus word frequency can be used as a measure of item difficulty on such tests. However, frequency data for words on naming measures has either not been used in the creation of these tests or has been derived from data on how frequently words have been used in written materials. The present study determined how frequently words on the Boston Naming Test (BNT), the Neuropsychological Assessment Battery (NAB) naming subtest, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) naming subtest, and auditory naming measures developed by Hamberger and Seidel (2003, Journal of the International Neuropsychological Society, 9, 479) and Brandt et al. (2010, The Clinical Neuropsychologist, 24, 1326) are used in spoken language. Items on the auditory naming measures had the highest mean frequency, and the BNT items 30-60 had the lowest mean frequency. Furthermore, item frequency on the full BNT, NAB naming forms 1 and 2, and RBANS forms A correlated with item number, indicating items increase in difficulty on these tests, with trends in the same direction found for RBANS form B and Hamberger and Seidel's auditory naming measure. Finally, differences in mean word frequency between tests underscore how interpretation of change in naming ability based on different measures should be made with caution. PMID- 23656299 TI - Dietary protein source influence on body size and composition in growing zebrafish. AB - The importance of nutritional components on growth and body composition outcomes has been demonstrated in multiple model organisms. Although zebrafish (Danio rerio) have an established role in research laboratories for its utility in understanding developmental biology and genetics, the influence of diet composition on basic growth outcomes is less well demonstrated. In the current study, four protein sources were tested in isolation using isonitrogenous diets or combined using a defined lab diet. Fish (n~60/group) were group housed (n<=10 fish/1.8 L tank) and fed ad libitum three times daily for 12 weeks. Fish were assessed for effects on length, body weight, and body composition (lean and fat mass). Individuals fed wheat gluten protein were significantly shorter in length, with significantly lower body weight and lean mass in both male and female fish, although percent body fat was high compared with other diets. Casein-fed fish similarly had significantly reduced body length, body weight, and lean and fat mass in both male and female fish, with a low percent body fat compared with other diets (leanest). Fish protein hydrolysate-fed fish had significantly lower lean mass and a high percent body fat, whereas soy protein isolate diet performed similarly to a mixed-protein control diet for all measured outcomes. These results suggest that the protein source, with accompanying amino acid ratios or additional protein source differences, has a significant impact on growth and body composition outcomes in zebrafish when fed in a semipurified, defined diet background. PMID- 23656301 TI - Investigating the autonomic nervous system and cognitive functions as potential mediators of an association between cardiovascular disease and driving performance. AB - Cardiovascular disease (CVD) impacts the autonomic nervous system and cognitive functions related to activities of daily living, including driving an automobile. Although CVD has been linked to unsafe driving, mechanisms underlying this relationship remain elusive. The aim of this study was to examine the role of cognitive functions and the autonomic nervous system as potential mediators of driving performance. Nineteen individuals having recently suffered a cardiac event and 16 individuals with no history of CVD completed a simulated drive using a STISIM simulator to assess driving performance. Heart rate was recorded throughout testing using a Polar RS800CX heart rate monitor, and measures of executive, orienting, and alerting functions were obtained through the Attention Network Test. We used the Baron and Kenny analysis method to assess potential mediating effects of the relationship between CVD and driving performance. Executive function was the only potential mediator investigated to be associated with driving (p < 0.01) and CVD (p < 0.05); however, it did not appear to play a mediating role (p = 0.28). These results suggest that individuals with CVD exhibit decrements in complex cognitive tasks such as driving and that further research is needed to better understand the mechanisms underlying this relationship. PMID- 23656302 TI - Effect of the Great Activity Programme on healthy lifestyle behaviours in 7-11 year olds. AB - The study investigated the effect of a school-based healthy lifestyles intervention on physical activity and dietary variables. In total 378 children (177 intervention, 201 control; age 9.75 +/- 0.82 years (mean +/- s)) took part in the 7-month intervention comprising: preparation for and participation in 3 highlight events (a dance festival, a walking event and a running event); an interactive website for pupils, teachers and parents; and vacation activity planners. Primary outcome measures were objectively measured physical activity (pedometers and accelerometers), endurance fitness and dietary variables. Multi level modelling was employed for data analysis. The increase in physical activity was greater in the intervention group than the control group (steps: 1049 vs 632 daily steps each month; moderate to vigorous physical activity (MVPA) total: 4.6 min . day(-1) . month(-1) vs 1.3 min . day(-1) . month(-1); MVPA bouts: 5.4 min . day(-1) . month(-1) vs 2.6 min . day(-1) . month(-1); all P < 0.05). The increase in multi-stage fitness test distance was greater for intervention participants (46 vs 29 m . month(-1) of intervention, group * month interaction, P < 0.05). There were no differences between groups in dietary variables, body composition, knowledge of healthy lifestyles or psychological variables. Thus an intervention centred around highlight events and including relatively few additional resources can impact positively on the objectively measured physical activity of children. PMID- 23656303 TI - Retrospective study of short and extra-short implants placed in posterior regions: influence of crown-to-implant ratio on marginal bone loss. AB - AIM: The aim of this study is to evaluate the influence of crown-to-implant (CI) ratio as well as other surgical, prosthetic and biomechanical variables on marginal bone loss (MBL) and on the survival rates of implant-supported prostheses in short implants (<=8.5 mm in length) placed in posterior areas of maxilla and mandible. MATERIAL & METHODS: This was a retrospective study based on clinical charts and follow-up recordings from a single private practice over a period of 10 years. Patients rehabilitated in the posterior region of the jaws by means of prostheses supported by implants of <=8.5 mm length were included. Patients-related, surgery-related. and implant-related variables, as well as other prosthetic and biomechanical variables. were registered. The data were split into two groups according to the value of CI ratio (CI < 2 and CI >= 2). MBL was measured from radiographs using an image analysis software. Implant and prosthesis survival rates were recorded. RESULTS: One hundred twenty-eight short implants placed in 63 patients were evaluated. The mean follow-up period was 21.88 months (standard deviation (SD): 22.9, range 7-113 months). Eighty-six implants (67.2%) had a CI ratio of <2, whereas it was >=2 in 42 implants (32.8%). The mean value of CI ratio was 1.82 (SD: 0.42; range 1.04-3.31). The average MBL after 1 year of follow-up was 0.35 (SD: 0.50), and it was 0.45 (SD: 0.46) mm for subsequent evaluations. Survival rates of implants and prosthesis were 100%. The presence of a cantilever had a negative influence on the first year MBL (p < .05). CONCLUSIONS: The CI ratio had not a significant influence on MBL in Biotechnology Institute (BTI; Vitoria, Spain) short implants humidified with PRGF Endoret and placed in posterior areas. The only variable that showed a significant negative influence on first year postloading MBL was the use of cantilever for rehabilitations. PMID- 23656304 TI - Palladium-catalyzed Hiyama-type cross-coupling reactions of arenesulfinates with organosilanes. AB - Palladium-catalyzed Hiyama-type cross-coupling reactions of various arenesulfinates with organosilanes were achieved in good to excellent yields under aerobic conditions at 70 degrees C. Fluoride is essential, and tetrabutylammonium fluoride (TBAF) was shown to be the most efficient additive for these cross-coupling reactions. These cross-coupling reactions of the arenesulfinates provide high yields and show wide functional group tolerance, making them attractive alternative transformations to traditional cross-coupling approaches for carbon-carbon bond construction. PMID- 23656305 TI - Student perception on external clinical teaching visits in a rural medical program. PMID- 23656306 TI - Statistics: using regression models. AB - In a previous article, we asked the simple question "Are we related?" and used scatterplots and correlation coefficients to provide an answer. In this article, we will take this question and reword it to "How are we related?" and will demonstrate the statistical techniques required to reach a conclusion. PMID- 23656308 TI - Induction therapy in heart transplantation: where are we now? AB - Although induction therapy has been used in heart transplantation for many years, its role has not been fully elucidated. Early safety concerns relating to OKT3 or intensive lymphocyte-depleting regimens have largely been addressed by modern induction protocols using rabbit antithymocyte globulin (rATG [Thymoglobuline((r)) or ATG-Fresenius]) and interleukin-2 receptor antagonist (IL 2RA) agents, but although the number of randomized controlled studies has expanded there are still gaps in the evidence base. Rejection prophylaxis may be somewhat more effective with rATG than IL-2RA agents, but this has not been proven conclusively. Administration of induction therapy to support delayed introduction of calcineurin inhibitors in patients at risk of renal dysfunction is relatively well documented and widely used. Increasingly, it is recognized that sensitized patients and individuals with primary graft function are suitable candidates for induction therapy, and the possibility that rATG may inhibit cardiac allograft vasculopathy is also of considerable interest. Until the question of whether rATG is associated with increased risk of infection, routine prophylaxis is advisable. IL-2RA induction has an excellent safety profile. Dosing rATG according to lymphocyte count reduces cumulative dose without compromising efficacy. Further controlled trials are required to determine when and how to deploy induction most effectively following heart transplantation. PMID- 23656307 TI - Flow cytometric assay detecting cytotoxicity against human endogenous retrovirus antigens expressed on cultured multiple sclerosis cells. AB - Damage of target cells by cytotoxicity, either mediated by specific lymphocytes or via antibody-dependent reactions, may play a decisive role in causing the central nervous system (CNS) lesions seen in multiple sclerosis (MS). Relevant epitopes, antibodies towards these epitopes and a reliable assay are all mandatory parts in detection and evaluation of the pertinence of such cytotoxicity reactions. We have adapted a flow cytometry assay detecting CD107a expression on the surface of cytotoxic effector cells to be applicable for analyses of the effect on target cells from MS patients expressing increased amounts of human endogenous retrovirus antigens. MS patients also have increased antibody levels to these antigens. The target cells are spontaneously growing peripheral blood mononuclear cells (PBMCs) of B cell lineage, expressing human endogenous retrovirus HERV epitopes on their surface. Polyclonal antibodies against defined peptides in the Env- and Gag-regions of the HERVs were raised in rabbits and used in antibody-dependent cell-mediated cytotoxicity (ADCC) -assays. Rituximab(r) (Roche), a chimeric monoclonal antibody against CD20 expressed primarily on B cells, was used as control antibody. Without antibodies this system is suitable for analyses of natural killer cell activity. In optimization of the assay we have used effector lymphocytes from healthy donors. The most effective effector cells are CD56(+) cells. CD8(+) T cells also express CD107a in ADCC. Using the adapted assay, we demonstrate significant ADCC activity to target cells expressing HERV epitopes, and additionally a low level of NK activity. PMID- 23656309 TI - Computational nanochemistry report on the oxicams--conceptual DFT indices and chemical reactivity. AB - A density functional theory study of eight oxicams was carried out in order to determine their global and local reactivities. These types of reactivities were measured by means of global and local reactivity descriptors coming from the conceptual density functional theory. Net electrophilicity as a global reactivity descriptor and local hypersoftness as a local reactivity descriptor were the used tools to distinguish reactivity and selectivity among these oxicams. Globally, isoxicam presents the highest electron donating capacity; meanwhile, the highest electron accepting capacity is exhibited by droxicam. Locally, two oxicams present neither nucleophilic nor electrophilic relevant reactivity in their peripheral pyridine ring, droxicam and tenoxicam, so that their more reactive zones are found on the respective fused rings. Oxicams have been divided into two subgroups in order to facilitate the local analysis of reactivity. One group is characterized because their most important condensed values for local hypersoftnes are well-separated: 4-meloxicam, lornoxicam, meloxicam, and normeloxicam. Meanwhile, the opposite situation is found in droxicam, isoxicam, piroxicam, and tenoxicam. As a whole, the nucleophilic characteristic noticeably predominates in these eight oxicams instead of an electrophilic behavior, thus meaning a greater tendency to donate electrons rather than withdrawing them; a consequence of this behavior implies a favorable interaction with a hypothetical receptor bearing one or more electron acceptor functional groups rather than electron donor functional groups; this would imply a maximization of this interaction from the covalent point of view. PMID- 23656310 TI - Bacterial invasion potential in water is determined by nutrient availability and the indigenous community. AB - In drinking water (DW) and the distribution systems, bacterial growth and biofilm formation have to be controlled both for limiting taste or odour development and preventing clogging or biocorrosion problems. After a contamination with undesired bacteria, factors like nutrient availability and temperature will influence the survival of these invaders. Understanding the conditions enabling invaders to proliferate is essential for a holistic approach towards microbial risk assessment in DW. Pseudomonas putida was used as a model invader because this easy-growing bacterium can use a wide range of substrates. Invasion experiments in oligo- to eutrophic waters showed the requirement of both a carbon and phosphate source for survival of P. putida in DW. Addition of C, N and P enabled P. putida to grow in DW from 5.80 * 10(4) to 1.84 * 10(8) cells mL(-1) and survive for at least 12 days. However, in surface water with similar nutrient concentrations, P. putida did not survive, indicating the concomitant importance of the present indigenous microbial community of the specific water sample. Either extensive carbon or phosphate limitation can be used in water treatment design in order to obtain a DW which is not susceptible for unwanted bacterial growth. PMID- 23656311 TI - Ax21-triggered immunity plays a significant role in rice defense against Xanthomonas oryzae pv. oryzicola. AB - XA21, as a pattern recognition receptor in rice, senses the quorum-sensing (QS) signal molecule Ax21 secreted by Xanthomonas oryzae pv. oryzae (Xoo) and mediates hypersensitive response-like immunity against the pathogen. However, for the infection of another pathovar, X. o. pv. oryzicola (Xoc), relatively weak defense responses are observed in XA21-containing rice cultivars. In the present study, we demonstrated that the Xoc Deltaax21 mutant caused more severe disease symptoms than the wild type in XA21 rice cv. IRBB21, but not in non-Xa21 rice cv. Taipei 309. The substance(s) secreted by the wild-type Xoc strain, but not those by the ax21 mutant triggered host immunity against Xoo PXO99 Deltaax21 in Xa21 rice. Immunoblot analysis corroborated that Xoc, like Xoo, synthesizes and secretes Ax21. Furthermore, the membrane fusion protein RaxA was demonstrated to be required, but the ATP-binding cassette transporter RaxB was dispensable for Ax21 secretion in Xoc. In addition, we demonstrated that Ax21 functions as a QS signal molecule that regulates biofilm formation in Xoc. However, Ax21 signaling is dispensable for bacterial motility, the production of extracellular polysaccharide and protease secretion in Xoc. Interestingly, the two-component system RaxR/H was involved in the regulation of bacterial motility and the regulation was likely independent on Ax21 signaling in Xoc. Taken together, the results indicated that Ax21 secreted by Xoc might induce plant immunity that plays a significant role in rice defense against the pathogen infection. PMID- 23656312 TI - Association of a DNA virus with grapevines affected by red blotch disease in California. AB - In the Napa Valley of California, vineyards of 'Cabernet Franc' (CF) clone 214, 'Cabernet Sauvignon' clone 337, and 'Zinfandel' clone 1A (Z1A) with grapevines exhibiting foliar symptoms of red blotches, marginal reddening, and red veins that were accompanied by reduced sugar accumulation in fruit at harvest were initially suspected to be infected with leafroll-associated viruses. However, reverse-transcription polymerase chain reaction (PCR) tests were negative for all known leafroll-associated viruses, with the exception of Grapevine leafroll associated virus 2 in Z1A. Metagenomic analysis of cDNA libraries obtained from double-stranded RNA enriched nucleic acid (NA) preparations from bark scrapings of dormant canes on an Illumina platform revealed sequences having a distant relationship with members of the family Geminiviridae. Sequencing of products obtained by PCR assays using overlapping primers and rolling circle amplification (RCA) confirmed the presence of a single circular genome of 3,206 nucleotides which was nearly identical to the genome of a recently reported Grapevine cabernet franc-associated virus found in declining grapevines in New York. We propose to call this virus "Grapevine red blotch-associated virus" (GRBaV) to describe its association with grapevine red blotch disease. Primers specific to GRBaV amplified a product of expected size (557 bp) from NA preparations obtained from petioles of several diseased source vines. Chip bud inoculations successfully transmitted GRBaV to test plants of CF, as confirmed by PCR analysis. This is the first report of a DNA virus associated with red blotch disease of grapevines in California. PMID- 23656313 TI - A new bioactive aminophenoxazinone alkaloid from a marine-derived actinomycete. AB - Chemical investigation of the marine Streptomyces sp. Eg25 led to the isolation of one new natural 2-aminophenoxazin-3-one-8-carboxylic acid methyl ester named maroxazinone (1) as well as the known compounds elloxazinone A (2), exfoliazone (3), carboxyexfoliazone (4), elloxazinone B (5) and venezueline D (6). The chemical structures of the isolated compounds were deduced from extensive studies of NMR ((1)H and (13)C NMR, (1)H-(1)H COSY, HMQC and HMBC) and mass spectra. The cytotoxic activities of the new maroxazinone (1) and venezueline D (6) against breast carcinoma cell line (MCF7), liver carcinoma cell line (HEPG2) and colon carcinoma cell line (HCT116) were investigated. PMID- 23656314 TI - Shock Hugoniot equations of state for binary ideal (toluene/fluorobenzene) and nonideal (ethanol/water) liquid mixtures. AB - Laser shock Hugoniot data were obtained using ultrafast dynamic ellipsometry (UDE) for both nonideal (ethanol/water solutions with mole percent chi(ethanol) = 0%, 3.4%, 5.4%, 7.5%, 9.7%, 11%, 18%, 33%, 56%, 100%) and ideal liquid mixtures (toluene/fluorobenzene solutions with mole percent chi(toluene) = 0%, 26.0%, 49.1%, 74.9%, 100%). The shock and particle velocities obtained from the UDE data were compared to the universal liquid Hugoniot (ULH) and to literature shock (plate impact) data where available. It was found that the water UDE data fit to a ULH-form equation suggests an intercept of 1.32 km/s, lower than the literature ambient sound speed in water of 1.495 km/s (Mijakovic et al. J. Mol. Liq. 2011, 164, 66-73). Similarly, the ethanol UDE data fit to a ULH-form equation suggests an intercept of 1.45 km/s, which lies above the literature ambient sound speed in ethanol of 1.14 km/s. Both the literature plate impact and UDE Hugoniot data lie below the ULH for water. Likewise, the literature plate impact and UDE Hugoniot data lie above the ULH for ethanol. The UDE Hugoniot data for the mixtures of water and ethanol cross the predictions of the ULH near the same concentration where the sound speed reaches a maximum. In contrast, the UDE data from the ideal liquids and their mixtures are well behaved and agree with ULH predictions across the concentration range. The deviations of the nonideal ethanol/water data from the ULH suggest that complex hydrogen bonding networks in ethanol/water mixtures alter the compressibility of the mixture. PMID- 23656315 TI - Acquiring surgical skills: the role of the Royal Australasian College of Surgeons. AB - Contemporary surgeons are expected to develop and maintain competence across a range of skills far broader than that demanded of last century's surgeons. This is increasingly difficult to achieve in a competitive clinical environment in which the effectiveness of the traditional apprenticeship model can be compromised. New training paradigms must be found to ensure that the quality of surgical training is maintained and enhanced. Acquiring technical skills in the operating theatre is expensive, but training using simulations in the skills laboratory is gaining credibility and validity as a means to augment the clinical experience and accelerate training. The emerging role of surgical skills courses extends to training in behaviour and attitude. At the same time, there is a rapidly growing demand for training courses in technical surgical skills, particularly from prevocational trainees aspiring to enter surgical training. This group has been neglected by the new Surgical Education and Training programme, and re-engagement with them is now a priority. Most skills courses rely on surgeons willing to teach pro bono, and paying tutors would impose a significant additional cost on surgical training. However, recruiting enough fellows to meet the demand for tutors remains a challenge. The Royal Australasian College of Surgeons is actively engaged in supporting and developing skills training courses and programmes to address the range of skills required for surgical competence. PMID- 23656316 TI - N-Doped graphene nanoplatelets as superior metal-free counter electrodes for organic dye-sensitized solar cells. AB - Highly efficient counter electrodes (CEs) for dye-sensitized solar cells (DSSCs) were developed using thin films of scalable and high-quality, nitrogen-doped graphene nanoplatelets (NGnP), which was synthesized by a simple two-step reaction sequence. The resultant NGnP was deposited on fluorine-doped SnO2 (FTO)/glass substrates by using electrospray (e-spray) coating, and their electrocatalytic activities were systematically evaluated for Co(bpy)3(3+/2+) redox couple in DSSCs with an organic sensitizer. The e-sprayed NGnP thin films exhibited outstanding performances as CEs for DSSCs. The optimized NGnP electrode showed better electrochemical stability under prolonged cycling potential, and its Rct at the interface of the CE/electrolyte decreased down to 1.73 Omega cm(2), a value much lower than that of the Pt electrode (3.15 Omega cm(2)). The DSSC with the optimized NGnP-CE had a higher fill factor (FF, 74.2%) and a cell efficiency (9.05%), whereas those of the DSSC using Pt-CE were only 70.6% and 8.43%, respectively. To the best of our knowledge, the extraordinarily better current-voltage characteristics of the DSSC-NGnP outperforming the DSSC-Pt for the Co(bpy)3(3+/2+) redox couple (in paticular, FF and short circuit current, Jsc) is highlighted for the first time. PMID- 23656317 TI - Immunohistopathological features of anaplastic large-cell lymphoma according to anaplastic lymphoma kinase expression and bone marrow involvement pattern. AB - AIMS: The immunohistopathological features of lesions involving the bone marrow (BM) were examined in patients with anaplastic large-cell lymphoma (ALCL) to identify the most useful markers for the detection of BM involvement in ALCL. METHODS AND RESULTS: A total of 80 patients with ALCL were enrolled, of whom 15 (18.8%) showed BM involvement. Anaplastic lymphoma kinase-negative (ALK-) patients (n = 11) showed a nodular BM involvement pattern more frequently than ALK+ patients (n = 4; 72.7% versus 25.0%, P = 0.095). Patients with interstitial BM involvement were more frequently ALK+ than those with nodular BM involvement (50.0% versus 11.1%, P = 0.095). CD30 positivity was the strongest indicator of the presence of BM lesions, regardless of the BM involvement pattern. The application of CD30 in cases without morphological evidence of BM involvement detected subtle BM involvement by ALCL in 13.7% of cases, which were predominantly ALK+. CONCLUSIONS: The immunohistopathological features of BM lesions in patients with ALCL differ according to ALK status and BM involvement pattern. CD30 is the most useful marker for the identification of BM lesions in ALCL patients and should be employed in all ALCL patients without exception, especially ALK+ cases. PMID- 23656318 TI - Multiplex immunoassay for persistent organic pollutants in tilapia: comparison of imaging- and flow cytometry-based platforms using spectrally encoded paramagnetic microspheres. AB - Recent developments in spectrally encoded microspheres (SEMs)-based technologies provide high multiplexing possibilities. Most SEMs-based assays require a flow cytometer with sophisticated fluidics and optics. A new imaging super paramagnetic SEMs-based alternative platform transports SEMs with considerably less fluid volume into a measuring chamber. Once there SEMs are held in a monolayer by a magnet. Light-emitting diodes (LEDs) are focused on the chamber to illuminate the SEMs - instead of lasers and they are imaged by a charge-coupled device (CCD) detector, offering a more compact sized, transportable and affordable system. The feasibility of utilising this system to develop a 3-plex SEMs-based imaging immunoassay (IMIA) for the screening of persistent organic pollutants (POPs) was studied. Moreover the performance characteristics of 3-plex IMIA were critically compared with the conventional 3-plex flow cytometric immunoassay (FCIA). Both SEM technologies have potential for the multiplex analysis of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and polycyclic aromatic hydrocarbons (PAHs) in buffer and fish extract with insignificant differences in assay sensitivities. Furthermore, we developed a faster and simpler, modified QuEChERS-like generic POPs extraction from tilapia fillet using sodium hydrogen carbonate as one of the salt additives and dispersive solid-phase extraction (dSPE) as a clean-up. Finally, a preliminary in house validation using 40 different blank and spiked tilapia fillet samples was performed in both systems and the results obtained were critically compared. The lower-cost imaging SEMs-based system performed similarly to the original flow cytometer and, in combination with the new quicker QuEChERS-like extraction, it has high potential for future rapid screening of POPs in several other sample matrices such as other fish species, vegetable refined oils and environmental samples. PMID- 23656321 TI - Scaffold diversification enhances effectiveness of a superlibrary of hyperthermophilic proteins. AB - The use of binding proteins from non-immunoglobulin scaffolds has become increasingly common in biotechnology and medicine. Typically, binders are isolated from a combinatorial library generated by mutating a single scaffold protein. In contrast, here we generated a "superlibrary" or "library-of libraries" of 4 * 10(8) protein variants by mutagenesis of seven different hyperthermophilic proteins; six of the seven proteins have not been used as scaffolds prior to this study. Binding proteins for five different model targets were successfully isolated from this library. Binders obtained were derived from five out of the seven scaffolds. Strikingly, binders from this modestly sized superlibrary have affinities comparable or higher than those obtained from a library with 1000-fold higher sequence diversity but derived from a single stable scaffold. Thus scaffold diversification, i.e., randomization of multiple different scaffolds, is a powerful alternate strategy for combinatorial library construction. PMID- 23656322 TI - Functional display of complex cellulosomes on the yeast surface via adaptive assembly. AB - A new adaptive strategy was developed for the ex vivo assembly of a functional tetravalent designer cellulosome on the yeast cell surface. The design is based on the use of (1) a surface-bound anchoring scaffoldin composed of two divergent cohesin domains, (2) two dockerin-tagged adaptor scaffoldins to amplify the number of enzyme loading sites based on the specific dockerin-cohesin interaction with the anchoring scaffoldin, and (3) two dockerin-tagged enzymatic subunits (the endoglucanse Gt and the beta-glucosidase Bglf) for cellulose hydrolysis. Cells displaying the tetravalent cellulosome on the surface exhibited a 4.2-fold enhancement in the hydrolysis of phosphoric acid swollen cellulose (PASC) compared with free enzymes. More importantly, cells displaying the tetravalent celluosome also exhibited an ~2-fold increase in ethanol production compared with cells displaying a divalent cellulosome using a similar enzyme loading. These results clearly indicate the more crucial role of enzyme proximity than just simply increasing the enzyme loading on the overall cellulosomal synergy. To the best of our knowledge, this is the first report that exploits the natural adaptive assembly strategy in creating artificial cellulosome structures. The unique feature of the anchoring and the adaptor scaffoldin strategy to amplify the number of enzymatic subunits can be easily extended to more complex cellulosomal structures to achieve an even higher level of enzyme synergy. PMID- 23656323 TI - TREX: a universal tool for the transfer and expression of biosynthetic pathways in bacteria. AB - Secondary metabolites represent a virtually inexhaustible source of natural molecules exhibiting a high potential as pharmaceuticals or chemical building blocks. To gain broad access to these compounds, sophisticated expression systems are needed that facilitate the transfer and expression of large chromosomal regions, whose genes encode complex metabolic pathways. Here, we report on the development of the novel system for the transfer and expression of biosynthetic pathways (TREX), which comprises all functional elements necessary for the delivery and concerted expression of clustered pathway genes in different bacteria. TREX employs (i) conjugation for DNA transfer, (ii) randomized transposition for its chromosomal insertion, and (iii) T7 RNA polymerase for unimpeded bidirectional gene expression. The applicability of the TREX system was demonstrated by establishing the biosynthetic pathways of two pigmented secondary metabolites, zeaxanthin and prodigiosin, in bacteria with different metabolic capacities. Thus, TREX represents a valuable tool for accessing natural products by allowing comparative expression studies with clustered genes. PMID- 23656324 TI - Synthetic oligonucleotide libraries reveal novel regulatory elements in Chlamydomonas chloroplast mRNAs. AB - Gene expression in chloroplasts is highly regulated during translation by sequence and secondary-structure elements in the 5' untranslated region (UTR) of mRNAs. These chloroplast mRNA 5' UTRs interact with nuclear-encoded factors to regulate mRNA processing, stability, and translation initiation. Although several UTR elements in chloroplast mRNAs have been identified by site-directed mutagenesis, the complete set of elements required for expression of plastid mRNAs remains undefined. Here we present a synthetic biology approach using an arrayed oligonucleotide library to examine in vivo hundreds of designed variants of endogenous UTRs from Chlamydomonas reinhardtii and quantitatively identify essential regions through next-generation sequencing of thousands of mutants. We validate this strategy by characterizing the relatively well-studied 5' UTR of the psbD mRNA encoding the D2 protein in photosystem II and find that our analysis generally agrees with previous work identifying regions of importance but significantly expands and clarifies the boundaries of these regulatory regions. We then use this strategy to characterize the previously unstudied psaA 5' UTR and obtain a detailed map of regions essential for both positive and negative regulation. This analysis can be performed in a high-throughput manner relative to previous site-directed mutagenesis methods, enabling compilation of a large unbiased data set of regulatory elements of chloroplast gene expression. Finally, we create a novel synthetic UTR based on aggregate sequence analysis from the libraries and demonstrate that it significantly increases accumulation of an exogenous protein, attesting to the utility of this strategy for enhancing protein production in algal chloroplasts. PMID- 23656325 TI - Transcription factor-based screens and synthetic selections for microbial small molecule biosynthesis. AB - Continued advances in metabolic engineering are increasing the number of small molecules being targeted for microbial production. Pathway yields and productivities, however, are often suboptimal, and strain improvement remains a persistent challenge given that the majority of small molecules are difficult to screen for and their biosynthesis does not improve host fitness. In this work, we have developed a generalized approach to screen or select for improved small molecule biosynthesis using transcription factor-based biosensors. Using a tetracycline resistance gene 3' of a small-molecule inducible promoter, host antibiotic resistance, and hence growth rate, was coupled to either small molecule concentration in the growth medium or a small-molecule production phenotype. Biosensors were constructed for two important chemical classes, dicarboxylic acids and alcohols, using transcription factor-promoter pairs derived from Pseudomonas putida, Thauera butanivorans, or E. coli. Transcription factors were selected for specific activation by either succinate, adipate, or 1 butanol, and we demonstrate product-dependent growth in E. coli using all three compounds. The 1-butanol biosensor was applied in a proof-of-principle liquid culture screen to optimize 1-butanol biosynthesis in engineered E. coli, identifying a pathway variant yielding a 35% increase in 1-butanol specific productivity through optimization of enzyme expression levels. Lastly, to demonstrate the capacity to select for enzymatic activity, the 1-butanol biosensor was applied as synthetic selection, coupling in vivo 1-butanol biosynthesis to E. coli fitness, and an 120-fold enrichment for a 1-butanol production phenotype was observed following a single round of positive selection. PMID- 23656326 TI - Expanding the product profile of a microbial alkane biosynthetic pathway. AB - Microbially produced alkanes are a new class of biofuels that closely match the chemical composition of petroleum-based fuels. Alkanes can be generated from the fatty acid biosynthetic pathway by the reduction of acyl-ACPs followed by decarbonylation of the resulting aldehydes. A current limitation of this pathway is the restricted product profile, which consists of n-alkanes of 13, 15, and 17 carbons in length. To expand the product profile, we incorporated a new part, FabH2 from Bacillus subtilis , an enzyme known to have a broader specificity profile for fatty acid initiation than the native FabH of Escherichia coli . When provided with the appropriate substrate, the addition of FabH2 resulted in an altered alkane product profile in which significant levels of n-alkanes of 14 and 16 carbons in length are produced. The production of even chain length alkanes represents initial steps toward the expansion of this recently discovered microbial alkane production pathway to synthesize complex fuels. This work was conceived and performed as part of the 2011 University of Washington international Genetically Engineered Machines (iGEM) project. PMID- 23656328 TI - Revelations of HIV-infected patients treated with highly active antiretroviral therapy (HAART) in rural Uganda. AB - The purpose of this qualitative study was to explore the psychosocial changes revealed by persons living with HIV/AIDS (PLWHA) in western Uganda as a result of the introduction of highly active antiretroviral therapy (HAART). Fourteen participants were interviewed on two occasions. Two focus groups discussions were also conducted. Patients experienced important personal benefits as a result of HAART and the resulting clinical improvement. These benefits included a restoration of hope, self-esteem and personal agency. Patients were also relieved of the great fear which they had about the conditions of their death. The financial and social struggles introduced by AIDS illness continued after the introduction of HAART. The conclusion is that the HAART programs should provide more holistic care to patients to address the persistent family issues identified in this study. PMID- 23656327 TI - Identification of substituted pyrimido[5,4-b]indoles as selective Toll-like receptor 4 ligands. AB - A cell-based high-throughput screen to identify small molecular weight stimulators of the innate immune system revealed substituted pyrimido[5,4 b]indoles as potent NFkappaB activators. The most potent hit compound selectively stimulated Toll-like receptor 4 (TLR4) in human and mouse cells. Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NFkappaB and type I interferon associated cytokines, IL-6 and interferon gamma-induced protein 10 (IP-10) respectively. Specifically, a subset of compounds bearing phenyl and substituted phenyl carboxamides induced lower IL-6 release while maintaining higher IP-10 production, skewing toward the type I interferon pathway. Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound. Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex. These small molecules, which stimulate innate immune cells with minimal toxicity, could potentially be used as adjuvants or immune modulators. PMID- 23656329 TI - Practical implications of understanding the influence of motivations on commitment to voluntary urban conservation stewardship. AB - Although the word commitment is prevalent in conservation biology literature and despite the importance of people's commitment to the success of conservation initiatives, commitment as a psychological phenomenon and its operation in specific conservation behaviors remains unexplored. Despite increasing calls for conservation psychology to play a greater role in meeting conservation goals, applications of the psychological sciences to specific conservation behaviors, illustrating their utility to conservation practice, are rare. We examined conservation volunteers' motivations and commitment to urban conservation volunteering. We interviewed key informant volunteers and used interview findings to develop psychometric scales that we used to assess motivations and commitment to volunteer. We surveyed 322 urban conservation volunteers and used factor analysis to reveal how volunteers structure their motivations and commitment to volunteer for urban conservation activities. Six categories of motivations and 2 categories of commitment emerged from factor analysis. Volunteers were motivated by desires to help the environment, defend and enhance the ego, career and learning opportunities, escape and exercise, social interactions, and community building. Two forms of commitment, affective and normative commitment, psychologically bind people to urban conservation volunteerism. We used linear regression models to examine how these categories of motivations influence volunteers' commitment to conservation volunteerism. Volunteers' tendency to continue to volunteer for urban conservation, even in the face of fluctuating counter urges, was motivated by personal, social, and community functions more than environmental motivations. The environment, otherwise marginally important, was a significant motivator of volunteers' commitment only when volunteering met volunteers' personal, social, and community-building goals. Attention to these personal, social, and community-building motivations may help enhance volunteers' commitment to conservation stewardship and address the pressing challenge of retaining urban conservation volunteers. PMID- 23656330 TI - The succinoglycan endoglycanase encoded by exoK is required for efficient symbiosis of Sinorhizobium meliloti 1021 with the host plants Medicago truncatula and Medicago sativa (Alfalfa). AB - The acidic polysaccharide succinoglycan produced by the nitrogen-fixing rhizobial symbiont Sinorhizobium meliloti 1021 is required for this bacterium to invade the host plant Medicago truncatula and to efficiently invade the host plant M. sativa (alfalfa). The beta-glucanase enzyme encoded by exoK has previously been demonstrated to cleave succinoglycan and participate in producing the low molecular weight form of this polysaccharide. Here, we show that exoK is required for efficient S. meliloti invasion of both M. truncatula and alfalfa. Deletion mutants of exoK have a substantial reduction in symbiotic productivity on both of these plant hosts. Insertion mutants of exoK have an even less productive symbiosis than the deletion mutants with the host M. truncatula that is caused by a secondary effect of the insertion itself, and may be due to a polar effect on the expression of the downstream exoLAMON genes. PMID- 23656331 TI - Subcellular dynamics and role of Arabidopsis beta-1,3-glucanases in cell-to-cell movement of tobamoviruses. AB - beta-1,3-Glucanases (BG) have been implicated in enhancing virus spread by degrading callose at plasmodesmata (Pd). Here, we investigate the role of Arabidopsis BG in tobamovirus spread. During Turnip vein clearing virus infection, the transcription of two pathogenesis-related (PR)-BG AtBG2 and AtBG3 increased but that of Pd-associated BG AtBG_pap did not change. In transgenic plants, AtBG2 was retained in the endoplasmic reticulum (ER) network and was not secreted. As a stress response mediated by salicylic acid, AtBG2 was secreted and appeared as a free extracellular protein localized in the entire apoplast but did not accumulate at Pd sites. At the leading edge of Tobacco mosaic virus spread, AtBG2 co-localized with the viral movement protein in the ER-derived bodies, similarly to other ER proteins, but was not secreted to the cell wall. In atbg2 mutants, callose levels at Pd and virus spread were unaffected. Likewise, AtBG2 overexpression had no effect on virus spread. However, in atbg_pap mutants, callose at Pd was increased and virus spread was reduced. Our results demonstrate that the constitutive Pd-associated BG but not the stress-regulated extracellular PR-BG are directly involved in regulation of callose at Pd and cell-to-cell transport in Arabidopsis, including the spread of viruses. PMID- 23656332 TI - Expression analysis of aquaporins from desert truffle mycorrhizal symbiosis reveals a fine-tuned regulation under drought. AB - We have performed the isolation, functional characterization, and expression analysis of aquaporins in roots and leaves of Helianthemum almeriense, in order to evaluate their roles in tolerance to water deficit. Five cDNAs, named HaPIP1;1, HaPIP1;2, HaPIP2;1, HaPIP2;2, and HaTIP1;1, were isolated from H. almeriense. A phylogenetic analysis of deduced proteins confirmed that they belong to the water channel proteins family. The HaPIP1;1, HaPIP2;1, and HaTIP1;1 genes encode functional water channel proteins, as indicated by expression assays in Saccharomyces cerevisiae, showing divergent roles in the transport of water, CO2, and NH3. The expression patterns of the genes isolated from H. almeriense and of a previously described gene from Terfezia claveryi (TcAQP1) were analyzed in mycorrhizal and nonmycorrhizal plants cultivated under well-watered or drought stress conditions. Some of the studied aquaporins were subjected to fine-tuned expression only under drought-stress conditions. A beneficial effect on plant physiological parameters was observed in mycorrhizal plants with respect to nonmycorrhizal ones. Moreover, stress induced a change in the mycorrhizal type formed, which was more intracellular under drought stress. The combination of a high intracellular colonization, together with the fine-tuned expression of aquaporins could result in a morphophysiological adaptation of this symbiosis to drought conditions. PMID- 23656334 TI - A call to ARMs: the promise of immunomodulatory small molecules. PMID- 23656335 TI - New medicines for type 2 diabetes in adolescents: many products, few patients. PMID- 23656333 TI - The role of Arabidopsis heterotrimeric G-protein subunits in MLO2 function and MAMP-triggered immunity. AB - Heterotrimeric G-proteins, composed of Galpha, Gbeta, and Ggamma subunits, regulate many fundamental processes in plants. In animals, ligand binding to seven transmembrane (7TM) cell surface receptors designated G-protein coupled receptors (GPCR) leads to heterotrimeric G-protein activation. Because the plant G-protein complex is constitutively active, the exact role of plant 7TM proteins in this process is unclear. Members of the mildew resistance locus O (MLO) family represent the best-characterized 7TM plant proteins. Although genetic ablation of either MLO2 or G-proteins alters susceptibility to pathogens in Arabidopsis thaliana, it is unknown whether G-proteins directly couple signaling through MLO2. Here, we exploited two well-documented phenotypes of mlo2 mutants, broad spectrum powdery mildew resistance and spontaneous callose deposition in leaf mesophyll cells, to assess the relationship of MLO2 proteins to the G-protein complex. Although our data reveal modulation of antifungal defense responses by Gbeta and Ggamma subunits and a role for the Ggamma1 subunit in mlo2-conditioned callose deposition, our findings overall are inconsistent with a role of MLO2 as a canonical GPCR. We discovered that mutants lacking the Gbeta subunit show delayed accumulation of a subset of defense-associated genes following exposure to the microbe-associated molecular pattern flg22. Moreover, Gbeta mutants were found to be hypersusceptible to spray inoculation with the bacterial pathogen Pseudomonas syringae. PMID- 23656337 TI - Fixed-dose combination of phentermine-topiramate for the treatment of obesity. AB - The aim of this article is to focus on the fixed-dose combination of phentermine and topiramate, a new antiobesity drug recently approved by the US FDA. The mechanisms of weight loss for each drug in monotherapy is described, followed by the rationale for its use as a combination therapy and a comprehensive review of recently published clinical trials that assessed its efficacy and safety. PMID- 23656338 TI - Regorafenib: from bench to bedside in colorectal cancer. AB - Colorectal cancer (CRC) remains the third cause of cancer-related mortality in the USA. Despite the advances in screening, many patients present with incurable metastatic disease. Chemotherapy forms the basis of treatment for patients with advanced disease. Angiogenesis is an important step in developing metastases and, therefore, blocking the VEGF pathway seems promising. The development of bevacizumab as a monoclonal antibody targeting the VEGF pathway improved progression-free survival and overall survival in the metastatic settings, with no improvement in disease-free or overall survival in the adjuvant settings. Small molecules such as tyrosine-kinase inhibitors have been long evaluated in metastatic CRC with disappointing results in improving outcome. Most recently, the CORRECT study has resulted in improved outcome in patients with metastatic CRC who were heavily pretreated when they received regorafenib. PMID- 23656340 TI - The pathophysiological and pharmacological basis of current drug treatment of migraine headache. AB - Migraine is a common neurological syndrome that affects approximately 10-20% of the population. The pathophysiology of migraine is unclear. 5-hydroxytriptamine is a key mediator in the pathogenesis of migraine and thus 5-HT1-receptor agonists are the principal drugs for acute migraine therapy. There are three classes of drugs for migraine: over-the-counter analgesics and nonsteroidal anti inflammatory drugs for acute mild migraine, specific prescription drugs (triptans and ergot alkaloids) for acute severe migraine and pharmacological agents for prophylaxis of migraine. Sumatriptan, naratriptan and others, referred to as 'triptans', are the mainstay for acute treatment of migraine. Ergot alkaloids (ergotamine, dihydroergotamine) are used in patients with frequent, moderate migraine, but are less effective than triptans. There are several agents for prevention of migraine occurrence in patients with frequent or severe disabling migraine attacks. New drugs with improved efficacy and reduced side effects are needed for effective treatment and prevention of migraine. PMID- 23656341 TI - The potential and promise of mefenamic acid. AB - Clinical use of mefenamic acid has generally declined in an era where other NSAID use has flourished. While having modes of action and general toxicities similar to other NSAIDs, mefenamic acid, as a member of the fenamates, nevertheless possesses some unique in vitro effects that have the potential to distinguish this agent from others. Use of this drug remains relevant for pain syndromes and some gynecological disorders, albeit with considerable competition from other NSAIDs. New basic science has considerably improved the understanding of the biochemistry of mefenamic acid. As well as maintaining its use in traditional settings, there is a tremendous potential for expanding the application of mefenamic acid to niche roles. PMID- 23656342 TI - Emerging artemisinin resistance in the border areas of Thailand. AB - Emergence of artemisinin resistance has been confirmed in Cambodia and the border areas of Thailand, the well-known hotspots of multidrug resistance Plasmodium falciparum. It appears to be spreading to the western border of Thailand along the Thai-Myanmar border, and will probably spread to other endemic areas of the world in the near future. This raises a serious concern on the long-term efficacy of artemisinin-based combination therapies, as these combination therapies currently constitute the last effective and most tolerable treatment for multidrug-resistant Plasmodium falciparum. Attempts have been made by a diverse array of stakeholders to prevent the emergence of new foci of artemisinin resistance, as well as to limit the spread of resistance to the original foci. The success in achieving this goal depends on effective integration of containment and surveillance programs with other malaria control measures, with support from both basic and operational research. PMID- 23656343 TI - Phosphodiesterase inhibitors in clinical urology. AB - To date, benign diseases of the male and female lower urinary and genital tract, such as erectile dysfunction, bladder overactivity, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and symptoms of female sexual dysfunction (including arousal and orgasmic disorders), can be therapeutically approached by influencing the function of the smooth musculature of the respective tissues. The use of isoenzyme-selective phosphodiesterase (PDE) inhibitors is considered a great opportunity to treat various diseases of the human urogenital tract. PDE inhibitors, in particular the PDE5 (cyclic GMP PDE) inhibitors avanafil, lodenafil, sildenafil, tadalafil, udenafil and vardenafil, are regarded as efficacious, having a fast onset of drug action and an improved effect-to-adverse event ratio, combining a high response rate with the advantage of an on-demand intake. The purpose of this review is to summarize recent as well as potential future indications, namely, erectile dysfunction, Peyronie's disease, overactive bladder, urinary stone disease, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and premature ejaculation, for the use of PDE inhibitors in clinical urology. PMID- 23656339 TI - A review of pharmacological interactions between HIV or hepatitis C virus medications and opioid agonist therapy: implications and management for clinical practice. AB - Global access to opioid agonist therapy and HIV/hepatitis C virus (HCV) treatment is expanding but when used concurrently, problematic pharmacokinetic and pharmacodynamic interactions may occur. Articles published from 1966 to 2012 in Medline were reviewed using the following keywords: HIV, AIDS, HIV therapy, HCV, HCV therapy, antiretroviral therapy, highly active antiretroviral therapy, drug interactions, methadone and buprenorphine. In addition, a review of abstracts from national and international meetings and conference proceedings was conducted; selected reports were reviewed as well. The metabolism of both opioid and antiretroviral therapies, description of their known interactions and clinical implications and management of these interactions were reviewed. Important pharmacokinetic and pharmacodynamic drug interactions affecting either methadone or HIV medications have been demonstrated within each class of antiretroviral agents. Drug interactions between methadone, buprenorphine and HIV medications are known and may have important clinical consequences. Clinicians must be alert to these interactions and have a basic knowledge regarding their management. PMID- 23656344 TI - Epilepsy in glioblastoma patients: basic mechanisms and current problems in treatment. AB - Glioblastoma-related epilepsy requires paying careful attention to a combination of factors with an integrated approach. Major interrelated issues must be considered in the seizure care of glioblastoma patients. Seizure control frequently requires the administration of antiepileptic drugs simultaneously with other treatments, including surgery, radiotherapy and chemotherapy, with complete seizure relief often being difficult to achieve. The pharmacological interactions between antiepileptic drugs and antineoplastic agents can modify the activity of both treatments, compromising their efficacy and increasing the probability of developing adverse events related to both therapies. This review summarizes the new pathophysiological pathways involved in the epileptogenesis of glioblastoma related seizures and the interactions between antiepileptic drugs and oncological treatment, paying special attention to its impact on survival and the current evidence of the antiepileptic treatment efficacy, including the potential usefulness of new third-generation compounds. PMID- 23656346 TI - The postschool outcomes of students with mild intellectual disability: does it get better with time? AB - BACKGROUND: Although students with mild intellectual disability (MID) present unique educational needs and considerations, in research and in practice, they are sometimes aggregated with students with learning disabilities and emotional disorders and considered mild disabilities or aggregated with students with moderate/severe intellectual disability and labelled as intellectual disability. METHOD: This study is a secondary analysis of the NLTS2 data to understand the immediate (i.e. within 2 years) and longer-term outcomes (i.e. within 4 years, within 6 years and within 8 years) of secondary students with MID. Frequency distributions and a significant test were conducted to analyse data from the NLTS2. RESULTS: Students with MID struggled with postschool success when considering employment, postsecondary education, and independent living. Across the span of time since graduation (i.e. within 2 years, within 4 years, within 6 years, and within 8 years), a lack of consistent pattern existed, in general, for these students with regards to outcomes. Students did not necessarily improve or decline in their outcomes the longer they were out of school. CONCLUSIONS: The postschool outcome data warrant critical examination of the factors contributing to the poor outcomes. The field needs to systematically understand what schools can control with regards to improved outcomes for students with MID - particularly employment regardless of the length of time out of school and independent living as the time since school exit increases - and then implement such practices. PMID- 23656347 TI - NCS 613 exhibits anti-inflammatory effects on PBMCs from lupus patients by inhibiting p38 MAPK and NF-kappaB signalling pathways while reducing proinflammatory cytokine production. AB - Systemic lupus erythematosus (SLE) is a polymorphic and multigenic autoimmune disease that evolves into progressive and chronic inflammation of multiple joints and organs. Phosphorylation and activation of p38 MAPK, along with the resulting overproduction of interleukin (IL)-1beta, IL-6, and tumour necrosis factor (TNF) alpha is a hallmark of inflammatory disorders. Here, we investigated the anti inflammatory pathway modulated by NCS 613, a specific PDE4 inhibitor, on human peripheral blood mononuclear cells (PBMCs) from 5 healthy donors and 12 SLE patients. PDE4 subtypes, p38 MAPK, and IkappaBalpha protein levels were analyzed by Western blot, while NF-kappaB and PDE4B immunostaining was assessed in control and lipopolysaccharide (LPS) -pretreated PBMCs. Proinflammatory cytokines were quantified by ELISA, while IL-1beta mRNA was resolved by RT-qPCR. NCS 613 treatment decreased PDE4B and upregulated PDE4C in human PBMCs from healthy donors and SLE patients. LPS stimulation increased p38 MAPK phosphorylation and NF-kappaB translocation to the nucleus, which was abolished by NCS 613 treatment. Concomitantly, NCS 613 restored IkappaBalpha detection levels in human PBMCs from both healthy donors and SLE patients. This compound also abolished LPS-induced inflammation in PBMCs by reducing IL-6, IL-8, and TNF-alpha cytokines. NCS 613 is a small molecule displaying anti-inflammatory properties that may provide an alternative or complementary strategy for SLE management. PMID- 23656348 TI - HgrA is necessary and sufficient to drive hyphal growth in the dimorphic pathogen Penicillium marneffei. AB - Fungi produce multiple morphological forms as part of developmental programs or in response to changing, often stressful, environmental conditions. An opportunistic pathogen of humans, Penicillium marneffei displays multicellular hyphal growth and asexual development (conidiation) in the environment at 25 degrees C and unicellular yeast growth in macrophages at 37 degrees C. We characterized the transcription factor, hgrA, which contains a C(2)H(2) DNA binding domain closely related to that of the stress-response regulators Msn2/4 of Saccharomyces cerevisiae. Northern hybridization analysis demonstrated that hgrA expression is specific to hyphal growth, and its constitutive overexpression prevents conidiation and yeast growth, even in the presence of inductive cues, and causes apical hyperbranching during hyphal growth. Consistent with its expression pattern, deletion of hgrA causes defects in hyphal morphogenesis and the dimorphic transition from yeast cells to hyphae. Specifically, loss of HgrA causes cell wall defects, reduced expression of cell wall biosynthetic enzymes and increased sensitvity to cell wall, oxidative, but not osmotic stress agents. These data suggest that HgrA does not have a direct role in the response to stress but is an inducer of the hyphal growth program and its activity must be downregulated to allow alternative developmental programs, including the morphogenesis of yeast cells in macrophages. PMID- 23656349 TI - A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands. AB - NF1 mutations are the underlying cause of neurofibromatosis type 1 (NF1), a neuro cardio-facio-cutaneous syndrome (NCFC). Because of the clinical overlap between NCFCs, genetic analysis of NF1 is necessary to confirm a clinical diagnosis NF1. This report describes the clinical and genetic findings of 18 years of NF1 molecular diagnostics in the Netherlands. A pathogenic mutation was found in 59.3% (1178/1985) of the index patients, mostly de novo (73.8%). The majority of the index patients (64.3%) fulfilled the National Institute of Health NF1 criteria, a pathogenic mutation was found in 80.9% of these patients. Seventy four percent of the index patients with an NF1 pathogenic mutation and not fulfilling the NF1 criteria is <12 years, in agreement with the fact that some NF1 symptoms appear after puberty. Genotype-phenotype correlations were studied for 527 index patients. NF1 patients with a type 1 microdeletion have a sixfold higher risk of special education vs NF1 patients with an intragenic mutation. No evidently milder NF1 phenotype for patients with a missense mutation was observed. Forty-six prenatal analyses were performed in 28 (2.4%) families, of which 29 (63%) showed heterozygosity for the familial pathogenic mutation. This indicates that there is a need for prenatal NF1 testing. PMID- 23656350 TI - Segmentally structured disk triboelectric nanogenerator for harvesting rotational mechanical energy. AB - We introduce an innovative design of a disk triboelectric nanogenerator (TENG) with segmental structures for harvesting rotational mechanical energy. Based on a cyclic in-plane charge separation between the segments that have distinct triboelectric polarities, the disk TENG generates electricity with unique characteristics, which have been studied by conjunction of experimental results with finite element calculations. The role played by the segmentation number is studied for maximizing output. A distinct relationship between the rotation speed and the electrical output has been thoroughly investigated, which not only shows power enhancement at high speed but also illuminates its potential application as a self-powered angular speed sensor. Owing to the nonintermittent and ultrafast rotation-induced charge transfer, the disk TENG has been demonstrated as an efficient power source for instantaneously or even continuously driving electronic devices and/or charging an energy storage unit. This work presents a novel working mode of TENGs and opens up many potential applications of nanogenerators for harvesting even large-scale energy. PMID- 23656352 TI - Long-term outcomes for the treatment of atrophic posterior maxilla: a systematic review of literature. AB - PURPOSE: The aim of the present systematic review was to estimate the implant survival rate in different types of techniques for the rehabilitation of posterior atrophic maxilla, after at least 3 years of follow-up. MATERIALS AND METHODS: MEDLINE database was searched using a combination of specific terms. A hand searching of the relevant journals and of the reference lists of systematic reviews was also performed. All retrospective and prospective studies evaluating short implants in posterior maxilla, osteotome sinus floor elevation and lateral approach sinus floor elevation, and having a follow-up of at least 3 years, were included. RESULTS: Forty-four articles were included in the review. In four studies reporting on a total of 901 short implants, the implant survival rate varied from 86.5% to 98.2% with up to 5 years follow-up. For the osteotome technique, 1,208 implants in eight studies were considered, showing a survival rate varying from 95.4% to 100% after 3-year follow-up. Twenty-nine studies, accounting for 6,940 implants placed in 2,707 sinuses augmented through lateral technique were considered. Implant survival rate varied from 75.57% to 100%. Only three comparative studies were found that showed no significant difference in clinical outcomes between lateral approach and osteotome technique. CONCLUSIONS: Sinus floor elevation with the lateral approach and with the osteotome technique is an effective and well-documented therapeutic option for the rehabilitation of atrophic posterior maxilla. The use of short implants is promising but needs further investigation to be considered as effective as the other techniques in the long term. However, the indication for the three different techniques is not perfectly equivalent and the treatment choice should be based on a careful evaluation of the individual case, in particular on the available residual bone. PMID- 23656351 TI - Is high oral dose L-arginine intake effective in leukoaraiosis? Preliminary data, study protocol and expert's opinion. AB - BACKGROUND: Leukoraraiosis is worldwide considered as a part of the normal aging process, although it is strongly associated with dementia and other disabilities. The pathogenesis of leukoaraiosis still has not been thoroughly acknowledged, even though chronic ischemia with consequent arteriolosclerosis probably due to endothelial dysfunction has been suggested. Treatment focuses on prevention of lesion formation and progression by aggressive control of risk factors, which should begin at an early age and continue on regular basis. Aim of our protocol is to evaluate the effect of long-term oral administration of high-dose L arginine (6 g/day at least for 24 months) on white matter lesions and neurological and cognitive functions. MATERIALS AND METHODS: Patients affected by mild to moderate leukoaraiosis will be enrolled in the study. After a complete neurovascular assessment (i.e. accurate blood test examinations, Echocardiography, Doppler ultrasound of the neck and peripheral arteries), they will undergo MRI, specific neuropsychological tests and gait analysis. Patients will be evaluated at baseline, at 6, 12, 18 and 24 month-follow up. Statistical Analysis will be performed using the software R. A significant level of P<0.05 will be set for all the tests. PRELIMINARY DATA: Two of the 4 patients currently enrolled in the study presented a mild improvement in cognitive function. DISCUSSION: Because of its high prevalence in over-65-year-old subjects, we hypothesized that treatment with 6 gr of Larginine, as supplementary dietary option, could be helpful in patients affected by leukoaraiosis to improve the cognitive and gait impairment often observed in these subjects (as demonstrated by the LADIS study). PMID- 23656353 TI - Simulation of two-dimensional sum-frequency generation response functions: application to amide I in proteins. AB - We present the implementation of an approach to simulate the two-dimensional sum frequency generation response functions of systems with numerous coupled chromophores using a quantum-classical simulation scheme that was previously applied successfully to simulate two-dimensional infrared spectra. We apply the simulation to the amide I band of a mechanosensitive channel protein. By examining the signal generated from different segments of the protein, we find that the overall signal is impossible to interpret without the aid of simulations due to the interference of the response generated on different segments of the protein. We do not find significant cross-peaks in the spectra, even when the waiting time is increased. The spectra are thus not sensitive to coupling between different structural elements. Despite this, we conclude that two-dimensional sum frequency generation spectroscopy will be a powerful tool to investigate membrane bound proteins. PMID- 23656354 TI - Workplace-based assessment in surgical training: experiences from the Intercollegiate Surgical Curriculum Programme. AB - BACKGROUND: The Intercollegiate Surgical Curriculum Programme was launched in the United Kingdom in 2007. At its heart was the reliance upon clear, defined curricula, competence-based training and the use of workplace-based assessments to assess the competence. The principle assessments used were Case-based Discussion, Procedure-based Assessments (PBA), Direct Observation of Procedural Skills, and Clinical Evaluation Exercise and a Multisource Feedback tool. METHODS: We report the initial experience with that system, and most importantly, the experience with workplace-based assessment. RESULTS: Themes include issues around faculty development, misuse of assessments, inappropriate timing of assessments, concerns about validity and reliability of the assessments and concerns about the actual process of workplace-based assessments. Of the assessments, the PBA performed best. CONCLUSIONS: As a consequence, there has been an increased focus upon faculty development, while some of the assessments have been redesigned in line with the PBA. A global rating scale has been introduced that uses clinical anchors. The rating scales have also been altered with a reduction in the number of ratings while an enhanced description of the complexity of the case has been introduced within the Case-based Discussion and the Clinical Evaluation Exercise. A re-evaluation will take place in the near future. PMID- 23656355 TI - Normal variability of children's scaled scores on subtests of the Dutch Wechsler Preschool and Primary scale of Intelligence - third edition. AB - Intelligence tests are included in millions of assessments of children and adults each year (Watkins, Glutting, & Lei, 2007a , Applied Neuropsychology, 14, 13). Clinicians often interpret large amounts of subtest scatter, or large differences between the highest and lowest scaled subtest scores, on an intelligence test battery as an index for abnormality or cognitive impairment. The purpose of the present study is to characterize "normal" patterns of variability among subtests of the Dutch Wechsler Preschool and Primary Scale of Intelligence - Third Edition (WPPSI-III-NL; Wechsler, 2010 ). Therefore, the frequencies of WPPSI-III-NL scaled subtest scatter were reported for 1039 healthy children aged 4:0-7:11 years. Results indicated that large differences between highest and lowest scaled subtest scores (or subtest scatter) were common in this sample. Furthermore, degree of subtest scatter was related to: (a) the magnitude of the highest scaled subtest score, i.e., more scatter was seen in children with the highest WPPSI-III NL scaled subtest scores, (b) Full Scale IQ (FSIQ) scores, i.e., higher FSIQ scores were associated with an increase in subtest scatter, and (c) sex differences, with boys showing a tendency to display more scatter than girls. In conclusion, viewing subtest scatter as an index for abnormality in WPPSI-III-NL scores is an oversimplification as this fails to recognize disparate subtest heterogeneity that occurs within a population of healthy children aged 4:0-7:11 years. PMID- 23656356 TI - Modelling training response in elite female gymnasts and optimal strategies of overload training and taper. AB - The aim of the study is the modelling of training responses with a variable dose response model in a sport discipline that requires highly complex coordination. We propose a method to optimise the training programme plan using the potential maximal performance gain associated with overload and tapering periods. Data from five female elite gymnasts were collected over a 3-month training period. The relationship between training amounts and performance was then assessed with a non-linear model. The optimal magnitude of training load reduction and its duration were investigated with and without an overload period using simulation procedures based on individual responses to training. The correlation between actual and modelled performances was significant (R2 = 0.81 +/- 0.02, P < 0.01). The standard error was 2.7%. Simulations revealed that taper preceded by an overload period allows a higher performance to be achieved compared to an absence of overload period (106.3 +/- 0.3% vs. 105.1 +/- 0.3%). With respect to the pre taper load, the model predicts that optimal load reductions during taper were 48.4 +/- 0.7% and 42.5 +/- 1.0% for overloading and non-overloading strategies, respectively. Moreover, optimal durations of the taper period were 34 +/- 0.5 days and 22 +/- 0.5 days for overloading and non-overloading strategies, respectively. In conclusion, the study showed that the variable dose-response model describes precisely the training response in gymnasts. PMID- 23656357 TI - Ab initio/GIAO-CCSD(T) calculated 13C-11B NMR chemical shift relationships in isoelectronic hypercoordinate carbonium and boronium as well as carbenium and borenium ions. AB - Good linear correlations between GIAO-CCSD(T) calculated (11)B NMR chemical shifts of hypercoordinate boronium 1-6b and borenium 7-9b ions and (13)C NMR chemical shifts of the corresponding isoelectronic carbonium 1-6a and carbenium 7 9a ions, respectively, were found. PMID- 23656358 TI - Fungal infections after liver transplantation: outcomes and risk factors revisited in the MELD era. AB - Antifungal prophylaxis is recommended in high-risk patients, but risk criteria remain unclear and the predictive value of Model of End-Stage Liver Disease (MELD) score is unknown. In a retrospective, single-center analysis of 667 liver transplants, potential risk factors for fungal infection were assessed, including MELD score. Antifungal prophylaxis was administered in 198 patients (29.4%). During follow-up (mean 43.6 +/- 29.6 months), 263 patients (39.4%) developed >= 1 episode of fungal infection, and 187 (28.0%) patients developed a probable or proven invasive fungal infection requiring systemic antifungal treatment. Patients receiving antifungal prophylaxis had a lower incidence of fungal infection (29.8% vs. 43.5% without prophylaxis, p < 0.001) and invasive fungal infection (17.7% vs. 32.4%, p < 0.001). One-yr patient survival was 91%, 85% and 69%, respectively, in patients with no fungal infection, fungal colonization and treated invasive fungal infection (p < 0.001); graft survival was 88%, 85% and 66% (p < 0.001). Multivariate analysis indicated that MELD score of 20-30 or >= 30 was associated with a 2.0-fold or 4.3-fold increase in relative risk of fungal infection, respectively, and a 2.1-fold or 3.1-fold increase in relative risk of invasive fungal infection. In conclusion, liver transplant patients with a MELD score >= 20, and particularly patients with a score >= 30, are candidates for antifungal prophylaxis. PMID- 23656359 TI - Impact of Euro-Canadian agrarian practices: in search of sustainable import substitution strategies to enhance food security in subarctic Ontario, Canada. AB - INTRODUCTION: In Canada, food insecurity exists among Aboriginal (Inuit, Metis and First Nations) people living in remote northern communities, in part, because of their reliance on the industrialized, import-based food system. Local food production as a substitute to imports would be an adaptive response, but enhancement of food security via food localization requires reflection on previous failings of conventional agricultural strategies so that informed decisions can be made. In light of potential reintroduction of local food production in remote First Nations communities, we investigated the cultural, social and ecological effects of a 20th century, Euro-Canadian agrarian settlement on the food system of a subarctic First Nation; this will act as the first step in developing a more sustainable local food program and enhancing food security in this community. METHODS: To investigate the socio-cultural impacts of the Euro-Canadian agrarian initiative on the food system of Fort Albany First Nation, purposive, semi-directive interviews were conducted with elders and other knowledgeable community members. Interview data were placed into themes using inductive analyses. To determine the biophysical impact of the agrarian initiative, soil samples were taken from one site within the cultivated area and from one site in an undisturbed forest area. Soil properties associated with agricultural use and productivity were assessed. To compare the means of a given soil property between the sites, one-tailed t-tests were employed. Vegetative analysis was conducted in both sites to assess disturbance. RESULTS: According to the interviewees, prior to the agrarian initiative, First Nation families harvested wild game and fish, and gathered berries as well as other forms of vegetation for sustenance. With the introduction of the residential school and agrarian initiative, traditional food practices were deemed inadequate, families were forced to work and live in the settlement (becoming less reliant on traditional foods), and yet little knowledge sharing of agricultural practices occurred. When the residential school and agrarian movement came to an end in the 1970s, First Nation community members were left to become reliant on an import food system. The mission's agrarian techniques resulted in overall degradation of soil quality and ecological integrity: compared the natural boreal forest, the cultivated area had been colonized by invasive species and had significantly lower soil levels of nitrogen, magnesium and organic carbon, and significantly higher levels of phosphorus and bulk density. CONCLUSIONS: Because the agrarian initiative was not a viable long-term approach to food security in Fort Albany, the people became more reliant on imported goods. Taking into account climate change, there exists an opportunity whereby fruits and vegetables, historically stunted-in-growth or outside the distributional range of subarctic Canada, could now grow in the north. Together, agroecosystem stewardship practices and community-based, autonomous food security programs have the potential to increase locally grown food availability in a sustainable manner. PMID- 23656360 TI - Optimized method of G-protein-coupled receptor homology modeling: its application to the discovery of novel CXCR7 ligands. AB - Homology modeling of G-protein-coupled seven-transmembrane receptors (GPCRs) remains a challenge despite the increasing number of released GPCR crystal structures. This challenge can be attributed to the low sequence identity and structural diversity of the ligand-binding pocket of GPCRs. We have developed an optimized GPCR structure modeling method based on multiple GPCR crystal structures. This method was designed to be applicable to distantly related receptors of known structural templates. CXC chemokine receptor (CXCR7) is a potential drug target for cancer chemotherapy. Homology modeling, docking, and virtual screening for CXCR7 were carried out using our method. The predicted docking poses of the known antagonists were different from the crystal structure of human CXCR4 with the small-molecule antagonist IT1t. Furthermore, 21 novel CXCR7 ligands with IC50 values of 1.29-11.4 MUM with various scaffolds were identified by structure-based virtual screening. PMID- 23656361 TI - Perceived unmet supportive care needs and determinants of quality of life among head and neck cancer survivors: a research protocol. AB - AIM: To describe a study protocol designed to explore the associations among the perceived unmet supportive care needs, quality of life and the demographic and clinical characteristics of head and neck cancer survivors. BACKGROUND: The prognoses for people with head and neck cancer are improving with medical advances. However, studies have reported that such cancer survivors experience poor quality of life. Current studies mainly focus on Western populations and there is limited research investigating the needs of head and neck cancer survivors. DESIGN: A mixed-design method is proposed, which will include two phases. Phase I will use a quantitative cross-sectional design and Phase II a qualitative descriptive approach. METHODS: The participants will be recruited from the outpatient departments of three public hospitals in Hong Kong. In Phase I, a questionnaire will be used to collect demographic and clinical characteristics, supportive care needs, necessary access to various supportive services and quality of life. Semi-structured interviews will be conducted in Phase II. The study is supported by a grant from the Health and Health Services Research Fund, Hong Kong, September 2011. DISCUSSION: The study will generate in depth information on the needs of head and neck cancer survivors, to help healthcare professionals allocate resources better and develop new services, which can be more person-centred, to meet the needs of the these survivors. PMID- 23656364 TI - Determination of imidocarb residues in bovine and ovine liver and milk by immunobiosensor. AB - Imidocarb (IMD) is a veterinary drug that has been used for more than 30 years to treat and prevent parasitic diseases. Pharmacokinetic studies have shown that substantial levels of IMD residues are retained in the edible tissues and milk of cattle and sheep for up to 6 months after administration. This has led to concern regarding the potential adverse effects posed through human consumption of edible tissue or milk from treated animals if the recommended withdrawal periods for the drug are not properly implemented. While MRLs have been established by the European Union, it is important that analytical methods are available to monitor food samples for potentially violative levels of IMD residues. A qualitative biosensor-based immunoassay was developed to allow the detection of IMD at less than the European Union MRLs of 50 MUg kg(-1) for milk and 2 mg kg(-1) for bovine and ovine liver. Validation of the developed methods provided a detection capability of <25 MUg kg(-1) in milk and <0.75 mg kg(-1) in liver. A comparison study was undertaken, with IMD incurred milk and ovine liver samples analysed by the newly developed procedures and results compared with those obtained by LC MS/MS. The newly developed screening method was applied to both incurred milk and liver samples. This faster, cheaper and reliable screening method has potential use in sample analysis to ensure compliance with legislative requirements. PMID- 23656366 TI - Structure-property relationship of perylene bisimide macrocycles probed by atomic force microscopy and single-molecule fluorescence spectroscopy. AB - Properties of a series of acetylene-linked perylene bisimide (PBI) macrocycles with different ring size composed of three to six PBI dyes were investigated by atomic force microscopy (AFM) and single-molecule fluorescence spectroscopy in a condensed phase. It was demonstrated that the structures of PBI cyclic arrays (CNs, N = 3, 4, 5, and 6) become distorted with increasing the ring size through molecular dynamics (MD) simulations (PM6-DH2 method) and AFM height images of CNs on highly ordered pyrolytic graphite (HOPG) surface. The MD simulations showed that only C5 and C6 rings are highly flexible molecules whose planarization goes along with a significant energetic penalty. Accordingly, both molecules did not show ordered adlayers on a HOPG surface. In contrast, C3 and C4 are far more rigid molecules leading to well-ordered hexagonal (C3) and rectangular (C4) 2D lattices. At the single-molecule level, we showed that the fluorescence properties of single CNs are affected by the structural changes. The fluorescence lifetimes of CNs became shorter and their distributions became broader due to the structural distortions with increasing the ring size. Furthermore, the CNs of smaller ring size exhibit a higher photostability and an efficient excitation energy transfer (EET) due to the more well-defined and planar structures compared to the larger CNs. Consequently, these observations provide evidence that not only PBI macrocycles are promising candidates for artificial light-harvesting systems, but also the photophysical properties of CNs are strongly related to the structural rigidity of CNs. PMID- 23656365 TI - Effects of a one-hour intervention on condom implementation intentions among drug users in Southern California. AB - Approximately 36% of HIV cases are related to substance abuse. Substance abusers, including non-injection drug users, are at a high-risk for contracting HIV due to risky behaviors, including unprotected sex. Due to these behavioral and infection risks, feasible interventions that focus on condom use within this population are imperative. The current study involved the development of brief intervention designed to increase implementation intentions (situation-linked action plans) to use condoms in convicted non-violent drug offenders participating in drug diversion programs in Southern California. Participants (n = 143) were randomized at the individual level to either waitlist control or experimental conditions. The randomized waitlist control group received the HIV survey for the pre-test before the intervention, while the experimental group received a neutral, non-HIV related, survey at pre-test. The experimental group received the HIV survey as the post-test after the intervention (waitlist control group received the neutral, non-HIV-related, survey). One-tailed Mann Whitney U tests were used to compare the waitlist control and experimental groups. The experimental group was more likely to report stronger implementation intentions to use condoms (p <0.001). These results indicate in the short term that a brief, easily disseminated HIV intervention can be effective for increasing implementation intentions to use condoms in an extremely high HIV-risk population. PMID- 23656367 TI - Delineating the contribution of long-term associations to immediate recall. AB - In the present study we examined the contribution of semantic associative links to short-term recall performance by using the separation effect first introduced in free recall studies (Glanzer, 1969). Pairs of associated words were inserted in the to-be-remembered lists. In two experiments associated words were better recalled than non-associated words, and were better recalled when they were adjacent in the list than when they were separated by one non-associated item. In addition results showed that forward associative links among pair members were as beneficial to immediate serial recall as backward associative links. Finally the benefit of associative links among pair members was observed with both forward and backward recall. PMID- 23656370 TI - 4th International Conference on Biomolecular Engineering tackles new challenges with synthetic biology. PMID- 23656371 TI - Reducing codon redundancy and screening effort of combinatorial protein libraries created by saturation mutagenesis. AB - Saturation mutagenesis probes define sections of the vast protein sequence space. However, even if randomization is limited this way, the combinatorial numbers problem is severe. Because diversity is created at the codon level, codon redundancy is a crucial factor determining the necessary effort for library screening. Additionally, due to the probabilistic nature of the sampling process, oversampling is required to ensure library completeness as well as a high probability to encounter all unique variants. Our trick employs a special mixture of three primers, creating a degeneracy of 22 unique codons coding for the 20 canonical amino acids. Therefore, codon redundancy and subsequent screening effort is significantly reduced, and a balanced distribution of codon per amino acid is achieved, as demonstrated exemplarily for a library of cyclohexanone monooxygenase. We show that this strategy is suitable for any saturation mutagenesis methodology to generate less-redundant libraries. PMID- 23656372 TI - Electrochemical analysis of Shewanella oneidensis engineered to bind gold electrodes. AB - Growth in three-electrode electrochemical cells allows quantitative analysis of mechanisms involved in electron flow from dissimilatory metal reducing bacteria to insoluble electron acceptors. In these systems, gold electrodes are a desirable surface to study the electrophysiology of extracellular respiration, yet previous research has shown that certain Shewanella species are unable to form productive biofilms on gold electrodes. To engineer attachment of Shewanella oneidensis to gold, five repeating units of a synthetic gold-binding peptide (5rGBP) were integrated within an Escherichia coli outer membrane protein, LamB, and displayed on the outer surface of S. oneidensis. Expression of LamB-5rGBP increased cellular attachment of S. oneidensis to unpoised gold surfaces but was also associated with the loss of certain outer membrane proteins required for extracellular respiration. Loss of these outer membrane proteins during expression of LamB-5rGBP decreased the rate at which S. oneidensis was able to reduce insoluble iron, riboflavin, and electrodes. Moreover, poising the gold electrode resulted in repulsion of the engineered cells. This study provides a strategy to specifically immobilize bacteria to electrodes while also outlining challenges involved in merging synthetic biology approaches with native cellular pathways and cell surface charge. PMID- 23656373 TI - Self-assembly of synthetic metabolons through synthetic protein scaffolds: one step purification, co-immobilization, and substrate channeling. AB - One-step purification of a multi-enzyme complex was developed based on a mixture of cell extracts containing three dockerin-containing enzymes and one family 3 cellulose-binding module (CBM3)-containing scaffoldin through high-affinity adsorption on low-cost solid regenerated amorphous cellulose (RAC). The three enzyme complex, called synthetic metabolon, was self-assembled through the high affinity interaction between the dockerin in each enzyme and three cohesins in the synthetic scaffoldin. The metabolons were either immobilized on the external surface of RAC or free when the scaffoldin contained an intein between the CBM3 and three cohesins. The immobilized and free metabolons containing triosephosphate isomerase, aldolase, and fructose 1,6-biphosphatase exhibited initial reaction rates 48 and 38 times, respectively, that of the non-complexed three-enzyme mixture at the same enzyme loading. Such reaction rate enhancements indicated strong substrate channeling among synthetic metabolons due to the close spatial organization among cascade enzymes. These results suggested that the construction of synthetic metabolons by using cohesins, dockerins, and cellulose binding modules from cellulosomes not only decreased protein purification labor and cost for in vitro synthetic biology projects but also accelerated reaction rates by 1 order of magnitude compared to non-complexed enzymes. Synthetic metabolons would be an important biocatalytic module for in vitro and in vivo synthetic biology projects. PMID- 23656374 TI - Promoter element arising from the fusion of standard BioBrick parts. AB - We characterize the appearance of a constitutive promoter element in the commonly used cI repressor-encoding BioBrick BBa_C0051. We have termed this promoter element pKAT. Full pKAT activity is created by the ordered assembly of sequences in BBa_C0051 downstream of the cI gene encoding the 11 amino acid LVA proteolytic degradation tag, a BioBrick standard double-TAA stop codon, a genetic barcode, and part of the RFC10 SpeI-XbaI BioBrick scar. Placing BBa_C0051 or other pKAT containing parts upstream of other functional RNA coding elements in a polycistronic context may therefore lead to the unintended transcription of the downstream elements. The frequent reuse of pKAT or pKAT-like containing basic parts in the Registry of Biological Parts has resulted in approximately 5% of registry parts encoding at least one instance of a predicted pKAT promoter located directly upstream of a ribosome binding site and ATG start codon. This example highlights that even seemingly simple modifications of a part's sequence (in this case addition of degradation tags and barcodes) may be sufficient to unexpectedly change the contextual behavior of a part and reaffirms the inherent challenge in carefully characterizing the behavior of standardized biological parts across a broad range of reasonable use scenarios. PMID- 23656375 TI - Nursing student perceptions of nurse-to-nurse collaboration in dedicated education units and in traditional clinical instruction units. AB - Changes within the health care system have created opportunities for emerging models of care delivery, including collaborative nursing teams. Collaboration between RNs and interprofessional teams supports improved care delivery outcomes. One promising strategy to enhance collaboration is the use of dedicated education units, which are academic-clinical partnerships that facilitate nursing student learning. This descriptive, quantitative study described and compared perceptions of nursing students about nurse-to-nurse collaboration witnessed in dedicated education units and traditional clinical units. Data gathered with the Nurse-to Nurse Collaboration Scale (NNCS) were analyzed using descriptive statistics and t tests. Findings demonstrate a significant difference on the visual analogue scales for nurse-to-nurse and nurse-to-nursing student collaboration, by type of unit. The NNCS findings indicated differences in the shared processes, coordination, communication, and conflict management subdomains. Further research in the area of collaboration among nurses and dedicated education units is recommended. PMID- 23656376 TI - Interprofessional learning objectives for health team simulations. AB - Interprofessional health team simulations are often developed using learning objectives that relate to competency statements. Educators then assume these learning objectives are relevant to students participating in the simulation. However, evaluating the link between learning objectives and outcomes is often difficult in authentic simulation environments with multiple human factors. This article suggests one process for revising learning objectives based on review of the simulation, the debriefing, and the student feedback on reported learning. Implications for curriculum integration are discussed. PMID- 23656377 TI - Trends and opportunities in geropsychiatric nursing: enhancing practice through specialization and interprofessional education. AB - Forecasted changes in the demographics of the United States suggest there will be an unprecedented need for health care professionals with specific training in geropsychiatric care. An aging society, the dearth of geropsychiatric health care professionals, the shortage of educators, and the lack of interprofessional geropsychiatric education require new strategies for nursing education to address these issues. The vision of the Institute of Medicine serves as a foundation for transforming geropsychiatric nursing and interprofessional education to prepare the next generation of nurses and the geropsychiatric workforce to improve the mental health care of older adults. This article aims to describe the importance and implications of implementing the recently released Geropsychiatric Nursing Competency Enhancements and the Core Competencies for Interprofessional Collaborative Practice to improve the mental health care of older Americans. A secondary aim is to discuss how to overcome barriers in implementing interprofessional education in geropsychiatric nursing care. PMID- 23656378 TI - Recent progress in robot-based systems for crystallography and their contribution to drug discovery. AB - INTRODUCTION: X-ray crystallography is the main tool for macromolecular structure solution at atomic resolution. It provides key information for the understanding of protein function, opening opportunities for the modulation of enzymatic mechanisms, and protein-ligand interactions. As a consequence, macromolecular crystallography plays an essential role in drug design, as well as in the a posteriori validation of drug mechanisms. AREAS COVERED: The demand for method developments and also tools for macromolecular crystallography has significantly increased over the past 10 years. As a consequence, access to the facilities required for these investigations, such as synchrotron beamlines, became more difficult and significant efforts were dedicated to the automation of the experimental setup in laboratories. In this article, the authors describe how this was accomplished and how robot-based systems contribute to the enhancement of the macromolecular structure solution pipeline. EXPERT OPINION: The evolution in robot technology, together with progress in X-ray beam performance and software developments, contributes to a new era in macromolecular X-ray crystallography. Highly integrated experimental environments open new possibilities for crystallography experiments. It is likely that it will also change the way this technique will be used in the future, opening the field to a larger community. PMID- 23656379 TI - The effect of portacaval anastomosis on the expression of glutamine synthetase and ornithine aminotransferase in perivenous hepatocytes. AB - There is functional zonation of metabolism across the liver acinus, with glutamine synthetase restricted to a narrow band of cells around the terminal hepatic venules. Portacaval anastomosis, where there is a major rerouting of portal blood flow from the portal vein directly to the vena cava bypassing the liver, has been reported to result in a marked decrease in the activity of glutamine synthetase. It is not known whether this represents a loss of perivenous hepatocytes or whether there is a specific loss of glutamine synthetase. To answer this question, we have determined the activity of glutamine synthetase and another enzyme from the perivenous compartment, ornithine aminotransferase, as well as the immunochemical localization of both glutamine synthetase and ornithine aminotransferase in rats with a portacaval shunt. The portacaval shunt caused a marked decrease in glutamine synthetase activity and an increase in ornithine aminotransferase activity. Immunohistochemical analysis showed that the glutamine synthetase and ornithine aminotransferase proteins maintained their location in the perivenous cells. These results indicate that there is no generalized loss of perivenous hepatocytes, but rather, there is a significant alteration in the expression of these proteins and hence metabolism in this cell population. PMID- 23656380 TI - Microbial community analysis of deeply buried marine sediments of the New Jersey shallow shelf (IODP Expedition 313). AB - The investigated deeply buried marine sediments of the shallow shelf off New Jersey, USA, are characterized by low organic carbon content and total cell counts of < 10(7) cells per mL sediment. The qPCR data for Bacteria and Archaea were in the same orders of magnitude as the total cell counts. Archaea and Bacteria occurred in similar 16S rRNA gene copy numbers in the upper part of the sediments, but Bacteria dominated in the lowermost part of the analyzed sediment cores down to a maximum analyzed depth of c. 50 meters below seafloor (mbsf). The bacterial candidate division JS1 and the classes Anaerolineae and Caldinilineae of the Chloroflexi were almost as highly abundant as the total Bacteria. Similarly high dsrA gene copy numbers were found for sulfate reducers. The abundance of the Fe(III) and Mn(IV) reducers comprising Geobacteraceae in the upper c. 15 mbsf correlated with concentrations of manganese and iron in the pore water. The isolated 16S rRNA gene sequences of Archaea in clone libraries could be allocated to the phyla Thaumarchaeota, Euryarchaeota, and Crenarchaeota with 1%, 14%, and 85%, respectively. The typical deep subsurface sediment-associated groups MBG-B, MBG-D, MCG, and SAGMEG were represented in the sediment community. MCG was the dominant group with a high diversity of the isolated 16S rRNA gene sequences. PMID- 23656381 TI - Roles and identities in transition: boundaries of work and inter-professional relationships at the interface between telehealth and primary care. AB - Shifting the balance of care towards home and community is viewed as requiring interventions which enhance or complement primary care. Technology-based interventions are seen as key to the future in this work. Telehealthcare implicates a new agenda for inter-professional working across boundaries of healthcare. One such interface is between telehealthcare professionals and professionals located in primary care. This study reports the findings from a qualitative study forming part of a broader project examining the potential of developing and implementing telehealth interventions to support patients with long-term conditions. Semi-structured interviews were undertaken with telehealth nurse care managers, practice nurses and general practitioners in their respective work settings (39 interviews with 62 participants). Observation was undertaken at a telehealth call centre. The research took place between April 2010 and March 2011. Thematic analysis of qualitative data was undertaken. Telehealth nurse care managers' interviews suggested narrative constructions of new roles and identities to fit telehealth work, combining a holistic ideal and retro-appeal with 'traditional' values of nursing, which distinguished and distanced them from counterparts in general practices. Practice nurses and general practitioners were ambivalent and often sceptical about the contribution of telehealth to long-term condition work. Practice nurses' accounts suggested a sense of protectiveness about maintaining boundaries around established remits of managing long-term conditions; general practitioners, having devolved much of the care of long-term conditions to nurses, were keen to retain their positions as gatekeepers to resources. Perceptions of shifts of professional roles, new ways of working and how they are valued form a relevant contextual element to the introduction of telehealth interventions. A pre-emptive view and response to how professionals understand and approach increasingly complex and multi-faceted roles within primary care is likely to prepare and facilitate the introduction and integration of telehealth innovations into existing patient services. PMID- 23656382 TI - Sub-acute and chronic MRI findings in bilateral canine fibrotic contracture of the infraspinatus muscle. AB - A six-year-old, 30-kg female German pointer dog was presented for examination with a history of pre-existing right-forelimb lameness and more recent (3 months) persistent lameness in the left-forelimb. Physical examination revealed mild left forelimb lameness and a mild circumduction movement. There were no signs of pain or crepitation detected during manipulation of the shoulders, but the animal was unable to fully flex both glenohumeral joints. Magnetic resonance imaging, using fast recovery fast spin echo T2-weighted and fat saturated proton density sequences, revealed abnormal heterogeneous hypointensity in the right infraspinatus muscle and a heterogeneous hyperintense area in the left infraspinatus muscle. Surgical treatment consisting of a bilateral infraspinatus tenectomy resulted in improved limb function. Histopathological examination demonstrated tissue changes in the right infraspinatus, characterised by myofibre degeneration and fibrosis, compatible with a chronic degenerative process, while changes in the left infraspinatus muscle were characterised by variable degrees of fibre degeneration, haemorrhage and interstitial oedema. PMID- 23656383 TI - Cigarette smoking, nicotine levels and increased risk for metabolic syndrome in women with polycystic ovary syndrome. AB - Women with polycystic ovary syndrome (PCOS) are at risk for metabolic syndrome, which may be exacerbated by smoking. We hypothesized that smoking worsens androgen levels and the metabolic profile in women with PCOS. PCOS smokers (n = 47) and non-smokers (n = 64) and control smokers (n = 30) and non-smokers (n = 28), aged 18-45 years, underwent anthropomorphic measurements, pelvic ultrasound and blood sampling. Smokers had higher cotinine (801 +/- 83 versus <11 nmol/L; smokers versus non-smokers, respectively; p < 0.001) and nicotine levels (37 +/- 4 versus <12 umol/L; p < 0.001). Triglyceride levels were higher in women with PCOS who smoked compared to non-smokers (1.55 +/- 0.18 versus 0.95 +/- 0.08 mmol/L; p < 0.001), even when adjusted for BMI. Metabolic syndrome was more common in smokers with PCOS compared to non-smokers with PCOS and smokers who were controls (28.6 versus 3.6%; p = 0.02). There were no differences in reproductive parameters including androgen levels. Cotinine (r = 0.3; p < 0.001) and nicotine levels (r = 0.2; p = 0.005) correlated with triglycerides. Nicotine levels also correlated with pulse rate (r = 0.2; p = 0.02) and waist:hip ratio (WHR; r = 0.2; p = 0.02). Taken together, smoking may worsen the already high risk for metabolic syndrome in women with PCOS. PMID- 23656384 TI - Unfavorable lipid profile and higher frequency of hot flashes during perimenopausal years after fallopian tube ligation. AB - AIM: We sought to study the effect of tubal ligation on lipid profile, ovarian reserve and hot flashes during perimenopausal years. METHODS: A total of 210 perimenopausal women complaining of abnormal vaginal bleeding were enrolled for the study. Subjects' menstrual, reproductive and medical histories were recorded. Serum FSH, LH and estradiol levels were screened in all women to determine menopausal status. In order to rule out any gynecologic pathology, all subjects underwent transvaginal sonography. Women were divided into two groups according to presence (study group, n = 68) or absence (control group, n = 142) of tubal ligation history. Lipid profiles and ovarian reserve tests were compared between groups. RESULTS: Mean age, parity, serum hemoglobin (Hb), high density lipoprotein (HDL-C), triglyceride, estradiol levels, endometrial thickness and frequency of hot flashes were significantly different between groups (p < 0.05). Mean age was 42.8 +/- 1.9 years in women with tubal ligation and 45.9 +/- 3.5 years in control group. Mean serum estradiol level was lower in group with tubal ligation (41.4 versus 92.5 pg/ml). Mean endometrial thickness was higher in control group (10.2 versus 7.5 mm). Age-adjusted serum Hb, HDL-C, triglyceride, estradiol, FSH level, endometrial thickness and frequency of hot flashes remained significantly different between groups (p < 0.05). CONCLUSION: Tubal ligation is associated with unfavorable lipid profile and higher frequency of hot flashes during perimenopausal years. PMID- 23656385 TI - The metabolic syndrome and its components in postmenopausal women. AB - BACKGROUND: Prevalence of the metabolic syndrome (METS) increases significantly after the menopause. OBJECTIVE: To assess the prevalence of the METS and its components in postmenopausal women. Factors relating to each of the composing items of the METS were also analyzed. METHODS: Natural postmenopausal women (40 65 years) were invited to participate in this cross-sectional study in order to assess the presence of the METS using modified Adult Treatment Panel III (ATP III) criteria. Participants were also requested to fill out a general socio demographic questionnaire. RESULTS: A total of 204 women were surveyed with a median age of 56 years. A 52.9% presented the METS according to modified ATP-III criteria, with 37.3% presenting hyperglycemia, 51.5% hypertension, 58.3% abdominal obesity, 45.6% high triglyceride levels and 56.4% low HDL-C levels. Women with the METS presented a higher rate of dyslipidemia (high triglyceride and low HDL-C levels), hyperglycemia, hypertension and abdominal obesity than those without the syndrome. Those with abdominal obesity and hyperglycemia significantly displayed higher rates of low HDL-C levels (bivariate analysis). Multiple linear regression analysis found a positive correlation between glucose and triglyceride levels. Systolic blood pressure significantly and positively correlated to age and abdominal circumference. Abdominal circumference displayed an inverse correlation with educational level. CONCLUSION: Prevalence of the METS in this postmenopausal female sample was high and associated to metabolic and lipid derangements. As abdominal obesity was significantly associated to lower education, there is an urgent need of implementing educational programs directed to high-risk populations in order to increase awareness of the problem. PMID- 23656387 TI - Cytogenetic analysis of 179 Iranian women with premature ovarian failure. AB - The importance of chromosomal abnormalities in etiology of premature ovarian failure (POF) is well known but in many cases, POF still remains idiopathic. We investigated the frequency and type of chromosomal aberrations in Iranian women diagnosed with idiopathic POF. Standard cytogenetic analysis was carried out in a total of 179 patients. Karyotype analysis of these patients revealed that 161 (89.95%) patients had normal female karyotype and 18 (10.05%) patients had abnormal karyotypes. The abnormal karyotypes included sex reverse sex determining region Y (SRY) negative (five Cases), X chromosome mosaicism (five cases), abnormal X chromosomes (three cases), abnormal autosomes (three cases) and X autosome translocation (two cases). The overall prevalence of chromosomal abnormalities was 10.05% in this first large-scale report of chromosomal aberrations in Iranian women with POF. The results confirm previous observations and emphasis on the critical role of X chromosome abnormalities as one of the possible etiologies for POF. PMID- 23656386 TI - Circulating kisspeptin and pituitary adenylate cyclase-activating polypeptide (PACAP) do not correlate with gonadotropin serum levels. AB - Kisspeptins are known to be the principle regulators of the hypothalamic pituitary gonadal (HPG) axis. In addition, the role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the regulation of pituitary gonadotropins has been elucidated. We measured plasma concentrations of kisspeptin and PACAP and determined whether the levels of these peptides varied in proportion to circulating gonadotropin levels. Plasma luteinizing hormone (LH) levels were higher in postmenopausal women and in patients with premature ovarian failure (POF) and lower in patients with idiopathic hypogonadotropic hypogonadism (IHH) compared with the LH level in normally menstruating women. Similarly, serum follicle-stimulating hormone levels were higher in postmenopausal women and in patients with POF but lower in pregnant women and patients with IHH compared with normally menstruating women. Plasma levels of kisspeptins were significantly higher in pregnant women compared with normally menstruating women. However, no significant differences were observed in postmenopausal women, patients with POF, and patients with IHH. On the other hand, plasma levels of PACAP were significantly lower in pregnant women, patients with POF, and in IHH patients when compared with normally menstruating women. No significant differences were observed in PACAP concentration between postmenopausal women and in normally menstruating women. Our observations suggest that the serum levels of kisspeptins and PACAP did not correlate with variations in serum gonadotropin levels. PMID- 23656388 TI - First trimester maternal serum pregnancy-associated plasma protein-A is a predictive factor for early preterm delivery in normotensive pregnancies. AB - In this study, we investigated whether the concentrations of pregnancy-associated plasma protein-A (PAPP-A) or free beta-hCG (fbetahCG) in the first trimester can identify women at increased risk of subsequent preterm delivery in the absence of hypertensive disorders. Preterm and early preterm deliveries are defined as those deliveries before completing 37 and 34 weeks, respectively. A total of 868 women were enrolled into this study. According to the level of the markers, the patients were evaluated in three groups: 1 - maternal serum level <= 5 th percentile, 2 - between 5th and 95th percentiles, 3 - >= 95 th percentile. In the group of patients with a PAPP-A level <= 5 th percentile [<= 0.35 multiples of the median (MoM)], mean gestational age (GA) at delivery, mean birth weight and the number of the cases with early preterm delivery were significantly lower than the others. Mean level of PAPP-A was significantly lower in cases with early preterm than term deliveries (0.58 +/- 0.32 versus 1.09 +/- 0.69; p = 0.01). Maternal serum level of fbetahCG did not show significant difference between these groups (0.84 +/- 0.45 versus 1.17 +/- 0.77; p = 0.15). Low levels of maternal serum PAPP-A (<= 0.35 MoM) (Odds ratio = 7; 95% confidence interval 1.8 27.7; p = 0.0048) significantly predicted early preterm delivery in normotensive pregnancies. Women with low levels of PAPP-A at first trimester have a higher risk of early preterm delivery even in the absence of hypertensive disorders. PMID- 23656389 TI - Thyroid function in pregnant women: iodine deficiency after iodine enrichment program. AB - OBJECTIVE: Significant changes in thyroid function occur during pregnancy which can complicate the interpretation of thyroid function tests. Therefore, normative gestational related reference ranges for thyroid hormones tests are required. The aim of this study was to determine the reference ranges for free triiodothyronine (FT3), free thyroxin (FT4) and thyroid stimulating hormone (TSH) in Iranian pregnant women. METHODS: This study was a cross-sectional observational study conducted in the Obstetrics and Gynecology department, Akbarabadi University Hospital. A single blood sample from 584 pregnant women was analyzed for thyroid function. Serum levels of TSH, FT4, FT3, total T4 (TT4), T3 resin uptake (T3RU) and anti-thyroid peroxidase antibody (TPO Ab) were measured. Urinary iodine was determined in some cases. Reference intervals based on 2.5th and 97.5th percentiles were calculated. RESULTS: The composition of reference population comprising 584 women included 162 in first trimester and 422 in the third trimester. The 2.5th and 97.5th percentiles values were used to determine the reference ranges for FT3, FT4, TT4, T3RU and TSH. These values were T3 1.4 and 2.9 pmol/L, FT4 7.1 and 18 pmol/L, TT4 7.2 and 13.5 ug/dL and TSH 0.5 and 3.9 ug/L, respectively. The level of urinary iodine in 80.5% of the subjects was less than normal. CONCLUSIONS: Serum levels of thyroid hormones are different in Iranian population that could be due to racial differences or differences in iodine intake. PMID- 23656390 TI - The impact of single embryo transfer policy on pregnancy outcomes after legislative change. AB - We evaluated the effect of mandatory single embryo transfer (SET) on live birth rates and pregnancy outcomes in Turkey. A retrospective study was conducted in Zekai Tahir Burak Women's Health Education and Research Hospital. Four hundred and four patients undergoing intracytoplasmic sperm injection (ICSI) cycles were included in the study. In Turkey, the number of embryos to be transferred in an assisted cycle was limited to three under normal circumstances until 6 March 2010. After that, new legislation was introduced to promote the application of SET. Outcomes were compared in periods of 1 year before and after the new law. We compared pregnancy outcomes of all assisted reproductive cycles in SET cycles (group 1: n = 281) with double embryo transfer (DET) cycles (group 2: n = 123). There were significant differences in oocyte number, multiple pregnancy, gestational age, birth weight and perinatal fetal morbidity between the groups (p = 0.023, 0.001, 0.001, 0.001, 0.001, respectively). But there were no differences in age, baseline FSH, infertility period, stimulation protocol, stimulation day, gonadotrophin dose, clinical pregnancy rate, abortion rate, live birth rate and cesarean rate (p > 0.05). These results suggest that under the new legislation multiple pregnancy rates and perinatal complications are significantly reduced without causing a significant decline in the pregnancy rates. PMID- 23656391 TI - High-resolution array-comparative genomic hybridization profiling reveals 20q13.33 alterations associated with ovarian endometriosis. AB - OBJECTIVE: The purpose of this study is to investigate the potential genetic alterations at DNA level in patients with ovarian endometriosis by high resolution array-based comparative genomic hybridization (array-CGH) analysis. METHODS: Following the laparoscopic surgical and the post-operative pathological examination, genomic DNA was extracted from endometriomas of 11 women with endometriosis and endometrial tissue of the controls and analyzed by array-CGH. Real-time PCR was used for confirmation the result of array-CGH analysis and detected the DNA copy number variations of the eutopic endometrium from the five patients with the duplication in 20q13.33 region. RESULTS: All 11 patients with ovarian endometriosis were diagnosed through the laparoscopic surgical and the post-operative pathological examination. We found occurrence of genomic duplication at 20q13.33 chromosomal region with gain of GATA5 and SLCO4A1 genes in 5 of 11 endometriomas from patients. CONCLUSION: The results of the present study suggest that there was 20q13.33 duplication in women with ovarian endometriosis. This effect might be due to the alterations of GATA5 and SLCO4A1 genes in the gain region, through involving the metabolism of the steroid hormone. PMID- 23656392 TI - Effect of duration of the GnRH agonists in the luteal phase in the outcome of assisted reproduction cycles. AB - The effect of long-acting GnRHa, in the luteal phase, during ART cycles varies from one patient to another. The aim of this study was to evaluate whether the effect of long-acting GnRHa in the luteal phase, in ART cycles, affects pregnancy rates according to the duration of its action in such phase. This is a retrospective study of 367 patients submitted to ovulation induction for in vitro fertilization/intracytoplasmic sperm injection procedures that used long-acting depot GnRHa for pituitary suppression. Patients were stratified according to the period of action of the agonist in the luteal phase: group 1, <= 6 days; group 2, 7 to 12 days; and group 3, >12 days. The following variables were analyzed: ovarian response, age, infertility causes and pregnancy rates. Group 1 (n = 53) had a mean age of 33.8 +/- 4.55 years (23-44 years) and a pregnancy rate of 45.2%. In group 2 (n = 118), mean age was 33.7 +/- 4.5 years (24-44 years) and the pregnancy rate was 38.9%. In group 3 (n = 196), mean age was 33.7 +/- 4.4 years (23-43 years) and the pregnancy rate was 47.4%. Regardless of the duration of depot GnRHa action in the luteal phase, no significant association with pregnancy rates was found. PMID- 23656393 TI - Assisted reproductive technique increases the risk of placental polyp. AB - The purpose of this study was to clarify the risk factors and outcomes of placental polyp. This retrospective study was conducted on 1645 patients delivered or aborted in Sapporo Medical University from 2007 through 2011. Transvaginal color Doppler ultrasonography, hysteroscopy, contrast-enhanced MRI or 3D-CT angiography were performed. There were 1532 deliveries and 113 abortions. Seventy-one (4.3%) were ART-conceived and the remaining 1574 (95.7%) were non-ART pregnancies. Fifteen (0.91%) cases were confirmed as having placental polyp. Nine cases of placental polyp were identified among the 1574 (0.57%) as non-ART-related pregnancies, and 6 were identified among the 71 (8.5%) as ART-related pregnancies. Thus, pregnancies achieved through ART showed 20x greater incidence of complicating placental polyp than pregnancies achieved through without ART (p = 9.02 * 10(-6); odds ratio, 19.59; 95% confidence interval, 5.27-72.84, logistic regression analysis). Evaluation of blood flow within the polyp showed that in five of seven patients with low blood flow, the polyps spontaneously dropped off 79-115 days postpartum. Thus, ART-related pregnancies may be a risk factor of placental polyp, and spontaneous drop-off of the polyp is often observed in cases with low blood flow within the mass. PMID- 23656394 TI - Birth weight and childhood growth in daughters of women with irregular menstrual cycles. AB - Menstrual irregularity has been associated with insulin resistance, type 2 diabetes mellitus and markers of metabolic dysfunction. This study aimed to determine whether irregular menstrual cycles (MCs) in reproductive-age women are associated with the weight of their daughters at birth and growth up to age five. We studied 4863 pregnant women with menstrual history data in a prospective cohort, recruited from the Kaiser Health Plan (1959-1966). Serial measures of their daughters' weight and height were abstracted from medical records. We used analysis of covariance, stratified by maternal body mass index, to explore the association between maternal MC and infant birth weight (BW). We included 4774 daughters in a repeated measures analysis to compare the effect of maternal MC on childhood weight through age five. Daughters of non-obese women with irregular MC had a statistically significant lower BW compared to daughters of women with regular MC; this difference was notably amplified among obese women. The daughters' weights were not statistically different when growth was assessed from birth to five years. We conclude that daughters of obese women with irregular MC, in particular, had significantly lower BW compared to daughters of women with regular MC, which did not persist over five years of follow-up. PMID- 23656395 TI - Whole exome sequencing and functional studies identify an intronic mutation in TRAPPC2 that causes SEDT. AB - Skeletal dysplasias are challenging to diagnose because of their phenotypic variability, genetic heterogeneity, and diverse inheritance patterns. We conducted whole exome sequencing of a Turkish male with a suspected X-linked skeletal dysplasia of unknown etiology as well as his unaffected mother and maternal uncle. Bioinformatic filtering of variants implicated in skeletal system development revealed a novel hemizygous mutation, c.341-(11_9)delAAT, in an intron of TRAPPC2, the causative locus of spondyloepiphyseal dysplasia tarda (SEDT). We show that this deletion leads to the loss of wild-type TRAPPC2 and the generation of two functionally impaired mRNAs in patient cells. These consequences are predicted to disrupt function of SEDLIN/TRAPPC2. The clinical and research data were returned, with appropriate caveats, to the patient and informed his disease status and reproductive choices. Our findings expand the allelic repertoire of SEDT and show how prior filtering of the morbid human genome informed by inheritance pattern and phenotype, when combined with appropriate functional tests in patient-derived cells, can expedite discovery, overcome issues of missing data and help interpret variants of unknown significance. Finally, this example shows how the return of a clinically confirmed mutational finding, supported by research allele pathogenicity data, can assist individuals with inherited disorders with life choices. PMID- 23656396 TI - Nurse practitioners, certified nurse-midwives, and physician assistants can safely perform first-trimester aspiration abortions. PMID- 23656397 TI - Nutrition labelling and the choices logo in Israel: positions and perceptions of leading health policy makers. AB - BACKGROUND: Based on the Social Marketing approach and Diffusion of Innovations Theory that indicates the importance of opinion leaders with respect to the spreading of new ideas, concepts or practices within a community, the present study aimed to examine positions and perceptions of Israeli leading dietitians and health officials regarding nutrition labelling and the Choices logo, before it was launched in Israel in February 2011, as well as how they would communicate it to the public as agents of influence. METHODS: The study involved in-depth face-to-face and telephone interviews with 15 senior dietitians and Health Ministry officials using semi-structured protocols including questions about nutrition labelling and the Choices logo. RESULTS: The respondents considered that the nutrition facts panels usually found on the backs of packages are too complicated for the average consumer. Simiularly, fronts of packages are cluttered with advertisements and health claims, causing confusion. The study participants would like to see an integrative label on the front of the package to facilitate consumers' decisions. However, the Choices logo raises ethical and social questions about the conflict between corporate interests and public health: (i) the label's relativity versus objectivity; (ii) the consumer's responsibility to create a balanced diet; (iii) the label's credibility; and (iv) bias against companies, products and audiences. CONCLUSIONS: The results of the present study highlight the importance of a need for an integrated programme of nutrition promotion, including the use of social marketing based on a cooperative effort between the food industry, regulators and professionals, to recommend changes and adjustments in nutritional front of package labelling with the aim of promoting healthier nutrition consumption. PMID- 23656398 TI - Mechanism and kinetics of the atmospheric oxidative degradation of dimethylphenol isomers initiated by OH radical. AB - Dimethylphenols are highly reactive in the atmosphere, and their oxidation plays a vital role in the autoignition and combustion processes. The dominant oxidation process for dimethylphenols is by gas-phase reaction with OH radical. In the present study, the reaction of OH radical with dimethylphenol isomers is studied using density functional theory methods, B3LYP, M06-2X, and MPW1K, and also at the MP2 level of theory using 6-31G(d,p) and 6-31+G(d,p) basis sets. The activation energy values have also been calculated using the CCSD(T) method with 6-31G(d,p) and 6-311+G(d,p) basis sets using the geometries optimized at the M06 2X/6-31G(d,p) level of theory. The reactions subsequent to the principal oxidation steps are studied, and the different reaction pathways are modeled. The positions of the OH and CH3 substituents in the aromatic ring have a great influence on the reactivity of dimethylphenol toward OH radical. Accordingly, the reaction is initiated in four different ways: H-atom abstraction from the phenol group, H-atom abstraction from a methyl group, H-atom abstraction from the aromatic ring by OH radical, or electrophilic addition of OH radical to the aromatic ring. Aromatic peroxy radicals arising from initial H-atom abstraction and subsequent O2 addition lead to the formation of hydroperoxide adducts and alkoxy radicals. The O2 additions to dimethylphenol-OH adduct results in the formation of epoxide and bicyclic radicals. The rate constants for the most favorable reaction pathways are calculated using canonical variational transition state theory with small curvature tunneling corrections. This study provides thermochemical and kinetic data for the oxidation of dimethylphenol in the atmosphere and demonstrates the mechanism for the conversion of peroxy radical into aldehydes, hydroperoxides, epoxides, and bicyclic radicals, and their lifetimes in the atmosphere. PMID- 23656399 TI - Tamoxifen citrate loaded ethosomes for transdermal drug delivery system: preparation and characterization. AB - Long term tamoxifen citrate therapy is imperative to treat several dermatological and hormonal sensitive disorders. Successful oral and parenteral administration of tamoxifen citrate has been challenging since it undergoes enzymatic degradation and has poor aqueous solubility issues. In the present work, tamoxifen citrate loaded ethosomes were prepared and characterized for transdermal applications. The prepared formulations were characterized for morphological features, particle size distribution, calorimetric attributes, zeta potential and drug entrapment. Permeation profile of prepared ethosomes was compared with liposomes and hydroethonalic solution across cellophane membrane and human cadaver skin. Results of the permeation studies indicate that ethosomes were able to deliver >90% drug within 24 hours of application, while liposomes and hydroethanolic solution delivered only 39.04% and 36.55% respectively. Skin deposition and stability studies are also reported. PMID- 23656400 TI - Crystalloid flush with backward unclamping may decrease post-reperfusion cardiac arrest and improve short-term graft function when compared to portal blood flush with forward unclamping during liver transplantation. AB - During liver transplant (LT), the release of vasoactive substances into the systemic circulation is associated with severe hemodynamic instability that is injurious to the recipient and/or the post-ischemic graft. Crystalloid flush with backward unclamping (CB) and portal blood flush with forward unclamping (PF) are two reperfusion methods to reduce reperfusion-related cardiovascular perturbations in our center. The primary aim of this study was to compare these two methods. After institutional review board (IRB) approval, cadaveric whole LT cases performed between 2003 and 2008 were reviewed. Patients were divided into two groups based on reperfusion methods: CB or PF. After background matching with propensity score, the effect of each method on post-operative graft function was assessed in detail. In our cohort of 478 patients, CB was used in 313 grafts and PF in 165. Thirty-day graft survival was lower, and risk of retransplantation was higher in PF. Multivariable model showed that CB is an independent factor to reduce primary non-function, cardiac arrest and improve 30-d graft survival. Also, the incidence of ischemic-type biliary lesions was significantly higher in the PF group. Reperfusion methods affect intraoperative hemodynamics and post transplant outcome. CB allows for control over temperature and composition of the perfusate, perfusion pressure, and the rate of infusion. PMID- 23656401 TI - Type 1/type 2 cytokine serum levels and role of interleukin-18 in children with steroid-sensitive nephrotic syndrome. AB - INTRODUCTION: In view of the conflicting evidence of helper T cell type 1 (Th1) or type 2 (Th2) pattern of cytokine synthesis in steroid sensitive nephrotic syndrome (SSNS), this study aimed to assess type-1/type-2 cytokines level in different stages of SSNS and to evaluate the role of IL-18. METHODS: We prospectively studied thirty children with SSNS, aged 2-12 years. The children were evaluated in the active stage before treatment initiation and re-evaluated again during remission while still on steroid treatment. A subgroup of children (21/30) was also evaluated during remission after steroid withdrawal. The control group included 30 healthy age- and sex-matched siblings. Serum levels of IL-2, IFN-gamma, IotaL-4, IL-13 and IL-18 were measured by ELISA. RESULTS: IL-2 levels were not significantly different between children in different stages of SSNS and controls (p>0.05). Levels of IL-4, IL-13 and IL-18 were significantly higher during the active stage of SSNS compared to remission and controls (p<0.05). Serum IFN-gamma was significantly lower in children with active disease compared to remission stages and controls (p<0.05). In children with SSNS, serum levels of IL-18 correlated significantly with both IL-4 and IL-13 during all stages (r=0.72 and p<0.0001, r=0.82 and p<0.0001, respectively). CONCLUSION: Children with active SSNS seem to have a shift to type-2 cytokine production, and IL-18 expression is significantly correlated with this type-2 immune response. PMID- 23656402 TI - Parameters to assess nutritional status in a Moroccan hemodialysis cohort. AB - INTRODUCTION: Malnutrition is common in maintenance hemodialysis (HD) and is associated with increased mortality and morbidity in affected patients. The aim of this study was to determine the prevalence of malnutrition and correlate the methods of nutritional assessment. METHODS: We evaluated the nutritional status of 40 prevalent HD patients by subjective global assessment (SGA) score, anthropometrics [body mass index (BMI), arm circumference (AC), triceps skin-fold thicknesses (TSF), arm muscle circumference (AMC)], biochemical tests [normalized protein equivalent to total nitrogen appearance (nPNA), and pre-dialysis serum albumin and serum prealbumin levels] and bio-electrical impedance (BEI) analysis to estimate body composition [lean tissue index (LTI) and fat tissue index (FTI)]. RESULTS: The study assessed 40 patients (20 males and 20 females) with a mean age of 50.7+/-16.5 years. The prevalence of malnutrition according to the different methods ranged from 5 % to 65%. There were highly significant gender specific differences in AMC (p<0.001) and TSF (p<0.001). The BEI revealed a highly significant difference in LTI (p<0.001) but no difference in FTI (p=0.14) according to gender. There was a positive correlation between LTI and both serum albumin (r=0.37; p=0.018) and serum prealbumin (r=0.53; p<0.001). Also, there was a significant positive correlation between FTI and BMI (r=0.59; p<0.001), AC (r=0.44; p=0.004) and TSF (r=0.61; p<0.001). CONCLUSION: Our data suggest that BEI analysis provides a useful means of assessing nutritional status and was correlated with anthropometrics and biochemical findings. PMID- 23656403 TI - Adherence of healthcare professionals to evidence-based clinical practice guidelines in the management of hemodialysis patients, Khartoum State, Sudan. AB - INTRODUCTION: Hemodialysis (HD) is a complex procedure with many specifications and requires adherence to a set of particular clinical practice guidelines. These guidelines had already been established by globally acclaimed renal authorities and their implementation was shown to correlate with patients' morbidity and mortality. This study was conducted to evaluate the adherence of healthcare professionals to the evidence-based clinical practice patterns in Khartoum State HD units. METHODS: A cross-sectional study was conducted in Khartoum State HD units during the period from September 2010 to January of 2011. Data was collected from the healthcare professionals using a specially designed checklist. The checklist included the evidence-based clinical practice guidelines for the HD vascular access, HD adequacy, anemia of chronic kidney disease (CKD), nutrition, cardiovascular risk assessment, and hepatitis B and C virus infection control. Implementation of these guidelines was evaluated, and further graded using a Likert-type scale. RESULTS: Four randomly selected HD units were included in the study. The rate of implementation of the HD vascular access guidelines was 54.8%, adequacy guidelines 57%, anemia of CKD 68.8%, nutrition 58.4%, cardiovascular risk assessment 57%, and hepatitis B and C infection control guidelines was 79.2%. Overall, the four HD units assessed showed moderate deviations from the practice guidelines of anemia of CKD and hepatitis B and C infection control. Extreme deviations from the clinical practice guidelines were seen in HD vascular access practices, adequacy assessments, nutrition and cardiovascular risk assessment. CONCLUSION: Hemodialysis services in Khartoum State are in need of great improvements regarding adherence to protocols and the standards of care. PMID- 23656404 TI - Epidemiology and clinicopathologic outcome of pediatric chronic kidney disease in Nigeria, a single cenetr study. AB - INTRODUCTION: Due to dearth of data, chronic kidney disease (CKD) outcome in African children has been dismal owing to poor understanding of its etiology, manifestations and management. METHODS: We retrospectively analyzed the records of 154 CKD children and adolescents who were managed at Obafemi Awolowo University Teaching Hospitals Complex between 2000 and 2009 to evaluate the epidemiology and clinicopathologic outcome of pediatric CKD in Nigeria. RESULTS: Overall mean incidence was 11 (6-20) per million children population (pmcp)/year while prevalence averaged 48 (8-101) pmcp. There were 86 males (55.8%). Median age was 10.0 (0.2-15.5) years with 83.8%>=5 years old. Etiologies were glomerular disease (GMD, 90.26%), congenital and acquired urinary tract (7.79%) and hereditary disorders (1.95%). CKD stages at diagnosis were 45.5% CKD-1, 22.7% CKD 2, 10.4% CKD-3, 2.6% CKD-4 and 18.8% CKD-5. Median progression time through the CKD stages was 24.0 (3-108) months. Mean dialysis incidence and prevalence were 1 (0-4) pmcp/year and 4 (1-12) pmcp, respectively. Hypertension, heart failure (HF), malnutrition, anemia, acute-on-CKD, need for dialysis, azotemia, hypercreatininemia, and high calcium-phosphorous product (>=55 mg2/dL2) were mortality risk factors. CKD-1 survived significantly better than CKD stages 3-5 (p<0.05) but not CKD-2 (p=0.1). Hypertensive CKDs without HF survived better (73.0%) than hypertensive CKDs with HF (16.0%) [Hazard ratio (HR): 0.34, 95% CI: 0.14-0.83]. GMD survived better (68.5%) than non-GMD patients (33.0%) [HR: 2.87, 95% CI: 1.16-7.06]. CONCLUSION: CKD was commoner among school than pre-school age children. GMD was the predominant etiology with better outcome than non-GMD. Comorbidity prevalence increased significantly with increasing severity of CKD stage. PMID- 23656405 TI - Severe tricuspid valve endocarditis related to tunneled catheters in chronic hemodialysis patients: when should the catheter be removed? AB - INTRODUCTION: Hemodialysis (HD) patients are predisposed to infective endocarditis (IE) mainly due to repeated manipulation of the vascular access. However, catheter seeding and IE may also result from a distant infection site. CASE SERIES: A diabetic patient who was maintained on regular HD through a permanent catheter in the right internal jugular vein presented with septicemia of urinary origin due to Pseudomonas aeruginosa. He was treated with injectable antibiotics for 15 days. Few days after the end of the treatment period he presented with inflammation of the catheter exit site. Blood cultures revealed Pseudomonas aeruginosa and echocardiography showed a large vegetation on the tricuspid valve, confirming the diagnosis of IE. The patient improved after catheter removal and treatment with ceftazidime, vancomycin and amikacin. Another patient who was maintained on chronic HD through a tunneled catheter in the right internal jugular vein presented with a limited infection in the sub-cutaneous tunnel of the catheter that improved after treatment with injectable antibiotics. Two months later, he presented with severe sepsis without signs of local infection of the catheter. Chest radiography showed right sided infiltrates. Injectable antibiotic therapy was given without improvement. Blood cultures were negative but echocardiography showed a large tricuspid valve vegetation. Antibiotic regimen was modified to include vancomycin, amikacin and ceftazidime and the catheter was removed. Unfortunately, the patient died two days after diagnosing IE. CONCLUSION: catheter seeding and IE may be a consequence of sepsis originating away from the HD catheter site. Tunneled catheters may need to be preemptively removed in such situations to prevent serious IE. PMID- 23656406 TI - Evaluation of nurses awareness and practice of hemodialysis access care in Khartoum state, Sudan. AB - INTRODUCTION: In hemodialysis (HD) wards, nurses play a pivotal role in HD access care. Unfortunately, guideline recommendations for routine preventive care are not always followed. This study was designed to evaluate nurses' awareness and practice of HD access care in Khartoum state, Sudan. METHODS: The study included 50 randomly selected HD nurses. Nurses' knowledge was evaluated using a participant-filled questionnaire and their practice was evaluated by direct monitoring. Variables were summarized as frequencies and related to nurses' educational level. RESULTS: Females constituted 72% of study participants and 85% were university graduates. Half the nurses had more than two years experience in HD centers. Structured training on HD machines and HD access care was received by 56% and 54% of respondents respectively. All participants stated that proper HD access care helps prevent access infection but only 54% stated that it helps in preserving access function. Most nurses (98%) stated that hand hygiene in HD centers was necessary to prevent infection but only 70% were adherent to hand hygiene before access manipulation. Most nurses (98%) evaluated HD access function before connection but only 52% evaluated it for signs of infection. Nurses with a bachelor degree tended to be more adherent to hand hygiene (72.5 versus 42.9%, P=0.1) and the use of gloves (100% versus 85.7%, P=0.1) compared to nurses with a diploma degree, but the difference was not statistically significant. CONCLUSION: HD nurses adherence to the recommended infection control measures in studied HD centers was suboptimal. HD centers are required to organize adequate training on HD access care for their nursing staff. PMID- 23656408 TI - Making decisions in emergency surgery. AB - BACKGROUND: Good decision making is essential in surgery. In an emergency, the time for decision making is often short, and the information available is incomplete. The way experienced surgeons make decisions is often not well understood, and therefore is difficult to teach to trainees. METHODS: This paper examines how decisions are made, based on recent literature and the experience of the authors and their colleagues. DISCUSSION: An accurate assessment precedes decision making, and is directed towards the patient, the personnel and environment. Studies of other high-stakes professions have highlighted the existence of two distinct mental processing symptoms. One is fast and frugal, relying on pattern recognition or following a rule or protocol. This is often performed at a subconscious level. The other is a conscious, reasoned, analytical process. This requires adequate, available mental capacity. In reality, expert and experienced decision makers can adopt either or both approaches, and match their approach to the situation. Decisions made need to be constantly reviewed, particularly where there is mismatch between what was anticipated and what is encountered. CONCLUSION: An algorithm of decision making in emergency surgery has been developed that is based on assessment, the decision required and the outcome of the decision. The decision must also consider the urgency of the situation and the likely outcome if the plan made fails. PMID- 23656409 TI - Barriers faced by Vietnamese immigrant women in Taiwan who do not regularly undergo cervical screenings: a qualitative study. AB - AIM: To assess and understand the barriers faced by Vietnamese marital immigrant women who do not regularly undergo cervical screenings in Southeast Taiwan. BACKGROUND: Studies have shown a low uptake rate of preventive medical services among immigrants. As immigrant women may not be aware of the healthcare delivery system in their host country, their uptake of and access to healthcare services might be limited. DESIGN: A qualitative, descriptive inquiry design was adopted. METHODS: This qualitative study employed semi-structured, individual, in-depth interviews of 17 Vietnamese immigrant women. Data were collected from February July 2011 and analysed using content analysis. FINDINGS: The barriers to receiving cervical screening were lack of health literacy, lack of female healthcare providers, negative perceptions of cervical screening and personal reasons. CONCLUSION: The results might serve as a reference for government entities and healthcare providers in Taiwan to improve cervical screening rates; this should help enhance the effectiveness of healthcare services for Vietnamese immigrant women. The findings can also provide a reference for making appropriate healthcare policies for immigrant women in other countries. PMID- 23656407 TI - X-ray crystal structure of ERK5 (MAPK7) in complex with a specific inhibitor. AB - The protein kinase ERK5 (MAPK7) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role mediating cell proliferation, survival, epithelial-mesenchymal transition, and angiogenesis. To date, no three-dimensional structure has been published that would allow rational design of inhibitors. To address this, we determined the X-ray crystal structure of the human ERK5 kinase domain in complex with a highly specific benzo[e]pyrimido[5,4-b]diazepine-6(11H)-one inhibitor. The structure reveals that specific residue differences in the ATP-binding site, compared to the related ERKs p38s and JNKs, allow for the development of ERK5-specific inhibitors. The selectivity of previously observed ERK5 inhibitors can also be rationalized using this structure, which provides a template for future development of inhibitors with potential for treatment of disease. PMID- 23656410 TI - One-pot synthesis of 3-hydroxyquinolin-2(1H)-ones from N-phenylacetoacetamide via PhI(OCOCF3)2-mediated alpha-hydroxylation and H2SO4-promoted intramolecular cyclization. AB - A clean, one-pot synthesis of the biologically important 3-hydroxyquinolin-2(1H) one compounds has been realized from the readily available N-phenylacetoacetamide derivatives through a PhI(OCOCF3)2-mediated alpha-hydroxylation and a H2SO4 promoted intramolecular condensation. The hydroxyl group in the generated alpha hydroxylated intermediate can be well tolerated in the second H2SO4-promoted cyclization step. PMID- 23656411 TI - Transfer of tritium released into the marine environment by French nuclear facilities bordering the English Channel. AB - Controlled amounts of liquid tritium are discharged as tritiated water (HTO) by the nuclear industry into the English Channel. Because the isotopic discrimination between 3H and H is small, organically bound tritium (OBT) and HTO should show the same T/H ratio under steady-state conditions. We report data collected from the environment in the English Channel. Tritium concentrations measured in seawater HTO, as well as in biota HTO and OBT, confirm that tritium transfers from HTO to OBT result in conservation of the T/H ratio (ca. 1 * 10( 16)). The kinetics of the turnover of tritium between seawater HTO, biota HTO, and OBT was investigated. HTO in two algae and a mollusk is shown to exchange rapidly with seawater HTO. However, the overall tritium turnover between HTO and the whole-organism OBT is a slow process with a tritium biological half-life on the order of months. Nonsteady-state conditions exist where there are sharp changes in seawater HTO. As a consequence, for kinetic reasons, the T/H ratio in OBT may deviate transiently from that observed in HTO of samples from the marine ecosystem. Dynamic modeling is thus more realistic for predicting tritium transfers to biota OBT under nonsteady-state conditions. PMID- 23656413 TI - Partnership working and outcomes: do health and social care partnerships deliver for users and carers? AB - Working in partnership, both across social care and health and with service users, has been a persistent theme of the health and social care modernisation agenda in the United Kingdom. Despite a relatively underdeveloped evidence base, the development of health and social care partnerships has continued to feature in recent policy and legislative initiatives in the United Kingdom. At the same time there has been a major shift in focus towards the outcomes that support services deliver. A central question remaining is whether the policy initiatives driving the development of health and social care partnerships are delivering improved outcomes, particularly the outcomes valued by people who use services. This article outlines research designed to explore this issue across 15 health and social care partnerships in England and Scotland, building from previous research by the Social Policy Research Unit based at the University of York. It sought to assess the extent to which health and social care partnerships deliver the outcomes that people who use services value, and to determine the features of partnership working associated with the delivery of these outcomes. A robust outcomes framework was defined, which provided the basis for interviews with those receiving support from partnerships. Working with three user-researcher organisations, interviews were completed with 230 individuals in 2006. On the basis of this, some service users were able to identify features of partnership that particularly contributed to improved outcomes. These included continuity of staff and sufficient staff and a range of resources, including the availability of long-term and preventative services. Given the definitional and methodological complexity surrounding partnership working, and the challenges of attribution, the study faced some limitations in its ability to make wider inferences about partnership and outcomes. A theory of change should be employed in future studies of this type. PMID- 23656414 TI - Migration of mineral oil, photoinitiators and plasticisers from recycled paperboard into dry foods: a study under controlled conditions. AB - Migration from recycled paperboard was monitored after 2, 4 and 9 months of storage for six test foods industrially packed in five configurations, four with internal plastic films. After 9 months, the migration of mineral oil saturated hydrocarbons into foods directly packed in the paperboard amounted to 30-52 mg/kg, which corresponded to 65%-80% of those of a volatility up to that of the n alkane C24 in the paperboard. The concentration of the migrated aromatic hydrocarbons in the foods ranged from 5.5 to 9.4 mg/kg. More than half of this migration occurred in the first 2 months. Differences between the foods amounted to mostly less than a factor of 2 and seemed to be related to porosity or permeability more than fat content. Nine photoinitiators were detected in the paperboard, of which eight migrated into the packed food at up to 24%. Several plasticisers were present in the recycled paperboard, but only butyl phthalates showed significant migration. After 9 months, up to 40% of diisobutyl phthalate and 20% of dibutyl phthalate migrated into the food with direct contact. The internal polyethylene film hardly slowed migration, but the film and the tray absorbed approximately three times more mineral oil than the food, despite constituting merely 4% of the mass of the pack. Oriented polypropylene strongly slowed migration: The highest migration of saturated hydrocarbons measured after 9 months (2.3 mg/kg) corresponded to only 3% of the content in the paperboard and included migrated polyolefin oligomeric saturated hydrocarbons. Coating of polypropylene with an acrylate further slowed the migration, but the migration from the paperboard was still detectable in four of the six samples. Polyethylene terephthalate was a tight barrier. PMID- 23656415 TI - Hyaluronidase inhibiting activity and radical scavenging potential of flavonols in processed onion. AB - The flavonol content and anti-inflammatory and antioxidant activities of onion treated by high-pressure processing (HPP) and HPP combined with freeze-drying and pulverization (HPP-FD-P) were evaluated. Allium cepa L. var. cepa, 'Recas' was treated at T1 (200 MPa/25 degrees C/5 min), T2 (400 MPa/25 degrees C/5 min), and T3 (600 MPa/25 degrees C/5 min). After treatment, HP-treated and untreated samples were frozen (diced onion, HP-treated). Subsequently, part of the diced samples was freeze-dried and pulverized (pulverized onion, HP-treated and freeze dried). Flavonol content and anti-inflammatory and antioxidant activities (hyaluronidase inhibiting activity, NO(*), ABTS(*+), and DPPH(*) scavenging capacity, ferric reducing antioxidant power, and antioxidative capacity by photochemiluminescence) were measured in nonhydrolyzed and hydrolyzed extracts. Hydrolysis was carried out in order to evaluate the effect of HPP and HPP-FD-P on both anti-inflammatory and antioxidant activities of extracts mainly containing aglycone forms. HPP-FD-P increased quercetin 3,4'-diglucoside, quercetin 4' glucoside, quercetin 3-glucoside, and isorhamnetin 3,4'-diglucoside extractability. The present study suggests that HPP (especially treatment at 400 MPa) and HPP-FD-P may be of benefit for obtaining functional ingredients from onion, as suggested by increased NO(*) scavenging capacity and maintenance of the antioxidant activity mainly in hydrolyzed extracts. PMID- 23656416 TI - Mouse aortic muscle cells respond to oxygen following cytochrome P450 3A13 gene transfer. AB - We have previously shown that a cytochrome P450 (CYP450) hemoprotein from the 3A subfamily CYP3A13 for the mouse, serves as the sensor in the contraction of the ductus arteriosus in response to increased oxygen tension. In addition, we have identified endothelin-1 (ET-1) as the effector for this response. Here, we examined whether Cyp3a13 gene transfer confers oxygen sensitivity to cultured muscle cells from mouse aorta. Coincidentally, we determined whether the same hemoprotein is normally present in the vessel. Cyp3a13-transfected aortic cells responded to oxygen, whereas no significant response was seen in native cells or in cells transfected with an empty vector. Furthermore, this oxygen effect was curtailed by the ET-1/ETA receptor antagonist BQ-123. We also found that CYP3A13 occurs naturally in aortic tissue and its isolated muscle cells in culture. We conclude that CYP3A13 is involved in oxygen sensing, and its action in the transfected muscle cells of the aorta, as in the native cells of the ductus, takes place through a linkage to ET-1. However, the response of aortic muscle to oxygen, conceivably entailing the presence of CYP3A13 at some special site, is not seen in the native situation, and may instead unfold upon transfection of the parent gene. PMID- 23656417 TI - Improved EIS performance of an electrochemical cytosensor using three-dimensional architecture Au@BSA as sensing layer. AB - An ultrasensitive electrochemical cytosensor for quantitative determination of carcinoembryonic antigen (CEA)-positive tumor cells was developed using three dimensional (3D) architecture Au@BSA microspheres as sensing layer with the conjugation of targeting molecule monoclonal anti-CEA antibody (anti-CEA). The prepared Au@BSA microspheres exhibited satisfactory biocompatibility for cell proliferation via evaluation from thiazolyl blue tetrazolium bromide (MTT) assay, providing a suitable platform for cell adhesion study. Attributed to the excellent electroconductivity of Au@BSA, amplified electrochemical signals could be obtained and resulted in the greatly enhanced detection sensitivity. Electrochemical testing techniques including electrochemical impedance spectroscopy (EIS), differential pulse voltammetry (DPV), and cyclic voltammetry (CV) were applied to assess the optimal conditions, specificity, and detection performance of as-fabricated cytosensor. The attachment of CEA-positive BXPC-3 cells onto the anti-CEA immobilized sensing layer led to the increased EIS responses, which changed linearly in the cell concentration range from 5.2 * 10(1) to 5.2 * 10(7) cells mL(-1) with a detection limit of 18 cells mL(-1). This proposed cytosensing strategy revealed high specificity to CEA-positive cells, acceptable intra-assay precision, excellent fabrication reproducibility with the RSD of 3.5%, and good stability owing to the outside BSA biocompatible layer, developing a promising technique for early monitoring of tumor cells at a lower level. PMID- 23656418 TI - Commentary: phlebotomy in non-alcoholic fatty liver disease. PMID- 23656419 TI - Commentary: prognostication of chronic hepatitis B--are Fibrotest and Fibroscan the final answers? PMID- 23656420 TI - Commentary: prognostication of chronic hepatitis B - are Fibrotest and Fibroscan the final answers? Authors' reply. PMID- 23656421 TI - Letter: the burden of co-morbidity in the population contributes more to upper gastrointestinal bleeding than aspirin. PMID- 23656422 TI - Letter: coeliac disease and ischaemic heart disease--a true additional risk factor? PMID- 23656423 TI - Letter: the burden of co-morbidity in the population contributes more to upper gastrointestinal bleeding than aspirin--authors' reply. PMID- 23656424 TI - Letter: coeliac disease and ischaemic heart disease--a true additional risk factor? Authors' reply. PMID- 23656425 TI - Letter: impact of mild alcohol consumption in chronic hepatitis C treatment. PMID- 23656426 TI - Interplay between nonadiabatic dynamics and Frenkel exciton transfer in molecular aggregates: formulation and application to a perylene bismide model. AB - The quantum dynamics of linear molecular aggregates in the presence of S0 -> S1 and S0 -> S2 transitions is investigated by putting emphasis on the interplay between local nonadiabatic S2 to S1 deactivation and Frenkel exciton transfer. The theoretical approach combines aspects of the linear vibronic coupling and Frenkel exciton models. Dynamics calculations are performed for the absorption spectrum and the electronic state populations using the multiconfiguration time dependent Hartree approach. As an application, perylene bisimde J-type dimer and trimer aggregates are considered, including four tuning and one coupling mode per monomer. This leads to a dynamical model comprising up to 7 electronic states and 15 vibrational modes. The unknown nonadiabatic coupling strength is treated as a parameter that is chosen in accordance with available absorption spectra. This leaves some flexibility that can be limited by the clearly distinguishable population dynamics. PMID- 23656427 TI - Postpartum hemorrhages are more common in planned hospital births compared with planned home births. PMID- 23656428 TI - Cotton plasma membrane intrinsic protein 2s (PIP2s) selectively interact to regulate their water channel activities and are required for fibre development. AB - Aquaporins are thought to be associated with water transport and play important roles in cotton (Gossypium hirsutum) fibre elongation. Among aquaporins, plasma membrane intrinsic proteins (PIPs) constitute a plasma-membrane-specific subfamily and are further subdivided into PIP1 and PIP2 groups. In this study, four fibre-preferential GhPIP2 genes were functionally characterized. The selective interactions among GhPIP2s and their interaction proteins were studied in detail to elucidate the molecular mechanism of cotton fibre development. GhPIP2;3 interacted with GhPIP2;4 and GhPIP2;6, but GhPIP2;6 did not interact with GhPIP2;4. Coexpression of GhPIP2;3/2;4 or GhPIP2;3/2;6 resulted in a positive cooperative effect which increased the permeability coefficient of oocytes, while GhPIP2;4/2;6 did not. GhBCP2 (a blue copper-binding protein) inhibited GhPIP2;6 water channel activity through their interaction. Overexpression of GhPIP2 genes in yeast induced longitudinal growth of the host cells. By contrast, knockdown of expression of GhPIP2 genes in cotton by RNA interference markedly hindered fibre elongation. In conclusion, GhPIP2 proteins are the primary aquaporin isoforms in fibres. They selectively form hetero oligomers in order to regulate their activities to meet the requirements for rapid fibre elongation. PMID- 23656429 TI - Photorespiratory compensation: a driver for biological diversity. AB - This paper reviews how terrestrial plants reduce photorespiration and thus compensate for its inhibitory effects. As shown in the equation phi = (1/Sc/o )O/C, where phi is the ratio of oxygenation to carboxylation, Sc/o is the relative specificity of Rubisco, O is stromal O2 level and C is the stromal CO2 concentration, plants can reduce photorespiration by increasing Sc/o or C, or by reducing O. By far the most effective means of reducing phi is by concentrating CO2, as occurs in C4 and CAM plants, and to a lesser extent in plants using a glycine shuttle to concentrate CO2 into the bundle sheath. Trapping and refixation of photorespired CO2 by a sheath of chloroplasts around the mesophyll cell periphery in C3 plants also enhances C, particularly at low atmospheric CO2. O2 removal is not practical because high energy and protein investment is needed to have more than a negligible effect. Sc/o enhancement provides for modest reductions in phi, but at the potential cost of limiting the kcat of Rubisco. An effective means of decreasing phi and enhancing carbon gain is to lower leaf temperature by reducing absorbance of solar radiation, or where water is abundant, opening stomata. By using a combination of mechanisms, C3 plants can achieve substantial (>30%) reductions in phi. This may have allowed many C3 species to withstand severe competition from C4 plants in low CO2 atmospheres of recent geological time, thereby preserving some of the Earth's floristic diversity that accumulated over millions of years. PMID- 23656430 TI - Global coherence in younger and older adults: Influence of cognitive processes and discourse type. AB - The purpose of the present research was to examine the influence of cognitive processes on discourse global coherence ability measured across different discourse tasks and collected from younger (n = 40; 20-39 years) and older (n = 40; 70-87 years) cognitively healthy adults. Study participants produced oral language samples in response to five commonly used discourse elicitation tasks and they were analyzed for maintenance of global coherence. Participants also completed memory and attention measures. Group differences on the global coherence scale were found for only one type of discourse-recounts. Across discourse elicitation tasks the lowest global coherence scores were found for recounts compared to the other discourse elicitation tasks. The influence of cognitive processes on maintenance of global coherence differed for the two age groups. For the younger group, there were no observed significant relationships. For the older group, cognitive measures were related to global coherence of stories and procedures. PMID- 23656431 TI - Encouragement toward employment for those with disabilities. PMID- 23656432 TI - Effect of recombinant Ganoderma lucidum immunoregulatory protein on cyclophosphamide-induced leukopenia in mice. AB - The aim of the study is to investigate the effect of recombinant Ganoderma lucidum immunoregulatory protein (rLZ-8) on mouse models of cyclophosphamide induced leukopenia, which we have established with both single-phase and multi phase administration methods. Treatment with rLZ-8 had a strong effect on both models of cyclophosphamide-induced leukopenia. In particular, it increased the number of neutrophils, lymphocytes and monocytes. rLZ-8 treatment also increased the percentage of CD4(+) T cells and the levels of secreted IL-3 and IL-4, which contributed to the cyclophosphamide-induced immune dysfunction and immune system imbalance. In conclusion, rLZ-8 treatment benefitted mice with cyclophosphamide induced leukopenia by improving overall immune function and by specifically increasing the number of white blood cells. PMID- 23656433 TI - Impact of surgical waiting time on paediatric spinal deformity patients. AB - BACKGROUND: Scoliosis has been shown to affect quality of life of young people. There can be a lengthy wait for surgery. We aim to assess whether the length of time waiting for surgery has an impact on quality of life and surgical outcomes. METHODS: Patients who were waiting for or had completed surgery for paediatric spinal deformity in the last 3 years were contacted and asked to complete the Scoliosis Research Society-30 (SRS-30) questionnaire as well as a questionnaire designed to specifically assess the impact of waiting for surgery. Hospital records and X-rays were reviewed to determine surgical outcomes. RESULTS: Longer waiting time was associated with both lower SRS scores (0.13 points per 6 months, P = 0.01) and lower wait time questionnaire values (0.12 points per 6 months, P < 0.01). Within the SRS-30 questionnaire, pain, satisfaction with management and self-image domains showed a statistically significant decrease with increasing wait time (P = 0.02, 0.05, >0.01 respectively). Cobb angles progressed with increased waiting time, but progression was not statistically significant. No correlation was found between waiting times and the other surgical outcomes measured (surgical duration, hospital stay, blood transfusion, return to theatre or other complications). CONCLUSION: Increased waiting time for surgery has a negative impact on quality of life of patients with scoliosis. PMID- 23656436 TI - Tuning primary metabolism for heterologous pathway productivity. AB - Tuning expression of competing endogenous pathways has been identified as an effective strategy in the optimization of heterologous production pathways. However, intervention at the first step of glycolysis, where no alternate routes of carbon utilization exist, remains unexplored. In this work we have engineered a viable E. coli host that decouples glucose transport and phosphorylation, enabling independent control of glucose flux to a heterologous pathway of interest through glucokinase (glk) expression. Using community sourced and curated promoters, glk expression was varied over a 3-fold range while maintaining cellular viability. The effects of glk expression on the productivity of a model glucose-consuming pathway were also studied. Through control of glycolytic flux we were able to explore a number of cellular phenotypes and vary the yield of our model pathway by up to 2-fold in a controllable manner. PMID- 23656437 TI - Engineered quorum sensing using pheromone-mediated cell-to-cell communication in Saccharomyces cerevisiae. AB - Population-density-dependent control of gene expression, or quorum sensing, is widespread in nature and is used to coordinate complex population-wide phenotypes through space and time. We have engineered quorum sensing in S. cerevisiae by rewiring the native pheromone communication system that is normally used by haploid cells to detect potential mating partners. In our system, populations consisting of only mating type "a" cells produce and respond to extracellular alpha-type pheromone by arresting growth and expressing GFP in a population density-dependent manner. Positive feedback quorum sensing dynamics were tuned by varying alpha-pheromone production levels using different versions of the pheromone-responsive FUS1 promoter as well as different versions of pheromone genes (mfalpha1 or mfalpha2). In a second system, pheromone communication was rendered conditional upon the presence of aromatic amino acids in the growth medium by controlling alpha-pheromone expression with the aromatic amino acid responsive ARO9 promoter. In these circuits, pheromone communication and response could be fine-tuned according to aromatic amino acid type and concentration. The genetic control programs developed here are responsive to dynamic spatiotemporal and chemical cellular environments, resulting in up-regulation of gene expression. These programs could be used to control biochemical pathways for the production of fuels and chemicals that are toxic or place a heavy metabolic burden on cell growth. PMID- 23656438 TI - Tuning promoter strengths for improved synthesis and function of electron conduits in Escherichia coli. AB - Introduction of the electron transfer complex MtrCAB from Shewanella oneidensis MR-1 into a heterologous host provides a modular and molecularly defined route for electrons to be transferred to an extracellular inorganic solid. However, an Escherichia coli strain expressing this pathway displayed limited control of MtrCAB expression and impaired cell growth. To overcome these limitations and to improve heterologous extracellular electron transfer, we used an E. coli host with a more tunable induction system and a panel of constitutive promoters to generate a library of strains that separately transcribe the mtr and cytochrome c maturation (ccm) operons over 3 orders of magnitude. From this library, we identified strains that show 2.2 times higher levels of MtrC and MtrA and that have improved cell growth. We find that a ~300-fold decrease in the efficiency of MtrC and MtrA synthesis with increasing mtr promoter activity critically limits the maximum expression level of MtrC and MtrA. We also tested the extracellular electron transfer capabilities of a subset of the strains using a three-electrode microbial electrochemical system. Interestingly, the strain with improved cell growth and fewer morphological changes generated the largest maximal current per cfu, rather than the strain with more MtrC and MtrA. This strain also showed ~30 fold greater maximal current per cfu than its ccm-only control strain. Thus, the conditions for optimal MtrCAB expression and anode reduction are distinct, and minimal perturbations to cell morphology are correlated with improved extracellular electron transfer in E. coli. PMID- 23656439 TI - Effect of clarithromycin in experimental empyema by multidrug-resistant Pseudomonas aeruginosa. AB - Evidence from a recent randomized study of our group suggests that intravenous clarithromycin resulted in earlier resolution of ventilator-associated pneumonia. The need to understand the mechanism of action of clarithromycin guided to the study of a model of experimental empyema by multidrug-resistant Pseudomonas aeruginosa in 40 rabbits. Animals were randomized into controls (group A); treatment with clarithromycin (group B); treatment with piperacillin/tazobactam (group C); and treatment with both agents (group D). Pleural fluid was collected at regular time intervals for quantitative culture, estimation of cell apoptosis and of concentrations of tumour necrosis factor-alpha (TNFalpha). After 7 days, animals were euthanized for estimation of tissue growth. Bacterial growth in the pleural fluid of group D was significantly decreased compared with the other groups on day 5. Lung growth of group D was lower than group A. That was also the case of cytokine stimulation by pleural fluid samples on U937 monocytes. It is concluded that administration of clarithromycin enhanced the antimicrobial efficacy of piperacillin/tazobactam and decreased bacterial growth in the pleural fluid and in tissues. It also attenuated the pro-inflammatory phenomena induced by the beta-lactam. PMID- 23656440 TI - The association of self-perception of body fat changes and quality of life in the Women's Interagency HIV Study. AB - Body fat changes are of concern to HIV-seropositive adults on highly active antiretroviral therapy (HAART). Studies examining the association of body fat changes and quality of life (QOL) in the setting of HIV infection have been conducted predominately in men. We examined the relationship of self-perceived body fat change with QOL among 1671 HAART-using HIV-seropositive women (mean age 40+/-8 years; 54% African-American, 24% reporting <95% HAART adherence) from the Women's Interagency HIV Study. Self-perception of any fat loss was associated with lower overall QOL. Report of any peripheral fat loss was strongly associated with nearly all QOL domains (i.e., physical functioning, role functioning, energy/fatigue, social functioning, pain, emotional well-being, health perception, and perceived health index) except cognitive functioning, whereas report of any central fat loss was significantly associated with lower social and cognitive functioning. Report of any central fat gain was associated with lower overall QOL, but only physical functioning, energy/fatigue, and cognitive functioning were significantly affected. A significant association of report of any peripheral fat gain with overall QOL was not observed, however, peripheral fat gain was significantly associated with lower physical functioning and pain. We found that any report of fat loss, especially in peripheral body sites was associated with lower QOL, as was any report of central fat gain. Ultimately health providers and patients need to be informed of these associations so as to better support HIV-seropositive women who live with these effects. PMID- 23656441 TI - A cluster randomised controlled trial of a nutrition education intervention in the community. AB - BACKGROUND: Patients with enteral feeding tubes are increasingly managed in their home environment and these patients require support from a range of healthcare professionals. METHODS: A cluster randomised trial of an educational intervention was undertaken among General Practitioners and nurses both in the community and in nursing home caring for patients recently discharged to primary care. This was a short, duration (<1 h), nutrition education programme delivered in the work place soon after the patient was discharged from hospital. The primary outcome was an improvement in knowledge immediately after the intervention and the secondary outcome was knowledge at 6 months. RESULTS: Those in the intervention group had improved knowledge, which was significantly greater than those in the control group (P < 0.001), although this knowledge was not sustained at 6 months. CONCLUSIONS: A short, work-based targeted nutrition education programme is effective for improving knowledge among general practitioners and nurses both in the community and in nursing homes. PMID- 23656442 TI - The future of risk communication and the role of the pharmaceutical industry. AB - Risk communication is an interactive two-way process that various stakeholders (e.g., patients, regulators, industry) utilize to address prescription drug safety. This paper will specifically examine the pharmaceutical industry's engagement with risk communication as a tool for information exchange with patients and other stakeholders about the associated risks related to its medicines. Risk communications are not solely meant to inform; and rather effective two-way risk communications have the potential to change behavioral outcomes for the purpose of individual and societal benefit. Despite this indispensable role of risk communication for the pharmaceutical industry, more research is needed for the appropriate development and dissemination of risk communications. A crucial missing component for the crafting of pharmaceutical risk communications is the understanding of risk perceptions from the patient/consumer's perspective. This is necessary to see where any divergences in views may lie between the industry and its final consumer, which is crucial in tailoring communications to target a specific erroneous belief or to address what might be deemed as a needed behavioral shift. It is also necessary to develop communications in consideration of the levels of public trust in the industry as well as other perceived actors in the healthcare system. Even the most meticulously crafted and tested risk communications will fail to fulfill their purpose if the role of trust is not taken into consideration. These considerations can lead to the establishment of a "social contract" that effectively addresses what is required from both parties for continued and mutually beneficial interactions. Conducting risk perception research, addressing the role of trust, establishing a social contract, and having a realistic outlook on the impact of risk communications are necessary considerations as pharmaceutical risk communication evolves for the future. PMID- 23656443 TI - Improving the effect of FDA-mandated drug safety alerts with Internet-based continuing medical education. AB - The US Food and Drug Administration (FDA) requires risk communication as an element of Risk Evaluation and Mitigation Strategies (REMS) to alert and educate healthcare providers about severe toxicities associated with approved drugs. The educational effectiveness of this approach has not been evaluated. To support the communication plan element of the ipilimumab REMS, a Medscape Safe Use Alert (SUA) letter was distributed by Medscape via email and mobile device distribution to clinicians specified in the REMS. This alert contained the FDA-approved Dear Healthcare Provider (DHCP) letter mandated for distribution. A continuing medical education (CME) activity describing ipilimumab toxicities and the appropriate management was simultaneously posted on the website and distributed to Medscape members. Data were collected over a 6-month period regarding the handling of the letter and the responses to pre- and post-test questions for those who participated in the CME activity. Analysis of the answers to the pre- and posttest questions showed that participation in the CME activity resulted in an improvement in correct answer responses of 47%. Our experience shows that there are likely distinct information sources that are utilized by different HCP groups. The ready availability of a brief CME activity was utilized by 24,063 individuals, the majority of whom showed enhanced understanding of ipilimumab toxicity by improvement in post-test scores, educational data that are not available via implementation of standard safety alert communications. These results demonstrate that improvement in understanding of specific drug toxicities is enhanced by a CME intervention. PMID- 23656444 TI - The practicing clinician and regulatory safety concerns. AB - Pharmaceutical agents are prescribed to produce a therapeutic effect, but safety concerns require constant attention to the benefit:risk relationship inherent in their use and the needs of the individual patient. Such calculations involve assumptions about the likely tolerability of harm, in that greater safety risks may be acceptable for use of a lifesaving drug, compared with those acceptable for an agent providing only improved "quality of life." Making such assumptions is an activity integral to the bedside clinician's role, is done during many (perhaps most) patient encounters, and is often undertaken with inadequate information. The historical mandates for regulatory agencies, such as the Food and Drug Administration (FDA) in the United States, have evolved over the past decades to include an intense focus on drug safety. Communicating information about medicinal risk remains a major responsibility for the FDA and similar bodies, but the initiatives undertaken have had variable, and often limited, effectiveness in penetrating the physician-patient interaction. Barriers to the successful communication of safety-related issues include the myriad of influences on and within the FDA, the time constraints on physicians involved in clinical practice, and the methodologies used to share information about both established and new drugs. Current efforts to assess the effectiveness of regulatory efforts at risk communications should lead to changes in the approaches used and, ultimately, improvement in the safe use of both new and established drugs. PMID- 23656445 TI - Defining the pharmaceutical system to support proactive drug safety. AB - The military, aviation, nuclear, and transportation industries have transformed their safety records by using a systems approach to safety and risk mitigation. This article creates a preliminary model of the U.S. pharmaceutical system using available literature including academic publications, policies, and guidelines established by regulatory bodies and drug industry trade publications. Drawing from the current literature, the goals, roles, and individualized processes of pharmaceutical subsystems will be defined. Defining the pharmaceutical system provides a vehicle to assess and address known problems within the system, and provides a means to conduct proactive risk analyses, which would create significant pharmaceutical safety advancement. PMID- 23656446 TI - A chief safety officer as the driver and guardian of a great safety rating. AB - If the Pharmaceutical Industry were to align to broad metrics that objectively state each product's "Safety Rating" two things would happen. First, Life Sciences companies would refocus dramatically on safety (followed by outcomes). Second, companies that have the highest aggregate "Safety Rating" would enjoy a significant competitive advantage. To achieve and maintain a high safety rating, the role of Safety officer needs to be elevated to the C-Suite. PMID- 23656447 TI - Medicines counterfeiting is a complex problem: a review of key challenges across the supply chain. AB - The paper begins by asking why there is a market for counterfeit medicines, which in effect creates the problem of counterfeiting itself. Contributing factors include supply chain complexity and the lack of whole-systems thinking. These two underpin the author's view that counterfeiting is a complex (i.e. wicked) problem, and that corporate, public policy and regulatory actions need to be mindful of how their actions may be causal. The paper offers a problem-based review of key components of this complexity, viz., the knowledge end users/consumers have of medicines; whether restrictive information policies may hamper information provision to patients; the internet's direct access to consumers; internet-enabled distribution of unsafe and counterfeit medicines; whether the internet is a parallel and competitive supply chain to legitimate routes; organised crime as an emerging medicines manufacturer and supplier and whether substandard medicines is really the bigger problem. Solutions respect the perceived complexity of the supply chain challenges. The paper identifies the need to avoid technologically-driven solutions, calling for 'technological agnosticism'. Both regulation and public policy need to reflect the dynamic nature of the problem and avoid creating perverse incentives; it may be, for instance, that medicines pricing and reimbursement policies, which affect consumer/patient access may act as market signals to counterfeiters, since this creates a cash market in cheaper drugs. PMID- 23656448 TI - Unifying drug safety and clinical databases. AB - Clinical and drugs safety organisations run their operation independently and use separate databases designed to comply with different data standards. This separation is neither efficient nor effective since investigators need to report serious adverse events both to the clinical and drug safety departments, causing the respective databases to contain partially overlapping data sets containing common elements that need to be reconciled. Electronic data capture provides the opportunity to avoid duplicate storage and obviate reconciliation. It also introduces the risk of non-compliance due to late submission of unexpected serious adverse reactions to competent authorities. This raises the potential for a clinical department to receive a case that the drug safety department is unaware of. However, the most significant inefficiency probably lies in the preparation of aggregate reports and regulatory documents that need to be prepared using data originating from both databases. In a resource-constrained world, unnecessary activities and associated costs are unwelcome, particularly when they are avoidable. The Clinical Data Interchange Consortium (CDISC) has set the standards for clinical trial data, while the International Conference of Harmonization (ICH) dictates drug safety ones. CDISC is expanding its Clinical Data Acquisition Standards Harmonisation (CDASH) model to capture adverse event data associated with ICH E2B. All common data items have two labels that have been mapped. This exercise is showing that there is no scientific justification for data segregation. The differences between these two standards can be attributed to conventions or arise from new technology that renders unnecessary the keying in of certain context information (dates, times and recorder ID). Once this mapping is completed then a common data acquisition process will become feasible. This is the prerequisite to ultimately unifying the two databases and to implementing more efficient processes. The Authors also propose a new workflow to provide safety with the array of benefits that technology and process harmonisation offers and ultimately unifying the clinical drug safety processes. PMID- 23656449 TI - Domperidone in Parkinson's disease: a perilous arrhythmogenic or the gold standard? AB - Domperidone, a dopamine antagonist that does not easily cross the blood-brain barrier, is considered the gold standard for treating gastrointestinal symptoms in patients with Parkinson's disease (PD) because the risk of developing extrapyramidal adverse effects is considered minimal. On the other hand, cardiotoxicity related to domperidone is not a new issue. In fact, arrhythmias, sudden death and cardiac arrest were reported with high intravenous doses in the 80s. Concern about the cardiotoxicity of oral domperidone has arisen more recently after the publication of two case-control studies which have questioned domperidone's safety even further, especially in patients > 60 years and in doses >30 mg/day. Very little is known about domperidone's cardiac effects in patients with PD. In addtion, pharmacoepidemiological data about specific antiemetic use in these patients is scarce, with almost anecdotal reports of inappropriate centrally acting antidopaminergic drugs like metoclopramide in the hospital setting. As a result, and even no cases of serious arrhythmias or sudden cardiac death associated with domperidone concerning patients with PD have been reported, no definitive conclusions can be drawn about its safety. In conclusion, despite domperidone is still recognized as the first choice for treating gastrointestinal symptoms PD, doses above 30 mg/daily should only be considered with special caution taking into account its potential cardiotoxic effects. PMID- 23656450 TI - Nevirapine and/or co-trimoxazole induced Stevens Johnson syndrome in HIV infected patient--a case report. AB - A 46 years old HIV reactive patient developed Stevens Johnson syndrome (SJS) probably due to nevirapine and/or co-trimoxazole. Patient was on zidovudine + lamivudine + nevirapine along with Co-trimoxazole since last two months. After 15 days, zidovudine was replaced with stavudine due to development of anemia. All these drugs were stopped after development of reaction. Temporal association was found between stavudine, lamivudine, nevirapine, cotrimoxazole and development of the reaction. Nevirapine and Co-trimoxazole were suspected to cause this reaction most probably due to associated hepatotoxicity and their common potential to cause SJS. In our case, patient died despite stopping of all medications. PMID- 23656451 TI - Sodium valproate induced tremor in a patient with epilepsy and Down's syndrome. AB - Some papers reported the development of adverse drug reactions in patients with Down's syndrome during the treatment with antiepileptic drugs. However, at this time, no data have been published concerning the development of tremor in patients with Down's syndrome treated with sodium valproate. We report a 17-year old man with epilepsy and Down's syndrome who experienced tremor during the treatment with a low dosage of sodium valproate. The Naranjo probability scale documented a possible association between tremor and sodium valproate. Sodium valproate was changed to lamotrigine with both a rapid improvement of tremor and an optimal control of symptoms. In conclusion we documented that sodium valproate is able to induce in a patient with epilepsy and Down's syndrome, the development of tremor probably through the decreased activity of GABAergic neurotrasmission; however, further studies may be performed in order to validate this observation. PMID- 23656452 TI - Epidemiology of major congenital malformations with specific focus on teratogens. AB - BACKGROUND: Major congenital malformations (MCMs) are a significant cause of infant morbidity and mortality and constitute an important societal and economic burden. METHODS: We conducted a literature review to synthesize current evidence on MCMs. Specific objectives were to: 1) summarize internationally reported prevalence of MCMs based on registries and surveillance systems; 2) describe the epidemiology of different MCM types including critical periods and causative factors; 3) to identify the role played by principal known teratogens on the increase in the risk of MCMs; and 4) determine challenges associated with the epidemiologic assessment of potential risk factors for MCMs as well as potential preventive measures. RESULTS: It is estimated that 7.9 million infants worldwide are born every year with a MCM, yet there is considerable variation in reported rates across countries. This may be attributable to varying definitions arising from heterogeneity among different classes with respect to critical periods for embryogenesis and organogenesis. There is also substantial etiologic heterogeneity among MCMs classes that potentially contribute to challenges in epidemiologic studies. Modifiable factors such as pharmacologic exposures have received considerable attention and a number of drugs have been shown to be teratogenic including folic acid antagonists, angiotensin converting enzyme inhibitors, antidepressants, anticonvulsants, coumarin derivatives and retinoids including isotretinoin. CONCLUSION: The majority of MCMs are due to unexplained causes. Other contributing factors include genetics, environmental factors, multifactorial inheritance, maternal-related conditions, and maternal drug or chemical exposure. However, there remains a need to better understand the epidemiology of MCMs when studying drug effect during gestation. PMID- 23656453 TI - Carcinogenicity and chronic rodent toxicity of the selective progesterone receptor modulator ulipristal acetate. AB - Carcinogenic properties of ulipristal acetate (UPA), a selective progesterone receptor modulator developed for the treatment of benign gynecological conditions such as uterine fibroids, were assessed in a 26-week carcinogenicity study in transgenic TgRasH2 mice and a 104-week study in Sprague Dawley rats. Dose levels used in the mouse study were 15, 45, or 130 mg/kg/day and for the ratstudy the doses used were 1, 3, or 10 mg/kg/day. Vehicle and water controls were part of both studies and a positive control, N-Nitroso-N-methylurea intraperitoneally, was included in the transgenic mouse assay. Survival at all dose levels was similar to vehicle controls in both sexes of both species and there was no evidence of any UPA-induced carcinogenicity in either species. Rats receiving UPA had decreased incidences of fibroadenomas and adenocarcinomas in the mammary gland in all treated groups. UPA exposure [AUC(0-24h)] at the highest dose in rats was 67 times human therapeutic exposure at 10 mg/day. In mice, no tumor of any type increased at UPA exposures up to 313 times of therapeutic exposure. UPA related findings in mice were limited to organ weight changes in the liver, pituitary, thyroid/parathyroid glands, and epididymis as well as minimal panlobular hepatocellular hypertrophy in male and female mice receiving 130 mg/kg/day. Rats had UPA-related non-neoplastic findings in the reproductive system (mammary gland, ovary, uterus, vagina, seminal vesicle, prostate), endocrine system (adrenal, pituitary), thymus, muscle, liver, pancreas and lungs most of which are considered to be due to exaggerated pharmacological action of the compound. PMID- 23656454 TI - Kinetic study on Michael-type reactions of beta-nitrostyrenes with cyclic secondary amines in acetonitrile: transition-state structures and reaction mechanism deduced from negative enthalpy of activation and analyses of LFERs. AB - A kinetic study is reported for the Michael-type reactions of X-substituted beta nitrostyrenes (1a-j) with a series of cyclic secondary amines in MeCN. The plots of pseudo-first-order rate constant k(obsd) vs [amine] curve upward, indicating that the reactions proceed through catalyzed and uncatalyzed routes. The dissection of k(obsd) into Kk2 and Kk3 (i.e., the rate constants for the uncatalyzed and catalyzed routes, respectively) revealed that Kk3 is much larger than Kk2, implying that the reactions proceed mainly through the catalyzed route when [amine] > 0.01 M. Strikingly, the reactivity of beta-nitrostyrene (1g) toward piperidine decreases as the reaction temperature increases. Consequently, a negative enthalpy of activation is obtained, indicating that the reaction proceeds through a relatively stable intermediate. The Bronsted-type plots for the reactions of 1g are linear with beta(nuc) = 0.51 and 0.61, and the Hammett plots for the reactions of 1a-j are also linear with rhoX = 0.84 and 2.10 for the uncatalyzed and catalyzed routes, respectively. The reactions are concluded to proceed through six-membered cyclic transition states for both the catalyzed and uncatalyzed routes. The effects of the substituent X on reactivity and factors influencing beta(nuc) and rhoX obtained in this study are discussed. PMID- 23656455 TI - Binding mechanism of the farnesoid X receptor marine antagonist suvanine reveals a strategy to forestall drug modulation on nuclear receptors. Design, synthesis, and biological evaluation of novel ligands. AB - Here, we report suvanine, a marine sponge sesterterpene, as an antagonist of the mammalian bile acid sensor farnesoid-X-receptor (FXR). Using suvanine as a template, we shed light on the molecular bases of FXR antagonism, identifying the essential conformational changes responsible for the transition from the agonist to the antagonist form. Molecular characterization of the nuclear corepressor NCoR and coactivator Src-1 revealed that receptor conformational changes are associated with a specific dynamic of recruitment of these cofactors to the promoter of OSTalpha, a FXR regulated gene. Using suvanine as a novel hit, a library of semisynthetic derivatives has been designed and prepared, leading to pharmacological profiles ranging from agonism to antagonism toward FXR. Deep pharmacological evaluation demonstrated that derivative 19 represents a new chemotype of FXR modulator, whereas alcohol 6, with a simplified molecular scaffold, exhibits excellent antagonistic activity. PMID- 23656456 TI - The influence of self-efficacy, pre-stroke depression and perceived social support on self-reported depressive symptoms during stroke rehabilitation. AB - Post-stroke depression (PSD) is the most common mental disorder following stroke; however, little is known about its pathogenesis. We investigated the predictive value and mutual relationship of psychological factors such as self-efficacy and social support and known risk factors such as pre-stroke depression, activities of daily living (ADL), cognitive functioning, and age for the emergence of depressive symptoms in the acute phase after stroke. Ninety-six ischaemic stroke inpatients residing at a rehabilitation centre completed an interview about 6.5 weeks post-stroke. The interview included demographic data, psychiatric anamnesis, the Barthel Index, Mini-Mental State Examination, Social Support Questionnaire, Generalized Self-Efficacy Scale, Stroke Self-Efficacy Questionnaire, and the Geriatric Depression Scale. A multiple regression analysis was performed to ascertain the predictive value of the factors on depressive symptoms. High self-efficacy, no history of pre-stroke depression, and high levels of perceived social support were the strongest protective factors for depressive symptoms. The influence of cognitive functioning on depressive symptoms was fully mediated by general self-efficacy, and general self-efficacy was a stronger predictor than stroke-specific self-efficacy. Neither ADL nor age significantly predicted depressive symptoms. Our findings suggest that consideration of self-efficacy and perceived social support in the inpatient rehabilitation setting may help prevent PSD. PMID- 23656457 TI - Nurse practitioners' perceptions of interprofessional team functioning with implications for nurse managers. AB - AIMS: To determine the perceptions of nurse practitioners (NPs) about the level of functioning of their interprofessional teams. BACKGROUND: Interprofessional teams are a global trend, and nurses play leadership roles in their management. Little is known about the impact of specific barriers to team functioning and the role of the nurse manager on team functioning. METHODS: Ninety-eight NPs at a conference completed the Interprofessional Team Functioning Survey (ITFS). RESULTS: The survey items with the lowest mean scores were related to organisational systems. These items included workplace policies that support interprofessional teamwork, in particular, orientation to the interprofessional team. Items that generated lower mean scores were adequate time to work as a member of the interprofessional team, team dynamics, collaboration among team members and the sharing of responsibility. CONCLUSION: Organisational and team relational issues can be addressed through organisational management strategies. Nurse managers have an important role in facilitating high functioning interprofessional teams. IMPLICATIONS FOR NURSING MANAGEMENT: Strategies for managers to support interprofessional team functioning emerged. These strategies include ensuring that there are appropriate policies, orientation of new members, allocation of time to support interprofessional teamwork, leadership to enhance team collaboration and clear delineation of responsibilities of each member. PMID- 23656458 TI - In-house validation and factorial effect analysis of a LC-MS/MS method for the determination of steroids in bovine and porcine blood plasma. AB - Anabolic steroids are banned from use in food-producing animals in the European Union (Council Directive 96/22/EC). To control the zero-tolerance concept, an LC MS/MS method for the screening and confirmation of most of the relevant natural and synthetic estrogenic and androgenic steroids in bovine and porcine blood plasma was developed and validated. The method permits confirmation and quantification of all analytes above a concentration of 0.65 ug L(-1). The validation was carried out according to Commission Decision 2002/657/EC, Chapter 3.1.3 "Alternative Validation", by applying a matrix-comprehensive in-house validation concept. Decision limit CCalpha, detection capability CCbeta, recovery, repeatability, within-laboratory reproducibility and the uncertainty of measurement were calculated. Furthermore, a factorial effect analysis was carried out to identify factors that have a significant influence on the method. Factors considered to be relevant for the method in routine analysis (e.g., operator, storage duration of the extracts before measurement and different cartridge lots) were systematically varied on two levels. PMID- 23656459 TI - HAART has no major impact on hematological and plasma bilirubin changes in HIV infected patients with congenital G-6-PD deficiency. AB - Hematological effects of antiretroviral (ARV) drugs in HIV-infected patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency are unclear. The aim of this study was to assess effects of highly active antiretroviral therapy (HAART) on hematological and plasma bilirubin changes in these patients. A hundred and nine HIV-infected Thai patients were tested for G-6-PD deficiency and its variant by using fluorescent spot test and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, accordingly. Changes of hematological parameters and plasma bilirubin at baseline and 6 months of HAART were analyzed in G-6-PD deficiency patients. G-6-PD deficiency was found in 10 (9.17%) patients and G-6-PD Canton1376G>T was the most frequent. Of these, 3 patients had coinheritance of G-6-PD deficiency and thalassemia. Increased mean levels of lymphocyte counts, CD4+ T-cells, mean corpuscular hemoglobin (MCH) and hemoglobin from baseline to 6 months of HAART were observed. Whereas, mean levels of total bilirubin and direct bilirubin at baseline were not significantly different from those at 6 months of HAART. Therefore, HAART did not cause hemolytic anemia and hyperbilirubinemia in HIV-infected patients with G-6-PD deficiency. On the other hand, the effective use of HAART is associated with improvements in hemoglobin and MCH levels of these patients. PMID- 23656460 TI - Small cationic antimicrobial peptidomimetics: emerging candidate for the development of potential anti-infective agents. AB - Rapid increase in the emergence and spread of microbes resistant to conventionally used antibiotics has become a major threat to global health care. Antimicrobial peptides (AMPs) are considered as a potential source of novel antibiotics because of their numerous advantages such as broad-spectrum activity, lower tendency to induce resistance, immunomodulatory response and unique mode of action. However, AMPs have several drawbacks such as; susceptibility to protease degradation, toxicity and high costs of manufacturing. Therefore, extensive research efforts are underway to explore the therapeutic potential of these fascinating natural compounds. This review highlights the potential of small cationic antimicrobial peptidomimetics (SCAMPs; M.W. ? 700 Da) as new generation antibiotics. In particular, we focused on recently identified small active pharmacophore from bulky templates of native AMPs, beta-peptides, and lipopeptides. In addition, various design strategies recently undertaken to improve the physicochemical properties (proteolytic stability & plasma protein binding) of small cationic peptides have also been discussed. PMID- 23656461 TI - Calix[n]arenes as goldmines for the development of chemical entities of pharmaceutical interest. AB - Calix[n]arenes are macrocyclic cone-shaped compounds formed from phenolic units linked by methylene groups in the ortho position. Structural features make calix[n]arenes a versatile class of molecules that are of great interest, particularly in the pharmaceutical field. The cavity-like shape gives calix[n]arenes the ability to selectively encapsulate ions or neutral molecules, which can be used to generate carrier systems capable of increasing the solubility and diffusivity of chemical species. These resulting systems can function as deliverers of bioactive guest molecules. Host-guest molecular interactions act as the cornerstone that prompts the application of calix[n]arenes in the pharmaceutical field. Understanding their interactions in host-guest complexes is essential for the development and application of new therapeutics. In the present review, the most utilized analytical techniques for characterizing calix[n]arene inclusion complexes are discussed, and an overview of the ability of a variety of calix[n]arenes to work as host molecules for the development of chemical entities of pharmaceutical interest is also presented. PMID- 23656462 TI - An entomoparasitic adult form in Bursaphelenchus doui (Nematoda: Tylenchomorpha) associated with Acalolepta fraudatrix. AB - The nematode family Aphelenchoididae (Rhabditida: Tylenchomorpha) includes species with various feeding habitats. Bursaphelenchus, a member of the family, has for a long time been considered as a home for plant parasitic or mycophagous species (or both). However, recent intensive biological studies on the family revealed that the genus contains several insect parasitic species. Dauer juveniles of Bursaphelenchus doui were isolated from Acalolepta fraudatrix during a field study of longhorn beetle-Bursaphelenchus nematode associations. Two different insect-associated forms, an "entomoparasitic adult form" and a regular dauer juvenile, were isolated from a single individual beetle in a subsequent laboratory investigation of the B. doui-A. fraudatrix relationship. Thus these 2 distinct, insect-associated forms were confirmed to occur simultaneously. The entomoparasitic form is morphologically similar to that of Bursaphelenchus luxuriosae, with a dome-shaped head and vacuole-like spots assumed to be an internal structure of sensory organ, a stylet, a metacorpus (median bulb), and a moderately-developed and seemingly fully functional reproductive system. It is distinguishable from B. luxuriosae based on male spicule morphology and female tail morphology. A degenerate ingestive-digestive system distinguishes the entomoparasitic form from the propagative form and, unlike dauer juveniles, it has a moderately-developed reproductive system. The presence of this characteristic parasitic adult form is known only in these 2 Bursaphelenchus species. However, these 2 species did not form a clear monophyletic clade within the Bursaphelenchus xylophilus group and, thus, this characteristic parasitic form may occur independently in each species. PMID- 23656463 TI - The impact of nutritional supplementation on quality of life in patients infected with hepatitis C virus. AB - BACKGROUND: The present study aimed to evaluate the impact of animal and vegetable protein supplementation on health-related quality of life (HRQL) in patients with hepatitis C virus (HCV) and to investigate clinical and nutritional variables related to quality of life in these patients. METHODS: One hundred and forty patients infected with HCV were randomly assigned to one of two groups: the Soy Group (SG; n = 72), where patients received a soy supplement diet and the Casein Group (CG; n = 68), where patients received casein as a supplement. Anthropometric, biochemical and clinical assessments were performed in all patients, and the Short-Form Health Survey was applied at baseline and 12 weeks after study initiation. RESULTS: Before supplementation, poor HRQL scores were associated with female sex (P = 0.004) and advanced fibrosis (F3/F4; P = 0.04). Reduced HRQL scores were correlated with age (r = -0.263; P = 0.002), serum albumin levels (r = 0.245; P = 0.004), lean mass (r = 0.301; P < 0.0001) and body fat percentage (r = -0.262; P = 0.002). After 12 weeks of intervention, patients in both supplementation groups showed significantly increased HRQL scores, with no difference being observed between the SG and the CG. CONCLUSIONS: Nutritional therapy with either soybean or casein supplementation improved quality of life in patients infected with HCV. Quality of life was influenced by anthropometric, biochemical, clinical and sociodemographic factors in patients with HCV before nutritional supplementation. PMID- 23656464 TI - A G matrix analogue to capture the cumulative effects of nongenetic inheritance. AB - The genetic variance-covariance (G) matrix describes the variances and covariances of genetic traits under strict genetic inheritance. Genetically expressed traits often influence trait expression in another via nongenetic forms of transmission and inheritance, however. The importance of non-genetic influences on phenotypic evolution is increasingly clear, but how genetic and nongenetic inheritance interact to determine the response to selection is not well understood. Here, we use the 'reachability matrix' - a key analytical tool of geometric control theory - to integrate both forms of inheritance, capturing how the consequences of generation-lagged maternal effects accumulate. Building on the classic Lande and Kirkpatrick model that showed how nongenetic (maternal) inheritance fundamentally alters the expected path of phenotypic evolution, we make novel inferences through decomposition of the reachability matrix. In particular, we quantify how nongenetic inheritance affects the distribution (orientation and shape) of ellipses of phenotypic change and how these distributions influence subsequent evolution. This interweaving of phenotypic means and variances accumulates generation by generation and is described analytically by the reachability matrix, which acts as an analogue of G when genetic and nongenetic inheritance both act. PMID- 23656465 TI - Pilot study: miscellaneous therapy is highly successful for Helicobacter pylori eradication. AB - BACKGROUND: Success in H. pylori eradication with conventional therapies has decreased to unacceptable levels (<=80%). New schemes of combined treatment are currently needed. AIM: To test a miscellaneous therapy for H. pylori eradication. METHODS/PATIENTS: Open-label, pilot, single-centre and prospective study. Patients received a 15-day treatment scheme that consisted of 5 initial days of lansoprazole 30 mg b.d., amoxicillin 1 g b.d., and metronidazole 500 mg t.d.s.; days 6 to 10: lansoprazole 30 mg q.d.s. and metronidazole 500 mg t.d.s.; days 11 to 15: lansoprazole 30 mg b.d., clarithromycin 500 mg b.d. and metronidazole 500 mg t.d.s. Each patient underwent an upper endoscopy before treatment and a second follow-up endoscopy at least 4 weeks after therapy. Success was defined on the basis of an eradication rate following a per-protocol analysis >=95%. Biopsies before and after therapy were obtained for histological evaluation and rapid urease test. RESULTS: One hundred and twenty-two patients were enrolled and 118 patients completed the study. The eradication rate for H. pylori with miscellaneous therapy was 94% (confidence Interval (CI) 95%, 90-98.3%) in the per protocol analysis (PP) and 91% (95% CI, 86-96%) in the intention-to-treat (ITT) analysis. Adherence to treatment was 96% (113 patients). Among patients who completed treatment, 55% presented adverse events, mainly nausea and abdominal pain. CONCLUSION: A miscellaneous therapy, based on the combination of multiple medications in high doses for 2 weeks, and with gastric pH elevation, is a highly effective treatment as a first-line therapy for the eradication of H. pylori. PMID- 23656468 TI - Ortho-to-para ratio in interstellar water on the sightline toward Sagittarius B2(N). AB - The determination of the water ortho-to-para ratio (OPR) is of great interest for studies of the formation and thermal history of water ices in the interstellar medium and protoplanetary disk environments. We present new Herschel observations of the fundamental rotational transitions of ortho- and para-water on the sightline toward Sagittarius B2(N), which allow improved estimates of the measurement uncertainties due to instrumental effects and assumptions about the excitation of water molecules. These new measurements, suggesting a spin temperature of 24-32 K, confirm the earlier findings of an OPR below the high temperature value on the nearby sightline toward Sagittarius B2(M). The exact implications of the low OPR in the galactic center molecular gas remain unclear and will greatly benefit from future laboratory measurements involving water freeze-out and evaporation processes under low-temperature conditions, similar to those present in the galactic interstellar medium. Given the specific conditions in the central region of the Milky Way, akin to those encountered in active Galactic nuclei, gas-phase processes under the influence of strong X-ray and cosmic ray ionization also have to be carefully considered. We summarize some of the latest laboratory measurements and their implications here. PMID- 23656466 TI - Computed tomographic measures of pulmonary vascular morphology in smokers and their clinical implications. AB - RATIONALE: Angiographic investigation suggests that pulmonary vascular remodeling in smokers is characterized by distal pruning of the blood vessels. OBJECTIVES: Using volumetric computed tomography scans of the chest we sought to quantitatively evaluate this process and assess its clinical associations. METHODS: Pulmonary vessels were automatically identified, segmented, and measured. Total blood vessel volume (TBV) and the aggregate vessel volume for vessels less than 5 mm(2) (BV5) were calculated for all lobes. The lobe-specific BV5 measures were normalized to the TBV of that lobe and the nonvascular tissue volume (BV5/T(issue)V) to calculate lobe-specific BV5/TBV and BV5/T(issue)V ratios. Densitometric measures of emphysema were obtained using a Hounsfield unit threshold of -950 (%LAA-950). Measures of chronic obstructive pulmonary disease severity included single breath measures of diffusing capacity of carbon monoxide, oxygen saturation, the 6-minute-walk distance, St George's Respiratory Questionnaire total score (SGRQ), and the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index. MEASUREMENTS AND MAIN RESULTS: The %LAA-950 was inversely related to all calculated vascular ratios. In multivariate models including age, sex, and %LAA-950, lobe-specific measurements of BV5/TBV were directly related to resting oxygen saturation and inversely associated with both the SGRQ and BODE scores. In similar multivariate adjustment lobe-specific BV5/T(issue)V ratios were inversely related to resting oxygen saturation, diffusing capacity of carbon monoxide, 6-minute-walk distance, and directly related to the SGRQ and BODE. CONCLUSIONS: Smoking-related chronic obstructive pulmonary disease is characterized by distal pruning of the small blood vessels (<5 mm(2)) and loss of tissue in excess of the vasculature. The magnitude of these changes predicts the clinical severity of disease. PMID- 23656467 TI - Hepatectomy and liver regeneration: from experimental research to clinical application. AB - BACKGROUND: The mechanisms and kinetics of hepatic growth have continuously been investigated. This study concerns liver regeneration in animal and patients who underwent partial hepatectomy evaluated by the hepatic extraction fraction (HEF) calculated through radioisotopic methods. METHODS: Thirty normal Wistar rats were submitted to an 85% hepatectomy, and 95 patients with primary and secondary liver tumours were included. In animal study, the liver regeneration kinetics was assessed by HEF using 99mTc-mebrofenin, the ratio liver/bodyweight and by using bromodeoxyuridine deoxyribonucleic acid incorporation. In patient study, the liver regeneration was evaluated by calculation of HEF before surgery, 5 and 30 days after hepatectomy. RESULTS: In animal, we verified a positive correlation between HEF kinetics and liver/bodyweight ratio or hepatocyte proliferation evaluated by bromodeoxyuridine deoxyribonucleic acid staining after 85% hepatectomy. In the clinical arm, no statistical differences of the HEF before hepatectomy, 5 and 30 days after hepatectomy, were observed. CONCLUSIONS: Our results support the view that human liver regeneration commences early, is fast, non-anatomical and functionally complete 5 days after hepatectomy. The fast functional liver regeneration may have a high clinical impact particularly concerning the post-operative oncological therapeutic approaches. PMID- 23656469 TI - The long chain fatty acid oleate activates mouse intestinal afferent nerves in vitro. AB - Vagal afferents innervating the gastrointestinal tract serve an important nutrient-sensing function, and these signals contribute to satiety. Detection of nutrients occurs largely through the release of mediators from specialized enteroendocrine cells within the mucosa of the gastrointestinal tract. The signaling pathways leading to vagal afferent activation are not clear; however, previous in-vivo studies have implicated a role for cholecystokinin (CCK). We used an in vitro intestinal afferent extracellular recording preparation to study the effect of luminal perfusion of the long chain fatty acid oleate on mouse intestinal afferent activity. Oleate activated intestinal afferents in a concentration-dependent fashion, with an EC50 value of approximately 25 mmol/L. The L-type calcium channel blocker nicardipine attenuated the effect of oleate. Vagotomy resulted in a significant (>60%) reduction of the responses to both oleate and CCK. The CCK-1 receptor antagonist lorglumide nearly abolished responses to CCK and oleate. Our experiments therefore suggest that oleate activates intestinal afferents, with vagal afferents primarily involved; however, nonvagal fibres also contribute. The activation is dependent on CCK release, likely via activation of L-type channels on mucosal enteroendocrine cells, finally resulting in activation of CCK-1 receptors on the afferent terminals. PMID- 23656470 TI - Enteric-coated alendronate sodium nanoliposomes: a novel formula to overcome barriers for the treatment of osteoporosis. AB - BACKGROUND AND OBJECTIVES: Alendronate sodium (ALS) is the most common drug used for the treatment of osteoporosis. The challenges facing ALS use include: very poor oral bioavailability (0.6%), esophageal ulcers, and complicated instructions for its use. The objective of this research is to utilize nanotechnology to formulate ALS into enteric-coated nanoliposomes (NLS) to overcome the previously mentioned drawbacks. METHODS: NLS were prepared with lipid components of phosphatidylcholine (PC), cholesterol (CH), and lecithin (Lec) in ratios 4:1:1, 4:2:1, 4:3:1, and 4:4:1, respectively. Formulas that showed the highest entrapment efficiency were prepared either alone or mixed with positive and negative charge-inducing agents and coated with Eudragit L100. Eudragit-coated NLS (EuC-NLS) were evaluated for particle size, zeta potential, morphological examination, and drug release in pH 1.2 and pH 7.4 media. The pharmacokinetic study was carried out in rabbits. RESULTS: Spherical NLS were successfully developed with a mean size range from 70 to 150 nm. EuC-NLS with PC:CH:Lec:dicetyl phosphate (4:3:1:1) successfully resist the release of ALS in acidic environments and enhanced the bioavailability in rabbits 12-fold compared with the marketed tablets. CONCLUSIONS: EuC-NLS is a promising novel formula for ALS with higher bioavailability and a lower dose, avoiding the side effects of esophageal ulceration. PMID- 23656471 TI - How to become a tree without wood--biomechanical analysis of the stem of Carica papaya L. AB - Carica papaya L. does not contain wood, according to the botanical definition of wood as lignified secondary xylem. Despite its parenchymatous secondary xylem, these plants are able to grow up to 10-m high. This is surprising, as wooden structural elements are the ubiquitous strategy for supporting height growth in plants. Proposed possible alternative principles to explain the compensation for lack of wood in C. papaya are turgor pressure of the parenchyma, lignified phloem fibres in the bark, or a combination of the two. Interestingly, lignified tissue comprises only 5-8% of the entire stem mass. Furthermore, the phloem fibres do not form a compact tube enclosing the xylem, but instead form a mesh tubular structure. To investigate the mechanism of papaya's unusually high mechanical strength, a set of mechanical measurements were undertaken on whole stems and tissue sections of secondary phloem and xylem. The structural Young's modulus of mature stems reached 2.5 GPa. Since this is low compared to woody plants, the flexural rigidity of papaya stem construction may mainly be based on a higher second moment of inertia. Additionally, stem turgor pressure was determined indirectly by immersing specimens in sucrose solutions of different osmolalities, followed by mechanical tests; turgor pressure was between 0.82 and 1.25 MPa, indicating that turgor is essential for flexural rigidity of the entire stem. PMID- 23656474 TI - The First Annual Winter q-bio Meeting: quantitative biology on the Hawaiian Islands. PMID- 23656475 TI - Programming membrane fusion and subsequent apoptosis into mammalian cells. AB - By the delivery of specific natural or engineered proteins, mammalian cells can be programmed to perform increasingly sophisticated and useful functions. Here, we introduce a set of proteins that has potential value in cell-based therapies by programming a cell to target tumor cells. First, the delivery of VSV-G (vesicular stomatitis virus glycoprotein) allowed the cell to undergo membrane fusion with adjacent cells to form syncytia (i.e., a multinucleated cell) in conditions of low pH typically occurring at a tumor site. The formation of syncytia caused the clustering of nuclei along with an integration of the microtubule network and ER. Interestingly, the formation of syncytia between cells that are dynamically blebbing, a mode of migration preferred during tumor metastasis, resulted in the loss of these morphology changes. Lastly, the codelivery of VSV-G with L57R (an engineered photoactivated caspase-7) allowed cells to undergo low pH-dependent membrane fusion followed by blue light dependent apoptosis. In cell-based therapies, the clearance of syncytia between tumor cells might further trigger an immune response against the tumor. PMID- 23656476 TI - Complex DNA nanostructures from oligonucleotide ensembles. AB - The first synthetic DNA nanostructures were created by self-assembly of a small number of oligonucleotides. Introduction of the DNA origami method provided a new paradigm for designing and creating two- and three-dimensional DNA nanostructures by folding a large single-stranded DNA and 'stapling' it together with a library of oligonucleotides. Despite its power and wide-ranging implementation, the DNA origami technique suffers from some limitations. Foremost among these is the limited number of useful single-stranded scaffolds of biological origin. This report describes a new approach to creating large DNA nanostructures exclusively from synthetic oligonucleotides. The essence of this approach is to replace the single-stranded scaffold in DNA origami with a library of oligonucleotides termed "scaples" (scaffold staples). Scaples eliminate the need for scaffolds of biological origin and create new opportunities for producing larger and more diverse DNA nanostructures as well as simultaneous assembly of distinct structures in a "single-pot" reaction. PMID- 23656477 TI - Linking genotype and phenotype in protein synthesizing liposomes with external supply of resources. AB - Reconstituting an elementary gene expression system inside self-assembled lipid vesicles to mimic the cellular synthesis machinery is at the core of the development of a minimal cell following a bottom-up synthetic biology approach. The ability to operate the expression of multiple genes in a controlled manner and to generate the output proteins with predictable dynamics in liposomes relies on the link between genotype and phenotype. Here, we established this link in surface-tethered liposomes producing proteins from a linear DNA template using a reconstituted transcription/translation/aminoacylation apparatus fuelled by external supply of feedstock. The amounts of entrapped DNA molecules and synthesized proteins were visualized by fluorescence confocal microscopy in individual vesicles. We showed that there exists no linear correlation between the amount of encapsulated genes and the level of output proteins, which is a consequence of the compositional heterogeneity between liposomes due to the low copy number of some constituents, as well as interfacing differences with the nutrient-containing environment. In order to decouple gene activity from those sources of variability and, thus, infer the probabilistic occupancy of transcriptionally active genes in protein synthesizing liposomes, we developed a dual gene expression assay consisting of the production of two fluorescent reporter proteins of distinguishable colors from two different DNA templates. The stochastic color-coding of the vesicles was analyzed and compared to the color pattern expected from a Poisson distribution of encapsulated genes. Unexpectedly, we found that the apparent number of transcriptionally active DNA molecules in liposomes corresponds only to ca. 10% of the bulk concentration. We believe that our study provides new insights about the relationship between the genotype and phenotype in protein synthesizing liposomes, which is of primary importance toward the construction of a programmable artificial cell implemented with regulatory gene networks of predictable dynamics. PMID- 23656478 TI - Photoswitch nucleic acid catalytic activity by regulating topological structure with a universal supraphotoswitch. AB - We demonstrated the generality of a strategy for photoswitching the activity of functional oligonucleotides by modulating their topological structure. Our strategy was proved to be versatile because it can be used to photoregulate functional oligonucleotides, e.g., ribozymes and DNAzymes, which have two binding arms and a catalytic loop. Repeated reversible photoregulation of RNA cleavage by a ribozyme or a DNAzyme was achieved by attaching two photoresponsive strands, artificial oligomers involving azobenzene moieties and nucleobases capable of forming a duplex as the supraphotoswitch. Individual strands were attached to the 3' and 5' ends of a RNA-cleavage oligonucleotide. Thus, the topological structure of the ribozyme or DNAzyme was constrained, and RNA cleavage was greatly suppressed when the supraphotoswitch duplex formed (OFF state). In contrast, RNA cleavage resumed when the supraphotoswitch duplex dissociated (ON state). Light irradiation was used to repeatedly switch the supraphotoswitch between the ON and OFF states so that RNA cleavage activity could be efficiently photoregulated. Analysis of the regulatory mechanism showed that topological constraints suppressed the RNA cleavage by causing both structural changes at the catalytic site and lower binding affinity between the RNA substrates and the functional oligonucleotides. PMID- 23656479 TI - Effects of unconventional gas development on groundwater: a call for total dissolved gas pressure field measurements. PMID- 23656480 TI - Can synthetic oxytocin be turned off in active labor? PMID- 23656482 TI - Environmental assessment of management options for nutrient flows in the food chain in China. AB - The nitrogen (N) and phosphorus (P) costs of food production have increased greatly in China during the last 30 years, leading to eutrophication of surface waters, nitrate leaching to groundwater, and greenhouse gas emissions. Here, we present the results of scenario analyses in which possible changes in food production-consumption in China for the year 2030 were explored. Changes in food chain structure, improvements in technology and management, and combinations of these on food supply and environmental quality were analyzed with the NUFER model. In the business as usual scenario, N and P fertilizer consumption in 2030 will be driven by population growth and diet changes and will both increase by 25%. N and P losses will increase by 44 and 73%, respectively, relative to the reference year 2005. Scenarios with increased imports of animal products and feed instead of domestic production, and with changes in the human diet, indicate reductions in fertilizer consumption and N and P losses relative to the business as usual scenario. Implementation of a package of integrated nutrient management measures may roughly nullify the increases in losses in the business as usual scenario and may greatly increase the efficiency of N and P throughout the whole food chain. PMID- 23656481 TI - Defective endochondral ossification-derived matrix and bone cells alter the lymphopoietic niche in collagen X mouse models. AB - Despite the appreciated interdependence of skeletal and hematopoietic development, the cell and matrix components of the hematopoietic niche remain to be fully defined. Utilizing mice with disrupted function of collagen X (ColX), a major hypertrophic cartilage matrix protein associated with endochondral ossification, our data identified a cytokine defect in trabecular bone cells at the chondro-osseous hematopoietic niche as a cause for aberrant B lymphopoiesis in these mice. Specifically, analysis of ColX transgenic and null mouse chondro osseous regions via micro-computed tomography revealed an altered trabecular bone environment. Additionally, cocultures with hematopoietic and chondro-osseous cell types highlighted impaired hematopoietic support by ColX transgenic and null mouse derived trabecular bone cells. Further, cytokine arrays with conditioned media from the trabecular osteoblast cocultures suggested an aberrant hematopoietic cytokine milieu within the chondro-osseous niche of the ColX deficient mice. Accordingly, B lymphopoiesis was rescued in the ColX mouse derived trabecular osteoblast cocultures with interlukin-7, stem cell factor, and stromal derived factor-1 supplementation. Moreover, B cell development was restored in vivo after injections of interlukin-7. These data support our hypothesis that endrochondrally-derived trabecular bone cells and matrix constituents provide cytokine-rich niches for hematopoiesis. Furthermore, this study contributes to the emerging concept that niche defects may underlie certain immuno-osseous and hematopoietic disorders. PMID- 23656483 TI - Impact of a family-focused intervention on self-concept after acquired brain injury. AB - The present study examined the impact of a family inclusive intervention on the multidimensional self-concept of individuals with traumatic brain injury (TBI). Forty one individuals with TBI and a matched control group completed the Tennessee Self-Concept Scale: Second Edition (TSCS: 2), the Rosenberg Self-Esteem Scale (RSE), the Family Assessment Device (FAD), and the Hospital Anxiety and Depression Scale (HADS) on two occasions: at immediate contact (pre-group, T1) and post-group (3 months after initial contact, T2). Controls did not attend the intervention. Total scores for the measures, as well as scores on subdomains of self-concept, taken pre- and post-intervention for the TBI sample and at the same time for matched controls were compared between groups using Multivariate Analysis of Variance (MANOVA); followed by a series of repeated measures analyses of variance (ANOVA) to determine whether significant changes occurred. Contrary to the main aim, the use of a family-focused intervention did not result in self concept improvement, either globally or across self-concept domains. Nor did mood or family functioning improve for the TBI sample. Measures remained stable across time for the controls. PMID- 23656485 TI - Reducing the financial impact of pathogen inactivation technology for platelet components: our experience. AB - BACKGROUND: Pathogen inactivation (PI) technology for blood components enhances blood safety by inactivating viruses, bacteria, parasites, and white blood cells. Additionally, PI for platelet (PLT) components has the potential to extend PLT storage time from 5 to 7 days. STUDY DESIGN AND METHODS: A retrospective analysis was conducted into the percentage of outdated PLT components during the 3 years before and after the adoption of PLT PI technology in our institution. The PLT transfusion dose for both pre-PI and post-PI periods was similar. A retrospective analysis to study clinical safety and component utilization was also performed in the Balearic Islands University Hospital. RESULTS: As a result of PI implementation in our institution, the PLT production cost increased by 85.5%. However, due to the extension of PLT storage time, the percentage of outdated PLT units substantially decreased (-83.9%) and, consequently, the cost associated with outdated units (-69.8%). This decrease represented a 13.7% reduction of the initial cost increase which, together with the saving in blood transportation (0.1%), led to a saving of 13.8% over the initial cost. Therefore, the initial 85.5% increase in the cost of PLT production was markedly reduced to 71.7%. The mean number of PLT concentrates per patient was similar during both periods. CONCLUSIONS: The extension of PLT storage time can substantially contribute to reducing the financial impact of PI by decreasing the percentage of outdated PLTs while improving blood safety. Since the adoption of PI, there have been no documented cases of PLT transfusion-related sepsis in our region. PMID- 23656484 TI - The impact of unstable housing on emergency department use in a cohort of HIV positive people in a Canadian setting. AB - The social-structural challenges experienced by people living with HIV (PHA) have been shown to contribute to increased use of the emergency department (ED). This study identified factors associated with frequent and nonurgent ED use within a cohort of people accessing antiretroviral therapy (ART) in a Canadian setting. Interviewer-administered surveys collected socio-demographic information; clinical variables were obtained through linkages with the provincial drug treatment registry; and ED admission data were abstracted from the Department of Emergency Medicine database. Multivariate logistic regression was used to compute odds of frequent and nonurgent ED use. Unstable housing was independently associated with ED use (adjusted odds ratio [AOR] =1.94, 95% confidence interval [CI] 1.24-3.04]), having three or more ED visits within 6 months of the interview date [AOR: 2.03 (95% CI: 1.07-3.83)] and being triaged as nonurgent (AOR = 2.71, 95% CI: 1.19-6.17). Frequent and nonurgent use of the ED in this setting is associated with conditions requiring interventions at the social-structural level. Supportive housing may contribute to decreased health-care costs and improved health outcomes amongst marginalized PHA. PMID- 23656486 TI - Clonal dissemination of Klebsiella pneumoniae ST512 carrying blaKPC-3 in a hospital in southern Italy. AB - Strains of Klebsiella pneumoniae producing KPC-carbapenemase have emerged as one of the most important multidrug-resistant Gram-negative nosocomial pathogens. Here, we report the first isolation and subsequent dissemination of a K. pneumoniae ST512 producing KPC-3 carbapenemase in a hospital in southern Italy. Isolates were obtained from blood, throat swabs, sputum, catheters, and urine of patients admitted to different hospital wards. Antimicrobial MICs were determined for all isolates by automated systems and confirmed by Etest. Carbapenemase production was confirmed by the modified Hodge test and by a disc synergy test, and carbapenemase genes were investigated by PCR. All isolates were characterized by pulse-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) analysis. Most isolates were multidrug resistant with exception of some isolates intermediately susceptible to gentamicin, tigecycline, and trimethoprim sulfamethoxazole. PCR analysis showed that isolates harbored the bla(KPC-3) gene associated with bla(TEM) and bla(SVH). PFGE and MLST showed that all isolates belonged to the same ST512 clone recently described in Israel. PMID- 23656487 TI - Baylisascaris procyonis infection in white-footed mice: predicting patterns of infection from landscape habitat attributes. AB - There is a growing body of evidence that habitat fragmentation resulting from anthropogenic land use can alter the transmission dynamics of infectious disease. Baylisascaris procyonis , a parasitic roundworm with the ability to cause fatal central nervous system disease in many mammals, including humans, is a zoonotic threat, and research suggests that parasite recruitment rates by intermediate hosts are highly variable among forest patches in fragmented landscapes. During 2008, we sampled 353 white-footed mice ( Peromyscus leucopus ) from 22 forest patches distributed throughout a fragmented agricultural ecosystem to determine the influence of landscape-level habitat attributes on infection rates of B. procyonis in mice. We characterized each mouse in terms of infection status and intensity of infection, and calculated (on a patch-wide basis) prevalence, mean abundance of B. procyonis , and mean intensity of infection. We used an information-theoretic approach to develop a suite of candidate models characterizing the influence of landscape attributes on each of our measured characteristics of B. procyonis infection in white-footed mice, based on previous knowledge of raccoon ( Procyon lotor ) ecology and B. procyonis distribution in agricultural ecosystems. We observed evidence of B. procyonis infection in mice across all 22 habitat patches sampled. However, parasite recruitment rates and intensity were highly variable among patches, and the results of our analyses suggest that spatial variability in B. procyonis infections was primarily driven by emergent properties of fragmented ecosystems. In particular, prevalence, abundance, and intensity of B. procyonis infections in mice were negatively associated with the size and connectivity of forest patches. These results support previous studies indicating that habitat fragmentation can alter the transmission dynamics of infectious disease, and suggest that factors below the scale of landscape, i.e., fine-scale habitat structure or demographic and behavioral attributes of intermediate and/or definitive hosts, also may be important for predicting patterns of B. procyonis infection in intermediate hosts. PMID- 23656488 TI - Synthesis, 18F-radiolabeling, and in vivo biodistribution studies of N fluorohydroxybutyl isatin sulfonamides using positron emission tomography. AB - The effector caspases-3 and -7 play a central role in programmed type I cell death (apoptosis). Molecular imaging using positron emission tomography (PET) by tracking the activity of executing caspases might allow the detection of the early onset as well as therapy monitoring of various diseases induced by dysregulated apoptosis. Herein, four new fluorinated diastereo- and enantiopure isatin sulfonamide-based potent and selective caspase-3 and -7 inhibitors were prepared by cyclic sulfate ring-opening with fluoride. All fluorohydrins exhibited excellent in vitro affinities (up to IC50 = 11.8 and 0.951 nM for caspase-3 and -7, respectively), which makes them appropriate PET radiotracer candidates. Therefore, N-(4-[(18)F]fluoro-3(R)-hydroxybutyl)- and N-(3(S) [(18)F]fluoro-4-hydroxybutyl)-5-[1-(2(S) (methoxymethyl)pyrrolidinyl)sulfonyl]isatin were synthesized in 140 min with 24% and 10% overall radiochemical yields and specific activities of 10-127 GBq/MUmol using [(18)F]fluoride in the presence of Kryptofix and subsequent acidic hydrolysis. In vivo biodistribution studies in wild-type mice using PET/computed tomography imaging proved fast clearance of the tracer after tail vein injection. PMID- 23656489 TI - Effects of providing patient progress feedback and clinical support tools to psychotherapists in an inpatient eating disorders treatment program: a randomized controlled study. AB - Research on the effects of progress feedback and clinician problem-solving tools on patient outcome has been limited to a few clinical problems and settings (Shimokawa, Lambert, & Smart, 2010). Although these interventions work well in outpatient settings their effects so far have not been investigated with eating disordered patients or in inpatient care. In this study, the effect of providing feedback interventions was investigated in a randomized clinical trial involving 133 females diagnosed with anorexia nervosa, bulimia nervosa, or eating disorders not otherwise specified. Comparisons were made between the outcomes of patients randomly assigned to either treatment-as-usual (TAU) or an experimental condition (Fb) within therapists (the same therapists provided both treatments). Patients in the Fb condition more frequently experienced clinically significant change than those who had TAU (52.95% vs. 28.6%). Similar trends were noted within diagnostic groups. In terms of pre to post change in mental health functioning, large effect sizes favored Fb over TAU. Patients' BMI improved substantially in both TAU and the feedback condition. The effects of feedback were consistent with past research on these approaches although the effect size was smaller in this study. Suggestions for further research are delineated. PMID- 23656490 TI - Roxbin B is cuspinin: structural revision and total synthesis. AB - Prompted by the outcome that the synthesized roxbin B was not identical to the natural roxbin B, the structural determination process and spectral data were re examined, with the finding that roxbin B was very likely to be 1-O-galloyl-2,3 (R);4,6-(S)-bis-O-hexahydroxydiphenoyl-beta-d-glucose (cuspinin). Because the (R) axial chirality is rare in natural products when the hexahydroxydiphenoyl group bridges the 2- and 3-oxygens, the proposed structure of cuspinin was confirmed by the total synthesis, leading to the conclusion that roxbin B is the same as cuspinin. PMID- 23656491 TI - The preterm births epidemic in Greece. PMID- 23656492 TI - Malnutrition and obesity: influence in mortality and readmissions in chronic obstructive pulmonary disease patients. AB - BACKGROUND: The present study aimed to assess the association of obesity and malnutrition with the mortality of hospitalised patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) and the risk of readmission in <30 days. METHODS: A retrospective chart review of consecutive patients admitted with COPD as the primary reason for discharge in Spain between 1 January 2006 and 31 December 2007 was performed. Patients with a diagnosis of obesity or malnutrition in the hospital discharge clinical report were identified. The in hospital mortality and re-admittance 30 days after discharge indices of obese and malnourished patients were compared against the subpopulation without these diagnoses. RESULTS: Of the 313 233 COPD admittances analysed, there were 22 582 (7.2%) diagnoses of obesity and 6354 (2.0%) diagnoses of malnutrition. In hospital global mortality and the re-admittance risk were 12.0% and 16.7%, respectively. Obese patients showed a lower in-hospital mortality risk [odds ratio (OR) = 0.52; 95% confidence interval (CI) = 0.49-0.55] and early re admittance risk (OR = 0.87; 95% CI = 0.85-0.92) compared to non-obese patients. Malnourished patients had a much higher risk of death when in hospital (OR = 1.73; 95% CI = 1.62-1.85) or of being re-admitted within 30 days after discharge (OR = 1.29; 95% CI = 1.22-1.38), even after adjusting for possible confounding factors. CONCLUSIONS: Obesity in patients hospitalised for COPD substantially reduces in-hospital mortality risk and the possibility of early re-admittance. Malnutrition is associated with an important increase in in-hospital mortality and risk of re-admittance in the 30 days following discharge. PMID- 23656493 TI - Plasma TNF-alpha levels are higher in early pregnancy in patients with secondary compared with primary recurrent miscarriage. AB - PROBLEM: Specific pro-inflammatory cytokine profiles in plasma may characterize women with recurrent miscarriage (RM) but the dynamics of the cytokine profiles with progressing pregnancy is largely unknown. METHOD OF STUDY: Plasma was repeatedly sampled in the first trimester from 47 RM patients. The concentrations of five cytokines including tumour necrosis factor alpha (TNF-alpha) were measured. TNF-alpha levels were correlated to carriage of five TNFA promoter polymorphisms. RESULTS: TNF-alpha levels increased (P = 0.014) with progressing pregnancy, with higher levels in secondary than primary RM (P = 0.042) but with no significant impact on outcome. Carriage of TNFA -863C and TNFA -1031T was associated with higher TNF-alpha levels, and the former was found more often in secondary than primary RM (P < 0.02). CONCLUSION: Plasma TNF-alpha levels increase during early pregnancy in RM women regardless of outcome, but are higher in secondary than primary RM, which may be partly genetically determined. PMID- 23656494 TI - Digital quantitation of potential therapeutic target RNAs. AB - Accurate determination of the amount of a given RNA within a cell is necessary to gain a full understanding of the RNA's function and regulation. Typically, the abundance of RNA is measured by quantitative polymerase chain reaction (qPCR). With qPCR, however, absolute quantification is not possible unless an adequate reference standard curve is generated. The method is not well suited for detecting low copy number templates and values vary depending on the specific primers used. To overcome these drawbacks, digital PCR (dPCR) has been developed to obtain exact values for RNA copies in a sample. Here we report the characterization of droplet digital PCR (ddPCR). We used ddPCR to quantify long noncoding RNAs from various subcellular compartments within human cells and found that results obtained using ddPCR parallel those from qPCR. Mutant huntingtin (HTT) protein is the cause of Huntington's Disease, and we show that we can quantify human HTT messenger RNA and discriminate between the mutant and wild type HTT alleles using ddPCR. These results reveal insights into the design of experiments using ddPCR and show that ddPCR can be a robust tool for identifying the number of RNA species inside of cells. PMID- 23656495 TI - Long double-stranded multiplex siRNAs for dual genes silencing. AB - Simultaneous suppression of multiple oncogenes is an attractive strategy to treat cancers. Herein we present a series of long double-stranded multiplex small interfering RNAs (multi-siRNAs) that is suitable for dual genes silencing through a sequence-specific RNA interference process without inducing significant immune responses. A gap feature structurally designed in either of the nucleotide strands of the multi-siRNAs was proved to be essential toward silencing target genes and avoiding immune responses. Furthermore, the silencing effect of multi siRNAs against SURVIVIN and BCL-2 genes was shown to be effective and resulted in up-regulation of caspase-3 related apoptosis and, in turn, inhibition of bladder cancer cell proliferation. Our observation suggested that the rationally designed multi-siRNAs would have great potential for therapeutic siRNA design. PMID- 23656497 TI - Review article: proton pump inhibitor therapy for suspected eosinophilic oesophagitis. AB - BACKGROUND: Recent advances in eosinophilic oesophagitis (EoE) have confirmed the existence of a new disease phenotype, proton pump inhibitor (PPI)-responsive oesophageal eosinophilia (PPI-REE). AIM: To summarise evidence supporting the use of PPI therapy in patients with suspected EoE (oesophageal dysfunction plus >15 eos/HPF in oesophageal biopsies). METHODS: A literature search was conducted through MEDLINE, using the MeSH search terms 'eosinophilic oesophagitis', 'proton pump inhibitors' and 'oesophageal eosinophilia'. Relevant articles and their reference lists were identified through manual review. RESULTS: Ten articles, including 258 patients with suspected EoE (152 children, 106 adults) undergoing clinico-histological re-evaluation after PPI therapy, were identified. In children, clinical response ranged from 78% to 86% and histological remission from 23% to 40%. In adults, symptom response ranged from 25% to 80% and histological remission from 33% to 61%. Among PPI-REE patients with oesophageal pH-monitoring, 35 showed pathological and 10 normal studies. PPI-REE was significantly commoner with documented gastro-oesophageal reflux disease (GERD) when compared to patients with negative pH monitoring (70% vs. 29%, P < 0.001). Symptom improvement/resolution occurred in 50-85% of patients without histological remission on PPI therapy. Six PPI-REE patients demonstrated clinico histological relapse on PPI therapy. CONCLUSIONS: At least one third of patients with suspected EoE achieve clinico-histological remission on PPI therapy. Response is more limited in children compared with that in adults. pH monitoring does not accurately predict response to PPI therapy, albeit histological remission is significantly higher, up to 70%, upon documented GERD. Symptom improvement is common with PPI therapy despite persistent eosinophilic infiltration. PMID- 23656496 TI - Genomic and proteomic dissection of the ubiquitous plant pathogen, Armillaria mellea: toward a new infection model system. AB - Armillaria mellea is a major plant pathogen. Yet, no large-scale "-omics" data are available to enable new studies, and limited experimental models are available to investigate basidiomycete pathogenicity. Here we reveal that the A. mellea genome comprises 58.35 Mb, contains 14473 gene models, of average length 1575 bp (4.72 introns/gene). Tandem mass spectrometry identified 921 mycelial (n = 629 unique) and secreted (n = 183 unique) proteins. Almost 100 mycelial proteins were either species-specific or previously unidentified at the protein level. A number of proteins (n = 111) was detected in both mycelia and culture supernatant extracts. Signal sequence occurrence was 4-fold greater for secreted (50.2%) compared to mycelial (12%) proteins. Analyses revealed a rich reservoir of carbohydrate degrading enzymes, laccases, and lignin peroxidases in the A. mellea proteome, reminiscent of both basidiomycete and ascomycete glycodegradative arsenals. We discovered that A. mellea exhibits a specific killing effect against Candida albicans during coculture. Proteomic investigation of this interaction revealed the unique expression of defensive and potentially offensive A. mellea proteins (n = 30). Overall, our data reveal new insights into the origin of basidiomycete virulence and we present a new model system for further studies aimed at deciphering fungal pathogenic mechanisms. PMID- 23656498 TI - Potential nephroprotective effects of l-carnitine against drug-induced nephropathy: a review of literature. AB - INTRODUCTION: Drug-induced nephrotoxicity (DIN) has been reported with a great number of medications and contributes to ~ 20% of hospital admissions. l carnitine owing to its antioxidant, anti-inflammatory and antiapoptotic properties has been proposed as a candidate for nephroprotection against DIN. Increasing need to use nephrotoxic therapeutic agents necessitated this review. AREAS COVERED: The present review covers all published clinical and animal researches on nephroprotective effects of l-carnitine against DIN. l-carnitine significantly ameliorates DIN in animal studies especially against cisplatin induced renal damage. Inhibition of reactive oxygen species generation, lipid peroxidation, matrix remodeling and apoptosis, anti-inflammatory properties and improvement in carnitine deficiency has been suggested as probable nephroprotective mechanisms of l-carnitine. EXPERT OPINION: In spite of the evidences that support the nephroprotective effect of l-carnitine, the main problems in this area are inadequacy of reliable studies in humans and difficulty of translating the experimental results into clinical practice. In most of the described studies, l-carnitine treatment is prophylactically given. Use of l carnitine as a prophylactic agent in clinical situations with an indication for nephrotoxic therapies is rarely possible except for contrast-induced nephrotoxicity. Development of validated early biomarkers to detect DIN may provide the opportunity to use prophylactic nephroprotective agents at golden time. PMID- 23656499 TI - Quercetin prevents experimental glucocorticoid-induced osteoporosis: a comparative study with alendronate. AB - Glucocorticoid-induced osteoporosis (GIO) is the most common type of secondary osteoporosis. The aim of this study was to compare the efficacy of quercetin, a plant-derived flavonoid, with alendronate in the prevention of GIO. Fifty-six Sprague-Dawley rats were randomly distributed among 7 groups (8 rats per group) and treated for 6 weeks with one of the following: (i) normal saline; (ii) 40 mg methylprednisolone sodium succinate (MP)/kg body mass; (iii) MP + 40 MUg alendronate/kg; (iv) MP + 50 mg quercetin/kg; (v) MP + 40 MUg alendronate/kg + 50 mg quercetin/kg; (vi) MP + 150 mg quercetin/kg; and (vii) MP + 40 MUg alendronate/kg + 150 mg quercetin/kg. MP and alendronate were injected subcutaneously and quercetin was administered by oral gavage 3 days a week. At the end of the study, femur breaking strength was significantly decreased as a consequence of MP injection. This decrease was completely compensated for in groups receiving 50 mg quercetin/kg plus alendronate, and 150 mg quercetin/kg with or without alendronate. Quercetin noticeably elevated osteocalcin as a bone formation marker, while alendronate did not show such an effect. In addition, administration of 150 mg quercetin/kg increased femoral trabecular and cortical thickness by 36% and 22%, respectively, compared with the MP-treated group. These data suggest that 150 mg quercetin/kg, alone or in combination with alendronate, can completely prevent GIO through its bone formation stimulatory effect. PMID- 23656500 TI - AtMYB44 regulates resistance to the green peach aphid and diamondback moth by activating EIN2-affected defences in Arabidopsis. AB - Recently we showed that the transcription activator AtMYB44 regulates expression of EIN2, a gene essential for ethylene signalling and insect resistance, in Arabidopsis thaliana (Arabidopsis). To link the transactivation with insect resistance, we investigated the wild-type and atmyb44 mutant plants, genetically Complemented atmyb44 (Catmyb44) and AtMYB44-Overexpression Transgenic Arabidopsis (MYB44OTA). We found that AtMYB44 played a critical role in Arabidopsis resistance to the phloem-feeding generalist green peach aphid (Myzus persicae Sulzer) and leaf-chewing specialist caterpillar diamondback moth (Plutella xylostella L.). AtMYB44 was required not only for the development of constitutive resistance but also for the induction of resistance by both herbivorous insects. Levels of constitutive and herbivore-induced resistance were consistent with corresponding amounts of the AtMYB44 protein constitutively produced in MYB44OTA and induced by herbivory in Catmyb44. In both cases, AtMYB44 promoted EIN2 expression to a greater extent in MYB44OTA than in Catmyb44. However, AtMYB44 promoted EIN2 expression was arrested with reduced resistance levels in the EIN2 deficient Arabidopsis mutant ein2-1 and the MYB44OTA ein2-1 hybrid. In the different plant genotypes, only MYB44OTA constitutively displayed phloem-based defences, which are specific to phloem-feeding insects, and robust expression of genes involved in the biosynthesis of glucosinolates, which are the secondary plant metabolites known as deterrents to generalist herbivores. Phloem-based defences and glucosinolate-related gene expression were not detected in ein2-1 and MYB44OTA ein2-1. These results establish a genetic connection between the regulatory role of AtMYB44 in EIN2 expression and the development of Arabidopsis resistance to insects. PMID- 23656501 TI - Nonresponse rates are a problematic indicator of nonresponse bias in survey research. PMID- 23656502 TI - Enzymatic product-mediated stabilization of CdS quantum dots produced in situ: application for detection of reduced glutathione, NADPH, and glutathione reductase activity. AB - Glutathione is the most abundant nonprotein molecule in the cell and plays an important role in many biological processes, including the maintenance of intracellular redox states, detoxification, and metabolism. Furthermore, glutathione levels have been linked to several human diseases, such as AIDS, Alzheimer disease, alcoholic liver disease, cardiovascular disease, diabetes mellitus, and cancer. A novel concept in bioanalysis is introduced and applied to the highly sensitive and inexpensive detection of reduced glutathione (GSH), over its oxidized form (GSSG), and glutathione reductase (GR) in human serum. This new fluorogenic bioanalytical system is based on the GSH-mediated stabilization of growing CdS nanoparticles. The sensitivity of this new assay is 5 pM of GR, which is 3 orders of magnitude better than other fluorogenic methods previously reported. PMID- 23656503 TI - Ultraviolet resonance Raman spectroscopy of explosives in solution and the solid state. AB - Resonance Raman cross sections of common explosives have been measured by use of excitation wavelengths in the deep-UV from 229 to 262 nm. These measurements were performed both in solution and in the native solid state for comparison. While measurements of UV Raman cross sections in solution with an internal standard are straightforward and commonly found in the literature, measurements on the solid phase are rare. This is due to the difficulty in preparing a solid sample in which the molecules of the internal standard and absorbing analyte/explosive experience the same laser intensity. This requires producing solid samples that are mixtures of strongly absorbing explosives and an internal standard transparent at the UV wavelengths used. For the solid-state measurements, it is necessary to use nanostructured mixtures of the explosive and the internal standard in order to avoid this bias due to the strong UV absorption of the explosive. In this study we used a facile spray-drying technique where the analyte of interest was codeposited with the nonresonant standard onto an aluminum-coated microscope slide. The generated resonance enhancement profiles and quantitative UV-vis absorption spectra were then used to plot the relative Raman return as a function of excitation wavelength and particle size. PMID- 23656505 TI - Sensing of carboxylate drugs in urine by a supramolecular sensor array. AB - A supramolecular sensor array consisting of eight chemosensors embedded in a hydrogel matrix was used to sense carboxylate drugs. The discriminatory power of the array has been evaluated using principal component analysis and linear discriminant analysis. The eight-member sensor array has been shown to accurately identify 14 carboxylates in water with 100% classification accuracy. To demonstrate the potential for practical utility in the physiological environment, analysis of carboxylate drugs in human urine was also performed achieving 100% correct classification. In addition, the array performance in semiquantitative identification of nonsteroidal anti-inflammatory drugs has been investigated, and the results show that the sensor array is able to differentiate six typical nonsteroidal anti-inflammatory drugs at concentrations of 0.5-100 ppm. This illustrates the potential utility of the designed sensor array for diagnostic and environmental monitoring applications. PMID- 23656504 TI - In vitro evidence of the presence of mesenchymal stromal cells in cervical cancer and their role in protecting cancer cells from cytotoxic T cell activity. AB - Mesenchymal stromal cells (MSCs) have been isolated from different tumors and it has been suggested that they support tumor growth through immunosuppression processes that favor tumor cell evasion from the immune system. To date, however, the presence of MSCs in cervical cancer (CeCa) and their possible role in tumor growth remains unknown. Herein we report on the presence of MSCs in cervical tissue, both in normal conditions (NCx-MSCs) and in CeCa (CeCa-MSCs), and described several biological properties of such cells. Our study showed similar patterns of cell surface antigen expression, but distinct differentiation potentials, when we compared both cervical MSC populations to MSCs from normal bone marrow (BM-MSCs, the gold standard). Interestingly, CeCa-MSCs were negative for the presence of human papilloma virus, indicating that these cells are not infected by such a viral agent. Also, interestingly, and in contrast to NCx-MSCs, CeCa-MSCs induced significant downregulation of surface HLA class I molecules (HLA-A*0201) on CaSki cells and other CeCa cell lines. We further observed that CeCa-MSCs inhibited antigen-specific T cell recognition of CaSki cells by cytotoxic T lymphocytes (CTLs). HLA class I downregulation on CeCa cells correlated with the production of IL-10 in cell cocultures. Importantly, this cytokine strongly suppressed recognition of CeCa cells by CTLs. In summary, this study demonstrates the presence of MSCs in CeCa and suggests that tumor-derived MSCs may provide immune protection to tumor cells by inducing downregulation of HLA class I molecules. This mechanism may have important implications in tumor growth. PMID- 23656506 TI - Two-step sensitivity testing of parametrized and regionalized life cycle assessments: methodology and case study. AB - Comprehensive sensitivity analysis is a significant tool to interpret and improve life cycle assessment (LCA) models, but is rarely performed. Sensitivity analysis will increase in importance as inventory databases become regionalized, increasing the number of system parameters, and parametrized, adding complexity through variables and nonlinear formulas. We propose and implement a new two-step approach to sensitivity analysis. First, we identify parameters with high global sensitivities for further examination and analysis with a screening step, the method of elementary effects. Second, the more computationally intensive contribution to variance test is used to quantify the relative importance of these parameters. The two-step sensitivity test is illustrated on a regionalized, nonlinear case study of the biodiversity impacts from land use of cocoa production, including a worldwide cocoa products trade model. Our simplified trade model can be used for transformable commodities where one is assessing market shares that vary over time. In the case study, the highly uncertain characterization factors for the Ivory Coast and Ghana contributed more than 50% of variance for almost all countries and years examined. The two-step sensitivity test allows for the interpretation, understanding, and improvement of large, complex, and nonlinear LCA systems. PMID- 23656507 TI - Autologous fat transfer for breast augmentation: a systematic review. AB - BACKGROUND: The role of autologous fat transfer (AFT) for cosmetic breast augmentation is uncertain due to ongoing concerns regarding its safety and efficacy compared with other breast augmentation techniques. OBJECTIVES: The aim of this systematic review was to assess the safety and efficacy of AFT for cosmetic breast augmentation in comparison with saline and cohesive silicone gel implants. METHODS: A systematic search of several electronic databases, including PubMed and EMBASE, was used to identify relevant studies for inclusion. The inclusion of studies was established through the application of a predetermined protocol by two independent reviewers. RESULTS: There were no comparative studies available, necessitating that all comparisons be indirect. Eighteen studies were included, 11 of which reported outcomes for AFT. Complications associated with AFT occurred in only a small proportion of patients, with fat necrosis, cysts and lumps most commonly reported. No data examining the effect of complications such as microcalcification on long-term mammographic and cancer-related outcomes were identified. Reabsorption of fat occurred to varying degrees, usually during the first 12 months following the procedure. Patient satisfaction following AFT was high. Limitation in breast volume increase was the main complaint associated with this procedure. CONCLUSIONS: Based on the limited evidence available, AFT was considered to be at least as safe as the nominated comparator procedures in regard to complications; however, its safety in regard to cancer detection could not be determined. The efficacy of AFT could not be determined. PMID- 23656508 TI - Phosphodiesterase-4 inhibitor therapy for lung diseases. AB - Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyze the breakdown of cAMP and/or cyclic guanosine monophosphate (GMP) to their inactive form. PDE4 is the main selective cAMP-metabolizing enzyme in inflammatory and immune cells. Because PDE4 is highly expressed in leukocytes and other inflammatory cells involved in the pathogenesis of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), inhibition of PDE4 has been predicted to have an antiinflammatory effect and thus therapeutic efficacy. The limited and inconsistent efficacy and side effects of the early compounds made their further development less desirable in asthma, given the excellent efficacy/tolerability ratio of inhaled steroids. The lack of effective antiinflammatory drug treatment for COPD has thus shifted the interest in development toward COPD. Roflumilast, the only PDE4 inhibitor that has reached the market because of the good efficacy/tolerability ratio, is recommended for patients with COPD with severe airflow limitation, symptoms of chronic bronchitis, and a history of exacerbations, whose disease is not adequately controlled by long-acting bronchodilators. Albeit safe, it maintains significant side effects (diarrhea, nausea, weight loss) that make it intolerable in some patients. Future developments of PDE4 inhibitors include extended indications of roflumilast (1) in patients with COPD, and (2) in other respiratory (e.g., asthma) and nonrespiratory chronic inflammatory/metabolic conditions (e.g., diabetes), as well as (3) the development of new molecules with PDE4 inhibitory properties with an improved efficacy/tolerability profile. PMID- 23656509 TI - Chemical vapor deposition and characterization of aligned and incommensurate graphene/hexagonal boron nitride heterostack on Cu(111). AB - Two limiting factors for a new technology of graphene-based electronic devices are the difficulty of growing large areas of defect-free material and the integration of graphene with an atomically flat and insulating substrate material. Chemical vapor deposition (CVD) on metal surfaces, in particular on copper, may offer a solution to the first problem, while hexagonal boron nitride (h-BN) has been identified as an ideal insulating substrate material. The bottom up growth of graphene/h-BN stacks on copper surfaces appears therefore as a promising route for future device fabrication. As an important step, we demonstrate the consecutive growth of well-aligned graphene on h-BN, both as single layers, by low-pressure CVD on Cu(111) in an ultrahigh vacuum environment. The resulting films show a largely predominant orientation, defined by the substrate, where the graphene lattice aligns parallel to the h-BN lattice, while each layer maintains its own lattice constant. The lattice mismatch of 1.6% between h-BN and graphene leads to a moire pattern with a periodicity of about 9 nm, as observed with scanning tunneling microscopy. Accordingly, angle-resolved photoemission data reveal two slightly different Brillouin zones for electronic states localized in graphene and in h-BN, reflecting the vertical decoupling of the two layers. The graphene appears n-doped and shows no gap opening at the K[overline] point of the two-dimensional Brillouin zone. PMID- 23656510 TI - Treatment motivation in adolescents with psychosis or at high risk: determinants and impact on improvements in symptoms and cognitive functioning, preliminary results. AB - Low motivation is frequent in chronic disorders such as psychosis and may limit treatment efficacy. Although some evidence supports this view in adults, few studies so far have focused on adolescents. We assessed the impact of baseline symptoms, cognitive deficits and cognitive treatment characteristics on treatment motivation (TM), and examined whether TM affected treatment outcome. Twenty-eight adolescents with psychotic disorders participated in 16 sessions of computerized cognitive remediation or games. TM was assessed for each session. Lower TM was predicted by more severe symptoms at baseline, and was associated with smaller improvements in symptoms and both cognitive and psychosocial functioning at the end of the intervention. Experiencing success in the treatment exercises enhanced TM in all patients. PMID- 23656511 TI - Enteric Gram-negative bacilli suppress Candida biofilms on Foley urinary catheters. AB - Mixed Candida-bacterial biofilms in urinary catheters are common in hospitalized patients. (i) The aims of this study were to evaluate, quantitatively and qualitatively, the in vitro development of mono- and dual-species biofilms (MSBs and DSBs) of Candida albicans and two enteric gram-negative bacilli (EGNB; Pseudomonas aeruginosa or Escherichia coli) on Foley catheter (FC) discs, (ii) to determine the biofilm growth in tryptic soy broth or glucose supplemented artificial urine (AU) and (iii) to assess the inhibitory effects of EGNB and their lipopolysaccharides (LPS) on Candida biofilm growth. The growth of MSBs and DSBs on FC discs was monitored by cell counts and SEM. The metabolic activity of LPS-treated Candida biofilms was determined by the XTT reduction assay. Candida albicans and EGNB demonstrated significant inter- and intra-species differences in biofilm growth on FC discs (p < 0.01). Pseudomonas aeruginosa suppressed Candida albicans significantly (p < 0.001) in DSBs. Compared with MSBs, DSB of EGNB in glucose supplemented AU demonstrated robust growth. Escherichia coli and its LPS, significantly suppressed Candida biofilm growth, compared with Pseudomonas aeruginosa and its LPS (p < 0.001). Candida albicans and EGNB colonization in FC is significantly increased in AU with glucose, and variably modified by Escherichia coli, Pseudomonas aeruginosa and their corresponding LPS. PMID- 23656512 TI - 1-Phenyl-4-benzoyl-1H-1,2,3-triazoles as orally bioavailable transcriptional function suppressors of estrogen-related receptor alpha. AB - Estrogen-related receptor alpha is a potential candidate target for therapeutic treatment of breast cancer. We describe the discovery and structure-activity relationship study of a series of 1-phenyl-4-benzoyl-1H-1,2,3-triazoles as novel suppressors of ERRalpha transcriptional functions. The most promising compound, 2 aminophenyl-(1-(3-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone (14n), potently suppressed the transcriptional functions of ERRalpha with IC50 = 0.021 MUM in a cell-based reporter gene assay and also decreased both the mRNA levels and the protein levels of ERRalpha and the downstream targets. This compound inhibited the proliferation and migration of breast cancer cells with high level of ERRalpha. Preliminary pharmacokinetic studies suggested that it possessed a good pharmacokinetic profile with an oral bioavailability of 71.8%. The compounds may serve as novel small molecule probes for further validation of ERRalpha as a molecular target for anticancer drug development. PMID- 23656513 TI - New African species of Echinobothrium (Cestoda: Diphyllidea) and implications for the identities of their skate hosts. AB - Two new species of diphyllidean cestodes of the genus Echinobothrium, each hosted by a different skate species in the Raja miraletus complex, are described. Echinobothrium mercedesae n. sp. is described from R. cf. miraletus 2 off Senegal. Echinobothrium yiae n. sp. is described from R. cf. miraletus 1 off South Africa. Both species are small worms that differ from their 29 described congeners in the combination of number of cephalic peduncle spines per column, hook formula, number and arrangement of testes, and arrangement of vitelline follicles. They are easily distinguished from one another in that whereas the vitelline follicles of E. yiae n. sp. are circumcortical, they are lateral in E. mercedesae n. sp., and also in number of cephalic peduncle spines per column (14 17 vs. 10-12). Echinobothrium yiae n. sp. is also unusual in that the cephalic peduncle spines stop short of the anterior margin of the peduncle. In addition, although the paucity of available material precluded their formal description, evidence of 2 additional new species parasitizing R. miraletus also from Senegal is presented. In combination these worms provide support for the interpretation that what is currently recognized as Raja miraletus actually consists of a complex of geographically restricted species, rather than a polymorphic species of multiple parapatric or allopatrically distributed populations. This interpretation is not only supported by previously published molecular data, but also by newly collected morphological data involving differences in the color patterns of disc ocelli among host specimens of the 3 forms available as a result of digital efforts to ensure the accuracy of host identifications, which are also presented here. PMID- 23656514 TI - The connection between serious life events, anti-retroviral adherence, and mental health among HIV-positive individuals in the Western Cape, South Africa. AB - South Africa currently has one of the world's largest rates of HIV infection. A majority of the existing research focuses on individual risk behaviors that lead to increased risk of HIV contraction while also acknowledging the importance of the social and contextual determinants of HIV transmission and disease progression. Therefore, the present study aims to understand the ways in which experience of serious life events increases risk of both adherence lapse and mental illness in HIV-positive populations. Strikingly, our findings suggest that HIV-positive individuals are approximately 24 times as likely to have an anti retroviral adherence lapse and are nearly four times likely to report mental health issues if they have experienced a recent serious life event. Implications of our results include the incorporation of socially relevant assessment tools and the development of interventions that address social and contextual issues for effecting adherence behaviors. PMID- 23656516 TI - Late-onset, preventative, combination treatments: the triple challenge facing the most promising anti-aging research paradigm. PMID- 23656517 TI - Determination of clinical cellular immune markers in women with recurrent pregnancy loss. AB - PROBLEM: Dysregulated natural killer (NK) immunity and T-cell immunity are associated with recurrent pregnancy loss (RPL). We aim to define clinically relevant NK and T-cell parameters for RPL and determine their cutoff values. METHODS OF STUDY: Ninety-five women with RPL (>3) including 42 idiopathic and 53 known-etiology RPL, and 29 age-matched fertile controls were enrolled. Peripheral blood immunophenotype, NK cell cytotoxicity (NKC), and T-helper (Th) 1 and Th2 cytokine producing cell ratios (Th1/Th2) were measured using flowcytometry. The cutoff values were determined using Youden's J with likelihood ratio (LR) >2. RESULTS: Natural killer cell percentage and NKC, TNF-alpha(+) Th1 cells, and TNF alpha/IL-10 producing Th1/Th2 cell ratio were significantly higher in idiopathic RPL than controls. By the area under the curve (AUC) analysis, NK cell percentage (AUC = 0.691), NKC (AUC = 0.649), TNF-alpha(+) Th1 cells (AUC = 0.681) and Th1/Th2 cell ratio (AUC = 0.660) were highly specific for RPL. The cutoff values for NK cell percentage, NKC (E:T cell ratio 25:1), and TNF-alpha/IL-10 producing Th1/Th2 cell ratio are 16.1, 23.8, and 36.2%, respectively. Seventy-six percent of idiopathic RPL showed at least one of more immune abnormalities by these criteria. CONCLUSION: Differences in NK cell percentages, NKC and Th1/Th2 cell ratio differentiated RPL from fertile controls. PMID- 23656519 TI - Synthesis of a structural analogue of the repeating unit from Streptococcus pneumoniae 19F capsular polysaccharide based on the cross-metathesis selenocyclization reaction sequence. AB - Pseudo-oligosaccharides have attracted much interest as scaffolds for the synthesis of sugar mimics endowed with very similar biological properties but structurally and synthetically simpler than their natural counterparts. Herein, the synthesis of pseudo-oligosaccharides using the cross-metathesis reaction between distinct sugar-olefins followed by intramolecular selenocyclization of the obtained heterodimer as key steps is first investigated. This methodology has been then applied to the preparation of structural analogues of the trisaccharide repeating unit from Streptococcus pneumoniae 19F. The inhibition abilities of the synthetic molecules were evaluated by a competitive ELISA assay using a rabbit polyclonal anti-19F serum. PMID- 23656518 TI - Intranasal application of vasopressin fails to elicit changes in brain immediate early gene expression, neural activity and behavioural performance of rats. AB - Intranasal administration has been widely used to investigate the effects of the neuropeptides vasopressin and oxytocin on human behaviour and neurological disorders, although exactly what happens when these neuropeptides are administered intranasally is far from clear. In particular, it is not clear whether a physiological significant amount of peptide enters the brain to account for the observed effects. In the present study, we investigated whether the intranasal administration of vasopressin and oxytocin to rats induces the expression of the immediate-early gene product Fos in brain areas that are sensitive to centrally-administered peptide, whether it alters neuronal activity in the way that centrally-administered peptide does, and whether it affects behaviour in the ways that are expected from studies of centrally-administered peptide. We found that, whereas i.c.v. injection of very low doses of vasopressin or oxytocin increased Fos expression in several distinct brain regions, intranasal administration of large doses of the peptides had no significant effect. By contrast to the effects of vasopressin applied topically to the main olfactory bulb, we saw no changes in the electrical activity of olfactory bulb mitral cells after intranasal vasopressin administration. In addition, vasopressin given intranasally had no significant effects on social recognition or short-term recognition memory. Finally, intranasal infusions of vasopressin had no significant effects on the parameters monitored on the elevated plus maze, a rodent model of anxiety. Our data obtained in rats suggest that, after intranasal administration, significant amounts of vasopressin and oxytocin do not reach areas in the brain at levels sufficient to change immediate early gene expression, neural activity or behaviour in the ways described for central administration of the peptides. PMID- 23656520 TI - Ranking the effectiveness of autologous blood conservation measures through validated modeling of independent clinical data. AB - BACKGROUND: Future supply with allogeneic blood transfusions faces several crucial challenges that warrant thorough (re-)evaluation of existing alternatives. Meta-analyses have indicated a significant potential for autologous blood conservation (ABC) measures to reduce the need for allogeneic blood transfusions. The quality of currently available studies, however, prohibits definite conclusions. Under these circumstances, mathematical modeling offers unique opportunities to compare various ABC measures and to test the impact of different variables on efficacy and effectiveness. STUDY DESIGN AND METHODS: We performed an extensive search for clinical ABC studies, focusing on acute normovolemic hemodilution (ANH), intraoperative blood salvage (IBS), or preoperative autologous deposit (PAD). Only ABC studies providing a minimum set of clinical variables were included. Using a clinically validated mathematical model, we then calculated maximal allowable blood loss (efficacy) and increase in red blood cell (RBC) mass (effectiveness) to rank the three techniques. RESULTS: We identified 21 clinical ABC studies, including 3926 patients, as suitable for our model. Our model shows that IBS with high recovery rates is the most efficacious and effective ABC measure. PAD will reveal nearly similar efficacy and effectiveness, only if sufficient time for RBC regeneration has passed and if 4 PAD units or more are available. Our model further demonstrates that ANH as well as IBS with low recovery rates are the least efficacious and effective alternatives. CONCLUSIONS: IBS appears to be the most efficacious and effective ABC measure. PAD can only reduce the need for allogeneic blood transfusions under certain circumstances. ANH does not appear to play an important role in ABC. PMID- 23656521 TI - Ready synthetic access to enantiopure allylic alpha(F)-branched fluoroalkenes. AB - Convenient access to homochiral fluoroalkenes is described via a Julia-Kocienski olefination reaction. The required homochiral fluorosulfone is synthesized by a Mitsunobu reaction from readily available enantiopure secondary alcohols. PMID- 23656523 TI - Mechanism of the cis-[Pt(1R,2R-DACH)(H2O)2]2+ intrastrand binding to the double stranded (pGpG).(CpC) dinucleotide in aqueous solution: a computational DFT study. AB - A mechanism of the intrastrand 1,2-cross-link formation between the double stranded pGpG.CpC dinucleotide (ds(pGpG)) and fully aquated oxaliplatin cis [Pt(DACH)(H2O)2](2+) (DACH = cyclohexane-1R,2R-diamine) is presented. All structures of the reaction pathways including the transition states (TSs) were fully optimized in water solvent using DFT methodology with dispersion corrections. Both 5' -> 3' and 3' -> 5' binding directions were considered. In the first step there is a slight kinetic preference for 5'-guanine (5'G) monoadduct formation with an activation Gibbs free energy of 18.7 kcal/mol since the N7 center of the 5'G base is fully exposed to the solvent. On the other hand, the N7 atom of 3'-guanine (3'G) is sterically shielded by 5'G. The lowest energy path for formation of the 3'G monoadduct with an activation barrier of 19.3 kcal/mol is connected with a disruption of the 'DNA-like' structure of ds(pGpG). Monoadduct formation is the rate-determining process. The second step, chelate formation, is kinetically preferred in the 3' -> 5' direction. The whole process of the platination is exergonic by up to -18.8 kcal/mol. Structural changes of ds(pGpG), charge transfer effects, and the influence of platination on the G.C base pair interaction strengths are also discussed in detail. PMID- 23656522 TI - Cancer 'survivor-care': II. Disruption of prefrontal brain activation top-down control of working memory capacity as possible mechanism for chemo-fog/brain (chemotherapy-associated cognitive impairment). AB - WHAT IS KNOWN AND OBJECTIVE: Cancer chemotherapy-associated cognitive impairments (termed 'chemo-fog' or 'chemo-brain'), particularly in memory, have been self reported or identified in cancer survivors previously treated with chemotherapy. Although a variety of deficits have been detected, a consistent theme is a detriment in visuospatial working memory. The parietal cortex, a major site of storage of such memory, is implicated in chemotherapy-induced damage. However, if the findings of two recent publications are combined, the (pre)frontal cortex might be an equally viable target. Two recent studies, one postulating a mechanism for 'top-down control' of working memory capacity and another visualizing chemotherapy-induced alterations in brain activation during working memory processing, are reviewed and integrated. COMMENT: A computational model and the proposal that the prefrontal cortex plays a role in working memory via top-down control of parietal working memory capacity is consistent with a recent demonstration of decreased frontal hyperactivation following chemotherapy. WHAT IS NEW AND CONCLUSION: Chemotherapy-associated impairment of visuospatial working memory might include the (pre)frontal cortex in addition to the parietal cortex. This provides new opportunity for basic science and clinical investigation. PMID- 23656524 TI - Executive functioning in chronic alcoholism and Korsakoff syndrome. AB - Korsakoff syndrome (KS) is characterized by dense anterograde and retrograde amnesia. There is often a temporal gradient to the retrograde amnesia, with earlier memories more readily recalled than recent memories. Executive functioning has also been found to be impaired in KS. However, research comparing executive functioning between chronic alcoholics (AL) and patients with KS has been relatively sparse to date. In a group comparison design, executive functioning in 15 KS patients and 16 chronic alcoholic patients was assessed using the Behavioural Assessment of the Dysexecutive Syndrome test (BADS) and other secondary measures. The KS group was found to be significantly more impaired than the AL group on overall performance on the BADS (p < .05). Korsakoff patients are significantly more impaired in executive functioning than non-Korsakoff chronic alcoholics. We thank the participants of the study and also acknowledge the support of the University of Nottingham, particularly Nadina Lincoln, and the North East London NHS Foundation Trust. We are also very grateful to the anonymous reviewers of earlier drafts of this manuscript for their invaluable comments. PMID- 23656525 TI - Recent developments in the treatment of heart failure: highlights from the American Heart Association's Scientific Sessions, Los Angeles, California, 3 - 7 December 2012. AB - Over the last decade, the treatment of heart failure has seen the introduction of several novel therapeutic avenues into the guidelines; however, these were mostly devoted to device therapies. Not much has changed with regards to the pharmacological treatment of this syndrome. Serelaxin, a recombinant form of the human peptide hormone relaxin-2, is a promising treatment candidate for patients presenting with acute heart failure. The Relaxin in Acute Heart Failure (RELAX AHF) trial has shown beneficial effects in terms of relief of dyspnea and congestion in these patients. Even beneficial effects on short-term survival were reported. Another treatment approach to acute heart failure was pursued in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial but the ultrafiltration used here lead to significantly worsened renal function as compared to standard pharmacologic care. Multicenter Automatic Defibrillator Implantation Trial - Reduce Inappropriate Therapy (MADIT-RIT) randomized patients with heart failure with a primary preventive indication for the implantation of an implantable cardioverter defibrillator to one of three algorithms for anti tachycardia pacing (ATP) and shock. The authors found that initiation of such therapies only at higher heart rates than commonly used as threshold and longer time delays before the initiation of therapy may have two big advantages: the more conservative algorithms lead to a significant reduction in the cumulative probability of first inappropriate therapy and, even more striking, a reduced probability of death during follow-up. Biventricular versus Right Ventricular Pacing in Patients with Left Ventricular Dysfunction and Atrioventricular Block (BLOCK-HF) showed beneficial outcomes for cardiac resynchronization therapy in heart failure patients with a mere pacemaker indication. Other studies discussed here embraced the course of body wasting, particularly cachexia, and muscle wasting in patients with heart failure and the influence of eating behavior. PMID- 23656527 TI - Underground signals carried through common mycelial networks warn neighbouring plants of aphid attack. AB - The roots of most land plants are colonised by mycorrhizal fungi that provide mineral nutrients in exchange for carbon. Here, we show that mycorrhizal mycelia can also act as a conduit for signalling between plants, acting as an early warning system for herbivore attack. Insect herbivory causes systemic changes in the production of plant volatiles, particularly methyl salicylate, making bean plants, Vicia faba, repellent to aphids but attractive to aphid enemies such as parasitoids. We demonstrate that these effects can also occur in aphid-free plants but only when they are connected to aphid-infested plants via a common mycorrhizal mycelial network. This underground messaging system allows neighbouring plants to invoke herbivore defences before attack. Our findings demonstrate that common mycorrhizal mycelial networks can determine the outcome of multitrophic interactions by communicating information on herbivore attack between plants, thereby influencing the behaviour of both herbivores and their natural enemies. PMID- 23656526 TI - Substrates and controls for the quantitative detection of active botulinum neurotoxin in protease-containing samples. AB - Botulinum neurotoxins (BoNTs) are used in a wide variety of medical applications, but there is limited pharmacokinetic data on active BoNT. Monitoring BoNT activity in the circulation is challenging because BoNTs are highly toxic and are rapidly taken up by neurons and removed from the bloodstream. Previously we reported a sensitive BoNT "Assay with a Large Immunosorbent Surface Area" that uses conversion of fluorogenic peptide substrates to measure the intrinsic endopeptidase activity of bead-captured BoNT. However, in complex biological samples, protease contaminants can also cleave the substrates, reducing sensitivity and specificity of the assay. Here, we present a novel set of fluorogenic peptides that serve as BoNT-specific substrates and protease sensitive controls. BoNT-cleavable substrates contain a C-terminal Nle, while BoNT-noncleavable controls contain its isomer epsilon-Ahx. The substrates are cleaved by BoNT subtypes A1-A3 and A5. Substrates and control peptides can be cleaved by non-BoNT proteases (e.g., trypsin, proteinase K, and thermolysin) while obeying Michaelis-Menten kinetics. Using this novel substrate/control set, we studied BoNT/A1 activity in two mouse models of botulism. We detected BoNT/A serum activities ranging from ~3600 to 10 amol/L in blood of mice that had been intravenously injected 1 h prior with BoNT/A1 complex (100 to 4 pg/mouse). We also detected the endopeptidase activity of orally administered BoNT/A1 complex (1 MUg) in blood 5 h after administration; activity was greatest 7 h after administration. Redistribution and elevation rates for active toxin were measured and are comparable to those reported for inactive toxin. PMID- 23656528 TI - Regrowth of transected retinal ganglion cell axons despite persistent astrogliosis in the lizard (Gallotia galloti). AB - We analysed the astroglia response that is concurrent with spontaneous axonal regrowth after optic nerve (ON) transection in the lizard Gallotia galloti. At different post-lesional time points (0.5, 1, 3, 6, 9 and 12 months) we used conventional electron microscopy and specific markers for astrocytes [glial fibrillary acidic protein (GFAP), vimentin (Vim), sex-determining region Y-box-9 (Sox9), paired box-2 (Pax2) cluster differentiation-44 (CD44)] and for proliferating cells (PCNA). The experimental retina showed a limited glial response since the increase of gliofilaments was not significant when compared with controls, and proliferating cells were undetectable. Conversely, PCNA(+) cells populated the regenerating ON, optic tract (OTr) and ventricular wall of both the hypothalamus and optic tectum (OT). Subpopulations of these PCNA(+) cells were identified as GFAP(+) and Vim(+) reactive astrocytes and radial glia. Reactive astrocytes up-regulated Vim at 1 month post-lesion, and both Vim and GFAP at 12 months post-lesion in the ON-OTr, indicating long-term astrogliosis. They also expressed Pax2, Sox9 and CD44 in the ON, and Sox9 in the OTr. Concomitantly, persistent tissue cavities and disorganised regrowing fibre bundles reaching the OT were observed. Our ultrastructural data confirm abundant gliofilaments in reactive astrocytes joined by desmosomes. Remarkably, they also accumulated myelin debris and lipid droplets until late stages, indicating their participation in myelin removal. These data suggest that persistent mammalian like astrogliosis in the adult lizard ON contributes to a permissive structural scaffold for long-term axonal regeneration and provides a useful model to study the molecular mechanisms involved in these beneficial neuron-glia interactions. PMID- 23656530 TI - Menopausal hot flushes do not associate with changes in heart rate variability in controlled testing: a randomized trial on hormone therapy. AB - OBJECTIVE: To compare in controlled cardiovascular autonomic function tests the effects of hormone therapy (HT) on heart rate variability (HRV) responses in postmenopausal women with and without pretreatment hot flushes. DESIGN: A randomized placebo-controlled trial. SETTING: Finland, Helsinki University Central Hospital. POPULATION: A total of 150 recently postmenopausal and healthy women with prospectively evaluated hot flushes. METHODS: Women (72 with and 78 without hot flushes) were randomized to receive estradiol alone or in combination with medroxyprogesterone acetate or placebo for 6 months. Time and frequency domain measures of HRV were assessed at baseline and after HT with short-term recordings during paced quiet and deep breathing and with active orthostatic tests, both under carefully controlled laboratory conditions to avoid confounding factors present in long-term ambulatory HRV measurements. MAIN OUTCOME MEASURES: Responses of time and frequency domain measures of HRV to HT. RESULTS: At baseline HRV was similar in women with and without hot flushes. Pretreatment hot flushes did not associate with changes in time domain parameters of HRV during controlled quiet or deep breathing or active orthostatic tests after different types of HT. However, HT reduced HRV in very low frequency power in women with pretreatment hot flushes (from 371 +/- 40 to 258 +/- 28 ms(2) , p = 0.018). HT did not have an effect on other frequency domain measures during quiet breathing or active orthostatic tests. CONCLUSIONS: Hormone therapy did not significantly modify the HRV responses in women with or without hot flushes under controlled short-term measurements of the cardiovascular autonomic nervous system. PMID- 23656531 TI - Three-body nonadditive potential for argon with estimated uncertainties and third virial coefficient. AB - The three-body nonadditive interaction energy between argon atoms was calculated at 300 geometries using coupled cluster methods up to single, double, triple, and noniterative quadruple excitations [CCSDT(Q)], and including the core correlation and relativistic effects. The uncertainty of the calculated energy was estimated at each geometry. The analytic function fitted to the energies is currently the most accurate three-body argon potential. Values of the third virial coefficient C(T) with full account of quantum effects were computed from 80 to 10000 K by a path-integral Monte Carlo method. The calculation made use of an existing high quality pair potential [Patkowski, K.; Szalewicz, K. J. Chem. Phys. 2010, 133, 094304] and of the three-body potential derived in the present work. Uncertainties in the potential were propagated to estimate uncertainties in C(T). The results were compared with available experimental data, including some values of C(T) newly derived in this work from previously published high-accuracy density measurements. Our results are generally consistent with the available experimental data in the limited range of temperatures where data exist, but at many conditions, especially at higher temperatures, the uncertainties of our calculated values are smaller than the uncertainties of the experimental values. PMID- 23656529 TI - Epigenetic regulation of the electrophysiological phenotype of human embryonic stem cell-derived ventricular cardiomyocytes: insights for driven maturation and hypertrophic growth. AB - Epigenetic regulation is implicated in embryonic development and the control of gene expression in a cell-specific manner. However, little is known about the role of histone methylation changes on human cardiac differentiation and maturation. Using human embryonic stem cells (hESCs) and their derived ventricular (V) cardiomyocytes (CMs) as a model, we examined trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) on promoters of genes associated with cardiac electrophysiology, contraction, and Ca(2+) handling. To avoid ambiguities due to heterogeneous chamber-specific types, hESC-derived ventricular cardiomyocytes (VCMs) were selected by dual zeocin-GFP expression under the transcriptional control of the MLC2v promoter and confirmed electrophysiologically by its signature action potential phenotype. High levels of H3K4me3 are present on pluripotency genes in hESCs with an absence of H3K27me3. Human ESC-VCMS, relative to hESCs, were characterized by a profound loss of H3K27me3 and an enrichment of H3K4me3 marks on cardiac-specific genes, including MYH6, MYH7, MYL2, cTNT, and ANF. Gene transcripts encoding key voltage gated ion channels and Ca(2+)-handling proteins in hESC-VCMs were significantly increased, which could be attributed to a distinct pattern of differential H3K4me3 and H3K27me3 profiles. Treatment of hESC-VCMs with the histone deacetylase inhibitor valproic acid increased H3K4me3 on gene promoters, induced hypertrophic growth (as gauged by cell volume and capacitance), and augmented cardiac gene expression, but it did not affect electrophysiological properties of these cells. Hence, cardiac differentiation of hESCs involves a dynamic shift in histone methylation, which differentially affects VCM gene expression and function. We conclude that the epigenetic state of hESC-VCMs is dynamic and primed to promote growth and developmental maturation, but that proper environmental stimuli with chromatin remodeling will be required to synergistically trigger global CM maturation to a more adult-like phenotype. PMID- 23656532 TI - Lean on me: effects of social support on low socioeconomic-status pregnant women. AB - This study identified how close relationships are related to low-income pregnant women's ability to cope and overall health. Previous research has shown that stress during pregnancy is related to long-term negative physical and psychological health outcomes for both the mother and the infant. Lower socioeconomic status has been related to higher morbidity and mortality across the lifespan. Women typically rely on close relationships for social support to help reduce stress. However, stress levels can be elevated when women engage in co-rumination. Co-rumination is defined as excessive problem discussion with negative-affect focus. Thirty-one low-income pregnant women from central Oklahoma, USA, reported their daily stressors, social support, communication habits with friends and family, and general health in a series of questionnaires at a prenatal visit. The results revealed that daily stressors, co-rumination with friends, and the relationship with the baby's father were related to physical pain and depressive symptoms. The results suggested that specific social support dynamics, such as co-rumination, during pregnancy have implications for the health of low-income mothers and their infants. PMID- 23656533 TI - Emergence of mutation-based linezolid-resistant invasive Enterococcus faecalis in a haemodialysis patient in Norway. PMID- 23656534 TI - Linguistic measures of the referential process in psychodynamic treatment: the English and Italian versions. AB - The referential process is defined in the context of Bucci's multiple code theory as the process by which nonverbal experience is connected to language. The English computerized measures of the referential process, which have been applied in psychotherapy research, include the Weighted Referential Activity Dictionary (WRAD), and measures of Reflection, Affect and Disfluency. This paper presents the development of the Italian version of the IWRAD by modeling Italian texts scored by judges, and shows the application of the IWRAD and other Italian measures in three psychodynamic treatments evaluated for personality change using the Shedler-Westen Assessment Procedure (SWAP-200). Clinical predictions based on applications of the English measures were supported. PMID- 23656535 TI - First detection in Europe of the metallo-beta-lactamase IMP-15 in clinical strains of Pseudomonas putida and Pseudomonas aeruginosa. AB - In a prospective study (2009-2011) in healthcare institutions from the Canary Islands (Spain), 6 out of 298 carbapenem non-susceptible Pseudomonas aeruginosa isolates produced a metallo-beta-lactamase: four IMP-15, two VIM-2 (including one IMP-15-positive isolate) and one VIM-1. Multilocus sequence typing identified the single VIM-1-producing isolate as clone ST111 and two IMP-15-producing isolates as ST606, but, strikingly, bacterial re-identification revealed that the other three isolates (producing IMP-15 and/or VIM-2) were actually Pseudomonas putida. Further retrospective analysis revealed a very high prevalence (close to 50%) of carbapenem resistance in this environmental species. Hence, we report the simultaneous emergence in hospitals on the Canary Islands of P. putida and P. aeruginosa strains producing IMP-15, a metallo-beta-lactamase not previously detected in Europe, and suggest an underestimated role of P. putida as a nosocomial reservoir of worrying transferable resistance determinants. PMID- 23656536 TI - On the Morphology and Taxonomy of Griphobilharzia amoena Platt and Blair, 1991 (Schistosomatoidea), a Dioecious Digenetic Trematode Parasite of the Freshwater Crocodile, Crocodylus johnstoni, in Australia. AB - Abstract Griphobilharzia amoena Platt and Blair, 1991 was originally described as a dioecious trematode parasitic in the circulatory system of the Australian freshwater crocodile, Crocodylus johnstoni, with the female completely enclosed in a gynecophoric chamber of the male, and the 2 worms oriented anti-parallel to each other. A recent publication questions the original description arguing that G. amoena is monoecious and as a consequence, the species was transferred to Vasotrema Stunkard, 1928 (Spirorchiidae) as V. amoena n. comb. We provide photomicrographic evidence that the original description of G. amoena is correct and that Griphobilharzia Platt and Blair, 1991, is a valid monotypic genus containing G. amoena. An accurate understanding of the anatomy of G. amoena is not trivial and has implications for revealing the complex origins and evolution of the dioecious condition within the Schistosomatoidea. PMID- 23656537 TI - Oxytocin in Brattleboro rats: increased synthesis is contrasted by blunted intrahypothalamic release from supraoptic nucleus neurones. AB - Adult male Brattleboro rats were used to investigate the impact of the congenital absence of vasopressin on the release pattern of oxytocin (OXT) within the hypothalamic supraoptic nucleus (SON) in response to a 10-min forced swimming session and osmotic stimulation. Both immunohistochemical and in situ hybridisation data suggest that vasopressin-deficient animals have more oxytocin synthesising neurones in the SON than homozygous wild-type controls. Unexpectedly, both forced swimming and peripheral osmotic stimulation resulted in a blunted release profile of oxytocin within the SON of vasopressin-deficient rats compared to controls. A similar intranuclear OXT response to direct osmotic stimulation of the SON by retrodialysis with hypertonic Ringer's solution in both genotypes confirmed the capability of SON neurones to locally release oxytocin in vasopressin-deficient rats, indicating an altered processing of information originating from multisynaptic inputs rather than a deficit in release capacity. Taken together with data obtained in previous studies, the present findings provide evidence suggesting that autocrine and paracrine signalling of magnocellular neurones differs within the paraventricular nucleus and the SON. Thus, significant alterations in intra-SON oxytocin mRNA levels cannot easily be extrapolated to intranuclear release profiles and the local signal intensity of this neuropeptide after physiological stimulation. PMID- 23656538 TI - Inactivation of Plasmodium falciparum in whole blood by riboflavin plus irradiation. AB - BACKGROUND: Malaria parasites are frequently transmitted by unscreened blood transfusions in Africa. Pathogen reduction methods in whole blood would thus greatly improve blood safety. We aimed to determine the efficacy of riboflavin plus irradiation for treatment of whole blood infected with Plasmodium falciparum. STUDY DESIGN AND METHODS: Blood was inoculated with 10(4) or 10(5) parasites/mL and riboflavin treated with or without ultraviolet (UV) irradiation (40-160 J/mL red blood cells [mL(RBCs)]). Parasite genome integrity was assessed by quantitative amplification inhibition assays, and P. falciparum viability was monitored in vitro. RESULTS: Riboflavin alone did not affect parasite genome integrity or parasite viability. Application of UV after riboflavin treatment disrupted parasite genome integrity, reducing polymerase-dependent amplification by up to 2 logs (99%). At 80 J/mL(RBCs), riboflavin plus irradiation prevented recovery of viable parasites in vitro for 2 weeks, whereas untreated controls typically recovered to approximately 2% parasitemia after 4 days of in vitro culture. Exposure of blood to 160 J/mL(RBCs) was not associated with significant hemolysis. CONCLUSIONS: Riboflavin plus irradiation treatment of whole blood damages parasite genomes and drastically reduces P. falciparum viability in vitro. In the absence of suitable malaria screening assays, parasite inactivation should be investigated for prevention of transfusion-transmitted malaria in highly endemic areas. PMID- 23656539 TI - Further thoughts on the utility of risk matrices. AB - Risk matrices are commonly encountered devices for rating hazards in numerous areas of risk management. Part of their popularity is predicated on their apparent simplicity and transparency. Recent research, however, has identified serious mathematical defects and inconsistencies. This article further examines the reliability and utility of risk matrices for ranking hazards, specifically in the context of public leisure activities including travel. We find that (1) different risk assessors may assign vastly different ratings to the same hazard, (2) even following lengthy reflection and learning scatter remains high, and (3) the underlying drivers of disparate ratings relate to fundamentally different worldviews, beliefs, and a panoply of psychosocial factors that are seldom explicitly acknowledged. It appears that risk matrices when used in this context may be creating no more than an artificial and even untrustworthy picture of the relative importance of hazards, which may be of little or no benefit to those trying to manage risk effectively and rationally. PMID- 23656541 TI - One-pot synthesis of 2,5-disubstituted pyrimidines from nitriles. AB - A practical, one-step process for the synthesis of 2,5-disubstituted pyrimidines is presented. The protocol proved to be general for the synthesis of a variety of pyrimidine-containing compounds bearing an assortment of functional groups. PMID- 23656542 TI - Nursing workforce policy and the economic crisis: a global overview. AB - PURPOSE: To assess the impact of the global financial crisis on the nursing workforce and identify appropriate policy responses. ORGANIZING CONSTRUCT AND METHODS: This article draws from international data sources (Organisation for Economic Co-operation and Development [OECD] and World Health Organization), from national data sources (nursing regulatory authorities), and the literature to provide a context in which to examine trends in labor market and health spending indicators, nurse employment, and nurse migration patterns. FINDINGS: A variable impact of the crisis at the country level was shown by different changes in unemployment rates and funding of the health sector. Some evidence was obtained of reductions in nurse staffing in a small number of countries. A significant and variable change in the patterns of nurse migration also was observed. CONCLUSIONS: The crisis has had a variable impact; nursing shortages are likely to reappear in some OECD countries. Policy responses will have to take account of the changed economic reality in many countries. CLINICAL RELEVANCE: This article highlights key trends and issues for the global nursing workforce; it then identifies policy interventions appropriate to the new economic realities in many OECD countries. PMID- 23656543 TI - Synthesis of fluoro- and perfluoroalkyl arenes via palladium-catalyzed [4 + 2] benzannulation reaction. AB - An efficient entry into densely substituted fluorinated and perfluoroalkylated benzene derivatives via chemo- and regioselective Pd-catalyzed [4 + 2] cross benzannulation is presented. The synthetic utility of these products for the synthesis of various aromatic and heteroaromatic compounds is also demonstrated. This strategy offers a viable and quite general alternative to existing fluorination and perfluoroalkylation methods for securing these valuable molecules. PMID- 23656544 TI - Are stress and mixed urinary incontinence associated with impaired executive control in community-dwelling older women? AB - OBJECTIVES: To assess whether stress or mixed urinary incontinence (UI) is associated with deficits in executive functioning among community-dwelling women. DESIGN: An observational study comparing the performance, using multivariate analyses of variance (MANOVAs) and Bonferroni post hoc test, of continent women and women with stress or mixed UI during executive control tasks. SETTING: The research center of the Institut universitaire de geriatrie de Montreal. PARTICIPANTS: One hundred and fifty-five community-dwelling women aged 60 and older participated in the study. MEASUREMENTS: Based on the Urogenital Distress Inventory (UDI), participants were split into three groups: 35 continent women, 43 women with stress UI, and 78 women with mixed UI. Participants completed a battery of neuropsychological tests and a computerized dual-task test. RESULTS: Women with mixed UI showed poorer performances than continent and stress UI women in executive control functions. Deficits were specific to tests involving switching and sharing/dividing attention between two tasks. CONCLUSION: Results of this study suggest that mixed UI can be associated with executive control deficits in community-dwelling older women. Future intervention studies in the treatment of UI should take the higher risk of an executive control deficit in women with UI under consideration. PMID- 23656545 TI - Formation of new melasma lesions in the periorbital area following high-fluence, 1064-nm, Q-switched Nd/YAG laser. AB - Although ultraviolet (UV) light or exogenous hormones have been associated with the development or exacerbation of melasma, the use of laser as a treatment modality has not been cited as a factor linked to the development of melasma lesions. It is unclear whether epidermal trauma caused by laser or other treatment can lead to the formation of a new melasma lesion. We report on the formation of new melasma lesions in a patient who was treated for acquired bilateral nevus of Ota-like macules (ABNOM) with a high-fluence 1064 nm Q switched (QS) neodymium-doped yttrium aluminum garnet (Nd/YAG) laser. PMID- 23656546 TI - A real-time eco-evolutionary dead-end strategy is mediated by the traits of lineage progenitors and interactions with colony invaders. AB - Evolutionary dead-end strategies are characterized by short-term productivity benefits and long-term evolutionary costs. Here, I detail a real-time dead-end strategy associated with the behavioural traits of lineage progenitors in the social spider Anelosimus studiosus. Specifically, colony lineages founded by docile spiders were eight times more likely to suffer extinction, despite their superior reproductive output. However, when inquilines were experimentally removed from progenitor colonies, differences in extinction probability among lineages vanished. Similarly, among lineages founded by purely docile or aggressive individuals, the descendants of lineages with the highest reproductive output suffered the lowest survivorship, whereas lineages founded by a mixture of docile/aggressive lacked such a trade-off. Finally, lineages with shorter progenitor-descendant distances gained more inquilines and their descendants had lower survivorship, relative to more diffuse lineages. Overall, this study demonstrates how the traits of lineage progenitors and species interactions can unite to determine the fates of entire lineages. PMID- 23656547 TI - Prevalence of Candida spp., xerostomia, and hyposalivation in oral lichen planus- a controlled study. AB - OBJECTIVE: To determine the frequency of Candida spp., xerostomia, and salivary flow rate (SFR) in three different groups: patients with OLP (OLP group), patients with oral mucosal lesions other than OLP (non-OLP group), and subjects without oral mucosal lesions (control group). MATERIAL AND METHODS: Xerostomia as well as SFR was investigated in the three groups. Samples for isolation of Candida spp. were collected from OLP lesions (38 patients), non-OLP lesions (28 patients), and healthy subjects (32 subjects). RESULTS: There was no statistically significant difference regarding the frequency of xerostomia and hyposalivation among the three groups (P > 0.05). A higher prevalence for colonization by Candida spp. was found in the healthy subject as compared to that of patients with OLP (P = 0.03) and non-OLP (P = 0.02) groups. Low SFR was not a factor for colonization by Candida spp. CONCLUSIONS: Xerostomia and hyposalivation occur with similar frequency in subjects with and without oral lesions; also, the presence of oral lesions does not increase the susceptibility to colonization by Candida spp. It seems that any study implicating Candida spp. in the malignant transformation of oral lesions should be carried out mostly on a biochemical basis, that is, by testing the capability of Candida spp. to produce carcinogenic enzyme. PMID- 23656549 TI - Definitions and roles of a skilled birth attendant: a mapping exercise from four South-Asian countries. AB - OBJECTIVE: To identify which cadres of healthcare providers are considered to be skilled birth attendants in South Asia, which of the signal functions of emergency obstetric care each cadre is reported to provide and whether this is included in their training and legislation. DESIGN: Cross-sectional, descriptive study. SETTING: Bangladesh, India, Nepal and Pakistan. SAMPLE: Thirty-three key informants involved in training, regulation, recruitment and deployment of healthcare providers. METHODS: Between November 2011 and March 2012, structured questionnaires were sent out to key informants by email followed up by face-to face or telephone interviews. MAIN OUTCOME MEASURES: Mapping of definitions and roles of healthcare providers in four South Asian countries to assess which cadres are skilled birth attendants. RESULTS: Cadres of healthcare providers expected to provide skilled birth attendance differ across countries. Although most identified cadres administer parenteral antibiotics, oxytocics and perform newborn resuscitation; administration of anticonvulsants varies by country. Manual removal of the placenta, removal of retained products of conception and assisted vaginal delivery are not provided by all cadres expected to provide skilled birth attendance. CONCLUSION: Key signal functions of emergency obstetric care are often provided by medical doctors only. Provision of such potentially life-saving interventions by more healthcare provider cadres expected to function as skilled birth attendants can save lives. Ensuring better training and legislation are in place for this is crucial. PMID- 23656550 TI - In situ study of the antibacterial activity and mechanism of action of silver nanoparticles by surface-enhanced Raman spectroscopy. AB - Silver nanoparticles (Ag NPs) are extensively used as an antibacterial additive in commercial products and their release has caused environmental risk. However, conventional methods for the toxicity detection of Ag NPs are very time consuming and the mechanisms of action are not clear. We developed a new, in situ, rapid, and sensitive fingerprinting approach, using surface-enhanced Raman spectroscopy (SERS), to study the antibacterial activity and mechanism of Ag NPs of 80 and 18 nm (Ag80 and Ag18, respectively), by using the strong electromagnetic enhancement generated by Ag NPs. Sensitive spectra changes representing various biomolecules in bacteria were observed with increasing concentrations of Ag NPs. They not only allowed SERS to monitor the antibacterial activity of Ag NPs of different sizes in different water media but also to study the antibacterial mechanism at the molecular level. Ag18 were found to be more toxic than Ag80 in water, but their toxicity declined to a similar level in the PBS medium. The antibacterial mechanism was proposed on the basis of a careful identification of the chemical origins by comparing the SERS spectra with model compounds. The dramatic change in protein, hypoxanthine, adenosine, and guanosine bands suggested that Ag NPs have a significant impact on the protein and metabolic processes of purine. Finally, by adding nontoxic and SERS active Au NPs, SERS was successfully utilized to study the action mode of the NPs unable to produce an observable SERS signal. This work opens a window for the future extensive SERS studies of the antibacterial mechanism of a great variety of non-SERS-active NPs. PMID- 23656552 TI - Comparative inhibition of tetrameric carbonyl reductase activity in pig heart cytosol by alkyl 4-pyridyl ketones. AB - CONTEXT AND OBJECTIVE: The present study is to elucidate the comparative inhibition of tetrameric carbonyl reductase (TCBR) activity by alkyl 4-pyridyl ketones, and to characterize its substrate-binding domain. MATERIALS AND METHODS: The inhibitory effects of alkyl 4-pyridyl ketones on the stereoselective reduction of 4-benzoylpyridine (4-BP) catalyzed by TCBR were examined in the cytosolic fraction of pig heart. RESULTS: Of alkyl 4-pyridyl ketones, 4 hexanoylpyridine, which has a straight-chain alkyl group of five carbon atoms, inhibited most potently TCBR activity and was a competitive inhibitor. Furthermore, cyclohexyl pentyl ketone, which is substituted by cyclohexyl group instead of phenyl group of hexanophenone, had much lower ability to be reduced than hexanophenone. DISCUSSION AND CONCLUSION: These results suggest that in addition to a hydrophobic cleft corresponding to a straight-chain alkyl group of five carbon atoms, a hydrophobic pocket with affinity for an aromatic group is located in the substrate-binding domain of TCBR. PMID- 23656551 TI - Global maize trade and food security: implications from a social network model. AB - In this study, we developed a social network model of the global trade of maize: one of the most important food, feed, and industrial crops worldwide, and critical to food security. We used this model to analyze patterns of maize trade among nations, and to determine where vulnerabilities in food security might arise if maize availability was decreased due to factors such as diversion to nonfood uses, climatic factors, or plant diseases. Using data on imports and exports from the U.N. Commodity Trade Statistics Database for each year from 2000 to 2009 inclusive, we summarized statistics on volumes of maize trade between pairs of nations for 217 nations. There is evidence of market segregation among clusters of nations; with three prominent clusters representing Europe, Brazil and Argentina, and the United States. The United States is by far the largest exporter of maize worldwide, whereas Japan and the Republic of Korea are the largest maize importers. In particular, the star-shaped cluster of the network that represents U.S. maize trade to other nations indicates the potential for food security risks because of the lack of trade these other nations conduct with other maize exporters. If a scenario arose in which U.S. maize could not be exported in as large quantities, maize supplies in many nations could be jeopardized. We discuss this in the context of recent maize ethanol production and its attendant impacts on food prices elsewhere worldwide. PMID- 23656553 TI - Microbiology of folliculitis: a histological study of 39 cases. AB - Folliculitis is a common inflammatory skin syndrome. Several microbial organisms have been put forward as causative agents, but few studies visualized microbes directly in inflamed hair follicles. This retrospective study investigated bacterial and fungal colonization of inflamed hair follicles in patients with clinically diagnosed non-infectious folliculitis. Skin biopsies from 39 folliculitis patients and 27 controls were screened by fluorescence in situ hybridization (FISH) using broad-range bacterial and fungal probes and by immunofluorescence microscopy using a monoclonal antibody towards Gram-positive bacteria. Specific monoclonal and polyclonal antibodies towards Staphylococcus spp. and Propionibacterium acnes were applied for further species identification. Inflamed follicles were associated with bacterial colonization in 10 samples (26%) and fungal colonization in three samples (8%). Staphylococcus spp. were observed in inflamed follicles in seven samples (18%). Two samples were positive for P. acnes, which were identified as either type II or type IB/type III. Both Staphylococcus spp. and P. acnes were seen in macrocolonies/biofilm structures. In conclusion, one-third of patients with clinically diagnosed, non-infectious folliculitis exhibited microbial colonization with predominance of Staphylococcus spp. PMID- 23656554 TI - Selective enhancements in 2D Fourier transform optical spectroscopy with tailored pulse shapes. AB - Spectral features in two-dimensional Fourier transform optical spectroscopy were selectively enhanced using pulse shapes and sequences designed to amplify specific excited-state resonances. The enhancement was achieved by tailoring a small set of input parameters that control the amplitude and phase profiles of the excitation fields, coherently driving or suppressing selected resonances. The tailored pulse shapes were applied to enhance exciton and biexciton coherences in a semiconductor quantum well. Enhancement of selected resonances was demonstrated even in cases of spectrally overlapping features and complex many-body interactions. Modifications in the 2D spectral line shapes due to the tailored waveforms were calculated using the optical Bloch equations. PMID- 23656555 TI - Reactivity of a bis(amidinato)iron(II) complex [Fe(MesC(NPr(i))2)2] toward some oxidizing reagents. AB - A diversified reactivity of the mononuclear bis(amidinato)iron(II) complex [Fe(MesC(NPr(i))2)2] (1) toward oxidizing reagents has been disclosed. The bis(amidinato)iron(II) complex was synthesized from the reaction of [Fe(Mes)2]2 with 4 equiv of diisopropyl carbodiimide in good yield. Treatment of 1 with 1 equiv of benzyl chloride gives the high-spin ferric complex [FeCl(MesC(NPr(i))2)2] (2), with 0.25 equiv of S8 affords the sulfur-insertion product [Fe(MesC(NPr(i))(NPr(i)S))2] (3), with 1 equiv of 3,5-dimethylphenyl azide or phenyl azide yields nitrene-insertion product [Fe(MesC(NPr(i))2)(Pr(i)NC(Mes)N(Pr(i))NAr)] (Ar = 3,5-dimethylphenyl, 4a; phenyl, 4b), and with 1 equiv of oxo-transfer reagent, trimethylamine oxide or 2,6-dichloropyridine oxide, generates the oxo-bridged diferric complex [(MesC(NPr(i))2)2FeOFe(MesC(NPr(i))2)2] (5). Complexes 1-3, 4a, and 5 have been characterized by (1)H NMR, UV-vis, IR, elemental analysis, and single-crystal X ray diffraction studies. The formations of these unusual sulfur- and nitrene insertion products 3, 4a, and 4b, can be explained by the sequential redox reaction between 1 and the oxidants, followed by migratory insertion steps. PMID- 23656556 TI - 19-[(1'S,4'R)-4'-Hydroxy-1'-methoxy-2'-oxopentyl]geldanamycin, a natural geldanamycin analogue from Streptomyces hygroscopicus 17997. AB - A novel natural geldanamycin analogue was discovered in Streptomyces hygroscopicus 17997. Its 4,5-dihydro form was also identified in the gdmP gene disruption mutant of Streptomyces hygroscopicus 17997. The structures of the two compounds were determined to be 19-[(1'S,4'R)-4'-hydroxy-1'-methoxy-2' oxopentyl]geldanamycin (1) and 19-[(1'S,4'R)-4'-hydroxy-1'-methoxy-2'-oxopentyl] 4,5-dihydrogeldanamycin (2), respectively, by extensive spectroscopic data analysis, including 2D NMR, modified Mosher's method, and electronic circular dichroism. Compared to geldanamycin, 1 and 2 showed increased water solubility and decreased cytotoxicity against HepG2 cells. PMID- 23656557 TI - Magnetic resonance imaging in paediatric psychoneuroendocrinology: a new frontier for understanding the impact of hormones on emotion and cognition. AB - Mounting magnetic resonance imaging (MRI) research is characterising the neurobiological trajectories of healthy human brain development. In parallel, studies increasingly acknowledge the relevance of perturbations of these trajectories for adolescent and adult psychopathology. Although an influence of steroid hormones on mood and anxiety disorders has been demonstrated in adults, very little is known about how steroid hormones alter human brain development and contribute to adolescent psychopathology. This review focuses on recent evidence obtained from structural and functional MRI in children and adolescents with genetic endocrine disorders and with characteristic fluctuations in androgen or oestrogen levels (familial male precocious puberty, congenital adrenal hyperplasia, Klinefelter syndrome and Turner syndrome). It aims to highlight how neurobiological findings from these paediatric endocrine disorders can provide insight into the contribution of sex steroids with respect to the development of neurocircuitry involved in affective processing (amygdala, hippocampus) and cognitive control (prefrontal cortex, inferior frontal gyrus, striatum). In addition, findings from these populations may also provide important information on aberrant psychological processes relevant for the clinical care and management of these populations. Finally, the findings are discussed within the context of current frameworks in animal models, such as the organisational-activational hypothesis or the aromatisation hypothesis. The review ends with a discussion of open questions for future enquiry with the goal of integrating translational models with current knowledge of endocrine disorders and developmental studies in healthy populations. PMID- 23656558 TI - Towards a clean slit: how medicine and notions of normality are shaping female genital aesthetics. AB - In the West, a specific ideal has emerged for female genitalia. The ideal is one of absence, a clean slit that can be attained through the removal of pubic hair and, increasingly, through female genital cosmetic surgery. This ideal is largely created in the media, which generates contradictory messages for women. The popular press, backed by medical opinion, explicitly acknowledges that a wide range of variation is normal--female genitals vary in appearance 'about as much as snowflakes'--but by showing only altered minimalist clean slits, it carries an implicit message that women should be worried if their genitals do not match up to this exacting ideal. Consequently, some women feel their genitals are not satisfactory and choose surgery. Using biomedicine to fix normal body parts in order to fashion desirable femininity, releases medicine from its rigid scientific underpinnings exposing it as an increasingly cultural and commercial pursuit. PMID- 23656559 TI - A review of the health hazards posed by cobalt. AB - Cobalt (Co) is an essential element with ubiquitous dietary exposure and possible incremental exposure due to dietary supplements, occupation and medical devices. Adverse health effects, such as cardiomyopathy and vision or hearing impairment, were reported at peak blood Co concentrations typically over 700 ug/L (8-40 weeks), while reversible hypothyroidism and polycythemia were reported in humans at ~300 ug/L and higher (>=2 weeks). Lung cancer risks associated with certain inhalation exposures have not been observed following Co ingestion and Co alloy implants. The mode of action for systemic toxicity relates directly to free Co(II) ion interactions with various receptors, ion channels and biomolecules resulting in generally reversible effects. Certain dose-response anomalies for Co toxicity likely relate to rare disease states known to reduce systemic Co(II)-ion binding to blood proteins. Based on the available information, most people with clearly elevated serum Co, like supplement users and hip implant patients, have >90% of Co as albumin-bound, with considerable excess binding capacity to sequester Co(II) ions. This paper reviews the scientific literature regarding the chemistry, pharmacokinetics and systemic toxicology of Co, and the likely role of free Co(II) ions to explain dose-response relationships. Based on currently available data, it might be useful to monitor implant patients for signs of hypothyroidism and polycythemia starting at blood or serum Co concentrations above 100 ug/L. This concentration is derived by applying an uncertainty factor of 3 to the 300 ug/L point of departure and this should adequately account for the fact that persons in the various studies were exposed for less than one year. A higher uncertainty factor could be warranted but Co has a relatively fast elimination, and many of the populations studied were of children and those with kidney problems. Closer follow-up of patients who also exhibit chronic disease states leading to clinically important hypoalbuminemia and/or severe ischemia modified albumin (IMA) elevations should be considered. PMID- 23656560 TI - A toxicological review of the propylene glycols. AB - The toxicological profiles of monopropylene glycol (MPG), dipropylene glycol (DPG), tripropylene glycol (TPG) and polypropylene glycols (PPG; including tetra rich oligomers) are collectively reviewed, and assessed considering regulatory toxicology endpoints. The review confirms a rich data set for these compounds, covering all of the major toxicological endpoints of interest. The metabolism of these compounds share common pathways, and a consistent profile of toxicity is observed. The common metabolism provides scientific justification for adopting a read-across approach to describing expected hazard potential from data gaps that may exist for specific oligomers. None of the glycols reviewed presented evidence of carcinogenic, mutagenic or reproductive/developmental toxicity potential to humans. The pathologies reported in some animal studies either occurred at doses that exceeded experimental guidelines, or involved mechanisms that are likely irrelevant to human physiology and therefore are not pertinent to the exposures experienced by consumers or workers. At very high chronic doses, MPG causes a transient, slight decrease in hemoglobin in dogs and at somewhat lower doses causes Heinz bodies to form in cats in the absence of any clinical signs of anemia. Some evidence for rare, idiosyncratic skin reactions exists for MPG. However, the larger data set indicates that these compounds have low sensitization potential in animal studies, and therefore are unlikely to represent human allergens. The existing safety evaluations of the FDA, USEPA, NTP and ATSDR for these compounds are consistent and point to the conclusion that the propylene glycols present a very low risk to human health. PMID- 23656561 TI - Sub-internal limiting membrane cavity in anaemic retinopathy evident on spectral domain optical coherence tomography. AB - A 25-year-old woman was diagnosed with anaemic retinopathy following Plasmodium falciparum malaria. The serial clinical and spectral domain optical coherence tomography (SD-OCT) changes are described, including sub-internal limiting membrane (sub-ILM) haemorrhage at the macula with the formation of a corresponding sub-ILM cavity evident on SD-OCT. The patient was managed conservatively and showed complete recovery of fundus and SD-OCT changes after one year. To the best of our knowledge, this is the first documentation of formation of a temporary sub-ILM cavity following anaemic retinopathy. PMID- 23656562 TI - Transitional phase inversion of emulsions monitored by in situ near-infrared spectroscopy. AB - Water-heptane/toluene model emulsions were prepared to study emulsion transitional phase inversion by in situ near-infrared spectroscopy (NIR). The first emulsion contained a small amount of ionic surfactant (0.27 wt % of sodium dodecyl sulfate) and n-pentanol as a cosurfactant. In this emulsion, the study was guided by an inversion coordinate route based on a phase behavior study previously performed. The morphology changes were induced by rising aqueous phase salinity in a "steady-state" inversion protocol. The second emulsion contained a nonionic surfactant (ethoxylated nonylphenol) at a concentration of 3 wt %. A continuous temperature change induced two distinct transitional phase inversions: one occurred during the heating of the system and another during the cooling. NIR spectroscopy was able to detect phase inversion in these emulsions due to differences between light scattered/absorbed by water in oil (W/O) and oil in water (O/W) morphologies. It was observed that the two model emulsions exhibit different inversion mechanisms closely related to different quantities of the middle phases formed during the three-phase behavior of Winsor type III. PMID- 23656563 TI - Human platelets pathogen reduced with riboflavin and ultraviolet light do not cause acute lung injury in a two-event SCID mouse model. AB - BACKGROUND: Pathogen reduction technologies (PRTs) can induce platelet (PLT) lesions that reduce PLT survival and recovery from circulation and may be associated with acute lung injury (ALI). STUDY DESIGN AND METHODS: Human PLTs (hPLTs) in plasma with or without single or multiple Mirasol PRT treatments were assessed in vitro by aggregation and percentage of P-selectin expression. In vivo studies included PLT recovery in SCID mice and assessment of ALI in a two-event mouse model in which the sensitizing event was lipopolysaccharide injection and the second event was infusion of Mirasol-treated hPLTs. RESULTS: A single-dose Mirasol treatment (5 J/cm(2) ) did not induce any change in aggregation in response to adenosine 5'-diphosphate (ADP) while a five-times-repeat Mirasol treatment (5*) increased aggregation response to low concentration of ADP. Mirasol PLTs (1*-5*) had increased percentage of P-selectin-positive PLTs after treatment and decreased aggregation with TRAP as the agonist. In vivo recovery in SCID mice was reduced extensively with Mirasol treatments (1* and 5*). In the two event model of ALI, only the 5* Mirasol PLTs accumulated in the lung and this was not accompanied by changes in lung histology or increases in MIP-2 levels in bronchoalveolar lavage fluid. CONCLUSIONS: Mirasol PRT treatment induced PLT activation and reduced in vivo recovery in a SCID mouse model of transfusion. In our two-event mouse model of ALI, the 5* Mirasol hPLTs accumulated in the lung, but did not cause signs of ALI. The 1* Mirasol treatment did not lead to PLT lung accumulation or ALI in this model. PMID- 23656564 TI - How the observed create ethical dilemmas for the observers: experiences from studies conducted in clinical settings in the UK and Australia. AB - Observational research has a history of controversy, particularly when the research is conducted in a clinical setting. Existing ethical approval processes focus on protecting participants and the researcher's responsibilities, in particular where vulnerable populations are concerned. In this study, the authors explored the less overt and often understated ethical challenges that can arise when conducting observational research in a clinical setting. Reflecting on two recent studies conducted in different clinical settings, the authors described the challenges of blurring role boundaries, the risk of collecting redundant data, and the impact of reverse power relationships between researchers, clinicians, and managers. From their experiences, the authors suggested that the preparatory work undertaken with clinicians and managers onsite, which typically focuses on how the researchers will maintain the ethical robustness of the research and protect the rights of participants and the vulnerable, should also highlight the sometimes overlooked ethical issues associated with participatory research. This can help ensure that participants and managers understand the scope and limitations of the research, and consider the ways in which the observed can influence the researcher and the findings. PMID- 23656565 TI - Dietary modification of the microbiome affects risk for cardiovascular disease. AB - The incidence of cardiovascular disease (CVD) increases with age and is associated with some syndromes that exhibit aspects of premature aging, such as progeria. Various factors are thought to contribute to the progression of CVD, including hypertension, hypercholesterolemia, diets rich in saturated and trans fats, etc. Recent reports have uncovered an important connection between diet, the microbiome, and CVD. Dietary carnitine (present predominately in red meat) and lecithin (phosphatidyl choline) are shown to be metabolized by gut microbes to trimethylamine (TMA), which in turn is metabolized by liver flavin monoxygenases (especially FMO3 and FMO1) to form trimethylamine-N-oxide (TMAO). High levels of TMAO in the blood strongly correlate with CVD and associated acute clinical events. Plasma TMAO levels may be an important clinical biomarker for CVD. The data suggest that that presence of specific as yet unidentified microorganisms in the gut linked to diet are required for high TMAO levels and TMAO-mediated CVD progression. Development of novel therapeutic approaches to manipulate gut flora may help treat CVD. PMID- 23656566 TI - The eyes have it: long-distance dispersal by an intraorbital leech parasite of birds. AB - A leech was found parasitizing the ocular orbit of a common redstart captured during a faunistic survey of Antikythira in the Aegean Sea during the spring migration of 2012. Morphological and molecular characterizations placed the leech in the mucous-membrane specific leech family Praobdellidae and definitively as the species Parapraobdella lineata. This is the first record of any leech parasitizing a passerine bird, Phoenicurus phoenicurus , and the first of a praobdellid leech on any avian host. PMID- 23656567 TI - Concentrated arabinoxylan in wheat bread has beneficial effects as rye breads on glucose and changes in gene expressions in insulin-sensitive tissues of Zucker diabetic fatty (ZDF) rats. AB - The health-promoting effects of dietary fiber may vary with content, structure, and composition in the diet. The aim was to study how low-fiber wheat bread (WB), wheat bread supplemented with wheat arabinoxylan (AX) or oat beta-glucan (BG), whole meal rye bread (RM), and rye bread with kernels (RK) affected central parameters of glucose and lipid metabolism and gene changes of Zucker diabetic fatty rats. Blood glucose response areas after an oral glucose tolerance test were significantly lower after AX (mean +/- SEM; 2117 +/- 170 mmol/L.180 min), RM (1978 +/- 206 mmol/L.180 min), and RK (2234 +/- 262 mmol/L.180 min) breads than after WB (3586 +/- 100 mmol/L.180 min; p < 0.0001). AX, RK, and RM changed expressions of adipose GAPDH, AMPK, FAS, SREBP-1c, and hepatic PCG-1alpha, whereas BG had similar effects as WB. Thus, arabinoxylan added to wheat bread had beneficial effects on glycemic control as whole grain rye bread in this animal model. PMID- 23656568 TI - Treatment of idiopathic guttate hypomelanosis with fractional carbon dioxide lasers. AB - Abstract Objective: Idiopathic guttate hypomelanosis (IGH) is an acquired leukoderma found in all races. The treatment of choice is still controversial. This study aimed at evaluating the effect of CO2FL on IGH. Methods: A total of 240 patients with IGH were enrolled. The hypopigmented lesions were treated using a 10 600-nm carbon dioxide fractional laser (CO2FL). Two months after a single treatment, physicians' clinical assessments were performed and the patients' overall satisfaction was evaluated. Results: 240 patients (40 men and 200 women) were followed. The mean age of the patients was 54.32 +/- 8.64 years. The mean duration of IGH was 2.64 +/- 0.36 years. Two months after a single treatment session, 115 patients (47.9%) exhibited more than 75% clinical improvement. 100 patients (41.6%) achieved 51-75% clinical improvement, whereas 25 patients (10.3%) showed 25-50% clinical improvement. In addition, 95 of the 240 patients (39.6%) were very satisfied with their clinical outcomes, 102 (42.5%) were satisfied and 43 patients (17.9%) were slightly satisfied. Conclusion: CO2FL might be very effective without any considerable side effects for the treatment of IGH. PMID- 23656569 TI - Evolution in technique: use of hyalurostructure for lips rejuvenation as an alternative to needle injection without troncular anesthesia. AB - PURPOSE: To enhance lips ageing rejuvenation with specific microcannula and hyaluronic acid. METHOD: Clinical review was conducted from December 2010 to December 2011 among 46 patients complaining of predictable changes on lips and perioral region such as deficiency in contour definition, volume and projection. Lips rejuvenation injections were made using the hyalurostructure technique. RESULTS: Forty-two patients (92%) with a 6-month follow-up were satisfied or very satisfied with the aesthetic results after the hyalurostructure of the lips and the perioral region rejuvenation. The use of the specially designed cannula led to fewer complications. We noticed 40 oedemas (87%) that appeared 24-48 h after the injection and seven patients (15.2%) with haematomas. We noted fewer surface irregularities and a better distribution of the product. Patients' records showed the procedure was painless. CONCLUSION: The hyalurostructure technique reduces the number of punctures compared to that of the conventional method. The microcannula's blunt tip reduces the risks of intravascular injection of the substance and of reach and disruption of the key structures like vessels and nerves. Results revealed that the hyalurostructure used for lips rejuvenation and helps to maintain a natural effect and avoids pain. PMID- 23656570 TI - Effect of low-level laser therapy on the release of interleukin-6 and basic fibroblast growth factor from cultured human skin fibroblasts in normal and high glucose mediums. AB - INTRODUCTION: This study evaluated the effects of low-level laser therapy (LLLT) on human skin fibroblasts (HSFs) that have been cultured in high glucose concentration media. MATERIALS AND METHODS: HSFs were cultured under physiological glucose condition medium, and then cultured in high glucose concentration medium (15 mM/L) for 1 or 2 weeks prior to LLLT. Experimental HSFs were irradiated with three energy densities (0.5, 1, and 2 J/cm(2)) once daily for three consecutive days. Release of interleukin-6 (IL-6) and basic fibroblast growth factor (bFGF) was evaluated using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Statistical analysis showed three doses of 0.5 (p = 0.049), 1 (p = 0.027), and 2 J/cm(2) (p = 0.004) stimulated the release of IL-6 in HSFs cultured in high glucose concentration medium compared with that of non irradiated HSFs that were cultured in the same medium. LLLT with 2 J/cm(2) induced the release of bFGF from HSFs cultured in high glucose concentration medium for 1 or 2 weeks (both p = 0.04). CONCLUSION: Our study showed that LLLT stimulated the release of IL-6 and bFGF from HSFs cultured in high glucose concentration medium. LLLT was more effective in releasing IL-6 and bFGF while HSFs which were cultured in physiologic glucose concentration medium during laser irradiation. PMID- 23656571 TI - Antimicrobial resistance, presence of integrons and biofilm formation of Salmonella Pullorum isolates from Eastern China (1962-2010). AB - Three hundred and thirty-seven isolates of Salmonella Pullorum from eastern China between 1962 and 2010 were characterized for antimicrobial susceptibility (disk diffusion method), the presence of integrons (polymerase chain reaction followed by sequencing) and the ability to form biofilms (semi-quantitative adherence assay). Two hundred and fifty-eight isolates (76.6%) exhibited multiple drug resistance (MDR; resistant to at least three different classes of antimicrobials), and the level of drug resistance is increasing with time. There were three isolates (9.4%) exhibiting MDR from 1962 to 1968. MDR rates began to increase for isolates between 1970 to 1979 and 1980 to 1987 (64.6 to 78.7%). The MDR rates reached 96.6% for isolates between 1990 and 2010. Polymerase chain reaction screening for integrons showed that 75 isolates (22.3%) were positive for class 1 integrons while none were positive for class 2 integrons. All of the class 1 integron-positive isolates exhibited MDR and were more frequently resistant than the negative isolates. Two hundred and twenty isolates (65.3%) had the ability to form biofilms, and bacterial resistance levels to cefamandole, trimethoprim and trimethoprim/sulfamethoxazole were significantly higher for biofilm-positive groups than the biofilm-negative groups. Our data show that multidrug resistance is common among S. Pullorum isolated from eastern China, being more frequent after 1990 than before 1990, and the presence of class 1 integrons is associated with multidrug resistance. PMID- 23656572 TI - 'Be Clear on Cancer': the impact of the UK National Bowel Cancer Awareness Campaign. AB - AIM: The National Bowel Cancer Awareness Campaign ('Be Clear on Cancer') was launched by the UK government in January 2012, encouraging people with bowel symptoms to present to primary care. Our aim was to evaluate the impact of the campaign on colorectal services in secondary care. METHOD: Suspected cancer 2 week-wait (2WW) patients 3 months before and 3 months after the launch of the campaign were included. Demographics, reason for referral, investigations performed, cost analysis and eventual diagnoses were collected. RESULTS: Three hundred and forty-three patients [median age 70 (36-100) years, 194 (57%) women] were seen and investigated in the 3 months prior to the launch of the campaign at an average cost of L575 per patient. Twenty-seven (8%) were diagnosed with lower gastrointestinal cancer and 29 (8%) with polyps. In the 3 months following the launch, 544 patients [median age 68 (30-92) years, 290 (53%) women] were reviewed (59% increase; P = 0.004). The 'did not attend' rate fell from 10% to 1%. Thirty two (6%) patients were diagnosed with a lower gastrointestinal cancer and 20 (4%) with colorectal polyps. The cost per colorectal cancer detected rose from L7585.58 before the campaign to L9662.72 after launch (P = 0.04). CONCLUSION: The 'Be Clear on Cancer' campaign has substantially increased the number of referrals under the 2WW rule, but mainly in the worried well. This has increased demands on both resources (59% more tests) and finance. Cost per cancer detected rose by 27% with no increase in funding to support the increased activity. PMID- 23656573 TI - Human mesenchymal stem cells overexpressing the IL-33 antagonist soluble IL-1 receptor-like-1 attenuate endotoxin-induced acute lung injury. AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by pulmonary edema attributable to alveolar epithelial-interstitial endothelial injury, associated with profound inflammation and respiratory dysfunction. The IL-33/IL-1 receptor-like-1 (ST2) axis plays a key role in the development of immune-inflammatory responses in the lung. Cell-based therapy has been recently proposed as an effective alternative for the treatment of ALI and ARDS. Here, we engineered human adipose tissue-derived mesenchymal stem cells (hASCs) overexpressing soluble IL-1 receptor-like-1 (sST2), a decoy receptor for IL-33, in order to enhance their immunoregulatory and anti-inflammatory properties when applied in a murine ALI model. We administered both hASCs and hASC-sST2 systemically at 6 hours after intranasal LPS instillation, when pathological changes had already occurred. Bioluminescence imaging, immunohistochemistry, and focused transcriptional profiling confirmed the increased presence of hASCs in the injured lungs and the activation of an immunoregulatory program (CXCR-4, tumor necrosis factor-stimulated gene 6 protein, and indoleamine 2,3-dioxygenase up-regulation) in these cells, 48 hours after endotoxin challenge. A comparative evaluation of hASCs and the actions of hASC-sST2 revealed that local sST2 overproduction by hASC-sST2 further prevented IL-33, Toll-like receptor-4, IL-1beta, and IFN-gamma induction, but increased IL 10 expression in the injured lungs. This synergy caused a substantial decrease in lung airspace inflammation and vascular leakage, characterized by significant reductions in protein content, differential neutrophil counts, and proinflammatory cytokine (TNF-alpha, IL-6, and macrophage inflammatory protein 2) concentrations in bronchoalveolar lavage fluid. In addition, hASC-sST2-treated ALI lungs showed preserved alveolar architecture, an absence of apoptosis, and minimal inflammatory cell infiltration. These results suggest that hASCs genetically engineered to produce sST2 could become a promising therapeutic strategy for ALI/ARDS management. PMID- 23656574 TI - Synthesis and solvatochromic fluorescence of biaryl pyrimidine nucleosides. AB - Fluorescent pyrimidine analogs containing a fused biphenyl unit were prepared in high yields using stereoselective N-glycosylation and Suzuki-Miyaura cross coupling reactions. The resulting "push-pull" fluorophores exhibit highly solvatochromic emissions from twisted intramolecular charge-transfer (TICT) states. PMID- 23656575 TI - Use of ultrasound and fluoroscopy guidance in percutaneous radiofrequency lesioning of the sensory branches of the femoral and obturator nerves. AB - Hip pain is a common condition that is often seen in patients with multiple comorbidities. Often surgery is not an option due to these comorbidities. Percutaneous radiofrequency lesioning of the articular branches of the obturator and femoral nerves is an alternative treatment for hip pain. Traditionally, fluoroscopy is used to guide needle placement. We report a case where a novel approach was used with ultrasound guidance to visualize vascular and soft tissue structures in real time. The use of ultrasound might help to guide the needle to avoid vascular complications due to anatomical variation between patients. PMID- 23656576 TI - Spinal and bulbar muscular atrophy: pathogenesis and clinical management. AB - Spinal and bulbar muscular atrophy, or Kennedy's disease, is an X-linked motor neuron disease caused by polyglutamine repeat expansion in the androgen receptor. The disease is characterised by weakness, atrophy and fasciculations in the limb and bulbar muscles. Affected males may have signs of androgen insensitivity, such as gynaecomastia and reduced fertility. Neurophysiological studies are typically consistent with diffuse denervation atrophy, and serum creatine kinase is usually elevated 2-5 times above normal. Progression of the disease is slow, and the focus of spinal and bulbar muscular atrophy (SBMA) management is to prevent complications. PMID- 23656577 TI - Implementation of shared decision making in anaesthesia and its influence on patient satisfaction. AB - There is a lack of data about the implementation of shared decision making in anaesthesia. To assess patients' preference to be involved in medical decision making and its influence on patient satisfaction, we studied 197 matched pairs (patients and anaesthetists) using two previously validated questionnaires. Before surgery, patients had to decide between general vs regional anaesthesia and, where appropriate, between conventional postoperative pain therapy vs catheter techniques. One hundred and eighty-six patients (94%) wished to be involved in shared decision making. One hundred and twenty-two patients (62%) experienced the exact amount of shared decision making that they wanted; 44 (22%) were slightly more involved and 20 (10%) slightly less involved in shared decision making than they desired. Preferences regarding involvement in shared decision making were similar between patients and anaesthetists with mean (SD) points of 54.1 (16.2) vs 56.4 (27.6) (p=0.244), respectively on a 0-100 scale; however, patients were found to have a stronger preference for a totally balanced shared decision-making process (65% vs 32%). Overall patient satisfaction was high: 88% were very satisfied and 12% satisfied with a mean (SD) value of 96.1 (10.6) on a 0-100 scale. Shared decision making is important for providing high levels of patient satisfaction. PMID- 23656578 TI - Qualitative study on the placement of Huntington disease patients in a psychiatric hospital: perceptions of Maltese nurses. AB - Individuals with adult or juvenile Huntington disease can be cared for within psychiatric hospitals. In this paper, nurses' perceptions about the appropriateness of a psychiatric setting for these patients were explored. Semistructured interviews were conducted with 10 Maltese nurses involved in the care of these individuals. Their responses were analyzed using thematic analysis. Three main themes were identified from this study: (i) Huntington disease is not a mental illness; (ii) the lack of specialized staff and equipment within a psychiatric setting; and (iii) a need for alternative care options. The findings provide an insight into the perceptions of nurses, as they play a key role in the care and management of individuals with Huntington disease in a psychiatric setting. The findings demonstrated the need to provide alternative residential options in the community, and to improve the care and support provided both within psychiatric hospitals and the community through staff education and the provision of necessary facilities and equipment. PMID- 23656580 TI - Laser ablation surface-enhanced Raman microspectroscopy. AB - Improved identification of trace organic compounds in complex matrixes is critical for a variety of fields such as material science, heritage science, and forensics. Surface-enhanced Raman scattering (SERS) is a vibrational spectroscopy technique that can attain single-molecule sensitivity and has been shown to complement mass spectrometry, but lacks widespread application without a robust method that utilizes the effect. We demonstrate a new, highly sensitive, and widely applicable approach to SERS analysis based on laser ablation in the presence of a tailored plasmonic substrate. We analyze several challenging compounds, including non-water-soluble pigments and dyed leather from an ancient Egyptian chariot, achieving sensitivity as high as 120 amol for a 1:1 signal-to noise ratio and 5 MUm spatial resolution. This represents orders of magnitude improvement in spatial resolution and sensitivity compared to those of other SERS approaches intended for widespread application, greatly increasing the applicability of SERS. PMID- 23656581 TI - The novel human polyomaviruses HPyV6, 7, 9 and beyond. AB - Since the discovery of Merkel cell polyomavirus and its causative association with Merkel cell carcinoma (MCC), six human polyomaviruses (HPyVs) have been identified that, so far, lack any disease association, which include the human polyomaviruses (HPyV) 6, 7, 9, 10 and 12 as well as the Saint Louis polyomavirus (STLPyV). PCR studies revealed that HPyV6 and HPyV7 are shed from the skin of healthy subjects and of patients suffering from various skin tumours. HPyV6, 7 and 9 were sporadically detected in body fluids and excretions of immunocompromised patients and healthy subjects. HPyV10 was identified in papillomavirus-induced anal condylomas, and variants of HPyV10, named MWPyV and MX polyomavirus (human) (MXPyV), as well as STLPyV were detected in faeces of diarrheal and healthy children. HPyV12 was discovered in organs of the digestive tract of patients suffering from various malignant diseases. Serological studies using capsomer-based or virus-like particle (VLP)-based enzyme-linked immunosorbent assay (ELISA) revealed that HPyV6, 7, 9 and 12 are circulating in the human population. As all other HPyVs, the novel polyomaviruses encode small and large T antigens and thus are potentially oncogenic. However, several studies have revealed a lack of association of HPyV6, 7 and 9 with numerous human tumours. In the future, it will be important to unravel the cell types and body compartments of the novel HPyVs' reservoir and to search for possible associations with cancer and non-malignant diseases. PMID- 23656582 TI - Modulated neural processing of Western harmony in folk musicians. AB - A chord deviating from the conventions of Western tonal music elicits an early right anterior negativity (ERAN) in inferofrontal brain regions. Here, we tested whether the ERAN is modulated by expertise in more than one music culture, as typical of folk musicians. Finnish folk musicians and nonmusicians participated in electroencephalography recordings. The cadences consisted of seven chords. In incongruous cadences, the third, fifth, or seventh chord was a Neapolitan. The ERAN to the Neapolitans was enhanced in folk musicians compared to nonmusicians. Folk musicians showed an enhanced P3a for the ending Neapolitan. The Neapolitan at the fifth position was perceived differently and elicited a late enhanced ERAN in folk musicians. Hence, expertise in more than one music culture seems to modify chord processing by enhancing the ERAN to ambivalent chords and the P3a to incongruous chords, and by altering their perceptual attributes. PMID- 23656583 TI - Improved perioperative blood pressure control leads to reduced hospital costs. AB - BACKGROUND: Perioperative hypertension affects 80% of cardiac surgery patients and is associated with an increased risk of complications. OBJECTIVE: To determine the relationship between perioperative blood pressure (BP) control and hospital costs for cardiac surgery in the United States (US) and estimate the potential cost reductions associated with effective therapies. METHODS: The analysis estimated hospitalization costs (2011 US dollars (USD)) for cardiac surgery when BP was controlled with intravenous (IV) antihypertensives. Patient characteristics, hospital length of stay, and clinical event rates during the initial hospitalization and post-discharge 30 days after study drug infusion were based on the ECLIPSE (Evaluation of CLevidipine In the Perioperative Treatment of Hypertension Assessing Safety Events) trials. These clinical trial data were combined with data from the Massachusetts Acute Hospital Case Mix Database 2007 - 2009 (MA Case Mix Database) to estimate total hospitalization costs. RESULTS: Effective perioperative BP control in patients requiring IV antihypertensives was associated with a 7% decrease in hospital costs compared with less effective BP control. Reductions in total hospital costs associated with clevidipine versus other IV antihypertensives averaged $394 per patient overall. Cost savings with clevidipine exceeded $500 per patient versus sodium nitroprusside and nitroglycerin, but only $22 compared to nicardipine. CONCLUSION: Improved perioperative BP control may reduce hospital costs. Given the low cost of IV antihypertensives, the total hospital cost reductions may offset any incremental cost increases associated with newer, more effective therapies. PMID- 23656584 TI - Determination of the major phenolic compounds in pomegranate juices by HPLC-DAD ESI-MS. AB - Traditionally, pomegranate (Punica granatum L.) has been consumed as fresh fruit or as pomegranate juice. In this study, the main phenolic compounds of 12 pomegranate varieties and 5 pomegranate clones were determined by HPLC-DAD-ESI MS. Two chromatographic methods with a fused-core C18 column and a classical HPLC system were developed. Thirteen anthocyanins and fourteen other phenolic compounds were determined in the pomegranate juices. As far as we are concerned, a new flavonol-glycoside, phellatin or its isomer amurensin, has been tentatively identified for the first time in pomegranate juices. Total phenolic content ranged from 580.8 to 2551.3 mg/L of pomegranate juice. Anthocyanins varied between 20 to 82% of total phenolic content. Flavonoids were 1.6-23.6% of total phenolic compounds, while phenolic acids and ellagitannins were in the range 16.4 65.8%. The five clones reported a phenolic content comparable with that of the other pomegranate samples. PMID- 23656585 TI - Stability and dynamics of forebrain vasopressin receptor and oxytocin receptor during pregnancy in prairie voles. AB - During pregnancy, females undergo several physiologically driven changes that facilitate adaptive behaviours and prepare the mother to care for her developing offspring. The nonapeptide hormone oxytocin is best recognised for its involvement in mammalian pregnancy and has been tightly associated with maternal care, in addition to its roles in pregnancy, parturition and lactation. A closely related nonapeptide hormone, arganine vasopressin, has received considerably less attention for its role in pregnancy, although it has recently been implicated in modulating maternal care and aggression. In the present study, we examined the expression patterns of receptors for oxytocin (OXTR) and vasopressin (V1aR) over the course of pregnancy, ranging from non-mated virgin to immediately postpartum female prairie voles (Microtus ochrogaster). Unexpectedly, we found that OXTR was highly stable in all measured structures in the forebrain. V1aR was also stable throughout most of the brain. Two exceptions to this were found in the ventral pallidum (VPall) and the paraventricular nucleus of the hypothalamus (PVN); both significantly correlated with the length of time that females were pregnant. Changes in the PVN may reflect functional feedback in vasopressin release, or preparatory changes for ensuing maternal behaviour. The results also indicate an unappreciated role for VPall V1aR in pregnancy, which may relate to the function of the VPall in hedonic 'liking' and motivational 'wanting.' Taken together, our data indicate that, with a few compelling exceptions, nonapeptide dynamics during prairie vole pregnancy are largely limited to changes in the synthesis and release of oxytocin and vasopressin, and not the receptors to which they bind. PMID- 23656587 TI - Saving specimens after Sandy. PMID- 23656586 TI - Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. AB - BACKGROUND: The Sturge-Weber syndrome is a sporadic congenital neurocutaneous disorder characterized by a port-wine stain affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary venous vessels in the leptomeninges of the brain and choroid, glaucoma, seizures, stroke, and intellectual disability. It has been hypothesized that somatic mosaic mutations disrupting vascular development cause both the Sturge-Weber syndrome and port-wine stains, and the severity and extent of presentation are determined by the developmental time point at which the mutations occurred. To date, no such mutation has been identified. METHODS: We performed whole-genome sequencing of DNA from paired samples of visibly affected and normal tissue from 3 persons with the Sturge-Weber syndrome. We tested for the presence of a somatic mosaic mutation in 97 samples from 50 persons with the Sturge-Weber syndrome, a port wine stain, or neither (controls), using amplicon sequencing and SNaPshot assays, and investigated the effects of the mutation on downstream signaling, using phosphorylation-specific antibodies for relevant effectors and a luciferase reporter assay. RESULTS: We identified a nonsynonymous single-nucleotide variant (c.548G->A, p.Arg183Gln) in GNAQ in samples of affected tissue from 88% of the participants (23 of 26) with the Sturge-Weber syndrome and from 92% of the participants (12 of 13) with apparently nonsyndromic port-wine stains, but not in any of the samples of affected tissue from 4 participants with an unrelated cerebrovascular malformation or in any of the samples from the 6 controls. The prevalence of the mutant allele in affected tissues ranged from 1.0 to 18.1%. Extracellular signal-regulated kinase activity was modestly increased during transgenic expression of mutant Galphaq. CONCLUSIONS: The Sturge-Weber syndrome and port-wine stains are caused by a somatic activating mutation in GNAQ. This finding confirms a long-standing hypothesis. (Funded by the National Institutes of Health and Hunter's Dream for a Cure Foundation.). PMID- 23656589 TI - An undetectable polymerase chain reaction signal in routine HIV plasma viral load monitoring is associated with better virological outcomes in patients receiving highly active antiretroviral therapy. AB - OBJECTIVES: The aim of the study was to assess whether patients with undetectable viraemia [a negative polymerase chain reaction result (PCR(neg) )] and those with plasma viral load (PVL) < 40 HIV-1 RNA copies/mL but a detectable (positive) PCR signal (PCR(pos) ) had different outcomes in terms of the development of blips and virological failure (VF). METHODS: A multicentre observational database analysis was carried out. Data for patients whose highly active antiretroviral therapy (HAART) regime had been unchanged for >= 6 months by 1 January 2008, whose first two PVL measurements of 2008 were < 40 copies/mL and who had at least five PVL measurements between 1 January 2008 and 31 December 2010 were extracted from a multicentre observational database of 4928 patients receiving HAART. PVL assays used during this period had a detection threshold of 20 or 40 copies/mL. Undetectable PVL at baseline (BL PCR(neg) ) was defined as PCR(neg) at the first two PVL determinations of 2008. Multivariable Cox regression analysis was performed to investigate factors associated with the occurrence of blips and VF, defined as two consecutive PVL measurements > 40 copies/mL. RESULTS: Of the 1957 patients included in the study (mean age 47 years; median antiretroviral exposure 10.3 years), 1312 had BL PCR(neg) . Outcome events included 322 blips and 139 VFs, with incidence rates being significantly lower in patients with BL PCR(neg) than in those with BL PCR(pos) [13.0% vs. 23.4% (P < 0.0001) and 5.1% vs. 11.2% (P < 0.0001), respectively]. In multivariable analysis, BL PCR(neg) was associated with a reduced risk of blips [hazard ratio (HR) 0.58; 95% confidence interval (CI) 0.47-0.73; P < 0.0001] and VF (HR 0.44; 95% CI 0.31-0.62; P < 0.0001). CONCLUSIONS: Patients with PCR(neg) had better virological outcomes than those with PVL < 40 copies/mL but detectable viraemia. This suggests that the 'no signal' information provided by currently commercially available HIV RNA quantification assays should be used routinely. PMID- 23656591 TI - Exploring a new structure family: alkali borosulfates Na5[B(SO4)4], A3[B(SO4)3] (A = K, Rb), Li[B(SO4)2], and Li[B(S2O7)2]. AB - New alkali borosulfates were obtained by precipitation from oleum, solid-state reactions, or thermal decomposition. The crystal structures were characterized with single-crystal data. They are all based on corner-linked BO4 and SO4 tetrahedra with varying coordination of the alkali cations. According to the ratio of BO4 and SO4 tetrahedra, different frameworks are observed, i.e., noncondensed complex anions (1:4), one-dimensional chains (1:3), or three dimensional (3D) networks (1:2). This is in analogy to silicates, where the ratio Si/O relates to the dimensionality also. For Na5[B(SO4)4], which exists in two different polymorphs, there are noncondensed pentameric units. Na5[B(SO4)4]-I: space group Pca21, a = 10.730(2) A, b = 13.891(3) A, c = 18.197(4) A. Na5[B(SO4)4]-II: space group P212121, a = 8.624(2) A, b = 9.275(2) A, c = 16.671(3) A. A3[B(SO4)3] (A = K, Rb) are isotypic with Ba3[B(PO4)3] adopting space group Ibca [K3[B(SO4)3], a = 7.074(4) A, b = 14.266(9) A, c = 22.578(14) A; Rb3[B(SO4)3], a = 7.2759(5) A, b = 14.7936(11) A, c = 22.637(2) A] with vierer chains of BO4tetrahedra based on two bridging and two terminal SO4 tetrahedra. Li[B(SO4)2] [space group Pc, a = 7.6353(15) A, b = 9.342(2) A, c = 8.432(2) A, and beta = 92.55(2) degrees ] comprises a 3D network that is closely related to beta-tridymite. Li[B(S2O7)2] [space group P212121, a = 10.862(2) A, b = 10.877(2) A, c = 17.769(4) A] represents the first example of a disulfate complex with noncondensed [B(S2O7)2](-) units. Vibrational spectra were recorded from all compounds, and the thermal behavior was also investigated. PMID- 23656590 TI - A pilot theory-based intervention to improve resilience, psychosocial well-being, and quality of life among people living with HIV in rural China. AB - This pilot study aimed at fostering resilience among people living with HIV and improving the HIV-negative participants' acceptance of people living with HIV. A group of 75 people living with HIV who were former blood/plasma donors and 36 HIV negative fellow villagers in rural China participated in the intervention. The 8 sessions lasted for 4 months and were facilitated by trained local family planning officers. Efficacy of the intervention was assessed using a pre- and postprogram study design; measurements were made at baseline, at completion, and 3 months afterward completion. The authors found that the HIV-positive participants increased their levels of resilience, social support, and quality of life and that they reported fewer symptoms of depression, anxiety, and stress at the completion of the intervention; most of these changes were sustained at the 3 month follow-up. Such participants also reported subjective improvements on problem-solving skills, self-confidence, and a feeling of being cared for by others. In addition, the HIV-negative participants' discriminatory attitudes toward people living with HIV were reduced after completing the intervention. The majority of the participants was satisfied with the intervention and would recommend it to others. The train-the-trainer approach was used effectively. Positive effects of the intervention have been revealed and future randomized controlled studies are warranted. PMID- 23656588 TI - Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. AB - BACKGROUND: The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive. METHODS: We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model. RESULTS: Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis. CONCLUSIONS: The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.). PMID- 23656592 TI - Human UDP-alpha-d-xylose synthase forms a catalytically important tetramer that has not been observed in crystal structures. AB - Human UDP-alpha-d-xylose synthase (hUXS) is a member of the extended short chain dehydrogenase/reductase (SDR) family of enzymes. Previous crystallographic studies have shown that hUXS conserves the same dimeric quaternary structure observed in other SDR enzymes. Here, we present evidence that hUXS also forms a tetramer in solution that is important for activity. Sedimentation velocity studies show that two hUXS dimers undergo a concentration-dependent association to form a tetramer with a Kd of 2.9 MUM. The tetrameric complex is also observed in small-angle X-ray scattering (SAXS). The specific activity for the production of the reaction intermediate UDP-alpha-d-4-keto-xylose displays a hyperbolic dependence on protein concentration that is well modeled by an isotherm using the 2.9 MUM Kd of the tetramer. Likewise, the rate of UDP-alpha-d-xylose production in the presence of increasing concentrations of the small molecule crowder trimethylamine N-oxide is consistent with the formation of a higher activity tetramer. We present several possible structural models of the hUXS tetramer based on (i) hUXS crystal packing, (ii) homology modeling, or (iii) ab initio simulated annealing of dimers. We analyze the models in terms of packing quality and agreement with SAXS data. The higher activity of the tetramer coupled with the relative instability of the complex suggests that an association-dissociation mechanism may regulate hUXS activity. PMID- 23656593 TI - Copper-diffused AgInS2 ternary nanocrystals in hybrid bulk-heterojunction solar cells: near-infrared active nanophotovoltaics. AB - We have grown copper-diffused AgInS2 ternary nanocrystals in order to introduce the nanoparticles in organic/inorganic bulk-heterojunction devices for photovoltaic applications. Here, copper diffuses to vacant sites and improves conductivity of the nanocrystals. Upon use of such copper-diffused nanoparticles that led to a decrease in internal resistance of sandwiched devices based on the bulk-heterojunction, there has been a marked improvement in short-circuit current under white light illumination. Due to a red-shift in the optical absorption spectrum of the nanoparticles upon copper diffusion, the devices moreover acted as near-infrared (IR) active photovoltaic solar cells. From current-voltage characteristics and impedance spectroscopy of the devices, we optimized performance of the photovoltaic devices. To do so, we have varied the content of diffused copper in AgInS2 nanoparticles and also the weight-ratio between the polymer and the nanoparticles of the hybrid bulk-heterojunction devices. PMID- 23656594 TI - Effect of Probiotics Containing Lactobacillus paracasei SD1 on Salivary Mutans Streptococci and Lactobacilli in Orthodontic Cleft Patients: A Double-Blinded, Randomized, Placebo-Controlled Study. AB - Objective : (1) To investigate the effect of probiotic bacterium Lactobacillus paracasei SD1 on the level of salivary mutans streptococci and lactobacilli, and (2) the oral persistence of L. paracasei SD1 in orthodontically treated nonsyndromic cleft lip and palate patients. Design : Double-blinded, randomized, placebo-controlled study. Participants : A total of 30 orthodontically treated nonsyndromic cleft lip and palate patients (aged 19.22 +/- 3.66 years): 15 in the intervention group (A) and 15 in the control group (B). Interventions : Milk with or without L. paracasei SD1. Average daily consumption of milk in both groups was 50 mL for 4 weeks. Main Outcome Measures : Salivary mutans streptococci and lactobacilli were enumerated using a quantitative differential culture at baseline and once a week after the end of the administration period for 4 weeks. The persistence of L. paracasei SD1 was traced using arbitrarily primed polymerase chain reaction of the DNA fingerprinting. Results : A statistically significant reduction in mutans streptococci counts occurred in group A, in contrast to group B (P < .001). A significant increase of lactobacilli numbers was found in group A (P < .001), and L. paracasei SD1 could be detected up to 4 weeks following cessation of dosing. Conclusions : The probiotic milk powder containing L. paracasei SD1 could reduce mutans streptococci counts and was apparently able to colonize the oral cavity of the orthodontically treated cleft lip and palate patients. However, the potentially beneficial influence of the probiotic milk on the complex oral microflora justifies further studies with a larger group of volunteers. PMID- 23656595 TI - The relationship between erectile dysfunction and open urethroplasty: a systematic review and meta-analysis. AB - INTRODUCTION: Various urethroplasty techniques have been used to treat urethral stricture. Whether the patient erectile function is affected by this open surgery is still controversial. AIM: The aim of this study is to determine the relationship between erectile function and open urethroplasty. METHODS: A systematic review of the literature was performed using Medline, Embase, the Web of Science, and the Cochrane Library databases through October 2012 to identify articles published in any language that examined the effect of open urethroplasty on the risk of erectile dysfunction (ED). This meta-analysis was conducted according to the guidelines for the meta-analysis of observational studies in epidemiology. MAIN OUTCOME MEASURES: The incidence of ED after urethroplasty. RESULTS: This meta-analysis consisted of 23 cohort studies, which included 1,729 cases. No significant difference was noticed in patients with anterior urethral stricture before or after intervention (odds ratio [OR] = 0.86; 95% confidence interval [CI]: 0.52-1.40; P = 0.53). While statistical difference in the incidence of ED was revealed in patients before and after intervention for a posterior urethral (OR = 2.51; 95% CI: 1.82-3.45; P < 0.001), further comparisons demonstrated that most anterior urethroplasties did not have an obvious effect on patient erectile function. However, it seems that the incidence of ED was higher in the bulbar anastomosis group than in the oral graft urethroplasty group (OR = 0.32 95% CI: 0.11-0.93; P = 0.04). For the posterior urethroplasty, previous operative history did not show a strong relationship with ED. No statistically significant difference in the risk of ED was demonstrated comparing the posterior urethral reconstructive techniques included in this analysis. CONCLUSION: The adverse effect of urethroplasty itself on erectile function is limited, as more patients recover erectile function after urethral reconstruction. For anterior urethroplasty, bulbar anastomosis might cause a slightly higher incidence of ED than other operations. For posterior urethroplasty, trauma might be the main cause of ED. PMID- 23656596 TI - The informal European Parliamentary Working Group on Risk--history, remit, and future plans: a personal view. AB - On September 5, 2012 the inaugural meeting of the European Parliamentary Working Group on Risk (WGR) took place in the European Parliament in Brussels. It is chaired by Mrs. Julie Girling (U.K. Conservative), Member of the European Parliament (MEP), and involves some 10-12 other MEPs representing a wide array of European political parties from across the EU member state countries, including Sweden, the Netherlands, and Hungary. The WGR is supported by a small secretariat reporting directly to Julie Girling MEP. In this background article of WGR, I discuss the background to why WGR was set up, the remit of the committee, and some of its possible future plans. I do this very much in a personal capacity, having suggested the formation of the committee in the first place and persuaded Mrs. Girling to chair it. PMID- 23656597 TI - T cell-induced airway smooth muscle cell proliferation via the epidermal growth factor receptor. AB - Allergic asthma is a heterogeneous disease with no curative therapies. T cells infiltrate the airway smooth muscle (ASM) layer and may be implicated in airway remodeling and the increase of ASM mass, a cardinal feature of asthma. The mechanism by which CD4(+) T cells drive airway remodeling remains unknown. This study sought to determine the T cell-mediated mechanism of ASM cell proliferation. We hypothesized that CD4(+) T cells adhere to ASM cells via CD44, and induce ASM cell proliferation through the activation of the epidermal growth factor receptor (EGFR). A coculture model showed that the contact of antigen stimulated CD4(+) T cells with ASM cells induced high levels of EGFR ligand expression in CD4(+) T cells and the activation of matrix metalloproteinase (MMP) 9, required for the shedding of EGFR ligands. The inhibition of EGFR and MMP-9 prevented the increase of ASM cell proliferation after coculture. The hyaluronan receptor CD44 is the dominant mediator of the tight adherence of T cells to ASM and is colocalized with MMP-9 on the cell surface. Moreover, the neutralization of CD44 prevents ASM cell hyperplasia. These data provide a novel mechanism by which antigen-stimulated CD4(+) T cells induce the remodeling indicative of a direct trophic role for CD4(+) T cells. PMID- 23656598 TI - dsRNA sensing during viral infection: lessons from plants, worms, insects, and mammals. AB - Host defense systems often rely on direct and indirect pattern recognition to sense the presence of invading pathogens. Patterns can be molecules directly produced by the pathogen or indirectly generated by changes in host parameters as a consequence of infection. Viruses are intracellular pathogens that hijack the cellular machinery to synthesize their own molecules making direct recognition of viral molecules a great challenge. Antiviral systems in prokaryotes and eukaryotes commonly exploit aberrant nucleic acid sensing to recognize virus infection as host and viral nucleic acid metabolism can greatly differ. Indeed, the generation of dsRNA is often associated with viral infection. In this review, we discuss current knowledge on the mechanisms of viral dsRNA sensing utilized by 2 important antiviral defense systems, RNA interference (RNAi) and the vertebrate immune system. The major viral sensors of the vertebrate immune systems are RIG like receptors, while RNAi pathways depend on Dicer proteins. These 2 families of sensors share a similar helicase domain with high specificity for dsRNA, which is necessary, but not sufficient for efficient recognition by these receptors. Additional intrinsic features to the dsRNA molecule are also necessary for activation of antiviral systems. Studies utilizing synthetic ligands, in vitro biochemistry and reporter systems have greatly helped increase our knowledge on intrinsic features of dsRNA recognition. However, characteristics such as subcellular localization are extrinsic to the dsRNA itself, but certainly influence the recognition in vivo. Thus, mechanisms of viral dsRNA recognition must address how cellular sensors are recruited to nucleic acids or vice versa. Accessory proteins are likely important for in vivo recognition of extrinsic features of viral RNA, but have mostly remained undiscovered due to the limitations of previous strategies. Hence, the identification of novel components of antiviral systems must take into account the complexities involved in viral recognition in vivo. PMID- 23656599 TI - Potential prognostic value of intracellular cytokine detection by flow cytometry in pulmonary sarcoidosis. AB - In pulmonary sarcoidosis, differential cytokine production in the lungs could be related to variable prognosis of patients at different stages of disease. Twenty patients with pulmonary sarcoidosis (10 at radiographic stage I and 10 at stages II-IV), as well as 10 age-matched healthy volunteers participated in the study. A 4-colour flow cytometric technique was used to measure interferon-gamma (IFN gamma), interleukin (IL)-2, tumour necrosis factor-alpha (TNF-alpha), IL-4, and IL-13 production in phorbol myristate acetate (PMA)/ionomycin-stimulated CD4+ and CD8+ T cells from bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) of patients, and PB of control subjects. CD4+ T cells from patients showed higher expression of IFN-gamma in BALF than in PB. Significant correlations were observed between the percentages of BALF CD4+ and CD8+ T cells expressing intracellular IFN-gamma, IL-2, and TNF-alpha. Stage I patients had lower percentages of IFN-gamma-producing CD4+ and CD8+ T cells, as well as TNF-alpha producing CD8+ T cells, in BALF (but not in PB) than stage II-IV patients. A decreased TH1 and TC1 response was demonstrated in BALF of patients at stage I of disease, which could explain their anticipated better prognosis. PMID- 23656600 TI - Evaporation kinetics of sessile water droplets on micropillared superhydrophobic surfaces. AB - Evaporation modes and kinetics of sessile droplets of water on micropillared superhydrophobic surfaces are experimentally investigated. The results show that a constant contact radius (CCR) mode and a constant contact angle (CCA) mode are two dominating evaporation modes during droplet evaporation on the superhydrophobic surfaces. With the decrease in the solid fraction of the superhydrophobic surfaces, the duration of a CCR mode is reduced and that of a CCA mode is increased. Compared to Rowan's kinetic model, which is based on the vapor diffusion across the droplet boundary, the change in a contact angle in a CCR (pinned) mode shows a remarkable deviation, decreasing at a slower rate on the superhydrophobic surfaces with less-solid fractions. In a CCA (receding) mode, the change in a contact radius agrees well with the theoretical expectation, and the receding speed is slower on the superhydrophobic surfaces with lower solid fractions. The discrepancy between experimental results and Rowan's model is attributed to the initial large contact angle of a droplet on superhydrophobic surfaces. The droplet geometry with a large contact angle results in a narrow wedge region of air along the contact boundary, where the liquid-vapor diffusion is significantly restricted. Such an effect becomes minor as the evaporation proceeds with the decrease in a contact angle. In both the CCR and CCA modes, the evaporative mass transfer shows the linear relationship between mass(2/3) and evaporation time. However, the evaporation rate is slower on the superhydrophobic surfaces, which is more significant on the surfaces with lower solid fractions. As a result, the superhydrophobic surfaces slow down the drying process of a sessile droplet on them. PMID- 23656601 TI - The effects of exercise therapy for the improvement of jaw movement and psychological intervention to reduce parafunctional activities on chronic pain in the craniocervical region. AB - PURPOSE: Apparent organic abnormalities are sometimes not identified among patients suffering from chronic pain in the craniocervical region. In some cases, parafunctional activities (PAs) are recognized. PAs are nonfunctional oromandibular activities that include jaw clenching and bruxism, but are considered as factors that contribute to craniomandibular disorders (CMDs). It is now recognized that PAs and CMDs influence musculoskeletal conditions of the upper quarter. Exercise therapy (ET) to improve jaw movement and psychological intervention (PI) to reduce PAs are useful for PAs and CMDs. We hypothesized that ET and PI would be effective for craniocervical pain without organic abnormalities. METHODS: Thirty-nine subjects suffering from craniocervical chronic pain were allocated into 3 groups: The control group received only pharmacological treatment; the ET group received jaw movement exercise (JME); and the ET-PI group received JME and PI. Pain and jaw movement were evaluated using a numerical rating scale (NRS). RESULTS: After interventions, the NRS scores were significantly lower in the ET-PI group, compared with those in the other groups. Jaw movement improved 100% in the ET group, 92% in the ET-PI group, and 0% in the control group. CONCLUSION: A combination of jaw exercise and psychological intervention to reduce parafunctional activities is more effective than jaw exercise alone for the improvement of craniocervical pain without apparent organic abnormalities. PMID- 23656602 TI - Men's experiences of sexuality after cancer: a material discursive intra-psychic approach. AB - Men can experience significant changes to their sexuality following the onset of cancer. However, research on men's sexuality post-cancer has focused almost exclusively on those with prostate and testicular cancer, despite evidence that the diagnosis and treatment for most cancers can impact on men's sexuality. This Australian qualitative study explores the experiences of changes to sexuality for 21 men across a range of cancer types and stages, sexual orientations and relationship contexts. Semi-structured interviews were analysed with theoretical thematic analysis guided by a material discursive intra-psychic approach, recognising the materiality of sexual changes, men's intrapsychic experience of such changes within a relational context and the influence of the discursive construction of masculine sexuality. Material changes included erectile difficulty, decreased desire, and difficulty with orgasm. The use of medical aids to minimise the impact of erectile difficulties was shaped by discursive constructions of 'normal' masculine sexuality. The majority of men reported accepting the changes to their sexuality post-cancer and normalised them as part of the natural ageing process. Men's relationship status and context played a key role managing the changes to their sexuality. We conclude by discussing the implications for clinical practice. PMID- 23656603 TI - Real-time PCR-based quantification of Eimeria genomes: a method to outweigh underestimation of genome numbers due to PCR inhibition. AB - Eimeria species parasites can cause the disease coccidiosis in all livestock species, most notably poultry. Traditional diagnostics such as faecal microscopy have now been supplemented by molecular assays including genus-specific and species-specific quantitative polymerase chain reaction (qPCR), although DNA extracted from faecal samples is commonly affected by PCR inhibition. This was confirmed when genomic DNA extracted from chicken faeces inhibited the threshold cycle value of internal positive control (IPC) DNA amplification by 15.33%. Hence, the objective of the present study was to use IPC qPCR to determine PCR inhibition in a series of experimental samples and use the increase in IPC qPCR threshold cycle value as an individual (sample-specific) correction factor for an established 5S rDNA qPCR used to estimate total Eimeria genome numbers. IPC corrected genome counts were correlated with conventional oocyst per gram counts and compared with non-corrected counts, revealing a 0.1769 increase in correlation coefficient to outweigh underestimation of oocyst counts. Though the sample size used in this study is small, this limitation would be offset by the sample-specific correction factor determined using the IPC along with each sample. PMID- 23656604 TI - The distance between the carina and the distal margin of the right upper lobe orifice measured by computerised tomography as a guide to right-sided double lumen endobronchial tube use. AB - Our hypothesis was that the incidence of malposition of a right-sided double lumen endobronchial tube and right upper lobe collapse may increase when the distance between the carina and the distal margin of the right upper lobe orifice is less than 23 mm, measured from a computerised tomography scan. A total of 76 patients undergoing left-sided thoracic surgery were enrolled. Patients with a measured distance of <23 mm (n=38) were compared with age-, sex- and body mass index-matched patients with a distance>=23 mm (n=38). Right-sided double-lumen endobronchial tubes were used universally. We monitored endobronchial tube malposition and incidence of right upper lobe collapse throughout surgery. There was a significantly higher incidence of bronchial cuff herniation in patients with a distance<23 mm in both the supine position and the lateral decubitus position (p<0.001). The incidence of intra-operative malposition in the <23 mm group was also significantly higher than in the >=23 mm group (31 (82%) vs 8 (21%), respectively, p<0.001). Right upper lobe collapse was detected postoperatively in five patients (13%) in the distance<23 mm group, compared to none in the >=23 mm group. We recommend that the distance between the carina and the distal margin of the right upper lobe bronchus should be routinely measured on the pre-operative computerised tomography scan, and if it is <23 mm, consideration should be given to using a left-sided endobronchial double-lumen tube in preference to a right-sided one. PMID- 23656605 TI - Dendritic cells and their role in periodontal disease. AB - T cells, particularly CD4+ T cells, play a central role in both progression and control of periodontal disease, whereas the contribution of the various CD4+ T helper subsets to periodontal destruction remains controversial, the activation, and regulation of these cells is orchestrated by dendritic cells. As sentinels of the oral mucosa, dendritic cells encounter and capture oral microbes, then migrate to the lymph node where they regulate the differentiation of CD4+ T cells. It is thus clear that dendritic cells are of major importance in the course of periodontitis, as they hold the immunological cues delivered by the pathogen and the surrounding environment, allowing them to induce destructive immunity. In recent years, advanced immunological techniques and new mouse models have facilitated in vivo studies that have provided new insights into the developmental and functional aspects of dendritic cells. This progress has also benefited the characterization of oral dendritic cells, as well as to their function in periodontitis. Here, we provide an overview of the various gingival dendritic cell subsets and their distribution, while focusing on their role in periodontal bone loss. PMID- 23656606 TI - Implementation of geriatric acute care best practices: initial results of the NICHE SITE self-evaluation. AB - Nurses Improving Care of Healthsystem Elders (NICHE) provides hospitals with tools and resources to implement an initiative to improve health outcomes in older adults and their families. Beginning in 2011, members have engaged in a process of program self-evaluation, designed to evaluate internal progress toward developing, sustaining, and disseminating NICHE. This manuscript describes the NICHE Site Self-evaluation and reports the inaugural self-evaluation data in 180 North American hospitals. NICHE members evaluate their program utilizing the following dimensions of a geriatric acute care program: guiding principles, organizational structures, leadership, geriatric staff competence, interdisciplinary resources and processes, patient- and family-centered approaches, environment of care, and quality metrics. The majority of NICHE sites were at the progressive implementation level (n = 100, 55.6%), having implemented interdisciplinary geriatric education and the geriatric resource nurse (GRN) model on at least one unit; 29% have implemented the GRN model on multiple units, including specialty areas. Bed size, teaching status, and Magnet status were not associated with level of implementation, suggesting that NICHE implementation can be successful in a variety of settings and communities. PMID- 23656608 TI - Excimer laser surface ablation: a review of recent literature. AB - The aim was to review the recently published literature on excimer laser surface ablation procedures, including photorefractive keratectomy (PRK), laser sub epithelial keratomileusis (LASEK), microkeratome-assisted PRK (epi-LASIK) and trans-epithelial (laser-assisted) PRK, to help elucidate where and how surface ablation may best fit into current refractive surgical practice. The emphasis was on publications within the last three years and included systemic reviews, meta analyses and randomised controlled trials. Where such evidence did not exist, selective large series cohort studies, case-controlled studies and case series with follow-up preferably greater than six months were examined and included. Refractive and visual outcomes are excellent and comparable to those after LASIK even in complex cases after previous corneal surgery. Indeed, surface ablation combined with corneal collagen cross-linking may be used in selected eyes with biomechanical instability, where LASIK is contraindicated. In addition, there is evidence to suggest that there may be less induction of higher order aberrations with surface techniques. Long-term stability and safety appear to be extremely satisfactory. The literature supports the use of modern excimer laser surface treatments, with outcomes comparable to those after LASIK and evidence of less induction of higher-order aberrations. Follow-up studies at 10 to 20 years indicate excellent stability and safety. PMID- 23656607 TI - The microbiome of chronic rhinosinusitis: culture, molecular diagnostics and biofilm detection. AB - BACKGROUND: Bacteria and fungi are believed to influence mucosal inflammation in chronic rhinosinusitis (CRS). However their presence and relationship to disease is debated. This study used multiple detection methods to compare microbial diversity and microbial abundance in healthy and diseased sinonasal mucosa. The utility of contemporary detection methods is also examined. METHODS: Sinonasal mucosa was analyzed from 38 CRS and 6 controls. Bacterial and fungal analysis was performed using conventional culture, molecular diagnostics (polymerase chain reaction coupled with electrospray ionization time-of-flight mass spectrometry) and fluorescence in situ hybridization. RESULTS: Microbes were detected in all samples, including controls, and were often polymicrobial. 33 different bacterial species were detected in CRS, 5 in control patients, with frequent recovery of anaerobes. Staphylococcus aureus and Propionibacterium acnes were the most common organisms in CRS and controls, respectively. Using a model organism, FISH had a sensitivity of 78%, and a specificity of 93%. Many species were detected in both CRS and controls however, microbial abundance was associated with disease manifestation. CONCLUSIONS: This study highlights some cornerstones of microbial variations in healthy and diseased paranasal sinuses. Whilst the healthy sinus is clearly not sterile, it appears prevalence and abundance of organisms is critical in determining disease. Evidence from high-sensitivity techniques, limits the role of fungi in CRS to a small group of patients. Comparison with molecular analysis suggests that the detection threshold of FISH and culture is related to organism abundance and, furthermore, culture tends to select for rapidly growing organisms. PMID- 23656609 TI - Synthesis of benzoxazoles via an amine-catalyzed [4 + 1] annulation. AB - An unprecedented simple pyrrolidine catalyzed [4 + 1] annulation reaction of ynals with N-protected-2-aminophenols is reported. The utilization of the unique property and reactivity of the C=C triple bond in ynals leads to two consecutive conjugate addition reactions at the same beta-position with pyrrolidine via iminium activation. The powerful cascade process affords a new alternative approach to biologically and synthetically important benzoxazoles in high yields (83-95%). PMID- 23656610 TI - Mutations in exon 2 of TBX3 are rare in common human tumors. PMID- 23656611 TI - Basal cell carcinoma: a paradigm for targeted therapies. AB - INTRODUCTION: Basal cell carcinoma (BCC) is the most frequent cancer with increasing incidence over the last decades. Standard of care is surgical excision, upon which complete tumour clearance is achieved in most cases. However, a small subgroup of patients will have remnants of disease post-excision and require further treatment options. Over 90% of all BCCs carry a mutation in PTCH 1 or SMO, two conducting proteins of the Hedgehog pathway (Hh). Therefore, inhibition of the Hh pathway is a promising option for systemic first-line therapy. Vismodegib was the first developed of these small molecules, which was approved by the FDA in January 2012. AREAS COVERED: The authors review current treatment modalities for BCC and discuss current developments in pharmacological therapy. The current literature including meta-analyses, the Cochrane database and registered as well as completed randomized controlled trials. EXPERT OPINION: Hh inhibitors are a new promising treatment option for patients with advanced or metastatic BCC. Phase I and II clinical trials with the Hh inhibitor, vismodegib, showed a significant reduction in tumour size and appearance of new tumours with relatively good tolerability. Nevertheless, further investigation on new molecules and the effectiveness of an intermittent dosing regimen is necessary. PMID- 23656612 TI - Cardiac defense in response to imminent threat in women with multiple trauma and severe PTSD. AB - Posttraumatic stress disorder (PTSD) arises as a long-term result of exposure to trauma and brings with it an altered autonomic response to potentially threatening stimuli. The present study investigates the dynamic sequence of cardiac defense in women with and without PTSD. An acoustic noise of 0.5-s duration and 105 dB was used to elicit the cardiac defense reaction. The stimulus was repeated three times. Within the PTSD sample, respondents who suffered from more severe PTSD showed a higher heart rate at rest, a higher baseline, and a greater response. Compared to the healthy subjects, the PTSD group showed an elevated heart rate from 6 s to 25 s following the presentation of the first stimulus. There was evidence of habituation in the PTSD group and hints of differential effects on the cardiac defense of traumatic experiences with a high proximity of danger. PMID- 23656613 TI - Literature review on production process to obtain extra virgin olive oil enriched in bioactive compounds. Potential use of byproducts as alternative sources of polyphenols. AB - This review describes the olive oil production process to obtain extra virgin olive oil (EVOO) enriched in polyphenol and byproducts generated as sources of antioxidants. EVOO is obtained exclusively by mechanical and physical processes including collecting, washing, and crushing of olives, malaxation of olive paste, centrifugation, storage, and filtration. The effect of each step is discussed to minimize losses of polyphenols from large quantities of wastes. Phenolic compounds including phenolic acids, alcohols, secoiridoids, lignans, and flavonoids are characterized in olive oil mill wastewater, olive pomace, storage byproducts, and filter cake. Different industrial pilot plant processes are developed to recover phenolic compounds from olive oil byproducts with antioxidant and bioactive properties. The technological information compiled in this review will help olive oil producers to improve EVOO quality and establish new processes to obtain valuable extracts enriched in polyphenols from byproducts with food ingredient applications. PMID- 23656615 TI - Early prosthetic hip joint infection treated with debridement, prosthesis retention and biofilm-active antibiotics: functional outcomes, quality of life and complications. AB - BACKGROUND: Patients treated for early prosthetic joint infection (PJI) with surgical debridement, prosthesis retention and biofilm-active antibiotics, such as rifampicin or fluoroquinolones have a rate of successful infection eradication that is similar to patients treated with the traditional approach of prosthesis exchange. It is therefore important to consider other outcomes after PJI treatment that may influence management decisions, such as function, quality of life (QOL) and treatment-associated complications. AIMS: To describe rates of successful treatment for patients with PJI undergoing surgical debridement, prosthesis retention and biofilm-active antibiotics and compare their functional outcomes, QOL and complication rates to patients without PJI. METHODS: Nineteen patients treated for PJI after hip arthroplasty with debridement, prosthesis retention and biofilm-active antibiotics were matched to 76 controls who underwent hip arthroplasty with no infection. RESULTS: Cumulative survival free from treatment failure at 2 years was 88% (95% confidence interval, 59-97%). PJI cases had significant improvement from pre-arthroplasty to 12-months post arthroplasty in function according to Harris Hip Score and QOL according to the 12-item Short Form Health Survey Physical Component Summary. There was no significant difference in the improvement between controls and cases. PJI was not a risk factor for poor function or QOL. Medical complications occurred more frequently in cases (6/19 (32%)) than controls (9/76 (12%); P = 0.04), with this difference being accounted for by drug reactions. Surgical complications were the same in the two groups. CONCLUSIONS: Treatment of PJI with debridement, prosthesis retention and biofilm-active antibiotics is successful, well tolerated and results in significant improvements in function and QOL, which are similar to patients without PJI. PMID- 23656616 TI - Localized versus centralized nurse-delivered telephone services for people in follow up for cancer: opinions of cancer clinicians. AB - AIM: Telephone-delivered supportive care interventions hold potential as a sustainable, low-resource option to improve patients' outcomes. Such interventions may be delivered centrally or locally. There is limited information about clinicians' preferences for these alternative models of service delivery. This study investigated the views of cancer clinicians who had experience of a centralized model. METHODS: Interviews were conducted with 16 surgeons and nurses across New South Wales, Australia, who had participated in a trial of a centralized telephone-based supportive care intervention. Content analysis was conducted. Data were analyzed inductively and responses organized into categories and then higher order themes. RESULTS: All clinicians valued the role of telephone follow ups as they would allow patients to ask questions and receive reassurance. Clinicians believed these services could reduce hospital presentations and provide equity and standardized care, particularly to those outside metropolitan centers. Although clinicians accepted a centralized model of delivery would be cheaper, most (n = 15) indicated a preference for local delivery. This preference was based on the perception that local nurses would have superior knowledge of the local context. Despite the improved feasibility of a telephone-only service, clinicians felt some face-to-face contact with patients was essential. Key at-risk groups to target were identified. Clinicians acknowledged there could be overlap with cancer nurses locally requiring local decisions about implementation. CONCLUSION: There was clear endorsement of additional telephone support with a preference for a local model of service delivery. The limited acceptability of centralized telephone-based supportive care interventions may restrict their uptake. PMID- 23656617 TI - Characterization of low-temperature cofired ceramic tiles as platforms for gas chromatographic separations. AB - A gas chromatography (GC) column is fabricated within a low-temperature cofired ceramic (LTCC) tile, and its analytical properties are characterized. By using a dual-spiral design, a 100 MUm wide square channel up to 15 m in length is produced within an 11 cm * 5.5 cm LTCC tile. The channel is dynamically coated with an OV-101 stationary phase that is cross-linked with dicumyl peroxide. While the uncoated LTCC tiles were able to separate a mixture of n-alkanes, the peak shapes were broad (base width of ~2 min) and tailing. In contrast to this, the coated LTCC tiles produced sharp (base width of ~8-10 s), symmetrical, well resolved peaks for the same analytes. By using a 7.5 m long channel, about 15,000 plates were obtained for a dodecane test analyte. Further, the coated LTCC tiles were found to produce plate heights that were about 3-fold smaller than those obtained from a conventional capillary GC column of similar length, dimension, and coating operated under the same conditions. As a result, test analyte separations were slightly improved in the LTCC tiles, and their overall performance fared well. In terms of temperature programming, it was found that a series of n-alkanes separated on the LTCC tile provided a cumulative peak capacity of around 54 peaks when using C8 to C13 as analyte markers. Results indicate that LTCC tiles provide a viable and useful alternative platform for performing good quality GC separations. PMID- 23656622 TI - The genomic landscape of chronic lymphocytic leukemia: clinical implications. AB - A precise understanding of the genomic and epigenomic features of chronic lymphocytic leukemia (CLL) may benefit the study of the disease's staging and treatment. While recent reports have shed some light on these aspects, several challenges need to be addressed before translating this research into clinical practice. Thus, even the best candidate driver genes display low mutational rates compared to other tumors. This means that a large percentage of cases do not display clear tumor-driving point mutations, or show candidate driving point mutations with no obvious biochemical relationship to the more frequently mutated genes. This genomic landscape probably reflects either an unknown underlying biochemical mechanism playing a key role in CLL or multiple biochemical pathways independently driving the development of this tumor. The elucidation of either scenario will have important consequences on the clinical management of CLL. Herein, we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterize the underlying biochemical events that drive this disease. PMID- 23656623 TI - Phosphodiesterase-4 inhibition augments human lung fibroblast vascular endothelial growth factor production induced by prostaglandin E2. AB - Lung fibroblasts are believed to be a major source of vascular endothelial growth factor (VEGF), which supports the survival of lung endothelial cells and modulates the maintenance of the pulmonary microvasculature. VEGF has been related to the pathogenesis of lung diseases, including chronic obstructive pulmonary disease (COPD). Prostaglandin E2 (PGE2) stimulates VEGF production from lung fibroblasts via the E-prostanoid (EP)-2 receptor. The EP2 signaling pathway uses cyclic adenosine monophosphate (cAMP) as a second messenger, and cAMP is degraded by phosphodiesterases (PDEs). This study investigates whether phosphodiesterase inhibition modulates the human lung fibroblast VEGF production induced by PGE2. Human fetal lung fibroblasts were cultured with PGE2 and PDE inhibitors. The PDE4 inhibitors roflumilast, roflumilast N-oxide, and rolipram with PGE2 increased VEGF release, as quantified in supernatant media by ELISA. In contrast, PDE3, PDE5, and PDE7 inhibitors did not affect VEGF release. Roflumilast increased VEGF release with either an EP2 or an EP4 agonist. Roflumilast augmented the cytosolic cAMP levels induced by PGE2 and VEGF release with other agents that use the cAMP signaling pathway. Roflumilast-augmented VEGF release was completely inhibited by a protein kinase A (PKA) inhibitor. Roflumilast with PGE2 increased VEGF mRNA levels, and the blockade of mRNA synthesis inhibited the augmented VEGF release. The stimulatory effect of roflumilast on VEGF release was replicated using primary healthy and COPD lung fibroblasts. These findings demonstrate that PDE4 inhibition can modulate human lung fibroblast VEGF release by PGE2 acting through the EP2 and EP4 receptor cAMP/PKA signaling pathway. Through this action, PDE4 inhibitors such as roflumilast could contribute to the survival of lung endothelial cells. PMID- 23656624 TI - Applying representational state transfer (REST) architecture to archetype-based electronic health record systems. AB - BACKGROUND: The openEHR project and the closely related ISO 13606 standard have defined structures supporting the content of Electronic Health Records (EHRs). However, there is not yet any finalized openEHR specification of a service interface to aid application developers in creating, accessing, and storing the EHR content.The aim of this paper is to explore how the Representational State Transfer (REST) architectural style can be used as a basis for a platform independent, HTTP-based openEHR service interface. Associated benefits and tradeoffs of such a design are also explored. RESULTS: The main contribution is the formalization of the openEHR storage, retrieval, and version-handling semantics and related services into an implementable HTTP-based service interface. The modular design makes it possible to prototype, test, replicate, distribute, cache, and load-balance the system using ordinary web technology. Other contributions are approaches to query and retrieval of the EHR content that takes caching, logging, and distribution into account. Triggering on EHR change events is also explored.A final contribution is an open source openEHR implementation using the above-mentioned approaches to create LiU EEE, an educational EHR environment intended to help newcomers and developers experiment with and learn about the archetype-based EHR approach and enable rapid prototyping. CONCLUSIONS: Using REST addressed many architectural concerns in a successful way, but an additional messaging component was needed to address some architectural aspects. Many of our approaches are likely of value to other archetype-based EHR implementations and may contribute to associated service model specifications. PMID- 23656625 TI - Pilot study of radical hysterectomy versus radical trachelectomy on sexual distress. AB - Radical trachelectomy, which leaves the uterus intact, has emerged as a desirable surgical option for eligible women with early-stage cervical cancer who wish to preserve fertility. The available data suggest excellent obstetrical outcomes with radical trachelectomy, and no differences in sexual responding between radical trachelectomy and radical hysterectomy. There is a need to examine the effect of radical hysterectomy on sexual distress given that it is distinct from sexual function. Participants were 34 women diagnosed with early-stage cervical cancer. The authors report 1-month postsurgery data for 29 women (radical hysterectomy group: n = 17, M age = 41.8 years; radical trachelectomy group: n = 12, M age = 31.8 years), and 6-month follow-up data on 26 women. Whereas both groups experienced an increase in sex-related distress immediately after surgery, distress continued to increase 6 months after surgery for the radical hysterectomy group but decreased in the radical trachelectomy group. There were no between-group differences in mood, anxiety, or general measures of health. The decrease in sex-related distress in the radical trachelectomy but not in the radical hysterectomy group suggests that the preservation of fertility may have attenuated sex-related distress. Care providers should counsel women exploring surgical options for cervical cancer about potential sex distress-related sequelae. PMID- 23656626 TI - Reduction of the use of antimicrobial drugs following the rapid detection of Streptococcus agalactiae in the vagina at delivery by real-time PCR assay. AB - OBJECTIVE: To assess whether the determination of the presence of group B streptococci (GBS) in the vagina using a rapid polymerase chain reaction (PCR) assay at delivery was able to spare useless antimicrobial treatments, as compared with conventional culture at 34-38 weeks of gestation. DESIGN: Practical evaluation and prospective cost-effectiveness analysis. SETTING: A university hospital in France. POPULATION: A cohort of 225 women in labour at the University Hospital of Saint-Etienne. METHODS: Each woman had a conventional culture performed at 34-38 weeks of gestation. At the beginning of labour, two vaginal swabs were sampled for rapid PCR testing and culture. The decision to prescribe a prophylactic antimicrobial treatment or not was taken according to the result of the PCR test. A comparative cost-effectiveness analysis of the two diagnostic strategies was carried out. MAIN OUTCOME MEASURES: Number of women receiving inadequate prophylactic antimicrobial drugs following each testing strategy, costs of PCR testing and culture, frequency of vaginal GBS, and diagnostic performance of the PCR test at delivery. RESULTS: The percentage of unnecessarily treated women was significantly reduced using the rapid test versus conventional culture (4.5 and 13.6%, respectively; P < 0.001). The rate of vaginal GBS at delivery was 12.5%. The incremental cost-effectiveness ratio (ICER) for each inadequate management avoided was ?36 and ?173 from the point of view of the healthcare system and hospital, respectively. CONCLUSIONS: The PCR assay reduced the number of inadequate antimicrobial treatments aimed to prevent the early onset of GBS disease. However, this strategy generates extra costs that must be put into balance with its clinical benefits. PMID- 23656627 TI - Ethnicity and children's diets: the practices and perceptions of mothers in two minority ethnic groups in Denmark. AB - This study explores concerns and dilemmas connected with diet, health and child feeding in families with ethnic minority background. The aim is to contribute to better targeting of dietary advice to ethnic minority parents in Denmark. Four focus group interviews were carried out with mothers of children between 4 months and 2 and a half years who were descendants of Turkish or Pakistani immigrants. The focus groups investigated: (1) everyday feeding practices; (2) values and concerns behind food choice; (3) social and cultural norms influencing feeding and eating practices; (4) experienced dilemmas in dietary change; and (5) sources of nutritional advice. Public health authorities in Denmark tend to link diet related health problems among ethnic minority populations with their ethnic identity, dichotomising ethnic and Danish dietary habits. This may overlook values and concerns other than those related to ethnicity that are sometimes more important in determining food habits. The present study found that child-feeding practices were shaped by two main aims: (1) securing and improving child health; and (2) ensuring multi-cultural eating competence in children. The results confirm that ethnic distinctions do matter in the concerns and dilemmas mothers experience when feeding their children, but they also challenge the health authorities' reliance on dichotomies in promoting health among immigrant families. The participants' ethnic self-identification through food practices did not refer primarily to the birthplaces of their parents. Rather, it was context dependent and directed simultaneously towards majority and minority culture. PMID- 23656628 TI - On how to deal with deep uncertainties in a risk assessment and management context. AB - Recently, several authors have presented interesting contributions on how to meet deep or severe uncertainties in a risk analysis setting. In this article, we provide some reflections on some of the foundational pillars that this work is based on, including the meaning of concepts such as deep uncertainty, known probabilities, and correct models, the aim being to contribute to a strengthening of the scientific platform of the work, as well as providing new insights on how to best implement management policies meeting these uncertainties. We also provide perspectives on the boundaries and limitations of analytical approaches for supporting decision making in cases of deep uncertainties. A main conclusion of the article is that deep uncertainties call for managerial review and judgment that sees beyond the analytical frameworks studied in risk assessment and risk management contexts, including those now often suggested to be used, such as robust optimization techniques. This managerial review and judgment should be seen as a basic element of the risk management. PMID- 23656629 TI - Glycoprotein nonmetastatic B as a prognostic indicator in small cell lung cancer. AB - Glycoprotein nonmetastatic melanoma B (GPNMB) is a type I transmembrane glycoprotein which is overexpressed in many tumors and seems to play a critical role in metastasis of malignant tumors. The purpose of this study was to determine GPNMB expression in small cell lung cancer (SCLC) and analyze the prognostic value in patients with SCLC. A total of 132 cases of SCLCs were analyzed immunohistochemically on tissue microarrays (TMAs). Patients were divided into weak-positive and strong-positive GPNMB groups. In addition, serum GPNMB was evaluated by enzyme-linked immunosorbent assay (ELISA). The average serum GPNMB concentration was 1054.15 +/- 363.71 pg/mL in the weak-positive group, 2611.52 +/- 457.57 pg/mL in the strong-positive group, and 427.61 +/- 273.9 pg/mL in the control. The strong-positive group showed significantly higher serum GPNMB levels than the weak-positive group and healthy control (p < 0.01). Overall survival in the weak-positive GPNMB group was significantly longer than in the strong-positive group (27 months vs 15 months, p < 0.01). These results suggest that the expression of GPNMB may be useful as a prognostic indicator in patients with SCLC. PMID- 23656631 TI - Self-report and behavioral measures of reward sensitivity predict the feedback negativity. AB - Rewards are integral to learning associations that aid in survival. The feedback negativity (FN), an event-related potential that differentiates outcomes indicating monetary losses versus gains, has recently emerged as a possible neural measure of reward processing. If this view is correct, then the FN should correlate with measures of reward sensitivity in other domains, although few studies have investigated this question. In the current study, 46 participants completed a self-report measure of reward responsiveness, a signal detection task that generated a behavioral measure of reward sensitivity, and a gambling task that elicited an FN. Consistent with the view that the FN reflects reward-related neural activity, a larger FN correlated with increased behavioral and self-report measures of sensitivity to reward. PMID- 23656632 TI - From diminished men to conditionally masculine: sexuality and Australian men and adolescent boys with intellectual disability. AB - Men and boys with intellectual disability represent a unique group who have hitherto been overlooked by researchers and theorists exploring men and masculinities. Qualitative data from an Australian ethnographic study focused on the sexual health needs of men and adolescent boys with moderate to profound intellectual disability. Findings suggest that masculinity for this group of men is more a biopsychosocial phenomenon than a social construct organised around heteronormative ideals. The conditional masculinity of the men participating in the study was based instead on a number of intrinsic and external factors, which are described in detail. PMID- 23656633 TI - Functional expression of amyloidogenic human stefins A and B in Pichia pastoris using codon optimization. AB - Complementary DNAs encoding human stefins A (HSA) and B (HSB) were synthesized using Pichia-preferred codons by overlap extension PCR. The full-length genes were ligated downstream of the glyceraldehyde-3-phosphate dehydrogenase promoter in the Pichia expression vector pGAPZalphaC and successfully expressed in Pichia pastoris strain X-33. Functional recombinant HSA and HSB proteins were purified from culture medium at yields of 121.3 +/- 13.5 (n = 3) and 95.4 +/- 4.1 (n = 3) mg/L, respectively. Using this expression strategy, we demonstrated that high levels of bioactive recombinant HSA and HSB can be produced by fermentation in P. pastoris. PMID- 23656634 TI - The assessment of risk factors for the Central/East African Genotype of chikungunya virus infections in the state of Kelantan: a case control study in Malaysia. AB - BACKGROUND: The aims of the study were to assess the risk factors in relation to cross border activities, exposure to mosquito bite and preventive measures taken.An outbreak of chikungunya virus (CHIKV) infection in Malaysia has been reported in Klang, Selangor (1998) and Bagan Panchor, Perak (2006). In 2009, CHIKV infection re-emerged in some states in Malaysia. It raises the possibilities that re-emergence is part of the epidemics in neighbouring countries or the disease is endemic in Malaysia. For this reason, A community based case control study was carried out in the state of Kelantan. METHODS: Prospective case finding was performed from June to December 2009. Those who presented with signs and symptoms of CHIKV infection were investigated. We designed a case control study to assess the risk factors. Assessment consisted of answering questions, undergoing a medical examination, and being tested for the presence of IgM antibodies to CHIKV. Descriptive epidemiological studies were conducted by reviewing both the national surveillance and laboratory data. Multivariable logistic regression analysis was performed to determine risk factors contributing to the illness. Cases were determined by positive to RT-PCR or serological for antibodies by IgM. CHIKV specificity was confirmed by DNA sequencing. RESULTS: There were 129 suspected cases and 176 controls. Among suspected cases, 54.4% were diagnosed to have CHIKV infection. Among the controls, 30.1% were found to be positive to serology for antibodies [IgM, 14.2% and IgG, 15.9%]. For analytic study and based on laboratory case definition, 95 were considered as cases and 123 as controls. Those who were positive to IgG were excluded. CHIKV infection affected all ages and mostly between 50-59 years old. Staying together in the same house with infected patients and working as rubber tappers were at a higher risk of infection. The usage of Mosquito coil insecticide had shown to be a significant protective factor. Most cases were treated as outpatient, only 7.5% needed hospitalization. The CHIKV infection was attributable to central/east African genotype CHIKV. CONCLUSIONS: In this study, cross border activity was not a significant risk factor although Thailand and Malaysia shared the same CHIKV genotype during the episode of infections. PMID- 23656635 TI - Cytologic appearance of retinal cells included in a fine-needle aspirate of a meningioma around the optic nerve of a dog. AB - A 6-year-old Wirehair Dachshund had a meningioma around the optic nerve that caused exophthalmos. A benign mesenchymal tumor was suspected based on the cytologic pattern of a fine-needle aspirate, and a meningioma was diagnosed by histopathologic examination. In addition to the meningioma cells, the cytologic smears included groups of cells from apparently 4 layers of normal retina. In particular, uniform rod-shaped structures in the cytologic sample could suggest rod-shaped bacteria, but these structures were identified as cylindrical outer segments of photoreceptor rod cells. Other retinal structures recognized included pigmented epithelial layer cells with their uniquely formed pigment granules, the characteristic bi-lobed, cleaved nuclei from the outer nuclear layer, and nerve tissue likely from the outer plexiform layer of the retina. PMID- 23656636 TI - The biopsychosocial processes in autism spectrum disorder. AB - BACKGROUND: Autism is a disorder characterized by pervasive social and communicative impairments, repetitive and stereotyped behaviors and restricted interests. Its causes and effects have been researched from various neurocognitive theoretical perspectives and with the aid of neuroimaging technology. We aimed to describe biopsychosocial processes characteristic of the Autism Spectrum Disorders. METHOD: Literature review using Medline and Scopus databases published between 2001 and 2011, with the keywords "autism", "theory of mind", "executive functions", "central coherence" and "fMRI". RESULTS: The studies found were plotted and organized into tables and an explanatory diagram of the main findings was produced. CONCLUSIONS: The most popular neurocognitive theories are still unable to fully explain the characteristics of the complications that autistic spectrum disorder causes to the quality of life of individuals living with autism. The association of clinical research and neuroimaging may contribute to a better understanding of the functioning of the brain affected by the disorder. PMID- 23656638 TI - Description of the Western Sydney and Nepean Blue Mountains local health districts' influenza prevention programme. AB - BACKGROUND: Influenza is a major cause of morbidity and mortality. In 2011, influenza vaccination was provided free for people at greatest risk of severe disease: people aged 65 years and over, Aboriginal Australians 15 years and older, pregnant women, and individuals aged 6 months and over who suffered chronic medical conditions. AIMS: To evaluate the Western Sydney and Nepean Blue Mountains Local Health District Influenza Prevention Program and to identify some of the enablers and barriers to vaccination in the hospital outpatient setting. METHODS: Western Sydney and Nepean Blue Mountains local health districts' influenza prevention programme provided influenza vaccine in hospital outpatient settings between 21 March 2011 and 30 June 2011. Accredited nurse immunisers vaccinated 2824 individuals and recorded their primary reason for vaccination. Nurse immunisers were interviewed to identify barriers and enablers to influenza immunisation uptake. RESULTS: Two thousand, eight hundred and twenty-four doses of influenza vaccine were administered to people at high risk of influenza in four hospitals in the region: two tertiary facilities and two district hospitals. The primary indication for vaccination was chronic disease in 50% and pregnancy in 37%. Estimated direct cost of the programme was $19 per dose. CONCLUSIONS: A hospital-based influenza vaccination programme can be an effective way to improve influenza vaccination rates among specific population groups at high risk of severe disease with influenza, particularly pregnant women and those younger than 65 years with a chronic medical condition. PMID- 23656637 TI - Genetic variability in the rat Aplec C-type lectin gene cluster regulates lymphocyte trafficking and motor neuron survival after traumatic nerve root injury. AB - BACKGROUND: C-type lectin (CLEC) receptors are important for initiating and shaping immune responses; however, their role in inflammatory reactions in the central nervous system after traumatic injuries is not known. The antigen presenting lectin-like receptor gene complex (Aplec) contains a few CLEC genes, which differ genetically among inbred rat strains. It was originally thought to be a region that regulates susceptibility to autoimmune arthritis, autoimmune neuroinflammation and infection. METHODS: The inbred rat strains DA and PVG differ substantially in degree of spinal cord motor neuron death following ventral root avulsion (VRA), which is a reproducible model of localized nerve root injury. A large F2 (DAxPVG) intercross was bred and genotyped after which global expressional profiling was performed on spinal cords from F2 rats subjected to VRA. A congenic strain, Aplec, created by transferring a small PVG segment containing only seven genes, all C-type lectins, ontoDA background, was used for further experiments together with the parental strains. RESULTS: Global expressional profiling of F2 (DAxPVG) spinal cords after VRA and genome-wide eQTL mapping identified a strong cis-regulated difference in the expression of Clec4a3 (Dcir3), a C-type lectin gene that is a part of the Aplec cluster. Second, we demonstrate significantly improved motor neuron survival and also increased T cell infiltration into the spinal cord of congenic rats carrying Aplec from PVG on DA background compared to the parental DA strain. In vitro studies demonstrate that the Aplec genes are expressed on microglia and upregulated upon inflammatory stimuli. However, there were no differences in expression of general microglial activation markers between Aplec and parental DA rats, suggesting that the Aplec genes are involved in the signaling events rather than the primary activation of microglia occurring upon nerve root injury. CONCLUSIONS: In summary, we demonstrate that a genetic variation in Aplec occurring among inbred strains regulates both survival of axotomized motor neurons and the degree of lymphocyte infiltration. These results demonstrate a hitherto unknown role for CLECs for intercellular communication that occurs after damage to the nervous system, which is relevant for neuronal survival. PMID- 23656639 TI - Energy intakes of US children and adults by food purchase location and by specific food source. AB - BACKGROUND: To our knowledge, no studies have examined energy intakes by food purchase location and food source using a representative sample of US children, adolescents and adults. Evaluations of purchase location and food sources of energy may inform public health policy. METHODS: Analyses were based on the first day of 24-hour recall for 22,852 persons in the 2003-4, 2005-6, and 2007-8 National Health and Nutrition Examination Surveys (NHANES). The most common food purchase locations were stores (grocery store, supermarket, convenience store, or specialty store), quick-service restaurants/pizza (QSR), full-service restaurants (FSR), school cafeterias, or food from someone else/gifts. Specific food sources of energy were identified using the National Cancer Institute aggregation scheme. Separate analyses were conducted for children ages 6-11y, adolescents ages 12 19y, and adults aged 20-50y and >=51y. RESULTS: Stores (grocery, convenience, and specialty) were the food purchase locations for between 63.3% and 70.3% of dietary energy in the US diet. Restaurants provided between 16.9% and 26.3% of total energy. Depending on the respondents' age, QSR provided between 12.5% and 17.5% of energy, whereas FSR provided between 4.7% and 10.4% of energy. School meals provided 9.8% of energy for children and 5.5% for adolescents. Vending machines provided <1% of energy. Pizza from QSR, the top food away from home (FAFH) item, provided 2.2% of energy in the diets of children and 3.4% in the diets of adolescents. Soda, energy, and sports drinks from QSR provided approximately 1.2% of dietary energy. CONCLUSIONS: Refining dietary surveillance approaches by incorporating food purchase location may help inform public health policy. Characterizing the important sources of energy, in terms of both purchase location and source may be useful in anticipating the population-level impacts of proposed policy or educational interventions. These data show that stores provide a majority of energy for the population, followed by quick-service and full service restaurants. All food purchase locations, including stores, restaurants and schools play an important role in stemming the obesity epidemic. PMID- 23656640 TI - Dietary fibre affects intestinal mucosal barrier function and regulates intestinal bacteria in weaning piglets. AB - The objective of the present study was to evaluate the effects of fibre source on intestinal mucosal barrier function in weaning piglets. A total of 125 piglets were randomly allotted on the basis of their body weight and litters to one of five experimental diets, i.e. a control diet without fibre source (CT), and diets in which expanded maize was replaced by 10% maize fibre (MF), 10% soyabean fibre (SF), 10% wheat bran fibre (WBF) or 10% pea fibre (PF). The diets and water were fed ad libitum for 30 d. Piglets on the WBF and PF diets had lower diarrhoea incidence compared with the MF- and SF-fed animals. A higher ratio of villous height:crypt depth in the ileum of WBF-fed piglets and higher colonic goblet cells in WBF- and PF-fed piglets were observed compared with CT-, MF- and SF-fed piglets. In the intestinal digesta, feeding WBF and PF resulted in increased Lactobacillus counts in the ileum and Bifidobacterium counts in the colon. Lower Escherichia coli counts occurred in the ileum and colon of WBF-fed piglets than in SF-fed piglets. Tight junction protein (zonula occludens 1; ZO-1) and Toll like receptor 2 (TLR2) gene mRNA levels were up-regulated in the ileum and colon of pigs fed WBF; however, feeding MF and SF raised IL-1alpha and TNF-alpha mRNA levels. Furthermore, higher diamine oxidase activities, transforming growth factor-alpha, trefoil factor family and MHC-II concentration occurred when feeding WBF and PF. In conclusion, the various fibre sources had different effects on the ileal and colonic barrier function. Clearly, WBF and PF improved the intestinal barrier function, probably mediated by changes in microbiota composition and concomitant changes in TLR2 gene expression. PMID- 23656641 TI - Improving obesity prevention at the local level--emerging opportunities. PMID- 23656642 TI - A no-prophylaxis platelet-transfusion strategy for hematologic cancers. AB - BACKGROUND: The effectiveness of platelet transfusions to prevent bleeding in patients with hematologic cancers remains unclear. This trial assessed whether a policy of not giving prophylactic platelet transfusions was as effective and safe as a policy of providing prophylaxis. METHODS: We conducted this randomized, open label, noninferiority trial at 14 centers in the United Kingdom and Australia. Patients were randomly assigned to receive, or not to receive, prophylactic platelet transfusions when morning platelet counts were less than 10*10(9) per liter. Eligible patients were persons 16 years of age or older who were receiving chemotherapy or undergoing stem-cell transplantation and who had or were expected to have thrombocytopenia. The primary end point was bleeding of World Health Organization (WHO) grade 2, 3, or 4 up to 30 days after randomization. RESULTS: A total of 600 patients (301 in the no-prophylaxis group and 299 in the prophylaxis group) underwent randomization between 2006 and 2011. Bleeding of WHO grade 2, 3, or 4 occurred in 151 of 300 patients (50%) in the no-prophylaxis group, as compared with 128 of 298 (43%) in the prophylaxis group (adjusted difference in proportions, 8.4 percentage points; 90% confidence interval, 1.7 to 15.2; P=0.06 for noninferiority). Patients in the no-prophylaxis group had more days with bleeding and a shorter time to the first bleeding episode than did patients in the prophylaxis group. Platelet use was markedly reduced in the no-prophylaxis group. A prespecified subgroup analysis identified similar rates of bleeding in the two study groups among patients undergoing autologous stem-cell transplantation. CONCLUSIONS: The results of our study support the need for the continued use of prophylaxis with platelet transfusion and show the benefit of such prophylaxis for reducing bleeding, as compared with no prophylaxis. A significant number of patients had bleeding despite prophylaxis. (Funded by the National Health Service Blood and Transplant Research and Development Committee and the Australian Red Cross Blood Service; TOPPS Controlled-Trials.com number, ISRCTN08758735.). PMID- 23656643 TI - Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. AB - BACKGROUND: The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative-myelodysplastic overlap neoplasms. METHODS: To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies. RESULTS: We identified activating mutations in the gene encoding the receptor for colony stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib. CONCLUSIONS: Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.). PMID- 23656644 TI - Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. AB - BACKGROUND: Respiratory syncytial virus (RSV) infection is associated with subsequent recurrent wheeze. Observational studies cannot determine whether RSV infection is the cause of recurrent wheeze or the first indication of preexistent pulmonary vulnerability in preterm infants. The monoclonal antibody palivizumab has shown efficacy in preventing severe RSV infection in high-risk infants. METHODS: In the double-blind, placebo-controlled MAKI trial, we randomly assigned 429 otherwise healthy preterm infants born at a gestational age of 33 to 35 weeks to receive either monthly palivizumab injections (214 infants) or placebo (215 infants) during the RSV season. The prespecified primary outcome was the total number of parent-reported wheezing days in the first year of life. Nasopharyngeal swabs were taken during respiratory episodes for viral analysis. RESULTS: Palivizumab treatment resulted in a relative reduction of 61% (95% confidence interval, 56 to 65) in the total number of wheezing days during the first year of life (930 of 53,075 days in the RSV-prevention group [1.8%] vs. 2309 of 51,726 days [4.5%] in the placebo group). During this time, the proportion of infants with recurrent wheeze was 10 percentage points lower in patients treated with palivizumab (11% vs. 21%, P=0.01). CONCLUSIONS: In otherwise healthy preterm infants, palivizumab treatment resulted in a significant reduction in wheezing days during the first year of life, even after the end of treatment. These findings implicate RSV infection as an important mechanism of recurrent wheeze during the first year of life in such infants. (Funded by Abbott Laboratories and by the Netherlands Organization for Health Research and Development; MAKI Controlled Clinical Trials number, ISRCTN73641710.). PMID- 23656647 TI - Enteropathogens and chronic illness in returning travelers. PMID- 23656648 TI - Images in clinical medicine. A ticking time bomb. PMID- 23656646 TI - WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. AB - This report identifies human skeletal diseases associated with mutations in WNT1. In 10 family members with dominantly inherited, early-onset osteoporosis, we identified a heterozygous missense mutation in WNT1, c.652T->G (p.Cys218Gly). In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884C->A, p.Ser295*. In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. In mice, Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in these diseases. PMID- 23656649 TI - Case records of the Massachusetts General Hospital. Case 14-2013. A 70-year-old woman with vaginal bleeding. PMID- 23656650 TI - Eliminate prophylactic platelet transfusions? PMID- 23656651 TI - Genetically informed therapy in leukemia. PMID- 23656652 TI - Early-life wheezing and respiratory syncytial virus prevention. PMID- 23656653 TI - Cinacalcet for cardiovascular disease in patients undergoing dialysis. PMID- 23656654 TI - Cinacalcet for cardiovascular disease in patients undergoing dialysis. PMID- 23656655 TI - Cinacalcet for cardiovascular disease in patients undergoing dialysis. PMID- 23656656 TI - Cinacalcet for cardiovascular disease in patients undergoing dialysis. PMID- 23656657 TI - Cinacalcet for cardiovascular disease in patients undergoing dialysis. PMID- 23656658 TI - Autophagy in human health and disease. PMID- 23656659 TI - Autophagy in human health and disease. PMID- 23656660 TI - Tragedy's legacy. PMID- 23656661 TI - Tragedy's legacy. PMID- 23656662 TI - Tragedy's legacy. PMID- 23656663 TI - Pooled platelet concentrates or apheresis platelets? PMID- 23656664 TI - Pooled platelet concentrates or apheresis platelets? PMID- 23656665 TI - HLA-mismatched renal transplantation without maintenance immunosuppression. PMID- 23656667 TI - Videos in clinical medicine. Needle aspiration of primary spontaneous pneumothorax. PMID- 23656668 TI - Images in clinical medicine. Nutcracker esophagus. PMID- 23656671 TI - New coumarin derivatives as carbonic anhydrase inhibitors. AB - In the current study, a series of 4-chloromethyl-7-hydroxy-coumarin derivatives containing imidazolium, benzimidazolium, bisbenzimidazolium and quaternary ammonium salts were synthesized, characterized and the inhibition effects of the derivatives on human carbonic anhydrases (hCA I and hCA II) were investigated as in vitro. Structures of these coumarins were confirmed by FT-IR, (1)H NMR, (13)C NMR and LC-MS analyses. Structure activity relationship study showed that 3d (IC50: 79 MUM for hCA I and 88 MUM for hCA II) performed higher inhibitory activity than others. PMID- 23656670 TI - Oleic acid vesicles: a new approach for topical delivery of antifungal agent. AB - The occurrence of topical fungal infections is increasing nowadays. Cutaneous fungal infections like cutaneous candidiasis are more prominent in patients associated with AIDS. Current available strategies for the treatment of cutaneous fungal infections are creams or gels which show various adverse effects on skin along with systemic absorption. These drawbacks can be overcome by using various novel drug delivery systems. So, the present investigation aims at exploring the potential of fatty acid vesicles (ufasomes) for the topical delivery of clotrimazole. Oleic acid was employed as a fatty material for the preparation of vesicles. Clotrimazole-loaded oleic acid vesicles were prepared using a thin film hydration method. Prepared vesicles were characterized for size, size distribution, shape, thermal behaviour (differential scanning calorimetry), in vitro release, in vitro antifungal activity, in vitro skin permeation and retention studies and for in vivo antifungal activity. Transmission electron microscopic (TEM) images confirmed the formation of vesicular dispersion (ufasomes) of clotrimazole. Oleic acid vesicles possessed high drug entrapment (49.5 +/- 1.0%) and optimum size (455 +/- 22 nm) along with good colloidal characteristics (polydispersity index = 0.210 +/- 0.035 & zeta potential = - 22.45 +/- 0.25 mV) at 4:6 drug-to-oleic acid ratio. In vitro drug release study showed sustained release of drug from the vesicular dispersion. Skin permeation and skin retention studies suggested accumulation of drug in the epidermal part of the skin. In vivo study confirmed prolonged release of drug from oleic acid vesicle up to five days indicating its usefulness for long-term therapy. So, it can be concluded from the present study that fatty acid vesicle may be a good approach to treat topical fungal infections. PMID- 23656672 TI - Riding the wave. PMID- 23656673 TI - Centrally organised bedside teaching led by junior doctors. AB - BACKGROUND: Clinical bedside teaching is arguably the most favoured form of teaching by medical students, but has been on the decline in recent years. Junior doctors are often underused as teachers and, with adequate training, may help to solve this problem. Bedside Teachers is a junior doctor-led teaching programme that is delivered throughout South-East Scotland, and is now in its third year. This study aimed to investigate the perceptions of final-year medical students participating in the Bedside Teachers programme, and how they compared this with teaching from senior staff. METHODS: Anonymised questionnaires were issued to all participants. Students were asked to rate statements relating to: (i) the quality of bedside teaching tutorials; and (ii) the teaching delivered by junior doctors compared with that delivered by senior staff. RESULTS: All students indicated that the tutorials improved their confidence in clinical examination. Eighty-seven per cent indicated that it provided a useful clinical experience that they would otherwise not have received. All respondents indicated that junior doctors were more approachable than senior staff. The majority of students indicated that they thought junior doctors covered more relevant material to being a good junior doctor, and that junior doctor-led teaching was at least as good or better than teaching by senior staff on a number of other criteria. CONCLUSIONS: With adequate training, junior doctors can be a useful resource for increasing the bedside teaching opportunities available to students, with potential advantages over using senior staff. PMID- 23656645 TI - n-3 fatty acids in patients with multiple cardiovascular risk factors. AB - BACKGROUND: Trials have shown a beneficial effect of n-3 polyunsaturated fatty acids in patients with a previous myocardial infarction or heart failure. We evaluated the potential benefit of such therapy in patients with multiple cardiovascular risk factors or atherosclerotic vascular disease who had not had a myocardial infarction. METHODS: In this double-blind, placebo-controlled clinical trial, we enrolled a cohort of patients who were followed by a network of 860 general practitioners in Italy. Eligible patients were men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction. Patients were randomly assigned to n-3 fatty acids (1 g daily) or placebo (olive oil). The initially specified primary end point was the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after the event rate was found to be lower than anticipated, the primary end point was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes. RESULTS: Of the 12,513 patients enrolled, 6244 were randomly assigned to n-3 fatty acids and 6269 to placebo. With a median of 5 years of follow-up, the primary end point occurred in 1478 of 12,505 patients included in the analysis (11.8%), of whom 733 of 6239 (11.7%) had received n-3 fatty acids and 745 of 6266 (11.9%) had received placebo (adjusted hazard ratio with n-3 fatty acids, 0.97; 95% confidence interval, 0.88 to 1.08; P=0.58). The same null results were observed for all the secondary end points. CONCLUSIONS: In a large general-practice cohort of patients with multiple cardiovascular risk factors, daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity. (Funded by Societa Prodotti Antibiotici and others; ClinicalTrials.gov number, NCT00317707.). PMID- 23656674 TI - Teaching skills training for medical students. AB - BACKGROUND: The UK General Medical Council has recommended that medical students be taught how to teach; however, the current state of teaching skills training in England has not yet been investigated. AIMS: To explore the current state of undergraduate teaching skills training at medical schools in England. METHODS: A questionnaire survey was sent to all 24 medical schools in England, enquiring about the basic structure, content areas, staffing, delivery and assessment methods of compulsory courses. RESULTS: A response rate of 22/24 (92%) was achieved, and 18/22 (82%) of the responding institutions offered some form of teaching skills training. The most frequently covered content areas were small group facilitation skills, large group teaching skills and use of effective feedback. Teaching was delivered by a combination of hospital doctors, non physician educators or general practitioner educators in the majority of courses. Six of the nine (67%) compulsory courses featured student assessments. The main barriers to implementing these courses were staffing limitations, insufficient time and lack of student engagement. CONCLUSIONS: Our study demonstrates both the similarities and variation between undergraduate teaching skills courses across England. However, further research will be necessary to determine whether the long-term impact of such training will result in better educators, and ultimately in improved patient care. PMID- 23656675 TI - The evaluation of a peer-led question-writing task. AB - BACKGROUND: Novel studies have previously highlighted the educational benefits of peer-led learning and peer marking of examinations. Limited data exist about the educational value of students writing their own exam questions and sharing these with other students. AIM: To evaluate the potential for medical students to learn about palliative care through the process of writing examination questions. methods: Fourth-year medical students on a palliative medicine rotation were invited to write a short-answer exam question in a similar format to the official examination run by the medical school. The questions were checked for accuracy and applicability by the coordinator, and were then distributed to students. The answers to the student-generated questions were discussed in a feedback forum at the end of the rotation. RESULTS: Twenty students took part in the exercise. All agreed the exercise was beneficial to their learning. Eighteen (90%) students did not feel the task was too much additional work. Eight (40%) students felt more confident in passing the official medical school exams. Students enjoyed the exercise, with 19 (95%) indicating that they were keen to repeat this in the future. CONCLUSION: Peer-led examination question writing could complement the delivery of palliative care teaching for medical students. PMID- 23656676 TI - Graduates from vertically integrated curricula. AB - BACKGROUND: Vertical integration (VI) has been recommended as an undergraduate medical curriculum structure that fosters the transition to postgraduate training. Our definition of VI includes: (1) the provision of early clinical experience; (2) the integration of biomedical sciences with clinical cases; (3) long clerkships during the final year; and (4) increasing levels of clinical responsibility for students. The aim of the current study is to support the hypothesis that medical graduates from VI programmes meet the expectations of postgraduate supervisors better than those from non-VI curricula. METHODS: A questionnaire study was carried out among supervisors of postgraduate training programmes run at Utrecht (the Netherlands, VI; n = 128) and Hamburg (Germany, non-VI; n = 114). The supervisors were asked about their medical graduates' preparedness for work, knowledge and capabilities to manage some specific parts of the work as a doctor. They evaluated their performances on a five-point Likert scale. RESULTS: The two groups of supervisors did not differ in their judgment of their graduates' preparedness for work and level of knowledge. However, supervisors in Utrecht evaluated their graduates higher with respect to capability to work independently, solving medical problems, managing unfamiliar medical situations, prioritising tasks, collaborating with other people, estimating when they need to consult their supervisors and reflecting on their activities. DISCUSSION: Graduates from VI medical curricula appeared to be more capable in several facets of a doctor's job. Research into the actual performance of graduates from VI and non-VI curricula is needed to further support a firm recommendation for VI curricula. PMID- 23656677 TI - Promoting health behaviours in medical education. AB - BACKGROUND: In light of the global trends of increasing obesity, the education of doctors and other health professionals warrants greater attention to promoting effective weight management through health behaviours related to eating and exercise. CONTEXT: Gaps in training in these areas have been identified related to weight management and wellness. Diverse benefits of healthy lifestyle interventions have been noted. INNOVATION: Recommendation for developing immersion programmes for medical students and other health professionals involving practical experience in weight management through lifestyle modification, addressing nutritional and caloric intake and energy expenditure through exercise. IMPLICATIONS: Integrating healthy lifestyle programmes into medical and health professional education could yield several benefits. Enhancing curriculum and educational processes by promoting medical and health professional students' awareness of, participation and immersion in, healthy lifestyle interventions may ultimately lead to better health outcomes for health professionals and their patients. PMID- 23656678 TI - Developing ideas of professionalism. AB - BACKGROUND: Professionalism is widely acknowledged as being central to medical practice, and is taught at most UK medical schools. The impact of this teaching in the context of competing influences on a student's developing view of themselves as professional is, however, unclear. We explored the understanding of professionalism in third-year medical students who have recently completed this element of their formal teaching, and related this understanding to previously unexplored wider influences placed upon them during their development. METHODS: A questionnaire consisting of two closed questions and two open questions was distributed via e-mail to third-year students at Imperial College School of Medicine, London. The closed questions explored both beliefs about what constitutes medical professionalism and preferences for the teaching of professionalism. The open questions explored the contexts within which students believed their understanding of professionalism was derived. Content analysis of text-based questions was performed. RESULTS AND DISCUSSION: The most commonly cited aspects of professionalism by students in this study were confidentiality, good medical knowledge and practical skill. Students also cited promptness, hygiene and appearance as being important, although these factors are rarely cited in the literature. Students cited role models, the media and parents as the three most important influences on their view of professionalism. These merit further consideration in future research and course design. Most students agreed that professionalism should be taught at medical school, but that this would be best achieved within a clinical setting. The favoured model for acquisition of views on professionalism was observation of doctors rather than formal teaching. PMID- 23656679 TI - Non-technical skills training to enhance patient safety. AB - BACKGROUND: Patient safety is an increasingly recognised issue in health care. Systems-based and organisational methods of quality improvement, as well as education focusing on key clinical areas, are common, but there are few reports of educational interventions that focus on non-technical skills to address human factor sources of error. A flexible model for non-technical skills training for health care professionals has been designed based on the best available evidence, and with sound theoretical foundations. CONTEXT: Educational sessions to improve non-technical skills in health care have been described before. The descriptions lack the details to allow educators to replicate and innovate further. INNOVATION: A non-technical skills training course that can be delivered as either a half- or full-day intervention has been designed and delivered to a number of mixed groups of undergraduate medical students and doctors in postgraduate training. Participant satisfaction has been high and patient safety attitudes have improved post-intervention. IMPLICATIONS: This non-technical skills educational intervention has been built on a sound evidence base, and is described so as to facilitate replication and dissemination. With the key themes laid out, clinical educators will be able to build interventions focused on numerous clinical issues that pay attention to human factor contributors to safety. PMID- 23656680 TI - A training programme in screening echocardiography. AB - BACKGROUND: Although the value of echocardiography in acutely unwell patients is well established, it is often difficult to deliver conventional studies immediately. This has led to the development of training programmes in screening echocardiography. CONTEXT: Echocardiography is a difficult skill to master and requires an integration of knowledge-based learning and mentored practical training. INNOVATION: We developed a three-stage programme: (1) a 1-day course containing didactic lectures on normal and abnormal pathology, a 2-hour practical element with rotation through different tutors then seminars and self-assessment, with an interactive quiz; (2) a period of consolidation via apprenticeship with a recognised trainer; and (3) formal assessment. IMPLICATIONS: We propose a specific training programme to teach the difficult practical skill of screening echocardiography. The use of theoretical and practical elements with structured teaching and an apprenticeship may serve as a model for teaching other practical skills in clinical medicine. PMID- 23656681 TI - A gynaecologic clinic dedicated to student teaching. AB - BACKGROUND: To compare medical student experiences in an innovative out-patient clinic, in which women are cared for directly by medical students, versus the traditional resident continuity clinics (RCCs). METHODS: A prospective study with medical students randomly assigned to either the Medical Student Out-patient Clinic (MSOC) or the RCC. Students rated their preceptors on a five-point Likert scale and completed an experience log. The primary outcome was student perception of overall teaching quality. Secondary outcomes included the numbers of patients they saw, as well as the number of speculum examinations, bimanual examinations and breast examinations they personally performed, and the number of sessions in which a preceptor did not submit an evaluation of the student. RESULTS: A total of 62 out of 63 students (98%) completed surveys during the study period. MSOC students performed more bimanual exams (1.7 versus 1.2, p = 0.015) and breast exams (1.0 versus 0.3, p < 0.001), saw fewer patients (1.8 versus 4.2, p < 0.001), and rated both the overall teaching quality (4.8 versus 4.0, p < 0.001) and the preceptor (5.0 versus 4.2, p < 0.001) higher. MSOC students received more feedback from their preceptors. CONCLUSIONS: The MSOC programme provided our students with an improved learning experience. The high ratings were likely to have resulted from the one-on-one teaching from the attending physician and the absence of competing resident learners. PMID- 23656682 TI - We know what they did wrong, but not why: the case for 'frame-based' feedback. AB - BACKGROUND: Actionable feedback targeted to the learner's needs is one of the strongest predictors of improved performance in learning. Unfortunately, when a trainee makes an error, although instructors may understand what a trainee has done wrong, they can erroneously assume they know why. CONTEXT: There is a growing recognition that cognitive biases impede clinical diagnosis, however, the same biases can also undermine accurate and effective feedback. INNOVATION: Instead of focusing primarily on correcting actions, it is often crucial to diagnose trainees' 'frames'-- the thought processes that drive their actions. We offer an efficient three-step algorithm for providing this 'frame-based' feedback: (1) describe how the trainee is doing according to the instructor; (2) diagnose the trainee's immediate learning needs using inquiry to elicit their frame; and (3) direct instruction to those needs. IMPLICATIONS: 'Misdiagnosis' of the trainee's actual needs wastes time when instructors teaching unneeded material, diminishes the trainee's faith in the value of instruction and undermines patient safety when incorrect frames about important clinical processes persist. PMID- 23656683 TI - Training tomorrow's doctors in the preoperative clinic. AB - BACKGROUND: The reduction in the length of hospital stay for surgical patients at a time of expanding medical student numbers has created challenges in the provision of adequate exposure to surgical patients. This has required the use of surgical learning opportunities in the ambulatory setting, including the preoperative assessment clinic. At Keele University, fourth-year medical students follow patient journeys through the preoperative assessment process, gaining experience of history taking, examination, prescribing and practical skills. This is followed by group discussion with a clinical teaching fellow, focusing on management and clinical reasoning. We audited the experience our students gained in the preoperative assessment clinic against the relevant Tomorrow's Doctors outcomes. METHODS: An audit tool was created by reviewing the patient journey to identify potential learning opportunities. These were then mapped to the relevant Tomorrow's Doctors outcomes. Audit pro formas were completed for each student at the end of the clinic by the clinical educator, with a total of 42 sessions audited. RESULTS: Our findings show that it is possible for students to gain experience in all nine of the identified Tomorrow's Doctors outcomes in the preoperative assessment clinic. Practical procedure experience was gained by 92 per cent of students, and 70 per cent demonstrated clinical judgment and decision skills. DISCUSSION: This study shows that students can gain experience in multiple Tomorrow's Doctors outcomes in the preoperative assessment clinic. In particular, it is a useful environment to learn and teach practical procedures, clinical reasoning and decision-making skills. PMID- 23656684 TI - Feedback on trainee doctors: a faculty group review in practice. PMID- 23656685 TI - The transition from student peer-tutor to junior doctor teacher. PMID- 23656686 TI - The role of clinical electives. PMID- 23656691 TI - WNT3A signalling pathway in buffalo (Bubalus bubalis) embryonic stem cells. AB - The aim of this study was to investigate the transcriptional profile and role of WNT3A signalling in maintaining buffalo embryonic stem (ES) cells in a pluripotent state and in the induction of their differentiation. ES cells were derived from embryos produced by in vitro fertilisation (iESC), parthenogenesis (pESC) and hand-made cloning (cESC). The expression of WNT3A, its receptors and intermediate signalling pathways were found to be conserved in ES cells derived from the three different sources. WNT3A was expressed in ES cells but not in embryoid bodies derived from iESC or in buffalo fetal fibroblast cells. It was revealed by real-time polymerase chain reaction analysis that following supplementation of culture medium with WNT3A (100, 200 or 400ngmL(-1)) a significant increase (P<0.05) was observed in the expression level of beta CATENIN, which indicated the activation of the canonical WNT pathway. WNT3A, in combination with exogenous fibroblast growth factor-2 and leukaemia inhibitory factor, induced proliferation of undifferentiated ES cells. Differentiation studies showed that WNT3A caused formation of scaffold-like structures and inhibition of differentiation into neuron-like cells. In conclusion, the WNT3A signalling pathway is necessary both for maintaining undifferentiated buffalo ES cells as well as for directing their differentiation. PMID- 23656692 TI - The effect of acute mental stress on limb vasodilation is unrelated to total peripheral resistance. AB - Mental stress can trigger myocardial infarction, with poor vascular responses to stress implicated as a pathway. Vascular stress reactivity can be assessed by different methods, such as total peripheral resistance (TPR) and forearm blood flow (FBF). Little is known about how these vascular assessments are linked. This was examined in two separate studies. Healthy men (Study 1: N = 29, Study 2: N = 23) completed rest and mental arithmetic (Study 1: 8 min, Study 2: 16 min). In both studies, heart rate, mean arterial pressure, and FBF increased in response to stress. In Study 1, no changes in TPR were seen, but Study 2 found stress induced increases in TPR. FBF was not linked to TPR at any time (all ps > .05). It appears that limb vasculature and TPR responses to stress do not give the same information about impairments of the vasculature. These findings are relevant to the interpretation of prior research findings and the design of future studies on stress and vascular responses. PMID- 23656693 TI - Increasing caesarean section rates among low-risk groups: a panel study classifying deliveries according to Robson at a university hospital in Tanzania. AB - BACKGROUND: Rising caesarean section (CS) rates have been observed worldwide in recent decades. This study sought to analyse trends in CS rates and outcomes among a variety of obstetric groups at a university hospital in a low-income country. METHODS: We conducted a hospital-based panel study at Muhimbili National Hospital, Dar es Salaam, Tanzania. All deliveries between 2000 and 2011 with gestational age >= 28 weeks were included in the study. The 12 years were divided into four periods: 2000 to 2002, 2003 to 2005, 2006 to 2008, and 2009 to 2011. Main outcome measures included CS rate, relative size of obstetric groups, contribution to overall CS rate, perinatal mortality ratio, neonatal distress, and maternal mortality ratio. Time trends were analysed within the ten Robson groups, based on maternal and obstetric characteristics. We applied the chi2 test for trend to determine whether changes were statistically significant. Odds ratios of CS were evaluated using multivariate logistic regression, accounting for maternal age, referral status, and private healthcare insurance. RESULTS: We included 137,094 deliveries. The total CS rate rose from 19% to 49%, involving nine out of ten groups. Multipara without previous CS with single, cephalic pregnancies in spontaneous labour had a CS rate of 33% in 2009 to 2011. Adjusted analysis explained some of the increase. Perinatal mortality and neonatal distress decreased in multiple pregnancies (p < 0.001 and p = 0.003) and nullipara with breech pregnancies (p < 0.001 and p = 0.024). Although not statistically significant, there was an increase in perinatal mortality (p = 0.381) and neonatal distress (p = 0.171) among multipara with single cephalic pregnancies in spontaneous labour. The maternal mortality ratio increased from 463/100, 000 live births in 2000 to 2002 to 650/100, 000 live births in 2009 to 2011 (p = 0.031). CONCLUSION: The high CS rate among low-risk groups suggests that many CSs might have been performed on questionable indications. Such a trend may result in even higher CS rates in the future. While CS can improve perinatal outcomes, it does not necessarily do so if performed routinely in low-risk groups. PMID- 23656694 TI - Desulfurization activity and reusability of magnetite nanoparticle-coated Rhodococcus erythropolis FMF and R. erythropolis IGTS8 bacterial cells. AB - The application of Fe3 O4 nanoparticles to the separation of desulfurizing bacterial cells and their influence on the desulfurization activity and reusability of the two bacterial strains Rhodococcus erythropolis FMF and R. erythropolis IGTS8 were investigated. Magnetite nanoparticles were synthesized via the reverse coprecipitation method. Transmission electron microscopy (TEM) images showed that the magnetite nanoparticles had sizes of 5.35 +/- 1.13 (F1 nanoparticles) and 8.74 +/- 1.18 nm (F2 nanoparticles) when glycine was added during the synthesis of nanoparticles and when it was absent from the reaction mixture, respectively. Glycine was added after the synthesis of both F1 and F2 nanoparticles to stabilize the nanoparticle dispersion. TEM images of cells treated with magnetite nanoparticles indicated that F1 nanoparticles were immobilized on the surface of bacterial cells more evenly than the F2 nanoparticles. Desulfurization activities of the F1 magnetite nanoparticle-coated R. erythropolis FMF and R. erythropolis IGTS8 cells (with sulfur-removal percentage values of 70 +/- 4 and 73 +/- 3, respectively), as examined with the spectrophotometric Gibbs assay (based on dibenzothiophene degradation and sulfur removal percentage), were not significantly different from those for the free bacterial cells (67 +/- 3 and 69 +/- 4, respectively). These results indicate that magnetite nanoparticles cannot affect the desulfurization activity of cells examined in this work. Isolation of bacterial cells from the suspension using a magnet and evaluation of desulfurization activity of separated cells showed that Fe3 O4 nanoparticles can provide a high-efficiency recovery of bacterial cells from a suspension, with the reused magnetite nanoparticle-coated bacterial cells being able to maintain their desulfurization activity efficiently. PMID- 23656695 TI - A new method to estimate parameters of the growth model for metastatic tumours. AB - PURPOSE: Knowledge of natural tumour growth is valuable for understanding tumour biology, optimising screening programs, prognostication, optimal scheduling of chemotherapy, and assessing tumour spread. However, mathematical modelling in individuals is hampered by the limited data available. We aimed to develop a method to estimate parameters of the growth model and formation rate of metastases in individual patients. MATERIALS AND METHODS: Data from one patient with liver metastases from a primary ileum carcinoid and one patient with lung metastases from a primary renal cell carcinoma were used to demonstrate this new method. Metastatic growth models were estimated by direct curve fitting, as well as with the new proposed method based on the relationship between tumour growth rate and tumour volume. The new model was derived from the Gompertzian growth model by eliminating the time factor (age of metastases), which made it possible to perform the calculations using data from all metastases in each patient. Finally, the formation time of each metastasis and, consecutively, the formation rate of metastases in each patient were estimated. RESULTS: With limited measurements in clinical studies, fitting different growth curves was insufficient to estimate true tumour growth, even if patients were followed for several years. Growth of liver metastases was well described with a general growth model for all metastases. However, the lung metastases from renal cell carcinoma were better described by heterogeneous exponential growth with various growth rates. CONCLUSION: Analysis of the regression of tumour growth rate with the logarithm of tumour volume can be used to estimate parameters of the tumour growth model and metastasis formation rates, and therefore the number and size distribution of metastases in individuals. PMID- 23656696 TI - The wooly mutation (wly) on mouse chromosome 11 is associated with a genetic defect in Fam83g. AB - BACKGROUND: Mice homozygous for the spontaneous wooly mutation (abbreviated wly) are recognized as early as 3-4 weeks of age by the rough or matted appearance of their coats. Previous genetic analysis has placed wly in a 5.9 Mb interval on Chromosome 11 that contains over 200 known genes. Assignment of wly to one of these genes is needed in order to provide probes that would ultimately facilitate a complete molecular analysis of that gene's role in the normal and disrupted development of the mammalian integument. RESULTS: Here, a large intraspecific backcross family was used to genetically map wly to a smaller (0.8 Mb) span on mouse Chromosome 11 that includes fewer than 20 genes. DNA sequencing of the coding regions in two of these candidates known to be expressed in skin has revealed a 955 bp, wly-specific deletion. This deletion, which lies within the coordinates of both Slc5a10 [for solute carrier family 5 (sodium/glucose cotransporter), member 10] and Fam83g (for family with sequence similarity 83, member G), alters the splicing of mutant Fam83g transcripts only, and is predicted to result in a severely truncated (probably non-functional) protein product. CONCLUSION: We suggest that this mutation in Fam83g is the likely basis of the mouse wooly phenotype. PMID- 23656697 TI - Haemoglobin Kenitra detected by HPLC assay and its compromising effect on the measurement of HbA1c. PMID- 23656699 TI - Companion biomarkers: paving the pathway to personalized treatment for cancer. AB - BACKGROUND: Companion biomarkers are biomarkers that are used in combination with specific therapies and that prospectively help predict likely response or severe toxicity. In this article we review the role of companion biomarkers in guiding treatment in patients with cancer. CONTENT: In addition to the established companion biomarkers such as estrogen receptors and HER2 (human epidermal growth factor receptor 2) in breast cancer, several new companion biomarkers have become available in recent years. These include v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations for the selection of patients with advanced colorectal cancer who are unlikely to benefit from anti-epidermal growth factor receptor antibodies (cetuximab or panitumumab), epidermal growth factor receptor (EGFR) mutations for selecting patients with advanced non-small cell lung cancer (NSCLC) for treatment with tyrosine kinase inhibitors (gefitinib or erlotinib), v raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations for selecting patients with advanced melanoma for treatment with anti-BRAF agents (vemurafenib and dabrafenib), and anaplastic lymphoma receptor tyrosine kinase (ALK) translocations for identifying patients with NSCLC likely to benefit from crizotinib. SUMMARY: The availability of companion biomarkers should improve drug efficacy, decrease toxicity, and lead to a more individualized approach to cancer treatment. PMID- 23656700 TI - Task shifting and sharing in maternal and reproductive health in low-income countries: a narrative synthesis of current evidence. AB - Reducing maternal mortality and providing universal access to reproductive health in resource poor settings has been severely constrained by a shortage of health workers required to deliver interventions. The aim of this article is to determine evidence to optimize health worker roles through task shifting/sharing to address Millennium Development Goal 5 and reduce maternal mortality and provide universal access to reproductive health. A narrative synthesis of peer reviewed literature from 2000 to 2011 was undertaken with retrieved documents assessed using an inclusion/exclusion criterion and quality appraisal guided by critical assessment tools. Concepts were analysed thematically. The analysis identified a focus on clinical tasks (the delivery of obstetric surgery, anaesthesia and abortion) that were shifted to and/or shared with doctors, non physician clinicians, nurses and midwives. Findings indicate that shifting and sharing these tasks may increase access to and availability of maternal and reproductive health (MRH) services without compromising performance or patient outcomes and may be cost effective. However, a number of issues and barriers were identified with health workers calling for improved in-service training, supervision, career progression and incentive packages to better support their practice. Collaborative approaches involving community members and health workers at all levels have the potential to deliver MRH interventions effectively if accompanied by ongoing investment in the health care system. PMID- 23656698 TI - Prenatal and perinatal analgesic exposure and autism: an ecological link. AB - BACKGROUND: Autism and Autism Spectrum Disorder (ASD) are complex neurodevelopmental disorders. Susceptibility is believed to be the interaction of genetic heritability and environmental factors. The synchronous rises in autism/ASD prevalence and paracetamol (acetaminophen) use, as well as biologic plausibility have led to the hypothesis that paracetamol exposure may increase autism/ASD risk. METHODS: To explore the relationship of antenatal paracetamol exposure to ASD, population weighted average autism prevalence rates and paracetamol usage rates were compared. To explore the relationship of early neonatal paracetamol exposure to autism/ASD, population weighted average male autism prevalence rates for all available countries and U.S. states were compared to male circumcision rates - a procedure for which paracetamol has been widely prescribed since the mid-1990s. Prevalence studies were extracted from the U.S. Centers for Disease Control and Prevention Summary of Autism/ASD Prevalence Studies database. Maternal paracetamol usage and circumcision rates were identified by searches on Pub Med. RESULTS: Using all available country-level data (n = 8) for the period 1984 to 2005, prenatal use of paracetamol was correlated with autism/ASD prevalence (r = 0.80). For studies including boys born after 1995, there was a strong correlation between country-level (n = 9) autism/ASD prevalence in males and a country's circumcision rate (r = 0.98). A very similar pattern was seen among U.S. states and when comparing the 3 main racial/ethnic groups in the U.S. The country-level correlation between autism/ASD prevalence in males and paracetamol was considerably weaker before 1995 when the drug became widely used during circumcision. CONCLUSIONS: This ecological analysis identified country-level correlations between indicators of prenatal and perinatal paracetamol exposure and autism/ASD. State level correlation was also identified for the indicator of perinatal paracetamol exposure and autism/ASD. Like all ecological analyses, these data cannot provide strong evidence of causality. However, biologic plausibility is provided by a growing body of experimental and clinical evidence linking paracetamol metabolism to pathways shown to be important in autism and related developmental abnormalities. Taken together, these ecological findings and mechanistic evidence suggest the need for formal study of the role of paracetamol in autism. PMID- 23656701 TI - Measures of satisfaction with care during labour and birth: a comparative review. AB - BACKGROUND: Satisfaction is the one of the most frequently reported outcome measures for quality of care. Assessment of satisfaction with maternity services is crucial, and psychometrically sound measures are needed if this is to inform health practices. This paper comparatively reviews current measures of satisfaction with care during labour and birth. METHODS: A review of the literature was conducted. Studies were located through computerised databases and hand searching references of identified articles and reviews. Inclusion criteria were that the questionnaire was a multi-item scale of satisfaction with care during labour and birth, and some form of psychometric information (either information about questionnaire construction, or reliability, or validity) had to be reported. RESULTS: Nine questionnaires of satisfaction with care during labour and birth were identified. Instruments varied in psychometric properties and dimensions. Most described questionnaire construction and tested some form of reliability and validity. Measures were generally not based on the main theoretical models of satisfaction and varied in scope and application to different types of samples (e.g. satisfaction following caesarean section). For an in-depth measure of satisfaction with intrapartum care, the Intrapartal Specific Quality from the Patient's Perspective questionnaire (QPP-I) is recommended. Brief measures with good reliability and validity are provided by the Six Simple Questions (SSQ) or Perceptions of Care Adjective Checklist (PCACL R). CONCLUSIONS: Despite the interest in measures of satisfaction there are only a small number of validated measures of satisfaction with care during labour and birth. It is important that brief, reliable and valid measures are available for use in general and specific populations in order to assist research and inform practice. PMID- 23656703 TI - Tuning surface mechanical properties by amplified polyelectrolyte self-assembly: where "grafting-from" meets "grafting-to". AB - We report the interaction of surface-tethered weak polyacid brushes, poly(methacrylic acid), with a weak polybase poly(L-lysine)-graft-poly(ethylene glycol), in solution. The grafted polyacid brushes, grown directly from the silicon substrate by UVLED surface-initiated polymerization, act as a nanotemplate for the solution-phase polybase, which penetrates into the brushes, forming a polyelectrolyte complex (PEC), whose mechanical and nanotribological properties are markedly influenced by the electrostatic assembly conditions. The mechanical effects are amplified due to the architecture of the specific polybase used, which contributes approximately 2k Da per unit charge to the overall system, resulting in an efficient filling of the polyacid brushes, which thus acts as a scaffold. The distribution of the adsorbed copolymers in the PEC films has been investigated by means of confocal microscopy. The unique structure of the PEC films provides a system whose mechanical and nanotribological properties can be tuned over a wide range. PMID- 23656702 TI - Laminar stream of detergents for subcellular neurite damage in a microfluidic device: a simple tool for the study of neuroregeneration. AB - OBJECTIVE: The regeneration and repair of damaged neuronal networks is a difficult process to study in vivo, leading to the development of multiple in vitro models and techniques for studying nerve injury. Here we describe an approach for generating a well-defined subcellular neurite injury in a microfluidic device. APPROACH: A defined laminar stream of sodium dodecyl sulfate (SDS) was used to damage selected portions of neurites of individual neurons. The somata and neurites unaffected by the SDS stream remained viable, thereby enabling the study of neuronal regeneration. MAIN RESULTS: By using well characterized neurons from Aplysia californica cultured in vitro, we demonstrate that our approach is useful in creating neurite damage, investigating neurotrophic factors, and monitoring somata migration during regeneration. Supplementing the culture medium with acetylcholinesterase (AChE) or Aplysia hemolymph facilitated the regeneration of the peptidergic Aplysia neurons within 72 h, with longer (p < 0.05) and more branched (p < 0.05) neurites than in the control medium. After the neurons were transected, their somata migrated; intriguingly, for the control cultures, the migration direction was always away from the injury site (7/7). In the supplemented cultures, the number decreased to 6/8 in AChE and 4/8 in hemolymph, with reduced migration distances in both cases. SIGNIFICANCE: The SDS transection approach is simple and inexpensive, yet provides flexibility in studying neuroregeneration, particularly when it is important to make sure there are no retrograde signals from the distal segments affecting regeneration. Neurons are known to not only be under tension but also balanced in terms of force, and the balance is obviously disrupted by transection. Our experimental platform, verified with Aplysia, can be extended to mammalian systems, and help us gain insight into the role that neurotrophic factors and mechanical tension play during neuronal regeneration. PMID- 23656704 TI - DRIFTSEL: an R package for detecting signals of natural selection in quantitative traits. AB - Approaches and tools to differentiate between natural selection and genetic drift as causes of population differentiation are of frequent demand in evolutionary biology. Based on the approach of Ovaskainen et al. (2011), we have developed an R package (DRIFTSEL) that can be used to differentiate between stabilizing selection, diversifying selection and random genetic drift as causes of population differentiation in quantitative traits when neutral marker and quantitative genetic data are available. Apart from illustrating the use of this method and the interpretation of results using simulated data, we apply the package on data from three-spined sticklebacks (Gasterosteus aculeatus) to highlight its virtues. DRIFTSEL can also be used to perform usual quantitative genetic analyses in common-garden study designs. PMID- 23656705 TI - Comparison of intensive care unit medication errors reported to the United States' MedMarx and the United Kingdom's National Reporting and Learning System: a cross-sectional study. AB - The objective was to compare the characteristics of medication errors reported to 2 national error reporting systems by conducting a cross-sectional analysis of errors reported from adult intensive care units to the UK National Reporting and Learning System and the US MedMarx system. Outcome measures were error types, severity of patient harm, stage of medication process, and involved medications. The authors analyzed 2837 UK error reports and 56 368 US reports. Differences were observed between UK and US errors for wrong dose (44% vs 29%), omitted dose (8.6% vs 27%), and stage of medication process (prescribing: 14% vs 49%; administration: 71% vs 42%). Moderate/severe harm or death was reported in 4.9% of UK versus 3.4% of US errors. Gentamicin was cited in 7.4% of the UK versus 0.7% of the US reports (odds ratio = 9.25). There were differences in the types of errors reported and the medications most often involved. These differences warrant further examination. PMID- 23656706 TI - Neural recruitment after mild traumatic brain injury is task dependent: a meta analysis. AB - Individuals with mild traumatic brain injury (TBI) often have deficits in processing speed and working memory (WM) and there is a growing literature using functional imaging studies to document these deficits. However, divergent results from these studies revealed both hypoactivation and hyperactivation of neural resources after injury. We hypothesized that at least part of this variance can be explained by distinct demands between WM tasks. Notably, in this literature some WM tasks use discrete periods of encoding, maintenance, and retrieval, whereas others place continuous demands on WM. The purpose of this meta-analysis is to examine the differences in neural recruitment after mTBI to determine if divergent findings can be explained as a function of task demand and cognitive load. A comprehensive literature review revealed 14 studies using functional magnetic resonance imaging to examine brain activity of individuals with mTBI during working memory tasks. Three of the fourteen studies included reported hypoactivity, five reported hyperactivity, and the remaining six reported both hypoactivity and hyperactivity. Studies were grouped according to task type and submitted to GingerALE maximum likelihood meta-analyses to determine the most consistent brain activation patterns. The primary findings from this meta analysis suggest that the discrepancy in activation patterns is at least partially attributable to the classification of WM task, with hyperactivation being observed in continuous tasks and hypoactivation being observed during discrete tasks. We anticipate that differential task load expressed in continuous and discrete WM tasks contributes to these differences. Implications for the interpretation of fMRI signals in clinical samples are discussed. PMID- 23656708 TI - Individualized fracture risk assessment: progresses and challenges. AB - PURPOSE OF REVIEW: Fragility fracture is a major public health burden, because it is associated with a substantial morbidity and mortality. Risk prediction models, including the Fracture Risk Assessment Tool (FRAX) and Garvan Fracture Risk Calculator (GFRC), have been developed to provide a useful clinical framework for communicating the risk of fracture. The present review examines the validation of risk prediction models in osteoporosis and identifies some major challenges. RECENT FINDINGS: Recent validation studies suggested that the area under the ROC curve in fracture discrimination ranged from 0.61 to 0.83 for FRAX, and from 0.63 to 0.88 for GFRC, with hip fracture having a better discrimination than fragility fractures as a group. FRAX substantially underestimated the risk of fracture, whereas the predicted risk by GFRC was close to or slightly higher than the actual risk. Results of post-hoc analyses of clinical trials indicated the antifracture efficacy of alendronate, coronate, bazedoxifene, and denosumab was greater in patients with higher predicted risk of fracture. However, there was no correlation between antifracture efficacy and predicted fracture risk among patients on raloxifene and strontium ranelate. SUMMARY: The prognostic performance of FRAX and GFRC for fracture prediction is not perfect, but these predictive models can aid patients and doctors to communicate about fracture risk in the medium term and to make rational decisions. However, the application of these predictive models in making decisions for an individual should take into account the individual's perception of the importance of the risk of fracture and its severity outcomes. PMID- 23656707 TI - Postprandial lipid responses to standard carbohydrates used to determine glycaemic index values. AB - Prior studies assessing the metabolic effects of different types of carbohydrates have focused on their glycaemic response. However, the response of postprandial cardiometabolic risk indicators has not been considered in these studies. The present study assessed postprandial lipid responses to two forms of carbohydrates used as reference foods for glycaemic index determinations, white bread (50 g available carbohydrate) and glucose (50 g), under controlled conditions and with intra-individual replicate determinations. A total of twenty adults (20-70 years) underwent two cycles of challenges with each pair of reference foods (four challenges/person), administered in a random order on separate days under standard conditions. Serum lipids (total cholesterol, LDL-cholesterol, HDL cholesterol, TAG and NEFA), glucose and insulin were monitored for 5 h post ingestion. Oral glucose resulted in greater glycaemic and insulinaemic responses than white bread for the first 90 min and a greater subsequent decline after 120 min (P =0.0001). The initial decline in serum NEFA concentrations was greater after the oral glucose than after the white bread challenge, as was the rebound after 150 min (P = 0.001). Nevertheless, the type of carbohydrate had no significant effect on postprandial total cholesterol, LDL-cholesterol and HDL cholesterol concentrations. Following an initial modest rise in TAG concentrations in response to both challenges, the values dropped below the fasting values for oral glucose but not for the white bread challenge. These data suggest that the type of carbohydrate used to determine the glycaemic index, bread or glucose, has little or modest effects on postprandial plasma cholesterol concentrations. Differences in TAG and NEFA concentrations over the 5 h time period were modest, and their clinical relevance is unclear. PMID- 23656709 TI - Autoimmunity in viral myocarditis. AB - PURPOSE OF REVIEW: To review how autoimmunity is induced in viral myocarditis. RECENT FINDINGS: Clinical and experimental myocarditis follows microbial infections, but autoimmunity to cardiac antigens leads to heart failure since infected myocytes are sparse and virus clearance is rapid. In mice, CD4+ T cells specific for cardiac alpha myosin heavy chain (alphaMYHC) cause myocarditis and mice tolerized to alphaMYHC are protected from virus challenge proving pathogenesis depends upon autoimmunity. Most importantly, multiple microbes share the same mimicking epitope with alphaMYHC. Serial infections with very different microbes could result in memory responses to the shared epitope leading to aggressive and severe heart failure. A similar phenomenon may explain autoimmune diseases with suspected infectious causes, where specific pathogens have not been identified. Production of the relevant cardiac epitope for antigen presentation requires more than myosin release from dead myocytes. Otherwise, myocarditis would commonly follow myocardial infarcts. The inherent nature of the innate immune response associated with viral infections in the heart is crucial to cardiac epitope expression. SUMMARY: Antigenic mimicry between microbes and cardiac proteins causes autoimmunity in myocarditis. Characteristics of innate immunity associated with cardiac infection determine relevant epitope expression (cryptic epitopes). PMID- 23656711 TI - The role of natural killer cells, gamma delta T-cells and other innate immune cells in spondyloarthritis. AB - PURPOSE OF REVIEW: Natural killer (NK) cells, gamma delta (gammadelta) T-cells and other innate immune cells are important lymphocyte subsets able both to produce cytokines including the pro-inflammatory cytokine IL-17 and to kill cellular targets. This review describes the features of NK cells, gammadelta T cells and other innate immune cells, and outlines the evidence for their potential pathogenic roles in spondyloarthritis (SpA). RECENT FINDINGS: NK cells and T cells both express receptors that recognize aberrantly folded human leucocyte antigen. This interaction seems to polarize towards a type 17 immunity programme which has been increasingly implicated in SpA pathology. gammadelta T cells have also been shown to be polarized towards a type 17 immunity programme in SpA. Gut interactions with the microbiome can influence NK and innate lymphoid immune responses in SpA and other related diseases. A newly identified population of resident lymphoid cells at the enthesis for the first time offers an explanation for the anatomical localization of SpA. SUMMARY: NK cells, gammadelta T-cells and other innate immune cells are capable of sharing expression of both transcription factors, including RORgammat, and cell surface receptors, such as the killer immunoglobulin-like receptors. There is increasing genetic and functional evidence that they contribute to the RORgammat-driven inflammatory type 17 immune responses, and they may link gut inflammation and joint pathology in SpA. PMID- 23656710 TI - Multiple sclerosis: autoimmunity and viruses. AB - PURPOSE OF REVIEW: This review will explore two new aspects of the involvement of viruses in multiple sclerosis pathogenesis. The first aspect is the complex interactions between viruses. The second aspect is the proposal of a mechanism by which autoreactive T cells are able to escape thymic selection and potentially recognize self and a pathogen. RECENT FINDINGS: With regard to viruses, recent work has demonstrated that one virus may enhance the replication of another virus, potentially leading to an increase in inflammation and disease progression. Also, interactions between human endogenous retroviruses, which likely do not replicate, and certain herpes viruses, may also play a role in disease pathogenesis. Mechanistically, T cells expressing dual T-cell receptors would be able to recognize self and a foreign antigen specifically. Therefore, human endogenous retroviruses potentially play a role in multiple sclerosis pathogenesis, and both interactions between multiple viruses and autoreactive CD8(+) T cells with dual T-cell receptors may play a role in the pathogenesis of the disease. SUMMARY: The complex interactions between multiple viral infections, either within the central nervous system or in the periphery, and the host immune response to viral infection may be such that a variety of viral specificities result in the activation of T cells that recognize self and induce multiple sclerosis. Therefore, it is unlikely that any one microbe will be determined to be the causative agent of multiple sclerosis as reflected by the number of potential triggering mechanisms of the disease. PMID- 23656712 TI - HLA-B27-mediated protection in HIV and hepatitis C virus infection and pathogenesis in spondyloarthritis: two sides of the same coin? AB - PURPOSE OF REVIEW: HLA-B27 is associated with low viral load and long-term nonprogression in HIV infection as well as spontaneous clearance of hepatitis C virus (HCV) infection. This review summarizes mechanisms that have been suggested to be involved in this protective effect of HLA-B27, and highlights possible lessons for the role of HLA-B27 in spondyloarthritis. RECENT FINDINGS: Recent studies linked protection by HLA-B27 in HIV and HCV infection to virological mechanisms such as a complicated pathways of viral escape from immunodominant HLA B27-restricted virus-specific CD8+ T-cell epitopes. In addition, several immunological mechanisms have been proposed, including CD8+ T-cell polyfunctionality and functional avidity, thymic selection of CD8+ T-cell precursors, specific T-cell receptor repertoires and clonotypes, efficient antigen processing, and evasion from regulatory T-cell-mediated suppression. SUMMARY: Multiple virological and immunological mechanisms have been suggested to contribute to HLA-B27-mediated protection in HIV and HCV infection. Some of these mechanisms may also be involved in HLA-B27-associated pathogenesis in spondyloarthritis. PMID- 23656713 TI - ERAP1 in ankylosing spondylitis: genetics, biology and pathogenetic role. AB - PURPOSE OF REVIEW: Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an aminopeptidase of the endoplasmic reticulum involved in trimming of peptides to their optimal size for binding to major histocompatibility complex class I molecules. Natural ERAP1 polymorphism resulting in altered enzymatic activity is associated with ankylosing spondylitis, an inflammatory disorder very strongly linked to HLA-B27. RECENT FINDINGS: This review will summarize recent advances in the genetics of ERAP1 association with this disease, in the molecular basis of ERAP1 function and in the mechanism of functional interaction between ERAP1 and HLA-B27. SUMMARY: The findings suggest that the pathogenetic role of ERAP1 in ankylosing spondylitis is due to allotype-dependent alterations of the HLA-B27 peptidome that affect the immunologic and other features of HLA-B27. PMID- 23656714 TI - Study design considerations for a large simple trial of bisphosphonates. AB - PURPOSE OF REVIEW: To evaluate design considerations for an osteoporosis large simple trial (LST). RECENT FINDINGS: There is a growing need for more comparative effectiveness studies in osteoporosis. However, the design of such studies is challenged by issues surrounding study design, choosing comparator therapies, participant and outcome selection, data acquisition and data analysis. SUMMARY: LSTs are real-world studies that can have high levels of generalizability, if designed properly. We propose novel approaches to LSTs focusing on some of the challenges associated with comparative effectiveness research in osteoporosis. In this review, we discuss these considerations in the context of bisphosphonate active comparator initiation and discontinuation trials, while presenting advantages and disadvantages of the various design aspects for such studies. PMID- 23656715 TI - The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness. AB - PURPOSE OF REVIEW: To illustrate how microbes might participate in the pathogenesis of neuropsychiatric illness by triggering the production of autoantibodies that bind to brain targets. RECENT FINDINGS: Some studies link exposure to infectious agents to development of brain disorders; others have identified autoantibodies in individuals with these conditions without finding evidence of pathogens. Neither line of work demonstrates consistent associations between a specific neuropsychiatric disease and a particular environmental trigger or immune marker. Growing evidence suggests that the microbiome conditions host immunity to microbes and xenobiotics, and regulates autoimmune responses that can affect the central nervous system (CNS). The presence of CNS receptors for cytokines and other immune molecules underscores the importance of brain-immune crosstalk in maintaining normal function. An increased prevalence of familial autoimmunity, exposure to pathogens prenatally and postnatally, and findings of antibrain antibodies is common in disorders as diverse as schizophrenia, obsessive-compulsive disorder and autism, and suggests that differences in exposure timing and genetic vulnerability toward autoimmunity are important determinants of neuropsychiatric outcomes. SUMMARY: Microbes, both pathogenic and commensal, can induce autoantibodies that bind to brain and affect behavior in susceptible hosts. Interventions that correct the microbial balance or diminish autoantibody binding may be effective in diverse neuropsychiatric conditions mediated by autoimmunity. PMID- 23656716 TI - A registry of ankylosing spondylitis registries and prospects for global interfacing. AB - PURPOSE OF REVIEW: To review the optimal criteria and conditions for establishing a clinical registry, as well as detailing their application in a number of ankylosing spondylitis (AS) and axial spondyloarthritis (axSpA) Registries already in existence. RECENT FINDINGS: Recent genetic studies and studies of long term treatment efficacy and side-effects have underscored the need for large numbers of patients, much larger than would be possible from a single center or consortium. An optimal Registry should have its aims established upfront, with appropriate governance and oversight, and inclusion and exclusion criteria for participating collaborators and subject defined. Collaborators contributing subjects to a Registry should use validated instruments for which they have been previously trained. The numerous cross-sectional and longitudinal Registries on AS and axSpA have been recently established that differ widely depending on the referral and selection issues. SUMMARY: The challenge of large-scale examinations of genetics, comorbidities, medication usage, and side-effects in spondyloarthritis underscores the need for combining data from well characterized registries of AS patients which require careful planning. There are currently many such registries available internationally, offering promise for collaborations and data pooling that can answer some of the pressing questions facing rheumatology clinicians and researchers. PMID- 23656717 TI - Effects of airborne pollutants on mitochondrial DNA methylation. AB - BACKGROUND: Mitochondria have small mitochondrial DNA (mtDNA) molecules independent from the nuclear DNA, a separate epigenetic machinery that generates mtDNA methylation, and are primary sources of oxidative-stress generation in response to exogenous environments. However, no study has yet investigated whether mitochondrial DNA methylation is sensitive to pro-oxidant environmental exposures. METHODS: We sampled 40 male participants (20 high-, 20 low-exposure) from each of three studies on airborne pollutants, including investigations of steel workers exposed to metal-rich particulate matter (measured as PM1) in Brescia, Italy (Study 1); gas-station attendants exposed to air benzene in Milan, Italy (Study 2); and truck drivers exposed to traffic-derived Elemental Carbon (EC) in Beijing, China (Study 3). We have measured DNA methylation from buffy coats of the participants. We measured methylation by bisulfite-Pyrosequencing in three mtDNA regions, i.e., the transfer RNA phenylalanine (MT-TF), 12S ribosomal RNA (MT-RNR1) gene and "D-loop" control region. All analyses were adjusted for age and smoking. RESULTS: In Study 1, participants with high metal-rich PM1 exposure showed higher MT-TF and MT-RNR1 methylation than low-exposed controls (difference = 1.41, P = 0.002); MT-TF and MT-RNR1 methylation was significantly associated with PM1 exposure (beta = 1.35, P = 0.025); and MT-RNR1 methylation was positively correlated with mtDNA copy number (r = 0.36; P = 0.02). D-loop methylation was not associated with PM1 exposure. We found no effects on mtDNA methylation from air benzene (Study 2) and traffic-derived EC exposure (Study 3). CONCLUSIONS: Mitochondrial MT-TF and MT-RNR1 DNA methylation was associated with metal-rich PM1 exposure and mtDNA copy number. Our results suggest that locus specific mtDNA methylation is correlated to selected exposures and mtDNA damage. Larger studies are needed to validate our observations. PMID- 23656718 TI - Baseline predictors of maintenance of intervention-induced changes in physical activity and sitting time among diabetic and pre-diabetic patients: a descriptive case series. AB - BACKGROUND: The aim of this study was to explore the predictive value of baseline characteristics in relation to changes in physical activity (PA) and sedentary behaviour among diabetic and pre-diabetic patients participating in a primary care based exercise intervention. We used a descriptive case series among diabetic and pre-diabetic patients (n = 119, 50.8% male, mean age 65.5 (SD = 7.8)). Measurements took place with questionnaires at baseline and two years after the start of the intervention. Predictor variables included demographic factors, Body Mass Index, baseline PA and sitting time, and baseline socio cognitive profile. RESULTS: At follow-up, respondents spent more time being physically active than at baseline. For the total group, the average sitting time remained almost unchanged between the two measurements. Further exploration showed that respondents who had relatively high levels of PA at the start of the intervention, increased their total sitting time, while respondents with relatively low levels of PA at the start decreased their sitting time. The socio cognitive profile did not predict behaviour change. The intervention appeared to be suitable for people with a low-education level, but the results should be interpreted in view of the limitations of the study such as the non-controlled design, self-reported outcomes and selective drop-out of participants. CONCLUSIONS: Interventions for this specific target group may need to put more emphasis on the prevention of increased sitting time. The finding that the socio cognitive profile did not predict behaviour change may underline the proposition that decisions to initiate and maintain PA behaviour change are to a large extend non-linear events. Acknowledging the possible non-linearity of the relationship between socio-cognitive determinants and behaviour change will help our understanding of this complex and dynamic process. PMID- 23656719 TI - 6-Formylindolo (3,2-b)carbazole (FICZ) enhances retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells. AB - BACKGROUND: The aryl hydrocarbon receptor (AhR) ligand 6-Formylindolo(3,2 b)carbazole (FICZ) has received increasing attention since its identification as an endogenous AhR ligand and a photoproduct of tryptophan. FICZ and its metabolites have been detected in human fluids. We recently reported that AhR promotes retinoic acid (RA)-induced granulocytic differentiation of HL-60 myeloblastic leukemia cells by restricting the nuclear abundance of the stem cell associated transcription factor Oct4. The standard clinical management of acute promyelocytic leukemia (APL) is differentiation induction therapy using RA. But RA is not effective for other myeloid leukemias, making the mechanism of RA induced differentiation observed in a non-APL myeloid leukemia of interest. To our knowledge, this is the first study regarding the influence of FICZ on RA induced differentiation in any type of leukemic blasts. METHODS: Using flow cytometry and Western blotting assays, we determined the effects of FICZ on RA induced differentiation of HL-60 human leukemia cells. All experiments were performed in triplicate. The groups RA and FICZ + RA were compared using the Paired-Samples T-Test. Western blot figures present the typical blots. RESULTS: We demonstrate that FICZ enhances RA-induced differentiation, assessed by the expression of the membrane differentiation marker CD11b; cell cycle arrest; and the functional differentiation marker, inducible-oxidative metabolism. FICZ causes changes in signaling events that are known to drive differentiation, and notably augments the RA-induced sustained activation of the RAF/MEK/ERK axis of the mitogen-activated protein kinase (MAPK) cascade. FICZ also augments expression of the known MAPK signaling regulatory molecules c-Cbl, VAV1, pY458 p85 PI3K, Src-family kinases (SFKs), and IRF-1, a transcription factor associated with this putative signalsome that promotes RA-induced differentiation. Moreover, FICZ in combination with RA also increases expression of AhR and even more so of both Cyp1A2 and p47phox, which are known to be transcriptionally regulated by AhR. pY1021 PDGFRbeta, a marker associated with retinoic acid syndrome was also increased. CONCLUSIONS: Our data suggest that FICZ modulates intracellular signaling pathways and enhances RA-induced differentiation. PMID- 23656720 TI - Improving the prediction of malignancy in cytologically suspicious thyroid nodules. AB - BACKGROUND: Fine needle cytology aspirates (FNA) classified as THY4 are a heterogeneous group suspicious for malignancy [papillary thyroid cancer (PTC)], which is confirmed in 50-80% of cases after surgery. AIM: To better stratify THY4 FNA specimens for the relative risk of malignancy. METHODS: We retrospectively analyzed 78 thyroid nodules classified as THY4 because of the presence of atypical cells, hypercellular trabeculae and/or intranuclear inclusions (ICI), in the absence of papillae. Two subgroups were identified: group 1 (38 nodules), showing ICI with (no.=17) or without (no.=21) trabeculae and cellular atypia, and group 2 (40 nodules), showing trabeculae and atypia but without ICI. RESULTS: PTC was detected at histology in 56/78 of the patients (71.8%). Malignancy occurred in 36/38 (94.7%) of the patients in group 1 and in 20/40 (50.0%) of the patients in group 2. Therefore, the positive predictive value (PPV) for PTC was 97.3% in the ICI+ specimens (group 1), with a sensitivity of 64.3% and specificity of 95.2%. When only ICI was present, without atypia and trabeculae, the PPV and specificity were similar (95.0 and 95.2%, respectively), but the sensitivity was decreased (48.7%). In specimens without ICI (group 2), the PPV was only 50.0%; however, combined with young age (<40 yr) and male gender, it reached a value similar to that of group1. CONCLUSIONS: In ICI+ specimens compared to ICI-, the risk of PTC is nearly doubled, since PPV increases from 50.0% to 97.3%. This observation suggests that surgery should be considered mandatory in all lesions classified THY4 at FNA, although the relevant difference in terms of cancer risk between ICI- vs ICI+ nodules might be an useful information for both the clinician and the patient. PMID- 23656721 TI - A resource of genome-wide single-nucleotide polymorphisms generated by RAD tag sequencing in the critically endangered European eel. AB - Reduced representation genome sequencing such as restriction-site-associated DNA (RAD) sequencing is finding increased use to identify and genotype large numbers of single-nucleotide polymorphisms (SNPs) in model and nonmodel species. We generated a unique resource of novel SNP markers for the European eel using the RAD sequencing approach that was simultaneously identified and scored in a genome wide scan of 30 individuals. Whereas genomic resources are increasingly becoming available for this species, including the recent release of a draft genome, no genome-wide set of SNP markers was available until now. The generated SNPs were widely distributed across the eel genome, aligning to 4779 different contigs and 19,703 different scaffolds. Significant variation was identified, with an average nucleotide diversity of 0.00529 across individuals. Results varied widely across the genome, ranging from 0.00048 to 0.00737 per locus. Based on the average nucleotide diversity across all loci, long-term effective population size was estimated to range between 132,000 and 1,320,000, which is much higher than previous estimates based on microsatellite loci. The generated SNP resource consisting of 82,425 loci and 376,918 associated SNPs provides a valuable tool for future population genetics and genomics studies and allows for targeting specific genes and particularly interesting regions of the eel genome. PMID- 23656722 TI - (3 + 1)D superspace description of the incommensurate modulation in the premartensite phase of Ni2MnGa: a high resolution synchrotron x-ray powder diffraction study. AB - Le Bail and Rietveld analysis of high resolution synchrotron x-ray powder diffraction (SXRPD) data shows unambiguous signatures of the failure of the commensurate 3M modulation model. Using (3 + 1) dimensional superspace group formalism, we have not only confirmed the incommensurate modulation in the premartensite phase with a modulation wavevector of q = 0.337 61(5)c* but also determined the superspace group (Immm(00gamma)s00), atomic positions and amplitude of modulations for the incommensurate premartensite phase of Ni2MnGa for the first time. Our results may have important implications in the understanding of the martensitic transition and hence the magnetic field induced strains. PMID- 23656723 TI - Understanding the etiology of prescription opioid abuse: implications for prevention and treatment. AB - Although studies on the initiation of substance abuse abound, the body of literature on prescription opioid abuse (POA) etiology is small. Little is known about why and how the onset of POA occurs, especially among high-risk populations. In this study we aimed to fill this important knowledge gap by exploring the POA initiation experiences of 90 prescription opioid abusers currently in treatment and their narrative accounts of the circumstances surrounding their POA onset. This research was conducted within a storyline framework, which operates on the premise that the path to drug abuse represents a biography or a process rather than a static condition. Audiotapes of in-depth interviews were transcribed, coded, and thematically analyzed. Analyses revealed the presence of four trajectories leading to POA. This study adds to the limited research on POA etiology by not only illuminating the psychosocial factors that contribute to POA onset, but also by situating initiation experiences within broader life processes. The study findings provide crucial insights to policymakers and interventionists in identifying who is at risk for POA, and more important, when and how to intervene most efficaciously. PMID- 23656725 TI - Management of the most common ENT presentations. PMID- 23656724 TI - Effects of a ketogenic diet during pregnancy on embryonic growth in the mouse. AB - BACKGROUND: The increasing use of the ketogenic diet (KD), particularly by women of child-bearing age, raises a question about its suitability during gestation. To date, no studies have thoroughly investigated the direct implications of a gestational ketogenic diet on embryonic development. METHODS: To fill this knowledge gap we imaged CD-1 mouse embryos whose mothers were fed either a Standard Diet (SD) or a KD 30 days prior to, as well as during gestation. Images were collected at embryonic days (E) 13.5 using Optical Projection Tomography (OPT) and at E17.5 using Magnetic Resonance Imaging (MRI). RESULTS: An anatomical comparison of the SD and KD embryos revealed that at E13.5 the average KD embryo was volumetrically larger, possessed a relatively larger heart but smaller brain, and had a smaller pharynx, cervical spinal cord, hypothalamus, midbrain, and pons, compared with the average SD embryo. At E17.5 the KD embryo was found to be volumetrically smaller with a relatively smaller heart and thymus, but with enlarged cervical spine, thalamus, midbrain and pons. CONCLUSION: A ketogenic diet during gestation results in alterations in embryonic organ growth. Such alterations may be associated with organ dysfunction and potentially behavioral changes in postnatal life. PMID- 23656726 TI - Effects of long-term administration of saturated and n-3 fatty acid-rich diets on lipid utilisation and oxidative stress in rat liver and muscle tissues. AB - The incidence of metabolic syndrome components including obesity, lipid deregulation, insulin resistance (IR) and non-alcoholic fatty liver disease is increasing rapidly in wealthy societies. The present study was designed to determine the effect of different nutritional lipid patterns (quantity and quality) on lipid utilisation and oxidative stress in the liver and muscle of rats in an integrated fashion. A total of forty-eight Wistar male rats were fed for 12 weeks with a mixed, lard or fish-oil diet, containing either 50 or 300 g lipid/kg. Rats developed liver steatosis associated with moderate liver injury when fed the 30% lipid diets, in spite of the absence of overt obesity or IR, except when fed the lard 30% lipid diet. The intake of the 30% lipid diets decreased hepatic lipogenesis and mitochondriogenesis and increased lipid peroxidation and protein oxidation. Surprisingly, muscle lipid content was not modified whatever the administered diet. The intake of the 30% lipid diets increased the muscle protein expression of fatty acid (FA) translocase/cluster of differentiation 36 (FAT/CD36), PPARg co-activator 1a (PGC-1a) and muscle carnitine palmitoyltransferase 1 (m-CPT1), reflecting increased FA transport in the muscle associated with increased oxidative metabolism. The lard 30% lipid diet led to IR without modifying the muscle lipid content. The fish-oil 30% lipid diet failed to prevent the development of hepatic steatosis and made the tissues more prone to oxidation. Overall, the present study suggests that the FA composition of muscle is more important than lipid accumulation itself in the modulation of insulin sensitivity, and indicates that precaution should be taken when advising an unphysiologically high (pharmacological) supplementation with long-chain n-3 PUFA. PMID- 23656727 TI - Expectations of iPad use in an internal medicine residency program: is it worth the "hype"? AB - BACKGROUND: While early reports highlight the benefits of tablet computing in hospitals, introducing any new technology can result in inflated expectations. OBJECTIVE: The aim of the study is to compare anticipated expectations of Apple iPad use and perceptions after deployment among residents. METHODS: 115 internal medicine residents received Apple iPads in October 2010. Residents completed matched surveys on anticipated usage and perceptions after distribution 1 month prior and 4 months after deployment. RESULTS: In total, 99% (114/115) of residents responded. Prior to deployment, most residents believed that the iPad would improve patient care and efficiency on the wards; however, fewer residents "strongly agreed" after deployment (34% vs 15% for patient care, P<.001; 41% vs 24% for efficiency, P=.005). Residents with higher expectations were more likely to report using the iPad for placing orders post call and during admission (71% vs 44% post call, P=.01, and 16% vs 0% admission, P=.04). Previous Apple iOS product owners were also more likely to use the iPad in key areas. Overall, 84% of residents thought the iPad was a good investment for the residency program, and over half of residents (58%) reported that patients commented on the iPad in a positive way. CONCLUSIONS: While the use of tablets such as the iPad by residents is generally well received, high initial expectations highlight the danger of implementing new technologies. Education on the realistic expectations of iPad benefits may be warranted. PMID- 23656728 TI - Transfusion suppresses erythropoiesis and increases hepcidin in adult patients with beta-thalassemia major: a longitudinal study. AB - beta-Thalassemia major causes ineffective erythropoiesis and chronic anemia and is associated with iron overload due to both transfused iron and increased iron absorption, the latter mediated by suppression of the iron-regulatory hormone hepcidin. We sought to determine whether, in beta-thalassemia major, transfusion mediated inhibition of erythropoiesis dynamically affects hepcidin. We recruited 31 chronically transfused patients with beta-thalassemia major and collected samples immediately before and 4 to 8 days after transfusion. Pretransfusion hepcidin was positively correlated with hemoglobin and ferritin and inversely with erythropoiesis. The hepcidin-ferritin ratio indicated hepcidin was relatively suppressed given the degree of iron loading. Posttransfusion, hemoglobin and hepcidin increased, and erythropoietin and growth differentiation factor-15 decreased. By multiple regression, pre- and posttransfusion hepcidin concentrations were both associated positively with hemoglobin, inversely with erythropoiesis, and positively with ferritin. Although men and women had similar pretransfusion hemoglobin, men had significantly increased erythropoiesis and lower hepcidin, received a lower transfusion volume per liter blood volume, and experienced a smaller posttransfusion reduction in erythropoiesis and hepcidin rise. Age of blood was not associated with posttransfusion hemoglobin or ferritin change. Hepcidin levels in patients with beta-thalassemia major dynamically reflect competing influences from erythropoiesis, anemia, and iron overload. Measurement of these indices could assist clinical monitoring. PMID- 23656729 TI - Recombinant HPA-1a antibody therapy for treatment of fetomaternal alloimmune thrombocytopenia: proof of principle in human volunteers. AB - Fetomaternal alloimmune thrombocytopenia, caused by the maternal generation of antibodies against fetal human platelet antigen-1a (HPA-1a), can result in intracranial hemorrhage and intrauterine death. We have developed a therapeutic human recombinant high-affinity HPA-1a antibody (B2G1Deltanab) that competes for binding to the HPA-1a epitope but carries a modified constant region that does not bind to Fcgamma receptors. In vitro studies with a range of clinical anti-HPA 1a sera have shown that B2G1Deltanab blocks monocyte chemiluminescence by >75%. In this first-in-man study, we demonstrate that HPA-1a1b autologous platelets (matching fetal phenotype) sensitized with B2G1Deltanab have the same intravascular survival as unsensitized platelets (190 hours), while platelets sensitized with a destructive immunoglobulin G1 version of the antibody (B2G1) are cleared from the circulation in 2 hours. Mimicking the situation in fetuses receiving B2G1Deltanab as therapy, we show that platelets sensitized with a combination of B2G1 (representing destructive HPA-1a antibody) and B2G1Deltanab survive 3 times as long in circulation compared with platelets sensitized with B2G1 alone. This confirms the therapeutic potential of B2G1Deltanab. The efficient clearance of platelets sensitized with B2G1 also opens up the opportunity to carry out studies of prophylaxis to prevent alloimmunization in HPA-1a-negative mothers. PMID- 23656731 TI - High-throughput sequencing of B- and T-lymphocyte antigen receptors in hematology. AB - Application of high-throughput DNA sequencing to the analysis of B- and T lymphocyte antigen receptors has great potential for improving the monitoring of lymphoid malignancies, assessing immune reconstitution after hematopoietic cell transplantation, and characterizing the composition of lymphocyte repertoires. Current technology can define the number and frequency of immunoglobulin heavy, T cell receptor (TCR)alpha, TCRbeta, or TCRgamma chains expressed in a population of lymphocytes; techniques for determining the number of antigen receptor heterodimers, such as TCRalphabeta pairs, expressed in the population are under development. PMID- 23656732 TI - Health promotion in Australian multi-disciplinary primary health care services: case studies from South Australia and the Northern Territory. AB - This paper reports on the health promotion and disease prevention conducted at Australian multi-disciplinary primary health care (PHC) services and considers the ways in which the organizational environment affects the extent and type of health promotion and disease prevention activity. The study involves five PHC services in Adelaide and one in Alice Springs. Four are managed by a state health department and two by boards of governance. The study is based on an audit of activities and on 68 interviews conducted with staff. All the sites undertake health promotion and recognize its importance but all report that this activity is under constant pressure resulting from the need to provide services to people who have health problems. We also found an increased focus on chronic disease management and prevention which prioritized individuals and behavioural change strategies rather than addressing social determinants affecting whole communities. There was little health promotion work that reflected a salutogenic approach to the creation of health. Most activity falls under three types: parenting and child development, chronic disease prevention and mental health. Only the non-government organizations reported advocacy on broader policy issues. Health reform and consequent reorganizations were seen to reduce the ability of some services to undertake health promotion. The paper concludes that PHC in Australia plays an important role in disease prevention, but that there is considerable scope to increase the amount of community-based health promotion which focuses on a salutogenic view of health and which engages in community partnerships. PMID- 23656733 TI - Participation in paediatric cancer studies: timing and approach to recruitment. AB - BACKGROUND: Participation in epidemiological studies has fallen significantly over the past 30 years; this has been attributed to a busier lifestyle and longer working hours. In case-control studies, participation among cases is usually higher than among controls due to the personal relevance. In Australia, between 2003 and 2011, we conducted three national population-based case-control studies of risk factors for childhood cancers; brain tumors, acute leukemia and neuroblastoma and Wilms' tumor. In this sub-study, we aimed to investigate factors that may have influenced study participation and completeness of survey completion. FINDINGS: The proportion of incident cases that were eligible to participate was lowest in the brain tumor study (Aus-CBT) (83.1%), as was the proportion of eligible families that consented (57%). The percentage of eligible cases that consented was highest in the leukemia study (Aus-ALL) (80.2%). The mode of invitation used was associated with families' consent in each of the studies. Families invited in person, at clinic appointments, were more likely to consent than families invited by letter or phone. Timing of invitation following the child's diagnosis differed among studies but, the likelihood of consent did not appear to be directly related to this. The return of questionnaires, completion of interview, and provision of DNA (blood sample) was highest in Aus ALL (93%) and lowest in Aus-CBT (81%). CONCLUSIONS: Studies of childhood cancer, and possibly other childhood diseases, should arrange for the family to be invited in person and, where possible, by a doctor with whom they are familiar. Whilst telephone interviews are time consuming and costly, particularly for large studies, they should be preferred over questionnaires for obtaining complete data. PMID- 23656730 TI - The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML. AB - Mutations of the NPM1 gene (NPM1mut) are among the most common genetic alterations in acute myeloid leukemia and are suitable for minimal residual disease detection. We retrospectively investigated the prognostic impact of NPM1mut-based minimal residual disease detection from bone marrow for development of relapse by using a newly developed real-time polymerase chain reaction based on locked nucleic acid-containing primers in 174 patients, 155 of whom were treated within prospective protocols. The prognostic value of 5 cutoff values after completion of treatment or after allogeneic transplantation was studied by using cause-specific hazard models. Subsequent validation using cross-validated partial likelihood analysis revealed that an increase of more than 1% NPM1mut/ABL1 was most prognostic for relapse after chemotherapy, whereas an increase of more than 10% NPM1mut/ABL1 was most prognostic for relapse after allogeneic transplantation. Univariate and multivariate analysis of disease-free survival and overall survival revealed a significantly worse outcome in patients with >1% NPM1mut/ABL1 and >10% NPM1mut/ABL1, respectively, which remained significant after adjustment for FLT3-internal tandem duplication status. Our results in a large data set define and optimize cutoff values for early diagnosis of molecular relapse. These results may be especially important for defining triggers for early therapeutic intervention. PMID- 23656734 TI - Proteolytic activation transforms heparin cofactor II into a host defense molecule. AB - The abundant serine proteinase inhibitor heparin cofactor II (HCII) has been proposed to inhibit extravascular thrombin. However, the exact physiological role of this plasma protein remains enigmatic. In this study, we demonstrate a previously unknown role for HCII in host defense. Proteolytic cleavage of the molecule induced a conformational change, thereby inducing endotoxin-binding and antimicrobial properties. Analyses employing representative peptide epitopes mapped these effects to helices A and D. Mice deficient in HCII showed increased susceptibility to invasive infection by Pseudomonas aeruginosa, along with a significantly increased cytokine response. Correspondingly, decreased levels of HCII were observed in wild-type animals challenged with bacteria or endotoxin. In humans, proteolytically cleaved HCII forms were detected during wounding and in association with bacteria. Thus, the protease-induced uncovering of cryptic epitopes in HCII, which transforms the molecule into a host defense factor, represents a previously unknown regulatory mechanism in HCII biology and innate immunity. PMID- 23656735 TI - Mechanism of IL-1beta modulation of intestinal epithelial barrier involves p38 kinase and activating transcription factor-2 activation. AB - The defective intestinal epithelial tight junction (TJ) barrier has been postulated to be an important pathogenic factor contributing to intestinal inflammation. It has been shown that the proinflammatory cytokine IL-1beta causes an increase in intestinal permeability; however, the signaling pathways and the molecular mechanisms involved remain unclear. The major purpose of this study was to investigate the role of the p38 kinase pathway and the molecular processes involved. In these studies, the in vitro intestinal epithelial model system (Caco 2 monolayers) was used to delineate the cellular and molecular mechanisms, and a complementary in vivo mouse model system (intestinal perfusion) was used to assess the in vivo relevance of the in vitro findings. Our data indicated that the IL-1beta increase in Caco-2 TJ permeability correlated with an activation of p38 kinase. The activation of p38 kinase caused phosphorylation and activation of p38 kinase substrate, activating transcription factor (ATF)-2. The activated ATF 2 translocated to the nucleus where it attached to its binding motif on the myosin L chain kinase (MLCK) promoter region, leading to the activation of MLCK promoter activity and gene transcription. Small interfering RNA induced silencing of ATF-2, or mutation of the ATF-2 binding motif prevented the activation of MLCK promoter and MLCK mRNA transcription. Additionally, in vivo intestinal perfusion studies also indicated that the IL-1beta increase in mouse intestinal permeability required p38 kinase-dependent activation of ATF-2. In conclusion, these studies show that the IL-1beta-induced increase in intestinal TJ permeability in vitro and in vivo was regulated by p38 kinase activation of ATF-2 and by ATF-2 regulation of MLCK gene activity. PMID- 23656736 TI - PD-L1/B7-H1 regulates the survival but not the function of CD8+ T cells in herpes simplex virus type 1 latently infected trigeminal ganglia. AB - HSV type 1 (HSV-1)-specific CD8(+) T cells provide immunosurveillance of trigeminal ganglion (TG) neurons that harbor latent HSV-1. In C57BL/6 mice, the TG-resident CD8(+) T cells are HSV specific and maintain a 1:1 ratio of cells recognizing an immunodominant epitope on viral glycoprotein B (gB498-505-Tet(+)) and cells reactive to subdominant epitopes (gB-Tet(-)). The gB-Tet(-) CD8(+) T cells maintain their frequency in TG by balancing a higher rate of proliferation with a correspondingly higher rate of apoptosis. The increased apoptosis is associated with higher expression of programmed death-1 (PD-1) on gB-Tet(-) CD8(+) T cells and the interaction with PD-1 ligand (PD-L1/B7-H1). IFN-gamma regulated expression of the PD-1 ligand (PD-L1/B7-H1) on neurons bearing higher copies of latent viral genome. In latently infected TG of B7-H1(-/-) mice, the number and frequency of PD-1(+) gB-Tet(-) CD8(+) T cells increases dramatically, but gB-Tet(-) CD8(+) T cells remain largely nonfunctional and do not provide increased protection from HSV-1 reactivation in ex vivo cultures of latently infected TG. Unlike observations in some chronic infection models, B7-H1 blockade did not increase the function of exhausted gB-Tet(-) CD8 T cells in latently infected TG. PMID- 23656737 TI - CXCR3 deficiency prolongs Th1-type contact hypersensitivity. AB - Sensitization and challenge using dinitrofluorobenzene (DNFB) induce contact hypersensitivity (CHS) with Th1 cell infiltration, whereas those using FITC generate CHS with Th2 cell infiltration. In this study, we attempted to determine the role of CXCR3, a chemokine receptor, in Th1- and Th2-type CHS induced by DNFB or FITC using CXCR3-deficient (CXCR3(-/-)) mice. Ear swelling was prolonged after DNFB challenge in CXCR3(-/-) mice, which was accompanied by increased Th1 cytokines and decreased TGF-beta and IL-10 expression at a late time point of CHS, whereas there was no significant difference between wild-type and CXCR3(-/-) mice in FITC-induced CHS. In Th1-type CHS, the number of regulatory T cells (Tregs) was decreased in the challenged ear of CXCR3(-/-) mice compared with that of wild-type mice, suggesting that CXCR3 would be important in migration of Tregs into the site of inflammation. Moreover, we examined the characteristics of CXCR3(+) Tregs both in vitro and in vivo, revealing that CXCR3(+) Tregs expressed high levels of TGF-beta and IL-10 as well as IFN-gamma compared with CXCR3(-) Tregs. When CXCR3(-/-) mice were injected with CXCR3(+) Tregs, the prolonged ear swelling induced by DNFB was normalized. Taken together, our results suggest that CXCR3(+) Tregs play a key role for quenching Th1-type CHS. PMID- 23656739 TI - Solvent-free enzymatic synthesis of 1, 3-diacylglycerols by direct esterification of glycerol with saturated fatty acids. AB - BACKGROUND: Pure 1, 3-diacylglycerols (1, 3-DAG) have been considered to be significant surfactants in food, cosmetics and pharmaceutical industries, as well as the effect on obesity prevention. METHODS: In this study, a vacuum-driven air bubbling operation mode was developed and evaluated for the enzymatic synthesis of 1, 3-DAG of saturated fatty acids, by direct esterification of glycerol with fatty acids in a solvent-free system. The employed vacuum-driven air bubbling operation mode was comparable to vacuum-driven N2 bubbling protocol, in terms of lauric acid conversion and 1, 3-dilaurin content. RESULTS: Some operation parameters were optimized, and 95.3% of lauric acid conversion and 80.3% of 1, 3 dilaurin content was obtained after 3-h reaction at 50 degrees C, with 5 wt% of Lipozyme RM IM (based on reactants) amount. Of the lipases studied, both Lipozyme RM IM and Novozym 435 exhibited good performance in terms of lauric acid conversion. Lipozyme TL IM, however, showed low activity. Lipozyme RM IM showed good operational stability in this operation protocol, 80.2% of the original catalytic activity remained after 10 consecutive batch applications. Some other 1, 3-DAG were prepared and high content was obtained after purification: 98.5% for 1, 3-dicaprylin, 99.2% for 1, 3-dicaprin, 99.1% for 1, 3-dilaurin, 99.5 for 1, 3-dipalmitin and 99.4% for 1, 3-disterin. CONCLUSION: The established vacuum driven air bubbling operation protocol had been demonstrated to be a simple operating, cost-effective, application practical and efficient methodology for 1, 3-DAG preparation. PMID- 23656738 TI - Markers of nonselective and specific NK cell activation. AB - NK cell activation is controlled by the integration of signals from cytokine receptors and germline-encoded activation and inhibitory receptors. NK cells undergo two distinct phases of activation during murine CMV (MCMV) infection: a nonselective phase mediated by proinflammatory cytokines and a specific phase driven by signaling through Ly49H, an NK cell activation receptor that recognizes infected cells. We sought to delineate cell surface markers that could distinguish NK cells that had been activated nonselectively from those that had been specifically activated through NK cell receptors. We demonstrated that stem cell Ag 1 (Sca-1) is highly upregulated during viral infections (to an even greater extent than CD69) and serves as a novel marker of early, nonselective NK cell activation. Indeed, a greater proportion of Sca-1(+) NK cells produced IFN gamma compared with Sca-1(-) NK cells during MCMV infection. In contrast to the universal upregulation of Sca-1 (as well as KLRG1) on NK cells early during MCMV infection, differential expression of Sca-1, as well as CD27 and KLRG1, was observed on Ly49H(+) and Ly49H(-) NK cells late during MCMV infection. Persistently elevated levels of KLRG1 in the context of downregulation of Sca-1 and CD27 were observed on NK cells that expressed Ly49H. Furthermore, the differential expression patterns of these cell surface markers were dependent on Ly49H recognition of its ligand and did not occur solely as a result of cellular proliferation. These findings demonstrate that a combination of Sca-1, CD27, and KLRG1 can distinguish NK cells nonselectively activated by cytokines from those specifically stimulated through activation receptors. PMID- 23656740 TI - Glucose-stimulated insulin secretion: Effects of high-fat diet and acute stress. AB - BACKGROUND: One of the major topics in modern societies is the study of relationships between diet, stress and incidence of metabolic disorders. AIM: This study aimed to investigate possible impairment in glucose-stimulated insulin secretion induced by a high-fat (cow intra-abdominal fat) diet in response to acute stress. MATERIALS AND METHODS: Male Wistar rats were divided into high-fat and normal diet groups and each group was further divided into stress and control subgroups. Stress was induced by a communication box. Plasma levels of glucose, insulin and corticosterone were measured in both diet groups. Glucose tolerance, homeostasis model assessment of insulin resistance (HOMA-IR) index, glucose stimulated insulin secretion from isolated islets, food and energy intake as well as body weight were also evaluated. RESULTS: In the normal diet group, physical stress increased plasma glucose concentrations. In both diet groups, plasma corticosterone levels increased after stress. HOMA-IR index decreased in high-fat fed rats. Food intake decreased while energy intake increased in the high-fat diet rats. Body weight in both diet groups increased in a similar manner. The high-fat diet did not affect insulin secretion; however, stress decreased insulin secretion from isolated islets of both diet groups. Only in the high fat diet group did physical stress increase insulin secretion at 16.7 mM glucose. CONCLUSIONS: The cow intra-abdominal fat, did not affect either plasma glucose and insulin concentrations or glucose-induced insulin secretion. Interestingly, it seems that the high-fat diet enabled the islets of the physically stressed rats to secrete more insulin in response to high glucose concentrations. PMID- 23656741 TI - A first-principles study on defect association and oxygen ion migration of Sm3+ and Gd3+ co-doped ceria. AB - First-principles calculations based on density functional theory were performed to investigate the co-doping effects of Sm and Gd in ceria on its oxygen ion conduction. The focus of this study is on the interactions between the cation dopants and an oxygen vacancy within the two adjacent tetrahedral sites of fluorite structure surrounding the oxygen migration path. Vacancy formation energies, dopant-vacancy association energies, and migration energies were calculated to elucidate the doping effects on oxygen ion conduction. The migration energies show remarkable dependences on the ionic radii of the cations located at the edges of the migration path. A simple relation between migration energy and vacancy formation energy is proposed. This work provides an informative insight into vacancy diffusion that could be useful in optimizing doping materials for improving oxygen ion conductivity in doped ceria. PMID- 23656743 TI - Guideline for the management of acute asthma in adults: 2013 update. AB - Acute asthma attacks (asthma exacerbations) are increasing episodes of shortness of breath, cough, wheezing or chest tightness associated with a decrease in airflow that can be quantified and monitored by measurement of lung function (peak expiratory flow (PEF) or forced expiratory volume in the 1st second) and requiring emergency room treatment or admission to hospital for acute asthma and/or systemic glucocorticosteroids for management. The goals of treatment are to relieve hypoxaemia and airflow obstruction as quickly as possible, restore lung function, and provide a suitable plan to avoid relapse. Severe exacerbations are potentially life-threatening and their treatment requires baseline assessment of severity, close monitoring, and frequent reassessment using objective measures of lung function (PEF) and oxygen saturation. Patients at high risk of asthma related death require particular attention. First-line therapy consists of oxygen supplementation, repeated administration of inhaled short-acting bronchodilators (beta-2-agonists and ipratropium bromide), and early systemic glucocorticosteroids. Intravenous magnesium sulphate and aminophylline are second and third-line treatment strategies, respectively, for poorly responding patients. Intensive care is indicated for severe asthma that is not responsive to first-line treatment. Antibiotics are only indicated when there are definite features of bacterial infection. Factors that precipitated the acute asthma episode should be identified and preventive measures implemented. Acute asthma is preventable with optimal control of chronic asthma. PMID- 23656742 TI - Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. AB - The aims of severe perioperative bleeding management are three-fold. First, preoperative identification by anamesis and laboratory testing of those patients for whom the perioperative bleeding risk may be increased. Second, implementation of strategies for correcting preoperative anaemia and stabilisation of the macro- and microcirculations in order to optimise the patient's tolerance to bleeding. Third, targeted procoagulant interventions to reduce the amount of bleeding, morbidity, mortality and costs. The purpose of these guidelines is to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthetists throughout Europe to integrate this knowledge into daily patient care wherever possible. The Guidelines Committee of the European Society of Anaesthesiology (ESA) formed a task force with members of scientific subcommittees and individual expert members of the ESA. Electronic databases were searched without language restrictions from the year 2000 until 2012. These searches produced 20 664 abstracts. Relevant systematic reviews with meta-analyses, randomised controlled trials, cohort studies, case-control studies and cross-sectional surveys were selected. At the suggestion of the ESA Guideline Committee, the Scottish Intercollegiate Guidelines Network (SIGN) grading system was initially used to assess the level of evidence and to grade recommendations. During the process of guideline development, the official position of the ESA changed to favour the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. This report includes general recommendations as well as specific recommendations in various fields of surgical interventions. The final draft guideline was posted on the ESA website for four weeks and the link was sent to all ESA members. Comments were collated and the guidelines amended as appropriate. When the final draft was complete, the Guidelines Committee and ESA Board ratified the guidelines. PMID- 23656745 TI - Guideline for the management of acute asthma in children: 2013 update. AB - BACKGROUND: Acute asthma exacerbations remain a common cause of hospitalisation and healthcare utilisation in South African children. AIM: To update the South African paediatric acute asthma guidelines according to current evidence, and produce separate recommendations for children above and below 2 years of age. METHODS: A working group of the South African Childhood Asthma Group was established to review the published literature on acute asthma in children from 2000 to 2012, and to revise the South African guidelines accordingly. RECOMMENDATIONS: Short-acting inhaled bronchodilators remain the first-line treatment of acute asthma. A metered-dose inhaler with spacer is preferable to nebulisation for bronchodilator therapy to treat mild to moderate asthma. Two to four puffs of a short-acting bronchodilator given every 20 - 30 minutes, depending on clinical response, should be given for mild attacks; up to 10 puffs may be needed for more severe asthma. Children with severe asthma or oxygen saturation (SpO2) <92% should receive oxygen and frequent doses of nebulised beta 2-agonists, and be referred to hospital. Nebulised ipratropium bromide (via nebulisation or multidosing via pMDI-spacer combination) should be added if there is a poor response to three doses of beta2-agonist or if the symptoms are severe. Early use of corticosteroids reduces the need for hospital admission and prevents relapse; oral therapy is preferable. Assessment of acute asthma in children below the age of 2 years can be difficult, and other causes of wheezing must be excluded. Treatment of acute asthma in this age group is similar to that of older children. CONCLUSION: Effective therapy for treatment of acute asthma - primarily inhaled short-acting beta2-agonists, oral corticosteroids and oxygen with appropriate delivery systems - should be available in all healthcare facilities and rapidly instituted for treatment of acute asthma in children. ENDORSEMENT: The guideline document was endorsed by the Allergy Society of South Africa (ALLSA), the South African Thoracic Society (SATS), the National Asthma Education Programme (NAEP), the South African Paediatric Association (SAPA) and the South African Academy of Family Practice. PMID- 23656746 TI - One-year cardiovascular risk and quality of life changes in participants of a health trainer service. AB - AIMS: To explore 12-month changes in cardiovascular disease (CVD) risk and health related quality of life (HRQoL) in participants of a health trainer (HT) programme. METHODS: Participants were 994 adults with at least one established CVD risk factor who were referred to a HT programme. The primary outcome was 12 month change in Framingham 10 year CVD risk score. Secondary outcomes included change in individual risk factors and HRQoL. Intention to treat analysis was used to explore 12-month changes for the overall population and those classified 'high risk' (>=20% CVD risk) at baseline. RESULTS: At baseline, 33.6% of participants were classified as 'high CVD risk' and 95.7% were overweight or obese. There were modest 12-month improvements in most modifiable CVD risk factors, but not overall CVD risk (-0.25+/-6.50%). In 'high-risk' participants significant reductions were evident for overall CVD risk (-2.34+/-8.13%) and individual risk factors. Small, significant 12-month HRQoL improvements were observed, but these were not associated with CVD risk change. CONCLUSIONS: Significant CVD risk reductions in participants in this HT programme with high baseline CVD risk (.20%) in HRQoL in the population as a whole indicated that the programme in its current form should target high-risk patients. PMID- 23656747 TI - Therapeutic alliance in early schizophrenia spectrum disorders: a cross-sectional study. AB - BACKGROUND: The therapeutic alliance is related to better course and outcome of treatment in schizophrenia. This study explores predictors and characteristics of the therapeutic alliance in recent-onset schizophrenia spectrum disorders including the agreement between patient and therapist alliance ratings. METHODS: Forty-two patients were assessed with demographic, neurocognitive, and clinical measures including the Positive and Negative Syndrome Scale (PANSS). The therapeutic alliance was measured with the Working Alliance Inventory - Short Form (WAI-S). RESULTS: Patient WAI-S total scores were predicted by age and PANSS excitative symptoms. Therapist WAI-S total scores were predicted by PANSS insight. Patient and therapist WAI-S total scores were moderately associated. Neurocognition was not associated with working alliance. CONCLUSION: Working alliance is associated with specific demographic and symptom characteristics in patients with recent-onset schizophrenia spectrum disorders. There is moderate agreement between patients and therapists on the total quality of their working alliance. Findings highlight aspects that may increase therapists' specificity in the use of alliance-enhancing strategies. PMID- 23656748 TI - Efficacy, safety, and medication errors associated with the use of inhaled epoprostenol for adults with acute respiratory distress syndrome: a pilot study. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is a type of hypoxic respiratory failure that results from ventilation and perfusion mismatching. Inhaled epoprostenol induces relaxation of smooth muscle in pulmonary vasculature, leading to improved oxygenation. OBJECTIVE: To determine if the use of inhaled epoprostenol produced a 10% or greater increase in the ratio of arterial partial pressure of oxygen (PaO2) to fraction of inspired oxygen (FiO2) in ARDS patients and to review adverse events and medication errors. METHODS: An observational chart review was performed based on a report generated from the electronic medical record system. Patients who received at least 1 dose of inhaled epoprostenol from January 1, 2008, to December 31, 2010, at any hospital within the Florida Hospital Health System were considered for inclusion. Demographics, dose, duration of therapy, adverse effects, medication errors, and outcomes data were collected. RESULTS: Sixteen patients were included in the study. Oxygenation improved by 10% or more in 62.5% (10/16) of the patients, with an initial (within the first 4 hours) median increase of 44.5% in PaO2/FiO2. The mean (SD) starting dose was 30 (10) ng/kg/min. Medication errors were observed in 25% (4/16) of patients. Hypotension was the most frequently observed adverse event, with a rate of 18.8% (3/16). CONCLUSIONS: Based on study findings, inhaled epoprostenol may improve oxygenation in patients with ARDS, with findings suggesting a 62.5% response to therapy. The significance of these effects on improving survival remains unknown. The frequency of medication errors observed in this study poses a significant concern regarding the administration of epoprostenol. Further controlled prospective studies are needed to determine the role of inhaled epoprostenol in improving survival in patients with ARDS. PMID- 23656749 TI - Ranibizumab: the first vascular endothelial growth factor inhibitor approved for the treatment of diabetic macular edema. AB - OBJECTIVE: To review the pharmacology, efficacy, and safety data available for ranibizumab and compare the drug to other therapeutic options for diabetic macular edema (DME) to determine its likely role in therapy. DATA SOURCES: A PubMed search was initially used to identify all trials pertaining to the use of ranibizumab for DME. This search was conducted in February 2013 without a time frame for exclusion of older trials (all references included were published between January 1987 and February 2013). Following a review of the references of these articles, additional sources were obtained from PubMed, the manufacturer's website, and clinicaltrials.gov. STUDY SELECTION AND DATA EXTRACTION: Trials conducted in animals and those written in a language other than English were excluded. Abstracts of remaining trials were reviewed for determination of relevance to this review. Preference was given to randomized controlled trials. Additional information sources were obtained from a review of references as deemed necessary by the authors. DATA SYNTHESIS: Six Phase 2 or 3 randomized controlled trials studying the effects of ranibizumab in patients with DME were identified. Within these trials, ranibizumab consistently produced significantly greater gains in mean best corrected visual acuity than focal/grid laser photocoagulation or sham (7.4-12.5 letter improvement with ranibizumab vs 0.5-3 letters following focal/grid laser photocoagulation monotherapy) with a favorable safety and tolerability profile. Ranibizumab was also studied in combination with focal/grid laser photocoagulation, showing no additional gains in vision versus ranibizumab monotherapy. CONCLUSIONS: The identified trials provide support for the safety and efficacy of ranibizumab in the treatment of vision loss due to DME and present a strong case for the shift to first-line treatment with vascular endothelial growth factor inhibitors from focal/grid laser photocoagulation, the standard of care since the Early Treatment Diabetic Retinopathy Study of 1985. PMID- 23656751 TI - Pharmacist-physician collaboration for diabetes care: the diabetes initiative program. AB - BACKGROUND: Multiple complications can arise secondary to poor control of glucose, blood pressure, and cholesterol in a patient with diabetes. OBJECTIVE: To evaluate the effect of a pharmacist-physician collaboration on attainment of diabetes-related measures of control. METHODS: This was a prospective, multicenter, cohort study. Patients were enrolled from 7 practice sites throughout Tennessee if they had been diagnosed with type 2 diabetes, were aged 18 years or older with a life expectancy greater than 1 year, and were English speaking. Pregnant women were excluded. Patients were followed for 12 months following enrollment by informed consent. The pharmacist-physician collaboration method was established prior to study initiation. Primary outcomes included hemoglobin A1c (A1C), number of patients with A1C less than 7%, and percentage of patients with A1C greater than 9%. RESULTS: Of the 206 patients enrolled, the mean age was 59.73 years, and most were male (59.71%) and white (66.02%). The A1C was reduced by an average of 1.16% (p < 0.0001). The proportion of patients with A1C less than 7% increased from 12.75% at baseline to 36.76% at study conclusion (p = 0.0002). The proportion of patients with A1C greater than 9% decreased from 34.15% to 16.50%, (p < 0.0001). CONCLUSIONS: Pharmacist-physician collaborative management at multiple practice locations and types of setting (eg, private, academic, Veterans Affairs medical center) has a positive impact on glycemic control and diabetes-related health maintenance. This was accomplished without increasing the total number of antihyperglycemic agents prescribed and without an increase in patient-reported episodes of hypoglycemia. PMID- 23656752 TI - The impact of pharmacist-directed patient education and anticoagulant care coordination on patient satisfaction. AB - BACKGROUND: Patient satisfaction data played a role in determining Medicare reimbursement as of October 2012. Clinical pharmacy services could improve satisfaction of hospital inpatients but it is unclear whether this relates to performance on standardized hospital surveys. OBJECTIVE: To describe the impact on patient satisfaction of patient education and follow-up care coordination provided by an inpatient pharmacist-directed anticoagulation service (PDAS). METHODS: This study was conducted at an urban, tertiary care hospital. PDAS is a clinical pharmacy service that has improved transition-of-care, safety, and efficacy involving anticoagulation at our institution. Patients receiving inpatient anticoagulation during February 2001-April 2007 (pre-PDAS) and December 2008-December 2010 (post-PDAS), who responded to a mail-in survey, were included. Survey items included satisfaction ("How satisfied were you with the medical care?"), amount of information ("Was the amount of information you received about your medicine...?"), clarity of information ("Was the clarity of the information about your medicine...?"), answer quality ("Were the answers to your questions about your medicine...?"), and spoke to a pharmacist ("Did a pharmacist speak with you during your stay?"). Response options for amount of information, clarity of information, answer quality, and satisfaction used a symmetric 5-point Likert type scale, with options 1-5 indicating most to least positive, respectively. Options 1-2 were considered positive and options 3-5 were considered negative. Primary analysis compared patient satisfaction (defined as rate of positive responses) between pre-PDAS and post-PDAS respondents. chi2 test was used for all comparisons. RESULTS: Surveys were distributed to 1694 patients after discharge, with 687 (40.6%) responding. Post-PDAS respondents had improved patient satisfaction for all positive response items, compared to pre-PDAS scores. Amount of information increased by 37.2%, clarity of information increased by 35.2%, answer quality increased by 29.5%, and satisfaction increased by 10.6% (p < 0.001 for all comparisons). CONCLUSIONS: Hospitals deploying focused programs with systematic approaches to patient-pharmacist communication may positively impact patient satisfaction. PMID- 23656753 TI - Consider a patient's weight and the weight of the evidence when calculating renal function. PMID- 23656754 TI - Grape juice concentrate protects reproductive parameters of male rats against cadmium-induced damage: a chronic assay. AB - The aim of the present study was to investigate the effects of long-term grape juice concentrate (GJC) consumption, in two dosages, on the reproductive parameters of cadmium-exposed male rats. The effects of the concentrate on body mass gain, plasma testosterone levels, reproductive organ weights, daily sperm production, sperm morphology, testis histopathological and histomorphometrical parameters, and testicular antioxidant markers were investigated. Wistar rats (n 54) were distributed into six groups: CdCl2; cadmium and grape juice I (1.18 g/kg per d); cadmium and grape juice II (2.36 g/kg per d); grape juice I (1.18 g/kg per d); grape juice II (2.36 g/kg per d); control. A single dose of CdCl2 (1.2 mg/kg body weight (BW)) was injected intraperitoneally and the grape juice was administered orally for 56 d. The results indicated that cadmium changed all reproductive and antioxidant parameters. At dosage I (1.18 g/kg BW), GJC consumption did not show the effects against cadmium-induced damages. In contrast, at dosage II (2.36 g/kg BW), the GJC improved the gonadosomatic index (P= 0.003), serum testosterone levels (P= 0.001), the relative weight of epididymis (P= 0.013) and ventral prostate (P= 0.052), the percentage of normal sperm (P= 0.001), and histopathological and histomorphometrical parameters. In addition, at this dosage, normalisation of the enzymatic activity of superoxide dismutase (P= 0.001) and of testicular levels of glutathione (P= 0.03) were observed. The parameters of the non-exposed rats did not depict significant alterations. In conclusion, the product was able to act as a protector of reproductive function against cadmium-induced damage. Such a property was expressed in a dose-dependent manner as the more effective dose was dosage II. The GJC acted possibly by antioxidant mechanisms. PMID- 23656755 TI - Age dependence of tumor genetics in unfavorable neuroblastoma: arrayCGH profiles of 34 consecutive cases, using a Swedish 25-year neuroblastoma cohort for validation. AB - BACKGROUND: Aggressive neuroblastoma remains a significant cause of childhood cancer death despite current intensive multimodal treatment protocols. The purpose of the present work was to characterize the genetic and clinical diversity of such tumors by high resolution arrayCGH profiling. METHODS: Based on a 32K BAC whole-genome tiling path array and using 50-250K Affymetrix SNP array platforms for verification, DNA copy number profiles were generated for 34 consecutive high-risk or lethal outcome neuroblastomas. In addition, age and MYCN amplification (MNA) status were retrieved for 112 unfavorable neuroblastomas of the Swedish Childhood Cancer Registry, representing a 25-year neuroblastoma cohort of Sweden, here used for validation of the findings. Statistical tests used were: Fisher's exact test, Bayes moderated t-test, independent samples t test, and correlation analysis. RESULTS: MNA or segmental 11q loss (11q-) was found in 28/34 tumors. With two exceptions, these aberrations were mutually exclusive. Children with MNA tumors were diagnosed at significantly younger ages than those with 11q- tumors (mean: 27.4 vs. 69.5 months; p=0.008; n=14/12), and MNA tumors had significantly fewer segmental chromosomal aberrations (mean: 5.5 vs. 12.0; p<0.001). Furthermore, in the 11q- tumor group a positive correlation was seen between the number of segmental aberrations and the age at diagnosis (Pearson Correlation 0.606; p=0.037). Among nonMNA/non11q- tumors (n=6), one tumor displayed amplicons on 11q and 12q and three others bore evidence of progression from low-risk tumors due to retrospective evidence of disease six years before diagnosis, or due to tumor profiles with high proportions of numerical chromosomal aberrations. An early age at diagnosis of MNA neuroblastomas was verified by registry data, with an average of 29.2 months for 43 cases that were not included in the present study. CONCLUSION: MNA and segmental 11q loss define two major genetic variants of unfavorable neuroblastoma with apparent differences in their pace of tumor evolution and in genomic integrity. Other possible, but less common, routes in the development of aggressive tumors are progression of low-risk infant-type lesions, and gene amplifications other than MYCN. Knowledge on such nosological diversity of aggressive neuroblastoma might influence future strategies for therapy. PMID- 23656756 TI - Single nucleotide polymorphisms in CETP, SLC46A1, SLC19A1, CD36, BCMO1, APOA5, and ABCA1 are significant predictors of plasma HDL in healthy adults. AB - BACKGROUND: In a marker-trait association study we estimated the statistical significance of 65 single nucleotide polymorphisms (SNP) in 23 candidate genes on HDL levels of two independent Caucasian populations. Each population consisted of men and women and their HDL levels were adjusted for gender and body weight. We used a linear regression model. Selected genes corresponded to folate metabolism, vitamins B-12, A, and E, and cholesterol pathways or lipid metabolism. METHODS: Extracted DNA from both the Sacramento and Beltsville populations was analyzed using an allele discrimination assay with a MALDI-TOF mass spectrometry platform. The adjusted phenotype, y, was HDL levels adjusted for gender and body weight only statistical analyses were performed using the genotype association and regression modules from the SNP Variation Suite v7. RESULTS: Statistically significant SNP (where P values were adjusted for false discovery rate) included: CETP (rs7499892 and rs5882); SLC46A1 (rs37514694; rs739439); SLC19A1 (rs3788199); CD36 (rs3211956); BCMO1 (rs6564851), APOA5 (rs662799), and ABCA1 (rs4149267). Many prior association trends of the SNP with HDL were replicated in our cross validation study. Significantly, the association of SNP in folate transporters (SLC46A1 rs37514694 and rs739439; SLC19A1 rs3788199) with HDL was identified in our study. CONCLUSIONS: Given recent literature on the role of niacin in the biogenesis of HDL, focus on status and metabolism of B-vitamins and metabolites of eccentric cleavage of beta-carotene with lipid metabolism is exciting for future study. PMID- 23656758 TI - Electronic structure of EuFe2As2. AB - Employing high resolution photoemission spectroscopy, we studied the temperature evolution of the electronic structure of EuFe2As2, a unique pnictide, where antiferromagnetism of the Eu layer survives within the superconducting phase due to 'FeAs' layers, achieved via substitution and/or pressure. High energy and angle resolution helped to reveal the signature of peak-dip features, having significant p orbital character and spin density wave transition induced band folding in the electronic structure. A significant spectral weight redistribution is observed below 20 K manifesting the influence of antiferromagnetic order on the conduction electrons. PMID- 23656757 TI - Blocking the attachment of cancer cells in vivo with DNA aptamers displaying anti adhesive properties against the carcinoembryonic antigen. AB - The formation of metastatic foci occurs through a series of cellular events, initiated by the attachment and aggregation of cancer cells leading to the establishment of micrometastases. We report the derivation of synthetic DNA aptamers bearing anti-adhesive properties directed at cancer cells expressing the carcinoembryonic antigen (CEA). Two DNA aptamers targeting the homotypic and heterotypic IgV-like binding domain of CEA were shown to block the cell adhesion properties of CEA, while not recognizing other IgV-like domains of CEACAM family members that share strong sequence and structural homologies. More importantly, the pre-treatment of CEA-expressing tumour cells with these aptamers prior to their intraperitoneal implantation resulted in the prevention of peritoneal tumour foci formation. Taken together, these results highlight the effectiveness of targeting the cell adhesion properties of cancer cells with aptamers in preventing tumour implantation. PMID- 23656759 TI - The importance of quality of life in patients with alcohol abuse and dependence. AB - LEARNING OBJECTIVES: After participating in this educational activity, the reader should be better able to identify the instruments that are currently being used to measure quality of life (QoL) in alcohol abuse and dependence; determine the impact of alcohol abuse and dependence on QoL; and evaluate the impact of treating alcohol abuse and dependence on QoL. OBJECTIVE: Quality of life, which consists of the physical, mental, and social domains, has been shown to be negatively affected by alcohol abuse and dependence. This review aims to examine QoL in alcohol abuse and dependence by reviewing the instruments used to measure it and by analyzing the impact of alcohol abuse and dependence and of treatment on QoL. METHODS: Studies were identified using a database search of PubMed and PsycINFO from the past 40 years (1971-2011) using the following keywords: abuse OR dependence, OR use AND alcohol, AND Quality of Life, QoL, Health-related quality of life, HRQOL. Two authors agreed independently on including 50 studies that met specific selection criteria. RESULTS: Although several global measures of QoL have established reliability and validity, many alcohol-specific measures of QoL have not yet been validated. Nevertheless, QoL has been shown to be significantly impaired in those with alcohol abuse and dependence, particularly in the domains of mental health and social functioning, the very areas that show the greatest improvement with abstinence and its maintenance. Moreover, the literature demonstrates the utility of using QoL measures throughout assessment and treatment as a motivational tool and as a marker for treatment efficacy. CONCLUSIONS: Measuring and monitoring QoL during assessment and treatment can add important value to patient recovery, for QoL improves with treatment and successful abstinence. Therefore, targeted, disease-specific assessments of QoL are warranted to address the impairments in the physical, mental, and social domains in alcohol abuse and dependence, thereby improving long-term outcomes. PMID- 23656760 TI - The psychopharmacology algorithm project at the Harvard South Shore Program: an update on schizophrenia. AB - This article is an update of the algorithm for schizophrenia from the Psychopharmacology Algorithm Project at the Harvard South Shore Program. A literature review was conducted focusing on new data since the last published version (1999-2001). The first-line treatment recommendation for new-onset schizophrenia is with amisulpride, aripiprazole, risperidone, or ziprasidone for four to six weeks. In some settings the trial could be shorter, considering that evidence of clear improvement with antipsychotics usually occurs within the first two weeks. If the trial of the first antipsychotic cannot be completed due to intolerance, try another until one of the four is tolerated and given an adequate trial. There should be evidence of bioavailability. If the response to this adequate trial is unsatisfactory, try a second monotherapy. If the response to this second adequate trial is also unsatisfactory, and if at least one of the first two trials was with risperidone, olanzapine, or a first-generation (typical) antipsychotic, then clozapine is recommended for the third trial. If neither trial was with any these three options, a third trial prior to clozapine should occur, using one of those three. If the response to monotherapy with clozapine (with dose adjusted by using plasma levels) is unsatisfactory, consider adding risperidone, lamotrigine, or ECT. Beyond that point, there is little solid evidence to support further psychopharmacological treatment choices, though we do review possible options. PMID- 23656761 TI - From the neuropsychiatric to the analytic: three perspectives on dissociative identity disorder. PMID- 23656762 TI - Erving Goffman's asylums and institutional culture in the mid-twentieth-century United States. AB - Sociologist Erving Goffman based his seminal work Asylums (1961) on a year of field research at St. Elizabeths Hospital in Washington, DC. Goffman described the mental hospital as a "total institution," in which regimentation dominated every aspect of daily life and patients were denied even the most basic means of self-expression; rather than promote recovery, such conditions produced the sorts of disordered behavior for which men and women were ostensibly admitted. A closer look at the changes transforming St. Elizabeths around the time of Goffman's research reveals a far richer portrait of institutional culture. Group therapy, psychodrama, art and dance therapy, patient newspapers, and patient self government-each of which debuted at the hospital in the 1940s and 1950s-provided novel opportunities for men and women to make themselves heard and to take their fate into their own hands. While these initiatives did not reach all of the patients at St. Elizabeths, surviving documentation suggests that those who participated found their involvement rewarding and empowering. Goffman explicitly set out to describe "the social world of the hospital inmate." His failure to appreciate fully the capacities of his subjects, however, appears to have led him to underestimate the importance of these developments. PMID- 23656763 TI - [Focus on sequencing management of prolonged mechanical ventilated patient]. PMID- 23656764 TI - [A preliminary study of using the expiratory limb of the pressure-volume curve to estimate the dead space in patients suffering from acute respiratory distress syndrome]. AB - OBJECTIVE: To trace pressure-volume curves (P-V curves) with quasi-static technique in acute respiratory distress syndrome (ARDS) patients, and using it to explain the relationship between the end point of the expiratory limb and the change in the dead space of expiration. METHODS: A prospective study was conducted. Fourteen ARDS patients receiving mechanical ventilation were included in the study. When P-V curves were traced with quasi-static technique, the spirometer was connected to the flow sensor. The start point of the expiratory limb was defined as tidal volume 1 (VT1) and the end point as VT2, and the difference between them (DeltaVT=VT1-VT2) was calculated. The VT of spirometer (named VT3) and the predetermined VT (VT4) were recorded. Correlations of DeltaVT and VT3, as well as VT4 and VT1, were analyzed with correlation analysis. RESULTS: DeltaVTwas (417.40+/-119.68) ml, and VT3 was (399.29+/-121.36) ml, DeltaVT and VT3 showed a good correlation (r=0.99, P=0.000), demonstrating that the DeltaVT of the expiratory limb was correlated with the volume trapped in lung. VT4 was (908.21+/-106.52) ml, and VT1 was(892.26+/-106.32) ml, and they showed a good correlation (r=0.99, P=0.000). CONCLUSION: Because of part of the gas trapped at the end of expiration in ARDS patients, the dead space is increased, showing that the expiratory limb of the P-V curve cannot return to the base points, and the DeltaVT of the expiratory limb is inversely proportional to the gas volume trapped in lung. PMID- 23656765 TI - [High glucose enhances permeability of human pulmonary microvascular endothelial cells by lipopolysaccharide stimulation in vitro and effect of DDAH/NOS/NO imbalance on its pathogenesis]. AB - OBJECTIVE: To investigate the damage to endothelial cells incubated in high concentration of glucose challenged by lipopolysaccharide (LPS), and the likely mechanisms of injury. METHODS: Human pulmonary microvascular endothelial cells (PMVECs) were divided into the following groups: normal glucose group (NG), normal glucose + LPS stimulation group (NGL), high glucose stimulation group (HG), and high glucose + LPS stimulation group (HGL). The cells were incubated with normal glucose (5.5 mmol/L, contained 10% calf serum) or high glucose (33 mmol/L) for 5 days to form a monolayer of cells before LPS stimulation (10 mg/L) for 24 hours. The microfilaments (F-actin) were investigated by immuno fluorescence, and the number and size change in fenestrae were examined by scanning electron microscopy. The permeability of vascular endothelial cell was assessed by trans-PMVEC horseradish peroxidase (HRP) flux. Western blotting was used to determine the expressions of dimethylarginine dimethylaminohydrolase 2 (DDAH2), inducible nitricoxide synthase (iNOS) and endothelial nitricoxide synthase (eNOS). Nitric oxide (NO) was assessed by Griess method. RESULTS: When stimulated with LPS, cells incubated with high glucose showed obvious microfilament rearrangement, a larger average diameter and increased number of F actin, as well as higher HRP permeability on the hyperglycemic PMVECs compared with PMVECs cultured with normal glucose [(53.62+/-6.70)% vs. (23.63+/-3.92)%, P<0.01]. Furthermore, high glucose down-regulated DDAH2 expression (arbitrary units, AU, 0.33+/-0.08 vs. 0.77+/-0.14 , P<0.01) and up-regulated LPS-stimulated iNOS production (1.40+/-0.29 vs. 1.04+/-0.09, P<0.01), as well as increased LPS stimulated nitrite/nitrate and stable NO end products compared with normal (20.36+/-2.25 MUmol/L vs. 7.99+/-0.33 MUmol/L, P<0.01) and reduction of eNOS levels was observed (0.67+/-0.09 vs. 0.91+/-0.17, P<0.05). CONCLUSION: It demonstrated that, in vitro high glucose deteriorate LPS-stimulated F-actin rearrangement and hyperpermeability of an endothelial monolayer, and the worsened imbalance of the NO pathway may lead to endothelial damage in microcirculation. PMID- 23656766 TI - [Effect of continuous high-volume hemofiltration in patients with severe acute respiratory distress syndrome]. AB - OBJECTIVE: To investigate the effect of continuous high-volume hemofiltration (CHVHF) in patients with severe acute respiratory distress syndrome (ARDS). METHODS: A prospective randomized controlled trial was conducted. Sixty-five patients with severe ARDS admitted to intensive care unit (ICU) from June 2007 to June 2011 were divided into control group (n=28) and treatment group (n=37). Patients in treatment group were treated with CHVHF and other routine treatments. Patients in control group received routine treatments only. The oxygenation index (PaO2/FiO2), extravascular lung water index (EVLWI), arterial partial pressure of carbon dioxide (PaCO2), heart rate (HR), mean arterial pressure (MAP) were compared between control group and treatment group before and 6, 24, 48, 72 hours after treatment. The duration of mechanical ventilation (MV), ICU stay time, percentage of weaning from MV, and 28-day survival rate were also compared. RESULTS: The indexes of pulmonary function were improved after treatment in both groups. With prolonged time of treatment, PaO2/FiO2 was elevated, and EVLWI, PaCO2 were lowered, and the improvements were more marked in treatment group compared with control group (6-hour PaO2/FiO2: 92.6+/-7.2 mm Hg vs. 83.8+/-11.4 mm Hg, 24-hour EVLWI: 10.8+/-3.7 ml/kg vs. 12.6+/-4.5 ml/kg, 24-hour PaCO2: 47.2+/-8.5 mm Hg vs. 51.4+/-4.8 mm Hg, all P<0.05). HR and MAP were improved after the treatment in both groups, and there was no significant difference between groups. Compared with control group, the duration of MV and ICU stay were shortened in treatment group (duration of MV: 12+/-4 days vs. 19+/-6 days, ICU stay time: 21+/-4 days vs. 33+/-8 days, both P<0.05), and percentage of successful weaning from MV and 28-day survival rate were higher in treatment group (percentage of successful weaning from MV: 81.1% vs. 64.3%, 28-day survival rate: 86.5% vs. 71.4%, both P<0.05). CONCLUSIONS: CHVHF is an effective adjuvant treatment for severe ARDS. It can improve the lung function, shorten the duration of MV, improve the percentage of successful weaning from MV, and the survival rate, and it lowers the mortality, but it imparts no obvious influence to hemodynamics in patients. PMID- 23656767 TI - [The effect of neuromuscular blocking agents on prognosis of patients with acute respiratory distress syndrome: a meta analysis]. AB - OBJECTIVE: To determine the effects of neuromuscular blocking agent (NMBA) on prognosis of patients with acute respiratory distress syndrome (ARDS). METHODS: PubMed database, the Cochrane Library, EMBASE, Excepta Media, CBM, CNKI and other sources were used for retrieving the pertinent literature. All randomized controlled trials (RCTs) on NMBA treating ARDS patients were enrolled. The Cochrance Collaboration's software RevMan 5.0 was used for data analysis. Two authors independently extracted data and assessed study quality using standardized instruments. RESULTS: Three studies were included in the final analysis, providing a sample of 431 patients. The combined results demonstrated a decrease in 28 days mortality [Peto odds ratio (OR) =0.57, 95% confidence interval (95%CI) 0.37-0.88, P=0.01] and lower incidence of barotrauma (OR=0.42, 95%CI 0.20-0.91,P=0.003) after NMBA treatment for patients with ARDS as compared with control group. The incidence of acquired neuromyopathy was similar between NMBA group and control group (OR=1.20, 95%CI 0.67-2.14, P=0.54). As compared with the control group at 48 hours, there was no statistical difference in ventilator parameters including total positive end expiratory pressure (PEEP, OR=0.09, 95%CI -0.50-0.68, P=0.77) and plateau pressure (Pplat, OR=0.62, 95%CI -0.32-1.57, P=0.20). There was no heterogeneity (P>0.1, I (2)<50%). At 120 hours after NMBA treatment, the total PEEP was significantly lower than that of control group (OR= 1.22, 95%CI -2.39 to -0.04, P=0.04), and the difference in Pplat showed statistical difference compared with the control group (OR=-2.61, 95%CI -4.50 to 0.73, P=0.007). CONCLUSION: Early administration of NMBA for ARDS patients results in a significant reduction in 28 days mortality, and it improves outcome. PMID- 23656768 TI - [The effects of mechanical ventilation with different tidal volumes on the expression of caveolin-1 in lung tissue and its related downstream signaling in rats]. AB - OBJECTIVE: To investigate the expression of caveolin-1 (cav-1) and its downstream signal under mechanical ventilation with different tidal volumes (VT) in lung tissue of rats. METHODS: Forty healthy male Sprague-Dawley (SD) rats were randomly assigned into five groups (each n=8). The rats in control group (group A) remained to have spontaneous breathing but underwent tracheostomy only. The rats in protective ventilation group underwent protective ventilation for 1 hour or 2 hours (group B1, B2), with VT set at 6 ml/kg. The rats in high VT ventilation group were given mechanical ventilation for 1 hour or 2 hours (group C1, C2), with VT set at 30 ml/kg. After incision of trachea in group A, and mechanical ventilation was given for 1 hour or 2 hours in ventilation groups. Rats of group A were sacrificed immediately. Rats of other groups were sacrificed 1 hour or 2 hours after mechanical ventilation. Specimens of lung tissues and bronchoalveolar lavage fluid (BALF) were harvested. Lung pathological changes were observed with optical microscope. The expression levels of cav-1 mRNA and eNOS mRNA in lung tissue were measured by reverse transcription-polymerase chain reaction (RT-PCR). The protein levels of cav-1, endothelial nitric oxide synthase (eNOS), interleukin-1 receptor-associated kinase 4 (IRAK4) and nuclear factor KappaB (NF-KappaB) p65 in lung tissues were assayed with immunohistochemistry staining. Lung myeloperoxidase (MPO) activity was measured by colorimetric analysis, and wet/dry weight ratio (W/D) was calculated. The levels of tumor necrosis factor-alpha (TNF-alpha) in BALF was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: No statistical significance in the mRNA expression of cav-1 and eNOS, the protein expression of cav-1, eNOS, IRAK4, NF KappaBp65, as well as W/D ratio, MPO and TNF-alpha in BALF was found among group A, group B1 and group B2. The expression of cav-1 mRNA (A value ratio) and cav-1, IRAK4, NF-KappaBp65 protein (A value) were significantly up-regulated (cav-1 mRNA: 0.833+/-0.085 vs. 0.384+/-0.011, 1.162+/-0.166 vs. 0.388+/-0.014; cav-1 protein: 0.188+/-0.011 vs. 0.140+/-0.052, 0.210+/-0.013 vs. 0.125+/-0.014; IRAK4 protein: 0.181+/-0.009 vs. 0.150+/-0.008, 0.205+/-0.085 vs. 0.155+/-0.012;NF KappaBp65 protein: 0.294+/-0.011 vs. 0.236+/-0.015, 0.304+/-0.012 vs. 0.239+/ 0.005), the expression of eNOS mRNA (A value ratio) and protein (A value) was significantly down-regulated (eNOS mRNA: 0.174+/-0.016 vs. 0.278+/-0.021, 0.107+/ 0.014 vs. 0.262+/-0.045; eNOS protein: 0.180+/-0.017 vs. 0.211+/-0.010, 0.161+/ 0.016 vs. 0.216+/-0.013), while W/D ratio, MPO and TNF-alpha in BALF were significantly increased (W/D: 5.64+/-0.42 vs. 4.63+/-0.12, 6.73+/-0.83 vs. 4.70+/ 0.15; MPO: 1.86+/-0.26 U/g vs. 0.85+/-0.11 U/g, 2.14+/-0.24 U/g vs. 0.88+/-0.18 U/g; TNF-alpha: 386.53+/-29.12 ng/L vs. 50.57+/-10.98 ng/L, 455.77+/-37.78 ng/L vs. 52.11+/-9.92 ng/L) in group C1 and group C2 compared with those in group B1 and group B2 (all P<0.05). With prolongation of time of mechanical ventilation, changes in those parameters were more obvious in group C2 as compared with group C1 (all P<0.05). CONCLUSION: Cav-1 and the activation of downstream signals in lung tissue participate in the development of the ventilator-induced lung injury. PMID- 23656769 TI - [The influence of pre-B-cell colony enhancing factor on adhesive molecule in pulmonary cells in rats with acute lung injury/acute respiratory distress syndrome]. AB - OBJECTIVE: To observe the influence of pre-B-cell colony enhancing factor (PBEF) on intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in lung tissue of rats with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) induced by oleic acid. METHODS: A total of 40 male adult Sprague-Dawley (SD) rats were divided into control, model, drug intervention and vehicle control groups according to the random digits table with 10 rats in each group. ALI/ARDS was reproduced in the rats of model, drug intervention and vehicle control groups by injection of oleic acid (0.15 ml/kg) through the tail vein. The rats in drug intervention and vehicle control groups received the specific PBEF inhibitor FK866 (10 mg/kg), while vehicle control group received the same volume of the vehicle only. Six hours after ALI/ARDS was successfully reproduced, bronchoalveolar alveolar lavage fluid (BALF) was obtained for the measurement of the contents of tumor necrosis factor-alpha (TNF alpha) and interleukin-1beta (IL-1beta) by enzyme linked immunosorbent assay (ELISA). Lung tissue was obtained for pathological examination, and also for the measurement of the expression of PBEF, ICAM-1 and VCAM-1 mRNA by reverse transcription-polymerase chain reaction (RT-PCR), and also the protein levels of PBEF, ICAM-1 and VCAM-1 by immunohistochemistry. RESULTS: Compared with rats in control group, the lung tissue of rats in model group showed distinctive pathological changes, the contents of TNF-alpha and IL-1beta in BALF were increased (TNF-alpha: 656.51+/-47.13 ng/L vs. 84.82+/-7.84 ng/L, IL-1beta: 379.60+/-31.55 ng/L vs. 74.56+/-8.51 ng/L, both P<0.01), the mRNA and protein expression of PBEF, ICAM-1 and VCAM-1 were significantly increased (PBEF mRNA: 0.581+/-0.079 vs. 0.186+/-0.051, ICAM-1 mRNA: 0.558+/-0.060 vs. 0.176+/-0.070, VCAM-1 mRNA: 0.646+/-0.059 vs. 0.226+/-0.047; PBEF protein: 0.089+/-0.024 vs. 0.037+/-0.011, ICAM-1 protein: 0.061+/-0.012 vs. 0.025+/-0.008, VCAM-1 protein: 0.072+/-0.013 vs. 0.033+/-0.010, all P<0.01). Compared with model group, amelioration of pathological change was found in lung tissue of rats in drug intervention group, the contents of TNF-alpha and IL-1beta in BALF were reduced (TNF-alpha: 478.80+/-72.93 ng/L vs. 656.51+/-47.13 ng/L, IL-1beta: 244.62+/-52.17 ng/L vs. 379.60+/-31.55 ng/L, both P<0.05), and the mRNA and protein expression of PBEF, ICAM-1 and VCAM-1 were lowered (PBEF mRNA: 0.456+/-0.110 vs. 0.581+/ 0.079, ICAM-1 mRNA: 0.413+/-0.073 vs. 0.558+/-0.060, VCAM-1 mRNA: 0.483+/-0.062 vs. 0.646+/-0.059; PBEF protein: 0.059+/-0.010 vs. 0.089+/-0.024, ICAM-1 protein: 0.043+/-0.007 vs. 0.061+/-0.012, VCAM-1 protein: 0.050+/-0.009 vs. 0.072+/-0.013, all P<0.05). CONCLUSION: PBEF could aggravate migration of pro-inflammatory cells to infiltrate the lung tissue by increasing the expression of ICAM-1 and VCAM-1, thus it plays an important role in the development of ALI/ARDS. PMID- 23656770 TI - [Down-regulation of expression of alpha- smooth muscle actin in airway smooth muscle cells by allicin and its mechanisms]. AB - OBJECTIVE: To investigate the effect of allicin on the expression of alpha-smooth muscle actin (alpha-SMA) in airway smooth muscle cells (ASMC), and to evaluate the mechanism of allicin on inhibition of airway remodeling. METHODS: The human ASMCs were treated for 48 hours with 0, 2.5, 5.0, and 10.0 MUmol/L allicin, respectively, and the total RNA and protein of the cells were collected. The mRNA expression of alpha-SMA was determined by real-time polymerase chain reaction (PCR) analysis. The protein expression of alpha-SMA and phosphorylation Smad1 (p Smad1) were assessed by Western blotting analysis. RESULTS: After the treatment with allicin for 48 hours in a dose of 0, 2.5, 5.0, and 10.0 MUmol/L respectively, the mRNA expression of alpha-SMA was down-regulated (0.543+/-0.121, 0.354+/-0.072, 0.223+/-0.058, and 0.191+/-0.034, respectively), with statistically significant difference among groups (all P<0.05), and the protein expression of alpha-SMA and p-Smad1 was also gradually down-regulated in a dose dependent manner [alpha-SMA protein (grad value ratio): 0.96+/-0.02, 0.72+/-0.16, 0.54+/-0.11, and 0.31+/-0.14, respectively; p-Smad1 protein (grad value ratio): 0.94+/-0.03, 0.76+/-0.13, 0.62+/-0.11, and 0.43+/-0.12, respectively), with statistically significant difference among groups (all P<0.05). CONCLUSION: Allicin depresses the mRNA and protein expression of alpha-SMA, and inhibits p Smad1 in a dose-dependent manner, thus interrupts the transforming growth factor beta and Rho kinase signal pathway. PMID- 23656771 TI - [Use of an electromagnetic device for insertion of bedside nasojejunal feeding tube in critically ill patients]. AB - OBJECTIVE: To evaluate the efficacy of an electromagnetic device for correct bedside placement of nasojejunal feeding tube for patients in intensive care unit (ICU). METHODS: The clinical data of 109 patients in ICU who accepted bedside nasojejunal feeding tube placement from January 2010 to September 2012 were retrospectively analyzed. All the patients were divided into three groups according to the difference in type of nasojejunal feeding tube and the placement technique: control group 1 (n=48, Flocare feeding tube and bedside blind insertion group), control group 2 (n=28, Corflo((r)) feeding tube and bedside blind insertion group), observation group (n=33, Corflo((r)) feeding tube and electromagnetic tube placement device group). The success rate, the times of placement, duration of nasojejunal feeding, and safety were compared among three groups. RESULTS: The success rate of control group 2 and observation group were higher than control group 1 (71.43%, 90.91% vs. 33.33%), rate of partial success and failure rate were lower than those of control group 1 (partial success rate: 17.86%, 3.03% vs. 35.42%; failure rate: 10.71%, 6.06% vs. 31.25%, all P<0.05), and no differences were found between control group 2 and observation group. The average times for successful placement in observation group was lower than that of control group 1 and control group 2 (1.6+/-0.5 vs. 6.6+/-3.2, 5.8+/-2.3, both P<0.05), and the average time for successful placement was shorter in observation group than that of control group 1 and control group 2 (12.48+/-3.78 minutes vs. 25.27+/-3.61 minutes, 23.58+/-4.87 minutes, both P<0.05), but there was no difference between control group 1 and control group 2. No complications occurred in all three groups. CONCLUSION: Placement of a nasojejunal tube with the aid of an electromagnetic device is an excellent method for enteral nutrition, as it is safer, more efficient, with high successful rate, less time spending, and easier to master for beginners. PMID- 23656772 TI - [The value of bispectral index in the unconscious patients with acute brain injury due to different pathogenic factors]. AB - OBJECTIVE: To observe the differences in bispectral index (BIS) in unconscious patients with acute brain injury due to different pathogenic factors, and approach its clinical significance. METHODS: A retrospective study was conducted. One hundred and twenty-two unconscious patients with acute brain injured admitted to the intensive care unit (ICU) from March 2009 to August 2012 were involved. According to the pathogenic factors, all patients were divided into direct injury group (n=66) and indirect injury group (n=56). Based on BIS value, all patients were divided into the BIS<60 group (n=80) and the BIS>=60 group (n=42). The BIS was continuously measured for 12 hours during the first 3 days, or 24 hours after stoppage of sedative after admission to ICU. The mean value of BIS (BISmean) was evaluated. The acute physiology and chronic health evaluationII (APACHEII) score, probability of survival (PS) and Glasgow coma score (GCS) were recorded. On the same day, the serum protein S100 and neuron-specific enolase (NSE) were determined. The mortality and the rate of the poor neurological outcome were analyzed. RESULTS: (1) There were no significant differences in the age, sex, APACHEII score, PS and days of stay in ICU between the direct and indirect injury groups. (2) BISmean and GCS in direct injury group were significantly lower than those of the indirect injury group [BISmean: 39.0 (2.5, 58.0) vs. 59.0 (42.0, 71.0), GCS score: 3 (3, 5) vs. 4 (3, 6), both P<0.01], while serum S100 levels was significantly higher [2.30 (0.75, 6.66) mg/L vs. 0.84 (0.40, 3.62) mg/L, P<0.01]. There was no significant difference in the NSE level between the direct and indirect injury groups. (3) The mortality rate and poor neurological outcome rate in BIS<60 group were significantly higher than the BIS>=60 group (mortality rate: 67.50% vs. 40.48%, poor neurological outcome rate: 86.25% vs. 66.67%, P<0.01 and P<0.05). In the BIS<60 group, there were no significant differences in the mortality and poor neurological outcome rate between direct and indirect injury group. CONCLUSIONS: There are differences in pathogenic factors, the injury mechanism, and the degree of the brain injury between the direct and indirect injury groups. BIS monitoring could help judge the degree of different kinds of brain injury. BIS<60 indicates poor prognosis and neurological outcome in spite of the inducing factor of brain injury. PMID- 23656773 TI - [Therapeutic strategies for severe acute respiratory distress syndrome]. PMID- 23656774 TI - [Advances in the study of regulatory mechanisms of endothelial intercellular junction]. PMID- 23656775 TI - Cellular immortalization and neoplastic transformation: Simultaneous, sequential or independent? Telomeres, telomerase or karyotypic variations? PMID- 23656776 TI - Carbonic anhydrase IX from cancer-associated fibroblasts drives epithelial mesenchymal transition in prostate carcinoma cells. AB - Extracellular acidification, a mandatory feature of several malignancies, has been mainly correlated with metabolic reprogramming of tumor cells toward Warburg metabolism, as well as to the expression of carbonic anydrases or proton pumps by malignant tumor cells. We report herein that for aggressive prostate carcinoma, acknowledged to be reprogrammed toward an anabolic phenotype and to upload lactate to drive proliferation, extracellular acidification is mainly mediated by stromal cells engaged in a molecular cross-talk circuitry with cancer cells. Indeed, cancer-associated fibroblasts, upon their activation by cancer delivered soluble factors, rapidly express carbonic anhydrase IX (CA IX). While expression of CAIX in cancer cells has already been correlated with poor prognosis in various human tumors, the novelty of our findings is the upregulation of CAIX in stromal cells upon activation. The de novo expression of CA IX, which is not addicted to hypoxic conditions, is driven by redox-based stabilization of hypoxia inducible factor-1. Extracellular acidification due to carbonic anhydrase IX is mandatory to elicit activation of stromal fibroblasts delivered metalloprotease-2 and -9, driving in cancer cells the epithelial-mesenchymal transition epigenetic program, a key event associated with increased motility, survival and stemness. Both genetic silencing and pharmacological inhibition of CA IX (with sulfonamide/sulfamides potent inhibitors) or metalloprotease-9 are sufficient to impede epithelial-mesenchymal transition and invasiveness of prostate cancer cells induced by contact with cancer-associated fibroblasts. We also confirmed in vivo the upstream hierarchical role of stromal CA IX to drive successful metastatic spread of prostate carcinoma cells. These data include stromal cells, as cancer-associated fibroblasts as ideal targets for carbonic anhydrase IX directed anticancer therapies. PMID- 23656777 TI - Ran GTPase promotes oocyte polarization by regulating ERM (Ezrin/Radixin/Moesin) inactivation. AB - Asymmetric meiotic divisions in mammalian oocytes are driven by the eccentric positioning of the spindle, along with a dramatic reorganization of the overlying cortex, including a loss of microvilli and formation of a thick actin cap. Actin polarization relies on a Ran-GTP gradient centered on metaphase chromosomes; however, the downstream signaling cascade is not completely understood. In a recent study, we have shown that Ran promotes actin cap formation via the polarized activation of Cdc42. The related GTPase Rac is also activated in a polarized fashion in the oocyte cortex and co-localizes with active Cdc42. In other cells, microvilli collapse can be triggered by inactivation of the ERM (Ezrin/Radixin/Moesin) family of actin-membrane crosslinkers under the control of Rac. Accordingly, we show here that Ran-GTP promotes a substantial loss of phosphorylated ERMs in the cortex overlying the spindle in mouse oocytes. However, this polarized phospho-ERM exclusion zone was unaffected by Rac or Cdc42 inhibition. Therefore, we suggest that Ran activates two distinct pathways to regulate actin cap formation and microvilli disassembly in the polarized cortex of mouse oocytes. The possibility of a crosstalk between Rho GTPase and ERM signaling and a role for ERM inactivation in promoting cortical actin dynamics are also discussed. PMID- 23656778 TI - Brc1 links replication stress response and centromere function. AB - Protection of genome integrity depends on the coordinated activities of DNA replication, DNA repair, chromatin assembly and chromosome segregation mechanisms. DNA lesions are detected by the master checkpoint kinases ATM (Tel1) and ATR (Rad3/Mec1), which phosphorylate multiple substrates, including a C terminal SQ motif in histone H2A or H2AX. The 6-BRCT domain protein Brc1, which is required for efficient recovery from replication fork arrest and collapse in fission yeast, binds phospho-histone H2A (gammaH2A)-coated chromatin at stalled and damaged replication forks. We recently found that Brc1 co-localizes with gammaH2A that appears in pericentromeric heterochromatin during S-phase. Our studies indicate that Brc1 contributes to the maintenance of pericentromeric heterochromatin, which is required for efficient chromosome segregation during mitosis. Here, we review these studies and present additional results that establish the functional requirements for the N-terminal BRCT domains of Brc1 in the replication stress response and resistance to the microtubule destabilizing drug thiabendazole (TBZ). We also identify the nuclear localization signal (NLS) in Brc1, which closely abuts the C-terminal pair of BRCT domains that form the gammaH2A-binding pocket. This compact arrangement of localization domains may be a shared feature of other gammaH2A-binding proteins, including Rtt107, PTIP and Mdc1. PMID- 23656779 TI - Exposure to light at night accelerates aging and spontaneous uterine carcinogenesis in female 129/Sv mice. AB - The effect of the constant illumination on the development of spontaneous tumors in female 129/Sv mice was investigated. Forty-six female 129/Sv mice starting from the age of 2 mo were kept under standard light/dark regimen [12 h light (70 lx):12 hr dark; LD, control group], and 46 of 129/Sv mice were kept under constant illumination (24 h a day, 2,500 lx, LL) from the age of 5 mo until to natural death. The exposure to the LL regimen significantly accelerated body weight gain, increased body temperature as well as acceleration of age-related disturbances in estrous function, followed by significant acceleration of the development of the spontaneous uterine tumors in female 129/Sv mice. Total tumor incidence as well as a total number of total or malignant tumors was similar in LL and LD group (p > 0.05). The mice from the LL groups survived less than those from the LD group (chi ( 2) = 8.5; p = 0.00351, log-rank test). According to the estimated parameters of the Cox's regression model, constant light regimen increased the relative risk of death in female mice compared with the control (LD) group (p = 0.0041). The data demonstrate in the first time that the exposure to constant illumination was followed by the acceleration of aging and spontaneous uterine tumorigenesis in female 129/Sv mice. PMID- 23656780 TI - Recruitment of cyclin G2 to promyelocytic leukemia nuclear bodies promotes dephosphorylation of gammaH2AX following treatment with ionizing radiation. AB - Cyclin G2 (CycG2) and Cyclin G1 (CycG1), two members of the Cyclin G subfamily, share high amino acid homology in their Cyclin G boxes. Functionally, they play a common role as association partners of the B'gamma subunit of protein phosphatase 2A (PP2A) and regulate PP2A function, and their expression is increased following DNA damage. However, whether or not CycG1 and CycG2 have distinct roles during the cellular DNA damage response has remained unclear. Here, we report that CycG2, but not CycG1, co-localized with promyelocytic leukemia (PML) and gammaH2AX, forming foci following ionizing radiation (IR), suggesting that CycG2 is recruited to sites of DNA repair and that CycG1 and CycG2 have distinct functions. PML failed to localize to nuclear foci when CycG2 was depleted, and vice versa. This suggests that PML and CycG2 mutually influence each other's functions following IR. Furthermore, we generated CycG2-knockout (Ccng2 (-/-) ) mice to investigate the functions of CycG2. These mice were born healthy and developed normally. However, CycG2-deficient mouse embryonic fibroblasts displayed an abnormal response to IR. Dephosphorylation of gammaH2AX and checkpoint kinase 2 following IR was delayed in Ccng2 (-/-) cells, suggesting that DNA damage repair may be perturbed in the absence of CycG2. Although knockdown of B'gamma in wild-type cells also delayed dephosphorylation of gammaH2AX, knockdown of B'gamma in Ccng2 (-/-) cells prolonged this delay, suggesting that CycG2 cooperates with B'gamma to dephosphorylate gammaH2AX. Taken together, we conclude that CycG2 is localized at DNA repair foci following DNA damage, and that CycG2 regulates the dephosphorylation of several factors necessary for DNA repair. PMID- 23656781 TI - Evidence for centriolar satellite localization of CDK1 and cyclin B2. PMID- 23656782 TI - Myocardin related transcription factors are required for coordinated cell cycle progression. AB - Myocardin related transcription factors A and B (MRTFs) activate serum response factor-driven transcription in response to Rho signaling and changes in actin dynamics. Myocardin and MRTFs have been implicated in anti-proliferative effects on a range of cell types. The precise mechanisms, however, remained elusive. We employed double knockdown of MRTF-A and MRTF-B in NIH 3T3 fibroblasts to evaluate its effects on cell cycle progression and proliferation. We show that transient depletion of MRTFs conveys a modest anti-proliferative effect and impinges on normal cell cycle progression, resulting in significantly shortened G 1 phase and slightly extended S and G 2 phase under normal growth conditions. Under serum starved conditions we observed aberrant entry into the S and G 2 phases without subsequent cell division. This was accompanied by downregulation of cyclin-CDK inhibitors p27Kip1, p18Ink4c and 19Ink4d as well as upregulation of p21Waf1 and cyclin D1. Extended knockdown led to increased formation of micronuclei, while cells stably depleted of MRTFs tend to become aneuploid and polyploid. Thus, MRTFs are required for accurate cell cycle progression and maintenance of genomic stability in fibroblast cells. PMID- 23656783 TI - Rat retinal transcriptome: effects of aging and AMD-like retinopathy. AB - Pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, remains poorly understood due to the paucity of animal models that fully replicate the human disease. Recently, we showed that senescence-accelerated OXYS rats develop a retinopathy similar to human AMD. To identify alterations in response to normal aging and progression of AMD-like retinopathy, we compared gene expression profiles of retina from 3- and 18-mo-old OXYS and control Wistar rats by means of high-throughput RNA sequencing (RNA Seq). We identified 160 and 146 age-regulated genes in Wistar and OXYS retinas, respectively. The majority of them are related to the immune system and extracellular matrix turnover. Only 24 age-regulated genes were common for the two strains, suggestive of different rates and mechanisms of aging. Over 600 genes showed significant differences in expression between the two strains. These genes are involved in disease-associated pathways such as immune response, inflammation, apoptosis, Ca ( 2+) homeostasis and oxidative stress. The altered expression for selected genes was confirmed by qRT-PCR analysis. To our knowledge, this study represents the first analysis of retinal transcriptome from young and old rats with biologic replicates generated by RNA-Seq technology. We can conclude that the development of AMD-like retinopathy in OXYS rats is associated with an imbalance in immune and inflammatory responses. Aging alters the expression profile of numerous genes in the retina, and the genetic background of OXYS rats has a profound impact on the development of AMD-like retinopathy. PMID- 23656784 TI - Molecular and structural insight into lysine selection on substrate and ubiquitin lysine 48 by the ubiquitin-conjugating enzyme Cdc34. AB - The attachment of ubiquitin (Ub) to lysines on substrates or itself by ubiquitin conjugating (E2) and ubiquitin ligase (E3) enzymes results in protein ubiquitination. Lysine selection is important for generating diverse substrate-Ub structures and targeting proteins to different fates; however, the mechanisms of lysine selection are not clearly understood. The positioning of lysine(s) toward the E2/E3 active site and residues proximal to lysines are critical in their selection. We investigated determinants of lysine specificity of the ubiquitin conjugating enzyme Cdc34, toward substrate and Ub lysines. Evaluation of the relative importance of different residues positioned -2, -1, +1 and +2 toward ubiquitination of its substrate, Sic1, on lysine 50 showed that charged residues in the -1 and -2 positions negatively impact on ubiquitination. Modeling suggests that charged residues at these positions alter the native salt-bridge interactions in Ub and Cdc34, resulting in misplacement of Sic1 lysine 50 in the Cdc34 catalytic cleft. During polyubiquitination, Cdc34 showed a strong preference for Ub lysine 48 (K48), with lower activity towards lysine 11 (K11) and lysine 63 (K63). Mutating the -2, -1, +1 and +2 sites surrounding K11 and K63 to mimic those surrounding K48 did not improve their ubiquitination, indicating that further determinants are important for Ub K48 specificity. Modeling the ternary structure of acceptor Ub with the Cdc34~Ub complex as well as in vitro ubiquitination assays unveiled the importance of K6 and Q62 of acceptor Ub for Ub K48 polyubiquitination. These findings provide molecular and structural insight into substrate lysine and Ub K48 specificity by Cdc34. PMID- 23656785 TI - K562 cell proliferation is modulated by PLCbeta1 through a PKCalpha-mediated pathway. AB - Phospholipase C beta1 (PLCbeta1) is known to play an important role in cell proliferation. Previous studies reported an involvement of PLCbeta1 in G 0-G 1/S transition and G 2/M progression in Friend murine erythroleukemia cells (FELC). However, little has been found about its role in human models. Here, we used K562 cell line as human homologous of FELC in order to investigate the possible key regulatory role of PLCbeta1 during cell proliferation of this human cell line. Our studies on the effects of the overexpression of both these isoforms showed a specific and positive connection between cyclin D3 and PLCbeta1 in K562 cells, which led to a prolonged S phase of the cell cycle and a delay in cell proliferation. In order to shed light on this mechanism, we decided to study the possible involvement of protein kinases C (PKC), known to be direct targets of PLC signaling and important regulators of cell proliferation. Our data showed a peculiar decrease of PKCalpha levels in cells overexpressing PLCbeta1. Moreover, when we silenced PKCalpha, by RNAi technique, in order to mimic the effects of PLCbeta1, we caused the same upregulation of cyclin D3 levels and the same decrease of cell proliferation found in PLCbeta1-overexpressing cells. The key features emerging from our studies in K562 cells is that PLCbeta1 targets cyclin D3, likely through a PKCalpha-mediated-pathway, and that, as a downstream effect of its activity, K562 cells undergo an accumulation in the S phase of the cell cycle. PMID- 23656786 TI - Loss of PML cooperates with mutant p53 to drive more aggressive cancers in a gender-dependent manner. AB - p53 mutations and downregulation of promyelocytic leukemia (PML) are common genetic alterations in human cancers. In healthy cells these two key tumor suppressors exist in a positive regulatory loop, promoting cell death and cellular senescence. However, the influence of their interplay on tumorigenesis has not been explored directly in vivo. The contribution of PML to mutant p53 driven cancer was evaluated in a mouse model harboring a p53 mutation (p53 (wild type/R172H) ) that recapitulates a frequent p53 mutation (p53 (R175H) ) in human sporadic and Li-Fraumeni cancers. These mice with PML displayed perturbation of the hematopoietic compartment, manifested either as lymphoma or extramedullary hematopoiesis (EMH). EMH was associated with peripheral blood leucocytosis and macrocytic anemia, suggestive of myeloproliferative- myelodysplastic overlap. In contrast, a complete loss of PML from these mice resulted in a marked alteration in tumor profile. While the incidence of lymphomas was unaltered, EMH was not detected and the majority of mice succumbed to sarcomas. Further, males lacking PML exhibited a high incidence of soft tissue sarcomas and reduced survival, while females largely developed osteosarcomas, without impact on survival. Together, these findings demonstrate that PML is an important tumor suppressor dictating disease development in a pertinent mouse model of human cancer. KEY POINTS: (1) A mutant p53 allele disrupts hematopoiesis in mice, by promoting lymphomas and myeloproliferative / myelodysplastic overlap. (2) Coincidental p53 allele mutation and PML loss shifts the tumor profile toward sarcoma formation, which is paralleled in human leiomyosarcomas (indicated by immunohistochemistry; IHC). PMID- 23656787 TI - The cell death protease Kex1p is essential for hypochlorite-induced apoptosis in yeast. AB - Following microbial pathogen invasion, the human immune system of activated phagocytes generates and releases the potent oxidant hypochlorous acid (HOCl), which contributes to the killing of menacing microorganisms. Though tightly controlled, HOCl generation by the myeloperoxidase-hydrogen peroxide-chloride system of neutrophils/monocytes may occur in excess and lead to tissue damage. It is thus of marked importance to delineate the molecular pathways underlying HOCl cytotoxicity in both microbial and human cells. Here, we show that HOCl induces the generation of reactive oxygen species (ROS), apoptotic cell death and the formation of specific HOCl-modified epitopes in the budding yeast Saccharomyces cerevisiae. Interestingly, HOCl cytotoxicity can be prevented by treatment with ROS scavengers, suggesting oxidative stress to mediate the lethal effect. The executing pathway involves the pro-apoptotic protease Kex1p, since its absence diminishes HOCl-induced production of ROS, apoptosis and protein modification. By characterizing HOCl-induced cell death in yeast and identifying a corresponding central executor, these results pave the way for the use of Saccharomyces cerevisiae in HOCl research, not least given that it combines both being a microorganism as well as a model for programmed cell death in higher eukaryotes. PMID- 23656788 TI - TrkB is responsible for EMT transition in malignant pleural effusions derived cultures from adenocarcinoma of the lung. AB - Lung cancer is the leading cause of cancer-related mortality worldwide. Recent evidence indicates that tumors contain a subpopulation of cancer stem cells (CSCs) that are responsible for tumor maintenance and spread. CSCs have recently been linked to the occurrence of epithelial-to-mesenchymal transition (EMT). Neurotrophins (NTs) are growth factors that regulate the biology of embryonic stem cells and cancer cells, but still little is known about the role NTs in the progression of lung cancer. In this work, we investigated the role of the NTs and their receptors using as a study system primary cell cultures derived from malignant pleural effusions (MPEs) of patients with adenocarcinoma of the lung. We assessed the expression of NTs and their receptors in MPE-derived adherent cultures vs. spheroids enriched in CSC markers. We observed in spheroids a selectively enhanced expression of TrkB, both at the mRNA and protein levels. Both K252a, a known inhibitor of Trk activity, and a siRNA against TrkB strongly affected spheroid morphology, induced anoikis and decreased spheroid forming efficiency. Treatment with neurotrophins reversed the inhibitory effect of K252a. Importantly, TrkB inhibition caused loss of vimentin expression as well as that of a set of transcription factors known to be linked to EMT. These ex vivo results nicely correlated with an inverse relationship between TrkB and E cadherin expression measured by immunohistochemistry in a panel of lung adenocarcinoma samples. We conclude that TrkB is involved in full acquisition of EMT in lung cancer, and that its inhibition results in a less aggressive phenotype. PMID- 23656789 TI - Acetylation dynamics of human nuclear proteins during the ionizing radiation induced DNA damage response. AB - Genotoxic insults, such as ionizing radiation (IR), cause DNA damage that evokes a multifaceted cellular DNA damage response (DDR). DNA damage signaling events that control protein activity, subcellular localization, DNA binding, protein protein interactions, etc. rely heavily on time-dependent posttranslational modifications (PTMs). To complement our previous analysis of IR-induced temporal dynamics of nuclear phosphoproteome, we now identify a range of human nuclear proteins that are dynamically regulated by acetylation, and predominantly deacetylation, during IR-induced DDR by using mass spectrometry-based proteomic approaches. Apart from cataloging acetylation sites through SILAC proteomic analyses before IR and at 5 and 60 min after IR exposure of U2OS cells, we report that: (1) key components of the transcriptional machinery, such as EP300 and CREBBP, are dynamically acetylated; (2) that nuclear acetyltransferases themselves are regulated, not on the protein abundance level, but by (de)acetylation; and (3) that the recently reported p53 co-activator and methyltransferase MLL3 is acetylated on five lysines during the DDR. For selected examples, protein immunoprecipitation and immunoblotting were used to assess lysine acetylation status and thereby validate the mass spectrometry data. We thus present evidence that nuclear proteins, including those known to regulate cellular functions via epigenetic modifications of histones, are regulated by (de)acetylation in a timely manner upon cell's exposure to genotoxic insults. Overall, these results present a resource of temporal profiles of a spectrum of protein acetylation sites during DDR and provide further insights into the highly dynamic nature of regulatory PTMs that help orchestrate the maintenance of genome integrity. PMID- 23656790 TI - Oncogenic miR-181a/b affect the DNA damage response in aggressive breast cancer. AB - Breast cancer is a heterogeneous tumor type characterized by a complex spectrum of molecular aberrations, resulting in a diverse array of malignant features and clinical outcomes. Deciphering the molecular mechanisms that fuel breast cancer development and act as determinants of aggressiveness is a primary need to improve patient management. Among other alterations, aberrant expression of microRNAs has been found in breast cancer and other human tumors, where they act as either oncogenes or tumor suppressors by virtue of their ability to finely modulate gene expression at the post-transcriptional level. In this study, we describe a new role for miR-181a/b as negative regulators of the DNA damage response in breast cancer, impacting on the expression and activity of the stress sensor kinase ataxia telangiectasia mutated (ATM). We report that miR-181a and miR-181b were overexpressed in more aggressive breast cancers, and their expression correlates inversely with ATM levels. Moreover we demonstrate that deregulated expression of miR-181a/b determines the sensitivity of triple negative breast cancer cells to the poly-ADP-ribose-polymerase1 (PARP1) inhibition. These evidences suggest that monitoring the expression of miR-181a/b could be helpful in tailoring more effective treatments based on inhibition of PARP1 in breast and other tumor types. PMID- 23656791 TI - Gamma aminobutyric acid transporter subtype 1 gene knockout mice: a new model for attention deficit/hyperactivity disorder. AB - Attention deficit/hyperactivity disorder (ADHD) is characterized by hyperactivity, impaired sustained attention, impulsivity, and is usually accompanied by varying degrees of learning difficulties and lack of motor coordination. However, the pathophysiology and etiology of ADHD remain inconclusive so far. Our previous studies have demonstrated that the gamma aminobutyric acid transporter subtype 1 (GAT1) gene knockout (ko) mouse (gat1-/-) is hyperactive and exhibited impaired memory performance in the Morris water maze. In the current study, we found that the gat1-/- mice showed low levels of attentional focusing and increased impulsivity. In addition, the gat1-/- mice displayed ataxia characterized by defects in motor coordination and balance skills. The hyperactivity in the ko mice was reduced by both methylphenidate and amphetamine. Collectively, these results suggest that GAT1 ko mouse is a new animal model for ADHD studying and GAT1 may be a new target to treat ADHD. PMID- 23656792 TI - HER2 expression and relevant clinicopathological features in gastric and gastroesophageal junction adenocarcinoma in a Chinese population. AB - BACKGROUND: With varied immunohistochemistry scoring criteria and patient cohorts, HER2-positivity rates in gastric cancer (GC) and gastroesophageal junction (GEJ) adenocarcinoma have been reported with a wide range. Recently standardized scoring criteria for GC and GEJ cancer has been established and recommended. In this study, the frequency of HER2 expression and the relationship between HER2 expression and clinicopathological features were examined in a large cohort of Chinese GC and GEJ cancer patients. METHODS: A total of 1463 patients, including 929 primary GCs and 534 primary GEJ adenocarcinomas, was retrospectively analyzed for HER2 overexpression by immunohistochemistry (IHC). Fluorescence in situ hybridization (FISH) analysis was used in 308 GCs and GEJ adenocarcinoma cases to assess HER2 gene amplification. RESULTS: HER2 overexpression (3+) was detected in 9.8% of carcinomas and more frequently observed in GEJ cancer cases, in the intestinal type, and in the well or moderately differentiated type (P=0.003, 0.000, and 0.000, respectively). HER2 equivocal (2+) was detected in 14.4% of cases. As for the 308 cases analyzed by FISH, 39 (of 40, 97.5%) IHC 3+ cases, 11 (of 38, 28.9%) IHC 2+ cases, and 3 (of 230, 1.3%) IHC 1+/0 cases showed HER2 gene amplification. A high concordance rate (98.5%) between IHC and FISH was demonstrated. CONCLUSIONS: Approximately 10% of Chinese patients with primary GC and GEJ adenocarcinoma were HER2-positive on IHC. HER2 overexpression was associated with GEJ site, intestinal cancer subtype, and well or moderately differentiated carcinomas. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1935951199941072. PMID- 23656793 TI - Celecoxib increases SMN and survival in a severe spinal muscular atrophy mouse model via p38 pathway activation. AB - The loss of functional Survival Motor Neuron (SMN) protein due to mutations or deletion in the SMN1 gene causes autosomal recessive neurodegenerative spinal muscle atrophy (SMA). A potential treatment strategy for SMA is to upregulate the amount of SMN protein originating from the highly homologous SMN2 gene, compensating in part for the absence of the functional SMN1 gene. We have previously shown that in vitro activation of the p38 pathway stabilizes and increases SMN mRNA levels leading to increased SMN protein levels. In this report, we explore the impact of the p38 activating, FDA-approved, blood brain barrier permeating compound celecoxib on SMN levels in vitro and in a mouse model of SMA. We demonstrate a significant induction of SMN protein levels in human and mouse neuronal cells upon treatment with celecoxib. We show that activation of the p38 pathway by low doses celecoxib increases SMN protein in a HuR protein dependent manner. Furthermore, celecoxib treatment induces SMN expression in brain and spinal cord samples of wild-type mice in vivo. Critically, celecoxib treatment increased SMN levels, improved motor function and enhanced survival in a severe SMA mouse model. Our results identify low dose celecoxib as a potential new member of the SMA therapeutic armamentarium. PMID- 23656794 TI - Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma. AB - BACKGROUND: Adoptive transfer of chimeric antigen receptor (CAR)-modified T cells appears to be a promising immunotherapeutic strategy. CAR combines the specificity of antibody and cytotoxicity of cytotoxic T lymphocytes, enhancing T cells' ability to specifically target antigens and to effectively kill cancer cells. Recent efforts have been made to integrate the costimulatory signals in the CAR to improve the antitumor efficacy. Epidermal growth factor receptor variant III (EGFRvIII) is an attractive therapeutic target as it frequently expresses in glioma and many other types of cancers. Our current study aimed to investigate the specific and efficient antitumor effect of T cells modified with CAR containing inducible costimulator (ICOS) signaling domain. METHODS: A second generation of EGFRvIII/CAR was generated and it contained the EGFRvIII single chain variable fragment, ICOS signaling domain and CD3zeta chain. Lentiviral EGFRvIII/CAR was prepared and human CD3+ T cells were infected by lentivirus encoding EGFRvIII/CAR. The expression of EGFRvIII/CAR on CD3+ T cells was confirmed by flow cytometry and Western blot. The functions of EGFRvIII/CAR+ T cells were evaluated using in vitro and in vivo methods including cytotoxicity assay, cytokine release assay and xenograft tumor mouse model. RESULTS: Chimeric EGFRvIIIscFv-ICOS-CD3zeta (EGFRvIII/CAR) was constructed and lentiviral EGFRvIII/CAR were made to titer of 106 TU/ml. The transduction efficiency of lentiviral EGFRvIII/CAR on T cells reached around 70% and expression of EGFRvIII/CAR protein was verified by immunoblotting as a band of about 57 kDa. Four hour 51Cr release assays demonstrated specific and efficient cytotoxicity of EGFRvIII/CAR+ T cells against EGFRvIII expressing U87 cells. A robust increase in the IFN-gamma secretion was detected in the co-culture supernatant of the EGFRvIII/CAR+ T cells and the EGFRvIII expressing U87 cells. Intravenous and intratumor injection of EGFRvIII/CAR+ T cells inhibited the in vivo growth of the EGFRvIII expressing glioma cells. CONCLUSIONS: Our study demonstrates that the EGFRvIII/CAR-modified T cells can destroy glioma cells efficiently in an EGFRvIII specific manner and release IFN-gamma in an antigen dependent manner. The specific recognition and effective killing activity of the EGFRvIII-directed T cells with ICOS signaling domain lays a foundation for us to employ such approach in future cancer treatment. PMID- 23656795 TI - An exploratory study on the feasibility and appropriateness of family psychoeducation for postpartum women with psychosis in Uganda. AB - BACKGROUND: We explored how family psychoeducation could be made culturally sensitive for postpartum mothers with psychotic illness in a Ugandan setting. METHODS: A qualitative multi-method approach using an already existing family psychoeducation Tool Kit was adapted to incorporate lay perceptions related to psychotic illness in the postpartum period in this Ugandan setting. The participants consisted of postpartum women with psychotic illness, caregivers/family members, psychiatric nurses and psychologists. A modified version of a family psychoeducation programme for postpartum women with psychosis was formulated and pilot-tested. RESULTS: Modifications in the standard family psychoeducation programme were both in the process and content of family psychoeducation. Under process, effective communication, cultural background, appropriate dress, involving only one family member, low literacy, and flexibility in timekeeping were raised. The theme of content yielded the incorporation of lay perceptions of mental illness, family planning, income generating, and an emphasis of premorbid and morbid personalities of the patients. CONCLUSION: The basic principles and assumptions underlying psychoeducation remained the same. Changes made in the process and content of family psychoeducation reflected the social, cultural and gender reality of the population. PMID- 23656796 TI - Dietary arginine affects energy metabolism through polyamine turnover in juvenile Atlantic salmon (Salmo salar). AB - In the present study, quadruplicate groups of juvenile Atlantic salmon (Salmo salar) were fed plant protein-based diets with increasing arginine inclusions (range 28.8-37.4 g/kg DM) to investigate whether arginine supplementation affects growth and lipid accumulation through an elevated polyamine turnover. Dietary lysine was held at a constant concentration, just below the requirement. All other amino acids were balanced and equal in the diets. Arginine supplementation increased protein and fat accretion, without affecting the hepatosomatic or visceralsomatic indices. Dietary arginine correlated with putrescine in the liver (R 0.78, P= 0.01) and with ornithine in the muscle, liver and plasma (P= 0.0002, 0.003 and 0.0002, respectively). The mRNA of ornithine decarboxylase, the enzyme producing putrescine, was up-regulated in the white adipose tissue of fish fed the high-arginine inclusion compared with those fed the low-arginine diet. Concomitantly, spermidine/spermine-(N1)-acetyltransferase, the rate-limiting enzyme for polyamine turnover that consumes acetyl-CoA, showed an increased activity in the liver of fish fed the arginine-supplemented diets. In addition, lower acetyl-CoA concentrations were observed in the liver of fish fed the high arginine diet, while ATP, which is used in the process of synthesising spermidine and spermine, did not show a similar trend. Gene expression of the rate-limiting enzyme for beta-oxidation of long-chain fatty acids, carnitine palmitoyl transferase-1, was up-regulated in the liver of fish fed the high-arginine diet. Taken together, the data support that increased dietary arginine activates polyamine turnover and beta-oxidation in the liver of juvenile Atlantic salmon and may act to improve the metabolic status of the fish. PMID- 23656797 TI - Effects of NS Lactobacillus strains on lipid metabolism of rats fed a high cholesterol diet. AB - BACKGROUND: Elevated serum cholesterol level is generally considered to be a risk factor for the development of cardiovascular diseases which seriously threaten human health. The cholesterol-lowering effects of lactic acid bacteria have recently become an area of great interest and controversy for many researchers. In this study, we investigated the effects of two NS lactobacillus strains, Lactobacillus plantarum NS5 and Lactobacillus delbrueckii subsp. bulgaricus NS12, on lipid metabolism of rats fed a high cholesterol diet. METHODS: Thirty-two SD rats were assigned to four groups and fed either a normal or a high-cholesterol diet. The NS lactobacillus treated groups received the high-cholesterol diet supplemented with Lactobacillus plantarum NS5 or Lactobacillus delbrueckii subsp. bulgaricus NS12 in drinking water. The rats were sacrificed after a 6-week feeding period. Body weights, visceral organ and fat weights, serum and liver cholesterol and lipid levels, intestinal microbiota and liver mRNA expression levels related to cholesterol metabolism were analyzed. Liver lipid deposition and adipocyte size were evaluated histologically. RESULTS: Compared with rats fed a high cholesterol diet, serum total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B and free fatty acids levels were decreased and apolipoprotein A-I level was increased in NS5 or NS12 strain treated rats, and with no significant change in high-density lipoprotein cholesterol level. Liver cholesterol and triglyceride levels were also significantly decreased in NS lactobacillus strains treated groups. Meanwhile, the NS lactobacillus strains obviously alleviated hepatic injuries, decreased liver lipid deposition and reduced adipocyte size of high cholesterol diet fed rats. NS lactobacillus strains restored the changes in intestinal microbiota compositions, such as the increase in Bacteroides and the decrease in Clostridium. NS lactobacillus strains also regulated the mRNA expression levels of liver enzymes related to cholesterol metabolism, including the down regulation of acyl-CoA:cholesterol acyltransferase (ACAT) and the upregulation of cholesterol 7alpha-hydroxylase (CYP7A1). CONCLUSION: This study suggested that the two NS lactobacillus strains may affect lipid metabolism and have cholesterol-lowering effects in rats fed a high cholesterol diet. PMID- 23656798 TI - Prostate cancer risk in pre-diabetic men: a matched cohort study. AB - BACKGROUND: Diagnosis and duration of type 2 diabetes mellitus (DM) appear to be associated with decreased prostate cancer risk. Limitations of previous studies include methods of subject selection and accurate definition of DM diagnosis. We examined the temporal relationship between DM and prostate cancer risk exploring the period of greatest risk starting from the prediabetic to the post-diabetic period using clinical and administrative data to accurately define the date of DM diagnosis. METHODS: We identified 5,813 men who developed DM between January 1, 1995 and December 31, 2009 (reference date, date of DM onset or matched date for non-diabetic cohort) and 28,019 non-diabetic men matched by age, smoking history, residence, and reference date. Prostate cancer incidence before and after the reference date was assessed using Cox regression modeling adjusted for matching variables, body mass index, insurance status, and comorbidities. Primary outcomes included hazard ratio (HR) and number needed to be exposed to DM for one additional person to be harmed (NNEH) or benefit (NNEB) with respect to prostate cancer risk. RESULTS: After full adjustment, the HR for prostate cancer before DM diagnosis was 0.96 (95% CI 0.85-1.08; P=0.4752), and the NNEB was 974 at DM diagnosis. After the reference date, the fully-adjusted HR for prostate cancer in diabetic men was 0.84 (95% CI 0.72-0.97, P=0.0167), and the NNEB 3 years after DM onset was 425. The NNEB continued to decrease over time, reaching 63 at 15 years after DM onset, suggesting an increasing protective effect of DM on prostate cancer risk over time. No significant difference between the diabetic and non diabetic cohort was found prior to reference date. CONCLUSION: Prostate cancer risk is not reduced in pre-diabetic men but decreases after DM diagnosis and the protective effect of DM onset on prostate cancer risk increases with DM duration. PMID- 23656799 TI - Limited scleroderma with pauci-immune glomerulonephritis in the presence of renal cell carcinoma. AB - Connective tissue disorders increase the risk of malignancy; conversely, they may manifest as rheumatological paraneoplastic syndromes due to an underlying malignancy. We describe the case of a patient with limited scleroderma whose rapid disease progression coincided with the discovery of a renal tumor. A woman, age 75 years, presented with a 3-month history of progressive difficulty grasping objects, unsteadiness, dyspnea, xerostomia, xerophthalmia, and significant weight loss. She had a 10-year history of gastroesophageal reflux and Raynaud's phenomenon. Pertinent physical examination findings included facial telangiectasias, bibasilar inspiratory rales, sclerodactyly, and absent pinprick and vibratory sensation in her toes. She also had swelling and tenderness in several metacarpophalangeal and interphalangeal joints and in both ankles. A renal mass was demonstrated on abdominal computed tomography. A left partial nephrectomy was performed, confirming an unclassified type of renal cell carcinoma, along with a focal proliferative crescentic pauci-immune glomerulonephritis. Medical therapy with rituximab, pulse methylprednisolone, and prednisone led to improvement in her symptoms. The patient's presentation is consistent with a rapid progression of pre-existing limited scleroderma with the development of new rheumatological symptoms, including vasculitis. We propose that this progression was secondary to paraneoplastic stimulation by the renal cell carcinoma. Clinicians should consider looking for a malignancy in patients with connective tissue disorders who present with a myriad of new symptoms. PMID- 23656800 TI - Coexistence of a congenital arteriovenous fistula of the left breast with a true aneurysm of the right internal mammary artery. AB - Arteriovenous fistulas (AVF) and true aneurysms are uncommon arterial vascular disorders of the breast. The etiology can be either acquired or congenital. Coexistence of a congenital AVF and true aneurysm of internal mammary artery (IMA) branches is a very rare condition. We present a case of congenital AVF and true aneurysm of the IMA in a woman, age 56 years. To the best of our knowledge, this is the first published case of the coexistence of a congenital AVF with a true aneurysm of the breast. The radiologic findings of these rare entities have been reviewed according to the literature. PMID- 23656801 TI - A novel case of diabetic muscle necrosis in a patient with cystic fibrosis related diabetes. AB - Cystic fibrosis is a recessive autosomal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. Cystic fibrosis-related diabetes (CFRD) is a common comorbidity of cystic fibrosis. Diabetic myonecrosis is a rare self-limited complication of poorly controlled diabetes mellitus that commonly presents with acute, intense pain and swelling of lower extremities and responds well to conservative management. We report the first case of diabetic myonecrosis in a patient with CFRD. PMID- 23656802 TI - Chronic total occlusion and successful drug-eluting stent placement in Takayasu arteritis-induced renal artery stenosis. AB - Takayasu arteritis-induced renal artery stenosis (TARAS) is a condition rarely described in the literature. Although percutaneous transluminal angioplasty and stenting has been well-described in the treatment of atherosclerotic renal artery stenosis, its role has not been established in non-atherosclerotic TARAS. We report a case of a female, age 17 years, with Takayasu arteritis who presented to the hospital with seizures and hypertensive crisis. A renal angiogram showed chronic total occlusion (CTO) of the left renal artery. Renal angioplasty and stenting was successfully performed after multiple attempts to deliver a wire distal to the CTO. After sequential balloon predilation, a drug-eluting stent was deployed, resulting in full reperfusion of the kidney. The patient's blood pressure improved dramatically, and patency of the stent was demonstrated with magnetic resonance angiography over 9 months after the procedure. PMID- 23656803 TI - Does CALU SNP rs1043550 contribute variability to therapeutic warfarin dosing requirements? AB - OBJECTIVES: Calumenin, a molecular chaperone, exerts a regulatory effect on the vitamin K-dependent gamma-carboxylation redox cycle that inhibits transfer of the reduced vitamin K from VKORC1, the pharmacological target of warfarin, to the gamma-carboxylase. Because of its polymorphic structure and central role in the warfarin metabolic pathway, a contributory role for calumenin to warfarin dose variability has been posited. The current study sought to validate modulation of therapeutic dosing requirements by a single nucleotide polymorphisms (SNP) occurring in the calumenin gene (CALU) reported in previous studies. The CALU SNP was further modeled to detect interaction with SNPs occurring in VKORC1, CYP2C9, and CYP4F2 genes and characterize any additional contribution to variability in therapeutic warfarin dose requirement. SETTING: The study was undertaken in an established, well-characterized cohort of subjects treated with warfarin in the Anticoagulation Clinic of Marshfield Clinic in Marshfield, Wisconsin. METHODS: Subjects (N=491) previously genotyped for SNPS known to contribute variability to therapeutic warfarin dose requirement were genotyped for CALU SNP rs1043550, using TaqMan assays. Contribution of CALU SNP rs1043550 was modeled relative to other genotypic and phenotypic characteristics including gender, diagnosis, age, body surface area, underlying indication for warfarin, comorbidities, and pharmacological exposures. Interaction between SNPs impacting on warfarin dose requirements and calumenin SNPs was also modeled. RESULTS: Small differences in warfarin dosing requirements detected among individuals encoding the mutant G allele in the calumenin SNP were not statistically or clinically significant relative to therapeutic warfarin dose requirement and did not independently contribute significantly to the warfarin dosing model. Interaction between calumenin and VKORC1 SNPs contributed only minor additional variability to that ascribed to the wild type VKORC1 genotype. CONCLUSIONS: The impact of the CALU SNP on warfarin dose variability was minor and did not contribute significantly to therapeutic warfarin dose requirement in our study cohort. While no contribution was noted for the SNP examined in the present study, further examination of interaction between genetic elements contributing major impact on therapeutic warfarin dose requirements and genes exhibiting a lesser contribution is warranted. PMID- 23656804 TI - Quantification and visualization of carotid segmentation accuracy and precision using a 2D standardized carotid map. AB - This paper describes a framework for vascular image segmentation evaluation. Since the size of vessel wall and plaque burden is defined by the lumen and wall boundaries in vascular segmentation, these two boundaries should be considered as a pair in statistical evaluation of a segmentation algorithm. This work proposed statistical metrics to evaluate the difference of local vessel wall thickness (VWT) produced by manual and algorithm-based semi-automatic segmentation methods (DeltaT) with the local segmentation standard deviation of the wall and lumen boundaries considered. DeltaT was further approximately decomposed into the local wall and lumen boundary differences (DeltaW and DeltaL respectively) in order to provide information regarding which of the wall and lumen segmentation errors contribute more to the VWT difference. In this study, the lumen and wall boundaries in 3D carotid ultrasound images acquired for 21 subjects were each segmented five times manually and by a level-set segmentation algorithm. The (absolute) difference measures (i.e., DeltaT, DeltaW, DeltaL and their absolute values) and the pooled local standard deviation of manually and algorithmically segmented wall and lumen boundaries were computed for each subject and represented in a 2D standardized map. The local accuracy and variability of the segmentation algorithm at each point can be quantified by the average of these metrics for the whole group of subjects and visualized on the 2D standardized map. Based on the results shown on the 2D standardized map, a variety of strategies, such as adding anchor points and adjusting weights of different forces in the algorithm, can be introduced to improve the accuracy and variability of the algorithm. PMID- 23656806 TI - [Development and challenge in otorhinolaryngology head and neck surgery]. PMID- 23656807 TI - [Classification and typing of otitis media (2012)]. PMID- 23656805 TI - [To look back the 60 years history of otorhinolaryngology and to acquire more progress]. PMID- 23656808 TI - [Analysis on standard for classification and typing of otitis media (2012)]. PMID- 23656809 TI - [Quality of life survey on patients with peripheral facial paralysis by using Chinese version of the FaCE scale]. AB - OBJECTIVE: To explore the health related quality of life (QOL) status of patients with peripheral facial paralysis. METHODS: By introducing, translating and adjusting of the FaCE (Facial Clinimetric Evaluation) scale, a Chinese version came into being. The scale was further strictly tested in eighty-one patients with peripheral facial paralysis and thirty healthy volunteers. RESULTS: The feasibility, reliability, validity and responsibility of Chinese version of FaCE scale all passed the test. The split-half reliability, Cronbach's alpha and intraclass correlation coefficient were 0.79, 0.88 and 0.87, respectively. The criteria validity calculated between FaCE and SF-36 was 0.41 (P < 0.05). Factor analysis of the construct validity showed that the 15 items were classified into six domains, which were in accordance with the original version. Every domain was sensitive and effective to discriminate between patient population and healthy population (P < 0.05). Chinese version of FaCE scale showed significant correlation with HBGS and SBGS scores (r = -0.40 and 0.42, P < 0.05). CONCLUSION: Chinese version of the FaCE scale can effectively assess QOL status of patients with facial paralysis in China. PMID- 23656810 TI - [Efficacy and safety of sublingual immunotherapy of allergic rhinitis in children between 4 and 5 years age group and 11 and 12 years age group]. AB - OBJECTIVE: To evaluate the efficacy and safety of the sublingual immunotherapy with Dermatophagoides fannie drops on children with allergic rhinitis of different age groups (4 - 5 years old group and 11 - 12 years old group). METHODS: Sixty-two children aged 4 - 5 years, and 71 children aged 11 - 12 years, who suffered from dust mite induced allergic rhinitis, was randomly divided into the sublingual immunotherapy (SLIT) + drug group and drug group. SLIT + drug group was treated with a standardized sublingual immunotherapy drops of Dermatophagoides fannie and combined with symptomatic therapy, drug group was treated with mometasone furoate nasal spray and desloratadine tablets as symptomatic treatment. These children were followed up for 2 years with one visit in every 3 months, then visited at the end of the study and 2-years after the treatment ended. Symptom scores and medication scores were recorded at each visit. Comprehensive evaluation of symptoms, medication, and patients' degree of satisfaction were used. RESULTS: Two years after SLIT finished, symptom scores (SLIT + drug group: 1.13 +/- 1.05; drug group: 4.68 +/- 3.09), medication scores (SLIT + drug group: 0.07 +/- 0.04; drug group: 0.36 +/- 0.25) of SLIT + drug group were significantly lower than those in drug group (t value were -8.43, 8.87, respectively, all P < 0.01). Also, the subjective assessment of patients' symptoms, medication, and treatment satisfaction in SLIT + drug group was significantly lower than those in drug group. Subjective assessment symptoms, medication, and treatment satisfaction in age group 4 - 5 was the same as in age group 11 - 12. After SLIT ended for 2 years, subjective assessment and treatment satisfaction in age 11 - 12 group was better than those in age 4-5 group in medication score. CONCLUSIONS: SLIT demonstrated clinical improvement in children of different ages during 2 years treatment. Two years after withdrawal, the symptom scores, medication score and subjective satisfaction in 11 years old group are better than those in 4-5 years old group. PMID- 23656811 TI - [Analysis of association between the IRF5 gene single nucleotide polymorphism and allergic rhinitis]. AB - OBJECTIVE: To study the possible association between interferon regulatory factor 5 (IRF5) gene polymorphism and allergic rhinitis (AR). METHODS: Six independent single nucleotide polymorphism (SNP, rs729302, rs4728142, rs3807306, rs2070197, rs11770589, rs2280714) were analyzed. The genotype and allele frequencies were detected in 110 AR patients and 101 healthy controls in Singapore Chinese population by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: Rs729302 was rejected as it was not polymorphic. For others SNP, no statistically significant difference was detected in genotype between AR and healthy control group (chi(2) value were 0.21, 5.02, 0.01, 2.91, 0.37, all P > 0.05). No statistically significant difference was detected in allele frequencies between AR and healthy control group (chi(2) value were 0.00, 2.78, 0.01, 2.31, 0.00, all P > 0.05). CONCLUSION: No association is observed between IRF5 and AR in Singapore Chinese population. PMID- 23656812 TI - [Construction of recombinant house dust mite group 1 allergen vaccine and study on immune response induced by nasal immunization]. AB - OBJECTIVE: To study the preparation of recombinant house dust mite group 1 allergen vaccine (chitosan-pVAX1-Derp1 nanoparticles, pVAX1-Derp1/CS) and to investigate the efficacy and mechanism of intranasally given chitosan-pVAX1-Derp1 nanoparticles on mouse model with allergic rhinitis (AR). METHODS: The chitosan pVAX1-Derp1 nanoparticles was prepared by complex coacervation, and its nature was identified and analysed. A total of 40 BALB/c rats were randomly divided into 5 groups: the normal group (group A), the AR model group (group B), the chitosan (CS) prevention group (group C), the pVAX1-Derp1 prevention group (group D), and the pVAX1-Derp1/CS prevention group (group E). The nasal cavity of rats in the group B, C, D and E were dripped with phosphate buffered saline (20 ul), CS (20 ul), pVAX1-Der p1 (20 ul), pVAX1-Derp1/CS nanoparticles (20 ul) on the first day and day 8, once daily. Rats in the latter 4 group were sensitized with Der p1 and Al(OH)3 in day 15 and day 22, and challenged with Der p1 to establish AR model from day 36 to day 43, while rats in group A were treated with PBS. Then the level of cytokines in serum was assayed by ELISA, inflammatory reactions in nasal mucosa were analyzed by haematoxylin and eosin staining. RESULTS: pVAX1-Derp1/CS nanoparticles was successfully constructed, the mean grain size of pVAX1-Derp1/CS was (205.3 +/- 12.8) nm, and the zeta potential was (30.5 +/- 5.6) mV. In nasal mucosa tissue, group B and C showed significant allergic inflammation, while group D and E showed lighter allergic inflammation. Compared with the group B, the group D and E could effectively reduced serum IgE level and IL-4 level [group B: (120.0 +/- 8.8) ng/ml, (248.7 +/- 10.6) pg/ml; group D: (109.6 +/- 14.5) ng/ml, (192.5 +/- 10.2) pg/ml; group E: (88.1 +/- 8.3) ng/ml, (165.7 +/- 9.7) pg/ml; IgE: t value were 3.5, 6.9, all P < 0.01; IL-4: t value were 10.0, 15.2, all P < 0.01], and increased IFN-gamma level [group B: (709.0 +/- 26.5) pg/ml; group D: (856.3 +/- 37.4) pg/ml; group E: (904.8 +/- 37.7) pg/ml; t value were 8.2, 10.8, all P < 0.01)]. IL-10 level of group D [(129.9 +/- 16.1) pg/ml] and E [(107.1 +/- 11.8) pg/ml] was lower than IL-10 level of group B [(160.6 +/- 24.2) pg/ml]. The difference were significantly (t value were 2.9, 5.5, all P < 0.05). CONCLUSIONS: Chitosan can effectively encapsulate pVAX1-Derp 1 and inhibit nuclease degradation of the plasmid, the DNA vaccine has some preventive effect on AR animal model by nasal immunization. PMID- 23656814 TI - [Anatomical study of improved lateral arm free flap]. AB - OBJECTIVE: To study the anatomy and preparation methods of an improved lateral arm free flap (LAFF) for the future clinical application. METHODS: Twenty-two adult upper extremities from cadavers after injected with red latex through common carotid arteries were used. The course, branches, distribution and variations of the blood vessels and nerves of the improved LAFF were observed. The outer diameters of the vessels were measured. RESULTS: The mean length of vascular pedicle of the improved LAFF was (14.85 +/- 1.28) cm, significantly more than that (5.46 +/- 2.60) of traditional LAFF (t = -8.483, P < 0.001). The mean outer diameters of pedicle arteries and veins in the improved LAFF were (2.24 +/- 0.66) mm and (2.22 +/- 0.52) mm, significantly more than those (1.15 +/- 0.21 and 1.26 +/- 0.23) in traditional LAFF (t = -8.690, P < 0.001; t = -15.057, P < 0.001), respectively. CONCLUSION: The improved LAFF has a longer vascular pedicle and larger artery and vein in diameter than conventional LAFF, and is more suitable for the repair of the small and medium-sized defects of the head and neck. PMID- 23656813 TI - [Squamous cell carcinoma of cervical lymph nodes from an unknown primary site: a retrospective analysis of treatment strategies and prognosis]. AB - OBJECTIVE: To analyze the treatment strategies and prognosis of squamous cell carcinoma of cervical lymph nodes from an unknown primary site (SCCUP). METHODS: A total of 125 cases with SCCUP was retrospectively analyzed from January 2001 to December 2011. Ninety-seven of the cases were treated with neck dissection (ND), including 24 with classic radical ND, 62 with modified ND and 11 with extended radical ND. Of 125 cases with SCCUP, 72 cases were supplemented with radiotherapy and 52 cases with chemotherapy. Radiotherapy was applied with extensive field in 36 cases, bilateral neck in 15 cases, and ipsilateral neck in 21 cases. The patients were followed up and the Kaplan-Meier method was used to calculate survival curves. Cox's analysis and logistic regression were used to evaluate the prognosis factors for SCCUP. RESULTS: The 5-year overall survival rate and disease free survival rate of the cohort were 66.2% and 60.0%, respectively. The median survival time was 70 months. Cox's analysis showed N-stage, extracapsular spread, bilateral neck metastasis and ND were independent prognostic factors for SCCUP. Logistic regression suggested that N-stage was the main factor for nodal recurrence or uncontrolled. The primary tumor sites emerged in 27 patients (21.6%) within 3 - 96 months after treatment (median time was 15 months), but only 4 patients (11.1%) existed in 36 cases underwent radiotherapy with extensive field. CONCLUSIONS: N-stage and extracapsular spread are two major factors influencing the prognosis of SCCUP. ND may improve the locoregional control and long-term survival. PMID- 23656815 TI - [Study on conditional myosin light chain kinase gene knockout mice resulting in hearing loss]. AB - OBJECTIVE: To investigate the function of myosin light chain kinase (MLCK) in hearing in mouse by generating inner hair cell-specific Mlck knockout mice and analyze the effect on their hearing. METHODS: Cross Mlck floxed mice with IHC-Cre mice, the genotype and knockout efficiency were confirmed by PCR. We used auditory brain stem response (ABR) to evaluate mice hearing function at different frequencies. RESULTS: Mlck knockout mice were selected by mice tail DNA genotyping and confirmed the deletion of the target gene by isolated inner hair cell DNA genotyping. Mlck-deficient mice showed impaired hearing with a rise in ABR threshold response to click and three different pure tones (8 kHz, 16 kHz, 32 kHz), and the rise was over 20 dB at high-frequency(32 kHz). Further analyses of waveforms showed that wave-I amplitudes on 60 dB SPL, 50 dB SPL and 40 dBSPL in response to tone (16 kHz) were less than control group(P < 0.05) on average, but the ratio of wave I/II and I/III were not difference (P > 0.05). CONCLUSIONS: Mlck is successfully deleted in inner hair cell-specific Mlck knockout mice. Mlck knockout mice display a significantly higher threshold in response to click and tones, especially in high-frequencies. PMID- 23656816 TI - [Preliminary study on Aspergillus fumigatus-induced IKKalpha controlled maspin protein expression in respiratory epithelial cells of rats]. AB - OBJECTIVE: To study if the expression of maspin protein in respiratory epithelial cells was downregulated through IkappaB kinase-alpha (IKKalpha)-controlled mechanism in an Aspergillus fumigatus-induced model in rat. METHODS: Inactivated Aspergillus fumigatus hyphae (AFH) suspension was used to induce respiratory epithelial cells (REC) cultured in vitro in rat, with PBS buffer as control. By RT-PCR, the mRNA expression of maspin was quantified, and by immunocytochemistry, the expression of maspin and IKKalpha in REC was observed. Furthermore AFH (from level 1 to level 3) suspension was prepared to induce REC. Then Western blot hybridization technique was used to detect the expression of maspin and IKKalpha protein. All data were processed by analysis of variance and two-variable correlation analysis. RESULTS: By RT-PCR, a statistically significant (t = 2.463, P < 0.05) expression of maspin mRNA was found (0.128 +/- 0.059 in AFH group, 2.972 +/- 0.353 in control group). By Immunocytochemistry, the difference of maspin protein color in different groups was shown statistically significant in integrated scoring (t = 3.721, P < 0.05, weak positive in AFH group, moderately positive in control group). While in IKKalpha color study, the difference between the two groups was also statistically significant (t = 6.825, P < 0.05) in integrated scoring, with a moderate positive in AFH group and weak positive in control group. By Western Blot hybridization, grayscale ratio of maspin and beta actin was 0.912 +/- 0.023 in control group, 0.607 +/- 0.030, 0.476 +/- 0.019, 0.416 +/- 0.017 in AFH 1-3 groups, respectively, with a statistically significant difference within the four groups (F = 281.91, P < 0.05); While grayscale ratio of IKKalpha and beta-actin was 0.624 +/- 0.012 in control group, 0.739 +/- 0.020, 0.778 +/- 0.010, 0.927 +/- 0.017, respectively, in AFH 1-3 groups; with a statistically significant difference within the four groups(F = 200.91, P < 0.05). Moreover, the difference between any two groups from both AFH group (including subgroup 1, 2 and 3) and control group was statistically significant. Two-variable correlation analysis indicated a negative correlation between expression of maspin and IKKalpha (r = -0.911, P < 0.05). CONCLUSIONS: Induced by Aspergillus fumigatus, the rat respiratory epithelia might upregulate the expression of IKKalpha with a downregulated expression of maspin protein. PMID- 23656817 TI - [Study on decellularized laryngeal scaffold in dogs]. AB - OBJECTIVE: To explore the survivorship and character of decellularized laryngeal scaffold in pectoralis major muscle flap in canine. METHODS: Eighteen donor larynx in experimental group were decellularized by perfusing sodium dodecyl sulphate. Three of them were used to detect the character of histology. The other fifteen ones were embedded in right pectoralis major muscle flap of acceptor canine. Donor larynx in control group were not perfused. Other experimental procedure was the same as experimental group. The specimens were harvested at two weeks, one month and two months after operation, respectively. Macroscopic view, histological examination and trypan blue staining were performed in the experimental group and control group. RESULTS: The size of the specimens decreased remarkably into disappearance in control group, there was statistical significance between the experimental group and the control group (which used least significant difference t test P < 0.05). There was only little neutrophils and lymphocytes infiltrating around the laryngeal scaffold at 2 weeks in the experimental group. One month after operation, loose connective tissue begin to form around the laryngeal scaffold. After two months of transplantation, the connective tissue became thicker and the number of blood vessels increased than before. There was a large number of lymphocytes and neutrophil infiltration around the laryngeal specimens in the control group at 2nd week. The perichondrium in the control group was damaged at one month post operation. The cartilage cells could not be detected two months after surgery. The survival rate of cartilage cell between experimental group (86.8% +/- 3.2%) and the control group (88.6% +/- 3.1%) did not show statistical significance before implantation (chi(2) = 0.19, P > 0.05). The survival rate of cartilage cell decreased insignificantly in experimental group while the survival rate declined obviously in the control group at two weeks and one month after operation, the difference had statistical significance (chi(2) were respectively 5.52 and 20.55, P were respectively < 0.05 and < 0.01), the survival rate of cartilage cell in experimental group was (65.8% +/- 2.6%) at two months after operation, while the cartilage cell all disappeared in control group. CONCLUSIONS: Perfused decellularation technique can construct a low immunogenicity laryngeal cartilage scaffold which can survive in the chest muscle package and establish a good blood supplement. The decellularized laryngeal scaffold could be used as a biological scaffold for whole laryngeal reconstruction. PMID- 23656818 TI - [Detection of lymph node of rabbit thyroid by real-time fluorescence imaging]. AB - OBJECTIVE: To detect the lymph nodes (LN) of rabbit thyroid by fluorescence imaging and to provide experimental evidence for its clinical application. METHODS: Each of 50 lateral thyroid lobes of 25 rabbits was injected with 0.02 ml of indocyanine green (ICG), and 0.02 ml methylene followed. ICG fluorescence was detected using photodynamic eye (PDE). The methylene staining in LN was also observed. The onset time of ICG staining in LN was measured. RESULTS: The detection rate of fluorescence imaging and blue dye imaging were respectively 86.0% (43/50) and 66.0% (33/50), with a significant difference (P = 0.034), and the accuracy were respectively 85.5% (53/62) and 70.7% (41/58). The onset time (x(-) +/- s) of ICG staining in LN was (118.3 +/- 16.1) s. CONCLUSIONS: Fluorescence imaging showed satisfied detection rate and accuracy. The detection rate of LN by fluorescence imaging was higher than that by blue dye imaging. Fluorescence imaging could be an alternative method for the detection of LN of thyroid in future clinical practice. PMID- 23656819 TI - [A case of ethmoid sinus cyst infection with blindness]. PMID- 23656820 TI - [Emergency treatment of tracheo-innominate artery fistula after tracheostomy]. PMID- 23656821 TI - [Pharyngeal and laryngeal syphilis-report of three cases]. PMID- 23656822 TI - [Multi-slice spiral CT in the diagnosis of cervical ectopic thymoma: a case report]. PMID- 23656823 TI - [Typical carcinoid tumor of the larynx with inguinal lymphatic metastasis]. PMID- 23656824 TI - [One case of giant cell arteritis with otitis media with effusion]. PMID- 23656825 TI - [Adult nasal embryonic rhabdomyosarcoma with neck lymph node metastasis: report of a case]. PMID- 23656826 TI - [Genetic research of age-related hearing impairment]. PMID- 23656827 TI - [Factors of individual differences in olfactory function]. PMID- 23656828 TI - Isolation of mycobacteria from clinical samples collected in the United States from 2004 to 2011. AB - BACKGROUND: Mycobacteria other than M. bovis may interfere with current bovine tuberculosis diagnostic tests resulting in false positive test results. As the prevalence of M. bovis decreases in the United States, interference from other mycobacteria play an increasingly important role in preventing the eradication of M. bovis. To identify mycobacteria other than M. bovis that may be interfering with current diagnostic tests, a retrospective study was performed to identify mycobacteria isolated from clinical tissues at the National Veterinary Services Laboratories between 1 January 2004 and 9 October 2011. RESULTS: During the study period, 2,366 mycobacteria other than M. bovis were isolated from samples submitted for clinical diagnosis of M. bovis. Fifty-five mycobacterial species were isolated during this time period. In cattle, M. avium complex, M. fortuitum/fortuitum complex, M. smegmatis, M. kansasii, and M. terrae complex were the predominate species other than M. bovis isolated from tissues submitted for culture. Mycobacteria other than M. bovis isolated from deer were predominantly M. avium complex, M. terrae/terrae complex, and M. fortuitum/fortuitum complex. CONCLUSIONS: These data provide information characterizing the species and relative prevalence of mycobacteria other than M. bovis that may interfere with current diagnostic tests. PMID- 23656829 TI - The development and validation of the major life changing decision profile (MLCDP). AB - BACKGROUND: Chronic diseases may influence patients taking major life changing decisions (MLCDs) concerning for example education, career, relationships, having children and retirement. A validated measure is needed to evaluate the impact of chronic diseases on MLCDs, improving assessment of their life-long burden. The aims of this study were to develop a validated questionnaire, the "Major Life Changing Decision Profile" (MLCDP) and to evaluate its psychometric properties. METHODS: 50 interviews with dermatology patients and 258 questionnaires, completed by cardiology, rheumatology, nephrology, diabetes and respiratory disorder patients, were analysed for qualitative data using Nvivo8 software. Content validation was carried out by a panel of experts. The first version of the MLCDP was completed by 210 patients and an iterative process of multiple Exploratory Factor Analyses and item prevalence was used to guide item reduction. Face validity and practicability was assessed by patients. RESULTS: 48 MLCDs were selected from analysis of the transcripts and questionnaires for the first version of the MLCDP, and reduced to 45 by combination of similar themes. There was a high intraclass correlation coefficient (0.7) between the 13 members of the content validation panel. Four more items were deleted leaving a 41-item MLCDP that was completed by 210 patients. The most frequently recorded MLCDs were decisions to change eating habits (71.4%), to change smoking/drinking alcohol habits (58.5%) and not to travel or go for holidays abroad (50.9%).Factor analysis suggested item number reduction from 41 to 34, to 29, then 23 items. However after taking into account item prevalence data as well as factor analysis results, 32 items were retained. The 32-item MLCDP has five domains education (3 items), job/career (9), family/relationships (5), social (10) and physical (5). The MLCDP score is expressed as the absolute number of decisions that have been affected. CONCLUSIONS: The 32-item (5 domains) MLCDP has been developed as an easy to complete generic tool for use in clinical practice and for quality of life and epidemiological research. Further validation is required. PMID- 23656830 TI - Depressive symptoms after CABG surgery: a meta-analysis. AB - LEARNING OBJECTIVES: After participating in this educational activity, the reader should be better able to measure the risk of depression before and after coronary artery bypass graft (CABG) surgery; examine the course of depression after CABG; and apply the results of the study to the treatment of patients. OBJECTIVE: Depression is highly comorbid with coronary artery disease. Clinicians face the question of whether patients' depressive symptoms will improve after coronary artery bypass graft surgery (CABG). The objective of this meta-analysis is to determine the course of depressive symptoms after CABG. METHODS: EMBASE, PubMed, and PsycINFO were searched for studies assessing depression before and after CABG. Meta-analyses were performed for depression at early (1-2 weeks), recovery (>2 weeks to 2 months), mid (>2 months to 6 months), and late (>6 months) postoperative time points. Heterogeneity and publication bias were analyzed. RESULTS: Thirty-nine studies were included in the meta-analysis. Twelve reported dichotomous outcomes; 18 reported continuous outcomes; and 9 reported both. Risk of depression was increased early (relative risk [RR] = 1.27; 95% confidence interval [CI], 1.01-1.61). There was a significantly decreased risk of depression at recovery (RR = 0.78; 95% CI, 0.67-0.90), mid (RR = 0.64; 95% CI, 0.58-0.70), and late (RR = 0.68; 95% CI, 0.58-0.79) time points without heterogeneity. All studies reporting continuous depression scales had significant heterogeneity. CONCLUSIONS: The risk of depression decreased post-CABG when depression was measured dichotomously. While depression improves overall and remits for some patients after CABG, the majority of patients will not experience remission of depression. Preoperative and postoperative depression monitoring is important. PMID- 23656832 TI - A Vietnam war veteran with posttraumatic stress disorder, status-post-myocardial infarction, in therapy with an Asian therapist. PMID- 23656833 TI - Sudden discovery of a previous nonclinical relationship with a potential patient: implications for subsequent psychiatric treatment. AB - Suddenly encountering a patient who happens to be a person with whom a therapist has had a previous nonclinical relationship poses special problems for both the therapist and patient. The problems--including countertransference issues, dual relationships, and other concerns surrounding subsequent therapy--are discussed in this column through the use of examples. The authors conclude that the potential disadvantages of treating such patients outweigh any advantages that might come from previous relationships. The consequent recommendation is that such patients be referred to other clinicians. PMID- 23656831 TI - Interventions for children affected by war: an ecological perspective on psychosocial support and mental health care. AB - BACKGROUND: Children and adolescents exposed to armed conflict are at high risk of developing mental health problems. To date, a range of psychosocial approaches and clinical/psychiatric interventions has been used to address mental health needs in these groups. AIMS: To provide an overview of peer-reviewed psychosocial and mental health interventions designed to address mental health needs of conflict-affected children, and to highlight areas in which policy and research need strengthening. METHODS: We used standard review methodology to identify interventions aimed at improving or treating mental health problems in conflict affected youth. An ecological lens was used to organize studies according to the individual, family, peer/school, and community factors targeted by each intervention. Interventions were also evaluated for their orientation toward prevention, treatment, or maintenance, and for the strength of the scientific evidence of reported effects. RESULTS: Of 2305 studies returned from online searches of the literature and 21 sources identified through bibliography mining, 58 qualified for full review, with 40 peer-reviewed studies included in the final narrative synthesis. Overall, the peer-reviewed literature focused largely on school-based interventions. Very few family and community-based interventions have been empirically evaluated. Only two studies assessed multilevel or stepped care packages. CONCLUSIONS: The evidence base on effective and efficacious interventions for conflict-affected youth requires strengthening. Postconflict development agendas must be retooled to target the vulnerabilities characterizing conflict-affected youth, and these approaches must be collaborative across bodies responsible for the care of youth and families. PMID- 23656834 TI - Nucleosomal DNA binding drives the recognition of H3K36-methylated nucleosomes by the PSIP1-PWWP domain. AB - BACKGROUND: Recognition of histone modifications by specialized protein domains is a key step in the regulation of DNA-mediated processes like gene transcription. The structural basis of these interactions is usually studied using histone peptide models, neglecting the nucleosomal context. Here, we provide the structural and thermodynamic basis for the recognition of H3K36 methylated (H3K36me) nucleosomes by the PSIP1-PWWP domain, based on extensive mutational analysis, advanced nuclear magnetic resonance (NMR), and computational approaches. RESULTS: The PSIP1-PWWP domain binds H3K36me3 peptide and DNA with low affinity, through distinct, adjacent binding surfaces. PWWP binding to H3K36me nucleosomes is enhanced approximately 10,000-fold compared to a methylated peptide. Based on mutational analyses and NMR data, we derive a structure of the complex showing that the PWWP domain is bound to H3K36me nucleosomes through simultaneous interactions with both methylated histone tail and nucleosomal DNA. CONCLUSION: Concerted binding to the methylated histone tail and nucleosomal DNA underlies the high- affinity, specific recognition of H3K36me nucleosomes by the PSIP1-PWWP domain. We propose that this bipartite binding mechanism is a distinctive and general property in the recognition of histone modifications close to the nucleosome core. PMID- 23656835 TI - Burden of self-reported acute gastrointestinal illness in China: a population based survey. AB - BACKGROUND: Acute gastrointestinal illness (AGI) is an important public-health problem worldwide. Previous national studies of the incidence of AGI in China were performed decades ago, and detailed information was not available. This study therefore sought to determine the magnitude, distribution, and burden of self-reported AGI in China. METHODS: Twelve-month, retrospective face-to-face surveys were conducted in 20 sentinel sites from six provinces between July 2010 and July 2011. RESULTS: In total, 39686 interviews were completed. The overall adjusted monthly prevalence of AGI was 4.2% (95% confidence interval, 4.0-4.4), corresponding to 0.56 episodes of AGI per person-year. Rates of AGI were highest in children aged < 5 years. Healthcare was sought by 56.1% of those reporting illness. Of the cases who visited a doctor, 32.7% submitted a stool sample. The use of antibiotics was reported by 49.7% of the cases who sought medical care and 54.0% took antidiarrhoeals. In the multivariable model, gender, age, education, household type, residence, season, province and travel were significant risk factors of being a case of AGI. CONCLUSIONS: This first population-based study in China indicated that AGI represents a substantial burden of health. Further research into the specific pathogens is needed to better estimate the burden of AGI and foodborne disease in China. PMID- 23656836 TI - An innovative pay-for-performance (P4P) strategy for improving malaria management in rural Kenya: protocol for a cluster randomized controlled trial. AB - BACKGROUND: In high-resource settings, 'pay-for-performance' (P4P) programs have generated interest as a potential mechanism to improve health service delivery and accountability. However, there has been little or no experimental evidence to guide the development or assess the effectiveness of P4P incentive programs in developing countries. In the developing world, P4P programs are likely to rely, at least initially, on external funding from donors. Under these circumstances, the sustainability of such programs is in doubt and needs assessment. METHODS/DESIGN: We describe a cluster-randomized controlled trial underway in 18 health centers in western Kenya that is testing an innovative incentive strategy to improve management of an epidemiologically and economically important problem- diagnosis and treatment of malaria. The incentive scheme in this trial promotes adherence to Ministry of Health guidelines for laboratory confirmation of malaria before treatment, a priority area for the Ministry of Health. There are three important innovations that are unique to this study among those from other resource-constrained settings: the behavior being incentivized is quality of care rather than volume of service delivery; the incentives are applied at the facility-level rather than the individual level, thus benefiting facility infrastructure and performance overall; and the incentives are designed to be budget-neutral if effective. DISCUSSION: Linking appropriate case management for malaria to financial incentives has the potential to improve patient care and reduce wastage of expensive antimalarials. In our study facilities, on average only 25% of reported malaria cases were confirmed by laboratory diagnosis prior to the intervention, and the total treatment courses of antimalarials dispensed did not correspond to the number of cases reported. This study will demonstrate whether facility rather than individual incentives are compelling enough to improve case management, and whether these incentives lead to offsetting cost savings as a result of reduced drug consumption. TRIAL REGISTRATION: ClinicalTrials.gov Registration Number NCT01809873. PMID- 23656837 TI - Differentially regulated expression of neurokinin B (NKB)/NK3 receptor system in uterine leiomyomata. AB - STUDY QUESTION: Are the vasoactive peptide neurokinin B (NKB) and its preferred NK3 receptor (NK3R) differentially expressed in leiomyomas compared with normal myometrium? SUMMARY ANSWER: In leiomyomas, NKB is up-regulated and delocalized, while its preferred NK3R is also differentially regulated. WHAT IS KNOWN ALREADY: The expression of NKB/NK3R in the central nervous system is essential for proper function of the human reproductive axis. Additionally, this system is also widely expressed throughout the female genital tract. Leiomyomas impair fertility and are a major source of abnormal uterine bleeding. The aberrant synthesis of local factors can contribute to the pathological symptoms observed in women with leiomyomata. NKB could be one of these factors, since a vasoactive role of this peptide at a peripheral level has been observed in different systems and species, including humans. NK3R is strongly regulated by estrogens and its activation leads to nuclear translocation affecting chromatin structure and gene expression. STUDY DESIGN, SIZE, DURATION: Samples were obtained between 2006 and 2012 from 28 women of reproductive age at different stages of the menstrual cycle by hysterectomy. Leiomyomas and matched macroscopically normal myometrium from each woman were analysed in vitro. PARTICIPANTS/MATERIALS, SETTING, METHODS: RT-PCR, quantitative real time, immunohistochemistry and in situ hybridization were used to investigate the pattern of expression of NKB/NK3R in tissue samples. MAIN RESULTS AND THE ROLE OF CHANCE: Expression of the gene encoding NKB (TAC3) was up regulated 20-fold in leiomyomas, compared with matched myometrium (P = 0.0008). In tumour tissue, not only connective cells, but also myometrial, endothelial and vascular smooth muscle cells express TAC3 mRNA. Immunoreactivity to NKB was preferentially located in the smooth muscle cell nuclei from normal myometrium in the secretory phase, unlike matched leiomyoma, which showed a predominant cytoplasmic expression pattern. In the normal myometrium, TACR3 mRNA showed variable expression throughout the menstrual phases, with samples showing strong, reduced or no amplification. In leiomyoma, TACR3 was significantly up-regulated compared with matched myometrium (P = 0.0349). LIMITATIONS, REASONS FOR CAUTION: This study is descriptive and although we observed clear differential regulation of the NKB/NK3R system at mRNA and immunohistochemical staining levels in leiomyoma, future functional studies are needed to determine the precise role of NKB in the myometrium in normal and pathological conditions. In addition, further analysis (e.g. in cell culture models) will be required to determine the role of NKB in the nucleus of normal smooth muscle cells, whether nuclear translocation is mediated by NK3R and the consequences of the cytoplasmic expression of NKB in tumour cells. WIDER IMPLICATIONS OF THE FINDINGS: The NKB/NK3R system dysregulation observed in leiomyoma may contribute to the pathological symptoms observed in women with leiomyomata. PMID- 23656838 TI - Copy number variation genotyping using family information. AB - BACKGROUND: In recent years there has been a growing interest in the role of copy number variations (CNV) in genetic diseases. Though there has been rapid development of technologies and statistical methods devoted to detection in CNVs from array data, the inherent challenges in data quality associated with most hybridization techniques remains a challenging problem in CNV association studies. RESULTS: To help address these data quality issues in the context of family-based association studies, we introduce a statistical framework for the intensity-based array data that takes into account the family information for copy-number assignment. The method is an adaptation of traditional methods for modeling SNP genotype data that assume Gaussian mixture model, whereby CNV calling is performed for all family members simultaneously and leveraging within family-data to reduce CNV calls that are incompatible with Mendelian inheritance while still allowing de-novo CNVs. Applying this method to simulation studies and a genome-wide association study in asthma, we find that our approach significantly improves CNV calls accuracy, and reduces the Mendelian inconsistency rates and false positive genotype calls. The results were validated using qPCR experiments. CONCLUSIONS: In conclusion, we have demonstrated that the use of family information can improve the quality of CNV calling and hopefully give more powerful association test of CNVs. PMID- 23656840 TI - The effects of the Affordable Care Act on the practice of psychiatry. PMID- 23656841 TI - Efficacy and safety of levomilnacipran sustained release in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled, proof of-concept study. AB - OBJECTIVE: To investigate the efficacy and safety of levomilnacipran sustained release (SR), an antidepressant candidate in late-stage development, in major depressive disorder (MDD). METHOD: Between December 2006 and October 2007, a 10 week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, flexible-dose trial assessed once-daily levomilnacipran SR (75 mg or 100 mg) in outpatients (18-70 years) meeting DSM-IV criteria for a major depressive episode (duration >= 1 month) with a 17-item Hamilton Depression Rating Scale (HDRS17) score > 22 and Sheehan Disability Scale (SDS) score >= 10. Levomilnacipran SR dose was increased to 100 mg/d over 12 days. The primary efficacy measure was Montgomery Asberg Depression Rating Scale (MADRS) score change from baseline to week 10; secondary efficacy measures were the HDRS17, SDS, Clinical Global Impressions-Improvement scale, and MADRS response (>= 50% decrease from baseline) and remission (score <= 10). Safety was evaluated according to adverse events, laboratory investigations, and vital signs/physical findings. RESULTS: Efficacy analyses included 276 levomilnacipran SR-treated patients and 277 placebo-treated patients. Levomilnacipran SR was significantly superior to placebo on MADRS total score change from baseline to week 10 (least squares mean difference [LSMD] = 4.2 [95% CI, -5.7 to -2.6]; P < .0001). Statistical significance in favor of levomilnacipran SR was demonstrated on change from baseline to week 10 in HDRS17 total score (LSMD = -3.4 [95% CI, -4.7 to -2.2]; P < .0001) and SDS total score (LSMD = -3.4 [95% CI, -4.6 to -2.2]; P < .0001) and subscales. Significantly more levomilnacipran SR patients versus placebo patients achieved MADRS response (59.1% vs 42.2%; P < .0001) and remission (46.4% vs 26.0%; P < .0001). Levomilnacipran SR was generally safe and well tolerated; more levomilnacipran SR patients (9.4%) versus placebo patients (6.5%) discontinued due to adverse events, but more placebo patients versus levomilnacipran SR patients discontinued overall (24.9% vs 20.2%). CONCLUSIONS: Levomilnacipran SR demonstrated robust efficacy on all measures and was generally well tolerated. TRIAL REGISTRATION: EudraCT number: 2006-002404-34 PMID- 23656842 TI - A case of atypical antipsychotic-induced somnambulism: a class effect. PMID- 23656843 TI - Pregnancy and psychiatric disorders: inherent risks and treatment decisions. PMID- 23656844 TI - Achieving the balance: treating depressed pregnant women with antidepressants. PMID- 23656845 TI - Risk of obsessive-compulsive disorder in pregnant and postpartum women: a meta analysis. AB - OBJECTIVE: Although pregnant and postpartum women are presumed to be at greater risk of obsessive-compulsive disorder (OCD) than the general population, the evidence has been inconclusive. This meta-analysis provides an estimate of OCD prevalence in pregnant and postpartum women and synthesizes the evidence that pregnant and postpartum women are at greater risk of OCD compared to the general population. DATA SOURCES: An electronic search of Google Scholar, PsycINFO, PsychARTICLES, and PubMed was performed by using the search terms OCD, obsessive compulsive disorder, pregnancy, postpartum, prevalence, and epidemiology. We supplemented our search with articles referenced in the obtained sources. The search was conducted until August 2012 without date restrictions. STUDY SELECTION: We included English-language studies reporting OCD prevalence (diagnosed according to DSM-III-R, DSM-IV, or ICD-10 criteria) in pregnant (12 studies) or postpartum (up to 12 months; 7 studies) women using structured diagnostic interviews. We also included a sample of regionally matched control studies (10 studies) estimating 12-month prevalence in the general female population for comparison. The control studies were limited to those conducted during the same time frame as the pregnant and postpartum studies. DATA EXTRACTION: We extracted author name, year of publication, diagnostic measure, sample size, diagnostic criteria, country, assessment time, subject population, and the point prevalence of OCD. RESULTS: Mixed- and random-effects models revealed an increase in OCD prevalence across pregnancy and the postpartum period with the lowest prevalence in the general population (mean = 1.08%) followed by pregnant (mean = 2.07%) and postpartum women (mean = 2.43%). An exploratory analysis of regionally matched risk-ratios revealed both pregnant (mean = 1.45) and postpartum (mean = 2.38) women to be at greater risk of experiencing OCD compared to the general female population, with an aggregate risk ratio of 1.79. CONCLUSIONS: Pregnant and postpartum women are more likely to experience OCD compared to the general population. PMID- 23656846 TI - Psychological response and cortisol reactivity to in vitro fertilization treatment in women with a lifetime anxiety or unipolar mood disorder diagnosis. AB - OBJECTIVE: Knowledge regarding the emotional and physiologic response of women with psychiatric disorders undergoing in vitro fertilization (IVF) treatments is rather limited. We evaluated psychological adjustment and cortisol reactivity to IVF treatment in women with a lifetime diagnosis of a unipolar mood or anxiety disorder compared to those without such a diagnosis. METHOD: Women undergoing IVF treatments (N = 121) were interviewed from January 2006 to December 2007 to assess for the presence of a history of a lifetime DSM-IV-TR unipolar mood or anxiety disorder. They were evaluated prospectively at baseline, at ovulation, and before the pregnancy test. Primary outcome measures included assessments of depressive and anxiety symptoms (Center for Epidemiologic Studies Depression Scale and State-Trait Anxiety Inventory, respectively) and plasma cortisol levels. RESULTS: Of 108 participants included in the study, 19.4% (n = 21) were determined to have a lifetime Axis I unipolar mood or anxiety diagnosis. Women with lifetime Axis I psychopathology showed significantly greater symptom elevation for depression (F2,194 = 10.97, P < .001) and for anxiety (F2,194 = 3.4813, P = .033) compared to the group without psychopathology. A different physiologic pattern was observed for cortisol response: whereas the group without psychopathology responded physiologically to the stressful treatment with continuously elevated cortisol levels, a blunted cortisol response was observed for the group with lifetime psychopathology (F2,200 = 2.9, P = .05). CONCLUSIONS: Women diagnosed with a lifetime unipolar mood or anxiety disorder developed robust symptom exacerbation during IVF treatment compared to women without an Axis I diagnosis. Conversely, the women with a lifetime diagnosis are characterized by a blunted cortisol response, indicating a pattern of dissociation between the robust increase in anxiety and depression and cortisol response to the acute psychological stress. This study emphasizes the need for a psychiatric screening prior to IVF treatment and for the utilization of preventive psychiatric and psychological interventions. PMID- 23656847 TI - A controlled clinical treatment trial of interpersonal psychotherapy for depressed pregnant women at 3 New York City sites. AB - OBJECTIVE: While treatment decisions for antepartum depression must be personalized to each woman and her illness, guidelines from the American Psychiatric Association and the American College of Obstetrics and Gynecology include the recommendation of psychotherapy for mild-to-moderate depression in pregnant women. Although we previously demonstrated the efficacy of interpersonal psychotherapy for antepartum depression in a sample of Hispanic women, this study provides a larger, more diverse sample of African American, Hispanic, and white pregnant women from 3 New York City sites in order to provide greater generalizability. METHOD: A 12-week bilingual, parallel-design, controlled clinical treatment trial compared interpersonal psychotherapy for antepartum depression to a parenting education program control group. An outpatient sample of 142 women who met DSM-IV criteria for major depressive disorder was randomly assigned to interpersonal psychotherapy or the parenting education program from September 2005 to May 2011. The 17-item Hamilton Depression Rating Scale (HDRS 17) was the primary outcome measure of mood. Other outcome scales included the Edinburgh Postnatal Depression Scale (EPDS) and the Clinical Global Impressions scale (CGI). The Maternal Fetal Attachment Scale (MFAS) assessed mother's interaction with the fetus. RESULTS: Although this study replicated previous findings that interpersonal psychotherapy is a beneficial treatment for antepartum depression, the parenting education program control condition showed equal benefit as measured by the HDRS-17, EPDS, CGI, and MFAS. CONCLUSIONS: This study supports the recommendation for the use of interpersonal psychotherapy for mild-to-moderate major depressive disorder in pregnancy. The parenting education program may be an alternative treatment that requires further study. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00251043 PMID- 23656849 TI - Residual symptoms in major depressive disorder: prevalence, effects, and management. PMID- 23656848 TI - Bupropion for overweight women with binge-eating disorder: a randomized, double blind, placebo-controlled trial. AB - BACKGROUND: Binge-eating disorder (BED) is defined by recurrent binge eating (eating unusually large quantities of food during which a subjective loss of control is experienced), marked distress about the binge eating, and the absence of inappropriate weight compensatory behaviors. BED is strongly associated with excess weight, and many available psychological and pharmacologic approaches fail to produce much weight loss. The objective of this study was to perform a randomized placebo-controlled trial to evaluate the short-term efficacy of bupropion for the treatment of BED in overweight and obese women. METHOD: Sixty one overweight and obese (mean body mass index [BMI] = 35.8) women who met DSM-IV TR research criteria for BED were randomly assigned to receive bupropion (300 mg/d) or placebo for 8 weeks. Participants were enrolled from November 2006 to December 2010. No dietary or lifestyle intervention was given. Primary outcome measures were binge-eating frequency and percent BMI loss. Secondary outcome measures were dimensional measures of eating disorder psychopathology, food craving, and depression levels. RESULTS: Eighty-nine percent (n = 54) of randomized participants completed the trial, without differential dropout between the bupropion and placebo groups. Mixed-effects analyses revealed significant time effects for all outcomes but no significant differences between bupropion and placebo on any outcome measure except for weight loss. Participants taking bupropion lost significantly more weight (1.8% vs 0.6% BMI loss; F = 10.57, P = .002). CONCLUSIONS: Bupropion was well tolerated and produced significantly greater-albeit quite modest-short-term weight loss in overweight and obese women with BED. Bupropion did not improve binge eating, food craving, or associated eating disorder features or depression relative to placebo. Our findings do not support bupropion as a stand-alone treatment for BED. The preliminary findings regarding short-term weight losses suggest the need for larger and longer-term trials to evaluate the potential utility of bupropion for enhancing outcomes of psychological interventions that have demonstrated effectiveness for BED but fail to produce weight loss. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00414167 PMID- 23656850 TI - Lessons learned from D-cycloserine: the promise and limits of drug facilitation of exposure therapy. PMID- 23656851 TI - Improving patient outcomes in depression through guideline-concordant, measurement-based care. AB - Because patients often seek treatment for depression in primary care, primary care physicians need the tools and knowledge to properly assess and manage major depressive disorder. Effective management includes using guideline-based treatment, measurement-based assessment, collaboration, and comorbid disease treatment. Treatment guidelines enable clinicians to create an effective, evidence-based management plan, and measurement tools allow for objective assessment and tracking of patients' symptoms and side effects over the course of treatment. Collaboration among primary care clinicians, case managers, and mental health specialists can improve adherence and outcomes for patients with major depressive disorder, including those with comorbid medical or psychiatric conditions. These approaches to patient care provide individualized treatment to help patients with depression. PMID- 23656852 TI - Does using marijuana increase the risk for developing schizophrenia? AB - As more US states and other countries consider legalizing marijuana, clinicians need to know the possible effects of this drug. Research has shown a connection between marijuana use and an increased risk for schizophrenia in young people who are vulnerable to developing psychosis. An international panel of experts addresses topics such as risk factors for schizophrenia, the potency and effects of cannabis use on adolescents, the effects of concurrent drug use with cannabis on schizophrenia risk, and current attitudes toward marijuana. PMID- 23656853 TI - Severe neuropsychiatric outcomes following discontinuation of long-term glucocorticoid therapy: a cohort study. AB - BACKGROUND: It has been estimated that, at any point in time, about 1% of the general adult population of the United Kingdom is receiving long-term (ie, >= 3 months) oral glucocorticoid therapy. These patients may develop neuropsychiatric disorders when the drug is discontinued. METHOD: Data were obtained for all adult patients registered from January 1, 1990, through December 31, 2008, at UK general practices that were contributors to The Health Improvement Network database. Data from 21,995 adult patients who had been exposed to long-term oral glucocorticoids and who had discontinued the drugs after an exposure ranging from 1 to 3 years were analyzed. The within-person incidence rate ratios (IRRs) for Read codes and/or prescriptions for depression, delirium/confusion, mania, panic disorders, and suicide or suicide attempt during the withdrawal period were estimated using a self-controlled case series methodology. The predictors of the outcomes were ascertained using Cox proportional hazards models. RESULTS: The risk of depression (IRR = 1.13; 95% CI, 1.00-1.28; P = .04) and of delirium/confusion (IRR = 2.67; 95% CI, 1.96-3.63; P < .001) was significantly higher during the discontinuation period compared to a reference period defined as ranging from 5 to 3 months before the drug cessation. Older people were at higher risk of delirium/confusion. The use of long-acting glucocorticoids was associated with a higher risk of both depression (adjusted hazard ratio [HR] = 1.92; 95% CI, 1.07-3.46) and delirium/confusion (adjusted HR = 4.96; 95% CI, 2.60 9.49) during the withdrawal period. CONCLUSIONS: Discontinuation of long-term glucocorticoid therapy is associated with an increased risk of both depression and delirium/confusion. People treated with long-acting glucocorticoids are particularly at risk. PMID- 23656854 TI - The type 2 diabetes mellitus susceptibility gene IGF2BP2 is associated with schizophrenia in a Han Chinese population. AB - BACKGROUND: Patients with schizophrenia have an increased prevalence of type 2 diabetes mellitus, and type 2 diabetes mellitus has shown an association with the rs4402960 gene polymorphism in the insulin-like growth factor II messenger RNA (mRNA)-binding protein 2 gene (IGF2BP2). We tested this polymorphism and mRNA expression levels of IGF2BP2 for an association in Han Chinese patients with schizophrenia compared to healthy controls. METHOD: The rs4402960 polymorphism was genotyped in 790 chronic schizophrenic patients (diagnosed according to DSM IV) and 1,083 unrelated healthy controls in a case-control design. The IGF2BP2 gene expression levels were assayed in 34 patients with chronic schizophrenia and 30 healthy controls by using real-time polymerase chain reaction (PCR). The study was conducted between 2005 and 2007. RESULTS: We found significant differences in the rs4402960 genotype (chi(2)2 = 7.316, P = .026) and allele (chi(2)1 = 7.056, P = .008) distributions between the patient and control groups. The rs4402960 T allelic frequency was significantly higher in male schizophrenic patients than male controls (28.9% vs 23.5%; P = .004) but not in female patients compared to female controls (27.1% vs 25.5%; P = .498). When real-time PCR was used, the IGF2BP2 gene's isoform B expression levels were significantly greater in schizophrenia than controls (P = .0008). CONCLUSIONS: These results suggest that the IGF2BP2 gene may play a role in susceptibility to schizophrenia, supporting the hypothesis that the co-occurrence of type 2 diabetes mellitus and schizophrenia may be explained by shared genetic risk variants. However, this finding remains preliminary since this association has yet to be replicated. PMID- 23656855 TI - Antidepressant exposure during pregnancy and congenital malformations: is there an association? A systematic review and meta-analysis of the best evidence. AB - OBJECTIVE: Depression is often not optimally treated during pregnancy, partially because of conflicting data regarding antidepressant medication risk. This meta analysis was conducted to determine whether antenatal antidepressant exposure is associated with congenital malformations and to assess the effect of known methodological limitations. DATA SOURCES: EMBASE, CINAHL, PsycINFO, and MEDLINE were searched from their start dates to June 2010. Keywords of various combinations were used, including, but not limited to depressive/mood disorder, pregnancy, antidepressant drug/agent, congenital malformation, and cardiac malformation. STUDY SELECTION: English language studies reporting congenital malformations associated with antidepressants were included. Of 3,074 abstracts reviewed, 735 studies were retrieved and 27 studies were included. DATA EXTRACTION: Two reviewers working independently assessed article quality. Data on use of any antidepressant, including fluoxetine and paroxetine specifically, were extracted. Outcomes included congenital malformations, major congenital malformations, cardiovascular defects, septal heart defects (ventral septal defects and atrial septal defects), and ventral septal defects only. RESULTS: Nineteen studies were above quality threshold and make up the primary meta analyses. Pooled relative risks (RRs) were derived by using random-effects methods. Antidepressant exposure was not associated with congenital malformations (RR = 0.93; 95% CI, 0.85-1.02; P = .113) or major malformations (RR = 1.07; 95% CI, 0.99-1.17; P = .095). However, increased risk for cardiovascular malformations (RR = 1.36; 95% CI, 1.08-1.71; P = .008) and septal heart defects (RR = 1.40; 95% CI, 1.10-1.77; P = .005) were found; the RR for ventral septal defects was similar to septal defects, although not significant (RR = 1.54; 95% CI, 0.71-3.33; P = .274). Pooled effects were significant for paroxetine and cardiovascular malformations (RR = 1.43; 95% CI, 1.08-1.88; P = .012). These results are contrasted with those addressing methodological limitations but are typically consistent. CONCLUSIONS: Overall, antidepressants do not appear to be associated with an increased risk of congenital malformations, but statistical significance was found for cardiovascular malformations. Results were robust in several sensitivity analyses. Given that the RRs are marginal, they may be the result of uncontrolled confounders. Although the RRs were statistically significant, none reached clinically significant levels. PMID- 23656856 TI - The effect of prenatal antidepressant exposure on neonatal adaptation: a systematic review and meta-analysis. AB - OBJECTIVE: Conflicting reports on potential risks of antidepressant exposure during gestation for the infant have been reported in the literature. This systematic review and meta-analysis on immediate neonatal outcomes were conducted to clarify what, if any, risks are faced by infants exposed to antidepressants in utero. Subanalyses address known methodological limitations in the field. DATA SOURCES: MEDLINE, EMBASE, CINAHL, and PsycINFO were searched from their start dates to June 2010. Various combinations of keywords were utilized including, but not limited to, depressive/mood disorder, pregnancy/pregnancy trimesters, antidepressant drugs, and neonatal effects. STUDY SELECTION: English language and cohort and case-control studies reporting on a cluster of signs defined as poor neonatal adaptation syndrome (PNAS) or individual clinical signs (respiratory distress and tremors) associated with pharmacologic treatment were selected. Of 3,074 abstracts reviewed, 735 articles were retrieved and 12 were included in this analysis. DATA EXTRACTION: Two independent reviewers extracted data and assessed the quality of the articles. RESULTS: Twelve studies were retrieved that examined PNAS or the signs of respiratory distress and tremors in the infant. There was a significant association between exposure to antidepressants during pregnancy and overall occurrence of PNAS (odds ratio [OR] = 5.07; 95% CI, 3.25 7.90; P < .0001). Respiratory distress (OR = 2.20; 95% CI, 1.81-2.66; P < .0001) and tremors (OR = 7.89; 95% CI, 3.33-18.73; P < .0001) were also significantly associated with antidepressant exposure. For the respiratory outcome, studies using convenience samples had significantly higher ORs (Q1 = 5.4, P = .020). No differences were found in any other moderator analyses. CONCLUSIONS: An increased risk of PNAS exists in infants exposed to antidepressant medication during pregnancy; respiratory distress and tremors also show associations. Neonatologists need to be prepared and updated in their management, and clinicians must inform their patients of this risk. PMID- 23656857 TI - The impact of maternal depression during pregnancy on perinatal outcomes: a systematic review and meta-analysis. AB - OBJECTIVE: Depression often remains undertreated during pregnancy and there is growing evidence that untoward perinatal outcomes can result. Our systematic review and meta-analysis was conducted to determine whether maternal depression during pregnancy is associated with adverse perinatal and infant outcomes. DATA SOURCES: MEDLINE, EMBASE, CINAHL, and PsycINFO were searched from their start dates to June 2010. Keywords utilized included depressive/mood disorder, postpartum/postnatal, pregnancy/pregnancy trimesters, prenatal or antenatal, infant/neonatal outcomes, premature delivery, gestational age, birth weight, NICU, preeclampsia, breastfeeding, and Apgar. STUDY SELECTION: English language studies reporting on perinatal or child outcomes associated with maternal depression were included, 3,074 abstracts were reviewed, 735 articles retrieved, and 30 studies included. DATA EXTRACTION: Two independent reviewers extracted data and assessed article quality. All studies were included in the primary analyses, and between-group differences for subanalyses are also reported. RESULTS: Thirty studies were eligible for inclusion. Premature delivery and decrease in breastfeeding initiation were significantly associated with maternal depression (odds ratio [OR] = 1.37; 95% CI, 1.04 to 1.81; P = .024; and OR = 0.68; 95% CI, 0.61 to 0.76; P < .0001, respectively). While birth weight (mean difference = -19.53 g; 95% CI, -64.27 to 25.20; P = .392), low birth weight (OR = 1.21; 95% CI, 0.91 to 1.60; P = .195), neonatal intensive care unit admissions (OR = 1.43; 95% CI, 0.83 to 2.47; P = .195), and preeclampsia (OR = 1.35; 95% CI, 0.95 to 1.92; P = .089) did not show significant associations in the main analyses, some subanalyses were significant. Gestational age (mean difference = 0.19 weeks; 95% CI, -0.53 to 0.14; P = .262) and Apgar scores at 1 (mean difference = -0.05; 95% CI, -0.28 to 0.17; P = .638) and 5 minutes (mean difference = 0.01; 95% CI, -0.08 to 0.11; P = .782) did not demonstrate any significant associations with depression. For premature delivery, a convenience sample study design was associated with higher ORs (OR = 2.43; 95% CI, 1.47 to 4.01; P = .001). CONCLUSIONS: Maternal depression during pregnancy is associated with increased odds for premature delivery and decreased breastfeeding initiation; however, the effects are modest. More research of higher methodological quality is needed. PMID- 23656858 TI - Psychometric evaluation of a Swedish version of Minneapolis-Manchester quality of life-youth form and adolescent form. AB - BACKGROUND: It has become important to measure long-term effects and quality of life in survivors of childhood cancer. The Minneapolis- Manchester Quality of Life (MMQL) instrument has been proven to better capture the quality of life (QoL) perspective of health than other instruments. The instrument has age appropriate versions and is therefore favourable for longitudinal studies of QoL of children surviving from cancer. The aim of this study was to evaluate the psychometric properties of the Swedish version of MMQL-Youth Form and the Adolescent Form focusing on: 1) face and content validity 2) the internal consistency and 3) the test-retest reliability. METHODS: The sample consisted of 950 pupils (11-16 years old) from 7 schools in the western Sweden who completed the questionnaire. For the test-retest evaluation 230 respondents completed the questionnaire two weeks later. RESULTS: Face and content validity was supported and internal consistency was found to be acceptable for the total scale for both the MMQL-Youth Form (8-12 years of age) and the Adolescent Form (13-20 years of age). Test-retest reliability for the MMQL-Youth Form was moderate for 50% of the items and good for the remaining. For the MMQL-Adolescent Form the test-retest showed moderate or good agreement for 80% of the items and fair for 20%. CONCLUSIONS: The result indicated that the Swedish version of the MMQL-Youth Form and Adolescent Form was valid and reliable in a sample of healthy children in a Swedish context. It is recommended to test the instrument among diverse samples of children such as survivors of childhood cancer in order to validate its usefulness in research and clinical settings. PMID- 23656859 TI - Increasing intracellular bioavailable copper selectively targets prostate cancer cells. AB - The therapeutic efficacy of two bis(thiosemicarbazonato) copper complexes, glyoxalbis[N4-methylthiosemicarbazonato]Cu(II) [Cu(II)(gtsm)] and diacetylbis[N4 methylthiosemicarbazonato]Cu(II) [Cu(II)(atsm)], for the treatment of prostate cancer was assessed in cell culture and animal models. Distinctively, copper dissociates intracellularly from Cu(II)(gtsm) but is retained by Cu(II)(atsm). We further demonstrated that intracellular H2gtsm [reduced Cu(II)(gtsm)] continues to redistribute copper into a bioavailable (exchangeable) pool. Both Cu(II)(gtsm) and Cu(II)(atsm) selectively kill transformed (hyperplastic and carcinoma) prostate cell lines but, importantly, do not affect the viability of primary prostate epithelial cells. Increasing extracellular copper concentrations enhanced the therapeutic capacity of both Cu(II)(gtsm) and Cu(II)(atsm), and their ligands (H2gtsm and H2atsm) were toxic only toward cancerous prostate cells when combined with copper. Treatment of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model with Cu(II)(gtsm) (2.5 mg/kg) significantly reduced prostate cancer burden (~70%) and severity (grade), while treatment with Cu(II)(atsm) (30 mg/kg) was ineffective at the given dose. However, Cu(II)(gtsm) caused mild kidney toxicity in the mice, associated primarily with interstitial nephritis and luminal distention. Mechanistically, we demonstrated that Cu(II)(gtsm) inhibits proteasomal chymotrypsin-like activity, a feature further established as being common to copper-ionophores that increase intracellular bioavailable copper. We have demonstrated that increasing intracellular bioavailable copper can selectively kill cancerous prostate cells in vitro and in vivo and have revealed the potential for bis(thiosemicarbazone) copper complexes to be developed as therapeutics for prostate cancer. PMID- 23656860 TI - Associations of dietary glycaemic index and glycaemic load with food and nutrient intake and general and central obesity in British adults. AB - Inconsistent associations between dietary glycaemic index (GI) and glycaemic load (GL) and body fatness may be partly due to differences in the underlying dietary patterns or energy under-reporting. In the present study, we examined the cross sectional associations of dietary GI and GL with food and nutrient intake and general and central obesity, accounting for energy under-reporting. The subjects were 1487 British adults aged 19-64 years. Dietary intake was assessed using a 7 d weighed dietary record. Breads and potatoes were the positive predictive foods for dietary GI, while fruit, other cereals and dairy products were the negative predictors. These foods were similarly identified in the analysis of only acceptable reporters (AR; ratio of reported energy intake:estimated energy requirement within 0.665-1.335) and under-reporters (UR; ratio < 0.665). Dietary GL was closely correlated with carbohydrate intake. Multiple linear regression analyses showed that dietary GI was independently associated with a higher risk of general obesity (BMI >= 30 kg/m2) and central obesity (waist circumference >= 102 cm in men and >= 88 cm in women). Dietary GL was also associated with general (only women) and central obesity. Similarly, in the analysis of AR, the GI showed positive associations with general and central obesity, and, only in women, the GL showed positive associations with general and central obesity. Conversely, in the analysis of UR, the associations were generally weaker and many of them failed to reach statistical significance. In conclusion, we found independent positive associations of dietary GI and GL with general and central obesity in British adults. PMID- 23656861 TI - Performance-optimized clinical IMRT planning on modern CPUs. AB - Intensity modulated treatment plan optimization is a computationally expensive task. The feasibility of advanced applications in intensity modulated radiation therapy as every day treatment planning, frequent re-planning for adaptive radiation therapy and large-scale planning research severely depends on the runtime of the plan optimization implementation. Modern computational systems are built as parallel architectures to yield high performance. The use of GPUs, as one class of parallel systems, has become very popular in the field of medical physics. In contrast we utilize the multi-core central processing unit (CPU), which is the heart of every modern computer and does not have to be purchased additionally. In this work we present an ultra-fast, high precision implementation of the inverse plan optimization problem using a quasi-Newton method on pre-calculated dose influence data sets. We redefined the classical optimization algorithm to achieve a minimal runtime and high scalability on CPUs. Using the proposed methods in this work, a total plan optimization process can be carried out in only a few seconds on a low-cost CPU-based desktop computer at clinical resolution and quality. We have shown that our implementation uses the CPU hardware resources efficiently with runtimes comparable to GPU implementations, at lower costs. PMID- 23656862 TI - Does chemical aposematic (warning) signaling occur between host plants and their potential parasitic plants? AB - Aposematism (warning) signaling is a common defensive mechanism toward predatory or herbivorous animals, i.e., interactions between different trophic levels. I propose that it should be considered at least as a working hypothesis that chemical aposematism operates between certain host plants and their plant predators, parasitic plants, and that although they are also plants, they belong to a higher trophic level. Specific host plant genotypes emit known repelling chemical signals toward parasitic plants, which reduce the level of, slow the directional parasite growth (attack) toward the signaling hosts, or even cause parasitic plants to grow away from them in response to these chemicals. Chemical host aposematism toward parasitic plants may be a common but overlooked defense from parasitic plants. PMID- 23656863 TI - Arabidopsis thaliana: proliferating cell nuclear antigen 1 and 2 possibly form homo- and hetero-trimeric complexes in the plant cell. AB - The proliferating cell nuclear antigen (PCNA) is a key component of the eukaryotic DNA replication machinery. It also plays an important role in DNA repair mechanisms. Despite the intense scientific research on yeast and human PCNA, information describing the function of this protein in plants is still very limited. In the previous study Arabidopsis PCNA2 but not PCNA1 was proposed to be functionally important in DNA polymerase eta-dependent postreplication repair. In addition to the above study, PCNA2 but not PCNA1 was also shown to be necessary for Arabidopsis DNA polymerase lambda-dependent oxidative DNA damage bypass. Taking into account the reported differences between PCNA1 and PCNA2, we tested the idea of a possible cooperation between PCNA1 and PCNA2 in the plant cell. In a bimolecular fluorescence complementation assay an interaction between PCNA1 and PCNA2 was observed in the nucleus, as well as in the cytoplasm. This finding, together with our previous results, indicates that PCNA1 and PCNA2 may cooperate in planta by forming homo- and heterotrimeric rings. The observed interaction might be relevant when distinct functions for PCNA1 and PCNA2 are considered. PMID- 23656864 TI - The involvement of Medicago truncatula non-specific lipid transfer protein N5 in the control of rhizobial infection. AB - Cysteine-rich proteins seem to play important regulatory roles in Medicago truncatula/Sinorhizobium meliloti symbiosis. In particular, a large family of nodule-specific cysteine-rich (NCR) peptides is crucial for the differentiation of nitrogen-fixing bacteroids. The Medicago truncatula N5 protein (MtN5) is currently the only reported non-specific lipid transfer protein necessary for successful rhizobial symbiosis; in addition, MtN5 shares several characteristics with NCR peptides: a small size, a conserved cysteine-rich motif, an N-terminal signal peptide for secretion and antimicrobial activity. Unlike NCR peptides, MtN5 expression is not restricted to the root nodules and is induced during the early phases of symbiosis in root hairs and nodule primordia. Recently, MtN5 was determined to be involved in the regulation of root tissue invasion; while, it was dispensable for nodule primordia formation. Here, we discuss the hypothesis that MtN5 participates in linking the progression of bacterial invasion with restricting the competence of root hairs for infection. PMID- 23656865 TI - MicroFilament Analyzer identifies actin network organizations in epidermal cells of Arabidopsis thaliana roots. AB - The plant cytoskeleton plays a crucial role in the cells' growth and development during different developmental stages and it undergoes many rearrangements. In order to describe the arrangements of the F-actin cytoskeleton in root epidermal cells of Arabidopsis thaliana, the recently developed software MicroFilament Analyzer (MFA) was exploited. This software enables high-throughput identification and quantification of the orientation of filamentous structures on digital images in a highly standardized and fast way. Using confocal microscopy and transgenic GFP-FABD2-GFP plants the actin cytoskeleton was visualized in the root epidermis. MFA analysis revealed that during the early stages of cell development F-actin is organized in a mainly random pattern. As the cells grow, they preferentially adopt a longitudinal organization, a pattern that is also preserved in the largest cells. In the evolution from young to old cells, an approximately even distribution of transverse, oblique or combined orientations is always present besides the switch from random to a longitudinal oriented actin cytoskeleton. PMID- 23656867 TI - Ospapst1, a useful mutant for identifying seed purity and authenticity in hybrid rice. AB - The stability and completeness of male sterility is still a challenge in some male sterile rice lines, especially those of photoperiod/thermo-sensitive genic male sterility (P/TGMS). Leaf color marker is a widely practiced approach to reduce the impact of self-pollinated seeds of male sterile lines. The papst1 is a leaf color mutant. The newly emerged leaves of papst1 are chlorosis and have an impaired photosynthesis. But the other agronomic traits, such as germination rate, duration of maturation and seed weight, are not changed. The papst1/PAPST1 F1 showed the wild-type leaf phenotype. The papst1/PAPST1 F2 progenies displayed an approximately 3:1 segregation ratio of WT phenotype:mutant phenotype (72: 28, chi(2) = 0.48, p > 0.05), suggesting that papst1 mutant phenotype is caused by a single repressive gene. Map-based cloning and sequencing analysis revealed that a point mutation was occurred in Os01 g16040 (OsPAPST1). Given these results, the Ospapst1 mutant is a useful mutant for identifying seed purity and authenticity in hybrid rice. PMID- 23656866 TI - A role for GIGANTEA: keeping the balance between flowering and salinity stress tolerance. AB - The initiation of flowering in Arabidopsis is retarded or abolished by environmental stresses. Focusing on salt stress, we provide a molecular explanation for this well-known fact. A protein complex consisting of GI, a clock component important for flowering and SOS2, a kinase activating the [Na(+)] antiporter SOS1, exists under no stress conditions. GI prevents SOS2 from activating SOS1. In the presence of NaCl, the SOS2/GI complex disintegrates and GI is degraded. SO2, together with the Ca (2+)-activated sensor of sodium ions, SOS3, activates SOS1. In gi mutants, SOS1 is constitutively activated and gi plants are more highly salt tolerant than wild type Arabidopsis. The model shows GI as a transitory regulator of SOS pathway activity whose presence or amount connects flowering to environmental conditions. PMID- 23656868 TI - Complexity of potassium acquisition: how much flows through channels? AB - The involvement of potassium (K(+))-selective, Shaker-type channels, particularly AKT1, in primary K(+) acquisition in roots of higher plants has long been of interest, particularly in the context of low-affinity K(+) uptake, at high K(+) concentrations, as well as uptake from low-K(+) media under ammonium (NH4(+)) stress. We recently demonstrated that K(+) channels cannot mediate K(+) acquisition in roots of intact barley (Hordeum vulgare L.) seedlings at low (22.5 uM) external K(+) concentrations ([K(+)](ext)) and in the presence of high (10 mM) external NH4(+), while the model species Arabidopsis thaliana L. utilizes channels under comparable conditions. However, when external NH4(+) was suddenly withdrawn, a thermodynamic shift to passive (channel-mediated) K(+) influx was observed in barley and both species demonstrated immediate and dramatic stimulations in K(+) influx, illustrating a hitherto unexplored magnitude and rapidity of K(+)-uptake capacity and plasticity. Here, we expand on our previous work by offering further characterization of channel-mediated K(+) fluxes in intact barley, with particular focus on anion effects, root respiration and pharmacological sensitivity and highlight key additions to the current model of K(+) acquisition. PMID- 23656869 TI - Cis- and trans-zeatin differentially modulate plant immunity. AB - Phytohormones are essential regulators of various processes in plant growth and development. Several phytohormones are also known to regulate plant responses to environmental stress and pathogens. Only recently, cytokinins have been demonstrated to play an important role in plant immunity. Increased levels of cytokinins such as trans-zeatin, which are considered highly active, induced resistance against mainly (hemi)biotrophic pathogens in different plant species. In contrast, cis-zeatin is commonly regarded as a cytokinin exhibiting low or no activity. Here we comparatively study the impact of both zeatin isomers on the infection of Nicotiana tabacum by the (hemi)biotrophic microbial pathogen Pseudomonas syringae. We demonstrate a biological effect of cis-zeatin and a differential effect of the two zeatin isomers on symptom development, defense responses and bacterial multiplication. PMID- 23656870 TI - Architectural remodeling of the tonoplast during fluid-phase endocytosis. AB - During fluid phase endocytosis (FPE) in plant storage cells, the vacuole receives a considerable amount of membrane and fluid contents. If allowed to accumulate over a period of time, the enlarging tonoplast and increase in fluids would invariably disrupt the structural equilibrium of the mature cells. Therefore, a membrane retrieval process must exist that will guarantee membrane homeostasis in light of tonoplast expansion by membrane addition during FPE. We examined the morphological changes to the vacuolar structure during endocytosis in red beet hypocotyl tissue using scanning laser confocal microscopy and immunohistochemistry. The heavily pigmented storage vacuole allowed us to visualize all architectural transformations during treatment. When red beet tissue was incubated in 200 mM sucrose, a portion of the sucrose accumulated entered the cell by means of FPE. The accumulation process was accompanied by the development of vacuole-derived vesicles which transiently counterbalanced the addition of surplus endocytic membrane during rapid rates of endocytosis. Topographic fluorescent confocal micrographs showed an ensuing reduction in the size of the vacuole-derived vesicles and further suggest their reincorporation into the vacuole to maintain vacuolar unity and solute concentration. PMID- 23656871 TI - Assessing the regulation of leaf redox status under water stress conditions in Arabidopsis thaliana: Col-0 ecotype (wild-type and vtc-2), expressing mitochondrial and cytosolic roGFP1. AB - Using Arabidopsis plants Col-0 and vtc2 transformed with a redox sensitive green fluorescent protein, (c-roGFP) and (m-roGFP), we investigated the effects of a progressive water stress and re-watering on the redox status of the cytosol and the mitochondria. Our results establish that water stress affects redox status differently in these two compartments, depending on phenotype and leaf age, furthermore we conclude that ascorbate plays a pivotal role in mediating redox status homeostasis and that Col-0 Arabidopsis subjected to water stress increase the synthesis of ascorbate suggesting that ascorbate may play a role in buffering changes in redox status in the mitochondria and the cytosol, with the presumed buffering capacity of ascorbate being more noticeable in young compared with mature leaves. Re-watering of water-stressed plants was paralleled by a return of both the redox status and ascorbate to the levels of well-watered plants. In contrast to the effects of water stress on ascorbate levels, there were no significant changes in the levels of glutathione, thereby suggesting that the regeneration and increase in ascorbate in water-stressed plants may occur by other processes in addition to the regeneration of ascorbate via the glutathione. Under water stress in vtc2 lines it was observed stronger differences in redox status in relation to leaf age, than due to water stress conditions compared with Col-0 plants. In the vtc2 an increase in DHA was observed in water-stressed plants. Furthermore, this work confirms the accuracy and sensitivity of the roGFP1 biosensor as a reporter for variations in water stress-associated changes in redox potentials. PMID- 23656873 TI - Trehalases: a neglected carbon metabolism regulator? AB - Trehalases are enzymes that carry out the degradation of the non-reducing disaccharide trehalose. Trehalase phylogeny unveiled three major branches comprising those from bacteria; plant and animals; and those from fungal origin. Comparative analysis between several deduced trehalase structures and the crystallographic structure of bacterial trehalase indicated that these enzyme's structures are highly conserved in spite of the marked differences found at the sequence level. These results suggest a bacterial origin for the trehalases in contrast to an eukaryotic origin, as previously proposed. Trehalases structural analysis showed that they contain six discrete motifs which are characteristic of each phylogenetic group, suggesting a positive evolutionary selection pressure for the structural conservation. Interestingly, trehalases are involved in multiple regulatory functions: In the response against pathogens (plant-pathogen interactions); the regulation of bacterial viability in symbiotic interactions (legume-Rhizobium); carbon partitioning in plants; regulating chitin biosynthesis, as well as energy supply in the hemolymph for flight, in insects. In summary, trehalases seem to have a prokaryotic origin and play an active role in carbon metabolism and other diverse regulatory effects on cell physiology. PMID- 23656872 TI - Arabidopsis sos1 mutant in a salt-tolerant accession revealed an importance of salt acclimation ability in plant salt tolerance. AB - An analysis of the salinity tolerance of 354 Arabidopsis thaliana accessions showed that some accessions were more tolerant to salt shock than the reference accession, Col-0, when transferred from 0 to 225 mM NaCl. In addition, several accessions, including Zu-0, showed marked acquired salt tolerance after exposure to moderate salt stress. It is likely therefore that Arabidopsis plants have at least two types of tolerance, salt shock tolerance and acquired salt tolerance. To evaluate a role of well-known salt shock tolerant gene SOS1 in acquired salt tolerance, we isolated a sos1 mutant from ion-beam-mutagenized Zu-0 seedlings. The mutant showed severe growth inhibition under salt shock stress owing to a single base deletion in the SOS1 gene and was even more salt sensitive than Col 0. Nevertheless, it was able to survive after acclimation on 100 mM NaCl for 7 d followed by 750 mM sorbitol for 20 d, whereas Col-0 became chlorotic under the same conditions. We propose that genes for salt acclimation ability are different from genes for salt shock tolerance and play an important role in the acquisition of salt or osmotic tolerance. PMID- 23656874 TI - Effect of external and internal factors on the expression of reporter genes driven by the N resistance gene promoter. AB - The role of resistance (R) genes in plant pathogen interaction has been studied extensively due to its economical impact on agriculture. Interaction between tobacco mosaic virus (TMV) and the N protein from tobacco is one of the most widely used models to understand various aspects of pathogen resistance. The transcription activity governed by N gene promoter is one of the least understood elements of the model. In this study, the N gene promoter was cloned and fused with two different reporter genes, one encoding beta-glucuronidase (N::GUS) and another, luciferase (N::LUC). Tobacco plants transformed with the N::GUS or N::LUC reporter constructs were screened for homozygosity and stable expression. Histochemical analysis of N::GUS tobacco plants revealed that the expression is organ specific and developmentally regulated. Whereas two week old plants expressed GUS in midveins only, 6-wk-old plants also expressed GUS in leaf lamella. Roots did not show GUS expression at any time during development. Experiments to address effects of external stress were performed using N::LUC tobacco plants. These experiments showed that N gene promoter expression was suppressed when plants were exposed to high but not low temperatures. Expression was also upregulated in response to TMV, but no changes were observed in plants treated with SA. PMID- 23656875 TI - Salt overly sensitive pathway members are influenced by diurnal rhythm in rice. AB - The diurnal rhythm controls many aspects of plant physiology such as flowering, photosynthesis and growth. Rice is one of the staple foods for world's population. Abiotic stresses such as salinity, drought, heat and cold severely affect rice production. Under salinity stress, maintenance of ion homeostasis is a major challenge, which also defines the tolerance level of a given genotype. Salt overly sensitive (SOS) pathway is well documented to play a key role in maintaining the Na(+) homeostasis in plant cell. However, it is not reported yet whether the transcriptional regulation of genes of this pathway are influenced by diurnal rhythm. In the present work, we have studied the diurnal pattern of transcript abundance of SOS pathway genes in rice at seedling stage.To rule out the effect of temperature fluctuations on the expression patterns of these genes, the seedlings were grown under constant temperature. We found that OsSOS3 and OsSOS2 exhibited a rhythmic and diurnal expression pattern, while OsSOS1did not have any specific pattern of expression. This analysis establishes a cross-link between diurnal rhythm and SOS pathway and suggests that SOS pathway is influenced by diurnal rhythm in rice. PMID- 23656876 TI - Cytokinin inhibition of leaf senescence. AB - The senescence delaying effect of cytokinin is well known, however, the details behind how this process occurs remain unclear. Efforts to improve understanding of this phenomenon have led to the identification in Arabidopsis of specific cytokinin signaling components through which senescence signal responses are regulated. These include the cytokinin receptor (AHK3), the type-B response regulator (ARR2) and the recently identified cytokinin response factor (CRF6). At the mechanistic end of this process, it was found that increased cell-wall invertase activity which occurs in response to cytokinin is both necessary and sufficient for the inhibition of senescence. Yet, a direct link between the signaling and mechanistic steps of a cytokinin regulated senescence process has yet to be demonstrated. This may be in part because the relationship between senescence and primary metabolism implied by the key role of cell-wall invertase is the subject of two apparently opposing bodies of evidence. Here we briefly summarize and propose a model in which cytokinin mediated changes in sink/source relationships leads to delayed senescence which is consistent with existing evidence both for and against sugars as a trigger for developmental senescence. PMID- 23656877 TI - Emerging role of SUMOylation in plant development. AB - Post-translational attachment of small ubiquitin-like modifier (SUMO), defined as SUMOylation, has emerged as a new mechanism of protein regulation in plant biology. In plant, SUMOylation has been shown to play crucial roles in a variety of biotic and abiotic stress responses. Recent work using viable mutants with defective SUMOylation have indicated an important role for SUMOylation in a wide range of developmental processes, such as cell division, expansion, survival and differentiation, vegetative growth and reproductive development. This review will summarize the currently emerging information regarding the function of SUMOylation in plant development. PMID- 23656878 TI - Separation anxiety: an analysis of ethylene-induced cleavage of EIN2. AB - Since the discovery of the CTR1 protein kinase and the endoplasmic reticulum (ER) localized EIN2 protein nearly 20 y ago, plant biologists have wondered how these proteins respectively serve as negative and positive regulators of ethylene mediated signal transduction in plants. Now with the publication of four studies, it can be concluded that in the absence of ethylene (ET) in Arabidopsis thaliana, CTR1 phosphorylates EIN2 thereby inactivating ET signal transduction, while in the presence of ET, CTR1 no longer phosphorylates EIN2 and the cytosolic C terminus of EIN2 is released from the ER to translocate to the nucleus to promote gene transcription. Chen et al. (2011) showed that EIN2 is differentially phosphorylated at amino acids (a.a.) S(645) and S(924) after ET treatment. Ju et al. (2012) then proved that CTR1 phosphorylates EIN2 at those positions and that the lack of phosphorylation at S(645) and S(924) leads to the translocation of an EIN2 C-terminus peptide. Wen et al. (2012) and Qiao et al. (2012) also demonstrated ET-induced translocation of an EIN2 C-terminus peptide, while Qiao et al. (2012) proved that EIN2 has a nuclear localization signal sequence required for translocation, confirmed phosphorylation at S(645) and said that proteolytic cleavage occurs at S(645) in absence of phosphorylation there. Despite the revelation of this elegant switch, there are contradictory indications for specific cleavage at EIN2 S(645). This article investigates the data and concludes that EIN2 may be cleaved at alternative positions. PMID- 23656879 TI - Distinct salt-dependent effects impair Fremyella diplosiphon pigmentation and cellular shape. AB - Salt impairs cellular morphology and photosynthetic pigment accumulation in the cyanobacterium Fremyella diplosiphon. Recent findings indicated that the impact of salt on cellular morphology was attributable to salt-associated effects on osmotic regulation, as the impact on morphology was reversible when cells were treated with an osmoticum in the presence of salt. The impact of salt on photosynthetic pigment accumulation was associated with ionic effects of salt on the cells, as pigment levels remained low when salt-treated cells were incubated together with an osmoticum or an antioxidant, the latter to mitigate the impact of a salt-associated accumulation of reactive oxygen species. Here, we provide evidence that the transcripts for genes encoding the phycobiliproteins are not reduced in the presence of salt. These results suggest that the negative impact of salt-mediated changes on pigment accumulation occurs post-transcriptionally. A greater understanding of the mechanisms which impact growth of strains such as F. diplosiphon, which harbor pigments that allow low-light and shade-tolerated growth, may facilitate the development or adaptation of such strains as useful for remediation of salt-impacted soils or biofuel production. PMID- 23656880 TI - Pharmacological and genetical evidence supporting nitric oxide requirement for 2,4-epibrassinolide regulation of root architecture in Arabidopsis thaliana. AB - Brassinosteroids (BRs) regulate various physiological processes, such as tolerance to stresses and root growth. Recently, a connection was reported between BRs and nitric oxide (NO) in plant responses to abiotic stress. Here we present evidence supporting NO functions in BR signaling during root growth process. Arabidopsis seedlings treated with BR 24-epibrassinolide (BL) show increased lateral roots (LR) density, inhibition of primary root (PR) elongation and NO accumulation. Similar effects were observed adding the NO donor GSNO to BR receptor mutant bri1-1. Furthermore, BL-induced responses in the root were abolished by the specific NO scavenger c-PTIO. The activities of nitrate reductase (NR) and nitric oxide synthase (NOS)-like, two NO generating enzymes were involved in BR signaling. These results demonstrate that BR increases the NO concentration in root cells, which is required for BR-induced changes in root architecture. PMID- 23656881 TI - Arabidopsis thaliana vacuolar TPK channels form functional K+ uptake pathways in Escherichia coli. AB - Very few vacuolar two pore potassium channels (TPKs) have been functionally characterized. In this paper we have used complementation of K(+) uptake deficient Escherichia coli mutant LB2003 to analyze the functional properties of Arabidopsis thaliana TPK family members. The four isoforms of AtTPKs were cloned and expressed in LB2003 E. coli background.The expression of channels in bacteria was analyzed by RT-PCR. Our results show that AtTPK1, AtTPK2 and AtTPK5 are restoring the LB2003 growth on low K(+) media. The analysis of potassium uptake exhibited elevated level of K(+) uptake in the same three types of AtTPKs transformants. PMID- 23656882 TI - Small changes in ambient temperature affect alternative splicing in Arabidopsis thaliana. AB - Alternative splicing (AS) gives rise to multiple mRNA isoforms from the same gene, providing possibilities to regulate gene expression beyond the level of transcription. In a recent paper in Nucleic Acids Research we used a high resolution RT-PCR based panel to study changes in AS patterns in plants with altered levels of an hnRNP-like RNA-binding protein in Arabidopsis thaliana. Furthermore, we detected significant changes in AS patterns between different Arabidopsis ecotypes. Here we investigated how small changes in ambient temperature affect AS. We found significant changes in AS for 12 of 28 investigated events (43%) upon transfer of Arabidopsis plants from 20 degrees C to 16 degrees C and for 6 of the 28 investigated events (21%) upon transfer from 20 degrees C to 24 degrees C. PMID- 23656883 TI - Adapting the SLIM diabetes prevention intervention to a Dutch real-life setting: joint decision making by science and practice. AB - BACKGROUND: Although many evidence-based diabetes prevention interventions exist, they are not easily applicable in real-life settings. Moreover, there is a lack of examples which describe the adaptation process of these interventions to practice. In this paper we present an example of such an adaptation. We adapted the SLIM (Study on Lifestyle intervention and Impaired glucose tolerance Maastricht) diabetes prevention intervention to a Dutch real-life setting, in a joint decision making process of intervention developers and local health care professionals. METHODS: We used 3 adaptation steps in accordance with current adaptation frameworks. In the first step, the elements of the SLIM intervention were identified. In the second step, these elements were judged for their applicability in a real-life setting. In the third step, adaptations were proposed and discussed for those elements which were deemed not applicable. Participants invited for this process included intervention developers and local health care professionals (n=19). RESULTS: In the first adaptation step, a total of 22 intervention elements were identified. In the second step, 12 of these 22 intervention elements were judged as inapplicable. In the third step, a consensus was achieved for the adaptations of all 12 elements. The adapted elements were in the following categories: target population, techniques, intensity, delivery mode, materials, organisational structure, and political and financial conditions. The adaptations either lay in changing the SLIM protocol (6 elements) or the real-life working procedures (1 element), or a combination of both (4 elements). CONCLUSIONS: The positive result of this study is that a consensus was achieved within a relatively short time period (nine months) between the developers of the SLIM intervention and local health care professionals on the adaptations needed to make SLIM applicable in a Dutch real-life setting. Our example shows that it is possible to combine the perspectives of scientists and practitioners, and to find a balance between evidence-base and applicability concerns. PMID- 23656884 TI - Guideline adaptation and implementation planning: a prospective observational study. AB - BACKGROUND: Adaptation of high-quality practice guidelines for local use has been advanced as an efficient means to improve acceptability and applicability of evidence-informed care. In a pan-Canadian study, we examined how cancer care groups adapted pre-existing guidelines to their unique context and began implementation planning. METHODS: Using a mixed-methods, case-study design, five cases were purposefully sampled from self-identified groups and followed as they used a structured method and resources for guideline adaptation. Cases received the ADAPTE Collaboration toolkit, facilitation, methodological and logistical support, resources and assistance as required. Documentary and primary data collection methods captured individual case experience, including monthly summaries of meeting and field notes, email/telephone correspondence, and project records. Site visits, process audits, interviews, and a final evaluation forum with all cases contributed to a comprehensive account of participant experience. RESULTS: Study cases took 12 to >24 months to complete guideline adaptation. Although participants appreciated the structure, most found the ADAPTE method complex and lacking practical aspects. They needed assistance establishing individual guideline mandate and infrastructure, articulating health questions, executing search strategies, appraising evidence, and achieving consensus. Facilitation was described as a multi-faceted process, a team effort, and an essential ingredient for guideline adaptation. While front-line care providers implicitly identified implementation issues during adaptation, they identified a need to add an explicit implementation planning component. CONCLUSIONS: Guideline adaptation is a positive initial step toward evidence-informed care, but adaptation (vs. 'de novo' development) did not meet expectations for reducing time or resource commitments. Undertaking adaptation is as much about the process (engagement and capacity building) as it is about the product (adapted guideline). To adequately address local concerns, cases found it necessary to also search and appraise primary studies, resulting in hybrid (adaptation plus de novo) guideline development strategies that required advanced methodological skills.Adaptation was found to be an action element in the knowledge translation continuum that required integration of an implementation perspective. Accordingly, the adaptation methodology and resources were reformulated and substantially augmented to provide practical assistance to groups not supported by a dedicated guideline panel and to provide more implementation planning support. The resulting framework is called CAN-IMPLEMENT. PMID- 23656886 TI - Singlet exciton fission in polycrystalline pentacene: from photophysics toward devices. AB - Singlet exciton fission is the process in conjugated organic molecules bywhich a photogenerated singlet exciton couples to a nearby chromophore in the ground state, creating a pair of triplet excitons. Researchers first reported this phenomenon in the 1960s, an event that sparked further studies in the following decade. These investigations used fluorescence spectroscopy to establish that exciton fission occurred in single crystals of several acenes. However, research interest has been recently rekindled by the possibility that singlet fission could be used as a carrier multiplication technique to enhance the efficiency of photovoltaic cells. The most successful architecture to-date involves sensitizing a red-absorbing photoactive layer with a blue-absorbing material that undergoes fission, thereby generating additional photocurrent from higher-energy photons. The quest for improved solar cells has spurred a drive to better understand the fission process, which has received timely aid from modern techniques for time resolved spectroscopy, quantum chemistry, and small-molecule device fabrication. However, the consensus interpretation of the initial studies using ultrafast transient absorption spectroscopy was that exciton fission was suppressed in polycrystalline thin films of pentacene, a material that would be otherwise expected to be an ideal model system, as well as a viable candidate for fission sensitized photovoltaic devices. In this Account, we review the results of our recent transient absorption and device-based studies of polycrystalline pentacene. We address the controversy surrounding the assignment of spectroscopic features in transient absorption data, and illustrate how a consistent interpretation is possible. This work underpins our conclusion that singlet fission in pentacene is extraordinarily rapid (~80 fs) and is thus the dominant decay channel for the photoexcited singlet exciton. Further, we discuss our demonstration that triplet excitons generated via singlet fission in pentacene can be dissociated at an interface with a suitable electron acceptor, such as fullerenes and infrared-absorbing inorganic semiconducting quantum dots. We highlight our recent reports of a pentacene/PbSe hybrid solar cell with a power conversion efficiency of 4.7% and of a pentacene/PbSe/amorphous silicon photovoltaic device. Although substantive challenges remain, both to better our understanding of the mechanism of singlet exciton fission and to optimize device performance, this realization of a solar cell where photocurrent is simultaneously contributed from a blue-absorbing fission-capable material and an infrared-absorbing conventional cell is an important step towards a dual-bandgap, single-junction, fission-enhanced photovoltaic device, which could one day surpass the Shockley-Queisser limit. PMID- 23656885 TI - Candidate gene association studies: a comprehensive guide to useful in silico tools. AB - The candidate gene approach has been a pioneer in the field of genetic epidemiology, identifying risk alleles and their association with clinical traits. With the advent of rapidly changing technology, there has been an explosion of in silico tools available to researchers, giving them fast, efficient resources and reliable strategies important to find casual gene variants for candidate or genome wide association studies (GWAS). In this review, following a description of candidate gene prioritisation, we summarise the approaches to single nucleotide polymorphism (SNP) prioritisation and discuss the tools available to assess functional relevance of the risk variant with consideration to its genomic location. The strategy and the tools discussed are applicable to any study investigating genetic risk factors associated with a particular disease. Some of the tools are also applicable for the functional validation of variants relevant to the era of GWAS and next generation sequencing (NGS). PMID- 23656887 TI - Npas4 is a novel activity-regulated cytoprotective factor in pancreatic beta cells. AB - Cellular homeostasis requires intrinsic sensing mechanisms to temper function in the face of prolonged activity. In the pancreatic beta-cell, glucose is likely a physiological trigger that activates an adaptive response to stimulation, thereby maintaining cellular homeostasis. Immediate early genes (IEGs) are activated as a first line of defense in cellular homeostasis and are largely responsible for transmitting an environmental cue to a cellular response. Here we examine the regulation and function of the novel beta-cell IEG, neuronal PAS domain protein 4 (Npas4). Using MIN6 cells, mouse and human islets, as well as in vivo infusions, we demonstrate that Npas4 is expressed within pancreatic islets and is upregulated by beta-cell depolarizing agents. Npas4 tempers beta-cell function through a direct inhibitory interaction with the insulin promoter and by blocking the potentiating effects of GLP-1 without significantly reducing glucose stimulated secretion. Finally, Npas4 expression is induced by classical endoplasmic reticulum (ER) stressors and can prevent thapsigargin- and palmitate induced dysfunction and cell death. These results suggest that Npas4 is a key activity-dependent regulator that improves beta-cell efficiency in the face of stress. We posit that Npas4 could be a novel therapeutic target in type 2 diabetes that could both reduce ER stress and cell death and maintain basal cell function. PMID- 23656888 TI - Leptin administration enhances islet transplant performance in diabetic mice. AB - Islet transplantation is an effective method to obtain long-term glycemic control for patients with type 1 diabetes, yet its widespread use is limited by an inadequate supply of donor islets. The hormone leptin has profound glucose lowering and insulin-sensitizing action in type 1 diabetic rodent models. We hypothesized that leptin administration could reduce the dose of transplanted islets required to achieve metabolic control in a mouse model of type 1 diabetes. We first performed a leptin dose-response study in C57Bl/6 mice with streptozotocin (STZ)-induced diabetes to determine a leptin dose insufficient to reverse hyperglycemia. Subsequently, we compared the ability of suboptimal islet transplants of 50 or 125 syngeneic islets to achieve glycemic control in STZ induced diabetic C57Bl/6 mice treated with or without this dose of leptin. The dose-response study revealed that leptin reverses STZ-induced diabetes in a dose dependent manner. Supraphysiological leptin levels were necessary to restore euglycemia but simultaneously increased risk of hypoglycemia, and also lost efficacy after 12 days of administration. In contrast, 1 ug/day leptin only modestly reduced blood glucose but maintained efficacy throughout the study duration. We then administered 1 ug/day leptin to diabetic mice that underwent transplantation of 50 or 125 islets. Although these islet doses were insufficient to ameliorate hyperglycemia alone, coadministration of leptin with islet transplantation robustly improved control of glucose and lipid metabolism, without increasing circulating insulin levels. This study reveals that low-dose leptin administration can reduce the number of transplanted islets required to achieve metabolic control in STZ-induced diabetic mice. PMID- 23656890 TI - Residual motion compensation in ECG-gated interventional cardiac vasculature reconstruction. AB - Three-dimensional reconstruction of cardiac vasculature from angiographic C-arm CT (rotational angiography) data is a major challenge. Motion artefacts corrupt image quality, reducing usability for diagnosis and guidance. Many state-of-the art approaches depend on retrospective ECG-gating of projection data for image reconstruction. A trade-off has to be made regarding the size of the ECG-gating window. A large temporal window is desirable to avoid undersampling. However, residual motion will occur in a large window, causing motion artefacts. We present an algorithm to correct for residual motion. Our approach is based on a deformable 2D-2D registration between the forward projection of an initial, ECG gated reconstruction, and the original projection data. The approach is fully automatic and does not require any complex segmentation of vasculature, or landmarks. The estimated motion is compensated for during the backprojection step of a subsequent reconstruction. We evaluated the method using the publicly available CAVAREV platform and on six human clinical datasets. We found a better visibility of structure, reduced motion artefacts, and increased sharpness of the vessels in the compensated reconstructions compared to the initial reconstructions. At the time of writing, our algorithm outperforms the leading result of the CAVAREV ranking list. For the clinical datasets, we found an average reduction of motion artefacts by 13 +/- 6%. Vessel sharpness was improved by 25 +/- 12% on average. PMID- 23656889 TI - Blockade of KCa3.1 ameliorates renal fibrosis through the TGF-beta1/Smad pathway in diabetic mice. AB - The Ca(2+)-activated K(+) channel KCa3.1 mediates cellular signaling processes associated with dysfunction of vasculature. However, the role of KCa3.1 in diabetic nephropathy is unknown. We sought to assess whether KCa3.1 mediates the development of renal fibrosis in two animal models of diabetic nephropathy. Wild type and KCa3.1(-/-) mice, and secondly eNOS(-/-) mice, had diabetes induced with streptozotocin and then were treated with/without a selective inhibitor of KCa3.1 (TRAM34). Our results show that the albumin-to-creatinine ratio significantly decreased in diabetic KCa3.1(-/-) mice compared with diabetic wild-type mice and in diabetic eNOS(-/-) mice treated with TRAM34 compared with diabetic mice. The expression of monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule 1 (ICAM1), F4/80, plasminogen activator inhibitor type 1 (PAI-1), and type III and IV collagen significantly decreased (P < 0.01) in kidneys of diabetic KCa3.1(-/-) mice compared with diabetic wild-type mice. Similarly, TRAM34 reduced the expression of the inflammatory and fibrotic markers described above in diabetic eNOS(-/-) mice. Furthermore, blocking the KCa3.1 channel in both animal models led to a reduction of transforming growth factor-beta1 (TGF beta1) and TGF-beta1 type II receptor (TbetaRII) and phosphorylation of Smad2/3. Our results provide evidence that KCa3.1 mediates renal fibrosis in diabetic nephropathy through the TGF-beta1/Smad signaling pathway. Blockade of KCa3.1 may be a novel target for therapeutic intervention in patients with diabetic nephropathy. PMID- 23656891 TI - In vitro and in vivo effects of hesperidin treatment on adult worms of Schistosoma mansoni. AB - Hesperidin has been reported to exert a wide range of pharmacological effects, including antifungal, antiviral, antioxidant, anti-inflammatory and anticarcinogenic activities. Herein, the schistosomicidal activity of this compound was evaluated in vitro and in vivo. Using an in vitro assay, a concentration of 200 MUg/ml of hesperidin resulted in the mortality of 100% adult worms of Schistosoma (S.) mansoni within 72 h and a partial tegumental alteration in 10% of worms. However, after 144 h incubation, 50 and 100 MUg/ml concentrations showed 0% and 10% mortality in adult worms, respectively, without any changes to the tegument. Sublethal doses did not influence egg output nor the development of eggs deposited by pairs of adult worms. In an in vivo study, mice infected with S. mansoni and treated with 600 mg hesperidin/kg body weight showed a respective reduction of 50, 45.2, 50 and 47.5% of males, females, worm pairs and total worm burden. In addition, a respective reduction, based on the number of eggs/g tissue, of 41.5, 63.7 and 58.6% was observed in the liver, intestine and liver/intestinal tissue combined. Furthermore, S. mansoni-specific IgG level significantly increased with hesperidin treatment, whereas IgA and IgE levels were not significantly changed. IgM levels decreased in response to cercarial antigen preparation but were not altered in response to soluble worm or soluble egg antigen. As in hesperidin-treated mice, praziquantel-treated mice showed a similar pattern of specific antibody response to S. mansoni antigens. The present study represents the first report on the effects of the schistosomicidal activity of hesperidin. PMID- 23656892 TI - Quantification of extracellular carbonic anhydrase activity in two marine diatoms and investigation of its role. AB - Many microalgae induce an extracellular carbonic anhydrase (eCA), associated with the cell surface, at low carbon dioxide (CO2) concentrations. This enzyme is thought to aid inorganic carbon uptake by generating CO2 at the cell surface, but alternative roles have been proposed. We developed a new approach to quantify eCA activity in which a reaction-diffusion model is fit to data on (18)O removal from inorganic carbon. In contrast to previous methods, eCA activity is treated as a surface process, allowing the effects of eCA on cell boundary-layer chemistry to be assessed. Using this approach, we measured eCA activity in two marine diatoms (Thalassiosira pseudonana and Thalassiosira weissflogii), characterized the kinetics of this enzyme, and studied its regulation as a function of culture pH and CO2 concentration. In support of a role for eCA in CO2 supply, eCA activity specifically responded to low CO2 rather than to changes in pH or HCO3(-), and the rates of eCA activity are nearly optimal for maintaining cell surface CO2 concentrations near those in the bulk solution. Although the CO2 gradients abolished by eCA are small (less than 0.5 MUm concentration difference between bulk and cell surface), CO2 uptake in these diatoms is a passive process driven by small concentration gradients. Analysis of the effects of short-term and long term eCA inhibition on photosynthesis and growth indicates that eCA provides a small energetic benefit by reducing the surface-to-bulk CO2 gradient. Alternative roles for eCA in CO2 recovery as HCO3(-) and surface pH regulation were investigated, but eCA was found to have minimal effects on these processes. PMID- 23656893 TI - Glutamate receptor-like channel3.3 is involved in mediating glutathione-triggered cytosolic calcium transients, transcriptional changes, and innate immunity responses in Arabidopsis. AB - The tripeptide reduced glutathione (GSH; gamma-glutamate [Glu]-cysteine [Cys] glycine) is a major endogenous antioxidant in both animal and plant cells. It also functions as a neurotransmitter mediating communication among neurons in the central nervous system of animals through modulating specific ionotropic Glu receptors (GLRs) in the membrane. Little is known about such signaling roles in plant cells. Here, we report that transient rises in cytosolic calcium triggered by exogenous GSH in Arabidopsis (Arabidopsis thaliana) leaves were sensitive to GLR antagonists and abolished in loss-of-function atglr3.3 mutants. Like the GSH biosynthesis-defective mutant PHYTOALEXIN DEFICIENT2, atglr3.3 showed enhanced susceptibility to the bacterial pathogen Pseudomonas syringae pv tomato DC3000. Pathogen-induced defense marker gene expression was also decreased in atglr3.3 mutants. Twenty-seven percent of genes that were rapidly responsive to GSH treatment of seedlings were defense genes, most of which were dependent on functional AtGLR3.3, while GSH suppressed pathogen propagation through the AtGLR3.3-dependent pathway. Eight previously identified putative AtGLR3.3 ligands, GSH, oxidized glutathione, alanine, asparagine, Cys, Glu, glycine, and serine, all elicited the AtGLR3.3-dependent cytosolic calcium transients, but only GSH and Cys induced the defense response, with the Glu-induced AtGLR3.3 dependent transcription response being much less apparent than that triggered by GSH. Together, these observations suggest that AtGLR3.3 is required for several signaling effects mediated by extracellular GSH, even though these effects may not be causally related. PMID- 23656894 TI - Deciphering herbivory-induced gene-to-metabolite dynamics in Nicotiana attenuata tissues using a multifactorial approach. AB - In response to biotic stresses, such as herbivore attack, plants reorganize their transcriptomes and reconfigure their physiologies not only in attacked tissues but throughout the plant. These whole-organismic reconfigurations are coordinated by a poorly understood network of signal transduction cascades. To explore tissue based interdependencies in the resistance of Nicotiana attenuata to insect attack, we conducted time-series transcriptome and metabolome profiling of herbivory-elicited source leaves and unelicited sink leaves and roots. To probe the multidimensionality of these molecular responses, we designed a novel approach of combining an extended self-organizing maps-based dimensionality reduction method with bootstrap-based nonparametric analysis of variance models to identify the onset and context of signaling and metabolic pathway activations. We illustrate the value of this analysis by revisiting dynamic changes in the expression of regulatory and structural genes of the oxylipin pathway and by studying nonlinearities in gene-metabolite associations involved in the acyclic diterpene glucoside pathway after selectively extracting modules based on their dynamic response patterns. This novel dimensionality reduction approach is broadly applicable to capture the dynamic rewiring of gene and metabolite networks in experimental design with multiple factors. PMID- 23656895 TI - CYCLIN H;1 regulates drought stress responses and blue light-induced stomatal opening by inhibiting reactive oxygen species accumulation in Arabidopsis. AB - Arabidopsis (Arabidopsis thaliana) CYCLIN-DEPENDENT KINASE Ds (CDKDs) phosphorylate the C-terminal domain of the largest subunit of RNA polymerase II. Arabidopsis CYCLIN H;1 (CYCH;1) interacts with and activates CDKDs; however, the physiological function of CYCH;1 has not been determined. Here, we report that CYCH;1, which is localized to the nucleus, positively regulates blue light induced stomatal opening. Reduced-function cych;1 RNA interference (cych;1 RNAi) plants exhibited a drought tolerance phenotype. CYCH;1 is predominantly expressed in guard cells, and its expression was substantially down-regulated by dehydration. Transpiration of intact leaves was reduced in cych;1 RNAi plants compared with the wild-type control in light but not in darkness. CYCH;1 down regulation impaired blue light-induced stomatal opening but did not affect guard cell development or abscisic acid-mediated stomatal closure. Microarray and real time polymerase chain reaction analyses indicated that CYCH;1 did not regulate the expression of abscisic acid-responsive genes or light-induced stomatal opening signaling determinants, such as MYB60, MYB61, Hypersensitive to red and blue1, and Protein phosphatase7. CYCH;1 down-regulation induced the expression of redox homeostasis genes, such as LIPOXYGENASE3 (LOX3), LOX4, ARABIDOPSIS GLUTATHIONE PEROXIDASE 7 (ATGPX7), EARLY LIGHT-INDUCIBLE PROTEIN1 (ELIP1), and ELIP2, and increased hydrogen peroxide production in guard cells. Furthermore, loss-of-function mutations in CDKD;2 or CDKD;3 did not affect responsiveness to drought stress, suggesting that CYCH;1 regulates the drought stress response in a CDKD-independent manner. We propose that CYCH;1 regulates blue light-mediated stomatal opening by controlling reactive oxygen species homeostasis. PMID- 23656896 TI - De novo inflammatory bowel disease and its mimics after organ transplantation. AB - Diarrhea is a common symptom after solid organ transplantation or hematopoietic stem cell transplantation, with a reported prevalence up to 72%. One of the uncommon causes for diarrhea in the posttransplant setting is development of de novo inflammatory bowel disease (IBD). The incidence of posttransplantation de novo IBD was shown to be higher than that in the general population (206 versus 20 per 100,000 cases annually). The frequency seems to be much higher following orthotopic liver transplantation than the transplantation of other solid organs. De novo IBD has also been described in the setting of bone marrow transplantation though not as commonly as after SOT. While IBD is considered an immune-mediated disorder and responds favorably to immunosuppressive, de novo IBD or IBD-like conditions can occur in the posttransplant period despite antirejection immunosuppressive therapy. Damage or pathogen-associated molecular pattern molecules and their associated ongoing inflammation within the transplanted organ and the recipients' intestine have been implicated as possible etiologies. Various viral, bacterial, and protozoal infections can mimic IBD in postorgan transplantation. Common IBD mimickers in the postbone marrow transplant setting are graft-versus-host disease, infectious enteritis/colitis, and less commonly "cord colitis" that is described in detail below. In this article, we discuss the epidemiology, clinical features, and outcomes of de novo IBD after transplantation and highlight their differences in presentation, diagnosis, and management. PMID- 23656898 TI - Development of salutogenetic factors in mental health - Antonovsky's sense of coherence and Bandura's self-efficacy related to Derogatis' symptom check list (SCL-90-R). AB - BACKGROUND: The paper analyses how resilience factors and mental health problems interrelate in a 3-year-longitudinal study with 16-19 year olds. METHODS: Resilience was measured with a 13-item short version of the Life-Orientation Scale by Antonovsky (sense-of-coherence, SOC) and a 10-item self-efficacy-scale (SWE) by Jerusalem and Schwarzer. Mental health problems were measured with Derogatis Symptom Check list (SCL-90-R). The data set included 155 participants and was analyzed using Structural Equation Modeling (SEM) designed to examine mutual influence in longitudinal data with Mplus software. RESULTS: The descriptive data analysis indicates (1) negative correlations between SOC and SCL 90-R at both age 16 and 19 in all subscales but somatization and likewise (2) between self-efficacy and SCL-90-R. (3) SOC correlates positively with SWE at age 16 and 19. Results of SEM analysis were based on the assumption of two latent variables at two points in time: resilience as measured with mean SOC and mean self-efficacy scores and health problems measured with sub scale scores of SCL-90 R - both at ages 16 and 19. The first SEM model included all possible paths between the two latent variables across time. We found (4) that resilience influences mental health problems cross-sectionally at age 16 and at age 19 but not across time. (5) Both resilience and mental health problems influenced their own development over time. A respecified SEM model included only significant paths. (6) Resilience at age 16 significantly influences health problems at age 16 as well as resilience at age 19. Health problems at age 16 influence those at age 19 and resilience at age 19 influences health problems at age 19. CONCLUSION: (a) SOC and self-efficacy instruments measure similar phenomena. (b) Since an influence of resilience on mental health problems and vice versa over time could not be shown there must be additional factors important to development. (c) SOC and self-efficacy are both very stable at 16 and 19 years. This refutes Antonovsky's assumption that SOC achieves stability first around the age of 30. SOC and self-efficacy are protective factors but they seem to form in (early) childhood. PMID- 23656899 TI - High dose rate brachytherapy as monotherapy for localised prostate cancer: a hypofractionated two-implant approach in 351 consecutive patients. AB - BACKGROUND: To report the clinical outcome of high dose rate brachytherapy as sole treatment for clinically localised prostate cancer. METHODS: Between March 2004 and January 2008, a total of 351 consecutive patients with clinically localised prostate cancer were treated with transrectal ultrasound guided high dose rate brachytherapy. The prescribed dose was 38.0 Gy in four fractions (two implants of two fractions each of 9.5 Gy with an interval of 14 days between the implants) delivered to an intraoperative transrectal ultrasound real-time defined planning treatment volume. Biochemical failure was defined according to the Phoenix Consensus and toxicity evaluated using the Common Toxicity Criteria for Adverse Events version 3. RESULTS: The median follow-up time was 59.3 months. The 36 and 60 month biochemical control and metastasis-free survival rates were respectively 98%, 94% and 99%, 98%. Toxicity was scored per event with 4.8% acute Grade 3 genitourinary and no acute Grade 3 gastrointestinal toxicity. Late Grade 3 genitourinary and gastrointestinal toxicity were respectively 3.4% and 1.4%. No instances of Grade 4 or greater acute or late adverse events were reported. CONCLUSIONS: Our results confirm high dose rate brachytherapy as safe and effective monotherapy for clinically organ-confined prostate cancer. PMID- 23656900 TI - The outcomes of hip resurfacing compared to standard primary total hip arthroplasty in Men. AB - BACKGROUND: The purpose of this study was to evaluate the clinical and radiographic outcomes of hip resurfacing patients and compare them to standard primary total hip arthroplasty procedures performed during the same period of time. METHODS: One hundred and fourteen consecutive men who had a mean age of 50 years (range, 20 to 85 years) and who had undergone 120 hip resurfacing arthroplasties between 2007 and 2009 were compared to 117 consecutive men (120 hips) who had undergone a standard total hip arthroplasty during the same time period. The mean follow-up was 42 months (range, 24 to 55 months) for both groups. Outcomes evaluated included implant survivorship, hip scores, activity levels, and complication rates. RESULTS: In the resurfacing hip arthroplasty cohort, implant survivorship was 98% with two patients requiring a revision surgery one for femoral neck fracture and another for femoral head loosening. In comparison, implant survivorship was 99% in the standard total hip arthroplasty cohort, with 1 revision due to peri-prosthetic fracture which was successfully treated with a femoral component revision. In the resurfacing and standard hip arthroplasty cohorts, the mean post-operative Harris hip scores had improved to 96 and 94 points, respectively and were statistically similar. The resurfacing cohort had achieved a significantly higher mean post-operative University of California Activity Score (6.7 versus 5 points). There were no differences in the complication rates between the two cohorts. CONCLUSION: When patients meet the appropriate selection criteria in the hands of experienced and high-volume arthroplasty surgeons, hip resurfacing provides excellent results at short- to mid-term follow-up. PMID- 23656897 TI - Induced and natural regulatory T cells in the development of inflammatory bowel disease. AB - The mucosal immune system mediates contact between the host and the trillions of microbes that symbiotically colonize the gastrointestinal tract. Failure to tolerate the antigens within this "extended self" can result in inflammatory bowel disease (IBD). Within the adaptive immune system, the most significant cells modulating this interaction are Foxp3 regulatory T (Treg) cells. Treg cells can be divided into 2 primary subsets: "natural" Treg cells and "adaptive" or "induced" Treg. Recent research suggests that these subsets serve to play both independent and synergistic roles in mucosal tolerance. Studies from both mouse models and human patients suggest that defects in Treg cells can play distinct causative roles in IBD. Numerous genetic, microbial, nutritional, and environmental factors that associate with IBD may also affect Treg cells. In this review, we summarize the development and function of Treg cells and how their regulatory mechanisms may fail, leading to a loss of mucosal tolerance. We discuss both animal models and studies of patients with IBD suggesting Treg cell involvement in IBD and consider how Treg cells may be used in future therapies. PMID- 23656901 TI - Unraveling the digestion of milk protein. PMID- 23656902 TI - You are what your mother ate? PMID- 23656903 TI - Plasma 25-hydroxyvitamin D associated with pulmonary function in Canadian adults with excess adiposity. AB - BACKGROUND: Vitamin D deficiency is an important health issue, particularly among people residing in northern countries. Low concentrations of 25-hydroxyvitamin D [25(OH)D] have been linked to several health conditions. OBJECTIVE: The objective was to determine the association between plasma 25(OH)D and pulmonary function and the effect modifications of sex and body mass index (BMI) in adults. DESIGN: A cross-sectional study included 3359 adults aged >=18 y who participated in the Canadian Health Measures Survey, and a 2-stage multiple linear regression analysis was conducted. RESULTS: Overall, 26% of the adults had a plasma 25(OH)D concentration <50 nmol/L, which is considered deficient (ie, hypovitaminosis D). This deficiency was more prevalent among men than among women (30% compared with 23%). Regression analysis showed that deficient plasma 25(OH)D was associated with lower mean residual forced vital capacity and forced expiratory volume in 1 s in men after adjustment for covariates. When further stratified by BMI, the associations were more marked in overweight and obese men. Vitamin D deficiency associated with pulmonary function was not statistically significant in normal weight men or in women, regardless of BMI categories. Similar results were obtained when plasma 25(OH)D was examined as a continuous variable in the models. CONCLUSIONS: Hypovitaminosis D may be a risk factor for lung dysfunction, especially for overweight and obese men. Further research is necessary to determine the mechanism of the interrelation between vitamin D, adiposity, and pulmonary function. PMID- 23656905 TI - Reply: To PMID 22653543. PMID- 23656906 TI - Difficulty in confirming the diagnosis of bullous amyloidosis. PMID- 23656904 TI - Dietary glycine and blood pressure: the International Study on Macro/Micronutrients and Blood Pressure. AB - BACKGROUND: Available data have indicated independent direct relations of dietary animal protein and meat to the blood pressure (BP) of individuals. OBJECTIVE: In this study, we aimed to assess whether BP is associated with the intake of dietary amino acids higher relatively in animal than in vegetable protein (alanine, arginine, aspartic acid, glycine, histidine, lysine, methionine, and threonine). DESIGN: The study was a cross-sectional epidemiologic study that involved 4680 persons aged 40-59 y from 17 random population samples in the People's Republic of China, Japan, the United Kingdom, and the United States. BP was measured 8 times at 4 visits; dietary data (83 nutrients and 18 amino acids) were from four 24-h dietary recalls and two 24-h urine collections. RESULTS: Dietary glycine and alanine (the percentage of total protein intake) were considered singly related directly to BP; with these 2 amino acids together in regression models (from model 1, which was controlled for age, sex, and sample, to model 5, which was controlled for 16 possible confounders), glycine, but not alanine, was significantly related to BP. Estimated average BP differences associated with a 2-SD higher glycine intake (0.71 g/24 h) were 2.0-3.0-mm Hg systolic BP (z = 2.97-4.32) stronger in Western than in East Asian participants. In Westerners, meat was the main dietary source of glycine but not in East Asians (Chinese: grains/flour and rice/noodles; Japanese: fish/shellfish and rice/noodles). CONCLUSION: Dietary glycine may have an independent adverse effect on BP, which possibly contributes to direct relations of animal protein and meat to BP. PMID- 23656907 TI - Lichen aureus: an unusual histopathological presentation: a case report and a review of literature. AB - Lichen aureus (LA) presents an inflammatory infiltrate with a lichenoid pattern, which mainly localizes to the superficial dermis, and it is admixed with extravasated erythrocytes. We present the case of a 12-year-old male who had a 1.3-cm golden-brown-color patch on the right upper back for 2 weeks. Histopathologic examination revealed a lichenoid, superficial, and deep perivascular lymphocytic infiltrate with perineural and periappendageal involvement, extravasated erythrocytes, papillary dermal edema, and hemosiderophages. The perineural and periappendageal infiltrate is unusual for LA and suggestive of lichen striatus (LS). In addition, the presence of perineural inflammation is not a common feature for either LA or LS. However, given the clinical findings, taken together, these features were interpreted as being most consistent with LA. To the best of our knowledge, no previous case of LA has been reported with histological features of perineural inflammation and LS. PMID- 23656908 TI - Expression of lumican in hidroacanthoma simplex and clonal-type seborrheic keratosis as a potent differential diagnostic marker. AB - Lumican, a member of the small leucine-rich proteoglycan family, regulates the assembly and diameter of collagen fibers in the extracellular matrix of various tissues. The lumican expression correlates with pathological conditions and the growth and metastasis of various malignancies. In cutaneous neoplasms, the lumican expression is lower in advanced-stage malignant melanomas that invade the dermis than in early-stage melanomas. Furthermore, we have recently reported that the expression pattern of lumican is different from that of actinic keratosis and the Bowen disease. Lumican is positive in the poroid cells of intraepidermal sweat ducts; therefore, we examined the expression patterns of lumican in acanthotic-type seborrheic keratosis and Pinkus-type poroma followed by clonal type seborrheic keratosis and hidroacanthoma simplex. The neoplastic cells of acanthotic-type seborrheic keratosis exhibited positive immunostaining in only 1 of 31 cases (3.23%), whereas the poroid cells of Pinkus-type poroma exhibited positive immunoreactivity in 26 of 28 patients (92.8%). In the hidroacanthoma simplex cases, lumican was expressed in poroid cells forming intraepidermal nests in 22 of 28 patients (78.6%), whereas the neoplastic cells in most cases of clonal-type seborrheic keratosis were negative for lumican. In some seborrheic keratosis cases that were positive for lumican in neoplastic cells, lumican was observed in squamoid cells but not in basaloid cells. Therefore, it is necessary to evaluate the immunoreactivity of lumican in seborrheic keratosis and in basaloid cells. These findings suggest that lumican is a potent differential diagnostic marker that distinguishes hidroacanthoma simplex from clonal-type seborrheic keratosis. PMID- 23656909 TI - Discovering chromatin motifs using FAIRE sequencing and the human diploid genome. AB - BACKGROUND: Specific chromatin structures are associated with active or inactive gene transcription. The gene regulatory elements are intrinsically dynamic and alternate between inactive and active states through the recruitment of DNA binding proteins, such as chromatin-remodeling proteins. RESULTS: We developed a unique genome-wide method to discover DNA motifs associated with chromatin accessibility using formaldehyde-assisted isolation of regulatory elements with high-throughput sequencing (FAIRE-seq). We aligned the FAIRE-seq reads to the GM12878 diploid genome and subsequently identified differential chromatin-state regions (DCSRs) using heterozygous SNPs. The DCSR pairs represent the locations of imbalances of chromatin accessibility between alleles and are ideal to reveal chromatin motifs that may directly modulate chromatin accessibility. In this study, we used DNA 6-10mer sequences to interrogate all DCSRs, and subsequently discovered conserved chromatin motifs with significant changes in the occurrence frequency. To investigate their likely roles in biology, we studied the annotated protein associated with each of the top ten chromatin motifs genome-wide, in the intergenic regions and in genes, respectively. As a result, we found that most of these annotated motifs are associated with chromatin remodeling, reflecting their significance in biology. CONCLUSIONS: Our method is the first one using fully phased diploid genome and FAIRE-seq to discover motifs associated with chromatin accessibility. Our results were collected to construct the first chromatin motif database (CMD), providing the potential DNA motifs recognized by chromatin remodeling proteins and is freely available at http://syslab.nchu.edu.tw/chromatin. PMID- 23656910 TI - Trichinella britovi in the jackal Canis aureus from south-west Iran. AB - Trichinellosis is an important helminthic food-borne zoonosis, which is caused by nematodes of the genus Trichinella. Although, Trichinella spp. has been detected frequently in Iranian wildlife, this parasitic infection is not considered a major public health problem. This is largely because Islamic codes forbid consumption of pork meat in this country. However, knowledge about this zoonotic pathogen is important because human trichinellosis has been documented in countries where most of the population is Muslim. The aims of the present work were to investigate whether Trichinella spp. was still circulating in wildlife of the Khuzestan Province (south-west Iran) about 30 years after the first investigation, to identify the aetiological agent at the species level by molecular analyses, and to review the literature on Trichinella spp. in animals of Iran. During the winter 2009-2010, muscle samples from 32 road-killed animals (14 dogs and 18 jackals, Canis aureus) were collected. Muscle samples were digested and Trichinella sp. larvae were isolated from two jackals. The Trichinella sp. larvae have been identified as Trichinella britovi by molecular analyses. These results confirm that T. britovi is the prevalent species circulating in wild animals of Iran. PMID- 23656911 TI - Betabox: a beta particle imaging system based on a position sensitive avalanche photodiode. AB - A beta camera has been developed that allows planar imaging of the spatial and temporal distribution of beta particles using a 14 * 14 mm(2) position sensitive avalanche photodiode (PSAPD). This camera system, which we call Betabox, can be directly coupled to microfluidic chips designed for cell incubation or other biological applications. Betabox allows for imaging the cellular uptake of molecular imaging probes labeled with charged particle emitters such as (18)F inside these chips. In this work, we investigate the quantitative imaging capabilities of Betabox for (18)F beta particles, in terms of background rate, efficiency, spatial resolution, and count rate. Measurements of background and spatial resolution are considered both at room temperature (21 degrees C +/- 1 degrees C) and at an elevated operating temperature (37 degrees C +/- 1 degrees C), as is often required for biological assays. The background rate measured with a 4 keV energy cutoff is below 2 cph mm(-2) at both 21 and 37 degrees C. The absolute efficiency of Betabox for the detection of (18)F positron sources in contact with a PSAPD with the surface passivated from ambient light and damage is 46% +/- 1%. The lower detection limit is estimated using the Rose Criterion to be 0.2 cps mm(-2) for 1 min acquisitions and a 62 * 62 um(2) pixel size. The upper detection limit is approximately 21 000 cps. The spatial resolution at both 21 and 37 degrees C ranges from 0.4 mm FWHM at the center of the field of view (FOV), and degrades to 1 mm at a distance of 5 mm away from center yielding a useful FOV of approximately 10 * 10 mm(2). We also investigate the effects on spatial resolution and sensitivity that result from the use of a polymer based microfluidic chip. For these studies we place varying layers of low-density polyethylene (LDPE) between the detector and the source and find that the spatial resolution degrades by ~180 um for every 100 um of LDPE film. Sensitivity is reduced by half with the inclusion of ~200 um of additional LDPE film. Lastly, we demonstrate the practical utilization of Betabox, with an imaging test of its linearity, when coupled to a polydimethylsiloxane microfluidic chip designed for cell based assays. PMID- 23656913 TI - Saccular aneurysm of the left main trunk. PMID- 23656912 TI - Maternal nutrient restriction in the ewe from early to midgestation programs reduced steroidogenic enzyme expression and tended to reduce progesterone content of corpora lutea, as well as circulating progesterone in nonpregnant aged female offspring. AB - BACKGROUND: Previously we reported decreased circulating progesterone and fertility in one and two year old ewes born to undernourished mothers. This study was designed to investigate if this reduction in progesterone persisted into old age, and if it did, what mechanisms are involved. METHODS: Ewes were fed a nutrient restricted (NR, 50% of NRC recommendations) or control (C, 100% of NRC) diets from day 28 to 78 of gestation, then all were fed to requirements through parturition and weaning. Female offspring (4 per treatment group) were maintained as a group and fed to requirements from weaning until assigned to this study at 6 years of age. Ewes were synchronized for estrus (day 0) and blood samples were collected daily from day 0 to day 11 before necropsy on day 12. Blood serum and luteal tissue were assayed for progesterone concentrations by validated radioimmunoassay. RESULTS: Circulation progesterone concentrations tended to be lower (P = 0.06) in NR than C offspring from day 0 to 11 of the estrous cycle. While total luteal weight was similar across groups, total progesterone content also tended to be reduced (P = 0.07) in luteal tissue of NR than C offspring. Activity of hepatic progesterone catabolizing enzymes and selected angiogenic factors in luteal tissue were similar between groups. Messenger RNA expression of steroidogenic enzymes StAR and P450scc were reduced (P < 0.05), while protein expression of StAR tended to be reduced (P < 0.07) and P450scc was reduced (P < 0.05) in luteal tissue of NR versus C offspring. CONCLUSIONS: There appears to be no difference in hepatic steroid catabolism that could have led to the decreased serum progesterone. However, these data are consistent with the programming of decreased steroidogenic enzyme expression in CL of NR offspring, leading to reduced synthesis and secretion of progesterone. PMID- 23656914 TI - Left ventricular function and right ventricular pacing for isolated congenital heart block. AB - BACKGROUND: Right ventricular pacing has been the treatment of choice in patients with congenital complete atrioventricular block (CAVB). However, the effect of chronic right ventricular pacing on left ventricular function in young patients is still controversial. AIM: The aim of the study was to assess the change in left ventricular systolic function in young patients (age <=20 years) paced for isolated CAVB and to identify possible predictors of left ventricular systolic dysfunction. METHODS: We studied 55 young patients who underwent permanent right ventricular pacemaker implantation for CAVB in the absence of significant structural heart disease. We excluded patients affected by any condition known to affect left ventricular function. Echocardiographic data prior to and after pacemaker implantation were obtained. RESULTS: The mean age at the time of pacemaker implantation was 20 months, range 2.3-72 months. The mean duration of follow-up was 94.86 (range: 2-268 months). Chronic right ventricular pacing affected left ventricular shortening fraction (LVSF) significantly (pre = 37.8 +/ 7.8 vs. post = 32.8 +/- 5.5%, P = 0.0036). In 14 patients (25.4%), LVSF decreased by at least 7% (group A). The only parameter studied able to significantly discriminate the two groups was a better baseline LVSF in group A (baseline LVSF: 42.1 +/- 5.2 vs. 32.2 +/- 2.2%, P = 0.019; cut-off value >39%, P <0.0001; area under the curve = 0.887). CONCLUSION: Chronic right ventricular pacing in young patients without significant structural heart disease is responsible for a significant reduction in left ventricular systolic function, especially in patients with a good baseline LVSF. These patients need close follow-up not only for pacing parameters but also for left ventricular functional evaluation. PMID- 23656915 TI - HIV-related mechanisms in atherosclerosis and cardiovascular diseases. AB - HIV-infected patients have a significantly higher risk of developing cardiovascular events during the progression of HIV disease. Atherosclerosis, myocardial infarction, cerebrovascular injury, pulmonary hypertension and thrombosis are consistently described in both combined antiretroviral therapy (cART)-treated and naive HIV-positive patients as major clinical complications. Recent studies indicate that the pathogenesis of cardiovascular lesions in HIV positive patients is related to direct and indirect effects of HIV infection on vessel structures, independently of traditional risk factors. HIV infection strongly interferes with the biology of several cellular targets such as macrophage and endothelial cells. Moreover, HIV induces a profound derangement of lipid metabolism and inflammatory cytokine networks that are directly involved in atherogenesis and progressive impairment of the cardiovascular system.In this review, we discuss these major HIV-related mechanisms able to promote atherosclerosis and cardiovascular diseases in HIV-positive patients. PMID- 23656916 TI - Multidisciplinary treatment of subclavian artery injury after catheterization for atrial fibrillation ablation. AB - Subclavian vein cannulation is frequently performed in patients undergoing electrophysiologic procedures in order to facilitate catheterization of the coronary sinus. We present a rare case of massive haemothorax, secondary to subclavian artery injury, during an ablation of atrial fibrillation. Following the procedure, a chest radiograph revealed a massive left haemothorax and the angiographic phase of a computed tomography scan indicated the presence of active bleeding due to left subclavian artery injury. Active bleeding was initially managed through embolization of the subclavian artery branches and the patient was subsequently treated with combined endovascular stenting and video-assisted thoracic surgery. PMID- 23656917 TI - A re-entry tachycardia triggered by the spontaneous interruption of an atrial tachycardia. AB - The common atrioventricular nodal re-entry tachycardia is the most common form of paroxysmal supraventricular tachycardia. It starts frequently with a supraventricular ectopic beat that, on finding the fast pathway in refractory period, travels in the slow pathway as to appear as a prolongation of the PR interval on the ECG. In this study, we show a singular case of a common atrioventricular nodal re-entry tachycardia triggered by the spontaneous interruption of an atrial tachycardia. PMID- 23656919 TI - CD14 contributes to warm hepatic ischemia-reperfusion injury in mice. AB - INTRODUCTION: Ischemia/reperfusion (I/R) of the liver contributes to the pathobiology of liver injury in transplantation, liver surgery, and hemorrhagic shock. Ischemia/reperfusion induces an inflammatory response that is driven, in part, by Toll-like receptor 4 (TLR) signaling. CD14 is known to participate in the function of TLR4. We hypothesized that CD14 would be involved in the pathobiology of warm hepatic I/R. METHODS: Using a 70% liver inflow inclusion model, CD14 knockout and wild-type (WT) mice were subjected to 1-h warm ischemia followed by reperfusion. CD14 mRNA, circulating transaminase, interleukin 6, soluble CD14, and high-mobility group box 1 (HMGB1) levels were measured. CD14 neutralizing antibody or isotype control antibody was given before ischemia or reperfusion for CD14 blockade in WT mice. Recombinant HMGB1 was given before reperfusion in some experiments to test if liver injury worsens. RESULTS: There was an upregulation of CD14 mRNA in reperfused livers together with increased soluble CD14 levels in the circulation. Compared with WT control mice, CD14 knockout mice had much lower alanine aminotransferase and interleukin 6 levels at 6 and 24 h following I/R, and much less liver necrosis by histology. TUNEL (terminal deoxynucleotidyl-transferase dUTP nick end labeling) staining displayed less apoptosis at 24 h in the absence of CD14. CD14 blockage by neutralizing antibody also attenuated liver injury and the inflammatory response in C57BL/6 mice following I/R, but did not provide additional protection to TLR4 mutant C3H/Hej mice. CD14 deficiency did not change circulating HMGB1 levels following I/R (6 h). A dose of recombinant HMGB1, which worsened hepatic injury when given before reperfusion in WT mice, did not increase liver damage in CD14-deficient mice. CONCLUSIONS: CD14 is actively involved in hepatic I/R injury. Its deficiency or blockade ischemia attenuates liver injury and inflammatory response. CD14 mediates liver damage and inflammatory responses in the setting of warm hepatic I/R in mice. PMID- 23656920 TI - Prognostic impact of postoperative radiation in patients undergoing radical esophagectomy for pathologic lymph node positive esophageal cancer. AB - PURPOSE: Though postoperative radiation for esophageal squamous cell carcinoma is offered in selected cases, there is conflicting evidence as to whether it improves overall survival (OS). A retrospective investigation was performed to analyze the prognostic impact of postoperative radiation therapy (PORT) in a large cohort of patients. METHODS: From 2001 to 2009, 725 patients underwent radical esophagectomy (R0) with or without PORT were eligible for retrospective analysis. Patients were grouped into surgery alone (n = 467) and surgery plus PORT (n = 258). Median irradiation doses were 50 Gy (range: 40-56 Gy). Radiation fields encompassed the bilateral supraclavicular fossa, mediastinum, subcarinal area, and the tumor bed for the upper/middle-third disease; the bilateral supraclavicular fossa, mediastinum, the tumor bed, subcarinal area, and lower thoracic paraesophageal area for the lower-third disease. Kaplan-Meier and Cox regression analysis were used to compare OS. RESULTS: After median follow-up of 53 months, the median OS was 29 months in the PORT group and 23 months in the surgery alone group. The addition of PORT improved OS at 3 years from 36.6 to 43.6% compared with surgery alone. The use of PORT was associated with significantly improved OS (p = 0.018). For American Joint Committee on Cancer (AJCC) stage III esophageal cancer (T1-2N2M0, T3N1-2M0, T4N1-3M0), there was significant improvement in OS (p = 0.002) in the PORT group, not only for lymph node metastatic ratio (LNMR) >=0.25 (p = 0.001), but also for LNMR <0.25 (p = 0.043). However, for stage IIB disease (T1-2N1M0) there was no significant differences. The addition of POCT didn't prolong the OS significantly (Surgery alone group, p = 0.079; PORT group, p = 0.111). CONCLUSIONS: This large retrospective analysis supports the use of PORT for pathologic lymph node positive stage III esophageal squamous cell carcinoma. Given the retrospective nature of this study, the results should be confirmed by appropriately powered randomized trials. Further development of adjuvant therapy in EC is warranted. PMID- 23656921 TI - Cardiac troponins: bench to bedside interpretation in cardiac disease. AB - Cardiac troponins are the preferred biomarkers for the determination of acute myocardial necrosis. The high sensitivity of the available assays has significantly increased the detection of microscopic amounts of myocardial damage. Although compelling evidence indicates that elevated cardiac troponins are markers of poor prognosis and increased mortality, irrespective of the clinical scenario, small elevations can be seen in protean conditions and may confound the diagnosis of acute coronary syndromes. Emerging evidence suggests multiple different cellular mechanisms leading to cardiac troponin release, which challenge long held paradigms such as equivalency between troponin release into the circulation and irreversible cell death. Hence, knowledge of the physiology and pathophysiology of these cardiac biomarkers is essential for their accurate interpretation and consequent correct clinical diagnosis. Herein, the current relevant information about cardiac troponins is discussed, with special emphasis on pathophysiology and clinical correlates. PMID- 23656922 TI - Pregnancy and hemolysis, elevated liver enzymes and low platelet count syndrome in patients with Eisenmenger's syndrome. AB - Eisenmenger's syndrome is characterized by a right-to-left or bidirectional shunt in congenital heart diseases. Hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome, commonly occurring during pregnancy, includes hemolysis, elevated liver enzymes and low platelet counts. HELLP syndrome and pregnancy are extremely rare in patients with Eisenmenger's syndrome. The authors report 4 cases of pregnancy complicated by the HELLP and Eisenmenger's syndrome and describe their initial intervention and the in-hospital outcomes of these cases. Special emphasis is given to elaborate about the hemodynamic monitoring, magnesium sulphate for convulsions, corticosteroid treatment, anticoagulation therapy, management of pulmonary hypertension, the timing of delivery, and blood product transfusion. PMID- 23656918 TI - Cardiac rehabilitation in chronic heart failure: data from the Italian SurveY on carDiac rEhabilitation (ISYDE-2008). AB - BACKGROUND: Using data from the Italian SurveY on carDiac rEhabilitation (ISYDE 2008), this study provides insight into the level of implementation of cardiac rehabilitation in patients with chronic heart failure (CHF). METHODS: Data from 165 Italian cardiac rehabilitation units were collected online from 28 January to 10 February 2008. RESULTS: The study cohort consisted of 2281 patients (66.9 +/- 11.8 years): 285 (71.3 +/- 12.2 years, 66% male) CHF patients and 1996 (66.3 +/- 11.6 years, 74% male) non-CHF patients. Compared with non-CHF, CHF patients were older, showed more comorbidity, had lower left ventricular (LV) ejection fraction and reduced access to functional evaluation, underwent more complications during cardiac rehabilitation, and had longer length of in-hospital stay. CHF patients were also more likely to be transferred to ICU (9 versus 3%, P < 0.0001), and less likely to be discharged home (85 versus 92%, respectively, P < 0.0001). Also, discharge prescriptions were significantly different from those of non-CHF patients. Finally, CHF patients had higher mortality during cardiac rehabilitation (1.7 versus 0.5%, P = 0.01). After adjusting for age, ejection fraction, comorbidity, previous interventions and complications during cardiac rehabilitation, multivariate logistic analysis showed that not performing any of the physical performance tests [odds ratio (OR) = 7.0, 95% confidence interval (CI), 1.9-25.8, P = 0.003], acute respiratory failure (OR = 2.3, 95% CI, 1.3-4.1, P = 0.002), acute kidney insufficiency or worsening of chronic kidney disease (OR = 2.9, 95% CI, 1.5-5.6, P = 0.001) and worsening of cognitive impairment (OR = 3.7, 95% CI, 2.0-6.7, P < 0.001) were significant predictors of death in CHF patients. CONCLUSION: The ISYDE-2008 survey provided a detailed snapshot of cardiac rehabilitation in CHF patients, and confirmed the complexity and the more severe clinical course of these patients during cardiac rehabilitation. PMID- 23656923 TI - Food impaction due to nutcracker esophagus. AB - Nutcracker esophagus is an esophageal motility disorder characterized by the presence of hypertensive contraction waves. These waves can have very high amplitudes, but they maintain a peristaltic pattern and therefore, bolus passage is minimally affected. Esophageal food impactions are rare in nutcracker esophagus. Our patient was a previously asymptomatic man who presented with an esophageal meat impaction due to nutcracker esophagus in which high-resolution manometry played a key role in the diagnosis. Although a rare etiology, nutcracker esophagus can result in esophageal food impaction. High-resolution manometry plays a critical role in the diagnosis of specific motility disorders, even in the setting of minimal symptoms. PMID- 23656924 TI - B-type natriuretic peptide as a biochemical marker of left ventricular diastolic function: assessment in asymptomatic patients 1 year after valve replacement for aortic stenosis. AB - OBJECTIVES Left ventricular (LV) diastolic dysfunction after aortic valve replacement (AVR) carries a substantial risk of development of heart failure and reduced survival. In addition to echocardiography, B-type natriuretic peptide (BNP) provides a powerful incremental assessment of diastolic function. This study evaluates BNP as a marker of LV diastolic dysfunction in a cohort of patients with preserved LV ejection fraction who underwent AVR for pure aortic stenosis and the relationship between BNP values and the grade of LV diastolic dysfunction. METHODS A total of 113 patients were included in the study. Echocardiographic evaluation was performed preoperatively, 5 days postoperatively and at 12-month follow-up, to assess LV dimensional and functional parameters. Diastolic function was labelled as normal, mild, moderate or severe dysfunction. Concomitantly, BNP levels were evaluated. RESULTS Mild to severe diastolic dysfunction occurred preoperatively in all patients. At 12-month follow-up, 65 (62.5%) patients had mild and 25 (24.1%) moderate to severe diastolic dysfunction. BNP values, categorized for quartile distribution, correlated with diastolic dysfunction grade (P<0.001 for each comparison). At receiver operating characteristic analysis, the BNP level of 120 pg/ml was 91% sensitive and 85% specific for diastolic disease, while 300 pg/ml was 80% sensitive and 91% specific for moderate or severe diastolic dysfunction. Twelve months after AVR, BNP values were strongly correlated with the significant echocardiographic parameters suggestive of diastolic dysfunction (P<=0.006 in all cases). CONCLUSIONS The BNP level following AVR is related to diastolic disease severity and may complement echocardiographic evaluation when symptoms are unclear and LV function is difficult to interpret. PMID- 23656925 TI - In lung cancer patients where a malignant pleural effusion is found at operation could resection ever still be justified? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether surgery could ever be justified in non-small cell lung cancer patients with an unexpected malignant pleural effusion at surgery. Eight papers were chosen to answer the question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. Study limitations included a lack of retrospective studies, the heterogeneous patient population and various treatments applied. Three papers found that surgery--compared to exploratory thoracotomy--was associated with a survival advantage in cases of minimal pleural disease. One paper showed that the median survival time of 58.8 months in patients with pleural effusion was better than that of patients with more extensive pleural dissemination as pleural nodule (10 months; P=0.0001) or pleural nodule with effusion (19.3 months; P=0.019). Another study showed that pleural effusion patients with N0-1 status had a median survival time more than 5 years longer than patients with similar or more extensive pleural dissemination but with N2-N3 status. A further study showed a better 5-year survival time in patients with pleural effusion, than in patients with pleural nodule (22.9% vs 8.9%, respectively; P=0.45). In two papers, surgery vs exploratory thoracotomy had better survival in cases of N0 status and of complete tumour resection independently of pleural dissemination. Different strategies were employed to obtain freedom from macroscopic residual tumour, including pneumonectomy, lobar resection or, to a lesser extent, pleurectomy in patients having pleural dissemination. Only one paper reported a worse median survival time after pneumonectomy than for more limited resections (12.8 vs 24.1 months, respectively; P=0.0018). In the remaining papers, no comparison between the different resections was made. In all studies except one, surgery was a component of multimodal treatment. Intrapleural chemotherapy was largely applied with systemic adjuvant chemotherapy and/or radiotherapy. The study period and/or year of publication of most papers was 10 years or more, this may explain the different chemotherapy regimens used in the various studies. No current guidelines support surgery over conservative therapy and the identified studies in this review are not strong enough to change this recommendation. PMID- 23656926 TI - Type A dissection and chronic dilatation: tenascin-C as a key factor in destabilization of the aortic wall. AB - OBJECTIVES: Tenascin-C plays an important role in myocardial and vascular remodelling. We hypothesized that tenascin-C is a key factor in the development of degenerative disease of the ascending aorta, leading to chronic dilatation and acute aortic dissection. METHODS: Ascending aortic wall specimens were obtained during surgery for chronic dilatation (n=52) and acute Type A dissection (n=30). Patients (n=12) undergoing aortic valve replacement served as controls. Tenascin C expression was evaluated by immunostaining and semi-quantitatively assessed using the ImageJ software. TN-C levels in peripheral blood were determined by enzyme-linked immunosorbent assay. RESULTS: Histological examination showed a clear difference between chronic dilatation and acute dissection. In chronic dilatation, tenascin-C staining was homogenously distributed throughout the media parallel to vascular smooth muscle cells. In acute dissection, a strong staining with a heterogenous and spotty distribution was detected. Control aortas showed no tenascin-C staining. Tenascin-C expression was significantly higher in Type-A dissection compared with chronic dilatation. This was accompanied by a significant elevation of tenascin-C levels in peripheral blood in acute dissection. There was no statistical correlation between the tenascin-C level in peripheral blood and the aortic diameter either in dissection or in dilatation. CONCLUSIONS: Tenascin-C is a marker of progressive destabilization of the aortic wall independent of size in chronic dilatation and acute dissection. Therefore, it might be a valuable tool in guiding intervention strategies in patients with disease of the ascending aorta. PMID- 23656928 TI - Validation of an advanced practice physiotherapy model of care in an orthopaedic outpatient clinic. AB - BACKGROUND: In Canada, new models of orthopaedic care involving advanced practice physiotherapists (APP) are being implemented. In these new models, aimed at improving the efficiency of care for patients with musculoskeletal disorders, APPs diagnose, triage and conservatively treat patients. Formal validation of the efficiency and appropriateness of these emerging models is scarce. The purpose of this study is to assess the diagnostic agreement of an APP compared to orthopaedic surgeons as well as to assess treatment concordance, healthcare resource use, and patient satisfaction in this new model. METHODS: 120 patients presenting for an initial consult for hip or knee complaints in an outpatient orthopaedic hospital clinic in Montreal, Canada, were independently assessed by an APP and by one of three participating orthopaedic surgeons. Each health care provider independently diagnosed the patients and provided triage recommendations (conservative or surgical management). Proportion of raw agreement and Cohen's kappa were used to assess inter-rater agreement for diagnosis, triage, treatment recommendations and imaging tests ordered. Chi-Square tests were done in order to compare the type of conservative treatment recommendations made by the APP and the surgeons and Student t-tests to compare patient satisfaction between the two types of care. RESULTS: The majority of patients assessed were female (54%), mean age was 54.1 years and 91% consulted for a knee complaint. The raw agreement proportion for diagnosis was 88% and diagnostic inter-rater agreement was very high (kappa=0.86; 95% CI: 0.80-0.93). The triage recommendations (conservative or surgical management) raw agreement proportion was found to be 88% and inter-rater agreement for triage recommendation was high (kappa=0.77; 95% CI: 0.65-0.88). No differences were found between providers with respect to imaging tests ordered (p>=0.05). In terms of conservative treatment recommendations made, the APP gave significantly more education and prescribed more NSAIDs, joint injections, exercises and supervised physiotherapy (p<0.05). Patient satisfaction was significantly higher for APP care than for the surgeons care (p<0.05). CONCLUSION: The diagnoses and triage recommendations for patients with hip and knee disorders made by the APP were similar to the orthopaedic surgeons. These results provide evidence supporting the APP model for orthopaedic care. PMID- 23656927 TI - Identification of a novel lipin homologue from the parasitic protozoan Trypanosoma brucei. AB - BACKGROUND: Arginine methylation is a post-translational modification that expands the functional diversity of proteins. Kinetoplastid parasites contain a relatively large group of protein arginine methyltransferases (PRMTs) compared to other single celled eukaryotes. Several T. brucei proteins have been shown to serve as TbPRMT substrates in vitro, and a great number of proteins likely to undergo methylation are predicted by the T. brucei genome. This indicates that a large number of proteins whose functions are modulated by arginine methylation await discovery in trypanosomes. Here, we employed a yeast two-hybrid screen using as bait the major T. brucei type I PRMT, TbPRMT1, to identify potential substrates of this enzyme. RESULTS: We identified a protein containing N-LIP and C-LIP domains that we term TbLpn. These domains are usually present in a family of proteins known as lipins, and involved in phospholipid biosynthesis and gene regulation. Far western and co-immunoprecipitation assays confirmed the TbPRMT1 TbLpn interaction. We also demonstrated that TbLpn is localized mainly to the cytosol, and is methylated in vivo. In addition, we showed that, similar to mammalian and yeast proteins with N-LIP and C-LIP domains, recombinant TbLpn exhibits phosphatidic acid phosphatase activity, and that two conserved aspartic acid residues present in the C-LIP domain are critical for its enzymatic activity. CONCLUSIONS: This study reports the characterization of a novel trypanosome protein and provides insight into its enzymatic activity and function in phospholipid biosynthesis. It also indicates that TbLpn functions may be modulated by arginine methylation. PMID- 23656929 TI - N2O emission from full-scale urban wastewater treatment plants: a comparison between A(2)O and SBR. AB - The emission of nitrous oxide (N2O) from full-scale anoxic/anaerobic/oxic (A(2)O) and sequencing batch reactor (SBR) processes was measured to evaluate N2O emission from urban wastewater treatment plants (WWTPs). The results showed that N2O flux in the A(2)O WWTP followed an order of A(2)O-oxic zone > aerated grit tank >> A(2)O-anaerobic zone > A(2)O-anoxic zone > final clarifier > primary clarifier, while in the SBR WWTP the order was SBR tank >> swirl grit tank > wastewater distribution tank and within the SBR tank in an order of SBR-feeding period > SBR-aeration period > SBR-settling period > SBR-decanting period. N2O emission from the A(2)O WWTP was approximately 486.61 kg d(-1), 96.9% of which was from the A(2)O-oxic zone. In the SBR WWTP, the emission of N2O was 339.24 kg d(-1) with 99.9% of the total emission coming from the periods of feeding and aeration. There was 6.52% of nitrogen-load in the influent being transformed to the emitted N2O in the SBR WWTP; the percentage was 3.35 times higher than that in the A(2)O WWTP. PMID- 23656930 TI - Removal of heavy metals from industrial effluent using Pinus roxburghii leaves as biosorbent: equilibrium modelling. AB - In the present study, biosorption capability of pine (Pinus roxburghii) leaves for the removal Cr(6+), Cu(2+), Fe(2+) and Zn(2+) ions, present in brass and electroplating industry effluent, were investigated with respect to different adsorbent doses, contact time and pH. Heavy metals concentrations were estimated by atomic absorption spectrophotometry. Initial concentration of Cr(6+), Cu(2+), Fe(2+) and Zn(2+) ions in the effluent were found to be 2.741, 4.551, 8.820 and 5.529 mg/L respectively. Biosorption studies revealed that Cr(6+), Cu(2+), Fe(2+) and Zn(2+) showed maximum removal of 99.85, 94.54, 97.10 and 89% at pH 4, 4, 4 and 8, respectively, with 4 g pine leaves when shaken at 150 rpm for 60 min. The applicability of the three equilibrium isotherm models was investigated and the data obtained fitted the three investigated isothermal models in the order: Langmuir > Temkin > Freundlich for all the studied metal ions. The adsorption isotherm coefficients, Qmax, b, Kf, n, at, bt were also calculated. Very high regression correlation coefficients (R(2) > 0.9) were found for Cu(2+), Fe(2+) and Zn(2+); Cr(6+) (Temkin isotherm) when pH (2-8) was varied; Cr(6+), Cu(2+),Fe(2+) and Zn(2+) when contact time (15-60 min) was varied; Cu(2+) (Langmuir isotherm) Fe(2+) (Freundlich and Temkin isotherms) when adsorbent was varied from 2 to 5 g. Results also revealed that among all the studied ions Cr(6+) at varied pH and Fe(2+) at different adsorbent doses satisfy the Temkin and Freundlich isotherm models to describe the biosorption equilibrium by pine (Pinus roxburghii) adsorbent. PMID- 23656931 TI - Stabilization of source-separated human urine by chemical oxidation. AB - The inhibitory effect of ozone and hydrogen peroxide (HP) on urea hydrolysis in stored urine was investigated and compared. Ozone showed less effect on urea hydrolysis due to the complicated composition of urine (including a large amount of urease-producing bacteria) and bacteria regeneration. Ozone concentration and total heterotrophic bacteria analysis demonstrated that residual ozone concentration decreased by 43% within 15 hr from 13.50 to 7.72 mg/L in the one time ozonation urine test, and finally completely decomposed within 4 days. In addition, bacteria regenerated quickly after ozone completely decomposed. However, HP showed a significant effect on inhibiting urea hydrolysis not only in stored urine but also in fecal-contaminated urine. The suitable doses of applied HP to inhibit urea hydrolysis in stored urine, concentrations of 0.5 and 1.0 g feces per liter of fecal-contaminated urine, were 0.03, 0.16 and 0.23 mol/L, respectively. The urea concentrations after 2 months stored were 7,145, 7,109 and 7,234 mg/L, respectively. PMID- 23656932 TI - Influence of initial pesticide concentrations in water on chlorpyrifos toxicity and removal by Iris pseudacorus. AB - For understanding the influence of initial concentrations of pesticides in the water body on removal efficiency of the contaminant by aquatic plants, one hydroponics experiment was used to investigate the influence of initial concentration (1-16 mg L(-1)) on toxicity and chlorpyrifos removal potential of Iris pseudacorus for 20 days under greenhouse conditions. An increased sensitivity to and reduced removal rate for chlorpyrifos were observed with increasing chlorpyrifos concentration. The relative growth rate (RGR) of I. pseudacorus was significantly inhibited in the presence of 4, 8 and 16 mg L(-1) chlorpyrifos, and a negative relationship was also found between RGR and initial pesticide concentration. The half-life of chlorpyrifos was shortened in the hydroponic system with plants, indicating that I. pseudacorus accelerated chlorpyrifos removal from water. But the contribution of the plant to chlorpyrifos removal in the hydroponic phytoremediation system decreased with the increase of initial concentration of chlorpyrifos. The results also indicated that I. pseudacorus can efficiently eliminate chlorpyrifos and may ultimately serve as phytoremediation agents in the natural water body. PMID- 23656933 TI - Effects of pH on chromate(VI) adsorption by Spirulina platensis biomass: batch tests and FT-IR studies. AB - Raw and methylated biomass of Spirulina platensis was employed in chromate batch adsorption tests at pH range 1-7. The acid conditions seemed to favour the removal of chromium (Cr) with a yield of 87.0 and 97.6% by using raw and methylated biomass, respectively. However, the chromate and total chromium determination, carried out in the same sample, evidenced that a fraction of the initial chromate present in solution was reduced to Cr(III). This was ascribed to the presence of reducing groups on the biomass surface, active in the acid medium. The data showed that the methylated biomass was able to operate an effective Cr(VI) removal only. In fact, the biomass treatment allowed a lowering of the amount of negative functional groups, making the biomass surface available to bind the anions. The real best efficiency of Cr(VI) removal (83.5%) was obtained by methylated biomass of S. platensis at pH about 7.0. The nature of the biomass/chromate interactions was investigated by Fourier transform infrared spectroscopy (FT-IR) analysis. The bands ascribing to the adsorbed Cr(VI) species were well evident in the spectra of the biomass after adsorption, confirming this experimental finding. PMID- 23656934 TI - A concept for planning and management of on-site and centralised municipal wastewater treatment systems, a case study in Bangkok, Thailand. I: pollutant discharge indicators and pollutant removal efficiency functions. AB - The concept of pollution load indicators for planning and management of the mixture conditions of centralised and on-site wastewater treatment systems has not been discussed in detail so far. In this paper, pollutant discharge (load) indicators and pollutant removal efficiencies were quantitatively analysed to develop a part of a strategy for planning and management of municipal wastewater treatment systems (WWTSs) under the mixture conditions in Bangkok, Thailand, as a case study. Pollutant discharge indicators of on-site WWTSs were estimated based on the relevant literature. Three kinds of pollutant removal efficiency function at centralised wastewater treatment plants (CWWTPs) were empirically developed for biological oxygen demand, chemical oxygen demand, total nitrogen, total phosphorus, total coliforms and faecal coliforms based on the existing CWWTP management data. These results will be integrated into the scenario-based analysis in the second paper in the series. The results will be base datasets, and the concept and estimation methods can be applied for wastewater treatment planning and management in other areas. PMID- 23656935 TI - A concept for planning and management of on-site and centralised municipal wastewater treatment systems, a case study in Bangkok, Thailand. II: scenario based pollutant load analysis. AB - Scenario-based pollutant load analysis was conducted to develop a part of a concept for planning and management of wastewater treatment systems (WWTSs) under the mixture conditions of centralised and on-site WWTSs. Pollutant discharge indicators and pollutant removal efficiency functions were applied from another paper in the series, which were developed based on the existing conditions in urban and peri-urban areas of Bangkok, Thailand. Two scenarios were developed to describe development directions of the mixture conditions. Scenario 1 involves keeping the on-site wastewater treatment plants (WWTPs) within the areas of centralised WWTSs. Scenario 2 is dividing the centralised and on-site WWTS areas. Comparison of the smallest values of total pollutant discharge per capita (PDCtotal) between Scenarios 1 and 2 showed that the smallest PDCtotal in Scenario 1 was smaller than that in Scenario 2 for biological oxygen demand, chemical oxygen demand and total phosphorus whereas the smallest PDCtotal in Scenario 2 was smaller than that in Scenario 1 for total nitrogen, total coliforms and faecal coliforms. The results suggest that the mixture conditions could be a possible reason for smaller pollutant concentrations at centralised WWTPs. Quantitative scenario-based estimation of PDCtotal is useful and a prerequisite in planning and management of WWTSs. PMID- 23656936 TI - Water Sensitive Urban Design retrofits in Copenhagen - 40% to the sewer, 60% to the city. AB - Water Sensitive Urban Design (WSUD) is emerging in Denmark. This interdisciplinary desk study investigated the options for WSUD retrofitting in a 15 km(2) combined sewer catchment area in Copenhagen. The study was developed in collaboration with the City of Copenhagen and its water utility, and involved researchers representing hydrogeology, sewer hydraulics, environmental chemistry/economics/engineering, landscape architecture and urban planning. The resulting catchment strategy suggests the implementation of five sub-strategies. First, disconnection is focused within sites that are relatively easy to disconnect, due to stormwater quality, soil conditions, stakeholder issues, and the provision of unbuilt sites. Second, stormwater runoff is infiltrated in areas with relatively deep groundwater levels at a ratio that doesn't create a critical rise in the groundwater table to the surface. Third, neighbourhoods located near low-lying streams and public parks are disconnected from the sewer system and the sloping terrain is utilised to convey runoff. Fourth, the promotion of coherent blue and green wedges in the city is linked with WSUD retrofits and urban climate proofing. Fifth, WSUD is implemented with delayed and regulated overflows to the sewer system. The results are partially adopted by the City of Copenhagen and currently under pilot testing. PMID- 23656937 TI - Phosphorus release mechanisms during digestion of EBPR sludge under anaerobic, anoxic and aerobic conditions. AB - Three laboratory-scale digesters were operated in parallel under anaerobic, anoxic and aerobic conditions to reveal the release mechanisms of phosphorus when digesting enhanced biological phosphorus removal (EBPR) sludge. The variation rates of the parameters associated with phosphorus release were calculated and compared with that of a typical EBPR anaerobic process. The results show that both phosphorus-accumulating organisms (PAOs) and denitrifying phosphorus accumulating organisms (DPAOs) played important roles in the phosphorus release during the digestion processes. Under anaerobic conditions, the PAOs hydrolyzed internal polyphosphorus (poly-P) into PO4(3-)-P concurrent with synthesis of polyhydroxyalkanoates (PHA). Under anoxic or aerobic conditions, PAOs and/or DPAOs assimilated part of the PO4(3-)-P from the digestive liquid using nitrate or oxygen as terminal electron acceptors. Nevertheless, the biological activities of PAOs under anaerobic conditions and DPAOs under anoxic conditions were limited. Moreover, it was the biomass hydrolysis degree that determined the phosphorus release capacity of the sludge, regardless of whether anaerobic, anoxic or aerobic conditions were adopted. Assuming that nitrate was the sole electron acceptor during anoxic digestion of EBPR biomass, the relationship between the consumption of nitrate and uptake of PO4(3-)-P associated with the denitrifying phosphorus removal (DPR) can be expressed as DeltaP = 0.11 * DeltaN. PMID- 23656938 TI - Ternary cycle treatment of high saline wastewater from pesticide production using a salt-tolerant microorganism. AB - The material of this study is provided by biological aerobic treatment of high saline wastewater from pesticide production. The microorganism used for biodegradation has been identified by gene-sequencing as a strain of Bacillus sp. SCUN. The best growth condition for the salt-tolerant microorganism has been studied by varying the pH, immobilized microorganism dosage and temperature conditions. The feasibility of pretreating wastewater in ethyl chloride production containing 4% NaCl has been discussed. It was found that under the pH range of 6.0-8.0, immobilized microorganism dosage of 1.5 g/L, temperature of 30 degrees C, and NaCl concentration of 0-3%, the microorganism achieves the best growth for biodegradation. After domestication, the strain can grow under 4% NaCl. This salt-tolerant microorganism is effective in the pretreated high saline wastewater. With a newly developed ternary cycle treatment, the chemical oxygen demand removal approaches 58.3%. The theoretical basis and a new method for biological treatments in biodegradation of high saline wastewater in ethyl chloride production are discussed. PMID- 23656939 TI - Combined risk prediction in the water environment based on an MS-AR model and Copula theory. AB - Making a quantitative prediction on the combined risk of the water body is helpful for the objective evaluation of the water environment system's state of health, and also has important results for the water environment system's safety management. In this paper, the Markov status switching theory (Markov Switching, MS), Monte Carlo method (Monte Carlo, MC) and Copula theory were used together, to establish a method for the water environment system's combined risk assessment. This method firstly using MS theory established the water quality time series' autoregression model (MS-AR); then the MS-AR model and MC method were used to carry out random simulation on the water quality time series; finally, multi-dimensional joint distribution among random simulation results were established by Copula function, and this distribution utilized to make a quantitative analysis of the water environment system's combined risk. By means of the above combined risk analysis model, the combined risk prediction and correlation analysis of the water quality of the Guohe River bridge section were carried out. The results showed that the total phosphorus (TP) and 5-day biochemical oxygen demand (BOD5) had an important effect on the Guohe River water environment's state of health, and there was a strong positive correlation between TP and BOD5. PMID- 23656940 TI - Treatment of petroleum refinery wastewater using a sequential anaerobic-aerobic moving-bed biofilm reactor system based on suspended ceramsite. AB - In this study, a novel suspended ceramsite was prepared, which has high strength, optimum density (close to water), and high porosity. The ceramsite was used to feed a moving-bed biofilm reactor (MBBR) system with an anaerobic-aerobic (A/O) arrangement to treat petroleum refinery wastewater for simultaneous removal of chemical oxygen demand (COD) and ammonium. The hydraulic retention time (HRT) of the anaerobic-aerobic MBBR system was varied from 72 to 18 h. The anaerobic aerobic system had a strong tolerance to shock loading. Compared with the professional emission standard of China, the effluent concentrations of COD and NH3-N in the system could satisfy grade I at HRTs of 72 and 36 h, and grade II at HRT of 18 h. The average sludge yield of the anaerobic reactor was estimated to be 0.0575 g suspended solid/g CODremoved. This work demonstrated that the anaerobic-aerobic MBBR system using the suspended ceramsite as bio-carrier could be applied to achieving high wastewater treatment efficiency. PMID- 23656941 TI - Assessment of the state of the art of technologies for the processing of digestate residue from anaerobic digesters. AB - Anaerobic digestion is widely used as an important source of renewable energy. With the increasing number and capacity of biogas plants also, adequate treatment technologies for whole digestate - the residue from anaerobic digestion - are gaining attention. In this study the state of the art of digestate processing is analysed, and currently used treatment schemes and the various technological processes involved are evaluated. The study combines data and experiences from existing large-scale digestate processing facilities in Austria, Germany, Switzerland and Italy, as well as know-how from technology providers and relevant research projects. However, the field of digestate processing is still quite new and little detailed information about the performance of different technologies at industrial scale is available. Digestate processing is gaining importance since digestate utilisation can become an important bottleneck when increasing biogas production. In addition, the production of renewable fertiliser from digestate is increasingly of interest to replace fossil fertilisers. This study is the first profound attempt to establish an assessment of the state-of-the-art technologies in use. PMID- 23656942 TI - Permeability decline in nanofiltration/reverse osmosis membranes fed with municipal wastewater treated by a membrane bioreactor. AB - Decline in the permeability in nanofiltration (NF)/reverse osmosis (RO) membranes that filtered effluents from a membrane bioreactor (MBR) treating municipal wastewater was investigated in this study. Four different 2-inch spiral-wound NF/RO membrane elements were continuously operated for 40 days. The results showed that the amount of deposits on the membrane surface did not affect the degree of permeability decline. Laboratory-scale filtration tests with coupons obtained from the fouled membranes also revealed that the contribution of the gel/cake layer to total filtration resistance was minor. Rather, constituents that were strongly bound to the membranes were mainly responsible for permeability decline. Chemical cleaning of the fouled membranes carried out after removal of the cake showed that silica played an important role in the decline in permeability. A considerable amount of organic matter which was mainly composed of carbohydrates and proteins was also desorbed from the fouled membranes. PMID- 23656943 TI - Assessing transmissivity from specific capacity in an alluvial aquifer in the middle Venetian plain (NE Italy). AB - Defining aquifer permeability distribution accurately over large areas is often debated in hydrogeology. The operational efforts to calculate hydraulic conductivity with classical aquifer tests are significant; however, accurate knowledge of permeability areal distribution is fundamental both from a hydrogeological and a modeling standpoint. This paper presents an empirical relationship between the transmissivity (T) and the specific capacity (SC) values obtained from experimental aquifer and well tests. All experimental values were obtained from 50 mm wells in middle Venetian plain artesian gravel aquifers. Many other authors have presented empirical relationships between T and SC, but most are related to fissured/karst aquifers, and only a few concern alluvial porous aquifers. Analysis of the T vs. SC relationship standardized residuals shows that a linear relationship produces statistically significant normal residuals compared with an exponential relationship. PMID- 23656944 TI - Distribution and accumulation of heavy metals in surface sediments from a subtropical bay affected by the Special Economic Zone, China. AB - The concentrations of nine metals (Cd, Cr, Cu, Ni, Mn, Pb, Zn, Fe, and Al) in surface sediments from 14 sampling sites in Shantou Bay were determined in order to understand current metal levels and spatial distribution due to the rapid development of the Shantou Special Economic Zone. Results showed that metal concentrations in surface sediments varied from 0.31 to 1.74 mg kg(-1) for Cd, 35.98 to 74.19 mg kg(-1) for Cr, 24.43 to 79.24 mg kg(-1) for Cu, 428.45 to 809.87 mg kg(-1) for Mn, 16.91 to 31.51 mg kg(-1) for Ni, 35.59 to 64.84 mg kg( 1) for Pb, 84.91 to 246.51 mg kg(-1) for Zn, 2.93 to 3.93% for Fe, and 5.25 to 9.28% for Al. Although all metal concentrations in sediments meet Chinese National Standard Criteria for Marine Sediment Quality, both enrichment factor (EF) and geo-accumulation index (Igeo) show Pb and Cd pollution existed in the upper and middle bay, and pollution of other metals is also recorded in some sites depending on the sources; river input, sewage discharge, and port activities are the main sources of pollutant to the bay. PMID- 23656945 TI - Experimental design optimization for electrochemical removal of gentamicin: toxicity evaluation and degradation pathway. AB - Electrochemical degradation of gentamicin was achieved using a laboratory scale electrochemical reactor by optimizing pH, current density and treatment time. A two step statistical optimization was performed as per factorial design and center composite design (CCD). A Pareto chart was used for selecting statistically significant effects and an analysis of variance (ANOVA) table indicated significant curvature. Thus adding additional experimental runs improved the model fitting through a second order model. Maximum degradation was predicted at a pH of 6.7, 70 A m(-2) and 45 min. The experimental data fitted well through a reduced quadratic model with R(2) equal to 0.945. The toxicity of degradation products as determined by disc diffusion assay employing Pseudomonas aeruginosa strain was found to be reduced by 55%. The degradation pathway of gentamicin was studied using mass spectral (MS) analysis. Pure gentamicin showed a molecular ion peak at m/z 478 ([M + 1](+)), and after addition of NaCl as electrolyte, the mass peak was observed at m/z 523. After 15 min of electrochemical treatment, a new peak appeared at m/z 316 due to the loss of one pyran moiety. After 45 min of electrochemical treatment, another peak appeared at m/z of 478 due to loss of two Na(+) from gentamicin. PMID- 23656946 TI - Limitation of hardness from thermal water by means of nanofiltration. AB - Geothermal conditions are extremely favourable in Hungary. Thermal water is accessible in 70% of the territory of the country, with a lowest temperature of 30 degrees C. For energetic purposes, it can be utilized in two different ways: for supplying heat or generating electricity. In relation to utilization, one of the most serious problems derives from the chemical composition of thermal water. The present paper investigates the opportunities of preventing scaling by nanofiltration. Experiments were performed on a Thin Film NF DK membrane, thermostated at 50 degrees C and at a pressure of 3.5 MPa with four different samples (from four Hungarian cities - Eger, Mezokovesd, Bogacs, Miskolc-Tapolca) using batch plant. Reproducibility of experiments was also investigated using water samples from Komarom at 50 and 60 degrees C. The results showed that NF DK could achieve high retention of divalent ions. The results of the second phase of the experiments proved that water flux and rejections were very stable. After filtration, the scaling properties of thermal water were simulated with the help of chemical equilibrium modelling software, called Visual MINTEQ 3.0. The results of the permeate samples prove that nanofiltration is a successful process in preventing scaling of thermal water for further use. PMID- 23656947 TI - Growth and development of tomato plants Lycopersicon Esculentum Mill. under different saline conditions by fertirrigation with pretreated cheese whey wastewater. AB - Pretreated cheese whey wastewater (CWW) has been used at different salinity levels: 1.75, 2.22, 3.22, 5.02 and 10.02 dS m(-1) and compared with fresh water (1.44 dS m(-1)). Two cultivars (cv.) of the tomato plant Lycopersicon Esculentum Mill. (Roma and Rio Grande) were exposed to saline conditions for 72 days. Salinity level (treatment) had no significant effects on the fresh weight and dry matter of the leaves, stems and roots. Similar results were found when specific leaf area, leaflet area, ramifications number of 1st order/plant, stem diameter and length, nodes number/stem and primary root length were considered. Conversely, the salinity level significantly influenced the Soil Plant Analysis Development (SPAD) index and the distance between nodes in the plant stem. In the first case, an increase of 21% was obtained in the salinity levels of 5.02 and 10.02 dS m(-1) for cv. Rio Grande, compared with the control run. The results showed that the pretreated CWW can be a source of nutrients for tomato plants, with reduced effects on growth and development. PMID- 23656948 TI - Bio-desulfurization and denitrification by anaerobic-anoxic process for the treatment of wastewater from flue gas washing. AB - For amine-based carbon dioxide capture, nitrogen oxides and sulfur oxides were the main pollutants that had a negative effect on the regeneration of solvent. Before carbon dioxide capture, the sulfur oxides in flue gas should be removed by the method of calcium salt, and then washed by alkaline solution to eliminate the residual nitrogen oxides and sulfur oxides. The washing wastewater containing sulfate and nitrate needs to be treated. In this study, a novel anaerobic-anoxic process was built up for the treatment of this washing wastewater. Nitrate was reduced to nitrogen by denitrifying bacteria. Sulfate was firstly reduced to sulfide by sulfate reducing bacteria, and then selectively oxidized to element sulfur by sulfide oxidizing bacteria. The treated liquid could be reused as absorption after the adjustment of pH value. The performances of this bioprocess were investigated under various pH values and S/N ratios. It was found that the optimal pH value of influent was 6.0, the percentages of denitrification and sulfate reducing could reach 90 and 89%, respectively. Seventy-six percent of sulfate was transformed into element sulfur. Nitrate significantly had a negative effect on sulfate reduction above 10 mM. As 20 mM nitrate, the sulfate reducing percentage would drop to 67%. These results showed that the anaerobic-anoxic process was feasible for the treatment of flue gas washing wastewater. It would be prospectively applied to other wastewater with the higher ratio of SO4(2 )/NO3(-). PMID- 23656949 TI - Simulation of the spatial and temporal changes of complex non-point source loads in a lake watershed of central China. AB - In this study, a coupling model of agricultural and urban non-point source (AUNPS) is established in order to estimate complex non-point source (NPS) pollutant loads in the urban-rural fringe. Furthermore, a spatial-temporal change model of non-point source (CA-AUNPS) is established by the coupling of AUNPS and cellular automata (CA) models. The total nitrogen (TN) and total phosphorus (TP) loads in Tangxun watershed were simulated during 1991-2020, and the results show that: (1) the CA-AUNPS model is an effective tool to simulate the spatial temporal changes of NPS pollutant loads in urban-rural fringe; (2) in terms of the spatial changes, the TN and TP loads generally showed as rural/urban construction land > farmland > forest/green land, and the high-value areas of NPS pollutant loads expanded from north to south with the increase of construction land; with regard to temporal changes, the TN and TP loads generally displayed an increasing tendency during 1991-2020, and by 2020 the TN and TP loads will increase to 370.06 and 33.89 t yr(-1), respectively; (3) the spatial-temporal changes of TN and TP loads in Tangxun watershed correlate strongly with the land use, slope, and rainfall. PMID- 23656950 TI - Energy benchmarking of South Australian WWTPs. AB - Optimising the energy consumption and energy generation of wastewater treatment plants (WWTPs) is a topic with increasing importance for water utilities in times of rising energy costs and pressures to reduce greenhouse gas (GHG) emissions. Assessing the energy efficiency and energy optimisation of a WWTP are difficult tasks as most plants vary greatly in size, process layout and other influencing factors. To overcome these limits it is necessary to compare energy efficiency with a statistically relevant base to identify shortfalls and optimisation potential. Such energy benchmarks have been successfully developed and used in central Europe over the last two decades. This paper demonstrates how the latest available energy benchmarks from Germany have been applied to 24 WWTPs in South Australia. It shows how energy benchmarking can be used to identify shortfalls in current performance, prioritise detailed energy assessments and help inform decisions on capital investment. PMID- 23656951 TI - Modeling hydrolysis of slowly biodegradable organic compounds in biological nutrient removal activated sludge systems. AB - Hydrolysis is an important process in biological wastewater treatment and is known to be the rate-limiting step in organic carbon removal from municipal or industrial wastewater. The influence of the readily biodegradable chemical oxygen demand fraction in biological wastewater treatment systems has been extensively investigated, but little is known about the effects of slowly biodegradable substrate (XS) on denitrification and enhanced biological phosphorus removal. The biodegradation of XS is initiated by hydrolysis, which is an integral part of activated sludge models, such as the Activated Sludge Model no. 2d (ASM2d). This process is slower than heterotrophic growth and thus becomes the rate-limiting step for the biodegradation of organic compounds. The aim of this study was to evaluate different concepts of modeling the hydrolysis process using the original and modified version of ASM2d. Batch test results obtained at a large biological nutrient removal (BNR) plant in Gdansk (Poland) provided an experimental database for comparison of the two model predictions. Both models were compared in terms of their predictions for the most important process rates in BNR activated sludge systems. In comparison with the orginal ASM2d, the modified model had no or only minor effect on the predicted nitrate utilization rate, phosphate release rate and anoxic/aerobic phosphate uptake rate, but better predicted the oxygen uptake rate. The average ARDs (average relative deviations) were 19.0 and 29.3% (original ASM2d) vs. 13.4 and 20.4% (modified ASM2d), respectively, for the settled wastewater without pretreatment and after coagulation-flocculation. PMID- 23656952 TI - Response surface method for the optimisation of micropollutant removal in municipal wastewater treatment plant effluent with the UV/H2O2 advanced oxidation process. AB - Experiments with the ultraviolet (UV)/H2O2 advanced oxidation process (AOP) were conducted to investigate the abatement of micropollutants in wastewater treatment plant effluent. The fluence and the starting concentration of H2O2 in a bench scale batch reactor were varied according to response surface method (RSM) to examine their influence on the treatment efficiency. It was shown that the investigated AOP is very effective for the abatement of micropollutants with conversion rates typically higher than 90%. Empirical relationships between fluence, H2O2 dosage and the resulting concentration of micropollutants were established by RSM. By this means it was shown that X-ray-contrast media had been degraded only by UV light. Nevertheless, most substances were degraded by the combination of UV irradiation and H2O2. Based on RSM an optimisation of multiple responses was conducted to find the minimal fluence and H2O2 dosage that are needed to reach an efficient abatement of micropollutants. PMID- 23656953 TI - Cycle-time determination and process control of sequencing batch membrane bioreactors. AB - In this paper a method to determine the cycle time for sequencing batch membrane bioreactors (SBMBRs) is introduced. One of the advantages of SBMBRs is the simplicity of adapting them to varying wastewater composition. The benefit of this flexibility can only be fully utilised if the cycle times are optimised for the specific inlet load conditions. This requires either proactive and ongoing operator adjustment or active predictive instrument-based control. Determination of the cycle times for conventional sequencing batch reactor (SBR) plants is usually based on experience. Due to the higher mixed liquor suspended solids concentrations in SBMBRs and the limited experience with their application, a new approach to calculate the cycle time had to be developed. Based on results from a semi-technical pilot plant, the paper presents an approach for calculating the cycle time in relation to the influent concentration according to the Activated Sludge Model No. 1 and the German HSG (Hochschulgruppe) Approach. The approach presented in this paper considers the increased solid contents in the reactor and the resultant shortened reaction times. This allows for an exact calculation of the nitrification and denitrification cycles with a tolerance of only a few minutes. Ultimately the same approach can be used for a predictive control strategy and for conventional SBR plants. PMID- 23656954 TI - Decentralised systems - definition and drivers in the current context. AB - This paper explores the current context for decentralised approaches in the provision of urban water services. It examines the recent history of decentralised systems' implementation in Australia and identifies its drivers. The drivers included addressing capacity constraints of centralised systems, mitigating the environmental impact of urban development, and increasing the resilience of urban water systems to episodic droughts and the projected impacts of climate change. The concepts of integrated urban water management and water sensitive urban design were prevalent in many of the innovative approaches used for the provision of decentralised urban water services. However, there remains a degree of confusion among water professionals in the terminology adopted for on site and decentralised systems. Based on a literature review, consultation with water industry professionals and examination of decentralised urban developments in Australia, this paper has developed a generalised definition of decentralised systems for adoption across the water sector. The definition encompasses the various development scales in which decentralised systems are implemented, and reflects the new functions and characteristics inherent to those systems. PMID- 23656955 TI - Fouling mitigation in humic acid ultrafiltration using polysulfone/SAPO-34 mixed matrix membrane. AB - Although ultrafiltration (UF) membranes are applicable in wastewater and water treatment, most UF membranes are hydrophobic and susceptible to severe fouling by natural organic matter. In this work, polysulfone (PSf) membrane was blended with silicaluminophosphate (SAPO) nanoparticles, SAPO-34, to study the effect of SAPO 34 incorporation in humic acid (HA) fouling mitigation. The casting solution was prepared by blending 5-20 wt% of SAPO-34 nanoparticles into the mixture of PSf, 1 methyl-2-pyrrolidinone and polyvinyl alcohol at 75 degrees C. All membrane samples were then prepared using the phase inversion method. Blending SAPO-34 zeolite into PSf membranes caused augmentation in surface hydrophilicity and pore size, leading to higher water permeation. In the HA filtration test, mixed matrix membranes (MMMs) with SAPO-34 zeolite showed reduced HA fouling initiated from pore blocking. The MMM with 20 wt% SAPO-34 loading exhibited the highest increment of water permeation (83%) and maintained about 75% of permeate flux after 2.5 h. However, the SAPO-34 fillers agglomerated in the PSf matrix and induced macrovoid formation on the membrane surface when excessive zeolite was added. PMID- 23656956 TI - Application of the SWAT model to the Xiangjiang river watershed in subtropical central China. AB - The Soil and Water Assessment Tool (SWAT) model was applied to simulate the water balance in the Xiangjiang river watershed for current and planning scenarios of land uses. The model was first calibrated for the period from 1998 to 2002 and then validated for the period from 2003 to 2007 using the observed stream flow data from four monitoring gages within the watershed. The determination coefficient of linear regression of the observed and simulated monthly stream flows (R(2)) and their Nash-Sutcliffe Index (NSI) was used to evaluate model performance. All values of R(2) and NSI were above 0.8 and ranged from 0.82 to 0.92, which indicates that the SWAT model was capable of simulating the stream flow in the Xiangjiang river watershed. The calibrated and validated SWAT model was then applied to study the hydrological response of three land use change scenarios. Runoff was reduced by increasing the areas of forest and grassland while simultaneously decreasing the areas of agricultural and urban land. In the recent and future land use planning for the Xiangjiang river watershed, the hydrological effect should be considered in regional water management and erosion control. PMID- 23656957 TI - Influence of nanoparticles on the polymer-conditioned dewatering of wastewater sludges. AB - The effect of using small-scale, high surface area, nanoparticles to supplement polymer-conditioned wastewater sludge dewatering was investigated. Aerobically digested sludge and waste activated sludge sourced from the Hunter Valley, NSW, Australia, were tested with titanium dioxide nanoparticles. The sludge samples were dosed with the nanoparticles in an attempt to adsorb a component of the charged biopolymer surfactants present naturally in sludge. The sludge was conditioned with a cationic polymer. The dewatering characteristics were assessed by measuring the specific resistance to filtration through a modified time-to filter testing apparatus. The solids content of the dosed samples was determined by a mass balance and compared to the original solids content in the activated sludge. Test results indicated that nanoparticle addition modified the structure of the sludge and provided benefits in terms of the dewatering rate. The samples dosed with nanoparticles exhibited faster water removal, indicating a more permeable filter cake and hence more permeable sludge. A concentration of 2-4% nanoparticles was required to achieve a noticeable benefit. As a comparison, the sludge samples were also tested with a larger particle size, powdered activated carbon (PAC). It was found that the PAC did provide some minor benefits to sludge dewatering but was outperformed by the nanoparticles. The solids content of the final sludge was increased by a maximum of up to 0.6%. The impact of the order sequence of particles and polymer was also investigated. It was found that nanoparticles added before polymer addition provided the best dewatering performance. This outcome was consistent with current theories and previous research through the literature. An economic analysis was undertaken to confirm the viability of the technology for implementation at a full-scale plant. It was found that, currently, this technology is unlikely to be favourable unless the nanoparticles can be sourced for a low cost. PMID- 23656958 TI - Recalcitrant organic matter removal from textile wastewater by an aerobic cell immobilized pellet column. AB - The treatment of textile wastewater is difficult because of its recalcitrant organic content. The biological removal of recalcitrant organics requires a long retention time for microbial growth. Activated sludge was immobilized in a polyethylene glycol pellet to allow for sufficient sludge retention time. The pellets were filled in an aerobic cell-immobilized pellet column (CIPC) reactor in order to investigate the removal of recalcitrant organics from textile wastewater. A textile wastewater effluent treated by a conventional activated sludge reactor was used as a target wastewater. The chemical oxygen demand (COD) removal efficiency of the aerobic CIPC reactor at various empty bed contact times was in the range of 42.2-60.5%. Half of the input COD was removed in the lower part (bottom 25% of the reactor volume) of the reactor when the organic loading rate was less than 1.5 kg COD/(m(3)*d). About 15-30% of the input COD was removed in the remaining part of the column reactor. The COD removed in this region was limitedly biodegradable. The biodegradation of recalcitrant organics could be carried out by the interactional functions of the various bacteria consortia by using a cell-immobilization process. The CIPC process could effectively treat textile wastewater using a short retention time because the microorganisms that degrade limitedly biodegradable organics were dominant in the reactor. PMID- 23656959 TI - Arthroplasty versus fusion in single-level cervical degenerative disc disease: a Cochrane review. AB - STUDY DESIGN: A systematic review of randomized controlled trials (RCTs). OBJECTIVE: To assess the effects of arthroplasty versus fusion in the treatment of radiculopathy or myelopathy, or both, due to single-level cervical degenerative disc disease. SUMMARY OF BACKGROUND DATA: There is ongoing debate about whether fusion or arthroplasty is superior in the treatment of single-level cervical degenerative disc disease. Mainly because the intended advantage of arthroplasty compared with fusion, prevention of symptoms due to adjacent segment degeneration in the long term, is not confirmed yet. Until sufficient long-term results become available, it is important to know whether results of 1 of the 2 treatments are superior to the other in the first 1 to 2 years. METHODS: We searched electronic databases for randomized controlled trials. We included randomized controlled trials that directly compared any type of cervical fusion with any type of cervical arthroplasty, with at least 1 year of follow-up. Study selection was performed independently by 3 review authors, and "risk of bias" assessment and data extraction were independently performed by 2 review authors. In case of missing data, we contacted the study authors or the study sponsor. We assessed the quality of evidence. RESULTS: Nine studies (2400 participants) were included in this review; 5 of these studies had a low risk of bias. Results for the arthroplasty group were better than the fusion group for all primary comparisons, often statistically significant. For none of the primary outcomes was a clinically relevant difference in effect size shown. Quality of the evidence was low to moderate. CONCLUSION: There is low to moderate quality evidence that results are consistently in favor of arthroplasty, often statistically significant. However, differences in effect size were invariably small and not clinically relevant for all primary outcomes. LEVEL OF EVIDENCE: 1. PMID- 23656960 TI - Re: Goertz CM, Long CR, Hondras MA, et al. Adding chiropractic to standard medical therapy for nonspecific low back pain. Spine (Phila Pa 1976). 2013;38:627 34. PMID- 23656961 TI - Growth guidance system for early-onset scoliosis: comparison of experimental and retrieval wear. AB - STUDY DESIGN: Laboratory study conducted using an in vitro wear simulator with a growth guidance system. Analysis of variance performed to compare in vitro specimens (n = 6) with in vivo retrieval components (n = 5). OBJECTIVE: To characterize the stainless steel, wear debris potential of a spinal growth guidance system by developing an in vitro model and validating tested implants with retrospectively obtained retrievals. SUMMARY OF BACKGROUND DATA: Growth enabling, surgical treatments have been developed to provide fusionless options for patients with early-onset scoliosis. There exist few data regarding the wear debris associated with such spinal systems. METHODS: In this study, we determined in vitro wear from the stainless steel components of the SHILLATM Growth Guidance System. An analogue lumbar spine model was adapted from ISO 12189:2008 to assess the growth guidance system. In a multistation wear simulator, 6 assembled constructs were tested under displacement control for 5 million cycles (Mc) with diluted bovine serum, and the wear was measured gravimetrically at end of the test. The components were compared quantitatively for wear scar depth with retrieved growth guidance implants (n = 5), and qualitatively for wear, corrosion, and other surface damage. RESULTS: The average total wear rate over 5 Mc was 0.39 +/- 0.13 mm/Mc (3.12 +/- 1.01 mg/Mc) with an average particle size of 1.3 MUm in equivalent circular diameter. Prominent wear scars were noticed on both the tested and retrieved specimens with no statistical difference in the wear scar depths of the tested and retrieved components when set and multiaxial screws when compared collectively. CONCLUSION: An in vitro wear analysis for a spinal growth guidance system was conducted using a novel protocol and validated against retrieved implants. This is the first study establishing a baseline value for the wear of "growth enabling" devices for the treatment of early-onset scoliosis. PMID- 23656962 TI - Novel experimental scoliosis model in immature rat using nickel-titanium coil spring. AB - STUDY DESIGN: Follow-up of animals after surgically initiated scoliosis. OBJECTIVE: To develop quantitatively asymmetric loads on rat lumbar to create scoliosis. SUMMARY OF BACKGROUND DATA: Current animal models for scoliosis use mostly rigid or flexible posterior asymmetric tethers. The curve progression can only be expected for the growth potential, leading to insufficient growth potential for validation of corrective techniques. METHODS: Scoliosis was induced in 55 five-week-old female Sprague-Dawley rats using a nickel-titanium coil spring. The experimental rats were randomly divided into 2 groups: in group A (n = 15), the nickel-titanium coil spring was not removed until these rats reached physical maturity (age, 12 wk). Group B (n = 40) was further randomly subdivided into 5 subgroups (n = 8 for each subgroup): removal of the spring after 1 week (group B1), 2 weeks (group B2), 3 weeks (group B3), 4 weeks (group B4), and 5 weeks (group B5). All rats were followed for a 7-week period with serial radiographs to document change of the deformity. RESULTS: All experimental animals of group A developed progressive, structural scoliotic curves convex to the left in the lumbar segment. In group B, the deformity of the lumbar progressed after the spring load was applied and regressed after the spring was removed. The scoliosis in group B1-B3 (the spring removed before sexual maturity) regressed after spring removal until the rats reached sexual maturity (4 wk after spring implant surgery). The scoliosis in group B4-B5 (the spring removed after sexual maturity) regressed only during the first week after spring removal surgery. The average coronal Cobb angle was 7.8 degrees +/- 1.3 degrees (range: 6.0 degrees -10.2 degrees ) in group B1 at the final follow-up, and there was only 1 experimental rat that maintained a curve more than 108. The models of group B2-B5 maintained stable scoliotic curves (coronal Cobb angle of L2-L5 > 10 degrees ) convex to the left in the lumbar segment at the final follow-up. CONCLUSION: This study establishes a rat lumbar scoliosis model via asymmetric load. This method develops lumbar scoliosis in a short time and maintains the essential elements along the curve. It is suitable for the investigation of scoliosis. PMID- 23656964 TI - Traumatic brain injury, mental health, substance use, and offending among incarcerated young people. AB - OBJECTIVE: Despite being at high risk, little is known about traumatic brain injuries (TBIs) among incarcerated young people. This study aims to describe the prevalence of TBI among incarcerated young people and assess the association with mental health, substance use, and offending behaviors. SETTING: The 2009 NSW Young People in Custody Health Survey was conducted in 9 juvenile detention centers. PARTICIPANTS: A total of 361 young people agreed to participate, representing 80% of all incarcerated young people. MAIN MEASURES: Young people were asked if they ever had a head injury where they became unconscious or "blacked-out." The survey used the Kiddie Schedule for Affective Disorders for Children to assess for psychiatric disorders, the Alcohol Use Disorder Identification Test, and the Severity of Dependence Scale to measure problematic substance use. RESULTS: The sample comprised 88% man, 48% Aboriginal, with an average age of 17 years. One-third (32%) of young people reported ever experiencing a TBI, and 13% reported multiple TBIs. The majority (92%) of "most serious" TBIs were defined as mild, and the most common cause was an assault (62% woman, 34% man). Young people who reported a history of TBI (compared with those reporting no TBI) were significantly more likely to be diagnosed with a mental health disorder, psychological distress, a history of bullying, problematic substance use, participation in fights, and offending behaviors. Reporting multiple (>2) TBIs conferred a higher risk of psychological disorders and problematic substance use. CONCLUSIONS: Incarcerated young people have high rates of TBI. Enhanced detection of TBI among incarcerated young people will assist clinicians in addressing the associated psychosocial sequelae. PMID- 23656965 TI - A perspective on the support of scientific research. PMID- 23656963 TI - Use of V(D)J recombination excision circles to identify T- and B-cell defects and to monitor the treatment in primary and acquired immunodeficiencies. AB - T-cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) are circular DNA segments generated in T and B cells during their maturation in the thymus and bone marrow. These circularized DNA elements persist in the cells, are unable to replicate, and are diluted as a result of cell division, thus are considered markers of new lymphocyte output. The quantification of TRECs and KRECs, which can be reliably performed using singleplex or duplex real-time quantitative PCR, provides novel information in the management of T- and B-cell immunity-related diseases. In primary immunodeficiencies, when combined with flow cytometric analysis of T- and B-cell subpopulations, the measure of TRECs and KRECs has contributed to an improved characterization of the diseases, to the identification of patients' subgroups, and to the monitoring of stem cell transplantation and enzyme replacement therapy. For the same diseases, the TREC and KREC assays, introduced in the newborn screening program, allow early disease identification and may lead to discovery of new genetic defects. TREC and KREC levels can also been used as a surrogate marker of lymphocyte output in acquired immunodeficiencies. The low number of TRECs, which has in fact been extensively documented in untreated HIV infected subjects, has been shown to increase following antiretroviral therapy. Differently, KREC number, which is in the normal range in these patients, has been shown to decrease following long-lasting therapy. Whether changes of KREC levels have relevance in the biology and in the clinical aspects of primary and acquired immunodeficiencies remains to be firmly established. PMID- 23656966 TI - Credibility and comprehension of healthy volunteers in lengthy inpatient drug studies. AB - Early clinical trials rely upon paid healthy volunteers. Concern has been raised regarding the characteristics of these individuals, how well they understand their rights and the risks of clinical research, and how they may be influenced by manipulation or coercion. Therefore, we investigated (1) the motivations of subjects in clinical trials, (2) how well these individuals comprehend a consent form they sign, and (3) the effect of the stipend on the reliability of information reported by volunteers in clinical trials. Thirty healthy subjects (age, 21-45 years) in a long-duration clinical trial were administered a questionnaire gathering demographic information and testing their comprehension of the consent form. In a separate chart review of 10 clinical trials, 374 subjects were studied to determine their reliability in reporting abnormalities in their medical history and in reporting adverse events, and an association was examined between the incidence of unreliable reporting and the stipend paid to them for participating in the clinical trial. A large percentage of subjects who were enrolled in the long-duration clinical trial failed to comprehend a variety of basic concepts related to the consent form and their participation in the drug study. The chart review demonstrated that subjects who are paid larger stipends may not be more likely to report abnormalities on their medical history. Further studies should be undertaken with larger numbers of subjects enrolled in clinical trials, and possible associations between demographic data (eg, income, level of education, number of previous studies) and the reliability of information provided by normal healthy research volunteers should be examined. PMID- 23656967 TI - A review of the etiology, associated comorbidities, and treatment of orthostatic hypotension. AB - The magnitude of increase in systolic blood pressure in response to the shift from supine to upright posture is considered to reflect the adequacy of orthostatic regulation. Orthostatic integrity is largely maintained by the interaction between the skeletal muscle pump, neurovascular compensation, neurohumoral effects, and cerebral blood flow regulation. Various physiological states and disease conditions may disrupt these mechanisms as seen in vasovagal syncope, dysautonomic orthostatic intolerance, and postural orthostatic tachycardia syndrome. Orthostatic hypotension (OH) and decreased cerebral blood flow are strongly related. Even subclinical OH has been associated to different degrees with impaired cognitive function, decreased effort, reduced motivation, increased hopelessness, and signs of attention-deficit hyperactivity disorder and dementia, diabetes mellitus, and Parkinson disease. Furthermore, subclinical levels of inadequate blood pressure regulation in response to orthostasis have been linked to increased depression and anxiety and intergenerational behavioral sequelae between mother and child. Identifying causes of subclinical and clinical OH is critical in improving quality of life for both children and older adults. A better understanding of the underlying causes responsible for the etiology of OH could lead to a rational design of novel effective therapeutic regimens for the treatment of this condition and associated comorbidities. PMID- 23656968 TI - Structurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment as components of fossil fuels and by-products of combustion. These multi-ring chemicals differentially activate the aryl hydrocarbon receptor (AHR) in a structurally dependent manner, and induce toxicity via both AHR-dependent and independent mechanisms. PAH exposure is known to induce developmental malformations in zebrafish embryos, and recent studies have shown cardiac toxicity induced by compounds with low AHR affinity. Unraveling the potentially diverse molecular mechanisms of PAH toxicity is essential for understanding the hazard posed by complex PAH mixtures present in the environment. We analyzed transcriptional responses to PAH exposure in zebrafish embryos exposed to benz(a)anthracene (BAA), dibenzothiophene (DBT) and pyrene (PYR) at concentrations that induced developmental malformations by 120 h post fertilization (hpf). Whole genome microarray analysis of mRNA expression at 24 and 48 hpf identified genes that were differentially regulated over time and in response to the three PAH structures. PAH body burdens were analyzed at both time points using GC-MS, and demonstrated differences in PAH uptake into the embryos. This was important for discerning dose-related differences from those that represented unique molecular mechanisms. While BAA misregulated the least number of transcripts, it caused strong induction of cyp1a and other genes known to be downstream of the AHR, which were not induced by the other two PAHs. Analysis of functional roles of misregulated genes and their predicted regulatory transcription factors also distinguished the BAA response from regulatory networks disrupted by DBT and PYR exposure. These results indicate that systems approaches can be used to classify the toxicity of PAHs based on the networks perturbed following exposure, and may provide a path for unraveling the toxicity of complex PAH mixtures. PMID- 23656969 TI - Diallylsulfide attenuates excessive collagen production and apoptosis in a rat model of bleomycin induced pulmonary fibrosis through the involvement of protease activated receptor-2. AB - Pulmonary fibrosis (PF) can be a devastating lung disease. It is primarily caused by inflammation leading to severe damage of the alveolar epithelial cells. The pathophysiology of PF is not yet been clearly defined, but studying lung parenchymal injury by involving reactive oxygen species (ROS) through the activation of protease activated receptor-2 (PAR-2) may provide promising results. PAR-2 is a G-protein coupled receptor is known to play an important role in the development of PF. In this study, we investigated the inhibitory role of diallylsulfide (DAS) against ROS mediated activation of PAR-2 and collagen production accompanied by epithelial cell apoptosis. Bleomycin induced ROS levels may prompt to induce the expression of PAR-2 as well as extracellular matrix proteins (ECM), such as MMP 2 and 9, collagen specific proteins HSP-47, alpha SMA, and cytokines IL-6, and IL-8RA. Importantly DAS treatment effectively decreased the expression of all these proteins. The inhibitory effect of DAS on profibrotic molecules is mediated by blocking the ROS level. To identify apoptotic signaling as a mediator of PF induction, we performed apoptotic protein expression, DNA fragmentation analysis and ultrastructural details of the lung tissue were performed. DAS treatment restored all these changes to near normalcy. In conclusion, treatment of PF bearing rats with DAS results in amelioration of the ROS production, PAR-2 activation, ECM production, collagen synthesis and alveolar epithelial cell apoptosis during bleomycin induction. We attained the first evidence that treatment of DAS decreases the ROS levels and may provide a potential therapeutic effect attenuating bleomycin induced PF. PMID- 23656971 TI - Acquired cholesteatoma: summary of the cascade of molecular events. AB - BACKGROUND: Cholesteatoma is considered a benign, gradually expanding and destructive epithelial lesion of the temporal bone. The pathogenesis of different classifications of cholesteatoma is marked by similar underlying cellular and molecular processes. Stepwise explanations of the histopathogenesis have been described previously. The current paper focuses on expounding the molecular events of cholesteatoma. METHOD AND RESULTS: Cholesteatoma pathogenesis encompasses a complex network of signalling pathways during: epidermal hyperplasia, perimatrix-matrix interactions and mucosal disease. This paper presents a review of the molecular events driven by inflammatory mediators and enzymes during: cholesteatoma growth (cell proliferation and apoptosis); maintenance and deterioration (angiogenesis and hypoxia, oxidative stress and toxicity); and complications (bone erosion and hearing loss). The cascade of molecular events applicable to atelectasis and cholesteatoma that coexist with chronic otitis media and bone erosion as sequelae is summarised. CONCLUSION: The role of lipids in this disease is relatively unexplored, but there is evidence in support of fatty acid role-players that needs confirmation. Future directions in lipid research to delineate molecular mechanisms are proposed. PMID- 23656970 TI - Natural history of Barth syndrome: a national cohort study of 22 patients. AB - BACKGROUND: This study describes the natural history of Barth syndrome (BTHS). METHODS: The medical records of all patients with BTHS living in France were identified in multiple sources and reviewed. RESULTS: We identified 16 BTHS pedigrees that included 22 patients. TAZ mutations were observed in 15 pedigrees. The estimated incidence of BTHS was 1.5 cases per million births (95%CI: 0.2 2.3). The median age at presentation was 3.1 weeks (range, 0-1.4 years), and the median age at last follow-up was 4.75 years (range, 3-15 years). Eleven patients died at a median age of 5.1 months; 9 deaths were related to cardiomyopathy and 2 to sepsis. The 5-year survival rate was 51%, and no deaths were observed in patients >=3 years. Fourteen patients presented with cardiomyopathy, and cardiomyopathy was documented in 20 during follow-up. Left ventricular systolic function was very poor during the first year of life and tended to normalize over time. Nineteen patients had neutropenia. Metabolic investigations revealed inconstant moderate 3-methylglutaconic aciduria and plasma arginine levels that were reduced or in the low-normal range. Survival correlated with two prognostic factors: severe neutropenia at diagnosis (<0.5 * 109/L) and birth year. Specifically, the survival rate was 70% for patients born after 2000 and 20% for those born before 2000. CONCLUSIONS: This survey found that BTHS outcome was affected by cardiac events and by a risk of infection that was related to neutropenia. Modern management of heart failure and prevention of infection in infancy may improve the survival of patients with BTHS without the need for heart transplantation. PMID- 23656973 TI - Incidental atypical proliferative lesions in reduction mammoplasty specimens: analysis of 2498 cases from 2 tertiary women's health centers. AB - Atypical proliferative lesions (APLs) are occasionally found in breast reduction specimens. The aim of the study was to investigate the prevalence of APL in reduction mammoplasty specimens from patients who were treated mainly for macromastia. A retrospective medical record review of pathology records on patients who underwent reduction mammoplasty from 2006 to 2012 generated 2498 cases. The sole exclusion criterion was a history of invasive and/or ductal carcinoma in situ (DCIS). Laterality, specimen weight, number of blocks submitted, and presence of APL were recorded and analyzed. We defined APL as invasive carcinoma, DCIS or lobular carcinoma in situ, atypical ductal (ADH) or lobular hyperplasia, and flat epithelial atypia (FEA). The presence of papillomas, radial scars, and fibroadenomas was also recorded. At least 1 APL was identified in 107 (4.3%) of 2498 reduction mammoplasty specimens including invasive duct carcinoma (n = 2), DCIS (n = 4), ADH/FEA (n = 47), and lobular carcinoma in situ/atypical lobular hyperplasia (n = 54). One hundred four (97%) of the 107 patients underwent bilateral, and 3 (3%) underwent unilateral reductions. In conclusion, the frequency of detection of APLs in patients with no history of breast cancer is low (4.3%). Detection of invasive and DCIS lesions is extraordinarily low at 0.2%. The most common APL is lobular neoplasia (2.2%), whereas ADH and FEA are seen in 1.9%. Our findings provide data on the distribution of these lesions in this setting, as well as some insight into their prevalence in the general population. A protocol for submitting tissues from these specimens is also proposed. PMID- 23656972 TI - The natural history of secondary muscle-invasive bladder cancer. AB - BACKGROUND: The management of patients with high-grade non muscle invasive bladder cancer (NMIBC) brings diagnostic and therapeutic challenges. In the current study, we sought to study the natural history of progression to "secondary" muscle-invasive bladder cancer (MIBC)-cancer that developed during follow up of patients presenting with non-muscle invasive bladder cancer (NMIBC). METHODS: Between 1998 and 2008, 760 patients were treated for bladder cancer. Primary MIBC (>=T2) tumors (present upon presentation) were diagnosed in 114 patients. All patients with high-grade NMIBC were treated with intravesical BCG. Mean follow-up was 44 months. RESULTS: Forty patients (6.1%) developed secondary MIBC after a mean period of 21 months from initial diagnosis of bladder cancer. The 2- and 5-year disease-specific survival rates were better for patients with secondary MIBC (90% and 56% compared to 69% and 42% for patients with primary disease, p=0.03). The Kaplan-Meier curves of the two groups were parallel but displaced by approximately 2 years. CONCLUSION: In the current series, MIBC progression occurred among initially presenting patients with NMIBC in 6.1%. In most patients, the initial diagnosis of NMIBC is correct and muscle invasion occurs after a mean period of about 2 years. This supports a non-radical approach in patients with high-grade T1, Ta or Tis. Meticulous follow-up with liberal biopsy of any suspicious lesion may provide early diagnosis of invasive disease. PMID- 23656974 TI - Proton magnetic resonance metabolomic characterization of ovarian serous carcinoma effusions: chemotherapy-related effects and comparison with malignant mesothelioma and breast carcinoma. AB - Malignant serous effusions are a common manifestation of advanced cancer, associated with significant morbidity and mortality. The aim of this study was to identify the metabolic differences between ovarian serous carcinoma effusions obtained pre- and post-chemotherapy, as well as to compare ovarian carcinoma (OC) effusions with breast carcinoma and malignant mesothelioma specimens. The supernatants of 115 effusion samples were analyzed by high-resolution magnetic resonance spectroscopy in vitro and multivariate analysis. The samples comprised pleural and peritoneal effusions from 95 OC, 10 breast carcinomas, and 10 malignant mesotheliomas. Among the OC, 8 were paired peritoneal specimens obtained pre- and post-chemotherapy from the same patient. OC had elevated levels of ketones (aceto-acetate and beta-hydroxybutyrate) and lactate compared to malignant mesotheliomas and breast carcinomas, whereas the latter had more glucose, alanine, and pyruvate. Multivariate analysis of paired effusions in OC showed a significant increase in glucose and lipid levels in the post-treatment spectra (P = .039). Magnetic resonance spectroscopy is a promising technique for comprehensive and comparative studies of metabolites in malignant serous effusions, and our study shows that small metabolites associated with effusions might improve our understanding of tumor biology and disease progression and has diagnostic potential in this differential diagnosis. PMID- 23656975 TI - Characterization of alpha-fetoprotein levels in three dolphin species: development of sensitive immunoassays for analysis of the pregnancy-associated variations. AB - A single radial immunodiffusion (SRID) assay and a chemiluminescent immunoassay (CLIA) were initially developed for alpha-fetoprotein (AFP) of the striped dolphin. Utilizing these developed assays, we investigated pregnancy-associated changes in the levels of AFP in the sera of fetuses and pregnant females of three dolphin species; samples were either collected from captive individuals or obtained as fishery by-products. The concentrations of AFP in the fetal serum ranged from 419.0 to 2026.3 MUg/ml in the striped dolphin, 12.6 to 1218.7 MUg/ml (for an AFP equivalent; eqAFP) in the common bottlenose dolphin and 770.6 to 3129.1 MUg eqAFP/ml in the Risso's dolphin. AFP levels decreased with increased fetal size in fetuses over 20 cm in length. The concentrations of AFP in sera of pregnant females ranged from 7.18 to 8068.7 ng/ml in the striped dolphin, 6.6 to 1241.1 ng eqAFP/ml in the common bottlenose dolphin and 3.4 to 2868.7 ng eqAFP/ml in the Risso's dolphin. The levels in most pregnant females were equal to or lower than those found in males and nonpregnant individuals, although a few pregnant females exhibited extremely high levels (in the range of hundreds to thousands of nanograms per milliliter). Such high levels of AFP were not observed during pseudopregnancy. To our knowledge, this is the first report on basal profiles for serum AFP levels in small odontocetes. The profiles indicated that AFP may play a significant role during embryonic development, although maternal levels do not appear to be a diagnostic biomarker for monitoring pregnancy. PMID- 23656976 TI - Dual effect of Lutzomyia longipalpis saliva on Leishmania braziliensis infection is mediated by distinct saliva-induced cellular recruitment into BALB/c mice ear. AB - BACKGROUND: Leishmania parasites are transmitted to their vertebrate hosts by infected Phlebotomine sand flies during the blood meal of the flies. Sand fly saliva is known to enhance Leishmania spp. infection, while pre-exposure to saliva protects mice against parasitic infections. In this study, we investigated the initial inflammatory leucocyte composition induced by one or three inocula of salivary gland extract (SGE) from Lutzomyia longipalpis in the presence or absence of Leishmania braziliensis. RESULTS: We demonstrated that inoculating SGE once (SGE-1X) or three times (SGE-3X), which represented a co-inoculation or a pre-exposure to saliva, respectively, resulted in different cellular infiltrate profiles. Whereas SGE-1X led to the recruitment of all leucocytes subtypes including CD4(+) T cells, CD4(+)CD25(+) T cells, dendritic cells, macrophages and neutrophils, the immune cell profile in the SGE-3X group differed dramatically, as CD4(+) T cells, CD4(+)CD25(+) T cells, dendritic cells, macrophages and neutrophils were decreased and CD8(+) T cells were increased. The SGE-1X group did not show differences in the ear lesion size; however, the SGE-1X group harbored a higher number of parasites. On the other hand, the SGE-3X group demonstrated a protective effect against parasitic disease, as the parasite burden was lower even in the earlier stages of the infection, a period in which the SGE-1X group presented with larger and more severe lesions. These effects were also reflected in the cytokine profiles of both groups. Whereas the SGE-1X group presented with a substantial increase in IL-10 production, the SGE-3X group showed an increase in IFN-gamma production in the draining lymph nodes. Analysis of the inflammatory cell populations present within the ear lesions, the SGE-1X group showed an increase in CD4(+)FOXP3(+) cells, whereas the CD4(+)FOXP3(+) population was reduced in the SGE-3X group. Moreover, CD4(+) T cells and CD8(+) T cells producing IFN-gamma were highly detected in the ears of the SGE-3X mice prior to infection. In addition, upon treatment of SGE-3X mice with anti-IFN gamma monoclonal antibody, we observed a decrease in the protective effect of SGE 3X against L. braziliensis infection. CONCLUSIONS: These results indicate that different inocula of Lutzomyia longipalpis salivary gland extract can markedly modify the cellular immune response, which is reflected in the pattern of susceptibility or resistance to Leishmania braziliensis infection. PMID- 23656978 TI - Evaluation of the humoral and cellular immune responses elicited by the live attenuated and inactivated influenza vaccines and their roles in heterologous protection in ferrets. AB - The humoral and cellular immune responses elicited by the trivalent live attenuated influenza vaccine (LAIV) and the trivalent inactivated influenza vaccine (TIV) were evaluated in the ferret model, using newly developed ferret immunological reagents and assays. In contrast to the TIV, which only induced immune responses in primed animals, LAIV induced strong influenza virus-specific serum antibody and T-cell responses in both naive and influenza-seropositive animals. The LAIV offered significant protection against a heterologous H1N1 virus challenge infection in the upper respiratory tract. Influenza virus specific immunoglobulin A (IgA) and immunoglobulin G (IgG) antibody-secreting cells (ASCs) and influenza virus-specific CD4(+) and CD8(+) T cells were detected in the circulation and local paratracheal draining lymph nodes. The frequency of the influenza-specific ASCs in the local lymph nodes appeared to correlate with the degree of protection in the upper respiratory tract. The protection conferred by the LAIV could be attributed not only to the antibody response but also to the cell-mediated and local mucosal immune responses, particularly in naive ferrets. These findings may explain why the LAIV is immunologically superior and offers immediate protection after a single dose in children. PMID- 23656977 TI - Risk stratification of hepatocellular carcinoma in hepatitis B virus e antigen negative carriers by combining viral biomarkers. AB - BACKGROUND: The serum hepatitis B virus (HBV) surface antigen (HBsAg) level can predict hepatocellular carcinoma (HCC) development in hepatitis B e antigen (HBeAg)-negative patients with an HBV DNA level of <2000 IU/mL. However, little is known regarding how well the combination of both viral biomarkers stratifies HCC risk. METHODS: A total of 2165 Taiwanese HBeAg-negative noncirrhotic patients were followed for 14.9 years. The predictive power of the HBsAg level for HCC was analyzed for different viral load ranges. RESULTS: In patients with HBV DNA levels of 2000-19 999 IU/mL (intermediate viral load), a positive correlation between HBsAg level and HCC development was identified after adjustment for other risk factors (P = .002). In contrast, no association was found between HBsAg level and HCC in patients with higher viral loads. HBsAg level was subsequently included to stratify HCC risk in patients with low and intermediate viral loads. Receiver operating characteristic curve analysis showed that combining HBV DNA and HBsAg level better predicts 10-year HCC development as compared to using HBV DNA level alone in the overall cohort (P = .028). CONCLUSIONS: Serum HBsAg level helps stratify HCC risk in patients with intermediate viral loads. Combining HBV DNA and HBsAg levels better predicts HCC risk. PMID- 23656980 TI - Characteristics associated with maintenance of mean A1C<6.5% in people with dysglycemia in the ORIGIN trial. AB - OBJECTIVE: To assess the success and baseline predictors of maintaining glycemic control for up to 5 years of therapy using basal insulin glargine or standard glycemic care in people with dysglycemia treated with zero or one oral glucose lowering agents. RESEARCH DESIGN AND METHODS: Data from 12,537 participants in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were examined by baseline glycemic status (with or without type 2 diabetes) and by therapeutic approach (titrated insulin glargine or standard therapy) using an intention-to-treat analysis. Median values for fasting plasma glucose (FPG) and A1C and percentages with A1C<6.5% (48 mmol/mol) during randomized treatment were calculated. Factors independently associated with maintaining updated mean A1C<6.5% were analyzed with linear regression models. RESULTS: Median A1C in the whole population was 6.4% at baseline; at 5 years, it was 6.2% with glargine treatment and 6.5% with standard care. Of those with diabetes at baseline, 60% using glargine and 45% using standard care had A1C<6.5% at 5 years. Lack of diabetes and lower baseline A1C were independently associated with 5-year mean A1C<6.5%. Maintaining mean A1C<6.5% was more likely with glargine (odds ratio [OR] 2.98 [95% CI 2.67-3.32], P<0.001) than standard care after adjustment for other independent predictors. CONCLUSIONS: Systematic intervention with basal insulin glargine or standard care early in the natural history of dysglycemia can maintain glycemic control near baseline levels for at least 5 years, whether diabetes is present at baseline or not. Keeping mean A1C<6.5% is more likely in people with lower baseline A1C and with the glargine-based regimen. PMID- 23656979 TI - Glucose metabolism after renal transplantation. AB - OBJECTIVE: We determined prevalence, risk factors, phenotype, and pathophysiological mechanism of new-onset diabetes after transplantation (NODAT) to generate strategies for optimal pharmacological management of hyperglycemia in NODAT patients. RESEARCH DESIGN AND METHODS: Retrospective cohort study comparing demographics, laboratory data, and oral glucose tolerance test (OGTT)-derived metabolic parameters from kidney transplant recipients versus subjects not receiving transplants. RESULTS: Among 1,064 stable kidney transplant recipients (>= 6 months posttransplantation), 113 (11%) had a history of NODAT and 132 (12%) had pretransplant diabetes. In the remaining patients, randomly assigned OGTTs showed a high prevalence of abnormal glucose metabolism (11% diabetes; 32% impaired fasting glucose, impaired glucose tolerance, or both), predominantly in older patients who received tacrolimus as the primary immunosuppressant. Compared with 1,357 nontransplant subjects, stable kidney transplant recipients had lower basal glucose, higher glycated hemoglobin, lower insulin secretion, and greater insulin sensitivity in each of the three subgroups, defined by OGTT 2-h glucose (<140, 140-199, >= 200 mg/dL). These findings were reinforced in linear spline interpolation models of insulin secretion and sensitivity (all P < 0.001) and in another regression model in which the estimated oral glucose insulin sensitivity index was substantially higher (by 79-112 mL/min m(2)) for transplant versus nontransplant subjects despite adjustments for age, sex, and BMI (all P < 0.001). CONCLUSIONS: Glucose metabolism differs substantially between kidney transplant recipients and nontransplant controls. Because impaired insulin secretion appears to be the predominant pathophysiological feature after renal transplantation, early therapeutic interventions that preserve, maintain, or improve beta-cell function are potentially beneficial in this population. PMID- 23656981 TI - Fat distribution and glucose intolerance among Greenland Inuit. AB - OBJECTIVE: A high amount of subcutaneous fat is suggested to explain the observation of lower obesity-associated metabolic risk among Inuit than among Europeans. We examined the association between measures of obesity (visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT], BMI, waist circumference [WC], and percentage of body fat) and the indices of glucose metabolism (fasting and 2-h glucose levels, insulin resistance per homeostasis model assessment [HOMA IR], and the insulin sensitivity index [ISI0,120]) among Greenland Inuit. RESEARCH DESIGN AND METHODS: A total of 3,108 adult Inuit participated in a population-based study. The examination included a 75-g oral glucose tolerance test and anthropometric measurements. VAT and SAT were measured by ultrasound according to a validated protocol. Information on sociodemographic characteristics and health behaviors was obtained by interview. RESULTS: Mean SATs were 1.8 and 3.5 cm in men and women, respectively. Mean VATs were 7.0 and 6.3 cm in men and women, respectively. The total prevalence of type 2 diabetes was 9%. Percentage of body fat generally was most strongly associated with all outcomes. Both SAT and VAT were significantly associated with glucose intolerance, fasting and 2-h plasma glucose levels, HOMA-IR, and ISI0,120. VAT was more strongly associated with all outcomes than was SAT. After further adjustment for BMI or WC, VAT was associated with glucose intolerance and insulin resistance, whereas there was a trend toward a negative or no association with SAT. CONCLUSIONS: High mean values of SAT may to a large extent explain the high WC in Inuit populations, and this is suggested to contribute to the lower observed metabolic risk for a given level of obesity. PMID- 23656982 TI - Estimating the population prevalence of diagnosed and undiagnosed diabetes. AB - OBJECTIVE: Health administrative data are frequently used for diabetes surveillance, but validation studies are limited, and undiagnosed diabetes has not been considered in previous studies. We compared the test properties of an administrative definition with self-reported diabetes and estimated prevalence of undiagnosed diabetes by measuring glucose levels in mailed-in capillary blood samples. RESEARCH DESIGN AND METHODS: A stratified random sample of 6,247 individuals (Quebec province) was surveyed by telephone and asked to mail in fasting blood samples on filter paper to a central laboratory. An administrative definition was applied (two physician claims or one hospitalization for diabetes within a 2-year period) and compared with self-reported diabetes alone and with self-reported diabetes or elevated blood glucose level (>=7 mmol/L). Population level prevalence was estimated with the use of the administrative definition corrected for its sensitivity and specificity. RESULTS: Compared with self reported diabetes, sensitivity and specificity were 84.3% (95% CI 79.3-88.5%) and 97.9% (97.4-98.4%), respectively. Compared with diabetes by self-report and/or glucose testing, sensitivity was lower at 58.2% (52.2-64.6%), whereas specificity was similar at 98.7% (98.0-99.3%). Adjusted for sampling weights, population level prevalence of physician-diagnosed diabetes was 7.2% (6.3-8.0%). Prevalence of total diabetes (physician-diagnosed and undiagnosed) was 13.4% (11.7-15.0%), indicating that ~40% of diabetes cases are undiagnosed. CONCLUSIONS: A substantial proportion of diabetes cases are missed by surveillance methods that use health administrative databases. This finding is concerning because individuals with undiagnosed diabetes are likely to have a delay in treatment and, thus, a higher risk for diabetes-related complications. PMID- 23656983 TI - Management of hypophosphataemia. PMID- 23656984 TI - An introduction to anaesthesia. PMID- 23656985 TI - Deep vein thrombosis in children. PMID- 23656986 TI - Acne vulgaris. PMID- 23656987 TI - Enhanced efficiency of dye-sensitized solar cells doped with green phosphors LaPO4:Ce, Tb or (Mg, Zn)Al11O19:Eu. AB - We have successfully introduced green phosphors LaPO4:Ce, Tb (G4) or (Mg, Zn)Al11O19:Eu (G2) into TiO2 photoelectrode of dye-sensitized solar cells. The conversion efficiency of the G4-doped device was enhanced by 30% compared with the pristine TiO2 photoelectrode. The green phosphor doped at 5-wt.% ratio contributed to the reduction of resistances of the surface and interface of the photoelectrode and to the great enhancement of the absorption spectrum in UV visible and near-infrared regions. The internal resistances and absorbance of the photoelectrode directly affect the power conversion efficiency. Green phosphor plays an important role towards the realization of high-efficiency dye-sensitized solar cells. PMID- 23656988 TI - Consensus recommendations on pathologic changes in the hippocampus: a postmortem multicenter inter-rater study. AB - There is no consensus on the pathologic conditions or severity implied by the term "hippocampal sclerosis" (HS). In this study, a panel of experienced neuropathologists evaluated inter-rater agreement for pathologic diagnoses in the hippocampus and proposes consensus recommendations on the use of the term "HS." In a group of 251 cases of HS selected from a large autopsy cohort (1,388; 18%), a coordinating group identified 5 patterns of degenerative or vascular pathology. Four independent neuropathologists assessed a single set of hematoxylin and eosin stained sections following descriptive definitions to classify the appearances and assign the diagnosis of HS, if appropriate. Diagnostic agreement (range, 36% 70%) was highest for vascular lesions. Subsequent joint review of all cases highlighted the need to identify neurodegenerative lesions using immunohistochemistry. Initial agreement in assigning the diagnosis of HS varied from 0% to 86%. After a joint review, the group recommended that the term "HS" should be applied to all cases with complete/near-complete neuronal loss and gliosis in the subfields of the cornu Ammonis but not to hippocampal microinfarction. Therefore, the etiology of HS must be defined in association with a neurodegenerative process or as "lacking neurodegenerative markers," a pathologic condition presumed to arise from hypoxic/ischemic mechanisms. PMID- 23656989 TI - Differential relationships of reactive astrocytes and microglia to fibrillar amyloid deposits in Alzheimer disease. AB - Although it is clear that astrocytes and microglia cluster around dense-core amyloid plaques in Alzheimer disease (AD), whether they are primarily attracted to amyloid deposits or are just reacting to plaque-associated neuritic damage remains elusive. We postulate that astrocytes and microglia may differentially respond to fibrillar amyloid beta. Therefore, we quantified the size distribution of dense-core thioflavin-S (ThioS)-positive plaques in the temporal neocortex of 40 AD patients and the microglial and astrocyte responses in their vicinity (<=50 MUm) and performed correlations between both measures. As expected, both astrocytes and microglia were clearly spatially associated with ThioS-positive plaques (p = 0.0001, <=50 MUm vs. >50 MUm from their edge), but their relationship to ThioS-positive plaque size differed: larger ThioS-positive plaques were associated with more surrounding activated microglia (p = 0.0026), but this effect was not observed with reactive astrocytes. Microglial response to dense-core plaques seems to be proportional to their size, which we postulate reflects a chemotactic effect of amyloid beta. By contrast, plaque-associated astrocytic response does not correlate with plaque size and seems to parallel the behavior of plaque-associated neuritic damage. PMID- 23656990 TI - Distinct underlying mechanisms of limb and respiratory muscle fiber weaknesses in nemaline myopathy. AB - Nemaline myopathy is the most common congenital myopathy and is caused by mutations in various genes such as ACTA1 (encoding skeletal alpha-actin). It is associated with limb and respiratory muscle weakness. Despite increasing clinical and scientific interest, the molecular and cellular events leading to such weakness remain unknown, which prevents the development of specific therapeutic interventions. To unravel the potential mechanisms involved, we dissected lower limb and diaphragm muscles from a knock-in mouse model of severe nemaline myopathy expressing the ACTA1 His40Tyr actin mutation found in human patients. We then studied a broad range of structural and functional characteristics assessing single-myofiber contraction, protein expression, and electron microscopy. One of the major findings in the diaphragm was the presence of numerous noncontractile areas (including disrupted sarcomeric structures and nemaline bodies). This greatly reduced the number of functional sarcomeres, decreased the force generation capacity at the muscle fiber level, and likely would contribute to respiratory weakness. In limb muscle, by contrast, there were fewer noncontractile areas and they did not seem to have a major role in the pathogenesis of weakness. These divergent muscle-specific results provide new important insights into the pathophysiology of severe nemaline myopathy and crucial information for future development of therapeutic strategies. PMID- 23656991 TI - FBXO7 immunoreactivity in alpha-synuclein-containing inclusions in Parkinson disease and multiple system atrophy. AB - Mutations in the gene encoding the F-box only protein 7 (FBXO7) cause PARK15, an autosomal recessive form of juvenile parkinsonism. Although the brain pathology in PARK15 patients remains unexplored, in vivo imaging displays severe loss of nigrostriatal dopaminergic terminals. Understanding the pathogenesis of PARK15 might therefore illuminate the mechanisms of the selective dopaminergic neuronal degeneration, which could also be important for understanding idiopathic Parkinson disease (PD). The expression of FBXO7 in the human brain remains poorly characterized, and its expression in idiopathic PD and different neurodegenerative diseases has not been investigated. Here, we studied FBXO7 protein expression in brain samples of normal controls (n = 9) and from patients with PD (n = 13), multiple system atrophy (MSA) (n = 5), Alzheimer disease (AD) (n = 5), and progressive supranuclear palsy (PSP) (n = 5) using immunohistochemistry with 2 anti-FBXO7 antibodies. We detected widespread brain FBXO7 immunoreactivity, with the highest levels in neurons of the cerebral cortex, putamen, and cerebellum. There were no major differences between normal and PD brains overall, but FBXO7 immunoreactivity was detected in large proportions of alpha-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions), where it colocalized with alpha-synuclein in PD and MSA cases. By contrast, weak FBXO7 immunoreactivity was occasionally detected in tau-positive inclusions in AD and PSP. These findings suggest a role for FBXO7 in the pathogenesis of the synucleinopathies. PMID- 23656992 TI - Mediation of protection and recovery from experimental autoimmune encephalomyelitis by macrophages expressing the human voltage-gated sodium channel NaV1.5. AB - Multiple sclerosis (MS) is the most common nontraumatic cause of neurologic disability in young adults. Despite treatment, progressive tissue injury leads to accumulation of disability in many patients. Here, our goal was to develop an immune-mediated strategy to promote tissue repair and clinical recovery in an MS animal model. We previously demonstrated that a variant of the voltage-gated sodium channel NaV1.5 is expressed intracellularly in human macrophages, and that it regulates cellular signaling. This channel is not expressed in mouse macrophages, which has limited the study of its functions. To overcome this obstacle, we developed a novel transgenic mouse model (C57BL6), in which the human macrophage NaV1.5 splice variant is expressed in vivo in mouse macrophages. These mice were protected from experimental autoimmune encephalomyelitis, the mouse model of MS. During active inflammatory disease, NaV1.5-positive macrophages were found in spinal cord lesions where they formed phagocytic cell clusters; they expressed markers of alternative activation during recovery. NaV1.5-positive macrophages that were adoptively transferred into wild-type recipients with established experimental autoimmune encephalomyelitis homed to lesions and promoted recovery. These results suggest that NaV1.5-positive macrophages enhance recovery from CNS inflammatory disease and could potentially be developed as a cell-based therapy for the treatment of MS. PMID- 23656994 TI - Functional genomics reveals dysregulation of cortical olfactory receptors in Parkinson disease: novel putative chemoreceptors in the human brain. AB - Parkinson disease (PD) is no longer considered a complex motor disorder but rather a systemic disease with variable nonmotor deficits that may include impaired olfaction, depression, mood and sleep disorders, and altered cortical function. Increasing evidence indicates that multiple metabolic defects occur in regions outside the substantia nigra, including the cerebral cortex, even at premotor stages of the disease. We investigated changes in gene expression in the frontal cortex in PD patient brains using a transcriptomics approach. Functional genomics analysis indicated that cortical olfactory receptors (ORs) and taste receptors (TASRs) are altered in PD patients. Olfactory receptors OR2L13, OR1E1, OR2J3, OR52L1, and OR11H1 and taste receptors TAS2R5 and TAS2R50 were downregulated, but TAS2R10 and TAS2R13 were upregulated at premotor and parkinsonian stages in the frontal cortex area 8 in PD patient brains. Furthermore, we present novel evidence that, in addition to the ORs, obligate downstream components of OR function adenylyl cyclase 3 and olfactory G protein (Galphaolf), OR transporters, receptor transporter proteins 1 and 2 and receptor expression enhancing protein 1, and OR xenobiotic removing UDP glucuronosyltransferase 1 family polypeptide A6 are widely expressed in neurons of the cerebral cortex and other regions of the adult human brain. Together, these findings support the concept that ORs and TASRs in the cerebral cortex may have novel physiologic functions that are affected in PD patients. PMID- 23656993 TI - Disconnection of the ascending arousal system in traumatic coma. AB - Traumatic coma is associated with disruption of axonal pathways throughout the brain, but the specific pathways involved in humans are incompletely understood. In this study, we used high angular resolution diffusion imaging to map the connectivity of axonal pathways that mediate the 2 critical components of consciousness-arousal and awareness-in the postmortem brain of a 62-year-old woman with acute traumatic coma and in 2 control brains. High angular resolution diffusion imaging tractography guided tissue sampling in the neuropathologic analysis. High angular resolution diffusion imaging tractography demonstrated complete disruption of white matter pathways connecting brainstem arousal nuclei to the basal forebrain and thalamic intralaminar and reticular nuclei. In contrast, hemispheric arousal pathways connecting the thalamus and basal forebrain to the cerebral cortex were only partially disrupted, as were the cortical "awareness pathways." Neuropathologic examination, which used beta amyloid precursor protein and fractin immunomarkers, revealed axonal injury in the white matter of the brainstem and cerebral hemispheres that corresponded to sites of high angular resolution diffusion imaging tract disruption. Axonal injury was also present within the gray matter of the hypothalamus, thalamus, basal forebrain, and cerebral cortex. We propose that traumatic coma may be a subcortical disconnection syndrome related to the disconnection of specific brainstem arousal nuclei from the thalamus and basal forebrain. PMID- 23656997 TI - Single-nucleotide polymorphisms in adiponectin, AdipoR1, and AdipoR2 genes: insulin resistance and type 2 diabetes mellitus candidate genes. AB - It has already been a decade and a half since the discovery of adiponectin and its role as an insulin sensitizer and only 7 years since its receptors, AdipoR1 and AdipoR2, were described. A single-nucleotide polymorphism (SNP) is a DNA sequence variation that affects only one nucleotide; it may vary from one population to another with different predisposing factors to diseases and other ailments. Once some of the effects of adiponectin and its receptors were known, it was not long until an effort was made to find the associations between specific SNPs of the genes of this hormone and its receptors as genetic risk factors for insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, although these genes were investigated as possible candidates related to the development of these metabolic disorders. All of these possible associations were studied in different populations from France, Finland, the United Kingdom, North America, and Japan, showing hardly concluding results, and because of that it is highly controversial to directly associate one of the genes mentioned above to insulin resistance, type 2 diabetes mellitus, and metabolic syndrome. All of these inconsistencies lead to a review that summarizes the SNPs of the genes of adiponectin, AdipoR1, and AdipoR2 that are mostly related to insulin resistance syndrome, type 2 diabetes mellitus, and metabolic syndrome, although presenting the possible factors that should be taken into account to homogenize the results obtained until now. PMID- 23656998 TI - Differentiating stage I epithelial ovarian cancer from benign disease in women with adnexal tumors using biomarkers or the ROMA algorithm. PMID- 23656999 TI - Retrospective review of the use and costs of routine chest x rays in a trauma setting. AB - INTRODUCTION: Chest x-rays (CXR) are routinely obtained on blunt trauma patients. Many patients also receive additional imaging with thoracic computed tomography scans for other indications. We hypothesized that in hemodynamically normal, awake and alert blunt trauma patients, CXR can be deferred in those who will also receive a TCT with significant cost savings. METHODS: We retrospectively reviewed the charts of trauma patients from 1/1/2010 to 12/31/2010 who received both a CXR and TCT in the trauma room. Billing and cost data were collected from various hospital sources. RESULTS: 239 patients who met inclusion and exclusion criteria and received CXR and TCT between 1/1/2010 and 12/31/2010. The sensitivity of CXR was 19% (95% CI: 10.8% to 31%) and the specificity was 91.7% (95% CI: 86.7% to 95%). The false positive rate for CXR was 35.8% (95% CI: 21.7% to 52.8%) and the false negative rate was 24.5% (95% CI: 18.8% to 31.2%). The precision of CXR was 42.3% (95% CI: 25.5% to 61.1%) and the overall accuracy was 74.1% (95% CI: 68.1% to 79.2%). If routine chest xray were eliminated in these patients, the estimated cost savings ranged from $14,641 to $142,185, using three different methods of cost analysis. CONCLUSIONS: In patients who are hemodynamically normal and who will be receiving a TCT, deferring a CXR would result in an estimated cost savings up to $142,185. Additionally, TCT is more sensitive and specific than CXR in identifying injuries in patients who have sustained blunt trauma to the thorax. PMID- 23657001 TI - Killer Treg cells ameliorate inflammatory insulitis in non-obese diabetic mice through local and systemic immunomodulation. AB - Treg cells endowed with enhanced killing activity through decoration with Fas ligand (FasL) protein (killer Treg) have been effective in delay of hyperglycemia in prediabetic non-obese diabetic (NOD) mice. In this study, we assessed the therapeutic efficacy of these cells, harvested from age-matched euglycemic NOD donors, on the course of disease in new-onset diabetics. One dose of 4 * 10(6) killer Treg cells stabilized blood glucose associated with increased insulin levels in 5 of 9 mice and partially reversed the severity of islet inflammation, whereas naive Treg cells did not modulate the course of disease significantly. Killer Treg cells were shown to operate through induction of cell apoptosis within the pancreatic lymph nodes, resulting in reduced efficiency of adoptive disease transfer to NOD/SCID recipients. A second mechanism of action consisted of increased fractions of CD4(+)CD25(-)FoxP3(+) T cells in the pancreas and all lymphoid organs. Immunomodulation with FasL rather than Treg cells enhanced the expression of CD25 and FoxP3 in the thymus, suggesting a possible contribution of thymic output to prolonged stabilization of the glucose levels. Autologous Treg cells evolve as excellent vehicles for targeted delivery of FasL as an immunomodulatory protein, which delete pathogenic cells at the site of inflammation and induce systemic dominance of suppressor subsets. PMID- 23657000 TI - IL-7 production in murine lymphatic endothelial cells and induction in the setting of peripheral lymphopenia. AB - IL-7 is a required factor for T-cell homeostasis. Because of low expression levels and poor reagent availability, the cellular sources of IL-7 have proven challenging to characterize. In this study, we describe a reporter mouse in which enhanced GFP is expressed from the endogenous Il7 locus. We show that IL-7 is produced by lymphatic endothelial cells (LECs) distributed throughout the systemic lymphatic vasculature as well as by fibroblastic reticular cells, and that phosphorylation of STAT5 in lymphocytes is higher in lymphatics than in blood. Furthermore, in nodes depleted of lymphocytes, Il7 transcription is increased in stromal but not in myeloid subsets. These data support recent findings that lymphocyte homeostasis is influenced by access to secondary lymphoid organs and point to LECs as an important in vivo source of IL-7, bathing trafficking immune cells under both resting and lymphopenic conditions. PMID- 23657004 TI - Residual tumour after vestibular schwannoma surgery. AB - OBJECTIVE: To evaluate residual tumour occurrence after vestibular schwannoma surgery, based on intra-operative registration and magnetic resonance imaging one year post-operatively. METHODS: Patients undergoing translabyrinthine surgery for vestibular schwannoma in Denmark between 1976 and 2008 were registered in a national database covering 5.5 million inhabitants. RESULTS: Translabyrinthine surgery was undertaken on 1143 patients. Of these, 978 had total, 140 near-total and 25 subtotal tumour excision, as assessed intra-operatively by the surgeon. One year after surgery, 65 per cent of small tumour remnants and 11 per cent of large tumour remnants were not visible on magnetic resonance imaging. The mean pre-operative size was significantly smaller for totally excised tumours, compared with near-totally and subtotally excised tumours. Revision surgery was performed for 14 patients (1.2 per cent), of whom 2 had received total, 5 near total and 6 subtotal excisions initially. CONCLUSION: Most residual tumours disappear spontaneously, probably due to devascularisation. Few patients with a small residual vestibular schwannoma will require revision surgery or secondary radiotherapy. PMID- 23657002 TI - Linking the microbiota and metabolic disease with lymphotoxin. AB - The field of lymphotoxin biology has seen many advances in the past decade. Notably, a role for lymphotoxin as a key effector cytokine has emerged to add to its foundational contribution to lymphoid organogenesis. It is now clear that lymphotoxin contributes to host defense for a wide variety of pathogens, and the lymphotoxin receptor is a defining feature of and regulatory mechanism in both innate and adaptive immunities. Specifically, lymphotoxin contributes to Th education, licensing of IL-22 production from type 3 innate lymphoid cells, and even maintains innate myeloid populations within the fully developed lymph node. Most recently, lymphotoxin has been implicated in regulation of the microbiota and metabolic disease. Early studies revealed that lymphotoxin might influence composition of the commensal microbiota through its regulation of immunological compartmentalization in the gut. Additionally, several epidemiological studies have linked polymorphisms in lymphotoxin to metabolic disease. Studies exploring the role of lymphotoxin in metabolic disease have demonstrated that lymphotoxin may influence metabolism both directly in the liver and indirectly through regulation of gut immune responses. It now appears that lymphotoxin may bridge the gap between altered composition of the commensal microbiota and metabolism. PMID- 23657003 TI - Liver-derived endocrine IGF-I is not critical for activation of skeletal muscle protein synthesis following oral feeding. AB - BACKGROUND: Insulin-like growth factor-1 (IGF-1) is produced in various tissues to stimulate protein synthesis under different conditions. It is however, difficult to distinguish effects by locally produced IGF-1 compared to liver derived IGF-1 appearing in the circulation. In the present study the role of liver-derived endocrine IGF-I for activation of skeletal muscle protein synthesis following feeding was evaluated. RESULTS: Transgenic female mice with selective knockout of the IGF-I gene in hepatocytes were freely fed, starved overnight and subsequently refed for 3 hours and compared to wild types (wt). Liver IGF-I knockout mice had 70% reduced plasma IGF-I. Starvation decreased and refeeding increased muscle protein synthesis (p < 0.01), similarly in both IGF-I knockouts and wt mice. Phosphorylation of p70s6k and mTOR increased and 4EBP1 bound to eIF4E decreased in both IGF-I knockouts and wt mice after refeeding (p < 0.05). Muscle transcripts of IGF-I decreased and IGF-I receptor increased (p < 0.01) in wild types during starvation but similar alterations did not reach significance in knockouts (p>0.05). mTOR mRNA increased in knockouts only during starvation. Plasma glucose decreased during starvation in all groups in parallel to insulin, while plasma IGF-I and GH did not change significantly among the groups during starvation-refeeding. Plasma amino acids declined and increased during starvation refeeding in wild type mice (p < 0.05), but less so in IGF-I (-/-) knockouts (p < 0.08). CONCLUSION: This study demonstrates that re-synthesis of muscle proteins following starvation is not critically dependent on endocrine liver-derived IGF I. PMID- 23657006 TI - Pediatric emergencies: preparing at triage using height and weight. AB - Obtaining an actual weight is critical to accurate medication dosing. Knowledge of length/height is critical to equipment sizing. Rapid and accurate measurement of both upon arrival at the emergency department increases patient safety and staff comfort in the case of a decompensating child requiring resuscitation. Having a process in place that works with the layout, medical record, and budget of the department increases safety for the patient and may improve outcomes, and if the process is led by staff champions, acceptance of the process may be faster. Regardless of the actual method, patient safety and staff satisfaction can be improved with a simple process that prepares for an emergency in pediatric care. PMID- 23657005 TI - Transglucosidase improves the gut microbiota profile of type 2 diabetes mellitus patients: a randomized double-blind, placebo-controlled study. AB - BACKGROUND: Recently, the relationship between gut microbiota and obesity has been highlighted. The present randomized, double-blind, placebo-controlled study aimed to evaluate the efficacy of transglucosidase (TGD) in modulating blood glucose levels and body weight gain in patients with type 2 diabetes mellitus (T2DM) and to clarify the underlying mechanism by analyzing the gut microbiota of T2DM patients. METHODS: This study included 60 patients who received placebo or TGD orally (300 or 900 mg/day) for 12 weeks, and blood and fecal samples were collected before and after 12 weeks. Comparisons of fecal bacterial communities were performed before and after the TGD treatment and were performed between T2DM patients and 10 healthy individuals, using the terminal-restriction fragment length polymorphism analysis. RESULTS: The Clostridium cluster IV and subcluster XIVa components were significantly decreased, whereas the Lactobacillales and Bifidobacterium populations significantly increased in the T2DM patients compared with the healthy individuals. By dendrogram analysis, most of the healthy individuals (6/10) and T2DM patients (45/60) were classified into cluster I, indicating no significant difference in fecal bacterial communities between the healthy individuals and the T2DM patients. In the placebo and TGD groups, the bacterial communities were generally similar before and after the treatment. However, after 12 weeks of TGD therapy, the Bacteroidetes-to-Firmicutes ratio in the TGD groups significantly increased and was significantly higher compared with that in the placebo group, indicating that TGD improved the growth of the fecal bacterial communities in the T2DM patients. CONCLUSIONS: Therefore, TGD treatment decreased blood glucose levels and prevented body weight gain in the T2DM patients by inducing the production of oligosaccharides in the alimentary tract and modulating gut microbiota composition. TRIAL REGISTRATION: UMIN-CTR UMIN000010318. PMID- 23657007 TI - Propofol for procedural sedation and analgesia reduced dedicated emergency nursing time while maintaining safety in a community emergency department. AB - INTRODUCTION: Procedural sedation and analgesia is a core competency in emergency medicine. Propofol is replacing midazolam in many emergency departments. Barriers to performing procedural sedation include resource utilization. We hypothesized that emergency nursing time is shorter with propofol than midazolam, without increasing complications. METHODS: Retrospective analysis of a procedural sedation registry for two community emergency departments with combined census of 100,000 patients/year. Demographics, procedure, and ASA physical classification status of adult patients receiving procedural sedation between 2007-2010 with midazolam or propofol were analyzed. Primary outcome was dedicated emergency nursing time. Secondary outcomes were procedural success, ED length of stay, and complication rate. Comparative statistics were performed with Mann-Whitney, Kruskal-Wallis, chi-square, or Fisher's exact test. Linear regression was performed with log-transformed procedural sedation time to define predictors. RESULTS: Of 328 procedural sedation and analgesia, 316 met inclusion criteria, of which 60 received midazolam and 256 propofol. Sex distribution varied between groups (midazolam 3% male; propofol 55% male; P = 0.04). Age, procedure, and ASA status were not significantly different. Propofol had shorter procedural sedation time (propofol 32.5 +/- 24.2 minutes; midazolam 78.7 +/- 51.5 minutes; P < 0.001) and higher rates of procedural success (propofol 98%; midazolam 92%; P = 0.02). There were no significant differences between complication rates (propofol 14%; midazolam 13%; P = 0.88) or emergency department length of stay (propofol 262.5 +/- 132.8 minutes; midazolam 288.6 +/- 130.6 minutes; P = 0.09). DISCUSSION: Use of propofol resulted in shorter emergency nursing time and higher procedural success rate than midazolam with a comparable safety profile. PMID- 23657008 TI - Application techniques for plaster of paris back slab, resting splint, and thumb spica using ridged reinforcement. AB - Immobilization of fractures with plaster of Paris is a mainstay of management of stable, nondisplaced fractures not requiring fixation. However, application techniques can be variable and are often ineffective after the patient is discharged because of weakness and wear of the plaster. This can lead to displacement of fractures and inadequate analgesia. We describe a simple, inexpensive, effective technique to ensure plaster strength and immobilization. PMID- 23657009 TI - Phosphorylation of the CENP-A amino-terminus in mitotic centromeric chromatin is required for kinetochore function. AB - The role of the mitotic phosphorylation of the amino (NH2) terminus of Centromere Protein A (CENP-A), the histone variant epigenetic centromeric marker, remains elusive. Here, we show that the NH2 terminus of human CENP-A is essential for mitotic progression and that localization of CENP-C, another key centromeric protein, requires only phosphorylation of the CENP-A NH2 terminus, and is independent of the CENP-A NH2 terminus length and amino acid sequence. Mitotic CENP-A nucleosomal complexes contain CENP-C and phosphobinding 14-3-3 proteins. In contrast, mitotic nucleosomal complexes carrying nonphosphorylatable CENP-A S7A contained only low levels of CENP-C and no detectable 14-3-3 proteins. Direct interactions between the phosphorylated form of CENP-A and 14-3-3 proteins as well as between 14-3-3 proteins and CENP-C were demonstrated. Taken together, our results reveal that 14-3-3 proteins could act as specific mitotic "bridges," linking phosphorylated CENP-A and CENP-C, which are necessary for the platform function of CENP-A centromeric chromatin in the assembly and maintenance of active kinetochores. PMID- 23657010 TI - The age-specific force of natural selection and biodemographic walls of death. AB - W. D. Hamilton's celebrated formula for the age-specific force of natural selection furnishes predictions for senescent mortality due to mutation accumulation, at the price of reliance on a linear approximation. Applying to Hamilton's setting the full nonlinear demographic model for mutation accumulation recently developed by Evans, Steinsaltz, and Wachter, we find surprising differences. Nonlinear interactions cause the collapse of Hamilton-style predictions in the most commonly studied case, refine predictions in other cases, and allow walls of death at ages before the end of reproduction. Haldane's principle for genetic load has an exact but unfamiliar generalization. PMID- 23657011 TI - Reciprocal regulation of PKA and Rac signaling. AB - Activated G protein-coupled receptors (GPCRs) and receptor tyrosine kinases relay extracellular signals through spatial and temporal controlled kinase and GTPase entities. These enzymes are coordinated by multifunctional scaffolding proteins for precise intracellular signal processing. The cAMP-dependent protein kinase A (PKA) is the prime example for compartmentalized signal transmission downstream of distinct GPCRs. A-kinase anchoring proteins tether PKA to specific intracellular sites to ensure precision and directionality of PKA phosphorylation events. Here, we show that the Rho-GTPase Rac contains A-kinase anchoring protein properties and forms a dynamic cellular protein complex with PKA. The formation of this transient core complex depends on binary interactions with PKA subunits, cAMP levels and cellular GTP-loading accounting for bidirectional consequences on PKA and Rac downstream signaling. We show that GTP-Rac stabilizes the inactive PKA holoenzyme. However, beta-adrenergic receptor-mediated activation of GTP-Rac bound PKA routes signals to the Raf-Mek-Erk cascade, which is critically implicated in cell proliferation. We describe a further mechanism of how cAMP enhances nuclear Erk1/2 signaling: It emanates from transphosphorylation of p21 activated kinases in their evolutionary conserved kinase-activation loop through GTP-Rac compartmentalized PKA activities. Sole transphosphorylation of p21 activated kinases is not sufficient to activate Erk1/2. It requires complex formation of both kinases with GTP-Rac1 to unleash cAMP-PKA-boosted activation of Raf-Mek-Erk. Consequently GTP-Rac functions as a dual kinase-tuning scaffold that favors the PKA holoenzyme and contributes to potentiate Erk1/2 signaling. Our findings offer additional mechanistic insights how beta-adrenergic receptor controlled PKA activities enhance GTP-Rac-mediated activation of nuclear Erk1/2 signaling. PMID- 23657013 TI - Caution needed when linking weather extremes to amplified planetary waves. PMID- 23657012 TI - Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer. AB - Germ-line mutations in PALB2 lead to a familial predisposition to breast and pancreatic cancer or to Fanconi Anemia subtype N. PALB2 performs its tumor suppressor role, at least in part, by supporting homologous recombination-type double strand break repair (HR-DSBR) through physical interactions with BRCA1, BRCA2, and RAD51. To further understand the mechanisms underlying PALB2-mediated DNA repair and tumor suppression functions, we targeted Palb2 in the mouse. Palb2 deficient murine ES cells recapitulated DNA damage defects caused by PALB2 depletion in human cells, and germ-line deletion of Palb2 led to early embryonic lethality. Somatic deletion of Palb2 driven by K14-Cre led to mammary tumor formation with long latency. Codeletion of both Palb2 and Tumor protein 53 (Trp53) accelerated mammary tumor formation. Like BRCA1 and BRCA2 mutant breast cancers, these tumors were defective in RAD51 focus formation, reflecting a defect in Palb2 HR-DSBR function, a strongly suspected contributor to Brca1, Brca2, and Palb2 mammary tumor development. However, unlike the case of Brca1 mutant cells, Trp53bp1 deletion failed to rescue the genomic instability of Palb2 or Brca2-mutant primary lymphocytes. Therefore, Palb2-driven DNA damage control is, in part, distinct from that executed by Brca1 and more similar to that of Brca2. The mechanisms underlying Palb2 mammary tumor suppression functions can now be explored genetically in vivo. PMID- 23657014 TI - Selective enrichment of two different types of Nitrospira-like nitrite-oxidizing bacteria from a wastewater treatment plant. AB - Nitrification is an important step in nitrogen removal in biological wastewater treatment processes. Recently, Nitrospira have been recognized as the numerically dominant nitrite-oxidizing bacterial genus primarily responsible for the second step of aerobic nitrification; however, Nitrospira usually resist cultivation under laboratory conditions and only one species enriched from activated sludge has been described. In this study, a novel enrichment method for Nitrospira was successfully developed using continuous feeding bioreactors. By controlling nitrite concentrations strictly in the bioreactor at low levels below 10 mg-N L( 1), coexisting members of sublineages I and II of the genus Nitrospira were enriched selectively. The maximum ratios of sublineages I and II to total microbial cells achieved 88.3% and 53.8%, respectively. This enrichment method is potentially applicable to other uncultured Nitrospira. PMID- 23657016 TI - Resistive switching memory characteristics of Ge/GeOx nanowires and evidence of oxygen ion migration. AB - The resistive switching memory of Ge nanowires (NWs) in an IrOx/Al2O3/Ge NWs/SiO2/p-Si structure is investigated. Ge NWs with an average diameter of approximately 100 nm are grown by the vapor-liquid-solid technique. The core shell structure of the Ge/GeOx NWs is confirmed by both scanning electron microscopy and high-resolution transmission electron microscopy. Defects in the Ge/GeOx NWs are observed by X-ray photoelectron spectroscopy. Broad photoluminescence spectra from 10 to 300 K are observed because of defects in the Ge/GeOx NWs, which are also useful for nanoscale resistive switching memory. The resistive switching mechanism in an IrOx/GeOx/W structure involves migration of oxygen ions under external bias, which is also confirmed by real-time observation of the surface of the device. The porous IrOx top electrode readily allows the evolved O2 gas to escape from the device. The annealed device has a low operating voltage (<4 V), low RESET current (approximately 22 MUA), large resistance ratio (>103), long pulse read endurance of >105 cycles, and good data retention of >104 s. Its performance is better than that of the as-deposited device because the GeOx film in the annealed device contains more oxygen vacancies. Under SET operation, Ge/GeOx nanofilaments (or NWs) form in the GeOx film. The diameter of the conducting nanofilament is approximately 40 nm, which is calculated using a new method. PMID- 23657019 TI - Anaemia in congestive heart failure. PMID- 23657020 TI - Cardiac transplantation: who to refer and when. PMID- 23657021 TI - Cardiac resynchronization therapy. PMID- 23657022 TI - How to appraise a qualitative study. PMID- 23657023 TI - Systemic disease involvement of the hand: manifestations on plain radiograph. PMID- 23657024 TI - The future of surgical training. PMID- 23657025 TI - Quality improvement in low resource settings: an Ethiopian experience. AB - Improving surgical and anaesthetic mortality in the developing world is a global health priority. Quality improvement processes have a role to play in addressing this need and are applicable to low-resource settings despite difficulties in their implementation. International initiatives to reduce perioperative mortality can be focussed to support interventions at the level of individual departments, but this requires integration with existing local systems and an understanding of the specific needs of the institutions concerned. There is a small but growing evidence base for quality improvement in low resource settings, but this needs to be locally accessible to allow self-sustaining evidence-based quality improvement. PMID- 23657026 TI - Just Lucas-Championniere: pioneer of antiseptic surgery in France. PMID- 23657027 TI - Aortic dissection: an unusual presentation. PMID- 23657028 TI - Progressive periodic hypothermia and bradycardia. PMID- 23657030 TI - When is a heart attack not a heart attack? PMID- 23657031 TI - Francis report: the focus should be patients not policies. PMID- 23657033 TI - Long-term opioids: friend or foe? PMID- 23657034 TI - Assessment of item-writing flaws in multiple-choice questions. AB - This study evaluated the quality of multiple-choice questions used in a hospital's e-learning system. Constructing well-written questions is fraught with difficulty, and item-writing flaws are common. Study results revealed that most items contained flaws and were written at the knowledge/comprehension level. Few items had linked objectives, and no association was found between the presence of objectives and flaws. Recommendations include education for writing test questions. PMID- 23657035 TI - Rural hospital web-based, evidence-based practice professional development: challenges and opportunities. AB - To provide quality patient care and achieve positive patient outcomes, it is widely recognized that organizations must develop a supportive environment that encourages individuals to practice from a research- and evidence-based framework. This article describes a Web-based professional educational program designed to teach principles of evidence-based practice to nurses in rural hospitals. Nurses working in staff development will find this useful for designing educational programs for staff in rural hospitals. PMID- 23657036 TI - Traffic control: nursing practice calendar. AB - Educating nurses on the multitude of new and updated best practices, changes in regulatory standards, new equipment, and enhanced technology creates an "information traffic jam." Multiple practice changes occurring simultaneously pose challenges for nurses to retain information to practice safely and effectively. An absence of coordination between various nursing and allied health teaching initiatives compounds this problem. A nursing practice calendar was developed to facilitate the prioritization, communication, and education of hospital-wide initiatives affecting nursing practice. PMID- 23657037 TI - The effects of restorative care training on caregiver job satisfaction. AB - The job satisfaction of assisted living facility staff was examined as part of an evaluation study of a restorative care training program. Participants completed a job satisfaction survey at registration (before the training) and again at follow up 3 months after registration (1 month after the conclusion of the training). Researchers examined the effects of training on job satisfaction. Researchers found a high level of job dissatisfaction at registration. At follow-up, responses were more positive on most of the items suggesting a slight but significant change to a more positive attitude toward their jobs. Improving staff job satisfaction in the assisted living environment is an important goal and needs further investigation. Providing staff with inservice training may be one way to help nurse educators achieve that goal. PMID- 23657038 TI - Developing a nurse residency program curricular framework. AB - Curricular frameworks are integral to educational programs and are viewed as the roadmaps of curriculum. This article describes the importance of curricular frameworks and the creation of an evidence-based curricular framework for a pediatric nurse residency program that had been in place for several years before framework development. The concepts of the framework include leadership, professional socialization, clinical reasoning, and technical skills. This article presents an evidence-based approach to build a curricular framework for a nurse residency program. PMID- 23657039 TI - Inpatient insulin pump therapy: assessing the effectiveness of an educational program. AB - Technological advances in diabetes management include continuous subcutaneous insulin infusion. This article describes a pilot project using an educational intervention by a diabetes nurse educator aimed at familiarizing nurses with insulin pump therapy at a large teaching hospital. Teaching points included appropriate patient selection, principles of insulin therapy, and safe insulin pump operation. An embedded mixed-method design was employed to assess educational effectiveness. Results of the pretest and posttest analysis indicated that the program significantly increased knowledge and confidence among nurses for managing pump therapy. PMID- 23657040 TI - Nurse residency programs: a critical part of the future of nursing, part 1. PMID- 23657041 TI - Tracking evidence-based projects. PMID- 23657042 TI - Macrostomia: a spectrum of deformity. AB - BACKGROUND: Macrostomia is a rare facial cleft, with an incompletely described pathogenesis. This series highlights cases of isolated macrostomia presenting with several distinct phenotypes. We examine phenotypic differences in macrostomia patients, to further elucidate the etiopathogenesis. MATERIALS AND METHODS: We performed a retrospective review of macrostomia patients evaluated during a 10-year period. Patient demographics and clinical features are reported. RESULTS: We identified 25 macrostomia patients (13M/12F). Right-sided macrostomia occurred in 15, left-sided macrostomia occurred in 6, and bilateral macrostomia occurred in 4 patients. Of the bilateral cases, 100% existed in isolation of craniofacial microsomia (CFM) or other craniofacial abnormalities. Twelve patients presented with macrostomia in isolation of CFM; in this subgroup, the male-to-female ratio was 1:1. Bilateral macrostomia was present in 33% of patients. Unilateral macrostomia occurred more often on the right (5:2). Phenotypes included simple unilateral or bilateral macrostomia (67%), macrostomia associated with severe diastasis of the cheek musculature (8%), macrostomia associated with lateral facial clefts (17%), and diastasis of cheek musculature without significant macrostomia (8%). CONCLUSIONS: Macrostomia seen in isolation of CFM presents in phenotypically distinct forms. It is unlikely that a single mechanism is responsible for this range of phenotypes. We believe that both intrauterine trauma and failure of fusion of the mandibular and maxillary processes secondary to an aberration in FGF8 function are responsible. Additionally, diastasis of facial musculature may result from delayed fusion and subsequent decreased mesodermal penetration of the mandibular and maxillary processes. PMID- 23657043 TI - Color Doppler imaging of an ulnar artery perforator forearm flap for resurfacing finger defects. AB - BACKGROUND: Fingertip defect reconstruction with various free perforator flaps has been widely reported. We recommend a technique of using color Doppler imaging to locate ulnar artery perforator. And we used a free mesioforearm flap based on ulnar artery perforator for the reconstruction of fingertip defect. PATIENTS AND METHODS: Since 2010, 7 fingertip defect cases have been repaired at our hospital using free mesioforearm flaps, based on the ulnar artery perforator. The free flap was designed according to Doppler detection. The flap contained perforator vessels and cutaneous nerves. The donor site was directly sutured or skin grafted. RESULTS: All 7 flaps survived with good quality and esthetic contours and grasp function of the hand was satisfactory. They were evaluated by 2-point discrimination, with 5 cases with neurorrhaphy of 6 to 8 mm and 2 cases without neurorrhaphy of 10 to 12 mm. CONCLUSIONS: Ultrasound is a suitable method for preoperatively locating the vascular pedicle. The free mesioforearm flap based on ulnar artery perforator is a good option to repair fingertip defect. PMID- 23657044 TI - The postauricular fascia: classification, anatomy, and potential surgical applications. AB - In recent times, there has been evolving interest in the fascial structure of the ear, especially in relation to otoplasty techniques. Although the fascial tissues used in these procedures are referred to as "postauricular/retroauricular fascia," the sparse anatomical studies that exist use this terminology to describe what is the adjacent thicker and more fibrous structure of the superficial temporal area continuous with the mastoid region, rather than the tissue actually used in these procedures which is adherent to the posterior surface of the ear. There are clear clinical differences in the properties of these two structures, and this study set out to identify the anatomical nature of these differences, looking in detail at the anatomy and vascularity of the fascia directly posterior and adherent to the ear itself, highlighting its unique properties, and how it interfaces with the rest of the fascia. We provide a nomenclature to differentiate the fascia adherent to the posterior of the ear (the intrinsic postauricular fascia) from the more fibrous tissues continuous with the scalp fascia (the extrinsic postauricular fascia). Clinical applications for the fascia are suggested based on the vascularity and anatomy described, and our clinical experience. PMID- 23657045 TI - Adjuvant radiation therapy increases disease-free survival in stage IB Merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. Adjuvant radiation increases survival in advanced stages, but efficacy in stage I disease is unknown. A retrospective review included all patients treated for stage I MCC during a 15-year period at Vanderbilt University Medical Center. Among 42 patients, 26 (62%) had a negative sentinel lymph node biopsy (stage IA) and 16 (38%) had clinically negative lymph nodes (stage IB) at the time of resection. Analysis using Cox regression revealed that higher stage and absence of adjuvant radiation are associated with increased disease recurrence (hazard ratio, 6.29; P=0.003 and hazard ratio, 4.69; P=0.013, respectively). Controlling for stage, radiation therapy significantly increased disease-free survival among patients with stage IB disease (P=0.0026) in a log-rank test comparing Kaplan Meier curves. These findings support adjuvant radiation therapy in stage IB MCC patients with clinically negative lymph nodes who do not undergo sentinel lymph node biopsy. PMID- 23657046 TI - BMP-2-regenerated calvarial bone: a biomechanical appraisal in a large animal model. AB - Recombinant human bone morphogenetic protein-2 (rhBMP-2) is gaining popularity in craniofacial applications. Calvarial defects are, under normal circumstances, subjected to only minimal levels of the biomechanical stresses known to play an important role in osteogenesis, yet regenerated calvarial bone must be capable of withstanding traumatic forces such that the underlying neurocapsule is protected. The aim of this study is to, for the first time, assess the biomechanical properties of calvarial bone regenerated with derivations of a commercially available rhBMP-2-based system. Standardized calvarial defects were created in 23 adult male canines. These defects were treated with rhBMP-2 on one of several carriers. After 24 weeks, the biomechanical properties of the rhBMP-2-generated bone were compared to those of controls with a modified punch-out test (Bluehill 2; Instron, Norwood, Mass) and compared using a paired nonparametric analyses (SPSS, 17.0, Chicago, Ill). In a previously published report, defects across all the rhBMP-2 therapy groups were observed to have a mean rate of 99.5% radio opacity at 24 weeks indicating nearly full bony coverage of the calvarial defect (compared to 32.7% in surgical controls). For ultimate load, ultimate energy, and first peak energy, there were significant differences (P<0.05) with the control native bone having more robust biomechanical properties than the rhBMP-2 generated bone. We conclude from these findings that rhBMP-2-generated calvarial bone is significantly less protective against trauma than native bone at 6 months. Further investigation is required to assess the efficacy of rhBMP-2 in healing calvarial defects in the longer term. PMID- 23657047 TI - Desmoid tumor of the hand: a case report. AB - SUMMARY: Extra-abdominal desmoid tumors are extremely rare in the hand. These tumors do not metastasize; however, they are potentially locally invasive and have extremely high local recurrence rates after surgical excision with reports of up to 78% recurrence, specifically in the hand. We describe the first case of a desmoid tumor originating from the extensor mechanism of a digit and discuss our treatment approach. In addition, a literature review performed shows a male predominance of desmoid tumors in the hand in the 30- to 50-year-old age group. Current evidence supports aggressive early wide surgical excision and reconstruction to preserve function. PMID- 23657048 TI - Are auricular keloids and persistent hypertrophic scars resectable? The role of intrascar excision. PMID- 23657049 TI - The split radial forearm flap for lower leg defects. AB - The conventional free radial forearm flap is a very reliable, long-pedicled flap with thin, pliable skin. These properties make it an excellent choice for high risk reconstructions or defects requiring only a thin cover. The split radial forearm flap allows primary closure of the donor site and has a large variability in shape and size. In this report, the cutaneous perforators of the radial artery were investigated in fresh cadavers and we present our clinical experience with the split radial artery flap in 9 patients with lower leg defects. Sufficient perforators exist to safely divide the flap proximally and distally into segments. In all clinical cases, the donor site could be closed primarily. All flaps remained viable and 8 of 9 patients obtained an esthetically pleasing result. The split radial forearm free flap is an elegant option for reconstruction of small- to moderate-sized soft tissue defects in the lower extremity. PMID- 23657050 TI - Surgical treatment of multiple symmetric lipomatosis with ultrasound-assisted liposuction. AB - Multiple symmetric lipomatosis (MSL) is a rare disease of unknown etiology, characterized by the presence of multiple, symmetrical, noncapsulated lipomas, mostly in the neck and upper trunk. To date, there is no effective medical treatment of MSL. Surgical treatment is based on 2 options, namely, lipectomy and/or liposuction. In this retrospective study, we compare traditional lipectomy with ultrasound-assisted liposuction. Our initial experience demonstrates that the ultrasound-assisted liposuction procedure can be applied to patients with MSL, allowing simultaneous treatment of multiple areas in a single session and the removal of a substantial amount of fat, thus improving aesthetic results. If lipomas are circumscribed and isolated, traditional lipectomy is probably to be preferred. PMID- 23657051 TI - A role of university surgical societies in improving medical student exposure to plastic and reconstructive surgery: a UK perspective. PMID- 23657052 TI - KRAS mutational status in Japanese patients with colorectal cancer: results from a nationwide, multicenter, cross-sectional study. AB - OBJECTIVE: KRAS gene mutations are a useful predictive factor for the efficacy of anti-epidermal growth factor receptor therapeutics. Since there were no large scale studies among Asian populations, we designed an observational nationwide study in Japan. METHODS: Formalin-fixed paraffin-embedded tissue blocks or sections from primary or metastatic lesions were obtained from patients registered between 2009 and 2010 for genomic DNA extraction. KRAS gene was analyzed by direct sequencing or Luminex assay. The primary endpoint was the frequency of KRAS gene mutations and the secondary endpoints were differences in KRAS mutation rates by various stratification factors. Univariate and multivariate analyses were performed to investigate relationships between KRAS mutation rates and patient background factors. RESULTS: We analyzed 5790 eligible samples out of 5887 registered. The overall KRAS mutation rate was 37.6%, with 29.9% in codon 12 and 7.7% in codon 13, and wild type was 62.4%. A significant relationship with the KRAS mutation rate was found for gender, age, the year that the sample was prepared and the site of the primary lesion. CONCLUSION: The KRAS mutation rate of Japanese colorectal cancer patients was 37.6%. Gender, age, the site of the primary lesion and the year that the sample was prepared were independent risk factors for KRAS mutations. PMID- 23657053 TI - Novel real-time polymerase chain reactions for serogroup specific gene detection of Neisseria meningitidis serogroups B, C, W-135 and Y. AB - Novel real-time TaqMan primers and probes were developed to detect the serogroup specific genes of Neisseria meningitidis serogroups B, C, W-135 and Y. These assays were rapid, sensitive, and specific when extensively validated. PMID- 23657054 TI - Two years' performance of an in-house ELISA for diagnosis of Legionnaires' disease: detection of specific IgM and IgG antibodies against Legionella pneumophila serogroup 1, 3 and 6 in human serum. AB - The aim of this study was to evaluate the performance of an in-house ELISA for the diagnosis of Legionnaires' disease (LD) by detection of IgM and IgG antibodies against Legionella (L.) pneumophila serogroups (sg) 1, 3 and 6. The evaluation was done throughout a two-year period in a diagnostic routine laboratory. Furthermore, the sensitivity of four different methods, the in-house L. pneumophila antibody test (ELISA), the urinary antigen test (Binax(r) EIA), an in-house PCR and culture, both alone and in combination was evaluated. From 2008 to 2010, 12,158 serum samples from 10,503 patients were analysed. During the same period, 361 cases of laboratory-confirmed LD cases were recorded in Denmark, but of these only 113 had a serum sample examined. The positive predictive value of the in-house ELISA was calculated to be 12.8 and the negative predictive value was 99.6, using only the confirmed LD cases as true positives. The sensitivity of the in-house ELISA for the detection of IgM and IgG antibodies in the confirmed LD cases was 61% and 36%, respectively. By combining the two ELISA assays the sensitivity increased to 66%. The sensitivity of the Legionella urinary antigen test (Binax(r) EIA) was 63%, of the in-house PCR 87% and of culture 69%. When all the different methods were combined, a higher sensitivity was calculated--for in house ELISA (IgM+IgG) and Binax(r) EIA 91%, in-house ELISA (IgM+IgG) and in-house PCR 93%, in-house ELISA (IgM+IgG) and culture 93%, Binax(r) EIA and in-house PCR 79%, Binax(r) EIA and culture 68% and in-house PCR and culture 94%. This study confirms that the detection of IgG and IgM antibodies by ELISA is an important diagnostic tool, also during the initial phase of the disease. Furthermore, we showed that LD in Denmark with or without serum samples collected exhibits the same age and sex distribution and epidemiology, as in the rest of Europe, i.e., mostly men are infected, infections are mostly community acquired, followed by infection from travelling abroad. Apart from patients with notified LD, the patients investigated by serology were evenly distributed in all age groups; there was only a slightly higher ratio of men tested for "atypical pneumonia" in the serology laboratory. PMID- 23657055 TI - Structure and regulation of the cellulose degradome in Clostridium cellulolyticum. AB - BACKGROUND: Many bacteria efficiently degrade lignocellulose yet the underpinning genome-wide metabolic and regulatory networks remain elusive. Here we revealed the "cellulose degradome" for the model mesophilic cellulolytic bacterium Clostridium cellulolyticum ATCC 35319, via an integrated analysis of its complete genome, its transcriptomes under glucose, xylose, cellobiose, cellulose, xylan or corn stover and its extracellular proteomes under glucose, cellobiose or cellulose. RESULTS: Proteins for core metabolic functions, environment sensing, gene regulation and polysaccharide metabolism were enriched in the cellulose degradome. Analysis of differentially expressed genes revealed a "core" set of 48 CAZymes required for degrading cellulose-containing substrates as well as an "accessory" set of 76 CAZymes required for specific non-cellulose substrates. Gene co-expression analysis suggested that Carbon Catabolite Repression (CCR) related regulators sense intracellular glycolytic intermediates and control the core CAZymes that mainly include cellulosomal components, whereas 11 sets of Two Component Systems (TCSs) respond to availability of extracellular soluble sugars and respectively regulate most of the accessory CAZymes and associated transporters. Surprisingly, under glucose alone, the core cellulases were highly expressed at both transcript and protein levels. Furthermore, glucose enhanced cellulolysis in a dose-dependent manner, via inducing cellulase transcription at low concentrations. CONCLUSION: A molecular model of cellulose degradome in C. cellulolyticum (Ccel) was proposed, which revealed the substrate-specificity of CAZymes and the transcriptional regulation of core cellulases by CCR where the glucose acts as a CCR inhibitor instead of a trigger. These features represent a distinct environment-sensing strategy for competing while collaborating for cellulose utilization, which can be exploited for process and genetic engineering of microbial cellulolysis. PMID- 23657056 TI - A Case of simultaneous occurrence of Marine - Lenhart syndrome and a papillary thyroid microcarcinoma. AB - BACKGROUND: Marine-Lenhart syndrome is defined as the co-occurrence of Graves' disease and functional nodules. The vast majority of autonomous adenomas are benign, whereas functional thyroid carcinomas are considered to be rare. Here, we describe a case of simultaneous occurrence of Marine-Lenhart syndrome and a papillary microcarcinoma embedded in a functional nodule. CASE PRESENTATION: A 55 year-old, caucasian man presented with overt hyperthyroidism (thyrotropin (TSH) <0.01 MUIU/L; free thyroxine (FT4) 3.03 ng/dL), negative thyroid peroxidase and thyroglobulin autoantibodies, but elevated thyroid stimulating hormone receptor antibodies (TSH-RAb 2.6 IU/L). Ultrasound showed a highly vascularized hypoechoic nodule (1.1 * 0.9 * 2 cm) in the right lobe, which projected onto a hot area detected in the 99mtechnetium thyroid nuclear scan. Overall uptake was increased (4.29%), while the left lobe showed lower tracer uptake with no visible background-activity, supporting the notion that both Graves' disease and a toxic adenoma were present. After normal thyroid function was reinstalled with methimazole, the patient underwent thyroidectomy. Histological work up revealed a unifocal papillary microcarcinoma (9 mm, pT1a, R0), positively tested for the BRAF V600E mutation, embedded into the hyperfunctional nodular goiter. CONCLUSIONS: Neither the finding of an autonomously functioning thyroid nodule nor the presence of Graves' disease rule out papillary thyroid carcinoma. PMID- 23657057 TI - A rare case of Dirofilaria repens infection. AB - OBJECTIVE: This paper reports a case of Dirofilaria repens infection in a patient who presented with an anterolateral neck swelling. Dirofilaria repens infection of the neck region is rare even in countries where dirofilarial infestation is endemic. The diagnosis is made by identifying the worm in surgical or pathological specimens. CASE REPORT: A 47-year-old man presented with an 8-week history of non-tender, right-sided, lower anterolateral neck swelling and weight loss. An ultrasound scan showed a cystic lesion containing a living worm. The cyst was excised and the patient showed full recovery at follow up. CONCLUSION: To our knowledge, there has been no previous report of an anterolateral neck swelling secondary to Dirofilaria repens infection in Europe. Our case is unusual because of the rarity of Dirofilaria repens presenting as a neck swelling. PMID- 23657058 TI - Factors affecting center of pressure in older adults: the Framingham Foot Study. AB - BACKGROUND: Although aberrant foot movement during gait has been associated with adverse outcomes in the lower extremities in clinical patients, few studies have analyzed population differences in foot function. The purpose of this study was to assess demographic differences in foot function in a large population-based study of community-dwelling adults. METHODS: Participants in this study were from the Framingham Foot Study. Walking data were collected from both feet using a Tekscan Matscan pressure mat. Foot function was characterized using the center of pressure excursion index (CPEI). T-tests were used to assess differences between population subsets based on sex, and in men and women separately, age, body mass index (BMI), physical activity and in women, past high heel use. RESULTS: There were 2111 participants included in this analysis. Significant differences in CPEI were noted by sex (p< 0.0001), by age in women (p = 0.04), and by past high heel use in women (p = 0.04). CONCLUSIONS: Foot function during gait was affected by sex, as well as by age and shoe-wear in women, but not by BMI or physical activity. Future work will evaluate possible relations between CPEI and outcomes such as falls, sarcopenia, and lower extremity function. PMID- 23657059 TI - Requirement of E-cadherin interactions for Langerhans cell differentiation. PMID- 23657060 TI - Role of the placenta in adverse perinatal outcomes among HIV-1 seropositive women. AB - Women seropositive for human immunodeficiency virus type 1 (HIV-1) are at an increased risk for a number of adverse perinatal outcomes. Although efforts to reduce mother-to-child transmission of HIV (MTCT) remain a priority in resource limited countries, HIV testing and treatment have led to steep declines in MTCT in well-resourced countries. Even so, HIV seropositive pregnant women in the United States continue to deliver a disproportionately high number of preterm and low birth weight infants. In this mini-review, we address the role of the placenta in such HIV-related perinatal sequelae. We posit that adverse perinatal outcomes may result from two mutually non-exclusive routes: (1) HIV infection of the placenta proper, potentially leading to impaired maternal-fetal exchange; and (2) infection of the maternal decidual microenvironment, possibly disrupting normal placental implantation and development. Further research into the relationship between HIV-1 infection and placental pathology may lead to the development of novel strategies to improve birth outcomes among HIV-1 seropositive parturients. PMID- 23657061 TI - Dramatic alterations in the protein biosynthetic machinery accompany trophoblast fusion. AB - This report represents a summary of a seminar presentation at Nippon Medical School on September 24, 2012. It is a synopsis of some of our research on trophoblast fusion. PMID- 23657062 TI - Macrophages: are they involved in endometriosis, abortion and preeclampsia and how? AB - Macrophages hold a key role in both regulating and executing the body's own immune response under various conditions. Hence, although endometriosis, preeclampsia and abortions are clinically different, all three are regarded to involve highly complex immunological processes. The aim of our current work was to evaluate the role of macrophages within these gynaecological disorders. Macrophages have been shown to invade endometriosis lesions and to mediate propagation of endometriotic cyst growth. However this is the first time that significant GPER up-regulation in macrophages is demonstrated. This highlights a potential alternative way through which estrogen may modulate immune response of macrophages in endometriosis. In addition, during spontaneous miscarriages the macrophage population increases significantly. This deregulation may possibly support an inflammatory scheme further triggering abortive procedures. Macrophage mediated apoptosis of extravillous trophoblasts (EVT) has been associated with preeclampsia. Larger numbers of apoptotic EVT were detected in preeclamptic placentas compared with normal. In preeclamptic placentas, decidual macrophages were found to be Fas ligand (FasL)-positive. Our results highlight a new aspect of macrophage biology in endometriosis and pregnancy physiology and patho physiology. Further studies with larger samples are needed to verify the current results and evaluate their clinical impact. Our data strongly indicate that macrophages hold key roles in various gynaecological disorders and might be crucial to further elucidate their patho-physiology. PMID- 23657063 TI - Sleep disorders in functional dyspepsia and future therapy. AB - Sleep disorder is a common medical problem. Sleep disorder has been associated with several diseases, including pulmonary disease, gastroesophageal reflux disease (GERD) and fibromyalgia. Interest in sleep phenomenology and gastrointestinal functioning has recently increased, because sleep disorder causes significant morbidity, as evidenced by the increased need for general medical and mental health treatment for emotional problems. A number of studies have found an association between sleep disorders and functional gastrointestinal (GI) disorders. Although arousal from sleep serves several protective roles, such as increase in the speed of esophageal clearance and in airway refluxes to prevent aspiration, awakening from sleep unfortunately induces impairment of sleep quality. Some investigations about the relationship between psychogenic factors and gut motility are controversial. In addition, reports of alterations in gut motility during sleep have also been contradictory. We have evaluated sleep disorder in functional dyspepsia (FD) patients using Pittsburgh Sleep Quality Index (PSQI) score. In our recent data, PSQI score of FD patients was significantly higher compared to that in healthy volunteers. Another study has reported that the distribution of subjects who thought that they got enough sleep was significantly lower for the FD/irritable bowel syndrome (IBS) subjects than for control subjects. Several studies have reported that anti-acid therapy and prokinetic agents are effective for certain FD patients. In addition, previous study has reported tricyclic antidepressants (TCA) drugs are effective for some FD patients. Finally, new drug, actiamide, a muscarinic antagonist and cholinesterase inhibitor, significantly improves Postprandial Distress Syndrome (PDS) symptoms. It might be critical issues for determination of precise mechanism for functional gastrointestinal disorders to clarify the relationship between gut motility and sleep disorders. PMID- 23657064 TI - Assessment of cerebral circulation in the acute phase of subarachnoid hemorrhage using perfusion computed tomography. AB - BACKGROUND AND PURPOSE: Primary brain damage, caused by acute ischemic changes during initial hemorrhage, is an important cause of death and disability following subarachnoid hemorrhage (SAH). However, the mechanism underlying the reduction in cerebral circulation in patients in the acute stage of SAH remains unclear. The goal of this study was to clarify this mechanism with the aid of perfusion computed tomography (CT). METHODS: We prospectively evaluated 21 patients who had been undergone perfusion CT within 3 hours of SAH onset. Mean transit time (MTT) was estimated. Forty circular regions of interest 5 mm in diameter were delineated in the cortical region of the bilateral hemispheres on perfusion CT images. Neurological condition was graded with the Hunt and Hess scale, and initial CT findings were graded with the Fisher scale. We defined a good outcome as a modified Rankin scale (mRs) score of <=2 at 3 months after SAH onset. RESULTS: Global MTT was an independent predictor of outcome. The global MTT of patients with poor outcomes was longer than that of patients with good outcome. Furthermore, global MTT correlated significantly with Hunt & Hess grades, and disturbances in higher cerebral function. CONCLUSION: Hemodynamic disturbances frequently occur after SAH. These abnormalities probably reflect the primary brain damage caused by initial hemorrhage. Perfusion CT is valuable for detecting hemodynamic changes in the acute stages of SAH. PMID- 23657065 TI - Effects of reduced dialysis fluid flow in hemodialysis. AB - BACKGROUND: Hemodialysis is a treatment in which uremic toxins and excess water content are removed from the blood with a dialyzer and dialysis fluid. The efficiency of hemodialysis is strongly influenced by the following 3 parameters: the blood flow rate (QB), the dialysis fluid flow rate (QD), and the overall mass transfer area coefficient (K0A), an index of a dialyzer's performance. The flow ratio (QB : QD) to obtain a well-balanced dialysis efficiency is generally said to be 1 : 2. In Japan, the QB is controlled independently (from 200 to 250 mL/min) depending on individual conditions. However, the QD is usually set at around 500 mL/min regardless of the QB. MATERIALS AND METHODS: To investigate the effect on dialysis efficiency of decreasing the QD from 500 to 400 mL/min, 12 patients were divided into two groups: one in which the QB was 150 mL/min, with 1.3-m(2) membranes; and another in which the QB was 200 mL/min, with 1.6-m(2) membranes. We defined the conditions with the QD of 500 mL/min as condition A, and that with the QD of 400 mL/min as condition B. Each operating condition was assigned for 2 weeks as crossover trials. To evaluate solute removal, we calculated clearance, reduction rate, removal amount, clear space, the clear space rate, and albumin leakage. Furthermore, when dialysis efficiency decreased in condition B, we performed a supplementary test: we calculated the QB with the K0A equation to achieve a dialysis efficiency equivalent to that in condition A, defined as condition B', as the operating condition with the calculated QB and a QD of 400 mL/min, and re-evaluated. RESULTS: In condition B, a QB of 150 mL/min had no effect on the dialysis efficiency;whereas with a QB of 200 mL/min, slight yet significant differences were observed in the clearance of small molecular weight solutes. Condition B' (QB=210 mL/min) showed an equivalent or greater dialysis efficiency and demonstrated an association with theoretical values. CONCLUSIONS: In hemodialysis, the flow ratio (QB : QD) should be maintained at 1 : 2 to obtain a well-balanced dialysis efficiency. The present study has shown that the QD can be decreased while maintaining this flow ratio. A well-balanced QD setting can be financially and environmentally conscious. In addition, use of the K0A equation is a highly effective method to calculate a QB that allows an expected dialysis efficiency to be achieved in case the QD needs to be decreased uniformly, as when dialysis fluid is in short supply during times of disaster. PMID- 23657066 TI - Continuous infusion of dexmedetomidine improves renal ischemia-reperfusion injury in rat kidney. AB - BACKGROUND: Dexmedetomidine has shown beneficial effects in several inflammatory models, including ischemia-reperfusion injury (IRI). This study investigated whether the continuous infusion of dexmedetomidine could improve renal IRI in rats. METHODS: Rats were subjected to either a sham operation and given pentobarbital (10 mg/kg/h; n=6) or were subjected to 45 minutes of renal ischemia and anesthetized with pentobarbital (10 mg/kg/h; n=6), dexmedetomidine (10 or 20 MUg/kg/h; both n=6), or both pentobarbital (10 mg/kg/h) and dexmedetomidine (1.0 MUg/kg/h; n=6) for 6 hours of reperfusion. Blood urea nitrogen and serum creatinine were measured 6 hours after reperfusion. Gene expression mediated by inflammatory systems in the kidney was measured with the real-time reverse transcriptase polymerase chain reaction. RESULTS: Treatment with 10 or 20 MUg/kg/h of dexmedetomidine reduced renal dysfunction. The increases in the messenger RNA expression of interleukin-6, intercellular adhesion molecule 1, and inducible nitric oxide synthase caused by renal IRI were suppressed. Under In rats under pentobarbital anesthesia, 1.0 MUg/kg/h of dexmedetomidine also improved renal dysfunction after renal IRI. CONCLUSION: The present study demonstrates that continuous infusion of dexmedetomidine improves renal IRI. Moreover, with pentobarbital anesthesia, a dose of dexmedetomidine lower than the sedative dose also improves renal IRI. PMID- 23657067 TI - Concentration of PDGF-AB, BB and TGF-beta1 as valuable human serum parameters in adipose-derived stem cell proliferation. AB - INTRODUCTION: Human serum (HS) has attributes similar to fetal bovine serum (FBS) in the proliferation and differentiation of human adipose-derived stem cells (hASCs) when compared in vitro. The purpose of this study was to determine what types of HS, with respect to the concentrations of endogenous growth factors, could be made available for hASC proliferation. METHODS: HS was collected from 2 groups of healthy donor (freshly isolated HS [n=9], and HS preserved for 4 years [n=7]). All sera were isolated with a Cellaid HS isolation device (JMS Co., Ltd, Hiroshima, Japan) and then classified into 3 groups based on the concentrations (high, middle, and low) of platelet-derived growth factor (PDGF)-AB, PDGF-BB, and transforming growth factor-beta 1 (TGF-beta1) by means of enzyme-linked immunoassay screening. The hASCs were isolated from subcutaneous fat using a collagenase enzymatic digestion process and were cultured in control media, each supplemented with HS from a different group. Cell numbers were counted on days 2, 4, 7, and 14, and the relationship between cell proliferation and the level of each growth factor was investigated. RESULTS: The proliferation of hASCs correlated with the concentration of each growth factor. The cut-off points for PDGF-AB, PDGF-BB, and TGF-beta1 in HS [necessary for hASC proliferation when compared with FBS] were 10 ng/mL, 1.5 ng/mL, and 15 ng/mL, respectively. There was no correlation between the storage period of HS and the proliferation potential of hASCs. CONCLUSIONS: These results suggest that the effectiveness of HS on hASC proliferation depends on the concentrations of endogenous PDGFs. In addition, the Cellaid device used in this study allows the simultaneous release of several growth factors from platelets, and our results have shown that it can be used to collect HS for future hASC-based therapies. PMID- 23657068 TI - Long-term outcomes after Frey's procedure for chronic pancreatitis with an inflammatory mass of the pancreatic head, with special reference to locoregional complications. AB - BACKGROUND: Frey's procedure might be a good alternative to pylorus-preserving pancreaticoduodenectomy (PPPD) for patients with an inflammatory mass of the head of the pancreas, because it is technically easy and associated with low morbidity and good pain relief. PURPOSE: To analyze the short-term and long-term outcomes of Frey's procedure in comparison with PPPD and to evaluate the efficacy of Frey's procedure against preoperative locoregional complications. PATIENTS AND METHODS: From August 1997 through December 2007, 6 patients underwent Frey's procedure (as described by Frey and Smith), and 10 patients underwent PPPD. The mean follow-up times were 70.8 months (Frey's procedure) and 119.8 months (PPPD). Preoperative biliary stricture and duodenal stenosis were observed in 4 and 3 patients, respectively, of patients undergoing Frey's procedure. Pain intensity was assessed with a pain scoring system. Quality of life (QOL) was assessed with the European Organization for Research and Treatment of Cancer Quality of-Life Questionnaire-Core 30. Exocrine and endocrine pancreatic function was measured during follow-up. RESULTS: Significant reductions in total pain scores and all QOL scale scores were observed immediately after surgery in all patients (P<0.05). Frey's procedure was superior to PPPD with regard to physical status 7 years after surgery (P<0.05). One patient in the Frey group had a grade B pancreatic fistula, and 2 patients in the PPPD group had intra-abdominal bleeding and delayed gastric emptying. There were no re-operations or surgery-related deaths in either group. Diabetes developed postoperatively in 2 patients in the PPPD group. No patients with preoperative duodenal or biliary stricture or both had a relapse. Three patients in the PPPD group died during follow-up of diseases unrelated to chronic pancreatitis. CONCLUSION: Frey's procedure is safe and effective with regard to pain relief, preservation of pancreatic function, and improvement of QOL over the long term. Moreover, this procedure can also be used to treat preoperative biliary stricture and duodenal stenosis associated with an inflammatory mass of the pancreatic head. PMID- 23657069 TI - Efficacy of eculizumab in a patient with paroxysmal nocturnal hemoglobinuria requiring transfusions 14 years after a diagnosis in childhood. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal disorder characterized by chronic complement-mediated hemolysis. The humanized anti-C5 antibody eculizumab binds to the C5 protein and suppresses hemolysis by inhibiting C5b-9 generation. Here, we report on a 27-year-old woman who was found to have PNH in 1997 (at 13 years of age), without subsequent transfusions, thrombosis, or renal disorder. She had been experiencing frequent malaise and fatigue and was sometimes unable to participate in social activities. She had also experienced repeated hemolytic episodes due to infection, and the hemoglobin level had decreased from 7.0 to 5.0 g/dL several times since February 2010. Red blood cell transfusion was necessary, and 6 months later, treatment with eculizumab was started. The hemoglobin level stabilized, and the patient became transfusion-independent. Furthermore, the patient showed significant improvements in fatigue scale scores and quality of life. Six months after the start of eculizumab therapy, the percentage of PNH-type red blood cells was found to have increased from 82.0% (1.95 * 10(12) cells/L) to 89.1% (2.78 * 10(12) cells/L). Furthermore, during treatment with eculizumab, intravascular hemolysis occurred due to a viral infection accompanied by a high fever. We also observed a persistent elevation in reticulocytes and total bilirubin levels, as well as a persistent reduction in haptoglobin levels. Extravascular hemolytic findings were also observed. Because treatment with eculizumab was started at a young age (27 years) and will be continued for many years, careful observation of the patient is required. PMID- 23657070 TI - Laparoscopic resection of choledochal cyst: report of a case. AB - We report a choledochal cyst that was successfully treated with laparoscopic surgery. A 32-year-old Japanese woman was referred to our hospital with a suspected choledochal cyst. Magnetic resonance cholangiopancreatography and computed tomography showed the common bile duct to be grossly dilated to the hepatic confluence. A diagnosis of type-Ia choledochal cyst in the Todani classification was made, and laparoscopic resection was performed. The patient was placed in the lithotomy position under general anesthesia, and 4 ports were inserted. After the cystic duct was dissected, the hepatoduodenal ligament was incised and a choledochal cyst was identified. Next, the common bile duct was mobilized and dissected away from the surrounding vessels and tissues. Taping of the common bile duct allowed better exposure and dissection of the surrounding tissues. Mobilization of the bile duct and dissection of the surrounding tissue was performed to the bifurcation of the common hepatic duct. Then the common hepatic duct was transected just distal to the choledochal cyst. The inferior common bile duct was dissected from the pancreas to identify the distal end of the choledochal cyst and the pancreaticobiliary junction behind the duodenum. The narrow segment of the choledochal cyst was identified and divided after distal closure with clips. After the gall bladder was dissected from the liver bed, the choledochal cyst and gallbladder were removed. A Roux limb was created extracorporeally via the umbilical incision. The jejunum 30 cm distal to the ligament of Treitz was removed through the transumbilical incision and transected. To create the Roux limb, the mesentery of the jejunum was also extracorporeally separated. A 50-cm Roux limb was made by means of side-to-side anastomosis with an endostapler. After a jejunostomy for hepaticojejunostomy anastomosis was created, the Roux limb was returned to the abdominal cavity. Then, pneumoperitoneum was started again, and the Roux limb was brought up laparoscopically in a retrocolic fashion. An end-to-side hepaticojejunostomy was intracorporeally established with a continuous, single-layer full-thickness 4-0 vicryl suture. Total operation time was 715 minutes. Intraoperative body fluid loss was 250 mL, and the postoperative course was uneventful with no major complications. The patient was discharged from hospital on the 12th postoperative day. She remains asymptomatic with normal liver function after 24 months of follow-up. PMID- 23657071 TI - Adenocarcinoma of the minor duodenal papilla: report of a case. AB - We report a rare case of adenocarcinoma of the minor papilla of the duodenum treated with transduodenal minor papillectomy. A 64-year-old woman was treated for an asymptomatic duodenal tumor detected on gastroduodenoscopy. Endoscopy showed a 15-mm sessile mass in the descending duodenum proximal to the major papilla. The major papilla was a villous 24-mm-diameter polypoid tumor. Histopathologic examination of the biopsy specimen showed tubular adenoma with moderate epithelial atypia. Transduodenal major and minor papillectomies were performed. The orifice of the duct of Santorini and the pancreatic duct were re approximated to the duodenal wall to prevent acute pancreatitis caused by scarring and stenosis of the duct orifice. Histological findings were consistent with well-differentiated adenocarcinoma limited to the minor duodenal papilla, without infiltration of the duodenal wall submucosa, and confirmed complete resection. The patient had an uneventful postoperative course and has remained asymptomatic, without evidence of tumor recurrence or stenosis of the pancreatic duct orifice, for 4 years. PMID- 23657073 TI - Use of propensity scores in occupational health? PMID- 23657074 TI - Advancing workplace health protection and promotion for an aging workforce. AB - OBJECTIVE: To explore issues related to the aging workforce, including barriers to integrating health protection and promotion programs, and provide recommendations for best practices to maximize contributions by aging workers. METHODS: Workgroups reviewed literature and case studies to develop consensus statements and recommendations for a national approach to issues related to older workers. RESULTS: Consensus statements and actions steps were identified for each of the Summit goals and call-to-action statements were developed. CONCLUSIONS: A national dialogue to build awareness of integrated health protection and promotion for the aging workforce is needed. Workers will benefit from improved health and performance; employers will realize a more engaged and productive workforce; and the nation will gain a vital, competitive workforce. PMID- 23657072 TI - Behavioural and medical predictors of bacterial vaginosis recurrence among female sex workers: longitudinal analysis from a randomized controlled trial. AB - BACKGROUND: Data on risk factors of recurrent bacterial vaginosis (RBV) are still scarce. We used data from female sex workers (FSW) participating in a randomized controlled microbicide trial to examine predictors of BV recurrence. METHODS: Trial's participants with at least an episode of BV which was treated and/or followed by a negative BV result and at least one subsequent visit offering BV testing were included in the analysis. Behavioural and medical data were collected monthly while laboratory testing for STI and genital tract infections were performed quarterly. The Andersen-Gill proportional hazards model was used to determine predictors of BV recurrence both in bivariate and multivariate analyses. RESULTS: 440 women were included and the incidence rate for RBV was 20.8 recurrences/100 person-months (95% confidence interval (CI) =18.1-23.4). In the multivariate analysis controlling for the study site, recent vaginal cleansing as reported at baseline with adjusted hazard-ratio (aHR)=1.30, 95% CI = 1.02-1.64 increased the risk of BV recurrence, whereas consistent condom use (CCU) with the primary partner (aHR=0.68, 95% CI=0.49-0.93) and vaginal candidiasis (aHR=0.70, 95% CI=0.53-0.93), both treated as time-dependent variables, were associated with decreased risk of RBV. CONCLUSION: This study confirms the importance of counselling high-risk women with RBV about the adverse effects of vaginal cleansing and the protective effects of condom use with all types of partners for the prevention of sexually transmitted infections, including BV. More prospective studies on risk factors of BV recurrence are warranted. TRIAL REGISTRATION: Trial registration: NCT00153777. PMID- 23657077 TI - Reduced total antioxidant level and increased oxidative stress in patients with deficit schizophrenia: a preliminary study. AB - INTRODUCTION: Deficit schizophrenia (DS) is defined for identifying a relatively homogeneous subgroup of patients with diagnosis of schizophrenia, characterized by the presence of primary and enduring negative symptoms. There have been several studies which investigated the status of oxidative stress and total antioxidant level in patients with schizophrenia. However, there is not any study which researched differences between DS and nondeficit schizophrenia (NDS) in terms of status of oxidative stress and antioxidant level. We hypothesized that patients with DS would have different status of oxidative stress and antioxidant levels compared with patients with NDS. METHODS: Twenty-three patients with DS, 42 patients with NDS and 31 age, sex and smoking status matched healthy controls (HC) were included to study. Five milliliters of blood was drawn from control subjects and patients for assessing total antioxidant potential (TAOP) and total peroxide levels (TPEROX). The ratio of TPEROX to TAOP is referred as oxidative stress index (OSI). RESULTS: We noticed that serum TAOP level was significantly lower in DS group compared with NDS and HC groups. The OSI was also found to be higher in DS group compared with NDS and HC groups. Furthermore, serum TAOP level and status of OSI were similar between NDS and HC groups. CONCLUSION: Our study is the first to demonstrate differences between DS and NDS in terms of status of oxidative stress and serum total antioxidant level. We suggest that our study represents novel and important results in terms of supporting provides and hypothesis which considered DS as a different disease entity with respect to NDS. Further studies are needed for investigating the status of antioxidants and oxidative stress and their clinical implications in deficit schizophrenia. PMID- 23657078 TI - Development and evaluation of evidence-informed quality indicators for adult injury care. AB - OBJECTIVE: To develop and evaluate evidence-informed quality indicators of adult injury care. BACKGROUND: Injury is a leading cause of morbidity and mortality, but there is a lack of consensus regarding how to evaluate injury care. METHODS: Using a modification of the RAND/UCLA Appropriateness Methodology, a panel of 19 injury and quality of care experts serially rated and revised quality indicators identified from a systematic review of the literature and international audit of trauma center quality improvement practices. The quality indicators developed by the panel were sent to 133 verified trauma centers in the United States, Canada, Australia, and New Zealand for evaluation. RESULTS: A total of 84 quality indicators were rated and revised by the expert panel over 4 rounds of review producing 31 quality indicators of structure (n=5), process (n=21), and outcome (n=5), designed to assess the safety (n=8), effectiveness (n=17), efficiency (n=6), timeliness (n=16), equity (n=2), and patient-centeredness (n=1) of injury care spanning prehospital (n=8), hospital (n=19), and posthospital (n=2) care and secondary injury prevention (n=1). A total of 101 trauma centers (76% response rate) rated the indicators (1=strong disagreement, 9=strong agreement) as targeting important health improvements (median score 9, interquartile range [IQR] 8-9), easy to interpret (median score 8, IQR 8-9), easy to implement (median score 8, IQR 7-8), and globally good indicators (median score 8, IQR 8 9). CONCLUSIONS: Thirty-one evidence-informed quality indicators of adult injury care were developed, shown to have content validity, and can be used as performance measures to guide injury care quality improvement practices. PMID- 23657079 TI - Acute aortic dissection type A: age-related management and outcomes reported in the German Registry for Acute Aortic Dissection Type A (GERAADA) of over 2000 patients. AB - OBJECTIVE: To determine the association between age and clinical presentation, management and surgical outcomes in a large contemporary, prospective cohort of patients with acute aortic dissection type A (AADA). BACKGROUND: AADA is one of the most life-threatening cardiovascular diseases, and delayed surgery or overly conservative management can result in sudden death. METHODS: The perioperative and intraoperative conditions of 2137 patients prospectively reported to the multicenter German Registry for Acute Aortic Dissection Type A were analyzed. RESULTS: Of all patients with AADA, 640 (30%) were 70 years or older and 160 patients (7%) were younger than 40 years. The probability of aortic dissection extension to the supra-aortic vessels and abdominal aorta decreased with age (P < 0.0001 and P = 0.0017, respectively). In 1447 patients (69%), the aortic root was preserved and supracoronary replacement of the ascending aorta was done. The probability of this procedure increased with age (P < 0.0001). The incidence of new postoperative neurological disorders was not influenced by age. The lowest probability of 30-day mortality was noted in the youngest patients (11%-14% for patients aged between 20 and 40 years) and rose progressively with age, peaking at 25% in octogenarians. CONCLUSIONS: This study reflects current results after surgical treatment of AADA in relation to patient age. Current survival rates are acceptable, even in very elderly patients. The contemporary surgical mortality rate among young patients is lower than that previously reported in the literature. The postoperative stroke incidence does not increase with age. PMID- 23657081 TI - Employment status and work-related difficulties in lung cancer survivors compared with the general population. AB - OBJECTIVE: To investigate the employment status of lung cancer survivors and the work-related problems they face. BACKGROUND: Although the number of lung cancer survivors is increasing, little is known about their employment and work-related issues. METHODS: We enrolled 830 lung cancer survivors 12 months after lung cancer curative surgery (median time after diagnosis, 4.11 years) and 1000 volunteers from the general population. All participants completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30-item and a questionnaire that included items relating to their jobs. We used logistic regression analysis to identify independent predictors of unemployment. RESULTS: The employment rate of lung cancer survivors decreased from 68.6% at the time of diagnosis to 38.8% after treatment, which was significantly lower than the employment rate of the general population (63.5%; adjusted odds ratio = 2.31, 95% confidence interval: 1.66-3.22). The posttreatment unemployment rate was higher for women than for men. Among survivors, employment was inversely associated with older age, household income, number of comorbidities, and poor social functioning. Fatigue (78.6%) was the most common work-related problem reported by survivors. CONCLUSIONS: Lung cancer survivors experienced more difficulties in employment than did the general population. Age, monthly household income, number of comorbidities, and social functioning appear to be important factors influencing employment status. These findings suggest that lung cancer survivors need support to cope with the financial impact of cancer. PMID- 23657082 TI - Reliability of evaluating hospital quality by colorectal surgical site infection type. AB - OBJECTIVE: To determine whether risk-adjusted colorectal SSI rates are statistically reliable as hospital quality measures. BACKGROUND: Policymakers use surgical site infections (SSI) for public reporting of hospital quality and pay for-performance because they are a relatively common and costly cause of patient morbidity. METHODS: Patients who underwent a colorectal procedure in 2009 were identified from the American College of Surgeons National Surgical Quality Improvement Program. We developed hierarchical multivariate logistic models for (1) superficial SSI, (2) deep/organ-space SSI, and (3) "any SSI" and compared how each model ranked hospital-level risk-adjusted performance. Statistical reliability of hospital quality measurements was estimated on a scale from 0 to 1; with 0 indicating that apparent variation between a hospital's quality measurement and the average hospital is statistically unreliable, and 1 indicating that any observed variation is due to a real difference in performance. RESULTS: Mean reliability of hospital-level quality measurements was 0.650 for superficial, 0.404 for deep/organ-space, and 0.586 for "any SSI." Lower reliability was accounted for by relatively little variation in risk-adjusted SSI rates between hospitals and insufficient numbers of colorectal cases submitted by individual hospitals. In 2009, we estimate that 22.1% of all US hospitals performed a sufficient number of colorectal cases to report superficial SSI rates at a high standard of statistical reliability and 1.0% did for deep/organ-space SSI. CONCLUSIONS: As currently constructed, colorectal SSI quality measures might not meet a high standard of statistical reliability for most hospitals, limiting their ability to confidently differentiate high and low performance. Despite an expectation of improving statistical power, combining superficial and deep/organ space SSI into an "any SSI" measure worsens reliability. PMID- 23657084 TI - Imaging features to distinguish malignant and benign branch-duct type intraductal papillary mucinous neoplasms of the pancreas: a meta-analysis. AB - OBJECTIVE: To systematically determine the imaging findings for distinguishing malignant and benign branch-duct type intraductal papillary mucinous neoplasms (BD-IPMNs), including mixed type, and their diagnostic value through meta analysis of published studies. BACKGROUND: Management of BD-IPMNs, including mixed type, largely relies on imaging findings. The current knowledge on imaging findings to distinguish malignant and benign BD-IPMNs has weak evidence and is mostly from scattered individual retrospective studies. METHODS: Thorough literature search in Ovid-MEDLINE and EMBASE databases was conducted to identify studies where findings of computed tomography, magnetic resonance imaging, and endoscopic ultrasonography of BD-IPMNs with or without main pancreatic duct (MPD) dilatation were correlated with surgical/pathological findings. Review of 1128 article candidates, including full-text review of 102 articles, identified 23 eligible articles with a total of 1373 patients for meta-analysis. Dichotomous data regarding distinction between malignant and benign BD-IPMNs were pooled using random effects model to obtain the diagnostic odds ratios (DORs) and their 95% confidence intervals (CIs) of various individual imaging findings for diagnosing malignant BD-IPMN. RESULTS: Presence of mural nodules revealed the highest pooled DOR (95% CI) of 6.0 (4.1-8.8) followed by MPD dilatation [3.4 (2.3 5.2)], thick septum/wall [unadjusted, 3.3 (1.5-6.9); publication bias-adjusted, 2.3 (0.9-5.5)], and cyst size greater than 3 cm [2.3 (1.5-3.5)]. Multilocularity and multiplicity of the cystic lesions did not reveal statistically significant association with malignancy. CONCLUSIONS: Presence of mural nodules should be regarded highly suspicious for malignancy warranting a surgical excision whereas cyst size greater than 3 cm, MPD dilatation (5-9 mm), or thick septum/wall may better be managed by careful observation and/or further evaluation. PMID- 23657085 TI - Laparoscopic Thal fundoplication in children: a prospective 10- to 15-year follow up study. AB - OBJECTIVE: To study long-term (10-15 years) efficacy of antireflux surgery (ARS) in a prospectively followed cohort of pediatric patients with gastroesophageal reflux disease, using 24-hour pH monitoring and reflux-specific questionnaires. BACKGROUND: Studies on short-term outcome of ARS in pediatric patients with gastroesophageal reflux disease have shown good to excellent results; however, long-term follow-up studies are scarce, retrospective, and have not used objective measurements. METHODS: Between 1993 and 1998, a cohort of 57 pediatric patients (ages 1 month to 18 years; 46% with neurological impairment) underwent laparoscopic anterior partial fundoplication (Thal). Preoperatively and postoperatively (at 3-4 months and at 1-5 and 10-15 years), reflux-specific questionnaires were filled out, and 24-hour pH monitoring was performed. RESULTS: At 3 to 4 months, at 1 to 5 years, and at 10 to 15 years after ARS, 81%, 80%, and 73% of patients, respectively, were completely free of reflux symptoms. Disease free survival analysis, however, demonstrated that only 57% of patients were symptom free at 10 to 15 years after ARS. Total acid exposure time significantly decreased from 13.4% before ARS to 0.7% (P < 0.001) at 3 to 4 months after ARS; however, at 3 to 4 months after ARS, pH monitoring was still pathological in 18% of patients. At 10 to 15 years after ARS, the number of patients with pathological reflux had even significantly increased to 43% (P = 0.008). No significant differences were found comparing neurologically impaired and normally developed patients. CONCLUSIONS: As gastroesophageal reflux persists or recurs in 43% of children 10 to 15 years after laparoscopic Thal fundoplication, it is crucial to implement routine long-term follow-up after ARS in pediatric patients with gastroesophageal reflux disease. PMID- 23657083 TI - A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer. AB - OBJECTIVE: To determine whether 1 of 2 vaccines based on dendritic cells (DCs) and poxvectors encoding CEA (carcinoembryonic antigen) and MUC1 (PANVAC) would lengthen survival in patients with resected metastases of colorectal cancer (CRC). BACKGROUND: Recurrences after complete resections of metastatic CRC remain frequent. Immune responses to CRC are associated with fewer recurrences, suggesting a role for cancer vaccines as adjuvant therapy. Both DCs and poxvectors are potent stimulators of immune responses against cancer antigens. METHODS: Patients, disease-free after CRC metastasectomy and perioperative chemotherapy (n = 74), were randomized to injections of autologous DCs modified with PANVAC (DC/PANVAC) or PANVAC with per injection GM-CSF (granulocyte macrophage colony-stimulating factor). Endpoints were recurrence-free survival overall survival, and rate of CEA-specific immune responses. Clinical outcome was compared with that of an unvaccinated, contemporary group of patients who had undergone CRC metastasectomy, received similar perioperative therapy, and would have otherwise been eligible for the study. RESULTS: Recurrence-free survival at 2 years was similar (47% and 55% for DC/PANVAC and PANVAC/GM-CSF, respectively) (chi P = 0.48). At a median follow-up of 35.7 months, there were 2 of 37 deaths in the DC/PANVAC arm and 5 of 37 deaths in the PANVAC/GM-CSF arm. The rate and magnitude of T-cell responses against CEA was statistically similar between study arms. As a group, vaccinated patients had superior survival compared with the contemporary unvaccinated group. CONCLUSIONS: Both DC and poxvector vaccines have similar activity. Survival was longer for vaccinated patients than for a contemporary unvaccinated group, suggesting that a randomized trial of poxvector vaccinations compared with standard follow-up after metastasectomy is warranted. (NCT00103142). PMID- 23657086 TI - A retrospective study on risk factors associated with failed endoscopic treatment of biliary anastomotic stricture after right-lobe living donor liver transplantation with duct-to-duct anastomosis. AB - OBJECTIVE: This aim of this study is to determine the risk factors in failed endoscopic retrograde cholangiography (ERC). BACKGROUND: Endoscopic treatment is considered the first-line intervention for biliary anastomotic stricture (BAS) after right-lobe living donor liver transplantation with duct-to-duct anastomosis. METHODS: A retrospective study was performed on 287 patients who received right-lobe living donor liver transplantation with duct-to-duct anastomosis. The morphology of BAS was defined according to the shape of the distal side of duct-to-duct anastomosis shown on cholangiogram and was categorized into 3 types: pouched, intermediately pouched, and triangular. All cases of ERC were performed by operating surgeons. RESULTS: Fifty-nine patients (20.6%) had BAS and received ERC and balloon dilatation with or without stenting. The success rate was 73.2%. The median number of sessions needed for successful ERC was 3. In the 15 patients with failed ERC, 4 were successfully treated with percutaneous transhepatic biliary drainage and balloon dilatation and 11 underwent conversion hepaticojejunostomy (6 had external percutaneous transhepatic biliary drainage as a temporizing measure). On multivariate analysis, recipient age [odds ratio (OR): 0.922; 95% confidence interval (CI): 0.85-1.00; P = 0.049], operation time (OR: 1.007; 95% CI: 1.001-1.013; P = 0.025), and morphology of stricture (OR: 6.722; 95% CI: 1.31-34.48; P = 0.022) were independent risk factors associated with failed ERC. The success rates for the 3 types of BAS-pouched, intermediately pouched, and triangular-were 42.9%, 63.6%, and 88.9%, respectively (P = 0.021). Association was found between bile leak and pouched BAS (P = 0.008). CONCLUSIONS: ERC is highly effective in treating BAS. A success rate of 73%, the highest ever reported, has been achieved. Morphology of stricture is associated with outcome of ERC. Radiological or surgical intervention should be considered for patients with pouched BAS after endoscopic treatment fails for the first time. PMID- 23657087 TI - Identification of clinical outcome measures for recovery of gastrointestinal motility in postoperative ileus. AB - OBJECTIVE: To identify clinical hallmarks associated with recovery of gastrointestinal transit. BACKGROUND: Impaired gastrointestinal transit or postoperative ileus largely determines clinical recovery after abdominal surgery. However, validated clinical hallmarks of gastrointestinal recovery to evaluate new treatments and readiness for discharge from the hospital are lacking. METHODS: Gastric emptying and colonic transit were scintigraphically assessed from postoperative day 1 to 3 in 84 patients requiring elective colonic surgery and were compared with clinical parameters. The clinical hallmark that best reflected recovery of gastrointestinal transit was validated using data from a multicenter trial of 320 segmental colectomy patients. RESULTS: Seven of 84 patients developed a major complication with paralytic ileus characterized by total inhibition of gastrointestinal motility and were excluded from further analysis. In the remaining patients, recovery of colonic transit (defined as geometric center of radioactivity >=2 on day 3), but not gastric emptying, was significantly correlated with clinical recovery (rho = -0.59, P < 0.001). Conversely, the combined outcome measure of tolerance of solid food and having had defecation (SF + D) (area under the curve = 0.9, SE = 0.04, 95% CI = 0.79 0.95, P < 0.001), but not time to first flatus, best indicated recovery of gastrointestinal transit with a positive predictive value of 93% (95% CI = 78 99). Also in the main clinical trial, multiple regression analysis revealed that SF + D best predicted the duration of hospital stay. CONCLUSIONS: Our data indicate that the time to SF + D best reflects recovery of gastrointestinal transit and therefore should be considered as primary outcome measure in future clinical trials on postoperative ileus.(Netherlands National Trial Register, number NTR1884 and NTR222). PMID- 23657088 TI - Preoperative aspirin use and outcomes in cardiac surgery patients: a role of platelet function assessment. PMID- 23657089 TI - DDBJ read annotation pipeline: a cloud computing-based pipeline for high throughput analysis of next-generation sequencing data. AB - High-performance next-generation sequencing (NGS) technologies are advancing genomics and molecular biological research. However, the immense amount of sequence data requires computational skills and suitable hardware resources that are a challenge to molecular biologists. The DNA Data Bank of Japan (DDBJ) of the National Institute of Genetics (NIG) has initiated a cloud computing-based analytical pipeline, the DDBJ Read Annotation Pipeline (DDBJ Pipeline), for a high-throughput annotation of NGS reads. The DDBJ Pipeline offers a user-friendly graphical web interface and processes massive NGS datasets using decentralized processing by NIG supercomputers currently free of charge. The proposed pipeline consists of two analysis components: basic analysis for reference genome mapping and de novo assembly and subsequent high-level analysis of structural and functional annotations. Users may smoothly switch between the two components in the pipeline, facilitating web-based operations on a supercomputer for high throughput data analysis. Moreover, public NGS reads of the DDBJ Sequence Read Archive located on the same supercomputer can be imported into the pipeline through the input of only an accession number. This proposed pipeline will facilitate research by utilizing unified analytical workflows applied to the NGS data. The DDBJ Pipeline is accessible at http://p.ddbj.nig.ac.jp/. PMID- 23657090 TI - Telekin induces apoptosis associated with the mitochondria-mediated pathway in human hepatocellular carcinoma cells. AB - Telekin, a eudesmane-type sesquiterpene lactone compound isolated from Chinese folk medicine Carpesium divaricatum, has been reported to strongly inhibit the proliferation of cancer cells. In this study, the involvement of a mitochondria mediated pathway in the pro-apoptotic action of telekin was investigated in human hepatocellular carcinoma cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assays showed that telekin exhibited excellent anti-proliferation activity in hepatocellular carcinoma cells and low cytotoxicity to normal hepatocyte cells. Telekin-induced apoptosis was characterized by chromatin condensation, formation of apoptotic bodies, and exposure of phosphatidylserine on the extracellular surface, as revealed by 4,6 diamidino-2-phenylindole (DAPI) nuclear staining and flow cytometry. Flow cytometry analysis showed that telekin induced the loss of mitochondrial membrane potential (MMP), as well as increased the levels of intracellular free calcium and reactive oxygen species (ROS). Additionally, Western blot results demonstrated that telekin induced the decrease in Apaf-1 and Bcl-2 expression, increase in Bax expression, release of cytochrome C, and activation of caspase-9 and caspase-3 in HepG-2 cells. These findings indicate that telekin activates the mitochondria-mediated apoptotic pathway in hepatocellular carcinoma cells and may merit further investigation as a potential therapeutic agent for the treatment of hepatocellular carcinoma. PMID- 23657092 TI - The development of an instrument that can identify children with palliative care needs: the Paediatric Palliative Screening Scale (PaPaS Scale): a qualitative study approach. AB - BACKGROUND: The introduction of paediatric palliative care and referral to specialised teams still occurs late in the illness trajectory of children with life-limiting diseases. The aim of this ongoing multipart study was to develop a screening instrument for paediatricians that would improve the timely identification of children who could benefit from a palliative care approach. METHODS: We used a qualitative study approach with semi-structured interviews (Part 1) and a focus group discussion (Part 2) to define the domains and items of the screening instrument. Seven international paediatric palliative care experts from the UK, France, USA, and Canada took part in face-to-face interviews, and eleven paediatric health professionals from the University Children's Hospital, Zurich, participated in a subsequent focus group discussion. RESULTS: This preliminary phase of development and validation of the instrument revealed five domains relevant to identifying children with life-limiting diseases, who could benefit from palliative care: 1) trajectory of disease and impact on daily activities of the child; 2) expected outcome of disease-directed treatment and burden of treatment; 3) symptom and problem burden; 4) preferences of patient, parents or healthcare professional; and 5) estimated life expectancy. Where palliative care seems to be necessary, it would be introduced in a stepwise or graduated manner. CONCLUSIONS: This study is a preliminary report of the development of an instrument to facilitate timely introduction of palliative care in the illness trajectory of a severely ill child. The instrument demonstrated early validity and was evaluated as being a valuable approach towards effective paediatric palliative care. PMID- 23657091 TI - Characteristics, changes and influence of body composition during a 4486 km transcontinental ultramarathon: results from the TransEurope FootRace mobile whole body MRI-project. AB - BACKGROUND: Almost nothing is known about the medical aspects of runners doing a transcontinental ultramarathon over several weeks. The results of differentiated measurements of changes in body composition during the Transeurope Footrace 2009 using a mobile whole body magnetic resonance (MR) imager are presented and the proposed influence of visceral and somatic adipose and lean tissue distribution on performance tested. METHODS: 22 participants were randomly selected for the repeated MR measurements (intervals: 800 km) with a 1.5 Tesla MR scanner mounted on a mobile unit during the 64-stage 4,486 km ultramarathon. A standardized and validated MRI protocol was used: T1 weighted turbo spin echo sequence, echo time 12 ms, repetition time 490 ms, slice thickness 10 mm, slice distance 10 mm (breath holding examinations). For topographic tissue segmentation and mapping a modified fuzzy c-means algorithm was used. A semi-automatic post-processing of whole body MRI data sets allows reliable analysis of the following body tissue compartments: Total body volume (TV), total somatic (TSV) and total visceral volume (TVV), total adipose (TAT) and total lean tissue (TLT), somatic (SLT) and visceral lean tissue (VLT), somatic (SAT) and visceral adipose tissue (VAT) and somatic adipose soft tissue (SAST). Specific volume changes were tested on significance. Tests on difference and relationship regarding prerace and race performance and non-finishing were done using statistical software SPSS. RESULTS: Total, somatic and visceral volumes showed a significant decrease throughout the race. Adipose tissue showed a significant decrease compared to the start at all measurement times for TAT, SAST and VAT. Lean adipose tissues decreased until the end of the race, but not significantly. The mean relative volume changes of the different tissue compartments at the last measurement compared to the start were: TV -9.5% (SE 1.5%), TSV -9.4% (SE 1.5%), TVV -10.0% (SE 1.4%), TAT -41.3% (SE 2.3%), SAST -48.7% (SE 2.8%), VAT -64.5% (SE 4.6%), intraabdominal adipose tissue (IAAT) -67.3% (SE 4.3%), mediastinal adopose tissue (MAT) -41.5% (SE 7.1%), TLT 1.2% (SE 1.0%), SLT -1.4% (SE 1.1%). Before the start and during the early phase of the Transeurope Footrace 2009, the non-finisher group had a significantly higher percentage volume of TVV, TAT, SAST and VAT compared to the finisher group. VAT correlates significantly with prerace training volume and intensity one year before the race and with 50 km- and 24 hour-race records. Neither prerace body composition nor specific tissue compartment volume changes showed a significant relationship to performance in the last two thirds of the Transeurope Footrace 2009. CONCLUSIONS: With this mobile MRI field study the complex changes in body composition during a multistage ultramarathon could be demonstrated in detail in a new and differentiated way. Participants lost more than half of their adipose tissue. Even lean tissue volume (mainly skeletal muscle tissue) decreased due to the unpreventable chronic negative energy balance during the race. VAT has the fastest and highest decrease compared to SAST and lean tissue compartments during the race. It seems to be the most sensitive morphometric parameter regarding the risk of non-finishing a transcontinental footrace and shows a direct relationship to prerace-performance. However, body volume or body mass and, therefore, fat volume has no correlation with total race performances of ultra-athletes finishing a 4,500 km multistage race. PMID- 23657093 TI - Estimating the prevalence of hepatitis C infection in New York City using surveillance data. AB - Hepatitis C virus is the most common chronic blood-borne infection in the USA. Based on results of a serosurvey, national prevalence is estimated to be 1.3% or 3.2 million people. Sub-national estimates are not available for most jurisdictions. Hepatitis C surveillance data was adjusted for death, out migration, under-diagnosis, and undetectable blood RNA, to estimate prevalence in New York City (NYC). The prevalence of hepatitis C infection in adults aged ?20 years in NYC is 2.37% (range 1.53-4.90%) or 146 500 cases of hepatitis C. This analysis presents a mechanism for generating prevalence estimates using local surveillance data accounting for biases and difficulty in accessing hard to reach populations. As the cohort of patients with hepatitis C age and require additional medical care, local public health officials will need a method to generate prevalence estimates to allocate resources. This approach can serve as a guideline for generating local estimates using surveillance data that is less resource prohibitive. PMID- 23657094 TI - [Splenic rupture not always painful: diagnostics after blunt abdominal trauma]. AB - BACKGROUND: In blunt abdominal traumata the spleen is the most frequently and often the only injured organ. Splenic rupture can result in severe abdominal pain and haemodynamic instability, but may only have mild symptoms. A normal physical exam following abdominal trauma does not exclude splenic rupture. CASE DESCRIPTION: A general practitioner referred a 34-year-old patient with a clean medical history to our hospital for an abdominal ultrasound for progressive abdominal pain and blood cells in the urine after blunt abdominal trauma sustained in a bicycle accident two days previously. Because of intra-abdominal free fluid seen on ultrasound we performed a CT scan which showed a grade 3 splenic rupture. The patient was treated conservatively and discharged after two days of clinical observation. CONCLUSION: Intra-abdominal injuries after blunt abdominal trauma can present late and with only mild symptoms. New or progressive symptoms indicate the need for further imaging investigations. Non-operative treatment is indicated for most haemodynamically stable patients with splenic rupture; exercise restrictions and outpatient check-ups are necessary. PMID- 23657095 TI - [Treating asthma in children successfully: 10 tips]. AB - Although clinical studies show that childhood asthma can be controlled well with inhaled corticosteroids, many children with asthma remain symptomatic despite maintenance treatment with inhaled corticosteroids. In this article, we present 10 tips for successfully treating childhood asthma using only an inhaled corticosteroid and a short-acting bronchodilator. These 10 tips are: make the diagnosis based on the history; do not emphasize the role of lung function studies in the diagnostic process; treat asthma with appropriate medications once you have made the diagnosis; collaborate with the patient and his or her parents; pay attention to the non-drug aspects of therapy; choose an inhaler the child is able to use, train correct use; make follow-up appointments; monitor symptoms, exacerbations and impact on daily life; when children remain symptomatic despite the use of inhaled steroids: investigate potential causes; invest in mutual collaboration between primary and secondary care. PMID- 23657096 TI - [Task shifting and quality of care in practice; physician assistants compared with anaesthesiology residents in the preoperative anaesthesiology outpatient clinic]. AB - OBJECTIVE: To compare the clinical competencies of second-year anaesthesiology residents and physician assistants (PA) in the preoperative anaesthesiology outpatient clinic. DESIGN: Comparative qualitative observational study. METHOD: The two study groups were compared using 5 test stations representing 5 different cases of varying degrees of complexity with standardized patients. For each case, the patients and two anaesthesiologists assessed the results of the PAs and the residents using a quantitative scoring system for 4 clinical skills relevant to the preoperative anaesthesiology outpatient clinic. These skills were history taking, physical examination, communication, and reporting. At each station, a score was calculated for each skill. The groups' scores were subsequently compared. RESULTS: 9 PAs and 11 residents carried out the station tests. There were no significant differences between the two groups of participants. CONCLUSION: In this study in a preoperative anaesthesiology outpatient clinic no difference in clinical competencies was found between PAs and second-year anaesthesiology residents. PMID- 23657097 TI - [Concomitant use of proton pump inhibitors and systemic corticosteroids]. AB - OBJECTIVE: To provide an overview of the incidence of peptic ulcer in patients who use systemic corticosteroids and of the underlying mechanism of action, in order to determine whether there is a need for gastric protection using proton pump inhibitors in these patients. DESIGN: Systematic literature review of published meta-analyses and case-control studies, supported by relevant literature on the effects of corticosteroids in relation to the development of ulcers. METHOD: Analysis of literature was performed using the PubMed database with the search terms 'adrenal cortex hormones', 'peptic ulcer' and their synonyms. Meta-analyses and case-control studies with more than 1000 patients were included. RESULTS: The literature search resulted in 970 articles, of which 3 were classified as relevant meta-analyses and 3 as relevant case-control studies. All meta-analyses indicated that peptic ulcer is, at the most, a rare complication of systemic corticosteroid therapy occurring in less than 0.4-1.8% of patients. As the incidence is low, there is no indication for routine prophylaxis with proton pump inhibitors in combination with systemic corticosteroids. There is convincing evidence showing an increased risk of ulcers and a poorer recovery from these when NSAIDs and systemic corticosteroids are used concomitantly; this is a combination for which a proton pump inhibitor should be prescribed. CONCLUSION: Systemic corticosteroid therapy only rarely causes a peptic ulcer. Routine prophylaxis with proton pump inhibitors is therefore not indicated for short-term systemic corticosteroid use. PMID- 23657098 TI - [Bladder-conserving treatment for bladder cancer: potential of and developments in radiotherapy]. AB - The standard treatment for muscle-invasive bladder cancer is surgical removal of the bladder and construction of a neobladder. Recently, important improvements have been made in the potential for bladder-conserving treatment using radiotherapy. External beam radiotherapy has undergone technological improvements, as a result of which it is possible to radiate the tumour more precisely while decreasing radiation to healthy tissue. Radiochemotherapy improves local recurrence-free and overall survival compared with radiotherapy alone. The results of this combined treatment are comparable with those of surgery. Additionally, Dutch radiotherapy departments have collected data in a national database of 1040 selected patients with confined bladder cancer. These patients were treated with external beam radiation, limited surgery and brachytherapy. The 5-year local recurrence-free survival was 75%. Bladder conserving treatment options for muscle-invasive bladder cancer should be discussed during the multidisciplinary meeting. PMID- 23657099 TI - [Posterior sternoclavicular dislocation: diagnosis initially easy to miss]. AB - Posterior sternoclavicular (SC) dislocation is a rare diagnosis, which tends to be missed initially. Here we report two cases of a dislocated SC joint: one left and one right. The first case describes a 25-year-old male who sustained a direct injury caused by his seatbelt during a car accident. The diagnosis was made 3 months after the initial trauma following performance of a CT scan. His left SC joint was stabilized using a hamstring tendon allograft. The second patient, a 55 year-old female, sustained an indirect injury following a fall onto her right shoulder. The diagnosis was made 6 weeks after the trauma had occurred. Her SC joint was also stabilized using a tendon allograft reconstruction. The clinical outcome of both cases was very satisfactory. Better diagnostics - more attention for subtle symptoms during physical examination, the right choice of imaging (CT scan) and meticulous following of Advanced Trauma Life Support (ATLS) protocols - could diminish the number of delayed diagnoses in this rare but potentially dangerous injury. PMID- 23657100 TI - [A gymnast with painful wrists]. AB - A 11-year-old female gymnast presented with long-standing bilateral wrist pain. Radiographs showed physeal widening and irregularity of the left distal radial and ulnar metaphyses, and irregularity of the right distal radial and ulnar metaphyses without physeal widening. 'Gymnast wrist' was diagnosed and cessation of strenuous activities was advised. PMID- 23657101 TI - [The simulated setting for testing competencies; task shifting in outpatient anaesthesia]. AB - Pre-anaesthesia evaluation is a complex task requiring integration of information obtained from the patient's history, physical examination and the proposed surgery. This task, traditionally performed by physicians, is increasingly being executed by specialised nurses or physician assistants in daily practice. The conduction of pre-anaesthesia evaluation might be suitable for such a shift in tasks, but only if the quality of care is retained. A simulated setting could be used in which the competency of individual physician assistants executing pre anaesthesia evaluation with sufficient quality is measured. Simulation to test competencies requires properly described competencies within an adequate and validated simulation model, a suitable and validated assessment system, and an understanding of the causes of errors in measurement. A simulation study with an adequate sample size to detect a given sensitivity of physician assistants of 80% to identify significant comorbidity during pre-anaesthesia evaluation would require simulation of 1,000 to 1,500 consults. PMID- 23657102 TI - [A woman with a postoperative lumbar swelling]. AB - A 65-year-old woman had developed a large lumbar swelling in a period of four weeks following lumbar laminectomy. An MRI-scan revealed a large fluid collection, which had formed from the spinal canal. The diagnosis 'liquorcele', a rare complication of spine surgery, was established. PMID- 23657103 TI - [Splenic rupture days after falling: coordination by the surgeon]. AB - Delayed presentation of blunt abdominal trauma requires a specific work-up and treatment. Patients who present several days after blunt trauma are haemodynamically stable and therefore do not require standard Advanced Trauma Life Support (ATLS) management. These patients require a unique approach by a dedicated team to evaluate and treat possible occult injuries. In line with this, ultrasound alone is not sufficient and retroperitoneal evaluation by means of contrast-enhanced abdominal CT to rule out occult injuries is necessary. A delayed occult splenic injury, as presented here, requires angiography only if there are signs on CT that predict an increased risk of delayed rupture. In addition, hospitalisation of these patients is not always necessary. PMID- 23657104 TI - [Task differentiation, in pathology as well]. AB - The field of clinical pathology, like other medical professions, is becoming more and more complex, leading to a need for subspecialisation and task differentiation. Whereas the deployment of Physician Assistants is common in other specialties, it is still rare in pathology. Although legal regulations state that histopathological diagnoses can only be made by pathologists, this does not mean that Physician Assistants cannot play a role in pathology. Within the legal regulations they can assist in screening cytological specimens and 'simple' histological specimens. They can also assist in the preparation of macroscopical specimens. These not only include specimens such as gallbladders and appendices, but also oncological specimens such as colon carcinoma resection, in which it has been demonstrated that on average, Pathology Assistants find more lymph nodes than pathologists. PMID- 23657105 TI - [Severe asthma in adults]. AB - The Dutch guideline 'Diagnostics and treatment of severe asthma' provides recommendations on the diagnosis and treatment of patients older than 18 years with severe asthma. A checklist was developed to determine which diagnostic trajectory should be implemented in patients with 'difficult to treat asthma' before the diagnosis of 'severe asthma' can be made. Evidence-based recommendations are made in accordance with the GRADE method, with regard to additional treatment on top of the standard treatment of high dosages of inhaled corticosteroids combined with long-acting beta2 agonists. Furthermore, recommendations are made on the monitoring and follow-up of patients with severe asthma and on the setting up of specialized centres for patients suffering from severe asthma. This guideline is primarily meant for pulmonologists. However, it may also be useful for other disciplines involved in the care for patients with asthma. PMID- 23657106 TI - The ChEMBL database as linked open data. AB - BACKGROUND: Making data available as Linked Data using Resource Description Framework (RDF) promotes integration with other web resources. RDF documents can natively link to related data, and others can link back using Uniform Resource Identifiers (URIs). RDF makes the data machine-readable and uses extensible vocabularies for additional information, making it easier to scale up inference and data analysis. RESULTS: This paper describes recent developments in an ongoing project converting data from the ChEMBL database into RDF triples. Relative to earlier versions, this updated version of ChEMBL-RDF uses recently introduced ontologies, including CHEMINF and CiTO; exposes more information from the database; and is now available as dereferencable, linked data. To demonstrate these new features, we present novel use cases showing further integration with other web resources, including Bio2RDF, Chem2Bio2RDF, and ChemSpider, and showing the use of standard ontologies for querying. CONCLUSIONS: We have illustrated the advantages of using open standards and ontologies to link the ChEMBL database to other databases. Using those links and the knowledge encoded in standards and ontologies, the ChEMBL-RDF resource creates a foundation for integrated semantic web cheminformatics applications, such as the presented decision support. PMID- 23657107 TI - Bio-oil based biorefinery strategy for the production of succinic acid. AB - BACKGROUND: Succinic acid is one of the key platform chemicals which can be produced via biotechnology process instead of petrochemical process. Biomass derived bio-oil have been investigated intensively as an alternative of diesel and gasoline fuels. Bio-oil could be fractionized into organic phase and aqueous phase parts. The organic phase bio-oil can be easily upgraded to transport fuel. The aqueous phase bio-oil (AP-bio-oil) is of low value. There is no report for its usage or upgrading via biological methods. In this paper, the use of AP-bio oil for the production of succinic acid was investigated. RESULTS: The transgenic E. coli strain could grow in modified M9 medium containing 20 v/v% AP-bio-oil with an increase in OD from 0.25 to 1.09. And 0.38 g/L succinic acid was produced. With the presence of 4 g/L glucose in the medium, succinic acid concentration increased from 1.4 to 2.4 g/L by addition of 20 v/v% AP-bio-oil. When enzymatic hydrolysate of corn stover was used as carbon source, 10.3 g/L succinic acid was produced. The obtained succinic acid concentration increased to 11.5 g/L when 12.5 v/v% AP-bio-oil was added. However, it decreased to 8 g/L when 50 v/v% AP-bio-oil was added. GC-MS analysis revealed that some low molecular carbon compounds in the AP-bio-oil were utilized by E. coli. CONCLUSIONS: The results indicate that AP-bio-oil can be used by E. coli for cell growth and succinic acid production. PMID- 23657108 TI - Self-reported increased confusion or memory loss and associated functional difficulties among adults aged >= 60 years - 21 States, 2011. AB - Declines in cognitive function vary among persons and can include changes in attention, memory, learning, executive function, and language capabilities that negatively affect quality of life, personal relationships, and the capacity for making informed decisions about health care and other matters. Memory problems typically are one of the first warning signs of cognitive decline, and mild cognitive impairment might be present when memory problems are greater than normal for a person's age but not as severe as problems experienced with Alzheimer's disease. Some, but not all, persons with mild cognitive impairment develop Alzheimer's disease; others can recover from mild cognitive impairment if certain causes (e.g., medication side effects or depression) are detected and treated. In 2012, the U.S. Department of Health and Human Services published the National Plan to Address Alzheimer's Disease, calling for expanding data collection and surveillance efforts to track the prevalence and impact of Alzheimer's and other types of dementia (4). To estimate the prevalence of self reported increased confusion or memory loss and associated functional difficulties among adults aged >=60 years, CDC analyzed data from 21 states that administered an optional module in the 2011 Behavioral Risk Factor Surveillance System (BRFSS) survey. The results indicated that 12.7% of respondents reported increased confusion or memory loss in the preceding 12 months. Among those reporting increased confusion or memory loss, 35.2% reported experiencing functional difficulties. These results provide baseline information about the number of noninstitutionalized older adults with increased confusion or memory loss that is causing functional difficulties and might require services and supports now or in the future. PMID- 23657109 TI - Racial/Ethnic disparities in the awareness, treatment, and control of hypertension - United States, 2003-2010. AB - Hypertension is a leading cause of cardiovascular disease and affects nearly one third of U.S. adults. Because the risk for cardiovascular disease mortality increases as blood pressure increases, clinical recommendations for persons with stage 2 hypertension (systolic blood pressure [SBP] >=160 mmHg or diastolic blood pressure [DBP] >=100 mmHg) include a more extensive treatment and follow-up regime than for those with stage 1 hypertension (SBP 140-159 mmHg or DBP 90-99 mmHg). Although racial/ethnic disparities in the prevalence of hypertension have been well documented; ethnic disparities in the awareness, treatment, and control within blood pressure stages have not. To examine racial/ethnic disparities in awareness, treatment, and control of high blood pressure by hypertension stages, CDC analyzed data from the National Health and Nutrition Examination Survey (NHANES) for the period 2003-2010. This report describes the results of that analysis, which indicated that the proportion of Mexican-Americans and blacks with stage 1 and stage 2 hypertension was greater than for whites.* Among those with stage 1 hypertension, treatment with medication was significantly lower for Mexican-Americans compared with their non-Hispanic counterparts. Although treatment among persons with stage 2 hypertension did not differ by race/ethnicity, less than 60% of those with stage 2 hypertension were treated with medication. More efforts are needed to reduce barriers to accessing health care and low-cost medication, as well as increasing clinicians' hypertension treatment knowledge and adherence to clinical guidelines. PMID- 23657110 TI - Prevention and control of influenza with vaccines: interim recommendations of the Advisory Committee on Immunization Practices (ACIP), 2013. AB - This report summarizes recommendations approved on February 21, 2013, by the Advisory Committee on Immunization Practices (ACIP) for the use of influenza vaccines. An expanded 2013 ACIP influenza vaccination recommendation statement is scheduled to be published in MMWR Recommendations and Reports before the start of the 2013-14 influenza season. Providers should consult the expanded 2013 ACIP influenza vaccination statement for complete and updated information. PMID- 23657111 TI - Vital signs: evaluation of hepatitis C virus infection testing and reporting - eight U.S. sites, 2005-2011. AB - BACKGROUND: Hepatitis C virus (HCV) infection is a serious public health problem. New infections continue to occur, and morbidity and mortality are increasing among an estimated 2.7-3.9 million persons in the United States living with HCV infection. Most persons are unaware of their infection status. Existing CDC guidelines for laboratory testing and reporting of antibody to HCV do not distinguish between past infection that has resolved and current infection that requires care and evaluation for treatment. To identify current infection, a test for HCV RNA is needed. METHODS: Surveillance data reported to CDC from eight U.S. sites during 2005-2011 were analyzed to determine the proportion of persons newly reported on the basis of a positive test result for HCV infection. Persons reported with a positive result from an HCV antibody test only were compared with persons reported with a positive result for HCV RNA and examined by birth cohort (1945-1965 compared with all other years), surveillance site, and number of reported deaths. Annual rates of persons newly reported with HCV infection in 2011 also were calculated for each site. RESULTS: Of 217,755 persons newly reported, 107,209 (49.2%) were HCV antibody positive only, and 110,546 (50.8%) were reported with a positive HCV RNA result that confirmed current HCV infection. In both groups, persons were most likely to have been born during 1945 1965 (58.5% of those who were HCV antibody positive only; 67.2% of those who were HCV RNA positive). Among all persons newly reported for whom death data were available, 6,734 (3.4%) were known to have died; deaths were most likely among persons aged 50-59 years. In 2011, across all sites, the annual rate of persons newly reported with HCV infection (positive HCV antibody only and HCV RNA positive) was 84.7 per 100,000 population. CONCLUSIONS: Hepatitis C is a commonly reported disease predominantly affecting persons born during 1945-1965, with deaths more frequent among persons of relatively young age. The lack of an HCV RNA test for approximately one half of persons newly reported suggests that testing and reporting must improve to detect all persons with current infection. IMPLICATIONS FOR PUBLIC HEALTH: In an era of continued HCV transmission and expanding options for curative antiviral therapies, surveillance that identifies current HCV infection can help assess the need for services and link persons with infection to appropriate care and treatment. PMID- 23657112 TI - Testing for HCV infection: an update of guidance for clinicians and laboratorians. AB - In the United States, an estimated 4.1 million persons have been infected with hepatitis C virus (HCV), of whom an estimated 3.2 (95% confidence interval [CI] = 2.7-3.9) million are living with the infection. New infections continue to be reported particularly among persons who inject drugs and persons exposed to HCV contaminated blood in health-care settings with inadequate infection control. PMID- 23657113 TI - Emergence of avian influenza A(H7N9) virus causing severe human illness - China, February-April 2013. AB - On March 29, 2013, the Chinese Center for Disease Control and Prevention completed laboratory confirmation of three human infections with an avian influenza A(H7N9) virus not previously reported in humans. These infections were reported to the World Health Organization (WHO) on March 31, 2013, in accordance with International Health Regulations. The cases involved two adults in Shanghai and one in Anhui Province. All three patients had severe pneumonia, developed acute respiratory distress syndrome (ARDS), and died from their illness. The cases were not epidemiologically linked. The detection of these cases initiated a cascade of activities in China, including diagnostic test development, enhanced surveillance for new cases, and investigations to identify the source(s) of infection. No evidence of sustained human-to-human transmission has been found, and no human cases of H7N9 virus infection have been detected outside China, including the United States. This report summarizes recent findings and recommendations for preparing and responding to potential H7N9 cases in the United States. Clinicians should consider the diagnosis of avian influenza A(H7N9) virus infection in persons with acute respiratory illness and relevant exposure history and should contact their state health departments regarding specimen collection and facilitation of confirmatory testing. PMID- 23657114 TI - Prevalence of rotavirus and adenovirus associated with diarrhea among displaced communities in Khartoum, Sudan. AB - BACKGROUND: Diarrheal diseases represent a major worldwide public health problem particularly in developing countries. Each year, at least four million children under five years of age die from diarrhea. Rotavirus, enteric adenovirus and some bacterial species are the most common identified infectious agents responsible for diarrhea in young children worldwide. This study was conducted to determine prevalence of rotavirus and adenovirus associated with diarrhea among displaced communities in Khartoum state, Sudan. METHODS: A total of seven hundred and ten patients, children and adults, suffering from diarrhea were examined. The clinical history, socio-demographic characteristics, physical examination findings and laboratory investigations were recorded. Stool samples or rectal swabs were collected and tested for rotavirus and adenovirus antigens using the immuno-chromatography test (ICT). Characterization of the identified Rotaviruses, as a major cause of diarrhea, was then made using real time-reverse transcription PCR. To make the study legal, an ethical clearance was obtained from Sudan Ministry of health- Research Ethical Committee. Written consent was taken from adult subjects, and also from children mothers.The participants were informed using simple language about the infection, aim of the research and the benefits of the study. RESULTS: Out of the 710 patients, viral pathogens were detected in only 99 cases (13.9%). Of the 99 cases of viral diarrhea, 83 (83.8%) were due to rotaviruses while 16 (16.2%) attributed to adenovirus. Of the 83 rotaviruses identified, 42 were characterized by RT-PCR, of these 40 (95.2%) were proved as type A (VP6), and 2 (4.8%) type C (VP7). Type C (VP7) rotavirus was detected in samples collected from children under 5 years only. CONCLUSIONS: In conclusion, most cases of viral diarrhea are found to be caused by rotavirus especially among children less than five years. Most of the identified rotavirus belonged to type A (VP6).It was also evident that most patients are those who drank untreated water obtained from donkey carts source and who had no access to latrines, and lived in poor environmental conditions would acquire diarrheal infection. PMID- 23657115 TI - Liver X receptor activation inhibits osteoclastogenesis by suppressing NF-kappaB activity and c-Fos induction and prevents inflammatory bone loss in mice. AB - LXRs are nuclear receptors that function as important regulators of lipid homeostasis and inflammatory responses. LXR activation has been shown to suppress RANKL-induced osteoclast differentiation, but its underlying mechanisms and its influence on inflammatory bone destruction remain unclear. In this study, we report that the LXR agonists T0901317 and GW3965 inhibit osteoclastogenesis from primary BMMs in a dose-dependent manner. LXR activation suppressed RANKL-induced transcriptional activity of NF-kappaB without affecting IkappaBalpha degradation and the phosphorylation of p38. LXR agonists significantly suppressed RANKL induced expression of c-Fos and NFATc1, which are crucial transcription factors for osteoclastogenesis. The activation of LXRs also inhibited RANKL-mediated AP-1 transcriptional activity. Furthermore, LXR activation attenuated PPARgamma ligand induced c-Fos expression, and LXR suppressed AP-1 promoter activity by PPARgamma. The inhibitory effect of LXR activation on osteoclastogenesis was reversed by overexpression of c-Fos, suggesting that c-Fos is a downstream target of the antiosteoclastogenic action of LXRs. In addition to osteoclast differentiation, LXR activation accelerated apoptosis in mature osteoclasts by the induction of caspase-3 and -9 activity and Bim expression. Consistent with the in vitro effects we observed, the administration of a LXR agonist protected from bone loss induced by LPS in vivo. Together, our data provide evidence that LXRs may have potential as therapeutic targets for bone resorption-associated diseases. PMID- 23657116 TI - Maf1, repressor of tRNA transcription, is involved in the control of gluconeogenetic genes in Saccharomyces cerevisiae. AB - Maf1 is a negative regulator of RNA polymerase III (Pol III) in yeast. Maf1 depleted cells manifest elevated tRNA transcription and inability to grow on non fermentable carbon source, such as glycerol. Using genomic microarray approach, we examined the effect of Maf1 deletion on expression of Pol II-transcribed genes in yeast grown in medium containing glycerol. We found that transcription of FBP1 and PCK1, two major genes controlling gluconeogenesis, was decreased in maf1Delta cells. FBP1 is located on chromosome XII in close proximity to a tRNA-Lys gene. Accordingly we hypothesized that decreased FBP1 mRNA level could be due to the effect of Maf1 on tgm silencing (tRNA gene mediated silencing). Two approaches were used to verify this hypothesis. First, we inactivated tRNA-Lys gene on chromosome XII by inserting a deletion cassette in a control wild type strain and in maf1Delta mutant. Second, we introduced a point mutation in the promoter of the tRNA-Lys gene cloned with the adjacent FBP1 in a plasmid and expressed in fbp1Delta or fbp1Delta maf1Delta cells. The levels of FBP1 mRNA were determined by RT-qPCR in each strain. Although the inactivation of the chromosomal tRNA-Lys gene increased expression of the neighboring FBP1, the mutation preventing transcription of the plasmid-born tRNA-Lys gene had no significant effect on FBP1 transcription. Taken together, those results do not support the concept of tgm silencing of FBP1. Other possible mechanisms are discussed. PMID- 23657117 TI - Skeletal dysplasias with increased bone density: evolution of molecular pathogenesis in the last century. AB - Skeletal dysplasias (SKD) with increased bone density form a discrete group of SKDs as per the Nosology and Classification of Genetic Skeletal Disorders, 2010 Revision. This group, with the prototype disorder being osteopetrosis, has evolved over the last century, with new entities being described & their molecular basis being increasingly elucidated. Osteopetrosis, which remained an enigma in the early part of its description, is now known to be genetically heterogenous. Other disorders in this group, which were initially described as variant forms of osteopetrosis, are now recognised to be distinct conditions. However, all these SKDs with increased bone density share their molecular pathogenesis as majority arise due to mutations in the genes governing osteoclast formation and function. PMID- 23657118 TI - Alterations in endogenous pain modulation in endurance athletes: an experimental study using quantitative sensory testing and the cold-pressor task. AB - There is evidence for long-term alterations in pain tolerance among athletes compared with normally active controls. However, scientific data on pain thresholds in this population are inconsistent, and the underlying mechanisms for the differences remain unclear. Therefore, we assessed differences and similarities in pain perception and conditioned pain modulation (CPM) at rest in endurance athletes and normally active controls. The standardised quantitative sensory testing protocol (QST) of the 'German-Research-Network-on-Neuropathic Pain' was used to obtain comprehensive profiles on somatosensory functions. The protocol consisted of thermal and mechanical detection as well as pain thresholds, vibration thresholds, and pain sensitivity to sharp and blunt mechanical stimuli. CPM (the diffuse-noxious-inhibitory-control-like effect) was measured using 2 tonic heat pain test stimuli (at the temperature exceeding a subjective pain rating of 50/100) separated by a 2-min cold-pressor task (CPM TASK; conditioning stimulus). Pain ratings were measured with a numerical rating scale. Endurance capacity was validated by assessment of maximum oxygen uptake (VO2max). Participants included 25 pain-free male endurance athletes (VO2max>60mL/min*kg) and 26 pain-free normally active controls (VO2max<45mL/min*kg) matched based on age and body mass index. Athletes were significantly less sensitive to mechanical pain but showed higher sensitivity to vibration (P<0.05). In athletes, CPM was significantly less activated by the conditioning stimuli (P<0.05) when compared with normally active controls. Our data show that somatosensory processing in athletes differs in comparison with controls, and suggest that the endogenous pain inhibitory system may be less responsive. This finding may explain the paradoxical propensity of athletes to develop chronic widespread pain. PMID- 23657119 TI - Illness and injuries in elite football players--a prospective cohort study during the FIFA Confederations Cup 2009. AB - OBJECTIVE: The incidence of injury during elite-level football tournaments has been well documented, but the incidence of illness and medical conditions has not been well studied. The main objective was to analyze the incidence and nature of medical illnesses and injuries in football players. DESIGN: Prospective cohort study. SETTING: 2009 Federation Internationale de Football Association Confederations Cup soccer tournament. PARTICIPANTS: One hundred eighty-four soccer players (8 teams of 23 players). MAIN OUTCOME MEASURES: Incidence (per 1000 player days) of illnesses and injuries. Each team physician was requested to complete a daily report of injury (match and training) and medical illness of their players during the tournament (2070 player days). A total of 63 daily reports were obtained (70% response rate). RESULTS: A total of 56 injuries and 35 illness incidents were recorded, resulting in an overall rate of 16.9 illnesses per 1000 player days and 27.0 injuries (match and training) per 1000 player days. The overall injury rate was 64.4 per 1000 match hours or 2.1 per match. About 0.88 days were lost per injury, and 0.46 days were lost per illness. Thirteen (37%) illnesses were because of conditions of the ear, nose, and throat, and 7 (20%) illnesses were because of other respiratory tract symptoms. The lower limb was the most commonly injured body part, with thigh (20%) being the most frequent location, and contusion (44%) the most frequent type of injury. CONCLUSIONS: Illnesses are as common but less severe compared with match and training injuries during an international football tournament. Illnesses comprise an important component in the day-to-day medical care of a traveling football team. Medical illness therefore needs to be considered by the team physicians when planning for and managing the medical needs of elite football teams. PMID- 23657120 TI - A cluster of exertional rhabdomyolysis affecting a Division I Football team. AB - OBJECTIVE: To identify risk factors for exertional rhabdomyolysis (ER) among collegiate football athletes. We hypothesized that a back squat workout triggered ER in some players, and that the risk of ER was altered by players' characteristics or other exposures. DESIGN: Case report and case-control study. SETTING: National Collegiate Athletic Association Division I Football Program and an academic medical center. PARTICIPANTS: National Collegiate Athletic Association Division I football players. INDEPENDENT VARIABLES: Characteristics, performance during the implicated workout, and exposures of players. MAIN OUTCOME MEASURES: Exertional rhabdomyolysis was the primary outcome; the hypotheses were formulated before data were collected. RESULTS: Initial serum creatine kinase and creatinine values ranged from 96,987 to 331,044 U/L and from 1.0 to 3.4 mg/dL, respectively. The risk of ER increased as the time and number of sets needed to complete 100 back squats increased [odds ratio (OR), 1.11; 95% confidence interval (CI), 1.03-1.19; P = 0.0051 and OR, 1.33; 95% CI, 1.09-1.63; P = 0.0056, respectively]. Affected players were significantly more likely than unaffected players to report that they went to muscle failure (P = 0.006), did not think they could complete the workout (P = 0.02), and performed extra squats (P = 0.02) during the back squat assignment. For athletes playing skilled or semiskilled positions, the risk of ER increased as the percent body weight lifted increased [OR (corresponding to a 10% increase), 1.77; 95% CI, 1.06-2.94; P = 0.0292]. Drinking protein shakes after the implicated workout was associated with a decreased risk (OR, 0.70; 95% CI, 0.51-0.96; P = 0.0284); the odds decreased about 30% per shake. CONCLUSIONS: Percent body weight lifted, the number of sets, and time needed to complete 100 back squats were significantly associated with increased risk of ER. Affected athletes were more likely to report going to muscle failure, thinking they could complete the workout, and performing extra squats during the back squat assignment. Consuming protein shakes after the implicated workout was associated with a decreased risk. Clinicians, athletes, and athletic program staff must know risk factors for ER and early symptoms of ER. PMID- 23657121 TI - Effects of footwear on lead limb knee and ankle joint kinematics in a fast bowler with a history of posterior ankle joint impingement-a case report. AB - This case study reports the kinematic effect of 2 different cricket shoes on a fast bowler who reports a history of posterior ankle joint impingement. The participant bowled 6 trials in 2 pairs of cricket shoes. The 3-dimensional kinematics of the joints of the front leg was quantified during stance phase of the delivery stride. Wearing the high-cut shoe resulted in the ankle being 7.7 degree angle more plantarflexed at initial contact compared with the low-cut shoe. Again, when wearing the high-cut shoe compared with the low-cut shoe, the ankle joint was 15.5-degree angle more adducted and the knee was 4.1-degree angle less externally rotated at initial contact. This case study identifies the bowler's preferred shoe (high-cut shoe) as a potential contributing factor to the symptoms he was experiencing. PMID- 23657122 TI - Six-week combined vibration and wobble board training on balance and stability in footballers with functional ankle instability. AB - OBJECTIVE: To compare the effectiveness of a combination of vibration and wobble board training against wobble board training alone in footballers suffering from functional ankle instability (FAI). DESIGN: A 2 * 3 prefactorial-postfactorial design. SETTING: University research laboratory. PARTICIPANTS: Thirty-three male semiprofessional footballers with self-reported unilateral FAI were randomly assigned in 3 groups: vibration and wobble board (mean age 22.2 years), wobble board (mean age 22.7 years), and control (mean age 23.1 years). INTERVENTIONS: Participants in each intervention group performed a 6-week progressive rehabilitation program using a wobble board, either with or without the addition of vibration stimulus. MAIN OUTCOME MEASURES: Absolute center of mass (COM) distribution during single-leg stance, modified star excursion balance test (SEBT) reach distances, and single-leg triple hop for distance (SLTHD) were measured before and after 6-week intervention. RESULTS: Combined vibration and wobble board training resulted in reduced COM distribution [P <= 0.001, effect size (ES) = 0.66], increased SEBT reach distances (P <= 0.01 and P <= 0.002, ES = 0.19 and 0.29, respectively), and increased SLTHD (P <= 0.001, ES = 0.33) compared with wobble board training alone during the course of the 6-week training intervention. CONCLUSIONS: Combined vibration and wobble board training improves COM distribution, modified SEBT scores, and SLTHD among footballers suffering FAI compared with wobble board training alone. PMID- 23657123 TI - Drug eluting balloons for de novo coronary lesions - a systematic review and meta analysis. AB - BACKGROUND: The role of drug-eluting balloons (DEB) is unclear. Increasing evidence has shown a benefit for the treatment of in-stent restenosis. Its effect on de novo coronary lesions is more controversial. Several smaller randomized trials found conflicting results. METHODS: This is a systematic review and meta analysis of randomized controlled trials (RCT) evaluating the effect of local Paclitaxel delivery/drug eluting balloons (DEB) (+/- bare metal stent) compared to current standard therapy (stenting) to treat de novo coronary lesions. Data sources for RCT were identified through a literature search from 2005 through 28 December 2012. The main endpoints of interest were target lesion revascularization (TLR), major adverse cardiac events (MACE), binary in-segment restenosis, stent thrombosis (ST), myocardial infarction (MI), late lumen loss (LLL) and mortality. A random effects model was used to calculate the pooled relative risks (RR) with 95% confidence intervals. RESULTS: Eight studies (11 subgroups) and a total of 1,706 patients were included in this analysis. Follow up duration ranged from 6 to 12 months. Overall, DEB showed similar results to the comparator treatment. The relative risk (RR) for MACE was 0.95 (0.64 to 1.39); P = 0.776, for mortality it was 0.79 (0.30 to 2.11), P = 0.644, for stent thrombosis it was 1.45 (0.42 to 5.01), P = 0.560, for MI it was 1.26 (0.49 to 3.21), P = 0.629, for TLR it was 1.09 (0.71 to 1.68); P = 0.700 and for binary in stent restenosis it was 0.96 (0.48 to 1.93), P = 0.918. Compared to bare metal stents (BMS), DEB showed a lower LLL (- 0.26 mm (-0.51 to 0.01)) and a trend towards a lower MACE risk (RR 0.66 (0.43 to 1.02)). CONCLUSION: Overall, drug eluting balloons (+/- bare metal stent) are not superior to current standard therapies (BMS or drug eluting stent (DES)) in treating de novo coronary lesions. However, the performance of DEB seems to lie in between DES and BMS with a trend towards superiority over BMS alone. Therefore, DEB may be considered in patients with contraindications for DES. The heterogeneity between the included studies is a limitation of this meta-analysis; different drug-eluting balloons have been used. PMID- 23657124 TI - In vivo embryo production in cows superovulated 1 or 2 days after ovum pick-up. AB - The present study evaluated superovulatory responses and in vivo embryo production in cows treated with FSH starting 1 or 2 days after ovum pick-up (OPU). Thirty-three non-lactating Nelore cows were subjected to aspiration of all follicles >=3mm for OPU. After OPU, cows were randomly divided into two groups in which the follicle superstimulatory treatments with FSH started 1 or 2 days after OPU (Groups D1 and D2, respectively). Data are presented as the least squares mean+/-s.e.m. The number of follicles >=3mm before OPU was similar between groups (~34); however, cows in Group D2 had more follicles >=3mm on the first day of FSH (15.2+/-2.3 vs 7.6+/-1.7; P=0.04) and a higher ratio of the number of follicles at first FSH/number of follicles before OPU (0.41+/-0.04 vs 0.24+/-0.02; P=0.01). In addition, Group D2 cows had a greater superovulatory response than did cows in Group D1 (18.9+/-2.8 vs 9.1+/-1.9 corpora lutea, respectively; P<0.03). However, there was no difference in the total number of recovered ova and embryos from cows in Groups D2 and D1 (5.1+/-1.4 vs 4.9+/-1.3, respectively; P>0.10). Nevertheless Group D2 cows had more freezable embryos than Group D1 cows (3.2+/ 1.1 vs 1.3+/-0.5, respectively; P<0.05). Cows from Group D2 had a much higher proportion (P<0.001) of follicles >=8mm compared with follicles >=6mm and <8mm at the time of the last treatment with FSH. In conclusion, to obtain a greater production of viable embryos in superovulated cows after OPU, it is recommended to wait at least 2 days before starting FSH treatment. PMID- 23657125 TI - Neuromodulation device therapy for treatment of hypertensive heart disease. AB - Hypertensive heart disease (HHD) is the leading cause of mortality and morbidity in the United States. Despite the availability of medical therapy it remains a challenge to treat. Autonomic nervous system imbalance resulting in overactivity of the sympathetic nervous system and under activity of the parasympathetic nervous system is integral in the development of hypertension and ultimately the development of HHD. Emerging data suggest that neuromodulation device therapy for treatment of HHD is promising. PMID- 23657126 TI - Effect of toll-like receptor in periodontal bacteria-accelerated abdominal aortic aneurysms. PMID- 23657127 TI - Current profile of infective endocarditis in Japan. PMID- 23657128 TI - Atrial fibrillation (AF) termination by ablation in patients with persistent AF- what is that supposed to mean? PMID- 23657129 TI - Guidelines for elective percutaneous coronary intervention in patients with stable coronary artery disease (JCS 2011) published in 2012--digest version. PMID- 23657130 TI - Surgical treatment for isolated tricuspid valve endocarditis- long-term follow-up at a single institution. AB - BACKGROUND: Systematic long-term data on tricuspid valve (TV) endocarditis are limited. The aim of this study was to investigate the outcome of surgery for isolated TV endocarditis. METHODS AND RESULTS: A total of 637 patients who underwent TV surgery between June 1996 and September 2012 at Hannover Medical School were retrospectively investigated. Of the 637 patients, 33 (14 female, mean age, 49 +/- 21 years) underwent isolated TV surgery for endocarditis: biological TV replacement, n=14; mechanical TV replacement, n=4; TV reconstruction, n=15. A total of 28 cases were associated with i.v. drug abuse (n=14) or pacemaker infection (n=14). Staphylococcus (S.) aureus was the most common microorganism detected on preoperative blood culture. Mean follow-up was 6.0 +/- 4.1 years (83% completed). Three patients (9%) died during the first 30 postoperative days. Survival at 1, 5 and 10 years was 88%, 73%, and 73%, respectively. Freedom from reoperation was 100%, 95%, and 88%, respectively. During follow-up New York Heart Association class improved significantly, and echocardiography identified remaining TV insufficiency grade >= II degrees only in 2 patients. Statistical analysis identified advanced age, logistic EuroSCORE and positive blood culture for S. aureus as significant risk factors for long term mortality. CONCLUSIONS: Isolated TV endocarditis is strongly associated with i.v. drug abuse or pacemaker infection. Long-term outcome is acceptable, independent of the surgical procedure. PMID- 23657131 TI - Stroke prevention with oral anticoagulation therapy in patients with atrial fibrillation--focus on the elderly. AB - Atrial fibrillation (AF) is a major risk factor for stroke and the prevalence increases with age. Oral anticoagulants (OACs) are effective, but underused in elderly patients, primarily because of concerns about bleeding. Clinical study data on the efficacy (stroke/systemic embolism) and safety (bleeding events) of OACs in elderly patients with AF, including studies of vitamin K antagonists and newer OACs, were evaluated to determine whether treatment effects vary in elderly vs. younger patients, and whether OACs provide a net clinical benefit for elderly patients. In general, elderly patients had greater risk of both thromboembolic and bleeding events compared with younger patients. Nevertheless, OACs were associated with significant efficacy, with most studies reporting no difference in the risk of bleeding relative to control treatments. In trials of the newer OACs, no interaction was seen between age and relative treatment effects for apixaban or rivaroxaban compared with warfarin, although the rates of extracranial bleeding events increased in older patients treated with dabigatran. In conclusion, OAC therapy is associated with a positive benefit-risk balance in elderly patients. Irrespective of age, treatment decisions regarding stroke thromboprophylaxis in all patients with AF should be based on consideration of individual potential benefits and risks of treatment and patient preferences. PMID- 23657132 TI - Effects of pretreatment on morphology, chemical composition and enzymatic digestibility of eucalyptus bark: a potentially valuable source of fermentable sugars for biofuel production - part 1. AB - BACKGROUND: In recent years, the growing demand for biofuels has encouraged the search for different sources of underutilized lignocellulosic feedstocks that are available in sufficient abundance to be used for sustainable biofuel production. Much attention has been focused on biomass from grass. However, large amounts of timber residues such as eucalyptus bark are available and represent a potential source for conversion to bioethanol. In the present paper, we investigate the effects of a delignification process with increasing sodium hydroxide concentrations, preceded or not by diluted acid, on the bark of two eucalyptus clones: Eucalyptus grandis (EG) and the hybrid, E. grandis x urophylla (HGU). The enzymatic digestibility and total cellulose conversion were measured, along with the effect on the composition of the solid and the liquor fractions. Barks were also assessed using Fourier-transform infrared spectroscopy (FTIR), solid-state nuclear magnetic resonance (NMR), X-Ray diffraction, and scanning electron microscopy (SEM). RESULTS: Compositional analysis revealed an increase in the cellulose content, reaching around 81% and 76% of glucose for HGU and EG, respectively, using a two-step treatment with HCl 1%, followed by 4% NaOH. Lignin removal was 84% (HGU) and 79% (EG), while the hemicellulose removal was 95% and 97% for HGU and EG, respectively. However, when we applied a one-step treatment, with 4% NaOH, higher hydrolysis efficiencies were found after 48 h for both clones, reaching almost 100% for HGU and 80% for EG, in spite of the lower lignin and hemicellulose removal. Total cellulose conversion increased from 5% and 7% to around 65% for HGU and 59% for EG. NMR and FTIR provided important insight into the lignin and hemicellulose removal and SEM studies shed light on the cell-wall unstructuring after pretreatment and lignin migration and precipitation on the fibers surface, which explain the different hydrolysis rates found for the clones. CONCLUSION: Our results show that the single step alkaline pretreatment improves the enzymatic digestibility of Eucalyptus bark. Furthermore, the chemical and physical methods combined in this study provide a better comprehension of the pretreatment effects on cell-wall and the factors that influence enzymatic digestibility of this forest residue. PMID- 23657133 TI - Oral administration of Bifidobacterium longum CECT 7347 ameliorates gliadin induced alterations in liver iron mobilisation. AB - Coeliac disease is an autoimmune disorder triggered by gluten intake, causing intestinal inflammation and mucosal damage commonly associated with the malabsorption of nutrients and ferropenic anaemia. The present study evaluates the effects of the oral administration of Bifidobacterium longum CECT 7347 on gliadin-mediated alterations in hepatic Fe deposition and Hb concentration, liver transferrin receptor (TfR)-2, IL-6, TNF-alpha and hepcidin (Hamp) expression (mRNA), and active hepcidin peptide production by liquid chromatography-MS/MS. Weanling rats, sensitised or not with interferon (IFN)-gamma, were fed with gliadins and/or the bifidobacterial strain. Gliadin feeding increased hepatic Fe deposition; however, only gliadin-fed sensitised animals showed lower Hb concentrations than the controls. TfR2 expression decreased after gliadins were fed to both sensitised and non-sensitised animals,and restored by the administration of B. longum. These observations were accompanied by increases in IL-6 expression levels in all the treatment groups; however, TNF-alpha expression only increased significantly in animals fed gliadins alone or together with B. longum if they had previously been sensitised with IFN-gamma. Liver expression levels of Hamp diminished in all cases to the lowest values in animals sensitised with IFN-gamma after being fed with gliadins and/or bifidobacteria. In these animals, plasma Hamp active peptide concentrations significantly increased when compared with the controls. Significant correlations were calculated between Hamp expression and liver Fe contents (liver Fe = 1/0.0032 + 0.032 x Hamp(exp)), and Hb concentrations (Hb = 11.49 + 10.13 x (Hamp(exp))1/2). These data indicate that oral administration of B. longum ameliorates gliadin-mediated perturbations in liver Fe deposition and mobilisation. PMID- 23657134 TI - Mycobacterium bovis (bovine tuberculosis) infection in North American wildlife: current status and opportunities for mitigation of risks of further infection in wildlife populations. AB - Mycobacterium bovis (M. bovis), the causative agent of bovine tuberculosis, has been identified in nine geographically distinct wildlife populations in North America and Hawaii and is endemic in at least three populations, including members of the Bovidae, Cervidae, and Suidae families. The emergence of M. bovis in North American wildlife poses a serious and growing risk for livestock and human health and for the recreational hunting industry. Experience in many countries, including the USA and Canada, has shown that while M. bovis can be controlled when restricted to livestock species, it is almost impossible to eradicate once it has spread into ecosystems with free-ranging maintenance hosts. Therefore, preventing transmission of M. bovis to wildlife may be the most effective way to mitigate economic and health costs of this bacterial pathogen. Here we review the status of M. bovis infection in wildlife of North America and identify risks for its establishment in uninfected North American wildlife populations where eradication or control would be difficult and costly. We identified four common risk factors associated with establishment of M. bovis in uninfected wildlife populations in North America, (1) commingling of infected cattle with susceptible wildlife, (2) supplemental feeding of wildlife, (3) inadequate surveillance of at-risk wildlife, and (4) unrecognized emergence of alternate wildlife species as successful maintenance hosts. We then propose the use of integrated and adaptive disease management to mitigate these risk factors to prevent establishment of M. bovis in susceptible North American wildlife species. PMID- 23657135 TI - Identification and evolution of an NFAT gene involving Branchiostoma belcheri innate immunity. AB - The Nuclear Factor of Activated T cells (NFAT) plays an important role in innate and adaptive immunity, but no NFAT genes have yet been identified in amphioxus species. Here we identified and characterized an NFAT-like gene from Branchiostoma belcheri, and also studied extensively the evolutionary history of NFAT family genes. We found that the amphioxus genome contains an AmphiNFAT gene encoding an NFAT homolog. The AmphiNFAT gene was found to be involved in the innate immune response to LPS stimulation in B. belcheri and was ubiquitously and differentially expressed in all investigated tissues. The NFAT family genes were present in a common ancestor with cnidaria, and NFAT1-4 paralogs were lost early in Branchiostoma and Strongylocentrotus genomes. We discovered that NFAT family genes underwent strong purifying selection. Taken together, our findings provide an insight into the innate immune response of amphioxus and the evolution of the NFAT gene family. PMID- 23657136 TI - Bacteremia and resistant gram-negative pathogens among under-fives in Tanzania. AB - BACKGROUND: Antibiotic resistance is one of the most serious public health concerns worldwide and is increasing at an alarming rate, making daily treatment decisions more challenging. This study is aimed at identifying local bacterial isolates and their antimicrobial susceptibility patterns to avoid irrational antibiotic use, especially in settings where unguided management occurs and febrile illnesses are predominant. MATERIAL AND METHODS: A hospital-based prospective cross-sectional study was conducted from September 2011 to February 2012. Febrile children were serially recruited and demographic and clinical data were collected using a standardized data collection tool. A blood culture was performed and identification of the isolates was undertaken using in-house biochemical tests. Susceptibility to common antibiotics was investigated using the disc diffusion methods. RESULTS: Of the 1081 children admitted during the study period, 317 (29.3%) met the inclusion criteria and were recruited, of whom 195 (61.5%) and 122 (38.5%) were male and female respectively. The median age was 18 months with an interquartile range of 9 to 36 months. Of the 317 children, 251 (79.2%) were below or equal to 36 months of age. The prevalence of bacteremia was 6.6%. A higher prevalence of bacteraemia was observed in children below 36 months than in those >= 36 months (7.5% vs. 3.0%, p = 0.001). Predictors of bacteraemia were an axillary temperature of >38.5 degrees C (OR =7, 95% CI = 2.2 - 14.8, p value = 0.0001), a positive malaria slide (OR =5, 95% CI = 3.0 - 21.2, p-value = 0.0001) and a high neutrophils' count (OR =21 95% CI = 5.6 - 84, p-value = 0.0001). Escherichia coli and Klebsiella pneumoniae accounted for 7 (33.3%) and 6 (28.6%) of all the isolates respectively. Others gram-negatives bacteria were Citrobacter spp 2 (9.5%), Enterobacter spp 1 (4.25%), Pseudomonas spp 2 (9.5%), Proteus spp 1 (4.25%) and Salmonella spp 1 (4.25%). These isolates were highly resistant to ampicillin (95%), co-trimoxazole (90%), tetracycline (90%), gentamicin (80%), augmentin (80%), chloramphenicol (65%), ceftriaxone (35%), cefotaxime (35%) ciprofloxacin (30%), amikacin (30%), ceftazidime (25%) and norfloxacine (10%). CONCLUSION: Multi-resistant gram-negative bacteria are the commonest cause of bacteremia in under-fives attending the Bugando Medical Centre, Mwanza, Tanzania. A high body temperature, a positive malaria slide and a high absolute neutrophils' count were all independent risk factors found to predict bacteremia. A higher mortality rate was observed in children with bacteraemia. Continuous epidemiological surveillance should be conducted so that a proper and effective antibiotics management can be instituted, especially in children with a high grade fever, a positive malaria slide and a high neutrophils' count. PMID- 23657137 TI - More evidence supporting unified theory of stellate ganglion block. PMID- 23657138 TI - Anti-CTLA4 antibody therapy related complications on FDG PET/CT. AB - Anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody therapy is a new class of drug which has demonstrated increased overall survival in patients with metastatic melanoma. Anti-CTLA-4 antibody therapy inhibits the CTLA-4 inhibitory signal, thereby enhancing the anti-tumor response of the cytotoxic T lymphocytes. This response can lead to a variety of immune-related adverse events. Many of these events are present on follow-up PET/CT examinations performed to assess response to therapy. It is important for the interpreting physician to be aware of the findings on PET/CT to avoid diagnosing adverse events as progressive disease and to alert clinicians regarding these complications. PMID- 23657139 TI - Combined 18F-FDG PET/CT and 99mTc 3PRGD2 SPECT/CT imaging in a case of pituitary metastases. AB - We compare F-FDG PET/CT and 99mTc 3PRGD2 SPECT/CT scans in a case of histologically proved pituitary metastases. The ratio of tumor to cerebellum (T/C) of 99mTc 3PRGD2 SPECT is much higher than that for 18F-FDG PET. We then conduct the same scans for a pituitary adenoma patient for better comparison. The T/C of 18F-FDG is not able to differentiate pituitary metastases from pituitary adenoma. However, The T/C of 99mTc 3PRGD2 observed in pituitary metastases was higher than that in pituitary adenoma. PMID- 23657140 TI - Blood volume determination, a nuclear medicine test in evolution. AB - The method for determining blood volume has evolved substantially since first attempts were made in the latter part of the nineteenth century with the exsanguination of animals. The now accepted methods are based on indicator dilution methodologies. First attempts utilized inert dyes such as Evans Blue and Cardiogreen. These were found to be impractical due, primarily, to their rapid clearance from the blood. For many years, the most accepted method for blood volume determination was the dual isotope technique. This procedure utilizes chromium 51 or 99mTc to label autologous red cells and radioiodine 125 or 131 to label human serum albumin (HSA). Plasma and red cell volumes are measured separately and the results "combined". The procedure requires on-site labeling of autologous red cells and HSA, and meticulous preparation of standards and doses. The complexity of this method leads to performance times of 6 to 8 hours. An FDA approved single isotope method is now employed in over 60 major institutions. HSA is labeled with radioiodine 131 at an FDA radiopharmaceutical facility, and test doses and standards are provided to laboratories in kit form. The red cell volume is derived by a calculation utilizing the measured plasma volume and the value for the average whole-body hematocrit. All calculations are carried out by a dedicated microprocessor, and a final report is generated and printed. The results are compared with predicted normal values for male and female patients based on percentage deviation from normal weight. Preliminary results are available in 30 minutes and complete calculations in 90 minutes. PMID- 23657141 TI - A rare case of primary pulmonary epithelioid angiosarcoma detected by (18)F-FDG PET/CT. AB - We describe a rare case of primary pulmonary epithelioid angiosarcoma detected by F-FDG PET/CT. A 54-year-old female patient with history of non-Hodgkin lymphoma underwent F-FDG PET/CT for follow-up. PET/CT detected an area of increased F-FDG uptake corresponding to a 4-cm mass located in the inferior lobe of the left lung. Based on this PET/CT finding, the patient underwent left inferior pulmonary lobectomy. Histology demonstrated the presence of a pulmonary epithelioid angiosarcoma. Other sites of disease were excluded. In our case, F-FDG PET/CT has been useful in detecting and staging this rare primary pulmonary tumor. PMID- 23657142 TI - Improved quality of life after surgery for pelvic organ prolapse in Nepalese women. AB - BACKGROUND: Pelvic organ prolapse (POP) is a common gynecological condition that can affect quality of life (QOL) in women. In Nepal, the prevalence of POP is high, but many affected women are still deprived of treatment. Vaginal hysterectomy with pelvic floor repair is one of the common treatment options for advanced POP. However, QOL outcomes after surgery have not been reported in low income countries. Thus, we aimed to examine changes in QOL among Nepalese women with POP after such surgery. METHODS: This longitudinal study was conducted in the selected central and peripheral hospitals in Nepal where vaginal hysterectomy was being performed free of cost for POP. A baseline study first measured the QOL domains (physical, psychological, social relationships and environment) among 252 women with advanced POP. Follow-up data was then collected at six weeks and three months after surgery. Among the 177 women that were available at six weeks post surgery, 166 participated in the follow-up study at three months post-surgery. To evaluate QOL at baseline, 142 women with no history of POP were included as a comparison group. RESULTS: The mean scores across QOL domains improved from baseline to 3 months after surgery. The baseline score for the physical domain increased from 11.2 to 12.8 at six weeks and 13.5 at three months post-surgery (p < 0.001); the psychological domain score increased from 11.6 to 13.1 at six weeks and 13.8 at three months post-surgery (p < 0.001); the social relationships domain score increased from 13.6 to 14.4 at six weeks and 15.0 at three months post-surgery (p < 0.001); and the environmental domain score increased from 12.9 to 13.9 at six weeks and 14.0 at three months post-surgery (p < 0.001). CONCLUSION: QOL progressively improved among women undergoing surgery for POP. Such surgical services need to be scaled up for treatment of advanced POP in low income countries. PMID- 23657143 TI - Serum beta2-microglobulin at discharge predicts mortality and graft loss following kidney transplantation. AB - Serum beta(2)-microglobulin (beta(2)M), a novel marker of kidney function, predicts mortality and kidney failure in the general population, and its elevation following transplantation is a marker of acute rejection. The association between post-transplant serum beta(2)M and outcomes following kidney transplantation, however, is unknown. To help determine this, we conducted a retrospective cohort study of 2190 individuals receiving a primary kidney transplant with serum beta(2)M measured at discharge. A total of 452 deaths and 347 graft failures before death (669 total graft losses) occurred over a median of 4.1 years of follow-up. After adjustment, the highest quintile of beta(2)M (5.0 mg/l and above), compared with the lowest quintile (<2.3 mg/l), was associated with a hazard ratio of 4.6 (95% confidence interval 2.8, 7.5) for death, 4.1 (2.4, 7.0) for death-censored graft loss, and 3.8 (2.5, 5.6) for total graft loss. Serum beta(2)M was more strongly associated with each outcome than was serum creatinine. Higher serum beta(2)M at discharge was independently associated with each outcome in models stratified by the presence of delayed graft function, donor type, or estimated glomerular filtration rate at discharge. Thus, serum beta(2)M at discharge is a potent predictor of long-term mortality and graft loss in kidney transplant recipients, providing information on allograft function beyond that of serum creatinine. PMID- 23657144 TI - Plasma FGF23 levels increase rapidly after acute kidney injury. AB - Emerging evidence suggests that fibroblast growth factor 23 (FGF23) levels are elevated in patients with acute kidney injury (AKI). In order to determine how early this increase occurs, we used a murine folic acid-induced nephropathy model and found that plasma FGF23 levels increased significantly from baseline already after 1 h of AKI, with an 18-fold increase at 24 h. Similar elevations of FGF23 levels were found when AKI was induced in mice with osteocyte-specific parathyroid hormone receptor ablation or the global deletion of parathyroid hormone or the vitamin D receptor, indicating that the increase in FGF23 was independent of parathyroid hormone and vitamin D signaling. Furthermore, FGF23 levels increased to a similar extent in wild-type mice maintained on normal or phosphate-depleted diets prior to induction of AKI, indicating that the marked FGF23 elevation is at least partially independent of dietary phosphate. Bone production of FGF23 was significantly increased in AKI. The half-life of intravenously administered recombinant FGF23 was only modestly increased. Consistent with the mouse data, plasma FGF23 levels rose 15.9-fold by 24 h following cardiac surgery in patients who developed AKI. The levels were significantly higher than in those without postoperative AKI. Thus, circulating FGF23 levels rise rapidly during AKI in rodents and humans. In mice, this increase is independent of established modulators of FGF23 secretion. PMID- 23657145 TI - Submicroscopic deletion involving the fibroblast growth factor receptor 1 gene in a patient with combined pituitary hormone deficiency. AB - Combined pituitary hormone deficiency (CPHD), isolated hypogonadotropic hypogonadism (IHH), Kallmann syndrome (KS), and septo-optic dysplasia (SOD) are genetically related conditions caused by abnormal development of the anterior midline in the forebrain. Although mutations in the fibroblast growth factor receptor 1 (FGFR1) gene have been implicated in the development of IHH, KS, and SOD, the relevance of FGFR1 abnormalities to CPHD remains to be elucidated. Here, we report a Japanese female patient with CPHD and FGFR1 haploinsufficiency. The patient was identified through copy-number analyses and direct sequencing of FGFR1 performed for 69 patients with CPHD. The patient presented with a combined deficiency of GH, LH and FSH, and multiple neurological abnormalities. In addition, normal TSH values along with a low free T4 level indicated the presence of central hypothyroidism. Molecular analyses identified a heterozygous ~ 8.5 Mb deletion involving 56 genes and pseudogenes. None of these genes except FGFR1 have been associated with brain development. No FGFR1 abnormalities were identified in the remaining 68 patients, although two patients carried nucleotide substitutions (p.V102I and p.S107L) that were assessed as benign polymorphism by in vitro functional assays. These results indicate a possible role of FGFR1 in anterior pituitary function and the rarity of FGFR1 abnormalities in patients with CPHD. PMID- 23657147 TI - Seeing human: distinct and overlapping neural signatures associated with two forms of dehumanization. AB - The process of dehumanization, or thinking of others as less than human, is a phenomenon with significant societal implications. According to Haslam's (2006) model, two concepts of humanness derive from comparing humans with either animals or machines: individuals may be dehumanized by likening them to either animals or machines, or humanized by emphasizing differences from animals or machines. Recent work in cognitive neuroscience emphasizes understanding cognitive processes in terms of interactions between distributed cortical networks. It has been found that reasoning about internal mental states is associated with activation of the default mode network (DMN) and deactivation of the task positive network (TPN); whereas reasoning about mechanical processes produces the opposite pattern. We conducted two neuroimaging studies. The first examined the neural bases of dehumanization and its relation to these two brain networks, using images and voice-over social narratives which either implicitly contrasted or implicitly likened humans to either animals or machines. The second study addressed a discrepancy between findings from the first study and prior work on the neural correlates of dehumanization: using a design similar to prior work we examined neural responses to pictures of humans, animals and machines, presented without any social context. In both studies, human and humanizing conditions were associated with relatively high activity in the DMN and relatively low activity in the TPN. However, the non-human and dehumanizing conditions deviated in different ways: they demonstrated more marked changes either in the DMN or in the TPN. Notably, differences between the animal dehumanizing and humanizing conditions were most evident in regions associated with mechanistic reasoning, not in the mentalizing network. Conjunction analysis of contrasts from both paradigms revealed that only one region was consistently more active when participants saw human, a medial parietal region regarded as the central hub of the DMN. These findings provide a neural basis for Haslam's distinction between two types of dehumanization, and suggest that the DMN and TPN play opposing roles in creating a sense of moral concern. PMID- 23657146 TI - Prominent role for T cell-derived tumour necrosis factor for sustained control of Mycobacterium tuberculosis infection. AB - Tumour Necrosis Factor (TNF) is critical for host control of M. tuberculosis, but the relative contribution of TNF from innate and adaptive immune responses during tuberculosis infection is unclear. Myeloid versus T-cell-derived TNF function in tuberculosis was investigated using cell type-specific TNF deletion. Mice deficient for TNF expression in macrophages/neutrophils displayed early, transient susceptibility to M. tuberculosis but recruited activated, TNF producing CD4(+) and CD8(+) T-cells and controlled chronic infection. Strikingly, deficient TNF expression in T-cells resulted in early control but susceptibility and eventual mortality during chronic infection with increased pulmonary pathology. TNF inactivation in both myeloid and T-cells rendered mice critically susceptible to infection with a phenotype resembling complete TNF deficient mice, indicating that myeloid and T-cells are the primary TNF sources collaborating for host control of tuberculosis. Thus, while TNF from myeloid cells mediates early immune function, T-cell derived TNF is essential to sustain protection during chronic tuberculosis infection. PMID- 23657148 TI - Open-label parallel dose tolerability study of three subcutaneous immunotherapy regimens in house dust mite allergic patients. AB - BACKGROUND: The current maintenance dose (10,000 AUeq/monthly) of a subcutaneous allergoid for house dust mite (HDM) immunotherapy has previously shown significant clinical efficacy in patients with HDM induced allergic rhinitis or rhinoconjunctivitis. In order to comply with the 2009 EMA guidelines on immunotherapy products, a study was conducted to evaluate the safety, tolerability and short-term treatment effects of up-dosing regimens with high doses (up to 40,000 AUeq) of allergoid HDM immunotherapy. METHODS: In total 48 patients with HDM-allergic rhinitis or rhinoconjunctivitis (29 M/19 F; 18-53 years) were included and enrolled into one of three up-dosing regimens (1:4:4): 1) a regular regimen with up-dosing to 40,000 AUeq followed by two maintenance doses (total duration 17 weeks), 2) an intermediate regimen (14 weeks) or 3) a fast regimen (11 weeks). Safety and tolerability were evaluated by monitoring of early and late local reactions and systemic reactions. In addition, short-term effects were assessed by conjunctival provocation test (CPT) and levels of serum allergen-specific IgE, IgG and IgG4. RESULTS: Thirty-nine patients completed the study according to protocol. No early local reactions occurred. Late local reactions (LLR) were observed in 12% of the injections. In total, 31 systemic reactions, all grade 1, were reported of which two needed oral antihistamine treatment. No grade 2 or higher systemic reactions were observed. Six patients (15%) did not reach the highest dose due to LLR and/or systemic reactions needing antihistamines (20% in the regular regimen, 16% in the intermediate regimen and 13% in the fast regimen). At the end of the study, an improvement in the CPT was observed in 82.1% of patients, indirectly indicating an early treatment effect at the current dose and higher doses. In addition, IgG4 immunoglobulin levels were significantly increased in all groups following treatment. CONCLUSIONS: In this open-label study, allergoid HDM immunotherapy in doses up to 40,000 AUeq was generally well tolerated and no clinically relevant safety issues were identified. In the safety aspects of the three up-dosing regimens no clinically relevant differences were encountered. Therefore, these dose ranges and up-dosing regimens can be safely included in future dose-finding efficacy studies. PMID- 23657149 TI - The road to medical vibrational spectroscopy--a history. AB - The present Editorial chronicles the journey from classical infrared and Raman spectroscopy to medical vibrational spectroscopy, as experienced by a contemporary witness of the times. During the second half of the last century vibrational biospectroscopy became a topic of increasing global interest and has spawned a number of international conferences of which the most recent, SPEC 2012 - Shedding New Light on Disease, constitutes the basis of the present themed issue. PMID- 23657150 TI - A diet enriched in linoleic acid compromises the cryotolerance of embryos from superovulated beef heifers. AB - Dietary rumen-protected fat rich in linoleic acid may affect the superovulatory response and embryo yield; however, its effects on in vivo embryo cryotolerance are unknown in zebu cattle. The present study evaluated the production and cryotolerance after freezing or vitrification of embryos from Nelore heifers supplemented with rumen-protected polyunsaturated fatty acids (PUFA). Forty heifers kept in pasture were randomly distributed into two groups according to the type of feed supplement (F, supplement with rumen-protected PUFA, predominantly linoleic; C, control fat-free supplement with additional corn). Supplements were formulated to be isocaloric and isonitrogenous. Each heifer underwent both treatments in a crossover design with 70 days between replicates. After 50 days feeding, heifers were superovulated. Embryos were evaluated morphologically and vitrified or frozen. After thawing or warming, embryo development was evaluated in vitro. There was no difference between the F and C groups (P>0.10) in terms of embryo production. Regardless of the cryopreservation method used, Group C embryos had a greater hatching rate after 72h in vitro culture than Group F embryos (44.3+/-4.2% (n=148) vs 30.9+/-4.0% (n=137), respectively; P=0.04). Moreover, vitrified and frozen embryos had similar hatching rates (P>0.10). In conclusion, dietary rumen-protected PUFA rich in linoleic acid did not improve embryo production and compromised the cryotolerance of conventionally frozen or vitrified embryos from Nelore heifers. PMID- 23657151 TI - Carbohydrate intake and nonalcoholic fatty liver disease. AB - PURPOSE OF REVIEW: Carbohydrate consumption has been implicated in the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). Reviewed here is basis for this relationship and the recent additional evidence that excessive dietary carbohydrate consumption, especially excessive fructose or sucrose consumption, is playing a role in the epidemic of NAFLD. RECENT FINDINGS: A recent cross sectional epidemiological study has linked fructose consumption to the severity of fibrosis in patients with NAFLD. Clinical trials have shown that consumption of fructose-containing beverages, either has fructose or sucrose, contribute to the development of NAFLD compared to isocaloric alternatives, and that genetic polymorphisms that increase the entry of glucose into lipogenic pathways are associated with fatty liver disease. New animal studies provide additional evidence on the role of carbohydrate-induced de-novo lipogenesis and the gut microbiome in fructose-induced NAFLD. Data also suggest that fructose-induced uric acid production in the liver also plays a role in NAFLD independent of the role of fructose as a substrate for lipogenesis. SUMMARY: Epidemiological studies, clinical trials, and animal studies continue to point to excess dietary carbohydrate, and especially fructose, in contributing to the risk factors for NAFLD. PMID- 23657152 TI - High-sugar diets, type 2 diabetes and Alzheimer's disease. AB - PURPOSE OF REVIEW: Recent findings suggest that high-sugar diets can lead to cognitive impairment predisposing to neurodegenerative disorders such as Alzheimer's disease. This article discusses metabolic derangements induced by high-fructose/sucrose diets and presents evidence for the involvement of insulin resistance in sporadic Alzheimer's disease pathogenesis. RECENT FINDINGS: There has been much concern regarding the role of dietary sugars (fructose/sucrose) in the development of type 2 diabetes (T2D). Accumulating evidence has also demonstrated a connection between T2D and Alzheimer's disease. The risk for developing T2D and Alzheimer's disease increases exponentially with age and having T2D increases the risk of developing Alzheimer's disease. SUMMARY: The incidence of T2D increased dramatically over the last decades mainly due to Western lifestyle factors such as lack of exercise and high calorie diets. In fact, high-sugar diets are thought to promote weight gain and insulin resistance predisposing to T2D. To aggravate this scenario, it has been consistently shown that T2D is a risk factor for Alzheimer's disease and both disorders share similar demographic profiles, risk factors, and clinical and biochemical features (e.g. insulin resistance). Therefore, dietary changes can significantly reduce the risk of T2D and Alzheimer's disease and thereby increase the quality of life and improve longevity. PMID- 23657153 TI - Epigenetic impact of dietary isothiocyanates in cancer chemoprevention. AB - PURPOSE OF REVIEW: There is growing evidence that cancer chemopreventive agents including isothiocyanates (ITCs) from cruciferous vegetables target epigenetic mechanisms. The present report will summarize novel findings of ITCs on histone deacetylase activity, DNA methylation, and short noncoding microRNAs, focusing on sulforaphane (SFN) from broccoli and phenethylisothiocyanate from watercress. RECENT FINDINGS: In a human intervention study, broccoli sprouts led to more efficient histone deacetylase inhibition in blood cells than a broccoli sprout supplement, correlating with higher levels of urinary ITC metabolites. A proteomics study with 14C-labeled ITCs revealed among others a direct interaction with histones and chromatin-modulating proteins. The well investigated Kelch-like erythroid-cell-derived protein with CNC homology-associated protein 1/nuclear factor erythroid 2-related factor 2/antioxidant-response element pathway is both affected by and mechanistically involved in epigenetic activities of ITCs. Accordingly, reduction of oxidative stress is shown to prevent hypertension associated global hypomethylation in rats. Combination of SFN with (-) epigallocatechin gallate as a demethylating agent is identified as an effective approach for re-expression of estrogen receptor in hormone negative breast cancer. Induction of miR-200c by SFN prevents epithelial-mesenchymal-transition and could be relevant for prevention of metastases. SUMMARY: The last year has identified interesting areas of ITCs affecting epigenetic mechanisms that will have implications for translational cancer (prevention) research once validated in animal studies and human intervention studies. PMID- 23657154 TI - Long chain fatty acids and gene expression in inflammation and immunity. AB - PURPOSE OF REVIEW: The purpose of this review is to discuss recent studies reporting on the influence of fatty acids on gene expression in relation to inflammation and immune responses. RECENT FINDINGS: Saturated fatty acids promote, whereas several n-3 fatty acids, in particular eicosapentaenoic and docosahexaenoic acids, some isomers of conjugated linoleic acid, and punicic acid suppress, expression of inflammatory genes. The most common targets of fatty acids are genes encoding cytokines, chemokines, cyclooxygenase, nitric oxide synthase, and matrix metalloproteinases. The anti-inflammatory actions of fatty acids often involve inhibition of activation of nuclear factor-kappaB and activation of peroxisome proliferator-activated receptors alpha and gamma. Common upstream events include actions on Toll-like receptors and via G-protein coupled receptors. Fatty acids can influence expression of genes involved in immune and inflammatory cell development and differentiation. Recent studies using genome wide analyses demonstrate that dietary fatty acids can alter expression of a large number (many hundreds) of genes in human peripheral blood mononuclear cells. SUMMARY: A wide range of fatty acids alter expression of genes involved in development, differentiation, and function of cells involved in inflammation and immunity. PMID- 23657155 TI - Editorial: genes and cell metabolism. PMID- 23657157 TI - Surveillance of antibiotic susceptibility of Enterobacteriaceae isolated from urine samples collected from community patients in a large metropolitan area, 2010-2012. AB - Antibiotic susceptibilities of large cohorts of Enterobacteriaceae isolated from urine collected in the community are scarce. We report the susceptibilities of Enterobacteriaceae isolated from urine of non-selected community populations in a metropolitan area (Leeds and Bradford, UK) over 2 years. Isolates (n = 6614) were identified as follows: Escherichia coli (n = 5436), Klebsiella spp. (n = 525), Proteus mirabilis (n = 305), and 15 other species (n = 290); 58 isolates were unidentified. Ampicillin resistance was observed in 53% E. coli and 28% P. mirabilis; >=34% E. coli and P. mirabilis were non-susceptible to trimethoprim compared to 20% Klebsiella spp.; nitrofurantoin resistance was observed in 3% E. coli and 15% Klebsiella spp. The occurrence of extended-spectrum beta-lactamases (ESBL) was low (6%), as was non-susceptibility to carbapenems, cefipime and tigecycline (<2%). Further surveillance is required to monitor this level of resistance and additional clinical studies are needed to understand the impact on the outcome of current empirical prescribing decisions. PMID- 23657156 TI - Metabolomic profiling of urine: response to a randomised, controlled feeding study of select fruits and vegetables, and application to an observational study. AB - Metabolomic profiles were used to characterise the effects of consuming a high phytochemical diet compared with a diet devoid of fruits and vegetables (F&V) in a randomised trial and cross-sectional study. In the trial, 8 h fasting urine from healthy men (n 5) and women (n 5) was collected after a 2-week randomised, controlled trial of two diet periods: a diet rich in cruciferous vegetables, citrus and soya (F&V), and a fruit- and vegetable-free (basal) diet. Among the ions found to differentiate the diets, 176 were putatively annotated with compound identifications, with forty-six supported by MS/MS fragment evidence. Metabolites more abundant in the F&V diet included markers of the dietary intervention (e.g. crucifers, citrus and soya), fatty acids and niacin metabolites. Ions more abundant in the basal diet included riboflavin, several acylcarnitines and amino acid metabolites. In the cross-sectional study, we compared the participants based on the tertiles of crucifers, citrus and soya from 3 d food records (n 36) and FFQ (n 57); intake was separately divided into the tertiles of total fruit and vegetable intake for FFQ. As a group, ions individually differential between the experimental diets differentiated the observational study participants. However, only four ions were significant individually, differentiating the third v. first tertile of crucifer, citrus and soya intake based on 3 d food records. One of these ions was putatively annotated: proline betaine, a marker of citrus consumption. There were no ions significantly distinguishing tertiles by FFQ. The metabolomic assessment of controlled dietary interventions provides a more accurate and stronger characterisation of the diet than observational data. PMID- 23657158 TI - Lifestyle and nutritional imbalances associated with Western diseases: causes and consequences of chronic systemic low-grade inflammation in an evolutionary context. AB - In this review, we focus on lifestyle changes, especially dietary habits, that are at the basis of chronic systemic low grade inflammation, insulin resistance and Western diseases. Our sensitivity to develop insulin resistance traces back to our rapid brain growth in the past 2.5 million years. An inflammatory reaction jeopardizes the high glucose needs of our brain, causing various adaptations, including insulin resistance, functional reallocation of energy-rich nutrients and changing serum lipoprotein composition. The latter aims at redistribution of lipids, modulation of the immune reaction, and active inhibition of reverse cholesterol transport for damage repair. With the advent of the agricultural and industrial revolutions, we have introduced numerous false inflammatory triggers in our lifestyle, driving us to a state of chronic systemic low grade inflammation that eventually leads to typically Western diseases via an evolutionary conserved interaction between our immune system and metabolism. The underlying triggers are an abnormal dietary composition and microbial flora, insufficient physical activity and sleep, chronic stress and environmental pollution. The disturbance of our inflammatory/anti-inflammatory balance is illustrated by dietary fatty acids and antioxidants. The current decrease in years without chronic disease is rather due to "nurture" than "nature," since less than 5% of the typically Western diseases are primary attributable to genetic factors. Resolution of the conflict between environment and our ancient genome might be the only effective manner for "healthy aging," and to achieve this we might have to return to the lifestyle of the Paleolithic era as translated to the 21st century culture. PMID- 23657159 TI - Gemfibrozil impairs imatinib absorption and inhibits the CYP2C8-mediated formation of its main metabolite. AB - Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, gemfibrozil reduced the peak plasma concentration (Cmax) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the Cmax and area under the plasma concentration-time curve (AUC0-infinity) of N-desmethylimatinib by 56 and 48% (P < 0.001), respectively, whereas the AUC0-infinity of imatinib was unaffected. Furthermore, gemfibrozil reduced the Cmax/plasma concentration at 24 h (C24 h) ratios of imatinib and N-desmethylimatinib by 44 and 17% (P < 0.05), suggesting diminished daily fluctuation of imatinib plasma concentrations during concomitant use with gemfibrozil. Our findings indicate significant participation of CYP2C8 in the metabolism of imatinib in humans, and support involvement of an intestinal influx transporter in imatinib absorption. PMID- 23657160 TI - Industry and regulatory performance in 2012: a year in review. AB - 2012 was a robust year for new molecular entity (NME) approvals in the major geographic regions. What is behind this apparent improved performance? Has the pharmaceutical industry turned the tide in research and development productivity? In this analysis, we look not only at the number of approvals in 2012 but also at their clinical and market potential. We discuss how changes in the regulatory and reimbursement environment impact current industry performance and how this might evolve. PMID- 23657161 TI - A systematic approach to the development of novel therapeutics for lung cancer using genomic analyses. AB - Molecularly targeted drugs for cancer therapy represent a therapeutic advance, but the proportion of patients who receive clinical benefit is still very limited. We present here the rationale and initial results of our program to define molecules involved in lung carcinogenesis with the goal of identifying new therapeutic targets and/or predictive biomarkers for drug response. We have used gene expression analysis of 120 lung cancers followed by RNA interference, tumor tissue microarray analysis, and functional analyses to systematically distinguish potential target molecules specifically expressed in cancer cells. Through this approach, we have identified oncoproteins that provide the starting point for the development of therapeutic antibodies, dominant negative peptides, small-molecule inhibitors, and therapeutic cancer vaccines. We believe that the approach we describe should result in new molecularly targeted therapies with minimal risk of adverse events. PMID- 23657162 TI - Depressed systolic function after a prolonged and strenuous exercise. AB - INTRODUCTION: Prolonged and strenuous exercise (PSE) induces transient left ventricular (LV) dysfunction. Although a consensus exists regarding the decrease in diastolic function, the existence of a decrease in systolic function by a PSE remains controversial, probably due to the transient tachycardia and changes in loading conditions observed upon the completion of exercise. Therefore, the objective was to evaluate LV systolic function before and after a PSE using two dimensional speckle tracking echocardiography not only at rest but also during incremental tests to adjust heart rates (HR). METHODS AND RESULTS: Sixteen healthy young men (23 +/- 3 yr old) performed a 3-h period of intensity controlled upright cycling. LV strain (S), systolic strain rate (SR), rotation, and systolic rotational rate were evaluated by two-dimensional speckle tracking echocardiography before and after a 3-h period of PSE at rest and during incremental tests. Posttest evaluation was performed once the HR had returned to the pretest value. Under resting conditions, parameters of systolic function were either unchanged or increased after the PSE. However, during the incremental test, all LV systolic SR and apical rotational rates were decreased after PSE (radial SR at workload 3 (W3): 2.21 +/- 0.12.s(-1) vs 1.87 +/- 0.10.s(-1), P < 0.01 and apical rotational rate at W3: 128 +/- 28 deg.s(-1) vs 105 +/- 26 deg.s( 1), P < 0.05). Regression analyses between LV systolic SR and HR showed lower y intercepts without differences in slopes, suggesting a decrease of both global and regional systolic functions irrespective of HR after the PSE. CONCLUSION: Our findings based on LV S and SR data during incremental tests demonstrate that the 3-h period of PSE induces LV systolic dysfunction. PMID- 23657163 TI - High prevalence of exercise-induced laryngeal obstruction in athletes. AB - INTRODUCTION: Unexplained respiratory symptoms reported by athletes are often incorrectly considered secondary to exercise-induced asthma. We hypothesized that this may be related to exercise-induced laryngeal obstruction (EILO). This study evaluates the prevalence of EILO in an unselected cohort of athletes. METHODS: We retrospectively reviewed the prevalence of EILO in a cohort of athletes (n = 91) referred consecutively during a 2-yr period for asthma workup including continuous laryngoscopy during exercise (CLE) testing. We compared clinical characteristics and bronchial hyperreactivity between athletes with and without EILO. RESULTS: Of 88 athletes who completed a full workup, 31 (35.2%) had EILO and 38 (43.2%) had a positive bronchoprovocation or bronchodilator reversibility test. The presence of inspiratory symptoms did not differentiate athletes with and without EILO. Sixty-one percent of athletes with EILO and negative bronchoprovocation and bronchodilator reversibility tests used regular asthma medication at referral. CONCLUSIONS: In athletes with unexplained respiratory symptoms, EILO is an important differential diagnosis not discerned from other etiologies by clinical features. These findings have important implications for the assessment and management of athletes presenting with persistent respiratory symptoms despite asthma therapy. PMID- 23657164 TI - Development of an injury risk function for first metatarsophalangeal joint sprains. AB - INTRODUCTION: Sprains of the first metatarsophalangeal (1MTP) joint, also known as turf toe, are debilitating athletic injuries. Because 85% of 1MTP sprains result from excessive hallux dorsiflexion, interventions that limit motion to subinjurious levels would greatly benefit athletes. Hallux dorsiflexion range of motion (hdROM) cannot be overly constrained, however, lest athletic performance be compromised. Therefore, the tolerance of the 1MTP joint to excessive dorsiflexion injury must be quantified before appropriate hdROM limitations may be developed. The purpose of this study was to develop a quantitative injury risk function for 1MTP sprains on the basis of hallux dorsiflexion angle. METHODS: Twenty cadaveric limbs were tested to both subinjurious and injurious levels of hallux dorsiflexion. Motion capture techniques were used to track six-degree-of freedom motion of the first proximal phalanx, first metatarsal, and calcaneus. Specimens were examined by physicians posttest to diagnose injury occurrence and ensure clinical relevance of the injuries. RESULTS: A two-parameter Weibull hazard function analysis reveals that a 50% risk of injury occurs at 78 degrees of dorsiflexion from anatomical zero. CONCLUSION: Methods presented here drove cadaveric 1MTP joints to various degrees of dorsiflexion, resulting in both noninjurious and injurious trials, which were formed into an injury risk function. PMID- 23657165 TI - Nonuniform muscle hypertrophy: its relation to muscle activation in training session. AB - PURPOSE: Muscle hypertrophy in response to resistance training has been reported to occur nonuniformly along the length of the muscle. The purpose of the present study was to examine whether the regional difference in muscle hypertrophy induced by a training intervention corresponds to the regional difference in muscle activation in the training session. METHODS: Twelve young men participated in a training intervention program for the elbow extensors with a multijoint resistance exercise for 12 wk (3 d . wk(-1)). Before and after the intervention, cross-sectional areas of the triceps brachii along its length were measured with magnetic resonance images. A series of transverse relaxation time (T2)-weighted magnetic resonance images was recorded before and immediately after the first session of training intervention. The T2 was calculated for each pixel within the triceps brachii. In the images recorded after the session, the number of pixels with a T2 greater than the threshold (mean + 1 SD of T2 before the session) was expressed as the ratio to the whole number of pixels within the muscle and used as an index of muscle activation (percent activated area). RESULTS: The percent activated area of the triceps brachii in the first session was significantly higher in the middle regions than that in the most proximal region. Similarly, the relative change in cross-sectional area induced by the training intervention was also significantly greater in the middle regions than the most proximal region. CONCLUSION: The results suggest that nonuniform muscle hypertrophy after training intervention is due to the region-specific muscle activation during the training session. PMID- 23657166 TI - Gait kinematics of subjects with ankle instability using a multisegmented foot model. AB - PURPOSE: Many patients who sustain an acute lateral ankle sprain develop chronic ankle instability (CAI). Altered ankle kinematics have been reported to play a role in the underlying mechanisms of CAI. In previous studies, however, the foot was modeled as one rigid segment, ignoring the complexity of the ankle and foot anatomy and kinematics. The purpose of this study was to evaluate stance phase kinematics of subjects with CAI, copers, and controls during walking and running using both a rigid and a multisegmented foot model. METHODS: Foot and ankle kinematics of 77 subjects (29 subjects with self-reported CAI, 24 copers, and 24 controls) were measured during barefoot walking and running using a rigid foot model and a six-segment Ghent Foot Model. Data were collected on a 20-m-long instrumented runway embedded with a force plate and a six-camera optoelectronic system. Groups were compared using statistical parametric mapping. RESULTS: Both the CAI and the coper group showed similar differences during midstance and late stance compared with the control group (P < 0.05). The rigid foot segment showed a more everted position during walking compared with the control group. Based on the Ghent Foot Model, the rear foot also showed a more everted position during running. The medial forefoot showed a more inverted position for both running and walking compared with the control group. CONCLUSION: Our study revealed significant midstance and late stance differences in rigid foot, rear foot, and medial forefoot kinematics The multisegmented foot model demonstrated intricate behavior of the foot that is not detectable with rigid foot modeling. Further research using these models is necessary to expand knowledge of foot kinematics in subjects with CAI. PMID- 23657167 TI - A longitudinal study of strength and gait after arthroscopic partial meniscectomy. AB - PURPOSE: Individuals after arthroscopic partial meniscectomy (APM) are at increased risk of developing knee osteoarthritis (OA). Knee muscle weakness and a higher external knee adduction moment (KAM) are potential risk factors for knee OA. This exploratory longitudinal study assessed these risk factors at baseline in an APM group (3 months after surgery) and control group, and again 2 yrs later (follow-up). METHODS: Eighty-two participants with medial APM and 38 healthy controls were assessed at baseline, with 66 (79%) and 23 (61%), respectively, retested at follow-up. Outcome measures included isokinetic knee muscle strength and medial knee joint load inferred through indices of the KAM during normal and fast-pace walking. RESULTS: Knee muscle strength was reduced by 14%-16% in the APM leg compared with controls at baseline (P <= 0.006). However, strength increased in the APM leg over the 2 yrs such that there were no differences compared with controls at follow-up. KAM impulse was at least 20% higher for the APM group (both legs) when compared with controls at baseline and remained similarly higher 2 yrs later (P <= 0.022). At baseline peak, KAM was 18% higher in the APM leg as compared with controls only during fast-pace walking (P = 0.013). The peak KAM increased over the 2 yrs in the APM leg by 8%-9% (P <= 0.032), although there were no differences in change in KAM between the APM leg and controls. CONCLUSION: This study found that although knee muscle strength improved, dynamic medial joint load increased over the 2 yrs after APM surgery. These findings may aid in developing therapeutic interventions aimed to prevent or delay the onset of knee OA after APM. PMID- 23657168 TI - Menstrual cycle mediates vastus medialis and vastus medialis oblique muscle activity. AB - PURPOSE: Sports medicine professionals commonly describe two functionally different units of the vastus medialis (VM), the VM, and the vastus medialis oblique (VMO), but the anatomical support is equivocal. The functional difference of the VMO is principle to rehabilitation programs designed to alleviate anterior knee pain, a pathology that is known to have a greater occurrence in women. The purpose of this study was to determine whether the motor units of the VM and VMO are differentially recruited and if this recruitment pattern has an effect of sex or menstrual cycle phase. METHODS: Single motor unit recordings from the VM and VMO were obtained for men and women during an isometric ramp knee extension. Eleven men were tested once. Seven women were tested during five different phases of the menstrual cycle, determined by basal body temperature mapping. The recruitment threshold and the initial firing rate at recruitment were determined from 510 motor unit recordings. RESULTS: The initial firing rate was lower in the VMO than that in the VM in women (P < 0.001) but not in men. There was no difference in recruitment thresholds for the VM and VMO in either sex or across the menstrual cycle. There was a main effect of menstrual phase on initial firing rate, showing increases from the early follicular to late luteal phase (P = 0.003). The initial firing rate in the VMO was lower than that in the VM during ovulatory (P = 0.009) and midluteal (P = 0.009) phases. CONCLUSION: The relative control of the VM and VMO changes across the menstrual cycle. This could influence patellar pathologies that have a higher incidence in women. PMID- 23657169 TI - Footwear traction and lower extremity noncontact injury. AB - PURPOSE: Football is the most popular high school sport; however, it has the highest rate of injury. Speculation has been prevalent that foot fixation due to high footwear traction contributes to injury risk. Therefore, the purpose of the study was to determine whether a relationship exists between the athlete's specific footwear traction (measured with their own shoes on the field of play) and lower extremity noncontact injury in high school football. METHODS: For 3 yr, 555 high school football athletes had their footwear traction measured on the actual field of play at the start of the season, and any injury the athletes suffered during a game was recorded. Lower extremity noncontact injury rates, grouped based on the athlete's specific footwear traction (both translational and rotational), were compared. RESULTS: For translational traction, injury rate reached a peak of 23.3 injuries/1000 game exposures within the midrange of translational traction, before decreasing to 5.0 injuries/1000 game exposures in the high range of traction. For rotational traction, there was a steady increase in injury rate as footwear traction increased, starting at 4.2 injuries/1000 game exposures at low traction and reaching 19.2 injuries/1000 game exposures at high traction. CONCLUSIONS: A relationship exists between footwear traction and noncontact lower extremity injury, with increases in rotational traction leading to a greater injury rate and increases in translational traction leading to a decrease in injury. It is recommended that athletes consider selecting footwear with the lowest rotational traction values for which no detriment in performance results. PMID- 23657170 TI - Identification of temporal pathomechanical factors during the tennis serve. AB - PURPOSE: The purpose of this study was twofold: (a) to measure the effects of temporal parameters on both ball velocity and upper limb joint kinetics to identify pathomechanical factors during the tennis serve and (b) to validate these pathomechanical factors by comparing injured and noninjured players. METHODS: The serves of expert tennis players were recorded with an optoelectronic motion capture system. These experts were then followed during two seasons to identify overuse injuries of the upper limb. Correlation coefficients assessed the relationships between temporal parameters, ball velocity, and peaks of upper limb joint kinetics to identify pathomechanical factors. Temporal parameters and ball velocity were compared between injured and noninjured groups. RESULTS: Temporal pathomechanical factors were identified. The timings of peak angular velocities of pelvis longitudinal rotation, upper torso longitudinal rotation, trunk sagittal rotation, and trunk transverse rotation and the duration between instants of shoulder horizontal adduction and external rotation were significantly related to upper limb joint kinetics and ball velocity. Injured players demonstrated later timings of trunk rotations, improper differences in time between instants of shoulder horizontal adduction and external rotation, lower ball velocities, and higher joint kinetics. CONCLUSIONS: The findings of this study imply that improper temporal mechanics during the tennis serve can decrease ball velocity, increase upper limb joint kinetics, and thus possibly increase overuse injuries of the upper limb. PMID- 23657171 TI - Physical activity and lower limb lymphedema among uterine cancer survivors. AB - PURPOSE: Physical activity (PA) is known to provide physical and mental health benefits to uterine cancer survivors. However, it is unknown if PA is associated with lower limb lymphedema (LLL), an accumulation of protein-rich fluid in the lower limbs. Therefore, we sought to examine the association between PA and LLL in uterine cancer survivors, with a focus on walking. METHODS: We conducted a cross-sectional study using mailed surveys among uterine cancer survivors who received care at a university-based cancer center. We asked about PA, walking, and LLL symptoms using validated self-report questionnaires. PA was calculated using MET-hours per week, and walking was calculated using blocks per day. RESULTS: The response rate to our survey was 43%. Among the 213 uterine cancer survivors in our survey, 36% were classified as having LLL. Compared with participants who reported <3 MET . h . wk of PA, participants who reported >= 18.0 MET . h . wk of PA had an odds ratio of LLL of 0.32 (95% confidence interval, 0.15-0.69; P trend = 0.003). Stratified analyses suggested the association between PA and LLL existed only among women with body mass index (BMI) <30 kg . m (P trend = 0.007) compared with women with BMI >= 30 kg . m (P trend = 0.47). Compared with participants who reported <4.0 blocks per day of walking, participants who reported >= 12 blocks per day of walking had an odds ratio of LLL of 0.19 (95% confidence interval, 0.09-0.43; P trend < 0.0001). Stratified analyses suggested the association between walking and LLL was similar among women with BMI <30 kg . m (P trend = 0.007) and women with BMI >= 30 kg . m (P trend = 0.03). CONCLUSION: Participation in higher levels of PA or walking is associated with reduced proportions of LLL in dose-response fashion. These findings should be interpreted as preliminary and should be investigated in future studies. PMID- 23657172 TI - Partial weight bearing does not prevent musculoskeletal losses associated with disuse. AB - PURPOSE: The purpose of this study was to investigate whether partial weight bearing activity, at either one-sixth or one-third of body mass, blunts the deleterious effects of simulated microgravity (0G) after 21 d on muscle mass and quantitative/qualitative measures of bone. METHODS: Using a novel, previously validated partial weight-bearing suspension device, mice were subjected to 16% (G/3, i.e., simulated lunar gravity) or 33% (G/6, i.e., simulated Martian gravity) weight bearing for 21 d. One gravity control (1G, i.e., Earth gravity) and tail-suspended mice (0G, i.e., simulated microgravity) served as controls to compare the effects of simulated lunar and Martian gravity to both Earth and microgravity. RESULTS: Simulated microgravity (0G) resulted in an 8% reduction in body mass and a 28% lower total plantarflexor muscle mass (for both, P < 0.01) as compared with 1G controls, but one-sixth and one-third partial weight-bearing activity attenuated losses. Relative to 1G controls, trabecular bone volume fraction (-9% to -13%) and trabecular thickness (-10% to -14%) were significantly lower in all groups (P < 0.01). In addition, cancellous and cortical bone formation rates (BFR) were lower in all reduced weight-bearing groups compared with 1G controls (-46% to -57%, trabecular BFR; -73% to -85%, cortical BFR; P < 0.001). Animals experiencing one-third but not one-sixth weight bearing exhibited attenuated deficits in femoral neck mechanical strength associated with 0G. CONCLUSION: These results suggest that partial weight bearing (up to 33% of body mass) is not sufficient to protect against bone loss observed with simulated 0 g but does mitigate reductions in soleus mass in skeletally mature female mice. PMID- 23657174 TI - Admission hyperglycemia predicts inhospital mortality and major adverse cardiac events after primary percutaneous coronary intervention in patients without diabetes mellitus. AB - Admission hyperglycemia is associated with high inhospital and long-term adverse events in patients that undergo primary percutaneous coronary intervention (PCI). We aimed to evaluate whether hyperglycemia predicts inhospital mortality. We prospectively analyzed 503 consecutive patients. The patients were divided into tertiles according to the admission glucose levels. Tertile I: glucose <118 mg/dL (n = 166), tertile II: glucose 118 to 145 mg/dL (n = 168), and tertile III: glucose >145 mg/dL (n = 169). Inhospital mortality was 0 in tertile I, 2 in tertile II, and 9 in tertile III (P < .02). Cardiogenic shock occurred more frequently in tertile III compared to tertiles I and II (10% vs 4.1% and 0.6%, respectively, P = .01). Multivariate logistic regression analysis revealed that patients in tertile III had significantly higher risk of inhospital major adverse cardiac events compared to patients in tertile I (odds ratio: 9.55, P < .02). Admission hyperglycemia predicts inhospital adverse cardiac events in mortality and acute ST-segment elevation myocardial infarction in patients that underwent primary PCI. PMID- 23657175 TI - Anxiety score as a risk factor for radial artery vasospasm during radial interventions: a pilot study. AB - We determined the role of anxiety level on radial artery spasm during transradial coronary angiography. Eighty-one patients who had an indication for coronary angiography were enrolled. Radial artery vasospasm was determined by addressing 5 signs: persistent forearm pain, pain response to catheter manipulation, pain response to sheath withdrawal, difficult catheter manipulation after being "trapped" by the radial artery, and considerable resistance on withdrawal of sheath. Radial spasm defined as at least 2 of the 5 signs. The Hamilton Anxiety scale questionnaire was used to determine the level of anxiety. Vasospasm was observed in 19.1% of the patients. Anxiety score was significantly higher in women (11.1 +/- 7.2 vs 17.6 +/- 7.3; P < .001). Vasospasm was significantly correlated with female sex (P < .001, r = .43) and anxiety score (P = .007, r = .29). Female sex was associated with higher anxiety scores (P < .001, r = .43). In conclusion, higher anxiety scores and female sex are important risk factors for radial artery vasospasm. PMID- 23657176 TI - Neutrophil-to-lymphocyte ratio is associated with severity of coronary artery ectasia. AB - We investigated the association between coronary artery ectasia (CAE) and Neutrophil-to-lymphocyte ratio (NLR), an indicator of the inflammatory state. The study population included 434 patients (247 males, mean age 62 +/- 10 years) including 230 patients with isolated CAE and 104 patients with coronary artery disease and 100 patientss with normal coronary arteries. The NLR was measured at admission and 30 days after coronary angiography in all the patients. The NLR was significantly higher in patients with CAE than those with normal coronary arteries (2.2 +/- 0.6-1.3 +/- 0.6, P < .001). Linear regression analyses revealed that NLR (coefficient beta = -.61, P < .001) was significantly associated with severity of CAE. The NLR is significantly higher in patients with CAE compared to controls with normal coronary arteries, and NLR is associated with severity of CAE. PMID- 23657177 TI - Health-related quality of life among patients with peripheral arterial disease. AB - We evaluated health-related quality of life (HRQoL) among patients with peripheral arterial disease (PAD) and compared the results with those of the general population. We also evaluated the possible association between some demographic and clinical characteristics of patients with PAD and HRQoL. A cross sectional study involved 102 consecutive patients with verified PAD referred to the Dedinje Vascular Surgery Clinic in Belgrade. The HRQoL was measured using Medical Outcome Survey Short Form 36 (SF-36). Patients with PAD had significantly lower mean SF-36 scores for physical functioning, role-physical, bodily pain, social functioning, role-emotional, and mental health in comparison with the general population. The HRQoL was significantly more impaired in patients with severe PAD. Patients with PAD had a reduced HRQoL compared with the general population. The impact of PAD on HRQoL was independent of other factors related to both the disease and the HRQoL. PMID- 23657178 TI - EAACI International Severe Asthma Forum (ISAF 2012) Gothenburg, Sweden. 11-13 October 2012. Abstracts. PMID- 23657179 TI - The ACACA and SREBF1 genes are promising markers for pig carcass and performance traits, but not for fatty acid content in the longissimus dorsi muscle and adipose tissue. AB - Among functional and positional candidate genes for pig fatness traits, there are genes encoding acetyl-CoA carboxylase alpha (ACACA) and sterol regulatory element binding transcription factor 1 (SREBF1). In our study, 5 known and 2 novel SNPs in the ACACA gene and 2 known and 6 novel polymorphisms in the SREBF1 were found. The SNPs segregated as 6 and 10 haplotypes in ACACA and SREBF1, respectively. Two SNPs in ACACA were associated with fatness and performance traits in Polish breeds. In the SREBF1 gene, two novel SNPs were associated with daily gain and one, within a potential intronic micro-RNA gene, showed an association with fatness traits. Breed-specific differences in the transcript level were observed for ACACA only. No correlation between the transcript levels and fatty acid compositions was found in muscle and fat tissues. We concluded that polymorphisms of the ACACA and SREBF1 genes are promising markers for pig carcass and performance traits. PMID- 23657180 TI - Acne vulgaris. PMID- 23657181 TI - Acute leg ischaemia. PMID- 23657182 TI - Revising the Declaration of Helsinki. PMID- 23657183 TI - Pros and cons of drugs to prevent breast cancer. PMID- 23657184 TI - Prophylactic penicillin cuts risk of recurrent cellulitis. PMID- 23657185 TI - Viruses from ducks and chickens dominate the family tree of H7N9. PMID- 23657186 TI - Azithromycin does not look cardiotoxic in a general population. PMID- 23657187 TI - Seven ways to hone your ethics skills. PMID- 23657188 TI - MEP proposes tighter tests on potentially risky medical devices. PMID- 23657189 TI - India remains on US trade "priority watch list" for failing to uphold international drug company patents. PMID- 23657190 TI - Director of top research organization for mental health criticizes DSM for lack of validity. PMID- 23657191 TI - Implications of universal screening for HIV infection. PMID- 23657192 TI - The European Medicines Agency's plans for sharing data from clinical trials. PMID- 23657193 TI - Oak moth caterpillar that causes rash is spreading in southeast England. PMID- 23657194 TI - New drug pricing scheme could politicise decisions and reduce access, says think tank. PMID- 23657195 TI - First UK prosecution for female genital mutilation moves a step closer. PMID- 23657196 TI - What place for ?racecadotril? AB - Worldwide, there are about two billion cases of diarrhoeal disease every year and it is the second leading cause of death in children under 5 years of age, killing 1.5 million children annually.(1) The most severe threat posed by diarrhoea is dehydration. In the UK, the incidence of diarrhoea is about one episode per person per year,(2) and approximately 10% of children younger than 5 years old present to healthcare services with gastroenteritis each year.(3) ?Racecadotril (Hidrasec) is the first in a new class of antidiarrhoeal drug ('enkephalinase inhibitor') that has an antisecretory mechanism and is licensed in adults, children and infants (over 3 months of age) for symptomatic treatment of acute diarrhoea or as complementary treatment when causal treatment is possible.(4-6) Here we review the evidence for racecadotril and its place in the management of acute diarrhoea. PMID- 23657197 TI - What are biosimilars and are they important? AB - All prescribers will be familiar with the issues associated with the use of branded and generic 'chemical' medicines.(1) For biological products (e.g. epoetin, filgrastim), a biosmilar medicine is a new biological product that is similar to a medicine that has already been authorised to be marketed in the EU (the biological reference medicine).(2) Six biosimilar medicinal products are currently marketed in the UK-three versions of filgrastim (?Nivestim, ?Tevagrastim and Zarzio),(3-5) two versions of epoetin (Binocrit and Retacrit)(6,7) and one version of somatropin (Omnitrope).(8) Applications for biosimilar versions of follitropin alfa and infliximab are under evaluation by the European Medicine's Agency (EMA) Committee for Medicinal Products for Human Use.(9) In the future there may also be biosimilar versions of insulins, recombinant vaccines, interferons and monoclonal antibodies such as rituximab and trastuzumab.(10) It is estimated that about 50% of the current UK market for biological medicines by spend may be subject to biosimilar competition by 2019. In this article, we will consider the background to developing biosimilar medicines, how and why they differ from traditional generic medicines in their licensing requirements and the issues that may arise as they are introduced to clinical practice. PMID- 23657198 TI - Limitless longevity: comment on the Contribution of rectangularization to the secular increase of life expectancy. PMID- 23657199 TI - Authors' response to 'Limitless longevity': the contribution of rectangularization to the secular increase in life expectancy: an empirical study. PMID- 23657201 TI - Embryo development and sex ratio of in vitro-produced porcine embryos are affected by the energy substrate and hyaluronic acid added to the culture medium. AB - In the present study, the effects of replacing glucose with pyruvate-lactate and supplementing these in vitro culture (IVC) media with hyaluronic acid (HA) on porcine embryo development and sex ratio were examined. The in vitro-produced (IVP) porcine embryos were cultured in NCSU-23 medium with 0.0, 0.5 or 1.0mgmL( 1) HA, and with either 5.55mM glucose (IVC-Glu) or pyruvate (0.17mM)-lactate (2.73mM) from 0 to 48h post insemination (h.p.i.) and then with glucose from 48 to 168h.p.i. (IVC-PL). Those embryos cultured with IVC-PL had significantly higher blastocyst rates (23.7+/-1.5%) than those cultured with IVC-Glu (14.27+/ 2.75%). At 1.0mgmL(-1), HA tended to skew the sex ratio of blastocysts towards males in those embryos cultured in IVC-PL, and led to a significant decrease in the blastocyst rate compared with embryos cultured in the presence of 0.5 and 0.0mgmL(-1) HA and IVC-Glu (4.28+/-0.28% vs 11.01+/-1.42% and 10.14+/-2.77%, respectively) and IVC-PL (14.37+/-1.35% vs 20.96+/-2.85% and 22.99+/-1.39%, respectively). In contrast, there were no significant differences in the total cell number per blastocyst or in apoptosis rates. In conclusion, pyruvate and lactate were the preferred energy substrates in the early stages of IVP porcine embryos. Moreover, 1.0mgmL(-1) HA significantly decreased the percentage of blastocyst rates in both the IVC-Glu and IVC-PL groups, but only by a preferential loss of female embryos for those cultured in IVC-PL. PMID- 23657200 TI - Mobile phone use and risk of brain neoplasms and other cancers: prospective study. AB - BACKGROUND: Results from some retrospective studies suggest a possible increased risk of glioma and acoustic neuroma in users of mobile phones. METHODS: The relation between mobile phone use and incidence of intracranial central nervous system (CNS) tumours and other cancers was examined in 791,710 middle-aged women in a UK prospective cohort, the Million Women Study. Cox regression models were used to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs). Women reported mobile phone use in 1999 to 2005 and again in 2009. RESULTS: During 7 years' follow-up, 51,680 incident invasive cancers and 1,261 incident intracranial CNS tumours occurred. Risk among ever vs never users of mobile phones was not increased for all intracranial CNS tumours (RR = 1.01, 95% CI = 0.90-1.14, P = 0.82), for specified CNS tumour types nor for cancer at 18 other specified sites. For long-term users compared with never users, there was no appreciable association for glioma (10+ years: RR = 0.78, 95% CI = 0.55-1.10, P = 0.16) or meningioma (10+ years: RR = 1.10, 95% CI = 0.66-1.84, P = 0.71). For acoustic neuroma, there was an increase in risk with long term use vs never use (10+ years: RR = 2.46, 95% CI = 1.07-5.64, P = 0.03), the risk increasing with duration of use (trend among users, P = 0.03). CONCLUSIONS: In this large prospective study, mobile phone use was not associated with increased incidence of glioma, meningioma or non-CNS cancers. PMID- 23657202 TI - Spatial variation in the risk of hospitalization with childhood pneumonia and empyema in the North of England. AB - The aim of this study was to investigate spatial variation in risk of hospitalization in childhood pneumonia and empyema in the North of England and associated risk factors. Data on childhood (0-14 years) hospital admissions with a diagnosis pneumonia or empyema were linked to postcode districts. Bayesian conditional autoregressive models were used to evaluate spatial variation and the relevance of specific spatial covariates in an area-based study using postcode as the areal unit. There was a sixfold variation in the risk of hospitalization due to pneumonia across the study region. Variation in risk was associated with material deprivation, Child Well-being Index (CWI) health domain score, number of children requiring local authority support, and distance to hospital. No significant spatial variation in risk for empyema was found. PMID- 23657204 TI - Spectroscopic properties and reactivity of a mononuclear oxomanganese(IV) complex. AB - A non-porphyrinic, mononuclear oxomanganese(IV) complex was generated at room temperature and characterized by spectroscopic methods. The Mn(IV)=O adduct is capable of activating C-H bonds by a H-atom transfer mechanism and is more reactive in this regard than most Mn(IV)=O species. PMID- 23657206 TI - Derived patterns in binocular rivalry networks. AB - Binocular rivalry is the alternation in visual perception that can occur when the two eyes are presented with different images. Wilson proposed a class of neuronal network models that generalize rivalry to multiple competing patterns. The networks are assumed to have learned several patterns, and rivalry is identified with time periodic states that have periods of dominance of different patterns. Here, we show that these networks can also support patterns that were not learned, which we call derived. This is important because there is evidence for perception of derived patterns in the binocular rivalry experiments of Kovacs, Papathomas, Yang, and Feher. We construct modified Wilson networks for these experiments and use symmetry breaking to make predictions regarding states that a subject might perceive. Specifically, we modify the networks to include lateral coupling, which is inspired by the known structure of the primary visual cortex. The modified network models make expected the surprising outcomes observed in these experiments. PMID- 23657205 TI - Existence of G-quadruplex structures in promoter region of oncogenes confirmed by G-quadruplex DNA cross-linking strategy. AB - Existence of G-quadruplex DNA in vivo always attract widespread interest in the field of biology and biological chemistry. We reported our findings for the existence of G-quadruplex structures in promoter region of oncogenes confirmed by G-quadruplex DNA cross-linking strategy. Probes for selective G-quadruplex cross linking was designed and synthesized that show high selectivity for G-quadruplex cross-linking. Further biological studies demonstrated its good inhibition activity against murine melanoma cells. To further investigate if G-quadruplex DNA was formed in vivo and as the target, a derivative was synthesized and pull down process toward chromosome DNAs combined with circular dichroism and high throughput deep sequencing were performed. Several simulated intracellular conditions, including X. laevis oocytes, Ficoll 70 and PEG, was used to investigate the compound's pure cross-linking ability upon preformed G quadruplex. Thus, as a potent G-quadruplex cross-linking agent, our strategy provided both valuable evidence of G-quadruplex structures in vivo and intense potential in anti-cancer therapy. PMID- 23657207 TI - Tunable Pt nanocatalysts for the aerobic selox of cinnamyl alcohol. AB - The selective aerobic oxidation of cinnamyl alcohol over Pt nanoparticles has been tuned via the use of mesoporous silica supports to control their dispersion and oxidation state. High area two-dimensional SBA-15, and three-dimensional, interconnected KIT-6 silica significantly enhance Pt dispersion, and thus surface PtO2 concentration, over that achievable via commercial low surface area silica. Selective oxidation activity scales with Pt dispersion in the order KIT-6 >= SBA 15 > SiO2, evidencing surface PtO2 as the active site for cinnamyl alcohol selox to cinnamaldehyde. Kinetic mapping has quantified key reaction pathways, and the importance of high O2 partial pressures for cinnamaldehyde production. PMID- 23657208 TI - Microbiologic findings in acute facial palsy in children. AB - OBJECTIVE: Microbiologic causes of facial palsy in children were investigated. STUDY DESIGN: Prospective clinical study. SETTING: Tertiary referral center. PATIENTS: Forty-six children aged 0 to 16 years with peripheral facial palsy. INTERVENTIONS: Paired serum samples and cerebrospinal fluid were tested to find indications of microbes associated with facial palsy. The microbes tested were herpes simplex virus 1 and 2, varicella-zoster virus, human herpesvirus-6, Mycoplasma pneumoniae, Borrelia burgdorferi, influenza A and B virus, picorna, cytomegalovirus, parainfluenza virus, respiratory syncytial virus, coxsackie B5 virus, adenovirus, and enterovirus, Chlamydia psittaci, and Toxoplasma gondii. Besides the routine tests in clinical practice, serum and cerebrospinal fluid samples were tested with a highly sensitive microarray assay for DNA of herpes simplex virus 1 and 2; human herpes virus 6A, 6B, and 7; Epstein-Barr virus, cytomegalovirus, and varicella zoster virus. RESULTS: Incidence for facial palsy was 8.6/100,000/children/year. Cause was highly plausible in 67% and probable in an additional 11% of cases. Borrelia burgdorferi caused facial palsy in 14 patients (30%), varicella zoster virus in 5 (11%) (one with concomitant adenovirus), influenza A in 3 (6%), herpes simplex virus 1 in 2 (4%) (one with concomitant enterovirus), otitis media in 2 (4%), and human herpesvirus 6 in 2 (4%). Mycoplasma pneumoniae, neurofibromatosis, and neonatal age facial palsy affected 1 child (2%) each. CONCLUSION: Microbiologic etiology association of pediatric facial palsy could frequently be confirmed. Borreliosis was the single most common cause; hence, cerebrospinal fluid sampling is recommended for all pediatric cases in endemic areas. Varicella zoster virus accounted for 11% of the cases, being the second most common factor. PMID- 23657209 TI - Response to "Re: Rapid cVEMP and oVEMP responses elicited by a novel head striker and recording device". PMID- 23657210 TI - Hearing handicap in adults with unilateral deafness and bilateral hearing loss. AB - OBJECTIVE: To assess the perception of hearing handicap in adult patients with unilateral sudden sensorineural hearing loss (SNHL) compared with those with bilateral SNHL or unilateral congenital SNHL. STUDY DESIGN: Retrospective chart review. SETTING: Multicenter department of otolaryngology referrals. PATIENTS: Seventy-one subjects in the unilateral severe-profound (>70 dB) sudden SNHL group (Group 1), 17 subjects in the unilateral prelingual or congenital SNHL group (Group 2), and 121 subjects in the bilateral SNHL group (Group 3). INTERVENTIONS: Questionnaire. MAIN OUTCOME MEASURES: Hearing Handicap Inventory for Adults (HHIA) and visual analogue scale (VAS) measurements of hearing handicap. RESULTS: Average levels of hearing loss were 92 dB in Group 1, 109 dB in Group 2, and 67 dB in Group 3. The relative percentage scores of HHIA and VAS compared with Group 3 were 72.6% and 81.0% in Group 1 and 25.4% and 50.3% in Group 2, respectively. A mild correlation between the HHIA subscale or VAS scores and degree of hearing loss could be found in Group 3. No significant correlation was found between the HHIA subscale or VAS scores and duration of hearing loss in Group 1 or Group 3. Higher scores were obtained in male subjects than in female subjects. Patients in Group 1 who were troubled by tinnitus scored significantly higher in the HHIA. In multiple logistic regression analysis, presence of tinnitus, older age, higher average hearing loss level, and group (bilateral SNHL>unilateral sudden SNHL>unilateral precongenital SNHL) revealed a significant positive association with high score (>42) of HHIA (odds ratio, 3.171, 1.021, 1.031, and 6.690, respectively). CONCLUSION: The results of HHIA and VAS suggest that not only patients with bilateral SNHL but also those with unilateral sudden SNHL, particularly those who have tinnitus, experience a hearing handicap. PMID- 23657211 TI - Early computed tomography findings of the inner ear after stapes surgery and its clinical correlations. AB - OBJECTIVE: Pneumolabyrinth resulting from temporal bone trauma and stapes luxation has been associated with sensorineural hearing loss (SNHL). The principal purpose of this study was to determine the incidence and volume of pneumolabyrinth after stapedotomy in which iatrogenic perilymphatic fistula is created and to also correlate this with possible hearing loss and vertigo. STUDY DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS AND METHODS: Fifty stapedotomy patients were operated on for otosclerosis, and of those 50, 20 underwent high-resolution computed tomography (CT) on the first day, 10 on the third day, and 20 on the seventh day. The patients followed up regarding SNHL and vertigo that could develop postoperatively, and the correlation of such complications with HRCT findings was examined. RESULTS: The 20 patients who had high-resolution CT (HRCT) on the first day all presented with pneumolabyrinth, and none of the 20 patients who underwent HRCT on the seventh day had pneumolabyrinth. Postoperatively, 92% of the patients had less than 20 dB and 62% had less than 10 dB air-bone gap. None of the patients had SNHL or persistent vertigo. There was no correlation between pneumolabyrinth and hearing loss or vertigo. CONCLUSION: Pneumolabyrinth is a radiological sign of perilymphatic fistula and has no effect on sensorineural hearing loss and vertigo. Observing pneumolabyrinth during the early postoperative stage should not necessarily implicate a complication; however, pneumolabyrinth after the first week supported with the clinical symptoms of perilymphatic fistula would be a meaningful finding. PMID- 23657213 TI - Association between leisure time, physical activity, and mood disorder levels in individuals with epilepsy. AB - The aim of this study was to investigate the association between physical activity levels (occupational, sports, and leisure time activities), depression, anxiety, and epilepsy. The behavioral outcomes of individuals with epilepsy (E) were also compared with healthy control subjects (C). The sample included 31 individuals with epilepsy (12 with idiopathic generalized epilepsy and 19 with partial epilepsy) and 31 control subjects. Self-rating questionnaires were used to assess mood (State-Trait Anxiety Inventory and Beck Depression Inventory), anxiety, and depression as well as habitual physical activity. Patients with epilepsy were more severely impaired compared to control subjects in both mood questionnaires and presented higher levels of depression (35%), state anxiety (18%), and trait anxiety (12.6%) when compared to the C group. Although physical activity level did not differ significantly between groups, linear regression analyses showed that the physical activity leisure level predicted 31% of depression levels and 26% of anxiety levels in the E group. These data suggest that low levels of physical activity may be considered a risk factor for the development of depression and anxiety and can play an important role in the quality of life of individuals with epilepsy. PMID- 23657215 TI - Asymmetric hydrogenation of beta-amino ketones with the bimetallic complex RuPHOX Ru as the chiral catalyst. AB - Asymmetric hydrogenations of a series of beta-amino ketones were carried out with a bimetallic complex (RuPHOX-Ru) as the chiral catalyst. Almost all the reactions (performed in a mixed solvent system of toluene and H2O in the presence of KOH) gave quantitative conversions into their respective products with up to 99.9% ee. The RuPHOX-Ru catalyst is stable to both moisture and air. The procedure has the benefits of being inexpensive, environmentally friendly and highly efficient. Under a relatively low catalyst loading (TON = 2000), key intermediates of fluoxetine, tomoxetine and nisoxetine could be obtained in quantitative yield and in up to 99.9% ee. This methodology represents a promising alternative to the synthesis of the aforementioned drugs and their analogues. PMID- 23657214 TI - Stereoselective cross aldol condensation of bicyclo[3.2.0]alkanones. AB - A cross aldol reaction between [(S)-(-)] or [(R)-(+)]-benzyloxypropanal and silyl enol ethers derived from bicyclo[3.2.0]alkanones was carried out in the presence of TiCl4, leading with total stereoselectivity to a 1 : 1 mixture of enantiomerically pure diastereomers isolated in 81% overall yield. Thus, 5 stereogenic centers could be created starting from one. Furthermore, an efficient access to an enantiomerically pure tricyclo[5.3.0.0(2,6)]decane scaffold was possible via a 4 step reaction sequence. PMID- 23657218 TI - Hospital antibiotic use and its relationship to age-adjusted comorbidity and alcohol-based hand rub consumption. AB - The objective of this study was to evaluate the effect of age-adjusted comorbidity and alcohol-based hand rub on monthly hospital antibiotic usage, retrospectively. A multivariate autoregressive integrated moving average (ARIMA) model was built to relate the monthly use of all antibiotics grouped together with age-adjusted comorbidity and alcohol-based hand rub over a 5-year period (April 2005-March 2010). The results showed that monthly antibiotic use was positively related to the age-adjusted comorbidity index (concomitant effect, coefficient 1.103, P = 0.0002), and negatively related to the use of alcohol based hand rub (2-month delay, coefficient -0.069, P = 0.0533). Alcohol-based hand rub is considered a modifiable factor and as such can be identified as a target for quality improvement programmes. Time-series analysis may provide a suitable methodology for identifying possible predictive variables that explain antibiotic use in healthcare settings. Future research should examine the relationship between infection control practices and antibiotic use, identify other infection control predictive factors for hospital antibiotic use, and evaluate the impact of enhancing different infection control practices on antibiotic use in a healthcare setting. PMID- 23657219 TI - Infection-induced autoantibodies and pregnancy related pathology: an animal model. AB - In addition to being the main cause of mortality worldwide, bacterial and viral infections can be the cause of autoimmune and pregnancy disorders as well. The production of autoantibodies during infection can be explained by various mechanisms, including molecular mimicry, bystander cell activation and epitope spreading. Conversely, bacterial and viral infections during pregnancy are especially dangerous for the fetus. It is documented that infection-induced inflammatory processes mediated by Toll-like receptors (TLR) represent the main cause of preterm labour. We used two crucial bacterial components and TLR ligands, namely peptidoglycan and lipopolysaccharide, to stimulate BALB/c mice before immunisation with tetanus toxoid. Tetanus toxoid is an inactive form of the toxin produced by bacterium Clostridium tetani and shares structural similarity with plasma protein beta2-glycoprotein I. Treatment with peptidoglycan and lipopolysaccharide in combination with tetanus toxoid induced the production of pathological autoantibodies, different fluctuations in natural autoantibodies and different types of reproductive pathology in treated animals, with peptidoglycan treatment being more deleterious. We propose that the production of pathological autoantibodies, TLR activation and changes in natural autoantibodies play crucial roles in infection-induced reproductive pathology in our animal model. PMID- 23657220 TI - Expression of endoglin (CD105) and endothelial nitric oxide synthase in head and neck arteriovenous malformations. AB - IMPORTANCE: Endoglin (CD105) and endothelial nitric oxide synthase (eNOS) assist in regulating vascular development. Variation in expression of these factors is linked to errors in vascular growth and remodeling in invasive lesions. OBJECTIVE: To clarify the role of endoglin and eNOS in the growth of extracranial head and neck arteriovenous malformations (AVMs), an invasive and high-flow vascular anomaly. DESIGN AND SETTING: Immunohistochemistry and Western blot study at an academic research center. SPECIMENS: Frozen and formalin-fixed paraffin processed human AVMs (n = 14) were examined for expression of CD105 and eNOS. Expression in infantile hemangiomas (n = 9) and in normal skin with subcutaneous tissue (n = 9) was used for comparison. MAIN OUTCOME MEASURES: Quantitative assessment and localization of CD105 and eNOS protein expression were performed on each specimen by immunohistochemistry and Western blot analysis. Protein expression levels were compared with beta-actin level and were semiquantitatively assessed. RESULTS: Abundant CD105 protein was found in AVMs but was not present in infantile hemangiomas or normal skin with subcutaneous tissue. Expression of eNOS protein in AVMs and infantile hemangiomas was similar (P = .20) and was significantly greater than that in normal skin with subcutaneous tissue (P < .001 and P = .008, respectively). Immunohistochemistry demonstrated that CD105 and eNOS are predominantly located in AVM vascular endothelial cells. CONCLUSIONS AND RELEVANCE: CD105 and eNOS are present and significantly expressed in head and neck AVMs. Expression of CD105 and eNOS may have an important role in the angiogenesis and vascular remodeling of AVMs. CD105 can be used as a specific marker for AVM endothelial cells. PMID- 23657221 TI - Densitometry based microassay for the determination of lipase depolymerizing activity on polyhydroxyalkanoate. AB - A novel method for the assay of polyhydroxyalkanoate (PHA)-degrading ability of triacylglycerol lipases was developed. By applying the natural affinity of lipases towards hydrophobic interfaces, a sensitive and rapid densitometry analysis for the evaluation of hydrolytic activity of lipase droplets towards PHA coated surface was successfully carried out. We found that 12 out of 14 tested lipases which are of fungal, bacterial and animal origin were able to hydrolyze P(3HB-co-92 mol% 4HB) thin film. The patterns and opacity of the hydrolysis spots of lipases on PHA films allowed easy comparison of PHA-hydrolytic strength of lipases. Lipase from the bacterium Chromobacterium viscosum exhibited the highest PHA-degrading activity. The hydrolytic activity of lipases on water insoluble PHA, emulsified p-nitrophenyl laurate and olive oil were also compared and interestingly some lipases showed better activity when PHA was used as a substrate. PMID- 23657222 TI - Dementia. PMID- 23657224 TI - Cutting down on your Cola drinks. PMID- 23657227 TI - Reconnecting health visiting and public health. PMID- 23657228 TI - A celebration of Scotland - Malawi Youth Links: building international connections for a better world, for better health. PMID- 23657229 TI - Policy report: working to improve mental health and wellbeing. PMID- 23657230 TI - In practice: working towards dementia friendly societies. PMID- 23657231 TI - Feature: the 2014 Research Excellence Framework assessment. PMID- 23657232 TI - Public health and crisis leadership in the 21st century. AB - Public health crises are becoming increasingly complex, and as such leaders need to revisit their roles and consider new problems arising for public health today. Dr Luke Lawton, of Redcliffe Hospital in Queensland, Australia examines the nature of leadership and provides some pointers on crisis planning. PMID- 23657233 TI - Action needed to combat food and drink companies' social media marketing to adolescents. AB - Reports have shown how behavioural marketing through social media sites is heavily dominated by soft drink and fast food franchises, with additional concern arising due to the direct targeting of this marketing at 13 to 17-year-olds. Dr Simon Williams from Northwestern University, Chicago, USA suggests ways in which the medical community can tackle this threat to public health. PMID- 23657234 TI - Malnutrition in the UK. AB - Malnutrition is estimated to cost the UK twice that of obesity every year, but it is still an often overlooked problem. Dr Mabel Blades, a freelance Registered Dietician and Nutritionist, looks at the problems that malnutrition presents and the solutions that we can use to combat it. PMID- 23657235 TI - Should we be gritting pavements to prevent pedestrian injuries? AB - Unintentional injuries are an important public health issue, and are a significant burden on health and social services, especially during the winter months. Dr Rob Atenstaedt, Consultant in Public Health Medicine, Public Health Wales & Honorary Senior Lecturer, Bangor University and Professor Michael Rees, University Director of Medical Development & Professor of Cardiovascular Studies, Bangor University look at the importance of pavement gritting in preventing injuries and falls in pedestrians. PMID- 23657238 TI - Toll-like receptor-associated sequence variants and prostate cancer risk among men of African descent. AB - Recent advances demonstrate a relationship between chronic/recurrent inflammation and prostate cancer (PCA). Among inflammatory regulators, toll-like receptors (TLRs) have a critical role in innate immune responses. However, it remains unclear whether variant TLR genes influence PCA risk among men of African descent. Therefore, we evaluated the impact of 32 TLR-associated single nucleotide polymorphisms (SNPs) on PCA risk among African Americans and Jamaicans. SNP profiles of 814 subjects were evaluated using Illumina's Veracode genotyping platform. Single and combined effects of SNPs in relation to PCA risk were assessed using age-adjusted logistic regression and entropy-based multifactor dimensionality reduction (MDR) models. Seven sequence variants detected in TLR6, TOLLIP (Toll-interacting protein), IRAK4 (interleukin-1 receptor-associated kinase 4) and IRF3 (interferon regulatory factor 3) were marginally related to PCA. However, none of these effects remained significant after adjusting for multiple hypothesis testing. Nevertheless, MDR modeling revealed a complex interaction between IRAK4 rs4251545 and TLR2 rs1898830 as a significant predictor of PCA risk among US men (permutation testing P value=0.001). However, these findings require further assessment and validation. PMID- 23657239 TI - Hydrochlorothiazide and high-fat diets reduce plasma magnesium levels and increase hepatic oxidative stress in rats. AB - This study was designed to develop a rodent model of hydrochlorothiazide (HCTZ) toxicity by associating its intake with a high-fat (HF) diet. Rats were fed for 16 weeks with a control diet or with an HF diet supplemented or not with different doses of HCTZ. HCTZ, in a similar way to the HF diet, caused a significant increase in fructosamine levels. HCTZ and HF diet intake caused a significant reduction in magnesium and potassium levels, as well as an increase in lipid peroxidation and vitamin C in liver. Importantly, negative correlations were found between magnesium and glucose levels as well as between magnesium and fructosamine levels. The association between HCTZ and the HF diet caused additional worsening of biochemical parameters related to glucose homeostasis, and further increased hepatic oxidative stress. Our results suggest that chronic intake of HCTZ or an HF diet causes metabolic changes that are consistent with the development of insulin resistance. In addition, the association of an HF diet and HCTZ treatment can exacerbate some of these biochemical alterations, suggesting that this model might be useful for studying HCTZ metabolic toxicity. PMID- 23657240 TI - Molecular evolution of human adenoviruses. AB - The recent emergence of highly virulent human adenoviruses (HAdVs) with new tissue tropisms underscores the need to determine their ontogeny. Here we report complete high quality genome sequences and analyses for all the previously unsequenced HAdV serotypes (n = 20) within HAdV species D. Analysis of nucleotide sequence variability for these in conjunction with another 40 HAdV prototypes, comprising all seven HAdV species, confirmed the uniquely hypervariable regions within species. The mutation rate among HAdV-Ds was low when compared to other HAdV species. Homologous recombination was identified in at least two of five examined hypervariable regions for every virus, suggesting the evolution of HAdV Ds has been highly dependent on homologous recombination. Patterns of alternating GC and AT rich motifs correlated well with hypervariable region recombination sites across the HAdV-D genomes, suggesting foci of DNA instability lead to formulaic patterns of homologous recombination and confer agility to adenovirus evolution. PMID- 23657241 TI - Chronic lower back pain in a 24 year old man. Osteoid osteoma. PMID- 23657242 TI - End-of-life care in the pediatric ICU. AB - PURPOSE OF REVIEW: Pediatric ICUs frequently provide end-of-life (EOL) care to children. Our understanding of how EOL care is delivered to children and what constitutes effective care for dying children and their families in the ICU setting continues to evolve. This review identifies recent work describing events related to the death of a child in the ICU as well as interventional efforts to improve family and provider support. RECENT FINDINGS: Pediatric ICUs (PICUs) often provide EOL care to children who die in the developed world. Areas of active investigation include identifying effective communication techniques, meeting the needs of patients and parents, and providing support to care providers. SUMMARY: PICU practitioners are developing flexible and novel approaches to pediatric EOL care in the ICU setting. PMID- 23657243 TI - Control of serum glucose concentration in critical illness. AB - PURPOSE OF REVIEW: Hyperglycemia is a significant problem for children in the ICU. Use of tight glycemic control (TGC) to manage hyperglycemia remains controversial, especially given the potential risk of insulin-induced hypoglycemia. This review will address the latest evidence regarding TGC in critically ill children. RECENT FINDINGS: Two randomized controlled trials (RCT) involving primarily postoperative cardiac surgery patients demonstrated the feasibility and safety of TGC in pediatric patients. The trials, however, had discrepant results with regards to the benefit of TGC. There is also uncertainty about the generalizability of these results to nonpostoperative cardiac patients. There is only one published study addressing the long-term safety of TGC in children. In this study, hypoglycemia was not associated with adverse effects on neurocognitive development. In contrast, articles from adult studies demonstrate increased risk of death with hypoglycemia. SUMMARY: Although the clinical benefit of TGC in critically ill children is still unclear, TGC can be done safely in this population. PMID- 23657244 TI - Acute respiratory distress syndrome in children: physiology and management. AB - PURPOSE OF REVIEW: The present review seeks to review the pathophysiologic processes that underlie the development of acute respiratory distress syndrome (ARDS) in children. The review intends to provide the physiologic foundation for the treatment strategies that are associated with the most optimal outcome. RECENT FINDINGS: In infants and children, ARDS remains a significant cause of morbidity and mortality. Although any infant or child can develop ARDS, children who have experienced trauma, pneumonia, aspiration, or immune compromise are at increased risk. Data indicate that adoption of an open-lung ventilation strategy, characterized by sufficient positive end-expiratory pressure to avoid atelectasis, a tidal volume that is limited to less than 5-7 cc/kg per breath and a plateau pressure of 30 cm of water or less provides the greatest likelihood of survival and minimizes lung injury. The relative benefits of strategies such as high frequency oscillatory ventilation, surfactant replacement therapy and inhaled nitric oxide are considered. SUMMARY: ARDS remains a cause of significant mortality and morbidity in children. By employing sound physiologic principles, clinical outcomes can be optimized. PMID- 23657245 TI - Respiratory syncytial virus and asthma: speed-dating or long-term relationship? AB - PURPOSE OF REVIEW: Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and young children worldwide. Furthermore, epidemiological evidence has been accumulating that RSV lower respiratory tract infection in infants may be linked to subsequent development of recurrent wheezing and asthma in childhood. This article reviews the epidemiological evidence linking RSV and asthma and some new hypotheses of the cellular and molecular mechanisms of postviral airway inflammation and hyperreactivity that have been proposed to explain the epidemiological link. RECENT FINDINGS: New epidemiological studies have suggested that viral pathogens other than RSV, especially human rhinoviruses (HRV), may play an important role in the inception of atopic asthma. Also, recent experimental evidence is challenging the widely accepted axiom that RSV is cleared from immunocompetent hosts within weeks from the onset of the infection. In particular, bone marrow stromal cells may be a frequent target of human RSV infection, develop structural and functional changes when infected, participate actively in the pathogenesis of the acute disease, and harbor the virus chronically, allowing persistence of the infection. SUMMARY: RSV - and possibly other common respiratory pathogens - play an important role not only in the exacerbation, but also in the inception of asthma. The latter effect may involve the persistence of latent virus in extrapulmonary tissues, similar to what has been recently found for some bacterial species. The most immediate consequence of these discoveries is that future prophylactic and therapeutic strategies for common infections caused by viral or bacterial pathogens may have to address the coverage of remote sites of latent persistence or replication, in order to avoid chronic sequelae-recurrent wheezing and asthma. PMID- 23657246 TI - Surgery for metastatic disease. AB - PURPOSE OF REVIEW: Outcomes for children with cancer have steadily improved and the long-term survival for most early-stage childhood malignancies is now greater than 90%. On the contrary, the prognosis for children with metastatic cancer, though significantly improved from a generation ago, is generally still very disappointing. Surgery continues to play a role in the increasingly aggressive treatment of children with metastatic disease with the ultimate goal of prolonging survival and improving quality of life. RECENT FINDINGS: Most childhood tumors are relatively rare and are therefore studied using a multi institutional cooperative group model that standardizes protocols and pools resources and data, accounting for the remarkable progress that has been made in the care of children with cancer. In some cases, this has also allowed us to recognize the utility of certain surgical therapies and the need to further study others. SUMMARY: Modern surgery and critical care allow us to consider offering children with metastatic disease more aggressive surgical options in circumstances where the data suggest the potential for long-term survival. In situations where data are lacking, children might be offered a surgical option as part of an ongoing trial. PMID- 23657247 TI - Pectus carinatum. AB - PURPOSE OF REVIEW: Pectus carinatum has been termed the undertreated chest wall deformity. Recent advances in patient evaluation and management, including the development of nonoperative bracing protocols, have improved the care of children with this condition. RECENT FINDINGS: Recent evidence confirms that children with pectus carinatum have a disturbed body image and a reduced quality of life. Treatment has been shown to improve the psychosocial outcome of these patients. SUMMARY: Patients with pectus carinatum are at risk for a disturbed body image and reduced quality of life. Until recently, treatment required surgical reconstruction. A growing body of literature, however, now supports the use of orthotic bracing as a nonoperative alternative in select patients. This article reviews the current literature and describes the evaluation and management of children with pectus carinatum deformity. PMID- 23657248 TI - The intestinal microbiome and necrotizing enterocolitis. AB - PURPOSE OF REVIEW: Necrotizing enterocolitis (NEC) continues to be a major cause of morbidity and mortality in low birth weight infants. Although decades of research point to a role for gut bacteria in the pathogenesis of the disease, the exact relationship between microbes and NEC has not been elucidated. In this review, we describe recent advances in the use of molecular methods to compare gut bacteria in infants with and without NEC. RECENT FINDINGS: Our understanding of how bacteria contribute to NEC pathogenesis has been limited by the use of traditional, culture-based investigations. Recent advances in microbial ecology and DNA sequencing have made it possible to comprehensively study gut bacterial populations and to understand their physiologic importance. Several studies have identified differences in the microbiota among infants with and without NEC, but the findings have often varied across studies. SUMMARY: To date, no single change in the gut microbiota has definitively been identified as a risk factor or cause of NEC. The findings at present suggest that NEC does not result from growth of a single causative pathogen, but rather that the disease results from a generalized disturbance of normal colonization patterns in the developing gut. PMID- 23657250 TI - The role of vanadium haloperoxidases in the formation of volatile brominated compounds and their impact on the environment. AB - Vanadium haloperoxidases differ strongly from heme peroxidases in substrate specificity and stability and in contrast to a heme group they contain the bare metal oxide vanadate as a prosthetic group. These enzymes specifically oxidize halides in the presence of hydrogen peroxide into hypohalous acids. These reactive halogen intermediates will react rapidly and aspecifically with many organic molecules. Marine algae and diatoms containing these iodo- and bromoperoxidases produce short-lived brominated methanes (bromoform, CHBr3 and dibromomethane CH2Br2) or iodinated compounds. Some seas and oceans are supersaturated with these compounds and they form an important source of bromine to the troposphere and lower stratosphere and contribute significantly to the global budget of halogenated hydrocarbons. This perspective focuses, in particular, on the biosynthesis of these volatile compounds and the direct or indirect involvement of vanadium haloperoxidases in the production of huge amounts of bromoform and dibromomethane. Some of the global sources are discussed and from the literature a picture emerges in which oxidized brominated species generated by phytoplankton, seaweeds and cyanobacteria react with dissolved organic matter in seawater, resulting in the formation of intermediate brominated compounds. These compounds are unstable and decay via a haloform reaction to form an array of volatile brominated compounds of which bromoform is the major component followed by dibromomethane. PMID- 23657249 TI - Viper venom-induced oxidative stress and activation of inflammatory cytokines: a therapeutic approach for overlooked issues of snakebite management. AB - BACKGROUND AND OBJECTIVE: The snakebite mortality rate has been significantly reduced due to effective anti-venin therapy. The intravenously infused anti-venom will neutralize free and target-bound toxins but fails to neutralize venom induced inflammation and oxidative stress, as the antigen-antibody complex itself is pro-inflammatory. Therefore, an auxiliary therapy is necessary to treat secondary/overlooked envenomation complications. MATERIALS AND METHODS: Blood samples from healthy donors were treated with viper venom (100 MUg/ml) for 2 h. The venom-induced inflammation, oxidative damage and effect of crocin pre treatment were determined by assessing the serum levels of cytoplasmic, lysosomal and oxidative stress markers along with pro-inflammatory mediators such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and cyclo-oxygenase (COX)-2. RESULTS: Significantly increased stress markers, cytoplasmic, lysosomal and extracellular matrix-degrading enzymes as well as the pro-inflammatory mediators TNF-alpha, IL-1beta, IL-6 and COX-2 indicated increased cellular damage but significantly reduced oxidative damage and inflammation in crocin pre-treated groups. CONCLUSION: The data clearly suggest that venom-induced oxidative stress and inflammation is also responsible for oxidative burst and cell death in the circulation, which may worsen even after anti-venin therapy. Hence, the current study demands a supportive therapy in addition to anti-venin therapy to neutralize the overlooked issues of snakebite. PMID- 23657251 TI - Is pannexin the pore associated with the P2X7 receptor? AB - The P2X7 receptor (P2X7R), an ATP-gated cation channel, is expressed predominantly in leukocytes. Activation of P2X7R has been implicated in the formation of a cytolytic pore (i.e., a large conductance channel) that allows the passage of molecules up to 900 Da in macrophages. At least two hypotheses have been presented to explain the conversion of a nonselective cation channel to a cytolytic pore. One hypothesis suggests that the pore is a separate molecular structure activated by P2X7R, and the second asserts that this is an intrinsic property of P2X7R (pore dilation). Based on connexin knockout and hemichannel antagonist studies, some groups have concluded that connexins and pannexins, the hemichannel-forming proteins in vertebrates, are fundamental components of the large conductance channel associated with P2X7R. Dye uptake and electrophysiology experiments were used to evaluate the efficacy and specificity of some hemichannel antagonists under conditions known to open the large conductance channel associated with P2X7R. Hemichannel antagonists and interference RNA (RNAi) targeting pannexin-1 did not affect P2X7R macroscopic currents [ATP, 1,570+/-189 pA; ATP+100 MUM carbenoxolone (CBX), 1,498+/-100 pA; ATP+1 mM probenecid (Prob), 1,522+/-9 pA] or dye uptake in a FACS assay (ATP, 63+/-5%; ATP+100 MUM CBX, 51.51+/-8.4%; ATP+1 mM Prob, 57.7+/-4.3%) in mouse macrophages. These findings strongly suggest that the high-permeability pore evident after prolonged P2X7R activation does not occur through connexin or pannexin hemichannels in murine macrophages. Another membrane protein may be involved in P2X7R pore formation. PMID- 23657252 TI - beta2-Adrenoceptor-mediated regulation of glucose uptake in skeletal muscle- ligand-directed signalling or a reflection of system complexity? AB - The capacity of G protein-coupled receptors (GPCRs) to activate multiple G protein isoforms and additional effectors such as beta-arrestins has become a well-established paradigm and provides the basis for developing drugs that preferentially activate beneficial signalling pathways. There are many published examples of ligand-directed signalling, and recent studies have provided direct evidence that different agonists stabilise distinct GPCR conformations. This field is rapidly evolving, but a key question is whether signalling bias observed in heterologous cell expression systems can be translated to physiological systems of therapeutic relevance. The paper by Ngala et al. in this issue of the journal addresses the capacity of agonists acting at the beta2-adrenoceptor to engender signalling bias in relation to glucose uptake in isolated skeletal muscle, an area of considerable potential interest in targeting insulin independent pathways for the treatment of type 2 diabetes. The authors show that clenbuterol and BRL37344 have opposite effects on glucose uptake, despite both having agonist actions at beta2-adrenoceptors. This study underlines some of the obstacles associated with studies in a complex physiological system but nonetheless highlights the need to consider signalling bias in the relevant target tissue when developing novel drugs. PMID- 23657253 TI - Metallurgy: iron production electrified. PMID- 23657254 TI - A new anode material for oxygen evolution in molten oxide electrolysis. AB - Molten oxide electrolysis (MOE) is an electrometallurgical technique that enables the direct production of metal in the liquid state from oxide feedstock, and compared with traditional methods of extractive metallurgy offers both a substantial simplification of the process and a significant reduction in energy consumption. MOE is also considered a promising route for mitigation of CO2 emissions in steelmaking, production of metals free of carbon, and generation of oxygen for extra-terrestrial exploration. Until now, MOE has been demonstrated using anode materials that are consumable (graphite for use with ferro-alloys and titanium) or unaffordable for terrestrial applications (iridium for use with iron). To enable metal production without process carbon, MOE requires an anode material that resists depletion while sustaining oxygen evolution. The challenges for iron production are threefold. First, the process temperature is in excess of 1,538 degrees Celsius (ref. 10). Second, under anodic polarization most metals inevitably corrode in such conditions. Third, iron oxide undergoes spontaneous reduction on contact with most refractory metals and even carbon. Here we show that anodes comprising chromium-based alloys exhibit limited consumption during iron extraction and oxygen evolution by MOE. The anode stability is due to the formation of an electronically conductive solid solution of chromium(iii) and aluminium oxides in the corundum structure. These findings make practicable larger-scale evaluation of MOE for the production of steel, and potentially provide a key material component enabling mitigation of greenhouse-gas emissions while producing metal of superior metallurgical quality. PMID- 23657255 TI - DNA replication: driving past four-stranded snags. PMID- 23657257 TI - Immune surveillance by CD8alphaalpha+ skin-resident T cells in human herpes virus infection. AB - Most herpes simplex virus 2 (HSV-2) reactivations in humans are subclinical and associated with rapid expansion and containment of virus. Previous studies have shown that CD8(+) T cells persist in genital skin and mucosa at the dermal epidermal junction (DEJ)--the portal of neuronal release of reactivating virus- for prolonged time periods after herpes lesions are cleared. The phenotype and function of this persistent CD8(+) T-cell population remain unknown. Here, using cell-type-specific laser capture microdissection, transcriptional profiling and T cell antigen receptor beta-chain (TCRbeta) genotyping on sequential genital skin biopsies, we show that CD8alphaalpha(+) T cells are the dominant resident population of DEJ CD8(+) T cells that persist at the site of previous HSV-2 reactivation. CD8alphaalpha(+) T cells located at the DEJ lack chemokine-receptor expression required for lymphocyte egress and recirculation, express gene signatures of T-cell activation and antiviral activity, and produce cytolytic granules during clinical and virological quiescent time periods. Sequencing of the TCR beta-chain repertoire reveals that the DEJ CD8alphaalpha(+) T cells are oligoclonal with diverse usage of TCR variable-beta genes, which differ from those commonly described for mucosa-associated invariant T cells and natural killer T cells. Dominant clonotypes are shown to overlap among multiple recurrences over a period of two-and-a-half years. Episodes of rapid asymptomatic HSV-2 containment were also associated with a high CD8 effector-to-target ratio and focal enrichment of CD8alphaalpha(+) T cells. These studies indicate that DEJ CD8alphaalpha(+) T cells are tissue-resident cells that seem to have a fundamental role in immune surveillance and in initial containment of HSV-2 reactivation in human peripheral tissue. Elicitation of CD8alphaalpha(+) T cells may be a critical component for developing effective vaccines against skin and mucosal infections. PMID- 23657258 TI - Inferring ancient divergences requires genes with strong phylogenetic signals. AB - To tackle incongruence, the topological conflict between different gene trees, phylogenomic studies couple concatenation with practices such as rogue taxon removal or the use of slowly evolving genes. Phylogenomic analysis of 1,070 orthologues from 23 yeast genomes identified 1,070 distinct gene trees, which were all incongruent with the phylogeny inferred from concatenation. Incongruence severity increased for shorter internodes located deeper in the phylogeny. Notably, whereas most practices had little or negative impact on the yeast phylogeny, the use of genes or internodes with high average internode support significantly improved the robustness of inference. We obtained similar results in analyses of vertebrate and metazoan phylogenomic data sets. These results question the exclusive reliance on concatenation and associated practices, and argue that selecting genes with strong phylogenetic signals and demonstrating the absence of significant incongruence are essential for accurately reconstructing ancient divergences. PMID- 23657259 TI - Psl trails guide exploration and microcolony formation in Pseudomonas aeruginosa biofilms. AB - Bacterial biofilms are surface-associated, multicellular, morphologically complex microbial communities. Biofilm-forming bacteria such as the opportunistic pathogen Pseudomonas aeruginosa are phenotypically distinct from their free swimming, planktonic counterparts. Much work has focused on factors affecting surface adhesion, and it is known that P. aeruginosa secretes the Psl exopolysaccharide, which promotes surface attachment by acting as 'molecular glue'. However, how individual surface-attached bacteria self-organize into microcolonies, the first step in communal biofilm organization, is not well understood. Here we identify a new role for Psl in early biofilm development using a massively parallel cell-tracking algorithm to extract the motility history of every cell on a newly colonized surface. By combining this technique with fluorescent Psl staining and computer simulations, we show that P. aeruginosa deposits a trail of Psl as it moves on a surface, which influences the surface motility of subsequent cells that encounter these trails and thus generates positive feedback. Both experiments and simulations indicate that the web of secreted Psl controls the distribution of surface visit frequencies, which can be approximated by a power law. This Pareto-type behaviour indicates that the bacterial community self-organizes in a manner analogous to a capitalist economic system, a 'rich-get-richer' mechanism of Psl accumulation that results in a small number of 'elite' cells becoming extremely enriched in communally produced Psl. Using engineered strains with inducible Psl production, we show that local Psl concentrations determine post-division cell fates and that high local Psl concentrations ultimately allow elite cells to serve as the founding population for initial microcolony development. PMID- 23657260 TI - Microbiology: bacterial communities as capitalist economies. PMID- 23657261 TI - Pif1 family helicases suppress genome instability at G-quadruplex motifs. AB - The Saccharomyces cerevisiae Pif1 helicase is the prototypical member of the Pif1 DNA helicase family, which is conserved from bacteria to humans. Here we show that exceptionally potent G-quadruplex unwinding is conserved among Pif1 helicases. Moreover, Pif1 helicases from organisms separated by more than 3 billion years of evolution suppressed DNA damage at G-quadruplex motifs in yeast. The G-quadruplex-induced damage generated in the absence of Pif1 helicases led to new genetic and epigenetic changes. Furthermore, when expressed in yeast, human PIF1 suppressed both G-quadruplex-associated DNA damage and telomere lengthening. PMID- 23657262 TI - Surface-engineered nanomaterials as X-ray absorbing adjuvant agents for Auger mediated chemo-radiation. AB - We report a prototype approach to formulate gold nanoparticle-based X-ray absorbing agents through surface-engineering of a cisplatin pharmacophore with modified polyacrylate. The resulting agents exhibit both chemo-therapeutic potency to cancer cells and Auger-mediated secondary electron emission, showing great potential to improve the therapeutic efficacy of chemo-radiation. PMID- 23657263 TI - Prognostic value of chronotropic incompetence in elderly patients undergoing exercise echocardiography. AB - BACKGROUND: Chronotropic incompetence (CI), defined as failure to achieve less than 80% of age-expected heart rate, is a predictor of mortality and adverse cardiovascular events and may confer a worse prognosis in elderly diabetic individuals. OBJECTIVE: To evaluate the prognostic value of chronotropic incompetence (CI) in elderly diabetic patients considering endpoints with acute myocardial infarction (AMI), cerebrovascular disease (CVD) and overall mortality and compare clinical and echocardiographic characteristics between patients with and without CI. METHOD: A total of 298 elderly diabetic patients undergoing exercise echocardiography (EE) were studied from January 2001 to December 2010. Of these, 109 were chronotropic incompetent (group 1) and were compared with the chronotropic competent ones (group 2) regarding the occurrence of cardiovascular events, clinical and echocardiographic characteristics. RESULTS: Chronotropic incompetents patients showed a higher frequency of cerebrovascular disease (9.2% vs. 3.2, p = 0.027) and higher mortality was observed in those who had cerebrovascular disease or acute myocardial infarction. The presence of typical angina and dyspnea prior to the performance of EE and male gender were more frequent in group 1. Rest and exercise left ventricular wall motion score index, rate of left ventricle mass and left atrium diameter were higher in chronotropic incompetent individuals. CONCLUSION: Chronotropic incompetence was independently associated with the occurrence of cerebrovascular disease in elderly diabetic individuals. PMID- 23657264 TI - Prognostic value of perioperative N-terminal pro-B-type natriuretic peptide in noncardiac surgery. AB - BACKGROUND: Preoperative NT-proBNP has been shown to predict adverse cardiac outcomes, although recent studies suggested that postoperative NT-proBNP determination could provide additional information in patients submitted to noncardiac surgery. OBJECTIVE: To evaluate the prognostic value of perioperative NT-proBNP in intermediate and high risk cardiovascular patients undergoing noncardiac surgery. METHODS: This study prospectively enrolled 145 patients aged >= 45 years, with at least one Revised Cardiac Risk Index risk factor and submitted to intermediate or high risk noncardiac surgery. NT-proBNP levels were measured pre- and postoperatively. Short-term cardiac outcome predictors were evaluated by logistic regression models. RESULTS: During a median follow-up of 29 days, 17 patients (11.7%) experienced major adverse cardiac events (MACE- 14 nonfatal myocardial infarctions, 2 nonfatal cardiac arrests and 3 cardiac deaths). The optimum discriminatory threshold levels for pre- and postoperative NT-proBNP were 917 and 2962 pg/mL, respectively. Pre- and postoperative NT-proBNP (OR 4.7; 95% CI 1.62-13.73; p=0.005 and OR 4.5; 95% CI 1.53-13.16; p=0.006) were significantly associated with MACE. Preoperative NT-proBNP was significantly and independently associated with adverse cardiac events in multivariate regression analysis (adjusted OR 4.2; 95% CI 1.38-12.62; p=0.011). CONCLUSION: NT-proBNP is a powerful short-term marker of perioperative cardiovascular events in high risk patients. Postoperative levels were less informative than preoperative levels. A single preoperative NT-proBNP measurement should be considered in the preoperative risk assessment. PMID- 23657265 TI - Non invasive assessment of left ventricular filling pressure and remodeling after acute myocardial infarction. AB - BACKGROUND: Left ventricular (LV) dilation after acute myocardial infarction (AMI) is an important determinant of prognosis. The ratio of early mitral inflow velocity (E) and peak early diastolic annular velocity (e') provides the best single index for noninvasive detection of acute elevation of LV filling pressure. OBJECTIVE: To assess whether E/e' ratio predicts LV remodeling after properly treated AMI compared with traditional clinical, laboratory and echocardiographic data. METHODS: Comprehensive echocardiograms were performed in a series of consecutive patients with first AMI successfully treated with primary percutaneous transluminal angioplasty (PTCA), both 48 hours after intervention and 60 days later. Mean E/e' was determined from four sites of the mitral annulus. LV remodeling was defined as more than 15% increase in end-systolic volume estimated by Simpson method. Statistical analysis included Student's t test, receiver-operator curves (ROC) and multivariate logistic regression (all significant with p < 0.05). RESULTS: Fifty-five patients were included, with mean age 58 +/- 11 years, 43 men. The group of patients who underwent LV remodeling (n = 13) had higher baseline E/e' than those without (13 +/- 4 versus 8.5 +/- 2, p < 0.001). The ROC curve showed E/e' > 15 as a predictor of remodeling (AUC = 0.81, p = 0.001). In addition, regression analysis (comprising clinical, laboratory and echocardiographic variables along with AMI site) confirmed the independent value of E/e' in the prediction of LV remodeling (odds ratio 1.42, p = 0.01). CONCLUSION: The E/e' ratio is a useful predictor of LV remodeling after AMI, indicating patients with increased cardiovascular risk. PMID- 23657266 TI - Right ventricular assessment by tissue-Doppler echocardiography in acute pulmonary embolism. AB - BACKGROUND: Assessment of the right ventricular (RV) function by echocardiography in patients with pulmonary thromboembolism (PTE) is complex and frequently qualitative. Tissue Doppler has been used for the semiquantitative assessment of this chamber, although with some limitations. OBJECTIVE: To evaluate RV function in PTE using tissue-Doppler echocardiography, in addition to atrial natriuretic peptide (BNP). METHODS: Patients with PTE were studied using tissue-Doppler echocardiography and BNP up to 24 hours after diagnosis; myocardial velocities (s'), strain, strain rate and RV myocardial performance index were obtained. RV dysfunction was diagnosed by chamber hypokinesia, abnormal septal motion and a RV/LV ratio >1. According to their BNP levels, the patients were divided into Group I, BNP < 50 pg/mL and Group II, BNP > 50 pg/mL. RESULTS: Of 118 patients, 100 (60 men, age = 55 +/- 17 years) were analyzed; RV dysfunction was observed in 28%, more frequently in group II (19 vs. 9 patients, p < 0.001). Patients in group II were older (64 +/- 19 vs. 50 +/- 15 years), and had lower s' velocity (10.5 +/- 3.5 vs. 13.2 +/- 3.1 cm/s), and higher pulmonary pressure (48 +/- 11 vs. 35 +/- 11 mmHg), p < 0.001. The cut-off point of s' for RV dysfunction was 10.8 cm/s (specificity = 85%, sensitivity = 54%), with moderate correlation between BNP and s' wave (r = -0.39). CONCLUSION: In PTE, RV dysfunction on echocardiography is accompanied by BNP elevation; although tissue-Doppler imaging adequately confirms the presence of RV dysfunction, it has a limited sensitivity for this diagnosis. PMID- 23657267 TI - Phenotypic characteristics of resistant hypertension in the Brazilian population. AB - Resistant hypertension (RH) is defined as blood pressure that remains above target in spite of the concurrent use of three or more classes of antihypertensive drugs at optimized doses (UCRH), with one of them being a diuretic. Moreover, patients whose blood pressure is controlled while using four or more antihypertensive medications are also considered controlled resistant hypertensive (CRH) subjects. Although this definition may be useful in terms of categorizing a larger group of resistant hypertensive individuals, as these two subgroups share high cardiovascular risk, some important clinical and pathophysiologic particularities need to be better evaluated, before considering resistant controlled and uncontrolled patients as part of the same group. We compared cardiovascular characteristics of these two subgroups with resistant hypertension. In spite of some similar features, the UCRH subgroup has cardiovascular phenotypes with worse prognosis, such as increased vascular stiffness and left ventricular hypertrophy, as well as more impaired endothelial function and lower nocturnal blood pressure dipping, among others. Considering these differences, the UCRH subgroup is associated with greater cardiovascular risk and may be considered as more resistant to antihypertensive treatment. In addition to the importance of better prevention and treatment of resistant hypertension by identifying early risk factors and optimizing drug therapy, some clinical implications must be considered when managing controlled and uncontrolled patients as similar to the resistant hypertension group. PMID- 23657268 TI - Acute coronary syndrome behavior: results of a Brazilian registry. AB - BACKGROUND: Brazil lacks published multicenter registries of acute coronary syndrome. OBJECTIVE: The Brazilian Registry of Acute Coronary Syndrome is a multicenter national study aiming at providing data on clinical aspects, management and hospital outcomes of acute coronary syndrome in our country. METHODS: A total of 23 hospitals from 14 cities, participated in this study. Eligible patients were those who came to the emergency wards with suspected acute coronary syndrome within the first 24 hours of symptom onset, associated with compatible electrocardiographic alterations and/or altered necrosis biomarkers. Follow-up lasted until hospital discharge or death, whichever occurred first. RESULTS: Between 2003 and 2008, 2,693 ACS patients were enrolled, of which 864 (32.1%) were females. T he final diagnosis was unstable angina in 1,141 patients, (42.4%), with a mortality rate of 3.06%, non-ST elevation acute myocardial infarction (AMI) in 529 (19.6%), with mortality of 6.8%, ST-elevation AMI 950 (35.3%), with mortality of 8.1% and non-confirmed diagnosis 73 (2.7%), with mortality of 1.36%. The overall mortality was 5.53%. The multiple logistic regression model identified the following as risk factors for death regarding demographic factors and interventions: female gender (OR=1.45), diabetes mellitus (OR=1.59), body mass index (OR=1.27) and percutaneous coronary intervention (OR=0.70). A second model for death due to major complications identified: cardiogenic shock/acute pulmonary edema (OR=4.57), reinfarction (OR=3.48), stroke (OR=21.56), major bleeding (OR=3.33), cardiopulmonary arrest (OR=40.27) and Killip functional class (OR=3.37). CONCLUSION: The Brazilian Registry of Acute Coronary Syndrome data do not differ from other data collected abroad. The understanding of their findings may help promote better planning and management of acute coronary syndrome care in public and private health services. PMID- 23657269 TI - Cardiovascular magnetic resonance imaging-derived mitral valve geometry in determining mitral regurgitation severity. AB - BACKGROUND: Mitral regurgitation is the most common valvular heart disease worldwide. Magnetic resonance may be a useful tool to analyze mitral valve parameters. OBJECTIVE: To distinguish mitral valve geometric patterns in patients with different severities of mitral regurgitation (MR) based on cardiovascular magnetic resonance imaging. METHODS: Sixty-three patients underwent cardiovascular magnetic resonance imaging. Mitral valve parameters analyzed were: tenting area (mm2) and angle (degrees), ventricle height (mm), tenting height (mm), anterior leaflet, posterior leaflet length and annulus diameter (mm). Patients were divided into two groups, one including patients who required mitral valve surgery and another which did not. RESULTS: Thirty-six patients had trace to mild (1-2+) MR and 27 had moderate to severe MR (3-4+). Ten (15.9%) out of 63 patients underwent surgery. Patients with more severe MR had a larger left ventricle end systolic diameter (38.6 +/- 10.2 vs 45.4 +/- 16.8, p<0.05) and left end diastolic diameter (52.9 +/- 6.8 vs 60.1 +/- 12.3, p= 0.005). On multivariate analysis, the tenting area was the strongest determinant of MR severity (r= 0.62, p=0.035). Annulus length (36.1 +/- 4.7 vs 41 +/- 6.7, p< 0.001), tenting area (190.7 +/- 149.7 vs 130 +/- 71.3, p= 0.048) and posterior leaflet length (15.1 +/ 4.1 vs 12.2 +/- 3.5, p= 0.023) were larger on patients requiring mitral valve surgery. CONCLUSIONS: Tenting area, annulus and posterior leaflet length are possible determinants of MR severity. These geometric parameters could be used to determine severity and could, in the future, direct specific patient care based on individual mitral apparatus anatomy. PMID- 23657270 TI - Renal dysfunction and inflammatory markers in hypertensive patients seen in a university hospital. AB - BACKGROUND: Today, chronic kidney diseases represent a great challenge to public health as regards the acquisition of knowledge to support interventions that can slow the progression of renal function loss. OBJECTIVE: To analyze the magnitude of the renal function deficit in hypertensive adult patients and its relationship with the following inflammatory markers: high-sensitivity C reactive protein, erythrocyte sedimentation rate, and neutrophil/lymphocyte ratio. METHODS: Cross sectional study including 1,273 adult hypertensive patients of both genders, of whom 1,052 had renal function deficit, and 221 had no deficit, as diagnosed by the Modification of Diet in Renal Disease equation. The odds ratio (OR) and the prevalence ratio (PR) were used to determine the probability of the occurrence of inflammatory activity in renal disease. RESULTS: Renal function deficit was diagnosed in 82.6% of the patients assessed, and most of the sample (70.8%) was classified as in stage 2 of chronic kidney disease. In the regression model, metabolic syndrome (PR adjusted = 1.09 [95%CI: 1.04-1.14]), high-sensitivity C reactive protein (PR adjusted = 1.54 [95%CI: 1.40-1.69]) and erythrocyte sedimentation rate (PR adjusted = 1.20 [95%CI: 1.12-1.28]) remained independently associated with the renal function deficit. However, considering the individuals classified as in stage 2 of renal function deficit, the chance of abnormalities in inflammatory markers were OR = 10.25 (95%CI: 7.00-15.05) for high-sensitivity C reactive protein, OR = 8.50 (95%CI: 5.70-12.71) for neutrophil/lymphocyte ratio, and OR = 7.18 (95%CI: 4.87-10.61) for erythrocyte sedimentation rate. CONCLUSION: The results show an association of inflammatory activity and metabolic syndrome with renal function deficit. PMID- 23657271 TI - Impact of ventricular geometric pattern on cardiac remodeling after myocardial infarction. AB - BACKGROUND: The relevance of left ventricular (LV) geometric pattern after myocardial infarction is not known. OBJECTIVES: To analyze the presence of different LV geometric patterns and their impact as a predictor of remodeling in patients with myocardial infarction. METHODS: Patients with anterior acute myocardial infarction (n = 80) were divided according to the geometric pattern: normal (normal left ventricular mass index [LVMI] and normal relative wall thickness [RWT]), concentric remodeling (normal LVMI and increased RWT), concentric hypertrophy (increased LVMI and RWT) and eccentric hypertrophy (increased LVMI and normal RWT). After six months, echocardiographic assessment was repeated. RESULTS: Four patients died. Of the survivors, 41 showed remodeling (R +), whereas 39 did not (R-). Considering the geometric pattern, the cases were distributed as follows: 24 patients with normal pattern, 13 with concentric remodeling, 29 with concentric hypertrophy and 14 with eccentric hypertrophy. Patients who showed remodeling had larger infarction sizes analyzed by peak CPK (R + = 4,610 (1,688-7,970), R- = 1,442 (775-4247), p <0.001) and CK-MB (R + = 441 (246 - 666), R- = 183 (101-465), p <0.001), trend towards higher prevalence of concentric remodeling (R+ = 10, R- = 3, p = 0.08) and lower prevalence of eccentric hypertrophy (R + = 2 R- = 12, p = 0.006). In the multivariate regression analysis, infarction size was a predictor (OR = 1.01, p = 0.020) and eccentric hypertrophy was a protective factor (OR = 0.189, p = 0.046) of ventricular remodeling after coronary occlusion. CONCLUSION: The LV geometric pattern of can have an impact on the remodeling process in patients with myocardial infarction. PMID- 23657272 TI - World soccer cup as a trigger of cardiovascular events. AB - BACKGROUND: Acute coronary syndromes are the major cause of death in Brazil and in the world. External stimuli, known also as triggers, such as emotional state and activity, may generate physiopathological changes that can trigger acute coronary syndromes. Among the studied triggers, the impact of stressful events, such as soccer championships, are controversial in literature and there is no effective data on the Brazilian population. OBJECTIVE: To evaluate the acute effects of environmental stress induced by soccer games of the World Soccer Cup on increased incidence of cardiovascular diseases in Brazil. METHODS: Public data were obtained from the Unified Health System (Sistema Unico de Saude), regarding hospital admissions that had the International Code Disease of acute coronary syndromes from May to August, in 1998, 2002, 2006 and 2010 (155,992 admissions). Analysis was restricted to patients older than 35 years and admitted by clinical specialties. The incidence of myocardial infarction, angina and mortality were compared among days without World Cup soccer games (Group I: 144,166; 61.7 +/- 12.3; 59.4% males); on days when there were no Brazil's soccer team matches (Group II: 9,768; 61.8 +/- 12.3; 60.0% males); and days when there were Brazil's soccer team matches (Group III; 2,058; 61.6 +/- 12.6; 57.8% males). Logistic regression was used to adjust to age, gender, population density and number of medical assistance units. RESULTS: The incidence of myocardial infarction increased during the period of World Cup soccer games (1.09; 95%CI = 1.05-1.15) and days when there were Brazil's matches (1.16; 95%CI = 1.06-1.27). There was no impact on mortality during the Cup (1.00; CI 95% = 0.93-1.08) and Brazil's matches (1.04; 95%CI = 0.93-1.22). CONCLUSION: World Cup soccer games and, specially, Brazil's matches have an impact on the incidence of myocardial infarction, but not on in-hospital mortality. PMID- 23657273 TI - After the gold rush. PMID- 23657275 TI - Suicide attempts and self-harm behaviors in psychiatric sex offenders. AB - Suicidality and self-harm behaviors among sex offenders remain underreported in the clinical literature and are often misunderstood in this complex population. The present study aims to identify rates of suicide attempts and self-injurious behaviors in a sample of 1,184 psychiatric inpatients, 462 of whom are sexual offenders. Between-group comparisons revealed significant differences in history of suicide attempts and self-harm behaviors, with sexual offenders evidencing greater rates of both. Significant psychiatric correlates of suicide attempts and self-harm behaviors among sex offenders varied by group and included a variety of psychiatric symptom presentations. These are compared with the general literature on suicide risk and the sex offender population. Implications for treatment of these behaviors in a sex offender population are discussed. PMID- 23657274 TI - Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle. AB - Intracellular protein trafficking pathways are hijacked by viruses at various stages of viral life-cycle. Heterotetrameric adaptor protein complexes (APs) mediate vesicular trafficking at distinct intracellular sites and are essential for maintaining the organellar homeostasis. In the present study, we studied the effect of AP-1 and AP-3 deficiency on flavivirus infection in cells functionally lacking these proteins. We show that AP-1 and AP-3 participate in flavivirus life cycle at distinct stages. AP-3-deficient cells showed delay in initiation of Japanese encephalitis virus and dengue virus RNA replication, which resulted in reduction of infectious virus production. AP-3 was found to colocalize with RNA replication compartments in infected wild-type cells. AP-1 deficiency affected later stages of dengue virus infection where increased intracellular accumulation of infectious virus was observed. Therefore, our results propose a novel role for AP-1 and AP-3 at distinct stages of infection of some of the RNA viruses. PMID- 23657276 TI - Comparison of fibular and scapular osseous free flaps for oromandibular reconstruction: a patient-centered approach to flap selection. AB - IMPORTANCE: Provides an approach to osseous free flap selection for reconstruction of segmental mandible defects that takes into consideration general medical status of the patient and reconstruction requirements; demonstrates the complementary qualities of fibular and subscapular system free flaps; and describes the different surgical indications for lateral border scapular and scapular tip free flaps. OBJECTIVES: To review our experience with osseous mandible reconstruction comparing the fibular and subscapular system free flaps, determine reconstruction-specific and general health variables that may differ between these patient groups, and present our approach to oromandibular reconstruction. DESIGN: Retrospective study. SETTING: Academic tertiary care medical center. PARTICIPANTS: A total of 110 patients (68 male, 42 female) undergoing single-stage oromandibular reconstructions with free-tissue transfers between May 1, 2006, and May 30, 2012. INTERVENTION: Single-stage oromandibular reconstruction with free-tissue transfer. MAIN OUTCOME MEASURES: Differences in patient demographics, bone and soft-tissue aspects of the reconstruction, operative time, flap outcomes, and major postoperative complications between fibular, lateral scapular border, and scapular tip free flaps. RESULTS: A total of 110 patients underwent 113 reconstructions, including 58 fibular free flaps (FFFs) (51.3%) and 55 subscapular system flaps (48.7%). Of the subscapular system free flaps, 27 flaps (49%) were scapular tip free flaps (STFFs) based on the angular artery branch of the thoracodorsal pedicle; the remaining 28 cases were lateral scapular border flaps (LSBFs). Patients undergoing reconstruction with FFFs were significantly younger than their subscapular system flap counterparts (56 vs 70 years, P < .001). Mean mandible defect lengths were similar for patients undergoing FFF and LSBF reconstruction (7.8 and 7.7 cm, respectively); STFFs were used to reconstruct significantly shorter defects (mean, 6.0 cm, P < .001). The FFFs were more commonly used for anterior mandible defects in which multiple osteotomies and limited soft tissue were required, while subscapular flaps were more commonly used for linear mandible defects with complex soft tissue requirements. A single complete flap loss occurred in a patient who underwent reconstruction with an STFF; other complication rates were similar between groups. CONCLUSIONS AND RELEVANCE: The FFFs and subscapular flaps are complementary options for oromandibular reconstruction. The FFF is ideal for younger patients, extended defects, multiple osteotomies, and limited soft-tissue requirements. The subscapular system free flaps (LSBF and STFF) are excellent options for (1) elderly patients; (2) those with significant comorbidities, such as peripheral vascular disease; and (3) mandible defects associated with complex soft-tissue requirements. Furthermore, the STFF offers a reliable option to reconstruct short-segment defects, in particular, defects involving the angle of the mandible. PMID- 23657277 TI - Letter to Dr. Kounis. PMID- 23657278 TI - Behavioral and modeling studies of sound localization in cats: effects of stimulus level and duration. AB - Sound localization accuracy in elevation can be affected by sound spectrum alteration. Correspondingly, any stimulus manipulation that causes a change in the peripheral representation of the spectrum may degrade localization ability in elevation. The present study examined the influence of sound duration and level on localization performance in cats with the head unrestrained. Two cats were trained using operant conditioning to indicate the apparent location of a sound via gaze shift, which was measured with a search-coil technique. Overall, neither sound level nor duration had a notable effect on localization accuracy in azimuth, except at near-threshold levels. In contrast, localization accuracy in elevation improved as sound duration increased, and sound level also had a large effect on localization in elevation. For short-duration noise, the performance peaked at intermediate levels and deteriorated at low and high levels; for long duration noise, this "negative level effect" at high levels was not observed. Simulations based on an auditory nerve model were used to explain the above observations and to test several hypotheses. Our results indicated that neither the flatness of sound spectrum (before the sound reaches the inner ear) nor the peripheral adaptation influences spectral coding at the periphery for localization in elevation, whereas neural computation that relies on "multiple looks" of the spectral analysis is critical in explaining the effect of sound duration, but not level. The release of negative level effect observed for long duration sound could not be explained at the periphery and, therefore, is likely a result of processing at higher centers. PMID- 23657279 TI - Analysis of stimulus-related activity in rat auditory cortex using complex spectral coefficients. AB - The neural mechanisms of sensory responses recorded from the scalp or cortical surface remain controversial. Evoked vs. induced response components (i.e., changes in mean vs. variance) are associated with bottom-up vs. top-down processing, but trial-by-trial response variability can confound this interpretation. Phase reset of ongoing oscillations has also been postulated to contribute to sensory responses. In this article, we present evidence that responses under passive listening conditions are dominated by variable evoked response components. We measured the mean, variance, and phase of complex time frequency coefficients of epidurally recorded responses to acoustic stimuli in rats. During the stimulus, changes in mean, variance, and phase tended to co occur. After the stimulus, there was a small, low-frequency offset response in the mean and modest, prolonged desynchronization in the alpha band. Simulations showed that trial-by-trial variability in the mean can account for most of the variance and phase changes observed during the stimulus. This variability was state dependent, with smallest variability during periods of greatest arousal. Our data suggest that cortical responses to auditory stimuli reflect variable inputs to the cortical network. These analyses suggest that caution should be exercised when interpreting variance and phase changes in terms of top-down cortical processing. PMID- 23657280 TI - Developmental changes in GABAergic neurotransmission to presympathetic and cardiac parasympathetic neurons in the brainstem. AB - Cardiovascular function is regulated by a dynamic balance composed of sympathetic and parasympathetic activity. Sympathoexcitatory presympathetic neurons (PSNs) in the rostral ventrolateral medulla project directly to cardiac and vasomotor sympathetic preganglionic neurons in the spinal cord. In proximity to the PSNs in the medulla, there are preganglionic cardiac vagal neurons (CVNs) within the nucleus ambiguus, which are critical for parasympathetic control of heart rate. Both CVNs and PSNs receive GABAergic synaptic inputs that change with challenges such as hypoxia and hypercapnia (H/H). Autonomic control of cardiovascular function undergoes significant changes during early postnatal development; however, little is known regarding postnatal maturation of GABAergic neurotransmission to these neurons. In this study, we compared changes in GABAergic inhibitory postsynaptic currents (IPSCs) in CVNs and PSNs under control conditions and during H/H in postnatal day 2-5 (P5), 16-20 (P20), and 27-30 (P30) rats using an in vitro brainstem slice preparation. There was a significant enhancement in GABAergic neurotransmission to both CVNs and PSNs at age P20 compared with P5 and P30, with a more pronounced increase in PSNs. H/H did not significantly alter this enhanced GABAergic neurotransmission to PSNs in P20 animals. However, the frequency of GABAergic IPSCs in PSNs was reduced by H/H in P5 and P30 animals. In CVNs, H/H elicited an inhibition of GABAergic neurotransmission in all ages studied, with the most pronounced inhibition occurring at P20. In conclusion, there are critical development periods at which significant rearrangement occurs in the central regulation of cardiovascular function. PMID- 23657281 TI - Amygdala inputs drive feedforward inhibition in the medial prefrontal cortex. AB - Although interactions between the amygdala and prefrontal cortex (PFC) are critical for emotional guidance of behavior, the manner in which amygdala affects PFC function is not clear. Whereas basolateral amygdala (BLA) output neurons exhibit many characteristics associated with excitatory neurotransmission, BLA stimulation typically inhibits PFC cell firing. This apparent discrepancy could be explained if local PFC inhibitory interneurons were activated by BLA inputs. Here, we used in vivo juxtacellular and intracellular recordings in anesthetized rats to investigate whether BLA inputs evoke feedforward inhibition in the PFC. Juxtacellular recordings revealed that BLA stimulation evoked action potentials in PFC interneurons and silenced most pyramidal neurons. Intracellular recordings from PFC pyramidal neurons showed depolarizing postsynaptic potentials, with multiple components evoked by BLA stimulation. These responses exhibited a relatively negative reversal potential (Erev), suggesting the contribution of a chloride component. Intracellular administration or pressure ejection of the GABA A antagonist picrotoxin resulted in action-potential firing during the BLA-evoked response, which had a more depolarized Erev. These results suggest that BLA stimulation engages a powerful inhibitory mechanism within the PFC mediated by local circuit interneurons. PMID- 23657282 TI - Visual receptive field properties of cells in the optic tectum of the archer fish. AB - The archer fish is well known for its extreme visual behavior in shooting water jets at prey hanging on vegetation above water. This fish is a promising model in the study of visual system function because it can be trained to respond to artificial targets and thus to provide valuable psychophysical data. Although much behavioral data have indeed been collected over the past two decades, little is known about the functional organization of the main visual area supporting this visual behavior, namely, the fish optic tectum. In this article we focus on a fundamental aspect of this functional organization and provide a detailed analysis of receptive field properties of cells in the archer fish optic tectum. Using extracellular measurements to record activities of single cells, we first measure their retinotectal mapping. We then determine their receptive field properties such as size, selectivity for stimulus direction and orientation, tuning for spatial frequency, and tuning for temporal frequency. Finally, on the basis of all these measurements, we demonstrate that optic tectum cells can be classified into three categories: orientation-tuned cells, direction-tuned cells, and direction-agnostic cells. Our results provide an essential basis for future investigations of information processing in the archer fish visual system. PMID- 23657283 TI - Input-output organization of inhibitory neurons in the interstitial nucleus of Cajal projecting to the contralateral trochlear and oculomotor nucleus. AB - Neurons in the interstitial nucleus of Cajal (INC) that are known to be involved in eye and head movements are excitatory. We investigated the input-output organization of inhibitory INC neurons involved in controlling vertical saccades. Intracellular recordings were made in INC neurons activated antidromically by stimulation of the contralateral trochlear or oculomotor nucleus, and their synaptic input properties from the superior colliculi (SCs) and the contralateral INC were analyzed in anesthetized cats. Many INC neurons projected to the contralateral trochlear nucleus, Forel's field H, INC, and oculomotor nucleus, and mainly received monosynaptic excitation followed by disynaptic inhibition from the ipsi- and contralateral SCs. After sectioning the commissural connections between the SCs, these neurons received monosynaptic excitation from the ipsilateral medial SC and disynaptic inhibition via the INC from the contralateral lateral SC. Another group of INC neurons were antidromically activated from the contralateral oculomotor nucleus, INC and Forel's field H, but not from the trochlear nucleus, and received monosynaptic excitation from the ipsilateral lateral SC and disynaptic inhibition from the contralateral medial SC. The former group was considered to inhibit contralateral trochlear and inferior rectus motoneurons in upward saccades, whereas the latter was considered to inhibit contralateral superior rectus and inferior oblique motoneurons in downward saccades. The mutual inhibition existed between these two groups of INC neurons for upward saccades on one side and downward saccades on the other. This pattern of input-output organization of inhibitory INC neurons suggests that the basic neural circuits for horizontal and vertical saccades are similar. PMID- 23657284 TI - Slow changes in Ca2(+) cause prolonged release from GABAergic retinal amacrine cells. AB - The timing of neurotransmitter release from neurons can be modulated by many presynaptic mechanisms. The retina uses synaptic ribbons to mediate slow graded glutamate release from bipolar cells that carry photoreceptor inputs. However, many inhibitory amacrine cells, which modulate bipolar cell output, spike and do not have ribbons for graded release. Despite this, slow glutamate release from bipolar cells is modulated by slow GABAergic inputs that shorten the output of bipolar cells, changing the timing of visual signaling. The time course of light evoked inhibition is slow due to a combination of receptor properties and prolonged neurotransmitter release. However, the light-evoked release of GABA requires activation of neurons upstream from the amacrine cells, so it is possible that prolonged release is due to slow amacrine cell activation, rather than slow inherent release properties of the amacrine cells. To test this idea, we directly activated primarily action potential-dependent amacrine cell inputs to bipolar cells with electrical stimulation. We found that the decay of GABAC receptor-mediated electrically evoked inhibitory currents was significantly longer than would be predicted by GABAC receptor kinetics, and GABA release, estimated by deconvolution analysis, was inherently slow. Release became more transient after increasing slow Ca(2+) buffering or blocking prolonged L-type Ca(2+) channels and Ca(2+) release from intracellular stores. Our results suggest that GABAergic amacrine cells have a prolonged buildup of Ca(2+) in their terminals that causes slow, asynchronous release. This could be a mechanism of matching the time course of amacrine cell inhibition to bipolar cell glutamate release. PMID- 23657285 TI - Primary motor cortical discharge during force field adaptation reflects muscle like dynamics. AB - We often make reaching movements having similar trajectories within very different mechanical environments, for example, with and without an added load in the hand. Under these varying conditions, our kinematic intentions must be transformed into muscle commands that move the limbs. Primary motor cortex (M1) has been implicated in the neural mechanism that mediates this adaptation to new movement dynamics, but our recent experiments suggest otherwise. We have recorded from electrode arrays that were chronically implanted in M1 as monkeys made reaching movements under two different dynamic conditions: the movements were opposed by either a clockwise or counterclockwise velocity-dependent force field acting at the hand. Under these conditions, the preferred direction (PD) of neural discharge for nearly all neurons rotated in the direction of the applied field, as did those of proximal limb electromyograms (EMGs), although the median neural rotation was significantly smaller than that of muscles. For a given neuron, the rotation angle was very consistent, even across multiple sessions. Within the limits of measurement uncertainty, both the neural and EMG changes occurred nearly instantaneously, reaching a steady state despite ongoing behavioral adaptation. Our results suggest that M1 is not directly involved in the adaptive changes that occurred within an experimental session. Rather, most M1 neurons are directly related to the dynamics of muscle activation that themselves reflect the external load. It appears as though gain modulation, the differential recruitment of M1 neurons by higher motor areas, can account for the load and behavioral adaptation-related changes in M1 discharge. PMID- 23657286 TI - Zingerone enhances glutamatergic spontaneous excitatory transmission by activating TRPA1 but not TRPV1 channels in the adult rat substantia gelatinosa. AB - Transient receptor potential (TRP) channels are thought to play a role in regulating nociceptive transmission to spinal substantia gelatinosa (SG) neurons. It remains to be unveiled whether the TRP channels in the central nervous system are different in property from those involved in receiving nociceptive stimuli in the peripheral nervous system. We examined the effect of the vanilloid compound zingerone, which activates TRPV1 channels in the cell body of a primary afferent neuron, on glutamatergic excitatory transmission in the SG neurons of adult rat spinal cord slices by using the whole cell patch-clamp technique. Bath-applied zingerone reversibly and concentration-dependently increased spontaneous excitatory postsynaptic current (EPSC) frequency. This effect was accompanied by an inward current at -70 mV that was resistant to glutamate receptor antagonists. These zingerone effects were repeated and persisted in Na(+)-channel blocker tetrodotoxin-, La(3+)-, or IP3-induced Ca(2+)-release inhibitor 2 aminoethoxydiphenyl borate-containing or Ca(2+)-free Krebs solution. Zingerone activity was resistant to the selective TRPV1 antagonist capsazepine but sensitive to the nonselective TRP antagonist ruthenium red, the TRPA1 antagonist HC-030031, and the Ca(2+)-induced Ca(2+)-release inhibitor dantrolene. TRPA1 agonist allyl isothiocyanate but not capsaicin inhibited the facilitatory effect of zingerone. On the other hand, zingerone reduced monosynaptically evoked EPSC amplitudes, as did TRPA1 agonists. Like allyl isothiocyanate, zingerone enhanced GABAergic spontaneous inhibitory transmission in a manner sensitive to tetrodotoxin. We conclude that zingerone presynaptically facilitates spontaneous excitatory transmission, probably through Ca(2+)-induced Ca(2+)-release mechanisms, and produces a membrane depolarization in SG neurons by activating TRPA1 but not TRPV1 channels. PMID- 23657287 TI - Surface-length index: a novel index for rapid detection of right ventricles with abnormal ejection fraction using cardiac MRI. AB - OBJECTIVE: To validate a new index, the surface-length index (SLI) based on area change in a short-axis view and length reduction in the horizontal long-axis view, which is used to quickly (<1 min) detect right ventricles with an abnormal ejection fraction (EF) during a cardiac MRI examination. SLI can be used to avoid a complete delineation of the endocardial contours of normal right ventricles. METHODS: Sixty patients (group A) were retrospectively included to calibrate the SLI formula by optimisation of the area under the ROC curves and SLI thresholds were chosen to obtain 100 % sensitivity. Another 340 patients (group B) were prospectively recruited to test SLI's capacity to detect right ventricles (RVs) with an abnormal EF (<0.5). RESULTS: The appropriate threshold to obtain 100 % sensitivity in group A was 0.58. In group B, with the 0.58 threshold, SLI yielded a sensitivity of 100 % and specificity of 51 %. SLI would have saved 35 % of the RV studies in our population, without inducing any diagnostic error. SLI and EF correlation was good (r (2) = 0.64). CONCLUSION: SLI combines two simple RV measures, and brings significant improvement in post-processing efficiency by preselecting RVs that require a complete study. KEY POINTS: * Assessment of right ventricle ejection fraction (RVEF) with cine-MRI is time consuming. * Therefore, RVEF is not always assessed during cardiac MRI. * Surface-length index (SLI) allows rapid detection of abnormal RVEF during cardiac MRI. * SLI saves one third of the operator time. * Every cardiac MRI could include RVEF assessment by means of SLI. PMID- 23657288 TI - MR guidance and thermometry of percutaneous laser disc decompression in open MRI: an initial clinical investigation. AB - OBJECTIVES: To assess the feasibility, safety and efficacy of real-time MR guidance and thermometry of percutaneous laser disc decompression (PLDD). METHODS: Twenty-four discs in 22 patients with chronic low-back and radicular pain were treated by PLDD using open 1.0-T magnetic-resonance imaging (MRI). A fluoroscopic proton-density-weighted turbo spin-echo (PDw TSE) sequence was used to position the laser fibre. Non-spoiled gradient-echo (GRE) sequences were employed for real-time thermal monitoring based on proton resonance frequency (PRF). Radicular pain was assessed over 6 months with a numerical rating scale (NRS). RESULTS: PLDD was technically successful in all cases, with adequate image quality for laser positioning. The PRF-based real-time temperature monitoring was found to be feasible in practice. After 6 months, 21 % reported complete remission of radicular pain, 63 % at least great pain relief and 74 % at least mild relief. We found a significant decrease in the NRS score between the pre intervention and the 6-month follow-up assessment (P < 0.001). No major complications occurred; the single adverse event recorded, moderate motor impairment, resolved. CONCLUSIONS: Real-time MR guidance and PRF-based thermometry of PLDD in the lumbar spine under open 1.0-T MRI appears feasible, safe and effective and may pave the way to more precise operating procedures. KEY POINTS: * Percutaneous laser disc decompression (PLDD) is increasingly used instead of conventional surgery. * Open 1.0-T MRI with temperature mapping seems technically successful in monitoring PLDD. * Pain relief was at least 'great' in 64 % of patients. * No major complications occurred. * Open 1.0-T MRI appears a safe and effective option for patient-tailored PLDD. PMID- 23657289 TI - Safety and efficacy of radiological percutaneous jejunostomy for decompression of malignant small bowel obstruction. AB - OBJECTIVES: This study aimed to evaluate the safety and efficacy of percutaneous radiological jejunostomy (PRJ) and stent placement in patients with malignant small bowel obstructions (MSBO). METHODS: A total of 21 patients (mean age 60 years) with single (n = 4) or multiple (n = 17) MSBO underwent PRJ following jejunopexy. The medical records and imaging studies were retrospectively reviewed to evaluate the technical/clinical success and complications. Clinical success was determined by symptomatic relief and radiologic bowel decompression. RESULTS: PRJ using a 12- or 14-F drainage catheter was technically successful in all patients. Eleven patients required placement of an 18-F nasogastric tube across one (n = 3), two (n = 6) and three (n = 2) obstructions to achieve clinical success. Subsequently, self-expandable stents were placed through the PRJ tracts to recanalise MSBO in four patients. Clinical success was achieved in 18 patients (85.7 %). The median food intake capacity score improved from 4.0 to 2.0 (P = 0.001). There were one major (peritonitis, 4.8 %) and six minor complications (28.6 %) CONCLUSIONS: PRJ using a nasogastric tube across the obstructions is an effective palliative treatment for MSBO. The PRJ tract can be used as an approach route for stent placement to recanalise MSBO. However, dedicated devices should be developed to reduce frequent procedure-related complications. KEY POINTS: * Bowel decompression provides palliative treatment in malignant small bowel obstruction * Percutaneous radiological jejunostomy (PRJ) is a safe and effective palliative treatment. * Long tube placement across obstructions facilitates adequate drainage of multiple bowel obstructions. * PRJ tract can be used for stent placement to approach MSBO recanalisation. PMID- 23657293 TI - Protein binding by dinuclear polypyridyl ruthenium(II) complexes and the effect of cucurbit[10]uril encapsulation. AB - The effect of human serum on the minimum inhibitory/bactericidal concentrations of the potential antimicrobial agents DeltaDelta-[{Ru(phen)2}2(MU-bb(n))](4+) {DeltaDelta-Rubb(n); where phen = 1,10-phenanthroline, bb(n) = 1,n-bis[4(4' methyl-2,2'-bipyridyl)]-alkane for n = 12 and 16} against four strains of bacteria--Gram positive Staphylococcus aureus and methicillin-resistant S. aureus (MRSA), and Gram negative Escherichia coli and Pseudomonas aeruginosa--has been determined. The results demonstrated that the ruthenium(ii) complexes have significantly decreased in vitro activity in serum. Fluorescence spectroscopy was used to confirm that the decrease in antimicrobial activity was due to the strong binding of the ruthenium complexes with the serum proteins human serum albumin (HSA) and transferrin. A series of ruthenium complexes showed stronger binding to HSA than apo-transferrin but comparable or less than with holo-transferrin, with the binding affinity to all three proteins decreasing in the order trinuclear > dinuclear > mononuclear. The dinuclear complex DeltaDelta-Rubb12 displaced warfarin from HSA, tentatively suggesting that the ruthenium complexes bind at or near the warfarin-binding site, Sudlow's site 1. The binding of DeltaDelta-Rubb12 and DeltaDelta-Rubb16 to the macrocyclic host molecule cucurbit[10]uril (Q[10]) was examined by NMR spectroscopy. The large upfield (1)H NMR chemical shift changes observed for the methylene protons in the bridging ligands upon addition of Q[10], coupled with the observation of a range of intermolecular ROEs in ROESY spectra, indicated that the dinuclear complexes bound Q[10] with the bridging ligand within the cavity and the metal centres positioned outside the portals. NMR and fluorescence spectroscopy demonstrated that the Q[10]-encapsulated ruthenium complexes directly bound HSA, and with similar affinity to the corresponding free metal complexes. PMID- 23657294 TI - Risk factors for Staphylococcus aureus nasal colonization in Danish middle-aged and elderly twins. AB - Staphylococcus aureus is a human commensal bacterium found in the nasal cavity and other body sites. Identifying risk factors for S. aureus nasal carriage is of interest, as nasal carriage is a risk factor for subsequent invasive infection. We recently investigated the influence of host genetics on S. aureus carriage in Danish middle-aged and elderly twins, which indicated no significant heritability that could account for the observed S. aureus carriage. In the present study, we performed a questionnaire-based study of S. aureus colonization on the same cohort of 2,196 Danish middle-aged and elderly twins to identify specific risk factors for S. aureus nasal colonization, including analyzing the paired twins (n = 478) that were discordant for S. aureus colonization. We found associations between risk factors and S. aureus nasal colonization among middle-aged and elderly twins, including age, male gender, psoriasis, and atopic diseases. Also, present living on a farm is clearly associated with S. aureus colonization, while smoking had a borderline statistically significant protective effect. PMID- 23657295 TI - S-nitrosylation of ERK inhibits ERK phosphorylation and induces apoptosis. AB - Extracellular signal-regulated kinase (ERK) belongs to the mitogen-activated protein kinases (MAPK) superfamily. Aberrant upregulation and activation of ERK cascades may often lead to tumor cell development. However, how ERK is involved in tumor progression is yet to be defined. In current study, we described that ERK undergoes S-nitrosylation by nitric oxide (NO). ERK S-nitrosylation inhibits its phosphorylation and triggers apoptotic program as verified by massive apoptosis in fluorescence staining. The proapoptotic effect of NO induced S nitrosylation is reversed by NO scavenger Haemoglobin (HB). Furthermore, an S nitrosylation dead ERK mutant C183A also demolishes the proapoptotic potential of NO and favors cell survival. Therefore, Cys(183) might be a potential S nitrosylation site in ERK. In addition, S-nitrosylation is a general phenomenon that regulates ERK activity. These findings identify a novel link between NO mediated S-nitrosylation and ERK regulation, which provide critical insights into the control of apoptosis and tumor development. PMID- 23657297 TI - Lower-limb pulse wave velocity: correlations and clinical value. PMID- 23657296 TI - Changes in serum aldosterone are associated with changes in obesity-related factors in normotensive overweight and obese young adults. AB - Recent data suggest excess circulating aldosterone promotes cardiometabolic decline. Weight loss may lower aldosterone levels, but little longitudinal data is available in normotensive adults. We aimed to determine whether, independent of changes in sodium excretion, reductions in serum aldosterone are associated with favorable changes in obesity-related factors in normotensive overweight/obese young adults. We studied 285 overweight/obese young adult participants (body mass index >= 25 and<40 kg m-2, age 20-45 years) in a clinical trial examining the effects of a 1-year diet and physical activity intervention with or without sodium restriction on vascular health. Body weight, serum aldosterone, 24-h sodium and potassium excretion and obesity-related factors were measured at baseline, 6, 12 and 24 months. Weight loss was significant at 6 (7%), 12 (6%) and 24 months (4%; all P<0.0001). Decreases in aldosterone were associated with decreases in C-reactive protein, leptin, insulin, homeostasis assessment of insulin resistance, heart rate, tonic cardiac sympathovagal balance and increases in adiponectin (all P<0.05) in models adjusting for baseline age, sex, race, intervention arm, time since baseline, and sodium and potassium excretion. Weight loss and reductions in thigh intermuscular fat (intermuscular adipose tissue area; IMAT) were associated with decreases in aldosterone in the subgroup (n=98) with metabolic syndrome (MetS) at baseline (MetS * weight loss, P=0.04; MetS * change in IMAT, P=0.04). Favorable changes in obesity-related factors are associated with reductions in aldosterone in young adults with no risk factors besides excess weight, an important finding, given aldosterone's emergence as an important cardiometabolic risk factor. PMID- 23657298 TI - [Arquivos de Gastroenterology - 50 years]. PMID- 23657299 TI - Carcinoid tumor of the duodenum: a rare tumor at an unusual site. Case series from a single institution. AB - CONTEXT: Duodenal carcinoids are extremely rare, and their characteristics and biological behavior have not been fully elucidated. OBJECTIVE: To analyze the clinicopathological characteristics of patients with resected duodenal carcinoids. METHODS: Twenty patients (12 females and 8 males) were investigated. Their average age was 66.4 +/- 5.8 years old (43 to 88 years old). The data corresponding to the clinical picture, diagnosis, treatment, and prognosis of patients with duodenal carcinoid tumors subjected to resection over a period of 18 years (1993-2011) were analyzed. RESULTS: The most common symptoms were dyspepsia (50%) and epigastric pain (45%) followed by weight loss (10%) and vomiting (5%). Carcinoid syndrome was not observed in any patient. The lesion was located on the first part of the duodenum in 15 (75%) patients, the second part in 4 (20%) patients, and the third part in 1 (5%) patient. The diagnosis of a carcinoid tumor was established through an endoscopic excision biopsy in 19 (95%) patients and an histopathological examination of the surgical specimen in 1 (5%) patient. The average tumor size was 1.1 cm +/- 0.4 cm (0.3 cm to 6.0 cm). Nineteen (95%) patients were initially treated by endoscopic resection of the duodenal lesion. One patient (5%), whose tumor was on the third part of the duodenum underwent a duodenectomy of the third and fourth duodenal parts and duodenojejunal anastomosis. The duodenal carcinoid resection margin was involved in four (20%) patients. Four (20%) patients were subjected to a partial gastrectomy to fully remove the lesion. The tumor was restricted to the submucosal layer in 16 (80%) cases, and it penetrated into the muscular layer in 4 (20%) cases. All patients exhibited positive chromogranin A, neuron-specific enolase, and/or synaptophysin immunostaining. The average duration of the follow up period was 39.6 months (3 to 96 months). Twelve (60%) of the 20 cases in this series are alive without any evidence of active disease. Only one (5%) patient died due to liver metastases of the duodenal carcinoid. CONCLUSIONS: Duodenal carcinoids are rare and indolent tumors usually associated with a benign progression. Duodenoscopy, computerized tomography, and endoscopic ultrasound should be performed to evaluate the tumor size, the level of wall invasion, and the presence of regional or distant lymphatic metastases. Endoscopic removal of tumors smaller than 1.0 cm without periampullary localization or evidence of muscular propria layer invasion assessed by histology and/or endoscopic ultrasound is recommended. The endoscopic resection with a carcinoid tumor size between 1.0 cm and 2.0 cm can be incomplete and require new endoscopic resection or even surgical removal. Duodenal carcinoid larger than 2.0 cm require full thickness resection and concomitant lymphadenectomy. PMID- 23657300 TI - Pancreatic splenosis mimicking neuroendocrine tumors: microhistological diagnosis by endoscopic ultrasound guided fine needle aspiration. AB - CONTEXT: Pancreatic splenosis is a benign condition which can mimic a pancreatic neoplasm. OBJECTIVE: To describe the role of the endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic nodules suspicious for pancreatic splenosis. METHOD: From 1997 to 2011, patients with pancreatic solid tumors suspicious for splenosis by computed tomography and/or magnetic resonance imaging were referred to EUS-FNA. Those cases with pancreatic splenosis confirmed by EUS FNA or surgery were included. Endosonographic findings and clinicopathologic features were also analysed. RESULTS: A total of 2,060 patients with pancreatic solid tumors underwent EUS-FNA. Fourteen (0.6%) cases with pancreatic splenosis were found. After applying exclusion criteria, 11 patients were selected. Most patients were male (7), young (mean age: 42 years) and asymptomatic (8). Endoscopic ultrasound imaging alone suspected pancreatic splenosis in 6 cases, and neuroendocrine tumors in 5 cases. Pancreatic splenosis was found most commonly in the tail, was round, hypoechoic, with homogeneous pattern, regular borders, and with scintigraphy negative for somatostatin receptors. The average diameter of these nodules identified by endoscopic ultrasound was 2.15 cm. Microhistology obtained by EUS-FNA confirmed the diagnosis in 9/10 patients. CONCLUSION: Pancreatic splenosis can be diagnosed by EUS-FNA. Microhistology prevents unnecessary surgeries, and reassures asymptomatic patients with hypoechoic, homogeneous, and well circumscribed pancreatic nodules. PMID- 23657301 TI - Hepatic steatosis assessment: a comparative study between surgeon evaluation and forward histopathologic findings. AB - CONTEXT: Liver transplantation is one of the last viable resources for patients with end-stage liver disease. Many strategies are been used to improve the number of available organs and overcome waiting list delay. However, hepatic steatosis is one of the mainly concerns when organs are consider to transplantation due to it is importance as a risk factor for primary dysfunction. Surgeons play an important role to decide each organ will be accept or decline and its righteous allocation. OBJECTIVE: Retrospectively evaluate the surgeon assessment of steatosis degree and its confrontation with further histopathologic findings. METHODS: We analyzed 117 patients underwent deceased liver transplantation for end-stage liver disease in University Hospital Walter Cantideo, Fortaleza, CE, Brazil. A matrix table was organized to estimate the categorical data observed. We clustered the subjects into mild (0%-30%) and moderate (30%-60%) steatosis degree under the clinical criteria of organ suitability for transplantation. We categorized the organs as suitable organ for transplant and as non-suitable organ for transplant. Evaluations between the two first assessments, before perfusion (pre-perfusion) vs biopsy findings and after perfusion vs biopsy findings observations were analyzed and also a comparison between pre-perfusion and after perfusion data was performed. RESULTS: On the first assessment, we obtained a 93% of agreement (n = 109) between the two evaluations. On the second assessment, we had an 8% (n = 9) of mistaken allocation. Comparing the observation before (pre perfusion) and after (after perfusion), we obtained a strong agreement between the surgeons. CONCLUSIONS: Although our experienced surgeon team, we have wrongly evaluated feasible organs for transplantation. Nonetheless, our faulty percentage is low comparing to worldwide percentage. PMID- 23657302 TI - Progression of liver fibrosis in monoinfected patients by hepatitis C virus and coinfected by HCV and human immunodeficiency virus. AB - CONTEXT: The progression of liver fibrosis in patients coinfected by hepatitis C virus and human immunodeficiency virus (HCV/HIV) has been increasingly studied in the past decade. Studies made before the highly active antiretroviral therapy suggest that HIV can change the natural history of the HCV infection, leading to a faster progression of the liver fibrosis. OBJECTIVE: To evaluate and compare the fibrosis progression in two groups of patients (HCV/HIV coinfected and HCV monoinfected) METHODS: Seventy patients HCV monoinfected and 26 patients HCV/HIV coinfected who had not undertaken HCV treatment and were submitted to serial percutaneous liver biopsies were retrospectively evaluated. There was no difference in the fibrosis progression between the two groups. CONCLUSION: The fibrosis grade evolution was not worse in the coinfected patients. The immunosuppression absence and the shortest time period between the biopsies in the coinfected group are possible explanations. PMID- 23657303 TI - What are the most important factors regarding acceptance to the colonoscopy?: study of related tolerance parameters. AB - CONTEXT: Colonoscopy plays an indubitable role in the setting of clinical practice, however, it is an invasive exam; complex, lengthy, embarrassing, not devoid of risks and discomfort that yields fear and anxiety in the majority of patients. In a new era of rising competition between health institutions, where the quality of health care and client satisfaction are praised, studies regarding tolerance-related colonoscopy issues yield great potential to be explored. In the present study, tolerance is defined as willingness to repeat the exam. OBJECTIVES: Evaluate information associated to bowel preparation, the exam itself and post-examination period that might interfere with the tolerance to the colonoscopy. METHODS: Analysis of the tolerance to the colonoscopy at three stages (pre, post, and during) through a checklist: patient's questionnaire and a medical assessment form were used. RESULTS: In this present study, 91.2% of 373 patients exhibited positive tolerance to the colonoscopy. Aspects related to a negative level of tolerance were patient gender (12.9% of women versus 3.2% of men would not repeat the exam), age extremes (less than 20 years and greater than 80 years of age), and abdominal pain, both during the bowel preparation and after the procedure. CONCLUSIONS: Gender, age, patient cooperation and abdominal pain were the decisive components regarding tolerance to the colonoscopy. Notably, in two phases of the exam, the abdominal pain was the most important feature associated to a lessened tolerance. PMID- 23657304 TI - Effect of a bitter bolus on oral, pharyngeal and esophageal transit of healthy subjects. AB - CONTEXT: During swallowing, boluses stimulate sensory receptors of the oral, pharyngeal, laryngeal, and esophageal regions. Sweet and tasteless foods are more acceptable for swallowing than bitter foods. A bitter bolus is unpleasant for most subjects. Our hypothesis was that the ingestion of a bitter bolus might alter the oral behavior, pharyngeal and esophageal transit when compared to a sweet bolus. OBJECTIVE: To evaluate whether the bitter taste of a liquid bolus causes alteration on oral, pharyngeal and/or esophageal transit in normal subjects in comparison with sweet bolus.' METHOD: Scintigraphic evaluation of oral, pharyngeal and esophageal transit was performed in 43 asymptomatic subjects, 22 women and 21 men, ages 23-71 years, without problems with the ingestion of liquid and solid foods, and without digestive, cardiac or neurologic diseases. Each subject swallowed in random sequence and at room temperature 5 mL of a liquid bolus with bitter taste, prepared with 50 mL of water with 2 g of leaves of Peumus boldus, heated until boiling (boldus tea), and 5 mL of a liquid bolus with sweet taste, prepared with 50 mL of water with 3 g of sucrose, both labeled with 37 MBq of technetium phytate (Tc99m). RESULTS: There was no difference between the bitter bolus and the sweet bolus in mouth, pharynx and esophageal transit and clearance duration and in the amount of residues. CONCLUSION: A bitter bolus, considered an unpleasant bolus, does not alter the duration of oral, pharyngeal and esophageal phases of swallowing, when compared with a sweet bolus, considered a pleasant bolus. PMID- 23657305 TI - Hfe mutations and iron overload in patients with alcoholic liver disease. AB - CONTEXT: Alcoholic liver disease (ALD) is generally associated with iron overload, which may contribute to its pathogenesis, through increased oxidative stress and cellular damage. There are conflicting reports in literature about hemochromatosis (HFE) gene mutations and the severity of liver disease in alcoholic patients. OBJECTIVES: To compare the prevalence of mutations in the hemochromatosis (HFE) gene between patients with ALD and healthy controls; to assess the relation of HFE mutations with liver iron stores and liver disease severity. METHODS: Liver biopsy specimens were obtained from 63 ALD patients (during routine treatment) and 52 healthy controls (during elective cholecystectomy). All individuals underwent routine liver function tests and HFE genotyping (to detect wild-type sequences and C282Y, H63D, S65C, E168Q, E168X, V59M, H63H, P160delC, Q127H, Q283P, V53M and W164X mutations). Associations between HFE mutations and risk of excessive liver iron stores, abnormal serum ferritin, liver fibrosis, or necroinflammatory activity were assessed by multivariate logistic regression analysis. RESULTS: ALD patients had significantly higher serum ferritin and transferrin saturation than controls (both P<0.05), but the distribution of HFE mutations was similar between the two groups. For ALD patients, the odds ratio for having at least one HFE mutation and excessive liver iron stores was 17.23 (95% confidence interval (CI): 2.09-142.34, P = 0.008). However, the presence of at least one HFE mutation was not associated with an increased risk of liver fibrosis or necroinflammatory activity. Active alcohol ingestion showed the strongest association to increased serum ferritin (OR = 8.87, 95% CI: 2.11-34.78, P = 0.003). CONCLUSION: s ALD patients do not present with a differential profile of HFE mutations from healthy controls. In ALD patients, however, the presence of at least one HFE mutation increases the risk of having excessive liver iron stores but has no detectable effects on liver disease activity or severity. PMID- 23657306 TI - Dysphagia and sialorrhea: the relationship to Parkinson's disease. AB - CONTEXT: Dysphagia and sialorrhea in patients with Parkinson's disease are both automatically accepted as dependent on this neurological disease. OBJECTIVE: The aim were to establish if these two complaints are a consequence or associated manifestations of Parkinson's disease. METHOD: Two Parkinson's diseases groups from the same outpatients' population were studied. Patients in the first group, with dysphagia, were studied by videofluoroscopy. The second, with sialorrhea, were studied by the scintigraphic method, RESULTS: Videofluoroscopic examination of the oral, pharyngeal and esophageal phases of swallowing showed that 94% of Parkinson's diseases patients present, structural causes, not related to Parkinson's diseases, able to produce or intensify the observed disphagia. The scintigraphic examination of Parkinson's diseases patients with sialorrhea showed that there is no increase of serous saliva production. Nevertheless, showed a significantly higher velocity of saliva excretion in the Parkinson's diseases patients. CONCLUSIONS: Dysphagia can be due to the muscular rigidity often present in the Parkinson's diseases patient, or more usually by non Parkinson's disease associated causes. In Parkinson's diseases patients, sialorrhea is produced by saliva retention. Nevertheless, sialorrhea can produce discomfort in swallowing, although without a formal complaint of dysphagia. In this case, subclinical dysphagia must be considered. Sialorrhea is indicative of dysphagia or at least of subclinical dysphagia. As final conclusion, Parkinson's diseases can be an isolated cause of dysphagia and/or sialorrhea, but frequently, a factor unrelated to Parkinson's diseases is the main cause of or at least aggravates the dysphagia. PMID- 23657307 TI - Early complications in bariatric surgery: incidence, diagnosis and treatment. AB - CONTEXT: Bariatric surgery has proven to be the most effective method of treating severe obesity. Nevertheless, the acceptance of bariatric surgery is still questioned. The surgical complications observed in the early postoperative period following surgeries performed to treat severe obesity are similar to those associated with other major surgeries of the gastrointestinal tract. However, given the more frequent occurrence of medical comorbidities, these patients require special attention in the early postoperative follow-up. Early diagnosis and appropriate treatment of these complications are directly associated with a greater probability of control. METHOD: The medical records of 538 morbidly obese patients who underwent surgical treatment (Roux-en-Y gastric bypass surgery) were reviewed. Ninety-three (17.2%) patients were male and 445 (82.8%) were female. The ages of the patients ranged from 18 to 70 years (average = 46), and their body mass indices ranged from 34.6 to 77 kg/m2. RESULTS: Early complications occurred in 9.6% and were distributed as follows: 2.6% presented bleeding, intestinal obstruction occurred in 1.1%, peritoneal infections occurred in 3.2%, and 2.2% developed abdominal wall infections that required hospitalization. Three (0.5%) patients experienced pulmonary thromboembolism. The mortality rate was 0,55%. CONCLUSION: The incidence of early complications was low. The diagnosis of these complications was mostly clinical, based on the presence of signs and symptoms. The value of the clinical signs and early treatment, specially in cases of sepsis, were essential to the favorable surgical outcome. The mortality was mainly related to thromboembolism and advanced age, over 65 years. PMID- 23657309 TI - Increase income and mortality of colorrectal cancer in Brazil, 2001-2009. AB - CONTEXT: Several international studies have observed a correlation between the improvement of socio-demographic indicators and rates of incidence and mortality from cancer of the colon and rectum. OBJECTIVE: The objective of this study is to estimate the correlation between average per capita income and the rate of colorectal cancer mortality in Brazil between 2001 and 2009. METHODS: We obtained data on income inequality (Gini index), population with low incomes (1/2 infer the minimum wage/month), average family income, per capita ICP and mortality from colon cancer and straight between 2001-2009 by DATASUS. A trend analysis was performed using linear regression, and correlation between variables by Pearson's correlation coefficient. RESULTS: There was a declining trend in poverty and income inequality, and growth in ICP per capita and median family income and standardized mortality rate for colorectal cancer in Brazil. There was also strong positive correlation between mortality from this site of cancer and inequality (men r = -0.30, P = 0.06, women r = -0.33, P = 0.05) income low income (men r = -0.80, P<0.001, women r = -0.76, P<0.001), median family income (men r = 0.79, P = 0.06, women r = 0.76, P<0.001) and ICP per capita (men r = 0.73, P<0.001, women r = 0.68, P<0.001) throughout the study period. CONCLUSION: The increase of income and reducing inequality may partially explain the increased occurrence of colorectal cancer and this is possibly due to differential access to food recognized as a risk factor, such as red meat and high in fat. It is important therefore to assess the priority of public health programs addressing nutrition in countries of intermediate economy, as is the case of Brazil. PMID- 23657308 TI - Improvement of intestinal permeability with alanyl-glutamine in HIV patients: a randomized, double blinded, placebo-controlled clinical trial. AB - CONTEXT: Glutamine is the main source of energy of the enterocyte and diarrhea and weight loss are frequent in HIV infected patients. OBJECTIVE: To determine the effect of alanyl-glutamine supplementation on intestinal permeability and absorption in these patients. METHODS: Randomized double-blinded, placebo controlled study using isonitrogenous doses of alanyl-glutamine (24 g/day) and placebo (glycine, 25 g/day) during 10 days. Before and after this nutritional supplementation lactulose and mannitol urinary excretion were determined by high performance liquid chromatography. RESULTS: Forty six patients with HIV/AIDS, 36 of whom were male, with 37.28 +/- 3 (mean +/- standard error) years were enrolled. Twenty two and 24 subjects were treated with alanyl-glutamine and with glycine respectively. In nine patients among all in the study protocol that reported diarrhea in the 14 days preceding the beginning of the study, mannitol urinary excretion was significantly lower than patients who did not report this symptom [median (range): 10.51 (3.01-19.75) vs. 15.37 (3.93-46.73); P = 0.0281] and lactulose/mannitol ratio was significantly higher [median (range): 0.04 (0.00 2.89) vs. 0.02 (0.00-0.19); P = 0.0317]. There was also a significant increase in mannitol urinary excretion in the group treated with alanyl-glutamine [median (range): 14.38 (8.25-23.98) before vs 21.24 (6.27-32.99) after treatment; n = 14, P = 0.0382]. CONCLUSION: Our results suggest that the integrity and intestinal absorption are more intensely affected in patients with HIV/AIDS who recently have had diarrhea. Additionally, nutritional supplementation with alanyl glutamine was associated with an improvement in intestinal absorption. PMID- 23657310 TI - Evaluation of the ultrastructure of the small intestine of hiv infected children by transmission and scanning electronic microscopy. AB - OBJECTIVES: To describe HIV children's small intestinal ultrastructural findings. METHODS: Descriptive, observational study of small intestine biopsies performed between August 1994 and May 1995 at Sao Paulo, SP, Brazil. This material pertained to 11 HIV infected children and was stored in a laboratory in paraffin blocks. Scanning and transmission electronic microscopy were used to view those intestine samples and ultrastructural findings were described by analyzing digitalized photos of this material. Ethical Committee approval was obtained. RESULTS: In most samples scanning microscopy showed various degrees of shortening and decreasing number of microvilli and also completes effacements in some areas. Derangement of the enterocytes was seen frequently and sometimes cells well defined borders limits seemed to be loosened. In some areas a mucous-fibrin like membrane with variable thickness and extension appeared to partially or totally coat the epithelial surface. Fat drops were present in the intestinal lumen in various samples and a bacterium morphologically resembling bacilli was seen in two occasions. Scanning microscopy confirmed transmission microscopy microvilli findings and also showed little "tufts" of those structures. In addition, it showed an increased number of vacuoles and multivesicular bodies inside various enterocytes, an increased presence of intraepithelial lymphocytes, mitochondrial vacuolization and basement membrane enlargement in the majority of samples analyzed. However, some samples exhibited normal aspect. CONCLUSIONS: Our study showed the common occurrence of various important intestinal ultrastructural alterations with variable degrees among HIV infected children, some of them in our knowledge not described before. PMID- 23657311 TI - Right to remain silent. PMID- 23657312 TI - The cleaner state. PMID- 23657313 TI - Voice of Pro-Test. PMID- 23657314 TI - China's citizens must act to save their environment. PMID- 23657326 TI - US warheads to get a facelift. PMID- 23657327 TI - Oceans under surveillance. PMID- 23657328 TI - US bill would keep helium store afloat. PMID- 23657329 TI - Symmetry study deemed a fraud. PMID- 23657330 TI - Privacy protections: The genome hacker. PMID- 23657331 TI - Neuroprosthetics: once more, with feeling. PMID- 23657332 TI - Global warming: A call for peace on climate and conflict. PMID- 23657333 TI - Sustainable mobility: A vision of our transport future. PMID- 23657334 TI - Palaeontology: Free digital scans of human fossils. PMID- 23657339 TI - History: Non-coding RNA foreseen 48 years ago. PMID- 23657340 TI - Forests: Oil-palm concerns in Brazilian Amazon. PMID- 23657341 TI - Environment: Overhaul pesticide testing on bees. PMID- 23657343 TI - Climate mitigation: An open dialogue on solar engineering. PMID- 23657344 TI - Nuclear physics: Exotic pear-shaped nuclei. PMID- 23657345 TI - Galaxy formation: The cosmic web in focus. PMID- 23657346 TI - Immunology: Memory cells sound the alarm. PMID- 23657348 TI - Studies of pear-shaped nuclei using accelerated radioactive beams. AB - There is strong circumstantial evidence that certain heavy, unstable atomic nuclei are 'octupole deformed', that is, distorted into a pear shape. This contrasts with the more prevalent rugby-ball shape of nuclei with reflection symmetric, quadrupole deformations. The elusive octupole deformed nuclei are of importance for nuclear structure theory, and also in searches for physics beyond the standard model; any measurable electric-dipole moment (a signature of the latter) is expected to be amplified in such nuclei. Here we determine electric octupole transition strengths (a direct measure of octupole correlations) for short-lived isotopes of radon and radium. Coulomb excitation experiments were performed using accelerated beams of heavy, radioactive ions. Our data on (220)Rn and (224)Ra show clear evidence for stronger octupole deformation in the latter. The results enable discrimination between differing theoretical approaches to octupole correlations, and help to constrain suitable candidates for experimental studies of atomic electric-dipole moments that might reveal extensions to the standard model. PMID- 23657349 TI - Discrete clouds of neutral gas between the galaxies M31 and M33. AB - Spiral galaxies must acquire gas to maintain their observed level of star formation beyond the next few billion years. A source of this material may be the gas that resides between galaxies, but our understanding of the state and distribution of this gas is incomplete. Radio observations of the Local Group of galaxies have revealed hydrogen gas extending from the disk of the galaxy M31 at least halfway to M33. This feature has been interpreted to be the neutral component of a condensing intergalactic filament, which would be able to fuel star formation in M31 and M33, but simulations suggest that such a feature could also result from an interaction between both galaxies within the past few billion years (ref. 5). Here we report radio observations showing that about 50 per cent of this gas is composed of clouds, with the rest distributed in an extended, diffuse component. The clouds have velocities comparable to those of M31 and M33, and have properties suggesting that they are unrelated to other Local Group objects. We conclude that the clouds are likely to be transient condensations of gas embedded in an intergalactic filament and are therefore a potential source of fuel for future star formation in M31 and M33. PMID- 23657350 TI - Future sea-level rise from Greenland's main outlet glaciers in a warming climate. AB - Over the past decade, ice loss from the Greenland Ice Sheet increased as a result of both increased surface melting and ice discharge to the ocean. The latter is controlled by the acceleration of ice flow and subsequent thinning of fast flowing marine-terminating outlet glaciers. Quantifying the future dynamic contribution of such glaciers to sea-level rise (SLR) remains a major challenge because outlet glacier dynamics are poorly understood. Here we present a glacier flow model that includes a fully dynamic treatment of marine termini. We use this model to simulate behaviour of four major marine-terminating outlet glaciers, which collectively drain about 22 per cent of the Greenland Ice Sheet. Using atmospheric and oceanic forcing from a mid-range future warming scenario that predicts warming by 2.8 degrees Celsius by 2100, we project a contribution of 19 to 30 millimetres to SLR from these glaciers by 2200. This contribution is largely (80 per cent) dynamic in origin and is caused by several episodic retreats past overdeepenings in outlet glacier troughs. After initial increases, however, dynamic losses from these four outlets remain relatively constant and contribute to SLR individually at rates of about 0.01 to 0.06 millimetres per year. These rates correspond to ice fluxes that are less than twice those of the late 1990s, well below previous upper bounds. For a more extreme future warming scenario (warming by 4.5 degrees Celsius by 2100), the projected losses increase by more than 50 per cent, producing a cumulative SLR of 29 to 49 millimetres by 2200. PMID- 23657352 TI - Long-term speech perception in elderly cochlear implant users. AB - IMPORTANCE: A review of a test battery presented in both quiet and noise may clarify what the progression of speech perception abilities is in older adult cochlear implant users and whether the performance declines with advancing age. OBJECTIVE: To examine whether older adults (>=65 years) with cochlear implants maintain stable speech perception performance after at least 10 years of listening experience with an external speech processor. DESIGN AND SETTING: Retrospective analysis performed in an academic tertiary care center. PARTICIPANTS: Fourteen older adult cochlear implant recipients with at least 10 years of listening experience. MAIN OUTCOME MEASURES: Speech perception outcomes as measured with Consonant-Nucleus-Consonant words in quiet and Hearing in Noise Test sentences in quiet and steady-state noise were analyzed retrospectively at the 6-month and 1-, 5-, and 10-year postoperative follow-up intervals. RESULTS: Consonant-Nucleus-Consonant word scores remained stable between 6 months and 1 year of listening experience, improved significantly (P < .001) between 1 year and 5 years, and remained stable between 5 years and 10 years. Hearing in Noise Test sentence scores in quiet and noise showed a similar pattern, with stability in performance between the 6-month to 1-year and 5-year to 10-year follow-up intervals, and significantly improved performance (P = .04) between the 1-year and 5-year follow-up intervals. CONCLUSIONS AND RELEVANCE: On average, patients who undergo cochlear implantation at age 65 years or older do not experience a decline in speech perception performance with extended listening experience and may potentially continue to see improvements beyond the 1-year follow-up interval. PMID- 23657353 TI - Male chronic pelvic pain syndrome and the role of interdisciplinary pain management. AB - INTRODUCTION: This paper is a team collaboration which aims to describe the multidisciplinary chronic pelvic pain (CPP) service for men in a major London teaching hospital. METHOD: Evidence from the European Association for Urology Guidelines and the small pool of relevant psychological literature is reviewed as well as results from our pelvic pain programme (LINK) in association with a description of the programme. RESULTS: Treatment targets for men with CPP are outlined. The roles of the consultant in pain management, clinical nurse specialist, clinical psychologist and specialist physiotherapist in delivering treatment are described. This includes the journey from initial consultation through treatment options. Finally, we describe our pelvic pain programme (LINK) which aims to deliver an effective multidisciplinary intervention via single sex groups. CONCLUSION: This programme links all significant treatment dimensions as well as connecting groups of patients to reduce their sense of isolation. Evidence is presented from the formal evaluation of the programme. PMID- 23657354 TI - Safety and effectiveness of Thulium VapoEnucleation of the prostate (ThuVEP) in patients on anticoagulant therapy. AB - INTRODUCTION: To evaluate the safety and efficacy of Thulium VapoEnucleation of the prostate (ThuVEP) for patients on oral anticoagulants (OA) with symptomatic benign prostatic obstruction (BPO). METHODS: Fifty-six patients, undergoing ThuVEP at two institutions, were evaluated from May 2009 until June 2011. All patients were at high cardiopulmonary risk and presented with a median American Society of Anesthesiology score of 3 [interquartile range (IQR) 2-3]. Thirty-two patients were on aspirin, 8 were on clopidogrel or clopidogrel and aspirin, and 16 on phenprocoumon at the time of surgery. Patient demographic, perioperative, and follow-up data were analyzed. RESULTS: Median prostate volume was 50 (IQR 34 76) cc, and resected tissue weight was 32 (IQR 20-50) g. The median operative time was 61.5 (IQR 40-100.75) min, and the catheter time 2 (IQR 2-3) days. There were no perioperative thromboembolic events. Five patients (8.9%) required a second-look operation in the immediate postoperative course (hemorrhage n = 4, residual adenoma n = 1) and four (7.1%) blood transfusions. Complications within the first 30 days included urinary tract infections (1.7%), urinary retention (3.6%), and delayed bleeding (7.1%). These complications were managed conservatively. At 12-month follow-up, median QoL [5 (IQR 3.75-5) vs. 1 (IQR 1 2)], IPSS [21.5 (IQR 15.5-23.75) vs. 5 (IQR 3-8)], Qmax [7.7 (IQR 6.3-10) vs. 28.3 (IQR 21.25-39.2) ml/s], and postvoiding residual urine [100 (IQR 46-200) vs. 17.5 (IQR 0-36) ml] improved significantly (p < 0.002). CONCLUSIONS: Thulium VapoEnucleation of the prostate seems to be a safe and efficacious procedure for the treatment of symptomatic BPO in patients at high cardiopulmonary risk on OA. PMID- 23657356 TI - The electronic structure of MgO nanotubes. An ab initio quantum mechanical investigation. AB - The structural, vibrational and response properties of the (n,0) and (m,m) MgO nanotubes are computed by using a Gaussian type basis set, a hybrid functional (B3LYP) and the CRYSTAL09 code. Tubes in the range 6 <= n <= 140 and 3 <= m <= 70 were considered, being n = 2 * m the number of MgO units in the unit cell (so, the maximum number of atoms is 280). Tubes are built by rolling up the fully relaxed 2-D conventional cell (2 MgO units, with oxygen atoms protruding from the Mg plane alternately up and down by 0.38 A). The relative stability of the (n,0) with respect to the (m,m) family, the relaxation energy and equilibrium geometry, the band gap, the IR vibrational frequencies and intensities, and the electronic and ionic contributions to the polarizability are reported. All these properties are shown to converge smoothly to the monolayer values. Absence of negative vibrational frequencies confirms that the tubes have a stable structure. The parallel component of the polarizability alpha(?) converges very rapidly to the monolayer value, whereas alpha(?) is still changing at n = 140; however, when extrapolated to very large n values, it coincides with the monolayer value to within 1%. The electronic contribution to alpha is in all cases (alpha(?) and alpha(?); 6 <= n <= 140) smaller than the vibrational contribution by about a factor of three, at variance with respect to more covalent tubes such as the BN ones, for which the ratio between the two contributions is reversed. PMID- 23657355 TI - How far is the horizon? From current targets to future drugs in advanced renal cancer. AB - PURPOSE: The proliferative control of renal cell cancer (RCC) via vascular endothelial growth factor and mammalian target of rapamycin inhibition by targeted agents has substantially improved survival rates for RCC patients with metastatic (m) disease. However, the management of mRCC remains challenging because some patients are primarily refractory to the approved targeted agents and most therapies eventually fail because of the development of an intractable drug resistance. Tumor progression is closely related to a persistent or restored proliferation via direct and indirect oncogenic signals. Although the elucidation of cancer cell proliferation in the "-omics era" has revealed an enormous number of new potential targets, a comprehensive overview of the different pathways that might serve as new drug targets has become increasingly complex. METHODS/RESULTS: This review highlights the well-trodden pathways in mRCC that are inhibited by targeting agents and describes innovative modes of action within these pathways that are currently not targeted but are under exploration in clinical studies. Additionally, this paper highlights as future drug targets the components of tumor metabolism that supply the tumor cells with nutrition. CONCLUSIONS: These fundamental insights into RCC proliferation as a key driver of progression are urgently needed to overcome the currently improved but still limited targeted drug success. PMID- 23657357 TI - The benefits of selecting phenotype-specific variants for applications of mixed models in genomics. AB - Applications of linear mixed models (LMMs) to problems in genomics include phenotype prediction, correction for confounding in genome-wide association studies, estimation of narrow sense heritability, and testing sets of variants (e.g., rare variants) for association. In each of these applications, the LMM uses a genetic similarity matrix, which encodes the pairwise similarity between every two individuals in a cohort. Although ideally these similarities would be estimated using strictly variants relevant to the given phenotype, the identity of such variants is typically unknown. Consequently, relevant variants are excluded and irrelevant variants are included, both having deleterious effects. For each application of the LMM, we review known effects and describe new effects showing how variable selection can be used to mitigate them. PMID- 23657359 TI - Injectable bulking agents for passive faecal incontinence. PMID- 23657358 TI - Snake venoms: attractive antimicrobial proteinaceous compounds for therapeutic purposes. AB - Gram-positive and -negative bacteria are dangerous pathogens that may cause human infection diseases, especially due to the increasingly high prevalence of antibiotic resistance, which is becoming one of the most alarming clinical problems. In the search for novel antimicrobial compounds, snake venoms represent a rich source for such compounds, which are produced by specialized glands in the snake's jawbone. Several venom compounds have been used for antimicrobial effects. Among them are phospholipases A2, which hydrolyze phospholipids and could act on bacterial cell surfaces. Moreover, metalloproteinases and L-amino acid oxidases, which represent important enzyme classes with antimicrobial properties, are investigated in this study. Finally, antimicrobial peptides from multiple classes are also found in snake venoms and will be mentioned. All these molecules have demonstrated an interesting alternative for controlling microorganisms that are resistant to conventional antibiotics, contributing in medicine due to their differential mechanisms of action and versatility. In this review, snake venom antimicrobial compounds will be focused on, including their enormous biotechnological applications for drug development. PMID- 23657360 TI - Ammonia oxidation kinetics and temperature sensitivity of a natural marine community dominated by Archaea. AB - Archaeal ammonia oxidizers (AOAs) are increasingly recognized as prominent members of natural microbial assemblages. Evidence that links the presence of AOA with in situ ammonia oxidation activity is limited, and the abiotic factors that regulate the distribution of AOA natural assemblages are not well defined. We used quantitative PCR to enumerate amoA (encodes alpha-subunit of ammonia monooxygenase) abundances; AOA amoA gene copies greatly outnumbered ammonia oxidizing bacteria and amoA transcripts were derived primarily from AOA throughout the water column of Hood Canal, Puget Sound, WA, USA. We generated a Michaelis-Menten kinetics curve for ammonia oxidation by the natural community and found that the measured Km of 98+/-14 nmol l(-1) was close to that for cultivated AOA representative Nitrosopumilus maritimus SCM1. Temperature did not have a significant effect on ammonia oxidation rates for incubation temperatures ranging from 8 to 20 degrees C, which is within the temperature range for depths of measurable ammonia oxidation at the site. This study provides substantial evidence, through both amoA gene copies and transcript abundances and the kinetics response, that AOA are the dominant active ammonia oxidizers in this marine environment. We propose that future ammonia oxidation experiments use a Km for the natural community to better constrain ammonia oxidation rates determined with the commonly used (15)NH4(+) dilution technique. PMID- 23657362 TI - Chytrid epidemics may increase genetic diversity of a diatom spring-bloom. AB - Contrary to expectation, populations of clonal organisms are often genetically highly diverse. In phytoplankton, this diversity is maintained throughout periods of high population growth (that is, blooms), even though competitive exclusion among genotypes should hypothetically lead to the dominance of a few superior genotypes. Genotype-specific parasitism may be one mechanism that helps maintain such high-genotypic diversity of clonal organisms. Here, we present a comparison of population genetic similarity by estimating the beta-dispersion among genotypes of early and peak bloom populations of the diatom Asterionella formosa for three spring-blooms under high or low parasite pressure. The Asterionella population showed greater beta-dispersion at peak bloom than early bloom in the 2 years with high parasite pressure, whereas the within group dispersion did not change under low parasite pressure. Our findings support that high prevalence parasitism can promote genetic diversification of natural populations of clonal hosts. PMID- 23657361 TI - Genetic diversity in cultured and wild marine cyanomyoviruses reveals phosphorus stress as a strong selective agent. AB - Viruses that infect marine cyanobacteria-cyanophages-often carry genes with orthologs in their cyanobacterial hosts, and the frequency of these genes can vary with habitat. To explore habitat-influenced genomic diversity more deeply, we used the genomes of 28 cultured cyanomyoviruses as references to identify phage genes in three ocean habitats. Only about 6-11% of genes were consistently observed in the wild, revealing high gene-content variability in these populations. Numerous shared phage/host genes differed in relative frequency between environments, including genes related to phosphorous acquisition, photorespiration, photosynthesis and the pentose phosphate pathway, possibly reflecting environmental selection for these genes in cyanomyovirus genomes. The strongest emergent signal was related to phosphorous availability; a higher fraction of genomes from relatively low-phosphorus environments-the Sargasso and Mediterranean Sea-contained host-like phosphorus assimilation genes compared with those from the N. Pacific Gyre. These genes are known to be upregulated when the host is phosphorous starved, a response mediated by pho box motifs in phage genomes that bind a host regulatory protein. Eleven cyanomyoviruses have predicted pho boxes upstream of the phosphate-acquisition genes pstS and phoA; eight of these have a conserved cyanophage-specific gene (PhCOG173) between the pho box and pstS. PhCOG173 is also found upstream of other shared phage/host genes, suggesting a unique regulatory role. Pho boxes are found upstream of high light-inducible (hli) genes in cyanomyoviruses, suggesting that this motif may have a broader role than regulating phosphorous-stress responses in infected hosts or that these hlis are involved in the phosphorous-stress response. PMID- 23657363 TI - Lrs14 transcriptional regulators influence biofilm formation and cell motility of Crenarchaea. AB - Like bacteria, archaea predominately exist as biofilms in nature. However, the environmental cues and the molecular mechanisms driving archaeal biofilm development are not characterized. Here we provide data suggesting that the transcriptional regulators belonging to the Lrs14-like protein family constitute a key regulatory factor during Sulfolobus biofilm development. Among the six lrs14-like genes encoded by Sulfolobus acidocaldarius, the deletion of three led to markedly altered biofilm phenotypes. Although Deltasaci1223 and Deltasaci1242 deletion mutants were impaired in biofilm formation, the Deltasaci0446 deletion strain exhibited a highly increased extracellular polymeric substance (EPS) production, leading to a robust biofilm structure. Moreover, although the expression of the adhesive pili (aap) genes was upregulated, the genes of the motility structure, the archaellum (fla), were downregulated rendering the Deltasaci0446 strain non-motile. Gel shift assays confirmed that Saci0446 bound to the promoter regions of fla and aap thus controlling the expression of both cell surface structures. In addition, genetic epistasis analysis using Deltasaci0446 as background strain identified a gene cluster involved in the EPS biosynthetic pathway of S. acidocaldarius. These results provide insights into both the molecular mechanisms that govern biofilm formation in Crenarchaea and the functionality of the Lrs14-like proteins, an archaea-specific class of transcriptional regulators. PMID- 23657365 TI - Design of a bi-functional peptide for protein assays: observation of cortactin expression in human placenta. AB - A bi-functional peptide is designed to incorporate protein recognition and signal amplification functions into a single short peptide sequence. PMID- 23657364 TI - Development of an ecophysiological model for Diplosphaera colotermitum TAV2, a termite hindgut Verrucomicrobium. AB - Termite hindguts are populated by a dense and diverse community of microbial symbionts working in concert to transform lignocellulosic plant material and derived residues into acetate, to recycle and fix nitrogen, and to remove oxygen. Although much has been learned about the breadth of microbial diversity in the hindgut, the ecophysiological roles of its members is less understood. In this study, we present new information about the ecophysiology of microorganism Diplosphaera colotermitum strain TAV2, an autochthonous member of the Reticulitermes flavipes gut community. An integrated high-throughput approach was used to determine the transcriptomic and proteomic profiles of cells grown under hypoxia (2% O2) or atmospheric (20% O2) concentrations of oxygen. Our results revealed that genes and proteins associated with energy production and utilization, carbohydrate transport and metabolism, nitrogen fixation, and replication and recombination were upregulated under 2% O2. The metabolic map developed for TAV2 indicates that this microorganism may be involved in biological nitrogen fixation, amino-acid production, hemicellulose degradation and consumption of O2 in the termite hindgut. Variation of O2 concentration explained 55.9% of the variance in proteomic profiles, suggesting an adaptive evolution of TAV2 to the hypoxic periphery of the hindgut. Our findings advance the current understanding of microaerophilic microorganisms in the termite gut and expand our understanding of the ecological roles for members of the phylum Verrucomicrobia. PMID- 23657366 TI - Enhanced visible-light-driven photocatalytic activity of mesoporous TiO(2-x)N(x) derived from the ethylenediamine-based complex. AB - A facile solvent evaporation induced self-assembly (SEISA) strategy was developed to synthesize mesoporous N-doped anatase TiO2 (SE-meso-TON) using a single organic complex precursor derived in situ from titanium butoxide and ethylenediamine in ethanol solution. After the evaporation of ethanol in a fume hood and subsequent calcinations at 450 degrees C, the obtained N-doped TiO2 (meso-TON) anatase was of finite crystallite size, developed porosity, large surface area (101 m(2) g(-1)) and extended light absorption in the visible region. This SE-meso-TON also showed superior photocatalytic activity to the SG meso-TON anatase prepared via sol-gel synthesis. On the basis of characterization results from XRD, XPS, N2 adsorption-desorption and ESR, the enhanced visible light-responsive photocatalytic activity of SE-meso-TON was assigned to its developed mesoporosity and reduced oxygen vacancies. PMID- 23657367 TI - Response to the comment on Schecklmann et al.: a call to consider both "negative" and "positive" results in brain research on tinnitus. PMID- 23657368 TI - From N-benzoylpyridinium imides to pyrazolo[1,5-a]pyridines: a mechanistic discussion on a stoichiometric Cu protocol. AB - A Cu-mediated preparation of 2-substitiuted pyrazolo[1,5-a]pyridines from N benzoylpyridinium imides and terminal alkynes is described using stoichiometric Cu(OAc)2 as both the mediator and the oxidant. Extensive DFT calculations suggest a Cu(III) intermediate via disproportionation of Cu(II). PMID- 23657369 TI - Do no harm. PMID- 23657371 TI - Drugmakers plow more resources into autism. PMID- 23657373 TI - Footrace to clinic heats up for T-cell nuclear receptor inhibitors. PMID- 23657374 TI - Synthetic peptide allergy vaccine shows efficacy. PMID- 23657376 TI - Second oral MS drug wins FDA nod. PMID- 23657379 TI - FDA moves on breakthrough therapies. PMID- 23657380 TI - China overhauls drug regulation agency. PMID- 23657381 TI - No-fee university licenses spur biotech partnerships. PMID- 23657382 TI - Principia Biopharma. PMID- 23657383 TI - 1Q13--Stocks reach all-time high. PMID- 23657384 TI - Antimicrobial peptides stage a comeback. PMID- 23657385 TI - Academic-industry partnerships 2012. PMID- 23657386 TI - A P3G generic access agreement for population genomic studies. PMID- 23657387 TI - When bad science makes good headlines: Bt maize and regulatory bans. PMID- 23657389 TI - Recapitulating human cancer in a mouse. PMID- 23657390 TI - Biotech's wellspring: the health of private biotech in 2012. PMID- 23657391 TI - Not quite a myriad of gene patents. PMID- 23657393 TI - White matter from fibroblasts. PMID- 23657394 TI - Endowing cells with logic and memory. PMID- 23657395 TI - Antibiotic and ROS linkage questioned. PMID- 23657396 TI - Defining the path to hematopoietic stem cells. PMID- 23657398 TI - First-quarter biotech job picture. PMID- 23657400 TI - Macrophages promote tumour growth and liver metastasis in an orthotopic syngeneic mouse model of colon cancer. AB - PURPOSE: Tumour-associated macrophages have been shown to promote proliferation, angiogenesis and metastasis in several carcinomas. The effect on colon cancer has not yet been clarified. Furthermore, Kupffer cells in the liver might initiate the formation of metastases by directly binding tumour cells. METHODS: An orthotopic syngeneic mouse model of colon cancer as well as a liver metastases model has been studied, using murine CT-26 colon cancer cells in Balb/c-mice. Macrophages were depleted in both models by clodronate liposomes. Tumour sizes and metastases were determined using 7-Tesla MRI. The macrophage and vascular density in the orthotopic tumours as well as the Kupffer cell density in the livers were evaluated using immunohistochemistry. RESULTS: Animals in the macrophage-depleted group displayed significantly smaller primary tumours (37 +/- 20 mm(3)) compared to the control group (683 +/- 389 mm(3), p = 0.0072). None of the mice in the depleted group showed liver or peritoneal metastases, whereas four of six control mice displayed liver and five out of six mice peritoneal metastases. The vascular density was significantly lower in the macrophage depleted group (p = 0.0043). In the liver metastases model, animals of the Kupffer cell-depleted group (14.3 +/- 7.7) showed significantly less liver metastases than mice of the two control groups (PBS liposomes, 118.5 +/- 28.2, p = 0.0117; NaCl, 81.7 +/- 23.2, p = 0.0266). The number of liver metastases correlated directly with the Kupffer cell density (p = 0.0221). CONCLUSION: Macrophages promote tumour growth, angiogenesis and metastases in this orthotopic syngeneic mouse model. Kupffer cells enhance the formation of metastases in the liver. PMID- 23657401 TI - Normal values and pressure morphology for three-dimensional high-resolution anorectal manometry of asymptomatic adults: a study in 110 subjects. AB - OBJECTIVES: The purpose of this study is to evaluate normal values and pressure morphology of three-dimensional high-resolution anorectal manometry (3D-HRM) in asymptomatic volunteers and to determine the relationship between objective measurable values, gender, and age. PATIENTS AND METHODS: Anorectal pressures and rectal sensation were evaluated in 110 asymptomatic volunteers (46 females and 64 males) ranging in age from 18 to 80 years (median age, 52 years) in left lateral position by three-dimensional high-resolution manometry. RESULTS: Maximum squeeze pressure, residual anal pressure, and intrarectal pressure were significantly higher in males compared to females (p < 0.05 each). Duration of sustained squeeze was significantly lower in males compared to females (p < 0.05). Maximum resting pressure, mean resting pressure, and maximum squeeze pressure were inversely correlated (r = -0.310, p < 0.01, r = -0.276, p < 0.01, and r = -0.198, p < 0.05) with age. The value of rectoanal pressure differential was -13.1 +/- 5.8 mmHg which was negative during defecation. Overall variation coefficient in anorectal pressures ranged between 0.21 and 0.34. CONCLUSION: This study establishes normal values for anorectal pressure by 3D-HRM in asymptomatic volunteers. There are significant gender differences concerning squeeze patterns. Increasing age is associated with lower maximum resting pressure, mean resting pressure, and maximum squeeze pressure. Normal characteristic pressure morphology of anorectum can be obtained at rest, during squeeze, and bear down as in defecation by 3D-HRM. PMID- 23657402 TI - MicroRNA-21 in scleroderma fibrosis and its function in TGF-beta-regulated fibrosis-related genes expression. AB - Uncontrolled fibrosis in multiple organs is the main cause of death in systemic sclerosis (SSc), and transforming growth factor-beta (TGF-beta) activation plays a fundamental role in the process. Our previous study demonstrated that miR-21 was significantly up-regulated in SSc fibroblasts. Here, we found that TGF-beta regulated the expression of miR-21 and fibrosis-related genes, and decreased Smad7 expression. Over-expression of miR-21 in fibroblasts decreased the levels of Smad7, whereas knockdown of miR-21 increased its expression. Further study using a reporter gene assay demonstrated Smad7 was a direct target of miR-21. Similar to human SSc, the expression of miR-21 increased in the bleomycin induced skin fibrosis. Inhibition of fibrosis by treatment with anti-fibrosis drug bortezomib restored the levels of miR-21 and Smad7. MiR-21 may function in an amplifying circuit to enhance TGF-beta signaling events in SSc fibrosis, and suggesting that miR-21 may act as a potential therapeutic target. PMID- 23657403 TI - A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. AB - The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician's observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way. We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since. PMID- 23657404 TI - Social networks, social support mechanisms, and quality of life after breast cancer diagnosis. AB - We examined mechanisms through which social relationships influence quality of life (QOL) in breast cancer survivors. This study included 3,139 women from the Pathways Study who were diagnosed with breast cancer from 2006 to 2011 and provided data on social networks (the presence of a spouse or intimate partner, religious/social ties, volunteering, and numbers of close friends and relatives), social support (tangible support, emotional/informational support, affection, positive social interaction), and QOL, measured by the FACT-B, approximately 2 months post diagnosis. We used logistic models to evaluate associations between social network size, social support, and lower versus higher than median QOL scores. We further stratified by stage at diagnosis and treatment. In multivariate-adjusted analyses, women who were characterized as socially isolated had significantly lower FACT-B (OR = 2.18, 95 % CI: 1.72-2.77), physical well being (WB) (OR = 1.61, 95 % CI: 1.27-2.03), functional WB (OR = 2.08, 95 % CI: 1.65-2.63), social WB (OR = 3.46, 95 % CI: 2.73-4.39), and emotional WB (OR = 1.67, 95 % CI: 1.33-2.11) scores and higher breast cancer symptoms (OR = 1.48, 95 % CI: 1.18-1.87) compared with socially integrated women. Each social network member independently predicted higher QOL. Simultaneous adjustment for social networks and social support partially attenuated associations between social networks and QOL. The strongest mediator and type of social support that was most predictive of QOL outcomes was "positive social interaction." However, each type of support was important depending on outcome, stage, and treatment status. Larger social networks and greater social support were related to higher QOL after a diagnosis of breast cancer. Effective social support interventions need to evolve beyond social-emotional interventions and need to account for disease severity and treatment status. PMID- 23657405 TI - Immunohistochemical evaluation of MMP-2, MMP-9 and CD31/microvascular density in squamous cell carcinomas of the floor of the mouth. AB - The aim of this study was to evaluate the immunoexpression of MMP-2, MMP-9 and CD31/microvascular density in squamous cell carcinomas of the floor of the mouth and to correlate the results with demographic, survival, clinical (TNM staging) and histopathological variables (tumor grade, perineural invasion, embolization and bone invasion). Data from medical records and diagnoses of 41 patients were reviewed. Histological sections were subjected to immunostaining using primary antibodies for human MMP-2, MMP-9 and CD31 and streptavidin-biotin immunoperoxidase system. Histomorphometric analyses quantified positivity for MMPs (20 fields per slide, 100 points grade, *200) and for CD31 (microvessels <50 um in the area of the highest vascularization, 5 fields per slide, 100 points grade, *400). Statistical design was composed by non-parametric Mann-Whitney U test (investigating the association between numerical variables and immunostainings), chi-square frequency test (in contingency tables), Fisher's exact test (when at least one expected frequency was less than 5 in 2*2 tables), Kaplan-Meier method (estimated probabilities of overall survival) and Iogrank test (comparison of survival curves), all with a significance level of 5%. There was a statistically significant correlation between immunostaining for MMP-2 and lymph node metastasis. Factors associated negatively with survival were N stage, histopathological grade, perineural invasion and immunostaining for MMP-9. There was no significant association between immunoexpression of CD31 and the other variables. The intensity of immunostaining for MMP-2 can be indicative of metastasis in lymph nodes and for MMP-9 of a lower probability of survival. PMID- 23657406 TI - Rat subcutaneous tissue response to MTA Fillapex(r) and Portland cement. AB - The aim of this study was to evaluate the response of rat subcutaneous tissue to MTA Fillapex(r) (Angelus), an experimental root canal filling material based on Portland cement and propylene glycol (PCPG), and a zinc oxide, eugenol and iodoform (ZOEI) paste. These materials were placed in polyethylene tubes and implanted into the dorsal connective tissue of Wistar rats for 7 and 15 days. The specimens were stained with hematoxylin and eosin, and evaluated regarding inflammatory reaction parameters by optical microscopy. The intensity of inflammatory response against the sealers was analyzed by two blinded and previously calibrated examiners for all experimental periods (kappa=0.96). The histological evaluation showed that all materials caused a moderate inflammatory reaction at 7 days, which subsided with time. A greater inflammatory reaction was observed at 7 days in the tubes filled with ZOEI paste. Tubes filled with MTA Fillapex presented some giant cells, macrophages and lymphocytes after 7 days. At 15 days, the presence of fibroblasts and collagen fibers was observed indicating normal tissue healing. The tubes filled with PCPG showed similar results to those observed in MTA Fillapex. At 15 days, the inflammatory reaction was almost absent at the tissue, with several collagen fibers indicating normal tissue healing. Data were analyzed by the nonparametric Kruskal-Wallis test (alpha=0.05). Statistically significant difference (p<0.05) was found only between PCPG at 15 days and ZOEI at 7 days groups. No significant differences were observed among the other groups/periods (p>0.05). MTA Fillapex and Portland cement added with propylene glycol had greater tissue compatibility than the PCPG paste. PMID- 23657407 TI - Cytotoxicity of root canal sealers on endothelial cell cultures. AB - This study evaluated, in vitro, the cytotoxicity of six root canal sealers after 12, 24 and 72 h of contact time, using an endothelial ECV-304 cell line. The MTT assay was used for analysis of cell viability. Twelve specimens of each sealer were prepared and randomly assigned to 6 groups according to the commercial brands (n=4/time). A control group was also formed, which was not subjected to the contact with sealers. To assess the effects of sealers on endothelial cells, the specimens were placed in culture plate wells and incubated at 37 degrees C with 5% CO2 and 100% humidity. MTT assays were performed in quadruplicate after 12, 24 and 72 h of contact of the sealer specimens with monolayers. Statistical analysis was performed by two-way ANOVA with Bonferroni post-hoc test at a significance level of 5%. Analysis of absorbance in the experimental groups showed that GuttaFlow presented the lowest cytotoxicity, with a mean absorbance of 0.048, followed by Pulp Canal Sealer (0.038), Sealer 26 (0.038), Endo Densell (0.036) and Pulp Fill (0.035). The control group had a mean absorbance of 0.098. Based on the results, Endofill and GuttaFlow were the most and the least cytotoxic sealers, respectively. PMID- 23657408 TI - Efficacy of four irrigation needles in cleaning the apical third of root canals. AB - This study aimed to evaluate the influence of irrigation needle gauge and design, and the final root canal diameter on the apical cleaning efficacy. Twelve human mandibular incisors were used. At different stages of root canal widening (sizes 20, 30 and 40 K-files), root canals were filled with radiopaque contrast medium. Four different needles were evaluated: 23G with side opening, 22G with apical opening, 30G with side opening and 30G with apical opening. Irrigation was carried out with 2mL distilled water. The same tooth was radiographed with a digital system several times to assess the four types of needle in those three stages of canal widening. Pre-irrigation (canals filled with contrast) and post irrigation (canals with remaining contrast) images were submitted to digital subtraction using the Adobe Photoshop CS4 program. Pre-irrigation (filled with contrast) and subtracted (cleaned by irrigation) areas were outlined by a trained and blinded operator using the Image Tool 3.0 software. Their ratio was calculated to express the percentage of apical cleaning in each stage of canal widening (sizes 20, 30 and 40 K-files) with each of the four needles. Data obtained were subjected to one-way ANOVA and Tukey's tests. The 30G needles with side and apical opening promoted better apical cleaning at all stages of root canal widening (p<0.05). In conclusion, smaller diameter needles were more efficacious in cleaning the apical third of the root canals, regardless of their design. PMID- 23657409 TI - Intracanal medications versus placebo in reducing postoperative endodontic pain- a double-blind randomized clinical trial. AB - This prospective randomized, double-blind factorial study aimed to compare the efficacy of three different intracanal medicaments with the placebo in controlling the postoperative pain after complete root canal preparation. The study was performed on 64 mandibular molars of 64 patients with diagnosis of pulp necrosis and acute apical periodontitis. After chemomechanical procedures using the stepback technique and 1% sodium hypochlorite, the teeth were randomized into four treatment groups (n=16). In group I, canals were filled with calcium hydroxide paste mixed with 2% chlorhexidine gel, group II received 2% chlorhexidine gel, group III was treated with calcium hydroxide paste, and group IV received no dressing (control). Before dismissal, preoperative pain experience was recorded using a visual analog pain scale. Patients were then instructed to quantify the degree of pain experienced 4h after treatment and daily for a further 24, 48, 72 and 96h. Two-way repeated measures ANOVA test and post hoc Tukey's HSD test revealed that at each time interval groups I and II were significantly more effective in reducing the postoperative pain values than groups III and IV (p<0.05). Dunnett's test showed that groups I and II differed significantly from control whereas difference between group III and control was not significant (p>0.05). Patients with pulp necrosis and acute apical periodontitis that had been dressed with chlorhexidine alone and calcium hydroxide plus chlorhexidine gave rise to less pain than that experienced by patients who had a calcium hydroxide dressing alone or no dressing at all. PMID- 23657410 TI - A methodology to measure cervical vertebral bone maturation in a sample from low income children. AB - This study evaluated the applicability of the regression method for determining vertebral age developed by Caldas et al. (2007) by testing this method in children from low-income families of the rural zone. The sample comprised cephalometric and hand-wrist radiographs of 76 boys and 64 girls aged 7.0 to 14.9 years living in a medium-sized city in the desert region of the northeastern region of Brazil, with an HDI of 0.678. C3 and C4 vertebrae were traced and measured on cephalometric radiographs to estimate the bone age. The average age, average hand-wrist age and average error estimated for girls and boys were, respectively, 10.62 and 10.44 years, 11.28 and 10.57 years, and 1.42 and 1.18 years. Based on these results, the formula proposed by Caldas et al. (2007) was not applicable to the studied population, and new multiple regression models were developed to obtain the children's vertebral bone age accurately. PMID- 23657411 TI - Effect of low fluoride acidic dentifrices on dental remineralization. AB - This study evaluated the capacity of fluoride acidic dentifrices (pH 4.5) to promote enamel remineralization using a pH cycling model, comparing them with a standard dentifrice (1,100 ugF/g). Enamel blocks had their surface polished and surface hardness determined (SH). Next, they were submitted to subsurface enamel demineralization and to post-demineralization surface hardness analysis. The blocks were divided into 6 experimental groups (n=10): placebo (without F, pH 4.5, negative control), 275, 412, 550, 1,100 ugF/g and a standard dentifrice (positive control). The blocks were submitted to pH cycling for 6 days and treatment with dentifrice slurries twice a day. After pH cycling, surface and cross-sectional hardness were assessed to obtain the percentage of surface hardness recovery (%SHR) and the integrated loss of subsurface hardness (DeltaKHN). The results showed that %SHR was similar among acidic dentifrices with 412, 550, 1,100 ugF/g and to the positive control (Tukey's test; p>0.05). For DeltaKHN, the acidic dentifrice with 550 ug F/g showed a better performance when compared with the positive control. It can be concluded that acidic dentifrice 550 ugF/g had similar remineralization capacity to that of positive control. PMID- 23657412 TI - Effect of investment type and mold temperature on casting accuracy and titanium ceramic bond. AB - This study evaluated the casting accuracy of crown margins and metal-ceramic shear bond strength (SBS) of pure titanium injected into casting molds made using 2 investment types at 3 mold temperatures. Sixty crown (30-degree beveled finish line) and 60 cylinder (5mm diameter * 8mm high) patterns were divided into 6 groups (n=10), and cast using a phosphate-bonded investment (P) and a magnesium oxide-bonded investment (U), at 400 degrees C (groups P400 and U400), 550 degrees C (groups P550 and U550) and 700 degrees C (groups P700 and U700) mold temperatures. Crown margins were recorded in impression material, the degree of marginal rounding was measured and margin length deficiencies (um) were calculated. Titanium-ceramic specimens were prepared using Triceram ceramic (2mm high) and SBS was tested. Failure modes were assessed by optical microscopy. Data were subjected to two-way ANOVA and Tukey's HSD test (alpha=0.05). For casting accuracy, expressed by marginal deficiency (um), investment U provided more accurate results (64 +/- 11) than P (81 +/- 23) (p<0.001). The increase in temperature resulted in different effects for the tested investments (p<0.001), as it provided better casting accuracy for U700 (55 +/- 7) and worse for P700 (109 +/- 18). Casting accuracy at 700 degrees C (82 +/- 31) was significantly different from 400 degrees C (69 +/- 9) and 550 degrees C (68 +/- 9) (p<0.05). For SBS, there was no significant differences among the groups for factors investment (p=0.062) and temperature (p=0.224), or for their interaction (p=0.149). Investment U provided better casting accuracy than investment P. The SBS was similar for all combinations of investments and temperatures. PMID- 23657414 TI - Job satisfaction among dental assistants in Brazil. AB - The aim of the present study was to investigate the expressed levels of job satisfaction of dental assistants working in Brazil and whether there are relationships among professional formation standards, workplace relations and job satisfaction. An analytical cross-sectional study was carried out with a calculated sample of 443 dental assistants. A questionnaire was developed for this purpose and its validity was verified in a pilot study. The questionnaire provided data for socioeconomic and demographic categorization and identified the variables that could be correlated to professional satisfaction. Job satisfaction was stratified into satisfaction and no satisfaction. All participants signed an informed consent form. Data were analyzed using SPSS software, version 13.0. Pearson's chi-square and Fisher's exact tests were performed. Among the 443 participants, 94.6% were women, 72.7% were aged between 21 and 40 years and 65.0% were single. Over half had 37 or more months of job experience and had completed their course at a public institution. The majority earned between US$141.00 and US$190.00 per month. Job satisfaction was mentioned by 81.5% of the dental personnel. It was found that most subjects were satisfied with their job, and that the level satisfaction is influenced negatively by salary, workplace, workload and dentist's personality. PMID- 23657413 TI - Complete denture biofilm after brushing with specific denture paste, neutral soap and artificial saliva. AB - This study compared the levels of biofilm in maxillary and mandibular complete dentures and evaluated the number of colony-forming units (cfu) of yeasts, after using auxiliary brushing agents and artificial saliva. Twenty-three denture wearers with hyposalivation and xerostomia were instructed to brush the dentures 3 times a day during 3 weeks with the following products: Corega Brite denture dentifrice, neutral liquid soap, Corega Brite combined with Oral Balance (artificial saliva) or tap water. For biofilm quantification, the internal surfaces of the dentures were disclosed, photographed and measured using a software. For microbiological analysis, the biofilm was scrapped off, and the harvested material was diluted, sown in CHROMagarTM Candida and incubated at 37 degrees C for 48 h. Data were analyzed statistically by two-way ANOVA and Tukey's test (alpha=0.05). Mandibular dentures presented a mean biofilm percentage (u=26.90 +/- 21.10) significantly greater than the maxillary ones (u=18.0 +/- 15.0) (p<0.05). Brushing using Corega Brite combined with Oral Balance (u=15.87 +/- 18.47) was more effective (p<0.05) than using the denture dentifrice (u=19.47 +/- 17.24), neutral soap (u=23.90 +/- 18.63) or tap water (control; u=32.50 +/- 20.68). For the microbiological analysis, the chi-square test did not indicate significant difference between the hygiene products for either type of denture. The more frequently isolated species of yeasts were C. albicans, C. tropicalis and C. glabrata. In conclusion, mandibular dentures had more biofilm formation than maxillary ones. Denture brushing with Corega Brite dentifrice combined with the use of Oral Balance was the most effective method for reduction of biofilm levels, but the use of products did not show difference in yeast cfu counts. PMID- 23657415 TI - Use of laser fluorescence in dental caries diagnosis: a fluorescence x biomolecular vibrational spectroscopic comparative study. AB - The aim of this work was to verify the existence of correlation between Raman spectroscopy readings of phosphate apatite (~960 cm-1), fluoridated apatite (~575 cm-1) and organic matrix (~1450 cm-1) levels and Diagnodent(r) readings at different stages of dental caries in extracted human teeth. The mean peak value of fluorescence in the carious area was recorded and teeth were divided in enamel caries, dentin caries and sound dental structure. After fluorescence readings, Raman spectroscopy was carried out on the same sites. The results showed significant difference (ANOVA, p<0.05) between the fluorescence readings for enamel (16.4 +/- 2.3) and dentin (57.6 +/- 23.7) on carious teeth. Raman peaks of enamel and dentin revealed that ~575 and ~960 cm-1 peaks were more intense in enamel caries. There was significant negative correlation (p<0.05) between the ~575 and ~960 cm-1 peaks and dentin caries. It may be concluded that the higher the fluorescence detected by Diagnodent the lower the peaks of phosphate apatite and fluoridated apatite. As the early diagnosis of caries is directly related to the identification of changes in the inorganic tooth components, Raman spectroscopy was more sensitive to variations of these components than Diagnodent. PMID- 23657416 TI - Identification of occlusal prematurity by clinical examination and cone-beam computed tomography. AB - The aim of this study was to evaluate the ability to identify occlusal prematurity by images from paraxial slices of cone-beam computed tomography (CBCT). For such purpose, a pilot study was performed in which 16 asymptomatic young patients were subjected to a clinical examination, including a careful occlusal analysis and then individual deprogrammer devices ("Lucia's JIG") were fabricated. Premature contacts were clinically identified in centric relation (CR) for each patient by jaw manipulation and interocclusal marking with articulating paper (Accufilm). Subsequently, these devices were adjusted in CR and used during the tomographic exams in such a way that CBCT in CR could be obtained. After routine processing, the images were analyzed in order to identify occlusal prematurity on the displayed images by 30 professionals divided according to areas of activity (occlusion specialist, general practitioner and radiologist; n=10 per area) and time of professional experience (less than 5, between 5 and 10, and over 10 years). By comparing the premature contacts identified in the clinical analysis and CBCT images, an agreement index between these two variables was calculated. Data were analyzed statistically by ANOVA and Scott-Knott test (alpha=0.05). The results showed that the identification of occlusal prematurity by paraxial CBCT slices was proven to be a method of average reliability. PMID- 23657417 TI - Use of glass ionomer cement containing antibiotics to seal off infected dentin: a randomized clinical trial. AB - Dental materials with antibacterial properties can prevent the harmful effects caused by oral cariogenic bacteria. This double-blind controlled clinical trial evaluated the performance of a glass ionomer cement (GIC) added with antibiotics for sealing infected dentin in atraumatic restorations of primary molars. The study enrolled 45 children (45 teeth) between 5 and 8 years of age, of both genders, divided into two groups: GC (n=22), where cavities were lined with a conventional GIC (Vidrion F) and GA (n=23), with cavities lined with Vidrion F added with 1% each of metronidazole, ciprofloxacin and cefaclor antibiotic. Both groups were restored with Ketac Molar Easymix. Molars with carious lesions on the inner half of dentin without clinical or radiographic pulp damage were selected. Patients were evaluated clinically (pain, fistulas or mobility) and radiographically (area of caries, periapical region and furcation) after 1, 3, 6 and 12 months. For statistical analysis, chi-squared or Fisher's exact tests were used with a 5% significance level. GA (82.6-95.7%) had better results than GC (12.5-36.4%) in all evaluations (p<0.05) and the difference in the success rate was 46.2-72.5% higher for GA. The use of the antibiotic-containing GIC liner on infected dentin proved satisfactory when applied in deciduous teeth. PMID- 23657418 TI - Clinical and imagiological findings of central giant cell lesion and cherubism. AB - Cone beam computed tomography (CBCT) is the best examination for bone lesions of the maxilla, allowing the dentist to evaluate precisely the behavior and components of the lesion and their relationship to the surrounding structures. Central giant cell lesion and cherubism are histologically very similar lesions. Therefore clinical and radiological examinations are fundamentally important for the diagnosis. The aim of this paper is to report two cases diagnosed as central giant cell lesions and cherubism using CBCT. This imaging modality was very important for the diagnosis of the lesions presented in the current study. It also allowed observing precisely the limits of the lesions, the components, the behavior and the exact relationship to adjacent structures. PMID- 23657419 TI - Anterior and medial angulations of the styloid process in subjects with TMD: clinical and radiographic findings. AB - This study investigated the existence of association between the angulation of the styloid process on the anterior and medial directions with the intensity of temporomandibular dysfunction (TMD) symptoms. Fifty patients (8 men and 42 women) aged 25 to 70 years, with relevant TMD symptoms were evaluated. Clinical examinations were performed to determine the severity of TMD symptoms (orofacial pain, headache, tinnitus and dizziness) based on the RDC/TMD criteria and the visual analogue scale (VAS), and digital radiographic images of the styloid process were obtained: lateral cephalometric skull radiograph (analysis of anterior angulation) and posteroanterior skull radiograph (reverse Towne's projection) (analysis of medial angulation). The anterior angulation average of the styloid process was 20.89 degrees while the medial angulation average was 19.1 degrees in the right side and 19.04 degrees in the left side. There was no statistically significant difference among the patient groups (severe, moderate and mild symptoms) associating the TMD symptoms and the anterior or medial angulation of the styloid process (p>0.05). There was no correlation between the intensity of the TMD symptoms and the measurements of anterior and medial angulation of the styloid process using either lateral cephalometric or posteroanterior radiographs (reverse Towne's projection). PMID- 23657420 TI - Tetraplatinum cluster complexes bearing hydrophilic anchors as precursors for gamma-Al2O3-supported platinum nanoparticles. AB - Tetraplatinum cluster complexes bearing hydrophilic anchors, [Pt4(MU-OCOCH3)4(MU OCOC6H4OH-4)4] (2a), [Pt4(MU-OCOCH3)4(MU-OCOC6H4B(OH)2-4)4] (2b), and [Pt4(MU OCOCH3)4(MU-OCOC6H4NH2-4)4] (2c), were successfully prepared by a selective substitution reaction of four in-plane acetates of [Pt4(MU-OCOCH3)8] (1) with the corresponding p-substituted benzoic acids. Solid-state structure determination of 2a revealed the 3D network structure through intermolecular hydrogen bonding between the hydroxy group of the p-hydroxybenzoate ligand and the oxygen atom of the carboxylate ligand of 2a. UV-vis analysis of 2a-c in CH3CN or CH3CN-H2O in the presence of gamma-Al2O3 clearly indicated the adsorption efficiency of these platinum clusters on gamma-Al2O3: 2a bearing a hydroxyl group and 2b bearing a B(OH)2 group were effectively deposited onto gamma-Al2O3 from CH3CN solution, whereas less than 40% of 1 and 2c were chemically adsorbed onto gamma-Al2O3. Highly dispersed and very small platinum nanoparticles (less than 1 nm) on gamma Al2O3 were obtained by thermal treatment of Pt4-deposited gamma-Al2O3 at 500 degrees C. PMID- 23657421 TI - Arctic-nesting birds find physiological relief in the face of trophic constraints. AB - A climate-induced phenological mismatch between the timing of reproduction and the timing of food resource peaks is one of the key hypothesized effects of climate change on wildlife. Though supported as a mechanism of population decline in birds, few studies have investigated whether the same temperature increases that drive this mismatch have the potential to decrease energetic costs of growth and compensate for the potential negative effects of reduced food availability. We generated independent indices of climate and resource availability and quantified their effects on growth of Dunlin (Calidris alpina) chicks, in the sub arctic tundra of Churchill, Manitoba during the summers of 2010-2011 and found that when resource availability was below average, above average growth could be maintained in the presence of increasing temperatures. These results provide evidence that chicks may find physiological relief from the trophic constraints hypothesized by climate change studies. PMID- 23657423 TI - Differential mechanisms underlie the regulation of serotonergic transmission in the dorsal and median raphe nuclei by mirtazapine: a dual probe microdialysis study. AB - RATIONALE: Blockade of alpha2 adrenoceptors and histamine H1 receptors plays important roles in the antidepressant and hypnotic effects of mirtazapine. OBJECTIVES: However, it remains unclear how mirtazapine's actions at these receptors interact to affect serotonergic transmission in the dorsal (DRN) and median (MRN) raphe nuclei. METHOD: Using dual-probe microdialysis, we determined the roles of alpha2 and H1 receptors in the effects of mirtazapine on serotonergic transmission in the DRN and MRN and their respective projection regions, the frontal (FC) and entorhinal (EC) cortices. RESULTS: Mirtazapine (<30 MUM) failed to alter extracellular serotonin levels when perfused alone into the raphe nuclei, but when co-perfused with a 5-HT1A receptor antagonist, mirtazapine increased serotonin levels in the DRN, MRN, FC, and EC. Serotonin levels in the DRN and FC were decreased by blockade and increased by activation of H1 receptors in the DRN. Serotonin levels in the MRN and EC were not affected by H1 agonists/antagonists perfused in the MRN. The increase in serotonin levels in the DRN and FC induced by DRN H1 receptor activation was attenuated by co-perfusion with mirtazapine. Furthermore, the increase in serotonin levels (DRN/FC) induced by DRN alpha2 adrenoceptor blockade was attenuated by concurrent DRN H1 blockade, whereas the increase in serotonin levels (MRN/EC) induced by MRN alpha2 adrenoceptor inhibition was unaffected by concurrent MRN H1 receptor blockade. CONCLUSION: These results suggest that enhanced serotonergic transmission resulting from alpha2 adrenoceptor blockade is offset by subsequent activation of 5-HT1A receptors and, in the DRN but not MRN, H1 receptor inhibition. These pharmacological actions of mirtazapine may explain its antidepressant and hypnotic actions. PMID- 23657424 TI - Benzodiazepine therapy in psychiatric outpatients is associated with deliberate self-poisoning events at emergency departments-a population-based nested case control study. AB - RATIONALE: Deliberate self-poisoning (DSP), the most common form of deliberate self-harm, is closely associated with suicide. Identifying risk factors of DSP is necessary for implementing prevention strategies. OBJECTIVES: This study aimed to evaluate the relationship between benzodiazepine (BZD) treatment in psychiatric outpatients and DSP cases at emergency departments (EDs). METHODS: We performed a retrospective nested case-control study of psychiatric patients receiving BZD therapy to evaluate the relationship between BZD use and the diagnosis of DSP at EDs using data from the nationwide Taiwan National Health Insurance Research Database. RESULTS: Regression analysis yielded an odds ratio (OR) and 95 % confidence interval (95 % CI) indicating that the use of BZDs in psychiatric outpatients was significantly associated with DSP cases at EDs (OR = 4.46, 95 % CI = 3.59-5.53). Having a history of DSP, sleep disorders, anxiety disorders, schizophrenia, depression, or bipolar disorder was associated with a DSP diagnosis at EDs (OR = 13.27, 95 % CI = 8.28-21.29; OR = 5.04, 95 % CI = 4.25 5.98; OR = 3.95, 95 % CI = 3.32-4.70; OR = 7.80, 95 % CI = 5.28-11.52; OR = 15.20, 95 % CI = 12.22-18.91; and OR = 18.48, 95 % CI = 10.13-33.7, respectively). After adjusting for potential confounders, BZD use remained significantly associated with a subsequent DSP diagnosis (adjusted OR = 2.47, 95 % CI = 1.93-3.17). Patients taking higher average cumulative BZD doses were at greater risk of DSP. CONCLUSION: Vigilant evaluation of the psychiatric status of patients prescribed with BZD therapy is critical for the prevention of DSP events at EDs. PMID- 23657425 TI - Posttonsillectomy hemorrhage in children with von Willebrand disease or hemophilia. AB - IMPORTANCE: It is uncertain whether children with bleeding disorders are at higher risk of posttonsillectomy hemorrhage compared with the general pediatric population. OBJECTIVES: To estimate the national rate of posttonsillectomy hemorrhage in children previously diagnosed with von Willebrand disease (VWD) or hemophilia, and to analyze potential risk factors for postoperative bleeding in these children. DESIGN: A cross-sectional analysis of the Healthcare Cost and Utilization Project Kids' Inpatient Database (KID) from the Agency for Healthcare Research and Quality for 2000, 2003, 2006, and 2009. SETTING: Academic and community-based nonrehabilitation hospitals from 44 states participating in the KID project. PARTICIPANTS: An estimated 508 children with either VWD or hemophilia. INTERVENTIONS: Tonsillectomy with and without adenoidectomy, and subsequent hospitalization. MAIN OUTCOME MEASURE: Treatment for posttonsillectomy hemorrhage. METHODS: We extracted all cases of tonsillectomy, adenotonsillectomy, and posttonsillectomy hemorrhage in patients with VWD or hemophilia using International Classification of Diseases, Ninth Revision diagnostic and procedure codes and applied national weights to estimate rates of posttonsillectomy hemorrhage. Using data regarding patient demographic characteristics, surgical indication, blood transfusion, hospital length of stay, and mortality, we conducted bivariate analyses to identify associations between possible risk factors and posttonsillectomy hemorrhage. RESULTS: Mean age was 7 years, and most patients were male, white, urbanites who had private insurance and underwent tonsillectomy for airway obstruction. The hemorrhage rate within 1 day of tonsillectomy (immediate) was 1.6% while the hemorrhage rate at least 2 days after tonsillectomy (delayed) was estimated at 15%. Delayed hemorrhage was associated with older age (P < .001) and was as high as 35% in children at least 16 years old. The rate of blood transfusion was 2.4%. There were no fatalities. CONCLUSIONS AND RELEVANCE: The frequency of immediate posttonsillectomy hemorrhage in children with VWD or hemophilia is similar to rates in the general healthy population. However, among children with VWD or hemophilia, the rate of delayed hemorrhage is substantially higher, especially in older children. PMID- 23657426 TI - Important and critical scientific aspects in pharmacogenomics analysis: lessons from controversial results of tamoxifen and CYP2D6 studies. AB - Tamoxifen contributes to decreased recurrence and mortality of patients with hormone receptor-positive breast cancer. As this drug is metabolized by phase I and phase II enzymes, the interindividual variations of their enzymatic activity are thought to be associated with individual responses to tamoxifen. Among these enzymes, CYP2D6 is considered to be a rate-limiting enzyme in the generation of endoxifen, a principal active metabolite of tamoxifen, and the genetic polymorphisms of CYP2D6 have been extensively investigated in association with the plasma endoxifen concentrations and clinical outcome of tamoxifen therapy. In addition to CYP2D6, other genetic factors including polymorphisms in various drug metabolizing enzymes and drug transporters have been implicated to their relations to clinical outcome of tamoxifen therapy, but their effects would be small. Although the results of association studies are controversial, accumulation of the evidence has revealed us the important and critical issues in the tamoxifen pharmacogenomics study, namely the quality of genotyping, the coverage of genetic variations, the criteria for sample collection and the source of DNAs, which are considered to be common problematic issues in pharmacogenomics studies. This review points out common critical issues in pharmacogenomics studies through the lessons we have learned from tamoxifen pharmacogenomics, as well as summarizes the results of pharmacogenomics studies for tamoxifen treatment. PMID- 23657427 TI - Characteristics of pharmacogenomics/biomarker-guided clinical trials for regulatory approval of anti-cancer drugs in Japan. AB - Pharmacogenomics (PGx) or biomarker (BM) has the potential to facilitate the development of safer and more effective drugs in terms of their benefit/risk profiles by stratifying population into categories such as responders/non responders and high-/low-risks to drug-induced serious adverse reactions. In the past decade, practical use of PGx or BM has advanced the field of anti-cancer drug development. To identify the characteristics of the PGx/BM-guided clinical trials for regulatory approval of anti-cancer drugs in Japan, we collected information on design features of 'key trials' in the review reports of anti cancer drugs that were approved after the implementation of the 'Revised Guideline for the Clinical Evaluation of Anti-cancer drugs' in April 2006. On the basis of the information available on the regulatory review data for the newly approved anti-cancer drugs in Japan, this article aims to explain the limitations and points to consider in the study design of PGx/BM-guided clinical trials. PMID- 23657428 TI - Pharmacogenetics of warfarin: challenges and opportunities. AB - Since the introduction in the 1950s, warfarin has become the commonly used oral anticoagulant for the prevention of thromboembolism in patients with deep vein thrombosis, atrial fibrillation or prosthetic heart valve replacement. Warfarin is highly efficacious; however, achieving the desired anticoagulation is difficult because of its narrow therapeutic window and highly variable dose response among individuals. Bleeding is often associated with overdose of warfarin. There is overwhelming evidence that an individual's warfarin maintenance is associated with clinical factors and genetic variations, most notably polymorphisms in cytochrome P450 2C9 and vitamin K epoxide reductase subunit 1. Numerous dose-prediction algorithms incorporating both genetic and clinical factors have been developed and tested clinically. However, results from major clinical trials are not available yet. This review aims to provide an overview of the field of warfarin which includes information about the drug, genetics of warfarin dose requirements, dosing algorithms developed and the challenges for the clinical implementation of warfarin pharmacogenetics. PMID- 23657429 TI - Pneumococcal vaccine and opsonic pneumococcal antibody. AB - Streptococcus pneumoniae is a major human pathogen responsible for the majority of bacterial pneumonia cases as well as invasive pneumococcal diseases with high mortality and morbidity. Use of conjugate vaccines targeting the pneumococcal capsule has dramatically reduced the incidence of invasive diseases, and there are active efforts to further improve the conjugate vaccines. However, in children new pneumococcal vaccines can no longer be tested with placebo-based clinical trials because effective vaccines are currently available. Thus, vaccine studies must depend on surrogate markers of vaccine efficacy. Although traditional antibody levels (e.g., ELISA) are useful as a surrogate marker of protection, they have limitations, and a bioassay measuring the capacity of antibodies to opsonize pneumococci has been developed. This opsonophagocytosis assay (OPA) replicates the in vivo mechanism of antibody protection and should therefore better reflect protection by vaccine-induced antibodies. Technical improvements of OPA have made this bioassay rapid, multiplexed, and practical for analyzing small samples including those from children. Strong correlations between ELISA and OPA have been observed in many studies of young children. However, poor correlations have been found in some important clinical situations (such as determination of protection by cross-reactive antibodies) and populations (such as elderly adults and immunodeficient patients). In these settings, OPA has become a useful supplementary measure of pneumococcal vaccine immunogenicity. Current efforts to standardize OPA will further expand its uses. PMID- 23657430 TI - Magnetic resonance imaging appearance of primary spinal extradural Ewing's sarcoma: case report and literature review. AB - PURPOSE: Primary spinal extradural Ewing's sarcoma (PSEES) or primitive neuroectodermal tumor (PNET) is uncommon. The present study summarizes the magnetic resonance (MR) imaging appearance of PSEES. METHODS: Literature search from 1994 to 2012 with our representative case presentation. RESULTS: Twenty-one patients, 12 males and 9 females, aged 3 weeks to 44 years, were identified. The thoracic spine was most frequently affected, followed by the cervical, cervicothoracic, and thoracolumbar spine. Superior-inferior extension of lesions was three vertebral levels in 7, two in 7, five in 4, four in 1, one in 1 and unknown in 1. PSEESs appeared isointense in 9 cases, hypointense in 2, hyperintense in 1, and no description in 9 on T1-weighted imaging, while hyperintense in 6, hypointense in 3, heterogeneous in 1, and no description in 11 on T2-weighted imaging. Varying enhancement was noted in 13 cases (62 %), with no description of contrast study in the other 8 cases. Dumbbell-shaped configuration of PSEES was found in 5 cases, foraminal widening in 4, and erosions or scalloping of the adjacent vertebral bodies in 4. CONCLUSION: The MR imaging appearance of PSEESs is indistinguishable from other tumors. PSEES should be assumed as the differential diagnosis of spinal extradural tumors in pediatric, adolescent, and young adult patients, and prompt surgical exploration should be performed. PMID- 23657431 TI - CuO/SiO2 as a simple, effective and recoverable catalyst for alkylation of indole derivatives with diazo compounds. AB - The purely inorganic copper oxide on silica catalyzes the reaction of methyl phenyldiazoacetate with N-methyl indole under mild reaction conditions, giving the alkylation (formally a C-H insertion) in position 3, and the catalyst can be recovered and reused at least in 5 consecutive runs with only minor loss in activity. The scope of the reaction includes various diazo compounds and indole or pyrrole derivatives leading to alkylation or cyclopropanation depending on the heterocycle structure. An alternative mechanism, without reduction of Cu(II) to Cu(I), is proposed on the basis of the obtained results. PMID- 23657433 TI - The pathological spectrum of left-ventricular hypoplasia. AB - Left-ventricular (LV) hypoplasia encompasses a range of LV sizes, varying from a mildly underdeveloped, but functionally adequate, chamber to the miniscule, barely perceptible LV cavity seen in hypoplastic left-heart syndrome. Associated malformations include obstructive lesions of LV inflow, outflow, and the aortic arch, often in combination. Repair of complex combinations and/or severe LV hypoplasia usually results in a single-ventricle anatomy with the right ventricle serving as the systemic ventricle. New therapeutic interventions, including fetal procedures, are expanding the spectrum of lesions and LV sizes that may be amenable to a biventricular repair. These surgical considerations place renewed emphasis on understanding the anatomical features associated with LV hypoplasia. This review details pathological features of the full spectrum of LV hypoplasia, particularly those with borderline severe hypoplasia. Primary defining lesions are described as well as additional lesions that may affect clinical symptoms, surgical repair, and long-term outcome. PMID- 23657432 TI - Door-to-implantation time of extracorporeal life support systems predicts mortality in patients with out-of-hospital cardiac arrest. AB - OBJECTIVE: This study aimed to identify predictors of mortality in patients with out-of-hospital cardiac arrest (OHCA) undergoing in-hospital extracorporeal life support system (ECLS) treatment. METHODS: We retrospectively studied the characteristics and clinical outcomes of 28 patients (January 2010 and December 2011) with OHCA and veno-arterial ECLS implemented during ongoing cardiopulmonary resuscitation (CPR) upon admission to the cath lab. Baseline left ventricular ejection fraction (LVEF) was determined after ECLS implantation and then every 24 h during and after successful weaning from ECLS. RESULTS: Overall 30-day survival rate was 39.3 % (11 of 28 patients). Baseline characteristics, initial laboratory measurements, and LVEF on admission were not significantly different between survivors and non-survivors. There was no difference regarding median CPR duration [survivors 44.0 min (IQR 31.0-45.0) vs. non-survivors 53.0 min (IQR 40.0 61.3); P = 0.23]. Door-to-ECLS implantation time was significantly longer in non survivors [42.5 min (IQR 28.0-56.5) vs. 25.0 min (IQR 21.0-30.0); P < 0.01]. ECLS treatment duration was not significantly different between the two groups [survivors: 4.0 days (IQR 1.5-7.5) vs. non-survivors 6.5 days (IQR 1.0-8.0); P = 0.69]. LVEF significantly improved in survivors during ECLS treatment (mean +/- SD survivor 47.5 +/- 14.7 % vs. non-survivor 23.3 +/- 14.9 %; P < 0.01). The door to-ECLS implantation time was the only significant and independent predictor of 30-day mortality in multivariate Cox regression analysis (P = 0.04). Kaplan-Meier survival analysis showed a benefit favouring patients with a door-to-ECLS implantation time <30 min (log rank 6.29; P = 0.01). CONCLUSION: A door-to-ECLS implantation time <30 min significantly improves 30-day outcomes in patients with OHCA. PMID- 23657434 TI - Surgical considerations in the management of hypoplastic left heart syndrome. AB - Hypoplastic left heart syndrome is a congenital heart defect characterized by hypoplasia of left heart structures. Over the past 3 decades, there have been advances in techniques and management in the care of these patients. We discuss shunt selection, operative strategies, transplantation, and outline various facets of management at the University of Florida. This is a review of the literature highlighting some of the technical aspects of the preoperative, operative, and postoperative care that are important in today's management of hypoplastic left heart syndrome. PMID- 23657435 TI - Enantioselective total synthesis of (+)-brazilin, (-)-brazilein and (+)-brazilide A. AB - An enantioselective strategy for the synthesis of (+)-brazilin, (-)-brazilein and (+)-brazilide A has been developed. A Lewis acid mediated lactonization established the novel fused bis-lactone core of brazilide A and finalized the first total synthesis of (+)-brazilide A. PMID- 23657436 TI - Defensive allomones function as aggregation pheromones in diapausing Ladybird Beetles, Hippodamia convergens. AB - Identification of the stimuli responsible for the formation of an aggregation can be used to distinguish between social and non-social aggregations and help in the process of identifying the adaptive benefits of the gregarious behavior. The convergent ladybird beetle, Hippodamia convergens, forms dense aggregations during winter diapause. The mechanisms of conspecific attraction and hibernacula site selection of H. convergens are not well understood. In laboratory and field bioassays, we evaluated the role of three defensive compounds in the formation of H. convergens aggregations. Diapausing H. convergens aggregated within the section of an arena exposed to alkylmethoxypyrazines. 2-Isobutyl-3 methoxypyrazine (IBMP) caused the strongest aggregative effect. Beetles also aggregated to some doses of 2-sec-butyl-3-methoxypyrazine, but appeared to be repelled at higher doses. A third constituent, 2-isopropyl-3-methoxypyrazine, generally had little effect on the distribution of beetles, although the highest dose tested was repellent. Beetles also aggregated to a blend of these alkylmethoxypyrazines at their natural ratio. During fall migration to overwintering sites, more beetles aggregated in artificial hibernacula baited with IBMP, confirming its function as an aggregation pheromone. These three pyrazines also function as warning odors that, in conjunction with other aposematic displays (contrasting red and black coloration, gregarious behavior, reflex bleeding), contribute to the multi-modal, anti-predatory defense of coccinellid beetles and some other arthropods. Confirmation of the role of some alkylmethoxypyrazines in coccinellid aggregations suggests that these defensive allomones have been co-opted for intraspecific communication. PMID- 23657437 TI - Mesoporous silica nanoparticles as antigen carriers and adjuvants for vaccine delivery. AB - Vaccines have been at the forefront of improving human health for over two centuries. The challenges faced in developing effective vaccines flow from complexities associated with the immune system and requirement of an efficient and safe adjuvant to induce a strong adaptive immune response. Development of an efficient vaccine formulation requires careful selection of a potent antigen, efficient adjuvant and route of delivery. Adjuvants are immunological agents that activate the antigen presenting cells (APCs) and elicit a strong immune response. In the past decade, the use of mesoporous silica nanoparticles (MSNs) has gained significant attention as potential delivery vehicles for various biomolecules. In this review, we aim to highlight the potential of MSNs as vaccine delivery vehicles and their ability to act as adjuvants. We have provided an overview on the latest progress on synthesis, adsorption and release kinetics and biocompatibility of MSNs as next generation antigen carriers and adjuvants. A comprehensive summary on the ability of MSNs to deliver antigens and elicit both humoral and cellular immune responses is provided. Finally, we give insight on fundamental challenges and some future prospects of these nanoparticles as adjuvants. PMID- 23657438 TI - Chronic interferon-alpha decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates. AB - Neuroimaging studies in humans have demonstrated that inflammatory cytokines target basal ganglia function and presynaptic dopamine (DA), leading to symptoms of depression. Cytokine-treated nonhuman primates also exhibit evidence of altered DA metabolism in association with depressive-like behaviors. To further examine cytokine effects on striatal DA function, eight rhesus monkeys (four male, four female) were administered interferon (IFN)-alpha (20 MIU/m(2) s.c.) or saline for 4 weeks. In vivo microdialysis was used to investigate IFN-alpha effects on DA release in the striatum. In addition, positron emission tomography (PET) with [(11)C]raclopride was used to examine IFN-alpha-induced changes in DA2 receptor (D2R) binding potential before and after intravenous amphetamine administration. DA transporter binding was measured by PET using [(18)F]2beta carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane. Anhedonia-like behavior (sucrose consumption) was assessed during saline and IFN-alpha administration. In vivo microdialysis demonstrated decreased release of DA after 4 weeks of IFN-alpha administration compared with saline. PET neuroimaging also revealed decreased DA release after 4 weeks of IFN-alpha as evidenced by reduced displacement of [(11)C]raclopride following amphetamine administration. In addition, 4 weeks of IFN-alpha was associated with decreased D2R binding but no change in the DA transporter. Sucrose consumption was reduced during IFN-alpha administration and was correlated with decreased DA release at 4 weeks as measured by in vivo microdialysis. Taken together, these findings indicate that chronic peripheral IFN-alpha exposure reduces striatal DA release in association with anhedonia-like behavior in nonhuman primates. Future studies examining the mechanisms of cytokine effects on DA release and potential therapeutic strategies to reverse these changes are warranted. PMID- 23657439 TI - A novel translational assay of response inhibition and impulsivity: effects of prefrontal cortex lesions, drugs used in ADHD, and serotonin 2C receptor antagonism. AB - Animal models are making an increasing contribution to our understanding of the psychology and brain mechanisms underlying behavioral inhibition and impulsivity. The aim here was to develop, for the first time, a mouse analog of the stop signal reaction time task with high translational validity in order to be able to exploit this species in genetic and molecular investigations of impulsive behaviors. Cohorts of mice were trained to nose-poke to presentations of visual stimuli. Control of responding was manipulated by altering the onset of an auditory 'stop-signal' during the go response. The anticipated systematic changes in action cancellation were observed as stopping was made more difficult by placing the stop-signal closer to the execution of the action. Excitotoxic lesions of medial prefrontal cortex resulted in impaired stopping, while the clinically effective drugs methylphenidate and atomoxetine enhanced stopping abilities. The specific 5-HT2C receptor antagonist SB242084 also led to enhanced response control in this task. We conclude that stop-signal reaction time task performance can be successfully modeled in mice and is sensitive to prefrontal cortex dysfunction and drug treatments in a qualitatively similar manner to humans and previous rat models. Additionally, using this model we show novel and highly discrete effects of 5-HT2C receptor antagonism that suggest manipulation of 5-HT2C receptor function may be of use in correcting maladaptive impulsive behaviors and provide further evidence for dissociable contributions of serotonergic transmission to response control. PMID- 23657441 TI - Quality of life in youth with severe to profound sensorineural hearing loss. AB - IMPORTANCE: Adolescence is a life stage with rapid and major developmental changes, yet little is known about how these changes influence the quality of life of young people who are deaf or hard of hearing (DHH). OBJECTIVE: To determine differences in the 3 domains of a hearing-specific quality-of-life instrument between youth who had severe to profound sensorineural hearing loss based on whether they used no technology, hearing aids, or cochlear implants. DESIGN AND SETTING: A multi-institutional prospective cohort study. PARTICIPANTS: A convenience sample of 11- to 18-year-old youths with severe to profound sensorineural hearing loss recruited between January 1 and December 31, 2008. MAIN OUTCOME MEASURES: Youth Quality of Life-Research Instrument and Youth Quality of Life Instrument-Deaf and Hard of Hearing (YQoL-DHH) scores. The YQoL DHH was composed of 3 domains: participation, self-acceptance/advocacy, and stigma-related quality of life. RESULTS: A total of 157 individuals participated. Overall mean (SD) age was 14.1 (2.3) years, and the female-male ratio was 82:75. Forty-nine individuals (31.2%) were not using any technology, 45 (28.7%) were using hearing aids, and 63 (40.1%) were using cochlear implants. Mean age of unilateral or first cochlear implant was 62.9 months. Thirty-eight individuals (24.2%) attended schools with DHH programs, 55 (35.0%) attended schools without DHH programs, and 58 (36.9%) attended schools for the deaf. Statistically significant differences were noted in YQoL-DHH participation and perceived stigma scores between the groups when stratified by technology used and school setting. CONCLUSIONS: These data suggest that the domains of quality of life as measured by our instrument differ significantly among youth based on technology used and school setting. Youth using no technology or cochlear implants tended to score higher than those using hearing aids in mainstream schools with or without DHH programs and in schools for the deaf. The YQoL-DHH instrument is able to detect differences in quality of life within a group of youth with severe to profound hearing loss. PMID- 23657440 TI - CRF mediates the anxiogenic and anti-rewarding, but not the anorectic effects of PACAP. AB - Anxiety disorders represent the most common mental disturbances in the world, and they are characterized by an abnormal response to stress. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1 have been proposed to have a key role in mediating the responses to stress as well as the regulation of food intake and body weight. Corticotropin-releasing factor (CRF), the major stress peptide in the brain, has been hypothesized to be involved in PACAP effects, but the reports are conflicting so far. The present study was aimed at further characterizing the behavioral effects of PACAP in rats and at determining the role of central CRF receptors. We found that intracerebroventricular PACAP treatment induced anxiety-like behavior in the elevated plus maze test and elevated intracranial self-stimulation thresholds; both of these effects were fully blocked by concurrent treatment with the CRF receptor antagonist D-Phe CRF(12-41). Interestingly, the CRF antagonist had no effect on PACAP-induced increased plasma corticosterone, reduction of food intake, and body weight loss. Finally, we found that PACAP increased CRF levels in the paraventricular nucleus of the hypothalamus and, importantly, in the central nucleus of the amygdala, as measured by solid phase radioimmunoassay and quantitative real-time PCR. Our results strengthen the notion that PACAP is a strong mediator of the behavioral response to stress and prove for the first time that this neuropeptide has anti rewarding (ie, pro-depressant) effects. In addition, we identified the mechanism by which PACAP exerts its anxiogenic and pro-depressant effects, via the recruitment of the central CRF system and independently from HPA axis activation. PMID- 23657442 TI - Solvent-induced reversible single-crystal-to-single-crystal transformations observed in lanthanide complexes. AB - In this work, a rare 0D->0D single-crystal-to-single-crystal transformation (SCSC) is observed in lanthanide compounds, which is triggered by the removal or retake of solvent molecules. This advantage prompted us to explore the magnetic property of them, and some interesting magnetic properties are obtained. PMID- 23657443 TI - Analysis of polar organic contaminants in surface water of the northern Adriatic Sea by solid-phase extraction followed by ultrahigh-pressure liquid chromatography-QTRAP(r) MS using a hybrid triple-quadrupole linear ion trap instrument. AB - Water-soluble polar organic contaminants are discharged by rivers, cities, and ships into the oceans. Little is known on the fate, pollution effects, and thresholds of toxic chemical mixtures in the marine environment. A new trace analytical method was developed for the multi-compound analysis of polar organic chemical contaminants in marine waters. The method is based on automated solid phase extraction (SPE) of one-liter water samples followed by ultrahigh-pressure liquid chromatography triple-quadrupole linear ion-trap mass spectrometry (UHPLC QTRAP((r)) MS). Marine water samples from the open Adriatic Sea taken 16 km offshore from Venice (Italy) were analyzed. Method limits of quantification (LOQs) in the low picogram per liter (pg/l) concentration range were achieved. Among the 67 target chemicals analyzed, 45 substances could be detected above the LOQ. The chemicals detected at the highest concentrations were caffeine (up to 367 ng/l), nitrophenol (36 ng/l), 2,4-dinitrophenol (34 ng/l), 5-methyl-1H benzotriazole (18.5 ng/l), sucralose (11 ng/l), 1H-benzotriazole (9.2 ng/l), terbuthylazine (9 ng/l), alachlor (7.7 ng/l), atrazine-desisopropyl (6.6 ng/l), diethyltoluamide (DEET) (5.0 ng/l), terbuthylazine-desethyl (4.3 ng/l), metolachlor (2.8 ng/l), perfluorooctanoic acid (PFOA) (2.5 ng/l), perfluoropentanoic acid (PFPeA) (2.3 ng/l), linuron (2.3 ng/l), perfluorohexanoic acid (PFHxA) (2.2 ng/l), diuron (2.0 ng/l), perfluorohexane sulfonate (PFHxS) (1.6 ng/l), simazine (1.6 ng/l), atrazine (1.5 ng/l), and perfluorooctane sulfonate (PFOS) (1.3 ng/l). Higher concentrations were detected during summer due to increased levels of tourist activity during this period. PMID- 23657444 TI - Analysis of human blood plasma and hen egg white by chiroptical spectroscopic methods (ECD, VCD, ROA). AB - Chiroptical methods are widely used in structural and conformational analyses of biopolymers. The application of these methods to investigations of biofluids would provide new avenues for the molecular diagnosis of protein-misfolding diseases. In this work, samples of human blood plasma and hen egg white were analyzed using a combination of conventional and chiroptical methods: ultraviolet absorption/electronic circular dichroism (UV/ECD), Fourier transform infrared absorption/vibrational circular dichroism (FTIR/VCD), and Raman scattering/Raman optical activity (Raman/ROA). For comparison, the main components of these substances--human serum albumin (HSA) and ovalbumin (Ova)--were also analyzed by these methods. The ultraviolet region of the ECD spectrum was analyzed using the CDNN CD software package to evaluate the secondary structures of the proteins. The UV/ECD, FTIR/VCD, and Raman/ROA spectra of the substances were quite similar to those of the corresponding major proteins, while some differences were also detected and explained. The conclusions drawn from the FTIR/VCD and Raman/ROA data were in good agreement with the secondary structures calculated from ECD. The results obtained in this work demonstrate that the chiroptical methods used here can be applied to analyze not only pure protein solutions but also more complex systems, such as biological fluids. PMID- 23657445 TI - Detection of catecholamines in single specimens of groundwater amphipods. AB - Catecholamines play essential roles in several physiological processes in vertebrates as well as in invertebrates. While several studies have shown the presence of these substances in surface water invertebrates, their occurrence in groundwater fauna is unproven. In the present study, the presence of different catecholamines (i.e., noradrenaline, adrenaline, and dopamine) in individual specimens of groundwater amphipods of the genus Niphargus (mostly Niphargus inopinatus) was investigated via two independent analytical methods: HPLC/EcD and UPLC/TOF-MS. Mean values for catecholamine levels were 533 pg mg(-1) fresh weight for noradrenaline, 314 pg mg(-1) for adrenaline, and 16.4 ng mg(-1) for dopamine. The optimized protocol allowed the detection of CAs in single organisms of less than 1 mg fresh weight. Catecholamine concentration patterns in groundwater invertebrates are briefly discussed here with respect to their evolutionary adaptation to an environmentally stable, energy-poor habitat. PMID- 23657446 TI - Modified capillary electrophoresis based measurement of the binding between DNA aptamers and an unknown concentration target. AB - The recognition of targets such as biomacromolecules, viruses and cells by their aptamers is crucial in aptamer-based biosensor platforms and research into protein function. However, it is difficult to evaluate the binding constant of aptamers and their targets that are hard to purify and quantify, especially when the targets are undefined. Therefore, we aimed to develop a modified capillary electrophoresis based method to determine the dissociation constant of aptamers whose targets are hard to quantify. A protein target, human thrombin, and one of its aptamers were used to validate our modified method. We demonstrated that the result calculated by our method, only depending on the aptamer's concentrations, was consistent with the classical method, which depended on the concentrations of both the aptamers and the targets. Furthermore, a series of DNA aptamers binding with avian influenza virus H9N2 were confirmed by a four-round selection of capillary electrophoresis-systematic evolution of ligands by exponential enrichment, and we identified the binding constant of these aptamers by directly using the whole virus as the target with the modified method. In conclusion, our modified method was validated to study the interaction between the aptamer and its target, and it may also advance the evaluation of other receptor-ligand interactions. PMID- 23657447 TI - Profiling and semiquantitative analysis of the cell surface proteome in human mesenchymal stem cells. AB - Mulitpotent mesenchymal stem cells (MSCs) derived from human bone marrow are promising candidates for the development of cell therapeutic strategies. MSC surface protein profiles provide novel biological knowledge concerning the proliferation and differentiation of these cells, including the potential for identifying therapeutic targets. Basic fibroblast growth factor (bFGF) affects cell surface proteins, which are associated with increased growth rate, differentiation potential, as well as morphological changes of MSCs in vitro. Cell surface proteins were isolated using a biotinylation-mediated method and identified using a combination of one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis and mass spectrometry. The resulting gel lines were cut into 20 bands and digested with trypsin. Each tryptic fragment was analyzed by liquid chromatography-electrospray ionization tandem mass spectrometry. Proteins were identified using the Mascot search program and the International Protein Index human database. Noble MSC surface proteins (n = 1,001) were identified from cells cultured either with (n = 857) or without (n = 667) bFGF-containing medium in three independent experiments. The proteins were classified using FatiGO to elucidate their function. We also confirmed the proteomics results using Western blotting and immunofluorescence microscopic analysis. The nature of the proteins identified makes it clear that MSCs express a wide variety of signaling molecules, including those related to cell differentiation. Among the latter proteins, four Ras-related Rab proteins, laminin-R, and three 14-3-3 proteins that were fractionated from MSCs cultured on bFGF-containing medium are implicated in bFGF-induced signal transduction of MSCs. Consequently, these finding provide insight into the understanding of the surface proteome of human MSCs. PMID- 23657449 TI - New advances in molecular recognition based on biomolecular scaffolds. AB - In this review, we summarize recent advances in the development of molecular recognition components based on the biomolecular scaffolds of proteins and nucleic acids for specific recognition of miscellaneous targets. In addition to the widely adopted recombinant antibody fragments, designed ankyrin repeat proteins and modular peptide repeats of transcription-activator-like effectors for base-specific recognition of DNA sequence are also briefly introduced. For the nucleic acid based molecular recognition systems, aptamers, including slow off-rate modified aptamers, DNAzymes, and synthetic DNA-like oligomers for versatile biorecognition are described. Finally, we discuss the remaining challenges and future research directions in the field. PMID- 23657448 TI - Use of entrapment and high-performance affinity chromatography to compare the binding of drugs and site-specific probes with normal and glycated human serum albumin. AB - Protein entrapment and high-performance affinity chromatography were used with zonal elution to examine the changes in binding that occurred for site-specific probes and various sulfonylurea drugs with normal and glycated forms of human serum albumin (HSA). Samples of this protein in a soluble form were physically entrapped within porous silica particles by using glycogen-capped hydrazide activated silica; these supports were then placed into 1.0 cm * 2.1 mm inner diameter columns. Initial zonal elution studies were performed using (R)-warfarin and L-tryptophan as probes for Sudlow sites I and II (i.e., the major drug binding sites of HSA), giving quantitative measures of binding affinities in good agreement with literature values. It was also found for solutes with multisite binding to the same proteins, such as many sulfonylurea drugs, that this method could be used to estimate the global affinity of the solute for the entrapped protein. This entrapment and zonal approach provided retention information with precisions of +/-0.1-3.3% (+/- one standard deviation) and elution within 0.50 3.00 min for solutes with binding affinities of 1 * 10(4)-3 * 10(5) M(-1). Each entrapped-protein column was used for many binding studies, which decreased the cost and amount of protein needed per injection (e.g., the equivalent of only 125 145 pmol of immobilized HSA or glycated HSA per injection over 60 sample application cycles). This method can be adapted for use with other proteins and solutes and should be valuable in high-throughput screening or quantitative studies of drug-protein binding or related biointeractions. PMID- 23657450 TI - Bioaerosol analysis based on a label-free microarray readout method using surface enhanced Raman scattering. AB - Bacterial contamination of indoor air is a serious threat to human health. Pathogenic germs can be transferred from the liquid to the aerosol phase, for instance, when water is sprayed in the air, such as in shower rooms, air conditioners, or fountains. Existing analytical methods for biological indoor air quality assessment and contamination monitoring are mostly time consuming as they generally require a cultivation step. The need for a rapid, sensitive, and selective detection method for bioaerosols is evident. Our approach is based on the combination of a commercial wet particle sampler (Coriolis MU, Bertin Technologies, France) and a label-free microarray readout based on surface enhanced Raman scattering (SERS) for detection, which was established in our laboratories. Heat-inactivated Escherichia coli bacteria were used as test microorganisms. An E. coli suspension was sprayed into the chamber by a jet air nebulizer. The resulting bioaerosol was dried, neutralized, and then collected by a Coriolis MU sampler. The bacteria collected were detected by a recently developed microarray readout system, based on label-free SERS detection. A special data evaluation procedure was applied in order to fully exploit the selectivity of the detection scheme, resulting in a detection limit of 144 particles per cubic centimeter. PMID- 23657451 TI - NMR assignments and the acid-base characterization of the pomegranate ellagitannin punicalagin in the acidic pH-range. AB - In exploring the capability of nuclear magnetic resonance (NMR) spectroscopy for pomegranate juice analysis, the eight aromatic singlet resonances of alpha- and beta-punicalagin were clearly identified in the (1)H NMR spectra of juice samples. The four downfield resonances were found to be sensitive to small pH changes around pH 3.50 where the NMR spectra of the juice samples were recorded. To understand this unusual behavior, the (1)H and (13)C resonance assignments of the punicalagin anomers were determined in aqueous solution and pH titrations with UV and (1)H NMR detection carried out to characterize the acid-base properties of punicalagin over the pH range 2-8. Simultaneous fitting of all of the pH-sensitive (1)H NMR signals produced similar but significantly different pKa values for the first two deprotonation equilibria of the gallagic acid moiety of the punicalagin alpha- (pKa1 = 4.57 +/- 0.02, pKa2 = 5.63 +/- 0.03) and beta- (pKa1 = 4.36 +/- 0.01, pKa2 = 5.47 +/- 0.02) anomers. Equivalent pKa values, (alpha : 6.64 +/- 0.01, beta : 6.63+/- 0.01) were measured for the third deprotonation step involving the ellagic acid group, in good agreement with a prior literature report. The punicalagin anomer equilibrium readjusts in parallel with the proton dissociation steps as the pH is raised such that beta-punicalagin becomes the most abundant anomer at neutral pH. The unusual upfield shifts observed for the glucose H3 and H5 resonances with increasing pH along with the shift in the alpha/beta anomer equilibrium are likely the consequence of a conformational rearrangement. PMID- 23657452 TI - Dual cloud point extraction coupled with hydrodynamic-electrokinetic two-step injection followed by micellar electrokinetic chromatography for simultaneous determination of trace phenolic estrogens in water samples. AB - A dual cloud point extraction (dCPE) off-line enrichment procedure coupled with a hydrodynamic-electrokinetic two-step injection online enrichment technique was successfully developed for simultaneous preconcentration of trace phenolic estrogens (hexestrol, dienestrol, and diethylstilbestrol) in water samples followed by micellar electrokinetic chromatography (MEKC) analysis. Several parameters affecting the extraction and online injection conditions were optimized. Under optimal dCPE-two-step injection-MEKC conditions, detection limits of 7.9-8.9 ng/mL and good linearity in the range from 0.05 to 5 MUg/mL with correlation coefficients R(2) >= 0.9990 were achieved. Satisfactory recoveries ranging from 83 to 108% were obtained with lake and tap water spiked at 0.1 and 0.5 MUg/mL, respectively, with relative standard deviations (n = 6) of 1.3-3.1%. This method was demonstrated to be convenient, rapid, cost-effective, and environmentally benign, and could be used as an alternative to existing methods for analyzing trace residues of phenolic estrogens in water samples. PMID- 23657453 TI - Using forensic science to teach method development in the undergraduate analytical laboratory. PMID- 23657454 TI - Detection of EPO injections using a rapid lateral flow isoform test. AB - Misuse of recombinant human erythropoietin (rhEPO) is a major concern in competitive sports, and the implementation of tests allowing for higher detection rates than what current tests are capable of is required. In this study, a novel lateral flow EPO isoform test kit, EPO WGA MAIIA, is evaluated on the basis of plasma and urine samples obtained from eight healthy males in connection with a 28-day rhEPO injection period. rhEPO was injected every other day during the first 14 days of the study, and the method proved to be 100% effective in detecting rhEPO in the concomitantly obtained samples. Seven days after the last injection, three positive (>99.99% confidence limit (CL)) subjects were found. When using 99% CL as the cut-off limit, six of the eight subjects (75%) were found to be suspected of doping. Samples obtained 14 and 21 days after the last injection showed no detectable trace of rhEPO. A previous study using indirect methods to determine EPO doping on the same samples indicated only that two of the subjects had suspicious values 7-21 days after the last injection. We propose implementing the easy to-use EPO WGA MAIIA test as an initial screening procedure in anti-doping work to (1) increase the detection rate of potential rhEPO doping athletes and (2) allow for a 10- to 20-fold higher analytical rate than what is possible today. PMID- 23657455 TI - Gas chromatography-triple quadrupole tandem mass spectrometry: a powerful tool for the (ultra)trace analysis of multiclass environmental contaminants in fish and fish feed. AB - A new method for rapid determination of 73 target organic environmental contaminants including 18 polychlorinated biphenyls, 16 organochlorinated pesticides, 14 brominated flame retardants and 25 polycyclic aromatic hydrocarbons in fish and fish feed using gas chromatography coupled with triple quadrupole tandem mass spectrometry (GC-MS/MS) was developed and validated. GC MS/MS in electron ionization mode was shown to be a powerful tool for the (ultra)trace analysis of multiclass environmental contaminants in complex matrices, providing measurements with high selectivity and sensitivity. Another positive aspect characterizing the newly developed method is a substantial simplification of the sample preparation, which was achieved by an ethyl acetate QuEChERS (quick, easy, cheap, effective, rugged and safe) based extraction followed by silica minicolumn clean-up. With use of this sample preparation approach the sample laboratory throughput was increased not only because six samples may be prepared in approximately 1 h, but also because all the above mentioned groups of contaminants can be determined in a single GC-MS/MS run. Under the optimized conditions, the recoveries of all target analytes in both matrices were within the range from 70 to 120% and the repeatabilities were 20% or less. The method quantification limits were in the range from 0.005 to 1 MUg kg(-1) and from 0.05 to 10 MUg kg(-1) for fish muscle tissue and fish feed, respectively. The developed method was successfully applied to the determination of halogenated persistent organic pollutants and polycyclic aromatic hydrocarbons in fish and fish feed samples. PMID- 23657456 TI - Green chromatography separation of analytes of greatly differing properties using a polyethylene glycol stationary phase and a low-toxic water-based mobile phase. AB - A simple, rapid, and environmentally friendly HPLC method was developed and validated for the separation of four compounds (4-aminophenol, caffeine, paracetamol, and propyphenazone) with different chemical properties. A "green" mobile phase, employing water as the major eluent, was proposed and applied to the separation of analytes with different polarity on polyethylene glycol (PEG) stationary phase. The chromatography separation of all compounds and internal standard benzoic acid was performed using isocratic elution with a low-toxicity mobile phase consisting of 0.04% (v/v) triethylamine and water. HPLC separation was carried out using a PEG reversed-phase stationary phase Supelco Discovery HS PEG column (15 * 4 mm; particle size 3 MUm) at a temperature of 30 degrees C and flow rate at 1.0 mL min(-1). The UV detector was set at 210 nm. In this study, a PEG stationary phase was shown to be suitable for the efficient isocratic separation of compounds that differ widely in hydrophobicity and acid-base properties, particularly 4-aminophenol (log P, 0.30), caffeine (log P, -0.25), and propyphenazone (log P, 2.27). A polar PEG stationary phase provided specific selectivity which allowed traditional chromatographic problems related to the separation of analytes with different polarities to be solved. The retention properties of the group of structurally similar substances (aromatic amines, phenolic compounds, and xanthine derivatives) were tested with different mobile phases. The proposed green chromatography method was successfully applied to the analysis of active substances and one degradation impurity (4-aminophenol) in commercial preparation. Under the optimum chromatographic conditions, standard calibration was carried out with good linearity correlation coefficients for all compounds in the range (0.99914-0.99997, n = 6) between the peak areas and concentration of compounds. Recovery of the sample preparation was in the range 100 +/- 5% for all compounds. The intraday method precision was determined as RSD, and the values were lower than 1.00%. PMID- 23657457 TI - Analysis of esterified and nonesterified fatty acids in serum from obese individuals after intake of breakfasts prepared with oils heated at frying temperature. AB - In this study, levels of esterified and nonesterified fatty acids (EFAs and NEFAs, respectively) were compared in obese individuals (body mass index between 30 and 47 kg m(-2)) in basal state and after intake of four different breakfasts prepared with oils heated at frying temperature. The target oils were three sunflower oils--pure, enriched with dimethylsiloxane (400 MUg mL(-1)) as lipophilic oxidation inhibitor, and enriched with phenolic compounds (400 MUg mL( 1)) as hydrophilic oxidation inhibitors--and virgin olive oil with a natural content of phenolic compounds of 400 MUg mL(-1). The intake of breakfasts was randomized to avoid trends associated to this variability source. EFAs and NEFAs were subjected to a sequential derivatization step for independent gas chromatography-mass spectrometry analysis of both fractions of metabolites in human serum. Derivatization was assisted by ultrasonic energy to accelerate the reaction kinetics, as required for high-throughput analysis. Statistical analysis supported on univariate (multifactor ANOVA) and multivariate approaches (principal component analysis and partial least squares-discriminant analysis) allowed identification of the main variability sources and also discriminating between individuals after intake of each breakfast. Individuals' samples after intake of breakfasts prepared with virgin olive oil were clearly separated from those who ingested the remaining breakfasts. The main compounds contributing to discrimination were omega-3 and omega-6 EFAs with special emphasis on arachidonic acid and eicosapentaenoic acid. These two polyunsaturated fatty acids are the precursors of eicosanoid metabolites, which are of vital importance as they play important roles in inflammation and in the pathogenesis of vascular and malignant diseases as cancer. PMID- 23657458 TI - Looking into individual coffee beans during the roasting process: direct micro probe sampling on-line photo-ionisation mass spectrometric analysis of coffee roasting gases. AB - A micro-probe (MU-probe) gas sampling device for on-line analysis of gases evolving in confined, small objects by single-photon ionisation time-of-flight mass spectrometry (SPI-TOFMS) was developed. The technique is applied for the first time in a feasibility study to record the formation of volatile and flavour compounds during the roasting process within (inside) or in the direct vicinity (outside) of individual coffee beans. A real-time on-line analysis of evolving volatile and semi-volatile organic compounds (VOC and SVOC) as they are formed under the mild pyrolytic conditions of the roasting process was performed. The soft-ionisation mass spectra depict a molecular ion signature, which is well corresponding with the existing knowledge of coffee roasting and evolving compounds. Additionally, thereby it is possible to discriminate between Coffea arabica (Arabica) and Coffea canephora (Robusta). The recognized differences in the roasting gas profiles reflect the differences in the precursor composition of the coffee cultivars very well. Furthermore, a well-known set of marker compounds for Arabica and Robusta, namely the lipids kahweol and cafestol (detected in their dehydrated form at m/z 296 and m/z 298, respectively) were observed. If the variation in time of different compounds is observed, distinctly different evolution behaviours were detected. Here, phenol (m/z 94) and caffeine (m/z 194) are exemplary chosen, whereas phenol shows very sharp emission peaks, caffeine do not have this highly transient behaviour. Finally, the changes of the chemical signature as a function of the roasting time, the influence of sampling position (inside, outside) and cultivar (Arabica, Robusta) is investigated by multivariate statistics (PCA). In summary, this pilot study demonstrates the high potential of the measurement technique to enhance the fundamental knowledge of the formation processes of volatile and semi-volatile flavour compounds inside the individual coffee bean. PMID- 23657459 TI - SERS-based DNA detection in aqueous solutions using oligonucleotide-modified Ag nanoprisms and gold nanoparticles. AB - Oligonucleotide-modified nanoparticle conjugates show highly promising potential for SERS-based DNA detection. However, it remains challenging to carry out the SERS-based DNA detection in aqueous solutions directly using oligonucleotide modified nanoparticles, because the Raman reporters would exhibit lower signals when they are dispersed in aqueous solutions than laid on "dry" metal nanoparticles. Here, we synthesized stable oligonucleotide-modified Ag nanoprism conjugates, and performed SERS-based DNA detection in aqueous solution directly by using such conjugates in combination with Raman reporter-labeled, oligonucleotide-modified gold nanoparticles. The experimental results indicate that this SERS-based DNA detection approach exhibited a good linear correlation between SERS signal intensity and the logarithm of target DNA concentration ranging from 10(-11)~10(-8) M. This sensitivity is comparable to those SERS-based DNA detection approaches with the "dry" process. Additionally, a similar correlation could also be observed in duplex target DNA detection by SERS hybrid probes. Our results suggest that the oligonucleotide-modified Ag nanoprisms may be developed as a powerful SERS-based DNA detection tool. PMID- 23657461 TI - [Improved breast MRI specificity in nonmalignant breast lesions using additional diffusion-weighted sequences without significant increases in examination time]. PMID- 23657460 TI - Consumption of sugary foods and drinks and risk of endometrial cancer. AB - Consumption of foods high in sugar promotes insulin production, which has been linked to endometrial carcinogenesis. We evaluated the impact of dietary intake of sugary foods and beverages, as well as added sugar and total sugar on endometrial cancer risk in a population-based case-control study, including 424 cases and 398 controls. Participants completed an interview and food frequency questionnaire, and provided self-recorded waist and hip measurements. Women in the highest quartile of added sugar intake had significantly increased endometrial cancer risk (OR = 1.84, 95% CI 1.16-2.92). Among women with waist-to hip ratio >=0.85, risk was significantly higher for the highest versus lowest tertile of added sugar intakes (OR = 2.50, 95% CI 1.38-4.52). The association with added sugar also became stronger when analyses were restricted to never users of hormone replacement therapy (OR = 2.03; 95% CI 1.27-3.26, for highest versus lowest tertile). There was little evidence of effect modification by body mass index or physical activity. Given the high prevalence of intake of sugary foods and drinks in Western populations, additional research is warranted to confirm our findings on endometrial cancer. PMID- 23657462 TI - In vivo anthelmintic activity of Anogeissus leiocarpus Guill & Perr (Combretaceae) against nematodes in naturally infected sheep. AB - The identification of new anthelmintic drugs becomes a priority because of the availability of a handful of drugs, cost of treatments, and recent emergence of drug resistance. Medicinal plants are a good source of bioactive compounds for development of drugs. In this study, in vivo efficacy of Anogeissus leiocarpus was assessed in sheep naturally infected with gastrointestinal nematodes. Fecal examination, serological analyses, and necropsy were carried out to determine the egg and worm-burden reduction. The administration of ethanolic extract (single oral dose of 80 mg/kg) of A. leiocarpus induced a moderate fecal egg reduction (81 %) and adult worm-burden reduction (87 %) against Haemonchus contortus and Trichostrongylus colubriformis (82 %). The plant exhibited high efficacy against adult Strongyloides papillosus (100 %), Gaigeria pachyscelis (90 %), Cooperia curticei (100 %), and Oesophagostomum columbianum (95 %) but low efficacy against Trichostrongylus axei (67 %) and Trichuris globulosa (79 %). All these helminthes were sensitive to fenbendazole, except O. columbianum which showed a decrease susceptibility (17 %). The plant extract also improved certain biological parameters by increasing bodyweight from 0.7 +/- 2.9 to 3.3 +/- 1.9 % and improving hematocrit of 6.9 +/- 1.6 % 3-week posttreatment. It emerges from the results that the plant possesses significant effectiveness on diarrhea; all treated animals gave normal feces. This study has shown that A. leiocarpus could find an application in the control of multiparasitism in small ruminants. PMID- 23657463 TI - [ECG changes in primary neurological disorders, systemic diseases and primary cardioymopathies]. AB - ECG diagnostic is not only an easy to use, cost efficient, extensively available method for cardiological patients, but also a potential tool in diagnostic for other morbidities. As a well-known example, cerebral hemorrhage and ischemia can show an ECG, that resembles an acute coronary syndrome. Furthermore systemic diseases may show characteristic ECG; often as a malfunction of the conductive system (e.g., AV block). Exclusion of cardiac involvement when dealing with sarcoidosis is important, and the ECG may be a first hint. Besides, in Ixodid endemic areas a cardiological manifestation of Borreliosis should be considered. ECG may also show almost specific findings in primary cardiomyopathies, such as the "pseudo-infarction Q - wave" in hypertrophic cardiomyopathy or "epsilon potentials" in arrhythmogenic right ventricular cardiomyopathy. The takotsubo cardiomyopathy commonly reveals transient ST-segment elevation and therefore depicts an important differential diagnosis of acute coronary syndromes. PMID- 23657464 TI - alpha(1,3) Fucosyltransferases IV and VII are essential for the initial recruitment of basophils in chronic allergic inflammation. AB - Basophils act as initiator cells for the development of IgE-mediated chronic allergic inflammation (IgE-CAI). However, detailed mechanisms of initial recruitment of basophils into the skin have yet to be clarified. Selectins mediate leukocyte capture and rolling on the vascular endothelium for extravasation. Counter-receptor activity of selectins is regulated by alpha(1, 3) fucosyltransferases (FTs) IV and VII. To clarify the contribution of selectin ligands regulated by FTs for initial basophil recruitment, IgE-CAI was induced in mice deficient in FT-IV and/or FT-VII genes. Although FT-IV(-/-) and FT-VII(-/-) mice exhibited comparable skin responses to wild-type mice, the FT-IV(-/-)/FT VII(-/-) mice showed significantly impaired inflammation. Although the transfer of basophils to FcRgamma(-/-) mice induced IgE-CAI, this induction was completely absent when basophils from FT-IV(-/-)/FT-VII(-/-) mice were transferred. L selectin, but not P- and E-selectin, blocking Abs inhibited skin inflammation in vivo. P-selectin glycoprotein-1 (PSGL-1) antibody also ameliorated skin inflammation, and basophils were bound to L-selectin in a PSGL-1-dependent manner, which was regulated by FT-IV/VII. Functional PSGL-1 generated by basophil FT-IV/VII and its subsequent binding to L-selectin could be one of the essential steps required for initial basophil recruitment and the development of IgE-CAI in mice. PMID- 23657466 TI - The human skin-associated autoantigen alpha-NAC activates monocytes and dendritic cells via TLR-2 and primes an IL-12-dependent Th1 response. PMID- 23657465 TI - Epidermal ADAM17 is dispensable for notch activation. PMID- 23657467 TI - Does contact with a podiatrist prevent the occurrence of a lower extremity amputation in people with diabetes? A systematic review and meta-analysis. AB - OBJECTIVE: To determine the effect of contact with a podiatrist on the occurrence of Lower Extremity Amputation (LEA) in people with diabetes. DESIGN AND DATA SOURCES: We conducted a systematic review of available literature on the effect of contact with a podiatrist on the risk of LEA in people with diabetes. Eligible studies, published in English, were identified through searches of PubMed, CINAHL, EMBASE and Cochrane databases. The key terms, 'podiatry', 'amputation' and 'diabetes', were searched as Medical Subject Heading terms. Reference lists of selected papers were hand-searched for additional articles. No date restrictions were imposed. STUDY SELECTION: Published randomised and analytical observational studies of the effect of contact with a podiatrist on the risk of LEA in people with diabetes were included. Cross-sectional studies, review articles, chart reviews and case series were excluded. Two reviewers independently assessed titles, abstracts and full articles to identify eligible studies and extracted data related to the study design, characteristics of participants, interventions, outcomes, control for confounding factors and risk estimates. ANALYSIS: Meta-analysis was performed separately for randomised and non-randomised studies. Relative risks (RRs) with 95% CIs were estimated with fixed and random effects models as appropriate. RESULTS: Six studies met the inclusion criteria and five provided data included in meta-analysis. The identified studies were heterogenous in design and included people with diabetes at both low and high risk of amputation. Contact with a podiatrist did not significantly affect the RR of LEA in a meta-analysis of available data from randomised controlled trials (RCTs); (1.41, 95% CI 0.20 to 9.78, 2 RCTs) or from cohort studies; (0.73, 95% CI 0.39 to 1.33, 3 Cohort studies with four substudies in one cohort). CONCLUSIONS: There are very limited data available on the effect of contact with a podiatrist on the risk of LEA in people with diabetes. PMID- 23657468 TI - Patients' subjective assessment of the duration of cataract surgery: a case series. AB - OBJECTIVES: Surgery duration is a source of preoperative anxiety for patients undergoing cataract surgery. To better inform patients, we evaluated the agreement between objective and patient-perceived surgery durations. DESIGN: Case series. SETTING: Public teaching university hospital (Paris, France). PARTICIPANTS: During the study period, 368 cataract surgery cases performed on 285 patients were included, 85 cases were excluded from the final analysis. All patients who had uneventful phacoemulsification were included. Cases with any significant intraoperative adverse event or cases requiring additional anaesthesia other than topical were excluded. Resident performed cases were also excluded. PRIMARY AND SECONDARY OUTCOMES: Procedures were timed (objective duration) and patients were asked, immediately afterwards, to assess the duration of their surgery (patient-assessed duration). The agreement between objective and patient-assessed durations as well as influencing factors was studied. RESULTS: Mean objective duration (13.9+/-5 min) and patient-assessed duration (15.3+/-6.9 min) were significantly correlated (Spearman's r=0.452, p<0.0001). Furthermore, Bland-Altman analysis and the intraclass correlation coefficient (0.341, 95% CI 0.23 to 0.44) were quite in agreement. On univariate analysis, senior-performed procedures were significantly shorter than those performed by juniors (13.4 vs 17.8 min, p=0.0001). Pain was recorded as 'no sensation' (31.5% of the cases), 'mild sensation' (41%), 'moderate pain' (23.3%), 'intense pain' (3.5%) and 'unbearable pain' (0.7%). Groups with high pain score had significantly longer procedures (p<0.001). Multivariate analysis revealed that the only independent factors associated with both the objective and patient-assessed durations of surgery were surgeon's experience and pain-score. CONCLUSIONS: In our study, patients' estimated and real duration of the surgery showed moderate agreement, suggesting that emotions associated with eye surgery under topical anaesthesia did not dramatically hinder the patients' perception of time. However, the benefit of preoperative counselling regarding the duration of surgery will need further evaluation. PMID- 23657469 TI - Randomised controlled trial of an education and support package for stroke patients and their carers. AB - OBJECTIVE: Tailoring stroke information and providing reinforcement opportunities are two strategies proposed to enhance the effectiveness of education. This study aimed to evaluate the effects of an education package which utilised both strategies on the knowledge, health and psychosocial outcomes of stroke patients and carers. DESIGN: Multisite, randomised trial comparing usual care with an education and support package. SETTING: Two acute stroke units. PARTICIPANTS: Patients and their carers (N=138) were randomised (control n=67, intervention n=71) of which data for 119 participants (control n=59, intervention n=60) were analysed. INTERVENTION: The package consisted of a computer-generated, tailored written information booklet and verbal reinforcement provided prior to, and for 3 months following, discharge. OUTCOME MEASURES: Outcome measures were administered prior to hospital discharge and at 3-month follow-up by blinded assessors. The primary outcome was stroke knowledge (score range: 0-25). Secondary outcomes were: self-efficacy (1-10), anxiety and depression (0-21), ratings of importance of information (1-10), feelings of being informed (1-10), satisfaction with information (1-10), caregiver burden (carers) (0-13) and quality of life (patients) (1-5). RESULTS: Intervention group participants reported better: self efficacy for accessing stroke information (adjusted mean difference (MD) of 1.0, 95% CI 0.3 to 1.7, p=0.004); feeling informed (MD 0.9, 95% CI 0.2 to 1.6, p=0.008); and satisfaction with medical (MD 2.0, 95% CI 1.1 to 2.8, p<0.001); practical (MD 1.1, 95% CI 0.3 to 1.9, p=0.008), services and benefits (MD 0.9, 95% CI 0.1 to 1.8, p=0.036) and secondary prevention information (MD 1.7, 95% CI 0.9 to 2.5, p<0.001). There was no significant effect on other outcomes. CONCLUSIONS: Intervention group participants had improved self-efficacy for accessing stroke information and satisfaction with information, but other outcomes were not significantly affected. Evaluation of a more intensive intervention in a trial with a larger sample size is required to establish the value of an educational intervention that uses tailoring and reinforcement strategies. ACTRN12608000469314. PMID- 23657470 TI - Highly efficient asymmetric construction of quaternary carbon-containing homoallylic and homopropargylic amines. AB - A highly efficient method for the asymmetric synthesis of chiral quaternary carbon-containing homoallylic and homopropargylic amines under mild conditions was achieved with good yields and high diastereoselectivities. PMID- 23657471 TI - High efficiency solid state dye sensitized solar cells with graphene-polyethylene oxide composite electrolytes. AB - Novel and highly effective composite electrolytes were prepared by combining the two dimensional graphene (Gra) and polyethylene oxide (PEO) for the solid electrolyte of dye sensitized solar cells (DSSCs). Gra sheets were uniformly coated by the polymer layer through the ester carboxylate bonding between oxygenated species on Gra sheets and PEO. The Gra-PEO composite electrolyte showed the large scale generation of iodide ions in a redox couple. From rheological analysis, the decrease in viscosity after the addition of LiI and I2 in the Gra-PEO electrolyte might be explained by the dipolar interactions being severely disrupted by the ionic interactions of Li(+), I(-), and I3(-) ions. A composite electrolyte with 0.5 wt% Gra presented a higher ionic conductivity (3.32 mS cm(-1)) than those of PEO and other composite electrolytes at room temperature. A high overall conversion efficiency (~5.23%) with a very high short circuit current (JSC) of 18.32 mA cm(-2), open circuit voltage (VOC) of 0.592 V and fill factor (FF) of 0.48 was achieved in DSSCs fabricated with the 0.5 wt% Gra-PEO composite electrolyte. This enhanced photovoltaic performance might be attributed to the large scale formation of iodide ions in the redox electrolyte and the relatively high ionic conductivity. PMID- 23657472 TI - Synthesis and analytical application of a novel fluorescent Hg2+ probe 3', 6' bis(diethylamino)-2-((2,4-dimethoxybenzylidene)amino)spiro[isoindoline-1,9' xanthene]-3-thione. AB - A novel probe, 3',6' - bis(diethylamino) -2- ((2,4-dimethoxybenzylidene)amino) spiro [isoindoline-1,9'-xanthene]-3-thione (RBS), was designed and synthesized. Its structure was characterized with elemental analysis, IR spectra and (1)H NMR. The probe displayed highly selective and sensitive recognition of Hg(2+). Reacting with mercury ions in aqueous solution, its fluorescence intensity was enhanced significantly, while its color was changed from colorless to pink. So, a new fluorescence method of detection of Hg(2+) was proposed. Its dynamic response concentration range and detection limit for Hg(2+) were 5.00 * 10(-9) M to 1.00 * 10(-6) M detected and 1.83 * 10(-9) M, respectively. Satisfying results were obtained when the probe was applied to detect spiked Hg(2+) in samples. PMID- 23657473 TI - The effects of different solvents and excitation wavelength on the photophysical properties of two novel Ir(III) complexes based on phenylcinnoline ligand. AB - Two novel cyclometalated iridium(III) complexes, Ir(pcl)2(pic) and Ir(pcl)2(fpic) (pcl: 3-phenylcinnoline, pic: picolinic acid, fpic: 5-fluoro-2-picolinic acid) were synthesized and characterized by FTIR, (1)H NMR spectroscopy, UV-vis, PL, and MALDI-TOF. These two Ir-complexes geometry were predicted using the Sparkle/PM6 model and suggested to a chemical environment of very low symmetry around the Ir ions (C 1). The PL spectrum of Ir(pcl)2(pic) and Ir(pcl)2(fpic) indicated that these complex belonged to red light emission, and maximum emission wavelength located at 647 and 641 nm, respectively. Most importantly, the effects of different solvents on their photoluminescent properties were detailed investigated. The results indicated that the polarity of solvent played an important role for their emission spectra. With introducing fluoro group to the pyridyl ring, the maximum emission wavelength of Ir(pcl)2(fpic) was blue shifted about 6 nm, and the quantum yield was slightly higher than that of Ir(pcl)2(pic). In addition, the thermal properties of these two Ir-complexes were measured by TGA, and results indicated that they had relative good thermal properties. PMID- 23657474 TI - Regio- and chemoselective palladium-catalyzed benzylallylation of activated olefins: the remarkable effect of palladium nanoparticles. AB - The palladium-catalyzed three-component reactions of benzyl halides, activated olefins, and allyltributylstannane were successfully conducted to produce the corresponding benzylallylation products in satisfactory to high yields. The benzylallylation reaction proceeded smoothly under mild conditions in the presence of palladium nanoparticles in tetrahydrofuran. PMID- 23657475 TI - Cd-free CIGS solar cells with buffer layer based on the In2S3 derivatives. AB - This study guided by device evaluations was conducted to reveal the reasons for the loss of the photo-generated carriers in CIGS cells with the buffer based on In2S3 derivatives. Chemical bath deposited Inx(OOH,S)y films have been employed as a Cd-free buffer layers. When compared to solar cells with CdS buffer layer, the Cu0.9(In0.7,Ga0.3)Se2.1 (Eg = 1.18 eV) cells with the Inx(OOH,S)y buffer exhibited strong voltage-dependent carrier collection and poor spectral response above 500 nm, presumably, due to energy barrier at the junction. In order to improve the charge collection by upward shift of the conduction band minimum of CIGS absorber, Inx(OOH,S)y/Cu0.9(In0.55,Ga0.45)Se2.1 (Eg = 1.30 eV) solar cells were also fabricated and their spectral responses were examined. When compared to the Cu0.9(In0.7,Ga0.3)Se2.1 cells, the improved spectral response and voltage dependent carrier collection were obtained. Nevertheless, considerable loss in charge collection above 500 nm was still observed. The efficiency reached 9.3% while the Cu0.9(In0.7,Ga0.3)Se2.1 cell exhibited only the efficiency of 3.4%. Finally, CIGS (Eg = 1.18 eV) solar cells with n-ZnO/i-ZnO/Inx(OOH,S)y/CdS/CIGS and n-ZnO/i-ZnO/CdS/Inx(OOH,S)y/CIGS configurations were fabricated. The influence of the TCO/buffer interface on the device characteristics was also addressed by means of comparison between the characteristics of two cells employing different interfaces. A 13.0% efficient cell has been achieved from n ZnO/i-ZnO/CdS/Inx(OOH,S)y/CIGS configuration. The obtained data suggested that the limitation of the device efficiency was mainly related to the i ZnO/Inx(OOH,S)y interface. The experimental results provide the knowledge base for further optimization of the interface properties to form high-quality p-n junction in the CIGS solar cells employing the CBD In2S3 buffer layer. PMID- 23657476 TI - Valuing health at the end of life: an empirical study of public preferences. AB - In 2009, the National Institute for Health and Clinical Excellence (NICE) issued supplementary advice to its Appraisal Committees to be taken into account when appraising life-extending, 'end-of-life' treatments. This indicated that if certain criteria are met, it may be appropriate to recommend the use of such treatments even if they would not normally be considered cost-effective. However, NICE's public consultation revealed concerns that there is little scientific evidence to support such a policy. This study examines whether there is public support for giving higher priority to life-extending, end-of-life treatments than to other types of treatment. In face-to-face interviews, respondents answered six questions asking them to choose which of two hypothetical patients they would prefer to treat, assuming that the health service has enough funds to treat one but not both of them. The various scenarios were designed so as to control for age- and time-related preferences. Fifty members of the general public in England were interviewed in July 2011. We find some evidence of support for giving priority to the patient with shorter remaining life expectancy, but note that a nontrivial minority of respondents expressed the opposite preference. Substantial preference for quality-of-life improvement over life extension was observed. Very few respondents expressed indifference or unwillingness to choose between the patients. Whilst there cannot be described to be a single 'consensus' set of preferences, we conclude that there are ways in which the results suggest that the current NICE policy may be insufficient. PMID- 23657477 TI - Robotic hybrid technique in rectal surgery for deep pelvic endometriosis. AB - BACKGROUND: Deep pelvic endometriosis is a complex disorder that affects 6% to 12% of all women in childbearing age. The incidence of bowel endometriosis ranges between 5.3% and 12%, with rectum and sigma being the most frequently involved tracts, accounting for about 80% of cases. It has been reported that segmental colorectal resection is the best surgical option in terms of recurrence rate and improvement of symptoms. The aim of this study is to analyze indications, feasibility, limits, and short-term results of robotic (Da Vinci Surgical System) assisted laparoscopic rectal sigmoidectomy for the treatment of deep pelvic endometriosis. PATIENTS AND METHODS: Between January 2006 and December 2010, 19 women with bowel endometriosis underwent colorectal resection through the robotic assisted laparoscopic approach. Intraoperative and postoperative data were collected. All procedures were performed in a single center and short-term complications were evaluated. RESULTS: Nineteen robotic-assisted laparoscopic colorectal resections for infiltrating endometriosis were achieved. Additional procedures were performed in 7 patients (37%). No laparotomic conversion was performed. No intraoperative complications were observed. The mean operative time was 370 minutes (range = 250-720 minutes), and the estimated blood loss was 250 mL (range = 50-350 mL). The overall complication rate was 10% (2 rectovaginal fistulae). CONCLUSIONS: Deep pelvic endometriosis is a benign condition but may have substantial impact on quality of life due to severe pelvic symptoms. We believe that robotic-assisted laparoscopic colorectal resection is a feasible and relatively safe procedure in the context of close collaboration between gynecologists and surgeons for treatment of deep pelvic endometriosis with intestinal involvement, with low rates of complications and significant improvement of intestinal symptoms. PMID- 23657478 TI - Epigenetics: Legionella makes its mark on histones. PMID- 23657479 TI - Understanding the origin of species with genome-scale data: modelling gene flow. AB - As it becomes easier to sequence multiple genomes from closely related species, evolutionary biologists working on speciation are struggling to get the most out of very large population genomic data sets. Such data hold the potential to resolve long-standing questions in evolutionary biology about the role of gene exchange in species formation. In principle, the new population genomic data can be used to disentangle the conflicting roles of natural selection and gene flow during the divergence process. However, there are great challenges in taking full advantage of such data, especially with regard to including recombination in genetic models of the divergence process. Current data, models, methods and the potential pitfalls in using them will be considered here. PMID- 23657482 TI - Population genetics: Mobile elements across human populations. PMID- 23657483 TI - Eric Olson. Interview by Hannah Stower. PMID- 23657480 TI - Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. AB - How DNA is organized in three dimensions inside the cell nucleus and how this affects the ways in which cells access, read and interpret genetic information are among the longest standing questions in cell biology. Using newly developed molecular, genomic and computational approaches based on the chromosome conformation capture technology (such as 3C, 4C, 5C and Hi-C), the spatial organization of genomes is being explored at unprecedented resolution. Interpreting the increasingly large chromatin interaction data sets is now posing novel challenges. Here we describe several types of statistical and computational approaches that have recently been developed to analyse chromatin interaction data. PMID- 23657484 TI - Association between self-rated oral appearance and the need for dental prostheses among elderly Brazilians. AB - We investigated the association between poor self-rated oral appearance and the need for dental prostheses among elderly Brazilians. National data from an epidemiological survey on oral health in Brazil conducted from 2002 to 2003 by the Ministry of Health (SB, Brazil) with a multistage random sample of 4,839 individuals aged 65-74 years in 250 towns were analyzed. The dependent variable was self-rated oral appearance, dichotomized into "poor" (poor/very poor) and "good" (fair/good/very good). The main independent variable was the need for an upper or lower dental prosthesis. Other variables included sociodemographic characteristics, approach to dental care, oral health conditions, and self reported oral disadvantage. Data were analyzed using the chi-square test and Poisson regression models at a 95% significance level. The prevalence of poor self-rated oral appearance was 20.6% and was higher in the elderly who needed a partial or complete upper or lower prosthesis, independent of other variables. This prevalence was associated with age, the use of dental services, access to information about oral disease prevention, number of decayed teeth, self perception of the need for treatment, dental pain, chewing ability, and the perception that oral health affects relationships with other people. The elderly who needed dental prostheses had a higher prevalence of poor self-rated oral appearance than those who did not need any. PMID- 23657481 TI - Meta-analysis methods for genome-wide association studies and beyond. AB - Meta-analysis of genome-wide association studies (GWASs) has become a popular method for discovering genetic risk variants. Here, we overview both widely applied and newer statistical methods for GWAS meta-analysis, including issues of interpretation and assessment of sources of heterogeneity. We also discuss extensions of these meta-analysis methods to complex data. Where possible, we provide guidelines for researchers who are planning to use these methods. Furthermore, we address special issues that may arise for meta-analysis of sequencing data and rare variants. Finally, we discuss challenges and solutions surrounding the goals of making meta-analysis data publicly available and building powerful consortia. PMID- 23657485 TI - Evaluation of bone alterations in the jaws of HIV-infected menopausal women. AB - The advent of highly active antiretroviral therapy (HAART) has caused a reduction in mortality, thus contributing to an increase in the number of women with HIV?AIDS who reach the climacteric period, experience decline in ovarian function, and develop complications of viral infection and HAART, which can accelerate bone loss. The aim of this study was to detect possible alterations in the jaws of HIV-infected women by panoramic radiography. The study comprised a total of 120 women above 40 years of age who were divided into the following two groups: women who are HIV positive (Group I) and women with no known HIV infection (Group II). Measurement of the following three radiomorphometric indexes was performed by panoramic radiography: Mental Index (MI), Panoramic Mandibular Index (PMI) and Antegonial Depth (AD). A total of 70% of women in the control group and 50% of women in the HIV group were in the postmenopausal period, and the average values of both MI (p = 0.0054) and AD (p < 0.0001) for this period were lower in the HIV group than in the control group. For patients who were in the premenopausal period, the average AD was lower in the HIV group than in the control group (p = 0.0003). Despite the difference in the average age between groups, greater bone resorption in the mandible was found in the group of HIV-positive women. PMID- 23657486 TI - Comparative analysis of preemptive analgesic effect of dexamethasone and diclofenac following third molar surgery. AB - The objective of the study was to compare the analgesic effectiveness of dexamethasone and diclofenac sodium administered preemptively after surgical removal of third molars. Forty-four ASA (American Society of Anesthesiologists) I patients (19 men, 35 women; 16-28 years old) randomly and double-blindly received diclofenac sodium (50 mg) or dexamethasone (8 mg) or placebo 1 h before surgery. Intensity of pain, measured with a visual analog scale (VAS), was the variable studied at different postoperative times (1 h, 2 h, 3 h, 6 h, 8 h, 12 h, 48 h, 4 d and 7 d). The total amount of rescue medication (TARM) ingested (paracetamol) was another variable of the study. The Kruskal-Wallis statistical test was used. A p value of < .05 was adopted to reject the null hypothesis. The dexamethasone group showed lower pain intensity (p < .05) than the diclofenac sodium and placebo groups (p < .05). No difference in TARM was observed among the groups (p < .05). Preemptively administered, dexamethasone was effective in controlling postoperative pain. PMID- 23657487 TI - The prevalence of elder abuse in the Porto Alegre metropolitan area. AB - Abuse of the elderly is a form of violence to come to the public's attention. Dental professionals are in an ideal position to identify physical abuse. The aim of this study was to assess the prevalence of elderly abuse and analyze the database of injury reports that can be identified by dental teams. A documentary analysis study developed by the Elderly Protection Police Station of Porto Alegre, Rio Grande do Sul, was carried out. The information used came from 2,304 complaints filed at the aforementioned institution between the years of 2004 and 2006. The records of abuse are categorized as injury, neglect, mistreatment, theft, financial abuse, threat, disturbing the peace, atypical fact, and others. The injuries that could be identified by the dental team were classified according to the injury's location in the area of the head, face, mouth and neck. Descriptive analysis was performed, and chi-square tests were used to evaluate the distributions of the types of elder abuse in relation to sex and age. The most frequent of the different types of abuse was theft, with a prevalence of 17.8%, followed by disturbing the peace at 11.8%. Disturbing the peace, threat, and bodily injury were significantly associated with women. Elder abuse among women and men declines with age. The prevalence of head injury was 25% of the total injuries, most often in females, and in those aged < 70 years. Based on these results, it is necessary that the dental team observe the elderly person's appearance for suspicious physical signs. PMID- 23657488 TI - Influence of disinfectant solutions on test materials used for the determination of masticatory performance. AB - Masticatory function can be evaluated objectively as the capacity of an individual to fragment solid food after a fixed number of chewing cycles, the so called masticatory performance (MP). The objective of this study was to evaluate the reliability of four different test materials (Optosil, Optocal, Zetapuls, and Perfil) and five disinfection protocols by aspersion and immersion (no disinfection, 2% glutaraldehyde, 2% chlorhexidine, 5.25% sodium hypochlorite, and 70% alcohol) on the MP, determined at three moments (24 hours, 15 and 60 days) after storing the fragmented blocks. MP was evaluated by calculating X50 through the sieving technique and the Rosim-Ramler equation. The weight and microbiologic count (colony forming units, CFUs) of chewed blocks were measured to identify any variations that would make MP determination unfeasible. Differences in MP were observed among the materials (p < 0.01). Perfil presented the highest X50 value (worst MP determination), followed by Zetaplus (both p < 0.05), Optosil, and Optocal (both p > 0.05). The time and disinfection type had no influence on MP (p > 0.05). The number of CFUs differed between the nondisinfected group and all other disinfection groups at all time points (p < 0.01). No other significant difference in CFU count between disinfection groups was observed. In conclusion, disinfection did not alter the reliability of the test materials for the MP calculation for up to 60 days. PMID- 23657490 TI - Effect of peer-based low back pain information and reassurance at the workplace on sick leave: a cluster randomized trial. AB - PURPOSE: To evaluate whether information and reassurance about low back pain (LBP) given to employees at the workplace could reduce sick leave. METHODS: A Cluster randomized controlled trial with 135 work units of about 3,500 public sector employees in two Norwegian municipalities, randomized into two intervention groups; Education and peer support (EPS) (n = 45 units), education and "peer support and access to an outpatient clinic" (EPSOC) (n = 48 units), and a control group (n = 42 units). Both interventions consisted of educational meetings based on a "non-injury model" and a "peer adviser" appointed by colleagues. Employees in the EPSOC group had access to an outpatient clinic for medical examination and further education. The control group received no intervention. The main outcome was sick leave based on municipal records. Secondary outcomes were self-reported pain, pain related fear of movement, coping, and beliefs about LBP from survey data of 1,746 employees (response rate about 50 %). RESULTS: EPS reduced sick leave by 7 % and EPSOC reduced sick leave by 4 % during the intervention year, while sick leave in the control group was increased by 7 % during the same period. Overall, Rate Ratios (RR) were statistically significant for EPSOC (RR = .84 (C.I = 0.71-.99) but not EPS (RR = .92 (C.I = 0.78-1.09)) in a mixed Poisson regression analysis. Faulty beliefs about LBP were reduced in both intervention groups. CONCLUSIONS: Educational meetings, combined with peer support and access to an outpatient clinic, were effective in reducing sick leave in public sector employees. PMID- 23657489 TI - Cadherin-mediated cell-cell adhesion and signaling in the skeleton. AB - Direct cell-to-cell interactions via cell adhesion molecules, in particular cadherins, are critical for morphogenesis, tissue architecture, and cell sorting and differentiation. Partially overlapping, yet distinct roles of N-cadherin (cadherin-2) and cadherin-11 in the skeletal system have emerged from mouse genetics and in vitro studies. Both cadherins are important for precursor commitment to the osteogenic lineage, and genetic ablation of Cdh2 and Cdh11 results in skeletal growth defects and impaired bone formation. While Cdh11 defines the osteogenic lineage, persistence of Cdh2 in osteoblasts in vivo actually inhibits their terminal differentiation and impairs bone formation. The action of cadherins involves both cell-cell adhesion and interference with intracellular signaling, and in particular the Wnt/beta-catenin pathway. Both cadherin-2 and cadherin-11 bind to beta-catenin, thus modulating its cytoplasmic pools and transcriptional activity. Recent data demonstrate that cadherin-2 also interferes with Lrp5/6 signaling by sequestering these receptors in inactive pools via axin binding. These data extend the biologic action of cadherins in bone forming cells, and provide novel mechanisms for development of therapeutic strategies aimed at enhancing bone formation. PMID- 23657491 TI - Reduction of some Pt(IV) complexes with biologically important sulfur-donor ligands. AB - The reduction of the Pt(IV) complexes [PtCl4(bipy)], [PtCl4(dach)] and [PtCl4(en)] by glutathione (GSH), L-cysteine (L-Cys) and L-methionine (L-Met) was investigated by stopped-flow spectrophotometry at pH 2.0 (in 0.01 M perchloric acid) and at pH 7.2 (in 25 mM Hepes buffer). Kinetic measurements were performed under pseudo-first order conditions with an excess of the reducing agent. The order of the reactivity of the studied complexes was [PtCl4(bipy)] > [PtCl4(dach)] > [PtCl4(en)], and reactivity of investigated reducing agents followed the order GSH > L-Cys > L-Met. All the reactions between the selected Pt(IV) complexes and the sulfur donor biomolecules proceeded by a reductive elimination process that included nucleophilic attack by the reducing agent on one of the mutually trans-coordinated chloride ligands, which led to a two electron transfer process. The final products of the redox reactions were the corresponding reduced Pt(II) complexes and the oxidized form of the reducing agents. PMID- 23657492 TI - Identification and bioanalysis of natural products from insect symbionts and pathogens. AB - : With the development of several novel methods in genome sequencing, molecular biology, and analytical chemistry a new area of natural product chemistry is currently starting that allows the analysis of minute amounts of complex biological samples. The combination of these methods, as discussed in this review, also enables the analysis of bacteria living in symbiosis or being pathogenic to insects, which might be the largest reservoir for novel microbes associated with higher organisms due to the huge number of insect species. PMID- 23657494 TI - Left atrial volume index is a predictor of silent myocardial ischemia in high risk patients with end-stage renal disease. AB - Silent myocardial ischemia is highly prevalent in patients with end-stage renal disease (ESRD), and is associated with poor cardiovascular outcomes. However, the criteria for coronary artery disease screening remain unclear in asymptomatic patients. The goal of this study was to evaluate whether baseline echocardiographic parameters can predict myocardial ischemia in asymptomatic patients with ESRD. We investigated 259 high-risk asymptomatic patients with ESRD who underwent both echocardiography and myocardial perfusion single-photon emission computed tomography at the initiation of dialysis. We defined the presence of myocardial ischemia as a reversible or fixed perfusion defect. Silent myocardial ischemia was found in 99 (38.2 %) high-risk asymptomatic patients with ESRD at the initiation of dialysis. In patients with myocardial ischemia, left ventricular (LV) end systolic volume index, LV mass index, left atrial volume index (LAVI), and the ratio of early mitral inflow velocity to peak mitral annulus velocity were significantly higher, and LV ejection fraction was significantly lower, than those without myocardial ischemia. Multivariate analysis showed that LAVI, LV ejection fraction, and regional wall motion abnormalities were independently associated with the presence of silent myocardial ischemia. Severe (LA) enlargement was independently associated with the presence of silent myocardial ischemia (odds ratio 1.97; 95 % confidence interval 1.08-3.57; p = 0.026). LA enlargement is a potential marker for identifying patients with ESRD at high risk of silent myocardial ischemia. PMID- 23657495 TI - Stem cells: a gated exit from pluripotency. PMID- 23657497 TI - Metabolism: Putting energy into mitophagy. PMID- 23657498 TI - Pathology quiz case 1. Primary cutaneous osteosarcoma of the left temple. PMID- 23657496 TI - Mechanisms and function of substrate recruitment by F-box proteins. AB - S phase kinase-associated protein 1 (SKP1)-cullin 1 (CUL1)-F-box protein (SCF) ubiquitin ligase complexes use a family of F-box proteins as substrate adaptors to mediate the degradation of a large number of regulatory proteins involved in diverse processes. The dysregulation of SCF complexes and their substrates contributes to multiple pathologies. In the 14 years since the identification and annotation of the F-box protein family, the continued identification and characterization of novel substrates has greatly expanded our knowledge of the regulation of substrate targeting and the roles of F-box proteins in biological processes. Here, we focus on the evolution of our understanding of substrate recruitment by F-box proteins, the dysregulation of substrate recruitment in disease and potential avenues for F-box protein-directed disease therapies. PMID- 23657500 TI - The U.S. prevalence of common warts in childhood: a population-based study. PMID- 23657499 TI - Response to letter to the editor (NRAD-13-78) re: variations in the origin of the vertebral artery and its level of entry into the transverse foramen diagnosed by CT angiography Dan Meila; Marcin Tysiac; Friedhelm Brassel. PMID- 23657501 TI - MAPKAP kinase 2 (MK2)-dependent and -independent models of blister formation in pemphigus vulgaris. AB - Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by autoantibodies to the keratinocyte adhesion protein desmoglein 3 (Dsg3). Previous studies suggest that PV pathogenesis involves p38 mitogen-activated protein kinase-dependent and -independent pathways. However, p38 is a difficult protein to study and therapeutically target because it has four isoforms and multiple downstream effectors. In this study, we identify MAPKAP (mitogen-activated protein kinase-activated protein) kinase 2 (MK2) as a downstream effector of p38 signaling in PV and describe MK2-dependent and -independent mechanisms of blister formation using passive transfer of human anti-Dsg IgG4 mAbs to neonatal mice. In human keratinocytes, PV mAbs activate MK2 in a dose-dependent manner. MK2 is also activated in human pemphigus skin blisters, causing translocation of MK2 from the nucleus to the cytosol. Small-molecule inhibition of MK2 and silencing of MK2 expression block PV mAb-induced Dsg3 endocytosis in human keratinocytes. In addition, small-molecule inhibition and genetic deletion of p38alpha and MK2 inhibit spontaneous but not induced suprabasal blisters by PV mAbs in mouse passive transfer models. Collectively, these data suggest that MK2 is a key downstream effector of p38 that can modulate PV autoantibody pathogenicity. MK2 inhibition may be a valuable adjunctive therapy for control of pemphigus blistering. PMID- 23657502 TI - Risk of rosacea in patients with diabetes using insulin or oral antidiabetic drugs. PMID- 23657503 TI - IL-25 enhances HSV-1 replication by inhibiting filaggrin expression, and acts synergistically with Th2 cytokines to enhance HSV-1 replication. AB - Atopic dermatitis (AD) is characterized by epidermal barrier defects and recurrent microbial skin infections. AD patients with a history of eczema herpeticum (ADEH+) have more severe skin disease and more highly T helper type 2 (Th2)-polarized immune responses as compared with uncomplicated AD (ADEH-). However, the mechanisms linking epidermal barrier defects and viral skin infection are not well understood. Recently, it has been reported that interleukin-25 may play a role in augmenting Th2 responses. We examined protein expression of IL-25 in the skin biopsies from normal subjects (n=10), ADEH- (n=18), ADEH+ (n=7), and psoriasis (n=9). IL-25 expression was increased in the skin from ADEH-, ADEH+, and psoriasis as compared with normal skin, and was significantly greater in lesional ADEH+ skin than in lesional ADEH- skin. Importantly, we demonstrated that IL-25 enhances herpes simplex virus (HSV)-1 and vaccinia virus replication by inhibiting filaggrin expression, and IL-25 acts synergistically with IL-4 and IL-13 to enhance HSV-1 replication in vitro. In contrast, IFN-gamma inhibited HSV-1 replication in vitro. In addition, we demonstrate that filaggrin is a critical protein to inhibit HSV-1 replication because filaggrin small interfering RNA knockdown enhances HSV-1 replication in vitro. Filaggrin breakdown products, however, inhibited HSV-1 replication in vitro. PMID- 23657506 TI - Metal dication cross-linked polymer network colloids as an approach to form and stabilize unusually small metal nanoparticles. AB - Reduction of Cu(II) cations immobilized as cross-linkers in polyacrylate network colloids produce relatively small (~3 nm) Cu metal particles which are further tuned to smaller size (~1.5 nm) by partially substituting Ca(+2) for Cu(+2) in the polymer network colloid. PMID- 23657504 TI - Epigenomic association analysis identifies smoking-related DNA methylation sites in African Americans. AB - Cigarette smoking is an environmental risk factor for many chronic diseases, and disease risk can often be managed by smoking control. Smoking can induce cellular and molecular changes, including epigenetic modification, but the short- and long term epigenetic modifications caused by cigarette smoking at the gene level have not been well understood. Recent studies have identified smoking-related DNA methylation (DNAm) sites in Caucasians. To determine whether the same DNAm sites associate with smoking in African Americans, and to identify novel smoking related DNAm sites, we conducted a methylome-wide association study of cigarette smoking using a discovery sample of 972 African Americans, and a replication sample of 239 African Americans with two array-based methods. Among 15 DNAm sites significantly associated with smoking after correction for multiple testing in our discovery sample, 5 DNAm sites are replicated in an independent cohort, and 14 sites in the replication sample have effects in the same direction as in the discovery sample. The top two smoking-related DNAm sites in F2RL3 (factor II receptor-like 3) and GPR15 (G-protein-coupled receptor 15) observed in African Americans are consistent with previous findings in Caucasians. The associations between the replicated DNAm sites and smoking remain significant after adjusting for genetic background. Despite the distinct genetic background between African Americans and Caucasians, the DNAm from the two ethnic groups shares common associations with cigarette smoking, which suggests a common molecular mechanism of epigenetic modification influenced by environmental exposure. PMID- 23657507 TI - Minimally invasive surgery: a concept already incorporated. PMID- 23657505 TI - Role of TRAV locus in low caries experience. AB - Caries is the most common chronic, multifactorial disease in the world today; and little is still known about the genetic factors influencing susceptibility. Our previous genome-wide linkage scan has identified five loci related to caries susceptibility: 5q13.3, 13q31.1, 14q11.2, 14q 24.3, and Xq27. In the present study, we fine mapped the 14q11.2 locus to identify genetic contributors to caries susceptibility. Four hundred seventy-seven subjects from 72 pedigrees with similar cultural and behavioral habits and limited access to dental care living in the Philippines were studied. An additional 387 DNA samples from unrelated individuals were used to determine allele frequencies. For replication purposes, a total of 1,446 independent subjects from four different populations were analyzed based on their caries experience (low versus high). Forty-eight markers in 14q11.2 were genotyped using TaqMan chemistry. Transmission disequilibrium test was used to detect over transmission of alleles in the Filipino families, and Chi-square, Fisher's exact and logistic regression were used to test for association between low caries experience and variant alleles in the replication data sets. We finally assessed the mRNA expression of TRAV4 in the saliva of 143 study subjects. In the Filipino families, statistically significant associations were found between low caries experience and markers in TRAV4. We were able to replicate these results in the populations studied that were characteristically from underserved areas. Direct sequencing of 22 subjects carrying the associated alleles detects one missense mutation (Y30R) that is predicted to be probably damaging. Finally, we observed higher expression in children and teenagers with low caries experience, correlating with specific alleles in TRAV4. Our results suggest that TRAV4 may have a role in protecting against caries. PMID- 23657508 TI - Expression of claudin, paxillin and FRA-1 in non-nodular breast lesions in association with microcalcifications. AB - CONTEXT AND OBJECTIVE: The possible role of adhesion molecules in early breast carcinogenesis has been shown in the literature. We aimed to analyze early adhesion imbalances in non-nodular breast lesions and their association with precursor lesions, in order to ascertain whether these alterations exist and contribute towards early carcinogenesis. DESIGN AND SETTING: Retrospective cross sectional study based on medical records at a private radiological clinic in Sao Paulo, Brazil. METHODS: We retrospectively reviewed the medical records of all consecutive women attended between August 2006 and July 2007 who presented mammographic evidence of breast microcalcifications classified as Breast Imaging Reporting and Data System Atlas (BI-RADS) type 4. These women underwent stereotaxic biopsy. Clinical, radiological and pathological data were collected, and immunohistochemical assays searched for claudin, paxillin, FRA-1 and HER-2. RESULTS: Over this period, 127 patients were evaluated. Previous BI-RADS diagnoses showed that 69 cases were in category 4A, 47 in 4B and 11 in 4C. Morphological assessment showed benign entities in 86.5%. Most of the benign lesions showed preserved claudin expression, associated with paxillin (P < 0.001). Paxillin and HER-2 expressions were correlated. FRA-1 expression was also strongly associated with HER-2 expression (P < 0.001). CONCLUSIONS: Although already present in smaller amounts, imbalance of adhesion molecules is not necessarily prevalent in non-nodular breast lesions. Since FRA-1 expression reached statistically significant correlations with radiological and morphological diagnoses and HER-2 status, it may have a predictive role in this setting. PMID- 23657509 TI - Is neuromuscular electrical stimulation effective for improving pain, function and activities of daily living of knee osteoarthritis patients? A randomized clinical trial. AB - CONTEXT AND OBJECTIVE: Neuromuscular electrical stimulation (NMES) has been used in rehabilitation protocols for patients suffering from muscle weakness resulting from knee osteoarthritis. The purpose of the present study was to assess the effectiveness of an eight-week treatment program of NMES combined with exercises, for improving pain and function among patients with knee osteoarthritis. DESIGN AND SETTING: Randomized clinical trial at Interlagos Specialty Ambulatory Clinic, Sao Paulo, Brazil. METHODS: One hundred were randomized into two groups: NMES group and control group. The following evaluation measurements were used: numerical pain scale from 0 to 10, timed up and go (TUG) test, Lequesne index and activities of daily living (ADL) scale. RESULTS: Eighty-two patients completed the study. From intention-to-treat (ITT) analysis comparing the groups, the NMES group showed a statistically significant improvement in relation to the control group, regarding pain intensity (difference between means: 1.67 [0.31 to 3.02]; P = 0.01), Lequesne index (difference between means: 1.98 [0.15 to 3.79]; P = 0.03) and ADL scale (difference between means: -11.23 [-19.88 to -2.57]; P = 0.01). CONCLUSION: NMES, within a rehabilitation protocol for patients with knee osteoarthritis, is effective for improving pain, function and activities of daily living, in comparison with a group that received an orientation program. CLINICAL TRIAL REGISTRATION ACTRN012607000357459. PMID- 23657510 TI - Cross-cultural adaptation of The Beliefs about Medicines Questionnaire into Portuguese. AB - CONTEXT AND OBJECTIVES: The Beliefs about Medicines Questionnaire (BMQ-Specific) has proven useful for measuring patients' beliefs and associating them with non adherence to treatment in several illness groups. The aim was to cross-culturally adapt the BMQ-Specific into Portuguese for the general population of medicine users. DESIGN AND SETTING: Cross-sectional study conducted among users of public hospitals and outpatient clinics in Guarda and Covilha, Portugal. METHODS: The BMQ-Specific was translated using international recommendations for performing cross-cultural adaptation and was administered to 300 patients. An initial principal component analysis (PCA) was conducted with the extraction criterion of eigenvalue > 1.0, followed by a second PCA with restriction to two components. Reliability was assessed by calculating Cronbach's alpha coefficient. RESULTS: The mean scores obtained for the Necessity and Concerns subscales of the Portuguese BMQ-Specific were 19.9 (standard deviation, SD = 2.8) (range 10 to 25) and 17.7 (SD = 3.9) (range 6 to 30), respectively. The first PCA produced an unstable three-component structure for the Portuguese BMQ-Specific. The final PCA solution yielded a two-component structure identical to the original English version (a five-item Necessity and a six-item Concerns subscale), and explained 44% of the variance. Cronbach's alpha for the complete Portuguese BMQ-Specific was 0.70, and 0.76 and 0.67 for the Necessity and Concerns subscales, respectively. CONCLUSION: A cross-culturally adapted Portuguese version of the BMQ-Specific questionnaire for use among the general population of medicine users was obtained, presenting good internal consistency and component structure identical to the original English version. PMID- 23657511 TI - Prevalence of urinary incontinence and pelvic floor muscle dysfunction in primiparae two years after cesarean section: cross-sectional study. AB - CONTEXT AND OBJECTIVE: There is uncertainty in the literature regarding the theory that obstetric events and pelvic floor injuries give rise to lower risk of subsequent urinary incontinence among women delivering via cesarean section than among women delivering vaginally. The objective of this study was to assess the two-year postpartum prevalence of urinary incontinence and pelvic floor muscle dysfunction and the factors responsible for them. DESIGN AND SETTING: Cross sectional study, conducted in a public university. METHODS: 220 women who had undergone elective cesarean section or vaginal childbirth two years earlier were selected. Their urinary incontinence symptoms were investigated, and their pelvic floor muscle dysfunction was assessed using digital palpation and a perineometer. RESULTS: The two-year urinary incontinence prevalences following vaginal childbirth and cesarean section were 17% and 18.9%, respectively. The only risk factor for pelvic floor muscle dysfunction was weight gain during pregnancy. Body mass index less than 25 kg/m 2 and normal pelvic floor muscle function protected against urinary incontinence. Gestational urinary incontinence increased the risk of two-year postpartum urinary incontinence. CONCLUSION: Gestational urinary incontinence was a crucial precursor of postpartum urinary incontinence. Weight gain during pregnancy increased the subsequent risk of pelvic floor muscle dysfunction, and elective cesarean section did not prevent urinary incontinence. PMID- 23657512 TI - Carotid intima-media thickness in spondyloarthritis patients. AB - CONTEXT AND OBJECTIVE: Accelerated atherosclerosis has become a major problem in rheumatic inflammatory disease. The aim here was to analyze carotid intima-media thickness (IMT) in spondyloarthritis (SpA) patients and correlate this with clinical parameters and inflammatory markers. DESIGN AND SETTING: Cross-sectional analytical study at Rheumatology Outpatient Clinic, Evangelical University Hospital, Curitiba. METHODS: IMTs (measured using Doppler ultrasonography) of 36 SpA patients were compared with controls. The IMT in SpA patients was associated with inflammatory markers, like erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); and with clinical parameters, like axial or peripheral involvement, dactylitis, HLA B27, uveitis occurrence, Bath Ankylosing Spondylitis Functional Index (BASFI) and lipid profile. RESULTS: The mean IMT in SpA patients was 0.72 +/- 0.21 mm; in controls, 0.57 +/- 0.13 mm (P = 0.0007). There were no associations with ESR, CRP, BASDAI or clinical data. In univariate analysis, greater IMT was seen in patients with longer disease duration (P = 0.014; Pearson R = 0.40; 95% confidence interval, CI = 0.06 to 0.65); higher triglycerides (P = 0.02; Spearman R = 0.37; 95% CI = 0.03 to 0.64); and older age (P = 0.0014; Pearson R 0.51; 95% CI = 0.21 to 0.72). CONCLUSION: SpA patients have a higher degree of subclinical atherosclerosis than in controls, thus supporting clinical evidence of increased cardiovascular risk in rheumatic patients. PMID- 23657513 TI - Natriuria and calciuria levels in preeclampsia: a cross-sectional study. AB - CONTEXT AND OBJECTIVE: Sodium excretion abnormalities in preeclampsia have been studied in relation to several factors. The objective of this study was to compare natriuria (mEq/24 h) and calciuria levels (mg/24 h) in preeclamptic patients. DESIGN AND SETTING: An analytical cross-sectional study with a control group was conducted in the obstetric center and the high-risk pregnancy outpatient clinic at a university hospital in southern Brazil, and in a primary healthcare unit in the same city, including pregnant women with mild preeclampsia, severe preeclampsia or chronic hypertension, and women with normal pregnancies (14 patients in each group). METHOD: Natriuria was measured using an ion-selective electrode in an automated clinical chemistry analyzer (Hitache 917, Roche). All the patients collected 24-hour urine, at home or at the hospital, for analysis of proteins, creatinine, calcium, sodium and uric acid. Quantitative variables with asymmetrical distribution were described using the median, minimum and maximum, and were compared using the Kruskal-Wallis test. The results were logarithmically transformed, with one-way analysis of variance (ANOVA) by ranks and then the post-hoc Tukey test, and were analyzed by means of the Spearman correlation and receiver operating characteristic (ROC) curve. The significance level used was 0.05. RESULTS: There were significant differences between the groups in comparing severe preeclampsia with chronic hypertension and severe preeclampsia with controls (P < 0.0001 for both measurements). CONCLUSION: Natriuria levels may be lower in preeclampsia when associated with calciuria. Natriuria assessment is an additional test for differential diagnosis of hypertensive diseases in pregnancy, but is a poor predictor when used alone. PMID- 23657514 TI - Measuring spirituality and religiosity in clinical research: a systematic review of instruments available in the Portuguese language. AB - CONTEXT AND OBJECTIVES: Despite numerous spirituality and/or religiosity (S/R) measurement tools for use in research worldwide, there is little information on S/R instruments in the Portuguese language. The aim of the present study was to map out the S/R scales available for research in the Portuguese language. DESIGN AND SETTING: Systematic review of studies found in databases. METHODS: A systematic review was conducted in three phases. Phases 1 and 2: articles in Portuguese, Spanish and English, published up to November 2011, dealing with the Portuguese translation and/or validation of S/R measurement tools for clinical research, were selected from six databases. Phase 3: the instruments were grouped according to authorship, cross-cultural adaptation, internal consistency, concurrent and discriminative validity and test-retest procedures. RESULTS: Twenty instruments were found. Forty-five percent of these evaluated religiosity, 40% spirituality, 10% religious/spiritual coping and 5% S/R. Among these, 90% had been produced in (n = 3) or translated to (n = 15) Brazilian Portuguese and two (10%) solely to European Portuguese. Nevertheless, the majority of the instruments had not undergone in-depth psychometric analysis. Only 40% of the instruments presented concurrent validity, 45% discriminative validity and 15% a test-retest procedure. The characteristics of each instrument were analyzed separately, yielding advantages, disadvantages and psychometric properties. CONCLUSION: Currently, 20 instruments for measuring S/R are available in the Portuguese language. Most have been translated (n = 15) or developed (n = 3) in Brazil and present good internal consistency. Nevertheless, few instruments have been assessed regarding all their psychometric qualities. PMID- 23657515 TI - Acute splenic sequestration in a pregnant woman with homozygous sickle-cell anemia. AB - CONTEXT: Homozygous (SS) sickle-cell anemia complicated by acute splenic sequestration in adults is a rare event, and it has never been reported during pregnancy. CASE REPORT: A 25-year-old woman with homozygous (SS) sickle-cell disease was hospitalized at 32 weeks' of gestation presenting weakness, abdominal pain, fever and hemoglobin of 2.4 g/dl. Abnormal fetal heart rate was detected by means of cardiotocography, and 5 units of packed red cells were transfused. Cesarean was performed at 37 weeks. Both mother and baby were discharged in a good general condition. CONCLUSION: This case report demonstrates the importance of immediate blood transfusion for treatment of fetal distress in cases of splenic sequestration during pregnancy. This treatment is essential for avoiding maternal and fetal complications. PMID- 23657516 TI - Diastrophic dysplasia: prenatal diagnosis and review of the literature. AB - CONTEXT: Diastrophic dysplasia is a type of osteochondrodysplasia caused by homozygous mutation in the gene DTDST (diastrophic dysplasia sulfate transporter gene). Abnormalities occurring particularly in the skeletal and cartilaginous system are typical of the disease, which has an incidence of 1 in 100,000 live births. CASE REPORT: The case of a pregnant woman, without any consanguineous relationship with her husband, whose fetus was diagnosed with skeletal dysplasia based on ultrasound findings and DNA tests, is described. An obstetric ultrasound scan produced in the 16th week of gestation revealed characteristics that guided the clinical diagnosis. Prominent among these characteristics were rhizomelia of the lower and upper limbs (shortening of the proximal portions) and mesomelia (shortening of the intermediate portions). Both upper limbs showed marked curvature, with the first finger of the upper limbs in abduction and clinodactyly of the fifth finger. Molecular analysis using the polymerase chain reaction (PCR) and gene sequencing detected mutations that had already been described in the literature for the gene DTDST, named c.862C > T and c.2147_2148insCT. Therefore, the fetus was a compound heterozygote, carrying two different mutations. CONCLUSIONS: Prenatal diagnosis of this condition allowed a more realistic interpretation of the prognosis, and of the couple's reproductive future. This case report shows the contribution of molecular genetics towards the prenatal diagnosis, for which there are few descriptions in the literature. PMID- 23657517 TI - Trisomy 18 (Edwards syndrome) and major gastrointestinal malformations. PMID- 23657518 TI - Loci identified through genome-wide association studies and lung cancer risk: is there anything more? PMID- 23657519 TI - Response to letter to the editor: let's be attentive to the CD83 antigen expression in dendritic cell! PMID- 23657522 TI - Evaluation of two delirium screening tools for detecting post-operative delirium in the elderly. AB - BACKGROUND: Postoperative delirium in the elderly is common and associated with poor outcomes, but often goes unrecognized. Delirium screening tools, validated in postoperative settings are lacking. This study compares two screening tools [Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and Nursing Delirium Symptom Checklist (NuDESC)] with a DSM-IV-based diagnosis of delirium, conducted by neuropsychiatric examination in postoperative settings. METHODS: Consecutive English-speaking patients, >=70 yr, undergoing surgery with general anaesthesia and capable of providing informed consent, were recruited. Diagnostic test characteristics were compared for each screening tool vs neuropsychiatric examination, both in the Post-Anaesthesia Care Unit (PACU), and daily during inpatient hospitalization, adjusting for repeated measures. RESULTS: Neuropsychiatric examination identified delirium in 45% of 91 patients evaluated in the PACU and in 32% of 166 subsequent delirium assessments on the ward in the 58 admitted patients. The sensitivity [95% confidence interval (CI)] of delirium detection of the CAM-ICU in the PACU, and in all repeated assessments was 28% (16 45%) and 28% (17-42%), respectively; for the NuDESC (scoring threshold >=2), 32% (19-48%) and 29% (19-42%), respectively, and the NuDESC (threshold >=1), 80% (65 91%) and 72% (60-82%), respectively. Specificity was >90% for both the CAM-ICU and the NuDESC (threshold >=2); specificity for the NuDESC (threshold >=1), in the PACU was 69% (54-80%) and 80% (73-85%) for all assessments. CONCLUSIONS: While highly specific, neither CAM-ICU nor NuDESC (threshold >=2) are adequately sensitive to identify delirium post-operatively; NuDESC (threshold >=1) increases sensitivity, but reduces specificity. PMID- 23657523 TI - Determination of the binding epitope of RGD-peptidomimetics to alphavbeta3 and alpha(IIb)beta3 integrin-rich intact cells by NMR and computational studies. AB - NMR experiments (transferred NOE and Saturation Transfer Difference) were used to shed light on the binding epitope of RGD peptidomimetics 1-3 with integrins alphavbeta3 and alpha(IIb)beta3, expressed on the membrane of ECV304 bladder cancer cells and human platelets, respectively. The NMR results were supported by docking calculations of 1-3 in the active sites of alphavbeta3 and alpha(IIb)beta3 integrin receptors and were compared to the results of competitive alphavbeta3 receptor binding assays and competitive ECV304 cell adhesion experiments. While cis RGD ligand 1 interacts mainly with the alpha integrin subunit through its basic guanidine group, trans RGD ligands 2 and 3 are able to interact with both the alpha and beta integrin subunits via an electrostatic clamp. PMID- 23657524 TI - Screening of reducing agents for the PEGylation of recombinant human IL-10. AB - PEGylation is a technology commonly used to enhance the bioavailability of therapeutic proteins in patients. Reductive alkylation of a protein amino terminal alpha amine in the presence of a polyethylene glycol (PEG) chain derivatized with propionaldehyde and a reducing agent, typically sodium cyanoborohydride, is one of the technologies available to achieve quantitative and site specific PEGylation. While cyanoborohydride has proven to be a robust and efficient reagent for this type of reaction, it generates aqueous cyanide as a reaction by-product (and its corollary, the very volatile hydrogen cyanide). We report here the screening of reducing agents such as dimethylamine borane, trimethylamine borane, triethylamine borane, tert-butylamine borane, morpholine borane, pyridine borane, 2-picoline borane, and 5-ethyl-2-methyl-pyridine borane as alternatives to cyanoborohydride for the PEGylation of recombinant human IL 10. The results of our study show that pyridine borane and 2-picoline borane promote rhIL-10 PEGylation at levels comparable to those observed with cyanoborohydride. PMID- 23657525 TI - Spectroscopic studies of the supramolecular interactions between uracil and 5 hydroxy-6-methyluracil with bovine serum albumin and its bilirubin complex. AB - Using fluorescence and absorption spectroscopy the interaction of bovine serum albumin and its bilirubin complex with uracil and 5-hydroxy-6-methyluracil in phosphate buffer at pH 7.4 was investigated. The parameters of forming intermolecular complexes (binding constants, quenching rate constants, the radius of the quenching sphere and etc.) were determined. The interaction between serum albumin and uracils is carried out by the static quenching of protein fluorescence and has predominantly hydrophobic character. Using synchronous fluorescence spectroscopy the influence of uracil and 5-hydroxy-6-methyluracil on the conformational changes of the protein molecule was studied. Uracils effectively binds to bilirubin-albumin complex compared to free protein, which is caused by the interaction with tetrapyrrolic pigment in macromolecular complex. Molecular docking calculations also being presented. PMID- 23657526 TI - Isolated sinusitis sphenoidalis caused by Trichoderma longibrachiatum in an immunocompetent patient with headache. AB - We present a case of isolated sinusitis sphenoidalis caused by Trichoderma longibrachiatum, an emerging causal agent of fungal infections with an often fatal outcome. A Trichoderma strain was isolated from secretion obtained from the sinus sphenoidalis of a rhinosinusitis patient and identified by sequence analysis of two loci as Trichoderma longibrachiatum from the Longibrachiatum Clade of the genus Trichoderma. T. longibrachiatum can trigger a fatal pathomechanism in immunodeficient patients, but only rarely causes disease in healthy people. The case presented is unique because the patient was not immunocompromised. PMID- 23657528 TI - Antifungal mechanism of essential oil from Anethum graveolens seeds against Candida albicans. AB - This work studied the antifungal mechanism of dill seed essential oil (DSEO) against Candida albicans. Flow cytometric analysis and inhibition of ergosterol synthesis were performed to clarify the mechanism of action of DSEO on C. albicans. Upon treatment of cells with DSEO, propidium iodide penetrated C. albicans through a lesion in its plasma membrane. DSEO also significantly reduced the amount of ergosterol. These findings indicate that the plasma membrane of C. albicans was damaged by DSEO. The effect of DSEO on the functions of the mitochondria in C. albicans was also studied. We assayed the mitochondrial membrane potential (mtDeltapsi) using rhodamine 123 and determined the production of mitochondrial dysfunction-induced reactive oxygen species (ROS) via flow cytometry. The effects of the antioxidant l-cysteine (Cys) on DSEO-induced ROS production and the antifungal effect of DSEO on C. albicans were investigated. Exposure to DSEO increased mtDeltapsi. Dysfunctions in the mitochondria caused ROS accumulation in C. albicans. This increase in the level of ROS production and DSEO-induced decrease in cell viability were prevented by the addition of Cys, indicating that ROS are an important mediator of the antifungal action of DSEO. These findings indicate that the cytoplasmic membrane and mitochondria are the main anti-Candida targets of DSEO. PMID- 23657527 TI - Proteolytic processing of the Yersinia pestis YapG autotransporter by the omptin protease Pla and the contribution of YapG to murine plague pathogenesis. AB - Autotransporter protein secretion represents one of the simplest forms of secretion across Gram-negative bacterial membranes. Once secreted, autotransporter proteins either remain tethered to the bacterial surface or are released following proteolytic cleavage. Autotransporters possess a diverse array of virulence-associated functions such as motility, cytotoxicity, adherence and autoaggregation. To better understand the role of autotransporters in disease, our research focused on the autotransporters of Yersinia pestis, the aetiological agent of plague. Y. pestis strain CO92 has nine functional conventional autotransporters, referred to as Yaps for Yersinia autotransporter proteins. Three Yaps have been directly implicated in virulence using established mouse models of plague infection (YapE, YapJ and YapK). Whilst previous studies from our laboratory have shown that most of the CO92 Yaps are cell associated, YapE and YapG are processed and released by the omptin protease Pla. In this study, we identified the Pla cleavage sites in YapG that result in many released forms of YapG in Y. pestis, but not in the evolutionarily related gastrointestinal pathogen, Yersinia pseudotuberculosis, which lacks Pla. Furthermore, we showed that YapG does not contribute to Y. pestis virulence in established mouse models of bubonic and pneumonic infection. As Y. pestis has a complex life cycle involving a wide range of mammalian hosts and a flea vector for transmission, it remains to be elucidated whether YapG has a measurable role in any other stage of plague disease. PMID- 23657529 TI - Changes in serotype prevalence and antimicrobial resistance among invasive Streptococcus pneumoniae isolates in Korea, 1996-2008. AB - We investigated changes in serotypes and antimicrobial susceptibilities among 386 isolates of invasive Streptococcus pneumoniae collected from numerous hospitals in Korea from 1996 to 2008. Serotypes 19F (9.8 %), 23F (8.3 %), 19A (7.8 %), 6A (7.5 %), 3 (7.3 %), 9V (6.5 %), 6B (6.2 %), 14 (4.9 %), 1 (3.9 %), 11A (3.9 %) and 4 (3.1 %) represented 69.2 % of all isolates. While the overall proportion of PCV7 serotypes was stable over time, we observed modest decreases in children <5 years old and in adults >=65 years old between 1996-1999 and 2007-2008. An increased prevalence of non-PCV7 serotypes in these age groups was primarily attributable to an increase in serotypes 3, 6A and 19A. Most invasive S. pneumoniae isolates showed high resistance rates to erythromycin (74.9 %), tetracycline (71.1 %) and clindamycin (61.7 %). Between 1996-2003 and 2004-2008, non-susceptibility rates to cefotaxime and multi-drugs (three or more classes) in PCV7 serotypes showed a declining trend, while in non-PCV7 serotypes there was an increasing trend. Non-PCV7 serotypes 6A and 19A, which mostly exhibited multidrug resistant phenotypes (69.0 % and 76.7 % respectively), increased between 1996 2003 and 2004-2008. Although PCV7 was introduced in Korea in November 2003, pneumococcal vaccination has not been included in the national child vaccination programme. Our results provide details of serotype occurrence that will be useful when adoption of universal pneumococcal vaccination in Korea is being considered. PMID- 23657530 TI - Successful substitution of fetal calf serum by human plasma for bulk cultivation of Leishmania donovani promastigotes. AB - The potential of human plasma (HP) or serum (HS) as a replacement for fetal calf serum (FCS) was evaluated in a liver infusion tryptose (LIT) medium for bulk cultivation of Leishmania donovani promastigotes. The promastigote yield with the LIT-FCS standard medium was 0.4-1.8*10(7) ml(-1), and yields of 0.5-3.4*10(7) (P = 0.527) and 0.4-2.4*10(7) (P = 0.062) were recorded for two LIT medium variants containing HP or HS as supplement instead of FCS. Significantly, higher promastigote yields of 1.3-4.9*10(7) ml(-1) were demonstrated when LIT medium was supplemented with HP of blood group O but not A, B, AB or equally pooled ABO (P = 0.007-0.020). Matching (P = 0.56) strong positive (1 : 10 2400 to >=1 : 262 144 00) and weak negative (1 : 5-1 : 160) direct agglutination test (DAT) titres, respectively, were demonstrated in 24 visceral leishmaniasis (VL) and 45 non-VL sera for both standard LIT-FCS and alternative LIT-HP derived antigens. Our findings indicate strong potential for sustainable production of promastigotes for important diagnostic procedures such as DAT in the VL affected areas. PMID- 23657531 TI - Evaluation of the Cobas TaqMan MTB real-time PCR assay for direct detection of Mycobacterium tuberculosis in respiratory specimens. AB - The Cobas TaqMan MTB assay is a real-time PCR (qPCR) kit for rapid detection of Mycobacterium tuberculosis from clinical specimens. There are, however, limited studies validating its performance. We performed a prospective study in two hospitals in Taiwan on 586 respiratory specimens. By using culture as the reference method, the sensitivity and specificity of the Cobas TaqMan MTB assay were found to be 82.7 and 96.5 %, respectively. The sensitivity of the Cobas TaqMan MTB assay in acid-fast stain-negative respiratory specimens was only 34.9 %. Five specimens from five patients were positive for M. tuberculosis by the Cobas TaqMan MTB assay but were negative for M. tuberculosis by conventional culture methods. A diagnosis of pulmonary tuberculosis (TB) was made based on clinical and radiological findings as well as the response to anti-TB treatment in these five patients. Addition of data from these five specimens with discrepant results (PCR vs culture) from patients with symptoms clinically compatible with TB increased the sensitivity of the Cobas TaqMan MTB assay to 83.1 %. The Cobas TaqMan MTB assay is a rapid identification tool with a high degree of specificity for the direct detection of M. tuberculosis in respiratory specimens. The sensitivity for detecting acid-fast smear-negative respiratory specimens, however, is low. PMID- 23657533 TI - [On preoperative risk evaluation of adult patients before elective non-cardiac surgery: results of a survey on clinical practice in the Federal State of Hessen]. AB - BACKGROUND: The German Societies of Anesthesiology and Intensive Care Medicine, Internal Medicine and Surgery have recently published for the first time joint recommendations for the evaluation of adult patients prior to elective non cardiac surgery. In these recommendations indications for preoperative diagnostic procedures were critically revised and updated. It was unclear to what extent these recommendations were known among German anesthesiologists, how the recommendations were perceived and to what extent they were put into practice. The indications of five common diagnostic procedures in the context of the preoperative evaluation were also unknown. METHODS: Three months after publication of the recommendations, all anesthesiologists employed at hospitals in the state of Hessen were requested to take part in an online survey (OS). In the first part of the OS participants were asked about familiarity with the recommendations, opinions concerning the utility of the recommendations and to what extent they were implemented. In the second part of the OS participants were questioned in general and in the context of two common case scenarios about indications for electrocardiograms (ECG), chest radiographs (chest x-ray), echocardiograms, spirometry and extended cardiac diagnostics, such as stress ECG. In addition, participants of the OS were requested to take part in an interview survey (IS) addressing the same topics. The purpose of the IS was to detect any bias caused by the anonymous character of the OS which could lead to an overestimated self-assessment. Answers of the IS were not compared to the results of the corresponding answers given online by the same anesthesiologist but only analyzed together with the other results of the IS for comparison with the results of the OS. RESULTS: Of the contacted anesthesiologists 396 (29 %) took part in the OS of which 100 took part in the IS. According to the OS 30 % were familiar and 34 % were partially familiar with the recommendations, 20 % just knew that recommendations had been published and 16 % did not even know about the publication. The corresponding results of the IS were 16 %, 36 %, 28 % and 20 %, respectively. Of the participants 90 % (OS) and 89 % (IS) considered the recommendations at least to be predominantly reasonable and useful and 66 % (OS) of the participants tried to implement or at least to partially implement the recommendations (IS only 33 %). Concerning the indications for the different diagnostic procedures, the results of the OS showed that hospital guidelines (44 %) and patient age (32 %) were the most frequent indications for a preoperative ECG. Hospital guidelines (40 %) and own judgement (39 %) were the most common indications for a preoperative chest x-ray and patient age still accounted for 18 % of the indications. In contrast, echocardiography (67 %), spirometry (61 %) and extended cardiac diagnostics (70 %) were primarily indicated based on own judgement. However, reasons given in this context were frequently (77 %) not in agreement with the recommendations. Comparing the results of the OS to those of the IS with respect to the indications of the different diagnostic procedures for the common case scenarios showed a varying degree of consistency with the recommendations. In both cases responses to the IS concerning the indications for the different diagnostic procedures were mostly in accordance with the recommendations compared to answers obtained in the OS. Indications for the chest x-ray showed the worst degree of consistency with the recommendations. CONCLUSIONS: Corresponding to the high significance of local standards for the decision of indicating preoperative diagnostic procedures, the development of local standards that are in agreement with the recommendations seems to be a reasonable way to facilitate the implementation of the recommendations. PMID- 23657534 TI - [Anesthesiological considerations for patients with trisomy 21 (Down syndrome)]. AB - The most common chromosomal abnormality is trisomy 21 which is also known as Down syndrome and occurs in approximately 1 in 800 births. The majority of the resulting disabling conditions cannot be cured and affect people of all ages, ethnicity and economic levels. Life expectancy has increased with advances in medical care in the same way as in the rest of the population. One of the major tasks for health care professionals is to help these differently abled children and their families function in the most effective way possible as they learn to accept the limitations imposed by a persistent disability. Signs and symptoms of trisomy 21 are very variable based on the trias of mental retardation to a variable degree, hand anomalies and cardiac complications. Other abnormalities are atlantoaxial instability (AAI), tracheal stenosis, a predisposition to respiratory complications, chronic hypothyroidism, microgenia and macroglossia. These conditions are relevant to anesthetic procedures and patients with Down syndrome and their families have specific expectations and attitudes towards medical and anesthetic treatment. PMID- 23657535 TI - [Transversus abdominis plane block: anesthesia procedure for abdominal wall surgery only]. AB - The transversus abdominis plane (TAP) block is a well known method for postoperative pain control after abdominal surgery. From an anatomical and physiological point of view it should be possible to perform abdominal wall surgery, e.g. wound debridement, using a TAP block only. To the authors knowledge no studies have been published with respect to the use of TAP only. This article presents a case report demonstrating that it is possible to perform three consecutive operation procedures within 7 days using only a bilateral TAP catheter technique. The TAP block without any co-medication provides high patient comfort and should be recognized as a good alternative for abdominal wall surgery. PMID- 23657536 TI - [Patients at the end of life in the intensive care unit: cultural aspects of accompaniment]. AB - The accompaniment of people in the face of death offers insights into dimensions which are mostly not seen in ordinary life. These insights also exist in intensive care in German hospitals and are highly relevant in medical decision making. End-of-life decisions in particular often determine medical, cultural and spiritual aspects concerning medical treatment and therapeutic targets and if necessary new therapy targets. The following article especially illuminates cultural aspects and their characteristics in patients at the end of life in the intensive care unit. PMID- 23657537 TI - [Assessment of prehospital injury severity in children: challenge for emergency physicians]. AB - BACKGROUND: The prognosis of polytraumatized patients is dependent on the quality of emergency room (ER) management and a smooth transition from prehospital to ER therapy is essential. The accurate assessment of prehospital injury severity by emergency physicians influences prehospital therapy and level of care of the destination hospital. It also helps to ensure that medical resources are immediately available. Overestimation of injury severity wastes resources and underestimation puts patients at risk. The assessment of prehospital injury severity in adults is unreliable. In children, the assessment of injury severity seems to be even more challenging. MATERIALS AND METHODS: For the comparison of the prehospital documented injury severity and injury severity diagnosed after the ER phase, the injury severity score (ISS) and trauma-ISS (TRISS) were calculated. The TRISS consists of the ISS and the revised trauma score (RTS). All diagnoses of the prehospital and admission charts were collected and an injury severity was allocated according to the abbreviated injury scale (AIS). The concordance of the injury severity within different tolerances was evaluated. A tolerance of the prehospital documented injury severity of more than +/- 25 % to the injury severity calculated after ER diagnostics was considered as overestimation or underestimation. The concordance of the prehospital documented diagnosed injury severity and the severity diagnosed after the ER phase of different body regions according to the AIS was evaluated. The documented mechanism of injury in the emergency physician protocol was judged as being detailed, satisfactory or poor. RESULTS: The results showed that 69 % of the children reached the ER during on-call hours. Furthermore 92 % of the children reached the ER during the daytime between 08.00 h and 20.00 h. The transportation of 25 % of the children was on a private basis. The mean ER-ISS was 10 points (range 1-57). In 42 % of cases the ISS of the emergency physician protocol within a tolerance of +/- 25 % was concordant with the ER-ISS. According to this criterion in 38 % of cases an overestimation of the assessment of the injury severity of the emergency physician was found and in 20 % an underestimation. Within a tolerance of +/- 75 % based on the ER-ISS, the ISS of the emergency physician protocol was concordant in more than half of the cases (52 %). Using the TRISS with a tolerance of +/- 25 % a concordance was observed in 46 % of the cases. Within a tolerance of +/- 50 % based on the ER-ISS the ISS calculated after ER diagnostics was concordant in 50 % of the cases. A high concordance of the prehospital and hospital injury severity was found in the region of the face (75 %). The concordance in the body regions of the head, thorax, extremities and pelvis and soft tissue ranged between 43 % and 50 % of the cases. Of the children 38 % suffered a traffic accident, 52 % a fall of less than 3 m and 10 % of more than 3 m. The mechanism of injury was documented in detail in 70 % and satisfactory in 8 %. CONCLUSIONS: The assessment of prehospital injury severity in children is unreliable. In order to evaluate injury severity the use of anatomical trauma scores alone is insufficient. The adequate documentation of the mechanism of injury implies that the mechanism of injury seems to play a relevant role in the assessment of prehospital injury severity. The unreliable assessment of the injury severity, the arrival in the ER in on-call hours and the private transport to the hospital is a challenge to the ER leader in trauma life support for children. PMID- 23657538 TI - Humanised xenograft models of bone metastasis revisited: novel insights into species-specific mechanisms of cancer cell osteotropism. AB - The determinants and key mechanisms of cancer cell osteotropism have not been identified, mainly due to the lack of reproducible animal models representing the biological, genetic and clinical features seen in humans. An ideal model should be capable of recapitulating as many steps of the metastatic cascade as possible, thus facilitating the development of prognostic markers and novel therapeutic strategies. Most animal models of bone metastasis still have to be derived experimentally as most syngeneic and transgeneic approaches do not provide a robust skeletal phenotype and do not recapitulate the biological processes seen in humans. The xenotransplantation of human cancer cells or tumour tissue into immunocompromised murine hosts provides the possibility to simulate early and late stages of the human disease. Human bone or tissue-engineered human bone constructs can be implanted into the animal to recapitulate more subtle, species specific aspects of the mutual interaction between human cancer cells and the human bone microenvironment. Moreover, the replication of the entire "organ" bone makes it possible to analyse the interaction between cancer cells and the haematopoietic niche and to confer at least a partial human immunity to the murine host. This process of humanisation is facilitated by novel immunocompromised mouse strains that allow a high engraftment rate of human cells or tissue. These humanised xenograft models provide an important research tool to study human biological processes of bone metastasis. PMID- 23657539 TI - Synthesis of metal selenide colloidal nanocrystals by the hot injection of selenium powder. AB - We describe the synthesis of metal selenide nanocrystals, including CdSe, ZnSe, CuInSe2 and Cu2(Zn,Sn)Se4, by the hot injection of selenium powder dispersed in a carrier solvent. Since this results in a fast and high yield nanocrystal formation, we argue that the approach is well suited for the low cost, large volume production of nanocrystals. PMID- 23657540 TI - Unaltered R-R interval variability and bradycardia in cyclists as compared with non-athletes. AB - PURPOSE: To test whether elite mountain bikers display a cardiac autonomic modulation pattern that is distinctive from that of active non-athletes. BACKGROUND: The relationship between autonomic adaptation and bradycardia during physical exercise, including high-performance sports such as the mountain biking, remains to be elucidated. METHODS: Twelve elite mountain bikers and 11 matched non-athletes controls were evaluated for time- and frequency-domain heart rate variability based on a 5-min ECG R-R intervals series obtained in both the supine and the orthostatic positions. Oxygen uptake and pulse rate were obtained at ventilatory thresholds and peak effort during an incremental cardiopulmonary exercise test. Significance of differences between medians (25th, 75th percentiles) from the two groups was evaluated by the Mann-Whitney test at p <= 0.05. RESULTS: Athletes had lower heart rate [50 (47, 59) versus 63 (60, 69) bpm; p = 0.0004] and higher cardiopulmonary performance than controls [70.9 (64.6, 74.4) versus 47.7 (41.0, 51.9) mL (kg min)(-1); p = 0.01]. No statistical difference was found in heart rate variability in the group of athletes (p = 0.17 0.97), except for trend toward having lower coefficient of variation and low frequency absolute power indices both in supine position (p = 0.06). CONCLUSIONS: Bradycardia and higher oxygen uptake were found in association with unaltered cardiac autonomic modulation in elite mountain bikers athletes in supine and orthostatic positions, compared to active non-athletes. This bradycardia was not dependent on distinctive resting autonomic modulation. Intrinsic adaptation of sinus node and/or a peculiar state of autonomic adaptation to this exercise can be possible mechanisms. PMID- 23657541 TI - Immunohistochemical detection of meconium in the fetal lung: report of autopsied cases. PMID- 23657543 TI - Quantitative analysis of dendron-conjugated cisplatin-complexed gold nanoparticles using scanning particle mobility mass spectrometry. AB - We report a high-resolution and traceable method to quantify the drug loading on nanoparticle-based cancer therapeutics, and demonstrate this method using a model cisplatin functionalized dendron-gold nanoparticle (AuNP) conjugate. Electrospray differential mobility analysis (ES-DMA) provides upstream size classification based on the electrical mobility of AuNP conjugates in aerosol form following electrospray conversion from the aqueous suspension. A condensation particle counter (CPC) and inductively coupled plasma mass spectrometer (ICP-MS) provide the principal downstream quantification. CPC and ICP-MS yield complementary number-based and elemental mass-based particle size distributions, respectively. Conjugation using three different dendron formulations was differentiated based on changes in the mean mobility particle size. The subsequent cisplatin complexation to the dendron conjugates was quantified by coupling ES-DMA with ICP MS. Discrete AuNP clusters (e.g., dimers, trimers) could be resolved from the relative quantity of atoms (i.e., Au and Pt) per particle after separation by ES DMA. Surface density of cisplatin on Au was shown to be proportional to the density of carboxylic groups present and was independent of the state of AuNP clustering. Additionally, we found that colloidal stability of the conjugate is inversely proportional to the surface loading of cisplatin. This study demonstrates a prototype methodology to provide traceable quantification and to determine other important formulation factors relevant to therapeutic performance. PMID- 23657544 TI - Fate of pathogenic bacteria in microcosms mimicking human body sites. AB - During the infectious process, pathogens may reach anatomical sites where they are exposed to substances interfering with their growth. These substances can include molecules produced by the host, and his resident microbial population, as well as exogenous antibacterial drugs. Suboptimal concentrations of inhibitory molecules and stress conditions found in vivo (high or low temperatures, lack of oxygen, extreme pH) might induce in bacteria the activation of survival mechanisms blocking their division capability but allowing them to stay alive. These "dormant" bacteria can be reactivated in particular circumstances and would be able to express their virulence traits. In this study, it was evaluated the effect of some environmental conditions, such as optimal and suboptimal temperatures, direct light and antibiotic sub-inhibitory concentrations doses of antibiotic, on the human pathogens Escherichia coli and Enterococcus faecalis when incubated in fluids accumulated in the body of patients with different pathologies. It is shown that inoculation in a number of accumulated body fluids and the presence of gentamicin, reliable conditions encountered during pathological states, induce stress-responding strategies enabling bacteria to persist in microcosms mimicking the human body. Significant differences were detected in Gram-negative and Gram-positive species with E. faecalis surviving, as starved or viable but non-culturable forms, in any microcosm and condition tested and E. coli activating a viable but non-culturable state only in some clinical samples. The persistence of bacteria under these conditions, being non culturable, might explain some recurrent infections without isolation of the causative agent after application of the standard microbiological methods. PMID- 23657545 TI - Continuous flow blood pumps: the new gold standard for advanced heart failure? PMID- 23657546 TI - Intraoperative neuroprotective drugs without beneficial effects? Results of the German Registry for Acute Aortic Dissection Type A (GERAADA). AB - OBJECTIVES: Cerebral protection during acute aortic dissection Type A (AADA) surgery may be affected by perfusion strategies and ischaemic protective drugs. METHODS: We analysed the impact of intraoperative barbiturate, steroid and mannitol use and adjunctive cerebral perfusion (CP), on 30-day mortality and new postoperative mortality-corrected permanent neurological dysfunction (PNDmc) in the German Registry for Acute Aortic Dissection Type A. RESULTS: Two thousand one hundred and thirty-seven AADA patients were registered over a 4-year period. The overall 30-day mortality was 16.9%, and the overall rate of PNDmc was 10.0%. A total of 48% of patients received no neuroprotective drugs (control group), steroid monotherapy was used in 11.2% of patients, barbiturates in 8.4%, mannitol in 7.3% and the remainder (25.1%) received a combination of these drugs. The PNDmc rate was 10.6% in the control group and lower (7.1%) in the steroid group (adjusted odds ratio [OR] 0.50; 95% confidence interval [95% CI] 0.24-0.96; P = 0.049). No PNDmc reduction was observed for mannitol or barbiturates. Thirty-day mortality was 18.7% in the control group and with 8.9% lower (P = 0.003) in the mannitol group (adjusted OR 0.58; 95% CI 0.19-1.49; P = 0.295). Hypothermic circulatory arrest that exceeded 30 min was associated with an increased 30-day mortality rate (31.4%) compared with patients who received adjunctive CP >30 min during aortic arch intervention (21.4%) (P = 0.04). We were unable to demonstrate a significant protective effect of any neuroprotective drug on 30-day mortality, or PNDmc rates during prolonged (>=30 min) cerebral ischaemia. CONCLUSION: Mannitol may be associated with decreased mortality in patients undergoing AADA surgery. Steroid administration may be associated with improved neurological outcomes, but more investigation is required. PMID- 23657547 TI - Is lobectomy really more effective than sublobar resection in the surgical treatment of second primary lung cancer? AB - OBJECTIVES: Sublobar resection for early-stage lung cancer is still a controversial issue. We sought to compare sublobar resection (segmentectomy or wedge resection) with lobectomy in the treatment of patients with a second primary lung cancer. METHODS: From January 1995 to December 2010, 121 patients with second primary lung cancer, classified by the criteria proposed by Martini and Melamed, were treated at our Institution. We had 23 patients with a synchronous tumour and 98 with metachronous. As second treatment, we performed 61 lobectomies (17 of these were completion pneumonectomies), 38 atypical resections and 22 segmentectomies. Histology was adenocarcinoma in 49, squamous in 38, bronchoalveolar carcinomas in 14, adenosquamous in 8, large cells in 2, anaplastic in 5 and other histologies in 5. RESULTS: Overall 5-year survival from second surgery was 42%; overall operative mortality was 2.5% (3 patients), while morbidity was 19% (22 patients). Morbidity was comparable between the lobectomy group, sublobar resection and completion pneumonectomies (12.8, 27.7 and 30.8%, respectively, P = 0.21). Regarding the type of surgery, the lobectomy group showed a better 5-year survival than sublobar resection (57.5 and 36%, respectively, P = 0.016). Compared with lobectomies, completion pneumonectomies showed a significantly less-favourable survival (57.5 and 20%, respectively, P = 0.001). CONCLUSIONS: From our experience, lobectomy should still be considered as the treatment of choice in the management of second primary lung cancer, but sublobar resection remains a valid option in high-risk patients with limited pulmonary function. Completion pneumonectomy was a negative prognostic factor in long-term survival. PMID- 23657548 TI - Predicting systolic anterior motion after mitral valve reconstruction: using intraoperative transoesophageal echocardiography to identify those at greatest risk. AB - OBJECTIVES: We set out to determine if intraoperative pre-bypass transoesophageal echocardiography could assist in predicting which patients are at greatest risk for systolic anterior motion (SAM) after mitral valve repair (MVR). METHODS: Three hundred and seventy-five consecutive patients who underwent reconstructive MVR surgery for degenerative disease were included. Data were collected using intraoperative echocardiographic images taken prior to the initiation of cardiopulmonary bypass. Based on the physiology of SAM, we postulated that 11 parameters could be potential risk factors for SAM: left ventricular ejection fraction (LVEF), left ventricular end-systolic dimension, left ventricular end diastolic dimension (LVEDD), basal septal diameter (basal-interventricular septal diameter in diastole (IVDd)), mid-ventricular septal diameter (mid-IVDd), coaptation-septal distance (c-sept), anterior leaflet height, posterior leaflet height, aorto-mitral angle, mitral annular diameter and left atrial diameter. These parameters were measured and recorded by a blinded single operator. Independent predictors of SAM were identified using multiple logistic regression analysis. RESULTS: Of the 375 patients, 345 (92%) did not develop SAM (No-SAM group), while 30 (8%) developed intraoperative or postoperative SAM (SAM group). The mean age was 56.8 +/- 12.8 and 56.7 +/- 13.8 in the No-SAM and SAM groups, respectively. The incidence of fibroelastic deficiency, forme fruste and Barlow's disease was similar in both groups. All patients received a complete annuloplasty ring as part of the repair. There was no statistical difference in the mean ring size used in each group. EF was similar in the No-SAM (56.2% +/- 8.1) and SAM (57.0% +/- 9.2) P = 0.63) groups. Independent predictors of developing SAM after valve repair were: EDD <45 mm [odds ratio (OR) 3.90; P = 0.028], aorto-mitral angle <120 degrees (OR 2.74; P = 0.041), coaptation-septum distance <25 mm (OR 5.09; P = 0.003), posterior leaflet height >15 mm (OR 3.80; P = 0.012) and basal septal diameter >= 15 mm (OR 3.63; P = 0.039). CONCLUSIONS: The risk for SAM can be predicted using intraoperative transoesophageal echocardiography. The combination of a smaller left ventricle, tall posterior leaflet, narrow aorto mitral angle and enlarged basal septum significantly increases the risk for SAM. Knowing these parameters prior to valve repair can assist the surgeon in adjusting their repair technique to minimize the risk. PMID- 23657549 TI - Survival in patients with acute kidney injury requiring dialysis after coronary artery bypass grafting. AB - OBJECTIVES: The aim was a nationwide analysis of need for dialysis and survival in all patients who had coronary artery bypass grafting (CABG) in Sweden during 2002 up to 2008. METHODS: Primary isolated CABG was performed in 28 220 patients without preoperative need for dialysis. Survival was analysed in patients suffering postoperative acute kidney injury requiring dialysis. RESULTS: Postoperative dialysis was needed in 162 patients (0.6%). Old age, female gender, reduced glomerular filtration rate (GFR), diabetes mellitus, peripheral vascular disease, chronic obstructive pulmonary disease, prior myocardial infarction, prior stroke and reduced left ventricular function were associated with need for dialysis. Only 0.3% of the patients with GFR>60 ml/min/1.73 m2 needed postoperative dialysis compared with 9.5% if GFR was <30 ml/min/1.73 m2. Sixteen of 54 patients (27%) with GFR<30 l/min/1.73 m2 and a >=50% increase in postoperative serum creatinine needed dialysis. There were 42 deaths (26%) within 30 days in patients who needed dialysis and 1% if dialysis was not required. Early mortality was markedly higher in patients who required dialysis than in those without dialysis after multivariable adjustment for age, sex, diabetes mellitus, left ventricular function and GFR (odds ratio 19, 95% confidence interval 13-29). The corresponding risk of late death was 2-fold higher in patients who survived for 90 days and had required dialysis compared with those who did not (hazard ratio 2.4, 95% confidence interval 1.7-3.3). Five-year survival was 43 and 89%, respectively. The risk of death increased with age. Five year survival after dialysis was 66% in patients younger than 65 years, but 32% in those aged over 70 years. Fifty-one per cent (14 of 27) of patients 80 years of age or older who required dialysis died early compared with 3% (68 of 2426) of those who did not (P<0.001). Nine survivors who needed dialysis developed end stage renal disease. CONCLUSIONS: Need for dialysis after non-emergency was an uncommon serious complication associated with high early mortality and an increased risk of late death. Old age and impaired preoperative renal function were strong predictors of need for dialysis after CABG. Postoperative dialysis after CABG was a marker of poor outcome but could, in some patients, be life saving. PMID- 23657550 TI - Safe, effective and durable epicardial left atrial appendage clip occlusion in patients with atrial fibrillation undergoing cardiac surgery: first long-term results from a prospective device trial. AB - OBJECTIVES: Atrial fibrillation (AF) is a significant risk factor for embolic stroke originating from the left atrial appendage (LAA). This is the first report of long-term safety and efficacy data on LAA closure using a novel epicardial LAA clip device in patients undergoing cardiac surgery. METHODS: Forty patients with AF were enrolled in this prospective 'first-in-man' trial. The inclusion criterion was elective cardiac surgery in adult patients with AF for which a concomitant ablation procedure was planned. Intraoperative transoesophageal echocardiography (TEE) was used to exclude LAA thrombus at baseline and evaluate LAA perfusion after the procedure, while computed tomography (CT) was used for serial imagery workup at baseline, 3-, 12-, 24- and 36-month follow-up. RESULTS: Early mortality was 10% due to non-device-related reasons, and thus 36 patients were included in the follow-up consisting of 1285 patient-days and mean duration of 3.5 +/- 0.5 years. On CT, clips were found to be stable, showing no secondary dislocation 36 months after surgery. No intracardial thrombi were seen, none of the LAA was reperfused and in regard to LAA stump, none of the patients demonstrated a residual neck >1 cm. Apart from one unrelated transient ischaemic attack (TIA) that occurred 2 years after surgery in a patient with carotid plaque, no other strokes and/or neurological events demonstrated in any of the studied patients during follow-up. CONCLUSION: This is the first prospective trial in which concomitant epicardial LAA occlusion using this novel epicardial LAA clip device is 100% effective, safe and durable in the long term. Closure of the LAA by epicardial clipping is applicable to all-comers regardless of LAA morphology. Minimal access epicardial LAA clip closure may become an interesting therapeutic option for patients in AF who are not amenable to anticoagulation and/or catheter closure. Further data are necessary to establish LAA occlusion as a true and viable therapy for stroke prevention. CLINICAL TRIAL REGISTRATION: The trial is registered at www.ClinicalTrials.gov, reference: NCT00567515. PMID- 23657551 TI - Transcatheter aortic valve implantation using anatomically oriented, marrow stromal cell-based, stented, tissue-engineered heart valves: technical considerations and implications for translational cell-based heart valve concepts. AB - OBJECTIVES: While transcatheter aortic valve implantation (TAVI) has rapidly evolved for the treatment of aortic valve disease, the currently used bioprostheses are prone to continuous calcific degeneration. Thus, autologous, cell-based, living, tissue-engineered heart valves (TEHVs) with regeneration potential have been suggested to overcome these limitations. We investigate the technical feasibility of combining the concept of TEHV with transapical implantation technology using a state-of-the-art transcatheter delivery system facilitating the exact anatomical position in the systemic circulation. METHODS: Trileaflet TEHVs fabricated from biodegradable synthetic scaffolds were sewn onto self-expanding Nitinol stents seeded with autologous marrow stromal cells, crimped and transapically delivered into the orthotopic aortic valve position of adult sheep (n = 4) using the JenaValve transapical TAVI System (JenaValve, Munich, Germany). Delivery, positioning and functionality were assessed by angiography and echocardiography before the TEHV underwent post-mortem gross examination. For three-dimensional reconstruction of the stent position of the anatomically oriented system, a computed tomography analysis was performed post mortem. RESULTS: Anatomically oriented, transapical delivery of marrow stromal cell-based TEHV into the orthotopic aortic valve position was successful in all animals (n = 4), with a duration from cell harvest to TEHV implantation of 101 +/ 6 min. Fluoroscopy and echocardiography displayed sufficient positioning, thereby entirely excluding the native leaflets. There were no signs of coronary obstruction. All TEHV tolerated the loading pressure of the systemic circulation and no acute ruptures occurred. Animals displayed intact and mobile leaflets with an adequate functionality. The mean transvalvular gradient was 7.8 +/- 0.9 mmHg, and the mean effective orifice area was 1.73 +/- 0.02 cm(2). Paravalvular leakage was present in two animals, and central aortic regurgitation due to a single leaflet prolapse was detected in two, which was primarily related to the leaflet design. No stent dislocation, migration or affection of the mitral valve was observed. CONCLUSIONS: For the first time, we demonstrate the technical feasibility of a transapical TEHV delivery into the aortic valve position using a commercially available and clinically applied transapical implantation system that allows for exact anatomical positioning. Our data indicate that the combination of TEHV and a state-of-the-art transapical delivery system is feasible, representing an important step towards translational, transcatheter based TEHV concepts. PMID- 23657552 TI - Heart transplant systolic and diastolic function is impaired by prolonged pretransplant graft ischaemic time and high donor age: an echocardiographic study. AB - OBJECTIVES: Due to the need for suitable donors for heart transplantation (HTx), older grafts and grafts with prolonged graft ischaemic time (GIT) are accepted. The impact of GIT and donor age on post-transplant cardiac function has not been examined with either newer echocardiographic techniques (tissue Doppler imaging, TDI) or cardiopulmonary exercise testing (CPET). Thus, we studied the influence of GIT and donor age on post-transplant cardiac function and exercise capacity. METHODS: Fifty-two stable recipients underwent echocardiography with colour TDI and CPET at a median of 4 years after HTx. Left ventricular (LV) systolic (s') and early diastolic (e') mitral annular velocities, right ventricular (RV) s', RVe' as well as LV ejection fraction (EF) and VO(2peak) were analysed. RESULTS: HTx recipients with GIT >= median value (200 min) had significantly lower septal LVs' (15%, P = 0.005), LVEF (9%, P = 0.015), RVs' (21%, P = 0.007), septal LVe' (22%, P = 0.001) and RVe' velocities (23%, P = 0.011), and slightly lower VO(2peak) (P = 0.098). Recipients with grafts from donor >= median age (37 years) had significantly lower LVe' velocities (septal LVe' P = 0.047 and lateral LVe' P = 0.010), but not LV systolic or RV parameters. CONCLUSIONS: Prolonged GIT impairs both systolic and diastolic function at the interventricular septum and RV free wall, while increasing donor age impairs LV diastolic function. The duration of graft ischaemia and donor age should be taken into account when evaluating for cardiac dysfunction in HTx recipients. PMID- 23657553 TI - Spatial processing: Place cells as route planners. PMID- 23657555 TI - Learning and memory: Learning with peaks and troughs. PMID- 23657559 TI - Predation-risk effects of predator identity on the foraging behaviors of frugivorous bats. AB - Predators directly and indirectly affect the density and the behavior of prey. These effects may potentially cascade down to lower trophic levels. In this study, we tested the effects of predator calls (playbacks of bird vocalizations: Tyto alba, Speotyto cunicularia, and Vanellus chilensis), predator visual stimuli (stuffed birds) and interactions of visual and auditory cues, on the behavior of frugivore phyllostomid bats in the field. In addition, we tested if the effects of predation risk cascade down to other trophic levels by measuring rates of seed dispersal of the tree Muntingia calabura. Using video recording, we found that bats significantly decreased the foraging frequency on trees when a visual cue of T. alba was present. However, no stimuli of potential predatory birds, including vocalization of T. alba, affected bat foraging frequency. There was a change in bat behavior during 7 min, but then their frequency of activity gradually increased. Consequently, the presence of T. alba decreased by up to ten times the rate of seed removal. These results indicate that risk sensitivity of frugivorous phyllostomid bats depends on predator identity and presence. Among the predators used in this study, only T. alba is an effective bat predator in the Neotropics. Sound stimuli of T. alba seem not to be a cue of predation risk, possibly because their vocalizations are used only for intraspecific communication. This study emphasizes the importance of evaluating different predator stimuli on the behavior of vertebrates, as well as the effects of these stimuli on trait mediated trophic cascades. PMID- 23657561 TI - Pathophysiology of GHRH-growth hormone-IGF1 axis in HIV/AIDS. AB - Aberrations in GHRH-GH -IGF-I axis are common in the complex of HIV, HAART and AIDS. There are 2 distinct mechanisms at play in HIV and AIDS. One is primarly associated with development of lipodystrophy and results in complications such as chronic inflammation, insulin resistance, lipid and metabolic abnormalities. HIV lipodystrophy is found especially in those on highly active anti-retroviral therapy (HAART). The various processes involved in lipodystrophy result in the suppression of pituitary GH production. The mechanism of low GH levels relates to increased somatostatin tone, decreased Ghrelin, increased free fatty acids (FFA) and insulin resistance. On the other hand in AIDS wasting syndrome; elevated GH and low IGF-1 levels are seen suggesting GH resistance. The GHRH analog Tesamorelin is the only treatment option, which is FDA approved for use in reduction of excess abdominal fat in patients with HIV-associated lipodystrophy. Although long-term clinical trials and experience is needed to further study the benefits and risks of Tesamorelin. PMID- 23657560 TI - Antioxidant treatment strategies for hyperphenylalaninemia. AB - Hyperphenylalaninemia (HPA) leads to increased oxidative stress in patients with phenylketonuria (PKU) and in animal models of PKU. Early diagnosis and immediate adherence to a phenylalanine-restricted diet prevents HPA and, consequently, severe brain damage. However, treated adolescent and adult PKU patients have difficulties complying with the diet, leading to an oscillation of phenylalanine levels and associated oxidative stress. The brain is especially susceptible to reactive species, and oxidative stress might add to the impaired cognitive function found in these patients. The restricted PKU diet has a very limited nutrient content from natural foods and almost no animal protein, which reduces the intake of important compounds. These specific compounds can act as scavengers of reactive species and can be co-factors of antioxidant enzymes. Supplementation with nutrients, vitamins, and tetrahydropterin has given quite promising results in patients and animal models. Antioxidant supplementation has been studied in HPA, however there is no consensus about its always beneficial effects. In this way, regular exercise could be a beneficial addition on antioxidant status in PKU patients. A deeper understanding of PKU molecular biochemistry, and genetics, as well as the need for improved targeted treatment options, could lead to the development of new therapeutic strategies. PMID- 23657562 TI - Bone and vitamin D metabolism in HIV. AB - Human immunodeficiency virus (HIV) infection has progressed to a chronic disease and HIV positive individuals are living longer lives. This has lead to an increase in morbidity and mortality due to secondary issues, one being HIV bone disease. HIV infected pediatric and adult populations have a greater incidence in reduction of BMD as compared to the controls. Osteoporosis has been reported to be present in up to 15 % of HIV positive patients. We are starting to understand the mechanism behind the changes in HIV bone disease. Viral proteins interfere with osteoblastic activity either by direct interaction or by the inflammatory process that they induce. Anti-viral management, including highly active antiretroviral therapy (HAART), protease inhibitors, and nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) also are involved in disrupting proper bone metabolism. Vitamin D levels have strong correlation with bone disease in HIV patients, and are dependent not only to chronic disease state, but interaction of pharmacologic management and inflammatory process as well. Work up of the secondary causes of osteopenia and osteoporosis should be undertaken in all patients. DEXA scan is recommended in all post-menopausal women with HIV, all HIV infected men 50 years of age or older and in those with a history of fragility fractures regardless of age or gender. Preventive measures include adequate nutrition, calcium and Vitamin D intake daily, muscle strengthening and balance exercises to increase BMD and reduce fractures. Bisphosphonates are considered to be the first line for the treatment of HIV associated bone disease. This review will describe how the balanced mechanism of bone metabolism is interrupted by the HIV infection itself, the complications that arise from HIV/AIDS, and its treatment options. PMID- 23657564 TI - Threaded structures based on the benzo-21-crown-7/secondary ammonium salt recognition motif using esters as end groups. AB - It was demonstrated that various threaded structures could be constructed by employing different esters as end groups based on the benzo-21-crown-7/secondary ammonium salt recognition motif. The chemical structures of all synthesized compounds were confirmed by (1)H and (13)C NMR spectroscopy as well as mass spectrometry. Single crystal X-ray analysis revealed that all compounds are threaded structures in the solid state. NMR experiments distinguished the rotaxane-like entities from [2]rotaxanes. The threaded structures capped by linear n-alkyl end groups are rotaxane-like entities. The gradual elongation of the ester alkyl chain tails results in the increased stability of the corresponding threaded structures. When the tail is an isopropyl group, a mechanically interlocked rotaxane can be constructed. PMID- 23657563 TI - Glucagon-like peptide-1 receptor agonist liraglutide inhibits endothelin-1 in endothelial cell by repressing nuclear factor-kappa B activation. AB - PURPOSE: The increase in endothelin-1 (ET-1) and the decrease in endothelial nitric oxide synthase (eNOS) both induce vasoconstriction and lead to molecular changes associated with diabetes mellitus and atherosclerosis. Glucagon-like peptide-1 (GLP-1) activation stimulates insulin secretion and may prevent atherosclerosis by increasing eNOS synthesis. However, there is paucity of information on the effect of GLP-1 activation on ET-1 expression. This study was conducted to address this issue. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) were incubated with different concentrations of liraglutide, a GLP-1 agonist, and the expression of ET-1 and eNOS and activity of NF-kappaB were measured. Liraglutide, in a concentration-dependent manner, was observed to promote eNOS expression and to inhibit ET-1 expression both at mRNA and protein levels. Liraglutide also inhibited NF-kappaB phosphorylation and its translocation from cytoplasm to the nucleus. To ascertain the role of NF-kappaB activation in the altered expression of ET-1 and eNOS, we treated HUVECs with phorbol 12-myristate 13-acetate (PMA). PMA activated NF-kappaB and reversed the effects of liraglutide on eNOS and ET-1 expression. The effects of PMA on eNOS and ET-1 expression were reproduced in experiments wherein cells were treated with TNF-alpha. Further, we measured the generation of IL-6, apowerful pro inflammatory molecule released by endothelial cells, as a measure of cellular function. PMA increased IL-6 generation, and this effect was blocked by liraglutide. CONCLUSIONS: Our observations suggest liraglutide suppresses ET-1 expression by inhibiting the phosphorylation of NF-kappaB. This mechanism may underlie the potential anti-atherosclerotic effects of GLP-1 agonists. Of note, these effects of liraglutide were seen in an in vitro setting wherein cellular glucose concentrations were elevated. PMID- 23657567 TI - Targeting endothelial adhesion molecule mRNA to control inflammation: novel insights into potential anti-inflammatory effects of IL-19. Focus on "Interleukin 19 decreases leukocyte-endothelial cell interactions by reduction in endothelial cell adhesion molecule mRNA stability". PMID- 23657566 TI - Matrix metalloproteinase 9 is a distal-less 3 target-gene in placental trophoblast cells. AB - Matrix metalloproteinases (MMPs) are enzymes that regulate extracellular matrix composition and contribute to cell migration. Microarray studies in mouse placenta suggested that MMP-9 transcript abundance was dependent on distal-less 3 (Dlx3), a placental-specific transcriptional regulator; however, it was not clear if this was a direct or indirect effect. Here we investigate mechanism(s) for Dlx3-dependent MMP-9 gene transcription and gelatinase activity in placental trophoblasts. Initial studies confirmed that MMP-9 activity was reduced in placental explants from Dlx3(-/-) mice and that murine MMP-9 promoter activity was induced by Dlx3 overexpression. Two binding sites within a murine MMP-9 promoter fragment bound Dlx3, and mutations in both elements reduced basal MMP-9 luciferase reporter activity and abolished regulation by Dlx3. Chromatin immunoprecipitation studies in JEG3 cells confirmed Dlx3 binding to the endogenous human MMP-9 promoter at three distinct sites and knockdown of human Dlx3 resulted in reduced endogenous MMP-9 transcripts and secreted activity. These studies provide novel evidence that Dlx3 is involved directly in the transcriptional regulation of mouse and human MMP-9 gene expression in placental trophoblasts. PMID- 23657569 TI - Altered phenotypic gene expression of 10T1/2 mesenchymal cells in nonuniformly stretched PEGDA hydrogels. AB - Disease-related phenotype modulation of many cell types has been shown to be closely related to mechanical loading conditions; for example, vascular smooth muscle cell (SMC) phenotype shift from a mature, contractile state to a proliferative, synthetic state contributes to the formation of neointimal tissue during atherosclerosis and restenosis development and is related to SMC mechanical loading in vivo. The majority of past in vitro cell-stretching experiments have employed simplistic (uniform, uniaxial or biaxial) stretching environments to elucidate mechanobiological pathways involved in phenotypic shifts. However, the in vivo mechanics of the vascular wall consists of highly nonuniform stretch. Here we subjected 10T1/2 murine mesenchymal cells (an SMC precursor) to two- and three-dimensional nonuniform stretch environments. After 24 h of stretch, cells on an elastomeric membrane demonstrated varied proliferation [assessed by 5-bromo-2'-deoxyuridine (BrdU) incorporation] depending on location upon the membrane, with maximal proliferation occurring in a region of high, uniaxial stretch. Cells subjected to a nonuniform stretching regimen within three-dimensional polyethylene glycol diacrylate (PEGDA) hydrogel constructs demonstrated marked changes in mRNA expression of several phenotype related proteins, indicating a sort of "hybrid" phenotype with contractile and synthetic markers being both upregulated and downregulated. Furthermore, expression levels of mRNAs were significantly different between various locations within the stretched gel. With the proliferation results, these data exhibit the capability of nonuniform stretching devices to induce heterogeneous cell responses, potentially indicative of spatial distributions of disease-related behaviors in vivo. PMID- 23657568 TI - NHE8 plays an important role in mucosal protection via its effect on bacterial adhesion. AB - The Na+/H+ exchanger NHE8 is expressed on the apical membrane of intestinal epithelial cells and is particularly abundant in the colon. Our previous study showed that Muc2 expression was significantly reduced in NHE8-knockout (NHE8-/-) mice, suggesting that NHE8 plays a role in mucosal protection in the colon. The current study confirms and extends our studies on the role of NHE8 in mucosal protection. The number of bacteria attached on the distal colon was significantly increased in NHE8-/- mice compared with their wild-type littermates. As expected, IL-4 expression was markedly increased in NHE8-/- mice compared with wild-type mice. Immunohistochemistry showed disorganization in the mucin layer of NHE8-/- mice, suggesting a possible direct bacteria-epithelia interaction. Furthermore, NHE8-/- mice were susceptible to dextran sodium sulfate-induced mucosal injury. In wild-type mice, dextran sodium sulfate treatment inhibited colonic NHE8 expression. In Caco-2 cells, the absence of NHE8 expression resulted in higher adhesion rates of Salmonella typhimurium but not Lactobacillus plantarum. Similarly, in vivo, S. typhimurium adhesion rate was increased in NHE8-/- mice compared with wild-type mice. Our study suggests that NHE8 plays important roles in protecting intestinal epithelia from infectious bacterial adherence. PMID- 23657570 TI - Opposing effects of podocin on the gating of podocyte TRPC6 channels evoked by membrane stretch or diacylglycerol. AB - Gain-of-function mutations in the transient receptor potential (TRP) cation channel subfamily C member 6 (TRPC6) gene and mutations in the NPHS2 gene encoding podocin result in nephrotic syndromes. The purpose of this study was to determine the functional significance of biochemical interactions between these proteins. We observed that gating of TRPC6 channels in podocytes is markedly mechanosensitive and can be activated by hyposmotic stretch or indentation of the plasma membrane. Stretch activation of cationic currents was blocked by small interfering RNA knockdown of TRPC6, as well as by SKF-96365 or micromolar La(3+). Stretch activation of podocyte TRPC6 persisted in the presence of inhibitors of phospholipase C (U-73122) and phospholipase A2 (ONO-RS-082). Robust stretch responses also persisted when recording electrodes contained guanosine 5'-O-(2 thiodiphosphate) at concentrations that completely suppressed responses to ANG II. Stretch responses were enhanced by cytochalasin D but were abolished by the peptide GsMTx4, suggesting that forces are transmitted to the channels through the plasma membrane. Podocin and TRPC6 interact at their respective COOH termini. Knockdown of podocin markedly increased stretch-evoked activation of TRPC6 but nearly abolished TRPC6 activation evoked by a diacylglycerol analog. These data suggest that podocin acts as a switch to determine the preferred mode of TRPC6 activation. They also suggest that podocin deficiencies will result in Ca(2+) overload in foot processes, as with gain-of-function mutations in the TRPC6 gene. Finally, they suggest that mechanical activation of TRP family channels and the preferred mode of TRP channel activation may depend on whether members of the stomatin/prohibitin family of hairpin loop proteins are present. PMID- 23657571 TI - Increasing our IQ of vascular smooth muscle cell migration with IQGAP1. Focus on "IQGAP1 links PDGF receptor-beta signal to focal adhesions involved in vascular smooth muscle cell migration: role in neointimal formation after vascular injury". PMID- 23657572 TI - Potential link between cysteinyl-leukotriene receptors and release of bioactive amino acids in regulation of lung function. Focus on "Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5 lipoxygenase". PMID- 23657574 TI - Pathology quiz case 2. Epithelioid hemangioendothelioma. PMID- 23657575 TI - Response to "Letter to the Editor" by Balta et al. entitled "Other inflammatory markers ought to be kept in mind when assessing the mean platelet volume in clinical practice". PMID- 23657573 TI - IQGAP1 links PDGF receptor-beta signal to focal adhesions involved in vascular smooth muscle cell migration: role in neointimal formation after vascular injury. AB - Platelet-derived growth factor (PDGF) stimulates vascular smooth muscle cell (VSMC) migration and neointimal formation in response to injury. We previously identified IQ-domain GTPase-activating protein 1 (IQGAP1) as a novel VEGF receptor 2 binding scaffold protein involved in endothelial migration. However, its role in VSMC migration and neointimal formation in vivo is unknown. Here we show that PDGF stimulation rapidly promotes IQGAP1 association with PDGF receptor beta (PDGFR) as well as IQGAP1 tyrosine phosphorylation in cultured VSMC. Overexpression or knockdown of IQGAP1 enhances or inhibits PDGFR autophosphorylation (p-PDGFR), respectively. Immunofluorescence and cell fractionation analysis reveals that PDGF-induced p-PDGFR localized in focal adhesions (FAs), but not caveolae/lipid rafts, is inhibited by IQGAP1 knockdown with siRNA. PDGF stimulation promotes IQGAP1 association with PDGFR/FA signaling protein complex. Functionally, IQGAP1 siRNA inhibits PDGF-induced FA formation as well as VSMC migration induced by PDGF. In vivo, IQGAP1 expression is markedly increased at neointimal VSMC in wire-injured femoral arteries. Mice lacking IQGAP1 exhibit impaired neointimal formation in response to vascular injury. In summary, IQGAP1, through interaction with PDGFR and FA signaling proteins, promotes activation of PDGFR in FAs as well as FA formation, which may contribute to VSMC migration and neointimal formation after injury. Our findings provide insight into IQGAP1 as a potential therapeutic target for vascular migration related diseases. PMID- 23657576 TI - Would an endosteal CI-electrode make sense? Comparison of the auditory nerve excitability from different stimulation sites using ESRT measurements and mathematical models. AB - Regarding potential endosteal cochlear implant electrodes, the primary goal of this paper is to compare different intra- and extra-cochlear stimulation sites in terms of current strengths needed for stimulating the auditory nerve. Our study was performed during routine cochlear implantation using needle electrodes for electric stimulation and by visually recording electrically elicited stapedius reflexes (ESRT) as a measure for the stimulus transfer. Of course this rather simple setup only allows rough estimations, which, however, may provide further arguments whether or not to proceed with the concept of an endosteal electrode. In addition, a mathematical model is being developed. In a pilot study, intra operative electric stimuli were applied via a needle electrode commonly used for the promontory stimulation test. Thus, stapedius reflex thresholds (ESRTs), electrically elicited via the needle from different points inside and outside the cochlea served as indicators for the suitability of different electrode positions towards the modiolus. Tests were performed on 11 CI-recipients. In addition, the extension of electrical fields from different stimulation sites is simulated in a mathematical cochlea model. In most patients ESRT measurements could be performed and evaluated. Thus an "endosteal" stimulation seems possible, although the current intensities must be higher than at intraluminal stimulation sites. Moreover, our model calculations confirm that the extension of electric fields is less favourable with increasing distance from the electrode to the ganglion nerve cells. In terms of hearing, the concept of an endosteal electrode should only be promoted, if its superiority for hearing preservation can be proven, e.g. in animal experiments. However, for other indications like the electric suppression of tinnitus, further research seems advisable. LEVELS OF EVIDENCE: N/A. PMID- 23657577 TI - The challenges and future of applied Islamic ethics discourse: a radical reform? AB - In this paper, I explore the concept of applied Islamic ethics, the facts, its challenges, and its future. I aim to highlight some of the deep-rooted issues that Muslims have faced historically and continue to experience today as they apply religious guidance to their daily lives. I consider the causes and rationale behind the current situation and look beyond to suggest ways in which this may evolve, calling for a radical reform. Muslims throughout the world are experiencing a deepening crisis of identity and confusion about their faith's principles and practices. I suggest how improvements might be achieved, in order to gain more coherence and understanding. This approach recognizes the importance of inviting an in-depth, deliberate analysis of relevant dialogues between religious experts of the text (scholars) and practitioners, those working at the grassroots. This approach remains faithful to the fundamental principles of the Islamic sources but also considers our present context. I recommend a shift in authority from scholars alone to a more inclusive, critical engagement of practitioners. Through this more comprehensive methodology of applied Islamic ethics, I suggest that Muslim communities, organizations, and individuals can remain faithful to their religious principles while, at the same time, actively participating in and contributing to our evolving societies. While I recognize that this will be a long process, I am confident that with applied Islamic ethics, the current feelings of confusion, self-doubt, and even apathy, given the previous failed processes of adaptation and reform, will give way to a new confidence in knowing how to address contemporary challenges. PMID- 23657578 TI - 'I hope that I get old before I die': ageing and the concept of disease. AB - Ageing is often deemed bad for people and something that ought to be eliminated. An important aspect of this normative aspect of ageing is whether ageing, i.e., senescence, is a disease. In this essay, I defend a theory of disease that concludes that ageing is not a disease, based on an account of natural function. I also criticize other arguments that lead to the same conclusion. It is important to be clear about valid reasons in this debate, since the failure of bad analyses is exploited by proponents of the view that ageing is indeed a disease. Finally, I argue that there could be other reasons for attempting to eradicate senescence, which have to do with an evaluative assessment of ageing in relation to the good life. I touch on some reasons why ageing might be good for people and conclude that we cannot justify generalized statements in this regard. PMID- 23657580 TI - Nobel prizes, chocolate and milk: the statistical view. PMID- 23657581 TI - Increased plasma beta-hydroxybutyrate levels during the fasting test in patients with endogenous hyperinsulinaemic hypoglycaemia. AB - OBJECTIVE: The objective of the present study was to determine whether a plasma beta-hydroxybutyrate (BOHB) level >2700 MUmol/l during the 72-h fasting test is sufficient to rule out the diagnosis of endogenous hyperinsulinaemic hypoglycaemia (EHH). RESEARCH DESIGN AND METHODS: We retrospectively studied BOHB levels in 39 patients with EHH who had undergone a 72-H fasting test to make the diagnosis of EHH, and we compared EHH patients with BOHB levels 2700 MOL/L (group 1), EHH PATIENTS with BOHB levels 2700 MOL/L (group 2) and 59 controls (median glycaemia: 3.2 mmol/l and median BOHB: 6095 MUmol/l). RESULTS: During a 72-h fasting test, nine patients (group 1) had BOHB levels >2700 MUmol/l (median 6140 and range 2957-7824) and 30 patients (group 2) had BOHB levels <2700 MUmol/l (median 542 and range 0-2607). In group 1, four patients had undergone partial pancreatectomy previously and were evaluated for the recurrence of hypoglycaemia, whereas none of the group 2 patients had been operated. The duration of the fasting test was longer in group 1 than in group 2 (P<0.0001), and at the end of the fasting test, plasma glucose concentrations were not significantly different (P=0.0617), but insulin (P=0.004), C-peptide (P=0.0015) and proinsulin (P=0.0038) levels were significantly lower in group 1 patients than in group 2 patients, suggesting lower insulin secretion and/or impaired glycaemic counter-regulation. CONCLUSION: During a fasting test, a BOHB level >2700 MUmol/l is observed in some EHH patients, suggesting that BOHB levels cannot rule out the recurrence of EHH, in particular, after partial pancreatectomy. PMID- 23657582 TI - Production of human lysozyme in biofilm reactor and optimization of growth parameters of Kluyveromyces lactis K7. AB - Lysozyme (1,4-beta-N-acetylmuramidase) is a lytic enzyme, which degrades the bacterial cell wall. Lysozyme has been of interest in medicine, cosmetics, and food industries because of its anti-bactericidal effect. Kluyveromyces lactis K7 is a genetically modified organism that expresses human lysozyme. There is a need to improve the human lysozyme production by K. lactis K7 to make the human lysozyme more affordable. Biofilm reactor provides high biomass by including a solid support, which microorganisms grow around and within. Therefore, the aim of this study was to produce the human lysozyme in biofilm reactor and optimize the growth conditions of K. lactis K7 for the human lysozyme production in biofilm reactor with plastic composite support (PCS). The PCS, which includes polypropylene, soybean hull, soybean flour, bovine albumin, and salts, was selected based on biofilm formation on PCS (CFU/g), human lysozyme production (U/ml), and absorption of lysozyme inside the support. To find the optimum combination of growth parameters, a three-factor Box-Behnken design of response surface method was used. The results suggested that the optimum conditions for biomass and lysozyme productions were different (27 degrees C, pH 6, 1.33 vvm for biomass production; 25 degrees C, pH 4, no aeration for lysozyme production). Then, different pH and aeration shift strategies were tested to increase the biomass at the first step and then secrete the lysozyme after the shift. As a result, the lysozyme production amount (141 U/ml) at 25 degrees C without pH and aeration control was significantly higher than the lysozyme amount at evaluated pH and aeration shift conditions (p < 0.05). PMID- 23657583 TI - Thermophilic biological nitrogen removal in industrial wastewater treatment. AB - Nitrification is an integral part of biological nitrogen removal processes and usually the limiting step in wastewater treatment systems. Since nitrification is often considered not feasible at temperatures higher than 40 degrees C, warm industrial effluents (with operating temperatures higher than 40 degrees C) need to be cooled down prior to biological treatment, which increases the energy and operating costs of the plants for cooling purposes. This study describes the occurrence of thermophilic biological nitrogen removal activity (nitritation, nitratation, and denitrification) at a temperature as high as 50 degrees C in an activated sludge wastewater treatment plant treating wastewater from an oil refinery. Using a modified two-step nitrification-two-step denitrification mathematical model extended with the incorporation of double Arrhenius equations, the nitrification (nitrititation and nitratation) and denitrification activities were described including the cease in biomass activity at 55 degrees C. Fluorescence in situ hybridization (FISH) analyses revealed that Nitrosomonas halotolerant and obligatehalophilic and Nitrosomonas oligotropha (known ammonia oxidizing organisms) and Nitrospira sublineage II (nitrite-oxidizing organism (NOB)) were observed using the FISH probes applied in this study. In particular, this is the first time that Nitrospira sublineage II, a moderatedly thermophilic NOB, is observed in an engineered full-scale (industrial) wastewater treatment system at temperatures as high as 50 degrees C. These observations suggest that thermophilic biological nitrogen removal can be attained in wastewater treatment systems, which may further contribute to the optimization of the biological nitrogen removal processes in wastewater treatment systems that treat warm wastewater streams. PMID- 23657584 TI - Non-enzymatic oxalic acid sensor using platinum nanoparticles modified on graphene nanosheets. AB - An enzyme-free oxalic acid (OA) electrochemical sensor was assembled using a platinum nanoparticle-loaded graphene nanosheets (PtNPGNs)-modified electrode. The PtNPGNs, with a high yield of PtNPs dispersed on the graphene nanosheets, were successfully achieved by a green, rapid, one-step and template-free method. The resulting PtNPGNs were characterized by transmission electron microscopy (TEM), high-resolution TEM, energy-dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, and an X-ray diffraction technique. Electrochemical oxidation of OA on the PtNPGNs-modified electrode was investigated by cyclic voltammetry and differential pulse voltammetry methods. Based on the results, the modified electrode exhibited high electrochemical activity with well-defined peaks of OA oxidation and a notably decreased overpotential compared to the bare or even the GNs-modified electrode. Under optimized conditions, a good linear response was observed for the concentration of OA and its current response was in the range of 0.1-15 mM and 15-50 mM with a detection limit (S/N = 3) of 10 MUM. Furthermore, the electrochemical sensor presented good characteristics in terms of stability and reproducibility, promising the applicability of the sensor in practical analysis. PMID- 23657585 TI - Streptomycin resistance-aided genome shuffling to improve doramectin productivity of Streptomyces avermitilis NEAU1069. AB - Genome shuffling is an efficient approach for the rapid engineering of microbial strains with desirable industrial phenotypes. In this study, a strategy of incorporating streptomycin resistance screening into genome shuffling (GS-SR) was applied for rapid improvement of doramectin production by Streptomyces avermitilis NEAU1069. The starting mutant population was generated through treatment of the spores with N-methyl-N'-nitro-N-nitrosoguanidine and ultraviolet (UV) irradiation, respectively, and five mutants with higher productivity of doramectin were selected as starting strains for GS-SR. Finally, a genetically stable strain F4-137 was obtained and characterized to be able to yield 992 +/- 4.4 mg/l doramectin in a shake flask, which was 7.3-fold and 11.2-fold higher than that of the starting strain UV-45 and initial strain NEAU1069, respectively. The doramectin yield by F4-137 in a 50-l fermentor reached 930.3 +/- 3.8 mg/l. Furthermore, the factors associated with the improved doramectin yield were investigated and the results suggested that mutations in ribosomal protein S12 and the enhanced production of cyclohexanecarboxylic coenzyme A may contribute to the improved performance of the shuffled strains. The random amplified polymorphic DNA analysis showed a genetic diversity among the shuffled strains, which confirmed the occurrence of genome shuffling. In conclusion, our results demonstrated that GS-SR is a powerful method for enhancing the production of secondary metabolites in Streptomyces. PMID- 23657588 TI - What next for the small renal mass? PMID- 23657586 TI - Improved xylose fermentation of Kluyveromyces marxianus at elevated temperature through construction of a xylose isomerase pathway. AB - To improve the xylose fermentation ability of Kluyveromyces marxianus, a xylose assimilation pathway through xylose isomerase was constructed. The genes encoding xylose reductase (KmXyl1) and xylitol dehydrogenase (KmXyl2) were disrupted in K. marxianus YHJ010 and the resultant strain was named YRL002. A codon-optimized xylose isomerase gene from Orpinomyces was transformed into K. marxianus YRL002 and expressed under GAPDH promoter. The transformant was adapted in the SD medium containing 1 % casamino acid with 2 % xylose as sole carbon source. After 32 times of trans-inoculation, a strain named YRL005, which can grow at a specific growth rate of 0.137/h with xylose as carbon source, was obtained. K. marxianus YRL005 could ferment 30.15 g/l of xylose and produce 11.52 g/l ethanol with a yield of 0.38 g/g, production rate of 0.069 g/l/h at 42 degrees C, and also could ferment 16.60 g/l xylose to produce 5.21 g/l ethanol with a yield of 0.31 g/g, and production rate of 0.054 g/l h at 45 degrees C. Co-fermentation with 2 % glucose could not improve the amount and yield of ethanol fermented from xylose obviously, but it could improve the production rate. Furthermore, K. marxianus YRL005 can ferment with the corn cob hydrolysate, which contained 20.04 g/l xylose to produce 8.25 g/l ethanol. It is a good platform to construct thermo tolerant xylose fermentation yeast. PMID- 23657589 TI - Reversal of target-specific oral anticoagulants. AB - The target-specific oral anticoagulants represent the first new oral anti thrombotic therapy in over 50 years and have the potential to make therapy easier and hence more accessible to many patients. Like any new therapy, the potential benefits must be weighed against the potential challenges and one of the most concerning aspects of the new target-specific oral anticoagulants is the lack of a proven method to reverse their effect. Unlike the vitamin K antagonist, i.e. warfarin, there is no specific antidote for these medications. This paper will review the limited data on the use of non-specific therapies to reverse anticoagulation for the new agents. We hope to prepare clinicians who are faced with a patient who has serious bleeding or needs emergent surgery while taking dabigatran, rivaroxaban or apixaban. PMID- 23657590 TI - Effect of okadaic acid on carpet shell clam (Ruditapes decussatus) haemocytes by in vitro exposure and harmful algal bloom simulation assays. AB - Okadaic acid (OA), produced by dinoflagellates during harmful algal blooms (HAB), belongs to the Diarrheic Shellfish Poisoning toxins that cause gastrointestinal symptoms in humans after consumption. In the present work, Ruditapes decussatus haemocytes were selected to evaluate the effect of OA on cell viability, enzymatic status and immune capacity through the measure by flow cytometry of apoptosis-cell death, non-specific esterase activity and phagocytosis. In order to compare different exposure conditions, two experiments were developed: in vitro exposure to OA and HAB simulation by feeding clams with the OA producer, Prorocentrum lima. Apoptosis was not OA dose-dependent and cell death increased in both assays. Phagocytosis of latex beads and esterase activity decreased in haemocytes incubated with OA. In contrast, esterases increased during the feeding with P. lima. Our results showed that OA and the simulated HAB caused damages on haemocyte functions and viability. PMID- 23657591 TI - Nanofiber-based polyethersulfone scaffold and efficient differentiation of human induced pluripotent stem cells into osteoblastic lineage. AB - Human induced pluripotent stem cells (iPSCs) have been shown to have promising potential for regenerative medicine and tissue engineering applications. In the present study, osteogenic differentiation of human iPSCs was evaluated on polyethersulfone (PES) nanofibrous scaffold. According to the results, higher significant expressions of common osteogenic-related genes such as runx2, collagen type I, osteocalcin and osteonectin was observed in PES seeded human iPSCs compared with control. Alizarin red staining and alkaline phosphatase activity of differentiated iPSCs demonstrated significant osteoblastic differentiation potential of these cells. In this study biocompatibility of PES nanofibrous scaffold confirmed by flattened and spreading morphology of iPSCs under osteoblastic differentiation inductive culture. Taking together, nanofiber based PES scaffold seeded iPSCs showed the highest capacity for differentiation into osteoblasts-like cells. These cells and PES scaffold were demonstrated to have great efficiency for treatment of bone damages and lesions. PMID- 23657592 TI - Angiotensin-converting enzyme insertion/deletion polymorphism genotyping error: the cause and a possible solution to the problem. AB - Rigat and colleagues were the first ones to develop a rapid PCR-based assay for identifying the angiotensin converting enzyme insertion/deletion (I/D) polymorphism. Due to a big difference between the length of the wild-type and mute alleles the PCR method is prone to mistyping because of preferential amplification of the D allele causing depicting I/D heterozygotes as D/D homozygotes. The aim of this study was to investigate whether this preferential amplification can be repressed by amplifying a longer DNA fragment in a so called Long PCR protocol. We also aimed to compare the results of genotyping using five different PCR protocols and to estimate the mistyping rate. The study included 200 samples which were genotyped using standard method used in our laboratory, a stepdown PCR, PCR protocol with the inclusion of 4 % DMSO, PCR with the use of insertion specific primers and new Long PCR method. The results of this study have shown that accurate ACE I/D polymorphism genotyping can be accomplished with the standard and the Long PCR method. Also, as of our results, accurate ACE I/D polymorphism genotyping can be accomplished regardless of the method used. Therefore, if the standard method is optimized more cautiously, accurate results can be obtained by this simple, inexpensive and rapid PCR protocol. PMID- 23657593 TI - Sequence analysis and identification of new variations in the 5'-flanking region of alphaS2-casein gene in Indian zebu cattle. AB - Regulatory region of milk protein alpha S2-casein (alphaS2-CN) gene sequence was characterized and analyzed for nucleotide variations in animals representing 13 Indian zebu cattle (Bos indicus) breeds. A total of 15 variations; 11 in promoter region (1.56 Kb): -1481 (C>T), -1412 (C>T), -1342 (C>T), -1084 (G>A), -979 (A>G), -657 (A>T), -508 (A>G), -186 (T>C), -184 (T>C), -151 (T>C) and -135 (C>T); 1 in 5'-UTR (44 bp): 7 (C>T) while, 3 in intron-I region (73 bp): 186 (C>T), 194 (A>C) and 301 (A>T) were identified. Additionally, single deletion was observed at -975 (A>-) but not involve any known potential transcription factor binding sites (TFBS). Comparison with Bos taurus sequence revealed two additional variations 1085 (T>C) and -739 (A>G). Out of the total 18 variations observed between indicine and taurine alphaS2-CN regulatory region sequence, 15 were novel to B. indicus and are reported for the first time. Among these, four variations were located within the potential TFBSs; -1342 (C>T) within HNF-3beta, -739 (A>G) within C/EBP-alpha while -657 (A>T) and -508 (A>G) were found within glucocorticoid receptor TFBSs. Variations located within or in proximity to putative TFBSs could possibly influence the binding affinity of nuclear factors towards DNA binding domains, thus affecting transcriptional rate of alphaS2-CN gene. Phylogenetically, as expected, Indian zebu cattle were grouped close to B. taurus and were most distantly placed in comparison to human. The study indicated possible genetic variations in the regulatory regions of alphaS2-CN gene within Indian native cattle (B. indicus) and also its comparison with evolutionary different B. taurus breeds. PMID- 23657594 TI - mRNA expression pattern and association study with growth traits of bovine vaspin gene. AB - Visceral adipose tissue-derived serine protease inhibitor (vaspin) is an interesting novel adipocytokine with insulin-sensitizing effects. Some studies have suggested that vaspin could play an important role in the development of obesity and metabolic disorders. However, the tissue expression patterns in cattle and impact of vaspin gene variants on the growth traits has not been determined yet. Herein, we firstly investigated the tissue expression patterns of vaspin gene in new born and adult cattle. The results showed that vaspin was ubiquitously expressed in most tissues and strongly expressed in the heart, skeletal muscle and fat. Then, genetic variants within bovine vaspin gene were screened in 1235 individuals from five Chinese indigenous cattle breeds. Two novel mutations in coding region (NW_001494061: g.1124477 G>A and g.1118561 T>C) of bovine vaspin gene were identified using MspI PCR-RFLP and HhaI ACRS PCR-RFLP detection. Association analysis revealed both two mutations were significantly associated with bodyweight and chest girth at 24 months in cattle (P < 0.05). Therefore, the MspI and HhaI genetic variants of bovine vaspin gene were recommended as DNA markers related to growth traits through marker-assisted selection for genetics and breeding in cattle. PMID- 23657595 TI - The expression and phylogenetic analysis of four AP3-like paralogs in the stamens, carpels, and single-whorl perianth of the paleoherb Asarum caudigerum. AB - The paleoherb species Asarum caudigerum (Aristolochiaceae) is important for research into the origin and evolution of angiosperm flowers due to its basal position in the angiosperm phylogeny. In this study, four MADS-box-containing transcripts were isolated from A. caudigerum by rapid amplification of cDNA ends (RACE). Sequence comparisons and phylogenetic analyses indicated that they possess high homology to AP3 subfamily genes, which have been shown previously to be involved in petal and stamen development in eudicots. Reverse-transcription quantitative PCR (RT-qPCR) and in situ hybridization analyses showed AcAP3-A expression mainly in the second whorl (stamens) and AcAP3-B expression in whorls 1 and 3 (perianth and carpels). Compared with eudicot AP3 homologs, premature translation termination codons were caused by an insertion in the K1 domain of AcAP3-C, and by a deletion in the 7th exon of AcAP3-D. Sequence analyses suggested that the A. caudigerum AP3 lineage had undergone gene duplication and subfunctionalization, diverging in expression patterns during perianth, stamen, and carpel development. Based on comparative genomic and phylogenetic analyses, we concluded that subfunctionalization has likely contributed to the persistence of two functional AP3 paralogs, that two other copies may have become pseudogenes, and that these AP3 duplication and subfunctionalization events may have contributed to the evolution of the unusual floral morphology of A. caudigerum. PMID- 23657596 TI - Exploring the dermal "template effect" and its structure. AB - Scar formation is the problem for clinic surgery. Recent studies showed that the scar formation was closely related to the dermal defect. Three-dimensional (3-d) structures of dermal tissues act as a template to modulate cell functions that are essential the regeneration of skin structure and function. The dermal tissue's integrity and continuity is a prerequisite for repair to take place. Loss of the dermal tissue integrity and continuity due to trauma leads to a lack of the template effect, which may be one important mechanism that hinders the recovery of cell function, resulting in scar formation. These studies give us two questions: what is the three-dimensional (3-d) structure of the dermal tissue? How do the tissues form? Up to now, it is well known that the molecular structure of collagen, the micro-structure of microfibril, however, the mesoscopic structure of dermal tissues is still unclear. Our recently rudimentary studies showed the problem might be resolved by phase-contrast micro-tomography with synchrotron radiation, which is likely to open new avenues for further investigations on wound regeneration and skin tissue engineering. PMID- 23657597 TI - JNK signaling plays an important role in the effects of TNF-alpha and IL-1beta on in vitro osteoblastic differentiation of cultured human periosteal-derived cells. AB - The purpose of this study was to examine the effects of TNF-alpha and IL-1beta on in vitro osteoblastic differentiation of cultured human periosteal-derived cells. To examine the effects of TNF-alpha and IL-1beta on in vitro osteoblastic differentiation of cultured human periosteal-derived cells, the cells cultured in the osteogenic induction medium were treated with 0.1-10 ng/ml TNF-alpha and 0.01 1 ng/ml IL-1beta. TNF-alpha and IL-1beta enhanced the alkaline phosphatase (ALP) activity and alizarin red S staining in cultured human periosteal-derived cells. However, these cytokines did not stimulate the Runt-related transcription factor (Runx) 2 activity and osteocalcin secretion. The ALP activity was decreased in the periosteal-derived cells pretreated with mitogen activated protein kinase (MAPK) inhibitors and then treated with TNF-alpha or IL-1beta. Among the periosteal-derived cells pretreated with MAPK inhibitors, the ALP activity was markedly decreased in the cells pretreated with SP 600125, the specific inhibitor of C-Jun N-terminal kinase (JNK). The periosteal-derived cells treated with TNF alpha and IL-1beta showed an increase in extracellular signal-regulated kinase (ERK) and JNK phosphorylation. Among the ERK and JNK phosphorylation, JNK phosphorylation was strongly observed in the cells. These results suggest that TNF-alpha and IL-1beta increased the in vitro osteoblastic differentiation of cultured human periosteal-derived cells by enhancing the ALP activity and mineralization process, but not by Runx2 activation. The functional role of TNF alpha and IL-1beta in increasing the ALP activity and mineralization of periosteal-derived cells primarily depends on the JNK signaling among the MAPK pathways. PMID- 23657598 TI - High glucose induces mitochondrial p53 phosphorylation by p38 MAPK in pancreatic RINm5F cells. AB - Pancreatic beta-cell death in type 2 diabetes has been related to p53 subcellular localisation and phosphorylation. However, the mechanisms by which p53 is phosphorylated and its activation in response to oxidative stress remain poorly understood. Therefore, the aim of this study was to investigate mitochondrial p53 phosphorylation, its subcellular localisation and its relationship with apoptotic induction in RINm5F cells cultured under high glucose conditions. Our results show that p53 phosphorylation in the mitochondrial fraction was greater at ser392 than at ser15. This increased phosphorylation correlated with an increase in reactive oxygen species, a decrease in the Bcl-2/Bax ratio, a release of cytochrome c and an increase in the rate of apoptosis. We also observed a decline in ERK 1/2 phosphorylation over time, which is an indicator of cell proliferation. To identify the kinase responsible for phosphorylating p53, p38 mitogen-activated protein kinase (MAPK) activation was analysed. We found that high glucose induced an increase in p38 MAPK phosphorylation in the mitochondria after 24-72 h. Moreover, the phosphorylation of p53 (ser392) by p38 MAPK in mitochondria was confirmed by colocalisation studies with confocal microscopy. The addition of a specific p38 MAPK inhibitor (SB203580) to the culture medium during high glucose treatment blocked p53 mobilisation to the mitochondria and phosphorylation; thus, the release of cytochrome c and the apoptosis rate in RINm5F cells decreased. These results suggest that mitochondrial p53 phosphorylation by p38 MAPK plays an important role in RINm5F cell death under high glucose conditions. PMID- 23657599 TI - Transferability of simple sequence repeat (SSR) markers developed in guava (Psidium guajava L.) to four Myrtaceae species. AB - Present study demonstrated the cross-genera transferability of 23 simple sequence repeat (SSR) primer pairs developed for guava (Psidium guajava L.) to four new targets, two species of eucalypts (Eucalyptus citriodora, Eucalyptus camaldulensis), bottlebrush (Callistemon lanceolatus) and clove (Syzygium aromaticum), belonging to the family Myrtaceae and subfamily Myrtoideae. Off the 23 SSR loci assayed, 18 (78.2%) gave cross-amplification in E. citriodora, 14 (60.8%) in E. camaldulensis and 17-17 (73.9%) in C. lanceolatus and S. aromaticum. Eight primer pairs were found to be transferable to all four species. The number of alleles detected at each locus ranged from one to nine, with an average of 4.8, 2.6, 4.5 and 4.6 alleles in E. citriodora, E. camaldulensis, C. lanceolatus and S. aromaticum, respectively. The high levels of cross-genera transferability of guava SSRs may be applicable for the analysis of intra- and inter specific genetic diversity of target species, especially in E. citriodora, C. lanceolatus and S. aromaticum, for which till date no information about EST derived as well as genomic SSR is available. PMID- 23657600 TI - Association between tumor necrosis factor-alpha promoter -308 A/G, -238 A/G, interleukin-6 -174 G/C and -572 G/C polymorphisms and periodontal disease: a meta analysis. AB - The aim of this study was to determine whether tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) promoter polymorphisms confer susceptibility to periodontitis in ethnically different populations. A literature search was performed using PubMed and Embase and a meta-analysis of the identified studies was conducted to explore the associations between TNF-alpha -308 A/G, -238 A/G, IL-6 promoter -174 G/C and -572 G/C polymorphisms and periodontitis. Seventeen comparison studies for the TNF-alpha -308 A/G polymorphism and three studies for the TNF-alpha -238 A/G polymorphism were included in the meta-analysis. And 16 separate studies for the IL-6 -174 G/C polymorphism and 10 studies for the IL-6 572 G/C polymorphism were considered in our meta-analysis. Analysis after stratification by ethnicity indicated that the TNF-alpha -308 A allele was associated with periodontitis in Brazilian, Asian, and Turkish populations (OR=0.637, 95% CI=0.447-0.907, p=0.013; OR=0.403, 95% CI=0.204-0.707, p=0.009; OR=1.818, 95; % CI=1.036-3.189, p=0.037). The meta-analysis showed no association between the TNF-alpha -238 A/G polymorphism and periodontitis. The meta-analysis indicated an association of the IL-6 -174 G/C polymorphisms with periodontitis in Brazilian populations (OR for GG+GC=2.394, 95% CI=1.081-5.302, p=0.031). Stratification by ethnicity and disease type indicated an association between the IL-6 -572 G allele and chronic periodontitis (OR=1.585, 95 % CI=1.030-2.439, p=0.036), and periodontitis in Europeans (OR=2.118, 95% CI=1.254-3.577, p=0.005). This meta-analysis demonstrates that the TNF-alpha -308 A/G polymorphism confers susceptibility to periodontitis in Brazilian, Asian and Turkish populations. The IL-6 -174 G/C polymorphism may confer susceptibility to periodontitis in Brazilians, and the IL-6 -572 G/C polymorphism may be associated with susceptibility to periodontitis in Europeans, and chronic periodontitis. PMID- 23657601 TI - Regulation of adipocyte differentiation and gene expression-crosstalk between TGFbeta and wnt signaling pathways. AB - Obesity results in reduced differentiation potential of adipocytes leading to adipose tissue insulin resistance. Elevated proinflammatory cytokines from adipose tissue in obesity, such as TNFalpha have been implicated in the reduced adipocyte differentiation. Other mediators of reduced adipocyte differentiation include TGFbeta and wnt proteins. Although some overlap exists in the signaling cascades of the wnt and TGFbeta pathways it is unknown if TGFbeta or wnt proteins reciprocally induce the expression of each other to maximize their biological effects in adipocytes. Therefore, we investigated the possible involvement of TGFbeta signaling in wnt induced gene expression and vice versa in 3T3-L1 adipocyte. Effect of TGFbeta and Wnt pathways on differentiation was studied in preadipocytes induced to differentiate in the presence of Wnt3a or TGFbeta1 and their inhibitors (FZ8-CRD and SB431542, respectively). Regulation of intracellular signaling and gene expression was also studied in mature adipocytes. Our results show that both TGFbeta1 and Wnt3a lead to increased accumulation of beta-catenin, phosphorylation of AKT and p44/42 MAPK. However, differences were found in the pattern of gene expression induced by the two proteins suggesting that distinct, but complex, signaling pathways are activated by TGFbeta and wnt proteins to independently regulate adipocyte function. PMID- 23657602 TI - Transcriptome meta-analysis of peripheral lymphomononuclear cells indicates that gestational diabetes is closer to type 1 diabetes than to type 2 diabetes mellitus. AB - We performed a meta-analysis of the transcription profiles of type 1, type 2 and gestational diabetes to evaluate similarities and dissimilarities among these diabetes types. cRNA samples obtained from peripheral blood lymphomononuclear cells (PBMC) of 56 diabetes mellitus patients (type 1 = 19; type 2 = 20; gestational = 17) were hybridized to the same whole human genome oligomicroarray platform, encompassing 44,000 transcripts. The GeneSpring software was used to perform analysis and hierarchical clustering, and the DAVID database was used for gene ontology. The gene expression profiles showed more similarity between gestational and type 1 diabetes rather than between type 2 and gestational diabetes, a finding that was not influenced by patient gender and age. The meta analysis of the three types of diabetes disclosed 3,747 differentially and significantly expressed genes. A total of 486 genes were characteristic of gestational diabetes, 202 genes of type 1, and 651 genes of type 2 diabetes. 19 known genes were shared by type 1, type 2 and gestational diabetes, highlighting EGF, FAM46C, HBEGF, ID1, SH3BGRL2, VEPH1, and TMEM158 genes. The meta-analysis of PBMC transcription profiles characterized each type of diabetes revealing that gestational and type 1 diabetes were transcriptionally related. PMID- 23657604 TI - Angiotensin-converting enzyme (ACE) gene polymorphisms are associated with idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea and worsening lung function. ACE is increased in the bronchoalveolar lavage fluid from patients with IPF, suggesting the role of ACE in the pathogenesis of IPF. We evaluated the role of single-nucleotide polymorphisms (SNPs) in the development risk of IPF. METHODS: Two-hundred twenty patients with IPF and 456 healthy subjects were included in this study. Eleven polymorphisms were selected among those reported previously. Genotype was performed by single base extension. RESULTS: Although absolute LD (|D'|= 1 and r(2 )= 1) was not present, 11 SNPs showed tight LDs. The logistic analysis of the all of 11 SNPs on the ACE genes between patients with IPF and healthy subjects were found to be related with the risk of IPF in recessive type. However, in patients with IPF diagnosed by surgical lung biopsy, only two SNP of -5538T>C and +21288_insdel SNPs were related with the risk of IPF in co-dominant type, and there were no SNPs related with the risk of IPF in dominant type. In patients with IPF diagnosed by clinical criteria or surgical lung biopsy, four SNPs on promoter ( 5538T>C, -5508A>C, -3927T>C, -115T>C), one on intron (+15276A>G), one on exon (+21181G>A), and one in three prime region (+21288_insdel) were related with the risk of IPF. CONCLUSIONS: This study showed a newly discovered SNP of ACE associated with the risk of development of IPF. ACE -5538T>C and -5508A>C significantly associated with risk of IPF in Korea. PMID- 23657605 TI - Synthesis and biological evaluation of benzo[a]phenazine derivatives as a dual inhibitor of topoisomerase I and II. AB - Topoisomerases (Topo I and Topo II) are very important players in DNA replication, repair, and transcription, and are a promising class of antitumor target. In present study, a series of benzo[a]phenazine derivatives with alkylamino side chains at C-5 were designed, synthesized, and their biological activities were evaluated. Most of derivatives showed good antiproliferative activity with a range of IC50 values of 1-10 MUM on the four cancer cell lines HeLa, A549, MCF-7, and HL-60. Topoisomerase-mediated DNA relaxation assay results showed that derivatives could effectively inhibit the activity of both Topo I and Topo II, and the structure-activity relationship studies indicated the importance of introducing an alkylamino side chain. Further mechanism studies revealed that the compounds could stabilize the Topo I-DNA cleavage complexes and inhibit the ATPase activity of hTopo II, indicating that they are a rare class of dual topoisomerase inhibitors by acting as Topo I poisons and Topo II catalytic inhibitors. Moreover, flow cytometric analysis and caspase-3/7 activation assay showed that this class of compounds could induce apoptosis of HL-60 cells. PMID- 23657606 TI - Lone-pair distribution and plumbite network formation in high lead silicate glass, 80PbO.20SiO2. AB - For the first time a detailed structural model has been determined which shows how the lone-pairs of electrons are arranged relative to each other in a glass network containing lone-pair cations. High energy X-ray and neutron diffraction patterns of a very high lead content silicate glass (80PbO.20SiO2) have been used to build three-dimensional models using empirical potential structure refinement. Coordination number and bond angle distributions reveal structural similarity to crystalline Pb11Si3O17 and alpha- and beta-PbO, and therefore strong evidence for a plumbite glass network built from pyramidal [PbO(m)] polyhedra (m ~ 3-4), with stereochemically active lone-pairs, although with greater disorder in the first coordination shell of lead compared to the first coordination shell of silicon. The oxygen atoms are coordinated predominantly to four cations. Explicit introduction of lone-pair entities into some models leads to modification of the local Pb environment, whilst still allowing for reproduction of the measured diffraction patterns, thus demonstrating the non-uniqueness of the solutions. Nonetheless, the models share many features with crystalline Pb11Si3O17, including the O-Pb-O bond angle distribution, which is more highly structured than reported for lower Pb content glasses using reverse Monte Carlo techniques. The lone-pair separation of 2.85 A in the model glasses compares favourably with that estimated in alpha-PbO as 2.88 A, and these lone-pairs organise to create voids in the glass, just as they create channels in Pb11Si3O17 and interlayer spaces in the PbO polymorphs. PMID- 23657607 TI - Validity and reliability of the Japanese version of the Patient Assessment of Constipation Quality of Life questionnaire. AB - BACKGROUND: This study aimed to provide a psychometric evaluation of the Japanese version of the Patient Assessment of Constipation Quality of Life questionnaire (JPAC-QOL). METHODS: Data for scoring were collected prospectively from patients with constipation who visited our center from 2008 to 2010, and analyzed retrospectively. Reliability of the JPAC-QOL was evaluated using Cronbach's alpha to calculate internal consistency, and a test-retest study was performed to evaluate reproducibility. For concurrent validity assessment, the JPAC-QOL scores were compared with Constipation Scoring System (CSS) scores. In assessing responsiveness, the JPAC-QOL scores before and after treatments were compared in patients whose modified CSS (mCSS) scores decreased by >50 %. RESULTS: Internal consistency was assessed in 295 patients (165 women; mean age 67.0 years). Cronbach's alpha was >0.7 for the overall score and all four subscales, showing a strong internal consistency. The intraclass correlations for the 145 patients available for the test-retest study were >0.7 for the overall score and for all subscales except satisfaction. The JPAC-QOL scores were significantly associated with the CSS scores in 284 patients, demonstrating concurrent validity in all four subscales and the overall score. The mean JPAC-QOL score improved significantly after treatment in the 72 patients whose mCSS scores decreased by >50 %, indicating good responsiveness in all four subscales and in the overall score. CONCLUSIONS: Our study data confirmed the validity and reliability of the JPAC-QOL and demonstrated it ready for use in evaluating the symptom-specific QOL in Japanese patients with constipation. PMID- 23657608 TI - The expression and role of Aquaporin 5 in esophageal squamous cell carcinoma. AB - BACKGROUND: Aquaporins (AQPs) are water channel proteins that facilitate transcellular water movements. Recent studies have shown that AQP5 is expressed in various cancers, and plays a role in tumor progression. However, its expression and role in esophageal squamous cell carcinoma (ESCC) have not been investigated. We examined the pathophysiologic role of AQP5 in cell proliferation and survival, and also investigated its expression and effects on the prognosis of ESCC patients. METHODS: AQP5 expression in human ESCC cell lines was analyzed by Western blot testing. Knockdown experiments with AQP5 siRNA were conducted, and the effects on cell proliferation, cell cycle progression, and cell survival were analyzed. The cells' gene expression profiles were analyzed by microarray analysis. Immunohistochemistry of AQP5 for 68 primary tumor samples obtained from ESCC patients undergoing esophagectomy was performed. RESULTS: AQP5 expression was high in TE2 and TE5 cells. In these cells, the knockdown of AQP5 using siRNA inhibited cell proliferation and G1-S phase progression, and induced apoptosis. The AQP5 siRNA transfected TE5 cells showed significant increase in p21 and decrease in CCND1 mRNA expression, respectively. The expression pattern of AQP5 and p21 protein was sharply contrasted, but AQP5 and CCND1 protein expression showed a similar pattern in ESCC tissue. These findings agree with the microarray results. Immunohistochemical staining of 68 ESCC patients showed the AQP5 expression is associated with tumor size, histological type, and tumor recurrence. CONCLUSION: The AQP5 expression in ESCC cells may affect cell proliferation and survival, and impact on the prognosis of ESCC patients. PMID- 23657610 TI - Equilibrium gas-oil ratio measurements using a microfluidic technique. AB - A method for measuring the equilibrium GOR (gas-oil ratio) of reservoir fluids using microfluidic technology is developed. Live crude oils (crude oil with dissolved gas) are injected into a long serpentine microchannel at reservoir pressure. The fluid forms a segmented flow as it travels through the channel. Gas and liquid phases are produced from the exit port of the channel that is maintained at atmospheric conditions. The process is analogous to the production of crude oil from a formation. By using compositional analysis and thermodynamic principles of hydrocarbon fluids, we show excellent equilibrium between the produced gas and liquid phases is achieved. The GOR of a reservoir fluid is a key parameter in determining the equation of state of a crude oil. Equations of state that are commonly used in petroleum engineering and reservoir simulations describe the phase behaviour of a fluid at equilibrium state. Therefore, to accurately determine the coefficients of an equation of state, the produced gas and liquid phases have to be as close to the thermodynamic equilibrium as possible. In the examples presented here, the GORs measured with the microfluidic technique agreed with GOR values obtained from conventional methods. Furthermore, when compared to conventional methods, the microfluidic technique was simpler to perform, required less equipment, and yielded better repeatability. PMID- 23657609 TI - An observational study of nurse staffing ratios and hospital readmission among children admitted for common conditions. AB - BACKGROUND: Hospital patient-to-nurse staffing ratios are associated with quality outcomes in adult patient populations but little is known about how these factors affect paediatric care. We examined the relationship between staffing ratios and all-cause readmission (within 14 days, 15-30 days) among children admitted for common medical and surgical conditions. METHODS: We conducted an observational cross-sectional study of readmissions of children in 225 hospitals by linking nurse surveys, inpatient discharge data and information from the American Hospital Association Annual Survey. Registered Nurses (N=14 194) providing direct patient care in study hospitals (N=225) and children hospitalised for common conditions (N=90 459) were included. RESULTS: Each one patient increase in a hospital's average paediatric staffing ratio increased a medical child's odds of readmission within 15-30 days by a factor of 1.11, or by 11% (95% CI 1.02 to 1.20) and a surgical child's likelihood of readmission within 15-30 days by a factor of 1.48, or by 48% (95% CI 1.27 to 1.73). Children treated in hospitals with paediatric staffing ratios of 1 : 4 or less were significantly less likely to be readmitted within 15-30 days. There were no significant effects of nurse staffing ratios on readmissions within 14 days. DISCUSSION: Children with common conditions treated in hospitals in which nurses care for fewer patients each are significantly less likely to experience readmission between 15 and 30 days after discharge. Lower patient-to-nurse ratios hold promise for preventing unnecessary hospital readmissions for children through more effective predischarge monitoring of patient conditions, improved discharge preparation and enhanced quality improvement success. PMID- 23657611 TI - A ganglion of the patellar tendon in patellar tendon-lateral femoral condyle friction syndrome. AB - Intratendinous ganglia are rare. We report the case of a sedentary woman with chronic mechanical anterolateral pain of the knee and an extensive ganglion of the patellar tendon as indicated on magnetic resonance (MR) and ultrasound (US) examinations. There was evidence of a high-riding patella, patellar malalignment and patellar tendon-lateral femoral condyle friction syndrome with significantly close contact between the patellar tendon and the lateral facet of the femoral trochlea. The ultrasound-guided aspiration of the ganglion enabled a localized injection of an anti-inflammatory drug (cortivazol) and the cytopathological examination of the fluid, which confirmed the diagnosis. Clinical improvement was maintained with knee rehabilitation and was satisfactory at follow-up after 1 year. To our knowledge, we report the first case of a ganglion of the patellar tendon subsequent to patellar tendon-lateral femoral condyle friction syndrome. We found that this case was illustrative of mucoid degeneration in connective tissue due to chronic repetitive microtraumas. Additionally, this case provided the opportunity to discuss the management of this condition in a sedentary individual with a high-riding patella and patellar malalignment. PMID- 23657612 TI - High resolution morphologic imaging and T2 mapping of cartilage at 7 Tesla: comparison of cartilage repair patients and healthy controls. AB - OBJECT: Our objective was to use 7 T MRI to compare cartilage morphology (thickness) and collagen composition (T2 values) in cartilage repair patients and healthy controls. MATERIALS AND METHODS: We scanned the knees of 11 cartilage repair patients and 11 controls on a 7 T MRI scanner using a high-resolution, gradient-echo sequence to measure cartilage thickness and a multi-echo spin-echo sequence to measure cartilage T2 values. We used two-tailed t tests to compare cartilage thickness and T2 values in: repair tissue (RT) versus adjacent cartilage (AC); RT versus healthy control cartilage (HC); AC versus HC. RESULTS: Mean thickness in RT, AC, HC were: 2.2+/-1.4, 3.6+/-1.1, 3.3+/-0.7 mm. Differences in thickness between RT-AC (p=0.01) and RT-HC (p=0.02) were significant, but not AC-HC (p=0.45). Mean T2 values in RT, AC, HC were: 51.6+/ 7.6, 40.0+/-4.7, 45.9+/-3.7 ms. Differences in T2 values between RT-AC (p=0.0005), RT-HC (p=0.04), and AC-HC (p=0.004) were significant. CONCLUSION: 7 T MRI allows detection of differences in morphology and collagen architecture in: (1) cartilage repair tissue compared to adjacent cartilage and (2) cartilage repair tissue compared to cartilage from healthy controls. Although cartilage adjacent to repair tissue may be normal in thickness, it can demonstrate altered collagen composition. PMID- 23657614 TI - A preliminary study of the variability in location of the ureteral orifices with bladder filling by fluoroscopic guidance: the gender difference. AB - BACKGROUND AND PURPOSE: To determine landmarks for stent positioning in both ureteral orifices (UOs) and the gender differences in their location in men and women. PATIENTS AND METHODS: The location of the UO and the bladder neck (BN) was measured fluoroscopically by the intravesical distal location of an open-ended catheter marked with radiopaque materials. We compared the location in men (n = 12) and women (n = 12) with a full bladder (hydrostatic pressure of 50 cmH2O) or an empty bladder. RESULTS: The mean distances from BN to UO in men and women were significantly different both in an empty bladder (2.5 +/- 0.4 and 2.1 +/- 0.3 cm, respectively) and in a full bladder (2.9 +/- 1.0 and 2.3 +/- 0.6 cm, respectively). The location of UO was changed by bladder filling in women but not in men. In women, most UOs were found superior to the symphysis pubis (SP) in empty bladder (66.6 %). Most of this location was observed at behind the upper boarder of SP in full bladder of women (75 %). The BN of women was located at the lower level in basal state compared to men. Also, the location of BN was markedly changed by bladder fulling in women (p = 0.04) but not in men. CONCLUSIONS: Significant gender differences were observed in the location of UO and BN. Clinicians should keep in mind the anatomical differences between men and women during fluoroscopic-guided procedure. PMID- 23657615 TI - Synthesis, insecticidal activity, and structure-activity relationship (SAR) of anthranilic diamides analogs containing oxadiazole rings. AB - A series of anthranilic diamides analogs (3-11, 16-24) containing 1,2,4- or 1,3,4 oxadiazole rings were synthesized and characterized by (1)H NMR, MS and elemental analyses. The structure of 3-bromo-N-(2-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl) 4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (18, CCDC-) was determined by X-ray diffraction crystallography. The insecticidal activities against Plutella xylostella and Spodoptera exigua were evaluated. The results showed that most of title compounds displayed good larvicidal activities against P. xylostella, especially compound 3-bromo-N-(4-chloro-2-methyl-6-(5 (methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5 carboxamide (6), which displayed 71.43% activity against P. xylostella at 0.4 MUg mL(-1) and 33.33% against S. exigua at 1 MUg mL(-1). The structure-activity relationship showed that compounds decorated with a 1,3,4-oxadiazole were more potent than compounds decorated with a 1,2,4-oxadiazole, and different substituents attached to the oxadiazole ring also affected the insecticidal activity. This work provides some hints for further structure modification and the enhancement of insecticidal activity. PMID- 23657616 TI - Nonspecific, reversible inhibition of voltage-gated calcium channels by CaMKII inhibitor CK59. AB - Investigation of kinase-related processes often uses pharmacological inhibition to reveal pathways in which kinases are involved. However, one concern about using such kinase inhibitors is their potential lack of specificity. Here, we report that the calcium-calmodulin-dependent kinase II (CaMKII) inhibitor CK59 inhibited multiple voltage-gated calcium channels, including the L-type channel during depolarization in a dose-dependent manner. The use of another CaMKII inhibitor, cell-permeable autocamtide-2 related inhibitory peptide II (Ant-AIP II), failed to similarly decrease calcium current or entry in hippocampal cultures, as shown by ratiometric calcium imaging and whole-cell patch clamp electrophysiology. Notably, inhibition due to CK59 was reversible; washout of the drug brought calcium levels back to control values upon depolarization. Furthermore, the IC50 for CK59 was approximately 50 MUM, which is only fivefold larger than the reported IC50 values for CaMKII inhibition. Similar nonspecific actions of other CaMKII inhibitors KN93 and KN62 have previously been reported. In the case of all three kinase inhibitors, the IC50 for calcium current inhibition falls near that of CaMKII inhibition. Our findings demonstrate that CK59 attenuates activity of voltage-gated calcium channels, and thus provide more evidence for caution when relying on pharmacological inhibition to examine kinase dependent phenomena. PMID- 23657617 TI - [Vertebral osteomyelitis]. AB - Infections of the vertebra and neighboring disc create the characteristic lesions of vertebral osteomyelitis. The incidence has been estimated to range from 0.3 to 6.5 cases/100,000 persons. The hematogenous route of infection is predominant while direct inoculation through iatrogenic procedures and contiguous spread from adjacent tissue are rare. Most patients with hematogenous vertebral osteomyelitis exhibit predisposing factors, such as advanced age and diabetes mellitus. Diagnosis is often delayed due to the nonspecific nature of back pain, the main symptom. Furthermore, fever is frequently absent. Staphylococcus aureus is the most prevalent pathogen of pyogenic vertebral osteomyelitis in Europe. Magnetic resonance imaging (MRI) is the method of choice for the radiological diagnosis and blood cultures belong to the standard procedures. In cases of negative blood cultures a biopsy is generally warranted for microbiological diagnosis, either by computed tomography (CT)-guided needle biopsy or open surgery. Randomized trials that have addressed different antibiotic regimens are lacking. The recommended duration of treatment ranges from 6 weeks to 3 months. Patients with abscesses and implant devices in particular should be treated for 3 months. PMID- 23657618 TI - [Esophageal precancerous lesions: early diagnosis, treatment, and preservation of quality of life]. AB - Modern high-resolution video endoscopes allow detailed examination of the esophageal mucosa and diagnosis of early neoplastic changes in the gastrointestinal tract. Whereas Barrett's esophagus is a precancerous condition that can develop into adenocarcinoma, there is no defined precancerous lesion for squamous cell carcinoma. Various diseases are associated with the development of esophageal squamous cell carcinoma. Chromoendoscopy has become an established method in the diagnostic work-up for better visualization of early neoplasia. If Barrett's esophagus is present, acetic acid spraying or virtual chromoendoscopy can be used to accentuate the display of superficial gyriform structures in the mucosa. The gold standard for detecting squamous cell carcinoma is still the use of Lugol solution. When early neoplasia is suspected, diagnostic endoscopic resection should be performed. This allows precise histological assessment of the tumor. Early diagnosis of neoplastic changes in the esophagus provides patients not only with the option of curative therapy but also with a good quality of life through preservation of the esophagus. PMID- 23657620 TI - [Precancerous tumors and carcinomas in situ of the skin]. AB - Precancerous skin lesions and carcinomas in situ of the skin represent the early stages of epithelial skin tumors. There is no invasive tumor growth, so the basement membrane is completely intact. These lesions show a wide variation of clinical and histological appearances on the skin or mucosa. The precancerous and carcinoma in situ lesions that are described in this text are actinic keratosis, actinic cheilitis, cutaneous horns, arsenical keratosis, tar-induced dermatosis, X-ray irradiation-related keratosis, Bowen's disease, erythroplasia of Queyrat, bowenoid papulosis, intraepithelial neoplasia (vulvar, penile and anal). Because they all can progress into invasive carcinoma, therapy is mandatory. Many noninvasive therapeutic approaches exist nowadays in the form of gels, creams, photodynamic therapy and invasive techniques such as laser therapy and cryotherapy, curettage and excision of lesional skin. Depending on the treatment process, different rates of general clearance and recurrence of the lesions are discussed in this article. PMID- 23657619 TI - [Myelodysplastic syndromes]. AB - The myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells. The transformation rate to acute myeloid leukemia reaches 30-40 %. In early phases of the disease, the clonal cells have a growth advantage but suffer from premature apoptosis, which explains the paradox of a cellular bone marrow coupled to peripheral blood cytopenias. At later stages, additional genetic aberrations accumulate and lead to proliferation with leukemic transformation. Patients with early MDS benefit from supportive therapy or growth factors. Sometimes, immunological or immunomodulatory treatments can suppress the malignant clone and strengthen normal hematopoiesis for sustained periods. Patients with advanced MDS are usually treated with cytotoxic therapy followed by allogeneic stem cell transplantation or with epigenetic therapy to initiate differentiation and slow down proliferation. PMID- 23657621 TI - Correlation between 99mTc-HYNIC-octreotide SPECT/CT somatostatin receptor scintigraphy and pathological grading of meningioma. AB - The aim of this study was to explore the association of (99m)Tc-HYNIC-octreotide SPECT/CT somatostatin receptor scintigraphy (SRS) with the pathological grading and expression of somatostatin receptor 2 (SSTR2) for meningioma, and to define possible roles of SRS in the pathological grading of meningioma. Thirty patients with meningiomas diagnosed by MRI and treated with (99m)Tc-HYNIC-octreotide SPECT/CT SRS. Meningioma tissues were obtained from analyzing pathological grading and measuring the expression of SSTR2 with immunohistochemical staining. The meningioma side (T) to the contralateral side (NT) ratios (T/TN) of radioactive counts were calculated to investigate their association with the pathological grading of meningioma and the expression of SSTR2. All 30 cases showed high meningioma radioactivity accumulation using SRS with a sensitivity of 100 %, while CT scans only detected 25 cases with a sensitivity of 83 %. Twenty cases with grade I meningioma had a T/NT ratio of 3.80 +/- 1.67, which was significantly lower than the other 10 cases (9.57 +/- 3.78) with a grade II meningioma (P < 0.01). All meningiomas expressed SSTR2 as detected by immunohistochemical staining, and the T/NT ratio was positively associated with the pathological grading of meningioma and the expression of SSTR2 (with r of 0.784 and 0.805, respectively). (99m)Tc-HYNIC-octreotide SPECT/CT SRS is a sensitive technique for detecting meningioma, and the T/NT ratio of the SRS data closely correlates with the pathological grade of meningioma and the expression of SSTR2. PMID- 23657622 TI - Radiology quiz case 1. Common carotid artery mycotic pseudoaneurysm. PMID- 23657623 TI - Is tranexamic acid effective and safe in spinal surgery? A meta-analysis of randomized controlled trials. AB - PURPOSE: The present meta-analysis aimed at assessing the effectiveness and safety of tranexamic acid (TXA) in reducing blood loss and transfusion in spinal surgery. METHODS: Systematic searches of all studies published through March 2012 were identified from PubMed, EMBase, Cochrane library, Science Direct, and other databases. Only randomized controlled trials (RCTs) were included in the present study. Two independent reviewers searched and assessed the literature. Mean difference (MD) of blood loss and blood transfusions, risk ratios (RR) of transfusion rate and of deep vein thrombosis rate in the TXA-treated group versus placebo group were pooled throughout the study. The meta-analysis was conducted by RevMan 5.1 software. RESULTS: Six placebo-controlled RCTs encompassing 411 patients met the inclusion criteria for our meta-analysis. The use of TXA significantly reduced both total blood loss [MD = -285.35, 95 % CI (-507.03 to 63.67), P = 0.01] as well as the number of patients requiring blood transfusion [RR = 0.71, 95 % CI (0.54-0.92), P = 0.01]. None of the patients in the treatment group had deep-vein thrombosis (DVT) or pulmonary embolism. CONCLUSIONS: Intravenous use of TXA for patients undergoing spinal surgery is effective and safe. It reduces total blood loss and the need for blood transfusion, particularly in the using of high dosage of TXA (>= 15 mg/kg), yet does not increase the risk of postoperative DVT. Due to the limitation of the quality of the evidence currently available, high-quality RCTs are required. PMID- 23657624 TI - Anterior approach versus posterior approach for the treatment of multilevel cervical spondylotic myelopathy: a systemic review and meta-analysis. AB - PURPOSE: To compare the clinical outcomes, complications, and surgical trauma between anterior and posterior approaches for the treatment of multilevel cervical spondylotic myelopathy. STUDY DESIGN: Systematic review and meta analysis. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases for randomized controlled trials or non-randomized controlled trials that compared anterior and posterior surgical approaches for the treatment of multilevel cervical spondylotic myelopathy. Exclusion criteria were non-controlled studies, combined anterior and posterior surgery, follow-up <1 year, cervical kyphosis >15 degrees , and cervical myelopathy caused by ossification of the posterior longitudinal ligament. The main end points included: recovery rate; Japanese Orthopedic Association (JOA) score; reoperation rate; complication rate; blood loss; and operation time. Subgroup analysis was conducted according to the mean number of surgical segments. RESULT: A total of eight studies were included in the meta-analysis; none of which were randomized controlled trials. All of the selected studies were of high quality as indicated by the Newcastle-Ottawa scale. In five studies involving 351 patients, the preoperative JOA score was similar between the anterior and posterior groups [P > 0.05, WMD: -0.00 (-0.56, 0.56)]. In four studies involving 268 patients, the postoperative JOA score was higher in the anterior group compared with the posterior group [P < 0.05, WMD: 0.79 (0.16, 1.42)]. For recovery rate, there was significant heterogeneity among the four studies involving 304 patients, hence, only descriptive analysis was performed. In seven studies involving 447 patients, the postoperative complication rate was significant higher in the anterior group compared with the posterior group [P < 0.05, odds ratio: 2.60 (1.63, 4.15)]. Of the 245 patients in the 8 studies who received anterior surgery, 21 (8.57%) received reoperation. Of the 285 patients who received posterior surgery, only 1 (0.3%) received reoperation. The reoperation rate was significantly higher in the anterior group compared with the posterior group (P < 0.001). In the 3 studies involving 236 patients compared subtotal corpectomy and laminoplasty/laminectomy, blood loss and operation time were significantly higher in the anterior subtotal corpectomy group compared with the posterior laminoplasty/laminectomy group [P < 0.05, WMD: 150.10 (63.53, 236.66) and P < 0.05, WMD: 59.17 (45.69, 72.66)]. CONCLUSION: The anterior approach was associated with better postoperative neural function than the posterior approach in the treatment of multilevel cervical spondylotic myelopathy. There was no apparent difference in the neural function recovery rate. The complication and reoperation rates were significantly higher in the anterior group compared with the posterior group. The surgical trauma associated with corpectomy was significantly higher than that associated with laminoplasty/laminectomy. PMID- 23657625 TI - Synergistic switching of plasmonic resonances and molecular spin states. AB - Plasmonic resonance properties of a series of lithographically patterned gold nanorod arrays, spin coated by thin films of an iron(II)-triazole type spin crossover complex, were investigated upon heating/cooling and also under 633 nm laser irradiation. In both cases a reversible shift of the localised surface plasmon resonance wavelength was observed and quantitatively linked to the refractive index change accompanying the spin transition. These results show that molecular spin state switching can be very efficiently triggered by the photo thermal effect, which - in turn - allows for an active tuning of the plasmon resonance. PMID- 23657626 TI - A1R-A2AR heteromers coupled to Gs and G i/0 proteins modulate GABA transport into astrocytes. AB - Astrocytes play a key role in modulating synaptic transmission by controlling extracellular gamma-aminobutyric acid (GABA) levels via GAT-1 and GAT-3 GABA transporters (GATs). Using primary cultures of rat astrocytes, we show here that a further level of regulation of GABA uptake occurs via modulation of the GATs by the adenosine A1 (A1R) and A2A (A2AR) receptors. This regulation occurs through A1R-A2AR heteromers that signal via two different G proteins, Gs and Gi/0, and either enhances (A2AR) or inhibits (A1R) GABA uptake. These results provide novel mechanistic insight into how GPCR heteromers signal. Furthermore, we uncover a previously unknown mechanism where adenosine, in a concentration-dependent manner, acts via a heterocomplex of adenosine receptors in astrocytes to significantly contribute to neurotransmission at the tripartite (neuron-glia neuron) synapse. PMID- 23657627 TI - Simple, distance-based measurement for paper analytical devices. AB - Paper-based analytical devices (PADs) represent a growing class of elegant, yet inexpensive chemical sensor technologies designed for point-of-use applications. Most PADs, however, still utilize some form of instrumentation such as a camera for quantitative detection. We describe here a simple technique to render PAD measurements more quantitative and straightforward using the distance of colour development as a detection motif. The so-called distance-based detection enables PAD chemistries that are more portable and less resource intensive compared to classical approaches that rely on the use of peripheral equipment for quantitative measurement. We demonstrate the utility and broad applicability of this technique with measurements of glucose, nickel, and glutathione using three different detection chemistries: enzymatic reactions, metal complexation, and nanoparticle aggregation, respectively. The results show excellent quantitative agreement with certified standards in complex sample matrices. This work provides the first demonstration of distance-based PAD detection with broad application as a class of new, inexpensive sensor technologies designed for point-of-use applications. PMID- 23657628 TI - Blocking retinoic acid receptor-alpha enhances the efficacy of a dendritic cell vaccine against tumours by suppressing the induction of regulatory T cells. AB - The immune system has evolved regulatory mechanisms to control immune responses to self-antigens. Regulatory T (Treg) cells play a pivotal role in maintaining immune tolerance, but tumour growth is associated with local immunosuppression, which can subvert effector immune responses. Indeed, the induction and recruitment of Treg cells by tumours is a major barrier in the development of effective immunotherapeutics and vaccines against cancer. Retinoic acid (RA) has been shown to promote conversion of naive T cells into Treg cells. This study addresses the hypothesis that blocking RA receptor alpha (RARalpha) may enhance the efficacy of a tumour vaccine by inhibiting the induction of Treg cells. We found that RA significantly enhanced TGF-beta-induced expression of Foxp3 on naive and committed T cells in vitro and that this was blocked by an antagonist of RARalpha (RARi). In addition, RARi significantly suppressed TGF-beta and IL-10 and enhanced IL-12 production by dendritic cells (DC) in response to killed tumour cells or TLR agonists. Furthermore, RARi augmented the efficacy of an antigen-pulsed and TLR-activated DC vaccine, significantly attenuating growth of B16 tumours in vivo and enhancing survival of mice. This protective effect was associated with significant reduction in tumour-infiltrating FoxP3(+) and IL 10(+) Treg cells and a corresponding increase in tumour-infiltrating CD4(+) and CD8(+) T cells that secreted IFN-gamma. Our findings demonstrate that RARalpha is an important target for the development of effective anti-tumour immunotherapeutics and for improving the efficacy of cancer vaccines. PMID- 23657629 TI - Activation, dysfunction and retention of T cells in vaccine sites after injection of incomplete Freund's adjuvant, with or without peptide. AB - We conducted a randomized clinical trial in 45 patients with resected AJCC stage IIB-IV melanoma to characterize cellular and molecular events at sites of immunization with incomplete Freund's adjuvant (IFA) alone, or a melanoma vaccine in IFA. At a primary vaccine site, all patients received a multi-peptide melanoma vaccine in IFA. At a replicate vaccine site, which was biopsied, group 1 received IFA only; group 2 received vaccine in IFA. Lymphocytes isolated from replicate vaccine site microenvironments (VSME) were compared to time-matched peripheral blood mononuclear cells (PBMC) in ELISpot and flow cytometry assays. Compared to PBMC, the VSME had fewer naive and greater proportions of effector memory CD8(+) T cells (TCD8). The vast majority of TCD8 within the VSME were activated (CD69(+)), with a concentration of antigen-specific (tetramer(pos)) cells in the VSME, particularly in vaccine sites with peptide (group 2). CXCR3(+) lymphocytes were concentrated in the VSME of all patients, suggesting IFA-induced chemokine recruitment. TCD8 expression of retention integrins alphaEbeta7 and alpha1beta1 was elevated in VSME, with the highest levels observed in antigen-specific cells in VSME containing peptide (group 2). TCD8 retained in the VSME of both groups were strikingly dysfunctional, with minimal IFN-gamma production in response to peptide stimulation and few tetramer(pos) cells producing IFN-gamma. These data suggest that vaccine-induced selective retention and dysfunction of antigen specific TCD8 within VSME may represent a significant mechanism underlying transient immune responses and low clinical response rates to peptide vaccines administered in IFA. PMID- 23657630 TI - In-vitro generation of human adipose tissue derived insulin secreting cells: up regulation of Pax-6, Ipf-1 and Isl-1. AB - We present a study of up-regulation of genes responsible for pancreatic development in glucose-sensitive insulin-secreting mesenchymal stem cells (IS MSC) generated and differentiated from human adipose tissue (h-AD), with use of our specific differentiation media and without use of any xenogenic material. Anterior wall abdominal fat was collected from 56 volunteers and cultured in self designed proliferation medium for 10 days. Cells were harvested by trypsinization and differentiated into insulin-expressing cells using self-designed differentiation medium for 3 days followed by evaluation for transcriptional factors Pax-6, Ipf-1, Isl-1, C-peptide and insulin secretion. Generated IS-MSC showed expression of Pax-6, Pdx-6 and Isl-1. Non-differentiated MSC as well as their further culture in absence of differentiation medium were used as negative controls. Generated 56 IS-MSC cell-lines were glucose responsive i.e. mean C Peptide and insulin secretion levels were measured 0.41 ng/ml and 13.13 MUU/ml, respectively, in absence of glucose which rose to 1.18 ng/ml and 83.42 MUU/ml, respectively, following glucose challenge (p < 0.001). The mean rise in C-peptide and insulin secretion levels was 2.88 and 6.35 fold, respectively. To conclude insulin-secreting h-AD-MSC can be generated safely and effectively with application of specific differentiation media without xenogeneic material/any genetic modification, showing expression of transcriptional factors Pax-6, Ipf-1 and Isl-1. PMID- 23657631 TI - Extracellular matrix is required for muscle differentiation in primary cell cultures of larval Mytilus trossulus (Mollusca: Bivalvia). AB - Components of the extracellular matrix may modulate the growth factor effects that play important roles in the proliferation and differentiation of precursor cells. We developed an in vitro cultivation protocol for cells of the larval marine bivalve Mytilus trossulus to study the role that extracellular matrix components may play in myodifferentiation and replication-mediated DNA synthesis using immunofluorescence and confocal laser scanning microscopy. Here, we demonstrate that the extracellular matrix regulates the expression of muscle proteins, leading to their assembly and the terminal muscle differentiation of larval cells during cultivation. We further show that the myogenesis process progresses in cells cultivated on fibronectin, carbon or poly-L-lysine but is inhibited in cells grown on a collagen carpet. Consistent with a decrease in muscle protein expression in cells cultivated on collagen, we demonstrate an increase in the number of BrdU-positive cells in comparison with cells cultured on other substrates during the entire cultivation period. Moreover, we demonstrate that the matrix-dependent myogenic differentiation of larval mussel cells is reversible. Round-shaped cells cultivated on collagen were able to differentiate into muscle cells after reseeding on fibronectin, carbon or poly-L lysine. In addition, cells cultured on collagen and then transplanted to fibronectin exhibited distinct cross-striation and contractile activity. Taken together, our data suggest that the extracellular matrix participates in the regulation of the proliferation and myodifferentiation of mussel trochophore progenitor cells and validate novel approaches for successfully culturing cells from bivalves over extended periods. PMID- 23657632 TI - Generalized myoclonus as a prominent symptom in a patient with FTLD-TDP. PMID- 23657633 TI - (E)-5,5'-di(thiophen-2-yl)-3,3'-bi[thiophen-3(2H)-ylidene]-2,2'-diones--from conspicuous blue impurities to "quasi-metallic" golden-bronze crystals. AB - (E)-5,5'-Di(thiophen-2-yl)-3,3'-bi[thiophen-3(2H)-ylidene]-2,2'-dione () has caught the eye of several chemists who have encountered it as a trace by-product in a variety of reactions. We report here the first deliberate synthesis of this intense blue dye (lambda(max) 635 nm; epsilon(max) 32,400 L cm(-1) mol(-1)). We prove on the basis of predictions made with TDDFT that 1a has previously been misassigned as a structural isomer and we correct the visible absorption data that was reported. Derivatives of 1a equipped with pentyl (1b) and butylsulfanyl (1c) groups are readily prepared with our divergent synthetic route (3-7% yield over five steps). Crystals of 1b and 1c exhibit an attractive "quasi-metallic" golden-bronze lustre. This effect is rare in molecular crystals and is observed only with the most intense dyes. PMID- 23657634 TI - Coronary stent embolization of peroneal artery. AB - Embolization of coronary artery stents is a rare but well-recognized complication of percutaneous coronary intervention. Although intracardiac stent migration carries a significant risk to the patient, peripheral embolization is largely benign despite carrying a theoretical risk of distal ischemia. Furthermore, stents lost to the periphery are often never found. Here, we describe a case of an embolized stent to the peroneal artery which was accurately located using on table fluoroscopy and ultrasound duplex. PMID- 23657635 TI - Repair of a complex thoracic aneurysm from relapsing polychondritis. AB - A 29-year-old female with a history of relapsing polychondritis (RP) and open repair of a proximal descending thoracic aneurysm presented with 2 areas of asymptomatic thoracic aortic aneurysmal dilatation. The patient returned 3 months later with symptomatic aneurysm expansion, and she underwent ascending aortic arch replacement. She subsequently underwent staged endovascular repair of the distal descending thoracic aorta. RP is a rare disorder with an incidence of 3.5 per million persons annually, 4% to 7% of whom develop aneurysmal disease. Because of the aneurysmal potential of this disease, it is important for vascular surgeons to be aware of its presentation and treatment. To our knowledge, this is the first reported case describing endovascular technique to treat such a patient. PMID- 23657636 TI - Microinjection of adenosine into the hypothalamic ventrolateral preoptic area enhances wakefulness via the A1 receptor in rats. AB - Adenosine (AD) is a nucleic acid component that is critical for energy metabolism in the body. AD modulates numerous neural functions in the central nervous system, including the sleep-wake cycle. Previous studies have indicated that the A1 receptor (A1R) or A2A receptor (A2AR) may mediate the effects of AD on the sleep-wake cycle. The hypothalamic ventrolateral preoptic area (VLPO) initiates and maintains normal sleep. Histological studies have shown A1R are widely expressed in brain tissue, whereas A2AR expression is limited in the brain and undetectable in the VLPO. We hypothesize therefore, that AD modulates the sleep wake cycle through A1R in the VLPO. In the present study, bilateral microinjection of AD or an AD transporter inhibitor (s-(4-nitrobenzyl)-6 thioinosine) into the VLPO of rats decreased non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. An A1R agonist (N6-cyclohexyladenosine) produced similar effects in the VLPO. Microinjection of an A1R antagonist (8-cyclopentyl 1,3-dimethylxanthine) into the VLPO enhanced NREM sleep and diminished AD-induced wakefulness. These data indicate that AD enhances wakefulness in the VLPO via A1R in rats. PMID- 23657637 TI - Renale osteodystrophie. AB - The incidence of renal osteodystrophy (ROD) increases with deteriorating kidney function, affecting virtually every patient on chronic dialysis treatment. ROD can persist after kidney transplantation and may be aggravated by immunosuppressants, mainly glucocorticoids. Fracture risk, including hip fractures, is markedly elevated in patients with renal disease compared to the general population. Depending on the type of ROD, high or low bone turnover can be found. Because of poor positive and negative predictive values of serological markers of bone turnover and limited technical capabilities of various bone imaging modalities, the only reliable method to correctly classify ROD is the transiliac bone biopsy. Elevated bone turnover can be successfully treated with active vitamin D, cinacalcet, or parathyreoidectomy, but all of these therapies may lead to oversuppression of bone metabolism. Currently, no specific therapy is available for low turnover bone disease. Bisphosphonates can be a therapeutic option for selected patients after renal transplantation. PMID- 23657638 TI - Dim light at night interacts with intermittent hypoxia to alter cognitive and affective responses. AB - Obstructive sleep apnea (OSA) and dim light at night (dLAN) have both been independently associated with alterations in mood and cognition. We aimed to determine whether dLAN would interact with intermittent hypoxia (IH), a condition characteristic of OSA, to alter the behavioral, cognitive, and affective responses. Adult male mice were housed in either standard lighting conditions (14:10-h light-dark cycle; 150 lux:0 lux) or dLAN (150 lux:5 lux). Mice were then exposed to IH (15 cycles/h, 8 h/day, FiO2 nadir of 5%) for 3 wk, then tested in assays of affective and cognitive responses; brains were collected for dendritic morphology and PCR analysis. Exposure to dLAN and IH increased anxiety-like behaviors, as assessed in the open field, elevated plus maze, and the light/dark box. dLAN and IH increased depressive-like behaviors in the forced swim test. IH impaired learning and memory performance in the passive avoidance task; however, no differences were observed in spatial working memory, as assessed by y-maze or object recognition. IH combined with dLAN decreased cell body area in the CA1 and CA3 regions of the hippocampus. Overall, IH decreased apical spine density in the CA3, whereas dLAN decreased spine density in the CA1 of the hippocampus. TNF alpha gene expression was not altered by IH or lighting condition, whereas VEGF expression was increased by dLAN. The combination of IH and dLAN provokes negative effects on hippocampal dendritic morphology, affect, and cognition, suggesting that limiting nighttime exposure to light in combination with other established treatments may be of benefit to patients with OSA. PMID- 23657639 TI - Similar efficacy of human banked milk and bovine colostrum to decrease incidence of necrotizing enterocolitis in preterm piglets. AB - Preterm birth and formula feeding predispose to necrotizing enterocolitis (NEC) in infants. As mother's milk is often absent following preterm delivery, infant formula (IF) and human donor milk (HM) are frequently used as alternatives. We have previously shown that porcine and bovine colostrum (BC) provide similar NEC protection in preterm piglets relative to IF. We hypothesized that HM exerts similar effects and that this effect is partly species-independent. Preterm piglets (n = 40) received 2 days of total parenteral nutrition, followed by a rapid transition to full enteral feeding (15 ml.kg(-1).2 h(-1)) for 2 days using BC (n = 13), HM (n = 13), or IF (n = 14). Intestinal passage time and hexose absorption were tested in vivo. Body and organ weights were recorded on day 5, and macroscopic NEC lesions in the gastrointestinal tract were assessed. Intestinal samples were collected for determination of histomorphology, histopathology, tissue IL-6 and IL-8, organic acids, bacterial adherence by fluorescence in situ hybridization score, and digestive enzyme activities. Relative to IF, pigs from BC and HM showed longer intestinal passage time; higher weight gain, hexose absorptive capacity, mucosal proportion, and enzyme activities; lower NEC incidence, organic acid concentration, and IL-8 concentration; and reduced histopathology lesions. Tissue IL-6 concentration and bacterial adherence score were lower for HM, relative to both BC and IF groups. We conclude that BC and HM are both superior to IF in stimulating gut structure, function, and NEC resistance in preterm piglets. BC may be a relevant alternative to HM when mother's milk is unavailable during the first week after preterm birth. PMID- 23657641 TI - Mitochondrial ROS in the prohypertensive immune response. AB - In the past decade, it has become clear that reactive oxygen species (ROS) and inflammation play an important role in the development of hypertension. Scavenging of mitochondrial superoxide and blocking either IL-17 or tumor necrosis factor-alpha (TNF-alpha) attenuates hypertension. T-cells, critical for development of hypertension, once activated intensively produce cytokines, proliferate, and differentiate. Thus T-cell activation leads to expanded energy demand. To fulfill these needs, T-cells through tightly regulated mechanisms, supported by mitochondrial ROS (mtROS), alter their metabolic phenotype. In this review we summarize data and show evidence supporting new concept that mtROS directly contributes to prohypertensive response of immune cells. PMID- 23657640 TI - Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression. AB - Stress exacerbates symptoms of functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) in humans, but mechanisms contributing to symptom worsening are unknown. These studies address stress-induced changes in the structure and function of the micturition reflex using an animal model of stress in male rats. Rats were exposed to 7 days of repeated variate stress (RVS). Target organ (urinary bladder, thymus, adrenal gland) tissues were collected and weighed following RVS. Evans blue (EB) concentration and histamine, myeloperoxidase (MPO), nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), and CXCL12 protein content (ELISA) were measured in the urinary bladder, and somatic sensitivity of the hindpaw and pelvic regions was determined following RVS. Bladder function was evaluated using continuous, open outlet intravesical infusion of saline in conscious rats. Increases in body weight gain were significantly (P <= 0.01) attenuated by day 5 of RVS, and adrenal weight was significantly (P <= 0.05) increased. Histamine, MPO, NGF, and CXCL12 protein expression was significantly (P <= 0.01) increased in the urinary bladder after RVS. Somatic sensitivity of the hindpaw and pelvic regions was significantly (P <= 0.01) increased at all monofilament forces tested (0.1-4 g) after RVS. Intercontraction interval, infused volume, and void volume were significantly (P <= 0.01) decreased after RVS. These studies demonstrate increased voiding frequency, histamine, MPO, NGF, and CXCL12 bladder content and somatic sensitivity after RVS suggesting an inflammatory component to stress-induced changes in bladder function and somatic sensitivity. PMID- 23657644 TI - Massive hemorrhage after Kasai portoenterostomy in a patient with a congenital extrahepatic portosystemic shunt, malrotation and a double aortic arch: report of a case. AB - A newborn female was transferred to our hospital presenting with severe respiratory distress. She underwent tracheal intubation and nasogastric tubing. Investigations revealed a congenital extrahepatic portosystemic shunt (CEPS) type 1, biliary atresia, heterotaxia, polysplenia, malrotation and a double aortic arch (DAA). She underwent the Kasai portoenterostomy and the Ladd procedure when she was 29 days old. On postoperative day 20, she developed sudden hematemesis with bright red blood. Endoscopy showed massive bleeding from an esophageal ulcer, and endoscopic therapy was performed successfully. During left thoracotomy, an aortoesophageal fistula (AEF) was detected and repaired by direct suturing. The postoperative course was uneventful. CEPS type 1 is commonly associated with other congenital malformations; however, there have been no previous reports of an association between CEPS and DAA. Nasogastric tube insertion in a patient with DAA can result in catastrophic AEF. The treatment strategy should be carefully considered in patients with CEPS type 1 and multiple congenital fetal anomalies. PMID- 23657643 TI - Adhesions after abdominal surgery: a systematic review of the incidence, distribution and severity. AB - Abdominal adhesions are associated with increased postoperative complications, cost and workload. We performed a systematic review with statistical pooling to estimate the formation rate, distribution and severity of postoperative adhesions in patients undergoing abdominal surgery. A literature search was carried out for all articles reporting on the incidence, distribution and severity of adhesions between January 1990 and July 2011. Twenty-five articles fulfilled the inclusion criteria. The weighted mean formation rate of adhesions after abdominal surgery was 54 % (95 % confidence interval [CI] 40-68 %), and was 66 % (95 % CI 38-94 %) after gastrointestinal surgery, 51 % (95 % CI 40-63 %) after obstetric and gynaecological surgery and 22 % (95 % CI 7-38 %) after urological surgery. The mean overall severity score was 1.11 +/- 0.98 according to the Operative Laparoscopy Study Group classification. Laparoscopic surgery reduced the adhesion formation rate by 25 % and decreased the adhesion severity score (laparoscopic; 0.36 +/- 0.69 vs. open; 2.14 +/- 0.84) for gastrointestinal surgery. Our results demonstrate that the incidence and severity of abdominal adhesions varies between surgical specialties and procedures. An increased awareness of adhesions can help in identifying the underlying mechanisms of adhesion formation and novel therapeutic approaches, while also improving the surgical consent process. PMID- 23657646 TI - Tailored nanostructured titania integrated on titanium micropillars with outstanding wicking properties. AB - A novel wicking material using nanostructured titania grown on high aspect ratio titanium micropillars is demonstrated. High aspect ratio titanium micropillars were micromachined from bulk titanium sheets. Nanostructured titania was then grown on the surface of titanium micropillars by oxidation in aqueous hydrogen peroxide solution followed by thermal annealing. The nanostructured titania formed has an open porous structure with a nanoscale pore diameter and wall thickness. X-ray diffraction and pole figure studies indicate the formation of anatase phase of titania and the absence of a preferred orientation in the porous film. The hybrid nanostructured titania on titanium micropillars has excellent hydrophilic properties with a water capillary speed comparable to or exceeding that of conventional wick materials commonly used in heat pipes for the thermal management of electronic devices. PMID- 23657645 TI - Development of gelatin flakes, a new type of anti-adhesive material: a preliminary study of in vivo rat adhesion models. AB - To overcome the problems associated with sheet- or film-type anti-adhesive materials, we developed a new type of anti-adhesive material, gelatin flakes. We made two types of gelatin flakes with or without thermal cross-linking, and preliminarily examined their basic properties and the anti-adhesive efficacy using a rodent adhesion model. Both types of the gelatin flakes rapidly turned into gel and tightly attached the injured surfaces, absorbing the moisture and blood, when applied onto the abraded sites of rats. In addition, these flakes could be sprayed into the desired area by compressed air through a device with a long, thin tube, which could be used in laparoscopic surgery. The anti-adhesive effects of both types of gelatin flakes were similar, and both types were significantly superior compared to the non-treated group. Although further investigations are necessary, the gelatin flakes have unique and useful properties and satisfactory anti-adhesive effects, which indicate that they may be applicable in laparoscopic surgery. PMID- 23657647 TI - Solution of the problem of nonspecific binding in solid-phase noninstrumental dot immunoassay. AB - In this work, we evaluated blocking properties of various reagents used in dot immunoassay test systems on nitrocellulose membranes employing carbon-based diagnosticum to determine antibodies to tetanus anatoxin, thermostable toxin of Yersinia pseudotuberculosis, and HIV-I. The results support the usage of a nonionic detergent Tween 20 which efficiently inhibited nonspecific protein binding to the solid-phase reagent surface and did not decrease sensitivity of the analysis. PMID- 23657648 TI - Effect of microwave electromagnetic radiation (UHF EMR) on tumor cell viability in experiment. PMID- 23657649 TI - Expression of acetylcholine receptors in the brain of mice at the presymptomatic stage of Parkinson's disease. PMID- 23657650 TI - New alternative promoter in regulation of the Oct-1 human gene transcription. AB - For the first time, the presence of a new alternative promoter in the gene of the oct-1 transcription factor from which a previously unknown mRNA isoform Oct-1X, with 5'-terminus different from the previously described isoforms, was demonstrated. The nucleotide sequence of the Oct-1X cDNA was determined and the presence of a long open reading frame which starts with the first ATG codon of the second exon was demonstrated. A protein shortened on its N-terminus is assumed to be the product of a new mRNA isoform. Expression of the new isoform was studied in various human cell lines; the results indicate the ubiquitous nature of the Oct-1X expression. Therefore, in the work, the third alternative promoter of human oct-1 gene (earlier, a ubiquitous promoter U and an inducible tissue-specific promoter L were described) contributing to the fine regulation of mRNA isoform synthesis and formation of structural and functional diversity of Oct-1 protein isoforms in cells was revealed. PMID- 23657651 TI - Effect of acid pH on the core and peripheral light-harvesting complexes of purple bacteria. PMID- 23657652 TI - On the mechanism of luminescence of the fungus Neonothopanus nambi. PMID- 23657653 TI - Effect of ricin on photodynamic damage to the plasma membrane. PMID- 23657654 TI - A new selective inhibitor of mouse blood plasma carboxylesterase. PMID- 23657655 TI - Proteomic analysis of the effect of methyl jasmonate on pea seedling roots. PMID- 23657656 TI - Stability of stationary states with variable concentration of hydrogen ions in enzyme systems: applications to treatment of diabetic ketoacidosis. PMID- 23657657 TI - Structures of beta-glycosidase from acidilobus saccharovorans in complexes with tris and glycerol. PMID- 23657658 TI - Effect of hypoosmotic shock on the volume of renal collecting duct epithelial cells of brattleboro rats with hereditarily defective vasopressin synthesis. PMID- 23657659 TI - Accuracy of quantitative real-time PCR analysis. PMID- 23657660 TI - Hetlaxin, a new toxin from the Heterometrus laoticus scorpion venom, interacts with voltage-gated potassium channel Kv1.3. PMID- 23657661 TI - Molecular analysis of transcription start sites of separate copies of the suffix short retroelement in genome of Drosophila. AB - In order to study TSS in the suffix element, we used total RNA isolated from ovaries of Drosophila melanogaster. Using a 5'-RACE System (Invitrogen) and 454 sequencing, we found the full-length suffix sense transcripts. However, most 5' RACE reads (>70%) correspond to 5'-truncated transcripts lacking the first 33-39 nucleotides. The data may indicate that these RNAs are products of the RNAi related silencing mech-anism producing small RNAs that are larger than piRNAs. The full-length suffix transcripts could arise either from the F element or from active separate copies of suffix. PMID- 23657662 TI - Screening of divinyl ether synthase activity in nonphotosynthetic tissue of asparagales. PMID- 23657663 TI - Tripod index: a new radiographic parameter assessing foot alignment. AB - BACKGROUND: No single radiographic measurement takes into account complete foot alignment. We have created the Tripod Index (TI) to allow assessment of complex foot deformities using a standing anteroposterior (AP) radiograph of the foot. We hypothesized that TI would demonstrate good intraobserver and interobserver reliability and correlate with currently accepted radiographic parameters, in both flatfoot and cavovarus foot deformities. METHODS: Three groups of patients were studied: 26 patients (30 feet) with flatfoot, 29 patients (30 feet) with cavovarus foot, and 51 patients (60 feet) without foot deformity as controls. Weight-bearing radiographs were obtained: foot AP with a hemispherical marker around the heel plus standard lateral and hindfoot alignment views. Radiographic measurements were made by 2 blinded investigators. Statistical analysis included intraclass correlation coefficients (ICCs), correlation of the TI with existing radiographic measurements using Pearson coefficients, and comparison between patient groups using analysis of variance. RESULTS: Intraobserver and interobserver ICCs of TI (0.99 and 0.98, respectively) were excellent. In the flatfoot group, TI significantly correlated with AP talonavicular coverage angle (r = 0.43), medial cuneiform-fifth metatarsal height (r = -0.59), coronal plane hindfoot alignment (r = 0.53), and clinical hindfoot alignment (r = 0.39). In the cavovarus foot group, TI correlated significantly with AP talonavicular coverage angle (r = 0.77), calcaneal pitch angle (r = 0.39), medial cuneiform-fifth metatarsal height (r = -0.65), coronal plane hindfoot alignment (r = 0.55), and clinical hindfoot alignment (r = 0.61). Statistically significant differences between flatfoot-control and cavovarus foot-control were found in TI, AP talonavicular coverage angle, lateral talo-first metatarsal angle, calcaneal pitch angle, medial cuneiform-fifth metatarsal height, coronal plane hindfoot alignment, and clinical assessment of hindfoot alignment (all with P < .001). CONCLUSION: The TI was demonstrated to be a valid and reliable radiographic measurement to quantify the magnitude of complex foot deformities when evaluating flatfoot and cavovarus foot. CLINICAL RELEVANCE: The TI may be helpful as an integrated assessment of complex foot deformities. Further clinical studies are recommended. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 23657665 TI - Functional short- and long-term effects of nasal CPAP with and without humidification on the ciliary function of the nasal respiratory epithelium. AB - PURPOSE: Continuous positive airway pressure (CPAP) is the gold standard in the treatment of obstructive sleep apnea (OSA), but its impact on ciliary function is unclear to date. Furthermore, CPAP is associated with numerous side effects related to the nose and upper airway. Humidified CPAP is used to relieve these symptoms, but again, little is known regarding its effect on ciliary function of the nasal respiratory epithelium. METHODS: In this prospective, randomized, crossover trial, 31 patients with OSA (AHI >15/h) were randomized to two treatment arms: nasal continuous positive airway pressure (nCPAP) with humidification or nCPAP without humidification for one night in each modality to assess short-term effects of ciliary beat frequency (CBF) and mucus transport time (MTT) and consecutively for 8 weeks in each modality to assess long-term effects in a crossover fashion. RESULTS: The baseline CBF was 4.8 +/- 0.6 Hz, and baseline MTT was 540 +/- 221 s. After one night of CPAP with and without humidification, ciliary function increased moderately yet with statistical significance (p <0.05). The short-term groups with and without humidification did not differ statistically significant. Regarding long-term effects of CPAP, a statistically significant increase in ciliary function above the baseline level and above the short-term level was shown without humidification (7.2 +/- 0.4 Hz; 402 +/- 176 s; p <0.01). The increase above baseline level was even more pronounced with humidification (9.3 +/- 0.7 Hz; 313 +/- 95 s; p <0.01). There was a statistically significant difference between both groups at long-term assessment with regard to CBF (p <0.01). CONCLUSIONS: Independent of airway humidification, nCPAP has moderate effects on short-term ciliary function of the nasal respiratory epithelium. However, a significant increase in ciliary function both in terms of an increased CBF and a decreased MTT-was detected after long term use. The effect was more pronounced when humidification was used during nCPAP. PMID- 23657666 TI - Carotid body tumors are not associated with an increased risk for sleep disordered breathing. AB - PURPOSE: Tumors in the carotid bodies may interfere with their function as peripheral chemoreceptors. An altered control of ventilation may predispose to sleep-disordered breathing. This study aimed to assess whether patients with unilateral or bilateral carotid body tumors (uCBT or bCBT, respectively) or bilateral CBT resection (bCBR) display sleep-disordered breathing and to evaluate the global contribution of the peripheral chemoreceptor to the hypercapnic ventilatory response. METHODS: Eight uCBT, eight bCBT, and nine bCBR patients and matched controls underwent polysomnography. The peripheral chemoreflex drive was assessed using euoxic and hyperoxic CO2 rebreathing tests. Daytime sleepiness and fatigue were assessed with the Epworth Sleepiness Scale and the Multidimensional Fatigue Index. RESULTS: All patient groups reported significant fatigue-related complaints, but no differences in excessive daytime sleepiness (EDS) were found. The apnea/hypopnea index (AHI) did not differ significantly between patient groups and controls. Only in bCBT patients, a trend towards a higher AHI was observed, but this did not reach significance (p=0.06). No differences in the peripheral chemoreflex drive were found between patients and controls. CONCLUSIONS: Patients with (resection of) CBTs have more complaints of fatigue but are not at risk for EDS. The presence or resection of CBTs is neither associated with an altered peripheral chemoreflex drive nor with sleep-disordered breathing. PMID- 23657667 TI - Gender differences in the effect of comorbid insomnia symptom on depression, anxiety, fatigue, and daytime sleepiness in patients with obstructive sleep apnea. AB - PURPOSE: This study investigated gender differences in the effect of comorbid insomnia symptom on depression, anxiety, fatigue, daytime sleepiness, and quality of life in patients with obstructive sleep apnea. There are gender differences in the presentation of obstructive sleep apnea. However, the influence of gender on the presentation of comorbid insomnia symptom and obstructive sleep apnea is not known. METHODS: Allparticipantsperformed overnightpolysomnography and completed a battery of questionnaires including Beck Depression Inventory, State-Trait Anxiety Inventory, Multidimensional Fatigue Inventory, Epworth Sleepiness Scale, and Short Form-36 Health Survey. Insomnia symptom was defined as present if a patient had any insomnia complaints longer than 1 month and at least one time per week. RESULTS: Six hundred fifty-five adult patients with obstructive sleep apnea were enrolled; 233 (35.5 %) reported comorbid insomnia symptom with obstructive sleep apnea. The severity of obstructive sleep apnea was not related to comorbid insomnia symptom. Based on linear regression, women had higher depression, fatigue, and daytime sleepiness and lower health-related quality of life than men (all, p<0.05). The presence of insomnia symptom had negative effects on fatigue (p=0.005) and quality of life only (p=0.015) in men but not in women when taking gender-by-insomnia interaction into consideration. There were significant differences in polysomnography-based sleep architecture between the obstructive sleep apnea-only and obstructive sleep apnea-insomnia groups, but only in the subgroup of men. CONCLUSIONS: Men are more prone to the negative impact of comorbid insomnia symptom and obstructive sleep apnea on their level of fatigue and quality of life than women. PMID- 23657668 TI - A randomized crossover study comparing two mandibular repositioning appliances for treatment of obstructive sleep apnea. AB - PURPOSE: The purpose of this study was to determine whether treatment outcomes vary according to the design of the mandibular repositioning appliance (MRA). Two titratable MRA's were compared. The designs differ in advancement hardware and configuration of acrylic both in bulk and interocclusal contact. MATERIALS AND METHODS: The primary treatment outcome was the Respiratory Disturbance Index (RDI). Other outcomes that were compared included Sleep Apnea Quality of Life Index (SAQLI), Epworth Sleepiness Scale, oxygen saturation, and subjective feedback regarding experiences with the appliances. Twenty-four subjects were recruited from consecutive referrals for MRA therapy following diagnosis of obstructive sleep apnea (OSA) by polysomnography. Subjects were randomly assigned to a treatment arm of the crossover study. Each subject underwent an initial sleep study with a type III home monitor to establish a baseline RDI. Subjects were then treated with one of the two MRAs determined by random assignment. The MRA self-titration phase was monitored until a treatment position was determined, and the home sleep study was repeated. After a 2-week period without any OSA treatment, subjects received the second MRA and the self-titration treatment protocol was repeated. At completion of treatment with each appliance, subjects answered questionnaires and underwent a sleep study with the type III monitor. The outcome data for each appliance were compared using analysis of variance. RESULTS: Eighteen subjects completed the treatment protocol. There were no significant statistical differences in treatment outcomes between the two appliances. There was a statistically significant (p <= 0.05) preference for a MRA design with minimal coverage of teeth and palate. The subjects' appliance selection was consistent with a corresponding reduction in SAQLI score for the selected appliance. CONCLUSION: Although no statistically significant difference was observed between the two appliances in the outcomes measured, there was a trend toward greater improvement with the appliance with less acrylic resin bulk and less interocclusal contact. MRA selection should favor titratable, unobtrusive designs with appropriate construction to promote acceptance and adherence to MRA therapy. PMID- 23657669 TI - Temperature dependence of CO2 and N2 core-electron excitation spectra at high pressure. AB - We report a study on the temperature dependence of the core-electron excitation spectra of CO2 and N2, performed using non-resonant inelastic X-ray scattering spectroscopy. The spectra were measured at two temperatures (300 K and 850 K) and at high pressure (40 bar). For CO2 a clear temperature dependence was observed at the C and O near-edge regions. The spectra of CO2 were simulated by density functional theory calculations, and the temperature was accounted for by sampling the initial state molecular geometries using the Metropolis algorithm. This model is able to account for the experimentally observed temperature dependence of the spectrum. The experiment fortifies the status of the non-resonant inelastic X-ray scattering spectroscopy as a valuable technique for physics and chemistry for in situ studies under extreme sample conditions. Especially in the case of gas phase the sample conditions of considerably elevated temperature and pressure are unfeasible for many other spectroscopic techniques. PMID- 23657671 TI - Degradation of polypropylene carbonate through plasmonic heating. AB - We report the thermal degradation of a solid film of polypropylene carbonate, driven by the photothermal effect of gold nanoparticles. We provide characterization of the products of this chemical reaction and use the known activation barrier for this chemical reaction to discuss the temperatures obtained in the film. In addition, we report the efficiency of the reaction as a function of nanoparticle concentration and find nanoparticles to be significantly more effective than an organic dye at driving this reaction. PMID- 23657670 TI - Migrating oligodendrocyte progenitor cells swell prior to soma dislocation. AB - The migration of oligodendrocyte progenitor cells (OPCs) to the white matter is an indispensable requirement for an intact brain function. The mechanism of cell migration in general is not yet completely understood. Nevertheless, evidence is accumulating that besides the coordinated rearrangement of the cytoskeleton, a finetuned interplay of ion and water fluxes across the cell membrane is essential for cell migration. One part of a general hypothesis is that a local volume increase towards the direction of movement triggers a mechano-activated calcium influx that regulates various procedures at the rear end of a migrating cell. Here, we investigated cell volume changes of migrating OPCs using scanning ion conductance microscopy. We found that during accelerated migration OPCs undergo an increase in the frontal cell body volume. These findings are supplemented with time lapse calcium imaging data that hint an increase in calcium content the frontal part of the cell soma. PMID- 23657672 TI - Cognitive ability correlates positively with son birth and predicts cross cultural variation of the offspring sex ratio. AB - Human populations show remarkable variation in the sex ratio at birth which is believed to be related to the parental condition. In the present study, the global variation of sex ratio at birth (SRB, proportion of male offspring born) was analyzed with respect to indirect measure of condition, the intelligence quotient (IQ). IQ correlates strongly with lifespan across nations, which makes it a good indicator of health of the large populations. Relation between three standard measures of average national IQ and SRB was studied using multiple linear regression models. Average national IQ was positively correlated with SRB (r = 0.54 to 0.57, p < 0.001). Further, IQ emerged as a powerful predictor of SRB after controlling for the effects of all the known covariates like fertility, maternal age, polygyny prevalence, wealth, son preference, latitude, low birth weight, and neonatal mortality in the regression models. These results suggest that the striking variation of offspring sex ratio across nations could be caused in part by the difference in general condition of populations. PMID- 23657673 TI - A novel technique to treat Grisel's syndrome: results of a simplified, therapeutical algorithm. AB - PURPOSE: Grisel's syndrome is a rare entity and usually develops in paediatric patients after otolaryngologic surgery or infection. It is defined as a fixed torticollis combined with a rotatory atlanto-axial subluxation. The success rate of physiotherapy is low. Conventional therapy concepts imply stage-related recommendations based on the Fielding classification (type I-IV). This classification was introduced in 1977 to assess the degree of subluxation between atlas (C1) and axis (C2). Thus, instability increases from type I to IV. Higher stages may require surgical intervention. The purpose of this study was to evaluate the value of an alternative, less invasive treatment protocol in Grisel's syndrome. METHODS: Irrespective of the underlying Fielding type we treated five children (Fielding type I-III) by manual repositioning under general anaesthesia. Consecutively, the cervical spine was immobilized with a Minerva cast for four to eight weeks. Additional surgical treatment or immobilization in a Halo-Fixateur was not necessary. RESULTS: Overall period of treatment was reduced, even in patients with delayed diagnosis. No case of recurrence was observed within a follow-up of six months. CONCLUSIONS: Current conventional recommendations suggest invasive treatment with Halo-Fixateur in patients with higher degrees of subluxation (e.g., Fielding type III) or after delayed diagnosis. Even in those patients, this novel therapy concept enables us to achieve excellent clinical results without surgical intervention. PMID- 23657674 TI - Percutaneous endoscopic transforaminal lumbar interbody fusion: is it worth it? AB - PURPOSE: Interbody spine fusion with cages was first described by Bagby and has been performed for a long time now in a variety of different conditions. We developed a percutaneous endoscopic lumbar fusion technique based on the principles of Kambin and an original titanium cage. MATERIALS AND METHODS: From 2004 to 2010, 57 patients were operated on, 17 patients were male with a mean age of 50.29 years (range 34-71 years) and 40 were female with a mean age of 57.42 years (29-90 years). Nineteen patients had a previous operation. Patients were operated on under local anaesthesia in the prone position under image intensifier and a transforaminal percutaneous endoscopic approach. RESULTS: Fifty cases had a bilateral cage through a bilateral endoscopic approach, and seven cases had a unilateral endoscopic approach only; of those, three cases had only one cage. Eleven patients had a contemporary posterior plate fixation at the same time of the endoscopic cage fusion. Eight patients had a postoperative radicular pain with paresthesias. Asymptomatic migration of the cages occurred in two cases and symptomatic migration requiring a conventional secondary reoperation in 13 cases after a mean delay of eight months (range three to 36 months). The mean ODI after two years or more was 34.3 % (initial ODI 69.4 %). CONCLUSIONS: The technique was introduced in our practice to take care of difficult or grave co-morbidity patients, and some patients had excellent lasting results following a very short procedure and hospital stay. However, given the 36 % complication rate in this series, we do not recommend it unless decisive technical improvements are made. PMID- 23657675 TI - Novel biotinylated lipid prodrugs of acyclovir for the treatment of herpetic keratitis (HK): transporter recognition, tissue stability and antiviral activity. AB - PURPOSE: Biotinylated lipid prodrugs of acyclovir (ACV) were designed to target the sodium dependent multivitamin transporter (SMVT) on the cornea to facilitate enhanced cellular absorption of ACV. METHODS: All the prodrugs were screened for in vitro cellular uptake, interaction with SMVT, docking analysis, cytotoxicity, enzymatic stability and antiviral activity. RESULTS: Uptake of biotinylated lipid prodrugs of ACV (B-R-ACV and B-12HS-ACV) was significantly higher than biotinylated prodrug (B-ACV), lipid prodrugs (R-ACV and 12HS-ACV) and ACV in corneal cells. Transepithelial transport across rabbit corneas indicated the recognition of the prodrugs by SMVT. Average Vina scores obtained from docking studies further confirmed that biotinylated lipid prodrugs possess enhanced affinity towards SMVT. All the prodrugs studied did not cause any cytotoxicity and were found to be safe and non-toxic. B-R-ACV and B-12HS-ACV were found to be relatively more stable in ocular tissue homogenates and exhibited excellent antiviral activity. CONCLUSIONS: Biotinylated lipid prodrugs demonstrated synergistic improvement in cellular uptake due to recognition of the prodrugs by SMVT on the cornea and lipid mediated transcellular diffusion. These biotinylated lipid prodrugs appear to be promising drug candidates for the treatment of herpetic keratitis (HK) and may lower ACV resistance in patients with poor clinical response. PMID- 23657677 TI - Effects of steroid administration and transcorneal electrical stimulation on the anatomic and electrophysiologic deterioration of nonarteritic ischemic optic neuropathy in a rodent model. AB - PURPOSE: To elucidate the effectiveness of steroid administration and transcorneal electrical stimulation (TES) on anatomic changes and visual function in a rodent model of nonarteritic ischemic optic neuropathy (rNAION). METHODS: Methylprednisolone (20 mg/kg) was injected through a central venous catheter twice a day for 3 days. TES was delivered with biphasic square pulses of 1 ms/phase, 100 MUA of current, and 20 Hz of frequency for 60 min 3 h after induction on the 1st, 4th, 7th, 14th, and 28th days. RESULTS: Intravenous infusion of methylprednisolone significantly decreased the degree of acute disc edema but did not preserve the inner retinal thinning, decreasing the amplitude of scotopic threshold responses (STR) and decreasing retinal ganglion cell (RGC) numbers in rNAION. TES preserved the decreasing STR amplitude and the decreasing RGC numbers in rNAION. CONCLUSION: Steroids are effective for reducing disc edema in the acute stage in rNAION. TES is effective for preserving decreasing RGC numbers and function in the chronic stage of rNAION. PMID- 23657678 TI - Relationship between aspirin/clopidogrel resistance and intra-stent thrombi assessed by follow-up optical coherence tomography after drug-eluting stent implantation. AB - AIMS: No data exist regarding the relationship between aspirin/clopidogrel resistance and intra-stent thrombi on follow-up optical coherence tomography (OCT) after drug-eluting stent (DES) implantation. The purpose of this study was to evaluate the relationship between aspirin/clopidogrel resistance and intra stent thrombi on the follow-up OCT in DES-treated patients. METHODS AND RESULTS: A total of 308 DES-treated patients who underwent follow-up OCT and simultaneous measurement of aspirin reaction unit (ARU) and P2Y12 reaction unit (PRU) using the VerifyNow assay system were selected for the study. Aspirin and clopidogrel resistance were defined as ARU >=550 and PRU >=275, respectively. Intra-stent thrombi were detected in 29 patients (9.4%). The mean time interval from DES implantation to OCT was 195 +/- 133 days (202.9 +/- 103.0 days for patients with intra-stent thrombi vs. 194.7 +/- 136.0 days for patients without intra-stent thrombi; P = 0.750). There were no significant differences between patients with and without intra-stent thrombi with regard to the incidence of aspirin resistance (13.8 vs. 11.1%, respectively; P = 0.630) or clopidogrel resistance (72.4 vs. 50.5%, respectively; P = 0.056). The percentage of uncovered struts was 17.9 +/- 15.8% in patients with intra-stent thrombi and 12.7 +/- 17.3% in patients without intra-stent thrombi (P = 0.098). Stent length was significantly longer in patients with intra-stent thrombi (22.9 +/- 6.0 vs. 19.4 +/- 5.0 mm, P = 0.006). Multivariate logistic regression analysis showed that stent length (odds ratio = 1.152, 95% confidential interval 1.025-1.295; P = 0.017) was the only independent risk factor for the presence of intra-stent thrombi on OCT. CONCLUSION: This OCT study suggested that the presence of intra-stent thrombi may not be associated with aspirin/clopidogrel resistance in DES-treated patients. PMID- 23657679 TI - YgfX (CptA) is a multimeric membrane protein that interacts with the succinate dehydrogenase assembly factor SdhE (YgfY). AB - Serratia sp. strain ATCC 39006 produces the red-pigmented antibiotic prodigiosin. Prodigiosin biosynthesis is regulated by a complex hierarchy that includes the uncharacterized protein YgfX (DUF1434). The ygfX gene is co-transcribed with sdhE, an FAD assembly factor essential for the flavinylation and activation of the SdhA subunit of succinate dehydrogenase (SDH), a central enzyme in the tricarboxylic acid cycle and electron transport chain. The sdhEygfX operon is highly conserved within the Enterobacteriaceae, suggesting that SdhE and YgfX function together. We performed an extensive mutagenesis to gain molecular insights into the uncharacterized protein YgfX, and have investigated the relationship between YgfX and SdhE. YgfX localized to the membrane, interacted with itself, forming dimers or larger multimers, and interacted with SdhE. The transmembrane helices of YgfX were critical for protein function and the formation of YgfX multimers. Site-directed mutagenesis of residues conserved in DUF1434 proteins revealed a periplasmic tryptophan and a cytoplasmic aspartate that were crucial for YgfX activity. Both of these amino acids were required for the formation of YgfX multimers and interactions with SdhE but not membrane localization. Multiple cell division proteins were identified as putative interaction partners of YgfX and overexpression of YgfX had effects on cell morphology. These findings represent an important step in understanding the function of DUF1434 proteins. In contrast to a recent report, we found no evidence that YgfX and SdhE form a toxin-antitoxin system. In summary, YgfX functions as a multimeric membrane-bound protein that interacts with SdhE, an important FAD assembly factor that controls SDH activity. PMID- 23657680 TI - Biotin sulfoxide reductase contributes to oxidative stress tolerance and virulence in Salmonella enterica serovar Typhimurium. AB - Oxidative stress converts sulfur residues of molecules like biotin and methionine into their oxidized forms. Here we show that the biotin sulfoxide reductase BisC of Salmonella enterica serovar Typhimurium (S. Typhimurium) repairs both oxidized biotin and oxidized methionine. Exposure to H2O2 in vitro reduced survival of a S. Typhimurium DeltabisC mutant. Furthermore, replication of the DeltabisC mutant inside IFN-gamma activated macrophages was reduced. In vitro tolerance of the mutant to H2O2 was restored by plasmids carrying either bisC or msrA; the latter encodes a methioinine sulfoxide reductase. In contrast, the proliferation defect inside IFN-gamma activated macrophages was rescued by bisC but not by msrA. Thus growth of the DeltabisC mutant in IFN-gamma activated macrophages required repair of oxidized biotin. Both the DeltabisC and a biotin auxotrophic (DeltabioB) mutant were attenuated in mice, suggesting that besides biotin biosynthesis, biotin repair was essential for virulence of S. Typhimurium in vivo. Attenuation of the DeltabisC mutant was more pronounced in 129 mice that produce a stronger oxidative response. These results show that BisC is essential for full virulence of Salmonella by contributing to the defence of S. Typhimurium against host derived stress, and provides an attractive drug target since it is not present in mammals. PMID- 23657681 TI - RaoN, a small RNA encoded within Salmonella pathogenicity island-11, confers resistance to macrophage-induced stress. AB - Bacterial small non-coding RNAs act as important regulators that control numerous cellular processes. Here we identified RaoN, a novel small RNA encoded in the cspH-envE intergenic region on Salmonella pathogenicity island-11 (SPI-11). RaoN contributes to survival under conditions of acid and oxidative stress combined with nutrient limitation, which partially mimic the intramacrophage environment. Indeed, inactivation of raoN reduces the intramacrophage replication of Salmonella enterica serovar Typhimurium. Genome-wide transcriptome analysis revealed that the lactate dehydrogenase gene ldhA is upregulated in the raoN knockout mutant. Notably, both inactivation and overexpression of ldhA in the WT strain render Salmonella more sensitive to oxidative stress, particularly when combined with nutrient limitation. However, ldhA is not the sole determinant of RaoN function in facilitating intramacrophage survival of Salmonella. Together, our data suggest that balanced regulation of ldhA expression by RaoN is necessary for survival under in vitro stress conditions and contributes to the intramacrophage growth of Salmonella. PMID- 23657682 TI - MalF is essential for persistence of Mycoplasma gallisepticum in vivo. AB - There is limited understanding of the molecular basis of virulence in the important avian pathogen Mycoplasma gallisepticum. To define genes that may be involved in colonization of chickens, a collection of mutants of the virulent Ap3AS strain of M. gallisepticum were generated by signature-tagged transposon mutagenesis. The collection included mutants with single insertions in the genes encoding the adhesin GapA and the cytadherence-related protein CrmA, and Western blotting confirmed that these mutants did not express these proteins. In two separate in vivo screenings, two GapA-deficient mutants (ST mutants 02-1 and 06 1) were occasionally recovered from birds, suggesting that GapA expression may not always be essential for persistence of strain Ap3AS. CrmA-deficient ST mutant 33-1 colonized birds poorly and had reduced virulence, indicating that CrmA was a significant virulence factor, but was not absolutely essential for colonization. ST mutant 04-1 contained a single transposon insertion in malF, a predicted ABC sugar transport permease, and could not be reisolated even when inoculated by itself into a group of birds, suggesting that expression of MalF was essential for persistence of M. galliseptium strain Ap3AS in infected birds. PMID- 23657683 TI - Comparative proteomic analysis reveals new components of the PhoP regulon and highlights a role for PhoP in the regulation of genes encoding the F1F0 ATP synthase in Edwardsiella tarda. AB - Edwardsiella tarda is an important cause of haemorrhagic septicaemia in fish and also of gastro- and extra-intestinal infections in humans. We have recently demonstrated that the PhoP-PhoQ two-component regulatory system plays important roles in both virulence and stress tolerance in E. tarda. In this study, the proteomes of the WT and phoP mutant strains were compared to define components of the PhoP regulon in E. tarda EIB202. Overall, 18 proteins whose expression levels exhibited a twofold or greater change were identified; 13 of these proteins were found to require the presence of PhoP for full expression, while five were expressed at a higher level in the phoP mutant background. Identified proteins represented diverse functional categories, including energy production, amino acid metabolism and oxidative stress defence. Quantitative real-time PCR analysis of the mRNA levels for the identified proteins confirmed the proteomics data. Interestingly, the beta subunit of the F1F0 ATP synthase, playing an important role in growth and virulence of E. tarda, was listed as one of the proteins whose expression was greatly dependent on PhoP. The F1F0 ATP synthase was encoded in a gene cluster (atpIBEFHAGDC) and the nine genes were transcribed as an operon. PhoP positively regulated the transcription of the nine ATP synthase genes and exerted this effect through direct binding to the promoter of atpI. Overall, the results provide new insights into the PhoP regulon and unravel a novel role for PhoP in the regulation of the F1F0 ATP synthase. PMID- 23657684 TI - Phosphate starvation relayed by PhoB activates the expression of the Pseudomonas aeruginosa sigmavreI ECF factor and its target genes. AB - The cell-surface signalling (CSS) system represents an important regulatory mechanism by which Gram-negative bacteria respond to the environment. Gene regulation by CSS systems is particularly present and important in the opportunistic human pathogen Pseudomonas aeruginosa. In this bacterium, these mechanisms regulate mainly the uptake of iron, but also virulence functions. The latter is the case for the P. aeruginosa PUMA3 CSS system formed by the putative VreA receptor, the sigma(VreI) extracytoplasmic function sigma factor and the VreR anti-sigma factor. A role for this system in P. aeruginosa virulence has been demonstrated previously. However, the conditions under which this system is expressed and activated have not been elucidated so far. In this work, we have identified and characterized the global regulatory cascade activating the expression of the PUMA3 system. We show that the PhoB transcriptional regulator, part of the PhoB-PhoR two-component signalling system, can sense a limitation of inorganic phosphate to turn on the expression of the vreA, vreI and vreR genes, which constitute an operon. Upon expression of these genes in this condition, sigma(VreI) factor mediates transcription of most, but not all, of the previously identified sigma(VreI)-regulated genes. Indeed, we found new sigma(VreI)-targeted genes and we show that sigma(VreI)-regulon genes are all located immediately downstream to the vreAIR gene cluster. PMID- 23657685 TI - Occurrence of mutations impairing sigma factor B (SigB) function upon inactivation of Listeria monocytogenes genes encoding surface proteins. AB - Bacteria of the genus Listeria contain the largest family of LPXTG surface proteins covalently anchored to the peptidoglycan. The extent to which these proteins may function or be regulated cooperatively is at present unknown. Because of their unique cellular location, we reasoned that distinct LPXTG proteins could act as elements contributing to cell wall homeostasis or influencing the stability of other surface proteins bound to peptidoglycan. To test this hypothesis, we used proteomics to analyse mutants of the intracellular pathogen Listeria monocytogenes lacking distinct LPXTG proteins implicated in pathogen-host interactions, such as InlA, InlF, InlG, InlH, InlJ, LapB and Vip. Changes in the cell wall proteome were found in inlG and vip mutants, which exhibited reduced levels of the LPXTG proteins InlH, Lmo0610, Lmo0880 and Lmo2085, all regulated by the stress-related sigma factor SigB. The ultimate basis of this alteration was uncovered by genome sequencing, which revealed that these inlG and vip mutants carried loss-of-function mutations in the rsbS, rsbU and rsbV genes encoding regulatory proteins that control SigB activity. Attempts to recapitulate this negative selection of SigB in a large series of new inlG or vip mutants constructed for this purpose were, however, unsuccessful. These results indicate that inadvertent secondary mutations affecting SigB functionality can randomly arise in L. monocytogenes when using common genetic procedures or during subculturing. Testing of SigB activity could be therefore valuable when manipulating genetically L. monocytogenes prior to any subsequent phenotypic analysis. This test may be even more justified when generating deletions affecting cell envelope components. PMID- 23657686 TI - FOLFIRINOX in locally advanced pancreatic cancer: the Massachusetts General Hospital Cancer Center experience. AB - The objective of our retrospective institutional experience is to report the overall response rate, R0 resection rate, progression-free survival, and safety/toxicity of neoadjuvant FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, irinotecan, and leucovorin) and chemoradiation in patients with locally advanced pancreatic cancer (LAPC). Patients with LAPC treated with FOLFIRINOX were identified via the Massachusetts General Hospital Cancer Center pharmacy database. Demographic information, clinical characteristics, and safety/tolerability data were compiled. Formal radiographic review was performed to determine overall response rates (ORRs). Twenty-two patients with LAPC began treatment with FOLFIRINOX between July 2010 and February 2012. The ORR was 27.3%, and the median progression-free survival was 11.7 months. Five of 22 patients were able to undergo R0 resections following neoadjuvant FOLFIRINOX and chemoradiation. Three of the five patients have experienced distant recurrence within 5 months. Thirty-two percent of patients required at least one emergency department visit or hospitalization while being treated with FOLFIRINOX. FOLFIRINOX possesses substantial activity in patients with LAPC. The use of FOLFIRINOX was associated with conversion to resectability in >20% of patients. However, the recurrences following R0 resection in three of five patients and the toxicities observed with the use of this regimen raise important questions about how to best treat patients with LAPC. PMID- 23657687 TI - Content usage and the most frequently read articles by issue in 2012. PMID- 23657688 TI - Communities of solution: partnerships for population health. AB - Communities of solution (COSs) are the key principle for improving population health. The 1967 Folsom Report explains that the COS concept arose from the recognition that complex political and administrative structures often hinder problem solving by creating barriers to communication and compromise. A 2012 reexamination of the Folsom Report resurrects the idea of the COS and presents 13 grand challenges that define the critical links among community, public health, and primary care and call for ongoing demonstrations of COSs grounded in patient centered care. In this issue, examples of COSs from around the country demonstrate core principles and propose visions of the future. Essential themes of each COS are the crossing of "jurisdictional boundaries," community-led or oriented initiatives, measurement of outcomes, and creating durable connections with public health. PMID- 23657689 TI - Cold-spotting: linking primary care and public health to create communities of solution. AB - By providing enhanced primary care and social services to patients with high utilization of expensive emergency and hospital care, there is evidence that their health can improve and their costs can be lowered. This type of "hot spotting" improves the care of individual patients. It may be that these patients live in communities with disintegrated social determinants of health, little community support, and poor access to primary care. These "cold spots" in the community may be amenable to interventions targeted at linking primary care and public health at broader community and population levels. Building local communities of solution that address the individual and population may help decrease these cold spots, thereby eliminating the hot spots as well. PMID- 23657690 TI - Working together in the best interest of patients. AB - The findings by Peterson et al. show that over half of all family physicians work with nurse practitioners, physician assistants, and certified nurse midwives. While tensions surrounding leadership of teams remain an issue, there are many systems problems that all primary care providers need to face together. This commentary presents the challenges we need to address in order to keep the focus of our care on the patient. PMID- 23657691 TI - Most family physicians work routinely with nurse practitioners, physician assistants, or certified nurse midwives. AB - The U.S. physician workforce is struggling to keep pace with the demand for health care services, a situation that may worsen without efforts to enhance team based care. More than half of family physicians work with nurse practitioners, physician assistants, or certified nurse midwives, and doing so helps ensure access to health care services, particularly in rural areas. PMID- 23657692 TI - Increasing access to care for Brazos Valley, Texas: a rural community of solution. AB - Compared with their urban counterparts, rural populations face substantial disparities in terms of health care and health outcomes, particularly with regard to access to health services. To address ongoing inequities, community perspectives are increasingly important in identifying health issues and developing local solutions that are effective and sustainable. This article has been developed by both academic and community representatives and presents a brief case study of the evolution of a regional community of solution (COS) servicing a 7-county region called the Brazos Valley, Texas. The regional COS gave rise to multiple, more localized COSs that implemented similar strategies designed to address access to care within rural communities. The regional COS, known as the Brazos Valley Health Partnership, was a result of a 2002 health status assessment that revealed that rural residents face poorer access to health services and their care is often fragmented. Their localized strategy, called a health resource center, was created as a "one-stop shop" where multiple health and social service providers could be housed to deliver services to rural residents. Initially piloted in Madison County, the resource center model was expanded into Burleson, Grimes, and Leon Counties because of community buy-in at each of these sites. The resource center concept allowed service providers, who previously were able to offer services only in more populous areas, to expand into the rural communities because of reduced overhead costs. The services provided at the health resource centers include transportation, information and referral, and case management along with others, depending on the location. To ensure successful ongoing operations and future planning of the resource centers, local oversight bodies known as health resource commissions were organized within each of the rural communities to represent local COSs. Through collaboration with local entities, these partnerships have been successful in continuing to expand services and initiating health improvements within their rural communities. PMID- 23657693 TI - Boot camp translation: a method for building a community of solution. AB - OBJECTIVE: A crucial yet currently insufficient step in biomedical research is the translation of scientific, evidence-based guidelines and recommendations into constructs and language accessible to every-day patients. By building a community of solution that integrates primary care with public health and community-based organizations, evidence-based medical care can be translated into language and constructs accessible to community members and readily implemented to improve health. METHODS: Using a community-based participatory research approach, the High Plains Research Network (HPRN) and its Community Advisory Council developed a process to translate evidence into messages and dissemination methods to improve health in rural Colorado. This process, called Boot Camp Translation, has brought together various community members, organizations, and primary care practices to build a community of solution to address local health problems. RESULTS: The HPRN has conducted 4 Boot Camp Translations on topics including colon cancer prevention, asthma diagnosis and management, hypertension, and the patient-centered medical home. Thus far, the HPRN has used Boot Camp Translations to engage more than 1000 rural community members and providers. Dissemination of boot camp messaging through the community of solution has led to increased colon cancer screening, improved care for asthma, and increased rates of controlled blood pressure. CONCLUSIONS: Boot Camp Translation successfully engages community members in a process to translate evidence-based medical care into locally relevant and culturally appropriate language and constructs. Boot Camp Translation is an appropriate method for engaging community members in patient centered outcomes research and may be an appropriate first step in building a local or regional community of solution. PMID- 23657694 TI - The military health system: a community of solutions for medical education, health care delivery, and public health. AB - Multiple strategies have been proposed to improve health care in the United States. These include the development of communities of solution (COSs), implementation of patient-centered medical homes (PCMHs), and lengthening family medicine residency training. There is scant literature on how to build and integrate these ideal models of care, and no literature about how to build a model of care integrating all 3 strategies is available. The Military Health System has adopted the PCMH model and will offer some 4-year family medicine residency positions starting in 2013. Lengthening residency training to 4 years represents an unprecedented opportunity to weave experiential COS instruction throughout a family physician's graduate medical education, providing future family physicians the skills needed to foster a COS in their future practice. This article describes our COS effort to synergize 3 aspects of modern military medicine: self-defined community populations, the transition to the PCMH model, and the initiation of the 4-year length of training pilot program in family medicine residency training. In this way we provide a starting point and general how-to guide that can be used to create a COS integrated with other current concepts in medicine. PMID- 23657695 TI - The OCHIN community information network: bringing together community health centers, information technology, and data to support a patient-centered medical village. AB - Creating integrated, comprehensive care practices requires access to data and informatics expertise. Information technology (IT) resources are not readily available to individual practices. One model of shared IT resources and learning is a "patient-centered medical village." We describe the OCHIN Community Health Information Network as an example of this model; community practices have come together collectively to form an organization that leverages shared IT expertise, resources, and data, providing members with the means to fully capitalize on new technologies that support improved care. This collaborative facilitates the identification of "problem sheds" through surveillance of network-wide data, enables shared learning regarding best practices, and provides a "community laboratory" for practice-based research. As an example of a community of solution, OCHIN uses health IT and data-sharing innovations to enhance partnerships between public health leaders, clinicians in community health centers, informatics experts, and policy makers. OCHIN community partners benefit from the shared IT resource (eg, a linked electronic health record, centralized data warehouse, informatics, and improvement expertise). This patient-centered medical village provides (1) the collective mechanism to build community-tailored IT solutions, (2) "neighbors" to share data and improvement strategies, and (3) infrastructure to support innovations based on electronic health records across communities, using experimental approaches. PMID- 23657696 TI - A primary care-public health partnership addressing homelessness, serious mental illness, and health disparities. AB - BACKGROUND: People with histories of homelessness and serious mental illness experience profound health disparities. Housing First is an evidenced-based practice that is working to end homelessness for these individuals through a combination of permanent housing and community-based supports. METHODS: The Jefferson Department of Family and Community Medicine and a Housing First agency, Pathways to Housing-PA, has formed a partnership to address multiple levels of health care needs for this group. We present a preliminary program evaluation of this partnership using the framework of the patient-centered medical home and the "10 Essential Public Health Services." RESULTS: Preliminary program evaluation results suggest that this partnership is evolving to function as an integrated person-centered health home and an effective local public health monitoring system. CONCLUSION: The Pathways to Housing-PA/Jefferson Department of Family and Community Medicine partnership represents a community of solution, and multiple measures provide preliminary evidence that this model is feasible and can address the "grand challenges" of integrated community health services. PMID- 23657697 TI - Advanced primary care in San Antonio: linking practice and community strategies to improve health. AB - Improving health among people living in poverty often transcends narrowly focused illness care. Meaningful success is unlikely without confronting the complex social origins of illness. We describe an emerging community of solution to improve health outcomes for a population of 6000 San Antonio, Texas, residents enrolled in a county health care program. The community of solution comprises a county health system, a family medicine residency program, a metropolitan public health department, and local nonprofit organizations and businesses. Community based activities responding to the needs of individuals and their neighborhoods are driven by a cohort of promotores (community health workers) whose mission encompasses change at both the individual and community levels. Centered on patients' functional goals, promotores mobilize family and community resources and consider what community-level action will address the social determinants of health. On the clinical side, care teams implement population-based risk assessment and nurse care management with a focus on care transitions as well as other measures to meet the needs of patients with high morbidity and high use of health care. Population-based outcome metrics include reductions in hospitalizations, emergency department and urgent care visits, and the associated charges. Promotores also assess patients' progress along the trajectory of their selected functional goals. PMID- 23657699 TI - Breaking barriers to care: a community of solution for chronic disease management. AB - For 10 years the Medical College of Wisconsin and Columbia St. Mary's Hospital have joined together in a partnership to work within some of Milwaukee's most impoverished neighborhoods. Beginning simply by providing health care through a free clinic, the partnership soon was confronted with numerous examples of barriers to care being experienced by patients. A community-based participatory action process allowed the local population to give voice to the local realities of barriers to care. Here we combine our anecdotal clinical experience, the neighborhood's input, and an example of a successful program from a low-resource international setting to create a novel approach to treating chronic disease in uninsured populations. This model of care has been successful for 2 reasons. First, the model shows good health outcomes at low cost. Second, solid community partnerships with care providers, churches, and other groups have been formed in support of the model, ensuring its credibility and sustainability. PMID- 23657698 TI - HeartBeat Connections: A Rural Community of Solution for Cardiovascular Health. AB - BACKGROUND: Cardiovascular disease (CVD) continues to be the leading cause of death among Americans. National guidelines emphasize early identification and control of CVD risk factors, but challenges remain in the primary care setting in terms of engaging patients and improving medical therapy adherence. The rapid growth of electronic health records (EHRs) provides a new way to proactively identify populations of high-risk patients and target them with prevention strategies. The HeartBeat Connections (HBC) program was developed as part of a population-based demonstration project aimed at reducing myocardial infarctions. METHODS: HBC uses EHR data to identify residents at high CVD risk in a rural community. Participants receive coaching from a registered dietitian or a registered nurse focused on lifestyle behavior changes and preventive medication initiation/titration. DISCUSSION: HBC provides patients with access to nonprescribing professionals on a more frequent basis than typical office visits, and it is focused specifically on helping patients improve lifestyle behaviors and medication adherence as they relate to the primary prevention of CVD. CONCLUSION: Innovative population health approaches that use EHR data to address common barriers to CVD prevention and engage communities in addressing population health needs are needed to help more patients prevent coronary events. PMID- 23657700 TI - Early lessons and challenges from the healthy Mendocino community of solution. AB - Northern California's Mendocino County is joining the national movement to upgrade the quantity and quality of local data available for assessing and improving local health. A broad-based coalition in the county has successfully engaged 20 community partners in funding a web-based tool for this purpose. HealthyMendocino.org, launched in January 2013, is designed to support setting local priorities, planning and evaluating the program, and building community by giving easy access to timely data on 90 indicators of local health and its determinants compiled from a range of state and federal sources. This article, written before the site's launch by the Chair of the Healthy Mendocino Steering Committee, describes the community of solution that came together to envision, publicize, raise support for, and bring to fruition this new resource. Mendocino is a rural county with limited financial capacity but rich social assets, including a strong collaborative tradition and an infrastructure of dynamic coalitions. This article outlines the anticipated benefits, early lessons, and challenges of the initiative and explains how the organizers leveraged connections with other communities of solution that already are working to improve the quality of life in the area. The article also notes ways in which this local initiative illustrates and aligns with several of the grand challenges outlined in the modern Folsom Report-specifically, challenges 7, 8, 11, 12, and above all 13, which concerns the use of health information technology to enable the flow of knowledge to the community of solution. PMID- 23657701 TI - Community of solution for the U.S. health care system: lessons from the U.S. educational system. AB - The Folsom Group asserts that radical changes are needed to fix the health care system in the United States. The U.S. education system is one potential model to emulate. Could a future health care system-level community of solution be modeled after the U.S. education system? Could community health care services be planned, organized, and delivered at the neighborhood level by district, similar to the structure for delivering public education? Could community health centers, governed by community boards, serve every neighborhood? This essay imagines how U.S. health care system reforms could be designed using our public school system as a roadmap. Our intention is to challenge readers to recognize the urgent need for radical reform in the U.S. health care system, to introduce one potential model for reform, and to encourage creative thinking about other system-level communities of solution that could lead to profound change and improvements in the U.S. health care system. PMID- 23657702 TI - Physician payment disclosure under health care reform: will the sun shine? AB - Pharmaceutical marketing has become a mainstay in U.S. health care delivery and traditionally has been directed toward physicians. In an attempt to address potential undue influence of industry and conflicts of interest that arise, states and the recently upheld health care reform act have passed transparency, or "sunshine," laws requiring disclosure of industry payments to physicians. The Centers for Medicare & Medicaid Services recently announced the final rule for the Sunshine Provisions as part of the reform act. However, the future effectiveness of these provisions are questionable and may be limited given the changing landscape of pharmaceutical marketing away from physician detailing to other forms of promotion. To address this changing paradigm, more proactive policy solutions will be necessary to ensure adequate and ethical regulation of pharmaceutical promotion. PMID- 23657703 TI - Breaking up is hard to do: lessons learned from a pharma-free practice transformation. AB - BACKGROUND: Academic medical centers are examining relationships with the pharmaceutical industry and making changes to limit interactions. Most doctors, however, practice outside of academic institutions and see pharmaceutical detailers and accept drug samples and gifts. Little guidance for practicing physicians exists about transforming practices to become pharma-free. Consideration must be given to the impact on practice culture, staff views, and patient needs. METHODS: A small private practice, setting out to transform into a pharma-free clinic, used a practice transformation process that examined the industry presence in the clinic, educated the doctors on potential conflicts of interest, and improved practice flow. Staff were given the opportunity to share concerns, and their issues were acknowledged. Educational interventions were developed to help providers keep current. Finally, efforts were made to educate patients about the policy. RESULTS: The clinic recorded the degree to which it was detailed. Loss of gifts, keeping current with new drugs, and managing without samples were noted concerns. Policy change champions developed strategies to address concerns. DISCUSSION: A shift in practice culture to a pharma-free clinic is achievable and maintainable over time. Barriers to success can be identified and overcome with attention given to careful gathering of information, staff input, and stakeholder education. PMID- 23657704 TI - Re: home visits and the social context. PMID- 23657705 TI - Re: the impact of prior authorization requirements on primary care physicians' offices: report of two parallel network studies. PMID- 23657706 TI - Controlled microfluidic switching in arbitrary time-sequences with low drag. AB - The ability to test the response of cells and proteins to a changing biochemical environment is of interest for studies of fundamental cell physiology and molecular interactions. In a common experimental scheme the cells or molecules of interest are attached to a surface and the composition of the surrounding fluid is changed. It is desirable to be able to switch several different biochemical reagents in any arbitrary order, and to keep the flow velocity low enough so that the cells and molecules remain attached and can be expected to retain their function. Here we develop a device with these capabilities, using U-shaped access channels. We use total-internal reflection fluorescence microscopy to characterize the time-dependent change in concentration during switching of solutions near the device surface. Well-defined fluid interfaces are formed in the immediate vicinity of the surface ensuring distinct switching events. We show that the experimental data agrees well with Taylor-Aris theory in its range of validity. In addition, we find that well-defined interfaces are achieved also in the immediate vicinity of the surface, where analytic approaches and numerical models become inaccurate. Assisted by finite-element modelling, the details of our device were designed for use with a specific artificial protein motor, but the key results are general and can be applied to a wide range of biochemical studies in which switching is important. PMID- 23657708 TI - Laughing at funerals. PMID- 23657709 TI - Those mysterious neurological diseases. PMID- 23657710 TI - Possible mechanism of deep brain stimulation for pedunculopontine nucleus-induced urinary incontinence: a virally mediated transsynaptic tracing study in a transgenic mouse model. PMID- 23657711 TI - Radiology quiz case 2. Recurrent inverted papilloma (IP) with focal hyperostosis in the right maxillary sinus. PMID- 23657707 TI - Cardiorespiratory fitness in males, and upper limbs muscular strength in females, are positively related with 25-hydroxyvitamin D plasma concentrations in European adolescents: the HELENA study. AB - BACKGROUND: High prevalence of vitamin D insufficiency (<75 nmol/l) has been previously reported in European adolescents. Vitamin D deficiency has been related to physical fitness and adiposity but it is not clearly known whether this relationship applies to growing children and adolescents. AIM: To determine how body composition and physical fitness are related to 25-hydroxyvitamin D [25(OH)D] concentrations in European adolescents. DESIGN: The HEalthy Lifestyle in Europe by Nutrition in Adolescence-CSS study was a multi-centre cross sectional study. METHODS: Plasma 25(OH)D, body composition and physical fitness measures were obtained in 1006 European adolescents (470 males) aged 12.5-17.5 years. Stepwise regression and ANCOVA were performed by gender using 25(OH)D as dependent variable, with body composition, physical fitness as independent variables controlling for age, seasonality and latitude. RESULTS: For males, maximum oxygen consumption (VO2max) (B = 0.189) and body mass index (BMI) (B = 0.124) were independently associated with 25(OH)D concentrations (both P < 0.05). For females, handgrip strength (B = 0.168; P < 0.01) was independently associated with 25(OH)D concentrations. Those adolescents at lower BMI and high fitness score presented significant higher 25(OH)D concentrations than those at lower fitness score in the other BMI groups (P < 0.05). CONCLUSION: Cardiorespiratory fitness and upper limbs muscular strength are positively associated with 25(OH)D concentrations in male and female adolescents, respectively. Adiposity in males and low fat free mass in females are related to hypovitaminosis D. The interaction between fitness and BMI has a positive effect on 25(OH)D concentrations. Therapeutic interventions to correct the high rates of vitamin D deficiency in adolescents should consider physical fitness. PMID- 23657712 TI - The spectrum of cerebral visual impairment as a sequel to premature birth: an overview. AB - PURPOSE: In children born prematurely, impairment of vision due to damage to the brain is more common than due to retinopathy of prematurity. Yet, the diagnosis of cerebral visual impairment may be missed. The subject of cerebral visual impairment in children is reviewed in order to explain and draw attention to the types of visual deficits and behaviours that may result as a sequel to premature birth. METHODS: A wide range of sources of data has been employed to assemble this overview. The principal reference source is PubMed. RESULTS: The material presented highlights the origin and range of visual deficits that result from damage to the brain, related to premature birth. Deficits of primary visual functions, perceptual dysfunction, simultanagnostic visual disorders and impaired visual guidance of movement (optic ataxia), as well as disorders of visual attention and memory, can occur in a variety of combinations and degrees. The resulting behavioural outcomes are described. CONCLUSION: Identification and characterisation of impaired vision, due to prematurity associated damage to the brain, are essential. This is required so as to ensure that affected children are not inappropriately disadvantaged on account of the diagnosis being missed or inadequately acted upon, but instead, they are managed optimally, both at home and at school, so that their development is enhanced to the greatest advantage. PMID- 23657713 TI - Romantic relationships and health among African American young adults: linking patterns of relationship quality over time to changes in physical and mental health. AB - With trends in delayed marriage, scholars have begun to explore how a wide range of romantic relationships contribute to health. Although a welcome shift, this largely cross-sectional work ignores potential (in)stability in relationship supports and stressors thought to affect health. Using Family and Community Health Study data on 634 African American young adults, we extend this work by demonstrating the value of a holistic, multidimensional assessment of relationship quality for understanding the link between relationships and health. In addition, however, we also show that there is substantial instability in both the presence and quality of romantic relationships during the transition to adulthood. Importantly, particular patterns of instability are uniquely associated with changes in mental and physical health. Given persistent racial inequalities across both relationships and health, such findings prove theoretically and practically important. In particular, they highlight the need for more contextualized, life course-sensitive approaches in future work. PMID- 23657716 TI - High energy X-rays and the frontiers of materials chemistry. PMID- 23657717 TI - Seasonal variations of particle-associated nitrosamines by gas chromatography mass spectrometry in the atmospheric environment of Zonguldak, Turkey. AB - A gas chromatography-mass spectrometry method has been proposed for the determination of low-level mutagenic and carcinogenic nitrosamines in particulate matter. The method includes the collection of particulate matters (PM2.5 and PM10) using a dichotomous Partisol 2025 sampler and extraction of the compounds from aqueous solution with dichloromethane/2-propanol after sonication with a slightly basic water solution prior to their GC-MS analysis in electron impact mode. The obtained recoveries of nitrosamines ranged from 92.4 to 99.2 %, and the precision of this method, as indicated by the relative standard deviations, was within the range of 0.95-2.46 %. The detection limits obtained from calculations using the GC-MS results based on S/N=3 were found within the range from 4 to 22 pg/m(3). The predominant nitrosamines determined in particulate matter were N nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosodibutylamine and N nitrosomorpholine. Furthermore, N-mono- and dinitrosopiperazine and N nitrosoethylbutylamine were also determined. N-dinitrosopiperazine was detected in PM2.5 samples at the highest concentrations of up to 22.85 ng/m(3) and in PM2.5-10 samples at concentrations up to 7.60 ng/m(3) in winter, whereas it was found in PM2.5 samples up to 5.15 ng/m(3) and in PM2.5-10 samples up to 3.12 ng/m(3) in summer. The total concentrations of nitrosamines were up to 161.4 ng/m(3) in fine and 53.90 ng/m(3) in coarse fractions in winter, whereas in summer were up to 35.24 and 12.60 ng/m(3), respectively. The concentration levels of nitrosamines fluctuated significantly within a year, with higher means and peak concentrations in the winter compared to that in the summertime. The seasonal variations of particle-associated nitrosamine concentrations were investigated together with their relationships with meteorological parameters using Pearson's correlation analysis in the winter and summer periods. Analysis of variance was used to determine which concentrations of nitrosamines were statistically different from one another and, together with meteorological parameters and discriminant analysis, was used to classify the particle samples by particle size according to seasons. The classification results of the particle samples in different seasons were very satisfactory, allowing 99.5 % of cases to be correctly grouped. PMID- 23657718 TI - The negative effects of cadmium on Bermuda grass growth might be offset by submergence. AB - Revegetation in the water-level-fluctuation zone (WLFZ) could stabilize riverbanks, maintain local biodiversity, and improve reservoir water quality in the Three Gorges Reservoir Region (TGRR). However, submergence and cadmium (Cd) may seriously affect the survival of transplantations. Bermuda grass (Cynodon dactylon) is a stoloniferous and rhizomatous prostrate weed displaying high growth rate. A previous study has demonstrated that Bermuda grass can tolerate deep submergence and Cd stress, respectively. In the present study, we further analyzed physiological responses of Bermuda grass induced by Cd-and-submergence stress. The ultimate goal was to explore the possibility of using Bermuda grass for revegetation in the WLFZ of China's TGRR and other riparian areas. The Cd-and submergence-treated plants had higher malondialdehyde contents and peroxidase than control, and both increased with the Cd concentration increase. All treated plants catalase activity increased with the experimental duration increases, and their superoxide dismutase also gradually increased with the Cd concentration from 1 day to 15 days. Total biomass of the same Cd-and-submergence plants increased along the experimental duration as well. Plants exposed to Cd-and submergence stress showed shoot elongation. The heights of all treated plants were taller than those of the control. Leaf chlorophyll contents, maximum leaf length, and soluble sugars contents of all the Cd-and-submergence-treated plants were more than those of the untreated control. Although Cd inhibits plants growth, decreases chlorophyll and biomass content, and with the submergence induced the leaf and shoot elongation, more part of the Cd-and-submergence stress plants appeared in the air, exhibited fast growth with maintenance of leaf color, which guaranteed the plants' photosynthesis, and ensured the total biomass and carbohydrate sustainability, further promoting Cd-and-submergence tolerance. The results imply that the negative effects of cadmium on Bermuda grass growth might be offset by submergence. PMID- 23657719 TI - A 'dual click' strategy for the fabrication of bioselective, glycosylated self assembled monolayers as glycocalyx models. AB - Solid surfaces decorated with specific saccharide patterns can serve as a model for the chemically and structurally highly complex glycocalyx of eukaryotic cells. Here we present an approach based on self-assembled monolayers on gold, which are built up in a three-step manner to provide a solid basis, a biorepulsive oligoethylene glycol part, and a specific carbohydrate terminus in a modular way. Of the different reaction sequences, the one with two consecutive 'click reactions' (the copper(i)-catalysed 1,3-dipolar cycloaddition of alkynes with azides and the thiourea-bridging of isothiocyanates with amines) directly 'on SAM' results in the densest layers, as demonstrated by infrared absorption reflection spectroscopy and ellipsometry. As a 'real life' test, the surfaces obtained this way were used for bacterial adhesion experiments. Here the biorepulsivity of the middle part of the SAMs as well as specific binding to the carbohydrate termini could be clearly demonstrated. PMID- 23657720 TI - Spheroid-based three-dimensional liver-on-a-chip to investigate hepatocyte hepatic stellate cell interactions and flow effects. AB - We have developed a three-dimensional (3D) liver-on-a-chip to investigate the interaction of hepatocytes and hepatic stellate cells (HSCs) in which primary 3D hepatocyte spheroids and HSCs are co-cultured without direct cell-cell contact. Here, we show that the 3D liver chip offers substantial advantages for the formation and harvesting of spheroids. The most important feature of this liver chip is that it enables continuous flow of medium to the cells through osmotic pumping, and thus requires only minimal handling and no external power source. We also demonstrate that flow assists the formation and long-term maintenance of spheroids. Additionally, we quantitatively and qualitatively investigated the paracrine effects of HSCs, demonstrating that HSCs assist in the maintenance of hepatocyte spheroids and play an important role in the formation of tight cell cell contacts, thereby improving liver-specific function. Spheroids derived from co-cultures exhibited improved albumin and urea secretion rates compared to mono cultured spheroids after 9 days. Immunostaining for cytochrome P450 revealed that the enzymatic activity of spheroids co-cultured for 8 days was greater than that of mono-cultured spheroids. These results indicate that this system has the potential for further development as a unique model for studying cellular interactions or as a tool that can be incorporated into other models aimed at creating hepatic structure and prolonging hepatocyte function in culture. PMID- 23657721 TI - Vacuum-assisted adipose tissue suction technique (VAST) to optimize fat harvesting. AB - BACKGROUND: Nowadays, fat grafting is a widespread technique that is commonly used in plastic and reconstructive surgery. The classical fat-harvesting method in which a 10-cc syringe and a 3.0-mm cannula are used, may be time-consuming when a large quantity of adipose tissue is required. We describe a novel technique to optimize fat harvesting, the vacuum-assisted adipose tissue suction technique (VAST), in which disposable sterile components are used. This study compares the adipose tissue harvesting speed and the adipocyte volume between the VAST and the 10-cc-syringe technique. METHODS: From May 2010 to May 2012, a total of 32 patients who had structural fat grafting for breast reconstruction were enrolled in this prospective study. In 16 patients (control group) fat was harvested by the classical 10-cc-syringe technique, and in the other 16 patients (VAST group) fat was harvested by the VAST. Adipose tissue was harvested from the abdomen area in all patients. The volume of harvested adipose tissue was noted every minute during the operative procedure. The operative harvesting speed was calculated for each patient after 5 min. The volume harvested in 5 min was centrifuged, and the remaining adipocyte volume was noted after centrifugation. The operative harvesting speed and the remaining adipocyte rate were compared in both groups. RESULTS: The average volume of harvested adipose tissue was 18.1 ml in the control group and 156.2 ml in the VAST group (p < 0.001). The average harvesting speed was 3.6 ml/min in the control group using a 10-cc syringe and 31.2 ml/min in the VAST group (p < 0.001). The average remaining adipocyte volume, after centrifugation, was 13.5 ml in the control group, and 118.2 ml in the VAST group (p < 0.001). The average remaining adipocyte rate, after centrifugation, was 74.3 % in the control group and 75.4 % in the VAST group (p = 0.27). CONCLUSIONS: Adipose tissue harvesting can be optimized safely by using the VAST before structural fat grafting. Its quickness, low cost, and efficiency make us choose this method in breast reconstruction when a significant volume of adipocytes is required. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23657722 TI - Evaluation of the histologic changes in the fat-grafted facial skin: clinical trial. AB - BACKGROUND: Fat grafting is increasingly common in plastic surgery procedures. The discovery of stem cells in fat tissue has given a new direction to the use of fat as a therapeutic tool for other patient conditions. Only one experimental study in rats shows dermal changes after application of lipofilling. For this reason, the authors conducted this study to evaluate skin changes in patients after application of the technique. This study aimed to observe histologic changes in the skin of patients undergoing fat grafting. METHODS: Fat grafting was performed in the preauricular region on one side of patients undergoing face lifts at the Jalisco Reconstructive Surgery Institute, Guadalajara, Mexico. Preauricular skin was used in this procedure as a withdrawal study and control condition. Hematoxylin-eosin and Masson staining was performed to assess dermal and epidermal thickness, vascularity, and collagen behavior. No inferential statistics were registered with the Wilcoxon test. RESULTS: The study investigated 16 patients to observe statistically significant differences in dermal thickness, the presence of immature collagen (neoformation), and arteries. No difference in epidermal thickness was observed. CONCLUSIONS: The study showed a regenerative effect with fat grafting that included an increased thickness of the dermis, collagen neoformation, and the presence of increased vascularity in local skin subjected to treatment. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23657723 TI - Triple-plane technique for breast augmentation: solving animation deformities. AB - An unpleasant consequence of subpectoral implant placement is the occurrence of animation deformities during pectoralis muscle contraction. This study aimed to review the results achieved for 524 patients undergoing the triple-plane technique with respect to loss of animation deformities. The evaluation was performed by a group of three plastic surgeons according to the Spear grading system for breast distortion using a 4-point scale. Of the 524 patients evaluated, 351 (67 %) were rated as grade 1 (no distortion), 156 (29.77 %) as grade 2 (mild distortion), 17 (3 %) as grade 3 (moderate distortion), and 0 (0 %) as 4 (severe distortion).The excellent results achieved can be explained by the horizontal sectioning of the major pectoralis muscle at the areola level to the sternal margin. In fact, it determines that superior to sectioning of the muscle, its activity remains normal, with a low degree of dynamic deformities. On the contrary, inferiorly, at the muscular-aponeurotic plane level, no activity is detected, with no resultant animation deformities. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23657724 TI - Treatment of a supernumerary large breast with medial pedicle reduction mammaplasty. AB - Accessory breast tissues including nipples, areolas, and glandular tissue may develop on the chest in addition to two normal breasts. An accessory breast with a complete ductal system, areola, and nipple is termed a "supernumerary breast." Supernumerary nipples are fairly common, but complete supernumerary breasts are rare. This report describes an 18-year-old woman who presented with a complete supernumerary breast including a nipple-areola complex located on the upper outer quadrant of her left breast and causing severe breast asymmetry. She was referred to the authors for aesthetic reasons. Unilateral reduction mammaplasty was performed to remove the supernumerary breast and correct the breast asymmetry. The medial pedicle Wise technique was used for en bloc resection of the ectopic breast, including the nipple-areola complex together with the upper outer breast quadrant. The woman's postoperative course was uneventful. At 8 months after surgery, she was very satisfied with the results. Ectopic breast tissue can be treated by a variety of methods such as liposuction or excision. However, breast deformation because of a complete supernumerary breast is very rare, and research on the treatment of such patients is lacking. No reports describing surgical treatment for this condition were identified in the literature. The authors suggest that unilateral breast reduction is the most appropriate treatment, allowing excision of the accessory tissues, with the best possible cosmetic outcome. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23657725 TI - Endoscopic latissimus dorsi muscle flap for breast reconstruction after skin sparing total mastectomy: report of 14 cases. AB - BACKGROUND: Some authors have mentioned that the endoscopic harvesting of the latissimus dorsi muscle flap for breast reconstruction is an uncommon technique that has been abandoned due to its technical complexity. Therefore, its use for immediate breast reconstruction after skin-sparing total mastectomies is reported for only a few patients, without clinical images of the reconstructed breast or of the donor site. This report describes 14 breast reconstructions using the aforementioned approach, with the latissimus dorsi muscle flap harvested by endoscopy plus the insertion of a breast implant in a single surgical procedure. The objective is to show images of the long-range clinical aesthetic results, both in the reconstructed breast and at the donor site as well as the complications so the reader can evaluate the advantages and disadvantages of the technique. CLINICAL CASES: From 2008 to 2011, 12 women who experienced skin sparing total mastectomy and 2 women who underwent modified radical mastectomy were reconstructed using the aforementioned technique. The average age was 42 years (range 30-58 years), and the average body mass index was 29 kg/m(2) (range 22-34 kg/m(2)). Three patients were heavy smokers: one had undergone a previous abdominoplasty; one had hepatitis C; and one had undergone massive weight loss. Immediate reconstructions were performed for 11 patients, and 3 reconstructions were delayed. The implant volume ranged from 355 to 640 ml. The average endoscopic harvesting time was 163.5 min (range 120-240 min), and the average bleeding was 300 ml. Four patients experienced seromas at the donor site. Acceptance of the reconstructed breast was good in six cases, moderate in seven cases, and poor in one case. Acceptance of the donor site was good in 13 cases and moderate for 1 case. CONCLUSIONS: Endoscopic harvesting of the latissimus dorsi muscle has technical difficulties that have limited its acceptance. However, this technique offers the same quality of breast reconstruction as the open harvesting technique, with the advantage of a smaller scar at the donor site. Based on the results, the authors consider the reported technique to be useful and valid. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23657726 TI - Midterm peer feedback in problem-based learning groups: the effect on individual contributions and achievement. AB - Even though peer process feedback is an often used tool to enhance the effectiveness of collaborative learning environments like PBL, the conditions under which it is best facilitated still need to be investigated. Therefore, this study investigated the effects of individual versus shared reflection and goal setting on students' individual contributions to the group and their academic achievement. In addition, the influence of prior knowledge on the effectiveness of peer feedback was studied. In this pretest-intervention-posttest study 242 first year students were divided into three conditions: condition 1 (individual reflection and goal setting), condition 2 (individual and shared reflection and goal setting), and condition 3 (control group). Results indicated that the quality of individual contributions to the tutorial group did not improve after receiving the peer feedback, nor did it differ between the three conditions. With regard to academic achievement, only males in conditions 1 and 2 showed better academic achievement compared with condition 3. However, there was no difference between both ways of reflection and goal setting with regard to achievement, indicating that both ways are equally effective. Nevertheless, it is still too early to conclude that peer feedback combined with reflection and goal setting is not effective in enhancing students' individual contributions. Students only had a limited number of opportunities to improve their contributions. Therefore, future research should investigate whether an increase in number of tutorial group meetings can enhance the effectiveness of peer feedback. In addition, the effect of quality of reflection and goal setting could be taken into consideration in future research. PMID- 23657727 TI - Aging-associated excess formaldehyde leads to spatial memory deficits. AB - Recent studies show that formaldehyde participates in DNA demethylation/methylation cycle. Emerging evidence identifies that neuronal activity induces global DNA demethylation and re-methylation; and DNA methylation is a critical step for memory formation. These data suggest that endogenous formaldehyde may intrinsically link learning-responsive DNA methylation status and memory formation. Here, we report that during spatial memory formation process, spatial training induces an initial global DNA demethylation and subsequent re-methylation associated with hippocampal formaldehyde elevation then decline to baseline level in Sprague Dawley rats. Scavenging this elevated formaldehyde by formaldehyde-degrading enzyme (FDH), or enhancing DNA demethylation by a DNA demethylating agent, both led to spatial memory deficits by blocking DNA re-methylation in rats. Furthermore, we found that the normal adult rats intrahippocampally injected with excess formaldehyde can imitate the aged-related spatial memory deficits and global DNA methylation decline. These findings indicate that aging-associated excess formaldheyde contributes to cognitive decline during aging. PMID- 23657728 TI - N-terminal pro brain natriuretic peptide-guided management in patients with heart failure and preserved ejection fraction: findings from the Trial of Intensified versus standard medical therapy in elderly patients with congestive heart failure (TIME-CHF). AB - AIMS: To assess the effects of an NT-proBNP-guided medical management on 18-month outcomes in patients with heart failure (HF) and preserved LVEF ( HFpEF). METHODS AND RESULTS: Patients with HFpEF (LVEF >45%; n = 123) and HF with reduced LVEF (HFrEF; LVEF <=45%; n = 499) with age >=60 years, NYHA class >= II, and elevated NT-proBNP (>400 ng/L or >800 ng/L depending on age) were randomized to medical therapy titrated only to reduce symptoms to NYHA <=II (symptom-guided) or also to reduce NT-proBNP below the inclusion threshold (NT-proBNP-guided) during a 6 month period. Patients were followed for an additional 12 months. Despite similar treatment escalation, NT-proBNP reduction and symptom relief were less in HFpEF than in HFrEF. Hospitalization-free survival at 18 months was worse in HFpEF than in HFrEF (P = 0.02), while survival and HF hospitalization-free survival did not differ. Among HFpEF patients, NT-proBNP reduction and symptom relief were similar in the symptom-guided (n = 59) and NT-proBNP-guided (n = 64) group despite more aggressive treatment in the NT-proBNP-guided group. In contrast to effects in HFrEF, NT-proBNP-guided management tended to worsen 18-month outcomes in HFpEF, with P-values for the interactions between LVEF stratum and management strategy of 0.2 for hospitalization-free survival, 0.03 for survival, and 0.01 for HF hospitalization-free survival. CONCLUSIONS: Outcomes in HFpEF were not better than in HFrEF, and opposite effects of NT-proBNP-guided management were observed in HFpEF compared with HFrEF. These preliminary findings suggest that, in contrast to HFrEF, NT-proBNP-guided therapy may not be beneficial in HFpEF. Trial registration ISRCTN43596477. PMID- 23657729 TI - Comparison of keratocyte density after femtosecond laser vs mechanical microkeratome from 3 months up to 5 years after LASIK. AB - BACKGROUND: To compare keratocyte density after mechanical microkeratome LASIK (MK-LASIK) and femtosecond-laser assisted LASIK (FS-LASIK). METHODS: We performed a prospective study of myopic patients that underwent MK-LASIK or FS-LASIK. We measured keratocyte density 3 and 15 months, and 3-5 years after the surgery using confocal microscopy, and compared them with healthy, non-operated corneas. RESULTS: Thirty-one eyes were included in the FS-LASIK group, 30 in the MK-LASIK group and 28 in the control group. Three months postoperatively, there was an increase in the keratocyte population of the whole cornea, mainly due to the mid and posterior stromal layers, in both treatment groups. It was also increased in the stromal bed after MK-LASIK, but not after FS-LASIK. In both groups, this was followed by a normalisation and stabilisation of cell density in those deeper layers 15 months after the surgery. Keratocyte density in the flap and stromal bed was decreased 15 months after FS- and MK-LASIK compared to 3 months postoperatively and compared to controls. It seemed to remain stable thereafter. In spite of this decrease, the average cell density throughout the cornea was not decreased compared to controls at any time point. CONCLUSION: We found a reorganization of keratocytes density after LASIK, with an initial increase, followed by a decrease in the stromal flap and stromal bed 15 months postoperatively, and stable from then onwards, but still maintaining normal average densities in the total cornea. There were no differences between MK- and FS-LASIK. PMID- 23657730 TI - Postural control in strabismic children versus non strabismic age-matched children. AB - BACKGROUND: Several studies have shown that achieving a dual task modifies postural control; however, their results are conflicting. The goal of the present study is to compare the effect of a simple task (eye fixation) to the effect of a dual task (saccadic eye movements) on postural balance in strabismic and in non strabismic children. METHODS: Postural stability was recorded with a platform (Techno Concept(c)) in ten strabismic children aged from 5.4 to 13.8 years (mean age: 8.8 +/- 2.5 years). Data were compared to that of ten age-matched non strabismic control children. We analyzed the surface area, the length and the mean speed of the center of pressure (CoP). RESULTS: Strabismic children are more instable than control children. The surface (340 mm(2)), the length (402 mm) and the mean speed (16 mm/s) of the CoP are significantly higher in strabismic children than in control children (160 mm(2), 280 mm and 11 mm/s, respectively). In addition, both strabismic and control children have a better postural control during saccades than during a fixation task. Surface, length and mean speed of the CoP are significantly reduced during the saccade task (214 mm(2), 306 mm and 12.5 mm/s, respectively) than during the fixation task (285 mm(2), 376 mm and 14.8 mm/s, respectively). CONCLUSIONS: Abnormal postural control in strabismic children could be due to their visual deficits. The postural improvement observed in a dual task (saccades) vs. a simple task (fixation) might be due to the fact that postural control becomes more automatic during saccadic eye movements. PMID- 23657732 TI - [Surveillance in the group of schizophrenia: key to understanding the etiology]. PMID- 23657731 TI - [Expression, identification and experience of emotions in mental diseases. An overview]. AB - Several studies in clinical neuroscience have focused on the analysis of expression of emotions, identification of emotions and experience of emotions. These empirical studies produced certain insights into emotional competency in different mental diseases, most of them in schizophrenia. The current article gives a description of the scientific data about alterations in emotional competency in several mental diseases (e.g. schizophrenia, depression, bipolar and borderline diseases) and links the data, if possible, with clinical relevance with a special focus on emotional competency in prodromal schizophrenia. PMID- 23657733 TI - A monitoring of environmental effects from household greywater reuse for garden irrigation. AB - The option of reusing greywater is proving to be increasingly attractive to address the water shortage issue in many arid and semiarid countries. Greywater represents a constant resource, since an approximately constant amount of greywater is generated from kitchen, laundries, bathroom in every household daily, independent of the weather. However, the use of greywater for irrigation in particular for household gardening may pose major hazards that have not been studied thoroughly. In this study, a 1-year monitoring was conducted in four selected households in Perth, Western Australia. The aim of the monitoring works is to investigate the variability in the greywater flow and quality, and to understand its impact in the surrounding environments. Case studies were selected based on different family structure including number, ages of the occupants, and greywater system they used. Samples of greywater effluent (showers, laundries, bathtub, and sinks), leachate, soil, and plants at each case study were collected between October 2008 and December 2009 which covered the high (spring/summer) and low (autumn/winter) production of greywater. Physical and chemical tests were based on the literature and expected components of laundry and bathroom greywater particularly on greywater components likely to have detrimental impacts on soils, plants, and other water bodies. Monitoring results showed the greywater quality values for BOD, TSS, and pH which sometimes fell outside the range as stipulated in the guidelines. The soil analyses results showed that salinity, SAR, and the organic content of the soil increased as a function of time and affected the plant growth. Nutrient leaching or losses from soil irrigated with greywater shows the movement of nutrients and the sole impact from greywater in uncontrolled plots in case studies is difficult to predicted due to the influence of land dynamics and activities. Investigative and research monitoring was used to understand greywater irrigation in households. Greywater quality is very site specific and difficult to predetermine or control except for the use of some recommended household products when using greywater. Investigative and research monitoring was indicated that greywater quality is very site specific and difficult to predetermine or control except for the use of some recommended household products when using greywater. PMID- 23657734 TI - Using discriminant analysis to assess polycyclic aromatic hydrocarbons contamination in Yongding New River. AB - Yongding New River has been polluted by polycyclic aromatic hydrocarbons (PAHs) which are carcinogenic and mutagenic. In three periods (the abundant water period, mean water period, dry water period), ten sites (totally 30 samples) in Yongding New River were clustered into four categories by hierarchical cluster analysis (hierarchical CA). In the same cluster, the samples had the same approximate contamination situation. In order to eliminate the dimensional differences, the data in each sample, containing 16 kinds of PAHs, were standardized with normal standardization and maximum difference standardization. According to the results of the cubic clustering criterion, pseudo F, and pseudo t (2) (PST2), the proper number of clustering for the 30 samples is 4. Before conducting hierarchical CA and K-means cluster analysis on the samples, we used principal component analysis to obtain another group data set. This data set was composed of the principal component scores which are uncorrelated variables. Hierarchical CA and K-means cluster analysis were used to classify the two data sets into four categories. With the classification results of hierarchical CA and K-means cluster analysis, discriminant analysis is applied to determine which method was better for normalization of the original data and which one was proper to cluster the samples and establish discriminant functions so that a new sample can be grouped into the right categories. PMID- 23657735 TI - Copper, zinc, and cadmium body concentrations in Hexaplex trunculus collected from the Tunisian coast. AB - Copper, Zn, and Cd were analyzed in the soft tissues of the edible gastropod Hexaplex trunculus collected from seven localities along the Tunisian coast. The body concentration of these metals was significantly different depending on the gender and site. Copper and Zn varied, respectively, from 47.70 to 343.64 MUg/g dry weight (dw) and 149.46 to 530.44 MUg/g dw, being higher in males. Cadmium varied from 0.22 to 18.95 MUg/g dw and was always higher in females. Overall, the highest concentrations of the three metals were all recorded in Gabes fishing harbor. Comparison of metal concentrations with the European standards compiled by the Food and Agriculture Organization showed that values exceeded standards in several localities. Imposex had been previously recorded in H. trunculus along the Tunisian coast; however, it does not seem to be related with Cu, Zn, and Cd pollution because the body concentration of these metals is not correlated with imposex degree. Nevertheless, interactive effects resulting from the combination of different pollutants and other stressors cannot be disregarded. PMID- 23657736 TI - Environmental assessment of 2-mercaptobenzimidazole based on the surface plasmon resonance band of gold nanoparticles. AB - A colorimetric assay method is described for the environmental detection of 2 mercaptobenzimidazole (MBI) using surface plasmon resonance of gold nanoparticles (AuNPs). Stable and dispersed AuNPs with intensified plasmon resonance were prepared in situ using a simple, rapid, and eco-friendly procedure by applying ascorbic acid as a reducer and cetyltrimethylammonium bromide as a stabilizer. The presence of MBI has a strong effect on the plasmon absorbance of AuNPs, which was employed for the detection of MBI. The calibration curve was linear in the range of 1.0 * 10(-6)-5.5 * 10(-5) mol/L of MBI; the detection limit was 8.4 * 10(-7) mol/L. The relative standard deviations for eight replicate measurements of 3.0 * 10(-6) and 5 * 10(-5) mol/L MBI were 3.9 and 1.4%, respectively. The method was successfully applied to the determination of MBI in tap, river, sea, and heat exchanger cooling water samples. PMID- 23657737 TI - Detection criteria and preventive measures for occupational disease in the mines of Almaden (Spain). AB - This research focuses on the metallurgy and underground mining job positions in the historic mines of Almaden (Spain). We introduce a preventive methodology for hydrargyrism in work environments known by the name of Methodology for Operational Units Action Levels for Health Indicators (MUONAIS). The methodology allows critical levels to be established using environmental and clinical biological indicators. The prevention plan concentrated on 15 job positions in the metallurgy department that employed more than 100 workers between the years 1986 and 1997. The development of this preventive methodology managed to keep workers' mercury levels below 60 MUg/l in blood and 200 MUg/l in urine, values that present no negative effects on human health. MUONAIS has proven very effective in protecting workers' health. During this period, some cases of micro mercurialism were detected, yet were completely reversible, allowing us to affirm that the terrible disease of hydrargyrism was totally eradicated. PMID- 23657738 TI - Dissipation dynamic and residue distribution of flusilazole in mandarin. AB - In this paper, dissipation dynamic and terminal residue of flusilazole in mandarin and soil, as well as residue distribution of flusilazole in mandarin, were studied at three sites in China. Mandarin peel, mandarin pulp, whole mandarin, and soil samples were extracted by acetonitrile, cleaned up with dispersive solid-phase extraction, then analyzed by gas chromatography-mass spectrometry. The dissipation half-lives of flusilazole in mandarin and soil at all three experiment sites were 6.3-8.4 days and 5.5-13.4 days, respectively, with the exception of the soil dissipation at the Hunan site, which showed an increase-decrease process. Flusilazole residue levels in whole mandarin were all below 0.1 mg/kg on 14 days after the last application. Terminal residue study showed that flusilazole was mostly distributed in mandarin peel, which indicates minimal risk for eating mandarin pulp. These results could provide guidance for the proper and safe use of flusilazole on citrus fruits, and further our understanding of pesticide distribution in citrus fruits. PMID- 23657739 TI - K-edge XANES investigation of octakis(DMSO)lanthanoid(III) complexes in DMSO solution and solid iodides. AB - The potential of high energy XANES (X-ray absorption near edge structure) as a tool for the structural analysis of lanthanoid-containing systems has been explored. The K-edge XANES spectra of La(3+), Gd(3+), and Lu(3+) ions both in DMSO solution and solid octakis(DMSO)lanthanoid(III) iodides have been analysed. Although the K-edges of lanthanoids cover the energy range of 38 (La) to 65 (Lu) keV, the large widths of the core hole states do not appreciably reduce the potential structural information of the XANES data. We show that, for lanthanoid compounds, accurate structural parameters are obtained from the analysis of K edge XANES signals if a deconvolution procedure is carried out. We found that in solid octakis(DMSO)lanthanoid(III) iodides the Ln(3+) ions are coordinated by eight DMSO ligands arranged in a quite symmetric fashion. In DMSO solution the Ln(3+) ions retain a regular eight-coordination structure and the coordination number does not change along the series. In contrast to when in water the second coordination shell has been found to provide a negligible contribution to the XANES spectra of Ln(3+) ions in DMSO solution. PMID- 23657740 TI - Battery ingestion leading to bilateral vocal cord paresis. AB - IMPORTANCE: Disk battery ingestion is common in the pediatric population, with over 50,000 ingestions reported annually. In the upper aerodigestive tract, consequences of such ingestions vary widely from superficial mucosal ulcerations to death from erosion through vital structures. This report describes a battery ingestion complication, vocal cord paralysis, to our knowledge not previously described in the otolaryngology literature. OBSERVATIONS: We describe a patient who presented with biphasic stridor and drooling after upper esophageal disk battery ingestion. The battery was removed 5 hours after ingestion, but stridor with respiratory distress persisted. To stabilize the airway, a tracheotomy was performed after a several-week period of inpatient observation. Two years after ingestion, the patient is tracheostomy dependent. CONCLUSIONS AND RELEVANCE: Disk battery ingestion has the potential for recurrent laryngeal nerve damage and vocal cord paralysis. Expeditious battery removal and long-term care are crucial for successful ingestion management, as ingestion complications can be significant. PMID- 23657741 TI - Recovery of avirulent, thermostable Newcastle disease virus strain NDV4-C from cloned cDNA and stable expression of an inserted foreign gene. AB - A reverse genetics system for thermostable Newcastle disease virus (NDV) is not currently available. In this study, we developed a reverse genetics system for the avirulent and thermostable NDV4-C strain. Successful recovery of NDV4-C was achieved by using either T7 RNA polymerase or cellular RNA polymerase II to drive transcription of the full-length virus antigenome from cloned cDNA. The recovered viruses rNDV4-C (T7) and rNDV4-C (CMV) showed similar growth properties, thermostability, and virulence as the parental strain NDV4-C. The potential of rNDV4-C (T7) to serve as a viral vector was assessed by generating a recombinant virus, rNDV4-eGFP, which expressed enhanced green fluorescent protein. The rNDV4 eGFP could stably carry and express eGFP for at least fifteen passages. The reverse genetics system for NDV4-C will make it possible to analyze the genetic elements that determine thermostability and the oncolytic properties of NDV. PMID- 23657743 TI - Coherent control of plasmonic nanoantennas using optical eigenmodes. AB - The last decade has seen subwavelength focusing of the electromagnetic field in the proximity of nanoplasmonic structures with various designs. However, a shared issue is the spatial confinement of the field, which is mostly inflexible and limited to fixed locations determined by the geometry of the nanostructures, which hampers many applications. Here, we coherently address numerically and experimentally single and multiple plasmonic nanostructures chosen from a given array, resorting to the principle of optical eigenmodes. By decomposing the light field into optical eigenmodes, specifically tailored to the nanostructure, we create a subwavelength, selective and dynamic control of the incident light. The coherent control of plasmonic nanoantennas using this approach shows an almost zero crosstalk. This approach is applicable even in the presence of large transmission aberrations, such as present in holographic diffusers and multimode fibres. The method presents a paradigm shift for the addressing of plasmonic nanostructures by light. PMID- 23657745 TI - Effects of probiotics in periodontal diseases: a systematic review. AB - OBJECTIVES: This study was designed to determine the effects of probiotics in prevention and/or treatment of periodontal diseases. MATERIALS AND METHODS: We performed broad searches in the MEDLINE, Embase, and Cochrane databases and selected articles that satisfied the description of randomized clinical trials comparing the administration of probiotics versus placebo or another intervention to prevent or treat periodontal diseases in adult patients. RESULTS: Four randomized clinical trials were analyzed in the final review process. For the primary outcome, probing pocket depth, there would be no clinical beneficial effect of probiotics. For secondary outcomes, probiotics have shown small benefits on plaque index and gingival inflammation. CONCLUSIONS: Based on the results of this review, the effectiveness of probiotics on the prevention and treatment of periodontal diseases is questionable. There is currently insufficient evidence demonstrating the benefits of systematic preventative use of probiotics in patients with periodontal diseases. CLINICAL RELEVANCE: The use of probiotics are described to prevent or treat periodontal diseases in some clinical trials; therefore, a systematic review of the evidence for the effect of periodontal diseases is needed. PMID- 23657746 TI - Time-linked concurrence of sleep bruxism, periodic limb movements, and EEG arousals in sleep bruxers and healthy controls. AB - OBJECTIVE: Sleep bruxism (SB) and periodic limb movements during sleep (PLMS) may have a common underlying neurophysiologic mechanism, especially in relation to the occurrence of sleep-related electroencephalographic (EEG) arousals. To test this hypothesis, three research questions were assessed. First, it was assessed whether PLMS events occur more frequently in SB patients than in individuals without SB. Second, the question was put forward whether the combined presence of SB and PLMS events is more common than that of isolated SB or PLMS events in a group of SB patients. Third, as to further unravel the possible role of EEG arousals in the underlying neurophysiologic mechanism of SB and PLMS, it was assessed in a group of SB patients whether combined SB/PLMS events with associated EEG arousals are more common than those without associated EEG arousals. Positive answers to these questions could suggest a common neurophysiological basis for both movement disorders. MATERIALS AND METHODS: Seventeen SB patients and 11 healthy controls were polysomnographically studied. SB, PLMS, and EEG arousals were scored. An association was noted when the occurrence was within a 3-s association zone. RESULTS: The PLMS index was higher in SB patients than in healthy controls (P < 0.001). Within the group of SB patients, the combined SB/PLMS index was higher than the isolated SB index (P < 0.001) and the isolated PLMS index (P = 0.018). Similarly, the combined SB/PLMS index with EEG arousal was higher than the combined SB/PLMS index without EEG arousal in SB patients (P < 0.001). CONCLUSION: The results of this study indicate that SB, PLMS, and EEG arousals commonly concur during sleep in a time linked manner. CLINICAL RELEVANCE: SB and PLMS probably have a common underlying neurophysiological mechanism. PMID- 23657747 TI - Immunohistochemical analysis of staged guided bone regeneration and osseointegration of titanium implants using a polyethylene glycol membrane. AB - OBJECTIVES: This study aimed to immunohistochemically evaluate staged guided bone regeneration and osseointegration of titanium implants using two bone graft substitutes in combination with a polyethylene glycol (PEG) membrane in a dog model. MATERIALS AND METHODS: Saddle-type alveolar ridge defects were prepared in the lower jaws of 12 foxhounds and randomly filled with a natural bone mineral (NBM) or a biphasic calcium phosphate (SBC) and covered with an in situ gelling PEG membrane. After a healing period of 8 and 12 weeks (six animals each), modSLA titanium implants were inserted to heal in a submerged position. At 8 + 2 and 12 + 2 weeks, respectively, dissected blocks were processed for immunohistochemical analysis [osteocalcin (OC)]. RESULTS: After 8 + 2 weeks, mean OC values (%) tended to be higher in the NBM group (NBM, 32.7 +/- 8.9%), but failed to reach statistical significance over the SBC group (SBC, 24.4 +/- 6.6%). After 12 + 2 weeks, mean OC values decreased in both groups and was almost identical in both groups (NBM 1.6 +/- 1.2%/SBC 2.1 +/- 1.4%). CONCLUSION: It was concluded that all augmentation procedures investigated were characterised by a comparable OC activity during the process of bone regeneration and osseointegration of modSLA titanium implants. PMID- 23657749 TI - Resection of at-risk mesenteric lymph nodes is associated with improved survival in patients with small bowel neuroendocrine tumors. AB - BACKGROUND: Neuroendocrine tumors of the small intestine commonly metastasize to regional lymph nodes (LNs). Single-institution reports suggest that removal of LNs improves outcome, but comprehensive data are lacking. We hypothesized that the extent of lymphadenectomy reported in a large administrative database would be associated with overall survival for jejunal and ileal neuroendocrine tumors. METHODS: A search of the Surveillance Epidemiology and End Results database was performed for patients with jejunal and ileal neuroendocrine tumors from 1977 to 2004. Descriptive patient characteristics were collected to include age at diagnosis, sex, race, grade, primary tumor size, LN status, number of LNs resected, presence of distant metastasis, and the type of operation. Statistical analyses were limited to patients with only one primary tumor to exclude patients with other malignancies. Univariate and multivariate analyses were performed to analyze the number of LNs resected and the LN ratio (number of positive LNs/total number of LNs removed) to determine the effect on cancer-specific survival. RESULTS: Altogether, 1,364 patients were included in this analysis. Removal of any LNs was associated with improved cancer-specific survival when compared to patients with no LN removal reported (p = 0.0027) on univariate analysis. Among those who had any LNs removed, a median of eight LNs were identified in resection specimens with a median LN ratio of 0.29 (range 0-1). On multivariate analysis (adjusting for age and tumor size), patients with >7 LNs removed experienced better cancer-specific survival than those with <= 7 LNs removed (median survival not reached vs. 140 months): hazard ratio and 95 % confidence interval were 0.573 (0.402, 0.817) (p = 0.002). CONCLUSIONS: This review of a large number of surgical patients demonstrates that regional mesenteric lymphadenectomy in conjunction with resection of the primary tumor is associated with improved survival of patients with small bowel neuroendocrine tumors. PMID- 23657750 TI - Therapeutic approach to patients with a lower-pitched voice after thyroidectomy. AB - BACKGROUND: A lower-pitched voice is one of the most common voice alterations after thyroidectomy without laryngeal nerve injury. The aim of this study was to evaluate the acoustic and stroboscopic changes and the treatment outcomes in patients with a lower-pitched voice with the goal of eventually establishing a therapeutic guideline. METHODS: Patients with a lower-pitched voice were selected according to the results of acoustic analysis among thyroidectomized patients. According to their pitch-gliding ability, patients were classified into a "gliding group" and "nongliding group," and direct voice therapy was performed. For those who did not respond, indirect voice therapy with subsequent identical direct voice therapy was performed. Video-stroboscopy, acoustic and perceptual analysis, and subjective analysis using a questionnaire were performed before and after treatment. The results of the two groups were compared. RESULTS: Fifty patients were enrolled. Decreased vocal cord tension was the most common stroboscopic finding in these patients. After direct voice therapy, 87 % of patients in the gliding group showed restoration of pitch 2 months after thyroidectomy. None of the patients in the nongliding group showed improvement. After indirect voice therapy and subsequent direct voice therapy, these nonresponders finally showed improvement 4.5 months after thyroidectomy. Several characteristic stroboscopic findings of the nongliding group were identified. CONCLUSIONS: The pitch-gliding ability and several specific stroboscopic findings were predictive of a response to direct voice therapy. Based on these findings, an individualized therapeutic approach could be applied, and the pitch of patients with a lower-pitched voice after thyroidectomy was restored earlier than expected. PMID- 23657751 TI - Usefulness of an inflammation-based prognostic score (mGPS) for predicting survival in patients with unresectable malignant biliary obstruction. AB - BACKGROUND: An inflammation-based prognostic score, the modified Glasgow Prognostic Score (mGPS), has been established as a useful tool for predicting postoperative outcome in patients with cancer. However, no studies have investigated the usefulness of the mGPS for prognostication in patients undergoing palliative surgery for unresectable malignant biliary obstruction (UMBO). The present study was conducted to investigate whether the mGPS is useful for predicting the postoperative survival of patients undergoing intraoperative placement of an expandable metal stent for UMBO, or not. METHODS: The mGPS was calculated as follows: patients with both an elevated level of C-reactive protein (CRP) (>1.0 mg/dL) and hypoalbuminemia (<3.5 g/dL) were allocated a score of 2. Patients with only an elevated CRP level were allocated a score of 1, and patients without an elevated CRP level (<=1.0 mg/dL) were allocated a score of 0. Postoperative survival was evaluated by Kaplan-Meier analysis and log rank test. The significance of risk factors for postoperative survival was evaluated with the Cox proportional hazards model. RESULTS: Kaplan-Meier analysis revealed that patients with mGPS 0 (n = 36) and 1 (n = 7) had better postoperative survival (p = 0.017) than patients with mGPS 2 (n = 17). The 6-month and 1-year survival rates of patients with mGPS 0 and 1 were 58.1 and 27.3 %, and those for patients with mGPS 2 were 25.0 and 6.2 %, respectively. Multivariate analysis revealed that mGPS (0, 1/2) was a significant risk factor for postoperative survival (hazard ratio 3.271; 95 % CI 1.109-9.649; p = 0.032). CONCLUSION: The mGPS is not only one of the most significant predictors of postoperative survival for UMBO patients receiving intraoperative biliary stenting but also a useful indicator capable of dividing such patients into two independent groups before surgery. PMID- 23657752 TI - Saucerization: a modified uncapitonnage method of surgery for pulmonary hydatidosis. AB - BACKGROUND: There are contrary opinions regarding the surgical treatment of pulmonary hydatid cysts. We report our experience performing a modified version of uncapitonnage surgery, called "saucerization," for treating pulmonary hydatid cysts. METHODS: A total of 78 patients with pulmonary hydatid cysts were studied regarding their surgery outcome and the complication rate. The procedure used for cyst evacuation depended on whether the cyst had ruptured. If ruptured, cystotomy was done; otherwise, enucleation was preferred. To deal with the residual cavity in an uncapitonnage manner, we removed the thin margins of the pericyst and closed the bronchial openings at the cavity floor. All patients were followed up at least for 6 months. RESULTS: The intensive care unit stay ranged from 1 to 9 days. Incomplete lung expansion (six patients) was the main postoperative complication followed by wound infection (four patients) and persistent air leak (>=7 days) (one patient). There was one death. Dependence on mechanical ventilation and subsequent septic shock were also observed. The other patients exhibited no complications during the follow-up period. CONCLUSIONS: Our experience demonstrated a low complication rate associated with removing the thin margins of the residual cavity and changing the shape of it into a "saucer." The results were satisfactory and comparable to the results of other studies on pulmonary hydatid cysts. PMID- 23657753 TI - Children's behavioral health system transformation: one state's context and strategies for sustained change. AB - The purpose of this paper was to examine the State of Maryland as a case study of sustained change efforts in the service delivery system for children with significant behavioral health needs and their families. A punctuated equilibrium paradigm is introduced to describe Maryland's behavioral health system transformation over the course of three decades. The context and specific strategies that characterized Maryland's execution of its recent Mental Health Transformation State Incentive Grant are highlighted. There is a discussion of one of the pinnacle achievements of Maryland's transformation efforts, the recent statewide establishment of care management entities for children with behavioral health challenges, and its implications for behavioral health in the context of health care reform changes. This case study illustrates how a state can systematically and incrementally develop systems of care for children and families that are values-based, sustainable, and flexible. PMID- 23657755 TI - Inadequate management of medicines by the older-aged living in a retirement village. AB - BACKGROUND: A comparison of the management of medicines by the older-aged living in freehold (fully owned) and rental homes in retirement villages has suggested that the older-aged living in rental, but not freehold, retirement villages may require help to manage their medicines. OBJECTIVE: The objective of this study was to investigate the management of medicines by the older-aged living independently in a leasehold (partly owned) home in retirement village to determine whether they also need help in managing their medicines. METHOD: Semi structured interviews were conducted with 22 older-aged residents living in a leasehold retirement village. MAIN OUTCOME MEASURE: The main outcome measure was the perception of present and ongoing adherence. RESULTS: Amongst participants in the leasehold retirement village, with an average age of 82.9 years, the perceptions of present and ongoing adherence indicated that only 55 % of older aged participants were adherent at the time of the study, and not likely to have problems with adherence within the next 6-12 months. Participants from the leasehold retirement village had a good understanding of 58 % of their illnesses. A mean of 9.8 medicines per person were prescribed. Cardiovascular medicines were the most commonly prescribed at 86 %. CONCLUSION: The older-aged living in leasehold retirement villages may require extra assistance/resources to manage their medicines. PMID- 23657754 TI - A cluster randomized trial of adding peer specialists to intensive case management teams in the Veterans Health Administration. AB - Use of peer specialists (PSs)--individuals with serious mental illness who use their experiences to help others with serious mental illness--is increasing. However, their impact on patient outcomes has not been demonstrated definitively. This cluster randomized, controlled trial within the Veterans Health Administration compared patients served by three intensive case management teams that each deployed two PSs for 1 year, to the patients of three similar teams without PSs (Usual Care). All patients (PS group = 149, Usual Care = 133) had substantial psychiatric inpatient histories and a primary Axis 1 psychiatric disorder. Before and after the year PSs worked, patients were surveyed on their recovery, quality of life, activation (health self-management efficacy), interpersonal relations, and symptoms. Patients in the PS group improved significantly more (z = 2.00, df = 1, p = 0.05) than those receiving Usual Care on activation. There were no other significant differences. PSs helped patients become more active in treatment, which can promote recovery. PMID- 23657756 TI - Elucidation of structure and nature of the PdO-Pd transformation using in situ PDF and XAS techniques. AB - The PdO-Pd phase transformation in a 4 wt% Pd/Al2O3 catalyst has been investigated using in situ X-ray absorption spectroscopy (XAS) and in situ X-ray total scattering (also known as high-energy X-ray diffraction) techniques. Both the partial and total pair distribution functions (PDF) from these respective techniques have been analysed in depth. New information from PDF analysis of total scattering data has been garnered using the differential PDF (d-PDF) approach where only correlations orginating from PdO and metallic Pd are extracted. This method circumvents problems encountered in characerising the catalytically active components due to the diffuse scattering from the disordered gamma-Al2O3 support phase. Quantitative analysis of the palladium components within the catalyst allowed for the phase composition to be established at various temperatures. Above 850 degrees C it was found that PdO had converted to metallic Pd, however, the extent of reduction was of the order ca. 70% Pd metal and 30% PdO. Complementary in situ XANES and EXAFS were performed, with heating to high temperature and subsequent cooling in air, and the results of the analyses support the observations, that residual PdO is detected at elevated temperatures. Hysteresis in the transformation upon cooling is confirmed from XAS studies where reoxidation occurs below 680 degrees C. PMID- 23657757 TI - Patterns of homelessness and implications for HIV health after release from jail. AB - This empirical study examines the association between substance abuse, mental illness, health behaviors and different patterns of homelessness among recently released, HIV-infected jail detainees. Using longitudinal data from a 10-site study, we examine correlates of homelessness, transitions to and from stable housing and the effect of housing on HIV treatment outcomes. Based on our analysis, we found evidence that the transitions from homelessness are closely associated with a reduction in the use of alcohol and illicit drugs, a decline in drug addiction severity, and an improvement in mental health. In addition, we found evidence that disparities in the housing status contributed substantially to the observed gap in the HIV treatment outcomes between homeless and non homeless patients, including in achievement of virological suppression over time. PMID- 23657758 TI - The impact of rapid HIV home test use with sexual partners on subsequent sexual behavior among men who have sex with men. AB - This study explores the sexual behavior of 27 men who have sex with men (MSM) who regularly engage in unprotected anal intercourse (UAI), in the context of HIV home test (HT) use with potential sex partners. Participants were given 16 HT kits to use over 3 months. Among 40 sexual occasions following HIV-negative HT results, there were 25 UAI occasions (16 based on not typically using condoms and nine on HT results), 15 occasions in which condoms were used, and three in which sex did not occur. In the seven occasions where a potential partner received HIV positive HT results, the sexual encounter ended. Almost all participants encountered potential partners who refused HT. Over half of these participants ended sexual encounters when HT was refused, perceiving these partners as HIV positive or too high risk. Some participants reported that HT use heightened their awareness of HIV risk and their commitment to reducing it. PMID- 23657759 TI - Do lifestyle factors influence colorectal cancer risk in Lynch syndrome? AB - Lynch syndrome (LS) is one of the inherited colorectal cancer (CRC) syndromes and is due to germline mutations in one of the mismatch repair (MMR) genes. Within LS affected-families the expression of the syndrome varies, which suggests that other factors, such as lifestyle factors, have an influence on the LS phenotype. This review gives an overview of studies that assessed the role of lifestyle factors in the development of CRC in LS. Several published studies investigated smoking habits or body fatness (BMI) in relation to colorectal tumours. Those studies fairly consistently suggest that smoking and a high BMI markedly increase the risk of CRC in persons with LS. Other lifestyle factors, such as physical activity, alcohol or diet have not or only scarcely been studied. Lifestyle factors may indeed affect CRC risk in LS. However, more prospective studies with only confirmed MMR gene mutation carriers should be done to further elucidate the role of all lifestyle factors in CRC and in other types of cancer in persons with LS. Information on the role of lifestyle factors in the development of LS associated cancers may help in establishing lifestyle and dietary recommendations with the ultimate goal of decreasing cancer risk in persons with LS. PMID- 23657760 TI - Association of the BRCA1 promoter polymorphism rs11655505 with the risk of familial breast and/or ovarian cancer. AB - Germline mutations in the BRCA1 tumor suppressor gene predispose affected individuals to breast cancer; however, incomplete cancer penetrance and the presence of phenocopies in BRCA1 families also indicate genetic and environmental modifiers of breast cancer risk. In this study, we have tested the single nucleotide polymorphism rs1655505 of the BRCA1 promoter, as candidate for the modifier of breast cancer risk. The polymorphic variants were genotyped in BRCA1 negative (729), familial breast and/or ovarian cancer cases (FBOC), including cases with a reported maternal history (154), nonfamilal (sporadic) cases (600), hereditary breast/ovarian cases with BRCA1 mutations (190) and population controls (1,590) from Central Poland. An association with the risk of FBOC was observed for the minor (T) allele and (TT) genotype (T: p = 0.006, OR = 1.40, 95% CI = 1.10-1.79; TT: p = 0.001, OR = 2.23, 95% CI = 1.37-3.62) in female cases with a reported maternal history, specifically in women with the onset of disease after 50 years of age (T: p = 0.004, OR = 1.77, 95% CI = 1.20-2.62; TT: p = 0.001, OR = 3.7, 95% CI = 1.62-8.46). The presented evidence suggests a need to conduct larger studies on the association between genetic variations at the BRCA1 promoter and the breast cancer risk, according to maternal/paternal lineage. PMID- 23657761 TI - Effectiveness and Duration of Effect of Open-Label Lisdexamfetamine Dimesylate in Adults With ADHD. AB - OBJECTIVES: (a) Evaluate the efficacy and duration of effect of lisdexamfetamine dimesylate (LDX) in adult ADHD. (b) Assess the reliability and validity of the Adult ADHD Medication Smoothness of Effect Scale (AMSES) and Adult ADHD Medication Rebound Scale (AMRS). METHOD: Adults ( N = 40) with ADHD were treated with LDX for up to 12 weeks. The primary efficacy measure was the ADHD Rating Scale (ADHD-RS). The psychometric properties of the AMSES and AMRS are analyzed and compared with the ADHD-RS, ADHD Self-Report Scale (ASRS) v1.1 Symptom Checklist, and Time-Sensitive ADHD Symptom Scale (TASS). RESULTS: ADHD-RS scores were significantly improved with LDX. The AMSES and AMRS had high internal consistency and were correlated with the ADHD-RS, ASRS v1.1 Symptom Checklist, and TASS. CONCLUSION: LDX is effective in treating adult ADHD and has a smooth drug effect throughout the day with limited symptom rebound. The AMSES and AMRS are valid and reliable measures. PMID- 23657763 TI - Novel biomarkers for the progression of diabetic nephropathy: soluble TNF receptors. AB - Despite 2 decades of advances in therapy of diabetic patients, the prevalence of diabetic nephropathy among patients with diabetes has not decreased. However, large-scale multicenter studies have achieved great success in terms of the reduction of albuminuria, suggesting that albuminuria might not be an accurate surrogate marker for slowing the rate of renal function decline. It is important to be able to identify individuals at high risk for renal function decline, or ultimately, end-stage kidney disease (ESKD) and its associated cardiovascular disease (CVD). More sensitive early biomarkers, other than albuminuria and the estimated glomerular filtration rate (eGFR), should be required. Recently, serum concentrations of soluble tumor necrosis factor (TNF), receptor 1 (TNFR1), and TNFR2 have predicted future GFR loss and ESKD in patients of a wide variety of stages and both types of diabetes. Longitudinal interventional studies are needed to validate these biomarkers in a broad range of populations prior to implementation in routine diabetes management. PMID- 23657764 TI - Current state of care for diabetic retinopathy in India. AB - In this article we review the current state of care of diabetic retinopathy in India. We discuss the magnitude of the problem; diabetes, and diabetic retinopathy in India. We highlight the causes of vision loss in diabetic retinopathy. The current level of awareness among general population and physicians is a concern. Current screening strategies practiced in India and the situational analysis of ophthalmologists in India are also reviewed. We review the current management of diabetic macular edema and proliferative diabetic retinopathy. To know the current practice pattern among retinal surgeons in India, a survey was done and the results of the survey are presented. There are few studies in the Indian population which have found some genetic risk and protective factors and a summary of these studies are also presented in this article. PMID- 23657767 TI - Electrochemically-gated delivery of analyte bands in microfluidic devices using bipolar electrodes. AB - A method for controlling enrichment, separation, and delivery of analytes into different secondary microchannels using simple microfluidic architecture is described. The approach, which is based on bipolar electrochemistry, requires only easily fabricated electrodes and a low-voltage DC power supply: no pumps or valves are necessary. Upon application of a voltage between two driving electrodes, passive bipolar electrodes (BPEs) are activated that result in formation of a local electric field gradient. This gradient leads to separation and enrichment of a pair of fluorescent analytes within a primary microfluidic channel. Subsequently, other passive BPEs can be activated to deliver the enriched tracers to separate secondary microchannels. The principles and performance underpinning the method are described. PMID- 23657766 TI - Whole body vibration training improves leg blood flow and adiposity in patients with type 2 diabetes mellitus. AB - This study aimed at examined the effect of a 12-week whole body vibration (WBV) training program on leg blood flow and body composition in people with type 2 diabetes mellitus (T2DM). Forty participants were randomly assigned to either a WBV training group (WBV; n = 20) or usual-care control group (CON; n = 20). Body composition [waist circumference, waist to hip ratio (WHR), weight, height, percentage of body fat and fat-free mass], heart rate, and blood flow [femoral artery diameter, maximum systolic velocity, maximum diastolic velocity (DV), time averaged mean, pulsatility index and resistance index (RI), mean velocity (V med), and peak blood velocities (PBV)] were assessed at baseline and after 12 weeks. There were significant increases in the blood flow (p = 0.046), V med (p = 0.050), and DV (p = 0.037) after WBV compared with CON. Within-group analysis showed significant differences in V med, PBV, and DV in the WBV group. Significant decreases after the intervention in weight (p < 0.001), waist circumference (p < 0.001), WHR (p < 0.05), and body fat (p < 0.05) were also found, with significant between-groups decreases in all these outcomes in the WBV group. Significant correlations existed between changes in percent body fat and blood flow [blood flow (-0.761), V med (-0.607), PBV (-0.677), and RI (0.0510)]. WBV training can be considered an effective means to increase leg blood flow and to reduce adiposity in patients with T2DM. PMID- 23657768 TI - [Urethral strictures: a difficult path to standardized and simultaneously individualized therapy]. PMID- 23657769 TI - [Anatomy and anatomical foundations of urethral surgery]. AB - To achieve an optimal outcome after urethral reconstructive surgery knowledge of urethral and urogenital anatomy is mandatory. It is necessary to know the anatomical characteristics of grafts and flaps to achieve successful surgical results. An ideal graft is not yet available and an optimal surgical outcome depends on the technique of harvesting, graft handling and histological transplant characteristics. Surgical technique and experience are building a successful urethral surgery out of the challenge. PMID- 23657770 TI - [Oral mucosa for reconstructive urethral surgery]. AB - The use of oral mucosa for urethral stricture repair has become the standard approach in reconstructive urethral surgery. Compared to other tissues oral mucosa shows several advantages, such as simple harvesting, good urine tolerance and low harvesting morbidity. For defects of the male bulbar urethra measuring 2 cm or longer, urethral reconstruction with oral mucosa is the procedure of choice. The oral mucosa graft can be used as an inlay or as an onlay graft. Most repairs can be completed in one stage but for complex strictures two stages are needed. PMID- 23657771 TI - [Prepuce as free transplant]. AB - Graft urethroplasty using free transplants has become a standard procedure in the therapy of complicated urethral strictures. Various types of tissues can be used as graft material and different criteria are important for the suitability of tissues for urethroplasty. It was recognized early on that the prepuce was an easy to harvest tissue with low morbidity and excellent functional results. In this article the suitability of this tissue for functional results will be discussed within the context of the biology of free transplants and the available literature. PMID- 23657772 TI - [Pedicled prepuce flap plasty: results in patients with hypospadias or urethral sticture]. AB - BACKGROUND: Operative interventions of the urethra remain challenging procedures. The vascular onlay flap of the inner prepuce is a possible technique for short and long segment urethral defects. PATIENTS AND METHODS: A total of 195 patients were surgically treated with a vascular prepuce flap between 1994 and 2010 at the Urology Department of Essen Medical University. Patient data were analyzed retrospectively and a questionnaire was sent to all patients. RESULTS: Of the patients 115 answered the questionnaires and were included in the study. Of these 61 patients were treated in childhood due to hypospadias and 54 patients suffered from acquired urethral stricture. Major complications were postoperative fistulas in 8.2 % and 7.4 % and hematomas in 6.6 % and 11.1 % of cases, respectively. Operative revision had to be performed in 13.1 % and 14.8 % of cases and severe obstructive micturition problems (IPSS score >= 20) were observed in only 3.3 % and 11.1% of patients, respectively. Subjective overall satisfaction with the result of the operation was high (67.2 % and 88.9 %, respectively). CONCLUSION: The vascular prepuce flap is a reliable method for correction of short and long segment urethral defects and is associated with high patient satisfaction. PMID- 23657773 TI - [Management of urethral strictures: practical guidelines]. AB - For the diagnosis of urethral strictures it is of utmost importance to determine the exact position and length of the strictured area. The optimal method for this purpose is retrograde urethrography which can be combined with a voiding cystourethrography. Endoscopic treatment of urethral strictures is only reasonable for cases with short segment bulbar strictures (<1.5 cm) otherwise recurrence rates are very high. For long segment or recurrent strictures only open urethroplasty provides good results in terms of recurrence-free survival. In these open techniques care must be taken in early postoperative management to obtain the best results. PMID- 23657775 TI - [ASS and cancer risk]. PMID- 23657776 TI - [Hernia surgery in urology: part 1: inguinal, femoral and umbilical hernias - fundamentals of clinical diagnostics and treatment]. AB - Hernias are a common occurrence with correspondingly huge clinical and economic impacts on the healthcare system. The most common forms of hernia which need to be diagnosed and treated in routine urological work are inguinal and umbilical hernias. With the objective of reconstructing and stabilizing the inguinal canal there are the possibilities of open and minimally invasive surgery and both methods can be performed with suture or mesh repair. Indications for surgery of umbilical hernias are infrequent although this is possible with little effort under local anesthesia. This article presents an overview of the epidemiology, pathogenesis, clinical symptoms, diagnostics and therapy of inguinal, femoral and umbilical hernias. PMID- 23657781 TI - Embolization of life-threatening arterial rupture in patients with vascular Ehlers-Danlos syndrome. AB - PURPOSE: To evaluate the safety and efficacy of transarterial embolization of life-threatening arterial rupture in patients with vascular Ehlers-Danlos syndrome (vEDS) in a single tertiary referral center. METHODS: We retrospectively analyzed transarterial embolization for vEDS performed at our institution from 2000 to 2012. The indication of embolization was spontaneous arterial rupture or pseudoaneurysm with acute bleeding. All interventions used a percutaneous approach through a 5F or less introducer sheath. Embolic agents were microcoils and glue in 3 procedures, glue alone in 2, and microcoils alone in 2. RESULTS: Five consecutive vEDS patients were treated by 7 embolization procedures (4 women, mean age 29.8 years). All procedures were successfully performed. Two patients required a second procedure for newly arterial lesions at a different site from the first procedure. Four of the five patients were still alive after a mean follow-up of 19.4 (range 1-74.7) months. One patient died of multiple organ failure 2 days after procedure. Minor procedural complications were observed in 3 procedures (43 %), all directly managed during the same session. Remote arterial lesions occurred after 3 procedures (43 %); one underwent a second embolization, and the other 2 were observed conservatively. Puncture site complication was observed in only one procedure (14 %). CONCLUSION: Embolization for vEDS is a safe and effective method to manage life-threatening arterial rupture. PMID- 23657782 TI - Critical limb ischemia in association with Charcot neuroarthropathy: complex endovascular therapy for limb salvage. AB - Charcot neuroarthropathy is a low-incidence complication of diabetic foot and is associated with ankle and hind foot deformity. Patients who have not developed deep ulcers are managed with offloading and supportive bracing or orthopedic arthrodesis. In patients who have developed ulcers and severe ankle instability and deformity, below-the-knee amputation is often indicated, especially when deformity and cutaneous involvement result in osteomyelitis. Ischemic association has not been described but can be present as a part of peripheral arterial disease in the diabetic population. In this extreme and advanced stage of combined neuroischemic diabetic foot disease, revascularization strategies can support surgical and orthopedic therapy, thus preventing osteomyelitis and leading to limb and foot salvage. PMID- 23657783 TI - Enhanced labelling on alcoholic drinks: reviewing the evidence to guide alcohol policy. AB - BACKGROUND: Consumer and public health organizations have called for better labelling on alcoholic drinks. However, there is a lack of consensus about the best elements to include. This review summarizes alcohol labelling policy worldwide and examines available evidence to support enhanced labelling. METHODS: A literature review was carried out in June-July 2012 on Scopus using the key word 'alcohol' combined with 'allergens', 'labels', 'nutrition information', 'ingredients', 'consumer information' and/or 'warning'. Articles discussing advertising and promotion of alcohol were excluded. A search through Google and the System for Grey Literature in Europe (SIGLE) identified additional sources on alcohol labelling policies, mainly from governmental and organizational websites. RESULTS: Five elements were identified as potentially useful to consumers: (i) a list of ingredients, (ii) nutritional information, (iii) serving size and servings per container, (iv) a definition of 'moderate' intake and (v) a health warning. Alcohol labelling policy with regard to these aspects is quite rudimentary in most countries, with few requiring a list of ingredients or health warnings, and none requiring basic nutritional information. Only one country (Australia) requires serving size and servings per container to be displayed. Our study suggests that there are both potential advantages and disadvantages to providing consumers with more information about alcohol products. CONCLUSIONS: Current evidence seems to support prompt inclusion of a list of ingredients, nutritional information (usually only kcal) and health warnings on labels. Standard drink and serving size is useful only when combined with other health education efforts. A definition of 'moderate intake' and recommended drinking guidelines are best suited to other contexts. PMID- 23657784 TI - Conformational disorder in energy transfer: beyond Forster theory. AB - Energy transfer in donor-acceptor chromophore pairs, where the absorption of each species is well separated while donor emission and acceptor absorption overlap, can be understood through a Forster resonance energy transfer model. The picture is more complex for organic conjugated polymers, where the total absorption spectrum can be described as a sum of the individual contributions from each subunit (chromophore), whose absorption is not well separated. Although excitations in these systems tend to be well localized, traditional donors and acceptors cannot be defined and energy transfer can occur through various pathways where each subunit (chromophore) is capable of playing either role. In addition, fast torsional motions between individual monomers can break conjugation and lead to reordering of excited state energy levels. Fast torsional fluctuations occur on the same timescale as electronic transitions leading to multiple trivial unavoided crossings between excited states during dynamics. We use the non-adiabatic excited state molecular dynamics (NA-ESMD) approach to simulate energy transfer between two poly-phenylene vinylene (PPV) oligomers composed of 3-rings and 4-rings, respectively, separated by varying distances. The change in the spatial localization of the transient electronic transition density, initially localized on the donors, is used to determine the transfer rate. Our analysis shows that evolution of the intramolecular transition density can be decomposed into contributions from multiple transfer pathways. Here we present a detailed analysis of ensemble dynamics as well as a few representative trajectories which demonstrate the intertwined role of electronic and conformational processes. Our study reveals the complex nature of energy transfer in organic conjugated polymer systems and emphasizes the caution that must be taken in performing such an analysis when a single simple unidirectional pathway is unlikely. PMID- 23657786 TI - Formation of C=N bonds by the release of H2: a new strategy for synthesis of imines and benzazoles. AB - A new strategy for synthesis of imines using the approach of release of H2 has been developed. This oxidant- and acceptor-free Pd/C catalysis protocol is further applied to synthesis of benzoxazoles, benzimidazoles, and benzothiazoles through a one-pot cascade reaction with notably high yields. PMID- 23657788 TI - Induction therapy for patients with multiple sclerosis: why? When? How? AB - The concept of induction treatment followed by long-term maintenance treatment in multiple sclerosis (MS) has attracted considerable attention. The combination of mitoxantrone as the induction therapy followed by an immunomodulatory drug (e.g., interferon beta or glatiramer acetate) as the maintenance therapy is of particular interest. This approach is suitable for patients with particularly aggressive disease, characterised by frequent relapses with incomplete recovery and the accumulation of focal lesions visible on magnetic resonance imaging. A long-term study has shown that a short (6 month) course of mitoxantrone followed by maintenance therapy with an immunomodulatory drug brings about a rapid reduction in disease activity and subsequent sustained disease control for at least 5 years. Furthermore, randomised studies have demonstrated that induction with mitoxantrone followed by maintenance treatment affords better disease control than monotherapy with an interferon beta. Natalizumab is also effective in patients with very active MS, but has a propensity to result in rebound inflammatory disease activity on withdrawal. More recently, a mere 5-day course of 12-mg intravenous perfusions of alemtuzumab was found to bring long-term clinical benefits in early relapsing MS patients at risk of developing severe systemic autoimmune disease within the space of a few years. PMID- 23657787 TI - Role of orexin in the pathophysiology of depression: potential for pharmacological intervention. AB - Depression is a devastating mental disorder with an increasing impact throughout the world, whereas the efficacy of currently available pharmacological treatment is still limited. Growing evidence from preclinical and clinical studies suggests that orexins (neuropeptides that are also known as hypocretins) and their receptors are involved in the physiopathology of depression. Indeed, the orexinergic system regulates functions that are disturbed in depressive states such as sleep, reward system, feeding behavior, the stress response and monoaminergic neurotransmission. Nevertheless, the precise role of orexins in behavioral and neurophysiological impairments observed in depression is still unclear. Both hypoactivity and hyperactivity of orexin signaling pathways have been found to be associated with depression. These discrepancies in the literature prompted the necessity for additional investigations, as the orexinergic system appears to be a promising target to treat the symptoms of depression. This assumption is underlined by recent data suggesting that pharmacological blockade of orexin receptors induces a robust antidepressant-like effect in an animal model of depression. Further preclinical and clinical studies are needed to progress the overall understanding of the orexinergic alterations in depression, which will eventually translate preliminary observations into real therapeutic potential. The aim of this paper is to provide an overview of human and animal research dedicated to the study of the specific involvement of orexins in depression, and to propose a framework in which disturbances of the orexinergic system are regarded as an integral component of the etiology of depression. PMID- 23657789 TI - Mutation-specific antibody detects mutant BRAFV600E protein expression in human colon carcinomas. AB - BACKGROUND: A point mutation (V600E) in the BRAF oncogene is a prognostic biomarker and may predict for nonresponse to anti-EGFR antibody therapy in patients with colorectal carcinoma. BRAFV600E mutations are frequently detected in tumors with microsatellite instability and indicate a sporadic origin. We used a mutation-specific antibody to examine mutant BRAFV600E protein expression and its concordance with BRAFV600E mutation data. METHODS: Primary stage III colon carcinomas were analyzed for BRAFV600E mutations in exon 15, and 50 BRAFV600E mutation carriers and 25 wild-type tumors were selected for analysis of BRAF proteins by immunohistochemistry (IHC). IHC was performed in archival tissue specimens using a pan-BRAF antibody and a mutation-specific antibody against BRAFV600E proteins. Staining was scored by 2 pathologists who were blinded to clinical and mutation data. RESULTS: Using a pan-BRAF antibody, total BRAF protein expression was observed in the tumor cell cytoplasm in 74 of 75 colon carcinomas. A mutation-specific antibody identified diffuse cytoplasmic staining of mutant BRAFV600E proteins in 49 of 74 cancers. Analysis using a polymerase chain reaction-based assay revealed that all 49 of these cancers carried BRAFV600E mutations. In contrast, BRAFV600E staining was absent in all 25 tumors that carried wild-type copies of BRAF. CONCLUSIONS: A BRAF mutation-specific (V600E) antibody detected tumors with BRAFV600E mutations and exhibited complete concordance with a DNA-based method. These results support the use of IHC as a simplified strategy to screen colorectal cancers for BRAFV600E mutations in clinical practice. PMID- 23657790 TI - Alternative splicing is required for RCT1-mediated disease resistance in Medicago truncatula. AB - RCT1 is a TIR-NBS-LRR-type resistance (R) gene in Medicago truncatula that confers resistance to multiple races of Colletotrichum trifolii, a hemi biotrophic fungal pathogen that causes anthracnose disease in Medicago and other closely related legumes. RCT1 undergoes alternative splicing at both coding and 3'-untranslated regions, thereby producing multiple transcript variants in its expression profile. Alternative splicing of RCT1 in the coding region results from the retention of intron 4. Because intron 4 lies downstream of the LRR encoding exons and contains an in-frame stop codon, the alternative transcript is predicted to encode a truncated protein consisting of the entire portion of the TIR, NBS, and LRR domains but lacks the C-terminal domain of the full-length RCT1 protein encoded by the regular transcript. Here we provide evidence that the RCT1 mediated disease resistance requires the combined presence of the regular and alternative transcripts. Neither the regular nor the alternative RCT1 transcript alone is sufficient to confer resistance against the pathogen. This study, in addition to the reports on the tobacco N and Arabidopsis RPS4 genes, adds another significant example showing the involvement of alternative splicing in R gene mediated plant immunity. PMID- 23657791 TI - Regulation of the angiogenesis of acquired middle ear cholesteatomas by inhibitor of DNA binding transcription factor. AB - IMPORTANCE: The aggressive growth of cholesteatoma in the middle ear involves the angiogenesis of the cholesteatomal perimatrix. However, which transcription factor is involved in this process remains unclear. OBJECTIVE: To identify a transcription factor that supports the aggressive growth of cholesteatoma by controlling the angiogenesis of cholesteatoma in the middle ear milieu. DESIGN: We used clinical specimens for the profiling of angiogenic factors and their regulatory transcription factors in cholesteatoma. Human skin keratinocytes and endothelial cells were used for evaluation of the effects of candidate transcription factor on the angiogenic factor regulation and endothelial cell proliferation. SETTING: University departments of otolaryngology-head and neck surgery. PARTICIPANTS: Eight clinical cholesteatomal and 8 control specimens were used for cellular and molecular biologic evaluation. An additional 8 cholesteatomal and 8 aural skin specimens were used for microarray studies. MAIN OUTCOME MEASURES: The expression of vascular endothelial growth factor, interleukin 8, and cyclooxygenase 2 as measured by means of immunohistochemistry and molecular biologic methods. RESULTS: Human aural cholesteatomal specimens were rich in the expression of angiogenic factors such as vascular endothelial growth factor in the cholesteatomal matrix and perimatrix, accompanied by the transcription factor inhibitor of DNA binding (Id1). We found Id1 to be an essential regulator of vascular endothelial growth factor. In addition, potent angiogenic factors, including interleukin 8 and cyclooxygenase 2, were regulated by Id1 via different molecular mechanisms. CONCLUSIONS AND RELEVANCE: The transcription factor Id1 controls the angiogenesis of cholesteatoma through the regulation of vascular endothelial growth factor, interleukin 8, and cyclooxygenase 2, which are responsible for the angiogenesis of cholesteatoma. Id1 may serve as a good target for the treatment of cholesteatomal progression in the middle ear milieu. PMID- 23657793 TI - Clostridium difficile infection in patients with HIV/AIDS. AB - Clostridium difficile infection (CDI) affects significant numbers of hospitalized patients and is an increasing problem in the community. It is also among the most commonly isolated pathogens in HIV patients with diarrheal illness and is >=2 fold more common in HIV-seropositive individuals. This association is stronger in those with low absolute CD4 T cell counts or meeting clinical criteria for an AIDS diagnosis, and was most pronounced before the wide availability of highly active antiretroviral therapy. The presentation and outcome of CDI in HIV appears similar to the general population. The increased risk can in part be attributed to increased hospitalization and antimicrobial use, but HIV related alterations in fecal microbiota, gut mucosal integrity, and humoral and cell mediated immunity are also likely to play a role. Here we review the evidence for these observations and the relevance of recent advances in the diagnosis and management of CDI for the HIV clinician. PMID- 23657794 TI - Functional evaluation of iodoacetic acid induced photoreceptor degeneration in the cat. AB - Iodoacetic acid (IAA) has been applied to different species to acutely induce photoreceptor degeneration. The purpose of the present study was to use this toxin to thoroughly eliminate photoreceptors and induce complete blindness in the cat. IAA was delivered by single ear vein injection (20 mg kg(-1)). Six months after the IAA treatment, functional evaluations including pupillary light reflex (PLR), electroretinogram (ERG), visual behavior tests were performed. Morphological examinations were carried out after the functional evaluation. The present result shows that, six months after the IAA application, animals lost visual functions and became completely blind. High dose IAA application via ear vein delivery created an acute and reliable complete photoreceptor degeneration model in the cat. This model can be applied to genetic and cellular therapies for visual function restoration. PMID- 23657795 TI - Environmental connections of novel avian-origin H7N9 influenza virus infection and virus adaptation to the human. AB - A novel H7N9 influenza A virus has been discovered as the causative identity of the emerging acute respiratory infection cases in Shanghai, China. This virus has also been identified in cases of infection in the neighboring area Hangzhou City in Zhejiang Province. In this study, epidemiologic, clinical, and virological data from three patients in Hangzhou who were confirmed to be infected by the novel H7N9 influenza A virus were collected and analyzed. Human respiratory specimens and chicken feces from a contacted free market were tested for influenza virus by real-time reverse transcription PCR (RT-PCR) and sequencing. The clinical features of the three cases were similar featured with high fever and severe respiratory symptoms; however, only one of the patients died. A certain degree of diversity was observed among the three Hangzhou viruses sequenced from human samples compared with other reported H7N9 influenza A viruses. The sequences of the novel avian-origin H7N9 influenza viruses from Hangzhou City contained important amino acid substitutions related to human adaptation. One of the Hangzhou viruses had gained a novel amino acid substitution (Q226I) in the receptor binding region of hemagglutinin. More importantly, the virus sequenced from the chicken feces had a 627E substitution in the PB2 protein instead of the mammalian-adapted 627K substitution that was found in the PB2 proteins from the Hangzhou viruses from the three patients. Therefore, the newly-emerging H7N9 virus might be under adaptation pressure that will help it "jump" from avian to human hosts. The significance of these substitutions needs further exploration, with both laboratory experiments and extensive field surveillance. PMID- 23657797 TI - MtDNA depletion and deletions may also have a role in myelodysplastic syndrome. PMID- 23657796 TI - An ecosystem-based intervention to reduce HIV transmission risk and increase medication adherence among inmates being released to the community. AB - HIV+ inmates reentering their communities are at increased risk for poor health outcomes and for transmitting HIV. This article reports on a randomized trial comparing an ecosystem-based intervention and an individually focused intervention for reducing HIV transmission risk and improving medication adherence. Reincarceration was considered as a secondary variable. Both groups decreased sexual risk behavior over the 12-month follow-up period. Unexpectedly, the ecosystem intervention group was less likely to be taking medication or to be adherent and more likely to have been reincarcerated. Failure to demonstrate a significant advantage of the ecosystem intervention may have resulted from the difficulty of engaging family and other ecosystem members in the intervention. Implications for developing and applying interventions for this population are discussed. PMID- 23657798 TI - Regression of conjunctival maltoma with topical antibiotics and steroids. PMID- 23657799 TI - Next-generation sequencing for viruses in children with rapid-onset type 1 diabetes. AB - AIMS/HYPOTHESIS: Viruses are candidate causative agents in the pathogenesis of autoimmune (type 1) diabetes. We hypothesised that children with a rapid onset of type 1 diabetes may have been exposed to such agents shortly before the initiation of islet autoimmunity, possibly at high dose, and thus study of these children could help identify viruses involved in the development of autoimmune diabetes. METHODS: We used next-generation sequencing to search for viruses in plasma samples and examined the history of infection and fever in children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study who progressed to type 1 diabetes within 6 months from the appearance of islet autoimmunity, and in matched islet-autoantibody-negative controls. RESULTS: Viruses were not detected more frequently in plasma from rapid-onset patients than in controls during the period surrounding seroconversion. In addition, infection histories were found to be similar between children with rapid-onset diabetes and control children, although episodes of fever were reported less frequently in children with rapid-onset diabetes. CONCLUSIONS/INTERPRETATION: These findings do not support the presence of viraemia around the time of seroconversion in young children with rapid-onset type 1 diabetes. PMID- 23657801 TI - Development of a novel non-radioactive cell-based method for the screening of SGLT1 and SGLT2 inhibitors using 1-NBDG. AB - Sodium-coupled glucose co-transporters SGLT1 and SGLT2 play important roles in intestinal absorption and renal reabsorption of glucose, respectively. Blocking SGLT2 is a novel mechanism for lowering the blood glucose level by inhibiting renal glucose reabsorption and selective SGLT2 inhibitors are under development for treatment of type 2 diabetes. Furthermore, it has been reported that perturbation of SGLT1 is associated with cardiomyopathy and cancer. Therefore, both SGLT1 and SGLT2 are potential therapeutic targets. Here we report the development of a non-radioactive cell-based method for the screening of SGLT inhibitors using COS-7 cells transiently expressing human SGLT1 (hSGLT1), CHO-K1 cells stably expressing human SGLT2 (hSGLT2), and a novel fluorescent d-glucose analogue 1-NBDG as a substrate. Our data indicate that 1-NBDG can be a good replacement for the currently used isotope-labeled SGLT substrate, (14)C-AMG. The Michaelis constant of 1-NBDG transport (0.55 mM) is similar to that of d-glucose (0.51 mM) and AMG (0.40 mM) transport through hSGLT1. The IC50 values of a SGLT inhibitor phlorizin for hSGLT1 obtained using 1-NBDG and (14)C-AMG were identical (0.11 MUM) in our cell-based system. The IC50 values of dapagliflozin, a well known selective SGLT2 inhibitor, for hSGLT2 and hSGLT1 determined using 1-NBDG were 1.86 nM and 880 nM, respectively, which are comparable to the published results obtained using (14)C-AMG. Compared to (14)C-AMG, the use of 1-NBDG is cost-effective, convenient and potentially more sensitive. Taken together, a non radioactive system using 1-NBDG has been validated as a rapid and reliable method for the screening of SGLT1 and SGLT2 inhibitors. PMID- 23657802 TI - Method for simultaneous analysis of nine second-line anti-tuberculosis drugs using UPLC-MS/MS. AB - OBJECTIVES: Therapeutic drug monitoring (TDM) of anti-tuberculosis (TB) drugs is beneficial for patients responding slowly to treatment and those with multidrug resistant TB. We used ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to develop a rapid method for simultaneously measuring the blood concentrations of nine second-line anti-TB drugs: streptomycin, kanamycin, clarithromycin, cycloserine, moxifloxacin, levofloxacin, para aminosalicylic acid, prothionamide and linezolid. METHODS: Serum samples were extracted with acidified methanol and neutralized with NaOH. A Waters Acquity HSS T3 column and gradients of ammonium formate and acetonitrile in 0.1% formic acid were used for UPLC separation. Drug concentrations were determined by multiple reaction monitoring in positive ion mode, and assay performance was evaluated. We applied this method to TDM, analysing random serum samples from 85 patients treated with second-line drugs. RESULTS: Sample preparation using acidified methanol extraction followed by neutralization yielded good recovery and ionization efficiency, with chromatographic separation achieved within 3 min per sample. Within-run and between-run precisions were 1.7%-7.5% and 1.7%-12.4%, respectively, at concentrations representing low and high levels for the nine drugs. Lower limits of detection and quantification were 0.025-0.5 and 0.25-5.0 MUg/mL, respectively. Linearity was acceptable at five concentrations for each drug. No ion suppression was observed at the retention time for most compounds, except for streptomycin, kanamycin and cycloserine, which were eluted close to the void volume of the column. In a limited pilot study, all quantifiable human samples had values within the validated assay ranges. CONCLUSIONS: The performance of our MS/MS detection technique was generally acceptable. The method provided rapid, sensitive and reproducible quantification of nine second-line anti-TB drugs and should facilitate drug monitoring during treatment. PMID- 23657800 TI - The prenatal environment and type 1 diabetes. AB - There is ample evidence that environmental factors are involved in the aetiology of type 1 diabetes, but the nature and timing of the interactions are poorly understood. The intrauterine environment is known to play a role in the later development of type 2 diabetes, and this review considers a possible role in type 1 diabetes. Autoimmune type 1 diabetes is rare in those diagnosed before 6 months of age, but endogenous autoantibodies predictive of future type 1 diabetes may be detectable by 6-12 months of age, suggesting that environmental factors may operate before this age in some cases. Indirect evidence of a protective effect for the intrauterine environment comes from the observation that mothers with type 1 diabetes are less likely than affected fathers to transmit diabetes to their offspring, although the precise role (if any) is unclear. The risk of childhood-onset type 1 diabetes increases with maternal age at delivery, and with high birthweight, but these associations are weak and heterogeneous, and these factors are unlikely to be directly causally related to type 1 diabetes. No firm conclusion can be drawn from studies of maternal enteroviral infection or from various nutritional exposures. The birth process itself may play a role, as suggested by the slightly increased risk in children born by Caesarean section; lack of contact with maternal bacteria is one suggested mechanism. In sum, there is circumstantial evidence, but no proof of principle, that maternal or intrauterine conditions may modulate genetic risk of type 1 diabetes. The disease process culminating in type 1 diabetes typically begins in early life, but it is not clear whether the trail begins before or after birth. PMID- 23657803 TI - Increasing prevalence and diversity of ESBL/AmpC-type beta-lactamase genes in Escherichia coli isolated from veal calves from 1997 to 2010. AB - OBJECTIVES: Several studies on faecal carriage of extended-spectrum beta lactamase (ESBL)/AmpC-producing Escherichia coli have been performed in cattle, but little is known about faecal carriage in veal calves. This study describes the prevalence and molecular characteristics of ESBL/AmpC genes in E. coli isolated from faecal samples of veal calves from 1997 to 2010. METHODS: Pooled faecal samples were inoculated using selective enrichment broth and subsequently selective MacConkey agar. All isolates with reduced susceptibility to cefotaxime were screened by PCR and sequencing analysis for the presence of ESBL/AmpC genes. RESULTS: The prevalence of E. coli with reduced susceptibility to cefotaxime showed a discontinuous increasing trend, ranging from 4% in 1998 and 1999 to 39% in 2010. Promoter mutations of the chromosomal ampC gene were present in all years. In 2000, ESBL genes blaCTX-M-1, blaTEM-52 and blaTEM-20 were first observed. Before 2005 the majority of E. coli with reduced susceptibility to cefotaxime harboured ampC promoter mutations. From 2005 onwards the majority harboured blaCTX-M genes, of which blaCTX-M-1 was the most abundant, followed by blaCTX-M-14 and blaCTX-M-15. The diversity of blaCTX-M genes gradually increased from one variant in 2000 to six variants in 2010. The prevalence of blaTEM-52 was relatively low, but it was detected from 2000 onwards. blaCMY and blaSHV were found sporadically. CONCLUSIONS: The prevalence and molecular diversity of genes encoding cefotaxime resistance in E. coli isolated from veal calves over a 14 year period showed an increasing trend. From 2005 onwards, blaCTX-M genes were most abundant, especially blaCTX-M-1. PMID- 23657805 TI - Antiviral activity of Bifidobacterium adolescentis SPM0212 against Hepatitis B virus. AB - Bifidobacteria are considered one of the most beneficial probiotics and have been widely studied for their effects in preventing and treating specific pathological conditions. The present study explored the antiviral activity of Bifidobacterium adolescentis SPM0212 isolated from healthy Koreans against hepatitis B virus (HBV) and its mechanism of action. To determine the effect of B. adolescentis SPM0212 against HBV, the level of HBV surface antigen (HBsAg) in the culture medium and the levels of viral transcripts in HepG2.2.15 cells were measured by enzyme-linked immunosorbent assay and reverse transcription-quantitative PCR (RT qPCR), respectively. To clarify the mechanism, we performed RT-qPCR using specific primers for genes encoding Interferon (IFN)-signaling components and IFN inducible antiviral effectors. The cell extract of B. adolescentis SPM0212 dose dependently decreased the extracellular HBsAg level by up to 50 %. Its gene expression in HepG2.2.15 cells was also inhibited by 40 %. This extract significantly increased the expression level of myxovirus resistance A, which is an IFN-inducible antiviral effector. Furthermore, the antiviral activity was observed in the fraction of compound(s) with molecular weights under 30 kDa. Thus, the cell extract of B. adolescentis SPM0212 inhibits HBV and its antiviral mechanism is associated with the Mx GTPase pathway. PMID- 23657804 TI - Vaginal concentrations of lactic acid potently inactivate HIV. AB - OBJECTIVES: When Lactobacillus spp. dominate the vaginal microbiota of women of reproductive age they acidify the vagina to pH <4.0 by producing ~1% lactic acid in a nearly racemic mixture of d- and l-isomers. We determined the HIV virucidal activity of racemic lactic acid, and its d- and l-isomers, compared with acetic acid and acidity alone (by the addition of HCl). METHODS: HIV-1 and HIV-2 were transiently treated with acids in the absence or presence of human genital secretions at 37 degrees C for different time intervals, then immediately neutralized and residual infectivity determined in the TZM-bl reporter cell line. RESULTS: l-lactic acid at 0.3% (w/w) was 17-fold more potent than d-lactic acid in inactivating HIVBa-L. Complete inactivation of different HIV-1 subtypes and HIV-2 was achieved with >=0.4% (w/w) l-lactic acid. At a typical vaginal pH of 3.8, l-lactic acid at 1% (w/w) more potently and rapidly inactivated HIVBa-L and HIV-1 transmitter/founder strains compared with 1% (w/w) acetic acid and with acidity alone, all adjusted to pH 3.8. A final concentration of 1% (w/w) l-lactic acid maximally inactivated HIVBa-L in the presence of cervicovaginal secretions and seminal plasma. The anti-HIV activity of l-lactic acid was pH dependent, being abrogated at neutral pH, indicating that its virucidal activity is mediated by protonated lactic acid and not the lactate anion. CONCLUSIONS: l-lactic acid at physiological concentrations demonstrates potent HIV virucidal activity distinct from acidity alone and greater than acetic acid, suggesting a protective role in the sexual transmission of HIV. PMID- 23657806 TI - Synthesis and biological evaluation of some novel urea and thiourea derivatives of isoxazolo[4,5-d]pyridazine and structurally related thiazolo[4,5-d]pyridazine as antimicrobial agents. AB - This study reports the synthesis of some novel isoxazolo[4,5-d]pyridazines and structurally related thiazolo[4,5-d]pyridazines, and their biological evaluation as antimicrobial agents. The proposed compounds were designed to contain pharmacophores such as urea, thiourea, sulfonylurea (thiourea) and some derived functionalities that are believed to contribute to the anticipated biological activities. The results revealed that 25 compounds displayed broad spectrum of antibacterial activity, with greater inhibitory effect on the growth of the tested Gram positive strains compared to Gram negative ones. Moreover, 14 compounds were able to produce appreciable growth inhibitory activity against Candida albicans fungus when compared to Clotrimazole. Most of the tested isoxazolo[4,5-d]pyridazines displayed better antimicrobial profile than their corresponding thiazolo[4,5-d]pyridazine congeners. Four compounds namely, p-(3,7 dimethyl-4-oxo-4H-isoxazolo [4,5-d]pyridazine-5-yl)benzenesulfonylthioureas (11c d), 3-substituted-2-[p-(3,7-dimethyl-4-oxo-4H-isoxazolo[4,5-d]pyridazine-5-yl) benzene-sufonylimino]-4-oxothiazolidines (13d) and p-(2,7-dimethyl-4-oxo-4H thiazolo[4,5-d]pyridazin-5-yl)benzenesulfonylthiourea (24c) were found to be most active antimicrobial members in present study. PMID- 23657807 TI - Monacolin K affects lipid metabolism through SIRT1/AMPK pathway in HepG2 cells. AB - Monacolin K is the secondary metabolite isolated from Monascus spp. It is the natural form of lovastatin, which is clinically used to reduce the synthesis of cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase. In the present study, monacolin K increased protein expression of SIRT1 and phosphorylation level of AMP-activated protein kinase (AMPK) in HepG2 cells. Through activation of SIRT1/AMPK pathway, monacolin K increased phosphorylation of acetyl CoA carboxylase and caused nuclear translocation of forkhead box O1. The western blotting results showed that monacolin K increased expression of adipose triglyceride lipase but decreased abundances of fatty acid synthase (FAS) and sterol regulatory element-binding protein 1 (SREBP1). Monacolin K also decreased the intracellular accumulation of lipids as demonstrated by Oil Red O staining. In addition, the immunostaining showed that monacolin K prevented the nuclear translocation of SREBP1, indicating the association with down-regulation of FAS. All the demonstrated effects of monacolin K were counteracted by nicotinamide or compound C, the inhibitors of SIRT1 or AMPK. In summary, monacolin K reduces the lipid content through SIRT1/AMPK pathway in HepG2 cells, which promotes catabolism and inhibits anabolism of lipid. PMID- 23657809 TI - Sonographic diagnosis of bilateral pneumothorax following an acupuncture session. AB - We present the case of a 57-year-old woman who presented with the acute onset of chest pain and dyspnea, which started while undergoing acupuncture for neck pain. A bedside ultrasound revealed bilateral pneumothoraces, which were confirmed radiographically. We discuss the details of the case, the sonographic features of pneumothorax, and the role of bedside ultrasonography in the assessment of an acutely dyspneic patient. PMID- 23657810 TI - Effects of a tattoo on men's behavior and attitudes towards women: An experimental field study. AB - Previous studies have indicated negative evaluations of women with tattoos. However, a study by Swami and Furnham (2007) showed that tattooed women were rated as less physically attractive but more sexually promiscuous. Given that men interpret women's sexual intent according to their physical appearance, we predicted that women with tattoos would be more favorably approached by men. A temporary tattoo was placed on confederates' lower back, or not, and all confederates were instructed to read a book while lying flat on their stomach on a well-known beach. Two experiments were conducted. The first experiment showed that more men (N = 220) approached the tattooed confederates and that the mean latency of their approach was quicker. A second experiment showed that men (N = 440) estimated to have more chances to have a date and to have sex on the first date with tattooed confederates. However, the level of physical attractiveness attributed to the confederate was not influenced by the tattoo condition. These results were discussed with respect to men's possible misinterpretation of women wearing tattoos and the risks associated with this misinterpretation. PMID- 23657812 TI - Sexuality and suicidality: matched-pairs analyses reveal unique characteristics in non-heterosexual suicidal behaviors. AB - The present findings offer new perspectives on differences between suicide-risk heterosexuals and non-heterosexuals (lesbian, gay, bisexual, and questioning: LGBQ). Results from an anonymous online survey, employing standardized scales, showed that LGBQ participants reported significantly greater suicide-risk than heterosexuals. Seventy-nine matched pairs of suicide-risk LGBQ and heterosexuals were examined by individual suicide risk factors. Results showed no significant differences on separate measures of suicidal ideation; however, LGBQ participants were more likely to report suicide attempts, disclosure of suicidal intentions, and prediction of future suicide attempts. The LGBQ group also indicated greater likelihood of going online to develop new personal relationships. Multiple regression modeling was conducted to guide outreach and support efforts, revealing unique factors predicting help-seeking denial of suicide-risk LGBQ. Implications include the importance of online support and considering sexual minorities not just as a potential high-risk group, but also as a population with unique suicide risks and behaviors. PMID- 23657811 TI - Predictors of sexual hookups: a theory-based, prospective study of first-year college women. AB - Hooking up, or engaging in sexual interactions outside of committed relationships, has become increasingly common among college students. This study sought to identify predictors of sexual hookup behavior among first-year college women using a prospective longitudinal design. We used problem behavior theory (Jessor, 1991) as an organizing conceptual framework and examined risk and protective factors for hooking up from three domains: personality, behavior, and perceived environment. Participants (N = 483, 67 % White) completed an initial baseline survey that assessed risk and protective factors, and nine monthly follow-up surveys that assessed the number of hookups involving performing oral sex, receiving oral sex, and vaginal sex. Over the course of the school year, 20 % of women engaged in at least one hookup involving receiving oral sex, 25 % engaged in at least one hookup involving performing oral sex, and 25 % engaged in at least one hookup involving vaginal sex. Using two-part modeling with logistic and negative binomial regression, we identified predictors of hooking up. Risk factors for sexual hookups included hookup intentions, impulsivity, sensation seeking, pre-college hookups, alcohol use, marijuana use, social comparison orientation, and situational triggers for hookups. Protective factors against sexual hookups included subjective religiosity, self-esteem, religious service attendance, and having married parents. Race/ethnicity, socioeconomic status, hookup attitudes, depression, cigarette smoking, academic achievement, injunctive norms, parental connectedness, and being in a romantic relationship were not consistent predictors of sexual hookups. Future research on hookups should consider the array of individual and social factors that influence this behavior. PMID- 23657813 TI - Conformational regulation of substituted azepanes through selective monofluorination. AB - Substituted azepanes are common bioactive epitopes with flexible ring structures. The conformational effects of monofluorination in model azepane rings were investigated by (1)H NMR spectroscopy and computational modelling. A single fluorine atom, installed diastereoselectively, was found to bias the azepane ring to one major conformation for one diastereomer. PMID- 23657815 TI - Regulation of lipid droplet and membrane biogenesis by the acidic tail of the phosphatidate phosphatase Pah1p. AB - Lipins are evolutionarily conserved phosphatidate phosphatases that perform key functions in phospholipid, triglyceride, and membrane biogenesis. Translocation of lipins on membranes requires their dephosphorylation by the Nem1p-Spo7p transmembrane phosphatase complex through a poorly understood mechanism. Here we identify the carboxy-terminal acidic tail of the yeast lipin Pah1p as an important regulator of this step. Deletion or mutations of the tail disrupt binding of Pah1p to the Nem1p-Spo7p complex and Pah1p membrane translocation. Overexpression of Nem1p-Spo7p drives the recruitment of Pah1p in the vicinity of lipid droplets in an acidic tail-dependent manner and induces lipid droplet biogenesis. Genetic analysis shows that the acidic tail is essential for the Nem1p-Spo7p-dependent activation of Pah1p but not for the function of Pah1p itself once it is dephosphorylated. Loss of the tail disrupts nuclear structure, INO1 gene expression, and triglyceride synthesis. Similar acidic sequences are present in the carboxy-terminal ends of all yeast lipin orthologues. We propose that acidic tail-dependent binding and dephosphorylation of Pah1p by the Nem1p Spo7p complex is an important determinant of its function in lipid and membrane biogenesis. PMID- 23657814 TI - Transforming growth factor-beta1 selectively inhibits hepatocyte growth factor expression via a micro-RNA-199-dependent posttranscriptional mechanism. AB - Hepatocyte growth factor (HGF) is a multipotent endogenous repair factor secreted primarily by mesenchymal cells with effects on cells expressing its receptor, Met. HGF promotes normal tissue regeneration and inhibits fibrotic remodeling in part by promoting proliferation and migration of endothelial and epithelial cells and protecting these cells from apoptosis. HGF also inhibits myofibroblast proliferation. The profibrotic cytokine transforming growth factor beta 1 (TGF beta1) suppresses HGF expression but not the expression of NK2, an HGF splice variant that antagonizes HGF-induced proliferation. We investigated the mechanism for differential regulation of HGF and NK2 by TGF-beta1. TGF-beta1 down-regulated HGF in primary human adult pulmonary fibroblasts (HLFb) and increased the expression of miR-199a-3p, a microRNA (miRNA) associated with fibrotic remodeling. HGF and NK2 contain completely different 3' untranslated regions (UTRs), and we determined that miR-199a-3p targeted HGF mRNA for suppression but not NK2. A pre-miR-199 mimic inhibited the expression of a luciferase reporter harboring the HGF 3' UTR but not a pmirGLO reporter containing the NK2 3' UTR. In contrast, an anti-miRNA inhibitor specific for miR-199a-3p prevented TGF-beta1 induced reduction of both HGF mRNA and HGF protein secretion. Taken together, these findings demonstrate that HGF is distinctly regulated at the posttranscriptional level from its antagonist NK2. PMID- 23657816 TI - Chemoattractant stimulation of TORC2 is regulated by receptor/G protein-targeted inhibitory mechanisms that function upstream and independently of an essential GEF/Ras activation pathway in Dictyostelium. AB - Global stimulation of Dictyostelium with different chemoattractants elicits multiple transient signaling responses, including synthesis of cAMP and cGMP, actin polymerization, activation of kinases ERK2, TORC2, and phosphatidylinositide 3-kinase, and Ras-GTP accumulation. Mechanisms that down regulate these responses are poorly understood. Here we examine transient activation of TORC2 in response to chemically distinct chemoattractants, cAMP and folate, and suggest that TORC2 is regulated by adaptive, desensitizing responses to stimulatory ligands that are independent of downstream, feedback, or feedforward circuits. Cells with acquired insensitivity to either folate or cAMP remain fully responsive to TORC2 activation if stimulated with the other ligand. Thus TORC2 responses to cAMP or folate are not cross-inhibitory. Using a series of signaling mutants, we show that folate and cAMP activate TORC2 through an identical GEF/Ras pathway but separate receptors and G protein couplings. Because the common GEF/Ras pathway also remains fully responsive to one chemoattractant after desensitization to the other, GEF/Ras must act downstream and independent of adaptation to persistent ligand stimulation. When initial chemoattractant concentrations are immediately diluted, cells rapidly regain full responsiveness. We suggest that ligand adaptation functions in upstream inhibitory pathways that involve chemoattractant-specific receptor/G protein complexes and regulate multiple response pathways. PMID- 23657817 TI - Galectin-3- and phospho-caveolin-1-dependent outside-in integrin signaling mediates the EGF motogenic response in mammary cancer cells. AB - In murine mammary epithelial cancer cells, galectin-3 binding to beta1,6 acetylglucosaminyltransferase V (Mgat5)-modified N-glycans restricts epidermal growth factor (EGF) receptor mobility in the plasma membrane and acts synergistically with phospho-caveolin-1 to promote integrin-dependent matrix remodeling and cell migration. We show that EGF signaling to RhoA is galectin-3 and phospho-caveolin-1 dependent and promotes the formation of transient, actin rich, circular dorsal ruffles (CDRs), cell migration, and fibronectin fibrillogenesis via Src- and integrin-linked kinase (ILK)-dependent signaling. ILK, Src, and galectin-3 also mediate EGF stimulation of caveolin-1 phosphorylation. Direct activation of integrin with Mn2+ induces galectin-3, ILK, and Src-dependent RhoA activation and caveolin-1 phosphorylation. This suggests that in response to EGF, galectin-3 enables outside-in integrin signaling stimulating phospho-caveolin-1-dependent RhoA activation, actin reorganization in CDRs, cell migration, and fibronectin remodeling. Similarly, caveolin-1/galectin 3-dependent EGF signaling induces motility, peripheral actin ruffling, and RhoA activation in MDA-MB-231 human breast carcinoma cells, but not HeLa cells. These studies define a galectin-3/phospho-caveolin-1/RhoA signaling module that mediates integrin signaling downstream of growth factor activation, leading to actin and matrix remodeling and tumor cell migration in metastatic cancer cells. PMID- 23657818 TI - Loss of actomyosin regulation in distal arthrogryposis myopathy due to mutant myosin binding protein-C slow. AB - Myosin binding protein C (MyBP-C) is expressed in striated muscles, where it plays key roles in the modulation of actomyosin cross-bridges. Slow MyBP-C (sMyBP C) consists of multiple variants sharing common domains but also containing unique segments within the NH2 and COOH termini. Two missense mutations in the NH2 terminus (W236R) and COOH terminus (Y856H) of sMyBP-C have been causally linked to the development of distal arthrogryposis-1 (DA-1), a severe skeletal muscle disorder. Using a combination of in vitro binding and motility assays, we show that the COOH terminus mediates binding of sMyBP-C to thick filaments, while the NH2 terminus modulates the formation of actomyosin cross-bridges in a variant specific manner. Consistent with this, a recombinant NH2-terminal peptide that excludes residues 34-59 reduces the sliding velocity of actin filaments past myosin heads from 9.0 +/- 1.3 to 5.7 +/- 1.0 MUm/s at 0.1 MUM, while a recombinant peptide that excludes residues 21-59 fails to do so. Notably, the actomyosin regulatory properties of sMyBP-C are completely abolished by the presence of the DA-1 mutations. In summary, our studies are the first to show that the NH2 and COOH termini of sMyBP-C have distinct functions, which are regulated by differential splicing, and are compromized by the presence of missense point mutations linked to muscle disease. PMID- 23657819 TI - Expression of freeze-responsive proteins, Fr10 and Li16, from freeze-tolerant frogs enhances freezing survival of BmN insect cells. AB - To date, two novel freeze-responsive proteins, Fr10 and Li16, have been discovered in the wood frog, Rana sylvatica, and likely support freezing survival. Although previous studies have established tissue distribution of each protein, there have been no studies that explore their functional consequences in intolerant cells. To assess the ability of Fr10 and Li16 to confer freeze tolerance, we transfected each protein into a freeze-intolerant silkworm cell line (BmN). Selected controls were the transfection of an unrelated protein (CAT) and a no-transfection sample. Li16 and Fr10 showed 1.8 +/- 0.1- and 1.7 +/- 0.2 fold, respectively, greater survival after freezing at -6 degrees C for 1 h than did transfection controls. To investigate how these novel proteins protect cells from freezing damage, protein structures were predicted from primary amino acid sequences. Analysis of the structures indicated that Fr10 is a secreted protein and may be a new type IV antifreeze protein, whereas Li16 may have intracellular membrane associated functions. This study shows that freezing protection can be provided to intolerant cells by the overexpression of transfected Li16 and Fr10 frog proteins. Results from this study will provide new insights into adapting intolerant cells for medical organ cryoprotection using a natural vertebrate model of tolerance. PMID- 23657820 TI - Prevalence and management of hypertension in patients with acute coronary syndrome vary with gender: Observations from the Chinese registry of acute coronary events (CRACE). AB - Hypertension affects one billion people worldwide and is an independent risk factor for death after acute coronary syndrome (ACS). The aim of this study was to examine the prevalence and medical treatment of hypertension among 1,301 ACS patients enrolled into the Chinese registry of acute coronary events (CRACE) trial. Analyses were performed by gender, with both genders combined and according to international practice. Multivariable models identified factors associated with use of different classes of antihypertensive medication, and examined the correlation between hypertension and gender with mortality. The use of angiotensin-converting enzyme inhibitors (ACEI), beta-blockers, calcium channel blockers (CCBs) and diuretics increased in both genders during management of presenting ACS. Hypertensive men were more likely to have been receiving beta blockers when they were discharged (77.2%) than women (69.2%). Hypertensive women were more likely to have received diuretics when they were discharged (28.4%) than men (22%). ACEI use increased by ~60% (absolute increase) in both women and men as a result of ACS treatment, but remained similar between the genders, and the same phenomenon was observed in the use of CCBs. Moreover, hypertensive women were less likely to receive evidence-based medication to treat their acute coronary event than men (for women and men, respectively: beta-blocker, 69.2 vs. 77.2%; ACEI, 85.8 vs. 87.5%). Hypertension is more prevalent in women than in men with ACS, and its medical management varies with gender, but it has a similar association with mortality in both genders. Opportunities exist to improve medical therapy and outcomes for women with hypertension. PMID- 23657821 TI - Robotic surgery of the kidney and ureter in pediatric patients. AB - Robotic actuators have revolutionized surgery for urologic disorders in pediatric patients. Robotic procedures have become widely available for several different ablative and reconstructive operations in children. The success rates have paralleled those of open surgical techniques and provide the benefit of smaller incisions and less manipulation of tissue during the procedures. Robotics employs increased dexterity, better visualization, and less fatigue, allowing greater precision. We must continue to evolve with the ever-changing advancements in technology and take a keen interest in maintaining our skills to ensure excellent outcomes and patient safety. PMID- 23657822 TI - Necrotic and apoptotic cells serve as nuclei for calcification on osteoblastic differentiation of human mesenchymal stem cells in vitro. AB - A close relationship between cell death and pathological calcification has recently been reported, such as vascular calcification in atherosclerosis. However, the roles of cell death in calcification by osteoblast lineage have not been elucidated in detail. In this study, we investigated whether cell death is involved in the calcification on osteoblastic differentiation of human bone marrow mesenchymal stem cells (hMSC) under osteogenic culture in vitro. Apoptosis and necrosis occurred in an osteogenic culture of hMSC, and cell death preceded calcification. The generation of intracellular reactive oxygen species, chromatin condensation and fragmentation, and caspase-3 activation increased in this culture. A pan-caspase inhibitor (Z-VAD-FMK) and anti-oxidants (Tiron and n acetylcysteine) inhibited osteogenic culture-induced cell death and calcification. Furthermore, calcification was significantly promoted by the addition of necrotic dead cells or its membrane fraction. Spontaneously dead cells by osteogenic culture and exogenously added necrotic cells were surrounded by calcium deposits. Induction of localized cell death by photodynamic treatment in the osteogenic culture resulted in co-localized calcification. These findings show that necrotic and apoptotic cell deaths were induced in an osteogenic culture of hMSC and indicated that both necrotic and apoptotic cells of osteoblast lineage served as nuclei for calcification on osteoblastic differentiation of hMSC in vitro. PMID- 23657823 TI - Neuropsychiatric events with varenicline: a modified prescription-event monitoring study in general practice in England. AB - BACKGROUND: Varenicline (Champix((r))), launched in the UK in December 2006, is indicated for the treatment of smoking cessation in adults (>=18 years of age). In 2008, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK issued a warning suggesting that varenicline was associated with disparate neuropsychiatric symptoms, including depression, suicidal thoughts and behaviour. In response to this regulatory warning, the Drug Safety Research Unit conducted a modified prescription-event monitoring (M-PEM) study to monitor the safety of varenicline. OBJECTIVE: The aim of this study was to estimate the incidence and examine the pattern of neuropsychiatric events reported to general practitioners (GPs) in England during the immediate postmarketing period for varenicline. METHODS: A postmarketing surveillance study was conducted using the observational cohort technique of M-PEM. Patients were identified from dispensed prescriptions issued by primary care physicians between December 2006 and March 2007. Data on exposure, previous history of psychiatric illness and events reported during and after treatment were collected from questionnaires. In order to determine whether hazards for neuropsychiatric events of interest (depression, anxiety, aggression, suicidal ideation, non-fatal self-harm) were non-constant over time (which could indicate a possible association with the drug), the pattern of events was examined by plotting the smoothed hazard function estimate and then fitting a Weibull model. The Weibull model shape parameter (beta) and 95 % confidence interval were used as a test for a non-constant hazard function (where a value of 1 indicates a constant hazard over time). In addition to this analysis, the difference in incidence densities (IDs) between month 1 and months 2-3 were calculated and compared. RESULTS: The cohort comprised of 12,159 patients (median age 47 years [interquartile range 19]; 56.9 % [n = 6924 female]). The number of events reported during treatment, reason for stopping, adverse drug reactions (ADRs), and the p-value for the Weibull shape parameter were as follows: depression (n = 94; 42; 19; p = 0.144); anxiety (n = 94; 49; 9; p = 0.009); aggression (n = 7; 4; 2; p = 0.465); suicidal ideation (n = 8; 4; 1; p = 0.989) and non-fatal self-harm (n = 5; 1; 0; p = 0.771). No differences in the IDs between months 1 and months 2-3 were found for any of the events. CONCLUSION: Whilst between 7 and 17 % of neuropsychiatric events were attributed to the drug by GPs and approximately 20-50 % were given as reasons for stopping, no signal was raised using the ID differences approach, and only anxiety was flagged as a potential signal for an ADR using the Weibull model. The signal for anxiety requires further evaluation to determine whether the drug plays a part in the development of anxiety or whether it is a withdrawal symptom caused by smoking cessation. Analysis methods will lack power when the numbers of events are low even when a large number of participants are included in the study. PMID- 23657824 TI - Data mining for prospective early detection of safety signals in the Vaccine Adverse Event Reporting System (VAERS): a case study of febrile seizures after a 2010-2011 seasonal influenza virus vaccine. AB - BACKGROUND: Reports of data mining results as an initial indication of a prospectively detected safety signal in the US Vaccine Adverse Event Reporting System (VAERS) have been limited. In April 2010 a vaccine safety signal for febrile seizures after Fluvax((r)) and Fluvax((r)) Junior was identified in Australia without the aid of data mining. In order to refine Northern Hemisphere influenza vaccine safety surveillance, VAERS data mining analyses based on vaccine brand name were initiated during the 2010-2011 influenza season. OBJECTIVE: We describe the strategies that led to the finding of a novel safety signal using empirical Bayesian data mining. METHODS: The primary US VAERS analysis calculated an empirical Bayesian geometric mean (EBGM), which was adjusted for age group, sex and year received. A secondary age-stratified analysis calculated a separate EBGM for 11 pre-defined age subsets. These bi weekly analyses were generated with database restrictions that separated live and inactivated vaccines as well as with the US VAERS database. A cutoff of 2.0 at the fifth percentile of the confidence interval (CI) for the EBGM, the EB05, was used to identify vaccine adverse event combinations for further evaluation. Examination of potential interactions among concomitantly administered vaccines is based on the Interaction Signal Score (INTSS), which is a relative measure of how much excess disproportionality is present in the three-dimensional combination of two vaccines and one adverse event term. An INTSS >1 indicates that the CI for the three-dimensional analysis is larger than and does not overlap with the CI from the highest two-dimensional analysis. We subsequently examined the possibility of masking by removing all 2,095 Fluzone((r)) 2010-2011 reports from the 10 December 2010 version of the VAERS database. In addition, we calculated relative reporting ratios to observe the relative contribution of adjustment and the Multi-Item Gamma Poisson Shrinker (MGPS) algorithm to EBGM values. RESULTS: On 10 December 2010, US VAERS analyses we found an EB05 >2 for Fluzone((r)) 2010-2011 and the Medical Dictionary for Regulatory Activities (MedDRA((r))) term "febrile seizure". MedDRA((r)) terminology is the medical terminology developed under the auspices of the International Conference on Harmonization of technical requirements for Registration of Pharmaceuticals for Human Use (ICH). No other vaccine products had independent vaccine-febrile seizure combinations with an EB05 >2. Three-dimensional analyses to examine possible interactions among vaccine products concomitantly administered with Fluzone((r)) 2010-2011 yielded Interaction Signal Score values <1. Removal of all Fluzone((r)) 2010-2011 reports from the VAERS database failed to demonstrate a previously masked vaccine adverse event pair with an EB05 >2. The inactivated vaccine database restriction resulted in a 41 % reduction in background VAERS reports and a 24 % reduction in foreground VAERS reports. CONCLUSION: Empirical Bayesian data mining in VAERS prospectively detected the safety signal for febrile seizures after Fluzone((r)) 2010-2011 in young children. The EB05 threshold, database restrictions, adjustment and baseline data mining were strategies adopted a priori to enhance the specificity of the 2010-2011 influenza vaccine data mining analyses. A database restriction used to separate live vaccines resulted in a reduced EB05. Adjustment of data mining analyses had a larger effect on estimates of disproportionality than the MGPS algorithm. Masking did not appear to influence our findings. This case study illustrates the value of VAERS data mining for vaccine safety monitoring. PMID- 23657826 TI - Aromatic ring size effects on the photophysics and photochemistry of styrylbenzothiazole. AB - The effect of ring size on the photophysics and photochemistry of styrylbenzothiazole has been investigated via systematic replacement of the phenyl ring of 1-phenyl-2-(2-benzothiazolyl)ethene with naphthyl and phenanthryl rings. Steady state absorption and fluorescence techniques have been employed to record the spectra in a variety of solvents, in conjunction with density functional theory (DFT) calculations, to probe absorption spectra and other properties of relevance to photo-excitation. Important experimental parameters were determined, such as fluorescence quantum yield and quantum yields of photochemical E-Z isomerisation. In addition, the computed potential energy surfaces of the ground and excited states were constructed using DFT/TD-DFT methods that showed that the photo-reaction is based on an adiabatic mechanism, in the sense that the reaction occurs via the excited-state potential energy surface. Based on the significant blue shift of the Z-isomer absorption maximum relative to that of the E-isomer, and the high percentage of Z-isomers in the photo-stationary state, these compounds may serve as potential promising candidates for optical data storage applications. PMID- 23657825 TI - The impact of direct healthcare professional communication on prescribing practice in the UK hospital setting: an interrupted time series analysis. AB - BACKGROUND: Direct Healthcare Professional Communications (DHPCs) aim to quickly disseminate information to key healthcare professionals to inform practice and minimize patient harm. The Medicines and Healthcare products Regulatory Agency (MHRA) issues warnings and alerts to communicate safety information effectively in the UK. OBJECTIVE: To investigate the impact of MHRA DHPCs on prescribing practice in the secondary-care setting, looking specifically at a drug-drug interaction-the concomitant use of clopidogrel and proton pump inhibitors (PPIs) [as omeprazole]-and a drug-disease contraindication-the use of conventional (typical) antipsychotics in dementia. METHODS: The effects of the MHRA DHPCs were analysed using segmented binary logistic regression of interrupted time series. This allowed for the detection of any significant changes in prescribing practice occurring after the MHRA warnings were issued, whilst controlling for the baseline period. RESULTS: Of the patients concomitantly prescribed clopidogrel and omeprazole on admission, the rate at which omeprazole was substituted for either another PPI (with the exception of esomeprazole), or for a histamine H2 antagonist showed a significant step-change increase after the DHPC was issued. The modelled rate increased from 5.1 % in the month directly before the intervention to 25.1 % in the following month (odds ratio [OR] 6.18; p < 0.001). However, the action taken in the switching of therapy was not always consistent with the advice from the current MHRA warning. The rate of typical antipsychotic prescribing in patients with dementia was declining significantly by 3.9 % per quarter prior to the DHPC being issued (OR 0.970; p = 0.035). No significant step change was detected immediately after the DHPC (p = 0.962). However, the rate of decline increased significantly in the post-warning period to 12.3 % per quarter (OR 0.938; p = 0.006). CONCLUSION: This study has shown that DHPCs issued by the MHRA as warnings are associated with changes in prescribing practices in secondary care. However, their impact is variable depending on the intervention described by the warning. A national initiative to ensure patient safety information is effectively translated into practice and the effect of the warning continues beyond the period of the issue would be beneficial. PMID- 23657827 TI - Using leaf optical properties to detect ozone effects on foliar biochemistry. AB - Efficient methods for accurate and meaningful high-throughput plant phenotyping are limiting the development and breeding of stress-tolerant crops. A number of emerging techniques, specifically remote sensing methods, have been identified as promising tools for plant phenotyping. These remote sensing methods can be used to accurately and rapidly relate variations in leaf optical properties with important plant characteristics, such as chemistry, morphology, and photosynthetic properties at the leaf and canopy scales. In this study, we explored the potential to utilize optical (lambda = 500-2,400 nm) near-surface remote sensing reflectance spectroscopy to evaluate the effects of ozone pollution on photosynthetic capacity of soybean (Glycine max Merr.). The research was conducted at the Soybean Free Air Concentration Enrichment (SoyFACE) facility where we subjected plants to ambient (44 nL L(-1)) and elevated ozone (79-82 nL L(-1) target) concentrations throughout the growing season. Exposure to elevated ozone resulted in a significant loss of productivity, with the ozone-treated plants displaying a ~30 % average decrease in seed yield. From leaf reflectance data, it was also clear that elevated ozone decreased leaf nitrogen and chlorophyll content as well as the photochemical reflectance index (PRI), an optical indicator of the epoxidation state of xanthophyll cycle pigments and thus physiological status. We assessed the potential to use leaf reflectance properties and partial least-squares regression (PLSR) modeling as an alternative, rapid approach to standard gas exchange for the estimation of the maximum rates of RuBP carboxylation (V c,max), an important parameter describing plant photosynthetic capacity. While we did not find a significant impact of ozone fumigation on V c,max, standardized to a reference temperature of 25 degrees C, the PLSR approach provided accurate and precise estimates of V c,max across ambient plots and ozone treatments (r (2) = 0.88 and RMSE = 13.4 MUmol m( 2) s(-1)) based only on the variation in leaf optical properties and despite significant variability in leaf nutritional status. The results of this study illustrate the potential for combining the phenotyping methods used here with high-throughput genotyping methods as a promising approach for elucidating the basis for ozone tolerance in sensitive crops. PMID- 23657828 TI - Effect of micro-vibration culture system on embryo development. AB - PURPOSE: Micro-vibration culture system was examined to determine the effects on mouse and human embryo development and possible improvement of clinical outcomes in poor responders. MATERIALS AND METHODS: The embryonic development rates and cell numbers of blastocysts were compared between a static culture group (n = 178) and a micro-vibration culture group (n = 181) in mice. The embryonic development rates and clinical results were compared between a static culture group (n = 159 cycles) and a micro-vibration culture group (n = 166 cycles) in poor responders. A micro-vibrator was set at a frequency of 42 Hz, 5 s/60 min duration for mouse and human embryo development. RESULTS: The embryonic development rate was significantly improved in the micro-vibration culture group in mice (p < 0.05). The cell numbers of mouse blastocysts were significantly higher in the micro-vibration group than in the static culture group (p < 0.05). In the poor responders, the rate of high grade embryos was not significantly improved in the micro-vibration culture group on day 3. However, the optimal embryonic development rate on day 5 was improved in the micro-vibration group, and the total pregnancy rate and implantation rate were significantly higher in the micro-vibration group than in the static culture group (p < 0.05). CONCLUSIONS: Micro-vibration culture methods have a beneficial effect on embryonic development in mouse embryos. In poor responders, the embryo development rate was improved to a limited extent under the micro-vibration culture conditions, but the clinical results were significantly improved. PMID- 23657830 TI - Central tolerance induction. AB - A critical function of the thymus is to help enforce tolerance to self. The importance of central tolerance in preventing autoimmunity has been enlightened by a deeper understanding of the interactions of developing T cells with a diverse population of thymic antigen presenting cell populations. Furthermore, there has been rapid progress in our understanding of how autoreactive T cell specificities are diverted into the T regulatory lineage. Here we review and highlight the recent progress in how tolerance is imposed on the developing thymocyte repertoire. PMID- 23657829 TI - Bilateral changes of cannabinoid receptor type 2 protein and mRNA in the dorsal root ganglia of a rat neuropathic pain model. AB - Cannabinoid receptor type 2 (CB2R) plays a critical role in nociception. In contrast to cannabinoid receptor type 1 ligands, CB2R agonists do not produce undesirable central nervous system effects and thus promise to treat neuropathic pain that is often resistant to medical therapy. In the study presented here, we evaluated the bilateral distribution of the CB2R protein and messenger RNA (mRNA) in rat dorsal root ganglia (DRG) after unilateral peripheral nerve injury using immunohistochemistry, western blot, and in situ hybridization analysis. Unilateral chronic constriction injury (CCI) of the sciatic nerve induced neuropathic pain behavior and bilateral elevation of both CB2R protein and mRNA in lumbar L4-L5 as well as cervical C7-C8 DRG when compared with naive animals. CB2R protein and mRNA were increased not only in DRG neurons but also in satellite glial cells. The fact that changes appear bilaterally and (albeit at a lower level) even in the remote cervical DRG can be related to propagation of neuroinflammation alongside the neuraxis and to the neuroprotective effects of CB2R. PMID- 23657831 TI - Use of the carbon dioxide laser for tracheobronchial lesions in children. AB - IMPORTANCE: Obstructing tracheobronchial diseases in children can be treated by a variety of techniques. The nonfiberoptic delivery of the carbon dioxide laser coupled to a rigid bronchoscope has rarely been described for this purpose and has unique advantages over other treatment methods. OBJECTIVES: To report the indications, safety, efficacy, and limitations of the carbon dioxide laser delivered through a rigid bronchoscope for tracheobronchial lesions in the pediatric population. DESIGN: Case series of patients undergoing treatment for tracheobronchial lesions at a single institution from December 2, 2001, through December 14, 2011. SETTING: Tertiary care children's hospital. PARTICIPANTS: Seventeen patients aged 3 months to 17 years with endotracheal and endobronchial disease. INTERVENTION: Carbon dioxide laser treatment through a rigid bronchoscope. MAIN OUTCOME MEASURES: Reduction in tumor burden or improvement of ventilation. RESULTS: A total of 234 laser bronchoscopies were performed on 17 patients. Mean operative time was 29 (range, 2-89) minutes. Blood loss and complications were minimal. Sixteen patients received carbon dioxide laser delivered through a rigid bronchoscope with a proximal coupler or flexible fiber. The most common indication was tracheobronchial granulation tissue (n = 10), followed by prolapsed cartilage causing tracheal obstruction (n = 3), recurrent respiratory papillomatosis (n = 2), and granular cell tumor (n = 1). Of these patients, 15 (94%) underwent successful treatment. One patient was treated electively with the Nd:YAG laser owing to a vascular malformation. CONCLUSIONS AND RELEVANCE: The carbon dioxide laser delivered through a rigid bronchoscope is a suitable tool for managing nonvascular endotracheal and endobronchial lesions in the pediatric population. Its unique wavelength properties offer a safe, effective alternative to other lasers and open resection. PMID- 23657832 TI - Development of a generative model of magnetoencephalography noise that enables brain signal extraction from single-epoch data. AB - We presented a method of rejecting sensor-specific and environmental noise during magnetoencephalography (MEG) measurement that enables the extraction of brain signals from single-epoch data. The method assumes a parametric generative model of MEG data. The model's optimal parameters were determined from single-epoch data, and noise reduction was performed by the decomposition of data within the optimal model. We confirmed our method's validity through multiple experiments. Moreover, we compared our method's performance with that of several previous noise-reduction methods. Finally, we confirmed that the proposed method followed by spatial filtering reduced noise more efficiently. PMID- 23657833 TI - Characterizing the normal range of myocardial blood flow with 82rubidium and 13N ammonia PET imaging. AB - BACKGROUND: Diagnosis of coronary disease and microvascular dysfunction may be improved by comparing myocardial perfusion scans with a database defining the lower limit of normal myocardial blood flow and flow reserve (MFR). To maximize disease detection sensitivity, a small normal range is desirable. Both (13)N ammonia and (82)Rb tracers are used to quantify blood flow and MFR using positron emission tomography (PET). The goal of this study was to investigate the trade off between noise and accuracy in both (82)Rb and (13)N-ammonia normal databases formed using a net retention model. METHODS: Fourteen subjects with <5% risk of CAD underwent rest and stress (82)Rb and (13)N-ammonia dynamic PET imaging in a randomized order within 2 weeks. Myocardial blood flow was quantified using a one compartment model for (82)Rb, and a two-compartment model for (13)N-ammonia. A simplified model was used to estimate tracer retention, with tracer-specific net extraction functions derived to obtain flow estimates. RESULTS: Normal variability of retention reserve was equivalent for both tracers (+/-15% globally, +/-16% regionally) and was lower in comparison to compartment model results (P < .05). The two-compartment model for (13)N-ammonia had the smallest normal range of global blood flow resulting in a lower limit of normal MFR = 2.2 (mean - 2 SD). CONCLUSION: These results suggest that the retention model may have higher sensitivity for detection and localization of abnormal flow and MFR using (82)Rb and (13)N-ammonia, whereas the (13)N-ammonia two-compartment model has higher precision for absolute flow quantification. PMID- 23657834 TI - Lentiviral vector-mediated siRNA knockdown of c-MYC: cell growth inhibition and cell cycle arrest at G2/M phase in Jijoye cells. AB - Inhibition of c-MYC has been considered as a potential therapy for lymphoma treatment. We explored a lentiviral vector-mediated small interfering RNA (siRNA) expression vector to stably reduce c-MYC expression in B cell line Jijoye cells and investigated the effects of c-MYC downregulation on cell growth, cell cycle, and apoptosis in vitro. The expression of c-MYC mRNA and protein levels were inhibited significantly by c-MYC siRNA. The c-MYC downregulation resulted in the inhibition of cell proliferation and cell cycle arrest at G2/M phase, which was associated with decreased expression of cyclin B and cyclin-dependent kinase 1 (CDK1) and increased expression of CDK inhibitor p21 proteins. In addition, downregulation of c-MYC induced cell apoptosis characterized by DNA fragmentation and caspase-3 activation. Taken together, these results suggest that lentiviral vector-mediated siRNA for c-MYC may be a promising approach for targeting c-MYC in the treatment of Burkitt lymphoma. PMID- 23657836 TI - Hyperlipidemia revealed by erythrocyte morphology. PMID- 23657837 TI - One-pot synthesis of branched oligosaccharides by use of galacto- and mannopyranosyl thioglycoside diols as key glycosylating agents. AB - We describe in this paper the efficient four-component one-pot synthesis of three fully protected oligosaccharides 22, 36, and 50 with di-branched structures by employing D-galacto- and mannopyranosyl thioglycoside diols as central glycosylating agents. After global deprotection, they were converted respectively into the 3-aminopropyl linker-containing free oligosaccharide fragments 14, 24, and 38 structurally related to cell wall oligosaccharides from Atractylodes lancea DC, the marine fungus Lineolata rhizophorae and pathogenic Mycobacterium tuberculosis. The 3-aminopropyl linker at the anomeric carbon can enable conjugation of these synthetic oligomers to a suitable protein carrier. PMID- 23657835 TI - Tumor-associated macrophages: functional diversity, clinical significance, and open questions. AB - Inflammation is now a well-recognized hallmark of cancer progression. Tumor associated macrophages (TAMs) are one of the major inflammatory cells that infiltrate murine and human tumors. While epidemiological studies indicate a clear correlation between TAM density and poor prognosis in a number of human cancers, transgenic studies and transcriptome profiling of TAMs in mice have established their crucial role in cancer progression. In fact, TAMs affect diverse aspects of cancer progression including tumor cell growth and survival, invasion, metastasis, angiogenesis, inflammation, and immunoregulation. New evidences have extended the repertoire of these cells to other tumor promoting activities like interactions with cancer stem cells, response to chemotherapy, and tumor relapse. These findings have triggered efforts to target TAMs and their associated molecules to modulate tumor progression. In particular, "re-education" to activate their anti-tumor potential or elimination of tumor promoting TAMs are strategies undergoing preclinical and clinical evaluation. Proof-of-principle studies indicate that TAM-centered therapeutic strategies may contribute to cancer therapy. PMID- 23657838 TI - Segmental hair analysis after a single dose of zolpidem: comparison with a previous study. AB - Hair is a useful aid and sometimes even the only matrix in the analytical strategy in drug-facilitated crime (DFC) investigations. In this novel study, segmental hair analysis was performed after a single 10 mg dose of zolpidem was given to 20 Chinese volunteers. Hair was collected 1 month after administration and was analyzed using ultra-high-pressure liquid chromatography/electrospray ionization tandem mass spectrometry. Zolpidem concentrations were found to be in the range of 135.0-554.6 pg/mg in the proximal 0-2 cm segments. These results were markedly different from those reported by Villain et al., who used volunteers administered equal doses of zolpidem. The analytical method used, as well as the volunteers' hair color, inter-individual variations such as metabolic capacity, hair growth rate, drug incorporation rates, physical state of the hair, age, gender, body weight, etc. and diffusion from sweat or other secretions are all factors that should be considered when interpreting the DFC results. PMID- 23657839 TI - A nitrogen-doped graphene/carbon nanotube nanocomposite with synergistically enhanced electrochemical activity. AB - A new kind of nitrogen-doped graphene/carbon nanotube nanocomposite can be synthesized by a facile hydrothermal process under mild conditions, which exhibits synergistically enhanced electrochemical activity for the oxygen reduction reaction. This research provides a new route to access a metal-free electrocatalyst with high activity under mild conditions. PMID- 23657840 TI - Hydraulic characteristics of water-refilling process in excised roots of Arabidopsis. AB - Plants have efficient water-transporting vascular networks with a self-recovery function from embolism, which causes fatal discontinuity in sap flow. However, the embolism-refilling process in xylem vessel is still unclear. The water refilling processes in the individual xylem vessels of excised Arabidopsis roots were visualized in this study using synchrotron X-ray micro-imaging technique with high spatial resolution up to 1 MUm per pixel and temporal resolution up to 24 fps. In normal continuous water-refilling process, we could observe various flow patterns affected by the morphological structures of the xylem vessels, especially when water passed through perforation plates. A simple criterion based on the variation in dynamic pressure was suggested to evaluate the contribution of individual perforation plates to the water-refilling process. Meanwhile, the water-refilling embolized sections of xylem vessels through radial pathways were also observed. Separated water columns were formed from this discontinuous water refilling process and the water influx rates through the radial pathways were estimated to be 478 and 928 MUm(3) s(-1). The dynamic behavior of the separated water columns were quantitatively analyzed from the stoppage of volume growth to the translational phase. These water-refilling processes in excised roots of Arabidopsis may shed light on understanding the water refilling in the embolism vessels of intact plants and the interconnectivity of xylem vessel networks in vascular plants. PMID- 23657841 TI - Time-order effects of vitamin C on hexavalent chromium-induced mitochondrial damage and DNA-protein crosslinks in cultured rat peripheral blood lymphocytes. AB - Hexavalent chromium [Cr(VI)] and its compounds have extensive applications in many industries and are widely known to cause occupational diseases as well as carcinogenic effects in humans. Mitochondrial damage, which is important in Cr(VI)-induced cytotoxicity, may be characterized by the opening status of the permeability transition pore, the maintenance of the mitochondrial membrane potential and the level of malondialdehyde. The formation of DNA-protein crosslinks (DPCs) in target tissues appears to be the direct and primary genotoxic effect of Cr(VI) exposure, and the lymphocytic DPCs may be viewed as a biomarker of internal Cr(VI) accumulation. It is well known that vitamin C (vit C) is an important biological reducing agent in humans and animals, which is capable of reducing Cr(VI). Regardless of the evidence from cell culture and in vivo experiments of the protective effect of the antioxidant, vit C, following exposure to Cr(VI), no studies have been conducted to date to demonstrate the time-order effects of vit C on Cr(VI)-induced mitochondrial damage and DPC formation. In the present study, by using peripheral blood lymphocytes from Sprague-Dawley rats, we demonstrated that vit C pre- and co-treatment have a protective effect against Cr(VI)-induced loss of cell viability and mitochondrial damage, while only vit C co-treatment has a protective effect against the Cr(VI) induced increase in DPCs. The mechanistic investigation revealed that cellular reactive oxygen species levels are correlated with Cr(VI)-induced mitochondrial damage, and that p53 expression is correlated with the Cr(VI)-induced increase in DPCs. We concluded that vit C exerts different time-order effects on Cr(VI) induced mitochondrial damage and DPC formation, and that biomarkers, including DPC and p53, may be used in the assessment of the development of Cr(VI)-induced cancer. These findings facilitate more detailed follow-up of the Cr(VI)-exposure populations for secondary prevention. PMID- 23657842 TI - NMR studies on protein-nucleic acid interaction. PMID- 23657843 TI - PINT: a software for integration of peak volumes and extraction of relaxation rates. AB - We present the software Peak INTegration (PINT), designed to perform integration of peaks in NMR spectra. The program is very simple to run, yet powerful enough to handle complicated spectra. Peaks are integrated by fitting predefined line shapes to experimental data and the fitting can be customized to deal with, for instance, heavily overlapped peaks. The results can be inspected visually, which facilitates systematic optimization of the line shape fitting. Finally, integrated peak volumes can be used to extract parameters such as relaxation rates and information about low populated states. The utility of PINT is demonstrated by applications to the 59 residue SH3 domain of the yeast protein Abp1p and the 289 residue kinase domain of murine EphB2. PMID- 23657844 TI - Selective diagonal-free (13)C, (13)C-edited aliphatic-aromatic NOESY experiment with non-uniform sampling. AB - A band-selective aromatic-aliphatic C,C-edited four-dimensional NOESY experiment is proposed here. Its key advantage is the absence of auto-correlation signals which makes it very attractive for joint use with non-uniform sampling. It is demonstrated here that the sensitivity of the experiment is not significantly affected by utilization of selective pulses (for either aromatic-13C or aliphatic 13C spins). The method was applied to the sample of E32Q mutant of human S100A1 protein, a homodimer of total molecular mass ~20 kDa. High-resolution 4D spectra were obtained from ~1.5 % of sampling points required conventionally. It is shown that superior resolution facilitates unambiguous assignment of observed aliphatic aromatic cross-peaks. Additionally, the addition of aliphatic-13C dimension enables to resolve peaks with degenerated aliphatic (1)H chemical shifts. All observed cross-peaks were validated against previously determined 3D structure of E32Q mutant of S100A1 protein (PDB 2LHL). The increased reliability of structural constraints obtained from the proposed high-resolution 4D 13C(ali),13C(aro) edited NOESY can be exploited in the automated protocols of structure determination of proteins. PMID- 23657845 TI - Safe Treatment of Seizures in the Setting of HIV/AIDS. AB - OPINION STATEMENT: HIV(+) patients are at increased risk for developing seizures due to the vulnerability of the central nervous system to HIV-associated diseases, immune dysfunction, and metabolic disturbances. In patients with acute seizures, standard protocols still apply with urgent seizure cessation being the priority. Management of the person with established epilepsy who contracts HIV is challenging, but the decision to initiate chronic antiepileptic drug (AED) therapy in an HIV(+) patient is also difficult. Chronic treatment guidelines emphasize the interactions between AEDs and antiretroviral (ARV) medications, but provide no explicit advice regarding when to initiate an AED, what medication to select, and/or the duration of treatment. Epidemiologic data regarding seizure recurrence risk in HIV(+) individuals is not available. The risk of further seizures likely depends upon the underlying etiology for the seizure(s) and patients' immune status and may be increased by the use of efavirenz (an ARV). The issues for consideration include AED-ARV interactions, organ dysfunction, seizure type, and drug side effects, which may worsen or be confused with symptoms of HIV and/or epilepsy. Co-administration of enzyme inducing (EI)-AEDs and ARVs can result in virological failure, breakthrough seizure activity, AED toxicity, and/or ARV toxicity. Where available, the AED of choice in HIV(+) patients is levetiracetam due to its broad spectrum activity, ease of use, minimal drug interactions, and favorable side effect profile. Lacosamide, gabapentin, and pregabalin are also favored choices in patients with partial onset seizures and/or those failing levetiracetam. Where newer AEDs are not available, valproic acid may be the treatment of choice in terms of an AED, which will not cause enzyme induction-associated ARV failure, but its side effect profile causes other obvious problems. In resource-limited settings (RLS) where only EI-AEDs are available, there are no good treatment options and further pressure needs to be placed upon policymakers to address this care gap and public health threat. PMID- 23657846 TI - Adapted physical activity programme and self-perception in obese adolescents with intellectual disability: between morphological awareness and positive illusory bias. AB - BACKGROUND: In adolescent with intellectual disability, the management of obesity is a crucial issue, yet also quite complex because of their particular perception of themselves. This study investigated the relationship between self-perception variables and morphological variables and their changes after a 9-month Adapted Physical Activity (APA) programme. MATERIALS AND METHODS: Twenty-three adolescents with intellectual disability responded to an adapted questionnaire, including the PSI-VSF-ID and a nine-drawing body silhouette scale. Anthropometric and body composition indicators were measured before and after the APA programme. RESULTS: The main predictor of the adolescents' self-perceptions was the inclination towards positive illusory bias before the intervention; obesity awareness ranked second. Morphological measurements did not contribute in the same way to self-perceptions in the initial and final data. CONCLUSIONS: This study confirms the interest of weight management programmes for adolescents with intellectual disability and points to the need to take positive illusory bias more fully into account in the study of self-perception. PMID- 23657847 TI - Influence of coffee brew in metabolic syndrome and type 2 diabetes. AB - This study aimed to evaluate the effect of coffee drinking on clinical markers of diabetes and metabolic syndrome in Zucker rats. Diabetic Zucker rats with metabolic syndrome and control Zucker rats were used for in vivo tests. The animals received daily doses of coffee drink by gavage for 30 days. After the treatment, the levels of glucose, triglycerides, total cholesterol and fractions, creatinine, uric acid, activity of aspartate aminotransferase and alanine aminotransferase were evaluated. Urea and creatinine levels were also analyzed in urine. By collaborating in the modulation of the metabolic syndrome and diabetes mellitus type 2, coffee drink helped in reducing serum glucose, total cholesterol and triglycerides. The results demonstrate that treatment with roasted coffee drink, because of its hypoglycemic and hypolipidemic effect, is efficient in the protection of animals with metabolic syndrome and diabetes mellitus type 2. PMID- 23657848 TI - Nutritional status and its association with physical fitness, physical activity and parasitological indicators in youths from rural Mozambique. AB - BACKGROUND: Little information exists about the relationship of nutritional status and motor performance conditional on asymptomatic parasitemia in rural African children. AIMS: The aims of this study were to (1) determine if malnourished youths from rural African areas have lower levels of physical fitness (PF) and physical activity (PA) compared to normal weight youths, (2) verify the biological relevance of anthropometric criteria used to classify nutritional status in youth, and (3) determine the prevalence of parasitological indicators, and its association with nutritional status and PF. METHODS: The sample comprised 794 youths (6-17 years) from Calanga, a rural community in Mozambique. PF tests were selected from standardized test batteries, and PA was estimated by accelerometry. Nutritional status was defined according to WHO recommendations for stunting, wasting and normal weight. Parasitological indicators were determined based on stool specimens' analysis. RESULTS: In general terms the normal group out-performed the other nutritional groups (stunted and wasted) for PF. However, no significant differences were found for PA among nutritional groups. There were also no significant differences in prevalence of intestinal parasites. CONCLUSIONS: Nutritional status was not associated with PA levels or the prevalence of parasitological indicators in youth, but was related to physical performance. PMID- 23657849 TI - The effect of energy substrates on PHB accumulation of Acidiphilium cryptum DX1 1. AB - The effect of glucose and elemental sulfur on the growth and PHB accumulation of Acidiphilium cryptum DX1-1 was investigated. Meanwhile, the differential expressions of 19 genes related with PHB accumulation, sulfur metabolism and carbon fixed in heterotrophy, phytotrophy and mixotrophy were studied by RT-qPCR. The results showed that strain DX1-1 could accumulate PHB with sulfur as the energy substance and atmospheric CO2 as carbon resource. Glucose could improve the growth of strain DX1-1 cultured in medium with sulfur as the energy substance, and almost all the key enzyme-encoding genes related with PHB, sulfur metabolism and carbon fixed were basically up-regulated. PHB polymerase (Arcy_3030), ribulose-bisphosphate carboxylase (Acry_0825), ribulose-phosphate epimerase (Acry_0022), and cysteine synthase A (Acry_2560) played important role in PHB accumulation, the modified expression of which could influence the PHB yield. With CO2 as carbon resource, the main initial substance of PHB accumulation for strain DX1-1 was acetyl-CoA, instead of acetate with the glucose as the carbon resource. Because of accumulating PHB by fixed atmospheric CO2 while independent of light, A. cryptum DX1-1 may have specifically potential in production of PHB. PMID- 23657850 TI - Zyxin regulates migration of renal epithelial cells through activation of hepatocyte nuclear factor-1beta. AB - Hepatocyte nuclear factor-1beta (HNF-1beta) is an epithelial tissue-specific transcription factor that regulates gene expression in the kidney, liver, pancreas, intestine, and other organs. Mutations of HNF-1beta in humans produce renal cysts and congenital kidney anomalies. Here, we identify the LIM-domain protein zyxin as a novel binding partner of HNF-1beta in renal epithelial cells. Zyxin shuttles to the nucleus where it colocalizes with HNF-1beta. Immunoprecipitation of zyxin in leptomycin B-treated cells results in coprecipitation of HNF-1beta. The protein interaction requires the second LIM domain of zyxin and two distinct domains of HNF-1beta. Overexpression of zyxin stimulates the transcriptional activity of HNF-1beta, whereas small interfering RNA silencing of zyxin inhibits HNF-1beta-dependent transcription. Epidermal growth factor (EGF) induces translocation of zyxin into the nucleus and stimulates HNF-1beta-dependent promoter activity. The EGF-mediated nuclear translocation of zyxin requires activation of Akt. Expression of dominant negative mutant HNF-1beta, knockdown of zyxin, or inhibition of Akt inhibits EGF stimulated cell migration. These findings reveal a novel pathway by which extracellular signals are transmitted to the nucleus to regulate the activity of a transcription factor that is essential for renal epithelial differentiation. PMID- 23657851 TI - Galectin-3 mediates oligomerization of secreted hensin using its carbohydrate recognition domain. AB - A multidomain, multifunctional 230-kDa extracellular matrix (ECM) protein, hensin, regulates the adaptation of rabbit kidney to metabolic acidosis by remodeling collecting duct intercalated cells. Conditional deletion of hensin in intercalated cells of the mouse kidney leads to distal renal tubular acidosis and to a significant reduction in the number of cells expressing the basolateral chloride-bicarbonate exchanger kAE1, a characteristic marker of alpha intercalated cells. Although hensin is secreted as a monomer, its polymerization and ECM assembly are essential for its role in the adaptation of the kidney to metabolic acidosis. Galectin-3, a unique lectin with specific affinity for beta galactoside glycoconjugates, directly interacts with hensin. Acidotic rabbits had a significant increase in the number of cells expressing galectin-3 in the collecting duct and exhibited colocalization of galectin-3 with hensin in the ECM of microdissected tubules. In this study, we confirmed the increased expression of galectin-3 in acidotic rabbit kidneys by real-time RT-PCR. Galectin-3 interacted with hensin in vitro via its carbohydrate-binding COOH-terminal domain, and the interaction was competitively inhibited by lactose, removal of the COOH-terminal domain of galectin-3, and deglycosylation of hensin. Galectin 9, a lectin with two carbohydrate-recognition domains, is also present in the rabbit kidney; galectin-9 partially oligomerized hensin in vitro. Our results demonstrate that galectin-3 plays a critical role in hensin ECM assembly by oligomerizing secreted monomeric hensin. Both the NH2-terminal and COOH-terminal domains are required for this function. We suggest that in the case of galectin-3 null mice galectin-9 may partially substitute for the function of galectin-3. PMID- 23657852 TI - Obesity-metabolic derangement preserves hemodynamics but promotes intrarenal adiposity and macrophage infiltration in swine renovascular disease. AB - Obesity-metabolic disorders (ObM) often accompany renal artery stenosis (RAS). We hypothesized that the coexistence of ObM and RAS magnifies inflammation and microvascular remodeling in the stenotic kidney (STK) and aggravates renal scarring. Twenty-eight obesity-prone Ossabaw pigs were studied after 16 wk of a high-fat/high-fructose diet or standard chow including ObM-sham, ObM-RAS, Lean RAS, or Lean-sham (normal control) groups. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed by multidetector computed tomography (CT), renal oxygenation and tubular transport capability by blood oxygen-level-dependent MRI, and microcirculation by micro-CT for vessel density, and Western blotting for protein expressions of angiogenic factors (VEGF/FLK-1). Renal vein and inferior vena cava levels of inflammatory cytokines were measured to evaluate systemic and kidney inflammation. Macrophage (MO) infiltration and subpopulations, fat deposition in the kidney, and inflammation in perirenal and abdominal fat were also examined. GFR and RBF were decreased in Lean-STK but relatively preserved in ObM-STK. However, ObM-STK showed impaired tubular transport function, suppressed microcirculation, and stimulated glomerulosclerosis. ObM diet interacted with RAS to blunt angiogenesis in the STK, facilitated the release of inflammatory cytokines, and led to greater oxidative stress than Lean-STK. The ObM diet also induced fat deposition in the kidney and infiltration of proinflammatory M1-MO, as also in perirenal and abdominal fat. Coexistence of ObM and RAS amplifies renal inflammation, aggravates microvascular remodeling, and accelerates glomerulosclerosis. Increased adiposity and MO-accentuated inflammation induced by an ObM diet may contribute to structural injury in the post-STK kidney. PMID- 23657853 TI - NF-kappaB activation mediates crystal translocation and interstitial inflammation in adenine overload nephropathy. AB - Adenine overload promotes intratubular crystal precipitation and interstitial nephritis. We showed recently that these abnormalities are strongly attenuated in mice knockout for Toll-like receptors-2, -4, MyD88, ASC, or caspase-1. We now investigated whether NF-kappaB activation also plays a pathogenic role in this model. Adult male Munich-Wistar rats were distributed among three groups: C (n = 17), receiving standard chow; ADE (n = 17), given adenine in the chow at 0.7% for 1 wk and 0.5% for 2 wk; and ADE + pyrrolidine dithiocarbamate (PDTC; n = 14), receiving adenine as above and the NF-kappaB inhibitor PDTC (120 mg.kg-1.day-1 in the drinking water). After 3 wk, widespread crystal deposition was seen in tubular lumina and in the renal interstitium, along with granuloma formation, collagen accumulation, intense tubulointerstitial proliferation, and increased interstitial expression of inflammatory mediators. Part of the crystals were segregated from tubular lumina by a newly formed cell layer and, at more advanced stages, appeared to be extruded to the interstitium. p65 nuclear translocation and IKK-alpha increased abundance indicated activation of the NF-kappaB system. PDTC treatment prevented p65 migration and normalized IKK-alpha, limited crystal shift to the interstitium, and strongly attenuated interstitial fibrosis/inflammation. These findings indicate that the complex inflammatory phenomena associated with this model depend, at least in part, on NF-kappaB activation, and suggest that the NF-kappaB system may become a therapeutic target in the treatment of chronic kidney disease. PMID- 23657854 TI - Reactive oxygen species and IRF1 stimulate IFNalpha production by proximal tubules during ischemic AKI. AB - We previously reported that expression of the transcription factor interferon regulatory factor 1 (IRF1) is an early, critical maladaptive signal expressed by renal tubules during murine ischemic acute kidney injury (AKI). We now show that IRF1 mediates signals from reactive oxygen species (ROS) generated during ischemic AKI and that these signals ultimately result in production of alpha subtypes of type I interferons (IFNalphas). We found that genetic knockout of the common type I IFN receptor (IFNARI-/-) improved kidney function and histology during AKI. There are major differences in the spatial-temporal production of the two major IFN subtypes, IFNbeta and IFNalphas: IFNbeta expression peaks at 4 h, earlier than IFNalphas, and continues at the same level at 24 h; expression of IFNalphas also increases at 4 h but continues to increase through 24 h. The magnitude of the increase in IFNalphas relative to baseline is much greater than that of IFNbeta. We show by immunohistology and study of isolated cells that IFNbeta is produced by renal leukocytes and IFNalphas are produced by renal tubules. IRF1, IFNalphas, and IFNARI were found on the same renal tubules during ischemic AKI. Furthermore, we found that ROS induced IFNalpha expression by renal tubules in vitro. This expression was inhibited by small interfering RNA knockdown of IRF1. Overexpression of IRF1 resulted in the production of IFNalphas. Furthermore, we found that IFNalpha stimulated production of maladaptive proinflammatory CXCL2 by renal tubular cells. Altogether our data support the following autocrine pathway in renal tubular cells: ROS > IRF1 > IFNalpha > IFNARI > CXCL2. PMID- 23657855 TI - Gender-specific role of HDAC11 in kidney ischemia- and reperfusion-induced PAI-1 expression and injury. AB - Male gender and the male hormone testosterone increase susceptibility to kidney ischemia and reperfusion (I/R) injury, which is associated with inflammatory responses. Possible involvement of histone deacetylase (HDAC) in inflammatory responses has been suggested. We investigated the gender-specific role of HDACs in plasminogen activator inhibitor type-1 (PAI-1) expression and I/R injury. PAI 1 inhibition protected the kidney from I/R-induced inflammation and functional loss. Among HDACs, only HDAC11 negatively regulated PAI-1 expression in I/R subjected kidney gender specifically and lipopolysaccharide (LPS)-stimulated mouse monocytes/macrophages. HDAC11 gene silencing increased PAI-1 expression. Chromatin immunoprecipitation assay confirmed binding of HDAC11 to the promoter region of PAI-1 and then release by I/R insult or LPS treatment. I/R-induced HDAC11 release was inhibited by orchiectomy and reversed by dihydrotestosterone treatment. Release of HDAC11 increased acetylation of histone H3. In conclusion, male gender and male hormones accelerate I/R-induced decreases in expression and binding of HDAC11, resulting in an increase in PAI-1 expression. These data provide important insight into gender dimorphism offering HDAC11 as a novel target for I/R injury. PMID- 23657856 TI - Scavengers of reactive oxygen species, paracalcitol, RhoA, and Rac-1 inhibitors and tacrolimus inhibit angiotensin II-induced actions on glomerular permeability. AB - Systemic infusions of ANG II rapidly induce large, dynamic increases in the permeability of the glomerular filtration barrier (GFB) in rats. After binding to its receptor(s), ANG II generates reactive oxygen species (ROS) and produces Ca2+ influx into cells, leading to activation of a plethora of signaling cascades, including, e.g., calcineurin and small GTPases, such as Rac-1 and RhoA. In the present study we sought to interact with some of these cascades to test potential novel antiproteinuric agents. In anesthetized Wistar rats, the left urether was cannulated for urine collection, and blood access was achieved. Rats were infused with ANG II (16 ng.kg-1.min-1) alone, or together with the ROS scavengers tempol or dimethylthiourea (DMTU) or the D-vitamin analog paracalcitol, the RhoA-kinase inhibitor Y-27632, the Rac-1 inhibitor NSC-23766, or the calcineurin inhibitor tacrolimus. FITC-Ficoll-70/400 (mol.radius 10-80 A) and 51Cr-EDTA were infused throughout the experiment. Plasma and urine samples were taken during baseline and at 5 and 15 min after the start of the infusions and analyzed by high performance size-exclusion chromatography for determination of glomerular sieving coefficients (theta) for Ficoll10-80A. ANG II infusion into rats caused marked increases in glomerular permeability to large Ficoll molecules (Ficoll50-80A), which were abrogated by the ROS scavenger tempol and partly by DMTU. Paracalcitol, RhoA, and Rac-1 inhibition, and, to some extent tacrolimus, but not prostacyclin, could also inhibit the glomerular permeability actions of ANG II. Our data suggest that cellular ROS generation and active Ca2+ signaling are involved in ANG II-induced increases in glomerular permeability. PMID- 23657857 TI - Nitric oxide-angiotensin II interactions and renal hemodynamic function in patients with uncomplicated type 1 diabetes. AB - The objective is to elucidate the effect of nitric oxide (NO)-renin-angiotensin system (RAS) interactions on renal hemodynamic function in uncomplicated, type 1 diabetes mellitus (DM). In 14 salt-replete, male healthy volunteers (C) and 9 male DM patients on euglycemia, glomerular filtration rate (GFR), renal blood flow (RBF), filtration fraction (FF), and sodium excretion (UNaV) were measured at baseline and during a 90-min infusion of 3.0 MUg.kg-1.min-1 NG-nitro-L arginine-methyl-ester (L-NAME) after 3 days of pretreatment with either placebo (PL) or 50 mg losartan (LOS). Baseline GFR, RBF, and FF were higher in DM (P < 0.005). In the C group, PL + L-NAME caused declines in GFR (101 +/- 3 to 90 +/- 3 ml.min-1.1.73 m-2), RBF (931 +/- 22 to 754 +/- 31 ml.min-1.1.73 m-2), and UNaV (158 +/- 12 to 82 +/- 18 MUmol/min) and an increase in FF (0.19 +/- 0.02 to 0.21 +/- 02; P < 0.001), which were not influenced by LOS pretreatment (P > 0.05 for LOS + L-NAME-C vs. PL + l-NAME-C). In DM, PL + L-NAME resulted in exaggerated renal effects, with changes in GFR (128 +/- 3 to 104 +/- 3 ml.min-1.1.73 m-2), RBF (1,019 +/- 27 to 699 +/- 34 ml.min-1.1.73 m-2), UNaV (150 +/- 13 to 39 +/- 14 MUmol/min), and FF (0.22 +/- 0.03 to 0.26 +/- 0.02) that were significantly greater vs. PL + L-NAME-C (P < 0.005). LOS pretreatment blunted GFR, RBF, FF, and UNaV responses to L-NAME in DM (P < 0.005 vs. PL + L-NAME-DM), resulting in a response profile that was similar to PL + L-NAME and LOS + L-NAME in C (P > 0.05). Renal responses to L-NAME in uncomplicated, type 1 DM are exaggerated vs. C, consistent with an upregulation of NO bioactivity. LOS, without effects in C, prevents the accentuated actions of L-NAME in DM, thus indicating an augmented role for NO-RAS interactions in renal hemodynamic function in DM. PMID- 23657858 TI - Chronic elevation of IL-1beta induces diuresis via a cyclooxygenase 2-mediated mechanism. AB - Chronic renal inflammation is an increasingly recognized phenomenon in multiple disease states, but the impact of specific cytokines on renal function is unclear. Previously, we found that 14-day interleukin-1beta (IL-1beta) infusion increased urine flow in mice. To determine the mechanism by which this occurs, the current study tested the possible involvement of three classical prodiuretic pathways. Chronic IL-1beta infusion significantly increased urine flow (6.5 +/- 1 ml/day at day 14 vs. 2.3 +/- 0.3 ml/day in vehicle group; P < 0.05) and expression of cyclooxygenase (COX)-2, all three nitric oxide synthase (NOS) isoforms, and endothelin (ET)-1 in the kidney (P < 0.05 in all cases). Urinary prostaglandin E metabolite (PGEM) excretion was also significantly increased at day 14 of IL-1beta infusion (1.21 +/- 0.26 vs. 0.29 +/- 0.06 ng/day in vehicle infused mice; P = 0.001). The selective COX-2 inhibitor celecoxib markedly attenuated urinary PGEM excretion and abolished the diuretic response to chronic IL-1beta infusion. In contrast, deletion of NOS3, or inhibition of NOS1 with L VNIO, did not blunt the diuretic effect of IL-1beta, nor did pharmacological blockade of endothelin ETA and ETB receptors with A-182086. Consistent with a primary effect on water transport, IL-1beta infusion markedly reduced inner medullary aquaporin-2 expression (P < 0.05) and did not alter urinary Na+ or K+ excretion. These data indicate a critical role for COX-2 in mediating the effects of chronic IL-1beta elevation on the kidney. PMID- 23657859 TI - Hybrid ventral hernia repair: technique and results. AB - BACKGROUND: Open and laparoscopic approaches to ventral hernia repair are generally exclusive of each other. However, select patients with difficult hernias may benefit from combined open/laparoscopic hybrid techniques to avoid dissection of large subcutaneous flaps. METHODS: Seven patients underwent combined laparoscopic and open approaches for ventral hernia repair. Records were reviewed for technical details, demographics, hernia and mesh characteristics, and postoperative outcomes. RESULTS: Two hybrid techniques were used: (1) initial laparoscopic approach converted to open adhesiolysis followed by totally laparoscopic mesh fixation and (2) open repair and adhesiolysis with laparoscopic assisted mesh fixation. In the first approach, after conversion to open adhesiolysis, mesh with four quadrant sutures was placed intraabdominally. Pneumoperitoneum was re-established, and the mesh was fixed laparoscopically with sutures and tacks in standard fashion. For the second hybrid approach, after hernia reduction and adhesiolysis, mesh was anchored with sutures placed at 3-4 cm intervals with a Reverdin needle and further secured posteriorly with a hernia tacker over 180 degrees circumference. Prior to tying the contralateral transfascial sutures, two 5-mm laparoscopic ports were placed lateral to the mesh under direct vision on the opposite side. Once the facial sutures were tied, pneumoperitoneum was established, and the contralateral side of mesh was tacked laparoscopically. Mean patient age was 65 years and BMI 38. Mean defect size was 10.6 cm * 8.3 cm and mean mesh size was 25 cm * 19 cm. Operative time was 318 min (210-405 min). Hospital stay was 5 days (4-7 days). Morbidity was 57 % including one deep wound infection and a chronic sinus requiring reoperation. There were no hernia recurrences with average follow-up of 15 months (3-63 months). CONCLUSIONS: Hybrid laparoscopic and open techniques may be used in obese patients with difficult incisional hernias requiring open adhesiolysis. Further studies need to be done to better delineate hernia characteristics of patients that may benefit from this approach. PMID- 23657860 TI - Lessons and challenges during a 5-year follow-up of 21 Composix Kugel implantations. AB - INTRODUCTION: From its introduction in 2000 until its US recall in December 2005, the Composix Kugel mesh was implanted in an estimated 350,000 patients worldwide. In our patients, minor postoperative complications were followed after a few years by more serious problems (persistent abdominal pain, infections, intestinal perforations). In this study, we take stock after a 5-year follow-up and issue a plea for improved product development strategies and the creation of hernia registries. PATIENTS AND METHODS: Between 2003 and 2006, we implanted the Bard((r)) Composix((r)) Kugel((r)) mesh in 21 patients (11 men, 10 women, mean age 63.2 +/- 13.7 years) with incisional hernias using the open intraperitoneal onlay mesh technique. The mesh is made on one side of ePTFE and on the other of polypropylene and is expanded by a polyethylene (PET) memory recoil ring. The average follow-up was 45.5 months. All patients had at least one risk factor for hernia recurrence. Explanted prostheses were analyzed by scanning electron microscopy (SEM) and subjected to mechanical strength tests. RESULTS: During the postoperative course, six patients suffered a wound healing disorder. Ten patients complained of persistent abdominal wall pain and four experienced recurrence of the hernia. In one patient, the mesh had to be explanted due to chronic infection. In one patient, the PET memory recoil ring broke after 5 years of follow-up with consequent small bowel perforation. The PET memory recoil ring exhibited clear signs of degradation on SEM and unmistakable signs of material fatigue in a materials testing machine. CONCLUSIONS: Patients with recalled Composix Kugel meshes face a singular risk for complications that may occur even many years after implantation. The most serious complication is the breakage of its PET memory recoil ring. Since the recall of the Composix Kugel Mesh, we have discontinued its use. It is necessary that future complications are documented in a common post-market surveillance registry. Algorithms need to be developed and promoted to support affected patients and surgeons. PMID- 23657861 TI - Fibrin sealant for mesh fixation in laparoscopic umbilical hernia repair: 1-year results of a randomized controlled double-blinded study. AB - PURPOSE: Fibrin sealant for mesh fixation has significant positive effects on early outcome after laparoscopic ventral hernia repair (LVHR) compared with titanium tacks. Whether fibrin sealant fixation also results in better long-term outcome is unknown. METHODS: We performed a randomized controlled trial including patients with umbilical hernia defects from 1.5 to 5 cm at three Danish hernia centres. We used a 12 cm circular mesh. Participants were randomized to fibrin sealant or titanium tack fixation. Patients were seen in the outpatient clinic at 1 and 12 months follow-up. RESULTS: Forty patients were included of whom 34 were available for intention to treat analysis after 1 year. There were no significant differences in pain, discomfort, fatigue, satisfaction or quality of life between the two groups at the 1-year follow-up. Five patients (26 %) in the fibrin sealant group and one (6 %) in the tack group were diagnosed with a recurrence at the 1-year follow-up (p = 0.182) (overall recurrence rate 17 %). Hernia defects in patients with recurrence were significantly larger than in those without recurrence (median 4.0 vs. 2.8 cm, p = 0.009). CONCLUSION: Patients with larger hernia defects and fibrin sealant mesh fixation had higher recurrence rates than expected, although the study was not powered for assessment of recurrence. There was no significant difference between groups in any parameters after the 1-year follow-up. The beneficial effects of mesh fixation with fibrin sealant on early outcome warrant further studies on optimization of the surgical technique to prevent recurrence. PMID- 23657862 TI - Randomized clinical trial comparing lightweight or heavyweight mesh for mesh plug repair of primary inguinal hernia. AB - BACKGROUND: The aim of this study was to assess whether the application of a lightweight mesh for mesh plug repair (MPR) for primary inguinal hernia could reduce chronic pain or other symptoms associated with the insertion of the prosthesis. METHODS: Patients over 20 years of age with a unilateral primary inguinal hernia were eligible to participate in the study. The patients were randomly assigned to a lightweight mesh (LWM) or a heavyweight mesh (HWM) group. All the operations were performed under local anesthesia. The operative details, including the hernia type and the nerves that were identified, and the postoperative complications were recorded. All follow-up and outcome measures were obtained based on a physical examination and a questionnaire regarding pain and other symptoms at 1 week, 1, 3, 6, and 12 months after the surgery in a double-blinded manner. RESULTS: The use of LWM significantly reduced foreign body sensation after 12 months to one-third of the incidence reported for the use of HWM (5.8 vs. 17.9%; P = 0.013), while no significant differences were found in pain parameters, including the use of pain relief medications, between the groups throughout the study period. CONCLUSION: This study indicated that the use of LWM in the MPR decreases the incidence of foreign body sensation at 1 year after surgery for primary inguinal hernia. LWM may be preferable to MPR, similar to results described previously for Lichtenstein repair. PMID- 23657863 TI - Aquagenic pruritus in polycythemia vera: characteristics and influence on quality of life in 441 patients. AB - Aquagenic pruritus (AP) is a symptom typical for polycythemia vera, but very little is known about its exact frequency, characteristics, influence on quality of life, and proper treatment. Therefore, we investigated these aspects in a large cohort of German patients with polycythemia vera using a patient directed questionnaire. Our analysis revealed that 301 of 441 analyzed patients suffered from AP. In 64.8%, AP occurred on average 2.9 years prior to diagnosis of polycythemia vera. Only in 15.4% did this lead to a hematological investigation. AP occurs primarily on the trunk and proximal parts of the extremities. Most patients complain about itching (71.8%), the remainder about tickling, stinging, or burning sensations. Forty-four patients (14.6%) classified the pruritus as "unbearable." Patients with AP reported reduced global health status and higher fatigue, pain, and dyspnea. Only 24% of patients received pruritus specific treatment for pruritus consisting mostly of histamine antagonists, which ameliorated symptoms in about half of the patients. In 5.6% of patients, polycythemia vera directed therapy (phlebotomy/cytoreduction) resolved the symptoms. In summary, AP is a serious symptom in patients with polycythemia vera, which until recently was difficult to treat. The advent of the novel JAK2 inhibitors, however, may open new ways for therapy. PMID- 23657864 TI - Structural mechanisms of heavy-metal extrusion by the Cus efflux system. AB - Resistance-nodulation-cell division (RND) superfamily efflux systems are responsible for the active transport of toxic compounds from the Gram-negative bacterial cell. These pumps typically assemble as tripartite complexes, spanning the inner and outer membranes of the cell envelope. In Escherichia coli, the CusC(F)BA complex, which exports copper(I) and silver(I) and mediates resistance to these two metal ions, is the only known RND transporter with a specificity for heavy metals. We have determined the crystal structures of both the inner membrane pump CusA and membrane fusion protein CusB, as well as the adaptor transporter CusBA complex formed by these two efflux proteins. In addition, the crystal structures of the outer membrane channel CusC and the periplasmic metallochaperone CusF have been resolved. Based on these structures, the entire assembled model of the tripartite efflux system has been developed, and this efflux complex should be in the form of CusC3-CusB6-CusA3. It has been shown that CusA utilizes methionine clusters to bind and export Cu(I) and Ag(I). This pump is likely to undergo a conformational change, and utilize a relay network of methionine clusters as well as conserved charged residues to extrude the metal ions from the bacterial cell. PMID- 23657865 TI - Chronic administration of iron and copper potentiates adipogenic effect of high fat diet in Wistar rats. AB - The primary objective of this research project is explore a possible adipogenic effect of iron and/or copper in albino Wistar rats kept on standard (STD) and high-fat (HFD) diets. The female Wistar rats in the study were divided into eight experimental groups (n = 6). Rats maintained on STD and HFD received 3 mg/l FeSO4?7H2O, 4.88 mg/l CuSO4 and a combination of 1.5 mg/l FeSO4?7H2O and 2.44 mg/l CuSO4 with drinking water. Control groups were kept on STD and HFD and received pure water without metal salts. Consumption of iron and copper in the groups of rats maintained on an STD did not produce a significant increase in weight, adipose tissue content or body mass index. However, the adipocyte size and infiltration were increased in the adipose tissue of STD-fed rats receiving a mixture of iron and copper with drinking water. The rats fed iron and copper and, especially, their combination on a HFD background had a significantly higher weight gain, adipose tissue content, morphometric parameters values and adipocyte size compared to STD- and HFD-fed controls. Iron and copper consumption produced their accumulation in the rats' adipose tissue. Moreover, the studied metals reduced adipose tissue concentration of chromium and vanadium. The lipoprotein profile and serum oxidative stress biomarkers were affected in the rats receiving the metals and STD. Hyperglycemia was observed in the rats receiving the studied metals on HFD-background. Based on the analysis of the test subjects, the study suggests that iron and copper administration, especially combined, may potentiate adipogenic effect of HFD. PMID- 23657866 TI - Effects of water-holding capability of the PVF sponge on the adhesion and differentiation of rat bone marrow stem cell culture. AB - The aim of the study is to estimate the effects of the water-holding capability of the polyvinyl formal (PVF) sponges on osteogenic response in vitro experiments. The rat bone marrow stem cells (BMCs) were seeded and cultured for up to 4 weeks under static conditions in osteogenic media to evaluate the adhesion, proliferation, differentiation, and mineralization on the Dextran coated PVF sponges with or without water-holding capability. The BMCs seeded onto the PVF sponges with water-holding capability showed more significant increases in DNA content, alkaline phosphatase (ALP) activity, osteocalcin content, and calcium deposition than those without water-holding capability. These results suggest that the Dextran-coated PVF sponges with high water-holding capability would have potential uses as both a new scaffold to bone tissue engineering and as a new biomaterial. PMID- 23657868 TI - Highly reversible lithium storage in hierarchical Ca2Ge7O16 nanowire arrays/carbon textile anodes. AB - Aligned Ca2Ge7O16 nanowire arrays were successfully grown on carbon textiles to form hierarchical 3D structures by using a facile hydrothermal method on a large scale. Typical Ca2Ge7O16 nanowires are single crystals that show preferred growth along the [001] direction. The 3D hierarchical structures were used as binder free anodes for lithium-ion batteries, which showed the features of highly reversible capacity (900-1100 mA h g(-1) at a current density of 300 mA g(-1)), remarkable cycling stability, even over 100 cycles, and good rate capability, with a capacity of about 500 mA h g(-1) at 3 A g(-1). Furthermore, highly bendable full cells were also fabricated, which showed high flexibility, with little voltage change after bending 600 times, and superior temperature tolerance within the range 4-60 degrees C, thus demonstrating their promising potential for applications in high-performance lithium-ion batteries. PMID- 23657867 TI - Human bulbar conjunctival hemodynamics in hemoglobin SS and SC disease. AB - The known biophysical variations of hemoglobin (Hb) S and Hb C may result in hemodynamic differences between subjects with SS and SC disease. The purpose of this study was to measure and compare conjunctival hemodynamics between subjects with Hb SS and SC hemoglobinopathies. Image sequences of the conjunctival microcirculation were acquired in 9 healthy control subjects (Hb AA), 24 subjects with SC disease, and 18 subjects with SS disease, using a prototype imaging system. Diameter (D) and blood velocity (V) measurements were obtained in multiple venules of each subject. Data were categorized according to venule caliber by averaging V and D for venules with diameters less than (vessel size 1) or greater than (vessel size 2) 15 um. V in vessel size 2 was significantly greater than V in vessel size 1 in the AA and SS groups (P >= 0.009), but not in the SC group (P = 0.1). V was significantly lower in the SC group as compared to the SS group (P = 0.03). In AA and SS groups, V correlated with D (P <= 0.005), but the correlation was not statistically significant in the SC group (P = 0.08). V was inversely correlated with hematocrit in the SS group for large vessels (P = 0.03); however, no significant correlation was found in the SC group (P >= 0.2). Quantitative assessment of conjunctival microvascular hemodynamics in SS and SC disease may advance understanding of sickle cell disease pathophysiology and thereby improve therapeutic interventions. PMID- 23657869 TI - Two steps in one pot: enzyme cascade for the synthesis of nor(pseudo)ephedrine from inexpensive starting materials. PMID- 23657870 TI - Gender depended potentiality of differentiation of human umbilical cord mesenchymal stem cells into oocyte-Like cells in vitro. AB - Recent studies have demonstrated that germ-like cells could be differentiated from human umbilical cord mesenchymal stem cells (hUC-MSCs) in vitro. Whether the sexuality of hUC-MSCs affects the formation efficiency of germ-like cells derived from hUC-MSCs is still unclear. To clearly test the formation efficiency of oocyte-like cells from male and female hUC-MSCs, obtained hUC-MSCs were induced by 20% follicular fluid (FF) according to the method that has been proved by our previous studies. Results showed that hUC-MSCs differentiated into oocyte-like structures and expressed germ cell makers. It was noted that the presence of advanced oocyte-like cells in male hUC-MSCs (m-hUC-MSCs) was similar as that in female hUC-MSCs (f-hUC-MSCs); however, the expression of germ cell's specific markers in m-hUC-MSCs was delayed compared with that in f-hUC-MSCs. In addition, immunofluorescence analysis demonstrated that germ cell-specific markers, Oct4, Vasa, Dazl, ZP2, ZP3 and Stra8, were expressed on the 14th day after induction in both f-hUC-MSCs and m-hUC-MSCs. However, the size of oocyte-like cells from f-hUC MSCs was larger than that in m-hUC-MSCs. The level of secreted oestradiol was significantly higher in f-hUC-MSCs than m-hUC-MSCs. We sought to determine whether critical germ cell's transcription factor-Figlalpha will promote the development of oocyte-like cells. Some germ cell-specific markers were increased when exogenous Figlalpha was transfected into hUC-MSCs. This process implied that germ-like cells might be produced by over-expression of exogenous germ cell specific gene, and this process was similar as that in production of germ cells in induced pluripotent stem cells (iPSCs). Finally, to verify the feasibility that hUC-MSCs differentiate into germ cells, hUC-MSCs were transplanted into seminiferous tubules and kidney capsule of mouse, respectively, and we found the transplanted cells differentiated into germ-like cells in recipient's seminiferous tubules and kidney capsule. This study will provide a simple model to study mammalian germ cell specification using hUC-MSCs in vitro. PMID- 23657871 TI - Renal artery stenosis due to fibromuscular dysplasia in a transplanted kidney from a deceased donor: a difficult diagnosis at color Doppler ultrasonography. AB - Atherosclerotic renal artery stenosis is a frequent cause of arterial hypertension and/or allograft dysfunction after kidney transplantation and is usually located at the iliac artery anastomosis. Fibromuscular dysplasia is a less frequent, nonatherosclerotic, vascular disease, inducing stenosis at the proximal/mid-distal part of the renal artery. We report the case of a 44-year-old woman, in whom serum creatinine concentration increased and arterial hypertension developed 3 months after renal transplantation. Color Doppler ultrasonography showed a low arterial resistance index and prolonged acceleration time in the interlobar arteries, and a significantly increased peak systolic velocity at the mid third of the renal artery, demonstrating hemodynamically significant stenosis. Percutaneous transluminal angioplasty allowed stenosis correction and was followed by creatinine concentration and arterial blood pressure normalization. PMID- 23657872 TI - Treatment of acne vulgaris during pregnancy and lactation. AB - Acne vulgaris is a common problem encountered by pregnant and lactating women. Unfortunately, in clinical practice, treatment is often not optimized as a result of the lack of safety data and unified recommendations on the use of the various anti-acne therapies. In this narrative review, current data on their safety is summarized. We recommend the use of topical medications as first-line treatment for acne vulgaris in pregnant and lactating women. These include antibiotics (erythromycin, clindamycin, metronidazole and dapsone), benzoyl peroxide, azelaic acid and salicylic acid. Oral agents and/or light-based therapy may be considered as second-line treatment. The former consists of oral macrolides (erythromycin and azithromycin), cephalexin or zinc compounds. Blue-violet or red light phototherapy may be used as monotherapy or in addition to topical and/or oral therapies. Hormonal therapy, antibiotics consisting of tetracyclines, co trimoxazole and fluoroquinolones, and both oral and topical retinoids should be avoided. PMID- 23657873 TI - Receptor mediated amelioration of the detrimental effects of sperm agglutinating factor on sperm parameters. AB - Sperm agglutinating factor (SAF) isolated from Staphylococcus aureus immobilizes spermatozoa by agglutination and causes sperm death. This interaction of SAF with spermatozoa is receptor mediated and this receptor has been isolated and purified from human spermatozoa. In this study we attempt to study whether the receptor could ameliorate the detrimental effects of SAF on sperm parameters. Receptor was evaluated against SAF mediated compromised sperm parameters such as Mg(2+) dependent ATPase activity, acrosome status and apoptosis, in vitro using fluorescent microscopy and flow cytometry as well as in vivo by studying the impact on fertility in mice. Incubation of SAF (80 MUg) with spermatozoa resulted in reduced Mg(2+) dependent ATPase activity and premature acrosomal loss whereas a higher concentration (100 MUg), induced apoptosis. However, in the presence of receptor a dose dependent blockage of SAF induced inhibition of Mg(2+) dependent ATPase activity was observed. At higher concentrations 100 and 125 MUg, receptor could inhibit both the premature acrosomal loss and apoptosis. In vivo studies showed that receptor (50 MUg) could alleviate SAF induced infertility in female Balb/c mice following a single intravaginal application before mating. The work highlights the efficacy of the receptor as a corrective measure against negative influence of SAF on functional parameters of spermatozoa as well as fertility and presents receptor as a potential therapeutic intervention against SAF induced infertility. PMID- 23657875 TI - EphrinA5-EphA7 complex induces apoptotic cell death via TNFR1. AB - A previous study showed that the EphA7 receptor regulates apoptotic cell death during early brain development. In this study, we provide evidence that the EphA7 receptor interacts with death receptors such as tumor necrosis factor receptor 1 (TNFR1) to decrease cell viability. We showed that ephrinA5 stimulates EphA7 to activate the TNFR1-mediated apoptotic signaling pathway. In addition, a pull-down assay using biotinylated ephrinA5-Fc revealed that ephrinA5-EphA7 complexes recruit TNFR1 to form a multi-protein complex. Immunocytochemical staining analysis showed that EphA7 was co-localized with TNFR1 on the cell surface when cells were incubated with ephrinA5 at low temperatures. Finally, both the internalization motif and death domain of TNFR1 was important for interacting with an intracytoplasmic region of EphA7; this interaction was essential for inducing the apoptotic signaling cascade. This result suggests that a distinct multi-protein complex comprising ephrinA5, EphA7, and TNFR1 may constitute a platform for inducing caspase-dependent apoptotic cell death. PMID- 23657874 TI - The effects of market integration on childhood growth and nutritional status: the dual burden of under- and over-nutrition in the Northern Ecuadorian Amazon. AB - OBJECTIVES: Market integration is an important source of cultural change exposing indigenous populations to epidemiologic and nutrition transitions. As children and adolescents are biologically sensitive to the health effects of market integration, we examine community variation of anthropometric indicators of nutritional status and growth among a cross-cultural sample of Kichwa, Shuar, Huaorani, and Cofan indigenous groups in the northern Ecuadorian Amazon. METHODS: We measured height, weight, body mass index (BMI), upper arm circumference, and triceps skinfolds of 186 children and adolescents aged 2 to 18 years from seven communities. Anthropometric z-scores were calculated based on the National Health and Nutritional Examination Survey. Comparisons were made with this US reference group, along with between community differences to contextually explore the impacts of varying degrees of market integration. RESULTS: We found a high prevalence of stunting in both boys (40%) and girls (34%). Adiposity increased with age and 40% of girls between 15 and 18 years old were overweight. There were large sex differences in body composition with higher BMI, arm circumference, and triceps skinfolds in adolescent girls. The Kichwa demonstrated the poorest growth outcomes and nutritional stress followed by the Huaorani and Shuar; yet distinctions in under- and over-nutrition were evident within groups. CONCLUSION: Market integration is a major factor influencing the developmental and lifestyle mismatch associated with the epidemiologic and nutrition transition in general, and the dual burden pattern of high rates of stunting yet adequate to above average short-term nutritional status indicators found among indigenous Amazonian populations. PMID- 23657877 TI - Reliability of overcoverage parameters with varying morphologic pincer features: comparison of EOS(r) and radiography. AB - BACKGROUND: Multiple radiographic parameters used for diagnosis and quantification of morphologic pincer features have emerged, but the degree to which pelvic tilt or rotation affects conventional radiography and EOS((r)) is unknown. QUESTION/PURPOSES: We asked: (1) What is the reliability of EOS((r)) and conventional radiography at increasing sizes of morphologic pincer features with varying degrees of tilt and rotation? (2) What is the effect of tilt and rotation on acetabular overcoverage measurements? METHODS: Using a dry cadaveric pelvis, AP conventional radiographs and EOS((r)) images were taken at intervals of increasing modeled pincer size with 0 degrees to 15 degrees varying tilt and rotation. Lateral center-edge angle, Sharp angle, Tonnis angle, crossover sign, and retroversion index were measured on all images. Statistical analysis was conducted. RESULTS: The intermodality intraclass correlation coefficients for conventional radiography and EOS((r)) radiography across all pincer sizes, rotations, and tilts were excellent (0.93-0.98). Crossover sign was in perfect agreement in conventional radiography and EOS((r)). Rotation of the hip away from the beam source and/or increased anterior tilt falsely increased all overcoverage parameters except for Tonnis angle. Rotation away from the beam of 10 degrees or greater or anterior tilt of 5 degrees or greater produced a false-positive crossover sign. CONCLUSIONS: EOS((r)) radiography maintained excellent reliability in comparison to conventional radiography but both were equally vulnerable to the effects of tilt and rotation for quantification of hip parameters used in acetabular overcoverage assessment. A standardized pelvic radiograph ensuring that the pelvis is not excessively tilted or rotated should be used for assessing acetabular overcoverage parameters. PMID- 23657876 TI - Public opinion on imposing restrictions to people with an alcohol- or drug addiction: a cross-sectional survey. AB - PURPOSE: Alcohol- and drug addiction tends to evoke disapproval and rejection among people. This study provides insight into the origin of people's negative attitudes towards these people. Corrigan's attribution model is used to examine intentions of the Dutch public to impose restrictions to people who are addicted to alcohol or illicit drugs. METHODS: Data were derived from a cross-sectional survey among a representative panel of the Dutch population (N = 2,793). Path analyses were conducted to test the influence of attribution beliefs, emotional responses and familiarity with addictions on people's intentions to impose restrictions to these people. RESULTS: More than half of the respondents agreed with imposing restrictions to someone with an addiction such as excluding from taking public office or forbid to care for children. Corrigan's attribution model was partially applicable to explain people's intentions to impose restrictions, since only a rather small percentage of the variance in people's intentions was explained by the model. The perception of personal responsibility for an addiction and high expectancy of aggressiveness have a positive influence on intentions to impose restrictions. Feelings of anger and fear were also predictors of intentions to impose restrictions. CONCLUSIONS: The Dutch public showed high intentions to restrict people with an alcohol- or drug addiction which has an extensive impact on their life opportunities. Perceived aggressiveness, feeling of anger and fear, and perceived responsibility were associated with higher intentions to impose restrictions. PMID- 23657878 TI - Does additional head trauma affect the long-term outcome after upper extremity trauma in multiple traumatized patients: is there an additional effect of traumatic brain injury? AB - BACKGROUND: Musculoskeletal injuries are common in patients with multiple trauma resulting in pain, functional deficits, and disability. Traumatic brain injuries (TBIs) are common in severely injured patients potentially resulting in neurological impairment and permanent disability that would add to that from the musculoskeletal injuries. However, it is unclear to what degree the combination affects impairment. QUESTIONS/PURPOSES: We therefore asked whether added upper extremity injuries or TBI worsened the functional, psychological, and vocational status in multiple trauma patients. METHODS: We retrospectively reviewed 281 patients with multiple trauma: 229 with upper extremity injuries but without TBI (Group I), 32 with concomitant upper extremity injuries and TBI (Group II), and 20 with TBI but no upper extremity injuries (Group III). We assessed patients with the Glasgow Outcome Score (GOS), Hannover Score for Polytrauma Outcome, SF 12 (Physical Component Summary Score and Mental Component Summary Score), medical aid requirements, need of psychological support, and vocational living circumstances. The minimum followup was 10 years (median, 17.5 years; range, 10 28 years). RESULTS: Additional TBI in multiple trauma patients led to reduced function (GOS: Group I: 4.9 +/- 0.2, Group II: 4.5 +/- 0.7, Group III: 4.5 +/- 0.8) resulting in vocational restrictions (job change: Group I: 74%, Group II: 91%, Group III: 90%). The combination of upper extremity and TBIs did not result in worse long-term scores compared with TBI alone. CONCLUSIONS: Rehabilitation and social reintegration in multiple trauma patients with TBI requires particular emphasis to minimize disability and vocational isolation. Musculoskeletal injuries should not be neglected to ensure the maximum extremity function given the impaired cognitive functions after TBI. PMID- 23657879 TI - Intraarticular fibrinogen does not reduce blood loss in TKA: a randomized clinical trial. AB - BACKGROUND: Bleeding remains an ongoing concern after total knee arthroplasty (TKA). Intraarticular application of human fibrinogen with a topical thrombin has been described to stop diffuse bleeding in knee arthroplasty. QUESTIONS/PURPOSES: It was hypothesized that the use of human fibrinogen as a topical agent would result in a reduction of bleeding and transfusions required after TKA; secondary end points included comparison of early clinical results including pain scores and range of motion (ROM) at 6 weeks and complications after surgery. METHODS: Two hundred patients undergoing TKA were randomized into a double-blind clinical trial to receive either intraarticular fibrinogen 2 minutes before tourniquet release or no such treatment. Postoperative hemoglobin and hematocrit levels, drain output, and transfusion requirements were recorded and blood loss was calculated. Clinical outcomes and adverse events were tracked prospectively. Descriptive analysis was performed using a two-sample t-test. RESULTS: There were no differences in calculated blood loss between the fibrinogen and the control groups; the mean postoperative drain output was 780 +/- 378 mL in the fibrinogen group compared with 673 +/- 301 mL in the control group (p = 0.029), but the hemoglobin drop at Day 2 was 3.47 +/- 1.53 g/L in the fibrinogen group and 3.84 +/- 1.24 g/Ll in the control group (p = 0.051). There were no differences in in transfusions, early ROM, visual analog pain scores, or complications between the groups. CONCLUSIONS: The use of fibrinogen in TKA did not lead to a significant reduction of blood loss or transfusions in primary TKA for osteoarthritis. Given the lack of benefits and the costs this procedure adds to TKA, its routine use cannot be justified during primary TKA for osteoarthritis. PMID- 23657880 TI - Total knee arthroplasty after high tibial osteotomy: no differences between medial and lateral osteotomy approaches. AB - BACKGROUND: High tibial osteotomy (HTO) has long been accepted as an effective treatment for unicompartmental osteoarthritis of the knee in young, active adults. For varus knees, the two most commonly performed valgus-producing HTOs are the lateral closing wedge and the medial opening wedge. Regardless of technique, some HTOs fail and are converted to TKA. To our knowledge, no studies have directly compared TKAs done after lateral closing-wedge osteotomies to those done after medial opening-wedge osteotomies. QUESTIONS/PURPOSES: We compared pain and function-related outcomes and survivorship of TKAs in patients who previously underwent medial opening-wedge and lateral closing-wedge HTOs. METHODS: We reviewed our institutional database to identify all patients having undergone a HTO with subsequent conversion to TKA and identified 188 lateral closing-wedge HTOs and 77 medial opening-wedge HTOs. Mean followup was 88 months (range, 3-264 months) for the lateral closing-wedge HTO cohort and 59 months (range, 3-180 months) for the medial opening-wedge cohort. SF-12, WOMAC, and Knee Society Scores, as well as survivorship at 5 years, were compared between the two groups. Statistical analysis was completed using the independent-samples t-test. RESULTS: No differences were found between groups in postoperative SF-12 scores (p = 0.77 for the mental component summary score and p = 0.21 for the physical component summary score), WOMAC scores (p = 0.67), or Knee Society Scores (p = 0.80). No difference was found in survivorship between groups at 5 years. CONCLUSIONS: Our results suggest there is no difference in functional outcomes or survivorship of TKA in patients having previously undergone medial opening-wedge and lateral closing-wedge HTOs. PMID- 23657881 TI - Patients with unstable slipped capital femoral epiphysis have antecedent symptoms. AB - BACKGROUND: The characteristics of patients who sustain unstable slipped capital femoral epiphyses (SCFEs) are not well described compared to their counterparts who sustain stable SCFE. Although patients with unstable slips are usually identified owing to acute symptoms, it is unclear whether these patients have premonitory symptoms that could heighten the awareness of treating physicians to the possibility of an unstable slip and lead to timely diagnosis and treatment. QUESTIONS/PURPOSE: We determined whether most patients experienced pain and limp before developing an unstable SCFE. METHODS: We retrospectively reviewed 582 patients and identified 82 (41 boys, 41 girls; 85 hips) with unstable SCFEs. Patient records were reviewed for sex, age at onset, weight at onset, and presence and location of pain and/or limp before the unstable slip. Boys averaged 13 years of age at the time occurrence and weighed on average in the 77th percentile. Girls averaged 12 years of age at the time of occurrence and weighed on average in the 79th percentile. RESULTS: For all patients, 73 of 82 (88%) had pain in their hips, thighs, or knees for an average of 42 days before sustaining unstable SCFEs. Sex distribution was equal for patients with unstable SCFEs. CONCLUSIONS: Patients who sustained unstable SCFEs had premonitory pain in the limb. Early recognition and an appropriate diagnosis provide a critical opportunity to prevent a morbid unstable SCFE. LEVEL OF EVIDENCE: Level IV, diagnostic study, See Instructions for Authors for a complete description of levels of evidence. PMID- 23657882 TI - Editorial comment: Nanoscience in musculoskeletal medicine. PMID- 23657883 TI - NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits. AB - We delineated and analyzed directly oriented paralogous low-copy repeats (DP LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically derived large data set allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR) mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/velocardiofacial syndrome, 166). In the ~25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5'-CCNCCNTNNCCNC-3', correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13, were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR-mediated genomic instability and further elucidates the role of NAHR in human disease. PMID- 23657884 TI - HIV infection reveals widespread expansion of novel centromeric human endogenous retroviruses. AB - Human endogenous retroviruses (HERVs) make up 8% of the human genome. The HERV-K (HML-2) family is the most recent group of these viruses to have inserted into the genome, and we have detected the activation of HERV-K (HML-2) proviruses in the blood of patients with HIV-1 infection. We report that HIV-1 infection activates expression of a novel HERV-K (HML-2) provirus, termed K111, present in multiple copies in the centromeres of chromosomes throughout the human genome yet not annotated in the most recent human genome assembly. Infection with HIV-1 or stimulation with the HIV-1 Tat protein leads to the activation of K111 proviruses. K111 is present as a single copy in the genome of the chimpanzee, yet K111 is not found in the genomes of other primates. Remarkably, K111 proviruses appear in the genomes of the extinct Neanderthal and Denisovan, while modern humans have at least 100 K111 proviruses spread across the centromeres of 15 chromosomes. Our studies suggest that the progenitor K111 integrated before the Homo-Pan divergence and expanded in copy number during the evolution of hominins, perhaps by recombination. The expansion of K111 provides sequence evidence suggesting that recombination between the centromeres of various chromosomes took place during the evolution of humans. K111 proviruses show significant sequence variations in each individual centromere, which may serve as markers in future efforts to annotate human centromere sequences. Further, this work is an example of the potential to discover previously unknown genomic sequences through the analysis of nucleic acids found in the blood of patients. PMID- 23657885 TI - DNase-seq predicts regions of rotational nucleosome stability across diverse human cell types. AB - DNase-seq is primarily used to identify nucleosome-depleted DNase I hypersensitive (DHS) sites genome-wide that correspond to active regulatory elements. However, ~ 40 yr ago it was demonstrated that DNase I also digests with a ~ 10-bp periodicity around nucleosomes matching the exposure of the DNA minor groove as it wraps around histones. Here, we use DNase-seq data from 49 samples representing diverse cell types to reveal this digestion pattern at individual loci and predict genomic locations where nucleosome rotational positioning, the orientation of DNA with respect to the histone surface, is stably maintained. We call these regions DNase I annotated regions of nucleosome stability (DARNS). Compared to MNase-seq experiments, we show DARNS correspond well to annotated nucleosomes. Interestingly, many DARNS are positioned over only one side of annotated nucleosomes, suggesting that the periodic digestion pattern attenuates over the nucleosome dyad. DARNS reproduce the arrangement of nucleosomes around transcription start sites and are depleted at ubiquitous DHS sites. We also generated DARNS from multiple lymphoblast cell line (LCL) samples. We found that LCL DARNS were enriched at DHS sites present in most of the original 49 samples but absent in LCLs, while multi-cell-type DARNS were enriched at LCL-specific DHS sites. This indicates that variably open DHS sites are often occupied by rotationally stable nucleosomes in cell types where the DHS site is closed. DARNS provide additional information about precise DNA orientation within individual nucleosomes not available from other nucleosome positioning assays and contribute to understanding the role of chromatin in gene regulation. PMID- 23657886 TI - Platelet monoamine oxidase-A activity and aging: effect of carnosine. AB - Platelet mitochondrial MAO-A activity of male albino rats (Wistar strain) was significantly inhibited with an inhibition of its only V max during aging. This age-induced inhibition of platelet MAO-A activity became reversed following the application of higher dosages (2.0-2.5 MUg/kg/day, i.t. for 21 consecutive days) of carnosine. Though carnosine at lower dosage (0.5 MUg/kg/day, i.t. for 21 consecutive days) was ineffective to platelet mitochondrial MAO-A activity in both young and aged rats, at higher dosages (2.0-2.5 MUg/kg/day, i.t. for 21 consecutive days) under similar condition this enzyme activity was significantly enhanced. Carnosine at 1.0 MUg/kg/day, i.t. for 21 consecutive days significantly enhanced MAO-A activity only in aged (18 and 24 months) rats. These results suggest that carnosine withdraws the aging-induced inhibition of mammalian blood platelet MAO-A activity and restores its activity towards that (MAO-A activity) observed in young mammalian blood platelets. PMID- 23657887 TI - Real-time contrast-enhanced transrectal US-guided prostate biopsy: diagnostic accuracy in men with previously negative biopsy results and positive MR imaging findings. AB - PURPOSE: To retrospectively evaluate diagnostic accuracy of real-time contrast material-enhanced (CE) ultrasonography (US) transrectal US-guided biopsies in patients with persistently elevated prostate-specific antigen (PSA) levels, previous negative systematic transrectal US-guided biopsy results, and positive prostate multiparametric magnetic resonance (MR) findings. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study. Informed consent was waived. From 2007 to 2011, 178 patients with increased PSA levels (mean, 10.7 ng/mL [10.7 MUg/L]), previous negative findings of random biopsies, and targets depicted at multiparametric MR imaging underwent transrectal US-guided prostate biopsies after injection of sulfur hexafluoride microbubbles. CE US-targeted biopsies were performed systematically in cancer suggestive regions, followed by random acquisition of 12 nontargeted cores in all other regions. Diagnostic accuracy of CE US-targeted biopsies was measured with sensitivity, specificity, and positive and negative predictive values. Fisher exact and Mann-Whitney U tests were used to compare subgroups of patients. Potential predictive variables were examined with a logistic regression model. RESULTS: CE US findings were positive in a first group of 158 patients and negative in a second group of 20 patients. Prostate carcinoma (PCa) was detected in 75 patients in the first group (47.5%) and in eight of the second group (40.0%). Overall cancer detection rate was 46.6% (83 of 178). In the first group, PCa was detected with targeted biopsies alone in 18 patients (24%), with nontargeted biopsies alone in 23 (30.7%), and with both in 34 (45.3%). Mean number of CE US-targeted cores per cancer-suggestive region was 2.2. CE US targeted biopsies had a positive overall detection rate of 30.9%, while it was 6.9% for 12-core nontargeted biopsies (P < .001). PSA level and Gleason score were associated with positivity of CE US-targeted biopsies (P = .031 and P = .015, respectively). CONCLUSION: Real-time CE US-targeted transrectal US biopsy offers excellent sensitivity for PCa detection in men with previous negative biopsy results and positive findings at multiparametric MR imaging. It may be combined with conventional random biopsies to increase specificity. PMID- 23657888 TI - Cardiac allograft vasculopathy after heart transplantation: electrocardiographically gated cardiac CT angiography for assessment. AB - PURPOSE: To evaluate the diagnostic accuracy of cardiac computed tomographic (CT) angiography without the use of beta-blockers compared with that of invasive angiography for the detection of cardiac allograft vasculopathy (CAV) in heart transplant recipients. MATERIALS AND METHODS: The study was approved by the research ethics committee and informed consent was obtained. Heart transplant recipients (n = 138) scheduled for routine invasive angiography were prospectively enrolled to undergo CT to evaluate coronary artery calcification and retrospectively gated cardiac CT angiography with a 64-section scanner. The cardiac CT angiographic images were systematically analyzed for image quality. Degree of CAV was assessed by using a 15-coronary segments model. The area under the receiver operating characteristic curve, sensitivity, specificity, and negative and positive predictive values of cardiac CT angiography for detection of CAV with any degree of stenosis and greater than or equal to 50% stenosis were calculated. RESULTS: Coronary artery calcification was absent in 82 patients, five (6%) of whom had CAV with 50% or more stenosis. Interpretable image quality was obtained in 130 (96%) of the 136 patients who completed the study and 1900 (98%) of 1948 segments. At the patient level, cardiac CT angiography had an area under the receiver operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of 0.880 (95% confidence interval: 0.819, 0.941), 98%, 78%, 77%, and 98%, respectively, for diagnosis of CAV with any degree of stenosis, but for CAV with 50% or more stenosis, the corresponding values were 0.942 (95% confidence interval: 0.885, 1.000), 96%, 93%, 72%, and 99%, respectively. None of the 61 patients with normal cardiac CT angiographic results had CAV on the basis of invasive angiographic images. CONCLUSION: The study results show that cardiac CT angiography compares favorably with invasive angiography in detecting CAV in heart transplant recipients and may be a preferable screening technique because of its noninvasive nature. The absence of coronary artery calcification alone is not reliable enough for excluding CAV. PMID- 23657889 TI - Femoroacetabular cam-type impingement: global assessment of the femoral head-neck junction on a single reformatted MR image. AB - PURPOSE: To characterize the imaging appearance of femoral head-neck contour abnormalities on a short-axis magnetic resonance (MR) image compared with the usual anterior alpha angle measurements and multiple alpha angle measurements on radial reformatted MR images, with surgery as the reference standard. MATERIALS AND METHODS: After institutional review board approval of this HIPAA-compliant study, 21 patients who underwent arthroscopy and 24 patients who did not, all of whom were evaluated with three-dimensional MR imaging, during 1 year were identified. Short-axis MR images of the femoral head-neck junction were reformatted with multiple radial images along the axis of the femoral neck. The following measurements were made at each hour of a clock face: (a) presence and size of bone contour abnormality visible beyond a best-fit circle and (b) femoral head-neck offset angles. Mann-Whitney, Fisher exact, and Wilcoxon matched-pair signed rank tests were performed. Intra- and interreader agreement were calculated as the Cohen kappa. RESULTS: Of the 21 subjects who underwent surgery, 16 were confirmed to have cam-type femoroacetabular impingement (FAI) at surgery. Comparing findings from short-axis images with those at surgery, average accuracy was 81%. Comparing findings from head-neck offset angles with those at surgery, average accuracy was 80%. On short-axis images, average bone elevation was 3.2 mm in patients with cam-type FAI and 1.4 mm in those without it. In eight of 24 subjects who did not undergo surgery, the alpha angle was normal but the short axis MR image showed abnormal bone contour. CONCLUSION: An abnormal bone contour identified on a short-axis MR image at the femoral head-neck junction correlates with surgical findings and may allow for a global characterization of the bone abnormality with regard to location, extent, and amount of elevation compared with the alpha angle and multiple head-neck offset angles. PMID- 23657890 TI - Simultaneously acquired MR/PET images compared with sequential MR/PET and PET/CT: alignment quality. AB - PURPOSE: To compare anatomic alignment between morphologic and positron emission tomography (PET) images acquired in the abdomen and pelvis by using simultaneous magnetic resonance (MR)/PET, PET/computed tomography (CT), and retrospective MR/PET fusion and to compare alignment between MR and PET in simultaneous and sequential thoracic MR/PET by using different breathing, registration, and gating protocols. MATERIALS AND METHODS: Informed consent and institutional review board approval were obtained. The misalignment in 28 abdominal patient datasets was analyzed in simultaneous MR/PET, PET/CT, and retrospective MR/PET fusion. In seven thoracic MR/PET datasets, the effect of different breathing protocols, simultaneous, sequential, and MR-gated data acquisition was evaluated, and the effect of rigid registration versus nonregistered images was evaluated. Analysis of variance and subsequent Tukey test were used for statistical analysis. RESULTS: The misalignment in all abdominal organs was reduced in simultaneous MR/PET compared with retrospectively fused MR and PET images (means, 5.8 mm vs 11.9 mm; P < .001), and in the urinary bladder compared with PET/CT (means, 5.9 mm vs 11.0 mm; P < .007). Thoracic MR/PET with inspiratory breath-hold MR showed the largest misalignment (mean, 24.5 mm; P < .001). None of the other thoracic protocols that were composed of different acquisition, registration, or gating procedures differed significantly from one another. CONCLUSION: The alignment of hybrid datasets acquired in simultaneous whole-body MR/PET was more accurate than retrospective fusion in all investigated abdominal organs, and more accurate than PET/CT in the urinary bladder; the alignment of thoracic MR/PET with expiratory breath hold or free-breathing MR was more exact than with inspiratory MR. However in this preliminary work the clinical importance of these degrees of misalignment was not assessed. PMID- 23657891 TI - Recurrent variceal bleeding and shunt patency: prospective randomized controlled trial of transjugular intrahepatic portosystemic shunt alone or combined with coronary vein embolization. AB - PURPOSE: To prospectively evaluate the efficacy of a transjugular intrahepatic portosystemic shunt (TIPS) alone and TIPS in association with embolotherapy (TIPS+E) in the variceal coronary vein to prevent recurrent variceal bleeding and stent dysfunction after TIPS creation. MATERIALS AND METHODS: Institutional review board approval was obtained; all participants provided informed consent. A total of 106 patients (66 men, 40 women; age range, 18-70 years) with recurrent variceal bleeding due to hepatic cirrhosis were assigned randomly to the TIPS+E (n = 54) or TIPS (n = 52) group from May 2007 to July 2011. The TIPS was created by using covered stents. Patients in the TIPS+E group underwent embolotherapy via the jugular vein before TIPS implantation. Rates of recurrent variceal bleeding, stent patency, and survival were evaluated. Scores for liver function and life quality were calculated. RESULTS: TIPS placement was successful in all patients. Recurrent variceal bleeding ranked second among causes of death after TIPS placement. Although the 3-year cumulative rates of shunt patency, recurrent variceal bleeding, and survival in the two groups were not significantly different (P > .05), the 6-month overall rate of shunt patency in the TIPS+E group was significantly higher than that in the TIPS group (96.2% vs 82.0%, P = .019), and the 6-month overall rate of recurrent variceal bleeding was also significantly lower than that in the TIPS group (5.7% vs 20.0%, P = .029). CONCLUSION: The TIPS+E regimen may reduce the risk of recurrent variceal bleeding during the first 6 months after the TIPS procedure by preventing shunt dysfunction, which may improve liver function and quality of life. (c) RSNA, 2013. PMID- 23657892 TI - Solitary painful osseous metastases: correlation of imaging features with pain palliation after radiofrequency ablation--a multicenter american college of radiology imaging network study. AB - PURPOSE: To identify the correlation of pre- and postablation imaging features with pain relief, pain intensity, and patient mood after radiofrequency (RF) ablation of solitary painful osseous metastases. MATERIALS AND METHODS: This prospective, multicenter group trial was approved by each institutional review board. Participants were enrolled between November 1, 2001, and April 6, 2006. Written informed consent was obtained from all subjects, and patient confidentiality protocols were followed in compliance with HIPAA. Computed tomography (CT)-guided RF ablation and contrast material-enhanced 1-month follow up CT and/or magnetic resonance imaging were performed in 49 subjects (24 men, 25 women; age range, 34-83 years) with a confirmed malignant solitary bone lesion of maximum dimension of 8 cm or smaller that was causing intractable pain. Pain intensity and patient mood were measured before and after RF ablation. Tumor imaging features were recorded. Unadjusted and adjusted linear mixed-effects models, with a random intercept for each subject, were used to model patient mood, pain relief, and pain intensity scores at three times after ablation as a function of each tumor characteristic. RESULTS: Decreased postablation tumor pain correlated with preablation tumor volume (P = .02) and pathologic fracture (P = .01), while pain relief correlated with pathologic fracture (P = .03) and percentage of bone-tumor interface (BTI) ablated (P = .02). Conversely, presence of an irregular rim after ablation (P = .02) and rim thickness (P = .01) correlated with increased pain. There was no evidence in this study that RF ablation of larger tumor percentage or larger volume leads to better pain relief or decreased pain (P > .05). CONCLUSION: Existing pathologic fracture and smaller tumor size appear to be predictive parameters of success when selecting patients for palliative RF ablation of painful solitary osseous metastases. Successful palliation also appears to be related to the percentage of BTI ablated. PMID- 23657893 TI - Evaluation of the kinetic properties of background parenchymal enhancement throughout the phases of the menstrual cycle. AB - PURPOSE: To develop and apply a semiautomatic method of segmenting fibroglandular tissue to quantify magnetic resonance (MR) imaging contrast material-enhancement kinetics of breast background parenchyma (BP) and lesions throughout the phases of the menstrual cycle in women with benign and malignant lesions. MATERIALS AND METHODS: The institutional review board approved this retrospective HIPAA compliant study, and informed consent was waived. From December 2008 to August 2011, 58 premenopausal women who had undergone contrast material-enhanced MR imaging and MR imaging-guided biopsy were identified. The longest time from the start of the last known period was 34 days. One lesion per patient (37 benign and 21 malignant) was analyzed. The patient groups were stratified according to the week of the menstrual cycle when MR imaging was performed. A method based on principal component analysis (PCA) was applied for quantitative analysis of signal enhancement in the BP and lesions by using the percentage of slope and percentage of enhancement. Linear regression and the Mann-Whitney U test were used to assess the association between the kinetic parameters and the week of the menstrual cycle. RESULTS: In the women with benign lesions, percentages of slope and enhancement for both BP and lesions during week 2 were significantly (P < .05) lower than those in week 4. Percentage of enhancement in the lesion in week 2 was lower than that in week 3 (P < .05). The MR images of women with malignant lesions showed no significant difference between the weeks for any of the parameters. There was a strong positive correlation between lesion and BP percentage of slope (r = 0.72) and between lesion and BP percentage of enhancement (r = 0.67) in the benign group. There was also a significant (P = .03) difference in lesion percentage of slope between the benign and malignant groups at week 2. CONCLUSION: The PCA-based method can quantify contrast enhancement kinetics of BP semiautomatically, and kinetics of BP and lesions vary according to the week of the menstrual cycle in benign but not in malignant lesions. PMID- 23657894 TI - Tumor volume of resectable adenocarcinoma of the esophagogastric junction at multidetector CT: association with regional lymph node metastasis and N stage. AB - PURPOSE: To determine whether the volume of resectable adenocarcinoma of the esophagogastric junction (AEG) measured at multidetector computed tomography (CT) is associated with regional lymph node metastasis and N stage. MATERIALS AND METHODS: The study was approved by the institutional ethics committee, and written informed consent was obtained from each participant. Two hundred sixteen patients with resectable AEG prospectively underwent contrast material-enhanced thoracoabdominal multidetector CT less than 2 weeks before curative resection. Gross tumor volume was retrospectively measured on CT scans. Univariate and multivariate analyses were performed to identify whether gross tumor volume is associated with regional lymph node metastasis. The Mann-Whitney U test was performed to compare gross tumor volume among N stages, with Bonferroni correction for multigroup comparisons. Receiver operating characteristic analysis was performed to determine if gross tumor volume could help classify N stage. RESULTS: Univariate analysis showed that gross tumor volume is associated with regional lymph node metastasis (P < .0001). Multivariate analysis revealed that gross tumor volume is an independent risk factor of lymph node metastasis (P = .023, odds ratio = 2.791). The Mann-Whitney U test showed that gross tumor volume could help differentiate between stage N0 and stages N1-N2 or N1-N3 disease and between stages N1-N2 and stage N3 disease (P < .0001 for all). In patients with stage T1-T3 AEG, gross tumor volume could help differentiate between stage N0 and stages N1-N2 (cutoff, 15.23 cm(3)) or N1-N3 (cutoff, 17.16 cm(3)) disease and between stages N1-N2 and stage N3 disease (cutoff, 33.96 cm(3)). In patients with stage T3 AEG, gross tumor volume could help differentiate stage N0 from stages N1 N2 (cutoff, 18.41 cm(3)) or N1-N3 (cutoff, 19.30 cm(3)) disease and stages N1-N2 from stage N3 disease (cutoff, 33.96 cm(3)). CONCLUSION: Gross tumor volume of AEG measured with multidetector CT is associated with regional lymph node metastasis and N stage. PMID- 23657895 TI - Subcutaneous blood pressure monitoring with an implantable optical sensor. AB - We introduce a minimally invasive, implantable system that uses pulse transit time to determine blood pressure. In contrast to previous approaches, the pulse wave is detected by a photoplethysmographic (PPG) signal, acquired with high quality directly on subcutaneous muscle tissue. Electrocardiograms (ECG) were measured with flexible, implantable electrodes on the same tissue. PPG detection is realized by a flat 20 mm x 6 mm optoelectronic pulse oximeter working in reflection mode. The optical sensor as well as the ECG electrodes can be implanted using minimally invasive techniques, with only a small incision into the skin, making long-term monitoring of blood pressure in day-to-day life for high-risk patients possible. The in vivo measurements presented here show that the deviation to intra-arterial reference measurements of the systolic blood pressure in a physiologically relevant range is only 5.5 mmHg, demonstrated for more than 12 000 pulses. This makes the presented sensor a grade B blood pressure monitor. PMID- 23657896 TI - A predictive pharmacokinetic/pharmacodynamic model of fentanyl for analgesia/sedation in neonates based on a semi-physiologic approach. AB - BACKGROUND AND OBJECTIVES: Fentanyl is a synthetic opioid commonly used as an anesthetic and also increasingly popular as a sedative agent in neonates. Initial dosage regimens in this population are often empirically derived from adults on a body weight basis. However, ontogenic maturation processes related to drug disposition are not necessarily always body weight correlates. We developed a predictive pharmacokinetic/pharmacodynamic model that includes growth and maturation physiologic changes for fentanyl in neonatal care. METHODS: Key pharmacokinetic variables and principles (protein binding, clearance, distribution) as related to fentanyl pharmacokinetic/pharmacodynamic behavior in adults (tricompartmental model) and to neonatal physiologic data (organ weights and blood flows, body composition, renal and hepatic function, etc.) were used to guide the building of a semi-physiologic ontogenic model. The model applies to a normal-term neonate without any other intervention. Then, extension to a pharmacokinetic/pharmacodynamic link model for fentanyl was made. The final model was evaluated by predicting the time course of plasma concentrations and the effect of a standard regimen of 10.5 MUg/kg over a 1-h period followed by 1.5 MUg/kg/h for 48 h. RESULTS: Hepatic clearance was linked to ontogeny of unbound fraction and of alpha1-acid glycoprotein. All parameters were reduced in the neonate compared to adults but in a differing proportion due to qualitative changes in physiology that are analyzed and accounted for. Systemic clearance (CLS), volume of the central compartment (V1) and steady-state volume of distribution predicted by the model were 0.028 L/min, 1.26 L, and 22.04 L, respectively. Weight-corrected parameters generally decreased in adults compared with neonates, but differentially, e.g., CLS = 0.0093 versus 0.0088 L/min/kg, while V1 = 0.42 versus 0.18 L/kg (neonates vs. adults). Under such complexity a pharmacokinetic/pharmacodynamic model is the appropriate method for rational efficacy targeting. Fentanyl pharmacodynamics in neonates were considered to be similar to those in adults except for the equilibrium rate constant, which was also scaled on an ontogenic basis. The model adequately predicted the reported mean expected concentration-time profiles for the standard regimen. CONCLUSIONS: Integrated pharmacokinetic/pharmacodynamic modeling showed that the usually prescribed dosage regimens of fentanyl in neonates may not always provide the optimum degree of sedation. The model could be used in optimal design of clinical trials for this vulnerable population. Prospective clinical testing is the reasonable next step. PMID- 23657897 TI - Chronic toxicity of nickel-spiked freshwater sediments: variation in toxicity among eight invertebrate taxa and eight sediments. AB - This study evaluated the chronic toxicity of Ni-spiked freshwater sediments to benthic invertebrates. A 2-step spiking procedure (spiking and sediment dilution) and a 2-stage equilibration period (10 wk anaerobic and 1 wk aerobic) were used to spike 8 freshwater sediments with wide ranges of acid-volatile sulfide (AVS; 0.94-38 umol/g) and total organic carbon (TOC; 0.42-10%). Chronic sediment toxicity tests were conducted with 8 invertebrates (Hyalella azteca, Gammarus pseudolimnaeus, Chironomus riparius, Chironomus dilutus, Hexagenia sp., Lumbriculus variegatus, Tubifex tubifex, and Lampsilis siliquoidea) in 2 spiked sediments. Nickel toxicity thresholds estimated from species-sensitivity distributions were 97 ug/g and 752 ug/g (total recoverable Ni; dry wt basis) for sediments with low and high concentrations of AVS and TOC, respectively. Sensitive species were tested with 6 additional sediments. The 20% effect concentrations (EC20s) for Hyalella and Gammarus, but not Hexagenia, were consistent with US Environmental Protection Agency benchmarks based on Ni in porewater and in simultaneously extracted metals (SEM) normalized to AVS and TOC. For Hexagenia, sediment EC20s increased at less than an equimolar basis with increased AVS, and toxicity occurred in several sediments with Ni concentrations in SEM less than AVS. The authors hypothesize that circulation of oxygenated water by Hexagenia led to oxidation of AVS in burrows, creating microenvironments with high Ni exposure. Despite these unexpected results, a strong relationship between Hexagenia EC20s and AVS could provide a basis for conservative site specific sediment quality guidelines for Ni. PMID- 23657898 TI - Liquid-phase RNA synthesis by using alkyl-chain-soluble support. AB - Recent progress in the RNA therapeutics has increased demand for the synthesis of large quantities of oligoribonucleotides. The assembly of RNA oligomers relies mainly on solid-phase approaches. These allow rapid product purification and the ability to drive a target reaction to completion through the use of excess reagents. Despite the known advantages of solid-phase synthesis, some issues in the process remain to be addressed, such as low and limited scale, reagent accessibility, and the use of a very large excess of reagents. Herein, we report a highly efficient and practical method of liquid-phase synthesis of RNA oligomers by using alkyl-chain-soluble support. We demonstrate the utility of the liquid-phase method through 21-mer RNA synthesis on a gram scale. PMID- 23657899 TI - The velocity of fetal growth is associated with the breadth of the placental surface, but not with the length. AB - OBJECTIVES: Studies of the placenta in pregnancies complicated by pre-eclampsia have led to the suggestion that tissue along the length and breadth of its surface has different functions. A recent study in Saudi Arabia showed that the body size of newborn babies was related to the breadth of the surface at birth but not to its length. We have now examined whether the association between placental breadth and body size reflects large size of the baby from an early stage of gestation or rapid growth between early and late gestation. METHODS: We studied 230 women who gave birth to singleton babies in King Khalid Hospital, Riyadh, Saudi Arabia. In total, 176 had ultrasound measurements both before 28 weeks and at 28 weeks or later, which we define as early and late gestation. We used these to calculate growth velocities between early and late gestation, which we expressed as the change in standard deviation scores over a 10-week period. RESULTS: The breadth of the placental surface was correlated with fetal growth velocity. The correlation coefficients were 0.24 (P = 0.002) for the head circumference, 0.24 (P = 0.001) for the biparietal diameter and 0.34 (P < 0.001) for the abdominal circumference. The length of the surface was not related to fetal growth velocity. CONCLUSIONS: Tissue along the breadth of the placental surface may be more important than tissue along the length in the transfer of nutrients from mother to baby. This may be part of a wider phenomenon of regional differences in function across the placental surface. PMID- 23657900 TI - Formation of C-SCF3 bonds through direct trifluoromethylthiolation. PMID- 23657901 TI - Activation of nucleotide-binding oligomerization domain 1 (NOD1) receptor signaling in Labeo rohita by iE-DAP and identification of ligand-binding key motifs in NOD1 by molecular modeling and docking. AB - The nucleotide-binding oligomerization domain 1 (NOD1) receptor recognizes various pattern-associated structures of microbes through its leucine-rich repeat (LRR) domain and activates signaling cascades to induce innate immunity. This report describes the activation of NOD1 receptor signaling by gamma-D-glutamyl meso-diaminopimelic acid (or gamma-D-Glu-mDAP [iE-DAP]) in a commercially important fish species, rohu (Labeo rohita). It also described critical motifs in the NOD1-LRR domain that could be involved in binding iE-DAP, lipopolysaccharide (LPS), and polyinosinic:polycytidylic acid (poly I:C). The activation of NOD1 receptor signaling was studied by injecting iE-DAP, and analysis of tissue samples for NOD1 and receptor-interacting serine/threonine kinase (RICK) expression was done by quantitative real-time polymerase chain reaction (qRT-PCR) assay. To identify ligand-binding motifs in NOD1, the 3D model of NOD1-LRR was generated, followed by a 6-ns molecular dynamics simulation. Molecular docking of LPS with NOD1-LRR was executed at the Hex and PatchDock servers, and iE-DAP and poly I:C in the AutoDock 4.2, FlexX 2.1, Glide 5.5, and GOLD 4.1 programs. The results of qRT-PCR revealed significant (p < 0.05) upregulation of NOD1 and RICK expression. Molecular docking revealed that the amino acid residues at LRR1-2, LRR3-7, and LRR8-9 could be involved in poly I:C, LPS, and iE-DAP binding, respectively. In fish, this is the first report describing the 3D structure of NOD1-LRR and its critical ligand-binding motifs. PMID- 23657902 TI - Application of intelligent techniques for classification of bacteria using protein sequence-derived features. AB - Standard molecular experimental methodologies and mathematical procedures often fail to answer many phylogeny and classification related issues. Modern artificial intelligent-based techniques, such as radial basis function, genetic algorithm, artificial neural network, and support vector machines are of ample potential in this regard. Reliance on a large number of essential parameters will aid in enhanced robustness, reliability, and better accuracy as opposed to single molecular parameter. This study was conducted with dataset of computed protein physicochemical properties belonging to 20 different bacterial genera. A total of 57 sequential and structural parameters derived from protein sequences were considered for the initial classification. Feature selection based techniques were employed to find out the most important features influencing the dataset. Various amino acids, hydrophobicity, relative sulfur percentage, and codon number were selected as important parameters during the study. Comparative analyses were performed applying RapidMiner data mining platform. Support vector machine proved to be the best method with maximum accuracy of more than 91%. PMID- 23657903 TI - Electrophoretic deposition of multi-walled carbon nanotube on a stainless steel electrode for use in sediment microbial fuel cells. AB - Sediment microbial fuel cells (SMFCs) could be used as power sources and one type of new technology for the removal of organic matters in sediments. In order to improve electrode materials and enhance their effect on the performance, we deposited multi-walled carbon nanotube (MWNT) on stainless steel net (SSN). Electrophoretic deposition technique as a method with low cost, process simplicity, and thickness control was used for this electrode modification and produced this novel SSN-MWNT electrode. The performances of SMFCs with SSN-MWNT as electrode were investigated. The results showed that the maximum power density of SMFC with SSN-MWNT cathode was 31.6 mW m(-2), which was 3.2 times that of SMFC with an uncoated stainless steel cathode. However, no significant increase in the maximum power density of SMFC with SSN-MWNT anode was detected. Further electrochemical analysis showed that when SSN-MWNT was used as the cathode, the cathodic electrochemical activity and oxygen reduction rate were significantly improved. This study demonstrates that the electrophoretic deposition of carbon nanotubes on conductive substrate can be applied for improving the performance of SMFC. PMID- 23657904 TI - Activated apoptotic and anti-survival effects on rat hearts with fructose induced metabolic syndrome. AB - Consumption of fructose has been linked to the development of metabolic syndrome, whereas the cardiomyopathic changes and cardiac apoptosis of dietary high fructose intake have not yet been clarified. The purpose of this study was to evaluate the effects of high-fructose on cardiac apoptotic and survival pathways. Thirty-two Wistar rats were randomly divided into a control group (CON), which received a standard chow diet, and a fructose-induced metabolic syndrome group (FIMS), which received a 50% fructose-content diet for 13 weeks. Histopathological analysis, TUNEL assays and Western blotting were performed on the excised hearts from both groups. The blood pressure, glucose, insulin, triglyceride and cholesterol levels were significantly increased in the FIMS group, compared with the CON group. The abnormal myocardial architecture, enlarged interstitial space and increased cardiac TUNEL-positive apoptotic cells were observed in the FIMS group. The TNF-alpha, TNF receptor 1, Fas ligand, Fas receptor, FADD, and activated caspase-3 and 8 protein levels (Fas pathway) and the Bax, Bak, Bax/Bcl-2, Bak/Bcl-xL, cytosolic cytochrome c, and activated caspase-3 and nine protein levels (mitochondria pathway) were increased in the FIMS group compared with those in the CON group. The IGFI, IGFI-R, p-PI3K, p-Akt, Bcl-2 and Bcl-xL protein levels (survival pathway) were all significantly decreased in the FIMS group compared with those in the CON group. High-fructose intake elevated blood pressure and glucose levels; moreover, high-fructose diet activated cardiac Fas-dependent and mitochondria-dependent apoptotic pathways and suppressed the survival pathway, which might provide one possible mechanism for developing heart failure in patients with metabolic syndrome. PMID- 23657906 TI - [Pediatric orthopedics]. PMID- 23657905 TI - Adolescent experiences of violence and relation to violence perpetration beyond young adulthood among an urban sample of Black and African American males. AB - The purpose of this study is to determine if experiences of physical violence during early and late adolescence (12-21 years) places urban Black males at increased risk for interpersonal violence perpetration beyond young adulthood (30 years and older). Participants of this cross-sectional study were Black and African American men (N = 455) between the ages of 30 and 65 years, recruited from four urban clinical sites in the Northeast. Multivariate logistic regression models were used to analyze the relation of adolescent experiences of violence to: (1) past 6 month street violence involvement and (2) past year intimate partner violence perpetration. Ten percent of the sample reported that they experienced adolescent victimization. Men reporting adolescent victimization were significantly more likely to report past 6-month street violence involvement (Adjusted Odds Ratio (AOR) = 3.2, 95 % CI = 1.7-6.3) and past 6 month intimate partner violence perpetration (AOR = 2.8, 95 % CI = 1.8-5.4) compared to men who did not report such victimization. Study findings suggest that in order to prevent adulthood perpetration of violence, more work is needed to address experiences of victimization among young Black males, particularly violence experienced during adolescence. PMID- 23657907 TI - The impact of frequently encountered cardiovascular risk factors on sexual dysfunction in rheumatic disorders. AB - Traditional cardiovascular risk factors have been acknowledged as major contributors to sexual dysfunction in the general population. The purpose of this study was to explore their impact on sexual function in rheumatologic patients. A total of 557 consecutive rheumatologic patients, 449 females and 108 males, had their sexual function evaluated with the Female Sexual Functioning Index (FSFI) and the International Index of Erectile Function (IIEF) questionnaire respectively. Personal data regarding presence of cardiovascular risk factors were collected and analysed in association with the FSFI and IIEF scores. Mean age of the participants was 54.1 +/- 14.1 years, mean body mass index was 27.5 +/ 5.29 and mean systolic and diastolic blood pressure was 130.5 +/- 19.82 and 79.5 +/- 10.51 mmHg respectively. Hypertension was present in 39% of the participants, diabetes mellitus in 10.2%, dyslipidaemia in 33.6% and history of cardiovascular events in 8.6%, whereas smoking was recorded by 28.4% and alcohol consumption by 7.4%. Sexual dysfunction affected 68.6% of our study population (73.5% of females and 48.1% of males, p < 0.001). Logistic regression analysis revealed that age was the only factor associated with a significantly higher prevalence of sexual dysfunction (p < 0.001 for both genders, p = 0.013 in males and p < 0.001 in females). Increased age was identified as the only independent predictor of sexual dysfunction in our population. Apart from age, traditional cardiovascular risk factors failed to explain the increased prevalence of sexual dysfunction in these patients. Other contributing factors (physical and/or psychological) might account for the increased occurrence of sexual dysfunction in rheumatic disorders. PMID- 23657908 TI - Circulation of two mumps virus genotypes in an unimmunized population in India. AB - Two separate outbreaks of fever with parotitis were reported from the Apsinga and Pimpla villages in the Osmanabad district of the Maharashtra State, India during February and March 2012. Meningo-encephalitis was noted in two patients resulting in the death of an 11-year male. Samples of blood and throat swabs were collected from patients with fever and parotitis. Serum samples from suspected (n=62) and convalescent (n=19) patients were tested for mumps virus specific IgM and/or IgG antibodies. Mumps virus specific IgM antibodies were detected in 44 of 62 serum samples (71%). Of the 19 convalescent phase sera 16 had both, anti-mumps virus IgM and IgG antibodies. Twenty-eight throat swabs collected from patients with parotitis were tested by RT-PCR for the SH gene. Twenty-three specimens were found to be positive and nucleotide sequencing of the amplified PCR products revealed circulation of two distinct genotypes that were village specific. Mumps virus genotype C (n=18) was detected in Apsinga village and genotype G (n=5) in Pimpla village. Two mumps virus isolates were also obtained using Vero cells. This is the first report from India confirming simultaneous circulation of mumps virus genotype C in one village and the G genotype in another village only 37 km away. PMID- 23657909 TI - Comparison between the Truview PCDTM or the GlideScope(r) video laryngoscope and direct laryngoscopy for tracheal intubation in pediatric patients. PMID- 23657910 TI - Delineation of a region responsible for panhypopituitarism in 20p11.2. AB - We report on the case of a young woman with a de novo 20p11.21p11.23 deletion, discovered by array-CGH. She has behavioral troubles with autistic traits, intellectual disability, panhypopituitarism, severe hypoglycemia, epilepsy, and scoliosis. The majority of the reported 20p deletions are located on the 20p12 region, covering the JAG1 gene responsible for the Alagille syndrome. More proximal deletions are even rarer, with very few cases described in the literature to date. The deletion carried by our patient is, to our knowledge, the smallest described de novo proximal 20p11.2 deletion. It was first discovered by 0.5 Mb BAC array-CGH, further delineated using an oligonucleotide array, and finally confirmed by fluorescence in situ hybridization. The deletion is 4.22 Mb in size, with the exact location on chr20: 19.810.034-24.031.344 (Feb. 2009, GRCh37/hg19). In light of the other reported cases that display genomic and phenotypic overlap with our patient, we discuss the phenotype of our patient, in order to further delineate the 20p proximal deletion phenotype. We propose a minimal critical region responsible for panhypopituitarism with global developmental delay, intellectual disability, scoliosis and facial dysmorphism. Moreover, considering the deleted genes, we highlight the impact of the deletion of this minimal critical region on the Shh signaling pathway. PMID- 23657911 TI - Simultaneous fracture dislocation of the hamate, lunate fracture and scapholunate ligament lesion. PMID- 23657912 TI - Three-dimensional analysis of the proximal articulating surfaces of the lunate and capitate. PMID- 23657913 TI - Treatment changes and improved outcomes in RA: an overview of a large inception cohort from 1989 to 2009. AB - OBJECTIVE: The introduction of effective treatment strategies in the past two decades has changed the management of RA dramatically. The objective was to analyse the changes in disease activity, function, joint damage and incidence of orthopaedic surgery over a period of 20 years (1989-2009) for patients with RA. METHODS: Data acquired from 1989 to 2008 inclusive from the Nijmegen RA inception cohort were studied. By repeated measures analysis the course of the population mean disease activity score (DAS28) and the Health Assessment Questionnaire Disability Index (HAQ-DI) corrected for age, gender, RF and disease duration was determined. Orthopaedic interventions were analysed as incidence rates with a Poisson distribution. We calculated the prevalence of the various therapies that patients were receiving. RESULTS: By 2009, 992 patients with RA had been included and 273 had been excluded. From 1989 onwards, the proportion of patients using MTX increased from 5% (8 of 164) to 62% (486 of 780), and biologic response modifiers from 0% to 22% (168 of 780) in 2008. The average MTX dosage increased to 16.1 +/- 5.5 mg/week in 2008. The mean DAS28 (3.1) and HAQ-DI (0.47) were least (P < 0.008) in 2008 compared with previous years. There was a significant trend towards lower incidence rates of orthopaedic intervention in the period 2006-2008 than in almost all previous years. CONCLUSION: Treatment strategy changed in a large inception cohort of patients with RA which coincided with decreased disease activity, increased functional ability and fewer orthopaedic interventions since the early 1990s. PMID- 23657914 TI - Site-selective catalytic C(sp2)-H bond azidations. PMID- 23657915 TI - Well-defined molecular magnesium hydride clusters: relationship between size and hydrogen-elimination temperature. AB - A new tetranuclear magnesium hydride cluster, [{NN-(MgH)2}2], which was based on a N-N-coupled bis-beta-diketiminate ligand (NN(2-)), was obtained from the reaction of [{NN-(MgnBu)2}2] with PhSiH3. Its crystal structure reveals an almost tetrahedral arrangement of Mg atoms and two different sets of hydride ions, which give rise to a coupling in the NMR spectrum (J = 8.5 Hz). To shed light on the relationship between the cluster size and H2 release, the thermal decomposition of [{NN-(MgH)2}2] and two closely related systems that were based on similar ligands, that is, an octanuclear magnesium hydride cluster and a dimeric magnesium hydride species, have been investigated in detail. A lowering of the H2 desorption temperature with decreasing cluster size is observed, in line with previously reported theoretical predictions on (MgH2)n model systems. Deuterium labeling studies further demonstrate that the released H2 solely originates from the oxidative coupling of two hydride ligands and not from other hydrogen sources, such as the beta-diketiminate ligands. Analysis of the DFT-computed electron density in [{NN-(MgH)2}2] reveals a counterintuitive interaction between two formally closed-shell H(-) ligands that are separated by 3.106 A. This weak interaction could play an important role in H2 desorption. Although the molecular product after H2 release could not be characterized experimentally, DFT calculations on the proposed decomposition product, that is, the low-valence tetranuclear Mg(I) cluster [(NN-Mg2)2], predict a structure with two almost parallel, localized Mg-Mg bonds. As in a previously reported beta-diketiminate Mg(I) dimer, the Mg-Mg bond is not characterized by a bond critical point, but instead displays a local maximum of electron density midway between the atoms, that is, a non-nuclear attractor (NNA). Interestingly, both of the NNAs in [(NN Mg2)2] are connected through a bond path that suggests that there is bonding between all four Mg(I) atoms. PMID- 23657916 TI - Congenital myasthenic syndrome and minicore-like myopathy with DOK7 mutation. PMID- 23657917 TI - Preparation and characterization of nickel-spiked freshwater sediments for toxicity tests: toward more environmentally realistic nickel partitioning. AB - Two spiking methods were compared and nickel (Ni) partitioning was evaluated during a series of toxicity tests with 8 different freshwater sediments having a range of physicochemical characteristics. A 2-step spiking approach with immediate pH adjustment by addition of NaOH at a 2:1 molar ratio to the spiked Ni was effective in producing consistent pH and other chemical characteristics across a range of Ni spiking levels. When Ni was spiked into sediment having a high acid-volatile sulfide and organic matter content, a total equilibration period of at least 10 wk was needed to stabilize Ni partitioning. However, highest spiking levels evidently exceeded sediment binding capacities; therefore, a 7-d equilibration in toxicity test chambers and 8 volume-additions/d of aerobic overlying water were used to avoid unrealistic Ni partitioning during toxicity testing. The 7-d pretest equilibration allowed excess spiked Ni and other ions from pH adjustment to diffuse from sediment porewater and promoted development of an environmentally relevant, 0.5- to 1-cm oxic/suboxic sediment layer in the test chambers. Among the 8 different spiked sediments, the logarithm of sediment/porewater distribution coefficient values (log Kd ) for Ni during the toxicity tests ranged from 3.5 to 4.5. These Kd values closely match the range of values reported for various field Ni-contaminated sediments, indicating that testing conditions with our spiked sediments were environmentally realistic. PMID- 23657919 TI - Current research trends on arsenic toxicology. PMID- 23657918 TI - Real-world cost-effectiveness of oxaliplatin in stage III colon cancer: a synthesis of clinical trial and daily practice evidence. AB - OBJECTIVES: Previous cost-effectiveness analyses of oxaliplatin have been based on randomised trials whereas current Dutch policy requires evidence from daily practice. The objective of this study was to examine the real-world cost effectiveness of oxaliplatin plus fluoropyrimidines (FL) versus FL-only as adjuvant treatment of stage III colon cancer. METHODS: A Markov model was developed to estimate lifetime cost and quality-adjusted life-years from a hospital perspective. The effectiveness of the oxaliplatin arm was modelled by combining published efficacy data from the pivotal clinical registration trial (MOSAIC trial) with real-world (RW) data from a Dutch population-based observational study. RW patients were categorised into "eligible" or "ineligible", depending on whether the patients fulfilled the MOSAIC trial eligibility criteria. Ineligible RW patients (18 %) had a poorer prognosis than eligible RW patients (82 %) and MOSAIC trial patients. The effectiveness of the comparator was modelled using MOSAIC trial results. All cost inputs were based on RW patients and reported in Euro 2012. Cost-effectiveness analyses were performed for four different scenarios: (1) cost-effectiveness analyses based on MOSAIC trial patients; (2) cost-effectiveness analyses using MOSAIC and eligible RW patients; (3) cost-effectiveness analyses using MOSAIC and both eligible and ineligible RW patients, assuming oxaliplatin had an equal effect in ineligible and eligible patients; (4) cost-effectiveness analyses using MOSAIC and both eligible and ineligible RW patients, assuming oxaliplatin had no effect amongst ineligibles. For each scenario, univariate and probabilistic sensitivity analyses were undertaken. RESULTS: MOSAIC trial patients and eligible RW patients treated with oxaliplatin had comparable 2-year disease-free survivals (79.5 vs. 78.4 %). Oxaliplatin showed an incremental QALY gain of 1.02, 1.13, 1.17 and 0.93 and incremental cost of 9,961, 11,055, 9,814 and 11,854 in scenarios 1-4, respectively. The corresponding incremental cost-effectiveness ratios (ICERs) were 9,766, 9,783, 8,388 and 12,746 in scenarios 1-4, respectively. In all scenarios, univariate and probabilistic sensitivity analyses indicated that the ICERs are acceptable and robust under a wide range of model assumptions. CONCLUSIONS: The ICERs of the different scenarios that resulted from combining MOSAIC trial data with data from Dutch daily practice all suggest that FL + oxaliplatin is cost-effective versus FL alone in the adjuvant treatment of colon cancer. This article illustrates how one could design and implement a real-world cost-effectiveness study to yield internally valid results that could also be generalisable. PMID- 23657920 TI - Comparison of release and penetration of tacrolimus ointment reference and trial formulation after dermal application to pigs by liquid chromatography electrospray ionization tandem mass spectrometry. AB - To investigate the consistency and bioequivalence of tacrolimus ointment reference and trial formulation, the tacrolimus concentrations in blood and skin were determined by HPLC-ESI-MS/MS following topical application of two kinds of ointment in porcine skin in a parallel, cross-over trial. The plasma protein of blood was precipitated by acetonitrile and the tacrolimus in skin was extracted by acetonitrile before HPLC-ESI-MS/MS analysis. The internal calibration method (diazepam was the internal standard) was used for quantification analysis (R(2) > 0.9999), with linear range from 0.05 to 5 ng/mL for blood samples and from 1 to 200 ng/mL for skin samples. The limits of detection for the porcine blood and skin were 0.005 and 0.5 ng/mL, respectively. The average recoveries for the porcine blood and skin spiked at three levels were 97.56-109.53 and 96.48 103.57%, respectively. The precision expressed in RSDs was from 3.43 to 10.83% for porcine blood and from 3.10 to 8.69% for porcine skin. For the same pig, the tacrolimus concentrations and variation with time of the two kinds of ointment in porcine skin were similar, although variation occurred with different individuals. These results showed that the release and penetration of tacrolimus from the reference and trial formulation are similar. PMID- 23657921 TI - DC electric fields direct breast cancer cell migration, induce EGFR polarization, and increase the intracellular level of calcium ions. AB - Migration of cancer cells leads to invasion of primary tumors to distant organs (i.e., metastasis). Growing number of studies have demonstrated the migration of various cancer cell types directed by applied direct current electric fields (dcEF), i.e., electrotaxis, and suggested its potential implications in metastasis. MDA-MB-231 cell, a human metastatic breast cancer cell line, has been shown to migrate toward the anode of dcEF. Further characterizations of MDA-MB 231 cell electrotaxis and investigation of its underlying signaling mechanisms will lead to a better understanding of electrically guided cancer cell migration and metastasis. Therefore, we quantitatively characterized MDA-MB-231 cell electrotaxis and a few associated signaling events. Using a microfluidic device that can create well-controlled dcEF, we showed the anode-directing migration of MDA-MB-231 cells. In addition, surface staining of epidermal growth factor receptor (EGFR) and confocal microscopy showed the dcEF-induced anodal EGFR polarization in MDA-MB-231 cells. Furthermore, we showed an increase of intracellular calcium ions in MDA-MB-231 cells upon dcEF stimulation. Altogether, our study provided quantitative measurements of electrotactic migration of MDA-MB 231 cells, and demonstrated the electric field-mediated EGFR and calcium signaling events, suggesting their involvement in breast cancer cell electrotaxis. PMID- 23657922 TI - Hepatoma feeding arteriogram created by CT during aortography using IVR 64 multidetector-row CT for catheterization in transcatheter arterial chemoembolization for hepatocellular carcinoma. AB - CT during aortography (CTAo) using IVR 64-multidetector-row CT (IVR-64MDCT) enables the rapid and simultaneous depiction of both the hepatic and extrahepatic feeding arteries in hepatocellular carcinoma (HCC), and can be achieved using a reasonable volume of contrast medium. The scan time is approximately 6 s from the diaphragm to the kidney using CTAo with 64MDCT with a slice thickness and slice interval of 0.5 mm. The hepatoma feeding arteriogram appears in the angiographic monitor after CTAo, and can then be used to guide catheterization. We introduce the process for creating a hepatoma feeding arteriogram, synthesized from the following three volume-rendered images: background bone, aorta to hepatic-branch artery, and hepatoma to feeding artery. Uniquely, the hepatoma feeding arteriogram enables investigation of the feeding artery from the tumor side, rather than from the aorta side, and appears superior to selective arteriography in terms of detecting small HCC and its accompanying fine feeding arteries. Identification of these arteries by CT angiography with intravenous contrast medium injection is difficult because of the similarity in CT values between the feeding artery and the surrounding liver, thereby preventing the creation of a hepatoma feeding arteriogram. CTAo accelerates the process of deciding upon the catheter treatment strategy, shifting the decision to the point at which the feeding artery is investigated, because the hepatoma feeding arteriogram enables instant identification of the feeding artery and its connection to the hepatic branch artery. CTAo with IVR-64MDCT can potentially contribute to remarkable advances in IVR, especially transcatheter arterial chemoembolization for HCC. PMID- 23657923 TI - Early diagnostic clues in neonatal chronic gastric volvulus. AB - PURPOSE: Neonatal gastric volvulus (GV) is a rare clinical entity with a challenging diagnosis. In this study, we aimed to identify clinical and radiological findings to aid in early diagnosis in neonatal GV. MATERIALS AND METHODS: The medical records of all neonates with GV were retrospectively reviewed. Diagnosis was made based on clinical findings and radiological images, and was documented by an upper gastrointestinal (UGI) contrast study. RESULTS: A total of eight neonates were included in the study. The most common clinical presentations were non-bilious vomiting and epigastric distention. The findings highly suggestive for GV in plain radiographs include gastric double bubble, abnormal gastric distention despite a nasogastric tube, distended stomach lying in a horizontal plane and an air-fluid level in the epigastrium. CONCLUSION: GV should be suspected in any newborn with non-bilious vomiting and epigastric distention. It is also important to focus on the clues in the plain radiographs. Gastric double bubble, abnormal gastric distention despite a nasogastric tube, distended stomach lying in a horizontal plane and an air-fluid level in the epigastrium must alert the physicians to the possibility of GV. PMID- 23657924 TI - A review of the reliability and validity of OPCRIT in relation to its use for the routine clinical assessment of mental health patients. AB - The OPCRIT program is a symptom checklist with accompanying algorithms producing operationally defined diagnoses. We undertook a review of studies which had used OPCRIT and had reported statistics concerning its reliability and validity, producing summary measures from 44 studies. The first main measure of interest was inter-rater reliability where mean kappa values indicated that agreement between raters was "substantial" with a marginal improvement at the diagnostic (0.76) versus individual item (0.69) level. The second main measure of interest was convergent validity - the agreement between OPCRIT and clinical diagnoses. Most studies reported these figures as concordance rates suggesting mean agreement, unadjusted for chance, of 69%. Very few studies used the chance adjusted kappa statistic but where this was used agreement was "fair" (0.39). Agreement between OPCRIT and other research diagnoses was "moderate" (0.60). We also considered differences between the way OPCRIT has traditionally been used in research settings and the naturalistic manner in which it will be employed in the hospital ward. This review provides a summary of the reliability and validity of OPCRIT, which will be considered during the preparation for its use in the routine characterization of mental health patients in clinical settings. PMID- 23657925 TI - Synchrotron high energy X-ray methods coupled to phase sensitive analysis to characterize aging of solid catalysts with enhanced sensitivity. AB - X-ray absorption spectroscopy and X-ray diffraction are suitable probes of the chemical state of a catalyst under working conditions but are limited to bulk information. Here we show in two case studies related to hydrothermal aging and chemical modification of model automotive catalysts that enhanced detailed information of structural changes can be obtained when the two methods are combined with a concentration modulated excitation (cME) approach and phase sensitive detection (PSD). The catalysts are subject to a modulation experiment consisting of the periodic variation of the gas feed composition to the catalyst and the time-resolved data are additionally treated by PSD. In the case of a 2 wt% Rh/Al2O3 catalyst, a very small fraction (ca. 2%) of Rh remaining exposed at the alumina surface after hydrothermal aging at 1273 K can be detected by PSD. This Rh is sensitive to the red-ox oscillations of the experiment and is likely responsible for the observed catalytic activity and selectivity during NO reduction by CO. In the case of a 1.6 wt% Pd/Al2O3-Ce(1-x)Zr(x)O2 catalyst, preliminary results of cME-XRD demonstrate that access to the kinetics of the whole material at work can be obtained. Both the red-ox processes involving the oxygen storage support and the Pd component can be followed with great precision. PSD enables the differentiation between Pd deposited on Al2O3 or on Ce(1 x)Zr(x)O2. Modification of the catalyst by phosphorous clearly induces loss of the structural dynamics required for oxygen storage capacity that is provided by the Ce(4+)/Ce(3+) pair. The two case studies demonstrate that detailed kinetics of subtle changes can be uncovered by the combination of in situ X-ray absorption and high energy diffraction methods with PSD. PMID- 23657926 TI - Efficient delivery of p53 and cytochrome c by supramolecular assembly of a dendritic multi-domain delivery system. AB - Versatile nanocarrier systems facilitating uptake of exogenous proteins are highly alluring in evaluating these proteins for therapeutic applications. The self-assembly of an efficient nano-sized protein transporter consisting of three different entities is presented: A streptavidin protein core functioning as an adapter, second generation polyamidoamine dendrons for facilitating cell uptake as well as two different therapeutic proteins (tumor suppressor p53 or pro apoptotic cytochrome c as cargo). Well-defined dendrons containing a biotin core are prepared and display no cytotoxic behavior upon conjugation to streptavidin. The integration of biotinylated human recombinant p53 (B-p53) into the three component system allows excellent internalization into HeLa, A549 and SaOS osteosarcoma cells monitored via confocal microscopy, immunoblot analysis and co localization studies. In addition, the conjugation of B-p53 to dendronized streptavidin preserves its specific DNA-binding in vitro, and its delivery into SaOS cells impairs cell viability with concomitant activation of caspases 3 and 7. The versatility of this system is further exhibited by the significant enhancement of the pro-apoptotic effects of internalized cytochrome c which is analyzed by flow cytometry and cell viability assays. These results demonstrate that the "bio-click" self-assembly of biotinylated dendrons and proteins on a streptavidin adapter yields a stable supramolecular complex. This efficient bionanotransporter provides an attractive platform for mediating the delivery of functional proteins of interest into living mammalian cells in a facile and rapid way. PMID- 23657928 TI - Expanding the phenotype associated with missense mutations of the ARX gene. PMID- 23657929 TI - An n-type to p-type switchable photoelectrode assembled from alternating exfoliated titania nanosheets and polyaniline layers. PMID- 23657927 TI - Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer's disease. AB - This review describes the preclinical mechanisms that may underlie the increased therapeutic benefit of combination therapy-with the N-methyl-D-aspartate receptor antagonist, memantine, and an acetylcholinesterase inhibitor (AChEI)-for the treatment of Alzheimer's disease (AD). Memantine, and the AChEIs target two different aspects of AD pathology. Both drug types have shown significant efficacy as monotherapies for the treatment of AD. Furthermore, clinical observations indicate that their complementary mechanisms offer superior benefit as combination therapy. Based on the available literature, the authors have considered the preclinical mechanisms that could underlie such a combined approach. Memantine addresses dysfunction in glutamatergic transmission, while the AChEIs serve to increase pathologically lowered levels of the neurotransmitter acetylcholine. In addition, preclinical studies have shown that memantine has neuroprotective effects, acting to prevent glutamatergic over stimulation and the resulting neurotoxicity. Interrelations between the glutamatergic and cholinergic pathways in regions of the brain that control learning and memory mean that combination treatment has the potential for a complex influence on disease pathology. Moreover, studies in animal models have shown that the combined use of memantine and the AChEIs can produce greater improvements in measures of memory than either treatment alone. As an effective approach in the clinical setting, combination therapy with memantine and an AChEI has been a welcome advance for the treatment of patients with AD. Preclinical data have shown how these drugs act via two different, but interconnected, pathological pathways, and that their complementary activity may produce greater effects than either drug individually. PMID- 23657930 TI - Comparison between the efficacy of ginger and sumatriptan in the ablative treatment of the common migraine. AB - Frequency and torment caused by migraines direct patients toward a variety of remedies. Few studies to date have proposed ginger derivates for migraine relief. This study aims to evaluate the efficacy of ginger in the ablation of common migraine attack in comparison to sumatriptan therapy. In this double-blinded randomized clinical trial, 100 patients who had acute migraine without aura were randomly allocated to receive either ginger powder or sumatriptan. Time of headache onset, its severity, time interval from headache beginning to taking drug and patient self-estimation about response for five subsequent migraine attacks were recorded by patients. Patients(,) satisfaction from treatment efficacy and their willingness to continue it was also evaluated after 1 month following intervention. Two hours after using either drug, mean headaches severity decreased significantly. Efficacy of ginger powder and sumatriptan was similar. Clinical adverse effects of ginger powder were less than sumatriptan. Patients' satisfaction and willingness to continue did not differ. The effectiveness of ginger powder in the treatment of common migraine attacks is statistically comparable to sumatriptan. Ginger also poses a better side effect profile than sumatriptan. PMID- 23657932 TI - Stress fractures of the ribs and upper extremities: causation, evaluation, and management. AB - Stress fractures are common troublesome injuries in athletes and non-athletes. Historically, stress fractures have been thought to predominate in the lower extremities secondary to the repetitive stresses of impact loading. Stress injuries of the ribs and upper extremities are much less common and often unrecognized. Consequently, these injuries are often omitted from the differential diagnosis of rib or upper extremity pain. Given the infrequency of this diagnosis, few case reports or case series have reported on their precipitating activities and common locations. Appropriate evaluation for these injuries requires a thorough history and physical examination. Radiographs may be negative early, requiring bone scintigraphy or MRI to confirm the diagnosis. Nonoperative and operative treatment recommendations are made based on location, injury classification, and causative activity. An understanding of the most common locations of upper extremity stress fractures and their associated causative activities is essential for prompt diagnosis and optimal treatment. PMID- 23657931 TI - Vitamin d and physical performance. AB - Vitamin D is an essential nutrient obtained from the diet and exposure to sunlight. Roles for vitamin D have been established in the function of the cardiovascular, immune, and musculoskeletal systems. An electronic database search was conducted using EMBASE (1967 to August 2012), MEDLINE (1966 to August 2012), SPORTDiscusTM (1975 to August 2012), and the Scientific Electronic Library Online (SciELO) (1998 to August 2012) with no limits of language of publication. Articles that described vitamin D and performance were considered eligible for this review. Recent studies suggest that vitamin D maintains physical performance in athletes and other active populations, e.g., maximal oxygen consumption may be related to vitamin D status. Poor vitamin D status affects muscle strength, and vitamin D may participate in protein synthesis through the actions of the vitamin D receptor in muscle tissue. Vitamin D may protect against overuse injuries, such as stress fracture, through its well-documented role in calcium metabolism. The objective of this manuscript is to review recent evidence regarding the importance of vitamin D for maintaining physical performance, and includes specific examples of how vitamin D supports the cardiovascular, immune, and musculoskeletal systems. PMID- 23657933 TI - Authors' reply to periard: "cardiovascular determinants involved in pacing under heat stress" : the complex skill of pacing: is there an interplay between central and peripheral determinants? PMID- 23657936 TI - Response to 'Immediate and long-term results following balloon mitral valvotomy in patients with atrial fibrillation'. PMID- 23657935 TI - Strategies of dietary carbohydrate manipulation and their effects on performance in cycling time trials. AB - The relationship between carbohydrate (CHO) availability and exercise performance has been thoroughly discussed. CHO improves performance in both prolonged, low intensity and short, high-intensity exercises. Most studies have focused on the effects of CHO supplementation on the performance of constant-load, time-to exhaustion exercises. Nevertheless, in the last 20 years, there has been a consistent increase in research on the effects of different forms of CHO supplementation (e.g., diet manipulation, CHO supplementation before or during exercise) on performance during closed-loop exercises, such as cycling time trials (TTs). A TT is a highly reproducible exercise and reflects a more realistic scenario of competition compared with the time-to-exhaustion test. CHO manipulation has been performed in various time periods, such as days before, minutes before, during a TT or in a matched manner (e.g. before and during a TT). The purpose of this review is to address the possible effects of these different forms of CHO manipulation on the performance during a cycling TT. Previous data suggest that when a high-CHO diet (~70% of CHO) is consumed before a TT (24-72 h before), the mean power output increases and reduces the TT time. When participants are supplemented with CHO (from 45 to 400 g) prior to a TT (from 2 min to 6 h before the TT), mean power output and time seem to improve due to an increase in CHO oxidation. Similarly, this performance also seems to increase when participants ingest CHO during a TT because such consumption maintains plasma glucose levels. A CHO mouth rinse also improves performance by activating several brain areas related to reward and motor control through CHO receptors in the oral cavity. However, some studies reported controversial results concerning the benefits of CHO on TT performance. Methodological issues such as time of supplementation, quantity, concentration and type of CHO ingested, as well as the TT duration and intensity, should be considered in future studies because small variations in any of these factors may have beneficial or adverse effects on TT performance. PMID- 23657937 TI - Ultrafast localized two-dimensional magnetic resonance correlated spectroscopy via spatially encoded technique. AB - PURPOSE: To speed up acquisition of localized two-dimensional (2D) correlated spectroscopy (LCOSY). METHODS: A new pulse sequence, dubbed as spatially encoded localized COSY (SLCOSY), based on spatially encoded technique, was developed for localized 2D correlated spectroscopy. It can be used to collect a full 2D spectrum in a single scan and thus on a subsecond timescale. RESULTS: SLCOSY spectrum of a two-compartment phantom was obtained with a total acquisition time of 773 ms, with its volume localization confirmed. Localized 2D COSY spectrum of a proton magnetic resonance spectroscopy brain phantom within 12 s shows the ability of SLCOSY to detect the metabolites at physiological concentrations. All 10 constituent metabolites in this phantom are reliably detected. SLCOSY spectrum of a sample of pig brain tissue with the acquisition time of 32 s demonstrates the feasibility of SLCOSY for the detection of biological tissues. Twelve pairs of cross peaks are identified. CONCLUSION: The new method proposed herein enables ultrafast collection of a full 2D COSY spectrum, and it can also be used for fast in vivo analysis of metabolites, when signal-to-noise ratio is not a limiting factor. PMID- 23657934 TI - Eccentric exercise training: modalities, applications and perspectives. AB - Eccentric (ECC) exercise is classically used to improve muscle strength and power in healthy subjects and athletes. Due to its specific physiological and mechanical properties, there is an increasing interest in employing ECC muscle work for rehabilitation and clinical purposes. Nowadays, ECC muscle actions can be generated using various exercise modalities that target small or large muscle masses with minimal or no muscle damage or pain. The most interesting feature of ECC muscle actions is to combine high muscle force with a low energy cost (typically 4- to 5-times lower than concentric muscle work) when measured during leg cycle ergometry at a similar mechanical power output. Therefore, if caution is taken to minimize the occurrence of muscle damage, ECC muscle exercise can be proposed not only to athletes and healthy subjects, but also to individuals with moderately to severely limited exercise capacity, with the ultimate goal being to improve their functional capacity and quality of life. The first part of this review article describes the available exercise modalities to generate ECC muscle work, including strength and conditioning exercises using the body's weight and/or additional external loads, classical isotonic or isokinetic exercises and, in addition, the oldest and newest specifically designed ECC ergometers. The second part highlights the physiological and mechanical properties of ECC muscle actions, such as the well-known higher muscle force-generating capacity and also the often overlooked specific cardiovascular and metabolic responses. This point is particularly emphasized by comparing ECC and concentric muscle work performed at similar mechanical (i.e., cycling mechanical power) or metabolic power (i.e., oxygen uptake, VO2). In particular, at a similar mechanical power, ECC muscle work induces lower metabolic and cardiovascular responses than concentric muscle work. However, when both exercise modes are performed at a similar level of VO2, a greater cardiovascular stress is observed during ECC muscle work. This observation underlines the need of cautious interpretation of the heart rate values for training load management because the same training heart rate actually elicits a lower VO2 in ECC muscle work than in concentric muscle work. The last part of this article reviews the documented applications of ECC exercise training and, when possible, presents information on single-joint movement training and cycling or running training programs, respectively. The available knowledge is then summarized according to the specific training objectives including performance improvement for healthy subjects and athletes, and prevention of and/or rehabilitation after injury. The final part of the article also details the current knowledge on the effects of ECC exercise training in elderly populations and in patients with chronic cardiac, respiratory, metabolic or neurological disease, as well as cancer. In conclusion, ECC exercise is a promising training modality with many different domains of application. However, more research work is needed to better understand how the neuromuscular system adapts to ECC exercise training in order to optimize and better individualize future ECC training strategies. PMID- 23657938 TI - Can delayed time to referral to a tertiary level urologist with an abnormal PSA level affect subsequent Gleason grade in the opportunistically screened population? AB - PURPOSE: There is growing conflict in the literature describing the effect of delayed treatment on outcomes following radical prostatectomy. There is also evidence to suggest progression of low-risk prostate cancer to develop higher grades and volumes of prostate cancer during active surveillance. It is unknown as to what affect a delay in referral of those men with abnormal screened-PSA levels have on subsequent Gleason grade. METHODS: We identified 350 men through our rapid access prostate clinic who underwent TRUS biopsy for abnormal age related PSA and/or abnormal clinical examination. Clinicopathological findings were compared for those with positive versus negative TRUS biopsies, and for those with initial delays in referral (<12 months, 12-18 months, and >18 months). We used ANOVA and Student's t-tests amongst other statistical tools to examine significance of clinical findings. RESULTS: Of the 350 men who underwent TRUS biopsy, those with a delay in referral of 12 months or more were significantly associated with higher PSA titers, clinically palpable disease and likelihood of diagnosis with prostate cancer. A delay of 18 months or more led to a significantly higher risk of being diagnosed with a leading grade 4 prostate cancer, which was further supported using PSA velocity as a diagnostic tool (change >0.4 ng/ml/year). CONCLUSION: We recommend that repeated asymptomatic abnormal age-related PSA readings and/or abnormal clinical examination in the screened population be referred without delay to a urologist for further assessment, enrolment into an active surveillance program or definitive subsequent treatment. PMID- 23657940 TI - Spectrum of injuries associated with paediatric ACL tears: an MRI pictorial review. AB - OBJECTIVE: Magnetic resonance imaging (MRI) findings in anterior cruciate ligament (ACL) injury are well known, but most published reviews show obvious examples of associated injuries and give little focus to paediatric patients. Here, we demonstrate the spectrum of MRI appearances at common sites of associated injury in adolescents with ACL tears, emphasising age-specific issues. METHODS: Pictorial review using images from children with surgically confirmed ACL tears after athletic injury. RESULTS: ACL injury usually occurs with axial rotation in the valgus near full extension. The MRI findings can be obvious and important to management (ACL rupture), subtle but clinically important (lateral meniscus posterior attachment avulsion), obvious and unimportant to management (femoral condyle impaction injury), or subtle and possibly important (medial meniscocapsular junction tear). Paediatric-specific issues of note include tibial spine avulsion, normal difficulty visualising a thin ACL and posterolateral corner structures, and differentiation between incompletely closed physis and impaction fracture. CONCLUSION: ACL tear is only the most obvious sign of a complex injury involving multiple structures. Awareness of the spectrum of secondary findings illustrated here and the features distinguishing them from normal variation can aid in accurate assessment of ACL tears and related injuries, enabling effective treatment planning and assessment of prognosis. TEACHING POINTS: * The ACL in children normally appears thin or attenuated, while thickening and oedema suggest tear. * Displaced medial meniscal tears are significantly more common later post-injury than immediately. * The meniscofemoral ligaments merge with the posterior lateral meniscus, complicating tear assessment. * Tibial plateau impaction fractures can be difficult to distinguish from a partially closed physis. * Axial MR sequences are more sensitive/specific than coronal for diagnosis of medial collateral ligament (MCL) injury. PMID- 23657941 TI - Regional disparities in self-reported health: evidence from chinese older adults. AB - Despite the subjectivity inherent in individuals' interpretation of good health, self-reported health is widely used in health-related studies. With data from the pilot survey of the new China Health and Retirement Longitudinal Study, this paper applies the vignette method to control for differences in individual response scales and examines regional differences in self-reported health among the elderly in China. The results show that people in different provinces seem to use different criteria when assessing their health conditions. Regional health disparities are underestimated if differentials in response scales are not accounted for. A substantial share of the disparities cannot be explained by the observed differences in respondents' chronic health condition, demographic characteristics, and household wealth, a finding confirmed by a test based on inpatient-care information. PMID- 23657939 TI - Affinity purification of T7 RNA transcripts with homogeneous ends using ARiBo and CRISPR tags. AB - Affinity purification of RNA using the ARiBo tag technology currently provides an ideal approach to quickly prepare RNA with 3' homogeneity. Here, we explored strategies to also ensure 5' homogeneity of affinity-purified RNAs. First, we systematically investigated the effect of starting nucleotides on the 5' heterogeneity of a small SLI RNA substrate from the Neurospora VS ribozyme purified from an SLI-ARiBo precursor. A series of 32 SLI RNA sequences with variations in the +1 to +3 region was produced from two T7 promoters (class III consensus and class II 2.5) using either the wild-type T7 RNA polymerase or the P266L mutant. Although the P266L mutant helps decrease the levels of 5'-sequence heterogeneity in several cases, significant levels of 5' heterogeneity (>=1.5%) remain for transcripts starting with GGG, GAG, GCG, GGC, AGG, AGA, AAA, ACA, AUA, AAC, ACC, AUC, and AAU. To provide a more general approach to purifying RNA with 5' homogeneity, we tested the suitability of using a small CRISPR RNA stem-loop at the 5' end of the SLI-ARiBo RNA. Interestingly, we found that complete cleavage of the 5'-CRISPR tag with the Cse3 endoribonuclease can be achieved quickly from CRISPR-SLI-ARiBo transcripts. With this procedure, it is possible to generate SLI-ARiBo RNAs starting with any of the four standard nucleotides (G, C, A, or U) involved in either a single- or a double-stranded structure. Moreover, the 5'-CRISPR-based strategy can be combined with affinity purification using the 3'-ARiBo tag for quick purification of RNA with both 5' and 3' homogeneity. PMID- 23657942 TI - A mitochondria-targeting gold-peptide nanoassembly for enhanced cancer-cell killing. AB - Design and construction of multifunctional nanoparticles for effective delivery and therapeutic application remains a challenging task. It is desirable that nanoparticles can overcome multiple biological barriers and reach specific cellular locations to achieve maximum therapeutic effects. This aim often requires the fine tuning of nanoparticles' chemical and physical properties, as well as better understanding of their interaction with live cells. A peptide modified gold-nanoparticle platform is designed, which consists of a 20-nm gold core stabilized with a layer of biotinylated CALNN-based peptides and a further layer of tetrameric streptavidins for functionalization with biotinylated molecules. The nanoassembly undergoes an efficient dynamin-dependent and caveolae mediated endocytosis pathway, and displays highly specific localization to mitochondria, organelles of great therapeutic importance. When functionalized with a cytotoxic peptide (KLA: (KLAKLAK)2 ), the KLA-anchored nanoassembly exhibits dramatically enhanced anticancer activity, thousands of times stronger than that of the free KLA peptide, likely because of its improved cell entry efficiency, mitochondria-specific delivery, and the polyvalent effect of the nanoassembly. The study opens up the possibility of developing mitochondria targeted nanomedicines. PMID- 23657943 TI - A simple system to predict perihilar cholangiocarcinoma resectability. AB - BACKGROUND: The aim of this study was to retrospectively validate a new system to predict perihilar cholangiocarcinoma (PHC) resectability. We hypothesized that when the left lateral section (segments II-III) duct confluence (LLC) is free, the left lateral section might be preserved for curative resection. When the LLC is invaded, vascular invasion is frequent and radical resection might often be impossible without complex vascular reconstruction. METHOD: Radiological files of patients operated for PHC at our institution were reviewed and PHC was classified depending on whether LLC was invaded (type X) or free (type Y). Peroperative findings and follow-up were then matched with our XY classification. RESULTS: Thirty-seven patients were included, 28 (78 %) type Y and nine (22 %) type X PHCs. Hepatic artery (HA) invasion was present in 14 % of type Y and 100 % of type X PHCs (P < 0.001). Left HA was never involved in type Y and always involved in type X. Portal vein invasion was present in 25 and 78 % of type Y and type X PHC, respectively (P = 0.014). Complete resection rates without HA in type Y and X patients were 89 % (84 % R0 and 16 % R1) and 33 % (37.5 % R0 and 12.5 % R1), respectively (P = 0.01). Sensitivity, specificity, and precision of the XY classification to predict resectability were 84, 67, and 84 %, respectively. CONCLUSION: XY classification for PHCs suggests that in type Y (free LLC), the tumor is most often resectable, while in type X (LLC involved), the tumor is only resectable using complex vascular reconstructions. PMID- 23657944 TI - NF-kappaB inhibition by bortezomib permits IFN-gamma-activated RIP1 kinase dependent necrosis in renal cell carcinoma. AB - Advanced renal cell carcinoma (RCC) is an invariably fatal cancer. Currently, small-molecule inhibitors that target cell growth, angiogenesis, or nutrient sensing pathways represent the primary pharmacologic interventions for this disease, but these inhibitors only delay tumor progression and are not curative. The cytokine IFN-gamma showed the potential to provide lasting remission in several phase I/II trials for advanced RCCs, but subsequent trials, including a multicenter phase III study using IFN-gamma as a monotherapy for RCCs, were less promising. Notably, these trials were designed to exploit the indirect immunomodulatory effects of IFN-gamma, whereas its direct antitumor properties- including its ability to trigger programmed cell death in tumors-remain mostly untapped. Here, we show that the proteasome inhibitor bortezomib (PS-341, Velcade) sensitizes otherwise resistant RCC cells to direct necrotic death by IFN gamma. Mechanistically, we show that bortezomib functions, at least in part, by inhibiting prosurvival NF-kappaB signaling. In the absence of this signal, IFN gamma triggers programmed necrosis (or "necroptosis") dependent on the kinase RIP1. When taken together with the observation that NF-kappaB signaling is elevated in RCCs, these results provide rationale for the combined use of IFN gamma and bortezomib in the treatment of metastatic RCCs. PMID- 23657945 TI - Drug repurposing for gastrointestinal stromal tumor. AB - Despite significant treatment advances over the past decade, metastatic gastrointestinal stromal tumor (GIST) remains largely incurable. Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25 to 30 million people in the United States alone. Given the costs associated with the discovery, development, and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, "drug repurposing" or "repositioning," has emerged as an alternative to the traditional drug development process. In this study, we screened 796 U.S. Food and Drug Administration (FDA)-approved drugs and found that two of these compounds, auranofin (Ridaura) and fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs, including imatinib-resistant cells. One of the most notable drug hits, auranofin, an oral, gold-containing agent approved by the FDA in 1985 for the treatment of rheumatoid arthritis, was found to inhibit thioredoxin reductase activity and induce reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anticancer activity associated with auranofin was independent of imatinib-resistant status, but was closely related to the endogenous and inducible levels of ROS. Coupled with the fact that auranofin has an established safety profile in patients, these findings suggest for the first time that auranofin may have clinical benefit for patients with GIST, particularly in those suffering from imatinib-resistant and recurrent forms of this disease. PMID- 23657946 TI - Fibroblast growth factor receptor 3 is a rational therapeutic target in bladder cancer. AB - Activating mutations of fibroblast growth factor receptor-3 (FGFR3) have been described in approximately 75% of low-grade papillary bladder tumors. In muscle invasive disease, FGFR3 mutations are found in 20% of tumors, but overexpression of FGFR3 is observed in about half of cases. Therefore, FGFR3 is a particularly promising target for therapy in bladder cancer. Up to now, most drugs tested for inhibition of FGFR3 have been small molecule, multityrosine kinase inhibitors. More recently, a specific inhibitory monoclonal antibody targeting FGFR3 (R3Mab) has been described and tested preclinically. In this study, we have evaluated mutation and expression status of FGFR3 in 19 urothelial cancer cell lines and a cohort of 170 American patients with bladder cancer. We have shown inhibitory activity of R3Mab on tumor growth and corresponding cell signaling in three different orthotopic xenografts of bladder cancer. Our results provide the preclinical proof of principle necessary to translate FGFR3 inhibition with R3Mab into clinical trials in patients with bladder cancer. PMID- 23657947 TI - The effects of sulfonylureas plus metformin on lipids, blood pressure, and adverse events in type 2 diabetes: a meta-analysis of randomized controlled trials. AB - To compare the effects of sulfonylureas and metformin versus metformin on lipid profiles, blood pressure, and adverse events. PubMed, EMbase, Chinese BioMedical Literature on disc, China National Knowledge Infrastructure, VIP database, and Wanfang database were searched for randomized controlled trials (RCTs), from inception to August 2012. Key outcomes were low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), total cholesterol (TC), blood pressure (BP), hemoglobin A1c (HbA1c), fasting insulin, and adverse events. Twenty RCTs were included in the analysis. Compared to metformin, the combination therapy of sulfonylureas and metformin slightly reduced HDL-C [-0.03, 95 % CI (-0.06, -0.01)] and HbA1c (-0.79, 95 % CI -0.96 to 0.63). However, it showed little effects on LDL-C, TG, TC, and BP. Glipizide plus metformin significantly increased fasting insulin [2.33, 95 % CI (1.94, 2.73)]. Hypoglycemia and nervous system side events were more frequent among patients treated with sulfonylureas plus metformin than metformin alone (RR = 6.79, 95 % CI 3.79-12.17; RR = 1.27, 95 % CI 1.03-1.57; respectively), but less in digestive symptoms (RR = 0.75, 95 % CI 0.67-0.84). Combination therapy with sulfonylureas and metformin may be more effective than metformin alone in improving HbA1c and reducing gastrointestinal reactions. But it had disadvantage of decreasing HDL-C, increasing the risk of hypoglycemia and nervous system side events. PMID- 23657948 TI - Spatial organization of proteins in metastasizing cells. AB - The ability of tumor cells to invade into the surrounding tissue is linked to defective adhesive and mechanical properties of the cells, which are regulated by cell surface adhesions and the intracellular filamentous cytoskeleton, respectively. With the aim to further reveal the underlying mechanisms and provide new strategies for early cancer diagnostics, we have used ultrahigh resolution stimulated emission depletion (STED) microscopy as a means to identify metastasizing cells, based on their subcellular protein distribution patterns reflecting their specific adhesive and mechanical properties. We have compared the spatial distribution of cell-matrix adhesion sites and the vimentin filamentous systems in a matched pair of primary, normal, and metastatic human fibroblast cells. We found that the metastatic cells showed significantly increased densities and more homogenous distributions of nanoscale adhesion related particles. Moreover, they showed an increase in the number but reduced sizes of the areas of cell-matrix adhesion complexes. The organization of the vimentin intermediate filaments was also found to be significantly different in the metastasizing cells, showing an increased entanglement and loss of directionality. Image analysis procedures were established, allowing an objective detection and characterization of these features and distinction of metastatic cells from their normal counterparts. In conclusion, our results suggest that STED microscopy provides a novel tool to identify metastasizing cells from a very sparse number of cells, based on the altered spatial distribution of the cell matrix adhesions and intermediate filaments. PMID- 23657949 TI - Preparation of nano- and microcapsules by electrophoretic polymer assembly. PMID- 23657950 TI - Reply: To PMID 23553899. PMID- 23657951 TI - Trimethoxy-resveratrol and piceatannol administered orally suppress and inhibit tumor formation and growth in prostate cancer xenografts. AB - BACKGROUND: Resveratrol (Res) is recognized as a promising cancer chemoprevention dietary polyphenol with antioxidative, anti-inflammatory, and anticancer properties. However, the role of its analogues in prostate cancer (PCa) chemoprevention is unknown. METHODS: We synthesized several natural and synthetic analogues of Res and characterized their effects on PCa cells in vitro using a cell proliferation assay. A colony formation assay and in vitro validation of luciferase (Luc) activity was done for LNCaP-Luc cells that were consequently used for in vivo studies. The efficacy of Res, trimethoxy-resveratrol (3M-Res) and piceatannol (PIC) was studied in a subcutaneous (s.c.) model of PCa using oral gavage. Tumor progression was monitored by traditional caliper and bioluminescent imaging. The levels of cytokines in serum were examined by ELISA, and the levels of compounds in serum and tumor tissues were determined by gas chromatography-mass spectrometry. RESULTS: We examined the anti-proliferative activities of Res/analogues in three PCa cell lines. We further compared the chemopreventive effects of oral Res, 3M-Res, and PIC in LNCaP-Luc-xenografts. We found that 2 weeks pretreatment with the compounds diminished cell colonization, reduced tumor volume, and decreased tumor growth in the xenografts. Both 3M-Res and PIC demonstrated higher potency in inhibiting tumor progression compared to Res. Notably, 3M-Res was the most active in inhibiting cell proliferation and suppressing colony formation, and its accumulation in both serum and tumor tissues was the highest. CONCLUSIONS: Our findings offer strong pre-clinical evidence for the utilization of dietary stilbenes, particularly 3M-Res, as novel, potent, effective chemopreventive agents in PCa. PMID- 23657952 TI - Identification of common glycosyl groups of flavonoid O-glycosides by serial mass spectrometry of sodiated species. AB - Flavonoid O-glycosides are a ubiquitous and important group of plant natural products in which a wide variety of sugars are O-linked to an aglycone. Determining the identity of the sugars, and the manner in which they are linked, by mass spectrometry alone is challenging. To improve the identification of common O-linked di- and trisaccharides when analysing mixtures of flavonoid O glycosides by liquid chromatography/mass spectrometry (LC/MS), the fragmentation of electrosprayed sodium adducts in an ion trap mass spectrometer was investigated. The sodium adducts [M + Na](+) of kaempferol 3-O-glycosides generated sodiated glycosyl groups by the neutral loss of kaempferol. The product ion spectra of these sodiated glycosyl groups differed between four isomeric kaempferol 3-O-rhamnosylhexosides and four isomeric kaempferol 3-O glucosylhexosides in which the primary hexose was either glucose or galactose and bore the terminal glucose or rhamnose at either C-2 or C-6. Fragmentation of sodiated glycosyl groups from linear O-triglucosides and branched O-glucosyl-(1 > 2)-[rhamnosyl-(1 -> 6)]-hexosides produced sodiated disaccharide residues, and the product ion spectra of these ions assisted the identification of the complete sugar. The product ion spectra of the sodiated glycosyl groups were consistent among flavonoid O-glycosides differing in the position at which the sugar was O linked to the aglycone, and the nature of the aglycone. The abundance of sodiated species was enhanced by application of a pre-trap collision voltage, without the need to dope with salt, allowing automated LC/MS methods to be used to identify the glycosyl groups of common flavonoid O-glycosides, such as rutinosides, robinobiosides, neohesperidosides, gentiobiosides and sophorosides. PMID- 23657953 TI - Profiling the indole alkaloids in yohimbe bark with ultra-performance liquid chromatography coupled with ion mobility quadrupole time-of-flight mass spectrometry. AB - An ultra-performance liquid chromatography/ion mobility quadrupole time-of-flight mass spectrometry (UPLC/IM-QTOF-MS) method was developed for profiling the indole alkaloids in yohimbe bark. Many indole alkaloids with the yohimbine or ajmalicine core structure, plus methylated, oxidized and reduced species, were characterized. Common fragments and mass differences are described. It was shown that the use of IMS could provide another molecular descriptor, i.e. molecular shape by rotationally averaged collision cross-section; this is of great value for identification of constituents when reference materials are usually not available. Using the combination of high resolution (~40000) accurate mass measurement with time-aligned parallel (TAP) fragmentation, MS(E) (where E represents collision energy), ion mobility mass spectrometry (IMS) and UPLC chromatography, a total 55 indole alkaloids were characterized and a few new indole alkaloids are reported for the first time. PMID- 23657954 TI - Qualitative and quantitative analysis of THC, 11-hydroxy-THC and 11-nor-9-carboxy THC in whole blood by ultra-performance liquid chromatography/tandem mass spectrometry. AB - A qualitative and quantitative analytical method was developed for the simultaneous determination of Delta(9) -tetrahydrocannabinol (THC), 11-hydroxy Delta(9) -tetrahydrocannabinol (11-OH-THC) and l1-nor-9-carboxy-Delta(9) tetrahydrocannabinol (THC-COOH) in whole blood. The samples were prepared by solid-phase extraction followed by ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) analysis using positive ion electrospray ionization and multiple reaction monitoring. The chromatographic separation was performed with an Acquity UPLC(r) HSS T3 (50 * 2.1 mm i.d., 1.8 um) reversed phase column using a methanol/2 mM ammonium formate (formic acid 0.1%) gradient in a total run time of 9.5 min. MS/MS detection was achieved with two precursor product ion transitions per substance. The method was fully validated, including selectivity and capacity of identification, according to the identification criteria (two transitions per substance, signal-to-noise ratio, relative retention time and ion ratio) without the presence of interferences, limit of detection (0.2 ug/L for THC and 0.5 ug/L for 11-OH-THC and THC-COOH), limit of quantitation (0.5 ug/L for all cannabinoids), recovery (53-115%), carryover, matrix effect (34-43%), linearity (0.5-100 ug/L), intra-assay precision (CV < 10% for the relative peak area ratios and <0.1% for the relative retention time), inter-assay accuracy (mean relative error <10%) and precision (CV <11%). The method has already been successfully used in proficiency tests and subsequently applied to authentic samples in routine forensic analysis. PMID- 23657955 TI - Sulfate migration in oligosaccharides induced by negative ion mode ion trap collision-induced dissociation. AB - Migration of sulfate groups between hydroxyl groups was identified after collision-induced dissociation (CID) of sulfated oligosaccharides in an ion trap mass spectrometer in negative ion mode. Analysis of various sulfated oligosaccharides showed that this was a common phenomenon and was particularly prominent in sulfated oligosaccharides also containing sialic acid. It was also shown that the level of migration was increased when the sulfate was positioned on the flexible areas of the oligosaccharides not involved in the pyranose ring, such as the extra-cyclic C-6 carbon of hexoses or N-acetylhexosamines, or on reduced oligosaccharide. This suggested that migration is dependent on the spatial availability of the sulfate in the ion trap during collision. It is proposed that the migration is initiated when the negatively charged -SO3 (-) residue attached to the oligosaccharide precursor becomes protonated by a CID induced proton transfer. This is supported by the CID fragmentation of precursor ions depleted of acidic protons such as doubly charged [M - 2H](2-) ions or the sodiated [M + Na - 2H](-) ions of oligosaccharides containing one sulfate and one sialic acid in the same molecule. Compared to the CID fragmentation of their monocharged [M - H](-) ions, no migration was observed in CID of proton depleted precursors. Alternative fragmentation parameters to suppress migration of sulfated oligosaccharides also showed that it was not present when sulfated oligosaccharides were fragmented by HCD (High-Energy C-trap Dissociation) in an Orbitrap mass spectrometer. PMID- 23657956 TI - Phosphatidylcholine dimers can be easily misinterpreted as cardiolipins in complex lipid mixtures: a matrix-assisted laser desorption/ionization time-of flight mass spectrometric study of lipids from hepatocytes. AB - The liver is an important organ that is particularly involved in the lipid metabolism of the organism. Thus, high interest is nowadays focused on the lipid composition of the liver and particularly the liver parenchymal cells, the hepatocytes. Hepatocytes contain common phospholipids (PL) such as phosphatidylcholines, -ethanolamines and -inositols, for instance, that can be easily analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) even without previous separation of the PL mixture. However, in addition to common PL, hepatocytes possess also significant amounts of cardiolipin (CLP). The MS analysis of this PL is quite challenging because it (a) has a higher mass than common lipids and (b) possesses a higher negative charge. We will show here that caution is required if CLP is analyzed directly from the total lipid extract because PC dimers may be interpreted as cardiolipins if the positive ion MALDI mass spectra are analyzed. PMID- 23657957 TI - Unexpected linear ion trap collision-induced dissociation and Fourier transform ion cyclotron resonance infrared multi-photon dissociation fragmentation of a hydrated C-glycoside of 5-fluorouridine formed by the action of the pseudouridine synthases RluA and TruB. AB - As part of the investigation of the pseudouridine synthases, 5-fluorouridine in RNA was employed as a mechanistic probe. The hydrated, rearranged product of 5 fluorouridine was isolated as part of a dinucleotide and found to undergo unusual fragmentation during mass spectrometry, with the facile loss of HNCO from the product pyrimidine ring favored over phosphodiester bond rupture. Although the loss of HNCO from uridine and pseudouridine is well established, the pericyclic process leading to their fragmentation cannot operate with the saturated pyrimidine ring in the product of 5-fluorouridine. Based on the MS(n) results and calculations reported here, a new mechanism relying on the peculiar disposition of the functional groups of the product pyrimidine ring is proposed to account for the unusually facile fragmentation. PMID- 23657958 TI - A metabonomic analysis of urine from rats treated with rhizoma alismatis using ultra-performance liquid chromatography/mass spectrometry. AB - A metabonomic approach based on ultra-performance liquid chromatography coupled to mass spectrometry (UPLC/MS) was used to study the nephrotoxicity of rhizoma alismatis (RA) in rats. Potential biomarkers of RA toxicity were identified and the toxicological mechanism is discussed. Urine samples were collected from control and treated rats at various stages and analyzed by UPLC/MS in positive ionization mode. Histopathological analysis was used to evaluate renal function. The differences in the metabolic profiles of the control and treated rats were clearly distinguishable with principal components analysis (PCA) of the chromatographic data, and significant changes in 13 metabolite biomarkers were detected in the urine. This metabonomic method combined with PCA could discriminate the treated rats from the control rats on days 60, 120, and 180 after treatment, before serious organic renal damage was apparent on day 180 with histopathology. This research indicates that UPLC/MS-based metabonomic analysis of urine samples can be used to predict the chronic nephrotoxicity induced by rhizoma alismatis. PMID- 23657959 TI - A rapid one-step method for the characterization of membrane lipid remodeling in Francisella using matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry. AB - Lipids are essential components of all bacterial membranes. The most common membrane-associated lipids in Gram-negative bacteria are phospholipids and lipid A, the hydrophobic anchor of lipopolysaccharide. Diversity in these lipids arises through structural modifications that include changes in the length and location of fatty acids, and the addition of phosphate and carbohydrate moieties. Analysis of individual structural modifications normally requires large quantities of starting material and multiple methods for the isolation, hydrolysis, and analysis. In this study, we developed a novel one-step protocol for the combined isolation of phospholipids and lipid A from Francisella subspecies followed by analysis using matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry. The total time for lipid isolation and analysis was approximately 15 min and with a lower limit of detection of approximately 100 ng of purified lipid. This protocol identified the major lipid structures using both wild-type Ft subspecies strains and lipid A biosynthesis mutants. We also determined the relative levels of individual lipid A and phospholipids after growth under conditions that mimic the mammalian infection process. This analysis showed that the bacterial membranes remodeled rapidly to adapt to changes in environmental growth conditions and may be important for Francisella pathogenesis. PMID- 23657960 TI - Diagnostic di- and triphosphate cyclisation in the negative ion electrospray mass spectra of phosphoSer peptides. AB - It has been shown previously that [M-H](-) anions of small peptides containing two phosphate residues undergo cyclisation of the phosphate groups, following collision-induced dissociation (CID), to form a characteristic singly charged anion A (H3P2O7(-), m/z 177). In the present study it is shown that the precursor anions derived from the diphosphopeptides of caerin 1.1 [GLLSVLGSVAKHVLPHVVPVIAEHL(NH2)] and frenatin 3 [GLMSVLGHAVGNVLGGLFKPKS(OH)] also form the characteristic product anion A (m/z 177). Both of the precursor peptides show random structures in water, but partial helices in membrane-mimicking solvents [e.g. in d3-trifluoroethanol/water (1:1)]. In both cases the diphosphopeptide precursor anions must have flexible conformations in order to allow approach of the phosphate groups with consequent formation of A: for example, the two pSer groups of 4,22-diphosphofrenatin 3 are seventeen residues apart. Finally, CID tandem mass spectrometric (MS/MS) data from the [M-H](-) anion of the model triphosphoSer-containing peptide GpSGLGpSGLGpSGL(OH) show the presence of both product anions A (m/z 177) and D (m/z 257, H4P3O10(-)). Ab initio calculations at the HF/6-31+G(d)//AM1 level of theory suggest that cyclisation of the three phosphate groups occurs by a stepwise cascade mechanism in an energetically favourable reaction (DeltaG = -245 kJ mol(-1)) with a maximum barrier of +123 kJ mol(-1). PMID- 23657961 TI - Structural determination by atmospheric pressure photoionization tandem mass spectrometry of some compounds isolated from the SARA fractions obtained from bitumen. AB - We have identified compounds obtained from the SARA fractions of bitumen by using atmospheric pressure photoionization mass spectrometry and low-energy collision tandem mass spectrometric analyses with a QqToF-MS/MS hybrid instrument. The identified compounds were isolated from the maltene saturated oil and the aromatic fractions of the SARA components of a bitumen. The QqToF instrument had sufficient mass resolution to provide accurate molecular weight information and to enhance the tandem mass spectrometry results. The APPI-QqToF-MS analysis of the separated compounds showed a series of protonated molecules [M + H](+) and molecular ions [M](+?) of the same mass but having different chemical structures, in the maltene saturated oil and the aromatic SARA fractions. These isobaric ions were a molecular ion [M2 ](+?) at m/z 418.2787 and a protonated molecule [M5 + H](+) at m/z 287.1625 in the saturated oil fraction, and molecular ions [M6 ](+?) at m/z 418.1584 and [M7 ](+?) at m/z 287.1285 in the aromatic fraction. The identification of this series of chemical compounds was achieved by performing CID-MS/MS analyses of the molecular ions [M](+?) ([M1 ](+?) at m/z 446. 2980, [M2 ](+?) at m/z 418.2787, [M3 ](+?) at m/z 360.3350 and [M4 ](+?) at m/z 346.2095) in the saturated oil fraction and of the [M5 + H](+) ion at m/z 287.1625 also in the saturated oil fraction. The observed CID-MS/MS fragmentation differences were explained by proposed different breakdown processes of the precursor ions. The presented tandem mass spectrometric study shows the capability of MS/MS experiments to differentiate between different classes of chemical compounds of the SARA components of bitumen and to explain the reasons for the observed mass spectrometric differences. However, greater mass resolution than that provided by the QqToF-MS/MS instrument would be required for the analysis of the asphaltene fraction of bitumen. PMID- 23657962 TI - Antihypertensive response to combination of olmesartan and amlodipine does not depend on method and time of drug administration. AB - Fixed combinations of antihypertensive drugs have the potentiality to improve blood pressure (BP) control. However, when pharmacokinetic parameters of the two drugs are different, both method and time of administration of the two drugs may modify the antihypertensive response. In an open-label, single-blind, randomized study we compared antihypertensive effect of four administration schemes of a combination therapy of olmesartan and amlodipine in the same group of hypertensive patients, using ambulatory blood pressure monitoring (ABPM). The olmesartan + amlodipine combination has demonstrated to provide a good control of BP, with systolic and diastolic BP constantly below 130 and 85 mmHg over the 24 h. The simultaneous or separate administration of the 2 drugs fully overlapped, suggesting that the fixed combination and the separate administration induce a similar and sustained BP control. PMID- 23657963 TI - Multicenter R2* mapping in the healthy brain. AB - PURPOSE: The R2* relaxation rate constant has been suggested as a sensitive measure for iron accumulation. The aim of this multi-center study was to assess the inter-scanner and inter-subject variability of R2* mapping and to investigate the relationship between brain volume and R2* in specific structures. METHODS: R2* mapping was performed in 81 healthy subjects in seven centers using different 3 T systems. R2* was calculated from a dual-echo gradient echo sequence and was assessed in several deep gray matter structures. The inter-scanner and inter subject variability of R2* was calculated by means of the coefficient of variation before and after correcting for age. RESULTS: Significant center effects were seen in some regions which get lost after age correction. The coefficient of variation for the inter-center variability was much lower (<5.6%) than for the intra-subject variability (6.7%-11.7%). R2* in the putamen and red nucleus scaled with cortical volume while R2* in the globus pallidus and the substantia nigra was negatively associated with white matter volume. CONCLUSION: R2* is a robust and reproducible measure in a multicenter setting provided that a standardized MRI protocol is used. The relationship between iron concentration in deep gray matter and volume of specific brain compartments needs further investigation. PMID- 23657964 TI - Decreased expression of BTG3 was linked to carcinogenesis, aggressiveness, and prognosis of ovarian carcinoma. AB - B-cell translocation gene 3 (BTG3) is a member of the BTG family which inhibits cell proliferation, metastasis, and angiogenesis, and also regulates cell-cycle progression and differentiation in a variety of cell types. However, there is no study to analyze BTG3 expression in epithelial ovarian carcinoma (EOC). Here, we investigated the expression of BTG3 in EOC carcinogenesis and subsequent progression. BTG3 mRNA expression was detected by real-time RT-PCR in ovarian benign and malignant tumors. The expression of BTG3 protein was examined by immunohistochemistry on tissue microarrays containing ovarian normal tissue, benign and borderline epithelial ovarian tumors, and EOCs. Relationships of BTG3 with both EOC clinicopathology and prognosis were analyzed statistically. The expression of BTG3 protein was also evaluated in ovarian normal tissue, benign tumors, and EOCs by western blot. The BTG3 mRNA expression level was higher in ovarian normal tissue and benign tumors than that in borderline, primary, and metastatic carcinoma (p < 0.05), and was negatively correlated with dedifferentiation and FIGO staging of EOC (p < 0.05). Using western blot, BTG3 protein was found lower in EOCs compared to the normal and benign tumors (p < 0.05), and poorly differentiated EOCs showed lower BTG3 expression than well differentiated and moderately differentiated EOCs (p < 0.05). Immunohistochemically, BTG3 protein expression was statistically lower in EOCs than normal tissue and benign tumors (p < 0.05). EOC patients with low BTG3 protein expression showed a higher incidence of metastasis (p = 0.020), poor differentiation (p = 0.030), and shorter disease-free time and overall survival time (p < 0.05). By using Cox's proportional hazard model, BTG3 protein expression and FIGO staging were independent prognostic factors for both disease free time and overall survival time of EOCs (p < 0.05). It was suggested that down-regulated BTG3 expression might play roles in the pathogenesis and aggressiveness of EOC. BTG3 protein expression may be considered as a good marker to indicate the favorable prognosis of EOCs. PMID- 23657966 TI - Capsule commentary on Kaplan et al., reducing racial/ethnic disparities in diabetes: the Coached Care (R2D2C2) project. PMID- 23657965 TI - Monocyte chemotactic protein-1 and CC chemokine receptor 2 polymorphisms and prognosis of renal cell carcinoma. AB - Monocyte chemoattractant protein-1 (MCP-1) and its receptor CC chemokine receptor 2 (CCR2) play a major role in inflammation and proliferation of cancers. We investigated a possible association between polymorphisms in MCP-1 and CCR2 genes (MCP-1 -2518A/G and CCR2 190G/A or V64I) and the risk as well as prognosis of renal cell carcinoma (RCC). Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism in 416 RCC cases and 458 age matched healthy controls. Frequency of MCP-1 2518GG genotype for cases and controls was 0.384 and 0.286, respectively; individuals carrying the GG genotype had a 1.89-fold increased risk of RCC than those with AA genotype (95 % confidence interval [CI] 1.24-2.81, p = 0.002; data were adjusted for age and sex). Frequency of CCR2 190AA (64I/64I) genotype for cases and controls was 0.175 and 0.076, respectively; subjects having AA genotype had a 2.68-fold increased risk of RCC compared to those with the wild-type GG genotype (95 %CI 1.71-4.17, p = 4.3 * 10(-6); data were adjusted for age and sex). When analyzing the survival rate of RCC, patients with MCP-1 -2518GG genotype revealed significantly shorter survival time compared to cases with MCP-1 -2518AA and AG genotypes (p = 0.003). Similarly, RCC cases carrying CCR2 190AA genotype showed significantly shorter survival rate than patients with GG or GA genotypes (p < 0.001). These data suggested that MCP-1 -2518A/G and CCR2 190G/A polymorphisms are new risk factors for RCC and could be used as prognostic markers for this malignancy. PMID- 23657967 TI - Characterization of neuroendocrine tumors of the pancreas by real-time quantitative polymerase chain reaction. A methodological approach. AB - The aim of this study was to assess the suitability of using real-time quantitative PCR (RT-qPCR) to characterize neuroendocrine (NE) tumors of the pancreas. For a series of tumors, we evaluated several genes of interest, and the data were matched with the "classical" immunohistochemical (IHC) features. In 21 cases, we extracted RNA from formalin-fixed paraffin-embedded (FFPE) blocks, and in nine cases, we also extracted RNA from fresh-frozen tissue. The RT-qPCR procedure was performed using two sets of customized arrays. The test using the first set, covering 96 genes of interest, was focused on assessing the feasibility of the procedure, and the results were used to select 18 genes indicative of NE differentiation, clinical behavior, and therapeutic responsiveness for use in the second set of arrays. Threshold cycle (Ct) values were used to calculate the fold-changes in gene expression using the 2-??Ct method. Statistical procedures were used to analyze the results, which were matched with the IHC and follow-up data. Material from fresh-frozen samples performed better in terms of the level of amplification, but acceptable and concordant results were also obtained from FFPE samples. In addition, high concordance was observed between the mRNA and protein expression levels of somatostatin receptor type 2A (R = 0.52, p = 0.016). Genes associated with NE differentiation, as well as the gastrin-releasing peptide receptor and O-6 methylguanine-DNA methyltransferase genes, were underexpressed, whereas angiogenesis-associated markers (CDH13 and SLIT2) were overexpressed in tissues with malignant behavior. The RT-qPCR procedure is practical and feasible in economic terms for the characterization of NE tumors of the pancreas and can complement morphological and IHC-based evaluations. Thus, the results of the RT qPCR procedure might offer an objective basis for therapeutic choices. PMID- 23657968 TI - Editorial: the birth of endocrine pathology. PMID- 23657970 TI - Royal jelly prevents the progression of sarcopenia in aged mice in vivo and in vitro. AB - Sarcopenia is characterized by the age-related loss of muscle mass and strength. One of the mechanisms of sarcopenia is the loss in the function and number of muscle satellite cells. Royal jelly (RJ) is a health food used worldwide. To obtain better digestion and absorption than RJ, protease-treated RJ (pRJ) has been developed. RJ and pRJ have been suggested to have potential pharmacological benefits such as prolonging the life span and reducing fatigue. Because these effects may improve sarcopenia and the functions of satellite cells, we examined the effects of RJ or pRJ treatment on the skeletal muscles in an animal model using aged mice. In vivo, RJ/pRJ treatment attenuated the decrease in the muscle weight and grip strength and increased the regenerating capacity of injured muscles and the serum insulin-like growth factor-1 levels compared with controls. In vitro, using isolated satellite cells from aged mice, pRJ treatment increased the cell proliferation rate, promoted cell differentiation, and activated Akt intracellular signaling pathway compared with controls. These findings suggest that RJ/pRJ treatment had a beneficial effect on age-related sarcopenia. PMID- 23657969 TI - Tibetan sound meditation for cognitive dysfunction: results of a randomized controlled pilot trial. AB - OBJECTIVE: Although chemotherapy-induced cognitive impairment is common among breast cancer patients, evidence for effective interventions addressing cognitive deficits is limited. This randomized controlled trial examined the feasibility and preliminary efficacy of a Tibetan Sound Meditation (TSM) program to improve cognitive function and quality of life in breast cancer patients. METHODS: Forty seven breast cancer patients (mean age 56.3 years), who were staged I-III at diagnosis, 6-60 months post-chemotherapy, and reported cognitive impairment at study entry were recruited. Participants were randomized to either two weekly TSM sessions for 6 weeks or a wait list control group. Neuropsychological assessments were completed at baseline and 1 month post-treatment. Self-report measures of cognitive function (Functional Assessment of Cancer Therapy (FACT)-Cog), quality of life (SF-36), depressive symptoms (Center for Epidemiologic Studies Depression Scale), sleep disturbance (Pittsburgh Sleep Quality Index), fatigue (Brief Fatigue Inventory), and spirituality (FACT-Sp) were completed at baseline, the end of treatment, and 1 month later. RESULTS: Relative to the control group, women in the TSM group performed better on the verbal memory test (Rey Auditory Verbal Learning Test trial 1) (p = 0.06) and the short-term memory and processing speed task (Digit Symbol) (p = 0.09) and reported improved cognitive function (p = 0.06), cognitive abilities (p = 0.08), mental health (p = 0.04), and spirituality (p = 0.05) at the end of treatment but not 1 month later. CONCLUSIONS: This randomized controlled trial revealed that TSM program appears to be a feasible and acceptable intervention and may be associated with short term improvements in objective and subjective cognitive function as well as mental health and spirituality in breast cancer patients. PMID- 23657971 TI - Mutation of the protein kinase I alpha leucine zipper domain produces hypertension and progressive left ventricular hypertrophy: a novel mouse model of age-dependent hypertensive heart disease. AB - Hypertensive heart disease causes significant mortality in older patients, yet there is an incomplete understanding of molecular mechanisms that regulate age dependent hypertensive left ventricular hypertrophy (LVH). Therefore, we tested the hypothesis that the cGMP-dependent protein kinase G I alpha (PKGIalpha) attenuates hypertensive LVH by evaluating the cardiac phenotype in mice with selective mutations of the PKGIalpha leucine zipper domain. These leucine zipper mutant (LZM) mice develop basal hypertension. Compared with wild-type controls, 8 month-old adult LZM mice developed increased left ventricular end-diastolic pressure but without frank LVH. In advanced age (15 months), the LZM mice developed overt pathological LVH. These findings reveal a role of PKGIalpha in normally attenuating hypertensive LVH. Therefore, mutation of the PKGIalpha LZ domain produces a clinically relevant model for hypertensive heart disease of aging. PMID- 23657972 TI - A comparison of straight- and curved-path walking tests among mobility-limited older adults. AB - BACKGROUND: Habitual gait speed (HGS) and the figure-of-8 walking test (F8WT) are measures of walking ability that have been associated with mobility outcomes and disability among older adults. Our objective was to contrast the physiologic, health, and behavioral attributes underlying performance of these two walking tests among older adults with mobility limitations. METHODS: HGS and F8WT were the primary outcomes. HGS was measured as time needed to walk a 4-m straight course at usual pace from standstill position. F8WT was measured as time to walk in a figure-of-8 pattern at self-selected usual pace from standstill position. Separate multivariable linear regression models were constructed that predicted walking performance. Independent variables included physiologic, cognitive behavioral health attributes, and demographic information. RESULTS: Of 430 participants, 414 completed both walking tests. Participants were 67.7% female, had a mean age of 76.5 +/- 7.0 years and a mean of 4.1 +/- 2.0 chronic conditions. Mean HGS was 0.94 +/- 0.23 m/s and mean F8WT was 8.80 +/- 2.90 seconds. Within separate multivariable linear regression models (HGS: R (2) = .46, p model < .001; F8WT: R (2) = .47, p model < .001), attributes statistically significant within both models included: trunk extension endurance, ankle range of motion, leg press velocity at peak power, executive function, and sensory loss. Cognitive and physiologic attributes uniquely associated with F8WT were cognitive processing speed and self-efficacy, and reaction time and heel-to-floor time. Pain and peak leg press strength were associated with only HGS. CONCLUSIONS: Both HGS and F8WT are useful tests of walking performance. Factors uniquely associated with F8WT suggest that it may be well suited for use among older adult patients with balance problems or at risk for falls. PMID- 23657973 TI - Associations between frailty and serum 25-hydroxyvitamin D and 1,25 dihydroxyvitamin D concentrations in older Australian men: the Concord Health and Ageing in Men Project. AB - BACKGROUND: Poor vitamin D status and frailty are common in older people and associated with adverse health outcomes. The aim of this study was to examine the associations between serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels and frailty and components of frailty in older Australian men. METHODS: Cross sectional analysis of the Concord Health and Ageing in Men Project, a large epidemiological study conducted in Sydney, Australia, between January 2005 and May 2007. Participants included 1,659 community-dwelling men. Main outcome measurements were frailty (assessed using the Cardiovascular Health Study), frailty criteria comprising five core components: weight loss; reduced muscular strength/weakness; slow walking speed; exhaustion; and low activity level, and the separate components of frailty. Covariates included serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels measured by radioimmunoassay, age, country of birth, season of blood collection, sun exposure, body mass index, vitamin D supplement use, income, measures of health, parathyroid hormone, estimated glomerular function. RESULTS: Frailty was present in 9.2% of the sample. Low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were independently associated with frailty and with four of the five components of frailty (except weight loss). CONCLUSIONS: 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D levels were independently associated with frailty in older men. This suggests that there might be a number of different biological mechanisms for how low vitamin D status might contribute to the frailty syndrome. In addition, the possibility that improving vitamin D status may specifically influence the incidence and progression of frailty needs to be explored. PMID- 23657974 TI - Adipogenic differentiation is impaired in replicative senescent human subcutaneous adipose-derived stromal/progenitor cells. AB - We demonstrate that adipose-derived stromal/progenitor cells isolated from abdominal subcutaneous fat pads of adult donors successively enter replicative senescence after long-term cultivation. This is characterized by enlarged cell size, flattened morphology, and upregulated senescence-associated beta galactosidase activity. Moreover, the senescence- associated cyclin-dependent kinase inhibitors p16(Ink4A) and p21(Cip1) were induced correlating with activation of the G1/S cell cycle inhibitor retinoblastoma protein and terminal proliferation arrest. The number of cells in the adipose-derived stromal/progenitor cell population with high adipogenic capacity declined inversely with the increase of senescent cells. Adipogenic hormone cocktail induced expression of the adipogenic key regulators peroxisome proliferator activated receptor-gamma2 and CCAAT/enhancer-binding protein alpha was significantly reduced in senescent adipose-derived stromal/ progenitor cells. Furthermore, the expression of the adipogenic differentiation genes fatty acid binding protein-4, adiponectin, and leptin and the formation of fat droplets were impaired. We conclude cellular senescence contributes to dysfunctions in adipose derived stromal/progenitor cell replication, adipogenesis, triglyceride storage, and adipokine secretion. PMID- 23657976 TI - Human ASH-1 promotes neuroendocrine differentiation in androgen deprivation conditions and interferes with androgen responsiveness in prostate cancer cells. AB - BACKGROUND: Neuroendocrine differentiation in prostate cancer is a dynamic process associated to the onset of hormone-refractory disease in vivo. The molecular mechanisms underlying this process are poorly recognized. Our study aimed at testing in vitro the role of hASH-1, a transcription factor implicated in neuroendocrine differentiation, in the onset of neuroendocrine phenotype in prostate cancer cells. METHODS: Androgen sensitive LNCAP, androgen insensitive PC 3, and three immortalized prostate cancer cell lines were cultured in standard and androgen deprivation conditions. Expression of hASH-1 was modulated by either specific lentiviral transduction or shRNA interference. Inhibitors of WNT-11, a WNT family member associated to the development of neuroendocrine differentiation in prostate cancer, were also used. Cell viability was measured using the MTS method. Neuroendocrine phenotype was assessed by morphology, immunohistochemistry and real time PCR for several neuroendocrine markers. RESULTS: hASH-1 was up modulated by androgen deprivation in LNCaP cells and in androgen-sensitive immortalized prostate cancer cells, and associated with the onset of a neuroendocrine phenotype. Silencing of hASH-1 prevented neuroendocrine differentiation, as did also the selective interference with the WNT-11 pathway. Moreover, hASH-1 over-expression in LNCaP cells was sufficient to promote neuroendocrine differentiation and increased cell viability at basal and androgen deprived growth conditions. CONCLUSION: In summary, the present data support previous evidence that the acquisition of a neuroendocrine phenotype is linked to androgen responsiveness profiles and suggest a pivotal role of hASH-1 transcription factor, whose activity might be explored as a potential therapeutic target in prostate cancer, with special reference to hormone refractory disease. PMID- 23657975 TI - Assessment of mitochondrial biogenesis and mTORC1 signaling during chronic rapamycin feeding in male and female mice. AB - Chronic inhibition of the protein synthesis regulator mTORC1 through rapamycin extends life span in mice, with longer extension in females than in males. Whether rapamycin treatment inhibits protein synthesis or whether it does so differently between sexes has not been examined. UM-HET3 mice were fed a control or rapamycin-supplemented (Rap) diet for 12 weeks. Protein synthesis in mixed, cytosolic (cyto), and mitochondrial (mito) fractions and DNA synthesis and mTORC1 signaling were determined in skeletal muscle, heart, and liver. In both sexes, mito protein synthesis was maintained in skeletal muscle from Rap despite decreases in mixed and cyto fractions, DNA synthesis, and rpS6 phosphorylation. In the heart, no change in protein synthesis occurred despite the decreased DNA synthesis. In the heart and liver, Rap males were more sensitive to mTORC1 inhibition than Rap females. In conclusion, we show changes in protein synthesis and mTORC1 signaling that differ by sex and tissue. PMID- 23657977 TI - Spondyloepiphyseal dysplasias and bilateral legg-calve-perthes disease: diagnostic considerations for mucopolysaccharidoses. AB - Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome, MIM 253200 ) is an autosomal recessive lysosomal storage disease (LSD) caused by decreased activity of arylsulfatase B (N-acetylgalactosamine 4-sulfatase) enzyme resulting in dermatan sulfate accumulation; mucopolysaccharidosis type IVA (MPS IVA, Morquio syndrome A, MIM 253000 ) by decreased activity of N-acetylgalactosamine 6 sulfatase enzyme resulting in accumulation of keratan sulfate. Clinical symptoms include coarse facial features, joint stiffness, hepatosplenomegaly, hip osteonecrosis, and dysostosis multiplex. MPS IVA symptoms are similar but with joint hypermobility.With suspicion of MPS disease, clinicians request urine studies for quantitative and qualitative glycosaminoglycans (GAGs). Diagnosis is confirmed by decreased enzyme activity in leukocytes or cultured skin fibroblasts. Further confirmation is obtained with identification of two mutations in the ARSB gene for MPS VI or mutations in the GALNS gene for MPS IVA.We report slowly progressing patients, one with MPS VI and two with MPS IVA, who presented with skeletal changes and hip findings resembling Legg-Calve Perthes disease or spondyloepiphyseal dysplasia and normal/near normal urine GAG levels. The urine analysis data presented suggest that present screening techniques for MPS are inadequate in milder patients and result in delayed or missed diagnoses. The patients presented in this paper emphasize the importance of enzymatic and molecular testing. PMID- 23657978 TI - On the structures of 55-atom transition-metal clusters and their relationship to the crystalline bulk. AB - Correlation of cluster and bulk structure: Electron-diffraction measurements of homonuclear 55-atom transition-metal cluster anions covering essentially all 3d and 4d elements show only four main structure families. Elements with the same bulk lattice morphology generally have a common cluster structure type. The cluster structure types differ in maximum atomic coordination numbers in analogy to the coordination numbers in the corresponding bulk lattices. PMID- 23657979 TI - PEGylated upconverting luminescent hollow nanospheres for drug delivery and in vivo imaging. AB - Upconversion luminescent hollow Y2 O3 :Yb(3+) /Er(3+) nanospheres can be synthesized by an etching-free process, which hold promising potential for applications such as drug delivery, angiography, and high-contrast cellular as well as tissue imaging, with no damage from radiation or toxicity. PMID- 23657980 TI - Investigation of resolution effects using a specialized diffusion tensor phantom. AB - PURPOSE: The clinical potential of the diffusion imaging-based analysis of fine brain structures such as fornix or cingulum is high due to the central role of these structures in psychiatric diseases. However, the quantification of diffusion parameters in fine structures is especially prone to partial volume effects (PVEs). METHODS: In this study, a phantom for the investigation of PVEs and their influence on diffusion parameters in fine structures of different diameter is presented. The phantom is produced by winding wet polyester fibers onto a spindle. The resulting fiber strands have well defined square cross sections of 1-25 mm(2) and provide a homogeneous and high fractional anisotropy (FA ~ 0.9). RESULTS: Several PVEs are demonstrated and analyzed. It is shown that inferred results such as the fiber geometry and diffusion parameters strongly depend on the relative position of the structure of interest to the voxel-grid. Several implications of PVEs on post-processing methods such as Tract-based Spatial Statistics and fiber tractography are demonstrated. CONCLUSION: These results show that the handling of PVEs in common post-processing tasks can be problematic, and that the presented phantom provides a valuable tool for the improvement and evaluation of these effects. PMID- 23657981 TI - Detection of serum Alu element hypomethylation for the diagnosis and prognosis of glioma. AB - Global genomic hypomethylation is a hallmark of cancer in humans. In the present study, the feasibility of measuring hypomethylation of Alu elements (Alu) in serum and its clinical utility were investigated. Tumor tissues and matched serum specimens from 65 glioma patients and serum samples from 30 healthy controls were examined for Alu hypomethylation by bisulfite sequencing. The median serum Alu methylation level was 47.30 % in patients (interquartile range (IQR), 35.40-54.25 %) and 57.90 % in the controls (IQR, 55.25-61.45 %). The median Alu methylation level in tumor samples was 40.30 % (IQR, 36.80-54.20 %), which shows the correlation of Alu hypomethylation between tumor and serum samples (r = 0.882) in the study group. The methylation level was higher in the low-grade glioma group than in the high-grade group both in tumor and serum samples. A correlation between high methylation level and longer survival time was detected in tumor and serum samples. Receiver operating characteristic curve analysis showed that the area under the curve for diagnosis was 0.861 (95 % confidence interval, 0.789 0.933), suggesting that Alu hypomethylation in serum may be of diagnostic value. Our results indicate that the detection of Alu hypomethylation in serum may be clinically useful for the diagnosis and prognosis of glioma. PMID- 23657983 TI - Sustained ibuprofen release using composite poly(lactic-co-glycolic acid)/titanium dioxide nanotubes from Ti implant surface. AB - Developing coatings on implant surface as drug carriers can reduce organ toxicity and effectively deliver drug locally to the target compared with the oral approach. Titanium dioxide (TiO2) nanotube has great potential for this application for widely used Ti implants because of its high surface area, ability to promote bone growth, and biocompatibility. However, there are two issues needed to be solved before further advancing TiO2 nanotubes technology as drug carriers: uncontrolled drug release and poor mechanical properties. In this study, a drug carrier using a composite of biodegradable polymer/TiO2 nanotubes is engineered. Ibuprofen is selected as a concept drug because it is a commonly used anti-inflammatory, fever, and pain-reducing drug. In addition, ibuprofen has a very short plasma half-life of only 1-3 h. A simple characterization method is developed to investigate the infiltration of polymer into TiO2 nanotubes. Good infiltration was observed of polymer into TiO2 nanotubes. The synthesized drug carrier demonstrated much better sustained drug release profiles for ibuprofen of 5 days (low-molecular-weight polymer) and 9 days (high-molecular-weight polymer) compared with 30 min of pure TiO2 nanotubes. The drug carrier also exhibited much improved mechanical strength and flexibility compared with pure TiO2 nanotubes. PMID- 23657982 TI - Edaravone prevents neurotoxicity of mutant L166P DJ-1 in Parkinson's disease. AB - Parkinson's disease (PD), which is estimated to affect approximately 1 % of the population over the age of 65, is the second most common neurodegenerative disorder after Alzheimer's disease. It was reported that pathogenic mutations in DJ-1 lead to autosomal recessive early-onset familial Parkinsonism. The L166P mutant of DJ-1 is the most commonly studied loss-of-function mutation in early onset familial PD, but the underlying mechanisms are still unknown. Edaravone is a powerful free radical scavenger used in clinical treatment for cerebral ischemic stroke. In the present study, we investigated the effects of edaravone on the neurotoxicity in PD-induced isoforms of DJ-1 containing the mutation L166P. Our results indicated that edaravone was able to significantly attenuate oxidative stress and improve mitochondrial function. Furthermore, edaravone was found to reduce apoptosis in Neuro2a cells through modulation of mitochondria dependent apoptosis pathways. Interestingly, our result also demonstrated that edaravone was able to up-regulate VMAT2 expression in N2a cells in a dose dependent manner. Our findings enhance the understanding of the neuro-protective effects of edaravone in cell models and suggest that edaravone offers significant protection in a PD-related in vitro model. PMID- 23657984 TI - Effect of glycosylation on the partition behavior of a human antibody in aqueous two-phase systems. AB - Human proteins are expressed in some hosts wrongly glycosylated or nonglycosylated. Although it is accepted that glycosylation contributes to the stability of the protein in solution, the effect of glycosylation on the stability of human antibodies is not fully understood. In this work, we present solubility studies of two human antibodies that have the same primary structure but different glycosylation pattern. The studies were done by monitoring the partitioning behavior of both proteins in a series of aqueous two-phase systems at and away the isoelectric point of the proteins and at different temperatures. Our studies show that in the absence of direct electrostatic forces, the partitioning behavior of the antibodies depends on the presence or absence of the polysaccharide chains. Overall, the nonglycosylated protein is less soluble than the glycosylated one. The potential of aqueous two-phase systems for the separation of the glycosylated and nonglycosylated proteins was also explored. A simple series of extractions seems to be enough to separate the glycosylated variety from the nonglycosylated one at high purity but low yields. PMID- 23657985 TI - Computational and experimental investigation of DNA repair protein photolyase interactions with low molecular weight drugs. AB - This paper reports the previously unknown interactions between eight low molecular weight commercially available drugs (130-800 Da) and DNA repair protein photolyase using computational docking simulations and surface plasmon resonance (SPR) experiments. Theoretical dissociation constants, K(d), obtained from molecular docking simulations were compared with the values found from SPR experiments. Among the eight drugs analyzed, computational and experimental values showed similar binding affinities between selected drug and protein pairs. We found no significant differences in binding interactions between pure and commercial forms of the drug lornoxicam and DNA photolyase. Among the eight drugs studied, prednisone, desloratadine, and azelastine exhibited the highest binding affinity (K(d) = 1.65, 2.05, and 8.47 MUM, respectively) toward DNA photolyase. Results obtained in this study are promising for use in the prediction of unknown interactions of common drugs with specific proteins such as human clock protein cryptochrome. PMID- 23657986 TI - Insight into the molecular recognition of spermine by DNA quadruplexes from an NMR study of the association of spermine with the thrombin-binding aptamer. AB - The preferred residence sites and the conformation of DNA-bound polyamines are central to understanding the regulatory roles of polyamines. To this end, we have used a series of selective (13)C-edited and selective total correlation spectroscopy-edited one-dimensional (1D) nuclear Overhauser effect spectroscopy NMR experiments to determine a number of intramolecular (1)H nuclear Overhauser effect (NOE) connectivities in (13)C-labelled spermine bound to the thrombin binding aptamer. The results provide evidence that the aptamer-bound spermine adopts a conformation that optimizes electrostatic and hydrogen bond contacts with the aptamer backbone. The distance between the nitrogen atoms of the central aminobutyl is reduced by an increase in the population of gauche conformers at the C6-C7 bonds, which results in either a curved or S-shaped spermine conformation. Molecular modelling contributes insight toward the mode of spermine binding of these spermine structures within the narrow grooves of DNA quadruplexes. In each case, the N5 ammonium group makes hydrogen bonds with two nearby phosphates across the narrow groove. Our results have implications for the understanding of chromatin structure and the rational design of quadruplex binding drugs. PMID- 23657987 TI - siRNA associated with immunonanoparticles directed against cd99 antigen improves gene expression inhibition in vivo in Ewing's sarcoma. AB - Ewing's sarcoma is a rare, mostly pediatric bone cancer that presents a chromosome abnormality called EWS/Fli-1, responsible for the development of the tumor. In vivo, tumor growth can be inhibited specifically by delivering small interfering RNA (siRNA) associated with nanoparticles. The aim of the work was to design targeted nanoparticles against the cell membrane glycoprotein cd99, which is overexpressed in Ewing's sarcoma cells to improve siRNA delivery to tumor cells. Biotinylated poly(isobutylcyanoacrylate) nanoparticles were conceived as a platform to design targeted nanoparticles with biotinylated ligands and using the biotin-streptavidin coupling method. The targeted nanoparticles were validated in vivo for the targeted delivery of siRNA after systemic administration to mice bearing a tumor model of the Ewing's sarcoma. The expression of the gene responsible of Ewing's sarcoma was inhibited at 78% +/- 6% by associating the siRNA with the cd99-targeted nanoparticles compared with an inhibition of only 41% +/- 9% achieved with the nontargeted nanoparticles. PMID- 23657990 TI - A victim of the Occam's razor. PMID- 23657991 TI - Posttraumatic growth as experienced by childhood cancer survivors and their families: a narrative synthesis of qualitative and quantitative research. AB - Confronting with a life-threatening illness may serve as an opportunity for self renewal and spiritual and personal growth. Posttraumatic growth refers to the experience of positive change resulting from the struggle and/or cognitive engagement with the existential challenges of life events. The more stressful a life situation is, the more potential it provides for personal growth. This article is a report of a narrative synthesis of empirical research reporting the positive effects of cancer perceived by the childhood cancer survivors and their families. A total of 35 studies included 20 quantitative, 12 qualitative, and 3 mixed studies (involving 2087 childhood cancer survivors, 1115 parents, and 159 healthy siblings). They were published between 1975 and 2010 and conducted in 9 countries. Five themes were identified: (1) meaning-making, (2) appreciation of life, (3) self-awareness, (4) closeness and family togetherness, and (5) a desire to pay back society. The findings suggest that illness becomes our best teacher to get to know ourselves at a deeper level and the world in a new dimension with new meaning. Working through an illness brings out our best, teaching us what life is all about. PMID- 23657989 TI - Physical activity for the prevention and treatment of metabolic disorders. AB - Metabolic syndrome and its various features (obesity, hypertension, dyslipidemia, diabetes, and nonalcoholic fatty liver disease) are increasing worldwide and constitute a severe risk for the sustainability of the present universal Italian health care system. Lifestyle interventions should be the first therapeutic strategy to prevent/treat metabolic diseases, far before pharmacologic treatment. The role of diet and weight loss has been fully ascertained, whereas the role of physical activity is frequently overlooked both by physicians and by patients. Physical activity has favorable effects on all components of the metabolic syndrome and on the resulting cardiovascular risk, the cornerstone in the development of cardiometabolic diseases. The quantity and the frequency of physical activity necessary to produce beneficial effects has not been defined as yet, but brisk walking is considered particularly appropriate, as it can be practiced by a large number of individuals, without any additional cost, and has a low rate of injury. The effects of exercise and leisure time physical activity extend from prevention to treatment of the various components of the metabolic syndrome, as well as to mood and quality of life. Any effort should be done to favor adherence to protocols of physical activity in the community. PMID- 23657992 TI - [SGLT2 inhibition: an effective therapeutic approach in the treatment of diabetes mellitus?]. AB - Since end of 2012 a new therapeutical approach for the treatment of type 2 diabetes is available in Germany. It relies on the modulation of glucose re absorption in the kidney by inhibition of so called Sodium Glucose Linked Transporters (SGLT) thereby leading to therapeutical glucosuria. Putting the kidney in the centre of therapeutical approach of glucose regulation is unfamiliar for physicians. Therefore, it is helpful to elucidate the underlying renal mechanisms and to present the advantages and disadvantages of this new therapeutic class. PMID- 23657993 TI - Capillary electrophoresis for monitoring bioprocesses. AB - Chemical characterization and monitoring of fermentation broths and cell culture media provide significant information on the changes occurring within these complex and dynamic systems. Analytical methods based on CE in capillaries and microchips are attractive for integration in instrumental tools to obtain this critical data, improving the understanding and control of bioprocesses. In this review, the use of CE for chemical characterization and monitoring fermentations is discussed, organized by analyte class, including organic acids, pharmaceuticals, proteins, sugars, amino acids, and metabolites published between 1992 and October 2012. A section is dedicated to the roles CE plays throughout the wine making process, where applications range from characterization and increase in fundamental understanding of the fermentation to forensic applications, verifying the authenticity of the wine. PMID- 23657994 TI - Photosensitization of DNA by 5-methyl-2-pyrimidone deoxyribonucleoside: (6-4) photoproduct as a possible Trojan horse. PMID- 23657995 TI - Three-dimensional neural differentiation of embryonic stem cells with ACM induction in microfibrous matrices in bioreactors. AB - The clinical use of pluripotent stem cell (PSC)-derived neural cells requires an efficient differentiation process for mass production in a bioreactor. Toward this goal, neural differentiation of murine embryonic stem cells (ESCs) in three dimensional (3D) polyethylene terephthalate microfibrous matrices was investigated in this study. To streamline the process and provide a platform for process integration, the neural differentiation of ESCs was induced with astrocyte-conditioned medium without the formation of embryoid bodies, starting from undifferentiated ESC aggregates expanded in a suspension bioreactor. The 3D neural differentiation was able to generate a complex neural network in the matrices. When compared to 2D differentiation, 3D differentiation in microfibrous matrices resulted in a higher percentage of nestin-positive cells (68% vs. 54%) and upregulated gene expressions of nestin, Nurr1, and tyrosine hydroxylase. High purity of neural differentiation in 3D microfibrous matrix was also demonstrated in a spinner bioreactor with 74% nestin + cells. This study demonstrated the feasibility of a scalable process based on 3D differentiation in microfibrous matrices for the production of ESC-derived neural cells. PMID- 23657997 TI - Glucose metabolism, hyperosmotic stress, and reprogramming of somatic cells. AB - The availability of glucose and oxygen are important regulatory elements that help directing stem cell fate. In the undifferentiated state, stem cells, and their artificially reprogrammed equivalent-induced pluripotent stem cells (iPS) are characterized by limited oxidative capacity and active anaerobic glycolysis. Recent studies have shown that pluripotency-a characteristic of staminality-is associated with a poorly developed mitochondrial patrimony, while differentiation is accompanied by an activation of mitochondrial biogenesis. Besides being an important energy source in hypoxia, high glucose level results in hyperosmotic stress. The identification of specific metabolic pathways and biophysical factors that regulate stem cell fate, including high glucose in the extracellular medium, may therefore facilitate reprogramming efficiency and control the differentiation and fate of iPS cells, which are increasingly being explored as therapeutic tools. In this article, we review recent knowledge of the role of glucose metabolism and high glucose level as major anaerobic energy source, and a determinant of osmolarity as possible tools for reprogramming therapies in clinical applications. As in the diabetic setting hyperglycemia negatively affect the stem/progenitor cell fate and likely somatic reprogramming, we also discuss the in vivo potential transferability of the available in vitro findings. PMID- 23657998 TI - Bone marrow fat quantification in the presence of trabecular bone: initial comparison between water-fat imaging and single-voxel MRS. AB - PURPOSE: The purpose of the present study was to test the relative performance of chemical shift-based water-fat imaging in measuring bone marrow fat fraction in the presence of trabecular bone, having as reference standard the single-voxel magnetic resonance spectroscopy (MRS). METHODS: Six-echo gradient echo imaging and single-voxel MRS measurements were performed on the proximal femur of seven healthy volunteers. The bone marrow fat spectrum was characterized based on the magnitude of measurable fat peaks and an a priori knowledge of the chemical structure of triglycerides, in order to accurately extract the water peak from the overlapping broad fat peaks in MRS. The imaging-based fat fraction results were then compared to the MRS-based results both without and with taking into consideration the presence of short T2* water components in MRS. RESULTS: There was a significant underestimation of the fat fraction using the MRS model not accounting for short T2* species with respect to the imaging-based fat fraction. A good equivalency was observed between the fat fraction using the MRS model accounting for short T2* species and the imaging-based fat fraction (R(2) = 0.87). CONCLUSION: The consideration of the short T2* water species effect on bone marrow fat quantification is essential when comparing MRS-based and imaging based fat fraction results. PMID- 23657999 TI - Absolute measurement of species differences in sodium taurocholate cotransporting polypeptide (NTCP/Ntcp) and its modulation in cultured hepatocytes. AB - Species differences among membrane transporters can be remarkable and difficult to properly assess by conventional methods. Herein, we employed the first use of stable isotope labeling in mammals or stable isotope-labeled peptides combined with mass spectrometry to identify species differences in sodium taurocholate cotransporting polypeptide (NTCP/Ntcp) protein expression in liver tissue and to characterize the modulation of protein expression in sandwich-cultured human (SCHH) and rat hepatocytes (SCRH). The lower limit of quantification was established to be 5 fmol on column with a standard curve that was linear up to 2000 fmol. The accuracy and precision were evaluated with three quality control samples and known amounts of synthetic proteotypic peptides that were spiked into the membrane protein extracts. The overall relative error and coefficient of variation were less than 10%. The expression of Ntcp in mouse and rat was significant higher than that in human (five-fold) and monkey (two-fold) and ranked as mouse > rat >> monkey > human. In the cultured hepatocytes, although significant downregulation of Ntcp expression in SCRH at day 5 after the culture was detected, NTCP expression in SCHH was comparable to the suspension hepatocytes. The results suggested that NTCP/Ntcp modulation in cultured hepatocytes is species specific. PMID- 23658000 TI - How to record ductus venosus blood velocity in the second half of pregnancy. PMID- 23658001 TI - Mechanized silica nanoparticles based on pillar[5]arenes for on-command cargo release. AB - Mechanized silica nanoparticles, equipped with pillar[5]arene-[2]pseudorotaxane nanovalves, operate in biological media to trap cargos within their nanopores, but release them when the pH is lowered or a competitive binding agent is added. Although cargo size plays an important role in cargo loading, cargo charge-type does not appear to have any significant influence on the amount of cargo loading or its release. These findings open up the possibility of using pillar[n]arene and its derivatives for the formation of robust and dynamic nanosystems that are capable of performing useful functions. PMID- 23658002 TI - Memory decay and susceptibility to amnesia dissociate punishment--from relief learning. AB - Painful events shape future behaviour in two ways: stimuli associated with pain onset subsequently support learned avoidance (i.e. punishment-learning) because they signal future, upcoming pain. Stimuli associated with pain offset in turn signal relief and later on support learned approach (i.e. relief-learning). The relative strengths of such punishment- and relief-learning can be crucial for the adaptive organization of behaviour in the aftermath of painful events. Using Drosophila, we compare punishment- and relief-memories in terms of their temporal decay and sensitivity to retrograde amnesia. During the first 75 min following training, relief-memory is stable, whereas punishment-memory decays to half of the initial score. By 24 h after training, however, relief-memory is lost, whereas a third of punishment-memory scores still remain. In accordance with such rapid temporal decay from 75 min on, retrograde amnesia erases relief-memory but leaves a half of punishment-memory scores intact. These findings suggest differential mechanistic bases for punishment- and relief-memory, thus offering possibilities for separately interfering with either of them. PMID- 23658003 TI - Facial morphology predicts male fitness and rank but not survival in Second World War Finnish soldiers. AB - We investigated fitness, military rank and survival of facial phenotypes in large scale warfare using 795 Finnish soldiers who fought in the Winter War (1939 1940). We measured facial width-to-height ratio-a trait known to predict aggressive behaviour in males-and assessed whether facial morphology could predict survival, lifetime reproductive success (LRS) and social status. We found no difference in survival along the phenotypic gradient, however, wider-faced individuals had greater LRS, but achieved a lower military rank. PMID- 23658004 TI - Anthelmintic treatment alters the parasite community in a wild mouse host. AB - Individuals are often co-infected with several parasite species, yet the consequences of drug treatment on the dynamics of parasite communities in wild populations have rarely been measured. Here, we experimentally reduced nematode infection in a wild mouse population and measured the effects on other non-target parasites. A single oral dose of the anthelmintic, ivermectin, significantly reduced nematode infection, but resulted in a reciprocal increase in other gastrointestinal parasites, specifically coccidial protozoans and cestodes. These results highlight the possibility that drug therapy may have unintended consequences for non-target parasites and that host-parasite dynamics cannot always be fully understood in the framework of single host-parasite interactions. PMID- 23658005 TI - Extremely high frequency sensitivity in a 'simple' ear. AB - An evolutionary war is being played out between the bat, which uses ultrasonic calls to locate insect prey, and the moth, which uses microscale ears to listen for the approaching bat. While the highest known frequency of bat echolocation calls is 212 kHz, the upper limit of moth hearing is considered much lower. Here, we show that the greater wax moth, Galleria mellonella, is capable of hearing ultrasonic frequencies approaching 300 kHz; the highest frequency sensitivity of any animal. With auditory frequency sensitivity that is unprecedented in the animal kingdom, the greater wax moth is ready and armed for any echolocation call adaptations made by the bat in the on-going bat-moth evolutionary war. PMID- 23658006 TI - Ancient DNA complements microfossil record in deep-sea subsurface sediments. AB - Deep-sea subsurface sediments are the most important archives of marine biodiversity. Until now, these archives were studied mainly using the microfossil record, disregarding large amounts of DNA accumulated on the deep-sea floor. Accessing ancient DNA (aDNA) molecules preserved down-core would offer unique insights into the history of marine biodiversity, including both fossilized and non-fossilized taxa. Here, we recover aDNA of eukaryotic origin across four cores collected at abyssal depths in the South Atlantic, in up to 32.5 thousand-year old sediment layers. Our study focuses on Foraminifera and Radiolaria, two major groups of marine microfossils also comprising diverse non-fossilized taxa. We describe their assemblages in down-core sediment layers applying both micropalaeontological and environmental DNA sequencing approaches. Short fragments of the foraminiferal and radiolarian small subunit rRNA gene recovered from sedimentary DNA extracts provide evidence that eukaryotic aDNA is preserved in deep-sea sediments encompassing the last glacial maximum. Most aDNA were assigned to non-fossilized taxa that also dominate in molecular studies of modern environments. Our study reveals the potential of aDNA to better document the evolution of past marine ecosystems and opens new horizons for the development of deep-sea palaeogenomics. PMID- 23658007 TI - Constraints on decision making: implications from genetics, personality, and addiction. AB - An influential neurocomputational theory of the biological mechanisms of decision making, the "basal ganglia go/no-go model," holds that individual variability in decision making is determined by differences in the makeup of a striatal system for approach and avoidance learning. The model has been tested empirically with the probabilistic selection task (PST), which determines whether individuals learn better from positive or negative feedback. In accordance with the model, in the present study we examined whether an individual's ability to learn from positive and negative reinforcement can be predicted by genetic factors related to the midbrain dopamine system. We also asked whether psychiatric and personality factors related to substance dependence and dopamine affect PST performance. Although we found characteristics that predicted individual differences in approach versus avoidance learning, these observations were qualified by additional findings that appear inconsistent with the predictions of the go/no-go model. These results highlight a need for future research to validate the PST as a measure of basal ganglia reward learning. PMID- 23658008 TI - Low molecular weight fucoidan improves endoplasmic reticulum stress-reduced insulin sensitivity through AMP-activated protein kinase activation in L6 myotubes and restores lipid homeostasis in a mouse model of type 2 diabetes. AB - Low molecular weight fucoidan (LMWF) is widely used to treat metabolic disorders, but its physiologic effects have not been well determined. In the present study, we investigated the metabolic effects of LMWF in obese diabetic mice (leptin receptor-deficient db/db mice) and the underlying molecular mechanisms involved in endoplasmic reticulum (ER) stress-responsive L6 myotubes. The effect of LMWF mediated AMP-activated protein kinase (AMPK) activation on insulin resistance via regulation of the ER stress-dependent pathway was examined in vitro and in vivo. In db/db mice, LMWF markedly reduced serum glucose, triglyceride, cholesterol, and low-density lipoprotein levels, and gradually reduced body weights by reducing lipid parameters. Furthermore, it effectively ameliorated glucose homeostasis by elevating glucose tolerance. In addition, the phosphorylation levels of AMPK and Akt were markedly reduced by ER stressor, and subsequently, glucose uptake and fatty acid oxidation were also reduced. However, these adverse effects of ER stress were significantly ameliorated by LMWF. Finally, in L6 myotubes, LMWF markedly reduced the ER stress-induced upregulation of the mammalian target of rapamycin-p70S61 kinase network and subsequently improved the action of insulin via AMPK stimulation. Our findings suggest that AMPK activation by LMWF could prevent metabolic diseases by controlling the ER stress-dependent pathway and that this beneficial effect of LMWF provides a potential therapeutic strategy for ameliorating ER stress-mediated metabolic dysfunctions. PMID- 23658009 TI - Sub-10 nm lanthanide-doped CaF2 nanoprobes for time-resolved luminescent biodetection. PMID- 23658010 TI - Transcatheter aortic valve replacement: an update. AB - Aortic stenosis affects many people worldwide with a significant impact on morbidity and mortality with uncorrected, symptomatic aortic valve stenosis carrying mortality of 50% at one year. Degenerative calcific pathology, the most common cause of aortic stenosis, increases in prevalence with age; estimated prevalence of 5% in individuals over 75 years of age. Despite the malignant prognosis without valve replacement, many patients are not offered surgery due to advanced age and co-existing medical conditions; reported to be a third of symptomatic patients. In the last several years, transcatheter aortic valve replacement has emerged as an alternative treatment in patients with high or prohibitive open surgical risk. The PARTNER cohort B data, employing the Sapien valve, demonstrated a 20% absolute mortality benefit at one year compared with medical therapy. In this review, we provide an update of this technology and discuss patient selection, procedural planning, complications, and look toward the future of transcatheter heart valves in the treatment of aortic stenosis. PMID- 23658011 TI - Liver fatty acid-binding protein binds monoacylglycerol in vitro and in mouse liver cytosol. AB - Liver fatty acid-binding protein (LFABP; FABP1) is expressed both in liver and intestinal mucosa. Mice null for LFABP were recently shown to have altered metabolism of not only fatty acids but also monoacylglycerol, the two major products of dietary triacylglycerol hydrolysis (Lagakos, W. S., Gajda, A. M., Agellon, L., Binas, B., Choi, V., Mandap, B., Russnak, T., Zhou, Y. X., and Storch, J. (2011) Am. J. Physiol. Gastrointest. Liver Physiol. 300, G803-G814). Nevertheless, the binding and transport of monoacylglycerol (MG) by LFABP are uncertain, with conflicting reports in the literature as to whether this single chain amphiphile is in fact bound by LFABP. In the present studies, gel filtration chromatography of liver cytosol from LFABP(-/-) mice shows the absence of the low molecular weight peak of radiolabeled monoolein present in the fractions that contain LFABP in cytosol from wild type mice, indicating that LFABP binds sn-2 MG in vivo. Furthermore, solution-state NMR spectroscopy demonstrates two molecules of sn-2 monoolein bound in the LFABP binding pocket in positions similar to those found for oleate binding. Equilibrium binding affinities are ~2-fold lower for MG compared with fatty acid. Finally, kinetic studies examining the transfer of a fluorescent MG analog show that the rate of transfer of MG is 7-fold faster from LFABP to phospholipid membranes than from membranes to membranes and occurs by an aqueous diffusion mechanism. These results provide strong support for monoacylglycerol as a physiological ligand for LFABP and further suggest that LFABP functions in the efficient intracellular transport of MG. PMID- 23658012 TI - Control of RhoA methylation by carboxylesterase I. AB - A number of proteins that play key roles in cell signaling are post translationally modified by the prenylation pathway. The final step in this pathway is methylation of the carboxyl terminus of the prenylated protein by isoprenylcysteine carboxylmethyltransferase. Due to the impact of methylation on Rho function, we sought to determine if the process was reversible and hence could control Rho function in a dynamic fashion. Elevating isoprenylcysteine carboxylmethyltransferase activity in cells has profound effects on MDA-MB-231 cell morphology, implying the presence of a pool of unmethylated prenyl proteins in these cells under normal conditions. Using a knockdown approach, we identified a specific esterase, carboxylesterase 1, whose function had a clear impact not only on the methylation status of RhoA but also RhoA activation and cell morphology. These data provide compelling evidence that C-terminal modification of prenyl proteins, rather than being purely a constitutive process, can serve as a point of regulation of function for this important class of protein. PMID- 23658013 TI - Structural basis for complement evasion by Lyme disease pathogen Borrelia burgdorferi. AB - Borrelia burgdorferi spirochetes that cause Lyme borreliosis survive for a long time in human serum because they successfully evade the complement system, an important arm of innate immunity. The outer surface protein E (OspE) of B. burgdorferi is needed for this because it recruits complement regulator factor H (FH) onto the bacterial surface to evade complement-mediated cell lysis. To understand this process at the molecular level, we used a structural approach. First, we solved the solution structure of OspE by NMR, revealing a fold that has not been seen before in proteins involved in complement regulation. Next, we solved the x-ray structure of the complex between OspE and the FH C-terminal domains 19 and 20 (FH19-20) at 2.83 A resolution. The structure shows that OspE binds FH19-20 in a way similar to, but not identical with, that used by endothelial cells to bind FH via glycosaminoglycans. The observed interaction of OspE with FH19-20 allows the full function of FH in down-regulation of complement activation on the bacteria. This reveals the molecular basis for how B. burgdorferi evades innate immunity and suggests how OspE could be used as a potential vaccine antigen. PMID- 23658014 TI - Crystal structures of the catalytic domain of a novel glycohydrolase family 23 chitinase from Ralstonia sp. A-471 reveals a unique arrangement of the catalytic residues for inverting chitin hydrolysis. AB - Chitinase C from Ralstonia sp. A-471 (Ra-ChiC) has a catalytic domain sequence similar to goose-type (G-type) lysozymes and, unlike other chitinases, belongs to glycohydrolase (GH) family 23. Using NMR spectroscopy, however, Ra-ChiC was found to interact only with the chitin dimer but not with the peptidoglycan fragment. Here we report the crystal structures of wild-type, E141Q, and E162Q of the catalytic domain of Ra-ChiC with or without chitin oligosaccharides. Ra-ChiC has a substrate-binding site including a tunnel-shaped cavity, which determines the substrate specificity. Mutation analyses based on this structural information indicated that a highly conserved Glu-141 acts as a catalytic acid, and that Asp 226 located at the roof of the tunnel activates a water molecule as a catalytic base. The unique arrangement of the catalytic residues makes a clear contrast to the other GH23 members and also to inverting GH19 chitinases. PMID- 23658015 TI - Insights into beta-lactamases from Burkholderia species, two phylogenetically related yet distinct resistance determinants. AB - Burkholderia cepacia complex and Burkholderia pseudomallei are opportunistic human pathogens. Resistance to beta-lactams among Burkholderia spp. is attributable to expression of beta-lactamases (e.g. PenA in B. cepacia complex and PenI in B. pseudomallei). Phylogenetic comparisons reveal that PenA and PenI are highly related. However, the analyses presented here reveal that PenA is an inhibitor-resistant carbapenemase, most similar to KPC-2 (the most clinically significant serine carbapenemase), whereas PenI is an extended spectrum beta lactamase. PenA hydrolyzes beta-lactams with k(cat) values ranging from 0.38 +/- 0.04 to 460 +/- 46 s(-1) and possesses high k(cat)/k(inact) values of 2000, 1500, and 75 for beta-lactamase inhibitors. PenI demonstrates the highest kcat value for cefotaxime of 9.0 +/- 0.9 s(-1). Crystal structure determination of PenA and PenI reveals important differences that aid in understanding their contrasting phenotypes. Changes in the positioning of conserved catalytic residues (e.g. Lys 73, Ser-130, and Tyr-105) as well as altered anchoring and decreased occupancy of the deacylation water explain the lower k(cat) values of PenI. The crystal structure of PenA with imipenem docked into the active site suggests why this carbapenem is hydrolyzed and the important role of Arg-220, which was functionally confirmed by mutagenesis and biochemical characterization. Conversely, the conformation of Tyr-105 hindered docking of imipenem into the active site of PenI. The structural and biochemical analyses of PenA and PenI provide key insights into the hydrolytic mechanisms of beta-lactamases, which can lead to the rational design of novel agents against these pathogens. PMID- 23658016 TI - High density lipoprotein protects against polymicrobe-induced sepsis in mice. AB - HDL has been considered to be a protective factor in sepsis; however, most contributing studies were conducted using the endotoxic animal model, and evidence from clinically relevant septic animal models remains limited and controversial. Furthermore, little is known about the roles of HDL in sepsis other than LPS neutralization. In this study, we employed cecal ligation and puncture (CLP), a clinically relevant septic animal model, and utilized apoA-I knock-out (KO) and transgenic mice to elucidate the roles of HDL in sepsis. ApoA I-KO mice were more susceptible to CLP-induced septic death as shown by the 47.1% survival of apoA-I-KO mice versus the 76.7% survival of C57BL/6J (B6) mice (p = 0.038). ApoA-I-KO mice had exacerbated inflammatory cytokine production during sepsis compared with B6 mice. Further study indicated that serum from apoA-I-KO mice displayed less capacity for LPS neutralization compared with serum from B6 mice. In addition, apoA-I-KO mice had less LPS clearance, reduced corticosterone generation, and impaired leukocyte recruitment in sepsis. In contrast to apoA-I KO mice, apoA-I transgenic mice were moderately resistant to CLP-induced septic death compared with B6 mice. In conclusion, our findings reveal multiple protective roles of HDL in CLP-induced sepsis. In addition to its well established role in neutralization of LPS, HDL exerts its protection against sepsis through promoting LPS clearance and modulating corticosterone production and leukocyte recruitment. Our study supports efforts to raise HDL levels as a therapeutic approach for sepsis. PMID- 23658017 TI - "Snapshots" of ispinesib-induced conformational changes in the mitotic kinesin Eg5. AB - Kinesins comprise a superfamily of molecular motors that drive a wide variety of cellular physiologies, from cytoplasmic transport to formation of the bipolar spindle in mitosis. These differing roles are reflected in corresponding polymorphisms in key kinesin structural elements. One of these is a unique loop and stem motif found in all kinesins and referred to as loop 5 (L5). This loop is longest in the mitotic kinesin Eg5 and is the target for a number of small molecule inhibitors, including ispinesib, which is being used in clinical trials in patients with cancer. In this study, we have used x-ray crystallography to identify a new structure of an Eg5-ispinesib complex and have combined this with transient state kinetics to identify a plausible sequence of conformational changes that occur in response to ispinesib binding. Our results demonstrate that ispinesib-induced structural changes in L5 from Eg5 lead to subsequent changes in the conformation of the switch II loop and helix and in the neck linker. We conclude that L5 in Eg5 simultaneously regulates the structure of both the ATP binding site and the motor's mechanical elements that generate force. PMID- 23658018 TI - Rate and regulation of copper transport by human copper transporter 1 (hCTR1). AB - Human copper transporter 1 (hCTR1) is a homotrimer of a 190-amino acid monomer having three transmembrane domains believed to form a pore for copper permeation through the plasma membrane. The hCTR1-mediated copper transport mechanism is not well understood, nor has any measurement been made of the rate at which copper ions are transported by hCTR1. In this study, we estimated the rate of copper transport by the hCTR1 trimer in cultured cells using (64)Cu uptake assays and quantification of plasma membrane hCTR1. For endogenous hCTR1, we estimated a turnover number of about 10 ions/trimer/s. When overexpressed in HEK293 cells, a second transmembrane domain mutant of hCTR1 (H139R) had a 3-fold higher Km value and a 4-fold higher turnover number than WT. Truncations of the intracellular C terminal tail and an AAA substitution of the putative metal-binding HCH C terminal tripeptide (thought to be required for transport) also exhibited elevated transport rates and Km values when compared with WT hCTR1. Unlike WT hCTR1, H139R and the C-terminal mutants did not undergo regulatory endocytosis in elevated copper. hCTR1 mutants combining methionine substitutions that block transport (M150L,M154L) on the extracellular side of the pore and the high transport H139R or AAA intracellular side mutations exhibited the blocked transport of M150L,M154L, confirming that Cu(+) first interacts with the methionines during permeation. Our results show that hCTR1 elements on the intracellular side of the hCTR1 pore, including the carboxyl tail, are not essential for permeation, but serve to regulate the rate of copper entry. PMID- 23658019 TI - Interleukin-17 (IL-17) and IL-1 activate translation of overlapping sets of mRNAs, including that of the negative regulator of inflammation, MCPIP1. AB - Changes in gene expression during inflammation are in part caused by post transcriptional mechanisms. A transcriptome-wide screen for changes in ribosome occupancy indicated that the inflammatory cytokine IL-17 activates translation of a group of mRNAs that overlaps partially with those affected similarly by IL-1. Included are mRNAs of IkappaBzeta and of MCPIP1, important regulators of the quality and course of immune and inflammatory responses. Evidence for increased ribosome association of these mRNAs was also obtained in LPS-activated RAW264.7 macrophages and human peripheral blood mononuclear cells. Like IL-1, IL-17 activated translation of IkappaBzeta mRNA by counteracting the function of a translational silencing element in its 3'-UTR defined previously. Translational silencing of MCPIP1 mRNA in unstimulated cells resulted from the combined suppressive activities of its 5'-UTR, which contains upstream open reading frames, and of its 3'-UTR, which silences independently of the 5'-UTR. Only the silencing function of the 3'-UTR was counteracted by IL-17 as well as by IL-1. Translational silencing by the 3'-UTR was dependent on a putative stem-loop forming region previously associated with rapid degradation of the mRNA. The results suggest that translational control exerted by IL-1 and IL-17 plays an important role in the coordination of an inflammatory reaction. PMID- 23658020 TI - On the origin of large flexibility of P-glycoprotein in the inward-facing state. AB - P-glycoprotein (Pgp) is one of the most biomedically relevant transporters in the ATP binding cassette (ABC) superfamily due to its involvement in developing multidrug resistance in cancer cells. Employing molecular dynamics simulations and double electron-electron resonance spectroscopy, we have investigated the structural dynamics of membrane-bound Pgp in the inward-facing state and found that Pgp adopts an unexpectedly wide range of conformations, highlighted by the degree of separation between the two nucleotide-binding domains (NBDs). The distance between the two NBDs in the equilibrium simulations covers a range of at least 20 A, including, both, more open and more closed NBD configurations than the crystal structure. The double electron-electron resonance measurements on spin-labeled Pgp mutants also show wide distributions covering both longer and shorter distances than those observed in the crystal structure. Based on structural and sequence analyses, we propose that the transmembrane domains of Pgp might be more flexible than other structurally known ABC exporters. The structural flexibility of Pgp demonstrated here is not only in close agreement with, but also helps rationalize, the reported high NBD fluctuations in several ABC exporters and possibly represents a fundamental difference in the transport mechanism between ABC exporters and ABC importers. In addition, during the simulations we have captured partial entrance of a lipid molecule from the bilayer into the lumen of Pgp, reaching the putative drug binding site. The location of the protruding lipid suggests a putative pathway for direct drug recruitment from the membrane. PMID- 23658021 TI - The yeast ATP-binding cassette (ABC) transporter Ycf1p enhances the recruitment of the soluble SNARE Vam7p to vacuoles for efficient membrane fusion. AB - The Saccharomyces cerevisiae vacuole contains five ATP-binding cassette class C (ABCC) transporters, including Ycf1p, a family member that was originally characterized as a Cd(2+) transporter. Ycf1p has also been found to physically interact with a wide array of proteins, including factors that regulate vacuole homeostasis. In this study, we examined the role of Ycf1p and other ABCC transporters in the regulation of vacuole homotypic fusion. We found that deletion of YCF1 attenuated in vitro vacuole fusion by up to 40% relative to wild type vacuoles. Plasmid-expressed wild-type Ycf1p rescued the deletion phenotype; however, Ycf1p containing a mutation of the conserved Lys-669 to Met in the Walker A box of the first nucleotide-binding domain (Ycf1p(K669M)) was unable to complement the fusion defect of ycf1Delta vacuoles. This indicates that the ATPase activity of Ycf1p is required for its function in regulating fusion. In addition, we found that deleting YCF1 caused a striking decrease in vacuolar levels of the soluble SNARE Vam7p, whereas total cellular levels were not altered. The attenuated fusion of ycf1Delta vacuoles was rescued by the addition of recombinant Vam7p to in vitro experiments. Thus, Ycf1p contributes in the recruitment of Vam7p to the vacuole for efficient membrane fusion. PMID- 23658022 TI - A new class of endoplasmic reticulum export signal PhiXPhiXPhi for transmembrane proteins and its selective interaction with Sec24C. AB - Protein export from the endoplasmic reticulum (ER) depends on the interaction between a signal motif on the cargo and a cargo recognition site on the coatomer protein complex II. A hydrophobic sequence in the N terminus of the bovine anion exchanger 1 (AE1) anion exchanger facilitated the ER export of human AE1Delta11, an ER-retained AE1 mutant, through interaction with a specific Sec24 isoform. The cell surface expression and N-glycan processing of various substitution mutants or chimeras of human and bovine AE1 proteins and their Delta11 mutants in HEK293 cells were examined. The N-terminal sequence (V/L/F)X(I/L)X(M/L), (26)VSIPM(30) in bovine AE1, which is comparable with PhiXPhiXPhi, acted as the ER export signal for AE1 and AE1Delta11 (Phi is a hydrophobic amino acid, and X is any amino acid). The AE1-Ly49E chimeric protein possessing the PhiXPhiXPhi motif exhibited effective cell surface expression and N-glycan maturation via the coatomer protein complex II pathway, whereas a chimera lacking this motif was retained in the ER. A synthetic polypeptide containing the N terminus of bovine AE1 bound the Sec23A-Sec24C complex through a selective interaction with Sec24C. Co-transfection of Sec24C-AAA, in which the residues (895)LIL(897) (the binding site for another ER export signal motif IXM on Sec24C and Sec24D) were mutated to (895)AAA(897), specifically increased ER retention of the AE1-Ly49E chimera. These findings demonstrate that the PhiXPhiXPhi sequence functions as a novel signal motif for the ER export of cargo proteins through an exclusive interaction with Sec24C. PMID- 23658025 TI - Mass production of spores of lactic acid-producing Rhizopus oryzae NBRC 5384 on agar plate. AB - Mass production of sporangiospores (spores) of Rhizopus oryzae NBRC 5384 (identical to NRRL 395 and ATCC 9363) on potato-dextrose-agar medium was studied aiming at starting its L(+)-lactic acid fermentation directly from spore inoculation. Various parameters including harvest time, sowed spore density, size of agar plate, height of air space, and incubation mode of plate (agar-on-bottom or agar-on-top) were studied. Ordinarily used shallow Petri dishes were found out to be unsuitable for the full growth of R. oryzae sporangiophores. In a very wide range of the sowed spore density, the smaller it was, the greater the number of the harvested spores was. It was also interesting to find out that R. oryzae grown downward vertically with a deep air space in an agar-on-top mode gave larger amount of spores than in an agar-on-bottom mode at 30 degrees C for 7-day cultivation. Scale-up of the agar plate culture from 26.4 to 292 cm(2) was studied, resulting in the proportional relationship between the number of the harvested spores/plate and the plate area in the deep Petri dishes. The number of plates of 50 cm in diameter needed for 100 m(3) industrial submerged fermentation started directly from 2 * 10(5) spores/mL inoculum size was estimated as about 6, from which it was inferred that such a fermentation would be feasible. Designing a 50 cm plate and a method of spreading and collecting the spores were suggested. Bioprocess technological significance of the "full-scale industrial submerged fermentation started directly from spore inoculation omitting pre-culture" has been discussed. PMID- 23658023 TI - Comparative proteomic analysis of supportive and unsupportive extracellular matrix substrates for human embryonic stem cell maintenance. AB - Human embryonic stem cells (hESCs) are pluripotent cells that have indefinite replicative potential and the ability to differentiate into derivatives of all three germ layers. hESCs are conventionally grown on mitotically inactivated mouse embryonic fibroblasts (MEFs) or feeder cells of human origin. In addition, feeder-free culture systems can be used to support hESCs, in which the adhesive substrate plays a key role in the regulation of stem cell self-renewal or differentiation. Extracellular matrix (ECM) components define the microenvironment of the niche for many types of stem cells, but their role in the maintenance of hESCs remains poorly understood. We used a proteomic approach to characterize in detail the composition and interaction networks of ECMs that support the growth of self-renewing hESCs. Whereas many ECM components were produced by supportive and unsupportive MEF and human placental stromal fibroblast feeder cells, some proteins were only expressed in supportive ECM, suggestive of a role in the maintenance of pluripotency. We show that identified candidate molecules can support attachment and self-renewal of hESCs alone (fibrillin-1) or in combination with fibronectin (perlecan, fibulin-2), in the absence of feeder cells. Together, these data highlight the importance of specific ECM interactions in the regulation of hESC phenotype and provide a resource for future studies of hESC self-renewal. PMID- 23658024 TI - Mutations in the paxillin-binding site of integrin-linked kinase (ILK) destabilize the pseudokinase domain and cause embryonic lethality in mice. AB - Integrin-linked kinase (ILK) localizes to focal adhesions (FAs) where it regulates cell spreading, migration, and growth factor receptor signaling. Previous reports showed that overexpressed ILK in which Val(386) and Thr(387) were substituted with glycine residues (ILK-VT/GG) could neither interact with paxillin nor localize to FA in cells expressing endogenous wild-type ILK, implying that paxillin binding to ILK is required for its localization to FAs. Here, we show that introducing this mutation into the germ line of mice (ILK VT/GG) caused vasculogenesis defects, resulting in a general developmental delay and death at around embryonic day 12.5. Fibroblasts isolated from ILK-VT/GG mice contained mutant ILK in FAs, showed normal adhesion to and spreading on extracellular matrix substrates but displayed impaired migration. Biochemical analysis revealed that VT/GG substitutions decreased ILK protein stability leading to decreased ILK levels and reduced binding to paxillin and alpha-parvin. Because paxillin depletion did not affect ILK localization to FAs, the embryonic lethality and the in vitro migration defects are likely due to the reduced levels of ILK-VT/GG and diminished binding to parvins. PMID- 23658026 TI - Fermentative and growth performances of Dekkera bruxellensis in different batch systems and the effect of initial low cell counts in co-cultures with Saccharomyces cerevisiae. AB - Dekkera bruxellensis is a multifaceted yeast present in the fermentative processes used for alcoholic beverage and fuel alcohol production - in the latter, normally regarded as a contaminant. We evaluated the fermentation and growth performance of a strain isolated from water in an alcohol-producing unit, in batch systems with/without cell recycling in pure and co-cultures with Saccharomyces cerevisiae. The ethanol resistance and aeration dependence for ethanol/acid production were verified. Ethanol had an effect on the growth of D. bruxellensis in that it lowered or inhibited growth depending on the concentration. Acid production was verified in agitated cultures either with glucose or sucrose, but more ethanol was produced with glucose in agitated cultures. Regardless of the batch system, low sugar consumption and alcohol production and expressive growth were found with D. bruxellensis. Despite a similar ethanol yield compared to S. cerevisiae in the batch system without cell recycling, ethanol productivity was approximately four times lower. However, with cell recycling, ethanol yield was almost half that of S. cerevisiae. At initial low cell counts of D. bruxellensis (10 and 1000 cells/ml) in co-cultures with S. cerevisiae, a decrease in fermentative efficiency and a substantial growth throughout the fermentative cycles were displayed by D. bruxellensis. Due to the peculiarity of cell repitching in Brazilian fermentation processes, D. bruxellensis is able to establish itself in the process, even when present in low numbers initially, substantially impairing bioethanol production due to the low ethanol productivity, in spite of comparable ethanol yields. PMID- 23658028 TI - How to record uterine artery Doppler in the first trimester. PMID- 23658027 TI - Perturbations of RNA helicases in cancer. AB - Helicases are implicated in most stages of the gene expression pathway, ranging from DNA replication, RNA transcription, splicing, RNA transport, ribosome biogenesis, mRNA translation, RNA storage and decay. These enzymes utilize energy derived from nucleotide triphosphate hydrolysis to remodel ribonucleoprotein complexes, RNA, or DNA and in this manner affect the information content or output of RNA. Several RNA helicases have been implicated in the oncogenic process--either through altered expression levels, mutations, or due to their role in pathways required for tumor initiation, progression, maintenance, or chemosensitivity. The purpose of this review is to highlight those RNA helicases for which there is significant evidence implicating them in cancer biology. PMID- 23658029 TI - Inhibition of crystal nucleation and growth by water-soluble polymers and its impact on the supersaturation profiles of amorphous drugs. AB - The impact of water-soluble polymers on drug supersaturation behavior was investigated to elucidate the role of water-soluble polymers in enhancing the supersaturation levels of amorphous pharmaceuticals. Hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and Eudragit L-100 (Eudragit) were used as representative polymers, and griseofulvin and danazol were used as model drugs. Supersaturation profiles of amorphous drugs were measured in biorelevant dissolution tests. Crystal growth rate was measured from the decrease in dissolved drug concentration in the presence of seed crystals. Nucleation kinetics was evaluated by measuring the induction time for nucleation. All experiments were performed in the presence and absence of polymers. The degree of supersaturation of the amorphous model drugs increased with an increase in the inhibitory efficiency of polymers against crystal nucleation and growth (HPMC > PVP > Eudragit). In the presence of HPMC, the addition of seed crystals diminished the supersaturation ratio dramatically for griseofulvin and moderately for danazol. The results demonstrated that the polymers contributed to drug supersaturation by inhibiting both nucleation and growth. The effect of the polymers was drug dependent. The detailed characterization of polymers would allow selection of appropriate crystallization inhibitors and a planned quality control strategy for the development of supersaturable formulations. PMID- 23658030 TI - Cross-language influences: translation status affects intraword sense relatedness. AB - Many words have more than one meaning, and these meanings vary in their degree of relatedness. In the present experiment, we examined whether this degree of relatedness is influenced by whether or not the two meanings share a translation in a bilingual's other language. Native English speakers with Spanish as a second language (i.e., English-Spanish bilinguals) and native Spanish speakers with English as a second language (i.e., Spanish-English bilinguals) were presented with pairs of phrases instantiating different senses of ambiguous English words (e.g., dinner date-expiration date) and were asked to decide whether the two senses were related in meaning. Critically, for some pairs of phrases, a single Spanish translation encompassed both meanings of the ambiguous word (joint translation condition; e.g., mercado in Spanish refers to both a flea market and the housing market), but for others, each sense corresponded to a different Spanish translation (split-translation condition; e.g., cita in Spanish refers to a dinner date, but fecha refers to an expiration date). The proportions of "yes" (related) responses revealed that, relative to monolingual English speakers, Spanish-English bilinguals consider joint-translation senses to be less related than split-translation senses. These findings exemplify semantic cross-language influences from a first to a second language and reveal the semantic structure of the bilingual lexicon. PMID- 23658031 TI - [Healthcare management of an epilepsy clinic: factors involved in the demand for health care and clinical situation of patients]. AB - INTRODUCTION: Epilepsy is a chronic illness that requires a long-term periodic follow-up of the patient and this means that as time goes by the number of patients attended increases, with the ensuing added cost for the healthcare system. AIM: To determine the factors involved in the time until an epileptic patient's next visit. PATIENTS AND METHODS: Our sample consisted of a selection of patients who visited the epilepsy clinic at our hospital consecutively during one year. Their clinical situation and relationship with the medical advice they were given, together with the factors involved in the time elapsed until the next visit, were analysed by means of predictive econometric models. RESULTS: There is a clear association between the patient's clinical situation and the modification of the treatment proposed by the neurologist in the previous visit. The factors involved in the time until the next visit were the frequency of seizures, adverse side effects from medicines -above all those that affect cognition- and the medical advice given to the patient. Polytherapy, psychoaffective disorders or the patient's social situation were not found to be significant. CONCLUSIONS: Follow-up visits in a specific epilepsy clinic improves the patient's situation. This is the first analysis of the demand for healthcare in patients with epilepsy conducted by means of econometric methods and from a mixed physician-patient perspective. Since the factors that determine the time until the next visit can be modified, the number of visits per year could be reduced, thus improving patients' clinical situation. We suggest a greater amount of time should be spent per visit so as to be able to have a bearing on it and thereby cut costs in the long term. PMID- 23658032 TI - [Description of the follow-up protocol for idiopathic intracranial hypertension in the neuro-ophthalmological unit of a tertiary hospital]. AB - AIM: To review the results of implementing a protocol for following up patients with idiopathic intracranial hypertension (IICH) in a neuro-ophthalmological unit (NOU). PATIENTS AND METHODS: A review of the literature was conducted in order to determine the examinations that needed to be included in the follow-up protocol, as well as the optimum frequency of visits and the most adequate duration of the follow-up. Later, a prospective review was performed of the patients that have been included since the NOU was set up and they were compared with the patients included in the IICH register prior to the creation of the NOU. RESULTS: Since the protocol was implemented, visual acuity and the visual field have been evaluated in 100% of patients at three months, at six months and at one year after diagnosis. Moreover, the visual field was examined at three months, at six months and at one year after diagnosis in 91%, 72.8% and 100% of patients with IICH, respectively. Before our follow-up protocol was implemented, 190 had been carried out, which is roughly three per patient. Eleven lumbar punctures have been performed since the NOU was set up. CONCLUSIONS: The creation of a multidisciplinary NOU makes it possible to optimise resources and improve the care given to patients with IICH. This should result in an improvement in the functional prognosis of these patients. PMID- 23658033 TI - [Is necessary to perform a transthoracic echocardiogram in all the patients with cryptogenic stroke during hospitalization?]. AB - INTRODUCTION: From 15 to 30% of all ischemic strokes are cardioembolic. Transthoracic echocardiography plays a key role in the evaluation, diagnosis and management of the embolic source. The absence of official recommendations for the use of echocardiography in patients with ischemic stroke leads to a universal application showing low diagnostic efficiency. AIM: To analyze the diagnostic accuracy of echocardiograpm in patients with ischemic stroke in two situations: with universal indication and after the application of risk clinical criteria. PATIENTS AND METHODS: Analysis of the echocardiograms performed on patients with acute ischemic stroke from the stroke unit during the years 2009-2011. We study the diagnostic and etiological contribution to the etiological study. Apply a selection criteria: 'high risk patient with need of test performance during admission' (age < 60 years, abnormal baseline electrocardiogram, cardiomegaly on chest radiograph or baseline history of heart disease, suspected endocarditis and/or active neoplasia) and analyzed their validity. RESULTS: From 930 inpatients, 201 (21.6%), underwent echocardiogram. Cardioembolic source was detected in 9.95%. After application of selection criteria, only 97 patients (10.4%) should have undergone it. The proposed criteria have a sensitivity 95%, specificity 56.9%, positive predictive value 19.6% and negative predictive value of 99%. CONCLUSIONS: The application of our criteria in undetermined stroke patients help us to identify with high efficiency cardioembolic sources postponing the test to an ambulatory scenario in the rest of the patients. PMID- 23658034 TI - [Chorea due to TITF1/NKX2-1 mutation: phenotypical description and therapeutic response in a family]. AB - INTRODUCTION: Chorea due to a mutation in the TITF1 gene, which is also known as benign hereditary chorea, is an autosomal dominant disorder that usually begins before the age of 5 years. In most cases, the chorea tends to improve as the child gets older. It may be associated to hypothyroidism and respiratory problems, such as neonatal alveolar respiratory distress syndrome or interstitial disease, since TITF1 is a transcription factor that is essential for the development of the brain, thyroid gland and lung. CASE REPORTS: We report on the clinical phenotype of a family with chorea, in which two sisters presented congenital hypothyroidism and one of them also had alveolar respiratory distress syndrome. A mutation was detected in TITF1 (c.825delC) in both of them and clinical improvement was observed in the response to treatment with low doses of levodopa-carbidopa. CONCLUSIONS: Chorea due to mutation of TITF1 is an underdiagnosed cause of chorea in children. Since it is possible to conduct a genetic diagnosis, we believe that performing it is always indicated in dominant familial cases, bearing in mind the variable penetrance, as well as in patients who present concomitant involvement of the lungs or hypothyroidism. Occasionally, it may be recommendable in cases of chorea with an unknown causation, which will enable us to avoid other tests, give a non-degenerative prognosis, offer genetic counselling and carry out more guided and effective therapeutic trials. For the time being, levodopa seems to be the preferred symptomatic treatment. PMID- 23658035 TI - [Pathogenesis of spinal cord injuries and mechanisms of repair induced by olfactory ensheathing cells]. AB - INTRODUCTION: Spinal cord injury is a catastrophic event with permanent consequences during the all life. Treatment research has been based in the development of therapies that reduce the discapacity, but since the nineties there has been an important advance and several cellular transplants have been tested in spinal cord animal models, like Schwann cells, astrocytes and olfactory and olfactory ensheathing cells (OEC). AIM: Detailed account of spinal cord injury pathogeny, primary and secondary, and the OEC mechanisms for the regeneration effects that have been described in the literature. DEVELOPMENT: After the trauma, spinal cord injury develops in two phases, the primary injury with characteristics compression lesions, and the secondary produce for several factors that occur in parallel and include: vascular, cellular and molecular factors, and glial scar formation. The most of spinal cord models and OEC transplants have been reported functional recovery, remielinization and axonal regeneration. These cells exert their action in a direct way by producing grow factors and in an indirect way inducing directly neuronal an axonal regeneration and remielinization. CONCLUSIONS: OEC are a therapeutic option in patients with spinal cord injury, because they induce in a direct or indirect way, neuronal and axonal regeneration, remielinization, decrease the glial scar and produce other effects that conduce a functional recovery. PMID- 23658037 TI - [Cerebritis and cerebral abscess due to Streptococcus pneumoniae in a newborn]. PMID- 23658038 TI - [Nikola Tesla: flashes of inspiration]. PMID- 23658039 TI - Highly efficient blue-emitting cyclometalated platinum(II) complexes by judicious molecular design. PMID- 23658040 TI - X-ray-verified fractures are associated with finite element analysis-derived bone strength and trabecular microstructure in young adult men. AB - It has been suggested that fracture during childhood could be a predictor of low peak bone mass and thereby a potential risk factor for osteoporosis and fragility fractures later in life. The aim of this cross-sectional, population-based study was to investigate whether prevalent fractures, occurring from birth to young adulthood, were related to high-resolution peripheral quantitative computed tomography (HR-pQCT)-derived trabecular and cortical microstructure, as well as bone strength estimated by finite element (FEA) analysis of the radius and tibia in 833 young adult men around the time of peak bone mass (ages 23 to 25 years). In total, 292 subjects with prevalent X-ray-verified fractures were found. Men with prevalent fractures had lower trabecular bone volume fraction (BV/TV) at the radius (5.5%, p < 0.001) and tibia (3.7%, p < 0.001), as well as lower cortical thickness (5.1%, p < 0.01) and cortical cross-sectional area (4.1%, p < 0.01) at the tibia. No significant differences were seen for the cortical porosity or mean pore diameter. Using a logistic regression model (including age, smoking, physical activity, calcium intake, height, and weight as covariates), every SD decrease of FEA-estimated failure load was associated with an increased prevalence of fractures at both the radius (odds ratio [OR] 1.22 [1.03-1.45]) and tibia (OR 1.32 [1.11-1.56]). Including dual-energy X-ray absorptiometry (DXA) derived radius areal bone mineral density (aBMD), cortical thickness, and trabecular BV/TV simultaneously in a logistic regression model (with age, smoking, physical activity, calcium intake, height, and weight as covariates), BV/TV was inversely and independently associated with prevalent fractures (OR 1.28 [1.04-1.59]), whereas aBMD and cortical thickness were not (OR 1.19 [0.92 1.55] and OR 0.91 [0.73-1.12], respectively). In conclusion, prevalent fractures in young adult men were associated with impaired trabecular BV/TV at the radius, independently of aBMD and cortical thickness, indicating that primarily trabecular bone deficits are of greatest importance for prevalent fracture in this population. PMID- 23658041 TI - Bone graft substitutes for anterior lumbar interbody fusion. AB - The procedure of anterior lumbar interbody fusion (ALIF) is commonly performed on patients suffering from pain and/or neurological symptoms associated with disorders of the lumbar spine caused by disc degeneration and trauma. Surgery is indicated when prolonged conservative management proves ineffective. Because an important objective of the ALIF procedure is solid arthrodesis of the degenerative spinal segment, bone graft selection is critical. Iliac crest bone grafts (ICBG) remain the "gold standard" for achieving lumbar fusion. However, patient dissatisfaction stemming from donor site morbidity, lengthier operating times and finite supply of ICBG has prompted a search for better alternatives. Here presented is a literature review evaluating available bone graft options assessed within the clinical setting. These options include autografts, allograft based, synthetic and cell-based technologies. The emphasis is on the contentious use of recombinant human bone morphogenetic proteins, which is in widespread use and has demonstrated both significant osteogenic potential and risk of complications. PMID- 23658042 TI - Charcot neuroarthropathy of the foot and ankle. AB - Charcot neuroarthropathy (CN) is a rare, progressive, deforming disease of bone and joints, especially affecting the foot and ankle and leading to considerable morbidity. It can also affect other joints such as the wrist, knee, spine and shoulder. This disease, described originally in reference to syphilis, is now one of the most common associates of diabetes mellitus. As the number of diabetics increase, the incidence of CN is bound to rise. Faster initial diagnosis and prompt institution of treatment may help to reduce its sequelae. There should be a low threshold for ordering investigations to assist coming to this diagnosis. No single investigation is the gold standard. Recent studies on pathogenesis and development of newer investigation modalities have helped to clarify the mystery of its pathogenesis and of its diagnosis in the acute phase. Various complementary investigations together allow the correct diagnosis to be made. Osteomyelitis continues to be confused with acute CN. Hybrid positron emission tomography has shown some promise in differentiating these conditions. A multispecialty approach involving diabetologists, orthopaedists and podiatrists should be used to tackle this difficult problem. The aim of this article is to describe current knowledge about CN with particular reference to the status of diagnostic indicators and management options. PMID- 23658043 TI - Does C1 fracture displacement correlate with transverse ligament integrity? AB - OBJECTIVE: The Rule of Spence states that displacement of the C1 lateral masses by >6.9-8.1 mm suggests loss of transverse ligament integrity. The purpose of this study was to establish the thresholds of C1 displacement on CT scans that correspond to transverse ligament disruption. METHODS: Over four years, consecutive patients with acute C1 fractures with at least three fracture lines were analyzed. CT measurements and MRI were assessed by blinded observers for bony displacement in the axial (internal and external lateral mass separation), coronal and sagittal planes and transverse ligament integrity. RESULTS: Eighteen patients were studied. Mean CT bony measurements were as follows: internal border lateral mass separation (ILM) 23.3 +/- 3.4 mm, external border lateral mass separation (ELM) 50.3 +/- 4.3 mm, total C1 lateral mass overhang over the C2 superior process (LMO) 5.4 +/- 1.3 mm. Twelve patients were identified as having intact transverse ligament and six had transverse ligament disruption. There was no difference in mean normalized ILM, ELM, or LMO between patients with or without transverse ligament integrity (P > 0.05). CONCLUSION: There was no correlation between bony displacement and transverse ligament integrity. CT scans post-injury may not show the position of maximal displacement. If there is clinical concern about a possible transverse ligament injury, MRI should be performed. PMID- 23658044 TI - Traumatic vertebral fractures with concomitant fractures of the first rib. AB - OBJECTIVE: To investigate the characteristics of patients with traumatic vertebral fractures and concomitant fractures of the first rib and their management. METHODS: From January 2001 to December 2010, 17/3142 patients (0.5%) with traumatic vertebral fractures who presented to our hospitals had concomitant fractures of the first rib. RESULTS: The study included 14 men (82.4%) and 3 women (17.6%) patients of age 32-57 years (mean, 46.6 years). The mechanisms of trauma were falls from heights in seven, motor vehicle accidents in five and direct collisions with blunt objects in five. Thirteen patients (76.5%) presented initially with pulmonary complications after sustaining trauma. Three patients sustained one rib fracture, two three rib fractures, three four rib fractures and 10 > five rib fractures. The injuries were right-sided in three cases, left sided in three and bilateral in eleven. Four patients (23.5%) presented with craniocerebral injuries. According to the American Spinal Injury Association (ASIA) classification, 10 patients (58.8% of the total study group) had motor and sensory deficits (ASIA A-D). There were no vascular injuries or deaths. CONCLUSION: Traumatic vertebral fractures with concomitant fractures of the first rib are associated with multisystem injuries, but not always with morbidity and mortality. A multidisciplinary approach, early diagnosis, appropriate treatment and observation in the intensive care unit may prevent morbidity and/or mortality. PMID- 23658045 TI - Single vertebra tuberculosis presenting with solitary localized osteolytic lesion in young adult lumbar spines. AB - OBJECTIVE: To describe the clinical and imaging findings in young adults with single vertebra tuberculosis presenting with solitary osteolytic lesions. METHODS: Six patients with proven tuberculosis of a single vertebra of the lumbar spine presenting with solitary osteolytic lesion were retrospectively evaluated. There were four male and two female patients with a mean age of 27.6 years (range, 22-38 years). The clinical and imaging features (plain radiographs, CT and MRI) were studied in all six patients. RESULTS: Involvement occurred from L1 to L5 vertebral levels. The patients presented with local back pain and tenderness but without any obvious deformity of spine or cold abscess. In each case, imaging demonstrated a well-defined, solitary, lytic lesion of average diameter 1.6 cm with thin sclerotic margins within a vertebral body. There were no fragments within the lesions and no paravertebral soft tissue extension around the affected vertebral bodies. The tuberculous eitology was confirmed by CT guided biopsy in two patients and by curettage of the lesion in four. CONCLUSION: Tuberculosis affecting a single vertebral body presenting with a localized solitary osteolytic lesion is an unusual form of single vertebra tuberculosis. MRI combined with CT scan of the vertebral body can be very helpful for precisely defining the location of the lesion and extent of osseous destruction. Such small, solitary, osteolytic lesions are often confused with other single vertebra diseases that can have similar appearances on imaging. PMID- 23658046 TI - Comparison of functional performance after total knee arthroplasty using rotating platform and fixed-bearing prostheses with or without patellar resurfacing. AB - OBJECTIVE: To retrospectively compare the functional performances of rotating platform and fixed-bearing total knee arthroplasties with or without patellar resurfacing. METHODS: One hundred and ninety-seven patients (205 knees) of mean age 66.4 years were randomly assigned to receive different prostheses. One hundred ninety-five patients, including 97 fixed-bearing prostheses with 37 patellae resurfaced and 106 rotating platform prostheses with 76 patellae resurfaced, were followed up for a mean duration of 32 months. RESULTS: Outcomes in the rotating platform with patellar resurfacing and fixed-bearing with patellar resurfacing groups did not differ significantly according to Hospital for Special Surgery (HSS) scores and flexion and extension angles. For total knee arthroplasties without patellar resurfacing, there were no significant differences in HSS score and flexion angle between the rotating platform and fixed-bearing subgroups. Although the extension angle of rotating platform prostheses was slightly better than that of the fixed-bearing in the patellar non resurfacing group, this difference was not clinically significant. CONCLUSIONS: Rotating platform and fixed-bearing prostheses have similar overall postoperative outcomes with regard to postoperative HSS scores and extension and flexion angles. Rotating platform prostheses are not superior to fixed bearing prostheses. PMID- 23658047 TI - Distal femoral fractures in post-poliomyelitis patients treated with locking compression plates. AB - OBJECTIVE: Treatment of distal femoral fracture in post-polio patients is difficult because the bone is usually osteopenic, small and deformed. This retrospective study aimed to investigate the outcomes of distal femoral fracture in post-polio patients treated by locking compression plates (LCP). METHODS: The medical records of 19 post-polio patients (mean age 49 years at time of surgery) were reviewed and intraoperative data retrieved. Fracture union and callus formation were evaluated on radiographs taken at each postoperative visit. Functional outcome assessments included range of motion and Hospital for Special Surgery (HSS) score of the ipsilateral knee joint. RESULTS: Sixteen femoral fractures occurred in the poliomyelitis-affected limbs. The mean duration of operation was 86 min and mean blood loss 120 mL. All fractures healed (mean, four months) but union was delayed in one. At the final follow-up 2 yrs after surgery, the mean range of knee flexion was 105 degrees (range, 90 degrees -130 degrees ), and mean HSS score 76 points (range, 60-93). There were no cases of nonunion, implant cutout, or other complications. CONCLUSIONS: LCP provides stable fixation of distal femoral fractures in post-polio patients. Bony union and good functional outcomes are achieved, but delayed union and minimal callus may occur. PMID- 23658048 TI - Surgical treatment of basicervical intertrochanteric fractures of the proximal femur with cephalomeduallary hip nails. AB - OBJECTIVE: To study the outcome of basicervical intertrochanteric fractures of the proximal femur treated with cephalomeduallary hip nails. METHODS: The clinical outcomes of 32 cases of basicervical intertrochanteric fractures treated with cephalomeduallary hip nails from January 2008 to June 2010 were retrospectively reviewed and the progress of fracture healing and occurrence of complications recorded. The function of the hip joints was evaluated by the Harris social index 2 years postoperatively. RESULTS: Thirty patients were followed up until fracture union for at least 24 months. Twenty-seven fractures had healed with no loss of position by 12 months postoperatively; the remaining three had mild varus deformity of the hip joint. No patient had evidence of avascular necrosis of the femoral head. No cut out of the helical blade was visible on radiographs. The mean Harris score was 86.5 (75-96) two years postoperatively, 11 patients having excellent scores, 15 good and 4 fair. CONCLUSION: Closed reduction and proximal femur intramedullary nail fixation for basicervical intertrochanteric fractures provides stable fixation and allows early exercise. It appears to have excellent outcomes in the short and medium term. PMID- 23658049 TI - Digital three-dimensional model of lumbar region 4-5 and its adjacent structures based on a virtual Chinese human. AB - OBJECTIVE: To study the methods for constructing a digitized three-dimensional (3D) model of a virtual lumbar region and its adjacent structures in order to assist anatomical study and virtual surgery. METHODS: Images of DSCF5375-p1 to DSCF5745-p1 were taken from the database of the digitized Virtual Chinese human of Southern Medical University in Guangzhou. This region encompasses the superior facet joint of L4 to the inferior edge of the intervertebral body of L5. The regions of interest were interactively segmented from the images utilizing Adobe Photoshop software. The images were further processed using format conversion and segmentation. Finally, a 3D model of the L4-5 region and its neighboring structures was reconstructed with the assistance of Mimics 10.01 software. RESULTS: A digitized 3D model of this part of the virtual lumbar spine and its adjacent structures was reconstructed. This model allows all constructed structures to be displayed individually or jointly, moved or rotated arbitrarily, setting of different transparencies and convenient measurement of the diameters and angles of the reconstructed structures. The 3D model precisely displays the anatomical relationships between all structures and provides a reliable 3D model for a spinal endoscopic surgery simulation system. CONCLUSION: Visualization of the digitized 3D reconstruction of the virtual lower lumbar region displays this region and its adjacent structures stereoscopically and in actuality, thus providing morphological data concerning anatomy, image diagnosis and virtual operations in this region. PMID- 23658050 TI - Hybrid technique for posterior lumbar interbody fusion: a combination of open decompression and percutaneous pedicle screw fixation. AB - The authors describe a hybrid technique that involves a combination of open decompression and posterior lumbar interbody fusion (PLIF) and percutaneously inserted pedicle screws. This technique allows performance of PLIF and decompression via a midline incision and approach without compromising operative time and visualization. Furthermore, compared to standard open decompression, this approach reduces post-operative wound pain because the small midline incision significantly reduces muscle trauma by obviating the need to dissect the paraspinal muscles off the facet joint complex and by avoiding posterolateral fusion, thus requiring limited lateral muscle dissection off the transverse processes. A series of patients with Grade I-II spondylolisthesis at L4-5 and moderate-severe canal/foraminal stenosis underwent midline PLIF at L4-5, with closure of the midline incision. Percutaneous pedicle screws were inserted, thereby minimizing local muscle trauma, reduction of the spondylolisthesis being performed by using a pedicle screw construct. Rods were inserted percutaneously to link the L4 and L5 pedicle screws. Image intensification was used to confirmed satisfactory screw placement and reduction of spondylolisthesis. The results of a prospective study comparing a standard open decompression and fusion technique for spondylolisthesis versus the minimally invasive hybrid technique are discussed. The minimally invasive technique resulted in shorter hospital stay, earlier mobilization and reduced postoperative narcotic usage. The long-term clinical outcomes were equivalent in the two groups. PMID- 23658051 TI - Lipoma arborescens of the knee joint after anterior cruciate ligament injury. PMID- 23658052 TI - Vertebral bone primary angiosarcoma: a case report. PMID- 23658053 TI - Multiple heterotopic ossification of scar following degloving injury: a case report. PMID- 23658054 TI - Enhancing operational stability and exhibition of enzyme activity by removing water in the immobilized lipase-catalyzed production of erythorbyl laurate. AB - Erythorbyl laurate was continuously synthesized by esterification in a packed-bed enzyme reactor with immobilized lipase from Candida antarctica. Response surface methodology based on a five-level three-factor central composite design was adopted to optimize conditions for the enzymatic esterification. The reaction variables, such as reaction temperature (10-70 degrees C), substrate molar ratio ([lauric acid]/[erythorbic acid], 5-15), and residence time (8-40 min) were evaluated and their optimum conditions were found to be 56.2 degrees C, 14.3, and 24.2 min, respectively. Under the optimum conditions, the molar conversion yield was 83.4%, which was not significantly different (P < 0.05) from the value predicted (84.4%). Especially, continuous water removal by adsorption on an ion exchange resin in a packed-bed enzyme reactor improved operational stability, resulting in prolongation of half-life (2.02 times longer compared to the control without water-removal system). Furthermore, in the case of batch-type reactor, it exhibited significant increase in initial velocity of molar conversion from 1.58% to 2.04%/min. PMID- 23658055 TI - Diminished autophagy limits cardiac injury in mouse models of type 1 diabetes. AB - Cardiac autophagy is inhibited in type 1 diabetes. However, it remains unknown if the reduced autophagy contributes to the pathogenesis of diabetic cardiomyopathy. We addressed this question using mouse models with gain- and loss-of-autophagy. Autophagic flux was inhibited in diabetic hearts when measured at multiple time points after diabetes induction by streptozotocin as assessed by protein levels of microtubule-associated protein light chain 3 form 2 (LC3-II) or GFP-LC3 puncta in the absence and presence of the lysosome inhibitor bafilomycin A1. Autophagy in diabetic hearts was further reduced in beclin 1- or Atg16-deficient mice but was restored partially or completely by overexpression of beclin 1 to different levels. Surprisingly, diabetes-induced cardiac damage was substantially attenuated in beclin 1- and Atg16-deficient mice as shown by improved cardiac function as well as reduced levels of oxidative stress, interstitial fibrosis, and myocyte apoptosis. In contrast, diabetic cardiac damage was dose-dependently exacerbated by beclin 1 overexpression. The cardioprotective effects of autophagy deficiency were reproduced in OVE26 diabetic mice. These effects were associated with partially restored mitophagy and increased expression and mitochondrial localization of Rab9, an essential regulator of a non-canonical alternative autophagic pathway. Together, these findings demonstrate that the diminished autophagy is an adaptive response that limits cardiac dysfunction in type 1 diabetes, presumably through up-regulation of alternative autophagy and mitophagy. PMID- 23658057 TI - Passivation of high-surface-energy sites of milled ibuprofen crystals via dry coating for reduced cohesion and improved flowability. AB - Ibuprofen micronization with dry coating is investigated to examine its influence on passivation/stabilization of high-surface-energy sites and reduced cohesion. A fluid energy mill was used to micronize ibuprofen particles down to 5-28 MUm with or without simultaneous nanosilica coating. Powder flow property and dispersibility were characterized using FT4 powder tester and Rodos/Helos laser diffraction particle sizer. Surface energy was characterized using a next generation inverse gas chromatography instrument. Uncoated micronized ibuprofen showed an increased Lifshitz-van der Waals (LW) dispersion component of surface energy with increasing milling intensity. In contrast, dry-coated milled powders showed a significant reduction in the LW component, whereas physical mixture of uncoated micronized ibuprofen and silica exhibited no reduction in surface energy, indicating that dry coating is necessary for the passivation of high energy sites of ibuprofen created during micronization. Surface energy of pure micronized ibuprofen was highly heterogeneous, whereas dry-coated ibuprofen had greatly reduced heterogeneity. Micronization with dry coating also improved flowability and bulk density as compared with pure active pharmaceutical ingredient micronization without coating, or just blending with silica. Overall, dry coating leads to decreased cohesion and improved flowability because of reduced LW dispersive component of surface energy and creating nanoscale surface roughness. PMID- 23658058 TI - From molecular complexes to complex metallic nanostructures--2H solid-state NMR studies of ruthenium-containing hydrogenation catalysts. AB - In the last years, the combination of (2)H solid-state NMR techniques with quantum-chemical calculations has evolved into a powerful spectroscopic tool for the characterization of the state of hydrogen on the surfaces of heterogeneous catalysts. In the present minireview, a brief summary of this development is given, in which investigations of the structure and dynamics of hydrogen in molecular complexes, clusters and nanoparticle systems are presented, aimed to understand the reaction mechanisms on the surface of hydrogenation catalysts. The surface state of deuterium/hydrogen is analyzed employing a combination of variable-temperature (2)H static and magic-angle spinning (MAS) solid-state NMR techniques, in which the dominant quadrupolar interactions of deuterium give information on the binding situation and local symmetry of deuterium/hydrogen on molecular species. Using a correlation database from molecular complexes and clusters, the possibility to distinguish between terminal Ru-D, bridged Ru2-D, three-fold Ru3-D, and interstitial Ru6-D is demonstrated. Combining these results with quantum-chemical density functional theory (DFT) calculations allows the interpretation of (2)H solid-state data of complex "real world" nanostructures, which yielded new insights into reaction pathways at the molecular level. PMID- 23658056 TI - Expression and prognostic role of c-Myb as a novel cell cycle protein in esophageal squamous cell carcinoma. AB - PURPOSE: The c-Myb transcription factor controls differentiation and proliferation in hematopoietic and other cell types, and has latent in regulation during the cell cycle. Recent studies suggested that deregulation of c-Myb expression plays a key role in oncogenesis. To investigate the potential roles of c-Myb in esophageal carcinoma, expression of c-Myb was examined in human esophageal carcinoma samples. METHODS: Immunohistochemistry and Western blot analysis were performed for c-Myb in 87 esophageal carcinoma samples. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine their prognostic significance. RESULTS: c-Myb was overexpressed in esophageal carcinoma as compared with the adjacent normal tissue. High expression of c-Myb was associated with histological grade and was positively correlated with proliferation marker Ki-67 (P = 0.001). Univariate analysis showed that c-Myb expression was associated with poor prognosis (P < 0.001). Multivariate analysis indicated that c-Myb was an independent prognostic marker for esophageal carcinoma (P < 0.001). While in vitro, following release from serum starvation of TE-1 esophageal carcinoma cell, the expression of c-Myb was upregulated. CONCLUSIONS: Our results suggested that c-Myb overexpression is involved in the pathogenesis of esophageal carcinoma; it may be a favorable independent poor prognostic parameter for esophageal carcinoma. PMID- 23658059 TI - Catching ease influences perceived speed: evidence for action-specific effects from action-based measures. AB - According to the action-specific account of perception, people perceive the environment in terms of their ability to act. Here, we directly tested this claim by using an action-based measure of perceived speed: Participants attempted to catch a virtual fish by releasing a virtual net. The net varied in size, making the task easier or harder. We measured perceived speed by using explicit judgment based measures and an action-based measure (time to release the net). Participants released the net later when playing with the big as compared with the small net, indicating that the fish looked to be moving more slowly when participants played with the big net. Explicit judgments of fish speed were similarly influenced by net size. These results provide converging evidence from both explicit and action-based measures that a perceiver's ability to act influences a common underlying process, most likely perceived speed, rather than postperceptual processes such as response formation. PMID- 23658060 TI - Common susceptibility alleles and SQSTM1 mutations predict disease extent and severity in a multinational study of patients with Paget's disease. AB - Paget's disease of bone (PDB) has a strong genetic component. Here, we investigated possible associations between genetic variants that predispose to PDB and disease severity. Allelic variants identified as predictors of PDB from genome-wide association studies were analyzed in 1940 PDB patients from the United Kingdom, Italy, Western Australia, and Spain. A cumulative risk allele score was constructed by adding the variants together and relating this to markers of disease severity, alone and in combination with SQSTM1 mutations. In SQSTM1-negative patients, risk allele scores in the highest tertile were associated with a 27% increase in disease extent compared with the lowest tertile (p < 0.00001) with intermediate values in the middle tertile (20% increase; p = 0.0007). The effects were similar for disease severity score, which was 15% (p = 0.01) and 25% (p < 0.00001) higher in the middle and upper tertiles, respectively. Risk allele score remained a significant predictor of extent and severity when SQSTM-positive individuals were included, with an effect size approximately one-third of that observed with SQSTM1 mutations. A genetic risk score was developed by combining information from both markers, which identified subgroups of individuals with low, medium, and high levels of severity with a specificity of 70% and sensitivity of 55%. Risk allele scores and SQSTM1 mutations both predict extent and severity of PDB. It is possible that with further refinement, genetic profiling may be of clinical value in identifying individuals at high risk of severe disease who might benefit from enhanced surveillance and early intervention. PMID- 23658061 TI - SDF-1 promotes ox-LDL induced vascular smooth muscle cell proliferation. AB - The mechanism of the regulatory roles of stromal cell derived factor-1 (SDF-1)/C X-C motif receptor 4 (CXCR4) on cell proliferation and apoptosis in vascular smooth muscle cells (VSMCs) via the protein kinase C (PKC) and nuclear factor kappa B (NF-kappaB) signalling pathways have been investigated. Rat aortic VSMCs were treated with control or an oxidised low-density lipoprotein (ox-LDL) atherosclerosis (AS) model. Cells exposed to the AS model were treated with SDF-1 plus inhibitors specific for PKC (Ro31-8220), CXCR4 (12G5) or NF-kappaB (pyrrolidine dithiocarbamate, PDTC). Cell proliferation was measured with 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis by flow cytometry. NF-kappaB protein expression was analysed using Western blotting. The proliferation rate in the AS model group was significantly higher than the control group, but lower than the SDF-1 group (P < 0.05). Apoptosis in the AS model group (ox-LDL) was significantly higher than the normal control group (P < 0.05). In addition, the apoptosis rate in the SDF-1 group was significantly lower than the normal control group (P < 0.05); however, there was no difference from the Ro31-8220 group. NF-kappaB protein expression in the SDF-1 group was significantly higher than the AS model (ox-LDL) group (P < 0.05). In conclusion, SDF-1 can promote the proliferation of VSMCs induced by ox-LDL and inhibit cell apoptosis, via the SDF-1/CXCR4 axis. PMID- 23658062 TI - Optimization of triazine nitriles as rhodesain inhibitors: structure-activity relationships, bioisosteric imidazopyridine nitriles, and X-ray crystal structure analysis with human cathepsin L. AB - The cysteine protease rhodesain of Trypanosoma brucei parasites causing African sleeping sickness has emerged as a target for the development of new drug candidates. Based on a triazine nitrile moiety as electrophilic headgroup, optimization studies on the substituents for the S1, S2, and S3 pockets of the enzyme were performed using structure-based design and resulted in inhibitors with inhibition constants in the single-digit nanomolar range. Comprehensive structure-activity relationships clarified the binding preferences of the individual pockets of the active site. The S1 pocket tolerates various substituents with a preference for flexible and basic side chains. Variation of the S2 substituent led to high-affinity ligands with inhibition constants down to 2 nM for compounds bearing cyclohexyl substituents. Systematic investigations on the S3 pocket revealed its potential to achieve high activities with aromatic vectors that undergo stacking interactions with the planar peptide backbone forming part of the pocket. X-ray crystal structure analysis with the structurally related enzyme human cathepsin L confirmed the binding mode of the triazine ligand series as proposed by molecular modeling. Sub-micromolar inhibition of the proliferation of cultured parasites was achieved for ligands decorated with the best substituents identified through the optimization cycles. In cell-based assays, the introduction of a basic side chain on the inhibitors resulted in a 35-fold increase in antitrypanosomal activity. Finally, bioisosteric imidazopyridine nitriles were studied in order to prevent off-target effects with unselective nucleophiles by decreasing the inherent electrophilicity of the triazine nitrile headgroup. Using this ligand, the stabilization by intramolecular hydrogen bonding of the thioimidate intermediate, formed upon attack of the catalytic cysteine residue, compensates for the lower reactivity of the headgroup. The imidazopyridine nitrile ligand showed excellent stability toward the thiol nucleophile glutathione in a quantitative in vitro assay and fourfold lower cytotoxicity than the parent triazine nitrile. PMID- 23658063 TI - Disseminated staphylococcal disease in healthy children-experience from two tertiary care hospitals of West Bengal. AB - OBJECTIVES: To assess the etiology, precipitating factors, treatment and outcome of disseminated staphylococcal disease (DSD) in healthy immunocompetent children. METHODS: This hospital based observational prospective study was conducted in two tertiary care hospitals of West Bengal, India during the period of March, 2011 through February, 2012. Inclusion criteria were 1) children between 1 and 12 y and 2) clinical features DSD characterized by i) involvement of at least two distant organs with presence of gram positive cocci in clusters and/or growth of Staphylococcus aureus from at least one normally sterile body fluid, ii) fever, persistent bacteremia despite antibiotics and focal involvement of two or more separate tissue sites (skin, bone, joint, kidney, lung, liver, heart). RESULTS: Thirty six cases fulfilled the criteria of DSD with mean age in years 6.03 +/- 3.04 (range 1-12). The age group of 5-12 y was found to be more vulnerable (p < 0.001). Septic arthritis following accidental blunt closed trauma, was the significant precipitating factor for DSD in this age group (p = 0.031). Methicillin resistant Staphylococcus aureus (MRSA) was the causative agent in all the cases. Vancomycin resistant Staphylococcus aureus (VRSA) was detected in 88.9 % of cases. All cases were sensitive to linezolid. No significant side effects were observed with 28 d of linezolid therapy. CONCLUSIONS: DSD is more common in 5-12 y age group. Trauma is a significant precipitating factor for DSD in this age group. Linezolid may be considered as the first line drug in DSD with MRSA. PMID- 23658064 TI - Human milk banks and their relevance in India. PMID- 23658065 TI - Adenine phosphoribosyl transferase 1 is a key enzyme catalyzing cytokinin conversion from nucleobases to nucleotides in Arabidopsis. AB - In plants, the cytokinin metabolic processes, including cytokinin biosynthesis, interconversion, inactivation, and degradation, play critical roles in the regulation of cytokinin homeostasis and plant development. Purine metabolic enzymes have been implied to catalyze the cytokinin interconversion in previous works. In this study, we report that Adenine Phosphoribosyl Transferase 1 (APT1) is the causal gene of the high-dose cytokinin-resistant mutants. APT1 catalyzes the cytokinin conversion from free bases to nucleotides, and is functionally predominant among the five members of the Arabidopsis Adenine Phosphoribosyl Transferase family. Loss of APT1 activity in plants leads to excess accumulation of cytokinin bases, thus evoking myriad cytokinin-regulated responses, such as delayed leaf senescence, anthocyanin accumulation, and downstream gene expression. Thus, our study defines APT1 as a key metabolic enzyme participating in the cytokinin inactivation by phosphoribosylation. PMID- 23658066 TI - Inositol polyphosphate phosphatidylinositol 5-phosphatase9 (At5ptase9) controls plant salt tolerance by regulating endocytosis. AB - Phosphatidylinositol 5-phosphatases (5PTases) that hydrolyze the 5' position of the inositol ring are key components of membrane trafficking system. Recently, we reported that mutation in At5PTase7 gene reduced production of reactive oxygen species (ROS) and decreased expression of stress-responsive genes, resulting in increased salt sensitivity. Here, we describe an even more salt-sensitive 5ptase mutant, At5ptase9, which also hydrolyzes the 5' phosphate groups specifically from membrane-bound phosphatidylinositides. Interestingly, the mutants were more tolerant to osmotic stress. We analyzed the main cellular processes that may be affected by the mutation, such as production of ROS, influx of calcium, and induction of salt-response genes. The At5ptase9 mutants showed reduced ROS production and Ca(2+) influx, as well as decreased fluid-phase endocytosis. Inhibition of endocytosis by phenylarsine oxide or Tyrphostin A23 in wild-type plants blocked these responses. Induction of salt-responsive genes in wild-type plants was also suppressed by the endocytosis inhibitors. Thus, inhibition of endocytosis in wild-type plants mimicked the salt stress responses, observed in the At5ptase9 mutants. In summary, our results show a key non-redundant role of At5PTase7 and 9 isozymes, and underscore the localization of membrane-bound PtdIns in regulating plant salt tolerance by coordinating the endocytosis, ROS production, Ca(2+) influx, and induction of stress-responsive genes. PMID- 23658067 TI - Studies on pharmacokinetic mechanism of phenytoin resistance in refractory epilepsy. AB - P-glycoprotein (P-gp) is a drug efflux pump in many organs, including the intestine and liver. Two single nucleotide polymorphisms (SNPs) of P-gp gene, 2677G>T and 3435C>T, were reported to influence function and expression of P-gp and have the controversial effects on drug disposition. Phenytoin is one substrate of P-gp. Persistent low phenytoin levels in plasma and P-gp overexpression in brain in several refractory epilepsy patients were reported. P gp polymorphisms may also affect phenytoin efficacy by altering its bioavailability (F). Because two P-gp SNPs, 2677G>T and 3435C>T, may affect P-gp expression in tissue, we examined phenytoin disposition in patients of different P-gp haplotypes, G/G2677C/C3435 and T/T2677T/T3435. We found that the mean absolute F of phenytoin in T/T2677T/T3435 subjects (91%) is slightly higher than in G/G2677C/C3435 subjects (82%). There was no difference in the maximum concentration (Cmax ) and the area under the serum concentration-time curve of phenytoin administered orally between two genotypic groups. However, the time of maximum concentration was higher in T/T2677T/T3435 subjects (10 h) than in G/G2677C/C3435 subjects (6 h). The study ruled out the possibility that genetic polymorphisms of P-gp may affect phenytoin efficacy through the decreased absorption or the increased elimination. P-gp SNPs could affect phenytoin efficacy in refractory epilepsy patients probably because of central nervous system. PMID- 23658068 TI - Return to Being Black, Living in the Red: a race gap in wealth that goes beyond social origins. AB - In the United States, racial disparities in wealth are vast, yet their causes are only partially understood. In Being Black, Living in the Red, Conley (1999) argued that the sociodemographic traits of young blacks and their parents, particularly parental wealth, wholly explain their wealth disadvantage. Using data from the 1980-2009 waves of the Panel Study of Income Dynamics, I show that this conclusion hinges on the specific sample considered and the treatment of debtors in the sample. I further document that prior research has paid insufficient attention to the possibility of variation in the association between wealth and race at different points of the net worth distribution. Among wealth holders, blacks remain significantly disadvantaged in assets compared with otherwise similar whites. Among debtors, however, young whites hold more debt than otherwise similar blacks. The results suggest that, among young adults, debt may reflect increased access to credit, not simply the absence of assets. The asset disadvantage for black net wealth holders also indicates that research and policy attention should not be focused only on young blacks "living in the red." PMID- 23658069 TI - Missing minorities? The phases of IRCA legislation and relative net undercounts of the 1990 vis-a-vis 2000 decennial census for foreign-born cohorts. AB - The quality of the decennial census of the United States is compromised by population undercount, which often misses immigrants and racial/ethnic minorities, thereby diminishing federal resources allocated to such groups. Using a modified version of demographic analysis and informed by the latest contributions of emigration scholarship, this research estimates net undercount for the 1990 census relative to the 2000 census by age, sex, year-of-entry, and place-of-birth cohorts. Ordinary least squares estimates suggest that males, recent arrivals, and cohorts aged 15-44 had higher relative net undercount for 1990 compared with 2000. Much higher relative net undercount was found for cohorts from Africa, Latin America, and the Caribbean (excluding Cuba and Puerto Rico) who were ineligible for amnesty under the Immigration Reform and Control Act of 1986 (i.e., those fitting the profile of an undocumented immigrant). Larger implications of these findings suggest that the political climate in which a person is embedded-particularly for persons who may feel threatened or marginalized by the government and/or the public-affects that person's willingness to respond to the census. PMID- 23658070 TI - Association analysis between the A118G polymorphism in the OPRM1 gene and treatment response to venlafaxine XR in generalized anxiety disorder. AB - Patients diagnosed with generalized anxiety disorder (GAD) exhibit differential responses to standard antidepressant pharmacotherapy. Mounting evidence demonstrates that genetic differences may be implicated in treatment response in disorders like GAD. In this study, we examined whether the OPRM1 gene, which has been implicated in antidepressant treatment response in major depressive disorder, also has an effect in GAD. In our study, 156 patients diagnosed with GAD received venlafaxine XR treatment as part of an 18-month relapse prevention study. Genotypes were obtained for the OPRM1 functional variant A118G for the entire sample (n = 151); however, only the European American population was considered (n = 108) for pharmacogenetic analysis. We found no significant association between A118G and antidepressant treatment response in our GAD population. Future studies that include different single nucleotide polymorphisms of the OPRM1 gene as well as larger populations will need to be conducted to further elucidate the pharmacogenetic role of the endogenous opioid system in anxiety disorders. PMID- 23658071 TI - Diabetes is not an independent risk factor for hepatocellular carcinoma. AB - BACKGROUND: It is controversial whether diabetes is a risk factor for hepatocellular carcinoma (HCC) in countries with high prevalence of viral hepatitis such as Taiwan. METHODS: From the Taiwanese National Health Insurance, 1 000 000 insurants were randomly selected for the study. Among them, 494 080 men and 502 841 women without HCC were followed from 2003 until 2005. Relative risks were estimated taking into account alcohol-related diagnoses, chronic liver disease, potential HCC detection examinations and other covariates. RESULTS: The diabetes patients were more likely to receive examinations of abdominal sonography, HBsAg, anti-HCV and alpha-fetoprotein. Multivariable-adjusted relative risk (95% confidence interval) was not significant for diabetes as a risk factor for HCC in either men or women: 0.932 (0.788-1.101) for men and 1.158 (0.968-1.386) for women. While comparing diabetes duration <1, 1-3 and >= 3 years to non-diabetes individuals, the respective relative risks were 1.043 (0.751 1.448), 0.945 (0.738-1.209) and 0.901 (0.744-1.091) for men; and were 0.950 (0.610-1.480), 1.169 (0.884-1.546) and 1.189 (0.974-1.452) for women. For both sexes, age, alcohol-related diagnoses, chronic liver disease and potential detection bias were significantly associated with higher risk, but dyslipidemia and stroke a lower risk. In addition, chronic obstructive pulmonary disease was associated with a lower risk and sulfonylurea a higher risk in men. Models that did not consider alcohol-related diagnoses, chronic liver disease and potential detection bias would result in spurious association between diabetes and HCC. CONCLUSIONS: Diabetes is not an independent risk factor for HCC after considering the effects of alcohol-related diagnoses, chronic liver disease and potential detection bias. PMID- 23658072 TI - Assessment of the sigma-1 receptor antagonist (SR1A): a model approach for preclinical analgesic drug discovery. PMID- 23658073 TI - Comment on Lekpa et al., 'socio-demographic and clinical profile of chronic pain with neuropathic characteristics in sub-Saharan African elderly'. PMID- 23658074 TI - Authors' reply to the comment by Pazzaglia et al. PMID- 23658075 TI - Transformational Science, transformational practice: a special issue dedicated to Michael Strober, Editor-In-Chief from 1983 to 2012. Foreword. PMID- 23658076 TI - The research-practice gap: bridging the schism between eating disorder researchers and practitioners. AB - OBJECTIVE: The field of eating disorders (EDs) treatment has been beset by a marked disjunction between scientific evidence and clinical application. We describe the nature and scope of the research-practice gap in the ED field. METHOD: We draw on surveys and broader literature to better understand the research-practice gap in ED treatment and reasons for resistance to evidence based practice. RESULTS: We identify three sources of the research-practice gap: (1) attitudinal factors, (2) differences in the definition of "evidence," and (3) cognitive factors, especially naive realism and confirmation bias. We affirm the role of science as a safeguard against human fallibility and as a means of bridging the research-practice gap, and delineate key principles of scientific thinking for ED researchers and practitioners. DISCUSSION: We conclude with proposals for narrowing the research-practice gap in ED treatment and enhancing the quality of interventions for ED clients. PMID- 23658077 TI - Classification. Introduction. PMID- 23658079 TI - Dimensions in the eating disorders: past, present, and future. Commentary on Wildes and Marcus: Incorporating dimensions into the classification of eating disorders. PMID- 23658078 TI - Incorporating dimensions into the classification of eating disorders: three models and their implications for research and clinical practice. AB - OBJECTIVE: Given renewed interest in dimensional approaches in psychiatric nosology, we review evidence for the utility of including dimensions of eating disorder (ED) psychopathology, comorbid psychopathology, and neurobiology in the classification of EDs. METHOD: We searched on-line databases and reference lists of published papers for articles on dimensional methods in psychiatric classification, with an emphasis on EDs. RESULTS: ED classification may be enhanced by including dimensional assessments. Specifically, some ED features appear to exist on a continuum with normality, and dimensional measures of ED severity are likely to have utility in clinical contexts. Furthermore, accumulating data support the validity of ED classification schemes that incorporate dimensions of comorbid psychopathology. Finally, neurobiological dimensions have gained increasing notice across the psychiatric literature and may be particularly salient to the classification of EDs. DISCUSSION: An approach to ED classification that incorporates multiple dimensional measures may have the greatest utility for advancing ED treatment. PMID- 23658080 TI - Classification, culture, and complexity: a global look at the diagnosis of eating disorders: Commentary on Wildes and Marcus: Incorporating dimensions into the classification of eating disorders. PMID- 23658081 TI - An idea worth researching: DSM diagnosis of mental disorders as a living document. PMID- 23658082 TI - Non-fat-phobic eating disorders: why we need to investigate implicit associations and neural correlates. PMID- 23658083 TI - Avoidant restrictive food intake disorder: an illustrative case example. AB - Avoidant/restrictive food intake disorder (ARFID) is a new diagnostic category in DSM-5. Although replacing Feeding Disorder of Infancy or Early Childhood, it is not restricted to childhood presentations. In keeping with the broader aim of revising and updating criteria and text to better reflect lifespan issues and clinical expression across the age range, ARFID is a diagnosis relevant to children, adolescents, and adults. This case example of a 13-year old boy with ARFID illustrates key issues in diagnosis and treatment planning. The issues discussed are not exhaustive, but serve as a guide for central diagnostic and treatment issues to be considered by the clinician. It is anticipated that the inclusion of specific criteria for ARFID as a category within Feeding and Eating Disorders in DSM-5 will stimulate research into its typology, prevalence, and incidence in different populations and facilitate the development of effective, evidence-based interventions for this patient group. PMID- 23658084 TI - Biological or psychosocial correlates and risk factors. Introduction. PMID- 23658085 TI - Neurocircuit function in eating disorders. AB - OBJECTIVE: Eating disorders are serious psychosomatic disorders with high morbidity and lifetime mortality. Inadequate response to current therapeutic interventions constitutes a challenging clinical problem. A better understanding of the underlying neurobiological mechanisms could improve psychotherapeutic and drug treatment strategies. METHOD: A review highlighting the current state of brain imaging in eating disorders related to the anxiety and pathological fear learning model of anorexia nervosa (AN) and the impulsivity model of binge eating in bulimia nervosa (BN). RESULTS: Available neuroimaging studies in patients with acute AN primarily suggest a hyper-responsive emotional and fear network to food, but not necessarily to eating disorder-unrelated, salient stimuli. Furthermore, patients with AN show decreased activation in the ventral fronto-striatal circuits during the performance of a cognitive flexibility task. Results in patients with BN primarily suggest a hypo-responsive reward system to food stimuli, especially to taste reward. Additionally, patients with BN exhibit impaired brain activation in the inhibitory control network during the performance of general response-inhibition tasks. DISCUSSION: Anxiety and pathological fear learning may lead to conditioned neural stimulus-response patterns to food stimuli and increased cognitive rigidity, which could account for the phobic avoidance of food intake in patients with acute AN. However, further neurobiological studies are required to investigate pathological fear learning in patients with AN. Patients with BN may binge eat to compensate for a hypo-responsive reward system. The impaired brain activation in the inhibitory control network may facilitate the loss of control over food intake in patients with BN. PMID- 23658086 TI - Psychosocial risk factors for eating disorders. AB - OBJECTIVE: One goal in identifying psychosocial risk factors is to discover opportunities for intervention. The purpose of this review is to examine psychosocial risk factors for disordered eating, placing research findings in the larger context of how etiological models for eating disorders can be transformed into models for intervention. METHOD: A qualitative literature review was conducted focusing on psychological and social factors that increase the risk for developing eating disorders, with an emphasis on well-replicated findings from prospective longitudinal studies. RESULTS: Epidemiological, cross-cultural, and longitudinal studies underscore the importance of the idealization of thinness and resulting weight concerns as psychosocial risk factors for eating disorders. Personality factors such as negative emotionality and perfectionism contribute to the development of eating disorders but may do so indirectly by increasing susceptibility to internalize the thin ideal or by influencing selection of peer environment. During adolescence, peers represent self-selected environments that influence risk. DISCUSSION: Peer context may represent a key opportunity for intervention, as peer groups represent the nexus in which individual differences in psychological risk factors shape the social environment and social environment shapes psychological risk factors. Thus, peer-based interventions that challenge internalization of the thin ideal can protect against the development of eating pathology. PMID- 23658087 TI - Risky circuitry? Psychosocial risk factors and neural circuits in the development and persistence of eating disorders. A commentary on Keel & Forney and Friederich et al. PMID- 23658088 TI - Brain development and neurocircuit modeling are the interface between genetic/environmental risk factors and eating disorders. A commentary on Keel & Forney and Friederich et al. PMID- 23658089 TI - Neuromodulation techniques and eating disorders. PMID- 23658091 TI - Bone health in adolescent females with anorexia nervosa: what is a clinician to do? AB - The objective of this case report is to present a pharmacologic strategy for treatment of adolescents with anorexia nervosa (AN) and low bone mineral density (BMD). We present a 17.5-year-old girl with a 3-year history of AN and longstanding inability to optimize nutrition and gain weight, and a decrease over time in her already low BMD. A year after treatment with the 17-beta estradiol patch (100 mcg twice weekly) with cyclic oral progesterone (2.5 mg medroxyprogesterone acetate daily for days 1-10 of every month), her spine and hip BMD Z-scores improved, and a further decrease was prevented. This novel treatment is a consideration for girls with AN at greatest risk for low BMD. Adolescents with AN are at risk for low BMD, and the most effective treatment is weight and menses restoration, which can be difficult to attain and to sustain. Recent studies have shown promising results with pharmacological therapy for low BMD in AN. This article discusses current concepts related to bone loss in AN, and new pharmacologic considerations for adolescents at greatest risk for low BMD. PMID- 23658090 TI - Pediatric disinhibited eating: toward a research domain criteria framework. PMID- 23658092 TI - Treatment and prevention. Introduction. PMID- 23658093 TI - A systematic review of evidence for psychological treatments in eating disorders: 2005-2012. AB - OBJECTIVE: To update new evidence for psychotherapies in eating disorders (EDs) since 2005-September 2012. METHOD: Completed and published in the English language randomized controlled trials (RCTs) were identified by SCOPUS search using terms "bulimia" or "binge eating disorder" (BED) or "anorexia nervosa" (AN) or "eating disorder" and "treatment," and 36 new RCTs met inclusion criteria. RESULTS: There has been progress in the evidence for family based treatment in adolescents with AN, for cognitive behavior therapy (CBT) in full and guided forms, and new modes of delivery for bulimia nervosa (BN), BED, and eating disorder not otherwise specified with binge eating. Risk of bias was low to moderate in 22 (61%) of RCTs. DISCUSSION: The evidence base for AN has improved and CBT has retained and extended its status as first-line therapy for BN. However, further research is needed, in particular noninferiority trials of active therapies and the best approach to addressing ED features and weight management in co-morbid BED and obesity. PMID- 23658094 TI - Biological therapies for eating disorders. AB - OBJECTIVE: To provide a comprehensive review of pharmacotherapy and other biological treatments for eating disorders. METHOD: Literature on this topic was systematically reviewed. RESULTS: The bulimia nervosa (BN) literature underscores the utility of antidepressants, particularly SSRIs, in improving the symptoms of the disorder. The literature on binge eating disorder supports efficacy on reduction in binge eating frequency for a variety of compounds. However, such compounds have only modest effects on weight. Certain antiepileptic agents such as topiramate, if tolerated, are probably more useful in terms of weight loss. The number of controlled trials in patients with anorexia nervosa (AN) in particular has been quite small, and recent meta-analyses show disappointing results using atypical antipsychotics in AN. DISCUSSION: The pharmacological treatment of eating disorders remains an underdeveloped field although drug therapy clearly plays a role in the treatment of those with BN and binge eating disorder. Other biological therapies have not been adequately studied. PMID- 23658095 TI - Eating disorder prevention: current evidence-base and future directions. AB - OBJECTIVE: This narrative review sought to (a) characterize prevention programs that have produced reliable, reproducible, and clinically meaningful effects in efficacy trials, (b) discuss effectiveness trials that have tested whether prevention programs produce intervention effects under ecologically valid real world conditions, (c) discuss dissemination efforts and research on dissemination, and (d) offer suggestions regarding directions for future research in this field. CONCLUSION: A literature revealed that 6 prevention programs have produced significant reductions in eating disorder symptoms through at least 6 month follow-up and that 2 have significantly reduced future eating disorder onset. Effectiveness trials indicate that 2 prevention programs have produced effects under ecologically valid conditions that are only slightly attenuated. Although there have been few dissemination efforts, evidence suggests that a community participatory approach is most effective. Lastly, it would be useful to develop programs that produce larger and more persistent reductions in eating disorder symptoms and eating disorder onset, focus more on effectiveness trials that confirm that prevention programs produce clinically meaningful effects under real-world conditions, conduct meditational, mechanisms of action, and moderator research that provides stronger support for the intervention theory of prevention programs, and investigate the optimal methods of disseminating and implementing evidence-based prevention programs. PMID- 23658096 TI - Promises, progress, and pathos: Commentary on "Treatment and prevention" papers by Stice & Becker, Hay, and Mitchell, Roenig & Steffan. PMID- 23658097 TI - Are we really paddling as fast as we can? Reflections on why eating disorders treatment and research always seem to be one step behind: commentary on Hay, Mitchell, and Stice & Becker: Prevention and treatment. PMID- 23658098 TI - Cognitive remediation therapy for anorexia nervosa: current evidence and future research directions. PMID- 23658099 TI - Attention bias modification: a new approach to the treatment of eating disorders? PMID- 23658100 TI - A system of evidenced-based techniques and collaborative clinical interventions with a chronically ill patient. AB - Although evidence-based treatments (EBTs) exist for both bulimia nervosa and binge eating disorder, there is far less evidence underpinning the treatment of anorexia nervosa (AN). Furthermore, there is no clearly defined standardized approach to patients who have not responded to treatment over an extended period of time. Chronic eating disorder patients in particular might need long-term engagement with treatment providers offering a wide range of interventions. This case study highlights how an experienced private practitioner systematically employed a variety of EBT techniques for a patient with a severe, long-term eating disorder and its comorbidities, within a model of attachment and collaboration. The practice of utilizing a wide variety of EBT techniques in a systematic manner guided by clinical expertise and supported by a therapy relationship of collaboration and attachment may prove to be a fruitful avenue for future research. PMID- 23658101 TI - Broadening access to care. Introduction. PMID- 23658102 TI - Harnessing the power of technology for the treatment and prevention of eating disorders. AB - OBJECTIVE: The objective of this article is to review the available literature regarding the development and evaluation of technology-enhanced interventions for eating disorders. METHOD: Literature was reviewed pertaining to interventions that use technology (e.g., Internet, mobile phones) for prevention, guided self help, treatment, relapse prevention, and carer support. RESULTS: A number of technology-enhanced approaches have been developed for each facet of the care spectrum, and experiences that are reported with their implementation are overall promising. However, only few of them have been evaluated in adequately designed and powered trials. DISCUSSION: This review suggests that technology-enhanced interventions offer multiple opportunities to improve care for eating disorders. More research is needed on the efficacy, effectiveness, cost-effectiveness, and reach of these approaches to ultimately estimate their public health impact. It is discussed to what extent innovative models of care integrating technology enhanced interventions and face-to-face interventions may improve service delivery for eating disorders. PMID- 23658103 TI - The dissemination and implementation of psychological treatments: problems and solutions. AB - Treatment researchers expend their efforts identifying effective treatments, and for whom and how they work, but there are matters over and above these that are of concern when it comes to dissemination and implementation. These include the clinical range of the interventions concerned, the ease with which they can be learned, and their mode of delivery. It is these three topics, as they apply to the psychological treatment of eating disorders, that form the focus of this article. Alongside these considerations, we discuss how modern technology has the potential to transform both treatment and training. PMID- 23658104 TI - Cheap and cheerful--can cybertherapy be compassionate too? Commentary on Fairburn & Wilson and Bauer & Moessner. PMID- 23658105 TI - Dissemination in the internet age: taming a wild thing. PMID- 23658106 TI - Reducing the burden of eating disorders: a model for population-based prevention and treatment for university and college campuses. PMID- 23658107 TI - Closing the "know-do" gap: training public health professionals in eating disorders prevention via case-method teaching. AB - Expansion of our societies' capacity to prevent eating disorders will require strategic integration of the topic into the curricula of professional training programs. An ideal way to integrate new content into educational programs is through the case-method approach, a teaching method that is more effective than traditional teaching techniques. The Strategic Training Initiative for the Prevention of Eating Disorders has begun developing cases designed to be used in classroom settings to engage students in topical, high-impact issues in public health approaches to eating disorders prevention and screening. Dissemination of these cases will provide an opportunity for students in public health training programs to learn material in a meaningful context by actively applying skills as they are learning them, helping to bridge the "know-do" gap. The new curriculum is an important step toward realizing the goal that public health practitioners be fully equipped to address the challenge of eating disorders prevention. PMID- 23658109 TI - Functional zeolitic-imidazolate-framework-templated porous carbon materials for CO2 capture and enhanced capacitors. AB - Three types of zeolitic imidazolate frameworks (ZIFs) with different topological structures and functional imidazolate-derived ligands, namely, ZIF-8, ZIF-68, and ZIF69, have been directly carbonized to prepare porous carbon materials at 1000 degrees C. These as-synthesized porous carbon materials were activated with fused KOH to increase their surface areas and pore volumes for use in gas storage and supercapacitors. The relationship between the local structure of the products and the composition of the precursors has been investigated in detail. The BET surface areas of the resultant activated carbon materials are 2437 (CZIF8a), 1861 (CZIF68a), and 2264 m(2) g(-1) (CZIF69a). CZIF8a exhibits the highest H2 -storage capacities of 2.59 wt.% at 1 atm and 77 K, whereas CZIF69a has the highest CO2 uptake of 4.76 mmol g(-1) at 1 atm and 273 K, owing to its local structure and pore chemical environment. The specific capacities are calculated from the CV curves. CZIF69a exhibits the highest supercapacitor performance of 168 F g(-1) at a scan speed of 5 mV s(-1). These results indicate that the functional chloride group on the benzimidazolate ligand plays a very important role in improving the surface area, pore volume, and, therefore, CO2-capture and supercapacitor properties of the corresponding porous carbon materials. PMID- 23658108 TI - Transcriptome analysis of injured human meniscus reveals a distinct phenotype of meniscus degeneration with aging. AB - OBJECTIVE: Meniscus tears are associated with a heightened risk of osteoarthritis. This study aimed to advance our understanding of the metabolic state of injured human meniscus at the time of arthroscopic partial meniscectomy through transcriptome-wide analysis of gene expression in relation to the patient's age and degree of cartilage chondrosis. METHODS: The degree of chondrosis of knee cartilage was recorded at the time of meniscectomy in symptomatic patients without radiographic osteoarthritis. RNA preparations from resected menisci (n = 12) were subjected to transcriptome-wide microarray and QuantiGene Plex analyses. Variations in the relative changes in gene expression with age and chondrosis were analyzed, and integrated biologic processes were investigated computationally. RESULTS: We identified a set of genes in torn menisci that were differentially expressed with age and chondrosis. There were 866 genes that were differentially regulated (>=1.5-fold difference and P < 0.05) with age and 49 with chondrosis. In older patients, genes associated with cartilage and skeletal development and extracellular matrix synthesis were repressed, while those involved in immune response, inflammation, cell cycle, and cellular proliferation were stimulated. With chondrosis, genes representing cell catabolism (cAMP catabolic process) and tissue and endothelial cell development were repressed, and those involved in T cell differentiation and apoptosis were elevated. CONCLUSION: Differences in age-related gene expression suggest that in older adults, meniscal cells might dedifferentiate and initiate a proliferative phenotype. Conversely, meniscal cells in younger patients appear to respond to injury, but they maintain the differentiated phenotype. Definitive molecular signatures identified in damaged meniscus could be segregated largely with age and, to a lesser extent, with chondrosis. PMID- 23658110 TI - Epigenetic modifications of Nrf2 by 3,3'-diindolylmethane in vitro in TRAMP C1 cell line and in vivo TRAMP prostate tumors. AB - 3,3'-diindolylmethane (DIM) is currently being investigated in many clinical trials including prostate, breast, and cervical cancers and has been shown to possess anticancer effects in several in vivo and in vitro models. Previously, DIM has been reported to possess cancer chemopreventive effects in prostate carcinogenesis in TRAMP mice; however, the in vivo mechanism is unclear. The present study aims to investigate the in vitro and in vivo epigenetics modulation of DIM in TRAMP-C1 cells and in TRAMP mouse model. In vitro study utilizing TRAMP C1 cells showed that DIM suppressed DNMT expression and reversed CpG methylation status of Nrf2 resulting in enhanced expression of Nrf2 and Nrf2-target gene NQO1. In vivo study, TRAMP mice fed with DIM-supplemented diet showed much lower incidence of tumorigenesis and metastasis than the untreated control group similar to what was reported previously. DIM increased apoptosis, decreased cell proliferation and enhanced Nrf2 and Nrf2-target gene NQO1 expression in prostate tissues. Importantly, immunohistochemical analysis showed that DIM reduced the global CpG 5-methylcytosine methylation. Focusing on one of the early cancer chemopreventive target gene Nrf2, bisulfite genomic sequencing showed that DIM decreased the methylation status of the first five CpGs of the Nrf2 promoter region, corroborating with the results of in vitro TRAMP-C1 cells. In summary, our current study shows that DIM is a potent cancer chemopreventive agent for prostate cancer and epigenetic modifications of the CpG including Nrf2 could be a potential mechanism by which DIM exerts its chemopreventive effects. PMID- 23658111 TI - Early anatomy ultrasound in women at increased risk of fetal anomalies. AB - OBJECTIVE: This study was designed to assess the accuracy of ultrasound anatomy screening before 17 weeks gestation in a population at high risk of fetal anomalies. METHODS: Retrospective review of anatomy ultrasound examinations carried out between 12-17 weeks gestation in a high-risk population. Early sonographic findings were compared with the 18-22 week anatomy ultrasound, karyotype, echocardiogram and postnatal/postmortem results. RESULTS: A complete anatomical survey was achieved in 68 of 101 screened fetuses (67%), with cardiac anatomy having the lowest completion rate (78/101; 77%). Anomalies were suspected on ultrasound in 23 fetuses. Four of these did not undergo pathologic examination but had clearly abnormal findings on ultrasound. Eighteen fetuses had a confirmed abnormal outcome. Sensitivity of early anatomy ultrasound was 83.3% (n = 15/18) and specificity 94.9% (n = 75/79). There were 3 false negative ultrasounds (16.6%: trisomy 21 with short humerus, choanal atresia and ventriculomegaly, and a ventricular septal defect). False positive rate was 4.0% (4 ventricular septal defects). CONCLUSION: The high rate of visualization of anatomic structures between 12-17 weeks gestation allows for either early detection of fetal anomalies or parental reassurance in many cases. Subtle anomalies of the heart remain difficult to diagnose. PMID- 23658112 TI - Masticatory myorhythmia following pontine hemorrhage. PMID- 23658113 TI - Span efficiency in hawkmoths. AB - Flight in animals is the result of aerodynamic forces generated as flight muscles drive the wings through air. Aerial performance is therefore limited by the efficiency with which momentum is imparted to the air, a property that can be measured using modern techniques. We measured the induced flow fields around six hawkmoth species flying tethered in a wind tunnel to assess span efficiency, ei, and from these measurements, determined the morphological and kinematic characters that predict efficient flight. The species were selected to represent a range in wingspan from 40 to 110 mm (2.75 times) and in mass from 0.2 to 1.5 g (7.5 times) but they were similar in their overall shape and their ecology. From high spatio-temporal resolution quantitative wake images, we extracted time resolved downwash distributions behind the hawkmoths, calculating instantaneous values of ei throughout the wingbeat cycle as well as multi-wingbeat averages. Span efficiency correlated positively with normalized lift and negatively with advance ratio. Average span efficiencies for the moths ranged from 0.31 to 0.60 showing that the standard generic value of 0.83 used in previous studies of animal flight is not a suitable approximation of aerodynamic performance in insects. PMID- 23658115 TI - An assessment of a modern touch-screen tablet computer with reference to core physical characteristics necessary for clinical vision testing. AB - There are a multitude of applications using modern tablet computers for vision testing that are accessible to ophthalmology patients. While these may be of potential future benefit, they are often unsupported by scientific assessment. This report investigates the pertinent physical characteristics behind one of the most common highest specification tablet computers with regard to its capacity for vision testing. We demonstrate through plotting of a gamma curve that it is feasible to produce a precise programmable range of central luminance levels on the device, even with varying background luminance levels. It may not be possible to display very low levels of contrast, but carefully using the gamma curve information allows a reasonable range of contrast sensitivity to be tested. When the screen is first powered on, it may require up to 15 min for the luminance values to stabilize. Finally, luminance of objects varies towards the edge of the screen and when viewed at an angle. However, the resulting effective contrast of objects is less variable. Details of our assessments are important to developers, users and prescribers of tablet clinical vision tests. Without awareness of such findings, these tests may never reach satisfactory levels of clinical validity and reliability. PMID- 23658114 TI - Modelling HIV-1 2-LTR dynamics following raltegravir intensification. AB - A model of reservoir activation and viral replication is introduced accounting for the production of 2-LTR HIV-1 DNA circles following antiviral intensification with the HIV integrase inhibitor raltegravir, considering contributions of de novo infection events and exogenous sources of infected cells, including quiescent infected cell activation. The model shows that a monotonic increase in measured 2-LTR concentration post intensification is consistent with limited de novo infection primarily maintained by sources of infected cells unaffected by raltegravir, such as quiescent cell activation, while a transient increase in measured 2-LTR concentration is consistent with significant levels of efficient (R0 > 1) de novo infection. The model is validated against patient data from the INTEGRAL study and is shown to have a statistically significant fit relative to the null hypothesis of random measurement variation about a mean. We obtain estimates and confidence intervals for the model parameters, including 2-LTR half life. Seven of the 13 patients with detectable 2-LTR concentrations from the INTEGRAL study have measured 2-LTR dynamics consistent with significant levels of efficient replication of the virus prior to treatment intensification. PMID- 23658116 TI - In search of the pitching momentum that enables some lizards to sustain bipedal running at constant speeds. AB - The forelimbs of lizards are often lifted from the ground when they start sprinting. Previous research pointed out that this is a consequence of the propulsive forces from the hindlimbs. However, despite forward acceleration being hypothesized as necessary to lift the head, trunk and forelimbs, some species of agamids, teiids and basilisks sustain running in a bipedal posture at a constant speed for a relatively long time. Biomechanical modelling of steady bipedal running in the agamid Ctenophorus cristatus now shows that a combination of three mechanisms must be present to generate the angular impulse needed to cancel or oppose the effect of gravity. First, the trunk must be lifted significantly to displace the centre of mass more towards the hip joint. Second, the nose-up pitching moment resulting from aerodynamic forces exerted at the lizard's surface must be taken into account. Third, the vertical ground-reaction forces at the hindlimb must show a certain degree of temporal asymmetry with higher forces closer to the instant of initial foot contact. Such asymmetrical vertical ground reaction force profiles, which differ from the classical spring-mass model of bipedal running, seem inherent to the windmilling, splayed-legged running style of lizards. PMID- 23658117 TI - Unravelling daily human mobility motifs. AB - Human mobility is differentiated by time scales. While the mechanism for long time scales has been studied, the underlying mechanism on the daily scale is still unrevealed. Here, we uncover the mechanism responsible for the daily mobility patterns by analysing the temporal and spatial trajectories of thousands of persons as individual networks. Using the concept of motifs from network theory, we find only 17 unique networks are present in daily mobility and they follow simple rules. These networks, called here motifs, are sufficient to capture up to 90 per cent of the population in surveys and mobile phone datasets for different countries. Each individual exhibits a characteristic motif, which seems to be stable over several months. Consequently, daily human mobility can be reproduced by an analytically tractable framework for Markov chains by modelling periods of high-frequency trips followed by periods of lower activity as the key ingredient. PMID- 23658118 TI - Sensitivity to changing contingencies in an impulsivity task. AB - Using a video-game-based escalating interest task, participants repeatedly encountered a reward that gradually increased in value over a 10-second interval. Responding early in the interval netted less immediate reward than responding later in the interval. Each participant experienced four different reward contingencies for waiting. These contingencies were changed three times as the experiment proceeded. Behavior tracked these changing contingencies, but wait times reflected long-term carryover from the previously assigned contingencies. Both the tendency to respond slowly and the optimality of behavior were affected by the order of contingencies experienced. Demographic variables only weakly predicted behavior, and delay discounting rate in a hypothetical money choice task predicted choice only when the contingencies in the game were weaker. PMID- 23658119 TI - Vitamin D supplements in geriatric major depression. PMID- 23658120 TI - Can quantitative sensory testing predict responses to analgesic treatment? AB - The role of quantitative sensory testing (QST) in prediction of analgesic effect in humans is scarcely investigated. This updated review assesses the effectiveness in predicting analgesic effects in healthy volunteers, surgical patients and patients with chronic pain. A systematic review of English written, peer-reviewed articles was conducted using PubMed and Embase (1980-2013). Additional studies were identified by chain searching. Search terms included 'quantitative sensory testing', 'sensory testing' and 'analgesics'. Studies on the relationship between QST and response to analgesic treatment in human adults were included. Appraisal of the methodological quality of the included studies was based on evaluative criteria for prognostic studies. Fourteen studies (including 720 individuals) met the inclusion criteria. Significant correlations were observed between responses to analgesics and several QST parameters including (1) heat pain threshold in experimental human pain, (2) electrical and heat pain thresholds, pressure pain tolerance and suprathreshold heat pain in surgical patients, and (3) electrical and heat pain threshold and conditioned pain modulation in patients with chronic pain. Heterogeneity among studies was observed especially with regard to application of QST and type and use of analgesics. Although promising, the current evidence is not sufficiently robust to recommend the use of any specific QST parameter in predicting analgesic response. Future studies should focus on a range of different experimental pain modalities rather than a single static pain stimulation paradigm. PMID- 23658121 TI - Evolving approaches to metastatic breast cancer patients pre-treated with anthracycline and taxane. AB - Metastatic breast cancer is currently incurable and the goals of therapy focus on prolonging survival and maintaining quality of life by controlling symptoms and minimizing toxicity. Treatments for metastatic breast cancer include chemotherapeutic agents from various classes, such as taxanes, vinca alkaloids, anthracyclines and antimetabolites. This review provides an overview of chemotherapeutic agents for the treatment of metastatic breast cancer patients previously treated with anthracyclines and taxanes, focusing on a clinical evaluation of eribulin, the most recently approved agent for the treatment of metastatic breast cancer. Eribulin is a synthetic derivative of halichondrin B, a tumour growth inhibitor found in marine sponges, which prevents microtubule growth and sequesters the tubulin molecules into unusual aggregates, initiating apoptosis. Studies of eribulin have shown that the drug is effective in the treatment of previously treated metastatic breast cancer, and has an acceptable toxicity profile. Importantly, in the phase III EMBRACE study, eribulin treatment resulted in a survival advantage, a difficult endpoint to achieve with a single chemotherapeutic agent. An additional phase III study showed that eribulin has similar efficacy to capecitabine in women treated with no more than three prior therapies. Furthermore, pre-specified exploratory analyses suggest that particular patient subgroups may have greater therapeutic benefit with eribulin and may warrant further study to explore the potential mechanisms. PMID- 23658123 TI - Vibration perception threshold for sight-threatening retinopathy screening in type 2 diabetic outpatients. AB - OBJECTIVE: We investigated the relationship between vibration perception threshold and diabetic retinopathy and verified the screening value of vibration perception threshold for severe diabetic retinopathy. METHODS: A total of 955 patients with type 2 diabetes were recruited and divided into three groups according to their fundus oculi photography results: no diabetic retinopathy (n = 654, 68.48%), non-sight-threatening diabetic retinopathy (n = 189, 19.79%) and sight-threatening diabetic retinopathy (n = 112, 11.73%). Their clinical and biochemical characteristics, vibration perception threshold and the diabetic retinopathy grades were detected and compared. RESULTS: There were significant differences in diabetes duration and blood glucose levels among three groups (all p < 0.05). The values of vibration perception threshold increased with the rising severity of retinopathy, and the vibration perception threshold level of sight threatening diabetic retinopathy group was significantly higher than both non sight-threatening diabetic retinopathy and no diabetic retinopathy groups (both p < 0.01). The prevalence of sight-threatening diabetic retinopathy in vibration perception threshold >25 V group was significantly higher than those in 16-24 V group (p < 0.01). The severity of diabetic retinopathy was positively associated with diabetes duration, blood glucose indexes and vibration perception threshold (all p < 0.01). Multiple stepwise regression analysis proved that glycosylated haemoglobin (beta = 0.385, p = 0.000), diabetes duration (beta = 0.275, p = 0.000) and vibration perception threshold (beta = 0.180, p = 0.015) were independent risk factors for diabetic retinopathy. Receiver operating characteristic analysis further revealed that vibration perception threshold higher than 18 V was the optimal cut point for reflecting high risk of sight threatening diabetic retinopathy (odds ratio = 4.20, 95% confidence interval = 2.67-6.59). CONCLUSION: There was a close association between vibration perception threshold and the severity of diabetic retinopathy. vibration perception threshold was a potential screening method for diabetic retinopathy, and its optimal cut-off for prompting high risk of sight-threatening retinopathy was 18 V. PMID- 23658124 TI - Two lanthanide(III)-copper(II) organic frameworks based on {OLn6 } clusters that exhibited a large magnetocaloric effect and slow relaxation of the magnetization. AB - Two new 3D lanthanide(III)-copper(II) organic frameworks based on unusual {OLn6} clusters have been successfully synthesized and fully characterized. Crystallographic studies showed that the {OLn6} clusters acted as 12-connected nodes that were linked together by [CuL2] (H2L = 3-hydroxypyrazine-2-carboxylic acid) moieties to construct an interesting 4,12-c net with the point symbol {4(36).6(30)}{4(4).6(2)}3. Magnetic studies revealed that these two isostructural heterometallic frameworks exhibited different magnetic properties, depending on the different anisotropies of the lanthanide spin carriers: Gd-Cu showed a large magnetocaloric effect, with an entropy change (-DeltaS(m)) of 35.76 J kg(-1) K( 1), which is one of the largest values in high-dimensional complexes, whilst Dy Cu exhibited slow relaxation of the magnetization at low temperatures. PMID- 23658122 TI - Brief report: ultraviolet radiation exposure is associated with clinical and autoantibody phenotypes in juvenile myositis. AB - OBJECTIVE: Genetic and environmental factors may contribute to the etiology of the juvenile idiopathic inflammatory myopathies (IIMs), which are systemic autoimmune diseases that are characterized by muscle and skin inflammation. We undertook this study to investigate the association between ultraviolet radiation (UVR) exposure and the clinical and autoantibody expression of juvenile IIM. METHODS: The relationship between UVR exposure in the month before symptom onset and the prevalence of juvenile dermatomyositis (DM), compared to juvenile polymyositis (PM), was assessed in 298 juvenile IIM patients. Among the patients with juvenile DM, the association between UVR exposure and presence of myositis autoantibodies was assessed. Regression models were stratified by sex and race. The association between the regional UV index in US geoclimatic zones and the clinical and autoantibody subgroups was examined by weighted least squares regression analysis. RESULTS: Among girls in this population, the odds of having juvenile DM, compared to juvenile PM, increased per unit increase in the patients' highest UV index in the month before symptom onset (odds ratio [OR] 1.18, 95% confidence interval 1.00-1.40). Moreover, both the mean and highest UV indices were associated with increasing odds of having anti-p155/140 autoantibodies, with the strongest odds in white males (ORs of 1.30 and 1.23, respectively). No association was observed between the UV index and presence of anti-MJ autoantibodies or lack of any myositis autoantibodies. Across all 9 US geoclimatic regions, the mean UV index was associated with increasing odds of having juvenile DM and anti-p155/140 autoantibodies, but decreasing odds of having anti-MJ autoantibodies. CONCLUSION: Short-term UVR exposure prior to illness onset may have a role in the clinical and serologic expression of juvenile myositis. Further research examining the mechanisms of action of UVR in the pathogenesis of juvenile IIM is suggested from these findings. PMID- 23658125 TI - Translating evidence into practice: next steps. PMID- 23658126 TI - Improving protein and vitamin D status of obese patients participating in physical rehabilitation. AB - PURPOSE: Sarcopenia and vitamin D deficiency increase risk of disability outcomes associated with a million hip and knee replacements annually. The purpose of the present study was to identify protein and vitamin D inadequacy in arthroplasty patients, and observe the effect of supplementation on metabolic markers on protein and vitamin D status. METHODS: One hundred and eighty obese arthroplasty patients admitted for inpatient rehabilitation, positive for protein and vitamin D insufficiency, received supplemental protein and vitamin D. RESULTS AND CONCLUSION: Following supplementation, normalization of protein and vitamin D status was achieved. Nutrient supplementation during physical rehabilitation provided an efficient and effective means to reverse nutrient deficiency in an obese, orthopedic population. CLINICAL RELEVANCE: Inpatient physical rehabilitation is an opportune environment for nurses to provide education and intervention of nutrient supplementation, which may lessen consequences of sarcopenic obesity and related frailty disorders. PMID- 23658127 TI - Occurrence and severity of agitated behavior after severe traumatic brain injury. AB - PURPOSE: To investigate the occurrence and severity of agitation in patients after severe traumatic brain injury (TBI), to identify predictors of agitation and to study interrater reliability for a translated version of the Agitated Behavior Scale (ABS). DESIGN: Prospective observational study. From November 1, 2006, through October 2007, 46 consecutive patients with TBI were included in the early rehabilitation phase following neurosurgical intervention. Agitated behavior was assessed by the ABS, which was implemented in clinical practice. Logistic regression analysis identified predictors of agitated behavior and Intra Class Correlation was used to analyze reliability. FINDINGS: Agitated behavior occurred in 41% of patients, of whom one third exhibited severely agitated behavior. The interrater reliability between three nurses was good to excellent. CONCLUSIONS: Using ABS as a tool in care of patients with agitated behavior may be effective through working as a common language. CLINICAL RELEVANCE: We recommend the use of ABS as a routine assessment in early rehabilitation of patients with TBI. PMID- 23658128 TI - A pilot for understanding interdisciplinary teams in rehabilitation practice. AB - Interdisciplinary teams in rehabilitation are effective for positive patient outcomes. They require skills in team building and interprofessional collaboration. The Institute of Medicine has interdisciplinary teams as one of the five core competencies for healthcare workers. In reviewing the literature on teams, several themes were developed, such as communication, collaboration, understanding of roles, and educational levels of team members. Using these themes, a survey was developed to assess perceptions of teams by rehabilitation nurses, physical therapists, and occupational therapists. Significant findings came from questions on educational levels of team members between nurses and occupational therapists and also within the nursing groups. Open-ended questions asked about barriers and facilitators for effective teams. We hope that these pilot results will lead to discussions on how to improve interdisciplinary teams and make them more effective for better patient outcomes. PMID- 23658129 TI - Reducing urine leakage after radical retropubic prostatectomy: pelvic floor exercises, magnetic innervation or no treatment? A quasi-experimental study. AB - BACKGROUND: In Italy, nurses can use pelvic floor muscle exercises (PFMEs) and extracorporeal magnetic innervation (ExMI) to treat urinary incontinence after radical retropubic prostatectomy (RRP). The efficacy of these treatments remains unclear. PURPOSE: To compare PFMEs, ExMI, in the management of post-RRP urinary incontinence. METHODOLOGY: This study compared PFMEs versus no treatment in reducing bladder continence difficulties, and PFMEs versus ExMI in reducing urine leakage. A total of 87 patients were treated with PFMEs, 23 with ExMI; 22 refused rehabilitation (control group). FINDINGS: Three months after RRP, both interventions reduced the International Prostate Symptom Score, when compared to control group. After 6 months, no significant differences between the treatments were found (p = .8346). After a complete ExMI treatment (6 weeks), 63.88% lost less than 10 grams of urine per day (32.73% in the PFMEs group, p < .0001). CONCLUSIONS: PFMEs are useful up to the 3rd month after surgery; ExMI reduces leakages faster than PFMEs. PMID- 23658130 TI - The concomitance of pneumoconiosis and stroke. PMID- 23658131 TI - Comparison of fallers and nonfallers at an inpatient rehabilitation facility: a retrospective review. PMID- 23658132 TI - A meta-analysis of HIF-1alpha and esophageal squamous cell carcinoma (ESCC) risk. AB - To investigate the correlation of hypoxia-inducible factor-1alpha (HIF-1alpha) expression with clinical prognosis and efficacy of radiochemotherapy in esophageal squamous cell carcinoma (ESCC). Studies assessing the clinical or prognostic significance of HIF-1alpha expression in ESCC published prior to December 2011 were selected by searching PubMed, EMBASE, Cochrane Library, and (China National Knowledge Infrastructure) CNKI. A meta-analysis was performed to clarify the impact of HIF-1alpha expression on clinicopathological parameters or survival in ESCC. A total of 16 studies met the inclusion criteria, which included 1261 patients with ESCC. Accordingly, the level of HIF-1alpha expression in esophageal tissues of patients with ESCC was significantly higher than that in normal patients (odds ratio, OR = 33.111, 95 % confidence interval, CI = 11.912 92.040). The expression of HIF-1alpha correlated with the depth of invasion (OR = 1.701, 95 % CI = 1.076-4.705), clinical TNM stage (OR = 2.160, 95%CI = 1.516 3.077), as well as lymph node metastasis (OR = 2.393, 95 % CI = 1.319-4.344), regardless of differentiation grading (OR = 1.185, 95 % CI = 0.859-1.635). Furthermore, there was a significant association of increased HIF-1alpha expression with poorer radiochemotherapy outcomes, 2-year overall survival (OR = 0.219, 95 % CI = 0.104-0.461) and survival (OR = 0.320, 95 % CI = 0.115-0.887, P < 0.05) in patients with ESCC. In addition, HIF-1alpha expression correlated with VEGF expression in the ESCCs (OR = 4.635, 95%CI = 2.591-8.292). Increased expression of HIF-1alpha plays an important role in the malignant biology of ESCC resulting in significantly poorer radiochemotherapy outcomes and 2-year overall survival. HIF-1alpha expression may be a prognostic factor, as well as a potential target for therapy in patients with ESCC. PMID- 23658133 TI - Collagen triple helix repeat containing-1 (CTHRC1) expression in invasive ductal carcinoma of the breast: the impact on prognosis and correlation to clinicopathologic features. AB - CTHRC1 has been known as a regulator of collagen expression and cell migration. The aim of this research was to clarify the clinicopathologic significance of CTHRC1 expression in human breast cancer. 22 cases of breast cancer tissues, randomly selected from clinically diagnosed patients, showed a significant increase of CTHRC1 mRNA expression compared to the normal tissue from the same patients using RT-PCR and real-time PCR. Additionally we investigated breast cancers from 189 patients by immunohistochemistry (IHC). A high level of CTHRC1 expression was observed in 111 (58.7 %) out of 189 breast cancer patients and the expression was significantly correlated with histologic grade (P = 0.026), nodal status (P < 0.001), and TNM pathologic stage (P = 0.002). High CTHRC1 expression was associated with a shorter recurrence free survival (P = 0.008). Taken together, the results showed that CTHRC1 over-expression was significantly associated with clinicopathological factors of poor prognosis in invasive ductal carcinoma. CTHRC1 could be used as a supplementary prognostic biomarker and a potential therapeutic target in breast cancer. PMID- 23658134 TI - Long-term neurodevelopmental and cardiovascular outcome after intrauterine transfusions for fetal anaemia: a review. AB - Perinatal survival rates after intrauterine transfusions (IUT) for red cell alloimmunisation now exceed 90%, which demonstrates the safety and efficacy of one of the most successful procedures in fetal therapy. However, improved perinatal survival could lead to an increased number of children with long-term disabilities. The importance of long-term follow-up studies in fetal therapy lies in both the necessity of evaluation of antenatal management as well as in evidence-based preconceptional and prenatal counselling. This review describes the possible long-term cardiovascular and neurodevelopmental sequelae after IUT treatment for different indications including red cell alloimmunisation, parvovirus B19 infection, fetomaternal haemorrhage and twin anaemia-polycythaemia sequence. PMID- 23658136 TI - A validated normal phase LC method for enantiomeric separation of rasagiline mesylate and its (S)-enantiomer on cellulose derivative-based chiral stationary phase. AB - A simple, sensitive, and robust normal-phase isocratic HPLC-UV method was developed and validated for the enantiomeric separation of rasagiline mesylate and its (S)-enantiomer. The rasagiline and its (S)-enantiomer were resolved on a Chiralcel-OJ-H (4-methylbenzoate cellulose coated on silica) column using a mobile phase consisting of n-hexane:isopropyl alcohol:ethanol:diethyl amine (96:2:2:0.01) at a flow rate of 1.0 ml/min. The column temperature was maintained at 27 degrees C and elution was monitored at 215 nm. The resolution (Rs ) between the enantiomers was found to be more than 2.0. The limit of detection and the limit of quantification of the (S)-enantiomer were found to be 0.35 and 1.05 ug/ml, respectively. The developed method was validated as per ICH guidelines with respect to linearity, limit of detection and quantification, accuracy, precision, and robustness-and satisfactory results were obtained. The sample solution and mobile phase were found to be stable up to 48 h. The method is useful for routine evaluation of the quality of rasagiline mesylate in bulk drug manufacturing units. PMID- 23658135 TI - Cognitive behavioral therapy age effects in child and adolescent anxiety: an individual patient data metaanalysis. AB - BACKGROUND: Investigations of age effects on youth anxiety outcomes in randomized trials (RCTs) of cognitive behavior therapy (CBT) have failed to yield a clear result due to inadequate statistical power and methodologic weaknesses. We conducted an individual patient data metaanalysis to address this gap. QUESTION: Does age moderate CBT effect size, measured by a clinically and statistically significant interaction between age and CBT exposure? METHODS: All English language RCTs of CBT for anxiety in 6-19 year olds were identified using systematic review methods. Investigators of eligible trials were invited to submit their individual patient data. The anxiety disorder interview schedule (ADIS) primary diagnosis severity score was the primary outcome. Age effects were investigated using multilevel modeling to account for study level data clustering and random effects. RESULTS: Data from 17 of 23 eligible trials were obtained (74%); 16 studies and 1,171 (78%) cases were available for the analysis. No interaction between age and CBT exposure was found in a model containing age, sex, ADIS baseline severity score, and comorbid depression diagnosis (power >= 80%). Sensitivity analyses, including modeling age as both a categorical and continuous variable, revealed this result was robust. CONCLUSIONS: Adolescents who receive CBT in efficacy research studies show benefits comparable to younger children. However, CBT protocol modifications routinely carried out by expert trial therapists may explain these findings. Adolescent CBT protocols are needed to facilitate the transportability of efficacy research effects to usual care settings where therapists may have less opportunity for CBT training and expertise development. PMID- 23658138 TI - The influence of image setting on intracranial translucency measurement by manual and semi-automated system. AB - OBJECTIVE: To investigate the agreement between manual and semi-automated system and the effect of different image settings on intracranial translucency (IT) measurement. METHODS: A prospective study was conducted on 55 women carrying singleton pregnancy who attended first trimester Down syndrome screening. IT was measured both manually and by semi-automated system at the same default image setting. The IT measurements were then repeated with the post-processing changes in the image setting one at a time. The difference in IT measurements between the altered and the original images were assessed. RESULTS: Intracranial translucency was successfully measured on 55 images both manually and by semi-automated method. There was strong agreement in IT measurements between the two methods with a mean difference (manual minus semi-automated) of 0.011 mm (95% confidence interval--0.052 mm-0.094 mm). There were statistically significant variations in both manual and semi-automated IT measurement after changing the Gain and the Contrast. The greatest changes occurred when the Contrast was reduced to 1 (IT reduced by 0.591 mm in semi-automated; 0.565 mm in manual), followed by when the Gain was increased to 15 (IT reduced by 0.424 mm in semi-automated; 0.524 mm in manual). CONCLUSIONS: The image settings may affect IT identification and measurement. Increased Gain and reduced Contrast are the most influential factors and may cause under-measurement of IT. PMID- 23658137 TI - Future of cholesteryl ester transfer protein (CETP) inhibitors: a pharmacological perspective. AB - In almost 30 years since the introduction of HMG-CoA reductase inhibitors (statins), no other class of lipid modulators has entered the market. Elevation of high-density lipoprotein-cholesterol (HDL-C) via inhibiting cholesteryl ester transfer protein (CETP) is an attractive strategy for reducing the risk of cardiovascular events in high-risk patients. Transfer of triglyceride and cholesteryl ester (CE) between lipoproteins is mediated by CETP; thus inhibition of this pathway can increase the concentration of HDL-C. Torcetrapib was the first CETP inhibitor evaluated in phase III clinical trials. Because of off target effects, torcetrapib raised blood pressure and increased the concentration of serum aldosterone, leading to higher cardiovascular events and mortality. Torcetrapib showed positive effects on cardiovascular risk especially in patients with a greater increase in HDL-C and apolipoprotein A-1 (apoA-1) levels. The phase III clinical trial of dalcetrapib, the second CETP inhibitor that has entered clinical development, was terminated because of ineffectiveness. Dalcetrapib is a CETP modulator that elevated HDL-C levels but did not reduce the concentration of low-density lipoprotein cholesterol (LDL-C). Both heterotypic and homotypic CE transfer between lipoproteins are mediated by some CETP inhibitors, including torcetrapib, anacetrapib, and evacetrapib, while dalcetrapib only affects the heterotypic CE transfer. Dalcetrapib has a chemical structure that is distinct from other CETP inhibitors, with a smaller molecular weight and a lack of trifluoride moieties. Moreover, dalcetrapib is a pro-drug that must be hydrolyzed to a pharmacologically active thiol form. Two other CETP inhibitors, anacetrapib and evacetrapib, are currently undergoing evaluation in phase III clinical trials. Both molecules have shown beneficial effects by increasing HDL-C and decreasing LDL-C concentration. The success of anacetrapib and evacetrapib remains to be confirmed upon the completion of phase III clinical trials in 2017 and 2015, respectively. Generally, the concentration of HDL-C has been considered a biomarker for the activity of CETP inhibitors. However, it is not clear whether a fundamental relationship exists between HDL-C levels and the risk of coronary artery diseases. The most crucial role for HDL is cholesterol efflux capacity in which HDL can reverse transport cholesterol from foam cells in atherosclerotic plaques. In view of the heterogeneity in HDL particle size, charge, and composition, the mere concentration of HDL-C may not be a good surrogate marker for HDL functionality. Recent clinical studies have reported that increased HDL functionality inversely correlates with the development of atherosclerotic plaque. Future development of CETP inhibitors may therefore benefit from the use of biomarkers of HDL functionality. PMID- 23658139 TI - Polymer bulk heterojunction solar cells with PEDOT:PSS bilayer structure as hole extraction layer. AB - A high current density obtained in a limited, nanometer-thick region is important for high efficiency polymer solar cells (PSCs). The conversion of incident photons to charge carriers only occurs in confined active layers; therefore, charge-carrier extraction from the active layer within the device by using solar light has an important impact on the current density and the related to power conversion efficiency. In this study, we observed a surprising result, that is, extracting the charge carrier generated in the active layer of a PSC device, with a thickness-controlled PEDOT:PSS bilayer that acted as a hole extraction layer (HEL), yielded a dramatically improved power conversion efficiency in two different model systems (P3HT:PC60BM and PCDTBT:PC70BM). To understand this phenomenon, we conducted optical strength simulation, photocurrent-voltage measurements, incident photon to charge carrier efficiency measurements, ultraviolet photoelectron spectroscopy, and AFM studies. The results revealed that approximately 60 nm was the optimum PEDOT:PSS bilayer HEL thickness in PSCs for producing the maximum power conversion efficiency. PMID- 23658140 TI - Smoking and suicidality in subjects with bipolar disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). AB - BACKGROUND: Smoking in patients with bipolar disorder is known to be related to suicidality. This link has not been investigated, however, in community-based samples. The aim of this study is to delineate the sociodemographic and clinical characteristics of bipolar smokers and examine the relationship between these characteristics and suicidal ideation or attempts in an epidemiologic database, the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). METHODS: Subjects (n = 1,643) with bipolar disorder I and II, defined by the DSM IV criteria, who had a history of low moods lasting more than 2 weeks were included in our analysis. Current smokers, former smokers, and lifetime nonsmokers were compared in terms of demographic, clinical characteristics, and functional level. Suicidality, evaluated by a history of suicide ideation and attempts while in low mood were compared. RESULTS: Current smokers with bipolar disorder showed a greater number of DSM-IV symptoms while in acute episodes, higher rate of alcohol, and drug use disorders, as well as poorer functional levels than nonsmokers. Previous smokers displayed intermediate characteristics between current smokers and nonsmokers. The logistic regression analysis revealed that current smoking status predicted the risk of having a history of attempted suicide (Odds ratio 1.35, 95% CI: 1.05-1.76) after adjusting for age, sex, race, bipolar subtype, lifetime axis II/anxiety/alcohol use/substance use disorder; however, lifetime smoking status did not. CONCLUSIONS: The present study confirms that current cigarette smoking can predict attempted suicide in a community representative sample of people with bipolar disorder. PMID- 23658141 TI - Stereodynamics of nitrogen chiral centers in aza-beta3-cyclodipeptides. AB - The present work is devoted to the synthesis, conformational analysis, and stereodynamic study of aza-beta(3)-cyclodipeptides. This pseudopeptidic ring shows E/Z hydrazide bond isomerism, eight-membered ring conformation, and chirotopic nitrogen atoms, all of which are elements that are prone to modulate the ring shape. The (E,E) twist boat conformation observed in the solid state by X-ray diffraction is also the ground conformation in solution, and emerges as the lowest in energy when using quantum chemical calculations. The relative configuration associated with ring chirality and with the two nitrogen chiral centers is governed by steric crowding and adopts the (P)S(N) S(N)/(M)R(N)R(N) combination which projects side chains in equatorial position. The nitrogen pyramidal inversion (NPI) at the two chiral centers is correlated with the ring reversal. The process is significantly hindered as was shown by VT-NMR experiments run in C2D2Cl4, which did not make it possible to determine the barrier to inversion. Finally, these findings make it conceivable to resolve enantiomers of aza-beta(3)-cyclodipeptides by modulating the backbone decoration appropriately. PMID- 23658142 TI - A skin rash and what lies beneath: paraneoplastic pemphigus, an atypical presentation of follicular cell lymphoma. PMID- 23658144 TI - Cell-free fetal DNA in maternal circulation after chorionic villous sampling. AB - OBJECTIVE: This study aims to estimate whether chorionic villous sampling (CVS) causes a significant increase of cell-free fetal DNA (cffDNA) in maternal circulation. METHOD: Fifty pregnant women with singleton pregnancy were recruited prior to CVS. Maternal peripheral blood was collected before and after CVS. A methylation-sensitive restriction enzyme digestion was used to select the placental-derived hypermethylated promoter of the RASSF1A gene in maternal plasma, thus differentiating cffDNA from mother's cell-free DNA (cfDNA), where the RASSF1A gene is normally hypomethylated. Total cfDNA and cffDNA amounts were compared before and after CVS in each patient. Data were compared using the Student t-test. RESULTS: No significant difference before and after CVS was found between the following: (i) total cfDNA concentration in plasma (p = 0.695); (ii) cffDNA concentration in plasma (p = 0.612); and (iii) percentage of fetal DNA in plasma (p = 0.835). After dividing the cases on the basis of the sex of the fetus, maternal age, gestational age, number of pregnancies, position of the placenta, and presence of trisomy of the fetus, no difference in fetal and total DNA concentrations before and after CVS was observed. CONCLUSION: The CVS does not seem to significantly disrupt the maternal-placental interface, as no significant increase of cffDNA in maternal plasma following CVS was observed. PMID- 23658145 TI - Effects of transitioning from conventional methods to liquid-based methods on unsatisfactory Papanicolaou tests: results from a multicenter US study. AB - BACKGROUND: Papanicolaou (Pap) testing has transitioned from conventional preparations (CPs) to liquid-based preparations (LBPs) because of the perceived superiority of LBPs. Many studies conclude that LBPs reduce unsatisfactory Pap tests; however, some believe that the evidence substantiating this claim is weak. The authors studied the effect of the transition from CPs to LBPs on the proportion of unsatisfactory Pap tests in 4 health care systems in the United States participating in the National Institutes of Health-funded Screening Effectiveness and Research in Community-Based Healthcare (SEARCH) project. METHODS: The study cohort consisted of 548,174 women ages 21 to 65 years who had 1443,725 total Pap tests between 2000 and 2010. Segmented regression analysis was used to estimate the effect of adopting LBPs on the proportion of unsatisfactory Pap tests after adjusting for age. RESULTS: Three sites that implemented SurePath LBP experienced significant reductions in unsatisfactory Pap tests (estimated effect: site 1, -2.46%; 95% confidence interval [CI], -1.47%, -3.45%; site 2, 1.78%; 95% CI, -1.54%, -2.02%; site 3, -8.25%; 95% CI, -7.33%, -9.17%). The fourth site that implemented ThinPrep LBP did not experience a reduction in unsatisfactory Pap tests. The relative risk of an unsatisfactory Pap test in women aged >= 50 years increased after the transition to LBPs (SurePath: relative risk, 2.1; 95% CI, 1.9-2.2; ThinPrep: relative risk, 1.7; 95% CI, 1.5-2.0). CONCLUSIONS: The observed changes in the proportion of unsatisfactory Pap tests varied across the participating sites and depended on the type of LBP technology, the age of women, and the rates before the implementation of this technology. PMID- 23658147 TI - Augmentation of youth cognitive behavioral and pharmacological interventions with attention modification: a preliminary investigation. AB - BACKGROUND: Recent research suggests the efficacy of attention modification programs (AMP) in treating adult anxiety.([1]) Though some research supports the success of AMP treatment in anxious youths,([2, 3]) to date no study has examined the efficacy of AMP as an adjunctive treatment to other psychosocial and pharmacological interventions for anxious youths within the community. METHODS: In the current study, we examined the efficacy of AMP as an adjunctive treatment to standard care at a residential anxiety treatment facility. Adolescents (N = 42) completed either an active (attention modification program, AMP; n = 21) or a control (attention control condition, ACC; n = 21) condition, in addition to the facility's standard treatment protocol, which included cognitive behavioral therapy with or without medication. RESULTS: While anxiety symptoms decreased for participants across both groups, participants in the AMP group experienced a significantly greater decrease in anxiety symptoms from point of intake to point of discharge, in comparison to participants in the ACC group. CONCLUSIONS: These results suggest that AMP is an effective adjunctive treatment to the standard treatments of choice for anxiety disorders, and may hold promise for improving treatment response in highly anxious youths. PMID- 23658148 TI - Spatial variation in herbicide leaching from a marine clay soil via subsurface drains. AB - BACKGROUND: Subsurface transport via tile drains can significantly contribute to pesticide contamination of surface waters. The spatial variation in subsurface leaching of normally applied herbicides was examined together with phosphorus losses in 24 experimental plots with water sampled flow-proportionally. The study site was a flat, tile-drained area with 60% marine clay in the topsoil in southeast Sweden. The objectives were to quantify the leaching of frequently used herbicides from a tile drained cracking clay soil and to evaluate the variation in leaching within the experimental area and relate this to topsoil management practices (tillage method and structure liming). RESULTS: In summer 2009, 0.14, 0.22 and 1.62%, respectively, of simultaneously applied amounts of MCPA, fluroxypyr and clopyralid were leached by heavy rain five days after spraying. In summer 2011, on average 0.70% of applied bentazone was leached by short bursts of intensive rain 12 days after application. Peak flow concentrations for 50% of the treated area for MCPA and 33% for bentazone exceeded the Swedish no-effect guideline values for aquatic ecosystems. Approximately 0.08% of the glyphosate applied was leached in dissolved form in the winters of 2008/2009 and 2010/2011. Based on measurements of glyphosate in particulate form, total glyphosate losses were twice as high (0.16%) in the second winter. The spatial inter-plot variation was large (72-115%) for all five herbicides studied, despite small variations (25%) in water discharge. CONCLUSIONS: The study shows the importance of local scale soil transport properties for herbicide leaching in cracking clay soils. PMID- 23658149 TI - Mir-142-3p target sequences reduce transgene-directed immunogenicity following intramuscular adeno-associated virus 1 vector-mediated gene delivery. AB - BACKGROUND: Muscle represents an important tissue target for adeno-associated virus (AAV) vector-mediated gene transfer in muscular, metabolic or blood-related genetic disorders. However, several studies have demonstrated the appearance of immune responses against the transgene product after intramuscular AAV vector delivery that resulted in a limited efficacy of the treatment. Use of microRNAs that are specifically expressed in antigen-presenting cells (APCs) is a promising approach for avoiding those immune responses. Cellular mir-142-3p, which is APC specific, is able to repress the translation of its target cellular transcripts by binding to a specific target sequences. METHODS: In the present study, we explored the potential of mir-142-3p specific target sequences with respect to reducing or abolishing immune responses directed against ovalbumin (OVA), a highly immunogenic protein, expressed as transgene and delivered by AAV1 vector administered intramuscularly. RESULTS: The occurrence of immune responses against OVA transgene following intramuscular delivery by AAV have been described previously and resulted in the loss of OVA protein expression. In the present study, we demonstrate that OVA protein expression was maintained when mir-142-3pT sequences were incorporated into the expression cassette. The sustained expression of OVA protein over time correlated with a reduced increase in anti OVA antibody levels. Furthermore, no cellular infiltrates were observed in the muscle tissue when AAV1 vectors containing four or eight repeats of mir-142-3p target sequences after the OVA sequence were used. CONCLUSIONS: The rising humoral and cellular immune responses against OVA protein after intramuscular delivery can be efficiently reduced by the use of mir-142-3p target sequences. PMID- 23658151 TI - Imbalances in prefrontal cortex CC-Homer1 versus CC-Homer2 expression promote cocaine preference. AB - Homer postsynaptic scaffolding proteins regulate forebrain glutamate transmission and thus, are likely molecular candidates mediating hypofrontality in addiction. Protracted withdrawal from cocaine experience increases the relative expression of Homer2 versus Homer1 isoforms within medial prefrontal cortex (mPFC). Thus, this study used virus-mediated gene transfer strategies to investigate the functional relevance of an imbalance in mPFC Homer1/2 expression as it relates to various measures of sensorimotor, cognitive, emotional and motivational processing, as well as accompanying alterations in extracellular glutamate in C57BL/6J mice. mPFC Homer2b overexpression elevated basal glutamate content and blunted cocaine-induced glutamate release within the mPFC, whereas Homer2b knockdown produced the opposite effects. Despite altering mPFC glutamate, Homer2b knockdown failed to influence cocaine-elicited conditioned place preferences, nor did it produce consistent effects on any other behavioral measures. In contrast, elevating the relative expression of Homer2b versus Homer1 within mPFC, by overexpressing Homer2b or knocking down Homer1c, shifted the dose-response function for cocaine-conditioned reward to the left, without affecting cocaine locomotion or sensitization. Intriguingly, both these transgenic manipulations produced glutamate anomalies within the nucleus accumbens (NAC) of cocaine-naive animals that are reminiscent of those observed in cocaine experienced animals, including reduced basal extracellular glutamate content, reduced Homer1/2 and glutamate receptor expression, and augmented cocaine-elicited glutamate release. Together, these data provide novel evidence in support of opposing roles for constitutively expressed Homer1 and Homer2 isoforms in regulating mPFC glutamate transmission in vivo and support the hypothesis that cocaine-elicited increases in the relative amount of mPFC Homer2 versus Homer1 signaling produces abnormalities in NAC glutamate transmission that enhance vulnerability to cocaine reward. PMID- 23658152 TI - beta-Actin and fascin-2 cooperate to maintain stereocilia length. AB - Stereocilia are actin-based protrusions on auditory sensory hair cells that are deflected by sound waves to initiate the conversion of mechanical energy to neuronal signals. Stereocilia maintenance is essential because auditory hair cells are not renewed in mammals. This process requires both beta-actin and gamma actin as knock-out mice lacking either isoform develop distinct stereocilia pathology during aging. In addition, stereocilia integrity may hinge on immobilizing actin, which outside of a small region at stereocilia tips turns over with a very slow, months-long half-life. Here, we establish that beta-actin and the actin crosslinking protein fascin-2 cooperate to maintain stereocilia length and auditory function. We observed that mice expressing mutant fascin-2 (p.R109H) or mice lacking beta-actin share a common phenotype including progressive, high-frequency hearing loss together with shortening of a defined subset of stereocilia in the hair cell bundle. Fascin-2 binds beta-actin and gamma-actin filaments with similar affinity in vitro and fascin-2 does not depend on beta-actin for localization in vivo. Nevertheless, double-mutant mice lacking beta-actin and expressing fascin-2 p.R109H have a more severe phenotype suggesting that each protein has a different function in a common stereocilia maintenance pathway. Because the fascin-2 p.R109H mutant binds but fails to efficiently crosslink actin filaments, we propose that fascin-2 crosslinks function to slow actin depolymerization at stereocilia tips to maintain stereocilia length. PMID- 23658153 TI - Widespread sensitivity to looming stimuli and small moving objects in the central complex of an insect brain. AB - In many situations animals are confronted with approaching objects. Depending on whether the approach represents a potential threat or is intended during a goal oriented approach, the adequate behavioral strategies differ. In all of these cases the visual system experiences an expanding or looming shape. The neuronal machinery mediating looming elicited behavioral responses has been studied most comprehensively in insects but is still far from being fully understood. It is particularly unknown how insects adjust their behavior to objects approaching from different directions. A brain structure that is thought to play an important role in spatial orientation in insects is the central complex (CC). We investigated whether CC neurons process information about approaching objects on a collision course. We recorded intracellularly from CC neurons in the locust Schistocerca gregaria during visual stimulation via lateral LCD screens. Many neurons in the locust CC, including columnar and tangential neurons, were sensitive to looming stimuli. Some of the neurons also responded to small moving targets. Several cell types showed binocular responses to looming objects, and some neurons were excited or inhibited depending on which eye was stimulated. These neurons may, therefore, detect the gross azimuthal direction of approaching objects and may mediate directional components of escape or steering movements. PMID- 23658154 TI - The novel gene tank, a tumor suppressor homolog, regulates ethanol sensitivity in Drosophila. AB - In both mammalian and insect models of ethanol intoxication, high doses of ethanol induce motor impairment and eventually sedation. Sensitivity to the sedative effects of ethanol is inversely correlated with risk for alcoholism. However, the genes regulating ethanol sensitivity are largely unknown. Based on a previous genetic screen in Drosophila for ethanol sedation mutants, we identified a novel gene, tank (CG15626), the homolog of the mammalian tumor suppressor EI24/PIG8, which has a strong role in regulating ethanol sedation sensitivity. Genetic and behavioral analyses revealed that tank acts in the adult nervous system to promote ethanol sensitivity. We localized the function of tank in regulating ethanol sensitivity to neurons within the pars intercerebralis that have not been implicated previously in ethanol responses. We show that acutely manipulating the activity of all tank-expressing neurons, or of pars intercerebralis neurons in particular, alters ethanol sensitivity in a sexually dimorphic manner, since neuronal activation enhanced ethanol sedation in males, but not females. Finally, we provide anatomical evidence that tank-expressing neurons form likely synaptic connections with neurons expressing the neural sex determination factor fruitless (fru), which have been implicated recently in the regulation of ethanol sensitivity. We suggest that a functional interaction with fru neurons, many of which are sexually dimorphic, may account for the sex specific effect induced by activating tank neurons. Overall, we have characterized a novel gene and corresponding set of neurons that regulate ethanol sensitivity in Drosophila. PMID- 23658155 TI - Amperometric resolution of a prespike stammer and evoked phases of fast release from retinal bipolar cells. AB - The neurotransmitter glutamate is used by most neurons in the brain to activate a multitude of different types of glutamate receptors and transporters involved in fast and relatively slower signaling. Synaptic ribbons are large presynaptic structures found in neurons involved in vision, balance, and hearing, which use a large number of glutamate-filled synaptic vesicles to meet their signaling demands. To directly measure synaptic vesicle release events, the ribbon-type presynaptic terminals of goldfish retinal bipolar cells were coaxed to release a false transmitter that could be monitored with amperometry by placing the carbon fiber directly on the larger synaptic terminal. Spontaneous secretion events formed a unimodal charge distribution, but single spike properties were heterogeneous. Larger events rose exponentially without interruption (tau ~ 30 MUs), and smaller events exhibited a stammer in their rising phase that is interpreted as a brief pause in pore dilation, a characteristic commonly associated with large dense core granule fusion pores. These events were entirely Ca(2+)-dependent. Holding the cells at -60 mV halted spontaneous release; and when the voltage was stepped to >-40 mV, secretion ensued. When stepping the voltage to 0 mV, novel kinetic phases of vesicle recruitment were revealed. Approximately 14 vesicles were released per ribbon in two kinetic phases with time constants of 1.5 and 16 ms, which are proposed to represent different primed states within the population of docked vesicles. PMID- 23658156 TI - Effects of prefrontal cortical inactivation on neural activity in the ventral tegmental area. AB - Dopamine (DA) cells have been suggested to signal discrepancies between expected and actual rewards in reinforcement learning. DA cells in the ventral tegmental area (VTA) receive direct projections from the medial prefrontal cortex (mPFC), a structure known to be one of the brain areas that represents expected future rewards. To investigate whether the mPFC contributes to generating reward prediction error signals of DA cells, we recorded VTA cells from rats foraging for different amounts of reward in a spatial working memory task. Our results showed that DA cells initially responded after the acquisition of rewards, but over training, they exhibited phasic responses when rats detected sensory cues originating from the rewards before obtaining them. We also observed two separate groups of non-DA cells activated in expectation of upcoming rewards or during reward consumption. Bilateral injections of muscimol, a GABAA agonist, into the mPFC significantly decreased the non-DA activity that encoded reward expectation. By contrast, the same manipulation of the mPFC elevated DA responses to reward predicting cues. However, neither DA nor non-DA responses elicited after reward acquisition were affected by mPFC inactivation. These results suggest that the mPFC provides information about expected rewards to the VTA, and its functional loss elevates DA responses to reward-predicting cues by altering expectations about forthcoming rewards. PMID- 23658158 TI - The nNOS-p38MAPK pathway is mediated by NOS1AP during neuronal death. AB - Neuronal nitric oxide synthase (nNOS) and p38MAPK are strongly implicated in excitotoxicity, a mechanism common to many neurodegenerative conditions, but the intermediary mechanism is unclear. NOS1AP is encoded by a gene recently associated with sudden cardiac death, diabetes-associated complications, and schizophrenia (Arking et al., 2006; Becker et al., 2008; Brzustowicz, 2008; Lehtinen et al., 2008). Here we find it interacts with p38MAPK-activating kinase MKK3. Excitotoxic stimulus induces recruitment of NOS1AP to nNOS in rat cortical neuron culture. Excitotoxic activation of p38MAPK and subsequent neuronal death are reduced by competing with the nNOS:NOS1AP interaction and by knockdown with NOS1AP-targeting siRNAs. We designed a cell-permeable peptide that competes for the unique PDZ domain of nNOS that interacts with NOS1AP. This peptide inhibits NMDA-induced recruitment of NOS1AP to nNOS and in vivo in rat, doubles surviving tissue in a severe model of neonatal hypoxia-ischemia, a major cause of neonatal death and pediatric disability. The highly unusual sequence specificity of the nNOS:NOS1AP interaction and involvement in excitotoxic signaling may provide future opportunities for generation of neuroprotectants with high specificity. PMID- 23658157 TI - Loss of Ahi1 affects early development by impairing BM88/Cend1-mediated neuronal differentiation. AB - Mutations in the Abelson helper integration site-1 (AHI1) gene result in N terminal Ahi1 fragments and cause Joubert syndrome, an autosomal recessive brain malformation disorder associated with delayed development. How AHI1 mutations lead to delayed development remains unclear. Here we report that full-length, but not N-terminal, Ahi1 binds Hap1, a huntingtin-associated protein that is essential for the postnatal survival of mice and that this binding is regulated during neuronal differentiation by nerve growth factor. Nerve growth factor induces dephosphorylation of Hap1A and decreases its association with Ahi1, correlating with increased Hap1A distribution in neurite tips. Consistently, Ahi1 associates with phosphorylated Hap1A in cytosolic, but not in synaptosomal, fractions isolated from mouse brain, suggesting that Ahi1 functions mainly in the soma of neurons. Mass spectrometry analysis of cytosolic Ahi1 immunoprecipitates reveals that Ahi1 also binds Cend1 (cell cycle exit and neuronal differentiation protein 1)/BM88, a neuronal protein that mediates neuronal differentiation and is highly expressed in postnatal mouse brain. Loss of Ahi1 reduces the levels of Cend1 in the hypothalamus of Ahi1 KO mice, which show retarded growth during postnatal days. Overexpressed Ahi1 can stabilize Cend1 in cultured cells. Furthermore, overexpression of Cend1 can rescue the neurite extension defects of hypothalamic neurons from Ahi1 KO mice. Our findings suggest that Cend1 is involved in Ahi1-associated hypothalamic neuronal differentiation in early development, giving us fresh insight into the mechanism behind the delayed development in Joubert syndrome. PMID- 23658159 TI - Extracellular pH and neuronal depolarization serve as dynamic switches to rapidly mobilize trkA to the membrane of adult sensory neurons. AB - Activation of the nerve growth factor (NGF) receptor trkA and tissue acidosis are critically linked to inflammation-associated nociceptor sensitization. This study explored how increased acidity is linked to sensory neuron sensitization to NGF. Adult Wistar rat primary sensory neurons grown at physiological pH 7.4, then either kept at pH 7.4 or challenged for 30 min in pH 6.5 medium, provided a model of acidosis. Nonpermeabilizing trkA immunofluorescence revealed a significant increase in trkA mobilization to the plasma membrane from intracellular stores in response to proton challenge. This was confirmed using a surface protein biotinylation assay and Brefeldin A disruption of the rough endoplasmic reticulum Golgi-trans-Golgi network. Mobilization of trkA to the membrane at pH 6.5 was abolished in neurons treated with the acid-sensitive ion channel blocker, amiloride. While elevated levels of NGF-independent trkA phosphorylation occurred at pH 6.5 alone, the level of activation was significantly increased in response to NGF challenge. Exposure of sensory neurons to pH 6.5 medium also resulted in strong calcium (Ca(2+)) transients that were reversible upon reintroduction to physiological pH. The pH 6.5-induced mobilization of trkA to the membrane was Ca(2+) dependent, as BAPTA-AM Ca(2+) chelation abrogated the response. Interestingly, KCl-induced depolarization was sufficient to induce mobilization of trkA to the cell surface at pH 7.4, but did not augment the response to pH 6.5. In conclusion, increased mobilization of trkA to neuronal membranes in response to either acidosis or neuronal depolarization provides two novel mechanisms by which sensory neurons can rapidly sensitize to NGF and has important implications for inflammatory pain states. PMID- 23658160 TI - Stabilization of spontaneous neurotransmitter release at ribbon synapses by ribbon-specific subtypes of complexin. AB - Ribbon synapses of tonically releasing sensory neurons must provide a large pool of releasable vesicles for sustained release, while minimizing spontaneous release in the absence of stimulation. Complexins are presynaptic proteins that may accomplish this dual task at conventional synapses by interacting with the molecular machinery of synaptic vesicle fusion at the active zone to retard spontaneous vesicle exocytosis yet facilitate release evoked by depolarization. However, ribbon synapses of photoreceptor cells and bipolar neurons in the retina express distinct complexin subtypes, perhaps reflecting the special requirements of these synapses for tonic release. To investigate the role of ribbon-specific complexins in transmitter release, we combined presynaptic voltage clamp, fluorescence imaging, electron microscopy, and behavioral assays of photoreceptive function in zebrafish. Acute interference with complexin function using a peptide derived from the SNARE-binding domain increased spontaneous synaptic vesicle fusion at ribbon synapses of retinal bipolar neurons without affecting release triggered by depolarization. Knockdown of complexin by injection of an antisense morpholino into zebrafish embryos prevented photoreceptor-driven migration of pigment in skin melanophores and caused the pigment distribution to remain in the dark-adapted state even when embryos were exposed to light. This suggests that loss of complexin function elevated spontaneous release in illuminated photoreceptors sufficiently to mimic the higher release rate normally associated with darkness, thus interfering with visual signaling. We conclude that visual system-specific complexins are required for proper illumination-dependent modulation of the rate of neurotransmitter release at visual system ribbon synapses. PMID- 23658161 TI - Free energy, precision and learning: the role of cholinergic neuromodulation. AB - Acetylcholine (ACh) is a neuromodulatory transmitter implicated in perception and learning under uncertainty. This study combined computational simulations and pharmaco-electroencephalography in humans, to test a formulation of perceptual inference based upon the free energy principle. This formulation suggests that ACh enhances the precision of bottom-up synaptic transmission in cortical hierarchies by optimizing the gain of supragranular pyramidal cells. Simulations of a mismatch negativity paradigm predicted a rapid trial-by-trial suppression of evoked sensory prediction error (PE) responses that is attenuated by cholinergic neuromodulation. We confirmed this prediction empirically with a placebo controlled study of cholinesterase inhibition. Furthermore, using dynamic causal modeling, we found that drug-induced differences in PE responses could be explained by gain modulation in supragranular pyramidal cells in primary sensory cortex. This suggests that ACh adaptively enhances sensory precision by boosting bottom-up signaling when stimuli are predictable, enabling the brain to respond optimally under different levels of environmental uncertainty. PMID- 23658163 TI - A substantial and unexpected enhancement of motion perception in autism. AB - Atypical perceptual processing in autism spectrum disorder (ASD) is well documented. In addition, growing evidence supports the hypothesis that an excitatory/inhibitory neurochemical imbalance might underlie ASD. Here we investigated putative behavioral consequences of the excitatory/inhibitory imbalance in the context of visual motion perception. As stimulus size increases, typical observers exhibit marked impairments in perceiving motion of high contrast stimuli. This result, termed "spatial suppression," is believed to reflect inhibitory motion-processing mechanisms. Motion processing is also affected by gain control, an inhibitory mechanism that underlies saturation of neural responses at high contrast. Motivated by these behavioral correlates of inhibitory function, we investigated motion perception in human children with ASD (n = 20) and typical development (n = 26). At high contrast, both groups exhibited similar impairments in motion perception with increasing stimulus size, revealing no apparent differences in spatial suppression. However, there was a substantial enhancement of motion perception in ASD: children with ASD exhibited a consistent twofold improvement in perceiving motion. Hypothesizing that this enhancement might indicate abnormal weakening of response gain control, we repeated our measurements at low contrast, where the effects of gain control should be negligible. At low contrast, we indeed found no group differences in motion discrimination thresholds. These low-contrast results, however, revealed weaker spatial suppression in ASD, suggesting the possibility that gain control abnormalities in ASD might have masked spatial suppression differences at high contrast. Overall, we report a pattern of motion perception abnormalities in ASD that includes substantial enhancements at high contrast and is consistent with an underlying excitatory/inhibitory imbalance. PMID- 23658164 TI - Multiple modes of phase locking between sniffing and whisking during active exploration. AB - Sense organs are often actively controlled by motor processes and such active sensing profoundly shapes the timing of sensory information flow. The temporal coordination between different active sensing processes is less well understood but is essential for multisensory integration, coordination between brain regions, and energetically optimal sampling strategies. Here we studied the coordination between sniffing and whisking, the motor processes in rodents that control the acquisition of smell and touch information, respectively. Sniffing, high-frequency respiratory bouts, and whisking, rapid back and forth movements of mystacial whiskers, occur in the same theta frequency range (4-12 Hz) leading to a hypothesis that these sensorimotor rhythms are phase locked. To test this, we monitored sniffing using a thermocouple in the nasal cavity and whisking with an electromyogram of the mystacial pad in rats engaged in an open field reward foraging behavior. During bouts of exploration, sniffing and whisking showed strong one-to-one phase locking within the theta frequency range (4-12 Hz). Interestingly, we also observed multimode phase locking with multiple whisks within a sniff cycle or multiple sniffs within a whisk cycle-always at the same preferred phase. This specific phase relationship coupled the acquisition phases of the two sensorimotor rhythms, inhalation and whisker protraction. Our results suggest that sniffing and whisking may be under the control of interdependent rhythm generators that dynamically coordinate active acquisition of olfactory and somatosensory information. PMID- 23658165 TI - Neural limits to representing objects still within view. AB - Visual working memory is an online workspace for temporarily representing visual information from the environment. The two most prevalent empirical characteristics of working memory are that it is supported by sustained neural activity over a delay period and it has a severely limited capacity for representing multiple items simultaneously. Traditionally, such delay activity and capacity limits have been considered to be exclusive for maintaining information about objects that are no longer visible to the observers. Here, by contrast, we provide both neurophysiological and psychophysical evidence that the sustained neural activity and capacity limits for items that are continuously visible to the human observer are indistinguishable from those measured for items that are no longer visible. This holds true even when the observers know that the objects will not disappear from the visual field. These results demonstrate that our explicit representation of objects that are still "in view" is far more limited than previously assumed. PMID- 23658166 TI - The feedback-related negativity signals salience prediction errors, not reward prediction errors. AB - Modulations of the feedback-related negativity (FRN) event-related potential (ERP) have been suggested as a potential biomarker in psychopathology. A dominant theory about this signal contends that it reflects the operation of the neural system underlying reinforcement learning in humans. The theory suggests that this frontocentral negative deflection in the ERP 230-270 ms after the delivery of a probabilistic reward expresses a prediction error signal derived from midbrain dopaminergic projections to the anterior cingulate cortex. We tested this theory by investigating whether FRN will also be observed for an inherently aversive outcome: physical pain. In another session, the outcome was monetary reward instead of pain. As predicted, unexpected reward omissions (a negative reward prediction error) yielded a more negative deflection relative to unexpected reward delivery. Surprisingly, unexpected pain omission (a positive reward prediction error) also yielded a negative deflection relative to unexpected pain delivery. Our data challenge the theory by showing that the FRN expresses aversive prediction errors with the same sign as reward prediction errors. Both FRNs were spatiotemporally and functionally equivalent. We suggest that FRN expresses salience prediction errors rather than reward prediction errors. PMID- 23658167 TI - Serotonin is required for exercise-induced adult hippocampal neurogenesis. AB - Voluntary wheel running has long been known to induce precursor cell proliferation in adult hippocampal neurogenesis in rodents. However, mechanisms that couple activity with the promitotic effect are not yet fully understood. Using tryptophan hydroxylase (TPH) 2 deficient (Tph2-deficient) mice that lack brain serotonin, we explored the relationship between serotonin signaling and exercise-induced neurogenesis. Surprisingly, Tph2-deficient mice exhibit normal baseline hippocampal neurogenesis but impaired activity-induced proliferation. Our data demonstrate that the proproliferative effect of running requires the release of central serotonin in young-adult and aged mice. Lack of brain serotonin further results in alterations at the stage of Sox2-positive precursor cells, suggesting physiological adaptations to changes in serotonin supply to maintain homeostasis in the neurogenic niche. We conclude that serotonin plays a direct and acute regulatory role in activity-dependent hippocampal neurogenesis. The understanding of exercise-induced neurogenesis might offer preventive but also therapeutic opportunities in depression and age-related cognitive decline. PMID- 23658168 TI - NMDA-dependent phase synchronization between septal and temporal CA3 hippocampal networks. AB - Increasing evidence suggests that synchronization between brain regions is essential for information exchange and memory processes. However, it remains incompletely known which synaptic mechanisms contribute to the process of synchronization. Here, we investigated whether NMDA receptor-mediated synaptic plasticity was an important player in synchronization between septal and temporal CA3 areas of the rat hippocampus. We found that both the septal and temporal CA3 regions intrinsically generate weakly synchronized delta frequency oscillations in the complete hippocampus in vitro. Septal and temporal oscillators differed in frequency, power, and rhythmicity, but both required GABAA and AMPA receptors. NMDA receptor activation, and most particularly the NR2B subunit, contributed considerably more to rhythm generation at the temporal than the septal region. Brief activation of NMDA receptors by application of extracellular calcium dramatically potentiated the septal-temporal coherence for long durations (>40 min), an effect blocked by the NMDA antagonist AP-5. This long-lasting NMDA receptor-dependent increase in coherence was also associated with an elevated phase locking of spikes locally and across regions. Changes in coherence between oscillators were associated with increases in phase locking between oscillators independent of oscillator amplitude. Finally, although the septal CA3 rhythm preceded the oscillations in temporal regions in control conditions, this was reversed during the NMDA-dependent enhancement in coherence, suggesting that NMDA receptor activation can change the direction of information flow along the septotemporal CA3 axis. These data demonstrate that plastic changes in communication between septal and temporal hippocampal regions can arise from the NMDA-dependent phase locking of neural oscillators. PMID- 23658162 TI - Brain changes in older adults at very low risk for Alzheimer's disease. AB - Alzheimer's disease (AD) has a slow onset, so it is challenging to distinguish brain changes in healthy elderly persons from incipient AD. One-year brain changes with a distinct frontotemporal pattern have been shown in older adults. However, it is not clear to what extent these changes may have been affected by undetected, early AD. To address this, we estimated 1-year atrophy by magnetic resonance imaging (MRI) in 132 healthy elderly persons who had remained free of diagnosed mild cognitive impairment or AD for at least 3 years. We found significant volumetric reductions throughout the brain. The sample was further divided into low-risk groups based on clinical, biomarker, genetic, or cognitive criteria. Although sample sizes varied, significant reductions were observed in all groups, with rates and topographical distribution of atrophy comparable to that of the full sample. Volume reductions were especially pronounced in the default mode network, closely matching the previously described frontotemporal pattern of changes in healthy aging. Atrophy in the hippocampus predicted change in memory, with no additional default mode network contributions. In conclusion, reductions in regional brain volumes can be detected over the course of 1 year even in older adults who are unlikely to be in a presymptomatic stage of AD. PMID- 23658169 TI - Limited encoding of effort by dopamine neurons in a cost-benefit trade-off task. AB - Animals are thought to evaluate the desirability of action options using a unified scale that combines predicted benefits ("rewards"), costs, and the animal's internal motivational state. Midbrain dopamine neurons have long been associated with the reward part of this equation, but it is unclear whether these neurons also estimate the costs of taking an action. We studied the spiking activity of dopamine neurons in the substantia nigra pars compacta of monkeys (Macaca mulatta) during a reaching task in which the energetic costs incurred (friction loads) and the benefits gained (drops of food) were manipulated independently. Although the majority of dopamine neurons encoded the upcoming reward alone, a subset predicted net utility of a course of action by signaling the expected reward magnitude discounted by the invested cost in terms of physical effort. In addition, the tonic activity of some dopamine neurons was slowly reduced in conjunction with the accumulated trials, which is consistent with the hypothesized role for tonic dopamine in the invigoration or motivation of instrumental responding. The present results shed light on an often hypothesized role for dopamine in the regulation of the balance in natural behaviors between the energy expended and the benefits gained, which could explain why dopamine disorders, such as Parkinson's disease, lead to a breakdown of that balance. PMID- 23658171 TI - "Master" neurons induced by operant conditioning in rat motor cortex during a brain-machine interface task. AB - Operant control of a prosthesis by neuronal cortical activity is one of the successful strategies for implementing brain-machine interfaces (BMI), by which the subject learns to exert a volitional control of goal-directed movements. However, it remains unknown if the induced brain circuit reorganization affects preferentially the conditioned neurons whose activity controlled the BMI actuator during training. Here, multiple extracellular single-units were recorded simultaneously in the motor cortex of head-fixed behaving rats. The firing rate of a single neuron was used to control the position of a one-dimensional actuator. Each time the firing rate crossed a predefined threshold, a water bottle moved toward the rat, until the cumulative displacement of the bottle allowed the animal to drink. After a learning period, most (88%) conditioned neurons raised their activity during the trials, such that the time to reward decreased across sessions: the conditioned neuron fired strongly, reliably and swiftly after trial onset, although no explicit instruction in the learning rule imposed a fast neuronal response. Moreover, the conditioned neuron fired significantly earlier and more strongly than nonconditioned neighboring neurons. During the first training sessions, an increase in firing rate variability was seen only for the highly conditionable neurons. This variability then decreased while the conditioning effect increased. These findings suggest that modifications during training target preferentially the neuron chosen to control the BMI, which acts then as a "master" neuron, leading in time the reconfiguration of activity in the local cortical network. PMID- 23658170 TI - The long-term structural plasticity of cerebellar parallel fiber axons and its modulation by motor learning. AB - Presynaptic axonal varicosities, like postsynaptic spines, are dynamically added and eliminated even in mature neuronal circuitry. To study the role of this axonal structural plasticity in behavioral learning, we performed two-photon in vivo imaging of cerebellar parallel fibers (PFs) in adult mice. PFs make excitatory synapses on Purkinje cells (PCs) in the cerebellar cortex, and long term potentiation and depression at PF-PC synapses are thought to play crucial roles in cerebellar-dependent learning. Time-lapse vital imaging of PFs revealed that, under a control condition (no behavioral training), ~10% of PF varicosities appeared and disappeared over a period of 2 weeks without changing the total number of varicosities. The fraction of dynamic PF varicosities significantly diminished during training on an acrobatic motor skill learning task, largely because of reduced addition of new varicosities. Thus, this form of motor learning was associated with greater structural stability of PFs and a slight decrease in the total number of varicosities. Together with prior findings that the number of PF-PC synapses increases during similar training, our results suggest that acrobatic motor skill learning involves a reduction of some PF inputs and a strengthening of others, probably via the conversion of some preexisting PF varicosities into multisynaptic terminals. PMID- 23658172 TI - Cholinergic control over attention in rats prone to attribute incentive salience to reward cues. AB - Some rats [sign-trackers (STs)] are especially prone to attribute incentive salience to reward cues, relative to others [goal-trackers (GTs)]. Thus, reward cues are more likely to promote maladaptive reward-seeking behavior in STs than GTs. Here, we asked whether STs and GTs differ on another trait that can contribute to poor restraint over behavior evoked by reward cues. We report that, relative to GTs, STs have poor control over attentional performance, due in part to insufficient cholinergic stimulation of cortical circuitry. We found that, relative to GTs, STs showed poor performance on a sustained attention task (SAT). Furthermore, their performance fluctuated rapidly between periods of good to near chance performance. This finding was reproduced using a separate cohort of rats. As demonstrated earlier, performance on the SAT was associated with increases in extracellular levels of cortical acetylcholine (ACh); however, SAT performance associated increases in ACh levels were significantly attenuated in STs relative to GTs. Consistent with the view that the modulatory effects of ACh involve stimulation of alpha4beta2* nicotinic ACh receptors (nAChRs), systemic administration of the partial nAChR agonist ABT-089 improved SAT performance in STs and abolished the difference between SAT-associated ACh levels in STs and GTs. Neither the nonselective nAChR agonist nicotine nor the psychostimulant amphetamine improved SAT performance. These findings suggest that individuals who have a propensity to attribute high-incentive salience to reward cues also exhibit relatively poor attentional control. A combination of these traits may render individuals especially vulnerable to disorders, such as obesity and addiction. PMID- 23658173 TI - The Munc13 proteins differentially regulate readily releasable pool dynamics and calcium-dependent recovery at a central synapse. AB - The Munc13 gene family encodes molecules located at the synaptic active zone that regulate the reliability of synapses to encode information over a wide range of frequencies in response to action potentials. In the CNS, proteins of the Munc13 family are critical in regulating neurotransmitter release and synaptic plasticity. Although Munc13-1 is essential for synaptic transmission, it is paradoxical that Munc13-2 and Munc13-3 are functionally dispensable at some synapses, although their loss in other synapses leads to increases in frequency dependent facilitation. We addressed this issue at the calyx of Held synapse, a giant glutamatergic synapse that we found to express all these Munc13 isoforms. We studied their roles in the regulation of synaptic transmission and their impact on the reliability of information transfer. Through detailed electrophysiological analyses of Munc13-2, Munc13-3, and Munc13-2-3 knock-out and wild-type mice, we report that the combined loss of Munc13-2 and Munc13-3 led to an increase in the rate of calcium-dependent recovery and a change in kinetics of release of the readily releasable pool. Furthermore, viral-mediated overexpression of a dominant-negative form of Munc13-1 at the calyx demonstrated that these effects are Munc13-1 dependent. Quantitative immunohistochemistry using Munc13-fluorescent protein knock-in mice revealed that Munc13-1 is the most highly expressed Munc13 isoform at the calyx and the only one highly colocalized with Bassoon at the active zone. Based on these data, we conclude that Munc13-2 and Munc13-3 isoforms limit the ability of Munc13-1 to regulate calcium-dependent replenishment of readily releasable pool and slow pool to fast pool conversion in central synapses. PMID- 23658174 TI - Parvalbumin-containing chandelier and basket cell boutons have distinctive modes of maturation in monkey prefrontal cortex. AB - Parvalbumin (PV)-containing cortical GABA neurons include chandelier cells (PVChCs) and basket cells (PVBCs), which innervate the axon initial segment (AIS) and soma/proximal dendrites of pyramidal cells, respectively. In monkey prefrontal cortex (PFC), the density of PVChC axon cartridges detectable by PV immunoreactivity peaks prior to the onset of puberty before declining markedly to adult levels, whereas the density of PV-immunoreactive (IR) puncta (presumed PVBC boutons) increases during adolescence. These inverse developmental changes in bouton density could explain why an electron microscopy study found no change in the density of symmetric, presumably GABAergic, synapses between infancy and adulthood in monkey PFC. Alternatively, the inverse developmental trajectories of PVChC and PVBC boutons could represent cell type-specific differences in the maturation of PV protein levels. To differentiate between these two alternatives, multilabel confocal microscopy was used to quantify the number of PVChC and PVBC boutons per pyramidal neuron in the PFC of 3-month-old and adult monkeys. The mean number of PVChC boutons per pyramidal neuron AIS was, significantly, 32% lower in adult compared with 3-month-old monkeys, whereas the density of PVBC boutons per pyramidal neuron did not differ between age groups. In contrast, relative levels of PV protein were approximately twofold higher in PVBC boutons in adult animals, whereas PV levels in PVChC boutons did not differ between age groups. These findings suggest cell type-specific mechanisms of maturation of PV containing GABAergic boutons in monkey PFC. PMID- 23658175 TI - A functional hierarchy within the parietofrontal network in stimulus selection and attention control. AB - Although we are confronted with an ever-changing environment, we do not have the capacity to analyze all incoming sensory information. Perception is selective and is guided both by salient events occurring in our visual field and by cognitive premises about what needs our attention. Although the lateral intraparietal area (LIP) and frontal eye field (FEF) are known to represent the position of visual attention, their respective contributions to its control are still unclear. Here, we report LIP and FEF neuronal activities recorded while monkeys performed a voluntary attention-orientation target-detection task. We show that both encode behaviorally significant events, but that the FEF plays a specific role in mapping abstract cue instructions onto a spatial priority map to voluntarily guide attention. On the basis of a latency analysis, we show that the coding of stimulus identity and position precedes the emergence of an explicit attentional signal within the FEF. We also describe dynamic temporal hierarchies between LIP and FEF: stimuli carrying the highest intrinsic saliency are signaled by LIP before FEF, whereas stimuli carrying the highest extrinsic saliency are signaled in FEF before LIP. This suggests that whereas the parietofrontal attentional network most probably processes visual information in a recurrent way, exogenous processing predominates in the parietal cortex and the endogenous control of attention takes place in the FEF. PMID- 23658176 TI - Double dissociation between the anterior cingulate cortex and nucleus accumbens core in encoding the context versus the content of pavlovian cocaine cue extinction. AB - One strategy proposed to treat addictive disorders is to extinguish the association between environmental stimuli (cues) and actions associated with drug use to reduce relapse. The context specificity of extinction learning, however, impairs the ability of addicts to generalize extinction training to the drug taking context. We previously reported that the NMDA receptor partial agonist d cycloserine administered after pavlovian extinction of cocaine cues in the nucleus accumbens core (NAc) reduced cue-induced renewal. Nevertheless, it was unclear whether this was due to disrupted contextual encoding of extinction or enhanced extinction consolidation. Thus, we examined the effect of the NMDA receptor antagonist d-AP5 on context encoding versus cue extinction learning. We also determined the role of the anterior cingulate cortex (ACC) in encoding the cue extinction memory or the context, due to its projections to NAc, and hypothesized the role in conflict monitoring and contextual modulation of decision making. Using rats, we observed that NMDA receptor antagonism in the NAc did not alter context encoding but did interfere with acquisition of the cue extinction memory, i.e., learning, conversely inactivation of the ACC reduced the contextual encoding of extinction but did not interfere with the acquisition or expression of extinction. The observed effects were not present in the absence of cue extinction training. Additionally, the contextual memory did not appear to be consolidated in the ACC as neither postsession inactivation nor protein synthesis inhibition impaired context-appropriate responding. These results have implications for overcoming the context specificity of extinction to treat psychiatric disorders including addiction. PMID- 23658177 TI - Differences between primary auditory cortex and auditory belt related to encoding and choice for AM sounds. AB - We recorded from middle-lateral (ML) and primary (A1) auditory cortex while macaques discriminated amplitude-modulated (AM) noise from unmodulated noise. Compared with A1, ML had a higher proportion of neurons that encoded increasing AM depth by decreasing their firing rates ("decreasing" neurons), particularly with responses that were not synchronized to the modulation. Choice probability (CP) analysis revealed that A1 and ML activity were different during the first half of the test stimulus. In A1, significant CP began before the test stimulus, remained relatively constant (or increased slightly) during the stimulus, and increased greatly within 200 ms of lever release. Neurons in ML behaved similarly, except that significant CP disappeared during the first half of the stimulus and reappeared during the second half and prerelease periods. CP differences between A1 and ML depend on neural response type. In ML (but not A1), when activity was lower during the first half of the stimulus in nonsynchronized, decreasing neurons, the monkey was more likely to report AM. Neurons that both increased firing rate with increasing modulation depth ("increasing" neurons) and synchronized their responses to AM had similar choice-related activity dynamics in ML and A1. These results suggest that, when ascending the auditory system, there is a transformation in coding AM from primarily synchronized increasing responses in A1 to nonsynchronized and dual (increasing/decreasing) coding in ML. This sensory transformation is accompanied by changes in the timing of activity related to choice, suggesting functional differences between A1 and ML related to attention and/or behavior. PMID- 23658178 TI - Inattention blindness to motion in middle temporal area. AB - Subjects naturally form and use expectations to solve familiar tasks, but the accuracy of these expectations and the neuronal mechanisms by which these expectations enhance behavior are unclear. We trained animals (Macaca mulatta) in a challenging perceptual task in which the likelihood of a very brief pulse of motion was consistently modulated over time and space. Pulse likelihood had dramatic effects on behavior: unexpected pulses were nearly invisible to the animals. To examine the neuronal basis of such inattention blindness, we recorded from single neurons in the middle temporal (MT) area, an area related to motion perception. Fluctuations in how reliably MT neurons both signaled stimulus events and predicted behavioral choices were highly correlated with changes in performance over the course of individual trials. A simple neuronal pooling model reveals that the dramatic behavioral effects of attention in this task can be completely explained by changes in the reliability of a small number of MT neurons. PMID- 23658179 TI - In vivo stimulus-induced vasodilation occurs without IP3 receptor activation and may precede astrocytic calcium increase. AB - Calcium-dependent release of vasoactive gliotransmitters is widely assumed to trigger vasodilation associated with rapid increases in neuronal activity. Inconsistent with this hypothesis, intact stimulus-induced vasodilation was observed in inositol 1,4,5-triphosphate (IP3) type-2 receptor (R2) knock-out (KO) mice, in which the primary mechanism of astrocytic calcium increase-the release of calcium from intracellular stores following activation of an IP3-dependent pathway-is lacking. Further, our results in wild-type (WT) mice indicate that in vivo onset of astrocytic calcium increase in response to sensory stimulus could be considerably delayed relative to the simultaneously measured onset of arteriolar dilation. Delayed calcium increases in WT mice were observed in both astrocytic cell bodies and perivascular endfeet. Thus, astrocytes may not play a role in the initiation of blood flow response, at least not via calcium-dependent mechanisms. Moreover, an increase in astrocytic intracellular calcium was not required for normal vasodilation in the IP3R2-KO animals. PMID- 23658180 TI - Elevation of brain magnesium prevents and reverses cognitive deficits and synaptic loss in Alzheimer's disease mouse model. AB - Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer's disease (AD) and might underlie memory impairment. Our previous work demonstrated that the magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we investigated whether elevation of brain magnesium by the use of a recently developed compound, magnesium-l-threonate (MgT), can ameliorate the AD-like pathologies and cognitive deficits in the APPswe/PS1dE9 mice, a transgenic (Tg) mouse model of AD. MgT treatment reduced Abeta plaque and prevented synapse loss and memory decline in the Tg mice. Strikingly, MgT treatment was effective even when given to the mice at the end stage of their AD like pathological progression. To explore how elevation of brain magnesium ameliorates the AD-like pathologies in the brains of Tg mice, we studied molecules critical for APP metabolism and signaling pathways implicated in synaptic plasticity/density. In the Tg mice, the NMDAR/CREB/BDNF signaling was downregulated, whereas calpain/calcineurin/Cdk5 neurodegenerative signaling and beta-secretase (BACE1) expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression, and reduced soluble APPbeta and beta-C-terminal fragments in the Tg mice. At the molecular level, elevation of extracellular magnesium prevented the high-Abeta-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices. Correlation studies suggested that the protection of NMDAR signaling might underlie the stabilization of BACE1 expression. Our results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of AD and may have therapeutic potential for treating AD in humans. PMID- 23658181 TI - Thalamic control of neocortical area formation in mice. AB - The mammalian neocortex undergoes dramatic transformation during development, from a seemingly homogenous sheet of neuroepithelial cells into a complex structure that is tangentially divided into discrete areas. This process is thought to be controlled by a combination of intrinsic patterning mechanisms within the cortex and afferent axonal projections from the thalamus. However, roles of thalamic afferents in the formation of areas are still poorly understood. In this study, we show that genetically increasing or decreasing the size of the lateral geniculate nucleus of the mouse thalamus resulted in a corresponding change in the size of the primary visual area. Furthermore, elimination of most thalamocortical projections from the outset of their development resulted in altered areal gene expression patterns, particularly in the primary visual and somatosensory areas, where they lost sharp boundaries with adjacent areas. Together, these results demonstrate the critical roles of thalamic afferents in the establishment of neocortical areas. PMID- 23658183 TI - Imbalance between excitation and inhibition in the somatosensory cortex produces postadaptation facilitation. AB - Adaptation is typically associated with attenuation of the neuronal response during sustained or repetitive sensory stimulation, followed by a gradual recovery of the response to its baseline level thereafter. Here, we examined the process of recovery from sensory adaptation in layer IV cells of the rat barrel cortex using in vivo intracellular recordings. Surprisingly, in approximately one third of the cells, the response to a test stimulus delivered a few hundred milliseconds after the adapting stimulation was significantly facilitated. Recordings under different holding potentials revealed that the enhanced response was the result of an imbalance between excitation and inhibition, where a faster recovery of excitation compared with inhibition facilitated the response. Hence, our data provide the first mechanistic explanation of sensory facilitation after adaptation and suggest that adaptation increases the sensitivity of cortical neurons to sensory stimulation by altering the balance between excitation and inhibition. PMID- 23658182 TI - Stage-specific deletion of Olig2 conveys opposing functions on differentiation and maturation of oligodendrocytes. AB - The temporal and spatial patterning involved in the specification, differentiation, and myelination by oligodendroglia is coordinated in part by the activation and repression of various transcriptional programs. Olig2 is a basic helix-loop-helix transcription factor necessary for oligodendroglial development and expressed continuously throughout the lineage. Despite evidence for the critical role of Olig2 in oligodendroglial specification and differentiation, the function for Olig2 during later stages of oligodendroglial development, namely, the transition into mature oligodendrocytes (OLs) and the formation of the myelin sheath, remains unclear. To address the possibility for a stage-specific role, we deleted Olig2 in oligodendrocyte precursor cells (OPCs) under the control of the CNPase-promoter or in immature OLs under the inducible proteolipid protein promoter. As expected, ablation of Olig2 in OPCs significantly inhibits differentiation, resulting in hypomyelination. However, deletion of the Olig2 gene in immature OLs significantly enhances the maturation process and accelerates the kinetics of myelination/remyelination. Underlying the stage specific roles for Olig2 is the compensatory expression and function of Olig1, a transcription factor that promotes OL maturation and (re)myelination. Olig1 expression is significantly reduced upon Olig2 deletion in OPCs but is dramatically increased by nearly threefold when deleted in immature OLs. By enforcing expression of Olig1 into OPCs in a null Olig2 background, we demonstrate that overexpression of Olig1 is sufficient to rescue the differentiation phenotype and partially compensates for the Olig2 deletion in vitro. Our results suggest a stage-specific regulatory role for Olig2, mediated by Olig1 that conveys opposing functions on the differentiation and maturation of oligodendrocytes. PMID- 23658184 TI - A Myosin Va mutant mouse with disruptions in glutamate synaptic development and mature plasticity in visual cortex. AB - Myosin Va (MyoVa) mediates F-actin-based vesicular transport toward the plasma membrane and is found at neuronal postsynaptic densities (PSDs), but the role of MyoVa in synaptic development and function is largely unknown. Here, in studies using the dominant-negative MyoVa neurological mutant mouse Flailer, we find that MyoVa plays an essential role in activity-dependent delivery of PSD-95 and other critical PSD molecules to synapses and in endocytosis of AMPA-type glutamate receptors (AMPAR) in the dendrites of CNS neurons. MyoVa is known to carry a complex containing the major scaffolding proteins of the mature PSD, PSD-95, SAPAP1/GKAP, Shank, and Homer to dendritic spine synapses. In Flailer, neurons show abnormal dendritic shaft localization of PSD-95, stargazin, dynamin3, AMPARs and abnormal spine morphology. Flailer neurons also have abnormally high AMPAR miniature current frequencies and spontaneous AMPAR currents that are more frequent and larger than in wild-type while numbers of NMDAR containing synapses remain normal. The AMPAR abnormalities are consistent with a severely disrupted developmental regulation of long-term depression that we find in cortical Flailer neurons. Thus MyoVa plays a fundamentally important role both in localizing mature glutamate synapses to spines and in organizing the synapse for normal function. For this reason Flailer mice will be valuable in further dissecting the role of MyoVa in normal synaptic and circuit refinement and also in studies of neurological and neuropsychiatric diseases where disruptions of normal glutamate synapses are frequently observed. PMID- 23658185 TI - Initiation, labile, and stabilization phases of experience-dependent plasticity at neocortical synapses. AB - Alteration of sensory input can change the strength of neocortical synapses. Selective activation of a subset of whiskers is sufficient to potentiate layer 4 layer 2/3 excitatory synapses in the mouse somatosensory (barrel) cortex, a process that is NMDAR dependent. By analyzing the time course of sensory-induced synaptic change, we have identified three distinct phases for synaptic strengthening in vivo. After an early, NMDAR-dependent phase where selective whisker activation is rapidly translated into increased synaptic strength, we identify a second phase where this potentiation is profoundly reduced by an input specific, NMDAR-dependent depression. This labile phase is transient, lasting only a few hours, and may require ongoing sensory input for synaptic weakening. Residual synaptic strength is maintained in a third phase, the stabilization phase, which requires mGluR5 signaling. Identification of these three phases will facilitate a molecular dissection of the pathways that regulate synaptic lability and stabilization, and suggest potential approaches to modulate learning. PMID- 23658186 TI - Viral tracing identifies parallel disynaptic pathways to the hippocampus. AB - Electrophysiological and lesion studies in rodents have shown that the dorsal (septal) and ventral (temporal) segments of the hippocampus have functional specializations that can be understood in terms of their anatomical connections with distinct brain areas. Here we explore the circuitry associated with the hippocampus using the pseudorabies virus-Bartha strain (PRV-Bartha) tracer in the rat to examine both direct (first-order) and indirect (second-order) projections to the hippocampus. Based on analysis of PRV-Bartha infection density, we demonstrate two parallel pathways from the limbic cortex to the hippocampus. A dorsal "spatial cognition" pathway provides disynaptic input from the retrosplenial, anterior cingulate, and orbital cortex to the dorsal hippocampus, with potential synaptic relays in the anterior thalamic nuclei and dorsolateral entorhinal cortex. A ventral "executive control" pathway provides disynaptic input from the prelimbic, infralimbic, and orbital cortex to the ventral hippocampus, with potential synaptic relays in the midline thalamic nuclei and the rostral caudomedial entorhinal cortex. These data suggest a new anatomical framework for understanding the functional interactions between the cortex and hippocampus, especially in cognitive disorders that involve both structures, such as frontotemporal dementia. PMID- 23658187 TI - Corticocortical feedback contributes to surround suppression in V1 of the alert primate. AB - Feedback connections are prevalent throughout the cerebral cortex, yet their function remains poorly understood. Previous studies in anesthetized monkeys found that inactivating feedback from extrastriate visual cortex produced effects in striate cortex that were relatively weak, generally suppressive, largest for visual stimuli confined to the receptive field center, and detectable only at low stimulus contrast. We studied the influence of corticocortical feedback in alert monkeys using cortical cooling to reversibly inactivate visual areas 2 (V2) and 3 (V3) while characterizing receptive field properties in primary visual cortex (V1). We show that inactivation of feedback from areas V2 and V3 results in both response suppression and facilitation for stimuli restricted to the receptive field center, in most cases leading to a small reduction in the degree of orientation selectivity but no change in orientation preference. For larger diameter stimuli that engage regions beyond the center of the receptive field, eliminating feedback from V2 and V3 results in strong and consistent response facilitation, effectively reducing the strength of surround suppression in V1 for stimuli of both low and high contrast. For extended contours, eliminating feedback had the effect of reducing end stopping. Inactivation effects were largest for neurons that exhibited strong surround suppression before inactivation, and their timing matched the dynamics of surround suppression under control conditions. Our results provide direct evidence that feedback contributes to surround suppression, which is an important source of contextual influences essential to vision. PMID- 23658188 TI - MPP3 is required for maintenance of the apical junctional complex, neuronal migration, and stratification in the developing cortex. AB - During mammalian cortical development, division of progenitor cells occurs at the apical ventricular zone. Apical complex proteins and adherens junctions regulate the different modes of division. Here, we have identified the membrane-associated guanylate kinase protein membrane palmitoylated protein 3 (MPP3) as an essential protein for the maintenance of these complexes. MPP3 localizes at the apical membrane in which it shows partial colocalization with adherens junction proteins and apical proteins. We generated Mpp3 conditional knock-out mice and specifically ablated Mpp3 expression in cortical progenitor cells. Conditional deletion of Mpp3 during cortical development resulted in a gradual loss of the apical complex proteins and disrupted adherens junctions. Although there is cellular disorganization in the ventricular zone, gross morphology of the cortex was unaffected during loss of MPP3. However, in the ventricular zone, removal of MPP3 resulted in randomization of spindle orientation and ectopically localized mitotic cells. Loss of MPP3 in the developing cortex resulted in delayed migration of progenitor cells, whereas the rate of cell division and exit from the cell cycle was not affected. This resulted in defects in cortical stratification and ectopically localized layer II-IV pyramidal neurons and interneurons. These data show that MPP3 is required for maintenance of the apical protein complex and adherens junctions and for stratification and proper migration of neurons during the development of the cortex. PMID- 23658189 TI - The human brain processes syntax in the absence of conscious awareness. AB - Syntax is the core computational component of language. A longstanding idea about syntactic processing is that it is generally not available to conscious access, operating autonomously and automatically. However, there is little direct neurocognitive evidence on this issue. By measuring event-related potentials while human observers performed a novel cross-modal distraction task, we demonstrated that syntactic violations that were not consciously detected nonetheless produced a characteristic early neural response pattern, and also significantly delayed reaction times to a concurrent task. This early neural response was distinct from later neural activity that was observed only to syntactic violations that were consciously detected. These findings provide direct evidence that the human brain reacts to violations of syntax even when these violations are not consciously detected, indicating that even highly complex computational processes such as syntactic processing can occur outside the narrow window of conscious awareness. PMID- 23658190 TI - Small-molecule screen in adult Drosophila identifies VMAT as a regulator of sleep. AB - Sleep is an important physiological state, but its function and regulation remain elusive. In Drosophila melanogaster, a useful model organism for studying sleep, forward genetic screens have identified important sleep-modulating genes and pathways; however, the results of such screens may be limited by developmental abnormalities or lethality associated with mutation of certain genes. To circumvent these limitations, we used a small-molecule screen to identify sleep modulating genes and pathways. We administered 1280 pharmacologically active small molecules to adult flies and monitored their sleep. We found that administration of reserpine, a small-molecule inhibitor of the vesicular monoamine transporter (VMAT) that repackages monoamines into presynaptic vesicles, resulted in an increase in sleep. Supporting the idea that VMAT is the sleep-relevant target of reserpine, we found that VMAT-null mutants have an increased sleep phenotype, as well as an increased arousal threshold and resistance to the effects of reserpine. However, although the VMAT mutants are consistently resistant to reserpine, other aspects of their sleep phenotype are dependent on genetic background. These findings indicate that small-molecule screens can be used effectively to identify sleep-modulating genes whose phenotypes may be suppressed in traditional genetic screens. Mutations affecting single monoamine pathways did not affect reserpine sensitivity, suggesting that effects of VMAT/reserpine on sleep are mediated by multiple monoamines. Overall, we identify VMAT as an important regulator of sleep in Drosophila and demonstrate that small-molecule screens provide an effective approach to identify genes and pathways that impact adult Drosophila behavior. PMID- 23658191 TI - Frontal theta overrides pavlovian learning biases. AB - Pavlovian biases influence learning and decision making by intricately coupling reward seeking with action invigoration and punishment avoidance with action suppression. This bias is not always adaptive-it can often interfere with instrumental requirements. The prefrontal cortex is thought to help resolve such conflict between motivational systems, but the nature of this control process remains unknown. EEG recordings of midfrontal theta band power are sensitive to conflict and predictive of adaptive control over behavior, but it is not clear whether this signal reflects control over conflict between motivational systems. Here we used a task that orthogonalized action requirements and outcome valence while recording concurrent EEG in human participants. By applying a computational model of task performance, we derived parameters reflective of the latent influence of Pavlovian bias and how it was modulated by midfrontal theta power during motivational conflict. Between subjects, those who performed better under Pavlovian conflict exhibited higher midfrontal theta power. Within subjects, trial-to-trial variance in theta power was predictive of ability to overcome the influence of the Pavlovian bias, and this effect was most pronounced in subjects with higher midfrontal theta to conflict. These findings demonstrate that midfrontal theta is not only a sensitive index of prefrontal control, but it can also reflect the application of top-down control over instrumental processes. PMID- 23658192 TI - Representations of facial identity information in the ventral visual stream investigated with multivoxel pattern analyses. AB - The neural basis of face recognition has been investigated extensively. Using fMRI, several regions have been identified in the human ventral visual stream that seem to be involved in processing and identifying faces, but the nature of the face representations in these regions is not well known. In particular, multivoxel pattern analyses have revealed distributed maps within these regions, but did not reveal the organizing principles of these maps. Here we isolated different types of perceptual and conceptual face properties to determine which properties are mapped in which regions. A set of faces was created with systematic manipulations of featural and configural visual characteristics. In a second part of the study, personal and spatial context information was added to all faces except one. The perceptual properties of faces were represented in face regions and in other regions of interest such as early visual and object selective cortex. Only representations in early visual cortex were correlated with pixel-based similarities between the stimuli. The representation of nonperceptual properties was less distributed. In particular, the spatial location associated with a face was only represented in the parahippocampal place area. These findings demonstrate a relatively distributed representation of perceptual and conceptual face properties that involves both face selective/sensitive and non-face-selective cortical regions. PMID- 23658193 TI - Split-belt walking alters the relationship between locomotor phases and cycle duration across speeds in intact and chronic spinalized adult cats. AB - During overground or treadmill walking, the stance phase and cycle durations are reduced as speed increases, whereas swing phase duration remains relatively invariant. When the speed of the left and right sides is unequal, as is the case during split-belt locomotion or when walking along a circular path, adjustments in stance and swing phases are observed, which could alter the phase/cycle duration relationships. Here, we tested this hypothesis in the left and right hindlimbs of four intact and two chronic spinal-transected adult cats during tied belt (i.e., equal left and right speeds) and split-belt (i.e., unequal left and right speeds) walking. During split-belt walking, one side (i.e., constant limb) walked at a constant speed while the other side (varying limb) varied its speed from 0.3 to 1.0 m/s. We show that the phase/cycle duration relationships differed in both hindlimbs concurrently during split-belt walking. Specifically, the slope of the phase/cycle duration relationships for the stance/extension phase increased in the varying limb from tied-belt to split-belt walking, whereas that of the swing/flexion phase decreased. In contrast, in the constant limb, the slope of the phase/cycle duration relationships for the stance/extension phase decreased, whereas that of the swing/flexion phase increased. The results were qualitatively similar in intact and spinal-transected cats, indicating that the modulation was mediated within the spinal cord. In conclusion, we propose that neuronal networks within the spinal cord that control left and right hindlimb locomotion can differentially and simultaneously modulate phase variations when the two sides walk at different speeds. PMID- 23658194 TI - Genomic imprinting effects of the X chromosome on brain morphology. AB - There is increasing evidence that genomic imprinting, a process by which certain genes are expressed in a parent-of-origin-specific manner, can influence neurogenetic and psychiatric manifestations. While some data suggest possible imprinting effects of the X chromosome on physical and cognitive characteristics in humans, there is no compelling evidence that X-linked imprinting affects brain morphology. To address this issue, we investigated regional cortical volume, thickness, and surface area in 27 healthy controls and 40 prepubescent girls with Turner syndrome (TS), a condition caused by the absence of one X chromosome. Of the young girls with TS, 23 inherited their X chromosome from their mother (X(m)) and 17 from their father (X(p)). Our results confirm the existence of significant differences in brain morphology between girls with TS and controls, and reveal the presence of a putative imprinting effect among the TS groups: girls with X(p) demonstrated thicker cortex than those with X(m) in the temporal regions bilaterally, while X(m) individuals showed bilateral enlargement of gray matter volume in the superior frontal regions compared with X(p). These data suggest the existence of imprinting effects of the X chromosome that influence both cortical thickness and volume during early brain development, and help to explain variability in cognitive and behavioral manifestations of TS with regard to the parental origin of the X chromosome. PMID- 23658196 TI - Vascular regenerative therapies for the treatment of erectile dysfunction: current approaches. AB - The pharmacological treatment of erectile dysfunction (ED) is mainly represented by the administration of inhibitors of phosphodiesterase-5 (PDE5). However, in the clinical practice many patients do not benefit from such a treatment, hence the scientific interest extends to other therapeutic strategies; in particular, to the vascular regenerative therapy. This review describes the main acquisitions related to this approach represented by the mesenchymal stem cell or adipose tissue stem cell transplantation and endothelial nitric oxide synthase or vascular endothelial growth factor gene therapy. Moreover, there are other two aspects of wide interest represented by the potential vascular regenerative effects exerted by the PDE5 inhibitors and the therapeutic strategies for a category of patients who more frequently do not respond to the conventional treatment for ED, the patients with diabetes mellitus. PMID- 23658195 TI - X11/Mint genes control polarized localization of axonal membrane proteins in vivo. AB - Mislocalization of axonal proteins can result in misassembly and/or miswiring of neural circuits, causing disease. To date, only a handful of genes that control polarized localization of axonal membrane proteins have been identified. Here we report that Drosophila X11/Mint proteins are required for targeting several proteins, including human amyloid precursor protein (APP) and Drosophila APP-like protein (APPL), to axonal membranes and for their exclusion from dendrites of the mushroom body in Drosophila, a brain structure involved in learning and memory. Axonal localization of APP is mediated by an endocytic motif, and loss of X11/Mint results in a dramatic increase in cell-surface levels of APPL, especially on dendrites. Mutations in genes required for endocytosis show similar mislocalization of these proteins to dendrites, and strongly enhance defects seen in X11/Mint mutants. These results suggest that X11/Mint-dependent endocytosis in dendrites may serve to promote the axonal localization of membrane proteins. Since X11/Mint binds to APP, and abnormal trafficking of APP contributes to Alzheimer's disease, deregulation of X11/Mint may be important for Alzheimer's disease pathogenesis. PMID- 23658197 TI - Xylem embolism threshold for catastrophic hydraulic failure in angiosperm trees. AB - Hydraulic failure is one of the main causes of tree mortality in conditions of severe drought. Resistance to cavitation is known to be strongly related to drought tolerance and species survival in conifers, but the threshold of water stress-induced embolism leading to catastrophic xylem dysfunction in angiosperms has been little studied. We investigated the link between drought tolerance, survival and xylem cavitation resistance in five angiosperm tree species known to have contrasting desiccation resistance thresholds. We exposed seedlings in a greenhouse to severe drought to generate extreme water stress. We monitored leaf water potential, total plant water loss rate, leaf transpiration, stomatal conductance and CO2 assimilation rate during drought exposure and after rewatering (recovery phase). The time required for the recovery of 50% of the maximum value of a given ecophysiological variable after rewatering was used to determine the critical water potential corresponding to the threshold beyond which the plant failed to recover. We also investigated the relationship between this potential and stem xylem cavitation resistance, as assessed from vulnerability curves. This minimum recoverable water potential was consistent between ecophysiological variables and varied considerably between species, from 3.4 to -6.0 MPa. This minimum recoverable water potential was strongly correlated with P50 and P88, the pressures inducing 50 and 88% losses of stem hydraulic conductance, respectively. Moreover, the embolism threshold leading to irreversible drought damage was found to be close to 88%, rather than the 50% previously reported for conifers. Hydraulic failure leading to irreversible drought-induced global dysfunction in angiosperm tree species occurred at a very high level of xylem embolism, possibly reflecting the physiological characteristics of their stem water-transport system. PMID- 23658198 TI - The impact of climate change on the structure of Pleistocene food webs across the mammoth steppe. AB - Species interactions form food webs, impacting community structure and, potentially, ecological dynamics. It is likely that global climatic perturbations that occur over long periods of time have a significant influence on species interaction patterns. Here, we integrate stable isotope analysis and network theory to reconstruct patterns of trophic interactions for six independent mammalian communities that inhabited mammoth steppe environments spanning western Europe to eastern Alaska (Beringia) during the Late Pleistocene. We use a Bayesian mixing model to quantify the contribution of prey to the diets of local predators, and assess how the structure of trophic interactions changed across space and the Last Glacial Maximum (LGM), a global climatic event that severely impacted mammoth steppe communities. We find that large felids had diets that were more constrained than those of co-occurring predators, and largely influenced by an increase in Rangifer abundance after the LGM. Moreover, the structural organization of Beringian and European communities strongly differed: compared with Europe, species interactions in Beringian communities before--and possibly after--the LGM were highly modular. We suggest that this difference in modularity may have been driven by the geographical insularity of Beringian communities. PMID- 23658199 TI - Competitive and demographic leverage points of community shifts under climate warming. AB - Accelerating rates of climate change and a paucity of whole-community studies of climate impacts limit our ability to forecast shifts in ecosystem structure and dynamics, particularly because climate change can lead to idiosyncratic responses via both demographic effects and altered species interactions. We used a multispecies model to predict which processes and species' responses are likely to drive shifts in the composition of a space-limited benthic marine community. Our model was parametrized from experimental manipulations of the community. Model simulations indicated shifts in species dominance patterns as temperatures increase, with projected shifts in composition primarily owing to the temperature dependence of growth, mortality and competition for three critical species. By contrast, warming impacts on two other species (rendering them weaker competitors for space) and recruitment rates of all species were of lesser importance in determining projected community changes. Our analysis reveals the importance of temperature-dependent competitive interactions for predicting effects of changing climate on such communities. Furthermore, by identifying processes and species that could disproportionately leverage shifts in community composition, our results contribute to a mechanistic understanding of climate change impacts, thereby allowing more insightful predictions of future biodiversity patterns. PMID- 23658200 TI - Cooperation during cultural group formation promotes trust towards members of out groups. AB - People often cooperate with members of their own group, and discriminate against members of other groups. Previous research establishes that cultural groups can form endogenously, and that these groups demonstrate in-group favouritism. Given the presence of cultural groups, the previous literature argues that cultural evolution selects for groups that exhibit parochial altruism. The source of initial variation in these traits, however, remains uninformed. We show here that a group's economic production environment may substantially influence parochial tendencies, with groups formed around more cooperative production (CP) displaying less parochialism than groups formed around more independent production (IP) processes. Participants randomized into CP and IP production tasks formed cultural groups, and subsequently played hidden-action trust games with in-group and out-group trustees. We found CP to be associated with significantly greater sharing and exchanging behaviours than IP. In trust games, significant parochial altruism (in-group favouritism combined with out-group discrimination) was displayed by members of IP groups. By contrast, members of CP groups did not engage in either in-group favouritism or out-group discrimination. Further, we found the absence of out-group discrimination in CP to persist even following 'betrayal'. Finally, belief data suggest that members of CP are not more intrinsically generous than IP members, but rather more likely to believe that out-group trustees will positively reciprocate. Our results have important implications for anyone interested in building cooperative teams, and shed new light on connections between culture and cooperation. PMID- 23658201 TI - Plant genotypic diversity reduces the rate of consumer resource utilization. AB - While plant species diversity can reduce herbivore densities and herbivory, little is known regarding how plant genotypic diversity alters resource utilization by herbivores. Here, we show that an invasive folivore--the Japanese beetle (Popillia japonica)--increases 28 per cent in abundance, but consumes 24 per cent less foliage in genotypic polycultures compared with monocultures of the common evening primrose (Oenothera biennis). We found strong complementarity for reduced herbivore damage among plant genotypes growing in polycultures and a weak dominance effect of particularly resistant genotypes. Sequential feeding by P. japonica on different genotypes from polycultures resulted in reduced consumption compared with feeding on different plants of the same genotype from monocultures. Thus, diet mixing among plant genotypes reduced herbivore consumption efficiency. Despite positive complementarity driving an increase in fruit production in polycultures, we observed a trade-off between complementarity for increased plant productivity and resistance to herbivory, suggesting costs in the complementary use of resources by plant genotypes may manifest across trophic levels. These results elucidate mechanisms for how plant genotypic diversity simultaneously alters resource utilization by both producers and consumers, and show that population genotypic diversity can increase the resistance of a native plant to an invasive herbivore. PMID- 23658202 TI - Genes versus environment: geography and phylogenetic relationships shape the chemical profiles of stingless bees on a global scale. AB - Chemical compounds are highly important in the ecology of animals. In social insects, compounds on the body surface represent a particularly interesting trait, because they comprise different compound classes that are involved in different functions, such as communication, recognition and protection, all of which can be differentially affected by evolutionary processes. Here, we investigate the widely unknown and possibly antagonistic influence of phylogenetic and environmental factors on the composition of the cuticular chemistry of tropical stingless bees. We chose stingless bees because some species are unique in expressing not only self-produced compounds, but also compounds that are taken up from the environment. By relating the cuticular chemistry of 40 bee species from all over the world to their molecular phylogeny and geographical occurrence, we found that distribution patterns of different groups of compounds were differentially affected by genetic relatedness and biogeography. The ability to acquire environmental compounds was, for example, highly correlated with the bees' phylogeny and predominated in evolutionarily derived species. Owing to the presence of environmentally derived compounds, those species further expressed a higher chemical and thus functional diversity. In Old World species, chemical similarity of both environmentally derived and self-produced compounds was particularly high among sympatric species, even when they were less related to each other than to allopatric species, revealing a strong environmental effect even on largely genetically determined compounds. Thus, our findings do not only reveal an unexpectedly strong influence of the environment on the cuticular chemistry of stingless bees, but also demonstrate that even within one morphological trait (an insect's cuticular profile), different components (compound classes) can be differentially affected by different drivers (relatedness and biogeography), depending on the functional context. PMID- 23658203 TI - Cultural phylogeography of the Bantu Languages of sub-Saharan Africa. AB - There is disagreement about the routes taken by populations speaking Bantu languages as they expanded to cover much of sub-Saharan Africa. Here, we build phylogenetic trees of Bantu languages and map them onto geographical space in order to assess the likely pathway of expansion and test between dispersal scenarios. The results clearly support a scenario in which groups first moved south through the rainforest from a homeland somewhere near the Nigeria-Cameroon border. Emerging on the south side of the rainforest, one branch moved south and west. Another branch moved towards the Great Lakes, eventually giving rise to the monophyletic clade of East Bantu languages that inhabit East and Southeastern Africa. These phylogenies also reveal information about more general processes involved in the diversification of human populations into distinct ethnolinguistic groups. Our study reveals that Bantu languages show a latitudinal gradient in covering greater areas with increasing distance from the equator. Analyses suggest that this pattern reflects a true ecological relationship rather than merely being an artefact of shared history. The study shows how a phylogeographic approach can address questions relating to the specific histories of certain groups, as well as general cultural evolutionary processes. PMID- 23658204 TI - Humans exploit the biomechanics of bipedal gait during visually guided walking over complex terrain. AB - How do humans achieve such remarkable energetic efficiency when walking over complex terrain such as a rocky trail? Recent research in biomechanics suggests that the efficiency of human walking over flat, obstacle-free terrain derives from the ability to exploit the physical dynamics of our bodies. In this study, we investigated whether this principle also applies to visually guided walking over complex terrain. We found that when humans can see the immediate foreground as little as two step lengths ahead, they are able to choose footholds that allow them to exploit their biomechanical structure as efficiently as they can with unlimited visual information. We conclude that when humans walk over complex terrain, they use visual information from two step lengths ahead to choose footholds that allow them to approximate the energetic efficiency of walking in flat, obstacle-free environments. PMID- 23658205 TI - Inferring patterns of influenza transmission in swine from multiple streams of surveillance data. AB - Swine populations are known to be an important source of new human strains of influenza A, including those responsible for global pandemics. Yet our knowledge of the epidemiology of influenza in swine is dismayingly poor, as highlighted by the emergence of the 2009 pandemic strain and the paucity of data describing its origins. Here, we analyse a unique dataset arising from surveillance of swine influenza at a Hong Kong abattoir from 1998 to 2010. We introduce a state-space model that estimates disease exposure histories by joint inference from multiple modes of surveillance, integrating both virological and serological data. We find that an observed decrease in virus isolation rates is not due to a reduction in the regional prevalence of influenza. Instead, a more likely explanation is increased infection of swine in production farms, creating greater immunity to disease early in life. Consistent with this, we find that the weekly risk of exposure on farms equals or exceeds the exposure risk during transport to slaughter. We discuss potential causes for these patterns, including competition between influenza strains and shifts in the Chinese pork industry, and suggest opportunities to improve knowledge and reduce prevalence of influenza in the region. PMID- 23658206 TI - Subcentimeter tumor lesion delineation for high-resolution 18F-FDG PET images: optimizing correction for partial-volume effects. AB - In PET, partial-volume effects cause errors in estimation of size and activity for small objects with radiopharmaceutical uptake. Recent methods for image reconstruction, compared with traditional reconstruction techniques, include algorithms for resolution recovery that result in images with higher resolution and enable quantification of size and activity of smaller objects. The purpose of this study was to evaluate a combination of 2 algorithms for volume delineation and partial-volume correction on uptake volumes smaller than 0.7 mL using image reconstruction algorithms with and without resolution recovery. METHODS: Volumes of interests (VOIs) were delineated using a threshold intensity calculated as a weighted sum of tumor and background intensities. These VOIs were used for calculating correction factors by convolving a tumor mask with the system point spread function. The methods algorithms were evaluated using a phantom constructed from 5 small different-sized balloons filled with (18)F-FDG in background activity. Six different backgrounds were used. Data were acquired using a PET/CT scanner, and the images were reconstructed using 2 iterative algorithms, one of which used a resolution recovery algorithm. RESULTS: For the images reconstructed using the resolution recovery algorithm, the method for volume delineation resulted in VOI sizes that were correct within 1 SD for all balloons of a volume of 0.35 mL (equivalent diameter, 8.8 mm) and larger, in all backgrounds. For the images reconstructed without resolution recovery, the VOI sizes were background-dependent and generally less accurate. Correct volume delineations generally led to accurate activity estimates. CONCLUSION: The algorithms tested on the phantom developed for this study could, for this PET camera and these reconstruction algorithms, be used for accurate volume delineation and activity quantification of lesions 0.35 mL and larger. PMID- 23658207 TI - Assessment of glomerular filtration rate measurement with plasma sampling: a technical review. AB - This article reviews available radionuclide-based techniques for glomerular filtration rate (GFR) measurement, focusing on clinical indications for GFR measurement, ideal GFR radiopharmaceutical tracer properties, and the 2 most common tracers in clinical use. Methods for full, 1-compartment, and single sample renal clearance characterization are discussed. GFR normalization and the role of GFR measurement in chemotherapy dosing are also considered. PMID- 23658208 TI - Mutations in human papillomavirus type 16 L1 hypervariable surface-exposed loops affect L2 binding and DNA encapsidation. AB - Prophylactic vaccines against human papillomavirus (HPV) based on virus-like particles (VLP) induce type-specific neutralizing antibodies against a small number of hypervariable residues positioned in surface-exposed loops of the major capsid protein L1. To investigate the importance of these residues for neutralization, cross-neutralization, L2 incorporation and genome encapsidation, ten surface-exposed amino acid residues in four hypervariable loops of L1 were mutated. VLPs containing mutated or WT L1, with or without WT L2, were produced in 293TT cells using pseudovirion expression vectors. The mutations reduced the ability to induce neutralizing antibodies and to incorporate the L2 protein in the capsid. Ability to induce cross-neutralizing antibodies and to encapsidate pseudogenomes were completely abrogated. In summary, the surface-exposed L1 loops are important for the function of the HPV particle. PMID- 23658209 TI - Integrins modulate the infection efficiency of West Nile virus into cells. AB - The underlying mechanisms allowing West Nile virus (WNV) to replicate in a large variety of different arthropod, bird and mammal species are largely unknown but are believed to rely on highly conserved proteins relevant for viral entry and replication. Consistent with this, the integrin alphavbeta3 has been proposed lately to function as the cellular receptor for WNV. More recently published data, however, are not in line with this concept. Integrins are highly conserved among diverse taxa and are expressed by almost every cell type at high numbers. Our study was designed to clarify the involvement of integrins in WNV infection of cells. A cell culture model, based on wild-type and specific integrin knockout cell lines lacking the integrin subunits alphav, beta1 or beta3, was used to investigate the susceptibility to WNV, and to evaluate binding and replication efficiencies of four distinct strains (New York 1999, Uganda 1937, Sarafend and Dakar). Though all cell lines were permissive, clear differences in replication efficiencies were observed. Rescue of the beta3-integrin subunit resulted in enhanced WNV yields of up to 90 %, regardless of the virus strain used. Similar results were obtained for beta1-expressing and non-expressing cells. Binding, however, was not affected by the expression of the integrins in question, and integrin blocking antibodies failed to have any effect. We conclude that integrins are involved in WNV infection but not at the level of binding to target cells. PMID- 23658211 TI - Uncertainty evaluation in the measurement of power frequency electric and magnetic fields from AC overhead power lines. AB - Measurements of power frequency electric and magnetic fields from alternating current power lines are carried out in order to evaluate the exposure levels of the human body on the general public. For any electromagnetic field measurement, it is necessary to define the sources of measurement uncertainty and determine the total measurement uncertainty. This paper is concerned with the problems of measurement uncertainty estimation, as the measurement uncertainty budget calculation techniques recommended in standardising documents and research studies are barely described. In this work the total uncertainty of power frequency field measurements near power lines in various measurement sites is assessed by considering not only all available equipment data, but also contributions that depend on the measurement procedures, environmental conditions and characteristics of the field source, which are considered to increase the error of measurement. A detailed application example for power frequency field measurements is presented here by accredited laboratory. PMID- 23658210 TI - Ultrastructural and genomic characterization of a second banchine polydnavirus confirms the existence of shared features within this ichnovirus lineage. AB - Polydnaviruses (PDVs) are symbiotic viruses carried by endoparasitic wasps and transmitted to caterpillar hosts during parasitization. Although they share several features, including a segmented dsDNA genome, a unique life cycle where replication is restricted to the wasp host, and immunodepressive/developmental effects on the caterpillar host, PDVs carried by ichneumonid and braconid wasps (referred to as ichnoviruses and bracoviruses, respectively) have different evolutionary origins. In addition, ichnoviruses (IVs) form two distinct lineages, with viral entities found in wasps belonging to the subfamilies Campopleginae and Banchinae displaying strikingly different virion morphologies and genomic features. However, the current description for banchine IVs is based on the characterization of a single species, namely that of the Glypta fumiferanae IV (GfIV). Here we provide an ultrastructural and genomic analysis of a second banchine IV isolated from the wasp Apophua simplicipes, and we show that this virus shares many features with GfIV, including a multi-nucleocapsid virion, an aggregate genome size of ~300 kb, genome segments <5 kb, an impressively high degree of genome segmentation and a very similar gene content (same gene families in both viruses). Altogether, the data presented here confirm the existence of shared characteristics within this banchine IV lineage. PMID- 23658212 TI - Comparison of measured and calculated concrete and rebar specific activity during decommissioning of the Dalhousie SLOWPOKE-2 reactor. AB - Following the defuelling and dismantling of the Dalhousie University SLOWPOKE-2 Reactor (DUSR) in 2011, the reactor pool concrete and rebar were sampled to support the unconditional free release of the material such that the facility could be classified for unrestricted use. A detailed MCNP5 model of the critical core assembly was simulated to calculate the thermal, intermediate and fast neutron flux profile below the reactor pool floor. The neutron fluxes were used to calculate the specific activity of significant radionuclides in the concrete and rebar. The calculated specific activity and consequently the calculated neutron fluxes were validated at a number of sample locations. The calculated concrete and rebar specific activity were found to be in good agreement with the measured specific activity at the sample locations. The unrestricted use of the facility was granted through the approval of the licence to abandon the facility in August 2011. PMID- 23658214 TI - The balanced survivor average causal effect. AB - Statistical analysis of longitudinal outcomes is often complicated by the absence of observable values in patients who die prior to their scheduled measurement. In such cases, the longitudinal data are said to be "truncated by death" to emphasize that the longitudinal measurements are not simply missing, but are undefined after death. Recently, the truncation by death problem has been investigated using the framework of principal stratification to define the target estimand as the survivor average causal effect (SACE), which in the context of a two-group randomized clinical trial is the mean difference in the longitudinal outcome between the treatment and control groups for the principal stratum of always-survivors. The SACE is not identified without untestable assumptions. These assumptions have often been formulated in terms of a monotonicity constraint requiring that the treatment does not reduce survival in any patient, in conjunction with assumed values for mean differences in the longitudinal outcome between certain principal strata. In this paper, we introduce an alternative estimand, the balanced-SACE, which is defined as the average causal effect on the longitudinal outcome in a particular subset of the always-survivors that is balanced with respect to the potential survival times under the treatment and control. We propose a simple estimator of the balanced-SACE that compares the longitudinal outcomes between equivalent fractions of the longest surviving patients between the treatment and control groups and does not require a monotonicity assumption. We provide expressions for the large sample bias of the estimator, along with sensitivity analyses and strategies to minimize this bias. We consider statistical inference under a bootstrap resampling procedure. PMID- 23658215 TI - Distance-based mapping of disease risk. AB - In this article, we consider the problem of comparing the distribution of observations in a planar region to a pre-specified null distribution. Our motivation is a surveillance setting where we map locations of incident disease, aiming to monitor these data over time, to locate potential areas of high/low incidence so as to direct public health actions. We propose a non-parametric approach to distance-based disease risk mapping inspired by tomographic imaging. We consider several one-dimensional projections via the observed distribution of distances to a chosen fixed point; we then compare this distribution to that expected under the null and average these comparisons across projections to compute a relative-risk-like score at each point in the region. The null distribution can be established from historical data. Scores are displayed on the map using a color scale. In addition, we give a detailed description of the method along with some desirable theoretical properties. To further assess the performance of this method, we compare it to the widely used log ratio of kernel density estimates. As a performance metric, we evaluate the accuracy to locate simulated spatial clusters superimposed on a uniform distribution in the unit disk. Results suggest that both methods can adequately locate this increased risk but each relies on an appropriate choice of parameters. Our proposed method, distance-based mapping (DBM), can also generalize to arbitrary metric spaces and/or high-dimensional data. PMID- 23658213 TI - Estimation of risk ratios in cohort studies with a common outcome: a simple and efficient two-stage approach. AB - The risk ratio effect measure is often the main parameter of interest in epidemiologic studies with a binary outcome. In this paper, the author presents a simple and efficient two-stage approach to estimate the risk ratios directly, which does not directly rely on consistency for an estimate of the baseline risk. This latter property is a key advantage of the approach over existing methods, because, unlike these other methods, the proposed approach obviates the need to restrict the predicted risk probabilities to fall below one, in order to recover efficient inferences about risk ratios. An additional appeal of the approach is that it is easy to implement. Finally, when the primary interest is in the effect of a specific binary exposure, a simple doubly robust closed-form estimator is derived, for the multiplicative effect of the exposure. Specifically, we show how one can adjust for confounding by incorporating a working regression model for the propensity score so that the correct inferences about the multiplicative effect of the exposure are recovered if either this model is correct or a working model for the association between confounders and outcome risk is correct, but both do not necessarily hold. PMID- 23658216 TI - Comparative analysis of transcriptional gene regulation indicates similar physiologic response in mouse tissues at low absorbed doses from intravenously administered 211At. AB - (211)At is a promising therapeutic radionuclide because of the nearly optimal biological effectiveness of emitted alpha-particles. Unbound (211)At accumulates in the thyroid gland and in other vital normal tissues. However, few studies have been performed that assess the (211)At-induced normal-tissue damage in vivo. Knowledge about the extent and quality of resulting responses in various organs offers a new venue for reducing risks and side effects and increasing the overall well-being of the patient during and after therapy. METHODS: Female BALB/c nude mice were injected intravenously with 0.064-42 kBq of (211)At or mock-treated, and the kidneys, liver, lungs, and spleen were excised 24 h after injection. A transcriptional gene expression analysis was performed in triplicate using RNA microarray technology. Biological processes associated with regulated transcripts were grouped into 8 main categories with 31 subcategories according to gene ontology terms for comparison of regulatory profiles. RESULTS: A substantial decrease in the total number of regulated transcripts was observed between 0.64 and 1.8 kBq of (211)At for all investigated tissues. Few genes were differentially regulated in each tissue at all absorbed doses. In all tissues, most of these genes showed a nonmonotonous dependence on absorbed dose. However, the direction of regulation generally remained uniform for a given gene. Few known radiation-associated genes were regulated on the transcriptional level, and their expression profile generally appeared to be dose-independent and tissue specific. The regulatory profiles of categorized biological processes were tissue specific and reflected the shift in regulatory intensity between 0.64 and 1.8 kBq of (211)At. The profiles revealed strongly regulated and nonregulated subcategories. CONCLUSION: The strong regulatory change observed between 0.64 and 1.8 kBq is hypothesized to result not only from low-dose effects in each tissue but also from physiologic responses to ionizing radiation-induced damage to, for example, the (211)At-accumulating thyroid gland. The presented results demonstrate the complexity of responses to radionuclides in vivo and highlight the need for further research to also consider physiology in ionizing radiation induced responses. PMID- 23658217 TI - The role of 18F-FDG PET/CT for initial staging of nasal type natural killer/T cell lymphoma: a comparison with conventional staging methods. AB - The utility of (18)F-FDG PET/CT in patients with nasal-type natural killer (NK)/T cell lymphoma has not been established. Therefore, we evaluated the role of (18)F FDG PET/CT for determining cancer staging by comparing its results to those of conventional staging methods (CSMs) (physical examination, CT with intravenous contrast, biopsies from primary sites, and bone marrow examinations) in patients with nasal-type NK/T-cell lymphoma. METHODS: In this study, 52 consecutive patients (34 men, 18 women; mean age, 49.4 y) with newly diagnosed nasal-type NK/T-cell lymphoma were studied. Anatomic regions (n = 1,300; 16 nodal and 9 extranodal regions per patient) were assessed with an (18)F-FDG PET/CT scan and with CSMs, and each anatomic region was classified as positive or negative for malignancy. Biopsy and clinical follow-up, including additional imaging studies, were used as the gold standard for diagnosis. RESULTS: Of the 59 nodal and 71 extranodal anatomic regions that were truly positive for malignancy, (18)F-FDG PET/CT detected 58 nodal and 69 extranodal. CSMs, however, detected only 44 of the nodal and 61 of the extranodal anatomic regions that were positive for malignancy (nodal comparison of PET/CT vs. CSMs, P < 0.001; extranodal comparison of PET/CT vs. CSMs, P = 0.008). PET/CT scans exhibited a significantly better sensitivity (97.7% vs. 80.7%, P < 0.001) than CSMs for the detection of malignant lesions. PET/CT findings altered the original staging category for 12 patients (21.2%) and affected treatment planning in 23 cases (44.2%). CONCLUSION: Our study demonstrated that (18)F-FDG PET/CT scanning is a valuable modality for staging and treatment planning in patients with nasal-type NK/T-cell lymphoma. PMID- 23658218 TI - PET imaging of chemokine receptors in vascular injury-accelerated atherosclerosis. AB - Atherosclerosis is the pathophysiologic process behind lethal cardiovascular diseases. It is a chronic inflammatory progression. Chemokines can strongly affect the initiation and progression of atherosclerosis by controlling the trafficking of inflammatory cells in vivo through interaction with their receptors. Some chemokine receptors have been reported to play an important role in plaque development and stability. However, the diagnostic potential of chemokine receptors has not yet been explored. The purpose of this study was to develop a positron emitter-radiolabeled probe to image the upregulation of chemokine receptor in a wire-injury-accelerated apolipoprotein E knockout (ApoE( /-)) mouse model of atherosclerosis. METHODS: A viral macrophage inflammatory protein II (vMIP-II) was used to image the upregulation of multiple chemokine receptors through conjugation with DOTA for (64)Cu radiolabeling and PET. Imaging studies were performed at 2 and 4 wk after injury in both wire-injured ApoE(-/-) and wild-type C57BL/6 mice. Competitive PET blocking studies with nonradiolabeled vMIP-II were performed to confirm the imaging specificity. Specific PET blocking with individual chemokine receptor antagonists was also performed to verify the upregulation of a particular chemokine receptor. In contrast, (18)F-FDG PET imaging was performed in both models to evaluate tracer uptake. Immunohistochemistry on the injury and sham tissues was performed to assess the upregulation of chemokine receptors. RESULTS: (15)O-CO PET showed decreased blood volume in the femoral artery after the injury. (64)Cu-DOTA-vMIP-II exhibited fast in vivo pharmacokinetics with major renal clearance. PET images showed specific accumulation around the injury site, with consistent expression during the study period. Quantitative analysis of tracer uptake at the injury lesion in the ApoE( /-) model showed a 3-fold increase over the sham-operated site and the sites in the injured wild-type mouse. (18)F-FDG PET showed significantly less tracer accumulation than (64)Cu-DOTA-vMIP-II, with no difference observed between injury and sham sites. PET blocking studies identified chemokine receptor-mediated (64)Cu-DOTA-vMIP-II uptake and verified the presence of 8 chemokine receptors, and this finding was confirmed by immunohistochemistry. CONCLUSION: (64)Cu-DOTA vMIP-II was proven a sensitive and useful PET imaging probe for the detection of 8 up-regulated chemokine receptors in a model of injury-accelerated atherosclerosis. PMID- 23658219 TI - Production at the Curie level of no-carrier-added 6-18F-fluoro-L-dopa. AB - 6-(18)F-fluoro-L-dopa ((18)F-FDOPA) has proven to be a useful radiopharmaceutical for the evaluation of presynaptic dopaminergic function using PET. In comparison to electrophilic synthesis, the no-carrier-added (NCA) nucleophilic method has several advantages. These include much higher available activity and specific activity. Recently, we have described an NCA enantioselective synthesis using a chiral phase-transfer catalyst. However, some chemicals were difficult to implement into a commercially available synthesizer, restricting access to this radiopharmaceutical to only a few PET centers. METHODS: In this paper, 2 important chemical improvements are proposed to simplify production of (18)F FDOPA, resulting in straightforward automation of the synthesis in a commercially available module. RESULTS: First, a fast, simple, and reliable synthesis of 2 (18)F-fluoro-4,5-dimethoxybenzyl iodide on a solid-phase support was developed. Second, a phase-transfer catalyst alkylation of a glycine derivative at room temperature was used to enable enantioselective carbon-carbon bond formation. After hydrolysis and high-performance liquid chromatography purification, a high enantiomeric excess of (18)F-FDOPA (~ 97%) was obtained using a chiral catalyst available from a biphenyl 3 substrate. The total synthesis time was 63 min, and the decay-corrected radiochemical yield was 36% +/- 3% (n = 8). CONCLUSION: By exploiting the advantages of this NCA approach, using a starting activity of 185 GBq of NCA (18)F-fluoride, high activities of (18)F-FDOPA (>45 GBq) with high specific activity (>= 753 GBq/MUmol) are now available at the end of synthesis for use in clinical investigations. PMID- 23658220 TI - The impact of trans-regulation on the evolutionary rates of metazoan proteins. AB - Transcription factor (TF) and microRNA (miRNA) are two crucial trans-regulatory factors that coordinately control gene expression. Understanding the impacts of these two factors on the rate of protein sequence evolution is of great importance in evolutionary biology. While many biological factors associated with evolutionary rate variations have been studied, evolutionary analysis of simultaneously accounting for TF and miRNA regulations across metazoans is still uninvestigated. Here, we provide a series of statistical analyses to assess the influences of TF and miRNA regulations on evolutionary rates across metazoans (human, mouse and fruit fly). Our results reveal that the negative correlations between trans-regulation and evolutionary rates hold well across metazoans, but the strength of TF regulation as a rate indicator becomes weak when the other confounding factors that may affect evolutionary rates are controlled. We show that miRNA regulation tends to be a more essential indicator of evolutionary rates than TF regulation, and the combination of TF and miRNA regulations has a significant dependent effect on protein evolutionary rates. We also show that trans-regulation (especially miRNA regulation) is much more important in human/mouse than in fruit fly in determining protein evolutionary rates, suggesting a considerable variation in rate determinants between vertebrates and invertebrates. PMID- 23658221 TI - Reprever: resolving low-copy duplicated sequences using template driven assembly. AB - Genomic sequence duplication is an important mechanism for genome evolution, often resulting in large sequence variations with implications for disease progression. Although paired-end sequencing technologies are commonly used for structural variation discovery, the discovery of novel duplicated sequences remains an unmet challenge. We analyze duplicons starting from identified high copy number variants. Given paired-end mapped reads, and a candidate high-copy region, our tool, Reprever, identifies (a) the insertion breakpoints where the extra duplicons inserted into the donor genome and (b) the actual sequence of the duplicon. Reprever resolves ambiguous mapping signatures from existing homologs, repetitive elements and sequencing errors to identify breakpoint. At each breakpoint, Reprever reconstructs the inserted sequence using profile hidden Markov model (PHMM)-based guided assembly. In a test on 1000 artificial genomes with simulated duplication, Reprever could identify novel duplicates up to 97% of genomes within 3 bp positional and 1% sequence errors. Validation on 680 fosmid sequences identified and reconstructed eight duplicated sequences with high accuracy. We applied Reprever to reanalyzing a re-sequenced data set from the African individual NA18507 to identify >800 novel duplicates, including insertions in genes and insertions with additional variation. polymerase chain reaction followed by capillary sequencing validated both the insertion locations of the strongest predictions and their predicted sequence. PMID- 23658222 TI - CABS-flex: Server for fast simulation of protein structure fluctuations. AB - The CABS-flex server (http://biocomp.chem.uw.edu.pl/CABSflex) implements CABS model-based protocol for the fast simulations of near-native dynamics of globular proteins. In this application, the CABS model was shown to be a computationally efficient alternative to all-atom molecular dynamics--a classical simulation approach. The simulation method has been validated on a large set of molecular dynamics simulation data. Using a single input (user-provided file in PDB format), the CABS-flex server outputs an ensemble of protein models (in all-atom PDB format) reflecting the flexibility of the input structure, together with the accompanying analysis (residue mean-square-fluctuation profile and others). The ensemble of predicted models can be used in structure-based studies of protein functions and interactions. PMID- 23658223 TI - The effect of LacI autoregulation on the performance of the lactose utilization system in Escherichia coli. AB - The lactose operon of Escherichia coli is a paradigm system for quantitative understanding of gene regulation in prokaryotes. Yet, none of the many mathematical models built so far to study the dynamics of this system considered the fact that the Lac repressor regulates its own transcription by forming a transcriptional roadblock at the O3 operator site. Here we study the effect of autoregulation on intracellular LacI levels and also show that cAMP-CRP binding does not affect the efficiency of autoregulation. We built a mathematical model to study the role of LacI autoregulation in the lactose utilization system. Previously, it has been argued that negative autoregulation can significantly reduce noise as well as increase the speed of response. We show that the particular molecular mechanism, a transcriptional roadblock, used to achieve self repression in the lac system does neither. Instead, LacI autoregulation balances two opposing states, one that allows quicker response to smaller pulses of external lactose, and the other that minimizes production costs in the absence of lactose. PMID- 23658224 TI - Mechanisms of in vivo binding site selection of the hematopoietic master transcription factor PU.1. AB - The transcription factor PU.1 is crucial for the development of many hematopoietic lineages and its binding patterns significantly change during differentiation processes. However, the 'rules' for binding or not-binding of potential binding sites are only partially understood. To unveil basic characteristics of PU.1 binding site selection in different cell types, we studied the binding properties of PU.1 during human macrophage differentiation. Using in vivo and in vitro binding assays, as well as computational prediction, we show that PU.1 selects its binding sites primarily based on sequence affinity, which results in the frequent autonomous binding of high affinity sites in DNase I inaccessible regions (25-45% of all occupied sites). Increasing PU.1 concentrations and the availability of cooperative transcription factor interactions during lineage differentiation both decrease affinity thresholds for in vivo binding and fine-tune cell type-specific PU.1 binding, which seems to be largely independent of DNA methylation. Occupied sites were predominantly detected in active chromatin domains, which are characterized by higher densities of PU.1 recognition sites and neighboring motifs for cooperative transcription factors. Our study supports a model of PU.1 binding control that involves motif binding affinity, PU.1 concentration, cooperativeness with neighboring transcription factor sites and chromatin domain accessibility, which likely applies to all PU.1 expressing cells. PMID- 23658225 TI - The pentatricopeptide repeat MTSF1 protein stabilizes the nad4 mRNA in Arabidopsis mitochondria. AB - Gene expression in plant mitochondria involves a complex collaboration of transcription initiation and termination, as well as subsequent mRNA processing to produce mature mRNAs. In this study, we describe the function of the Arabidopsis mitochondrial stability factor 1 (MTSF1) gene and show that it encodes a pentatricopeptide repeat protein essential for the 3'-processing of mitochondrial nad4 mRNA and its stability. The nad4 mRNA is highly destabilized in Arabidopsis mtsf1 mutant plants, which consequently accumulates low amounts of a truncated form of respiratory complex I. Biochemical and genetic analyses demonstrated that MTSF1 binds with high affinity to the last 20 nucleotides of nad4 mRNA. Our data support a model for MTSF1 functioning in which its association with the last nucleotides of the nad4 3' untranslated region stabilizes nad4 mRNA. Additionally, strict conservation of the MTSF1-binding sites strongly suggests that the protective function of MTSF1 on nad4 mRNA is conserved in dicots. These results demonstrate that the mRNA stabilization process initially identified in plastids, whereby proteins bound to RNA extremities constitute barriers to exoribonuclease progression occur in plant mitochondria to protect and concomitantly define the 3' end of mature mitochondrial mRNAs. Our study also reveals that short RNA molecules corresponding to pentatricopeptide repeat-binding sites accumulate also in plant mitochondria. PMID- 23658226 TI - Activation of a human chromosomal replication origin by protein tethering. AB - The specification of mammalian chromosomal replication origins is incompletely understood. To analyze the assembly and activation of prereplicative complexes (pre-RCs), we tested the effects of tethered binding of chromatin acetyltransferases and replication proteins on chromosomal c-myc origin deletion mutants containing a GAL4-binding cassette. GAL4(DBD) (DNA binding domain) fusions with Orc2, Cdt1, E2F1 or HBO1 coordinated the recruitment of the Mcm7 helicase subunit, the DNA unwinding element (DUE)-binding protein DUE-B and the minichromosome maintenance (MCM) helicase activator Cdc45 to the replicator, and restored origin activity. In contrast, replication protein binding and origin activity were not stimulated by fusion protein binding in the absence of flanking c-myc DNA. Substitution of the GAL4-binding site for the c-myc replicator DUE allowed Orc2 and Mcm7 binding, but eliminated origin activity, indicating that the DUE is essential for pre-RC activation. Additionally, tethering of DUE-B was not sufficient to recruit Cdc45 or activate pre-RCs formed in the absence of a DUE. These results show directly in a chromosomal background that chromatin acetylation, Orc2 or Cdt1 suffice to recruit all downstream replication initiation activities to a prospective origin, and that chromosomal origin activity requires singular DNA sequences. PMID- 23658227 TI - The proto-oncoprotein FBI-1 interacts with MBD3 to recruit the Mi-2/NuRD-HDAC complex and BCoR and to silence p21WAF/CDKN1A by DNA methylation. AB - The tumour-suppressor gene CDKN1A (encoding p21Waf/Cip1) is thought to be epigenetically repressed in cancer cells. FBI-1 (ZBTB7A) is a proto-oncogenic transcription factor repressing the alternative reading frame and p21WAF/CDKN1A genes of the p53 pathway. FBI-1 interacts directly with MBD3 (methyl-CpG-binding domain protein 3) in the nucleus. We demonstrated that FBI-1 binds both non methylated and methylated DNA and that MBD3 is recruited to the CDKN1A promoter through its interaction with FBI-1, where it enhances transcriptional repression by FBI-1. FBI-1 also interacts with the co-repressors nuclear receptor corepressor (NCoR), silencing mediator for retinoid and thyroid receptors (SMRT) and BCL-6 corepressor (BCoR) to repress transcription. MBD3 regulates a molecular interaction between the co-repressor and FBI-1. MBD3 decreases the interaction between FBI-1 and NCoR/SMRT but increases the interaction between FBI-1 and BCoR. Because MBD3 is a subunit of the Mi-2 autoantigen (Mi-2)/nucleosome remodelling and histone deacetylase (NuRD)-HDAC complex, FBI-1 recruits the Mi-2/NuRD-HDAC complex via MBD3. BCoR interacts with the Mi-2/NuRD-HDAC complex, DNMTs and HP1. MBD3 and BCoR play a significant role in the recruitment of the Mi-2/NuRD-HDAC complex- and the NuRD complex-associated proteins, DNMTs and HP. By recruiting DNMTs and HP1, Mi-2/NuRD-HDAC complex appears to play key roles in epigenetic repression of CDKN1A by DNA methylation. PMID- 23658228 TI - Recognition of RNA duplexes by chemically modified triplex-forming oligonucleotides. AB - Triplex is emerging as an important RNA tertiary structure motif, in which consecutive non-canonical base pairs form between a duplex and a third strand. RNA duplex region is also often functionally important site for protein binding. Thus, triplex-forming oligonucleotides (TFOs) may be developed to regulate various biological functions involving RNA, such as viral ribosomal frameshifting and reverse transcription. How chemical modification in TFOs affects RNA triplex stability, however, is not well understood. Here, we incorporated locked nucleic acid, 2-thio U- and 2'-O methyl-modified residues in a series of all pyrimidine RNA TFOs, and we studied the binding to two RNA hairpin structures. The 12-base triple major-groove pyrimidine-purine-pyrimidine triplex structures form between the duplex regions of RNA/DNA hairpins and the complementary RNA TFOs. Ultraviolet-absorbance-detected thermal melting studies reveal that the locked nucleic acid and 2-thio U modifications in TFOs strongly enhance triplex formation with both parental RNA and DNA duplex regions. In addition, we found that incorporation of 2'-O methyl-modified residues in a TFO destabilizes and stabilizes triplex formation with RNA and DNA duplex regions, respectively. The (de)stabilization of RNA triplex formation may be facilitated through modulation of van der Waals contact, base stacking, hydrogen bonding, backbone pre organization, geometric compatibility and/or dehydration energy. Better understanding of the molecular determinants of RNA triplex structure stability lays the foundation for designing and discovering novel sequence-specific duplex binding ligands as diagnostic and therapeutic agents targeting RNA. PMID- 23658229 TI - Red5 and three nuclear pore components are essential for efficient suppression of specific mRNAs during vegetative growth of fission yeast. AB - Zinc-finger domains are found in many nucleic acid-binding proteins in both prokaryotes and eukaryotes. Proteins carrying zinc-finger domains have important roles in various nuclear transactions, including transcription, mRNA processing and mRNA export; however, for many individual zinc-finger proteins in eukaryotes, the exact function of the protein is not fully understood. Here, we report that Red5 is involved in efficient suppression of specific mRNAs during vegetative growth of Schizosaccharomyces pombe. Red5, which contains five C3H1-type zinc finger domains, localizes to the nucleus where it forms discrete dots. A red5 point mutation, red5-2, results in the upregulation of specific meiotic mRNAs in vegetative mutant red5-2 cells; northern blot data indicated that these meiotic mRNAs in red5-2 cells have elongated poly(A) tails. RNA-fluorescence in situ hybridization results demonstrate that poly(A)(+) RNA species accumulate in the nucleolar regions of red5-deficient cells. Moreover, Red5 genetically interacts with several mRNA export factors. Unexpectedly, three components of the nuclear pore complex also suppress a specific set of meiotic mRNAs. These results indicate that Red5 function is important to meiotic mRNA degradation; they also suggest possible connections among selective mRNA decay, mRNA export and the nuclear pore complex in vegetative fission yeast. PMID- 23658230 TI - Life without tRNAArg-adenosine deaminase TadA: evolutionary consequences of decoding the four CGN codons as arginine in Mycoplasmas and other Mollicutes. AB - In most bacteria, two tRNAs decode the four arginine CGN codons. One tRNA harboring a wobble inosine (tRNA(Arg)ICG) reads the CGU, CGC and CGA codons, whereas a second tRNA harboring a wobble cytidine (tRNA(Arg)CCG) reads the remaining CGG codon. The reduced genomes of Mycoplasmas and other Mollicutes lack the gene encoding tRNA(Arg)CCG. This raises the question of how these organisms decode CGG codons. Examination of 36 Mollicute genomes for genes encoding tRNA(Arg) and the TadA enzyme, responsible for wobble inosine formation, suggested an evolutionary scenario where tadA gene mutations first occurred. This allowed the temporary accumulation of non-deaminated tRNA(Arg)ACG, capable of reading all CGN codons. This hypothesis was verified in Mycoplasma capricolum, which contains a small fraction of tRNA(Arg)ACG with a non-deaminated wobble adenosine. Subsets of Mollicutes continued to evolve by losing both the mutated tRNA(Arg)CCG and tadA, and then acquired a new tRNA(Arg)UCG. This permitted further tRNA(Arg)ACG mutations with tRNA(Arg)GCG or its disappearance, leaving a single tRNA(Arg)UCG to decode the four CGN codons. The key point of our model is that the A-to-I deamination activity had to be controlled before the loss of the tadA gene, allowing the stepwise evolution of Mollicutes toward an alternative decoding strategy. PMID- 23658231 TI - FANCD2 regulates BLM complex functions independently of FANCI to promote replication fork recovery. AB - Fanconi Anemia (FA) and Bloom Syndrome share overlapping phenotypes including spontaneous chromosomal abnormalities and increased cancer predisposition. The FA protein pathway comprises an upstream core complex that mediates recruitment of two central players, FANCD2 and FANCI, to sites of stalled replication forks. Successful fork recovery depends on the Bloom's helicase BLM that participates in a larger protein complex ('BLMcx') containing topoisomerase III alpha, RMI1, RMI2 and replication protein A. We show that FANCD2 is an essential regulator of BLMcx functions: it maintains BLM protein stability and is crucial for complete BLMcx assembly; moreover, it recruits BLMcx to replicating chromatin during normal S phase and mediates phosphorylation of BLMcx members in response to DNA damage. During replication stress, FANCD2 and BLM cooperate to promote restart of stalled replication forks while suppressing firing of new replication origins. In contrast, FANCI is dispensable for FANCD2-dependent BLMcx regulation, demonstrating functional separation of FANCD2 from FANCI. PMID- 23658232 TI - Quantitative assessment of Tet-induced oxidation products of 5-methylcytosine in cellular and tissue DNA. AB - Recent studies showed that Ten-eleven translocation (Tet) family dioxygenases can oxidize 5-methyl-2'-deoxycytidine (5-mdC) in DNA to yield the 5-hydroxymethyl, 5 formyl and 5-carboxyl derivatives of 2'-deoxycytidine (5-HmdC, 5-FodC and 5 CadC). 5-HmdC in DNA may be enzymatically deaminated to yield 5-hydroxymethyl-2' deoxyuridine (5-HmdU). After their formation at CpG dinucleotide sites, these oxidized pyrimidine nucleosides, particularly 5-FodC, 5-CadC, and 5-HmdU, may be cleaved from DNA by thymine DNA glycosylase, and subsequent action of base excision repair machinery restores unmethylated cytosine. These processes are proposed to be important in active DNA cytosine demethylation in mammals. Here we used a reversed-phase HPLC coupled with tandem mass spectrometry (LC-MS/MS/MS) method, along with the use of stable isotope-labeled standards, for accurate measurements of 5-HmdC, 5-FodC, 5-CadC and 5-HmdU in genomic DNA of cultured human cells and multiple mammalian tissues. We found that overexpression of the catalytic domain of human Tet1 led to marked increases in the levels of 5-HmdC, 5 FodC and 5-CadC, but only a modest increase in 5-HmdU, in genomic DNA of HEK293T cells. Moreover, 5-HmdC is present at a level that is approximately 2-3 and 3-4 orders of magnitude greater than 5-FodC and 5-CadC, respectively, and 35-400 times greater than 5-HmdU in the mouse brain and skin, and human brain. The robust analytical method built a solid foundation for dissecting the molecular mechanisms of active cytosine demethylation, for measuring these 5-mdC derivatives and assessing their involvement in epigenetic regulation in other organisms and for examining whether these 5-mdC derivatives can be used as biomarkers for human diseases. PMID- 23658234 TI - Observational studies of treatment effectiveness: useful, useless or somewhere in between? PMID- 23658233 TI - Pathological tremor prediction using surface electromyogram and acceleration: potential use in 'ON-OFF' demand driven deep brain stimulator design. AB - OBJECTIVE: We present a proof of concept for a novel method of predicting the onset of pathological tremor using non-invasively measured surface electromyogram (sEMG) and acceleration from tremor-affected extremities of patients with Parkinson's disease (PD) and essential tremor (ET). APPROACH: The tremor prediction algorithm uses a set of spectral (Fourier and wavelet) and nonlinear time series (entropy and recurrence rate) parameters extracted from the non invasively recorded sEMG and acceleration signals. MAIN RESULTS: The resulting algorithm is shown to successfully predict tremor onset for all 91 trials recorded in 4 PD patients and for all 91 trials recorded in 4 ET patients. The predictor achieves a 100% sensitivity for all trials considered, along with an overall accuracy of 85.7% for all ET trials and 80.2% for all PD trials. By using a Pearson's chi-square test, the prediction results are shown to significantly differ from a random prediction outcome. SIGNIFICANCE: The tremor prediction algorithm can be potentially used for designing the next generation of non invasive closed-loop predictive ON-OFF controllers for deep brain stimulation (DBS), used for suppressing pathological tremor in such patients. Such a system is based on alternating ON and OFF DBS periods, an incoming tremor being predicted during the time intervals when DBS is OFF, so as to turn DBS back ON. The prediction should be a few seconds before tremor re-appears so that the patient is tremor-free for the entire DBS ON-OFF cycle and the tremor-free DBS OFF interval should be maximized in order to minimize the current injected in the brain and battery usage. PMID- 23658235 TI - Cerebrospinal fluid oligoclonal bands are important in the diagnosis of multiple sclerosis, unreasonably downplayed by the McDonald criteria 2010: Yes. PMID- 23658236 TI - CSF oligoclonal bands are important in the diagnosis of multiple sclerosis, unreasonably downplayed by the McDonald criteria 2010: No. PMID- 23658237 TI - CSF oligoclonal bands are important in the diagnosis of multiple sclerosis, unreasonably downplayed by the McDonald criteria 2010: Commentary. PMID- 23658239 TI - HERVs: have we been here before? PMID- 23658240 TI - Re: Errors in the editorial by Christensen and Giovannoni [HERVs: have we been here before? MSJ 18(12) 1670-1672]. PMID- 23658241 TI - EndoClamp Aortic Catheter in the descending aorta for normothermic aortic arch replacement on the beating heart without circulatory arrest. PMID- 23658242 TI - Ethics, error, and initial trials of efficacy. AB - Clinical trial reforms aimed at boosting phase 2 positive predictivity may involve ethical and social trade-offs. PMID- 23658243 TI - Blocking the spread of resistance. AB - Understanding how Staphylococcus aureus is involved in conjugative plasmid transfer may lead to new strategies to combat antimicrobial resistance. PMID- 23658244 TI - Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies. AB - High-grade gliomas are extremely difficult to treat because they are invasive and therefore not curable by surgical resection; the toxicity of current chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles to target enzyme/prodrug therapy selectively to tumors. We used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, and are genetically and functionally stable. In vivo biodistribution studies demonstrated NSC retention of tumor tropism, even in mice pretreated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor-bearing and orthotopic glioma-bearing immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5 fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was about one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, nontoxic, and effective in mice. These data have led to approval of a first-in human study of an allogeneic NSC-mediated enzyme/prodrug-targeted cancer therapy in patients with recurrent high-grade glioma. PMID- 23658245 TI - Genomic diversity and fitness of E. coli strains recovered from the intestinal and urinary tracts of women with recurrent urinary tract infection. AB - Urinary tract infections (UTIs) are common in women, and recurrence is a major clinical problem. Most UTIs are caused by uropathogenic Escherichia coli (UPEC). UPEC are generally thought to migrate from the gut to the bladder to cause UTI. UPEC form specialized intracellular bacterial communities in the bladder urothelium as part of a pathogenic mechanism to establish a foothold during acute stages of infection. Evolutionarily, such a specific adaptation to the bladder environment would be predicted to result in decreased fitness in other habitats, such as the gut. To examine this prediction, we characterized 45 E. coli strains isolated from the feces and urine of four otherwise healthy women with recurrent UTI. Multilocus sequence typing and whole genome sequencing revealed that two patients maintained a clonal population in both these body habitats throughout their recurrent UTIs, whereas the other two exhibited a wholesale shift in the dominant UPEC strain colonizing both sites. In vivo competition studies in mouse models, using isolates taken from one of the patients with a wholesale population shift, revealed that the strain that dominated her last UTI episode had increased fitness in both the gut and the bladder relative to the strain that dominated in preceding episodes. Increased fitness correlated with differences in the strains' gene repertoires and carbohydrate and amino acid utilization profiles. Thus, UPEC appear capable of persisting in both the gut and urinary tract without a fitness trade-off, emphasizing the need to widen our consideration of potential reservoirs for strains causing recurrent UTI. PMID- 23658246 TI - Targeted imaging of esophageal neoplasia with a fluorescently labeled peptide: first-in-human results. AB - Esophageal adenocarcinoma is rising rapidly in incidence and usually develops from Barrett's esophagus, a precursor condition commonly found in patients with chronic acid reflux. Premalignant lesions are challenging to detect on conventional screening endoscopy because of their flat appearance. Molecular changes can be used to improve detection of early neoplasia. We have developed a peptide that binds specifically to high-grade dysplasia and adenocarcinoma. We first applied the peptide ex vivo to esophageal specimens from 17 patients to validate specific binding. Next, we performed confocal endomicroscopy in vivo in 25 human subjects after topical peptide administration and found 3.8-fold greater fluorescence intensity for esophageal neoplasia compared with Barrett's esophagus and squamous epithelium with 75% sensitivity and 97% specificity. No toxicity was attributed to the peptide in either animal or patient studies. Therefore, our first-in-human results show that this targeted imaging agent is safe and may be useful for guiding tissue biopsy and for early detection of esophageal neoplasia and potentially other cancers of epithelial origin, such as bladder, colon, lung, pancreas, and stomach. PMID- 23658247 TI - The impact of pay for performance on the control of blood pressure in people with chronic kidney disease stage 3-5. AB - BACKGROUND: The implementation of national estimated glomerular filatration rate reporting and the inclusion of renal-specific indicators in a primary care pay for performance (P4P) system since April 2006 has promoted identification and better management of risk factors related to chronic kidney disease (CKD). In the UK, the P4P framework is known as the Quality and Outcomes Framework (QOF). One of the key targets for intervention in primary care was hypertension. It is clear that hypertension is a major predictor of development and progression of CKD; thus, targeting better blood pressure control is likely to have a positive impact on outcomes in CKD. The aim of this study was to evaluate the effectiveness of renal indicators outlined in P4P on the management of hypertension in primary care. To estimate the cost implications of the resulting changes in prescribing patterns of antihypertensive medication following introduction of such indicators. METHODS: We performed a prospective cohort study using a large primary care database. This cohort was taken from a database collated as part of a clinical decision support system used to assist the management of CKD in primary care. We investigated a total population of 90 250 individuals on general practitioner (GP) registers with a valid serum creatinine estimation in the 6 year study period. A total of 10 040 patients had confirmed stage 3-5 CKD in the 2 years pre-QOF and formed the study cohort. Patients were studied over three time periods, pre-QOF (1 April 2004 to 31 March 2006), 2 years post-QOF (1 April 2006 to 31 March 2008) and finally the two subsequent years (1 April 2008 to 31 March 2010). The mean systolic and diastolic blood pressures (BP) together with antihypertensive medication were analysed over the three time periods. Cost calculation was based on 2009 British National Formulary list prices for antihypertensives. RESULTS: The mean age of the cohort at the start of the study period was 64.8 years, 55% were female. In those patients with stage 3-5 CKD 83.9% were hypertensive, defined by a pre-P4P BP of >140/85 or currently taking antihypertensive medication. The proportion of patients with CKD 3-5 attaining the BP target of 145/80 increased from 41.5% in the pre-QOF period to 50.0% in the post-QOF period. This increase was even more marked for those with hypertension in the pre-QOF period (28.8-45.1%). In the hypertensive patients, mean BP fell from 146/79 mmHg to 140/76 in the first 2 years post-P4P [P < 0.01, analysis of variance (ANOVA)]. This BP reduction was sustained in the last 2 years of the study, 139/75 (P < 0.01, ANOVA). The proportion of hypertensive patients taking angiotensin-converting enzyme inhibitors or angiotensin blockers increased, this was also sustained in the third time period. An increase in the prescribing of diuretics, calcium channel blockers and beta-blockers was also observed. The additional cost of increased prescribing was calculated to be ?25.00 per hypertensive patient based on GP prescription data. CONCLUSIONS: Population BP control has improved since the introduction of P4P renal indicators, and this improvement has been sustained. This was associated with a significant increase in the use of antihypertensive medication, resulting in increased prescription cost. Longer-term follow-up will establish whether or not this translates to improved outcomes in terms of progression of CKD, cardiovascular disease and patient mortality. PMID- 23658248 TI - Risk prediction models. AB - Prognostic research focuses on the prediction of the future course of a given disease in probability terms. Prognostication is performed by clinical decision makers by using risk prediction models that allow us to estimate the probability that a specific event occurs in a given patient over a predefined time period conditional on prognostic factors (predictors). Before application in clinical practice, risk prediction models should be properly validated by assessing their discrimination and calibration, or explained variation. Reclassification analyses allow us to evaluate the gain in risk prediction by using a new model compared with an established one. We discuss the concepts of developing and validating risk prediction models by means of two examples, the Framingham risk calculator for prediction of coronary heart disease (CHD), and the recently published Renal Risk Score to predict progression of chronic kidney disease (CKD). PMID- 23658249 TI - Assessment of living kidney donors and adherence to national live donor guidelines in the UK. AB - BACKGROUND: As in most industrialized countries, living kidney donation has increased considerably in the UK and now amounts to 38% of the total UK kidney transplant activity. Living kidney donation guidelines have been formulated by the relevant national societies. We were interested to study whether or not renal units across the UK adhere to those guidelines and to delineate areas of inconsistency and controversy. METHODS: Twenty-four adult kidney transplant centres and 50 adult non-transplant renal units across the UK were contacted by a postal questionnaire from January to April 2011. RESULTS: Twenty-one of 24 (88%) transplanting units and 23 of 50 (46%) non-transplanting units responded. Eighty one per cent of the responding transplanting units and only 30% of the non transplanting units have a dedicated live donor clinic. Eighty-six per cent of all units are without a set upper age limit for donors, whereas 7% of units excluded all potential donors older than 70 years. Twenty per cent of units accept donors with body mass indices (BMIs) up to 35, whereas 9% of units did not have an upper limit for BMI. Thirty-two per cent of centres exclude hypertensive donors on more than one antihypertensive drug, whereas 64% of units exclude donors only if they are on more than two anti-hypertensive drugs. of units rely on a spot urine sample to assess proteinuria, while 30% of units still perform 24 h urine collection. Sixty one per cent of units perform computed tomography (CT) angiography to assess the renal vessels prior to donation, while 32% use magnetic resonance (MR) angiography. Seventy-five per cent of centres assess split kidney function by radionuclide testing in all cases, whereas 25% perform this test only if there is a discrepancy in kidney size. The practice of suspension of recipients with potential living donor from the deceased waiting list is also remarkably inconsistent, whereby some centres suspend once a decision for living donation has been made in principle, whereas others suspend the recipient only once a date for surgery has been agreed. CONCLUSIONS: We demonstrate significant variability in accepting living kidney donors, particularly regarding age, BMI, and hypertension. Infrastructure setting for living donation and the live donor assessment are also remarkably inconsistent across the UK. It remains unclear as to why nephrologists decide not to adhere to established guidelines and further research should aim to find the lacking evidence in areas causing inconsistency in living donor assessment. PMID- 23658250 TI - Percutaneous renal sympathetic nerve ablation for loin pain haematuria syndrome. AB - Loin pain haematuria syndrome (LPHS) is a severe renal pain condition of uncertain origin and often resistant to treatment. Nephrectomy and renal autotrasplantation have occasionally been performed in very severe cases. Its pathogenesis is controversial. A 40-year-old hypertensive lady was diagnosed with LPHS after repeated diagnostic imaging procedures had ruled out any renal, abdominal or spinal conditions to justify pain. Notwithstanding treatment with three drugs, she had frequent hypertensive crises during which the loin pain was dramatically exacerbated. Vascular causes of the pain and hypertension were investigated and excluded. Her renal function was normal. The patient was referred to a multidisciplinary pain clinic, but had no significant improvement in her pain symptoms despite the use of non-steroidal anti-inflammatory drugs, adjuvant antidepressants and opioid-like agents. The pain and the discomfort were so severe that her quality of life was very poor, and her social and professional activities were compromised. Nephrectomy and renal autotransplantation have occasionally been performed in these cases. Since visceral pain signals flow through afferent sympathetic fibres, we felt that percutaneous catheter-based radiofrequency ablation of the renal sympathetic nerve fibres (recently introduced for the treatment of drug-resistant hypertension) could be valuable for pain relief. We treated the patient with radiofrequency ablation (Medtronic Symplicity Catheter) applied only to the right renal artery. After a 6-month follow-up, the patient is pain free and normotensive with all drugs withdrawn. She has experienced no hypertensive crises in the meantime. This observation suggests that percutaneous sympathetic denervation could prove to be an effective mini-invasive strategy for the treatment of chronic renal pain, and LPHS in particular. PMID- 23658251 TI - Concise review: heart regeneration and the role of cardiac stem cells. AB - Acute myocardial infarction leads to irreversible loss of cardiac myocytes, thereby diminishing the pump function of the heart. As a result, the strenuous workload imposed on the remaining cardiac myocytes often gives rise to subsequent cell loss until the vicious circle ends in chronic heart failure (CHF). Thus, we are in need of a therapy that could ameliorate or even reverse the disease progression of CHF. Endogenous regeneration of the mammalian heart has been shown in the neonatal heart, and the discovery that it may still persist in adulthood sparked hope for novel cardioregenerative therapies. As the basis for cardiomyocyte renewal, multipotent cardiac stem/progenitor cells (CSCs) that reside in the heart have been shown to differentiate into cardiac myocytes, smooth muscle cells, and vascular endothelial cells. These CSCs do have the potential to actively regenerate the heart but clearly fail to do so after abundant and segmental loss of cells, such as what occurs with myocardial infarction. Therefore, it is vital to continue research for the most optimal therapy based on the use or in situ stimulation of these CSCs. In this review, we discuss the current status of the cardioregenerative field. In particular, we summarize the current knowledge of CSCs as the regenerative substrate in the adult heart and their use in preclinical and clinical studies to repair the injured myocardium. PMID- 23658252 TI - Rapid generation of functional dopaminergic neurons from human induced pluripotent stem cells through a single-step procedure using cell lineage transcription factors. AB - Current protocols for in vitro differentiation of human induced pluripotent stem cells (hiPSCs) to generate dopamine (DA) neurons are laborious and time expensive. In order to accelerate the overall process, we have established a fast protocol by expressing the developmental transcription factors ASCL1, NURR1, and LMX1A. With this method, we were able to generate mature and functional dopaminergic neurons in as few as 21 days, skipping all the intermediate steps for inducting and selecting embryoid bodies and rosette-neural precursors. Strikingly, the resulting neuronal conversion process was very proficient, with an overall efficiency that was more than 93% of all the coinfected cells. hiPSC derived DA neurons expressed all the critical molecular markers of the DA molecular machinery and exhibited sophisticated functional features including spontaneous electrical activity and dopamine release. This one-step protocol holds important implications for in vitro disease modeling and is particularly amenable for exploitation in high-throughput screening protocols. PMID- 23658253 TI - Men seek social standing, women seek companionship: sex differences in deriving self-worth from relationships. AB - Do men base their self-worth on relationships less than do women? In an assessment of lay beliefs, men and women alike indicated that men are less reliant on relationships as a source of self-worth than are women (Study 1). Yet relationships may make a different important contribution to the self-esteem of men. Men reported basing their self-esteem on their own relationship status (whether or not they were in a relationship) more than did women, and this link was statistically mediated by the perceived importance of relationships as a source of social standing (Studies 1 and 2). Finally, when relationship status was threatened, men displayed increased social-standing concerns, whereas women displayed increased interdependence concerns (Study 3). Together, these findings demonstrate that both men and women rely on relationships for self-worth, but that they derive self-esteem from relationships in different ways. PMID- 23658254 TI - Ward-specific rates of nasal cocolonization with methicillin-susceptible and resistant Staphylococcus spp. and potential impact on molecular methicillin resistant Staphylococcus aureus screening tests. AB - We report that the rates of nasal cocolonization with methicillin-susceptible Staphylococcus aureus and methicillin-resistant coagulase-negative staphylococci can vary widely between patients admitted to different wards within a single hospital. Such cocolonization can greatly influence the performance of molecular methicillin-resistant S. aureus (MRSA) screening tests depending on the methods used and targets selected. PMID- 23658255 TI - Update of pneumococcal PCR serotyping assay for detection of a commonly occurring type 19F wzy variant in Brazil. PMID- 23658256 TI - Evaluation of Simplexa Flu A/B & RSV for direct detection of influenza viruses (A and B) and respiratory syncytial virus in patient clinical samples. AB - We evaluated the performance of the Simplexa Flu A/B & RSV kit on 170 prospective respiratory samples using a modified protocol, supplied by the manufacturer, that eliminates the RNA extraction step. Overall, compared against our laboratory developed assay, the assay's sensitivity, specificity, and positive and negative predictive values were 95.1%, 99.6%, 98.7%, and 98.6%, respectively. PMID- 23658257 TI - Rapid molecular detection of macrolide resistance in the Mycobacterium avium complex: are we there yet? AB - Macrolides are an important tool in the treatment of Mycobacterium avium complex infections. Here, we evaluate the use of 23S rRNA gene sequencing for the rapid detection of macrolide resistance. Routine sequencing of the 23S rRNA gene is highly specific for macrolide resistance but lacks in sensitivity. PMID- 23658258 TI - Use of Luminex MagPlex magnetic microspheres for high-throughput spoligotyping of Mycobacterium tuberculosis isolates in Port-au-Prince, Haiti. AB - Genotyping of Mycobacterium tuberculosis strains became indispensable for understanding tuberculosis transmission dynamics and designing measures to combat the disease. Unfortunately, typing involves sophisticated laboratory analysis, is expensive, and requires a high level of technical expertise, which limited its use in the resource-poor countries where the majority of tuberculosis cases occur. Spoligotyping is a PCR-based M. tuberculosis complex genotyping method with advantages of technical simplicity, numerical output, and high reproducibility. It is based on the presence or absence of 43 distinct "spacers" separating insertion elements in the direct repeat region of the M. tuberculosis genome. The spoligotyping assay involves reverse hybridization of PCR products to the capture spacers attached to nitrocellulose membranes or to microspheres. Here we report modification of the classic 43-spacer method using the new generation of Luminex multiplexing technology with magnetic microspheres. The method was successfully established and validated on strains with known spoligotypes in our laboratory in Haiti. The distribution of spoligotypes determined in a collection of 758 recent M. tuberculosis isolates was in accordance with previous data for Haitian isolates in the SITWITWEB international database, which were obtained with the traditional membrane-based method. In the present form, spoligotyping may be suitable as a high-throughput, first-line tool for genotyping of Mycobacterium tuberculosis in countries with limited resources. PMID- 23658259 TI - Identification of blaOXA-51-like, blaOXA-58, blaDIM-1, and blaVIM carbapenemase genes in hospital Enterobacteriaceae isolates from Sierra Leone. AB - We describe the results of a molecular epidemiological survey of 15 carbapenemase encoding genes from a recent collection of clinical isolates from Mercy Hospital in Bo, Sierra Leone. The most salient findings revealed that (i) 60% of the isolates harbored multiple carbapenemase genes; (ii) the blaDIM-1 gene, which has previously only been reported in The Netherlands, is also circulating in this environment; and (iii) blaOXA-51-like and blaOXA-58 genes, which were thought to reside exclusively in Acinetobacter species, can also be found in members of the Enterobacteriaceae. PMID- 23658260 TI - Clustering of tuberculosis cases based on variable-number tandem-repeat typing in relation to the population structure of Mycobacterium tuberculosis in the Netherlands. AB - The population structure of 3,776 Mycobacterium tuberculosis isolates was determined using variable-number tandem-repeat (VNTR) typing. The degree of clonality was so high that a more relaxed definition of clustering cannot be applied. Among recent immigrants with non-Euro-American isolates, transmission is overestimated if based on identical VNTR patterns. PMID- 23658261 TI - Multicenter evaluation of the Vitek MS matrix-assisted laser desorption ionization-time of flight mass spectrometry system for identification of Gram positive aerobic bacteria. AB - Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) is gaining momentum as a tool for bacterial identification in the clinical microbiology laboratory. Compared with conventional methods, this technology can more readily and conveniently identify a wide range of organisms. Here, we report the findings from a multicenter study to evaluate the Vitek MS v2.0 system (bioMerieux, Inc.) for the identification of aerobic Gram-positive bacteria. A total of 1,146 unique isolates, representing 13 genera and 42 species, were analyzed, and results were compared to those obtained by nucleic acid sequence-based identification as the reference method. For 1,063 of 1,146 isolates (92.8%), the Vitek MS provided a single identification that was accurate to the species level. For an additional 31 isolates (2.7%), multiple possible identifications were provided, all correct at the genus level. Mixed-genus or single-choice incorrect identifications were provided for 18 isolates (1.6%). Although no identification was obtained for 33 isolates (2.9%), there was no specific bacterial species for which the Vitek MS consistently failed to provide identification. In a subset of 463 isolates representing commonly encountered important pathogens, 95% were accurately identified to the species level and there were no misidentifications. Also, in all but one instance, the Vitek MS correctly differentiated Streptococcus pneumoniae from other viridans group streptococci. The findings demonstrate that the Vitek MS system is highly accurate for the identification of Gram-positive aerobic bacteria in the clinical laboratory setting. PMID- 23658262 TI - Clinical bovine piroplasmosis caused by Babesia occultans in Italy. AB - A clinical outbreak of bovine piroplasmosis was reported in Italy. The etiological agent was characterized as Babesia occultans, a parasite regarded as apathogenic and never detected before in continental Europe. This report paves the way for further studies to assess the occurrence of this tick-transmitted protozoan in other European regions. PMID- 23658263 TI - Helicobacter cinaedi and Helicobacter fennelliae transmission in a hospital from 2008 to 2012. AB - Forty-six Helicobacter cinaedi isolates from the same hospital were analyzed by multilocus sequence typing. Most H. cinaedi isolates exhibited clonal complex 9 and were mainly isolated from immunocompromised patients in the same ward. Three Helicobacter fennelliae isolates were obtained from the same ward and exhibited the same pulsed-field gel electrophoresis patterns. All isolates were resistant to clarithromycin and ciprofloxacin. H. cinaedi and H. fennelliae must be carefully monitored to prevent nosocomial infection. PMID- 23658264 TI - Targeting the treponemal microbiome of digital dermatitis infections by high resolution phylogenetic analyses and comparison with fluorescent in situ hybridization. AB - Modern pyrosequencing technology allows for a more comprehensive approach than traditional Sanger sequencing for elucidating the etiology of bovine digital dermatitis. We sought to describe the composition and diversity of treponemes in digital dermatitis lesions by using deep sequencing of the V3 and V4 hypervariable regions of the 16S rRNA gene coupled with species-level taxonomic identification. Treponema-specific 16S rRNA gene PCRs and pyrosequencing were performed on biopsy specimens originating from 10 different Catalan dairy herds (n = 36) with digital dermatitis, and this analysis yielded 75,297 sequences. We identified 20 different taxa, including a potentially novel phylotype that displayed 95% sequence identity to members of the Treponema denticola/Treponema pedis-like cluster. Species frequencies and abundances that were determined by pyrosequencing analysis were highly correlated with the results of fluorescent in situ hybridization using phylotype-specific oligonucleotide probes. In a limited number of animals from a single geographic region, we detected most of the Treponema phylotypes that were described in previous investigations of digital dermatitis. Additionally, we identified a number of phylotypes that mapped to oral treponemes of humans and dogs that had not been reported for digital dermatitis lesions. The results presented here support previous observations of a polytreponemal etiology of infections, with Treponema phagedenis-like, Treponema medium/Treponema vincentii-like, and T. denticola/T. pedis-like phylotypes being highly associated with disease. Using this new approach, it has become feasible to study large herds and their surrounding environments, which might provide a basis for a better understanding of the pathogenesis of this disease. PMID- 23658265 TI - Fluoroquinolone and macrolide resistance-associated mutations in Mycoplasma genitalium. AB - Mycoplasma genitalium is a significant sexually transmitted pathogen, causing up to 25% of cases of nongonococcal urethritis in men, and it is strongly associated with cervicitis and pelvic inflammatory disease in women. Currently, the usual first-line treatment is the macrolide antibiotic azithromycin, but an increasing incidence of treatment failure over the last 5 years suggests the emergence of antibiotic resistance. The mutations responsible for macrolide resistance have been found in the 23S rRNA gene in numerous M. genitalium populations. A second line antibiotic, the fluoroquinolone moxifloxacin, was thought to be a reliable alternative when azithromycin began to fail, but recent studies have identified mutations that may confer fluoroquinolone resistance in the genes parC and gyrA. The aim of this study was to determine the prevalence of antibiotic resistance in M. genitalium in Sydney, Australia, by detecting relevant mutations in the 23S rRNA gene, parC, and gyrA. M. genitalium-positive DNA extracts of specimens, collected from patients attending sexual health clinics in Sydney, were tested by PCR amplification and DNA sequence alignment. The 186 specimens tested included 143 initial patient specimens and 43 second, or subsequent, specimens from 24 patients. We identified known macrolide resistance-associated mutations in the 23S rRNA gene in 43% of the initial patient samples and mutations potentially associated with fluoroquinolone resistance in parC or gyrA sequences in 15% of the initial patient samples. These findings support anecdotal clinical reports of azithromycin and moxifloxacin treatment failures in Sydney. Our results indicate that further surveillance is needed, and testing and treatment protocols for M. genitalium infections may need to be reviewed. PMID- 23658266 TI - Highly sensitive detection of hepatitis B virus surface antigen by use of a semiautomated immune complex transfer chemiluminescence enzyme immunoassay. AB - The performance of hepatitis B surface antigen (HBsAg) screening assays is continuously improved to reduce the risk of transfusion-associated hepatitis B. In this study, a semiautomated immune complex transfer chemiluminescence enzyme immunoassay (ICT-CLEIA) for the detection of HBsAg, which is as sensitive as hepatitis B virus (HBV) DNA PCR, was developed; the ICT-CLEIA assay performance was compared with the performance of the Architect HBsAg QT assay and HBV DNA PCR. The specificities in the initial assay and after retesting were 99.50% (1,988/1,998 samples) and 99.95% (1,997/1,998 samples), respectively. The analytical detection limit was determined to be 0.2 mIU/ml using the 2nd International WHO HBsAg standard, and the cutoff value (0.5 mIU/ml) of the ICT CLEIA assay was 8.0 standard deviations (SD) above the mean of the HBsAg-negative specimens. The ICT-CLEIA assay could detect HBsAg even in the presence of anti HBs antibodies and demonstrated a 23.6-day-shorter window period using commercially available HBsAg seroconversion panels than the Architect HBsAg QT assay. Furthermore, the monitoring of the viral kinetics by the ICT-CLEIA assay and the HBV DNA PCR produced very similarly shaped curves during both the HBsAg seroconversion and reverse seroconversion periods. Therefore, the ICT-CLEIA assay may be useful not only for an earlier detection of HBV reactivation but also for the monitoring of hepatitis B patients. PMID- 23658267 TI - Multicenter study evaluating the Vitek MS system for identification of medically important yeasts. AB - The optimal management of fungal infections is correlated with timely organism identification. Matrix-assisted laser desorption ionization-time of flight (MALDI TOF) mass spectrometry (MS) is revolutionizing the identification of yeasts isolated from clinical specimens. We present a multicenter study assessing the performance of the Vitek MS system (bioMerieux) in identifying medically important yeasts. A collection of 852 isolates was tested, including 20 Candida species (626 isolates, including 58 C. albicans, 62 C. glabrata, and 53 C. krusei isolates), 35 Cryptococcus neoformans isolates, and 191 other clinically relevant yeast isolates; in total, 31 different species were evaluated. Isolates were directly applied to a target plate, followed by a formic acid overlay. Mass spectra were acquired using the Vitek MS system and were analyzed using the Vitek MS v2.0 database. The gold standard for identification was sequence analysis of the D2 region of the 26S rRNA gene. In total, 823 isolates (96.6%) were identified to the genus level and 819 isolates (96.1%) were identified to the species level. Twenty-four isolates (2.8%) were not identified, and five isolates (0.6%) were misidentified. Misidentified isolates included one isolate of C. albicans (n = 58) identified as Candida dubliniensis, one isolate of Candida parapsilosis (n = 73) identified as Candida pelliculosa, and three isolates of Geotrichum klebahnii (n = 6) identified as Geotrichum candidum. The identification of clinically relevant yeasts using MS is superior to the phenotypic identification systems currently employed in clinical microbiology laboratories. PMID- 23658268 TI - Rapid and reliable identification of Staphylococcus aureus capsular serotypes by means of artificial neural network-assisted Fourier transform infrared spectroscopy. AB - Staphylococcus aureus capsular polysaccharides (CP) are important virulence factors and represent putative targets for vaccine development. Therefore, the purpose of this study was to develop a high-throughput method to identify and discriminate the clinically important S. aureus capsular serotypes 5, 8, and NT (nontypeable). A comprehensive set of clinical isolates derived from different origins and control strains, representative for each serotype, were used to establish a CP typing system based on Fourier transform infrared (FTIR) spectroscopy and chemometric techniques. By combining FTIR spectroscopy with artificial neuronal network (ANN) analysis, a system was successfully established, allowing a rapid identification and discrimination of all three serotypes. The overall accuracy of the ANN-assisted FTIR spectroscopy CP typing system was 96.7% for the internal validation and 98.2% for the external validation. One isolate in the internal validation and one isolate in the external validation failed in the classification procedure, but none of the isolates was incorrectly classified. The present study demonstrates that ANN assisted FTIR spectroscopy allows a rapid and reliable discrimination of S. aureus capsular serotypes. It is suitable for diagnostic as well as large-scale epidemiologic surveillance of S. aureus capsule expression and provides useful information with respect to chronicity of infection. PMID- 23658269 TI - Asymptomatic carriage of sequence type 398, spa type t571 methicillin-susceptible Staphylococcus aureus in an urban jail: a newly emerging, transmissible pathogenic strain. AB - Sequence type 398 (ST398) Staphylococcus aureus, frequently carried by livestock, has caused severe human infections and often carries transmissible antibiotic resistance genes. Among methicillin-susceptible S. aureus isolates colonizing Dallas County Jail detainees, 13.2% were ST398, spa type t571, and were genetically similar to human colonization isolates from New York, Chicago, and the Dominican Republic. PMID- 23658270 TI - Use of colorimetric culture methods for detection of Mycobacterium tuberculosis complex isolates from sputum samples in resource-limited settings. AB - Despite recent advances, tuberculosis (TB) diagnosis remains imperfect in resource-limited settings due to its complexity and costs, poor sensitivity of available tests, or long times to reporting. We present a report on the use of colorimetric methods, based on the detection of mycobacterial growth using colorimetric indicators, for the detection of Mycobacterium tuberculosis in sputum specimens. We evaluated the nitrate reductase assay (NRA), a modified NRA using para-nitrobenzoic acid (PNB) (NRAp), and the resazurin tube assay using PNB (RETAp) to differentiate tuberculous and nontuberculous mycobacteria. The performances were assessed at days 18 and 28 using mycobacterium growth indicator tube (MGIT) and Lowenstein-Jensen (LJ) medium culture methods as the reference standards. We enrolled 690 adults with suspected pulmonary tuberculosis from a regional referral hospital in Uganda between March 2010 and June 2011. At day 18, the sensitivities and specificities were 84.6% and 90.0% for the NRA, 84.1% and 92.6% for the NRAp, and 71.2% and 99.3% for the RETAp, respectively. At day 28, the sensitivity of the RETAp increased to 82.6%. Among smear-negative patients with suspected TB, sensitivities at day 28 were 64.7% for the NRA, 61.3% for the NRAp, and 50% for the RETAp. Contamination rates were found to be 5.4% for the NRA and 6.7% for the RETAp, compared with 22.1% for LJ medium culture and 20.4% for MGIT culture. The median times to positivity were 10, 7, and 25 days for colorimetric methods, MGIT culture, and LJ medium culture,respectively. Whereas the low specificity of the NRA/NRAp precludes it from being used for TB diagnosis, the RETAp might provide an alternative to LJ medium culture to decrease the time to culture results in resource-poor settings. PMID- 23658271 TI - High genetic diversity of Newcastle disease virus in poultry in West and Central Africa: cocirculation of genotype XIV and newly defined genotypes XVII and XVIII. AB - Despite rampant Newcastle disease virus (NDV) outbreaks in Africa for decades, the information about the genetic characteristics of the virulent strains circulating in West and Central Africa is still scarce. In this study, 96 complete NDV fusion gene sequences were obtained from poultry sampled in Cameroon, Central African Republic, Cote d'Ivoire, and Nigeria between 2006 and 2011. Based on rational criteria recently proposed for the classification of NDV strains into classes, genotypes, and subgenotypes, we revisited the classification of virulent strains, in particular those from West and Central Africa, leading to their grouping into genotype XIV and newly defined genotypes XVII and XVIII, each with two subgenotypes. Phylogenetic analyses revealed that several (sub)genotypes are found in almost every country. In Cameroon, most strains were related to vaccine strains, but a single genotype XVII strain was also found. Only three highly similar genotype XVII strains were detected in Central African Republic. Subgenotypes XVIIa, XVIIIa, and XVIIIb cocirculated in Cote d'Ivoire, while subgenotypes XIVa, XIVb, XVIIa, XVIIb, and XVIIIb were found in Nigeria. While these genotypes are so far geographically restricted, local and international trade of domestic and exotic birds may lead to their spread beyond West and Central Africa. A high genetic diversity, mutations in important neutralizing epitopes paired with suboptimal vaccination, various levels of clinical responses of poultry and wild birds to virulent strains, strains with new cleavage sites, and other genetic modifications found in these genotypes tend to undermine and complicate NDV management in Africa. PMID- 23658272 TI - Predictive value of molecular drug resistance testing of Mycobacterium tuberculosis isolates in Valle del Cauca, Colombia. AB - Previous evaluations of the molecular GenoType tests have promoted their use to detect resistance to first- and second-line antituberculosis drugs in different geographical regions. However, there are known geographic variations in the mutations associated with drug resistance in Mycobacterium tuberculosis, and especially in South America, there is a paucity of information regarding the frequencies and types of mutations associated with resistance to first- and second-line antituberculosis drugs. We therefore evaluated the performance of the GenoType kits in this region by testing 228 M. tuberculosis isolates in Colombia, including 134 resistant and 94 pansusceptible strains. Overall, the sensitivity and specificity of the GenoType MTBDRplus test ranged from 92 to 96% and 97 to 100%, respectively; the agreement index was optimal (Cohen's kappa, >0.8). The sensitivity of the GenoType MTBDRsl test ranged from 84 to 100% and the specificity from 88 to 100%. The most common mutations were katG S315T1, rpoB S531L, embB M306V, gyrA D94G, and rrs A1401G. Our results reflect the utility of the GenoType tests in Colombia; however, as some discordance still exists between the conventional and molecular approaches in resistance testing, we adhere to the recommendation that the GenoType tests serve as early guides for therapy, followed by phenotypic drug susceptibility testing for all cases. PMID- 23658273 TI - Rapid molecular microbiologic diagnosis of prosthetic joint infection. AB - We previously showed that culture of samples obtained by prosthesis vortexing and sonication was more sensitive than tissue culture for prosthetic joint infection (PJI) diagnosis. Despite improved sensitivity, culture-negative cases remained; furthermore, culture has a long turnaround time. We designed a genus-/group specific rapid PCR assay panel targeting PJI bacteria and applied it to samples obtained by vortexing and sonicating explanted hip and knee prostheses, and we compared the results to those with sonicate fluid and periprosthetic tissue culture obtained at revision or resection arthroplasty. We studied 434 subjects with knee (n = 272) or hip (n = 162) prostheses; using a standardized definition, 144 had PJI. Sensitivities of tissue culture, of sonicate fluid culture, and of PCR were 70.1, 72.9, and 77.1%, respectively. Specificities were 97.9, 98.3, and 97.9%, respectively. Sonicate fluid PCR was more sensitive than tissue culture (P = 0.04). PCR of prosthesis sonication samples is more sensitive than tissue culture for the microbiologic diagnosis of prosthetic hip and knee infection and provides same-day PJI diagnosis with definition of microbiology. The high assay specificity suggests that typical PJI bacteria may not cause aseptic implant failure. PMID- 23658282 TI - Q&A: Powel Brown on cancer prevention research. PMID- 23658274 TI - Virus detection and semiquantitation in explanted heart tissues of idiopathic dilated cardiomyopathy adult patients by use of PCR coupled with mass spectrometry analysis. AB - Viral detection in heart tissues has become a central issue for the diagnosis and exploration of the pathogenesis of idiopathic dilated cardiomyopathy (IDCM). In the present study, common cardiotropic viruses in 67 explanted heart samples of 31 IDCM adult patients were detected and semiquantified by using for the first time a new technology based on PCR assay coupled to electrospray ionization-time of flight mass spectrometry analysis (PCR-MS), with comparison to reference quantitative real-time PCR (RT-qPCR) assay. PCR-MS identified single or mixed enterovirus (EV) and parvovirus B19 (PVB19) infections in 27 (40.2%) of 67 samples, corresponding to 15 (48.3%) of the 31 patients, whereas RT-qPCR identified viral infections in 26 (38.8%) samples, corresponding to 16 (51.6%) of the patients. The PCR-MS results correlated well with EV and PVB19 detection by RT-qPCR (kappa = 0.85 [95% confidence interval {CI}, 0.72 to 1.00] and kappa = 0.82 [95% CI, 0.66 to 0.99], respectively). The levels of EV RNA (median, 550 [range, 178 to 3,200] copies/MUg of total extracted nucleic acids) and of PVB19 DNA (median, 486 [range, 80 to 1,157] copies/MUg of total extracted nucleic acids) were measured using PCR-MS and correlated with those obtained by RT-qPCR (r(2) = 0.57, P = 0.002 and r(2) = 0.64, P < 0.001 for EV and PVB19, respectively). No viruses other than EV and PVB19 strains were detected using the new PCR-MS technology, which is capable of simultaneously identifying 84 known human viruses in one assay. In conclusion, we identified single or mixed EV and PVB19 cardiac infections as potential causes of IDCM. The PCR-MS analysis appeared to be a valuable tool to rapidly detect and semiquantify common viruses in cardiac tissues and may be of major interest to better understand the role of viruses in unexplained cardiomyopathies. PMID- 23658283 TI - Two drugs deemed breakthrough therapies. PMID- 23658294 TI - G34, another connection between MYCN and a pediatric tumor. AB - Recurrent mutations in H3F3A at K27 and G34 are frequent in pediatric glioblastoma, but it is unclear how these mutations promote tumorigenesis. In this issue of Cancer Discovery, Bjerke and colleagues identify mutations at G34 in H3F3A that result in elevated expression of MYCN as a potential mechanism in gliomagenesis. PMID- 23658295 TI - Deja Vu: EGF receptors drive resistance to BRAF inhibitors. AB - The promise of personalized medicine is upon us, and in some cancers, targeted therapies are rapidly becoming the mainstay of treatment for selected patients based on their molecular profile. The protein kinase BRAF is a driver oncogene in both thyroid cancer and melanoma, but while drugs that target BRAF and its downstream signaling pathway are effective in melanoma, they are ineffective in thyroid cancer. In this issue of Cancer Discovery, Montero-Conde and colleagues investigate why thyroid cancer is resistant to BRAF inhibitors despite the presence of BRAF mutation. PMID- 23658296 TI - Two is better than one: combining IGF1R and MEK blockade as a promising novel treatment strategy against KRAS-mutant lung cancer. AB - A small-molecule inhibitor screen on a panel of human lung cancer cell lines has uncovered an unexpected sensitivity of cells expressing oncogenic KRAS toward insulin-like growth factor 1 receptor (IGF1R) inhibition. Combining IGF1R and MAP ERK kinase blockade led to significant effects on viability in human non-small cell lung cancer (NSCLC) cell lines and in 2 mouse models of oncogenic KRAS driven lung cancer. The mechanistic basis for this effect seems to be an increased baseline activation of IGF1R-mediated activation of AKT in cells that express oncogenic KRAS. The studies thus point to a novel approach for treatment of KRAS-driven NSCLC, a particularly difficult subset of patients to treat with existing approaches. PMID- 23658297 TI - Discovering what makes STAT signaling TYK in T-ALL. AB - SUMMARY: RNA interference screening establishes TYK2 dependence in T-cell acute lymphoblastic leukemia (T-ALL), leading to identification of TYK2-activating mutations and increased IL-10 receptor signaling in T-ALL cell lines. Cancer Discov; 3(5); 494-6. (c)2013 AACR. PMID- 23658298 TI - A tale of metabolites: the cross-talk between chromatin and energy metabolism. AB - Mitochondrial metabolism influences histone and DNA modifications by retrograde signaling and activation of transcriptional programs. Considering the high number of putative sites for acetylation and methylation in chromatin, we propose in this perspective article that epigenetic modifications might impinge on cellular metabolism by affecting the pool of acetyl-CoA and S-adenosylmethionine. PMID- 23658320 TI - Fractional anisotropy of the optic radiations is associated with visual acuity loss in optic pathway gliomas of neurofibromatosis type 1. AB - BACKGROUND: No more than half of patients with neurofibromatosis type 1 (NF1) associated optic pathway gliomas (OPGs) develop vision loss. Prospectively identifying those who will require therapy remains challenging, because no reliable factors have yet been identified that predict future vision loss. To determine whether brain tissue microstructure is associated with visual acuity loss, we examined diffusion tensor imaging (DTI) and ophthalmologic evaluations in children with NF1-associated OPG. METHODS: We retrospectively reviewed ophthalmology records and concurrent DTI measurements of the optic nerves, tracts, and radiations from 50 children with NF1-associated OPGs. Multivariate linear regression measured the association between fiber trajectory quantity and white matter integrity on visual acuity measured by the logarithm of the minimal angle of resolution (logMAR). RESULTS: In multivariate analysis, fractional anisotropy (FA) of the optic radiations was associated with visual acuity loss (adjusted coefficient = -6.081 logMAR/FA; P = .006) after adjusting for age, extent of tumor, DTI acquisition type, prior chemotherapy, and fundus examination findings. The association remained after eliminating tumors involving the optic radiations. In an evaluation of 15 subjects with paired ophthalmologic examination and DTI a year apart, initial FA of the optic radiation was associated with a trend toward change in visual acuity a year later (coefficient = -2.652 logMAR/FA; P = .069). CONCLUSIONS: A decrease in FA of the optic radiations is associated with abnormal visual acuity in NF1-associated OPGs and may be predictive of visual acuity loss during the following year. PMID- 23658321 TI - Celecoxib enhances radiosensitivity of hypoxic glioblastoma cells through endoplasmic reticulum stress. AB - BACKGROUND: Refractoriness of glioblastoma multiforme (GBM) largely depends on its radioresistance. We investigated the radiosensitizing effects of celecoxib on GBM cell lines under both normoxic and hypoxic conditions. METHODS: Two human GBM cell lines, U87MG and U251MG, and a mouse GBM cell line, GL261, were treated with celecoxib or gamma-irradiation either alone or in combination under normoxic and hypoxic conditions. Radiosensitizing effects were analyzed by clonogenic survival assays and cell growth assays and by assessing apoptosis and autophagy. Expression of apoptosis-, autophagy-, and endoplasmic reticulum (ER) stress related genes was analyzed by immunoblotting. RESULTS: Celecoxib significantly enhanced the radiosensitivity of GBM cells under both normoxic and hypoxic conditions. In addition, combined treatment with celecoxib and gamma-irradiation induced marked autophagy, particularly in hypoxic cells. The mechanism underlying the radiosensitizing effect of celecoxib was determined to be ER stress loading on GBM cells. CONCLUSION: Celecoxib enhances the radiosensitivity of GBM cells by a mechanism that is different from cyclooxygenase-2 inhibition. Our results indicate that celecoxib may be a promising radiosensitizing drug for clinical use in patients with GBM. PMID- 23658322 TI - Intravenous injection of oncolytic picornavirus SVV-001 prolongs animal survival in a panel of primary tumor-based orthotopic xenograft mouse models of pediatric glioma. AB - BACKGROUND: Seneca Valley virus (SVV-001) is a nonpathogenic oncolytic virus that can be systemically administered and can pass through the blood-brain barrier. We examined its therapeutic efficacy and the mechanism of tumor cell infection in pediatric malignant gliomas. METHODS: In vitro antitumor activities were examined in primary cultures, preformed neurospheres, and self-renewing glioma cells derived from 6 patient tumor orthotopic xenograft mouse models (1 anaplastic astrocytoma and 5 GBM). In vivo therapeutic efficacy was examined by systemic treatment of preformed xenografts in 3 permissive and 2 resistant models. The functional role of sialic acid in mediating SVV-001 infection was investigated using neuraminidase and lectins that cleave or competitively bind to linkage specific sialic acids. RESULTS: SVV-001 at a multiplicity of infection of 0.5 to 25 replicated in and effectively killed primary cultures, preformed neurospheres, and self-renewing stemlike single glioma cells derived from 4 of the 6 glioma models in vitro. A single i.v. injection of SVV-001 (5 * 10(12) viral particles/kg) led to the infection of orthotopic xenografts without harming normal mouse brain cells, resulting in significantly prolonged survival in all 3 permissive and 1 resistant mouse models (P < .05). Treatment with neuraminidase and competitive binding using lectins specific for alpha2,3-linked and/or alpha2,6-linked sialic acid significantly suppressed SVV-001 infectivity (P < .01). CONCLUSION: SVV-001 possesses strong antitumor activity against pediatric malignant gliomas and utilizes alpha2,3-linked and alpha2,6-linked sialic acids as mediators of tumor cell infection. Our findings support the consideration of SVV-001 for clinical trials in children with malignant glioma. PMID- 23658323 TI - The expression status of CD133 is associated with the pattern and timing of primary glioblastoma recurrence. AB - BACKGROUND: Glioblastoma carries a poor prognosis primarily because of its high rate of recurrence. The ability to predict the recurrence pattern and timing would be highly useful for determining effective treatment strategies. We examined the correlation between prognostic factors and the pattern of recurrence in patients with primary glioblastoma. In particular, we examined whether there was a correlation between the expression of CD133 and glioblastoma recurrence. METHODS: We retrospectively analyzed 112 patients with primary glioblastoma. The timing and pattern (local or distant) of the initial recurrence were obtained from medical records. To identify factors predictive of recurrence, we examined CD133 expression by Western blots and immunohistochemistry, clinical (age, sex, KPS, Ki67 labeling index, surgery, ventricular entry) and genetic (IDH1, 7p, 9p, 10q, MGMT) factors. RESULTS: Of the 112 patients, 99 suffered recurrence. The first recurrence was local in 77 patients and distant in 22 patients. Among the factors to predict the pattern of recurrence, CD133 expression was significantly higher in distant than in local recurrence. Of the factors to predict the timing of recurrence, high CD133 expression was associated with shorter time to distant recurrence in both univariate and multivariate analyses (P = .0011 and P = .038, respectively). CONCLUSIONS: The expression of CD133 may be a predictor of the pattern and timing of recurrence of primary glioblastoma. PMID- 23658324 TI - Genetic variability for temperament indicators of Nellore cattle. AB - The aim of this study was to estimate genetic parameters of 4 temperament indicator traits for Nellore cattle and evaluate the possibility of using such traits as selection criteria in breeding programs. Temperament was assessed for 23,420 male and female animals at 550 d of age, which were born between 2002 and 2009. A temperament score (TS) was used, which is based on a scale from 1 to 5 and considers the reaction of animals after exiting the crush. Moreover, 9,150 individuals born in 2008 and 2009 were measured for these characteristics: movement score (MOV), where animals were scored from 1 to 5 according to their movement inside the crush; crush score (CS), which assigns scores from 1 to 4 for the general reactivity inside the crush; and flight speed (FS), which is a recording of the speed (m/s) at which animals exit the crush after being weighed. The weaning weight (WW) was included in the multitrait analysis to reduce the effect of the selection performed at weaning. Bayesian inference using Gibbs sampling was applied to estimate (co)variance components and breeding values of the animals. The model included random direct additive genetic and residual effects, fixed effects of contemporary groups, age of the dam (classes), and age of the animal as covariate (linear and quadratic effects for WW and TS, and only linear effects for the other traits). A linear model was applied to WW and FS, whereas a threshold model was used for TS, CS, and MOV. Heritability estimates for FS, TS, CS, and MOV were 0.35, 0.15, 0.19, and 0.18, respectively. The genetic correlation estimates of FS with TS (0.85), CS (0.85), and MOV (0.76) were high, although the phenotypic correlations were low (between 0.18 and 0.25). For CS and MOV, the genetic and phenotypic correlation estimates were high (0.99 and 0.71, respectively). We concluded that all of the temperament indicator traits addressed in this study presented enough genetic variability to respond to selection; however, the use of FS would result in a faster genetic gain. With regard to the practical applicability in breeding programs, the use of FS is also favorable because it produces data on a continuous scale, allows for recording of the data electronically, and requires low investment. PMID- 23658325 TI - Isoleucine requirement of pregnant sows. AB - The objective of this study was to determine the Ile requirement in early (d 39 to 61) and late (d 89 to 109) pregnancy using the indicator AA oxidation method. The same 7 Large White * Landrace sows in their fourth parity were used in early and late pregnancy. Each sow received 6 diets based on corn, corn starch, and sugar in both early and late pregnancy at constant feed allowances (2.5 kg/d). Diets provided Ile at 20, 40, 60, 80, 100, and 120% of the Ile requirement (6.2 g/d based on the 1998 NRC) in early and 60, 80, 100, 140, 160, and 180% in late pregnancy. After determination of (13)C background in expired CO2 and plasma free Phe for 1.5 h when confined in respiration chambers, sows were fed the tracer, L[1-(13)C]Phe, a rate of 2.0 mg/(kg BW.h) over 4 h divided into eight 30-min meals. Expired CO2 and plasma free Phe were analyzed for (13)C enrichment above background. Requirements were determined as the breakpoint in 2-phase nonlinear models. Sow BW was 246.5 kg in early and 271.6 kg in late pregnancy. Daily gain of the 6 sows was similar in early (344 g/d) and late pregnancy (543 g/d). During pregnancy, sow maternal gain was 19.1 +/- 4.4 kg and litters of 17.7 +/- 0.8 piglets weighed 22.6 +/- 0.9 kg at birth. The Ile requirement was 3.6 +/- 1.2 g/d (P = 0.001) in early pregnancy with a Phe retention (-0.59 g/d) and energy retention (-0.31 MJ/d) that were not different from 0. This indicates that the fourth parity sows had requirements close to maintenance in early pregnancy. The Ile requirement in late pregnancy was 9.7 +/- 1.9 g/d (P = 0.001) when sows retained 3.30 g/d of Phe and -1.45 MJ/d of energy. The greater Ile requirement in late pregnancy was probably caused by the increased conceptus growth after d 70 of pregnancy. Phenylalanine flux, oxidation, and nonoxidative disposal increased (P < 0.1) from early to late pregnancy, but body protein breakdown did not. Phenylalanine oxidation, nonoxidative disposal, and retention increased (P < 0.01) with increasing Ile intake in early pregnancy but were not affected by Ile intake in late pregnancy. Body protein breakdown did not respond to Ile intake in early or late pregnancy. Although energy retention was similar in early and late pregnancy, the respiratory quotient decreased (P = 0.047) from early (1.05) to late pregnancy (0.98), indicating lipid mobilization in late pregnancy when Ile was at or above the requirement. The results of this study show that the Ile requirement of sows increases from early to late pregnancy. PMID- 23658326 TI - Use of residual feed intake in Holsteins during early lactation shows potential to improve feed efficiency through genetic selection. AB - Improved feed efficiency is a primary goal in dairy production to reduce feed costs and negative impacts of production on the environment. Estimates for efficiency of feed conversion to milk production based on residual feed intake (RFI) in dairy cattle are limited, primarily due to a lack of individual feed intake measurements for lactating cows. Feed intake was measured in Holstein cows during the first 90 d of lactation to estimate the heritability and repeatability of RFI, minimum test duration for evaluating RFI in early lactation, and its association with other production traits. Data were obtained from 453 lactations (214 heifers and 239 multiparous cows) from 292 individual cows from September 2007 to December 2011. Cows were housed in a free-stall barn and monitored for individual daily feed consumption using the GrowSafe 4000 System (GrowSafe Systems, Ltd., Airdrie, AB, Canada). Animals were fed a total mixed ration 3 times daily, milked twice daily, and weighed every 10 to 14 d. Milk yield was measured at each milking. Feed DM percentage was measured daily, and nutrient composition was analyzed from a weekly composite. Milk composition was analyzed weekly, alternating between morning and evening milking periods. Estimates of RFI were determined as the difference between actual energy intake and predicted intake based on a linear model with fixed effects of parity (1, 2, >= 3) and regressions on metabolic BW, ADG, and energy-corrected milk yield. Heritability was estimated to be moderate (0.36 +/- 0.06), and repeatability was estimated at 0.56 across lactations. A test period through 53 d in milk (DIM) explained 81% of the variation provided by a test through 90 DIM. Multiple regression analysis indicated that high efficiency was associated with less time feeding per day and slower feeding rate, which may contribute to differences in RFI among cows. The heritability and repeatability of RFI suggest an opportunity to improve feed efficiency through genetic selection, which could reduce feed costs, manure output, and greenhouse gas emissions associated with dairy production. PMID- 23658327 TI - Technical note: An R package for fitting Bayesian regularized neural networks with applications in animal breeding. AB - In recent years, several statistical models have been developed for predicting genetic values for complex traits using information on dense molecular markers, pedigrees, or both. These models include, among others, the Bayesian regularized neural networks (BRNN) that have been widely used in prediction problems in other fields of application and, more recently, for genome-enabled prediction. The R package described here (brnn) implements BRNN models and extends these to include both additive and dominance effects. The implementation takes advantage of multicore architectures via a parallel computing approach using openMP (Open Multiprocessing) for the computations. This note briefly describes the classes of models that can be fitted using the brnn package, and it also illustrates its use through several real examples. PMID- 23658328 TI - Echium oil and linseed oil as alternatives for fish oil in the maternal diet: Blood fatty acid profiles and oxidative status of sows and piglets. AB - Echium oil (source of stearidonic acid) and linseed oil (source of alpha linolenic acid) were evaluated as alternatives for fish oil in the diet of sows to increase the docosahexaenoic acid (DHA) status of the offspring. The hypothesis was that echium oil would be more efficient than linseed oil to increase the DHA concentration, as it bypasses the enzyme Delta6-desaturase. In addition, it was determined whether adding PUFA to the diet affected the plasma oxidative status. Sows were fed either a palm oil diet or a diet containing 1% linseed oil, echium oil, or fish oil from d 73 of gestation and during lactation (n = 16 per dietary treatment). Total oil concentrations in the diets were similar among dietary treatments. Blood samples were taken for fatty acid analysis and oxidative status of sows on d 73 and 93 of gestation and at parturition and the lightest and heaviest piglet per litter at birth and weaning. Colostrum was also sampled. No effect of diet was observed on total number of piglets born (13.7 +/- 0.4), number of weaned piglets (10.8 +/- 0.4), and gestation length (114.8 +/- 0.2 d). Piglets from sows fed fish oil had lighter birth weights (1.41 +/- 0.03 kg) than piglets from the linseed oil diet (1.54 +/- 0.03 kg; P = 0.006), with no difference between the palm oil (1.45 +/- 0.03 kg) and echium oil diet (1.49 +/- 0.03 kg). Daily BW gain until weaning was less for piglets from sows fed the fish oil diet (214 +/- 5 g) compared with piglets from sows fed the echium oil (240 +/- 5 g; P < 0.001) or linseed oil diet (234 +/- 5 g; P = 0.02). Compared with the palm oil diet, echium and linseed oil in the maternal diet increased the DHA concentration in the colostrum and the sow and piglet plasma to the same extent (1.1 to 1.4-fold; P < 0.001). On the fish oil diet, 20.7-fold, 10-fold, and 2.4-fold increases in DHA in colostrum, sow, and piglet plasma, respectively, were observed (P < 0.001). At 1% in the maternal diet, echium oil had, thus, no benefit over linseed oil and resulted in a twofold less DHA concentration in the plasma of piglets compared with fish oil. Including n-3 PUFA in the maternal diet did not affect oxidative status of the mother or the offspring. PMID- 23658329 TI - 2011 and 2012 Early Careers Achievement Awards: recognizing achievement of young scholars working to foster the discovery, sharing, and application of knowledge concerning the responsible use of animals to enhance human life and well-being. PMID- 23658330 TI - Accuracy of prediction of genomic breeding values for residual feed intake and carcass and meat quality traits in Bos taurus, Bos indicus, and composite beef cattle. AB - The aim of this study was to assess the accuracy of genomic predictions for 19 traits including feed efficiency, growth, and carcass and meat quality traits in beef cattle. The 10,181 cattle in our study had real or imputed genotypes for 729,068 SNP although not all cattle were measured for all traits. Animals included Bos taurus, Brahman, composite, and crossbred animals. Genomic EBV (GEBV) were calculated using 2 methods of genomic prediction [BayesR and genomic BLUP (GBLUP)] either using a common training dataset for all breeds or using a training dataset comprising only animals of the same breed. Accuracies of GEBV were assessed using 5-fold cross-validation. The accuracy of genomic prediction varied by trait and by method. Traits with a large number of recorded and genotyped animals and with high heritability gave the greatest accuracy of GEBV. Using GBLUP, the average accuracy was 0.27 across traits and breeds, but the accuracies between breeds and between traits varied widely. When the training population was restricted to animals from the same breed as the validation population, GBLUP accuracies declined by an average of 0.04. The greatest decline in accuracy was found for the 4 composite breeds. The BayesR accuracies were greater by an average of 0.03 than GBLUP accuracies, particularly for traits with known genes of moderate to large effect mutations segregating. The accuracies of 0.43 to 0.48 for IGF-I traits were among the greatest in the study. Although accuracies are low compared with those observed in dairy cattle, genomic selection would still be beneficial for traits that are hard to improve by conventional selection, such as tenderness and residual feed intake. BayesR identified many of the same quantitative trait loci as a genomewide association study but appeared to map them more precisely. All traits appear to be highly polygenic with thousands of SNP independently associated with each trait. PMID- 23658332 TI - Growth performance and carcass quality of immunocastrated and surgically castrated pigs from crossbreds from Duroc and Pietrain sires. AB - In total, 240 pigs were used to compare growth performance and carcass quality traits of immunocastrated males (ICM), surgically castrated males (SCM), and intact females (IF) of crossbreds from Large White * Landrace females and Duroc (DU) or Pietrain (PI) sires destined to the dry-cured industry. Between the 2 Improvac injections (87 and 137 d of age), ICM and IF had less ADG than SCM (P < 0.01). Also, ICM ate less feed than IF and both less than SCM (2.33, 2.55, and 2.77 kg/d; respectively; P < 0.001) and consequently, ICM had better G:F than SCM and IF (P < 0.001). From second Improvac injection to slaughter (137 to 164 d of age), ICM were more efficient than IF and both more efficient than SCM (0.346, 0.323, and 0.300 g/g; respectively; P < 0.001). The differences in growth performance among genders observed in this period were more pronounced for the PI than for the DU crossbreds (P < 0.05 for the interaction). For the entire experimental period (87 to 164 d of age), gender did not affect ADG for DU crossbreds but for PI crossbreds ICM and SCM had greater ADG than IF (P < 0.05 for the interaction). The ICM pigs had better feed efficiency (0.406, 0.364, and 0.380; g/g; P < 0.001) and lower carcass yield (76.6, 78.1, and 78.8%; P < 0.001) than SCM or IF. Carcasses from IF were leaner than carcasses from SCM with carcasses from ICM being intermediate (P < 0.01). Ham and loin (P < 0.001) yields were greater for IF than for ICM or SCM. Intramuscular fat content was lower for IF than for SCM with that of ICM being intermediate (3.5 vs. 3.9 and 3.7%; P < 0.05). Cumulatively, crossbreds from DU sires had greater ADG (1.167 vs. 0.986 kg/d; P < 0.001) and ADFI (3.07 vs. 2.56 kg/d; P < 0.001) and more intramuscular fat (P < 0.001) but less ham and loin yields (P < 0.01) than crossbreds from PI sires. It is concluded that growth performance was better but carcass yield less for ICM than for SCM and IF. Intramuscular fat content in LM was less for IF than for SCM with ICM intermediate. Crossbreds from Duroc sires grew faster and had more intramuscular fat but less ham yield than crossbreds from Pietrain sires. Therefore, ICM should be preferred to SCM and Duroc crossbreds should be preferred to Pietrain crossbreds to produce carcasses destined to the production of primal cuts for the dry-cured industry. PMID- 23658333 TI - Predicting carcass and body fat composition using biometric measurements of grazing beef cattle. AB - This study was conducted to develop equations to predict carcass and body fat compositions using biometric measures (BM) and body postmortem measurements and to determine the relationships between BM and carcass fat and empty body fat compositions of 44 crossbred bulls under tropical grazing conditions. The bulls were serially slaughtered in 4 groups at approximately 0 d (n = 4), 84 d (n = 4), 168 d (n = 8), 235 d (n = 8), and 310 d (n = 20) of growth. The day before each slaughter, bulls were weighed, and BM were taken, including hook bone width, pin bone width, abdomen width, body length, rump height, height at withers, pelvic girdle length, rib depth, girth circumference, rump depth, body diagonal length, and thorax width. Others measurements included were total body surface (TBS), body volume (BV), subcutaneous fat (SF), internal fat (InF), intermuscular fat, carcass physical fat (CFp), empty body physical fat (EBFp), carcass chemical fat (CFch), empty body chemical fat (EBFch), fat thickness in the 12th rib (FT), and 9th- to 11th-rib section fat (HHF). The stepwise procedure was used to select the variables included in the model. The r(2) and the root-mean-square error (RMSE) were used to account for precision and variability. Our results indicated that lower rates of fat deposition can be attributed to young cattle and low concentration of dietary energy under grazing conditions. The BM improved estimates of TBS (r(2) = 0.999) and BV (r(2) = 0.997). The adequacy evaluation of the models developed to predict TBS and BV using theoretical equations indicated precision, but lower and intermediate accuracy (bias correction = 0.138 and 0.79), respectively, were observed. The data indicated that BM in association with shrunk BW (SBW) were precise in accounting for variability of SF (r(2) = 0.967 and RMSE = 0.94 kg), InF (r(2) = 0.984 and RMSE = 1.26 kg), CFp (r(2) = 0.981 and RMSE = 2.98 kg), EBFp (r(2) = 0.985 and RMSE = 3.99 kg), CFch (r(2) = 0.940 and RMSE = 2.34 kg), and EBFch (r(2) = 0.934 and RMSE = 3.91 kg). Results also suggested that approximately 70% of body fat was deposited as CFp and 30% as InF. Furthermore, the development of an equation using HHF as a predictor, in combination with SBW, was a better predictor of CFp and EBFp than using HHF by itself. We concluded that the prediction of physical and chemical CF and EBF composition of grazing cattle can be improved using BM as a predictor. PMID- 23658334 TI - Body chemical composition of Nellore bulls with different residual feed intakes. AB - Empty body and carcass chemical compositions, expressed as content of water, ether extract, protein, minerals, and energy, were evaluated in Nellore bulls with different residual feed intakes (RFI). Forty-nine not castrated males, with 343 kg of average initial BW and 398 kg of average slaughter BW, were studied. Animals were divided in two subgroups: reference group (RG) and ad libitum feeding group. At the end of the adaptation period, animals of subgroup RG were slaughtered and the other animals were finished in individual pens for approximately 100 d, until they reached a subcutaneous fat thickness over the LM of 4 mm, and were slaughtered at an average age of 540 d. Body composition was obtained after grinding, homogenizing, sampling, analyzing, and combining blood, hide, head + feet, viscera, and carcass. Tissue deposition rates and chemical composition of gain were also measured based on gains estimated by comparative slaughter technique. No significant differences in slaughter BW (P = 0.8639), empty BW (P = 0.7288), HCW (P = 0.6563), or empty body and carcass rates of gain were observed between RFI groups, demonstrating that the low (-0.331 kg DM/d) and high (+0.325 kg DM/d) RFI animals presented similar body sizes and growth rates. No significant differences in empty body or carcass content of water, ether extract, protein, minerals, and energy were observed between the low and high RFI animals. And also there were no significant differences in empty BW or carcass gain, demonstrating that low and high RFI animals had a similar growth potential. More efficient animals (low RFI) consumed less feed than less efficient animals (high RFI) but presented similar body sizes, growth rates, and empty body and carcass chemical composition. PMID- 23658335 TI - Impact of source of sulfur on ruminal hydrogen sulfide and logic for the ruminal available sulfur for reduction concept. AB - Effects of organic and inorganic sources of S on intake, intake pattern, ruminal pH, VFA profile, and ruminal H2S gas concentration ([H2S]) were evaluated, which lead to development of a procedure to measure ruminal S availability for reduction [ruminal available S (RAS)] as well as compare with an estimated number [adjusted ruminal protein S (ARPS)]. Ruminally cannulated crossbred beef steers (n = 5; BW = 548 +/- 46 kg) were assigned to 1 of 5 diets in a 5*5 Latin square design and fed ad libitum in five 21-d periods. Steers were fed a dry-rolled corn diet (CON), inorganic S source (ammonium sulfate; INORG), organic S source (corn gluten meal) fed at 9.8 (ORG-L) or 23% of diet DM (ORG-H), or wet distillers grains with solubles (WDGS) fed at 50% of diet DM. For the laboratory procedure, individual ingredients were incubated with ruminal fluid from heifers fed 60% corn-based diets (n = 2) and McDougall's buffer. Bottles were cooled in ice, centrifuged, and decanted, and the precipitate was analyzed for S. Steers fed INORG tended (P = 0.12) to consume 12% less DM. Total S intake was greater (P < 0.01) for steers fed WDGS (60 g/d) followed by ORG-H, and the lowest S intake was observed for CON (22 g/d). Intakes of ARPS and RAS were greater (P < 0.01) for steers fed WDGS followed by INORG, ORG-H, ORG-L, and CON diets. Steers fed WDGS and INORG diets spent 13% more time eating (P < 0.01) compared with other treatments. There was an interaction (P = 0.05) between treatment and time for ruminal [H2S]. Similar [H2S] were observed for steers fed INORG and WDGS diets (P = 0.28), which were greater (P <= 0.05) than other treatments. Greater ruminal [H2S] at 8 h compared with 13 h postfeeding was observed for steers fed ORG-H, ORG-L, and CON diets (P <= 0.04). Nearly 65% of ruminal [H2S] variation was explained (linear; P < 0.01) by RAS intake, ARPS explained 58% (linear; P < 0.01), S intake explained 29% (quadratic; P < 0.01), average ruminal pH explained 12% (linear; P < 0.01), and area below ruminal pH 5.6 explained 16% (linear, P < 0.01) of the variation. A 6% decrease in acetate (P = 0.01), 20% increase in propionate molar proportions (P = 0.02), and a lower acetate:proprionate ratio (P = 0.02) were observed for steers fed INORG compared with CON diet. The RAS concept is important for predicting ruminal [H2S] rather than just total S in the diet. Coefficients of RAS for individual ingredients can be predicted using in vitro procedures. Ruminal [H2S] may also modulate intake pattern. PMID- 23658336 TI - True digestible phosphorus requirement of 10- to 20-kg pigs. AB - The objective of this study was to determine the true digestible P requirement of 10- to 20-kg pigs by broken-line regression analysis of growth performance using 6 levels of true total-tract digestible P. In Exp. 1, 48 barrows were used to determine the true total-tract digestibility (TTTD) of P in monocalcium phosphate using the regression method. The dietary treatments included a negative control (3.30 g/kg total P) and 7 additional dietary treatments with incremental addition of 0.74 g/kg P through monocalcium phosphate, resulting in a dietary range of 3.30 to 8.45 g/kg total P. Limestone was added accordingly to maintain a constant Ca to P ratio of 1.25:1 across all diets. A 5-d adjustment period preceded a 5-d total collection of feces. Ferric oxide was used to time the initiation and termination of fecal collection. In Exp. 2, 108 barrows and gilts were used in a 3-wk growth performance study. Monocalcium phosphate was added to a corn-soybean meal-based diet to set up 6 levels of TTTD-based digestible P, ranging from 1.55 to 4.21 g/kg at an increment of 0.53 g/kg digestible P. Limestone was added accordingly to maintain a constant Ca level across all diets. The results of Exp.1 showed dietary P intake, fecal P output, and digested P increased linearly (P < 0.001) with the increasing P level, whereas the apparent total-tract digestibility of P increased both linearly and quadratically (P < 0.01). The regression of daily digested P against daily P intake gave a TTTD of 67.5% for P in monocalcium phosphate. In Exp. 2, ADG increased linearly (P < 0.001) with the increasing P level in wk 1. In wk 2, wk 3, and the overall 3-wk duration, both linear and quadratic effects of P level (P < 0.05) were observed for ADG. Average daily feed intake increased with the addition of monocalcium phosphate linearly in wk 2 (P < 0.05) and during the overall period (P < 0.001) and both linearly (P < 0.001) and quadratically (P < 0.05) in wk 3. For any period, the G:F was improved in both a linear (P < 0.001) and quadratic (P < 0.05) fashion. The true digestible P requirement, defined as the breakpoint using G:F of the overall duration, was estimated to be 3.22, 2.81, and 3.45 g/kg of diet with dietary DM averaged at 887 g/kg for pigs of mixed sex, barrows, and gilts, respectively. Using ADG, the corresponding P requirement was 3.19, 3.40, and 2.97 g/kg of diet. In conclusion, the true digestible P requirement of pigs from 10 to 20 kg BW was determined to be 3.2 g/kg of diet. PMID- 23658337 TI - Preference for tannin-containing supplements by sheep consuming endophyte infected tall fescue hay. AB - Tannins may bind to alkaloids in endophyte-infected (E+) tall fescue and attenuate fescue toxicosis. To test this hypothesis, thirty-two 4-mo-old lambs were randomly assigned to 4 treatments (8 lambs/treatment) in a 2 by 2 factorial design that included a basal diet of tall fescue hay [E+ or endophyte-free (E-)] supplemented with (TS) or without (CS) bioactive Quebracho tannins. The concentration of ergovaline in E+ fed in 2 successive phases was 65 +/- 21 ug/kg (Phase 1) and 128 +/- 4 ug/kg (Phase 2). After exposure to hays and supplements, all lambs were offered choices between TS and CS and between E+ and E- hays. During Phase 1, lambs offered E+ consumed more hay than lambs offered E- (P = 0.03). Lambs on E+/TS displayed the greatest intake of hay and the least intake of TS (P < 0.05). During Phase 2, when the concentration of ergovaline increased, lambs offered E+ consumed less hay than lambs fed E- (P < 0.0001). Lambs on E+/CS consumed less hay than lambs on E-/CS (P = 0.02), but hay intake by lambs on E /TS and E+/TS did not differ (P = 0.96). Lambs preferred CS to TS during preference tests (P < 0.0001) and lambs on E+/TS ingested the least amounts of supplement TS and the greatest amounts of supplement CS (P = 0.001). Lambs offered E+ displayed greater body temperatures than lambs offered E- in both phases (P < 0.05). When offered a choice among the 3 hays, lambs previously exposed to E+ preferred E+ (low content of ergovaline) > E- > E+ (greater content of ergovaline; P < 0.001). Thus, decreased concentrations of ergovaline increased rectal temperatures, and affected intake of and preference for tannins and fescue hay. Quebracho tannins did not attenuate the effects of E+ on body temperature and feed intake. Ingestion of E+ reduced intake of quebracho tannins, suggesting that alkaloids in E+ antagonized ingestion of condensed tannins. PMID- 23658338 TI - Effects of bulk density of steam-flaked corn in diets containing wet corn gluten feed on feedlot cattle performance, carcass characteristics, apparent total tract digestibility, and ruminal fermentation. AB - The effects of varying bulk density of steam-flaked corn (SFC) in diets containing wet corn gluten feed (WCGF; Sweet Bran; Cargill Corn Milling, Blair, NE) have not been defined. In Exp. 1, yearling steers (n = 108; initial BW = 367 +/- 1.18 kg) were housed in 27 pens (4 steers/pen) and received 1 of 3 different SFC bulk density treatments in a randomized complete block design. Bulk density treatments were 283, 335, or 386 g/L SFC in diets containing 25% WCGF (% of DM). Steers were fed once daily to provide ad libitum access to feed for an average of 163 d. For a 5-d period before d 70 of the experiment, DMI was measured, and fecal samples were collected from each pen for measurement of nutrient digestibility using dietary acid insoluble ash as a marker. Varying bulk densities of SFC did not affect (P >= 0.233) overall DMI, ADG, or G:F on a live- or carcass-adjusted basis. Dressing percent and LM area increased linearly (P <= 0.05) as bulk density increased, but other carcass traits were not affected by treatments. Intake of DM, OM, and CP during the 5-d digestion phase did not differ among bulk densities; however, starch intake increased linearly (P = 0.004) as bulk density of SFC increased. Digestibility of DM, OM, and CP tended (P <= 0.065) to decrease and starch digestibility decreased (P = 0.002) linearly as bulk density of SFC increased. In Exp. 2, a 3 * 3 Latin square design was used for collection of ruminal fluid from 3 ruminally cannulated Jersey steers adapted to the same diets used in Exp. 1. Bulk density did not affect NH3 concentrations, VFA molar proportions, ruminal fluid osmolality, and IVDMD of the diets. Total gas production increased linearly (P = 0.003) as bulk density of SFC increased from 283 to 335 g/L, but it decreased (P = 0.002) at 386 g/L. Present data suggest that bulk density can be increased up to 386 g/L in finishing diets containing 25% (DM basis) WCGF without affecting cattle performance and with limited effects on ruminal fermentation; however, digestibility of starch seemed to be affected negatively by increased bulk density in these diets. PMID- 23658339 TI - Effects of ractopamine administration and castration method on the response to preslaughter stress and carcass and meat quality in pigs of two Pietrain genotypes. AB - The objective of this study was to evaluate the effects of ractopamine supplementation, castration method, and their interaction on the behavioral and physiological response to preslaughter stress and carcass and meat quality of 2 Pietrain genotypes. A total of 1,488 male pigs (115 +/- 5 kg BW) were distributed according to a 2 * 2 * 2 factorial arrangement of treatments. The first factor was ractopamine supplementation with 2 groups of pigs (376 and 380 pigs each) receiving 7.5 mg/kg of ractopamine (RAC) or not (NRAC) in their diet during the last 28 d of the finishing period. The second factor was castration method, with 744 surgical castrates (SC) and 744 immunized males (IM), and the third factor was the genotype with 2 crossbreeds containing 50% (genotype A, GA; n = 744) or 25% (genotype B, GB; n = 744) Pietrain genetics. Surgical castration took place at 2 d of age, whereas immunization against gonadotropin-releasing factor (GnRF) was performed through 2 subcutaneous injections of GnRF analog (Improvest, 2 mL) at 10 and 4 wk before slaughter. At loading more vocal stimulation was needed by the handler to drive GB pigs forward through the farm alley (P = 0.01) and RAC fed GB pigs through the ramp (P = 0.02). Feeding RAC to IM increased the number of fights in lairage compared with SC (P = 0.03). Feeding RAC shortened fighting bouts compared with NRAC pigs (P = 0.05). The SC-GA pigs showed a greater gastrointestinal tract temperature during unloading (P = 0.05) and lairage time (P = 0.03). Blood creatine kinase (CK) concentrations were greater (P = 0.04) in SC compared with IM, and no difference was found in the concentrations of stress hormones in urine collected postmortem. Dressing yield was greater (P = 0.01) in RAC and SC-GB pigs. Carcasses from RAC pigs and IM were leaner than those from NRAC and SC pigs (P < 0.001 and P = 0.002, respectively). Feeding RAC to IM increased drip loss in the LM (P = 0.05). Warner-Bratzler shear force values were slightly greater in the LM from RAC-GB pigs and from IM compared with SC (P = 0.01 and P < 0.001, respectively) and in the semimembranosus muscle of RAC pigs (P = 0.006). In conclusion, immunization against GnRF more than the use of Pietrain genotypes appears to be a viable alternative to the use of ractopamine, as it seems to promote production of lean carcasses without compromising animal welfare and pork quality. PMID- 23658340 TI - Genetic parameters for two selection criteria for feed efficiency in rabbits. AB - Improvement of feed efficiency can be achieved by genetic selection directly on feed to BW gain ratio or for alternative traits. In the present study, 2 different traits were explored in the growing rabbit and their heritability and genetic correlations with traits recorded between weaning (30 d) and 63 d of age: i) residual feed intake (RFI), to select animals having low ad libitum feed intake independently from their production level, and ii) ADG under restricted feeding (ADGR; with a restriction level of 80% compared with ad libitum feeding of a control group), to select animals having high growth rate despite limited feed intake. To study these traits, 2 rabbit lines were established named i) ConsoResidual line and ii) ADGrestrict line. Under ad libitum or restricted feeding, it comes to select animals that waste less energy for maintenance, metabolism, or activity and retain more for tissue deposition. The selection process was similar in both lines. Data comprised records from generations 0 to 6 for about 1,800 rabbits per line measured for their BW at weaning and 63 d of age (BW63) and their individual feed consumption. Under ad libitum feeding, the heritability estimates were moderate for RFI (0.16 +/- 0.05), ADG (0.19 +/- 0.05), and feed conversion ratio (FCR; 0.22 +/- 0.05). The high genetic correlation estimated between RFI and FCR (0.96 +/- 0.03) was in accordance with the literature. The genetic correlation between RFI and ADG traits was not significant. Thus, selection for low RFI with ad libitum feeding was confirmed as a potential trait to improve FCR and reduce feed intake, with little effect on ADG. To our knowledge, there is no previous selection experiment on growing rabbits with restricted feeding. Our heritability estimates for ADGR and feed conversion ratio under restricted feeding (FCRR) were moderate (0.22 +/- 0.06 and 0.23 +/- 0.07, respectively) and had very high negative genetic correlation. Both selection criteria were found with high and favorable genetic correlations with feed efficiency recorded under each feeding regimen. However, their different genetic correlations with BW at weaning and at 63 d of age (BW63R; respectively, 0.85 and 0.17 for RFI and -0.25 and 0.81 for ADGR) suggested different impacts on major production traits that need further analyses to decipher the relative advantages of the 2 selection criteria, together with interactions between genotypes and feeding regimen. PMID- 23658341 TI - Effect of ramp configuration on easiness of handling, heart rate, and behavior of near-market weight pigs at unloading. AB - Three experiments, each using 280 pigs, were conducted in a simulated compartment to test the effect of angle of entrance (AOE) to the ramp (90 degrees , 60 degrees , 30 degrees , or 0 degrees ), ramp slope (0 degrees , 16 degrees , 21 degrees , or 26 degrees ), and an initial 20-cm step associated with 16 degrees or 21 degrees ramp slopes on the ease of handling, heart rate (HR), and behavior of near market-weight pigs during unloading. Heart rate (pigs and handler), unloading time, interventions of the handler, and reactions of the pigs were monitored. The results of the first experiment show that using a 90 degrees AOE had detrimental effects on ease of handling (P < 0.05), HR of the pig (P < 0.05), and behavior (P < 0.05). The 0 degrees and 30 degrees AOE appeared to improve the ease of unloading, whereas the 60 degrees AOE had an intermediate effect. The 30 degrees AOE appeared to be preferable, because pigs moved at this angle balked less frequently (P < 0.01) and required less manipulation (P < 0.05) than pigs moved with a 0 degrees AOE. The results of the second experiment show that the use of a flat ramp led to the easiest unloading, as demonstrated by the lower number of balks (P < 0.001) when pigs were moved to the ramp and less frequent use of paddle (P = 0.001) or voice (P < 0.001) on the ramp, compared with the other treatments. However, the flat ramp did not differ from the 21 degrees ramp in many of the variables reflecting ease of handling, which may be explained by the difference in configuration between the ramps. The results also show that the use of the steepest ramp slope had the most detrimental effect on balking and backing up behavior of pigs (P < 0.001), and handling (touches, slaps, and pushes; P < 0.05 for all) when moved to the ramp and on unloading time (P < 0.01). No differences in pig HR (P < 0.05) and ease of handling on the ramp (P < 0.05) were found between a 26 degrees and 16 degrees ramp slope, suggesting that the length of the ramp may be one of the factors that make unloading more difficult. The results of the last experiment show that an initial step made unloading physically more demanding for the handler (P < 0.001) and pigs on the ramp (P < 0.05) as demonstrated by their greater HR. The greater difficulty of handling (P < 0.01) and reluctance to move (P < 0.05) of pigs moved toward the 16 degrees ramp with a step suggest that pigs perceived this ramp as more psychologically challenging. Making a few changes in terms of the design of the ramp could improve the efficiency of handling and reduce stress in pigs. PMID- 23658342 TI - Effect of corn bran and steep inclusion in finishing diets on diet digestibility, cattle performance, and nutrient mass balance. AB - One metabolism trial and 2 finishing trials were conducted to evaluate the effects of adding corn bran and steep liquor (steep) in replacement of dry-rolled corn (DRC) on diet digestibility, cattle performance, and nutrient mass balance in open feedlot pens. The metabolism trial (Exp. 1) used 8 ruminally cannulated heifers in a 4 * 4 Latin square design and the 2 finishing trials used 128 steer calves fed for 167 d (Exp. 2) and 256 yearling steers fed for 126 d (Exp. 3). Dietary treatments for all trials included a DRC-based control (CON), 30% corn bran (30/0), 30% corn bran plus 15% steep (30/15), and 45% corn bran plus 15% steep (45/15), in which by-products replaced DRC and molasses in the diet (DM basis). Diets were not isonitrogenous or isoenergetic. In the metabolism trial, feeding the by-product diets produced greater rumen pH (5.95) than CON (5.76; P < 0.01). Total tract DM and OM digestibility were greater for heifers fed CON than the by-product diets (P < 0.01). Dry matter and NDF ruminal disappearance (%/h) of corn bran were numerically less for cattle fed the CON diet than the by product diets (2.36 vs. 2.84 and 0.72 vs. 1.66, respectively). In the performance trials, steers fed the by-product diets consumed more DM (P = 0.06) and G:F was either similar for all diets in Exp. 2 (P = 0.56) or less for cattle fed 30/0 than the other diets in Exp. 3 (P = 0.05). Percent N loss was reduced in Exp. 2 by including corn bran in diets compared with CON (P < 0.01). However, in Exp. 3, no differences in percent N loss were detected among treatments (P = 0.16), but more N was removed in the manure from pens where steers were fed by-products (P = 0.01). Although steep did not improve diet digestibility, it was beneficial in maintaining cattle performance in the feedlot studies. Feeding corn bran in combination with steep increased manure N removed and N in compost, but decreased percent N lost during the winter months only. PMID- 23658343 TI - Prenatal muscle fiber development and bundle structure in beef and dairy cattle. AB - Muscle fiber development during gestation determines the muscle structure at birth and establishes the conditions for muscle development in growing cattle. Differences in muscle structure among beef cattle breeds and between beef and dairy cattle are obvious already shortly after birth. The objective of the study was to investigate the development of muscle fibers and muscle fiber bundle structure in semitendinosus muscle of divergent cattle breeds from 3 mo of gestation until birth. Fetuses of German Angus (GA), Galloway (GW), Belgian Blue (BB), and Holstein Friesian (HF) were harvested at 3, 4.5, 6, or 9 mo of gestation. Muscle sections were analyzed for fiber size and types as well as for bundle structure. The results confirmed that primary muscle fiber development occurs mainly during the first trimester of gestation. All fibers were initially positive for fetal fast myosin. Slow myosin as a marker for fiber maturation was detected in primary fibers at 3 mo of gestation showing a weak immunostaining. During the second trimester, the intensity of immunostaining strongly increased indicating increased slow myosin protein expression. Concurrently, the shape of primary fibers changed from myotubes to myofibers whereas the size stayed nearly constant. The main increase in muscle mass during the second trimester was caused by secondary fiber development. As an example, the ratio between secondary and primary fibers increased in Holstein Friesian fetuses from 5.9 at 4.5 mo of gestation to 21.6 at 6 mo of gestation. Primary and secondary fibers continued to growth during the third trimester. Regional differences in the density of slow muscle fibers were detected leading to greater variation within the muscle than among breeds. Structural organization of muscle fibers in muscle fiber bundles developed early in fetal life. At first, large main bundles were visible. Smaller structural units defined as primary bundles were measurable at 6 mo of gestation when most fibers were developed. The size of primary bundles nearly doubled from 6 mo of gestation to birth in all breeds. In summary, differences among breeds in the early fetal muscle fiber development were detected in contractile differentiation and partly in muscle fiber bundle structure. A prolonged secondary fiber generation and altered contractile differentiation may be involved in breed differences of postnatal muscle development. PMID- 23658344 TI - Canalization analysis of birth weight in Bruna dels Pirineus beef cattle. AB - Although heteroskedasticity has been a main topic of interest in beef cattle during recent decades, the current availability of canalization models provided new insights for animal breeding programs. Within this context, birth BW (BWT) was analyzed in the Bruna dels Pirineus beef cattle breed by implementing canalization models that accounted for heterogeneous residual variances due to systematic, permanent environmental effects and additive genetic effects. Analyses were performed on BWT data from 8,130 calves born in 12 commercial breeding herds contributing to the yield recording scheme of the Bruna dels Pirineus breed. Analytical models accounted for direct additive genetic, permanent environmental, and 4 systematic effects (i.e., age of the dam, sex of the calf, birth type, and herd-year-season), and the same effects were evaluated as potential sources of variation in the residual term. Their relevance was checked by the deviance information criterion (DIC), and only residual additive genetic, permanent environmental, birth type, and herd-year-season remained in the operational model, all of them originating relevant reductions in the DIC parameter. Bruna dels Pirineus calves showed a moderate heritability of 0.30 (95% high posterior density, 0.19 to 0.40) for BWT; additional additive genetic variability was revealed in the residual term, this being positively correlated with the direct additive genetic component (0.44; 95% high posterior density, 0.37 to 0.54). Genetic trends were evaluated on both sources of additive genetic variance, and relevant patterns were identified in several herds. Although this breed did not evidence a homogeneous genetic trend for the whole population, herd specific positive and negative trends were revealed, suggesting the plausibility of genetic selection for canalization on BWT in beef cattle breeds. These results must be viewed as a contribution to the canalization research field, providing relevant information for the breeding scheme of the Bruna dels Pirineus breed, as well as important insights about the genetic background of BWT for the beef industry worldwide. PMID- 23658345 TI - Genetic selection for ovulation rate and litter size in rabbits: Estimation of genetic parameters and direct and correlated responses. AB - The aim of this work was to estimate direct and correlated responses in survival rates in an experiment of selection for ovulation rate (OR) and litter size (LS) in a line of rabbits (OR_LS). From generation 0 to 6 (first selection period), females were selected only for second gestation OR estimated by laparoscopy. From generation 7 to 13 (second selection period), a 2-stage selection for OR and LS was performed. In stage 1, females having the greatest OR at second gestation were selected. In stage 2, selection was for the greatest average LS of the first 2 parities of the females selected in stage 1. Total selection pressure in females was about 30%. The line had approximately 17 males and 75 females per generation. Traits recorded were OR estimated as the number of corpora lutea in both ovaries, number of implanted embryos (IE) estimated as the number of implantation sites, LS estimated as total number of rabbits born recorded at each parity, embryo survival (ES) estimated as IE/OR, fetal survival (FS) estimated as LS/IE, and prenatal survival (PS) estimated as LS/OR. Data were analyzed using Bayesian methodology. The estimated heritabilities of LS, OR, IE, ES, FS, and PS were 0.07, 0.21, 0.10, 0.07, 0.12, and 0.16, respectively. Direct and correlated responses from this study were estimated in each period of selection as the difference between the average genetic values of last and first generation. In the first selection period, OR increased 1.36 ova, but no correlated response was observed in LS due to a decrease on FS. Correlated responses for IE, ES, FS, and PS in the first selection period were 1.11, 0.00, -0.04, and -0.01, respectively. After 7 generations of 2-stage selection for OR and LS, OR increased 1.0 ova and response in LS was 0.9 kits. Correlated responses for IE, ES, FS, and PS in the second selection period were 1.14, 0.02, 0.02, and 0.07, respectively. Two-stage selection for OR and LS can be a promising procedure to improve LS in rabbits. PMID- 23658346 TI - Orally administered ovine serum immunoglobulins modulate the intestinal levels of Lactobacillus and enterobacteria in the growing rat. AB - The aim was to determine whether orally administered ovine serum immunoglobulins modulate the gut microbiota in the growing rat. Thirty Sprague-Dawley male rats were used in a 21-d study and fed either a basal control diet (control; no immunoglobulin) or a similar diet containing freeze-dried ovine immunoglobulin (ovine Ig) with 15 individually fed rats per diet. Bacterial DNA isolated from ileal and colonic digesta were subjected to PCR-denaturing gradient gel electrophoresis (PCR-DGGE). In the ileum, the DGGE band number and diversity index were greater (P < 0.05) for rats fed the ovine Ig than those fed the control diet. The DNA sequencing of a selected DGGE band in the ovine Ig-fed rats revealed 99% similarity to the Lactobacillus strains. The quantitative PCR data revealed that supplementation of the diet with the ovine Ig fraction supported the growth of Lactobacillus and conversely decreased the number of enterobacteria in ileal and colonic digesta. Inclusion of the ovine Ig fraction led to a greater (P < 0.05) ratio for total Lactobacillus to total bacteria and total Lactobacillus to enterobacteria. The results from the present study show that dietary supplementation with ovine Ig may alter the intestinal environment by a specific enrichment of Lactobacillus strains and depletion of enterobacteria. PMID- 23658347 TI - Effects of crude glycerin in steam-flaked corn-based diets fed to growing feedlot cattle. AB - Crude glycerin is a by-product of biodiesel production and has recently become more available as a livestock feed with the growth of the biofuel industry. Two experiments were conducted to evaluate the use of crude glycerin (GLY) as a feed ingredient in steam-flaked corn (SFC)-based growing diets fed to beef cattle. In Exp. 1, crossbred steers (n = 50; initial BW = 282 +/- 2 kg) were used to determine the effects of GLY when included at 0, 2.5, 5, 7.5, and 10% of DM in a growing diet on cattle performance. In Exp. 2, crossbred steers (n = 54; initial BW = 283 +/- 1 kg) were used to determine the effects of replacing SFC (REPSFC) or alfalfa hay (REPAH) with 7.5% GLY or a control diet without GLY (CON) on growing steer performance. In Exp. 1, final BW tended to respond in a quadratic manner (P = 0.09) in which it increased from 0 to 7.5% GLY and decreased from 7.5 to 10% GLY. Dry matter intake did not differ (P > 0.23), yet ADG responded quadratically (P = 0.04), where it increased from 0 to 7.5% GLY and decreased from 7.5 to 10% GLY. Feed efficiency (G:F) decreased linearly (P = 0.05) with increasing GLY concentration. In Exp. 2, final BW was greater for steers fed REPAH than CON or REPSFC (P = 0.04). Steers fed REPAH had a greater ADG than CON or REPSFC (P = 0.04). When GLY replaced SFC, ADG increased from 0 to 7.5% GLY where it was maximized before decreasing from 7.5 to 10% GLY inclusion. Replacing 7.5% of alfalfa hay (AH) in a growing diet with GLY can be beneficial to animal performance, which is likely the result of GLY being greater in energy than AH. PMID- 23658348 TI - Impact of health management, health treatments, and zilpaterol hydrochloride supplementation on carcass quality, color, and palatability traits in heifers. AB - Two hundred sixty-eight strip loins were collected from heifers fed at Oklahoma State University in Stillwater, OK. In Exp. 1, heifers (n = 127) were assigned to 1 of 3 health management treatment groups: antimicrobial administrations were given based on standard feedlot protocol (SFP) or ruminal temperature (RT) or given a metaphylactic treatment of tulathromycin (MT) followed by visual assessment (VA). In Exp. 2, heifers (n = 155) were assigned to the same treatment groups as above and were supplemented zilpaterol hydrochloride (ZH) or control (CON). Three steaks were collected from each strip loin, 1 each for retail display, sensory evaluation, and Warner-Bratzler shear force (WBSF). Color was evaluated from the retail display steak using a trained color panel and objectively using a HunterLab Miniscan XE. An Instron Universal Testing Machine with a Warner-Bratzler head was used for evaluation of instrumental tenderness, and a trained sensory panel was used to assess palatability traits. Heifers treated by VA had the least number of antimicrobial administrations and lowest yield grade and also had the lightest HCW (P < 0.05) compared with the heifers treated by the other health management protocols. There were no subjective color attribute differences or sensory panel differences (P > 0.05) across all health management systems or antimicrobial administrations. There were no differences in carcass and performance traits for any antimicrobial administrations treatment groups (P > 0.05). Heifers who had 0 or 1 antimicrobial administrations had lower (P < 0.05) a* (redness/greenness: positive values = red and negative values = green), and b* (yellowness/blueness: positive values = yellow and negative values = blue) values compared with those who had 2 antimicrobial administrations. In Exp. 2, heifers treated by VA had the least number (P < 0.05) of antimicrobial administrations when compared with MT and RT. Health management group did not have any other effects on carcass, sensory, or color attributes. Zilpaterol hydrochloride supplementation caused a decrease (P < 0.05) in internal fat and yield grade, but no interactions were observed between the number of antimicrobial administrations and ZH supplementation. With the supplementation of ZH, WBSF significantly increased (P < 0.05). At the end of retail display, the control group had a greater (P < 0.05) surface discoloration when compared with the ZH group. Treatment and detection of bovine respiratory diseases (BRD) is critical to the industry economically and results from this study show that different methods can be used to detect BRD without dramatically impacting carcass, sensory, and retail case life characteristics. PMID- 23658349 TI - Effects of standardized ileal digestible tryptophan:lysine in diets containing 30% dried distillers grains with solubles on finishing pig performance and carcass traits. AB - Two experiments were conducted to determine the effects of standardized ileal digestible (SID) Trp:Lys in grow-finish swine diets containing 30% dried distillers grains with solubles (DDGS). Within each experiment, crystalline Lys and Trp replaced soybean meal to alter the dietary SID Trp:Lys concentration but maintain minimum ratios of other AA to Lys. In Exp. 1, 638 pigs (36.3 kg initial BW) were used in a 105-d trial (6 pens per treatment). Pens of pigs were randomly allotted to 1 of 4 dietary treatments with SID Trp:Lys of 14.0, 15.0, 16.5, and 18.0%. From d 0 to 42, as Trp:Lys increased, ADG increased (quadratic; P = 0.05) and ADFI tended to increase (quadratic; P = 0.07) with no changes in G:F. Both ADG and ADFI were maximized at Trp:Lys of 16.5%. From d 42 to 105, increasing SID Trp:Lys increased (linear; P < 0.001) ADG and ADFI. Unlike data from d 0 to 42, the response was linear through the greatest SID Trp:Lys of 18.0%. Overall (d 0 to 105), increasing SID Trp:Lys increased (linear; P < 0.001) final BW, ADG, ADFI, and HCW. In Exp. 2, 1,214 pigs (66.3 kg initial BW) were used in a 73-d finishing trial (9 pens per treatment). Pens of pigs were randomly allotted to 1 of 5 dietary treatments with SID Trp:Lys of 15.0, 16.5, 18.0, and 19.5 and the 15.0% Trp:Lys diet with l-Trp added to achieve 18.0% SID Trp:Lys. Overall (d 0 to 73), ADG, ADFI, G:F, and final BW improved (linear; P < 0.03) as dietary SID Trp:Lys increased through 19.5%. No differences were found in growth performance between the 2 diets containing 18.0% SID Trp:Lys. For carcass traits, increasing SID Trp:Lys resulted in increased HCW (linear; P = 0.01) and a tendency toward a decreased (quadratic; P = 0.09) backfat depth and fat-free lean index (FFLI), with pigs fed diets containing 16.5 and 18.0% SID Trp:Lys having increased FFLI and lower backfat depth compared with pigs fed 15.0 and 19.5% SID Trp:Lys. Pigs fed the diet with added crystalline Trp tended to have increased (P = 0.08) backfat depth and decreased FFLI (P = 0.10) compared with pigs fed the same SID Trp:Lys without crystalline Trp. The results indicated that the optimal SID Trp:Lys was 16.5% from 36.3 to 72.6 kg but at least 19.5% from 72.6 to 120.2 kg in corn-soybean meal diets containing 30% DDGS. PMID- 23658350 TI - Effects of in ovo injection of carbohydrate solution on small intestine development in domestic pigeons (Columba livia). AB - The objective of this study was to test the hypothesis that in ovo injection of carbohydrates into pigeon (Columba livia) amnion may improve the small intestine development. At d 14.5 of incubation, 80 fertile eggs were injected with 200 MUL of carbohydrate solution, and 80 control eggs were not injected. The carbohydrate solution (wt/vol) contained 2.5% maltose + 2.5% sucrose, all dissolved in 0.75% saline. Twelve eggs from each treatment were randomly sampled at d 16 of incubation and the day of hatch, embryos or young pigeons were euthanized, and the jejunum samples were collected. Jejunal villus surface area, activity of the brush border enzymes, sucrase, maltase, aminopeptidase-N, and alkaline phosphatase, and mRNA expression of the digestion-absorption related genes oligopeptide transporter 1, sodium glucose transporter 1, glucose transporter 2, aminopeptidase-N, and sucrase-isomaltase were examined. Results showed that in ovo injection of carbohydrate solution caused a villus surface area increase of 38% on d 16 of incubation and 23% on day of hatch relative to controls (P < 0.05). The in ovo injected pigeons exhibited greater (P < 0.05) activities of jejunal sucrase, maltase, and alkaline phosphatase from d 16 of incubation to day of hatch compared with the controls. At day of hatch, aminopeptidase-N activity in embryos injected in ovo was approximately 27% greater (P < 0.05) than control embryos. Enhanced expressions of the jejunal sodium glucose transporter 1, glucose transporter 2, and aminopeptidase-N mRNA were found at d 16 of incubation in embryos that received carbohydrate solution into the amniotic fluid in comparison with the control group (P < 0.05). These results indicate that the in ovo injected pigeon may hatch with more mature enterocytes and greater intestinal digestive and absorptive capacity than the conventional hatchling. Therefore, the in ovo injected pigeons may become more precocial at hatch and easier to hand rear during the immediate posthatch period. PMID- 23658351 TI - Genomic selection for two traits in a maternal pig breeding scheme. AB - The objective of this study was to compare different implementations of genomic selection to a conventional maternal pig breeding scheme, when selection was based partly on production traits and partly on maternal traits. A nucleus pig breeding population with size and structure similar to Norwegian Landrace was simulated where equal weight was used for maternal and production traits. To genotype the boars at the boar station and base the final selection of boars on genomic breeding values increased total genetic gain by 13% and reduced the rate of inbreeding by 40%, without significantly affecting the relative contribution of each trait to total genetic gain. To increase the size of the reference population and thereby accuracy of selection, female sibs in the selected litters can also be genotyped to increase genetic gain for maternal traits more than for production traits, thereby resulting in an increased relative contribution of maternal traits to total genetic gain. Genotyping 2,400 females each year increased the relative contribution of maternal traits to total genetic gain from 16 to 32%. Performing preselection of males by allowing genotyping of 2 males per litter and allowing for selection across and within litters before the boar test increased genetic gain by 5 to 11%, compared with genotyping the boars at the boar station, without significant effects on the relative contribution of each trait to total genetic gain. Genotyping more animals consequently increased genetic gain. Genotyping females to build a larger reference base for maternal traits gave similar genetic gain as genotyping the same amount of additional males but with a lower rate of inbreeding and a greater contribution of maternal traits to total genetic gain. In conclusion, genotyping females should be prioritized before genotyping more males than the tested boars if the breeding goal is to increase maternal traits specifically over production traits or genomic selection is used as a tool to reduce the rate of inbreeding. PMID- 23658352 TI - Development of equations to estimate microbial contamination in ruminal incubation residues of forage produced under tropical conditions using 15N as a label. AB - The objective of this study was to use (15)N to label microbial cells to allow development of equations for estimating the microbial contamination in ruminal in situ incubation residues of forage produced under tropical conditions. A total of 24 tropical forages were ruminal incubated in 3 steers at 3 separate times. To determine microbial contamination of the incubated residues, ruminal bacteria were labeled with (15)N by continuous intraruminal infusion 60 h before the first incubation and continued until the last day of incubation. Ruminal digesta was collected for the isolation of bacteria before the first infusion of (15)N on adaptation period and after the infusion of (15)N on collection period. To determine the microbial contamination of CP fractions, restricted models were compared with the full model using the model identity test. A value of the corrected fraction "A" was estimated from the corresponding noncorrected fraction by this equation: Corrected "A" fraction (A(CP)C) = 1.99286 + 0.98256 * A" fraction without correction (A(CP)WC). The corrected fraction "B" was estimated from the corresponding noncorrected fraction and from CP, NDF, neutral detergent insoluble protein (NDIP), and indigestible NDF (iNDF) using the equation corrected "B" fraction (B(CP)C) = -17.2181 - 0.0344 * fraction "B" without correction (B(CP)WC) + 0.65433 * CP + 1.03787 * NDF + 2.66010 * NDIP - 0.85979 * iNDF. The corrected degradation rate of "B" fraction (kd)was estimated using the equation corrected degradation rate of "B" fraction (kd(CP)C) = 0.04667 + 0.35139 * degradation rate of "B" fraction without correction (kd(CP)WC) + 0.0020 * CP - 0.00055839 * NDF - 0.00336 * NDIP + 0.00075089 * iNDF. This equation was obtained to estimate the contamination using CP of the feeds: %C = 79.21 * (1 - e( 0.0555t)) * e(-0.0874CP). It was concluded that A and B fractions and kd of CP could be highly biased by microbial CP contamination, and therefore these corrected values could be obtained mathematically, replacing the use of microbial markers. The percentage of contamination and the corrected apparent degradability of CP could be obtained from values of CP and time of incubation for each feed, which could reduce cost and labor involved when using (15)N. PMID- 23658353 TI - Effects of dietary L-carnitine and dried distillers grains with solubles on growth, carcass characteristics, and loin and fat quality of growing-finishing pigs. AB - A total of 1104 barrows and gilts (PIC 337 * 1050, Pig Improvement Company, Hendersonville, TN), weighing 36 +/- 1 kg were used in a 109-d study to evaluate effects of dietary L-carnitine and dried distillers grains with solubles (DDGS) on growth, carcass traits, and loin and fat quality. Pigs were blocked by BW and randomly assigned to 1 of 6 treatments, with 7 pens per treatment. Treatments were arranged as a 2 * 3 factorial, with main effects of DDGS (30% in Phases 1, 2, and 3, and 20% in Phase 4) and L-carnitine (0, 50, or 100 mg/kg). Overall (d 0 to 109), dietary L-carnitine tended to improve ADG (linear, P = 0.07). Pigs fed 50 mg/kg L-carnitine but no DDGS had greater G:F than pigs fed 0 or 100 mg/kg, whereas when diets containing DDGS were fed, 50 mg/kg of L-carnitine reduced G:F compared with pigs fed 0 or 100 mg/kg (quadratic DDGS * L-carnitine, P < 0.01). There was no effect of DDGS * L-carnitine for any carcass traits, but pigs fed increasing dietary inclusion levels of L-carnitine produced heavier HCW (quadratic, P = 0.03), greater carcass yields (quadratic, P = 0.07), and greater fat depths (quadratic, P = 0.04), with the greatest response observed in pigs fed 50 mg/kg dietary L-carnitine. Feeding L-carnitine increased purge loss (linear, P = 0.03), whereas feeding DDGS tended to decrease (P = 0.06) LM marbling scores. The LM from pigs fed 50 mg/kg L-carnitine and DDGS had lower shear force values compared with LM chops from pigs fed either 0 or 100 mg/kg; however, shear force values were similar across dietary L-carnitine levels in diets devoid of DDGS (quadratic DDGS * L-carnitine, P < 0.01). Furthermore, increasing L-carnitine in DDGS diets increased fresh LM color scores, but pigs fed DDGS-free diets produced LM chops with similar subjective color scores (linear DDGS * L-carnitine, P = 0.03). As expected, feeding DDGS increased (P < 0.001) iodine value (IV) in jowl fat samples, but dietary L-carnitine did not alter IV. The concentrations of C18:2n-6 and C20:2 were decreased with increasing L-carnitine in DDGS-containing diets, but not in diets without DDGS (linear DDGS * L-carnitine, P <= 0.04). Results of this study indicate that dietary DDGS did not affect growth, but led to more unsaturation of jowl fat, whereas feeding 50 mg/kg of L-carnitine improved HCW and reduced C18:2n-6 in jowl fat when fed in combination with DDGS. PMID- 23658354 TI - Plane of nutrition x tick burden interaction in cattle: effect on fecal composition. AB - Effective tick management on grazing animals is facilitated by accurate noninvasive detection methods. Fecal analysis provides information about animal health and nutrition. Diet affects fecal composition; stress may do likewise. The constituents in feces that may be affected by tick burdens and in turn affect near-infrared spectra have not been reported. Our objective was to examine the interaction between plane of nutrition and tick burden on fecal composition in cattle. Angus cross steers (n = 28; 194 +/- 3.0 kg) were assigned to 1 of 4 treatments (n = 7 per group) in a 2 * 2 factorial arrangement: moderate (14.0 +/- 1.0% CP and 60 +/- 1.5% TDN) vs. low (9.0 +/- 1.0% CP and 58 +/- 1.5% TDN) plane of nutrition and control (no tick) vs. tick treatment [infestation of 300 pair of adult Lone Star ticks (Amblyomma americanum) per treated animal]. Fecal samples were collected at approximately 0700 h on d -7, 0, 7, 10, 14, 17, and 21 relative to tick infestation. Fecal constituents measured were DM, OM, pH, Lactobacillus spp., Escherchia coli, acetate, propionate, butyrate, isobutyrate, valerate, isovalerate, IgA, and cortisol. Experimental day affected (P < 0.05) all constituents measured. Plane of nutrition affected (P < 0.05) DM, OM, VFA, and IgA. Tick treatment numerically (P = 0.13) reduced cortisol. A multivariate stepwise selection model containing cortisol and E. coli values on d 10 and d 14 accounted for 33% of the variation in daily adult female tick feeding counts across both planes of nutrition (P < 0.07). Within the moderate plane of nutrition, a model containing only cortisol on d 10 and d 14 described 59% of the variation in the number of feeding ticks (P < 0.02). Similarly, a model including cortisol, propionate, isovalerate, and DM at d 10 and d 14 d described 95% of the variation in total feeding ticks in the low plane of nutrition. Of the constituents measured, fecal cortisol offers the best possibility of noninvasively assessing stress by way of a single assay but the presence of ticks would still need to be confirmed visually. Although several constituents measured in this study should exist in sufficient quantity to directly affect near infrared spectra, none stood out as a clear descriptor of prior observed differences in fecal spectra between tick-treated versus non-tick-treated animals. There were, however, groups of fecal constituents related to daily adult female tick feeding numbers (as a visual estimation of tick stress). PMID- 23658355 TI - Interactive effects of dietary ractopamine HCl and L-carnitine on finishing pigs: I. Growth performance. AB - A total of 2,152 pigs (C22 * 336 PIC) were used in 4 experiments to determine the interactive effects of dietary l-carnitine and ractopamine HCl (RAC) on finishing pig growth performance. All trials were arranged as factorial arrangements with main effects of l-carnitine (0, 25, or 50 mg/kg in Exp. 1 and 2 and 0 or 50 mg/kg in Exp. 3 and 4) and RAC (0, 5, or 10 mg/kg in Exp. 1 and 0 or 10 mg/kg in Exp. 2, 3, and 4). Dietary carnitine was fed from 38 to 109 kg (Exp. 1 and 3) or for the last 4 or 3 wk before slaughter (118 kg; Exp. 2 and 4, respectively). Ractopamine HCl was fed for 4 wk (Exp. 1, 2, and 3) or 3 wk (Exp. 4) before slaughter. Experiments 1 and 2 were conducted in university research facilities, and Exp. 3 and 4 were conducted in a commercial research facility. All diets were formulated to contain 1.00% total Lys during the last phase of each experiment. In all experiments, pigs fed RAC had increased (P < 0.05) ADG and G:F compared with pigs fed no RAC. Feeding l-carnitine before the RAC feeding period did not affect pig growth performance. In Exp. 1 and 2, l-carnitine did not affect ADG during the last 4 wk; however, in Exp. 2, G:F tended (quadratic; P = 0.07) to improve with increasing l-carnitine. In Exp. 3, l-carnitine * RAC interactions were observed (P < 0.04) for ADG and G:F. Both added l-carnitine and RAC improved performance, but the response was not additive. In Exp. 4, pigs fed l-carnitine had increased (P < 0.04) ADG (0.88 vs. 0.84 kg) and G:F (0.36 vs. 0.35) compared with pigs fed no l-carnitine, and the response was additive to that of RAC. Analysis of treatments common to all experiments showed that pigs fed RAC had increased (P < 0.01) ADG (1.03 vs. 0.93 kg) and G:F (0.40 vs. 0.35) compared with pigs fed no RAC. Pigs fed l-carnitine tended to have increased (P = 0.07) ADG (1.00 vs. 0.96 kg) and improved (P < 0.01) G:F (0.38 vs. 0.37) compared with pigs not fed l-carnitine. These results confirm that RAC improves growth performance of finishing pigs. Added l-carnitine improved growth performance of finishing pigs, and the greatest response was observed in Exp. 3 and 4, which were conducted in commercial research environments. These experiments imply that adding l-carnitine to a finishing diet does not enhance the growth effects of RAC and that effects of RAC and l-carnitine on ADG and G:F are independent. PMID- 23658356 TI - Effect of maturity at harvest on yield, chemical composition, and in situ degradability for annual cereals used for swath grazing. AB - The objective of this study was to determine how harvest maturity of whole-crop cereals commonly used in swath grazing systems in western Canada affects yield, chemical composition, and in situ digestibility. We hypothesized that the increase in yield with advancing maturity would not offset the decline in digestibility and, thus, the yield of effectively degradable DM (EDDM) would decline with advanced stages of maturity. Four replicate plots of barley (Hordeum vulgare L.; cv. CDC Cowboy), millet (Panicum milliaceum; cv. Red Proso), oat (Avena sativa L., spp.; CDC Weaver), and wheat (Triticum aestivum L.; cv. 07FOR21) were grown, with a subsection in each replicate harvested at 4 different maturities: head elongation, late milk, hard dough, and fully mature. At each stage of maturity, the wet and DM yields, and chemical composition (DM, OM, NDF, crude fat, and nonfiber carbohydrates; NFC) were determined. Whole-crop samples were ground (2-mm screen) and weighed into nylon bags (pore size of 53 +/- 10 um), and duplicate incubation runs were conducted by crop type. For each incubation run, nylon bags were randomly allocated (randomized by field replication, stage of maturity, and incubation time) to 1 of 7 heifers (32 bags/heifer during each run). Degradation rates were determined using a first order kinetic model and data were analyzed with stage of maturity as a fixed effect and plot as a random effect. The DM, OM, and NFC yields increased linearly for barley and oat (P < 0.001), and increased quadratically for millet and wheat (P <= 0.025). Neutral detergent fiber yield increased linearly for barley (P = 0.005) and quadratically for millet, oat, and wheat (P = 0.044). There were no changes in CP yield observed for barley, millet, or oat with advancing maturity, but there was a linear increase observed for wheat (P = 0.002). The NFC concentration increased linearly for barley, millet, and oat (P < 0.001), and quadratically for wheat (P < 0.001), whereas the EDDM concentration decreased quadratically for millet, oat, and wheat (P = 0.003). The degradation rate of NDF decreased linearly with advancing maturity (P <= 0.014) for millet, oat, and wheat, but was not affected for barley (P = 0.13). The yield EDDM increased linearly for barley and oat (P < 0.001), and increased quadratically for millet and wheat (P <= 0.025). These findings suggest that harvesting whole-crop annual cereals at the hard dough and mature stages may maximize the yield of EDDM. PMID- 23658357 TI - Effect of Mannheimia haemolytica pneumonia on behavior and physiologic responses of calves during high ambient environmental temperatures. AB - The objective of this study was to determine the effect of pneumonia during conditions of high (maximum >= 32 degrees C) ambient temperatures on physiological and behavioral responses of calves. Eighteen black beef heifers averaging 240 kg were blocked by BW and randomly assigned to 1 of 2 treatment groups: 1) pneumonia induced by bronchoselective endoscopic inoculation with Mannheimia haemolytica (MH; n = 10) and 2) noninoculated controls (CN; n = 8). Nasal passage and rectal temperatures were measured every 2 h for 24 h after challenge and then twice daily for 9 d. Accelerometers, pedometers, and positioning devices monitored cattle behavior within the pen for 9 d after challenge. Blood samples were collected on trial d 0, 0.5, 1, 2, 3, 7, and 9 and were analyzed to determine the concentration of substance P, cortisol, haptoglobin, and metalloproteinase. All calves in the MH group were euthanized and necropsied on trial d 9. All MH calves became clinically ill postchallenge. A treatment * time interaction (P < 0.05) was evident for nasal and rectal temperatures, behavior, weight, and blood analysis. Rectal temperatures in MH were higher (P < 0.01) than CN during the period from 6 to 24 h after challenge. Conversely, nasal passage temperatures were less in MH calves compared with CN at 12 to 22 h after challenge. Calves in MH spent less time at the grain bunk, less time at the hay feeder, and more time lying down during the early pneumonia period compared with CN calves. Also, MH calves had significantly greater concentrations of blood biomarkers of pain (substance P) on d 0.5 (P < 0.01); stress (cortisol) on d 0.5 and 1 (P < 0.01); haptoglobin on d 0.5, 1, 2, 3, 7 (P < 0.01); and metalloproteinase on d 1, 2, and 3 (P < 0.01) compared with CN calves. At necropsy, all MH calves had right cranioventral bronchopneumonia (median lung lesions = 6.8%). Mannheimia haemolytica pneumonia caused significantly more changes in behavior and increased biomarkers during high (maximum >=32 degrees C) ambient temperatures compared with control calves. The results of this study may guide research in the development of objective assessment tools for management of cattle affected with bovine respiratory disease during extreme summer conditions. PMID- 23658358 TI - Effects of reduced nocturnal temperature on pig performance and energy consumption in swine nursery rooms. AB - The objective of this investigation was to determine the effect of a reduced nocturnal temperature (RNT) regimen on performance of weaned pigs and energy consumption during the nursery phase of production. The age of weaned pigs assigned to experiments ranged from 16 to 22 d. In Exp. 1, 3 stations conducted 2 trials under a common protocol that provided data from 6 control rooms (CON; 820 pigs) and 6 RNT rooms (818 pigs). Two mirror-image nursery rooms were used at each station. Temperature in the CON room was set to 30 degrees C for the first 7 d, then reduced by 2 degrees C per week through the remainder of the experiment. Room temperature settings were held constant throughout the day and night. The temperature setting in the RNT room was the same as CON during the first 7 d, but beginning on the night of d 7, the room temperature setting was reduced 6 degrees C from the daytime temperature from 1900 to 0700 h. The use of heating fuel and electricity were measured weekly in each room. Overall, ADG (0.43 kg), ADFI (0.62 kg), and G:F (0.69) were identical for CON and RNT rooms. Consumption of heating fuel [9,658 vs. 7,958 British thermal units (Btu).pig(-1).d(-1)] and electricity (0.138 vs. 0.125 kilowatt-hour (kWh).pig(-1).d(-1)] were not statistically different for CON and RNT rooms, respectively. In Exp. 2, 4 stations conducted at least 2 trials that provided data from 9 CON rooms (2,122 pigs) and 10 RNT rooms (2,176 pigs). Experimental treatments and protocols were the same as Exp. 1, except that the RNT regimen was imposed on the night of d 5 and the targeted nighttime temperature reduction was 8.3 degrees C. Neither final pig BW (21.8 vs. 21.5 kg; SE = 0.64), ADG (0.45 vs. 0.44 kg; SE = 0.016), ADFI (0.61 vs. 0.60 kg; SE = 0.019), nor G:F (0.75 vs. 0.75; SE = 0.012) were different for pigs housed in CON or RNT rooms, respectively. Consumption of heating fuel and electricity was consistently reduced in RNT rooms for all 4 stations. Consumption of heating fuel (10,019 vs. 7,061 Btu.pig(-1).d(-1); SE = 1,467) and electricity (0.026 vs. 0.021 kWh.pig-1.d-1; SE = 0.004) were lower (P < 0.05) in the RNT rooms compared with CON rooms. This represents a 30% reduction in heating fuel use and a 20% reduction in electrical use with no differences in pig growth performance or health. From these experiments, we conclude that imposing a RNT regimen from 1900 to 0700 h is effective in reducing energy costs in the nursery without compromising pig performance, which will reduce production costs and decrease emissions of greenhouse gases. PMID- 23658359 TI - Effects of dietary inclusion of pea and faba bean as a replacement for soybean meal on grower and finisher pig performance and carcass quality. AB - To reduce reliance on imported soybean meal (SBM) in temperate environments, pea and faba bean may be alternative protein sources for pig diets. We assessed the effects of dietary pea and faba bean inclusion on grower and finisher pig performance and carcass quality. There were 9 dietary treatments tested on both grower (30 to 60 kg) and finisher (60 to 100 kg) pigs in a dose response feeding trial. The control diet included SBM at 14 and 12% for grower and finisher pigs, respectively, whereas in the test diets, pea or faba bean were included at 7.5, 15, 22.5, and 30%, gradually and completely replacing SBM. Diets were formulated to be isoenergetic for NE and with the same standard ileal digestible Lys content. After a 1-wk adaptation period, each diet was available on an ad libitum basis to 4 pens of pigs with 4 pigs per pen (2 entire males and 2 females) for 4 wk. Weekly BW for individual pigs, and pen intakes were recorded to assess ADG, ADFI, and G:F. Finisher pigs were then slaughtered at a commercial slaughter house to record carcass quality and assess skatole and indole concentration in the backfat. There were no effects (P > 0.10) on grower ADG, ADFI, and G:F, but pulse inclusion reduced finisher ADG (P = 0.04), with a quadratic effect of pulse inclusion (P = 0.03), as ADG tended to be reduced over initial inclusion levels only. There were no associated effects (P > 0.10) on ADFI or G:F, and pea and faba bean diets resulted in similar finisher performance. Increasing pulse inclusion linearly increased fecal DM content both in grower pigs (P = 0.02) and finisher pigs (P < 0.01). There were no effects on carcass quality or backfat skatole concentrations, but indole concentration was linearly reduced with increasing pulse inclusion (P = 0.05). It is concluded that pea and faba bean may be a viable alternative to SBM in grower and finisher pig diets. PMID- 23658361 TI - The effect of selenium supplementation on vaccination response and immune function in adult horses. AB - Selenium status has been reported to affect immune function across many different species. Yet few studies have focused on the effect of Se status on the equine immune system. This study examined the effect of Se supplementation on vaccination response and immune function in mature horses. Twenty-eight horses were blocked by age and sex and were randomly allocated to 1 of 4 dietary treatment groups: low Se (LS), adequate Se (AS), Se-yeast (SP), and sodium selenite (SS). For 35 wk, horses allocated to LS, SP, and SS received a low-Se diet (0.06 mg/kg DM) with the intention to lower Se stores, whereas AS received an adequate Se diet (0.12 mg/kg DM). A 29-wk repletion phase was as follows: LS and AS were kept on the diets fed during the depletion period, whereas SP and SS received the depletion diet plus their respective Se supplements to achieve a dietary Se concentration of 0.3 mg/kg DM. The Se status of the horses was monitored using whole blood Se and glutathione peroxidase (GSH-Px) activity as indicators. At wk 22 and 25 of the repletion phase, horses were vaccinated intramuscularly with 10 mg ovalbumin (OVA). Horses were also vaccinated against equine influenza at wk 25. Blood samples were collected for 7 wk after initial vaccination for serum separation and at 0, 3, and 5 wk postvaccination for peripheral blood mononuclear cell (PBMC) isolation and whole blood cytokine mRNA evaluation. At wk 22 of the repletion phase, both Se and GSH-Px were greater for SP and SS compared with AS and LS (P < 0.001). Serum vitamin E was similar between treatments. Response to OVA vaccination, evaluated as OVA-specific IgG production, cytokine mRNA expression of PBMC stimulated with OVA in vitro, and lymphocyte proliferation, was unaffected by Se status. Similarly, memory response to the influenza vaccine was not affected by Se status. However, decreased mRNA expression of selected cytokines was observed in PBMC stimulated with phorbol 12 myristate 13-acetate for LS compared with AS, SP, and SS (P < 0.05). Whole blood mRNA expression of IL-10 was greater for SS compared with LS, AS, and SP (P = 0.043). Although the OVA and influenza vaccination responses were unaffected by Se status, other measures of immune function did indicate that low Se status could adversely affect cell-mediated immunity. PMID- 23658362 TI - Differences in maternal plane of nutrition and body condition during late gestation coupled with estrus synchronization at weaning do not result in differences in embryonic development at 4 days of gestation. AB - This study was conducted to assess the effects of dietary energy in late pregnancy and hormone therapy at weaning on plasma metabolite profile, litter performance, reproductive parameters, and embryo viability in the second pregnancy. A total of 23 first-parity sows at 75 d of pregnancy were randomly allocated to 4 treatments. Treatments were factorial (2 * 2) combinations of 2 nutritional strategies [standard-energy feed (SEF) and high-energy feed (HEF)] and 2 hormone therapies [600 IU eCG and 2.5 mg swine LH 72 h later (HO) and no hormone (WH)]. Sows were weighed weekly from 75 d of pregnancy until 3 d before farrowing; 1 d after farrowing; 7, 14, and 21 d into lactation; and at weaning. Back fat (BF) was measured at 75 d of pregnancy, 3 d before farrowing, and at weaning. Average daily gain and ADFI were also calculated. Plasma metabolites were analyzed after 82, 89, 96, and 103 d of pregnancy, at farrowing, and after 7, 14, and 21 d of lactation. Embryo viability was assessed after 4.55 d of second pregnancy. During pregnancy, HEF-treated sows displayed greater BW (P < 0.05) compared with SEF-treated females, but no differences were observed during lactation. There were no differences in BW of the piglets caused by the treatments. High-energy-treated females showed superior BF (P > 0.05) in all periods; however, significant differences were detected only at the prefarrowing measurement (P < 0.05). No differences in ADFI were observed during lactation. The SEF group showed positive ADG, whereas the HEF group showed negative ADG (0.216 vs. -0.266 kg/d for SEF and HEF, respectively; P < 0.05). High-energy treated sows presented greater concentrations of total cholesterol after 89 and 103 d of pregnancy and greater concentrations of high-density lipid cholesterol (HDL) after 89 and 96 d. At farrowing and 14 and 21 d of lactation, NEFA concentrations were greater (P < 0.05) in the HEF group. After hormone treatment, no differences were observed on weaning-to-estrus intervals and estrus duration. Greater mobilization of body reserves observed in the HEF group during lactation did not affect reproductive performance negatively, suggesting that metabolic status was adequate for the first lactational catabolism. PMID- 23658363 TI - The admixed population structure in Danish Jersey dairy cattle challenges accurate genomic predictions. AB - The main purpose of this study was to evaluate whether the population structure in Danish Jersey (DJ) known from the history of the breed also is reflected in its genomic structure. This is done by comparing the linkage disequilibrium and persistence of phase for subgroups of Jersey animals with high proportions of Danish (DNK) or United States (USJ) origin. Furthermore, it is investigated whether a model explicitly incorporating breed origin of animals, inferred either through the known pedigree or from SNP marker data, leads to improved genomic predictions compared with a model ignoring breed origin. The study of the population structure incorporated 1,730 genotyped Jersey animals. In total 39,542 SNP markers were included in the analysis. The 1,079 genotyped bulls with de regressed proof for udder health were used in the analysis for the predictions of the genomic breeding values. A range of random regressions models that included the breed origin were analyzed and compared with a basic genomic model that assumes a homogeneous breed structure. The main finding in this study is that the importation of germplasm from the USJ population is readily reflected in the genomes of modern DJ animals. First, linkage disequilibrium in the group of admixed DJ animals is lower compared with the groups of the original DNK and USJ animals. Second, persistence of linkage disequilibrium phase is not conserved for longer marker distances between animals with mainly Danish or United States origin. Third, the STRUCTURE analysis could retrieve genomic-based breed proportions in alignment to the pedigree-based breed proportions. However, including this population structure in a random regression prediction model did not clearly improve the reliabilities of the genomic predictions compared with a basic genomic model. PMID- 23658364 TI - Response to selection for decreased backfat thickness at restrained intramuscular fat content in Duroc pigs. AB - Intramuscular fat (IMF) content is a relevant trait for the pig industry and consumers. However, selection for IMF has the undesired correlated effect of decreasing lean growth. A selection experiment was performed to investigate the effects of selection against backfat thickness (BT) at restrained IMF. Barrows from a purebred Duroc line were allocated into a selected (n = 165) or a control (n = 185) group based on their litter predicted EBV. Litters in the selected group were selected against BT at 180 d at restrained IMF in gluteus medius (GM) whereas those in the control group were chosen randomly. Realized selection intensities and genetic responses for BT, IMF in GM, and BW were estimated using a 3-trait multivariate animal mixed model under a Bayesian setting. Correlated responses for other traits were estimated similarly but using a 4-trait model, where other traits were added to the previous 3-trait model 1 at a time. Selected pigs had less BT than control pigs [-1.22 mm, with highest posterior density interval at 95% (HPD95; -2.47, -0.75)] with restrained decrease in IMF, both in GM [-0.16%; HPD95 (-0.36, +0.05)] and in LM [-0.15%; HPD95 (-0.37, +0.09)]. However, the realized selection intensity for IMF in GM denotes that the restriction on IMF was incomplete [-0.18; HPD95 (-0.36, +0.02)]. Selection decreased BW [-1.64 kg; HPD95 (-2.47, -0.75)] but increased carcass lean weight [+0.66 kg; HPD95 (+0.14, +1.22)], indicating that the response in BT offsets the unfavorable correlated response in BW. Selected pigs were shorter [-0.50 cm; HPD95 (-0.81, -0.20)] but with similar ham weight and loin depth. These results provide evidence that lean weight can be improved restraining the genetic change in IMF. However, they also stress that a complete restriction on IMF is difficult to achieve unless selection is practiced on a big population where IMF is accurately predicted. PMID- 23658365 TI - Feed intake, ruminal fermentation, and animal behavior of beef heifers fed forage free diets containing nonforage fiber sources. AB - Eight Simmental heifers (initial BW 313.4 +/- 13.2 kg) were randomly assigned to 1 of 4 experimental treatments in a 4 * 4 double Latin square design. The experiment was performed in four 28-d periods. Treatments tested were a control diet in which barley straw (BS) was used as a fiber source and 3 diets where the main difference was the nonforage fiber source used: soybean hulls (SH), beet pulp (BP) in pellets, and whole cottonseed (WCS). All ingredients, except the fiber sources, were ground through a 3-mm screen. Fiber ingredients were incorporated at 10, 17, 17, and 16% (on DM basis) in BS, SH, BP, and WCS, respectively. All diets were offered ad libitum as total mixed ration and designed to be isoenergetic (2.95 Mcal ME/kg DM), isonitrogenous (15% CP, DM basis), and with a NDF content of 20% (on DM basis) although there was a discrepancy between the theoretical and the actual chemical composition of the diets. Particle size separation was performed using the 3-screen Penn State Particle Separator. Animals were allotted in 8 individual roofed concrete pens equipped with a feedbunk and water trough. Intake was recorded over 7 d in the last week of each experimental period. Behavior was recorded for 24-h on d 2 and d 6 of each experimental week using a digital video recording device. A digital color camera was set up in front of each pen. Data recorded, except behavioral activities, were statistically analyzed using the MIXED procedure of SAS. To test treatment effect for each behavioral activity, analysis was performed using the GLIMMIX procedure of SAS. Diets ranked from greater to lesser proportion of particles of less than 1.18 mm as follows: SH, BS, WCS, and BP. Dry matter intake of heifers fed WCS was greater than the remaining treatments (P = 0.049). The greatest average ruminal pH was registered in heifers fed BS (6.4) and BP (6.3) whereas the smallest was recorded in SH diet (5.9), with WCS (6.2) occupying an intermediate position (P = 0.006). Total chewing time was greater (P = 0.001) in BS and WCS than in SH and BP. In conclusion, the nonforage fiber sources tested in this experiment can be used in forage-free diets fed to beef heifers as total mixed ration (TMR) without negative consequences in DMI in SH and BP diets and with an increased DMI in WCS diet. The WCS diet promoted rumination and total chewing time to the same degree as BS, which demonstrates that it is equally effective as this forage fiber source. PMID- 23658366 TI - Lactobacillus salivarius REN inhibits rat oral cancer induced by 4-nitroquioline 1-oxide. AB - Despite significant advances in cancer therapy, cancer-related mobility and mortality are still rising. Alternative strategies such as cancer prevention thus become essential. Probiotics represent an emerging option for cancer prevention, but studies are limited to colon cancers. The efficiency of probiotics in the prevention of other cancers and the correlative mechanism remains to be explored. A novel probiotics Lactobacillus salivarius REN (L. salivarius REN) was isolated from centenarians at Bama of China, which showed highly potent antigenotoxicity in an initial assay. 4-nitroquioline 1-oxide (4NQO)-induced oral cancer model was introduced to study the anticancer activity of L. salivarius REN in vivo. The results indicated that oral administration of probiotic L. salivarius REN or its secretions could effectively suppress 4NQO-induced oral carcinogenesis in the initial and postinitial stage, and the inhibition was in a dose-dependent manner. A significant decrease of neoplasm incidence (65%-0%) was detected in rats fed with the high dose of L. salivarius REN [5 * 10(10) CFU/kg body weight (bw)/d]. In vivo evidences indicated that the probiotics inhibited 4NQO-induced oral cancer by protecting DNA against oxidative damage and downregulating COX-2 expression. L. salivarius REN treatment significantly decreased the expression of proliferating cell nuclear antigen (PCNA) and induced apoptosis in a dose dependent manner. Our findings suggest that probiotics may act as potential agents for oral cancer prevention. This is the first report showing the inhibitory effect of the probiotics on oral carcinogenesis. PMID- 23658368 TI - Synergistic induction of adaptive antitumor immunity by codelivery of antigen with alpha-galactosylceramide on exosomes. AB - Exosomes and the invariant NKT (iNKT) immune cell ligand alpha-galactosylceramide (alphaGC) may offer novel tools for cancer immunotherapy. In this study, we investigated whether exosomes loaded with alphaGC can activate iNKT cells and potentiate a cancer-specific adaptive immune response. alphaGC loaded exosomes readily activated iNKT cells both in vitro and in vivo. Exosomes loaded with alphaGC plus the model antigen ovalbumin (OVA) induced potent NK and gammadelta T cell innate immune responses, and they also synergistically amplified T- and B cell responses that were OVA specific. In contrast to soluble alphaGC, which anergizes iNKT cells, we found that alphaGC/OVA-loaded exosomes did not induce iNKT cell anergy but were more potent than soluble alphaGC + OVA in inducing adaptive immune responses. In an OVA-expressing mouse model of melanoma, treatment of tumor-bearing mice with alphaGC/OVA-loaded exosomes decreased tumor growth, increased antigen-specific CD8(+) T-cell tumor infiltration, and increased median survival, relative to control mice immunized with soluble alphaGC + OVA alone. Notably, an additional injection of alphaGC/OVA-loaded exosomes further augmented the treatment effects. Our findings show that exosomes loaded with protein antigen and alphaGC will activate adaptive immunity in the absence of triggering iNKT-cell anergy, supporting their application in the design of a broad variety of cancer immunotherapy trials. PMID- 23658367 TI - Raw garlic consumption as a protective factor for lung cancer, a population-based case-control study in a Chinese population. AB - Protective effect of garlic on the development of cancer has been reported in the in vitro and in vivo experimental studies; however, few human epidemiologic studies have evaluated the relationship. A population-based case-control study has been conducted in a Chinese population from 2003 to 2010, with the aim to explore the association between raw garlic consumption and lung cancer. Epidemiologic data were collected by face-to-face interviews using a standard questionnaire among 1,424 lung cancer cases and 4,543 healthy controls. Unconditional logistic regression was used to estimate adjusted ORs and their 95% confidence intervals (CI), and to evaluate ratio of ORs (ROR) for multiplicative interactions between raw garlic consumption and other risk factors. After adjusting for potential confounding factors, raw garlic consumption of 2 times or more per week is inversely associated with lung cancer (OR = 0.56; 95% CI, 0.44 0.72) with a monotonic dose-response relationship (Ptrend < 0.001). Furthermore, strong interactions at either additive and/or multiplicative scales were observed between raw garlic consumption and tobacco smoking [synergy index (SI) = 0.70; 95% CI, 0.57-0.85; and ROR = 0.78; 95% CI, 0.67-0.90], as well as high temperature cooking oil fume (ROR = 0.77; 95% CI, 0.59-1.00). In conclusion, protective association between intake of raw garlic and lung cancer has been observed with a dose-response pattern, suggesting that garlic may potentially serve as a chemopreventive agent for lung cancer. Effective components in garlic in lung cancer chemoprevention warrant further in-depth investigation. PMID- 23658369 TI - MIZ1-regulated hydrotropism functions in the growth and survival of Arabidopsis thaliana under natural conditions. AB - BACKGROUND AND AIMS: Root hydrotropism is a response to water-potential gradients that makes roots bend towards areas of higher water potential. The gene MIZU KUSSEI1 (MIZ1) that is essential for hydrotropism in Arabidopsis roots has previously been identified. However, the role of root hydrotropism in plant growth and survival under natural conditions has not yet been proven. This study assessed how hydrotropic response contributes to drought avoidance in nature. METHODS: An experimental system was established for the study of Arabidopsis hydrotropism in soil. Characteristics of hydrotropism were analysed by comparing the responses of the miz1 mutant, transgenic plants overexpressing MIZ1 (MIZ1OE) and wild-type plants. KEY RESULTS: Wild-type plants developed root systems in regions with higher water potential, whereas the roots of miz1 mutant plants did not show a similar response. This pattern of root distribution induced by hydrotropism was more pronounced in MIZ1OE plants than in wild-type plants. In addition, shoot biomass and the number of plants that survived under drought conditions were much greater in MIZ1OE plants. CONCLUSIONS: These results show that hydrotropism plays an important role in root system development in soil and contributes to drought avoidance, which results in a greater yield and plant survival under water-limited conditions. The results also show that MIZ1 overexpression can be used for improving plant productivity in arid areas. PMID- 23658370 TI - Hydraulic resistance of developing Actinidia fruit. AB - BACKGROUND AND AIMS: Xylem flows into most fruits decline as the fruit develop, with important effects on mineral and carbohydrate accumulation. It has been hypothesized that an increase in xylem hydraulic resistance (RT) contributes to this process. This study examined changes in RT that occur during development of the berry of kiwifruit (Actinidia deliciosa), identified the region within the fruit where changes were occurring, and tested whether a decrease in irradiance during fruit development caused an increase in RT, potentially contributing to decreased mineral accumulation in shaded fruit. METHODS: RT was measured using pressure chamber and flow meter methods, the two methods were compared, and the flow meter was also used to partition RT between the pedicel, receptacle and proximal and distal portions of the berry. Dye was used as a tracer for xylem function. Artificial shading was used to test the effect of light on RT, dye entry and mineral accumulation. KEY RESULTS: RT decreased during the early phase of rapid fruit growth, but increased again as the fruit transitioned to a final period of slower growth. The most significant changes in resistance occurred in the receptacle, which initially contributed 20 % to RT, increasing to 90 % later in development. Dye also ceased moving beyond the receptacle from 70 d after anthesis. The two methods for measuring RT agreed in terms of the direction and timing of developmental changes in RT, but pressure chamber measurements were consistently higher than flow meter estimates of RT, prompting questions regarding which method is most appropriate for measuring fruit RT. Shading had no effect on berry growth but increased RT and decreased dye movement and calcium concentration. CONCLUSIONS: Increased RT in the receptacle zone coincides with slowing fresh weight growth, reduced transpiration and rapid starch accumulation by the fruit. Developmental changes in RT may be connected to changes in phloem functioning and the maintenance of water potential gradients between the stem and the fruit. The effect of shade on RT extends earlier reports that shading can affect fruit vascular differentiation, xylem flows and mineral accumulation independently of effects on transpiration. PMID- 23658371 TI - A comparative perspective on lipid storage in animals. AB - Lipid storage is an evolutionary conserved process that exists in all organisms from simple prokaryotes to humans. In Metazoa, long-term lipid accumulation is restricted to specialized cell types, while a dedicated tissue for lipid storage (adipose tissue) exists only in vertebrates. Excessive lipid accumulation is associated with serious health complications including insulin resistance, type 2 diabetes, cardiovascular diseases and cancer. Thus, significant advances have been made over the last decades to dissect out the molecular and cellular mechanisms involved in adipose tissue formation and maintenance. Our current understanding of adipose tissue development comes from in vitro cell culture and mouse models, as well as recent approaches to study lipid storage in genetically tractable lower organisms. This Commentary gives a comparative insight into lipid storage in uni- and multi-cellular organisms with a particular emphasis on vertebrate adipose tissue. We also highlight the molecular mechanisms and nutritional signals that regulate the formation of mammalian adipose tissue. PMID- 23658372 TI - High circulating estrogens and selective expression of ERbeta in prostate tumors of Americans: implications for racial disparity of prostate cancer. AB - Although estrogen receptor beta (ERbeta) has been implicated in prostate cancer (PCa) progression, its potential role in health disparity of PCa remains elusive. The objective of this study was to examine serum estrogens and prostate tumor ERbeta expression and examine their correlation with clinical and pathological parameters in African American (AA) versus Caucasian American (CA) men. The circulating 17beta-estradiol (E2) was measured by enzyme immunoassay in blood procured from racially stratified normal subjects and PCa patients. Differential expression profile analysis of ERbeta was analyzed by quantitative immunohistochemistry using ethnicity-based tissue microarray encompassing 300 PCa tissue cores. In situ ERbeta expression was validated by quantitative reverse transcription-PCR in matched microdissected normal prostate epithelium and tumor cells and datasets extracted from independent cohorts. In comparison with normal age-matched subjects, circulating E2 levels were significantly elevated in all PCa patients. Further analysis demonstrates an increase in blood E2 levels in AA men in both normal and PCa in comparison with age- and stage-matched counterparts of CA decent. Histochemical score analysis reveals intense nuclear immunoreactivity for ERbeta in tumor cores of AA men than in CA men. Gene expression analysis in microdissected tumors corroborated the biracial differences in ERbeta expression. Gene expression analysis from independent cohort datasets revealed correlation between ERbeta expression and PCa progression. However, unlike in CA men, adjusted multivariate analysis showed that ERbeta expression correlates with age at diagnosis and low prostate-specific antigen recurrence-free survival in AA men. Taken together, our results suggest that E2-ERbeta axis may have potential clinical utility in PCa diagnosis and clinical outcome among AA men. PMID- 23658373 TI - Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors. AB - BACKGROUND: Inhibition of the mammalian target of rapamycin (mTOR) is an established treatment for multiple malignancies. We carried out an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors. PATIENTS AND METHODS: PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to approved mTOR inhibitors (everolimus and temsirolimus) and reported on patients with cancer, randomized design and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: In all, 3193 patients from eight randomized, controlled trials (RCTs) were included, 2236 from everolimus trials and 957 from temsirolimus trials. The relative risk (RR) of FAEs related to mTOR inhibitors use was 2.20 (95% CI, 1.25-3.90; P = 0.006) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types [renal cell carcinoma (RCC) versus non RCC]. No evidence of publication bias was observed. CONCLUSION: The use of mTOR inhibitors is associated with a small but higher risk of FAEs compared to control patients. In the appropriate clinical scenario, the use of these drugs remains justified in their approved indications. PMID- 23658374 TI - Dynamic weighting of multisensory stimuli shapes decision-making in rats and humans. AB - Stimuli that animals encounter in the natural world are frequently time-varying and activate multiple sensory systems together. Such stimuli pose a major challenge for the brain: Successful multisensory integration requires subjects to estimate the reliability of each modality and use these estimates to weight each signal appropriately. Here, we examined whether humans and rats can estimate the reliability of time-varying multisensory stimuli when stimulus reliability changes unpredictably from trial to trial. Using an existing multisensory decision task that features time-varying audiovisual stimuli, we independently manipulated the signal-to-noise ratios of each modality and measured subjects' decisions on single- and multi-sensory trials. We report three main findings: (a) Sensory reliability influences how subjects weight multisensory evidence even for time-varying, stochastic stimuli. (b) The ability to exploit sensory reliability extends beyond human and nonhuman primates: Rodents and humans both weight incoming sensory information in a reliability-dependent manner. (c) Regardless of sensory reliability, most subjects are disinclined to make "snap judgments" and instead base decisions on evidence presented over the majority of the trial duration. Rare departures from this trend highlight the importance of using time varying stimuli that permit this analysis. Taken together, these results suggest that the brain's ability to use stimulus reliability to guide decision-making likely relies on computations that are conserved across species and operate over a wide range of stimulus conditions. PMID- 23658375 TI - Pediatric psychologist use of adherence assessments and interventions. AB - OBJECTIVE: To document current clinical practices for medical regimen adherence assessment and intervention in the field of pediatric psychology. METHODS: 113 members of the Society of Pediatric Psychology completed an anonymous online survey that assessed use of adherence assessments and interventions in clinical practice, barriers and facilitators to their use, and preferred resources for obtaining information on adherence assessments and interventions. RESULTS: Respondents reported using a range of adherence assessment and intervention strategies, some of which are evidence-based. Barriers to implementing these clinical strategies included time constraints and lack of familiarity with available clinical tools. Respondents reported that education about effective clinical tools would facilitate their use of adherence assessments and interventions. CONCLUSIONS: Future research and clinical efforts in adherence should consider developing practical tools for clinical practice, making accessible resources to promote dissemination of these tools, and increase understanding of clinician implementation of adherence assessments and interventions. PMID- 23658376 TI - Factor-Xa-induced mitogenesis and migration require sphingosine kinase activity and S1P formation in human vascular smooth muscle cells. AB - AIMS: Sphingosine-1-phosphate (S1P) is a cellular signalling lipid generated by sphingosine kinase-1 (SPHK1). The aim of the study was to investigate whether the activated coagulation factor-X (FXa) regulates SPHK1 transcription and the formation of S1P and subsequent mitogenesis and migration of human vascular smooth muscle cells (SMC). METHODS AND RESULTS: FXa induced a time- (3-6 h) and concentration-dependent (3-30 nmol/L) increase of SPHK1 mRNA and protein expression in human aortic SMC, resulting in an increased synthesis of S1P. FXa stimulated transcription of SPHK1 was mediated by the protease-activated receptor 1 (PAR-1) and PAR-2. In human carotid artery plaques, expression of SPHK1 was observed at SMC-rich sites and was co-localized with intraplaque FX/FXa content. FXa-induced SPHK1 transcription was attenuated by inhibitors of Rho kinase (Y27632) and by protein kinase C (PKC) isoforms (GF109203X). In addition, FXa rapidly induced the activation of the small GTPase Rho A. Inhibition of signalling pathways which regulate SPHK1 expression, inhibition of its activity or siRNA-mediated SPHK1 knockdown attenuated the mitogenic and chemotactic response of human SMC to FXa. CONCLUSION: These data suggest that FXa induces SPHK1 expression and increases S1P formation independent of thrombin and that this involves the activation of Rho A and PKC signalling. In addition to its key function in coagulation, this direct effect of FXa on human SMC may increase cell proliferation and migration at sites of vessel injury and thereby contribute to the progression of vascular lesions. PMID- 23658377 TI - 20-Hydroxyeicosatetraenoic acid inhibition attenuates balloon injury-induced neointima formation and vascular remodeling in rat carotid arteries. AB - 20-Hydroxyeicosatetraenoic acid (20-HETE) contributes to the migration and proliferation of vascular smooth muscle cells (VSMC) in vitro, but there are few studies that address its effects on vascular remodeling in vivo. The present study determined whether inhibition of 20-HETE production attenuates intimal hyperplasia (IH) and vascular remodeling after balloon injury (BI). Sprague Dawley rats underwent BI of the common carotid artery and were treated with vehicle, 1-aminobenzotriazole (ABT, 50 mg/kg i.p. once daily), or HET0016 (N hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine) (2 mg/kg s.c. twice daily) for 14 days. Fourteen days after BI and treatment, the animals underwent carotid angiography, and the arteries were harvested for morphometric, enzymatic and immunohistochemical analysis. There was a 96% reduction of angiographic stenosis in the rats treated with 1-ABT. There was a 61 and 66% reduction of the intima/media area ratios in the 1-ABT and HET0016 treated rats compared with the vehicle-treated group. 20-HETE levels were elevated in BI carotid arteries, and the levels were markedly suppressed in the groups treated with 1-ABT and HET0016 (P < 0.001). Immunostaining revealed that the expression of CYP4A enzyme was markedly increased in the neointima of BI arteries, and it colocalized with the expression of smooth muscle-specific actin, indicating increased proliferation of VSMC. An increase in the expression of CYP4A and the production of 20-HETE contributes to neointimal growth in BI rat carotid arteries. Systemic administration 1-ABT or HET0016 prevents the increase in 20-HETE levels and attenuates VSMC migration and proliferation, resulting in a marked reduction in IH and vascular remodeling after endothelial injury. PMID- 23658378 TI - Family history of idiopathic REM behavior disorder: a multicenter case-control study. AB - OBJECTIVE: To compare the frequency of proxy-reported REM sleep behavior disorder (RBD) among relatives of patients with polysomnogram-diagnosed idiopathic RBD (iRBD) in comparison to controls using a large multicenter clinic-based cohort. METHODS: A total of 316 patients with polysomnography-confirmed iRBD were recruited from 12 RBD study group centers, along with 316 controls matched on sex and age group. All subjects completed a self-administered questionnaire that collected proxy-reported information on family history of tremor, gait trouble, balance trouble, Parkinson disease, memory loss, and Alzheimer disease. The questionnaire also included a single question that asked about possible symptoms of RBD among first-degree relatives (siblings, parents, and children). RESULTS: A positive family history of dream enactment was reported in 13.8% of iRBD cases compared to 4.8% of controls (odds ratio [OR] = 3.9, 95% confidence interval [CI] 2.0-7.7). ORs were increased for both siblings (OR = 6.1, 95% CI 2.1-18.1) and parents (OR = 3.2, 95% CI 1.4-7.8). We found no significant difference in sex, current age (65.3 +/- 10.2 vs 66.9 +/- 10.2 years), or age at self-reported RBD onset (55.2 +/- 11.7 vs 56.6 +/- 15.1 years) in possible familial vs sporadic iRBD. No differences were found in family history of tremor, walking and balance troubles, Parkinson disease, memory loss, or Alzheimer disease. CONCLUSION: We found increased odds of proxy-reported family history of presumed RBD among individuals with confirmed iRBD. This suggests the possibility of a genetic contribution to RBD. PMID- 23658379 TI - Aquaporin-4 antibody-negative neuromyelitis optica: distinct assay sensitivity dependent entity. AB - OBJECTIVE: To optimize aquaporin-4 (AQP4) antibody (Ab) detection and to assess the influence of the increased sensitivity of the assay on the demographic and disease-related characteristics of a group of AQP4-Ab-negative patients. METHODS: Serum samples were obtained from patients included in the French NOMADMUS database with a definite diagnosis of neuromyelitis optica (NMO) (n = 87) and were compared with controls (n = 54). They were tested by indirect immunofluorescence and cell-based assays (CBAs) in various conditions and with several plasmids. RESULTS: We identified the CBA on live cells transfected with the untagged AQP4-M23 isoform as the best method, with a sensitivity of 74.4% and a specificity of 100%. We demonstrated a direct relationship between improvement of the sensitivity of the detection method and the distinctiveness and characteristics of the AQP4-Ab-negative NMO group. Whereas with the classic indirect immunofluorescence or current AQP4-M1 CBA we found only slight differences between the 2 populations, using the AQP4-M23 CBA, we demonstrated that patients with AQP4-Ab-negative NMO expressed specific demographic and disease-related features. They were characterized by an equal male/female ratio (p < 0.001), a Caucasian ethnicity (p = 0.029), and an overrepresentation of simultaneous optic neuritis and transverse myelitis at first episode (p = 0.015). In terms of disability, they experienced a better visual acuity at last follow-up compared with seropositive NMO (p = 0.007). CONCLUSION: This raises the question of a distinct physiopathology for patients with AQP4-Ab-negative NMO and of their place in the spectrum of the disease. PMID- 23658380 TI - Mild cognitive impairment: incidence and vascular risk factors in a population based cohort. AB - OBJECTIVE: We examined the incidence of mild cognitive impairment (MCI) and its potential vascular risk factors in a prospective population-based study. METHODS: An age-stratified random population-based cohort (baseline n = 1,982), followed for up to 4 years, was annually assessed for cognitive and everyday functioning. Incidence rates were calculated for both cognitive (neuropsychological [NP]-MCI) and functional (Clinical Dementia Rating [CDR] = 0.5) definitions of MCI. Several measures of vascular, metabolic, and inflammatory risk were assessed at baseline. Risk factor analyses used interval censoring survival models, followed by joint modeling of both MCI and attrition due to mortality and illness. RESULTS: Incidence rates for NP-MCI and CDR = 0.5 were 95 and 55 per 1,000 person-years. In individual joint models, risk factors for NP-MCI were diabetes and adiposity (waist: hip ratio), while APOE epsilon4 genotype and heart failure increased risk of attrition. Adiposity, stroke, heart failure, and diabetes were risk factors for nonamnestic MCI. For CDR = 0.5, risk factors were stroke and heart failure; heart failure and adiposity increased risk of attrition. In multivariable joint models combining all risk factors, adiposity increased risk of NP-MCI, while stroke and heart failure increased risk for CDR = 0.5. Current alcohol use appeared protective against all subtypes. CONCLUSION: Incidence of MCI increased with age regardless of definition and did not vary by sex or education. Several vascular risk factors elevated the risk of incident MCI, whether defined cognitively or functionally, but most were associated with nonamnestic MCI and CDR = 0.5. Controlling vascular risk may potentially reduce risk of MCI. PMID- 23658381 TI - Executive functions can help when deciding on the frontotemporal dementia diagnosis. PMID- 23658382 TI - Dissociable executive functions in behavioral variant frontotemporal and Alzheimer dementias. AB - OBJECTIVE: The objective of this study was to determine which aspects of executive functions are most affected in behavioral variant frontotemporal dementia (bvFTD) and best differentiate this syndrome from Alzheimer disease (AD). METHODS: We compared executive functions in 22 patients diagnosed with bvFTD, 26 with AD, and 31 neurologically healthy controls using a conceptually driven and comprehensive battery of executive function tests, the NIH EXAMINER battery (http://examiner.ucsf.edu). RESULTS: The bvFTD and the AD patients were similarly impaired compared with controls on tests of working memory, category fluency, and attention, but the patients with bvFTD showed significantly more severe impairments than the patients with AD on tests of letter fluency, antisaccade accuracy, social decision-making, and social behavior. Discriminant function analysis with jackknifed cross-validation classified the bvFTD and AD patient groups with 73% accuracy. CONCLUSIONS: Executive function assessment can support bvFTD diagnosis when measures are carefully selected to emphasize frontally specific functions. PMID- 23658383 TI - Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer. AB - OBJECTIVE: The aim of this study was to describe the clinical presentation of children and adolescents with anti-Hu antibodies (Hu-Abs). METHODS: This was a retrospective study of children and adolescents with Hu-Abs collected by the French Paraneoplastic Neurological Syndrome (PNS) Reference Center between January 1, 2000 and December 31, 2011. RESULTS: The center identified 251 patients with Hu-Abs. Only 8 patients were younger than 18 years. All of the 243 adult patients had PNS. In contrast, of the 8 children, only 2 (25%, Fisher exact test p = 0.0003) had neuroblastoma and opsoclonus-myoclonus. The other 6 children (5 female and 1 male) presented with limbic encephalitis (progressive personality changes, memory loss, and seizure) and were free of cancer (mean follow-up time: 50 months; range: 34-72 months). Brain MRI scans were abnormal in 4 of the 6 patients, with left, right, or bitemporal T2/fluid-attenuated inversion recovery hyperintensity. Protein levels and cell counts in the CSF were normal in all patients, but numerous oligoclonal bands were observed in 4 patients. All 6 patients received antiepileptic drugs and immunotherapy, but management of epilepsy was difficult in all of them. Five of the children developed cognitive impairments. CONCLUSION: In children, as in adults, Hu-Abs can be a marker of PNS. However, in contrast to adults, Hu-Abs in children are also associated with an aggressive form of autoimmune nonparaneoplastic limbic encephalitis. Future studies should be conducted to determine the incidence of this syndrome and whether earlier diagnosis and T-cell-directed immunotherapies may improve its prognosis. PMID- 23658384 TI - Vestibular impairment in patients with Charcot-Marie-tooth disease. AB - OBJECTIVE: This case-control study aimed to determine whether the imbalance in Charcot-Marie-tooth (CMT) disease is caused only by reduced proprioceptive input or whether the involvement of the vestibular nerve is an additional factor. METHODS: Fifteen patients with CMT disease (aged 48 +/- 17 years; 8 women) underwent cervical vestibular-evoked myogenic potentials, which reflect otolith spinal reflex function, and quantitative horizontal search-coil head-impulse testing, which assesses the high-acceleration vestibulo-ocular reflex of the semicircular canals. RESULTS: Relative to healthy age-matched control subjects, cervical vestibular-evoked myogenic potentials were found to be impaired in 75% of patients (average p13 latency: 23.0 +/- 2.7 milliseconds, p = 0.01; average n23 latency: 29.0 +/- 1.8 milliseconds, p = 0.01) and the quantitative head impulse test in 60% of patients (average gain +/- 1 SD: 0.67 +/- 0.24, p < 0.001). All patients with head-impulse test impairment also showed cervical vestibular-evoked myogenic potential abnormalities, while the reverse was not true. CONCLUSIONS: We conclude that the neuropathic process in patients with CMT disease frequently involves the vestibular nerve and that cervical vestibular evoked myogenic potentials may be more sensitive than quantitative head-impulse testing for detecting vestibular involvement, in particular at an early disease stage. PMID- 23658385 TI - Isolated buccofacial apraxia subsequent to a left ventral premotor cortex infarction. AB - Buccofacial apraxia (BFA, or oral apraxia) is a nonspeech skilled movement disorder that involves orofacial structures in the absence of paresis. BFA usually co-occurs with aphasia or apraxia of speech (AOS) and isolated BFA is an extremely rare phenomenon. The brain regions correlated with BFA have been studied in patients with concomitant aphasia or limb apraxia. Therefore, the exact brain regions responsible for BFA remain unclear. We report a patient with pure BFA and discuss the localization of the brain lesion. PMID- 23658386 TI - Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2. AB - OBJECTIVE: To describe the clinical and neurophysiologic phenotype of a family with hereditary sensory and autonomic neuropathy type 1 (HSANI) due to a novel mutation in SPTLC2 and to characterize the biochemical properties of this mutation. METHODS: We screened 107 patients with HSAN who were negative for other genetic causes for mutations in SPTLC2. The biochemical properties of a new mutation were characterized in cell-free and cell-based activity assays. RESULTS: A novel mutation (A182P) was found in 2 subjects of a single family. The phenotype of the 2 subjects was an ulcero-mutilating sensory-predominant neuropathy as described previously for patients with HSANI, but with prominent motor involvement and earlier disease onset in the first decade of life. Affected patients had elevated levels of plasma 1-deoxysphingolipids (1-deoxySLs). Biochemically, the A182P mutation was associated with a reduced canonical activity but an increased alternative activity with alanine, which results in largely increased 1-deoxySL levels, supporting their pathogenicity. CONCLUSION: This study confirms that mutations in SPTLC2 are associated with increased deoxySL formation causing HSANI. PMID- 23658387 TI - Seronegative NMO: a sensitive AQP4 antibody test clarifies clinical features and next challenges. PMID- 23658388 TI - Can fully automated detection of corticospinal tract damage be used in stroke patients? AB - OBJECTIVE: We compared manual infarct definition, which is time-consuming and open to bias, with an automated abnormal tissue detection method in measuring corticospinal tract-infarct overlap volumes in chronic stroke patients to help predict motor outcome. METHODS: Using diffusion tensor imaging and probabilistic tractography, 4 corticospinal tracts from the primary motor cortex, dorsal and ventral premotor cortices, and supplementary motor area to the ipsilateral lower pons were reconstructed in 23 healthy controls. Tract-infarct overlap volume of each of the 4 corticospinal tracts was determined by overlapping the patients' lesions onto the control tract templates, using both manually and automatically defined infarcts in 51 patients. Correlations with upper limb motor impairment were assessed and both methods were directly compared using intraclass correlations (ICC). RESULTS: Greater impairment was seen in patients with greater corticospinal tract-infarct overlap with either method (rmanual range = 0.32 0.46; rautomated range = 0.42-0.57). Consistency between manual and automated methods was good to excellent for all 4 corticospinal tracts (ICC range = 0.71 0.80). CONCLUSIONS: Our results demonstrate that automated infarct identification performs equally as well as a manual method in quantifying corticospinal tract infarct overlap following stroke. PMID- 23658389 TI - Marital status and its relationship with the risk and pattern of visual impairment in a multi-ethnic Asian population. AB - BACKGROUND: To examine whether marital status is a significant determinant of visual impairment (VI) in urban multi-ethnic Asian population. METHODS: We conducted a population-based study of Singapore-resident ethnic Malays, Indians and Chinese aged >=40 years. Ophthalmic examination included the assessment of presenting and best-corrected visual acuity (PVA and BCVA) using standardized procedures. Information regarding marital status and socioeconomic status were obtained from an interviewer-administered questionnaire. RESULTS: Among the 10 033 participants, 7756 (77.3%) were married; 589 (5.9%) were single; 407 (4.1%) were separated and 1265 (12.6%) were widowed. Being single (never married) or widowed were significantly associated with best-corrected VI (BCVA < 20/40) and presenting VI (PVA < 20/40) (odds ratios: 1.37-1.59) compared with married people even after adjustment for age, sex and socioeconomic status. A marginal prediction model showed that the negative effect of unmarried status on VI increased with age and was stronger among Malays and Indians, but the influence did not vary with gender, educational level and diabetic status. CONCLUSIONS: Unmarried status is associated with VI, particularly among elderly Malays and Indians. Our findings suggest that single and widowed adults may benefit from specific social support and eye care programmes. PMID- 23658390 TI - Non-compliance with the International Code of Marketing of Breast Milk Substitutes is not confined to the infant formula industry. AB - Infant feeding policy and practice continues to be a contentious area of global health care. The infant formula industry is widely considered to be the bete noire with frequent claims that they adopt marketing and sales practices that are not compliant with the WHO Code. However, failure to resolve these issues over three decades suggests that there may be wider systemic failings. Review of published papers, commentaries and reports relating to the implementation and governance of the WHO Code with specific reference to issues of non-compliance. The analysis set out in this paper indicates that there are systemic failings at all levels of the implementation and monitoring process including the failure of WHO to successfully 'urge' governments to implement the Code in its entirety; a lack of political will by Member States to implement and monitor the Code and a lack of formal and transparent governance structures. Non-compliance with the WHO Code is not confined to the infant formula industry and several actions are identified, including the need to address issues of partnership working and the establishment of governance systems that are robust, independent and transparent. PMID- 23658391 TI - Lack of serum antibodies against Borrelia burgdorferi in children with autism. AB - It has been proposed that Borrelia burgdorferi infection is present in ~25% of children with autism spectrum disorders. In this study, antibodies against Borrelia burgdorferi were assessed in autistic (n = 104), developmentally delayed (n = 24), and healthy control (n = 55) children. No seropositivity against Borrelia burgdorferi was detected in the children with and without autism. There was no evidence of an association between Lyme disease and autism. PMID- 23658392 TI - Evaluation of immunogenicity and efficacy of anthrax vaccine adsorbed for postexposure prophylaxis. AB - Antimicrobials administered postexposure can reduce the incidence or progression of anthrax disease, but they do not protect against the disease resulting from the germination of spores that may remain in the body after cessation of the antimicrobial regimen. Such additional protection may be achieved by postexposure vaccination; however, no anthrax vaccine is licensed for postexposure prophylaxis (PEP). In a rabbit PEP study, animals were subjected to lethal challenge with aerosolized Bacillus anthracis spores and then were treated with levofloxacin with or without concomitant intramuscular (i.m.) vaccination with anthrax vaccine adsorbed (AVA) (BioThrax; Emergent BioDefense Operations Lansing LLC, Lansing, MI), administered twice, 1 week apart. A significant increase in survival rates was observed among vaccinated animals compared to those treated with antibiotic alone. In preexposure prophylaxis studies in rabbits and nonhuman primates (NHPs), animals received two i.m. vaccinations 1 month apart and were challenged with aerosolized anthrax spores at day 70. Prechallenge toxin-neutralizing antibody (TNA) titers correlated with animal survival postchallenge and provided the means for deriving an antibody titer associated with a specific probability of survival in animals. In a clinical immunogenicity study, 82% of the subjects met or exceeded the prechallenge TNA value that was associated with a 70% probability of survival in rabbits and 88% probability of survival in NHPs, which was estimated based on the results of animal preexposure prophylaxis studies. The animal data provide initial information on protective antibody levels for anthrax, as well as support previous findings regarding the ability of AVA to provide added protection to B. anthracis-infected animals compared to antimicrobial treatment alone. PMID- 23658393 TI - Cytolytic activity of the human papillomavirus type 16 E711-20 epitope-specific cytotoxic T lymphocyte is enhanced by heat shock protein 110 in HLA-A*0201 transgenic mice. AB - Heat shock proteins (HSPs) have been successfully applied to a broad range of vaccines as biological adjuvants to enhance the immune response. The recently defined HSP110, in particular, exhibits strong protein binding affinity and is capable of enhancing the immunogenicity of protein antigens remarkably more than other HSP family members. In our previous study, we verified that murine HSP110 (mHSP110) significantly enhanced the immune response of a C57BL/6 mouse model to the H-2(d)-restricted human papillomavirus (HPV) E749-57 epitope (short peptide spanning the 49th to 57th amino acid residues in the E7 protein). To determine whether HSP110 similarly enhances the immunogenicity of human epitope peptides, we used the HLA-A2 transgenic mouse model to investigate the efficacy of the mHSP110 chaperone molecule as an immunoadjuvant of the human HLA-A2-restricted HPV16 E711-20 epitope vaccine. Results showed that mHSP110 efficiently formed a noncovalently bound complex with the E711-20 epitope. The mHSP110-E711-20 complex induced epitope-specific splenocyte proliferation and E711-20-specific gamma interferon (IFN-gamma) secretion. Importantly, cytotoxic T lymphocytes primed by the mHSP110-E711-20 complex exerted strong cytolytic effects on target T2 cells pulsed with the E711-20 peptide or TC-1 cells transfected with the HLA-A2 gene. In addition, the mHSP110-E711-20 complex elicited stronger ex vivo and in vivo antitumor responses than either emulsified complete Freund's adjuvant or HSP70 chaperoned E711-20 peptide. These collective data suggest that HSP110 is a promising immunomodulator candidate for peptide-based human cancer vaccines, such as for the HLA-A2-restricted E711-20 epitope. PMID- 23658394 TI - Concentration and high avidity of pneumococcal antibodies persist at least 4 years after immunization with pneumococcal conjugate vaccine in infancy. AB - To provide more extensive evidence of long-term effects of vaccination on immunity against Streptococcus pneumoniae, a follow-up study of the Finnish Otitis Media (FinOM) Vaccine Trial was conducted. One of the objectives was to assess the persistence and avidity of pneumococcal antibodies 4 years after pneumococcal vaccination given in infancy. Children with complete follow-up in the FinOM trial up to 24 months of age were invited to a single visit in their fifth year of life. A blood sample was taken from all children for determination of anticapsular antibody concentrations to vaccine serotypes and avidity of antibodies to three serotypes. Children had been vaccinated at 2, 4, 6, and 12 months of age with 7-valent pneumococcal capsular polysaccharide, CRM197 conjugate vaccine (PCV7), or a control vaccine. Serum IgG antibody concentrations to vaccine serotypes remained significantly higher in children who had received PCV7 than in control children for 4 years after the fourth PCV7 dose. Concentrations of antibodies to frequently carried serotypes (6B and 19F) declined less than those of antibodies to a rarely carried serotype (4), suggesting that natural boosting contributed to antibody persistence. Furthermore, antibody avidity was significantly higher in PCV7 than control vaccine recipients. Four doses of PCV7 given in infancy elicit long-lasting antibody responses with high avidity. (This study has been registered at ClinicalTrials.gov under registration no. NCT00378417.). PMID- 23658395 TI - Use of electronic cigarettes among state tobacco cessation quitline callers. AB - INTRODUCTION: Little is known about the prevalence of electronic cigarette (e cigarette) use among tobacco users who seek help from state tobacco quitlines, the reasons for its use, and whether e-cigarettes impact a user's ability to successfully quit tobacco. This study investigates these questions and describes differences among state quitline callers who used e-cigarettes for 1 month or more, used e-cigarettes for less than 1 month, or never tried e-cigarettes. METHODS: Data on e-cigarette use were collected from 2,758 callers to 6 state tobacco quitlines 7 months after they received intervention from the quitline program. RESULTS: Nearly one third (30.9%) of respondents reported ever using or trying e-cigarettes; most used for a short period of time (61.7% for less than 1 month). The most frequently reported reasons for use were to help quit other tobacco (51.3%) or to replace other tobacco (15.2%). Both e-cigarette user groups were significantly less likely to be tobacco abstinent at the 7-month survey compared with participants who had never tried e-cigarettes (30-day point prevalence quit rates: 21.7% and 16.6% vs. 31.3%, p < .001). Demographic differences between the 3 groups are discussed. CONCLUSIONS: This study offers a preliminary look at e-cigarette use among state quitline callers and is perhaps the first to describe e-cigarette use in a large group of tobacco users seeking treatment. The notable rates of e-cigarette use and use of e-cigarettes as cessation aids, even though the U.S. Food and Drug Administration has not approved e-cigarettes for this purpose, should inform policy and treatment discussions on this topic. PMID- 23658396 TI - Association between 8-oxo-7,8-dihydro-2'-deoxyguanosine excretion and risk of postmenopausal breast cancer: nested case-control study. AB - BACKGROUND: Oxidative stress may be important in carcinogenesis and a possible risk factor for breast cancer. The urinary excretion of oxidatively generated biomolecules, such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), represents biomarkers of oxidative stress, reflecting the rate of global damage to DNA in steady state. METHODS: In a nested case-control design, we examined associations between urinary excretion of 8-oxodG and risk of breast cancer in a population based cohort of 24,697 postmenopausal women aged 50 to 64 years with 3 to 7 years follow-up. The accruing cases of breast cancer were matched to controls by age at diagnosis, baseline age, and hormone replacement therapy (HRT). Spot urine samples collected at entry was analyzed for 8-oxodG by high-performance liquid chromatography with electrochemical detection. Incidence rate ratio (IRR; 95% confidence intervals) based on 336 matched pairs with all information was estimated per unit increase in 8-oxodG divided by creatinine for all and estrogen receptor (ER) positive and negative breast cancers. RESULTS: There was a borderline significant positive association between 8-oxodG and risk of all breast cancer (IRR: 1.08; 1.00-1.17 per unit increase in nmol/mmol creatinine). This association was significant with respect to the risk of ER-positive cancer (IRR: 1.11; 1.01-1.23) and among women not using HRT (IRR: 1.11; 0.97-1.26) or with low dietary iron intake (IRR: 1.10; 1.06-1.37 per unit increase) for all breast cancer. CONCLUSIONS: We observed positive association between 8-oxodG excretion and risk of especially ER-positive breast cancer. IMPACT: Our results suggest that oxidative stress with damage to DNA is important for the development of breast cancer. PMID- 23658397 TI - With growing evidence of successful methods to increase student diversity, what's needed now is commitment. PMID- 23658398 TI - Long-term outcomes of a dental postbaccalaureate program: increasing dental student diversity and oral health care access. AB - The University of California, San Francisco School of Dentistry established the Dental Postbaccalaureate Program in 1998 to provide reapplication assistance to students from economically and/or educationally disadvantaged backgrounds who were previously denied admission to dental school. The goals were to increase diversity in the dental school student population and improve access to dental services for underserved populations. This article assesses the program's short-, mid-, and long-term outcomes and is the first to examine long-term practice patterns after a dental postbaccalaureate program. Data collected on all participant (n=94) demographics, pre/post-program DAT scores, and post-program dental school admission results were used to assess short- and mid-term outcomes. Long-term outcomes and practice patterns were assessed using results of a census survey administered between 2009 and 2011 to the participants who had completed dental school and been in practice for at least two years (n=57). The survey had a response rate of 93 percent (n=53). Descriptive statistical techniques were used to examine the responses and to compare them to U.S. Census Bureau data and nationally available practice data for new dental graduates. Program participants' DAT scores improved by an average of two points, and 98 percent were accepted to dental school. All survey respondents were practicing dentistry, and 81 percent reported serving underserved populations. These participants treat more Medicaid recipients than do most dentists, and their patient population is more diverse than the general population. The outcomes demonstrate that the program's graduates are increasing diversity in the dental student population and that their practices are providing access to care for underserved populations. PMID- 23658400 TI - A survey of degree completion programs in dental hygiene education. AB - The purpose of this descriptive study was to identify specific information related to U.S. dental hygiene baccalaureate degree completion programs. Learning experiences, assessment methods, and baccalaureate institutional partnerships were assessed. Of the sixty dental hygiene programs that offer a degree completion program, the forty-two that met the inclusion criteria (including having operated for at least three years) were invited to participate in a thirty eight item online survey. A 62 percent (n=26) response rate was obtained. Learning experiences in responding programs included core dental hygiene courses, general education courses, and elective dental hygiene courses. Emphasis areas offered by various programs were in the specialty areas of education, public or community health, and research. Respondents reported that their graduates were employed in multiple settings (65 percent; n=17), with 19 percent (n=5) reporting employment in the combined grouping of private practice, education, and public health. Institutional partnerships included articulation agreements (88 percent; n=21), community college baccalaureate (8 percent; n=2), and university extension (4 percent; n=1) models. The findings of this study provide a baseline for assessing the educational composition and design of U.S. dental hygiene degree completion programs. However, results of this study showed inconsistencies among learning experiences that might raise concerns when considering students' level of preparation for graduate education and future leadership roles in the profession. PMID- 23658399 TI - Increasing dental student diversity through the UNLV Dental Prospects Program. AB - Adequately providing for the health care of the growing minority population in the United States requires increased racial and ethnic diversity of the health care workforce. Long-term diversity in the dental profession depends on a more diverse student population in dental schools. The University of Nevada, Las Vegas School of Dental Medicine's (UNLV SDM) Dental Prospects Club is a predental education program that has increased the number of underrepresented minority and disadvantaged students in the school by concentrating on outreach, recruitment, and retention initiatives. The approaches used by the club members and faculty advisors to increase the number of underrepresented minority students recruited to and enrolled in the UNLV SDM are discussed in this report. Also described are the strategies, methods, internal infrastructure, and organizational support used to increase the number of underrepresented minority students at the school. PMID- 23658401 TI - Framework for e-learning assessment in dental education: a global model for the future. AB - The framework presented in this article demonstrates strategies for a global approach to e-curricula in dental education by considering a collection of outcome assessment tools. By combining the outcomes for overall assessment, a global model for a pilot project that applies e-assessment tools to virtual learning environments (VLE), including haptics, is presented. Assessment strategies from two projects, HapTEL (Haptics in Technology Enhanced Learning) and UDENTE (Universal Dental E-learning), act as case-user studies that have helped develop the proposed global framework. They incorporate additional assessment tools and include evaluations from questionnaires and stakeholders' focus groups. These measure each of the factors affecting the classical teaching/learning theory framework as defined by Entwistle in a standardized manner. A mathematical combinatorial approach is proposed to join these results together as a global assessment. With the use of haptic-based simulation learning, exercises for tooth preparation assessing enamel and dentine were compared to plastic teeth in manikins. Equivalence for student performance for haptic versus traditional preparation methods was established, thus establishing the validity of the haptic solution for performing these exercises. Further data collected from HapTEL are still being analyzed, and pilots are being conducted to validate the proposed test measures. Initial results have been encouraging, but clearly the need persists to develop additional e-assessment methods for new learning domains. PMID- 23658402 TI - Predoctoral dental implant education at Creighton University School of Dentistry. AB - The purpose of this report is to describe the dental implant education that predoctoral students receive and to characterize the patient population receiving implants at Creighton University School of Dentistry (CDS). CDS has no postdoctoral residency programs. Therefore, clinical management of diagnosis, treatment planning, surgical aspects, restoration, complications, and maintenance of dental implants requires significant involvement by predoctoral dental students. CDS implant education involves radiology diagnostic assets of the General Dentistry Department (including the use of Cone Beam Computed Tomography), as well as faculty and equipment from the Departments of Oral and Maxillofacial Surgery, Periodontics, and Prosthodontics, with a majority of students satisfied with their didactic preparation for their clinical experiences. Focusing on a three-year window from August 2007 to August 2010 and using electronic health records, this study found that a total of 242 implants were placed, out of which six failed within one year of placement and had to be removed. The average age of the population of 153 patients was found to be 53.3 years, with a range of eighteen to eighty-nine. Treatment outcomes compared very favorably with those published in the literature. PMID- 23658403 TI - Oral health education for pediatric nurse practitioner students. AB - The aim of this study was to evaluate whether an interdisciplinary, multifaceted oral health education program delivered to pediatric nurse practitioner students at the University of California, San Francisco, would improve their knowledge, confidence, attitudes, and behaviors regarding the provision of oral health assessments, consultations, referrals, and services to young children during well child visits. Thirty pediatric nurse practitioner students were included in the study. Participants completed a written survey before and after receiving an interdisciplinary educational intervention that included didactic education, simulation exercises, and clinical observation by a pediatric dental resident. Between pre-intervention and post-intervention, a significant improvement was seen in the pediatric nurse practitioners' knowledge of oral health topics (p<0.001), confidence when providing oral health counseling (p<0.001), and attitudes about including oral health counseling in their examinations (p=0.006). In the post-intervention survey, 83 percent of the subjects reported having incorporated oral examinations into their well-child visits. Our study suggests that providing an interdisciplinary oral health educational program for pediatric nurse practitioner students can improve their knowledge, confidence, attitudes, and behaviors regarding the incorporation of oral health care services during routine well-child visits. PMID- 23658404 TI - Electronic health records: a valuable tool for dental school strategic planning. AB - The objective of this study was to investigate if electronic patient records have utility in dental school strategic planning. Electronic health records (EHRs) have been used by all predoctoral students and faculty members at Nova Southeastern University's College of Dental Medicine (NSU-CDM) since 2006. The study analyzed patient demographic and caries risk assessment data from October 2006 to May 2011 extracted from the axiUm EHR database. The purpose was to determine if there was a relationship between high oral health care needs and patient demographics, including gender, age, and median income of the zip code where they reside in order to support dental school strategic planning including the locations of future satellite clinics. The results showed that about 51 percent of patients serviced by the Broward County-based NSU-CDM oral health care facilities have high oral health care needs and that about 60 percent of this population resides in zip codes where the average income is below the median income for the county ($41,691). The results suggest that EHR data can be used adjunctively by dental schools when proposing potential sites for satellite clinics and planning for future oral health care programming. PMID- 23658405 TI - Can dental students be taught to use dental radiographs for osteoporosis screening? AB - This study investigated the possibility of teaching dental students to detect radiographic changes suggestive of osteoporosis. Twenty-five panoramic radiographs from dental school patients with a history of osteoporosis and radiographic changes suggestive of the disease and twenty-five normal panoramic radiographs were selected by a clinician from the database of the College of Dentistry, University of Tennessee Health Science Center. Twenty students were taught to use the mandibular cortical index (MCI) and detect changes suggestive of osteoporosis. Students also used a five-point scale to determine the diagnostic accuracy of panoramic images for osteoporosis. Intraclass Correlation Coefficient (ICCC) and Cronbach's alpha internal coefficiency statistical tests were used to evaluate interrater reliability among the twenty students and between the students and the radiologist. To test for differences in diagnosis between the gold standard (dental clinician) and the oral radiologist, we performed a McNemar's chi-square test for matched data. The interrater consistency was excellent for both the students (alpha=0.902) and between the students and the radiologist (alpha=0.909). The diagnostic accuracy of panoramic images was moderate (Az=0.81). No statistically significant difference between radiographic and clinical evaluations (McNemar's chi-square=3.063; p=0.0801) was observed. Teaching dental students to recognize radiographic changes suggestive of osteoporosis in routine panoramic radiographs should be emphasized to improve their awareness and identification of this disease. PMID- 23658406 TI - Current trends in community-based clinical teaching programs in U.K.and Ireland dental schools. AB - Community-based clinical teaching/outreach programs using a variety of approaches have been established in many predoctoral dental schools around the world. The aim of this article is to report current trends in the teaching of community based clinical teaching/outreach teaching in dental schools in the United Kingdom and Ireland. In late 2010-early 2011, a questionnaire was distributed by e-mail to deans of the eighteen established dental schools in the United Kingdom and Ireland. The questionnaire included both open and closed questions relating to current and anticipated trends in community-based clinical teaching. Fourteen responses were received (response rate=78 percent). All fourteen responding schools reported inclusion of a community-based clinical teaching program. Ten schools indicated that their program was based on total patient (comprehensive) care including the treatment of child patients. In nine schools, the program is directed by a senior clinical academic in restorative dentistry. As well as student dentists, ten schools and seven schools include teaching of student dental therapists and student dental hygienists, respectively. There is a varied experience within the schools surveyed in terms of the extent, nature, and content of these programs. Overall, however, community-based clinical teaching was seen as part of the future of dental school education in many schools as an ideal way of preparing graduates for Dental Foundation Training and subsequent independent practice. PMID- 23658407 TI - A critical appraisal of holistic teaching and its effects on dental student learning at University of Bergen, Norway. AB - The curriculum of the dental faculty at the University of Bergen, Norway, was revised and a new curriculum implemented in 1998 based on the principles of holistic teaching and patient-centered treatment. The first candidates graduated in 2003. The change of curricula, experience gained, and lack of an evidence base for holistic teaching justify a general discussion of all relevant aspects associated with this approach. The purpose of this article was to make a contribution towards such a discussion. A PubMed search regarding holistic teaching in dentistry was performed. Of the 211 entries on holistic teaching, few discussed holism in depth; none reported outcome measures comparing old and new curricula. Data collected from students graduating in 2003 (new curriculum) and 2000 (old curriculum) on their satisfaction with the teaching comprise a possible outcome measure. In most respects, using prosthodontics as an example, no differences between the two groups of students were found. Students studying under the new holistic curriculum were less satisfied than those studying under the old one regarding the number of available teachers and teachers' feedback on student performance. Both holistic teaching/patient-centered treatment and a more traditional subject-specific approach have advantages and disadvantages, and neither can be practiced in its pure form for ethical and practical reasons. The quantitative results of this study did not support the hypothesis that holism improved students' satisfaction with the teaching. A wide discussion of holism in dental education is needed, along with outcome measures when curricula are changed. PMID- 23658408 TI - Dental students' familiarity with the medical management of dental patients at Brazilian dental schools. AB - Drug therapy in dentistry is essential for patients' treatment and requires special care by dentists, so it must be part of a well-grounded education for predoctoral dental students. The aim of this study was to evaluate the knowledge of undergraduate students at dental schools in Brazil about the use of drugs in dental practice. The sample universe was comprised of all undergraduates enrolled in the last year of the dentistry course in three universities in 2010 (n=253). Inclusion criteria were students in their last year of enrollment and who agreed to participate in the research. The results were analyzed on Epi Info 3.5.1 software. Analyses were conducted with chi-square, Friedman, and Wilcoxon tests. Slightly more than half of the participants (51.9 percent) reported the ideal dose of anesthetic for a normal patient. However, their difficulties increased when asked about the relationship between the anesthetic and patients with systemic disease or those needing special care. Regarding drugs that usually cause allergic attack, only 29.2 percent and 36.6 percent, respectively, cited methyl methacrylate and latex. This study found that the knowledge of these undergraduates about the questions was deficient, so dental education should include more theoretical and clinical practice in recognizing the patient's medical needs. PMID- 23658409 TI - Teaching model for artificial teeth and endodontic apex locators. AB - Artificial teeth are a useful teaching aid during endodontic education. This article describes the development of a simple and inexpensive model that can be equipped with artificial teeth. It shows that working length determination in artificial root canals using electronic apex locators is possible and that the embedding media has no influence on measurements. The model supports the application of current endodontic techniques and facilitates a validated evaluation of the treatments between students. Artificial teeth can be removed for visualization and replaced for further endodontic exercises. PMID- 23658410 TI - Development of undergraduate gerodontology courses in Austria, Switzerland, and Germany from 2004 to 2009. AB - The growing number of individuals over the age of sixty-five with specific dental needs requires increased teaching efforts to adequately prepare predoctoral dental students. The study assessed whether such increases in undergraduate gerodontology teaching in German-speaking countries between 2004 and 2009 occurred. Questionnaires were mailed in 2004 and 2009 to all deans (n=37) and all department heads (n=140) of Austrian, Swiss, and German dental schools. Results show that gerodontology is still mostly included in traditional core subjects but that specific lecture series and practical teaching have increased. These cover a broad variety of subjects including geriatric medicine, gerontopsychiatry, nursing care, pharmacology, and public health. The number of departments with dedicated staff for gerodontology, research activities, and mean number of publications has increased. Barriers to the further integration of the subject include its continued exclusion from final examinations in Austria and Germany. Guidelines of the European College of Gerodontology (2009), which aim to prepare students to provide dental treatment to seniors by teaching theoretical knowledge, practical skills, patient management techniques, and the ethical foundation of gerodontology, need to be implemented. Continued professional education of faculty in all departments, intensified cooperation between universities, and the presence of faculty specializing in gerodontology are suggested. PMID- 23658411 TI - Structured student-generated videos for first-year students at a dental school in Malaysia. AB - Student-generated videos provide an authentic learning experience for students, enhance motivation and engagement, improve communication skills, and improve collaborative learning skills. This article describes the development and implementation of a student-generated video activity as part of a knowledge, observation, simulation, and experience (KOSE) program at the School of Dentistry, International Medical University, Kuala Lumpur, Malaysia. It also reports the students' perceptions of an activity that introduced first-year dental students (n=44) to clinical scenarios involving patients and dental team aiming to improve professional behavior and communication skills. The learning activity was divided into three phases: preparatory phase, video production phase, and video-watching. Students were organized into five groups and were instructed to generate videos addressing given clinical scenarios. Following the activity, students' perceptions were assessed with a questionnaire. The results showed that 86 percent and 88 percent, respectively, of the students agreed that preparation of the activity enhanced their understanding of the role of dentists in provision of health care and the role of enhanced teamwork. In addition, 86 percent and 75 percent, respectively, agreed that the activity improved their communication and project management skills. Overall, the dental students perceived that the student-generated video activity was a positive experience and enabled them to play the major role in driving their learning process. PMID- 23658412 TI - Learning experience in endodontics: Brazilian students' perceptions. AB - Including students' perceptions in the educational process is considered a key component in monitoring the quality of academic programs. This study aimed to evaluate the concept of one's learning experience in endodontic teaching from the perspective of a group of Brazilian students. A total of 126 self-administered, structured questionnaires were distributed to undergraduate dental students enrolled in endodontics courses during the second semester of the 2009 academic year. The questionnaires were administered during final examinations and focused on students' opinions concerning learning during endodontic treatments, time spent during endodontic treatments, difficulties found during endodontic treatments, quality of endodontic treatments performed, characteristics of the technique employed, and suggestions to improve endodontic teaching. Ninety-one percent of the questionnaires were returned for evaluation. The obtained answers were discussed and analyzed, thereby generating quantitative and qualitative data showing students' perceptions of their experiences in endodontics courses. The main points that can affect the teaching of endodontics, according to the undergraduate students, included patients' absences and delays, selection of patients, preclinical and clinical training, difficulties found, type of technique employed, and teachers' orientation during endodontic treatment. The students' perceptions provided valuable information about the development of the course and the teacher-student relationship, together with the added intention of enhancing the teaching of endodontics as well as other courses. PMID- 23658413 TI - Undergraduate dental English education in Japanese dental schools. AB - Dental schools in Japan are among many worldwide whose medium of instruction is not in English. With advances in science, technology, and communication, the demand for the globalization of professions increases. At present, dental schools in Asia, the Middle East, and Europe have started revising their dental curricula to either include English courses for dentistry or offer a full English dental curriculum. In Japan, dental English courses started to be introduced into curricula in the early 1990s. However, a survey conducted in 1999 found that English courses were not offered in Japan's twenty-nine dental schools and there was no consensus as to what such courses should include or when and how they should be taught. Ten years after that survey, the survey results reported in this article found that the problems reported in the 1999 survey still exist. Additionally, there are still differences among schools offering English courses in terms of the timing and contents of the courses. Since teachers and school officials will have an important role in curriculum development, this article recommends that a fact-finding meeting with educators, school, and education officials be initiated to discuss, develop, and implement a core curriculum for these dental English courses. PMID- 23658415 TI - Neoadjuvant short-course hyperfractionated accelerated radiotherapy (SC-HART) combined with S-1 for locally advanced rectal cancer. AB - The purpose of this study was to examine the safety and feasibility of a novel protocol of neoadjuvant short-course hyperfractionated accelerated radiotherapy (SC-HART) combined with S-1 for locally advanced rectal cancer. A total of 56 patients with lower rectal cancer of cT3N1M0 (Stage III b) was treated with SC HART followed by radical surgery, and were analyzed in the present study. SC-HART was performed with a dose of 2.5 Gy twice daily, with an interval of at least 6 hours between fractions, up to a total dose of 25 Gy (25 Gy in 10 fractions for 5 days) combined with S-1 for 10 days. Radical surgery was performed within three weeks following the end of the SC-HART. The median age was 64.6 (range, 39-85) years. The median follow-up term was 16.3 (range, 2-53) months. Of the 56 patients, 53 (94.4%) had no apparent adverse events before surgery; 55 (98.2%) completed the full course of neoadjuvant therapy, while one patient stopped chemotherapy because of Grade 3 gastrointestinal toxicity (CTCAE v.3). The sphincter preservation rate was 94.6%. Downstaging was observed in 45 patients (80.4%). Adjuvant chemotherapy was administered to 43 patients (76.8%). The local control rate, disease-free survival rate and disease-specific survival rate were 100%, 91.1% and 100%, respectively. To conclude, SC-HART combined with S-1 for locally advanced rectal cancer was well tolerated and produced good short-term outcomes. SC-HART therefore appeared to have a good feasibility for use in further clinical trials. PMID- 23658414 TI - Vitamin E: tocopherols and tocotrienols as potential radiation countermeasures. AB - Despite the potential devastating health consequences of intense total-body irradiation, and the decades of research, there still remains a dearth of safe and effective radiation countermeasures for emergency, radiological/nuclear contingencies that have been fully approved and sanctioned for use by the US FDA. Vitamin E is a well-known antioxidant, effective in scavenging free radicals generated by radiation exposure. Vitamin E analogs, collectively known as tocols, have been subject to active investigation for a long time as radioprotectors in patients undergoing radiotherapy and in the context of possible radiation accidents or terrorism scenarios. Eight major isoforms comprise the tocol group: four tocopherols and four tocotrienols. A number of these agents and their derivatives are being investigated actively as radiation countermeasures using animal models, and several appear promising. Although the tocols are well recognized as potent antioxidants and are generally thought to mediate radioprotection through 'free radical quenching', recent studies have suggested several alternative mechanisms: most notably, an 'indirect effect' of tocols in eliciting specific species of radioprotective growth factors/cytokines such as granulocyte colony-stimulating factor (G-CSF). The radioprotective efficacy of at least two tocols has been abrogated using a neutralizing antibody of G-CSF. Based on encouraging results of radioprotective efficacy, laboratory testing of gamma tocotrienol has moved from a small rodent model to a large nonhuman primate model for preclinical evaluation. In this brief review we identify and discuss selected tocols and their derivatives currently under development as radiation countermeasures, and attempt to describe in some detail their in vivo efficacy. PMID- 23658416 TI - A poor man's BLASTX--high-throughput metagenomic protein database search using PAUDA. AB - SUMMARY: In the context of metagenomics, we introduce a new approach to protein database search called PAUDA, which runs ~10,000 times faster than BLASTX, while achieving about one-third of the assignment rate of reads to KEGG orthology groups, and producing gene and taxon abundance profiles that are highly correlated to those obtained with BLASTX. PAUDA requires <80 CPU hours to analyze a dataset of 246 million Illumina DNA reads from permafrost soil for which a previous BLASTX analysis (on a subset of 176 million reads) reportedly required 800,000 CPU hours, leading to the same clustering of samples by functional profiles. AVAILABILITY: PAUDA is freely available from: http://ab.inf.uni tuebingen.de/software/pauda. Also supplementary method details are available from this website. PMID- 23658417 TI - TrioVis: a visualization approach for filtering genomic variants of parent-child trios. AB - SUMMARY: TrioVis is a visual analytics tool developed for filtering on coverage and variant frequency for genomic variants from exome sequencing of parent-child trios. In TrioVis, the variant data are organized by grouping each variant based on the laws of Mendelian inheritance. Taking three Variant Call Format files as input, TrioVis allows the user to test different coverage thresholds (i.e. different levels of stringency), to find the optimal threshold values tailored to their hypotheses and to gain insights into the global effects of filtering through interaction. AVAILABILITY: Executables, source code and sample data are available at https://bitbucket.org/biovizleuven/triovis. Screencast is available at http://vimeo.com/user6757771/triovis. CONTACT: ryo.sakai@esat.kuleuven.be. PMID- 23658418 TI - PconsC: combination of direct information methods and alignments improves contact prediction. AB - SUMMARY: Recently, several new contact prediction methods have been published. They use (i) large sets of multiple aligned sequences and (ii) assume that correlations between columns in these alignments can be the results of indirect interaction. These methods are clearly superior to earlier methods when it comes to predicting contacts in proteins. Here, we demonstrate that combining predictions from two prediction methods, PSICOV and plmDCA, and two alignment methods, HHblits and jackhmmer at four different e-value cut-offs, provides a relative improvement of 20% in comparison with the best single method, exceeding 70% correct predictions for one contact prediction per residue. AVAILABILITY: The source code for PconsC along with supplementary data is freely available at http://c.pcons.net/ CONTACT: arne@bioinfo.se SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23658419 TI - DAPPLE: a pipeline for the homology-based prediction of phosphorylation sites. AB - SUMMARY: While many experimentally characterized phosphorylation sites exist for certain organisms, such as human, rat and mouse, few sites are known for other organisms, hampering related research efforts. We have developed a software pipeline called DAPPLE that automates the process of using known phosphorylation sites from other organisms to identify putative sites in an organism of interest. AVAILABILITY: DAPPLE is available as a web server at http://saphire.usask.ca. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23658420 TI - Twine: display and analysis of cis-regulatory modules. AB - Many algorithms analyze enhancers for overrepresentation of known and novel motifs, with the goal of identifying binding sites for direct regulators of gene expression. Twine is a Java GUI with multiple graphical representations ('Views') of enhancer alignments that displays motifs, as IUPAC consensus sequences or position frequency matrices, in the context of phylogenetic conservation to facilitate cis-regulatory element discovery. Thresholds of phylogenetic conservation and motif stringency can be altered dynamically to facilitate detailed analysis of enhancer architecture. Views can be exported to vector graphics programs to generate high-quality figures for publication. Twine can be extended via Java plugins to manipulate alignments and analyze sequences. AVAILABILITY: Twine is freely available as a compiled Java .jar package or Java source code at http://labs.bio.unc.edu/crews/twine/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23658421 TI - Detection of significantly differentially methylated regions in targeted bisulfite sequencing data. AB - MOTIVATION: Bisulfite sequencing is currently the gold standard to obtain genome wide DNA methylation profiles in eukaryotes. In contrast to the rapid development of appropriate pre-processing and alignment software, methods for analyzing the resulting methylation profiles are relatively limited so far. For instance, an appropriate pipeline to detect DNA methylation differences between cancer and control samples is still required. RESULTS: We propose an algorithm that detects significantly differentially methylated regions in data obtained by targeted bisulfite sequencing approaches, such as reduced representation bisulfite sequencing. In a first step, this approach tests all target regions for methylation differences by taking spatial dependence into account. A false discovery rate procedure controls the expected proportion of incorrectly rejected regions. In a second step, the significant target regions are trimmed to the actually differentially methylated regions. This hierarchical procedure detects differentially methylated regions with increased power compared with existing methods. AVAILABILITY: R/Bioconductor package BiSeq. SUPPLEMENTARY INFORMATION: Supplementary Data are available at Bioinformatics online. PMID- 23658422 TI - FYPO: the fission yeast phenotype ontology. AB - MOTIVATION: To provide consistent computable descriptions of phenotype data, PomBase is developing a formal ontology of phenotypes observed in fission yeast. RESULTS: The fission yeast phenotype ontology (FYPO) is a modular ontology that uses several existing ontologies from the open biological and biomedical ontologies (OBO) collection as building blocks, including the phenotypic quality ontology PATO, the Gene Ontology and Chemical Entities of Biological Interest. Modular ontology development facilitates partially automated effective organization of detailed phenotype descriptions with complex relationships to each other and to underlying biological phenomena. As a result, FYPO supports sophisticated querying, computational analysis and comparison between different experiments and even between species. AVAILABILITY: FYPO releases are available from the Subversion repository at the PomBase SourceForge project page (https://sourceforge.net/p/pombase/code/HEAD/tree/phenotype_ontology/). The current version of FYPO is also available on the OBO Foundry Web site (http://obofoundry.org/). PMID- 23658423 TI - Adiponectin gene variant interacts with fish oil supplementation to influence serum adiponectin in older individuals. AB - Marine n3 polyunsaturated fatty acids (PUFAs) activate the transcription factor peroxisome proliferator-activated receptor (PPARgamma), which modulates the expression of adiponectin. We investigated the interaction of dietary n3 PUFAs with adiponectin gene (ADIPOQ) single nucleotide polymorphism (SNP) genotypes as a determinant of serum adiponectin concentration. The Modulation of Atherosclerosis Risk by Increasing Doses of n3 Fatty Acids study is a parallel design, double-blind, controlled trial. Serum adiponectin was measured in 142 healthy men and 225 women aged 45-70 y randomized to treatment with doses of 0.45, 0.9, and 1.8 g/d 20:5n3 and 22:6n3 (1.51:1), or placebo for 12 mo. The 310 participants who completed the study were genotyped for 5 SNPs at the ADIPOQ locus: -11391 G/A (rs17300539), -11377 C/G (rs266729), -10066 G/A (rs182052), +45 T/G (rs2241766), and +276 G/T (rs1501299). The -11391 A-allele was associated with a higher serum adiponectin concentration at baseline (n = 290; P < 0.001). The interaction between treatment and age as a determinant of adiponectin was significant in participants aged >58 y after the highest dose (n = 92; P = 0.020). The interaction between +45 T/G and treatment and age was a nominally significant determinant of serum adiponectin after adjustment for BMI, gender, and ethnicity (P = 0.029). Individuals homozygous for the +45 T-allele aged >58 y had a 22% increase in serum adiponectin concentration compared with baseline after the highest dose (P-treatment effect = 0.008). If substantiated in a larger sample, a diet high in n3 PUFAs may be recommended for older individuals, especially those of the +45 TT genotype who have reported increased risk of hypoadiponectinemia, type 2 diabetes, and obesity. PMID- 23658424 TI - Maternal and child dietary diversity are associated in Bangladesh, Vietnam, and Ethiopia. AB - Dietary diversity (DD) reflects micronutrient adequacy of the diet and is associated with better child growth. Emerging evidence suggests that maternal and child DD are associated. This could have measurement and programmatic implications. Data on mother-child (6-24 mo) dyads in Bangladesh, Vietnam, and Ethiopia were used to examine agreement and association between maternal and child DD and identify determinants of maternal and child DD. The DD scores were derived from a 24-h recall of intake of foods from 7 groups. Multivariable regression was used to examine for the association, adjusting for covariates at child, maternal, and household levels. There was mother/child agreement for staple foods across the 3 countries but disagreement for flesh foods, dairy, fruits, and vegetables. A strong positive association was seen between maternal and child DD; a difference of one food group in mother's consumption was associated with a difference of 0.29, 033, and 0.24 groups in child's consumption in Bangladesh, Vietnam, and Ethiopia, respectively. The odds of achieving minimum DD (>=4 groups) were higher among children whose mother consumed 4 groups compared with <=3 food groups [Bangladesh: OR = 2.73 (95% CI: 1.76, 4.25); Vietnam: OR = 2.30 (95% CI: 1.45, 3.43); Ethiopia: OR = 5.11 (95% CI: 2.36, 11.04)]. Maternal education was associated with both maternal and child DD; food security and socioeconomic status were associated only with maternal DD. Given the disagreements in mother/child intake for nutrient-rich foods, both maternal and child DD should be measured in surveys. Behavior change communications should focus on promoting both mother and child DD and encouraging mothers to feed young children all family foods, not just a subset. PMID- 23658425 TI - A whey protein hydrolysate promotes insulinotropic activity in a clonal pancreatic beta-cell line and enhances glycemic function in ob/ob mice. AB - Whey protein hydrolysates (WPHs) represent novel antidiabetic agents that affect glycemia in animals and humans, but little is known about their insulinotropic effects. The effects of a WPH were analyzed in vitro on acute glucose-induced insulin secretion in pancreatic BRIN-BD11 beta cells. WPH permeability across Caco-2 cell monolayers was determined in a 2-tiered intestinal model. WPH effects on insulin resistance were studied in vivo following an 8-wk oral ingestion (100 mg/kg body weight) by ob/ob (OB-WPH) and wild-type mice (WT-WPH) compared with vehicle control (OB and WT groups) using a 2 * 2 factorial design, genotype * treatment. BRIN-BD11 cells showed a robust and reproducible dose-dependent insulinotropic effect of WPH (from 0.01 to 5.00 g/L). WPH bioactive constituents were permeable across Caco-2 cell monolayers. In the OB-WPH and WT-WPH groups, WPH administration improved glucose clearance after a glucose challenge (2 g/kg body weight), as indicated by differences in the area under curves (AUCs) (P <= 0.05). The basal plasma glucose concentration was not affected by WPH treatment in either genotype. The plasma insulin concentration was lower in the OB-WPH than in the OB group (P <= 0.005) but was similar between the WT and WT-WPH groups; the interaction genotype * treatment was significant (P <= 0.005). Insulin release from pancreatic islets isolated from the OB-WPH group was greater (P <= 0.005) than that from the OB group but did not differ between the WT-WPH and WT groups; the interaction genotype * treatment was not significant. In conclusion, an 8-wk oral administration of WPH improved blood glucose clearance, reduced hyperinsulinemia, and restored the pancreatic islet capacity to secrete insulin in response to glucose in ob/ob mice. Hence, it may be useful in diabetes management. PMID- 23658426 TI - Does transfer of work from a public sector organisation to a commercial enterprise without staff reductions increase risk of long-term sickness absence among the staff? A cohort study of laboratory and radiology employees. AB - BACKGROUND: Privatisations of public sector organisations are not uncommon, and some studies suggest that such organisational changes may adversely affect employee health. In this study, we examined whether transfer of work from public sector hospital units to commercial enterprises, without major staff reductions, was associated with an increased risk of long-term sickness absence among employees. METHODS: A cohort study of 962 employees from four public hospital laboratory and radiology units in three hospitals which were privatised during the follow-up and 1832 employees from similar units without such organisational changes. Records of new long-term sick leaves (>90 days) were obtained from national health registers and were linked to the data. Mean follow-up was 9.2 years. RESULTS: Age- and sex-adjusted HR for long-term sickness absence after privatisation was 0.83 (95% CI 0.68 to 1.00) among employees whose work unit underwent a change from a public organisation to a commercial enterprise compared with employees in unchanged work units. Further adjustments for occupation, socioeconomic status, type of job contract, size of residence and sick leaves before privatisation had little impact on the observed association. A sensitivity analysis with harmonised occupations across the two groups replicated the finding (multivariable adjusted HR 0.92 (0.70-1.20)). CONCLUSIONS: In this study, transfer of work from public organisation to commercial enterprise did not increase the risk of long-term sickness absence among employees. PMID- 23658427 TI - Arabidopsis CIPK26 interacts with KEG, components of the ABA signalling network and is degraded by the ubiquitin-proteasome system. AB - The RING-type E3 ligase, Keep on Going (KEG), is required for early seedling establishment in Arabidopsis thaliana. Post-germination, KEG negatively regulates abscisic acid (ABA) signalling by targeting Abscisic Acid Insensitive 5 (ABI5) for ubiquitination and subsequent degradation. Previous reports suggest that the role of KEG during early seedling development is not limited to regulation of ABI5 abundance. Using a yeast two-hybrid screen, this study identified Calcineurin B-like Interacting Protein Kinase (CIPK) 26 as a KEG-interacting protein. In vitro pull-down and in planta bimolecular fluorescence complementation assays confirmed the interactions between CIPK26 and KEG. In planta experiments demonstrated that CIPK26 was ubiquitinated and degraded via the 26S proteasome. It was also found that turnover of CIPK26 was increased when KEG protein levels were elevated, suggesting that the RING-type E3 ligase is involved in targeting CIPK26 for degradation. CIPK26 was found to interact with the ABA signalling components ABI1, ABI2, and ABI5. In addition, CIPK26 was capable of phosphorylating ABI5 in vitro. Consistent with a role in ABA signalling, overexpression of CIPK26 increased the sensitivity of germinating seeds to the inhibitory effects of ABA. The data presented in this report suggest that KEG mediates the proteasomal degradation of CIPK26 and that CIPK26 is part of the ABA signalling network. PMID- 23658428 TI - Iron acquisition and allocation in stramenopile algae. AB - The essential element iron has a low biological availability in the surface ocean where photosynthetic organisms live. Recent advances in our understanding of iron acquisition mechanisms in brown algae and diatoms (stramenopile algae) show the importance of the reduction of ferric to ferrous iron prior to, or during, transport in the uptake process. The uses of iron in photosynthetic stramenopiles resembles that in other oxygenic organisms, although (with the exception of the diatom Thalassiosira oceanica from an iron-deficient part of the ocean) they lack plastocyanin, instead using cytochrome c 6, This same diatom further economizes genotypically on the use of iron in photosynthesis by decreasing the expression of photosystem I, cytochrome c 6, and the cytochrome b 6 f complex per cell and per photosystem II relative to the coastal Thalassiosira pseudonana; similar changes occur phenotypically in response to iron deficiency in other diatoms such as Phaeodactylum tricornutum. In some diatoms grown under iron-limiting conditions, essentially all of the iron in the cells can be accounted for by the iron occurring in catalytic proteins. However, stramenopiles can store iron. Genomic studies show that pennate, but not centric, diatoms have the iron storage protein ferritin. While Mossbauer and X-ray analysis of (57)Fe-labelled Ectocarpus siliculosus shows iron in an amorphous mineral phase resembling the core of ferritin, the genome shows no protein with significant sequence similarity to ferritin. PMID- 23658429 TI - Dynamic metabolic profiling of cyanobacterial glycogen biosynthesis under conditions of nitrate depletion. AB - Cyanobacteria represent a globally important biomass because they are responsible for a substantial proportion of primary production in the hydrosphere. Arthrospira platensis is a fast-growing halophilic cyanobacterium capable of accumulating glycogen and has the potential to serve as a feedstock in the fermentative production of third-generation biofuels. Accordingly, enhancing cyanobacterial glycogen production is a promising biofuel production strategy. However, the regulatory mechanism of glycogen metabolism in cyanobacteria is poorly understood. The aim of the present study was to determine the metabolic flux of glycogen biosynthesis using a dynamic metabolomic approach. Time-course profiling of widely targeted cyanobacterial metabolic intermediates demonstrated a global metabolic reprogramming that involves transient increases in the levels of some amino acids during the glycogen production phase induced by nitrate depletion. Also, in vivo labelling with NaH(13)CO3 enabled direct measurement of metabolic intermediate turnover in A. platensis, revealing that under conditions of nitrate depletion glycogen is biosynthesized with carbon derived from amino acids released from proteins via gluconeogenesis. This dynamic metabolic profiling approach provided conclusive evidence of temporal alterations in the metabolic profile in cyanobacterial cells. PMID- 23658430 TI - Bone morphogenetic protein 4 supports the initial differentiation of hen (Gallus gallus) granulosa cells. AB - In the hen ovary, selection of a follicle into the preovulatory hierarchy occurs from a small cohort of prehierarchal (6-8 mm) follicles. Prior to follicle selection the granulosa layer remains in an undifferentiated state despite elevated follicle-stimulating hormone receptor (FSHR) expression. The present studies describe a role for bone morphogenetic protein 4 (BMP4) in supporting FSHR mRNA expression in granulosa cells from prehierarchal follicles and promoting differentiation at follicle selection. Culture of undifferentiated granulosa cells in culture medium alone resulted in a significant decline in levels of FSHR mRNA (by ~80% compared to freshly collected cells). By comparison, granulosa cultured with BMP4 (10-100 ng/ml) maintained FSHR and expression at approximately in vivo levels. Because both granulosa and theca tissues from prehierarchal follicles express BMP4, it is suggested that BMP4 acts in a paracrine and/or autocrine fashion to support elevated FSHR expression prior to follicle selection. Granulosa cells cultured with BMP4 for 24 h also initiated FSH-induced cAMP production and indirectly initiated anti-Mullerian hormone (AMH), CYP11A, and STAR expression plus progesterone production. However, pretreatment with the BMP antagonist NOGGIN or the mitogen-activated protein kinase (MAPK) agonist transforming growth factor alpha attenuated or blocked each action promoted by BMP4. We conclude that prior to and immediately after selection, BMP4 serves to support FSHR expression within the granulosa layer, yet prior to selection, multiple factors (including inhibitory MAPK signaling, AMH, and BMP antagonists) can modulate FSHR expression and suppress FSH-mediated cell signaling to prevent granulosa cell differentiation prior to follicle selection. PMID- 23658432 TI - How much is a life worth? Food for thought. PMID- 23658431 TI - Gonadotropin-releasing hormone, estradiol, and inhibin regulation of follicle stimulating hormone and luteinizing hormone surges: implications for follicle emergence and selection in heifers. AB - Mechanisms regulating gonadotropin surges and gonadotropin requirements for follicle emergence and selection were studied in heifers. Experiment 1 evaluated whether follicular inhibins regulate the preovulatory luteinizing hormone (LH)/follicle-stimulating hormone (FSH) surges elicited by gonadotropin-releasing hormone (GnRH) injection (Hour = 0) and the subsequent periovulatory FSH surge. Treatments included control (n = 6), steroid-depleted bovine follicular fluid (bFF) at Hour -4 (n = 6), and bFF at Hour 6 (n = 6). Gonadotropins in blood were assessed hourly from Hours -6 to 36, and follicle growth tracked by ultrasound. Consistent with inhibin independence, bFF at Hour -4 did not impact the GnRH induced preovulatory FSH surge, whereas treatment at Hour 6 delayed onset of the periovulatory FSH surge and impeded growth of a new follicular wave. Experiment 2 examined GnRH and estradiol (E2) regulation of the periovulatory FSH surge. Treatment groups were control (n = 8), GnRH-receptor antagonist (GnRHr-ant, n = 8), and E2 + GnRHr-ant (n = 4). GnRHr-ant (acyline) did not reduce the concentrations of FSH during the periovulatory surge and early follicle development (<7.0 mm) was unaffected, although subsequent growth of a dominant follicle (>8.0 mm) was prevented by GnRHr-ant. Addition of E2 delayed both the onset of the periovulatory FSH surge and emergence of a follicular wave. Failure to select a dominant follicle in the GnRHr-ant group was associated with reduced concentrations of LH but not FSH. Maximum diameter of F1 in controls (13.3 +/- 0.5 mm) was greater than in both GnRHr-ant (7.7 +/- 0.3 mm) and E2 + GnRHr-ant (6.7 +/- 0.8 mm) groups. Results indicated that the periovulatory FSH surge stems from removal of negative stimuli (follicular E2 and inhibin), but is independent of GnRH stimulation. Emergence and early growth of follicles (until about 8 mm) requires the periovulatory FSH surge but not LH pulses. However, follicular deviation and late-stage growth of a single dominant follicle requires GnRH dependent LH pulses. PMID- 23658433 TI - Do patient data really support the clinical and laboratory standards institute recommendation for lowering third-generation cephalosporin interpretive breakpoints? PMID- 23658434 TI - Reply to Walk et al. PMID- 23658435 TI - Understanding increased mortality in Clostridium difficile-infected older adults. PMID- 23658436 TI - Intracoronary infusion of allogeneic mesenchymal precursor cells directly after experimental acute myocardial infarction reduces infarct size, abrogates adverse remodeling, and improves cardiac function. AB - RATIONALE: Mesenchymal precursor cells (MPCs) are a specific Stro-3+ subpopulation of mesenchymal stem cells isolated from bone marrow. MPCs exert extensive cardioprotective effects, and are considered to be immune privileged. OBJECTIVE: This study assessed the safety, feasibility, and efficacy of intracoronary delivery of allogeneic MPCs directly after acute myocardial infarction in sheep. METHODS AND RESULTS: Initially, intracoronary delivery conditions were optimized in 20 sheep. These conditions were applied in a randomized study of 68 sheep with an anterior acute myocardial infarction. Coronary flow was monitored during MPC infusion, and cardiac function was assessed using invasive hemodynamics and echocardiography at baseline and during 8 weeks follow-up. Coronary flow remained within thrombolysis in myocardial infarction III definitions in all sheep during MPC infusion. Global left ventricular ejection fraction as measured by pressure-volume loop analysis deteriorated in controls to 40.7+/-2.6% after 8 weeks. In contrast, MPC treatment improved cardiac function to 52.8+/-0.7%. Echocardiography revealed significant improvement of both global and regional cardiac functions. Infarct size decreased by 40% in treated sheep, whereas infarct and border zone thickness were enhanced. Left ventricular adverse remodeling was abrogated by MPC therapy, resulting in a marked reduction of left ventricular volumes. Blood vessel density increased by >50% in the infarct and border areas. Compensatory cardiomyocyte hypertrophy was reduced in border and remote segments, accompanied by reduced collagen deposition and apoptosis. No microinfarctions in remote myocardial segments or histological abnormalities in unrelated organs were found. CONCLUSIONS: Intracoronary infusion of allogeneic MPCs is safe, feasible, and markedly effective in a large animal model of acute myocardial infarction. PMID- 23658437 TI - Should bilateral internal thoracic artery grafting be used in elderly patients undergoing coronary artery bypass grafting? AB - BACKGROUND: Although bilateral internal thoracic artery grafting is associated with improved survival, the use of this technique in the elderly is controversial because of their increased surgical risk and shorter life expectancy. The purpose of this study was to evaluate the effect of age on outcome of patients undergoing bilateral internal thoracic artery grafting. METHODS AND RESULTS: Between 1996 and 2001, 1714 consecutive patients underwent skeletonized bilateral internal thoracic artery grafting, of whom 748 were <=65 years of age, 688 were between 65 and 75 years of age, and 278 were >=75 years of age. Operative mortality of the 3 age groups (1.2%, 4.1%, and 5.8%, respectively) was lower than the logistic EuroSCORE predicted mortality (3.9%, 6.5%, and 9.3%, respectively; P<0.001). There were no significant differences among the groups in occurrence of sternal infection (1.3%, 2.6%, and 1.4%, respectively; P=0.171). Mean follow-up was 11.5 years. Kaplan-Meier 10-year survival for patients <=65, 65 to 75, and >75 years of age was 85%, 65%, and 40%, respectively (P<0.001). These rates were better than the corresponding predicted Charlson Comorbidity Index survival rates (68%, 37%, and 20%, respectively; P<0.001 for all age groups), approaching survival of the sex- and age-matched general population (90%, 70%, and 41%, respectively). Age <=65 years (hazard ratio, 0.232; 95% confidence interval, 0.188-0.288) and age 65 to 75 years (hazard ratio, 0.499; 95% confidence interval, 0.414-0.602) were independent predictors of improved survival (Cox model). CONCLUSIONS: Bilateral internal thoracic artery grafting should be considered in patients >65 years of age because of the significant survival benefit obtained with this surgical technique with no additional risk of sternal wound infection related to age. PMID- 23658438 TI - Atorvastatin, etidronate, or both in patients at high risk for atherosclerotic aortic plaques: a randomized, controlled trial. AB - BACKGROUND: Statins are not effective in reducing atherosclerotic plaques of the abdominal aorta, and accumulating evidence suggests that bisphosphonates have the potential to induce the regression of atherosclerotic plaques of the abdominal aorta. METHODS AND RESULTS: A prospective, randomized, open-label, blinded-end point trial involving 108 participants with hypercholesterolemia was conducted. Participants received 20 mg atorvastatin daily, 400 mg etidronate daily, or both drugs daily. The primary end point was the percent change in maximal vessel wall thickness of atherosclerotic plaques in the thoracic and abdominal aortas as measured by magnetic resonance imaging after 12 months of treatment. In both the combination therapy and atorvastatin groups, maximal vessel wall thickness of the thoracic aorta was reduced by 13.8% (95% confidence interval, -16.4 to -11.3) and 12.3% (95% confidence interval, -14.9 to -9.7), respectively. These reduction rates were comparable between groups (P=0.61). Meanwhile, in the etidronate group, maximal vessel wall thickness of the thoracic aorta remained unchanged (2.2%; 95% confidence interval, -0.3 to 4.8). Conversely, maximal vessel wall thickness of the abdominal aorta was reduced more effectively in the combination therapy group (-11.4%) than in the atorvastatin group (-0.9%; P<0.001) and the etidronate group (5.5%; P=0.006). CONCLUSIONS: Atorvastatin plus etidronate combination therapy for 12 months significantly reduced both thoracic and abdominal aortic plaques, whereas atorvastatin monotherapy reduced only thoracic aortic plaques and etidronate monotherapy reduced only abdominal aortic plaques. The effectiveness of combination therapy in reducing atherosclerotic plaques in the abdominal aorta was significantly greater than for both atorvastatin and etidronate monotherapy. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN 000002635. PMID- 23658439 TI - ACCF/AHA/SCAI 2013 update of the clinical competence statement on coronary artery interventional procedures: a report of the American College of Cardiology Foundation/American Heart Association/American College of Physicians Task Force on Clinical Competence and Training (writing committee to revise the 2007 clinical competence statement on cardiac interventional procedures). PMID- 23658440 TI - A carboxy-terminally truncated human CPSF6 lacking residues encoded by exon 6 inhibits HIV-1 cDNA synthesis and promotes capsid disassembly. AB - Since HIV-1 replication is modulated at multiple stages by host cell factors, identification and characterization of those host cell factors are expected to contribute to the development of novel anti-HIV therapeutics. Previous studies showed that a C-terminally truncated cytosolic form of cleavage and polyadenylation-specific factor 6 (CPSF6-358) inhibits HIV-1 infection through interference with HIV-1 trafficking to the nucleus. Here we identified and characterized a different configuration of C-terminally truncated human CPSF6 (hCPSF6-375) through cDNA expression cloning coupled with ganciclovir-mediated lethal selection. Notably, hCPSF6-375, but not mouse CPSF6-358 (mCPSF6-358) as previously reported, remarkably interfered with viral cDNA synthesis after HIV-1 infection. Moreover, we found that hCPSF6-375 aberrantly accelerated the disassembly of the viral capsid in target cells, while CPSF6-358 did not. Sequence comparison of CPSF6-375 and CPSF6-358 cDNAs showed a lack of exon 6 and additional coding sequence for 54 amino acid residues in the C terminus of hCPSF6 375. Mutational analyses revealed that the residues encoded by exon 6, but not the C-terminal 54 residues in hCPSF6-375, is responsible for impaired viral cDNA synthesis by hCPSF6-375. This is the first report demonstrating a novel mode of HIV-1 inhibition by truncated forms of CPSF6 that involves rapid capsid disassembly and inhibition of viral cDNA synthesis. These findings could facilitate an increased understanding of viral cDNA synthesis in light of the viral capsid disassembly. PMID- 23658441 TI - Protection by immunoglobulin dual-affinity retargeting antibodies against dengue virus. AB - Dengue viruses are the most common arthropod-transmitted viral infection, with an estimated 390 million human infections annually and ~3.6 billion people at risk. Currently, there are no approved vaccines or therapeutics available to control the global dengue virus disease burden. In this study, we demonstrate the binding, neutralizing activity, and therapeutic capacity of a novel bispecific dual-affinity retargeting molecule (DART) that limits infection of all four serotypes of dengue virus. PMID- 23658442 TI - NS3 of bluetongue virus interferes with the induction of type I interferon. AB - Upon infection with Bluetongue virus (BTV), an arthropod-borne virus, type I interferon (IFN-I) is produced in vivo and in vitro. IFN-I is essential for the establishment of an antiviral cellular response, and most if not all viruses have elaborated strategies to counteract its action. In this study, we assessed the ability of BTV to interfere with IFN-I synthesis and identified the nonstructural viral protein NS3 as an antagonist of the IFN-I system. PMID- 23658443 TI - Comparison of the levels of infectious virus in respirable aerosols exhaled by ferrets infected with influenza viruses exhibiting diverse transmissibility phenotypes. AB - Influenza viruses pose a major public health burden to communities around the world by causing respiratory infections that can be highly contagious and spread rapidly through the population. Despite extensive research on influenza viruses, the modes of transmission occurring most often among humans are not entirely clear. Contributing to this knowledge gap is the lack of an understanding of the levels of infectious virus present in respirable aerosols exhaled from infected hosts. Here, we used the ferret model to evaluate aerosol shedding patterns and measure the amount of infectious virus present in exhaled respirable aerosols. By comparing these parameters among a panel of human and avian influenza viruses exhibiting diverse respiratory droplet transmission efficiencies, we are able to report that ferrets infected by highly transmissible influenza viruses exhale a greater number of aerosol particles and more infectious virus within respirable aerosols than ferrets infected by influenza viruses that do not readily transmit. Our findings improve our understanding of the ferret transmission model and provide support for the potential for influenza virus aerosol transmission. PMID- 23658444 TI - Specific amino acid substitutions in the S protein prevent its excretion in vitro and may contribute to occult hepatitis B virus infection. AB - Occult hepatitis B virus (HBV) infection (OBI) is defined as low plasma level of HBV DNA with undetectable HBV surface antigen (HBsAg) outside the preseroconversion window period. The mechanisms leading to OBI remain largely unknown. The potential role of specific amino acid substitutions in the S protein from OBI in HBsAg production and excretion was examined in vitro. HBsAg was quantified in culture supernatants and cell extracts of HuH-7 cells transiently transfected with plasmids containing the S gene of eight HBsAg(+) controls and 18 OBI clones. The intracellular (IC)/extracellular (EC) HBsAg production ratio was ~1.0 for the majority of controls. Three IC/EC HBsAg patterns were observed in OBI strains clones: pattern 1, an IC/EC ratio of 1.0, was found in 5/18 OBI clones, pattern 2, detectable IC but low or undetectable EC HBsAg (IC/EC, 7.0 to 800), was found in 6/18 OBIs, and pattern 3, low or undetectable IC and EC HBsAg, was found in 7/18 clones. Intracellular immunofluorescence staining showed that in pattern 2, HBsAg was concentrated around the nucleus, suggesting retention in the endoplasmic reticulum. The substitution M75T, Y100S, or P178R was present in 4/6 pattern 2 OBI clones. Site-directed-mutagenesis-corrected mutations reversed HBsAg excretion to pattern 1 and, when introduced into a control clone, induced pattern 2 except for Y100S. In a control and several OBIs, variants of a given quasispecies expressed HBsAg according to different patterns. However, the P178R substitution present in all cloned sequences of two OBI strains may contribute significantly to the OBI phenotype. PMID- 23658445 TI - A novel bivalent vaccine based on a PB2-knockout influenza virus protects mice from pandemic H1N1 and highly pathogenic H5N1 virus challenges. AB - Vaccination is an effective means to protect against influenza virus. Although inactivated and live-attenuated vaccines are currently available, each vaccine has disadvantages (e.g., immunogenicity and safety issues). To overcome these problems, we previously developed a replication-incompetent PB2-knockout (PB2-KO) influenza virus that replicates only in PB2 protein-expressing cells. Here, we generated two PB2-KO viruses whose PB2-coding regions were replaced with the HA genes of either A/California/04/2009 (H1N1pdm09) or A/Vietnam/1203/2004 (H5N1). The resultant viruses comparably, or in some cases more efficiently, induced virus-specific antibodies in the serum, nasal wash, and bronchoalveolar lavage fluid of mice relative to a conventional formalin-inactivated vaccine. Furthermore, mice immunized with these PB2-KO viruses were protected from lethal challenges with not only the backbone virus strain but also strains from which their foreign HAs originated, indicating that PB2-KO viruses with antigenically different HAs could serve as bivalent influenza vaccines. PMID- 23658446 TI - Infectious virion capture by HIV-1 gp120-specific IgG from RV144 vaccinees. AB - The detailed examination of the antibody repertoire from RV144 provides a unique template for understanding potentially protective antibody functions. Some potential immune correlates of protection were untested in the correlates analyses due to inherent assay limitations, as well as the need to keep the correlates analysis focused on a limited number of endpoints to achieve statistical power. In an RV144 pilot study, we determined that RV144 vaccination elicited antibodies that could bind infectious virions (including the vaccine strains HIV-1 CM244 and HIV-1 MN and an HIV-1 strain expressing transmitted/founder Env, B.WITO.c). Among vaccinees with the highest IgG binding antibody profile, the majority (78%) captured the infectious vaccine strain virus (CM244), while a smaller proportion of vaccinees (26%) captured HIV-1 transmitted/founder Env virus. We demonstrated that vaccine-elicited HIV-1 gp120 antibodies of multiple specificities (V3, V2, conformational C1, and gp120 conformational) mediated capture of infectious virions. Although capture of infectious HIV-1 correlated with other humoral immune responses, the extent of variation between these humoral responses and virion capture indicates that virion capture antibodies occupy unique immunological space. PMID- 23658447 TI - Hepatitis C virus infection upregulates CD55 expression on the hepatocyte surface and promotes association with virus particles. AB - CD55 limits excessive complement activation on the host cell surface by accelerating the decay of C3 convertases. In this study, we observed that hepatitis C virus (HCV) infection of hepatocytes or HCV core protein expression in transfected hepatocytes upregulated CD55 expression at the mRNA and protein levels. Further analysis suggested that the HCV core protein or full-length (FL) genome enhanced CD55 promoter activity in a luciferase-based assay, which was further augmented in the presence of interleukin-6. Mutation of the CREB or SP-1 binding site on the CD55 promoter impaired HCV core protein-mediated upregulation of CD55. HCV-infected or core protein-transfected Huh7.5 cells displayed greater viability in the presence of CD81 and CD55 antibodies and complement. Biochemical analysis revealed that CD55 was associated with cell culture-grown HCV after purification by sucrose density gradient ultracentrifugation. Consistent with this, a polyclonal antibody to CD55 captured cell culture-grown HCV. Blocking antibodies against CD55 or virus envelope glycoproteins in the presence of normal human serum as a source of complement inhibited HCV infection. The inhibition was enhanced in the presence of both the antibodies and serum complement. Collectively, these results suggest that HCV induces and associates with a negative regulator of the complement pathway, a likely mechanism for immune evasion. PMID- 23658448 TI - Crystal structure of the avian astrovirus capsid spike. AB - Astroviruses are small, nonenveloped, single-stranded RNA viruses that cause diarrhea in a wide variety of mammals and birds. On the surface of the viral capsid are globular spikes that are thought to be involved in attachment to host cells. To understand the basis of species specificity, we investigated the structure of an avian astrovirus capsid spike and compared it to a previously reported human astrovirus capsid spike structure. Here we report the crystal structure of the turkey astrovirus 2 (TAstV-2) capsid surface spike domain, determined to 1.5-A resolution, and identify three conserved patches on the surface of the spike that are candidate avian receptor-binding sites. Surprisingly, the overall TAstV-2 capsid spike structure is unique, with only distant structural similarities to the human astrovirus capsid spike and other viral capsid spikes. There is an absence of conserved putative receptor-binding sites between the human and avian spikes. However, there is evidence for carbohydrate-binding sites in both human and avian spikes, and studies with human astrovirus 1 (HAstV-1) suggest a minor role in infection for chondroitin sulfate but not heparin. Overall, our structural and functional studies provide new insights into astrovirus host cell entry, species specificity, and evolution. PMID- 23658449 TI - Polarized cell migration during cell-to-cell transmission of herpes simplex virus in human skin keratinocytes. AB - In addition to transmission involving extracellular free particles, a generally accepted model of virus propagation is one wherein virus replicates in one cell, producing infectious particles that transmit to the next cell via cell junctions or induced polarized contacts. This mechanism of spread is especially important in the presence of neutralizing antibody, and the concept underpins analysis of virus spread, plaque size, viral and host functions, and general mechanisms of virus propagation. Here, we demonstrate a novel process involved in cell-to-cell transmission of herpes simplex virus (HSV) in human skin cells that has not previously been appreciated. Using time-lapse microscopy of fluorescent viruses, we show that HSV infection induces the polarized migration of skin cells into the site of infection. In the presence of neutralizing antibody, uninfected skin cells migrate to the initial site of infection and spread over infected cells to become infected in a spatially confined cluster containing hundreds of cells. The cells in this cluster do not undergo cytocidal cell lysis but harbor abundant enveloped particles within cells and cell-free virus within interstitial regions below the cluster surface. Cells at the base and outside the cluster were generally negative for virus immediate-early expression. We further show, using spatially separated monolayer assays, that at least one component of this induced migration is the paracrine stimulation of a cytotactic response from infected cells to uninfected cells. The existence of this process changes our concept of virus transmission and the potential functions, virus, and host factors involved. PMID- 23658450 TI - Contribution of follicular dendritic cells to persistent HIV viremia. AB - HIV-1 infections cannot be completely eradicated by drug therapy, as the virus persists in reservoirs. Low-level plasma viremia has been detected in patients treated for over 7 years, but the cellular compartments that support this low level viremia have not been identified. The decay of HIV-1 during treatment appears to occur in four phases, with the 3rd and 4th phases occurring when the virus is below the limit of detection of conventional assays. Here, we focus on the 3rd phase of decay, which has been estimated to have a half-life of 39 months. We show that follicular dendritic cells (FDC), which have been identified as an HIV reservoir, can be the main source of the low-level viremia detected during the 3rd phase of decay and contribute to viremia at even longer times. Our calculations show that the kinetics of leakage of virus from FDC is consistent with three types of available clinical data. PMID- 23658451 TI - Accessory genes confer a high replication rate to virulent feline immunodeficiency virus. AB - Feline immunodeficiency virus (FIV) is a lentivirus that causes AIDS in domestic cats, similar to human immunodeficiency virus (HIV)/AIDS in humans. The FIV accessory protein Vif abrogates the inhibition of infection by cat APOBEC3 restriction factors. FIV also encodes a multifunctional OrfA accessory protein that has characteristics similar to HIV Tat, Vpu, Vpr, and Nef. To examine the role of vif and orfA accessory genes in FIV replication and pathogenicity, we generated chimeras between two FIV molecular clones with divergent disease potentials: a highly pathogenic isolate that replicates rapidly in vitro and is associated with significant immunopathology in vivo, FIV-C36 (referred to here as high-virulence FIV [HV-FIV]), and a less-pathogenic strain, FIV-PPR (referred to here as low-virulence FIV [LV-FIV]). Using PCR-driven overlap extension, we produced viruses in which vif, orfA, or both genes from virulent HV-FIV replaced equivalent genes in LV-FIV. The generation of these chimeras is more straightforward in FIV than in primate lentiviruses, since FIV accessory gene open reading frames have very little overlap with other genes. All three chimeric viruses exhibited increased replication kinetics in vitro compared to the replication kinetics of LV-FIV. Chimeras containing HV-Vif or Vif/OrfA had replication rates equivalent to those of the virulent HV-FIV parental virus. Furthermore, small interfering RNA knockdown of feline APOBEC3 genes resulted in equalization of replication rates between LV-FIV and LV-FIV encoding HV-FIV Vif. These findings demonstrate that Vif-APOBEC interactions play a key role in controlling the replication and pathogenicity of this immunodeficiency-inducing virus in its native host species and that accessory genes act as mediators of lentiviral strain-specific virulence. PMID- 23658452 TI - Assessment of the protective effect of Imvamune and Acam2000 vaccines against aerosolized monkeypox virus in cynomolgus macaques. AB - To support the licensure of a new and safer vaccine to protect people against smallpox, a monkeypox model of infection in cynomolgus macaques, which simulates smallpox in humans, was used to evaluate two vaccines, Acam2000 and Imvamune, for protection against disease. Animals vaccinated with a single immunization of Imvamune were not protected completely from severe and/or lethal infection, whereas those receiving either a prime and boost of Imvamune or a single immunization with Acam2000 were protected completely. Additional parameters, including clinical observations, radiographs, viral load in blood, throat swabs, and selected tissues, vaccinia virus-specific antibody responses, immunophenotyping, extracellular cytokine levels, and histopathology were assessed. There was no significant difference (P > 0.05) between the levels of neutralizing antibody in animals vaccinated with a single immunization of Acam2000 (132 U/ml) and the prime-boost Imvamune regime (69 U/ml) prior to challenge with monkeypox virus. After challenge, there was evidence of viral excretion from the throats of 2 of 6 animals in the prime-boost Imvamune group, whereas there was no confirmation of excreted live virus in the Acam2000 group. This evaluation of different human smallpox vaccines in cynomolgus macaques helps to provide information about optimal vaccine strategies in the absence of human challenge studies. PMID- 23658453 TI - A chemokine-like viral protein enhances alpha interferon production by plasmacytoid dendritic cells but delays CD8+ T cell activation and impairs viral clearance. AB - Murine cytomegalovirus encodes numerous proteins that act on a variety of pathways to modulate the innate and adaptive immune responses. Here, we demonstrate that a chemokine-like protein encoded by murine cytomegalovirus activates the early innate immune response and delays adaptive immunity, thereby impairing viral clearance. The protein, m131/129 (also known as MCK-2), is not required to establish infection in the spleen; however, a mutant virus lacking m131/129 was cleared more rapidly from this organ. In the absence of m131/129 expression, there was enhanced activation of dendritic cells (DC), and virus specific CD8(+) T cells were recruited into the immune response earlier. Viral mutants lacking m131/129 elicited weaker production of alpha interferon (IFN alpha) at 40 h postinfection, indicating that this protein exerts its effects during early rounds of viral replication in the spleen. Furthermore, while wild type and mutant viruses activated plasmacytoid dendritic cells (pDC) equally at this time, as measured by the upregulation of costimulatory molecules, the presence of m131/129 stimulated more pDC to secrete IFN-alpha, accounting for the stronger IFN-alpha response than from the wild-type virus. These data provide evidence for a novel immunomodulatory function of a viral chemokine and expose the multifunctionality of immune evasion proteins. In addition, these results broaden our understanding of the interplay between innate and adaptive immunity. PMID- 23658454 TI - The CD225 domain of IFITM3 is required for both IFITM protein association and inhibition of influenza A virus and dengue virus replication. AB - The interferon-induced transmembrane protein 3 (IFITM3) gene is an interferon stimulated gene that inhibits the replication of multiple pathogenic viruses in vitro and in vivo. IFITM3 is a member of a large protein superfamily, whose members share a functionally undefined area of high amino acid conservation, the CD225 domain. We performed mutational analyses of IFITM3 and identified multiple residues within the CD225 domain, consisting of the first intramembrane domain (intramembrane domain 1 [IM1]) and a conserved intracellular loop (CIL), that are required for restriction of both influenza A virus (IAV) and dengue virus (DENV) infection in vitro. Two phenylalanines within IM1 (F75 and F78) also mediate a physical association between IFITM proteins, and the loss of this interaction decreases IFITM3-mediated restriction. By extension, similar IM1-mediated associations may contribute to the functions of additional members of the CD225 domain family. IFITM3's distal N-terminal domain is also needed for full antiviral activity, including a tyrosine (Y20), whose alteration results in mislocalization of a portion of IFITM3 to the cell periphery and surface. Comparative analyses demonstrate that similar molecular determinants are needed for IFITM3's restriction of both IAV and DENV. However, a portion of the CIL including Y99 and R87 is preferentially needed for inhibition of the orthomyxovirus. Several IFITM3 proteins engineered with rare single-nucleotide polymorphisms demonstrated reduced expression or mislocalization, and these events were associated with enhanced viral replication in vitro, suggesting that possessing such alleles may impact an individual's risk for viral infection. On the basis of this and other data, we propose a model for IFITM3-mediated restriction. PMID- 23658455 TI - The resistance protein Tm-1 inhibits formation of a Tomato mosaic virus replication protein-host membrane protein complex. AB - The Tm-1 gene of tomato confers resistance to Tomato mosaic virus (ToMV). Tm-1 encodes a protein that binds ToMV replication proteins and inhibits the RNA dependent RNA replication of ToMV. The replication proteins of resistance breaking mutants of ToMV do not bind Tm-1, indicating that the binding is important for inhibition. In this study, we analyzed how Tm-1 inhibits ToMV RNA replication in a cell-free system using evacuolated tobacco protoplast extracts. In this system, ToMV RNA replication is catalyzed by replication proteins bound to membranes, and the RNA polymerase activity is unaffected by treatment with 0.5 M NaCl-containing buffer and remains associated with membranes. We show that in the presence of Tm-1, negative-strand RNA synthesis is inhibited; the replication proteins associate with membranes with binding that is sensitive to 0.5 M NaCl; the viral genomic RNA used as a translation template is not protected from nuclease digestion; and host membrane proteins TOM1, TOM2A, and ARL8 are not copurified with the membrane-bound 130K replication protein. Deletion of the polymerase read-through domain or of the 3' untranslated region (UTR) of the genome did not prevent the formation of complexes between the 130K protein and the host membrane proteins, the 0.5 M NaCl-resistant binding of the replication proteins to membranes, and the protection of the genomic RNA from nucleases. These results indicate that Tm-1 binds ToMV replication proteins to inhibit key events in replication complex formation on membranes that precede negative-strand RNA synthesis. PMID- 23658456 TI - DNA topoisomerase 1 facilitates the transcription and replication of the Ebola virus genome. AB - Ebola virus (EBOV) protein L (EBOL) acts as a viral RNA-dependent RNA polymerase. To better understand the mechanisms underlying the transcription and replication of the EBOV genome, we sought to identify cellular factors involved in these processes via their coimmunoprecipitation with EBOL and by mass spectrometry. Of 65 candidate proteins identified, we focused on DNA topoisomerase 1 (TOP1), which localizes to the nucleus and unwinds helical DNA. We found that in the presence of EBOL, TOP1 colocalizes and interacts with EBOL in the cytoplasm, where transcription and replication of the EBOV genome occur. Knockdown of TOP1 markedly reduced virus replication and viral polymerase activity. We also found that the phosphodiester bridge-cleaving and recombination activities of TOP1 are required for the polymerase activity of EBOL. These results demonstrate that TOP1 is an important cellular factor for the transcription and replication of the EBOV genome and, as such, plays a key role in the EBOV life cycle. PMID- 23658457 TI - Gender, cytidine deaminase, and 5-aza/decitabine--response. PMID- 23658458 TI - Gender, cytidine deaminase, and 5-aza/decitabine--letter. PMID- 23658459 TI - Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. AB - PURPOSE: Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers. EXPERIMENTAL DESIGN: Preclinical activity of dovitinib was evaluated in both breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included 4 groups of patients with human EGF receptor 2-negative metastatic breast cancer on the basis of FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative PCR (qPCR). RESULTS: Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified, but not FGFR-normal, breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease for more than 6 months was observed in 5 (25%) and 1 (3%) patient(s) with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway amplified breast cancer. CONCLUSION: Dovitinib showed antitumor activity in FGFR amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification. PMID- 23658460 TI - High prevalence of BRCA1 and BRCA2 germline mutations with loss of heterozygosity in a series of resected pancreatic adenocarcinoma and other neoplastic lesions. AB - PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with the breast ovarian cancer syndrome (BRCA1/BRCA2) mutations. It is unknown if this association is causal. EXPERIMENTAL DESIGN: This is a single-site study of patients who underwent surgical pancreatic tumor resection and self-identified as Ashkenazi Jewish. DNA from normal pancreatic tissue was genotyped for the three Ashkenazi Jewish BRCA1/2 founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, and loss of heterozygosity (LOH) was determined by sequencing DNA from microdissected tumor. When additional tumor tissue was available, p53 immunohistochemistry (IHC) was conducted. RESULTS: Thirty-seven patients underwent surgery for PDAC, seven for intraductal papillary mucinous neoplasm (IPMN), and 19 for other diseases. A high prevalence of BRCA1/2 mutations was found in the surgical cohort (12/63; 19.0%; P < 0.001), PDAC cohort (8/37; 21.6%; P < 0.001), and IPMN cohort (2/7; 28.6%; P = .01) compared with published control mutation frequency. A high prevalence of BRCA1 185delAG (8.1%; P < 0.001) and BRCA2 6174delT (10.8%; P < 0.001) in Ashkenazi Jewish patients with PDAC was shown. BRCA1/2 LOH was found in 2 of 4 BRCA1-associated PDACs and 3 of 4 BRCA2 associated PDACs. Positive p53 IHC was found in 5 of 8 BRCA1/2 PDACs. CONCLUSIONS: We show a high prevalence of BRCA1/2 mutations with LOH in an Ashkenazi Jewish cohort of surgically resected PDAC and neoplastic lesions, suggesting that these germline mutations are causal in selected individuals. PMID- 23658466 TI - Skeletal muscle evaluation by MRI in a rabbit model of acute ischaemia. AB - OBJECTIVE: To assess rhabdomyolysis-associated skeletal muscle changes induced by complete ischaemia in rabbits using MRI. METHODS: Acute ischaemia was induced in the right hind limb of 34 New Zealand white rabbits by arterial ligation. MRI of vastus lateralis was carried out pre-operatively and every hour post-operatively up to 7 h. T1 weighted images, T2 weighted images with fat suppression, T2 maps and diffusion tensor scans were obtained. The correlation of MRI findings with histopathological changes in biopsies of vastus lateralis was examined. RESULTS: Histopathology demonstrated early cellular oedema 1 h post ischaemia and irreversible injuries by 7 h, including loss of striation and broken muscle fibres. T2 weighted images with fat suppression showed inhomogeneous high signal intensity of vastus lateralis, which progressively increased from 2 h following ischaemia. The T2 relaxation rate of ischaemic vastus lateralis was significantly greater than normal muscle (p<0.001) and demonstrated a linear increase with time following ischaemia. A similar linear increase was also found in the ischaemic vastus lateralis apparent diffusion coefficient (ADC) 1-5 h post ischaemia (p=0.006). Both the T2 ADC and fractional anisotropy (FA) were significantly higher on the ischaemic side 7 h post ischaemia (for T2, p=0.02; for ADC, p=0.004). CONCLUSION: Muscle oedema is detectable on MR images and is reflected well by T2, ADC and FA values. MRI may have value in clinical evaluation of rhabdomyolysis. ADVANCES IN KNOWLEDGE: Ischaemic changes detected by MRI may have value in the diagnosis of rhabdomyolysis. PMID- 23658467 TI - Aggregate Morphology Evolution by Sintering: Number & Diameter of Primary Particles. AB - The structure of fractal-like agglomerates (physically-bonded) and aggregates (chemically- or sinter-bonded) is important in aerosol synthesis of nanoparticles, and in monitoring combustion emissions and atmospheric particles. It influences also particle mobility, scattering, and eventually performance of nanocomposites, suspensions and devices made with such particles. Here, aggregate sintering by viscous flow of amorphous materials (silica, polymers) and grain boundary diffusion of crystalline ceramics (titania, alumina) or metals (Ni, Fe, Ag etc.) is investigated. A scaling law is found between average aggregate projected area and equivalent number of constituent primary particles during sintering: from fractal-like agglomerates to aggregates and eventually compact particles (e.g. spheres). This is essentially a relation independent of time, material properties and sintering mechanisms. It is used to estimate the equivalent primary particle diameter and number in aggregates. The evolution of aggregate morphology or structure is quantified by the effective fractal dimension (Df ) and mass-mobility exponent (Dfm ) and the corresponding prefactors. The Dfm increases monotonically during sintering converging to 3 for a compact particle. Therefore Dfm and its prefactor could be used to gauge the degree or extent of sintering of agglomerates made by a known collision mechanism. This analysis is exemplified by comparison to experiments of silver nanoparticle aggregates sintered at different temperatures in an electric tube furnace. PMID- 23658468 TI - Matching observations and reality: using simulation models to improve monitoring under uncertainty in the Serengeti. AB - 1. Planning for conservation success requires identifying effective and efficient monitoring strategies but multiple types of uncertainty affect the accuracy and precision of wildlife abundance estimates. Observation uncertainty, a consequence of sampling effort and design as well as the process of observation, is still understudied, with little attention given to the multiple potential sources of error involved. To establish error minimization priorities and maximize monitoring efficiency, the direction and magnitude of multiple sources of uncertainty must be considered. 2. Using monitoring of two contrasting ungulate species in the Serengeti ecosystem as a case study, we developed a 'virtual ecologist' framework within which we carried out simulated tests of different monitoring strategies for different types of species. We investigated which components of monitoring should be prioritized to increase survey accuracy and precision and explored the robustness of population estimates under different budgetary scenarios. 3. The relative importance of each process affecting precision and accuracy varied according to the survey technique and biological characteristics of the species. While survey precision was mainly affected by population characteristics and sampling effort, the accuracy of the survey was greatly affected by observer effects, such as juvenile and herd detectability. 4.Synthesis and applications. Monitoring efficiency is of the utmost importance for conservation, especially in the context of limited budgets and other priorities. We provide insights into the likely effect of different types of observation and process error on population estimates for savanna ungulates, and more generally present a framework for evaluating monitoring programmes in a virtual environment. In highly aggregated species, the main focus should be on survey precision; sampling effort should be defined according to wildlife spatial distribution. For random or slightly aggregated species, accuracy is the key factor; this is most sensitive to observer effects which should be minimized by training and calibration by observer. PMID- 23658469 TI - Groundwater depletion in the Middle East from GRACE with implications for transboundary water management in the Tigris-Euphrates-Western Iran region. AB - In this study, we use observations from the Gravity Recovery and Climate Experiment (GRACE) satellite mission to evaluate freshwater storage trends in the north-central Middle East, including portions of the Tigris and Euphrates River Basins and western Iran, from January 2003 to December 2009. GRACE data show an alarming rate of decrease in total water storage of approximately -27.2+/-0.6 mm yr-1 equivalent water height, equal to a volume of 143.6 km3 during the course of the study period. Additional remote-sensing information and output from land surface models were used to identify that groundwater losses are the major source of this trend. The approach used in this study provides an example of "best current capabilities" in regions like the Middle East, where data access can be severely limited. Results indicate that the region lost 17.3+/-2.1 mm yr-1 equivalent water height of groundwater during the study period, or 91.3+/-10.9 km3 in volume. Furthermore, results raise important issues regarding water use in transboundary river basins and aquifers, including the necessity of international water use treaties and resolving discrepancies in international water law, while amplifying the need for increased monitoring for core components of the water budget. PMID- 23658470 TI - SOCIAL ROLE VALORIZATION IN COMMUNITY MENTAL HEALTH HOUSING: DOES IT CONTRIBUTE TO THE COMMUNITY INTEGRATION AND LIFE SATISFACTION OF PEOPLE WITH PSYCHIATRIC DISABILITIES? AB - Despite its importance as a theory in the development of programs for populations with disabilities, social role valorization (SRV) has received relatively little attention in community mental health research. We present findings of a study that examined the relationship of housing-related SRV to community integration and global life satisfaction of persons with psychiatric disabilities. The housing environments and associated supports of a group of 73 persons with psychiatric disabilities living in a mid-sized city were assessed using the PASSING rating system on the extent that their housing environments facilitated SRV. In addition, in-person interviews were conducted to determine the levels of physical integration, psychological integration, social integration, and life satisfaction of study participants. Results showed SRV contributing directly to all three types of community integration. Psychological integration was found to mediate the relationship between SRV and life satisfaction. Implications of the findings are discussed. (c) 2013 Wiley Periodicals, Inc. PMID- 23658471 TI - Design of Aerosol Coating Reactors: Precursor Injection. AB - Particles are coated with thin shells to facilitate their processing and incorporation into liquid or solid matrixes without altering core particle properties (coloristic, magnetic, etc.). Here, computational fluid and particle dynamics are combined to investigate the geometry of an aerosol reactor for continuous coating of freshly-made titanium dioxide core nanoparticles with nanothin silica shells by injection of hexamethyldisiloxane (HMDSO) vapor downstream of TiO2 particle formation. The focus is on the influence of HMDSO vapor jet number and direction in terms of azimuth and inclination jet angles on process temperature and coated particle characteristics (shell thickness and fraction of uncoated particles). Rapid and homogeneous mixing of core particle aerosol and coating precursor vapor facilitates synthesis of core-shell nanoparticles with uniform shell thickness and high coating efficiency (minimal uncoated core and free coating particles). PMID- 23658472 TI - HIV/STI Risk Behavior of Drug Court Participants. AB - Drug abusing offenders have high rates of HIV and other sexually transmitted infections (STI). To date, the HIV/STI prevention needs of offenders in drug court programs have been ignored. This multi-method study employed interviews to assess drug court professionals' perceptions of the need for an HIV risk reduction intervention to be integrated into the services provided to drug court participants. Then, surveys were completed by 235 drug court participants to assess whether their sexual risk behaviors affirmed the need for such an intervention. The survey also assessed demographic characteristics, drug use prior to program entry, HIV knowledge, and condom attitudes. The relationship between duration in the drug court program and sexual risk behavior was also examined. Implications for the development and delivery of HIV risk reduction interventions within drug court programs are discussed. PMID- 23658473 TI - A case of presumed acute retinal necrosis after intraocular foreign body injury. AB - The aim of this study was to report a case of acute retinal necrosis (ARN) after intraocular foreign body removal. A 32-year-old male presented with visual loss in the left eye. He was hit by an iron fragment while he was hammering. An intraocular foreign body was found with corneal laceration and traumatic cataract. On the day he was injured, primary closure of the laceration, lensectomy, and vitrectomy were performed, and the foreign body was removed. The day after the operation, there was no sign of retinal detachment or retinitis. Two days after the operation, retinal necrosis and accompanying vitreous inflammation were noted in the far periphery. On day 3, the necrosis spread circumferentially and inflammation became more distinct. ARN was presumed and intravenous acyclovir was administered. The necrotic areas were reduced 2 days later, and were resolved in 1 month. The final visual acuity in his left eye was 20/20 after implantation of an intraocular lens. This case is the first report of ARN after penetrating injury and an intraocular foreign body. ARN may develop after open-globe injury. PMID- 23658474 TI - Alternative ultraviolet A lamp for corneal collagen crosslinking. AB - In this paper, we describe an original, affordable, and available device for performing collagen crosslinking. This is carried out in a safe and reproducible way by means of a simple modification to an affordable ultraviolet A lamp and by preparing riboflavin 0.1% solution inhouse. PMID- 23658475 TI - Complications of vision loss and ophthalmoplegia during endoscopic sinus surgery. AB - OBJECTIVE: To describe two rare cases of concurrent vision loss and external ophthalmoplegia following powered endoscopic sinus surgery (ESS). DESIGN: Observational case report. RESULTS: The records of two patients who underwent powered ESS and developed multiple concurrent ophthalmic complications were retrospectively reviewed for clinical history, neuro-ophthalmologic examination, and imaging findings. Patient 1 developed a retinal vascular occlusion and complete loss of adduction. Patient 2 developed an orbital hemorrhage, optic neuropathy, and a restrictive global ophthalmoplegia. Similar published case reports were also reviewed. CONCLUSION: Despite advances in powered ESS technique and instrumentation, serious ophthalmic complications can still occur. Inadvertent entry into the medial orbital wall can result in a combination of blindness and ocular motility dysfunction. The variety of mechanisms responsible for these complications underscores the importance of thorough pre- and postoperative clinical examination and review of imaging studies. PMID- 23658476 TI - Is Duane retraction syndrome part of the VACTERL association? AB - We report here a patient with type 1 Duane's retraction syndrome and multiple congenital abnormalities as a result of the VACTERL association. The presented combination of Duane's retraction syndrome and the VACTERL association has not been reported in the literature. The present case was instructive for reviewing the continuous spectrum of ocular anomalies that accompany the VACTERL association. PMID- 23658477 TI - Acute visual loss in a patient with optic disc drusen. AB - Here we report a case of sudden, unilateral, painless visual loss in a middle aged patient. A 45-year-old gentleman with no known past medical history presented with acute painless left visual impairment. Clinically, he was found to have a left optic neuropathy associated with a swollen and hyperemic left optic disc. The right optic disc was noted to be small and crowded, and both optic discs were noted to have irregular margins. Humphrey perimetry revealed a constricted visual field in the left eye. Fundus autofluorescence imaging revealed autofluorescence, and B-scan ultrasonography showed hyperreflectivity within both nerve heads. Blood investigations for underlying ischemic and inflammatory markers revealed evidence of hyperlipidemia but were otherwise normal. A diagnosis of left nonarteritic anterior ischemic optic neuropathy (NAAION) was made, with associated optic disc drusen and hyperlipidemia. NAAION typically occurs in eyes with small, structurally crowded optic discs. The coexistence of optic disc drusen and vascular risk factors may further augment the risk of developing NAAION. PMID- 23658478 TI - Clinical presentation, treatment, and prognosis of periocular and orbital amyloidosis in a university-based referral center. AB - OBJECTIVE: The purpose was to present the demographic data, clinical presentation, and treatment options, and to evaluate prognosis, for periocular and orbital amyloidosis in patients at the Songklanagarind Hospital, Thailand. METHOD: This was a retrospective study that reviewed the clinical records of six patients who were diagnosed with periocular and orbital amyloidosis between January 1, 2002 and December 31, 2011. RESULTS: The series included six patients (five female and one male). The mean age was 39.7 years (range 15-79 years). There were five cases of unilateral lesion and one case of bilateral lesion. The most common symptom was a mass lesion (83.3%), followed by irritation (66.7%), bloody tears (16.7%), epiphora (16.7%), eye pain (16.7%), and ptosis (16.7%). Five cases had periocular involvement and one case had orbital involvement. Five cases were investigated to rule out systemic amyloidosis, and no systemic involvement was found in these cases. The median duration of symptoms was 6 months, but the mean was 31 months. The main treatment option was surgical excision. The mean follow-up time was 41 months. There was disease progression in 20% of cases after definitive treatment. CONCLUSION: Periocular and orbital amyloidosis presented with a variety of symptoms, depending on the location of the disease. A mass lesion was the most common symptom. The intent of the treatment modalities was to spare function. PMID- 23658479 TI - COPD patient satisfaction with ipratropium bromide/albuterol delivered via Respimat: a randomized, controlled study. AB - BACKGROUND: Ipratropium bromide/albuterol Respimat inhaler (CVT-R) was developed as an environmentally friendly alternative to ipratropium bromide/albuterol metered-dose inhaler (CVT-MDI), which uses a chlorofluorocarbon propellant. OBJECTIVE: The objective of this study was to evaluate patient satisfaction, device usage, and long-term safety of CVT-R compared to CVT-MDI, and to the simultaneous administration of ipratropium bromide hydrofluoroalkane (HFA; I) and albuterol HFA (A) metered-dose inhalers as dual monotherapies (I + A). DESIGN: This is a 48-week, open-label, randomized, active-controlled, parallel-group study (n = 470) comparing CVT-R to CVT-MDI and to I + A. PARTICIPANTS: Patients were at least 40 years of age, diagnosed with chronic obstructive pulmonary disease (COPD), and current or exsmokers. INTERVENTIONS: Patients were randomized to receive: (1) CVT-R, one inhalation four times daily (QID); or (2) CVT-MDI, two inhalations QID; or (3) I + A two inhalations of each inhaler QID. MAIN MEASURES: Patient Satisfaction and Preference Questionnaire (PASAPQ) performance score (primary endpoint) and adverse events. KEY RESULTS: PASAPQ performance score was significantly higher (CVT-R versus CVT-MDI, 9.6; and CVT-R versus I + A, 6.2; both P < 0.001) when using CVT-R compared to CVT-MDI or I + A at all visits starting from week 3, while CVT-MDI and I + A treatment groups were similar. Time to first COPD exacerbation was slightly longer in the CVT-R group compared to the other treatment groups, although it did not reach statistical significance (CVT-R versus CVT-MDI, P = 0.57; CVT-R versus I + A, P = 0.22). Rates of withdrawal and patient refusal to continue treatment were lower in CVT-R compared with CVT-MDI and I + A groups (CVT-R versus CVT-MDI, P = 0.09; CVT-R versus I + A, P = 0.005). The percentage of patients reporting adverse events and serious adverse events was similar across all three treatment groups. CONCLUSION: CVT-R is an effective, environmentally friendly inhaler that provides patients with a high level of user satisfaction and may positively impact clinical outcomes while having no adverse impacts on patients using the device. PMID- 23658480 TI - Anemia and performance status as prognostic markers in acute hypercapnic respiratory failure due to chronic obstructive pulmonary disease. AB - BACKGROUND: In patients with acute hypercapnic respiratory failure (AHRF) during exacerbations of COPD, mortality can be high despite noninvasive ventilation (NIV). For some, AHRF is terminal and NIV is inappropriate. However there is no definitive method of identifying patients who are unlikely to survive. The aim of this study was to identify factors associated with inpatient mortality from AHRF with respiratory acidosis due to COPD. METHODS: COPD patients presenting with AHRF and who were treated with NIV were studied prospectively. The forced expiratory volume in 1 second (FEV1), World Health Organization performance status (WHO-PS), clinical observations, a composite physiological score (Early Warning Score), routine hematology and biochemistry, and arterial blood gases prior to commencing NIV, were recorded. RESULTS: In total, 65 patients were included for study, 29 males and 36 females, with a mean age of 71 +/- 10.5 years. Inpatient mortality in the group was 33.8%. Mortality at 30 days and 12 months after admission were 38.5% and 58.5%, respectively. On univariate analysis, the variables associated with inpatient death were: WHO-PS >= 3, long term oxygen therapy, anemia, diastolic blood pressure < 70 mmHg, Early Warning Score >= 3, severe acidosis (pH < 7.20), and serum albumin < 35 g/L. On multivariate analysis, only anemia and WHO-PS >= 3 were significant. The presence of both predicted 68% of inpatient deaths, with a specificity of 98%. CONCLUSION: WHO-PS >= 3 and anemia are prognostic factors in AHRF with respiratory acidosis due to COPD. A combination of the two provides a simple method of identifying patients unlikely to benefit from NIV. PMID- 23658481 TI - Efficacy and safety of eco-friendly inhalers: focus on combination ipratropium bromide and albuterol in chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and its treatment is critical to improve quality of life, reduce symptoms, and diminish the frequency of COPD exacerbations. Due to the harmful environmental effects of pressurized metered-dose inhalers (pMDIs) containing chlorofluorocarbons (CFCs), newer systems for delivering respiratory medications have been developed. METHODS: A search of the literature in the PubMed database was undertaken using the keywords "COPD," "albuterol," "ipratropium bromide," and "Respimat(r) Soft Mist InhalerTM"; pertinent references within the identified citations were included. The environmental effect of CFC-pMDIs, the invention of the Respimat(r) Soft Mist InhalerTM (SMI) (Boehringer Ingelheim, Ingelheim, Germany), and its use to deliver the combination of albuterol and ipratropium bromide for the treatment of COPD were reviewed. RESULTS: The adverse environmental effects of CFC-pMDIs stimulated the invention of novel delivery systems including the Respimat SMI. This review presents its development, internal mechanism, and use to deliver the combination of albuterol and ipratropium bromide. CONCLUSION: CFC-pMDIs contributed to the depletion of the ozone layer and the surge in disorders caused by harmful ultraviolet B radiation. The banning of CFCs spurred the development of novel delivery systems for respiratory medications. The Respimat SMI is an innovative device that produces a vapor of inhalable droplets with reduced velocity and prolonged aerosol duration that enhance deposition within the lower airway and is associated with improved patient satisfaction. Clinical trials have demonstrated that the Respimat SMI can achieve effects equivalent to pMDIs but with lower medication doses. The long-term safety and efficacy remain to be determined. The Respimat SMI delivery device is a novel, efficient, and well-received system for the delivery of aerosolized albuterol and ipratropium bromide to patients with COPD; however, the presence of longer-acting, less frequently dosed respiratory medications provide patients and providers with other therapeutic options. PMID- 23658482 TI - Preparation, characterization, and in vitro and in vivo investigation of chitosan coated poly (d,l-lactide-co-glycolide) nanoparticles for intestinal delivery of exendin-4. AB - BACKGROUND: Exendin-4 is an incretin mimetic agent approved for type 2 diabetes treatment. However, the required frequent injections restrict its clinical application. Here, the potential use of chitosan-coated poly (d,l-lactide-co glycolide) (CS-PLGA) nanoparticles was investigated for intestinal delivery of exendin-4. METHODS AND RESULTS: Nanoparticles were prepared using a modified water-oil-water (w/o/w) emulsion solvent-evaporation method, followed by coating with chitosan. The physical properties, particle size, and cell toxicity of the nanoparticles were examined. The cellular uptake mechanism and transmembrane permeability were performed in Madin-Darby canine kidney-cell monolayers. Furthermore, in vivo intraduodenal administration of exendin-4-loaded nanoparticles was carried out in rats. The PLGA nanoparticle coating with chitosan led to a significant change in zeta potential, from negative to positive, accompanied by an increase in particle size of ~30 nm. Increases in both the molecular weight and degree of deacetylation of chitosan resulted in an observable increase in zeta potential but no apparent change in the particle size of ~300 nm. Both unmodified PLGA and chitosan-coated nanoparticles showed only slight cytotoxicity. Use of different temperatures and energy depletion suggested that the cellular uptake of both types of nanoparticles was energy-dependent. Further investigation revealed that the uptake of PLGA nanoparticles occurred via caveolin-mediated endocytosis and that of CS-PLGA nanoparticles involved both macropinocytosis and clathrin-mediated endocytosis, as evidenced by using endocytic inhibitors. However, under all conditions, CS-PLGA nanoparticles showed a greater potential to be transported into cells, as shown by flow cytometry and confocal microscopy. Transmembrane permeability analysis showed that unmodified and modified PLGA nanoparticles could improve the transport of exendin-4 by up to 8.9- and 16.5-fold, respectively, consistent with the evaluation in rats. CONCLUSION: The chitosan-coated nanoparticles have a higher transport potential over both free drug and unmodified particles, providing support for their potential development as a candidate oral delivery agent for exendin-4. PMID- 23658483 TI - A tissue-engineered subcutaneous pancreatic cancer model for antitumor drug evaluation. AB - The traditional xenograft subcutaneous pancreatic cancer model is notorious for its low incidence of tumor formation, inconsistent results for the chemotherapeutic effects of drug molecules of interest, and a poor predictive capability for the clinical efficacy of novel drugs. These drawbacks are attributed to a variety of factors, including inoculation of heterogeneous tumor cells from patients with different pathological histories, and use of poorly defined Matrigel((r)). In this study, we aimed to tissue-engineer a pancreatic cancer model that could readily cultivate a pancreatic tumor derived from highly homogenous CD24(+)CD44(+) pancreatic cancer stem cells delivered by a well defined electrospun scaffold of poly(glycolide-co-trimethylene carbonate) and gelatin. The scaffold supported in vitro tumorigenesis from CD24(+)CD44(+) cancer stem cells for up to 7 days without inducing apoptosis. Moreover, CD24(+)CD44(+) cancer stem cells delivered by the scaffold grew into a native-like mature pancreatic tumor within 8 weeks in vivo and exhibited accelerated tumorigenesis as well as a higher incidence of tumor formation than the traditional model. In the scaffold model, we discovered that oxaliplatin-gemcitabine (OXA-GEM), a chemotherapeutic regimen, induced tumor regression whereas gemcitabine alone only capped tumor growth. The mechanistic study attributed the superior antitumorigenic performance of OXA-GEM to its ability to induce apoptosis of CD24(+)CD44(+) cancer stem cells. Compared with the traditional model, the scaffold model demonstrated a higher incidence of tumor formation and accelerated tumor growth. Use of a tiny population of highly homogenous CD24(+)CD44(+) cancer stem cells delivered by a well defined scaffold greatly reduces the variability associated with the traditional model, which uses a heterogeneous tumor cell population and poorly defined Matrigel. The scaffold model is a robust platform for investigating the antitumorigenesis mechanism of novel chemotherapeutic drugs with a special focus on cancer stem cells. PMID- 23658484 TI - Reduced adhesion of Staphylococcus aureus to ZnO/PVC nanocomposites. AB - In hospitals and clinics worldwide, medical device surfaces have become a rapidly growing source of nosocomial infections. In particular, patients requiring mechanical ventilation (and, thus, intubation with an endotracheal tube) for extended lengths of time are faced with a high probability of contracting ventilator-associated pneumonia. Once inserted into the body, the endotracheal tube provides a surface to which bacteria can adhere and form a biofilm (a robust, sticky matrix that provides protection against the host immune system and antibiotic treatment). Adding to the severity of this problem is the spread of bacterial genetic tolerance to antibiotics, in part demonstrated by the recent and significant increase in the prevalence of methicillin-resistant Staphylococcus aureus. To combat these trends, different techniques in biomaterial design must be explored. Recent research has shown that nanomaterials (materials with at least one dimension less than 100 nm) may have the potential to prevent or disrupt bacterial processes that lead to infections. In this study, polyvinyl chloride (PVC) taken from a conventional endotracheal tube was embedded with varying concentrations of zinc oxide (ZnO) nanoparticles. S. aureus biofilms were then grown on these nanocomposite surfaces during a 24-hour culture. Following this, biofilms were removed from the surfaces and the number of colony forming units present was assessed. Bacterial proliferation on the samples embedded with the highest concentration of ZnO nanoparticles was 87% less when compared to the control, indicating that this technique is effective at reducing biofilm formation on PVC surfaces without the use of antibiotics. PMID- 23658485 TI - A novel submicron emulsion system loaded with vincristine-oleic acid ion-pair complex with improved anticancer effect: in vitro and in vivo studies. AB - BACKGROUND: Vincristine (VCR), which is a widely used antineoplastic drug, was integrated with a submicron-emulsion drug-delivery system to enhance the anticancer effect. METHODS: After the formation of a VCR-oleic acid ion-pair complex (VCR-OA), the VCR-OA-loaded submicron emulsion (VCR-OA-SME), prepared by classical high-pressure homogenization, was characterized and its in vitro anticancer effects were evaluated. RESULTS: The submicron-emulsion formulation exhibited a homogeneous round shape. The mean particle size, zeta potential, and encapsulation efficiency were 157.6 +/- 12.6 nm, -26.5 +/- 5.0 mV and 78.64% +/- 3.44%, respectively. An in vitro release study of the VCR-OA-SME revealed that 12.4% of the VCR was released within the first 2 hours (initial burst-release phase) and the rest of the drug was detected in the subsequent sustained-release phase. Compared with VCR solution, the pharmacokinetic study of VCR-OA-SME showed relatively longer mean residence time (mean residence time [0-infinity] increased from 187.19 to 227.56 minutes), higher maximum concentration (from 252.13 ng/mL to 533.34 ng/mL), and greater area under the curve (area under the curve [0 infinity] from 11,417.77 MUg/L/minute to 17,164.34 MUg/L/minute. Moreover, the VCR-OA-SME exhibited higher cytotoxicity (P < 0.05) on tumor cells by inducing cell arrest in the G2/M phase or even apoptosis (P < 0.05). CONCLUSION: The VCR OA-SME formulation in our study displayed great potential for an anticancer effect for VCR. PMID- 23658486 TI - Nano-BaSO4: a novel antimicrobial additive to pellethane. AB - Hospital-acquired infections remain a costly clinical problem. Barium sulfate (BaSO4, in micron particulate form) is a common radiopacifying agent that is added to catheters and endotracheal tubes. Due to the recently observed ability of nanostructured surface features to decrease functions of bacteria without the aid of antibiotics, the objective of this in vitro study was to incorporate nano barium sulfate into pellethane and determine the antimicrobial properties of the resulting composites. The results demonstrated for the first time that the incorporation of nano-barium sulfate into pellethane enhanced antimicrobial properties (using Staphylococcus aureus and Pseudomonas aeruginosa) compared to currently used pellethane; properties that warrant further investigation for a wide range of clinical applications. PMID- 23658487 TI - Lung toxicities of core-shell nanoparticles composed of carbon, cobalt, and silica. AB - We present here comparative assessments of murine lung toxicity (biocompatibility) after in vitro and in vivo exposures to carbon (C-SiO2 etched), carbon-silica (C-SiO2), carbon-cobalt-silica (C-Co-SiO2), and carbon cobalt oxide-silica (C-Co3O4-SiO2) nanoparticles. These nanoparticles have potential applications in clinical medicine and bioimaging, and thus their possible adverse events require thorough investigation. The primary aim of this work was to explore whether the nanoparticles are biocompatible with pneumatocyte bioenergetics (cellular respiration and adenosine triphosphate content). Other objectives included assessments of caspase activity, lung structure, and cellular organelles. Pneumatocyte bioenergetics of murine lung remained preserved after treatment with C-SiO2-etched or C-SiO2 nanoparticles. C-SiO2-etched nanoparticles, however, increased caspase activity and altered lung structure more than C-SiO2 did. Consistent with the known mitochondrial toxicity of cobalt, both C-Co-SiO2 and C-Co3O4-SiO2 impaired lung tissue bioenergetics. C-Co-SiO2, however, increased caspase activity and altered lung structure more than C-Co3O4 SiO2. The results indicate that silica shell is essential for biocompatibility. Furthermore, cobalt oxide is the preferred phase over the zerovalent Co(0) phase to impart biocompatibility to cobalt-based nanoparticles. PMID- 23658488 TI - Preclinical evaluation of sorafenib-eluting stent for suppression of human cholangiocarcinoma cells. AB - BACKGROUND: Cholangiocarcinoma is a malignant tumor arising from the epithelium of the bile ducts. In this study, we prepared sorafenib-loaded biliary stents for potential application as drug-delivery systems for localized treatment of extrahepatic cholangiocarcinoma. METHODS: A sorafenib-coated metal stent was prepared using an electrospray system with the aid of poly(epsilon-caprolactone) (PCL), and then its anticancer activity was investigated using human cholangiocellular carcinoma (HuCC)-T1 cells in vitro and a mouse tumor xenograft model in vivo. Anticancer activity of sorafenib against HuCC-T1 cells was evaluated by the proliferation test, matrix metalloproteinase (MMP) activity, cancer cell invasion, and angiogenesis assay in vitro and in vivo. RESULTS: The drug-release study showed that the increased drug content on the PCL film induced a faster drug-release rate. The growth of cancer cells on the sorafenib-loaded PCL film surfaces decreased in a dose-dependent manner. MMP-2 expression of HuCC T1 cells gradually decreased according to sorafenib concentration. Furthermore, cancer cell invasion and tube formation of human umbilical vein endothelial cells significantly decreased at sorafenib concentrations higher than 10 mM. In the mouse tumor xenograft model with HuCC-T1 cells, sorafenib-eluting PCL films significantly inhibited the growth of tumor mass and induced apoptosis of tumor cells. Various molecular signals, such as B-cell lymphoma (Bcl)-2, Bcl-2 associated death promoter, Bcl-x, caspase-3, cleaved caspase-3, Fas, signal transducer and activator of transcription 5, extracellular signal-regulated kinases, MMP-9 and pan-janus kinase/stress-activated protein kinase 1, indicated that apoptosis, inhibition of growth and invasion was cleared on sorafenib eluting PCL films. CONCLUSION: These sorafenib-loaded PCL films are effective in inhibiting angiogenesis, proliferation and invasion of cancer cells. We suggest that sorafenib-loaded PCL film is a promising candidate for the local treatment of cholangiocarcinoma. PMID- 23658489 TI - The prospective protective effect of selenium nanoparticles against chromium induced oxidative and cellular damage in rat thyroid. AB - BACKGROUND: Nanotechnology has enabled researchers to synthesize nanosize particles that possess increased surface areas. Compared to conventional microparticles, it has resulted in increased interactions with biological targets. OBJECTIVE: The objective of this study was to determine the protective ability of selenium nanoparticles against hexavalent chromium-induced thyrotoxicity. DESIGN: Twenty male rats were used in the study, and arbitrarily assigned to four groups. Group 1 was the control group, and was given phosphate buffered saline. Group 2 was the chromium-treated group and was given K2Cr2O7 60 MUg/kg body weight intraperitoneally as a single dose on the third day of administration. Group 3 was the nano-selenium-treated group and was given selenium nanoparticles (size 3-20 nm) 0.5 mg/kg body weight intraperitoneally daily for 5 consecutive days. Group 4 was the nano-selenium chromium-treated group, which received selenium nanoparticles for 5 days and a single dose of K2Cr2O7 on the third day of administration. MATERIALS AND METHODS: Blood samples were collected from rats for measuring thyroid hormones (free triiodothyronine [T3] and free thyroxine [T4]) and oxidative and antioxidant parameters (malondialdehyde [MDA], reduced glutathione [GSH], catalase, and superoxide dismutase [SOD]). Upon dissection, thyroid glands were taken for histopathological examination by using paraffin preparations stained with hematoxylin and eosin (H&E) and Masson's trichrome. Immunohistochemical staining was performed for detecting cellular proliferation using Ki67 antibodies. RESULTS: The present study shows that K2Cr2O7 has a toxic effect on the thyroid gland as a result of inducing a marked oxidative damage and release of reactive oxygen species. This was shown by the significant decrease in free T3 and T4 and GSH levels, which was accompanied by significant increases in catalase, SOD, and MDA in the chromium-treated group compared to the control group. Se nanoparticles have a protective effect on K2Cr2O7-induced thyroid damage, as a result of correcting the free T3 and T4 levels and GSH, catalase, SOD, and MDA compared to the K2Cr2O7-treated group. Administration of nano-selenium alone in the nano selenium-treated group had no toxic effect on rats' thyroid compared to the control group. The biochemical results were confirmed by histopathological, immunohistochemical and pathomorphological studies. PMID- 23658490 TI - Novel ionically crosslinked casein nanoparticles for flutamide delivery: formulation, characterization, and in vivo pharmacokinetics. AB - A novel particulate delivery matrix based on ionically crosslinked casein (CAS) nanoparticles was developed for controlled release of the poorly soluble anticancer drug flutamide (FLT). Nanoparticles were fabricated via oil-in-water emulsification then stabilized by ionic crosslinking of the positively charged CAS molecules below their isoelectric point, with the polyanionic crosslinker sodium tripolyphosphate. With the optimal preparation conditions, the drug loading and incorporation efficiency achieved were 8.73% and 64.55%, respectively. The nanoparticles exhibited a spherical shape with a size below 100 nm and a positive zeta potential (+7.54 to +17.3 mV). FLT was molecularly dispersed inside the nanoparticle protein matrix, as revealed by thermal analysis. The biodegradability of CAS nanoparticles in trypsin solution could be easily modulated by varying the sodium tripolyphosphate crosslinking density. A sustained release of FLT from CAS nanoparticles for up to 4 days was observed, depending on the crosslinking density. After intravenous administration of FLT CAS nanoparticles into rats, CAS nanoparticles exhibited a longer circulation time and a markedly delayed blood clearance of FLT, with the half-life of FLT extended from 0.88 hours to 14.64 hours, compared with drug cosolvent. The results offer a promising method for tailoring biodegradable, drug-loaded CAS nanoparticles as controlled, long-circulating drug delivery systems of hydrophobic anticancer drugs in aqueous vehicles. PMID- 23658491 TI - Hydrogen sulfide and sodium nitroprusside compete to activate/deactivate MMPs in bone tissue homogenates. AB - BACKGROUND: Bone microvascular remodeling is the primary predictor of bone structure and function. Remodeling by its very nature implies synthesis and degradation of the extracellular matrix. Normally, 50% of total protein in the vessel wall is elastin. During remodeling, elastin is degraded by specialized matrix metalloproteinases (MMPs). Because the turnover of elastin is 1000-fold slower than that of collagen, most of the elastin is replaced by stiffer collagen. Stiffer vessels impose pressure on the aortic valve, causing regurgitation and increased pulse pressure. On the other hand, high MMP activity will cause vascular dilatation, leading to aneurysm. Therefore, balanced constitutive remodeling is necessary for adequate bone structure and function. Interestingly, collagen-degrading MMPs are involved in various pathological conditions, including osteoporosis, osteoarthritis, and cardiovascular disease. Sodium nitroprusside is a nitric oxide donor that could potentially alter MMP activity via vasodilation in vivo, but can also produce peroxynitrite, which activates MMPs by combining with superoxide. Moreover, hydrogen sulfide is a known antioxidant as well as a vasodilator, and is also speculated to contribute directly to MMP activity. We hypothesized that hydrogen sulfide reduced activity of MMP in ex vivo bone tissue homogenates and that sodium nitroprusside would increase MMP activity in vitro. METHODS: We surgically removed the tibia and femur from anesthetized mice, and prepared bone tissue homogenates using a mortar and pestle, measured the protein concentration with a spectrophotometer, and detected MMP activity using gelatin gel zymography. RESULTS: Our data showed increased MMP activity at a sodium nitroprusside concentration of 1 MUM, and MMP activity increased exponentially. There was a decrease in MMP activity with increasing hydrogen sulfide, beginning at 16 MUM (P < 0.01) and continuing to 40 MUM. Moreover, sodium nitroprusside 3 MUM was able to overcome the decrease in MMP activity that occurred with hydrogen sulfide 40 MUM; this resulted in a more pronounced exponential increase in MMP activity. CONCLUSION: There are several substances that can potentially be used to decrease MMP activity and to alleviate pathological remodeling by MMPs. PMID- 23658492 TI - Perforation and mortality after cleansing enema for acute constipation are not rare but are preventable. AB - OBJECTIVES: Constipation is a common complaint, frequently treated with cleansing enema. Enemas can be very effective but may cause serious adverse events, such as perforation or metabolic derangement. Our aim was to evaluate the outcome of the use of cleansing enema for acute constipation and to assess adverse events within 30 days of therapy. METHODS: We performed a two-phase study: an initial retrospective and descriptive study in 2010, followed by a prospective study after intervention, in 2011. According to the results of the first phase we established guidelines for the treatment of constipation in the Emergency Department and then used these in the second phase. RESULTS: There were 269 and 286 cases of severe constipation in the first and second periods of the study, respectively. In the first study period, only Fleet(r) Enema was used, and in the second, this was changed to Easy Go enema (free of sodium phosphate). There was a 19.2% decrease in the total use of enema, in the second period of the study (P < 0.0001). Adverse events and especially, the perforation rate and the 30-day mortality in patients with constipation decreased significantly in the second phase: 3 (1.4%) versus 0 (P = 0.0001) and 8 (3.9%) versus 2 (0.7%) (P = 0.0001), for perforation and death in the first and second period of the study, respectively. CONCLUSION: Enema for the treatment of acute constipation is not without adverse events, especially in the elderly, and should be applied carefully. Perforation, hyperphosphatemia (after Fleet Enema), and sepsis may cause death in up to 4% of cases. Guidelines for the treatment of acute constipation and for enema administration are urgently needed. PMID- 23658493 TI - Treatment of chronic regional pain syndrome type 1 with palmitoylethanolamide and topical ketamine cream: modulation of nonneuronal cells. AB - Chronic regional pain syndrome (CRPS) can be intractable to treat and patients sometimes suffer for many years. Therefore, new treatment strategies are needed to alleviate symptoms in CRPS patients. This case report describes a patient suffering from intractable CRPS type 1 for 13 years. Due to her swollen painful feet and left knee she is wheelchair-bound. The combination of palmitoylethanolamide and ketamine 10% cream reduced her pain by more than 50% after 1 month of treatment, and a marked reduction in swelling and skin discoloration was noticed. Furthermore, she could walk independently again and she experienced no side effects. Thus, palmitoylethanolamide and topical ketamine could be a combination therapy option for treating CRPS patients. PMID- 23658494 TI - Results of switching to milnacipran in fibromyalgia patients with an inadequate response to duloxetine: a phase IV pilot study. AB - BACKGROUND: The purpose of this study was to evaluate the safety, tolerability, and efficacy of milnacipran following a direct switch from duloxetine in fibromyalgia patients experiencing inadequate clinical response to duloxetine after receiving treatment for 6 weeks or longer. METHODS: This exploratory study included 107 patients with fibromyalgia who had been treated with duloxetine 60 mg/day for at least 4 weeks prior to enrollment. Following a 2-week open-label period on duloxetine, patients who had visual analog scale pain scores >= 40 and were dissatisfied with current treatment were randomized 4:1 to milnacipran 100 mg/day (n = 86) or placebo (n = 21) for 10 weeks of double-blind treatment. The small placebo group was included solely to blind the study and minimize expectation bias among patients and investigators, and there was no preplanned statistical comparison between treatment groups. The primary efficacy parameter was the percentage of patients rating themselves as "much improved" or "very much improved" on the Patient Global Impression of Change (PGIC) at the final visit. Other efficacy parameters included changes in one-week recall visual analog scale pain, Fibromyalgia Impact Questionnaire Revised (FIQR), and Multiple Ability Self Report Questionnaire (MASQ). RESULTS: Of patients switched to milnacipran, 32.9% were classified as PGIC responders, and they also demonstrated improvement in visual analog scale pain, FIQR total, and MASQ total scores (mean changes from baseline were -12.3, -7.77, and -2.39, respectively). Nausea and dizziness were the most common treatment-emergent adverse events in patients switched to milnacipran, reported in 21% and 15%, respectively, of patients in this group. CONCLUSION: Results from this exploratory study suggest that switching from duloxetine to milnacipran may be beneficial in some patients with fibromyalgia who have an inadequate response to duloxetine. Further research investigating the efficacy and safety of switching fibromyalgia therapies is warranted. PMID- 23658495 TI - Effectiveness and gastrointestinal tolerability during conversion and titration with once-daily OROS(r) hydromorphone extended release in opioid-tolerant patients with chronic low back pain. AB - PURPOSE: To describe the efficacy and safety of hydromorphone extended-release tablets (OROS hydromorphone ER) during dose conversion and titration. PATIENTS AND METHODS: A total of 459 opioid-tolerant adults with chronic moderate to severe low back pain participated in an open-label, 2- to 4-week conversion/titration phase of a double-blind, placebo-controlled, randomized withdrawal trial, conducted at 70 centers in the United States. Patients were converted to once-daily OROS hydromorphone ER at 75% of the equianalgesic dose of their prior total daily opioid dose (5:1 conversion ratio), and titrated as frequently as every 3 days to a maximum dose of 64 mg/day. The primary outcome measure was change in pain intensity numeric rating scale; additional assessments included the Patient Global Assessment and the Roland-Morris Disability Questionnaire scores. Safety assessments were performed at each visit and consisted of recording and monitoring all adverse events (AEs) and serious AEs. RESULTS: Mean (standard deviation) final daily dose of OROS hydromorphone ER was 37.5 (17.8) mg. Mean (standard error of the mean [SEM]) numeric rating scale scores decreased from 6.6 (0.1) at screening to 4.3 (0.1) at the final titration visit (mean [SEM] change, -2.3 [0.1], representing a 34.8% reduction). Mean (SEM) change in Patient Global Assessment was -0.6 (0.1), and mean change (SEM) in the Roland-Morris Disability Questionnaire was -2.8 (0.3). Patients achieving a stable dose showed greater improvement than patients who discontinued during titration for each of these measures (P < 0.001). Almost 80% of patients achieving a stable dose (213/268) had a >=30% reduction in pain. Commonly reported AEs were constipation (15.4%), nausea (11.9%), somnolence (8.7%), headache (7.8%), and vomiting (6.5%); 13.0% discontinued from the study due to AEs. CONCLUSION: The majority of opioid-tolerant patients with chronic low back pain were successfully converted to effective doses of OROS hydromorphone ER within 2 to 4 weeks. PMID- 23658497 TI - The NordiNet(r) International Outcome Study and NovoNet(r) ANSWER Program(r): rationale, design, and methodology of two international pharmacoepidemiological registry-based studies monitoring long-term clinical and safety outcomes of growth hormone therapy (Norditropin(r)). AB - OBJECTIVE: Randomized controlled trials have shown that growth hormone (GH) therapy has effects on growth, metabolism, and body composition. GH therapy is prescribed for children with growth failure and adults with GH deficiency. Carefully conducted observational study of GH treatment affords the opportunity to assess long-term treatment outcomes and the clinical factors and variables affecting those outcomes, in patients receiving GH therapy in routine clinical practice. DESIGN: The NordiNet(r) International Outcome Study (IOS) and the American Norditropin(r) STUDIES: Web Enabled Research (ANSWER Program(r)) are two complementary, non-interventional, observational studies that adhere to current guidelines for pharmacoepidemiological data. PATIENTS: The studies include pediatric and adult patients receiving Norditropin(r), as prescribed by their physicians. MEASUREMENTS: The studies gather long-term data on the safety and effectiveness of reallife treatment with the recombinant human GH, Norditropin(r). We describe the origins, aims, objectives, and design methodology of the studies, as well as their governance and validity, strengths, and limitations. CONCLUSION: The NordiNet(r) IOS and ANSWER Program(r) studies will provide valid insights into the effectiveness and safety of GH treatment across a diverse and large patient population treated in accordance with real-world clinical practice and following the Good Pharmacoepidemiological Practice and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines. PMID- 23658496 TI - Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside? AB - The 118A>G single nucleotide polymorphism (SNP) in the MU-opioid receptor (OPRM1) gene has been the most described variant in pharmacogenetic studies regarding opioid drugs. Despite evidence for an altered biological function encoded by this variant, this knowledge is not yet utilized clinically. The aim of the present review was to collect and discuss the available information on the 118A>G SNP in the OPRM1 gene, at the molecular level and in its clinical manifestations. In vitro biochemical and molecular assays have shown that the variant receptor has higher binding affinity for beta-endorphins, that it has altered signal transduction cascade, and that it has a lower expression compared with wild-type OPRM1. Studies using animal models for 118A>G have revealed a double effect of the variant receptor, with an apparent gain of function with respect to the response to endogenous opioids but a loss of function with exogenous administered opioid drugs. Although patients with this variant have shown a lower pain threshold and a higher drug consumption in order to achieve the analgesic effect, clinical experiences have demonstrated that patients carrying the variant allele are not affected by the increased opioid consumption in terms of side effects. PMID- 23658498 TI - Registration of acute medical hospital admissions in the Danish National Patient Registry: a validation study. AB - BACKGROUND: In recent years, the number of acute hospital admissions has increased and this has imposed both organizational and financial strains on the health care system. Consequently, it is of crucial importance that we have valid data on admission types in the administrative databases in order to provide data for health care planning and research. OBJECTIVE: To examine the validity of registration of acute admissions among medical patients in the Danish National Patient Registry (DNPR) using medical record reviews as the reference standard. METHODS: We used the nationwide DNPR to identify a sample of 160 medical patients admitted to a hospital in the North Denmark Region during 2009. Data on admission type was obtained from the DNPR and confirmed by a medical record review. We computed positive predictive values, sensitivity, and specificity including 95% confidence intervals (CI) using the medical record review as the reference standard. RESULTS: Among the 160 medical inpatients identified in the DNPR, 128 were registered with an acute admission, and 32 were registered with a nonacute admission. Two medical records could not be located. Thus, the analyses included 158 medical patients. Among the 127 patients registered with acute admission, 124 were confirmed to be correctly classified. Correspondingly, 28 of the 31 patients with a registered nonacute admission were confirmed to be correctly classified. The overall positive predictive value of the acute admissions among medical patients was 97.6% (95% CI, 93.8%-99.3%). Sensitivity was 97.6% (95% CI, 93.8% 99.3%) and specificity was 90.3% (95% CI, 76.4%-97.2%). CONCLUSION: The registration of acute admission among medical patients in the DNPR has high validity. PMID- 23658500 TI - Safety and effectiveness of different dosage of mifepristone for the treatment of uterine fibroids: a double-blind randomized clinical trial. AB - OBJECTIVES: The aim of this study was to evaluate the safety and improvement in quality of life using 10 mg and 5 mg daily doses of mifepristone for the treatment of uterine fibroids. DESIGN: The research was a randomized double-blind clinical study undertaken at the Eusebio Hernandez Hospital in Havana, Cuba. SUBJECTS AND METHODS: Seventy subjects with symptomatic uterine fibroids took one daily capsule of 10 mg or 5 mg mifepristone orally for 9 months. One to three endometrial biopsies were performed. In evaluating safety, the variables studied were endometrial changes associated with mifepristone, elevation of hepatic transaminases, side effects of mifepristone, and instances and duration of irregular bleeding. RESULTS: There were 30/49 (61.2%) and 13/24 (54.2%) diagnoses of endometrial changes associated with mifepristone in the 10 mg and 5 mg groups, respectively (P = 0.282). At every evaluation visit the average endometrial thickness was significantly greater in the 10 mg group than in the 5 mg group (P = 0.013, P = 0.002, and P = 0.013, respectively). Only five subjects had slight elevations in their hepatic transaminases after 9 months' treatment. Sixteen of 35 (45.7%) and eight of 33 (24.2%) subjects had the occasional hot flush in the 10 mg and 5 mg groups, respectively (P = 0.032). In total, there were 12.9 +/- 4.6 (n = 21) and 9.1 +/- 3.9 (n = 18) days of irregular bleeding in the 10 mg and 5 mg groups, respectively (P = 0.009). CONCLUSION: According to the study findings, a 5 mg daily dose over 9 months has a relatively better safety profile than the 10 mg dose. PMID- 23658501 TI - Women's awareness and periconceptional use of folic acid: data from a large European survey. AB - OBJECTIVE: To investigate the awareness and use of folic acid in European women of child-bearing age, particularly in the setting of pregnancy and pregnancy planning. METHODS: Between November 2009 and December 2009, women aged 15-49 years old from 18 European countries completed a 30-minute structured questionnaire either online or via face-to-face interviews. To achieve nationally representative samples for each country quotas were set for age, education, income, and regional distribution. RESULTS: A total of 22,925 women participated in the survey. Of the respondents, 58% had at least one biological child, and of these 38% reported that their first pregnancy was not planned. Nearly 60% of women who planned their pregnancy indicated that they had stopped using their method of contraception without first consulting a doctor or another health care professional. Overall, 70% reported that they had heard of folic acid and 40% stated that they knew the benefits of folic acid. However, when prompted to indicate which diseases and/or birth defects folic acid can protect against, only 17% knew that folic acid can reduce the risk of neural tube defects/spina bifida. CONCLUSIONS: A large proportion of European women of child-bearing age in this survey were unaware that periconceptional folic acid supplementation reduces the risk of birth defects. PMID- 23658499 TI - Heart disease as a risk factor for dementia. AB - As life expectancy lengthens, dementia is becoming a significant human condition in terms of its prevalence and cost to society worldwide. It is important in that context to understand the preventable and treatable causes of dementia. This article exposes the link between dementia and heart disease in all its forms, including coronary artery disease, myocardial infarction, atrial fibrillation, valvular disease, and heart failure. This article also explores the cardiovascular risk factors and emphasizes that several of them are preventable and treatable. In addition to medical therapies, the lifestyle changes that may be useful in retarding the onset of dementia are also summarized. PMID- 23658502 TI - Precision intrauterine contraception may significantly increase continuation of use: a review of long-term clinical experience with frameless copper-releasing intrauterine contraception devices. AB - OBJECTIVE: The purpose of this paper is to review the experience with the frameless, anchored, GyneFix copper-releasing intrauterine contraceptive devices (IUCDs/IUDs) (Contrel Europe, Belgium), and to demonstrate their high acceptability and low rate of discontinuation of use, which could contribute to current efforts that aim to reduce radically the high number of unintended pregnancies and induced abortions, particularly in young women. MATERIALS AND METHODS: This paper is based on studies that examined the differences in uterine volume and cavity size, related to age and parity, and on original clinical research data and practical experience with frameless copper IUDs, as well as on literature data on the IUD-endometrial cavity relationship of conventional IUDs, with special reference to side effects and user discontinuation. RESULTS: The mean transverse diameter in nulliparous and parous women is significantly less than the length of the transverse arm of the TCu380A IUD (ParaGard, Duramed, NY, USA) or the levonorgestrel intrauterine system (Mirena, Bayer, Germany). Small, frameless, flexible, and unidimensional copper IUDs appear to be well tolerated, with less impact on menstrual bleeding, resulting in low discontinuation rates when compared with standard-size conventional IUDs, which often result in increased expulsion rates, complaints of pain and erratic or increased menstrual bleeding, and subsequent high rates of discontinuation, particularly in young women. CONCLUSION: The unidimensional GyneFix IUDs fit the majority of uterine cavities. An IUD that fits is likely to result in increased tolerance and continued use of the method. As this would appeal to women, the logical result should be greater use of the method and fewer unintended pregnancies and induced abortions. Recommending the standard TCu380A (ParaGard) IUD or the Mirena levonorgestrel intrauterine system, primarily developed for use in parous women, for general use in nulliparous and adolescent women should be done with caution in the light of current scientific evidence, except if 3-D sonography indicates that the uterine cavity is sufficiently large. PMID- 23658503 TI - Astroglia in neurological diseases. AB - Astroglia encompass a subset of versatile glial cells that fulfill a major homeostatic role in the mammalian brain. Since any brain disease results from failure in brain homeostasis, astroglial cells are involved in many, if not all, aspects of neurological and/or psychiatric disorders. In this article, the roles of astrocytes as homeostatic cells in healthy and diseased brains are surveyed. These cells can mount the defence response to the insult of the brain, astrogliosis, when and where they display hypertrophy. Interestingly, astrocytes can alternatively display atrophy in some pathological conditions. Various pathologies, including Alexander and Alzheimer's diseases, amyotrophic lateral sclerosis, stroke and epilepsy, to mention a few, are discussed. Astrocytes could represent a novel target for medical intervention in the treatment of brain disorders. PMID- 23658504 TI - Inference of R(0) and transmission heterogeneity from the size distribution of stuttering chains. AB - For many infectious disease processes such as emerging zoonoses and vaccine preventable diseases, [Formula: see text] and infections occur as self-limited stuttering transmission chains. A mechanistic understanding of transmission is essential for characterizing the risk of emerging diseases and monitoring spatio temporal dynamics. Thus methods for inferring [Formula: see text] and the degree of heterogeneity in transmission from stuttering chain data have important applications in disease surveillance and management. Previous researchers have used chain size distributions to infer [Formula: see text], but estimation of the degree of individual-level variation in infectiousness (as quantified by the dispersion parameter, [Formula: see text]) has typically required contact tracing data. Utilizing branching process theory along with a negative binomial offspring distribution, we demonstrate how maximum likelihood estimation can be applied to chain size data to infer both [Formula: see text] and the dispersion parameter that characterizes heterogeneity. While the maximum likelihood value for [Formula: see text] is a simple function of the average chain size, the associated confidence intervals are dependent on the inferred degree of transmission heterogeneity. As demonstrated for monkeypox data from the Democratic Republic of Congo, this impacts when a statistically significant change in [Formula: see text] is detectable. In addition, by allowing for superspreading events, inference of [Formula: see text] shifts the threshold above which a transmission chain should be considered anomalously large for a given value of [Formula: see text] (thus reducing the probability of false alarms about pathogen adaptation). Our analysis of monkeypox also clarifies the various ways that imperfect observation can impact inference of transmission parameters, and highlights the need to quantitatively evaluate whether observation is likely to significantly bias results. PMID- 23658505 TI - Cell patterns emerge from coupled chemical and physical fields with cell proliferation dynamics: the Arabidopsis thaliana root as a study system. AB - A central issue in developmental biology is to uncover the mechanisms by which stem cells maintain their capacity to regenerate, yet at the same time produce daughter cells that differentiate and attain their ultimate fate as a functional part of a tissue or an organ. In this paper we propose that, during development, cells within growing organs obtain positional information from a macroscopic physical field that is produced in space while cells are proliferating. This dynamical interaction triggers and responds to chemical and genetic processes that are specific to each biological system. We chose the root apical meristem of Arabidopsis thaliana to develop our dynamical model because this system is well studied at the molecular, genetic and cellular levels and has the key traits of multicellular stem-cell niches. We built a dynamical model that couples fundamental molecular mechanisms of the cell cycle to a tension physical field and to auxin dynamics, both of which are known to play a role in root development. We perform extensive numerical calculations that allow for quantitative comparison with experimental measurements that consider the cellular patterns at the root tip. Our model recovers, as an emergent pattern, the transition from proliferative to transition and elongation domains, characteristic of stem-cell niches in multicellular organisms. In addition, we successfully predict altered cellular patterns that are expected under various applied auxin treatments or modified physical growth conditions. Our modeling platform may be extended to explicitly consider gene regulatory networks or to treat other developmental systems. PMID- 23658506 TI - Modeling and measuring signal relay in noisy directed migration of cell groups. AB - We develop a coarse-grained stochastic model for the influence of signal relay on the collective behavior of migrating Dictyostelium discoideum cells. In the experiment, cells display a range of collective migration patterns, including uncorrelated motion, formation of partially localized streams, and clumping, depending on the type of cell and the strength of the external, linear concentration gradient of the signaling molecule cyclic adenosine monophosphate (cAMP). From our model, we find that the pattern of migration can be quantitatively described by the competition of two processes, the secretion rate of cAMP by the cells and the degradation rate of cAMP in the gradient chamber. Model simulations are compared to experiments for a wide range of strengths of an external linear-gradient signal. With degradation, the model secreting cells form streams and efficiently transverse the gradient, but without degradation, we find that model secreting cells form clumps without streaming. This indicates that the observed effective collective migration in streams requires not only signal relay but also degradation of the signal. In addition, our model allows us to detect and quantify precursors of correlated motion, even when cells do not exhibit obvious streaming. PMID- 23658507 TI - Bioinformatics and computational biology in Poland. PMID- 23658509 TI - Long-range order in canary song. AB - Bird songs range in form from the simple notes of a Chipping Sparrow to the rich performance of the nightingale. Non-adjacent correlations can be found in the syntax of some birdsongs, indicating that the choice of what to sing next is determined not only by the current syllable, but also by previous syllables sung. Here we examine the song of the domesticated canary, a complex singer whose song consists of syllables, grouped into phrases that are arranged in flexible sequences. Phrases are defined by a fundamental time-scale that is independent of the underlying syllable duration. We show that the ordering of phrases is governed by long-range rules: the choice of what phrase to sing next in a given context depends on the history of the song, and for some syllables, highly specific rules produce correlations in song over timescales of up to ten seconds. The neural basis of these long-range correlations may provide insight into how complex behaviors are assembled from more elementary, stereotyped modules. PMID- 23658508 TI - A kinetic platform to determine the fate of nitric oxide in Escherichia coli. AB - Nitric oxide (NO*) is generated by the innate immune response to neutralize pathogens. NO* and its autoxidation products have an extensive biochemical reaction network that includes reactions with iron-sulfur clusters, DNA, and thiols. The fate of NO* inside a pathogen depends on a kinetic competition among its many targets, and is of critical importance to infection outcomes. Due to the complexity of the NO* biochemical network, where many intermediates are short lived and at extremely low concentrations, several species can be measured, but stable products are non-unique, and damaged biomolecules are continually repaired or regenerated, kinetic models are required to understand and predict the outcome of NO* treatment. Here, we have constructed a comprehensive kinetic model that encompasses the broad reactivity of NO* in Escherichia coli. The incorporation of spontaneous and enzymatic reactions, as well as damage and repair of biomolecules, allowed for a detailed analysis of how NO* distributes in E. coli cultures. The model was informed with experimental measurements of NO* dynamics, and used to identify control parameters of the NO* distribution. Simulations predicted that NO* dioxygenase (Hmp) functions as a dominant NO* consumption pathway at O2 concentrations as low as 35 uM (microaerobic), and interestingly, loses utility as the NO* delivery rate increases. We confirmed these predictions experimentally by measuring NO* dynamics in wild-type and mutant cultures at different NO* delivery rates and O2 concentrations. These data suggest that the kinetics of NO* metabolism must be considered when assessing the importance of cellular components to NO* tolerance, and that models such as the one described here are necessary to rigorously investigate NO* stress in microbes. This model provides a platform to identify novel strategies to potentiate the effects of NO*, and will serve as a template from which analogous models can be generated for other organisms. PMID- 23658510 TI - Probing the energy landscape of activation gating of the bacterial potassium channel KcsA. AB - The bacterial potassium channel KcsA, which has been crystallized in several conformations, offers an ideal model to investigate activation gating of ion channels. In this study, essential dynamics simulations are applied to obtain insights into the transition pathways and the energy profile of KcsA pore gating. In agreement with previous hypotheses, our simulations reveal a two phasic activation gating process. In the first phase, local structural rearrangements in TM2 are observed leading to an intermediate channel conformation, followed by large structural rearrangements leading to full opening of KcsA. Conformational changes of a highly conserved phenylalanine, F114, at the bundle crossing region are crucial for the transition from a closed to an intermediate state. 3.9 us umbrella sampling calculations reveal that there are two well-defined energy barriers dividing closed, intermediate, and open channel states. In agreement with mutational studies, the closed state was found to be energetically more favorable compared to the open state. Further, the simulations provide new insights into the dynamical coupling effects of F103 between the activation gate and the selectivity filter. Investigations on individual subunits support cooperativity of subunits during activation gating. PMID- 23658511 TI - Detection of mixed infection from bacterial whole genome sequence data allows assessment of its role in Clostridium difficile transmission. AB - Bacterial whole genome sequencing offers the prospect of rapid and high precision investigation of infectious disease outbreaks. Close genetic relationships between microorganisms isolated from different infected cases suggest transmission is a strong possibility, whereas transmission between cases with genetically distinct bacterial isolates can be excluded. However, undetected mixed infections-infection with >=2 unrelated strains of the same species where only one is sequenced-potentially impairs exclusion of transmission with certainty, and may therefore limit the utility of this technique. We investigated the problem by developing a computationally efficient method for detecting mixed infection without the need for resource-intensive independent sequencing of multiple bacterial colonies. Given the relatively low density of single nucleotide polymorphisms within bacterial sequence data, direct reconstruction of mixed infection haplotypes from current short-read sequence data is not consistently possible. We therefore use a two-step maximum likelihood-based approach, assuming each sample contains up to two infecting strains. We jointly estimate the proportion of the infection arising from the dominant and minor strains, and the sequence divergence between these strains. In cases where mixed infection is confirmed, the dominant and minor haplotypes are then matched to a database of previously sequenced local isolates. We demonstrate the performance of our algorithm with in silico and in vitro mixed infection experiments, and apply it to transmission of an important healthcare-associated pathogen, Clostridium difficile. Using hospital ward movement data in a previously described stochastic transmission model, 15 pairs of cases enriched for likely transmission events associated with mixed infection were selected. Our method identified four previously undetected mixed infections, and a previously undetected transmission event, but no direct transmission between the pairs of cases under investigation. These results demonstrate that mixed infections can be detected without additional sequencing effort, and this will be important in assessing the extent of cryptic transmission in our hospitals. PMID- 23658512 TI - Estimation of vaccine efficacy and critical vaccination coverage in partially observed outbreaks. AB - Classical approaches to estimate vaccine efficacy are based on the assumption that a person's risk of infection does not depend on the infection status of others. This assumption is untenable for infectious disease data where such dependencies abound. We present a novel approach to estimating vaccine efficacy in a Bayesian framework using disease transmission models. The methodology is applied to outbreaks of mumps in primary schools in the Netherlands. The total study population consisted of 2,493 children in ten primary schools, of which 510 (20%) were known to have been infected, and 832 (33%) had unknown infection status. The apparent vaccination coverage ranged from 12% to 93%, and the apparent infection attack rate varied from 1% to 76%. Our analyses show that vaccination reduces the probability of infection per contact substantially but not perfectly ([Formula: see text] = 0.933; 95CrI: 0.908-0.954). Mumps virus appears to be moderately transmissible in the school setting, with each case yielding an estimated 2.5 secondary cases in an unvaccinated population ([Formula: see text] = 2.49; 95%CrI: 2.36-2.63), resulting in moderate estimates of the critical vaccination coverage (64.2%; 95%CrI: 61.7-66.7%). The indirect benefits of vaccination are highest in populations with vaccination coverage just below the critical vaccination coverage. In these populations, it is estimated that almost two infections can be prevented per vaccination. We discuss the implications for the optimal control of mumps in heterogeneously vaccinated populations. PMID- 23658513 TI - Regulatory T cells negatively affect IL-2 production of effector T cells through CD39/adenosine pathway in HIV infection. AB - The mechanisms by which Regulatory T cells suppress IL-2 production of effector CD4+ T cells in pathological conditions are unclear. A subpopulation of human Treg expresses the ectoenzyme CD39, which in association with CD73 converts ATP/ADP/AMP to adenosine. We show here that Treg/CD39+ suppress IL-2 expression of activated CD4+ T-cells more efficiently than Treg/CD39-. This inhibition is due to the demethylation of an essential CpG site of the il-2 gene promoter, which was reversed by an anti-CD39 mAb. By recapitulating the events downstream CD39/adenosine receptor (A2AR) axis, we show that A2AR agonist and soluble cAMP inhibit CpG site demethylation of the il-2 gene promoter. A high frequency of Treg/CD39+ is associated with a low clinical outcome in HIV infection. We show here that CD4+ T-cells from HIV-1 infected individuals express high levels of A2AR and intracellular cAMP. Following in vitro stimulation, these cells exhibit a lower degree of demethylation of il-2 gene promoter associated with a lower expression of IL-2, compared to healthy individuals. These results extend previous data on the role of Treg in HIV infection by filling the gap between expansion of Treg/CD39+ in HIV infection and the suppression of CD4+ T-cell function through inhibition of IL-2 production. PMID- 23658515 TI - Polyphosphate and its diverse functions in host cells and pathogens.